SUBSTITUTED AMINO ETHYL META BENZOIC ACID ESTERS
United States Patent 3870715
A series of substituted amino ethyl meta benzoic acid esters and their salts are useful as spasmolytics, psychotherapeutic agents and agents facilitating learning. These compounds may conveniently be prepared by hydrolysis of suitably substituted trifluoromethyl derivatives followed by esterification with a desired alcohol.
Application Number:
05/347287
Publication Date:
03/11/1975
Filing Date:
04/02/1973
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Export Citation:
Primary Class:
Other Classes:
546/240, 544/399, 564/376, 560/37, 548/578, 564/382, 564/356, 564/343, 544/178, 564/381, 562/442, 562/451, 564/363, 562/422, 546/192, 564/342, 564/374, 546/239, 568/812, 564/364, 544/177, 546/238, 560/42, 560/48, 562/457
International Classes:
C07C229/38; C07D295/155; C07C229/00; C07D295/00; C07D87/36
Field of Search:
260/247.2B,471R,293.81,293.82,326.47,326.5,268R
Primary Examiner:
Weinberger, Lorraine A.
Assistant Examiner:
Killos, Paul J.
Parent Case Data:
RELATED APPLICATIONS
This application is a continuation-in-part of copending U.S. Patent Application Ser. No. 233,339, filed Mar. 9, 1972, now abandoned which is a continuation-in-part of copending U.S. Patent Application Ser. No. 745,352, filed July 17, 1968, titled "AMINOALKYL-BENZOIC ACID DERIVATIVES" and Ser. No. 85,283, filed Oct. 29, 1970, now U.S. Pat. 3,792,048 titled "AMINO-ALKYL-BENZOIC ACID DERIVATIVES."
Claims:
I claim
1. A compound of the formula ##SPC7##
2. The compound of claim 1 wherein R1 and R2 both are hydrogen and R3 is lower alkyl.
3. The compound of claim 2 which is m-[2-(benzylmethylamino)-ethyl]benzoic acid methyl ester.
4. The compound of claim 2 which is m-[2-(benzylmethylamino)-ethyl]benzoic acid ethyl ester.
5. The compound of claim 2 which is m-[2-morpholino-ethyl)-benzoic]acid methyl ester.
6. The compound of claim 2 which is m-[2-(N-methylpiperazino)ethyl]benzoic acid methyl ester.
7. The compound of claim 2 which is m-(2-piperidinoethyl)-benzoic acid methyl ester.
8. The compound of claim 2 which is m-[2-(benzylethylamino)-ethyl]benzoic acid methyl ester.
9. The compound of claim 2 which is m-(2-diethylaminoethyl)-benzoic acid methyl ester.
10. The compound of claim 2 which is m-[2-(methylisopropylamino)-ethyl]benzoic acid methyl ester.
11. The compound of claim 2 which is m-[2-(benzylmethylamino)-ethyl]-benzoic acid n-propyl ester.
12. The compound of claim 2 which is m-[2-(benzylmethylamino)-ethyl]benzoic acid t-butyl ester.
13. The compound of claim 2 which is m-[2-(N-benzyl-N-(2-methoxyethyl)amino)-ethyl]benzoic acid methyl ester.
14. The compound of claim 1 wherein R1 is hydrogen and R2 and R3 are lower alkyl.
15. The compound of claim 14 which is m-[(2-methyl)(2-isopropylamino)-ethyl]benzoic acid methyl ester.
16. The compound of claim 14 which is m-[(2-methyl)(2-benzylmethylamino)-ethyl]benzoic acid methyl ester.
17. The compound of claim 1 wherein R1 is lower alkoxy, R2 is hydrogen and R3 is lower alkyl.
18. The compound of claim 17 which is m-[1-methoxy-2-(benzylmethylamino)ethyl]benzoic acid methyl ester.
19. The compound of claim 17 which is m-[1-methoxy-2-(benzylamino)-ethyl]benzoic acid methyl ester.
1. A compound of the formula ##SPC7##
2. The compound of claim 1 wherein R1 and R2 both are hydrogen and R3 is lower alkyl.
3. The compound of claim 2 which is m-[2-(benzylmethylamino)-ethyl]benzoic acid methyl ester.
4. The compound of claim 2 which is m-[2-(benzylmethylamino)-ethyl]benzoic acid ethyl ester.
5. The compound of claim 2 which is m-[2-morpholino-ethyl)-benzoic]acid methyl ester.
6. The compound of claim 2 which is m-[2-(N-methylpiperazino)ethyl]benzoic acid methyl ester.
7. The compound of claim 2 which is m-(2-piperidinoethyl)-benzoic acid methyl ester.
8. The compound of claim 2 which is m-[2-(benzylethylamino)-ethyl]benzoic acid methyl ester.
9. The compound of claim 2 which is m-(2-diethylaminoethyl)-benzoic acid methyl ester.
10. The compound of claim 2 which is m-[2-(methylisopropylamino)-ethyl]benzoic acid methyl ester.
11. The compound of claim 2 which is m-[2-(benzylmethylamino)-ethyl]-benzoic acid n-propyl ester.
12. The compound of claim 2 which is m-[2-(benzylmethylamino)-ethyl]benzoic acid t-butyl ester.
13. The compound of claim 2 which is m-[2-(N-benzyl-N-(2-methoxyethyl)amino)-ethyl]benzoic acid methyl ester.
14. The compound of claim 1 wherein R1 is hydrogen and R2 and R3 are lower alkyl.
15. The compound of claim 14 which is m-[(2-methyl)(2-isopropylamino)-ethyl]benzoic acid methyl ester.
16. The compound of claim 14 which is m-[(2-methyl)(2-benzylmethylamino)-ethyl]benzoic acid methyl ester.
17. The compound of claim 1 wherein R1 is lower alkoxy, R2 is hydrogen and R3 is lower alkyl.
18. The compound of claim 17 which is m-[1-methoxy-2-(benzylmethylamino)ethyl]benzoic acid methyl ester.
19. The compound of claim 17 which is m-[1-methoxy-2-(benzylamino)-ethyl]benzoic acid methyl ester.
Description:
BACKGROUND OF THE INVENTION
M-aminoethyl benzoic acid is described in Chemical Abstracts 52, 6404. Para-aminoethyl benzoic acid and its ethyl ester is disclosed in Chemical Abstracts 25, 2194. Diethylaminomethylbenzoic acid and its ethyl ester is shown in Beilstein XIV, 488. Various p-(amino-alkyl)benzoic acids and esters are disclosed in Chemical Abstracts 38, 732.
BRIEF DESCRIPTION OF THE INVENTION
The present invention relates to a series of substituted aminoethyl meta benzoic acid esters and their salts which compounds are useful as spasmolytics, psychotherapeutic agents and agents facilitating learning. The compounds of the present invention have the general structural formula ##SPC1##
Wherein R 1 is hydrogen, hydroxy, lower alkoxy or lower alkyl; R 2 is hydrogen or lower alkyl; R 3 is lower alkyl, aralkyl or lower alkyl aryl; R 4 taken independently is hydrogen, lower alkyl, aralkyl, lower alkyl aryl, hydroxy lower alkyl and lower alkoxy lower alkyl; R 5 taken independently is lower alkyl, aralkyl, lower alkyl aryl or lower alkoxy lower alkyl; and R 4 and R 5 taken together with the adjacent nitrogen atom form a saturated five or six membered heterocyclic ring which may contain one additional hetero atom selected from the group consisting of --O-- and --NR 6 -- where R 6 is hydrogen or lower alkyl
And the pharmaceutically acceptable acid addition salts thereof.
As used herein the term "lower" includes radical groups containing from 1 to 7 carbon atoms. The term "alkyl" is meant to include straight or branched chain hydrocarbon radicals such as methyl, ethyl, n-propyl, T-butyl, hexyl, heptyl, and the like. The term "alkoxy" is meant to include a radical group wherein an alkyl moiety is bonded to an oxygen atom through an ether linkage, the valence of the radical being derived from said oxygen atom. Suitable examples of alkoxy groups include methoxy, ethoxy, butoxy and the like. The term "aralkyl" is meant to include radical groups such as phenyl lower alkyl, especially radical groups such as benzyl, phenylethyl and the like. "Lower alkyl aryl" is meant to encompass groups such as lower alkyl phenyl, particularly tolyl, xylyl and the like. The term "lower alkoxy lower alkyl" is meant to include radical groups such as methoxy methyl, methoxy ethyl, ethoxy methyl, ethoxy ethyl, and the like. Examples of suitable heterocyclic radical groups obtained when R 4 and R 5 are taken together with the adjacent nitrogen atom include morpholino, piperidino, piperazino and N-lower alkyl piperazino.
The compounds of formula I form acid addition salts with a variety of inorganic and organic acids. Suitable inorganic acids for this purpose include the hydrohalic acids such as hydrochloric and hydrobromic acids, sulfuric acid, phosphoric acid, sulfamic acid and the like. Suitable organic acids for this purpose include tartaric acid, citric acid, maleic acid, hexonic acid, and the like. Compounds of formula I in the form of acid addition salts with pharmaceutically unacceptable acids can be converted to acid addition salts with pharmaceutically acceptable acids by ion exchange procedures known in the art.
Preferred compounds of formula I of the present invention are obtained when R 1 is hydrogen or lower alkoxy, preferably methoxy, R 2 is hydrogen, R 3 is lower alkyl, R 4 is hydrogen or lower alkyl and R 5 is lower alkyl, aralkyl, preferably benzyl or parachloro benzyl or lower alkoxy lower alkyl, preferably methoxy ethyl.
Exemplary of compounds of the present invention are the following:
m-[2-(benzylmethylamino)-ethyl]benzoic acid methyl ester
m-[2-(benzylmethylamino)-ethyl]benzoic acid ethyl ester
m-[2-morpholino-ethyl)-benzoic acid methyl ester
m-[2-(N-methylpiperazino)ethyl]benzoic acid methyl ester
m-(2-piperidinoethyl)-benzoic acid methyl ester
m-[2-(benzylethylamino)-ethyl]benzoic acid methyl ester
m-[2-(N-benzyl-N-(2-methoxyethyl)amino)-ethyl]benzoic acid methyl ester
m-(2-diethylaminoethyl)-benzoic acid methyl ester
m-[(2-methyl)(2-isopropylamino)-ethyl]benzoic acid methyl ester
m-[2-(methylisopropylamino)-ethyl]benzoic acid methyl ester
m-[2-(benzylmethylamino)-ethyl]-benzoic acid n-propyl ester
m-[2-(benzylmethylamino)-ethyl]benzoic acid t-butyl ester
m-[1-methoxy-2-(benzylmethylamino)-ethyl] benzoic acid methyl ester
m-[1-methoxy-2-(benzylamino)-ethyl]benzoic acid methyl ester
m-[(2-methyl)(2-benzylmethylamino)-ethyl]benzoic acid methyl ester
Compounds of formula I are conveniently prepared by esterifying correspondingly substituted m-benzoic acids of the formula ##SPC2##
where R 1 , R 2 , R 4 and R 5 are as above with alcohols of the formula
R 3 oh iii
where R 3 is as above.
The esterification is conducted in the presence of a strong acid, preferably a mineral acid, most preferably, concentrated sulfuric acid or an organic acid such as an aryl or alkyl sulfonic acid, e.g., tuluenesulfonic acid or methyl sulfonic acid at a temperature in the range of from about 40°C to the reflux temperature of the reaction medium. Excess amounts of the alcohol may be employed to serve as the solvent medium if desired. It is also possible to employ condensation reagents instead of acids in the esterification reaction. Suitable condensation reagents include the carbodiimides, most perferably dicyclocarbodiimide. Conditions for this reaction embodiment are known per se in the art.
It is also within the scope of the present invention to employ alternate procedures for the preparation of the esters of formula I from the acids of formula II. For example, activated derivatives of the carboxyl moiety such as an acid halide, i.e., acid chloride; acid anhydride or acid imidazole can be utilized in the esterification reaction with alcohols of formula III. These activated derivatives can be prepared from the benzoic acids of formula II by procedures well known in the art.
Additionally, the methyl and phenyl esters falling within the scope of formula I can be prepared by reacting the benzoic acids of formula II with diazomethyl or diazophenyl, respectively, under the conventional conditions for this procedure.
The benzoic acid compounds of formula II are derived from correspondingly substituted trifluoromethyl compounds of the formula ##SPC3##
where R 1 , R 2 , R 5 and R 6 are as above
by hydrolysis in the presence of a strong mineral acid such as sulfuric acid or hydrofluoric acid or a combination of these two acids or a combination of one or both of the above and another acid such as phosphoric acid, hydrochloric acid, alkyl-sulfonic acid (preferably methyl sulfonic acid or aryl sulfonic acid, preferably toluene sulfonic acid). This hydrolysis reaction may be conducted at a temperature in the range of from about 20°C. to the reflux temperature of the reaction mixture, most preferably at about the reflux temperature of the reaction mixture.
Compounds of formula II wherein R 2 , R 4 and R 5 are hydrogen may be obtained from the corresponding m-cyanomethylbenzoic acids by catalytic reduction using H 2 and Raney nickel in the manner described by Takegi et al., Chemical Abstracts 52, 6403(g). The product compounds may be converted to corresponding compounds of the present invention by esterifying as above and then reacting the primary amine ester compound under conventional conditions with the appropriate R 4 and/or R 5 derivative, such as for example, the halide derivative to alkylate the amine. Suitable halide derivatives for this purpose include benzyl chloride, methyl iodide and the like. Alternatively, alkylation may be accomplished using the desired aldehyde of a R 4 and/or R 5 compound, such as formaldehyde, benzaldehyde, etc. followed by reduction in a manner known per se.
Compounds of formula IV, where not already available in the art can be obtained starting from a m-trifluoromethylphenyl-magnesium Grignard reagent by reaction with an appropriate alkylene or substituted alkylene oxide, i.e., ethylene oxide, propylene oxide and the like, followed by halogenation of the resulting alcohol and then by reaction of the halide derivative with an amine of the formula ##SPC4##
where R 4 and R 5 are as above.
Examples of suitable amines falling within the scope of formula V and thus finding use in the present invention are the following: piperazine, N-methyl-piperazine, pyrrolidine, 2-methylpyrrolidine, 3-methylpyrrolidine, piperidine, 2-methylpiperidine, 3-methylpiperidine, 4-methylpiperidine, morpholine, di-beta-hydroxy-ethylamine, betahydroxyethyl-methylamine, betahydroxyethyl-benzylamine, benzyl-lower alkylamino, preferably benzyl-methyl-amine, benzyl-ethyl-amine and benzyl-propylamine and dibenzylamine; wherein the benzyl group may be substituted in any of the above with a non-interfering group in the 2, 3, 4 or alpha position. Suitable non-interfering groups include lower alkyl, preferably, methyl, lower alkoxy, preferably methoxy, halogen, preferably chloro, nitro, sulfates, phenyl and the like.
In an alternative to the above procedure, the aforesaid Grignard reagent can be reacted with ethyleneimine or a substituted homolog and the resultant primary amine can be alkylated as described hereinbefore to produce desired compounds of formula IV or, if desired, alkylation can be delayed until after hydrolysis of the trifluoromethyl group and esterification.
In another variant m-trifluoromethylacetophenone can be halogenated on the carbon adjacent to the keto group. The resulting haloketone can be reacted with an amine of formula V above and the resultant aminoketone reduced with a chemical reducing agent, such as a metal hydride, i.e., sodium hydride or a complex metal hydride, i.e., lithium aluminum hydride or sodium borohydride to yield the desired compounds of formula IV wherein R 1 is hydroxy.
The benzoic acid ester derivatives of the present invention can be conveniently prepared by a sequence of reactions as outlined above. These compounds are made readily accessible by such reaction sequences due to the relative inertness of the trifluoromethyl group which does not interfere with preparation of the Grignard reagents.
The preceding reactions can be illustrated by the following reaction schemes:
m--CF 3 --C 6 H 4 --Br + Mg➝m--CF 3 --C 6 H 4 --MgBr ##SPC5##
m--CF 3 --C 6 H 4 --CH 2 --CH 2 OH + SOCl 2 ➝m--CF 3 --C 6 H 4 --CH 2 --CH 2 Cl
m--CF 3 --C 6 H 4 --CH 2 --CH 2 Cl + HNR 4 R 5 ➝m--CF 3 --C 6 H 4 --CH 2 --CH 2 NR 4 R 5
m--CF 3 --C 6 H 4 --CH 2 --CH 2 NR 4 R 5 H O m--HOOC--C 6 H 4 --CH 2 --CH 2 NR 4 R 5
m--HOOC--C 6 H 4 --CH 2 --CH 2 --NR 4 R 5 + R 3 OH➝m--R 3 OOC--C 6 H 4 --CH 2 --CH 2 --NR 4 R 5
m--CF 3 --C 6 H 4 --CO--CF 3 + Br 2 ➝m--CF 3 --C 6 H 4 --CH 2 --CH 2 Br
m--CF 3 --C 6 H 4 --CO--CH 2 Br + HNR 4 R 5 ➝m--CF 3 --C 6 H 4 --COCH 2 NR 4 R 5
m--CF 3 --C 6 H 4 --CO--CH 2 NR 4 R 5 + LiAlH 4 ➝m--CF 3 --C 6 H 4 --CHOH--CH 2 NR 4 R 5
m--CF 3 --C 6 H 4 --CHOH--CH 2 NR 4 R 5 H O m--HOOC--C 6 H 4 --CHOH--CH 2 NR 4 R 5
m--HOOC--C 6 H 4 --CHOH--CH 2 NR 4 R 5 +R 3 OH➝m--R 3 OOC--C 6 H 4 --CHOH--CH 2 NR 4 R 5 ##SPC6##
m--HOOC--C 6 H 4 --CH 2 --CN H m--HOOC--C 6 H 4 --CH 2 --CH 2 --NH 2
m--HOOC--C 6 H 4 --CH 2 --CH 2 --NH 2 alkylation m--HOOC--C 6 H 4 --CH 2 --CH 2 --NR 4 R 5
m--HOOC--C 6 H 4 --CH 2 --CH 2 --NR 4 R 5 +R 3 OH➝m--R 3 OOC--C 6 H 4 --CH 2 --CH 2 --NR 4 R 5
m--HOOC--C 6 H 4 --CH 2 --CH 2 --NH 2 +R 3 OH➝m--R 3 OOC--C 6 H 4 --CH 2 --CH 2 --NH 2
m--R 3 OOC--C 6 H 4 --CH 2 --CH 2 NH 2 alkylation m--R 3 OOC--C 6 H 4 --CH 2 --CH 2 NR 4 R 5
The above reaction schemes are for purpose of illustration; it is within the skill of the art to utilize different sequences of the above reaction or to apply them to related compounds.
It is also within the scope of the present invention to prepare compounds of formula I bearing additional non-interfering groups on the aromatic ring. Such non-interfering groups include lower alkyl, halogen, hydroxy, lower alkoxy, nitro, sulfato and the like. Furthermore, compounds of formula I may contain asymmetric carbon atoms in the ethylene sidechain depending on secondary substitution or asymmetric centers in other places. Racemic mixtures as well as the optical enantiomers of such compounds are to be considered within the scope of this invention. Racemate pairs can be separated by conventional resolution procedures, such as, for example, fractional crystallization of diastereomer salts formed with an optically active acid, i.e., tartaric acid, camphorsulfonic acid and the like. Chromatographic procedures for effecting such resolution are also known in the art.
The compounds of formula I of the present invention are useful in facilitating certain parameters of intellectual performance in the experimental animal and in man, such as, for example, the enhancement of learning and memory. Additionally, the compounds of formula I are useful as cholinergic and spasmolytic agents. These compounds can be administered for prolonged periods of time without producing undesirable side effects as determined by standard pharmacological evaluation.
The spasmolytic activity of the instant compounds can be demonstrated by the effect on the isolated ileum stimulated by such spasmogens as acetyl chloine, barium chloride and histamine. Using papaverine as a standard, the following table demonstrates the comparable activity found as a result of this test.
______________________________________ Spasmolytic Activity in the Isolated Rabbit Ileum ______________________________________ Papaverine 100 % m-[2-(benzylmethylamino)-ethyl]benzoic acid methyl ester 300 % m-[2-(benzylmethylamino)-ethyl]benzoic acid ethyl ester 300 % m-(2-morpholinoethyl)benzoic acid methyl ester 30 % m-[2-(N-methylpiperazino)ethyl]benzoic acid methyl ester 80 % m-(2-piperidinoethyl)benzoic acid methyl ester 50 % m-[2-(benzylethylamino)ethyl]benzoic acid methyl ester 300 % m-[2-(N-benzyl-N-2-methoxyethylamino)- ethyl]- benzoic acid methyl ester 100 % ______________________________________
Both acquisition and memory retention appear improved in the experimental animal after treatment with the compounds of this invention. Standard avoidance response tests using negative reinforcement (electric shock) as well as maze tests using positive reinforcement (water reward) were conducted using rats as the experimental animal. Using m-[2-(benzylmethylamino)-ethyl]-benzoic acid methyl ester as the test compound, it was found that a compound of this structure facilitates the rats acquisition and increases subsequent retention.
The compounds of this invention not only exhibit the various activities hereinbefore described but moreover are of low toxicity and exhibit few undesirable side effects. For example, a preferred species of the invention m-[2-(benzylmethylamino)-ethyl]-benzoic acid methyl ester was found to have an oral LD 50 of about 500-700 mg/kg in mice.
Reproduction studies have been carried out through two offspring generations and no evidence of malformation has been found after treatment with compounds of this invention. Additionally, pathological examination of brains, livers, and other organs of rats at termination of chronic toxicity studies revealed no evidence of pathological changes due to drug action. Tolerance studies have been carried out in the dog and monkey where the compounds of formula I were found well tolerated in doses as high as 50 mg/kg.
When utilized to enhance mental performance in higher mammals, the compounds of formula I may be administered in oral dosages in the range of from about 0.01 to about 4 mg/kg, preferably in the range of from about 0.01 to about 2 mg/kg, most preferably from about 0.05 to about 1.2 mg/kg. Parenteral dosages of about 10 to 100 times these levels are preferred in laboratory test animals.
The desired compounds of this invention are employed in the described uses in the form of nontoxic acid addition salts and may be administered to mammalians as pure compounds. It is advisable, however, to first combine one or more of the novel compounds with a suitable pharmaceutical carrier to attain a more satisfactory size to dosage relationship.
Pharmaceutical carriers which are liquid or solid may be used, the preferred liquid carrier being water in a pharmaceutically acceptable emulsion, suspension or solution. Flavoring materials may be included in the solutions as desired.
Solid pharmaceutical carriers such as starch, sugar, talc, mannitol and the like may be used to form powders. The powders may be given directly or incorporated in tablet, capsule or suppository preparations.
EXAMPLE 1
A total of 20 g. of N-benzyl-N-methyl-3-trifluoromethyl-phenethylamine hydrochloride was dissolved in 40 g. of concentrated sulfuric acid and the resultant solution was heated on a water bath for 3 hours. The reaction mixture was then cooled and combined with 50 ml. of methyl alcohol. This solution was refluxed for 3 hours at which time most of the excess methyl alcohol was removed by distillation. The residual mixture was cooled and poured slowly into 200 ml. of cold water. The acid aqueous solution was carefully made alkaline and extracted with ether. The ether extract was dried and anhydrous hydrochloric acid/ether was added. The crude hydrochloride salt precipitated and was recrystallized from methyl alcohol/ether and then from isoamyl alcohol/ether mixtures. A total of 11.2 g. of white crystalline material consisting of m-[2-(benzylmethylamino)-ethyl]-benzoic acid methyl ester hydrochloride was obtained melting at 150°-151°C.
The hydrochloride salt was converted to the free base by addition of alkali hydroxide to the aqueous solution of the salt. The base was extracted with ether and the ether removed in vacuo.
______________________________________ Analysis: Calculated for C 18 H 21 NO 2 : Neut. Equiv., 283 Found: Neut. Equiv., 287 ______________________________________
The free benzoic acid derivative was obtained by hydrolysis of the hydrochloride salt of the ester with hydrochloric acid and after recrystallization there was obtained crude m-[2-(benzyl-methylamino)-ethyl]benzoic acid.
The starting material may be prepared as follows:
To a refluxing and vigorously stirred solution of the Grignard reagent prepared from 100 g. (0.444 moles) of m-trifluoromethylbromobenzene and 12 g. (0.5 moles) of magnesium in 400 ml. of anhydrous ether there was added an ether solution of 40 g. (0.89 mole) of ethylene oxide. Reflux was maintained by the exothermic reaction and continued after the addition was completed for four additional hours. The reaction mixture, after cooling, was decomposed by pouring into iced, diluted hydrochloric acid. The ether layer was separated, washed briefly, dried and distilled. The residue yielded 59 g. (65%)of 3-trifluoromethyl phenethyl alcohol, b.p. 73°-76°C/0.4 mm.
To a refluxing mixture of 95 g. (0.8 mole) of thionyl chloride in 300 ml. of chloroform and 0.5 g. of pyridine there was added dropwise with vigorous stirring 135 g. (0.71 mole) of 3-trifluoromethyl phenethyl alcohol. After the addition was completed reflux was continued for 2 hours. Excess thionyl chloride and hydrochloric acid was removed in vacuo. The chloroform solution was briefly washed with water, bicarbonate solution, and then water again. The organic layer was dried and distilled. Yield 140 g. (95%) of 3-trifluoromethyl-phenethyl-chloride boiling at 98°-100 °C/25 mm.
A mixture of 20 g. (0.1 mole) of 3-trifluoromethyl-phenethyl-chloride and 25 g. (0.2 mole) of benzylmethylamine was heated for 12 hours at 100°C. Upon cooling, the reaction mixture was acidified with aqueous hydrochloric acid and extracted with ether. The ether soluble portion was cooled, made alkaline with alkali hydroxide and the liberated base extracted with ether. The ether extract was dried and distilled to yield N-benzyl-N-methyl-3-trifluoromethyl-phenethyl-amine as a colorless liquid. The yield was 24 g. (82%), b.p. 109°-110°C/0.3 mm.
______________________________________ Analysis: Calculated for C 17 H 18 F 3 N: Neut. Equiv. 293 Found: Neut. Equiv. 204 ______________________________________
EXAMPLE 2
In analogy to the procedure of Example 1, hydrolysis of N-benzyl-N-methyl-3-trifluoromethyl-phenethylamine with sulfuric acid, followed by esterification with ethyl alcohol yielded m-[2-(benzylmethylamino)-ethyl]benzoic acid ethyl ester. M.p. 115°-117°C.
______________________________________ Analysis: Calculated for C 19 H 23 NO 2 : Neut. Equiv. 297 Found: Neut. Equiv. 301 ______________________________________
EXAMPLE 3
In analogous fashion to Example 1 N,N-diethyl-3-trifluoromethyl-phenethylamine was hydrolyzed with sulfuric acid followed by esterification with methyl alcohol to yield m-[2-diethylamino)-ethyl]benzoic acid methyl ester. Conversion to the hydrochloride salt as above yielded product melting at 116°C.
______________________________________ Analysis: Calculated for C 14 H 20 NO 2 : Neut. Equiv. 271 Found: Neut. Equiv. 270 ______________________________________
The starting materials may be prepared as follows:
A mixture of 15 g. (0.0685 mole) of 3-trifluoromethyl-phenethyl-chloride and 12 g. of (0.167 mole of diethylamine in isopropyl alcohol was heated in a pressure bottle at 110°C. for 12 hours. The reaction mixture was worked up in analogous fashion to that described in Example 1. Upon distillation 7.5 g. (48.5%) of N,N-diethyl-3-trifluoromethyl-phenethylamine was obtained boiling at 118°-120°C/25 mm.
______________________________________ Analysis: Calculated for C 13 H 18 F 3 N: Neut. Equiv., 245 Found: Neut. Equiv., 242 ______________________________________
EXAMPLE 4
Hydrolysis of N-(p-chlorobenzyl)-N-methyl-3-trifluoromethyl-phenethylamine with sulfuric acid, followed by esterification with methyl alcohol in analogy to the procedure of Example 1 yielded m-[2-(4-chlorobenzylmethylamino)-ethyl]benzoic acid methyl ester.
______________________________________ Analysis: Calculated for C 17 H 18 ClNO 2 : Neut. Equiv., 304 Found: Neut. Equiv., 307 ______________________________________
Conversion of the free base to the hydrochloride salt in the manner described in Example 1 yielded product melting at 228°C.
The starting material may be prepared as follows:
A total of 8 g. (0.038 mole) of 3-trifluoromethyl-phenethylchloride and 6 g. (0.038 mole) of N-(p-chlorophenyl)-N-methylamine in 20 ml. of isopropyl alcohol containing 6 g. (0.043 mole) of potassium carbonate were reacted at 100°C. for 14 hours. The reaction mixture was worked up in the manner analogous to that in Example 1. After distillation 4.7 g. (37.7%) of the free base of N-(p-chlorobenzyl)-N-methyl-3-trifluoromethyl-phenethylamine was obtained boiling at 132°-134°C/0.5 mm.
______________________________________ Analysis: Calculated for C 17 H 17 ClF 3 N: Neut. Equiv., 328 Found: Neut. Equiv., 324 ______________________________________
EXAMPLE 5
In analogy to the procedure of Example 1 N-isopropyl-α-methyl-3-trifluoromethyl-phenethylamine was hydrolyzed with sulfuric acid and then esterified with methyl alcohol to yield m-[(2-methyl) (2-isopropylamine)-ethyl]benzoic acid methyl ester which when converted to the hydrochloride salt melted at 211°C.
______________________________________ Analysis: Calculated for C 14 H 20 NO 2 : Neut. Equiv., 234 Found: Neut. Equiv., 236 ______________________________________
The starting material may be prepared as follows:
3-Trifluoromethyl-phenylmagnesium bromide and propylene oxide were reacted in analogous manner to that described in Example 1. The liquid α-methyl-3-trifluoromethyl-phenethyl alcohol obtained in 50% yield had a boiling point of 80°C/1 mm.
To a refluxing mixture of 77.3 g. (0.65 mole) of thionyl chloride in 350 ml. of chloroform and 0.5 g. of pyridine there was added dropwise with vigorous stirring 120.4 g. (0.589 mole) of α-methyl-3-trifluoromethyl-phenethyl alcohol. After the addition was completed reflux was continued for 2 hours. Excess thionyl chloride and hydrochloric acid were removed in vacuo. The chloroform solution was briefly washed with water, bicarbonate solution and water. It was dried and distilled to yield 110 g. (90%) of α-methyl-3-trifluoromethyl-phenethyl chloride boiling at 103°-105°C/25 mm.
EXAMPLE 6
By analogy to the procedures of Example 1 m-[(2-methyl)(2-benzylmethylamino)-ethyl]benzoic acid methyl ester was prepared by sulfuric acid hydrolysis and methanol esterification of N-benzyl-N-methyl-α-methyl-3-trifluoromethyl phenethylamine.
The starting material may be prepared as follows:
By a procedure analogous to Example 1 α-methyl-3-trifluoromethyl-phenethylchloride was reacted with benzylmethylamine to yield N-benzyl-N-methyl-αmethyl-3-trifluoromethyl phenethylamine boiling at 115°C/0.5 mm.
______________________________________ Analysis: Calculated for C 18 H 20 F 3 N: Neut. Equiv., 307 Found: Neut. Equiv., 307 ______________________________________
EXAMPLE 7
In analogy to the procedure of Example 1 3-trifluoromethyl-phenethyl-morpholine was hydrolyzed in sulfuric acid and esterified with methyl alcohol to produce m-(2-morpholinoethyl)-benzoic acid methyl ester. m.p. 207°-208°C. (acetone).
______________________________________ Analysis: Calculated for C 14 H 19 NO 3 : Neut. Equiv., 249 Found: Neut. Equiv., 250 ______________________________________
The starting material may be prepared as follows:
According to the procedure of Example 1 3-trifluoromethyl-phenethylchloride was reacted with morpholine to produce 3-trifluoromethyl-phenethyl morpholine in 84% yield, the pre-base product boiling at 80°C/0.3 mm.
______________________________________ Analysis: Calculated for C 14 H 18 F 3 N: Neut. Equiv., 247 Found: Neut. Equiv., 249 ______________________________________
EXAMPLE 8
In analogy to the procedure of Example 1 m-(2-piperidinoethyl)-benzoic acid methyl ester was prepared by the sulfuric acid hydrolysis and esterification with methyl alcohol of 3-trifluoromethyl-phenethylpiperidine.
______________________________________ Analysis: Calculated for C 15 H 21 NO 2 : Neut. Equiv., 247 Found: Neut. Equiv., 251 ______________________________________
The starting material may be prepared as follows:
In accordance with the procedure of Example 1 3-trifluoromethyl-phenethylchloride was reacted with piperidine to give 3-trifluoromethyl-phenethylpiperidine in 70% yield, boiling at 78°C/0.4 mm. m.p. 219°-220°C. (acetone).
______________________________________ Analysis: Calculated for C 14 H 18 F 3 N: Neut. Equiv., 257 Found: Neut. Equiv., 260 ______________________________________
EXAMPLE 9
A mixture of 4 grams of m-[2-(benzylmethylamino)-ethyl]-benzoic acid methyl ester, 10 g. of n-propylalcohol and 4 g. of concentrated sulfuric acid was heated to reflux temperature. Workup in the normal manner yielded m-[2-(benzylmethylamino)-ethyl]benzoic acid n-propyl ester which when converted to the hydrochloride salt had a melting point of 108°C.
______________________________________ Analysis: Calculated for C 20 H 25 NO 2 : Neut. Equiv., 311 Found: Neut. Equiv., 312 ______________________________________
EXAMPLE 10
Reaction of 5 grams (0.0163 mole) of m-[2-(benzylmethylamino)-ethyl]benzoic acid and 6 g. of thionyl chloride yielded the corresponding crude acid chloride which was then further reacted without purification with 74 g. (1 mole) of t-butyl alcohol at reflux. Upon removal of the excess alcohol the free base of m-[2-(benzylmethylamino)-ethyl]benzoic acid t-butyl ester is obtained. Conversion to the hydrochloride in the previously described manner followed by recrystallization of the hydrochloride salt from acetone ether yielded the pure hydrochloride salt melting at 196°C.
______________________________________ Analysis: Calculated for C 19 H 30 NO 2 : Neut. Equiv., 304 Found: Neut. Equiv., 308 ______________________________________
EXAMPLE 11
By analogy to the procedure of Example 1 3-trifluoromethylphenethyl-N-methylpiperazine was hydrolyzed in concentrated sulfuric acid and esterified with methyl alcohol to yield m-[2-(N-methylpiperazino)-ethyl]benzoic acid methyl ester. M.P. 229°-230°C.
______________________________________ Analysis: Calculated for C 15 H 22 N 2 O 2 : Neut. Equiv., 262 Found: Neut. Equiv., 264 ______________________________________
The starting material may be prepared as follows:
Utilizing the procedure of Example 1 3-trifluoromethylphenethyl chloride was reacted with N-methylpiperazine to give N-methyl-N'-(3-trifluoromethyl)-phenethylpiperazine in 68% yield boiling at 89°-90°C/0.3 mm.
______________________________________ Analysis: Calculated for C 14 H 19 F 3 N 2 : Neut. Equiv., 272 Found: Neut. Equiv., 275 ______________________________________
EXAMPLE 12
In analogy to the procedure of Example 1 concentrated sulfuric acid hydrolysis of N-benzyl-N-ethyl-3-trifluoromethylphenethylamine followed by esterification with methyl alcohol yielded m-[2-(benzylethylamino)-ethyl]benzoic acid methyl ester.
______________________________________ Analysis: Calculated for C 19 H 23 NO 2 : Neut. Equiv., 297 Found: Neut. Equiv., 299 ______________________________________
M.p. 125°-127°C. (acetone).
The starting material may be prepared as follows:
By the procedure described in Example 1 N-benzyl-N-ethyl-3-trifluoromethyl-phenethylamine was prepared by the reaction between 3-trifluoromethyl-phenethylchloride and benzylethylamine.
EXAMPLE 13
Analogous to the procedure of Example 1 N-benzyl-N-(2-methoxyethyl)-3-trifluoromethyl-phenethylamine was hydrolyzed in concentrated sulfuric acid followed by esterification with methyl alcohol to yield m-[2-(N-benzyl-N-(2-methoxyethyl)amino)-ethyl]benzoic acid methyl ester.
______________________________________ Analysis: Calculated for C 20 H 25 NO 3 : Neut. Equiv., 327 Found: Neut. Equiv., 330 ______________________________________
The starting material may be prepared as follows:
A total of 10 g. (0.05 mole) of 3-trifluoromethyl-phenethylchloride was reacted with 16 g. (0.1 mole) of 2-methoxyethylbenzylamine for 12 hours at 110°C. The reaction mixture was worked up in the manner described in Example 1 and after distillation 7.9 g (46.5%) of the free base of N-benzyl-N-(2-methoxyethyl)-3-trifluoromethyl-phenethylamine was obtained boiling at 120°C/0.3 mm.
______________________________________ Analysis: Calculated for C 19 H 22 F 3 NO: Neut. Equiv., 337 Found: Neut. Equiv., 341 ______________________________________
EXAMPLE 14
In a manner analogous to Example 1 N-benzyl-N-methyl-β-methoxy-3-trifluoromethyl-phenethylamin e was hydrolyzed with concentrated sulfuric acid followed by esterification with methyl alcohol. The solution of the product ester in acid of methanol was poured into an excess of ice cold water and the mixture was rendered alkaline with sodium hydroxide.
The free base was extracted with ether and the extract dried over potassium carbonate and distilled. Distillation yielded m-[1-methoxy-2-(benzylmethylamino)-ethyl]benzoic acid methyl ester boiling at 150°C/0.3 mm.
______________________________________ Analysis: Calculated for C 19 H 23 NO 3 : Neut Equiv., 313 Found: Neut Equiv., 316 ______________________________________
The starting material may be prepared as follows:
In analogy to the procedure of Example 1 a mixture of 14 g. (0.05 mole) of β-methoxy-3-trifluoromethyl-phenethyl bromide and 13 g. (0.1 mole) of benzylmethylamine was reacted at 100°C. for three hours. Distillation yielded N-benzyl-N-methyl-β-methoxy-3-trifluoromethyl-phenethylamin e boiling at 105°C/0.2 mm.
______________________________________ Analysis: Calculated for C 18 H 20 F 3 NO: Neut. Equiv., 323 Found: Neut. Equiv., 325 ______________________________________
EXAMPLE 15
In analogous manner to the procedure of Example 1 hydrolysis of N-benzyl-β-methoxy-3-trifluoromethyl-phenethylamine with concentrated sulfuric acid followed by esterification with methyl alcohol yielded m-[1-methoxy-2-(benzylamino)-ethyl]benzoic acid methyl ester. Conversion to the hydrochloride salt yielded material melting at 243°C.
______________________________________ Analysis: Calculated for C 18 H 21 NO 3 : Neut. Equiv., 299 Found: Neut. Equiv., 302 ______________________________________
The starting material may be prepared as follows:
In analogous fashion to the procedure of Example 1 a mixture of 25 g. (0.09 mole) of β-methoxy-3-trifluoromethylphenethyl bromide was reacted with 19 g. (0.18 mole) of benzylamine at 100°C. for 3 hours. Distillation yielded N-benzylβ-methoxy-3-trifluoromethyl-phenethylamine boiling at 137°C/0.3 mm.
______________________________________ Analysis: Calculated for C 18 H 19 F 3 NO: Neut. Equiv., 309 Found: Neut. Equiv., 311 ______________________________________
EXAMPLE 16
Tablet Formulation ______________________________________ Mg/Tablet ______________________________________ m-[2-(benzylmethylamino)-ethyl]benzoic acid methyl ester hydrochloride 25.0 Lactose 98.0 Corn Starch 61.0 Corn Starch as 10% Paste 5.0 Talcum 4.5 Magnesium Stearate 1.5 Corn Starch 5.0 Tablet Weight 200.0 ______________________________________
Procedure:
1. Mix the m-[2-(benzylmethylamino)ethyl]benzoic acid methyl ester hydrochloride, lactose and corn starch in a suitable mixing container and add the starch paste slowly to achieve a heavy, moist mass.
2. Pass this moist mass through a No. 10 mesh screen (or similar suitable coarse screen).
3. Place the moist granules on drying pans and dry at 110°F.
4. pass the dried granules through a No. 16 mesh screen, place in a suitable mixing container and add the talcum, magnesium stearate, and second portion of corn starch.
5. Mix well and compress into tablets on either a single or multiple tabletting machine to an individual tablet weight of 200 mgs. An 11/32 inch standard concave scored punch is suitable, yielding tablets with a thickness of approximately 3.35 mm.
EXAMPLE 17
Tablet Formulation ______________________________________ Per Tablet ______________________________________ m-[ 2-(benzylmethylamino)-ethyl]benzoic acid methyl ester hydrochloride 100 mg. Lactose, U.S.P. 202 mg. Corn Starch, U.S.P. 80 mg. Amijel BO11* 20 mg. Calcium Stearate 8 mg. Total Weight 410 mg. ______________________________________ *A prehydrolyzed food grade corn starch. Any similar prehydrolyzed corn starch may be used.
Procedure:
1. m-[2-(benzylmethylamino)-ethyl]benzoic acid methyl ester hydrochloride, lactose, corn starch, and Amijel BOll were blended in a suitable mixer.
2. The mixture was granulated to a heavy paste with water and the moist mass was passed through a No. 12 screen. It was then dried overnight at 110°F.
3. the dried granules were passed through a No. 16 screen and transferred to a suitable mixer. The calcium stearate was added and mixed until uniform.
4. The mixture was compressed at a tablet weight of 410 mg. using tablet punches having a diameter of approximately 3/8 inch. (Tablets may be either flat or biconvex and may be scored if desired.)
EXAMPLE 18
Capsule Formulation ______________________________________ Per Capsule ______________________________________ m-[2-(Benzylmethylamino)-ethyl]benzoic acid methyl ester hydrochloride 5 mg. Lactose 178 mg. Corn Starch 37 mg. Talc 5 mg. Total Weight 225 mg. ______________________________________
Procedure:
1. m-[2-(Benzylmethylamino)-ethyl]benzoic acid methyl ester hydrochloride was mixed with the lactose and corn starch in a suitable mixer.
2. The mixture was further blended by passing through a Fitzpatrick Comminuting Machine with a No. 1A screen with knives forward.
3. The blended powder was returned to the mixer, the talc added and blended thoroughly. The mixture was then filled into No. 4 hard shell gelatin capsules on a Parke Davis capsulating machine (any similar type machine may be used.)
EXAMPLE 19
Capsule Formulation ______________________________________ Per Capsule ______________________________________ m-[2-(Benzylmethylamino)-ethyl]benzoic acid methyl ester hydrochloride 50 mg. Lactose, U.S.P. 125 mg. Corn Starch, U.S.P. 30 mg. Talc, U.S.P. 5 mg. Total Weight 210 mg. ______________________________________
Procedure:
1. m-[2-(Benzylmethylamino)-ethyl]benzoic acid methyl ester hydrochloride was mixed with lactose and corn starch in a suitable mixer.
2. The mixture was further blended by passing through a Fitzpatrick Comminuting Machine with a No. 1A screen with knives forward.
3. The blended powder was returned to the mixer, the talc added and blended thoroughly.
4. The mixture was filled into No. 4 hard shell gelatin capsules on a Parke Davis capsulating machine.
EXAMPLE 20
Analogous to the procedure of Example 9, m-[2-(benzylamino)-ethyl]-benzoic acid methyl ester was transesterified with benzyl alcohol in the presence of concentrated sulfuric acid. After workup in the usual manner and conversion to the hydrochloride salt, the product m-[2-(benzylamino)-ethyl]benzoic acid benzyl ester hydrochloride was obtained, m.p. 153°-155°C.
EXAMPLE 21
By analogy to the procedure of Example 1 N-methyl-3-trifluoromethyl phenethylamine was hydrolyzed and then esterified with m-cresol followed by conversion to the hydrochloride to yield m-[2-(methylamino)-ethyl]benzoic acid, m-cresyl ester hydrochloride melting at 162°C.
______________________________________ Analysis: Calculated for C 17 H 19 NO 2 : Neut. Equiv., 269 Found: Neut. Equiv., 272 ______________________________________
The starting material may be prepared as follows:
In analogy to the procedure of Example 1, trifluoromethylphenethyl chloride was reacted with anhydrous monomethylamine in methanol in a pressure bottle for four hours at 110°C. Isolation in the usual manner yielded N-methyl-3-trifluoromethylphenethylamine boiling at 94°-96°C/40 mm.
______________________________________ Analysis: Calculated for C 10 H 12 F 3 N: Neut. Equiv., 203 Found: Neut. Equiv., 197 ______________________________________
Conversion to the hydrochloride in the usual manner yielded the salt melting at 146°-147°C.
EXAMPLE 22
In analogy to the procedure of Example 1, 3-trifluoromethylphenethyl pyrrolidine was hydrolyzed, esterified with methyl alcohol, and converted to the hydrochloride to yield m-(2-pyrrolidinoethyl)-benzoic acid methyl ester hydrochloride melting at 188°-189°C.
______________________________________ Analysis: Calculated for C 14 H 19 NO 2 : Neut. Equiv., 223 Found: Neut. Equiv., 223 ______________________________________
The starting material may be prepared inanalogy to the method of Example 1 wherein 3-trifluoromethylphenethyl chloride was reacted with pyrrolidine to produce 3-trifluoromethylphenethyl pyrrolidine in 51% yield as a liquid boiling at 117°C./30 mm.
______________________________________ Analysis: Calculated for C 13 H 16 F 3 N: Neut. Equiv., 243 Found: Neut. Equiv., 244 ______________________________________
EXAMPLE 23
In analogy to the procedure of Example 1, 3-trifluoromethylphenethyl-p-toluidene was hydrolyzed with concentrated sulfuric acid and esterified with methyl alcohol followed by conversion to the hydrochloride to yield m-2-(p-toluidinoethyl)-benzoic acid methyl ester hydrochloride, melting at 156°-157°C.
______________________________________ Analysis: Calculated for C 17 H 19 NO 2 : N. 4.58 Found: N. 4.45 ______________________________________
The starting material may be prepared as follows:
3-Trifluoromethylphenethyl chloride and p-toluidine were reacted in analogy to the procedure in Example 1 to yield 3-trifluoromethylphenethyl-p-toluidine boiling at 147°C./1.8 mm.
______________________________________ Analysis: Calculated for C 16 H 16 F 3 N: N. 4.45 Found: N. 4.25. ______________________________________
Conversion to the hydrochloride in the usual manner yielded the corresponding hydrochloride salt melting at 162°-163°C.
EXAMPLE 24
In analogy to the procedure of Example 1, N-methyl-N-2-hydroxy ethyl-β-hydroxy-α-methyl-3-trifluoromethylphenethylamine was hydrolyzed with concentrated sulfuric acid and esterified with methyl alcohol followed by conversion to the hydrochloride to yield m-2-(N-methyl-N-2-hydroxyethyl)amino-β-hydroxy-α-methyl-be nzoic acid, methyl ester hydrochloride, melting at 206°-207°C.
______________________________________ Analysis: Calculated for C 14 H 21 NO 4 .HCl: N. 4.62 Found: N. 4.37 Calculated for Cl: 11.3 Found: 11.1 ______________________________________
EXAMPLE 25
A total of 3.0 g. of m-2-cyclohexylaminoethyl-benzoic acid methyl ester hydrochloride was added to 20 ml. of methanol and there was thereafter added 1.15 g. of 1bromo-3-methyl butane and 3.5 g. of potassium carbonate. The reaction mixture was heated at reflux for 36 hours, cooled and then poured into 300 cc of ice water. The crystalline product was filtered off, washed with water and then with ether. The crude product was then recrystallized from methanol/acetone to yield m-(2-N-cyclohexyl-N-isopentylamino)-ethyl-benzoic acid methyl ester melting at 245°-246°C.
______________________________________ Analysis: Calculated for C 21 H 33 NO 2 : Neut. Equiv., 331 Found: Neut. Equiv., 331 ______________________________________
The starting material may be prepared as follows:
In analogy to the procedure of Example 1, 3-trifluoromethylphenethyl chloride was reacted with cyclohexylamine to yield 3-trifluoromethylphenethyl cyclohexylamine boiling at 116°C./1.1 mm.
______________________________________ Analysis: Calculated for C 15 H 20 F 3 N: Neut. Equiv., 271 Found: Neut. Equiv., 270 ______________________________________
Hydrolysis of 3-trifluoromethylphenethyl cyclohexylamine in analogy to the procedure of Example 1 with concentrated sulfuric acid followed by esterification with methyl alcohol and conversion to the hydrochloride yielded m-(2-cyclohexylamino)-ethyl benzoic acid methyl ester hydrochloride, melting at 210°-211°C.
______________________________________ Analysis: Calculated for C 16 H 23 NO 2 : Neut. Equiv., 261 Found: Neut. Equiv., 262 ______________________________________
M-aminoethyl benzoic acid is described in Chemical Abstracts 52, 6404. Para-aminoethyl benzoic acid and its ethyl ester is disclosed in Chemical Abstracts 25, 2194. Diethylaminomethylbenzoic acid and its ethyl ester is shown in Beilstein XIV, 488. Various p-(amino-alkyl)benzoic acids and esters are disclosed in Chemical Abstracts 38, 732.
BRIEF DESCRIPTION OF THE INVENTION
The present invention relates to a series of substituted aminoethyl meta benzoic acid esters and their salts which compounds are useful as spasmolytics, psychotherapeutic agents and agents facilitating learning. The compounds of the present invention have the general structural formula ##SPC1##
Wherein R 1 is hydrogen, hydroxy, lower alkoxy or lower alkyl; R 2 is hydrogen or lower alkyl; R 3 is lower alkyl, aralkyl or lower alkyl aryl; R 4 taken independently is hydrogen, lower alkyl, aralkyl, lower alkyl aryl, hydroxy lower alkyl and lower alkoxy lower alkyl; R 5 taken independently is lower alkyl, aralkyl, lower alkyl aryl or lower alkoxy lower alkyl; and R 4 and R 5 taken together with the adjacent nitrogen atom form a saturated five or six membered heterocyclic ring which may contain one additional hetero atom selected from the group consisting of --O-- and --NR 6 -- where R 6 is hydrogen or lower alkyl
And the pharmaceutically acceptable acid addition salts thereof.
As used herein the term "lower" includes radical groups containing from 1 to 7 carbon atoms. The term "alkyl" is meant to include straight or branched chain hydrocarbon radicals such as methyl, ethyl, n-propyl, T-butyl, hexyl, heptyl, and the like. The term "alkoxy" is meant to include a radical group wherein an alkyl moiety is bonded to an oxygen atom through an ether linkage, the valence of the radical being derived from said oxygen atom. Suitable examples of alkoxy groups include methoxy, ethoxy, butoxy and the like. The term "aralkyl" is meant to include radical groups such as phenyl lower alkyl, especially radical groups such as benzyl, phenylethyl and the like. "Lower alkyl aryl" is meant to encompass groups such as lower alkyl phenyl, particularly tolyl, xylyl and the like. The term "lower alkoxy lower alkyl" is meant to include radical groups such as methoxy methyl, methoxy ethyl, ethoxy methyl, ethoxy ethyl, and the like. Examples of suitable heterocyclic radical groups obtained when R 4 and R 5 are taken together with the adjacent nitrogen atom include morpholino, piperidino, piperazino and N-lower alkyl piperazino.
The compounds of formula I form acid addition salts with a variety of inorganic and organic acids. Suitable inorganic acids for this purpose include the hydrohalic acids such as hydrochloric and hydrobromic acids, sulfuric acid, phosphoric acid, sulfamic acid and the like. Suitable organic acids for this purpose include tartaric acid, citric acid, maleic acid, hexonic acid, and the like. Compounds of formula I in the form of acid addition salts with pharmaceutically unacceptable acids can be converted to acid addition salts with pharmaceutically acceptable acids by ion exchange procedures known in the art.
Preferred compounds of formula I of the present invention are obtained when R 1 is hydrogen or lower alkoxy, preferably methoxy, R 2 is hydrogen, R 3 is lower alkyl, R 4 is hydrogen or lower alkyl and R 5 is lower alkyl, aralkyl, preferably benzyl or parachloro benzyl or lower alkoxy lower alkyl, preferably methoxy ethyl.
Exemplary of compounds of the present invention are the following:
m-[2-(benzylmethylamino)-ethyl]benzoic acid methyl ester
m-[2-(benzylmethylamino)-ethyl]benzoic acid ethyl ester
m-[2-morpholino-ethyl)-benzoic acid methyl ester
m-[2-(N-methylpiperazino)ethyl]benzoic acid methyl ester
m-(2-piperidinoethyl)-benzoic acid methyl ester
m-[2-(benzylethylamino)-ethyl]benzoic acid methyl ester
m-[2-(N-benzyl-N-(2-methoxyethyl)amino)-ethyl]benzoic acid methyl ester
m-(2-diethylaminoethyl)-benzoic acid methyl ester
m-[(2-methyl)(2-isopropylamino)-ethyl]benzoic acid methyl ester
m-[2-(methylisopropylamino)-ethyl]benzoic acid methyl ester
m-[2-(benzylmethylamino)-ethyl]-benzoic acid n-propyl ester
m-[2-(benzylmethylamino)-ethyl]benzoic acid t-butyl ester
m-[1-methoxy-2-(benzylmethylamino)-ethyl] benzoic acid methyl ester
m-[1-methoxy-2-(benzylamino)-ethyl]benzoic acid methyl ester
m-[(2-methyl)(2-benzylmethylamino)-ethyl]benzoic acid methyl ester
Compounds of formula I are conveniently prepared by esterifying correspondingly substituted m-benzoic acids of the formula ##SPC2##
where R 1 , R 2 , R 4 and R 5 are as above with alcohols of the formula
R 3 oh iii
where R 3 is as above.
The esterification is conducted in the presence of a strong acid, preferably a mineral acid, most preferably, concentrated sulfuric acid or an organic acid such as an aryl or alkyl sulfonic acid, e.g., tuluenesulfonic acid or methyl sulfonic acid at a temperature in the range of from about 40°C to the reflux temperature of the reaction medium. Excess amounts of the alcohol may be employed to serve as the solvent medium if desired. It is also possible to employ condensation reagents instead of acids in the esterification reaction. Suitable condensation reagents include the carbodiimides, most perferably dicyclocarbodiimide. Conditions for this reaction embodiment are known per se in the art.
It is also within the scope of the present invention to employ alternate procedures for the preparation of the esters of formula I from the acids of formula II. For example, activated derivatives of the carboxyl moiety such as an acid halide, i.e., acid chloride; acid anhydride or acid imidazole can be utilized in the esterification reaction with alcohols of formula III. These activated derivatives can be prepared from the benzoic acids of formula II by procedures well known in the art.
Additionally, the methyl and phenyl esters falling within the scope of formula I can be prepared by reacting the benzoic acids of formula II with diazomethyl or diazophenyl, respectively, under the conventional conditions for this procedure.
The benzoic acid compounds of formula II are derived from correspondingly substituted trifluoromethyl compounds of the formula ##SPC3##
where R 1 , R 2 , R 5 and R 6 are as above
by hydrolysis in the presence of a strong mineral acid such as sulfuric acid or hydrofluoric acid or a combination of these two acids or a combination of one or both of the above and another acid such as phosphoric acid, hydrochloric acid, alkyl-sulfonic acid (preferably methyl sulfonic acid or aryl sulfonic acid, preferably toluene sulfonic acid). This hydrolysis reaction may be conducted at a temperature in the range of from about 20°C. to the reflux temperature of the reaction mixture, most preferably at about the reflux temperature of the reaction mixture.
Compounds of formula II wherein R 2 , R 4 and R 5 are hydrogen may be obtained from the corresponding m-cyanomethylbenzoic acids by catalytic reduction using H 2 and Raney nickel in the manner described by Takegi et al., Chemical Abstracts 52, 6403(g). The product compounds may be converted to corresponding compounds of the present invention by esterifying as above and then reacting the primary amine ester compound under conventional conditions with the appropriate R 4 and/or R 5 derivative, such as for example, the halide derivative to alkylate the amine. Suitable halide derivatives for this purpose include benzyl chloride, methyl iodide and the like. Alternatively, alkylation may be accomplished using the desired aldehyde of a R 4 and/or R 5 compound, such as formaldehyde, benzaldehyde, etc. followed by reduction in a manner known per se.
Compounds of formula IV, where not already available in the art can be obtained starting from a m-trifluoromethylphenyl-magnesium Grignard reagent by reaction with an appropriate alkylene or substituted alkylene oxide, i.e., ethylene oxide, propylene oxide and the like, followed by halogenation of the resulting alcohol and then by reaction of the halide derivative with an amine of the formula ##SPC4##
where R 4 and R 5 are as above.
Examples of suitable amines falling within the scope of formula V and thus finding use in the present invention are the following: piperazine, N-methyl-piperazine, pyrrolidine, 2-methylpyrrolidine, 3-methylpyrrolidine, piperidine, 2-methylpiperidine, 3-methylpiperidine, 4-methylpiperidine, morpholine, di-beta-hydroxy-ethylamine, betahydroxyethyl-methylamine, betahydroxyethyl-benzylamine, benzyl-lower alkylamino, preferably benzyl-methyl-amine, benzyl-ethyl-amine and benzyl-propylamine and dibenzylamine; wherein the benzyl group may be substituted in any of the above with a non-interfering group in the 2, 3, 4 or alpha position. Suitable non-interfering groups include lower alkyl, preferably, methyl, lower alkoxy, preferably methoxy, halogen, preferably chloro, nitro, sulfates, phenyl and the like.
In an alternative to the above procedure, the aforesaid Grignard reagent can be reacted with ethyleneimine or a substituted homolog and the resultant primary amine can be alkylated as described hereinbefore to produce desired compounds of formula IV or, if desired, alkylation can be delayed until after hydrolysis of the trifluoromethyl group and esterification.
In another variant m-trifluoromethylacetophenone can be halogenated on the carbon adjacent to the keto group. The resulting haloketone can be reacted with an amine of formula V above and the resultant aminoketone reduced with a chemical reducing agent, such as a metal hydride, i.e., sodium hydride or a complex metal hydride, i.e., lithium aluminum hydride or sodium borohydride to yield the desired compounds of formula IV wherein R 1 is hydroxy.
The benzoic acid ester derivatives of the present invention can be conveniently prepared by a sequence of reactions as outlined above. These compounds are made readily accessible by such reaction sequences due to the relative inertness of the trifluoromethyl group which does not interfere with preparation of the Grignard reagents.
The preceding reactions can be illustrated by the following reaction schemes:
m--CF 3 --C 6 H 4 --Br + Mg➝m--CF 3 --C 6 H 4 --MgBr ##SPC5##
m--CF 3 --C 6 H 4 --CH 2 --CH 2 OH + SOCl 2 ➝m--CF 3 --C 6 H 4 --CH 2 --CH 2 Cl
m--CF 3 --C 6 H 4 --CH 2 --CH 2 Cl + HNR 4 R 5 ➝m--CF 3 --C 6 H 4 --CH 2 --CH 2 NR 4 R 5
m--CF 3 --C 6 H 4 --CH 2 --CH 2 NR 4 R 5 H O m--HOOC--C 6 H 4 --CH 2 --CH 2 NR 4 R 5
m--HOOC--C 6 H 4 --CH 2 --CH 2 --NR 4 R 5 + R 3 OH➝m--R 3 OOC--C 6 H 4 --CH 2 --CH 2 --NR 4 R 5
m--CF 3 --C 6 H 4 --CO--CF 3 + Br 2 ➝m--CF 3 --C 6 H 4 --CH 2 --CH 2 Br
m--CF 3 --C 6 H 4 --CO--CH 2 Br + HNR 4 R 5 ➝m--CF 3 --C 6 H 4 --COCH 2 NR 4 R 5
m--CF 3 --C 6 H 4 --CO--CH 2 NR 4 R 5 + LiAlH 4 ➝m--CF 3 --C 6 H 4 --CHOH--CH 2 NR 4 R 5
m--CF 3 --C 6 H 4 --CHOH--CH 2 NR 4 R 5 H O m--HOOC--C 6 H 4 --CHOH--CH 2 NR 4 R 5
m--HOOC--C 6 H 4 --CHOH--CH 2 NR 4 R 5 +R 3 OH➝m--R 3 OOC--C 6 H 4 --CHOH--CH 2 NR 4 R 5 ##SPC6##
m--HOOC--C 6 H 4 --CH 2 --CN H m--HOOC--C 6 H 4 --CH 2 --CH 2 --NH 2
m--HOOC--C 6 H 4 --CH 2 --CH 2 --NH 2 alkylation m--HOOC--C 6 H 4 --CH 2 --CH 2 --NR 4 R 5
m--HOOC--C 6 H 4 --CH 2 --CH 2 --NR 4 R 5 +R 3 OH➝m--R 3 OOC--C 6 H 4 --CH 2 --CH 2 --NR 4 R 5
m--HOOC--C 6 H 4 --CH 2 --CH 2 --NH 2 +R 3 OH➝m--R 3 OOC--C 6 H 4 --CH 2 --CH 2 --NH 2
m--R 3 OOC--C 6 H 4 --CH 2 --CH 2 NH 2 alkylation m--R 3 OOC--C 6 H 4 --CH 2 --CH 2 NR 4 R 5
The above reaction schemes are for purpose of illustration; it is within the skill of the art to utilize different sequences of the above reaction or to apply them to related compounds.
It is also within the scope of the present invention to prepare compounds of formula I bearing additional non-interfering groups on the aromatic ring. Such non-interfering groups include lower alkyl, halogen, hydroxy, lower alkoxy, nitro, sulfato and the like. Furthermore, compounds of formula I may contain asymmetric carbon atoms in the ethylene sidechain depending on secondary substitution or asymmetric centers in other places. Racemic mixtures as well as the optical enantiomers of such compounds are to be considered within the scope of this invention. Racemate pairs can be separated by conventional resolution procedures, such as, for example, fractional crystallization of diastereomer salts formed with an optically active acid, i.e., tartaric acid, camphorsulfonic acid and the like. Chromatographic procedures for effecting such resolution are also known in the art.
The compounds of formula I of the present invention are useful in facilitating certain parameters of intellectual performance in the experimental animal and in man, such as, for example, the enhancement of learning and memory. Additionally, the compounds of formula I are useful as cholinergic and spasmolytic agents. These compounds can be administered for prolonged periods of time without producing undesirable side effects as determined by standard pharmacological evaluation.
The spasmolytic activity of the instant compounds can be demonstrated by the effect on the isolated ileum stimulated by such spasmogens as acetyl chloine, barium chloride and histamine. Using papaverine as a standard, the following table demonstrates the comparable activity found as a result of this test.
______________________________________ Spasmolytic Activity in the Isolated Rabbit Ileum ______________________________________ Papaverine 100 % m-[2-(benzylmethylamino)-ethyl]benzoic acid methyl ester 300 % m-[2-(benzylmethylamino)-ethyl]benzoic acid ethyl ester 300 % m-(2-morpholinoethyl)benzoic acid methyl ester 30 % m-[2-(N-methylpiperazino)ethyl]benzoic acid methyl ester 80 % m-(2-piperidinoethyl)benzoic acid methyl ester 50 % m-[2-(benzylethylamino)ethyl]benzoic acid methyl ester 300 % m-[2-(N-benzyl-N-2-methoxyethylamino)- ethyl]- benzoic acid methyl ester 100 % ______________________________________
Both acquisition and memory retention appear improved in the experimental animal after treatment with the compounds of this invention. Standard avoidance response tests using negative reinforcement (electric shock) as well as maze tests using positive reinforcement (water reward) were conducted using rats as the experimental animal. Using m-[2-(benzylmethylamino)-ethyl]-benzoic acid methyl ester as the test compound, it was found that a compound of this structure facilitates the rats acquisition and increases subsequent retention.
The compounds of this invention not only exhibit the various activities hereinbefore described but moreover are of low toxicity and exhibit few undesirable side effects. For example, a preferred species of the invention m-[2-(benzylmethylamino)-ethyl]-benzoic acid methyl ester was found to have an oral LD 50 of about 500-700 mg/kg in mice.
Reproduction studies have been carried out through two offspring generations and no evidence of malformation has been found after treatment with compounds of this invention. Additionally, pathological examination of brains, livers, and other organs of rats at termination of chronic toxicity studies revealed no evidence of pathological changes due to drug action. Tolerance studies have been carried out in the dog and monkey where the compounds of formula I were found well tolerated in doses as high as 50 mg/kg.
When utilized to enhance mental performance in higher mammals, the compounds of formula I may be administered in oral dosages in the range of from about 0.01 to about 4 mg/kg, preferably in the range of from about 0.01 to about 2 mg/kg, most preferably from about 0.05 to about 1.2 mg/kg. Parenteral dosages of about 10 to 100 times these levels are preferred in laboratory test animals.
The desired compounds of this invention are employed in the described uses in the form of nontoxic acid addition salts and may be administered to mammalians as pure compounds. It is advisable, however, to first combine one or more of the novel compounds with a suitable pharmaceutical carrier to attain a more satisfactory size to dosage relationship.
Pharmaceutical carriers which are liquid or solid may be used, the preferred liquid carrier being water in a pharmaceutically acceptable emulsion, suspension or solution. Flavoring materials may be included in the solutions as desired.
Solid pharmaceutical carriers such as starch, sugar, talc, mannitol and the like may be used to form powders. The powders may be given directly or incorporated in tablet, capsule or suppository preparations.
EXAMPLE 1
A total of 20 g. of N-benzyl-N-methyl-3-trifluoromethyl-phenethylamine hydrochloride was dissolved in 40 g. of concentrated sulfuric acid and the resultant solution was heated on a water bath for 3 hours. The reaction mixture was then cooled and combined with 50 ml. of methyl alcohol. This solution was refluxed for 3 hours at which time most of the excess methyl alcohol was removed by distillation. The residual mixture was cooled and poured slowly into 200 ml. of cold water. The acid aqueous solution was carefully made alkaline and extracted with ether. The ether extract was dried and anhydrous hydrochloric acid/ether was added. The crude hydrochloride salt precipitated and was recrystallized from methyl alcohol/ether and then from isoamyl alcohol/ether mixtures. A total of 11.2 g. of white crystalline material consisting of m-[2-(benzylmethylamino)-ethyl]-benzoic acid methyl ester hydrochloride was obtained melting at 150°-151°C.
The hydrochloride salt was converted to the free base by addition of alkali hydroxide to the aqueous solution of the salt. The base was extracted with ether and the ether removed in vacuo.
______________________________________ Analysis: Calculated for C 18 H 21 NO 2 : Neut. Equiv., 283 Found: Neut. Equiv., 287 ______________________________________
The free benzoic acid derivative was obtained by hydrolysis of the hydrochloride salt of the ester with hydrochloric acid and after recrystallization there was obtained crude m-[2-(benzyl-methylamino)-ethyl]benzoic acid.
The starting material may be prepared as follows:
To a refluxing and vigorously stirred solution of the Grignard reagent prepared from 100 g. (0.444 moles) of m-trifluoromethylbromobenzene and 12 g. (0.5 moles) of magnesium in 400 ml. of anhydrous ether there was added an ether solution of 40 g. (0.89 mole) of ethylene oxide. Reflux was maintained by the exothermic reaction and continued after the addition was completed for four additional hours. The reaction mixture, after cooling, was decomposed by pouring into iced, diluted hydrochloric acid. The ether layer was separated, washed briefly, dried and distilled. The residue yielded 59 g. (65%)of 3-trifluoromethyl phenethyl alcohol, b.p. 73°-76°C/0.4 mm.
To a refluxing mixture of 95 g. (0.8 mole) of thionyl chloride in 300 ml. of chloroform and 0.5 g. of pyridine there was added dropwise with vigorous stirring 135 g. (0.71 mole) of 3-trifluoromethyl phenethyl alcohol. After the addition was completed reflux was continued for 2 hours. Excess thionyl chloride and hydrochloric acid was removed in vacuo. The chloroform solution was briefly washed with water, bicarbonate solution, and then water again. The organic layer was dried and distilled. Yield 140 g. (95%) of 3-trifluoromethyl-phenethyl-chloride boiling at 98°-100 °C/25 mm.
A mixture of 20 g. (0.1 mole) of 3-trifluoromethyl-phenethyl-chloride and 25 g. (0.2 mole) of benzylmethylamine was heated for 12 hours at 100°C. Upon cooling, the reaction mixture was acidified with aqueous hydrochloric acid and extracted with ether. The ether soluble portion was cooled, made alkaline with alkali hydroxide and the liberated base extracted with ether. The ether extract was dried and distilled to yield N-benzyl-N-methyl-3-trifluoromethyl-phenethyl-amine as a colorless liquid. The yield was 24 g. (82%), b.p. 109°-110°C/0.3 mm.
______________________________________ Analysis: Calculated for C 17 H 18 F 3 N: Neut. Equiv. 293 Found: Neut. Equiv. 204 ______________________________________
EXAMPLE 2
In analogy to the procedure of Example 1, hydrolysis of N-benzyl-N-methyl-3-trifluoromethyl-phenethylamine with sulfuric acid, followed by esterification with ethyl alcohol yielded m-[2-(benzylmethylamino)-ethyl]benzoic acid ethyl ester. M.p. 115°-117°C.
______________________________________ Analysis: Calculated for C 19 H 23 NO 2 : Neut. Equiv. 297 Found: Neut. Equiv. 301 ______________________________________
EXAMPLE 3
In analogous fashion to Example 1 N,N-diethyl-3-trifluoromethyl-phenethylamine was hydrolyzed with sulfuric acid followed by esterification with methyl alcohol to yield m-[2-diethylamino)-ethyl]benzoic acid methyl ester. Conversion to the hydrochloride salt as above yielded product melting at 116°C.
______________________________________ Analysis: Calculated for C 14 H 20 NO 2 : Neut. Equiv. 271 Found: Neut. Equiv. 270 ______________________________________
The starting materials may be prepared as follows:
A mixture of 15 g. (0.0685 mole) of 3-trifluoromethyl-phenethyl-chloride and 12 g. of (0.167 mole of diethylamine in isopropyl alcohol was heated in a pressure bottle at 110°C. for 12 hours. The reaction mixture was worked up in analogous fashion to that described in Example 1. Upon distillation 7.5 g. (48.5%) of N,N-diethyl-3-trifluoromethyl-phenethylamine was obtained boiling at 118°-120°C/25 mm.
______________________________________ Analysis: Calculated for C 13 H 18 F 3 N: Neut. Equiv., 245 Found: Neut. Equiv., 242 ______________________________________
EXAMPLE 4
Hydrolysis of N-(p-chlorobenzyl)-N-methyl-3-trifluoromethyl-phenethylamine with sulfuric acid, followed by esterification with methyl alcohol in analogy to the procedure of Example 1 yielded m-[2-(4-chlorobenzylmethylamino)-ethyl]benzoic acid methyl ester.
______________________________________ Analysis: Calculated for C 17 H 18 ClNO 2 : Neut. Equiv., 304 Found: Neut. Equiv., 307 ______________________________________
Conversion of the free base to the hydrochloride salt in the manner described in Example 1 yielded product melting at 228°C.
The starting material may be prepared as follows:
A total of 8 g. (0.038 mole) of 3-trifluoromethyl-phenethylchloride and 6 g. (0.038 mole) of N-(p-chlorophenyl)-N-methylamine in 20 ml. of isopropyl alcohol containing 6 g. (0.043 mole) of potassium carbonate were reacted at 100°C. for 14 hours. The reaction mixture was worked up in the manner analogous to that in Example 1. After distillation 4.7 g. (37.7%) of the free base of N-(p-chlorobenzyl)-N-methyl-3-trifluoromethyl-phenethylamine was obtained boiling at 132°-134°C/0.5 mm.
______________________________________ Analysis: Calculated for C 17 H 17 ClF 3 N: Neut. Equiv., 328 Found: Neut. Equiv., 324 ______________________________________
EXAMPLE 5
In analogy to the procedure of Example 1 N-isopropyl-α-methyl-3-trifluoromethyl-phenethylamine was hydrolyzed with sulfuric acid and then esterified with methyl alcohol to yield m-[(2-methyl) (2-isopropylamine)-ethyl]benzoic acid methyl ester which when converted to the hydrochloride salt melted at 211°C.
______________________________________ Analysis: Calculated for C 14 H 20 NO 2 : Neut. Equiv., 234 Found: Neut. Equiv., 236 ______________________________________
The starting material may be prepared as follows:
3-Trifluoromethyl-phenylmagnesium bromide and propylene oxide were reacted in analogous manner to that described in Example 1. The liquid α-methyl-3-trifluoromethyl-phenethyl alcohol obtained in 50% yield had a boiling point of 80°C/1 mm.
To a refluxing mixture of 77.3 g. (0.65 mole) of thionyl chloride in 350 ml. of chloroform and 0.5 g. of pyridine there was added dropwise with vigorous stirring 120.4 g. (0.589 mole) of α-methyl-3-trifluoromethyl-phenethyl alcohol. After the addition was completed reflux was continued for 2 hours. Excess thionyl chloride and hydrochloric acid were removed in vacuo. The chloroform solution was briefly washed with water, bicarbonate solution and water. It was dried and distilled to yield 110 g. (90%) of α-methyl-3-trifluoromethyl-phenethyl chloride boiling at 103°-105°C/25 mm.
EXAMPLE 6
By analogy to the procedures of Example 1 m-[(2-methyl)(2-benzylmethylamino)-ethyl]benzoic acid methyl ester was prepared by sulfuric acid hydrolysis and methanol esterification of N-benzyl-N-methyl-α-methyl-3-trifluoromethyl phenethylamine.
The starting material may be prepared as follows:
By a procedure analogous to Example 1 α-methyl-3-trifluoromethyl-phenethylchloride was reacted with benzylmethylamine to yield N-benzyl-N-methyl-αmethyl-3-trifluoromethyl phenethylamine boiling at 115°C/0.5 mm.
______________________________________ Analysis: Calculated for C 18 H 20 F 3 N: Neut. Equiv., 307 Found: Neut. Equiv., 307 ______________________________________
EXAMPLE 7
In analogy to the procedure of Example 1 3-trifluoromethyl-phenethyl-morpholine was hydrolyzed in sulfuric acid and esterified with methyl alcohol to produce m-(2-morpholinoethyl)-benzoic acid methyl ester. m.p. 207°-208°C. (acetone).
______________________________________ Analysis: Calculated for C 14 H 19 NO 3 : Neut. Equiv., 249 Found: Neut. Equiv., 250 ______________________________________
The starting material may be prepared as follows:
According to the procedure of Example 1 3-trifluoromethyl-phenethylchloride was reacted with morpholine to produce 3-trifluoromethyl-phenethyl morpholine in 84% yield, the pre-base product boiling at 80°C/0.3 mm.
______________________________________ Analysis: Calculated for C 14 H 18 F 3 N: Neut. Equiv., 247 Found: Neut. Equiv., 249 ______________________________________
EXAMPLE 8
In analogy to the procedure of Example 1 m-(2-piperidinoethyl)-benzoic acid methyl ester was prepared by the sulfuric acid hydrolysis and esterification with methyl alcohol of 3-trifluoromethyl-phenethylpiperidine.
______________________________________ Analysis: Calculated for C 15 H 21 NO 2 : Neut. Equiv., 247 Found: Neut. Equiv., 251 ______________________________________
The starting material may be prepared as follows:
In accordance with the procedure of Example 1 3-trifluoromethyl-phenethylchloride was reacted with piperidine to give 3-trifluoromethyl-phenethylpiperidine in 70% yield, boiling at 78°C/0.4 mm. m.p. 219°-220°C. (acetone).
______________________________________ Analysis: Calculated for C 14 H 18 F 3 N: Neut. Equiv., 257 Found: Neut. Equiv., 260 ______________________________________
EXAMPLE 9
A mixture of 4 grams of m-[2-(benzylmethylamino)-ethyl]-benzoic acid methyl ester, 10 g. of n-propylalcohol and 4 g. of concentrated sulfuric acid was heated to reflux temperature. Workup in the normal manner yielded m-[2-(benzylmethylamino)-ethyl]benzoic acid n-propyl ester which when converted to the hydrochloride salt had a melting point of 108°C.
______________________________________ Analysis: Calculated for C 20 H 25 NO 2 : Neut. Equiv., 311 Found: Neut. Equiv., 312 ______________________________________
EXAMPLE 10
Reaction of 5 grams (0.0163 mole) of m-[2-(benzylmethylamino)-ethyl]benzoic acid and 6 g. of thionyl chloride yielded the corresponding crude acid chloride which was then further reacted without purification with 74 g. (1 mole) of t-butyl alcohol at reflux. Upon removal of the excess alcohol the free base of m-[2-(benzylmethylamino)-ethyl]benzoic acid t-butyl ester is obtained. Conversion to the hydrochloride in the previously described manner followed by recrystallization of the hydrochloride salt from acetone ether yielded the pure hydrochloride salt melting at 196°C.
______________________________________ Analysis: Calculated for C 19 H 30 NO 2 : Neut. Equiv., 304 Found: Neut. Equiv., 308 ______________________________________
EXAMPLE 11
By analogy to the procedure of Example 1 3-trifluoromethylphenethyl-N-methylpiperazine was hydrolyzed in concentrated sulfuric acid and esterified with methyl alcohol to yield m-[2-(N-methylpiperazino)-ethyl]benzoic acid methyl ester. M.P. 229°-230°C.
______________________________________ Analysis: Calculated for C 15 H 22 N 2 O 2 : Neut. Equiv., 262 Found: Neut. Equiv., 264 ______________________________________
The starting material may be prepared as follows:
Utilizing the procedure of Example 1 3-trifluoromethylphenethyl chloride was reacted with N-methylpiperazine to give N-methyl-N'-(3-trifluoromethyl)-phenethylpiperazine in 68% yield boiling at 89°-90°C/0.3 mm.
______________________________________ Analysis: Calculated for C 14 H 19 F 3 N 2 : Neut. Equiv., 272 Found: Neut. Equiv., 275 ______________________________________
EXAMPLE 12
In analogy to the procedure of Example 1 concentrated sulfuric acid hydrolysis of N-benzyl-N-ethyl-3-trifluoromethylphenethylamine followed by esterification with methyl alcohol yielded m-[2-(benzylethylamino)-ethyl]benzoic acid methyl ester.
______________________________________ Analysis: Calculated for C 19 H 23 NO 2 : Neut. Equiv., 297 Found: Neut. Equiv., 299 ______________________________________
M.p. 125°-127°C. (acetone).
The starting material may be prepared as follows:
By the procedure described in Example 1 N-benzyl-N-ethyl-3-trifluoromethyl-phenethylamine was prepared by the reaction between 3-trifluoromethyl-phenethylchloride and benzylethylamine.
EXAMPLE 13
Analogous to the procedure of Example 1 N-benzyl-N-(2-methoxyethyl)-3-trifluoromethyl-phenethylamine was hydrolyzed in concentrated sulfuric acid followed by esterification with methyl alcohol to yield m-[2-(N-benzyl-N-(2-methoxyethyl)amino)-ethyl]benzoic acid methyl ester.
______________________________________ Analysis: Calculated for C 20 H 25 NO 3 : Neut. Equiv., 327 Found: Neut. Equiv., 330 ______________________________________
The starting material may be prepared as follows:
A total of 10 g. (0.05 mole) of 3-trifluoromethyl-phenethylchloride was reacted with 16 g. (0.1 mole) of 2-methoxyethylbenzylamine for 12 hours at 110°C. The reaction mixture was worked up in the manner described in Example 1 and after distillation 7.9 g (46.5%) of the free base of N-benzyl-N-(2-methoxyethyl)-3-trifluoromethyl-phenethylamine was obtained boiling at 120°C/0.3 mm.
______________________________________ Analysis: Calculated for C 19 H 22 F 3 NO: Neut. Equiv., 337 Found: Neut. Equiv., 341 ______________________________________
EXAMPLE 14
In a manner analogous to Example 1 N-benzyl-N-methyl-β-methoxy-3-trifluoromethyl-phenethylamin e was hydrolyzed with concentrated sulfuric acid followed by esterification with methyl alcohol. The solution of the product ester in acid of methanol was poured into an excess of ice cold water and the mixture was rendered alkaline with sodium hydroxide.
The free base was extracted with ether and the extract dried over potassium carbonate and distilled. Distillation yielded m-[1-methoxy-2-(benzylmethylamino)-ethyl]benzoic acid methyl ester boiling at 150°C/0.3 mm.
______________________________________ Analysis: Calculated for C 19 H 23 NO 3 : Neut Equiv., 313 Found: Neut Equiv., 316 ______________________________________
The starting material may be prepared as follows:
In analogy to the procedure of Example 1 a mixture of 14 g. (0.05 mole) of β-methoxy-3-trifluoromethyl-phenethyl bromide and 13 g. (0.1 mole) of benzylmethylamine was reacted at 100°C. for three hours. Distillation yielded N-benzyl-N-methyl-β-methoxy-3-trifluoromethyl-phenethylamin e boiling at 105°C/0.2 mm.
______________________________________ Analysis: Calculated for C 18 H 20 F 3 NO: Neut. Equiv., 323 Found: Neut. Equiv., 325 ______________________________________
EXAMPLE 15
In analogous manner to the procedure of Example 1 hydrolysis of N-benzyl-β-methoxy-3-trifluoromethyl-phenethylamine with concentrated sulfuric acid followed by esterification with methyl alcohol yielded m-[1-methoxy-2-(benzylamino)-ethyl]benzoic acid methyl ester. Conversion to the hydrochloride salt yielded material melting at 243°C.
______________________________________ Analysis: Calculated for C 18 H 21 NO 3 : Neut. Equiv., 299 Found: Neut. Equiv., 302 ______________________________________
The starting material may be prepared as follows:
In analogous fashion to the procedure of Example 1 a mixture of 25 g. (0.09 mole) of β-methoxy-3-trifluoromethylphenethyl bromide was reacted with 19 g. (0.18 mole) of benzylamine at 100°C. for 3 hours. Distillation yielded N-benzylβ-methoxy-3-trifluoromethyl-phenethylamine boiling at 137°C/0.3 mm.
______________________________________ Analysis: Calculated for C 18 H 19 F 3 NO: Neut. Equiv., 309 Found: Neut. Equiv., 311 ______________________________________
EXAMPLE 16
Tablet Formulation ______________________________________ Mg/Tablet ______________________________________ m-[2-(benzylmethylamino)-ethyl]benzoic acid methyl ester hydrochloride 25.0 Lactose 98.0 Corn Starch 61.0 Corn Starch as 10% Paste 5.0 Talcum 4.5 Magnesium Stearate 1.5 Corn Starch 5.0 Tablet Weight 200.0 ______________________________________
Procedure:
1. Mix the m-[2-(benzylmethylamino)ethyl]benzoic acid methyl ester hydrochloride, lactose and corn starch in a suitable mixing container and add the starch paste slowly to achieve a heavy, moist mass.
2. Pass this moist mass through a No. 10 mesh screen (or similar suitable coarse screen).
3. Place the moist granules on drying pans and dry at 110°F.
4. pass the dried granules through a No. 16 mesh screen, place in a suitable mixing container and add the talcum, magnesium stearate, and second portion of corn starch.
5. Mix well and compress into tablets on either a single or multiple tabletting machine to an individual tablet weight of 200 mgs. An 11/32 inch standard concave scored punch is suitable, yielding tablets with a thickness of approximately 3.35 mm.
EXAMPLE 17
Tablet Formulation ______________________________________ Per Tablet ______________________________________ m-[ 2-(benzylmethylamino)-ethyl]benzoic acid methyl ester hydrochloride 100 mg. Lactose, U.S.P. 202 mg. Corn Starch, U.S.P. 80 mg. Amijel BO11* 20 mg. Calcium Stearate 8 mg. Total Weight 410 mg. ______________________________________ *A prehydrolyzed food grade corn starch. Any similar prehydrolyzed corn starch may be used.
Procedure:
1. m-[2-(benzylmethylamino)-ethyl]benzoic acid methyl ester hydrochloride, lactose, corn starch, and Amijel BOll were blended in a suitable mixer.
2. The mixture was granulated to a heavy paste with water and the moist mass was passed through a No. 12 screen. It was then dried overnight at 110°F.
3. the dried granules were passed through a No. 16 screen and transferred to a suitable mixer. The calcium stearate was added and mixed until uniform.
4. The mixture was compressed at a tablet weight of 410 mg. using tablet punches having a diameter of approximately 3/8 inch. (Tablets may be either flat or biconvex and may be scored if desired.)
EXAMPLE 18
Capsule Formulation ______________________________________ Per Capsule ______________________________________ m-[2-(Benzylmethylamino)-ethyl]benzoic acid methyl ester hydrochloride 5 mg. Lactose 178 mg. Corn Starch 37 mg. Talc 5 mg. Total Weight 225 mg. ______________________________________
Procedure:
1. m-[2-(Benzylmethylamino)-ethyl]benzoic acid methyl ester hydrochloride was mixed with the lactose and corn starch in a suitable mixer.
2. The mixture was further blended by passing through a Fitzpatrick Comminuting Machine with a No. 1A screen with knives forward.
3. The blended powder was returned to the mixer, the talc added and blended thoroughly. The mixture was then filled into No. 4 hard shell gelatin capsules on a Parke Davis capsulating machine (any similar type machine may be used.)
EXAMPLE 19
Capsule Formulation ______________________________________ Per Capsule ______________________________________ m-[2-(Benzylmethylamino)-ethyl]benzoic acid methyl ester hydrochloride 50 mg. Lactose, U.S.P. 125 mg. Corn Starch, U.S.P. 30 mg. Talc, U.S.P. 5 mg. Total Weight 210 mg. ______________________________________
Procedure:
1. m-[2-(Benzylmethylamino)-ethyl]benzoic acid methyl ester hydrochloride was mixed with lactose and corn starch in a suitable mixer.
2. The mixture was further blended by passing through a Fitzpatrick Comminuting Machine with a No. 1A screen with knives forward.
3. The blended powder was returned to the mixer, the talc added and blended thoroughly.
4. The mixture was filled into No. 4 hard shell gelatin capsules on a Parke Davis capsulating machine.
EXAMPLE 20
Analogous to the procedure of Example 9, m-[2-(benzylamino)-ethyl]-benzoic acid methyl ester was transesterified with benzyl alcohol in the presence of concentrated sulfuric acid. After workup in the usual manner and conversion to the hydrochloride salt, the product m-[2-(benzylamino)-ethyl]benzoic acid benzyl ester hydrochloride was obtained, m.p. 153°-155°C.
EXAMPLE 21
By analogy to the procedure of Example 1 N-methyl-3-trifluoromethyl phenethylamine was hydrolyzed and then esterified with m-cresol followed by conversion to the hydrochloride to yield m-[2-(methylamino)-ethyl]benzoic acid, m-cresyl ester hydrochloride melting at 162°C.
______________________________________ Analysis: Calculated for C 17 H 19 NO 2 : Neut. Equiv., 269 Found: Neut. Equiv., 272 ______________________________________
The starting material may be prepared as follows:
In analogy to the procedure of Example 1, trifluoromethylphenethyl chloride was reacted with anhydrous monomethylamine in methanol in a pressure bottle for four hours at 110°C. Isolation in the usual manner yielded N-methyl-3-trifluoromethylphenethylamine boiling at 94°-96°C/40 mm.
______________________________________ Analysis: Calculated for C 10 H 12 F 3 N: Neut. Equiv., 203 Found: Neut. Equiv., 197 ______________________________________
Conversion to the hydrochloride in the usual manner yielded the salt melting at 146°-147°C.
EXAMPLE 22
In analogy to the procedure of Example 1, 3-trifluoromethylphenethyl pyrrolidine was hydrolyzed, esterified with methyl alcohol, and converted to the hydrochloride to yield m-(2-pyrrolidinoethyl)-benzoic acid methyl ester hydrochloride melting at 188°-189°C.
______________________________________ Analysis: Calculated for C 14 H 19 NO 2 : Neut. Equiv., 223 Found: Neut. Equiv., 223 ______________________________________
The starting material may be prepared inanalogy to the method of Example 1 wherein 3-trifluoromethylphenethyl chloride was reacted with pyrrolidine to produce 3-trifluoromethylphenethyl pyrrolidine in 51% yield as a liquid boiling at 117°C./30 mm.
______________________________________ Analysis: Calculated for C 13 H 16 F 3 N: Neut. Equiv., 243 Found: Neut. Equiv., 244 ______________________________________
EXAMPLE 23
In analogy to the procedure of Example 1, 3-trifluoromethylphenethyl-p-toluidene was hydrolyzed with concentrated sulfuric acid and esterified with methyl alcohol followed by conversion to the hydrochloride to yield m-2-(p-toluidinoethyl)-benzoic acid methyl ester hydrochloride, melting at 156°-157°C.
______________________________________ Analysis: Calculated for C 17 H 19 NO 2 : N. 4.58 Found: N. 4.45 ______________________________________
The starting material may be prepared as follows:
3-Trifluoromethylphenethyl chloride and p-toluidine were reacted in analogy to the procedure in Example 1 to yield 3-trifluoromethylphenethyl-p-toluidine boiling at 147°C./1.8 mm.
______________________________________ Analysis: Calculated for C 16 H 16 F 3 N: N. 4.45 Found: N. 4.25. ______________________________________
Conversion to the hydrochloride in the usual manner yielded the corresponding hydrochloride salt melting at 162°-163°C.
EXAMPLE 24
In analogy to the procedure of Example 1, N-methyl-N-2-hydroxy ethyl-β-hydroxy-α-methyl-3-trifluoromethylphenethylamine was hydrolyzed with concentrated sulfuric acid and esterified with methyl alcohol followed by conversion to the hydrochloride to yield m-2-(N-methyl-N-2-hydroxyethyl)amino-β-hydroxy-α-methyl-be nzoic acid, methyl ester hydrochloride, melting at 206°-207°C.
______________________________________ Analysis: Calculated for C 14 H 21 NO 4 .HCl: N. 4.62 Found: N. 4.37 Calculated for Cl: 11.3 Found: 11.1 ______________________________________
EXAMPLE 25
A total of 3.0 g. of m-2-cyclohexylaminoethyl-benzoic acid methyl ester hydrochloride was added to 20 ml. of methanol and there was thereafter added 1.15 g. of 1bromo-3-methyl butane and 3.5 g. of potassium carbonate. The reaction mixture was heated at reflux for 36 hours, cooled and then poured into 300 cc of ice water. The crystalline product was filtered off, washed with water and then with ether. The crude product was then recrystallized from methanol/acetone to yield m-(2-N-cyclohexyl-N-isopentylamino)-ethyl-benzoic acid methyl ester melting at 245°-246°C.
______________________________________ Analysis: Calculated for C 21 H 33 NO 2 : Neut. Equiv., 331 Found: Neut. Equiv., 331 ______________________________________
The starting material may be prepared as follows:
In analogy to the procedure of Example 1, 3-trifluoromethylphenethyl chloride was reacted with cyclohexylamine to yield 3-trifluoromethylphenethyl cyclohexylamine boiling at 116°C./1.1 mm.
______________________________________ Analysis: Calculated for C 15 H 20 F 3 N: Neut. Equiv., 271 Found: Neut. Equiv., 270 ______________________________________
Hydrolysis of 3-trifluoromethylphenethyl cyclohexylamine in analogy to the procedure of Example 1 with concentrated sulfuric acid followed by esterification with methyl alcohol and conversion to the hydrochloride yielded m-(2-cyclohexylamino)-ethyl benzoic acid methyl ester hydrochloride, melting at 210°-211°C.
______________________________________ Analysis: Calculated for C 16 H 23 NO 2 : Neut. Equiv., 261 Found: Neut. Equiv., 262 ______________________________________