CS217945B1 - 1- (4-Cyclopentylphenyl) ethylamines and their salts - Google Patents

Abstract

The invention relates to new 1-(4-cyclopentylphenyl)ethylamines with a primary amino group NHg, a secondary amino group methylamino, a tertiary amino group dimethylamino, allylmethylamino or methylpropargylamino and an N-methyl-N-aminoacetamido group, where the amino group in the glycinamide residue is formed by a piperidine, morpholine or N-methylpiperazine residue. The invention also relates to salts of these substances with pharmaceutically acceptable inorganic or organic acids. The substances according to the invention are local anesthetics and spasmolytics and are useful for local anesthesia in surgery and also as agents for relieving painful smooth muscle contractions. The basic substance according to the invention, i.e. 1-(4-cyclopentylphenyl)ethylamine, is obtained by reduction of 4-cyclopentylacetophenone oxime and the other substances according to the invention are prepared from it by a sequence of alkylation, acylation, reduction and substitution reactions. Salts are obtained by neutralizing bases with the corresponding acids.

Description

The present invention relates to novel 1- (4-cyclopentylphenyl) ethylamines of formula I,

R ¹ /

CHN.

¹ \ ch ₃ p

Wherein R is hydrogen or methyl, R is hydrogen, methyl, allyl, propargyl. or aminoacetyl COCH 8 X, wherein X is a residue of piperidine, morpholine or N-methylpiperazine, and salts thereof with pharmaceutically acceptable inorganic or organic acids.

The compounds of formula (I) and their salts have locally anesthetic and spasmolytic activity, so that they are useful as medicaments for local anesthesia in minor surgical interventions and as a means of relieving painful contractions of smooth muscles, especially the gastrointestinal system. Said efficacy has been verified in pharmacological tests on animals and isolated organs as described for the individual compounds of the invention which have been tested in the form of said salts.

1- (4-Cyclopentylphenyl) ethylamine hydrochloride: locally anesthetic efficacy in guinea pig infiltration anesthesia assay; the effective concentration is 0.25% (the concentration that induces complete anesthesia in 50% of the animals). It is also effective in the corneal anesthesia test in rabbits; the effective concentration is 0.5% (the concentration inducing complete anesthesia of the rabbit eye cornea in 50% of the animals). Acute toxicity, LD ^ q = 50 mg / kg i.

N-Methyl-1- (4-cyclopentylphenyl) ethylamine hydrochloride: Acute toxicity, LD50 = 50 mg / kg i.v. Spasmolytic effect on acetylcholine and barium chloride contractions of isolated rat duodenum; an effective concentration of 1-10 µg / ml identical to both spasmogens (concentration causing a contraction reduction of 50%). At doses of 10 to 50 mg / kg p.o., the compound exhibits anticonvulsant activity against pentetrazole in mice.

N, N-Dimethyl-1- (4-cyclopentylphenyl) -ethylamine hydrochloride: Acute toxicity, ^LD 50 ^{= i 'v} · ^m · The mouse spasmolytic effect on acetylcholine and baryumchloridovým contractions; effective concentration of 10 µg / ml against both spasmogens.

N-Allyl-N-methyl-1- (4-cyclopentylphenyl) ethylamine hydrochloride: Acute toxicity in mice, = 37.5 mg / kg i.v. Local anesthetic efficacy in guinea pig infiltration anesthesia assay; an effective concentration of 0.1 to 0.5%. Spasmolytic activity against both acetylcholine and barium chloride contractions; an effective concentration of 1 to 10 µg / ml.

N-Methyl-N-propargyl-1- (4-cyclopentylphenyl) ethylamine hydrochloride: Acute toxicity in mice, LD50 = 75 mg / kg i.v. Spasmolytic activity against barium chloride contractions; the effective concentration is 10 µg / ml.

N- [1- (4-Cyclopentylphenyl) ethyl] -N-methylpiperidinoacetamide hydrogen maleate hemihydrate: Acute toxicity in mice, LD50 = 50 mg / kg i.v. Spasmolytic effect on acetylcholine contractions; an effective concentration of 1 to 10 µg / ml.

N- [1- (4-Cyclopentylphenyl) ethyl] -N-methylmorpholinoacetamide hydrogen maleate: Acute toxicity in mice, LD50 = 87.5 mg / kg i.v. Local anesthetic effect in guinea pig infiltration anesthesia test; an effective concentration of 0.1 to 0.5%.

N- (1- (4-cyclopentylphenyl) ethyl) -N-methyl- (4-methylpiperazino) acetamide dihydrochloride monohydrate: Acute toxicity in mice, LDj _C = 100 mg / kg iv Local anesthetic effect in corneal anesthesia test in rabbits ; the effective concentration is 1%. Spasmolytic effect on acetylcholine and barium chloride contractions; the effective concentration is 10 µg / ml against both spasmogens. The compound also has a diuretic effect in mice at a dose of 100 mg / kg po (a dose that increases diuresis by 100% over the control group).

The compounds of formula (I) are prepared by several methods, which are described in detail in the Examples 1 2. Thus the base compound of formula I, wherein R = R = H, is obtained by reducing sodium 4-cyclopentylacetophenone oxime (V. V. Hai et al., J. Org. Chem. 23, 39 (1958)) in ethanol. Formation of this basic primary amine by heating with ethyl formate in an autoclave at 110 to 120 ° C affords the corresponding N-formyl derivative which provides by reduction of the lithium aluminum hydride methylamino derivative of formula I wherein R ¹ = H and K ³ = CH ³ . Methylation of the primary amine with formaldehyde and formic acid affords the dimethylamino derivative of formula I wherein R ¹ = R ² = CH 3. Alkylation of the secondary amine with allyl bromide and propargyl bromide in 2-butanone in the presence of potassium carbonate affords tertiary amines of formula 1 wherein R 1 = CH 1 and R 2 = allyl or propargyl. Reaction of the secondary amine with chloroacetyl chloride affords the chloroacetamide derivative of formula II

CH, (TV

-CHN (II) ^CH 3 COCH ₂ Cl which is subjected to substitution reactions with piperidine, morpholine and 1-methylpiperazine in 2-butanone in the presence of potassium carbonate; to obtain substituted glycinamides of formula 2 wherein R = methyl and R = COCH2X, wherein X is a piperidine, morpholine or N-methylpiperazine residue.

The invention includes pharmaceutically acceptable salts of the compounds of formula I with inorganic or organic acids, which are more suitable than the free bases for pharmacological testing and for the preparation of dosage forms. Particularly suitable salts have been found to be crystalline and water-soluble hydrochlorides, as well as slightly water-soluble hydrogen maleate. The former are suitable for the preparation of injectable dosage forms, the latter for the preparation of oral dosage forms.

The identity of all products according to the invention was ensured both analytically and by conventional spectral methods.

Examples

Example 1

- (4-Cyclopentylphenyl) ethyl amine

A solution of 64 g of 4-cyclopentylacetophenone oxime (V. V. Hai et al., Cited) in 400 ml of ethanol is added dropwise to 195 g of sodium and slowly added to the mixture refluxing with 1,400 ml of ethanol to allow complete dissolution of sodium. The mixture is left overnight at room temperature, then quenched by the slow addition of 300 ml of water, the ethanol is evaporated off under reduced pressure, the residue is diluted with an additional 500 ml of water and extracted with a mixture of benzene and ether. Drying and evaporation of the extract gave 58.5 g (98%) of the desired oily base, a sample of which distilled at 130-132 ° C / 0.33 kPa, = 1.5322. Neutralization with hydrogen chloride in a mixture of ethanol and ether gives the hydrochloride melting in a pure state at 225 to 226 ° C (ethanol-ether).

Example 2

N-Methyl-1- (4-cyclopentylphenyl) ethylamine

A mixture of 42.8 g of 1- (4-cyclopentylphenyl) ethylamine (see Example 1) and 75 ml of ethyl formate was heated in an autoclave at 110-120 ° C for 6 h. After cooling, the mixture was diluted with benzene, the solution was washed with 1: 4 dilute hydrochloric acid and 8% sodium hydrogen carbonate solution, dried over sodium sulfate and evaporated. 47.0 g (96%) of crude N- [1- (4-cyclopentylphenylmethyl) formamide, melting at 7 ° to 80 ° C, is obtained. Crystallization from benzene / hexane gives pure intermediate melting at 100 to 101 ° C.

A solution of 46 g of the above formamide derivative in 250 ml of benzene is added dropwise to a stirred suspension of 16 g of lithium aluminum hydride in 200 ml of ether and the mixture is refluxed for 5 hours.

After cooling, it is quenched by the slow addition of 64 ml of 20% sodium hydroxide, stirred for 30 min. The solid is filtered off, washed with benzene and the filtrate is worked up by distillation. 41 g (95%) of the desired base are obtained, m.p. 133 DEG C./0.4 mbar, [.alpha.] D @ 20 = 1.5232. The hydrochloride obtained by neutralization crystallizes from a mixture of ethanol and ether and melts at 161-162 ° C.

Example 3

N, N-Dimethyl-1- (4-cyclopentylphenyl) ethyl amine

A mixture of 7.5 g of crude 1- (4-cyclopentylphenyl) ethylamine (see Example 1), 10 ml of water, 8 ml of 85% formic acid and 15 ml of 28% aqueous formaldehyde is refluxed for 8 h in a 120 ° bath. C. After cooling, the mixture was quenched with 25 ml of hydrochloric acid and evaporated under reduced pressure. The residue is dissolved in 60 ml of water with the addition of 2 ml of hydrochloric acid, the solution is washed with ether, basified with 20% sodium hydroxide and extracted with ether. Workup of the extract and distillation of the residue gave 7.9 g (92%) of the desired base, m.p.

136-138 ° C / 0.4 kPa, η ^ θ = 1.5154. As in the previous cases, the hydrochloride obtained crystallizes from a mixture of ethanol and ether and melts in a pure state at 243-244 ° C.

Example 4

N-Allyl-N-methyl-1- (4-cyclopentylphenyl) ethylamine

A mixture of 6.5 g of N-methyl-1- (4-cyclopentylphenyl) ethylamine (see Example 2), 5.8 g of allyl bromide, 6.6 g of potassium carbonate and 60 ml. The 2-butanone was stirred and heated at 60-70 ° C for 8 h. After cooling, the precipitated salts are filtered off, washed with acetone and the filtrate is evaporated. The residue was dissolved in a mixture of 1 L of benzene and ether and the base was extracted into a solution of 15 ml of hydrochloric acid in 65 ml of water. The separated aqueous layer was washed with ether, basified with 20% NaOH and extracted with a mixture of benzene and ether. Work-up of the extract gave 6.80 g (88%) of a crude oily base which was dissolved in 70 ml of ether and converted into the hydrochloride (6.7 g) by treatment with a solution of hydrogen chloride in ether, mp 145-146 ° C (ethanol-ether) .

Example 5

N-Methyl-N-propargyl-1- (4-cyclopentylphenyl) ethylamine

A mixture of 7.3 g of N-methyl-1- (4-cyclopentylphenyl) ethylamine (see Example 2), 6.4 g of propargyl bromide, 7.4 g of potassium carbonate and 60 ml of 2-butanone is stirred and heated at 60-60 ° C for 8 hours. 70 ° C. By treating the mixture in a similar manner as in the previous example, 6.8 g of crude base are obtained which is distilled; 5.90 g (68%), mp 158 ° C / 0.4 kPa, n = ² = 1.5302. Neutralization of the base gives the hydrochloride, which crystallizes from a mixture of ethanol and ether and melts at 191-192 ° C.

Example 6

N- [1- (4-Cyclopentylphenyl) ethyl] -N-methylpiperidinoacetamide

To a solution of 20.3 g of N-methyl-1- (4-cyclopentylphenyl) ethylamine (see Example 2) in 100 ml of chloroform was added 16.6 g of potassium carbonate, and a solution of 15 g of chloroacetylchloride in water was added dropwise over 40 min. 50 ml of chloroform and refluxed for 2 hours. After cooling, it is quenched by the addition of 150 ml of water, stirred for 10 min, the organic layer is separated, dried over sodium sulfate and evaporated under reduced pressure. The residue is 28.8 g (100%) of crude oily N- [1- (4-cyclopentylphenyl) ethyl] -N-methylchloroacetamide, which does not crystallize after chromatography and is further used in the crude state.

A mixture of 6.0 g of the preceding chloroacetamide derivative, 1.9 g of piperidine, 3.0 g of potassium carbonate and 60 ml of 2-butanone was stirred and refluxed for 8 hours. After cooling, the precipitated salts are filtered off, triturated with acetone, the filtrate is evaporated in vacuo and the residue is dissolved in a mixture of benzene and ether. The base is extracted into a solution of 15 ml of hydrochloric acid in 70 ml of water, the separated acidic layer is basified with 20% sodium hydroxide and the liberated base is isolated by extraction of a mixture of benzene and ether. The extract was washed with water, dried over sodium sulfate and evaporated under reduced pressure. 5.2 g (74%) of a crude oil base are obtained, which is dissolved in 70 ml of ether and the solution is neutralized by adding a solution of 1.9 g of maleic acid in 4 ml of 95% ethanol. 5.8 g of crystalline hydrogen maleate hemihydrate are obtained, which melts at 126 DEG -127 DEG C. (95% ethanol-ether).

Example 7

N- [1- (4-cyclopentylphenyl) ethyl] -N-methylmorpholinoaoetamide

A mixture of 6.0 g of crude N- [1- (4-cyclopentylphenyl) ethyl] -N-methylchloroacetamide (see Example 6), 1.9 g of morpholine, 3.0 g of potassium carbonate and 60 ml of 2-butanone is treated in a similar manner to in the previous example. 5.60 g (80%) of a crude oily base are obtained, which is converted by neutralization with maleic acid to crystalline hydrogen maleate, m.p. 116 DEG-117 DEG C. (ethanol-ether).

Example 8

N- [1- (4-Cyclopentylphenyl) ethyl] -N-methyl- (4-methylpiperazino) acetamide

A mixture of 6.0 g of crude N- [1- (4-cyclopentylphenyl) ethyl] -N-methylchloroacetamide, 2.2 g of 1-methylpiperazine, 3.0 g of potassium carbonate and 60 ml of chloroform is stirred and heated at 60 DEG for 7 h. C. After cooling, the solid is filtered off, the filtrate is washed with water and the base is extracted into a solution of 15 ml of hydrochloric acid in 70 ml of water. The aqueous hydrochloride solution was treated similarly to the previous example. 5.0 g (68%) of crude oil are obtained, which is converted by neutralization with a solution of hydrogen chloride in ether to the dihydrochloride (5.8 g), which crystallizes from 95% ethanol / ether as the monohydrate, mp 186-187 °. C.

Claims (1)

SUBJECT OF THE INVENTION 1- (4-Cyclopentylphenyl) ethylamines of formula I CHN I \ 2 ch ₃ " Wherein R represents a hydrogen atom or methyl, R represents a hydrogen atom, methyl, allyl, propargyl or aminoacetyl COCHgX, wherein X is a piperidine, morpholine or N-methylpiperazine residue, and salts thereof with pharmaceutically acceptable inorganic or organic acids.