JP2577216B2 - Benzyl isoquinoline derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel benzylisoquinoline derivatives.

It is known that bisbenzylisoquinoline-based alkaloids, such as cepharanthin, berbamine, tetrandrine, etc., contained in plants of the family Aphididae and other plants have a platelet aggregation inhibitory action (Cell Structure and Function Vol. 6, 263-267). 1981). In particular, the inhibitory effect of cepharanthin on platelet aggregation has been studied clinically, and its titer is reported to be approximately in the middle of more than 10 anti-platelet aggregating agents (Basic and Clinical Volume 16, 291 1982). However, cefalanthin is extracted from a spellfish plant, and it is difficult to mass-produce it due to the limitation of a raw material plant. Although a method for synthesizing cepharanthin is also known, this method has long steps and is unsuitable for industrial practice. The present inventors have created single benzyl isoquinoline derivatives having a simpler structure, and found that these compounds have an excellent platelet aggregation inhibitory action.

The present invention has the general formula (Wherein R represents a hydrogen atom or a methyl group, R ₁ and R ₃ represent a hydrogen atom or a benzyloxy group, R ₂ represents a methoxy group or a benzyloxy group, Bz represents a benzyl group, provided that R and R ₁ represent a hydrogen atom, Except that R ₂ is a methoxy group and R ₃ is a benzyloxy group).

The compound of formula I is a novel compound which has not been described in the literature, has an excellent platelet aggregation inhibitory action, and is useful as an antiplatelet aggregation agent. Compounds of formula I wherein the substituent R is hydrogen are
General formula (Each symbol in the formula has the same meaning as described above), which is obtained by allowing phosphorus oxychloride to act on the compound and reducing the compound.

Compounds of formula II have the formula (Wherein each symbol has the meaning described above), a compound represented by the general formula (Wherein Bz has the above-mentioned meaning, and X represents a halogen atom or a hydroxyl group).

The reaction of the compound of formula II with phosphorus oxychloride is preferably carried out in a solvent. As the solvent, for example, benzene, toluene, xylene and the like are used. The reaction temperature is from 80 to 130 ° C, preferably from 80 to 90 ° C. The reaction is usually completed in 2 to 4 hours.

After completion of the reaction, the reaction product is reduced to obtain a compound of the formula I wherein R is a hydrogen atom. Examples of the reduction method include a catalytic reduction method and a method using a reducing agent such as sodium cyanoborohydride.

A compound of the formula I in which R is a methyl group is obtained by reacting a compound of the formula I in which R is a hydrogen atom with formaldehyde and then reducing the compound.

The reaction of the compound of formula I wherein R is a hydrogen atom with formaldehyde is carried out in the presence of a solvent such as methanol, ethanol, water and the like. This reaction can be performed at room temperature. The above-mentioned method is used as a method for reducing the reaction product.

The compounds of the formula I can be converted into acid addition salts by customary methods. As the acid, physiologically harmless acids such as hydrochloric acid, sulfuric acid, inorganic acids such as phosphoric acid, acetic acid, fumaric acid, malic acid, citric acid,
Organic acids such as succinic acid are preferred.

Production Example 1 To a mixture of 1 g of 2-benzyloxy-3-methoxy-β-phenethylamine, 50 ml of dichloromethane and 20 ml of a 10% aqueous sodium hydroxide solution was added 0.4 ml of 4-benzyloxyphenylacetic acid.
An acid chloride prepared from 82 g and 1 ml of thionyl chloride was added dropwise under ice cooling. Next, after stirring at room temperature for 30 minutes, the dichloromethane layer was separated, washed with water and dried to obtain N- (2-
Benzyloxy-3-methoxyphenethyl) -2- (4
1.5 g of -benzyloxy) acetamide are obtained. 50 ml of benzene and 3 ml of phosphorus oxychloride are added to 1.5 g of this amide, and the mixture is heated and stirred for 2 hours. Then, after cooling to room temperature,
The benzene and phosphorus oxychloride are distilled off under reduced pressure and the residue is dissolved in 100 ml of methanol. 0.5 g of sodium cyanoborohydride is added to this solution, and the mixture is reduced at room temperature for 3 hours. After completion of the reaction, methanol was distilled off, and 50 ml of 5% ammonia water was added.
, And extracted twice with 100 ml of ethyl acetate. The extract was washed with water and dried, and 5-benzyloxy-6-methoxy-1,2,3,4-tetrahydro-1- (4-benzyloxybenzyl) was added. 0.72 g of isoquinoline is obtained. This compound was treated with hydrochloric acid and recrystallized from ethyl acetate to give
The hydrochloride is obtained as colorless needles. 190-192 ° C.

Production Example 2 0.2 g of 5-benzyloxy-6-methoxy-1,2,3,4-tetrahydro-1- (4-benzyloxybenzyl) -isoquinoline obtained in Production Example 1, 10 ml of methanol and 37% formalin The mixture of 1 ml of the aqueous solution is stirred at room temperature for 16 hours. Then, slowly add 1 g of sodium borohydride,
After stirring at room temperature for 30 minutes, 2N hydrochloric acid is added to decompose excess sodium borohydride, and methanol is distilled off under reduced pressure. To the residue was added 50 ml of a 2N aqueous sodium hydroxide solution, and the mixture was extracted three times with 50 ml of diethyl ether. The extract was washed with water and the solvent was removed to give 5-benzyloxy-6-methoxy-1,2,3,4-tetrahydro-. 0.15 g of 1- (4-benzyloxybenzyl) -2-methylisoquinoline is obtained. This compound is treated with hydrochloric acid and recrystallized from ethyl acetate to give the hydrochloride as an amorphous powder. Melting point 77-
79 ° C.

Production Example 3 Using 1.2 g of 3-benzyloxy-β-phenethylamine and 1 g of 4-benzyloxyphenylacetic acid in the same manner as in Production Example 1, 6-benzyloxy-1,2,3,4-tetrahydro- 1- (4-benzyloxybenzyl)-
1.5 g of isoquinoline are obtained. The hydrochloride of this compound is an amorphous powder with a melting point of 149-151 ° C.

Production Example 4 6-benzyloxy-1,2,3,4- obtained in Production Example 3
Tetrahydro-1- (4-benzyloxybenzyl)
Using 0.2 g of isoquinoline and treating in the same manner as in Example 2, 6-benzyloxy-1,2,3,4-tetrahydro-
0.13 g of 1- (4-benzyloxybenzyl) -2-methylisoquinoline is obtained. The hydrochloride of this compound is a pale yellow crystalline powder with a melting point of 195 ° C. (decomposition).

Production Example 5 1.5 g of 3,4-dimethoxy-β-phenethylamine and 4
When treated in the same manner as in Production Example 1 using 0.9 g of benzyloxyphenylacetic acid, 6,7-dibenzyloxy-1,2,3,4-
Tetrahydro-1- (4-benzyloxybenzyl)
1.2 g of isoquinoline are obtained. The hydrochloride of this compound is colorless needles and has a melting point of 157-158 ° C.

Production Example 6, 6,7-dibenzyloxy-1,2,2 obtained in Production Example 5
When 0.2 g of 3,4-tetrahydro-1- (4-benzyloxybenzyl) -isoquinoline is used and treated in the same manner as in Preparation Example 2, 6,7-dibenzyloxy-1,2,3,4-tetrahydroquinoline is obtained. 0.21 g of -1- (4-benzyloxybenzyl) -2-methylisoquinoline are obtained. The hydrochloride of this compound is a colorless crystalline powder with a melting point of 138-140 ° C.

Claims (1)

(57) [Claims] (1) General formula (Wherein R represents a hydrogen atom or a methyl group, R ₁ and R ₃ represent a hydrogen atom or a benzyloxy group, R ₂ represents a methoxy group or a benzyloxy group, Bz represents a benzyl group, provided that R and R ₁ represent a hydrogen atom, A benzyl isoquinoline derivative represented by the formula (1) except that R ₂ is a methoxy group and R ₃ is a benzyloxy group).