JPS6325585B2 - - Google Patents

Description

[Detailed description of the invention]

The novel carbostyril derivative of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula (1). general formula [In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, or a lower alkenyl group. ^R2 is a halogen atom, lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, carboxy group, lower alkylthio group, lower alkanoyl group, hydroxyl group, nitro group, amino group, or cyano group, and n is 0 or 1 to 3. Indicates an integer. Also-
In (R ² ) _o , two R ² may be bonded to each other to form a lower alkylenedioxy group. Also, A is

[Formula] or

[Formula], B represents a lower alkylene group, and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are a single bond or a double bond, respectively.
However, when R ¹ is a hydrogen atom, n is 0, and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are single bonds, B is

It must not be [Formula] (R is a hydrogen atom or a lower alkyl group). The compound of the present invention represented by the above general formula (1) is:
It has central nervous system depressant and antihistamine effects,
Useful as a central nervous system depressant and antihistamine. The compound of the present invention has the following characteristics as a central nervous system depressant. That is, the compound of the present invention has a strong effect on suppressing fighting behavior in mice isolated for long periods of time, and shows a remarkable effect on suppressing fighting behavior in mice compared to diazepam, which is conventionally thought to have a strong effect. Excellent as a depressant. In addition, the compound of the present invention has strong anesthetic and sleep-enhancing effects such as various anesthesia and sleeping pills, and has a strong suppressive effect on fighting behavior in mice as described above, and is also excellent as a pre-anesthetic drug and a sleep-inducing drug. In addition, the compound of the present invention has central nervous system depressing effects such as muscle relaxant, blepharoptosis, hypothermia, locomotor activity suppression, hyperemotional suppression in olfactory bulbectomized rats (OB rats), anti-methamphetamine effect, and methamphetamine effect. group toxicity reducing effect,
It has analgesic and antiepinephrine effects, but its anticholinergic, cardiac depressant, and catalepsy-inducing effects are extremely weak. Therefore, a central nervous system depressant containing the compound of the present invention as an active ingredient does not have most of the side effects of conventional central nervous system depressants, such as thirst, constipation, tachycardia, parkinsonism, and tardive dyskinesia. For example, central muscle relaxants, sleep-inducing drugs, presurgical drugs, antischizophrenic drugs, sedatives and sedatives, anxiolytics, antimanic-depressive drugs,
It is useful as an antipyretic analgesic, antihypertensive, etc. Furthermore, since the compounds of the present invention are susceptible to drug metabolism in vivo, they are useful as short-acting central nervous system depressants, particularly as sleep-inducing drugs and pre-surgery drugs, and have extremely few side effects on the liver. Furthermore, the compound of the present invention has the following characteristics as an antihistamine. That is, antihistamines are
Gutsman Gilman Pharmacology Book [Part 1] Basic and Clinical Drug Treatment, pp. 781-835, published by Hirokawa Shoten (1974), New Applied Pharmacology, written by Hisashi Hano, pp. 307-319
p., Nagai Shoten (1970), New Drugs and Clinical Practice, Vol. 20, No.
No. 11, pp. 129-133 (1971) and Basic and Clinical Research, No.
As described in Vol. 10, No. 10, pp. 17-27 (1976), rather than suppressing the release of bound histamine due to allergic antigen-antibody reactions, the release of active histamine and histamine receptors It exerts antihistamine action by blocking the binding with (competitive antagonism). Therefore, the antihistamine of the present invention can be used to treat various diseases caused by the binding of histamine to histamine receptors, such as allergic symptoms of the respiratory tract such as combing, nasal discharge, itching of the eyes, nose, and throat, hay fever, hay fever, and acute Ginmachine (itch, edema, redness, etc.), angioedema, pruritus, atopic dermatitis,
Contact dermatitis, such as insect stings and sumac rash;
It is effective as a therapeutic or prophylactic drug for allergic diseases such as serum sickness, edematous disorders, allergic rhinitis, allergic conjunctivitis, and keratitis. Furthermore, the antihistamine of the present invention can be used as an adjunct in treating systemic anaphylaxis in which autacoids other than histamine are thought to play an important role. Furthermore, the antihistamine of the present invention can also be used as a diagnostic agent for measuring the acid secretion ability of the stomach. In this specification, each group represented by R ¹ , R ² and B is more specifically as follows. Lower alkyl groups: methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl groups, etc. Phenyl lower alkyl group...benzyl, 2-phenylethyl, 1-phenylethyl, 3-
phenylpropyl, 4-phenylbutyl,
1.1-dimethyl-2-phenylethyl, 5
-phenylpentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl groups, etc. Lower alkenyl group...vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl group, etc. Halogen atoms: fluorine, chlorine, bromine and iodine atoms. Lower alkoxy group...methoxy, ethoxy, propoxy, isopropoxy, butoxy,
tert-butoxy, pentyloxy, hexyloxy groups, etc. Lower alkoxycarbonyl group...methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,
Butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl groups, etc. Lower alkylthio groups: methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, pentylthio, hexylthio groups, etc. Lower alkanoyl group...formyl, acetyl,
propionyl, butyryl, isobutyryl,
pentanoyl, tert-butylcarbonyl,
Hexanoyl group, etc. Lower alkylene group: methylene, ethylene, trimethylene, 2-methyltrimethylene,
2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, hexamethylene groups, etc. In the above general formula (1)

Group represented by [Formula]... phenyl, 2-chlorophenyl, 3-
Chlorphenyl, 4-chlorphenyl, 2
-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromphenyl, 3-bromphenyl, 4-bromphenyl, 2-iodophenyl, 4-iodophenyl, 3,5-dichlorophenyl,
2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,5-dibromphenyl, 3,4,
5-Trichlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 3-isopropylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 2, 5-
Dimethylphenyl, 3,4,5-trimethylphenyl, 2-methoxyphenyl, 3-
Methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 3,
4,5-trimethoxyphenyl, 2,5-
Dimethoxyphenyl, 2-carboxyphenyl, 3-carboxyphenyl, 4-carboxyphenyl, 3,4-dicarboxyphenyl, 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 4
-Methoxycarbonylphenyl, 2-ethoxycarbonylphenyl, 3-ethoxycarbonylphenyl, 4-ethoxycarbonylphenyl, 4-isopropoxycarbonylphenyl, 4-hexyloxycarbonylphenyl, 3,4-diethoxycarbonyl phenyl, 2-methylthiophenyl, 3
-Methylthiophenyl, 4-methylthiophenyl, 2-ethylthiophenyl, 3-ethylthiophenyl, 4-ethylthiophenyl, 4-isopropylthiophenyl, 4-
hexylthiophenyl, 3,4-dimethylthiophenyl, 2-acetylphenyl, 3
-Acetyl phenyl, 4-acetylphenyl, 4-formylphenyl, 2-propionyl phenyl, 3-butyryl phenyl, 4
-Hexanoylphenyl, 3,4-diacetylphenyl, 2-nitrophenyl, 3-
Nitrophenyl, 4-nitrophenyl,
2,4-dinitrophenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2,4-diaminophenyl, 2
-cyanophenyl, 3-cyanophenyl,
4-cyanophenyl, 2,4-dicyanophenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl,
2,3-methylenedioxyphenyl, 3-
Methyl-4-chlorophenyl, 2-chloro-6-methylphenyl, 2-methoxy-3
-chlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 3,4,5-trihydroxyphenyl groups, etc. Lower alkylenedioxy group...methylenedioxy, ethylenedioxy, trimethylenedioxy group, etc. Representative compounds included in the carbostyryl derivative represented by the above general formula (1) are illustrated below. The 3,4-position dehydrogenated product of each compound refers to a compound in which the 3- and 4-position bonds of the carbostyril skeleton are double bonds. Γ 6-[1-oxo-4-(4-phenylpiperazinyl)butyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 6-{1-oxo-4-[4 -(4-fluorophenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(2-fluorophenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 6-{1-oxo-4-[4-(4-methylphenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(3-methylphenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(2-methylphenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenator Γ 6-{1-oxo-4-[4-(4-chlorophenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 6-{1-oxo-4-[4-(3-chlorophenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenator Γ 6-{1-oxo-4-[4-(2-chlorophenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenator Γ 6-{1-oxo-4-[4-(4-bromphenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(2-methoxyphenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenator Γ 6-{1-oxo-4-[4-(2-ethoxyphenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenator Γ 6-{1-oxo-4-[4-(3,4-dimethoxyphenyl)piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 6-{1-oxo-4-[4-(3,4,5
-trimethoxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo -4-[4-(2,3-dimethylphenyl)piperazinyl ]Butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(2,6-dichlorophenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 6-{1-oxo-4-[4-(2-chloro-6-methylphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 6-{1-oxo-4-[4-(4-carboxyphenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(4-methoxycarbonylphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3 , 4-position dehydrogenase Γ 6-{1-oxo-4-[4-(4-nitrophenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(4-acetylphenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(4-aminophenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenator Γ 6-{1-oxo-4-[4-(4-cyanophenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(4-hydroxyphenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(4-methylthiophenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 6-[1-oxo-3-[4-phenylpiperazinyl)propyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation Element Γ 6-{1-oxo-3-[4-(3-chlorophenyl)piperazinyl]propyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 6-{1-oxo-3-[4-(2-chlorophenyl)piperazinyl]propyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 6-{1-oxo-3-[4-(4-methylphenyl)piperazinyl]propyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-3-[4-(2-methoxyphenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-3-[4-(2,3-dimethylphenyl)piperazinyl]propyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenation product Γ 6-{1-oxo-3-[4-(2-chloro-6-methylphenyl)piperazinyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 6 -[1-oxo -2-[4-phenylpiperazinyl)ethyl]carbostyryl Γ 6-{1-oxo -2-[4-(4-chlorophenyl)piperazinyl]ethyl}-3,4-
Dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 6-{1-oxo-2-[4-(3-methylphenyl)piperazinyl]ethyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-2-[4-(2-ethoxyphenyl)piperazinyl]ethyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 6-{1-oxo-2-[4-(3-chlorophenyl)piperazinyl]propyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-2-[4-(4-methylphenyl)piperazinyl]propyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-2-[4-(2-methoxyphenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-2-[4-(4-chlorophenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-2-[4-(3-methylphenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-2-[4-(2-ethoxyphenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 6-{1-oxo-4-[4-(3-fluorophenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(3,4-dichlorophenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 6-{1-oxo-4-[4-(3,4,5
-trichlorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-5-(4-phenylpiperazinyl)pentyl]-3, 4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 6-[1-oxo-6-(4-phenylpiperazinyl)hexyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation Element Γ 6-[1-oxo-3-methyl-4-(4-
phenylpiperazinyl)butyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[1-oxo-3,3-dimethyl-4
-(4-phenylpiperazinyl)butyl]-3,
4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 6-{1-oxo-3-methyl-4-[4-
(2-chlorophenyl)piperazinyl]butyl}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(3-methoxyphenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 6-{1-oxo-4-[4-(4-methoxyphenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(4-ethoxyphenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenator Γ 6-{1-oxo-4-[4-(4-isopropoxyphenyl)piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenator Γ 6-{1-oxo-4-[4-(4-hexyloxyphenyl)piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 6-{1-oxo-3-methyl-4-[4-
(2-methoxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(2-ethylphenyl)piperazinyl]butyl} -3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenator Γ 6-{1-oxo-4-[4-(3-ethylphenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(4-ethylphenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenator Γ 6-{1-oxo-4-[4-isopropylphenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(4-hexylphenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 6-{1-oxo-4-[4-(2-carboxyphenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(3-carboxyphenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(2-methoxycarbonylphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3 , 4-position dehydrogenation product Γ 6-{1-oxo-4-[4-(3-methoxycarbonylphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 6 -{1-oxo -4-[4-(2-ethoxycarbonylphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 6-{1-oxo -4- [4-(4-isopropoxycarbonylphenyl)piperazinyl]
6-{1-oxo-4-[4-(4-hexyloxycarbonylphenyl)piperazinyl]
6-{1-oxo-4-[4-(2-nitrophenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(3-nitrophenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(2-acetylphenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 6-{1-oxo-4-[4-(3-acetylphenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 6-{1-oxo-4-[4-(4-isobutyryl phenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 6-{1-oxo-4-[4-(2-aminophenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(3-aminophenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(2-cyanophenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenator Γ 6-{1-oxo-4-[4-(3-cyanophenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenator Γ 6-{1-oxo-4-[4-(2-hydroxyphenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(3-hydroxyphenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(3,4-dihydroxyphenyl)piperazinyl]butyl}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(2-methylthiophenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(3-methylthiophenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(4-isopropylthiophenyl)piperazinyl]butyl}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(4-hexylthiophenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(3,4-methylenedioxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(3,4-ethylenedioxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4 Dehydrogenated product Γ 6-{1-oxo-3-[4-(4-chlorophenyl)piperazinyl]propyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenator Γ 6-{1-oxo-3-[4-(2-fluorophenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-3-[4-(3-fluorophenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-3-[4-(4-fluorophenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-3-[4-(3-methoxyphenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 6-{1-oxo-3-[4-(4-methoxyphenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-3-[4-(2-methylphenyl)piperazinyl]propyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-3-[4-(3-methylphenyl)piperazinyl]propyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 6-{1-oxo-3-[4-(4-methylphenyl)piperazinyl]propyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-5-[4-(2-chlorophenyl)piperazinyl]pentyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-5-[4-(3-chlorophenyl)piperazinyl]pentyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-5-[4-(4-chlorophenyl)piperazinyl]pentyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-5-[4-(2-fluorophenyl)piperazinyl]pentyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-5-[4-(3-fluorophenyl)piperazinyl]pentyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-5-[4-(4-fluorophenyl)piperazinyl]pentyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-5-[4-(2-methylphenyl)piperazinyl]bentyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-5-[4-(3-methylphenyl)piperazinyl]pentyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 6-{1-oxo-5-[4-(4-methylphenyl)piperazinyl]pentyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenator Γ 6-{1-oxo-5-[4-(2,3-dimethylphenyl)piperazinyl]pentyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenase Γ 6-{1-oxo-5-[4-(2-methoxyphenyl)piperazinyl]pentyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 6-{1-oxo-5-[4-(3-methoxyphenyl)piperazinyl]pentyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-5-[4-(4-methoxyphenyl)piperazinyl]pentyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-6-[1-oxo-4-(4-
phenylpiperazinyl)butyl]-3,4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 1-ethyl-6-[1-oxo-4-(4-
phenylpiperazinyl)butyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-isopropyl-6-[1-oxo-4
-(4-phenylpiperazinyl)butyl]-3,
4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 1-Butyl-6-[1-oxo-4-(4-
phenylpiperazinyl)butyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-hexyl-6-[1-oxo-3-(4
-phenylpiperazinyl)propyl]-3,4
-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 1-methyl-6-[1-oxo-3-(4-
phenylpiperazinyl)propyl]-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-6-{1-oxo-4-[(4
-fluorophenyl)piperazinyl]butyl}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-6-{1-oxo-4-[4-
(2-chlorophenyl)piperazinyl]butyl}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-6-{1-oxo-4-[4-
(4-methylphenyl)piperazinyl]butyl}
-3,4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 1-methyl-6-{1-oxo-4-[4-
(2,3-dimethylphenyl)piperazinyl]
1-methyl-6-{1-oxo-4-[4-
(2-methoxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 1-methyl-6-{1-oxo-4-[4-
(4-Methoxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 1-methyl-6-{1-oxo-4-[4-
(4-carboxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 1-methyl-6-{1-oxo-4-[4-
(3,4-methylenedioxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 1-allyl-6-[1-oxo-3-(4-
phenylpiperazinyl)propyl]-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-crotyl-6-[1-oxo-4-(4
-phenylpiperazinyl)butyl]-3,4-
Dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 1-allyl-6-{1-oxo-4-[4-
(4-fluorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 1-allyl-6-{1-oxo-4-[4-
(2-fluorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 1-allyl-6-{1-oxo-4-[4-
(2-chlorophenyl)piperazinyl]butyl}
-3,4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 1-(2-hexenyl)-6-{1-oxo
-4-[4-(3-chlorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 1-allyl-6-{1-oxo-4-[4-
(2-methylphenyl)piperazinyl]butyl}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-allyl-6-{1-oxo-4-[4-
(3,4-dimethylphenyl)piperazinyl]
1-allyl-6-{1-oxo-4-[4-
(2-methoxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 1-allyl-6-{1-oxo-4-[4-
(4-methoxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 1-allyl-6-{1-oxo-4-[4-
(4-Methoxycarbonylphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 1-allyl-6-{1-oxo-4-[4-
(4-Methylthiophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-6-[1-oxo-3-(4
-phenylpiperazinyl)butyl]-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-(2-phenylethyl)-6-[1-oxo-4-(4-phenylpiperazinyl)butyl}-3,4-dihydrocarbostyryl and Its 3,4-position dehydrogenated product Γ 1-(6-phenylhexyl)-6-[1-oxo-4-(4-phenylpiperazinyl)butyl}-3,4-dihydrocarbostyryl and its 3,4 Dehydrogenated product Γ 1-benzyl-6-{1-oxo-4-[4
-(2-fluorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 1-benzyl-6-{1-oxo-4-[4
-(4-fluorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-6-{1-oxo-4-[4
-(2-chlorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 1-benzyl-6-{1-oxo-4-[4
-(2-methoxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 1-benzyl-6-{1-oxo-4-[4
-(4-methylphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 1-benzyl-6-{1-oxo-4-[4
-(2,3-dimethylphenyl)piperazinyl]
1-benzyl-6-{1-oxo-4-[4
-(4-nitrophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-6-{1-oxo-4-[4
-(4-cyanophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 1-benzyl-6-{1-oxo-4-[4
-(2-hydroxyphenyl)piperazinyl]
1-(2-propynyl)-6-[1-oxo
-3-(4-phenylpiperazinyl)propyl]
-3,4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 1-(2-butynyl)-6-[1-oxo-
4-(4-phenylpiperazinyl)butyl]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenase Γ 1-(2-hexynyl)-6-[1-oxo
-4-(4-phenylpiperazinyl)butyl]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 1-(2-propynyl)-6-{1-oxo
-4-[4-(2-chlorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-(2-propynyl)-6-{1-oxo
-4-[4-(4-methylphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-(2-propynyl)-6-{1-oxo
-4-[4-(2-methoxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[hydroxy-4-(4-phenylpiperazinyl) )butyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(4-fluorophenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(2-fluorophenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(4-methylphenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(3-methylphenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(2-methylphenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(4-chlorophenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(3-chlorophenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(2-chlorophenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(4-bromphenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(2-methoxyphenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(2-ethoxyphenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(3,4-
dimethoxyphenyl)piperazinyl]butyl}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(3,4,
5-trimethoxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(2,3-
dimethylphenyl)piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(2,6-
dichlorophenyl)piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenation product Γ 6-{1-hydroxy-4-[4-(2-chloro-6-methylphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 6 -{1-hydroxy-4-[4-(4-carboxyphenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 6-{1-hydroxy-4-[4-(4-methoxycarbonylphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3 , 4-position dehydrogenation product Γ 6-{1-hydroxy-4-[4-(4-nitrophenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(4-acetylphenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(4-aminophenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(4-cyanophenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(4-hydroxyphenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(4-methylthiophenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[1-hydroxy-3-[4-(4-phenylpiperazinyl]propyl]-3,4-dihydrocarbostyryl and its 3, 4-position dehydrogenation product Γ 6-{1-hydroxy-3-[4-(3-chlorophenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-3-[4-(2-chlorophenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-3-[4-(4-methylphenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-3-[4-(2-methoxyphenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-3-[4-(2,3-
dimethylphenyl)piperazinyl]propyl}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-3-[4-(2-chloro-6-methylphenyl)piperazinyl]propyl}-3,4-dihydrocarbo Styryl and its 3,4-position dehydrogenation product Γ 6-[1-hydroxy-2-(4-phenylpiperazinyl)ethyl] carbostyryl Γ 6-{1-hydroxy-2-[4-(4-chlorophenyl) piperazinyl]ethyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-2-[4-(3-methylphenyl)piperazinyl]ethyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-2-[4-(2-ethoxyphenyl)piperazinyl]ethyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-2-[4-(3-chlorophenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-2-[4-(4-methylphenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-2-[4-(2-methoxyphenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-2-[4-(4-chlorophenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-2-[4-(3-methylphenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-2-[4-(2-ethoxyphenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(3-fluorophenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(3,4-
dichlorophenyl)piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(3,4,
5-Trichlorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[1-hydroxy-5-(4-phenylpiperazinyl)pentyl]-3 , 4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[1-hydroxy-6-(4-phenylpiperazinyl)hexyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Dehydrogenate Γ 6-[1-hydroxy-3-methyl-4-(4
-phenylpiperazinyl)butyl]-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[1-hydroxy-3,3-dimethyl-
4-(4-phenylpiperazinyl)butyl]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 6-{1-hydroxy-3-methyl-4-[4
-(2-chlorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(3-methoxyphenyl)piperazinyl]butyl }-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(4-methoxyphenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(4-ethoxyphenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(4-isopropoxyphenyl)piperazinyl]butyl}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(4-hexyloxyphenyl)piperazinyl]butyl}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-3-methyl-4-[4
-(2-methoxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(2-ethylphenyl)piperazinyl]butyl }-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(3-ethylphenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(4-ethylphenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(4-isopropylphenyl)piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(4-hexylphenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(2-carboxyphenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(3-carboxyphenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(2-methoxycarbonylphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3 , 4-position dehydrogenation product Γ 6-{1-hydroxy-4-[4-(3-methoxycarbonylphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 6 -{1-hydroxy-4-[4-(2-ethoxycarbonylphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4- [4-(4-isopropoxycarbonylphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(4-hexyl) oxycarbonylphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(2-nitrophenyl)piperazinyl]butyl}-3 ,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(3-nitrophenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(2-acetylphenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(3-acetylphenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(4-isobutyryl phenyl)piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(2-aminophenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(3-aminophenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(4-cyanophenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(3-cyanophenyl)piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(2-hydroxyphenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(3-hydroxyphenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(3,4-
dihydroxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(2-methylthiophenyl)piperazinyl]butyl}- 3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(3-methylthiophenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(4-isopropylthiophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3 , 4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(4-hexylthiophenyl)piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(3,4-
methyldioxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(3,4-
ethylenedioxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-3-[4-(4-chlorophenyl)piperazinyl]propyl}- 3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-3-[4-(2-fluorophenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-3-[4-(3-fluorophenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-3-[4-(4-fluorophenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-3-[4-(3-methoxyphenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-3-[4-(4-methoxyphenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-3-[4-(2-methylphenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-3-[4-(3-methylphenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-3-[4-(4-methylphenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-5-[4-(2-chlorophenyl)piperazinyl]pentyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-5-[4-(3-chlorophenyl)piperazinyl]pentyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-5-[4-(4-chlorophenyl)piperazinyl]pentyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-5-[4-(2-fluorophenyl)piperazinyl]pentyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-5-[4-(3-fluorophenyl)piperazinyl]pentyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-5-[4-(4-fluorophenyl)piperazinyl]pentyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-5-[4-(2-methylphenyl)piperazinyl]pentyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-5-[4-(3-methylphenyl)piperazinyl]pentyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-5-[4-(4-methylphenyl)piperazinyl]pentyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-5-[4-(2,3-
dimethylphenyl)piperazinyl]pentyl}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-5-[4-(2-methoxyphenyl)piperazinyl]pentyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-5-[4-(3-methoxyphenyl)piperazinyl]pentyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-5-[4-(4-methoxyphenyl)piperazinyl]pentyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-6-[1-hydroxy-4-(4
-phenylpiperazinyl)butyl]-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-ethyl-6-[1-hydroxy-4-(4
-phenylpiperazinyl)butyl]-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-isopropyl-6-[1-hydroxy-
4-(4-phenylpiperazinyl)butyl]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 1-butyl-6-[1-hydroxy-4-(4
-phenylpiperazinyl)butyl]-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-hexyl-6-[1-hydroxy-3-
(4-phenylpiperazinyl)propyl]-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-6-[1-hydroxy-3-(4
-phenylpiperazinyl)propyl]-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-6-{1-hydroxy-4-[4
-(4-fluorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-6-{1-hydroxy-4-[4
-(2-chlorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 1-methyl-6-{1-hydroxy-4-[4
-(4-methylphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 1-methyl-6-{1-hydroxy-4-[4
-(2,3-dimethylphenyl)piperazinyl]
1-methyl-6-{1-hydroxy-4-[4
-(2-methoxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 1-methyl-6-{1-hydroxy-4-[4
-(4-methoxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-6-{1-hydroxy-4-[4
-(4-carboxyphenyl)piperazinyl]
1-methyl-6-{1-hydroxy-4-[4
1-allyl-6-[1-hydroxy-3-(4
-phenylpiperazinyl)propyl]-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-crotyl-6-[1-hydroxy-4-
(4-phenylpiperazinyl)butyl]-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-allyl-6-{1-hydroxy-4-[4
-(4-fluorophenyl)piperazinyl)butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-allyl-6-{1-hydroxy-4-[4
-(2-fluorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-allyl-6-{1-hydroxy-4-[4
1-(2-hexenyl)-6-{1-hydroxy-4-[4-(3 1-allyl-6-{1-hydroxy-4-[4
-(2-methylphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-allyl-6-{1-hydroxy-4-[4
-(3,4-dimethylphenyl)piperazinyl]
1-allyl-6-{1-hydroxy-4-[4
-(2-methoxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 1-allyl-6-{1-hydroxy-4-[4
-(4-methoxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 1-allyl-6-{1-hydroxy-4-[4
-(4-Methoxycarbonylphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 1-allyl-6-{1-hydroxy-4-[4
-(4-methylthiophenyl)piperazinyl]
1-benzyl-6-[1-hydroxy-3-
(4-phenylpiperazinyl)butyl]-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-(2-phenylethyl)-6-[1-hydroxy-4-(4-phenylpiperazinyl)butyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-(6-phenylhexyl)-6-[1-hydroxy-4-(4-phenylpiperazinyl)
1-benzyl-6-{1-hydroxy-4-
[4-(2-fluorophenyl)piperazinyl]
1-benzyl-6-{1-hydroxy-4-
[4-(4-fluorophenyl)piperazinyl]
1-benzyl-6-{1-hydroxy-4-
[4-(2-chlorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 1-benzyl-6-{1-hydroxy-4-
[4-(2-methoxyphenyl)piperazinyl]
1-benzyl-6-{1-hydroxy-4-
[4-(4-methylphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-6-{1-hydroxy-4-
[4-(2,3-dimethylphenylpiperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-6-{1-hydroxy-4-
[4-(4-nitrophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-6-{1-hydroxy-4-
[4-(4-cyanophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-6-{1-hydroxy-4-
[4-(2-hydroxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-(2-propynyl)-6-[1-hydroxy-3-( 4-phenylpiperazinyl)propyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-(2-butynyl)-6-[1-hydroxy-4-(4-phenyl) piperacinyl)butyl]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenator Γ 1-(2-hexynyl)-6-[1-hydroxy-4-(4-phenylpiperazinyl)butyl]
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-(2-propynyl)-6-{1-hydroxy-4-[4-(2-chlorophenyl)piperazinyl]butyl}-3, 4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-(2-propynyl)-6-{1-hydroxy-4-[4-(4-methylphenyl)piperazinyl]butyl}-3,4-dihydro Carbostyryl and its 3,4-position dehydrogenate Γ 1-(2-propynyl)-6-{1-hydroxy-4-[4-(2-methoxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbo Styryl and its 3,4-position dehydrogenate The compound of the present invention can be produced by various methods, and one preferred example thereof is produced by the method shown in the following reaction scheme-1. Reaction equation 1 [In the above formula, X represents a halogen atom.
R ¹ , R ² , n, A, B, and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. ] That is, the compound of the present invention represented by general formula (1) is
The carbostyril derivative represented by the general formula (2),
It is produced by reacting a piperazine derivative represented by general formula (3). The above reaction is carried out without a solvent or in a normal inert solvent at room temperature to about 200°C.
Preferably under temperature conditions of 60-120℃ for several hours to 24
It will be completed in about an hour. Examples of inert solvents include ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, and diethyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, methanol, ethanol,
Lower alcohols such as isopropanol, polar solvents such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, acetone, and acetonitrile can be used. The above reaction is more advantageously carried out using a basic compound as a deoxidizing agent. Examples of the basic compound include tertiary amines such as potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium amide, sodium hydride, triethylamine, tripropyleneamine, pyridine, and quinoline. The above reaction may be carried out by adding an alkali metal iodide compound such as potassium iodide or sodium iodide or hexamethylphosphoric acid triamide as a reaction promoter, if necessary. The ratio of the compound represented by the general formula (2) and the compound represented by the general formula (3) in the above reaction is not particularly limited and is appropriately selected within a wide range, but the latter is usually equal to the former. The molar to excess amount is preferably equimolar to 5 times the mole, more preferably 1 to 1.2 times the mole. The compound of general formula (2) used as a starting material includes known compounds and new compounds, and is produced, for example, by the method shown in Reaction Scheme-2 below. The compound of general formula (3) used as the starting material for the other one is a known compound [see JP-A-55-2693, JP-A-54-160389, West German Publication No. 2912105] or This compound is easily produced according to the method described in the publication. Reaction equation 2 [In the above formula, X′ represents a halogen atom, and R ³ represents a lower alkyl group, an aryl group, or an aralkyl group. R ¹ , B, X, and carbostyril skeleton 3
The carbon-carbon bond at position and 4-position is the same as above. ] That is, in the compound of general formula (2), A is

[Formula] A compound (compound of general formula (2a)) can be obtained by reacting a known compound of general formula (4) with a known compound of general formula (5) or a known compound of general formula (6). , or produced by reacting a compound of general formula (4) with a known compound of general formula (7), and then reacting the resulting compound of general formula (8) with a compound of general formula (9). Also, in the compound of general formula (2), A is

[Formula] A compound (compound of general formula (2b)) is produced by reacting a compound of general formula (2a) with sodium borohydride. Compound of general formula (4) and general formula (5) or general formula (6)
The reaction with the compound is generally called the Friedel-Crafts reaction, and this reaction is carried out in a solvent in the presence of a Lewis acid. As the solvent used in this case, those commonly used in this type of reaction are advantageously used, and examples thereof include carbon disulfide, nitrobenzene, chlorobenzene, dichloromethane, dichloroethane, trichloroethane, and tetrachloroethane. Furthermore, conventionally used Lewis acids are preferably used, such as aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, boron trifluoride, concentrated sulfuric acid, and the like. The amount of Lewis acid to be used may be determined appropriately, but it is usually about 2 to 6 times the mole, preferably about 3 to 4 times the mole of the compound of general formula (4). General formula (5)
The amount of the compound or the compound of general formula (6) to be used is:
The amount used is usually at least equimolar, preferably equimolar to twice the molar amount of the compound of general formula (4). The reaction temperature is selected appropriately, but is usually 20~
The temperature is preferably about 120°C, preferably about 40 to 70°C. The reaction time for this reaction varies depending on the raw materials, catalyst, reaction temperature, etc., and cannot be generalized, but it is usually 0.5~
The reaction is completed in about 6 hours. The reaction between the compound of general formula (4) and the compound of general formula (7) can be carried out in the same manner as the reaction between the compound of general formula (4) and the compound of general formula (5) or general formula (6). Bye. The reaction between the compound of general formula (8) and the compound of general formula (9) is carried out in the presence of the above-mentioned deoxidizing agent in a suitable inert solvent, usually at about -30°C to 50°C, preferably at 0°C to room temperature. It takes about 1 to 12 hours. The ratio of the compound of general formula (8) and the compound of general formula (9) to be used may be appropriately selected within a wide range, but usually the latter is about equal mole or more to the former, preferably equimolar to 2 It is better to use twice the molar amount. Examples of the inert solvent include halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as benzene and toluene, dimethyl sulfoxide, dimethylformamide, and pyridine. Specifically, the aryl group represented by R ³ in the above general formula (9) includes phenyl, 4-methylphenyl, 2-methylphenyl, 4-nitrophenyl, 4-methoxyphenyl, 3-chlorophenyl, substituted or Examples of unsubstituted aryl groups include benzyl, 2-phenylethyl, 4-phenylbutyl, 4-methylbenzyl, 2-methylbenzyl, 4-nitrobenzyl, 4-methoxybenzyl, 3- Examples include substituted or unsubstituted aralkyl groups such as chlorobenzyl and α-naphthylmethyl groups. The reaction between the compound of general formula (2a) and sodium borohydride is usually carried out at -60°C or more in a suitable inert solvent.
About 50℃, preferably -30℃ ~ 10 minutes at room temperature
It will take about 3 hours. Examples of inert solvents used include water, lower alcohols such as methanol, ethanol, and propanol, dioxane,
Ethers such as tetrahydrofuran can be mentioned. The amount of sodium borohydride to be used can be suitably determined within a wide range, but usually the amount of sodium borohydride is at least equimolar, preferably equimolar to 3 times the molar amount of the compound of general formula (2a). It is best to use a certain amount. Further, the compound of the present invention represented by the general formula (1) can be produced by the method shown in the following reaction scheme-3. Reaction equation 3 [In the above formula, R ¹ , R ² , n, A, B, X, and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. ] That is, the compound of the present invention is produced by reacting a carbostyril derivative represented by general formula (12) with a known benzene derivative represented by general formula (14). The compound of general formula (12) is the compound of general formula (2)
A compound of general formula (13) is reacted with a compound of general formula (13), or a compound of general formula (2) is reacted with a compound of general formula (10), and then the resulting compound of general formula (11) is debenzylated. Manufactured by The reaction between the compound of general formula (2) and the compound of formula (13) and the reaction between the compound of general formula (2) and the compound of general formula (10) are the reactions between the compound of general formula (2) and the compound of general formula (10). This can be carried out in the same manner as the reaction of the compound in 3). The debenzylation of the compound of general formula (11) is carried out by the usual de-N removal process.
- A wide range of conditions can be used for the benzylation reaction, for example, in the presence of a catalytic reduction catalyst such as palladium-carbon, palladium-black, etc. in an appropriate solvent at 0°C to around room temperature.
It takes about 0.5 to 3 hours. Examples of solvents include water, lower alcohols such as methanol, ethanol, and isopropanol, dioxane,
Examples include ethers such as tetrahydrofuran, acetic acid, and the like. The reaction between the compound of general formula (12) and the compound of general formula (14) is generally carried out in a suitable inert solvent in the presence or absence of a basic condensing agent. Examples of inert solvents used include aromatic hydrocarbons such as benzene, toluene, and xylene, methanol, ethanol, propanol, butanol, and
Examples include alcohols such as -methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, pyridine, acetone, dimethyl sulfoxide, dimethyl formamide, and hexamethyl phosphoric triamide. Examples of the basic condensing agent include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, and triethylamine. The ratio of the compound of general formula (12) and the compound of general formula (14) to be used is not particularly limited and may be appropriately selected within a wide range, but the latter is usually at least equimolar to the former. , preferably in an equimolar to 5-fold molar amount. The reaction is usually carried out at room temperature to about 180°C, preferably 100 to 150°C, and is generally completed in about 3 to 30 hours. Further, the compound of the present invention represented by the general formula (1) can be produced by the method shown in the following reaction scheme-4. Reaction equation 4 [In the above formula, X ¹ and X ² are halogen atoms,
It represents a lower alkanesulfonyloxy group, an arylsulfonyloxy group, or an aralkylsulfonyloxy group. R ¹ , R ² , n, A, B, and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. ] That is, the compound of the present invention is produced by reacting a carbostyryl derivative represented by general formula (15) with a known aniline derivative represented by general formula (16). The reaction between the compound of general formula (15) and the compound of general formula (16) is generally carried out in a suitable inert solvent in the presence or absence of a basic condensing agent. Examples of inert solvents that can be used include aromatic hydrocarbons such as benzene, toluene, and xylene, lower alcohols such as methanol, ethanol, isopropanol, and butanol, acetic acid, ethyl acetate, dimethyl sulfoxide, dimethylformamide, and hexamethyl phosphoric acid. Triamides and the like can be mentioned. Examples of the basic condensing agent include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, pyridine, and triethylamine. Compound of general formula (15) and general formula (16)
There is no particular limitation on the ratio of the compound to be used, and it may be selected appropriately within a wide range, but it is usually at least an equimolar amount of the latter, preferably an equimolar to 5 times the molar amount of the former. . The reaction is usually carried out at a temperature of about 40 to 120°C, preferably 70 to 100°C, and is generally completed in about 1 to 15 hours. In the above reaction, A is the compound of general formula (15).

When a compound represented by the formula is used, the carbonyl group of the compound of general formula (15) and the amino group of the compound of general formula (16) may be dehydrated and condensed to form a Schiff base compound. In this case, the Schiff base compound produced may be hydrolyzed in the presence of an acid. For this hydrolysis, usual conditions that can decompose Schiff's base into carbonyl groups can be adopted, for example, in the presence of an acid in a suitable inert solvent, usually at room temperature to about 100°C, preferably at room temperature to 50°C, and at a temperature of 0.5 to
Hydrolysis can be carried out in about 3 hours. Examples of the inert solvent that can be used include water, lower alcohols such as methanol, ethanol, and isopropanol, ethers such as dioxane and tetrahydrofuran, dimethyl sulfoxide, and dimethyl formamide. Examples of acids include mineral acids such as hydrochloric acid, sulfuric acid, and nitric acid. It is generally advisable to use the acid in a large excess amount relative to the Schiff base compound. The compound of general formula (15) used as a starting material is a new compound, for example, the following reaction scheme -
It is manufactured by the method shown in 5 or 6. Reaction equation 5 [In the above formula, R ¹ , B, X, X ¹ , X ² and the carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton are the same as above. ] Reaction equation 6 [In the above formula, R ¹ , A, B, X, X ¹ , X ² and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. ] According to reaction scheme-5, in the compound of general formula (15), A is

The compound represented by [Formula] (compound of general formula (15a)) is produced by reacting the compound of general formula (2a) with a known compound of formula (17), and then the resulting compound of general formula (18) is halogenated. It is produced by reacting a sulfonating agent or a sulfonating esterifying agent. Also, in the compound of general formula (15), A is

The compound represented by the formula (compound of general formula (15b)) is produced by reducing the compound of general formula (15a). General formula (2a) used here
The compound of formula (2) above is one in which A is

It is a compound having the formula: The reaction between the compound of general formula (2a) and the compound of formula (17) may be carried out in the same manner as the reaction between the compound of general formula (2) and the compound of general formula (3). The reaction between the compound of general formula (18) and the halogenating agent is carried out in a suitable inert solvent. Here, the halogenating agent is, for example, N,N-diethyl-
Examples include 1,2,2-trichlorovinylamide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, and the like. Examples of inert solvents include ethers such as dioxane and tetrahydrofuran, and halogenated hydrocarbons such as chloroform and methylene chloride. The compound of general formula (18) and the halogenating agent are used in a molar ratio of at least twice the amount of the latter relative to the former, usually in excess. The reaction is usually carried out at room temperature to about 100°C.
Preferably carried out at 40-70°C, generally 1-6
The reaction completes in about an hour. The reaction between the compound of general formula (18) and the sulfonating esterifying agent is carried out in a suitable inert solvent in the presence of a basic condensing agent. Examples of the sulfonating esterifying agent include alkanesulfonyl halides or arylsulfonyl halides such as mesityl chloride, mesitylbromide, and tosyl chloride. Examples of inert solvents include aromatic hydrocarbons such as benzene and toluene, ethers such as dioxane and tetrahydrofuran, pyridine, dimethyl sulfoxide, dimethylformamide, and hexamethylphosphoric acid triamide, and examples of basic condensing agents include triethylamine. , pyridine, tertiary amines such as N,N-dimethylaniline, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, and the like. General formula (18)
The ratio of the compound and the sulfonating esterifying agent is usually at least 2 times the former to the latter.
It is preferable to use twice the molar amount, preferably 2 to 4 times the molar amount. The reaction is usually carried out at -30 to 100°C, preferably at 0°C.
The reaction is carried out at ~50°C and generally completes in about 1 to 15 hours. Reduction of the compound of general formula (15a) is carried out using, for example, sodium borohydride. Such a reduction reaction may be carried out in the same manner as the reaction between the compound of general formula (2a) and sodium borohydride. According to Reaction Scheme-6, the compound of general formula (15) is the compound of general formula (19), which is the known general formula (19) of the compound of general formula (2).
It is produced by reacting the following compounds. The reaction between the compound of general formula (2) and the compound of general formula (19) may be carried out in the same manner as the reaction between the compound of general formula (2) and the compound of general formula (3). Reaction equation 7 [In the above formula, R ¹ , R ² , n, A, B, X,
X ¹ , X ² , and the 3rd and 4th positions of the carbostyril skeleton
The carbon-carbon bond at position is the same as above. ] That is, the compound of the present invention is produced by reacting a carbostyril derivative represented by general formula (22) with a known aniline derivative represented by general formula (23). The compound of general formula (22) is produced by reacting the compound of general formula (2) with a known compound of formula (20), and then debenzylating the resulting compound of general formula (21). . The reaction between the compound of general formula (2) and the compound of formula (20) may be carried out in the same manner as the reaction between the compound of general formula (2) and the compound of general formula (3). Further, the debenzylation of the compound of general formula (21) may be carried out in the same manner as the debenzylation of the compound of general formula (11). Further, the reaction between the compound of general formula (22) and the compound of general formula (23) may be carried out in the same manner as the reaction between the compound of general formula (15) and the compound of general formula (16). Further, the compound of the present invention represented by the general formula (1) can be produced by the method shown in the following reaction scheme-8. Reaction equation 8 [In the above formula, R ¹ , R ² , n, B, and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. ] That is, the compound of the present invention is produced by reacting a carbostyril derivative represented by the known general formula (24) with an aniline derivative represented by the known general formula (16). The reaction between the compound of general formula (24) and the compound of general formula (16) is carried out without a solvent or in the presence of an acid in a suitable solvent. Examples of the solvent used include high boiling point solvents such as tetralin, dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. Examples of acids include hydrochloric acid, sulfuric acid, and hydrobromic acid. The ratio of the compound of general formula (24) and the compound of general formula (16) to be used is not particularly limited and may be appropriately selected within a wide range, but usually the latter is preferably at least an equimolar amount to the former. is preferably used in an equimolar to twice molar amount. The reaction is usually 5
The reaction is preferably carried out at a temperature of about 150 to 200°C, preferably about 150 to 200°C, and the reaction is generally completed in about 1 to 24 hours. In this reaction, the substituent on the phenyl ring
In compounds where R ² is a lower alkoxycarbonyl group or a cyano group, these groups may be simultaneously converted into corresponding carboxy groups. Furthermore, in compounds where R ² is a lower alkoxy group and compounds where (R ² ) _o is a lower alkylenedioxy group, these groups may be simultaneously converted to the corresponding hydroxyl group. Furthermore, in the compound of the present invention represented by general formula (1), A is

The compound represented by [Formula] (compound of general formula (1b)) is A as shown in the following reaction scheme-9.
but

It can also be produced by reducing a compound represented by the formula (compound of general formula (1a)). Reaction equation 9 [In the above formula, R ¹ , R ² , n, B, and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. ] The reduction of the compound of general formula (1a) is carried out by a reduction method using a hydrogenation reducing agent, a catalytic reduction method, or the like. When a reduction method using a hydrogenation-reducing agent is employed, the hydrogenation-reduction agent used is, for example, sodium borohydride, lithium aluminum hydroxide, etc., and preferably sodium borohydride. The hydrogenation reducing agent is usually used in at least an equimolar amount, preferably an equimolar amount to the compound of general formula (1a).
It is preferable to use 3 times the molar amount. Reduction reactions using hydrogenation reducing agents include water, methanol, ethanol,
The reaction is carried out in a suitable solvent such as a lower alcohol such as isopropanol, or an ether such as tetrahydrofuran or ethyl ether, usually at a temperature of -60 to 50°C, preferably -30°C to room temperature, and the reaction is generally carried out for 10 minutes to 3 hours. It ends with about. In addition, when using lithium aluminum hydride as a reducing agent, it is preferable to use an anhydrous solvent such as ethyl ether or tetrahydrofuran. In addition, when using the catalytic reduction method,
As a reduction catalyst, for example, platinum oxide, palladium black,
Commonly used catalysts for catalytic reduction such as palladium on carbon and Raney-nickel are used. The amount of catalyst used is usually about 0.2 for the compound of general formula (1a).
It is best to make it ~0.5 times the weight. This catalytic reduction is carried out in a solvent such as water, methanol, ethanol, isopropanol, tetrahydrofuran, ethyl ether, etc. by stirring well in a hydrogen atmosphere, usually at 1 to 10 atm, preferably at 1 to 3 atm. The reduction is generally carried out in the range of -30°C to the boiling point of the solvent,
It is preferably carried out at a temperature of 0°C to around room temperature. In the above reduction reaction, in the case of catalytic reduction in the low temperature range of about 0°C to room temperature or in the case of reduction using a hydrogenation reducing agent, the 3rd and 4th positions of the carbostyril skeleton are
The double bond between the positions is hardly reduced, and a compound in which the carbonyl group at the 6th position is reduced (a compound of general formula (1b)) is mainly produced. In addition, in this reaction, a compound in which the substituent R ² on the phenyl ring is a halogen atom, a lower alkoxycarbonyl group, a lower alkylthio group, a lower alkanoyl group, a nitro group, or a cyano group, and a compound in which R ¹ is a lower alkenyl group or a lower alkynyl group In some compounds, these groups may be reduced simultaneously. Furthermore, among the compounds of the present invention represented by the general formula (1), compounds in which R ¹ represents a lower alkyl group, a phenyl lower alkyl group, a lower alkenyl group, or a lower alkynyl group (compounds of the general formula (1d)) can be used for the following reaction. It can also be produced by reacting a compound in which R ¹ represents a hydrogen atom (compound of general formula (1c)) with a known compound of general formula (25), as shown in process formula-10. Reaction equation 10 [In the above formula, R ¹ ' represents a lower alkyl group, a phenyl lower alkyl group, a lower alkenyl group, or a lower alkynyl group. R ² ' is a halogen atom, lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, carboxy group, lower alkylthio group, lower alkanoyl group, hydroxyl group, nitro group, or cyano group, and n is 0 or an integer from 1 to 3. show. In addition, in -(R ² ′) _o , two R ² ′s may be bonded to each other to form a lower alkylenedioxy group. A, B,
X and the carbon-carbon bonds at the 3rd and 4th positions of the carbostyril skeleton are the same as above. ] The reaction between the compound of general formula (1c) and the compound of general formula (25) is preferably carried out, for example, in the presence of a basic compound in a suitable solvent. Examples of the basic compound include sodium hydride, potassium, sodium, sodium amide, potassium amide, and the like. Examples of the solvent include ethers such as dioxane, diethylene glycol, and dimethyl ether, aromatic hydrocarbons such as toluene and xylene, dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. The ratio of the compound of general formula (1c) and the compound of general formula (25) to be used is not particularly limited and may be appropriately selected within a wide range.
Generally, it is preferable to use at least an equimolar amount of the latter to the former, preferably an equimolar to twice the molar amount. The reaction is usually carried out at a temperature of about 0 to 70°C, preferably 0 to 70°C.
The reaction is carried out at a temperature of 0.degree. C. to around room temperature, and generally completes in about 0.5 to 12 hours. In this reaction, in the case of a compound in which the substituent R ² ' on the phenyl ring is a carboxyl group or a hydroxyl group, these groups may be simultaneously converted into the corresponding ester group or ether group. In such cases, the desired compound can be obtained by subsequent heating and hydrolysis with an acid such as hydrochloric acid or hydrobromic acid. Further, among the compounds of the present invention represented by the general formula (1), a compound in which R ² represents an amino group can be easily produced by reducing a compound in which R ² represents a nitro group. For this reduction, for example, the usual conditions for reducing an aromatic nitro group to an aromatic amino group can be adopted, and more specifically, a method using a reducing agent such as sodium sulfite or sulfur dioxide gas, or a reducing catalyst such as palladium on carbon can be used. A catalytic reduction method or the like can be used. Further, among the compounds of the present invention represented by the general formula (1), a compound in which R ² represents a carboxyl group can be easily produced by hydrolyzing a compound in which R ² represents a lower alkoxycarbonyl group. For this hydrolysis, conditions for ordinary ester hydrolysis can be employed, for example, hydrolysis may be carried out in the presence of a catalyst such as hydrochloric acid, sulfuric acid, or sodium hydroxide. Furthermore, in the compound of the present invention represented by the general formula (1), the carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton are single bonds, and a substituent or side chain that is inert to dehydrogenation reaction. In the case of a compound having a double bond, the compound can be converted into a compound of the present invention in which the bond is a double bond by subjecting the compound to a dehydrogenation reaction with a dehydrogenating agent. Conversely, in the compound of the present invention represented by the general formula (1), the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are double bonds, and a substituent or a side group that is inert to catalytic reduction In the case of a compound having a chain, the compound can be converted into a compound of the invention in which the bond is a single bond by catalytic reduction of the compound. Furthermore, among the compounds of the present invention represented by the general formula (1), compounds in which R ¹ represents a hydrogen atom and the carbon bonds at the 3- and 4-positions of the carbostyril skeleton are double bonds can be expressed by the following reaction scheme - As shown in Figure 11, lactam-lactim tautomerism is possible. Reaction equation 11 [In the above formula, R ² , n, A and B are the same as above. ] The carbostyril derivative represented by the general formula (1) of the present invention can be easily converted into an acid addition salt by reacting with a pharmaceutically acceptable acid. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid. . Further, among the carbostyryl derivatives represented by the general formula (1) of the present invention, a compound having an acidic group can be easily formed into a salt by reacting with a pharmaceutically acceptable basic compound. Examples of the basic compound include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate, and the like. The target compounds obtained in each step can be easily isolated and purified by conventional separation means. Examples of the separation means include solvent extraction, dilution, recrystallization, column chromatography, preparative thin layer chromatography, and the like. Incidentally, the present invention naturally also includes optical isomers. When using the compound of general formula (1) and its salt as an antihistamine and a central nervous system depressant,
It is usually in the form of a pharmaceutical composition with a pharmaceutical carrier. As carriers, fillers, extenders, binders,
Examples include diluents or excipients such as wetting agents, disintegrants, surfactants, and lubricants. Various dosage unit forms for antihistamines and central nervous system depressants can be selected depending on the therapeutic purpose, and representative examples include tablets, pills, powders, liquids, suspensions, emulsions, granules, and capsules. ,
Examples include suppositories, injections (solutions, suspensions, etc.), ointments, and the like. When forming tablets, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propanol, simple syrup, glucose, starch solution, gelatin solution, carboxymethylcellulose, ceramic, methylcellulose,
Binders such as potassium phosphate and polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaria powder, sodium bicarbonate, calcium carbonate, Twin, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrants such as lactose, white sugar, Disintegration inhibitors such as stearin, cocoa butter, and hydrogenated oils; absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate; humectants such as glycerin and starch; starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. Examples include adsorbents such as purified talc, stearate, boric acid powder, macrogol, and lubricants such as solid polyethylene glycol. When forming into a pill form, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, and talc, powdered gum arabic, Binders such as tragacanth powder, gelatin, and ethanol,
Examples include disintegrants such as laminaria and agar. Furthermore, the tablets can be made into conventionally coated tablets, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets, if necessary. When forming into a suppository, a wide variety of conventionally known carriers can be used, such as polyethylene glycol, cacao butter,
Higher alcohols, esters of higher alcohols,
Examples include gelatin and semi-synthetic glycerides. When prepared as injections, solutions and suspensions are preferably sterile and isotonic with blood, and when formed into the form of solutions, emulsions and suspensions, diluents known in the art are used. All those commonly used in the art can be used, including water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, and the like. In this case, the therapeutic agent may contain a sufficient amount of salt, glucose, or glycerin to prepare an isotonic solution, and may also contain conventional solubilizing agents, buffers, soothing agents, preservatives, etc. Furthermore, coloring agents, preservatives, fragrances, flavoring agents, sweeteners, etc. and other pharmaceuticals may be included in the therapeutic agent as required. When forming into paste, cream and gel forms, diluent A wide variety of materials conventionally known in this field can be used as the material, such as white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite, and the like. The amount of the compound of general formula (1) or its salt to be contained in antihistamines and central nervous system depressants is not particularly limited and can be appropriately selected within a wide range, but it is usually 1 to 70% by weight of the total composition. good. Furthermore, the above-mentioned antihistamines and central nervous system depressants are not particularly limited in their use, and can be administered in a manner appropriate for various forms. For example, in the case of tablets, pills, solutions, suspensions, emulsions, granules, and capsules, it is administered orally, and in the case of injections, it is administered intravenously alone or mixed with normal replenishing fluids such as glucose and amino acids. If necessary, it is administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally; in the case of a suppository, it is administered rectally; and in the case of an ointment, it is applied. The dosage of the antihistamine and central nervous system depressant of the present invention is appropriately selected depending on the purpose of use, symptoms, etc., and the formulation usually contains about 40 μg to 2 mg/Kg/day of the compound of general formula (1) or its salt. The drug may be administered in 3 to 4 doses. The results of pharmacological tests on the compounds of the present invention are listed below. <Test compound> Compound 1 6-[1-oxo-3-(4-phenylpiperazinyl)propyl]-3,4-
Dihydrocarbostyryl Compound 2 6-[1-oxo-3-(4-phenylpiperazinyl)butyl]-3,4-dihydrocarbostyryl 1 hydrochloride Compound 3 6-{1-oxo-4-[4- (2-Chlorphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl monohydrochloride monohydrate Compound 4 6-{1-oxo-2-[4-(3-chlorphenyl)piperazinyl]butyl}carbostyryl Compound 5 6-{1-hydroxy-4-[4-(3
-chlorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl compound 6 6-{1-hydroxy-3-[4-(2,
3-dimethylphenyl)piperazinyl]propyl}-3,4-dihydrocarbostyryl compound 7 6-{1-oxo-3-[4-(3-chlorophenyl)piperazinyl]propyl}-3,4-dihydrocarbostyryl 1 Hydrochloride compound 8 6-methyl-6-[1-oxo-3-
(4-phenyl-1-piperazinyl)
propyl]-3,4-dihydrocarbostyryl oxalate compound 9 6-{1-hydroxy-2-[4-(3
-Chlorphenyl)-1-piperazinyl]butyl}carbostyryl compound 10 6-{1-oxo-4-[4-(3-chlorophenyl)-1-piperazinyl]
butyl}-3,4-dihydrocarbostyryl compound 11 6-{1-oxo-4-[4-(4-chlorophenyl)-1-piperazinyl]
butyl}-3,4-dihydrocarbostyryl compound 12 6-{1-oxo-4-[4-(4-methylphenyl)-1-piperazinyl]
butyl}-3,4-dihydrocarbostyryl compound 13 6-{1-oxo-4-[4-(3,5
-dichlorophenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyryl compound 14 1-benzyl-6-[1-oxo-3
-(4-phenyl-1-piperazinyl)
propyl]-3,4-dihydrocarbostyryl oxalate compound 15 1-allyl-6-[1-oxo-3-
(4-phenyl-1-piperazinyl)
propyl]-3,4-dihydrocarbostyryl oxalate compound 16 6-{1-oxo-4-[4-(4-cyanophenyl)-1-piperazinyl]
Butyl}-3,4-dihydrocarbostyryl compound 17 6-{1-oxo-4-[4-(4-carboxyphenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyryl hydrochloride compound 18 6-{1-oxo-4-[4-(4-methylthiophenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyryl compound 19 6-{1-oxo-4-[4-( 4-acetylphenyl)-1-piperazinyl]
Butyl}-3,4-dihydrocarbostyryl compound 20 6-{1-oxo-4-[4-(4-hydroxyphenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyryl hydrochloride compound 21 6-{1-hydroxy-4-[4-(4
-aminophenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyryl compound 22 6-{1-oxo-4-[4-(3,4
-dimethyleneoxophenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyryl hydrochloride compound 23 6-{1-oxo-4-[4-(4-ethoxycarbonylphenyl)-1- Piperazinyl]butyl}-3,4-dihydrocarbostyryl compound 24 6-{1-oxo-4-[4-(4-nitrophenyl)-1-piperazinyl]
butyl}-3,4-dihydrocarbostyryl compound 25 6-{1-oxo-3-[4-(2-ethoxyphenyl)-1-piperazinyl]
Propyl}-3,4-dihydrocarbostyryl Compound A Chlorpromazine (Comparative Compound) (A) Halothane Anesthesia Enhancement Effect DDY male mice weighing approximately 20 g are used. A group of 10 animals. An aqueous gum arabic suspension of the test compound (80 mg of test compound, 1 g of gum arabic/100 ml of physiological saline) was administered to each mouse at 16 doses per test compound.
Administer mg/Kg orally. One hour after administration, each mouse was placed in a gas inhalation box (13 x 13 x 24 cm), and the inhalation box was filled with oxygen containing 4% halothane [2-bromo-2-chloro-1,1,1-trifluoroethane]. Flow the gas at a flow rate of 2/min for 3 minutes. The anesthetized rat is taken outside and the time from induction of anesthesia to awakening is measured using the righting reflex as an index. Control group: 1%
Gum arabic physiological saline solution 0.1ml/10g body
Administer orally. [MJ.Turnbull and JW
Watkins: Br.J.Pharmac., 58 , 27-35 (1976)
reference〕. The results are shown in Table 1.

[Table] (B) Inhibitory effect on jumping behavior in mice induced by methamphetamine and L-dopa. DDY male mice weighing 17 to 25 g and fasted overnight are used. A group of 6 animals. The test compound is administered orally, 40 minutes later, 4 mg/Kg of methamphetamine is administered intraperitoneally, and 15 minutes after the administration of methamphetamine, 400 mg/Kg of L-dopa is administered intraperitoneally. L
- Measure the number of jumps of the mouse during 60 minutes after dopa administration. Mice were placed one by one in two glass beakers for measurement, and those who jumped 10 times or less within 1 hour after L-dopa administration were considered positive for inhibition, and those with more than 10 times were considered negative. Calculate the effective dose (ED ₅₀ value) of the test compound that can cause 3 out of 6 animals in a group to be positive. The number of jumping times per hour for the saline administration group is
150-200 times. [H.Lal.FCcolpaert and P.
Laduron, European J.Pharm., 30 , 113-116
(See 1975.) The results obtained are shown in Table 2A.

[Table] In addition, the test compounds shown in Table 2B below were administered to 10 mice at a rate of 16 mg/Kg each, and the same jumping effect as above was examined. The results are shown below.
Shown in Table 2B.

【table】

[Table] (C) Epinephrine antagonism in mice DDY male mice weighing 17 to 20 g that have been fasted overnight are used. A group of 10 animals. The test compound is administered orally, and 1 hour later, 40 mg/Kg of epinephrine is administered intraperitoneally. The number of surviving and dead mice is measured for 24 hours after administration of epinephrine, and the ED ₅₀ value is calculated from the number of survivors. In the saline-administered control group, all 10 animals died within a few minutes of epinephrine administration. [Loew.ERand
Micetich A., J.Pharmacol.Exp.Ther., 93 , 434
-443 (1948)] The results obtained are shown in Table 3A.

[Table] In addition, the test compounds shown in Table 3B below are administered to 10 mice at a rate of 16 mg/Kg each, and the number of surviving mice is determined in the same manner as above. The results are shown in Table 3B below.

[Table] (D) Mouse eyelid ptosis test DDY male mice weighing 18 to 20 g that have been fasted all day and night are used. A group of 10 animals. test compound
After oral administration at a rate of 64 mg/Kg, the state of drooping eyelids of each mouse after 1 hour was judged according to the following criteria, and the average value of the scores of 10 mice was calculated. [G.Chem and B.
Bolrner, J.Pharmac.Exptl.Tharap., 131 , 179
(1961)] 8: Both eyes are completely closed, 6: Both eyes are slightly open, 4: Both eyes are half closed, 2: Both eyes are slightly closed, 0: Completely The results obtained are shown in Table 4.

[Table] Acute toxicity test For the above test compounds 1 to 9, their LD ₅₀ values are
When determined by oral administration (administered as a 1% gum arabic suspension in physiological saline) to ddy mice (body weight 20-22 g, 10 mice per group), each dose was 500 mg/Kg.
That's all. All of the compounds of the present invention have low toxicity and can be effectively used as pharmaceuticals. Reference examples and examples are listed below. Reference Example 1 120 ml of γ-chlorobutyric acid chloride and 160 g of pulverized anhydrous aluminum chloride were suspended in 300 ml of carbon disulfide, and a solution of 29.4 g of 3.4-dihydrocarbostyryl suspended in 100 ml of carbon disulfide was heated under reflux.
After the dropwise addition took some time, the mixture was heated under reflux for 4 hours. The reaction solution was poured into ice water, and the precipitate was collected, washed with water and ether, and then recrystallized from acetone to give yellow needle-like crystals of 6-(4-chloro-1-oxobutyl)-3,
25.5 g of 4-dihydrocarbostyryl are obtained. Melting point: 158-160°C Reference Example 2 Recrystallized from methanol-chloroform in the same manner as in Reference Example 1 to obtain 6-chloroacetylcarbostyryl. Colorless needle crystals, melting point 233-234°C Reference Example 3 Recrystallization from isopropanol was performed in the same manner as in Reference Example 1 to obtain 1-methyl-6-(β-chloropropionyl)-3,4-dihydrocarbostyryl. Colorless needle crystals, melting point 121-123°C Reference example 4 6-(1-oxo-4-chlorobutyl)-3,4
-2.0g of dihydrocarbostyril in 100ml of methanol
ml and gradually add 1.0 g of sodium borohydride while stirring at room temperature. After stirring at room temperature for 2 hours, methanol was removed by distillation under reduced pressure. The residue is extracted with chloroform, the chloroform layer is washed with water, dehydrated, and the chloroform is distilled off. The residue was recrystallized from ethanol-water to obtain 1.2 g of 6-(1-hydroxy-4-chlorobutyl)-3,4-dihydrocarbostyryl. Colorless needle crystals, melting point 120-121°C Example 1 6-(1-oxo-4-chlorobutyl)-3,4
- 5.0 g of dihydrocarbostyryl and 3.5 g of sodium iodide are mixed in 100 ml of acetone, and after stirring at 40-50°C for 5 hours, 80 ml of dimethylformamide is added and the acetone is distilled off under reduced pressure. To this reaction solution, 5.0 g of 4-phenylpiperazine and 5 g of triethylamine were added, and the mixture was stirred at 70 to 80°C for 6 hours, concentrated under reduced pressure, and 50 ml of 5% sodium bicarbonate was added and stirred to crystallize. The precipitated crude crystals are taken, washed with water, dried, and then dispersed in 80 ml of chloroform and stirred at room temperature for 1 hour. After removing chloroform insoluble matter, add 50 ml of methanol and 10 ml of concentrated hydrochloric acid to the residue after distilling off the chloroform, and concentrate to dryness under reduced pressure. Add 50 ml of acetone to the residue and stir to crystallize. The crude crystals were collected, washed with acetone, and recrystallized from ethanol-water to give yellow powdery crystals of 6-
[1-oxo-4-(4-phenylpiperazinyl)
Butyl]-3,4-dihydrocarbostyryl 1
5.7 g of hydrochloride are obtained. Melting point 195-196℃ Elemental analysis value (as C ₂₃ H ₂₈ O ₂ N ₃ Cl) C H N Theoretical value (%) 66.74 6.82 10.15 Actual value (%) 66.83 6.60 10.23 Using appropriate starting materials, Example 1 and Compounds of Examples 2 to 5 are obtained in the same manner. Example 2 6-{1-oxo-3-[4-(3-chlorophenyl)piperazinyl]propyl}-3,4-dihydrocarbostyryl monohydrochloride Colorless needles (ethanol-water) Melting point 233-234°C (Decomposition) Example 3 6-{1-oxo-4-[4-(2-chlorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl monohydrochloride monohydrate Colorless needle crystals (water) Melting point: 266-268°C (decomposed) Example 4 6-{1-oxo-4-[4-(2-ethoxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl monohydrochloride Colorless needle crystals (ethanol-water) Melting point 240-241°C (decomposed) Example 5 6-{1-oxo-3-[4-(4-methylphenyl)piperazinyl]propyl}-3,4-dihydrocarbostyryl monohydrochloride pale Yellow needles (ethanol-water) Melting point 224-226°C Example 6 6-(1-oxo-3-chloropropyl)-3,
2.4 g of 4-dihydrocarbostyryl and 1.6 g of sodium iodide were mixed in 60 ml of isopropanol,
After stirring at 40-50°C for 2 hours, 2.0 g of 4-phenylpiperazine and 3.0 g of DBU were added, and the mixture was heated under reflux for 6 hours. The reaction solution was poured into 100 ml of 5% sodium hydrogen carbonate and stirred for 1 hour at room temperature. The insoluble material was removed, washed with water, dried, and then recrystallized from ethanol-chloroform to obtain colorless scaly crystals of 6-[1-oxo-3-(4-phenylpiperazinyl)propyl].
1.9 g of -3,4-dihydrocarbostyryl is obtained. Melting point 196-197℃ Elemental analysis value (as C ₂₂ H ₂₅ O ₂ N ₃ ) C H N Theoretical value (%) 72.70 6.93 11.56 Actual value (%) 72.52 7.80 11.81 Same as Example 6 using appropriate starting materials to obtain the compounds of Examples 7 to 10. Example 7 6-{1-oxo-3-[4-(2-fluorophenyl)piperazinyl]propyl}-3,4-
Dihydrocarbostyryl Colorless powder crystals (dimethylformamide-water) Melting point 200-201°C Example 8 6-{1-oxo-4-[4-(4-bromphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl Colorless needle crystals (ethanol-water) Melting point 184-185°C Example 9 6-{1-oxo-4-[4-(4-nitrophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl Yellow needle crystals (Dimethylformamide-water) Melting point 255-256°C (decomposition) Example 10 6-{1-oxo-4-[4-(4-ethoxycarbonylphenyl)piperazinyl]butyl}-
3,4-dihydrocarbostyryl Colorless needle crystals (ethanol) Melting point 191-192°C Example 11 6-(1-oxo-3-chloropropyl)-3,
2.4 g of 4-dihydrocarbostyryl and 4-(2,
4.5 g of 3-dimethylphenyl)piperazine is mixed with 80 ml of xylene and heated under reflux for 24 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was dissolved in 100 ml of chloroform.
The chloroform layer was washed twice with a 5% aqueous sodium bicarbonate solution and twice with water, dried over anhydrous sodium sulfate, and then the chloroform was distilled off. Ether-hexane was added to the residue, the insoluble material was removed, and recrystallized from concentrated hydrochloric acid-ethanol-water to give colorless needle-like crystals of 6-{1-oxo-3-[4-(2,3-
dimethylphenyl)piperazinyl]propyl}-
3,4-dihydrocarbostyryl monohydrochloride 2.6
get g. Melting point 273-274℃ (decomposed) Elemental analysis value (as C ₂₄ H ₃₀ O ₂ N ₃ Cl) C H N Theoretical value (%) 67.35 7.07 9.82 Actual value (%) 67.36 6.95 9.80 Example 12 Same as Example 11 and recrystallized from isopropanol to give 6-{1-oxo-4-[4-(3,5-
dichlorophenyl)piperazinyl]butyl}-3,
4-dihydrocarbostyryl is obtained. Colorless needle crystals, melting point 194-195°C Example 13 6-(1-oxo-2-bromoethyl)-3,4
- 3.0 g of dihydrocarbostyryl and 5.5 g of 4-(3-chlorophenyl)piperazine were added to 50 g of sioxane.
ml and stirred at 50°C for 5 hours. After cooling the reaction solution, insoluble materials are removed, and the dioxane mother liquor is concentrated to dryness under reduced pressure, and 80 ml of ether is added to crystallize to obtain crude crystals. The resulting crude crystals were recrystallized from dioxane-water to give pale yellow needle-shaped 6-{1-oxo-
2-[4-(3-chlorophenyl)piperazinyl]
Ethyl}-3,4-dihydrocarbostyryl 3.1g
get. Melting point 214-215°C Elemental analysis value (as C ₂₁ H ₂₂ O ₂ N ₃ Cl) C H N Theoretical value (%) 65.71 5.78 10.95 Actual value (%) 65.96 5.61 10.81 Using appropriate starting materials, Example 13 and Compounds of Examples 14 to 16 are obtained in the same manner. Example 14 6-{1-oxo-2-[4-(2,3-dimethylphenyl)piperazinyl]ethyl}carbostyryl Colorless needles (methanol-chloroform) Melting point 199-200°C (decomposition) Example 15 6-{1-oxo-2-[4-(3-chlorophenyl)piperazinyl]butyl}carbostyryl monohydrochloride Colorless needle crystals (isopropanol) Melting point 209-210℃ (decomposition) Example 16 6-{1- Oxo-2-[4-(3-chlorophenyl)piperazinyl]butyl}-3.4-dihydrocarbostyryl monooxalate Colorless needle crystals (isopropanol) Melting point 135-136°C Example 17 6-(1-oxo-4- Chlorbutyl)-3,4
- 5.0 g of dihydrocarbostyril and 7.5 g of sodium iodide were dispersed in 120 ml of anhydrous dimethylformamide, and after stirring at 50 to 60°C for 2 hours, 4-(3-
Add 10 g of (chlorophenyl)piperazine and 5 ml of triethylamine, stir at 50-60°C for 6 hours, and then stir at room temperature for 24 hours. Concentrate the reaction solution under reduced pressure,
Add 80 ml of 5% sodium hydrogen carbonate to the residue, and extract the organic layer with chloroform. After the chloroform layer is washed with water and dehydrated, the chloroform is distilled off. The residue was crystallized from ether, and the resulting crude crystals were recrystallized from ethanol to give colorless needle-like crystals of 6-{1-oxo-4-[4-(3-chlorophenyl)piperazinyl]butyl}-3,4-dihydro. Obtain 6.5 g of carbostyril. Melting point 158-159°C Elemental analysis value (as C ₂₃ H ₂₆ O ₂ N ₃ Cl) C H N Theoretical value (%) 67.06 6.36 10.20 Actual value (%) 66.98 6.40 10.20 Using appropriate starting materials, Example 17 and Compounds of Examples 18 to 26 are obtained in the same manner. Example 18 6-{1-oxo-4-[4-methylphenyl)
Piperazinyl]butyl}-3,4-dihydrocarbostyryl Pale yellow needles (ethanol) Melting point 200-201°C Example 19 6-{1-oxo-4-[4-(3,4,5-trimethoxyf) enyl)piperazinyl]butyl}
-3,4-dihydrocarbostyryl dihydrochloride Colorless powder crystals (methanol-water) Melting point 261-263°C (decomposition) Example 20 6-{1-oxo-3-[4-(4-cyanophenyl)piperazinyl ]Propyl}-3,4-dihydrocarbostyryl Colorless plate crystals (ethanol) Melting point 206-207°C Example 21 6-{1-oxo-4-[4-(4-acetylphenyl)piperazinyl]butyl}- 3,4-Dihydrocarbostyryl Yellow needles (dimethylformamide-water) Melting point 218-219°C Example 22 6-{1-oxo-4-[4-(4-methylthiophenyl)piperazinyl]butyl}-3 ,4-
Dihydrocarbostyryl Pale yellow needles (ethanol) Melting point 187-188°C Example 23 6-{1-oxo-3-[4-(2-methoxyphenyl)piperazinyl]propyl}-3,4-
Dihydrocarbostyryl monohydrochloride Pale yellow needles (dioxane-water) Melting point 212-212.5°C Example 24 6-{1-oxo-4-[4-(4-carboxyphenyl)piperazinyl]butyl}-3 ,4-
Dihydrocarbostyryl monohydrochloride Colorless powder crystals (ethanol) Melting point 264-265°C Example 25 6-{1-oxo-4-[4-(4-hydroxyphenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl Colorless powder crystals (ethanol) Melting point 192-194°C Example 26 6-{1-oxo-2-[4-(4-nitrophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl Yellow powder Crystal (ethanol) Melting point 239-242°C Example 27 1-Methyl-6-(1-oxo-3-chloropropyl)-3,4-dihydrocarbostyryl 2.6
g, 1.2 g of pyridine and 4-phenylpiperazine
2.0 in 30 ml of dimethylformamide and 70
Stir at ~80°C for 7 hours. The reaction solution was poured into 100 ml of 5% sodium hydrogen carbonate, and the organic layer was extracted with chloroform. The chloroform layer is washed with water, dehydrated, and the chloroform is distilled off. Dissolve the residue in acetone and then add 5% oxalic acid in acetone to adjust the pH.
4 and collect the precipitated crystals. The obtained crystals were recrystallized from ethanol-water to give 1-methyl-6-[1
-oxo-3-(4-phenylpiperazinyl)propyl}-3,4-dihydrocarbostyryl 1
Obtain 2.8 g of oxalate. Colorless scaly crystals Melting point 164-165℃ Elemental analysis value (as C ₂₃ H ₂₇ O ₂ N ₃ (COOH) ₂ ) C H N Theoretical value (%) 64.22 6.25 8.99 Actual value (%) 64.48 6.12 9.03 Suitable starting material Compounds of Examples 28 to 30 are obtained in the same manner as in Example 27. Example 28 1-hexyl-6-[1-oxo-3-(4-phenylpiperazinyl)propyl]-3,4-dihydrocarbostyryl 1-oxalate Colorless scaly crystals (ethanol-water) Melting point 142 ~144℃ Example 29 1-Benzyl-6-[1-oxo-3-(4-phenylpiperazinyl)propyl]-3,4-dihydrocarbostyryl monooxalate Colorless needle crystals (ethanol-water ) Melting point: 171-172°C Example 30 1-allyl-6-[1-oxo-3-(4-phenylpiperazinyl)propyl]-3,4-dihydrocarbostyryl monooxalate Colorless scaly crystals ( ethanol-water) Melting point 169-170°C Example 31 6-(1-oxo-4-chlorobutyl)-3,4
- 2.7 g of dihydrocarbostyril and 1.5 g of sodium iodide are mixed in 30 ml of dimethyl sulfoxide;
After stirring at 50°C for 2 hours, 2.0 g of 4-(3,4-methylenedioxyphenyl)piperazine and 3.0 DBU
g and stirred at 70-80°C for 5 hours. The reaction solution was poured into 100 ml of 2% sodium hydrogen carbonate, and the organic layer was extracted with chloroform. The chloroform layer is washed with water, dehydrated, and the chloroform is distilled off. Add 50 ml of methanol and 5 ml of concentrated hydrochloric acid to the residue, and concentrate to dryness under reduced pressure. The residue is crystallized by adding ethanol-acetone, and the resulting crude crystals are recrystallized from ethanol-water to give colorless powdery crystals of 6-{1-oxo-4.
2.1 g of -[4-(3,4-methylenedioxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl monohydrochloride is obtained. Melting point 246-248℃ (decomposition) Elemental analysis value (as C ₂₄ H ₂₇ O ₄ N ₃ HCl) C H N Theoretical value (%) 62.95 6.16 9.18 Actual value (%) 63.12 6.01 9.25 Example 32 6-[1- 1.8 g of oxo-3-(4-phenylpiperazinyl)propyl]-3,4-dihydrocarbostyryl and sodium hydride (50% oil)
Mix 0.24g in 50ml of dimethylformamide,
After stirring at room temperature for 3 hours, 0.9 g of p-toluenesulfonic acid methyl ester was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into 150 ml of saturated saline, and the organic layer was extracted with chloroform. The chloroform layer is washed with water, dehydrated, and the chloroform is distilled off. The residue was separated and purified by preparative thin layer chromatography, and the resulting compound was dissolved in acetone to give oxalate in the same manner as in Example 27, and recrystallized from ethanol-water to give 1-methyl-6-[ 1
-oxo-3-(4-phenylpiperazinyl)propyl]-3,4-dihydrocarbostyryl 1
Obtain 1.5 g of oxalate. Colorless scaly crystals Melting point 164-165℃ Elemental analysis value (as C ₂₃ H ₂₇ O ₂ N ₃ (COOH) ₂ ) C H N Theoretical value (%) 64.22 6.25 8.99 Actual value (%) 64.02 6.41 9.08 Suitable starting material Compounds of Examples 33 to 36 are obtained in the same manner as in Example 32. Example 33 1-Benzyl-6-[1-oxo-3-(4-phenylpiperazinyl)propyl]-3,4-dihydrocarbostyryl 1-oxalate Colorless needles (ethanol-water) Melting point 171 ~172℃ Example 34 1-allyl-6-[1-oxo-3-(4-phenylpiperazinyl)propyl]-3,4-dihydrocarbostyryl 1-oxalate Colorless scaly crystals (ethanol-water ) Melting point 169-170℃ Example 35 1-methyl-6-[1-hydroxy-3-(4-
phenylpiperazinyl)propyl]-3,4-
Dihydrocarbostyryl 1-oxalate Colorless scaly crystals (ethanol-water) Melting point 155-156°C Example 36 1-benzyl-6-[1-hydroxy-3-(4
-phenylpiperazinyl)propyl]-3,4
-Dihydrocarbostyryl monooxalate Colorless needle crystals (ethanol-water) Melting point 161-162°C Example 37 6-(1-hydroxy-4-chlorobutyl)-
2.8 g of 3,4-dihydrocarbostyryl and 1.8 g of sodium iodide are mixed in 60 ml of dimethylformamide, and after stirring at room temperature for 7 hours, 2 g of triethylamine and 2.5 g of 4-phenylpiperazine are added, followed by stirring at room temperature for 24 hours. The reaction solution was poured into 200 ml of 1% aqueous sodium hydrogen carbonate solution, and the organic layer was extracted with chloroform. The chloroform layer is washed with water, dehydrated, and the chloroform is distilled off. The residue was recrystallized from isopropanol to give 6-[1-hydroxy-4
-(4-phenylpiperazinyl)butyl]-3,4
- Obtain 2.5 g of dihydrocarbostyril. Colorless needle crystals Melting point 167-168℃ Elemental analysis value (as C ₂₃ H ₂₉ O ₂ N ₃ ) C H N Theoretical value (%) 72.79 7.70 11.07 Actual value (%) 78.01 7.59 11.21 Performed using appropriate starting materials Compounds of Examples 38 to 48 are obtained in the same manner as in Example 37. Example 38 6-[1-hydroxy-3-(4-phenylpiperazinyl)propyl]-3,4-dihydrocarbostyryl Colorless needles (isopropanol) Melting point 147-148°C Example 39 6-{1 -Hydroxy-4-[4-(2-chlorophenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl Colorless needle crystals (isopropanol) Melting point 163-164°C Example 40 6-{1-hydroxy-3-[4-(2-methoxyphenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl Colorless needle crystals (isopropanol) Melting point 145-147°C Example 41 6-{1-hydroxy-3-[4-(2,3-dimethylphenyl)piperazinyl]propyl}-
3,4-dihydrocarbostyryl Colorless needle crystals (ethanol) Melting point 173-175°C (decomposition) Example 42 6-{1-hydroxy-3-[4-(4-methylphenyl)piperazinyl]propyl}-3,4
-Dihydrocarbostyryl Colorless needle crystals (isopropanol) Melting point 171-172°C Example 43 6-{1-Hydroxy-4-[4-(3-chlorophenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl Colorless needle crystals (chloroform-ether) Melting point 156.5-157°C Example 44 6-{1-hydroxy-2-[4-(3-chlorophenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl Colorless scaly crystals (ethanol-chloroform) Melting point 215-216°C Example 45 6-{1-hydroxy-2-[4-(3-chlorophenyl)piperazinyl]butyl}carbostyryl Colorless needle-like crystals (isopropanol- Chloroform) Melting point: 243-244℃ (decomposition) Example 46 6-{1-Hydroxy-2-[4-(2,3-dimethylphenyl)piperazinyl]ethyl}carbostyryl Colorless needles (isopropanol-chloroform) Melting point 245-246℃ (decomposition) Example 47 1-Methyl-6-[1-hydroxy-3-(4-
phenylpiperazinyl)propyl]-3,4-
Dihydrocarbostyryl monooxalate Colorless scaly crystals (ethanol-water) Melting point 155-156°C Example 48 1-benzyl-6-[1-hydroxy-3-(4
-phenylpiperazinyl)propyl]-3,4
-Dihydrocarbostyryl monooxalate Colorless needle crystals (ethanol-water) Melting point 161-162°C Example 49 6-[1-oxo-4-(4-phenylpiperazinyl)butyl]-3,4- 2.0 g of dihydrocarbostyril and 0.5 g of palladium black are dispersed in 80 ml of water and stirred at room temperature under 2 atmospheres of hydrogen pressure for 5 hours. The reaction solution is filtered to remove palladium black, the mother liquor is concentrated under reduced pressure, and the residue is crystallized from acetone and a small amount of ethanol. The crude crystals were collected and recrystallized from isopropanol to give 6-[1-hydroxy-4-(4
1.5 g of -phenylpiperazinyl)butyl]-3,4-dihydrocarbostyryl are obtained. Colorless needle crystals Melting point 167-168℃ Elemental analysis value (as C ₂₃ H ₂₉ O ₂ N ₃ ) C H N Theoretical value (%) 72.79 7.70 11.07 Actual value (%) 72.94 7.48 11.31 Performed using appropriate starting materials Compounds of Examples 50-51 are obtained in the same manner as in Example 49. Example 50 6-{1-hydroxy-3-[4-(2-methoxyphenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl Colorless needle crystals (isopropanol) Melting point 145-147°C Example 51 6-{1-hydroxy-3-[4-(2,3-dimethylphenyl)piperazinyl]propyl}-
3,4-dihydrocarbostyryl Colorless needle crystals (ethanol) Melting point 173-175°C (decomposed) Example 52 6-[1-oxo-3-(4-phenylpiperazinyl)propyl]-3,4- 2.0 g of dihydrocarbostyryl and 0.6 g of 5% palladium on carbon are dispersed in 80 ml of ethanol and stirred at room temperature under 2 atmospheres of hydrogen pressure for 5 hours. The reaction solution is filtered to remove palladium on carbon, and the mother liquor is concentrated under reduced pressure. The residue was recrystallized from isopropanol to give 6-[1-hydroxy-
3-(4-phenylpiperazinyl)propyl]-
1.4 g of 3,4-dihydrocarbostyryl are obtained. Colorless needle crystals Melting point 147-148℃ Elemental analysis value (as C ₂₂ H ₂₉ O ₂ N ₃ ) C H N Theoretical value (%) 72.30 7.45 11.50 Actual value (%) 72.62 7.18 11.29 Performed using appropriate starting materials Compounds of Examples 53 to 55 are obtained in the same manner as in Example 52. Example 53 6-{1-hydroxy-3-[4-(2-methoxyphenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl Colorless needle crystals (isopropanol) Melting point 145-147°C Example 54 6-{1-hydroxy-3-[4-(4-methylphenyl)piperazinyl]propyl}-3,4
-Dihydrocarbostyryl Colorless needle crystals (isopropanol) Melting point 171-172℃ Example 55 6-{1-Hydroxy-2-[4-(2,3-dimethylphenyl)piperazinyl]ethyl}Carbostyryl Colorless needle crystals (Isopropanol-chloroform) Melting point 245-246°C (decomposition) Example 56 2.0 g of 6-{1-oxo-3-[4-(4-methylphenyl)piperazinyl]propyl}-3,4-dihydrocarbostyryl and hydrogenation 1.0g of lithium aluminum in 80ml of anhydrous tetrahydrofuran
After stirring at room temperature for 8 hours, gradually add 10 ml of acetone and stir for 1 hour. Saturated aqueous sodium sulfate solution is gradually added to the reaction mixture while stirring. The aluminum hydroxide and lithium hydroxide are precipitated and the tetrahydrofuran solution is decanted. Tetrahydrofuran was distilled off, and the residue was recrystallized from isopropanol to give 6-{1-hydroxy-3
-[4-(4-methylphenyl)piperazinyl]propyl}-3,4-dihydrocarbostyryl 0.9g
get. Colorless needle crystals Melting point 171-172℃ Elemental analysis value (as C ₂₃ H ₂₉ O ₂ N ₃ ) C H N Theoretical value (%) 72.79 7.70 11.07 Actual value (%) 73.01 7.58 11.31 Example 57 6-{1- Oxo-4-[4-(3-chlorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl (3.0 g) was added to 100 ml of methanol, and while stirring, 1.2 g of sodium borohydride was gradually added, and the mixture was heated to room temperature for 50 minutes. Stir for an hour. Add 5 ml of concentrated hydrochloric acid to the reaction solution, concentrate to dryness under reduced pressure, add 50 ml of a 2% aqueous sodium hydroxide solution, and extract the organic matter with dichloromethane. Wash the dichloromethane layer with water,
Dehydrate and distill off dichloromethane. The residue was purified by silica gel column chromatography and recrystallized from isopropanol to give colorless needle-like crystals of 6-{1-hydroxy-4-[4-(3-
Chlorphenyl)piperazinyl]butyl}-3,
2.2 g of 4-dihydrocarbostyryl are obtained. Melting point 156.5-157℃ Elemental analysis value (as C ₂₃ H ₂₈ O ₂ N ₃ Cl) C H N Theoretical value (%) 66.73 6.82 10.15 Actual value (%) 66.42 6.74 10.06 Using appropriate starting materials, Example 57 and Compounds of Examples 58 to 70 are obtained in the same manner. Example 58 6-[1-Hydroxy-4-(4-phenylpiperazinyl)butyl]-3,4-dihydrocarbostyryl Colorless needles (isopropanol) Melting point 167-168°C Example 59 6-{1 -Hydroxy-2-[4-(3-chlorophenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl Colorless scaly crystals (ethanol-chloroform) Melting point 215-216°C Example 60 6-{1-hydroxy-2-[4-(3-chlorophenyl)piperazinyl]butyl}carbostyryl Colorless needle-like crystals (isopropanol- Chloroform) Melting point: 243-244°C (decomposed) Example 61 6-{1-hydroxy-2-[4-(2,3-dimethylphenyl)piperazinyl]ethyl}carbostyryl Colorless needles (isopropanol-chloroform) Melting point 245-246℃ (decomposition) Example 62 6-{1-hydroxy-2-[4-(4-nitrophenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl Yellow powdery crystals Melting point 249-251°C Example 63 6-[1-hydroxy-3-(4-phenylpiperazinyl)propyl]-3,4-dihydrocarbostyryl Colorless needle crystals (isopropanol) Melting point 147-148°C Example 64 6-{1-hydroxy-4-[4-(2-chlorophenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl Colorless needle crystals (isopropanol) Melting point 163-164°C Example 65 6-{1-hydroxy-3-[4-(2-methoxyphenyl)piperazinyl]propyl}-3,
4-Dihydrocarbostyryl Colorless needle crystals (isopropanol) Melting point 145-147°C Example 66 6-{1-Hydroxy-3-[4-(2,3-dimethylphenyl)piperazinyl]propyl}-
3,4-dihydrocarbostyryl Colorless needle crystals (ethanol) Melting point 173-175°C (decomposition) Example 67 6-{1-hydroxy-3-[4-(4-methylphenyl)piperazinyl]propyl}-3,4
-dihydrocarbostyryl Colorless needle crystals (isopropanol) Melting point 171-172°C Example 68 1-Methyl-6-[1-hydroxy-3-(4-
phenylpiperazinyl)propyl]-3,4-
Dihydrocarbostyryl 1-oxalate Colorless scaly crystals (ethanol-water) Melting point 155-156°C Example 69 1-benzyl-6-[1-hydroxy-3-(4
-phenylpiperazinyl)propyl]-3,4
-Dihydrocarbostyryl monooxalate Colorless needle crystals (ethanol-water) Melting point 161-162°C Example 70 6-{1-Hydroxy-4-[4-(4-aminophenyl)piperazinyl]butyl}-3,4 −
Dihydrocarbostyryl Brown powder crystals (methanol) Melting point 243-245°C Example 71 (a) 6-(1-oxo-2-brombutyl)-3,
2.0 g of 4-dihydrocarbostyryl and 3 g of piperazine are mixed in 80 ml of dioxane and stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, 60 ml of 5% aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water, dehydrated, and the chloroform was distilled off to obtain crude 6-(1-oxo-2-piperazinylbutyl)-
1.8 g of 3,4-dihydrocarbostyryl are obtained. (b) 6-(1-oxo-2-piperazinylbutyl)
-3,4-dihydrocarbostyril 1.8g, p
- Bromnitrobenzene 2.0g, potassium carbonate
Disperse 1.2 g and 0.1 g of copper powder in 80 ml of ethyl cellosolve, and heat and stir at 120 to 150°C for 5 hours.
The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer is washed with water, dehydrated, and the chloroform is distilled off. The residue was separated and purified by preparative thin layer chromatography, and further recrystallized from ethanol to obtain yellow powdery crystals of 6-{1-oxo-2-[4-(4-nitrophenyl)piperazinyl]butyl}-3,
0.2 g of 4-dihydrocarbostyryl is obtained. Melting point 239-242℃ Elemental analysis value (as C ₂₃ H ₂₆ O ₄ N ₄ ) C H N Theoretical value (%) 65.38 6.20 13.26 Actual value (%) 65.02 6.51 13.59 Same as Example 71 using appropriate starting materials to obtain the compounds of Examples 72-74. Example 72 6-{1-oxo-4-[4-(4-nitrophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl Yellow needles (dimethylformamide-water) Melting point 255-256°C (decomposition) Example 73 6-{1-oxo-3-[4-(4-cyanophenyl)piperazinyl]propyl}-3,4-dihydrocarbostyryl Colorless platelet crystals (ethanol) Melting point 206-207°C Example 74 6-{ 1-Oxo-4-[4-(4-acetylphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl Yellow needles (dimethylformamide-water) Melting point 218-219°C Example 75 (a) 6 -(1-oxo-2-piperazinylbutyl)
2.5 g of -3,4-dihydrocarbostyryl is mixed in 80 ml of methanol, 1.6 g of sodium borohydride is added little by little over 15 minutes while stirring at room temperature, and the mixture is further stirred at room temperature for 2 hours. Add 5 ml of concentrated hydrochloric acid to the reaction solution, and concentrate to dryness under reduced pressure. Add 10 ml of water to dissolve the residue, add 2N aqueous sodium hydroxide solution at room temperature to adjust the pH to 6-7, and stir to precipitate crystals. Take this crystal, wash it with water,
6-(1-hydroxy-
1.2 g of 2-piperazinylbutyl)-3,4-dihydrocarbostyryl are obtained. (b) 6-(1-hydroxy-2-piperazinylbutyl)-3,4-dihydrocarbostyryl 5.0
3.5 g of p-bromnitroaniline, 1.8 g of potassium carbonate and 0.2 g of copper powder are mixed in 60 ml of 3-methoxybutanol and heated under reflux for 5 hours.
The reaction solution was filtered, the mother liquor was concentrated to dryness under reduced pressure, and the residue was extracted with methanol-chloroform. The chloroform layer was distilled off, and the resulting residue was separated by preparative silica gel thin layer chromatography to obtain yellow powdery crystals of 6-{1-hydroxy-2-[4-(4-nitrophenyl)piperazinyl]. 0.21 g of butyl}-3,4-dihydrocarbostyryl is obtained. Melting point 249-251°C Example 76 (a) 6-(1-oxo-4-chlorobutyl)-3,
2.8 g of 4-dihydrocarbostyryl and 2.0 g of sodium iodide are mixed in 50 ml of dimethylformamide, stirred at 50°C for 2 hours, then 5.0 g of diethanolamine is added and stirred at 70-80°C for 5 hours. The reaction solution was concentrated under reduced pressure, 50 ml of a 5% aqueous sodium bicarbonate solution was added to the residue, and the organic layer was stirred and extracted with chloroform. The chloroform layer is washed with water, dehydrated, and the chloroform is distilled off to obtain 2.5 g of crude paste-like 6-(1-oxo-4-diethanolaminobutyl)-3,4-dihydrocarbostyryl. (b) 6-(1-oxo-4-diethanolaminobutyl)-3,4-dihydrocarbostyryl 2.5
Add 30 ml of thionyl chloride to g, stir at room temperature for 5 hours, concentrate under reduced pressure, and add 50 ml of benzene. Repeat the operation of concentrating under reduced pressure three times to obtain 6-
{1-oxo-4-[di-(2-chloroethyl)
Amino]butyl}-3,4-dihydrocarbostyryl is obtained. This compound contains 1.5 g of aniline,
Add 2.2 g of potassium carbonate and 150 ml of ethanol, and heat under reflux for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform. The chloroform layer is washed with water, dehydrated, and the chloroform is distilled off. The residue was separated and purified by preparative thin layer chromatography, then concentrated to dryness after adding concentrated hydrochloric acid, and the residue was recrystallized from ethanol-water to give yellow powdery crystals of 6-[1-oxo- 4-(4-phenylpiperazinyl)-butyl]
-3,4-dihydrocarbostyryl monohydrochloride
Obtain 0.2g. Melting point: 195-196°C Compounds of Examples 77-104 are obtained in the same manner as in Example 76 using appropriate starting materials. Example 77 6-{1-oxo-3-[4-(3-chlorophenyl)piperazinyl]propyl}-3,4-dihydrocarbostyryl monohydrochloride Colorless needles (ethanol-water) Melting point 233-234°C (Decomposition) Example 78 6-{1-oxo-4-[4-(2-chlorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl monohydrochloride monohydrate Colorless needle crystals (water) Melting point: 266-268°C (decomposition) Example 79 6-{1-oxo-4-[4-(2-ethoxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl monohydrochloride Colorless needle crystals (ethanol-water) Melting point 240-241℃ (decomposition) Example 80 6-{1-oxo-3-[4-(4-methylphenyl)piperazinyl]propyl}-3,4-dihydrocarbostyryl monohydrochloride pale Yellow needles (ethanol-water) Melting point 224-226℃ Example 81 6-[1-oxo-3-(4-phenylpiperazinyl)propyl]-3,4-dihydrocarbostyryl Colorless scaly crystals ( ethanol-chloroform) Melting point 196-197°C Example 82 6-{1-oxo-3-[4-(2-fluorophenyl)piperazinyl]propyl}-3,4-
Dihydrocarbostyryl Colorless powder crystals (dimethylformamide-water) Melting point 200-201°C Example 83 6-{1-oxo-4-[4-(4-bromphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl Colorless needle crystals (ethanol-water) Melting point 184-185°C Example 84 6-{1-oxo-4-[4-(4-nitrophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl Yellow needle crystals (Dimethylformamide-water) Melting point 255-256°C (decomposition) Example 85 6-{1-oxo-4-[4-(4-ethoxycarbonylphenyl)piperazinyl]butyl}-
3,4-dihydrocarbostyryl Colorless needle crystals (ethanol) Melting point 191-192°C Example 86 6-{1-oxo-3-[4-(2,3-dimethylphenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl monohydrochloride Colorless needle crystals (concentrated hydrochloric acid-ethanol-water) Melting point 273-274°C (decomposition) Example 87 6-{1-oxo-4-[4-(3,5-dichlorophenyl) ) piperazinyl]butyl}-3,4
-Dihydrocarbostyryl Colorless needle crystals (isopropanol) Melting point 194-195°C Example 88 6-{1-oxo-2-[4-(3-chlorophenyl)piperazinyl]ethyl}-3,4-dihydrocarbostyryl Pale yellow Needle crystals (dioxane-water) Melting point 214-215℃ Example 89 6-{1-oxo-2-[4-(2,3-dimethylphenyl)piperazinyl]ethyl}carbostyryl Colorless needle crystals (ethanol- Chloroform) Melting point 199-200℃ (decomposed) Example 90 6-{1-oxo-2-[4-(3-chlorophenyl)piperazinyl]butyl}carbostyryl monohydrochloride Colorless needle crystals (isopropanol) Melting point 209- 210℃ (decomposition) Example 91 6-{1-oxo-2-[4-(3-chlorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl monooxalate Colorless needle crystals (isopropanol) Melting point 135 ~136℃ Example 92 6-{1-oxo-4-[4-(3-chlorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl Colorless needles (ethanol) Melting point 158-159℃ Example 93 6-{1-oxo-4-[4-(4-methylphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl Pale yellow needles (ethanol) Melting point 200-201 Example 94 6-{1-oxo -4-[4-(3,4,5-trimethoxyphenyl)piperazinyl]butyl}
-3,4-dihydrocarbostyryl dihydrochloride Colorless powder crystals (ethanol-water) Melting point 261-263°C (decomposed) Example 95 6-{1-oxo-3-[4-(4-cyanophenyl)piperazinyl ]Propyl}-3,4-dihydrocarbostyryl Colorless plate crystals (ethanol) Melting point 206-207°C Example 96 6-{1-oxo-4-[4-(4-acetylphenyl)piperazinyl]butyl}- 3,4-Dihydrocarbostyryl Yellow needles (dimethylformamide-water) Melting point 218-219°C Example 97 6-{1-oxo-4-[4-(4-methylthiophenyl)piperazinyl]butyl}-3 ,4-
Dihydrocarbostyryl Pale yellow needles (ethanol) Melting point 187-188°C Example 98 6-{1-oxo-3-[4-(2-methoxyphenyl)piperazinyl]propyl}-3,4-
Dihydrocarbostyryl monohydrochloride Pale yellow needles (dioxane-water) Melting point 213-212.5°C Example 99 6-{1-oxo-4-[4-(4-carboxyphenyl)piperazinyl]butyl}-3 ,4-
Dihydrocarbostyryl monohydrochloride Colorless powder crystals (ethanol) Melting point 264-265°C Example 100 6-{1-oxo-4-[4-(4-hydroxyphenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl Colorless powder crystals (ethanol) Melting point 192-194°C Example 101 1-Methyl-6-[1-oxo-3-(4-phenylpiperazinyl)propyl]-3,4-dihydrocarbostyryl・1-oxalate Colorless flaky crystals (ethanol-water) Melting point 164-165℃ Example 102 6-{1-oxo-4-[4-(3,4-methylenedioxyphenyl)piperazinyl]butyl}
-3,4-dihydrocarbostyryl monohydrochloride Colorless powder crystals (ethanol-water) Melting point 246-248°C (decomposed) Example 103 1-allyl-6-[1-oxo-3-(4-phenyl) Piperazinyl)propyl]-3,4-dihydrocarbostyryl monooxalate Colorless scaly crystals (ethanol-water) Melting point 169-170°C Example 104 1-benzyl-6-[1-oxo-3-(4 -Phenylpiperazinyl)propyl]-3,4-dihydrocarbostyryl monooxalate Colorless needle crystals (ethanol-water) Melting point 171-172°C Example 105 (a) 6-{1-oxo-4- 2.5 g of [di-(2-chloroethyl)amino]butyl}-3,4-dihydrocarbostyryl was mixed in 80 ml of methanol, and 1.6 g of sodium borohydride was added under stirring at room temperature.
was added little by little over 15 minutes and stirred for an additional 2 hours at room temperature. Add 5 ml of concentrated hydrochloric acid to the reaction solution,
Concentrate to dryness under reduced pressure. Add 10 ml of water to dissolve the residue, add 2N aqueous sodium hydroxide solution at room temperature to adjust the pH to 6-7, and stir to precipitate crystals.
The crystals were collected, washed with water, and dried to obtain 1.4 g of 6-{1-hydroxy-4-[di-(2-chloroethyl)amino]butyl-3,4-dihydrocarbostyryl in the form of a colorless powder. (b) Add 1.5 g of aniline, 2.2 g of potassium carbonate and 150 ml of ethanol to 2.5 g of 6-{1-hydroxy-4-[di-(2-chloroethyl)amino]butyl}-3,4-dihydrocarbostyryl for 24 hours. Heat to reflux. The reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform. The chloroform layer is washed with water, dehydrated, and the chloroform is distilled off. The residue was separated and purified by preparative thin layer chromatography and further recrystallized from isopropanol to yield 6-[1-hydroxy-4-(4-phenylpiperazinyl)butyl]-3,4-dihydrocarbostyryl 0.2 get g. Colorless needle crystals Melting point: 167-168°C Compounds of Examples 106-116 are obtained in the same manner as in Example 105 using appropriate starting materials. Example 106 6-{1-hydroxy-4-[4-(3-chlorophenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl Colorless needle crystals (chloroform-ether) Melting point 156.5-157°C Example 107 6-{1-Hydroxy-2-[4-(3-chlorophenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyril Colorless scaly crystals (ethanol-chloroform) Melting point 215-216°C Example 108 6-{1-hydroxy-2-[4-(3-chlorophenyl)piperazinyl]butyl}carbostyril Colorless needle-like crystals (isopropanol- Chloroform) Melting point 243-244℃ (decomposed) Example 109 6-{1-hydroxy-2-[4-(2,3-dimethylphenyl)piperazinyl]ethyl}carbostyryl Colorless needles (isopropanol-chloroform) Melting point 245-246℃ (decomposed) Example 110 6-[1-hydroxy-3-(4-phenylpiperazinyl)propyl]-3,4-dihydrocarbostyryl Colorless needles (isopropanol) Melting point 147-148℃ Example 111 6-{1-hydroxy-4-[4-(2-chlorophenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl Colorless needle crystals (isopropanol) Melting point 163-164°C Example 112 6-{1-hydroxy-3-[4-(2-methoxyphenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl Colorless needle crystals (isopropanol) Melting point 145-147°C Example 113 6-{1-hydroxy-3-[4-(2,3-dimethylphenyl)piperazinyl]propyl}-
3,4-Dihydrocarbostyryl Colorless needle crystals (ethanol) Melting point 173-175°C (decomposition) Example 114 6-{1-hydroxy-3-[4-(4-methylphenyl)piperazinyl]propyl}-3,4
-dihydrocarbostyryl Colorless needle crystals (isopropanol) Melting point 171-172°C Example 115 1-Methyl-6-[1-hydroxy-3-(4-
phenylpiperazinyl)propyl]-3,4-
Dihydrocarbostyryl monooxalate Colorless scaly crystals (ethanol-water) Melting point 155-156°C Example 116 1-benzyl-6-[1-hydroxy-3-(4
-phenylpiperazinyl)propyl]-3,4
-dihydrocarbostyryl monooxalate Colorless needle crystals (ethanol-water) Melting point 161-162°C Example 117 (a) 6-(1-oxo-2-chloroethyl)-3,
Disperse 5.0 g of 4-dihydrocarbostyryl and 6.0 g of morpholine in 120 ml of dioxane,
Stir for 12 hours at °C. Concentrate the reaction solution under reduced pressure.
Add ether to the residue and stir. The insoluble matter is removed, washed with water, dissolved under heating in 80 ml of methanol and 10 ml of concentrated hydrochloric acid, and then concentrated to dryness under reduced pressure. The residue was recrystallized twice from methanol-ether to obtain 5.9 g of 6-(1-oxo-2-morpholinoethyl)-3,4-dihydrocarbostyryl monohydrochloride as a colorless powder. Melting point 290℃ (decomposition) (b) 6-(1-oxo-2-morpholinoethyl)-
3,4-dihydrocarbostyryl monohydrochloride
5.0g and m-chloroaniline 5.0g in concentrated hydrochloric acid 30g
6ml at 200-220℃ while removing water.
Cool after heating for an hour. Next, 100 ml of 5N hydrochloric acid was added, dissolved under heating, and heated under reflux for 2 hours.
After cooling the reaction solution, add 8N sodium hydroxide aqueous solution.
The organic layer was extracted with chloroform. Chloroform was distilled off, the residue was separated and purified by preparative silica gel thin layer chromatography, and further recrystallized from dioxane-water to give pale yellow needle-like crystals of 6-{1-oxo-2-
[4-(3-chlorophenyl)piperazinyl]ethyl}-3,4-dihydrocarbostyryl 0.16
get g. Melting point 214-215°C Elemental analysis value (as C ₂₁ H ₂₂ O ₂ N ₃ Cl) C H N Theoretical value (%) 65.71 5.78 10.95 Actual value (%) 65.98 5.62 10.78 Using appropriate starting materials, Example 117 and Compounds of Examples 118 to 140 are obtained in the same manner. Example 118 6-{1-oxo-3-[4-(3-chlorophenyl)piperazinyl]propyl}-3,4-dihydrocarbostyryl monohydrochloride Colorless needles (ethanol-water) Melting point 233-234°C (Decomposition) Example 119 6-{1-oxo-4-[4-(2-chlorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl monohydrochloride monohydrate Colorless needle crystals (water) Melting point: 266-268°C (decomposition) Example 120 6-[1-oxo-4-(4-phenylpiperazinyl)butyl]-3,4-dihydrocarbostyryl monohydrochloride Yellow powder crystals (ethanol- water) Melting point 195-196℃ Example 121 6-{1-oxo-3-[4-(4-methylphenyl)piperazinyl]propyl}-3,4-dihydrocarbostyryl monohydrochloride Pale yellow needles (ethanol -Water) Melting point 224-226°C Example 122 6-[1-oxo-3-(4-phenylpiperazinyl)propyl]-3,4-dihydrocarbostyryl Colorless scaly crystals (ethanol-chloroform) Melting point 196 ~197℃ Example 123 6-{1-oxo-3-[4-(2-fluorophenyl)piperazinyl]propyl}-3,4-
Dihydrocarbostyryl Colorless powder crystals (dimethylformamide-water) Melting point 200-201°C Example 124 6-{1-oxo-4-[4-(4-bromphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl Colorless needle crystals (ethanol-water) Melting point 184-185°C Example 125 6-{1-oxo-4-[4-(4-nitrophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl Yellow needle crystals (Dimethylformamide-water) Melting point 255-156°C (decomposition) Example 126 6-{1-oxo-3-[4-(2,3-dimethylphenyl)piperazinyl]propyl}-3,
4-dihydrocarbostyryl monohydrochloride Colorless needle crystals (concentrated hydrochloric acid-ethanol-water) Melting point 273-274°C (decomposition) Example 127 6-{1-oxo-4-[4-(3,5-dichlorophenyl) ) piperazinyl]butyl}-3,4
-Dihydrocarbostyryl Colorless needle crystals (isopropanol) Melting point 194-195°C Example 128 6-[1-oxo-4-(4-phenylpiperazinyl)butyl]-3,4-dihydrocarbostyryl monohydrochloric acid Salt Yellow powdery crystals (ethanol-water) Melting point 195-196°C Example 129 6-{1-oxo-2-[4-(2,3-dimethylphenyl)piperazinyl]ethyl}carbostyryl Colorless needle crystals ( Methanol-chloroform) Melting point 199-200℃ (decomposed) Example 130 6-{1-oxo-2-[4-(3-chlorophenyl)piperazinyl]butyl}carbostyryl monohydrochloride Colorless needle crystals (isopropanol) Melting point 209-210℃ (decomposition) Example 131 6-{1-oxo-2-[4-(3-chlorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl monooxalate Colorless needle crystals (isopropanol) Melting point: 135-136°C Example 132 6-{1-oxo-4-[4-(3-chlorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl Colorless needles (ethanol) Melting point: 158-159°C Implementation Example 133 6-{1-oxo-4-[4-(4-methylphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl Pale yellow needles (ethanol) Melting point 200-201℃ Example 134 6-{ 1-Oxo-4-[4-(4-acetylphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl Yellow needles (dimethylformamide-water) Melting point 218-219°C Example 135 6-{1 -oxo-4-[4-(4-carboxyphenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl monohydrochloride Colorless powder crystals (ethanol) Melting point 264-265°C Example 136 6-{1-oxo-4-[4-(4-hydroxyphenyl)piperazinyl]butyl}-3,4-
Dihydrocarbostyryl Colorless powder crystals (ethanol) Melting point 192-194°C Example 137 1-Methyl-6-[1-oxo-3-(4-phenylpiperazinyl)propyl}-3,4-dihydrocarbostyryl・1-oxalate Colorless scaly crystals (ethanol-water) Melting point 164-165℃ Example 138 1-hexyl-6-[1-oxo-3-(4-phenylpiperazinyl)propyl]-3,4- Dihydrocarbostyryl monooxalate Colorless scaly crystals (ethanol-water) Melting point 142-144°C Example 139 1-benzyl-6-[1-oxo-3-(4-phenylpiperazinyl)propyl]-3 ,4-dihydrocarbostyryl 1-oxalate Colorless needle crystals (ethanol-water) Melting point 171-172°C Example 140 1-allyl-6-[1-oxo-3-(4-phenylpiperazinyl)propyl ]-3,4-dihydrocarbostyryl monooxalate Colorless scaly crystals (ethanol-water) Melting point 169-170°C Example 141 6-{1-oxo-4-[4-(4-nitrophenyl)piperazinyl]butyl }-3,4-dihydrocarbostyryl 1.5 g and 5% palladium-carbon 0.3 g were dispersed in 150 ml of ethanol, and the hydrogen pressure was 2.
Catalytic reduction is carried out under atmospheric pressure for 5 hours. Filter the reaction solution,
Concentrate the mother liquor under reduced pressure. The residue was recrystallized from methanol to give brown powdery crystals of 6-{1-hydroxy-4.
0.7 g of -[4-(4-aminophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl is obtained. Melting point 243-245℃ Elemental analysis value (as C ₂₃ H ₃₀ O ₂ N ₄ ) C H N Theoretical value (%) 70.02 7.67 14.20 Actual value (%) 70.38 7.41 14.02 Example 142 6-{1-oxo-4- 2.0 g of [4-(4-ethoxycarbonyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl and 0.6 g of sodium hydroxide are mixed in 70 ml of methanol and heated under reflux for 2 hours. Add 5 ml of concentrated hydrochloric acid to the reaction solution and concentrate to dryness under reduced pressure. The residue was recrystallized from ethanol-water to give colorless needle-like crystals of 6-{1-oxo-4-[4-
0.6 g of (4-carboxyphenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl monohydrochloride is obtained. Melting point 267-268℃ (decomposition) Elemental analysis value (as C ₂₄ H ₂₇ O ₄ N ₃・HCl) C H N Theoretical value (%) 62.95 6.16 9.18 Actual value (%) 62.58 6.32 9.41 Formulation example 1 6-{1 -Oxo-4-(4-phenylpiperazinyl)butyl]-3,4-dihydrocarbostyryl 10 mg Cornstarch 127 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Tablets of the above composition are prepared in a conventional manner. Production example 2 6-{1-oxo-4-[4-(2-chlorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl 5 mg Cornstarch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg The above in one tablet by the usual method Manufacturing tablets of the composition. Production Example 3 6-[1-Hydroxy-4-(4-phenylpiperazinyl)butyl]-3,4-dihydrocarbostyryl 5 mg Cornstarch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg The above composition in one tablet by the usual method Manufacture tablets.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, or a lower alkenyl group. ^R2 is a halogen atom, lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, carboxy group, lower alkylthio group, lower alkanoyl group, hydroxyl group, nitro group, amino group, or cyano group, and n is 0 or 1 to 3. Indicates an integer. Also-
In (R ² ) _o , two R ² may be bonded to each other to form a lower alkylenedioxy group. Further, A represents [Formula] or [Formula], B represents a lower alkylene group, and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are a single bond or a double bond, respectively.
However, when R ¹ is a hydrogen atom, n is 0, and the carbon-carbon bonds at the 3rd and 4th positions of the carbostyryl skeleton are single bonds, B is [Formula] (R is a hydrogen atom or a lower alkyl group) It must not be. ] A carbostyril derivative or a salt thereof represented by: 2 R ¹ is a hydrogen atom, R ² is a lower alkyl group,
The compound according to claim 1, which is a lower alkoxy group or a halogen atom. 3 General formula [In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, or a lower alkenyl group. A represents [Formula] or [Formula], B represents a lower alkylene group, and the 3rd and 4th positions of the carbostyril skeleton
The carbon-carbon bond at position represents a single bond or a double bond, respectively. X represents a halogen atom. ] Halogenated carbostyryl derivatives represented by and the general formula [In the formula, R ² is a halogen atom, a lower alkyl group,
A lower alkoxy group, a lower alkoxycarbonyl group, a carboxy group, a lower alkylthio group, a lower alkanoyl group, a hydroxyl group, a nitro group, an amino group or a cyano group, and n represents 0 or an integer of 1 to 3. In addition, in -(R ² ) _o , two R ² may be bonded to each other to form a lower alkylenedioxy group. ] by reacting with a piperazine derivative represented by the general formula [In the formula, R ¹ , R ² , n, A, B, and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. However, when R ¹ is a hydrogen atom, n is 0, and the carbon-carbon bonds at the 3rd and 4th positions of the carbostyryl skeleton are single bonds, B is [Formula] (R is a hydrogen atom or a lower alkyl group) It must not be. ] A method for producing a carbostyril derivative, the method comprising obtaining a carbostyril derivative represented by the formula: 4 General formula [In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, or a lower alkenyl group. A represents [Formula] or [Formula], B represents a lower alkylene group, and the 3rd and 4th positions of the carbostyril skeleton
The carbon-carbon bond at position represents a single bond or a double bond, respectively. ] Piperazine carbostyryl derivative represented by and the general formula [In the formula, R ² is a halogen atom, a lower alkyl group,
A lower alkoxy group, a lower alkoxycarbonyl group, a carboxy group, a lower alkylthio group, a lower alkanoyl group, a hydroxyl group, a nitro group, an amino group or a cyano group, and n represents 0 or an integer of 1 to 3. In addition, in -(R ² ) _o , two R ² may be bonded to each other to form a lower alkylenedioxy group. X represents a halogen atom. ] By reacting with a benzene derivative represented by the general formula [In the formula, R ¹ , R ² , n, A, B, and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. However, when R ¹ is a hydrogen atom, n is 0, and the carbon-carbon bonds at the 3rd and 4th positions of the carbostyryl skeleton are single bonds, B is [Formula] (R is a hydrogen atom or a lower alkyl group) It must not be. ] A method for producing a carbostyril derivative, the method comprising obtaining a carbostyril derivative represented by the formula: 5 General formula [In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, or a lower alkenyl group. A represents [Formula] or [Formula], B represents a lower alkylene group, and the 3rd and 4th positions of the carbostyril skeleton
The carbon-carbon bond at position represents a single bond or a double bond, respectively. X ¹ and X ² represent halogen atoms. ] Carbostyryl derivative and general formula represented by [In the formula, R ² is a halogen atom, a lower alkyl group,
A lower alkoxy group, a lower alkoxycarbonyl group, a carboxy group, a lower alkylthio group, a lower alkanoyl group, a hydroxyl group, a nitro group, an amino group or a cyano group, and n represents 0 or an integer of 1 to 3. In addition, in -(R ² ) _o , two R ² may be bonded to each other to form a lower alkylenedioxy group. ] By reacting with the aniline derivative represented by the general formula [In the formula, R ¹ , R ² , n, A, B, and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. However, when R ¹ is a hydrogen atom, n is 0, and the carbon-carbon bonds at the 3rd and 4th positions of the carbostyryl skeleton are single bonds, B is [Formula] (R is a hydrogen atom or a lower alkyl group) It must not be. ] A method for producing a carbostyril derivative, the method comprising obtaining a carbostyril derivative represented by the formula: 6 General formula [In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, or a lower alkenyl group. B represents a lower alkylene group, and the carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton represent a single bond or a double bond, respectively. ] Carbostyryl derivative and general formula represented by [In the formula, R ² is a halogen atom, a lower alkyl group,
A lower alkoxy group, a lower alkoxycarbonyl group, a carboxy group, a lower alkylthio group, a lower alkanoyl group, a hydroxyl group, a nitro group, an amino group or a cyano group, and n represents 0 or an integer of 1 to 3. In addition, in -(R ² ) _o , two R ² may be bonded to each other to form a lower alkylenedioxy group. ] By reacting with an aniline derivative represented by the general formula [In the formula, R ¹ , R ² , n, B, and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above.
However, when R ¹ is a hydrogen atom, n is 0, and the carbon-carbon bonds at the 3rd and 4th positions of the carbostyryl skeleton are single bonds, B is [Formula] (R is a hydrogen atom or a lower alkyl group) It must not be. ] A method for producing a carbostyril derivative, the method comprising obtaining a carbostyril derivative represented by the formula: