CS260089B1 - Piperazides of methoxyphenoxyacetic acids and their hydrochlorides - Google Patents

Abstract

The solution lies in the field of drug synthesis. The subject of the invention is the piperazides of methoxyphenoxyacetic acids of the formula I R ch3o G och2con n-x-ch R wherein R is hydrogen or meth-oxyl and X is either a direct bond, -CH 2 - or -CH-, and their hydrochlorides. ch3 The compounds of formula (I) and their hydrochlorides have a number of central and peripheral neurotropic effects which characterize them as potential antidepressants, anorectics, nootropics and spasmolytics. They can be prepared from 4-methoxyphenoxyacetyl chloride or 3,4,5-trimethoxyphenoxyacetic acid by reaction with 1-benzylpiperazine, 1- (2-phenylethyl) piperazine, and 1- (1- - phenyl-2-propyl) piperazine and neutralization with hydrogen chloride.

Description

The invention relates to methoxyphenoxyacetic acid piperazides of the formula I

R

CH ₃ O

_OCH2 CON ~ J4 -X- CH ₂ R wherein R is hydrogen or methoxy and X is either a direct bond, -CHj- or -CH-, and their hydrochlorides.

ch ₃

The compounds of the formula I according to the invention and their hydrochlorides have a number of central and peripheral neurotrophic and circulating pharmacological effects. In animal and isolated organ tests, they show in particular the following effects: antireserpine (corresponding to antidepressant effect in patients), centrally stimulating and anorectic at higher doses (leading to reduced food intake in obese patients), or centrally depressing and discoordinating, reduce amnesia induced halothane anesthesia (the possibility of favorably influencing the processes of learning and remembering), have a locally anesthetic, spasmolytic and antiarrhythmic effect.

For the individual compounds of the invention (all hydrochlorides), the following specific pharmacological properties can be mentioned:

1-Benzyl-4- (4-methoxyphenoxyacetyl) piperazine: Acute toxicity in mice, LDg _Q = 80 mg / kg iv At doses higher than 17 mg / kg iv, it acts slightly centrally in mice. At an oral dose of 85 mg / kg, it is anorectic in mice, i.e., that dose results in a 50% reduction in food intake. At a dose of 17 mg / kg ip, mice act antireserpine in the reserpine-induced hypothermia test.

1- (2-phenylethyl) -4- (4-methoxyphenoxyacetyl) pipreazine: Acute toxicity in mice, LDg ₀ = 125 mg / kg iv At doses greater than 25 mg / kg, the compound induces a slight excitation in mice followed by depression.

1- (2-phenylethyl) -4- (3,4,5-trimethoxyphenoxyacetyl) piperazine: Acute toxicity in mice,

LD ₅₀ = 100 mg / kg iv At doses higher than 20 mg / kg iv, the substance inhibits mouse activity and reactivity and induces ataxia. At an oral dose of 100 mg / kg, it is anorectic in the mouse, i.e., decreases food intake to about 50% compared to control.

1- (1-phenyl-2-propyl) -4- (3,4,5-trimethoxyphenoxyacetyl) piperazine: Acute toxicity in mice, LD _{5 ()} = 62.5 mg / kg iv At doses greater than 12 mg / kg iv induces activity and reactivity inhibition in mice.

The compounds of the invention are synthetically accessible by the methods described in the Examples. In the case of 4-methoxyphenoxyacetic acid derivatives, 4-methoxyphenoxyacetyl chloride (Fridman SG, 2nd Ob. Chim. 24, 642, 1954), which reacts with a slight excess of 1-benzylpiperazine (Craig JC, Young RJ, Org. Synth. Coll. Vol. 5, 88,

1973), 1- (2-phenylethyl) piperazine (Jílek J.O. et al., Collect. Czech. Chem. Coramun. 48 ',

3386, 1975) or 1- (1-phenyl-2-propyl) piperazine (Toldy L. et al., Acta Chim. Hung. 49,

265, 1966) in boiling chloroform. In the case of 3,4,5-trimethoxyphenoxyacetic acid derivatives, acid chloride cannot be used due to its instability. The preparation of the desired compounds is carried out by heating the appropriate piperazine salts of 3,4,5-trimethoxyphenoxyacetic acid (Ernest I. et al., Collect. Czech. Chem. Commun. 28, 1022, 1963) to 190 ° C. In all cases, the crude bases obtained convert the neutralization with hydrogen chloride to crystalline hydrochlorides.

Further details of the process for the preparation of the compounds of formula I are given in the examples, which are merely illustrative of the possibilities of the invention; of course, not all of these options can be listed. All of the compounds described herein are novel. Their identity was ensured both analytically and by usual spectral methods.

Example 1 1-benzyl-4- (4-methoxyphenoxyacetyl) piperazine

To a stirred solution of 3.9 g of 4-methoxyphenoxyacetyl chloride in 10 ml of chloroform was added dropwise 3.5 g of 1-benzylpiperazine in 10 ml of chloroform over 5 minutes. The temperature of the mixture increases spontaneously so that the mixture is brought to reflux without heating. Stir for 1.5 h and, after cooling, shake with a mixture of 25 ml of concentrated aqueous ammonia and 50 ml of water. The chloroform layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The crude oily base (6.1 g) was dissolved in 15 ml of ethanol and the solution was slightly acidified with a solution of hydrogen chloride in ether. On standing, 4.9 g (70%) of the hydrochloride of the desired compound crystallized from ethanol and melted at 203 DEG-204 DEG C. in pure state.

Example 2

1- (2-Phenylethyl) -4- (4-methoxyphenoxyacetyl) piperazine

A similar reaction of 4.85 g of 4-methoxyphenoxyacetyl chloride with 5.04 g of 1- (2-phenylethyl) piperazine in 35 ml of chloroform afforded 9.0 g of crude base which was converted to 9.1 g (93%) of hydrochloride, m.p. Mp 210-211.5 ° C (ethanol).

Example 3

1- (1-Phenyl-2-propyl) -4- (4-methoxyphenoxyacetyl) piperazine

To a stirred solution of 27.9 g of 1- (1-phenyl-2-propyl) piperazine in 100 ml of chloroform was added dropwise a solution of 29.7 g of 4-methoxyphenoxyacetyl chloride in 60 ml of chloroform over 50 minutes.

The temperature of the mixture rose spontaneously to about 50 ° C. The mixture was stirred at 50-55 ° C for 1.5 h, cooled to 20 ° C and 200 mL of ether was added. The precipitated product hydrochloride is filtered, washed with ethanol / ether and dried in vacuo. 51.8 g (93%) of a material which crystallizes from ethanol and melts in the pure state at 201.5 to 202.5 ° C are obtained.

Example 1-benzyl-4- (3,4,5-trimethoxyphenoxyacetyl) piperazine

A mixture of 9.6 g of 3,4,5-trimethoxyphenoxyacetic acid and 3.6 g of 1-benzylpiperazine is slowly heated in an open vessel to reach a temperature of 185 to 190 ° C over 30 min. It is kept at this temperature for a further 30 minutes, cooled, dissolved in 60 ml of chloroform, washed with dilute sodium hydroxide solution and water, dried over sodium sulphate, filtered with charcoal and evaporated. The residue (8.3 g) was dissolved in 100 ml of ethanol and a slight excess of a solution of hydrogen chloride in ether was added. Addition of an additional 20 ml of ether results in crystallization of 6.6 g (74%) of the hydrochloride of the desired compound, which melts at 159-161 ° C (ethanol-ether) in the pure state. By decomposing the hydrochloride with aqueous ammonia and extracting with ether, a crystalline base, m.p. Mp 100-101.5 ° C (2-propanol).

ExampleS

1- (2-Phenylethyl) -4- (3,4,5-trimethoxyphenoxyacetyl) piperazine

Prepared in analogy to the preceding compound from 9.6 g of 3,4,5-trimethoxyphenoxyacetic acid and 3.8 g of 1- (2-phenylethyl) piperazine. 7.3 g (81%) of the hydrochloride are obtained, which crystallizes from ethanol and melts at 176.5-177.5 ° C.

Example 6

1- (1-Phenyl-2-propyl) -4- (3,4,5-trimethoxyphenoxyacetyl) piperazine

A similar reaction of 6.75 g of 3,4,5-trimethoxyphenoxyacetic acid and 2.75 g of 1- (1-phenyl-2H-propyl) piperazine gives 5.3 g (85%) of the hydrochloride of the desired compound, which crystallizes from ethanol and melts at 161-163 ° C. The hydrochloride released from the hydrochloride also crystallizes from nole and has a melting point of m.p. 96-97 ° C.

Claims (1)

object of the invention Piperazides of methoxyphenoxyacetic acids of general formula I R ch ₃ or OCH ₂ CON_N-X- CH Wherein R is hydrogen or methoxy and X is either a direct bond, -CH 3 - or -CH-, and their hydrochlorides.