JPS62242667A - Benzylisoquinoline derivative - Google Patents

Abstract

NEW MATERIAL:A benzylisoquinoline derivative of formula I (R1-R3 are lower alkyl; R4 is >=3C alkyl, cycloalkyl or phenyl). EXAMPLE:1-(4-Propoxybenzyl)-2-methyl-6, 7-dimethoxy-1,2,3,4-tetrahydroisoquino line. USE:A platelet coagulation inhibitor. Useful for the remedy and prevention of cerebral thrombosis, myocardial infarction, etc. PREPARATION:The objective compound of formula I can be produced by reacting the compound of formula II with the compound of formula III (X is halogen; R4' is >=3C alkyl or phenyl) or with a cycloalkene. The starting compound of formula II is produced by the reaction of a 3,4-disubstituted- phenetylamine with p-hydroxyphenylacetic acid.

Description

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

It is known that bisbenzylisoquinoline alkaloids, such as cephalanthine, berbamine, and tetrandrine, contained in plants of the family Tiliaceae and other plants, have an inhibitory effect on platelet aggregation (Cell Structural and Function Vol. 6, 263- 267, 1981). In particular, the platelet aggregation inhibitory effect of cephalanthine has been clinically investigated, and its potency is reported to be approximately in the middle among the more than 10 types of antiplatelet aggregation agents (Basic and Clinical Studies Vol. 16, 291). (see page 1982)
. However, cephalanthine is extracted from a plant in the family Cepharantaceae, and mass production is difficult due to restrictions on raw material plants. A method for synthesizing cephalanthine is also known, but this method involves long steps and is unsuitable for industrial implementation. The inventors have created a single penzyline quinoline derivative with a simpler structure.

It has been found that these compounds have excellent platelet aggregation inhibiting effects.

The present invention is based on the general formula (In the formula, R, , R, and R1 may be the same or different.

Each of these is a benzyline quinoline derivative represented by a lower alkyl group s (R4 represents an alkyl group having 3 or more carbon atoms, a cycloalkyl group, or a haphenyl group).

The compound of formula I is a new compound that has not been described in any literature, and the alkyl group having 6 or more carbon atoms for R2 is, for example, a propyl group, a butyl group, or a pentyl group.

Examples include hexyl group. As the cycloalkyl group, a cyclohexyl group is preferred.

The compound of formula I is a compound represented by the general formula (in which each symbol has the above-mentioned meaning); or phenyl group) or a cycloalkene.

The compound of formula ■ is a 3,4-disubstituted phenethylamine p
- Obtained by reaction with hydroxyphenylacetic acid.

The reaction between the compound of formula (1) and the compound (2) or cycloalkene is carried out by the following method. (a) When producing a compound of formula I in which R4 is an alkyl group, the compound of formula (i) is reacted with, for example, sodium hydride to form a sodium salt, and then reacted with the compound of formula (ii). (b) When producing a compound of formula I in which R4 is a phenyl group, the compound of formula (1) is coupled with the compound of formula (2) by Ullmann reaction. (c) When producing compound 41 in which R4 is a cycloalkyl group, the compound of formula 1 and cycloalkene are condensed in the presence of an acid. Examples of acids include Lewis acids such as boron trifluoride, aluminum trichloride, titanium tetrachloride, and methanesulfonic acid.

Benzenesulfonic acid, p-)luenesulfonic acid.

Trifluoroacetic acid and the like are used.

Compounds of formula I can be converted into acid addition salts by conventional methods. As the acid, physiologically harmless acids 1, such as inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as acetic acid, fumaric acid, malic acid, citric acid, and succinic acid are preferred.

The compound of formula I and its acid addition salts have excellent platelet aggregation inhibitory effects. Therefore, the present invention further provides an antiplatelet aggregation agent containing a compound of Formula 1 (1) or an acid addition salt thereof as an active ingredient.

For the antiplatelet aggregation agent of the present invention, the compound of formula I or its acid addition salt may be used as it is, but usually excipients, binders, lubricants, solvents, stabilizers, etc. are added and one tablet is prepared. It is used in formulations such as powders, granules, capsules, and injections.

Examples of excipients include starch, lactose, methyl cellulose,
Examples of binders include crystalline cellulose, hydroxyglobil cellulose, and polyvinylpyrrolidone; and examples of lubricants include talc, magnesium stearate, and calcium stearate.

The antiplatelet aggregation agent of the present invention can contain, for example, a vasodilator, other antiplatelet aggregation agents, and the like.

The antiplatelet aggregation agent of the present invention is used for the treatment and prevention of cerebral thrombosis, myocardial infarction, and the like.

The dosage of the antiplatelet aggregation agent of the present invention varies depending on the type and degree of the target disease.

Normally, when administered orally, the active ingredient is 10 to 10% per day.
1000rn9, preferably 60 to 300 Da.

Example 1 1-(4-hydroxybenzyl)-2-may-6
．． 7-Simethoxy 1,2,3,4-tetrahydroisoquinoline (100 ~) was dissolved in 1 ml of dimethylformamide, 20'In9 of sodium hydride was suspended, 64 da of n-propylbromide was added dropwise with stirring, and the mixture was further stirred at room temperature. Stir for 60 minutes.

After the reaction was completed, the reaction mixture was washed with water, dried, and the solvent was distilled off, yielding 1-(4-glopoxypenzyl)-2-methyl-6,7-simethoxy1゜2.3.4-tetrahydroisoquinoline. can get.

Yield 98%, melting point 140-141°C (hydrochloride), MS
: M 355, m/z 206° Example 2 l-(4-hydroxybenzyl)-2-methyl-6,7
-Simethoxy 1,2,3,4-tetrahydroisoquinoline 10rn9 is dissolved in 11nt of dimethylformamide, 20ml of sodium hydride is suspended, 33rn9 of n-butyl bromide is added dropwise while stirring, and the mixture is further stirred at room temperature for 30 minutes. After the reaction was completed, the solvent was distilled off after washing with water and drying, resulting in 1-(4-butoxybenzyl)-2
-Methyl-6,7-simethoxy-1,2,3,4-tetrahydroisoquinoline is obtained. Yield 96%, melting point 1
44-145°C (hydrochloride), MS: M”397, m/
z 206° Example 3 l-(4-hydroxybenzyl)-2-methyl-6,7
-Dissolve 1100 W of cymethoxy 1.2,3.4-tetrahydroisoquinoline in 1 d of dimethylformamide, suspend 201 ng of sodium hydride, dropwise add 63 μ of n-hexylbromide while stirring, and add 3 ml of n-hexylbromide at room temperature.
Stir for 0 minutes.

After the reaction is completed, the solvent is distilled off after washing with water and drying.
1-(4-hexyloxybenzyl)-2-methyl-6
,7-Simethoxy1,2,3,4-tetrahydroisoquinoline is obtained. Yield 95%, melting point 155.5-1
56.5°C (hydrochloride), MS: M”397, m/z
206゜Example 4 l-(4-hydroxybenzyl)-2-methyl-6,7
-Simethoxy 1.2,3.4-tetrahydroisoquinoline 80o1n9, bromobenzene 3°0W19, copper oxide ([[) 0.5.9, potassium carbonate A 0.5 i,
0.5 ml of hirisin and 0.5 ml of dimethylformamide
The ml mixture is stirred for 2 hours at 190'C under nitrogen flow. Thereafter, the reaction mixture was filtered under reduced pressure, 50° of 2N sodium hydroxide solution was added to solution F, and extracted with ether. The ether layer was extracted three times with 2 Q ml of 1N hydrochloric acid, the pH was adjusted to 10 by adding 2N sodium hydroxide solution to the hydrochloric acid layer, and the mixture was extracted with ether. The extract was washed with water, dried, and the solvent was distilled off, resulting in 1-(4-phenoxybenzyl)
-2-methyl-6,7-simethoxy1,2,3.4-
Tetrahydroisoquinoline is obtained. Yield 60%, melting point 196-197°C (hydrochloride), MS: M 389
, m/z 206.190.77゜Example 5 l-(4-hydroxybenzyl)-2-methyl-6.7
-Simethoxy 1,2,3,4-tetrahytroin A mixture of 100 ml of quinoline, 2 rul of cyclohexene and 20 ml of boron trifluoride etherate is stirred at 100 DEG C. for 1.5 hours. From now on, the reaction mixture was mixed with 53 ml of 1N hydrochloric acid.
and extract with ether. Then add 2N- to the hydrochloric acid layer.
Add sodium hydroxide solution to pH 10 and extract with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off under reduced pressure to obtain 1-(4-cyclohexyloxybenzyl)-2-methyl-6,7-dimethoxy-1,2,3
, 4-tetrahydroisoquinoline is obtained. Yield 98
%, melting point 157-158°C, MS: M+395, m
/ z 206° Formulation Example 1 l-(4-hexyloxybenzyl)-2-methyl-6
, 7-Simethoxy 1.2.3.4-Tetrahydroisoquinoline 250m9, Lactose 3.0 II, Corn Starch 1.53Il, Hydroxypropyl Cellulose 20
0.0 mm and 20 parts of magnesium stearate are mixed, granulated, and then compressed into tablets with a weight of 1001 n9 per tablet.

Formulation Example 2 l-(4-phenoxybenzyl)-2-methyl-6,7
-Simethoxy 1,2,3.4-tetrahydroisoquinoline 500rn9, lactose 2.5g, potato starch 1.
75 g of crystalline cellulose 24 CL ~ and calcium stearate 101 n9 are mixed, and this mixture is filled into capsules to form capsules containing 101 n9 of the active ingredient per capsule.

Formulation Example 3 l-(4-Cyclohexyloxybenzyl)-2-methyl-6,7-simethoxy 1.2,3.4-tetrahydroisoquinoline hydrochloride 500rn9 and D-mannitol 1.0g were dissolved in distilled water for injection. The total amount is 100 go. This solution is passed through a 0.2μ membrane filter, dispensed into 2 ml ampoules, sealed and heat sterilized to obtain an injection.

Test Example According to the method of Ardley et al. (see Pritish Journal Φop Heratology Vol. 19, p. 7, 1970),
Washed platelet suspension from fresh rabbit blood (5 x 10'/m)
was prepared. A test compound is added to this platelet suspension,
Next, collagen (40 μm 171
6') and the degree of aggregation was measured by Born's method (see Journal of Physiology, Vol. 162, p. 67, 1962).

As test compounds, the compounds obtained in Examples 1 to 5,
and 1-(4-methoxybenzyl)-2 for comparison
-Methyl-6,7-simethoxy1.2,3.4-tetrahydroisoquinoline (Comparative Example 1), 1-(4-ethoxybenzyl)-2-methyl-6,7-simethoxy1.
2,3,4-tetrahydroisoquinoline (Comparative Example 2) and cephalanthine (Comparative Example 3) were used. The test results are shown in Table 1. The numerical values in the table are aggregation rates (%) when the control is taken as 100%. Also, the IC of the test compound.

＋ Mouret −−−1−−%−−−÷ Dislike JE −
1 ÷ 9t Rollo ^ Le ∆ is Comparative Examples 1 and 2
It has a superior action compared to the compounds of Examples 3 to 5.
The compound is known to have an effect equivalent to that of cephalanthine.

Table 2

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. , a cycloalkyl group or a phenyl group). 2. General formulas ▲ Numerical formulas, chemical formulas, tables, etc. An antiplatelet aggregation agent containing a benzylisoquinoline derivative represented by the group (indicating a group) or an acid addition salt thereof as an active ingredient.