JPS6016424B2 - carbostyril derivatives - Google Patents

Description

[Detailed description of the invention] The present invention relates to carbostyril derivatives.

The compound of the present invention is a novel compound disclosed in the literature, and has the general formula: Indicates a bond or a double bond, respectively.

] and its acid addition salts. This compound has an inhibitory effect on 8-adrenergic function and is extremely useful as an 8-flocker agent that selectively acts on 8-receptors, as well as a drug for heart diseases such as arrhythmia and angina pectoris, and an antihypertensive drug. It is also useful as The above single-pronged type (1)
Examples of the lower alkyl group represented by R include straight-chain or branched alkyl groups having 1 to 6 carbon atoms, specifically methyl, ethyl, propyl, isopropyl, butyl, ten-butyl, Examples include bentyl and hexyl groups.

The phenoxyalkyl group represented by R2 has 1 carbon number
Examples include groups in which a straight mirror or branched alkylene group and a phenyl group are bonded to each other, and specific examples include penzyl, 2-phenylethyl, 1-phenylethyl, 2-methyl-2-phenylpropyl, and 4-6. -Phenylbutyl, 6
-phenylhexyl, 1,1-dimethyl-2-phenylethyl, 2-methyl-4-phenylbutyl, 2-methyl-3-phenylpropyl and the like. Examples of the phenoxyalkyl group include groups in which a linear or branched alkylene group having 1 to 6 carbon atoms and a phenoxy group are bonded, and specifically, phenoxymethyl, 2-phenoxyethyl, 1-phenoxyethyl, 2-methyl-2-phenoxypropyl, 4-phenoxybutyl, 6-phenoxyhexyl, 1,1-dimethyl-2-phenoxyethyl, 2-methyl-4-phenoxybutyl, 2-methyl- Examples include 3-phenopropyl group. The above phenylalkyl group and phenoxyalkyl group may have one or two identical or different substituents on the phenyl ring. Examples of such substituents include lower alkoxy groups such as methoxy, ethoxy, propoxy, and isopropoxy groups, alkylene dioxy groups such as methylenedioxy and ethylenedioxy groups, and halogen atoms such as chlorine, bromine, iodine, and fluorine atoms. Examples include atoms. Such phenyl groups include 2-(4-fluorophenyl)ethyl, 2-(
3,4-dibromophenyl)ethyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(3,4-methylenedioxyphenyl)ethyl, 3-(3,5-dichlorophenyl)propyl , 2-(2-isopropoxyphenyl)
Ethyl, 2-(3,4-dimethoxyphenoxy)ethyl, 2-(3,5-dimethoxyphenoxy)ethyl, 2-(3,4-ethylenedioxyphenoxy)ethyl, 2-
(4-fluorophenoxy)ethyl, 2-((4-ter
Examples include t-butoxyphenoxy)ethyl, 3-(3,5-dichlorophenoxy)propyl, and 2-(4-methoxyphenoxy)ethyl groups. Representative compounds of the present invention are listed below.

0 8-methoxy-5-[3-(3,4-dimethoxyphenethylamino)-2-hydro.

xypropoxy]-3,4-dihydrocarbostyryl o
8-ethoxy-5-(3-phenethylami/12-hydroxypropoxy) 3,4-dihydrocarbostyryl o 8-methoxy5-[3-(1,1-dimethyl-2
-phenylethylamine/)-2-hydro.

xyproboxy]-3,4-dihydrocarbostyryl o
8-propoxy-5-[3-(6-phenylhexylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl o 8-isopropoxy-5-[3
1(2-Methyl-2-phenylpropylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyryl o 8-propoxy5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxy Propoxy]
-3,4-dihydrocarbostyryl o 8-butoxy 5-[3-(3,4-dimethoxyphenethylamino)-12-hyde xypropoxy]-3,4-dihydrocarbostyryl o 8-te-butoxy 5 - [31 (3,
4-Dimethoxyphenethylamino)-2-hydroxypropoxy]-3,4-dihydro Rubostyryl 8-hexyloxy-5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-1 3,4
-dihydrocarbostyryl o 8-butoxy-5-[3
-(1,1-dimethyl-2-phenylethylamino)-
2-hydroxypropoxy]-3,4-dihydrocarbostyryl o 8-poxy5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-rubostyryl o 8-methoxy-5-[3- (3,
4-dimethoxyphenethylamino)-2-hydroxypropoxy] 8-butoxy-5-[3
-(1,1-dimethyl-2-phenylethylamino)-2-hydroxypropoxy]carbostyryl o 8-t
en-butoxy5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]carpostyryl o 8-propoxy-5-[3-(3,4-methylenedioxyphenethylamino)-1 2-hydroxypropoxy]3,4-dihydrocarbostyryl o 8-butoxy5-{3-[4-(3,4-dimethoxyphenyl)butylamino]-2-hydroxypropoxy}-3
,4-dihydrocarbostyryl o 8-propoxy 5
-{3-[3-(3,4-dimethoxyfer)butylamino]-2-hydroxypropoxy}-3,4-dihydrocarbostyryl o 8-butoxy5-[3-(4-chlorophenethylamino) -2-hydroxypropoxy]-3,4-dihydrocarbostyryl o 8-ethoxy5-[3-(3,4-dichlorophenethylamino)-
2-hydroxypropoxy]-3,4-dihydrocarbostyryl o 8-propoxy-5-[3-(3,4-methylenedioxyphenethylamino)-22-hydroxypropoxy]carbostyryl o 8-poxy-5-( 3
-(4-Chlorphenethylamino)-2-hydroxypropoxy] Rubostyril o 8-Butoxy5-{3
-[2-(4-methoxyphenoxy)ethylamino]-
2-hydroxypropoxy}-3,4-dihydrocarbostyryl o 8-propoxy-5-{3-[2-(3,
4-dimethoxyphenoxy)ethylamino]-2-hydroxypropoxy}-3,4-dihydrocarbostyryl0 8-ethoxy5-(3-phenoxymethylamino-2-hydroxypropoxy)-3,4-dihydrocarbo styryl o 8-butoxy5-{3-[2-(1,
1-dimethyl-2-phenoxylamino)ethylamino]-121-hydroxypropoxy}-3,4-dihydrocarbostyryl0 8-ethoxy5-[3-(6-phenoxyxylamino)-121-hydroxypropoxy]-3 ,4-
Dihydrocarbostyryl o 8-butoxy {3-[2
1(4-chlorophenoxy)ethylamino]121hydroxypropoxy}13,4-dihydrocarbostyryl o 8-propoxy-{31[21(3,4-methylenedioxyphenoxy)ethyl Amino]-2-hydroxypropoxy}-3,4-dihydrocarbostyryl o 8
-Butoxy-{3-2-(4-methoxyphenoxy)ethylamino]-2-hydroxypropoxy]rubostyril o 8-propoxy-5-{3-[2-(3,4-dimethoxyphenoxy)ethylamino) [1-2-hydroxybropoxy]carbostyryl o 8-propoxy 5
-{3-(3,4-dimethoxyphenoxy)butylamino]-2-hydroxypropoxy}-3,4-dihydrocarpostyryl o 8-butoxy{3-[2-(4-
Chlorphenoxy)ethylamino]-2-hydroxypropoxy]ropostyryl o 8-ethoxy-5-(3
-phenethylamino-2-hydroxypropoxy. ) The compound of the present invention can be synthesized by various methods, one example being a known general formula [wherein Y represents or (X is a halogen atom)].

R, and the bonds at the 3rd and 4th positions are the same as above.

] and an amine represented by the general formula R2NQ (m) [wherein R2 is the same as above].

Compound Y of general formula (0) is a compound (epoxycarbostyryl conductor) and general formula (
The reaction with the compound m) can be carried out without a solvent, but for example, in addition to ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene, and xylene, water, dimethylformamide, and more preferably methanol and ethanol. The reaction is preferably carried out in a polar solvent such as , isopropanol or the like.

The amount of the compound of formula (m) to be used is not particularly limited and can be appropriately selected from a wide range, but it is usually used in an equimolar to excess amount, preferably 3 to 8 times the molar amount relative to the epoxycarbostyryl derivative. . The reaction is usually carried out at 0 to 10,000 qo, preferably 0 to 70 qo. General formula (0)
Compounds in which Y is (halogenocarbostyryl derivative) and the general formula (
The reaction with compound m) is carried out in the presence or absence of a base.

Examples of such bases include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and the like. Among them, it is preferable to use sodium carbonate and potassium carbonate. The reaction may be carried out without a solvent or in a solvent such as lower alcohols such as methanol, ethanol, propanol, and isopropanol, ethers such as ether, dioxane, and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene, and xylene, and water. It will be held in Preferably, the reaction is carried out in a solvent such as methanol, ethanol or isopropanol. The amount of the compound of formula (blood) to be used is not particularly limited and can be appropriately selected from a wide range, but it is usually in excess of the halogenocarbostyryl derivative, preferably 3 to 8
It is better to use twice the molar amount. The reaction is usually 0 to 1000○
, preferably 20 to 8 pi. Furthermore, the compound of the present invention can also be used with a mixture of the above-mentioned epoxycarbostyryl derivatives and halogenocarbostyryl derivatives.

When such a mixture is used, the same base as above may or may not be used, and the solvent and the amount of the compound of formula (m) are the same as above. The reaction proceeds at a temperature of 0 to 100 qC, preferably 50 to 80 pm. The compound of the present invention thus obtained can be made into an acid addition salt by reacting with a pharmacologically acceptable acid. Such acids include hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, inorganic acids such as thiocyanic acid, acetic acid, propionic acid, oxalic acid, maleic acid, succinic acid, tartaric acid, fumaric acid, malic acid, and ethane sulfone. Examples include organic acids such as acid and p-toluensulfonic acid. After completion of the reaction, the compound of the present invention is isolated from the reaction mixture according to conventional methods.

For example, it is purified by conventional means such as fractional recrystallization, column chromatography, and thin layer chromatography. Incidentally, the present invention naturally includes optical isomers of the carbostyril derivative of general formula (1).

In order to further clarify the present invention, production examples are listed below. Production Example 1 1.0 g of 5-(2,3-epoxypropoxy)-8-methoxy-3,4-dihydrocarbostyryl was dissolved in 15 parts of methanol, and 2-(3,4-dimethoxyphenyl)ethylamine 1. Add the gunwale and heat for 4 hours at 40-50°C.

After the reaction is complete, the solvent is distilled off under reduced pressure and the residue is purified by silica gel column chromatography. (Silica gel: Wako C-2
00, eluate: chloroform). Thereafter, the mixture is converted into a hydrochloride salt with ethanol saturated with hydrogen chloride gas, and the ethanol is distilled off under reduced pressure. Recrystallize the residue from ethanol to obtain colorless amorphous crystal 8.
-Methoxy 5-{3-[2-(3,4-dimethoxyphenyl)ethylamino]-2-hydroxypropoxy}
1.5 g of 3,4-dihydrocarbostyryl hydrochloride is obtained. Melting point: 154-1570 Production Examples 2-8 The compounds shown in the table below were obtained in the same manner as in Production Example 1.

Production Example 9 5-(2,3-epoxypropoxy)-8-propoxy 3,4-dihydrocarpostyryl 1. Dissolve the female in 15 ml of methanol and add 2-(3,4-dimethoxyphenyl)
Ethylamine 1. Add the oni and heat for 12 hours at 15-20℃.

Claims (1)

[Claims] 1 General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R_1 is a lower alkyl group, R_2 is a phenylalkyl group or a phenoxyalkyl group, The bond at position represents a single bond or a double bond, respectively. ] Carbostyryl derivatives and acid addition salts thereof.