CS254621B1 - 4-Amino-1- (4-cyclopentylphenyl) butan-1-one and salts thereof - Google Patents

Abstract

The solution falls into the field of drug synthesis. Its subject is 4-amino-1-(4-cyclopentylphenyl) butan-1-ones of the general formula in which the divalent radical X denotes either a divalent phenylcarbinol fragment or a nitrogen fragment, of the general formula = N-R where R is methyl, 2-hydroxyethyl, phenyl, tolyl, trifluoromethylphenyl, chlorophenyl or methoxyphenyl, and their salts with pharmaceutically acceptable inorganic or organic acids. The substances according to the invention exhibit in animal tests and in vitro tests discoordination, hypothermic, antiamphetamine and antireserpine effects, potentiating the effects of thiopental and inhibiting locomotor activity; some of them inhibit the growth of pathogenic microbes. The substance can therefore be described as tranquilizers and chemotherapeutics, with the focus of their applicability being in neurology. Their preparation consists in substitution reactions of 1-(4-cyclopentylphenyl)-4-chlorobutan-1-one with the corresponding derivatives of p-piperidine and piperazine. Of the salts, the hydrochlorides and maleates are particularly preferred.

Description

The present invention relates to 4-amino-1- (4-cyclopentylphenyl) butan-1-ones of formula 1

(I) wherein the bivalent radical X.značí BU3 fenylkarblnolový fragment \ / ^C 6 ^H 5

C or a nitrogen fragment (N-R) wherein R is methyl, 2-hydroxyethyl, phenyl, tolyl, trifluoromethylphenyl, chlorophenyl or methoxyphenyl, and their salts with pharmaceutically acceptable inorganic or organic acids.

The compounds of formula I and their salts exhibit therapeutically useful properties of tranquilizers. In tests in experimental animals, this is manifested by incoordination activity, potentiation of thiopental effects, hypothermic effect, inhibition of locomotor activity, antiamphetamine and anti-apomorphine activity. Thus, they show a total of centrally depressant effects, and in therapy they are used to soothe restless neurotics, to remove their psychomotor restlessness and to deepen sleep in patients suffering from insomnia. In addition, some of the compounds of the invention exhibit antimicrobial activity in in vitro assays, indicating their practical utility as chemotherapeutics.

The pharmacological and antimicrobial effects of some of the compounds of the invention, which have been found in in vivo or in vitro tests, are shown below.

1- (4-cyclopentylphenyl) -4- (4-phenyl-4-hydroxypiperidino) -butan-1-one was tested as the hydrochloride monohydrate. Its acute toxicity in the mouse LD _5Q is 500 mg / kg ρ.ο. At an oral dose of 50 mg / kg, it induces ataxia in a rotating rod test in 50% of the mice (incoordinating effect). At oral doses of 50 to 100 mg / kg, it exhibits a pronounced hypothermic effect in rats (decreasing the rectally measured body temperature by 1 ° C). At an oral dose of 100 mg / kg, it prolongs the sleep duration of mice induced by a standard dose of thiopental to twice the control value. In vitro tests inhibit growth of the following microorganisms at the following minimum concentrations (in µg / ml): Streptococcuc beta-haemolyticus, 25? Streptococcus faecalis, 25? Staphylococcus pyogenes aureus, 25? Escherichia coli, 12.5? Mycobacterium tuberculosis, 3.12? Trichophyton mentagrophytes, 25.

1- (4-cyclopentylphenyl) -4- (4-phenylpiperazino) butan-1-one was tested as the dihydrochloride. It is practically nontoxic, because the value of the oral acute toxicity (LD _5Q) is greater than 2.5 g / kg. At oral doses of 100-300 mg / kg, the duration of thiopental sleep in mice prolonged 200% of the control value.

1- (4-cyclopentylphenyl) -4- (4- (2-tolyl) piperazino) butan-1-one was tested as the monohydrochloride. Its oral acute toxicity is 750 mg / kg. At an oral dose of 150 mg / kg, it significantly suppressed the motor activity and reactivity of mice and induced ataxia at higher doses. At an oral dose of 50 mg / kg, it has a pronounced antiamphetamine effect (at this dose, 100% of the mice protect against the lethal effect of the standard amphetamine dose). At oral doses of 100 to 150 mg / kg, it shows a anticonvulsant effect against pentetrazole in mice (significantly prolonging the latency of pentetrazole-induced clonic seizures).

1- (4-Cyclopentylphenyl) -4- (4- (3-trifluoromethylphenyl) piperazino) butan-1-one was tested as the hydrochloride salt. Its oral acute toxicity LD 150 is 300 mg / kg. At oral doses of 25 to 60 mg / kg, thiopental sleep prolongs the mice to 200% of control. At an oral dose of 30 mg / kg, it inhibits apomorphine-induced stereotypes in rats, suggesting neuroleptic efficacy.

1- (4-Cyclopentylphenyl) -4- (4- (3-chlorophenyl) piperazino) butan-1-one was tested as a maleate.

Its oral acute toxicity in mice is 1.5 g / kg. At oral doses of 100 to 300 mg / kg it exhibits a significant hypothermic effect in rats. At doses of 10 to 50 mg / kg orally potentiates the effect of thiopental in mice at 200% of control value. At doses of 100-300 mg / kg orally, it induces ataxia in mice in a rotating rod test. At a dose of 300 mg / kg p.o. significantly attenuates locomotor activity of mice.

1- (4-Cyclopentylphenyl) -4- (4- (4-methoxyphenyl) piperazinoyl-butan-1-one) has been tested as dihydrochloride and has an oral LD50 of greater than 2.5 g / kg in mice. 300 mg / kg significantly inhibits the motility of the mice, and at the same dose it has a pronounced anticonvulsant effect against pentetrazole in mice.

The compounds of the formula I according to the invention can be prepared by substitution reactions of 1- (4-cyclopentylphenyl) -4-chlorobutan-1-one of the formula II

(II) with amines of formula (III) -

The substitution reactions are carried out in dimethylsulfoxide at 120 ° C in the presence of potassium carbonate, wherein the chloro derivative of the formula II and the amines of the formula III are used in approximately equimolecular amounts. The starting chloro derivative II is a new substance and its preparation is described in Example 1. Of the piperazines used, 1-methylpiperazine and 1- (2-hydroxyethyl) piperazine are commercially available. Others are prepared according to the literature: 1-phenylpiperazine (Vejdelek Z. J. et al. Collet. Czech. Camnun. 40, 1 204, 1975),

1- (2-tolyl) piperazine (Pollard, C. B., Wicker, T. J. Jr.; J. Am. Chem. Sou. 76, 1853, 1954),

1- (3-Trifluoromethylphenyl) piperazine (Holand, Pat. Application 55/4788; Chem. Abstr. 64, 9 744 1966),

1- (3-chlorophenyl) piperazine (Pollard C. B., cited above), 1- (4-methoxyphenyl) piperazine (Prelog V., Blazek Z. Collect. Czech. Chem. Coinmun. 6, 211, 1934). The processing of the reaction mixtures and the isolation of the products are described in the examples, which are, of course, merely illustrative of the possibilities of the invention. Most of the bases obtained are crystalline and their identity was confirmed by analyzes and spectra. All bases were converted to crystalline salts (hydrochlorides and, in one case, maleate).

Example 1

1- (4-Cyclopentylphenyl) -4- (4-phenyl-4-hydroxypiperidino) butan-1-one

To a mixture of 9.3 g of 4-phenylpiperidin-4-ol (Protiva M. et al., Collect. Czech. Chem. Commun.

47, 636 (1982), 7.5 g of potassium carbonate and 20 ml of dimethyl sulfoxide are added with stirring.

13.2 g of 1- (4-cyclopentylphenyl) -4-chlorobutan-1-one and the mixture is heated at 110 to 120 ° C for 16 h.

After cooling, it is diluted with 200 ml of water and extracted with chloroform. The extract was dried over sodium sulfate and evaporated. The residue is a crude oily base which is dissolved in a mixture of benzene and ether and the solution is shaken with a mixture of 10 ml of hydrochloric acid and 140 ml of water. Crystalline hydrochloride of the desired product precipitates, which is filtered off with suction, washed with a little water and dried in vacuo. It was obtained in a yield of 7.3 g (54%). This hydrochloride crystallizes from aqueous ethanol as the monohydrate and melts in the pure state at 237-238 ° C.

The required starting 1- (4-cyclopentylphenyl) -4-chlorobutan-1-one, which has not been previously described in the literature, is prepared by the following procedure: To a solution of 14.0 g of cyclopentylbenzene (Hai, V. et al .:

J. Org. Chem. (3, 39, 1958) and 14.0 g of 4-chlorobutyryl chloride in 100 ml of menzene are added in small portions at 0-5 ° C with 14.0 g of aluminum chloride.

The mixture is stirred for a further 1 hour with cooling, then for 2 hours at room temperature and finally poured into a stirred mixture of 100 g of ice and 20 ml of hydrochloric acid. The product was extracted with benzene, the extract was washed with dilute hydrochloric acid and saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated. The residue was distilled. 19.0 g (79%) of the desired substance are obtained, boiling at 190-195 ° C / 0.5 kPa. The distillate crystallizes on standing and the pure product can be prepared by crystallizing a sample from a mixture of benzene and hexane, m.p. 40-41 ° C.

Example 2

1- (4-Cyclopentylphenyl) -4- (methylpiperazino) butan-1-one

A mixture of 2.6 g of 1-methylpiperazine, 7.5 g of 1- (4-cyclopentylphenyl) -4-chlorobutan-1-one (see Example 1), 4.0 g of potassium carbonate and 15 ml of dimethylsulfoxide is stirred and heated. h to 115-125 ° C. After cooling, the mixture was diluted with 200 ml of water and extracted with chloroform. 7.9 g of crude oily product are obtained, which is dissolved in 150 ml of ether and the solution is neutralized with a solution of hydrogen chloride in 10 ml of ethanol. 50 ml of ether are added and left to crystallize in the refrigerator. The precipitated dihydrochloride is filtered off with suction, washed with a little acetone and dried in vacuo. 5.0 g (50%) of product melting at 237-239 ° C are obtained. Crystallization from an aqueous ethanol / ether mixture yields a hemidrate which melts at 223-224 ° C in pure form.

Example 3

1- (4-Cyclopentylphenyl) -4- (4- (2-hydroxyethyl) piperazino) butan-1-one

As in the previous example, 3.65 g of 1- (2-hydroxyethyl) piperazine is reacted with 7.5 g of 1- (4-cyclopentylphenyl) -4-chlorobutan-1-one in the presence of 4.0 g of potassium carbonate in 15 g of sodium carbonate. ml of dimethylsulfoxide at 110-120 ° C (16 h). Similar work-up gave 3.9 g (31%) of the dihydrochloride, which crystallized from a mixture of aqueous ethanol and ether and melted at 226-227 ° C. Decomposition of the dihydrochloride sample with aqueous ammonia and extraction with ether gave a crystalline base which crystallized from cyclohexane and melted in a pure state at 73-74 ° C.

Example 4

1- (4-Cyclopentylphenyl) -4- (4- (2-tolyl) piperazino) butan-1-one

To a stirred mixture of 4.6 g of 1- (2-tolyl) piperazine, 15 ml of dimethyl sulfoxide and 4.0 g of potassium carbonate was added 7.5 g of 1- (4-cyclopentylphenyl) -4-chlorobutan-1-one and the mixture was heated at 120 ° C for 16 h. After cooling, it is diluted with 250 ml of water and extracted with a mixture of benzene and ether. The extract is shaken with 150 ml of 1:10 dilute hydrochloric acid, the precipitated hydrochloride (2.0 g, m.p. 208 DEG-210 DEG C.) is filtered off with suction, the acidic aqueous solution is basified with aqueous ammonia and the desired base is isolated by extraction with ether; 2.80 g m.p. M.p. 76-77 ° C (cyclohexane). The total yield (base and hydrochloride) is 47%. The hydrochloride is purified by crystallization from ethanol and melts in the pure state at 212-213 ° C.

Example 5

1- (4-Cyclopentylphenyl) -4- (4-phenylpiperazino) butan-1-one

As in the previous example, 4.2 g of 1-phenylpiperazine and 7.5 g of 1- (4-cyclopentylphenyl) -4-chlorobutan-1-one are carried out in the presence of 4.0 g of potassium carbonate in 15 ml of dimethylsulfoxide at 115 DEG to 115 DEG C. 125 ° C (15h). After dilution with water, the crystalline base is extracted with 200 ml of benzene, the extract is dried and evaporated. 6.5 g (67%) of crystalline base are obtained, which is purified by crystallization from cyclohexane and melting at 123 DEG-124 DEG. Neutralization of the base in solution in a mixture of benzene and ethanol by addition of an ethanolic solution of hydrogen chloride and ether affords the dihydrochloride melting at 193-194 ° C (aqueous ethanol ether).

Example 6

1- (4-Cyclopentylphenyl) -4- (4- (3-trifluoromethylphenyl) piperazino) butan-1-one

As in Example 5, 17.0 g of 1- (3-trifluoromethylphenyl) piperazine are reacted with 19.0 g of 1- (4-cyclopentylphenyl) -4-chlorobutan-1-one in 35 ml of dimethylsulfoxide in the presence of 11.2 g of carbonate potassium hydroxide at 110-130 ° C (16 h). The oily base obtained afforded 27.8 g (78%) of the crude monohydrochloride salt by neutralization with ethereal hydrogen chloride in ether, melting at 184-186 ° C. Analytically pure hydrochloride melts at 188-189 ° C (ethanol-ether). The liberated base crystallizes from a mixture of cyclohexane and hexane and melts at 66-67 ° C

Example 7

1- (4-Cyclopentylphenyl) -4- (4- (3-chlorophenyl) piperazino) butan-1-one

As in Example 5, 5.1 g of 1- (3-chlorophenyl) piperazine are reacted with 7.5 g of 1- (4-cyclo-pentylphenyl) -4-chlorobutan-1-one in the presence of 4.0 g of potassium carbonate in 15 g. ml of dimethylsulfoxide at 115-125 ° C (16 h). The isolated crude base crystallizes from hexane? 4.0 g (33%), m.p. Mp 87-88 ° C. Neutralization with maleic acid in ethanol and addition of ether gives the maleate which crystallizes from a mixture of ethanol and ether and melts at 157-158 ° C.

Example 8

1- (4-Cyclopentylphenyl) -4- (4- (4-methoxyphenyl) piperazino) butan-1-one

As in the previous examples, 5.0 g of 1- (4-methoxyphenyl) piperazine are reacted with 7.0 g of 1- (4-cyclopentylphenyl) -4-chlorobutan-1-one in 15 ml of dimethylsulfoxide in the presence of 4.0 g of carbonate of potassium potassium at 110 to 120 ° C (16 h). 6.0 g (57%) of a crystalline base are obtained, which crystallizes from a mixture of benzene and hexane and melts at 125-126 ° C. This gives the dihydrochloride, which crystallizes from a mixture of aqueous ethanol and ether and melts at 202-203 ° C.

Claims (2)

SUBJECT OF THE INVENTION 4-Amino-l- (4-cyclopentylphenyl) butane-l-ones of formula I wherein X represents a bivalent radical either fenylkarbinolový fragment \ Z ^C 6 ^H 5 \ C, or the nitrogen fragment 'NR', where R is methyl, ( _AOH ) 2-hydroxyethyl, phenyl, tolyl, trifluoromethylphenyl, chlorophenyl or methoxyphenyl, and their salts with pharmaceutically acceptable inorganic or organic acids.