Title:
HIGH PENETRATION COMPOSITIONS AND USES THEREOF
Kind Code:
A1


Abstract:
The present invention relates to compositions and uses of novel high penetration compositions or high penetration prodrugs (HPP), in particular HPPs for non-steroidal anti-inflammatory agents (NSAIAs), which are capable of crossing biological barriers with high penetration efficiency. The HPPs herein are capable of being converted to parent active drugs or drug metabolites after crossing the biological barrier and thus can render treatments for the conditions that the parent drugs or metabolites can. Additionally, due to the ability of penetrating biological barriers, the HPPs herein are capable of reaching areas that parent drugs may not be able to access or to render a sufficient concentration at the target areas and therefore render novel treatments. The HPPs herein can be administered to a subject through various administration routes. For example, the HPPs can be locally delivered to an action site of a condition with a high concentration due to their ability of penetrating biological barriers and thus obviate the need for a systematic administration. For another example, the HPPs herein can be systematically administer to a biological subject and enter the general circulation with a faster rate.



Inventors:
Yu, Chongxi (Plainfield, IL, US)
Xu, Lina (Shanghai, CN)
Application Number:
12/351804
Publication Date:
09/24/2009
Filing Date:
01/09/2009
Primary Class:
Other Classes:
514/161, 514/163, 514/165, 514/159
International Classes:
A61K31/625; A61B10/00; A61K31/60; A61P9/04; A61P9/10; A61P9/12; A61P17/00; A61P17/06; A61P17/10; A61P19/02; A61P19/08; A61P19/10; A61P25/16; A61P25/28; A61P29/00; A61P35/00; A61P35/02; A61P37/02
View Patent Images:



Foreign References:
WO2004000300A12003-12-31
JPS543044A1979-01-11
JPS53130634A1978-11-14
Other References:
J. G. Cannon "Analog Design", Chapter Nineteen in Burger's Medicinal Chemistry and Drug Discovery, Fifth Edition, Volume I: Principles and Practice, Wiley-Interscience 1995, pp. 783-802, 784.
Ho et al. "The percutaneous penetration of prostaglandin E1 and its alkyl esters" Journal of Controlled Release, 1999, vol. 58, pp. 349-355.
Halen et al. "Combining Anticholinergic and Anti-inflammatory Activities into a single moiety: A novel Approach to Reduce Gastrointestinal Toxicity of Ibuprofen and Ketoprofen" Cehm Biol Drug Des, 2007, vol. 70, pp. 450-455.
Shanbhag et al. Journal of Pharmaceutical Sciences, 1992, vol. 81, 149-154.
Mork et al. "Stereoselective Enzymatic Hydrolysis of Various Ester Prodrugs of Ibuprofen and Flurbiprofen in Human Plasma" Pharmaceutical Research, 1992, vol. 9, no. 4, pp. 492-496.
Google machine translation, obtained August 4, 2016
National Center for Biotechnolog Invormation, PubChem Compound Database, create date June 16, 2018, CID=24811342, https:pubchem.ncbi.nlm.nih.gov/compound/24811342, pp 1-9.
Primary Examiner:
CARTER, KENDRA D
Attorney, Agent or Firm:
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER (LLP 901 NEW YORK AVENUE, NW, WASHINGTON, DC, 20001-4413, US)
Claims:
1. A high penetration composition comprising a) a functional unit; b) a transportational unit; wherein the functional unit is covalently linked to the transportational unit via a linker; the functional unit comprises a moiety of an agent; the transportational unit comprises a protonatable amine group; and the linker is or comprises a chemical bond that is capable of being cleaved after the high penetration composition penetrates across a biological barrier.

2. The high penetration composition according to claim 1, wherein the chemical bond is selected from the group consisting of a covalent chemical bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a carbonate bond, a carbamate bond, a phosphate bond, and an oxime bond.

3. The high penetration composition according to claim 1, wherein upon cleavage of the cleavable bond, the moiety of the agent is converted to the agent or a metabolite of the agent.

4. The high penetration composition according to claim 1, wherein the functional unit comprises a lipophilic derivative of a moiety of an agent.

5. The high penetration composition according to claim 4, wherein the lipophilic derivative is selected from the group consisting of carbonate, ester, amide, carbamate, N-mannich base, ether, thioether, thioester, phosphate, oxime and imine of the moiety of the agent.

6. The high penetration composition according to claim 1 wherein the agent is selected from the group consisting of a non-steroidal anti-inflammatory agent (NSAIA), an active NSAIA metabolite, an agent that can be metabolized into the NSAIA or the active NSAIA metabolite.

7. The high penetration composition according to claim 1, wherein the protonatable amine group is selected from the group consisting of a pharmaceutically acceptable substituted or unsubstituted primary amine group, a pharmaceutically acceptable substituted or unsubstituted secondary amine group, and a pharmaceutically acceptable substituted or unsubstituted tertiary amine group.

8. The high penetration composition according to claim 7, wherein the protonatable amine group is selected from Structure Na, Structure Nb, Structure Nc, Structure Nd, Structure Ne, Structure Nf, Structure Ng, Structure Nh, Structure Ni, Structure Nj, Structure Nk, Structure Nl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq, and Structure Nr. R11-R16 is independently selected from the group consisting of nothing, H, CH2COOR11, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, P, NR11, or any other pharmaceutically acceptable groups.

9. A high penetration composition having the following chemical structure: including stereoisomers and pharmaceutically acceptable salts thereof, wherein: T is selected from Group N as defined in claim 8; L1 is selected from the group consisting of nothing, O, S, —N(L3)-, —N(L3)-CH2—O, —N(L3)-CH2—N(L3)-, —O—CH2—O—, —O—CH(L3)-O, —S—CH(L3)-O—; L2 is selected from the group consisting of L1, —O— L3-, —N— L3-, —S— L3- and —N(L3)-L3-; L4 is selected from the group consisting of C═O, C═S, each L3 is independently selected from the group consisting of nothing, H, CH2COOR1, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, P, N L3, or any other pharmaceutically acceptable groups; F is a moiety of a NSAIA having a structure selected from Group F-1 and Group F-2, wherein Group F-1 includes the following structures: and Group F-2 includes the following structures; including stereoisomers and pharmaceutically acceptable salts thereof, wherein: each R, R1, R2, R5-R7 is independently selected from the group consisting of H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, N, P(O)OR6, CH═CH, C≡C, CHR6, CR5R6, aryl, heteroaryl, and cyclic groups; each R8-R10 is independently selected from the group consisting of nothing, H, R6, R6C(═O)—, R6NH(C═O), R6O(C═O), R6C(═NH)—, R6C(═S)—, CNR6 and R6OCO(CH2)nC(═O), wherein n is selected from the group of natural numbers; each Y and Y1 to Y13 is independently selected from the group consisting of H, halogen, CN, R10, CH3C≡C, CR6≡C, P(O)OR6, CF3, CF3O, CH3, CF3CF2, CF3CF2O, CH3CH2, CH3CH2CH2, (CH3)2CH, (CH3)2CHCH2, CH3CH2CH(CH3), (CH3)3C, C4H9, C5H11, CH3CO, CH3CH2CO, R5CO, CH3COO, R5COO, R5COOCH2, R6NHCOOCH2, CH3COS, CH3O, R50, HO, R10O, CF3CH2SCH2, CHCl2, CH2COOR6, CH3S, R5S, HS, R10S, CH3OCH2CH2, R5OCH2, R10OCH2CH2, R5O(C═O), C2H5OCONH, CH2NHR8, CH3OCONH, CH3SO2, CH3SO, R5SO2, R5SO, NH2SO2, C6H5CH2, NH2, NHR10, cyclobutyl, cyclopropyl, 4-chlorophenyl, 4-fluorophenyl, CH2═CH, CH2═CHCH2, CH3CH═CH, NHR5SO2, N(R5)2SO2, R5OCH2CH2CH2, and NO2; each X and X1 to X5 is independently selected from the group consisting of nothing, CH3SO, S, O NR6, C═O, R6, P(O)OR6; X6 is selected from the group consisting of R6, CONH, CSNH, COO, OCO, COS, COCH2, and CH2CO; m is selected from the group of integers; and W is selected from the group consisting of H, OH and halogen; and the composition is not any of the following structures:

10. The high penetration composition of claim 9 wherein the NSAIA is selected from the group consisting of a salicylate, an arylalkanoic acid, an aryl propionic acid, a heteroaryl propionic acid, an aryl acetic acid, a heteroaryl acetic acid, an N-arylanthranilic acid, a Pyrazolidine derivative, and an oxicam.

11. The high penetration composition of claim 10 wherein the NSAIA is the salicylate and the high penetration composition has a structure selected form the group consisting of Structure 1 and Structure 2: including stereoisomers and pharmaceutically acceptable salts thereof, wherein: Z is selected from the group consisting of O and S; X is selected from the group consisting of nothing, O, P(O)OR1, NH, NR1 and S; R is selected from the group consisting of a branched or straight chain —(CH2)n—, n=1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, . . . , in —(CH2)n—, any CH2 may be independently replaced with O, S, NR5, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl residues, and any other pharmaceutically acceptable groups; R1 and R2 are independently selected from the group consisting of H, C1-C12 alkyl, C1-C12 cycloalkyl, C1-C12 alkyloxyl, C1-C12 cycloalkyloxyl, C1-C12 alkenyl, C1-C12 cycloalkenyl, C1-C12 perfluoroalkyl, C1-C12 cycloperfluoroalkyl, C1-C12 alkyl halide, C1-C12 cycloalkyl halide, C1-C12 alkynyl, C1-C12 cycloalkynyl groups, aryl or heteroaryl moieties, and any CH2 may be independently replaced with O, S, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl groups and any other pharmaceutically acceptable groups; R5, R6 and R7 are independently selected from the group consisting of H, OH, Cl, F, Br, I, C1-C12 alkyl, C1-C12 cycloalkyl, C1-C12 alkyloxyl, C1-C12 cycloalkyloxyl, C1-C12 alkenyl, C1-C12 cycloalkenyl, C1-C12 perfluoroalkyl, C1-C12 cycloperfluoroalkyl, C1-C12 alkyl halide, C1-C12 cycloalkyl halide, C1-C12 alkynyl, C1-C12 cycloalkynyl, aryl and heteroaryl groups; is selected from the group consisting of alkyl, cycloalkyl, alkyloxyl, cycloalkyloxyl, alkenyl, cycloalkenyl, perfluoroalkyl, cycloperfluoroalkyl, alkyl halide, cycloalkyl halide, alkynyl, or cycloalkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties; HA represents none, HCl, HBr, HF, Hi, HOAC, citric acid, or any acids which are pharmaceutically acceptable; X1 is selected from the group consisting of O, and the following structures: Y1 and Y2 are independently selected from the group consisting of H, HO, CH3COO, R8COO, HS, NO2, CN, CH3COS, NH2, CH3CONH, R8CONH, CH3, CH3CH2, C3H7, C4H9, CH3O, CH3CH2O, C3H7O, Cl, F, Br, I, CH3S, CHF2O, CF3O, CF3CF2O, C3F7O, CF3, CF3CF2, C3F7, C4F9,CH3SO2, R8 SO2, CH3SO, R8SO, CH3CO, CH3CH2CO; all R, R1, R2, R5, R6, R7, R8, Y1, Y2, and —(CH2)n— groups are branched or straight chains and may include C, H, O, Cl, Br, F, I, P, S, N or any other atoms which are pharmaceutically acceptable and may have single, double, or/and triple bonds.

12. The high penetration composition of claim 11 having the following Structure 1a: including stereoisomers and pharmaceutically acceptable salts thereof, wherein: R1 is selected from the group consisting of CH3, C2H5, C3H7, and alkyl groups; R2, R3, R4 are independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkyloxyl, C1-C6 alkenyl, and aryl groups; X is selected from the group consisting of O, S and N; A is selected from the group consisting of Cl—, Br—, F—, I—, AcO—, acetylsalicylate, citrate, salicylate, and any pharmaceutically acceptable acid anion; and n is selected from the group of integers.

13. The high penetration composition of claim 12 wherein the salicylate is aspirin.

14. The high penetration composition of claim 10 wherein the salicylate is diflunisal

15. The high penetration composition of claim 10 wherein the salicylate is salicyl salicylate.

16. The high penetration composition of claim 10 wherein the arylalkanoic acid is diclofenac.

17. The high penetration composition of claim 10 wherein the arylpropionic acid is ibuprofen.

18. The high penetration composition of claim 10 wherein the arylpropionic acid is ketoprofen.

19. The high penetration composition of claim 10 wherein the arylpropionic acid is fenoprofen.

20. The high penetration composition of claim 10, wherein the composition is selected from the group consisting of Sdimethylaminoethyl acetylthiosalicylate, S-diethylaminoethyl propionylthiosalicylate, N-diethylaminopropyl acetylsalicylamide, dipropylaminoethyl acetylsalicylate, diethylaminoethyl 5-(2,4-difluorophenyl)salicylate, diethylaminoethyl salicylsalicylate dimethylaminoethyl salicylate, S-dimethylaminoethyl 5-(2,4-difluorophenyl)thiosalicylate, N-dimethylaminoethyl 5-(2,4-difluorophenyl)salicylamide, S-diethylaminoethyl thiosalicylate, ethyl 3-N,N-diethylaminopropionyl 5-(2,4-difluorophenyl)salicylate, ethyl 3-N,N-dimethylaminopropionyl 5-(2,4-difluorophenyl)salicylsalicylate, ethyl 3-N,N-dimethylaminopropionyl salicylate, diethylaminoethyl 2-(ρ-isobutylphenyl)propionate, dimethylaminoethyl 2-(ρ-isobutylphenyl)propionate, dipropylaminoethyl 2-(ρ-isobutylphenyl)propionate, dipropylaminoethyl 2-(ρ-isobutylphenyl)propionate, 3-piperidinemethyl 2-(ρ-isobutylphenyl)propionate, S-dimethylaminoethyl 2-(ρ-isobutylphenyl)thiopropionate, S-diethylaminoethyl 2-(ρ-isobutylphenyl)thiopropionate, N-dimethylaminoethyl 2-(ρ-isobutylphenyl)propionamide, N-dimethylaminopropyl 2-(ρ-isobutylphenyl)propionamide, diethylaminoethyl (Z)-5-fluoro-2-methyl-1-[(4-methylsulfinyl)phenylmethylene]-1H-indene-3-acetate, diethylaminoethyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate S-dimethylaminoethyl 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate, N-dimethylaminoethyl 5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetamide N-dimethylaminoethyl 1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetamide, diethylaminoethyl 3-chloro-4-(2-propenyloxy)benzeneacetate diethylaminoethyl 2-[(2,6-dichlorophenyl)amino]benzene acetate, dimethylaminoethyl 2-[(2,6-dichlorophenyl)amino]benzene acetate S-dimethylaminoethyl 2-[(2,6-dichlorophenyl)amino]benzene acetate, N-dimethylaminoethyl 2-[(2,6-dichlorophenyl)amino]benzene acetamide, dipropylaminoethyl 2-[(2,6-dichlorophenyl)amino]benzene acetate, dipropylaminoethyl dipropylaminoethyl 2-[(2,6-dichlorophenyl)amino]benzene acetate, 1-piperidinepropyl 2-[(2,6-dichlorophenyl)amino]benzene acetate, diethylaminoethyl 2-(3-benzoyphenyl)propionate dimethylaminoethyl 2-(3-phenoxyphenyl)propionate, S-dimethylaminoethyl 2-(3-phenoxyphenyl)thiopropionate, N-dimethylaminoethyl 2-(3-benzoyphenyl)propionate, diethylaminoethyl 2-(3-benzoyphenyl)propionate, diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate, diethylaminoethyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate, S-dimethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate, N-dimethylaminoethyl diethylaminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylamide, N-diethylaminoethyl 4,5-Diphenyl-2-oxazole propionamide, diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate, N-diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoamide, N-diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoamide, S-dimethylaminoethyl 2-[[(3-trifluoromethyl)phenyl]amino]benzoate, diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate and diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate, including stereoisomers and pharmaceutically acceptable salts thereof.

21. A pharmaceutical composition comprising a high penetration composition according any of claim 1 and a pharmaceutically acceptable carrier.

22. The pharmaceutical composition according to 21, wherein the pharmaceutically acceptable carrier is polar.

23. The pharmaceutical composition according to claim 22, wherein the pharmaceutically acceptable carrier is selected from the group of alcohol, acetone, ester, water, and aqueous solution.

24. A method for penetrating a biological barrier, comprising administrating to the biological barrier a pharmaceutical composition according to claim 1.

25. A method for screening a composition for a desired character, comprising the following steps: 1) covalently linking a functional unit to a transportational unit through a linker to form a test composition; 2) administrating a test composition to a biological subject or a biological barrier; and 3) determining whether the test composition has a desired character.

26. The method according to claim 25, wherein the desired character is selected from the group consisting of: 1) the ability of the test composition to penetrate the biological barriers; 2) the ability of the test composition to convert to a parent drug or to an active agent; 3) the penetration rate of the test composition; 4) the efficiency of the test composition; and 5) the efficacy of the test composition.

27. A method for diagnosing a condition in a biological subject, comprising the following steps: 1) administrating a composition according to claim 1 to the biological subject; 2) detecting the presence, location or amount of the composition in the biological subject; and 3) detecting a condition in the biological subject.

28. The method according to claim 27, wherein the composition is labeled.

29. A method for treating a condition of a biological subject, comprising administrating to the biological subject a high penetration composition of a NSAIA according to claim 9.

30. The method according to claim 29, wherein the condition is selected from the group consisting of metabolism disorder, abnormal blood pressure, tumor, cardiovascular diseases, neurodegenerative disease, skin condition, autoimmune disease, eye disease, pain, injuries, inflammation, fever, conditions related to platelet aggregation, dysmenorrheal, allergy, asthma, preeclamptic toxemia in high-risk women, IUD-associated uterine bleeding, radiation-induced conditions, and bone disease.

31. The method according to claim 30, wherein the metabolism disorder is selected from the group consisting of abnormal blood glucose level, abnormal blood lipid level, diabetes mellitus (type I or/and type II) and diabetes-induced complications, including diabetic retinopathy, necrobiotic ulcers, and diabetic proteinuria.

32. The method according to claim 30, wherein the abnormal blood pressure is hypertension or hypotension.

33. The method according to claim 30, wherein the cardiovascular disease is selected from the group consisting of heart attack, unstable angina, peripheral occlusive arterial disease and stroke.

34. The method according to claim 30, wherein the neurodegerative disease is Alzheimer's diseases or Parkinson's disease.

35. The method according to claim 30, wherein the autoimmune disease is selected from the group consisting of discoid lupus erythematosus, systemic lupus erythematosus (SLE), autoimmune hepatitis, cleroderma, Sjogren's syndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto's thyroiditis, juvenile diabetes mellitus, Addison disease, vitiligo, pernicious anemia, glomerulonephritis, pulmonary fibrosis, multiple sclerosis (MS) and Crohn's disease.

36. The method according to claim 30, wherein the inflammation is selected from the group consisting of prostate gland inflammation (prostatitis), prostatocystitis, prostate enlarge fibrosis, hemorrhoids, Kawasaki syndrome, gastroenteritis, type-1 membranoproliferative glomerulonephritis, Bartter's syndrome, chronic uveitis, ankylosing spondylitis, hemophilic arthropathy, inflammatory bowel disease, inflamed hemorrhoids, post irradiation (factitial) proctitis, chronic ulcerative colitis, cryptitis, periodontitis, arthritis, and an inflammatory condition in an organ selected from the group consisting of the liver, lung, stomach, brain, kidney, heart, ear, eye, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum, rectum stomach, colonrectum, intestine, vein, respiratory system, vascular, the anorectum and pruritus ani.

37. The method according to claim 30, wherein the skin condition is selected from the group of psoriasis and psoriatic disorders, acne, cystic acne, pus-filled or reddish bumps, comedones, papules, pustules, nodules, epidermoid cysts, keratosis pilaris, abnormal vascular skin lesions, birthmarks, moles (nevi), skin tags, scleroderma, vitiligo and related diseases, or aging spots (liver spots).

38. The method according to claim 30, wherein the tumor is benign tumor, breast cancer, colon-rectum cancer, oral cancer, lung or other respiratory system cancers, skin cancers, uterus cancer, pancreatic cancer, prostate cancer, genital cancer, urinary organs cancers, leukemia or other blood and lymph tissues cancer.

39. The method according to claim 30, wherein the condition related to platelet aggregation is selected from the group consisting of thromboembolis after surgery, carotid endarterectomy, the recurrence of stenosis after coronary angioplasty, thromboembolic complications in chronic arterial fibrillation, aortocornonary-artery-bypass graft occlusion, heart attack, stroke, multi-infract dementia, dementia, hemodialysis shunt thrombosis and arterial embolic complications in patients' prosthetic heart valves.

40. The method according to claim 30, wherein the eye disease is selected from the group consisting of glaucoma, ocular hypertension, loss of vision after ophthalmic surgery, vision of a warm-blooded animal impaired by cystoid macular edema and cataract.

41. The method according to claim 30, wherein the bone disease is selected from the group consisting of osteoporosis, Paget's disease and bone metastases.

42. The method according to claim 30, wherein the pharmaceutical composition is administered to the biological subject through a route selected from oral, enteral, buccal, nasal, topical, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, dermal, ophthalmic, pulmonary, subcutaneous, and parenteral administration.

43. The method according to claim 29 wherein the NSAIA is selected from the group consisting of aspirin, diflunisal, diclofenac, salicyl salicylate, ibuprofen, fenoprofen, ketoprofen, a heteroaryl propionic acid, an aryl acetic acid, a heteroaryl acetic acid, an N-arylanthranilic acid, a Pyrazolidine derivative, and an oxicam.

44. The method according to claim 29 wherein the condition is selected from the groups consisting of a condition treatable by aspirin, a condition treatable by salicylate, a condition treatable by ibuprofen, a condition treatable by ketoprofen, a condition treatable by fenoprofen, a condition treatable by a aryl acetic acid or a heteroaryl acetic acid, a condition treatable by aryl- and heteroarylpropionic acid, a condition treatable by a N-aryl anthranilic acid, and a condition treatable by oxicam.

45. The method according to claim 44 wherein the condition treatable by aspirin is selected from the group consisting of gouty arthritis, pain and inflammation of arthritic and other inflammatory conditions, heart attack; stroke, tumor, Kawasaki syndrome, thromboembolism after surgery, unstable angina, gastroenteritis, aortocoronary-artery-bypass graft occlusion, thromboembolic complications in chronic arterial fibrillation, platelet aggregatioartrial in carotid endarterectomy, cataracts, recurrence of stenosis after coronary angioplasty, multi-infract dementia, diabetes mellitus and diabetes-induced complications, cardiovascular disease, hemodialysis shunt thrombosis, renal disease, peripheral occlussive arterial disease, arterial embolic complications in patients' prosthetic heart valves, and pregnancy-induced hypertension and preeclamptic toxemia.

Description:

PRIORITY CLAIM

The present application is a continuation-in-part application of International Application PCT/WO2008/007171, with an international filing date of Jul. 9, 2006; a continuation-in-part application of International Application PCT/WO2008/010025, with an international filing date of Jul. 18, 2006; a continuation-in-part application of International Application PCT/WO2008/012602, with an international filing date of Jul. 25, 2006; a continuation-in-part application of International Application PCT/WO2008/012603, with an international filing date of Jul. 26, 2006; a continuation-in-part application of International Application PCT/WO2008/012605, with an international filing date of Jul. 27, 2006; a continuation-in-part application of International Application PCT/WO2008/017903, with an international filing date of Aug. 8, 2006; a continuation-in-part application of International Application PCT/WO2008/020270, with an international filing date of Aug. 15, 2006; a continuation-in-part application of International Application PCT/WO2008/029199, with an international filing date of Sep. 3, 2006; and a continuation-in-part application of International Application PCT/WO2008/044095, with an international filing date of Oct. 11, 2006; and designating the U.S., all of which are incorporated herein by reference. The present application also claims priority to U.S. Provisional Application 61/120,052, filed Dec. 4, 2008, which is incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to the field of pharmaceutical compositions and method of using the pharmaceutical compositions for penetrating one or more biological barriers, treating conditions, diagnosing conditions or screening for new compositions.

BACKGROUND

Active agents or drugs that are effective in vitro may not be as effective in vivo due to the delivery difficulties in vivo, in particular, their limited penetration ability across one or more biological barriers before reaching the site of action where diseases occur in vivo.

Currently many drugs are administered through systematic route, such as oral or parenteral administration, to reach the action site of a condition or disease. Since higher dosage of drugs is required to reach a distal location in the systematic administration, drugs delivered by such a route may cause adverse reactions. For example, non-steroidal anti-inflammatory agents (NSAIAs) are widely used for treatment of acute or chronic conditions where pain and inflammation are present. Although NSAIAs are absorbed in the stomach and intestinal mucosa, oral administration usually accompany adverse drug reactions such as gastrointestinal (GI) effects and renal effects. For instance, aspirin is known to cause gastric mucosal cell damage. The side effects of NSAIAs appear to be dose-dependent, and in many cases severe enough to pose the risk of dyspepsia, gastroduodenal bleeding, gastric ulcerations, gastritis, ulcer perforation, and even death.

Modifications of the known NSAIAs have been reported to improve their efficacy and decrease their side effects. However, to treat inflammation or pain at distal areas, a much higher plasma concentration of the active agent is required when the drug is administered orally than when the drug is administered accurately at the particular site of pain or injury (Fishman; Robert, U.S. Pat. No. 7,052,715).

Fishman and many others (Van Engelen et al. U.S. Pat. No. 6,416,772; Macrides et al. U.S. Pat. No. 6,346,278; Kirby et al. U.S. Pat. No. 6,444,234, Pearson et al. U.S. Pat. No. 6,528,040, and Botknecht et al. U.S. Pat. No. 5,885,597) have attempted to develop a delivery system for transdermal application by drug formulation to reduce the side effect associating with oral administration and achieve localized drug administrations with reduced systematic exposure. It is very difficult, however, to deliver therapeutically effective plasma levels of these drugs by the formulation.

Therefore, there is a need to develop novel compositions that are capable of being delivered efficiently and effectively to the action site of a condition (e.g., a disease) to prevent, reduce or treat conditions and minimize side effects.

SUMMARY OF THE INVENTION

One aspect of the invention relates to a high penetration prodrug (HPP) or a high penetration composition (HPC) comprising a functional unit covalently linked to a transportational unit through a linker.

In certain embodiments, the functional unit comprises a moiety of an agent wherein the delivery of the agent into a biological subject or transportation across a biological barrier is desired. In certain embodiments, the agent comprises an active agent or an agent that can be metabolized into an active agent or active metabolite.

In certain embodiments, the functional unit may be hydrophilic, lipophilic, or amphiphilic (hydrophilic and lipophilic). For example, the lipophilic nature of the function unit may be inherent or achieved by converting its hydrophilic moieties to lipophilic moieties.

In certain embodiments, the functional unit comprises a moiety of an agent wherein the agent is a non-steroidal anti-inflammatory agent (NSAIA), an active NSAIA metabolite or an agent that can be metabolized into a NSAIA or NSAIA metabolite after the HPP penetrates one or more BBs. Examples of NSAIA include, but are not limited to, aspirin, diflunisal, salsalate, salicylic acid, ibuprofen, ketoprofen, fenoprofen, naproxen, suprofen, acetaminophen, α-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, tolmetin, zomepirac, etodolac, amfenac, bromofenac, alclofenac, fenclofenac, acemetacin, fentiazac, indomethacin, sulindac, lonazolac, bendazac, 6MNA, diclofenac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, piroxicam, sudoxicam, lornoxicam, tenoxicam, ampiroxicam, lomoxicam, isoxicam, cinnoxicam, and meloxicam.

In certain embodiments, the transportational unit of the HPP comprises a protonatable amine group that is capable of facilitating the transportation or crossing of the HPP through one or more biological barriers (>100 times faster than the parent drug). In certain embodiments, the protonatable amine group is substantially protonated at the pH of the BBs the HPP penetrates through. In certain embodiment, the amine group can be reversibly protonated.

In certain embodiments, the linker covalently linking the functional unit and the transportational unit comprises a bond that is capable of being cleaved after the HPP penetrates across one or more BBs. The cleavable bond comprises, for example, a covalent bond, an ether, thioether, amide, ester, thioester, carbonate, carbamate, phosphate or oxime bond.

Another aspect of the invention relates to a pharmaceutical composition comprising one HPP and a pharmaceutically acceptable carrier.

Another aspect of the invention relates to the use of a composition of the invention in penetrating a biological barrier.

Another aspect of the invention relates to method for diagnosing the onset, development, or remission of a condition in a biological subject by using a HPP (or a HPC) of the invention. In certain embodiments, the HPP or the functional unit of the HPP of the composition is detectable. In certain embodiments, the HPP or the functional unit of the HPP is inherently labeled, or labeled or conjugated to a detectable agent.

Another aspect of the invention relates methods for screening a test functional unit, a test linker, or a test transportational unit with desired characters.

Another aspect of the invention relates to methods for preventing, ameliorating, or treating a condition in a biological subject by administering a composition of the present invention. In certain embodiments, the method relates to treating a condition treatable by an NSAIA by administering the NSAIA HPP. In certain embodiment, the composition of the present invention is administrated to a biological subject through various delivery routes such as oral, enteral, buccal, nasal, topical, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, dermal, ophthalmic, pulmonary, subcutaneous, and/or parenteral administration. In certain embodiments, the composition of the present invention is administered orally, transdermally, topically, subcutaneously and/or parenterally.

Another aspect of the invention relates to the advantages of HPP or HPC according to the present invention. The advantages include, for example, location administration of a HPP to the site of condition with less dosage but higher concentration, avoidance of systematic administration and reduction of adverse effects (e.g., pain of injection, gastrointestinal/renal effects, and other side effect), possible novel treatment due to high local concentration of the HPP or active agent. The advantages further include, for example, systematic administration of a HPP to a biological subject to achieve faster and more efficient bioavailability, penetration of biological barriers (e.g., the blood brain barrier) which have not been crossed by parent agents, and new indications thereof.

DESCRIPTION OF THE DRAWINGS

FIG. 1a: Cumulative amounts of acetylsalicylic acid (ASA), ethyl acetylsalicylate(E-ASA), and diethylaminoethyl acetylsalicylate.AcOH(DEAE-ASA) crossing isolated human skin tissue in Franz cells (n=5). ASA and E-ASA were applied as 20% suspensions. DEAE-ASA was applied as a 20% solution. In each case, the vehicle was pH 7.4 phosphate buffer (0.2 M).

FIG. 1b: Cumulative amounts of diethylaminoethyl 5-(2,4-difluorophenyl)salicylate.AcOH (A, 20% solution), diethylaminoethyl salicylsalicylate.AcOH (B, 20% solution), diethylaminoethyl salicylate.AcOH(C, 20% solution), diflunisal (D, 20% suspension), salsalate (E, 20% suspension), and salicylic acid (F, 20% suspension) crossing isolated human skin tissue in Franz cells (n=5). In each case, the vehicle was pH 7.4 phosphate buffer (0.2 M).

FIG. 1c: Cumulative amounts of 2-(ρ-isobutylphenyl)propionic acid (IBPP), ethyl 2-(ρ-isobutylphenyl)propionate (E-IBPP), and diethylaminoethyl 2-(ρ-isobutylphenyl)propionate. AcOH (DEAE-IBPP) crossing isolated human skin tissue in Franz cells (n=5). IBPP and E-IBPP were applied as a 30% suspension. DEAE-IBPP was applied as 30% solution. In each case, the vehicle was pH 7.4 phosphate buffer (0.2 M).

FIG. 1d: Cumulative amounts of diethylaminoethyl 2-(3-benzoylphenyl)propionate.AcOH (A, 20% solution), diethylaminoethyl 2-(3-phenoxyphenyl)propionate.AcOH (B, 20% solution), ketoprofen (C, 20% suspension), and fenoprofen (D, 20% suspension) crossing isolated human skin tissue in Franz cells (n=5). In each case, the vehicle was pH 7.4 phosphate buffer (0.2 M).

FIG. 1e-1: Cumulative amounts of diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH (A, 20% solution), diethylaminoethyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH (B, 20% solution), diethylaminoethyl α-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH(C, 20% solution), diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH (D, 20% solution), diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate.AcOH (E, 20% solution), naproxen (F, 20% suspension), suprofen (G, 20% suspension), α-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid (H, 20% suspension), flurbiprofen (I, 20% suspension), or carprofen (J, 20% suspension) crossing isolated human skin tissue in Franz cells (n=5). In each case, the vehicle was pH 7.4 phosphate buffer (0.2 M).

FIG. 1e-2: Cumulative amounts of diethylaminoethyl α-methyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetate.AcOH (A, 20% solution), diethylaminoethyl 2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetate.AcOH (B, 20% solution), diethylaminoethyl α-methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH(C, 20% solution), diethylaminoethyl 5-benzoyl-α-methyl-2-thiopheneacetate.AcOH (D, 20% solution), diethylaminoethyl 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-α-methyl benzeneacetate.AcOH (E, 20% solution), pranoprofen (F, 20% suspension), benoxaprofen (G, 20% suspension), alminoprofen (H, 20% suspension), tiaprofenic acid (I, 20% suspension), or pirprofen (J, 20% suspension) crossing isolated human skin tissue in Franz cells (n=5). In each case, the vehicle was pH 7.4 phosphate buffer (0.2 M).

FIG. 1e-3: Cumulative amounts of diethylaminoethyl 2-(10,11-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH (A, 20% solution), diethylaminoethyl 2-(8-methyl-10,11-dihydro-11-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH (B, 20% solution), diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH(C, 20% solution), diethylaminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate.AcOH (D, 20% solution), diethylaminoethylα,3-dichloro-4-cyclohexylbenzeneacetate.AcOH (E, 20% solution), zaltoprofen (F, 20% suspension), bermoprofen (G, 20% suspension), loxoprofen (H, 20% suspension), indoprofen (I, 20% suspension), or fenclorac (J, 20% suspension) crossing isolated human skin tissue in Franz cells (n=5). In each case, the vehicle was pH 7.4 phosphate buffer (0.2 M).

FIG. 1e-4: Cumulative amounts of diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH (A, 20% solution), diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH (B, 20% solution), diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH(C, 20% solution), diethylaminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.AcOH (D, 20% solution), diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylate.AcOH (E, 20% solution), oxaprozin (F, 20% suspension), fenbufen (G, 20% suspension), orpanoxin (H, 20% suspension), ketorolac (I, 20% suspension), or clidanac (J, 20% suspension) crossing isolated human skin tissue in Franz cells (n=5). In each case, the vehicle was pH 7.4 phosphate buffer (0.2 M).

FIG. 1f: Cumulative amounts of 2[(2,6-dichlorophenyl)amino]benzene acetic acid (diclofenac, A), ethyl 2[(2,6-dichlorophenyl)amino]benzene acetate (the non positive charged normal ester of diclofenac, B) and diethylaminoethyl 2[(2,6-dichlorophenyl)amino]benzene acetate.AcOH (C) crossing isolated human skin tissue in Franz cells (n=5). Diclofenac and ethyl 2-[(2,6-dichlorophenyl)amino]benzene acetate were applied as a 20% suspension; diethylaminoethyl 2-[(2,6-dichlorophenyl)amino]benzene acetate.AcOH was applied as 20% solution. In each case, the vehicle was pH 7.4 phosphate buffer (0.2 M).

FIG. 1g: Cumulative amounts of diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH (A, 20% solution), diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH (B, 20% solution), diethylaminoethyl 2-[[(3-(trifluoromethyl)phenyl)amino]benzoate.AcOH(C, 20% solution), diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH (D, 20% solution), diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH (E, 20% solution), mefenamic acid (F, 20% suspension), meclofenamic acid (G, 20% suspension), flufenamic acid (H, 20% suspension), niflumic acid (I, 20% suspension), flunixin (J, 20% suspension), crossing isolated human skin tissue in Franz cells (n=5). In each case, the vehicle was pH 7.4 phosphate buffer (0.2 M).

FIG. 1h: Cumulative amounts of 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,1,2-benzothiazine-3-carboxamide 1,1-dioxide.HCl (A, 20% solution), N-(2-thiazolyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H,1,2-benzothiazine-3-carboxamide 1,1-dioxide.HCl (B, 20% solution), 6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide.HCl (C, 20% solution), 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide.HCl (D, 20% solution), 8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridine-2-ylamino-methylidene)-3-methyl-2,2-dioxo-2λ6,7-dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one.HCl (E, 20% solution), 4-N,N-dimethylaminobutyryloxy-2-methyl-N-[5-Methyl-3-isoxolyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide].HCl (F, 20% solution), 4-N,N-dimethylaminobutyryloxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.HCl (G, 20% solution), Piroxicam (H, 20% suspension), sudoxiam (I, 20% suspension), lornoxicam (J, 20% suspension), tenoxicam (K, 20% suspension), lomoxicam (L, 20% suspension), isoxicam (M, 20% suspension), and meloxicam (N, 20% suspension) crossing isolated human skin tissue in Franz cells (n=5). In each case, the vehicle was pH 7.4 phosphate buffer (0.2 M).

FIG. 2a: Total plasma levels of salicylic acid (SA) after topical application of 300 mg of acetylsalicylic acid (ASA) or diethylaminoethyl acetylsalicylate.AcOH (DEAE-ASA) to the backs of hairless mice (n=5).

FIG. 2b-1: Total plasma levels of diflunisal after topical application of 300 mg of a 20% solution of diethylaminoethyl 5-(2,4-difluorophenyl)salicylate.AcOH, (A) or 5-(2,4-difluorophenyl)salicylic acid (diflunisal, B) in isopropanol to the backs of hairless mice (n=5).

FIG. 2b-2 Total plasma levels of salsalate after topical application of 300 mg of a 20% solution of diethylaminoethyl salsalate. AcOH, (A) or salsalate (B) in isopropanol to the backs of hairless mice (n=5).

FIG. 2b-3: Total plasma levels of salicylic acid after topical application of 300 mg of a 20% solution of diethylaminoethyl salicylate.AcOH (A), or salicylic acid (B) in isopropanol to the backs of hairless mice (n=5).

FIG. 2c: Total plasma levels of 2-(ρ-isobutylphenyl)propionic acid (IBPP) after topical application of 1 ml of a 20% suspension of 2-(ρ-isobutylphenyl)propionic acid (IBPP) or 20% solution of diethylaminoethyl 2-(ρ-isobutylphenyl)propionate.AcOH (DEAE-IBPP) to the backs of hairless mice (n=5).

FIG. 2d-1: Total plasma levels of ketoprofen after topical application of 1 ml of a 10% solution of diethylaminoethyl 2-(3-benzoylphenyl)propionate.AcOH, (A) or 2-(3-benzoylphenyl)propionic acid (ketoprofen, B) in isopropanol to the backs of hairless mice (n=5).

FIG. 2d-2: Total plasma levels of fenoprofen after topical application of 1 ml of a 10% solution of diethylaminoethyl 2-(3-phenyoxyphenyl)propionate.AcOH, (A) or fenoprofen (B) in isopropanol to the backs of hairless mice (n=5).

FIG. 2e-1: Total plasma levels of naproxen, suprofen, α-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen after topical application of 1 ml of a 20% solution of diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH (A), diethylaminoethyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH (B), diethylaminoethyl α-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH (C), diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH (D), diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate.AcOH (E), naproxen (F), suprofen (G), α-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid (H), flurbiprofen (I), or carprofen (J) in isopropanol to the backs of hairless mice (n=5).

FIG. 2e-2: Total plasma levels of pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, or pirprofen after topical application of diethylaminoethyl α-methyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetate.AcOH (A), diethylaminoethyl 2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetate.AcOH (B), diethylaminoethyl α-methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH (C), diethylaminoethyl 5-benzoyl-α-methyl-2-thiopheneacetate.AcOH (D), diethylaminoethyl 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-α-methyl benzeneacetate.AcOH (E), pranoprofen (F), benoxaprofen (G), alminoprofen (H), tiaprofenic acid (I), or pirprofen (J) 1 ml of a 20% solution of in isopropanol to the backs of hairless mice (n=5).

FIG. 2e-3: Total plasma levels of zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac after topical application of diethylaminoethyl 2-(10,11-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH (A), diethylaminoethyl 2-(8-methyl-10,11-dihydro-11-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH (B), diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH (C), diethylaminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate.AcOH (D), diethylaminoethylα,3-dichloro-4-cyclohexylbenzeneacetate.AcOH (E), zaltoprofen (F), bermoprofen (G), loxoprofen (H), indoprofen (I), fenclorac (J) 1 ml of a 20% solution of in isopropanol to the backs of hairless mice (n=5).

FIG. 2e-4: Total plasma levels of oxaprozin, fenbufen, orpanoxin, ketorolac, and clidanac after topical application of diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH (A), diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH (B), diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH (C), diethylaminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.AcOH (D), diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylate.AcOH (E), oxaprozin (F), fenbufen (G), orpanoxin (H), ketorolac (I), or clidanac (J) 1 ml of a 20% solution of in isopropanol to the backs of hairless mice (n=5).

FIG. 2f: Total plasma levels of diclofenac after topical application of 1 ml of a 30% solution of diethylaminoethyl 2-[(2,6-dichlorophenyl)amino]benzene acetate.AcOH and 2-[(2,6-dichlorophenyl)amino]benzene acetic acid (diclofenac) in isopropanol to the backs of hairless mice (n=5).

FIG. 2g: Total plasma levels of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, and flunixin after topical application of 1 ml of a 20% solution of diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH (A), diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH (B), diethylaminoethyl 2-[[(3-(trifluoromethyl)phenyl)amino]benzoate.AcOH (C), diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH (D), diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH (E), mefenamic acid (F), meclofenamic acid (G), flufenamic acid (H), niflumic acid (I), and flunixin (J) in ethanol to the backs of hairless mice (n=5).

FIG. 2h: Total plasma levels of drugs after topical application of 1 ml of 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,1,2-benzothiazine-3-carboxamide 1,1-dioxide.HCl, N-(2-thiazolyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H,1,2-benzothiazine-3-carboxamide 1,1-dioxide.HCl, 6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide.HCl, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide.HCl, 8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridine-2-ylamino-methylidene)-3-methyl-2,2-dioxo-2λ6,7-dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one.HCl, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-[5-Methyl-3-isoxolyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide].HCl, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.HCl, Piroxicam, and sudoxiam in isopropanol to the backs of hairless mice (n=5).

FIG. 3a. The prolongation time of the pain threshold of the mice tails after 200 mg/kg of aspirin (B) was administered orally, 200 mg/kg of diethylaminoethylsalicylate.AcOH was administered orally (C) and transdermally (D). A is the control line.

FIG. 3b: The prolongation time of the pain threshold of mice tails after 200 mg/kg of diflunisal (B) was administered orally, 200 mg/kg of diethylaminoethyl 5-(2,4-difluorophenyl)salicylate.AcOH (C), diethylaminoethyl salicylsalicylate.AcOH (D), and diethylaminoethyl salicylate.AcOH (E) were administered transdermally. A is the control line. The groups administered 200 mg/kg of diethylaminoethyl 5-(2,4-difluorophenyl)salicylate.AcOH (C), diethylaminoethyl salicylsalicylate.AcOH (D), and diethylaminoethyl salicylate.AcOH (E) transdermally were shown to exhibit stronger analgesic activity than the group administered 200 mg/kg of diflunisal.

FIG. 3c: The prolongation time of the pain threshold of mice tails after 200 mg/kg of ibuprofen (B) was administered orally, 200 mg/kg of diethylaminoethyl 2-(p-isobutylphenyl)propionate.AcOH was administered orally (C) and transdermally (D). A is the control line.

FIG. 3d: The prolongation time of the pain threshold of mice tails after 50 mg/kg of ketoprofen (B) was administered orally, 50 mg/kg of diethylaminoethyl 2-(3-benzoyphenyl)propionate.AcOH (C) and diethylaminoethyl 2-(3-phenoxyphenyl)propionate.AcOH (D) were administered transdermally. A group is the control group.

FIG. 3f: The prolongation time of the pain threshold of mice tails after 25 mg/kg of diclofenac (B) was administered orally, 25 mg/kg of diethylaminoethyl 2-[(2,6-dichlorophenyl)amino]benzene acetate.AcOH was administered orally (C) and transdermally (D). A is the control line.

FIG. 3g: The prolongation time of the pain threshold of mice tails after 50 mg/kg of diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH, diethylaminoethyl 2-[[(3-(trifluoromethyl)phenyl)amino]benzoate.AcOH, diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH, diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH were administered transdermally. Group A is the control group.

FIG. 3e-1: The prolongation time of the pain threshold of mice tails after 50 mg/kg of diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH (B), diethylaminoethyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH (C), diethylaminoethyl α-methyl-(p-chlorobenzoyl)-5-methoxy-2-methyl indole 3-acetate.AcOH (D), diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH (E), diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate.AcOH (F) were administered transdermally. Group A is the control group.

FIG. 3e-2: The prolongation time of the pain threshold of mice tails after 50 mg/kg of diethylaminoethyl α-methyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetate.AcOH (G), diethylaminoethyl 2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetate.AcOH (H), diethylaminoethyl α-methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH (I), diethylaminoethyl 5-benzoyl-α-methyl-2-thiopheneacetate.AcOH (J), diethylaminoethyl 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-α-methyl benzeneacetate.AcOH (K) were administered transdermally. Group A is the control group.

FIG. 3e-3: The prolongation time of the pain threshold of mice tails after 50 mg/kg of diethylaminoethyl 2-(10,11-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH (L), diethylaminoethyl 2-(8-methyl-10,11-dihydro-11-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH (M), diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH (N), diethylaminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate.AcOH (O), diethylaminoethyl α,3-dichloro-4-cyclohexylbenzeneacetate.AcOH (P), were administered transdermally. Group A is the control group.

FIG. 3e-4: The prolongation time of the pain threshold of mice tails after 50 mg/kg of diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH (O), diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH (R), diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH (S), diethylaminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.AcOH (T), diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylate.AcOH (U) were administered transdermally. Group A is the control group.

FIG. 3h: The prolongation time of the pain threshold of mice tails after 20 mg/kg of 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,1,2-benzothiazine-3-carboxamide 1,1-dioxide.HCl (B), N-(2-thiazoyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H,1,2-benzothiazine-3-carboxamide 1,1-dioxide.HCl (C), 6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide.HCl (D), 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide.HCl (E), 8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridine-2-ylamino-methylidene)-3-methyl-2,2-dioxo-2λ6,7-dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one.HCl (F), 4-N,N-dimethylaminobutyryloxy-2-methyl-N-[5-Methyl-3-isoxolyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide].HCl (G), and 4-N,N-dimethylaminobutyryloxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.HCl (H) were administered transdermally. Group A is the control group.

FIG. 4a. The rate of swelling (%) after a carrageenin injection. 1 hour before the carrageenin injection, 100 mg/kg of aspirin was administered orally (B), 100 mg/kg of diethylaminoethyl salicylate.AcOH (C) was administered orally and transdermally (D). A is the control line.

FIG. 4b. The rate of swelling (%) after a carrageenin injection. 1 hour before the carrageenin injection, 50 mg of 5-(2,4-difluorophenyl)salicylic acid (diflunisal, B) was administered orally, 50 mg of diethylaminoethyl 5-(2,4-difluorophenyl)salicylate.AcOH (C) was administered orally, and transdermally (D). A is the control group.

FIG. 4c. The rate of swelling (%) after a carrageenin injection. 1 hour before the carrageenin injection, 50 mg/kg of ibuprofen was administered orally (B), 50 mg/kg of diethylaminoethyl 2-(ρ-isobutylphenyl)propionate.AcOH was administered orally (C), and transdermally (D). A is the control group.

FIG. 4d. The rate of swelling (%) after a carrageenin injection. 1 hour before the carrageenin injection, 50 mg of 2-(3-benzoyphenyl)propionic acid (ketoprofen, B) was administered orally, 50 mg of diethylaminoethyl 2-(3-benzoyphenyl)propionate.AcOH was administered orally (C), and transdermally (D). A is the control group.

FIG. 4e-1. The rate of swelling (%) after a carrageenin injection. 1 Hour before the carrageenin injection, diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH (100 mg/kg, B), diethylaminoethyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH (100 mg/kg, C), diethylaminoethyl α-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH (100 mg/kg, D), diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH (100 mg/kg, E), diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate.AcOH (100 mg/kg, F) were administered transdermally. Group A is the control group.

FIG. 4e-2. The rate of swelling (%) after a carrageenin injection. 1 Hour before the carrageenin injection, diethylaminoethyl α-methyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetate.AcOH (100 mg/kg, G), diethylaminoethyl 2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetate.AcOH (100 mg/kg, H), diethylaminoethyl α-methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH (100 mg/kg, I), diethylaminoethyl 5-benzoyl-α-methyl-2-thiopheneacetate.AcOH (100 mg/kg, J), diethylaminoethyl 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-α-methyl benzeneacetate.AcOH (100 mg/kg, K) were administered transdermally. Group A is the control group.

FIG. 4e-3. The rate of swelling (%) after a carrageenin injection. 1 Hour before the carrageenin injection, diethylaminoethyl 2-(10,11-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH (100 mg/kg, L), diethylaminoethyl 2-(8-methyl-10,11-dihydro-11-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH (100 mg/kg, M), diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH (100 mg/kg, N), diethylaminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate.AcOH (100 mg/kg, O), diethylaminoethyl α,3-dichloro-4-cyclohexylbenzeneacetate.AcOH (100 mg/kg, P) were administered transdermally. Group A is the control group.

FIG. 4e-4. The rate of swelling (%) after a carrageenin injection. 1 Hour before the carrageenin injection, diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH (100 mg/kg, Q), diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH (100 mg/kg, R), diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH (100 mg/kg, S), diethylaminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.AcOH (100 mg/kg, T), diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylate.AcOH (100 mg/kg, U) were administered transdermally. Group A is the control group.

FIG. 4f. The rate of swelling (%) after a carrageenin injection. 1 hour before the carrageenin injection, 10 mg/kg of diclofenac was administered orally (B), 10 mg/kg of diethylaminoethyl 2[(2,6-dichlorophenyl)amino]benzene acetate.AcOH was administered orally (C), and transdermally (D). A is the control group.

FIG. 4g. The rate of swelling (%) after a carrageenin injection. 2 hour before the carrageenin injection, diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH (100 mg/kg, B), diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH (100 mg/kg, C), diethylaminoethyl 2-[[(3-(trifluoromethyl)phenyl)amino]benzoate.AcOH (100 mg/kg, D), diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH (100 mg/kg, E), diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH (100 mg/kg, F) were administered transdermally. Group A is the control group.

EXEMPLARY EMBODIMENTS OF THE INVENTION

I. Structure of High Penetration Prodrug (HPP) or High Penetration Composition (HPC)

One aspect of the invention relates to a high penetration prodrug (HPP) or a high penetration composition (HPC). The term “high penetration prodrug” or “HPP” or “high penetration composition” or “HPC” as used herein refers to a composition comprising a functional unit covalently linked to a transportational unit through a linker. The functional unit comprises a moiety of an agent (e.g., a drug). The functional unit has the properties including that 1) the delivery of the agent or the HPP into a biological subject or transportation across a biological barrier is desired, 2) the HPP is capable of penetrating or crossing a biological barrier, and 3) the HPP is capable of being cleaved so as to turn the moiety of the agent into an agent or active agent after cleavage. In certain embodiments, the agent comprises an active agent or an agent that can be metabolized into an active agent or active metabolite.

In certain embodiments, the functional unit may be hydrophilic, lipophilic, or amphiphilic (hydrophilic and lipophilic). The lipophilic moiety of the function unit may be inherent or achieved by converting its hydrophilic moieties to lipophilic moieties. For example, the lipophilic moiety of a functional unit is produced by converting one or more hydrophilic groups of the functional unit to lipophilic groups via traditional organic synthesis. Examples of the hydrophilic groups are carboxylic, hydroxyl, thiol, amine, phosphate/phosphonate and carbonyl groups. The lipophilic moieties produced via the modification of these hydrophilic groups are ethers, thioethers, esters, thioesters, carbonates, carbamates, amides, phosphates and oximes.

In certain embodiments, the agent is a non-steroidal anti-inflammatory agent (NSAIA), an active NSAIA metabolite, an agent that can be metabolized into a NSAIA or an active NSAIA metabolite after the HPP(NSAIA-HPP) penetrates one or more BBs. The agent of the functional unit can be further converted to lipophilic motif as described supra.

The term “non-steroidal anti-inflammatory agent” or “NSAIA” is well known in the art and is a non-steroidal agent used to treat inflammation related conditions. NSAIA has anti-inflammatory effect, and some examples of NSAIA also have analgesic and/or antipyretic effects. Examples of NSAIA include, but are not limited to, acetylsalicylic acid (aspirin), 5-(2,4-difluorophenyl)salicylic acid (diflunisal), salicylsalicylic acid (salsalate), salicylic acid, N-Acetyl-p-aminophenol (acetaminophen), 2-(ρ-isobutylphenyl)propionic acid (ibuprofen), 2-(3-benzoylphenyl)propionic acid (ketoprofen), 2-(3-phenoxyphenyl)propionic acid (fenoprofen), 2-(6-methoxy-2-naphthyl)propionic acid (naproxen), α-methyl-4-(2-thienylcarbonyl)benzeneacetic acid (suprofen), α-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, 2-(2-fluoro-4-biphenylyl)propionic acid (flurbiprofen), 6-chloro-α-methyl-9H-carbazole-2-acetic acid (carprofen), α-methyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetic acid (pranoprofen), 2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetic acid (benoxaprofen), α-methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetic acid (alminoprofen), 5-benzoyl-α-methyl-2-thiopheneacetic acid (tiaprofenic acid), 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-α-methyl benzeneacetic acid (pirprofen), 2-(10,11-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionic acid (zaltoprofen), 2-(8-methyl-10,11-dihydro-11-oxodibenz(b,f)oxepin-2-yl)propionic acid (bermoprofen), 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionic acid (loxoprofen), 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-α-methylbenzeneacetic acid (indoprofen), α,3-dichloro-4-cyclohexylbenzeneacetic acid (fenclorac), 2-aryl and heteroarylpropionic acids, 4,5-Diphenyl-2-oxazole propionic acid (oxaprozin), 3-(4-biphenylylcarbonyl)propionic acid (fenbufen), 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionic acid (orpanoxin), and related compounds are members of 3-aryl and heteroarylpropionic acid group of NSAIA. 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid (ketorolac), 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylic acid (clidanac), 1-Methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetic acid (tolmetin), 5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetic acid (zomepirac), 1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid (etodolac), 2-amino-3-benzoylbenzeneacetic acid (amfenac), 2-amino-3-(4-bromo-benzoyl)benzeneacetic acid (bromofenac), 3-chloro-4-(2-propenyloxy)benzeneacetic acid (alclofenac), 2-(2,4-dichlorophenoxy)benzeneacetic acid (fenclofenac), 1-(4-chlorobenzoyl-5-methoxy-2-methyl-1H-indole-3-acetic acid carboxymethyl ester (acemetacin), 4-(4-chlorophenyl)-2-phenyl-5-thiazoleacetic acid (fentiazac), 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid (indomethacin), (Z)-5-fluoro-2-methyl-1-[(4-methylsulfinyl)phenylmethylene]-1H-indene-3-acetic acid (sulindac), 3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-4-acetic acid (lonazolac), [(1-benzyl-1H-indazol-3-yl)oxy]acetic acid (bendazac), 6-methoxyl-2-naphthalene-2-acetic acid (6MNA), 2[(2,6-dichlorophenyl)amino]benzene acetic acid (diclofenac), 2-[(2,3-Dimethylphenyl)amino]benzoic acid (mefenamic acid), 2-[(2,6-dichloro-3-methylphenyl)amino]benzoic acid (meclofenamic acid), 2-[[(3-trifluoromethyl)phenyl]amino]benzoic acid (flufenamic acid), 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylic acid (niflumic acid), 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylic acid (flunixin), 4-hydroxy-2-methyl-N-2-pyridinyl-2H,1,2-benzothiazine-3-carboxamide 1,1-dioxide (piroxicam), sudoxiam, 6-chloro-4-hydroxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide (lornoxicam), 4-hydroxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide (tenoxicam), ethyl 1-[2-methyl-1,1-dioxo-3-(pyridin-2-ylcarbamoyl)benzo[e]thiazin-4-yl]oxyethyl carbonate (ampiroxicam), 8-chloro-(4-hydroxyl-4-pyridine-2-ylamino-methylidene)-3-methyl-2,2-dioxo-2λ6,7-dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one (lomoxicam), 4-hydroxy-2-methyl-N-[5-Methyl-3-isoxolyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide] (isoxicam), cinnoxicam and N-(2-thiazolyl)-4-hydroxy-2-methyl-2H,1,2-benzothiazine-3-arboxamide 1,1-dioxide (meloxicam).

In one embodiment, the functional unit of a NSAIA-HPP comprises a moiety having a structure selected from Group F-1 and Group F-2, wherein Group F-1 includes the following structures;

and Group F-2 includes the following structures;

including stereoisomers and pharmaceutically acceptable salts thereof. As used herein, unless specified otherwise, each R, R1, R2, R5-R7 is independently selected from the group consisting of H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, N, P(O)OR6, CH═CH, C≡C, CHR6, CR5R6, aryl, heteroaryl, and cyclic groups;

each R8-R10 is independently selected from the group consisting of nothing, H, R6, R6C(═O)—, R6NH(C═O), R6O(C═O), R6C(═NH)—, R6C(═S)—, CNR6 and R6OCO(CH2)nC(═O), wherein n is selected from the group of natural numbers;

each Y and Y1 to Y13 is independently selected from the group consisting of H, halogen, CN, R10, CH3C≡C, CR6≡C, P(O)OR6, CF3, CF3O, CH3, CF3CF2, CF3CF2O, CH3CH2, CH3CH2CH2, (CH3)2CH, (CH3)2CHCH2, CH3CH2CH(CH3), (CH3)3C, C4H9, C5H11, CH3CO, CH3CH2CO, R5CO, CH3COO, R5COO, R5COOCH2, R6NHCOOCH2, CH3COS, CH3O, R50, HO, R10O, CF3CH2SCH2, CHCl2, CH2COOR6, CH3S, R5S, HS, R10S, CH3OCH2CH2, R5OCH2, R10OCH2CH2, R5O(C═O), C2H5OCONH, CH2NHR8, CH3OCONH, CH3SO2, CH3SO, R5SO2, R5SO, NH2SO2, C6H5CH2, NH2, NHR10, cyclobutyl, cyclopropyl, 4-chlorophenyl, 4-fluorophenyl, CH2═CH, CH2═CHCH2, CH3CH═CH, NHR5SO2, N(R5)2SO2, R5OCH2CH2CH2, and NO2;

each X and X1 to X5 is independently selected from the group consisting of nothing, CH3SO, S, O NR6, C═O, R6, P(O)OR6;

X6 is selected from the group consisting of R6, CONH, CSNH, COO, OCO, COS, COCH2, and CH2CO;

m is selected from the group of integers; and

W is selected from the group consisting of H, OH and halogen.

As used herein, unless specified otherwise, the term “alkyl” means a branched or unbranched, saturated or unsaturated, monovalent or multivalent hydrocarbon group. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, t-butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene and dodecylene, In certain embodiments, the hydrocarbon group contains 1 to 30 carbons. In certain embodiments, the hydrocarbon group contains 1 to 20 carbons

As used herein, unless specified otherwise, the term “cycloalkyl” means an alkyl which contains at least one ring and no aromatic rings. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. In certain embodiments, the hydrocarbon chain contains 1 to 30 carbons. In certain embodiments, the hydrocarbon group contains 1 to 20 carbons.

As used herein, unless specified otherwise, the term “heterocycloalkyl” means a cycloalkyl wherein at least one ring atom is a non-carbon atom. Examples of the non-carbon ring atom include, but are not limited to, S, O and N.

As used herein, unless specified otherwise, the term “alkoxyl” means an alkyl, cycloalkyl or heterocycloalkyl, which contains one or more oxygen atoms. Examples of alkoxyl include, but are not limited to, —CH2—OH, —OCH3, —O-alkyl, -alkyl-OH, -alkyl-O-alkyl-, wherein the two alkyls can be the same or different.

As used herein, unless specified otherwise, the term “alkyl halide” means an alkyl, cycloalkyl or heterocycloalkyl, which contains one or more halogen atoms, wherein the halogen atoms can be the same or different. The term “halogen” means fluorine, chlorine, bromine or iodine. Examples of alkyl halide include, but are not limited to, -alkyl-F, -alkyl-Cl, -alkyl-Br, -alkyl-1, -alkyl(F)—, -alkyl(Cl)—, -alkyl(Br)— and -alkyl(I)—.

As used herein, unless specified otherwise, the term “alkylthio” means an alkyl, cycloalkyl or heterocycloalkyl, which contains one or more sulfur atoms. Examples of alkylthio include, but are not limited to, —CH2—SH, —SCH3, —S-alkyl, -alkyl-SH, -alkyl-5-alkyl-, wherein the two alkyls can be the same or different.

As used herein, unless specified otherwise, the term “alkylamino” means an alkyl, cycloalkyl or heterocycloalkyl, which contains one or more nitrogen atoms. Examples of alkylamino include, but are not limited to, —CH2—NH, —NCH3, —N(alkyl)-alkyl, —N-alkyl, -alkyl-NH2, -alkyl-N-alkyl and -alkyl-N(alkyl)-alkyl wherein the alkyls can be the same or different.

As used herein, unless specified otherwise, the term “perfluoroalkyl” means an alkyl, cycloalkyl or heterocycloalkyl, which contains one or more perfluoro group, including, without limitation, perfluoromethyl, perfluoroethyl, perfluoropropyl.

As used herein, unless specified otherwise, the term “aryl” means a chemical structure comprising one or more aromatic rings. In certain embodiments, the ring atoms are all carbon. In certain embodiments, one or more ring atoms are non-carbon, e.g. oxygen, nitrogen, or sulfur. Examples of aryl include, without limitation, phenyl, benzyl, naphthalenyl, anthracenyl, pyridyl, quinoyl, isoquinoyl, pyrazinyl, quinoxalinyl, acridinyl, pyrimidinyl, quinazolinyl, pyridazinyl, cinnolinyl, imidazolyl, benzimidazolyl, purinyl, indolyl, furanyl, benzofuranyl, isobenzofuranyl, pyrrolyl, indolyl, isoindolyl, thiophenyl, benzothiophenyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, thiaxolyl and benzothiazolyl.

In certain embodiments, the transportational unit of the HPP comprises a protonatable amine group that is capable of facilitating the transportation or crossing of the HPP through one or more biological barriers (>100 times faster than the parent drug). In certain embodiments, the protonatable amine group is substantially protonated at a physiological pH. In certain embodiment, the amine group can be reversibly protonated. In certain embodiment, the transportational unit may or may not be cleaved from the functional unit after the penetration of HPP through one or more biological barriers.

In certain embodiments, the protonatable amine group is selected from the group consisting of pharmaceutically acceptable substituted or unsubstituted primary amine groups, pharmaceutically acceptable substituted or unsubstituted secondary amine groups, and pharmaceutically acceptable substituted or unsubstituted tertiary amine groups.

In certain embodiments, the protonatable amine group is selected from Group N, wherein Group N includes Structure Na, Structure Nb, Structure Nc, Structure Nd, Structure Ne, Structure Nf, Structure Ng, Structure Nh, Structure Ni, Structure Nj, Structure Nk, Structure Nl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq and Structure Nr:

including stereoisomers and pharmaceutically acceptable salts thereof.

As used herein, unless specified otherwise, each R11-R16 is independently selected from the group consisting of nothing, H, CH2COOR11, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, P, NR11, or any other pharmaceutically acceptable groups.

As used herein, the term “HA” is nothing or a pharmaceutically acceptable acid, e.g. hydrochloride, hydrobromide, hydroiodide, nitric acid, sulfic acid, bisulfic acid, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, gentisinic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzensulfonic acid, p-toluenesulfonic acid and pamoic acid.

As used herein, “A” or “A” is nothing or a pharmaceutically acceptable anion, e.g. Cl—, Br—, F—, I—, acetylsalicylate, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate or any pharmaceutically acceptable anion.

In certain embodiments, the linker covalently linking the functional unit and the transportational unit comprises a bond that is capable of being cleaved after the HPP penetrates across one or more BBs. The cleavable bond comprises, for example, a covalent bond, an ether, thioether, amide, ester, thioester, carbonate, carbamate, phosphate or oxime bond.

In certain embodiments, HPP of NSAIA has the following Structure L:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

F is selected from Group F1 and Group F2;

T is selected from Group N;

L1 is selected from the group consisting of nothing, O, S, —N(L3)-, —N(L3)-CH2—O, —N(L3)-CH2—N(L3)-, —O—CH2—O—, —O—CH(L3)-O, —S—CH(L3)-O—;

L2 is selected from the group consisting of L1, —O-L3-, —N-L3-, —S-L3-, —N(L3)-L3- and L3;

L4 is selected from the group consisting of C═O, C═S,

each L3 is independently selected from the group consisting of nothing, H, CH2COOR1, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, and substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, wherein any carbon or hydrogen may be further independently replaced with O, S, P, N L3, or any other pharmaceutically acceptable groups.

I-1. Examples of HPP of Aspirin and Related Compounds

In certain embodiments, the HPP has the following Structure 1 or Structure 2:

including stereoisomers and pharmaceutically acceptable salts thereof.

In certain embodiments, the HPP has Structure 1 or Structure 2, including stereoisomers and pharmaceutically acceptable salts thereof wherein:

Z is selected from the group consisting of O, S, N;

X is selected from the group consisting of nothing, O, P(O)OR1, NH, NR1 and S;

R is a substituted or unsubstituted —(CH2)n—, n=1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, . . . , in —(CH2)n—, any CH2 may be independently replaced with O, S, NR5, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl residues, and any other moieties which are pharmaceutically acceptable;

R1 and R2 are independently selected from the group consisting of H, one of any alkyl, cycloalkyl, alkyloxyl, cycloalkyloxyl, alkenyl, cycloalkenyl, perfluoroalkyl, cycloperfluoroalkyl, alkyl halide, cycloalkyl halide, alkynyl, or cycloalkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties, wherein, any CH2 may be independently replaced with O, S, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl moieties, any other moieties which are pharmaceutically acceptable;

R5 and R6 are independently selected from the group consisting of H, OH, Cl, F, Br, I, alkyl, cycloalkyl, alkyloxyl, cycloalkyloxyl, alkenyl, cycloalkenyl, perfluoroalkyl, cycloperfluoroalkyl, alkyl halide, cycloalkyl halide, alkynyl, or cycloalkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties;

R7 is selected from the group consisting of one of any alkyl, cycloalkyl, alkyloxyl, cycloalkyloxyl, alkenyl, cycloalkenyl, perfluoroalkyl, cycloperfluoroalkyl, alkyl halide, cycloalkyl halide, alkynyl, or cycloalkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties;

X1 is selected from the group consisting of O, and the following structures:

Y1 and Y2 are independently selected from the group consisting of H, HO, CH3COO, R8COO, HS, NO2, CN, CH3COS, NH2, CH3CONH, R8CONH, CH3, CH3CH2, C3H7, C4H9, CH3O, CH3CH2O, C3H7O, Cl, F, Br, I, CH3S, CHF2O, CF3O, CF3CF2O, C3F7O, CF3, CF3CF2, C3F7, C4F9, CH3SO2, R8 SO2, CH3SO, R8SO, CH3CO, CH3CH2CO;

all R, R1, R2, R5, R6, R7, R8, Y1, Y2, and —(CH2)n— groups are branched or straight chains and may include C, H, O, Cl, Br, F, I, P, S, N or any other atoms which are pharmaceutically acceptable and may have single, double, or/and triple bonds.

In certain embodiments, the HPP of aspirin has the following Structure 1-b:

including stereoisomers and pharmaceutically acceptable salts thereof.

In certain embodiments, the HPP has Structure 1a, including stereoisomers and pharmaceutically acceptable salts thereof wherein:

R1 represents CH3, C2H5, C3H7, or other lower alkyl groups;

R2 represents H, one of any alkyl, alkyloxyl, or alkenyl residues having 1 to 6 carbon atoms, or aryl residues;

R3 represents H, one of any alkyl, alkyloxyl, or alkenyl residues having 1 to 6 carbon atoms, or aryl residues;

R4 represents H, one of any alkyl, alkyloxyl, or alkenyl residues having 1 to 6 carbon atoms, or aryl residues;

X represents O, S or N.

I-2. HPP of Diflunisal and Related Compounds

In certain embodiments, the HPP has the following Structure 3 or Structure 4:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

R represents a branched or straight chain —(CH2)n—, n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, . . . , in —(CH2)n—, any CH2 may be independently replaced with O, S, NR5, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl residues, or any other moieties which are pharmaceutically acceptable;

R1 represents OH, OCOR5, OCSR5, 2-hydroxylbenzoyloxyl (salicyloyloxyl, 2-OCO—C6H4—OH), 2-R5COO-benzoyloxyl (salicyloyloxyl, 2-OCO—C6H4—OCOR5), 2-R5CSO-benzoyloxyl (salicyloyloxyl, 2-OCO—C6H4—OCSR5), 2-OCO—C6H4—OCO—C6H4—O COR5, or 2-OCO—C6H4—OCO—C6H4—O CSR5;

R2 represents H, 2-fluorophenyl, 4-fluorophenyl, 2-chloro-4-fluorophenyl, 2-fluoro-4-chlorophenyl, 2,4-difluorophenyl, substituted 2,4-difluorophenyl, or substituted phenyl;

R3 and R4 are independently selected from the group consisting of H, any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties, wherein, any CH2 may be independently replaced with O, S, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl moieties, and any other moieties which are pharmaceutically acceptable;

X is selected from the group consisting of O, NH, NR5, S and nothing;

R5 represents H, OH, Cl, F, Br, I, one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties;

R6 represents H, OH, Cl, F, Br, I, one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties;

R8 represents one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties;

Y or Y1 represents independently H, HO, CH3COO, R8COO, HS, NO2, CN, CH3COS, NH2, CH3CONH, R8CONH, CH3, CH3CH2, C3H7, C4H9, CH3O, CH3CH2O, C3H7O, Cl, F, Br, I, CH3S, CHF2O, CF3O, CF3CF2O, C3F7O, CF3, CF3CF2, C3F7, C4F9, CH3SO2, R8SO2, CH3SO, R8SO, CH3CO, CH3CH2CO;

all R, R1, R2, R3, R4, R5, R6, R8, or —(CH2)n— groups are branched or straight chains and may include C, H, O, Cl, Br, F, I, P, S, N or any other atoms which are pharmaceutically acceptable and may have single, double, or/and triple bonds;

in structure 4, Z represents O or S;

X1 represents O, 2-OCO—C6H4—O, or 2-OCO—C6H4—OCO—C6H4—O;

R represents a branched or straight chain —(CH2)n—, n=1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, . . . , in —(CH2)n—, any CH2 may be replaced with O, S, NR5, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl residues, or any other moieties which are pharmaceutically acceptable;

R2 represents H, 2-fluorophenyl, 4-fluorophenyl, 2-chloro-4-fluorophenyl, 2-fluoro-4-chlorophenyl, 2,4-difluorophenyl, or substituted 2,4-difluorophenyl;

R3 represents H, one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties, wherein, any CH2 may be independently replaced with O, S, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl moieties, or any other moieties which are pharmaceutically acceptable;

R4 represents H, one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties, wherein, any CH2 may be independently replaced with O, S, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl moieties, or any other moieties which are pharmaceutically acceptable; X represents O, NH, NR5, S, or none;

R5 represents H, OH, Cl, F, Br, I, one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties;

R6 represents H, OH, Cl, F, Br, I, one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties;

R7 represents one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties;

R8 represents H, OH, Cl, F, Br, I, one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties;

Y, or Y1 represents independently H, HO, CH3COO, R8COO, HS, NO2, CN, CH3COS, NH2, CH3CONH, R8CONH, CH3, CH3CH2, C3H7, C4H9, CH3O, CH3CH2O, C3H7O, Cl, F, Br, I, CH3S, CHF2O, CF3O, CF3CF2O, C3F7O, CF3, CF3CF2, C3F7, C4F9, CH3SO2, R8SO2, CH3SO, R8SO, CH3CO, CH3CH2CO; and

all R, R1, R2, R3, R4, R5, R6, R7, R8, Y, Y1, or —(CH2)n— groups are branched or straight chains and may include C, H, O, Cl, Br, F, 1, P, S, N or any other atoms which are pharmaceutically acceptable and may have single, double, or/and triple bonds.

In certain embodiments, the HPP has the Structure 3 or Structure 4, including stereoisomers and pharmaceutically acceptable salts thereof, wherein all the substitutions are defined as the general definition.

In certain embodiments, the HPP has the following Structure 3-a:

including stereoisomers and pharmaceutically acceptable salts thereof.

In certain embodiments, the HPP has the Structure 3-1, including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

R1 represents OH, OCOCH3, OCOC2H5, OCOC3H7, OCOC4H9, OCOC5H11, OCOC6H13, 2-hydroxylbenzoyloxyl (salicyloyloxyl, 2-OCO—C6H4—OH), 2-acetyloxylbenzoyloxyl (acetylsalicyloyloxyl, 2-OCO—C6H4—OCOCH3), 2-propionyloxylbenzoyloxyl (propionylsalicyloyloxyl, 2-OCO—C6H4—OCOC2H5), or 2-butyryloxylbenzoyloxyl (butyrylsalicyloyloxyl, 2-OCO—C6H4—OCOC3H7);

R2 represents H or 2,4-difluorophenyl;

R3 represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues;

R4 represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues;

R5 represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; X represents O, S or NH; A represents Cl, Br, F, I, AcO, citrate, or any negative ions; and n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, . . . . All R groups may include C, H, O, S, N atoms and may have single, double, and treble bonds;

and any CH2 groups may be independently replaced with O, S, or NH.

In certain embodiments, the HPP has the following Structure 4-a

including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

X represents O or 2-OCO—C6H4—OH); R2 represents H or 2,4-difluorophenyl;

R3 is H;

R4-R6 represents H, one of any alkyl, alkyl, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues;

Z represents O or S; A represents Cl, Br, F, I, AcO, citrate, or any negative ions; and n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, . . . ; and

all R groups may include C, H, O, S, N atoms and may have single, double, and treble bonds. Any CH2 groups may be independently replaced with O, S, or NH.

I-3. HPP of Ibuprofen and Related Compounds

In certain embodiments, the HPP has the following Structure 5

including stereoisomers and pharmaceutically acceptable salts thereof.

In certain embodiments, the HPP has the Structure 5, including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

R represents nothing, linear or branched 1-20 carbon atoms alkyl, 1-20 carbon atoms alkyloxyl, 1-20 carbon atoms perfluoroalkyl, 1-20 carbon atoms alkyl halide, 2-20 carbon atoms alkenyl, 2-20 carbon atoms alkynyl moieties, aryl or heteroaryl moieties having 6-20 carbon atoms which are pharmaceutically acceptable, wherein, any CH2 may be independently replaced with O, S, NR5, or other groups;

R1 represents H, one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 20 carbon atoms, aryl or heteroaryl moieties, wherein, any CH2 may be independently replaced with O, S, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl moieties, or any other moieties which are pharmaceutically acceptable;

R2 represents H, one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 20 carbon atoms, aryl or heteroaryl moieties, wherein, any CH2 may be independently replaced with O, S, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl moieties, or any other moieties which are pharmaceutically acceptable; X represents O, NH, NR5, S, or none;

R5 represents H, OH, Cl, F, Br, I, one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 20 carbon atoms, aryl or heteroaryl moieties;

R6 represents H, OH, Cl, F, Br, I, one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 20 carbon atoms, aryl or heteroaryl moieties;

R7 represents one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 20 carbon atoms, aryl or heteroaryl moieties;

HA represents none, HCl, HBr, HF, Hi, HOAc, citric acid, or any acids which are pharmaceutically acceptable;

Y, Y1, Y2, Y3, or Y4 represents independently H, HO, CH3COO, R7COO, HS, NO2, CN, R7COS, NH2, CH3CONH, R7CONH, CH3, CH3CH2, C3H7, C4H9, CH3O, CH3CH2O, C3H7O, Cl, F, Br, I, CH3S, CHF2O, CF3O, CF3CF2O, C3F7O, CF3, CF3CF2, C3F7, C4F9, CH3SO2, R7SO2, CH3SO, R7SO, CH3CO, or CH3CH2CO;

all R, R1, R2, R5, R6, R7, or —(CH2)n— groups are branched or linear chains and may include C, H, O, Cl, Br, F, 1, P, S, N or any other atoms which are pharmaceutically acceptable and may have single, double, or/and triple bonds.

I-4. HPP of Ketoprofen, Fenoprofen and Related Compounds

In certain embodiments, the HPP has the following Structure 6:

including stereoisomers and pharmaceutically acceptable salts thereof.

In certain embodiments, the HPP has the Structure 6, including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

R represents a branched or straight chain —(CH2)n—, n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, . . . , in —(CH2)n—, any CH2 may be replaced with O, S, NR5, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl residues, or any other moieties which are pharmaceutically acceptable;

R1 represents H, one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties, wherein, any CH2 may be independently replaced with O, S, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl moieties, or any other moieties which are pharmaceutically acceptable;

R2 represents H, one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties, wherein, any CH2 may be independently replaced with O, S, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl moieties, or any other moieties which are pharmaceutically acceptable;

X represents O, NH, NR5, S, or none; X1 represents O or CO;

R5 represents H, OH, Cl, F, Br, I, one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties;

R6 represents H, OH, Cl, F, Br, I, one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties;

R7 represents one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties;

HA represents none, HCl, HBr, HF, Hi, HOAc, citric acid, or any acids which are pharmaceutically acceptable;

Y1, Y2, or Y3 represents independently H, HO, CH3COO, R7COO, HS, NO2, CN, CH3COS, NH2, CH3CONH, R7CONH, CH3, CH3CH2, C3H7, C4H9, CH3O, CH3CH2O, C3H7O, Cl, F, Br, I, CH3S, CHF2O, CF3O, CF3CF2O, C3F7O, CF3, CF3CF2, C3F7, C4F9, CH3SO2, R7SO2, CH3SO, R7SO, CH3CO, CH3CH2CO; and

all R, R1, R2, R5, R6, R7, or —(CH2)n— groups are branched or straight chains and may include C, H, O, Cl, Br, F, I, P, S, N or any other atoms which are pharmaceutically acceptable and may have single, double, or/and triple bonds.

In certain embodiments, the HPP has the following Structure 6-a:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

R1 is H;

R2-R3 are independently selected from the group consisting of H, one of any alkyl, alkyl, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues;

R4 represents

X represents O, S or NH; A represents Cl, Br, F, I, AcO, citrate, or any negative ions; and n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 . . . ; and

all R groups may include C, H, O, S, N atoms and may have single, double, and treble bonds, and any CH2 groups may be independently replaced with O, S, or NH.

I-5. HPP of Aryl- and Heteroaryl Propionic Acids and Related Compounds

A. HPP of 2-aryl Propionic Acids

In certain embodiments, the HPP has the following Structure 7:

including stereoisomers and pharmaceutically acceptable salts thereof.

In certain embodiments, the HPP has the Structure 7, including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

R represents a branched or straight chain —(CH2)n—, n=1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, . . . , in —(CH2)n—, any CH2 may be replaced with O, S, NR5, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl residues, or any other moieties which are pharmaceutically acceptable;

R1 represents H, one of any alkyl, cycloalkyl, alkyloxyl, cycloalkyloxyl, alkenyl, cycloalkenyl, perfluoroalkyl, cycloperfluoroalkyl, alkyl halide, cycloalkyl halide, alkynyl, or cycloalkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties, wherein, any CH2 may be independently replaced with O, S, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl moieties, or any other moieties which are pharmaceutically acceptable;

R2 represents H, one of any alkyl, cycloalkyl, alkyloxyl, cycloalkyloxyl, alkenyl, cycloalkenyl, perfluoroalkyl, cycloperfluoroalkyl, alkyl halide, cycloalkyl halide, alkynyl, or cycloalkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties, wherein, any CH2 may be independently replaced with O, S, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl moieties, or any other moieties which are pharmaceutically acceptable;

X represents O, OCR5, R6COO, OCR5, R6COS, OCR5R6CONR5, NR5, NR50, NR5NR6, S, or none;

Y represents H, CH3, CH3CH2, C3H7, C4H9, OH, OCOR7, Cl, F, I, or Br; R5 represents H, OH, Cl, F, Br, I, one of any alkyl, cycloalkyl, alkyloxyl, cycloalkyloxyl, alkenyl, cycloalkenyl, perfluoroalkyl, cycloperfluoroalkyl, alkyl halide, cycloalkyl halide, alkynyl, or cycloalkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties;

R6 represents H, OH, Cl, F, Br, I, one of any alkyl, cycloalkyl, alkyloxyl, cycloalkyloxyl, alkenyl, cycloalkenyl, perfluoroalkyl, cycloperfluoroalkyl, alkyl halide, cycloalkyl halide, alkynyl, or cycloalkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties;

represents one of any alkyl, cycloalkyl, alkyloxyl, cycloalkyloxyl, alkenyl, cycloalkenyl, perfluoroalkyl, cycloperfluoroalkyl, alkyl halide, cycloalkyl halide, alkynyl, or cycloalkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties;

HA represents none, HCl, HBr, HF, Hi, HOAc, citric acid, or any acids which are pharmaceutically acceptable;

all R, R1, R2, R5, R6, R7, or —(CH2)n— groups are branched or straight chains and may include C, H, O, Cl, Br, F, I, P, S, N or any other atoms which are pharmaceutically acceptable and may have single, double, or/and triple bonds;

aryl- represents:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

Y1, Y2, Y3, Y4, Y5, or Y6 represents independently H, HO, CH3COO, R7COO, HS, NO2, CN, ═N—OH, ═NOR8, NR5OR8, NR5OH, CH3COS, R7COS, NH2, CH3CONH, R7CONH, CH3, CH3CH2, C3H7, C4H9, CH3O, CH3CH2O, C3H7O, Cl, F, Br, I, CH3S, CHF2O, CF3O, CF3CF2O, C3F7O, CF3, CF3CF2, C3F7, C4F9, CH3SO2, R7SO2, CH3SO, R7SO, CH3CO, CH3CH2CO, C3H7CO, (CH3)2N, CH2═CH—CH2, CH2═CH—CH2O, CH3(CH2)3O, C3H7O, C4H9O, cycloalkyl, cycloalkenyl, cycloalkynyl, benzyl, substituted benzyl, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-iodophenyl, 3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl, 3-iodophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-iodophenyl, or other substituted phenyl;

R8 represents CH3CO, CH3CH2CO, C3H7CO, C4H9CO, CH3, CH3CH2, C3H7, C4H9;

X1 represents CH2, CO, O, NR5, or S;

X2 represents CH2, CO, NR5, O, or S;

X3 represents CH2, CO, NR5, O, or S;

all Y1, Y2, Y3, Y4, Y5, Y6, R5, R6, R7, R8, or —(CH2)n— groups are branched or straight chains and may include C, H, O, Cl, Br, F, I, P, S, N or any other atoms which are pharmaceutically acceptable and may have single, double, or/and triple bonds.

In certain embodiments, the HPP has the following Structure 7-a:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

R represents CH3, CH3CH2, C3H7, C4H9, OH, Cl, F, or Br;

R1-R3 are independently selected from the group consisting of H, alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, and aryl residues;

X represents O, S, NH, OCH2COO, OCH2COS, or OCH2CONH;

A represents Cl, Br, F, I, AcO, citrate, or any negative ions; n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 . . . ;

Aryl represents

All R groups may include C, H, O, S, or N atoms and may have single, double, and treble bonds. Any CH2 groups may be independently replaced with O, S, or NH.

B. Examples of HPP of 3-aryl- and Heteroaryl Propionic Acids and Related Compounds

4,5-Diphenyl-2-oxazole propionic acid (oxaprozin), 3-(4-biphenylylcarbonyl)propionic acid (fenbufen), 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropanoic acid (orpanoxin), and related compounds are members of 3-aryl and heteroarylpropionic acid group of NSAIA.

In certain embodiments, the HPP has the following Structure 8:

including stereoisomers and pharmaceutically acceptable salts thereof.

In certain embodiments, the HPP has the Structure 8, including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

W represents H, OH, Cl, F, I, or Br;

Y, X, R, R1, R2, and HA are defined as supra;

Aryl- represents:

Y1, Y2, Y3, or Y4, represents independently H, HO, CH3COO, R7COO, HS, NO2, CN, ═N—OH, ═NOR8, NR5OR8, NR5OH, CH3COS, R7COS, NH2, CH3CONH, R7CONH, CH3, CH3CH2, C3H7, C4H9, CH3O, CH3CH2O, C3H7O, Cl, F, Br, I, CH3S, CHF2O, CF3O, CF3CF2O, C3F7O, CF3, CF3CF2, C3F7, C4F9, CH3SO2, R7SO2, CH3SO, R7SO, CH3CO, CH3CH2CO, C3H7CO, (CH3)2N, CH2═CH—CH2, CH2═CH—CH2O, CH3(CH2)3O, C3H7O, C4H9O, cycloalkyl, substituted cycloalkyl, cycloalkenyl, cycloalkynyl, benzyl, substituted benzyl, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-iodophenyl, 3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl, 3-iodophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-iodophenyl, or other substituted phenyl; R8 represents CH3CO, CH3CH2CO, C3H7CO, C4H9CO, CH3, CH3CH2, C3H7, C4H9;

all Y1, Y2, Y3, Y4, R5, R6, R7, R8, or —(CH2)n— groups are branched or straight chains and may include C, H, O, Cl, Br, F, I, P, S, N or any other atoms which are pharmaceutically acceptable and may have single, double, or/and triple bonds.

In certain embodiments, the HPP has the following Structure 8-a:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein R1 is H.

In certain embodiments, the HPP has the Structure 5, including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

W represents H, OH, Cl, F, or Br;

R1 is H;

R2 and R3 are independently selected from the group consisting of H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues;

X represents O, S, NH, OCH2COO, OCH2COS, or OCH2CONH;

A represents Cl, Br, F, I, AcO, citrate, or any negative ions;

n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 . . . ;

Y represents H;

Z represents

all R groups may include C, H, O, S, N atoms and may have single, double, and treble bonds and any CH2 groups may be independently replaced with O, S, or NH.

C. HPP of Cyclized Aryl and Heteroarylpropionic Acid and Related Compounds

In certain embodiments, the HPP of cyclized aryl and heteroarylpropionic acid has Structure 8 as defined supra, including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

W represents H, OH, Cl, F, I, or Br;

Y, X, R, R1, R2, and HA are defined as supra;

Y and Z together represent:

Y1, Y2, Y3, Y4, Y5, or Y6 represents independently H, HO, CH3COO, R7COO, HS, NO2, CN, ═N—OH, ═NOR8, NR5OR8, NR5OH, CH3COS, R7COS, NH2, CH3CONH, R7CONH, CH3, CH3CH2, C3H7, C4H9, CH3O, CH3CH2O, C3H7O, Cl, F, Br, I, CH3S, CHF2O, CF3O, CF3CF2O, C3F7O, CF3, CF3CF2, C3F7, C4F9, CH3SO2, R7SO2, CH3SO, R7SO, CH3CO, CH3CH2CO, C3H7CO, (CH3)2N, CH2═CH—CH2, CH2═CH—CH2O, CH3(CH2)3O, C3H7O, C4H9O, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, benzyl, substituted benzyl, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-iodophenyl, 3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl, 3-iodophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-iodophenyl, or other substituted phenyl;

R8 represents CH3CO, CH3CH2CO, C3H7CO, C4H9CO, CH3, CH3CH2, C3H7, C4H9; X1 represents CH2, CO, O, NR5, or S;

all Y1, Y2, Y3, Y4, Y5, Y6, R, R1, R2, R5, R6, R7, R8, or —(CH2)n— groups are branched or straight chains and may include C, H, O, Cl, Br, F, I, P, S, N or any other atoms which are pharmaceutically acceptable and may have single, double, or/and triple bonds.

In certain embodiments, the HPP has Structure 8-a, including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

W represents H,

Y and Z together represent

and X represents Cl, F or Br.

I-6. HPP of Aryl- and Heteroaryl Acetic Acids and Related Compounds

In certain embodiments, the HPP has the following Structure 9,

including stereoisomers and pharmaceutically acceptable salts thereof.

In certain embodiments, the HPP has the Structure 9, including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

R represents a branched or straight chain —(CH2)n—, n=1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, . . . , in —(CH2)n—, any CH2 may be replaced with O, S, NR5, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl residues, or any other moieties which are pharmaceutically acceptable;

R1 represents H, one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties, wherein, any CH2 may be independently replaced with O, S, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl moieties, or any other moieties which are pharmaceutically acceptable;

R2 represents H, one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties, wherein, any CH2 may be independently replaced with O, S, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl moieties, or any other moieties which are pharmaceutically acceptable;

X represents O, OCH2COO, OCH2COS, OCH2CONR5, NH, NR5, NHO, NHNH, S, or none;

R5 represents H, OH, Cl, F, Br, I, one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties;

R6 represents H, OH, Cl, F, Br, I, one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties;

R7 represents one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties;

HA represents none, HCl, HBr, HF, Hi, HOAc, citric acid, or any acids which are pharmaceutically acceptable;

all R, R1, R2, R5, R6, R7, or —(CH2)n— groups are branched or straight chains and may include C, H, O, Cl, Br, F, I, P, S, N or any other atoms which are pharmaceutically acceptable and may have single, double, or/and triple bonds

Aryl- represents:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

Y, Y1, Y2, Y3, Y4, or Y5 represents independently H, HO, CH3COO, R7COO, HS, NO2, CN, ═N—OH, NR5OR8, NR5OH, CH3COS, R7COS, NH2, CH3CONH, R7CONH, CH3, CH3CH2, C3H7, C4H9, CH3O, CH3CH2O, C3H7O, Cl, F, Br, I, CH3S, CHF2O, CF3O, CF3CF2O, C3F7O, CF3, CF3CF2, C3F7, C4F9, CH3SO2, R7SO2, CH3SO, R7SO, CH3CO, CH3CH2CO, C3H7CO, (CH3)2N, CH2═CH—CH2, CH2═CH—CH2O, CH3(CH2)3O, C3H7O, C4H9O, benzyl, substituted benzyl, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-iodophenyl, 3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl, 3-iodophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-iodophenyl, or other substituted phenyl;

R8 represents CH3CO, CH3CH2CO, C3H7CO, C4H9CO, CH3, CH3CH2, C3H7, C4H9;

X1 represents CH2, CH═, CO, NR5, O, or S;

X2 represents CH2, CH═, CO, NR5, O, or S;

X3 represents CH2, CH═, CO, NR5, O, or S; all R, R1, R2, R5, R6, R7, R8, or —(CH2)n— groups are branched or straight chains and may include C, H, O, Cl, Br, F, I, P, S, N or any other atoms which are pharmaceutically acceptable and may have single, double, or/and triple bonds.

In certain embodiments, the HPP has the following Structure 9-a:

Structure 9-a

including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

R1 is H;

R2 and R3 are independently selected from the group consisting of H, one of any alkyl, alkyloxy, alkenyl and alkynyl residues having 1 to 12 carbon atoms, or aryl residues;

X represents O, S, NH, OCH2COO, OCH2COS, or OCH2CONH;

A represents Cl, Br, F, I, AcO, citrate, or any negative ions;

n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 . . . ;

Aryl represents

all R groups may include C, H, O, S, N atoms and may have single, double, and treble bonds. Any CH2 groups may be independently replaced with O, S, or NH.

I-7. Examples of HPP of Diclofenac and Related Compounds

In certain embodiments, the HPP has the following Structure 10:

including stereoisomers and pharmaceutically acceptable salts thereof.

In certain embodiments, the HPP has the Structure 10, including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

R represents a branched or straight chain —(CH2)n—, n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, . . . , in —(CH2)n—, any CH2 may be replaced with O, S, NR5, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl residues, or any other moieties which are pharmaceutically acceptable;

R1 and R2 taken alone are same or different and are H, one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties or taken together are —(CH2)n—, wherein n=2, 3, 4, 5, 6, 7, 8, 9, 10, . . . , and any CH2 may be independently replaced with O, S, NR5, CH═CH, C≡C, CR4R5, aryl or heteroaryl moieties, or other moieties which are pharmaceutically acceptable;

X represents O, NH, NR5, S, or none;

R5 represents H, OH, Cl, F, Br, I, one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties;

R6 represents H, OH, Cl, F, Br, I, one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl moieties;

HA represents none, HCl, HBr, HF, Hi, HOAc, citric acid, or any acids which are pharmaceutically acceptable;

Y1, Y2, Y3, or Y4, represents independently H, HO, CH3COO, RyCOO, HS, NO2, CN, CH3COS, NH2, CH3CONH, RCONH, CH3, CH3CH2, C3H7, C4H9, CH3O, CH3CH2O, C3H7O, Cl, F, Br, I, CH3S, CHF2O, CF3O, CF3CF2O, C3F7O, CF3, CF3CF2, C3F7, C4F9, CH3SO2, RySO2, CH3SO, RSO, CH3CO, CH3CH2CO. All R, R1, R2, R5, R6 or —(CH2)n-groups are branched or straight chains and may include C, H, O, Cl, Br, F, I, P, S, N or any other atoms which are pharmaceutically acceptable and may have single, double, or/and triple bonds.

In certain embodiments, the HPP has the following Structure 10-a:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

R1 is H;

R2 and R3 independently represent H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues;

X represents O, S or NH; A represents Cl, Br, F, I, AcO, citrate, or any negative ions;

n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 . . . ;

all R groups may include C, H, O, S, N atoms and may have single, double, and treble bonds; and

any CH2 groups may be independently replaced with O, S, or NH.

I-9. HPP of N-arylanthranilic Acids and Related Compounds

In certain embodiments, the HPP has the following Structure 11:

including stereoisomers and pharmaceutically acceptable salts thereof.

In certain embodiments, the HPP has the Structure 11, including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

R represents none (0 carbon atom), linear or branched 1-20 carbon atoms alkyl, 1-20 carbon atoms alkyloxyl, 1-20 carbon atoms perfluoroalkyl, 1-20 carbon atoms alkyl halide, 2-20 carbon atoms alkenyl, 2-20 carbon atoms alkynyl, 6-20 carbon atoms aryl, or 2-20 carbon atoms heteroaryl moieties which are pharmaceutically acceptable, wherein, any CH2 may be independently replaced with O, S, NR5, or other groups;

R1 represents H, one of any 1-20 carbon atoms alkyl, 1-20 carbon atoms alkyloxyl, 1-20 carbon atoms alkenyl, 1-20 carbon atoms perfluoroalkyl, 1-20 carbon atoms alkyl halide, 1-20 carbon atoms alkynyl, 6-20 carbon atoms aryl, or 2-20 carbon atoms heteroaryl moieties, wherein, any CH2 may be independently replaced with O, S, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl moieties, or any other moieties which are pharmaceutically acceptable;

R2 represents H, one of any 1-20 carbon atoms alkyl, 1-20 carbon atoms alkyloxyl, 1-20 carbon atoms alkenyl, 1-20 carbon atoms perfluoroalkyl, 1-20 carbon atoms alkyl halide, 1-20 carbon atoms alkynyl, 6-20 carbon atoms aryl, or 2-20 carbon atoms heteroaryl moieties, wherein, any CH2 may be independently replaced with O, S, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl moieties, or any other moieties which are pharmaceutically acceptable;

X represents O, NH, NR5, S, or none;

Z represents N or CH;

R5 represents H, OH, Cl, F, Br, I, one of any 1-20 carbon atoms alkyl, 1-20 carbon atoms alkyloxyl, 1-20 carbon atoms alkenyl, 1-20 carbon atoms perfluoroalkyl, 1-20 carbon atoms alkyl halide, 1-20 carbon atoms alkynyl, 6-20 carbon atoms aryl, or 2-20 carbon atoms heteroaryl moieties, wherein, any CH2 may be independently replaced with O, S, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl moieties, or any other moieties which are pharmaceutically acceptable;

R7 represents H, OH, Cl, F, Br, I, one of any 1-20 carbon atoms alkyl, 1-20 carbon atoms alkyloxyl, 1-20 carbon atoms alkenyl, 1-20 carbon atoms perfluoroalkyl, 1-20 carbon atoms alkyl halide, 1-20 carbon atoms alkynyl, 6-20 carbon atoms aryl, or 2-20 carbon atoms heteroaryl moieties, wherein, any CH2 may be independently replaced with O, S, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl moieties, or any other moieties which are pharmaceutically acceptable;

R7 represents one of any 1-20 carbon atoms alkyl, 1-20 carbon atoms alkyloxyl, 1-20 carbon atoms alkenyl, 1-20 carbon atoms perfluoroalkyl, 1-20 carbon atoms alkyl halide, 1-20 carbon atoms alkynyl, 6-20 carbon atoms aryl, or 2-20 carbon atoms heteroaryl moieties, wherein, any CH2 may be independently replaced with O, S, CH═CH, C≡C, CHR5, CR5R6, aryl or heteroaryl moieties, or any other moieties which are pharmaceutically acceptable;

Y1, Y2, Y3, Y4, Y5, Y6, Y7, or Y8 represents independently H, HO, CH3COO, R7COO, HS, NO2, CN, ═N—OH, ═NOR8, NR5OR8, NR5OH, CH3COS, R7COS, NH2, CH3CONH, R7CONH, CH3, CH3CH2, C3H7, C4H9, CH3O, CH3CH2O, C3H7O, Cl, F, Br, I, CH3S, CHF2O, CF3O, CF3CF2O, C3F7O, CF3, CF3CF2, C3F7, C4F9, CH3SO2, R7SO2, CH3SO, R7SO, CH3CO, CH3CH2CO, C3H7CO, (CH3)2N, CH2═CH—CH2, CH2═CH—CH2O, CH3(CH2)3O, C3H7O, C4H9O, cycloalkyl, cycloalkenyl, cycloalkynyl, benzyl, substituted benzyl, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-iodophenyl, 3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl, 3-iodophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-iodophenyl, or other substituted phenyl; R8 represents CH3CO, CH3CH2CO, C3H7CO, C4H9CO, CH3, CH3CH2, C3H7, C4H9; HA represents none, HCl, HBr, HF, Hi, HOAc, citric acid, or any acids which are pharmaceutically acceptable;

all Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, R, R1, R2, R5, R6, R7, R8, or —(CH2)n— groups are branched or straight chains and may include C, H, O, Cl, Br, F, I, P, S, N or any other atoms which are pharmaceutically acceptable and may have single, double, or/and triple bonds.

In certain embodiments, the HPP has the following Structure 11-a:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

R1 is H;

R2 and R3 independently represent H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues;

X represents O, S, or NH; A represents Cl, Br, F, I, AcO, citrate, or any negative ions;

Y1-Y3 independently represent H, Cl, F, CH3, CF3;

Z represents CH or N;

n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, . . . ;

all R groups may include C, H, O, S, or N atoms and may have single, double, and treble bonds; and

any CH2 groups may be independently replaced with O, S, or NH.

I-10. HPP of Oxicams and Related Compounds

In certain embodiments, the HPP has the following Structure 12:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

Transportational-unit has a structure selected from Group N;

R represents linear or branched 0-20 carbon atoms alkyl, 1-20 carbon atoms alkyloxyl, 1-20 carbon atoms perfluoroalkyl, 1-20 carbon atoms alkyl halide, 2-20 carbon atoms alkenyl, 2-20 carbon atoms alkynyl, 6-20 carbon atoms aryl, or 2-20 carbon atoms heteroaryl moieties which are pharmaceutically acceptable, wherein any CH2 may be independently replaced with O, S, NR4, or other groups;

R11 represents linear or branched 0-20 carbon atoms alkyl, 1-20 carbon atoms alkyloxyl, 1-20 carbon atoms perfluoroalkyl, 1-20 carbon atoms alkyl halide, 2-20 carbon atoms alkenyl, 2-20 carbon atoms alkynyl, 6-20 carbon atoms aryl, or 2-20 carbon atoms heteroaryl moieties which are pharmaceutically acceptable, wherein any CH2 may be independently replaced with O, S, NR4, or other groups;

R12 represents linear or branched 0-20 carbon atoms alkyl, 1-20 carbon atoms alkyloxyl, 1-20 carbon atoms perfluoroalkyl, 1-20 carbon atoms alkyl halide, 2-20 carbon atoms alkenyl, 2-20 carbon atoms alkynyl, 6-20 carbon atoms aryl, or 2-20 carbon atoms heteroaryl moieties which are pharmaceutically acceptable, wherein any CH2 may be independently replaced with O, S, NR4, or other groups;

R13 represents linear or branched 0-20 carbon atoms alkyl, 1-20 carbon atoms alkyloxyl, 1-20 carbon atoms perfluoroalkyl, 1-20 carbon atoms alkyl halide, 2-20 carbon atoms alkenyl, 2-20 carbon atoms alkynyl, 6-20 carbon atoms aryl, or 2-20 carbon atoms heteroaryl moieties which are pharmaceutically acceptable, wherein any CH2 may be independently replaced with O, S, NR4, or other groups;

R14 represents linear or branched 0-20 carbon atoms alkyl, 1-20 carbon atoms alkyloxyl, 1-20 carbon atoms perfluoroalkyl, 1-20 carbon atoms alkyl halide, 2-20 carbon atoms alkenyl, 2-20 carbon atoms alkynyl, 6-20 carbon atoms aryl, or 2-20 carbon atoms heteroaryl moieties which are pharmaceutically acceptable, wherein any CH2 may be independently replaced with O, S, NR4, or other groups;

R1 represents H or one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide, alkynyl, aryl, or heteroaryl moieties having 1 to 20 carbon atoms;

R2 represents H or one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide, alkynyl, aryl, or heteroaryl moieties having 1 to 20 carbon atoms;

R3 represents H or one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide, alkynyl, aryl, or heteroaryl moieties having 1 to 20 carbon atoms;

R4 represents H or one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide, alkynyl, aryl, or heteroaryl moieties having 1 to 20 carbon atoms;

R5 represents H or one of any alkyl, alkyloxyl, alkenyl, perfluoroalkyl, alkyl halide, alkynyl, aryl, or heteroaryl moieties having 1 to 20 carbon atoms;

HA represents nothing, HCl, HBr, HF, Hi, HOAc, citric acid, or any acids which are pharmaceutically acceptable;

oxicam- represents

R8 represents H, CH3, C2H5, C3H7, CF3, C2F5, or C3F7;

Ar1 represents aryl or heteroaryl system, they include, but are not limited to:

wherein, X1 and X2 represent H, F, Cl, Br, I, CF3, C2F5, SO2CF3, SO2CH3, NO2, alkyl, alkyloxyl, alkenyl or alkynyl residues having 1 to 8 carbon atoms;

represents ary or heteroaryl system, they include, but are not limited to:

X1 and X2 represent H, F, Cl, Br, I, CF3, C2F5, SO2CF3, SO2CH3, NO2, alkyl, alkyloxyl, alkenyl or alkynyl residues having 1 to 8 carbon atoms;

all X1, X2, R, R1, R2, R3, R4, R5, R8, R11, R12, R13, R14, —(CH2)n—, groups are branched or linear chains and may include C, H, O, Cl, Br, F, I, P, S, N or any other atoms which are pharmaceutically acceptable and may have single, double, and/or triple bonds.

In certain embodiments, the HPP has the following Structure 12-a1 or Structure 12-a2:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

R represents a branched or straight chain, —(CH2)n—, wherein n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 . . . , aryl residues or heteroaryl residues;

R1, is H;

R2 and R3 independently represent H, alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues;

R4 represents H, CH3, C2H5, CF3, or C2F5; A represents Cl, Br, F, I, AcO, citrate, or any negative ions; and n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 . . . ;

Ar1 and Ar are defined the same as supra; and

X1 and X2 represent H, F, Cl, Br, I, CF3, C2F5, SO2CF3, SO2CH3, NO2, alkyl, alkyloxyl, alkenyl or alkynyl residues having 1 to 8 carbon atoms. All R, —(CH2)n—, groups are branched or straight chains and may include C, H, O, S, or N atoms and may have single, double, and treble bonds. Any CH2 groups may be independently replaced with O, S, or NH.

II. Pharmaceutical Compositions Comprising HPPs

Another aspect of the invention relates to a pharmaceutical composition comprising a HPP and a pharmaceutically acceptable carrier.

The term “pharmaceutically acceptable carrier” as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a HPP from one location, body fluid, tissue, organ (interior or exterior), or portion of the body, to another location, body fluid, tissue, organ, or portion of the body.

Each carrier is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients, e.g., a HPP, of the formulation and suitable for use in contact with the tissue or organ of a biological system without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) alcohol, such as ethyl alcohol and propane alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations such as acetone.

The pharmaceutical compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.

In one embodiment, the pharmaceutically acceptable carrier is an aqueous carrier, e.g. buffered saline and the like. In certain embodiments, the pharmaceutically acceptable carrier is a polar solvent, e.g. acetone and alcohol.

The concentration of HPP in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight and the like in accordance with the particular mode of administration selected and the biological system's needs. For example, the concentration can be 0.1% to 99.5%, 10% to 70%, 5% to 20% wt.

The compositions of the invention can be administered for prophylactic, therapeutic, and/or hygienic use. Such administration can be topical, mucosal, e.g., oral, nasal, vaginal, rectal, parenteral, transdermal, subcutaneous, intramuscular, intravenous, via inhalation, ophthalmic and other convenient routes. The pharmaceutical compositions can be administered in a variety of unit dosage forms depending upon the method of administration. For example, unit dosage forms suitable for oral administration include powder, tablets, pills, capsules and lozenges.

Thus, a typical pharmaceutical composition for intravenous administration would be about 10−9 g to about 100 g, about 10−6 g to about 100 g, about 0.001 g to about 100 g, or about 0.01 g to about 10 g per subject per day. Dosages from about 0.01 mg, up to about 5 g, per subject per day may be used. Actual methods for preparing parenterally administrable compositions will be known or apparent to those skilled in the art and are described in more detail in such publications as Remington's Pharmaceutical Science, 15th ed., Mack Publishing Company, Easton, Pa. (1980).

In each embodiment, a pharmaceutical composition comprises a NSAIA-HPP according to the present invention (NSAIA-HPP composition).

III. Applications of HPPs

i) Methods for Penetrating a Biological Barrier.

Another aspect of the invention relates to a method of use of a composition of the invention in penetrating one or more BBs in a biological subject. The method comprises a step of administrating to a BB a HPP or a pharmaceutical composition of the invention. In one embodiment, a HPP shows more than 100 times (>about 200 time higher, >about 300 higher) higher penetration rate through one or more BBs than its parent drug.

The term “biological barrier” as used herein refers to a biological layer that separates an environment into different spatial areas or compartments, which separation is capable of modulating (e.g. restricting, limiting, enhancing or taking no action in) the passing through, penetrating or translocation of substance or matter from one compartment/area to another. The different spatial areas or compartments as referred to herein may have the same or different chemical or biological environment(s). The biological layer as referred herein includes, but is not limited to, a biological membrane, a layer of cells, a biological structure, an inner surface of subjects, organisms, organs or body cavities, an external surface of subjects, organisms, organs or body cavities, or any combination or plurality thereof.

Examples of biological membrane include a lipid bilayer structure, eukaryotic cell membrane, prokaryotic cell membrane, intracellular membrane (e.g., nucleus or organelle membrane, such as membrane or envelope of Golgi apparatus, rough and smooth endoplasmic reticulum (ER), ribosomes, vacuoles, vesicles, liposomes, mitochondria, lysosome, nucleus, chloroplasts, plastids, peroxisomes or microbodies. An organelle envelope may have more than two membranes.

The lipid bilayer referred to herein is a double layer of lipid-class molecules, including, but not limited to, phospholipids and cholesterol. In a particular embodiment, lipids for bilayer are amphiphilic molecules consisting of polar head groups and non-polar fatty acid tails. The bilayer is composed of two layers of lipids arranged so that their hydrocarbon tails face one another to form an oily core held together by the hydrophobic effect, while their charged heads face the aqueous solutions on either side of the membrane. In another particular embodiment, the lipid bilayer may contain one or more embedded protein and/or sugar molecule(s).

Examples of cell layer of layer of cells include lining of eukaryotic cells (e.g., epithelium, lamina propria and smooth muscle or muscularis mucosa (in gastrointestinal tract), lining of prokaryotic cells (e.g., surface layer or S-layer which refers to a two dimensional structure monomolecular layer composed of identical proteins or glycoproteins. Specifically, an S-layer refers to a part of the cell envelope commonly found in bacteria and archaea), a biofilm (a structured community of microorganisms encapsulated within a self-developed polymeric matrix and adherent to a living or inert surface), plant cell layer (e.g., empidermis). The cells may be normal cells or pathological cells (e.g. disease cells, cancer cells).

Examples of biological structures include structures sealed by tight or occluding junctions which provide a barrier to the entry of toxins, bacteria and viruses from the hostile exterior, e.g. the blood milk barrier and the blood brain barrier (BBB). In particular, BBB is composed of impermeable class of endothelium, which presents both a physical barrier through tight junctions adjoining neighboring endothelial cells and a transport barrier comprised of efflux transporters. BBB is a formidable barrier, e.g., to toxins as well as drugs for neurological disease treatment. The biological structure may also include a mixture of cells, proteins and sugars (e.g. blood clots).

Examples of inner surface of subjects, organisms, organs or body cavities include buccal mucosa, esophageal mucosa, gastric mucosa, intestinal mucosa, olfactory mucosa, oral mucosa, bronchial mucosa, uterine mucosa and endometrium (the mucosa of the uterus, inner layer of the wall of a pollen grain or the inner wall layer of a spore), or a combination or plurality thereof.

Examples of external surface of an subjects, organisms, organs or body cavities include capillaries (e.g. capillaries in the heart tissue), mucous membranes that are continuous with skin (e.g. such as at the nostrils, the lips, the ears, the genital area, and the anus) outer surface of an organ (e.g. liver, lung, stomach, brain, kidney, heart, ear, eye, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum, rectum stomach, colonrectum, intestine, vein, respiratory system, vascular, the anorectum and pruritus ani), skin, cuticle (e.g., dead layers of epidermal cells or keratinocytes or superficial layer of overlapping cells covering the hair shaft of an animal, a multi-layered structure outside the epidermis of many invertebrates, plant cuticles or polymers cutin and/or cutan), external layer of the wall of a pollen grain or the external wall layer of a spore), or a combination or plurality thereof.

In addition, a biological barrier further includes a sugar layer, a protein layer or any other biological layer, or a combination or plurality thereof. For example, skin is a biological barrier that has a plurality of biological layers. The outer surface of the skin is the epidermis, which itself contains several layers; the basal cell layer, the spinous cell layer, the granular cell layer, and the stratum corneum. The cells in the epidermis are called keratinocytes. The stratum corneum (“horny layer”) is the top layer of the epidermis, wherein cells here are flat and scale-like (“squamous”) in shape. These cells contain a lot of keratin and are arranged in overlapping layers that impart a tough and oilproof and waterproof character to the skin's surface.

ii) Methods for Diagnosing a Condition in a Biological System.

Another aspect of the invention relates to a method of use of a composition of the invention in diagnosing a condition in a biological system. The method comprises the following steps:

1) administrating a composition comprising a HPP to the biological subject;

2) detecting the presence, location or amount of the HPP in the biological subject; and

3) determining a condition in the biological system.

In certain embodiments, the HPP (or the agent cleaved from the HPP) aggregates in the site of action where a condition occurs. In certain embodiments, the presence, location or amount of the functional unit of the HPP is also detected. In certain embodiments, the onset, development, progress, or remission of a condition (e.g., an infection or a disease) associated is also determined.

In certain embodiments, the HPP is labeled with or conjugated to a detectable agent. Alternatively, the HPP is prepared to include radioisotopes for detection. Numerous detectable agents are available which can be generally grouped into the following categories:

(a) Radioisotopes, such as 35S, 14C, 13C, 15N, 125I, 3H, and 131I. The diagnostic agent can be labeled with the radioisotope using the techniques known in the art and radioactivity can be measured using scintillation counting; in addition, the diagnostic agent can be spin labeled for electron paramagnetic resonance for carbon and nitrogen labeling.

(b) Fluorescent agents such as BODIPY, BODIPY analogs, rare earth chelates

(europium chelates), fluorescein and its derivatives, FITC, 5,6 carboxyfluorescein, rhodamine and its derivatives, dansyl, Lissamine, phycoerythrin, green fluorescent protein, yellow fluorescent protein, red fluorescent protein and Texas Red. Fluorescence can be quantified using a fluorometer.

(c) Various enzyme-substrate agents, such luciferases (e.g., firefly luciferase and bacterial luciferase), luciferin, 2,3-dihydrophthalazinediones, malate dehydrogenase, urease, peroxidase such as horseradish peroxidase (HRPO), alkaline phosphatase, β-galactosidase, glucoamylase, lysozyme, saccharide oxidases (e.g., glucose oxidase, galactose oxidase, and glucose-6-phosphate dehydrogenase), heterocyclic oxidases (such as uricase and xanthine oxidase), lactoperoxidase, microperoxidase, and the like. Examples of enzyme-substrate combinations include, for example: (i) Horseradish peroxidase (HRPO) with hydrogen peroxidase as a substrate, wherein the hydrogen peroxidase oxidizes a dye precursor (e.g., orthophenylene diamine (OPD) or 3,3′,5,5′-tetramethyl benzidine hydrochloride (TMB)); (ii) alkaline phosphatase (AP) with para-Nitrophenyl phosphate as chromogenic substrate; and (iii) β-D-galactosidase (β-D-Gal) with a chromogenic substrate (e.g., p-nitrophenyl-β-D-galactosidase) or fluorogenic substrate 4-methylumbelliferyl-β-D-galactosidase.

In certain embodiments, the detectable agent is not necessarily conjugated to the diagnostic agent but is capable of recognizing the presence of the diagnostic agent and the diagnostic agent can be detected.

In certain embodiments, the HPP of the present invention can be provided in a kit, i.e., a packaged combination of reagents in predetermined amounts with instructions for performing the diagnostic assay. Where the HPP is labeled with an enzyme, the kit will include substrates and cofactors required by the enzyme (e.g., a substrate precursor which provides the detectable chromophore or fluorophore). In addition, other additives may be included such as stabilizers, buffers (e.g., a block buffer or lysis buffer) and the like. The relative amounts of the various reagents may be varied widely to provide for concentrations in solution of the reagents which substantially optimize the sensitivity of the assay. Particularly, the reagents may be provided as dry powders, usually lyophilized, including excipients which on dissolution will provide a reagent solution having the appropriate concentration.

iii) Methods for Screening a Substance for a Desired Character

Another aspect of the invention relates to a method of screening a HPP for a desired character.

In certain embodiments, the method comprises:

1) covalently linking the test functional unit to a transportational unit through a linker to form a test composition (or covalently linking a functional unit to a test transportational unit through a linker, or covalently linking a functional unit to a transportational unit through a test linker)
2) administrating a test composition a biological system; and
3) determining whether the test composition that has a desired character.

In one embodiment, the desired character may include, for example, 1) the ability of the test functional unit to form a high penetration composition or convert back to a parent drug, 2) the penetration ability and/or rate of the test composition, 3) the efficiency and/or efficacy of the test composition, 4) the transportational ability of the test transportational unit, 5) the cleavability of the test linker.

iv) Methods for Treating a Condition in a Biological Subject

Another aspect of the invention relates to a method of use of a composition of the invention in treating a condition in a biological system. The method comprises administrating the pharmaceutical composition to the biological system.

The term “treating” as used herein means curing, alleviating, inhibiting, or preventing. The term “treat” as used herein means cure, alleviate, inhibit, or prevent. The term “treatment” as used herein means cure, alleviation, inhibition or prevention.

The term “biological system,” “biological subject” or “subject” as used herein means an organ, a group of organs that work together to perform a certain task, an organism, or a group of organisms. The term “organism” as used herein means an assembly of molecules that function as a more or less stable whole and has the properties of life, such as animal, plant, fungus, or micro-organism. In at least some form, all organisms are capable of response to stimuli, reproduction, growth and development, and maintenance of homeostasis as a stable whole.

Some examples of the conditions the method can treat include conditions that can be treated by the parent drug of the HPP.

v). Methods of Use of a NSAIA-HPP Composition in Treatments.

Another aspect of the invention relates to a method of use of a NSAIA-HPP composition in treating a condition in a biological system by administrating a NSAIA-HPP to the biological system.

A) Conditions Treatable by the Method

Some examples of the conditions that are treated by the method include:

1) metabolism disorder, e.g. abnormal blood glucose level, abnormal blood lipid level, diabetes mellitus (type I or/and type II) and diabetes-induced complications, including diabetic retinopathy, necrobiotic ulcers, and diabetic proteinuria;
2) abnormal blood pressure, e.g. hypertension and hypotension;
3) tumor, e.g. benign tumor, breast cancer, colon-rectum cancer, oral cancer, lung or other respiratory system cancers, skin cancers, uterus cancer, pancreatic cancer, prostate cancer, genital cancer, urinary organs cancers, leukemia or other blood and lymph tissues cancer.
4) cardiovascular diseases, e.g. heart attack, unstable angina, peripheral occlusive arterial disease and stroke;
5) neurodegenerative disease, e.g. Alzheimer's diseases and Parkinson's disease;
6) skin condition, e.g. psoriasis and psoriatic disorders, acne, cystic acne, pus-filled or reddish bumps, comedones, papules, pustules, nodules, epidermoid cysts, keratosis pilaris, abnormal vascular skin lesions, birthmarks, moles (nevi), skin tags, scleroderma, vitiligo and related diseases, or aging spots (liver spots);
7) autoimmune disease, e.g. discoid lupus erythematosus, systemic lupus erythematosus (SLE), autoimmune hepatitis, cleroderma, Sjogren's syndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto's thyroiditis, juvenile diabetes mellitus, Addison disease, vitiligo, pernicious anemia, glomerulonephritis, pulmonary fibrosis, multiple sclerosis (MS) and Crohn's disease;
8) eye disease, e.g. glaucoma, ocular hypertension, loss of vision after ophthalmic surgery, vision of a warm-blooded animal impaired by cystoid macular edema and cataract;
9) pain;
10) injuries;
11) inflammation related conditions, e.g. prostate gland inflammation (prostatitis), prostatocystitis, prostate enlarge fibrosis, hemorrhoids, Kawasaki syndrome, gastroenteritis, type-1 membranoproliferative glomerulonephritis, Bartter's syndrome, chronic uveitis, ankylosing spondylitis, hemophilic arthropathy, inflamed hemorrhoids, post irradiation (factitial) proctitis, chronic ulcerative colitis, inflammatory bowel disease, cryptitis, periodontitis, arthritis, and an inflammatory condition in an organ selected from the group consisting of liver, lung, stomach, brain, kidney, heart, ear, eye, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum, rectum stomach, colonrectum, intestine, vein, respiratory system, vascular, the anorectum and pruritus ani;
12) fever;
13) conditions related to platelet aggregation, e.g. thromboembolis after surgery, carotid endarterectomy, the recurrence of stenosis after coronary angioplasty, thromboembolis complications in chronic arterial fibrillation, aortocornonary-artery-bypass graft occlusion, heart attack, stroke, multi-infract dementia, dementia, hemodialysis shunt thrombosis and arterial embolic complications in patients' prosthetic heart valves;
14) dysmenorrheal;
15) allergy;
16) asthma;
17) preeclamptic toxemia in high-risk women,
18) IUD-associated uterine bleeding,
19) radiation-induced conditions, and
20) bone disease, e.g. osteoporosis, Paget's disease and bone metastases.

In certain embodiments, the method of treating a condition amelioratable or treatable with Aspirin or Aspirin related compounds comprising administering a HPP of aspirin or aspirin related compounds to a subject. Examples of the condition include, for instance, gouty arthritis, pain and inflammation of arthritic and other inflammatory conditions, inflammatory bowel disease, heart attack (C. H. Hennekens, et al., N. Engl. J. Med., 321, 129 (1989)]; stroke (T. A. Gossel, U.S. Pharmacist, February, 1988, p. 34.], tumor (e.g. colon cancer (M. J. Thun, et al., N. Engl. J. Med., 325, 1393 (1991)], rectal cancer), Kawasaki syndrome, thromboembolism after surgery, unstable angina, gastroenteritis, aortocoronary-artery-bypass graft occlusion, thromboembolic complications in chronic arterial fibrillation, platelet aggregatioartrial in carotid endarterectomy, cataracts, recurrence of stenosis after coronary angioplasty, multi-infract dementia, diabetes mellitus and diabetes-induced complications (e.g. diabetic retinopathy, necrobiotic ulcers, and diabetic proteinuria), cardiovascular disease, hemodialysis shunt thrombosis, renal disease (e.g. type-1 membranoproliferative glomerulonephritis), peripheral occlussive arterial disease, arterial embolic complications in patients' prosthetic heart valves, pregnancy-induced hypertension and preeclamptic toxemia in high-risk women.

In certain embodiments, the method of treating a condition amelioratable or treatable with salicylate or salicyte related compounds (e.g., diflunisal or diflunisal related compounds) comprising administering a HPP of salicylate or salicyte related compounds to a subject. Examples of the condition include, for instance, pain, inflammation (e.g. osteoarthritis, gout and rheumatoid arthritis) dysmenorrheal, eye disease (e.g. the loss of vision due to ophthalmic surgery (Hirsch-Kauffmann, Dan J., U.S. Pat. No. 5,134,165), and the vision of a warm-blooded animal impaired by cystoid macular edema (Yung-Yu Hung, et al., U.S. Pat. No. 6,593,365).)

In certain embodiments, the method of treating a condition amelioratable or treatable with ibuprofen or ibuprofen related compounds comprising administering a HPP of ibuprofen related compounds to a subject. Examples of the condition include, for instance, inflammation, fever, dysmenorrhea, Bartter's syndrome, chronic uveitis, both anterior and posterior, IUD-associated uterine bleeding, radiation-induced vomiting in patients receiving pelvic irradiation, diabetic and related conditions, pain, hemophilic arthropathy, bone loss (Jee; Webster S. S. U.S. Pat. No. 5,604,259), and sunburn (Sunshine: Abraham. U.S. Pat. No. 5,100,918)

In certain embodiments, the method of treating a condition amelioratable or treatable with ketoprofen or ketoprofen related compounds comprising administering a HPP of ketoprofen or ketoprofen related compounds to a subject. Examples of the condition include, for instance, rheumatoid arthritis and osteoarthritis, dysmenorrhea, acute biliary colic, pain, fever. (PDR Generics, 1996, second edition, Medical Economics, Montvale, N.J., pg 1812), and bone regeneration (Alfano, M. C.; Troullos, E. S., U.S. Pat. No. 5,902,110).

In certain embodiments, the method of treating a condition amelioratable or treatable with fenoprofen or fenoprofen related compounds comprising administering a HPP of fenoprofen or fenoprofen related compounds to a subject. Examples of the condition include, for instance, pain, osteoarthritis and rheumatoid arthritis, gout (PDR Generics, 1996, second edition, Medical Economics, Montvale, N.J., pg 1290) and shock (Toth, P. D., U.S. Pat. No. 4,472,431).

In certain embodiments, the method of treating a condition amelioratable or treatable with aryl- and heteroarylpropionic acids comprising administering a HPP of aryl- and heteroarylpropionic acids to a subject. Examples of the condition include, for instance, rheumatoid arthritis, osteoarthritis, dysmenorrhea, gouty arthritis ankylosing spondylitis, and dementia (McGeer; Patrick L. et al. U.S. Pat. No. 5,192,753). In certain embodiments, the parent drug of aryl- and heteroarylpropionic acids the HPP is selected from the group consisting naproxen, suprofen, α-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, and clidanac.

In certain embodiments, the method of treating a condition amelioratable or treatable with aryl- and heteroarylacetic acids or related compounds thereof, comprising administering a HPP of aryl- and heteroarylacetic acids or related compounds thereof to a subject. Examples of the condition include, for instance, rheumatoid arthritis, osteoarthritis, dysmenorrheal, gouty arthritis, ankylosing spondylitis and dementia (McGeer; Patrick L. et al. U.S. Pat. No. 5,192,753).

In certain embodiments, the method of treating a condition amelioratable or treatable with N-aryl anthranilic acid or related compounds thereof, comprising administering a HPP of N-aryl anthranilic acid or related compounds thereof to a subject. Examples of the condition include, for instance, gouty arthritis and ankylosing spondylitis.

In certain embodiments, the method of treating a condition amelioratable or treatable with oxicam or related compounds thereof, comprising administering a HPP of oxicam or related compounds thereof to a subject. Examples of the condition include, for instance, rheumatoid arthritis and osteoarthritis.

In one embodiment, a NSAIA-HPP shows better analgesic activities comparing to its parent drug. In certain embodiments, a NSAIA-HPP shows better or similar antipyretic activities comparing to its parent drug. In certain embodiments, a NSAIA-HPP demonstrates better anti-inflammatory activities comparing to its parent drug. In certain embodiments, a NSAIA-HPP is used to treat asthma (Bianco, Sebastiano, U.S. Pat. No. 5,570,559) by spraying into the mouth or nose of a host.

In certain embodiments, a NSAIA-HPP reduces the undesired conditions of skin such as acne, roughness, freckles, moles, dark spots and other discolorations, fine lines, wrinkles with improved skin elasticity, firmness, texture and tone, and other endothelia dysfunctions that are treatable by anti-inflammatory agents.

In certain embodiments, administration of a NSAIA-HPP on cancer subjects reduces tumor size of the subjects without significant weight loss of the subjects.

In certain embodiments, a NSAIA-HPP lowers the blood glucose levels and blood lipid levels of diabetic biological subjects while the NSAIA-HPP do not affecting the blood glucose levels of normal subjects.

In certain embodiments, a NSAIA-HPP is capable of treating thrombotic activity and embolization-associated thrombus propagation in biological subjects, e.g. stroke.

In certain embodiments, a NSAIA-HPP is used to treat autoimmune diseases, e.g. psoriasis, discoid lupus erythematosus, systemic lupus erythematosus (SLE).

In certain embodiments, a NSAIA-HPP is effective to treat lesions similar to psoriasis of biological subjects.

In certain embodiments, a NSAIA-HPP shows effective anti-hypertensive activity. In certain embodiments, a NSAIA-HPP shows anti-Parkinson's disease activity. In certain embodiments, a NSAIA-HPP shows anti-Alzheimer disease activity. In certain embodiments, a NSAIA-HPP shows anti-glaucoma activity. In certain embodiments, a NSAIA-HPP is used to treat spinal cord injury in which the healing is stopped by the protected scars around the injured spinal cord. In certain embodiments, a NSAIA-HPP is effective in treating wounds with shrunk scar after healing.

B) Administration of the Compositions According to the Present Invention.

The HPP or the HPP composition can be administered to a biological system by any administration route known in the art, including without limitation, oral, enteral, buccal, nasal, topical, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, dermal, ophthalmic, pulmonary, subcutaneous, and/or parenteral administration. The pharmaceutical compositions can be administered in a variety of unit dosage forms depending upon the method of administration.

A parenteral administration refers to an administration route that typically relates to injection which includes but is not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intra cardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and/or intrasternal injection and/or infusion.

The HPP or the HPP composition can be given to a subject in the form of formulations or preparations suitable for each administration route. The formulations useful in the methods of the present invention include one or more HPPs, one or more pharmaceutically acceptable carriers therefor, and optionally other therapeutic ingredients. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration. The amount of a HPP which can be combined with a carrier material to produce a pharmaceutically effective dose will generally be that amount of a HPP which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of the HPP, preferably from about 20 percent to about 70 percent.

Methods of preparing these formulations or compositions include the step of bringing into association a HPP with one or more pharmaceutically acceptable carriers and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a HPP with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a HPP as an active ingredient. A compound may also be administered as a bolus, electuary, or paste.

In solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules and the like), the HPP is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (5) solution retarding agents, such as paraffin, (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered peptide or peptidomimetic moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of a HPP therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain pacifying agents and may be of a composition that they release the HPP(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The HPP can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the HPP, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the HPP, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more HPPs with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent. Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

Formulations for the topical or transdermal or epidermal or dermal administration of a HPP composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required. The ointments, pastes, creams and gels may contain, in addition to the HPP composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to the HPP composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

The HPP composition can be alternatively administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the HPPs. A nonaqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers can also be used. An aqueous aerosol is made by formulating an aqueous solution or suspension of the agent together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

Transdermal patches can also be used to deliver HPP compositions to an infection site. Such formulations can be made by dissolving or dispersing the agent in the proper medium. Absorption enhancers can also be used to increase the flux of the peptidomimetic across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the peptidomimetic in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.

Formulations suitable for parenteral administration comprise a HPP in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacterostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may be employed in the formulations suitable for parenteral administration include water, ethanol, polyols (e.g., such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

Formulations suitable for parenteral administration may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

Injectable depot forms are made by forming microencapsule matrices of a HPP or in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the HPP to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the HPP in liposomes or microemulsions which are compatible with body tissue.

In an embodiment of the invention, a HPP composition is delivered to a disease or infection site in a therapeutically effective dose. As is known in the art of pharmacology, the precise amount of the pharmaceutically effective dose of a HPP that will yield the most effective results in terms of efficacy of treatment in a given patient will depend upon, for example, the activity, the particular nature, pharmacokinetics, pharmacodynamics, and bioavailability of a particular HPP, physiological condition of the subject (including race, age, sex, weight, diet, disease type and stage, general physical condition, responsiveness to a given dosage and type of medication), the nature of pharmaceutically acceptable carriers in a formulation, the route and frequency of administration being used, and the severity or propensity of a disease caused by pathogenic target microbial organisms, to name a few. However, the above guidelines can be used as the basis for fine-tuning the treatment, e.g., determining the optimum dose of administration, which will require no more than routine experimentation consisting of monitoring the subject and adjusting the dosage. Remington: The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000).

In certain embodiments, a NSAIA-HPP composition is administrated to a biological system through any administration route known in the art, including without limitation, oral, enteral, buccal, nasal, topical, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, dermal, ophthalmic, pulmonary, subcutaneous, and/or parenteral administration.

IV. Advantages

In certain embodiments, since the HPP of the present invention is capable of crossing one or more biological barriers, the HPP can be administered locally (e.g., typically or transdermally) to reach a location where a condition occurs without the necessity of a systematic administration (e.g., oral or parenteral administration). The local administration and penetration of the HPP allows the HPP to reach the same level of local concentration of an agent or drug with much less amount or dosage of HPP in comparison to a systematic administration of a parent agent or drug, alternatively, a higher level of local concentration which may not be afforded in the systematic administration, or if possible, requires significantly higher dosage of an agent in the systematic administration. The high local concentration of the HPP or its parent agent if being cleaved enables the treatment of a condition more effectively or much faster than a systematically delivered parent agent and the treatment of new conditions that may not be possible or observed before. The local administration of the HPP may allow a biological subject to reduce potential sufferings from a systemic administration, e.g., adverse reactions associated with the systematic exposure to the agent, gastrointestinal/renal effects. Additionally, the local administration may allow the HPP to cross a plurality of biological barriers and reach systematically through, for example, general circulation and thus avoid the needs for systematic administration (e.g., injection) and obviate the pain associated with the parenteral injection.

In certain embodiments, the HPP according to the present invention can be administered systematically (e.g., orally or parenterally). The HPP or the active agent (e.g., drug or metabolite) of the HPP may enter the general circulation with a faster rate than the parent agent and gain faster access to the action site a condition. Additionally, the HPP can cross a biological barrier (e.g., BBB) which has not been penetrated if a parent agent is administered and thus offer novel treatment of conditions that may not be possible or observed before.

For example, the HPPs of NSAIA in the present invention demonstrate high penetration rate through a biological barrier (e.g., >about 100 times, >about 200 times, >about 300 times higher that the NSAIA alone). No gastroduodenal bleeding was observed from the subjects that took HPP of a NSAIA, while gastroduodenal bleeding was observed from the subjects that took the parent NSAIA at the similar dosage.

V. Examples

The following examples are provided to better illustrate the claimed invention and are not to be interpreted as limiting the scope of the invention. All specific compositions, materials, and methods described below, in whole or in part, fall within the scope of the present invention. These specific compositions, materials, and methods are not intended to limit the invention, but merely to illustrate specific embodiments falling within the scope of the invention. One skilled in the art may develop equivalent compositions, materials, and methods without the exercise of inventive capacity and without departing from the scope of the invention. It will be understood that many variations can be made in the procedures herein described while still remaining within the bounds of the present invention. It is the intention of the inventors that such variations are included within the scope of the invention.

Example 1

Preparation of a HPP from a Parent Drug

i) Preparation of a HPP from a Parent Drug which Contains at Least One Carboxylic Group.

In certain embodiments, the parent compound having the following Structure C:

is converted to a HPP having Structure A:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

X is selected from the group consisting of nothing, O, P(O)OR1, NH, NR1 and S; and

each R1, R2, R3 and R4 are independently selected from the group consisting of nothing, H, CH2COOR6, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl groups, wherein any CH2 in R1, R2, R3 and R4 may be further independently replaced with O, S, P, NR1, or any other pharmaceutically acceptable groups.

In certain embodiments of the invention, the HPP having Structure A are prepared according to the conventional organic synthesis by reacting the parent compounds or derivatives of the parent compounds having Structure D (e.g. acid halides, mixed anhydrides of the parent compounds, etc.):

wherein Y is selected from the group consisting of OH, halogen, alkoxycarbonyl and substituted aryloxycarbonyloxy,

with compounds of Structure E:

As used herein, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.

As used herein, the term “pharmaceutically acceptable salt” means those salts of compounds of the invention that are safe and effective for application in a subject and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in compounds of the invention. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., 1,11-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds of the invention can form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. For a review on pharmaceutically acceptable salts see BERGE ET AL., 66 J. PHARM. SCI. 1-19 (1977), incorporated herein by reference.

Preparation of diethylaminoethyl acetylsalicylate.AcOH

18 g (0.1 mol) of o-acetylsalicylic was dissolved in 180 ml of chloroform. 12.5 g of Sodium bicarbonate (0.15 mol) was added into the solution. Water (20 ml) was added with stirring. After the mixture had been stirred for 30 minutes, anhydrous sodium sulfate (200 g) was added. 39 g (0.15 mol) of diethylaminoethyl bromide.HBr was added into the mixture and the mixture was stirred for 5 hours at RT. 8.2 g (0.1 mol) of sodium acetate was added into the reaction mixture with stirring. The mixture is stirred for 2 hours. The solid was removed by filtration and washed with chloroform (3×50 ml). The solution is concentrated in vacuo to 100 ml. Then 300 ml of hexane was added into the solution. The solid product was collected by filtration and washed with hexane (3×100 ml). After drying, it yielded 31 g of the desired product (91%). Hygroscopic product; Solubility in water: 300 mg/ml; Elementary analysis: C17H25NO6; MW: 339.38. Calculated % C, 60.07; H, 7.44; N, 4.15; O, 28.22. Found % C, 60.16; H, 7.42; N, 4.13; O, 28.29. 1H-NMR (400 MHz, CDCL3): delta: 1.55 (t, 6H), 2.08 (s, 3H), 2.20 (s, 3H), 3.28 (m, 4H); 3.70 (m, 2H), 4.68 (m, 2H), 6.5 (b, 1H), 7.17 (m, 1H), 7.19 (m, 1H), 7.45 (m, 1H), 7.94 (m, 1H).

Preparation of dimethylaminoethyl acetylsalicylate.AcOH

19.9 g (0.1 mol) of o-acetoxybenzoyl chloride was dissolved in 100 ml of chloroform. The mixture was cooled to 0° C. 15 ml of triethylamine and 8.9 g of dimethylaminoethanol were added into the reaction mixture. The mixture is stirred for 3 hours at RT. 6 g of acetic acid is added into the reaction mixture with stirring. The solid side product was removed by filtration and washed with chloroform (3×30 ml). The organic solution was evaporated off. After drying, it yielded 29 g of the desired product (93%). Hygroscopic product; Solubility in water: 350 mg/ml; Elementary analysis: C15H21NO6; MW: 311.33. Calculated % C, 57.87; H, 6.80; N, 4.50; O: 30.83. Found % C, 57.82; H, 6.85; N, 4.48; O, 30.85. 1H-NMR (400 MHz, CDCL3): delta: 2.09 (s, 3H) 2.21 (s, 3H), 2.90 (s, 6H); 3.71 (m, 2H), 4.69 (m, 2H), 6.9 (b, 1H), 7.18 (m, 1H), 7.20 (m, 1H), 7.47 (m, 1H), 7.93 (m, 1H).

Preparation of diethylaminoethyl acetylsalicylate.acetylsalicylic acid

180 g of 2-acetylsalicyclic acid was dissolved in 1000 ml of chloroform. The mixture was cooled to 5° C. 103 g of 1,3-Dicyclohexylcarbodiimide was added into the mixture. The mixture is stirred for 2 h at RT. The solid waste is removed by filtration and washed with chloroform (3×300 ml). 59 g of diethylaminoethanol were added into the reaction mixture. The mixture was stirred for 3 hours at RT. The organic solution was evaporated off. After drying, it yielded 220 g of the desired product (96%). Elementary analysis: C24H29NO8; MW: 459.18. Calculated % C, 62.73; H, 6.36; N, 3.05; O, 27.86. Found % C, 62.70; H, 6.40; Cl: N, 3.01; O, 27.90.

Preparation of S-dimethylaminoethyl acetylthiosalicylate.AcOH

19.9 g (0.1 mol) of o-acetoxybenzoyl chloride was dissolved in 100 ml of chloroform. The mixture was cooled to 0° C. 15 ml of triethylamine and 9.3 g of dimethylaminoethyl mercaptan were added into the reaction mixture. The mixture was stirred for 3 hours at RT. 6 g of acetic acid was added into the reaction mixture with stirring. The solid side product was removed by filtration and washed with chloroform (3×30 ml). The organic solution was evaporated off. After drying, it yielded 28 g of the desired product (87%). Hygroscopic product; Solubility in water: 320 mg/ml; Elementary analysis: C15H21NO5S; MW: 327.4. Calculated % C, 55.03; H, 6.47; N, 4.28; O, 24.43 S: 9.79. Found % C, 55.02; H, 6.45; N, 4.35; O, 24.49; 9.69. 1H-NMR (400 MHz, CDCL3): delta: 2.09 (s, 3H) 2.21 (s, 3H), 2.90 (s, 6H); 3.31 (t, 2H), 3.91 (m, 2H), 6.9 (b, 1H), 7.26 (m, 1H), 7.28 (m, 1H), 7.55 (m, 1H), 7.94 (m, 1H).

Preparation of N-Dimethylaminoethyl acetylsalicylamide.AcOH

19.9 g (0.1 mol) of o-acetoxybenzoyl chloride was dissolved in 100 ml of chloroform. The mixture was cooled to 0° C. 15 ml of triethylamine and 8.9 g of dimethylaminoethylamine were added into the reaction mixture. The mixture was stirred for 3 hours at RT. 6 g of acetic acid was added into the reaction mixture with stirring. The solid side product was removed by filtration and washed with chloroform (3×30 ml). The organic solution was evaporated off. After drying, yielded 28 g of the desired product (90.2%). Hygroscopic product; Solubility in water: 350 mg/ml; Elementary analysis: C15H22N2O5; MW: 310.35. Calculated % C, 58.05; H, 7.15; N, 9.03; O, 25.78. Found % C, 58.02; H, 7.18; N, 8.98; O, 25.83. 1H-NMR (400 MHz, CDCL3): delta: 2.09 (s, 3H) 2.21 (s, 3H), 2.90 (s, 6H); 3.54 (m, 2H), 3.64 (t, 2H), 6.9 (b, 1H), 7.8 (b, 1H); 7.25 (m, 1H), 7.26 (m, 1H), 7.48 (m, 1H), 7.92 (m, 1H).

Preparation of S-diethylaminoethyl propionylthiosalicylate.AcOH

18 g (0.1 mol) of o-acetylsalicylic acid was dissolved in 100 ml of dichloromethane (DCM). The mixture was cooled to 0° C. 20.6 g of 1,3-Dicyclohexylcarbodiimid was added into the reaction mixture. The mixture was stirred for 30 minutes at 0° C. 14.8 g (0.1 mol) of diethylaminopropyl mercaptan was added into the reaction mixture. The mixture was stirred for 3 h at RT. 6 g of acetic acid was added into the reaction mixture with stirring. The solid side product was removed by filtration and washed with chloroform (3×50 ml). The organic solution was evaporated off. After drying, it yielded 32 g of the desired product (86.6%). Hygroscopic product; Solubility in water: 280 mg/ml; Elementary analysis: C18H27NO5S; MW: 369.48. Calculated % C, 58.51; H, 7.37; N, 3.79; O, 21.65; S, 8.68. Found % C, 58.53; H, 7.39; N, 3.75; O, 21.68; S, 8.65. 1H-NMR (400 MHz, CDCl3): delta: 1.09 (t, 3H), 1.56 (t, 6H), 2.21 (s, 3H), 2.27 (m, 2H) 3.28 (m, 4H), 3.31 (m, 2H); 3.91 (m, 2H), 6.8 (b, 1H), 7.25 (m, 1H), 7.26 (m, 1H), 7.48 (m, 1H), 7.92 (m, 1H).

Preparation of N-diethylaminopropyl acetylsalicylamide.AcOH

18 g (0.1 mol) of o-acetylsalicylic acid was dissolved in 100 ml of acetonitrile. 32.1 g of O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate and 30 ml of triethylamine were added into the reaction mixture. 13.1 g of dimethylaminopropylamine was added into the reaction mixture. The mixture was stirred for 3 hours at RT. The solvents were evaporated off. 250 ml of ethyl acetate was added into the reaction mixture and the mixture was washed with water (3×100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 6 g of acetic acid was added into the reaction mixture with stirring. Hexane (200 ml) was added. The solid product was collected by filtration. After drying, it yielded 32 g of the desired product (90.8%).Hygroscopic product; Solubility in water: 280 mg/ml; Elementary analysis: C18H28N2O5; MW: 352.43. Calculated % C, 61.34; H, 8.01; N, 7.95; O, 22.70. Found % C, 61.25; H, 8.05; N, 7.96; O, 22.74. 1H-NMR (400 MHz, CDCL3): delta: 1.56 (t, 6H) 2.03 (m, 2H) 2.09 (s, 3H), 2.21 (s, 3H), 3.24 (m, 2H), 3.20 (m, 2H); 3.24 (m, 2H), 6.9 (b, 1H), 7.8 (b, 1H); 7.25 (m, 1H), 7.26 (m, 1H), 7.48 (m, 1H), 7.92 (m, 1H).

Preparation of dipropylaminoethyl acetylsalicylate.AcOH

20.3 g (0.1 mol) of sodium o-acetylsalicylate was suspended in 180 ml of chloroform. 28.8 g (0.1 mol) of dipropylaminoethyl bromide.HBr was added into the mixture and the mixture was stirred for 5 hours at RT. 8.2 g (0.1 mol) of sodium acetate was added into the reaction mixture with stirring. The mixture is stirred for 2 hours. The solid was removed by filtration and washed with chloroform (3×50 ml). The solution is concentrated in vacuo to 100 ml. Then 300 ml of hexane was added into the solution. The solid product was collected by filtration and washed with hexane (3×100 ml). After drying, it yielded 30 g of the desired product (81.6%). Hygroscopic product; Solubility in water: 300 mg/ml; Elementary analysis: C17H25NO6; MW: 367.44. Calculated % C, 62.11; H, 7.96; N, 3.81; O, 26.13. Found % C, 62.07; H, 7.99; N, 3.78; O, 26.17. 1H-NMR (400 MHz, CDCl3): delta: 0.97 (t, 6H), 1.77 (m, 4H), 2.20 (s, 3H), 3.25 (m, 4H); 3.70 (m, 2H), 4.69 (m, 2H), 6.8 (b, 1H), 7.17 (m, 1H), 7.19 (m, 1H), 7.45 (m, 1H), 7.94 (m, 1H).

Preparation of dipropylaminoethyl acetylsalicylate.AcOH

60 g of Polymer-bound triethylamine (3 mmol/g, 100-200 mesh) was suspended in 180 ml of chloroform. 18 g (0.1 mol) of o-acetylsalicylic acid was added into the into the mixture and the mixture was stirred for 5 hours at RT. The polymer is removed by filtration and washed with tetrahydrofuran (3×50 ml). 8.2 g (0.1 mol) of sodium acetate was added into the reaction mixture with stirring. The mixture is stirred for 2 h. The solid was removed by filtration and washed with chloroform (3×50 ml). The solution is concentrated in vacuo to 100 ml. Then 300 ml of hexane was added into the solution. The solid product was collected by filtration and washed with hexane (3×100 ml). After drying, it yielded 31 g of the desired product (91%). Hygroscopic product; Solubility in water: 300 mg/ml; Elementary analysis: C17H25NO6; MW: 339.38. Calculated % C, 60.07; H, 7.44; N, 4.15; O, 28.22. Found % C, 60.16; H, 7.42; N, 4.13; O, 28.29. 1H-NMR (400 MHz, CDCl3): delta: 1.55 (t, 6H), 2.08 (s, 3H), 2.20 (s, 3H), 3.28 (m, 4H); 3.70 (m, 2H), 4.68 (m, 2H), 6.5 (b, 1H), 7.17 (m, 1H), 7.19 (m, 1H), 7.45 (m, 1H), 7.94 (m, 1H).

Preparation of diethylaminoethyl 5-(2,4-difluorophenyl) salicylate.AcOH

31.1 g (0.1 ml) of 5-(2,4-difluorophenyl)acetylsalicyl chloride was dissolved in 100 ml of chloroform. The mixture was cooled to 0° C. 15 ml of triethylamine and 11.7 g (0.1 mol) of diethylaminoethanol were added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is dissolved in methanol (300 ml), 5% sodium bicarbonate (200 ml) is added into the reaction mixture. The mixture is refluxed for 2 hr. The mixture is evaporated to dryness. Methanol (300 ml) is added into the residue with stirring. Solid is removed by filtration and washed with methanol. The solution is evaporated to dryness and the residue is dissolved in chloroform (200 ml). 6 g of acetic acid is added into the reaction mixture with stirring. Some solid is removed by filtration. Another 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 36 g of the desired product (88%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C21H25F2NO5; MW: 409.42. Calculated % C, 61.60; H, 6.15; F, 9.28; N, 3.42; O, 19.54. Found % C, 61.56; H, 6.18; F, 9.27; N, 3.40; O, 19.59. 1H-NMR (400 MHz, CDCl3): δ: 1.56 (t, 6H), 2.21 (s, 3H), 3.27 (m, 4H), 3.70 (m, 2H), 4.69 (t, 2H), 4.9 (b, 1H), 6.74 (m, 1H), 6.84 (m, 1H), 7.0 (b, H), 7.06 (b, 1H), 7.15 (m, 1H), 7.44 (m, 1H), 7.86 (m, 1H).

Preparation of diethylaminoethyl salicylsalicylate.AcOH

31.8 g (0.1 mol) of acetylsalicylsalicyl chloride was dissolved in 100 ml of chloroform. The mixture was cooled to 0° C. 15 ml of triethylamine and 8.9 g (0.1 mol) of diethylaminoethanol were added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is dissolved in methanol (300 ml), 5% sodium bicarbonate (200 ml) is added into the reaction mixture. The mixture is stirred for 3 hr. The mixture is evaporated to dryness. Methanol (300 ml) is added into the residue with stirring. Solid is removed by filtration and washed with methanol. The solution is evaporated to dryness and the residue is dissolved in chloroform (200 ml). 6 g of acetic acid is added into the reaction mixture with stirring. Some solid is removed by filtration. Another 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 32 g of the desired product (82%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C20H23NO7; MW: 389.40. Calculated % C, 61.69; H, 5.95; N, 3.60; O, 28.76. Found % C, 61.66; H, 5.98; N, 3.58; O, 28.78. 1H-NMR (400 MHz, CDCl3): δ: 2.21 (s, 3H), 2.90 (s, 6H), 3.70 (m, 2H), 4.69 (t, 2H), 4.9 (b, 1H), 6.74 (b, 1H), 6.88 (m, 1H), 7.0 (b, H), 7.26 (b, 1H), 7.27 (m, 1H), 7.35 (m, 1H) 7.54 (m, 1H), 7.97 (m, 1H), 8.06 (m, 1H).

Preparation of dimethylaminoethyl salicylate.AcOH

19.9 g (0.1 mol) of acetylsalicyl chloride was dissolved in 100 ml of chloroform. The mixture was cooled to 0° C. 15 ml of triethylamine and 8.9 g (0.1 mol) of dimethylaminoethanol was added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is dissolved in methanol (300 ml), 5% sodium bicarbonate (200 ml) is added into the reaction mixture. The mixture is refluxed for 2 hr. The mixture is evaporated to dryness. Methanol (300 ml) is added into the residue with stirring. Solid is removed by filtration and washed with methanol. The solution is evaporated to dryness and the residue is dissolved in chloroform (200 ml). 6 g of acetic acid is added into the reaction mixture with stirring. Some solid is removed by filtration. Another 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 23 g of the desired product (88%). Hygroscopic product; Solubility in water: 350 mg/ml; Elementary analysis: C13H19NO5; MW: 269.29. Calculated % C, 57.98; H, 7.11; N, 5.20; O, 29.71. Found % C, 57.96; H, 7.13; N, 5.17; O, 29.74. 1H-NMR (400 MHz, CDCl3): δ: 2.21 (s, 3H), 2.90 (s, 6H), 3.70 (m, 2H), 4.69 (t, 2H), 4.9 (b, 1H), 6.74 (b, 1H), 6.84 (m, 1H), 6.93 (b, 1H), 6.98 (b, 1H), 7.30 (b, 1H).

Preparation of S-dimethylaminoethyl 5-(2,4-difluorophenyl) thiosalicylate.AcOH

31.1 g (0.1 mol) of 5-(2,4-difluorophenyl)acetylsalicyl chloride was dissolved in 100 ml of chloroform. The mixture was cooled to 0° C. 15 ml of triethylamine and 9.3 g of dimethylaminoethyl mercaptan were added into the reaction mixture. The mixture is stirred for 3 h at RT. The solvents are evaporated off. The residue is dissolved in methanol (300 ml), 5% sodium bicarbonate (200 ml) is added into the reaction mixture. The mixture is refluxed for 2 hr. The mixture is evaporated to dryness. Methanol (300 ml) is added into the residue with stirring. Solid is removed by filtration and washed with methanol. The solution is evaporated to dryness and the residue is dissolved in chloroform (200 ml). 6 g of acetic acid is added into the reaction mixture with stirring. Some solid is removed by filtration. Another 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 32 g of the desired product (80.5%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C19H21F2NO4S; MW: 397.44. Calculated % C, 57.42; H, 5.33; F, 9.56; N, 3.52; O, 16.10; S, 8.07. Found % C, 57.40; H, 5.35; F, 9.53; N, 3.51; O, 16.15; S, 8.06. 1H-NMR (400 MHz, CDCl3): δ: 2.20 (s, 3H), 2.90 (s, 6H), 3.31 (t, 2H), 3.91 (t, 2H), 5.0 (b, 1H), 6.7 (b, 1H), 6.74 (m, 1H), 6.84 (m, 1H); 7.14 (m, 1H), 7.23 (m, 1H). 7.44 (m, 1H), 7.87 (m, 1H).

Preparation of N-dimethylaminoethyl 5-(2,4-difluorophenyl) salicylamide.AcOH

31.1 g (0.1 mol) of 5-(2,4-difluorophenyl)acetylsalicyl chloride was dissolved in 100 ml of chloroform. The mixture was cooled to 0° C. 15 ml of triethylamine and 8.8 g (0.1 mol) of dimethylaminoethylamine was added into the reaction mixture. The mixture is stirred for 3 h at RT. The solvents are evaporated off. The residue is dissolved in methanol (300 ml), 5% sodium bicarbonate (200 ml) is added into the reaction mixture. The mixture is refluxed for 2 hr. The mixture is evaporated to dryness. Methanol (300 ml) is added into the residue with stirring. Solid is removed by filtration and washed with methanol. The solution is evaporated to dryness and the residue is dissolved in chloroform (200 ml). 6 g of acetic acid is added into the reaction mixture with stirring. Some solid is removed by filtration. Another 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 33 g of the desired product (86.8%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C19H22F2N2O4; MW: 380.39. Calculated % C, 59.99; H, 5.83; F, 9.99; N, 7.36; O, 16.82. Found % C, 59.97; H, 5.85; F, 9.98; N, 7.35; O, 16.85. 1H-NMR (400 MHz, CDCl3): δ: 2.20 (s, 3H), 2.90 (s, 6H), 3.54 (t, 2H), 3.64 (t, 2H), 5.0 (b, 1H), 6.7 (b, 1H), 6.73 (m, 1H), 6.80 (m, 1H); 7.15 (m, 1H), 7.22 (m, 1H). 7.44 (m, 1H), 7.87 (m, 1H), 8.01 (b, 1H).

Preparation of S-Diethylaminoethyl thiosalicylate.AcOH

18 g (0.1 mol) of acetylsalicylic acid was dissolved in 100 ml of dichloromethane (DCM). The mixture was cooled to 0° C. 20.6 g of 1,3-Dicyclohexylcarbodiimid was added into the reaction mixture. The mixture was stirred for 30 minutes at 0° C. 13.4 g (0.1 mol) of diethylaminoethyl mercaptan was added into the reaction mixture. The mixture was stirred for 3 h at RT. The solvents are evaporated off. The residue is dissolved in methanol (300 ml), 5% sodium bicarbonate (200 ml) is added into the reaction mixture. The mixture is stirred for 20 h at RT. The mixture is evaporated to dryness. Methanol (300 ml) is added into the residue with stirring. Solid is removed by filtration and washed with methanol. The solution is evaporated to dryness and the residue is dissolved in chloroform (200 ml). 6 g of acetic acid is added into the reaction mixture with stirring. Some solid is removed by filtration. Another 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 29 g of the desired product (92.5%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C15H23NO4S; MW: 313.41. Calculated % C, 57.48; H, 7.40; N, 4.47; O, 20.42; S, 10.23. Found % C, 57.43; H, 7.42; N, 4.46; O, 20.47; S, 10.21. 1H-NMR (400 MHz, CDCl3): 1.56 (t, 6H) 2.20 (s, 3H), 3.26 (m, 4H), 3.31 (t, 2H), 3.91 (t, 2H), 5.0 (b, 1H), 6.8 (b, 1H), 6.92 (d, 1H), 7.41 (d, 1H), 7.81 (d, 1H).

Preparation of ethyl 3-N,N-diethylaminopropionyl 5-(2,4-difluorophenyl) salicylate.AcOH

27.8 g (0.1 mol) of ethyl 5-(2,4-difluorophenyl)salicylate was dissolved in 100 ml of chloroform (100 ml). The mixture was cooled to 0° C. 21 ml (0.2 mol) of triethylamine and 20.0 g (0.1 mol) of 3-N,N-diethylaminopropionyl chloride hydrochloride were added into the reaction mixture. The mixture is stirred for 3 h at RT. The solid is removed by filtration. Acetic acid (6 g) was added into the reaction mixture with stirring. Hexane (200 ml) was added. The solid product was collected by filtration. After drying, it yielded 40 g of the desired product (85.9%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C24H29F2NO6; MW: 465.49. Calculated % C, 61.93; H, 6.28; F, 8.16; N, 3.01; O, 20.62. Found % C, 61.90; H, 6.30; F, 8.15; N, 3.00; O, 20.65. 1H-NMR (400 MHz, CDCl3): δ: 1.30 (t, 3H), 1.56 (t, 6H), 2.20 (s, 3H), 2.67 (t, 2H); 3.28 (m, 4H), 3.50 (m, 2H), 4.29 (m, 2H), 6.8 (b, 1H), 6.70 (m, 1H), 6.81 (m, 1H), 7.40 (m, 2H), 7.44 (d, 1H), 7.9 (d, 1H).

Preparation of ethyl 3-N,N-dimethylaminopropionyl salicylsalicylate.AcOH

28.6 g (0.1 mol) of ethyl salicylsalicylate was dissolved in 100 ml of chloroform (100 ml). The mixture was cooled to 0° C. 21 ml (0.2 mol) of triethylamine and 17.2 g (0.1 mol) of 3-N,N-dimethylaminopropionyl chloride hydrochloride were added into the reaction mixture. The mixture is stirred for 3 h at RT. The solid is removed by filtration. Acetic acid (6 g) was added into the reaction mixture with stirring. Hexane (200 ml) was added. The solid product was collected by filtration. After drying, it yielded 42 g of the desired product (88.7%). Hygroscopic product; Solubility in water: 380 mg/ml; Elementary analysis: C25H31NO8; MW: 473.52. Calculated % C, 63.41; H, 6.60; N, 2.96; O, 27.03. Found % C, 63.40; H, 6.62; N, 2.93; O, 27.05. 1H-NMR (400 MHz, CDCl3): δ: 1.30 (t, 3H), 1.57 (t, 6H); 2.20 (s, 3H), 2.68 (t, 2H); 3.28 (m, 4H), 3.50 (m, 2H), 4.29 (m, 2H), 6.8 (b, 1H), 7.21 (m, 2H), 7.26 (m, 1H), 7.27 (m, 1H), 7.49 (m, 1H), 7.54 (m, 1H); 8.05 (m, 1H); 8.12 (m, 1H).

Preparation of ethyl 3-N,N-dimethylaminopropionyl salicylate.AcOH

16.6 g (0.1 mol) of ethyl salicylate was dissolved in 100 ml of chloroform (100 ml). The mixture was cooled to 0° C. 21 ml (0.2 mol) of triethylamine and 17.2 g (0.1 mol) of 3-N,N-dimethylaminopropionyl chloride hydrochloride were added into the reaction mixture. The mixture is stirred for 3 h at RT. The solid is removed by filtration. Acetic acid (6 g) was added into the reaction mixture with stirring. Hexane (200 ml) was added. The solid product was collected by filtration. After drying, it yielded 28 g of the desired product (85.9%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C16H23NO6; MW: 325.36. Calculated % C, 59.06; H, 7.13; N, 4.31; O: 29.50. Found % C, 59.03; H, 7.15; N, 4.30; O, 29.52. 1H-NMR (400 MHz, CDCl3): δ: 1.31 (t, 3H), 2.20 (s, 3H), 2.68 (t, 2H); 2.92 (m, 4H), 3.50 (m, 2H), 4.30 (m, 2H), 6.8 (b, 1H), 7.18 (m, 2H), 7.44 (m, 1H), 7.92 (m, 1H).

Preparation of diethylaminoethyl 2-(ρ-isobutylphenyl) propionate.AcOH

22.5 g (0.1 mol) of 2-(ρ-isobutylphenyl)propionyl chloride was dissolved in 100 ml of chloroform. The mixture was cooled to 0° C. 15 ml of triethylamine and 11.7 g of diethylaminoethanol were added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solid side product was removed by filtration and washed with chloroform (3×30 ml). 6 g of acetic acid is added into the chloroform solution with stirring. The organic solution was evaporated off. After drying, it yielded 35 g of the desired product (92%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C21H35NO4; MW: 365.51. Calculated % C, 69.01; H, 9.65; N, 3.83; O, 17.51. Found % C, 68.98; H, 9.68; N, 3.82; O, 17.52. 1H-NMR (400 MHz, CDCl3): δ: 1.10 (d, 6H), 1.52 (d, 3H), 1.56 (t, 6H), 2.21 (s, 3H), 2.22 (m, 1H); 2.51 (d, 2H), 3.28 (m, 4H), 3.52 (m, 2H), 3.78 (m, 1H), 4.52 (t, 2H), 6.8 (b, 1H), 7.06 (d, 2H), 7.07 (d, 2H).

Preparation of dimethylaminoethyl 2-(ρ-isobutylphenyl) propionate.AcOH

22.5 g (0.1 mol) of 2-(ρ-isobutylphenyl)propionyl chloride was dissolved in 100 ml of chloroform. The mixture was cooled to 0° C. 15 ml of triethylamine and 8.9 g of dimethylaminoethanol were added into the reaction mixture. The mixture is stirred for 3 hours at RT. 6 g of acetic acid is added into the reaction mixture with stirring. The solid side product was removed by filtration and washed with chloroform (3×30 ml). The organic solution was evaporated off. After drying, it yielded 31 g of the desired product (92%). Hygroscopic product; Solubility in water: 300 mg/ml; Elementary analysis: C19H31NO4; MW: 337.45. Calculated % C, 67.63; H, 9.26; N, 4.15; O, 18.96. Found % C, 67.60; H, 7.28; N, 4.14; O, 18.98. 1H-NMR (400 MHz, CDCl3): δ: 1.01 (d, 6H), 1.52 (d, 3H), 2.21 (s, 3H), 2.22 (m, 1H); 2.51 (d, 2H), 2.90 (s, 6H), 3.52 (m, 2H), 3.78 (m, 1H), 4.52 (t, 2H), 6.8 (b, 1H), 7.06 (d, 2H), 7.07 (d, 2H).

Preparation of dipropylaminoethyl 2-(ρ-isobutylphenyl) propionate.AcOH

22.3 g (0.1 mol) of sodium 2-(ρ-isobutylphenyl)propionate was suspended in 180 ml of chloroform. 28.8 g (0.1 mol) of dipropylaminoethyl bromide.HBr was added into the mixture and the mixture was stirred for 5 hours at RT. 8.2 g (0.1 mol) of sodium acetate was added into the reaction mixture with stirring. The mixture is stirred for 2 hours. The solid was removed by filtration and washed with chloroform (3×50 ml). The solution is concentrated in vacuo to 100 ml. Then 300 ml of hexane was added into the solution. The solid product was collected by filtration and washed with hexane (3×100 ml). After drying, it yielded 35 g of the desired product (88.9%). Hygroscopic product; Solubility in water: 300 mg/ml; Elementary analysis: C23H39NO4; MW: 393.56. Calculated % C, 70.19; H, 9.99; N, 3.56; O, 16.26. Found % C, 70.14; H, 10.03; N, 3.55; O: 16.28. 1H-NMR (400 MHz, CDCl3): δ: 0.96 (d, 6H), δ: 1.10 (d, 6H), 1.52 (d, 3H), 1.77 (m, 4H), 2.21 (s, 3H), 2.22 (m, 1H); 2.51 (d, 2H), 3.24 (m, 4H), 3.52 (m, 2H), 3.78 (m, 1H), 4.52 (t, 2H), 6.8 (b, 1H), 7.06 (d, 2H), 7.07 (d, 2H).

Preparation of dipropylaminoethyl 2-(ρ-isobutylphenyl) propionate.AcOH

60 g of Polymer-bound triethylamine (3 mmol/g, 100-200 mesh) was suspended in 180 ml of chloroform. 20.6 g (0.1 mol) of 2-(ρ-isobutylphenyl)propionic acid was added into the mixture with stirring. 43 g (0.15 mol) of dipropylaminoethyl bromide.HBr was added into the mixture and the mixture was stirred for 5 hours at RT. The polymer was removed by filtration and washed with tetrahydrofuran (3×50 ml). 8.2 g (0.1 mol) of sodium acetate was added into the reaction mixture with stirring. The mixture was stirred for 2 h. The solid was removed by filtration and washed with chloroform (3×50 ml). The solution was concentrated in vacuo to 100 ml. Then 300 ml of hexane was added into the solution. The solid product was collected by filtration and washed with hexane (3×100 ml). After drying, it yielded 36 g of the desired product (91.5%). Hygroscopic product; Solubility in water: 300 mg/ml; Elementary analysis: C23H39NO4; MW: 393.56. Calculated % C, 70.19; H, 9.99; N, 3.56; O, 16.26. Found % C, 70.14; H, 10.03; N, 3.55; O, 16.28. 1H-NMR (400 MHz, CDCl3): δ: 0.96 (d, 6H), δ: 1.10 (d, 6H), 1.52 (d, 3H), 1.77 (m, 4H), 2.21 (s, 3H), 2.22 (m, 1H); 2.51 (d, 2H), 3.24 (m, 4H), 3.52 (m, 2H), 3.78 (m, 1H), 4.52 (t, 2H), 6.8 (b, 1H), 7.06 (d, 2H), 7.07 (d, 2H).

Preparation of 3-piperidinemethyl 2-(ρ-isobutylphenyl) propionate.AcOH

60 g of Polymer-bound triethylamine (3 mmol/g, 100-200 mesh) was suspended in 180 ml of chloroform. 20.6 g (0.1 mol) of 2-(ρ-isobutylphenyl)propionic acid was added into the mixture with stirring. 39 g (0.15 mol) of 3-piperidinemethyl bromide.HBr was added into the mixture and the mixture was stirred for 5 hours at RT. The polymer is removed by filtration and washed with acetone (3×50 ml). 300 ml of 5% Na2CO3 was added into the solution with stirring. The mixture is stirred for 30 min. The chloroform solution is washed with water (3×100 ml) and dried over Na2SO4. Sodium sulfate is removed by filtration and washed with chloroform (3×100 ml). 6 g of acetic acid was added into the mixture. The solution is concentrated in vacuo to 100 ml. Then 300 ml of hexane was added into the solution. The solid product was collected by filtration and washed with hexane (3×100 ml). After drying, it yielded 35 g of the desired product (96%). Elementary analysis: C21H33NO4; MW: 363.49 Calculated % C, 69.39; H, 9.15; N, 3.85; O, 17.61. Found % C, 69.35; H, 9.18; N, 3.83; O, 17.64.

Preparation of S-dimethylaminoethyl 2-(ρ-isobutylphenyl) thiopropionate.AcOH

22.5 g (0.1 mol) of 2-(ρ-isobutylphenyl)propionyl chloride was dissolved in 100 ml of chloroform. The mixture was cooled to 0° C. 15 ml of triethylamine and 9.3 g of dimethylaminoethyl mercaptan were added into the reaction mixture. The mixture was stirred for 3 hours at RT. 6 g of acetic acid was added into the reaction mixture with stirring. The solid side product was removed by filtration and washed with chloroform (3×30 ml). The organic solution was evaporated off. After drying, it yielded 32 g of the desired product (90.5%). Hygroscopic product; Solubility in water: 300 mg/ml; Elementary analysis: C19H31NO3S; MW: 353.52. Calculated % C, 64.55; H, 8.84; N, 3.96; O: 13.58; S, 9.07. Found % C, 64.52; H, 8.86; N, 3.95; O, 13.62; S, 9.05. 1H-NMR (400 MHz, CDCl3): δ: 1.01 (d, 6H), 1.52 (d, 3H), 2.20 (s, 3H), 2.22 (m, 1H); 2.50 (d, 2H), 2.90 (s, 6H), 3.31 (t, 2H), 3.81 (t, 1H), 3.91 (t, 2H), 6.8 (b, 1H), 7.06 (d, 2H), 7.07 (d, 2H).

Preparation of S-diethylaminoethyl 2-(ρ-isobutylphenyl) thiopropionat.AcOH

20.6 g (0.1 mol) of 2-(ρ-isobutylphenyl)propionic acid was dissolved in 100 ml of dichloromethane (DCM). The mixture was cooled to 0° C. 20.6 g of 1,3-Dicyclohexylcarbodiimid was added into the reaction mixture. The mixture was stirred for 30 minutes at 0° C. 13.4 g (0.1 mol) of diethylaminoethyl mercaptan was added into the reaction mixture. The mixture was stirred for 3 h at RT. 6 g of acetic acid was added into the reaction mixture with stirring. The solid side product was removed by filtration and washed with chloroform (3×50 ml). The organic solution was evaporated off. After drying, it yielded 34 g of the desired product (89.1%). Hygroscopic product; Solubility in water: 300 mg/ml; Elementary analysis: C21H35NO3S; MW: 381.57. Calculated % C, 66.10; H, 9.25; N, 3.67; O, 12.58; S, 8.40. Found % C, 66.07; H, 9.29; N, 3.66; O, 12.60; S: 8.38. 1H-NMR (400 MHz, CDCl3): δ: 1.01 (d, 6H), 1.52 (d, 3H), 1.56 (t, 6H) 2.20 (s, 3H), 2.22 (m, 1H); 2.50 (d, 2H), 3.26 (m, 4H), 3.31 (t, 2H), 3.81 (t, 1H), 3.91 (t, 2H), 6.8 (b, 1H), 7.06 (d, 2H), 7.07 (d, 2H).

Preparation of N-dimethylaminoethyl 2-(ρ-isobutylphenyl) propionamide.AcOH

22.5 g (0.1 mol) of 2-(ρ-isobutylphenyl)propionyl chloride was dissolved in 100 ml of chloroform. The mixture was cooled to 0° C. 15 ml of triethylamine and 8.9 g of dimethylaminoethylamine were added into the reaction mixture. The mixture was stirred for 3 hours at RT. 6 g of acetic acid was added into the reaction mixture with stirring. The solid side product was removed by filtration and washed with chloroform (3×30 ml). The organic solution was evaporated off. After drying, yielded 30 g of the desired product (89.1%). Hygroscopic product; Solubility in water: 300 mg/ml; Elementary analysis: C19H32N2O3; MW: 336.47. Calculated % C, 67.82; H, 9.59; N, 8.33; O, 14.27. Found % C, 67.80; H, 9.61; N, 8.31; O, 14.26. 1H-NMR (400 MHz, CDCl3): δ: 1.01 (d, 6H), 1.52 (d, 3H), 2.20 (s, 3H), 2.22 (m, 1H); 2.50 (d, 2H), 2.90 (s, 6H), 3.50 (t, 2H), 3.64 (t, 2H), 3.89 (m, 1H), 6.8 (b, 1H), 7.06 (d, 2H), 7.07 (d, 2H), 7.8 (b, 1H).

Preparation of N-dimethylaminopropyl 2-(ρ-isobutylphenyl) propionamide.AcOH

20.6 g (0.1 mol) of 2-(ρ-isobutylphenyl)propionic acid was dissolved in 100 ml of acetonitrile. 32.1 g of O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate and 30 ml of triethylamine were added into the reaction mixture. 13.1 g of dimethylaminopropylamine was added into the reaction mixture. The mixture was stirred for 3 hours at RT. The solvents were evaporated off. 250 ml of ethyl acetate was added into the reaction mixture and the mixture was washed with water (3×100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 6 g of acetic acid was added into the reaction mixture with stirring. Hexane (200 ml) was added. The solid product was collected by filtration. After drying, it yielded 32 g of the desired product (91.2%). Hygroscopic product; Solubility in water: 320 mg/ml; Elementary analysis: C20H34N2O3; MW: 350.5. Calculated % C, 68.54; H, 9.78; N, 7.99; O, 13.69. Found % C, 68.51; H, 9.80; N, 7.98; O, 13.71. 1H-NMR (400 MHz, CDCl3): δ: 1.01 (d, 6H), 1.52 (d, 3H), 1.98 (m, 2H), 2.20 (s, 3H), 2.22 (m, 1H); 2.50 (d, 2H), 2.90 (s, 6H), 3.20 (m, 2H), 3.24 (m, 2H), 3.89 (m, 1H), 6.8 (b, 1H), 7.06 (d, 2H), 7.07 (d, 2H), 7.8 (b, 1H).

Preparation of diethylaminoethyl (Z)-5-fluoro-2-methyl-1-[(4-methylsulfinyl)phenylmethylene]-1H-indene-3-acetate.AcOH

1.3 g (0.2 mol) of (Z)-5-fluoro-2-methyl-1-[(4-methylsulfinyl)phenylmethylene]-1H-indene-3-acetic acid was dissolved in 500 ml of chloroform. DCC (R0283, 21) is added into the reaction mixture and the mixture was stirred for 2 h at 25 C. The solid was removed by filtration and washed with chloroform (3×100 ml). 11.7 g (0.1 mol) of diethylaminoethanol was added into the reaction mixture. The mixture was stirred for overnight at RT. The solution was concentrated to 100 ml. 300 ml of hexanes was added into the residue. The solid was collected by filtration and washed with hexanes. After drying, it yielded 75 g of the desired product (92.3%). Elementary analysis: C46H47F2NO6S2; MW: 812.00. Calculated % C, 68.04; H, 5.83; F, 4.68; N, 1.72; O, 11.82; S, 7.90. Found % C, 68.07; H, 5.85; F, 4.63; N, 1.72; O, 11.87; S, 7.86.

Preparation of diethylaminoethyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate.AcOH.

8.6 g (0.1 mol) of 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetyl chloride was dissolved in 100 ml of chloroform. The mixture was cooled to 0° C. 15 ml of triethylamine and 8.9 g (0.1 mol) of dimethylaminoethanol were added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is dissolved in methanol (300 ml), 5% sodium bicarbonate (200 ml) is added into the reaction mixture. The mixture is stirred for 3 hr. The mixture is evaporated to dryness. Methanol (300 ml) is added into the residue with stirring. Solid is removed by filtration and washed with methanol. The solution is evaporated to dryness and the residue is dissolved in chloroform (200 ml). 6 g of acetic acid is added into the reaction mixture with stirring. Some solid is removed by filtration. Another 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 37 g of the desired product (88.8%). Elementary analysis: C23H32N2O5; MW: 416.51. Calculated % C, 66.32; H, 7.74; N, 6.73; O, 19.21. Found % C, 66.29; H, 7.76; N, 6.73; O, 19.22.

Preparation of S-dimethylaminoethyl 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH.

0.4 g (0.1 mol) of dimethylaminoethyl mercaptan was dissolved in 10% sodium bicarbonate (200 ml) and acetone (100 ml). 37.6 g (0.1 mol) of 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetyl chloride was added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is suspended in ethyl acetate (500 ml). 5% sodium bicarbonate (200 ml) is added into the reaction mixture with stirring. Ethyl acetate layer is collected and washed with water (3×500 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate is removed by filtration. 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 46 g of the desired product (86.3%). Elementary analysis: C27H33ClN2O5S; MW: 533.08. Calculated % C, 60.83; H, 6.24; Cl, 6.65; N, 5.26; O, 15.01; S, 6.02. Found % C, 60.80; H, 6.26; Cl, 6.66; N, 5.25; O, 15.02; S, 6.01.

Preparation of N-dimethylaminoethyl 5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetamide.AcOH

8.8 g (0.1 mol) of dimethylaminoethylamine was dissolved in 10% sodium bicarbonate (200 ml) and acetone (100 ml). 31 g (0.1 mol) of 2-(3-benzoyphenyl)propionyl chloride was added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is suspended in ethyl acetate (500 ml). 5% sodium bicarbonate (200 ml) is added into the reaction mixture with stirring. Ethyl acetate layer is collected and washed with water (3×500 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate is removed by filtration. 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 33 g of the desired product (85.9%). Elementary analysis: C23H32ClN3O4; MW: 449.97. Calculated % C, 61.39; H, 7.17; Cl, 7.88; N, 9.34; O, 14.22. Found % C, 61.37; H, 7.18; Cl, 7.89; N, 9.32; O, 14.24.

Preparation of N-dimethylaminoethyl 1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetamide.AcOH

8.9 g (0.1 mol) of 1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid was dissolved in 100 ml of acetonitrile. 32.1 g of O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate and 30 ml of triethylamine were added into the reaction mixture. 11.7 g of dimethylaminoethylamine was added into the reaction mixture. The mixture was stirred for 3 hours at RT. The solvents were evaporated off. 250 ml of ethyl acetate was added into the reaction mixture and the mixture was washed with water (3×100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 6 g of acetic acid was added into the reaction mixture with stirring. Hexane (200 ml) was added. The solid product was collected by filtration. After drying, it yielded 40 g of the desired product (89.4%). C25H41N3O4; MW: 447.61. Calculated % C, 67.08; H, 9.23; N, 9.39; O, 14.30. Found % C, 67.05; H, 9.25; N, 9.38; O, 14.32.

Preparation of diethylaminoethyl 3-chloro-4-(2-propenyloxy) benzeneacetate.AcOH

0 g of Polymer-bound triethylamine (3 mol/g, 100-200 mesh) was suspended in 180 ml of chloroform. 22.7 g (0.1 mol) of 3-chloro-4-(2-propenyloxy)benzeneacetic acid was added into the mixture with stirring. 43 g (0.15 mol) of diethylaminoethyl bromide.HBr was added into the mixture and the mixture was stirred for 5 hours at RT. The polymer was removed by filtration and washed with tetrahydrofuran (3×50 ml). 8.2 g (0.1 mol) of sodium acetate was added into the reaction mixture with stirring. The mixture was stirred for 2 h. The solid was removed by filtration and washed with chloroform (3×50 ml). The solution was concentrated in vacuo to 100 ml. Then 300 ml of hexane was added into the solution. The solid product was collected by filtration and washed with hexane (3×100 ml). After drying, it yielded 34 g of the desired product (88.3%). Hygroscopic product; Elementary analysis: C19H29ClN2O4; MW: 384.9. Calculated % C, 59.29; H, 7.59; Cl, 9.21; N, 7.28; O, 16.63. Found % C, 59.26; H, 7.61; Cl, 9.22; N, 7.26; O, 16.65.

Preparation of diethylaminoethyl 2[(2,6-dichlorophenyl)amino]benzene acetate.AcOH

35.1 g (0.1 mol) of 2-[(2,6-dichlorophenyl)amino]benzene acetyl chloride hydrochloride was dissolved in 100 ml of chloroform. The mixture was cooled to 0° C. 30 ml of triethylamine and 11.7 g of diethylaminoethanol were added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solid side product was removed by filtration and washed with chloroform (3×30 ml). 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 39 g of the desired product (85.6%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C22H28Cl2N2O4; MW: 455.37. Calculated % C, 58.03; H, 6.20; Cl, 15.57; N, 6.15; O, 14.05. Found % C, 58.01; H, 6.22; Cl, 15.55; N, 6.14; O, 14.09. 1H-NMR (400 MHz, CDCl3): δ: 1.56 (t, 6H), 2.21 (s, 3H), 3.28 (m, 4H), 3.50 (s, 2H), 3.52 (m, 2H), 3.81 (b, 1H), 4.51 (t, 2H), 6.32 (d, 1H), 6.50 (m, 2H), 6.78 (b, 1H), 6.82 (m, 2H), 6.91 (d, 2H).

Preparation of dimethylaminoethyl 2[(2,6-dichlorophenyl)amino]benzene acetate.AcOH

2[(2,6-Dichlorophenyl)amino]benzene acetyl chloride hydrochloride (35.1 g, 0.1 mol) was dissolved in 100 ml of acetone. The mixture was cooled to 0° C. Dimethylaminoethanol (8.9 g, 0.1 mol) were added into the reaction mixture. Sodium bicarbonate (20 g) and water (100 ml) are added into the mixture. The mixture is stirred for 3 hours at RT. The solution is evaporated to dryness. Acetone (100 ml) is added into the residue. The solid side product was removed by filtration and washed with acetone (3×30 ml). 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 38 g of the desired product (88.9%). Hygroscopic product; Solubility in water: 410 mg/ml; Elementary analysis: C20H24Cl2N2O4; MW: 427.32. Calculated % C, 56.21; H, 5.66; Cl, 16.59; N, 6.56; O, 14.98. Found % C, 56.18; H, 5.68; Cl, 16.56; N, 6.55; O, 15.03. 1H-NMR (400 MHz, CDCl3): δ: 2.21 (s, 3H), 2.91 (s, 6H), 3.50 (s, 2H), 3.52 (m, 2H), 3.81 (b, 1H), 4.51 (t, 2H), 6.32 (d, 1H), 6.50 (m, 2H), 6.78 (b, 1H), 6.82 (m, 2H), 6.91 (d, 2H).

Preparation of S-dimethylaminoethyl 2-[(2,6-dichlorophenyl)amino]benzene acetate.AcOH

2-[(2,6-Dichlorophenyl)amino]benzene acetyl chloride hydrochloride (35.1 g, 0.1 mol) was dissolved in 100 ml of acetone. The mixture was cooled to 0° C. Dimethylaminoethyl mercaptan (9.3 g, 0.1 mol) were added into the reaction mixture. Sodium bicarbonate (20 g) and water (100 ml) are added into the mixture. The mixture is stirred for 3 hours at RT. The solution is evaporated to dryness. Acetone (100 ml) is added into the residue. The solid side product was removed by filtration and washed with acetone (3×30 ml). 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 40 g of the desired product (90.2%). Hygroscopic product; Solubility in water: 410 mg/ml; Elementary analysis: C20H24Cl2N2O3S; MW: 443.39. Calculated % C, 54.18; H, 5.46; Cl, 15.99; N, 6.32; O, 10.83; S, 7.22. Found % C, 54.16; H, 5.48; Cl, 15.97; N, 6.31; O, 10.86; S, 7.23. 1H-NMR (400 MHz, CDCl3): δ: 2.21 (s, 3H), 2.91 (s, 6H), 3.31 (t, 2H), 3.66 (s, 2H), 3.91 (m, 2H), 3.93 (b, 1H), 6.32 (d, 1H), 6.50 (m, 2H), 6.78 (b, 1H), 6.82 (m, 2H), 6.91 (d, 2H).

Preparation of N-dimethylaminoethyl 2[(2,6-dichlorophenyl)amino]benzene acetamide.AcOH

2[(2,6-Dichlorophenyl)amino]benzene acetyl chloride hydrochloride (35.1 g, 0.1 mol) was dissolved in 100 ml of acetone. The mixture was cooled to 0° C. Dimethylaminoethylamine (8.9 g) added into the reaction mixture. Sodium bicarbonate (20 g) and water (100 ml) are added into the mixture. The mixture is stirred for 3 hours at RT. The solution is evaporated to dryness. Acetone (100 ml) is added into the residue. The solid side product was removed by filtration and washed with acetone (3×30 ml). 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 40 g of the desired product (93.8%). Hygroscopic product; Solubility in water: 450 mg/ml; Elementary analysis: C20H25Cl2N2O3; MW: 426.34. Calculated % C, 56.34; H, 5.91; Cl, 16.63; N, 9.86; O, 11.26. Found % C, 56.31; H; 5.5.94; Cl, 16.61; N, 9.84; O, 11.30. 1H-NMR (400 MHz, CDCl3): δ: 2.21 (s, 3H), 2.91 (s, 6H), 3.44 (s, 2H), 3.51 (t, 2H), 3.64 (t, 2H), 3.93 (b, 1H), 6.32 (d, 1H), 6.50 (m, 2H), 6.78 (b, 1H), 6.82 (m, 2H), 6.91 (d, 2H), 8.0 (b, 1H).

Preparation of dipropylaminoethyl 2[(2,6-dichlorophenyl)amino] benzene acetate.AcOH

31.8 g (0.1 mol) of sodium 2-[(2,6-dichlorophenyl)amino]benzene acetate was suspended in 180 ml of chloroform. 28.8 g (0.1 mol) of dipropylaminoethyl bromide.HBr was added into the mixture and the mixture was stirred for 5 hours at RT. 8.2 g (0.1 mol) of sodium acetate was added into the reaction mixture with stirring. The mixture is stirred for 2 hours. The solid was removed by filtration and washed with chloroform (3×50 ml). The solution is concentrated in vacuo to 100 ml. Then 300 ml of hexane was added into the solution. The solid product was collected by filtration and washed with hexane (3×100 ml). After drying, it yielded 41 g of the desired product (87%). Hygroscopic product; Solubility in water: 300 mg/ml; Elementary analysis: C24H32Cl2N2O4; MW: 483.43 Calculated % C, 59.63; H, 6.67; Cl, 14.67; N, 5.79; O, 13.24. Found % C, 59.60; H, 6.70; Cl, 14.65; N, 5.78; O, 13.27. 1H-NMR (400 MHz, CDCl3): δ: 0.97 (t, 6H), 1.78 (m, 4H), 2.21 (s, 3H), 3.24 (t, 4H), 3.50 (s, 2H), 3.52 (m, 2H), 3.81 (b, 1H), 4.51 (t, 2H), 6.34 (d, 1H), 6.50 (m, 2H), 6.78 (b, 1H), 6.82 (m, 2H), 6.91 (d, 2H).

Preparation of dipropylaminoethyl dipropylaminoethyl 2[(2,6-dichlorophenyl)amino]benzene acetate.AcOH

60 g of Polymer-bound triethylamine (3 mmol/g, 100-200 mesh) was suspended in 180 ml of chloroform. 31.8 g (0.1 mol) of 2[(2,6-dichlorophenyl)amino]benzene acetic acid was added into the mixture with stirring. 43 g (0.15 mol) of dipropylaminoethyl bromide.HBr was added into the mixture and the mixture was stirred for 5 hours at RT. The polymer is removed by filtration and washed with tetrahydrofuran (3×50 ml). 8.2 g (0.1 mol) of sodium acetate was added into the reaction mixture with stirring. The mixture is stirred for 2 h. The solid was removed by filtration and washed with chloroform (3×50 ml). The solution is concentrated in vacuo to 100 ml. Then 300 ml of hexane was added into the solution. The solid product was collected by filtration and washed with hexane (3×100 ml). After drying, it yielded 45 g of the desired product (93.2%). Hygroscopic product; Solubility in water: 300 mg/ml; Elementary analysis: C24H32Cl2N2O4; MW: 483.43 Calculated % C, 59.63; H, 6.67; Cl, 14.67; N, 5.79; O, 13.24. Found % C, 59.60; H, 6.70; Cl, 14.65; N, 5.78; O, 13.27. 1H-NMR (400 MHz, CDCl3): δ: 0.97 (t, 6H), 1.78 (m, 4H), 2.21 (s, 3H), 3.24 (t, 4H), 3.50 (s, 2H), 3.52 (m, 2H), 3.81 (b, 1H), 4.51 (t, 2H), 6.34 (d, 1H), 6.50 (m, 2H), 6.78 (b, 1H), 6.82 (m, 2H), 6.91 (d, 2H).

Preparation of 1-piperidinepropyl 2[(2,6-dichlorophenyl)amino]benzene acetate.AcOH

31.8 g (0.1 mol) of sodium 2[(2,6-dichlorophenyl)amino]benzene acetate was suspended in 180 ml of chloroform. 28.6 g (0.1 mol) of 1-piperidinepropyl bromide.HBr was added into the mixture and the mixture was stirred for 5 hours at RT. The mixture is washed with 5% Na2CO3 (1×300 ml) and water (3×100 ml). The mixture is dried over anhydrous Na2SO4. Sodium sulfate was removed by filtration and washed with chloroform (3×50 ml). 6 g of acetic acid was added into the solution. The solution is concentrated in vacuo to 100 ml. Then 300 ml of hexane was added into the solution. The solid product was collected by filtration and washed with hexane (3×100 ml). After drying, it yielded 40 g of the desired product (86%). Elementary analysis: C24H30Cl2N2O4; MW: 481.43 Calculated % C, 59.88; H, 6.28; Cl, 14.73; N, 5.82; O, 13.29. Found % C, 59.83; H, 6.32; Cl, 14.71; N, 5.79; O, 13.35.

Preparation of diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH

11.7 g (0.1 mol) of diethylaminoethanol was dissolved in 10% sodium bicarbonate (200 ml) and acetone (100 ml). 27.3 g (0.1 mol) of 2-(3-benzoyphenyl)propionyl chloride was added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is suspended in ethyl acetate (500 ml). 5% sodium bicarbonate (200 ml) is added into the reaction mixture with stirring. Ethyl acetate layer is collected and washed with water (3×500 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate is removed by filtration. 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 36 g of the desired product (87%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C24H31NO5; MW: 413.51. Calculated % C, 69.71; H, 7.56; N, 3.39; O, 19.35. Found % C, 69.69; H, 7.59; N, 3.36; O, 19.36. 1H-NMR (400 MHz, CDCl3): δ: 1.51 (d, 3H), δ: 1.56 (t, 6H), 2.21 (s, 3H), 3.27 (m, 4H), 3.52 (m, 2H), 3.78 (m, 1H), 4.52 (t, 2H), 7.0 (b, 1H), 7.31 (m, 2H), 7.36 (m, 2H), 7.45 (m, 1H), 7.51 (m, 1H), 7.56 (m, 1H), 7.70 (m, 2H).

Preparation of dimethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH

26.1 g (0.1 mol) of 2-(3-phenoxyphenyl)propionyl chloride was dissolved in 100 ml of chloroform. The mixture was cooled to 0° C. 15 ml of triethylamine and 8.9 g (0.1 mol) of dimethylaminoethanol were added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is dissolved in methanol (300 ml), 5% sodium bicarbonate (200 ml) is added into the reaction mixture. The mixture is stirred for 3 hr. The mixture is evaporated to dryness. Methanol (300 ml) is added into the residue with stirring. Solid is removed by filtration and washed with methanol. The solution is evaporated to dryness and the residue is dissolved in chloroform (200 ml). 6 g of acetic acid is added into the reaction mixture with stirring. Some solid is removed by filtration. Another 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 32 g of the desired product (85.7%). Hygroscopic product; Solubility in water: 500 mg/ml; Elementary analysis: C21H27NO5; MW: 373.44. Calculated % C, 67.54; H, 7.29; N, 3.75; O, 21.42. Found % C, 67.51; H, 7.30; N, 3.74; O, 21.45. 1H-NMR (400 MHz, CDCl3): δ: 1.51 (d, 3H), δ: 2.21 (s, 3H), 2.91 (s, 6H), 3.52 (m, 2H), 3.78 (m, 1H), 4.51 (t, 2H), 6.70 (b, 1H), 6.74 (m, 1H), 6.78 (m, 1H), 6.84 (m, 1H), 6.92 (m, 2H), 6.98 (m, 1H), 7.17 (m, 1H), 7.22 (m, 2H).

Preparation of S-dimethylaminoethyl 2-(3-phenoxyphenyl) thiopropionate.AcOH

10.4 g (0.1 mol) of dimethylaminoethyl mercaptan was dissolved in 10% sodium bicarbonate (200 ml) and acetone (100 ml). 27.3 g (0.1 mol) of 2-(3-phenoxyphenyl)propionyl chloride was added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is suspended in ethyl acetate (500 ml). 5% sodium bicarbonate (200 ml) is added into the reaction mixture with stirring. Ethyl acetate layer is collected and washed with water (3×500 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate is removed by filtration. 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 34 g of the desired product (87.3%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C21H27NO4S; MW: 389.51. Calculated % C, 64.75; H, 6.99; N, 3.60; O, 16.43; S, 8.23. Found % C, 64.73; H, 6.98; N, 3.61; O, 16.46; S, 8.22. 1H-NMR (400 MHz, CDCl3): δ: 1.52 (d, 3H), δ: 2.20 (s, 3H), 2.91 (s, 6H), 3.31 (t, 2H), 3.81 (m, 1H), 3.91 (t, 2H), 6.70 (b, 1H), 6.74 (m, 1H), 6.78 (m, 1H), 6.84 (m, 1H), 6.92 (m, 2H), 6.98 (m, 1H), 7.17 (m, 1H), 7.22 (m, 2H).

Preparation of N-dimethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH

8.8 g (0.1 mol) of dimethylaminoethylamine was dissolved in 10% sodium bicarbonate (200 ml) and acetone (100 ml). 27.3 g (0.1 mol) of 2-(3-benzoyphenyl)propionyl chloride was added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is suspended in ethyl acetate (500 ml). 5% sodium bicarbonate (200 ml) is added into the reaction mixture with stirring. Ethyl acetate layer is collected and washed with water (3×500 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate is removed by filtration. 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 33 g of the desired product (85.9%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C22H28N2O5; MW: 384.20. Calculated % C, 68.73; H, 7.34; N, 7.29; O, 16.65. Found % C, 68.70; H, 7.35; N, 7.29; O, 16.66. 1H-NMR (400 MHz, CDCl3): δ: 1.51 (d, 3H), 2.21 (s, 3H), 2.90 (s, 6H), 3.50 (t, 2H), 3.65 (t, 2H), 3.89 (m, 1H), 7.0 (b, 1H), 7.33 (m, 2H), 7.37 (m, 2H), 7.47 (m, 1H), 7.52 (m, 1H), 7.57 (m, 1H), 7.72 (m, 2H), 7.80 (b, 1H).

Preparation of N-dimethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH

25.7 g (0.1 mol) of 2-(3-benzoyphenyl)propionic acid was dissolved in 100 ml of acetonitrile. 32.1 g of O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate and 30 ml of triethylamine were added into the reaction mixture. 11.7 g of dimethylaminoethylamine was added into the reaction mixture. The mixture was stirred for 3 hours at RT. The solvents were evaporated off. 250 ml of ethyl acetate was added into the reaction mixture and the mixture was washed with water (3×100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 6 g of acetic acid was added into the reaction mixture with stirring. Hexane (200 ml) was added. The solid product was collected by filtration. After drying, it yielded 32 g of the desired product (83.3%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C22H28N2O5; MW: 384.20. Calculated % C, 68.73; H, 7.34; N, 7.29; O, 16.65. Found % C, 68.70; H, 7.35; N, 7.29; O, 16.66. 1H-NMR (400 MHz, CDCl3): δ: 1.51 (d, 3H), 2.21 (s, 3H), 2.90 (s, 6H), 3.50 (t, 2H), 3.65 (t, 2H), 3.89 (m, 1H), 7.0 (b, 1H), 7.33 (m, 2H), 7.37 (m, 2H), 7.47 (m, 1H), 7.52 (m, 1H), 7.57 (m, 1H), 7.72 (m, 2H), 7.80 (b, 1H).

Preparation of diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH

60 g of Polymer-bound triethylamine (3 mol/g, 100-200 mesh) was suspended in 180 ml of chloroform. 25.7 g (0.1 mol) of 2-(3-benzoyphenyl)propionic acid was added into the mixture with stirring. 43 g (0.15 mol) of diethylaminoethyl bromide.HBr was added into the mixture and the mixture was stirred for 5 hours at RT. The polymer was removed by filtration and washed with tetrahydrofuran (3×50 ml). 8.2 g (0.1 mol) of sodium acetate was added into the reaction mixture with stirring. The mixture was stirred for 2 h. The solid was removed by filtration and washed with chloroform (3×50 ml). The solution was concentrated in vacuo to 100 ml. Then 300 ml of hexane was added into the solution. The solid product was collected by filtration and washed with hexane (3×100 ml). After drying, it yielded 36 g of the desired product (87%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C24H31NO5; MW: 413.51. Calculated % C, 69.71; H, 7.56; N, 3.39; O, 19.35. Found % C, 69.69; H, 7.59; N, 3.36; O, 19.36. 1H-NMR (400 MHz, CDCl3): δ: 1.51 (d, 3H), δ: 1.56 (t, 6H), 2.21 (s, 3H), 3.27 (m, 4H), 3.52 (m, 2H), 3.78 (m, 1H), 4.52 (t, 2H), 7.0 (b, 1H), 7.31 (m, 2H), 7.36 (m, 2H), 7.45 (m, 1H), 7.51 (m, 1H), 7.56 (m, 1H), 7.70 (m, 2H).

Preparation of diethylaminoethyl 2-(6-methoxy-2-naphthyl) propionate.AcOH

11.7 g (0.1 mol) of diethylaminoethanol was dissolved in 10% sodium bicarbonate (200 ml) and acetone (100 ml). 24.9 g (0.1 mol) of 2-(6-methoxy-2-naphthyl)propionyl chloride was added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is suspended in ethyl acetate (500 ml). 5% sodium bicarbonate (200 ml) is added into the reaction mixture with stirring. Ethyl acetate layer is collected and washed with water (3×500 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate is removed by filtration. 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 36 g of the desired product (89.9%). Hygroscopic product; Solubility in water: 300 mg/ml; Elementary analysis: C22H31NO5; MW: 389.49. Calculated % C, 67.84; H, 8.02; N, 3.60; O, 20.54. Found % C, 67.82; H, 8.04; N, 3.58; O, 20.56. 1H-NMR (400 MHz, D2O): δ: 1.36 (t, 6H), 1.50 (d, 3H), 2.11 (s, 3H), 3.20 (m, 4H), 3.47 (m, 2H), 3.70 (s, 3H), 3.78 (m, 1H), 4.48 (t, 2H), 6.88 (b, 1H), 6.98 (s, 1H), 7.03 (d, 1H), 7.18 (d, 1H), 7.43 (s, 1H), 7.50 (d, 1H), 7.54 (d, 1H).

Preparation of diethylaminoethyl α-methyl-4-(2-thienylcarbonyl) benzeneacetate.AcOH

28.1 g (0.1 mol) of α-methyl-4-(2-thienylcarbonyl)benzeneacetyl chloride was dissolved in 100 ml of chloroform. The mixture was cooled to 0° C. 15 ml of triethylamine and 11.7 g (0.1 mol) of diethylaminoethanol were added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is dissolved in methanol (300 ml), 5% sodium bicarbonate (200 ml) is added into the reaction mixture. The mixture is stirred for 3 hr. The mixture is evaporated to dryness. Methanol (300 ml) is added into the residue with stirring. Solid is removed by filtration and washed with methanol. The solution is evaporated to dryness and the residue is dissolved in chloroform (200 ml). 6 g of acetic acid is added into the reaction mixture with stirring. Some solid is removed by filtration. Another 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 35 g of the desired product (83.2%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C22H31NO5S; MW: 419.53. Calculated % C, 62.68; H, 7.41; N, 3.32; O, 18.98; S, 7.61. Found % C, 62.63; H, 7.45; N, 3.31; O, 19.01; S, 7.60. 1H-NMR (400 MHz, D2O): δ: 1.36 (t, 6H), 1.45 (d, 3H), 2.11 (s, 3H), 3.20 (m, 4H), 3.47 (m, 2H), 3.78 (m, 1H), 4.48 (t, 2H), 6.88 (b, 1H), 6.98 (s, 1H), 7.31 (d, 2H), 7.05 (m, 1H), 7.43 (m, 2H), 7.70 (d, 2H).

Preparation of S-dimethylaminoethyl 2-(2-fluoro-4-biphenylyl) propionate.AcOH

13.2 g (0.1 mol) of diethylaminoethyl mercaptan was dissolved in 10% sodium bicarbonate (200 ml) and acetone (100 ml). 26.3 g (0.1 mol) of 2-(2-fluoro-4-biphenylyl)propionyl chloride was added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is suspended in ethyl acetate (500 ml). 5% sodium bicarbonate (200 ml) is added into the reaction mixture with stirring. Ethyl acetate layer is collected and washed with water (3×500 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate is removed by filtration. 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 36 g of the desired product (85.8%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C23H30FNO3S; MW: 419.55. Calculated % C, 65.84; H, 7.21; F, 4.53; N, 3.34; O, 11.44; S: 7.64. Found % C, 65.80; H, 7.23; F, 4.55; N, 3.32; O, 11.47; S, 7.63. 1H-NMR (400 MHz, D2O): δ: 1.35 (t, 6H), 1.44 (d, 3H), 2.11 (s, 3H), 3.20 (m, 4H), 3.30 (t, 2H), 3.80 (m, 1H), 3.88 (t, 2H), 6.88 (b, 1H), 6.88 (m, 1H), 6.95 (m, 1H), 7.22 (m, 1H), 7.32 (m, 2H), 7.41 (m, 1H), 7.48 (m, 2H).

Preparation of N-dimethylaminoethyl diethylaminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylamide.AcOH.AcOH

11.7 g (0.1 mol) of diethylaminoethylamine was dissolved in 10% sodium bicarbonate (200 ml) and acetone (100 ml). 27.4 g (0.1 mol) of 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylyl chloride was added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is suspended in ethyl acetate (500 ml). 5% sodium bicarbonate (200 ml) is added into the reaction mixture with stirring. Ethyl acetate layer is collected and washed with water (3×500 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate is removed by filtration. 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 35 g of the desired product (84.8%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C23H31N3O4; MW: 412.50. Calculated % C, 66.81; H, 7.56; N, 10.16; O, 15.48. Found % C, 66.90; H, 7.38; N, 10.18; O, 15.54. 1H-NMR (400 MHz, D2O): δ: 1.39 (t, 6H), 2.10 (s, 3H), 2.27 (m, 2H), 3.22 (m, 4H), 3.50 (t, 2H), 3.60 (t, 2H), 3.80 (m, 2H), 3.71 (m, 1H), 5.85 (m, 1H), 6.70 (m, 1H), 6.85 (b, 1H), 7.32 (b, 1H), 7.40 (m, 1H), 7.45 (m, 2H), 7.78 (m, 2H).

Preparation of N-diethylaminoethyl 4,5-Diphenyl-2-oxazole propionamide.AcOH

29.3 g (0.1 mol) of 4,5-Diphenyl-2-oxazole propionic acid was dissolved in 100 ml of acetonitrile. 32.1 g of O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate and 30 ml of triethylamine were added into the reaction mixture. 11.6 g of diethylaminoethylamine was added into the reaction mixture. The mixture was stirred for 3 hours at RT. The solvents were evaporated off. 250 ml of ethyl acetate was added into the reaction mixture and the mixture was washed with water (3×100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 6 g of acetic acid was added into the reaction mixture with stirring. Hexane (200 ml) was added. The solid product was collected by filtration. After drying, it yielded 40 g of the desired product (88.6%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C26H33N3O4; MW: 451.56. Calculated % C, 69.16; H, 7.37; N, 9.31; O: 14.17. Found % C, 69.11; H, 7.40; N, 9.30; O, 14.19. 1H-NMR (400 MHz, D2O): δ: 1.41 (t, 6H), 2.10 (s, 3H), 2.45 (t, 2H), 2.76 (t, 2H), 3.22 (m, 4H), 3.49 (t, 2H), 3.60 (t, 2H), 6.87 (b, 1H), 7.22 (b, 1H), 7.22 (m, 2H), 7.32 (m, 4H), 7.47 (m, 4H).

Preparation of diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate.AcOH

60 g of Polymer-bound triethylamine (3 mol/g, 100-200 mesh) was suspended in 180 ml of chloroform. 27.4 g (0.1 mol) of 6-chloro-α-methyl-9H-carbazole-2-acetic acid was added into the mixture with stirring. 43 g (0.15 mol) of diethylaminoethyl bromide.HBr was added into the mixture and the mixture was stirred for 5 hours at RT. The polymer was removed by filtration and washed with tetrahydrofuran (3×50 ml). 8.2 g (0.1 mol) of sodium acetate was added into the reaction mixture with stirring. The mixture was stirred for 2 h. The solid was removed by filtration and washed with chloroform (3×50 ml). The solution was concentrated in vacuo to 100 ml. Then 300 ml of hexane was added into the solution. The solid product was collected by filtration and washed with hexane (3×100 ml). After drying, it yielded 38 g of the desired product (87.8%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C23H29ClN2O4; MW: 432.94. Calculated % C, 63.81; H, 6.75; Cl, 8.19; N, 6.47; O, 14.78. Found % C, 63.85; H, 6.78; Cl, 8.17; N, 6.44; O, 14.76. 1H-NMR (400 MHz, D2O): δ: 1.39 (t, 6H), 1.47 (d, 3H), 2.11 (s, 3H), 3.21 (m, 4H), 3.49 (m, 2H), 3.77 (m, 1H), 4.48 (t, 2H), 6.80 (b, 1H), 6.85 (m, 1H), 7.10 (m, 1H), 7.05 (m, 1H), 7.26 (m, 1H), 7.34 (m, 1H), 7.50 (m, 1H), 7.52 (m, 1H).

Preparation of N-diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoamide.AcOH.

24.1 g (0.1 mol) of 2-[(2,3-dimethylphenyl)amino]benzoic acid was dissolved in 100 ml of acetonitrile. 32.1 g of O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate and 30 ml of triethylamine were added into the reaction mixture. 11.6 g of dimethylaminoethylamine was added into the reaction mixture. The mixture was stirred for 3 hours at RT. The solvents were evaporated off. 250 ml of ethyl acetate was added into the reaction mixture and the mixture was washed with water (3×100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 6 g of acetic acid was added into the reaction mixture with stirring. Hexane (200 ml) was added. The solid product was collected by filtration. After drying, it yielded 37 g of the desired product (92.5%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C23H33N3O4; MW: 399.53. Calculated % C, 69.14; H, 8.33; N, 10.52; O, 12.01. Found % C, 69.11; H, 8.35; N, 10.51; O, 12.03. 1H-NMR (400 MHz, D2O): δ: 1.41 (t, 6H), 2.10 (s, 3H), 2.30 (s, 3H), 2.31 (s, 3H), 3.22 (m, 4H), 3.54 (m, 2H), 3.60 (m, 2H), 6.15 (m, 1H), 6.30 (m, 1H), 6.57 (m, 1H), 6.72 (m, 1H), 7.20 (m, 2H), 7.70 (m, 1H), 7.80 (b, 1H).

Preparation of N-diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino] benzoamide.AcOH.

29.6 g (0.1 mol) of 2-[(2,6-dichloro-3-methylphenyl)amino]benzoic acid was dissolved in 300 ml of chloroform. 20.6 g of N,N′-Dicyclohexylcarbodiimide was added into the reaction mixture. 11.7 g of diethylaminoethylamine was added into the reaction mixture. The mixture was stirred for 3 hours at RT. The solid is removed by filtration. The chloroform solution was washed with 5% NaHCO3 (2×100 ml) and water (3×100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 6 g of acetic acid was added into the reaction mixture with stirring. Hexane (200 ml) was added. The solid product was collected by filtration. After drying, it yielded 39 g of the desired product (85.8%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C22H29Cl2N3O3; MW: 454.39. Calculated % C, 58.15; H, 6.43; Cl, 15.60; N, 9.25; O, 10.56. Found % C, 58.10; H, 6.46; Cl, 15.62; N, 9.22; O, 10.60. 1H-NMR (400 MHz, D2O): δ: 1.43 (t, 6H), 2.11 (s, 3H), 2.28 (s, 3H), 3.23 (m, 4H), 3.49 (m, 2H), 3.63 (m, 2H), 6.30 (d, 1H), 6.57 (m, 1H), 6.72 (d, 1H), 6.80 (m, 1H), 7.20 (m, 1H), 7.68 (m, 1H), 7.70 (b, 1H).

Preparation of S-dimethylaminoethyl 2-[[(3-trifluoromethyl)phenyl]amino]benzoate.AcOH.

28.1 g (0.1 mol) of 2-[[(3-trifluoromethyl)phenyl]amino]benzoic acid was dissolved in 300 ml of chloroform. N,N′-Dicyclohexylcarbodiimide was added into the reaction mixture. 11.7 g of dimethylaminoethyl mercaptan was added into the reaction mixture. The mixture was stirred for 3 hours at RT. The solid is removed by filtration. The chloroform solution was washed with 5% NaHCO3 (2×100 ml) and water (3×100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 6 g of acetic acid was added into the reaction mixture with stirring. Hexane (200 ml) was added. The solid product was collected by filtration. After drying, it yielded 39 g of the desired product (88.5%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C21H26F3N3O3S; MW: 456.52. Calculated % C, 57.88; H, 5.96; F, 12.48; N, 6.14; O, 10.51; S, 7.02. Found % C, 57.84; H, 5.99; F, 12.45; N, 6.15; O, 10.56; S, 7.01. 1H-NMR (400 MHz, D2O): δ: 1.44 (t, 6H), 2.11 (s, 3H), 3.23 (m, 4H), 3.30 (m, 2H), 3.90 (m, 2H), 6.46 (m, 1H), 6.65 (m, 2H), 6.77 (m, 2H), 6.90 (m, 1H), 7.30 (m, 1H), 7.78 (m, 1H).

Preparation of diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH

28.2 g (0.1 mol) of 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylic acid was dissolved in 200 ml of 10% NaHCO3. 100 ml of acetone and 43 g (0.15 mol) of diethylaminoethyl bromide.HBr was added into the mixture and the mixture was stirred for 5 hours at RT. The mixture is extracted with ethyl acetate (2×300 ml). The ethyl acetate solution is dried over anhydrous sodium sulfate. 6 g of acetic acid is added into the solution. The solution was concentrated in vacuo to 100 ml. Then 300 ml of hexane was added into the solution. The solid product was collected by filtration and washed with hexane (3×100 ml). After drying, it yielded 38 g of the desired product (86.1%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C21H26F3N3O4; MW: 441.44. Calculated % C, 57.14; H, 5.94; F, 12.91; N, 9.52; O, 14.50. Found % C, 57.11; H, 5.97; F, 12.92; N, 9.50; O, 14.50. 1H-NMR (400 MHz, D2O): δ: 1.44 (t, 6H), 2.11 (s, 3H), 3.23 (m, 4H), 3.70 (m, 2H), 4.60 (m, 2H), 6.46 (m, 1H), 6.65 (s, 1H), 6.77 (m, 1H), 6.83 (m, 1H), 6.90 (m, 1H), 8.00 (m, 1H), 8.38 (m, 1H).

Preparation of diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH

60 g of Polymer-bound triethylamine (3 mol/g, 100-200 mesh) was suspended in 180 ml of chloroform. 29.6 g (0.1 mol) of 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylic acid was added into the mixture with stirring. 43 g (0.15 mol) of diethylaminoethyl bromide.HBr was added into the mixture and the mixture was stirred for 5 hours at RT. The polymer was removed by filtration and washed with tetrahydrofuran (3×50 ml). 8.2 g (0.1 mol) of sodium acetate was added into the reaction mixture with stirring. The mixture was stirred for 2 h. The solid was removed by filtration and washed with chloroform (3×50 ml). The solution was concentrated in vacuo to 100 ml. Then 300 ml of hexane was added into the solution. The solid product was collected by filtration and washed with hexane (3×100 ml). After drying, it yielded 40 g of the desired product (87.8%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C22H28F3N3O4; MW: 455.47. Calculated % C, 58.01; H, 6.20; F, 12.51; N, 9.23; O, 14.05. Found % C, 57.98; H, 6.23; F, 12.50; N, 9.21; O, 14.08. 1H-NMR (400 MHz, D2O): δ: 1.45 (t, 6H), 2.11 (s, 3H), 2.35 (s, 3H), 3.23 (m, 4H), 3.70 (m, 2H), 4.60 (m, 2H), 6.36 (m, 1H), 6.65 (m, 1H), 6.77 (m, 1H), 6.83 (m, 1H), 8.00 (m, 1H), 8.38 (m, 1H).

ii) Preparation of a HPP from a Parent Drug which Contains at Leas One Non-Carbonyl group.

In certain embodiments, the parent compound having the following

Structure F


Drug———X1H

Structure F

is converted to a HPP of Structure B:

including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

X1 is selected from the group consisting of O, P(O)OR1, NH, NR1 and S;

Z is selected from the group consisting of O and S. (Scheme 2)

In one embodiment of the invention, a HPP having Structure B is prepared according to the conventional organic synthesis by reacting the parent drug or derivatives of the parent compounds of Structure 7 (e.g. acid halides, mixed anhydrides of the parent compounds, etc.):


Drug———X1H

Structure G

wherein X1 is defined as supra,
with compounds of Structure H:

wherein Y, Z, R1, R2, and R3 are defined as supra.

Preparation of 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,1,2-benzothiazine-3-carboxamide 1,1-dioxide.HCL

33.1 g (0.1 mol) of 4-hydroxy-2-methyl-N-2-pyridinyl-2H,1,2-benzothiazine-3-carboxamide 1,1-dioxide was dissolved in 200 ml of acetone and 250 ml of 10% NaHCO3. 22.3 g (0.12 mol) of dimethylaminobutyryl chloride hydrochloride was added into the mixture. The mixture was stirred for 3 hours at RT. The solvents were evaporated off. 500 ml of ethyl acetate was added into the reaction mixture and the mixture was washed with 5% NaHCO3 (1×200 ml) and water (3×100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. HCl gas (4 g) is bubbled into the solution. The solid product was collected by filtration. After drying, it yielded 40 g of the hygroscopic desired product (83.2%). Solubility in water: 250 mg/ml; Elementary analysis: C21H25ClN4O5S; MW: 480.96. Calculated % C, 52.44; H, 5.24; Cl, 7.37; N, 11.65; O, 16.63; S, 6.67. Found % C, 52.40; H, 5.27; Cl, 7.42; N, 11.60; O: 16.70; S, 6.61. 1H-NMR (400 MHz, D2O): δ: 2.00 (m, 2H), 2.23 (m, 2H), 2.46 (s, 3H), 2.85 (s, 6H), 3.18 (m, 2H), 6.60-6.70 (m, 2H), 7.20 (m, 1H), 7.40-7.44 (m, 2H), 7.56 (m, 1H), 7.80 (m, 1H), 8.10 (m, 1H).

Preparation of N-(2-thiazolyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H,1,2-benzothiazine-3-carboxamide 1,1-dioxide.HCl

32.5 g (0.1 mol) of N-(2-thiazolyl)-4-hydroxy-2-methyl-2H,1,2-benzothiazine-3-carboxamide 1,1-dioxide and 16 g (0.1 mol) of diethylaminobutyric acid were dissolved in 300 ml of dichloromethylene. The mixture is cooled to 0° C. with ice bath. 20.6 g (0.1 mol) of N,N′-Dicyclohexylcarbodiimide was added into the reaction mixture. The mixture was stirred for 1 hour at 0° C. and 2 hours at RT. The solid is removed by filtration. The dichloromethylene solution was washed with 5% NaHCO3 (2×100 ml) and water (3×100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. HCl gas (4 g) is bubbled into the solution. The solid product was collected by filtration. After drying, it yielded 37 g of the hygroscopic desired product (76%). Solubility in water: 250 mg/ml; Elementary analysis: C19H23ClN4O5S2; MW: 486.99. Calculated % C, 46.86; H, 4.76; Cl, 7.28; N, 11.50; O, 16.43; S, 13.17. Found % C, 46.83; H, 4.78; Cl, 7.31; N, 11.52; O, 16.41; S, 13.15. 1H-NMR (400 MHz, D2O): δ: 2.01 (m, 2H), 2.22 (m, 2H), 2.44 (s, 3H), 2.85 (s, 6H), 3.18 (m, 2H), 6.50 (m, 1H), 7.20 (m, 1H), 7.40 (m, 1H), 7.50 (m, 1H), 7.58 (m, 1H), 7.85 (m, 1H).

Preparation of 6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide.HCl

36 g (0.1 mol) of 6-chloro-4-hydroxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide.HCl was dissolved in 200 ml of acetone and 200 ml of 10% NaHCO3. 22.3 g (0.12 mol) of dimethylaminobutyryl chloride hydrochloride was added into the mixture and the mixture was stirred for 3 hours at RT. The solvents were evaporated off. 500 ml of ethyl acetate was added into the reaction mixture and the mixture was washed with 10% NaHCO3 (1×500 ml) and water (3×100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. HCl gas is bubbled into the solution. The solid product was collected by filtration. After drying, it yielded 42 g of the hygroscopic desired product (80.5%). Solubility in water: 250 mg/ml; Elementary analysis: C19H22Cl2N4O5S2; MW: 521.44. Calculated % C, 43.76; H, 4.25; Cl, 13.60; N, 10.74; O, 15.34; S, 12.30. Found % C, 43.72; H, 4.27; Cl, 13.67; N, 10.70; O, 15.37; S, 12.27. 1H-NMR (400 MHz, D2O): δ: 2.02 (m, 2H), 2.21 (m, 2H), 2.47 (s, 3H), 2.86 (s, 6H), 3.18 (m, 2H), 6.60-6.70 (m, 2H), 7.10 (s, 1H), 7.44 (m, 1H), 8.10 (m, 1H).

Preparation of 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide.HCL

32.5 g (0.1 mol) of 4-hydroxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide and 16 g (0.1 mol) of diethylaminobutyric acid were dissolved in 300 ml of dichloromethylene. The mixture is cooled to 0° C. with ice bath. 20.6 g (0.1 mol) of N,N′-Dicyclohexylcarbodiimide was added into the reaction mixture. The mixture was stirred for 1 hour at 0° C. and 2 hours at RT. The solid is removed by filtration. The dichloromethylene solution was washed with 5% NaHCO3 (2×100 ml) and water (3×100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. HCl gas (4 g) is bubbled into the solution. The solid product was collected by filtration. After drying, it yielded 39 g of the hygroscopic desired product (80.1%). Solubility in water: 250 mg/ml; Elementary analysis: C19H23ClN4O5S2; MW: 486.99. Calculated % C, 46.86; H, 4.76; Cl, 7.28; N, 11.50, O, 16.43; S, 13.17. Found % C, 46.82; H, 4.77; Cl, 7.30; N, 11.47; O, 16.47; S, 13.15. 1H-NMR (400 MHz, D2O): δ: 2.02 (m, 2H), 2.21 (m, 2H), 2.47 (s, 3H), 2.86 (s, 6H), 3.18 (m, 2H), 6.61-6.70 (m, 2H), 7.30 (d, 1H), 7.45 (m, 1H), 7.60 (d, 1H), 8.11 (m, 1H).

Preparation of 4-N,N-dimethylaminobutyryloxy-2-methyl-N-[5-Methyl-3-isoxolyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide].HCl

32.5 g (0.1 mol) of 4-hydroxy-2-methyl-N-[5-Methyl-3-isoxolyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide].HCl and 16 g (0.1 mol) of diethylaminobutyric acid were dissolved in 300 ml of dichloromethylene. The mixture is cooled to 0° C. with ice bath. 20.6 g (0.1 mol) of N,N′-Dicyclohexylcarbodiimide was added into the reaction mixture. The mixture was stirred for 1 hour at 0° C. and 2 hours at RT. The solid is removed by filtration. The dichloromethylene solution was washed with 5% NaHCO3 (2×100 ml) and water (3×100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. HCl gas (4 g) is bubbled into the solution. The solid product was collected by filtration. After drying, it yielded 37 g of the hygroscopic desired product (78.7%). Solubility in water: 250 mg/ml; Elementary analysis: C19H23ClN4O6S; MW: 470.93. Calculated % C, 48.46; H, 4.92; Cl, 7.53; N, 11.90, O, 20.38; S, 6.81. Found % C, 48.43; H, 4.94; Cl, 7.57; N, 11.86; O, 20.41, S, 6.79. 1H-NMR (400 MHz, D2O): δ: 2.01 (m, 2H), 2.22 (m, 2H), 2.44 (s, 3H), 2.85 (s, 6H), 3.18 (m, 2H), 6.40 (m, 1H), 7.20 (m, 1H), 7.40 (m, 1H), 7.52 (m, 1H), 7.58 (m, 1H), 7.85 (m, 1H).

Example 2

The HPPs have Higher Aqueous Solubility Comparing to their Parent Drugs

HPPs have higher aqueous solubility comparing to their parent drugs (Table 1).

TABLE 1
Solubility of NSAIAs and NSAIA-HPPs
HPP(g/L)Parent Drug(g/L)
diethylaminoethyl acetylsalicylate•AcOH in pH 7>300Aspirin0.01
phosphate buffer
diethylaminoethyl 5-(2,4-difluorophenyl)salicylate•AcOH>400Diflunisal0.05
in water
diethylaminoethyl salicylsalicylate•AcOH>350Salsalate0.07
diethylaminoethyl salicylate•AcOH>400salicylic acid0.1
diethylaminoethyl 2-(ρ-isobutylphenyl) propionate•AcOH>300Ibuprofen0.05
in water
diethylaminoethyl 2-(3-benzoylphenyl)propionate•AcOH>450Ketoprofen0.1
in water
diethylaminoethyl 2-(3-phenoxyphenyl)propionate•AcOH>450Fenoprofen0.1
diethylaminoethyl 2-(6-methoxy-2->450Naproxen0.1,
naphthyl)propionate•AcOH
diethylaminoethyl α-methyl-4-(2->400Suprofen0.1
thienylcarbonyl)benzeneacetate•AcOH,
diethylaminoethyl α-methyl-(p-chlorobenzoyl)-5->450α-methyl-(p-0.2
methoxy-2-methylindole 3-acetate•AcOH,chlorobenzoyl)-5-
methoxy-2-
methylindole 3-
acetic acid
diethylaminoethyl 2-(2-fluoro-4->450Flurbiprofen0.2
biphenylyl)propionate•AcOH,
diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2->350Carprofen0.1
acetate•AcOH,
diethylaminoethyl α-methyl-5H-[1]benzopyrano[2,3->450Pranoprofen0.2
b]pyridine-7-acetate•AcOH,
diethylaminoethyl 2-(4-chlorophenyl)-α-methyl-5->400Benoxaprofen0.1
benzoxazoleacetate•AcOH
diethylaminoethyl α-methyl-4-[(2-methyl-2->450Alminoprofen0.1
propenyl)amino]benzeneacetate•AcOH,
diethylaminoethyl 5-benzoyl-α-methyl-2->400Tiaprofenic acid0.1
thiopheneacetate•AcOH,
diethylaminoethyl 3-chloro-4-(2,5-dihydro-1H-pyrrol->450Pirprofen0.1
1-yl)-α-methyl benzeneacetate•AcOH,
diethylaminoethyl 2-(10,11-dihydro-10->350Zaltoprofen0.1
oxodibenzo(b,f)thiepin-2-yl)propionate•AcOH,
diethylaminoethyl 2-(8-methyl-10,11-dihydro-11->400Bermoprofen0.1
oxodibenz(b,f)oxepin-2-yl)propionate•AcOH,
diethylaminoethyl 2-[4-(2-oxocyclopentyl->350Loxoprofen0.1
methyl)phenyl]propionate•AcOH,
diethylaminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol->400Indoprofen0.1
2-yl)-α-methylbenzeneacetate•AcOH,
diethylaminoethyl α,3-dichloro-4->350Fenclorac0.2
cyclohexylbenzeneacetate•AcOH,
diethylaminoethyl 4,5-Diphenyl-2-oxazole>400Oxaprozin0.1
propionate•AcOH,
diethylaminoethyl 3-(4->400Fenbufen0.1
biphenylylcarbonyl)propionate•AcOH,
diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2->350Orpanoxin0.1
furanpropionate•AcOH,
diethylaminoethyl 5-benzoyl-2,3-dihydro-1H->450Ketorolac0.1
pyrrolizine-1-carboxylate•AcOH,
diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro->350Clidanac0.1
1H-indene-1-carboxylate•AcOH
diethylaminoethyl 1-(p-chlorobenzoyl)-5-methoxy-2->250Indomethacin0.1
methylindole 3-acetate•AcOH
diethylaminoethyl (Z)-5-fluoro-2-methyl-1-[(4->200Sulindac0.1
methylsulfinyl) phenylmethylene]-1H-indene-3-
acetate•AcOH,
diethylaminoethyl 1-methyl-5-(4-methylbenzoyl)-1H->250Tolmetin0.2
pyrrole-2-acetate•AcOH,
diethylaminoethyl 5-(4-Chlorobenzoyl)-1,4-dimethyl->250Zomepirac0.2
1H-pyrrole-2-acetate•AcOH,
diethylaminoethyl 1,8-diethyl-1,3,4,9->250Etodolac0.1
tetrahydropyrano-[3,4-b]indole-1-acetate•AcOH,
diethylaminoethyl 2-amino-3->250Amfenac0.2
benzoylbenzeneacetate•AcOH,
diethylaminoethyl 2-amino-3-(4-bromo->200Bromofenac0.1
benzoyl)benzeneacetate•AcOH,
diethylaminoethyl 3-chloro-4-(2->200Alclofenac0.1
propenyloxy)benzeneacetate•AcOH,
diethylaminoethyl 2-(2,4->200Fenclofenac0.1
dichlorophenoxy)benzeneacetate•AcOH,
diethylaminoethyl 1-(4-chlorobenzoyl-5-methoxy-2->250Acemetacin0.1
methyl-1H-indole-3-acetoxyacetate•AcOH,
diethylaminoethyl 4-(4-chlorophenyl)-2-phenyl-5->150Fentiazac0.1
thiazoleacetate•AcOH,
diethylaminoethyl 3-(4-chlorophenyl)-1-phenyl-1H->200Lonazolac0.1
pyrazole-4-acetate•AcOH,
diethylaminoethyl [(1-benzyl-1H-indazol-3->250Bendazac0.1
yl)oxy]acetate•AcOH,
diethylaminoethyl 6-methoxyl-2-naphthalene-2->2006MNA0.1
acetate•AcOH,
diethylaminoethyl p-isobutylphenylacetate•AcOH,>250Ibufenac0.1
diethylaminoethyl 2[(2,6->300Diclofenac0.1
dichlorophenyl)amino]benzene acetate•AcOH in
water
diethylaminoethyl 2-[(2,3->400Mefenamic acid,<0.1
dimethylphenyl)amino]benzoate•AcOH,
diethylaminoethyl 2-[(2,6-dichloro-3->400Meclofenamic acid<0.1
methylphenyl)amino]benzoate•AcOH,
diethylaminoethyl 2-[[(3->400Flufenamic acid<0.1
(trifluoromethyl)phenyl)amino]benzoate•AcOH
diethylaminoethyl 2-[[3->400Niflumic acid,<0.1
(trifluoromethyl)phenyl]amino]-3-
pyridinecarboxylate•AcOH
diethylaminoethyl 2-[[2-methyl-3->400flunixin,<0.1
(trifluoromethyl)phenyl]amino]-3-
pyridinecarboxylate•AcOH,
diethylaminoethyl 2-[(3-chloro-2->400tolfenamic acid,<0.1
methylphenyl)amino]benzoate,
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2->300Piroxicam<0.1
pyridinyl-2H,1,2-benzothiazine-3-carboxamide 1,1-
dioxide•HCl,
N-(2-thiazolyl)-4-N,N-dimethylaminobutyryloxy-2->300Sudoxiam<0.1
methyl-2H,1,2-benzothiazine-3-carboxamide 1,1-
dioxide•HCl,
6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N->300lornoxicam<0.1
2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-
carboxamide 1,1-dioxide•HCl,
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2->300Tenoxicam<0.1
pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-
carboxamide 1,1-dioxide•HCl,
8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridine-2->300Lornoxicam<0.1
ylamino-methylidene)-3-methyl-2,2-dioxo-2λ6,7-
dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one•HCl
4-N,N-dimethylaminobutyryloxy-2-methyl-N-[5->300Isoxicam<0.1
Methyl-3-isoxolyl-2H-1,2-benzothiazine-3-
carboxamide 1,1-dioxide]•HCl
4-N,N-dimethylaminobutyryloxy-2-methyl-N-(5->300meloxicam<0.1
methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-
carboxamide-1,1-dioxide•HCl

Example 3

HPPs have Higher In Vitro Penetration Rates Across Human Skin Comparing to their Parent Drugs

The penetration rates of HPPs and their parent drugs through human skin are measured in vitro by modified Franz cells. The Franz cells have two chambers, the top sample chamber and the bottom receptor chamber. The human skin tissue (360-400 μm thick) that separates the top and the receptor chambers is isolated from the anterior or posterior thigh areas.

The compound tested (2 mL, 20% in 0.2 M phosphate buffer, pH. 7.4) are added to the sample chamber of a Franz cell. The receptor chamber contains 10 ml of 2% bovine serum albumin in saline which is stirred at 600 rpm. The amount of the tested compound penetrating the skin is determined by high-performance liquid chromatography (HPLC) method. The results are shown in FIG. 1. The apparent flux values of the tested compounds are calculated from the slopes in FIG. 1 and summarized in Table 2.

Because the lowest detectable apparent flux values in this method is 1 μg/cm2/h, parent drugs that shows a apparent flux value less than 1 μg/cm2/h are considered as not detectable for penetrating across the skin tissue. The HPPs of these parent drugs (e.g. aspirin, diflunisal, salsalate, salicylic acid, ketoprofen, fenoprofen, piroxicam, sudoxiam, lornoxicam, tenoxicam, lomoxicam, isoxicam and meloxicam) have detectable penetration across the skin tissue. For the parent drugs that have detectable apparent flux value, their HPPs have higher apparent flux value.

TABLE 2
In vitro Penetration Rate of Prodrug Compounds and their Parent
Compounds
Prodrug compoundsμg/cm2/hParent compoundsμg/cm2/h
diethylaminoethyl acetylsalicylate•AcOH1000Aspirin<1
diethylaminoethyl 5-(2,4-difluorophenyl)salicylate•AcOH100Diflunisal<1
diethylaminoethyl salicylsalicylate•AcOH80Salsalate<1
diethylaminoethyl salicylate•AcOH60salicylic acid<1
diethylaminoethyl 2-(ρ-isobutylphenyl)propionate•AcOH1250Ibuprofen50
diethylaminoethyl 2-(3-benzoylphenyl)propionate•AcOH1150Ketoprofen<1
diethylaminoethyl 2-(3-phenoxyphenyl)propionate•AcOH1250Fenoprofen<1
diethylaminoethyl 2-(6-methoxy-2-3500naproxen30
naphthyl)propionate•AcOH,
diethylaminoethyl α-methyl-4-(2-3000suprofen30
thienylcarbonyl)benzeneacetate•AcOH,
diethylaminoethyl α-methyl-(p-4000α-methyl-(p-30
chlorobenzoyl)-5-methoxy-2-chlorobenzoyl)-5-
methylindole 3-acetate•AcOH,methoxy-2-methylindole
3-acetic acid
diethylaminoethyl 2-(2-fluoro-4-3500flurbiprofen30
biphenylyl)propionate•AcOH,
diethylaminoethyl 6-chloro-α-methyl-9H-4000carprofen40
carbazole-2-acetate•AcOH,
diethylaminoethyl α-methyl-5H-3800pranoprofen30
[1]benzopyrano[2,3-b]pyridine-7-
acetate•AcOH,
diethylaminoethyl 2-(4-chlorophenyl)-α-4000benoxaprofen40
methyl-5-benzoxazoleacetate•AcOH,
diethylaminoethyl α-methyl-4-[(2-methyl-3500alminoprofen30
2-
propenyl)amino]benzeneacetate•AcOH,
diethylaminoethyl 5-benzoyl-α-methyl-2-4200tiaprofenic acid30
thiopheneacetate•AcOH,
diethylaminoethyl 3-chloro-4-(2,5-3500pirprofen30
dihydro-1H-pyrrol-1-yl)-α-methyl
benzeneacetate•AcOH,
diethylaminoethyl 2-(10,11-dihydro-10-3700zaltoprofen30
oxodibenzo(b,f)thiepin-2-
yl)propionate•AcOH,
diethylaminoethyl 2-(8-methyl-10,11-4100bermoprofen40
dihydro-11-oxodibenz(b,f)oxepin-2-
yl)propionate•AcOH,
diethylaminoethyl 2-[4-(2-oxocyclopentyl-3400loxoprofen30
methyl)phenyl]propionate•AcOH,
diethylaminoethyl 4-(1,3-dihydro-1-oxo-4200indoprofen30
2H-isoindol-2-yl)-α-
methylbenzeneacetate•AcOH,
diethylaminoethyl α,3-dichloro-4-3800fenclorac40
cyclohexylbenzeneacetate•AcOH,
diethylaminoethyl 4,5-Diphenyl-2-oxazolepropionate•AcOH,4000oxaprozin30
diethylaminoethyl 3-(4-3600fenbufen40
biphenylylcarbonyl)propionate•AcOH,
diethylaminoethyl 5-(4-chlorophenyl)-4100orpanoxin30
beta-hydroxy-2-furanpropionate•AcOH,
diethylaminoethyl 5-benzoyl-2,3-dihydro-3800ketorolac30
1H-pyrrolizine-1-carboxylate•AcOH,
diethylaminoethyl 6-chloro-5-cyclohexyl-4000clidanac40
2,3-dihydro-1H-indene-1-
carboxylate•AcOH,
diethylaminoethyl 1-(p-chlorobenzoyl)-5-1100Indomethacin10
methoxy-2-methylindole 3-acetate•AcOH
diethylaminoethyl (Z)-5-fluoro-2-methyl-900Sulindac10
1-[(4-methylsulfinyl) phenylmethylene]-
1H-indene-3-acetate•AcOH,
diethylaminoethyl 1-methyl-5-(4-1000Tolmetin10
methylbenzoyl)-1H-pyrrole-2-
acetate•AcOH,
diethylaminoethyl 5-(4-Chlorobenzoyl)-1200Zomepirac10
1,4-dimethyl-1H-pyrrole-2-acetate•AcOH,
diethylaminoethyl 1,8-diethyl-1,3,4,9-1300Etodolac10
tetrahydropyrano-[3,4-b]indole-1-
acetate•AcOH,
diethylaminoethyl 2-amino-3-800Amfenac10
benzoylbenzeneacetate•AcOH,
diethylaminoethyl 2-amino-3-(4-bromo-1100Bromofenac10
benzoyl)benzeneacetate•AcOH,
diethylaminoethyl 3-chloro-4-(2-1000Alclofenac10
propenyloxy)benzeneacetate•AcOH,
diethylaminoethyl 2-(2,4-1500Fenclofenac10
dichlorophenoxy)benzeneacetate•AcOH,
diethylaminoethyl 1-(4-chlorobenzoyl-5-1200Acemetacin10
methoxy-2-methyl-1H-indole-3-
acetoxyacetate•AcOH,
diethylaminoethyl 4-(4-chlorophenyl)-2-1300Fentiazac10
phenyl-5-thiazoleacetate•AcOH,
diethylaminoethyl 2[(2,6-5000Diclofenac20
dichlorophenyl)amino]benzeneacetate•AcOH
diethylaminoethyl 2-[(2,3-2100Mefenamic acid10
dimethylphenyl)amino]benzoate•AcOH,
diethylaminoethyl 2-[(2,6-dichloro-3-2000meclofenamic acid10
methylphenyl)amino]benzoate•AcOH,
diethylaminoethyl 2-[[(3-2200flufenamic acid,10
(trifluoromethyl)phenyl)amino]benzoate•AcOH
diethylaminoethyl 2-[[3-1800niflumic acid,10
(trifluoromethyl)phenyl]amino]-3-
pyridinecarboxylate•AcOH
diethylaminoethyl 2-[[2-methyl-3-1700flunixin10
(trifluoromethyl)phenyl]amino]-3-
pyridinecarboxlate•AcOH,
4-N,N-dimethylaminobutyryloxy-2-1700Piroxicam<1
methyl-N-2-pyridinyl-2H,1,2-
benzothiazine-3-carboxamide 1,1-
dioxide•HCl,
N-(2-thiazolyl)-4-N,N-1500Sudoxiam<1
dimethylaminobutyryloxy-2-methyl-
2H,1,2-benzothiazine-3-carboxamide
1,1-dioxide•HCl,
6-chloro-4-N,N-dimethylaminobutyryloxy-1600lornoxicam<1
2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-
1,2-thiazine-3-carboxamide 1,1-
dioxide•HCl,
4-N,N-dimethylaminobutyryloxy-2-1800Tenoxicam<1
methyl-N-2-pyridinyl-2H-thieno[2,3-e]-
1,2-thiazine-3-carboxamide 1,1-
dioxide•HCl,
8-chloro-(4-N,N-1700Lomoxicam<1
dimethylaminobutyryloxy-pyridine-2-
ylamino-methylidene)-3-methyl-2,2-
dioxo-2λ6,7-dithia-3-
azabicyclo[4,3,0]nona-8,10-dien-5-
one•HCl
4-N,N-dimethylaminobutyryloxy-2-1800Isoxicam<1
methyl-N-[5-Methyl-3-isoxolyl-2H-1,2-
benzothiazine-3-carboxamide 1,1-
dioxide]•HCl
4-N,N-dimethylaminobutyryloxy-2-1900meloxicam<1
methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-
benzothiazine-3-carboxamide-1,1-
dioxide•HCl

Example 4

In Vivo Transportation of Prodrug

A. Transportation of HPPs into Plasma

Tested compounds (20% solution or suspension in 1 mL isopropanol) are administered transdermally to the skin of intact hairless mice. The plasma levels of the parent compounds are determined by HPLC. The results show that HPP are converted to their parent drugs within a short period of time after administration. The peak levels of the active compounds in plasma are reached in less than 60 minutes after the transdermal administration of the HPPs (FIGS. 2a-2j), which is shorter than the time required to reach the plasma peak levels of the parent drugs when the parent drugs are taken orally. The Peak plasma levels of the prodrug compounds and the parent compounds are summarized in Table 3-a.

TABLE 3-a
Plasma concentration of the parent compounds after administration of
prodrug compounds and parent compounds.
tParentt
Prodrug compoundminmg/Lcompound(h)mg/L
diethylaminoethyl acetylsalicylate•AcOH2030Aspirin~20.1
Diethylaminoethyl 5-(2,4-difluorophenyl)salicylate•AcOH3050Diflunisal1-20.2
diethylaminoethyl salicylsalicylate•AcOH3040Salsalate1-20.1
diethylaminoethyl salicylate•AcOH3040salicylic acid1-20.1
diethylaminoethyl 2-(ρ-isobutylphenyl)propionate•AcOH30120Ibuprofen1-22
diethylaminoethyl 2-(3-benzoylphenyl)propionate•AcOH4020Ketoprofen1-21
diethylaminoethyl 2-(3-phenoxyphenyl)propionate•AcOH4020Fenoprofen1-21
diethylaminoethyl 2-(6-methoxy-2-502000naproxen2-410
naphthyl)propionate•AcOH,
diethylaminoethyl α-methyl-4-(2-502000suprofen2-410
thienylcarbonyl)benzeneacetate•AcOH,
diethylaminoethyl α-methyl-(p-502000α-methyl-(p-2-410
chlorobenzoyl)-5-methoxy-2-methylindolechlorobenzoyl)-
3-acetate•AcOH,5-methoxy-
2-
methylindole
3-acetic acid
diethylaminoethyl 2-(2-fluoro-4-502000flurbiprofen2-410
biphenylyl)propionate•AcOH,
diethylaminoethyl 6-chloro-α-methyl-9H-502000carprofen2-410
carbazole-2-acetate•AcOH,
diethylaminoethyl α-methyl-5H-502000pranoprofen2-410
[1]benzopyrano[2,3-b]pyridine-7-
acetate•AcOH,
diethylaminoethyl 2-(4-chlorophenyl)-α-502000benoxaprofen2-410
methyl-5-benzoxazoleacetate•AcOH,
diethylaminoethyl α-methyl-4-[(2-methyl-2-502000alminoprofen2-410
propenyl)amino]benzeneacetate•AcOH,
diethylaminoethyl 5-benzoyl-α-methyl-2-502000tiaprofenic2-410
thiopheneacetate•AcOH,acid
diethylaminoethyl 3-chloro-4-(2,5-dihydro-502000pirprofen2-410
1H-pyrrol-1-yl)-α-methylbenzeneacetate•AcOH,
diethylaminoethyl 2-(10,11-dihydro-10-502000zaltoprofen2-410
oxodibenzo(b,f)thiepin-2-
yl)propionate•AcOH,
diethylaminoethyl 2-(8-methyl-10,11-502000bermoprofen2-410
dihydro-11-oxodibenz(b,f)oxepin-2-
yl)propionate•AcOH,
diethylaminoethyl 2-[4-(2-oxocyclopentyl-502000loxoprofen2-410
methyl)phenyl]propionate•AcOH,
diethylaminoethyl 4-(1,3-dihydro-1-oxo-2H-502000indoprofen2-410
isoindol-2-yl)-α-
methylbenzeneacetate•AcOH,
diethylaminoethyl α,3-dichloro-4-502000fenclorac2-410
cyclohexylbenzeneacetate•AcOH,
diethylaminoethyl 4,5-Diphenyl-2-oxazole502000oxaprozin2-410
propionate•AcOH,
diethylaminoethyl 3-(4-502000fenbufen2-410
biphenylylcarbonyl)propionate•AcOH,
diethylaminoethyl 5-(4-chlorophenyl)-beta-502000orpanoxin2-410
hydroxy-2-furanpropionate•AcOH,
diethylaminoethyl 5-benzoyl-2,3-dihydro-502000ketorolac2-410
1H-pyrrolizine-1-carboxylate•AcOH,
diethylaminoethyl 6-chloro-5-cyclohexyl-502000Clidanac2-410
2,3-dihydro-1H-indene-1-
carboxylate•AcOH,
diethylaminoethyl 1-(p-chlorobenzoyl)-5-5020Indomethacin1-20.1
methoxy-2-methylindole 3-acetate•AcOH
diethylaminoethyl (Z)-5-fluoro-2-methyl-1-5020Sulindac1-20.1
[(4-methylsulfinyl) phenylmethylene]-1H-
indene-3-acetate•AcOH,
diethylaminoethyl 1-methyl-5-(4-5020Tolmetin1-20.1
methylbenzoyl)-1H-pyrrole-2-
acetate•AcOH,
diethylaminoethyl 5-(4-Chlorobenzoyl)-1,4-5020Zomepirac1-20.1
dimethyl-1H-pyrrole-2-acetate•AcOH,
diethylaminoethyl 1,8-diethyl-1,3,4,9-5020Etodolac1-20.1
tetrahydropyrano-[3,4-b]indole-1-
acetate•AcOH,
diethylaminoethyl 2-amino-3-5020Amfenac1-20.1
benzoylbenzeneacetate•AcOH,
diethylaminoethyl 2-amino-3-(4-bromo-5020Bromofenac1-20.1
benzoyl)benzeneacetate•AcOH,
diethylaminoethyl 3-chloro-4-(2-5020Alclofenac1-20.1
propenyloxy)benzeneacetate•AcOH,
diethylaminoethyl 2-(2,4-5020Fenclofenac1-20.1
dichlorophenoxy)benzeneacetate•AcOH,
diethylaminoethyl 1-(4-chlorobenzoyl-5-5020Acemetacin1-20.1
methoxy-2-methyl-1H-indole-3-
acetoxyacetate•AcOH,
diethylaminoethyl 4-(4-chlorophenyl)-2-5020Fentiazac1-20.1
phenyl-5-thiazoleacetate•AcOH,
diethylaminoethyl 3-(4-chlorophenyl)-1-5020Lonazolac1-20.1
phenyl-1H-pyrazole-4-acetate•AcOH,
diethylaminoethyl [(1-benzyl-1H-indazol-3-Bendazac1-20.1
yl)oxy]acetate•AcOH,
diethylaminoethyl 2[(2,6-402100Diclofenac1-21
dichlorophenyl)amino]benzeneacetate•AcOH
diethylaminoethyl 2-[(2,3-5020Mefenamic2-40.1
dimethylphenyl)amino]benzoate•AcOH,acid,
diethylaminoethyl 2-[(2,6-dichloro-3-5020meclofenamic2-40.1
methylphenyl)amino]benzoate•AcOH,acid,
diethylaminoethyl 2-[[(3-5020flufenamic2-40.1
(trifluoromethyl)phenyl)amino]benzoate•AcOHacid,
diethylaminoethyl 2-[[3-5020niflumic acid,2-40.1
(trifluoromethyl)phenyl]amino]-3-
pyridinecarboxylate•AcOH
diethylaminoethyl 2-[[2-methyl-3-5020flunixin,2-40.1
(trifluoromethyl)phenyl]amino]-3-
pyridinecarboxylate•AcOH,
4-N,N-dimethylaminobutyryloxy-2-methyl-5020Piroxicam2-40.1
N-2-pyridinyl-2H,1,2-benzothiazine-3-
carboxamide 1,1-dioxide•HCl,
N-(2-thiazolyl)-4-N,N-5020Sudoxiam2-40.1
dimethylaminobutyryloxy-2-methyl-2H,1,2-
benzothiazine-3-carboxamide 1,1-
dioxide•HCl,
6-chloro-4-N,N-dimethylaminobutyryloxy-5020lornoxicam2-40.1
2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-
1,2-thiazine-3-carboxamide 1,1-
dioxide•HCl,
4-N,N-dimethylaminobutyryloxy-2-methyl-5020Tenoxicam2-40.1
N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-
3-carboxamide 1,1-dioxide•HCl,
8-chloro-(4-N,N-dimethylaminobutyryloxy-5020Lomoxicam2-40.1
pyridine-2-ylamino-methylidene)-3-methyl-
2,2-dioxo-2λ6,7-dithia-3-
azabicyclo[4,3,0]nona-8,10-dien-5-one•HCl
4-N,N-dimethylaminobutyryloxy-2-methyl-5020Isoxicam2-40.1
N-[5-Methyl-3-isoxolyl-2H-1,2-
benzothiazine-3-carboxamide 1,1-
dioxide]•HCl
4-N,N-dimethylaminobutyryloxy-2-methyl-5020meloxicam2-40.1
N-(5-methyl-2-thiazolyl)-2H-1,2-
benzothiazine-3-carboxamide-1,1-
dioxide•HCl

B) Transportation of HPPs Through GI Tract

The in vivo rates of GI tract penetration of 2-(ρ-isobutylphenyl)propionic acid (IBPP) and diethylaminoethyl 2-(ρ-isobutylphenyl)propionate.AcOH (DEAE-IBPP) were compared. The donor consisted of either a 10% suspension of 2-(ρ-isobutylphenyl)propionic acid (IBPP) or 10% solution of diethylaminoethyl 2-(ρ-isobutylphenyl)propionate.AcOH (DEAE-IBPP) in 1 mL of pH 7.4 phosphate buffer were administrated orally to rats. Plasma levels of ibuprofen and diethylaminoethyl 2-(ρ-isobutylphenyl) propionate were determined by a specific high-performance liquid chromatography method. The results were shown in FIG. 2j.

The results show that diethylaminoethyl 2-(ρ-isobutylphenyl)propionate.AcOH penetrates the GI tract is much faster than that ibuprofen does. It takes ˜2 hours for ibuprofen to reach the peak ibuprofen level when it is taken orally, however, it takes only ˜15 min. for diethylaminoethyl 2-(ρ-isobutylphenyl)propionate.AcOH to reach the peak ibuprofen level when it is taken orally.

C) Transportation of HPPs Through the Intercellular and Intracellular Fluids.

Wistar rats were killed with CO2 and 50 mg/kg of diethylaminoethyl salicylic acid citric acid salt was applied to the back (hairs were shaved off) of the died rat which was kept at 37° C. and shaken for 3 h. The organ tissue (˜1 g) was taken out and homogenized immediately in 5 ml of methanol, using a tissue tearor at 30,000 rpm (about 2 min.). The mixture was centrifuged for 5 minutes at 16,000 rpm. The supernatant (2 ml) was collected and evaporated to dryness. The residue was diluted to 0.1 ml and the amounts of diethylaminoethyl acetylsalicylate (DEAE-ASA), diethylaminoethyl salicylate (DEAE-SA), aspirin, and salicylic acid were determined with HPLC. The results are shown in Table 3-b.

TABLE 3-B
The distribution of diethylaminoethyl acetylsalicylate•citric acid salt
and its metabolites in rats' body tissues and plasma.
Prodrug or
metabolitesPlasmaLiverBoneBrain
DEAE-ASA 8 ± 4 μg/ml 7 ± 4 μg/g 6 ± 4 μg/g 5 ± 3 μg/g
Aspirin 2 ± 1 μg/ml 3 ± 2 μg/g 3 ± 1 μg/g 2 ± 1 μg/g
DEAE-SA 10 ± 3 μg/ml11 ± 4 μg/g 5 ± 2 μg/g11 ± 2 μg/g
Salicylic65 ± 10 μg/ml45 ± 8 μg/g35 ± 6 μg/g30 ± 6 μg/g
acid

D) Transportation of HPP Through Blood-Milk Barrier

1 hour after 50 mg/kg of diethylaminoethyl 2-(ρ-isobutylphenyl)propionate. citric acid salt (ibuprofenamine citric acid salt, 10% aqueous solution) were applied to the back (30 cm2) of sheep, 55±8 μg/ml of ibuprofen and 10±5 μg/ml of ibuprofenamine were found out in the milk.

Example 5

Acute Toxicity of HPP and Parent Drug

The acute toxicity of the prodrug compounds and parent compounds are measured by LD50 of rat. The results (Table 4) show that the prodrug compounds are less toxic than the corresponding parent compounds.

TABLE 4
The acute toxicity of HPP and their parent drugs in rats(LD50).
LD50LD50
HPP(g/kg)Parent Drug(g/kg)
diethylaminoethyl acetylsalicylate•AcOH2.3Aspirin1.5
dimethylaminoethyl acetylsalicylate•AcOH2.2Aspirin1.5
diethylaminoethyl 5-(2,4-difluorophenyl)salicylate•AcOH1.0Diflunisal0.5
diethylaminoethyl salicylsalicylate•AcOH2.0Salsalate1.5
diethylaminoethyl salicylate•AcOH1.6salicylic acid1.3
diethylaminoethyl 2-(ρ-isobutylphenyl) propionate•AcOH1.8Ibuprofen1.5
dimethylaminoethyl 2-(ρ-isobutylphenyl) propionate•AcOH1.6Ibuprofen1.5
diethylaminoethyl 2-(3-benzoylphenyl)propionate•AcOH0.3Ketoprofen0.1
diethylaminoethyl 2-(3-phenoxyphenyl)propionate•AcOH1.5Fenoprofen0.8
diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate•AcOH2.2Naproxen1.2
diethylaminoethyl α-methyl-4-(2-0.8Suprofen0.59
thienylcarbonyl)benzeneacetate•AcOH
diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-0.7Carprofen0.40
acetate•AcOH
diethylaminoethyl α-methyl-5H-[1]benzopyrano[2,3-0.75Pranoprofen0.45
b]pyridine-7-acetate•AcOH
diethylaminoethyl 2-(4-chlorophenyl)-α-methyl-5-1.3Benoxaprofen0.80
benzoxazoleacetate•AcOH
diethylaminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-3.5Alminoprofen2.40
yl)-α-methylbenzeneacetate•AcOH
diethylaminoethyl α-methyl-4-[(2-methyl-2-1.1Indoprofen0.70
propenyl)amino]benzeneacetate•AcOH
diethylaminoethyl α,3-dichloro-4-0.6Fenclorac0.43
cyclohexylbenzeneacetate•AcOH
diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-0.2Clidanac0.035
1H-indene-1-carboxylate•AcOH
diethylaminoethyl 1-(p-chlorobenzoyl)-5-methoxy-2-0.1Indomethacin0.013
methylindole 3-acetate•AcOH
diethylaminoethyl (Z)-5-fluoro-2-methyl-1-[(4-0.5Sulindac0.26
methylsulfinyl) phenylmethylene]-1H-indene-3-
acetate•AcOH,
diethylaminoethyl 1-methyl-5-(4-methylbenzoyl)-1H-0.6Tolmetin0.35
pyrrole-2-acetate•AcOH,
diethylaminoethyl 5-(4-Chlorobenzoyl)-1,4-dimethyl-0.2Zomepirac0.027
1H-pyrrole-2-acetate•AcOH,
diethylaminoethyl 1,8-diethyl-1,3,4,9-tetrahydropyrano-0.6Etodolac0.46
[3,4-b]indole-1-acetate•AcOH,
diethylaminoethyl 2-amino-3-1.0Amfenac0.31
benzoylbenzeneacetate•AcOH,
diethylaminoethyl 2-amino-3-(4-bromo-1.6Bromofenac
benzoyl)benzeneacetate•AcOH,
diethylaminoethyl 3-chloro-4-(2-3.0Alclofenac1.05
propenyloxy)benzeneacetate•AcOH,
diethylaminoethyl 2-(2,4-0.2Fenclofenac2.28
dichlorophenoxy)benzeneacetate•AcOH,
diethylaminoethyl 1-(4-chlorobenzoyl-5-methoxy-2-1.2Acemetacin0.024
methyl-1H-indole-3-acetoxyacetate•AcOH,
diethylaminoethyl 4-(4-chlorophenyl)-2-phenyl-5-1.2Fentiazac0.70
thiazoleacetate•AcOH,
diethylaminoethyl 3-(4-chlorophenyl)-1-phenyl-1H-1.2Lonazolac1.0
pyrazole-4-acetate•AcOH,
diethylaminoethyl 2[(2,6-0.80Diclofenac0.45
dichlorophenyl)amino]benzene acetate•AcOH
dimethylaminoethyl 2[(2,6-0.7Diclofenac0.45
dichlorophenyl)amino]benzene acetate•AcOH
diethylaminoethyl 2-[(2,3-0.9Mefenamic0.6
dimethylphenyl)amino]benzoate•AcOH,acid
diethylaminoethyl 2-[(2,6-dichloro-3-1.0Meclofenamic
methylphenyl)amino]benzoate•AcOH,acid
diethylaminoethyl 2-[[(3-0.8Flufenamic0.72
(trifluoromethyl)phenyl)amino]benzoate•AcOHacid
diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-0.75Niflumic acid,0.65
3-pyridinecarboxylate•AcOH
diethylaminoethyl 2-[[2-methyl-3-1.1flunixin,
(trifluoromethyl)phenyl]amino]-3-
pyridinecarboxylate•AcOH,
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-0.55Piroxicam0.36
2H,1,2-benzothiazine-3-carboxamide 1,1-dioxide•HCl,
N-(2-thiazolyl)-4-N,N-dimethylaminobutyryloxy-2-0.67Sudoxiam
methyl-2H,1,2-benzothiazine-3-carboxamide 1,1-
dioxide•HCl,
6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-0.58lornoxicam
pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide
1,1-dioxide•HCl,
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-0.50Tenoxicam
2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-
dioxide•HCl,
8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridine-2-0.61Lornoxicam
ylamino-methylidene)-3-methyl-2,2-dioxo-2λ6,7-dithia-
3-azabicyclo[4,3,0]nona-8,10-dien-5-one•HCl
4-N,N-dimethylaminobutyryloxy-2-methyl-N-[5-Methyl-0.57Isoxicam
3-isoxolyl-2H-1,2-benzothiazine-3-carboxamide 1,1-
dioxide]•HCl
4-N,N-dimethylaminobutyryloxy-2-methyl-N-(5-0.59meloxicam
methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-
carboxamide-1,1-dioxide•HCl

Example 6

Gastroduodenal Bleeding Caused by Oral Administration of HPPs and their Parent Drugs

Rats (10 rats for each compound tested) are orally administered with 100 mg/kg of one HPP or parent drug every day for 21 days. The parent drug groups generate average of 2-5 mg of fecal blood per gram of feces and the HPP groups generate no fecal blood. Results show that no gastroduodenal bleeding is observed from rats that take prodrug compounds, while gastroduodenal bleeding is observed from all rats that take parent compounds at the similar dosage.

Example 7

Analgesic Activities of HPPs and their Parent Drugs

The analgesic activities of the prodrug compounds and parent compounds are determined using the D'Amour-Smith Method (J. Pharmacol. Exp. Ther., 72, 74 (1941)).

After the tested compounds are administered (the dosages for each test compounds are specified in FIG. 3, prodrug compounds are administered orally and transdermally respectively in different groups, while parent compounds are administered orally) to a group of mice (six mice every group), the tails of mice are exposed to heat and the prolongation time of pain threshold is determined. The results show that the same dosage of prodrug compounds has stronger analgesic activities than the corresponding parent compounds. The prodrug compounds show similar analgesic activities when the same dosages are administered orally or transdermally. (FIG. 3)

Acetic acid solution is administered intraperitoneally to a group of mice (6 mice every group) 30 minutes after a test compound administered to the mice at the dosage specified in the tables below. The prodrug compounds are administered either transdermally or orally. The parent compounds are administered orally. The number of writhing that occurred when mice are administered the acetic acid solution are counted, and the rate of inhibition based on the control group which was not pretreated with any test compounds is calculated. The results show that the prodrug compounds have better analgesic activities comparing to their corresponding parent compounds.

Aspirin (ASA, 50 mg/kg and 100 g) was administered to groups B1 and B2 of mice and diethylaminoethyl acetylsalicylate.AcOH (DEAE-ASA, 50 mg and 100 mg/kg) was administered orally to groups C1 and C2. Diethylaminoethyl acetylsalicylate.AcOH (DEAE-ASA, 50 mg and 100 mg/kg) was administered transdermally to groups D1 and D2. The A group is the control group. The test compounds were administered to the mice 30 minutes before the acetic acid solution was administered. The results are shown in Tables 4-12.

TABLE 4
The rate of writhing inhibition by aspirin and its HPP.
Group
AB1B2C1C2D1D2
Dose0501005010050100
(mg/kg)
No. of33.218.213.215.411.014.510.1
Writhing
%456054675670

Diflunisal (50 mg/kg and 100 mg/kg) was administered to groups B1 and B2 of mice, diethylaminoethyl 5-(2,4-difluorophenyl)salicylate.AcOH (50 mg/kg and 100 mg/kg) was administered transdermally to groups C1 and C2 of mice, diethylaminoethyl salicylsalicylate.AcOH (50 mg/kg and 100 mg/kg) was administered transdermally to groups D1 and D2 of mice, and diethylaminoethyl salicylate.AcOH (50 mg and 100 mg/kg) was administered transdermally to groups E1 and E2. The A group is the control group. The test compounds were administered to the mice 30 minutes before the acetic acid solution was administered. The results are shown in Table 5.

TABLE 5
The rate of writhing inhibition by diflunisal and its HPP.
Group
AB1B2C1C2D1D2E1E2
Dose050100501005010050100
(mg/kg)
No. of35.018.113.213.210.214.212.014.011.9
Writh-
ing
%4862627159656066

Ibuprofen (IBPP, 50 mg/kg and 100 mg) was administered to groups B1 and B2 of mice and diethylaminoethyl 2-(ρ-isobutylphenyl)propionate.AcOH (DEAE-IBPP, 50 mg and 100 mg/kg) was administered orally to groups C1 and C2. Diethylaminoethyl 2-(ρ-isobutylphenyl)propionate.AcOH (DEAE-IBPP, 50 mg and 100 mg/kg) was administered transdermally to groups D1 and D2. The A group is the control group. The test compounds were administered to the mice 30 minutes before the acetic acid solution was administered. The results are shown in Table 6.

TABLE 6
The rate of writhing inhibition by ibuprofen and its HPPs.
Group
AB1B2C1C2D1D2
Dose0501005010050100
(mg/kg)
No. of34.217.213.114.110.213.39.8
writhing
%506259706171

Ketoprofen (50 mg/kg) was administered to groups B of mice, fenoprofen (50 mg/kg) was administered to groups C of mice, diethylaminoethyl 2-(3-benzoylphenyl)propionate.AcOH (50 mg/kg) was administered transdermally to groups D of mice, and diethylaminoethyl 2-(3-phenoxyphenyl)propionate.AcOH (50 mg/kg) was administered transdermally to groups E of mice. The A group is the control group. The test compounds were administered to the mice 30 minutes before the acetic acid solution was administered. The results are shown in Table 7.

TABLE 7
The rate of writhing inhibition by fenoprofen,
ketoprofen and their HPPs.
Group
ABCDE
Dose (mg/kg)050505050
No. of Writhing35.018.113.214.214.0
%48625960

Diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH (100 mg/kg, B), diethylaminoethyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH (100 mg/kg, C), diethylaminoethyl α-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH (100 mg/kg, D), diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH (100 mg/kg, E), diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate.AcOH (100 mg/kg, F), diethylaminoethyl α-methyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetate.AcOH (100 mg/kg, G), diethylaminoethyl 2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetate.AcOH (100 mg/kg, H), diethylaminoethyl α-methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH (100 mg/kg, I), diethylaminoethyl 5-benzoyl-α-methyl-2-thiopheneacetate.AcOH (100 mg/kg, J), diethylaminoethyl 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-α-methyl benzeneacetate.AcOH (100 mg/kg, K), diethylaminoethyl 2-(10,11-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH (100 mg/kg, L), diethylaminoethyl 2-(8-methyl-10,11-dihydro-11-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH (100 mg/kg, M), diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH (100 mg/kg, N), diethylaminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate.AcOH (100 mg/kg, O), diethylaminoethyl α,3-dichloro-4-cyclohexylbenzeneacetate.AcOH (100 mg/kg, P), diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH (100 mg/kg, Q), diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH (100 mg/kg, R), diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH (100 mg/kg, S), diethylaminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.AcOH (100 mg/kg, T), diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylate.AcOH (100 mg/kg, U) were administered transdermally the mice 30 minutes before the acetic acid solution was administered. The A group is the control group. The results are shown in Table 8.

TABLE 8
The rate of writhing inhibition by aryl- and heteroarylpropionic acids and
their HPPs.
GroupDose (mg/kg)No. of Writhing%
A035.0
B10017.151
C10015.755
D10013.861
E10015.655
F10014.259
G10016.154
H10017.151
I10015.655
J10013.262
K10014.060
L10014.259
M10013.861
N10015.755
O10013.262
P10015.257
Q10015.755
R10014.259
S10015.655
T10016.154
U10015.257

Diethylaminoethyl 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH (100 mg/kg, B), diethylaminoethyl (Z)-5-fluoro-2-methyl-1-[(4-methylsulfinyl)phenylmethylene]-1H-indene-3-acetate.AcOH (100 mg/kg, C), diethylaminoethyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate.AcOH (100 mg/kg, D), diethylaminoethyl 5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate.AcOH (100 mg/kg, E), diethylaminoethyl 1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetate.AcOH (100 mg/kg, F), diethylaminoethyl 2-amino-3-benzoylbenzeneacetate.AcOH (100 mg/kg, G), diethylaminoethyl 2-amino-3-(4-bromo-benzoyl)benzeneacetate.AcOH (100 mg/kg, H), diethylaminoethyl 3-chloro-4-(2-propenyloxy)benzeneacetate.AcOH (100 mg/kg, I), diethylaminoethyl 2-(2,4-dichlorophenoxy)benzeneacetate.AcOH (100 mg/kg, J), diethylaminoethyl 1-(4-chlorobenzoyl-5-methoxy-2-methyl-1H-indole-3-acetoxyacetate.AcOH (100 mg/kg, K), diethylaminoethyl 4-(4-chlorophenyl)-2-phenyl-5-thiazoleacetate.AcOH (100 mg/kg, L), or diethylaminoethyl 3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-4-acetate.AcOH (100 mg/kg, M) were administered transdermally the mice 30 minutes before the acetic acid solution was administered. The A group is the control group. The results are shown in Table 9.

TABLE 9
The rate of writhing inhibition by aryl- and heteroarylacetic acids and
their HPPs.
GroupDose (mg/kg)No. of Writhing%
A 035.0
B10015.655
C10014.259
D10017.151
E10015.655
F10014.060
G10013.861
H10013.262
I10015.755
J10014.259
K10015.655
L10016.154
M10015.257

Diclofenac (10 mg and 20 mg/kg) was administered to groups B1 and B2 of mice and diethylaminoethyl 2[(2,6-dichlorophenyl)amino]benzene acetate.AcOH (10 mg and 20 mg/kg) was administered orally to groups C1 and C2. Diethylaminoethyl 2[(2,6-dichlorophenyl)amino]benzene acetate.AcOH (10 mg and 20 mg/kg) was administered transdermally to groups D1 and D2. The A group is the control group. The test compounds were administered to the mice 30 minutes before the acetic acid solution was administered. The results are shown in Table 10.

TABLE 10
The rate of writhing inhibition by diclofenac and its HPP.
Group
AB1B2C1C2D1D2
Dose0102010201020
(mg/kg)
No. of34.214.210.112.19.210.38.8
writhing
%58.570.564.673.169.974.3

Diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH (100 mg/kg, B), diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH (100 mg/kg, C), diethylaminoethyl 2-[[(3-(trifluoromethyl)phenyl)amino]benzoate.AcOH (100 mg/kg, D), diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH (100 mg/kg, E), diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH (100 mg/kg, F) were administered transdermally the mice 60 minutes before the acetic acid solution was administered. The group A is the control group. The results are shown in Table 11.

TABLE 11
The rate of writhing inhibition by arylanthranilic acids and their HPPs.
GroupDose (mg/kg)No. of Writhing%
A 035.0
B10015.655
C10014.259
D10016.154
E10015.257
F10015.755

4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,1,2-benzothiazine-3-carboxamide 1,1-dioxide.HCl (50 mg/kg, B), N-(2-thiazoyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H,1,2-benzothiazine-3-carboxamide 1,1-dioxide.HCl (50 mg/kg, C), 6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide.HCl (50 mg/kg, D), 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide.HCl (50 mg/kg, E),8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridine-2-ylamino-methylidene)-3-methyl-2,2-dioxo-2λ6,7-dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one.HCl (50 mg/kg, F), 4-N,N-dimethylaminobutyryloxy-2-methyl-N-[5-Methyl-3-isoxolyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide].HCl (50 mg/kg, G), and 4-N,N-dimethylaminobutyryloxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.HCl (50 mg/kg, H) were administered transdermally the mice 60 minutes before the acetic acid solution was administered. The group A is the control group. The results are shown in Table 12.

TABLE 12
The rate of writhing Inhibition by Oxicams and their HPPs.
GroupDose (mg/kg)No. of Writhing%
A 035.0
B5015.655
C5015.755
D5016.553
E5016.953
F5017.550
G5015.855
H5018.248

Example 8

Antipyretic Activities of Prodrug Compounds Comparing to their Parent Compounds

Rats are administered with sterilized E. coli suspension as a pyrogen. Each group of rats are administered with a prodrug compounds or parent compounds at a dosage specified below. The prodrug compounds are administered either orally or transdermally. The parent compounds are administered orally. Results show that the prodrug compounds have same or better antipyretic activities than their corresponding parent compounds (Tables 13-21).

The control group is group A. 2 hours later, Aspirin (ASA, B1 for 100 mg/kg and B2 for 150 mg/kg) and diethylaminoethyl acetylsalicylate.AcOH (DEAE-ASA, Cl for 100 mg/kg and C2 for 150 mg) were administered orally and diethylaminoethyl acetylsalicylate.AcOH (DEAE-ASA, D1 for 100 mg and D2 for 150 mg/kg) were administered transdermally. The body temperature of rats was taken at 90 min. intervals before and after the administration of the test compounds. The results are shown in the following Table 13.

TABLE 13
Antipyretic activity of aspirin and its HPP.
Compoundt = 0 mint = 90 mint = 180 mint = 270 min
Control group37.32 ± 0.0537.35 ± 0.0437.12 ± 0.0537.08 ± 0.04
(A)
ASA37.22 ± 0.0536.80 ± 0.0536.85 ± 0.0536.81 ± 0.05
(100 mg/kg,
B1)
ASA37.30 ± 0.0636.50 ± 0.0536.59 ± 0.0536.55 ± 0.05
(150 mg/kg,
B2)
DEAE-ASA37.25 ± 0.0936.40 ± 0.1536.50 ± 0.0936.40 ± 0.15
(100 mg/kg,
C1, orally)
DEAE-ASA37.18 ± 0.0736.30 ± 0.1536.28 ± 0.0736.20 ± 0.09
(150 mg/kg,
C2, orally)
DEAE-ASA37.19 ± 0.0736.40 ± 0.0536.38 ± 0.0536.40 ± 0.15
(100 mg/kg,
D1,
transdermally)
DEAE-ASA37.33 ± 0.0536.27 ± 0.1536.26 ± 0.0736.22 ± 0.08
(150 mg/kg,
D2,
transdermally)

The control group is group A. 2 hours later, diflunisal (B1 for 100 mg/kg and B2 for 150 mg/kg) was administered orally and diethylaminoethyl 5-(2,4-difluorophenyl)salicylate.AcOH (C1 for 100 mg/kg and C2 for 150 mg), diethylaminoethyl salicylsalicylate.AcOH (D1 for 100 mg/kg and D2 for 150 mg), and diethylaminoethyl salicylate.AcOH (E1 for 100 mg/kg and E2 for 150 mg) were administered transdermally. The body temperature of rats was taken at 90 min. intervals before and after the administration of the test compounds. The results are shown in Table 14.

TABLE 14
Antipyretic activity of diflunisal and its HPP.
Compoundt = 0 min.t = 90 min.t = 180 min.t = 270 min.
A, Control37.33 ± 0.0537.26 ± 0.0737.32 ± 0.0537.34 ± 0.08
group
B137.25 ± 0.0636.81 ± 0.0536.82 ± 0.0836.78 ± 0.07
(100 mg/kg)
B237.35 ± 0.0936.61 ± 0.0736.56 ± 0.0636.57 ± 0.05
(150 mg/kg)
C137.22 ± 0.0736.42 ± 0.0636.40 ± 0.0536.47 ± 0.08
(100 mg/kg)
C237.26 ± 0.0836.20 ± 0.0536.30 ± 0.0736.31 ± 0.08
(150 mg/kg)
D137.28 ± 0.0636.75 ± 0.0636.78 ± 0.0836.80 ± 0.07
(100 mg/kg)
D237.26 ± 0.0536.45 ± 0.0536.40 ± 0.0736.50 ± 0.05
(150 mg/kg)
E1 (100 mg/kg)37.28 ± 0.0636.85 ± 0.0636.88 ± 0.0836.86 ± 0.07
E2 (150 mg/kg)37.26 ± 0.0536.55 ± 0.0536.60 ± 0.0736.65 ± 0.05

The control group is group A. 2 hours later, ibuprofen (IBPP, B1 for 100 mg/kg and B2 for 150 mg/kg) and diethylaminoethyl 2-(ρ-isobutylphenyl)propionate.AcOH (DEAE-IBPP, C1 for 100 mg/kg and C2 for 150 mg) were administered orally and diethylaminoethyl 2-(ρ-isobutylphenyl)propionate.AcOH (DEAE-IBPP, D1 for 100 mg and D2 for 150 mg/kg) was administered transdermally. The body temperatures of the rats were taken at 90 min. intervals before and after the administration of the test compounds. The results are shown in Table 15.

TABLE 15
Antipyretic activity of ibuprofen and its HPP.
Compoundt = 0 min.t = 90 min.t = 180 min.t = 270 min.
Control group(A)37.35 ± 0.0537.25 ± 0.0737.33 ± 0.0537.32 ± 0.08
IBPP (100 mg/kg, B1)37.25 ± 0.0636.83 ± 0.0536.80 ± 0.0836.78 ± 0.07
IBPP (150 mg/kg, B2)37.35 ± 0.0936.59 ± 0.0736.53 ± 0.0636.55 ± 0.05
DEAE-IBPP37.22 ± 0.0736.40 ± 0.0636.50 ± 0.0536.45 ± 0.08
(100 mg/kg, C1, orally)
DEAE-IBPP37.24 ± 0.0836.30 ± 0.0536.35 ± 0.0736.38 ± 0.08
(150 mg/kg, C2, orally)
DEAE-IBPP37.27 ± 0.0636.30 ± 0.0636.35 ± 0.0836.31 ± 0.07
(100 mg/kg, D1,
transdermally)
DEAE-IBPP37.26 ± 0.0536.25 ± 0.0536.30 ± 0.0736.20 ± 0.05
(150 mg/kg, D2,
transdermally)

The control group is group A. 2 hours later, ketoprofen (50 mg/kg, B) and fenoprofen (50 mg/kg, C) were administered orally and diethylaminoethyl 2-(3-benzoyphenyl)propionate.AcOH (50 mg/kg, D) and diethylaminoethyl 2-(3-phenoxyphenyl)propionate.AcOH (50 mg/kg, E) were administered transdermally. The body temperature of rats was taken at 90 min. intervals before and after the administration of the test compounds. The results are shown in Table 16.

TABLE 16
Antipyretic Activity of ketoprofen and related compounds.
Compoundt = 0 min.t = 90 min.t = 180 min.t = 270 min.
A, Control37.33 ± 0.0537.26 ± 0.0737.32 ± 0.0537.34 ± 0.08
group
B (50 mg/kg)37.25 ± 0.0636.81 ± 0.0536.82 ± 0.0836.78 ± 0.07
C (50 mg/kg)37.22 ± 0.0736.82 ± 0.0636.80 ± 0.0536.77 ± 0.08
D (50 mg/kg)37.28 ± 0.0636.65 ± 0.0636.58 ± 0.0836.60 ± 0.07
E (50 mg/kg)37.28 ± 0.0636.65 ± 0.0636.58 ± 0.0836.56 ± 0.07

The control group is group A. 2 hours later, diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH (100 mg/kg, B), diethylaminoethyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH (100 mg/kg, C), diethylaminoethyl α-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH (100 mg/kg, D), diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH (100 mg/kg, E), diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate.AcOH (100 mg/kg, F), diethylaminoethyl α-methyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetate.AcOH (100 mg/kg, G), diethylaminoethyl 2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetate.AcOH (100 mg/kg, H), diethylaminoethyl α-methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH (100 mg/kg, I), diethylaminoethyl 5-benzoyl-α-methyl-2-thiopheneacetate.AcOH (100 mg/kg, J), diethylaminoethyl 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-α-methyl benzeneacetate.AcOH (100 mg/kg, K), diethylaminoethyl 2-(10,11-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH (100 mg/kg, L), diethylaminoethyl 2-(8-methyl-10,11-dihydro-11-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH (100 mg/kg, M), diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH (100 mg/kg, N), diethylaminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate.AcOH (100 mg/kg, O), diethylaminoethyl α,3-dichloro-4-cyclohexylbenzeneacetate.AcOH (100 mg/kg, P), diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH (100 mg/kg, Q), diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH (100 mg/kg, R), diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH (100 mg/kg, S), diethylaminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.AcOH (100 mg/kg, T), diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylate.AcOH (100 mg/kg, U) were administered transdermally. The body temperature of rats was taken at 90 min. intervals before and after the administration of the test compounds. The results are shown in Table 17.

TABLE 17
Antipyretic Activity of aryl- and heteroarylpropionic acids and their
HPPs.
Compoundt = 0 min.t = 90 min.t = 180 min.t = 270 min.
A (Control37.34 ± 0.0537.36 ± 0.0737.37 ± 0.0537.44 ± 0.08
group)
B (100 mg/kg)37.33 ± 0.0736.80 ± 0.0636.72 ± 0.0536.50 ± 0.08
C (100 mg/kg)37.28 ± 0.0636.65 ± 0.0636.58 ± 0.0836.45 ± 0.07
D (100 mg/kg)37.35 ± 0.0636.71 ± 0.0536.60 ± 0.0836.59 ± 0.07
E (100 mg/kg)37.29 ± 0.0736.82 ± 0.0636.70 ± 0.0536.67 ± 0.08
F (100 mg/kg)37.28 ± 0.0636.68 ± 0.0536.62 ± 0.0836.58 ± 0.07
G (100 mg/kg)37.27 ± 0.0636.76 ± 0.0536.65 ± 0.0836.49 ± 0.07
H (100 mg/kg)37.25 ± 0.0736.82 ± 0.0636.70 ± 0.0536.50 ± 0.08
I (100 mg/kg)37.23 ± 0.0636.69 ± 0.0636.52 ± 0.0836.40 ± 0.07
J (100 mg/kg)37.26 ± 0.0636.65 ± 0.0636.58 ± 0.0836.36 ± 0.07
K (100 mg/kg)37.27 ± 0.0636.68 ± 0.0536.62 ± 0.0836.58 ± 0.07
L (100 mg/kg)37.25 ± 0.0636.71 ± 0.0536.65 ± 0.0836.64 ± 0.07
M (100 mg/kg)37.26 ± 0.0736.80 ± 0.0636.70 ± 0.0536.57 ± 0.08
N (100 mg/kg)37.25 ± 0.0636.71 ± 0.0536.65 ± 0.0836.64 ± 0.07
O (100 mg/kg)37.28 ± 0.0636.65 ± 0.0636.58 ± 0.0836.56 ± 0.07
P (100 mg/kg)37.25 ± 0.0636.75 ± 0.0536.62 ± 0.0836.58 ± 0.07
Q (100 mg/kg)37.24 ± 0.0736.82 ± 0.0636.70 ± 0.0536.67 ± 0.08
R (100 mg/kg)37.23 ± 0.0636.81 ± 0.0536.65 ± 0.0836.61 ± 0.07
S (100 mg/kg)37.29 ± 0.0736.82 ± 0.0636.60 ± 0.0536.67 ± 0.08
T (100 mg/kg)37.22 ± 0.0636.65 ± 0.0636.58 ± 0.0836.51 ± 0.07
U (100 mg/kg)37.25 ± 0.0636.63 ± 0.0636.55 ± 0.0836.51 ± 0.07

The control group is group A. 2 hours later, diethylaminoethyl 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH (100 mg/kg, B), diethylaminoethyl (Z)-5-fluoro-2-methyl-1-[(4-methylsulfinyl)phenylmethylene]-1H-indene-3-acetate.AcOH (100 mg/kg, C), diethylaminoethyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate.AcOH (100 mg/kg, D), diethylaminoethyl 5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate.AcOH (100 mg/kg, E), diethylaminoethyl 1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetate.AcOH (100 mg/kg, F), diethylaminoethyl 2-amino-3-benzoylbenzeneacetate.AcOH (100 mg/kg, G), diethylaminoethyl 2-amino-3-(4-bromo-benzoyl)benzeneacetate.AcOH (100 mg/kg, H), diethylaminoethyl 3-chloro-4-(2-propenyloxy)benzeneacetate.AcOH (100 mg/kg, I), diethylaminoethyl 2-(2,4-dichlorophenoxy)benzeneacetate.AcOH (100 mg/kg, J), diethylaminoethyl 1-(4-chlorobenzoyl-5-methoxy-2-methyl-1H-indole-3-acetoxyacetate.AcOH (100 mg/kg, K), diethylaminoethyl 4-(4-chlorophenyl)-2-phenyl-5-thiazoleacetate.AcOH (100 mg/kg, L), or diethylaminoethyl 3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-4-acetate.AcOH (100 mg/kg, M) were administered transdermally. The body temperature of rats was taken at 90 min. intervals before and after the administration of the test compounds. The results are shown in Table 18.

TABLE 18
Antipyretic Activity of aryl- and heteroarylacetic acids and their HPPs.
Compoundt = 0 min.t = 90 min.t = 180 min.t = 270 min.
A (Control37.33 ± 0.0537.26 ± 0.0737.32 ± 0.0537.34 ± 0.08
group)
B (100 mg/kg)37.35 ± 0.0636.91 ± 0.0536.85 ± 0.0836.79 ± 0.07
C (100 mg/kg)37.28 ± 0.0636.65 ± 0.0536.62 ± 0.0836.58 ± 0.07
D (100 mg/kg)37.27 ± 0.0636.71 ± 0.0536.65 ± 0.0836.59 ± 0.07
E (100 mg/kg)37.21 ± 0.0736.82 ± 0.0636.70 ± 0.0536.70 ± 0.08
F (100 mg/kg)37.23 ± 0.0636.65 ± 0.0636.58 ± 0.0836.60 ± 0.07
G (100 mg/kg)37.22 ± 0.0636.65 ± 0.0536.62 ± 0.0836.58 ± 0.07
H (100 mg/kg)37.25 ± 0.0636.71 ± 0.0536.65 ± 0.0836.64 ± 0.07
I (100 mg/kg)37.23 ± 0.0736.80 ± 0.0636.70 ± 0.0536.67 ± 0.08
J (100 mg/kg)37.22 ± 0.0636.65 ± 0.0636.58 ± 0.0836.56 ± 0.07
K (100 mg/kg)37.21 ± 0.0636.75 ± 0.0536.62 ± 0.0836.58 ± 0.07
L (100 mg/kg)37.23 ± 0.0636.81 ± 0.0536.75 ± 0.0836.71 ± 0.07
M (100 mg/kg)37.22 ± 0.0736.82 ± 0.0636.80 ± 0.0536.77 ± 0.08

The control group is group A. 2 hours later, diclofenac (Ba1 for 10 mg/kg and B2 for 20 mg/kg) was administered orally and diethylaminoethyl 2[(2,6-dichlorophenyl)amino]benzene acetate.AcOH was administered orally (C1 for 10 mg/kg and C2 for 20 mg/kg) and transdermally (D1 for 10 mg/kg and D2 for 20 mg/kg). The body temperatures of rats were taken at 90 min. intervals before and after the administration of the test compounds. The results are shown in Table 19.

TABLE 19
Antipyretic activity of diclofenac and its HPP.
Compoundt = 0 min.t = 90 min.t = 180 min.t = 270 min.
Control37.56 ± 0.0537.55 ± 0.0737.53 ± 0.0537.52 ± 0.08
group (A)
(10 mg/kg, B1)37.56 ± 0.0636.90 ± 0.0536.91 ± 0.0836.92 ± 0.07
(20 mg/kg, B2)37.55 ± 0.0936.60 ± 0.0736.53 ± 0.0636.55 ± 0.05
(10 mg/kg,37.52 ± 0.0736.50 ± 0.0636.60 ± 0.0536.55 ± 0.08
C1, orally)
(20 mg/kg,37.54 ± 0.0836.30 ± 0.0536.35 ± 0.0736.38 ± 0.08
C2, orally)
(10 mg/kg, D1,37.58 ± 0.0636.30 ± 0.0636.35 ± 0.0836.31 ± 0.07
transdermally)
(20 mg/kg, D2,37.59 ± 0.0536.25 ± 0.0536.30 ± 0.0736.20 ± 0.05
transdermally)

The control group is group A. 2 hours later, diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH (100 mg/kg, B), diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH (100 mg/kg, C), diethylaminoethyl 2-[[(3-(trifluoromethyl)phenyl)amino]benzoate.AcOH (100 mg/kg, D), diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH (100 mg/kg, E), diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH (100 mg/kg, F) were administered transdermally. The body temperature of rats was taken at 90 min. intervals before and after the administration of the test compounds. The results are shown in Table 20.

TABLE 20
Antipyretic Activity of arylanthranilic acids and their HPPs.
Compoundt = 0 min.T = 90 min.t = 180 min.t = 270 min.
A37.34 ± 0.0537.36 ± 0.0737.37 ± 0.0537.44 ± 0.08
(Control group)
B (100 mg/kg)37.35 ± 0.0636.71 ± 0.0536.60 ± 0.0836.59 ± 0.07
C (100 mg/kg)37.28 ± 0.0636.68 ± 0.0536.62 ± 0.0836.58 ± 0.07
D (100 mg/kg)37.27 ± 0.0636.76 ± 0.0536.65 ± 0.0836.49 ± 0.07
E (100 mg/kg)37.25 ± 0.0736.82 ± 0.0636.70 ± 0.0536.50 ± 0.08
F (100 mg/kg)37.23 ± 0.0636.69 ± 0.0636.52 ± 0.0836.40 ± 0.07

The control group is group A. 2 hours later, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,1,2-benzothiazine-3-carboxamide 1,1-dioxide.HCl (25 mg/kg, B), N-(2-thiazoyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H,1,2-benzothiazine-3-carboxamide 1,1-dioxide.HCl (25 mg/kg, C), 6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide.HCl (25 mg/kg, D), 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide.HCl (25 mg/kg, E),8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridine-2-ylamino-methylidene)-3-methyl-2,2-dioxo-2λ6,7-dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one.HCl (25 mg/kg, F), 4-N,N-dimethylaminobutyryloxy-2-methyl-N-[5-Methyl-3-isoxolyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide].HCl (25 mg/kg, G), and 4-N,N-dimethylaminobutyryloxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.HCl (25 mg/kg, H) were administered transdermally. The body temperature of the rats was taken at 90 min. intervals before and after the administration of the test compounds. The results are shown in Table 21.

TABLE 21
Antipyretic activity of oxicams and their HPPs.
Compoundt = 0 min.t = 90 min.t = 180 min.t = 270 min.
A (Control37.54 ± 0.0537.66 ± 0.0737.67 ± 0.0537.64 ± 0.08
group)
B (25 mg/kg)37.57 ± 0.0636.51 ± 0.0536.40 ± 0.0636.45 ± 0.07
C (25 mg/kg)37.50 ± 0.0736.61 ± 0.0436.50 ± 0.0736.60 ± 0.05
D (25 mg/kg)37.55 ± 0.0536.66 ± 0.0636.60 ± 0.0636.61 ± 0.07
E (25 mg/kg)37.54 ± 0.0636.61 ± 0.0636.58 ± 0.0836.55 ± 0.05
F (25 mg/kg)37.53 ± 0.0536.57 ± 0.0536.52 ± 0.0736.51 ± 0.06
G (25 mg/kg)37.52 ± 0.0636.62 ± 0.0736.53 ± 0.0636.60 ± 0.05
H (25 mg/kg)37.57 ± 0.0736.53 ± 0.0836.52 ± 0.0836.50 ± 0.07

Example 9

Anti-Inflammatory Activities of HPPs and their Parent Drugs

A carrageenin solution is administered subcutaneously to the foot pads of a group of rats 60 min. after the rats are administered with a test compound. HPP is administered transdermally or orally, and its corresponding parent drug is administered orally. The volume of the hind paw was measured at every hour after the administration of the carrageenin, and the rate of increase in the volume of the paw was calculated and designated as the rate of swelling (%). The results show that HPPs have better anti-inflammatory activities than that of the corresponding parent drugs (FIG. 4). Other compounds of the general “Structure 1” shown similar anti-inflammatory activity.

50 mg/kg of diethylaminoethyl acetylsalicylate.AcOH was administered orally or transdermally to rats and 50 mg/kg of aspirin was administered orally. 60 minutes later, a carrageenin solution was administered subcutaneously to the foot pads of the rats. The volume of the hind paw was measured at every hour after the administration of the carrageenin, and the rate of increase in the volume of the paw was calculated and designated as the rate of swelling (%). The results obtained are shown in FIG. 4a.

50 mg/kg of diethylaminoethyl 5-(2,4-difluorophenyl)salicylate.AcOH was administered orally or transdermally to rats and 50 mg/kg of diflunisal was administered orally. 60 minutes later, a carrageenin solution was administered subcutaneously to the foot pads of the rats. The volume of the hind paw was measured at every hour after the administration of the carrageenin, and the rate of increase in the volume of the paw was calculated and designated as the rate of swelling (%). The results obtained are shown in FIG. 4b.

50 mg/kg of diethylaminoethyl 2-(ρ-isobutylphenyl)propionate.AcOH was administered orally or transdermally to rats and 50 mg/kg of ibuprofen was administered orally. 60 minutes later, a carrageenin solution was administered subcutaneously to the foot pads of the rats. The results obtained are shown in FIG. 4c.

10 mg/kg of diethylaminoethyl 2[(2,6-dichlorophenyl)amino]benzene acetate.AcOH was administered orally or transdermally to rats and 10 mg/kg of diclofenac was administered orally. 60 minutes later, a carrageenin solution was administered subcutaneously to the foot pads of the rats. The volume of the hind paw was measured at every hour after the administration of the carrageenin, and the rate of increase in the volume of the paw was calculated and designated as the rate of swelling (%). The results obtained are shown in FIG. 4d.

50 mg/kg of diethylaminoethyl 2-(3-benzoyphenyl)propionate.AcOH was administered orally or transdermally to rats and 50 mg/kg of ketoprofen was administered orally. 60 minutes later, a carrageenin solution was administered subcutaneously to the foot pads of the rats. The volume of the hind paw was measured at every hour after the administration of the carrageenin, and the rate of increase in the volume of the paw was calculated and designated as the rate of swelling (%). The results obtained are shown in FIG. 4e.

Diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH (100 mg/kg, B), diethylaminoethyl α-methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH (100 mg/kg, C), diethylaminoethyl α-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH (100 mg/kg, D), diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH (100 mg/kg, E), diethylaminoethyl 6-chloro-α-methyl-9H-carbazole-2-acetate.AcOH (100 mg/kg, F), diethylaminoethyl α-methyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetate.AcOH (100 mg/kg, G), diethylaminoethyl 2-(4-chlorophenyl)-α-methyl-5-benzoxazoleacetate.AcOH (100 mg/kg, H), diethylaminoethyl α-methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH (100 mg/kg, I), diethylaminoethyl 5-benzoyl-α-methyl-2-thiopheneacetate.AcOH (100 mg/kg, J), diethylaminoethyl 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-α-methyl benzeneacetate.AcOH (100 mg/kg, K), diethylaminoethyl 2-(10,11-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH (100 mg/kg, L), diethylaminoethyl 2-(8-methyl-10,11-dihydro-11-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH (100 mg/kg, M), diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH (100 mg/kg, N), diethylaminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-α-methylbenzeneacetate.AcOH (100 mg/kg, O), diethylaminoethyl α,3-dichloro-4-cyclohexylbenzeneacetate.AcOH (100 mg/kg, P), diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH (100 mg/kg, Q), diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH (100 mg/kg, R), diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH (100 mg/kg, S), diethylaminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.AcOH (100 mg/kg, T), diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylate.AcOH (100 mg/kg, U) were administered transdermally. Group A is the controlled group. 60 minutes later, a carrageenin solution was administered subcutaneously to the foot pads of the rats. The volume of the hind paw was measured at every hour after the administration of the carrageenin, and the rate of increase in the volume of the paw was calculated and designated as the rate of swelling (%). The results obtained are shown in FIG. 4f-i.

Diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH (100 mg/kg, B), diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH (100 mg/kg, C), diethylaminoethyl 2-[[(3-(trifluoromethyl)phenyl)amino]benzoate.AcOH (100 mg/kg, D), diethylaminoethyl 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH (100 mg/kg, E), diethylaminoethyl 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylate.AcOH (100 mg/kg, F) were administered transdermally. Group A is the controlled group. 60 minutes later, a carrageenin solution was administered subcutaneously to the feet pads of the rats. The volume of the hind paw was measured at every hour after the administration of the carrageenin, and the rate of increase in the volume of the paw was calculated and designated as the rate of swelling (%). The results obtained are shown in FIG. 4j.

Example 10

Antiasthmatic Activities of the Prodrug Compounds

It is also known that a high dose of oral acetylsalicylic acid shows an antireactive-antiasthmatic activity by inhibition of the cyclooxygenase activity (Bianco, Sebastiano, U.S. Pat. No. 5,570,559), Due to their very high membrane penetration rate, these pro-drugs can be used in treating asthma by spraying into the mouth or nose of a host. They can also be used to treat acne due to their anti-inflammatory properties. They can be used for the treatment and prevention of endothelia dysfunction as well.

Example 11

Application of the HPPs in Treating Skin Conditions

HPPs can also be used to treat psoriasis, acne, sunburn or other skin conditions due to inhibition of the cyclooxygenase activity and very high skin penetration rate.

Diethylaminoethyl acetylsalicylate.AcOH is applied to subjects' the sun damaged skin. The treated skin demonstrates an 97% reduction of acne, an 89% reduction in roughness, an 85% reduction in the look of freckles, moles, dark spots, and other discolorations, an 85% reduction in the appearance of fine lines and wrinkles. 92% of the subjects treated experienced improved elasticity and firmness, and 95% experienced overall improvement in texture and tone. The results shown that HPPs of aspirin and related compounds may be used to treat skin conditions.

Example 12

Application of HPPs in Treating Cancer

i) Breast Cancer.

Human breast cancer cells (BCAP-37, 2-3 mm3 of tumor tissue was used in each mouse) are subcutaneously xenografted into the front leg of nude mice (BALB, 12 groups, 7 mice each group). After 14 days, the tumors grow to the size of 50±10 mm3 (0.05 ml). Then 30 μl of 5% (equal to 1.5 mg of the HPPs)diethylaminoethyl acetylsalicylate.acetylsalicylic acid salt (P-1, in acetone); 1-piperidinepropyl 2[(2,6-dichlorophenyl)amino]benzene acetate.AcOH (P-2, in water), 1-pyrrolidinepropyl 2-(3-benzoylphenyl)propionate.AcOH (P-3, in water), 4-piperidinemethyl 2-(3-phenoxyphenyl)propionate.AcOH (P-4, in water), 3-piperidinemethyl 2-(ρ-isobutylphenyl)propionate.AcOH (P-5, in water), diethylaminoethyl 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate-AcOH (P-11, in water), 2-(4-morpholinyl)ethyl (Z)-5-fluoro-2-methyl-1-[(4-methylsulfinyl)phenylmethylene]-1H-indene-3-acetate-AcOH (P-12, in water), diethylaminoethyl

2-(2,4-dichlorophenoxy)benzeneacetate.AcOH (P-19, in water), diethylaminoethyl 2-(8-methyl-10,11-dihydro-11-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH (P-37, in water), 1-pyrrolidinepropyl 2-[[(3-(trifluoromethyl)phenyl)amino]benzoate.AcOH (P-48, in water), 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,1,2-benzothiazine-3-carboxamide 1,1-dioxide.HCl (P-51, in acetone) is topically applied to the human breast cancer cells-implanted area every 8 hours. On day 42, the tumors sizes and weight of the mice are shown in Table 22.

TABLE 22
The tumors size and the weights of the control group and the drug-treated
groups of nude mice on day 42.
HPPControlP-1P-2P-3P-4P-5
Tumor800 ± 100150 ± 50180 ± 50200 ± 50180 ± 50190 ± 50
size (mm3)
Mouse22 ± 2 22 ± 322 ± 221 ± 322 ± 323 ± 2
weight (g)
HPPP-11P-12P-19P-37P-48P-51
Tumor210 ± 100250 ± 50280 ± 50250 ± 50290 ± 50390 ± 50
size (mm3)
Mouse21 ± 2 23 ± 321 ± 223 ± 322 ± 323 ± 2
weight (g)

ii) Colon Cancer.

Human colon cancer cells (LS174J, 2-3 mm3 of tumor tissue was used in each mouse) are subcutaneously xenografted into the front leg of nude mice (BALB). After 7 days, the tumors grow to the size of 55±10 mm3 (0.055 ml). Then about 30 μl of 5% (equal to 1.5 mg of the pro-drugs) diethylaminoethyl acetylsalicylate.acetylsalicylic acid salt (P-1, in acetone); 1-piperidinepropyl 2-[(2,6-dichlorophenyl)amino]benzene acetate.AcOH (P-2, in water), 1-pyrrolidinepropyl 2-(3-benzoylphenyl)propionate.AcOH (P-3, in water), 4-piperidinemethyl 2-(3-phenoxyphenyl)propionate.AcOH (P-4, in water), 3-piperidinemethyl 2-(ρ-isobutylphenyl)propionate.AcOH (P-5, in water), diethylaminoethyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate.AcOH (P-13, in water), 2-(4-morpholinyl)ethyl 2-amino-3-benzoylbenzeneacetate.AcOH (P-16, in water), diethylaminoethyl 2-(10,11-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH (P-36), diethylaminoethyl 2-[(2,3-dimethylphenyl)amino]benzoate.AcOH (P-46, in water), diethylaminoethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.AcOH (P-47, in water), N-(2-thiazoyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H,1,2-benzothiazine-3-carboxamide 1,1-dioxide-HCl (P-52, in acetone) is topically applied to the human colon cancer cells-implanted area every 8 hours. On day 30, the tumors size and mouse weight are shown in Table 23.

TABLE 23
the tumors size and the weight of the control group and the HPP-treated
groups on day 30.
HPPControlP-1P-2P-3P-4P-5
Tumor size (mm3)1300 ± 300420 ± 100480 ± 180500 ± 150480 ± 120390 ± 110
Mouse weight (g)21 ± 222 ± 3 22 ± 2 21 ± 3 22 ± 3 23 ± 2 
HPPP-13P-16P-36P-46P-47P-52
Tumor size (mm3) 610 ± 200550 ± 150480 ± 180650 ± 250490 ± 150690 ± 250
Mouse weight (g)21 ± 223 ± 3 21 ± 2 23 ± 3 22 ± 3 23 ± 2 

The results show that NSAIA-HPPs have very strong anti-tumor activity and have little effect in reducing the treated subjects' body weight.

Example 13

Hypoglycemic Effect of NSAIA-HPPs

HPPs lower blood glucose level in rat models (SLAC/GK, type 2 diabetes, n=7). 50% acetone solution of diethylaminoethyl acetylsalicylate.acetylsalicylic acid salt (P-1, in acetone); 4-acetamidophenyl salicylyldimethylaminobutyrate.HCl (P-6), diethylaminoethyl 5-(2,4-difluorophenyl)acetylsalicylate.5-(2,4-difluorophenyl).acetylsalicylic acid salt (P-8), diethylaminoethyl salicylsalicylate.AcOH (P-9), diethylaminoethyl salicylate.AcOH (P-10), diethylaminoethyl 5-acetamido-acetylsalicylate (P-58), diethylaminoethyl acetylsalicylsalicylate.acetylsalicylsalicylic acid salt (P-59), diethylaminoethyl acetylsalicylsalicylate.acetylsalicylsalicylsalicylic acid salt (P-60) (equal to of 20 mg/kg of NSAIAs) are administered transdermally to the backs (about 1.5 cm2) of rats (fur was shaved) once per day (at 8 am) for 5 weeks. The blood glucose levels are measured once every 3 days at 3 μm (no fasting) from the second week to the fifth week (Table 24). The blood lipid levels are measured at the end of the fifth week (Table 25).

TABLE 24
Anti-diabetes activity of the pro-drugs of NSAIAs
ControlP-1P-6P-8P-9P-10P-58P-59P-60
HPPmmol/Lmmol/Lmmol/Lmmol/Lmmol/Lmmol/Lmmol/Lmmol/Lmmol/L
Baseline15.6 ± 316.1 ± 3 16.7 ± 4 17.1 ± 3 16.5 ± 4 15.8 ± 3 17.1 ± 3 16.3 ± 3 15.5 ± 3 
Average15.9 ± 36.5 ± 18.5 ± 28.1 ± 18.4 ± 18.2 ± 18.4 ± 18.7 ± 18.6 ± 1
Baseline 6.5 ± 16.4 ± 16.8 ± 17.1 ± 16.5 ± 16.8 ± 16.9 ± 17.2 ± 16.6 ± 1
Average 6.6 ± 16.3 ± 16.5 ± 16.8 ± 16.7 ± 16.9 ± 17.1 ± 17.3 ± 17.5 ± 1

The results showed that the NSAIA-HPPs lower blood glucose levels in diabetes rat models effectively and do not affect the blood glucose levels in normal rats. The blood glucose levels of the rats stay at normal level (7-8 mmol/L, no fasting) after the treatment is stopped for 30 days. This means that the HPPS not only lower blood glucose levels, but also may cure diabetes.

TABLE 25
Blood lipid-lowering activity of NSAIA-HPPs.
ControlP-1P-6P-8P-9P-10P-58P-59P-60
Prodrugmmol/Lmmol/Lmmol/Lmmol/Lmmol/Lmmol/Lmmol/Lmmol/Lmmol/L
Cholesterol
(total)
Baseline7.6 ± 0.57.7 ± 0.47.3 ± 0.57.6 ± 0.67.7 ± 0.57.1 ± 0.57.8 ± 0.57.6 ± 0.67.3 ± 0.6
Average7.9 ± 0.54.0 ± 0.34.7 ± 0.45.3 ± 0.34.8 ± 0.44.9 ± 0.45.6 ± 0.45.1 ± 0.35.6 ± 0.3
Cholesterol
(HDL)
Baseline1.4 ± 0.11.4 ± 0.21.3 ± 0.11.6 ± 0.21.3 ± 0.11.6 ± 0.21.3 ± 0.11.6 ± 0.21.3 ± 0.2
Average1.3 ± 0.11.5 ± 0.21.3 ± 0.21.5 ± 0.21.4 ± 0.21.5 ± 0.11.4 ± 0.21.6 ± 0.21.5 ± 0.2
Triglycerides
Baseline5.2 ± 0.75.4 ± 0.55.3 ± 0.55.6 ± 0.55.3 ± 0.55.6 ± 0.65.3 ± 0.55.6 ± 0.55.3 ± 0.6
Average5.5 ± 0.61.5 ± 0.22.3 ± 0.21.9 ± 0.22.4 ± 0.22.5 ± 0.22.4 ± 0.21.9 ± 0.22.5 ± 0.2

The results showed that HPP-NSAIAs lowered blood lipid levels (total cholesterol and triglycerides) in diabetes rat models effectively and do not affect HDL levels.

20% acetone solution of diethylaminoethyl acetylsalicylate.acetylsalicylic acid salt (P-1, in acetone); 4-acetamidophenyl salicylyldimethylaminobutyrate.HCl (P-6), diethylaminoethyl 5-(2,4-difluorophenyl)acetylsalicylate.5-(2,4-difluorophenyl)acetylsalicylic acid salt (P-8), diethylaminoethyl salicylsalicylate.AcOH (P-9), diethylaminoethyl salicylate.AcOH (P-10), diethylaminoethyl 5-acetamido-acetylsalicylate (P-58), diethylaminoethyl acetylsalicylsalicylate. acetylsalicylsalicylic acid salt (P-59), diethylaminoethyl acetylsalicylsalicylate. acetylsalicylsalicylsalicylic acid salt (P-60) (equal to of 20 mg/kg of NSAIAs) were mixed with food and were orally administered to the rats (SLAC/GK, type 2 diabetes, n=7) with food every day for 5 weeks. The blood glucose levels were measured once every 3 days at 3 pm (no fasting) from the second week to the fifth week. The results are shown in Table 26. The blood lipid levels were measured at the end of the fifth week. The results are shown in Table 27.

TABLE 26
Anti-diabetes activity of the NSAIA-HPPs
ControlP-1P-6P-8P-9P-10P-58P-59P-60
Prodrugmmol/Lmmol/Lmmol/Lmmol/Lmmol/Lmmol/Lmmol/Lmmol/Lmmol/L
DiabeticBaseline15.3 ± 316.5 ± 3 16.1 ± 4 16.1 ± 3 16.5 ± 4 15.6 ± 3 17.0 ± 3 15.3 ± 3 16.5 ± 3 
ratsAverage15.6 ± 36.5 ± 17.5 ± 27.3 ± 17.6 ± 17.8 ± 18.4 ± 18.6 ± 17.9 ± 1
NormalBaseline 6.6 ± 16.3 ± 16.5 ± 17.0 ± 16.3 ± 16.7 ± 16.9 ± 17.5 ± 16.8 ± 1
ratsAverage 6.5 ± 16.5 ± 16.4 ± 16.8 ± 16.6 ± 16.9 ± 17.2 ± 17.3 ± 17.3 ± 1

The results showed that the pro-drugs of NSAIAs lowered blood glucose levels in diabetic rat models very effectively and did not affect the blood glucose levels of normal rats when the pro-drugs were taken orally and the dosages are much smaller than that of the parent drugs.

TABLE 27
Blood lipid-lowering activity of the pro-drugs of NSAIAs
ControlP-1P-6P-8P-9P-10P-58P-59P-60
Prodrugmmol/Lmmol/Lmmol/Lmmol/Lmmol/Lmmol/Lmmol/Lmmol/Lmmol/L
Cholesterol
(total)
Baseline7.8 ± 0.67.6 ± 0.47.5 ± 0.47.8 ± 0.67.9 ± 0.57.6 ± 0.57.9 ± 0.57.7 ± 0.67.5 ± 0.5
Average7.9 ± 0.54.1 ± 0.34.9 ± 0.45.7 ± 0.35.6 ± 0.45.2 ± 0.55.8 ± 0.45.7 ± 0.35.5 ± 0.3
Cholesterol
(HDL)
Baseline1.6 ± 0.11.5 ± 0.21.5 ± 0.11.4 ± 0.21.5 ± 0.11.6 ± 0.21.8 ± 0.11.9 ± 0.21.5 ± 0.2
Average1.5 ± 0.11.6 ± 0.21.4 ± 0.21.3 ± 0.21.4 ± 0.21.7 ± 0.11.6 ± 0.21.8 ± 0.21.6 ± 0.2
Triglycerides
Baseline5.5 ± 0.65.7 ± 0.55.5 ± 0.55.6 ± 0.75.8 ± 0.65.7 ± 0.65.5 ± 0.55.4 ± 0.65.2 ± 0.5
Average5.5 ± 0.61.4 ± 0.21.8 ± 0.21.8 ± 0.22.7 ± 0.22.6 ± 0.21.8 ± 0.22.7 ± 0.22.5 ± 0.2

The results showed that the pro-drugs of NSAIAs lowered blood lipid levels (total cholesterol and triglycerides) in diabetic rat models very effectively when the pro-drugs were taken orally and the dosages are much smaller than that of the parent drugs.

The pro-drugs in this invention lower blood glucose levels in mouse models (SLAC:NOD-IDDM, type 1 diabetes, n=7). 50% acetone solution of diethylaminoethyl acetylsalicylate.acetylsalicylic acid salt (P-1, in acetone); 4-acetamidophenyl salicylyldimethylaminobutyrate.HCl (P-6), diethylaminoethyl 5-(2,4-difluorophenyl)acetylsalicylate.5-(2,4-difluorophenyl)acetylsalicylic acid salt (P-8), diethylaminoethyl salicylsalicylate.AcOH (P-9), diethylaminoethyl salicylate.AcOH (P-10), diethylaminoethyl 5-acetamido-acetylsalicylate (P-58), diethylaminoethyl acetylsalicylsalicylate. acetylsalicylsalicylic acid salt (P-59), diethylaminoethyl acetylsalicylsalicylate. acetylsalicylsalicylsalicylic acid salt (P-60) (equal to of 30 mg/kg of NSAIAs) were administered transdermally to the backs (about 1.5 cm2) of mice (fur was shaved) once per day (at 8 am) for 7 weeks. The blood glucose levels were measured once every 3 days at 3 pm (no fasting) from the fourth week to the seventh week. The results are shown in table 28.

TABLE 28
Anti-diabetes (type I) activity of the pro-drugs of NSAIAs
ControlP-1P-6P-8P-9P-10P-58P-59P-60
Prodrugmmol/Lmmol/Lmmol/Lmmol/Lmmol/Lmmol/Lmmol/Lmmol/Lmmol/L
Baseline28.6 ± 526.1 ± 527.7 ± 429.1 ± 526.5 ± 425.8 ± 327.1 ± 324.3 ± 325.5 ± 3
Average32.9 ± 5 6.5 ± 1 9.5 ± 2 9.1 ± 1 9.4 ± 1 8.2 ± 1 7.9 ± 1 8.7 ± 1 8.6 ± 1

The results showed that the pro-drugs of NSAIAs lowered blood glucose levels in diabetic (type I) mouse models effectively.

Example 14

NSAIA-HPPs Treat Psoriasis, Discoid Lupus Erythematosus, Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS) in Biological System

Heavy suspensions of Malassezia [Rosenberg, E. W., et al., Mycopathologia, 72, 147-154 (1980)] were applied to the shaved skin on the backs of the Chinese white rabbits (n=4×6) twice (at 7 am and 7 pm) per day for 2 weeks, lesions similar to psoriasis resulted. Then a 5% aqueous solution of 3-piperidinemethyl 2-(p-isobutylphenyl)propionate.AcOH (P-5), diethylaminoethyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate.AcOH (P-13), diethylaminoethyl 5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate.AcOH (P-14), diethylaminoethyl 1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetate.AcOH (P-15), diethylaminoethyl 2-amino-3-(4-bromo-benzoyl)benzeneacetate.AcOH (P-17)diethylaminoethyl 3-chloro-4-(2-propenyloxy)benzeneacetate.AcOH (P-18), diethylaminoethyl 1-(4-chlorobenzoyl-5-methoxy-2-methyl-1H-indole-3-acetoxyacetate.AcOH (P-20), diethylaminoethyl 4-(4-chlorophenyl)-2-phenyl-5-thiazoleacetate.AcOH (P-21), diethylaminoethyl 3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-4-acetate.AcOH (P-22) were applied to the same areas 3 hours (10 am and 10 pm) after the application of heavy suspensions of Malassezia (7 am and 7 pm). 10 days after the application of these pro-drugs, the lesions were resolved.

For evaluation of anti-lupus erythematosus activity, 5% diethylaminoethyl acetylsalicylate.acetylsalicylic acid salt (P-1, in acetone, 30 mg/kg) or 3-piperidinemethyl 2-(ρ-isobutylphenyl)propionate.AcOH (P-5, in water, 30 mg/kg) were topically applied to the skin on the backs of mice (MRL/LPR, n=5×3) with discoid lupus erythematosus and systemic lupus erythematosus twice per day. After 6 weeks, all skin lesions and lupus nephritis were resolved in the pro-drug treated mice, but the condition of the control mice were getting worse.

These results suggest that these pro-drugs of NSAIAs are promising agents for the treatment of psoriasis, discoid lupus erythematosus, systemic lupus erythematosus (SLE), multiple sclerosis (MS) and other autoimmune diseases in human.

Example 15

NSAIA-HPPs Treat Thrombotic Activity and Embolization-Associated Thrombus Propagation in Biological Subject

Eighteen Chinese White rabbits weighing between 3.0 and 3.5 kg (aged 6-7 months) were selected and divided into three groups (control, P-1 and P-10 groups, n=6). One hour before the experiment, thrombi were made by aspirating venous blood (1 ml) into a sterilized bottle to clot. To avoid fragmentation and slow lysis, the autologous blood clots were stabilized in temperature-controlled (70□) distilled water for 10 min. After anesthesia, the femoral veins were exposed and distally isolated, and autologous blood clots (0.05 g/kg) were injected through an indwelling catheter (20GA), which had been placed in the femoral vein isolated earlier. 50% acetone solution of diethylaminoethyl acetylsalicylate.acetylsalicylic acid salt (P-1, in acetone, 20 mg/kg) and diethylaminoethyl acetylsalicylsalicylate. acetylsalicylsalicylic acid salt (P-59, 20 mg/kg) were topically applied to the back of the rabbits. After 2 days, rabbits were euthanized with an excessive intravenous injection of sodium amobarbital (60 mg/kg). The lungs and hearts were isolated to observe whether thrombi were present in the pulmonary arteries. The lungs were immersed in 10% formalin for 24 h. Consecutive transverse sections along the obstructed pulmonary arteries were paraffin-embedded and stained with hematoxylin-eosine. In the control group, platelet thrombus and mixed thrombus surrounded the infused clots, which were present in large-sized vessels as well and stretched the vessel walls in both proximal and distal directions. There was excessive proliferation of endothelial cells and fibrocytes in these vessels. Additionally, there was acute pulmonary congestion. In the P-1 and P-59 groups, both lung tissue and vascular walls were normal. The results showed that thrombotic activity and that embolization-associated thrombus propagation can be prevented by these pro-drugs of NSAIAs. These pro-drugs can be very useful for preventing and treating blood clots—a major cause of strokes, heart attacks and organ transplant rejection.

Thrombosis was induced by electrical stimulation (1 mA for 3 minutes) of the carotid artery in spontaneously hypertensive and stroke prone rats (SLAC/SHRSP) by using a thrombosis formation instrument (YLS-14A, Shandong Academy of Medical Sciences, Shandong, China). The rats (Spragu Dawley, 25 weeks old, 380-450 g) were divided into 3 groups randomly, group A is the control group, groups B and C are aspirinamine-treated group. In group B, 100 mg/kg of aspirinamine citric acid salt (10% in water) was applied to the rats' back skin (˜5 cm2, fur was cut off) 2 hour before the operation and 1 hour after the operation, then 50 mg/kg of the drug was applied to the back of rats twice per day. In group C, 50 mg/kg of aspirinamine was applied to the back of rats twice per day starting from 24 hours after the operation. The recovery of motor functions of rats was evaluated every day. The operation process is outlined in the Method section in the supporting online materials. The HPP of aspirin is effective to protect rats from stroke without bleeding problem (Table 29), the HPP of aspirin is also capable of reversing paralysis from post-stroke rat without bleeding problem (Table 30). The HPP of aspirin is the first drug which can reverses paralysis from post-stroke.

TABLE 29
Anti-stroke activity by aspirinamine
Stroke-free ratsStroke-free ratsStroke-free rats
(2 hours)(1 day)(7 days)
Control group0/100/8 0/8
(A)(1 died)
Treated group8/109/1010/10
(B)

TABLE 30
Alleviation of the effects of strokes by aspirinamine
Weight
Stroke-Stroke-WeightStroke-WeightStroke-Loss
free ratsfree ratsLossfree ratsLossfree rats(14
(3 hrs)(2 day)(3 days)(7 day)(7 days)(14 days)days)
Control0/100/10−25 +/− 8%0/10−22 +/− 5% 1/10−18 +/− 6%
group(2 died)(1 more
died)
Treated0/104/10−13 +/− 7%9/10 −7 +/− 4%10/10 −4 +/− 2%
group

Example 15

Anti-Hypertensive Activity of HPP-NSAIA

20 Spontaneously hypertensive rats (SLAC/SHR, 19 weeks old, 300-350 g) were divided into 2 groups randomly. In group A, pure water (0.5 ml) was applied to the rats' back skin (˜5 cm2, fur was cut off) once per day for 6 weeks. In groups B, 50 mg/kg of aspirinamine citric acid salt (10% in water) was applied to the rats' back skin (˜5 cm2, fur was cut off) once per day. The aspirin-HPP shows anti-hypertensive activities. (Table 31). And the other NSAIA-HPPs have the same anti-hypertensive activities.

TABLE 31
Anti-hypertensive activity of diethylaminoethyl acetylsalicylate•citric
acid
Blood pressure (mmHg)Blood pressure (mmHg)
(week 0)(week 2 to week 6)
SystolicdiastolicSystolicdiastolic
Group A181.4 ± 16.7115.2 ± 15.1183.1 ± 15.7116.2 ± 13.3
Group B184.6 ± 15.1118.2 ± 13.1115.4 ± 14.683.5 ± 12.1

Hypertension patients' blood pressure is controlled by transdermally administering 100 mg of atenolol HCl salt in 1 ml of pure water per day without side effect of hypotension. 20 Hypertension patents were divided to 2 groups. Group A is control group (n=10, 1 ml of water was administrated to the chest of patients once per day) and group B is atenolol treated group (n=10, 100 mg of atenolol HCl salt was administrated to the chest of patients once per day) (Table 32).

TABLE 32
Anti-hypertension effect of atenolol which was administrated
transdermally
Blood Pressure (mmHg)Blood pressure(mmHg)
(before treatment)(2 weeks after treatment)
Group A162 ± 27/110 ± 21128 ± 15/81 ± 12 
Group B160 ± 22/110 ± 20163 ± 28/113 ± 23

Example 16

Anti-Parkinson's Disease Activity of NSAIA-HPP

Male C57/BL6 mice (24-26 g) were divided into 3 groups. Group A mice were i.p. injected 0.4% sodium carboxymethylcellulos (15 ml/kg per day) for 7 days. Group B and C mice were i.p. injected N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg per day) for 7 days. The mice were divided into 2 groups. In groups A and B, 0.1 ml of pure water was applied transdermally to the neck of mice once per day for 14 days. In group C, 30 mg/kg of diethylaminoethyl acetylsalicylate.citric acid (aspirinamine) in 0.1 ml of water was applied transdermally to the neck of mice once per day for 14 days. All mice were killed after the last treatment and the brain tissues were quickly frozen at −80° C. The contents of dopamine (DA) in the striatum were determined with spectrofluorophotometer (λEx=310 nm, λEm=390 nm, RF-5000), 5-HT (λEx=355 nm, λEm=495 nm), and noradrenaline (NA) (λEx=400 nm, λEm=500 nm). The contents of malondialdehyde (MDA) in the SN were measured with the thiobarbituric acid-reaction to indicate the LPO, and contents of glutathione (GSH) in the substantia nigra (SN) were based on the dithionitrobenzonic acid (DTNB) determination. The contents of GABA and Glu in the striatum and SN were shown by high performance amino acid auto-analyser. The results are shown in Table 33. Effects of diethylaminoethyl acetylsalicylate.citric acid on the contents of DA, NA, and 5-HT The content of DA, NA, and 5-HT in the striatum was significantly decreased in MPTP group compared with control group (P<0.05, n=10). Diethylaminoethyl acetylsalicylate.citric acid (30 mg/kg transdermally) increased DA, NA, and 5-HT contents compared with model group (P<0.05, n=10) (Table 33).

TABLE 33
Effects of diethylaminoethyl acetylsalicylate•citric acid on the
concentration DA, NA, and 5-HT in the striatum of PD mice induced
by MPTP. n = 10.
DANA5-HT
Groupμg/g wet tissue
Control885 ± 86618 ± 55306 ± 17
MPTP + water 515 ± 103419 ± 57248 ± 22
MPTP + aspirinamine817 ± 89602 ± 55302 ± 29
(30 mg/kg)
Mean ± SD.
bP < 0.05 vs the control group.
eP < 0.05 vs MPTP group.

Effects of Diethylaminoethyl Acetylsalicylate.Citric Acid on the Contents of MDA and GSH.

The level of nigral GSH in model group was markedly decreased (P<0.01, n=10) and the contents of nigral MDA was increased compared with those in control group (P<0.01, n=10). Diethylaminoethyl acetylsalicylate.citric acid markedly lowered the MDA level while relatively increased the GSH level in PD model (P<0.01, n=10). The results were shown in Table 34.

TABLE 34
Effects of diethylaminoethyl acetylsalicylate•citric acid on the
concentration GSH (μg/g protein) and MDA (μmol/g protein)
in the substantia nigra of PD mice induced by MPTP. n = 10.
GroupGSHMDA
Control152 ± 1213 ± 3
MPTP + water101 ± 1721 ± 4
MPTP + aspirinamine (30 mg/kg)143 ± 1314 ± 4
Mean ± SD.
P < 0.01 vs control group
P < 0.01 vs MPTP group.

Effect of Diethylaminoethyl Acetylsalicylate.Citric Acid on the Contents of GABA and Glu.

MPTP increased the striatal GABA level (P<0.01, n=10) while decreased GABA in the SN(P<0.05, n=10) compared with control group, which were reversed by diethylaminoethyl acetylsalicylate.citric acid (30 mg/kg). However, modafinil did not change the increase of nigrostriatal Glu release induced by MPTP (Table 35).

TABLE 35
Effects of diethylaminoethyl acetylsalicylate•citric acid on the
concentration of GABA (μmol/g wet tissue) and Glu in the
substantia nigra and striatum of PD mouse induced by MPTP.
n = 10.
Substantia
nigraStriatum
GroupGABAGluGABAGlu
Control5.1 ± 0.527.1 ± 2.54.7 ± 1.724.1 ± 2.6
MPTP + water2.2 ± 0.434.5 ± 2.78.4 ± 1.733.2 ± 4.5
MPTP + aspirinamine4.7 ± 0.529.5 ± 2.44.9 ± 1.626.5 ± 2.7
(30 mg/kg)
Mean ± SD.
P < 0.01 vs control group.
P > 0.05,
P < 0.05,
P < 0.01 vs MPTP group.

The contents of striatal NA and 5-HT in the MPTP mice were markedly lower than those of the normal mice, and the NSAIA-HPP treatment increased striatal DA, NA, and 5-HT levels. It can improve or reverse the progress of Parkinson's disease. The NSAIA-HPP also inhibited striatal GABA release in PD model. The NSAIA-HPP prevent the neurotoxicity of MPTP by anti-oxidation and modulation of the striatal NA and 5-HT and nigrostriate GABAergic activity. Therefore a NSAIA-HPP may be used for the treatment of Parkinson's disease.

Example 17

Anti-Alzheimer Disease Activity of Diethylaminopropyl Acetylsalicylate.HCl was Tested with Tg2576 Mouse Model of Alzheimer disease

The pathology of Alzheimer's disease (AD) shows a significant correlation between β-amyloid peptide (AβP) conformation and the clinical severity of dementia. For many years, efforts have been focused on the development of inhibitors of β-amyloid (A β) formation and its related neurotoxic effects. To determine the effect of diethylaminopropyl acetylsalicylate. HCl on in vivo Aβ accumulation, we administered transdermally diethylaminopropyl acetylsalicylate. HCl (50 mg/kg in water) to the Tg2576 mouse model of AD over 2 months resulted in a significant, non-overlapping 70-80% reduction in the number of senile plaques, one of the pathological hallmarks of AD. Three-month-old female transgenic mice overexpressing the human APP gene containing the Swedish mutation that causes familial AD (Tg2576 line) were used for testing the effects of diethylaminopropyl acetylsalicylate.HCl in vivo. 20 Tg2576 mice were divided into 2 groups. In group A (n=10), 0.2 ml of pure water was applied transdermally to the back of mouse once per day for 2 months. In group B (n=10), 50 mg/kg of diethylaminopropyl acetylsalicylate.HCl in 0.2 ml of pure water was applied to the back of mouse once per day for 2 months. Then the animals were killed and their brains were removed for analysis. For Aβ analysis, hemibrains were dounce homogenized in 70% formic acid at 150 mg tissue/ml formic acid solution. Homogenates were transferred to a chilled ultracentrifuge and were then spun at 100,000 g for 1 h at 4° C. Supernatants were collected and neutralized with formic acid neutralization buffer (1.0 M Tris base, 0.5 M NaH2PO4, and 0.05% NaN3; 1:20) for Aβ quantitation by ELISA. Aβ40 and Aβ42 were assayed by ELISA. Four individual experiments were performed. To compare across studies, the values for an individual study were normalized using the values obtained for the control animals included in each study. Values represent the mean±SE for the n number shown, after normalizing. As shown in table 36. The transdermal treatment of diethylaminopropyl acetylsalicylate.HCl (50 mg/kg) resulted in a significant reduction (70%) in Aβ42 concentration in the brain.

TABLE 36
The effect of diethylaminopropyl acetylsalicylate•HCl on the Aβ42
concentration.
diethylaminopropyl
acetylsalicylate•HCl
GroupControl (only water)(50 mg/kg)
Aβ42 concentration7.8 ± 0.42.3 ± 0.3
(pmol/g tissue)

Studies in the Tg2576 mouse model have indicated that transdermally administered 50 mg/kg of diethylaminopropyl acetylsalicylate.HCl results in a significant reduction (70%) the amount of Aβ detected in the brains of these animals at 2 months administration. To determine if the transdermal administration of diethylaminopropyl acetylsalicylate.HCl has beneficial functional consequences, we tested 2 months of diethylaminopropyl acetylsalicylate.HCl (50 mg/kg) in the transgenic model for Alzheimer's disease in which mice develop learning deficits as amyloid accumulates. The results show that diethylaminopropyl acetylsalicylate.HCl protects transgenic mice from the learning and age-related memory deficits that normally occur in this mouse model for Alzheimer's disease. In the diethylaminopropyl acetylsalicylate.HCl (50 mg/kg) treated group, all mice performed superbly on the radial-arm water-maze test of working memory and untreated transgenic mice show memory deficits. The diethylaminopropyl acetylsalicylate.HCl treated transgenic mice showed cognitive performance superior to that of the control transgenic mice and, ultimately, performed as well as nontransgenic mice. This therapeutic approach can thus prevent and treat Alzheimer's dementia.

Example 18

Anti-Glaucoma Activity of NSAIA-HPP

The ability of diethylaminoethyl acetylsalicylate.HCl to reduce intraocular pressure (IOP) was evaluated in cats with ocular hypertension produced by previously done laser trabeculoplastry. IOP was determined with a pneumatonometer after light corneal anesthesia with dilute proparacaine. 14 Cats were divided into 2 groups. Baseline IOP was determined prior to treatment with the test compound aqueous solution. In group A, 0.5 ml of water was applied transdermally to the area around eye (outside) of cat twice per day for 10 days. In group B, 30 mg/kg of diethylaminoethyl acetylsalicylate.HCl the area around eye (outside) of cat trice per day for 10 days. The results are shown in Table 37.

TABLE 37
Intraocular pressure reduction by diethylaminoethyl
acetylsalicylate•HCl.
End of treatment (day
GroupBase-line10)
A (only water)23.2 ± 0.622.2 ± 0.5
B (drug treated)24.1 ± 0.716.1 ± 0.5

Diethylaminoethyl acetylsalicylate.HCl shows very strong anti-glaucoma activity in animal model.

Example 19

NSAIA-HPP can be Used to Treat Spinal Cord Injury in which the Healing is Stopped by the Protected Scars Around the Injured Spinal Cord

A group of rat was anesthetized with chloral hydrate, the spinal cord of rats was hit to induce spinal cord injury. At the next day, 20 completely paralyzed rats were divided into 2 groups. In group A (n=10), 0.2 ml of pure water was applied transdermally to the area of injury (˜2×3 cm2) twice per day for 1 months. In group B (n=10), 5 mg of diethylaminopropyl acetylsalicylate.HCl in 0.2 ml of pure water was applied to the area of injury (˜2×3 cm2) twice per day for 1 months. After the treatment, all rats (10/10) in control group (group A) were still completely paralyzed. We were excited to see that all rats (10/10) in the diethylaminopropyl acetylsalicylate.HCl treated group (group B) could walk. 4 Rats of them were completely normal and other 6 rats walked more slowly and less confidently than their injury. This therapeutic approach can treat spinal cord injury in humans and animals.

Example 20

The NSAIA-HPP is Effective in Treating Wounds with Shrunk Scar after Healing

Chinese white rabbits were divided into 5 groups and hairs on the back of rabbits were removed (5×5 cm2). After anesthesia, The average scar area of the pro-drugs of NSAIAs (5% aqueous solution of 3-piperidinemethyl 2-(ρ-isobutylphenyl)propionate.HCl, diethylaminoethyl 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate.HCl, diethylaminoethyl 5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate.HCl, diethylaminoethyl 1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetate.HCl, diethylaminoethyl 2-amino-3-(4-bromo-benzoyl)benzeneacetate.HCl, diethylaminoethyl 3-chloro-4-(2-propenyloxy)benzeneacetate.HCl, diethylaminoethyl 1-(4-chlorobenzoyl-5-methoxy-2-methyl-1H-indole-3-acetoxyacetate.HCl, diethylaminoethyl 4-(4-chlorophenyl)-2-phenyl-5-thiazoleacetate.HCl, or diethylaminoethyl 3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-4-acetate.HCl were applied to the nearby area of wounds) areas treated rabbits is only a third of that of the control rabbits from same size cuts wounds in the Chinese white rabbit model and the scars are as soft as normal unscarred tissues.