JPH0215537B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel carbostyril derivatives. The 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). [In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, a lower alkenyl group, or a lower alkynyl group. A is the base

[Formula] Group

[Formula] Group

[Formula] or group

[Formula] is shown. Here, R ² represents a hydrogen atom. B represents a lower alkylene group. l represents 0 or 1. However, A is the base

[Formula] or group

In the case of [Formula], l shall represent 1. Z is a group N-R ³ or a group

[Formula] is shown. Here, R ₃ is a phenyl group that may have 1 to 3 groups selected from halogen atoms, lower alkyl groups, lower alkoxy groups, lower alkylthio groups, and hydroxyl groups as substituents on the phenyl ring, or a phenyl lower alkyl group. shows. R ⁴ is a phenyl group, a phenyl lower alkyl group, or a group that may have 1 to 3 groups selected from the group consisting of halogen atoms, lower alkyl groups, and lower alkoxy groups as substituents on the phenyl ring.

[Formula] is shown. R ⁵ represents a hydrogen atom, a hydroxyl group or a lower alkanoyl group. Also
When R ⁵ represents a hydrogen atom, the hydrogen atoms bonded to the 3rd and 4th positions of the piperidine skeleton are both dehydrogenated, and the carbon-carbon bond between the 3rd and 4th positions of the piperidine skeleton represents a double bond. You can also do it. The carbon-carbon bond between the 3rd and 4th positions of the carbostyril skeleton represents a single bond or a double bond. However, when ) Z is a group N-R ³ (where R ³ is a phenyl lower alkyl group,
and R ³ is a phenyl group having a lower alkylthio group, and A is a group

[Formula] or

[Formula] (R ² is the same as above), the side chain

[Formula] is substituted at the 5, 7 or 8 position of the carbostyril skeleton,
No substitution shall be made in the 6th position. ) R ¹ is a hydrogen atom, and the side chain

[Formula] (where A ¹ is a group

[Formula] or

[Formula], B ¹ is a group

[Formula] (R represents a hydrogen atom or a lower alkyl group), Z ¹ is a group N-R ³ ′ (R ³ ′ is a phenyl lower alkyl group) or a group CHR ⁴ ′ (R ⁴ ′ is a phenyl lower alkyl group) substituted phenyl group or phenyl lower alkyl group), respectively. ) is substituted at the 6-position of the carbostyril skeleton, the carbon-carbon bond between the 3-position and the 4-position of the carbostyril skeleton must not be a single bond. The compound of the present invention represented by the above general formula (1) has a central nervous system depressant effect and an antihistamine effect, and is useful as a central nervous system depressant and an antihistamine agent. 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 compounds of the present invention have central nervous system depressing effects such as muscle relaxation, blepharoptosis, hypothermia, locomotor activity suppression, hyperemotional suppression in olfactory bulbectomized rats (OB rats), antimethamphetamine effects, and methamphetamine 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, 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 the compound of general formula (1) above, Z is a group

The compound represented by the formula has a weak central nervous system depressing effect and a selective antihistamine effect, and is particularly useful as an antihistamine agent. In the compound of general formula (1) above, Z is a group N-R ³
and A is the base

[Formula] or group

The compound represented by the formula is easily metabolized in vivo, has little effect on the liver, and is a short-acting central nervous system depressant and antihistamine, and is particularly useful as a sleep-inducing drug and a preoperative drug. be. Furthermore, in the compound of the above general formula (1), Z is a group N-
R ³ and A is a group

[Formula] or group

The compound represented by [Formula] has a strong central nervous system depressant effect, a long action time (persistent), and low toxicity, and also has antidopaminergic and antiepinephyllinic effects. It is particularly useful as a treatment for schizophrenia and psychosis, and as an analgesic. More specifically, each group shown in this specification is as follows. Lower alkyl group...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 group, etc. Lower alkenyl group: vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl group, etc. Lower alkyl group...ethynyl, 2-propynyl,
2-butynyl, 3-butynyl, 1-methyl-2-
propynyl, 2-pentynyl, 2-hexynyl groups, etc. Lower alkylene group...methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene,
Methylmethylene, ethylmethylene, tetramethylene, pentamethylene, hexamethylene groups, etc. Halogen atoms: fluorine, chlorine, bromine and iodine atoms. Lower alkoxy groups: methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy 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. A group selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, and a hydroxyl group as a substituent on the phenyl ring.
Phenyl group that may have ~3... phenyl,
2-chlorophenyl, 3-chlorophenyl, 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 enyl, 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-methylthiophenyl, 3-methylthiophenyl, 4-methylthiophenyl, 2-ethylthiophenyl, 3-ethylthiophenyl, 4-ethylthiophenyl, 4-
Isopropylthiophenyl, 4-hexylthiophenyl, 3,4-dimethylthiophenyl, 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. A phenyl group that may have 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkoxy group as a substituent on the phenyl ring... phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 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-dibromophenyl, 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 groups, 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 carbon-carbon bond between the 3- and 4-positions of the carbostyril skeleton is a double bond. Γ 5-{1-oxo-4-[4-(4-fluorophenyl)-1-piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-oxo-4-[4-(4-methylphenyl)-1-piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-{1-oxo-4-[4-(2-methylphenyl)-1-piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{1-oxo-4-[4-(4-chlorophenyl)-1-piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-oxo-4-[4-(2-chlorophenyl)-1-piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-oxo-3-[4-(3-chlorophenyl)-1-piperazinyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-{1-oxo-4-[4-(3-fluorophenyl)-1-piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-oxo-4-[4-(3,4-dichlorophenyl)-1-piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 5-{1-oxo-3-methyl-4-[4-
(2-chlorophenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-oxo-4-[4-(3-methoxyphenyl)- 1-piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{1-oxo-4-[4-(4-methoxyphenyl)-1-piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-{1-oxo-4-[4-(4-ethoxyphenyl)-1-piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-oxo-4-[4-(4-isopropoxyphenyl)-1-piperazinyl]butyl}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-{1-oxo-4-[4-(2-ethylphenyl)-1-piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-oxo-4-[4-(4-ethylphenyl)-1-piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-oxo-4-[4-(4-isopropylphenyl)-1-piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenation product Γ 7-{1-oxo-4-[4-(3-methoxycarbonylphenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 5-{1-oxo-4-[4-(4-hexyloxycarbonylphenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{ 1-oxo-4-[4-(3,4-dihydroxyphenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-oxo- 4-[4-(3-methylthiophenyl)-1-piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenator Γ 5-{1-oxo-3-[4-(4-methoxyphenyl)-1-piperazinyl]propyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenation product Γ 7-{1-oxo-3-[4-(3-methylphenyl)-1-piperazinyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-5-{1-oxo-4-[4-
(4-methoxyphenyl)-1-piperazinyl]
1-allyl-7-{1-oxo-4-[4-
(2-methylphenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 1-(2-phenylethyl)-5-[1-oxo-4-(4- phenyl-1-piperazinyl]
1-(2-propynyl)-8-{1-oxo-
4-[4-(2-chlorophenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-hydroxy-4-[4-(4- Fluorophenyl)-1-piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenase Γ 5-{1-hydroxy-4-[4-(4-methylphenyl)-1-piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 8-{1-hydroxy-4-[4-(2-methylphenyl)-1-piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 7-{1-hydroxy-4-[4-(4-chlorophenyl)-1-piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 5-{1-hydroxy-4-[4-(2-chlorophenyl)-1-piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 5-{1-hydroxy-3-[4-(3-chlorophenyl)-1-piperazinyl]propyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 8-{1-hydroxy-4-[4-(3-fluorophenyl)-1-piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 5-{1-hydroxy-4-[4-(3,4-
dichlorophenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-hydroxy-3-methyl-4-[4
-(2-chlorophenyl)-1-piperazinyl]
butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-ohydroxy4-[4-(3-methoxyphenyl)-1-piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 7-{1-hydroxy-4-[4-(4-methoxyphenyl)-1-piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 8-{1-hydroxy-4-[4-(4-ethoxyphenyl)-1-piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenation product Γ 5-{1-hydroxy-4-[4-(4-isopropoxyphenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 8-{1-hydroxy-4-[4-(2-ethylphenyl)-1-piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenase Γ 5-{1-hydroxy-4-[4-(4-ethylphenyl)-1-piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenation product Γ 5-{1-hydroxy-4-[4-(4-isopropylphenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 7-{1-hydroxy-4-[4-(3,4-
dihydroxyphenyl)-1-piperazinyl]
butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-hydroxy-4-[4-(3-methylthiophenyl)-1-piperazinyl]butyl}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-hydroxy-3-[4-(4-methoxyphenyl)-1-piperazinyl]propyl}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{1-hydroxy-3-[4-(3-methylphenyl)-1-piperazinyl]propyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 1-methyl-5-{1-hydroxy-4-[4
-(4-methoxyphenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-allyl-5-{1-hydroxy-4-[4
-(2-methylphenyl)-1-piperazinyl]
1-(2-phenylethyl)5-[1-hydroxy-4(4-phenyl-1-piperazinyl)
1-(2-propynyl)-8-{1-hydroxy-4[4-(2-chlorophenyl)-1-piperazinyl]butyl }-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{4-[4-(4-fluorophenyl)-1
-piperazinyl]-1-butenyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{4-[4-(4-methylphenyl)-1-
piperazinyl]-1-butenyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-{4-[4-(2-methylphenyl)-1-
Piperazinyl]-1-butenyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{4-[4-(4-chlorophenyl)-1-
piperazinyl]-1-butenyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 5-{4-[4-(2-chlorophenyl)-1-
piperazinyl]-1-butenyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{3-[4-(3-chlorophenyl)-1-
piperazinyl]-1-propenyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenated product Γ 8-{4-[4-(3-fluorophenyl)-1
-piperazinyl]-1-butenyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{4-[4-(3,4-dichlorophenyl)
-1-piperazinyl]-1-butenyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{3-methyl-4-[4-(2-chlorophenyl)-1-piperazinyl]-1-butenyl}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{4-[4-(3-methoxyphenyl)-1
-piperazinyl]-1-butenyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{4-[4-(4-methoxyphenyl)-1
-Piperazinyl]-1-butenyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-{4-[4-(4-ethoxyphenyl)-1
-piperazinyl]-1-butenyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{4-[4-(4-isopropoxyphenyl)-1-piperazinyl]-1- butenyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-{4-[4-(2-ethylphenyl)-1-
piperazinyl]-1-butenyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{4-[4-(4-ethylphenyl)-1-
Piperazinyl]-1-butenyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{4-[4-(4-isopropylphenyl)
-1-piperazinyl]-1-butenyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{4-[4-(3,4-dihydroxyphenyl)-1-piperazinyl]-1-butenyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenation product Γ 5-{4-[4-(3-ethylthiophenyl)-
1-Piperazinyl]-1-butenyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{4-[4-(4-hexylthiophenyl)
-1-piperazinyl]-1-butenyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{3-[4-(4-methoxyphenyl)-1
-piperazinyl]-1-propenyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{3-[4-(3-methylphenyl)-1-
piperazinyl]-1-propenyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-5-{4-[4-(4-methoxyphenyl)-1-piperazinyl]- 1-Butenyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-allyl-7-{4-[4-(2-methylphenyl)-1-piperazinyl]-1-butenyl}
-3,4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 1-(2-phenylethyl)5-[4-(4-
Phenyl-1-piperazinyl)-1-butenyl]
-3,4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 1-(2-propynyl)8-{4-[4-(2-
5-{4-[4-(4-fluorophenyl)-1
5-{4-[4-(4-methylphenyl)-1-
piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-{4-[4-(2-methylphenyl)-1-
piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{4-[4-(4-chlorophenyl)-1-
piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 5-{4-[4-(2-chlorophenyl)-1-
piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{3-[4-(3-chlorophenyl)-1-
Piperazinyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-{4-[4-(3-fluorophenyl)-1
5-{4-[4-(3,4-dichlorophenyl)
-1-piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{3-methyl-4-[4-(2-chlorophenyl)-1-piperazinyl]butyl}- 3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{4-[4-(3-methoxyphenyl)-1
-piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{4-[4-(4-methoxyphenyl)-1
8-{4-[4-(4-ethoxyphenyl)-1
-Piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{4-[4-(4-isopropoxyphenyl)-1-piperazinyl]butyl}-3,4 -dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-{4-[4-(2-ethylphenyl)-1-
piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{4-[4-(4-ethylphenyl)-1-
piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenated product Γ 5-{4-[4-(4-isopropylphenyl)
-1-piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{4-[4-(3,4-dihydroxyphenyl)-1-piperazinyl]butyl}- 3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{4-[4-(3-methylthiophenyl)-
1-piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenator Γ 6-{4-[4-(4-hexylthiophenyl)
5-{3-[4-(4-methoxyphenyl)-1
7-{3-[4-(3-methylphenyl)-1-
Piperazinyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-5-{4-[4-(4-methoxyphenyl)-1-piperazinyl]butyl}-3 ，
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-allyl-7-{4-[4-(2-methylphenyl)-1-piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 1-(2-phenylethyl)5-[4-(4-
phenyl-1-piperazinyl)butyl]-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-(2-propynyl)-8-{4-[4-(2
6-{1-oxo-4-[4-(2-phenylethyl)-1-piperidyl] Butyl]-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-2-[4-(1-phenylethyl)-1-piperidyl]ethyl]-3,4-
Dihydrocarbostyryl 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(4-phenylbutyl)-1-piperidyl]butyl]-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-3-[4-(6-phenylhexyl)-1-piperidyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[1-hydroxy-4-(4-benzyl-
1-piperidyl)butyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[1-hydroxy-3-(4-benzyl-
1-piperidyl]propyl-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[1-hydroxy-4-[4-(2-phenylethyl)-1-piperidyl]butyl]-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[1-hydroxy-2-[4-(1-phenylethyl)-1-piperidyl]ethyl]-3,
4-dihydrocarbostyryl 3,4-position dehydrogenate Γ 6-[1-hydroxy-4-[4-(4-phenylbutyl)-1-piperidine]butyl]-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[1-hydroxy-3-[4-(6-phenylhexyl)-1-piperidyl]propyl]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenase Γ 5-[1-oxo-4-(4-benzyl-1-
piperidyl)butyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate
1-piperidyl]propyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-3-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]
6-{1-oxo-3-[4-(4-fluorophenyl)-4-hydroxy-1-piperidyl]
6-{1-oxo-2-[4-(2-fluorophenyl)-4-hydroxy-1-piperidyl]
ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-5-[4-(2-chlorophenyl)-4-hydroxy-1-piperidyl]
pentyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-6-[4-(3-chlorophenyl)-4-hydroxy-1-piperidyl]
6-{1-oxo-4-[4-(4-bromphenyl)-4-hydroxy-1-piperidyl]
6-{1-oxo-3-[4-(2,6-dichlorophenyl)-4-hydroxy-1-piperidyl] 6-{1-oxo-4-[4-(2-methylphenyl)-4-hydroxy-1-piperidyl]
butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(3-ethylphenyl)-4-hydroxy-1-piperidyl]
6-{1-oxo-4-[4-(2,3-dimethylphenyl)-4-hydroxy-1-piperidyl] 6-{1-oxo-3-[4-(2,3-dimethylphenyl)-4-hydroxy-1-piperidyl] 6-{1-oxo-2-[4-(4-methylphenyl)-4-hydroxy-1-piperidyl]
ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-3-[4-(3-hexylphenyl)-4-hydroxy-1-piperidyl]
6-{1-oxo-4-[4-(3-methoxyphenyl)-4-hydroxy-1-piperidyl]
6-{1-oxo-6-[4-(2-ethoxyphenyl)-4-hydroxy-1-piperidyl]
6-{1-oxo-3-[4-(4-methoxyphenyl)-4-hydroxy-1-piperidyl]
6-{1-oxo-2-[4-(4-hexyloxyphenyl)-4-hydroxy-1-piperidyl]ethyl }-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-6-[4-(2-methoxyphenyl)-4-hydroxy-1-piperidyl]
6-[1-oxo-4-(4-benzyl-4-
hydroxy-1-piperidyl)butyl]-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[1-oxo-4-[4-(2-phenylethyl)-4-hydroxy-1-piperidyl]
6-{1-oxo-3-[4-(1-phenylethyl)-4-hydroxy-1-piperidyl]
6-{1-oxo-2-[4-(3-phenylpropyl)-4-hydroxy-1-piperidyl]
ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-6-[4-(6-phenylhexyl)-4-hydroxy-1-piperidyl]
6-[1-oxo-3-(4-acetyl-4-
phenyl-1-piperidyl]propyl]-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[1-oxo-3-(4-propionyl-
4-phenyl 1-piperidyl propyl]-3,
4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 6-[1-oxo-4-(4-hexanoyl-
4-phenyl-1-piperidyl]butyl]-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[1-oxo-2-(4-acetyl-4-
Benzyl-1-piperidyl]ethyl]-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-6-[4-acetyl-4-
(4-chlorophenyl)-1-piperidyl]hexyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-acetyl-4-
(3-Methylphenyl)-1-piperidyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-acetyl-4-
(2,3-dimethylphenyl)-1-piperidyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-3-[4-acetyl-4-
(2-methoxyphenyl)-1-piperidyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(2-benzimidazolinone) -1-yl)-4-hydroxy-
1-piperidyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-3-[4-(2-benzimidazolinon-1-yl)4-acyl 6-{1-oxo-2-[4-(2-benzimidazolinon-1-yl)-4 -propionyl-1-piperidyl]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-6-[4-(2-benzimidazolinon-1-yl) 6-{1-oxo-3-[4-(3-bromphenyl)-1,2 ,5,6-tetrahydro-1
-pyridyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-3-[4-(2-iodophenyl)-1,2,5,6-tetrahydr -1
6-{1-oxo-4-[4-(3,4-dichlorophenyl)-1,2,5 ,6-tetrahydro-1-pyridyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(4-methylphenyl)-1,2 ,5,6-tetrahydro-1
-pyridyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-3-[4-(3-ethylphenyl)-1,2,5,6-tetrahydro -1
-pyridyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 6-{1-oxo-3-[4-(4-methylphenyl)-1,2,5,6-tetrahydr -1
6-{1-oxo-2-[4-(2-butylphenyl)-1,2,5,6-tetrahydro -1
6-{1-oxo-6-[4-(2,3-dimethylphenyl)-1,2,5 , 6-tetrahydro-1-pyridyl]hexyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-3-[4-(4-methoxyphenyl)-1 ,2,5,6-tetrahydro-
1-pyridyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 6-{1-oxo-4-[4-(3,4-dimethoxyphenyl)-1,2, 5,6-tetrahydro-1-pyridyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(2-ethoxyphenyl)- 1,2,5,6-tetrahydro-
1-pyridyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(3,4,5-
trimethoxyphenyl)-1,2,5,6-tetrahydro-1-pyridyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 6-[1-oxo-4-(4-benzyl-1,
2,5,6-tetrahydro-1-pyridyl)butyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[1-oxo-3-(4-benzyl-1,
2,5,6-tetrahydro-1-pyridyl)propyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(2-phenylethyl)- 1,2,5,6-tetrahydro-1
-pyridyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-4-[4-(1-phenylethyl)-1,2,5,6-tetrahydro -1
-pyridyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 6-{1-oxo-3-[4-(3-phenylpropyl)-1,2,5,6 -tetrahydro-
1-pyridyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-oxo-2-[4-(6-phenylhexyl)-1,2,5,6- Tetrahydro
1-pyridyl]ethyl}-3,4-dihydrocarbostyryl 3,4-position dehydrogenase Γ 6-[1-oxo-6-(4-benzyl-1,
2,5,6-tetrahydro-1-pyridyl]hexyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-6-[1-oxo-4-(4-phenyl- 1,2,5,6-tetrahydro-1-
pyridyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 1-benzyl-6-[1-oxo-3-(4-
Phenyl-1,2,5,6-tetrahydro-1
-pyridyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 1-allyl6-[1-oxo-4-(4-phenyl-1,2,5,6-tetrahydro- 1-pyridyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-6-[1-oxo-3-(4-benzyl-1piperidyl)propyl]-3, 4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-6-[1-oxo-4-(4-
benzyl-piperidyl)butyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-allyl-6-[1-oxo-3-(4-benzyl-piperidyl)propyl]-3,4 -dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 1-ethyl-6-[1-oxo-3-(4-phenyl--4hydroxy-1-piperidyl)propyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenated product Γ 1-benzyl-6-{1-oxo-3-[4-
(4-chlorophenyl)-4-hydroxy-1-
piperidyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-allyl-6-{1-oxo-4-[4-
(2,3-dimethylphenyl)-4-hydroxy-1-piperidyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase -(4-acetyl-4-phenyl-1-piperidyl)butyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 1-benzyl-6-{1-oxo-3-[4-
Acetyl-4-(2-methoxyphenyl)-1-
1-allyl-6-[1-oxo-4-(4-acetyl-4-benzyl-1-piperidyl)butyl] -3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-allyl-6-{1-oxo-3-[4-
(2-benzimidazolinon-1-yl)-1-
piperidyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-6-{1-oxo-4-[4-
(2-benzimidazolinon-1-yl)-4-
Hydroxy-1-piperidyl]butyl}-3,
4-Dicarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-6-{1-oxo-3-[4-
(2-benzimidazolinon-1-yl)-4-
Acetyl-1-piperidyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[1-hydroxy-4-(4-phenyl-
4-Hydroxy-1-piperidyl)butyl]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenation product Γ 6-{1-hydroxy-4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl)butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation Body Γ 6-{1-hydroxy-3-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl)propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6- {1-hydroxy-3-[4-(4-fluorophenyl)-4-hydroxy-1-piperidyl)propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy -2-[4-(2-fluorophenyl)-4-hydroxy-1-piperidyl]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-5 -[4-(2-chlorophenyl)-4-hydroxy-1-piperidyl]pentyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-6-[4- (3-chlorophenyl)-4-hydroxy-1-piperidyl]hexyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(4-bromphenyl) )-4-hydroxy-1-piperidyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate
6-{1-hydroxy-4-[4-(2-methylphenyl) 6-{1-hydroxy-4-[4-(3-ethylphenyl)-4-hydroxy 6-{1-hydroxy-4-[4-(2,3-
dimethylphenyl)-4-hydroxy-1-piperidyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-3-[4-(4-propylphenyl) 6-{1-hydroxy-2-[4-(4-heptylphenyl)-4 -hydroxy-1-piperidyl]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-3-[4-(3-hexylphenyl)-4-hydroxy-1 6-{1-hydroxy-4-[4-(3-methoxyphenyl)-4-hydroxy-1-piperidyl ]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-6-[4-(2-ethoxyphenyl)-4-hydroxy-1-piperidyl]hexyl }-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-3-[4-(4-methoxyphenyl)-4-hydroxy-1-piperidyl]butyl}- 3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-2-[4-(4-hexyloxyphenyl)-4-hydroxy-1-
6-{1-hydroxy-6-[4-(2,3-
dimethoxyphenyl)-4-hydroxy-1-
piperidyl]hexyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(2-phenylethyl)-4-hydroxy-1-piperidyl]butyl} -3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-3-[4-(1-phenylethyl)-4-hydroxy-1-piperidyl]propyl}-3,4 -dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-2-[4-(3-phenylpropyl)-4-hydroxy-1-piperidyl]ethyl}-3,4-dihydro Carbostyryl and its 3,4-position dehydrogenate 3,4-position dehydrogenate Γ 6-[1-hydroxy-4-(4-acetyl-
4-phenyl-1-piperidyl)butyl]-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[1-hydroxy-3-(4-acetyl-
4-phenyl-1-piperidyl)propyl]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenation product Γ 6-[1-hydroxy-3-(4-propionyl-4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 6- [1-Hydroxy-4-(4-hexanoyl-4-phenyl-1-piperidyl)butyl]
-3,4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 6-[1-hydroxy-2-(4-acetyl-
4-benzyl-1-piperidyl)ethyl]-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-6-[4-acetyl-
4-(4-chlorophenyl)-1-piperidyl]
6-{1-hydroxy-4-[4-acetyl-
4-(3methylphenyl)-1-piperidyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 6-{1-hydroxy-3-[4-acetyl-
4-(2-methoxyphenyl)-1-piperidyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase imidazolinon-1-yl)-1-piperidyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenant Γ 6-{1-hydroxy-4-[4-(2-benzimidazolinone) 6-{1-hydroxy-4-[4-(2-benzimidazolinone-1) 6-{1-Hydroxy-3-[4-(2-benzimidazolinone) -1-yl)-4-acetyl-1-piperidyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase 6-{1-hydroxy-6-[4-(2- benzimidazolin-1-yl)-4-hexanoyl-1-piperidyl]hexyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[1-hydroxy-4-(4-phenyl-
1,2,5,6-tetrahydro-1-pyridyl)butyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(4-chlorophenyl) )-1,2,5,6-tetrahydro-1-pyridyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate 6-{1-hydroxy-3-[4- (2-iodophenyl)-1,2,5,6-tetrahydro-1-pyridyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[ 4-(3,4-
dichlorophenyl)-1,2,5,6-tetrahydro-1-pyridyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4 -(4-methylphenyl)-1,2,5,6-tetrahydro-1-pyridyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-3- [4-(3-ethylphenyl)-1,2,5,6-tetrahydro-1-pyridyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy- 3-[4-(4-propylphenyl)-1,2,5,6-tetrahydro-1-pyridyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{ 1-Hydroxy-2-[4-(2-butylphenyl)-1,2,5,6-tetrahydro-1-pyridyl]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6 -{1-hydroxy-6-[4-(4-hexylphenyl)-1,2,5,6-tetrahydro-1-pyridyl]hexyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-3-[4-(4-methoxyphenyl)-1,2,5,6-tetrahydro-1-pyridyl]propyl}-3,4-dihydrocarbostyryl and its 3,4 Position dehydrogenator Γ 6-{1-hydroxy-4-[4-(3-propoxyphenyl)-1,2,5,6-tetrahydro-1-pyridyl]butyl}-3,4-dihydrocarbostyryl and Its 3,4-position dehydrogenation product Γ 6-{1-hydroxy-4-[4-(2-hexyloxyphenyl)-1,2,5,6-tetrahydro-1-pyridyl]butyl}-3,4 −
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(3,4,
5-trimethoxyphenyl)-1,2,5,6
-tetrahydro-1-pyridyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[1-hydroxy-4-(4-benzyl-
1,2,5,6-tetrahydro-1-pyridyl)butyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[1-hydroxy-3-(4-benzyl-
1,2,5,6-tetrahydro-1-pyridyl)propyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(2-phenylethyl) )-1,2,5,6-tetrahydro-1-pyridyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate -phenylethyl)-1,2,5,6-tetrahydro-1-pyridyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-3-[4- (3-phenylpropyl)-1,2,5,6-tetrahydro-1-pyridyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-2 -[4-(6-phenylhexyl)-1,2,5,6-tetrahydro-1-pyridyl]ethyl}-3,4-dihydrocarbostyryl 3,4-position dehydrogenate Γ 6-[1-hydroxy-6 -(4-benzyl-
1,2,5,6-tetrahydro-1-pyridyl]hexyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 1-methyl-6-[1-hydroxy-4-(4
-phenyl-1,2,5,6-tetrahydro-
1-pyridyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl6-[1-hydroxy-3-(4
-phenyl-1,2,5,6-tetrahydro-
1-pyridyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-allyl-6-[1-hydroxy-4-(4
-phenyl-1,2,5,6-tetrahydro-
1-pyridyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-6-[1-hydroxy-3-(4
-benzyl-1-piperidyl)propyl]-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-6-[1-hydroxy-4-
(4-benzyl-1-piperidyl)butyl]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 1-allyl-6-[1-hydroxy-3-(4
-benzyl-1-piperidyl)propyl]-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-6-[1-hydroxy-3-(4
-phenyl-4-hydroxy-1-piperidyl)propyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-6-{1-hydroxy-3-
[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-allyl-6-{1-hydroxy-4- [4
-(2,5-dimethylphenyl)-4-hydroxy-1-piperidyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase 4-(4
-acetyl-4-phenyl-1-piperidyl)
1-benzyl-6-{1-hydroxy-3-
[4-acetyl-4-(2-methoxyphenyl)
1-allyl-6-[1-hydroxy-4-(4
-acetyl-4-benzyl-1-piperidyl]
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-allyl-6-{1-hydroxy-3-[4
-(2-benzimidazolinon-1-yl)-1
1-methyl-6-{1-hydroxy-3-[4
-(2-benzimidazolinon-1-yl)-4
-acetyl-1-piperidyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-[oxo-3-(4-phenyl-4-hydroxy-1-piperidyl)propyl]-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-oxo-4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]
8-{1-oxo-3-[4-(2,6-dichlorophenyl)-4-hydroxy-1-piperidyl] 5-{1-oxo-3-[4-(6-phenylhexyl)-1-piperidyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-[1-hydroxy-4-[4-(2-phenylethyl)-1-piperidyl]butyl]-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-[1-oxo-4-(4-benzyl-1-
7-[1-oxo-3-(4-benzyl-1-
piperidyl)butyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-oxo-4-[4-(2-methylphenyl)-4-hydroxy-1-piperidyl]
5-{1-oxo-4-[4-(3-methoxyphenyl)-4-hydroxy-1-piperidyl]
8-{1-oxo-3-[4-(1-phenylethyl)-4-hydroxy-1-piperidyl]
5-[1-oxo-4-(4-benzyl-4-
hydroxy-1-piperidyl)butyl]-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-{1-oxo-4-[4-(2-methoxyphenyl)-4-hydroxy-1-piperidyl]
5-[1-oxo-4-(4-acetyl-4-
benzyl-1-piperidyl)butyl]-3,4
-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 8-[1-oxo-3-(4-acetyl-4-
benzyl-1-piperidyl)propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-oxo-3-[4-acetyl-4-
(3-Methylphenyl)-1-piperidyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-oxo-4-[4-(2-benzimidazolinone-1) -yl)-1-piperidyl]
5-{1-oxo-4-[4-(2-benzimidazolinon-1-yl)-4-hydroxy-
1-piperidyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-oxo-3-[4-(2-benzimidazolinon-1-yl)-4- Acetyl-1
8-{1-oxo-4-[4-(2-benzimidazolinon-1-yl)-1-piperidyl ]
7-{1-oxo-3-[4-(2-benzimidazolinon-1-yl)-4-hydroxy-
5-[1-oxo-4-(4-phenyl-1,
2,5,6-tetrahydro-1-pyridyl)butyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-[1-oxo-4-[4-(4-chlorophenyl)- 1,2,5,6-tetrahydro-1
-pyridyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 5-{1-oxo-3-[4-(3-ethylphenyl)-1,2,5,6-tetrahydro -1
-pyridyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 8-{1-oxo-3-[4-(4-methylphenyl)-1,2,5,6-tetrahydro -1
5-{1-oxo-4-[4-(3,4,5-
trimethoxyphenyl)-1,2,5,6-tetrahydro-1-pyridyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-oxo-3-(4-penzyl-1,
2,5,6-tetrahydro-1-pyridyl)propyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{1-oxo-4-[4-(1-phenylethyl)- 1,2,5,6-tetrahydro-1
-pyridyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 1-methyl-5-[1-oxo-4-(4-phenyl-1,2,5,6-tetrahydro -1-
pyridyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 1-benzyl-5-[1-oxo-3-(4-
Phenyl-1,2,5,6-tetrahydro-1
1-allyl-5-[1-oxo-4-(4-phenyl-1,2,5,6-tetrahydro) -1-
pyridyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 1-methyl-6-[1-oxo-3-(4-benzyl-1-piperidyl)propyl]-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-8-[1-oxo-4-(4-
benzyl-1-piperidyl)butyl]-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-allyl-6-[1-oxo-3-(4-benzyl-1-piperidyl)propyl]-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-7-[1-oxo-3-(4-phenyl-4-hydroxy-1-piperidyl)propyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenated product Γ 1-benzyl-5-{1-oxo-3-[4-
(4-chlorophenyl)-4-hydroxy-1-
piperidyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-allyl-5-{1-oxo-4-[4-
(2,3-dimethylphenyl)-4-hydroxy-1-piperidyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase -(4-acetyl-4-phenyl-1-piperidyl)butyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-7-{1-oxo-3-[4-
Acetyl-4-(2-methoxyphenyl)-1-
1-allyl-8-[1-oxo-4-(4-acetyl-4-benzyl-1-piperidyl)-3 ，
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-allyl-5-{1-oxo-3-[4-
(2-benzimidazolinon-1-yl)-1-
piperidyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-5-{1-oxo-4-[4-
(2-benzimidazolinon-1-yl)-4-
Hydroxy-1-piperidyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-5-{1-oxo-3-[4-
(2-benzimidazolinon-1-yl)-4-
Acetyl-1-piperidyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-8-{1-oxo-3-[4-
(2-benzimidazolinon-1-yl)-1-
1-methyl-7-[1-hydroxy-3-(4
-phenyl-4-hydroxy-1-piperidyl)propyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase
[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-allyl-5-{1-hydroxy-4- [4
-(2,3-dimethylphenyl)-4-hydroxy-1-piperidyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase 4-(4
-acetyl-4-phenyl-1-piperidyl)
1-benzyl-7-{1-hydroxy-3-
[4-acetyl-4-(2-methoxyphenyl)
1-allyl-8-[1-hydroxy-4-(4
-acetyl-4-benzyl-1-piperidyl]
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-allyl-5-{1-hydroxy-3-[4
-(2-benzimidazolinon-1-yl)-1
1-benzyl-5-{1-hydroxy-4-
[4-(2-benzimidazolinon-1-yl)
-4-hydroxy-1-piperidyl]butyl}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-5-{1-hydroxy-3-[4
-(2-benzimidazolinon-1-yl)-4
-acetyl-1-piperidyl]propyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-8-{1-hydroxy-3-[4
-(2-benzimidazolinon-1-yl)-1
5-[1-hydroxy-4-[4-(4-chlorophenyl)-1,2,5,6-tetrahydro] -1-pyridyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-hydroxy-3-[4-(3-ethylphenyl)-1,2,5,6 8-{1-hydroxy-3-[4-(4-methylphenyl)-1,2,5 ,6-tetrahydro-1-pyridyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-hydroxy-4-[4-(3,4,
5-trimethoxyphenyl)-1,2,5,6
-tetrahydro-1-pyridyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-hydroxy-3-(4-benzyl-
1,2,5,6-tetrahydro-1-pyridyl)propyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{1-hydroxy-4-[4-(1-phenylethyl) )-1,2,5,6-tetrahydropyridyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase
-phenyl-1,2,5,6-tetrahydro-
1-pyridyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-5-[1-hydroxy-3-
(4-phenyl-1,2,5,6-tetrahydro-1-pyridyl]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-allyl-5-[1-hydroxy- 4-(4
-phenyl-1,2,5,6-tetrahydro-
1-pyridyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-6-[1-hydroxy-3-(4
-benzyl-1-piperidyl]propyl]-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-8-[1-hydroxy-4-
(4-benzyl-1-piperidyl]butyl]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 1-allyl-6-[1-hydroxy-3-(4
-benzyl-1-piperidyl]propyl]-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-[1-hydroxy-3-(4-phenyl-
4-Hydroxy-1-piperidylpropyl
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-hydroxy-4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl)butyl}-3,4 -dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-{1-hydroxy-3-[4-(2,6-
5-{1-hydroxy-3-[4-(6-phenylhexyl) -1-piperidyl]propyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 5-[1-hydroxy-4-[4-(2-phenylethyl)-1-piperidyl]butyl]-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-[1-hydroxy-4-(4-benzyl-
1-piperidyl)butyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-[1-hydroxy-3-(4-benzyl-
1-piperidyl)butyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-hydroxy-4-[4-(2-methylphenyl)-4-hydroxy-1-piperidyl] butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-hydroxy-4-[4-(3-methoxyphenyl)-4-hydroxy-1-piperidyl]butyl} -3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-{1-hydroxy-3-[4-(1-phenylethyl)-4-hydroxy-1-piperidyl]propyl}-3,4 -dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-[1-hydroxy-4-(4-benzyl-
4-Hydroxy-1-piperidyl)butyl]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenator Γ 8-{1-hydroxy-4-[4-(2-methoxyphenyl)-4-hydroxy-1-piperidyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position Dehydrogenate Γ 5-[1-hydroxy-4-(4-acetyl-
4-benzyl-1-piperidyl)butyl]-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-[1-hydroxy-3-(4-acetyl-
4-benzyl-1-piperidyl)propyl]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 5-{1-hydroxy-3-[4-acetyl-
4-(3-methylphenyl)-1-piperidyl]
5-{1-hydroxy-4-[4-(2-benzimidazolinon-1-yl)-1-piperidyl]butyl} -3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{1-hydroxy-4-[4-(2-benzimidazolinon-1-yl)-4-hydroxy-1-piperidyl] 5-{1-hydroxy-3-[4-(2-benzimidazolinon-1-yl)-4-acetyl-1- 8-{1-hydroxy-4-[4-(2-benzimidazolinon-1-yl)-1-piperidyl] butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{1-hydroxy-3-[4-(2-benzimidazolinon-1-yl)-4-hydroxy-1- 5-[1-hydroxy-4-(4-phenyl-
1,2,5,6-tetrahydro-1-pyridyl)butyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[1-oxo-4-(4-benzyl-1-
5-{1-oxo-4-[4-(6-phenylhexyl)-1-piperazinyl]butyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-{1-oxo-3-[4-(2-phenylethyl)-1-piperazinyl]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-[1-hydroxy-4-(4-benzyl-
1-piperazinyl)butyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{1-hydroxy-4-[4-(6-phenylhexyl)-1-piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated product Γ 7-{1-hydroxy-3-[4-(2-phenylethyl)-1-piperazinyl]butyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenation product Γ 6-[4-(4-benzyl-1-piperazinyl-1-butenyl-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 5-{4-[4-( 6-phenylhexyl)-1
-piperazinyl]butyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-{3-[4-(2-phenylethyl)-1-
piperazinyl]-1-propenyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 6-{3-[4-(4-benzyl-1-piperazinyl)propyl}-3,4-dihydro Carbostyryl 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. [In the above formula, X represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group, or an aralkylsulfonyloxy group.
A, B, R ¹ , l, Z and the carbon-carbon bonds at the 3rd and 4th positions of the carbostyryl skeleton are the same as above. ] Here, the lower alkanesulfonyloxy group represented by Examples include sulfonyloxy groups, and specific examples of arylsulfonyloxy groups include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-methylphenylsulfonyloxy, and 4-methylphenylsulfonyloxy.
Examples include substituted or unsubstituted arylsulfonyloxy groups such as -nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy, and α-naphthylsulfonyloxy groups, and as aralkylsulfonyloxy groups. Specifically, benzylsulfonyloxy, 2-phenylethylsulfonyloxy,
4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, α
Examples include substituted or unsubstituted aralkylsulfonyloxy groups such as -naphthylmethylsulfonyloxy. The compound of the present invention represented by the general formula (1) is a carbostyryl derivative represented by the general formula (2).
It is produced by reacting the compound represented by (3). The above reaction is completed in about 1 hour to 30 hours at a temperature of room temperature to about 200°C, preferably room temperature to 150°C, without a solvent or in a common inert solvent. 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, lower alcohols such as methanol, ethanol, and isopropanol, dimethylformamide, and dimethyl. Polar solvents such as sulfoxide, hexamethylphosphoric triamide, acetone, acetonitrile, etc. 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 potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium amide, sodium hydride,
Examples include tertiary amines such as triethylamine, tripropylamine, 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 usually the latter is used in equimolar amounts to the former. The excess amount is preferably from equimolar to 5 times the mole, more preferably from 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 methods shown in reaction schemes 2 to 12 below. General formula used as starting material for one of the other
The compound (3) is a known compound [JP-A-55-2693
No., JP-A-54-160389, West German Publication No. 2912105] or is a compound that can be easily produced according to the methods described in these publications. [In the above formula, X′ represents a halogen atom, and R ⁷ represents a lower alkyl group, an aryl group, or an aralkyl group. R ¹ , B, X, l and the carbon-carbon bonds at the 3rd and 4th positions of the carbostyril skeleton are the same as above. ] That is, in the compound of general formula (2), the group -A-(B) _l -
X is substituted at the 6-position of the carbostyril skeleton, and A is a group

[Formula] Compounds (compounds of general formula (2a)) are compounds of known general formula (4) and compounds of general formula (2a)
(5) or a known compound of general formula (6), or a compound of general formula (4) is reacted with a known compound of general formula (7), and then the resulting general formula
It is produced by reacting the compound (8) with the compound of general formula (9). Furthermore, in the compound of general formula (2), the group -A-(B) _l -X is substituted at the 6-position of the carbostyryl skeleton, and A is the group

The compound represented by the formula (compound of general formula (2b)) is produced by reacting the 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, polyphosphoric acid, and concentrated sulfuric acid. 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). The amount of the compound of general formula (5) or the compound of general formula (6) to be used is usually at least an equimolar amount, preferably an equimolar amount to twice the molar amount of the compound of general formula (4). . The reaction temperature is appropriately selected, but is usually about 20 to 120°C, preferably about 40 to 70°C. Although the reaction time for this reaction varies depending on the raw materials, catalyst, reaction temperature, etc., it cannot be stated unconditionally, but the reaction is usually completed in about 0.5 to 24 hours, preferably about 0.5 to 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 ⁷ in the above general formula (9) is a substituted or Examples of unsubstituted aryl groups include benzyl, 2-phenylethyl, 4-phenylbutyl, 4-methylbenzyl, 2-methylbenzyl, 4-nitrobenzyl,
4-methoxybenzyl, 3-chlorobenzyl, α
Examples include substituted or unsubstituted aralkyl groups such as -naphthylmethyl group. Further, the reaction between the compound of general formula (8) 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 thionyl chloride. Examples of inert solvents include ethers such as dioxane and THF, and halogenated hydrocarbons such as chloroform and methylene chloride. The compound of general formula (8) 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 room temperature to 70°C, and is generally carried out at a temperature of 1 to 24°C.
The reaction completes in about an hour. 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,
Examples include ethers such as tetrahydrofuran. The amount of sodium borohydride to be used can be appropriately selected within a wide range, but usually the amount of sodium borohydride is at least equimolar, preferably equimolar to 3 times the amount of the compound of general formula (2a). It is preferable to use a molar amount. [In the formula, R ¹ , R ⁷ , B, 1, X, X' and the carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton are the same as above. However, the side chain

The substitution position in [Formula] is the ortho position or para position with respect to the hydroxyl group or the group -SO ₂ R ⁷ . ] In the compound of general formula (2), A is a group

[Formula] Compounds (compounds of general formula (2c)) have the reaction formula -
It is manufactured by the method shown in 3. In the reaction between the known compound of general formula (10) and the known compound of general formula (5), a known Lewis acid is usually used as a catalyst, such as aluminum chloride, zinc chloride, iron chloride, tin chloride, etc. It will be done. Further, although this reaction is carried out without a solvent, it may also be carried out in a solvent. Examples of the solvent include carbon disulfide, nitrobenzene, ether, and dioxane.
The compound of general formula (5) is used in an equimolar to large excess amount relative to the compound of general formula (10), but usually 1.5 to
It is preferable to use 5 times the molar amount. Reaction is −10 to 100
The process proceeds at a temperature of 0°C to 60°C, but is generally preferably carried out at a temperature of 0 to 60°C. Next, the rearrangement reaction of the compound of general formula (11) is generally known as Fries rearrangement, and in this reaction, a commonly known Lewis acid is used as a catalyst, such as aluminum chloride, zinc chloride, etc. ,
Examples include iron chloride and tin chloride. The reaction may be carried out without a solvent, but may also be carried out in a solvent. Examples of the solvent include carbon disulfide, nitrobenzene, ether, and dioxane. The reaction is at room temperature ~
The process proceeds at 150°C, but is generally preferably carried out at 50-100°C. The reaction proceeds even in the presence of the compound of general formula (5). The reaction between the compound of general formula (12) and the compound of general formula (9) can be carried out by reacting the compound of general formula (12) with an alkali metal hydride such as sodium hydride or potassium hydride,
Alkali metal amides such as sodium amide and potassium amide, alkali metals such as potassium metal and sodium metal, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium ethoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc. is reacted with an alkali metal hydroxide, a metal alkyl compound of n-butyllithium, etc., and the hydroxyl group substituted in the carbostyryl skeleton is introduced into an alkali metal salt. The reaction leading to the alkali metal salt is carried out by using the alkali metal or its compound in a suitable solvent, such as an aromatic solvent (benzene, toluene, xylene, etc.), n-hexane,
Cyclohexane, ether solvents (diethyl ether, 1,2-dimethoxyethane, dioxane,
0 in aprotic polar solvents (dimethylformamide, hexamethylphosphoric triamide, dimethyl sulfoxide, etc.)
Proceed at ~200°C, preferably at room temperature, for 30 minutes to 5 hours. Next, the compound of general formula (9) is added to the alkali metal salt of the compound of general formula (12) obtained, and the reaction temperature is 0 to 200°C, preferably 0 to room temperature.
By reacting for 5 hours, the reaction proceeds suitably and the compound of general formula (13) is obtained. The amount of alkali metal hydroxide or its compound to be used is usually 1.0 to 5.0 times, preferably 1.0 to 5.0 times the mole of the compound of general formula (12).
It is 1.2 times the mole. Further, the amount of the compound of general formula (9) to be used is usually 1.0 to 5.0 times the mole, preferably 1.0 to 1.2 times the mole of the compound of general formula (12). For example, the reduction reaction of the compound of general formula (13) can be carried out using water,
It is carried out in a solvent such as a 10% aqueous metal hydroxide solution, methanol, ethanol, isopropanol, ether, or dioxane. At this time, a hydrogenation catalyst such as palladium black, palladium carbon, platinum black, or Raney nickel, preferably 5 to 20% palladium carbon, is used as a catalyst, and the reaction temperature is in a hydrogen stream at normal pressure to 10 atm, preferably normal pressure. The reaction is carried out at 0°C to 40°C, preferably at room temperature, for 5 to 20 hours with thorough shaking or stirring. The amount of catalyst used is 0.1 to 30%, preferably 5 to 20%, based on the compound of general formula (13), and 10 to 20% for palladium on carbon.
It progresses well when used. [In the formula, R ⁸ represents a lower alkyl group. R ¹ , R ⁷ ,
B, l, X, X' and the carbon-carbon bonds at the 3rd and 4th positions of the carbostyril skeleton are the same as above. However, the side chain

The substitution position in [Formula] is the ortho or para position with respect to the group -OR ⁸ , the hydroxyl group, or the group -SO ₂ R ⁷ . ] Known compounds of general formula (14) and general formula (5) or (6)
The reaction of the compound with the general formula (4) and the general formula (5) or
It can be carried out in the same manner as the reaction of the compound (6). The dealkylation reaction of the compound of general formula (15) is
This can be carried out by reacting with hydrogen halide. Examples of hydrogen halides used in this case include hydrogen bromide, hydrogen chloride, and hydrogen iodide. These hydrogen halides are usually used in the form of hydrohalic acid in combination with a suitable solvent, especially water as a solvent. Preferred hydrogen halides include hydrogen bromide, which is usually
It is used by preparing a 10-50% (preferably 47%) aqueous solution. In this reaction, the amount of hydrogen halide used is usually an equivalent to a large excess relative to the compound of general formula (15), and a large excess is preferably used.
The reaction is carried out under heating, and advantageously proceeds by reacting normally at 100 to 150°C (preferably under heating and refluxing) for 5 to 20 hours. The reaction between the compound of general formula (12) and the compound of general formula (9) and the reduction reaction of the compound of general formula (13) are as described above. [In the above equation, −B′− is

[Formula] (R ² , B, and l are the same as above). ^R1 ,
R ² , B, 1, X and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. ] In the compound of general formula (2), A is a group

[Formula] The compound (compound of general formula (2d)) is produced by dehydrating the compound of general formula (16), and in the compound of general formula (2), A is a group.

The compound represented by the formula (compound of general formula (2e)) is produced by reducing the compound of general formula (2d). The dehydration reaction of general formula (16) is carried out by the action of an acid or an alkali in a solvent. The solvents used at this time are advantageously those commonly used in this type of reaction, such as pyridine, diacetone alcohol, collidine, dimethylformamide (DMF), THF, benzenesulfonic acid, benzene, xylene, acetic anhydride. , methanol, ethanol, dimethyl sulfoxide (DMSO), etc. Examples of acids include hydrochloric acid, sulfuric acid, boric acid, N-bromoacetamide-sulfur dioxide, florisil, bromic acid, iodine, mesityl chloride-sulfur dioxide, methylchlorosulfide, naphthalene-β-
Sulfonic acid, oxalic acid, phosphoryl chloride, phthalic anhydride, thionyl chloride, p-toluenesulfonic acid, p-toluenesulfonyl chloride,
Examples include potassium hydrogen sulfate and phosphorus pentoxide. Examples of the alkali include sodium hydroxide, potassium hydroxide, and triethylamine. The acid or alkali is usually used in an amount of about 1 to 10 times the amount of the compound of general formula (16), preferably about 1 to 8 times the amount of the compound of formula (16). The reaction temperature for this reaction is selected appropriately, but is usually 20 to 150°C, preferably 20 to 100°C.
The reaction is generally completed in about 10 minutes to 16 hours. The reduction of the compound of general formula (2d) 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, sodium borohydride, lithium aluminum hydride, etc. are used as the hydrogenation reducing agent, preferably sodium borohydride. The hydrogenation reducing agent is usually used in an amount of at least equimolar to the compound of general formula (2d), preferably equimolar to 3.
It is better to use twice the molar amount. Reduction reactions using hydrogenation reducing agents include water, lower alcohols such as methanol, ethanol, and isopropanol, THF,
The reaction is carried out in a suitable solvent such as ethers such as ethyl ether, usually at about -60 DEG to 50 DEG C., preferably at about -30 DEG C. to room temperature, and the reaction is generally completed in about 10 minutes to 3 hours. When using lithium aluminum hydride as a reducing agent, ethyl ether,
It is preferable to use an anhydrous solvent such as THF. Further, when employing the catalytic reduction method, commonly used catalysts for catalytic reduction such as platinum oxide, palladium black, palladium carbon, platinum black, and Raney nickel are used as the reduction catalyst. The amount of catalyst used is usually about 0.2 to 0.5 times the weight of the compound of general formula (2d). This catalytic reduction is usually carried out in a solvent such as water, methanol, ethanol, isopropanol, dioxane, THF, or ethyl ether.
This is carried out by shaking thoroughly in a hydrogen atmosphere of 10 atm, preferably 1 to 3 atm. The reduction is generally carried out in the range of -30°C to the boiling point of the solvent, preferably 0°C.
~Performed at 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
Compounds in which only the double bonds in the side chains are reduced, with almost no double bonds between positions being reduced, are mainly produced. In addition, in this reaction, a compound in which the substituent R ³ 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 R ¹
In compounds where is a lower alkenyl group or a lower alkynyl group, these groups may be reduced simultaneously. [In the above formula, R ¹ , R ² , B, B', 1, X and the carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton are the same as above. ] The compound of general formula (17) is reduced to form general formula (2d)
The reaction for obtaining the compound is generally called the Banford-Stevens reaction, and is carried out in the presence of a base in a suitable solvent by the action of p-toluenesulfonyl hydrazide. As the solvent, those commonly used in this type of reaction are advantageously used, such as methanol, ethanol, ethylene glycol, diethylene glycol, diethyl ether, THF, hexane, and the like.
Furthermore, conventionally used bases are preferably used, such as sodium methoxide, sodium ethoxide, sodium glycoside, lithium aluminum hydride, sodium borohydride, n-
Butyllithium and the like can be mentioned. The amount of the base to be used can be appropriately selected from a wide range, but it is usually preferably used in an amount of 2 times to an excess of the compound of general formula (17). Further, p-toluenesulfonyl hydrazide is usually used in an amount of at least equimolar, preferably equimolar to twice the molar amount of the compound of general formula (17). The reaction is usually carried out at a temperature of about 0 to 200°C, preferably 25 to 165°C, and generally
The reaction is completed in about 0.5 to 6 hours. [In the formula, R ¹ , R ² , B, B', l, R ⁷ , X, X' and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. ] The dehydration reaction of the compound of general formula (18) may be carried out in the same manner as the dehydration reaction of the compound of general formula (16). The reaction between the compound of general formula (19) and the compound of general formula (9) can be carried out in the same manner as the reaction between the compound of general formula (8) and the compound of general formula (9). The reaction between the compound of general formula (19) and the halogenating agent can be carried out in the same manner as the reaction between the compound of general formula (8) and the halogenating agent. [In the formula, R ¹ , R ² , B', B, 1, X and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. ] The compound of general formula (17) is reduced to form general formula (2e)
The following two methods can be used to obtain the compound. The first method is to apply a reaction called Clemensen reduction, which generally uses zinc or mercury and concentrated hydrochloric acid. As the solvent used in this reaction, those commonly used in this type of reaction are advantageously used, and examples include toluene and ethanol. In addition, zinc or mercury is usually about 10 to 30 times the molar amount of the compound of general formula (17).
It is preferable to use 14 to 23 times the molar amount. The reaction is usually carried out at a temperature of about 50 to 250°C, preferably 70 to 230°C, and is generally completed in about 8 to 30 hours. The second method is to apply a reaction called Wolff-Xyuner reduction, which generally uses hydrazine in the presence of a suitable base. As the solvent used in this reaction, those commonly used in this type of reaction are advantageously used, such as methanol, ethanol, n-butanol, ethylene glycol, propylene glycol, triethylene glycol, diethylene glycol, toluene, etc. Can be done. Examples of the base include sodium methoxide, sodium diethylene glycoside, potassium hydroxide, potassium t-butoxide, and the like. degree,
It is preferable to use 3 to 22 times the molar amount. The amount of hydrazine to be used can be determined as appropriate, but usually 2 to 2 to
It is preferable to use about 80 times the molar amount, preferably 3 to 74 times the molar amount. The reaction is usually carried out at a temperature of about 100 to 250°C, preferably 110 to 210°C, and is generally completed in about 4 to 60 hours. [In the above formula, R ¹ , R ² , R ⁷ , B, l, X,
The carbon-carbon bonds at the 3- and 4-positions of X' and carbostyryl skeleton are the same as above. ] The reduction of the compound of general formula (19) may be carried out in the same manner as the reduction of the compound of general formula (2d). The reaction between the compound of general formula (20) and the compound of general formula (9) and the reaction of the compound of general formula (20) with a halogenating agent are the reactions of the compound of general formula (8) and the general formula
The reaction may be carried out in the same manner as the reaction with the compound of formula (9) and the reaction of the compound of general formula (8) with a halogenating agent. [In the above formula, R ¹ , R ² , R ⁷ , B, B', l, X,
The carbon-carbon bonds at the 3- and 4-positions of X' and carbostyryl skeleton are the same as above. ] General formula (22) is obtained by reducing the compound of general formula (21).
The reaction to obtain the compound is usually carried out using a reduction catalyst in a solvent such as water, a lower alcohol such as methanol, ethanol, or isopropanol, or an ether such as dioxane, THF, or ethyl ether.
30℃ to around the boiling point of the solvent (preferably 60 to 100℃),
The reaction is carried out in a hydrogen atmosphere of 1 to 10 atmospheres (preferably 1 to 3 atmospheres). Examples of the reduction catalyst used include common catalysts for catalytic reduction such as platinum oxide, palladium black, palladium carbon, and Raney nickel. It is preferable to use such a catalyst in an amount of usually about 10 to 50% by weight based on the compound of general formula (21). Further, the reduction reaction can be promoted by adding an acid such as concentrated hydrochloric acid into the reaction system. The reaction between the compound of general formula (22) and the compound of general formula (9) and the reaction of the compound of general formula (22) with a halogenating agent are the reactions of the compound of general formula (8) and the general formula
The reaction may be carried out in the same manner as the reaction with the compound of formula (9) and the reaction of the compound of general formula (8) with a halogenating agent. [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. A, B, l, R ⁷ , X, X' and the carbon-carbon bonds at the 3rd and 4th positions of the carbostyril skeleton are the same as above. ] Acetylation of the compound of general formula (23) is carried out by allowing an acetylating agent to act in a suitable solvent in the presence of a suitable catalyst. Examples of the catalyst to be used include sulfuric acid, hydrochloric acid, boron trifluoride, pyridine, and sodium acetate, and examples of the solvent include acetic acid, pyridine, ethanol, methanol, and isopropanol. Examples of the acetylating agent include acetic anhydride, acetyl chloride, 2,3-acetoxypyridine, etc., and the acetylating agent is usually used in an amount of equimolar to 10 times the molar amount of the compound of general formula (23). It is preferable to use an equimolar to 7-fold molar amount. The reaction is usually carried out at a temperature of about 0 to 150°C, preferably
The reaction is carried out at a temperature of 20 to 110°C and is generally completed in about 0.5 to 6 hours. The reaction between the compound of general formula (24) 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 and diethylene glycol methyl ether, aromatic hydrocarbons such as toluene and xylene, dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. The ratio of the compound of general formula (24) and the compound of general formula (25) to be used is not particularly limited and may be appropriately selected within a wide range, but usually the latter is at least equimolar to the former,
It is preferable to use about equimolar to twice the molar amount. The reaction is usually carried out at about -50 to 70°C, preferably -
The reaction is carried out at around 30°C to room temperature, and the reaction is generally completed in about 0.5 to 12 hours. Hydrolysis of the compound of general formula (26) is carried out by the action of acid or alkali in a suitable solvent. Examples of the solvent used include water, methanol, ethanol, isopropanol, etc., examples of the acid include hydrochloric acid, sulfuric acid, etc., and examples of the alkali include potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, etc. The acid or alkali is preferably used in at least an equimolar amount, usually in large excess, relative to the compound of general formula (26). Reaction temperature is usually room temperature ~
The temperature is preferably about 100°C, and the reaction is generally completed in about 0.5 to 5 hours. The reaction between the compound of general formula (27) and the compound of general formula (9) and the reaction of the compound of general formula (27) with a halogenating agent are the reactions of the compound of general formula (8) and the compound of general formula (9), respectively. The reaction may be carried out in the same manner as the reaction with the compound of general formula (8) and the reaction of the compound of general formula (8) with a halogenating agent. As shown in reaction scheme-12, the compound of general formula (2) produced as described above is a compound (2g) in which the carbon-carbon bond at the 3- and 4-positions of the carbostyryl skeleton is a single bond, and It can be interconverted to a compound (2h) that shows a double bond. [In the above formula, R ¹ , A, B, X and l are the same as above. ] Among the compounds of the present invention represented by the above general formula (1), the compound in which Z represents a group N-R ³ (compound of general formula (1a)) is produced by the method shown in the following reaction scheme-13. . [In the above formula, R ¹ , R ³ , A, B, 1, 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 general formula (1a) is produced by reacting a carbostyryl derivative represented by general formula (31) with a known benzene derivative represented by general formula (32). The compound of general formula (31) can be obtained by reacting the compound of general formula (2) with a known compound of formula (30) or by reacting the compound of general formula (2) with a known compound of general formula (28). , is then produced by debenzylating the resulting compound of general formula (29). The reaction between the compound of general formula (2) and the compound of formula (30) and the reaction between the compound of general formula (2) and the compound of general formula (28) are the reactions between the compound of general formula (2) and the compound of general formula (28). This can be carried out in the same manner as the reaction of the compound in 3). The reaction between the compound of general formula (31) and the compound of general formula (32) 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. Moreover, the reaction proceeds easily by adding a catalyst such as copper powder. The ratio of the compound of general formula (31) and the compound of general formula (32) to be used is not particularly limited and may be appropriately selected within a wide range.
The latter is usually used in at least an equimolar amount, preferably an equimolar to 5 times the molar amount of the former. The reaction is usually carried out at room temperature to about 180°C, preferably
The reaction is carried out at 100 to 150°C and generally completes in about 3 to 30 hours. For debenzylation of the compound of general formula (29), conditions for ordinary de-N-benzylation reactions can be widely adopted;
For example, in the presence of a catalytic reduction catalyst such as palladium-carbon, palladium-black, platinum black, etc. in a suitable solvent from 0°C to
It is carried out for about 0.5 to 5 hours at around room temperature. Examples of solvents include water, lower alcohols such as methanol, ethanol, and isopropanol,
Examples include ethers such as dioxane and THF, and acetic acid. The catalytic reduction catalyst has the general formula (29)
It is usually used in an amount of about 10 to 50% by weight based on the compound. The reaction can also be accelerated by adding an acid such as concentrated hydrochloric acid into the reaction system. Further, the compound of the present invention represented by the general formula (1a) can be produced by the method shown in the following reaction scheme-14. [In the above formula, X ¹ and X ² represent a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group, an aralkylsulfonyloxy group, or a hydroxyl group. R ¹ , R ³ , A, B, 1, and the carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton are the same as above. ] That is, the compound of general formula (1a) is produced by reacting the carbostyryl derivative represented by general formula (33) with a known compound represented by general formula (34). Among the compounds of general formula (33) as starting materials
When using a compound in which X ^{1 and} The reaction 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 hexamethylphosphoric triamide. etc. can be mentioned. Examples of basic condensing agents include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; metal hydroxides such as sodium hydroxide and potassium hydroxide;
Examples include metal alcoholates such as sodium methylate and sodium ethylate, and tertiary amines such as pyridine and triethylamine. The ratio of the compound of general formula (38) and the compound of general formula (34) 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 is preferably used in an equimolar to 5-fold molar amount. The reaction is usually carried out at 40-120℃
The reaction is carried out at a temperature of 50 to 100°C, preferably 50 to 100°C, and the reaction is generally completed in about 5 to 30 hours. Among the compounds of general formula (33) as starting materials
When using ^a compound in which X ¹ and It will be held at Examples of the dehydration condensation agent used include condensed phosphoric acids such as polyphosphoric acid, phosphoric acids such as orthophosphoric acid, pyrophosphoric acid, and metaphosphoric acid, phosphorous acids such as orthophosphorous acid, and anhydrous phosphoric acids such as phosphorus pentoxide. , acids such as hydrochloric acid, sulfuric acid, and boric acid; metal phosphates such as sodium phosphate, boron phosphate, ferric phosphate, and aluminum phosphate;
Activated alumina, sodium bisulfate, Raney nickel, etc. can be mentioned. Examples of the solvent used include high boiling point solvents such as dimethylformamide and tetralin. The ratio of the compound of general formula (33) and the compound of general formula (34) to be used is not particularly limited and can be appropriately selected within a wide range, but usually the latter is used in an equimolar amount or more to the former, It is preferable to use equimolar to twice the molar amount. The amount of the dehydration condensing agent to be used is not particularly limited and can be appropriately selected from a wide range, but it is usually a catalytic amount or more, preferably about 0.5 to 5 times the molar amount of the compound of general formula (33).
In the above reaction, in order to prevent the advantageous oxidation reaction,
Preferably, the reaction is carried out in a stream of inert gas, such as carbon dioxide or nitrogen. Although the above reaction can be carried out either under normal pressure or under increased pressure, it is preferable to carry out the reaction under normal pressure. The above reaction normally proceeds suitably at a temperature of about 100 to 350°C, preferably 125 to 255°C, and is generally completed in about 3 to 10 hours. In the above reaction, the compound of general formula (34) may be used in the form of a salt. [In the above formula. R ¹ , B, 1, X and the carbon-carbon bonds at the 3rd and 4th positions of the carbostyril skeleton are the same as above. X ¹ ' and X ² ' represent a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group. ] [In the above formula, R ¹ , A, 1, 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-15, the compound of general formula (37) is obtained by reacting the compound of general formula (2) with the known compound of formula (35), and then the compound of general formula (36) is produced.
It is produced by reacting the compound with a halogenating agent or a sulfonating esterifying agent. The reaction between the compound of general formula (2) and the compound of formula (35) 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 (36) and the halogenating agent may be carried out in the same manner as the reaction between the compound of general formula (8) and the halogenating agent. The reaction between the compound of general formula (36) 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 esterification 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 THF, pyridine, DMSO, DMF, hexamethylphosphoric acid triamide, etc., and basic condensing agents such as triethylamine, pyridine, etc. Examples include tertiary amines such as N,N-dimethylaniline, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, and the like. General formula (36)
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. According to reaction scheme-16, the compound of general formula (33) is a compound of general formula (2) and the known general formula (38).
It is produced by reacting the following compounds. The reaction between the compound of general formula (2) and the compound of general formula (38) 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 compound of the present invention represented by the general formula (1a)) can be produced by the method shown in the following reaction scheme-17. [In the above formula, R ⁸ is a group

【formula】 or group

[Formula] is shown. R ¹ , R ³ , A, B, l, X, X', X ² 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 general formula (1a) is produced by reacting a carbostyryl derivative represented by general formula (42) with a known aniline derivative represented by general formula (43). The compound of general formula (42) is produced by reacting the compound of general formula (2) with a known compound of formula (39) or (40), and then debenzylating or acylating the resulting compound of general formula (41). Manufactured by The reaction between the compound of general formula (2) and the compound of formula (39) or (40) 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 (41) can be carried out under a wide variety of conditions for ordinary N-benzylation reactions, for example, by heating in an aqueous solution of hydrobromic acid. Further, the deacylation of the compound of general formula (41) can be carried out under the same conditions as for the hydrolysis of the compound of general formula (26). Furthermore, the reaction between the compound of general formula (42) and the compound of general formula (43) may be carried out in the same manner as the reaction between the compound of general formula (33) and the compound of general formula (34). Further, the compound of the present invention represented by the general formula (1a) can be produced by the method shown in the following reaction scheme-18. [In the above formula, R ¹ , R ³ , A, B, 1 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 general formula (1a) is produced by reacting the carbostyryl derivative represented by the known general formula (44) with the known compound represented by the general formula (34). The compound of general formula (44) is produced by reacting the compound of general formula (2) with morpholine. The reaction between the compound of general formula (2) and morpholine 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 (44) and the compound of general formula (34) 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 (44) and the compound of general formula (34) 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 50
It is best to carry out the reaction 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, in the case of a compound in which the substituent on the phenyl ring is a lower alkoxycarbonyl group or a cyano group, these groups may be simultaneously converted into the corresponding carboxy group. In addition, in compounds where the substituent on the phenyl ring is a lower alkoxy group or a lower alkylenedioxy group, these groups may be simultaneously converted to the corresponding hydroxyl group. Of the compounds of general formula (44) used in the above reaction scheme-18, A is

[Formula] In the case of a compound showing a group, A can be obtained by reducing the compound.

[Formula] It can be converted into a compound having a group. As the reducing conditions in this case, any of the reducing conditions for the compound of general formula (2d) above can be applied. Also, A

[Formula] In the case of a compound showing a group, by reducing the compound,
A is

[Formula] It can be converted into a compound having a group. As the reducing conditions in this case, any of the reducing conditions for the compound of general formula (2a) above can be applied. The compound of general formula (1) can also be produced by the method shown in Reaction Scheme-19. [In the above, R ¹ , R ² , B', B, 1, Z 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 (1b) 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, sodium borohydride, lithium aluminum hydride, etc. are used as the hydrogenation reducing agent, preferably sodium borohydride. The hydrogenation reducing agent is usually used in an amount of at least equimolar to the compound of general formula (1b), preferably equimolar to 3.
It is better to use twice the molar amount. The reduction reaction using a hydrogenation reducing agent is carried out in an appropriate solvent such as water, lower alcohols such as methanol, ethanol, and isopropanol, and ethers such as tetrahydrofuran and ethyl ether, usually at about -60 to 50°C, preferably -
The reaction is carried out at 30°C to room temperature, and generally completes in about 10 minutes to 3 hours. 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. Further, when a catalytic reduction method is employed, a commonly used catalytic reduction catalyst such as platinum oxide, palladium black, palladium carbon, Raney nickel, etc. is used as a reduction catalyst. The amount of catalyst used is usually from about 0.2 to
It is better 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, preferably from 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
A compound in which the carbonyl group bonded to the carbostyril skeleton is reduced (compound of general formula (1c)) is mainly produced with almost no reduction of the double bond between the positions. In addition, in this reaction, a compound in which the substituent 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 R ¹
In compounds where is a lower alkenyl group or a lower alkynyl group, these groups may be reduced simultaneously. General formula (1d) is obtained by reducing the compound of general formula (1e).
The reaction to obtain the compound of general formula (2d) can be carried out under the same conditions as the reaction to obtain the compound of general formula (2e)) by reducing the compound of general formula (2d). In addition, the dehydration reaction of the compound of general formula (1c) can be carried out using the above general formula (16).
This can be carried out in the same manner as the dehydration reaction of the compound.
Furthermore, the reaction of reducing the compound of general formula (1b) to obtain the compound of general formula (1d) and general formula (1c)
The reaction of reducing the compound of formula (1d) to obtain the compound of general formula (1d) can be carried out under the same conditions as the reaction of reducing the compound of general formula (21) to obtain the compound of general formula (22). 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 (1g)) 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 (1f)) with a known compound of general formula (25) as shown in process formula-20. [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. A, B, l, Z, 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 (1f) 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 and diethylene glycol dimethyl ether, aromatic hydrocarbons such as toluene and xylene, dimethylformamide, dimethyl sulfoxide, and hesakimethyl phosphoric triamide. The ratio of the compound of general formula (1f) and the compound of general formula (25) to be used is not particularly limited and may be appropriately selected within a wide range, but usually the latter is at least equimolar to the former, preferably It is preferable to use about 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 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. [In the formula, R ¹ , R ⁷ , B, 1, Z, X and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. ] The reaction between the compound of general formula (45) and the compound of general formula (3) is carried out under the same conditions as the reaction between the compound of general formula (2) and the compound of general formula (3). The reaction for obtaining the compound of general formula (47) from the compound of general formula (46) is carried out under the same conditions as the reaction for obtaining the compound of general formula (2b) from the compound of general formula (2a). The reaction to obtain the compound of general formula (1h) from the compound of general formula (46) and the reaction to obtain the compound of general formula (1i) from the compound of general formula (47) are both The reaction is carried out under similar conditions to the reaction to obtain the compound of formula (2c). [In the formula, R ¹ , R ² , R ⁷ , B, 1, Z, X and the carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton are the same as above. ] The reaction between the compound of general formula (48) and the compound of general formula (3) is carried out under the same conditions as the reaction between the compound of general formula (2) and the compound of general formula (3). The reaction for obtaining the compound of general formula (1j) from the compound of general formula (49) is carried out under the same conditions as the reaction for obtaining the compound of general formula (2e) from the compound of general formula (17). The compound of general formula (46) used in the above reaction scheme-21 and the compound of general formula (49) used in reaction scheme-22 are the compound of the following general formula (50) and the compound of general formula (51), respectively. It is also produced by sulfonylation of the compound. This sulfonylation is carried out between the compound of the general formula (12) and the general formula (9).
can be carried out under similar conditions to the reaction with the compound. [In the formula, R ¹ , R ² , Z and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. ] Mannitz reaction conditions are applied to the reaction with the compound of general formula (52), formaldehyde, and the compound of general formula (3). For example, the reaction is usually carried out in a suitable inert solvent at room temperature to about 150°C, preferably at 50°C.
It is carried out at ~100°C for about 1 to 10 hours. Examples of the inert solvent include lower alcohols such as methanol, ethanol, and propanol, ethers such as dioxane and tetrahydrofuran, fatty acids such as acetic acid and propionic acid, dimethyl sulfoxide, and dimethyl formamide. Examples of formaldehydes include formalin, paraformaldehyde, and trioxane. The amounts of formaldehydes and the compound of general formula (3) to be used are not particularly limited and can be appropriately selected within a wide range, but are usually at least equimolar amounts, preferably at least equivalent to the compound of general formula (52). It is preferable to use about equimolar to 3 times the molar amount. The compound of general formula (52) is a known or new compound, and is produced, for example, by the methods shown in (i) to (v) below. (i) The compound of general formula (4) has the general formula R ² −(B) _l −
COX' or a compound represented by the general formula (R ² -(B) _l -CO) ₂ O is reacted (reaction conditions are according to reaction scheme-2). (ii) The compound of general formula (10) has the general formula R ² −(B) _l −
A compound represented by COX' is reacted, and the following reaction scheme-3 is followed. (iii) The compound of general formula (14) has the general formula R ² −(B) _l −
COX′ or a compound represented by the general formula (R ² −(B) _l −CO) ₂ O is reacted, and the following reaction scheme-4
According to. (iv) General formula A compound represented by the general formula R ¹ 'X is reacted with the compound represented by
An R ¹ '- group is introduced at the position (reaction conditions are based on the conditions for the reaction between the compound of general formula (24) and the compound of general formula (25) in reaction scheme-11). (v) Among the compounds of general formula (52), compounds in which the carbon-carbon bond at the 3- and 4-positions of the carbostyril skeleton is a single bond and compounds in which the bond is a double bond are different from each other due to dehydrogenation and reduction reactions. Can be converted to each other. Furthermore, among the compounds of the present invention represented by general formula (1), compounds in which the substituent on the phenyl ring is an amino group can be easily produced by reducing a compound in which the substituent on the phenyl ring is a nitro group. Ru. For this reduction, for example, usual conditions for reducing an aromatic nitro group to an aromatic amino group can be employed, and more specifically, a method using a reducing agent such as sodium sulfite or sulfur dioxide gas can be used. Furthermore, among the compounds of the present invention represented by general formula (1), compounds in which the substituent on the phenyl ring is a carboxyl group can be easily obtained by hydrolyzing a compound in which the substituent on the phenyl ring is a lower alkoxycarbonyl group. Manufactured in For this hydrolysis, conditions for ordinary ester hydrolysis can be employed, and for example, the 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 carbostyril 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. [In the above formula, R ¹ , A, B, 1 and Z are the same as above. ] Conventional catalytic reduction conditions are applied to the reduction of the compound of general formula (1l). Examples of the catalyst that can be used include metals such as palladium, palladium-carbon, platinum, and Raney nickel, and it is preferable to use such metals in normal catalytic amounts. Examples of solvents that can be used include methanol, ethanol, isopropanol, dioxane, THF, hexane, cyclohexane, and ethyl acetate. The reduction reaction can be carried out either at normal pressure or under increased pressure, but it is usually carried out at normal pressure to 10 kg/cm ² , preferably at normal pressure to 3 kg/cm ² . The reaction temperature is usually about 0 to 100°C, preferably room temperature to 70°C. Further, the dehydrogenation reaction of the compound of general formula (1m) is carried out using an oxidizing agent in a suitable solvent. The oxidizing agent used is, for example, 2,3-dichloro-
5,6-dicyanobenzoquinone, chloranil (2,3,5,6-tetrachlorobenzoquinone)
Examples include halogenating agents such as benzoquinones such as N-bromosuccinimide, N-chlorosuccinimide, and bromine. The amount of the oxidizing agent to be used is not particularly limited and may be appropriately selected from a wide range, but it is usually used in an amount of 1 to 5 times, preferably 1 to 2 times, by mole relative to the compound of general formula (1m). It is better. Examples of solvents include ethers such as dioxane, THF, methoxyethanol, and dimethoxyethane; aromatic hydrocarbons such as benzene, toluene, xylene, tetralin, and cumene;
dichlorothane, dichloroethane, chloroform,
Halogenated hydrocarbons such as carbon tetrachloride, alcohols such as butanol, amyl alcohol, hexanol, polar protic solvents such as acetic acid, DMF,
Examples include polar aprotic solvents such as DMSO and hexamethylphosphoric triamide. The reaction is usually carried out at room temperature to 300°C, preferably room temperature to 200°C, and is generally completed in about 1 to 40 hours. 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 25, lactam-latatim type tautomerism is possible. [In the above formula, A, B, l and Z 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 liquid, gelatin liquid, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone,
Dry starch, sodium alginate, agar powder, laminaria powder, sodium bicarbonate, calcium carbonate, Twin, sodium lauryl sulfate,
Disintegrants such as stearic acid monoglyceride, starch, and lactose; disintegration inhibitors such as sucrose, stearin, cocoa butter, and hydrogenated oil; absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate; and humectants such as glycerin and starch. Examples include adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, macrogol, and solid polyethylene glycol. When forming into a pill form, a wide variety of carriers conventionally known in this field can be used, such as glucose, lactose,
Examples include excipients such as starch, cacao butter, hydrogenated vegetable oil, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, and 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, including polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like. 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, perfumes, flavoring agents, sweeteners, etc., and other pharmaceuticals may be included in the therapeutic agent, if necessary.
When forming into a paste, cream or gel form, a wide range of diluents conventionally known in this field can be used, such as white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite, etc. . 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 usually a pharmaceutical composition containing about 40 μg to 2 mg/Kg of the compound of general formula (1) or a salt thereof per day is used. 3
It may be administered in ~4 doses. The results of pharmacological tests on the compounds of the present invention are listed below. <Test compound> Compound 1 5-[3-(4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyryl monohydrochloride Compound 2 6-{3-[4-(4-methylphenyl)
-1,2,5,6-tetrahydropyridyl]-1-propenyl}-3,4-dihydrocarbostyryl compound 3 6-[1-oxo-3-(4-benzyl-1-piperidyl)propyl]-3, 4-
Dihydrocarbostyryl compound 4 6-{1-oxo-4-[4-(4-chlorophenyl)-1,2,5,6-tetrahydropyridyl]butyl}-3,4-dihydrocarbostyryl compound 5 6-{1 -oxo-3-[4-(4-methylphenyl)-1,2,5,6-tetrahydropyridyl]propyl}-3,4-dihydrocarbostyryl compound 6 6-{3-[4-(2-methoxyphenyl)-1,2,5,6-tetrahydropyridyl]propyl 6-[1-oxo-4-(4-phenyl-1,2 ,5,6-tetrahydropyridyl]butyl]-3,4-dihydrocarbostyryl compound 8 6-{3-[4-(2-methoxyphenyl)-1-piperidyl]propyl}-3,4
-Dihydrocarbostyryl 1-oxalate compound 9 7-[3-(4-phenyl-1-piperazinyl)-1-oxo-propyl]-3,4
-dihydrocarbostyryl compound 10 7-{3-[4-(2-ethoxyphenyl)-1-piperazinyl]-1-oxo-propyl}-3,4-dihydrocarbostyryl compound 11 1-isopentyl-6-[ 1-oxo-3-(4-phenyl-1-piperidyl)
propyl]-3,4-dihydrocarbostyryl hydrochloride compound 12 1-allyl-6-[1-oxo-3-
(4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyryl
Hydrochloride compound 13 1-(2-propynyl)-6-[1-oxo-3-(4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyryl hydrochloride compound 14 1-(3- phenylpropyl)-6-
[1-oxo-3-(4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyryl hydrochloride compound 15 6-{1-oxo-4-[4-(4-chlorophenyl)-4 -hydroxy-1-piperidyl]butyl}-3,4-dihydrocarbostyryl compound 16 6-{1-oxo-4-[4-(3,5
-dimethylphenyl)-1-piperidyl]
butyl}-3,4-dihydrocarbostyryl compound 17 6-{1-oxo-3-[4-(3-methoxyphenyl)-1,2,5,6-tetrahydro-1-pyridyl]butyl}-3 ，
4-dihydrocarbostyryl compound 18 7-{1-oxo-4-[4-(2,3
-dimethylphenyl)-1-piperazinyl]
butyl}-3,4-dihydrocarbostyryl (comparative test compound) Comparative compound 1 1-methyl-6-[3-(4-methylhyperazin-1-yl)-2-methylpropionyl]-1,2,3, 4-tetrahydroquinolin-2-one (Unexamined Japanese Patent Publication No. 1983-
83749 specification, page 9, lines 12-15) Comparative compound 2 1-Methyl-6-(3-piperidino-2-methylpropionyl)-1,2,
3,4-tetrahydroquinolin-2-one hydrochloride (JP-A-55-83749, compound of Example 1) Comparative compound 3 1-Methyl-6-(3-piperidino-1-hydroxy-2-methylpropyl )-1,2,3,4-tetrahydroquinolinone-2-one hydrochloride (Unexamined Japanese Patent Publication No. 1983-
No. 83749, Compound of Example 3) (A) 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 for 60 minutes after dopa administration. Mice were placed one by one in two glass beakers for measurement, and those that jumped 10 times or less within 1 hour after L-dopa administration were considered positive for inhibition, and those that jumped 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
(1975)] The results obtained are shown in Table 1.

[Table] (B) Epinephrine antagonism in mice DDY male mice weighing 17 to 25 g and 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 until 20 hours have passed 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 (1984) and LE Allen, H.C.Ferguson,
and RHCox, Jr., Arzneim-Forsch (Drug
Res.), 24, 917-922 (1974)] The results obtained are shown in Table 2.

[Table] (C) Antihistamine action test A method using isolated guinea pig ileum is generally accepted as a typical method for measuring antihistamine action in vitro, and this method was also used in the present invention. The antihistamine effect was measured in vitro. Male guinea pigs weighing 300 to 500 g were killed by exsanguination, the ileum 15 cm proximal to the ileocecal region was removed, and Tyrode's solution (8.0 g of NaCl, 0.2 g of KCl, 0.2 g of CaCl ₂ , 1.0 g of glucose, 1.0 g of NaHCO _{3 )} was removed. , NaH ₂ PO ₄・2H ₂ O
0.065 g and 0.2135 g of MgCl ₂ .6H ₂ O with water added to make a total volume of 1000 ml). Next, the organization
It was cut into 2.5-3.0 cm pieces and suspended in a bath filled with 30 ml of Tyrode's solution. The bath was kept at 36°C with 5% _CO2 and
A gas mixture of 95% _O2 was passed through. Histamine after 10 minutes
Histamine dose-response curve (control) after administration of 10 ^-6 M to examine tissue sensitivity.
I got it. After the control dose-response had stabilized, 10 ^-6 g/ml of the test compound was administered, and 5 minutes later histamine was administered to obtain a dose-response curve. Contraction is performed using an isotonic transducer [Nihon Kohden TD-
112S] and recorded on a pen recorder. The maximum contraction of control histamine is taken as 100%,
JMVan Rossam method
Arch, Int, Pharmacodyn., 143, 299 (1963)], PA ₂ was calculated. The results obtained are shown in Table 3 below.

【table】

[Table] (D) Acute toxicity test Each test compound is orally administered to male rats, and its acute toxicity (LD ₅₀ , mg/Kg) is determined. 4th result
Shown in the table.

[Table] Below are reference examples Reference example 1 120 ml of γ-chlorobutyric acid chloride and 160 g of crushed anhydrous aluminum chloride were suspended in 300 ml of carbon disulfide, and 29.4 g of 3,4-dihydrocarbostyryl was added to 100 ml of carbon disulfide under heating under reflux. The suspension was added dropwise over a period of 1 hour, and then heated under reflux for 4 hours. The reaction solution was poured into ice water, 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)-.
25.5 g of 3,4-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 Recrystallized from isopropanol 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 Reference example 5 6-(4-chloro-1-oxobutyl)-3,4
-4.0g of dihydrocarbostyril in 200ml of methanol
ml, and while stirring at room temperature, 2.0 g of sodium borohydride was gradually added, followed by stirring for 1 hour.
Add 3 ml of concentrated hydrochloric acid to the reaction solution, concentrate under reduced pressure while heating under reflux, extract the residue with chloroform, wash the chloroform layer with water, dehydrate, and then distill off the chloroform. When the residue is recrystallized from ethanol, the melting point
153-155℃, 6-(4-chloro-
2.4 g of 1-butenyl)-3,4-dihydrocarbostyryl are obtained. Reference example 6 3,4-dihydrocarbostyryl 14.4g and γ
- Mix 10 g of butyrolactone in 120 g of polyphosphoric acid and heat with stirring at 80-90°C for 10 hours, then pour the reaction solution into 300 ml of ice water and leave overnight. The precipitate was collected, washed with water, and recrystallized from ethanol-ethyl acetate to give colorless prismatic crystals with a melting point of 175-176°C.
-(4-hydroxy-1-oxobutyl)-3,4
-9.5 g of dihydrocarbostyril are obtained. 6
-(4-hydroxy-1-oxobutyl)-3,4
- 5g of dihydrocarbostyril and palladium black
Mix 0.5g with 160ml of ethanol and apply hydrogen pressure to 3 atmospheres.
Catalytic reduction was performed at 60°C for 6 hours. After cooling, 1 ml of concentrated hydrochloric acid was added and catalytic reduction was further carried out at 3 atm and room temperature for 6 hours. The reaction solution was filtered, the mother liquor was concentrated under reduced pressure, and recrystallized from ligroin to give 6-(4-
3.2 g of (hydroxybutyl)-3,4-dihydrocarbostyryl are obtained. 3.2 g of 6-(4-hydroxybutyl)-3,4-dihydrocarbostyryl and 5 ml of thionyl chloride are mixed in 50 ml of chloroform, stirred overnight at room temperature, concentrated under reduced pressure, and the residue is recrystallized from ligroin to give a melting point of 119-121°C. , 1.8 g of colorless prismatic 6-(4-chlorobutyl)-3,4-dihydrocarbostyryl is obtained. Reference example 7 2.8 g of 6-(4-chloro-1-butenyl)-3,4-dihydrocarbostyryl and sodium iodide
Mix 2.1g with 40ml of dimethylformamide,
After stirring at 50°C for 1 hour, 2.0 g of morpholine and 2.0 ml of triethylamine were added, and the mixture was stirred at 50°C for 5 hours. The reaction solution was concentrated under reduced pressure, 50 ml of 5% sodium bicarbonate was added to the residue, stirred, insoluble materials were removed, and after washing with water, recrystallization from ethanol gave a melting point of 136.
~139°C, colorless needle-shaped 6-(4-morpholino-1
2.2 g of -butenyl)-3,4-dihydrocarbostyryl are obtained. 6-(4-morpholino-1-butenyl)-3,4-dihydrocarbostyryl 2.2g
and 0.2 g of platinum black were mixed with 100 ml of ethanol and catalytically reduced at 3 atm hydrogen pressure and room temperature for 5 hours. The reaction solution was filtered, the mother liquor was concentrated under reduced pressure, and the residue was recrystallized from ligroin-benzene to give a melting point of 130-132.
°C, colorless scaly 6-(4-morpholinobutyl)-
1.8 g of 3,4-dihydrocarbostyryl are obtained. Reference example 8 6-(3-chloro-1-propenyl)-3,4-
2.3 g of dihydrocarbostyryl, 2.0 g of 4-benzylpiperazine and 2.0 ml of triethylamine are mixed in 50 ml of dimethylformamide and stirred at 50°C for 3 hours. The reaction solution was poured into a mixture of 50 ml of saturated brine and 50 ml of 5% sodium bicarbonate water, and the organic layer was extracted with chloroform. After washing the chloroform layer with water and dehydrating, the chloroform is distilled off and the residue is recrystallized from ethanol-water to give a melting point of 151-153.
2.1 g of 6-[3-(4-benzylpiperazinyl)-1-propenyl]-3,4-dihydrocarbostyryl are obtained as colorless needle-like crystals. 6-[3-(4
-benzylpiperazinyl)-1-propenyl]-
3,4-dihydrocarbostyryl 2.1g, platinum black
0.2 g and 2 ml of concentrated hydrochloric acid are mixed in 100 ml of ethanol and catalytically reduced at 3 atm hydrogen pressure and room temperature for 5 hours. The reaction solution was filtered, the mother liquor was concentrated under reduced pressure, and the residue was recrystallized from methanol to give 6-(3-piperidinopropyl)-3,4-dihydrocarbohydrate with a melting point of 275-278°C (decomposition) and colorless needle-shaped crystals. 1.8 g of styryl dihydrochloride is obtained. Reference Example 9 2.5 g of 6-(4-chloro-1-butenyl)-3,4-dihydrocarbostyryl and 2.3 g of DDQ are mixed in 160 ml of dioxane and heated under reflux for 6 hours. Next, add 1.1 g of DDQ for 3 hours, then add 1.1 g of DDQ and heat under reflux for 3 hours. The reaction solution was cooled, the precipitate was removed, the mother liquor was concentrated under reduced pressure, and the residue was dissolved in a mixture of 100 ml of chloroform and 5 ml of methanol.
Remove unreacted DDQ through a silica gel column,
When the residue is recrystallized from methanol, the melting point is 215 ~
At 218 DEG C., 1.6 g of 6-(4-chloro-1-butenyl)carbostyryl is obtained as yellow needle-like crystals. Reference example 10 6-(β-chloropropionyloxy)-3,4
- 20 g of dihydrocarbostyril, 60 g of ground anhydrous aluminum chloride, 6 g of sodium chloride and 6 g of potassium chloride are mixed, and the mixture is heated and melted and stirred at 150 to 170°C for 1 hour. The reaction solution was poured into ice water, left overnight to remove precipitated crystals, washed with water, dried, and recrystallized from methanol to obtain colorless needle-shaped 6-hydroxy-
12 g of 7-(3-chloropropionyl)-3,4-dihydrocarbostyryl are obtained. Elemental analysis (as C ₁₂ H ₁₂ O ₃ NCl) C H N Actual value (%) 56.98 4.51 5.44 Calculated value (%) 56.82 4.77 5.52 White crystal, mp205-208℃ Reference example 11 6-Hydroxy-7-(3- 5.06 g of (chloropropionyl)-3,4-dihydrocarbostyryl and 1.8 g of anhydrous pyridine were mixed with 50 ml of anhydrous dimethylformamide, and 2.5 g of mesityl chloride was added under ice cooling.
After stirring at room temperature for 3 hours, add saturated brine.
Pour into 100ml and extract with chloroform. After the chloroform layer is washed with water and dehydrated, the chloroform is distilled off. The residue was crystallized by adding 80 ml of hexane, and the crude crystals were taken and recrystallized from ethanol to obtain 4.5 g of 6-(methylsulfonyloxy)-7-(3-chloropropionyl)-3,4-dihydrocarbostyryl. obtain. Elemental analysis (as C ₁₃ H ₁₄ O ₅ SNCl) C H N Actual value (%) 47.33 4.02 4.19 Calculated value (%) 47.06 4.25 4.22 Reference example 12 6-Methylsulfonyloxy-7-(3-chloropropionyl)-3 , 30 g of 4-dihydrocarbostyryl and 0.5 g of palladium black in 200 g of ethanol.
ml and stirred at room temperature for 5 hours under a hydrogen pressure of 3 atm. The reaction solution was filtered, the mother liquor was concentrated under reduced pressure, and recrystallized from ethanol to obtain 1.2 g of 7-(3-chloropropionyl)-3,4-dihydrocarbostyryl. Colorless powder crystal, mp159-161℃ Elemental analysis (as C ₁₂ H ₁₂ O ₂ NCl) C H N Actual value (%) 60.59 5.24 5.91 Calculated value (%) 60.64 5.09 5.89 Reference example 13 6-(methylsulfonyloxy) -7-(3-chloropropionyl)-3,4-dihydrocarbostyryl 3.3g and sodium iodide 1.5g were added to acetone.
Disperse in 30 ml and stir at 40-50°C for 2 hours, then add 30 ml of dimethylformamide and distill off acetone under reduced pressure. Then 4-phenylpiperidine
Add 1.8g and 1.5ml of triethylamine, 60-70
Stir at ℃ for 7 hours. Add the reaction solution to saturated saline 150%
ml, extracted with chloroform, washed the chloroform layer with water, and then dehydrated. The chloroform layer was distilled off, and the residue was crystallized from hexane and recrystallized from ethanol-ligroin to give 6-(methylsulfonyloxy)-7-[1-oxo-3-(4-phenyl-1-piperidyl)propyl. ]-3,4-dihydrocarbostyryl 2.1 g is obtained. Elemental analysis (as C ₂₄ H ₂₈ O ₅ N ₂ S) C H N Actual value (%) 63.07 6.19 6.12 Calculated value (%) 63.14 6.18 6.14 Reference example 14 (a) 6-hydroxy-7-(3-chloropropionyl )-3,4-dihydrocarbostyryl 2.5g
and 1.8 g of sodium iodide are mixed with 30 ml of acetone, stirred at 50°C for 1 hour, then 30 ml of dimethylformamide is added, and the acetone is distilled off under reduced pressure. Add 3 ml of triethylamine and 2.0 g of 4-phenylpiperidine, and stir at 60-70°C for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was
% sodium bicarbonate, and the resulting crude crystals were recrystallized from methanol to give 6-hydroxy-7-[1-oxo-3-(4-phenyl-1
1.6 g of -piperidyl)propyl]-3,4-dihydrocarbostyryl are obtained. Elemental analysis (as C ₂₃ H ₂₆ O ₃ N ₂ ) C H N Actual value (%) 77.51 5.81 6.12 Calculated value (%) 77.90 5.67 6.06 White crystal, mp240-245℃ (b) 6-hydroxy-7-[3 -(4-phenyl-
1-piperidyl)-1-oxopropyl]-3,
2.3 g of 4-dihydrocarbostyryl and 0.4 g of potassium hydroxide were dispersed in 80 ml of methanol, stirred at room temperature for 2 hours, and then concentrated under reduced pressure. Add 40ml of dimethylformamide to the residue, disperse the residue, and add methanesulfonyl chloride to the residue.
Add 0.7g and stir at room temperature for 3 hours. The following treatment is carried out in the same manner as in Reference Example 13 to obtain 1.2 g of 6-(methylsulfonyloxy)-7-[1-oxo-3-(4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyryl. . Elemental analysis (as C ₂₄ H ₂₈ N ₂ O ₅ S) C H N Actual value (%) 63.14 6.18 6.14 Calculated value (%) 63.58 6.00 5.92 Reference example 15 (a) 8-methoxy-5-(3-chloropropionyl )-3,4-dihydrocarbostyryl 26.8g
and 16.5 g of sodium iodide were dissolved in 200 ml of dimethylformamide, and after stirring at 40°C for 1 hour, 11.1 g of triethylamine and 17.1 g of 4-phenylpiperazine were added, followed by further stirring at 40°C for 2 hours. The reaction solution was dried under reduced pressure, 5% aqueous sodium bicarbonate and ether were added to the residue, and the precipitated crystals were collected and recrystallized from ethanol to give 8-methoxy-
5-[1-oxo-3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyryl is obtained. Yield 27.5g Elemental analysis (as C ₂₃ H ₂₇ O ₃ N ₃ ) C H N Actual value (%) 70.00 6.99 10.48 Calculated value (%) 70.21 6.92 10.68 Pale yellow flocculent, mp 133-134℃ (b) 8- Methoxy-5-[1-oxo-3-(4-
phenyl-1-piperazinyl)propyl]-3,
300 ml of 47% hydrobromic acid was added to 19.7 g of 4-dihydrocarbostyril, and after refluxing for 18 hours, the reaction solution was dried under reduced pressure. Water is added to the residue, dried again under reduced pressure, acetone is added to the precipitated crystals, and the crystals are recrystallized from methanol. Suspend the recrystallized product in 500ml of water,
Neutralize with 5% sodium hydroxide, collect precipitated crystals, wash with water, and give 8-hydroxy-5-[1-oxo-3-(4-phenyl-1-piperazinyl)].
Propyl]-3,4-dihydrocarbostyryl
Obtain 17.1g. Elemental analysis (as C ₂₂ H ₂₅ O ₃ N ₃ ) C H N Actual value (%) 69.54 6.45 11.01 Calculated value (%) 69.64 6.64 11.07 White crystal mp287-291℃ Reference example 16 8-Hydroxy-5-[1- Oxo-3-(4-
phenyl-1-piperazinyl)propyl]-3,
37.9 g of 4-dihydrocarbostyryl and 5.9 g of potassium hydroxide were dissolved in 400 ml of water and dried under reduced pressure.
The residue was dissolved in 400 ml of dimethylformamide, 12.0 g of methanesulfonyl chloride was added dropwise under cooling, and ether was added after 1 hour. Take the precipitated crystals,
Washed with acetone and recrystallized from isopropanol to give 8-methanesulfonyloxy-5-[1-oxo-3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyryl 35.9
get g. Elemental analysis (as C ₂₃ H ₂₇ O ₅ N ₃ S) C H N Actual value (%) 60.19 6.01 9.15 Calculated value (%) 60.38 5.95 9.18 Light brown needle crystals, mp 165-167°C Reference example 17 6-acetyloxy Using -3,4-dihydrocarbostyryl as the starting material, 6-hydroxy-7-acetyl-3,4-dihydrocarbostyryl was obtained in the same manner as in Reference Example 10. Pale yellow-green needle crystals mp252-253℃ Reference Example 18 Using 6-hydroxy-7-acetyl-3,4-dihydrocarbostyryl as a starting material, 6-methylsulfonyloxy-7-
Acetyl-3,4-dihydrocarbostyryl was obtained. Colorless needle crystals mp219-221℃ Reference example 19 6-methylsulfonyloxy-7-acetyl-
Using 3,4-dihydrocarbostyryl as the starting material, 7-acetyl-3,
4-dihydrocarbostyryl was obtained. mp177-179℃ Colorless needle crystals Reference example 20 Dissolve 9.45g of 7-acetyl-3,4-dihydrocarbostyryl in 30ml of glacial acetic acid, and dropwise add a solution of 2.6ml of bromine dissolved in 10ml of glacial acetic acid at 20℃. .
After stirring at room temperature for 30 minutes, it was cooled on ice, the precipitated crystals were collected, washed with 50% ethanol, and 9.4 g of 7-α
-bromoacetyl-3,4-dihydrocarbostyryl was obtained. Elemental analysis (as C ₁₁ H ₁₀ NO ₂ Br) C H N Calculated value (%) 49.28 3.76 5.22 Actual value (%) 49.24 3.79 5.18 mp202-203℃ Colorless needle crystal production reference example 1 6-(1-oxo- 4-chlorobutyl)-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 washing the chloroform layer with water and dehydrating it, the chloroform layer 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-
6.5 g of oxo-4-[4-(3-chlorophenyl)piperazinyl]butyl}-3,4-dihydrocarbostyryl are obtained. Melting point 158-159℃ 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 Manufacturing reference example 1 using appropriate starting materials Compounds of Examples 1 to 9 are obtained in the same manner as described above. Examples 1 to 9 5-[1-oxo-3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyryl mp180 to 182°C (ethanol-methanol) Colorless needle crystals Example 2 5 -{1-oxo-3-[4-(2-ethoxyphenyl)-1-piperazinyl]propyl}-3,
4-dihydrocarbostyryl monohydrochloride mp223-235℃ (decomposition) White crystals (methanol-water) Example 3 5-{1-oxo-3-[4-(2-hydroxyphenyl)-1-piperazinyl] propyl}-
3,4-dihydrocarbostyryl Example 4 5-{1-oxo-3-[4-(4-n-butylphenyl)-1-piperazinyl]propyl}-
3,4-dihydrocarbostyryl monohydrochloride mp218-222℃ (decomposition) (ethanol-water) Colorless needle crystals Example 5 5-{1-oxo-3-[4-(2-chlorophenyl)-1- piperazinyl]propyl}-3,4
-Dihydrocarbostyryl Example 6 5-{1-oxo-3-[4-(2,3-dimethylphenyl)-1-piperazinyl)propyl]-
3,4-dihydrocarbostyryl monohydrochloride mp231-234°C (methanol-water) White crystal Example 7 6-[1-oxo-3-(4-benzyl-1-piperazinyl)propyl]-3,4- Dihydrocarbostyryl mp177-178℃ (ethanol-water) Colorless needle crystals Example 8 6-{1-oxo-3-[4-(1-tetralinyl)-1-piperazinyl]propyl}-3,4-
Dihydrocarbostyryl Colorless prismatic crystals (ethanol-water) mp187-188℃ Example 9 5-[1-oxo-2-(4-phenyl-1-piperazinyl)ethyl]-3,4-dihydrocarbostyryl mp195-198 °C (decomposition) (methanol) Colorless needle crystal production reference example 2 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 (%) 73.01 7.59 11.21 Manufactured using appropriate starting materials The compound of Example 10 is obtained in the same manner as in Reference Example 2. Example 10 5-[1-hydroxy-3-(4-phenyl-1
-Piperazinyl)propyl]-3,4-dihydrocarbostyryl mp158-160℃ (ethanol) Colorless needle crystal production reference example 3 6-{1-oxo-4-[4-(3-chlorophenyl)piperazinyl]butyl}- Add 3.0 g of 3,4-dihydrocarbostyryl to 100 ml of methanol, gradually add 1.2 g of sodium borohydride while stirring, and stir at room temperature for 5 hours. Add 5 ml of concentrated hydrochloric acid to the reaction mixture and concentrate under reduced pressure to a solid state. 50 ml of a 2% aqueous sodium hydroxide solution is added thereto, and the organic matter is extracted with dichloromethane. The dichloromethane layer is washed with water, dehydrated, and dichloromethane is distilled off. The residue was purified by silica gel column chromatography,
Further recrystallization from isopropanol yields colorless needle-like crystals of 6-{1-hydroxy-4-[4-(3-chlorophenyl)piperazinyl]butyl}-3,4-
2.2 g of dihydrocarbostyril 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 Manufacturing reference example 3 using appropriate starting materials The compound of Example 11 is obtained in the same manner as above. Example 11 5-[1-hydroxy-3-(4-phenyl-1
-piperazinyl)propyl]-3,4-dihydrocarbostyryl mp158-160℃ (ethanol) Reference example for production of colorless needles 4 (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 Using appropriate starting materials, Production Reference Example 4 and Compounds of Examples 12 to 13 are obtained in the same manner. Example 12 6-[1-oxo-3-(4-benzyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyryl mp177-178℃ Colorless needle crystals (ethanol-water) Example 13 6-{ 1-oxo-3-[4-(1-tetralinyl)-1-piperazinyl]propyl}-3,4-
Dihydrocarbostyryl mp187-188℃ (ethanol-water) Colorless prismatic crystal production reference example 5 (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, and 50 ml of a 5% aqueous sodium hydrogen carbonate solution was added to the residue, followed by stirring. Extract the organic layer 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-(4-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, concentrated hydrochloric acid was added, and concentrated to dryness.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 14-20 were obtained in the same manner as in Production Reference Example 5 using appropriate starting materials. Example 14 6-[1-oxo-3-(4-benzyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyryl mp177-178℃ Colorless needle crystals (ethanol-water) Example 15 6-{ 1-oxo-3-[4-(1-tetralinyl)-1-piperazinyl]propyl}-3,4-
Dihydrocarbostyryl mp187-188℃ (ethanol-water) Colorless prismatic crystal Example 16 5-[1-oxo-2-[4-phenyl-1-piperazinyl]ethyl]-3,4-dihydrocarbostyryl mp195-198 °C (methanol) Colorless needles Example 17 5-[1-oxo-3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyryl mp180-182 °C (ethanol-methanol) Colorless needles Crystal Example 18 5-{1-oxo-3-[4-(2-ethoxyphenyl)-1-piperazinyl]propyl}-3,
4-dihydrocarbostyryl monohydrochloride mp223-235℃ (decomposition) White crystals (methanol-water) Example 19 5-{1-oxo-3-[4-(4-n-butylphenyl)-1-piperazinyl] propyl}-
3,4-dihydrocarbostyryl monohydrochloride mp218-222℃ (decomposition) Colorless needle crystals (ethanol-water) Example 20 5-{1-oxo-3-[4-(2,3-dimethylphenyl) )-1-piperazinyl]propyl}-
3,4-dihydrocarbostyryl monohydrochloride mp231-234℃ White crystals (methanol-water) Production reference example 6 (a) 6-{1-oxo-4-[di-(2-chloroethyl)amino]butyl} - 2.5 g of 3,4-dihydrocarbostyryl was mixed in 80 ml of methanol, and 1.6 g of sodium borohydride was stirred 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 give 6-[1-hydroxy-4-(4-phenyl-1-piperazinyl)butyl]-3,4-
Obtain 0.2 g of dihydrocarbostyril. Colorless needle crystals Melting point: 167-168°C Compound of Example 21 was obtained in the same manner as in Production Reference Example 6 using appropriate starting materials. Example 21 5-[1-hydroxy-3-(4-phenyl-1
-piperazinyl)propyl]-3,4-dihydrocarbostyryl mp158-160℃ (ethanol) Colorless needle crystal production reference example 7 (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.
Add to 100ml and extract the organic layer 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-
0.16 g of [4-(3-chlorophenyl)-1-piperazinyl]ethyl}-3,4-dihydrocarbostyryl is obtained. Melting point 214-215℃ 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 Manufacturing reference example 7 using appropriate starting materials Compounds of Examples 21 to 26 are obtained in the same manner as above. Example 21 5-[1-oxo-3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyryl mp180-182°C (ethanol-methanol) Colorless needle crystals Example 22 5-{ 1-oxo-3-[4-(2-ethoxyphenyl)-1-piperazinyl]propyl}-3,
4-Dihydrocarbostyryl monohydrochloride mp223-235℃ (decomposition) (methanol-water) White crystal example 23 5-{1-oxo-3-[4-(4-n-butylphenyl)-1-piperazinyl] propyl}-
3,4-dihydrocarbostyryl monohydrochloride mp218-222℃ (decomposition) (ethanol-water) Colorless needle crystals Example 24 5-{1-oxo-3-[4-(2,3-dimethylphenyl) )-1-piperazinyl]propyl}-
3,4-dihydrocarbostyryl monohydrochloride mp231-234℃ (methanol-water) White crystals (Example 25 6-[1-oxo-3-(4-benzyl-1-piperazinyl)propyl]-3,4 -Dihydrocarbostyryl mp177-178℃ (ethanol-water) Colorless needle crystal Example 26 6-{1-oxo-3-[4-(1-tetralinyl)-1-piperazinyl]propyl}-3,4-
Dihydrocarbostyryl Colorless prismatic crystals (ethanol-water) mp187-188℃ Reference production example 8 6-{1-hydroxy-4-[4-(3-chlorophenyl)-1-piperazinyl]butyl}-3,4
-Dissolve 1.9 g of dihydrocarbostyril in 50 ml of acetic acid and add 2 ml of concentrated hydrochloric acid to this solution. then 80
Stir for 30 minutes at °C. The reaction solution was dried under reduced pressure, 10-NaOH and ether were added to the residue, and the mixture was stirred at room temperature for 30 minutes. The precipitated crystals are collected and separated by silica gel chromatography. Ethanol-
Recrystallized from chloroform to give 6-{4-[4-(3
-chlorophenyl)-1-piperazinyl]-1-butenyl}-3,4-dihydrocarbostyryl is obtained. Yield: 1.6 g, colorless prism crystals, melting point: 175-176°C Compounds of Examples 27-28 are obtained in the same manner as in Production Reference Example 8. Example 27 6-{4-[4-(4-methylthiophenyl)-1
-Piperazinyl]-1-butenyl-3,4-dihydrocarbostyryl Colorless needle crystals, melting point 175.5-177°C (ethanol-chloroform) Example 28 5-[3-(4-phenyl-1-piperazinyl)
-1-propenyl]-3,4-dihydrocarbostyryl mp177-180℃ (methanol) colorless prismatic crystals) Production reference example 9 6-(4-chloro-1-butenyl)-3,4-dihydrocarbostyryl 2.8 g , sodium iodide 2.1
Dissolve g in 40 ml of dimethylformamide. Then, stir at 50°C for 1 hour. 4-(2-chloro-
2.7 g of 6-methylphenyl)piperazine and 1.5 g of triethylamine were added, and the mixture was further stirred at 50°C for 5 hours. The reaction solution was dried under reduced pressure, and the residue was
Add NaOH and ether, and stir at room temperature for 30 minutes. The precipitated crystals are separated by silica gel chromatography. Ethanol - Chloroform -
Recrystallized from acetone to give 6-{4-[4-(2-chloro-6-methylphenyl)-1-piperazinyl]
-1-butenyl}-3,4-dihydrocarbostyryl is obtained. Yield: 2.7 g, colorless prism crystals, melting point: 179-180°C In the same manner as in Production Reference Example 9, the compound of Example 29 was obtained. Example 29 5-[3-(4-phenyl-1-piperazinyl)
-1-propenyl]-3,4-dihydrocarbostyryl mp177-180℃ (methanol) Colorless prismatic crystal production reference example 10 6-{1-oxo-3-[4-(3-tolyl)-1
-Piperazinyl]propyl}-3,4-dihydrocarbostyryl (5.0 g) is suspended in 250 ml of methanol. Gradually add 2.5 g of sodium borohydride under ice cooling. Stir for an additional 30 minutes after addition. Next, 10 ml of acetone is added, and the reaction solution is dried under reduced pressure.
Add 10N-NaOH and ether to the residue, and stir at room temperature for 30 minutes. Collect the precipitated crystals. Suspend the crystals in 250 ml of dioxane and add 10 ml of concentrated hydrochloric acid.
Reflux for 15 minutes and dry the reaction solution under reduced pressure. The residue was separated by silica gel chromatography and recrystallized from ethanol to give 6-{3-[4-(3-tolyl)
-1-piperazinyl]-1-propenyl}-3,4
- Obtain dihydrocarbostyril. Yield: 2.9 g, colorless prism crystals, melting point: 167-168°C Compound of Example 30 was obtained in the same manner as in Production Reference Example 10. Example 30 5-[3-(4-phenyl-1-piperazinyl)
-1-propenyl]-3,4-dihydrocarbostyryl mp177-180℃ (methanol) Colorless prismatic crystal production reference example 11 6-[1-hydroxy-4-(4-phenyl-1
1.57 g of -piperazinyl)butyl]-3,4-dihydrocarbostyryl and 0.2 g of palladium black are suspended in 100 ml of dioxane. Next, 10 ml of concentrated hydrochloric acid is added and catalytic hydrogenation is carried out at a hydrogen pressure of 1.5 to 3 Kg/cm ² and a temperature of 80 to 90°C. The catalyst was removed and the liquid was dried under reduced pressure. Add 10N-NaOH and ether to the residue, and stir at room temperature for 30 minutes. The precipitated crystals were collected and separated by silica gel chromatography, and then separated using isopropanol.
Recrystallized from diisopropyl ether to give 6-[4
-(4-phenyl-1-piperazinyl)butyl]-
3,4-dihydrocarbostyryl is obtained. Yield: 0.60 g, yield: 40%, colorless prism crystals, melting point: 151-152°C In the same manner as in Production Reference Example 11, the compound of Example 31 was obtained. Example 31 5-[3-(4-phenyl-1-piperazinyl)
-1-propyl]-3,4-dihydrocarbostyryl monohydrochloride mp230-233℃ (ethanol-water) Reference example for production of colorless needle crystals 12 6-(4-chlorobutyl)-3,4-dihydrocarbostyryl 2.5 g and 1.8 g of sodium iodide were mixed in 80 ml of acetone, and after stirring at 50°C for 2 hours,
After adding 80ml of DMF and distilling off the acetone under reduced pressure,
Add 2.0 g of -(4-tolyl)piperazine and 2.0 g of tolylethylamine and stir at 70-80°C for 5 hours. The reaction solution was concentrated under reduced pressure, and 50 ml of a 5% aqueous sodium bicarbonate solution was added to the residue and stirred. The precipitate was collected, washed with water, dried, and recrystallized from isopropanol-diisopropyl ether to give a melting point of 160-161.
℃, 3.1 g of colorless prismatic crystals of 6-{4-[4-(4-tolyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyryl are obtained. The compound of Example 32 is obtained in the same manner as in Production Reference Example 12. Example 32 5-[3-(4-phenyl-1-piperazinyl)
Propyl]-3,4-dihydrocarbostyryl monohydrochloride mp230-233℃ (ethanol-water) Colorless needle crystal production reference example 13 6-{4-[4-(2-chlorophenyl)-1-piperazinyl]- 1-Butenyl}-3,4-dihydrocarbostyryl 0.37g, 10%-palladium on carbon
Suspend 0.1 g in 40 ml of water. Add 0.2ml of concentrated hydrochloric acid,
Catalytic hydrogenation is carried out at a hydrogen pressure of 5 kg/cm ² and at room temperature. The catalyst was removed, 10N NaOH and ether were added to the solution, and the mixture was stirred at room temperature for 30 minutes. Take the precipitated crystals,
Recrystallized from isopropanol to give 6-{4-[4-
(2-chlorophenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyryl is obtained. Yield: 0.27 g, colorless prism crystals, melting point: 129-130°C In the same manner as in Production Reference Example 13, the compound of Example 33 was obtained. Example 33 5-[3-(4-phenyl-1-piperazinyl)
Propyl]-3,4-dihydrocarbostyryl monohydrochloride mp230-233℃ (ethanol-water) Colorless needle crystal production reference example 14 6-{1-oxo-3-[4-(2-ethoxyphenyl) -1-piperazinyl]propyl-3,4
- Suspend 2.0 g of dihydrocarbostyryl monohydrochloride and 0.4 g of palladium black in 100 ml of water, and
Kg/cm ² , catalytic hydrogenation at 80°C. Then 5 ml of concentrated hydrochloric acid
and further catalytic hydrogenation. remove the catalyst,
Add 10N-NaOH to the solution to neutralize it. Extract with chloroform, chloroform is distilled off, and the residue is purified by column chromatography. Recrystallization from ether gave 6-{3-[4-(2-ethoxyphenyl)-1-piperazinyl]propyl}-3,4-
Obtain dihydrocarbostyril. Yield: 0.8 g, colorless prismatic crystals, melting point: 122-123° C. In the same manner as in Production Reference Example 14, a compound of Example 34 was obtained. Example 34 5-[3-(4-phenyl-1-piperazinyl)
Propyl]-3,4-dihydrocarbostyryl monohydrochloride mp230-233℃ (ethanol-water) Colorless needle crystal production reference example 15 2.88 g of 6-(4-morpholinobutyl)-3,4-dihydrocarbostyryl and Place 10 ml of aniline in a sealed tube and heat at 170-200°C for 5 hours. Aniline was distilled off by concentration under reduced pressure, and the residue was separated and purified by silica gel column chromatography, and recrystallized from isopropanol-diisopropyl ether to give colorless prismatic crystals of 6-[4-(4-
phenyl-1-piperazinyl)butyl]-3,4
-0.36 g of dihydrocarbostyril is obtained. The compound of Example 35 is obtained in the same manner as in Production Reference Example 15. Example 35 5-[3-(4-phenyl-1-piperazinyl)
Propyl]-3,4-dihydrocarbostyryl monohydrochloride mp230-233℃ (ethanol-water) Colorless needle crystals Example 36 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, 2.2 g of 4-benzylpiperidine 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. Insoluble materials were removed, washed with water, dried, and then recrystallized from ethanol to give pale yellow plate-like crystals of 6-[1-oxo-3-(4-benzyl-1-piperidyl)propyl]-3,4-
1.8 g of dihydrocarbostyril was obtained. mp170-171℃ Example 37 6-(1-oxo-3-chloropropyl)-3,
2.4 g of 4-dihydrocarbostyryl and 3.6 g of 4-phenyl-4-hydroxydi-piperidine are mixed in 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. Add ether-hexane to the residue, remove insoluble matter, recrystallize from ethanol-chloroform,
1.7 g of 6-[1-oxo-4-(4-phenyl-4-hydroxy-1-piperidine)butyl]-3,4-dihydrocarbostyryl was obtained as colorless flaky crystals. mp196-197℃ Example 38 6-(1-oxo-4-chlorobutyl)-3,4
-Dihydrocarbostyril 2.6g, pyridine 1.2g
and 2.7 g of 4-phenyl-4-acetyl-1-piperidine were mixed in 30 ml of dimethylformamide,
Stir at 70-80°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. The residue was recrystallized from ethanol to give pale yellow plate-like crystals of 6-[1-oxo-4-(4-phenyl-4-acetyl-1-
2.1 g of piperidyl)butyl]-3,4-dihydrocarbostyl was obtained. mp166-167℃ Example 39 6-(1-oxo-4-chloropropyl)-3,
Disperse 5.0 g of 4-dihydrocarbostyryl and 7.5 g of sodium iodide in 120 ml of anhydrous dimethylformamide, stir at 50 to 60°C for 2 hours, and then dissolve 4-phenyl-1,2,5,6-tetrahydropyridine.
Add 8.1g and 5ml of triethylamine to 50-60℃
Stir for 6 hours at room temperature and then for 24 hours at room temperature.
The reaction solution was concentrated under reduced pressure, 80 ml of 5% sodium hydrogen carbonate was added to the residue, and the organic layer was extracted with chloroform. After the chloroform layer is washed with water and dehydrated, the chloroform is distilled off. Recrystallization from ethanol gives pale yellow plate-like crystals of 6-[1-oxo-3-(4-phenyl-1,2,5,6-tetrahydro-1-pyridyl)propyl]-3,4-dihydrocarbostyryl. 6.0g was obtained. mp167-168℃ Example 40 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. After adding 5.0 g of 4-phenylpiperidine and 5 g of triethylamine to this reaction solution and stirring at 70 to 80°C for 6 hours,
Concentrate under reduced pressure, add 50 ml of 5% sodium hydrogen carbonate, and stir 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. The chloroform insoluble matter was removed, and the residue after chloroform distillation was recrystallized with ethanol to give pale yellow plate-like crystals of 6-[1-
Oxo-4-(4-phenyl-1-piperidyl)
Butyl]-3,4-dihydrocarbostyryl 5.6g
get. mp167-168°C Compounds of Examples 41-70 were obtained in the same manner as in Example 40 using appropriate starting materials. Example 41 6-[1-oxo-3-(4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyryl Colorless needle crystals mp183-184°C (ethanol) Example 42 6-[1- Oxo-4-(4-benzyl-1-piperidyl)butyl]-3,4-dihydrocarbostyryl Pale yellow plate crystals mp120-121℃ (ethanol) Example 43 6-[1-oxo-3-(4- Benzyl-1-piperidyl)propyl]-3,4-dihydrocarbostyryl Pale yellow plate crystals mp170-171°C (ethanol) Example 44 6-[1-oxo-4-(4-phenyl-4-hydroxy-1) -piperidyl)butyl]-3,4
-Dihydrocarbostyryl Colorless scaly crystals mp196-197℃ (ethanol-chloroform) Example 45 6-[1-oxo-3-(4-phenyl-4-hydroxy-1-piperidyl)propyl]-3,
4-dihydrocarbostyryl Colorless needle crystals mp205-206℃ (ethanol-ethyl acetate) Example 46 6-{1-oxo-4-[4-chlorophenyl)
-4-hydroxy-1-piperidyl]butyl}
-3,4-dihydrocarbostyryl Pale yellow scaly crystals mp210-211℃ (ethanol-chloroform) Example 47 6-[1-oxo-4-(4-phenyl-4-acetyl-1-piperidyl)butyl]- 3,4-
Dihydrocarbostyryl Pale yellow plate crystals mp166-167℃ (ethanol) Example 48 6-{1-oxo-4-[4-(2-benzimidazolinon-1-yl)-1-piperidyl]butyl}-3 ,4-dihydrocarbostyryl Colorless powder crystals mp247-248°C (methanol) Example 49 6-{1-oxo-3-[4-(2-benzimidazolinon-1-yl)-1-piperidyl]propyl} -3,4-dihydrocarbostyryl
Monohydrochloride Colorless plate-like crystals mp242-243℃ (decomposition) (methanol-chloroform) Example 50 6-[1-oxo-4-(4-phenyl-1,
2,5,6-tetrahydro-1-pyridyl)butyl]-3,4-dihydrocarbostyryl 1
Hydrochloride Pale yellow plate-like crystals mp170-171℃ (ethanol) Example 51 6-[1-oxo-3-(4-phenyl-1,
2,5,6-tetrahydro-1-pyridyl)propyl]-3,4-dihydrocarbostyryl Pale yellow plate crystals mp167-168°C (ethanol) Example 52 6-{1-oxo-4-[4-( 4-chlorophenyl)-1,2,5,6-tetrahydro-1-
Pyridyl]butyl}-3,4-dihydrocarbostyryl monohydrochloride Colorless plate-like crystals mp188-189℃ (ethanol) Example 53 1-Isopentyl-6-[1-oxo-3-(4
-phenyl-1-piperidyl)propyl]-3,
4-Dihydrocarbostyryl monohydrochloride Colorless mica-like crystals mp205-206℃ (decomposition) (ethanol-water) Example 54 1-allyl-6-[1-oxo-3-(4-phenyl-1-piperidyl) Propyl]-3,4-
Dihydrocarbostyryl monohydrochloride Colorless plate-like crystals mp198-199℃ (decomposition) (ethanol-water) Example 55 1-(2-propynyl)-6-[1-oxo-3
-(4-phenyl-1-piperidyl)propyl]
-3,4-dihydrocarbostyryl monohydrochloride Colorless plate-like crystals mp203-204℃ (decomposition) (ethanol-water) Example 56 1-(3-phenylpropyl)-6-[1-oxo-3- (4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyryl
Monohydrochloride Colorless powder crystals mp164-165℃ (isopropanol) Example 57 1-Methyl-6-[1-oxo-3-(4-phenyl-1-piperidyl)propyl]-3,4-
Dihydrocarbostyryl monohydrochloride Pale yellow platelet crystals (ethanol-water) mp213-214℃ (decomposition) Example 58 6-{1-oxo-3-[4-(4-chlorophenyl)-1,2,5 ,6-tetrahydro-1-
Pyridyl]propyl}-3,4-dihydrocarbostyryl 1/4 hydrate Pale yellow scaly crystals mp170-171℃ (ethanol) Example 59 6-{1-oxo-4-[4-(4-chlorophenyl) )-4-hydroxy-1-piperidyl]butyl}-3,4-dihydrocarbostyryl Pale yellow scaly crystals mp210-211℃ (ethanol-chloroform) Example 60 6-{1-oxo-4-[4-( 3,5-dimethylphenyl)-1-piperidyl]butyl}-3,
4-Dihydrocarbostyryl Pale yellow powder crystals mp171-172°C (ethanol) Example 61 6-{1-oxo-3-[4-(4-methylphenyl)-1,2,5,6-tetrahydro-1-
Pyridyl]propyl}-3,4-dihydrocarbostyryl mp189-190℃ (methanol-water) Pale yellow mica crystal Example 62 6-{1-oxo-3-[4-(4-fluorophenyl)-1 ,2,5,6-tetrahydro-1
-pyridyl]propyl}-3,4-dihydrocarbostyryl mp181-182℃ (ethanol-water) Pale yellow plate crystals Example 63 6-{1-oxo-3-[4-(3-methylphenyl)-1, 2,5,6-tetrahydro-1-
Pyridyl]propyl}-3,4-dihydrocarbostyryl mp152-153℃ (ethanol-water) Pale yellow plate crystals Example 64 6-{1-oxo-3-[4-(3-methoxyphenyl)-1 ,2,5,6-tetrahydro-1
-pyridyl]propyl}-3,4-dihydrocarbostyryl mp155-156℃ (ethanol-water) Pale yellow needle crystals Example 65 7-[1-oxo-3-(4-phenyl-1-piperidyl)propyl] -3,4-dihydrocarbostyryl Colorless needle crystals mp171-173℃ (methanol) Example 66 7-{1-oxo-3-[4-(4-methylphenyl)-1-piperidyl]propyl}-3,4 −
Dihydrocarbostyryl monohydrochloride mp212-216℃ (decomposition) (ethanol-water) White crystal example 67 7-{1-oxo-3-[4-(2,4-dimethylphenyl)-1-piperidyl] propyl}-
3,4-dihydrocarbostyryl 1 hydrochloride mp226-229℃ (methanol-water) White crystal example 68 6-[1-oxo-2-(4-phenyl-1-piperidyl)butyl]-carbostyryl 1 Hydrochloride Colorless plate-like crystals mp180-190℃ (methanol) Example 69 6-[1-oxo-2-(4-benzyl-1-piperidyl)butyl]-carbostyryl monohydrochloride Colorless powder crystals mp178-179 °C (ethanol-water) Example 70 6-[1-oxo-2-(4-phenyl-1,
2,5,6-tetrahydro-1-pyridyl)butyl]-carbostyryl monohydrochloride Pale yellow plate-like crystals mp190-191℃ (ethanol-water) Example 71 6-[1-oxo-3-(4- Phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyryl 1.8 g and sodium hydride (50% oil)
Mix 0.24g in 50ml of dimethylformamide,
After stirring at room temperature for 3 hours, 0.8 g of methyl iodide was added.
Stir at room temperature for 3 hours. Add the reaction solution to saturated saline 150%
ml and extract the organic layer 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 to form the hydrochloride,
Recrystallized from ethanol-water to give pale yellow plate-like crystals.
1.5 g of -methyl-6-[1-oxo-3-(4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyryl monohydrochloride is obtained. mp213-214°C (decomposition) Compounds of Examples 72-75 are obtained in the same manner as in Example 71 using appropriate raw materials. Example 72 1-isopentyl-6-[1-oxo-3-(4
-phenyl-1-piperidyl)propyl]-3,
4-dihydrocarbostyryl monohydrochloride Colorless mica-like crystals mp205-206℃ (decomposition) (ethanol-water) Example 73 1-allyl-6-[1-oxo-3-(4-phenyl-1-piperidyl) Propyl]-3,4-
Dihydrocarbostyryl monohydrochloride Colorless plate-like crystals mp198-199℃ (decomposition) (ethanol-water) Example 74 1-(2-propynyl)-6-[1-oxo-3
-(4-phenyl-1-piperidyl)propyl]
-3,4-dihydrocarbostyryl monohydrochloride Colorless plate-like crystals mp203-204℃ (decomposition) (ethanol-water) Example 75 1-(3-phenylpropyl)-6-[1-oxo-3- (4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyryl
Monohydrochloride Colorless powder crystals mp164-165℃ (isopropanol) Example 76 6-(1-hydroxy-3-chloropropyl)-
2.6 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-phenylpiperidine are added, and the mixture is stirred 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 ethanol to give 6-[1-hydroxy-3-(4-
phenyl-1-piperidyl)propyl]-3,4
- Obtain 2.5 g of dihydrocarbostyril. Colorless plate crystals mp 155.5-156°C Compounds of Examples 77-84 are obtained in the same manner as in Example 76 using appropriate starting materials. Example 77 6-[1-hydroxy-3-(4-benzyl-1
-piperidyl)propyl]-3,4-dihydrocarbostyryl Colorless plate-like crystals p168-169℃ (methanol) Example 78 6-[1-hydroxy-3-(4-phenyl-4
-Hydroxy-1-piperidyl)propyl]-
3,4-dihydrocarbostyryl Colorless needle crystals mp102-103℃ (ethanol) Example 79 6-[1-hydroxy-3-(4-phenyl-
1,2,5,6-tetrahydro-1-pyridyl)propyl]-3,4-dihydrocarbostyryl Colorless plate-like crystals mp144-145°C (ethanol) Example 80 6-{1-hydroxy-3-[4- (4-chlorophenyl)-1,2,5,6-tetrahydro-
1-pyridyl]propyl}-3,4-dihydrocarbostyryl Colorless plate crystals mp169-170℃ (ethanol) Example 81 6-{1-hydroxy-3-[4-(4-chlorophenyl)-1,2, 5,6-tetrahydro-
1-pyridyl]propyl}-3,4-dihydrocarbostyryl mp169-170℃ (ethanol) Colorless plate crystals Example 82 6-{1-hydroxy-3-[4-(3-methylphenyl)-1,2, 5,6-tetrahydro-
1-pyridyl]propyl}-3,4-dihydrocarbostyryl mp142-143℃ Colorless platelet crystals (ethanol) Example 83 6-{1-hydroxy-3-[4-(4-methylphenyl)-1,2, 5,6-tetrahydro-
1-pyridyl]propyl}-3,4-dihydrocarbostyryl mp159-160℃ (ethanol) Colorless mica crystal Example 84 7-[1-hydroxy-3-(4-phenyl-1
-piperidyl)propyl]-3,4-dihydrocarbostyryl mp146-149℃ (ethanol) Colorless prismatic crystal Example 85 6-[1-oxo-3-(4-phenyl-1-piperidyl)propyl]-3, 1.9 g of 4-dihydrocarbostyryl 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 ethanol to give 6-[1-hydroxy-3-(4
-phenyl-1-piperidyl)propyl]-3,
1.4 g of 4-dihydrocarbostyryl are obtained. mp 155.5-156°C, colorless plate-like crystals Compounds of Examples 86-88 are obtained in the same manner as in Example 85 using appropriate starting materials. Example 86 6-[1-hydroxy-3-(4-phenyl-4
-Hydroxy-1-piperidyl)propyl]-
3,4-dihydrocarbostyryl Colorless needle crystals mp102-103℃ (ethanol) Example 87 6-[1-hydroxy-3-(4-phenyl-
1,2,5,6-Tetrahydro-1-pyridyl]propyl]-3,4-dihydrocarbostyryl Colorless plate-like crystals mp144-145°C (ethanol) Example 88 6-{1-hydroxy-3-[4- (4-chlorophenyl)-1,2,5,6-tetrahydro-
1-pyridyl]propyl}-3,4-dihydrocarbostyryl Colorless plate-like crystals mp169-170℃ (ethanol) Example 89 6-[1-oxo-3-(4-phenyl-1-piperidyl)propyl]-3 , 2.2 g of 4-dihydrocarbostyryl and 0.6 g of 5% palladium on carbon were 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 ethanol to give 6-[1-hydroxy-3
-(4-phenyl-1-piperidyl)propyl]-
1.5 g of 3,4-dihydrocarbostyryl are obtained. Colorless platelet crystals mp 155.5-156°C Compounds of Examples 90-92 are obtained in the same manner as in Example 89. Example 90 6-[1-hydroxy-3-(4-phenyl-4
-Hydroxy-1-piperidyl)propyl]-
3,4-dihydrocarbostyryl Colorless needle crystals mp102-103℃ (ethanol) Example 91 6-[1-hydroxy-3-(4-phenyl-
1,2,5,6-Tetrahydro-1-pyridyl]propyl]-3,4-dihydrocarbostyryl Colorless platelet crystals mp144-145°C (ethanol) Example 92 6-{1-hydroxy-3-[4- (4-chlorophenyl)-1,2,5,6-tetrahydro-
1-pyridyl]propyl}-3,4-dihydrocarbostyryl Colorless plate-like crystals mp169-170°C (ethanol) Example 93 6-[1-oxo-3-(4-phenyl-1,
1.9 g of 2,5,6-tetrahydro-1-pyridyl)propyl]-3,4-dihydrocarbostyryl and 1.0 g of lithium aluminum hydride are dispersed in 80 ml of anhydrous tetrahydrofuran and stirred at room temperature for 8 hours. Then, a saturated aqueous sodium sulfate solution is gradually added to the reaction mixture while stirring. After decanting the tetrahydrofuran solution, the tetrahydrofuran was distilled off, and the residue was recrystallized from ethanol to give 6-
[1-hydroxy-3-(4-phenyl-1,2,
0.8 g of 5,6-tetrahydro-1-pyridyl)propyl]-3,4-dihydrocarbostyryl is obtained. Colorless platelet crystals mp 144-145°C Compounds of Examples 94-97 are obtained in the same manner as in Example 93. Example 94 6-[1-hydroxy-3-(4-phenyl-1
-piperidyl)propyl]-3,4-dihydrocarbostyryl Colorless plate-like crystals mp155.5-156℃ (ethanol) Example 95 6-[1-hydroxy-3-(4-benzyl-1
-piperidyl)propyl]-3,4-dihydrocarbostyryl Colorless plate-like crystals mp168-169℃ (methanol) Example 96 6-[1-hydroxy-3-(4-phenyl-4
-Hydroxy-1-piperidyl)propyl]-
3,4-dihydrocarbostyryl Colorless needle crystals mp102-103℃ (ethanol) Example 97 6-{1-hydroxy-3-[4-(4-chlorophenyl)-1,2,5,6-tetrahydro-
1-pyridyl]propyl}-3,4-dihydrocarbostyryl Colorless plate-like crystals mp169-170℃ (ethanol) Example 98 6-{1-oxo-3-[4-(4-chlorophenyl)-1,2, 2.9 g of 5,6-tetrahydro-1-pyridyl]-3,4-dihydrocarbostyryl
was added to 100 ml of methanol, 1.2 g of sodium borohydride was gradually added while stirring, and the mixture was stirred at room temperature for 5 hours. Add 5 ml of concentrated hydrochloric acid to the reaction solution, concentrate to dryness under reduced pressure, and add 50 ml of 2% aqueous sodium hydroxide solution to the reaction solution.
ml and extract the organic matter with dichloromethane.
The dichloromethane layer is washed with water, dehydrated, and dichloromethane is distilled off. The residue was purified by silica gel column chromatography and further recrystallized from ethanol to give colorless plate-like crystals of 6-{1-hydroxy-3-[4-(4-chlorophenyl)-1,2,5,
6-tetrahydro-1-pyridyl]propyl}-
3,4-dihydrocarbostyryl is obtained. mp169-170°C Compounds of Examples 99-106 are obtained in the same manner as in Example 98. Example 99 6-[1-hydroxy-3-(4-phenyl-1
-piperidyl)propyl]-3,4-dihydrocarbostyryl Colorless plate-like crystals mp155.5-156℃ (ethanol) Example 100 6-[1-hydroxy-3-(4-benzyl-1)
-piperidyl)propyl]-3,4-dihydrocarbostyryl Colorless plate-like crystals mp168-169℃ (methanol) Example 101 6-[1-hydroxy-3-(4-phenyl-4
-Hydroxy-1-piperidyl)propyl]-
3,4-dihydrocarbostyryl Colorless needle crystals mp102-103℃ (ethanol) Example 102 6-[1-hydroxy-3-(4-phenyl-
1,2,5,6-tetrahydro-1-pyridyl)propyl]-3,4-dihydrocarbostyryl Colorless plate-like crystals mp144-145°C (ethanol) Example 103 6-{1-hydroxy-3-[4- (4-chlorophenyl)-1,2,5,6-tetrahydro-
1-pyridyl]propyl}-3,4-dihydrocarbostyryl mp169-170℃ (ethanol) Colorless plate crystal Example 104 6-{1-hydroxy-3-[4-(3-methylphenyl)-1,2, 5,6-tetrahydro-
1-pyridyl]propyl}-3,4-dihydrocarbostyryl mp142-143℃ (ethanol) Colorless plate crystals Example 105 6-{1-hydroxy-3-[4-(4-methylphenyl)-1,2, 5,6-tetrahydro-
1-pyridyl]propyl}-3,4-dihydrocarbostyryl mp159-160℃ (ethanol) Colorless mica crystal Example 106 7-[1-hydroxy-3-(4-phenyl-1
-piperidyl)propyl]-3,4-dihydrocarbostyryl mp146-149℃ (ethanol) (90) Colorless prismatic crystal Example 107 6-[1-hydroxy-3-chloropropyl]-
2.5 g of 3,4-dihydrocarbostyryl and 4-
3.0 g of phenyl-1,2,5,6-tetrahydropyridine was mixed with 50 ml of toluene, heated under reflux for 5 hours, the toluene was distilled off, 50 ml of 5% sodium bicarbonate was added to the residue, and the mixture was extracted with chloroform. , wash the chloroform layer with water and dehydrate. When the residue after chloroform distillation is recrystallized from ethanol, 6-
[3-(4-phenyl-1,2,5,6-tetrahydro-1-pyridyl)-1-propenyl]-3,4
-2.1 g of dihydrocarbostyril are obtained. Compounds of Examples 108 to 114 are obtained in the same manner as Example 107. Example 108 6-[3-(4-phenyl-1-piperidyl)-
1-propenyl]-3,4-dihydrocarbostyryl Colorless plate-like crystals mp163-164℃ (methanol) Example 109 6-[3-(4-benzyl-1-piperidyl)-
1-propenyl]-3,4-dihydrocarbostyryl Colorless needle crystals mp160-161℃ (ethanol) Example 110 6-[4-(4-phenyl-4-acetyl-1-
Piperidyl)-1-butenyl]-3,4-dihydrocarbostyryl Colorless plate-like crystals mp169-170℃ (ethanol) Example 111 6-{3-[4-(4-methylphenyl)-1,
2,5,6-tetrahydro-1-pyridyl]-
1-propenyl}-3,4-dihydrocarbostyryl mp214-215℃ (ethanol) Pale yellow plate crystals Example 112 6-[3-(4-phenyl-1,2,5,6-tetrahydro-1-pyridyl) )-1-propenyl]
-3,4-dihydrocarbostyryl mp182-183℃ (ethanol) Pale yellow plate crystals Example 113 7-[3-(4-phenyl-1-piperidyl)-
1-propenyl]-3,4-dihydrocarbostyryl mp165-168℃ (methanol) Colorless needle crystal Example 114 6-{3-[4-(2-methoxyphenyl)-1,
2,5,6-tetrahydropyridyl]-1-propenyl}-3,4-dihydrocarbostyryl monooxalate mp201-205°C (ethanol-water) Colorless scaly crystals Example 115 6-[1-hydroxy-3 -(4-phenyl-
After dissolving 1.0 g of 1,2,5,6-tetrahydropyridyl)propyl]-3,4-dihydrocarbostyryl in 30 ml of methanol, 2 ml of concentrated hydrochloric acid was added, and after heating under reflux for 2 hours, it was concentrated under reduced pressure to form a residue.
Add 50 ml of 0.5% sodium hydroxide aqueous solution and extract with chloroform. The chloroform layer was washed with water, dehydrated, and the residue after distilling off the chloroform at room temperature was recrystallized from ethanol to give pale yellow plate-like crystals, melting point 182 ~
6-[3-(4-phenyl-1,
2,5,6-tetrahydro-1-pyridyl)-1
-propenyl]-34-dihydrocarbostyryl
0.6g obtained. Compounds of Examples 116 to 122 are obtained in the same manner as in Example 115. Example 116 6-[3-(4-phenyl-1-piperidyl)-
1-propenyl]-3,4-dihydrocarbostyryl Colorless plate crystals mp163-164℃ (methanol) Example 117 6-[3-(4-benzyl-1-piperidyl)-
1-propenyl]-3,4-dihydrocarbostyryl Colorless needle crystals mp160-161℃ (ethanol) Example 118 6-[4-(4-phenyl-4-acetyl-1-
Piperidyl)-1-butenyl]-3,4-dihydrocarbostyryl Colorless plate-like crystals mp169-170℃ (ethanol) Example 119 6-{3-[4-(4-methylphenyl)-1,
2,5,6-tetrahydro-1-pyridyl]-
1-propenyl}-3,4-dihydrocarbostyryl mp214-215℃ (ethanol) Pale yellow plate crystals Example 120 6-[3-(4-phenyl-1,2,5,6-tetrahydro-1-pyridyl) )-1-propenyl]
-3,4-dihydrocarbostyryl mp182-183℃ (decomposition) (ethanol) Pale yellow plate crystals Example 121 7-[3-(4-phenyl-1-piperidyl)-
1-propenyl]-3,4-dihydrocarbostyryl mp165-168℃ (methanol) Colorless needle crystal Example 122 6-{3-[4-(2-methoxyphenyl)-1,
2,5,6-tetrahydro-1-pyridyl]-
1-propenyl}-3,4-dihydrocarbostyryl 1-oxalate mp201-205℃ (ethanol-water) Colorless scaly crystals Example 123 6-[3-(4-phenyl-1,2,5,6- Tetrahydro-1-pyridyl)-1-propenyl]-
2.0 g of 3,4-dihydrocarbostyryl and 0.2 g of palladium black were dispersed in 50 ml of dioxane, and after stirring for 5 hours at 2 atmospheres of hydrogen, the reaction solution was filtered, and 3 ml of concentrated hydrochloric acid was added to the mother liquor and concentrated under reduced pressure. Dry. A small amount of ethanol and acetone are added to the residue to crystallize it. Crude crystals are collected and recrystallized from methanol to give colorless plate-like crystals, melting point 232~
6-[3-(4-phenyl-1-
1.6 g of (piperidyl)propyl]-3,4-dihydrocarbostyryl monohydrochloride is obtained. Compounds of Examples 124 to 128 are obtained in the same manner as in Example 123. Example 124 6-[3-(4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyryl.
Monohydrochloride Colorless plate crystals mp 232-233℃ (methanol) Example 125 6-[3-(4-benzyl-1-piperidyl)propyl]-3,4-dihydrocarbostyryl Colorless plate crystals mp 99-100℃ ( ethanol) Example 126 6-{3-[4-(4-methylphenyl)-1-piperidyl]propyl}-3,4-dihydrocarbostyryl mp125-126°C (isopropanol-n-hexane) Colorless platelet crystal Example 127 7-[3-(4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyryl mp114-118℃ (ethanol-water) Colorless needle crystal Example 128 6-{3-[4-( 2-methoxyphenyl)-1-
Piperidyl]propyl}-3,4-dihydrocarbostyryl mp178-181℃ (ethanol-water) Colorless scaly crystals Example 129 8-methanesulfonyloxy-5-[1-oxo-3-(4-phenyl-1- Piperazinyl)propyl]-3,4-dihydrocarbostyryl 45.8
Dissolve g and 5.9 g of potassium hydroxide in ethanol, add 1.0 g of 5% palladium on carbon, and stir at room temperature.
After 8 hours of catalytic hydrogenation at normal pressure, the catalyst was removed and the mixture was dried under reduced pressure. The residue was washed with water, collected, and recrystallized from ethanol-chloroform to give 5-[1-oxo-3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyryl 26.4
get g. Elemental analysis (as C ₂₂ H ₂₅ O ₂ N ₃ ) C H N Actual value (%) 72.62 6.95 11.56 Calculated value (%) 72.70 6.93 11.56 Example 130 6-methanesulfonyloxy-7-[1-oxo-3- Disperse 2.0 g of (4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyryl and 0.5 g of palladium black in 50 ml of ethanol,
Catalytic reduction was carried out under a hydrogen pressure of 3 atm for 5 hours. The reaction solution was filtered, the mother liquor was concentrated under reduced pressure, and the residue was recrystallized from methanol to give colorless needle-like crystals with a melting point of 171-173°C.
1.1 g of [1-oxo-3-(4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyryl is obtained. Elemental analysis (as C ₂₃ H ₂₆ O ₂ N ₂ ) C H N Actual value (%) 76.01 7.28 7.92 Calculated value (%) 76.21 7.23 7.73 Compounds of Examples 131 to 153 are obtained in the same manner as in Example 130. Example 131 5-[1-oxo-3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyryl mp180-182°C (ethanol-methanol) Colorless needle crystals Example 132 5-{ 1-oxo-3-[4-(2-ethoxyphenyl)-1-piperazinyl]propyl}-3,
4-dihydrocarbostyryl monohydrochloride mp223-235℃ (decomposition) (methanol-water) White crystal example 133 5-{1-oxo-3-[4-(4-n-butylphenyl)-1-piperazinyl] propyl}-
3,4-dihydrocarbostyryl monohydrochloride mp218-222℃ (decomposition) (ethanol-water) Colorless needle crystal Example 134 5-{1-oxo-3-[4-(2,3-dimethyl)- 1-piperazinyl]propyl}-3,4-
Dihydrocarbostyryl monohydrochloride mp231-234℃ (methanol-water) White crystal example 135 7-[1-oxo-3-(4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyryl mp171 ~173℃ (methanol) Colorless needle crystal Example 136 7-{1-oxo-3-[4-(4-methylphenyl)-1-piperidyl]propyl}-3,4-
Dihydrocarbostyryl monohydrochloride mp212-216℃ (decomposition) White crystals (ethanol-water) Example 137 7-{1-oxo-3-[4-(2,4-dimethylphenyl)-1-piperidyl] propyl}-
3,4-dihydrocarbostyryl monohydrochloride mp226-229℃ (methanol-water) White crystal example 138 5-[1-hydroxy-3-(4-phenyl-1
-piperazinyl)propyl]-3,4-dihydrocarbostyryl mp158-160℃ (ethanol) Colorless needle crystals Example 139 7-[1-hydroxy-3-(4-phenyl-1
-piperidyl)propyl]-3,4-dihydrocarbostyryl mp146-149℃ (ethanol) Colorless prismatic crystal Example 140 5-[3-(4-phenyl-1-piperazinyl)
Propyl]-3,4-dihydrocarbostyryl monohydrochloride mp230-233℃ (ethanol-water) Colorless needle crystal Example 141 7-[3-(4-phenyl-1-piperidyl)propyl]-3,4 -Dihydrocarbostyryl mp114-118℃ (ethanol-water) Colorless needle crystal Example 142 6-[1-oxo-3-(4-benzyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyryl mp177- 178℃ Colorless needle crystals (ethanol-water) Example 143 6-{1-oxo-3-[4-(1-tetralinyl)-1-piperazinyl]propyl}-3,4-
Dihydrocarbostyryl mp187-188℃ (ethanol-water) Colorless prismatic crystals Example 144 1-(2-propynyl)-6-[1-oxo-3
-(4-phenyl-1-piperidyl)propyl]
-3,4-dihydrocarbostyryl monohydrochloride Colorless plate-like crystals mp203-204℃ (decomposition) (ethanol-water) Example 145 6-[1-oxo-3-(4-benzyl-1-piperidyl)propyl ]-3,4-dihydrocarbostyryl Pale yellow plate-like crystals mp170-171℃ (ethanol) Example 146 6-[1-oxo-(4-phenyl-4-acetyl-1-piperidyl)butyl]-3,4 -Dihydrocarbostyryl Pale yellow plate crystals mp166-167℃ (ethanol) Example 147 6-{1-oxo-3-[4-(2-benzimidazolinon-1-yl)-1-piperidyl]propyl}- 3,4-dihydrocarbostyryl
Monohydrochloride Colorless plate crystals mp242-243℃ (decomposition) (methanol-chloroform) Example 148 6-{1-hydroxy-3-[4-(4-phenyl-4-hydroxy-1-piperidyl)propyl}- 3,4-dihydrocarbostyryl Colorless needle crystals mp102-103℃ (ethanol) Example 149 6-[3-(4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyryl.
Monohydrochloride Colorless plate crystals mp 232-233℃ (methanol) Example 150 6-[3-(4-benzyl-1-piperidyl)propyl]-3,4-dihydrocarbostyryl Colorless plate crystals mp 99-100℃ ( ethanol) Example 151 6-{3-[4-(4-methylphenyl)-1-piperidyl]propyl}-3,4-dihydrocarbostyryl mp125-126°C (isopropanol-n-hexane) Colorless platelet crystal Example 152 5-[3-(4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyryl Example 153 6-{3-[4-(2-methoxyphenyl)1-
Piperidyl]propyl}-3,4-dihydrocarbostyryl monooxalate mp178-181℃ (ethanol-water) Colorless scaly crystals Example 154 4-(2,3-dimethylphenyl)piperazine hydrochloride (0.2 mol) and 37% formalin aqueous solution (0.2 mol) are mixed, and acetic anhydride (10 times the weight) is added dropwise at 80 to 90°C. After keeping the reaction solution at 80-90°C for 1 hour, 5-acetyl-3,4-dihydrocarbostyryl (0.1 mol) was added, and the mixture was heated at 80-90°C for 1 hour.
Stir for an hour. After the reaction is complete, add excess acetone and collect the precipitated crystals. The obtained crystals are dissolved in methanol, neutralized with a 1N aqueous solution of caustic soda, and then left to stand. The precipitated crystals were collected and converted into hydrochloride with methanol and concentrated hydrochloric acid, and the crude crystals were recrystallized from ethanol-water to give 5-{1-oxo-3-[4-
(2,3-dimethylphenyl)-1-piperazinyl]propyl}-3,4-dihydrocarbostyryl monohydrochloride is obtained. (Yield 35%) White crystals mp231-234°C Example 155 In the same manner as in Example 154 above, substitute 37% formalin aqueous solution with paraformaldehyde (0.2 mol)
5-{1-oxo-3-[4-(2,3-dimethylphenyl)-1-
Piperazinyl]propyl}-3,4-dihydrocarbostyryl monohydrochloride is obtained. Yield 34%, white crystals mp231-234°C Example 156 5-{1-oxo-3- [4
-(2,3-dimethylphenyl)-1-piperazinyl]propyl}-3,4-dihydrocarbostyryl monohydrochloride is obtained. Yield 39%, white crystals mp231-234°C The following example compound was obtained in the same manner as in Example 154 above. Example 157 5-{1-oxo-3-[4-(2-ethoxyphenyl)-1-piperazinyl]propyl}-3,
4-dihydrocarbostyryl monohydrochloride White crystals mp223-235℃ (decomposition) (methanol-water) Example 158 7-{1-oxo-3-[4-(4-methylphenyl)-1-piperidyl]propyl} -3,4-
Dihydrocarbostyryl monohydrochloride White crystals (ethanol-water) mp212-216℃ (decomposition) Example 159 7-{1-oxo-3-[4-(2,4-dimethylphenyl)-1-piperidyl] propyl}-
3,4-dihydrocarbostyryl monohydrochloride White crystals mp226-229℃ (methanol-water) Example 160 6-[1-oxo-3-(4-phenyl-1-piperazinyl)propyl]-3,4- Dihydrocarbostyryl Colorless phosphorus flakes mp196-197℃ Example 161 6-{1-oxo-3-[4-(2,3-dimethylphenyl)-1-piperazinyl]propyl}-
3,4-Dihydrocarbostyryl Colorless needle crystals mp273-274℃ (decomposed) Example 162 5-[1-oxo-3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyryl Colorless Needle crystals (ethanol-methanol) mp180-182℃ Example 163 6-[1-oxo-3-(4-benzyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyryl Colorless needle crystals mp177-178 °C (ethanol-water) Example 164 6-[1-oxo-3-[4-(1-tetralinyl)-1-piperazinyl]propyl}-3,4-
Dihydrocarbostyryl mp187-188℃ Colorless prismatic crystals (ethanol-water) Example 165 6-[1-oxo-3-(4-benzyl-1-piperidyl)propyl]-3,4-dihydrocarbostyryl Pale yellow plate Crystalline mp170-171℃ (ethanol) Example 166 6-[1-oxo-3-(4-phenyl-1,
2,5,6-tetrahydro-1-pyridyl)propyl]-3,4-dihydrocarbostyryl Pale yellow plate crystals (ethanol) mp167-168℃ Example 167 6-[1-oxo-3-(4-phenyl) -1-Piperidyl)propyl]-3,4-dihydrocarbostyryl Colorless needle crystals mp183-184℃ (ethanol) Example 168 6-[1-oxo-3-(4-phenyl-4-hydroxy-1-piperidyl) )propyl]-3,
4-dihydrocarbostyryl Colorless needle crystals mp205-206℃ (ethanol-ethyl acetate) Example 169 6-{1-oxo-3-[4-(2-benzimidazolinon-1-yl)-1-piperidyl] Propyl}-3,4-dihydrocarbostyryl
Monohydrochloride Colorless plate crystals mp242-243℃ (decomposition) (methanol-chloroform) Example 170 1-Isopentyl-6-[1-oxo-3-(4
-phenyl-1-piperidyl)propyl]-3,
4-Dihydrocarbostyryl monohydrochloride Colorless mica-like crystals mp205-206℃ (decomposition) (ethanol-water) Example 171 1-allyl-6-[1-oxo-3-(4-phenyl-1-piperidyl) Propyl]-3,4-
Dihydrocarbostyryl monohydrochloride Colorless plate-like crystals mp198-199℃ (decomposition) (ethanol-water) Example 172 1-(2-propynyl)-6-[1-oxo-3
-(4-phenyl-1-piperidyl)propyl]
-3,4-dihydrocarbostyryl monohydrochloride Colorless plate-like crystals mp203-204℃ (decomposition) (ethanol-water) Example 173 1-(3-phenylpropyl)-6-[1-oxo-3- (4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyryl
Monohydrochloride Colorless powder crystals mp164-165℃ (isopropanol) Example 174 1-Methyl-6-[1-oxo-3-(4-phenyl-1-piperidyl)propyl]-3,4-
Dihydrocarbostyryl monohydrochloride Pale yellow plate-like crystals mp213-214℃ (decomposition) (ethanol-water) Example 175 6-[1-oxo-3-[4-(4-chlorophenyl)-1,2,5 ,6-tetrahydro-1-
pyridyl]propyl}-3,4-dihydrocarbostyryl 1/4 hydrate pale yellow scaly crystals mp170-171℃ (ethanol) Example 176 6-{1-oxo-3-[4-(4-methylphenyl) )-1,2,5,6-tetrahydro-1-
Pyridyl]propyl}-3,4-dihydrocarbostyryl mp189-190℃ Pale yellow mica crystals (methanol-water) Example 177 6-{1-oxo-3-[4-(4-fluorophenyl)-1 ,2,5,6-tetrahydro-1
-pyridyl]propyl}-3,4-dihydrocarbostyryl mp181-182℃ (ethanol-water) Pale yellow plate crystals Example 178 6-{1-oxo-3-[4-(3-methylphenyl)-1, 2,5,6-tetrahydro-1-
Pyridyl]propyl}-3,4-dihydrocarbostyryl mp152-153℃ (ethanol-water) Pale yellow plate crystal Example 179 6-{1-oxo-3-[4-(3,5-dimethoxyphenyl) -1,2,5,6-tetrahydro-1-pyridyl]propyl}-3,4-dihydrocarbostyryl Example 180 6-{1-oxo-3-[4-(3-methoxyphenyl)-1, 2,5,6-tetrahydro-1-
Pyridyl]propyl}-3,4-dihydrocarbostyryl Pale yellow needle crystals mp155-156℃ (ethanol-water) Formulation example 1 6-{1-oxo-4-(4-phenyl-4-hydroxy-1-piperidyl) )butyl]-3,4
-Dihydrocarbostyril 10mg Cornstarch 127mg Magnesium stearate 18mg Lactose 45mg Total 200mg Tablets of the above composition are prepared in a conventional manner. Production example 2 6-[1-hydroxy-3-(4-benzyl-1
-Piperidyl)propyl]-3,4-dihydrocarbostyryl 5mg Cornstarch 132mg Magnesium stearate 18mg Lactose 45mg Total 200mg

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, a lower alkenyl group, or a lower alkynyl group. A represents a group [formula], a group [formula], a group [formula], or a group [formula]. Here, R ² represents a hydrogen atom. B represents a lower alkylene group. l represents 0 or 1. However, when A represents the group [Formula] or [Formula], l shall represent 1. Z represents a group N-R ³ or a group [Formula]. Here, R ³ is a phenyl group or phenyl lower alkyl which may have 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, and a hydroxyl group as a substituent on the phenyl ring. Indicates the group. R ⁴ represents a phenyl group, a phenyl lower alkyl group, or a group [Formula] which may have 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkoxy group as substituents on the phenyl ring. . R ⁵ represents a hydrogen atom, a hydroxyl group or a lower alkanoyl group. Also
When R ⁵ represents a hydrogen atom, the hydrogen atoms bonded to the 3rd and 4th positions of the piperidine skeleton are both dehydrogenated, and the carbon-carbon bond between the 3rd and 4th positions of the piperidine skeleton represents a double bond. You can also do it. The carbon-carbon bond between the 3rd and 4th positions of the carbostyryl skeleton represents a single bond or a double bond. However, when ) Z is a group N-R ³ (where R ³ is a phenyl lower alkyl group,
and, except when R ³ is a phenyl group having a lower alkylthio group and A is a group [formula] or [formula] (R ² is the same as above), the side chain [formula] is carbostyryl. Substituted at the 5, 7 or 8 position of the skeleton,
No substitution shall be made in the 6th position. ) R ¹ is a hydrogen atom, and the side chain [formula] (where A ¹ is a group [formula] or [formula], B ¹ is a group [formula] (R represents a hydrogen atom or a lower alkyl group) ), Z ¹ is a group N-R ³ ′ (R ³ ′ is a phenyl lower alkyl group) or a group CHR ⁴ ′ (R ⁴ ′ is an unsubstituted phenyl group or a phenyl lower alkyl group), ) is substituted at the 6-position of the carbostyril skeleton, the carbon-carbon bond between the 3-position and the 4-position of the carbostyril skeleton must not be a single bond. ] A carbostyril derivative represented by these and its salt.