KR830002895B1 - Process for preparing carbostyril derivatives - Google Patents

Abstract

Carboxtyril derivs. I were prepd. by reaction o II with III (R1=H, C1˜C6 alkyl, C2˜C4 alkyl, C1˜C4 alkylene, phenylalkyl; R2=H, C1˜C4 alkyl, phenyl,; R3=H, OH, C1˜C4 alkyl C1˜C4 alkanoyloxy, 3, 4, C1˜C4 alkyl 5-trimethoxybenzoyloxy; R4=H, C1˜C4 alkly; R6=H, OH, C1˜C4 alkyl; X=halo n=0˜2; Q=2˜3l, m=0˜6,l+m<=6; R13=halo, C1˜C4 alkyl, alkoxy C3˜C8 cyclo alkyl; DM E=-NH2, IV). Thus, 2g 5-[2-hydroxy-3-(4-phenypipe-razinyl)propoxy -3,4-dihydrocarbostyril in 30mL acetone was mixed with 12mL acetyl chloride and heated for 10 hrs. The resulting filtrate ws treated with chloroform to give. 0.5g 5-[2-acetyloxy-3-(4-phenyl piperazinyl) propoxy -3, 4-dihydro-carbostyril.

Description

Method for preparing carbostyryl derivative

The present invention relates to a method for preparing a novel carbostyryl derivative, which will be described in detail by reacting a compound of the following general formula (2) with a compound of the following general formula (3) of the carbostyryl derivative of the following general formula (1) It relates to a manufacturing method.

Wherein, R ¹ is a phenyl having an alkynyl group, an alkylene group having from 1 to 4 carbon atoms having from alkenyl groups, 2 to 4 carbon atoms having an alkyl group having from hydrogen atoms, 1 to 6 carbon atoms, and those 2 to 4 carbon atoms An alkyl group and R ² represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a phenyl group and R ³ represents a hydrogen atom, a hydroxy group or an alkyl group having 1 to 4 carbon atoms, an alkanoyl oxy group having 1 to 4 carbon atoms or Represents a 3, 4, 5-trimethoxybenzoyloxy group, R ⁴ represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, R ⁶ represents a hydrogen atom, a hydroxy group, or an alkyl group having from 1 to 4 carbon atoms, and X is Represents a halogen atom, n represents an integer of 0 or 1 or 2, Q represents an integer of 2 or 3, l and m represent integers of 0 or 1-6, respectively, but the sum of l and m is greater than 6 Number and R ¹³ is a cycloalkyl having from phenyl group, 3 to 8 carbon atoms having 1 to 3 substituents selected from the group consisting of alkoxy groups having from, 1 to 4 carbon atoms having from halogen atoms, alkyl groups from 1 to 4 carbon atoms, the substituents As an alkyl group having 1 to 4 carbon atoms having a phenyl group or an alkanoyloxy group having 1 to 4 carbon atoms,

D is a general formula

(Wherein Q is as described above, A represents a ethylene group which may be substituted with an alkyl group having 1 to 4 carbon atoms as a substituent, and X ⁹ may be substituted with a halogen atom or a halogen atom similarly) ) Or -NH ₂ group

E is -NH ₂ or general formula

을 나타낼 때는 E는 -NH₂기를 나타내고, 또 D가 -NH₂기를 나타낼 때는 E는 일반식

을 나타내며, 카르보스티릴 골격중 3- 및 4-위치 사이의 탄소-탄소 결합은 단일 결합이거나 이중 결합을 나타내며,Wherein A and Q are as described above and X ¹⁰ represents a halogen or other replaceable group capable of a similar substitution reaction with a halogen atom, provided that D is a general formula

When E represents a -NH ₂ group, and when D represents a -NH ₂ group, E represents a general formula.

Wherein the carbon-carbon bond between 3- and 4-position in the carbostyryl backbone is a single bond or represents a double bond,

General formula

The substitution position of the side chain of is any of 4-, 5-, 6-, 7- or 8-position of the carbostyryl skeleton,

의 측쇄의 치환 위치는 카르보스티릴 골격중 4-, 5-, 6-, 7- 또는 8-위치의 어느 하나이다.General formula

The substitution position of the side chain of is any of 4-, 5-, 6-, 7- or 8-position in the carbostyryl skeleton.

The compounds of the present invention are useful as antihistamines and central nervous system regulators because they have an antihistamine effect and a central nervous system regulation effect.

This is described in the following medical and pharmaceutical literature [Goodman. Gliman: “Pharmacoloy” (the first volume); “YAKUBUTSU CHIRYO NO KISO TO RINSHO” (Fundamental and Clinic of Pharmacotherapy), pp. 781-835 [Published by Hirogawa Shoten Corporation in 1974]; “SHIN-OYO YAKURIGAKU” (Kew applied Pharmacology) by Hisashi Uno, pp. 307-319 (published in 1970 by Nagai Shoten Co., Ltd.); "SHIN YAKU TO RINSHO" (Journal of New Remedies & Clinic) Vol. 20, No. 11, pp. 129-133 (1971) and “Kiso To RINSHO” (Laboratory and Clinic), Vol. 10, No. 10, pp. 17-27 (1976)], antihistamines generally do not inhibit the sequestration of complex histamines caused by allergen-antibody reactions, but the combination of the active forms of histamine and histamine receptors Synthetic antagonism) to inhibit antihistamine effects. Therefore, the antihistamines according to the present invention sneeze, nasal congestion, pain in the eyes, nose and throat, respiratory diseases, hay fever, hay fever, acute uriticaria (itch, swelling, overheating, etc.), conduits Edema, pruritus, atopic pyrritis, insect bites, dermatitis in contact forms such as urushi kabure, lymphatics, urticaria in diseases, edema dysfunction, allergic rhinitis, allergic contact It is effective as a therapeutic and prophylactic agent for various allergic diseases and symptoms resulting from the combination of histamine and histamine-receptor such as salt or corneitis. Antihistamines can also be used as a supplement to treat general anaphylactic hypersensitivity in which hormones other than histamine play an important role. Antihistamines can also be used as diagnostic reagents for measuring the acidity of the stomach.

And the type of the document to include the relevant pharmaceutical of the formula 5- (3-tert- butyl-2-hydroxy) propoxy-3,4-dihydro-carbostyril hydrochloride in the predetermined range (PA ₂ = 5. 02 Has been reported to have antihistamine effects.

〔Reference; OYO YAKURI (Applied pharmacology) Vol. 11, No. 4, pp. 437-462 (1976)

In addition, the Federal Republic of Germany Patent Application No. 2302027 (corresponding to U.S. Patent No. 3,910,924) discloses (2-hydroxy-3-amino) -propoxy-(3,4-di) having a β-adrener blocking action. Hydro) -carbostyryl derivatives are mentioned.

However, it is not known that the novel compounds of the present invention have antihistamine and central neuromodulation effects.

Central nervous system regulatory activity of the compounds according to the present invention can be confirmed from having a strong regulatory action against fighting the mice isolated for a long time. Compared with diazepam, which is known as a compound having strong activity, the compounds of the present invention have a significant modulatory effect on the fight of mice, so the compounds of the present invention are particularly useful as sedatives, mental depression treatments and the like. In addition, the compounds of the present invention have a strong effect of increasing anesthesia and hypnosis when used in a mixture of anesthetics and hypnotics.

The present invention is also useful as a preoperative anesthesia and hypnotic inducer in addition to the above strong regulatory effects on the fighting action of mice.

With respect to CNS activity, the compounds of the present invention are characterized by muscle relaxation, apopoline-vomiting action, eyelid sewage, hypothermia, spontaneous movement control, rat hypermotor control, antimethanepetamine action, methane It has several pharmacological activities, such as lowering toxicity, analgesic and anticholinergic activity, anti-noradrenaline action of the petamine group, but weak pharmacological action for antichlorine action, cardio-inhibition action, and induction of degradation. . Therefore, the compounds of the present invention do not exhibit side effects such as thirst, constipation, stool, Parkinson's disease, and delayed dyskinesia, which are exhibited by conventional central nervous system regulators, but are not associated with central muscle relaxants, face-inducing agents, preoperative agents, antipsychotics, and sedatives. Useful as anti-rage, anti-depressant and analgesic.

As used herein, an "alkyl group having 1 to 6 carbon atoms" refers to an alkyl group having a linear or branched form having 1 to 6 carbon atoms, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group isobutyl group, tert-butyl Group, sec-butylphenyl group, and hexyl group.

The "alkenyl group having 2 to 4 carbon atoms" refers to a linear or branched alkenyl group having 2 to 4 carbon atoms and includes, for example, a vinyl group, 2-butenyl group, 1-methyl-allyl group and the like. The term "alkylyl group having 2 to 4 carbon atoms" includes, for example, an ethynyl group, 2-propynyl group, 2-butynyl group, 1-methyl-2-propynyl group, and the like, The term "phenylalkyl group of alkylene group" means a phenylalkyl group composed of a linear and branched alkylene group having 1 to 4 carbon atoms and a phenyl group. Examples thereof include benzyl-2-phenylethyl group, 1-phenylethyl group, 3-phenylpropyl group, 4-phenylbutyl group, 1,1-dimethyl-2-phenylethyl group, and the like. The term “alkyl group having 1 to 4 carbon atoms” means a straight or branched alkyl group having 1 to 4 carbon atoms, and examples thereof include methyl group, ethyl group, propyl group, isopropyl group, butyl group and isobutyl group. , tert-butyl group and the like. The term "halogen atom" includes, for example, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The term "alkanoyloxy group having 1 to 4 carbon atoms" means a straight or branched alkanoyloxy group having 1 to 4 carbon atoms, for example, formyloxy group, acetyloxy group, propionyloxy group, butyl And a ryloxy group. The term "C _3-8 cycloalkyl group" means a cycloalkyl group having 3 to 8 carbon atoms and includes, for example, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and a cyclooctyl group. The term "C _1-4 -alkoxy group" means a straight or branched alkoxy group having 1 to 4 carbon atoms, examples of which are methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxide A period, an isobutoxy group, a tert-butoxy group, and the like.

Specific examples of the phenyl group having 1 to 3 substituents selected from halogen atom, C _1-4 alkyl group and C _1-4 alkoxy group include phenyl group, 2-methoxyphenyl group, 4-methoxyphenyl group, 3-methoxyphenyl group, 2 Ethoxyphenyl group, 3,4,5-trimethoxyphenyl group, 3-isopropoxyphenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-ethylphenyl group, 4-butylphenyl group, 3, 4-diethylphenyl group, 3,4,5-trimethylphenyl group, 2-chlorophenyl group, 3-bromophenyl group, fluorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-fluorophenyl group, 3,4- Dichlorophenyl group, 3,4,5-trichlorophenyl group, 4-chloro-3-methylphenyl group, 2-methoxy-3-chlorophenyl group, 4-bromophenyl group, 2-bromophenyl group, 4-iodophenyl group It includes.

The term “C _1-4 alkanoyl group” refers to a straight or branched chain alkanoyl group having 1 to 4 carbon atoms, and examples thereof include formyl group, acetyl group, propionyl group, butyryl group and isobutyryl group. do.

Specific examples of the C _1-4 alkyl group having one substituent such as hydroxy group, panyl group or C _1-4 alkanoyloxy group include hydroxymethyl group, 2-hydroxyethyl group, 3-hydroxypropyl group, 4-hydroxy Butyl group, 2-hydroxypropyl group, acetyloxymethyl group, 2-acetyloxyethyl group, 2-propionyloxyethyl group, 3-acetyloxypropyl group, 4-butyloxybutyl group, 2-acetyloxypropyl group, benzyl group , 2-phenylethyl group, 1-phenylethyl group, 3-phenylpropyl group, 4-phenylbutyl group, 1,1-dimethyl-2-phenylethyl group.

Representative examples of compounds prepared according to the invention are listed below. As described for each compound, it means that the carbon-carbon bond between the 3- and 4-positions of the carbostryl attack is a double bond. For example, “5- [2-hydroxy-3- (4-phenylpiperazinyl) -propoxy] -3,4-dihydrocarbostyryl and 5- [2-hydroxy-3- (4 -Phenylpiperazinyl) propoxy] -carbostyryl "is" 5- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3 , 4-dehydrogen compound ”.

6- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6- [3-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- [4-hydroxy-5- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-5- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-ethyl-6- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-7- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-8- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1- (3-methylbutyl) -5- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-hexyl-6- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-allyl-5- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1- (2-butenyl) -6- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-allyl-7- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-benzyl-5- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1- (3-phenylpropoxy) -5- [2-hydroxy-3-4- (4-methylphenyl) phenylpiperazinyl] propoxy] -3,4-dihydrocarbostyryl and its 3,4 Dehydrogenated compounds,

1- (4-phenylbutyl) -6- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-benzyl-7- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-benzyl-8- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy-3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-5-bromo-6- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6-fluoro-7- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-benzyl-5-chloro-8- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6,8-dichloro-5- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6-chloro-8-bromo-7- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-5,6-dibromo-8- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-5- {2-hydroxy-3- [4- (2-chlorophenyl) -piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6- {2-hydroxy-3- [4- (3-bromophenyl) -piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {2-hydroxy-3- [4- (4-fluorophenyl) -piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

5- {2-hydroxy-3- [4- (2-methylphenyl) -piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-benzyl-6- {2-hydroxy-3- [4- (3-methylphenyl) -piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-5- {2-hydroxy-3- [4- (4-ethylphenyl) -piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6- {2-hydroxy-3- [4- (2-propylphenyl) -piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

5- {2-hydroxy-3- [4- (2-methoxyphenyl) -piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-6- {2-hydroxy-3-4- (3-methoxyphenyl) -piperazinylpropoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {2-hydroxy-3- [4- (4-methoxyphenyl) -piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6- {2-hydroxy-3- [4- (2-ethoxyphenyl) -piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

8-chloro-5- {2-hydroxy-3- [4- (4-chlorophenyl) -piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-6-chloro-7- {2-hydroxy-3- [4- (4-chlorophenyl) -piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4 Dehydrogenated compounds,

1-allyl-6-chloro-7- {2-hydroxy-3- [4- (4-methoxyphenyl) -piperazinyl] propoxy} -3,4-dihydrocarbostyryl and 3, 4-dehydrogen compound,

6-chloro-5- {2-hydroxy-3- [4- (4-methylphenyl) -piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6,8-dibromo-5-2- {hydroxy-3- [4- (4-methylphenyl) -piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4- Dehydrogenation compounds,

5- (4-phenylpiperazinylmethoxy) -3,4-dihydrocarbostyryl and its 3,4 dehydrogen compound,

5- [2- (4-phenylpiperazinyl) ethoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

8- [2- (4-phenylpiperazinyl) ethoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

5- [3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- [3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6- [7- (4-phenylpiperazinyl) heptyloxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

5- [4- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- [4- (4-phenylpiperazinyl) butoxy-3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6- [5- (4-phenylpiperazinyl) pentyloxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

8- [5- (4-phenylpiperazinyl) pentyloxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7-6- (4-phenylpiperazinyl) hexyloxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-5- [2- (4-phenylpiperazinyl) ethoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-6- [3- (4-phenylpiperazinyl) propoxy-3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-7- [3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-hexyl-6- [3- (4-phenylpiperazinyl) propoxy-3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-allyl-5- [3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-allyl-6- [3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1- (1-methylallyl) -7- [3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1- (2-propynyl) -7- [3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-benzyl-5- [2- (4-phenylpiperazinyl) ethoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1- (2-phenylethyl) -6- [3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1- (4-phenylbutyl) -5- [3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-benzyl-7- [3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

5- {3- [4- (2-methoxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

5- {3- [4- (3-methylphenyl) piperazinyl] propoxy-3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6- {3- [4- (4-methylphenyl) piperazy] ylpropoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {2- [4- (4-propylphenyl) piperazinyl] ethoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

5- {3- [4- (4-chlorophenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6- {3- [4- (4-bromophenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {2- [4- (2-chlorophenyl) piperazinyl] ethoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-5- {3- [4- (4-chlorophenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-benzyl-6- {2- [4- (2-bromophenyl) piperazinyl] ethoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-allyl-7- {4- [4- (4-bromophenyl) piperazinyl] butoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-6- {3- [4- (4-methylphenyl) piperazinyl] propoxy-3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-benzyl-5- {3- [4- (2-methylphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-7- {3- [4- (4-methyloxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-benzyl-5- {3- [4- (4-methyloxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

8-bromo-5- [3- (4-piperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-5-bromo-6- [2- (4-phenylpiperazinyl) ethoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6-fluoro-7- [3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6-chloro-5- [2- (4-phenylpiperazinyl) ethoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6-chloro-5- {4- [4- (4-phenyl) piperazinyl] -butoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-allyl-6-chloro-7- {2- [4- (4-methoxyphenyl) piperazinyl] ethoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6,8-dichloro-5- [2- (4-phenylpiperazinyl) ethoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6-chloro-8-bromo-7- [3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-5,6-dibromo-8- [2- (4-phenylpiperazinyl) ethoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

8-chloro-5- {3- [4- (4-chlorophenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-6-chloro-7- {2- [4- (4-chlorophenyl) piperazinyl] ethoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-benzyl-6,8-dichloro-5- {2- [4- (2-bromophenyl) piperazinyl] ethoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound ,

7- {3- [4- (2-methoxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {3- [4- (3-methoxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {3- [4- (4-methoxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {3- [4- (2-ethoxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-7- {3- [4- (2-methoxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-allyl-7- {3- [4- (2-methoxyoxyphenol) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-benzyl-7- {3- [4- (2-methoxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1- (2-propynyl) -7- {3-4- (2-methoxyphenyl) piperazinylpropoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {3- [4- (3,4-dimethoxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {3- [4- (3,4,5-trimethoxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

5- {3- [4- (3,4-dimethoxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-7- {3- [4- (3,4-dimethoxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-benzyl-7- {3- [4-3,4-dichlorophenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {3- [4-3,4-dimethylphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

5- [2-methyl-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- [2-methyl-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

4-methyl-6- [3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- [4-methyl-5- (4-phenylpiperazinyl) pentyoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- [2-ethyl-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-7- [2-methyl-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-benzyl-7- [2-methyl-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-allyl-7- [2-methyl-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1- (2-pripinyl) -7- [2-methyl-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6-chloro-5- [2-methyl-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6-chloro-8-bromo-7- [2-methyl-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {2-methyl-3- [4- (2-methoxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-benzyl-5- {2-methyl-4- [4- (4-methylphenyl) piperazinyl] -butoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {2-methyl-3- [4-3,4dimethoxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- [2-methyl-3- (3-methyl-4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

5- [2-acetyloxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-6- [2-propionyloxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {2-acetyloxy-3- [4- (2-methoxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {3-acetyloxy-5- [4- (4-methylphenyl) piperazinyl] pentyloxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-benzyl- {2-acetyloxy-3- [4- (4-chlorophenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-allyl-8- [2-acetyloxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-chloro-5- [2-acetyloxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-ethyl-7- [2-acetyloxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1- (2-propynyl) -7- [2-acetyloxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {2-isobutyloxy-3- [4- (2-methoxyphenyl) piperazinyl] propoxy-3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

4- [2-acetyloxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

4-methyl-7- [2-acetyloxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

4-phenyl-7- [2-acetyloxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

5- [2- (3,4,5-trimethoxybenzoyloxy) -3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound ,

1-benzyl-6- [2- (3,4,5-trimethoxybenzoyloxy) -3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and 3, 4-dehydrogen compound,

7- [2- (3,4,5-trimethoxybenzoyloxy) -3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound ,

1-methyl-7- [2- (3,4,5-trimethoxybenzoyloxy) -3- (4-phenylpipezinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4 Dehydrogenated compounds,

7- {2- (3,4,5-trimethoxybenzoyloxy) -3- [4- (2-methoxyphenyl) phenazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compounds,

1-benzyl-7- [2- (3,4,5-trimethoxybenzoyloxy) -3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and 3, 4-dehydrogen compound,

4-methyl-7- [2- (3,4,5-trimethoxybenzoyloxy) -3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and 3, 4-dehydrogen compound,

4-phenyl-8- [2- (3,4,5-trimethoxybenzoyloxy) -3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and 3, 4-dehydrogen compound,

1-allyl-6-chloro-7- {2- (3,4,5-trimethoxybenzoyloxy) -3- [4- (3,4-dimethoxyphenyl) phenyrazinyl] propoxy-3, 4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- [2-hydroxy-3- (3-methyl-4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- [3- (3-methyl-4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {3- [3-methyl-4- (4-chlorophenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- [3- (1-methyl-4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {3- [3-methyl-4- (2-methoxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

8- [3- (3-ethyl-4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

4- [3- (3-metal-4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl- [3- (3-methyl-4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-benzyl- [3- (1-methyl-4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

4-methyl-7- [3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

4-phenyl-7- {3- [4- (2-methoxyphenyl) piperazinyl] propoxy} -3, -dihydrocarbostyryl and its 3,4-dehydrogen compound,

4- [3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

4-ethyl-7- {3- [4- (2-methoxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1,4-dimethyl-7- [3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-benzyl-4-phenyl-7- {3- [4- (2-chlorophenyl) piperazinyl] propoxy-3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

5- [2-hydroxy-3- (4-cyclohexylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6- [2-acetyloxy-3- (4-cyclohexylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- [3- (4-cyclohexylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

4- [3- (4-cyclohexylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-7- [3- (4-cyclohexylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-benzyl-7- [2-methyl-3- (4-cyclohexylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

5- [3- (4-cyclohexylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

4-methyl-7- [3- (4-cyclohexylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

4-phenyl-6- [2-methyl-3- (4-cyclohexylpiperazinyl) propoxy-3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1- (2-propynyl) -7- [4- (4-cyclohexylpiperazinyl) butoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6,8-dichloro-5- [3- (4-cyclohexylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

5- [2-acetyloxy-3- (4-benzylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6- [2-hydroxy-3- (4-benzylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- [3- (4-benzylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

4- [3- (4-benzylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6- [3- (4-benzylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-7- [2-methyl-3- (4-benzylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-benzyl-7- [3- (4-benzylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

4-methyl-7- [3- (4-benzylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

4-phenyl-7- [3- (4-benzylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-allyl-6- [4-benzylpiperazinyl) butoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1- (2-propynyl) -8- [2- (4-benzylpiperazinyl) ethoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6,8-dichloro-5- [3- (4-benzylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- [2-acetyloxy-3- (4-benzylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {3- [4- (1-phenylethyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {3- [4- (4-phenylbutyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

5- {2-hydroxy-3- [4- (2-acetyloxy) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {3- [4- (2-acetyloxyethyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

8- {2-methyl-3- [4- (2-acetyloxyethyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

4- {3- [4- (2-acetyloxyethyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {3- [4- (4-butyloxybutyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-7- {3- [4- (2-acetyloxyethyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

4-phenyl-7- {3- [4- (2-acetyloxyethyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {2-hydroxy-3- [4- (2-acetyloxyethyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

5- {2-acetyloxy-3- [4- (2-hydroxyethyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {3- [4- (2-hydroxyethyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {3- [4- (4-hydroxybutyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {3- [4- (1-hydroxyethyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

4- {2- [4- (2-hydroxyethyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

4-methyl-7- {3- [4- (2-hydroxyethyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {2-hydroxy-3- [4- (2-hydroxyethyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

5- [3- (4-benzoylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- [2-acetyloxy-3- (4-benzoylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- [3- (4-benzoylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

8- [3- (4-benzoylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-7- [3- (4-benzoylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

4-phenyl-7- [3- (4-benzoylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1- (2-propynyl) -5- [2- (4-benzoylpiperazinyl) ethoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6-chloro-5- [4- (4-benzoylpiperazinyl) butoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

5- [3- (4-acetylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- [3- (4-acetylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

8- [2-acetyloxy-3- (4-acetylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-benzyl-7- [3- (4-acetylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

4-methyl-7- [3- (4-acetylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

4- [3- (4-acetylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- [3- (4-acetylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl- [4- (4-propionylpiperazinyl) butoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

8-bromo-5- [3- (4-acetylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- [3- (4-phenyl-hexahydro-1,4-diazepin-1-yl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6- [3- (4-phenyl-hexahydro-1,4-diazepin-1-yl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

5- [3- (4-phenyl-hexahydro-1,4-diazepin-1-yl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

4- [4- (4-phenyl-hexahydro-1,4-diazepin-1-yl) butoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {3- [4- (2-methoxyphenyl) -hexahydro-1,4-diazepin-1-yl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6- {2- [4- (4-chlorophenyl) -hexahydro-1,4-diazepin-1-yl] ethoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound ,

7- [3- (4-phenyl-hexahydro-1,4-diazepin-1-yl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- [2-hydroxy-3- (4-phenyl-hexahydro-1,4-diazepin-1-yl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound ,

5- [2-4-methyl-3- (4-phenyl-hexahydro-1,4-diazepin-1-yl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-7- [3- (4-phenyl-hexahydro-1,4-diazepin-1-yl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-benzyl-7- [3- (4-phenyl-hexahydro-1,4-diazepin-1-yl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

4-phenyl-7- [3- (4-phenyl-hexahydro-1,4-diazepin-1-yl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

8-chloro-5- [3- (4-phenyl-hexahydro-1,4-diazepin-1-yl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {2-hydroxy-3- [4- (4-chlorophenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6-chloro-7- {2-hydroxy-3- [4- (2-methoxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4--dehydrogen compound ,

4-methyl-7- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6- {3- [4- (2-methyloxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-methyl-5- [3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

5- {2- [4- (4-methylphenyl) piperazinyl] ethoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

8- {3- [4- (2-methoxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {3- [4- (4-methoxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

5- {3- [4- (2-ethoxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6-chloro-7- [3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

6-bromo-7-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {3- [4- (2-chlorophenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {3- [4- (3-chlorofe) ylpiperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {3- [4- (4-chlorophenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-allyl-7- [3- (4-phenylpiperazinyl) propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-hexyl-7- [3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

1-benzyl-5- [3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

7- {3- [4- (3-fluorophenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

5- {3- [4- (2-fluorophenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

5- {3- [4- (3-fluorophenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

5- {3- [4- (3,4,5-trimethoxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl and its 3,4-dehydrogen compound,

Among the carbostyryl compounds of the general formula (1) of the present invention, compounds in which the carbon-carbon bonds at the 3- and 4- positions in the carbostyryl skeleton are single bonds are located at the 3- and 4- positions by dehydrogenation. The carbon-carbon bond can be converted to a compound which is a double bond.

In addition, among the carbostyryl compounds of the general formula (1) of the present invention, compounds in which the carbon-bonds at the 3- and 4- positions in the carbostyryl skeleton are double bonds are positioned at 3- and 4- positions by catalytic reduction. Carbon-carbon bonds are single bonds and can also be converted to compounds without halogen atoms, alkenyl and alkynyl groups.

In this method, the compounds of formula (1) can be converted to their acid-addition salts by reacting with pharmaceutically toxic acids, including inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, bromic acid, oxalic acid, Organic acids such as maleic acid, fumaric acid, malic acid, tartaric acid, citric acid and benzoic acid. Desired compounds prepared by the methods of the various schemes described above can be easily separated and purified by conventional separation methods such as solvent extraction, dilution, recrystallization, column chromatography and thin layer chromatography.

Compounds of the invention include or their engineering isomers.

Compounds of formula (1) as antihistamines and central nervous system modulators may be used in the form of pharmaceutical compositions with conventional pharmaceutical nontoxic carriers. Examples of carriers that can be used include fillers, diluents, binders, wetting agents, disintegrating agents, surfactants, lubricants, and the like, depending on the desired form of the pharmaceutical composition.

There is no particular limitation on dosage unit form and the compound is used in any desired unit form as antihistamines and central nervous system modifiers, and traditional unit forms are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions and Suspensions) and ointments. Carriers widely used in the art for the purpose of making tablets such as lactose, sugar, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, fillers such as: water, ethanol, propanol, single syrup, Binders such as glucose, starch solution, gelatin solution, carboxy methylcellulose, shellac, methylcellulose, calcium phosphate and polyvinylpyrrolidone: dried starch, sodium alginate, agar powder, lanai powder, sodium bicarbonate, carbonate Degradants such as calcium, Tweens, sodium laurylsulfate, monoglycerides of stearic acid, starch, lactose: degradants such as sugar, stearin, peanut butter, hydrogenated oil: tetravalent ammonium base, sodium lauryl sulfate Absorption accelerators like: Glycerin or starch Wetting agents: like starch, lactose, kaolin, bentonite, colloidal ciric acid Complexing agent: Use of purified talc, stearic acid salts, boric acid powder, Macrogol, styrene glycol, such as solid lubricants in a poly.

To form pills, carriers widely known in the art, such as glucose, lactose, starch, peanut butter, hydrogenated vegetable oils, accelerators such as kaolin and talc, powdered gum arabic, powdered taracanthant, gelatin and ethanol Binders: Degradants such as laminaria and agar are used. In the case of tablets, tablets may be further coated with sugar, coated with sugar, coated with sugar, tablets coated with gelatinous coating, tablets coated with enteric coating, tablets coated with film, or multilayer tablets. I can make it.

In order to form suppositories, carriers which are widely used in the art are known and include, for example, polystyrene glycol, peanut butter, higher alcohols, esters of higher alcohols, gelatin and semi-synthesized glycerides.

To make an injectable preparation, the solutions and suspensions are sterilized and preferably isotonic with respect to blood. Injectable preparations may be any of the carriers normally used in the formulation, e.g. water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene Sorbitol, sorbitan esters are used. In this case, an appropriate amount of sodium chloride, glucose or glycerin may be added to have isotonicity. Ordinary solubilizers, buffers, analgesics, preservatives may also be added, as well as colorings, flavorings, sweeteners and other agents as necessary to the desired formulation.

Diluents widely used in the art are known for preparing in the form of pastes and creams, including, for example, white petrolatum, paraffin, glycerin, cellulose derivatives, polyethyleneglycol, silicone and bentonite. .

The amount of the compound of formula (1) or acid acid salt thereof contained in the antihistamine and central nervous system regulator is not particularly limited and is selected within a wide range, but usually 1 to 70% by weight of the total composition is suitable.

The antihistamines and central nervous system regulators described above may be used in various forms depending on the purpose without any limitation. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally, injections are injected subcutaneously or in admixture with injections such as glucose or amino acid solutions, injections are required as a single muscle Administration is by injection, subcutaneous injection, intravenous injection or the like. Suppositories are administered intranasally and ointments are coated.

The unit dose of the antihistamine and the central nervous system of the present invention is appropriately selected depending on the conditions of use, purpose and symptoms, but usually 40 μg to 2 mg / kg. A pharmaceutical composition comprising one general formula (1) compound or an acid addition salt thereof is administered 3 to 4 times a day.

Formulation Example of Tablet-1

Formulation Example of Tablet-2

By the usual manufacturing method, the tablet which has the said composition is manufactured.

The results of the pharmacological test for the compound of the present invention are as follows.

(I) antihistamine activity test

As a test method for measuring the antihistamine activity of a compound in vivo, a method using mormot's ileum is reasonable.

Moromote males weighing 300-500 g were released by bleeding blood, and the 15 cm-long ileum was removed from the ileum area. Then, the Tirod solution (0.8 g NaCl, 0.2 g KCl, 0.2 g CaCl ₂ , 1.0 g Soak in glucose, 1.0 g NaHCO ₃ , 0 (065 g NaHPO ₄ .2H ₂ O and 0.2135 g MgCl ₂ .6H ₂ O to make up to 1000 ml total). Subsequently, the tissues of the ileum were cut into lengths of 2.5 to 3.0 cm, suspended in an engine bath filled with 30 ml of a thiroded solution, and the bath was kept at 36 ° C. and mixed gas composed of 5% carbon dioxide and 95% oxygen. Blow into the bath. Infuse 10 minutes and then add 10M- ⁶ histamine to investigate the sensitivity of the tissue and obtain a response curve (comparison) for the dose of histamine. After the dose of the histamine-response curve is constant, 10 g ⁻⁶ / ml of the compound to be tested is added to the bath and 5 minutes later, further histamine is added to obtain a dose-response curve. The ileum of the ileum is recorded on a pen-recorder using isotonic [TD-112S manufactured by converter Nihon Koden]. The antihistamine activity of the test compound was determined by the “Van Rossam” method [JM Van Rossam; Arch. Inst. Pharmacodyn. 143, shown as PA ₂ value by 299 (1963]. The results are shown in Table 1.

Test compound

Compounds of the Invention (Nos. 1-39)

30. 5- [3- (4-cyclohexylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl

TABLE 1

(Ⅱ) Anesthesia and Sleep Increase Activity

(A) Halotan anesthetic increased activity

One test group consists of 10 mice using ddy-type male mice weighing about 20 g. An aqueous gum gum suspension of test compound (80 mg of compound to be tested, 1 g of Arabic gum / 100 ml of physiological saline) is administered orally to each mouse in a dose of 8 mg / kg body weight. One hour after administration, each mouse was placed in a gas breathing chamber (13 × 13 × 24 cm) and contained oxygen containing 4% halotan [2-bromo-2-chloro-1,1,1-trifluoroethane]. Gas is injected into the respiratory chamber for 3 minutes at a rate of 2 l / min. Anesthetized rats are removed from the respiratory tract and the infusion of anesthetics and time to wake up are measured by righting reflex as an index. Mice of the comparative group were administered with a dose of 0.1ml / 10g body weight in a 1% Arabic gum solution. [Reference: M.J. Turnbull and Watkins: Br. J. Pharmac., 58. 27-35 (1976)].

The results are shown in Table 2.

TABLE 2

(B) halotan anesthesia increased activity

The amount of test compound administered orally was 0.5 mg / kg to determine the relationship between the dosage and the increase in anesthetic activity. 1mg / kg 2mg / kg and 4mg / kg change in 4 steps

Except for Keen, the same method as described for (II) -A was used.

The results are shown in Table 3.

TABLE 3

(C) hexabarbital sleep increase activity

Ddy-type male mice weighing 20-25 g are fasted 24 hours and one test group consists of 10 mice. An aqueous gum gum suspension of the test compound (0.05 g test compound and 1 g arabic gum / 100 ml physiological saline solution) is administered orally in the dosages described in Table 4. One hour after administration, 0.7% of hexabarbital sodium salt is administered subcutaneously at a dose of 70 mg / kg body weight. The time between start of sleep and wake-up is measured by righting reflex as an index [Ref. A. M. Hjort, De E.J. Beer and D. W. Passett: J. Pharmac. Exptl. Ther., 63, 421 (1963)].

TABLE 4

(III) Activity to Inhibit Fighting Behavior in Mice Isolated from Long-Term Singleization

Male mice of ddy-hematoma weighing 15 to 20 g each are reared for 1 month, and one test group consists of 10 pairs of mice. Each component of the pair of mice chooses to continually fight for 30 seconds when one mouse is placed in the cage of another mouse. ED ₅₀ values can be determined by administration to each group of test mice. The activity of inhibiting the fighting behavior of the test compound is determined to be positive if the administered mice continue to fight for 5 seconds within 1 minute. If the mouse continues to fight for more than 5 seconds, isolate the less injured mouse [Reference: CY Yen, RL Stanger and N. Millman; Arch. nt. Pharmarmacodyn. m 123, 179 (1959)].

The results are shown in Table 5.

TABLE 5

(Iv) analgesic activity

Ddy-line male mice weighing between 15 and 23 grams were used and each test group consisted of 10 mice. The compound to be tested is administered orally by a method similar to that described in (II). After 15 minutes of feeding, 0.1 ml of an aqueous 0.6% acetic acid solution / 10 g body weight is injected subcutaneously. In mice administered orally with the control compound (haloperidol), injection is performed 110 minutes after administration. The number of suffering mice shown after 10 minutes is counted for 10 minutes and the ED ₅₀ value of each compound is calculated by comparing the number of suffering mice shown by the control group [Ref. R. Koster, M. Anderson and EI Debeer; Fed. Proc., 18, 412, (1959).

TABLE 6

(Ⅴ) Toxicity test (LD ₅₀ )

One test group consists of 10 mice using ddy-hematoma mice weighing 20-22 g.

Oral administration:

Test compounds are suspended in an aqueous 1% Arabian gum physiological saline solution.

Subcutaneous administration:

Test compounds are dissolved in 50% aqueous propylene glycol solution.

The results are shown in Table 7.

Table 7 LD ₅₀

LD ₅₀ values (oral tours) of the compounds of the invention other than Compound Nos. 6,7,17,31 and 39 were measured at 800 mg / kg or more using male mice of ddy-hematoma.

Some reference examples for the preparation of compounds to be used as starting materials for the preparation of the desired compounds of the invention are given below.

Reference Example 1

20.5 g of 5-acetyloxy-3,4-dihydrocarbostyryl was dissolved in 200 ml of acetic acid, stirred with cooling with water, and then 60 ml of acetic acid urine containing 91 g of bromine were added dropwise for 30 minutes. The reaction is carried out for 2 hours at the temperature. The reaction mixture was poured into 300 ml of water and left to stand for 3 hours. Then, the precipitated crystals were separated by filtration and recrystallized with methanol. They were colorless needles and 21 g of 8-bromo having a melting point of 237 to 239 ° C. -5-acetyloxy-3,4-dihydrocarbosdiryl is obtained. The obtained 21 g of 8-bromo-5-acetyloxy-3,4-dihydrocarbosidryl was dispersed in 150 ml of 8N hydrochloric acid, and the dispersion was refluxed for 3 hours, and then cooled, and the resulting insoluble substance was separated by filtration. After washing with water, drying and recrystallization with methanol-water to give 14 g of 8-bromo-5-hydroxy-3,4-dihydrocarbostyryl having colorless needles and melting points of 212 to 213 캜.

Reference Example 2

Dissolve 16.4 g of 5-hydroxy-3,4-dihydrocarbostyryl in 300 ml of acetic acid, then stir the solution at room temperature, add 50 ml of acetic acid solution containing 7 g of chlorine dropwise, and stir for 3 hours. And react. The reaction mixture is poured into 500 ml of water and left to stand for 1 hour to precipitate. The precipitate is separated by filtration, dried after washing with water and recrystallized from ethanol-water to give a colorless needle. 13.5 having a melting point of 209 to 210 ° C. g of 6-chloro-5-hydroxy-3,4-dihydrocarbostyryl is obtained.

Reference Example 3

16.4 g of 5-hydroxy-3,4-dihydrocarbostyryl is dissolved in 300 ml of acetic acid and stirred at room temperature, followed by the dropwise addition of 80 ml of acetic acid solution containing 16.4 g of chlorine, followed by stirring for 3 hours. Let's do it. When the crude crystal is recrystallized from methanol in a similar manner as described in Reference Example 2, 16 g of 6,8-dichloro-5-hydroxy-3,4-dica having a melting point of 259 to 260 캜 as colorless acicular crystal Levostyryl is obtained.

Reference Example 4

35.4 g of 7-methoxy-3,4-dihydrocarbostyryl is dissolved in 300 ml of acetic acid, stirred under ice-cooling conditions, and then 100 ml of acetic acid solution containing 27 g of sulfuryl chloride is added dropwise and left overnight. The reaction mixture was poured into 1 liter of ice water, and the resulting precipitate was separated by filtration, washed with water, dried, and then recrystallized with methanol to give 30 g of 6-chloro-7-methoxy-3,4 as a colorless needle. Dihydrocarbostyryl is lingual.

The resulting 30 g of 6-chloro-7-methoxy-3,4-dihydrocarbostyryl was dispersed in 300 ml of an aqueous 47% bromic acid solution and then heated under reflux for 4 hours, followed by cooling the reaction mixture. The insoluble matters were separated, washed with water, dried over water, and recrystallized with methanol-chloroform to yield 25 g of 6-chloro-7-hydroxy-3,4-dihydrocarbostyryl having a melting point of 264 to 266 ° C as colorless needles.

Reference Example 5

35 g of 8-methoxy-3,4-dihydrocarbostyryl is dissolved in 200 ml of acetic acid and stirred under ice cooling, then 100 ml of acetic acid solution containing 16 g of chlorine is added dropwise and left overnight. When the reaction mixture is poured into 1 liter of water, precipitates are formed. The precipitates are separated by filtration, washed with water, and then recrystallized from chloroform. Methoxy-3,4-dihydrocarbostyryl is obtained.

The obtained 42 g of 5,6-dichloro-8-methoxy-3,4-dihydrocarbostyryl is dispersed in 500 ml of an aqueous 47% -bromic acid solution and then heated under reflux for 4 hours. The reaction mixture is then cooled and the resulting insoluble material is isolated by filtration and washed with water. Recrystallization of the obtained crude crystal with methanol yields 29 g of 5,6-dichloro-8-hydroxy-3,4-dihydrocarbostyryl having colorless needles and a melting point of 233 to 235 ° C.

Reference Example 6

In a similar manner as in Reference Example 5, colorless acicular crystal (recrystallized solvent is methanol) and (decomposition) 8-bromo-5-hydroxycarbostyryl having a melting point of 266 to 267 ° C is obtained.

Reference Example 7

22.7 g of 8-bromo-5-methoxy-3,4-dihydrocarbostyryl and 25 g of cuprous chloride were mixed with 100 ml of dimethyl sulfoxide and then stirred at 135-140 ° C. for 4 hours. After heating, when the reaction is completed, 200 g of ice and 50 ml of concentrated hydrochloric acid are mixed in the reaction mixture, and then stirred at room temperature for 1 hour. The precipitated crystals are separated by filtration, first washed with dilute hydrochloric acid, then with water and dried. Recrystallization of the obtained crude crystals with ligroin-benzene yields 13 g of 8-chloro-5-methoxy-3,4-dihydrocarbostyryl having a melting point of 165 DEG C as pale orange acicular crystals.

13 g of 8-chloro-5-methoxy-3,4-dihydrocarbostyryl and 35 g of aluminum chloride obtained were dispersed in 30 ml of benzene, and then heated under reflux for 2 hours, and then the reaction mixture was poured into ice-water. Precipitation occurs when the stock is separated, which is separated by filtration, washed with water, and recrystallized with isopropanol after drying. It is a colorless acicular crystal with 8 g of 8-chloro-5-hydroxy-3,4-di having a melting point of 206 to 207 캜. Hydrocarbostyryl is obtained.

Reference Example 8

20.0 g of 8-chloro-5-hydroxy-3,4-dihydrocarbostyryl and 18 g of potassium carbonate are suspended in 160 ml of isopropyl alcohol, 40 ml of epichlorohydrin is added, and then 70 to 80 ° C. React for 6 hours at. The residue obtained by concentrating the reaction mixture under reduced pressure was added with 100 ml of 2N-sodium hydroxide under ice-cooling, the resulting insoluble substance was separated by filtration, washed with water, and the crude crystals were recrystallized from isopanol to obtain colorless needles. 18.5 g of 8-chloro-5- (2,3-epoxypropoxy) -3,4-dihydrocarbostyryl having a melting point of 161 to 165 캜 is obtained.

Reference Example 9

20.0 g of 6-chloro-7-hydroxy-3,4-dihydrocarbostyryl, 3.7 g, and sodium hydroxide are mixed in 100 ml of methanol, stirred for 3 hours, and then 150 ml of epichlorohydrin is excited. And heated at reflux for 5 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to dryness, and the resulting residue was mixed with 100 ml of 2N-sodium hydroxide and stirred sufficiently. The crude crystals obtained by filtration and washing with water to dry the insoluble substance were recrystallized with methanol-ethanol to give 19.7 g of 6-chloro-7- (2,3-epoxypropoxy) -3 having a melting point of 190 to 192 캜 as colorless crystals 4-dihydrocarbostyryl is obtained.

Reference Examples 10 to 13

The compounds obtained according to methods similar to those in Reference Examples 8-9 are as follows.

Reference Example 14

24.3 g of 8-bromo-5-hydroxy-3,4-dihydrocarbostyryl and 9 g of potassium hydroxide are mixed together with 150 ml of isopropanol and stirred at 70 to 80 ° C. for 30 minutes, followed by 25 g 1,3-bromochloropropane was added and heated to reflux for 6 hours under reflux. After completion of the reaction, 200 ml of 2N aqueous sodium hydroxide solution is added to the reaction mixture to form an insoluble substance, which is separated by filtration and washed with water. Recrystallization of the obtained crude crystals with ethanol yields 21.5 g of 8-bromo-5- (3-chloropropoxy) -3,4-dihydrocarbostyryl having a melting point of 184 to 185 ° C as colorless needles. Lose.

Reference Example 15

5 g of 6-chloro-8-bromo-7-hydroxy-3,4-dihydrocarbostyryl and 3 g of sodium hydroxide are mixed with 12 ml of isopropanol and stirred at 50 to 60 ° C. for 1 hour and 10 ml of 3-bromo-1-chloropropane is added and stirred at 70-80 ° C. for 6 hours. The reaction mixture is concentrated under reduced pressure, dried and the residue is extracted with chloroform. The chloroform layer was washed with water and dried, and the residue obtained by distilling the chloroform was recrystallized with ethanol. It was colorless needle crystal. Propoxy) -3,4-dihydrocarbostyryl is obtained.

Reference Examples 16 to 19

The compound obtained according to a method similar to that in Reference Example 15 was as follows.

Example 1

2 g of 5- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl are mixed in 30 ml of acetone, to which 12 ml of acetyl chloride is added Heat under reflux for 10 hours. After cooling the reaction mixture, the precipitated product is collected by filtration and then washed with acetone. The obtained crude crystals are dissolved in 80 ml of water, made basic with ammonia-water, extracted with chloroform, dried and the chloroform is distilled off. Purification of the residue by silica gel chromatography gave colorless crystals and a melting point of 0.5 g of 5- [2-acetyloxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarb having a melting point of 159 to 161 캜. Bostyryl is obtained.

Example 2

In a manner similar to that in Example 1, 7- [2-acetyloxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydro having colorless crystals and a melting point of 130 to 132 캜; Get carbostyryl.

Example 3

1.9 g of 5- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] 3,4-dihydrocarbostyryl and 0.24 g of sodium hydride are dispersed in 40 ml of xylene and 1 under reflux conditions. After heating for an hour, the temperature of the dissolution tank is lowered to 13 ° C. or lower, and 1.40 g of 3,4,5-trimethoxybenzoyl chloride is slowly added, followed by heating under reflux for 8 hours. Xylene is distilled off from the reaction mixture, 80 ml of water is added to the residue, and chloroform is distilled off. The residue was recrystallized from ethanol to give 1.5 g of 5- [2-3,4,5-trimethoxybenzoyloxy) -3- (4-phenylpiperazinyl) propoxy having colorless crystals and a melting point of 125-127 ° C. ], 3,4-dihydrocarbostyryl is obtained.

Example 4

20 g of 5- (3-piperazinylpropoxy) -3,4-dihydrocarbostyryl with 15 ml of acetic anhydride and 10 ml of acetic acid are heated under reflux for 5 hours. The reaction mixture is then concentrated to dryness under reduced pressure. Recrystallization of the residue with ethanol yields 5- [3- (4-acetylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl having colorless needles and a melting point of 143 to 145 占 폚.

Example 5

2.0 g of 5- (3-piperazinylpropoxy) -3,4-dihydrocarbostyryl and 1.5 g of benzoyl chloride are mixed with 20 ml of pyridine and stirred at 50-60 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, dried and the residue was converted to its hydrochloride and recrystallized from methanol to give 5- [3- (4-benzoylpiperazinyl) propoxy having colorless plate crystals with a melting point of 240 ° C. (decomposition). ], 3,4-dihydrocarbostyryl hydrochloride is obtained.

Example 6

20 g of 5- (3-piperazinylpropoxy) -3,4-dihydrocasbostyryl, 3 ml of ethyl-2-bromoacetate and 1.5 ml of triacetylamine are stirred at 50-60 ° C. for 8 hours. While mixing with 20 ml of dimethylformamide. To the viscous residue obtained by concentrating the reaction mixture under reduced pressure, 30 ml of 2% aqueous sodium hydrogen carbonate solution is added and extracted with chloroform. The chloroform layer is washed with water and dried, and then chloroform is distilled off. The residue was purified by silica gel chromatography and recrystallized from isopropanol to give 5- {3- [4- (2-acetyloxyethyl) piperazinyl] propoxy} -3 having a melting point of 131 to 132 占 폚 as a colorless needle. , 4-dihydrocarbostyryl is obtained.

Example 7

2.0 g of 5- {3- [4- (2-acetyloxyethyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl are mixed with 30 ml of methanol and 5 ml of concentrated hydrochloric acid and refluxed under cooling conditions. Heat for 2 hours. The reaction mixture was concentrated under reduced pressure, dried, and the obtained residue was recrystallized from water to give 5- {3- [4- (2-hydroxyethyl) piperazinyl having colorless flake crystals and a melting point of 158-159 占 폚. Propoxy} -3,4-dihydrocarbostyryl is obtained.

Example 8

2.5 g of 1-benzyl-5-hydroxy-3,4-dihydrocarbostyryl and 0.48 g of 50% oily sodium hydride were mixed with 30 ml of dimethyl formamide and stirred, followed by 4 g of 1- Add chloro-3- (4-phenylpiperazinyl) propane and warm to 50-60 ° C. for 2.5 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was extracted with chloroform. After distilling off the chloroform, the obtained residue was recrystallized with ligroin. As a pale yellow needle, 2.1 g of 1-benzyl-5- [ 3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl is obtained.

Example 9

2.5 g of 1-methyl-7- [3- (N, N-diethanolamino) propyl] -3,4-dihydrocarbostyryl with 4.5 g of N, N-diethyl-1,2,2- Trichlorovinylamide is dispersed in 80 ml of tetrahydrofuran and then heated under reflux cooling for 3 hours. The reaction mixture was then concentrated and purified by silica gel chromatography to 30 ml of 1.5 g of 1-methyl-7- {3- [bis (β-chloroethyl) amino] propoxy} -3,4-dihydrocarbostyryl It is dissolved in dimethylform amide, and 1.2 g of aniline and 1.5 g of triethylamine are added thereto, followed by heating at 80 to 90 ° C. for 3 hours. To the residue obtained by concentrating the reaction mixture under reduced pressure, 50 ml of 5% aqueous sodium hydrogen carbonate solution and 50 ml of chloroform are added. After the mixture is shaken, chloroform is collected. Chloroform was distilled off and the residue obtained was purified by silica gel chromatography, and then concentrated hydrochloric acid was added to convert the target compound into a hydrochloride salt. 0.7 g of 1-methyl-7- [3- (4-pentylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl dihydrochloride having colorless crystals and a melting point of 204 to 270 ° C is obtained.

[Examples 10 to 33]

The following compounds were prepared in a similar manner to the method in Example 9.

Example 34

2.3 g of 7- [3- (N, N-diethanol amino) propoxy] -3,4-dihydrocarbostyryl are dissolved in 30 ml of pyridine, where 40 g of p-tylchloride is cooled down. After stirring slowly for 2 hours, the reaction mixture is poured into ice water and the organic layer is extracted with chloroform. Chloroform is then distilled off and the residue is further distilled under reduced pressure to remove pyridine remaining in the reaction mixture. The obtained residue was dissolved in 50 ml of ethanol, and 1.5 g of m-fluoroaniline was added to the solution, followed by heating under reflux for 10 hours, followed by 0.3 g of sodium carbonate, followed by heating under reflux for 10 hours. The reaction mixture was concentrated under reduced pressure, shaken by adding 5% sodium bicarbonate-water and chloroform to the residue, and the chloroform layer was separated and collected. Chloroform was distilled off and the residue was recrystallized from methanol to give a yellowish brown needle crystal and 1.2 g of 7- {3- [4- (3-fluorophenyl) piperazinyl] propoxy} -3 having a melting point of 174 to 176 캜. , 4-dihydrocarbostyryl is obtained.

[Examples 35 to 59]

In the same manner as in Example 34, the following compound was prepared.

Example 60

1.6 g 5- [2-hydroxy-3-aminopropoxy] -3,4-dihydrocarbostyryl with 1.2 g bis-N, N- (2-bromoethyl) aniline and 0.56 g hydroxide Potassium was added to 50 ml butanol, followed by the addition of three drops of water. It is heated to reflux for 19 hours, the reaction is completed and the solvent is dried by distillation under reduced pressure. The residue thus obtained is dissolved in chloroform, the chloroform solution is washed with water, and the solvent is distilled off. The residue thus obtained was purified by silica gel chromatography (elution solvent: chloroform), and then the target compound was converted into a hydrochloride salt thereof. -3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl.

[Examples 61-70]

The following compound was prepared by a method similar to the method in Example 60.

Example 71

50 ml of butanol in 1.5 g of 7- [3-amino propoxy] -3,4-dihydrocarbostyryl, 1.2 g of bis-N, N- (2-bromoethyl) aniline and 0.56 g of potassium hydroxide 3 drops of water are added thereto and then heated to reflux for 20 hours. After the reaction is completed, the solvent is removed by distillation under reduced pressure. The obtained residue was dissolved in chloroform, the chloroform extraction layer was washed with water, chloroform was distilled off, and the obtained residue was purified by silica gel chromatography (elution solvent: chloroform) to convert the target compound into hydrochloride, and then methanol-ether. When recrystallized with 7- [3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl having colorless needles and melting point of 213 to 215 캜. Dihydrochloride. 3/4 hydrate is obtained.

[Examples 72 to 95]

In a similar manner to the method in Example 71, the following compounds were prepared.

Claims (1)

A method for producing a carbostyryl derivative of the following general formula (1), wherein the compound of the following general formula (2) is reacted with a compound of the following general formula (3)

In the above formula, R ¹ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms, a phenylalkyl group having an alkylene group having 1 to 4 carbon atoms R ² represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a phenyl group R ³ represents a hydrogen atom, a hydroxy group or an alkyl group having 1 to 4 carbon atoms, an alkanoyloxy group having 1 to 4 carbon atoms or a 3,4,5-trimethoxybenzoyloxy group R ⁴ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms R ⁶ represents a hydrogen atom, a hydroxy group or an alkyl group having 1 to 4 carbon atoms X represents a halogen atom n represents 0 or an integer of 1 or 2 Q represents an integer of 2 or 3 l and m represent 0 or an integer from 1 to 6, respectively, but the sum of l and m cannot exceed 6 R ¹³ is a phenyl group having 1 to 3 substituents selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a substituent Represents an alkyl group having 1 to 4 carbon atoms having a phenyl group or an alkanoyloxy group having 1 to 4 carbon atoms D is a general formula

(Wherein Q is as described above, A represents a ethylene group which may be substituted with an alkyl group having 1 to 4 carbon atoms as a substituent, and X ^{9 ′} can be substituted with a halogen atom or a halogen atom similarly) Or another NHN group) or -NH ₂ group E is -NH ₂ or general formula

Wherein A and Q are as described above and X ¹⁰ represents a halogen or another replaceable group capable of a similar substitution reaction with a halogen atom, provided that D is a general formula

When E represents a -NH ₂ group, and when D represents a -NH ₂ group, E represents a general formula.

Wherein the carbon-carbon bond between the 3- and 4- positions in the carbostyryl backbone is a single bond or represents a double bond, and

The substitution position of the side chain of is any of 4-, 5-, 6-, 7- or 8-position of the carbostyryl skeleton, General formula

The substitution position of the side chain of is any of 4-, 5-, 6-, 7- or 8-position of the carbostyryl skeleton.