CS217957B2 - Method of making the new cis ev.trans 2-aminocyclohexancarboxyl or cis ev.trans i-aminocycloopentacarboxyl acids - Google Patents

Abstract

The invention relates to a method for preparing new ones cis or trans 2-aminocyclohexanecarboxylic acids or cis or trans 2- -aminocyclopentanecarboxylic acids of formula I. Compounds of formula I are prepared in such a way that the compounds are general of formula II Y (III are reacted with an amine of the formula III R 2 -NH 2 (III) then optionally reduced and optionally reduced hydrolyses and the obtained compounds of the general of formula I are optionally converted into their addition salts by reaction with acids. The obtained new compounds of the general formula I have valuable pharmacological effects, v first and foremost anti-inflammatory, further decreasing effects fever, pain-relieving and amplifying narcotic effects.

Description

The invention relates to a process for the preparation of novel cis or trans 2-aminocyclohexanecarboxylic acids or cis or trans 2-aminocyclopentanecarboxylic acids of the general formula (I).

Compounds of formula I are prepared by reacting compounds of formula II ^Y (III) with an amine of formula III

R ² -NH ₂ (III) is then optionally reduced and optionally hydrolysed and the resulting compound of formula I are optionally converted in their acid addition salts by reaction with acids.

The novel compounds of the formula I obtained have valuable pharmacological effects, primarily anti-inflammatory, fever-reducing, pain-relieving and potentiating narcotic effects.

The invention relates to a process for the preparation of novel stereoisomeric 2-aminocycloalkanecarboxylic fluids and derivatives thereof.

R ³ represents phenyl-C ^1-4 -alkyl group compounds of formula I

CH 2 CH-CO-R ¹ (I) wherein n represents 1 or; 2

R ¹ is -NH-R ³ where

R ³ represents a phenyl-C _1-4 -alkyl group,

R ² is phenyl or benzyl.

The compounds of formula I exhibit valuable pharmacological effects, in particular anti-inflammatory effects, fever-reducing effects, pain-relieving effects and potentiating narcotic effects. This is surprising since the literature has so far known quite different or no effects at all for related compounds. In US Patent ^sp: number is 3610 492 describes an antidiabetic and diuretic effect anillncykloaIkylaminů-2 and 2- (anilinOmetyl) -cycloalkylamino. Several 2-anrinocycloalkanecarboxylic acid derivatives forming the subject-matter of the present invention are mentioned as intermediates, but there is no report of their pharmacological effect. Although cis and trans derivatives are mentioned in the cited patent, the process described therein is not suitable for the production of stereospecific compounds, as evidenced by the reproduction experiments proper.

Hungarian Patent Specification No. 156,542 discloses cyclohexylmethylaminocyclohexylaimine and 2- (aminomethyl) cyclohexylamine derivatives which can be used as tranquillizers and as epilepsy treatment agents. The pharmacological effects of the compounds of the formula I described above are therefore surprising.

The process according to the invention is characterized in that the compounds of the formula (II) are prepared

CH (CH3)

CH, / _X CO- / T (in where o is 1 or · 2 in the case where X is - CO, Y is hydrogen and · in the case of X is ξξ CH Y forms another bond to C

R ⁴ is a hydroxyl group, a C _1-4 -alkoxy radical or an -NH-R ³ , where R ³ is as defined above, reacted with an amine of formula III

R ³ -NH ₂ (III), wherein R ³ is as hereinbefore defined, is then optionally reduced and optionally hydrolyzed and the compounds of formula I obtained are optionally converted in their acid addition salts by treatment with acids. ₍

Preferably, an excess of the amine is used as the reaction medium. The reaction is preferably carried out at an elevated temperature of 100 to 2 ° C. The boiling point of the amine used is also suitable. After completion of the reaction, the mixture was cooled and supplemented with ether, whereupon the product crystallized. If there is no crystallization, the excess amine is distilled off and the residue is purified by extraction and recrystallization.

The 2- (alkylamino) -cycloalkanecarboxylic acid trans amides, 2- (arylamino) cycloalkanecarboxylic acid trans amides or 2- (arylamino) -cycloalkanecarboxylic acid trans amides of formula (I) obtained as described above may, if It is preferably hydrolyzed in an aqueous mineral acid (e.g. hydrochloric acid) with heating, but bases may also be used to saponify the acid amide. evaporation, leaving the 2-aminocycloalkanecarboxylic acid derivative in the form of its hydrochloride, which is purified by recrystallization and / or the base is liberated.

In another embodiment of the process of the invention, the 2-oxocycloalkanecarboxylic acid ester of formula (II) is reacted with the amines of formula (III) to give the N-substituted 2-aminocycloalkanecarboxylic acid ester. The reaction is preferably carried out without solvent at room temperature, but may also be heated to increase the reaction rate. The crude product obtained is purified by recrystallization. If desired, the product can be converted by reduction to a 2-aminocycloalkanecarboxylic acid ester. The reduction is preferably carried out in an alcoholic solution. As catalytic hydrogenation, however, other methods can also be used. After reduction, the solution was filtered and evaporated to give the N-substituted 2-aminocycloalkanecarboxylic acid ester. They can be prepared from the product by hydrolysis of the corresponding N-substituted 2-aminocycloalkane carboxylic acid.

He did

To 0.02 mol of cis or trans amide

2- (Benzyloxycarbonylamino) -cyclohexanecarboxylic acid was added 40 ml of a 20% 217957 solution, hydrogen bromide acidified with glacial acetic acid. The reaction mixture was allowed to stand for one hour at room temperature and then supplemented with ether. This eliminates the carboxylic acid 2-amino-cyclohexanhydrotoromide amide in the form of an oily substance which is brought to crystallization by rubbing with a glass rod. Now the crystalline substance is filtered off and washed with ether. The base is liberated with 10% sodium carbonate solution.

In cases where the crystallization of the hydrobromide fails, the base is released from the oil of the TABLE 1 by ion exchange (Varion AD and Auto-exchange resin). For this purpose, the Var'on AD aionic resin is converted with 0.5 N sodium hydroxide solution in the OH form and the 2-aminocyclohexanecarboxylic acid amide solution, mixed with methanol / water 1: 1, is applied to the column. Elute with the same solvent mixture. The eluate was evaporated and the residue was recrystallized.

The properties of the 2-aminocycloxanecarboxylic acid amide thus produced are summarized in Tables 1 and 2.

Melting points, analysis results and yields of N-substituted 2-aminocyclohexanecarboxylic acid cis amides

amid form mp ^Q C and the solvent used for recrystallization analysis calculated / found yield % C% H% N% Br% n-ibutylamide base 39 to 42 66.63 11.18 14.13 54.17 (benzene - petroleum ether j 65.99 '10, 82 14.01 51.27 N-ibutyl amide hydro- 142 to 144 56.27 9.88 11.98 bromide (ethanol-ether) 55.80 10.19 11.78 '63, 06 cyclohexylamide hydro- 204 to 207 51.14 8.25 9.18 26.17 bromide decomposition (ethanol-ether) 51.67 8.49 9.53 26.08 anilide base 143 to 14.4 71.53 8.31 12.83 71.02 (ethanolj 72.11 8.33 12.03 68.27 amilide hydro- 18.8 to 191 52.19 6.40 9.36 26.71 bromide decomposition (ethanol) 51.73 6.21 9.18 26.67 71.21 o-toluidide base 92 to 93 72.39 8.68 12.06 (ether) 72.34 8.54 '11, 52 m-toluidide base 130 to 133 72.39 8.68 12.06 67.10 (benzene) 72.95 8 56 '11, 62 p-toluidide hydro- 200 to 20.3 53.69 6.76 8.95 25.51 78.15 bromide (ethanol) 53.77 7.08 8.71 25.52 m-fluoroanide hydro- 207 to 210 49.22 5.72 8.83 25.19 63.17 bromide decomposition (ethanol j 48.92 5.77 8.79 25.12 o-chloroanilide hydro- 3.68 to 173 46.79 5.44 8.40 23 94 77.51 bromide (ethanol) 46 39 5.75 8.33 23.68 m-chlorate lid base 121 to 123 61.77 6.78 11.09 69.31 (benzene) 61.85 6.68 10.90 p-chloroanilide hydro- 197 to 200 46.79 5.44 8 40 79.31 bromide (ethanolJ '47, 20 5.80 8.19 p-chloroanilide base 121 to 12.3 61.77 6.78 '11, 09 82,3.1 (ethanol) 61.75 6., 93 11.10 p-bromoanilide base 140 to 142 5,2,52 5.77 9.43 75.17 (ethanol j 52.02 5.81 9.59 m- (trifluoro- hydro- 169 to 172 '45, 80 4.94 7.64 2: 1.76 6.2,27 methyl) -anilide bromide (ethanolJ '45, 53 5.13 7.95 21.81 p-methoxyanir.d hydro- 135 to 138 51, 0.7 6.43 8.51 70,2.7 bromide (ethanol-ether) '51, 16 6.80 8.40

amid form melting point < 0 > C and solvent after recrystallization C% analysis calculated ·, 'found · Br% yield % H% N% p-ethoxynnil'd base 95 to 98 '68, 66 8.45 10.68 68.71 (benzene) 68.91 8.88 '10 56 p-ethoxyanilide hydro- 122 to 126 '52, 48 6.78 8.16 65.31 bromide (ethanolj 51,91 7.41 7.91 benzyl amide base 55 to 57 72 38 8 68 12.06 71.21 (ethanol-ether) 72, 0.3 8.53 '11, 54 p-chlorbem- hydro- 60 to 63 63.03 7.18 '10, 50 73.23 zylamrd bromide (ethanol-ether) • 63.40 7.31 1.0,86 -metoxyben- hydro- 194 to 196 '52, 48 6.75 8.08 2,3,28 68.31 zylamide bromide (ethanol) '52, 70 6.88 838 23.30 2- (phenylethyl) - 'base 86 to 88 7,3,12 9.00 1.1,37 6,9,45 amid (ethanol-ether) 73.24 8.81 11.86 2- (3,4-dimetho- base 69 to 71 66.24 8.55 9.14 70.15 xyfe, nyl) -ethyl- (ethanol-ether) '66, 25 8.81 9.42 amid 3-Pyridylamide base 131 to 133 65.72 7.81 8.04 63.21 (ethanol-ether) 65 87 9.16 8.94 2-ohinoxalyl- base 165 to 1.67 66, 41 7.06 51.20 amid (benzene) '66, 64 6.63 2- (2-Pyridyl) - base 69 to 62 67.99 8.56 16.99 95.30 ethylanfd (Ethane-ol-ether) 68.40 8.71 16 69 2-thiazolyl- base 156 to 158 '53, 31 6.71 18.65 69.87 amid (ethanol) 53.58 6.98 18.27 Table 2 Melting points, analysis results and yields N-substituted trans-amides 2-cyclohexane- carboxylic acids amid form melting point ° C analysis and a solvent calculated / found yield used to C% H% | N% Br% )% crystallization N-butyl amide base ¹ 72 to 75 66.6i3 11.18 14.13 49.11 (ethanol-ether) 66.49 11.40 13.42 p-toluidide base 140 to 141 72, 39 8.68 12.06 78.27 (ethanol) 72.67 8.75 11.37 p-toluidide hydro- 206 to 109 53.6) 8 6.76 8.95 65.15 bromide (ethanol) 54.20 6 79 8.70 p-chlorainilide base 161 to 16.3 61.77 6.78 11.09 77.21 (ethanol) • 64.41 7.05 11.73 p-chloroanilide hydro- 2.28 to 230 46.79 5.44 8.40 23.94 65.25 bromide (ethanol) 46.43 5.41 8,1.2 24,00 p-bromoanilide hydro- 255 to 257 41.30 4.80 7.41 21.14 70.03 bromide (ethanol) 41.14 4.39 7.44 20.93 -phenylethylamide base 98 to 101 73.12. 9.00 11.37 60.21 (ethanol) 72.83 9.21 11.12 2- (3,4-dimetho- base 12!) To 12.2 66.64 8.55 9.14 • 65.11 xyfemyljetyl- (ethanol-ether) 66.31 8.39 9.04

amid

Example 1 a d 2

5.0.4 g (0.04 mole) of 1-cyclohexenecarboxylic acid was boiled together with 21.43 g (0.2 mole) of benzylamine under reflux for 80 hours. The excess benzylamine is then distilled off in vacuo and the residue is taken up in 40 ml of ether. The substance starts to crystallize. The crystals are filtered off, washed with ether and then dried. Recrystallization from benzene gave 7.90 g (61.2%) of 2- (ben, zylamino) -cyclohexanecarboxylic acid trans benzylamide, melting at 116-118 [deg.] C. The hydrochloride recrystallized from ethanol-ether melts at 192-194. Deň: 32 ° C.

For C 21 H 26 N 2 O calculated:

% C, 78.21;% H, 8.13;% N / 8.69;

found:

78.27% C, 8.43% H, 8.54% N.

The ethereal mother liquor from the reaction mixture was evaporated and the residue was recrystallized from aqueous ethanol. 1.2 g of 1-cyclohexanecarboxylic acid benzylamide are obtained, melting at 88-90 ° C.

For C14H17NO calculated:

% C, 78.18;% H, 7.96;% N, 6.51;

found:

% C, 78.1;% H, 7.98;

Example 3

From 1.23 g (0.01 mol) of 1-cyclohexenecarboxylic acid and 3.73 g (0.04 mol) of aniline, 0.8 g (27.2%) of the trans anilides 2- (phenylamino) are prepared as described in Example 2. -cyclohexanecariboxylic acid, which melts at 194-196 ° C.

For C1OH22NO2 calculated ·:

% C, 77.52;% H, 7.53; found:

% C, 77.05;% H, 7.05;

Starting from 5.1 g (0.0.3 mol) of 2-oxocyclohexanecarboxylic acid ethyl ester and 5.44 g of homoveratrilamline, 8.8 g (80.7%) of ethyl 2 (Homoveriaitrilami) -cyclohexanecarboxylic acid ethyl ester was obtained as described in Example 17. The product is boiled in 100 ml of hydrochloric acid diluted 1: 2 for four hours under reflux. The reaction mixture was then evaporated to dryness. 8 g of a yellowish-white powder are obtained, which, after recrystallization twice from 80 ml of ethanol, yields 5.8 g (64.5%) of the hydrochloride.

2- (ihomoiveratriaminocyloxycyclohexanecarboxylic acid) melting at 227-228 ° C (predominantly cis isomer).

For C 17 H 26 NO 4 Cl calculated ·:

% C, 59.37;% H, 7.62; found ::

% C, 59.00;% H, 7.89.

Dissolve 5.09 g (0.03 mol) of silver nitrate in 40 ml of distilled water. To the solution was added 1.59 g (0.015 mol) of anhydrous sodium carbonate in 60 ml of distilled water. The resulting silver carbonate precipitate is filtered through a Buchner funnel and washed with distilled water until the silver is removed. This silver carbonate was added to a solution of 3.44 g (0.01 mol) of 2- (homover atrilamino) -cyclohexanecarboxylic acid hydrochloride in 80 ml of distilled water. The mixture is shaken for 2 hours, then made up to 50 ml of distilled water and filtered. The filtrate is purified with activated carbon and then evaporated to dryness. The residue was recrystallized from ethanol. 1.95 g (6.3.45%) are obtained.

2- (homoveratrilamino) -cyclohexanecarboxylic acid melting at 179-181 ° C.

For C17H25NO4 calculated:

H, 8.20; N, 4.56;

found:

H, 8.35; N, 4.56.

Example 5

The mixture, consisting of 11.21 g (0.1 mol) of (1-cyclopentine carboxylic acid) and 32.15 g (0.3 mol) of benzylamine, was refluxed under nitrogen for 70 hours. The residue is taken up in 100 ml of benzene and 100 ml of 5% hydrochloric acid and shaken vigorously. trans 2- (benzylamino) -cyclopeintanecarboxylic acid melting at 175-177 ° C.

For C 20 H 25 N 2 OCl calculated ·:

% C, 69.65;% H, 7.31;

10.28% Cl;

found:

% C, 69.26;% H, 7.32;% N / 7.99;

10.23% Cl.

1.2 g of 1-cycloipentenecarboxylic acid benzylamide is obtained from the benzene extract by recrystallization from benzene, m.p. 112-114 ° C.

For C 13 H 15 NO calculated:

% C, 77.57;% H, 7.51;

found ·:

% C, 77.57;% H, 7.73;

Pharmacological tests

Inflammatory, analgesic, temperature-lowering, and potentiating narcotic effects were investigated.

, 1. Effects against inflammation (kaolin swelling)

The effect was determined 3 hours after administration

12 test compounds and 2 hours after administration. Result of tests for an anti-inflammatory agent inducing inflammation. nek:

compound dose mg / kg p.o.% efficacy

JATÉ 23 2- (am: no-N-p-chlorophenyl) -cyclohexanecarboxylic acid hydrobromide trans amide 50 14,8 * JATÉ 28 N-p-chlorophenylhexahydroantranilic acid hydrobromide trans amide 50 14.2 JATÉ 33 2-Amino (N-p-Totyl) cyclohexanecarboxylic acid hydrobromide amide 100 ALIGN! , 22,5 * JATÉ 39 2-Amino-no- (N-2-thiazolyl) -cyclohexainecarboxylic acid amide 100 ALIGN! 31.4 *** phenyl butazone 50 27,5 * * * sodium sallcylan 100 ALIGN! 10.5 sodium salicylate 200 34.3 ***

* _p < 0.05 * < 0.001

2. Temperature-lowering effect (a) in animals having fever

The following compounds showed a temperature-lowering effect

compound dose mg / kg p. o. grain, temperature ° C lh 2h 3h JATÉ 1,3 2- (benzylamino- 50 —1.4 ** —1.3 ** -1,1 ** -N-benzyl) -cyclohexanecarboxylic acid 100 ALIGN! —2.0 *** —1.6 *** - -1.0 ** JATÉ 23 2- (amino-N-p-chlorophenyl) -cyclohexanecarhoixylic acid hydrobromide trans amide 100 ALIGN! —0.9 ** —0.9 ** -0.9 ** JATÉ 28 N-p-chlorophenylhexanhydroantrainilic acid hydrobromide trans amide 50 0 -0.4 -0.3 Phenylibutazone 50 —1.05 ** —1.07 ** - -0.76 * amidosophene 25 —1.17 *** —0.94 ** - -0,95 * * _p <0.05 ** _p <0.01 *** _p <0.001 bj in animals at normal body temperature compound dose temperature change ° C mg / kg lh 2h, p. o. JATÉ 30 2-Aminoacyclohexanecarboxylic acid amide ^, 100 ALIGN! —0.70 = 1.10 xylic acid hydrobromide JATÉ 31 Cis-2-amino (N-p-bromophenyl) cyclic amide 100 ALIGN! —0.92 —1.04 lohexanecarboxylic acids

3. Analgesic effect (hot plate method)

The increase in pain response versus time was tested 1 hour after administration of the test compound. Low analgesic efficacy was observed in the following cases:

compound dose mg / kg p.o. efficiency% JATÉ 23 2- (amino-N-p-chlorophenyl) cyclohexanecarboxylic acid hydrobromide trans amide 50 30.5 JATÉ 28 N-p-chlorophenylhexahydroamtranilic acid hydrobromide trans amide 50 22.8 JATÉ 39 cis-2-amino- (N-2-thiazolyl) -cyclo- amide 50 37.0

loihexainecarboxylic acids

4. Effect enhancing narcotic effects

Anesthesia sleep anesthesia at 40 mg / kg. Venobarbital was administered to animals. subjects treated with the following compounds: dose mg / kg p.o. time sleep control sec.léčba compound JATÉ 23 2- (amino-N-p-chlorophenyl) cyclohexanecarboxylic acid trans amide hydrobromide 50 167 322 JATÉ 28 N-p-chlorophenylhexahydroantrainilic acid hydrobromide trans amide 50 171 384 JATÉ 32 2-Amino (N-m-fluorophenyl) -cyclohexanecarboxylic acid cis amide hydrobromide 50 148 350 JATÉ 33 3-Amino (N-p-tolyl) -cyclohexane carboxylic acid cis amide hydrobromide 100 ALIGN! 147 538 JATÉ 35 2-Amino (N-m-trifluoromethylphenyl) cyclohexanecarboxylic acid hydrobromide ois amide 50 147 734 JATÉ 43 2-Amino (N-phenylethyl) cyclohexanecarboxylic acid amide 50 154 482 Andaxin 20 May 186 391 Based on the investigation of the anti-negative mg / kg p. I. Appropriate efficiency an-

The effect of JATÉ 23, 28 and 33 was found to be comparable to that of sodium salicylate and that of JATE 39 to that of femylbutazoin. The most significant analgesic effect is seen with compound JATE 39 at a dose of 50 daxin at a dose of 20 mg / kg. JATÉ 30 exhibits the most potent enhancement of the narcotic effect, the sleep time is prolonged by a dose of 50 mg / kg p.

Claims (6)

A process for the preparation of novel cis or trans 2-aminocyclohexanecarboxylic acids or cis or trans 2-aminoocycloipenetanecarboxylic acids of the general formula I ÍCHJ _a C 11 H 11 CH-CO-R R ¹ is -NH-R ³ , wherein R ³ is phenyl-C 1-4 -alkyl, R ² represents a phenyl or benzyl group, and their acid addition salts characterized in that a compound of formula II 2'ite io ^ ch-nh-r (li κ F 'ch' (II) where denote η 1 or 2 where .n is confused 1 or · 2 when X is = CO, Y is hydrogen and when X is means = CH forms Y additional bond to C R ⁴ is a hydroxyl group, a C _1-4 -alkoxy radical or -NH-R ³ , where R ³ is as defined above, reacted with an amine of formula III R ^{3 -} NH 2 (III), wherein R ³ is as hereinbefore defined, is then optionally reduced and optionally hydrolyzed, and the compounds of formula I obtained are optionally converted in their acid addition salts by reaction with acids. 2. The process according to claim 1, wherein an excess of the amine is preferably used as the reaction medium. Process according to Claim 1, characterized in that the reaction is carried out at a temperature between 100 and 200 ° C, preferably at the boiling point of the amine. 4. The process according to claim 1, wherein the reaction is preferably carried out without solvent at room temperature. Process according to claim 1, characterized in that the reduction is preferably carried out in an alcoholic solution such as catalytic hydrogeination. 6. A process according to claim 1, wherein the compounds of the formula II are stero-unity derivatives of cis or trans cycloalkanecarboxylic acids.