CS217957B2 - Process for the preparation of new cis or trans 2-aminocyclohexanecarboxylic or cis or trans 2-aminocyclo-pentanecarboxylic acids - Google Patents

Abstract

The invention relates to a process for the preparation of new cis or trans 2-aminocyclohexanecarboxylic or cis or trans 2-aminocyclopentanecarboxylic acids of the general formula I. The compounds of the general formula I are prepared by reacting the compounds of the general formula II Y (III with the amine of the general formula III R2—NH2 (III), then optionally reducing and optionally hydrolyzing, and the obtained compounds of the general 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, primarily anti-inflammatory, and also fever-reducing, pain-relieving and narcotic effects-enhancing.

Description

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

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

R ² —NH ₂ (III), then optionally reduced and optionally hydrolyzed and the compounds of general formula I obtained are optionally converted into their addition salts by reaction with acids.

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

The invention relates to a process for the production of novel stereoisomeric 2-aminocycloalkanecarboxylic liquids and their derivatives.

R ³ represents a phenyl-C ^1-4 alkyl group. The compounds correspond to the chemical formula I

CH^CH-CO-R ¹ (I) where n is 1 or; 2

R ¹ is a group —NH—R ³ , where

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

R ² represents a phenyl or benzyl group.

The compounds of the general formula I exhibit valuable pharmacological effects, primarily anti-inflammatory effects, as well as fever-reducing, pain-relieving and narcotic-enhancing effects. This is surprising, since completely different or no effects at all have been known from the literature for related compounds until now. In the US patent sp ^: with number 3610 492 the antidiabetic and diuretic effect of 2-anilinocycloalkylamines and 2-(anilinomethyl)-cycloalkylamines is described. Several derivatives of 2-anilinocycloalkanecarboxylic acid, forming the subject of the present invention, are mentioned as intermediates, but there is no report on their pharmacological effect. Although cis and trans derivatives are mentioned in the cited patent, the process described there is not suitable for the preparation of stereoidentical compounds, as was proven by our own reproduced experiments.

From Hungarian Patent No. 156,542, derivatives of cyclohexyl-methylaminocyclohexylamine and 2-(aminomethyl)cyclohexylamine are known, which can be used as tranquilizers and as agents for the treatment of epilepsy. The above-described pharmacological effects of the compounds of the general formula I are therefore surprising.

The essence of the process for producing compounds of general formula I according to the invention consists in that compounds of general formula II

CH (CH^

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 where X is ξξ CH Y forms an additional bond to C

R ⁴ is a hydroxyl group, a C _1-4 alkoxy radical or —-NH—R ³ , wherein R ³ has the meaning given above, are allowed to react with an amine of the general formula III

R ³ -NH ₂ (III), where R ³ has the meaning given above, is then optionally reduced and optionally hydrolyzed and the compounds of general formula I obtained are optionally converted into their addition salts by reaction with acids. ₍

The reaction medium is preferably an excess of amine. The reaction is preferably carried out at an elevated temperature of 100 to 200 °C. The boiling point of the amine used is also a suitable temperature. After the reaction is complete, the mixture is cooled and made up with ether, whereby the product crystallizes. If no crystallization occurs, the excess amine is distilled off and the residue is purified by extraction and recrystallization.

The trans amides of 2-(alkylamino)-cycloalkanecarboxylic acids, trans amides of 2-(aralkylamino)-cycloalkanecarboxylic acids or trans amides of 2-(arylamino)-cycloalkanecarboxylic acids of the general formula I obtained by the process described can, if desired, be converted by hydrolysis into the corresponding 2-aminocycloalkanecarboxylic acids. The hydrolysis is preferably carried out in aqueous mineral acid (for example hydrochloric acid) with heating. However, basic substances can also be used to saponify the acid amide. In the case of hydrolysis using hydrochloric acid, the reaction mixture is finally evaporated, leaving the 2-aminocycloalkanecarboxylic acid derivative in the form of its hydrochloride. This is purified by recrystallization and/or the base is liberated from it.

According to another embodiment of the process according to the invention, the 2-oxocycloalkanecarboxylic acid ester of the general formula II is reacted with amines of the general formula III, and in this way the N-substituted 2-aminocycloalkanecarboxylic acid ester is obtained. The reaction is preferably carried out without a solvent, at room temperature, but it can also be heated to increase the reaction rate. The crude product obtained is purified by recrystallization. If desired, the product can be converted into the 2-aminocycloalkanecarboxylic acid ester by reduction. The reduction is preferably carried out in an alcoholic solution. However, other methods can also be used, such as catalytic hydrogenation. After the reduction is complete, the solution is filtered and the N-substituted 2-aminocycloalkanecarboxylic acid ester is obtained by evaporation. The corresponding N-substituted 2-aminocycloalkanecarboxylic acids can be prepared from the product by hydrolysis.

Example

To 0.02 mole of cis or trans amide

40 ml of a 20% solution of hydrogen bromide acidified with glacial acetic acid are added to 2-(benzyloxycarbonylamino)-cyclohexanecarboxylic acid. The reaction mixture is left to stand for one hour at room temperature and then made up with ether. This separates out the amide of 2-amino-cyclohexanehydrobromide carboxylic acid in the form of an oily substance, which is brought to crystallization by rubbing with a glass rod. The crystalline substance is now filtered off and washed with ether. The base is liberated with a 10% solution of sodium carbonate.

In cases where the crystallization of the hydrobromide fails, the base is released from the oily substance using ion exchangers (Varion AD anion exchange resin). For this purpose, the Varion AD anion resin is converted into the OH-form with 0.5 N sodium hydroxide solution and a solution of 2-aminocyclohexanecarboxylic acid amide, loaded with a mixture of methanol and water, prepared in a ratio of 1: 1, is applied to the column. It is eluted with the same solvent mixture. The eluate is evaporated and the residue is recrystallized.

The properties of the 2-aminocyclohexanecarboxylic acid amide produced in this way are summarized in Tables 1 and 2.

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

amide form melting point ^Q C and 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-ibuthyamide 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-fluoran'lide 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-chloranilide 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-chlcran people base 121 to 123 61.77 6.78 11.09 69.31 (benzene) 61.85 6.68 10.90 p-chloranilide hydro- 197 to 200 46.79 5.44 8 40 79.31 bromide (ethanolJ '47.20 5.80 8.19 p-chloranilide base 121 to 12.3 61.77 6.78 '11.09 82,3.1 (ethanol) 61.75 6.93 11.10 p-bromanilide 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

amide form melting point °C and solvent used for 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-chlorben- hydro- 60 to 63 63.03 7.18 '10.50 73.23 zylamrd bromide (ethanol-ether) •63.40 7.31 1.0.86 -methoxyben- 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 amide (ethanol-ether) 73.24 8.81 11.86 2-(3 4-dimetho- base 69 to 71 66.24 8.55 9.14 70.15 xyphen,nyl)-ethyl- (ethanol-ether) '66.25 8.81 9.42 amide 3-pyridylamide base 131 to 133 65.72 7.81 8.04 63.21 (ethanol-ether) 65 87 9.16 8.94 2-Ochinoxalyl- base 165 to 1.67 66,,41 7.06 51.20 amide (benzene) '66.64 6.63 2-(2-pyridyl)- base 69 to 62 67.99 8.56 16.99 95.30 ethylanfd (ethanol ether) 68.40 8.71 16 69 2-thiazolyl- base 156 to 158 '53.31 6.71 18.65 69.87 amide (ethanol) 53.58 6.98 18.27 Table 2 Melting points, analysis results and yields N-substituted trans-amides 2-cyclohexane- carboxylic acids amide form melting point °C analysis and solvent calculated/found yield used to trans- C% H % |N % Br % )% crystallization •n-butylamide 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-chloranilide 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-bromanilide 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 xyphemyljetyl- (ethanol-ether) 66.31 8.39 9.04

amide

Example 1 and 2

5.0.4 g (0.04 mol) of 1-cyclohexenecarboxylic acid are boiled together with 21.43 g (0.2 mol) of benzylamine for 80 hours under a nitrogen atmosphere under reflux. The excess benzylamine is then distilled off in vacuo and the residue is taken up in 40 ml of ether. The substance begins to crystallize. The crystals are filtered off, washed with ether and then dried. After recrystallization from benzene, 7.90 g (61.2%) of trans benzylamide of 2-(benzylamino)-cyclohexanecarboxylic acid are obtained, which melts at 116 to 118 °C. The hydrochloride, recrystallized from a mixture of ethanol and ether, melts at 192 to 194 °C.

For C21H26N2O calculated:

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

found:

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

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

For C14H17NO calculated:

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

found:

78.1% C, 7.98% H, 6.96% N.

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 trans anilides of 2-(phenylamino)-cyclohexanecarboxylic acid, melting at 194-196°C, were prepared by the method described in Example 2.

For C1OH22NO2 calculated:

77.52% C, 7.53% H, 9.52% N; found:

77.05% C, 7.05% H, 9.60% N. Attached

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

2-(ihomoiveratri lamino· j - cyclohexanecarboxylic acid, melting at 227 to 228 °C (predominantly cis isomer).

For C17H26NO4CI calculated:

59.37% C, 7.62% H; found::

59.00% C, 7.89% H.

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

2-(homoveratrylamino)-cyclohexanecarboxylic acid, which melts at 179-181 °C.

For C17H25NO4 calculated:

66.42% C, 8.20% H, 4.56% N;

found:

65.92% C, 8.35% H, 4.56% N.

Example 5

A mixture consisting of 11.21 g (0.1 mol) of (1-cyclopentenecarboxylic acid and 32.15 g (0.3 mol) of benzylamine is boiled for 70 hours under reflux in a nitrogen atmosphere. Excess benzylamine is distilled off under reduced pressure. The residue is made up with 100 ml of benzene and 100 ml of 5% hydrochloric acid and shaken thoroughly. After separation of the phases, the 0•acidified phase with hydrochloric acid is evaporated and the residue is recrystallized from a mixture of ethanol and ether. In this way, 2.1 g of benzylamine hydrochloride trans 2-(benzylamino)-cyclopentanecarboxylic acid are obtained, which melts at 175-177 °C.

For C20H25N2OCI calculated:

69.65% C, 7.31% H, 8.12% N,

10.28% Cl;

found:

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

10.23% Cl.

From the benzene extract, 1.2 g of 1-cyclopentenecarboxylic acid benzylamide is obtained by recrystallization from benzene, melting point: 112-114°C.

For C13H15NO calculated:

77.57% C, 7.51% H, 6.96% N;

found:

77.57% C, 7.73% H, 6.91% N.

Pharmacological tests

The anti-inflammatory effects, analgesic effects, temperature-lowering effects and potentiating narcotic effects were investigated.

,1. Anti-inflammatory effects (kaolin swelling)

The effect was determined 3 hours after administration

12 test compound and 2 hours after administration Result of tests on anti-inflammatory agent, inducing inflammation. nek:

compound dose mg/kg p. o. % efficacy

JATE 23 2-(amino-N-p-chlorophenyl)-cyclohexanecarboxylic acid hydrobromide trans amide 50 14.8* JATE 28 trans amide of N-p-chlorophenylhexahydroanthranilic acid hydrobromide 50 14.2 JATE 33 ois amide of 2-amino (N-p-totyljcyclohexanecarboxylic acid hydrobromide 100 ,22.5* JATE 39 cis amide of 2-amino-(N-2-thiazolyl)-cyclohexanecarphooxylic acid 100 31.4*** phenylbutazone 50 27.5* * * sodium salicylate 100 10.5 sodium salicylate 200 34.3***

* _p < 0.05 *p < 0.001

2. Temperature-lowering effect a) in animals with fever

The following compounds exhibited a temperature-lowering effect

compound dose mg/kg p. o. grain, temperatures °C lh 2 hours 3h JATE 1.3 trans amide 2-(benzylamino- 50 —1.4** —1.3** -1.1** -N-benzyl)-cyclohexanecarboxylic acid 100 —2.0*** —1.6*** - -1.0** JATE 23 trans amide of 2-(amino-N-p-chlorophenyl)cyclohexanecarboxylic acid hydrobromide 100 —0.9** —0.9** -0.9** JATE 28 trans amide of N-p-chlorophenylhexanehydroanthranilic acid hydrobromide 50 0 -0.4 -0.3 Phenylbutazone 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 2 hours, p. o. JATE 30 ois amide 2-aminoacyclohexanecar ^, bo- 100 —0.70 = 1.10 xylic acid hydrobromide JATE 31 cis amide 2-aminoi(N-p-bromylphenyl)cyclo- 100 —0.92 —1.04 lohexanecarboxylic acids

3. Analgesic effect (hot plate method)

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

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

loihexaincarboxylic acids

4. Narcotic enhancing effect

Time of sleep during anesthesia at a dose of 40 mg/kg. Venobarbital was administered to animals- those treated with the following compounds: dose mg/kg p. o. time of sleep control secondary treatment compound JATE 23 trans amide of 2-(amino-N-p-chlorophenyl)cyclohexanecarboxylic acid hydrobromide 50 167 322 JATE 28 trans amide of N-p-chlorophenylhexahydroanthranilic acid hydrobromide 50 171 384 JATE 32 cis amide of 2-amine·(N-m-fluorophenyl j-cyclohexanecarboxylic acid hydrobromide 50 148 350 JATE 33 cis amide 3-amino(N-p-tolyl)-cyclohexane carboxylic acid hydrobromide 100 147 538 JATE 35 2-Ammo(N-m-trifluoromethylphenyl)cyclohexanecarboxylic acid hydrobromide oisamide 50 147 734 JATE 43 ois amide of 2-amino(N-phenylethylj-cyclohexanecarboxylic acid 50 154 482 Andaxin 20 186 391 Based on the investigation of the anti-inflammatory effect of mg/kg p. i. Efficiency corresponding effect of an-

dumbbell it was found that JATE 23, 28 and 33 can be compared with the effect of sodium salicylate and the effect of JATE 39 with the effect of femylbutazoin. The most significant analgesic effect can be observed with the compound JATE 39 in a dose of 50 daxiin in a dose of 20 mg/kg. JATE 30 shows the most significant potentiation of the narcotic effect, the duration of sleep is extended by a dose of 50 mg/kg p. o. fivefold.

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.