CS217947B1 - 2-benzylcyclopentylamine,methylderivatives thereof and salts - Google Patents

Abstract

The invention relates to a novel 2-benzylcyclopentyl amine, its new 1-methyl and N-methyl derivatives and their pharmaceutically acceptable salts inorganic or organic acids. These substances reduce blood pressure in experimental animals based on their ganglioplegic effect and are therefore applicable as drugs for short-term reduction blood pressure. Basic 2-benzylcyclopentylamine is obtained by reduction of 2-benzylcyclopentanone oxime with sodium and ethanol. Its 1-methyl derivative is obtained from 2-benzylcyclopentanone via N- (2-benzyl-1-methylcyclopentylformamide, which is alkaline hydrolyses. N-Methyl-2-benzyl-1-methylcyclopentylamine wins the reduction of the named formamide derivative with lithium aluminum hydride. Finally, N, N-dimethyl-2-benzyl-1-methylcyclopentylamine is obtained by methylation of the foregoing two products or mixtures thereof formaldehyde and formic acid. Gained bases are converted by neutralization with acids to the corresponding salts

Description

The present invention relates to a novel 2-benzylcyclopentylamine and its derivatives of formula (I)

NR ¹ R ² (i)

CH

Wherein R, R and R are the same or different and represent a hydrogen atom or a methyl group, and pharmaceutically acceptable salts thereof with inorganic or organic acids.

The compounds of formula I and their salts lower the blood pressure of test animals by virtue of their ganglioplegic effect and are therefore useful as medicaments for short-term lowering of blood pressure. The compounds were tested as hydrochlorides in normotensive rats by intravenous administration. By way of example, the toxicities of several compounds of the invention and their hypotensive effective doses are mentioned.

2-benzyl-1-metylcyklopentylamin Acute toxicity in mice, LD ^ ₀ ~ 35 mg / kg iv The iv dose of 7 mg / kg showed a mild and long-lasting hypotensive activity in normotensive rats.

N-Methyl-2-benzyl-1-metylcyklopentylamin Acute toxicity in mice, _LD-0-25 mg / kg iv

At an i.v. dose of 5 mg / kg, it causes a short-term decrease in blood pressure in normotensive rats.

N, N-Dimethyl-2-benzyl-1-methylcyclopentylamine: Acute toxicity in mice, LD 50 = 5 mg / kg i.v. At an intravenous dose of 3 mg / kg, it induces a long-term decrease in blood pressure in normotensive rats. Interestingly, it shows a positive chronotropic effect: at a concentration of 50 µg / ml, it increases the frequency of the isolated rabbit atrium by 25%. This substance exhibits a long-term hypotensive effect in unarcinated rats also when administered orally. After a dose of 30 mg / kg po, the decrease after 1 h after application is slight (about 1%), at 3 h after application it is already noticeable (about 5%) and at 24 h after application it is significant (by 15%) .

The compounds of the formula I according to the invention are prepared by the processes described in detail in the examples. 2-Benzylcyclopentylamine itself is prepared by reduction of 2-benzylcyclopentanone oxime (R. Cornubert et al., Bull. Soc. Chim. 11, 299 (1944); Chem. Abstr. 40 1 792, (1946)) with sodium and ethanol . Its molecule has two centers of asymmetry, and accordingly, two hydrochlorides can be isolated, the higher of which was characterized as a trans-isomer and the lower of which is a cis-isomer contaminated with about 20% of the trans-isomer. 2-Benzyl-1-methylcyclopentylamine is prepared from 2-benzylcyclopentanone, which is converted to 2-benzyl-1-methylcyclopentanol by reaction with methylmagnesium iodide, which is either partially or completely dehydrated by distillation to a mixture of the corresponding olefins (2-benzyl-1-methylcyclopentene and isomers). This material was subjected to a Ritter reaction with hydrogen cyanide (generated by the reaction of sodium cyanide with sulfuric acid in acetic acid) to give N- (2-benzyl-1-methylcyclopentyl) formamide. Hydrolysis of the material with aqueous alcoholic sodium hydroxide gives the desired amine. Its N-methyl derivative is obtained by reducing said formamide derivative with lithium aluminum hydride in tetrahydrofuran. Finally, the Ν, Ν-dimethyl derivative is prepared by methylation of the primary amine with formaldehyde and formic acid.

The compounds of the invention are basic in nature which, by neutralizing with pharmaceutically acceptable inorganic or organic acids, provides the appropriate salts which are more suitable for performing pharmacological tests and for preparing dosage forms than the free bases. Of the salts, particularly good crystalline hydrochlorides are water-soluble.

The identity of the end products according to the invention as well as the intermediates described in the examples were assured both analytically and by all conventional spectral methods

Examples

Example I

2-Benzylcyclopentylamine

A solution of 60 g of 2-benzylcyclopentanone oxime (literature cited) in 400 ml of ethanol is added dropwise over a period of 25 min to 195 g of coarsely cut sodium metal which is found in the flask under reflux. The mixture is allowed to boil by reaction and after the addition of sodium, 950 ml of ethanol are added dropwise over a period of 7 hours while continuously boiling. After complete dissolution of the sodium, the mixture is quenched by the slow addition of 45 ml of water and then subjected to steam distillation, the solution being charged with a solution of 90 ml of hydrochloric acid in 400 ml of water. 6 L of distillate are collected and evaporated to a volume of 100 ml under reduced pressure. This solution on standing gave 41.2 g (62%) of the hydrochloride A, m.p. 191-195 ° C. The mother liquor is evaporated to dryness in vacuo, and the solid residue is stirred in a small amount of ethanol / ether. Filtration gave 10.0 g (15%) of hydrochloride B, m.p. 132-134 ° C. Recrystallization of the hydrochloride A from ethanol gave 21 g of homogeneous stereoisomer A, mp 209.5-210 ° C, by analogy (W. Huckel and R. Kupka, Chem. Ber. 89, 1694, (1956); W). Hiickel and KD Thomas, Chem., Ber. 96, 2 514, (1963)), and on the basis of Skit's rule (f. -configuration. The hydrochloride released from the hydrochloride boils at 98 to 99 ° C / 67 Pa and is characterized as completely homogeneous by gas chromatography. The hydrochloride B can also be decomposed with sodium hydroxide solution and the base isolated by ether extraction, b.p. 160-162 ° C / 2.7 kPa. According to gas chromatography, this base consists of 80% cis-isomer and 20% trans-isomer.

Example 2

2-Benzyl-1-methylcyclopentylamine

2-Benzylcyclopentanone (W. Baker and WG Leeds, J. Chem. Soc. (1948), 974; W. Treibs et al., Chem. Ber. 87, 356, (1954)) (80 g) was dissolved in 160 g. ml of ether and the solution was added dropwise over 80 min to a stirred solution of methylmagnesium iodide (prepared by reacting 75 g of methyl iodide with 12.15 g of magnesium in 140 ml of ether), which was refluxed. The mixture is boiled for 3 h, left at room temperature overnight and then quenched by the slow addition of a solution of 50 g of ammonium chloride in 250 ml of water. The organic layer was separated, dried (MgSO 4) and evaporated; the residue is crude 2-benzyl-1-methylcyclopentanol. Its distillation yields 58 g of a mixture boiling at 103 to 107 ° C / 0.13 kPa, whose composition can be determined by gas chromatography and corresponds to 80% olefin (1-benzyl-2-methylcyclopentene and isomers) and 20% 2-benzyl-1. -methylcyclopentanol. Redistillation yields an oxygen-free product boiling at 80 ° C / 67 Pa, = 1.5340, which represents the olefin mixture.

In a cold mixture of 180 ml of acetic acid and 22 ml of sulfuric acid, 52 g of the once distilled previous product are dissolved, cooled to 5 ° C and 48 g of powdered sodium cyanide are added thereto under stirring (temperature not exceeding 8 ° C). . The mixture was stirred for 10 minutes and a mixture of 37 ml of acetic acid and 48 ml of sulfuric acid was added dropwise over a period of 50 minutes at a maximum temperature of 10 ° C. Stirring and cooling was continued for three hours and the mixture was then allowed to stand at room temperature for 48 hours. Pour into a mixture of 800 g of ice and 250 ml of water, neutralize with 20% sodium hydroxide with cooling (to pH 7-8), dilute with water to dissolve the precipitated sodium sulfate and extract with ether. The extract was dried (MgSO4) and evaporated. 54 g of oily N- (2-benzyl-1-methylcyclopentyl) formamide (mixture of stereoisomers) are obtained, which are dissolved in 50 ml of petroleum ether and the solution is subjected to crystallization in a refrigerator. 17.6 g of a crystalline product, which is a single homogeneous racemate of the desired composition, is deposited. After recrystallization from a mixture of benzene and hexane, it behaves as a chemical individual and melts at 77-78 ° C.

To a solution of 15.0 g of the above compound in 55 ml of ethanol is added a solution of 5.0 g of sodium hydroxide217947 in 45 ml of water, and the mixture is refluxed for 48 hours. After addition of 50 ml of 20% sodium hydroxide, the mixture is distilled with steam to a solution of 15 ml of hydrochloric acid in 80 ml of water. 2 L of distillate was collected and evaporated to 35 ml under reduced pressure and standing overnight in the refrigerator to give crystalline hydrochloride of the title compound; 15.5 g (100%) mp 226-227 ° C (ethanol-ether). Decomposition of the hydrochloride with sodium hydroxide solution and extraction with ether gave an oily base having a melting point of 94 DEG C./67 mbar, = 1.5295.

Example 3

N-Methyl-2-benzyl-1-methylcyclopentylamine

A solution of 17.0 g of N- (2-benzyl-1-methylcyclopentyl) formamide (see Example 2) in 50 ml of tetrahydrofuran was slowly added to a stirred suspension of 5.0 g of lithium aluminum hydride in 70 ml of ether and boiled for 3 h under reflux condenser. After cooling, it is quenched by the slow addition of 25 ml of 20% sodium hydroxide, the precipitate formed is filtered off, washed with ether and the filtrate is distilled. 13.0 g (82%) of a base boiling at 108 ° C / 0.13 kPa are obtained. Neutralization with hydrogen chloride in ethanol-ether gave crystalline hydrochloride melting at 208 ° C (ethanol-ether).

Example 4

N, N-Dimethyl-2-benzyl-1-methylcyclopentylamine

A mixture of 8.5 g of 2-benzyl-1-methylcyclopentylamine (see Example 2) and 5.2 g of N-methyl-2-benzyl-1-methylcyclopentylamine (see Example 3) is added to a mixture of 20 ml of water, 15 ml of 85% of formic acid and 20 ml of 36% aqueous formaldehyde and refluxed in a bath at 120-130 ° C for 5 h. After addition of 50 ml of hydrochloric acid, the mixture is evaporated to dryness under reduced pressure. The residue was dissolved in 75 mL of water, basified with 20% sodium hydroxide, and the base was extracted with ether. The extract was dried with solid potassium hydroxide and worked up by distillation. 14.6 g (93%) of a base boiling at 122 ° C / 0.27 kPa, = 1.5258, are obtained. Neutralization with hydrogen chloride in ethanol / ether gives crystalline hydrochloride melting at 214-215 ° C.

Claims (1)

2-Benzylcyclopentylamine and its methyl derivatives of the general formula I dl) Wherein R, R and R are the same or different and represent a hydrogen atom or a methyl group, and pharmaceutically acceptable salts thereof with inorganic or organic acids.