JPH02233670A - Piperazinosulfonic acid derivative - Google Patents

Abstract

NEW MATERIAL:Piperazinosulfonic acid derivative expressed by formula I (R1 and R2 are H, halogen or lower alkoxy; R3 is H or lower alkyl; n is 2-4). EXAMPLE:1-(3-sulfopropyl)-4-(diphenylmethyl) piperazine. USE:Medicine. Useful for prevention and remedy of arterial sclerosis, cerebral infarction, cardiac infarction, peripheral thrombus or emphraxis, etc., having excellent exasperating action of red corpuscle deformability and preventing action of platelet aggregation. PREPARATION:Diphenylchlormethane derivative expressed by formula II is reacted with piperazine derivative expressed by formula III in a solvent such as benzene at a temperature from room temperature to boiling point of solvent for 11-24 hour to generate a compound expressed by formula IV and said compound is reacted with cyclic sulfonic acid ester expressed by formula V in a solvent such as acetone at a temperature from 0 deg.C to refluxing temperature for several hour-several day to afford the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel piperazinosulfonic acid derivatives.

In recent years, in order to improve microcirculation under ischemic conditions, it has been recognized that simple treatment with vasodilators is not sufficient, and efforts have been made to actively improve blood properties by increasing red blood cell deformability and controlling platelet function. It is hoped that improvements will be made. That is, in the treatment of thrombosis and microcirculatory disorders, drugs that have red blood cell deformability enhancing effects and platelet aggregation inhibiting effects have been attracting attention. Therefore, existing cardiovascular drugs were examined from a hemorheological standpoint, and drugs such as bentxifylline, trapidil, and dirazep were found to be effective as drugs for improving blood properties. However, their blood property improving effects are still not satisfactory. Therefore, there is a demand for a drug that exhibits significant effects on blood fluid dynamics on microvascular flow, ie, red blood cell deformability redundancy and platelet aggregation inhibition.

The present invention is based on the general formula (wherein R1 and R2 are the same or different, a hydrogen atom,
Indicates a halogen atom or a lower alkoxy group.

R3 represents a hydrogen atom or a lower alkyl group. n is 2 to 4
indicates an integer. ) is related to the biperazinosulfonic acid derivative represented by

The biverazinosulfonic acid derivative of the present invention represented by the above general formula (I) is a new compound that has not been described in any literature, and has a stronger effect on red blood cell deformability than conventional drugs, and also has an effect on inhibiting platelet aggregation. It is useful for the prevention and treatment of diseases and microcirculatory disorders.

The lower alkyl group represented by R3 in the above general formula (I) is a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, proyl, butyl, t-
Examples include butyl, bentyl, hexyl groups, and the like. Examples of the halogen atoms represented by R and R2 include chlorine, bromine, fluorine, and iodine atoms. Examples of lower alkoxy groups include linear or branched alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, isobropoxy, and hexyloxy groups.

Compound (I) of the present invention can be produced, for example, by the following method.

(m) (in the formula, R, %R2, R3 and n are the same as above) diphenylchloromethane derivative (II) and piperazine derivative (
The reaction with m) is carried out in a suitable solvent. By this reaction, diphenylmethylbiperazine derivative (IV)
To obtain. can. The ratio of the diphenylmethane derivative (II) and the biperazine derivative (m) to be used is not particularly limited, but the ratio of the latter to the former is usually 2.0 to 2.2.
It is sufficient to use about a molar amount. Any solvent that does not affect the reaction can be used, such as lower alcohols such as methanol, ethanol, and propanol;
Ethers such as diethyl ether, isobrobyl ether, tetrahydrofuran, dioxane, benzene,
Examples include aromatic hydrocarbons such as toluene. The reaction proceeds advantageously in a range from room temperature to the boiling point of the solvent, and usually completes in about 11 to 24 hours.

The diphenylmethyl biverazine derivative (IV) obtained by the above method can be used in the next reaction with or without isolation.

The reaction between the diphenylmethylpiperazine derivative (IV) and the cyclic sulfonic acid ester (V) is carried out in a suitable solvent. The ratio of the diphenylmethylpiperazine derivative (IV) and the cyclic sulfonic acid ester (V) to be used is not particularly limited, but the latter should generally be used in an amount of about 1 to 1.5 times the molar amount of the former. Suitable solvents include, for example, lower alcohols such as methanol, ethanol, propanol, and isoprobanol, lower ketones such as acetone, methyl ethyl ketone, and diethyl ketone, benzene,
Examples include aromatic hydrocarbons such as toluene and mixed solvents thereof. The reaction is carried out under stirring at a temperature of room temperature to reflux temperature after adding the above two raw material compounds to a solvent at a temperature of about 0°C to room temperature, and usually completes in about several hours to several days. .

The compound (I) of the present invention thus obtained can be purified and isolated by conventional means. For example, after concentrating under reduced pressure or taking the precipitate produced as it is,
It can be purified and isolated by recrystallization from water or a mixed solvent of lower alcohols such as methanol, ethanol, propanol, isopropanol, acetone, methyl ethyl keto, etc.

Effects of the Invention The compound (I) of the present invention has excellent red blood cell deformability quantal action and platelet aggregation inhibiting action, and improves blood fluidity in the microcirculation area, thereby preventing arteriosclerosis, cerebral infarction, It is useful for the prevention and treatment of myocardial infarction, peripheral thrombosis, occlusion, etc.

Example The present invention will be specifically explained below with reference to Examples.

Example 1 A benzene solution of 4.1 g of diphenylmethyl chloride was added dropwise to a benzene solution of 4011IQ containing 3.5 g of piperazine while maintaining the temperature of the reaction solution at around 40°C. After the dropwise addition, heating and stirring were performed for 24 hours.

After cooling, the solvent was distilled off under reduced pressure, and to the resulting residual liquid were added Ether 100 formula and 30 mQ of diluted sodium bicarbonate solution for ether extraction. The ether layer was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain 2.8 g of oily diphenylmethylpiperazine. Subsequently, diphenylmethylbiverazine was dissolved in 50 g of acetone without purification, and a solution of 1.5 g of 1.3-propanesultone in 10 g of acetone was added to this solution.
- was added dropwise at room temperature. After the addition, the mixture was stirred at room temperature for 18 hours. After the reaction, the precipitate was collected and washed with acetone and then ether to give 3.4 g (45%) of 1-(3-sulfopyr)-4-(diphenylmethyl)biperazine (compound Ia).
) was obtained. Melting point 290°C decomposition and elemental analysis values are shown in Table 1.

Example 2 Compound Ib-Ie was synthesized in the same manner as in Example 1. Table 1 shows the respective melting points, yields, and elemental analysis values.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 and R_2 are the same or different and represent a hydrogen atom, a halogen atom, or a lower alkoxy group. R_3
represents a hydrogen atom or a lower alkyl group. n represents an integer of 2 to 4. ) A piperazinosulfonic acid derivative represented by