US3870715A - Substituted amino ethyl meta benzoic acid esters - Google Patents

Substituted amino ethyl meta benzoic acid esters Download PDF

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US3870715A
US3870715A US347287A US34728773A US3870715A US 3870715 A US3870715 A US 3870715A US 347287 A US347287 A US 347287A US 34728773 A US34728773 A US 34728773A US 3870715 A US3870715 A US 3870715A
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benzoic acid
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/38—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton

Definitions

  • 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-(aminoalkyl)benzoic acids and esters are disclosed in Chemical Abstracts 38, 732.
  • 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 COOR:
  • R is hydrogen, hydroxy, lower alkoxy or lower alkyl
  • R is hydrogen or lower alkyl
  • R;, is lower alkyl, aralkyl or lower alkyl aryl
  • R taken independently is hydrogen, lower alkyl, aralkyl, lower alkyl aryl, hydroxy lower alkyl and lower alkoxy lower alkyl
  • R taken independently is lower alkyl, aralkyl, lower alkyl aryl or lower alkoxy lower alkyl
  • R and R 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 where R., is hy drogen or lower alkyl and the pharmaceutically acceptable acid addition salts thereof.
  • alkyl is meant to include straight or branched chain hydrocarbon radicals such as methyl, ethyl, n-propyl, T-butyl, hexyl, heptyl, and the like.
  • 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.
  • 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,
  • lower alkoxy lower alkyl is meant to include radical groups such as methoxy methyl, methoxy ethyl, ethoxy methyl, ethoxy ethyl, and the like.
  • suitable heterocyclic radical groups obtained when R., and R 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.
  • R is hydrogen or lower alkoxy, preferably methoxy
  • R is hydrogen
  • R is lower alkyl
  • R is hydrogen or lower alkyl
  • R 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-[Z-(benzylethylamino)-ethyl]benzoic acid methyl ester m-[2-(N-benzyl-N-(2-methoxyethyl)amino)- ethyl]benzoic acid methyl ester m-(Z-diethylaminoethyl)-benzoic acid methyl ester m-[(2-methyl)(2-is
  • the esterification is conductedin 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 40C to the reflux temperature of the reaction medium.
  • 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
  • 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.
  • esters of formula I from the acids of formula II.
  • 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 111.
  • activated derivatives can be prepared from the benzoic acids of formula II by procedures well known in the art.
  • 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 ll are derived from correspondingly substituted trifluoromethyl compounds of the formula lll CFJ
  • R R R and R 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 C. to the reflux temperature of the reaction mixture, most preferably at about the reflux temperature of the reaction mixture.
  • R R and R are hydrogen
  • 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 and/or R 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.
  • alkylation may be accomplished using the desired aldehyde of a R, and/or R compound, such as formaldehyde, benzaldehyde, etc. followed by reduction in a manner known per se.
  • Suitable amines falling within the scope of formula V and thus finding use in the present invention are the following: piperazine, N-methylpiperazine, pyrrolidine, 2-methylpyrrolidine, 3- methylpyrrolidine, piperidine, 2-methylpiperidine, 3- methylpiperidine, 4-methylpiperidine, morpholine, dibeta-hydroxyethylamine, betahydroxyethylmethylamine, betahydroxyethyl-benzylamine, benzyllower 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, phen
  • 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.
  • 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, is hydroxy.
  • 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
  • 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.
  • noninterfering groups include lower alkyl, halogen, hydroxy, lower alkoxy, nitro, sulfate and the like.
  • compounds of formula I may contain asymmetric carbon atoms in the ethylene sidechain depending on secondary substitution or asymmetric centers in other places. Racemie 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 diastcreomer salts formed with an optically active acid, i.c., 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 evalnation.
  • 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.
  • spasmogens as acetyl chloine, barium chloride and histamine.
  • papaverine as a standard, the following table demonstrates the comparable activity found as a result of this test.
  • 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.
  • a preferred species of the invention m-[2-(benzylmethylamino)-ethyl]-benzoic acid methyl ester was found to have an oral LD of about 500-700 mg/kg in mice.
  • the compounds of formula I 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 l.2 mg/kg. Parenteral dosages of about 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.
  • compositions 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 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 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.
  • 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:
  • EXAMPLE 2 In analogy to the procedure of Example 1, hydrolysis of Nbenzyl-N-methyl-3-trifluoromethylphenethylamine with sulfuric acid, followed by esterification with ethyl alcohol yielded m-[Z-(benzylmethylamino)-ethyl]benzoic acid ethyl ester. M.p. 1 l5l 17C.
  • the starting material may be prepared as follows:
  • the starting material may be prepared as follows:
  • chloroform solution was briefly washed with water, bicarbonate solution and water. It was dried and distilled to yield 110 g. (90%) of a-methyl-3-trifluoromethylphenethyl chloride boiling at 103l05C/25 mm.
  • the starting material may be prepared as follows:
  • the starting material may be prepared as follows:
  • Example 1 3- trifluoromethyl-phenethylchloride was reacted with morpholine to produce 3-trifluoromethyl-phenethyl morpholine in 84% yield, the pre-base product boiling at C/0.3 mm.
  • EXAMPLE 8 In analogy to the procedure of Example 1 m-(Z-piperidinoethyl)-benzoic acid methyl ester was prepared by the sulfuric acid hydrolysis and esterification with methyl alcohol of 3-trifluoromethylphenethylpiperidine.
  • EXAMPLE 12 In analogy to the procedure of Example 1 concentrated sulfuric acid hydrolysis of N-benzyl-N-ethyl-3- 5 trifluoromethylphenethylamine followed by esterification with methyl alcohol yielded m-[Z-(benzyle- EXAMPLE 9 thylamino)-ethyl]benzoic acid methyl ester. A mixture of 4 grams of m-[2-(benzylmethylamino)- ethyl]-benzoic acid methyl ester, 10 g. of npropylalcohol and 4 g. of concentrated sulfuric acid 10 was heated to reflux temperature.
  • the starting material may be prepared as follows: was rendered alkaline with sodium hydroxide. Utilizing the procedure of Example 1 3-trifluorome- The free base was extracted with ether and the exthylphenethyl chloride was reacted with N-methylpiptract dried over potassium carbonate and distilled.
  • the starting material may be prepared as follows:
  • the starting material may be prepared as follows:
  • EXAMPLE 17 Tablet Formulation A prehydrolyzed food grade corn starch. Any similar prehydrolyzed corn starch may be used.
  • the mixture was granulated to a heavy paste with water and the moist mass was passed through a N o. 12 screen. It was then dried overnight at F.
  • 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.
  • the mixture was compressed at a tablet weight of 410 mg. using tablet punches having a diameter of approximately inch. (Tablets may be either flat or biconvex and may be scored if desired.)
  • EXAMPLE 19 Capsule Formulation Per Capsule m-l2-(Benzylmethylamino)-ethyllhenzoic acid 1. m-[2-(Benzylmethylamino)-ethyl]benzoic acid methyl ester hydrochloride was mixed with lactose and corn starch in a suitable mixer.
  • the mixture was filled into No. 4 hard shell gelatin capsules on a Parke Davis capsulating machine.
  • the starting material may be prepared as follows:
  • 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-pyrro1idinoethy1)-benzoic acid methyl ester hydrochloride melting at 188-189C.
  • the starting material may be prepared inanalogy to the method of Example 1 wherein 3-trifluoromethy1- phenethyl chloride was reacted with pyrrolidine to produce 3-trifluoromethy1phenethyl pyrrolidine in 51% yield as a liquid boiling at l17C./30 mm.
  • the starting material may be prepared as follows:
  • EXAMPLE 24 In analogy to the procedure of Example 1, N-methyl- N-Z-hydroxy ethyl-B-hydroxy-a-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-methyI-N-Z-hydroxyethyl)amino-B-hydroxy-amethyl-benzoic acid, methyl ester hydrochloride, melting at 206207C.
  • EXAMPLE 25 A total of 3.0 g. of m-2-cyclohexylaminoethylbenzoic acid methyl ester hydrochloride was added to 20 ml. of methanol and there was thereafter added 1.15
  • the starting material may be prepared as follows:
  • R is hydrogen, hydroxy, lower alkoxy or lower alkyl; R is hydrogen or lower alkyl; R is lower alkyl, aralkyl or lower alkyl aryl; R taken independently is hydrogen, lower alkyl, aralkyl, lower alkyl aryl, hydroxy lower alkyl and lower alkoxy lower alkyl; R taken independently is lower alkyl, aralkyl, lower alkyl aryl or lower alkoxy lower alkyl; and R and R 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 where R is hydrogen or lower alkyl and the optical antipodes and the pharmaceutically acceptable acid addition salts thereof.

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Abstract

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.

Description

United States Patent Hansl Mar. 11, 1975 I SUBSTITUTED AMINO ETl-IYL META [58] Field of Search 260/247.2 B, 471 R, 293.81. BENZOIC ACID ESTERS 260/293.82, 326.47, 326.5, 268 R [76] Inventor: Nikolaus R. Hansl, 196 La Vereda Rd., Santa Barbara, Calif. 93108 [56] References CM FOREIGN PATENTS OR APPLICATIONS [22] Flled: 1973 32-5564 7/1957 Japan 260/47] R 21 APPL 347 2 7 1,074,052 5/1956 Germany 260/471 R 631,855 6/1936 Germany 260/471 R Related U.S. Application Data [63] Continuation-impart of Ser. No. 233,339, March 9, Primary Examiner-Lorraine A. Weinberger 1972, abandoned, which is a continuation-in-part of Assistan/ Examiner-Paul ,1. Killos Ser. No. 745,352, July 17, 1968, and a continuationin-part of Ser. No. 85,283, Oct. 29, 1970, Pat. No. 57 ABSTRACT A series of substituted amino ethyl meta benzoic acid [52] U 5 Cl 260,247 2 B 260/247 260/247 2 R esters and their salts are useful as spasmolytics. psychotherapeutic agents and agents facilitating learning.
260/268 R, 260/293.81, 260/293.82, 260/326.47, 260/326.5, 260/471 R, 260/518 A, 260/518 R, 260/519, 260/570.5,
Int. Cl C07d 87/36 These compounds may conveniently be prepared by hydrolysis of suitably substituted trifluoromethyl derivatives followed by esterification with a desired alcohol.
19 Claims, N0 Drawings SUBSTITUTED AMINO ETI-IYL META BENZOIC ACID ESTERS RELATED APPLICATIONS This application is a continuation-in-part of copending US. Patent Application Ser. No. 233,339, filed Mar. 9, 1972, now abandoned which is a continuationin-part of copending US. 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 AMlNO-ALKYL-BENZOIC ACID DERIVA- TIVES.
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-(aminoalkyl)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 COOR:
H H R4 l l -N I l R1 R2 R I wherein R, is hydrogen, hydroxy, lower alkoxy or lower alkyl; R is hydrogen or lower alkyl; R;, is lower alkyl, aralkyl or lower alkyl aryl; R taken independently is hydrogen, lower alkyl, aralkyl, lower alkyl aryl, hydroxy lower alkyl and lower alkoxy lower alkyl; R taken independently is lower alkyl, aralkyl, lower alkyl aryl or lower alkoxy lower alkyl; and R and R 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 where R., is hy drogen 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., and R 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, is hydrogen or lower alkoxy, preferably methoxy, R is hydrogen, R is lower alkyl, R is hydrogen or lower alkyl and R 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-[Z-(benzylethylamino)-ethyl]benzoic acid methyl ester m-[2-(N-benzyl-N-(2-methoxyethyl)amino)- ethyl]benzoic acid methyl ester m-(Z-diethylaminoethyl)-benzoic acid methyl ester m-[(2-methyl)(2-isopropylamino)-ethyl]benzoic acid methyl ester m-[Z-(methylisopropylamino)-ethyl]benzoic acid methyl ester m-[2-(benzylmethylamino)-ethyl]-benzoic acid nacid where R R R and R are as above with alcohols of the formula R OH where R;, is as above. The esterification is conductedin 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 40C 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 111. 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 ll are derived from correspondingly substituted trifluoromethyl compounds of the formula lll CFJ
where R R R and R 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 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 R and R are hydrogen may be obtained from the corresponding mcyanomethylbenzoic acids by catalytic reduction using H and Raney nickel in the manner described by Takegi ct 11]., 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 and/or R 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, and/or R compound, such as formaldehyde, benzaldehyde, etc. followed by reduction in a manner known per se.
Compounds of formula N, where not already available in the art can be obtained starting from a mtrifluoromethylphenyl-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 where R, and R 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-methylpiperazine, pyrrolidine, 2-methylpyrrolidine, 3- methylpyrrolidine, piperidine, 2-methylpiperidine, 3- methylpiperidine, 4-methylpiperidine, morpholine, dibeta-hydroxyethylamine, betahydroxyethylmethylamine, betahydroxyethyl-benzylamine, benzyllower 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, 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 -C H -B Mg -+mCF;,C H MgBr ni-oia-unr -ii isiumfill:
O OH;
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 noninterfering groups include lower alkyl, halogen, hydroxy, lower alkoxy, nitro, sulfate 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. Racemie 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 diastcreomer salts formed with an optically active acid, i.c., 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 evalnation.
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 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 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 l.2 mg/kg. Parenteral dosages of about 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 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 l 1.2 g. of white crystalline material consisting of m-[2- (benzylmethylamino)-ethyl]-benzoic acid methyl ester hydrochloride was obtained melting at l50-l5lC.
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.
Neut. Equiv., 283
Analysis:
Found:
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. 7376C/0.4 mm.
To a refluxing mixture of 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 l35 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 g. (95%) of 3-trifluoromethylphenethyl-chloride boiling at 98-l00 C/25 mm.
A mixture of 20 g. (0.1 mole) of 3-trifluoromethylphenethyl-chloride and 25 g. (0.2 mole) of benzylmethylamine was heated for 12 hours at l00C. 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. l091l0C/0.3 mm.
Analysis: Calculated for C H F N: Neut. Equiv. 293 Found: Neut. Equiv. 204
EXAMPLE 2 In analogy to the procedure of Example 1, hydrolysis of Nbenzyl-N-methyl-3-trifluoromethylphenethylamine with sulfuric acid, followed by esterification with ethyl alcohol yielded m-[Z-(benzylmethylamino)-ethyl]benzoic acid ethyl ester. M.p. 1 l5l 17C.
Analysis: Calculated for C H NO 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-[Z-diethylamino)-ethyl]benzoic acid methyl ester. Conversion to the hydrochloride salt as above yielded product melting at l 16C.
Calculated for C H NO Neut. Equiv. 27l
Analysis:
Found: Neut. Equiv. 270
was
Analysis: Calculated for c H F Nz Neut. Equiv., 245 Found: Neut. Equiv., 242
EXAMPLE 4 Analysis: Calculated for C H ClNo 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 228C.
The starting material may be prepared as follows:
A total of 8 g. (0.038 mole) of 3-trifluoromethylphenethylchloride and 6 g. (0.038 mole) of N-(pchlorophenyl)N-methylamine in 20 ml. of isopropyl alcohol containing 6 g. (0.043 mole) of potassium carbonate were reacted at 100C. 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 l32-l34C/0.5'mm.
Calculated for C,,H,,CIF;,N: Neut. Equiv., 328
Analysis:
Found: Neut. Equiv., 324
EXAMPLE Calculated for C ,,H NO Neut. Equiv., 234
Analysis:
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 a-methyl-3-trifluoromethyl-phenethyl alcohol obtained in 50% yield had a boiling point of 80C/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 a-methyl-3-trifluoromethylphenethyl 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 a-methyl-3-trifluoromethylphenethyl chloride boiling at 103l05C/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-amethyl-3-trifluoromethyl phenethylamine.
The starting material may be prepared as follows:
By a procedure analogous to Example 1 a-methyl-3- trifluoromethyl-phenethylchloride was reacted with benzylmethylamine to yield N-benzyl-N-methylamethyl-3-trifluoromethyl phenethylamine boiling at ll5C/0.5 mm.
Analysis: Calculated for C H F 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. 207208C. (acetone).
Analysis: Calculated for C H NO 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 C/0.3 mm.
Analysis: Calculated for C H F N: Neut. Equiv., 247 Found: Neut. Equiv., 249
EXAMPLE 8 In analogy to the procedure of Example 1 m-(Z-piperidinoethyl)-benzoic acid methyl ester was prepared by the sulfuric acid hydrolysis and esterification with methyl alcohol of 3-trifluoromethylphenethylpiperidine.
Analysis: Calculated for C H NO Neut. Equiv., 247 Found: Neut. Equiv.. 25 1 Analysis: Calculated for C H F N: Neut. Equiv., 257 Found: Neut. Equiv., 260
EXAMPLE 12 In analogy to the procedure of Example 1 concentrated sulfuric acid hydrolysis of N-benzyl-N-ethyl-3- 5 trifluoromethylphenethylamine followed by esterification with methyl alcohol yielded m-[Z-(benzyle- EXAMPLE 9 thylamino)-ethyl]benzoic acid methyl ester. A mixture of 4 grams of m-[2-(benzylmethylamino)- ethyl]-benzoic acid methyl ester, 10 g. of npropylalcohol and 4 g. of concentrated sulfuric acid 10 was heated to reflux temperature. Workup in the nor- Analysls' Calculated for EfESj; 523:3: 33; mal manner yielded m-[2-(benzylmethylamino)- ethyl]benzoic acid n-propyl ester which when converted to the hydrochloride salt had a melting point of M.p. 125127C. (acetone). 108C. The starting material may be prepared as follows:
By the procedure described in Example 1 N'benzyl- N-ethyl-3-trifluoromethyl-phenethylamine was prei pared by the reaction between 3-trifluoromethyl- Analysls' Calculated for fiSg; phenethylchloride and benzylethylamine.
U EXAMPLE 13 Analogous to the procedure of Example 1 N-benzyl- N-(2-methoxyethyl)-3-trifluoromethyl- EXAMPLE l0 phenethylamine was hydrolyzed in concentrated sulfu- Reaction of 5 grams (0.0163 mole) of m-[2- ric acid followed by esterification with methyl alcohol (benzylmcthylamino)-ethyl]benzoic acid and 6 g. of to yield m-[2-(N-benzyl-N-(2-meth0xyethyl)amino)- thionyl chloride yielded the corresponding'crudeacid ethy1]benzoic acid methyl ester. 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 Analy Calculate? fifig; ester is obtained. Conversion to the hydrochloride in the previously described manner followed by recrystallization of the hydrochloride salt from acetone ether Th arting material may be prepared as follows: yielded the pure hydrochloride salt melting at 196C. A total 0f 10 g- H1016) 0f riflu0r me hylphenethylchloride was reacted with 16 g. (0.1 mole) of 2-methoxyethylbenzylamine for 12 hours at 110C. The reaction mixture was worked up in the manner de- I scribed in Example 1 and after distillation 7.9 g ws; #33:; 53353;; i833 40 (46.5%) of the free base of N-benzy|-N-(2 methoxyethyl)-3-trifluoromethyl-phenethylamine was obtained boiling at 120C/0.3 mm. EXAMPLE 11 By analogy to the procedure of Example 1 3- trifluoromethylphenethyl-N-methylpiperazine was hy- Analysis" Calculated gl lfil gl E233: drolyzed in concentrated sulfuric acid and esterified with methyl alcohol to yield m-[2-(N-methylpiperazino)-ethyl]benzoic acid methyl ester. M.P. 229-230C. EXAMPLE 14 In a manner analogous to Example 1 N-benzyl-N- methyl-B-methoxy-Sl-trifluoromethyl-phenethylamine was hydrolyzed with concentrated sulfuric acid fol- Amlys'sz Calculated for Q3 523:1; 52. lowed 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 The starting material may be prepared as follows: was rendered alkaline with sodium hydroxide. Utilizing the procedure of Example 1 3-trifluorome- The free base was extracted with ether and the exthylphenethyl chloride was reacted with N-methylpiptract dried over potassium carbonate and distilled. Diserazine to give N-methyl-N-(3-trifluoromethyl)- 6O tillation yielded m-[l-methoxy-Z-(benzylmephenethylpiperazine in 68% yield boiling at thylamino)-ethyl]benzoic acid methyl ester boiling at 89-90C/0.3 mm. l50C/0.3 mm.
Non! liquiv.. 313
Neut. Equiv., 272
Analysis:
Neut. Equiv., 275
Cnlculutcd for C H Fa I Found:
Analysis: Calculated l'or C H NO Found: Ncul Equiv., 3l6
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 ,B-methoxy-3-trifluoromethylphenethyl bromide and 13 g. (0.1 mole) of benzylmethylamine was reacted at 100C. for three hours. Distillation yielded N-benzyl-N-methyl-B-methoxy-3- trifluoromethyl-phenethylamine boiling at lOC/0.2 mm.
Analysis: Calculated for C l-l F NOz Neut. Equiv., 323 Found: Neut. Equiv., 325
EXAMPLE 15 In analogous manner to the procedure of Example 1 hydrolysis of N-benzyl-B-methoxy-3-trifluoromethyl phenethylamine with concentrated sulfuric acid followed by esterification with methyl alcohol yielded m- [l-methoxy-2-(benzylamino )-ethyl]benzoic acid methyl ester. Conversion to the hydrochloride salt yielded material melting at 243C.
Calculated for C H NO Neut. Equiv., 299
Analysis:
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 ,B-methoxy-3-trifluoromethylphenethyl bromide was reacted with 19 g. (0.18 mole) of benzylamine at 100C. for 3 hours. Distillation yielded N-benzylB-methoxy-3;trifluoromethylphenethylamine boiling at l37C/0.3 mm.
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. mesh screen (or similar suitable coarse screen).
3. Place the moist granules on drying pans and dry at 1 10F.
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 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 N o. 12 screen. It was then dried overnight at 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 inch. (Tablets may be either flat or biconvex and may be scored if desired.)
EXAMPLE l8 Capsule Formulation Per Capsule m-[2-(Benzylmethylamino)-ethyllbenzoic acid methyl ester hydrochloride 5 mg.
Lactose 178 mg. Corn Starch 37 mg. Tale 5 mg.
Total Weight 225 mg.
Procedure:
EXAMPLE 19 Capsule Formulation Per Capsule m-l2-(Benzylmethylamino)-ethyllhenzoic acid 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. '7
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. 153155C.
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-(methy1amino)- ethyllbenzoic acid, m-cresyl ester hydrochloride melting at 162C.
Analysis: Calculated for C H NO 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 1 C. Isolation in the usual manner yielded N-methyl-3-trifluoromethylphenethylamine boiling at 94-96C/40 mm.
Calculated for C H F N: Neut. Equiv., 203
Analysis:
Found: Neut. Equiv., 197
Conversion to the hydrochloride in the usual manner yielded the salt melting at l46-147C.
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-pyrro1idinoethy1)-benzoic acid methyl ester hydrochloride melting at 188-189C.
Analysis: Calculated for C H NO Neut. Equiv., 223 Found: Neut. Equiv., 223
The starting material may be prepared inanalogy to the method of Example 1 wherein 3-trifluoromethy1- phenethyl chloride was reacted with pyrrolidine to produce 3-trifluoromethy1phenethyl pyrrolidine in 51% yield as a liquid boiling at l17C./30 mm.
Analysis: Calculated for C H F Nz 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 156157C.
Analysis: Calculated for C H NO N. 4.58 Found: N. 4.45
The starting material may be prepared as follows:
B-Trifluoromethylphenethyl chloride and p-toluidine were reacted in analogy to the procedure in Example 1 to yield 3-trifluoromethylphenethyl-p-toluidine boiling at l47C./1.8 mm.
Analysis: Calculated for C H F Nz N. 4.45 I Found: N. 4.25.
Conversion to the hydrochloride in the usual manner yielded the corresponding hydrochloride salt melting at 162-l63C.
EXAMPLE 24 In analogy to the procedure of Example 1, N-methyl- N-Z-hydroxy ethyl-B-hydroxy-a-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-methyI-N-Z-hydroxyethyl)amino-B-hydroxy-amethyl-benzoic acid, methyl ester hydrochloride, melting at 206207C.
Analysis: Calculated for C,.,H ,NO .HCl: N. 4.62 Found: N. 4.37
Calculated for CI: 11.3 Found: 1 1.1
EXAMPLE 25 A total of 3.0 g. of m-2-cyclohexylaminoethylbenzoic acid methyl ester hydrochloride was added to 20 ml. of methanol and there was thereafter added 1.15
Analysis: Calculated for C H NO Neut. Equiv., 331 Found: Neut. Equiv., 331
The starting material may be prepared as follows:
In analogy to the procedure of Example 1, 3-trifiuoromethylphenethyl chloride was reacted with cyclohexylamine to yield 3-trifluoromethylphenethyl cyclohexylamine boiling at ll6C./l.1 mm.
Analysis: Calculated for C, H F;,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 2l0-2l 1C.
Analysis: Calculated for C H NO Neut. Equiv., 261 Found: Neut. Equiv., 262
I claim: 1. A compound of the formula 1|; H R. -t N R1 2 Rs wherein R is hydrogen, hydroxy, lower alkoxy or lower alkyl; R is hydrogen or lower alkyl; R is lower alkyl, aralkyl or lower alkyl aryl; R taken independently is hydrogen, lower alkyl, aralkyl, lower alkyl aryl, hydroxy lower alkyl and lower alkoxy lower alkyl; R taken independently is lower alkyl, aralkyl, lower alkyl aryl or lower alkoxy lower alkyl; and R and R 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 where R is hydrogen or lower alkyl and the optical antipodes and the pharmaceutically acceptable acid addition salts thereof.
2. The compound of claim 1 wherein R and R both are hydrogen and R 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-[Z- (methylisopropylamino)-ethyl]benzoic acid methyl ester.
11. The compound of claim 2 which is m-[2- (bentylmethylamino)-ethyl]benzoic acidn-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-[Z-(N- benzyl-N-(Z-methoxyethyl)amino)-ethyl]benzoic acid methyl ester.
14. The compound of claim 1 wherein R is hydrogen and R and R are lower alkyl.
15. The compound of claim 14 which is m-[(2- methyl)(2-isopropylamino)-ethyllbenzoic 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 R is lower alkoxy, R is hydrogen and R is lower alkyl.
18. The compound of claim 17 which is m-[lmethoxy-2-(benzylmethylamino)ethyl]benzoic acid methyl ester.
19. The compound of claim 17 which is m-[lmethoxy-2-(benzylamino)-ethyl]benzoic acid methyl ester.

Claims (19)

1. A COMPOUND OF THE FORMULA
1. A compound of the formula
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.
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US4690931A (en) * 1982-10-13 1987-09-01 Synthelabo Therapeutically useful 1-phenyl-2-piperidinoalkanol derivatives
US4754047A (en) * 1979-08-16 1988-06-28 American Cyanamid Company Phenylethanolamine derivatives and acid addition salts thereof for enhancing the growth rate of meat-producing animals and/or improving the efficiency of feed utilization thereby
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Cited By (17)

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US4182775A (en) * 1976-09-04 1980-01-08 Hoechst Aktiengesellschaft Benzoic acids and process for their preparation
US4654371A (en) * 1978-06-28 1987-03-31 Beecham Group P.L.C. Secondary amines, their preparation and use in pharmaceutical compositions
US4753962A (en) * 1978-06-28 1988-06-28 Beecham Group P.L.C. Secondary amines, their preparation and use in pharmaceutical compositions
US4845127A (en) * 1978-07-03 1989-07-04 Eli Lilly And Company Phenethanolamines, compositions containing the same and method for effecting weight control
US4754047A (en) * 1979-08-16 1988-06-28 American Cyanamid Company Phenylethanolamine derivatives and acid addition salts thereof for enhancing the growth rate of meat-producing animals and/or improving the efficiency of feed utilization thereby
US4690931A (en) * 1982-10-13 1987-09-01 Synthelabo Therapeutically useful 1-phenyl-2-piperidinoalkanol derivatives
US9675604B2 (en) 2009-01-20 2017-06-13 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical
US9649304B2 (en) 2009-01-20 2017-05-16 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical
EP2389187A4 (en) * 2009-01-20 2013-12-04 Los Angeles Biomed Res Inst SORBIC AND BENZOIC ACID AND DERIVATIVES THEREOF FOR ENHANCING THE ACTIVITY OF A NEUROPHARMACEUTICAL PRODUCT
US10039730B2 (en) 2009-01-20 2018-08-07 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical
US10149845B2 (en) 2009-01-20 2018-12-11 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical
US11529342B2 (en) 2009-01-20 2022-12-20 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Sorbic and benzoic acid and derivatives thereof enhance the activity of a neuropharmaceutical
US11731928B2 (en) 2016-06-13 2023-08-22 Syneurx International (Taiwan) Corp. Co-crystals of sodium benzoate and uses thereof
US11739046B2 (en) 2016-06-13 2023-08-29 Syneurx International (Taiwan) Corp. Co-crystals of lithium benzoate and uses thereof
US10336679B2 (en) 2016-10-24 2019-07-02 Syneurx International (Taiwan) Corp. Polymorphic forms of sodium benzoate and uses thereof
US11369579B2 (en) 2016-10-24 2022-06-28 Syneurx International (Taiwan) Corp. Polymorphic forms of sodium benzoate and uses thereof
US10098861B1 (en) 2017-10-24 2018-10-16 Syneurx International (Taiwan) Corp. Pharmaceutical composition comprising sodium benzoate compound and clozapine, and uses thereof

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