KR820002231B1 - Process for preparing novel carbostyril derivatives - Google Patents

Abstract

Carbostyrils I(R1 = H, lower alkyl, alkenyl alkny1; R2 = H, alkyl, phenyl; R3 = H, OH, alkyl, alkanoyloxy; R4 = H, alky1; r5=cycloalky1, pheny1, x = halogen; n = 0, 1, 2; Q = 2, 3; 1,m = 0 - 6 interger; l+m<=6), useful antihistamine and central nervous regulating agent, were prepd. by the reaction of compds. II and III. Thus, 5-(2,3-ethoxyporpoxy)-3,4-dihydrocarbostyril and 4-phenylpiperazine were dispersed into MeOOOH, reacted for 3hr at 50-60≰C, and concentrated to give colorless and needle type 5-≮2-hydroxy-3-(4-phenylpiperazinyl)propoxy≉-3,4-dihydrocarbostyilHCl.

Description

Method for preparing new carbostyryl derivative

The present invention relates to a method for producing a novel carbostyryl derivative, and more particularly to a method for producing a novel carbostyryl derivative represented by the following general formula (1) and acid addition salts thereof.

In the formula,

R ¹ is 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, or a phenylalkyl group having an alkylene group of 1 to 4 carbon atoms,

R ² is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a phenyl group,

R ³ is a hydrogen atom, a hydroxy group, 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 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,

R ⁵ has 1 to 3 substituted groups selected from the group consisting of a cycloalkyl group having 3 to 8 carbon atoms, a phenyl group (halogen atom, alkyl group having 1 to 4 carbon atoms and alkoxy group having 1 to 4 carbon atoms) An alkyl group having 1 to 4 carbon atoms (having one substitution group such as a phenyl group or an alkanoyloxa group having 1 to 4 carbon atoms), an alkanoyl group having 1 to 4 carbon atoms or a benzoyl group,

X is halogen,

n is 0 or an integer of 1 or 2,

Q is an integer of 2 or 3,

l and m are each 0 or an integer of 1 to 6, but the sum of l and m cannot exceed 6,

The carbon-carbon bonds at the 3- and 4- positions in the carbostyryl backbone are single or double bonds,

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

The compounds of the present invention have antihistamine and central nervous system control effects, and thus are useful as antihistamine and central nervous system regulators.

This is described in the following various medical and pharmaceutical literature references; Goodman, Gilman: "Pharmacology" (the first volume); "YAHUBUTSU CHIRYO NO KISO TO RINSHO" (Fundamental and Clinic of Pharmacotherapy), page 781-835 [Published by Hirogawa Shoten, 1974]; "SHIN-OYO YAKURIGAKU" (New applied pharmacology) by Hisashi Uno, published in 1970 by Nagai Shoten Company; "SHIN YAKU TO RINSHO" (Jouranal of New Remedies & Clinic) Vol 20, No 11, page 129-133 (1971) and "Kiso To RINSHO" (Laboratory and Clinic), Vol. 10, No. 10, page 17-27 (1976), antihistamines generally do not inhibit the sequestration of complex histamines caused by allergen-antibody reactions, but the active form of histamine and histamine receptor It inhibits association (synthetic antagonism) and shows 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.), Catheter edema, pruritus, atopic dermatitis, nasal bites, dermatitis in the form of contact such as urushi kabure, lymphatic fluid, uriticaria in the disease, edema dysfunction, allergic rhinitis, allergic contact It is effective as a therapeutic and prophylactic agent for various allergic diseases and symptoms caused by the combination of histamine and histamine-receptor such as salt or corneitis. Antihistamines can also be used as an adjunct to the treatment of common anaphylactic hyperplasia 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.

Several types of related pharmaceutical literature [see; OYO YAKURI (Applied pharmacology) Vol 11, No. 4, page 437 to 462 (1976), has a range of 5- (3-tert-butylamino-2-hydroxy) propoxy-3,4-dihydrocarbostyryl hydrochloride of the general formula (PA ₂ = 5.02) have been reported to exhibit antihistamine effects.

In addition, German Patent Application No. 2302027 (corresponding to US Pat. No. 3,910,924) discloses (2-hydroxy-3-amino) -propoxy- (3,4-dihydro) having a β-adrener blocking action. ) -Carbostyryl derivatives are mentioned.

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

Central nervous control 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 sleep when used in combination with anesthetics and hypnotics.

The compound of the present invention is also useful as a preliminary anesthetic and sleep inducing agent in addition to the above strong regulatory effects on fighting mice.

With respect to CNS activity, the compounds of the present invention are characterized by muscle relaxant, apomorphine-preventive action, eyelid sewage, hyposensitivity, spontaneous locomotor control, over-regulation of rats, anti-methane petamine action, It has several pharmacological activities, such as lowering toxicity, analgesic and anti-chorin and anti-noradrenaline effects of the methanepetamine group, but weak pharmacological action against anti-chlorine, cardio-inhibitory and ankylosing. . 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 modulators, but are not limited to central muscle relaxants, face-inducing agents, preoperative agents, antischizophrenia, and sedatives. Useful as anti-rage, anti-depressant and analgesic.

As used herein, the term "alkyl group having 1 to 6 carbon atoms" is 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, hexyl group and the like.

The term " alkenyl group having 2 to 4 carbon atoms " refers to a straight or branched alkenyl group having 2 to 4 carbon atoms, such as vinyl group, aryl group, 2-butenyl group, 1-methyl- Aryl groups and the like.

The term "alkynyl group having 2 to 4 carbon atoms" includes, for example, an ethyl group, 2-propynyl group, 2-butynyl group, 1-methyl-2-propynyl group, and the like.

The term " phenylalkyl group of alkylene group having 1 to 4 carbon atoms " means a phenylalkyl group consisting of alkylene groups and phenyl groups in straight and branched form having 1 to 4 carbon atoms, an example of which is 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 and butyl group. , Isobutyl group, tert-butyl group and the like.

Examples of the term "halogen atom" include fluorine atom, chlorine atom, bromine atom and 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 And a butyryloxy group group.

The term "C _3-8 cycloalkyl" means a cycloalkyl group having 3 to 8 carbon atoms and includes, for example, cyclopropyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group and 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, Butoxy group, isobutoxy group, tert-butoxy group and the like.

Specific examples of the phenyl group having 1 to 3 substituted groups 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-chloro Phenyl 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 and the like.

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 and the like.

Specific examples of the C _1-4 alkyl group having one substitution group such as a hydroxy group, a phenyl group or a C _1-4 alkanoyloxy group include a hydroxymethyl group, a 2-hydroxyethyl group and a 3-hydroxypropyl group. , 4-hydroxybutyl 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. A 3,4-dehydrogen compound as mentioned as a representative compound means that the carbon-carbon bond between the 3- and 4- positions in the carbostryl backbone is a double bond. For example, "5- [2-hydroxy-3- (4-phenylpiperazinyl) -propoxy] -3,4-dihydrocarabostyryl and 5- [2-hydroxy-3- (4 -Phenylpiperazinyl) propoxy] -carbostyryl "means" 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) pentyloxy] -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-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-dihydrocaabostyryl and its 3,4-dehydrogen compound,

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

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

1- (3-phenylpropoxy) -5- {2-hydroxy-3- [4- (4-methylphenyl) piperazinyl] propoxy} -3,4-dihydrocarabobostyryl and its 3, 4-dehydrogen compounds,

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

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

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

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

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

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

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

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

1-methyl-5,6-dibromo-8- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocabostyryl and its 3,4- Dehydrogenation Compound,

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

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

7- [2-hydroxy-3-4- (4-fluorophenyl) piperazinylpropoxy] -3,4-dihydrocarabostyryl and its 3,4-dehydrogen compound,

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

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

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

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

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

1-methyl-6- {2-hydroxy-3- [4- (3-methoxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarbobostyryl and its 3,4-dehydrogen compound,

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

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

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

1-methyl-6-chloro-7- {2-hydroxy-3- [4- (4-chlorophenyl) piperazinyl] propoxy} -3,4-dihydrocarabobostyryl and its 3,4- Dehydrogenation Compound,

1-allyl-6-chloro-7- {2-hydroxy-3- [4- (4-methoxyphenyl) piperazinyl] propoxy} -3,4-dihydrocarabobostyryl and its 3,4 Dehydrogenated compounds,

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

6,8-dibromo-5- {2-hydroxy-2- [4- (4-methylphenyl) piperazinyl] propoxy} -3,4-dihydrocarabobostyryl and its 3,4-dehydrogen compound,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

7- (2-acetyloxy-3- [4- (2-methoxyphenyl) paparazinyl] propoxy} -3,4-dihydrocarabostyryl and its 3,4-dehydrogen compound,

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

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

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

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

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

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

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

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

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

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

5- [2- (3,4,5-trimethoxybenzyloxy) -3- (4-phenylpiperazinyl) propoxy) -3,4-dihydrocarbobostyryl and its 3,4-dehydrogen compounds ,

1-benzyl-6- [2- (3,4,5-trimethoxybenzoloxy) -3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarabostyryl and its 3, 4-dehydrogen compounds,

7- [2- (3,4,5-trimethoxybenzoloxy) -3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbobostyryl and its 3,4-dehydrogen compounds ,

1-methyl-7- [2- (3,4,5-trimethoxybenzoloxy) -3- (4-phenylpiperazinyl) propoxy) -3,4-dihydrocarabostyryl and its 3, 4-dehydrogen compounds,

7- [2- (3,4,5-trimethoxybenzoloxy) -3] -4- (2-methoxyphenyl) piperazinyl propoxy-3,4-dihydrocarabobostyryl and its 3, 4-dehydrogen compounds,

1-benzyl-7- [2- (3,4,5-trimethoxybenzoloxy) -3- (4-phenylpiperazinyl) propoxy) -3,4-dihydrocarabostyryl and its 3, 4-dehydrogen compounds,

4-methyl-7- [2- (3,4,5-trimethoxybenzoloxy) -3- (4-phenylpiperazinyl) propoxy) -3,4-dihydrocarabostyryl and its 3, 4-dehydrogen compounds,

4-phenyl-8- [2- (3,4,5-trimethoxybenzoloxy) -3- (4-phenylpiperazinyl) propoxy) -3,4-dihydrocarabostyryl and its 3, 4-dehydrogen compounds,

1-allyl-6-chloro-7- {2- (3,4,5-trimethoxybenzoloxy) -3- [4- (3,4-dimethoxyphenyl) piperazinyl] propoxy} -3 , 4-dihydrocarbobostyryl and its 3,4-dehydrogenates,

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

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

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

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

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

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

4- [3- (3-methyl-4-phenylpiperazinyl) propoxy) -3,4-dihydrocarabobostyryl and its 3,4-dehydrogen compound,

1-methyl- [3- (3-phenyl-4-piperazinyl) propoxy] -3,4-dihydrocarabostyryl and its 3,4-dehydrogen compound,

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

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

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

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

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

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

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

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

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

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

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

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

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

5- [3- (4-sacyclohexylpiperazinyl) propoxy] -3,4-dihydrocarabostyryl and its 3,4-dehydrogenation compound,

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

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

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

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

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

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

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

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

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

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

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

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

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

1-allyl-6- [4-benzylpiperazinyl) butoxy] -3.4-dihydrocarabostyryl and its 3,4-dehydrogen compound,

1- (2-frfinyl) -8- [2- (4-benzylpiperazinyl) ethoxy-3,4-dihydrocarabostyryl and its 3,4-dehydrogen compound,

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

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

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

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

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

7- (3- [4- (3-acetyloxerethyl) piperazinyl) propoxy} -5,6-dihydrocarabostyryl and its 3,4-dehydrogen compound,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

4-phenyl-7- [3- (4-benzoylpiperazinyl) propoxy] -3,4-dihydrocarabostyryl and its 3,4-deoxygenated compound,

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

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

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

7- [3- (4-acetylpiperazinyl) propoxy] -3,4-dihydrocarabobostyryl and its 3,4-hydrocarbon compound,

8- [2-acetyloxy-3- (4-acetylpiperazinyl) propoxy] -3,4-dihydrocarbobostyrylpa 3,4-dehydrogen compound thereof,

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

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

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

7- [3- (4-butylpiperazinyl) propoxy] -3,4-dihydrocarabostiryl and its 3,4-dehydrogen compound, 1-methyl- [4- (4-propioylpiperazinyl ) Butoxy] -3,4-dihydrocarabostyryl and its 3,4-dehydrogen compound,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

7- {3- [4- (3-fluoronphenyl) piperazinyl) propoxy} -3,4-dihydrocarabostyryl and its 3,4-dehydrogen compound,

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

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

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

The carbostyryl derivative compound (1) of the present invention reacts a compound represented by the following general formula (2) with a compound represented by the following general formula (3), and optionally a compound wherein R ³ is a hydroxy group among the resulting compounds. It is prepared by reacting with (4) or (5).

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, or an alkylene group of 1 to 4 carbon atoms R ² is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a phenyl group,

R ³ is 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 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,

R ⁵ is phenyl having 1 to 3 substituted groups selected from the group consisting of a cycloalkyl group having 3 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms A substituted alkyl group having 1 to 4 carbon atoms having a group, a phenyl group or an alkanoyloxy group having 1 to 4 carbon atoms as a substituent, an alkanoyl group having 1 to 4 carbon atoms or a bengen group,

(However, when R ² is a phenyl group, R ⁵ should not be an alkyl group having 1 to 4 carbon atoms having a phenyl group as a substituent).

R ⁶ is a hydrogen atom, a hydroxy group or an alkyl group having 1 to 4 carbon atoms,

R ⁷ is an alkanoyloxy group or 3,4,5-trimethoxybenzoyloxy group having 1 to 4 carbon atoms,

과 n가 1일 경우 X¹과 R⁶은 에폭시 그룹을 형성할 수 있다)이며,X ¹ is a hydrogen atom or other substituent group capable of carrying out a substitution reaction similarly to a hydrogen atom (or

And when n is 1 X ¹ and R ⁶ may form an epoxy group),

X is a halogen atom,

는 0 또는 1 또는 2의 정수이며

Is 0 or an integer of 1 or 2

Q is an integer of 2 or 3

및

은 각각 0 또는 1내지 6의 정수(단

과

의 합은 6을 초과해서는 않된다)이며,

And

Are integers of 0 or 1 to 6, respectively

and

Must not exceed 6),

Carbon-carbon bonds at the 3- and 4- positions in the carbostyryl backbone are single or double bonds,

The substituted position of the side chain is any of the 4-, 5-, 6-, 7- or 8-position;

The reaction between the compound represented by the general formula (2) and the compound represented by the general formula (3) is several hours to 24 hours at a temperature range of 200 ° C, preferably 60 to 120 ° C, in the absence or presence of an inert solvent. Can be completed within. Examples of inert solvents include ethers such as dioxane, tetrahydrofuran, ethylene glycol and dimethyl ether, aromatic hydrocarbons such as benzene, toluene and xylene, lower alcohols such as methanol, ethanol and isopropanol and the like, such as dimethylformamide and dimethyl sulfoxide. Aprotic polar solvents can be used. The reaction can be effectively carried out by using a basic compound as the dehalogenating agent. The basic compounds that can be used for the reaction are potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium amide, sodium hydride, triethylamine or tripropylamine It can be selected from a wide range of known basic compounds, including tertiary amines, pyridine, quinoline, and the like. The reaction can also be effected effectively using alkali metal iodide compounds such as potassium iodide or sodium iodide as reaction promoters. The ratio of the amount of the compound represented by the general formula (2) to the compound represented by the general formula (3) in the reaction is not particularly limited, but in general, the compound of the general formula (3) and the compound of the general formula (3) The same molar amount or slightly excess is used, preferably the same molar amount to 5 times, more preferably the same molar amount to 1.2 times.

In addition, the reaction between the compound represented by the general formula (4) or (5) with a compound in which R ³ is a hydroxy group can be carried out in the absence or presence of a suitable solvent and in the absence or presence of a suitable basic compound. The reaction is preferably carried out in the presence of a basic compound.

Solvents that cannot be used for the reaction include aromatic hydrocarbons such as benzene, toluene, or xylene, halogenated hydrocarbons such as chloroform or methylene chloride, acetone, pyridine, dimethyl sulfoxide, dimethylformamide. Basic compounds which can be used for the reaction include tertiary amines such as triethylamine and pyridine, sodium hydroxide, potassium hydroxide and sodium hydride.

The ratio of the compound amount in which R <^3> is a hydroxy group among the compound represented by General formula (4) or (5) and a compound which is at least the same as the compound whose general formula (4) or (5) is a hydroxy group The number of moles, preferably the same molar amount to 5 times the molar amount. The reaction is carried out for several hours to 15 hours in the temperature range of room temperature to 150 ℃, preferably room temperature to 100 ℃.

Starting materials that are compounds represented by the general formula (2) used in the present invention include known compounds (US Pat. No. 4,072,683) or novel compounds which can be easily prepared by the following scheme 1.

Scheme 1

In the above formula

The carbon-carbon bonds at the 3- and 4- positions in the R1, R2, X and carbostyryl backbones are the same as above and the substituted positions of the hydroxy groups are 4-, 5-, 6-, Any one of 7- or 8- and n 'is an integer of 1 or 2,

R ⁸ is alkyl having 1 to 4 carbon atoms or alkanoyl having 1 to 4 or atoms.

The compound represented by formula (7) in Scheme 1 reacts the hydroxycarbostyryl represented by formula (6) with a halogenating agent or the alkoxy- or alkanoyloxy-carbostyryl represented by formula (8). The compound represented by formula (9) prepared by reacting with a halogenating agent can be obtained by hydrolysis. The above-mentioned halogenation reaction can be achieved by using a known halogenating agent, and examples of such halogenating agent include fluorine, chlorine bromine, iodine, xenon difluoride, sulfyl chloride, sodium hypochloride, hypochloric acid and hypobromic acid. , Bleaching powder, iodine chloride and the like. The amount of halogenating agent is selected at the light level according to the number of halogen atoms to be introduced into the compound of (6) or (8). When introducing one halogen, the halogenating agent has the same molar amount or excess as the starting material, especially 1-1.5. The ship is used. In the case of introducing two halogen atoms, the halogenating agent is used in an amount of at least twice the amount of each starting material, in particular in the amount of 2 to 3 times mole. This halogenation reaction is usually carried out in a suitable solvent such as water, methanol, ethanol, chloroform, carbon tetrachloride, acetic acid or mixtures thereof, and the reaction temperature is not particularly limited and is selected from a wide range of temperatures, but is usually -20 to 100 The reaction is complete in about 30 minutes to 20 hours at a temperature of " C, preferably 0 ° C. to room temperature.

The hydrolysis of the compound represented by formula (9) varies depending on the form of R ⁸ in formula (9). For example, when R ⁸ is an alkanoyl group having 1 to 4 carbon atoms, the hydrolysis reaction is water. Basic compounds such as sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, sodium bicarbonate, and inorganic acids such as sulfuric acid or hydrochloric acid, aromatic sulfonic acid in a solvent such as methanol, ethanol, acetone, dioxane, tetrahydrofuran, or benzene It is carried out in the presence of an organic acid such as. The reaction temperature is usually from room temperature to 150 ° C., preferably from 50 to 100 ° C., and the reaction is completed in 1-12 hours. In addition, when R ⁸ is an alkyl group having 1-4 carbon atoms, the hydrolysis reaction is carried out under conventional hydrolysis conditions of ether. This reaction uses aluminum chloride, boron salmonide, boron tribromide, bromic acid or trimethylsilyl chloride as a catalyst in a temperature range of 0 to 200 ° C., preferably in a solvent such as water, methanol, benzine, methylchloride or chloroform. It can be carried out for several hours to 12 hours at a temperature of room temperature to 120 ℃. The amount of catalyst used in the two hydrolysis reactions is not particularly limited, and an amount larger than that of the compound (9) to be hydrolyzed is usually used.

Scheme 2

,

,

, 카르보스티릴 골격내 3- 및 4-위치에 있는 탄소-탄소 결합 및-0-(CH₂)

의 촉쇄의 치환된 위치는 모두 상술한 바와 동일하고,Wherein R ¹ , R ² , R ⁶ , X, X ¹ ,

,

,

, Carbon-carbon bonds at the 3- and 4- positions in the carbostyryl backbone and -O- (CH ₂ )

The substituted positions of the catalysts of all are the same as described above,

X ³ is a halogen atom,

The substituted position of the hydroxy group is any of the 4-, 5-, 6-, 7-, or 8-positions of the carbostyryl backbone.

In Scheme 2, the reaction of the compound represented by the general formula (10) with the compound represented by the general formula (11) is carried out at room temperature to 200 ° C., preferably 50 to 150, in a suitable solvent using basic compounds as the dehalogenating agent. It is carried out for several hours to 15 hours at a temperature of ℃. Examples of suitable solvents include lower alkanols such as methanol, ethanol, or isopropanol, ketones such as acetone or methyl ethyl ketone, dioxane, ethers such as diethylene glycol dimethyl ether, aromatic hydrocarbons such as toluene or xylene, dimethylformamide , Dimethyl sulfoxide and hexamethylphosphoryltriamide and the like. Examples of basic compounds that can be used as the dehydrohalogenating agent include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide phosphate, potassium ethoxide, sodium hydride, potassium metal, sodium amide, pyridine, Such as quinoline, triethylamine or tripropylamine. Intercalating amines.

In the reaction, alkali metal iodine compounds such as potassium iodide or sodium iodide may be used as the reaction promoter. The ratio of the compound amount represented by the general formula (10) and the compound amount represented by the general formula (11) is not particularly limited, but the compound of the general formula (11) is the same molar amount or more than the compound of the general formula (10) And usually 1 to 1.5 times, preferably 1 to 1.2 times. As a result, it is possible to obtain a compound represented by the general formula (2) that can be used as a starting material of the present invention.

In Schemes 1 and 2, R ¹ is an alkyl group having ¹ to 6 carbon atoms, 2 to 4, among the compounds represented by the general formulas (6), (8) and (10), which are starting materials used in the reaction. Alkenyl groups having 2 carbon atoms, alkyl groups having 2 to 4 carbon atoms, and those having substituted groups in which the alkyl group is a phenylalkyl group having 1 to 4 carbon atoms include a novel compound. These compounds use known hydroxycarbostyryls wherein R ¹ is hydrogen as starting material and use them as alkyl halides, alkenyl halides, alkynyl halides or phenylalkyl halides, for example alkali metals such as sodium or potassium metals. In a suitable solvent such as benzene, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide, hexamethyl phosphoryltriamide in the presence of an alkali metal amide or sodium hydride such as sodium amide or potassium amide, Preferably, the reaction is carried out at 0 to room temperature for 30 minutes to 12 hours, and then the formed compound is hydrolyzed under conditions similar to the hydrolysis of the compound represented by formula (9) in which the alkyl represented by Scheme 3 has 1 to 4 carbon atoms. It can manufacture easily.

In the reaction, the ratio of the amount of the basic compound such as alkyl halide, alkenyl halide, alkynyl halide or phenylalkyl halide and the starting material is widely selected, but the basic compound is usually 1 to 10 times mole of the starting material, preferably 2 Use in an amount of -4 times the molar amount.

와

가 각각 1이고 R³가 하이드록시그룹인 일반식(1d)로 표시된 화합물은 하기 반응식 3에 의하여 제조할 수 있다.In this way, the target compound represented by General formula (1) can be manufactured. In the compound of the desired compound represented by General formula (1)

Wow

Are represented by Formula 1 (d) wherein each is 1 and R ³ is a hydroxy group can be prepared by the following Scheme 3.

Scheme 3

,Q, 카르보스티릴골격내 3-및 4-위치에 있는 탄소-탄소결합 및 하이드록시그룹의 치환된 위치는 모두 상술한 바와 동일하고, X⁴는 할로겐원자이며, Y는

또는

이고,

의 측쇄의 치환된 위치는 카르보스티릴 골격내의 4-, 5-, 6-, 7-또는 8-위치중 어느한 위치이다.Wherein R ¹ , R ² , R ⁴ , R ⁵ ,

The substituted positions of the carbon-carbon bonds and the hydroxy groups at the 3- and 4- positions in the Q, carbostyryl skeleton are all the same as described above, X ⁴ is a halogen atom, and Y is

or

ego,

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

In Scheme 3, the reaction of hydroxycarbostyryl represented by the general formula (10) with epihalo genohydrin represented by the general formula (12) is a suitable basic compound such as sodium hydroxide, potassium hydroxide, sodium carbonate, Inorganic basic compounds such as potassium carbonate, sodium methoxide, sodium ethoxide, sodium hydride, sodium metal, potassium metal or sodium amide or piperidine, pyridine, triarylamine liver are without solvent in the presence of an organic basic compound or For example, methane is used in solvents of lower alkanols such as ethanol, isopropanol, ketones such as acetone or methylethylkerone, dioxane, diethylene glycol, ethers such as dimethyl ether, aromatic hydrocarbons such as benzene, xylene, toluene and the like. Can be done.

The amount of the compound represented by the general formula (12) used in this reaction can be selected in a wide range, but is usually used in the same moles or more preferably 5 to 10 moles as the compound of the general formula (10). The reaction can be carried out in the range of 0 to 150 ° C., preferably 50 to 100 ° C., wherein the epihalogenohydrin represented by the general formula (12) is hydroxy of the compound represented by the general formula (10). Reaction with the group to form a compound having a (2,3-epoxy) propoxy group or a 3-halogeno-2-hydroxy propoxy group, generally the reaction product can be obtained as a mixture of such compounds.

The reaction product thus obtained can be reacted with the compound represented by the general formula (3) without undergoing any separation or purification process. In addition, the reaction product was subjected to conventional separation, recrystallization or column chromatography to obtain a purified compound having a 2,3-epoxypropoxy group or a 3-halogeno-2-hydroxypropoxy group. It can react with the amine represented by General formula (3).

The reaction between the compound represented by the general formula (13) and the compound represented by the general formula (3) is carried out in the temperature range of room temperature to 200 ° C, preferably 60 to 120 ° C, in the absence or in the presence of an inert solvent. It is completed in a few hours to 24 hours. Examples of inert solvents in the reaction include ethers such as dioxane, tetrahydrofuran, ethylene glycol and dimethyl ether, aromatic hydrocarbons such as benzene, toluene and xylene, lower such as methanol, ethanol, isopropanol, alcohol dimethylformamide, dimethyl sulfoxide Polar solvents such as;

In the above scheme, it is usually possible to add basic compounds. Examples of basic compounds include potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium amide and triethylamine, tripropylamine, amines such as parridine or quinoline It includes. The proportion of the amount of each compound to be reacted is selected within a wide range, but the compound represented by the general formula (3) is usually the same molar amount as the compound represented by the general formula (13) or more, and is usually the same mole to 5 times, especially 1 Use 1.2 times.

Among the desired compounds represented by the general formula (1), R ¹ is an alkyl group having ¹ to 6 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, and an alkylene group having 1 to 4 carbon atoms. The compound represented by the general formula (1f) may be prepared by reacting a halogen compound represented by the general formula (14) with a compound in which R ¹ is a hydrogen atom as described in Scheme 4 as follows.

Scheme 4

, 카르보스티릴골격내 3-및 4-위치에 있는 탄소-탄소 결합 및

의 측쇄의 치환된 위치는 모두 상술한 바와 같고, R⁹은 1∼6개의 탄소원자를 갖는 알킬그룹, 2∼4탄소원자의 알케닐그룹, 2∼4개의 탄소원자를 갖는 알키닐그룹, 알키렌그룹이 1∼4탄소 원자를 갖는 페닐알킬그룹이며, x는 할로겐 원자임.Wherein R ² , R ³ , R ⁴ , R ⁵ , x,

Carbon-carbon bonds at the 3- and 4- positions in the carbostyryl skeleton and

The substituted positions of the side chains of all are as described above, R ⁹ is 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, an alkylene group A phenylalkyl group having 1 to 4 carbon atoms, x being a halogen atom;

In the reaction between the compound represented by the general formula (1e) and the compound represented by the general formula (14), the amount of the compound represented by the general formula (14) is the same amount or three times the amount, preferably the compound of the general formula (1e). Preferably used in the same molar amount, wherein R ¹ is a hydrogen atom as defined in general formulas (6), (8) or (10), alkyl halides, alkenyl halides, alkynyl halides, or The same conditions as for reacting with phenylalkylhalide can be applied.

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-carbon bonds at the 3- and 4- positions in the carbostyryl skeleton are double bonds are formed at the 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.

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

The compounds of the present invention also include these and optical ideals.

Compounds of formula (1) as anti-hastamines 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 neuromodulators, and traditional unit forms are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions and Suspension) ointment. 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: water, ethanol, propanol, single syrup, Binders such as glucose, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, calcium phosphate and polyvinylpyrrolidone: dried starch, sodium alginate, agar powder, Lainaria powder, sodium bicarbonate, carbonate Degradants such as calcium, Tweens, sodium laurylsulfate, monoglycerides of stearic acid, starch, lactose: inhibitors of degradation such as sugar, stearin, peanut butter, hydrogenated oil: tetravalent ammonium base, sodium la Absorption accelerators such as urilsulfate: Wetting agents such as glycerin or starch: Adsorbents such as starch, lactose, kaolin, bentonite, and colloidal ciric acid Use lubricants such as refined talc, stearates, disperse powders, margolol, and polyethylenlycol solids.

In the form of pills, fillers such as glucose, lactose, starch, peanut butter, hydrogenated vegetable oils, kaolin and talc, which are widely used in the art, for example, are known: powdered gum, powdered taracanthant, gelatin and Binders of ethanol: Degradants such as Lainaria and agar are used. In the case of tablets, the tablets are usually further coated with a coating material to make a tablet coated with sugar, a tablet coated with a gelatinous coating, a tablet coated with an enteric coating, a film coated tablet or a double or multilayer tablet. Can be.

To form the left jaw, carriers which are widely used in the art are known, including for example polyethylene 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. All carriers commonly used in the art may be used as the injectable preparation, for example, water, ethyl alcohol, propylene glycol, ethoxylated isosteryl alcohol, polyoxylated isosteroyl alcohol, polyoxystyrene sorbent Beetle and sorbitan ester 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.

To prepare in the form of creams of pastes, diluents widely used in the art are known, for example white vaseline, paraffin, glycerin, cellulose derivatives, polystyreneglycol, silicone and bentonite It includes.

The amount of the compound of the general formula (1) or the acid addition salt thereof contained in the antihistamine and the 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 or intravenous injection. Suppositories are given in the anus 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 is usually a pharmaceutical formula including a compound of Formula (1) or an acid salt thereof at 40 µg-2 mg / kg. The composition is administered 3 times a day.

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

For the compounds of the present invention, the results of the pharmacological test are as follows.

(1) Antihistamine Chemistry Test

As a test method for measuring the antihistamine activity of a compound in vivo, a method using the ileum of Mormoto is suitable.

Mormort males weighing between 300 and 500 g were released by killing blood, and the 15 cm long ileum was removed from the ileum, and then loaded with a thi-load solution (0.8 g of NaCl, 0.2 g of KCl, 0.2 g of CaCl ₂ , 1.Og). glucose, immersed in _{NaHC0 3, NaHP0 4. 2H 2} 0 and water is added to the MgCl ₂ · 6H ₂ 0 0.2135g of the solution made with a total of 0.065g of 100㎖ 0.Og). Subsequently, the tissues of the ileum were cut into lengths of 2.5 to 3.0 cm and suspended in an engine bath filled with 30 ml of a tirod solution. The bath was kept at 36 ° C. and composed of 5% carbon dioxide gas and 95% oxygen. Blow the mixed gas into the bath. Blow for 10 minutes and then add 10 ^-6 M 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 ⁻⁶ g / 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. Contraction of the ileum is recorded on a pen-recorder using an isotonic transducer (TD-112S manufactured by Nippon Koden). The antihistamine activity of the test compounds was determined by the "Van Rossam" method [100] with the maximum contraction of the ileum caused by histamine shown in the comparison curve [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)

TABLE 1

(Ⅱ) Anesthesia and Sleep Increasing Activity

(A) Halotan (halothone) anesthesia increased activity

One test group consists of 10 mice using ddy-lined male mice weighing about 20 g. A water-soluble gum gum suspension of test compound (80 mg of compound to be tested, 1 g of gum gum / 100 ml of physiological saline) is administered orally to each mouse at a dosage of 8 mg of test compound / kg body weight. One hour after dosing, 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-trifluuroethane]. The gas is injected into the respiratory chamber for 3 minutes at a rate of 2 l / min. Anesthetized rats are taken out of the respiratory tract and the time of infusion and awakening of the anesthetic is measured by righting reflex as an index. Mice of the control group were administered with a dose of 0.1ml / 10g body weight of 1% gum arabic solution. [Reference: M.J.Turnbull and Watkins: Br.J. Pharmac. 58 27-35 (1976). The results are shown in Table 2.

Table 2 (Dose: 8mg / kg)]

(B) halotan anesthesia increased activity

To determine the relationship between the dosage and the increase in anesthesia activity, except for varying the amount of test compound administered orally in four steps, such as 0.5 mg / kg, 1 mg / kg, 2 mg / kg and 4 mg / kg (II The same method as described for) -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 Arabia 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. [Reference: A.M. HjortDe E. J. Beer and D.W. Fassett: J. Pharmac Exptl. Ther. 63. 421 (1963)]

TABLE 4

(III) Activity to Inhibit Fighting Behaviors of Mice Isolated from Long-Term Isolation

Male mice of ddy-hematoma weighing 15-20 g each are reared in cages for one month, and one test group consists of 10 rats. When each mouse of the stacked mice was placed in a cage of other mice, they chose to fight continuously for 30 seconds. The ED ₅₀ value can be determined by administering each test compound to each group of test mice. The inhibitory activity of the test compound is determined to be positive if the administered mice continue to fight for 5 seconds in 1 minute. If the mouse continues to fight for more than five seconds, isolate the less injured mouse. [References: CY Yen, RL Stander and N, Mitlman; Arch.nt, Pharmacodyn., 123-179 (1959)] The results are shown in Table 5.

TABLE 5

(Iv) analgesic activity

Ddy-type 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 0.6% aqueous acetic acid solution / 10 g body weight is injected subcutaneously. In the case of mice administered orally with the control compound (haloperidol), injection is performed 110 minutes after administration. To calculate the number of suffering mice shown after 10 minutes, the ED ₅₀ value of the compound is calculated by comparing the number of suffering mice shown by the control group. [References: R. Koster, M. Anderson and EI Debeer Fed. Proc., 18, 412, (1959)] The results are listed in Table 6.

TABLE 6

(V) Toxicity Test (LD ₅₀ )

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

Oral Administration: The test compound is suspended in 1% gum gum saline solution.

Subcutaneous administration: Dissolve the water to be tested in 50% aqueous propylene glycol solution. The results are shown in Table 7.

Table 7 (LD ₅₀ )]

LD ₅₀ values (oral administration) of the compounds of the present invention other than the compound Nos. 6, 7, 17, 31 and 39 were measured at 80 mg / kg or more using Dijong male mice.

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 is dissolved in 200 ml of acetic acid, stirred with cooling with water, and then added dropwise for 30 minutes to 60 ml of acetic acid solution containing 16 g of bromine. The reaction is carried out for 2 hours at the temperature. The reaction mixture was poured into 300 ml 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 237-239 ° C. 5-acetyloxy-3,4-dihydrocarbostyryl is obtained.

The obtained insoluble substance was dispersed by dispersing 21 g of 8-bromo-5-acetyloxy-3,4-dihydrocarbostyryl in 150 ml of 8N hydrochloric acid, refluxing the dispersion solution for 3 hours, and cooling the resulting insoluble substance. Separation, washing with water, solid, and recrystallization with methanol-water yielded 14 g of 8-bromo-5-hydroxy-3,4-dihydrocarbostyryl having colorless needles and melting point of 212-213 ° C.

Reference Example 2

Dissolve 16.4 g of 5-hydroxy-3,4-dihydrocarbostyryl in 300 ml acetic acid, then stir the solution at room temperature, add dropwise 50 ml acetic acid solution containing 7 g of chlorine, and stir for 3 hours. And react. The reaction mixture is poured into 500 ml of water and left 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 crystal. 13.5 having a melting point of 209-210 ° C. g of 6-chloro-5-hydroxy-3,4-dihydrocarbostyryl is obtained.

Reference Example 3

16.4 g of 5-hydroxy-3,4-dihydrocarbostyryl was dissolved in 300 ml of acetic acid and stirred at room temperature, followed by 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 to that described in Reference Example 2, 16 g of 6,8-dichloro-5-hydroxy-3,4-dica having a melting point of 259 to 260 ° C is a colorless needle. Levostyryl is obtained.

Reference Example 4

35.4 g of 7-methoxy-3,4-dihydrocarbostyryl is dissolved in 300 ml of acetic acid and stirred under ice-cooled conditions, followed by dropwise addition of 100 ml of acetic acid solution containing 27 g of sulfuryl chloride, and left overnight. Put it. The reaction mixture was poured into 1 liter of ice water, and the precipitate formed was separated by filtration, washed with water, dried, and then recrystallized with methanol. As a colorless needle, 30 g of 6-chloro-7-methoxy-3,4 having a melting point of 212 ° C. -Dihydrocarbostyryl is obtained.

The resulting 30 g of 6-chloro-7-methoxy-3,4-dihydrocarbostyryl was dispersed in 300 ml of an aqueous 47% bromic acid solution, heated at reflux for 4 hours, and then cooled to produce a reaction mixture. The insoluble material was separated, washed with water, dried over water and recrystallized with methanol-chloroform to give 25 g of 6-chloro-7-hydroxy-3,4-dihydrocarbostyryl having a melting point of 264-266 ° C. as a colorless needle.

Reference Example 5

35 g of 8-methoxy-3,4-dihydrocarbostyryl is dissolved in 200 ml 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 this reaction mixture is poured into 1 liter of water, precipitates are formed, which are separated by filtration, washed with water and dried again and recrystallized with chloroform. A light red acicular crystal has 42 g of 5,6-dichloro-8- with a melting point of 201 to 202 ° C. Methoxy-3,4-dihydrocarbostyryl is obtained.

The resulting 42 g of 5,6-dichloro-8-methoxy-3,4-dihydrocarbostyryl are dispersed in 500 ml of an aqueous 47% -bromic acid solution and then heated under reflux for 4 hours. Subsequently, after cooling the reaction mixture, the resulting insoluble substance is separated by filtration and washed with water. When the obtained crude crystal is recrystallized with methanol, 29 g of 5, 6- dichloro-8-hydroxy-3, 4- dihydrocarbostyryl of colorless needle crystal and melting | fusing point of 233-235 degreeC are obtained.

Reference Example 6

In a similar manner as in Reference Example 5, a (decomposed) 8-bromo-5-hydroxycarbostyryl having colorless needles (the recrystallization solvent is methanol) and 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 dimethylsulfoxide and stirred at 135-140 ° C. for 4 hours. After heating, the reaction mixture is completed, and the reaction mixture is mixed with 200 g of ice and 50 ml of concentrated hydrochloric acid, and then stirred at room temperature for 1 hour. The precipitated crystals are separated by filtration, first washed with dilute hydrochloric acid and 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 a pale orange acicular crystal.

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 added, which is separated by filtration, washed with water, dried, and then recrystallized with isopropanol. 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 ° C. Hydrocarbostyryl is obtained.

Reference Example 8

20.2 grams of 8-chloro-5-hydroxy-3,4-dihydrocarbostyryl and 18 g of potassium carbonate are suspended in 160 ml of isopropyl alcohol, then 40 ml of epichlorohydrin is added and then 70 to The reaction is carried out at 80 ° C. for 6 hours. 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 crystal was recrystallized from isopropanol to give a colorless acicular crystal. 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-dihydrocarbosstyryl and 3.7 g of sodium hydroxide are mixed in 100 ml of methanol, stirred for 3 hours, and then 150 ml of epiflo Hydrin is added thereto and heated at reflux for 5 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to harden, 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 insoluble matters were dried with methanol-ethanol, and colorless crystals of 19.7 g of 6-chloro-7- (2,3-epoxypropoxy) -3, having a melting point of 190 to 192 ° C, 4-dihydrocarbostyryl is obtained.

[Reference Examples 10-13]

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, stirred at 70 to 80 ° C. for 30 minutes, and then 25 g of 1,3-bromochloropropanol are added and heated at reflux for 6 hours. After completion of the reaction, 200 ml of 2N aqueous sodium hydroxide solution is added to the reaction mixture to produce 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-dihydrocarabostyryl having a melting point of 184 to 185 ° C as a colorless needle. .

Reference Example 15

5 g of 6-chloro-8-bromo-7-hydroxy-3,4-dihydrocarbostyryl and 3 g of sodium hydroxide are mixed with 120 ml of isopropane and then stirred at 50-60 DEG C for 1 hour and there To 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 chloroform was recrystallized from ethanol. It was colorless needle crystal. It was 6.2 g of 6-chloro-8-bromo-7- (3 having a melting point of 87-88 ° C. -Chloropropoxy) -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.

Reference Example 20

18.3 g of 3,4,5-trimethoxyaniline and 31.2 g of bis (β-bromoethyl) amine monohydrobromide are mixed with 170 ml of methanol and then refluxed under nitrogen gas vapor for 10 hours to cool the reaction mixture. Then 5.3 g of anhydrous sodium carbonate are added to the mixture and refluxed for another 10 hours. Under reduced pressure, about 70 ml of methanol are distilled off and left to cool on room temperature, then the precipitated crystals are collected by filtration and washed with a small amount of ethanol. Recrystallization from ethanol yields 38 g of 4- (3,4,5-trimethoxyphenyl) piperazine monohydrobromide having a melting point of 227 to 228 ° C as colorless plate crystals.

This compound is dissolved in 20% aqueous sodium hydroxide solution and then extracted with chloroform. Subsequently, the chloroform layer is washed three times with a saturated aqueous sodium chloride solution, dried, and the chloroform is distilled off. As a single substance, such as colorless viscous oil, 4- (3,4,5-trimethoxyphenyl) piperazine in free form is obtained as one substance. The chemical structure of this compound was confirmed by NMR and IR (Infrared Absorption Spectrum) methods.

Example 1

4.4 g of 5- (2,3-epoxypropoxy) 3,4-dihydrocarbostyryl and 3.4 g of 4-phenylpiperazine are dispersed in 60 ml of methanol and reacted at 50 to 60 ° C. for 3 hours. Subsequently, after the reaction was completed, 5 ml of concentrated hydrochloric acid and 30 ml of ethanol were added to the residue obtained by concentrating the reaction mixture under reduced pressure, and the residue was uniformly dissolved, and 200 ml of acetone was further added thereto. The precipitated crystals are collected by filtration and then dried. When recrystallized from water, 6.5 g of 5- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl having a melting point of 239 to 241 DEG C as a colorless needle crystal. Monohydrochloride is obtained.

Example 2

4.4 g of 6- (2,3-epoxypropoxy) -3,4-dihydrocarbostyryl and 3.4 g of 4-phenylpiperazine are dispersed in 80 ml of isopropanol and stirred at 50-60 ° C. for 3 hours. After the reaction, 5 ml of concentrated hydrochloric acid is added thereto, concentrated under reduced pressure and dried. The obtained residue was recrystallized with hot water to give 6.1 g of 6- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-di having a melting point of 223 to 224 캜 as a colorless needle. Hydrocarbostyryl monohydrochloride 1/2 hydrate is obtained.

Example 3

2.9 g of 1- (3-methylbutyl) -5- (2,3-epoxypropoxy) -3,4-dihydrocarbostyryl and 1.7 g of 4-phenylpiperazine are mixed in 50 ml of methanol, The reaction is carried out at 50 to 60 ° C. for 3 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was dissolved in 50 ml of acetone, and then, 20 ml of acetone solution containing 1.1 g of oxalic acid was added to the solution. A precipitate was formed, which was filtered and washed with acetone and dried. Recrystallization with ethanol-ether gave 2.1 g of 1- (3-methylbutyl) -5- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydro as colorless crystals. Carbostyryl monooxalate is obtained. This product was identified to be the same compound by silica gel thin layer chromatography.

(Developing solvent: chloroform: methanol 9: 1)

Elemental analysis: C ₂₉ H ₃₇ 0 ₇ N ₃

Calculated Value (%): C 64.30, H 7.26, N 7.76

Found (%): C 64.52, H 7.10, N 7.48

IR (Infrared Absorption Spectrum): 3400cm ^-1 (OH), 1680cm ^-1 (-CO-)

NMR ^* : δ = 6.8-7.3 ppm (aromatic proton, 8H)

= 0.92 ppm (methylproton, 6H)

^(NOTE: NMR measurements were carried out in ¹⁶ d -DMSO)

The obtained compound was neutralized in a usual manner, and the crude crystal was recrystallized from ethanol to give a colorless prism crystal of 1- (3-methylbutyl) -5- [2-hydroxy-3- (4 having a melting point of 156 to 157 캜. -Phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl is obtained.

Example 4

50 ml of 3.4 g of 1- (3-phenylpropyl) -5- (2,3-epoxypropoxy) -3,4-dihydrocarbostyryl and 2.Og of 4- (4-methylphenyl) piperazine Is mixed with methanol and reacted in a similar manner as in Example 3. The obtained crude crystal was recrystallized from methanol-ether to give 4.2 g of 1- (3-phenylpropyl) -5- {2-hydroxy-3- [4- (4methylphenyl) piperazinyl) prop as a colorless crystal. Foxy} -3,4 dihydrocarbostyryl monooxalate is obtained.

Elemental analysis: C ₃₄ H ₄₁ 0 ₇ N ₃

Calculated Value (%): C 67.64, H 6.85, N 6.96

Experimental value (%): C 67.85, H 6.52, N 6.81

IR (Infrared Absorption Spectrum): 3480 cm ^-1 (OH), 1675 cm ^-1 (C = 0)

NMR ^** : δ = 6.6-7.4 ppm (aromatic proton, 12H)

= 2.30 ppm (methylproton, 3H)

( ^** NMR measurement was performed with d ⁶ -DMSO)

[Examples 5 to 23]

In the same manner as in Examples 1 to 4, the following compounds were obtained.

Example 24

2.4 g of 4-methyl-7- (2,3-epoxypropoxy) carbostyryl and 1.8 g of 4-phenylpiperazine are mixed in 30 ml of ethanol and heated at reflux for 3 hours. After cooling the reaction mixture, the precipitated crystals are collected by filtration and washed with ether.

The resulting crude crystals were dissolved in 50 ml of methanol and 3 ml of concentrated hydrochloric acid, and the mixture was concentrated to dryness under reduced pressure. The obtained residue was recrystallized from ethanol-ether. 63%) of 4-methyl-7- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] carbostyryl monohydro chloride is obtained.

Example 25

4-methyl-6- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] with colorless crystals (recrystallized from ethanol) and melting point 212-213 ° C. in a similar manner as in Example 24; Obtain carbostyryl half hydrate.

Example 26

4.8 g of 5- (3-chloropropoxy) -3,4-dihydrocarbostyryl and 4 g of phenylpiperazine were mixed with 40 ml of toluene, heated at reflux for 24 hours, and the reaction mixture was concentrated under reduced pressure. The obtained residue is dissolved in 80 ml of chloroform, the chloroform layer is washed twice with 5.0% sodium hydrogen carbonate twice followed by water, dried over anhydrous sodium sulfate and the chloroform is distilled off. Hexane is added to the obtained residue to form an insoluble substance which is collected by filtration, dissolved in 30 ml of 5% hydrochloric acid-methanol solution and concentrated to dryness under reduced pressure. The obtained residue was recrystallized from methanol-ether to give colorless crystals of 3.2 g of 5- [3- (4-phenylpiperazinyl) propoxy-3,4-dihydrocarbostyryl and monohydrochloride having a melting point of 262 占 폚. Is obtained.

Example 27

4.5 g of 6- (2-chloroethoxy) -3,4-dihydrocarbostyryl and 3.3 g of sodium iodide are mixed with 50 ml of acetone and heated at reflux for 5 hours. 40 ml of dimethylformamide was added to the reaction mixture, acetone was distilled off at 40-45 ° C. under reduced pressure, and then 3.8 g of phenylhydrazine was added to the reaction mixture, followed by reaction at 60-70 ° C. for 7 hours with stirring. The residue obtained by concentrating and solidifying the reaction mixture under reduced pressure was dissolved in 80 ml of chloroform, and then the chloroform layer was washed twice with 5% aqueous sodium hydrogen carbonate solution and then twice with water. After drying the chloroform layer, chloroform is removed by distillation.

The obtained residue was purified through a silica gel chromatography column (silica gel: registered trademark wako gel C-200 purchased from Wako Chemical Industries, Ltd., eluting solvent = chloroform: methanol = 20: 1), and then the target compound was saturated with hydrogen chloride. After conversion to hydrochloride using ethanol, ethanol is distilled off under reduced pressure. The obtained residue was recrystallized from methanol-ether to give 3.8 g of 6- [2- (4-phenylpiperazinyl) ethoxy] -3,4-dihydrocarbostyryl mono having a melting point of 196 to 198 DEG C as colorless crystals. Hydrochloride. A single hydrate is obtained.

[Examples 28-72]

A compound similar to the method in Examples 26 to 27 was obtained.

Example 73

4.8 g of 7- (3-chloropropoxy) -3,4-dihydrocarbostyryl and 3.5 g of sodium iodide were mixed in 50 ml of acetone and heated at reflux for 3 hours, followed by 40 ml of dimethylformamide. After addition, the acetone was distilled off at 40-45 ° C. under reduced pressure, and 4.0 g of 4- (3-fluorophenyl) piperazine and 3.0 g of triethylamine were added and reacted for 27 hours with stirring at 70-80 ° C. The reaction mixture was concentrated under reduced pressure, dried and dried to add 60 ml of 5% aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The chloroform was extracted twice with water, dried and chloroform was removed by distillation. When ether was added to the obtained residue, an insoluble substance was formed. The filtrate was collected, dried, and recrystallized from methanol. The result was pale yellow needle crystals with 6.2 g of 7- {3-4- (3-fluorophenyl) having a melting point of 174 to 176 ° C. ) Piperazinyl] propoxy-3,4-polyhydrocarbostyryl is obtained.

Example 74

20 ml of dimethyl with 12.4 g of 7- (3-chloropropoxy) -3,4-dihydrocarbostyryl, 1 g pyridine and 2.6 g of 4- (3,4,5-trimethoxyphenyl) piperazine After mixing in sulfoxide, stirring at 80-90 ° C. for 5 hours, and adding the reaction mixture to 80 ml of 2% aqueous sodium hydrogen carbonate solution, an organic layer is formed, which is extracted with chloroform. The chloroform layer was washed with water and dried to remove chloroform by distillation. The obtained residue was dissolved in 30 ml of ethanol and blown with dry hydrogen chloride gas into an ethanol solution to give a crystalline precipitate. 3.2 g (yield: 61%) of 7- {3- [4-3,4,5-trimethoxyphenyl) piperazinyl] propoxy} -3 having a melting point of 225 to 227 캜 as colorless needles; 4-dihydrocarbostyryl dihydrochloride is obtained.

[Examples 75 to 80]

In a similar manner to the method in Example 74, the following compounds were obtained.

Example 81

2.5 g of 7- (3-chloro-2-methylpropoxy) -3,4-dihydrocarbostyryl and 1.8 g of sodium iodide were mixed with 30 ml of acetone and stirred at room temperature overnight, followed by 20 ml of dimethylformamide. After the addition of acetone, the acetone was distilled off under reduced pressure, and 1.5 g of triethylamine and 1.8 g of phenylpiperazine were added thereto and reacted with stirring at 70 to 80 ° C. for 6 hours. The reaction mixture is then poured into 70 ml of a 2% aqueous sodium hydrogen carbonate solution, the organic layer is extracted with chloroform, the chloroform layer is washed with water and dried.

The residue obtained by distilling chloroform was washed with petroleum ether and then recrystallized from methanol-water to give 2.8 g (yield: 74%) of 7- [2-methyl-3, a colorless flaky crystal with a melting point of 146-147 ° C. -(4-phenylpiperazinyl) propoxy] -3,4-dihydrocarbostyryl is obtained.

Example 82

5- [2-methyl-3- (4-phenylpiperazinyl) propoxy] having colorless needles (recrystallization solvent: ethanol) with melting point of 167-169 ° C. in a similar manner to Example 81; Obtain -3,4-dihydrocarbostyryl.

Example 83

2.7 g of 4-methyl-7- (3-chloropropoxy) carbostyryl and 1.8 g of sodium iodide are mixed with 50 ml of acetone, heated at reflux for 3 hours, and then 50 ml of dimethylformamide is added thereto and acetone Is distilled off under reduced pressure. Subsequently, 1.5 g of triethylamine and 1.8 g of 4-phenylpiperazine were added thereto, stirred at 80 to 90 ° C. for 3 hours, and dimethylformamide was removed by distillation under reduced pressure. To the obtained residue is added a 5% aqueous sodium hydrogen carbonate solution that affects the crystallization of the product. A precipitate is formed which is collected by filtration, washed with water, isopropanol and then ether and dried. The obtained crude crystal was dispersed in 80 ml of methanol, dissolved by adding 5 ml of concentrated hydrochloric acid, concentrated under reduced pressure and dried. The obtained residue was recrystallized from methanol-ether to give colorless crystals. 3.6 g having a melting point of 253 to 254 DEG C (decomposition). (Yield: 80%) of 4-methyl-7- [3- (4-phenylpiperazinyl) propoxy] carbostyryl dihydrochloride is obtained.

Example 84

4-Methyl-6- [3- (4-phenylpiperazinyl) propoxy] having pale brown crystals (with ethanol) and melting point 285-290 ° C. (decomposition) in a similar manner to Example 83; Carbostyryl, dihydrochloride, trihydrate are obtained.

Example 85

2.4 g of 5- (3-chloroproxy) -3,4-dihydrocarbostyryl and 1.7 g of sodium iodide are mixed with 30 ml of acetone, heated at reflux for 3 hours, and then 30 ml of dimethylformamide Is added, and acetone is removed by distillation under reduced pressure. Subsequently, 1.5 g of triethylamine and 1.8 g of 4-phenyl homopiperazine were added thereto, and the mixture was heated with stirring at 60 to 70 ° C. for 5 hours, and then the reaction mixture was poured into 80 ml of 3% aqueous sodium hydrogen carbonate solution and the organic layer. Was extracted with chloroform, the chloroform layer was washed with water and dried and the chloroform was distilled off. The obtained residue was recrystallized from ligroin-benzene to give a colorless flaky crystal, 3.2g (yield: 83%) of 5- [3- (4-phenylhomopiperazinyl) propoxy] having a melting point of 122-125 占 폚. -3,4-dihydrocarbostyryl is obtained.

[Examples 86 to 88]

In a similar manner to the method in Example 85, the following compounds were obtained.

Example 89

24 g of 5- (3-chloropropoxy) -3,4-dihydrocarabostyryl and 17 g of sodium iodide are mixed with 300 ml of acetone and heated under reflux for 3 hours, followed by 300 ml of dimethylformamide, 12 g Triethylamine and 18 g of 4-benzylpiperazine were added and reacted with stirring at 60 to 70 ° C. for 7 hours. The reaction mixture was concentrated under reduced pressure to obtain a viscous liquid. 300 ml of 3% aqueous sodium hydrogen carbonate solution was added thereto, the organic layer was extracted with chloroform, washed with water to dry the chloroform layer, and the chloroform was distilled off. The obtained residue was washed with ether and recrystallized from methanol to give 32 g (yield: 84%) of 5- [3- (4-benzylpiperazinyl) propoxy]-having a melting point of 157 to 159 ° C as colorless needles. 3,4-dihydrocarabostyryl is obtained.

[Examples 90 and 91]

In a similar manner to the method in Example 89, the following compounds are obtained.

Example 92

2.4 g of 7- (3-chloropropoxy) -3,4-dihydrocarbostyryl and 1.8 g of sodium iodide are mixed in 30 ml acetone, stirred at 50-60 ° C. for 3 hours, and then 30 ml Dimethylformamide is added. After distillation under reduced pressure to give acetone, 1.5 g of triethylamine and 2.3 g of 4- (4-chlorophenyl) -3-methylpiperazine were mixed together and stirred at 70 to 80 ° C. for 7 hours. . The reaction mixture is concentrated under reduced pressure, 50 ml of 3% aqueous sodium hydrogen carbonate solution is added to the obtained viscous residue, and the organic layer is extracted with chloroform. The chloroform layer is washed with water, dried and the chloroform is distilled off. 50 ml of methanol and 5 ml of concentrated hydrochloric acid were added to the obtained residue, and the mixture was concentrated under reduced pressure, dried, and then recrystallized from ethanol. Colorless crystals were 3.1 g (yield: 75%) having a melting point of 235 to 242 ° C. -{3- [3-methyl- (4-chlorophenyl) piperazinyl] propoxy} -3,4-dihydrocarbostyryl. Dihydrochloride is obtained.

[Examples 93 and 94]

In a similar manner to the method in Example 92, the following compounds were obtained.

Example 95

5.1 g of 7- (3-chloro-2-hydroxypropoxy) -3,4-dihydrocarbostyryl and 8 g of 4-phenylpiperazine are mixed with 50 ml of dimethylformamide and stirred at 50 to 60 ° C. React for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 80 ml of chloroform. The chloroform layer was washed three times with 5% aqueous sodium hydrogen carbonate solution, three times with water, and dried over anhydrous sodium sulfate. The residue obtained by distillation under reduced pressure of chloroform was purified by silica gel-chromatography [silica gel: Wako C-200, extraction solvent: chloroform: methanol = 30: 1 (V / V)]. The extract is then converted to its hydrochromide using ethanol with hydrogen chloride and the ethanol is removed by distillation under reduced pressure. The obtained residue was recrystallized from water to give 5.6 g of 7- [2-hydroxy-3- (4-phenylpiperazinyl) propoxy] -3,4-hydrocarbose with colorless crystals having a melting point of 122 占 폚 (decomposition). Tyrryl, monohydrochloride, half-hydrate are obtained.

[Examples 96-115]

In a similar manner to the method in Example 95, the following compounds are obtained.

Example 116

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 are added Heat under reflux for 10 hours. After cooling the reaction mixture, the precipitated product is collected by filtration and 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. The residue was purified by silica gel chromatography to give 0.5 g of 5- [2-acetyloxy-3- (4-phenylpiperazinyl) propoxy] -3,4-dihydrocar with colorless crystals and a melting point of 159-161 占 폚. Bostyryl is obtained.

Example 117

In a manner similar to that in Example 125, 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 118

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 under reflux conditions After heating for 1 hour, the temperature of the dissolution tank is below 30 ° C., 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, and then 80 ml of water is added to the residue and extracted with chloroform. The chloroform layer is washed with water, 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) having colorless crystals and a melting point of 125 to 127 캜. Propoxy] -3,4-dihydrocarbostyryl is obtained.

Claims (1)

The compound of formula (2) is reacted with the compound of formula (3), and if necessary, a compound in which R ³ of the compound (I) is a hydroxy group is reacted with formula (4) or (5). A method for producing a carbostyryl derivative represented by the following general formula (1), which is characterized by the following formula.

In the above formula R ¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, Alkenyl groups having 2 to 4 carbon atoms, Alkynyl groups having 2 to 4 carbon atoms, or A phenylalkyl group having an alkylene group of 1 to 4 carbon atoms, R ² is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a phenyl group, R ³ is 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-trimethoxy benzoyl oxy group, R ⁴ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R ⁵ is phenyl having 1 to 3 substituted groups selected from the group consisting of a cycloalkyl group having 3 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms A substituted alkyl group having 1 to 4 carbon atoms having a group, a phenyl group or an alkanoyloxy group having 1 to 4 carbon atoms as a substituent, an alkanoyl group having 1 to 4 carbon atoms or a benzyl group, (If R ² is a phenyl group, R ⁵ should not be an alkyl group having 1 to 4 carbon atoms having a phenyl group as a substituent.) R ⁶ is a hydrogen atom, a hydroxy group or an alkyl group having 1 to 4 carbon atoms, R ⁷ is an alkanoyloxy group or 3,4,5-trimethoxybenzoyloxy group having 1 to 4 carbon atoms, X ¹ is a halogen atom or other substituent group capable of performing a substitution reaction similarly to a halogen atom (or

and

Is 1, X ¹ and R ⁶ may form an epoxy group), X is a halogen atom,

Is 0 or an integer of 1 or 2, Q is an integer of 2 or 3,

And

Are integers of 0 or 1 to 6, respectively

and

Must not exceed 6), Carbon-carbon bonds at the 3- and 4- positions in the carbostyryl backbone are single or double bonds, constitutional formula

The substituted position of the side chain is either the 4-, 5-, 6-, 7-, or 8-position.