Title:
Arylindenopyridines and related therapeutic and prophylactic methods
Kind Code:
A1


Abstract:
This invention provides novel arylindenopyridines of the formula: embedded image and pharmaceutical compositions comprising same, useful for treating disorders ameliorated by reducing PDE activity in appropriate cells. This invention also provides therapeutic and prophylactic methods using the instant pharmaceutical compositions.



Inventors:
Heintzelman, Geoffrey R. (Annandale, NJ, US)
Averill, Kristin M. (High Bridge, NJ, US)
Dodd, John H. (Stockton, NJ, US)
Application Number:
11/196154
Publication Date:
01/12/2006
Filing Date:
08/03/2005
Primary Class:
Other Classes:
546/79
International Classes:
C07D221/22; A61K31/473; C07D221/16; C07D401/04; C07D401/12; C07D405/04; C07D409/04; C07D491/04
View Patent Images:



Primary Examiner:
SHIAO, REI TSANG
Attorney, Agent or Firm:
JOSEPH F. SHIRTZ (NEW BRUNSWICK, NJ, US)
Claims:
1. A compound having the structure embedded image wherein (a) R1 is selected from the group consisting of: (i) —COR5, wherein R5 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl; wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR20R21 taken together form a heterocycle or heteroaryl; (ii) COOR6, wherein R6 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl; wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR20R21 taken together form a heterocycle or heteroaryl; (iii) cyano; (iv) a lactone or lactam formed with R4; (v) —CONR7R8 wherein R7 and R8 are independently selected from H, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl; wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl, or R7 and R8 taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group; (b) R2 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl and optionally substituted C3-7 cycloalkyl; or R2 is embedded image (c) R3 is from one to four groups independently selected from the group consisting of: (i) hydrogen, halo, C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, aryl, heteroaryl, and heterocyclyl; (ii) —NR10R11 wherein R10 and R11 are independently selected from H, C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R10 and R11 taken together with the nitrogen form a heteroaryl or heterocyclyl group; (iii) —NR12COR13 wherein R12 is selected from hydrogen or alkyl and R13 is selected from hydrogen, alkyl, substituted alkyl, C1-3 alkoxyl, carboxyalkyl, R30R31N (CH2)p—, R30R31NCO(CH2)p—, aryl, arylalkyl, heteroaryl and heterocyclyl or R12 and R13 taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein , R30 and R31 are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6, (d) R4 is selected from the group consisting of (i) hydrogen, (ii) C1-3 straight or branched chain alkyl, (iii) benzyl and (iv) —NR13R14, wherein R13 and R14 are independently selected from hydrogen and C1-6 alkyl; wherein the C1-3alkyl and benzyl groups are optionally substituted with one or more groups selected from C3-7 cycloalkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, amino, NR13R14, aryl and heteroaryl; and (e) X is selected from S and O; with the proviso that when R4 is isopropyl, then R3 is not halogen, and with the proviso that one or more of R1, R2, R3 or R4 comprses heteroaryl or heterocycle and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.

2. The compound of claim 1, wherein R1 is COOR6, wherein R6 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl.

3. The compound of claim 2, wherein R6 is selected from H, or C1-8 straight or branched chain alkyl which may be optionally substituted with a substituent selected from CN and hydroxy.

4. The compound of claim 1, wherein R2 is selected from optionally substituted aryl and optionally substituted heteroaryl.

5. The compound of claim 4 wherein the aryl or heteroaryl groups are substituted with one to five members selected from the group consisting of halogen, alkyl, alkoxy, alkoxyphenyl, halo, triflouromethyl, trifluoro or difluoromethoxy, amino, alkylamino, hydroxy, cyano, and nitro.

6. The compound of claim 4 wherein, R2 is optionally substituted phenyl or napthyl or R2 is embedded image optionally substituted, wherein the optional substituents are from one to three members selected from the group consisting of halogen, alkyl, hydroxy, cyano, and nitro.

7. The compound of claim 1 wherein R3 is selected from: (i) hydrogen, halo, C1-8 straight or branched chain alkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, and hydroxy; (ii) —NR10R11 wherein R10 and R11 are independently selected from H, C1-8 straight or branched chain alkyl, arylC1-8alkyl, C3-7 cycloalkyl, carboxyC1-8alkyl, aryl, heteroaryl, and heterocyclyl or R10 and R11 taken together with the nitrogen form a heteroaryl or heterocyclyl group; (iii) —NR12COR13 wherein R12 is selected from hydrogen or alkyl and R13 is selected from hydrogen, alkyl, substituted alkyl, C1-3alkoxyl, carboxyC1-8alkyl, aryl, arylalkyl, R30R31N (CH2)p—, R30R31NCO(CH2)p—, heteroaryl and heterocyclyl or R12 and R13 taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R30 and R31 are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6.

8. The compound of claim 7, wherein R3 is selected from the group consisting of: embedded image

9. The compound of claim 1 wherein R4 is selected from hydrogen, and C1-3 straight or branched chain alkyl.

10. The compound of claim 9, wherein R4 is selected from methyl and amino.

11. The compound of claim 1 wherein R1 is COOR6 and R2 is selected from the group consisting of substituted phenyl, and substituted naphthyl.

12. The compound of claim 1 wherein R1 is COOR6 where R6 is alkyl, R2 is substituted phenyl or naphthyl, and R3 is selected from the group consisting of H, nitro, amino, NHAc, halo, hydroxy, alkoxy, or a moiety of the formulae: embedded image and R4 is selected from hydrogen, C1-3 straight or branched chain alkyl and amino and X is Oxygen.

13. A compound having the structure: embedded image wherein (a) R1 is selected from the group consisting of: (i) —COR5, wherein R5 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl; wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR20R21 taken together form a heterocycle or heteroaryl; (ii) COOR6, wherein R6 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl; wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR20R21 taken together form a heterocycle or heteroaryl; (iii) cyano; (iv) a lactone or lactam formed with R4; (v) —CONR7R8 wherein R7 and R8 are independently selected from H, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl; wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl, or R7 and R8 taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group; (b) R2 is —NR15R16 wherein R15 and R16 are independently selected from hydrogen, optionally substituted C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, aryl, heteroaryl, and heterocyclyl or R15 and R16 taken together with the nitrogen form a heteroaryl or heterocyclyl group; with the proviso that when R2 is NHR16, R1 is not —COOR6 where R6 is ethyl; (c) R3 is from one to four groups independently selected from the group consisting of: (i) hydrogen, halo, C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, aryl, heteroaryl, and heterocyclyl; (ii) —NR10R11 wherein R10 and R11 are independently selected from H, C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R10 and R11 taken together with the nitrogen form a heteroaryl or heterocyclyl group; (iii) —NR12COR13 wherein R12 is selected from hydrogen or alkyl and R13 is selected from hydrogen, alkyl, substituted alkyl, C1-3alkoxyl, carboxyalkyl, R30R31N (CH2)p—, R30R31NCO(CH2)p—, aryl, arylalkyl, heteroaryl and heterocyclyl or R12 and R13 taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R30 and R31 are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6, wherein the alkyl group may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl; (d) R4 is selected from the group consisting of (i) hydrogen, (ii) C13 straight or branched chain alkyl, (iii) benzyl and (iv) —NR13R14, wherein R13 and R14 are independently selected from hydrogen and C1-6 alkyl; wherein the C1-3alkyl and benzyl groups are optionally substituted with one or more groups selected from C3-7 cycloalkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, amino, NR13R14, aryl and heteroaryl; and (e) X is selected from S and O; with the proviso that one or more of R1, R2, R3 or R4 comprises heteroaryl or heterocycle and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.

14. The compound of claim 13, wherein R1 is COOR6 wherein R6 is alkyl, R2 is NR6R7, and R3 is selected from the group consisting of embedded image halogen, and hydrogen, and R4 is selected from hydrogen, C1-3 straight or branched chain alkyl and amino and X is Oxygen.

15. 15-47. (canceled)

Description:

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119(e) of provisional application Ser. No. 60/284,465, filed on Apr. 18, 2001 which is incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to novel arylindenopyridines and their therapeutic and prophylactic uses. Disorders treated and/or prevented using these compounds include inflammatory and AIDS-related disorders.

BACKGROUND OF THE INVENTION

There are eleven known families of phosphodiesterases (PDE) widely distributed in many cell types and tissues. In their nomenclature, the number indicating the family is followed by a capital letter that indicates a distinct gene. A PDE inhibitor increases the concentration of cAMP in tissue cells, and hence, is useful in the prophylaxis or treatment of various diseases caused by the decrease in cAMP level which is induced by the abnormal metabolism of cAMP. These diseases include conditions such as hypersensitivity, allergy, arthritis, asthma, bee sting, animal bite, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, premature labor, a urinary tract disorder, inflammatory bowel disease, stroke, erectile dysfunction, HIV/AIDS, cardiovascular disease, gastrointestinal motility disorder, and psoriasis.

Among known phosphodiesterases today, PDE1 family are activated by calcium-calmodulin; its members include PDE1A and PDE1B, which preferentially hydrolyze cGMP, and PDE1C which exhibits a high affinity for both cAMP and cGMP. PDE2 family is characterized as being specifically stimulated by cGMP. PDE2A is specifically inhibited by erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA). Enzymes in the PDE3 family (e.g. PDE3A, PDE3B) are specifically inhibited by cGMP. PDE4 (e.g. PDE4A, PDE4B, PDE4C, PDE4D) is a cAMP specific PDE present in T-cells, which is involved in inflammatory responses. A PDE3 and/or PDE4 inhibitor would be predicted to have utility in the following disorders: autoimmune disorders (e.g. arthritis), inflammatory bowel disease, bronchial disorders (e.g. asthma), HIV/AIDS, and psoriasis. A PDE5 (e.g. PDE5A) inhibitor would be useful for the treatment of the following disorders: cardiovascular disease and erectile dysfunction. The photoreceptor PDE6 (e.g. PDE6A, PDE6B, PDE6C) enzymes specifically hydrolyze cGMP. PDE8 family exhibits high affinity for hydrolysis of both cAMP and cGMP but relatively low sensitivity to enzyme inhibitors specific for other PDE families.

Phosphodiesterase 7 (PDE7A, PDE7B) is a cyclic nucleotide phosphodiesterase that is specific for cyclic adenosine monophosphate (cAMP). PDE7 catalyzes the conversion of cAMP to adenosine monophosphate (AMP) by hydrolyzing the 3′-phosphodiester bond of cAMP. By regulating this conversion, PDE7 allows for non-uniform intracellular distribution of cAMP and thus controls the activation of distinct kinase signalling pathways. PDE7A is primarily expressed in T-cells, and it has been shown that induction of PDE7A is required for T-cell activation (Li, L.; Yee, C.; Beavo, J. A. Science 1999, 283, 848). Since PDE7A activation is necessary for T-cell activation, small molecule inhibitors of PDE7 would be useful as immunosuppressants. An inhibitor of PDE7A would be predicted to have immunosuppressive effects with utility in therapeutic areas such as organ transplantation, autoimmune disorders (e.g. arthritis), HIV/AIDS, inflammatory bowel disease, asthma, allergies and psoriasis.

Few potent inhibitors of PDE7 have been reported. Most inhibitors of other phosphodiesterases have IC50's for PDE7 in the 100 μM range. Recently, Martinez, et al. (J. Med. Chem. 2000, 43, 683) reported a series of PDE7 inhibitors, among which the two best compounds have PDE7 IC50's of 8 and 13 μM. However, these compounds were only 2-3 times selective for PDE7 over PDE4 and PDE3.

Finally, the following compounds have been disclosed, and some of them are reported to show antimicrobial activity against strains such as Plasmodium falciparum, Candida albicans and Staphylococcus aureus (Gorlitzer, K.; Herbig, S.; Walter, R. D. Pharmazie 1997, 504): embedded image

SUMMARY OF THE INVENTION

This invention provides a compound having the structure of Formula I embedded image

or a pharmaceutically acceptable salt thereof, wherein

(a) R1 is selected from the group consisting of:

    • (i) —COR5, wherein R5 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;
      • wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR20R21 taken together form a heterocycle or heteroaryl;
    • (ii) COOR6, wherein R6 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;
      • wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR20R21 taken together form a heterocycle or heteroaryl;
    • (iii) cyano;
    • (iv) a lactone or lactam formed with R4;
    • (v) —CONR7R8 wherein R7 and R8 are independently selected from H, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl;
      • wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl,
      • or R7 and R8 taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group;

(b) R2 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl and optionally substituted C3-7 cycloalkyl;

(c) R3 is from one to four groups independently selected from the group consisting of:

    • (i) hydrogen, halo, C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, aryl, heteroaryl, and heterocyclyl;
    • (ii) —NR10R11 wherein R10 and R11 are independently selected from H, C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R10 and R11 taken together with the nitrogen form a heteroaryl or heterocyclyl group;
    • (iii) —NR12COR13 wherein R12 is selected from hydrogen or alkyl and R13 is selected from hydrogen, alkyl, substituted alkyl, C1-3alkoxyl, carboxyalkyl, R30R13N (CH2)p—, R30R31NCO(CH2)p—, aryl, arylalkyl, heteroaryl and heterocyclyl or R12 and R13 taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R30 and R31 are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6,
      • wherein the alkyl group may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl;

(c) R4 is selected from the group consisting of (i) hydrogen, (ii) C1-3 straight or branched chain alkyl, (iii) benzyl and (iv) —NR13R14, wherein R13 and R14 are independently selected from hydrogen and C1-6 alkyl;

    • wherein the C1-3alkyl and benzyl groups are optionally substituted with one or more groups selected from C3-7 cycloalkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, amino, NR13R14, aryl and heteroaryl; and

(e) X is selected from S and O;

with the proviso that when R4 is isopropyl, then R3 is not halogen.

In an alternative embodiment, the invention is directed to compounds of Formula I wherein R1, R3 and R4 are as described above and R2 is —NR15R16 wherein R15 and R16 are independently selected from hydrogen, optionally substituted C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, aryl, heteroaryl, and heterocyclyl or R15 and R16 taken together with the nitrogen form a heteroaryl or heterocyclyl group; with the proviso that when R2 is NHR16, R1 is not —COOR6 where R6 is ethyl.

This invention also provides a pharmaceutical composition comprising the instant compound and a pharmaceutically acceptable carrier.

This invention further provides a method of treating a subject having a disorder ameliorated by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.

Finally, this invention provides a method of preventing a disorder ameliorated by reducing PDE activity in appropriate cells in a subject, comprising administering to the subject a prophylactically effective dose of the compound of claim 1 either preceding or subsequent to an event anticipated to cause a disorder ameliorated by reducing PDE activity in appropriate cells in the subject.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of Formula I are potent small molecule phosphodiesterase inhibitors that have demonstrated potency for inhibition of PDE7, PDE5, and PDE4. Some of the compounds of this invention are potent small molecule PDE7 inhibitors which have also demonstrated good selectivity against PDE5 and PDE4.

Preferred embodiments for R1 are COOR6, wherein R6 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl. Preferably R6 is H, or C1-8 straight or branched chain alkyl which may be optionally substituted with a substituent selected from CN and hydroxy.

Preferred embodiments for R2 are optionally substituted aryl and optionally substituted heteroaryl. Preferred substituents are from one to three members selected from the group consisting of halogen, alkyl, alkoxy, alkoxyphenyl, halo, triflouromethyl, trifluoro or difluoromethoxy, amino, alkylamino, hydroxy, cyano, and nitro. Preferably, R2 is optionally substituted phenyl or napthyl or R2 is embedded image
optionally substituted with from one to three members selected from the group consisting of halogen, alkyl, hydroxy, cyano, and nitro. In another embodiment of the instant compound, R2 is —NR15R16.

Preferred substituents for R3 include:

    • (i) hydrogen, halo, C1-8 straight or branched chain alkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, and hydroxy;
    • (ii) —NR10R11 wherein R10and R11 are independently selected from H, C1-8 straight or branched chain alkyl, arylC1-8alkyl, C3-7 cycloalkyl, carboxyC1-8alkyl, aryl, heteroaryl, and heterocyclyl or R10 and R11 taken together with the nitrogen form a heteroaryl or heterocyclyl group;
    • (iii) —NR12COR13 wherein R12 is selected from hydrogen or alkyl and R13 is selected from hydrogen, alkyl, substituted alkyl, C1-3alkoxyl, carboxyC1-8alkyl, aryl, arylalkyl, R30R31N (CH2)p—, R30R31NCO(CH2)p—, heteroaryl and heterocyclyl or R12 and R13 taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein , R30 and R31 are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6.
      Particularly, R3 is selected from the group consisting of embedded image

Preferred embodiments for R4 include hydrogen, C1-3 straight or branched chain alkyl, particularly methyl, and amino.

In a further embodiment of the instant compound, R1 is COOR6 and R2 is selected from the group consisting of substituted phenyl, and substituted naphthyl or R2 is NR15R16.

More particularly, R1 is COOR6 where R6 is alkyl, R2 is substituted phenyl or naphthyl or R2 is NR15R16, and R3 is selected from the group consisting of H, nitro, amino, NHAc, halo, hydroxy, alkoxy, or a moiety of the formulae: embedded image
and R4 is selected from hydrogen, C1-3 straight or branched chain alkyl, particularly methyl, and amino.

In a preferred embodiment, the compound is selected from the group of compounds shown in Table 1 hereinafter.

More preferably, the compound is selected from the following compounds: embedded image

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 2-amino-4-(1,3-benzodioxol-5-yl)-5-oxo-, ethyl ester

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5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(6-bromo- 1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester

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5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-amino-4-( 1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester

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5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(6-bromo-1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, methyl ester

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5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester

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5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-(acetylamino)-4-(1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester

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5H-indeno[1,2-b]pyridine-3-carboxylic acid, 2-methyl-4-(3-methylphenyl)-5-oxo-, methyl ester

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5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-amino-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester

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5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-amino-2-methyl-4-(4-methyl-1-naphthalenyl)-5-oxo-, methyl ester

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5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-8-nitro-5-oxo-, methyl ester

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5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7,8-dichloro-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester

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5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-bromo-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester

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5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-bromo-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester

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5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-[(3-carboxy- 1-oxopropyl)amino]-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester

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5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-[(3-carboxy-1-oxopropyl)amino]-2-methyl-4-(4-methyl- 1-naphthalenyl)-5-oxo-, methyl ester

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5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-8-[[4-(hydroxyamino)- 1,4-dioxobutyl]amino]-2-methyl-5-oxo-, methyl ester

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5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-8-[[[(2-hydroxyethyl)amino]acetyl]amino]-2-methyl-5-oxo-, methyl ester

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5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-[(4-carboxy-1-oxobutyl)amino]-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester

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5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-8-[[[(2-hydroxyethyl)methylamino]acetyl]amino]-2-methyl-5-oxo-, methyl ester

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5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyl-8-[(4-morpholinylacetyl)amino]-5-oxo-, methyl ester

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5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyl-5-oxo-8-[(1-piperazinylacetyl)amino]-, methyl ester

The instant compounds can be isolated and used as free bases. They can also be isolated and used as pharmaceutically acceptable salts. Examples of such salts include hydrobromic, hydroiodic, hydrochloric, perchloric, sulfuric, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroethanesulfonic, benzenesulfonic, oxalic, palmoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic and saccharic.

This invention also provides a pharmaceutical composition comprising the instant compound and a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably 0.05 M phosphate buffer or 0.8% saline. Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media. Oral carriers can be elixirs, syrups, capsules, tablets and the like. The typical solid carrier is an inert substance such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like. Parenteral carriers include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose and the like. Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like. All carriers can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art.

This invention further provides a method of treating a subject having a condition ameliorated by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.

In one embodiment, the disorder is an inflammatory disorder. In another embodiment, the disorder is an AIDS-related disorder. Examples of disorders treacle by the instant pharmaceutical composition include, without limitation, organ transplantation, autoimmune disorders (e.g. arthritis), immune challenge such as a bee sting, inflammatory bowel disease, bronchial disorders (e.g. asthma), HIV/AIDS, cardiovascular disorder, erectile dysfunction, allergies, and psoriasis. In the preferred embodiment, the disorder is rheumatoid arthritis.

As used herein, the term “subject” includes, without limitation, any animal or artificially modified animal having a disorder ameliorated by reducing PDE activity in appropriate cells. In a preferred embodiment, the subject is a human. In a more preferred embodiment, the subject is a human.

As used herein, “appropriate cells” include, by way of example, cells which display PDE activity. Specific examples of appropriate cells include, without limitation, T-lymphocytes, muscle cells, neuro cells, adipose tissue cells, monocytes, macrophages, fibroblasts.

Administering the instant pharmaceutical composition can be effected or performed using any of the various methods known to those skilled in the art. The instant compounds can be administered, for example, intravenously, intramuscularly, orally and subcutaneously. In the preferred embodiment, the instant pharmaceutical composition is administered orally. Additionally, administration can comprise giving the subject a plurality of dosages over a suitable period of time. Such administration regimens can be determined according to routine methods.

As used herein, a “therapeutically effective dose” of a pharmaceutical composition is an amount sufficient to stop, reverse or reduce the progression of a disorder. A “prophylactically effective dose” of a pharmaceutical composition is an amount sufficient to prevent a disorder, i.e., eliminate, ameliorate and/or delay the disorder's onset. Methods are known in the art for determining therapeutically and prophylactically effective doses for the instant pharmaceutical composition. The effective dose for administering the pharmaceutical composition to a human, for example, can be determined mathematically from the results of animal studies.

In one embodiment, the therapeutically and/or prophylactically effective dose is a dose sufficient to deliver from about 0.001 mg/kg of body weight to about 200 mg/kg of body weight of the instant pharmaceutical composition. In another embodiment, the therapeutically and/or prophylactically effective dose is a dose sufficient to deliver from about 0.05 mg/kg of body weight to about 50 mg/kg of body weight. More specifically, in one embodiment, oral doses range from about 0.05 mg/kg to about 100 mg/kg daily. In another embodiment, oral doses range from about 0.05 mg/kg to about 50 mg/kg daily, and in a further embodiment, from about 0.05 mg/kg to about 20 mg/kg daily. In yet another embodiment, infusion doses range from about 1.0 μg/kg/min to about 10 mg/kg/min of inhibitor, admixed with a pharmaceutical carrier over a period ranging from about several minutes to about several days. In a further embodiment, for topical administration, the instant compound can be combined with a pharmaceutical carrier at a drug/carrier ratio of from about 0.001 to about 0.1.

This invention still further provides a method of preventing an inflammatory response in a subject, comprising administering to the subject a prophylactically effective amount of the instant pharmaceutical composition either preceding or subsequent to an event anticipated to cause the inflammatory response in the subject. In the preferred embodiment, the event is an insect sting or an animal bite.

DEFINITIONS AND NOMENCLATURE

Unless otherwise noted, under standard nomenclature used throughout this disclosure the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment.

As used herein, the following chemical terms shall have the meanings as set forth in the following paragraphs: “independently”, when in reference to chemical substituents, shall mean that when more than one substituent exists, the substituents may be the same or different;.

“Alkyl” shall mean straight, cyclic and branched-chain alkyl. Unless otherwise stated, the alkyl group will contain 1-20 carbon atoms. Unless otherwise stated, the alkyl group may be optionally substituted with one or more groups such as halogen, OH, CN, mercapto, nitro, amino, C1-C8-alkyl, C1-C8-alkoxyl, C1-C8-alkylthio, C1-C8-alkyl-amino, di(C1-C8-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C1-C8-alkyl-CO—O—, C1-C8-alkyl-CO—NH—, carboxamide, hydroxamic acid, sulfonamide, sulfonyl, thiol, aryl, aryl(c1-c8)alkyl, heterocyclyl, and heteroaryl.

“Alkoxy” shall mean —O-alkyl and unless otherwise stated, it will have 1-8 carbon atoms.

“Halogen” shall mean fluorine, chlorine, bromine or iodine; “PH” or “Ph” shall mean phenyl; “Ac” shall mean acyl; “Bn” shall mean benzyl.

The term “acyl” as used herein, whether used alone or as part of a substituent group, means an organic radical having 2 to 6 carbon atoms (branched or straight chain) derived from an organic acid by removal of the hydroxyl group. The term “Ac” as used herein, whether used alone or as part of a substituent group, means acetyl.

“Aryl” or “Ar,” whether used alone or as part of a substituent group, is a carbocyclic aromatic radical including, but not limited to, phenyl, 1- or 2-naphthyl and the like. The carbocyclic aromatic radical may be substituted by independent replacement of 1 to 5 of the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro, amino, C1-C8-alkyl, C1-C8-alkoxyl, C1-C8-alkylthio, C1-C8-alkyl-amino, di(C1-C8-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C1-C8-alkyl-CO—O—, C1-C8-alkyl-CO—NH—, or carboxamide. Illustrative aryl radicals include, for example, phenyl, naphthyl, biphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl and the like. “Ph” or “PH” denotes phenyl.

Whether used alone or as part of a substituent group, “heteroaryl” refers to a cyclic, fully unsaturated radical having from five to ten ring atoms of which one ring atom is selected from S, O, and N; 0-2 ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon. The radical may be joined to the rest of the molecule via any of the ring atoms. Exemplary heteroaryl groups include, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazolyl, triazinyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, indolyl, isothiazolyl, 2-oxazepinyl, azepinyl, N-oxo-pyridyl, 1-dioxothienyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl-N-oxide, benzimidazolyl, benzopyranyl, benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, indazolyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, or furo[2,3-b]pyridinyl), imidazopyridinyl (such as imidazo[4,5-b]pyridinyl or imidazo[4,5-c]pyridinyl), naphthyridinyl, phthalazinyl, purinyl, pyridopyridyl, quinazolinyl, thienofuryl, thienopyridyl, thienothienyl, and furyl. The heteroaryl group may be substituted by independent replacement of 1 to 5 of the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro, amino, C1-C8-alkyl, C1-C8-alkoxyl, C1-C8-alkylthio, C1-C8-alkyl-amino, di(C1-C8-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C1-C8-alkyl-CO—O—, C1-C8-alkyl-CO—NH—, or carboxamide. Heteroaryl may be substituted with a mono-oxo to give for example a 4-oxo-1H-quinoline.

The terms “heterocycle,” “heterocyclic,” and “heterocyclo” refer to an optionally substituted, fully or partially saturated cyclic group which is, for example, a 4- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, or 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized. The nitrogen atoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl; oxetanyl; pyrazolinyl; imidazolinyl; imidazolidinyl; oxazolyl; oxazolidinyl; isoxazolinyl; thiazolidinyl; isothiazolidinyl; tetrahydrofuryl; piperidinyl; piperazinyl; 2-oxopiperazinyl; 2-oxopiperidinyl; 2-oxopyrrolidinyl; 4-piperidonyl; tetrahydropyranyl; tetrahydrothiopyranyl; tetrahydrothiopyranyl sulfone; morpholinyl; thiomorpholinyl; thiomorpholinyl sulfoxide; thiomorpholinyl sulfone; 1,3-dioxolane; dioxanyl; thietanyl; thiiranyl; and the like. Exemplary bicyclic heterocyclic groups include quinuclidinyl; tetrahydroisoquinolinyl; dihydroisoindolyl; dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl); dihydrobenzofuryl; dihydrobenzothienyl; dihydrobenzothiopyranyl; dihydrobenzothiopyranyl sulfone; dihydrobenzopyranyl; indolinyl; isochromanyl; isoindolinyl; piperonyl; tetrahydroquinolinyl; and the like.

Substituted aryl, substituted heteroaryl, and substituted heterocycle may also be substituted with a second substituted-aryl, a second substituted-heteroaryl, or a second substituted-heterocycle to give, for example, a 4-pyrazol-1-yl-phenyl or 4-pyridin-2-yl-phenyl.

Designated numbers of carbon atoms (e.g., C1-8) shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.

Unless specified otherwise, it is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.

Where the compounds according to this invention have at least one stereogenic center, they may accordingly exist as enantiomers. Where the compounds possess two or more stereogenic centers, they may additionally exist as diastereomers. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.

Some of the compounds of the present invention may have trans and cis isomers. In addition, where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared as a single stereoisomer or in racemic form as a mixture of some possible stereoisomers. The non-racemic forms may be obtained by either synthesis or resolution. The compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation. The compounds may also be resolved by covalent linkage to a chiral auxiliary, followed by chromatographic separation and/or crystallographic separation, and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using chiral chromatography.

This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that these are only illustrative of the invention as described more fully in the claims which follow thereafter. Additionally, throughout this application, various publications are cited. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.

EXPERIMENTAL DETAILS

I. General Synthetic Schemes

Representative compounds of the present invention can be synthesized in accordance with the general synthetic methods described below and illustrated in the following general schemes. The products of some schemes can be used as intermediates to produce more than one of the instant compounds. The choice of intermediates to be used to produce subsequent compounds of the present invention is a matter of discretion that is well within the capabilities of those skilled in the art. embedded image

Procedures described in Scheme 1, wherein R3a, R3b, R3c, and R3d are independently any R3 group, and R1, R2, R3, and R4 are as described above, can be used to prepare compounds of the invention wherein X is O.

Benzylidenes 2 may be obtained by known methods (Bullington, J. L; Cameron, J. C.; Davis, J. E.; Dodd, J. H.; Harris, C. A.; Henry, J. R.; Pellegrino-Gensey, J. L.; Rupert, K. C.; Siekierka, J. J. Bioorg. Med. Chem. Lett. 1998, 8, 2489; Petrow, V.; Saper, J.; Sturgeon, B. J. Chem. Soc. 1949, 2134). Hantzsch reaction of the benzylidene compounds with enamines 3 can be performed in refluxing acetic acid (Petrow et al., supra). When the desired enamines are not available, alternate Hantzsch conditions may be utilized which involve adding ammonium acetate to the reaction. The resulting dihydropyridines 4 are oxidized with chromium trioxide to obtain the desired pyridines 1 (Petrow et al., supra). In cases where the substitution pattern on the fused aromatic ring (R3) leads to a mixture of regioisomers, the products can be separated by column chromatography.

In some cases, especially where R2 is an alkyl group, another modification of the Hantzsch may be performed which uses three components (Bocker, R. H.; Buengerich, P. J. Med. Chem. 1986, 29, 1596). Where R2 is an alkyl group it is also necessary to perform the oxidation with DDQ or MnO2 instead of chromium (VI) oxide (Vanden Eynde, J. J.; Delfosse, F.; Mayence, A.; Van Haverbeke, Y. Tetrahedron 1995, 51, 6511). embedded image

In order to obtain the corresponding carboxylic acids and amides, the cyanoethyl esters 5 are prepared as described above. The esters are converted to the carboxylic acids by treatment with sodium hydroxide in acetone and water (Ogawa, T.; Matsumoto, K.; Yokoo, C.; Hatayama, K.; Kitamura, K. J. Chem. Soc., Perkin Trans. 1 1993, 525). The corresponding amides can then be obtained from the acids using standard means. embedded image

The procedure for making compounds where R4 is NH2 may be slightly modified. These compounds are prepared in one step from the benzylidenes 2 and alkyl amidinoacetate (Kobayashi, T.; Inoue, T.; Kita, Z.; Yoshiya, H.; Nishino, S.; Oizumi, K.; Kimura, T. Chem. Pharm. Bull. 1995, 43, 788) as depicted in Scheme 4 wherein R is R5 or R6 as described above. embedded image

The dihydropyridine lactones 9 can be synthesized from benzylidenes 8 (Zimmer, H.; Hillstrom, W. W.; Schmidt, J. C.; Seemuth, P. D.; Vogeli, R. J. Org. Chem. 1978, 43, 1541) and 1,3-indanedione, as shown in Scheme 5, and the corresponding pyridine is then obtained by oxidation with manganese dioxide. embedded image

Representative schemes to modify substituents on the fused aromatic ring are shown below. The amines 11 are obtained from the corresponding nitro compounds 10 by reduction with tin (II) chloride (Scheme 6). Reaction of the amines with acetyl chloride provide the amides 12. embedded image

In accordance with Scheme 7 wherein Y is O, and n is an integer from 1-3, an alkyl chain with a carboxylic acid at the terminal end can also be added to the amines 11. For example, reaction with either succinic anhydride (Omuaru, V. O. T.; Indian J. Chem., Sect B. 1998, 37, 814) or β-propiolactone (Bradley, G.; Clark, J.; Kernick, W. J. Chem. Soc., Perkin Trans. 1 1972, 2019) can provide the corresponding carboxylic acids 13. These carboxylic acids are then converted to the hydroxamic acids 14 by treatment with ethyl chloroformate and hydroxylamine (Reddy, A. S.; Kumar, M. S.; Reddy, G. R. Tetrahedron Lett. 2000, 41, 6285). embedded image

The amines 11 can also be treated with glycolic acid to afford alcohols 15 (Jursic, B. S.; Zdravkovski, Z. Synthetic Comm. 1993, 23, 2761) as shown in Scheme 8. embedded image

As shown in Scheme 9, the aminoindenopyridines 11 may also be treated with chloroacetylchloride followed by amines to provide the more elaborate amines 16 (Weissman, S. A.; Lewis, S.; Askin, D.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1998, 39, 7459). Where R6 is a hydroxyethyl group, the compounds can be further converted to piperazinones 17. embedded image

The 4-aminoindenopyridines 18 can be synthesized from the 4-chloroindenopyridines 19 using a known procedure (Gorlitzer, K.; Herbig, S.; Walter, R. D. Pharmazie 1997, 504) or via palladium catalyzed coupling (Scheme 10). embedded image
II. Specific Compound Syntheses

Specific compounds which are representative of this invention can be prepared as per the following examples. No attempt has been made to optimize the yields obtained in these reactions. Based on the following, however, one skilled in the art would know how to increase yields through routine variations in reaction times, temperatures, solvents and/or reagents.

The products of certain syntheses can be used as intermediates to produce more than one of the instant compounds. In those cases, the choice of intermediates to be used to produce compounds of the present invention is a matter of discretion that is well within the capabilities of those skilled in the art.

EXAMPLE 1

Hantzsch Condensation to Form Dihydropyridine 4 (R1═COOMe; R2=3,5-dimethylphenyl; R3b,c═Cl; R3a,b═H; R4=Me)

To a refluxing solution of benzylidene 2 (0.500 g, 1.5 mmol) in acetic acid (10 mL) was added methyl-3-aminocrotonate (0.695 g, 6.0 mmol). The reaction was heated to reflux for 20 minutes, then water was added until a precipitate started to form. The reaction was cooled to room temperature. The mixture was filtered and washed with water to obtain 0.354 g (55%) of a red solid. MS m/z 450 (M++23), 428 (M++1).

EXAMPLE 2

Alternate Hantzsch Conditions to Form Dihydropyridine 4 (R1═CO2Me; R2=2,4-dimethylphenyl; R3═H; R4=Et)

To a refluxing solution of benzylidene 2 (1.00 g, 3.82 mmol) in acetic acid (12 Ml) was added methyl propionylacetate (1.98 g, 15.2 mmol) and ammonium acetate (1.17 g, 15.2 mmol). The reaction was heated for 20 min and then cooled to room temperature. No product precipitated from the solution, so the reaction was heated to reflux and then water was added until a solid began to precipitate. After cooling to room temperature, the mixture was filtered and the red solid washed with water to yield 1.29 g (90%) of product. MS m/z 396 (M++23), 374 (M++1).

EXAMPLE 3

Oxidation of Dihydropyridine 4 to Pyridine 1 (R1═COOMe; R2=3,5-dimethylphenyl; R3b,c═Cl; R3a,d═H; R4=Me)

To a refluxing solution of dihydropyridine 4 (0.250 g, 0.58 mmol) in acetic acid (10 mL) was added a solution of chromium (VI) oxide (0.584 g, 0.58 mmol) in 1 mL water. After 30 minutes at reflux, the reaction was diluted with water until a precipitate started to form. The mixture was cooled to room temperature and allowed to stand overnight. The mixture was filtered and washed with water to give 0.199 g (81%) of a yellow solid. MS m/z 448 (M++23), 426 (M++1).

EXAMPLE 4

Oxidation of Dihydropyridine 4 to Pyridine 1 (R1═COOMe; R2=(4-methyl)-1-naphthyl; R3b,c═H, NO2/NO2, H; R=Me)

To a refluxing suspension of regioisomeric dihydropyridines 4 (3.59 g, 8.16 mmol) in acetic acid (40 mL) was added a solution of chromium (VI) oxide (0.816 g, 8.16 mmol) in 3 mL water. After 20 minutes at reflux, the reaction was diluted with water until a precipitate started to form. The mixture was cooled to room temperature and allowed to stand overnight. The mixture was filtered and washed with water to yield the mixture of regioisomers as a yellow solid. The products were purified by column chromatography eluting with hexanes:ethyl acetate to yield 1.303 g (37%) of pyridine 1 (R3b═NO2; R3c═H) and 0.765 g (21%) of its regioisomer (R3b═H: R3c═NO2). MS m/z 461 (M++23), 439 (M++1).

EXAMPLE 5

Alternate Three Component Hantzsch Reaction to Form Dihydropyridine 4 (R1═CO2Me; R2=cyclohexyl; R3═H; R4=Me)

Cyclohexane carboxaldehyde (2.0 g, 17.8 mmol), 1,3-indandione (2.6 g, 17.8 mmol), methylacetoacetate (2.0 g, 17.8 mmol), and ammonium hydroxide (1 mL) were refluxed in 8 mL of methanol for 1.5 hours. The temperature was lowered to approximately 50° C. and the reaction was stirred overnight. The reaction was cooled to room temperature, filtered and the solid washed with water. The residue was then dissolved in hot ethanol and filtered while hot. The filtrate was concentrated to yield 4.1 g (68%) of the product which was used without purification. MS m/z 336 (M−1).

EXAMPLE 6

DDQ Oxidation of Dihydropyridine 4 (R1═CO2Me; R2=cyclohexyl; R3═H; R4=Me)

To a solution of dihydropyridine 4 (2.50 g, 7.40 mmol) in 15 mL of dichloromethane was added 2,3-dichloro-3,6-dicyano-1,4-benzoquinone (1.70 g, 7.40 mmol). The reaction was stirred at room temperature for four hours. The mixture was filtered and the residue was washed with dichloromethane. After the filtrate was concentrated, the residue was purified by column chromatography eluting with ethyl acetate: hexanes to yield 0.565 g (23%) of a yellow solid. MS m/z 358 (M++23), 336 (M++1).

EXAMPLE 7

MnO2 Oxidation of Dihydropyridine 4 (R1═CO2Me; R2=4-(dimethylamino)phenyl; R3═H; R4=Me)

To a solution of dihydropyridine 4 (0.50 g, 1.3 mmol) in 10 mL of dichloromethane was added manganese dioxide (2.5 g, 28.7 mmol). The reaction was stirred at room temperature overnight before filtering and washing with dichloromethane. The filtrate was concentrated to yield 0.43 g (88%) of orange solid 1. MS m/z 395 (M++23), 373 (M++1).

EXAMPLE 8

Cleavage of Carboxylic Ester 5 (R2=2,4-dimethylphenyl; R3═H; R4=Me)

To a suspension of ester 5 (2.75 g, 6.94 mmol) in acetone (50 mL) was added aqueous 1 M NaOH (100 mL). After stirring at room temperature for 24 hours, the reaction mixture was diluted with 100 mL of water and washed with dichloromethane (2×100 mL). The aqueous layer was cooled to 0° C. and acidified with concentrated HCl. The mixture was filtered and washed with water to yield 1.84 g (77%) yellow solid 6. MS m/z 366 (M++23), 343 (M++1).

EXAMPLE 9

Preparation of Amide 7 (R2=2,4-dimethylphenyl; R3═H; R4=Me; R5═H; R6=Me)

A solution of carboxylic acid 6 (0.337 g, 0.98 mmol) in thionyl chloride (10 mL) was heated at reflux for 1 hour. The solution was cooled and concentrated in vacuo. The residue was diluted with CCl4 and concentrated to remove the residual thionyl chloride. The residue was then dissolved in THF (3.5 mL) and added to a 0° C. solution of methylamine (1.47 mL of 2.0 M solution in THF, 2.94 mmol) in 6.5 mL THF. The reaction was warmed to room temperature and stirred overnight. The mixture was poured into water, filtered, washed with water and dried to yield 0.263 g (75%) of tan solid. MS m/z 357 (M++1).

EXAMPLE 10

Preparation of Pyridine 1 (R1═CO2Et; R2=4-nitrophenyl; R3═H; R4═NH2)

To a refluxing solution of benzylidene 2 (1.05 g, 3.76 mmol) in 10 mL of acetic acid was added ethyl amidinoacetate acetic acid salt (0.720 g, 3.76 mmol). The resulting solution was heated at reflux overnight. After cooling to room temperature, the resulting precipitate was removed by filtration and washed with water. This impure residue was heated in a minimal amount of ethanol and then filtered to yield 0.527 g (35%) of a yellow solid. MS m/z 412 (M++23), 390 (M++1).

EXAMPLE11

Hantzsch Condensation of Benzylidene 8 (R2=3-methoxyphenyl) and 1,3-indandione)

The benzylidene 8 (2.00 g, 9.2 mmol), 1,3-indandione (1.34 g, 0.2 mmmol) and ammonium acetate (2.83 g, 36.7 mmol) were added to 30 mL of ethanol and heated to reflux overnight. The reaction mixture was cooled to room temperature and diluted with ethanol. A yellow precipitate was collected by filtration, washed with ethanol, and dried under vacuum to yield 1.98 g (63%) of the dihydropyridine 9. MS m/z 346 (M++1).

EXAMPLE 12

Reduction to Prepare Amine 11 (R1═CO2Me; R2=4-methylnaphthyl; R4=Me)

To a refluxing suspension of pyridine 10 (0.862 g, 1.97 mmol) in 35 mL of ethanol was added a solution of tin (II) chloride dihydrate (1.33 g, 5.90 mmol) in 6 mL of 1:1 ethanol: concentrated HCl. The resulting solution was heated at reflux overnight. Water was added until a precipitate started to form and the reaction was cooled to room temperature. The mixture was then filtered and washed with water. After drying, the residue was purified by column chromatography eluting with hexanes: ethyl acetate to yield 0.551 g (69%) of an orange solid. MS m/z 431 (M++23), 409 (M++1).

EXAMPLE 13

Acetylation of Amine 11 (R1═CO2Et; R2=3,4-methylenedioxyphenyl; R4=Me)

To a solution of amine 11 (0.070 g, 0.174 mmol) in 15 mL of dichloromethane was added triethylamine (0.026 g, 0.261 mmol) and acetyl chloride (0.015 g, 0.192 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with water and then extracted with dichloromethane (3×35 mL). The combined organics were washed with brine, dried over MgSO4, and concentrated. The residue was purified by silica gel chromatography eluting with hexanes: ethyl acetate to yield 0.054 g (70%) of amide 12. MS m/z 467 (M++23), 445 (M++1).

EXAMPLE 14

Preparation of Carboxylic Acid 13 (R1═CO2Me; R2=3.5-dimethylphenyl; R4=Me; Y═O; n=2)

To a suspension of amine 11 (0.079 g, 0.212 mmol) in 5 mL of benzene was added succinic anhydride (0.021 g, 0.212 mmol). After heating at reflux for 24 hours, the reaction mixture was filtered and washed with benzene. The residue was dried under high vacuum and then washed with ether to remove the excess succinic anhydride. This yielded 0.063 g (63%) of carboxylic acid 13. MS m/z 473 (M++1).

EXAMPLE 15

Preparation of Carboxylic Acid 13 (R1═CO2Me; R2=3,5-dimethylphenyl; R4=Me; Y═H2; n=1)

To a refluxing solution of amine 11 (0.078 g, 0.210 mmol) in 5 mL of acetonitrile was added β-propiolactone (0.015 g, 0.210 mmol). The reaction was heated to reflux for 72 hours before cooling to room temperature. The reaction mixture was concentrated. The residue was mixed with 10% aqueous sodium hydroxide and washed sequentially with ether and ethyl acetate. The aqueous layer was acidified with concentrated HCl and extracted with dichloromethane (2×25 mL). The combined organics were dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography eluting with 5% MeOH in dichloromethane to yield 0.020 g (21%) of an orange solid. MS m/z 467 (M++23), 445 (M++1).

EXAMPLE 16

Preparation of Hydroxamic Acid 14 (R1═CO2Me; R2=(4-methyl)-1-naphthyl; Y═O; n=2; R4=Me)

To a 0° C. suspension of carboxylic acid 13 (0.054 g, 0.106 mmol) in 10 mL of diethyl ether was added triethylamine (0.014 g, 0.138 mmol) and then ethyl chloroformate (0.014 g, 0.127 mmol). The mixture was stirred at 0° C. for 30 minutes and them warmed to room temperature. A solution of hydroxylamine (0.159 mmol) in methanol was added and the reaction was stirred overnight at room temperature. The mixture was filtered and the residue was washed with ether and dried under vacuum to yield 0.030 g (54%) of a yellow solid. MS m/z 524 (M++1).

EXAMPLE 17

Preparation of Amide 15 (R1═CO2Me; R2=3,5-dimethylphenyl; R4=Me)

A mixture of amine 11 (0.201 g, 0.54 mmol) and glycolic acid (0.049 g, 0.65 mmol) was heated at 120-160° C. for 30 minutes. During heating, more glycolic acid was added to ensure that excess reagent was present. Once the starting material was consumed, the reaction was cooled to room temperature, and diluted with dichloromethane. The resulting mixture was extracted with 20% NaOH, followed by 10% HCl, and finally water. The combined organics were concentrated and triturated with ether. Purification by column chromatography eluting with ethyl acetate: hexanes yielded 0.012 g (5%) of a yellow solid. MS m/z 453 (M++23), 431 (M++1).

EXAMPLE 18

Preparation of Amide 16 (R1═CO2Me; R2=3,5-dimethylphenyl; R4=Me; NR6R7=morpholino)

To a 0° C. mixture of amine 11 (0.123 g, 0.331 mmol) in 2 mL of 20% aqueous NaHCO3 and 3 mL of ethyl acetate was added chloroacetyl chloride (0.047 g, 0.413 mmol). The reaction was warmed to room temperature and stirred for 45 minutes. The mixture was poured into a separatory funnel and the aqueous layer was removed. The organic layer containing the crude chloroamide was used without purification. To the ethyl acetate solution was added morpholine (0.086 g, 0.992 mmol) and the reaction was heated to approx. 65° C. overnight. The reaction was diluted with water and cooled to room temperature. After extraction with ethyl acetate (3×25 mL), the combined organics were washed with brine, dried over MgSO4 and concentrated to yield 0.130 g (79%) of a yellow solid. MS m/z 522 (M++23), 500 (M++1).

EXAMPLE 19

Preparation of piperazinone 17 (R1═CO2Me; R2=3,5-dimethylphenyl; R4=Me; R7═H)

To a 0° C. solution of amide 16 (R6═CH2CH2OH) (0.093 g, 0.20 mmol), tri n-butylphosphine (0.055 g, 0.27 mmol) in 0.35 mL ethyl acetate was slowly added di-tert-butyl azodicarboxylate (0.062 g, 0.27 mmol) in 0.20 mL ethyl acetate. The reaction was allowed to stand for 15 minutes and then heated to 40° C. overnight. 4.2 M ethanolic HCl was added dropwise. The mixture was cooled to 0° C. and allowed to stand for 2 hours. The mixture was filtered and washed with cold ethyl acetate. Purification by column chromatography with 1-5% MeOH in CH2Cl2 yielded 0.011 (12%) of a white solid. MS m/z 478 (M++23), 456 (M++1).

EXAMPLE 20

Preparation of 4-Aminoindenopyridine 19 (R1═CO2Me; R4=Me; R6=Me; R7=phenyl)

To a solution of 4-chloroindenopyridine 18 (0.069 g, 0.240 mmol) in 10 mL of 2-ethoxyethanol was added N-methylaniline (0.026 g, 0.240 mmol). The reaction was heated at reflux for 96 hours. After cooling to room temperature, the solution was concentrated. The residue was purified by column chromatography eluting with hexanes: ethyl acetate to yield 0.029 g (34%) of an orange solid. MS m/z 359 (M++1).

EXAMPLE 21

Preparation of 4-Aminoindenopyridine 19 (R1═CO2Me; R4=Me; R6═H; R7=cyclopentyl) by Palladium Catalyzed Coupling

A mixture of 4-chloroindenopyridine 18 (0.100 g, 0.347 mmol), cyclopentylamine (0.035 g, 0.416 mmol), palladium (II) acetate (0.004 g, 0.0017 mmol), 2-(di-t-butylphosphino)biphenyl (0.010 g, 0.0035 mmol), and cesium carbonate (0.124 g, 0.382 mmol) in 10 mL of dioxane was heated at reflux overnight. The reaction was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3×35 mL). The combined organics were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography eluting with ethyl acetate: hexanes. The purified oil was dissolved in ether and cooled to 0° C. To this solution was slowly added 1.0 M HCl in ether. The resulting precipitate was isolated by filtration, washed with ether, and dried under vacuum to yield 0.032 g (25%) of a yellow solid. MS m/z 359 (M++23), 337 (M++1).

Following the general synthetic procedures outlined above and in Examples 1-21, the compounds of Table 1 below were prepared.

TABLE 1
embedded image
No.R1R2R3aR3bR3cR3dR4MS (M + 1)
1CN embedded image HHHHMe341
C7H5O2
2CO2Et embedded image HHHHMe388
C7H5O2
3CO2t-Bu embedded image HHHHMe416
C7H5O2
4CO2t-Bu embedded image HHHHMe432
C8H9O2
5CO2Et embedded image HHHHMe389
C6H4NO2
6CO2H embedded image HHHHMe360
C7H5O2
7CO2Et embedded image HHHHMe480
C14H13O2
8CO2Et embedded image HHHHMe482
C8H8BrO2
9CO2Et embedded image HHHHMe424
C11H9O
10CO2H embedded image HHHHMe376
C8H9O2
11CO2EtPhHHHHMe344
12CO2Et embedded image HHHHMe374
C7H7O
13CO2Et embedded image HHHHMe434
C9H11O3
14CO2Et embedded image HHHHMe454
C6H4BrO2
15CO2Bn embedded image HHHHMe450
C7H5O2
16 embedded image embedded image HHHHMe507
C11H14NO2C7H5O2
17CO2Me embedded image HHHHMe390
C8H9O2
18CO2Me embedded image HHHHMe374
C7H5O2
19CO2Et embedded image HHHHMe404
C8H9O2
20CO2Et embedded image HHHHMe404
C8H9O2
21CO2Et embedded image HHHHMe454
C7H6BrO
22CO2Et embedded image HHHHNH2411 (M + 23)
C7H5O2
23CO2Et embedded image HHHHMe388
C7H5O2
25CO2Et embedded image HHHHNH2405
C8H9O2
26CO2Et embedded image HHHHNH2390
C6H4NO2
27CO2EtPhHHHHNH2345
28CO2Et embedded image HHHHMe402
C9H11O
29CO2Et embedded image HHHHMe483
C8H8BrO2
30CO2MePhHHHHMe330
31CO2Et embedded image HHHHMe402
C8H7O2
32CO2Et embedded image HNO2HHMe433
C7H5O2
33 embedded image embedded image HHHHMe413
C4H4NO2C7H5O2
34CO2Et embedded image HHHHMe433
C7H4NO4
35CO2Et embedded image HHNO2HMe433
C7H5O2
36CO2Me embedded image HHHHMe398
C7H4F3
37CO2Et embedded image HHNH2HMe403
C7H5O2
38CONH2 embedded image HHHHMe359
C7H5O2
39CO2Et embedded image HHHHMe372
C8H9
40CO2Et embedded image HNH2HHMe403
C7H5O2
41CO2Et embedded image HHHHMe334
C4H3O
42CO2Et2-ThienylHHHHMe350
43CO2Me embedded image HHHHMe358
C8H9
44CO2Me embedded image HHHHMe388
C8H7O2
45CO2Me embedded image HHHHMe419
C7H4NO4
46CO2Me embedded image HHHHMe388
C9H11O
47CO2Me4-PyridylHHHHMe331
48CO2Me embedded image HHHHMe374
C7H5O2
49CO2Me embedded image HHHHMe454
C7H4BrO2
50CO2Me embedded image HHHHMe439
C7H6BrO
51CO2Me embedded image HHHHMe358
C8H9
52CO2Et embedded image HHHHMe372
C8H9
53CO2Me embedded image HHHHMe410
C11H9O
54CO2Me embedded image HHHHMe375
C6H4NO2
55CO2Et embedded image HNHAcHHMe445
C7H5O2
56CO2Et embedded image HHNHAcHMe445
C7H5O2
57CO2Et embedded image HHHHMe358
C7H7
58CO2Et embedded image HHHHMe358
C7H7
59CO2Et embedded image HHHHMe358
C7H7
60CO2Et embedded image HNO2HHMe457
C7H4F3
61CO2Et embedded image HHNO2HMe457
C7H4F3
62CO2Me embedded image HHHHMe344
C7H7
63CO2Et embedded image HNH2HHMe427
C7H4F3
64CO2Et embedded image HHNH2HMe427
C7H4F3
65CO2Me embedded image HHHHMe466
C8H3F6
66CO2Me embedded image HHHHMe344
C7H7
67CO2Me embedded image HHHHMe344
C7H7
68CO2Me embedded image HNO2HHMe443
C7H4F3
69CO2Me embedded image HHNO2HMe443
C7H4F3
70CO2Et embedded image HHHHi-Pr400
C8H9
71CO2Me embedded image HNH2HHMe413
C7H4F3
72CO2Me embedded image HHHHMe399
C6H3Cl2
73CO2Me embedded image HHHHEt372
C8H9
74CO2Me embedded image HHHHMe398
C7H4F3
75CO2Me embedded image HHHHMe394
C11H9
76CO2Me embedded image HHHHMe372
C9H11
77CO2Me embedded image HNO2HHMe403
C8H9
78CO2Me embedded image HHNO2HMe403
C8H9
79CO2Me embedded image HHHHMe394
C11H9
80CO2Me embedded image HNHAcHHMe455
C7H4F3
81CO2Me embedded image HHHHMe488
C6H3Br2
82CO2Me embedded image HNH2HHMe373
C8H9
83CO2Me embedded image HHNH2HMe373
C8H9
84CO2Me embedded image HHHHMe362
C7H6F
85CO2Me embedded image HHHHMe431
C6H4Br
86CO2Me embedded image HHHHMe380
C10H7
87CO2Me embedded image HNO2HHMe439
C11H9
88CO2Me embedded image HHNO2HMe439
C11H9
89CO2Me embedded image HHHHMe430
C14H9
90CO2Me embedded image HNH2HHMe409
C11H9
91CO2Me embedded image HHNH2HMe409
C11H9
92 embedded image embedded image HHHHMe397
C4H4NO2C8H9
93CN embedded image HHHHMe325
C8H9
94CO2Me embedded image HHHHNH2359
C8H9
95CO2Me embedded image HHHHNH2395
C11H9
96CO2H embedded image HHHHMe344
C8H9
97 embedded image embedded image HHHHMe433
C4H4NO2C11H9
98CN embedded image HHHHMe361
C11H9
99 embedded image embedded image HHHHC2H2O2358
C2H2O2C7H5O2
100 embedded image embedded image HHHHC2H2O2357
C2H2O2/ C8H10N
101 embedded image PhHHHHC2H2O2314
C2H2O2
102 embedded image embedded image HHHHC2H2O2361
C2H2O2C6H6NO2
103 embedded image embedded image HHHHC2H2O2364
C2H2O2C10H7
104 embedded image embedded image HHHHC2H2O2342
C2H2O2C8H9
105CO2H embedded image HHHHMe380
C11H9
106CONH2 embedded image HHHHMe343
C8H9
107CONHMe embedded image HHHHMe357
C8H9
108CONMe2 embedded image HHHHMe371
C8H9
109 embedded image embedded image HHHHC2H2O2378
C2H2O2C11H9
110 embedded image embedded image HHHHC2H2O2328
C2H2O2C7H7
111 embedded image embedded image HHHHC2H2O2356
C2H2O2C9H11
112 embedded image embedded image HHHHC2H2O2328
C2H2O2C7H7
113CO2Me embedded image HHHHMe375
C6H4NO2
114 embedded image embedded image HHHHC2H2O2328
C2H2O2C7H7
115CO2Me embedded image HHHHMe373
C8H10N
116CONH2 embedded image HHHHMe379
C11H9
117 embedded image embedded image HHHHC2H2O2365
C2H2O2C9H6N
118CO2Me embedded image HHHHMe375
C6H4NO2
119CONHMe embedded image HHHHMe393
C11H9
120CONMe2 embedded image HHHHMe407
C11H9
121CO2Me embedded image HHHHMe381
C9H6N
122CO2Me embedded image HClClHMe463
C11H9
123CO2Me embedded image HClClHMe427
C8H9
124CO2Me embedded image HHHHMe381
C9H6N
125 CO2Et embedded image HHHHMe408
C11H9
126CO2Me embedded image HClClHMe555
C6H3Br2
127CO2Me embedded image ClHHClMe427
C8H9
128CO2Me embedded image HHHHMe421
C7H6NO4
129CO2Me embedded image ClHHClMe558
C6H3Br2
130CO2Me embedded image HHHHMe345
C6H6N
131CO2Et embedded image HClClHMe477
C11H9
132CO2Me embedded image HHHHMe503
C6H4Br2N
133Ac embedded image HHHHMe472
C6H3Br2
134Ac embedded image HHHHMe342
C8H9
135CO2Me embedded image HHHHMe331
C5H4N
136 embedded image embedded image HHHHMe527
C4H4NO2C6H3Br2
137 embedded image embedded image HHHHMe397
C4H4NO2C8H9
138CO2MeOH embedded image HHHHMe362
C6H5O2
139CO2H embedded image HHHHMe474
C6H3Br2
140CO2H embedded image HHHHMe344
C8H9
141CO2Me embedded image HHHHMe346
C6H5O
142CO2Me embedded image HHHHMe380
C10H7
143CO2Me embedded image HHHHMe486
C16H25O
144CO2Me embedded image HHHHMe436
C13H11O
145CO2Me embedded image HHHHMe518
C7H5Br2O
146 embedded image embedded image HHHHMe557
C4H4NO2C7H5Br2O
147 embedded image embedded image HClClHMe466
C4H4NO2C8H9
148CO2Et—NHPhHHHHMe359
149CO2Me embedded image HHHHMe360
C7H7O
150CO2Me embedded image HHHHMe504
C6H3Br2O
151 embedded image embedded image HHHHMe420
C4H4NO2C9H6N
152C3H5O3 embedded image HHHHMe534
C6H3Br2O
153 embedded image embedded image HHHHMe385
C4H4NO2C6H5O
154 embedded image embedded image HHHHMe373
C2H4NO2C8H9
155 embedded image embedded image HHNO2HMe574
C4H4NO2C6H3Br2
156CO2Me embedded image HBrHHMe473
C11H9
157CO2Me embedded image HHBrHMe473
C11H9
158 embedded image embedded image HClClHMe489
C4H4NO2C9H6N
159 embedded image embedded image HHNO2HMe590
C4H4NO2C6H3Br2O
160 embedded image embedded image HHHHMe411
C3H5O3C9H6N
161CO2Me embedded image HBrHHMe436
C8H9
162CO2Me embedded image HHBrHMe438
C8H9
163CO2Me embedded image HBrBrHMe516
C8H9
164 embedded image embedded image HClClHMe597
C4H4NO2C6H3Br2
165 embedded image embedded image HClClHMe480
C3H5O3C9H6N
166CO2Me embedded image HBrBrHMe552
C11H9
167CO2Et embedded image HBrBrHMe530
C8H9
168CO2Me embedded image FHHFMe540
C6H3Br2O
169CO2Me embedded image HHNO2HMe551
C6H3Br2O
170CO2Me embedded image HClClHMe573
C6H3Br2O
171 embedded image embedded image HHNO2HMe444
C4H4NO2C8H9
172 embedded image embedded image HNO2HHMe444
C4H4NO2C8H9
173CO2Me embedded image FHHFMe394
C8H9
174 embedded image embedded image FHHFMe433
C4H4NO2C8H9
175CO2Me embedded image HBrBrHMe548
C8H9O2
176CO2Me embedded image HHHHMe355
C7H4N
177CO2Me embedded image HNO2HHMe421
C8H9O
178CO2Me embedded image HHNO2HMe453 (M + 23)
C8H9O
179CO2Me embedded image HClClHMe443
C8H9O
180CN embedded image HHHHMe341
C8H9O
181CO2Me embedded image HHHHMe598
C6H3I2O
182CO2Me embedded image HClClHMe435
C6H3F2
183CO2Et embedded image HHHHMe387
C8H10N
184CO2Et embedded image HHHHMe373
C7H8N
185CO2Me embedded image HHHHMe612
C7H5I2O
186CO2Et embedded image HHHHMe410
C9H7N2
187CO2Me embedded image HHNO2HMe345
C6H3I2O
188CO2Me embedded image HClClHMe668
C6H3I2O
189CO2Me embedded image HHNO2HMe413
C6H3F2
190CO2H embedded image HClClHMe544
C6H3Br2
191CN embedded image HHHHMe565
C6H3I2O
192CO2Me embedded image HBrHHMe606 (M + 23)
C6H3Br2O
193CO2Me embedded image HHBrHMe584
C6H3Br2O
194CO2Et embedded image HHHHMe373
C7H8N
195CO2Et embedded image HHHHMe427
C6H4Cl2N
196CO2Et embedded image HClClHMe587
C6H3Br2O
197CO2Et embedded image HHHHMe437
C6H5BrN
198CO2Et embedded image HHHHMe389
C7H8NO
199CO2Et embedded image HHHHMe612
C6H3I2O
200CO2Et embedded image HClClHMe449
C6H3F2
201CO2Me embedded image HClClHMe450
C9H6N
202CO2Me embedded image HClClHMe465
C7H5F2O
203CO2Me embedded image HHHHMe396
C7H5F2O
204CO2Me embedded image H embedded image HHMe473
C8H9C4H6NO3
205CO2Me embedded image HHHHMe345
C6H6N
206CO2Me embedded image HHHHMe359
C7H8N
207CO2Me embedded image HClClHMe444
C6H4NO2
208CO2Me embedded image HHHHMe355
C7H4N
209CO2H embedded image HHHHMe366
C10H7
210CO2Me embedded image HClClHMe444
C6H4NO2
211CO2Me embedded image HClClHMe430
C7H6F
212CO2Me embedded image HHHHMe416
C7H3F4
213CO2Me embedded image HClClHMe430
C7H6F
214CO2Me embedded image HHHHMe413
C6H4Cl2N
215CO2Me embedded image HOMeOMeHMe418
C8H9
216CO2Me embedded image HOMeOMeHMe454
C11H9
217CO2Me embedded image HHHHMe362
C7H6F
218CO2Me embedded image H embedded image HHMe445
C8H9C3H6NO2
219CO2Me embedded image HHHHMe35
C7H8N
220CO2Me—NHPhHHHHMe345
221CO2Me embedded image HHHHMe423
C6H5BrN
222CO2Me2-PyridylHHHHMe353 (M + 23)
223CO2Me embedded image HOMeOMeHMe459
C6H3Cl2
224CO2Me embedded image HClClHMe485
C7H3F4
225CO2Me embedded image HHHHMe345
C6H6N
226CO2Me embedded image HHNO2HMe420
C6H4NO2
227CO2Me embedded image HHNO2HMe420
C6H4NO2
228CO2Me embedded image HHHHMe359
C7H8N
229CO2Me embedded image HHHHMe396
C9H7N2
230CO2Me embedded image HOHOHHMe426
C11H9
231CO2Me embedded image HHFHMe376
C8H9
232CO2Me embedded image HHNO2HMe461
C7H3F4
233CO2Me embedded image HClClHMe468
C10H6F
234CO2Me embedded image HHHHMe373
C8H10N
235CO2Me embedded image HHHHMe375
C7H8NO
236CO2Me embedded image HNO2HHMe443
C10H6F
237CO2Me embedded image HHNO2HMe443
C10H6F
238CO2Me embedded image HHHHMe398
C10H6F
239CO2Me embedded image HClClHMe491
C12H12N
240CO2Me embedded image H embedded image HHMe509
C11H9HC4H6NO3
241CO2Me embedded image HH embedded image HMe473
C8H9C4H6NO3
242CO2Me embedded image HH embedded image HMe509
C11H9C4H6NO3
243CO2Me embedded image HHHHMe310
C4H9
244CO2Me embedded image H embedded image HHMe524
C11H9C4H7N2O3
245CO2Me embedded image HH embedded image HMe488
C8H9C4H7N2O3
246CO2Me embedded image HHHHMe308
C4H7
247CO2Mei-PrHHHHMe296
248CO2Me embedded image HHHHMe336
Cyclohexyl
249CO2MeMeHHHHMe268
250CO2Me embedded image HH embedded image HMe474
C8H9C4H9N2O2
251CO2Me embedded image HH embedded image HMe487
C8H9C5H8NO3
252CO2MeN- MorpholinoHHHHMe339
253CO2Me embedded image HHHHMe337
C5H10N
254CO2Me embedded image HH embedded image HMe488
C8H9C5H11N2O2
255CO2Me embedded image H embedded image HHMe474
C8H9C4H9N2O2
256CO2Me embedded image H embedded image HHMe456
C8H9C4H7N2O
257CO2Me embedded image H embedded image HHMe431
C8H9C2H4NO2
258CO2Me embedded image H embedded image HHMe500
C8H9C6H11N2O2
259CO2Me embedded image H embedded image HHMe499
C8H9C6H12N3O
260CO2Me embedded image H embedded image HHMe481
C8H9C5H6N3O
261CO2Me embedded image HH embedded image HMe500
C8H9C6H11N2O2
262CO2Me embedded image HH embedded image HMe499
C8H9C6H12N3O
263CO2Me embedded image HH embedded image HMe431
C8H9C2H4NO2

III. Biological Assays and Activity

The assay of phosphodiesterase activity follows the homogeneous SPA (scintillation proximity assay) format under the principle that linear nucleotides preferentially bind yttrium silicate beads in the presence of zinc sulfate.

In this assay, the enzyme converts radioactively tagged cyclic nucleotides (reaction substrate) to linear nucleotides (reaction product) which are selectively captured via ion chelation on a scintillant-containing bead. Radiolabeled product bound to the bead surface results in energy transfer to the bead scintillant and generation of a quantifiable signal. Unbound radiolabel fails to achieve close proximity to the scintillant and therefore does not generate any signal.

Specifically, enzyme was diluted in PDE buffer (50 mM pH 7.4 Tris, 8.3 mM MgCl2, 1.7 mM EGTA) with 0.1% ovalbumin such that the final signal:noise (enzyme:no enzyme) ratio is 5-10. Substrate (2,8-3H-cAMP or 8-3H-cGMP, purchased from Amersham Pharmacia) was diluted in PDE (4, 5, 7A) buffer to 1 nCi per μl (or 1 gCi/ml). For each test well, 48 μl of enzyme was mixed with 47 μl substrate and 5 μl test compound (or DMSO) in a white Packard plate, followed by shaking to mix and incubation for 15 minutes at room temperature. A 50 μl aliquot of evenly suspended yttrium silicate SPA beads in zinc sulfate was added to each well to terminate the reaction and capture the product. The plate was sealed using Topseal-S (Packard) sheets, and the beads were allowed to settle by gravity for 15-20 minutes prior to counting on a Packard TopCount scintillation counter using a 3H glass program with color quench correction. Output was in color quench-corrected dpm.

Test compounds were diluted in 100% DMSO to a concentration 20× final assay concentration. DMSO vehicle alone was added to uninhibited control wells. Inhibition (%) was calculated as follows: Nonspecific binding (NSB)=the mean of CPM of the substrate+buffer+DMSO wells Total Binding (TB)=the mean of the enzyme+substrate+DMSO wells % Inhibition listed in Table 1=(1-(Sample CPM-NSB)TB-NSB)×100

The IC50 values were calculated using the Deltagraph 4-parameter curve-fitting program. The IC50 and % Inhibition data on PDE 4, 5, and 7A are listed for the indicated compounds in Table 2 below.

TABLE 2
Ia
embedded image
MSIC20 (μM)/% inh. @ μM
No.R1R2R3aR3bR3cR3dR4(M + 1)PDE7APDE4PDE5
6CO2H embedded image HHHHMe36045% @2049% @5
51CO2Me embedded image HHHHMe3580.0550.3532.7
56CO2Et embedded image HHNHAcHMe4450.0740.3332.5
70CO2Et embedded image HHHHi-Pr4002.11
73CO2Me embedded image HHHHEt3721.540.998
82CO2Me embedded image HNH2HHMe3730.0210.2041.11, 0.864
90CO2Me embedded image HNH2HHMe4090.0050.237, 0.1722.33
98CN embedded image HHHHMe3611.13
119CONHMe embedded image HHHHMe3930.65841% @20
133Ac embedded image HHHHMe4721.54
134Ac embedded image HHHHMe3421.14
169CO2Me embedded image HHNO2HMe5510.00530.184
170CO2Me embedded image HClClHMe5730.00870.557
190CO2H embedded image HClClHMe5445.9
191CN embedded image HHHHMe5650.593
197CO2Et embedded image HHHHMe4370.72869% @50.362
219CO2Me embedded image HHHHMe3590.96461% @51.1
220CO2Me—NHPhHHHHMe3450.0841.80.637
241CO2Me embedded image HH embedded image HMe4730.00350.9540.183
242CO2Me embedded image HH embedded image HMe5090.00380.7820.141
243CO2Me embedded image HHHHMe3102.6
245CO2Me embedded image HH embedded image HMe4880.00530.8750.185
248CO2Me embedded image HHHHMe3360.7830.1710.649
250CO2Me embedded image HH embedded image HMe4740.00740.6842.4
251CO2Me embedded image HH embedded image HMe4870.00540.7540.26
253CO2Me embedded image HHHHMe3370.9050.850.303
254CO2Me embedded image HH embedded image HMe4880.00670.6640.765
261CO2Me embedded image HH embedded image HMe5000.00630.4770.63
262CO2Me embedded image HH embedded image HMe4990.0080.7023.7