KR830000772B1 - Method for preparing isoquinoline derivative - Google Patents

Abstract

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Description

Method for preparing isoquinoline derivative

The present invention relates to the following general formula (I) isoquinoline derivatives useful as medicaments exhibiting antidepressant action and methods for the preparation of physiologically toxic salts thereof.

In the above general formula

m is 1 or 2

의 아미노그룹을 나타내고 [상기에서 R₉은 하이드록시, C₁-C₄-알콕시, C₁-C₄-디알킬아미노, 에틸렌디옥시, 트리메틸렌디옥시 또는

여기서 R₆및 R₇은 같거나 다르고, 수소 또는 탄소수 1 내지 6의 직쇄 또는 측쇄 알킬기이거나, 또는 질소원자와 함께 탄소수 7까지의 복소환 고리를 나타낸다]의 그룹에 의해, 또는 임의 치환된 페닐에 의해 임의로 치환된 직쇄 또는 측쇄 C₁-C₆-알킬기, 또는 C₃-C₈-알케닐 또는 C₃-C₈-알키닐기이고,R ₁ is a general formula

Wherein the amino group of R ₉ is hydroxy, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -dialkylamino, ethylenedioxy, trimethylenedioxy or

Wherein R ₆ and R ₇ are the same or different and are hydrogen or a straight or branched chain alkyl group of 1 to 6 carbon atoms, or represent a heterocyclic ring of up to 7 carbon atoms together with a nitrogen atom; or to an optionally substituted phenyl Straight or branched C ₁ -C ₆ -alkyl group optionally substituted by C ₃ -C ₈ -alkenyl or C ₃ -C ₈ -alkynyl group,

R ₂ is halogen, hydroxy, nitro, amino or substituted amino (optionally substituted with one or two aliphatic, cycloaliphatic or aromatic hydrocarbon groups of 2 to 18 carbon atoms and optionally containing nitrogen atoms in the heterocyclic ring), A phenyl group optionally mono or disubstituted by acylamino, alkyl or alkoxy having 1 to 6 carbon atoms, benzyloxy or trifluoro methyl, or a pyridyl or thienyl group,

R ₃ is hydrogen, halogen, hydroxy, alkyl having 1 to 6 carbon atoms or alkoxy, nitro, amino, benzyloxy, methylenedioxy or ethylenedioxy.

Preferred substituents for R ₂ are halogen, nitro, a phenyl group optionally mono- or disubstituted by an alkyl or alkoxy group having 1 to 4 carbon atoms, or an amino group, and R ₃ is hydrogen, halogen, hydroxy, nitro, amino, carbon number 1-4 alkyl or alkoxy.

Particularly major substituents for R ₂ are phenyl groups optionally mono- or di-substituted with halogen, hydroxy, nitro, amino or methoxy groups, and substituents for R ₃ are hydrogen, halogen, hydroxy or methoxy groups, Preferably in the 6- and / or 7-position.

3-amino-4-phenyl-isoquinoline derivatives acting on the central nervous system and 3-piperazino isoquinoline, which exhibits strong inhibitory action against platelet aggregation, are described in German Publication Nos. 2, 030, 675 and 2, 503, 961 Isoquinolines with basic substituents in the 3-position have been found, each of which is described in the foregoing, and which has valuable pharmaceutical properties, in particular as psychotherapeutic agents.

The compound of formula (I), which is a compound of the present invention, is a compound of formula (II) wherein the alkylating agent of formula ZR ₉ or a formula Cl-CO ₂ (C ₁ -C ₄ ) -alkyl, wherein alkyl is hydroxy or Prepared by reaction with a chloroformic ester of _1- C ₄ -alkoxy) or a compound of the general formula Cl-COR ₈ .

In the above general formula

R ₂ , R ₃ , R ₉ and m are as defined in the general formula (I) above,

R ₄ is piperazin-1-yl,

Z is iodine, chlorine or bromine,

R ₈ is thienyl, furyl, pyridyl, phenyl group or a (winning C ₁ -C ₄ - alkoxy, methylenedioxy, is optionally substituted by hydroxy, nitro or amino-alkyl, C ₁ -C _4).

The compounds of the present invention have valuable therapeutic action. Therefore, these compounds have an action on the central nervous system in addition to their pharmaceutical properties.

Compounds of the present invention prevent seizures induced by current, prolong hexabarbital anesthesia, as well as sewage caused by tetrabenazine in rats. Because of this property, the compound of the present invention is used as an active ingredient of a drug having antidepressant action.

The novel compounds are used either alone or in admixture with physiologically toxic adjuvants or carriers. When administered orally, the active compound is formulated in a suitable dosage unit form, for example, in the form of tablets, gelatin capsules, aqueous, alcoholic or oily suspensions or aqueous alcoholic or oily solutions, by mixing with a substance customary for this purpose in a conventional manner. Make up. As an inert carrier, magnesium carbonate, tactose or corn starch are used, and the composition is prepared in the form of anhydrous or wet granules. As the oily carrier or solvent, in particular, vegetable and animal oils such as sunflower oil or cod liver oil are used.

A particular method of administration is intravenous injection. For this purpose the active compound or its physiologically toxic salts are dissolved together with conventional materials. Physiologically nontoxic salts of this kind are for example hydrochloric acid, hydrobromic acid or hydroiodic acid, phosphoric acid, sulfuric acid, methylsulfuric acid, amidosulfonic acid, nitric acid, formic acid, acetic acid, propionic acid, succinic acid, tartaric acid, lactic acid, malonic acid, Fumaric acid, oxalic acid, citric acid, malic acid, mucinic acid, benzoic acid, salicylic acid, aceturic acid, embonic acid, naphthalene-1, 5-disulfonic acid, ascorbic acid, phenylacetic acid, p-amino-salicylic acid, hydroxyethane-sulfonic acid, It is formed together with a synthetic resin containing benzene-sulfonic acid or an acid group, for example a resin having an ion exchange effect. Solvents of physiologically toxic salts of the active compounds for intravenous injection include water, physiological saline or alcohols such as ethanol, propanediol or glycerol, moreover sugar solutions such as glucose or mannrol solutions or mixtures of the various solvents described above. have.

The following examples illustrate the invention.

Example 1

3-N-butyl-piperazino-1-phenyl-isoquinoline

6.65 g 3-piperazino-1-phenyl-isoquinoline and 4.73 g N-butylbromide are refluxed in 150 ml toluene for 4 days with 4.88 g sodium carbonate and 0.2 g potassium iodide. Cool and the reaction mixture is washed with water, dried and concentrated. The remaining brown oil is treated with ethanol hydrochloric acid to give 5.7 g of crystalline hydrochloride of 3-N-butyl piperazino-1-phenyl-isoquinoline. Melting Point: 216 ~ 218 ℃

Example 2

3-N- [3- (4-fluorobenzoyl) -propyl] -piperazine-1-phenyl-isoquinoline

6.65 g 3-piperazino-1-phenyl-isoquinoline, 6.9 g W-chloro-4-fluorobutyrophenone, 4.88 g sodium carbonate and 0.2 g potassium iodide are refluxed in 150 ml toluene for 5 days. . Treatment as described in Example 1 and 8.4 g of the dark resin is crystallized with ethanol hydrochloric acid to obtain the hydrochloride form. Melting point: 217 to 220 ° C. According to the above method, the following compounds are obtained. 3- (4- (3- (4-fluorobenzoyl) -propyl) -piperazin-1-yl) -1- (4-chlorophenyl) -isoquinoline (oil), hydrochloride Melting point: 193-1960 ° C.

3- (4- (4-fluorobenzoyl) -piperazin-1-yl) -1-phenylisoquinoline Melting Point: 167-169 ° C.

3- (4- (3- (4-fluorobenzoyl) -propyl) -piperazin-1-yl) -1- (2-fluorophenyl) -isoquinoline (oil), hydrochloride Melting point: 195-198 ° C .

3- (4- (3- (4-fluorobenzoyl) -propyl) -piperazin-1-yl) -1- (2-methylphenyl) -isoquinoline (oil), hydrochloride Melting point: 172 to 175 ° C.

3- (4-n-butylpiperazin-1-yl) -1- (2-fluorophenyl) -isoquinoline (oil), hydrochloride Melting point: 165 to 167 ° C.

3- (4- (3- (4-fluorobenzoyl) -propyl) -1,4-diazacycloheptan-1-yl) -1-phenylisoquinoline (oil) hydrochloride Melting point: 198 to 201 ° C.

3- (4- (3- (2,4-Difluorobenzoyl) -propyl) -piperazin-1-yl) -1-phenylisoquinoline (oil), hydrochloride Melting point: 187-189 ° C.

3- (4- (3- (4-fluorobenzoyl) -propyl) -piperazin-1-yl) -1- (2-methoxyphenyl) -isoquinoline (oil) hydrochloride Melting point: 92-94 ° C.

3- (4-carboethoxypiperazin-1-yl) -1-phenylisoquinoline

2.4 g of chloroformic acid ethyl ester was added dropwise to 5.8 g of 3-piperazin-1-yl-1-phenylisoquinoline and 4.24 g of sodium carbonate dissolved in 100 ml of toluene at room temperature, and the reaction mixture was refluxed for 2 hours. The inorganic precipitate is filtered off and the toluene solution is washed twice with water. The solution is dried and the solvent is evaporated in vacuo. The residue is recrystallized from diisopropyl ether. Melting point: 111-113 ° C.

Claims (1)

The following general formula (II) compounds are substituted with an alkylating agent of the general formula ZR ₉ or a general formula Cl-CO ₂ (C ₁ -C ₄ ) -alkyl, wherein alkyl carries a hydroxy or C ₁ -C ₄ -alkoxy group A process for preparing isoquinoline derivatives of the following general formula (I) characterized by reacting with a chloroformic acid ester of or a compound of general formula Cl-COR ₈ .

In the general formula m is 1 or 2 R ₁ is a general formula

R ₂ is halogen, hydroxy, nitro, amino or substituted amino (optionally substituted with one or two aliphatic, cycloaliphatic or aromatic hydrocarbon groups of 2 to 18 carbon atoms and optionally containing nitrogen atoms in the heterocyclic ring) Or a phenyl group optionally mono or disubstituted by benzyloxy or trifluoromethyl by acylamino, alkyl or alkoxy each having 1 to 6 carbon atoms, or a pyridyl or thienyl group, R ₃ is hydrogen, halogen, hydr Oxy, alkyl or alkoxy, nitro, amino, benzyloxy, methylenedioxy or ethylenedioxy having 1 to 6 carbon atoms. Z is iodine, chlorine or bromine, R ₄ is piperazin-1-yl and R ₈ is thienyl, furyl, pyridyl, or phenyl group (this group is C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, Optionally substituted with methylenedioxy, hydroxy, nitro or amino) and R ₉ is hydroxy, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -dialkylamino, ethylenedioxy, trimethylenedioxy or

Optionally substituted by a group of R ₆ and R _{7 which} are the same or different and are hydrogen or a straight or branched chain alkyl group having 1 to 6 carbon atoms or a heterocyclic ring having up to 7 carbon atoms with a nitrogen atom A straight or branched C ₁ -C ₆ -alkyl group optionally substituted by phenyl, or a C ₃ -C ₈ -alkenyl or C ₃ -C ₈ -alkynyl group.