JPS6320433B2 - - 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 is a hydrogen atom, a lower alkenyl group, a lower alkynyl group, or a lower alkyl group that may have a phenyl group as a substituent, R ² is a hydrogen atom, a lower alkyl group, or a phenyl group, and R ³ is a hydrogen atom, a lower alkyl group, or a phenyl group. 1 to 1 selected from the group consisting of a lower alkyl group having a phenyl group as a substituent, or a halogen atom, a lower alkyl group, and a lower alkoxy group on the phenyl ring
A phenyl group that may have 3 substituents, R ⁴ is a hydrogen atom, a hydroxyl group, or a lower alkanoyl group, X is a halogen atom, and Y is a lower alkylene group that may have a hydroxyl group as a substituent.
and n represents 0, 1 or 2. Also this R ³ and
R ⁴ is a group that is bonded to each other through a nitrogen atom together with the carbon atom to which they are bonded. (R° may represent a hydrogen atom or a lower alkyl group). However, when R ³ represents a lower alkyl group having a phenyl group as a substituent, R ⁴ must not be a hydroxyl group or a lower alkanoyl group.
Further, the carbon-carbon bond between the 3rd and 4th positions of the carbostyril skeleton represents a single bond or a double bond. ] The carbostyril derivative represented by the above general formula [1] of the present invention and its salt have an excellent antihistamine effect and are useful as an antihistamine agent. In particular, the compound of the present invention has weak side effects such as central nervous system depressing action and β-blocking action as a result of animal tests. Antihistamines are described in Gutsman-Gilman Pharmacology Book [1] Fundamentals and Clinical Practice of Drug Treatment, pp. 781-835.
Published by Hirokawa Shoten (1974), New Applied Pharmacology by Hisashi Hano, pp. 307-319, Nagai Shoten (1970), New Drugs and Clinical Practice, Vol. 20, No. 11, pp. 129-133 (1971) and Basics. As described in ``And Clinical Research'', 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 is and histamine receptor binding (competitive antagonism)
It exerts antihistamine action. The antihistamine of the present invention can be used to treat various diseases caused by the binding of histamine with 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 inflammatory syndrome. (itching, edema, redness, etc.), angioedema, pruritus,
Treatment or preliminary medicine for allergic diseases such as atopic dermatitis, insect stings, contact dermatitis such as poison poison rash, ginseng and edematous disorders during serum sickness, allergic rhinitis, allergic conjunctivitis, and keratitis. It is valid as 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 above general formula [1], R゜~R ⁴ , X and Y
More specifically, each group represented by is as follows. Lower alkenyl group...vinyl, allyl, 2-
Straight chain or branched alkenyl groups having 2 to 6 carbon atoms, such as butenyl, 1-methyl-2-butenyl, 2-pentenyl, 2-hexenyl groups. Lower alkynyl group: A linear or branched alkynyl group having 2 to 6 carbon atoms such as ethynyl, propargyl, 2-butynyl, 1-methyl-2-propargyl, 2-pentynyl, 2-hexynyl group, etc. Lower alkyl groups that may have phenyl groups as substituents: methyl, ethyl, propyl,
Isopropyl, butyl, tert-butyl, pentyl, hexyl, benzyl, 2-phenylethyl,
1-phenylethyl, 3-phenylpropyl, 4
- Straight chain or branched alkyl having 1 to 6 carbon atoms that may have a phenyl group as a substituent such as phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, diphenylmethyl group, etc. Base. Lower alkyl group: a straight chain or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl group, etc. Lower alkyl group having a phenyl group as a substituent: benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6 - A straight chain or branched alkyl group having 1 to 6 carbon atoms having a phenyl group as a substituent such as phenylhexyl or diphenylmethyl group. Halogen atoms: fluorine, chlorine, bromine and iodine atoms. Lower alkoxy group: a straight-chain or branched alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy group, etc. Lower alkanoyl group: A linear or branched alkanoyl group having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentyl, tert-butylcarbonyl, hexanoyl group, etc. Lower alkylene group that may have a hydroxyl group as a substituent: methylene, ethylene, trimethylene, 2-methyltrimethylene, 1-methyltrimethylene, tetramethylene, pentamethylene, hexamethylene, 2-ethylethylene, 2,2 - Straight chain with 1 to 6 carbon atoms that may have a hydroxyl group as a substituent such as dimethyltrimethylene, 2-hydroxytrimethylene, 2-hydroxytetramethylene, 2,3-dihydroxytetramethylene, 3-hydroxypentamethylene group, etc. Or a branched alkylene group. Representative compounds included in the carbostyryl derivative represented by the general formula [1] of the present invention are illustrated below. The 3,4-position dehydrogenated product of each compound refers to a compound in which the bond between the 3rd and 4th positions of the carbostyril skeleton is a double bond. Γ 5-[2-hydroxy-3-(4-phenyl-
1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[2-hydroxy-3-(4-phenyl-
1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-[2-hydroxy-3-(4-phenyl-
1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-5-[2-hydroxy-3-(4
-Phenyl-1-piperidyl)propoxy]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 1-methyl-7-[2-hydroxy-3-(4
-Phenyl-1-piperidyl)propoxy-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 1-methyl-8-[2-hydroxy-3-(4
-Phenyl-1-piperidyl)propoxy]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 1-allyl-5-[2-hydroxy-3-(4
-Phenyl-1-piperidyl)propoxy]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 1-allyl-7-[2-hydroxy-3-(4
-Phenyl-1-piperidyl)propoxy]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 1-benzyl-5-[2-hydroxy-3-
(4-phenyl-1-piperidyl)propoxy]
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-(4-phenylbutyl)-6-[2-hydroxy-3-(4-phenyl-1-piperidyl)
Propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-7-[2-hydroxy-3-
(4-phenyl-1-piperidyl)propoxy]
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-propargyl-5-[2-hydroxy-
3-(4-phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-propargyl-7-[2-hydroxy-
3-(4-phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-chloro-5-[2-hydroxy-3-(4
-Phenyl-1-piperidyl)propoxy]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated product Γ 1-methyl-5-bromo-6-[2-hydroxy-3-(4-phenyl-1-piperidyl)
Propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-furor-7-[2-hydroxy-3-(4
-Phenyl-1-piperidyl)propoxy]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated product Γ 1-benzyl-5-chloro-8-[2-hydroxy-3-(4-phenyl-1-piperidyl)
propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6,8-dichloro-5-[2-hydroxy-
3-(4-phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-chloro-8-bromo-7-[2-hydroxy-3-( 4-phenyl-1-piperidyl)
Propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-Methyl-5,6-dibromo-8-[2-
Hydroxy-3-(4-phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[2-hydroxy-3-(4-benzyl-
1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-[2-hydroxy-3-(4-benzyl-
1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-[2-hydroxy-3-(4-benzyl-
1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-5-[2-hydroxy-3-
(4-benzyl-1-piperidyl)propoxy]
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-[2-hydroxy-3-(4-benzyl-
1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-5-[2-hydroxy-3-(4
-benzyl-1-piperidyl)propoxy]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 1-methyl-7-[2-hydroxy-3-(4
-benzyl-1-piperidyl)propoxy]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 1-propargyl-7-[2-hydroxy-
3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-allyl-5-[2-hydroxy-3-(4
-benzyl-1-piperidyl)propoxy]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 8-bromo-5-[2-hydroxy-3-(4
-benzyl-1-piperidyl)propoxy]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated product Γ 1-methyl-6-chloro-7-[2-hydroxy-3-(4-benzyl-1-piperazyl)
propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-6,8-dichloro-5-[2
-Hydroxy-3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 1-allyl-6-chloro-7-[2-hydroxy- 3-(4-benzyl-1-piperidyl)
propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6,8-dibromo-5-[2-hydroxy-
3-(4-benzyl-1-piperazyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{2-hydroxy-3-[4-(2-phenylethyl)- 1-piperidyl)propoxy]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 1-methyl-7-{2-hydroxy-3-[4
-(1-phenylethyl)-1-piperazyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 1-benzyl-5-{2-hydroxy-3-
[4-(4-phenylbutyl)-1-piperazyl)
Propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 5-(4-benzyl-1-piperidylmethoxy)-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation Body Γ 5-[2-(4-benzyl-1-piperidyl)
Ethoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-[2-(4-benzyl-1-piperidyl)
Ethoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-[3-(4-benzyl-1-piperidyl)
Propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[3-(4-benzyl-1-piperidyl)
Propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-[3-(4-benzyl-1-piperidyl)
Propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-[3-(4-benzyl-1-piperidyl)
Propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-[4-(4-benzyl-1-piperidyl)
butoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-[5-(4-benzyl 1-1 piperidyl)
Pentyloxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-[6-(4-benzyl-1-piperidyl)
1-Methyl-5-[3-(4-benzyl-1-
1-Methyl-7-[3-(4-benzyl-1-
1-hexyl-7-[3-(4-benzyl-1)
1-allyl-5-[3-(4-benzyl-1-
1-allyl-7-[3-(4-benzyl-1-
1-(1-methylallyl)-7-[3-(4-benzyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
Dehydrogenated product Γ 1-propargyl-7-[3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 1-propargyl-5- [3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-5-[3-(4-benzyl-1
1-(4-phenylbutyl)-7-[3-(4-
benzyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
Position dehydrogenation product Γ 1-benzyl-7-[3-(4-benzyl-1
-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{3-[4-(2-phenylethyl)-1-
piperidyl]propoxy}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{4-[2-(2-phenylethyl)-1-
piperidyl]propoxy}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-5-{3-[4-(2-phenylethyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated product Γ 1-benzyl-7-{3-[4-(1-phenylethyl)-1-piperidyl)propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated product Γ 1-methyl-5-{3-[4-(4-phenylbutyl)-1-piperidyl]propoxy}-3,
4-dihydrocarbostyryl and its 3,4-
Position dehydrogenation product Γ 1-methyl-7-{3-[4-(6-phenylhexyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 8-bromo-5-[3-(4-benzyl-1-
1-methyl-5-bromo-6-[3-(4-benzyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
position dehydrogenate Γ 6-furor-7-[3-(4-benzyl-1-
1-benzyl-6-chloro-5-[2-(4-
benzyl-1-piperidyl)ethoxy]-3,
4-dihydrocarbostyryl and its 3,4-
position dehydrogenate Γ 1-benzyl-5-chloro-8-[3-(4-
benzyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
position dehydrogenate Γ 1-benzyl-6-chloro-7-[2-(4-
benzyl-1-piperidyl)ethoxy]-3,
4-dihydrocarbostyryl and its 3,4-
Dehydrogenated product Γ 6,8-dichloro-5-[3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 6-chloro- 8-bromo-7-[3-(4-benzyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
Dehydrogenated product Γ 5-[3-(4-phenyl-1-piperidyl)
Propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[3-(4-phenyl-1-piperidyl)
Propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-[3-(4-phenyl-1-piperidyl)
Propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-[3-(4-phenyl-1-piperidyl)
Propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-Methyl-5-[3-(4-phenyl-1-
1-benzyl-7-[3-(4-phenyl-1)
1-benzyl-5-[3-(4-phenyl-1
1-Methyl-7-[3-(4-phenyl-1-
1-propargyl-7-[3-(4-phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ Styryl and its 3,4-dehydrogenated product Γ 1-benzyl-6-chloro-5-[3-(4-
phenyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
Dehydrogenated product Γ 6,8-dichloro-5-[3-(4-phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ 1-benzyl- 6,8-dichloro-5-[3
-(4-phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-6-chloro-7-[3-(4-phenyl-1 -piperidyl)propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
Dehydrogenated product Γ 1-hexyl-7-[3-(4-phenyl-1
1-(3-phenylpropyl)-7-[3-(4
-Phenyl-1-piperidyl)propoxy]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 5-[2-methyl-3-(4-benzyl-1-
7-[2-methyl-3-(4-benzyl-1-
7-[2,2-dimethyl-3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenated product Γ Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-5-[2-methyl-3-(4-benzyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
position dehydrogenate Γ 1-benzyl-7-[2-methyl-3-(4-
benzyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
Position dehydrogenation product Γ 5-[2-methyl-(4-phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 7-[2-methyl-( 4-phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-5-[2-methyl-3-(4-phenyl-1-piperidyl) ) propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
position dehydrogenate Γ 1-benzyl-7-[2-methyl-3-(4-
phenyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
Position dehydrogenation product Γ 1-chloro-5-[2-methyl-3-(4-phenyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
position dehydrogenate Γ 4-methyl-5-[3-(4-benzyl-1-
4-Methyl-6-[3-(4-benzyl-1-
4-Methyl-7-[3-(4-benzyl-1-
1,4-dimethyl-5-[3-(4-benzyl-1-piperidyl)propoxy]-3,4- Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-4-methyl-7-[3-(4-
benzyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
Position dehydrogenation product Γ 4-methyl-5-[3-(4-phenyl-1-
4-Methyl-7-[3-(4-phenyl-1-
1,4-dimethyl-7-[3-(4-phenyl-1-piperidyl)propoxy]-3,4- Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 4-methyl-5-[2-hydroxy-3-(4
-benzyl-1-piperidyl)propoxy]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 1-benzyl-7-[2-hydroxy-3-
(4-benzyl-1-piperidyl)propoxy]
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1,4-dimethyl-5-[2-hydroxy-
3-(4-phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-[2-hydroxy-3-(4-phenyl-
1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenated product Γ 4-phenyl-5-[3-(4-benzyl-1
1-benzyl-4-phenyl-7-[3-(4
-benzyl-1-piperidyl)propoxy]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 1-methyl-4-phenyl-5-[3-(4-
phenyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
Position dehydrogenation product Γ 4-phenyl-7-[3-(4-phenyl-1
4-phenyl-5-[2-hydroxy-3-
(4-benzyl-1-piperidyl)propoxy]
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-4-phenyl-7-[2-hydroxy-3-(4-benzyl-1-piperidyl)
Propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 4-phenyl-7-[2-hydroxy-3-
(4-phenyl-1-piperidyl)propoxy]
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-4-phenyl-5-[2-hydroxy-3-(4-phenyl-1-piperidyl)propoxy]-3, 4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-chloro-7-{3-[4-(2,3-dimethylphenyl-1-piperidyl)propoxy}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{3-[4-(2-fluorophenyl)-1
7-{3-[4-(3-chlorophenyl)-1-
piperidyl]propoxy}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{3-[4-(4-chlorophenyl)-1-
piperidyl]propoxy}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{3-[4-(3,4-dichlorophenyl)
7-{3-[4-(2-fluorophenyl)-1
5-{3-[4-(2-methylphenyl)-1-
piperidyl]propoxy}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{3-[4-(3-ethylphenyl)-1-
7-{3-[4-(4-methylphenyl)-1-
piperidyl]propoxy}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{3-[4-(2,3-dimethylphenyl)
5-{3-[4-(4-methoxyphenyl)-1
7-{3-[4-(2-ethoxyphenyl)-1
8-{3-[4-(3-methoxyphenyl)-1
8-{3-[4-(3-methoxyphenyl)-1
-piperidyl]propoxy}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{3-[4-(3,4-dimethoxyphenyl)-1-piperidyl]propoxy}-3 ,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{3-[4-(3,4,5-trimethoxyphenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 7-{3-[4-(2-chlorophenyl)-1-
5-{3-[4-(4-fluorophenyl)-1
5-{3-[4-(3-methylphenyl)-1-
7-{3-[4-(2-methoxyphenyl)-1
-piperidyl]propoxy}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{2-hydroxy-3-[4-(2-fluorophenyl)-1-piperidyl]propoxy}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{2-hydroxy-3-[4-(4-chlorophenyl-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated product Γ 7-{2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperidyl]propoxy}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{2-hydroxy-3-[4-(3,4,
5-trimethoxyphenyl)-1-piperidyl]
propoxy}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{2-hydroxy-3-[4-(2-methylphenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 7-{2-hydroxy-3-[4-(2,3-
7-{2-hydroxy-3-[4-(3-methylphenyl)-1- Piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated product Γ 4-methyl-7-{3-[4-(2-chlorophenyl)-1-piperidyl]propoxy}-3,
4-dihydrocarbostyryl and its 3,4-
Position dehydrogenation product Γ 4-methyl-5-{3-[4-(3-methoxyphenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 4-methyl-7-{2-hydroxy-3-[4
-(2-methoxyphenyl)-1-piperidyl]
5-{3-[4-(2-fluorophenyl)-1
7-{3-[4-(4-fluorophenyl)-1
5-{3-[4-(3-methylphenyl)-1-
7-{3-[4-(3-methoxyphenyl)-1
-piperidyl]propoxy}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{2-hydroxy-3-[4-(2-fluorophenyl)-1-piperidyl]propoxy}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperidyl]propoxy}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{2-hydroxy-3-[4-(3-chlorophenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenase Γ 4-phenyl-1-[3-(2-oxo 1,
2,3,4-tetrahydroquinolin-7-yloxy)propyl]-1-methylpiperidinium iodide Γ 4-phenyl-1-[3-(2-oxo 1,
2,3,4-tetrahydroquinolin-5-yloxy)propyl]-1-methylpiperidinium iodide Γ 4-phenyl-1-[3-(1-methyl-2-
Oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)propyl]-1-methylpiperidinium iodide Γ 4-phenyl-1-[3-(1-allyl-2-
Oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)propyl]-1-methylpiperidinium iodide Γ 4-phenyl-1-[3-(1-benzyl-2
-oxo1,2,3,4-tetrahydroquinolin-5-yloxy)propyl]-1-ethylpiperidinium chloride. Γ 4-phenyl-1-[3-(1-propargyl-2-oxo-1,2,3,4-tetrahydroquinolin-5-yloxy)propyl]-1-
Methylpiperidinium chloride Γ 4-phenyl-1-[3-(6-chloro-2-
Oxo 1,2,3,4-tetrahydroquinolin-7-yloxy)propyl]-1-methylpiperidinium chloride Γ 4-(2-fluorophenyl)-1-[3-(2
-oxo1,2,3,4-tetrahydroquinolin-5-yloxy)propyl]-1-methylpiperidinium chloride Γ 4-(3-chlorophenyl)-1-[3-(2-
Oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)propyl]-1-methylpiperidinium iodide Γ 4-(3,4-dichlorophenyl)-1-[3
-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)propyl]-1
-Methylpiperidinium iodide Γ 4-(2-methylphenyl)-1-[3-(2-
Oxo 1,2,3,4-tetrahydroquinolin-7-yloxy)propyl]-1-methylpiperidinium iodide Γ 4-(4-methylphenyl)-1-[3-(2-
Oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)propyl]-1-methylpiperidinium iodide Γ 4-(2,3-dimethylphenyl)-1-[3
-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)propyl]-1
-Methylpiperidinium chloride Γ 4-(4-methoxyphenyl)-1-[3-(2
-oxo 1,2,3,4-tetrahydroquinolin-5-yloxy)propyl]-1-methylpiperidinium chloride Γ 4-(2-methoxyphenyl)-1-[3-(2
-oxo 1,2,3,4-tetrahydroquinolin-7-yloxy)propyl]-1-methylpiperidinium iodide Γ 4-(3,4-dimethoxyenyl)-1-[3
-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)propyl]-1
-Methylpiperidinium iodide Γ 4-(3,4,5-trimethoxyphenyl)-
1-[3-(2-oxo 1,2,3,4-tetrahydroquinolin-7-yloxy)propyl]-1-methylpiperidinium chloride Γ 4-benzyl-1-[3-(2-oxo 1,
2,3,4-tetrahydroquinolin-5-yloxy)propyl]-1-methylpiperidinium iodide Γ 4-benzyl-1-[3-(2-oxo 1,
2,3,4-tetrahydroquinolin-7-yloxy)propyl]-1-methylpiperidinium chloride Γ 4-phenyl-1-[3-(2-oxo 1,
2-dihydroquinolin-7-yloxy)propyl]-1-methylpiperidinium iodide Γ 4-(4-fluorophenyl)-1-[3-(2
-oxo1,2-dihydroquinolin-7-yloxy)propyl]-1-methylpiperidinium iodide Γ 4-(3-methylphenyl)-1-[3-(2-
Oxo-1,2-dihydroquinolin-5-yloxy)propyl]-1-methylpiperidinium iodide Γ 4-(3-methoxyphenyl)-1-[3-(2
-oxo1,2-dihydroquinolin-7-yloxy)propyl]-1-methylpiperidinium chloride Γ 4-benzyl-1-[3-(2-oxo1,
2-dihydroquinolin-7-yloxy)propyl]-1-methylpiperidinium iodide Γ 4-phenyl-1-[2-hydroxy-3-
(2-oxo-1,2,3,4-tetrahydroquinolin-5-yloxy)propyl]-1-
Methylpiperidinium iodide Γ 4-phenyl-1-[2-hydroxy-3-
(2-oxo1,2,3,4-tetrahydroquinolin-7-yloxy)propyl]-1-
Methylpiperidinium chloride Γ 4-phenyl-1-[2-hydroxy-3-
(1-methyl-2-oxo 1,2,3,4-
Tetrahydroquinolin-7-yloxy)propyl]-1-methylpiperidinium iodide Γ 4-phenyl-1-[2-hydroxy-3-
(1-benzyl-2-oxo 1,2,3,4
-tetrahydroquinolin-5-yloxy)propyl]-1-methylpiperidinium iodide Γ 4-phenyl-1-[2-hydroxy-3-
(6-chloro-2-oxo 1,2,3,4-
Tetrahydroquinolin-7-yloxy)propyl]-1-methylpiperidinium iodide Γ 4-phenyl-1-[2-hydroxy-3-
(6,8-dibromo-2-oxo 1,2,3,
4-tetrahydroquinolin-5-yloxy)
propyl]-1-methylpiperidinium chloride Γ 4-(2-fluorophenyl)-1-[2-hydroxy-3-(2-oxo 1,2,3,4
-tetrahydroquinolin-5-yloxy)propyl]-1-methylpiperidinium iodide Γ 4-(2-methoxyphenyl)-1-[2-hydroxy-3-(2-oxo 1,2,3,4
-tetrahydroquinolin-7-yloxy)propyl]-1-methylpiperidinium chloride Γ 4-(2,3-dimethylphenyl)-1-[2
-Hydroxy-3-(2-oxo 1,2,3,
4-tetrahydroquinolin-7-yloxy)
propyl]-1-methylpiperidinium chloride Γ 4-(3-chlorophenyl)-1-[2-hydroxy-3-(2-oxo-1,2-dihydroquinolin-7-yloxy)propyl]-1-
Methylpiperidinium iodide Γ 4-(4-methoxyphenyl)-1-[2-hydroxy-3-(2-oxo-1,2-dihydroquinolin-5-yloxy)propyl]-1
-Methylpiperidinium iodide Γ 4-(2-methylphenyl)-1-[2-hydroxy-3-(2-oxo-1,2-dihydroquinolin-7-yloxy)propyl]-1-
Methylpiperidinium iodide Γ 4-hydroxy-4-phenyl-1-[2-
Hydroxy-3-(2-oxo 1,2,3,
4-tetrahydroquinolin-5-yloxy)
propyl]-1-methylpiperidinium iodide Γ 4-acetyl-4-phenyl-1-[3-(2
-Oxo-1,2,3,4-tetrahydroquinolin-5-yloxy)propyl]-1-methylpiperidinium iodide Γ 4-hydroxy-4-phenyl-1-[2-
Hydroxy-3-(2-oxo 1,2,3,
4-tetrahydroquinolin-7-yloxy)
propyl]-1-methylpiperidinium iodide Γ 4-acetyl-4-phenyl-1-[3-(2
-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)propyl]-1-methylpiperidinium iodide Γ 5-[3-(5-phenyl-7-ethyl-1,
5,7-triazaspiro[4,5]-decane-
8-one-1-yl)proxy]3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ5-[3-(5-phenyl-7-isopropyl-1,5,7-triazaspiro] 4,5]-decane-8-one-1-yl)propoxy]3,
4-dihydrocarbostyryl and its 3,4-
Dehydrogenated product Γ 5-[3-(5-phenyl-7-butyl-1,
5,7-triazaspiro[4,5]-decane-
8-one-1-yl)propoxy]3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-[3-(5-phenyl-7-pentyl-
1,5,7-triazaspiro[4,5]-decane-8-one-1-yl)propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
Dehydrogenated product Γ 5-[3-(5-phenyl-7-hexyl-
1,5,7-triazaspiro[4,5]-decane-8-one-1-yl)propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
Dehydrogenated product Γ 6-[3-(5-phenyl-7-ethyl-1,
5,7-triazaspiro[4,5]-decane-
8-one-1-yl)propoxy]-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[3-(5-phenyl-7-isopropyl-1,5,7-triazaspiro[4,5]-decan-8-one-1-yl) ) propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
position dehydrogenate Γ 6-[3-(5-phenyl-7-butyl-1,
5,7-triazaspiro[4,5]-decane-
8-one-1-yl)propoxy]-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[3-(5-phenyl-7-pentyl-
1,5,7-triazaspiro[4,5]-decane-8-one-1-yl)propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
Dehydrogenated product Γ 6-[3-(5-phenyl-7-hexyl-
1,5,7-triazaspiro[4,5]-decane-8-one-1-yl)propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
Dehydrogenated product Γ 7-[3-(5-phenyl-7-ethyl-1,
5,7-triazaspiro[4,5]-decane-
8-one-1-yl)propoxy]-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-[3-(5-phenyl-7-isopropyl-1,5,7-triazaspiro[4,5]-decan-8-one-1-yl) ) propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
Dehydrogenated product Γ 7-[3-(5-phenyl-7-butyl-1,
5,7-triazaspiro[4,5]-decane-
8-one-1-yl)propoxy]-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-[3-(5-phenyl-7-pentyl-
1,5,7-triazaspiro[4,5]-decane-8-one-1-yl)propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
position dehydrogenate Γ 7-[3-(5-phenyl-7-hexyl-
1,5,7-triazaspiro[4,5]-decane-8-one-1-yl)propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
Dehydrogenated product Γ 8-[3-(5-phenyl-7-ethyl-1,
5,7-triazaspiro[4,5]-decane-
8-one-1-yl)propoxy]-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-[3-(5-phenyl-7-isopropyl-1,5,7-triazaspiro[4,5]-decan-8-one-1-yl) ) propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
Dehydrogenated product Γ 8-[3-(5-phenyl-7-butyl-1,
5,7-triazaspiro[4,5]-decane-
8-one-1-yl)propoxy]-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-[3-(5-phenyl-7-pentyl-
1,5,7-triazaspiro[4,5]-decane-8-one-1-yl)propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
Dehydrogenated product Γ 8-[3-(5-phenyl-7-hexyl-
1,5,7-triazaspiro[4,5]-decane-8-one-1-yl)propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
Dehydrogenated product Γ 5-[3-(4-hydroxy-4-phenyl-
1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-[3-(4-hydroxy-4-(4-chlorophenyl-1-piperidyl)propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated product Γ 5-{3-[4-hydroxy-4-(4-fluorophenyl-1-piperidyl]propoxy}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{3-[4-hydroxy-4-(2-fluorophenyl)-1-piperidyl]propoxy}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{3-[4-hydroxy-4-(2-chlorophenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated product Γ 5-{3-[4-hydroxy-4-(3-chlorophenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated product Γ 5-{3-[4-hydroxy-4-(4-bromphenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 5-{3-[4-hydroxy-4-(2,6-
dichlorophenyl)-1-piperidyl]propoxy}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{3-[4-hydroxy-4-(3-fluorophenyl)-1- Piperidyl [Propoxy]
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{3-[4-hydroxy-4-(3-bromphenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated product Γ 5-{3-[4-hydroxy-4-(2-bromphenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated product Γ 5-{3-[4-hydroxy-4-(4-iodophenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenase Γ 5-[3-(5-phenyl-1,5,7-triazaspiro[4,5]-decane-8-one-1
1-methyl-5-[3-(5-phenyl-7-
Methyl-1,5,7-triazaspiro[4,
5]-decane-8-one-1-yl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenated product Γ 1-benzyl-5-[3-(5-phenyl-7
5- 1-(4-hydroxy-4-phenyl-
1-piperidyl]methoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-[2-(4-hydroxy-4-phenyl-
1-piperidyl)ethoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenated product Γ 5-[3-(4-acetyl-4-phenyl-1
5-[3-(4-propionyl-4-phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ Carbostyryl and its 3,4-position dehydrogenation Γ 5-[3-(4-hexanoyl-4-phenyl-1-piperidyl]propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation Body Γ 1-benzyl-5[2-(4-hydroxy-4
-phenyl-1-piperidyl)ethoxy]-3,
4-dihydrocarbostyryl and its 3,4-
Position dehydrogenate Γ 5-[4-(4-hydroxy-4-phenyl-
1-piperidyl)butoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-[3-(4-hydroxy-4-phenyl-
1-piperidyl]propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{3-[4-hydroxy-4-(4-chlorophenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 6-{3-[4-hydroxy-4-(4-fluorophenyl)-1-piperidyl]propoxy}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{3-[4-hydroxy-4-(2-fluorophenyl)-1-piperidyl]propoxy}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{3-[4-hydroxy-4-(2-chlorophenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated product Γ 6-{3-[4-hydroxy-4-(3-chlorophenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 6-{3-[4-hydroxy-4-(4-bromphenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 6-{3-[4-hydroxy-4-(2,6-
dichlorophenyl)-1-piperidyl]propoxy}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{3-[4-hydroxy-4-(3-fluorophenyl)-1- Piperidyl [Propoxy]
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6-{3-[4-hydroxy-4-(3-bromphenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 6-{3-[4-hydroxy-4-(2-bromphenyl)-1-piperidyl]propoxy]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated product Γ 6-{3-[4-hydroxy-4-(4-iodophenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenase Γ 6-[3-(5-phenyl-1,5,7-triazaspiro[4,5]-decane-8-one-1
6-[3-(4-acetyl-4-phenyl-1)
6-[3-(4-propionyl-4-phenyl-1-piperidyl]propoxy]-3,4-dihydro Carbostyryl and its 3,4-position dehydrogenation product Γ 6-[3-[4-hexanoyl-4-phenyl-1-piperidyl]propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation Body Γ 7-[3-(4-hydroxy-4-phenyl-
1-piperidyl]propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{3-[4-hydroxy-4-(4-chlorophenyl)-1-piperidyl]propoxy]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated product Γ 7-{3-[4-hydroxy-4-(4-fluorophenyl)-1-piperidyl]propoxy}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{3-[4-hydroxy-4-(2-fluorophenyl)-1-piperidyl]propoxy}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{3-[4-hydroxy-4-(2-chlorophenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated product Γ 7-{3-[4-hydroxy-4-(3-chlorophenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated product Γ 7-{3-[4-hydroxy-4-(4-bromphenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 6-[2-(4-acetyl-4-phenyl-1
7-{3-[4-hydroxy-4-(2,6-
dichlorophenyl)-1-piperidyl]propoxy}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{3-[4-hydroxy-4-(3-fluorophenyl)-1- Piperidyl [Propoxy]
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-{3-[4-hydroxy-4-(3-bromphenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated product Γ 7-{3-[4-hydroxy-4-(2-bromphenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 7-{3-[4-hydroxy-4-(4-iodophenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 7-[3-(5-phenyl 1,5,7-triazaspiro[4,5]-decane-8-one-1-
propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenated product Γ 1-methyl-7-[3-(5-phenyl-7-
Methyl-1,5,7-triazaspiro[4,
5]-Decan-8-one-1-yl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-[3-(4-hydroxy-4-phenyl-
1-piperidyl]propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-{3-[4-hydroxy-4-(4-chlorophenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated product Γ 8-{3-[4-hydroxy-4-(4-fluorophenyl)-1-piperidyl]propoxy}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-{3-[4-hydroxy-4-(2-fluorophenyl)-1-piperidyl]propoxy}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-{3-[4-hydroxy-4-(2-chlorophenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated product Γ 8-{3-[4-hydroxy-4-(3-chlorophenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated product Γ 8-{3-[4-hydroxy-4-(4-bromphenyl)-1-piperidyl]propoxy]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 7-[3-(4-acetyl-4-phenyl-1
7-[3-[4-propionyl-4-phenyl-1-piperidyl]propoxy]-3,4-dihydro Carbostyryl and its 3,4-position dehydrogenation product Γ 7-[3-(4-hexanoyl-4-phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation Body Γ 7-[2-(4-hydroxy-4-phenyl-
1-piperidyl]ethoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-[6-(4-hydroxy-4-phenyl-
1-piperidyl]hexyloxy]-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-{3-[4-hydroxy-4-(2,6-
dichlorophenyl)-1-piperidyl]propoxy}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-{3-[4-hydroxy-4-(3-fluorophenyl)-1- Piperidyl Propoxy
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-{3-[4-hydroxy-4-(3-bromphenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 8-{3-[4-hydroxy-4-(2-bromphenyl)-1-piperidyl]propoxy]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated product Γ 8-{3-[4-hydroxy-4-(4-iodophenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 8-[3-(5-phenyl-1,5,7-triazaspiro[4,5]-decane-8-one-1
8-[3-(4-acetyl-4-phenyl-1)
8-[3-(4-propionyl-4-phenyl-1-piperidyl]propoxy]-3,4-dihydro Carbostyryl and its 3,4-position dehydrogenation product Γ 8-[3-(4-hexanoyl-4-phenyl-1-piperidyl]propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation Body Γ 7-{2-hydroxy-3-[4-acetyl-
4-phenyl-1-piperidyl propoxy
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8-[2-hydroxy-3-(4-acetyl-
4-phenyl-1-piperidyl propoxy
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{2-hydroxy-3-[4-hydroxy-(4-chlorophenyl)-1-piperidyl]propoxy}-3,4- Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-5-[2-hydroxy-3-
(4-hydroxy-4-phenyl-1-piperidyl]propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenated product Γ 6-{2-hydroxy-3-[4-acetyl-
4-(3-methoxyphenyl)-1-piperidyl]propoxy}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-{2-hydroxy-3-[4-acetyl-
4-(2,3-dimethylphenyl)-1-piperidyl)propoxy}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase −
4-phenyl-1-piperidyl propoxy
-4-Methyl-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 7-[2-hydroxy-3-(4-acetyl-
4-phenyl-1-piperidyl propoxy
-4-phenyl-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-[2-hydroxy-3-(4-hydroxy-4-phenyl-1-piperidyl]propoxy]-3, 4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-[3-(4-hydroxy-4-phenyl-
1-piperidyl)propoxy]-4-methyl-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 7-[3-(4-acetyl-4-phenyl-1
-piperidyl)propoxy]-4-phenyl-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 5-[2-hydroxy-3-(4-acetyl-
4-phenyl-1-piperidyl)propoxy]
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-5-[2-hydroxy-3-(4
-acetyl-4-phenyl-1-piperidyl)
Propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-benzyl-7-[2-hydroxy-3-
(4-acetyl-4-phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl-5-[2-hydroxy-3-(4
-hydroxy-4-phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ 5-[3-hydroxy-4-(4-acetyl-
4-phenyl-1-piperidyl)butoxy]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 7-[2-hydroxy-4-(4-hydroxy-4-phenyl-1-piperidyl)butoxy]
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 5-[2-hydroxy-3-(5-phenyl-
7-Ethyl-1,5,7-triazaspiro[4,5]-decan-8-one-1-yl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 6- [2-hydroxy-3-(5-phenyl-
7-Butyl-1,5,7-triazaspiro[4,5]-decan-8-one-1-yl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 8- [2-hydroxy-3-(5-phenyl-
5- {2-hydroxy-3-[4-hydroxy-4-(2,6-dichlorophenyl)-1-piperidyl]propoxy}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-methyl -5-[2-hydroxy-3-(5
-Phenyl-7-methyl-1,5,7-triazaspiro[4,5]-decane-8-one-1-
1-methyl-5-[3-(4-hydroxy-4
-Phenyl-1-piperidyl)propoxy]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 1-benzyl-7-[3-(4-acetyl-4
-Phenyl-1-piperidyl)propoxy]-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ 1-allyl-5-[3-(4-acetyl-4-
Phenyl 1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
Position dehydrogenation product Γ 1-propynyl-7-[3-(4-hydroxy-4-phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ 1- (4-phenylbutyl)-5-[3-(4-
Hydroxy-4-phenyl-1-piperidyl]
Propoxy]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ 1-Butyl-7-[3-(4-acetyl-4-
phenyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl and its 3,4-
Position dehydrogenation product Γ 1-crotyl-7-[3-(4-hydroxy-
4-phenyl-1-piperidyl)propoxy]
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate The compounds of the present invention can be produced by various methods. Specifically, it can be produced, for example, as shown in the following reaction scheme-1. [In the formula, R ¹ , R ² , R ³ , R ⁴ , X, Y, n and the carbon-carbon bonds between the 3rd and 4th positions of the carbostyl skeleton are the same as above. X ¹ represents a halogen atom. ] That is, it is produced by reacting a compound represented by general formula [2] with a known piperidine derivative represented by general formula [3]. The above reaction is
Without solvent or in a common inert solvent, from room temperature to 200
The process is completed in several hours to 24 hours at a temperature of about 60°C to 120°C. The inert solvent is not particularly limited and can be used as long as it does not adversely affect the reaction, such as dioxane, tetrahydrofuran (THF), ethers such as ethylene glycol and dimethyl ether, and aromatic carbonized solvents such as benzene, toluene and xylene. Examples include hydrogens, lower alcohols such as methanol, ethanol, and isopropanol, and polar solvents such as dimethylformamide (DMF) and dimethyl sulfoxide (DMSO). The above reaction is more advantageously carried out using a basic compound as dehydrohalogenating agent. The basic compound is not particularly limited and a wide variety of known compounds can be used, such as potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium amide, sodium hydride, triethylamine, tripropylamine,
Examples include tertiary amines such as pyridine and quinoline. The above reaction may be carried out by adding an alkali metal iodide compound such as potassium iodide or sodium iodide 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 usually about an equimolar to an excess amount of the latter to the former, preferably an equimolar to 5 times the molar amount. , more preferably 1 to 1.2 times the mole. The compounds represented by the general formula [2] used as raw materials in the above reaction scheme -1 include novel compounds, and these can be produced, for example, by the methods shown in the following reaction schemes -2 and -3. [In the formula, R ¹ , R ² , X and the carbon-carbon bond between the 3rd and 4th positions of the carbostyryl skeleton are the same as above, R ⁵ is a lower alkyl group or a lower alkanoyl group, and n' represents 1 or 2] [In the formula, R ¹ , R ² , X ₁ , X, Y, n and the carbon-carbon bonds between the 3rd and 4th positions of the carbostyril skeleton are the same as above. X ² represents a halogen atom. ] In Reaction Scheme-2, hydroxycarbostyryls represented by the known general formula [4] are reacted with a halogenating agent, or alkoxy or alkanoyloxycarbostyryls represented by the known general formula [6] are reacted. A compound represented by general formula [5] is obtained by hydrolyzing compound [7] obtained by reacting with a halogenating agent. The above halogenation reaction uses known halogenating agents such as fluorine, chlorine, bromine, iodine, xenon difluoride, sulfuryl chloride, sodium hypochlorite, hypochlorous acid, hypobromous acid, bleaching powder, iodine chloride, etc. It can be done using The amount of ethyleneating agent can be appropriately determined depending on the number of halogen atoms introduced into the raw material compound. For example, when introducing one halogen atom, the amount is usually equimolar to excess, preferably equimolar to 1.5 times the molar amount, relative to the raw material compound.
When two halogen atoms are introduced, they may be used in an amount ranging from 2 times the mole to a large excess, preferably 2 to 3 times the mole. The above reaction is usually carried out in a suitable solvent such as water, methanol, ethanol, chloroform, carbon tetrachloride, acetic acid, etc., or a mixed solvent thereof. The reaction temperature is usually about -20°C to 100°C, preferably 0°C to room temperature. The reaction is completed within about 30 minutes to 20 hours. Furthermore, the hydrolysis reaction of the compound represented by the above general formula [7] differs slightly depending on the type of R ⁵ in the compound [7]. For example, when R ⁵ is a lower alkanoyl group, normal ester hydrolysis reaction conditions are used. You can go downstairs. Specifically, basic compounds such as sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium hydrogen carbonate, etc.
Advantageously in the presence of a mineral acid such as sulfuric acid, hydrochloric acid, or an organic acid such as acetic acid or an aromatic sulfonic acid in a conventional suitable inert solvent such as water, methanol, ethanol, acetone, dioxane, THF, benzene, etc. Can be implemented. The reaction temperature is usually about room temperature to 150°C, preferably 50 to 100°C, and the reaction is completed in about 1 to 12 hours. Further, when R ⁵ is a lower alkyl group, the hydrolysis reaction conditions may be the same as those for ordinary ether hydrolysis reaction conditions. Specifically, for example, water, methanol,
The reaction may be carried out in a suitable solvent such as ethanol, benzene, methylene chloride, chloroform, etc. at a temperature of about 0 to 200°C, preferably from room temperature to 120°C, for several hours to about 12 hours. In any hydrolysis reaction, the amount of catalyst used may be generally in excess of the raw material compound. In the reaction scheme-3, the compound represented by the general formula [8] has the general formula

By reacting the compound represented by [9], a desired compound represented by general formula [2] can be obtained. This reaction uses a basic compound as a dehydrohalogenating agent,
Room temperature to about 200℃ in an appropriate solvent, preferably 50 to
It is carried out at 150°C for several hours to about 15 hours. In the above, the appropriate solvent is not particularly limited and can be used as long as it does not adversely affect the reaction. For example, the above-mentioned lower alcohols, ethers, aromatic hydrocarbons, DMF, DMSO, etc., acetone,
Examples include ketones such as methyl ethyl ketone. The dehydrohalogenating agent is not particularly limited and a wide variety of known agents can be used, and in addition to the various basic compounds mentioned above, examples include sodium methoxide, sodium ethoxide, potassium ethoxide, potassium metal, and the like. In the above reaction, an alkali metal iodide compound such as sodium iodide or potassium iodide may be added as a reaction promoter. Compound represented by general formula [8] and general formula

The ratio of the compound represented by [9] is usually about 1 mol or more, preferably 1 to 5 mol, more preferably 1 to 1.2 mol, of the latter per 1 mol of the former. In this way, the compound represented by the general formula [2], which is used as a starting material in the present invention, is obtained. In addition, in the compounds represented by the general formulas [4], [6] and [8] used as raw materials in the above reaction schemes -2 and -3, those in which R ¹ represents a group other than a hydrogen atom include new compounds. Ru. The compound is prepared by using a known hydroxycarbostyryl in which R ¹ is a hydrogen atom as a raw material, and adding a halide having the corresponding groups to an appropriate basic compound such as an alkali metal atom such as sodium or potassium, sodium amide, potassium amide, etc. For example, benzene,
After reacting for about 30 minutes to 12 hours in a solvent such as THF, dioxane, DMSO, DMF, hexamethylphosphoric acid triamide, etc. at 0°C to 70°C, preferably 0°C to room temperature, the obtained compound is It can be easily produced by hydrolysis under the same conditions as the hydrolysis reaction of the lower alkyl group of the compound represented by the general formula [7] shown in Reaction Scheme-2. In the above reaction, the proportions of the basic compound and halide to be used relative to the raw material compounds can be appropriately determined, but are usually about 2 to 10 times the mole, preferably 2 to 4 times the mole. The compound of the present invention can also be produced by the method shown in Reaction Scheme-4 below. [In the formula, R ¹ , R ² , R ³ , R ⁴ , X, X ² , Y, n and the carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above] The compound of the present invention can be produced by reacting the hydroxycarbostyryl derivative represented by the formula [10] with a compound represented by the general formula [10]. The reaction conditions in the above method may be the same as those for the dehydrohalogenation reaction of Reaction Scheme-3 described above. Among the compounds represented by the general formula [10] used in the above reaction scheme-4, there are novel compounds. These can be easily produced, for example, by the method shown in Reaction Scheme-5 below. [In the formula, X ¹ , X ² , Y, R ³ and R ⁴ are the same as above] The above reaction is performed by combining a compound with the general formula [3] represented by the general formula [2] shown in the reaction scheme-1 described above. ]
It can be carried out under the same conditions as the reaction with the compound represented by. Furthermore, the compound represented by the general formula [1] of the present invention in which Y represents a _-CH2CH (OH) _CH2- group can also be produced by the method shown in the following reaction scheme-6. [In ^the formula, R ¹ , R ² , R ³ , R 4 X ³ is a halogen atom and Z is

【Formula】Also teeth

[Formula]] In the above reaction scheme-6, the reaction between the compound represented by the general formula [8] and the epihalogenohydrin represented by the general formula [11] can be carried out using, for example, sodium hydroxide, potassium hydroxide, carbonate, etc. Ordinary basic compounds such as inorganic basic compounds such as sodium, potassium carbonate, sodium methoxide, sodium ethoxide, sodium hydride, metallic sodium, metallic potassium, and sodium amide, and organic basic compounds such as piperidine, pyridine, and triethylamine. The reaction is carried out in the presence of a solvent, or in an appropriate inert solvent such as the aforementioned lower alcohols, ketones, ethers, aromatic hydrocarbons, water, or the like. In the reaction, the amount of the compound represented by the general formula [11] to be used is usually about an equimolar to an excess amount, preferably 5 to 10 times the molar amount of the compound represented by the general formula [8]. Reaction is from 0℃ to 150℃
The process proceeds at a temperature of approximately 50°C to 100°C. In the above reaction, the epihalogenohydrin represented by the general formula [8] reacts with the hydroxyl group of the compound represented by the general formula [11], usually giving the compound a (2,3-epoxy)propoxy group or a 3-
Provides a halogeno-2-hydroxypropoxy group. Generally, the reaction product is obtained as a mixture of these. The reaction product obtained in this way can be reacted as a mixture with the piperidine derivative represented by the general formula [3] without any particular separation and purification, or by using commonly used purification methods such as fractional recrystallization and column chromatography. A compound having 2, 3. epoxypropoxy group or a compound having 3-halogeno-2-hydroxypropoxy group is separated and purified by adapting GRAPHIE etc., and each of these is converted into piperidine represented by the general formula [3]. It can also be reacted with derivatives. Compound represented by general formula [12] and general formula [3]
The reaction with the compound represented by is carried out without solvent or in a commonly used inert solvent at room temperature to about 200°C, preferably 60 to 120°C, and usually for several hours to about 200°C.
It will be completed in about 24 hours. In the above reaction, the inert solvent is not particularly limited and can be used as long as it does not adversely affect the reaction. Examples include the aforementioned ethers, aromatic hydrocarbons, lower alcohols, DMF, DMSO, etc. can. Further, in the above reaction, a common basic compound can be added as necessary. Examples of the basic compound include inorganic basic compounds such as potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium amide, and sodium hydride, and tertiary amines such as triethylamine, tripropylamine, pyridine, and quinoline. can be exemplified. The ratio of the compound represented by the general formula [3] to the compound represented by the general formula [12] is usually about an equimolar to an excess amount, preferably an equimolar to an excessive amount.
The molar amount is most preferably about 5 times the molar amount and about 1.2 times the molar amount. Furthermore, among the carbostyril derivatives represented by the general formula [1] of the present invention, compounds in which R ¹ is a group other than a hydrogen atom can be prepared using the compound of the present invention in which R ¹ is a hydrogen atom as a starting material, and the following reaction scheme - It can also be produced by the method shown in 7. [In the formula, R ² , R ³ , R ⁴ , X, Y, n and the carbon-carbon bonds between the 3rd and 4th positions of the carbostyril skeleton are the same as above. X ⁴ represents a halogen atom, and R ¹ ' represents a lower alkenyl group, a lower alkynyl group, or a lower alkyl group that may have a phenyl group as a substituent. ] The reaction conditions in the above reaction scheme-7 are such that the compound represented by the general formula [13] is converted into the compound represented by the general formula
The compounds represented by the above-mentioned general formulas [4], [6] and [8] in which R ¹ is a hydrogen atom are , the conditions may be similar to those for reacting halides having corresponding groups. Further, among the carbostyril derivatives represented by the general formula [1] of the present invention, 3 of the carbostyril skeleton
A compound in which the carbon-carbon bond between position and 4-position is a double bond can also be obtained by dehydrogenating a compound in which the above bond is a single bond, and conversely, a compound in which the above bond is a single bond can be obtained by dehydrogenating a compound in which the above bond is a single bond. can also be obtained by subjecting a compound in which the above bond is a double bond to a catalytic reduction reaction. However, in the latter case, it is inappropriate to use a compound having a halogen atom, lower alkenyl group or lower alkynyl group as a substituent. Furthermore, among the compounds of the present invention represented by the general formula [1], Y is a group.

The compound represented by the formula can also be produced by the method shown in Reaction Scheme-8 below. [In the formula, R ¹ , R ² , R ³ , R ⁴ , X ³ , n, Z and the carbon-carbon bonds between the 3- and 4-positions of the carbostyril skeleton are the same as above. ] In the above reaction scheme-8, the reaction between the compound of general formula [11] and the compound of general formula [3] is the same as the reaction between the compound of general formula [11] and the compound of general formula [8]. The reaction between the compound of general formula [14] and the compound of general formula [8] can be carried out under the same conditions as the reaction between the compound of general formula [12] and the compound of general formula [3]. It can be carried out under certain conditions. The carbostyril derivative produced in this way is
It can be easily converted into an acid addition salt by the action of a pharmaceutically acceptable acid, and the present invention also includes this acid addition salt. Examples of acids in the above include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, acetic acid, oxalic acid, succinic acid, maleic acid, fural acid, malic acid, tartaric acid, citric acid, malonic acid, and methanesulfonic acid. Organic acids such as acid, benbroic acid, etc. can be used. Further, among the compounds of the present invention, compounds in which the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are double bonds include, for example, bases such as metal hydroxides such as potassium hydroxide, sodium hydroxide, and calcium hydroxide. It can be easily converted into a salt by reacting with a chemical compound, and the present invention also includes this salt. Furthermore, the carbostyril derivative represented by the general formula [1] can be prepared by reacting the nitrogen atom of the piperidine ring with a lower alkyl halide.
It can also become a quaternary salt as shown in reaction scheme-9 below. [In the formula, R ⁶ represents a lower alkyl group, and Q represents a halogen atom. R ¹ , R ² , R ³ .R ⁴ , X, Y,
The carbon-carbon bonds between n and the 3rd and 4th positions of the carbostyril skeleton are the same as above. ] The above reaction is advantageously carried out in a suitable inert solvent. Examples of the solvent include lower alcohols such as methanol, ethanol, and propanol, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as tetrahydrofuran and dioxane, chloroform, trichloroethylene,
Examples include DMF, DMSO, hexametaphosphoric acid triamide, and the like. The amount of the compound represented by the general formula [15] to be used is usually at least an equimolar amount, preferably an equimolar to 5 times the molar amount of the compound represented by the general formula [1]. The reaction temperature is usually about 0 to 200°C, preferably room temperature to 80°C,
The reaction is completed in about 1 to 8 hours. When Q in the compound represented by the general formula [1e] produced by the above reaction scheme-9 is a halogen atom with a valence number larger than that of a chlorine atom, Q can be reduced by reacting silver chloride with the compound. It can be converted into a compound that is a chlorine atom. Similarly, a compound in which Q is a halogen atom having a valence number higher than that of a bromine atom can be converted into a compound in which Q is a bromine atom by reacting it with silver bromide. These conversion reactions of halogen atoms can be advantageously carried out using, for example, the above-mentioned lower alcohols, DMF, DMSO, or water as a solvent. The amount of silver halide used is at least equimolar to the raw material compound, preferably equimolar to 6 times the molar amount, and the reaction is 0 to 80 molar.
The reaction is carried out at a temperature of about 50° C., preferably from room temperature to 50° C., for about 5 to 24 hours. 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 the compound of the present invention represented by the general formula [1] and its salt is used as an antihistamine, it is usually put into the form of a pharmaceutical composition together with a pharmaceutical carrier. As carriers, diluents or excipients such as fillers, extenders, binders, humectants, disintegrating agents, surfactants, and lubricants that are commonly used to prepare drugs according to the usage form can be used. can be exemplified. Various dosage unit forms of antihistamines can be selected depending on the therapeutic purpose, and representative examples include tablets, pills, powders, liquids, suspensions,
Examples include emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.), ointments, and the like. When forming tablets, carriers include excipients such as lactose, sucrose, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid, water, ethanol, propanol, and simple syrup. , glucose, starch solution, gelatin solution, proboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binder such as polyvinylpyrrolidone, dried starch, sodium alginate, agar powder, laminaria powder, sodium bicarbonate, calcium carbonate, twine, lauryl Disintegrants such as sodium sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc., absorption enhancers such as quaternary ammonium bases, sodium lauryl sulfate, glycerin, starch, etc. Humectants such as starch, lactose, kaolin, bentonite, adsorbents such as colloidal silicic acid, lubricants such as purified talc, stearate, boric acid powder, macrogol, solid polyethylene glycol, etc. can be used. Furthermore, tablets can be obtained as tablets with conventional coatings, 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 pill form, carriers include excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc, binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol, and laminaria. , agar, etc. can be used. When forming into a suppository, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc. can be used as carriers. Injectables are preferably sterilized and isotonic with blood, and when forming into solutions, emulsions, and suspensions suitable for injectables, diluents such as water, ethyl alcohol, propylene glycol, Ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, etc. can be used. In this case, the injection 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, colorants, preservatives, fragrances, flavoring agents, sweeteners, and other pharmaceuticals may be included in the injection, if necessary. When forming pastes, creams and gels, diluents such as white petrolatum,
Paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicon, bentonite, etc. can be used. The amount of the compound of general formula [1] or its salt to be contained in the antihistamine agent of the present invention is not particularly limited and is appropriately selected from a wide range, but it is usually 1 to 70% by weight based on the total composition. . In addition, the antihistamines mentioned above are administered in various ways depending on the form; for example, in the case of tablets, pills, solutions, suspensions, emulsions, granules, and capsules, they are administered orally, and in the case of injections, they are administered alone. Alternatively, it can be administered intravenously mixed with normal replacement fluids such as glucose and amino acids, and if necessary, it can be administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally, and in the case of suppositories, it can be administered rectally. It can be applied as an ointment. The dosage of the anti-staminic agent of the present invention is determined based on the intended use,
A pharmaceutical composition containing approximately 40 μg to 2 mg/Kg of the compound of general formula [1] or its salt per day may be administered in 3 to 4 doses, which is selected as appropriate depending on the symptoms and the like. Pharmacological Tests A method using isolated guinea pig ileum is generally accepted as a typical method for measuring antihistamine effects in vitro. This test was conducted as follows according to the above method. i.e. weight 300
~500 g of male guinea pigs were killed by exsanguination, and the ileum 15 cm proximal to the ileocecal region was removed and treated with 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 , 1.0 g of NaHCO 3 ). ₂ PO ₄・2H ₂ O0.065
g and MgCl ₂・6H ₂ O0.2135g and add water to
(1000ml). Next, the tissue is 2.5~
Cut into 3.0 cm pieces and suspend in a bath filled with 30 ml of Tyrode's solution. Keep the bath at 36°C, 5% _CO2 and _0.295°C .
% gas mixture. Histamine 10 ^-6 M after 10 minutes
to determine tissue sensitivity and obtain a dose-response curve (control) with histamine. control dose-test compound after the response has stabilized.
A dose-response curve is obtained by administering 10 ^-6 g/ml and administering histamine again 5 minutes later. Contractions are recorded on a pen recorder via an isotonic transducer (Nihon Kohden TD-112S). The maximum contraction of control histamine was taken as 100%, and Van Rossam's method [JMVan Rossam, Arch.Int.
Rharmacodyn., 143, 299 (1963)],
Calculate PA ₂ . The results obtained are shown in Table 1 below. Test compound Compound No. 15-[3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl 21-methyl-7-[3-(4-benzyl-1-piperidyl)propoxy] -3,4-dihydrocarbostyryl 1-oxalate 31-propargyl-5-[3-(4-benzyl-
1-Piperidyl)propoxy]-3,4-dihydrocarbostyryl monohydrochloride monohydrate 41-Methyl-5-[3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl Styryl monohydrochloride 54-Methyl-7-[3-(4-benzyl-1-piperidyl)propoxy]carbostyryl 61-allyl-5-[2-hydroxy-(4-benzyl-1-piperidyl)propoxy]- 3,4
-dihydrocarbostyryl 1-oxalate 71-ethyl-5-[2-hydroxy-3-(4-
benzyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl 1-oxalate 88-bromo-5-[2-hydroxy-3-(4-
benzyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl 97-[2-hydroxy-3-(4-phenyl-1
-piperidyl)propoxy]-3,4-dihydrocarbostyryl101-methyl-5-[2-hydroxy-3-(4-
benzyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl 1-oxalate 114-phenyl-1-[2-hydroxy-3-(2
-oxo-1,2,3,4-tetrahydroquinolin-5-yloxy))propyl]-1-methylpiperidinium iodide 121-benzyl-5-[2-hydroxy-(4-benzyl-1-piperidyl) Propoxy]-3,
4-dihydrocarbostyryl 1-oxalate 134-phenyl-7-[3-(4-phenyl-1-
Piperidyl) propoxy] carbostyryl 1
Hydrochloride 145-[3-(4-hydroxy-4-phenyl-1
-piperidyl)propoxy]-3,4-dihydrocarbostyryl157-[3-[4-acetyl-4-phenyl-1-
(piperidyl)propoxy]-3,4-dihydrocarbostyryl The following was used as a control drug. Control drug A...Diphenhydramine hydrochloride Control drug B...Chlorphenylamine maleate

【table】

[Table] Below are examples of the production of raw materials for synthesizing the compound of general formula [1] as reference examples, and examples of production of raw materials for synthesizing the compound of general formula [1]
Examples of the production of compounds will be given as examples, but the present invention is not limited thereto. Reference Example 1 20.5 g of 5-acetyloxy-3,4-dihydrocarbostyryl was dissolved in 200 ml of acetic acid, and a solution of 16 g of bromine in 60 ml of acetic acid was added dropwise to this solution over 30 minutes while stirring and cooling with water, followed by reaction at the same temperature for 2 hours. do. Add 300ml of water to this reaction solution, leave it for 3 hours, remove the precipitated crystals,
Recrystallization from methanol gives colorless needle-like crystals of 8-
21 g of bromo-5-acetyloxy-3,4-dihydrocarbostyryl are obtained. Melting point: 237-239°C 21 g of 8-bromo-5-acetyloxy-3,4-dihydrocarbostyryl thus obtained
Dispersed in 150 ml of 8N hydrochloric acid, heated under reflux for 3 hours, cooled, removed undissolved matter, washed with water, dried, and recrystallized from methanol-water to obtain colorless needle-like crystals of 8-
14 g of bromo-5-hydroxy-3,4-dihydrocarbostyryl are obtained. Melting point: 212-213°C Reference Example 2 35.4 g of 7-methoxy-3,4-dihydrocarbostyryl is dissolved in 300 ml of acetic acid, and a solution of 27 g of sulfuryl chloride in 100 ml of acetic acid is added dropwise while stirring and cooling with ice, and the mixture is left overnight. The reaction solution was poured into ice water 1, the precipitate was removed, washed with water, dried, and recrystallized from methanol.
30 g of 6-chloro-7-methoxy-3,4-dihydrocarbostyryl are obtained in the form of colorless needle-like crystals with a melting point of 212 DEG C. 6-chloro-7-methoxy- thus obtained
30 g of 3,4-dihydrocarbostyryl was dispersed in 300 ml of a 47% aqueous hydrobromic acid solution and heated under reflux for 4 hours.
After cooling, remove insoluble matter, wash with water, dry, and add methanol to
Recrystallization from chloroform gives colorless needle-like crystals of 6-chloro-7-hydroxy-, melting point 264-266°C.
25 g of 3,4-dihydrocarbostyryl are obtained. Reference Example 3 16.4 g of 5-hydroxy-3,4-dihydrocarbostyryl was dissolved in 300 ml of acetic acid and stirred at room temperature.
Add dropwise 80 ml of acetic acid solution containing 14 g of chlorine and stir for 3 hours. This reaction solution was poured into 500 ml of water, left to stand for 1 hour, the precipitate was removed, washed with water, dried, and recrystallized from methanol to form colorless needle-like crystals of 6,8-dichloro-5-hydroxy-3,4-dihydrochloride. Obtain 16 g of Carbostyril. Melting point: 259-260°C Reference Example 4 After dispersing 20.0 g of 8-bromo-5-hydroxy-3,4-dihydrocarbostyryl and 18 g of potassium carbonate in 160 ml of isopropyl alcohol,
Add 40 ml of epichlorohydrin and react at 70-80°C for 6 hours. The reaction solution was concentrated under reduced pressure, and 100 ml of 2N sodium hydroxide was added to the residue under cooling, and the mixture was thoroughly stirred. The aqueous solution was taken out, washed with water, and dried. Recrystallization from crude crystalline methanol gave colorless needle-shaped crystals of 8-bromo-5-(2,3-epoxypropoxy)-3,4-
18.5 g of dihydrocarbostyril are obtained. Melting point 220-222°C Reference Example 5 16.4 g of 5-hydroxy-3,4-dihydrocarbostyryl and 3.7 g of sodium hydroxide were added to 100 ml of methanol and stirred at 40-50°C for 3 hours.
Add 150 ml of epichlorohydrin and heat under reflux for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was recrystallized with methanol/water (1:1) to give a melting point of 172-173.
℃Colorless amorphous crystals of 5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyryl 18.5
get g. Reference Example 6 16.3 g of 5-hydroxy-3,4-dihydrocarbostyryl and 9 g of potassium hydroxide were mixed in 150 ml of isopropyl alcohol, stirred at 70 to 80°C for 30 minutes, and then 1,3-bromochloropropane 25
g and heated under reflux for 6 hours. After the reaction was completed, the reaction solution was poured into 200ml of 2N-sodium hydroxide aqueous solution.
Remove insoluble matter, wash with water and dry. The crude crystals were recrystallized from ethanol to obtain 18.5 g of colorless needle-like crystals of 5-(3-chloropropoxy)-3,4-dihydrocarbostyryl. Melting point 176-178℃ Reference example 7 4-phenylpiperidine 16.0g, 1-chloro-
24 g of 3-bromopropane and 15 g of triethylamine
g in 100 ml of DMF and stirred at 50-60°C for 1 hour. Pour the reaction solution into 200ml of saturated saline,
The organic amount is extracted with chloroform, and the chloroform layer is washed with water, dehydrated, and the chloroform is distilled off.
The residue was separated and purified using silica gel column chromatography (only the main product at the top was separated) to obtain 15.3 g of 1-chloro-3-(4-phenylpiperidinyl)propane as a colorless oil. Distill this product under reduced pressure to obtain fraction 11 with a boiling point of 112-115℃ (0.1mmHg).
get g. A part of this is made into a hydrochloride and recrystallized from ethanol to obtain 1-chloro-3-(4-phenyl-1-piperidyl)propane monohydrochloride in the form of colorless needle crystals with a melting point of 167-169°C. Reference Example 8 1-chloro-2-methyl-3-(4-phenyl-1-piperidyl)propane is obtained in the same manner as in Reference Example 7. Colorless oil Boiling point 114-116℃/0.1mmHg Reference example 9 4-Hydroxy-4-phenylpiperidine 16.0
g, 24 g of 1-chloro-3-bromopropane and 15 g of triethylamine were mixed in 100 ml of DMF, and 50~
Stir at 60°C for 1 hour. The reaction solution was poured into 200ml of saturated saline, and the organic layer was extracted with chloroform.
After washing the chloroform layer with water, it is dehydrated and the chloroform is distilled off. The residue was separated and purified using silica gel column chromatography (only the main product at the top was separated) to obtain 1-chloro-3-(4) as a colorless oily substance.
-hydroxy-4-phenyl-1-piperidyl)
Obtain 14.3 g of propane. This material is distilled under reduced pressure,
The resulting fraction is converted into a hydrochloride and recrystallized from ethanol to give 1-chloro-3-(4-hydroxy-4-phenyl-1) as colorless needle-like crystals with a melting point of 192-195°C.
-piperidyl)propane monohydrochloride is obtained. Example 1 4.8 g of 5-(3-chloropropoxy)-3,4-dihydrocarbostyryl and 4.2 g of 4-benzylpiperidine are mixed in 40 ml of toluene and heated under reflux for 24 hours. After cooling the reaction solution, the precipitate was washed with water and recrystallized from ethanol to give colorless needle crystals.
-[3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl 6.3g
(yield 76%). Melting point 143-145°C Example 2 1-Methyl-7-(3-chloropropoxy)-
4.9 g of 3,4-dihydrocarbostyryl and 4-
4.2 g of benzylpiperidine and 3 g of triethylamine are mixed in 60 ml of DMF and heated at 70-80°C for 8 hours. After the reaction solution was concentrated to dryness under reduced pressure, 5% was added to the residue.
Add an aqueous sodium hydrogen carbonate solution, extract with chloroform, wash the chloroform layer with water, dehydrate, and distill off the chloroform. Dissolve the residue in 30 ml of acetone and add 5% oxalic acid acetone solution while stirring at room temperature, pH 4.5.
Leave it alone. The precipitate was collected, washed with acetone, and then recrystallized from ethanol-ether to obtain a colorless powder of 1-methyl-7-[3-(4-benzyl-1).
-piperidyl)propoxy]-3,4-dihydrocarbostyryl monooxalate (7.9 g (yield: 86%)). Melting point: 175-177°C Compounds of Examples 3-16 below are obtained in the same manner as in Example 2. Example 3 1-propargyl-5-[3-(4-benzyl-
1-Piperidyl)propoxy]-3,4-dihydrocarbostyryl monohydrochloride monohydrate Colorless needle crystals (methanol-ether) Melting point 172°C (decomposed) Example 4 1-Methyl-5-[3- (4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl monohydrochloride Colorless needle crystals (ethanol-ether) Melting point 130-133°C Example 5 1-hexyl-7-[3-( 4-phenyl-1-
1-(3-phenylpropyl)-7-[3-(4-
phenyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl monooxalate Colorless needle crystals (methanol-water) Melting point 210-213°C Example 7 6,8-dichloro-5-[2-methyl-3-(4
-Phenyl-1-piperidyl)propoxy]-
3,4-dihydrocarbostyryl Colorless needle crystals (ligroin) Melting point 125-126°C Example 8 5-[3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl monohydrochloride Melting point 213-215°C, colorless needle crystals (methanol) Example 9 5-[3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl Colorless needle crystals (ligroin-benzene) Melting point 143-145℃ Example 10 7-[3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl 1-oxalate Melting point 175-177℃ Example 11 7-[3-(4 -Phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl monohydrochloride Melting point 252-254°C (ethanol) Yellow needles Example 12 4-Methyl-7-[3-(4-benzyl- 1-piperidyl)propoxy]carbostyryl monohydrochloride dihydrate Melting point 241-242℃ (ethanol) Colorless needle crystals Example 13 5-[3-(4-phenyl-1-piperidyl)propoxy]carbostyryl - Monohydrochloride Melting point: 200℃ (methanol) Colorless needle crystals Example 14 4-Methyl-6-{3-[4-(4-methylphenyl)-1-piperidyl]propoxy} Carbostyryl monohydrochloride Melting point: 256~ 259℃ (decomposition) (methanol) Colorless needle crystal Example 15 4-Methyl-6-{3-[4-(4-chlorophenyl)-1-piperidyl]propoxy}-carbostyryl monohydrochloride Melting point 263-265 °C (methanol) Colorless needle crystals Example 16 1-Isopentyl-6-{2-hydroxy-3
-[4-(3,4,5-trimethoxyphenyl)
-1-Piperidyl]propoxy}-3,4-dihydrocarbostyryl monooxalate Melting point: 199-201°C (ethanol) Colorless scale crystal Example 17 7-(5-Bromopentoxy)-3,4-dihydrocarbostyryl 2.7 g of 4-benzylpiperidine, 2.0 g of triethylamine and 1.5 g of triethylamine were mixed in 30 ml of DMF and heated at 60-70°C for 6 hours. The reaction solution was concentrated to dryness under reduced pressure, and 5% aqueous sodium hydrogen carbonate solution was added to the residue, stirred to remove insoluble matter, washed with water, dried, and recrystallized from ligroin to give colorless plate-like crystals.
-[5-(4-benzyl-1-piperidyl)pentoxy]-3,4-dihydrocarbos 3.6 g (yield 88
%). Melting point: 100-102°C Example 18 2.5 g of 4-methyl-6-(3-chloropropoxy)carbostyryl and 1.8 g of sodium iodide were mixed in 50 ml of acetone, and after stirring at 50°C for 1 hour,
Add 50 ml of DMF and distill off the acetone under reduced pressure.
1.5 g of triethylamine and 1.6 g of 4-benzylpiperidine were added to the residue, heated and stirred at 70 to 80°C for 7 hours, and then concentrated to dryness under reduced pressure. Add 60 ml of 5% sodium bicarbonate aqueous solution to the residue, stir, remove insoluble matter, wash with water, and recrystallize from methanol to obtain yellow prism crystals of 4-methyl-6-[3-(4
3.2 g (yield: 82%) of -benzyl-1-piperidyl)propoxy]carbostyril is obtained. Melting point: 177-178°C Compounds of Examples 19-24 below are obtained in the same manner as in Example 18. Example 19 4-Methyl-7-[3-(4-benzyl-1-piperidyl)propoxy]carbostyryl Colorless needle crystals (methanol) Melting point 183-184°C Example 20 4-phenyl-7-[3-( 4-phenyl-1-
Piperidyl) propoxy] carbostyryl 1
Hydrochloride Melting point 238-241°C Colorless needle crystals (methanol-ether) Example 21 4-Methyl-6-[3-(4-benzyl-1-piperidyl)propoxy]-carbostyryl Melting point 177-178°C Yellow-brown prism Crystal (methanol) Example 22 4-Methyl-6-[3-(4-benzyl-1-piperidyl)propoxy]-carbostyryl 1
Hydrochloride Melting point 217℃ (ethanol-acetone-ether) Colorless powder crystal Example 23 4-Methyl-6-{3-(4-methylphenyl)
-1-Piperidyl]propoxy]carbostyryl monohydrochloride Melting point: 256-259°C (decomposition) (methanol) Colorless needle crystals Example 24 4-Methyl-6-{3-[4-(4-chlorophenyl)-1 -piperidyl)propoxy}carbostyryl monohydrochloride Melting point: 263-265°C (methanol) Colorless needle crystals Example 25 1-allyl-5-(2-hydroxy-3-chloropropoxy)-3,4-dihydrocarbostyryl 2.6g, triethylamine 1.5g and 4-benzylpiperazine 2.0g were mixed in 30ml of DMF and heated to 80-90℃.
Stir for 5 hours. The reaction solution was poured into 80 ml of a 5% aqueous sodium hydrogen carbonate solution, the organic layer was extracted with chloroform, the chloroform layer was washed with water and dehydrated, and the chloroform was distilled off. Dissolve the residue in 30 ml of acetone, add 5% oxalic acid in acetone to pH 4.5, collect the precipitated crystals, wash with acetone, and recrystallize from ethanol to obtain colorless needle-like crystals of 1-allyl-5.
Obtain 4.3 g of -[2-hydroxy-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl monooxalate (yield 82%) Melting point 178-180°C Same procedure as Example 25 The following compounds of Examples 26 to 36 are obtained. Example 26 1-benzyl-5-[2-hydroxy-(4-benzyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl 1-oxalate Melting point 141-143°C Colorless powder (recrystallization solvent: ethanol) Example 27 1-ethyl-5-[2-hydroxy-3-(4-
benzyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl monooxalate Melting point 164-169°C Colorless needles (ethanol) Example 28 8-bromo-5-[2-hydroxy-3-(4-
benzyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl Melting point 165-166°C Colorless needle crystals (ethanol) Example 29 5-[2-hydroxy-3-(4-phenyl-1)
-piperidyl)propoxy]-3,4-dihydrocarbostyryl Melting point 207-208°C Colorless needles (ethanol) Example 30 6-[2-hydroxy-3-(4-phenyl-1
-piperidyl)propoxy]-3,4-dihydrocarbostyryl Melting point 170-171°C Colorless needles (ethanol) Example 31 7-[2-hydroxy-3-(4-phenyl-1
-piperidyl)propoxy]-3,4-dihydrocarbostyryl Melting point 149-150°C Colorless needle crystals (isopropanol) Example 32 1-allyl-5-[2-hydroxy-3-(4-
phenyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl Melting point 92°C, colorless needle crystals (ligroin) Example 33 1-allyl-5-[2-hydroxy-3-(4-
phenyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl 1-oxalate Melting point: 208°C (decomposed) Yellow needles (methanol) Example 34 1-Methyl-5-[2-hydroxy-3-(4-
benzyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl 1-oxalate Melting point 150-152°C (ethanol-ether) Example 35 1-benzyl-5-[2-hydroxy-3-(4
-benzyl-1-piperidyl)propoxy]-
3,4-Dihydrocarbostyryl Melting point 141-143 (ethanol), colorless needles Example 36 1-Isopentyl-6-{2-hydroxy-3
-[4-(3,4,5-trimethoxyphenyl)
-1-Piperidyl]propoxy}-3,4-dihydrocarbostyryl monooxalate Melting point 199-201 (ethanol) Colorless scale crystals Example 37 1-Methyl-5-(2,3-epoxypropoxy)-3,4 - 2.4 g of dihydrocarbostyril and 2.0 g of 4-benzylpiperidine in 30 ml of methanol.
and heat under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 30 ml of acetone, and 5% oxalic acid in acetone was added to the solution while stirring at room temperature to adjust the pH to 4.5. After removing the precipitate and washing it with acetone, it was recrystallized from ethanol-ether to obtain colorless powder 1.
-Methyl-5-[2-hydroxy-3-(4-benzyl-1-piperidyl)propoxy]-3,4-
3.9 g of dihydrocarbostyryl monooxalate is obtained.
(Yield: 78%) Melting point: 150-152°C Compounds of Examples 38-47 below are obtained in the same manner as in Example 37 above. Example 38 6-[2-hydroxy-3-(4-phenyl-1
-piperidyl)propoxy-3,4-dihydrocarbostyryl Melting point 170-171°C Colorless plate crystals (ethanol) Example 39 1-ethyl-5-[2-hydroxy-3-(4-
benzyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl monooxalate Melting point 164-169°C Colorless needles (ethanol) Example 40 8-bromo-5-[2-hydroxy-3-(4-
benzyl-1-piperidyl)propoxy]3,
4-dihydrocarbostyryl Melting point 165-166°C Colorless needle crystals (ethanol) Example 41 7-[2-hydroxy-3-(4-phenyl-1)
-piperidyl)propoxy]-3,4-dihydrocarbostyryl Melting point 149-150℃ Colorless needle crystals (isopropanol) Example 42 5-[2-hydroxy-3-(4-phenyl-1)
-piperidyl)propoxy]-3,4-dihydrocarbostyryl Melting point 207-208°C Colorless needles (ethanol) Example 43 1-benzyl-5-[2-hydroxy-3-(4
-benzyl-1-piperidyl)propoxy]-
3,4-dihydrocarbostyryl Melting point 141-143°C (ethanol) Example 44 1-Isopentyl-6-{2-hydroxy-3
-[4-(3,4,5-trimethoxyphenyl)
-1-piperidyl]propoxy}-3,4-dihydrocarbostyryl monooxalate Melting point 199-201℃ (ethanol) Colorless scale crystal Example 45 1-Methyl-5-[2-hydroxy-3-(4-
benzyl-1-piperidyl)propoxy]3,
4-dihydrocarbostyryl monooxalate Melting point 150-152°C (ethanol-ether) Example 46 1-allyl-5-[2-hydroxy-3-(4-
phenyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl Melting point 92°C, colorless needle crystals (ligroin) Example 47 1-allyl-5-[2-hydroxy-3-(4-
phenyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl 1-oxalate Melting point 208°C (decomposed) Yellow needles (methanol) Example 48 5-[3-[4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl 3.8
g and 0.6 g of NaH (50% oil) in 60 ml of DMF, stirred for 1 hour, and then mixed with propargyl bromide.
Add 1.4 g and stir at room temperature for 2 hours. The reaction solution was poured into 100 ml of saturated saline solution, the organic layer was extracted with chloroform, washed with water, dehydrated, the chloroform was distilled off, the residue was crystallized from ethanol-hydrochloric acid, and the crude crystals were recrystallized from methanol-ether to give a colorless mixture. Needle-shaped crystals of 1-propargyl-5-[3-(4-benzyl-1-piperidyl)propoxy]-3,4-
Dihydrocarbostyril monohydrochloride monohydrate
Obtain 4.1 g (87% yield). Melting point: 172°C (decomposition) Compounds of Examples 49 to 54 are obtained in the same manner as in Example 48. Example 49 1-Methyl-5-[3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl monohydrochloride Melting point 130-133°C Colorless needle crystals (ethanol-ether) Implementation Example 50 1-n-hexyl-7-[3-(4-phenyl-
1-piperidyl)propoxy]-3,4-dihydrocarbostyryl monooxalate Melting point 168-170°C Colorless needle crystals (isopropanol) Example 51 1-(3-phenylpropyl)-7-[3-(4 −
phenyl-1-piperidyl)propoxy]-3,
4-Dihydrocarbostyryl 1-oxalate Colorless needle crystals (methanol-water) Melting point 210-213°C Example 52 1-Methyl-7-[3-(4-benzyl-1-piperidyl)propoxy]-3,4 -Dihydrocarbostyryl 1-oxalate Melting point 175-177°C Colorless powder (ethanol-ether) Example 53 1-benzyl-5-[2-hydroxy-3-(4
-benzyl-1-piperidyl)propoxy]-
3,4-dihydrocarbostyryl Melting point 141-143°C (ethanol) Example 54 1-Isopentyl-6-{2hydroxy-3-
[4-(3,4,5-trimethoxyphenyl)-
1-Piperidyl)propoxy}-3,4-dihydrocarbostyryl monooxalate Melting point 199-201°C (ethanol) Colorless scaly crystals Example 55 7-hydroxy-4-phenylcarbostyryl
2.4g and 0.8g of granular potassium hydroxide in methanol
Mix with 60 ml and concentrate to dryness under reduced pressure. Add 60 ml of DMF to the residue and mix, then add 5 g of 1-(3-chloropropyl)-4-phenylpiperidine.
Heat and stir at 70-80°C for 8 hours. The reaction solution was concentrated to dryness under reduced pressure, added with 60 ml of 5% aqueous sodium hydrogen carbonate solution, and extracted with chloroform. After the chloroform layer was washed with water and dehydrated, the chloroform was distilled off. To the residue, 30 ml of methanol and 5 ml of concentrated hydrochloric acid were added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethanol and recrystallized from methanol to obtain 4-phenyl as colorless needle-like crystals. -7-[3
-(4-phenyl-1-piperidyl)propoxy]
2.8 g (58%) of carbostyril monohydrochloride is obtained. Melting point: 238-241°C Compounds of Examples 56-76 are obtained in the same manner as in Example 55. Example 56 1-Methyl-7-[3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl monooxalate Melting point 175-177°C Colorless powder (ethanol-ether) Example 57 1-propargyl-5-[3-(4-benzyl-
1-Piperidyl)propoxy]-3,4-dihydrocarbostyryl monohydrochloride monohydrate Melting point 172°C (decomposition) Colorless needles (methanol-ether) Example 58 1-Methyl-5-[3- (4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl monohydrochloride Melting point 130-133°C Colorless needles (ethanol-ether) Example 59 1-hexyl-7-[3-( 4-phenyl-1-
piperidyl)propoxy]-3,4-dihydrocarbostyryl monooxalate Melting point 168-170℃ Colorless needle crystals (isopropanol) Example 60 1-(3-phenylpropyl)-7-[3-(4-
phenyl-1-piperidyl)propoxy]-3,
4-Dihydrocarbostyryl 1-oxalate Melting point 210-213°C Colorless needle crystals (methanol-water) Example 61 1-allyl-5-[2-hydroxy-(4-benzyl-1-piperidyl)propoxy]-3 ,4
-dihydrocarbostyryl monooxalate Melting point 178-180℃ Example 62 1-Methyl-5-[2-hydroxy-3-(4-
benzyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl 1-oxalate Melting point 150-152°C (ethanol-ether) Example 63 1-benzyl-5-[2-hydroxy-3-(4
-benzyl-1-piperidyl)propoxy]-
3,4-dihydrocarbostyryl Melting point 141-143°C (ethanol) Example 64 5-[3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl monohydrochloride Melting point 213-215 °C Example 65 5-[3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl Colorless needle crystals (ligroin-benzene) Melting point 143-145°C Example 66 7-[3- (4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl monooxalate Melting point 175-177°C, colorless prismatic crystals (ethanol) Example 67 1-allyl-5-[2-hydroxy-3 -(4-
phenyl-1-piperidyl)propoxy]-3,
4-Dihydrocarbostyryl Melting point 92°C, colorless needle crystals (ligroin) Example 68 1-allyl-5-[2-hydroxy-3-(4-
phenyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl monooxalate Melting point 208°C (decomposed) Yellow needles (methanol) Example 69 4-Methyl-6-[3-(4-benzyl-1-piperidyl)propoxy]carbostyryl Melting point 177~ 178℃ Yellow-brown prism crystals (methanol) Example 70 4-Methyl-6-[3-(4-benzyl-1-piperidyl)propoxy]carbostyryl monohydrochloride Melting point 217℃ (ethanol-acetone-ether) Colorless powder Crystal example 71 5-[3-(4-phenyl-1-piperidyl)propoxy]-carbostyryl monohydrochloride Melting point 200°C (methanol) Colorless needle crystal example 72 7-[3-(4-phenyl- 1-Piperidyl)propoxy]-3,4-dihydrocarbostyryl monohydrochloride Melting point 252-254°C (ethanol) Yellow needles Example 73 4-Methyl-7-[3-(4-benzyl-1-piperidyl) ) propoxy]-carbostyryl 1
Hydrochloride dihydrate Melting point 241-242℃ (ethanol) Colorless needle crystals Example 74 4-Methyl-6-{3-[4-(4-methylphenyl)-1-piperidyl]propoxy}-carbostyryl. Monohydrochloride Melting point 256-259℃ (decomposition) (methanol) Colorless needle crystals Example 75 4-Methyl-6-[3-[4-(4-chlorophenyl)-1-piperidyl]propoxy}-carbostyryl 1 Hydrochloride Melting point 263-265℃ (methanol) Colorless needle crystals Example 76 1-Isopentyl-6-{2-hydroxy-3
-[4-(3,4,5-trimethoxyphenyl)
-1-Piperidyl]propoxy}-3,4-dihydrocarbostyryl monooxalate Melting point 199-201°C (ethanol) Colorless scale crystal Example 77 6,8-dichloro-5-hydroxy-3,4-
2.4 g of dihydrocarbostyril and 0.8 g of granular potassium hydroxide are mixed in 60 ml of methanol and concentrated to dryness under reduced pressure. Add 60 ml of the residual DMF and mix, then add 5 g of 1-chloro-2-methyl-3-(4-phenylpiperidyl)propane and heat and stir at 70-80°C for 8 hours. The reaction solution was concentrated to dryness under reduced pressure to 5%
Add 60 ml of sodium bicarbonate aqueous solution and extract with chloroform. After washing the chloroform layer with water and dehydrating it, the chloroform was distilled off and the residue was purified by silica gel column chromatography and recrystallized from ligroin to give colorless needle-like crystals of 6,8-dichloro-5-[2-methyl- 1.6 g (yield 35%) of 3-(4-phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl is obtained. Melting point: 125-126°C Compounds of Examples 78-82 are obtained in the same manner as in Example 77. Example 78 5-[3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl Melting point 143-145°C Colorless needles (methanol) Example 79 7-[5-(4- Benzyl-1-piperidyl)pentoxy]-3,4-dihydrocarbostyryl Melting point 100-102°C Colorless needle crystals (ligroin) Example 80 4-Methyl-6-[3-(4-benzyl-1-piperidyl)propoxy ] Carbostyryl Melting point 177-178°C Yellow prismatic crystals (methanol) Example 81 4-Methyl-7-[3-(4-benzyl-1-piperidyl)propoxy] Carbostyril Melting point 183-184°C Colorless needle crystals (methanol) ) Example 82 8-bromo-5-[2-hydroxy-3-(4-
benzyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl Melting point 165-166°C Colorless needles (ethanol) Example 83 1-Methyl-5-hydroxy-3,4-dihydrocarbostyryl 1.8 g and 4-benzyl-1-
(2,3-epoxypropyl)piperidine 2,3
g was mixed with 30 ml of methanol and heated under reflux for 3 hours. Concentrate the reaction solution under reduced pressure and add 30ml of acetone to the residue.
Add 5% oxalic acid acetone solution while stirring at room temperature to adjust the pH to 4.5 and leave to stand. The precipitate was collected, washed with acetone, and then recrystallized from ethanol-ether to obtain 1-methyl-5-[2-hydroxy-3-(4-benzyl-1-piperidyl)] as a colorless powder.
Propoxy]-3,4-dihydrocarbostyryl monooxalate 3,5 (63%) is obtained. Melting point: 150-152°C Compounds of Examples 84-94 below are obtained in the same manner as in Example 83 above. Example 84 1-benzyl-5-[2-hydroxy-(4-benzyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl 1-oxalate Melting point 141-143°C Colorless powder (recrystallization solvent: ethanol) Example 85 1-ethyl-5-[2-hydroxy-3-(4-
benzyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl monooxalate Melting point 164-169°C Colorless needles (ethanol) Example 86 8-bromo-5-[2-hydroxy-3-(4-
benzyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl Melting point 165-166°C Colorless needle crystals (ethanol) Example 87 5-[2-hydroxy-3-(4-phenyl-1)
-piperidyl)propoxy]-3,4-dihydrocarbostyryl Melting point 207-208°C Colorless needles (ethanol) Example 88 6-[2-hydroxy-3-(4-phenyl-1
-piperidyl)propoxy]-3,4-dihydrocarbostyryl Melting point 170-171°C Colorless platelet crystals (ethanol) Example 89 7-[2-hydroxy-3-(4-phenyl-1
-piperidyl)propoxy]-3,4-dihydrocarbostyryl Melting point 149-150°C Colorless needle crystals (isopropanol) Example 90 1-allyl-5-[2-hydroxy-(4-benzyl-1-piperidyl)propoxy] -3,4-
Obtain 4.3 g of dihydrocarbostyryl 1-oxalate (yield 82%) Melting point 178-180°C Example 91 1-allyl-5-[2-hydroxy-3-(4-
phenyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl Melting point 92°C, colorless needle crystals (ligroin) Example 92 1-allyl-5-[2-hydroxy-3-(4-
phenyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl 1-oxalate Melting point: 208°C (decomposition) Yellow needles (methanol) Example 93 1-Methyl-5-[2-hydroxy-3-(4-
benzyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl monooxalate Melting point 150-152°C (ethanol-ether) Example 94 5-[2-hydroxy-3-(3,4,5-trimethoxyphenyl)propoxy]-3,4- Dihydrocarbostyryl 1-oxalate Melting point: 199-201°C Colorless scale crystals (methanol) Example 95 5-[2-hydroxy-3-(4-phenyl-1)
-piperidyl)propoxy]-3,4-dihydrocarbostyryl 2.0 g and methyl iodide 3 g.
Mix with 30 ml of DMF and stir at 50-60°C for 5 hours.
The reaction solution was concentrated under reduced pressure, 50 ml of acetone was added to the residue, stirred, the precipitate was washed with acetone, and recrystallized from methanol-ethanol to obtain colorless powder of 4-
Phenyl-1-[2-hydroxy-3-(2-oxo-1,2,3,4-tetrahydroquinoline-5
1.7 g of -yloxy)propyl]-1-methylpiperidinium iodide are obtained. Melting point: 242-243°C Compounds of Examples 96-97 are obtained in the same manner as in Example 95. Example 96 4-phenyl-1-[2-hydroxy-3-(1
-Allyl-2-oxo-1,2,3,4-tetrahydroquinolin-5-yloxy)propyl]-1-methylpiperidinium iodide Melting point 179-180°C Colorless needle crystals (isopropanol-acetone) Example 97 4-benzyl-1-[2-hydroxy-3-(1
-Benzyl-2-oxy-1,2,3,4-tetrahydroquinolin-5-yloxy)propyl]-1-methylpiperidinium iodide Melting point 135-139°C Yellow needles (ethanol-ether) Example 98 4-phenyl-1-[3-oxo-1,2,3,
4-Tetrahydroquinolin-7-yloxypropyl]-1-methylpiperidinium iodide 1/2 hydrate (2.0 g), methanol 150 ml, water
Dissolve in 100ml, then add 3.0g of silver chloride and stir in a cool, dark place for 24 hours. The reaction solution was filtered, the mother liquor was concentrated to dryness under reduced pressure, and the residue was recrystallized from isopropanol-acetone-ether to give colorless powdery crystals.
-phenyl-1-[3-(2-oxo-1,2,
1.0 g of 3,4-tetrahydroquinolin-7-yloxy)propyl]-1-methylpiperidinium chloride hemihydrate is obtained. Melting point 211-213°C Example 99 2.4 g of 7-(3-chloropropoxy)-3,4-dihydrocarbostyryl and 4-hydroxy-4
- Mix 4.0 g of phenylpiperidine with 150 ml of toluene and heat under reflux for 24 hours. After cooling the reaction solution, the precipitate was collected, washed with water, and recrystallized from ethanol to give colorless scale crystals of 7-[3-(4-hydroxy-4-
phenyl-1-piperidyl)propoxy]-3,
2.8 g of 4-dihydrocarbostyryl are obtained. Melting point: 215°C Compounds of Examples 100 to 107 are obtained in the same manner as in Example 99 using appropriate starting materials. Note that the solvent in parentheses in each example is a recrystallization solvent. Example 100 5-[3-(4-hydroxy-4-phenyl-1
-piperidyl)propoxy]-3,4-dihydrocarbostyryl Melting point 265-266°C Colorless needle crystals (methanol) Example 101 7-{3-[4-hydroxy-4-(4-chlorophenyl)-1-piperidyl) Propoxy]-
3,4-dihydrocarbostyryl Melting point 189-190℃ Colorless needle crystals (ethanol) Example 102 5-[3-(4-acetyl-4-phenyl-1-
piperidyl)propoxy]-3,4-dihydrocarbostyryl Melting point 165℃ Pale yellow prismatic crystals (ethanol) Example 103 7-[3-(4-acetyl-4-phenyl-1-
Piperidyl)propoxy]-3,4-dihydrocarbostyryl Melting point 159-160℃ Colorless needle crystals (isopropyl alcohol) Example 104 6-[2-(4-acetyl-4-phenyl-1-
Piperidyl)ethoxy]carbostyryl Melting point 158-160℃ Colorless needle crystals (ethanol) Example 105 7-[3-(4-hydroxy-4-(4-methylphenyl)-1-piperidyl]propoxy}-
3,4-Dihydrocarbostyryl Melting point 188-189°C Colorless scale crystals (ethanol) Example 106 7-{3-[4-hydroxy-4-(2-methoxyphenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl monohydrochloride Melting point 239-241°C (decomposed) Colorless powder crystals (methanol-water) Example 107 4-Methyl-{3-[4-(4-acetyl-4-
Phenyl)-1-piperidyl]propoxy}-carbostyryl Melting point 212-213°C Pale yellowish brown needles (methanol) Example 108 1-Methyl-6-(2-bromoethoxy)-3,
1.43 g of 4-dihydrocarbostyryl, 1.3 g of 4-acetyl-4-phenylpiperidine and 1 g of triethylamine are mixed in 30 ml of DMF and heated at 60-70°C for 5 hours. After the reaction solution was concentrated to dryness under reduced pressure, a 5% aqueous hydrogen carbonate solution was added to the residue, and the mixture was stirred. Insoluble matter was removed, washed with water, dried, and recrystallized from ethanol-water to obtain colorless prism crystals of 1-methyl-6.
1.3 g of -[2-(4-acetyl-4-phenyl-1-piperidyl)ethoxy]-3,4-dihydrocarbostyryl are obtained. Melting point: 101-103°C Compounds of Examples 109-111 are obtained in the same manner as in Example 108 using appropriate starting materials. Example 109 1-methyl-8-[3-(4-acetyl-4-phenyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl Melting point 103-105°C Colorless needle crystals (ligroin) Example 110 1-Methyl-6-[3-(4-acetyl-4-phenyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl Melting point 115-117°C Colorless needle crystals (ligroin) Example 111 4-Methyl-{3-[4-(4-acetyl-4-
Phenyl)-1-piperidyl)propoxy}-carbostyryl Melting point 212-213°C Pale yellowish brown needles (methanol) Example 112 2.4 g of 7-(3-chloropropoxy)-3,4-dihydrocarbostyryl and iodide Sodium 1.6g
Disperse in 60 ml of acetone, stir at 50-60°C for 1 hour, and then add 60 ml of DMF. Concentrate under reduced pressure to remove acetone, then 5-phenyl-1,5,7-triazabicyclo[4,5]-decane-8-one 2.5
g and 2 g of triethylamine are added and heated at 70-80°C for 7 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with chloroform. The chloroform layer is washed with water and dried, and the residue after distilling off the chloroform is crystallized from isopropanol. The resulting crude crystals were crystallized from methanol-water and further recrystallized from water to give colorless needle-like crystals of 7-[3-(5-phenyl-1,
5,7-triazaspiro[4,5]decane-8-
2.8 g of on-1-yl)propoxy]-3,4-dihydrocarbostyryl are obtained. Melting point: 270-271°C (decomposition) Compounds of Examples 113-114 are obtained in the same manner as in Example 112 using appropriate starting materials. Example 113 1-Methyl-7-[3-(5-phenyl-7-methyl-1,5,7-triazaspiro[4,5]
-decane-8-one-1-yl)propoxy]
-3,4-dihydrocarbostyryl Melting point 225-228°C Colorless needle crystals (methanol) Example 114 1-benzyl-7-[3-(5-phenyl-7-
Benzyl-1,5,7-triazaspiro [4,
5]-Decan-8-one-1-yl)propoxy]-3,4-dihydrocarbostyryl..1
Oxalate Melting point 212-214°C Colorless powder crystals (methanol) Example 115 1.65 g of 6-hydrocarbostyryl and 0.75 g of granular potassium hydroxide are mixed in 50 ml of methanol and concentrated to dryness under reduced pressure. Add 50ml of DMF to the residue,
After mixing 2.7 g of 1-(3-chloropropyl)-4-hydroxy-4-(4-chlorophenyl)piperidine
Add and heat and stir at 50°C for 6 hours. The reaction solution was concentrated to dryness under reduced pressure, and 5% aqueous sodium hydrogen carbonate solution was added.
Add 20ml and stir. Insoluble matter was removed, washed with water, dried, and recrystallized from ethanol to obtain colorless prism crystals.
1.2 g of -{3-[4-hydroxy-4-(4-chlorophenyl)-1-piperidyl]propoxy}carbostyryl is obtained. Melting point: 193.5-194.5°C Compounds of Examples 116-129 are obtained in the same manner as in Example 115 using appropriate starting materials. Example 116 5-[3-(4-hydroxy-4-phenyl-1
-piperidyl)propoxy]-3,4-dihydrocarbostyryl Melting point 265-266°C Colorless needles (methanol) Example 117 7-[3-(4-hydroxy-4-phenyl-1)
-piperidyl)propoxy]-3,4-dihydrocarbostyryl Melting point 215°C Colorless scale crystals (ethanol) Example 118 7-{3-(4-hydroxy-4-chlorophenyl)-1-piperidyl)propoxy}-3,4 −
Dihydrocarbostyryl Melting point 189-190℃ Colorless needle crystals (ethanol) Example 119 7-[3-(4-acetyl-4-phenyl-1-
Piperidyl)propoxy]-3,4-dihydrocarbostyryl Melting point 165℃ Pale yellow prismatic crystals (ethanol) Example 120 7-[3-(4-acetyl-4-phenyl-1-
piperidyl)propoxy]-3,4-dihydrocarbostyryl Melting point 159-160℃ Colorless needle crystals (isopropyl alcohol) Example 121 6-[2-(4-acetyl-4-phenyl-1-
Piperidyl)ethoxy]carbostyryl Melting point 158-160℃ Colorless needle crystals (ethanol) Example 122 7-{3-[4-hydroxy-4-(4-methylphenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl Melting point 188-189°C Colorless scale crystals (ethanol) Example 123 7-{3-[4-hydroxy-4-(2-methoxyphenyl)-1-piperidyl]propoxy}-
3,4-dihydrocarbostyryl monohydrochloride Melting point 239-241°C (decomposition) Colorless powder crystals (methanol-water) Example 124 1-Methyl-6-[2-(4-acetyl-4-phenyl-1) -piperidyl)ethoxy]-3,4
-dihydrocarbostyryl Melting point 101-103°C Colorless prismatic crystals (ethanol-water) Example 125 1-Methyl-8-[3-(4-acetyl-4-phenyl-1-piperidyl)propoxy]-3,
4-Dihydrocarbostyryl Melting point 103-105°C Colorless needle crystals (ligroin) Example 126 7-[3-(5-phenyl-1,5,7-triazaspiro[4,5]-decane-8-one-1) −
Propoxy]-3,4-dihydrocarbostyryl Melting point: 270-271°C (decomposition) Colorless needle crystals Example 127 1-Methyl-7-[3-(5-phenyl-7-methyl-1,5,7 -Triazaspiro [4,5]
-decane-8-one-1-yl)propoxy]
-3,4-dihydrocarbostyryl Melting point 225-228°C Colorless needle crystals (methanol) Example 128 1-benzyl-7-[3-(5-phenyl-7-
Benzyl-1,5,7-triazaspiro [4,
5]-Decan-8-one-1-yl)propoxy]-3,4-dihydrocarbostyryl monooxalate Melting point 212-214°C Colorless powder crystals (methanol) Example 129 4-Methyl-{3-[ 4-(4-acetyl-4-
Phenyl)-1-piperidyl)propoxy}-carbostyryl Melting point 212-213℃ Pale yellowish brown needle crystals (methanol) Example 130 6-[3-(4-acetyl-4-phenyl-1-
piperidyl)propoxy]-3,4-dihydrocarbostyryl 2.0 g and NaH (50% oily) 0.25 g.
After mixing in 30 ml of DMF and stirring for 1 hour, 0.7 g of methyl iodide was added and stirred at room temperature for 12 hours. The reaction solution was poured into 80 ml of saturated brine, the organic layer was extracted with chloroform, washed with water, and dehydrated. The chloroform was distilled off, the residue was crystallized from hexane, and the crude crystals were recrystallized from ligroin to obtain colorless needle-shaped crystals. 1-Methyl-6-[3-(4-acetyl-4-phenyl-1-
1.7 g of (piperidyl)propoxy]-3,4-dihydrocarbostyryl are obtained. Melting point: 115-117°C Compounds of Examples 131-133 were obtained in the same manner as Example 130. Example 131 1-methyl-8-[3-(4-acetyl-4-phenyl-1-piperidyl)propoxy]-3,
4-dihydrocarbostyryl Melting point 103-105°C Colorless needles (ligroin) Example 132 1-allyl-5-{2-hydroxy-3-[4-
Acetyl-4-phenyl)-1-piperidyl]
propoxy}-3,4-dihydrocarbostyryl Melting point 141-142℃ Colorless prismatic crystals (ligroin-benzene) Example 133 1-propargyl-5-{2-hydroxy-3
-[4-(4-hydroxy-4-(4-chlorophenyl))-1-piperidyl)propoxy}-3,
4-dihydrocarbostyryl Melting point 132-134°C Colorless needle crystals (ligroin-benzene-acetone) Example 134 4-phenyl-6-(2,3-epoxypropoxy)-3,4-dihydrocarbostyryl 2.9 g,
4-hydroxy-4-phenylpiperidine 2.0g
was mixed with 80 ml of methanol, and after heating under reflux for 5 hours,
The reaction solution was concentrated under reduced pressure, and the residue was crystallized from hexane-ether. The precipitated crystals were collected, dried, and then recrystallized from ethanol-water to give colorless prismatic crystals of 4-phenyl-6-[2] with a melting point of 177-178°C. 2.7 g of -hydroxy-3-(4-hydroxy-4-phenylpiperidyl)propoxy]-3,4-dihydrocarbostyryl are obtained. Compounds of Examples 135 to 136 below are obtained in the same manner as in Example 134. Example 135 1-propargyl-5-{2-hydroxy-3
-[4-(4-hydroxy-4-(2-chlorophenyl))-1-piperidyl]propoxy}-3,
4-dihydrocarbostyryl Melting point 132-134°C Colorless needle crystals (ligroin-benzene-acetone) Example 136 1-allyl-5-{2-hydroxy-3-[4-
(4-acetyl-4-phenyl)-1-piperidyl]propoxy}-3,4-dihydrocarbostyryl Melting point 141-142°C Colorless prismatic crystals (ligroin-benzene) Example 137 1-propyl-5-(2,3 -epoxypropoxy)-3,4-dihydrocarbostyryl 2.9 g and 4-acetyl-4-phenyl-piperidine 2.3
g was mixed with 30 ml of methanol and heated under reflux for 3 hours. Concentrate the reaction solution under reduced pressure and add 30ml of acetone to the residue.
Add 5% oxalic acid acetone solution to the solution while stirring at room temperature to adjust the pH to 4.5. The precipitate was collected, washed with acetone, and then recrystallized from ligroin-benzene to give colorless prismatic crystals of 1-allyl-5-{2-hydroxy-3-[4-(4-acetyl-4-phenyl)-1- 2.72 g of piperidyl]propoxy}-3,4-dihydrocarbostyryl are obtained. Melting point: 141-142°C The following Examples 138-
139 each compound is obtained. Example 138 1-propargyl-5-{2-hydroxy-3
-[4-(4-hydroxy-4-(2-chlorophenyl))-1-piperidyl]propoxy}-3,
4-dihydrocarbostyryl Melting point 132-134°C Colorless needle crystals (ligroin-benzene-acetone) Example 139 4-phenyl-6-{2-hydroxy-3-[4
-(4-hydroxy-4-phenyl)-1-piperidyl]propoxy}-3,4-dihydrocarbostyryl Melting point 177-178°C Colorless prismatic crystals (ethanol-water) Example 140 1-propyl-5-hydroxy-3 , 1.8 g of 4-dihydrocarbostyryl and 4-acetyl-4
-phenyl-1-(2,3-epoxypropyl)
Mix 2.6 g of piperidine with 30 ml of methanol,
Heat to reflux for an hour. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 30 ml of acetone, and while stirring at room temperature, 5% oxalic acid in acetone was added to adjust the pH to 4.5 and allowed to stand. The precipitate was collected, washed with acetone, and then recrystallized from ligroin-benzene to give 1-allyl-5-{2-hydroxy-3-[4-(4-acetyl-4-phenyl)-1-piperidyl]propoxy}- 2.62 g of 3,4-dihydrocarbostyryl are obtained. Melting point: 141-142°C The following Examples 141-
142 compounds are obtained. Example 141 1-propargyl-5-{2-hydroxy-3
-[4-(4-hydroxy-4-(2-chlorophenyl))-1-piperidyl]propoxy}-3,
4-dihydrocarbostyryl Melting point 132-134°C Colorless needle crystals (ligroin-benzene-acetone) Example 142 4-phenyl-6-{2-hydroxy-3-[4
-(4-Hydroxy-4-phenyl)-1-piperidyl]propoxy}-3,4-dihydrocarbostyryl Melting point 177-178°C Colorless prismatic crystals (ethanol-water) Example 143 5- [3-(4-phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl monohydrochloride is obtained. Colorless needle crystals Melting point 200°C (methanol) Example 144 6-[3-(4-acetyl-4-phenyl-1-piperidyl)propoxy] in the same manner as Example 99
Obtain Carbostyril. Colorless prismatic crystals (ethanol) Melting point 192.5-194°C Example 145 6-[2-(4-acetyl-1-phenyl-1-piperidyl)ethoxy] in the same manner as Example 115
-3,4-dihydrocarbostyryl is obtained. Colorless needle crystals (ethanol) Melting point 158-160°C Example 146 1-benzyl-5-[2
-Hydroxy-3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl (mono-oxalate) Melting point: 213-214°C Colorless powder (ethanol-ether) Formulation example 1 By normal method Tablets with each tablet having the following composition are manufactured. 1-Methyl-7-[3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl monooxalate 5mg Coastal starch 132mg Magnesium stearate 18mg Lactose 45mg Total 200mg Finished example 2 Ordinary Tablets having the following composition in one tablet are manufactured by the method. 1-Methyl-5-[3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyryl monohydrochloride 5mg Corn starch 132mg Magnesium stearate 18mg Lactose 45mg Total 200mg Production example 3 Usual method A tablet with the following composition per tablet is manufactured. 7-[2-hydroxy-3-(4-phenyl-1
-Piperidyl)propoxy]-3,4-dihydrocarbostyryl 10 mg Corn starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Manufactured Example 4 Tablets having the following composition per tablet are manufactured in a conventional manner. 4-phenyl-1-[3-(2-oxo-1,
2,3,4-tetrahydroquinon-7-yloxy)propyl]-1-methylpiperidinium chloride hemihydrate 5 mg Corn starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Formulation example 5 In one tablet by the usual method Tablets of the following composition are manufactured. 5-[3-(4-hydroxy-4-phenyl-1
-Piperidyl)propoxy]-3,4-dihydrocarbostyryl 5mg Corn starch 132mg Magnesium stearate 18mg Lactose 45mg Total 200mg

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is a hydrogen atom, a lower alkenyl group, a lower alkynyl group, or a lower alkyl group that may have a phenyl group as a substituent, R ² is a hydrogen atom, a lower alkyl group, or a phenyl group, and R ³ is a hydrogen atom, a lower alkyl group, or a phenyl group. 1 to 1 selected from the group consisting of a lower alkyl group having a phenyl group as a substituent, or a halogen atom, a lower alkyl group, and a lower alkoxy group on the phenyl ring
A phenyl group that may have 3 substituents, R ⁴ is a hydrogen atom, a hydroxyl group, or a lower alkanoyl group, X is a halogen atom, and Y is a lower alkylene group that may have a hydroxyl group as a substituent.
and n represents 0, 1 or 2. Also this R ³ and
R ⁴ is a group that is bonded to each other through a nitrogen atom together with the carbon atom to which these are bonded. (R° is a hydrogen atom or a lower alkyl group). However, when R ³ represents a lower alkyl group having a phenyl group as a substituent, R ⁴ must not be a hydroxyl group or a lower alkanoyl group.
Further, the carbon-carbon bond between the 3rd and 4th positions of the carbostyril skeleton represents a single bond or a double bond. ] Carbostyryl derivatives and salts thereof.