CS223496B1 - N-substitutive derivatives of the 4-cyclopentylamiline and the salts thereof - Google Patents

Abstract

The invention relates to an eyathethic field drugs. Its subject is N-eubetitucaí 4-cyclopeatylaailium derivatives of Formula 1 OO-N-x-CHaVR. * 1, t. Á * '· *)) » wherein Z1 is -CO- or -CHp-, and begins 1 or 2, R x is hydrogen and ethyl and R is a diethylammonium or piperidium radical, and their pharmaceutically acceptable salts inorganic or orgaic kyeelia. These substances can be prepared from 4-cy * klopeatylaaili.au or its N-ethyl derivative aeylaeí chloraoethyl chloride or With 3-chloropropionyl chloride, as follows by the eubetitation reactions of these chloramides with diethylamine or piperidium and coca by reducing hydrophilic ammonium amides lithaohliaitým. Salts ee are usual aeutralizing reactions. Salts of Formula Formula 1 ee are characterized by epaemolytic, locally aaeetetiekou, aatireeerpiaovou and zčáeti aaorektiekou and diuretic attractiveness, so they can be used as drugs in epaetics etaveeh of smooth digestive evals and the urogeaitania eyetema, further to the local numbness during surgery, to treat mental depression and finally also in obesity to reduce food intake.

Description

( ⁵⁴ ) N-Substituted 4-cyclopeatylaailium derivatives and their salts

The invention relates to the field of eyathetic drugs. It is directed to N-substituted derivatives of 4-cyclopeatylailal of formula (1)

OO-Nx-CHCHVR. ^{* 1} , _t .

Wherein Z is -CO- or -CHp-, and starts or 2, R ^x is hydrogen and ethyl and R is a diethylamino or piperidino radical, and their salts and pharmaceutically acceptable inorganic or orgaic cyeeliaams . These compounds can be prepared from 4-cyclopentyllaail or its N-ethyl derivative and chloroethyl chloride or

3-chloropropioayl chloride, the subsequent eubetitizing reactions of these chloramides with diethylammonium or piperidium, and caching by reducing any of the amiaoamides with lithium aluminum hydride. The salts are obtained by conventional aeutralizing reactions. The salts of the compounds of formula 1 ee are characterized by epaemolytic, locally aaeetetics, aatireeerpia, and initially aaorectic and diuretic effects, so that they can be used as medicaments in the epaietic etave of smooth gastrointestinal and urogealital eyetema, obesity to reduce food intake.

223 496

- 1,223 49β

The present invention relates to 4-cyclopentylaniline N-substituted derivatives of the general formula I wherein X is -CO- or -CH ₉ -, n is 1 or 2, R 2 is a compound of formula (I); R is hydrogen or ethyl and R is diethylamino or piperidino, and their salts with pharmaceutically acceptable inorganic or organic acids.

The compounds of the invention of formula I and their salts are characterized by pharmacodynamic activity which makes them useful as medicaments. The most typical activity of the compounds according to the invention is spasmolytic, in all cases of the neurotropic type (anticholinergic, parasympatholytic), in some cases also musculotropic. The compounds according to the invention are therefore suitable for the suppression of painful spasm of smooth nodules, in particular of the gastrointestinal and urogenital systems. Some of them are locally anesthetically effective and are suitable for local anesthesia in locally limited surgical procedures. Regarding the central nervous system effect, the compounds according to the invention exert an excitatory effect at higher doses, which is evidently related to the found incoordination effect of a part of the compounds in the rotating rod test in mice, antireserpine effects of many compounds in reserpine ptosis and reserpine hypothermia. anorectic effect of one of the substances. Substances with antireserpine activity are useful in the treatment of mental depression (antidepressants) and anorectic activity can be used in obese individuals to suppress appetite and thus reduce food consumption.

223 496

The individual compounds of the invention which have been tested by pharmacologists in animals or on isolated organs, their mean lethal doses in mice at i.v. administration (acute toxicity) and further individual effects found:

N- (4-Cyclopentylphenyl) diethylaminoacetamide has been tested as hydrochloride · LD50 → 50 mg / kg · At concentrations of 1 to 10 µg / ml it acts spasmolytically on isolated rats, duodenum against acetylcholines spasm (reduced to 50%) and in barium chloride spasms of isolated rat duodenum are similarly inhibited at the same concentrations. At concentrations of 0.05 to 0.5%, they act locally anesthetically in the corneal anesthesia test in the rabbit eye (in 50% of animals). At doses of 1-5 mg / kg i.v. induces ataxia in mice in a rotating rod test. In i.p. doses of 10 mg / kg have a statistically significant effect against reserpine ptosis in mice and antagonize reserpine hypothermia in mice (increasing the temperature by 1 ° C compared to the reserpine control group).

N- (2-Diethylaminoethyl) -4-cyclopentylaniline was tested as dihydro chloride. LD ^ q ≥70 mg / kg. At concentrations of 1-10 µg / ml, spasraolytic agents act against both acetylcholine and barium chloride spasms. At doses of 14 mg / kg i.p. has antireserpine activity in both the ptosis test and the mouse hypothermia test.

N- (4-Cyclopentylphenyl) piperidinoacetamide was tested as hydrochloride. LD50 = 62.5 mg / kg. At concentrations of 1 to 10 µg / ml, they act spasmolytically to both acetylcholine and barium chloride contractions. At doses of 5 to 12 mg / kg i.v. induces ataxia in mice in a rotating rod test.

N- (2-Piperidinoethyl) -4-cyclopentylaniline was tested as dihydro chloride. LD 60 q 60 mg / kg. At concentrations of 1 to 10 µg / ml it acts spasmolytically to both acetylcholine and barium chloride contractions of isolated duodenum. At a dose of 10 mg / kg i.v. induces ataxia in 50% of the mice in the rotating rod test. In i.p. doses of 12 mg / kg have a significant antireserpline effect in both ptosis and hypothermia in mice.

N- (4-Cyclopentylphenyl) -3-diethylaminopropionamide was tested as the hydrochloride salt. LD 50 q 75 mg / kg. At a concentration of 10 µg / ml, it acts spasmolytically to acetylcholine spasms. In i.v. doses of 5 to 15 mg / kg induces ataxia in mice in a rotating rod test.

In i.p. doses of 15 mg / kg act antireserpine in the test mice

223 49β reserpline ptosis and reserpine hypothermia. At an oral dose of 75 mg / kg it acts anorectically in mice (decreases food intake by 50%). · At an oral dose of 75 mg / kg, it also acts diuretically in mice (increases diuresis by 100% compared to control).

N- (3-Diethylaminopropyl) -4-cyclopentylaniline was tested as the dihydrochloride. LD 50 q 62.5 mg / kg. At a concentration of 10 µg / ml, it acts spasmolytically to acetylcholine contractions.

N- (4-Cyclopentylphenyl) -3-piperidinopropionamide was tested as the hydrochloride salt. LD 50 q 62.5 mg / kg. At a concentration of 10 it acts spasmolytically to acetylcholine contractions. In i.v. dose of 5 mg / kg induces ataxia in mice in the rotating rod test.

N- (3-Piperidinopropyl) -4-cyclopentylaniline was tested as dihydrochloride hemihydrate. LD 50 q 50 mg / kg. At 10 µg / ml, it acts spasmolytically to acetylcholine contractions.

N- (4-Cyclopentylphenyl) -N-ethyl-2-piperidinoacetamide was tested as hydrogen maleate. LD 50 q 43.7 mg / kg. At concentrations of 1 to 10 µg / ml, they act spasmolytically to acetylcholine contractions. At concentrations of 0.1 to 0.5%, it acts locally anesthetically in the test of corneal anesthesia in the rabbit eye and infiltration anesthesia in guinea pigs.

N-Ethyl-N- (2-piperidinoethyl) -4-cyclopentylaniline was tested as the dihydrochloride. LD 50 q 50 mg / kg. At concentrations of 1 to 10 µg / ml, they act spasmolytically to both acetylcholine and barium chloride contractions. At concentrations of 0.1 to 0.5%, it has a local anesthetic effect in the guinea pig infiltration anesthesia test.

The compounds according to the invention can be prepared from the known 4-cyclopentylaniline and resp. its N-acetyl derivative (P.V.Hai, N.P.Buu-Hoi and N.D.Xuong, J.Org.Chem. 23, 39, 1958). Reactions of 4-cyclopentylaniline or N-ethyl-4-cyclopentylaniline with chloroacetyl chloride or 3-chloropropionyl chloride (R. Wolffenstein and J.Rolle, Ber.Deut. Chem. Ges. 41, 736, 1908) in boiling chloroform in the presence of potassium carbonate give chloracylderivatives of formula II

00 · γ - <^ ^α _(II ,

223498 in which it and R ¹ have the same meaning as in formula I. These chloracylderiváty subjected substitution reactions with excess diethylamine or piperidine in refluxing benzene to give a first type of compounds of formula I, i.e. · basic amides (X »CO). Reduction of these amides with lithium aluminum hydride in ether gives the diamines of formula 1 (X &lt; 2 &gt; CH ₂ ). The amides of formula 1 (X with CO) are mostly crystalline and provide neutralization by acids to give crystalline salts. The diamines of formula I (X = CHg) are oily, but their salts are crystalline. All the novel compounds described in the invention, i.e. the myths of formula I and their salts, as well as all the novel intermediates, were assured by identity and by spectra, in particular IR and NMR spectra.

Example 1

N- (4-Cyclopentylphenyl) -2-diethylaminoacetamide. A mixture of 11.0 g of N- (4-cyclopentylphenyl) -2-chloroacetamide, 70 ml of benzene and 8.5 g of diethylamine is refluxed for 6 hours and then left to stand overnight. The precipitated diethylaraine hydrochloride is filtered off with suction, the filtrate is washed with water, dried over sodium sulphate and evaporated under reduced pressure. The theoretical yield (12.6 g) gave a crude oily base which crystallized from hexane and melted pure at 47-48 ° C. Neutralization with hydrogen chloride in ethanol and addition of ether gives a crystalline hydrochloride which crystallizes from ethanol and melts in the pure state at 187-188 ° C.

The starting N- (4-cyclopentylphenyl) -2-chloroacetamide is a novel substance obtained as follows: To a solution of 16.1 g of 4-cyclopentylaniline in 50 ml of chloroform is added 16.6 g of potassium carbonate (anhydrous), and with stirring for 45 min at room temperature, a solution of 15 g of chloroacetyl chloride in 50 ml of chloroform was added dropwise. It is then refluxed for 1.5 hours, cooled and diluted with 150 ml of chloroform to dissolve the precipitated product. The chloroform solution was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The solid residue is treated with 50 ml of hexane, filtered, washed with hexane and dried in vacuo. The desired product is obtained in a yield of 22.1 g (93%) and in this state (m.p. 145-147 ° C) is usable for further work. Crystallization of the sample from a mixture of benzene and hexane gave a pure material, melting at 151-152 ° C.

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Example 2

N- (2-Diethylaminoethyl) -4-cyclopentylaniline; A solution of 6.3 g of N- (4-cyclopentylphenyl) -2-diethylaminoacetamide (Example 1) in 50 ml of benzene is slowly added to a stirred suspension of 2.5 g of lithium aluminum hydride in 50 ml of ether, and the mixture is refluxed for 5 hours. After standing overnight, it is decomposed with stirring by the slow addition of 10 ml of 20% sodium hydroxide solution, the mixture is stirred for another 30 min, the solid is filtered off and washed with benzene. The filtrate is evaporated and the theoretical yield (6.0 g) gives crude oily product · Dissolve in 60 ml of ether and neutralize with ethanolic HCl · Evaporate in vacuo, dissolve the residue in 50 ml of acetone and add 70 ml of ethyl acetate. After standing overnight, filter 6.2 g of the precipitated product. dihydrochloride, which crystallizes from a mixture of acetone and ethyl acetate and melts in the pure state at 116-117 ° C.

Example 3

N- (4-Cyclopentylphenyl) -2-piperidinoacetamide. A solution of 11.0 g of N- (4-cyclopentylphenyl) -2-chloroacetamide (see Example 1) and 8.5 g of piperidine in 70 ml of benzene is refluxed for 6 hours. After standing overnight, the precipitated piperidine hydrochloride is removed by suction and the filtrate is evaporated under reduced pressure. In theoretical yield (13.2 g) a crude oily base is obtained which crystallizes on standing. Crystallization from hexane gives a pure product which melts at 79-79. 80 ° C. Neutralization with hydrogen chloride in a mixture of ethanol and ether gives the hydrochloride, which crystallizes from ethanol and melts in the pure state at 219-220 ° C.

Example 4

N- (2-Piperidinoethyl) -4-cyclopentylaniline. A solution of 7.2 g of N- (4-cyclopentylphenyl) -2-piperidinoacetamide (see Example 3) in 60 ml of benzene is slowly added dropwise to a stirred suspension of 3.0 g of lithium aluminum hydride in 50 ml of ether, and the mixture is added under stirring for 5 h. After standing overnight, 12 ml of 20% sodium hydroxide solution are added dropwise while stirring overnight, the mixture is stirred for 30 min and the solid is filtered off with suction and washed with ether. The filtrate is evaporated to give the theoretical quantity (6.9 g). Crude oil base. Neutralization with hydrogen chloride in ethanol / ether yields crystalline dihydrochloride (7.7 g) which is pure after recrystallization from ethanol and melts at 252-253 ° C.

Example 5 223 β

N- (4-Cyclopentylphenyl) -3-diethylaminopropionamide. To the solution

11.7 g of N- (4-cyclopentylphenyl) -3-chloropropionamide in 70 ml of benzene are added with 8.5 g of diethylamine and the mixture is refluxed for 8 h. After standing overnight, the precipitated diethylamine hydrochloride is removed by suction and washed with benzene. The filtrate was washed well with water, dried over sodium sulfate and evaporated under reduced pressure. The theoretical yield (13 * 3 g) gave a crude oily base. As it does not tend to crystallize, it is dissolved in a mixture of 60 ml of acetone and 60 ml of ether and a slight excess of a solution of hydrogen chloride in ethanol is added. After addition of 40 ml of ether, crystalline hydrochloride (14.0 g) is slowly precipitated, which, after crystallization from a mixture of ethanol and ether, is pure and melts at 180-181 ° C.

The starting material N- (4-cyclopentylphenyl) -3-chloropropionamide used is new and is obtained as follows: To a solution of 40.3 g of 4-cyclopentylaniline in 125 ml of chloroform is added 41.5 g of potassium carbonate and stirred for 90 min. a solution of 41 g of 3-chloropropionyl chloride in 125 ml of chloroform is added dropwise at room temperature. The mixture is refluxed for 1.5 h. After dilution with 580 ml of chloroform, it is cooled and washed with water. The organic phase is dried over sodium sulphate and evaporated. The residue crystallizes after mixing with 100 ml of hexane; 59.8 g (95%), m.p. Mp 135-138 ° C. The pure product is obtained by recrystallization from a mixture of benzene and hexane and melts at 138-139 ° C. Example 6

N- (3-Diethylaminopropyl) -4-cyclopentylaniline. As in the previous examples, a reduction of 7.0 g of N- (4-cyclopentylphenyl) 3-diethylaminopropionamide (see Example 5) was carried out with 3.0 g of lithium aluminum hydride in a mixture of 50 ml of ether and 50 ml of benzene. Workup yielded 6.4 g (96%) of an oily base. · Neutralization with hydrogen chloride in ethanol / ether gave 7.5 g of dihydrochloride, which crystallized from ethanol / ether containing free hydrogen chloride and melted at 157-158 ° C in pure state. .

Example 7

N- (4-Cyclopentylphenyl) -3-piperidinopropionamide. Reaction of 11.7 g of N- (4-cyclopentylphenyl) -3-clilorpropionamide (see Example 5) with

8.5 g of piperidine in 70 ml of benzene were carried out similarly as in the previous examples (reflux for 8 h). Working-up gave 13.4 g (96%) of the crude product which on standing of the crystal was 223 498 g. melting at 66-67 ° C. Neutralization with hydrogen chloride in a mixture of acetone and ethanol and addition of ether gives a crystalline hydrochloride which is pure after recrystallization from ethanol and melts at 223-224 ° C. Example 8

N- (3-Piperidinopropyl) -4-cyclopentylaniline. Similar to the previous examples, a reduction of 7.2 g of N- (4-cyclopentylphenyl) -3-piperidinopropionamide (see Example 7) is carried out with 3.0 g of 11-aluminum hydride in a mixture of 50 ml of ether and 60 ml of benzene (reflux for 5 hours). cooler). Workup yielded 6.7 g (98%) of an oily product which was neutralized with hydrogen chloride in ethanol. Addition of ether precipitates 7.5 g of the dihydrochloride which crystallizes from ethanol containing hydrogen chloride as the hemihydrate and melts in the pure state at 209-211 ° C (losing crystalline water at 193-195 ° C).

Example 9

N- (4-Cyclopentylphenyl) -N-ethyl-2-piperidinoacetamide. A mixture of N- (4-cyclopentylphenyl) -N-ethyl-2-chloroacetamide (5.0 g), potassium carbonate (2.7 g), piperidine (1.7 g) and acetone (60 ml) was stirred and refluxed for 7 h. After cooling, the precipitated inorganic salts are filtered off with suction and washed with acetone, the filtrate is evaporated under reduced pressure, the residue is dissolved in a mixture of benzene and ether and the base is extracted into dilute excess hydrochloric acid. The aqueous acidic solution was separated, basified with 20% sodium hydroxide solution and the base was isolated by extraction with a mixture of benzene and ether. After drying the extract with sodium sulfate and evaporation, 4.9 g (83%) of the oily base are obtained. 116-117 ° C ·

The starting N- (4-cyclopentylphenyl) -N-ethyl-2-chloroacetamide is a new substance obtained by the following procedure:

A solution of 14 g of N- (4-cyclopentylphenyl) acetamide (literature cited) in 100 ml of benzene is slowly added dropwise to a suspension of 5.0 g of aluminum hydride in 50 ml of ether and the mixture is refluxed for 5 hours. 20 ml of 20% sodium hydroxide solution are added dropwise with stirring, after 30 minutes of stirring the precipitated solid is filtered off with suction and washed with benzene and the filtrate.

223 49G evaporated · The residue is distilled. 12.0 g (90%) of pure N-ethyl-4-cyclopentylaniline are obtained, m.p. 122 DEG-124 DEG C./0.1 mbar.

To a solution of 18.9 g of N-ethyl-4-cyclopentylaniline in 100 ml of chloroform was added 16.6 g of potassium carbonate, and a solution of 15.0 g of chloroacetyl chloride in 50 ml of chloroform was added dropwise over 60 minutes. After cooling, it is washed with water, then with dilute hydrochloric acid and again with water, dried over sodium sulphate and evaporated.

in a theoretical yield (26.6 g) of a homogeneous oily product, i.e. N- (4-cyclopentylphenyl) -N-ethyl-2-chloroacetamide, which in this state is used for further work ·

Example 10

N-Ethyl-N- (2-piperidinoethyl) -4-cyclopentyl aniline. As in the previous examples, 7.2 g of N- (4-cyclopentylphenyl) -N-ethyl-2-piperidinoacetamide (see Example 9) were reduced with 3.0 g of lithium aluminum hydride in a mixture of 60 ml of ether and 60 ml of benzene (5 ml). h reflux) · Working up is obtained

6.8 g (99%) of an oily product which does not tend to crystallize. Therefore, it was neutralized with hydrogen chloride in ethanol to obtain 7.4 g of crystalline dihydrochloride. Crystallization from an ethanol / ether mixture gives a pure solid, m.p. 226-227 ° C.

Claims (1)

SUBJECT OF THE INVENTION 4-Cyclopentylaniline N-Substituted Derivatives of Formula _{(I) /} R ¹ wherein X represents -CO- or -Chg-, represents 1 or 2, denotes hydrogen or ethyl and R represents a diethylamino radical or piperidine, and their salts with pharmaceutically acceptable inorganic or organic acids cal.