JPH013182A - carbostyril derivatives - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Industrial applications The present invention relates to novel carbostyril derivatives.

DISCLOSURE OF THE INVENTION 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).

alkylenedioxy group, oxo group, hydroxyimino group, lower alkanoyloxyimino group, group -N-8 (A
represents a lower alkyl group, a phenyl lower alkyl group, a lower alkylsulfonyl group or a phenoxy lower alkyl group. ) or a group -NR'R"'(R' and R5 are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a phenyl lower alkyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, a phenyl ring A benzoyl group which may have 1 to 3 groups selected from the group consisting of a lower alkoxy group and a halogen atom as a substituent, a phenyl lower alkanoyl group, and a lower alkoxy group which may have a phenyl ring as a substituent. represents a phenyl lower alkenyl carbonyl group or a phenoxy lower alkyl group.Q represents O or 1.R2
represents a hydrogen atom or a lower alkyl group. R3 may have 1 to 3 groups selected from the group consisting of a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a lower alkoxy group, a halogen atom, and a nitro group as a substituent on the phenyl ring; A phenyl lower alkyl group, a benzoyl lower alkyl group, a phenyl lower alkenyl group, an alkenyl group, a phenoxy lower alkyl group, a phenylthio lower alkyl group, or an amine moiety which may be substituted with a halogen atom, cyan group or hydroxyl group as a substituent Indicates an anilino lower alkyl group which may have a lower alkyl group as a substituent. Furthermore, the carbon-carbon bonds at the 3rd and 4th positions of the carbostyril skeleton represent a single bond or a double bond.

However, when Q is O and R4 represents a hydrogen atom, a lower alkyl group, or a phenyl lower alkyl group, R5 must not be a hydrogen atom, a lower alkyl group, or a phenyl lower alkyl group. ] The carbostyril derivative represented by the above general formula (1) of the present invention and its salt have the effect of enhancing myocardial contraction (positive inotropic effect), the effect of increasing return blood flow, the antihypertensive effect, and the effect of norepinephrine-induced vascular It has contraction-inhibiting and anti-inflammatory effects,
For example, it is useful as a cardiotonic agent, an antihypertensive agent, and an antiinflammatory agent for the treatment of various heart diseases such as congestive heart failure, mitral valvular disease, atrial fibrillation, flutter, and paroxysmal atrial tachycardia. Especially the above-
The carbostyril derivative represented by the general formula (1) and its salt have excellent positive inotropic effect, return blood flow increasing effect, and antihypertensive effect, but they have almost no effect on increasing heart rate. It has characteristics. In addition, the above general formula (
The carbostyril derivative and its salt represented by 1) are:
It is also characterized by low toxicity and few central side effects such as vomiting, decreased motor function, and tremors.

In the above general formula (1), specific examples of winter grass defined are as follows.

Examples of lower alkylenedioxy groups include straight or branched alkylenedioxy groups having 1 to 4 carbon atoms, such as methylenedioxy, ethylenedioxy, trimethylenedioxy, and tetramethylenedioxy groups.

Examples of lower alkanoyloxy groups include formyloxy,
acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, tert
Examples include straight-chain or branched alkanoyloxy groups having 1 to 6 carbon atoms, such as -butylcarbonyloxy and hexanoyloxy groups.

Lower alkyl groups include methyl, ethyl, propyl,
isopropyl, butyl, tert-butyl, pentyl,
Examples include straight chain or branched alkyl groups having 1 to 6 carbon atoms such as hexyl group.

Examples of lower alkanoyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl,
Examples include straight chain or branched alkanoyl groups having 1 to 6 carbon atoms such as tert-butylcarbonyl and hexanoyl groups.

Examples of phenyl lower alkyl groups include benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-noenylpentyl, 6-phenylhexyl. , 2-methyl-3-phenylpropyl group and the like are phenylalkyl groups in which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms.

Examples of lower alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, ter
t-butoxycarbonyl, pentyloxycarbonyl,
Examples include linear or branched alkoxycarbonyl groups having 1 to 6 carbon atoms such as hexyloxycarbonyl groups.

Examples of lower alkylsulfonyl groups include straight-chain or branched alkylsulfonyl groups having 1 to 6 carbon atoms, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, and hexylsulfonyl groups. Examples include groups.

Examples of lower alkoxy groups include those having 1 to 1 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy groups.
6, a straight chain or branched alkoxy group can be exemplified.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

Examples of benzoyl groups that may have 1 to 3 groups selected from the group consisting of lower alkoxy groups and halogen atoms as substituents on the phenyl ring include benzoyl, 2-chlorobenzoyl, 3-chlorobenzoyl, and 4-chlorobenzoyl. , 4-fluorobenzoyl, 3-bromobenzoyl,
4-iodobenzoyl, 2,6-dichlorobenzoyl,
3,4-dichlorobenzoyl, 2,4-dibromobenzoyl, 2,4,6-drichlorobenzoyl, 4-methoxybenzoyl, 3-ethoxybenzoyl, 2-propoxybenzoyl, 4-n-butoxybenzoyl, 3-pentyloxy A substituent having 1 to 6 carbon atoms on the phenyl ring such as benzoyl, 2-hexyloxybenzoyl, 3,4-dimethoxybenzoyl, 2,6-dimethoxybenzoyl, 2゜4.6-1-rimethoxybenzoyl group, etc. Examples include benzoyl groups that may have 1 to 3 groups selected from the group consisting of linear or branched alkoxy groups and halogen atoms.

Examples of the phenyl lower alkanoyl group include 2-phenylacetyl, 3-phenylpropionyl, 4-phenylbutyryl, 5-phenylpentanoyl, 6-phenylhexanoyl, 2-methyl-3-phenylpropionyl, 2,
Examples include phenylalkanoyl groups in which the alkanoyl moiety is a linear or branched alkanoyl group having 2 to 6 carbon atoms, such as 2-dimethyl-3-phenylpropionyl group.

Examples of the phenyl lower alkenyl carbonyl group that may have a lower alkoxy group as a substituent on the phenyl ring include cinnamoyl, 4-phenyl-2-butenoyl, 5
-Phenyl-3-pentenoyl, 5-phenyl-4-pentenoyl, 4-phenyl-2-methyl-2-butenoyl, 6-phenyl-3-hexenoyl, 4-methoxycinnamoyl, 3,4-dimethoxycinnamoyl, 4 −(
3-ethoxyphenyl)-2-butenoyl, 5-(2-
propoxyphenyl)-3-pentenoyl, 5-(4-
n-butoxyphenyl)-4-pentenoyl, 4-(3
-Pentyloxyphenyl> -Carbon as a substituent on the phenyl ring such as -2-methyl-2-butenoyl, 6-(2-hexyloxyphenyl)-3-hexenoyl, 3゜4.5-trimethoxycinnamoyl group, etc. A phenylalkenylcarbonyl group in which the alkenylcarbonyl moiety is a linear or branched alkenylcarbonyl group having 3 to 6 carbon atoms, which may have 1 to 3 linear or branched alkoxy groups having 1 to 6 carbon atoms; can be exemplified.

Examples of the phenoxy lower alkyl group include phenoxymethyl, 2-phenoxyethyl, 1-phenoxyethyl, and 3-phenoxyethyl.
Phenoxyprovir, 4-phenoxybutyl, 1,1-
Phenoxyalkyl in which the alkyl moiety is a straight or branched alkyl group having 1 to 6 carbon atoms, such as dimethyl-2-phenoxyethyl, 5-phenoxypentyl, 6-phenoxyhexyl, 2-methyl-3-phenoxypropyl group, etc. Examples include groups.

The phenyl ring may have 1 to 3 groups selected from the group consisting of a lower alkoxy group, a halogen atom, and a nitro group as a substituent, and the alkyl portion may have a halogen atom, cyan group, or hydroxyl group as a substituent. In addition to the above phenyl lower alkyl groups, optionally substituted phenyl lower alkyl groups include 4-methoxybenzyl, 3-ethoxybenzyl, 2-propoxybenzyl, 4-n-butoxybenzyl, 3-pentyloxybenzyl, 2-hexyloxybenzyl, 4-nitrobenzyl, 3-nitrobenzyl, 2-nitrobenzyl, 2-(4-methoxyphenyl)ethyl, 1-(3-ethoxyphenyl)ethyl, 3-(2-propoxyphenyl) Propyl, 4-(
4-n-butoxyphenyl)butyl, 5-(2-nitrophenyl)pentyl, 4-fluorobenzyl, 3-bromobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 4-iodopenzyl , 2゜6-
Dichloropencyl, 3,4-dichlorobenzyl, 2,4
-dibromobenzyl, 2.4.6-dolichlorobenzyl, 3,4-dimethoxybenzyl, 2.6-dimethoxybenzyl, 2,4.6-dolichlorobenzyl, 2,4-
dinitrobenzyl, 6-(4-chlorophenyl)hexyl, 5-(2-chlorophenyl)pentyl, 3-(3
-chlorophenyl)propyl, 2-(2,6-cyclophenyl)ethyl, 2-phenyl-2-hydroxyethyl, 3-cyano-3-phenylpropyl, 1-phenyl-1-hydroxymethyl, 3-hydroxy-3 -phenylpropyl, 2-hydroxy-3-phenylpropyl, 4-hydroxy-4-phenylbutyl, 5-hydroxy-5-phenylpemethyl, 6-bitroxy-6-phenylhexyl, 2-hydroxy-4-phenylbutyl,
3-hydroxy-5-phenylpentyl, 4-hydroxy-6-phenylhexyl, 1-phenyl-1-chloromethyl, 2-phenyl-2-bromoethyl, 2-fluoro-3-phenylpropyl, 4-iodo-4- Phenylbutyl, 5-chloro-5-phenylpentyl, 6-chloro-6-phenylhexyl, 2-fluoro-4-phenylbutyl, 3-chloro-5-phenylpentyl, 4-bromo-6-phenylhexyl, diphenylmethyl , 2.
2-diphenylethyl, 3,3-diphenylpropyl,
3.4-diphenylbutyl, 4,5-diphenylpentyl, 6,6-diphenylhexyl, 1-phenyl-1-
cyanmethyl, 2-phenyl-2-cyanomethyl, 2-
Cyano-3-phenylpropyl, 4-cyano-4-phenylbutyl, 5-cyano-5-phenylpentyl, 6-
cyano-6-phenylhexyl, 2-cyano-4-phenylbutyl, 3-cyano-5-phenylpentyl, 4-
Cyano-6-phenylhexyl, 3-cyano-3=(4
-methoxyphenyl)propyl, 2-(2-chlorophenyl)-2-hydroxyethyl, 3-hydroxy-3
-(4-nitrophenyl)propyl, 3-hydroxy-
3-(3,4-dimethoxyphenyl)propyl, 2-(
3-chlorophenyl)-2-hydroxyethyl, 3-hydroxy-3-(4-chlorophenyl)propyl, 3-
cyano-3-(2,6-dichlorophenyl)propyl,
A substituent on the phenyl ring such as 3-cyano-3-(3-nitrophenyl)propyl group selected from the group consisting of a straight or branched alkoxy group having 1 to 6 carbon atoms, a halogen atom, and a nitro group. A linear or branched chain in which the alkyl part has 1 to 6 carbon atoms, which may have 1 to 3 groups, and which may be substituted with a halogen atom, cyan group, or hydroxyl group as a substituent. Examples include phenylalkyl groups, which are alkyl groups.

Examples of the benzoyl lower alkyl group include benzoylmethyl, 2-benzoylethyl, 1-benzoylethyl, 3-
Benzoylpropyl, 4-benzoylbutyl, 1,1-
Benzoyl alkyl in which the alkyl moiety is a straight or branched alkyl group having 1 to 6 carbon atoms, such as dimethyl-2-benzoylethyl, 5-benzoylpentyl, 6-benzoylhexyl, 2-methyl-3-benzoylpropyl group, etc. Examples include groups.

Examples of phenyl lower alkenyl groups include styryl, 3-phenyl-1-propenyl, 3-phenyl-2-propenyl, 4-phenyl-3-butenyl, 4-phenyl-2-
Butenyl, 5-phenyl-4-pentenyl, 5-phenyl-3-pentenyl, 5-phenyl-2-pentenyl,
6-phenyl-5-hexenyl, 6-phenyl-4-hexenyl, 6-phenyl-3-hexenyl, 6-phenyl-2-hexenyl, 2-methyl-4-phenyl-3-
Examples include phenylalkenyl groups in which the alkenyl moiety is a linear or branched alkenyl group having 2 to 6 carbon atoms, such as butenyl, 2-methyl-styryl, and 1-methyl-styryl.

Examples of alkenyl groups include vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl,
2-hexenyl, 1-heptenyl, 1-octenyl, 1
-nonenyl, 1-decenyl, 1-undecenyl, 1-dodecenyl, 1-hebutenyl, 3-hebutenyl, 2-methyl-4-heptenyl, 2-methyl-5-hebutenyl, 4
-Methyl-2-hebutenyl, 3-methyl-1-heptenyl, 1,3-hebutagenyl, 1,4-hebutagenyl, 1,5-hebutagenyl, 1,6-hebutagenyl,
2,4-hebutagenyl, 2-methyl-2,4-heptagenyl, 2,6-dimethyl-2゜4-hebutagenyl, 2,5-dimethyl-1,3-hebutagenyl, 2.4
．． 6-drimethyl-2゜4-hebutagenyl, 2-octenyl, 3-octenyl, 4-octenyl, 2-methyl-5-octenyl, 2-methyl-6-octenyl, 2-
Methyl-7-octenyl, 1,3-octagenyl, 1
．． 4-octagenyl, 1,5-octagenyl, 1,
6-octagenyl, 1,7-octagenyl, 2,4
-Octagenyl, 3,7-octagenyl, 4,8-
Dimethyl-3,7-octagenyl, 2.4.6-dolimethyl-3,7-octagenyl, 3,4-dimethyl-
2,5-octagenyl, 4,8-dimethyl-2,6-
Octagenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 2-methyl-5-nonenyl, 2-methyl-6-
nonenyl, 2-methyl-7-nonenyl, 2-methyl-8
-nonenyl, 1,3-nonajenyl, 1.4-nonajenyl, 1,5-nonajenyl, 1.6-nonajenyl,
1,7-nonajenyl, 1,8-nonajenyl, 2,4
-nonajenyl, 3.7-nonajenyl, 4,8-dimethyl-3°7-nonajenyl, 2. /1. ．． 6-drimethyl-3゜7-nonagenyl, 3,4-dimethyl-2,
5-nonajenyl, 4,8-dimethyl-2,6-nonajenyl, 2-decenyl, 3-decenyl, 4-decenyl,
5-decenyl, 2-methyl-6-decenyl, 3-methyl-7-decenyl, 4-methyl-8-decenyl, 5-methyl-9-decenyl, 1,3-decajenyl, 1,4-decajenyl, 1, 5-decajenyl, 1,6-decajenyl, 1,7-decajenyl, 1,8-decajenyl,
1,9-decadienyl, 2-methyl-2,4-decadienyl, 3-methyl-2,5-decadienyl, 4゜8-dimethyl-2,6-decadienyl, 2,4゜6-drimethyl-3,7-decadienyl , 2,9-dimethyl-3,7
-decajenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 2-methyl-
6-undecenyl, 3-methyl-7-undecenyl, 4
-Methyl-8-undecenyl, 5-methyl-9-undecenyl, 2-methyl-10-undecenyl, 1゜3-undecajenyl, 1,4-undecajenyl, 1,5-
undecajenyl, 1,6-undecajenyl, 1,7
-undecajenyl, 1,8-undecajenyl, 1,
9-Undecajenyl, 1, 10-Undecajenyl, 2-Methyl-2゜4-Undecajenyl, 3-Methyl-2,5-Undecajenyl, 4,8-dimethyl-2,
6-undecajenyl, 2,4.6-dolimethyl-3゜8-undecajenyl, 2,9-dimethyl-3゜8-undecajenyl, 2-dodecenyl, 3-dodecenyl,
4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 2
-Methyl-7-dodecenyl, 3-methyl-8-dodecenyl, 4-methyl-9-dodecenyl, 5-methyl-10-
Dodecenyl, 6-methyl-11-dodecenyl, 2-methyl-2,4-dodecagenyl, 3-methyl-2,5-dodecagenyl, 4,8-dimethyl-2,6-dodecagenyl, 2,4.6-dorimethyl-2 ,7-dodecagenyl, 2,10-dimethyl-2,8-dodecagenyl, 2
,5-dimethyl-3,7-dodecagenyl, 4,8.1
2-trimethyl-3,7゜11-dodecagenyl, 1,
3.5-hebutadienyl, 2,4.6-octagenyl, 1゜3.6-nonajenyl, 2,6,8-decatryl, 1.5.7-undecajenyl, etc. having 1 to 1 carbon atoms
Examples include 12 linear or branched alkenyl groups having 1 to 3 double bonds.

Examples of phenylthio lower alkyl groups include phenylthiomethyl, 2-phenylthioethyl, 1-phenylthioethyl, 3-phenylthiopropyl, 4-phenylthiobutyl, 1,1-dimethyl-2-phenylthioethyl, 5-
Phenylthiopentyl, 6-phenylthiohexyl, 2
Examples include phenylthioalkyl groups in which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, such as -methyl-3-phenylthiopropyl group.

Examples of the anilino lower alkyl group which may have a lower alkyl group as a substituent on the amine moiety include anilinomethyl, 2-anilinoethyl, 1-anilinoethyl, 3-anilinopropyl, 4-7nilinobutyl, 1,1-dimethyl- 2-anilinoethyl, 5-anilinopentyl, 6-
7-nylinohexyl, 2-methyl-3-anilinopropyl, N-methylanilinomethyl, 2-(N-methylanilino)ethyl, 1-(N-ethylanilino)ethyl, 3-
(N-propylanilino)propyl, 4-(N-butylanilino)butyl, 1,1-dimethyl-2-(N-pentylanilino)ethyl, 5-(N-hexylanilino)pentyl, 6-(N- methylanilino)hexyl, 2
- The amine moiety such as methyl-3-(N-ethylanilino)propyl group may have a linear or branched alkyl group having 1 to 6 carbon atoms as a substituent, and the alkyl moiety has 1 to 6 carbon atoms. An example is an anilinoalkyl group which is a straight chain or branched alkyl group in No. 6.

The compound of the present invention represented by the above general formula (1) can be produced by various methods, and one preferred example thereof is, for example, produced by the method shown below.

Reaction formula-1 HH (2> Same as (1a)) is shown. The carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton are the same as above. ] The method shown in Reaction-1 above involves the activation of a carbostyril derivative represented by general formula (2) or an activated derivative of its carboxy group and an amine represented by general formula (3) or its amine group. The reaction is carried out by reacting the compound in a conventional amide bond formation reaction. Conditions for known amide bond-forming reactions can be easily applied to this reaction. For example, (a) the mixed acid anhydride method, that is, the carbostyril derivative 2) is reacted with an alkylhalocarboxylic acid to form a mixed acid anhydride, and then the amine (3) is reacted with the carbostyril derivative 2).
(b) active ester method, that is, carbostyril derivative (2) is reacted with p-nitrophenyl ester,
Active esters such as N-hydroxysuccinimide ester and 1-hydroxybensitriazoyl ester,
A method of reacting this with amine (3), (iii) carbodiimide method, that is, carbostyril derivative (2) is reacted with amine (3).
(2) a method of condensing 3) in the presence of an activator such as dicyclohexylcarbodiimidobonyldiimidazole;
Other methods include converting carbostyryl derivative (2) into carboxylic acid anhydride with a dehydrating agent such as acetic anhydride, and reacting this with amine (3);
A method of reacting an amine (3) with an ester of 2) and a lower alcohol under high pressure and high temperature, carbostyryl derivative (2)
) to the acid halide, i.e. carboxylic acid halide, to the amine (
3) can be mentioned. In addition, carbostyril derivative (2) is triphenylphosphine,
It is also possible to use a method of activating with a phosphorus compound such as diethyl cyanophosphate or diethylchlorophosphonoate and reacting the activated phosphorus compound with the amine (3).

The mixed acid anhydride used in the mixed acid anhydride method is obtained by the usual Schotten-Baumann reaction, and the compound of general formula (1a) is produced by reacting it with the amine (3) without isolation. be done. short story
The Baumann reaction is carried out in the presence of a basic compound. As the basic compound used, compounds commonly used in the Schotten-Baumann reaction are used, such as triethylamine, trimethylamine, pyridine, dimethyl 7-diphosphorus,
N-methylmorpholine, 4-dimethylaminopyridine,
1,5-diazabicyclo(4,3°O)nonene-5(0
8N>, 1,8-diazabicyclo(5,4,0) undecene-7(DBU>, 1,4-diazabicyclo(2,2
, 2) Organic bases such as octane (DABCO), and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate. The reaction is usually carried out at -20 to 100'C1, preferably 0 to 50°C, and the reaction time is 5 minutes to 10 hours, preferably 5 minutes to
It is 2 hours. The reaction between the obtained mixed acid anhydride and amine (3) is usually carried out at -20 to 150°C, preferably at 10 to 50°C.
The reaction time is 5 minutes to 10 hours, preferably 5 minutes to 5 hours. The mixed acid anhydride method is carried out in or in the absence of a suitable solvent. Any solvent commonly used in the mixed acid anhydride method can be used as the solvent, specifically halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, and aromatic hydrocarbons such as benzene, toluene, and xylene. Hydrogens, diethyl ether,
Examples include ethers such as tetrahydrofuran and dimethoxyethane, esters such as methyl acetate and ethyl acetate, and non-proprietary polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide and hexamethylphosphoric triamide. The alkylhalocarboxylic acids used in the production of mixed acid anhydrides include, for example, OD methyl formate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, etc., and these are usually carbostyryl. It is used in at least an equimolar amount, preferably about 1 to 2 times the molar amount of the derivative (2). Further, the amine (3) is usually used in an amount of at least an equimolar amount, preferably about 1 to 2 times the molar amount of the carbostyryl derivative (2).

Further, the active ester method, for example when N-hydroxysuccinimide ester is used, is carried out in a suitable solvent that does not affect the reaction. Examples of the solvent include halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, benzene, toluene,
Aromatic hydrocarbons such as xylene, ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane,
Examples include esters such as methyl acetate and ethyl acetate, aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. The reaction is carried out at 0-150°C, preferably at 10-1
The process is completed in 5 to 30 hours at 00°C. Amine (3) and N
-The ratio of use with hydroxysuccinimide ester is
The former is usually at least equimolar to the latter, preferably equimolar to twice the molar amount.

Further, when a method of reacting the amine (3) with the carboxylic acid halide is adopted, the reaction is carried out in a suitable solvent in the presence of a dehydrohalogenating agent.

As the dehydrohalogenating agent, a common basic compound is used. As the basic compound, a wide variety of known compounds can be used. For example, in addition to the basic compounds used in the Schotten-Baumann reaction, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, silver carbonate,
Examples include alcoholades such as sodium methylate and sodium ethylate. Incidentally, the amine (3) can also be used as a dehydrohalogenation agent by using it in parallel.

Examples of solvents include, for example, in addition to the solvents used in the mixed acid anhydride method, alcohols such as methanol, ethanol, propatool, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, pyridine, and acetone. , acetonitrile, and mixed solvents thereof. The ratio of amine (3) and carboxylic acid halide to be used is not particularly limited and may be appropriately selected within a wide range, but usually the latter is at least equimolar to the former, preferably equimolar - 2 times. It is preferable to use a molar amount. The reaction is usually -30 to 180
The reaction is carried out at a temperature of about 150° C., preferably 0 to 150° C., and the reaction is generally completed in about 5 minutes to 30 hours.

In the above, the carboxylic acid halide is produced, for example, by reacting the carboxylic acid halide derivative (2) with a halogenating agent in the absence of a solvent or in the presence of a solvent. Any solvent can be used as long as it does not adversely affect the reaction.
Examples include aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as chloroform, methylene chloride, and carbon tetrachloride, ethers such as dioxane, tetrahydrofuran, and diethyl ether, dimethylformamide, and dimethyl sulfoxide. .

As the halogenating agent, a normal halogenating agent that converts the hydroxyl group of a carboxyl group into a halogen atom can be used, such as thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide, etc. Ru. The ratio of the carbostyril derivative 2) and the halogenating agent is not particularly limited and is selected as appropriate. However, when the reaction is carried out without a solvent, the latter is usually used in a large excess amount relative to the former, or when the solvent is used. When the reaction is carried out in a reactor, the latter is usually used in at least an equimolar amount, preferably 2 to 4 times the molar amount of the former. The reaction temperature (and reaction time) is also not particularly limited, but is usually about room temperature to 100°C, preferably 50 to 80°C.
C for about 30 minutes to 6 hours.

Further, a method of activating the carbostyril derivative (2) with a phosphorus compound such as triphenylphosphine, diethyl cyanophosphate, diethyl chlorophosphate, etc. and reacting it with the amine (3) can be carried out in a suitable solvent. Any solvent can be used as long as it does not affect the reaction, but specific examples include halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, and aromatic hydrocarbons such as benzene, toluene, and xylene. , ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane, esters such as methyl acetate and ethyl acetate, and aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. In the above reaction, since the amine (3) itself acts as a basic compound, the reaction may proceed well by using it in excess of the theoretical amount, or if necessary, a basic compound such as triethylamine, Trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, DBN, DBU, DAB
Organic bases such as CO and potassium carbonate, sodium carbonate,
Inorganic bases such as potassium hydrogen carbonate and sodium hydrogen carbonate can also be used. The reaction is carried out at about 0 to 150'C, preferably about 0 to 100'C, and the reaction time is about 1 to 30 hours. Carbostyryl derivative (2)
The proportion of the phosphorus compound and amine (3) to be used is usually at least about equimolar amounts, preferably 1 to 3
Double the molar amount.

Reaction formula-2 (1b) (1G>(1d> (Ie) 36 (1j) R8 represents 1 to 3 groups selected from the group consisting of a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkoxy group as a substituent on the phenyl ring, and a halogen atom.
This refers to a benzoyl group that may be present, a phenyl lower alkanoyl group, or a phenyl lower alkenylcarbonyl group that may have a lower alkoxy group as a substituent on the phenyl ring. R9 represents a lower alkyl group, a phenyl lower alkyl group, a lower alkylsulfonyl group or a phenoxy lower alkyl group. R9Z represents a hydrogen atom in addition to the above R9. Xl represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group, or an aralkylsulfonyloxy group. RIO and R+ represent a hydrogen atom or a lower alkyl group. ] In the compound represented by the above general formula (6), the halogen atom defined by Xl is specifically a chlorine, fluorine, bromine, and iodine atom, and the lower alkanesulfonyloxy group is specifically methanesulfonyl. Examples include oxy, ethanesulfonyloxy, propanesulfonyloxy, isopropanesulfonyloxy, butanesulfonyloxy, tert-butanesulfonyloxy, pentanesulfonyloxy, hexanesulfonyloxy groups, and specifically as the arylsulfonyloxy group, phenyl Sulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4
Examples include substituted or unsubstituted arylsulfonyloxy groups such as -nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy, and α-nanotylsulfonyloxy groups, and specific examples of aralkylsulfonyloxy groups include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, Examples include substituted or unsubstituted aralkylsulfonyloxy groups such as 3-chlorobenzylsulfonyloxy and α-naphthylmethylsulfonyloxy groups.

The reaction between the compound of general formula (1b) and hydroxylamine (4) can be carried out in a suitable inert solvent in the presence or absence of a basic compound. Examples of basic compounds used in this case include inorganic basic compounds such as sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate, and organic bases such as piperidine, pyridine, triethylamine, DBN, DBtJ, DABGO, and sodium acetate. can be exemplified. Any inert solvent may be used as long as it does not adversely affect the reaction, but examples include lower alcohols such as methanol, ethanol, and isopropanol, dioxychloride, tetrahydrofuran, and diethyl ether ethylene glycol. Ethers such as monomethyl ether, aromatic hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc. Can be mentioned. The amount of hydroxylamine (4) to be used is usually at least an equimolar amount, preferably an equimolar to 5 times the molar amount of the compound of general formula (1b).The reaction temperature is usually room temperature to About 200'C, preferably room temperature to 150'C
Generally, the reaction is completed in about 1 to 15 hours.

Reduction of the compound of general formula (1G) or (1d) can be carried out, for example, by catalytic hydrogenation in a suitable solvent in the presence of a catalyst. Examples of solvents used include water, alcohols such as acetic acid, methanol, ethanol, and isopropanol, hydrocarbons such as hexane and cyclohexane, ethers such as dioxane, tetrahydrofuran, diethyl ether, and diethylene glycol 7-methyl ether, and acetic acid. Examples include esters such as ethyl and methyl acetate, and aprotic polar solvents such as dimethylformamide. Examples of the catalyst used include palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, and Raney nickel. The amount of the catalyst to be used is generally about 0.02 to 1 times the amount of compound (1c) or (1d). The reaction temperature is usually -20°C to around room temperature, preferably O'
C to around room temperature, the hydrogen pressure is usually 1 to 10 atm, and the reaction is generally completed in about 0.5 to 10 hours.

In addition, for reduction of the compound of general formula (1c) or (1d),
A method using a hydrogenation reducing agent can be applied.

Examples of the hydrogenation reducing agent used here include sodium aluminum hydride, sodium borohydride, diborane, etc., and the amount used is usually at least equimolar to compound (1C) or (1d), preferably It is preferable that the amount is equivalent to -10 times the molar amount. This reduction reaction is
Usually a suitable solvent such as water, methanol, ethanol,
Lower alcohols such as isopropanol, ethers such as tetrahydrofuran, ethyl ether, diglyme, etc. are used, and the temperature is usually about -60 to 50'C, preferably -30'C.
C~ It is carried out at room temperature for about 10 minutes to about 15 hours. In addition, when lithium aluminum hydride or diborane is used as a reducing agent, it is preferable to use an anhydrous solvent such as tetrahydrofuran, diethyl ether, diglyme, or the like.

The reaction for converting the compound of general formula (1G) into the compound of general formula (1d) is carried out in the presence of a lower alkanoylating agent. Examples of the lower alkanoylating agent used include lower alkanoic acids such as formic acid, acetic acid, and propionic acid, lower alkanoic anhydrides such as acetic anhydride, and lower alkanoic acid halides such as acetyl chloride and propionyl bromide. When using an acid anhydride or an acid halide as the lower alkanoylating agent, a basic compound may be present in the reaction system. Examples of the basic compound used include alkali metals such as sodium metal and potassium metal, hydroxides, carbonates, and bicarbonates of these alkali metals, and organic bases such as triethylamine, pyridine, and piperidine. Although the reaction proceeds either without a solvent or in a solvent, it is usually carried out using a suitable solvent. Examples of solvents include ketones such as acetone and methyl ethyl ketone, ethers such as dioxane and diethyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, and halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride. Examples include acetic acid, acetic anhydride, water, pyridine and the like. The amount of the lower alkanoylating agent to be used is preferably at least an equimolar amount, generally an equimolar amount to a large excess amount, relative to compound (1G).

The reaction temperature is usually about ○ to 150°C, preferably about 0 to 100'C, and generally 5 minutes to 15 minutes.
The reaction is completed in about an hour. In addition, when lower alkanoic acids are used as lower alkanoylating agents, mineral acids such as sulfuric acid and hydrochloric acid, and sulfonic acids such as p-toluenesulfonic acid, benzenesulfonic acid and ethanesulfonic acid are added as dehydrating agents into the reaction system. In this case, the reaction temperature is particularly preferably about 50 to 120°C.

The reaction between the compound of general formula (1e) and the compound of general formula (5) and the reaction of the compound of general formula (1g) with the compound of general formula (5>) are the reactions of the compound of general formula (2) and the compound of general formula (5). (3)
can be carried out under similar reaction conditions to the reaction with the compound.

The reaction between the compound of the general formula (1e) and the compound of the general formula (6) can be carried out under the same operation and conditions as the method of reacting the carboxylic acid halide with the amine (3) described above.

The reaction of the compound of general formula (1e) or the compound of general formula (11) with the compound of general formula (7) is carried out without a solvent or in the presence of a reducing agent in a suitable solvent.

Examples of the solvent used here include water, alcohols such as methanol, ethanol, and isopropanol, ethers such as acetic acid, dioxane, tetrahydrofuran, diethyl ether, and diglyme, benzene, toluene,
Examples include aromatic hydrocarbons such as xylene. Reduction methods include formic acid, hydrogenated Il! l! Examples include a method using a hydrogenation reducing agent such as sodium chloride, sodium cyanoborohydride, lithium aluminum hydride, and a catalytic reduction method using a catalytic reduction catalyst such as palladium black, palladium carbon, platinum oxide, platinum black, Raney nickel, etc. can. When using formic acid as a reducing agent, the reaction temperature is usually room temperature to 200℃.
'C1 is preferably around 50 to 150'C,
The reaction is completed in about 1 to 10 hours. The amount of formic acid used is preferably in large excess relative to the compound of general formula (1e) or (11). In addition, when using a hydrogenation reducing agent, the reaction temperature is usually -30 to 100'C, preferably about 0 to 70'C, and the reaction is carried out for 30 minutes to 12
It will be completed in about an hour. The amount of reducing agent used is usually equimolar to the compound of general formula (1e) or (11>).
The amount is preferably 20 times the mole, preferably 1 to 5 times the mole.

Especially when using lithium aluminum hydride as a reducing agent, dioxane, tetrahydrofuran,
Preferably, ethers such as diethyl ether and diglyme, and aromatic hydrocarbons such as benzene, toluene and xylene are used. When using a catalytic reduction catalyst, the temperature is usually -30 to 100°C, preferably 0 to 60°C in a hydrogen atmosphere at normal pressure to 20 atm, preferably normal pressure to 10 atm.
The reaction ends at a temperature of . The amount of the catalyst used is usually 0.1 to 0.1 to the compound of general formula (1e) or (11).
The amount is preferably 40% by weight, preferably 1 to 20% by weight. In addition, the amount of compound (7) to be used is based on general formula (1e)
Or, it is usually used in at least an equimolar amount, preferably in an equimolar to large excess amount, relative to the compound (11).

Further, the general formula (1f) or (1
By reducing the compound of h), the compound of the general formula (1) in which R9 is a lower alkyl group or a phenyl lower alkyl group
Compound q) can be produced. For this reduction, a method of reducing the compound of the general formula (1C) or (1d) using a hydrogenation reducing agent can be applied. In this case, the reaction temperature is
Usually -60 to 150'C, preferably -30 to 100'C
It is better to

H(1q) [In the formula, R9, R9', Q and 3 of the carbostyril skeleton
The carbon-carbon bond at position and 4-position is the same as above. ] General formula (1b
The reaction between the compound of formula (8) and the compound of general formula (8) is carried out without a solvent or in a suitable solvent, in the absence or presence of a dehydrating agent. Examples of solvents used here include alcohols such as methanol, ethanol, and isopropanol, aromatic hydrocarbons such as benzene, toluene, and xylene, dimethylformamide, dimethylacetamide, and N-
Examples include aprotic polar solvents such as methylpyrrolidone. Examples of the dehydrating agent include drying agents used for dehydrating common solvents such as molecular sieves, mineral acids such as hydrochloric acid, sulfuric acid, and boron trifluoride, and organic acids such as p-toluenesulfonic acid. The reaction is usually carried out at room temperature to 250°C.
The reaction is carried out at a temperature of about 50°C to 200°C, and is generally completed in about 1 to 48 hours. Compound(
The amount of compound (8) used is not particularly limited, but the amount of compound (
It is usually used in at least an equimolar amount, preferably in large excess, relative to 1b). In addition, the amount of dehydrating agent used is
In the case of a desiccant, it is usually preferable to use a large excess amount, and in the case of an acid, it is preferable to use a catalytic amount.

The compound of general formula (1k) thus obtained is subjected to the next reduction reaction without being isolated.

The reduction reaction of the compound of general formula (1k) is as follows:
It can be carried out under the same reaction conditions as the reduction reaction of the compound in G) or (1d).

Note that the compound of general formula (8) used in the above reaction is R9
/ - When it is a hydrogen atom, the reaction between compound (1b) and compound (8) results in the general formula [wherein R9, Q and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. ] A compound represented by the general formula (in the formula, R9, Q, and the 3- and 4-positions of the carbostyril skeleton is formed) is produced by a subsequent reduction reaction.
The carbon-carbon bond at position is the same as above. ] is derived from the compound represented by

Reaction formula-4 [R2, X181 in the formula] 2 and 3 of the carposdiryl skeleton
The carbon-carbon bond at position and 4-position is the same as above. R12 represents a lower alkanoyl group. R+3 represents R3 other than a lower alkanoyl group and a hydrogen atom. ] The reaction between the compound of general formula (1n) and the compound of general formula (9) can be carried out under the same reaction conditions as the reaction between the compound of general formula (1e) and the compound of general formula (5).

Further, the reaction between the compound of general formula (1n) and the compound of general formula (10) is the reaction of the compound of general formula (1e) with the compound of general formula (6).
) can be carried out under similar reaction conditions to the reaction with the compound.

Among the compounds of the general formula (1p) obtained by the above reaction formula-4, the compounds in which R1'3 represents a phenyl lower alkyl group are:
The corresponding compound of general formula (1n) can be derived by dephenyl lower alkylation (for example, debenzylation). This dephenyl lower alkylation is carried out by oxidation in a suitable solvent, such as water, lower alcohols such as methanol, ethanol, and isopropanol, ethers such as dioxane and tetrahydrofuran, solvents such as acetic acid, or a mixed solvent thereof. Treat in the presence of a catalytic reduction catalyst such as platinum, palladium-carbon, or palladium-black at a temperature of 0 to 100°C and a hydrogen pressure of 1 to 10 atm for about 0.5 to 10 hours. (addition of acid may be added) or by heat treatment in an aqueous solution of hydrobromic acid.

In addition, the corresponding general formula (1n
). For the hydrolysis reaction, any conventional hydrolysis reaction conditions can be applied, such as basic compounds such as sodium hydroxide, potassium hydroxide, barium hydroxide, potassium carbonate, mineral acids such as sulfuric acid, hydrochloric acid, nitric acid, etc. , water in the presence of an organic acid such as acetic acid or aromatic sulfonic acid,
Alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone;
The reaction is carried out in an ether such as dioxane or ethylene glycol, a solvent such as acetic acid, or a mixed solvent thereof. The reaction is usually carried out at air temperature to 200°C, preferably room temperature to 15°C.
It progresses at around 0'C and generally ends in about 0.1 to 30 hours.

Furthermore, among the compounds of the above general formula (11)), a compound in which R+3 represents a phenyl lower alkyl group is prepared by mixing it in an alcohol such as methanol, ethanol, or isopropanol in the presence of formic acid and a catalyst such as palladium black. General formula (1p) in which R+3 represents a formyl group upon oxidation
can be derived from compounds of The oxidation reaction is usually O~100
℃, preferably around 0 to 70℃, and generally 1
The reaction is completed in about 0 minutes to 5 hours.

Furthermore, the general formula in which R1 represents a lower alkylenedioxy group (
The compound of formula (1) can be hydrolyzed to derive the corresponding compound of general formula (1) in which R1 is an oxo group. The reaction conditions for the hydrolysis reaction of the compound of general formula (10) above can be applied to this hydrolysis reaction.

Reaction formula-5 (11) (1q) [In the formula, R is the same as above. Rj4 represents a halogen atom. ] The cyclization reaction of the compound of general formula (11) is generally called the Friedel-Krach reaction, and is carried out in the presence of a Lewis acid in a suitable solvent. As the solvent used here, any solvent commonly used in this type of reaction can be used, such as carbon disulfide, nitrobenzene, chlorobenzene, dichloromethane, dichloroethane, trichloroethane, carbon tetrachloride, tetrachloroethane, etc. can be preferably exemplified. Examples of the Lewis acids that can be used include aluminum chloride, zinc chloride, ferrous chloride, tin chloride, boron tribromide, borium trifluoride, and concentrated sulfuric acid. The amount of Lewis acid used is usually 2 to 6 times, preferably 3 to 4 times, the amount of the compound of general formula (11). The reaction temperature is usually about 20 to 120°C, preferably about 40 to 70°C, and the reaction is generally completed in about 0.5 to 6 hours.

Reaction Formula-6 [In the formula, R, Rj 2 and the carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton are the same as above. R15 represents a hydroxyl group or a lower alkoxy group. ] The reaction to obtain the compound of general formula (13) by reducing the compound of general par. The reduction is carried out using a mixture of a salt and an acid or a metal or a metal salt and an alkali metal hydroxide, sulfide, ammonium salt, etc. as a reducing agent. ■When adopting the catalytic reduction method,
Examples of solvents used include water, alcohols such as acetic acid, methanol, ethanol, and isopropanol, hydrocarbons such as hexane and cyclohexane, ethers such as diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, and diethyl ether, ethyl acetate, Examples include esters such as methyl acetate, aprotic polar solvents such as dimethylformamide, and the like. The catalytic reduction catalyst used is, for example, palladium, palladium-
Black, palladium-carbon, platinum, platinum oxide, copper chromite, Raney nickel, etc. are used. The amount of catalyst used is 0.02 to 1.00 per the compound of general formula (1).
I wonder if it's double the weight. The reaction is carried out at -20'C to around room temperature, preferably at 0°C to around room temperature, at a hydrogen pressure of 1 to 10 atm, and generally takes about 0.5 to 10 hours to complete.

In addition, when method (■) is adopted, iron, zinc, tin or stannous chloride and a mineral acid such as hydrochloric acid or sulfuric acid, or
Zinc or tin and alkali metal hydroxides such as sodium hydroxide, sulfides such as ammonium sulfide, aqueous ammonia,
A mixture with ammonium salts such as ammonium chloride is used as reducing agent. Examples of the inert solvent used include water, acetic acid, methanol, ethanol, dioxane, and the like. The conditions for the above reduction reaction may be appropriately selected depending on the reducing agent used. For example, when stannous chloride and hydrochloric acid are used as reducing agents, it is advantageous to
The reaction is preferably carried out at around room temperature for about 0.5 to 10 hours. The amount of the reducing agent to be used is preferably at least equimolar, usually equimolar to 5 times the molar amount of the raw material compound.

In the above method (①), when the reaction is carried out at room temperature to around 150°C, the compound of the general formula (1) is formed through the compound of -par (13).
can be directly prepared.

Acylation of the compound of general formula (13) is carried out by the above-mentioned -per(1
The compound of G) can be carried out under similar reaction conditions to the reaction leading to the compound of general formula (1d).

The reaction of cyclizing the compound of -par (13) or the compound of -par (14) to obtain the compound of general formula (1) can be carried out in a suitable solvent in the presence of a basic compound or an acid, preferably an acid or in the absence of an acid. done in the presence of A wide range of known basic compounds can be used, such as triethylamine, trimethylamine, pyridine, dimethylaniline,
Organic bases such as N-methylmorpholine, DBN, DBU, DABCO, inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, potassium hydrogen carbonate, sodium hydrogen carbonate, etc. Can be mentioned. Examples of acids include inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, and polyphosphoric acid, and organic acids such as p-toluenesulfonic acid, ethanesulfonic acid, and trifluoroacetic acid. The solvent used is
Any substance can be used as long as it does not affect the reaction.
For example, alcohols such as methanol, ethanol, propatool, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, halogenated hydrocarbons such as pyridine, acetone, dichloromethane, dichloroethane, and chloroform, benzene, toluene, and xylene. Aromatic hydrocarbons such as dimel-xyethane, ethers such as tetrahydrofuran, diethyl ether, and diphenyl ether, esters such as ethyl acetate and methyl acetate, and aprotic properties such as dimethylformamide, dimethyl sulfoxide, and hexamethyl phosphoric acid triamide. Examples include polar solvents and mixed solvents thereof. The reaction is usually carried out at -20 to 150°C, preferably at 0 to 150'C, and is generally completed in 5 minutes to 30 hours.

-61= Reaction formula -7 (1r) [In the formula, R2 and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. RlB is a phenyl group that may have 1 to 3 groups selected from the group consisting of a lower alkoxy group, a halogen atom, and a nitro group as a substituent on the phenyl ring, or a lower alkoxy group as a substituent on the phenyl ring. , a phenyl lower alkyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom and a nitro group. RI7 does not represent a hydrogen atom or the above RIB. R+8 and RI9 are the same or different and represent a hydrogen atom or a lower alkyl group. ] Compound of general par 1r) and general formula (15
) is carried out in the presence or absence of a solvent and in the presence or absence of a basic compound.

The reaction is usually carried out at room temperature to 200°C, preferably 60 to 12°C.
The reaction proceeds suitably at around 0° C. and is generally completed in about 1 to 24 hours. Solvents used here include ethers such as dioxane, tetrahydrofuran, diethyl ether, and ethylene glycol dimethyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, lower alcohols such as methanol, ethanol, and isopropanol, Examples include polar solvents such as N-methylpyrrolidone, dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide.

Basic compounds include, for example, potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogen carbonate,
Examples include inorganic bases such as sodium amide, organic bases such as triethylamine, tripropylamine, pyridine, and quinoline. The amount of compound (15) to be used is usually at least equimolar, preferably equimolar to 5 times the molar amount of compound (1r).

Compound (15) used as a starting material is produced, for example, by the method shown in Reaction Formula-8 below.

Reaction formula-8 [In the formula, R+ 8 , R+ 7 , R+ 8 and R+9 are the same as above. ] The reaction between the compound of general formula (16) and sulfoylide (17) is carried out in a suitable solvent. Examples of the solvent used here include ethers such as tetrahydrofuran, polar solvents such as dimethylformamide, and dimethyl sulfoxide, and the like. The reaction is usually -50~
The reaction proceeds suitably at 70°C, preferably around -30 to 50'C, and is generally completed in about 10 minutes to 5 hours.

The sulfur ylide (17) used in the reaction is, for example, -par [wherein R+8 and R+9 are the same as above]. m represents O or 1. R20 and R2+ are the same or different and represent a lower alkyl group, a phenyl group, a lower alkylamino group, a phenyl lower alkyl group, a lower alkenyl group or a lower alkoxy group. ], etc. can be mentioned. The amount of sulfoylide (17) to be used is usually at least equimolar, preferably equimolar to twice the molar amount of compound (16).

Reaction formula-9 H(1U) [In the formula, R2 and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. ] Although various methods can be applied to the reduction reaction of the compound of general par 1t), for example, a method using a hydrogenation reducing agent is preferably used. Examples of the hydrogenation reducing agent used include lithium aluminum hydride, sodium borohydride, diborane, etc., and the amount of these used is usually at least equimolar to the compound (1t), preferably equimolar - 10 times. It is in the molar range. This reduction reaction is usually carried out using a suitable solvent, such as water, lower alcohols such as methanol, ethanol, and impropatol, ethers such as diglyme, tetrahydrofuran, and diethyl ether, polar solvents such as dimethylformamide, acetic acid, or a mixed solvent thereof. etc., usually at -60 to 50°C, preferably at 0°C.
It is carried out at room temperature for about 10 minutes to about 3 hours. In addition, when lithium aluminum hydride or diborane is used as a reducing agent, it is preferable to use an anhydrous solvent such as diethyl ether, tetrahydrofuran, or diglyme.

Reaction formula-10 (1x) [In the formula, R2 and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. R22 may have 1 to 3 groups selected from the group consisting of a lower alkoxy group, a halogen atom, and a nitro group as a substituent on the phenyl ring,
It also represents a phenyl lower alkyl group having a hydroxyl group as a substituent on the alkyl moiety. R23 may have 1 to 3 groups selected from the group consisting of a lower alkoxy group, a halogen atom, and a nitro group as a substituent on the phenyl ring,
It also represents a phenyl lower alkyl group having a halogen atom as a substituent on the alkyl moiety. R24 may have 1 to 3 groups selected from the group consisting of a lower alkoxy group, a halogen atom, and a nitro group as a substituent on the phenyl ring, and also has a cyan group as a substituent on the alkyl moiety; Indicates a lower alkyl group. ] The halogenation reaction of the compound of general formula (1) is carried out by reacting the compound of -par (1v) with a halogenating agent in a suitable solvent or without a solvent. Examples of solvents used here include aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride, ethers such as dioxane, tetrahydrofuran, and diethyl ether, and dimethyl Examples include formamide and dimethyl sulfoxide. As the halogenating agent, a wide range of common halogenating agents that can convert the hydroxyl group of a carboxy group into a halogen can be used, such as thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide, etc. Can be done. The ratio of compound (1v) and halogenating agent to be used is not particularly limited and can be appropriately selected within a wide range, but when the reaction is carried out without a solvent, the latter is usually used in large excess of the former. In addition, when the reaction is carried out in a solvent,
It is generally advisable to use at least an equimolar amount of the latter to the former, preferably 2 to 4 times the molar amount. The reaction temperature and reaction time are also not particularly limited, but are usually room temperature to 100'C.
It takes about 30 minutes to 10 hours depending on the time.

The reaction between the compound of general formula (1W) and MCN (18) is
It can be carried out in a suitable solvent. Here, examples of MCN include potassium cyanide, sodium cyanide,
Examples include cyanides such as silver cyanide, copper cyanide, and calcium cyanide.

Examples of solvents used include water, alcohols such as methanol, ethanol, and isopropanol, halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride, and polar solvents such as acetonitrile, dimethylformamide, and dimethyl sulfoxide. can. MCN (18
The amount of compound (1W) to be used is usually at least equimolar, preferably equimolar - 1.5 times the molar amount of compound (1W). The reaction is usually carried out at room temperature to 150°C.
, preferably around 50 to 120°C for 30 minutes to 10
It will finish in about an hour. In addition, in the reaction system, alkylammonium halides such as tri-n-butylammonium iodide and tetrabutylammonium bromide,
1,4,7゜10-tetraoxacyclododecane, 1
By adding phase transfer catalysts such as crown ethers such as ,4,7゜10.13-pentaoxacyclopentadecane, 1.4,7,10.13.16-hexaoxacyclooctadecane, etc., the above reaction can be carried out. Proceed favorably.

Reaction formula-11 (1y) In formula C, R is the same as above. B is a R25C1-1=CH- group (R25 is a lower alkoxy group or a halogen radical R2G Q
\ child), 7 /CHCH2- group (R26 and R27 are lower alkyl groups) or CH=C- group. ] The reaction between the compound of general formula (19) and the compound of general formula (20) can be carried out under the same reaction conditions as the reaction between the compound of -par (1e) and the compound of general formula (5).

The cyclization reaction of the compound of general formula (21) is carried out in the presence of an acid in the absence of a solvent or in a suitable solvent.

As the acid, there are no particular limitations, and a wide range of ordinary inorganic acids and organic acids can be used.Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, aluminum chloride, boron trifluoride, titanium tetrachloride, etc. Examples include organic acids such as Lewis acid, formic acid, acetic acid, ethanesulfonic acid, and p-toluenesulfonic acid. Among these acids, hydrochloric acid, hydrobromic acid, sulfuric acid, etc. are preferred. The amount of such acid to be used is not particularly limited and may be appropriately selected within a wide range, but usually the acid used is at least the same weight, preferably 10 to 50 times the weight of the compound of Par(21). It is better. As a solvent, a wide range of ordinary inert solvents can be used, such as water, lower alcohols such as methanol, ethanol, and propatool, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene and toluene, and chlorinated methylene, chloroform,
Examples include halogenated hydrocarbons such as carbon tetrachloride, acetone, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, and the like. Among these, water-soluble solvents such as the lower alcohols, ethers, acetone, dimethyl sulfoxide, dimethyl formamide, and hexamethyl phosphoric triamide are preferred. The reaction is
The reaction is usually carried out at a temperature of 0 to 100'C1, preferably room temperature to 60°C, and the reaction is usually completed in about 5 minutes to 6 hours.

In Reaction Formula-6 above, the compound of general formula (12) used as a starting material is produced, for example, according to the method shown in Reaction Formula-12 below.

23) [In the formula, R1, R+ 4 , R2G and R27 are the same as above. R15' represents a lower alkoxy group. ] General formula (2
The reaction between the compound 3) and the piperidine derivative of general formula (24) can be carried out in the presence of a solvent. Examples of solvents used include aromatic hydrocarbons such as benzene, toluene, and xylene; lower alcohols such as methanol, ethanol, and isopropanol; ethers such as dioxane, tetrahydrofuran, diethyl ether, and ethylene glycol dimethyl ether; -Polar solvents such as methylpyrrolidone, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc. may be mentioned. The reaction may more advantageously be carried out using a basic compound as a deoxidizing agent. Examples of the basic compound include potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium amide, sodium hydride, tertiary amines such as triethylamine and tripropylamine, pyridine, and quinoline. The amount of compound (24) to be used is usually 1 to 10 times the amount of compound (23), preferably 3 to 7 times the amount of compound (23). The reaction temperature is usually about 50 to 200°C, preferably about 50 to 150°C, and the reaction is generally completed in about 1.5 to 15 hours.

- The hydrolysis reaction of the compound of par (25) is carried out at a reaction temperature of room temperature to
The reaction is carried out at the boiling point temperature of the solvent for 30 minutes to 3 hours.

The reaction between the compound of -par (26) and malon@(27) is carried out in a suitable solvent in the presence of a basic compound. The solvent used is the compound (23) and the compound (
Any of the solvents used in the reaction with 24) can be used,
In addition, polar solvents such as pyridine can also be used. Examples of the basic compound include potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium amide, sodium hydride, tertiary amines such as triethylamine, tripropylamine, and piperidine, pyridine, and quinoline. The ratio of compound (26) and malon 1 (27>) to be used is usually at least equimolar, preferably equimolar to about 7 times molar, of the latter relative to the surface.

The reaction is usually carried out at 0 to 200°C, preferably 70 to 150°C.
The process is carried out at a temperature of about 100 C and takes about 1 to 10 hours to complete.

The esterification reaction of the compound of general formula (12a>) can be carried out, for example, in an alcohol such as methanol, ethanol or isopropanol, in an acid such as hydrochloric acid or sulfuric acid, or in thionyl chloride.
In the presence of a halogenating agent such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, etc., usually 0 to 150°C, preferably 50 to 1
00°C for about 1 to 10 hours. The amount of the acid to be used is preferably from a normal molar amount to 1.2 times the molar amount of the compound of the general formula (12a), and the amount of the halogenating agent to be used is the amount of the compound of the general formula (12a>). The amount should be at least equimolar, preferably 1 to 5 times the molar amount.

Reaction formula-13 (27> (1z) [in the formula R
1, R14, and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. ] The reaction between the compound of general formula (27) and the compound of general formula (24) is generally carried out in a suitable inert solvent in the presence or absence of a basic condensing agent.

Examples of inert solvents used include aromatic hydrocarbons such as benzene, toluene, and xylene, methanol, ethanol, propatool, butanol, and 3-methoxy-
Examples include alcohols such as 1-butanol, ethyl cellosolve, and methyl cellosolve, pyridine, acetate, dimethyl formamide, dimethyl sulfoxide, and hexamethyl phosphoric triamide. Examples of the basic condensing agent include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, and triethylamine. The ratio of the compound of general formula (27) and the compound of general formula (24) to be used is not particularly limited and can be appropriately selected within a wide range, but the latter is usually at least equimolar to the former. , preferably in an equimolar or 5-fold molar amount.

The reaction is usually carried out at room temperature to about 180'C, preferably at 10°C.
The reaction is carried out at 0 to 150°C and generally completes in about 3 to 30 hours. Further, in this reaction, the reaction proceeds advantageously when copper powder is used as a catalyst.

Reaction formula-14 RR [In the formula, R is the same as above. ] The dehydrogenation reaction of the compound of general formula (1A) is carried out using an oxidizing agent in a suitable solvent. Examples of the oxidizing agent used include benzoquinones such as 2,3-dichloro-5゜6-dicyazbenzoquinone and chloranil (2,3゜5.6-titrachloropenzoquinone), N-bromosuccinimide, N-bromosuccinimide, and -Chlorosuccinimide, halogenating agents such as bromine, selenium dioxide, palladium carbon, palladium black,
Dehydrogenation catalysts such as palladium oxide and Raney nickel can be mentioned. The amount of the oxidizing agent to be used is not particularly limited and may be appropriately selected from a wide range, but in the case of a halogenating agent, it is usually an equimolar to 5 times the molar amount of the compound of general formula (1A), preferably It is preferable to use equimolar to twice the molar amount, and in the case of a dehydrogenation catalyst, it is usually preferable to use an excess amount.

In addition, as a solvent, dioxane, tetrahydrofuran,
Ethers such as methoxymethanol and dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, xylene, and cumene, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, butanol, amyl alcohol, hexanol, etc. Alcohols, polar proton solvents such as acetic acid, dimethylformamide,
Examples include polar aprotic solvents such as dimethyl sulfoxide and hexamethyl phosphoric triamide.

The reaction is usually carried out at room temperature to 300'C1, preferably at room temperature to 2
The reaction is generally completed in about 1 to 40 hours.

Conventional catalytic reduction conditions are applied to the reduction of the compound of general formula (1B). The catalyst used is palladium,
Examples include metals such as palladium-carbon, platinum, and Raney nickel, and it is preferable to use such metals in conventional catalytic amounts. Examples of the solvent that can be used include water, methanol, ethanol, isopropanol, dioxane, tetrahydrofuran, hexane, cyclohexane, ethyl acetate, and a mixed solvent thereof. The reaction can be carried out either under normal pressure or increased pressure, but usually at normal pressure to 20 kq/cm 2 , preferably at normal pressure to 10 kq/cm 2
It is preferable to carry out the test at g/cm2. The reaction temperature is usually about 0 to 150°C, preferably room temperature to 100°C.
It is better to set it as C.

In Reaction Formula-4, the compound of general formula (10) used as a starting material is produced, for example, according to the method shown in Reaction Formula-15 below.

Reaction formula-15 [In the formula, x1 is the same as above. ×2 indicates a halogen atom.

D represents a lower alkylene group. R2B represents a phenyl group which may have 1 to 3 groups selected from the group consisting of lower alkoxy groups, halogen atoms and nitro groups as substituents on the phenyl ring. ] The reaction between the compound of general formula (28) and the compound of general formula (29) can be carried out in an appropriate solvent in the presence of a basic compound. The amount of compound (29) to be used is usually at least equimolar, preferably equimolar -1.5 to compound (28).
It is better to double the molar amount. The reaction is usually carried out at a temperature of ○ to 150°C.
, preferably at room temperature to around 100°C, and is generally completed in about 1 to 24 hours. Examples of solvents used here include water, alcohols such as methanol, ethanol, propatool, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, and halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform. aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as tetrahydrofuran, diethyl ether, and dimethoxyethane, ketones such as acetone and methyl ethyl ketone, pyridine, acetonitrile, etc., and mixed solvents thereof. . Examples of basic compounds include triethylamine, trimethylamine, pyridine, piperidine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, and DBN.

Organic bases such as DBU, DABCO, potassium acetate, sodium acetate, inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, silver carbonate , alcoholades such as sodium methylate, sodium ethylate, and the like.

In the reaction system, alkylammonium halides such as tri-butylammonium iodide and tetrabutylammonium bromide, 1,4,7°10-tetraoxacyclododecane, 1,4,7°10,13-penta Oxacyclopentadecane, 1.4,7,10,1
3. By adding phase transfer catalysts such as crown ethers such as 16-hexaoxacyclooctadecane,
The above reaction proceeds advantageously.

Furthermore, among the compounds represented by the general formula (1), the compound in which the carbon-carbon bond at the 3rd and 4th positions of the carbostyril skeleton is a double bond is a lactam-lactim-type compound as shown in Reaction Formula-16 below. Possible variability.

Reaction formula-16 1 (1G)
(1D) [In the formula, R is the same as above. ] Among the carbostyryl derivatives represented by the general formula (1) of the present invention, a compound having a basic group can be easily converted into an acid addition salt by the action of a pharmaceutically acceptable acid. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid. .

Furthermore, among the carbostyryl derivatives represented by the general formula (1) of the present invention, compounds having an acidic group can be easily formed into salts by the action of a pharmaceutically acceptable basic compound.

Examples of the basic compound include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate, and the like.

The target compounds obtained in each step can be easily isolated and purified by conventional separation means. Examples of the separation means include solvent extraction, dilution, recrystallization, column chromatography, and preparative thin layer chromatography.

Incidentally, the present invention naturally includes optical isomers and stereoisomers.

The compounds of the invention are usually used in the form of intramembrane pharmaceutical preparations. The formulation contains commonly used fillers, extenders, binders,
It is adjusted using diluents or excipients such as wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, emulsions, powders, liquids, suspensions, emulsions, granules, capsules, full-fill formulations, injections (liquids, (suspending agents, etc.), soft blue agents, etc. When forming into a tablet, carriers such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propatool, simple syrup, etc. , glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac,
Binders such as methylcellulose, potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, Disintegrants such as lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc.
Absorption enhancers such as grade ammonium bases and sodium lauryl sulfate, moisturizing agents such as glycerin and starch, starch,
Adsorbents such as lactose, kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol can be used. Furthermore, the tablets can be made into tablets with conventional coatings as required, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets. When forming into an emulsion, carriers such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin,
Excipients such as talc, binders such as gum arabic powder, tracanth powder, gelatin, ethanol, and disintegrants such as laminaran and agar can be used. When molding into a fully expanded form, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc. can be used as carriers. Capsules are prepared by mixing the compound of the present invention with the various carriers exemplified above and filling them into hard gelatin capsules, soft capsules, etc. according to conventional methods. When prepared as injections, solutions, emulsions, and suspensions are preferably sterilized and isotonic with blood, and when molded into these forms, diluents such as water, ethyl alcohol, and macrogol are used. , propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like can be used. In this case, a sufficient amount of salt, glucose, or glycerin may be included in the pharmaceutical preparation to adjust the isotonic solution, and usual solubilizing agents, buffers, soothing agents, etc. may be added. It's okay. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc., and other pharmaceuticals may be included in the pharmaceutical preparation, if necessary. When forming into a paste, cream or gel form, diluents such as white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone,
Bentonite etc. can be used.

The amount of the compound of the present invention to be contained in the pharmaceutical formulation of the present invention is not particularly limited and can be appropriately selected within a wide range, but it is usually 1 to 70% by weight, preferably 1 to 30% by weight in the pharmaceutical formulation. It is better.

The method of administering the above pharmaceutical preparation is not particularly limited and is determined depending on various preparation forms, age, sex and other conditions of the patient, degree of disease, etc. For example, tablets, emulsions, solutions, suspensions, emulsions, granules and capsules are administered orally. Injections are administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids, and if necessary, are administered alone intramuscularly, subcutaneously, subcutaneously, or intraperitoneally. Single agents are administered rectally.

The dosage of the above pharmaceutical preparation is appropriately selected depending on the usage, patient's age, sex and other conditions, degree of disease, etc., but usually the amount of the compound of general formula (1), which is the active ingredient, is per body tlkQ per day. It is preferable to set it to approximately 0.01 to 10no;+. Also, the amount of the active ingredient in the dosage unit form is 0.1 to 200%.
It is preferable to include mg.

Examples Reference examples, examples, pharmacological test results, and formulation examples are listed below.

Reference Example 1 A solution of 150 mQ of N-methylpyrrolidone containing 2-nitro-5-chlorobenzaldehyde dimethyl acetal 12C], 16.3 g of 4-acetylaminopiperidine hydrochloride, 13.70 g of sodium carbonate, and 13 mQ of triethylamine was heated to 120°C in a nitrogen stream. Heat and stir for 12 hours. After the reaction is completed, the solvent is concentrated, water is added to the resulting residue, and the mixture is extracted with dichloromethane. After washing with water-saturated saline,
Dry with sodium sulfate. The solvent was distilled off, diethyl ether was added to the resulting residue, and the precipitated crystals were collected in a 93-mm sieve to give 2-nitro-5-(4-acetylamino-1
-piperidyl)benzaldehyde dimethyl acetal 1
1.2 (gets 7).

NMR (CDC93) δppm: 1.22i, 70 (2H, m), 1.86-2.17 (5H, m), 1.99 (3H, s), 2.92-3.22 (2H, m ), 3.47 (6H,s), 3.76-4.20 (3H,m), 5.39 (1H,d, J=7Hz>, 6.06 (1
H, s), 6.78 (1H, dd, J=9Hz, 3Hz), 7.
19 (lt-(, d, J=3Hz>, 8.02 (1
H, d, J=9Hz> Reference Example 2 2-nitro-5-(4-acetylamino-1-piperidyl)benzaldehyde dimethyl acetal 0.3g, formalin aqueous solution 5ml 12. A mixture of 1 mQ of ethanol and 2 drops of concentrated hydrochloric acid is heated and fast-flowed for 2 hours. After the reaction is completed, water is added to the residue obtained by distilling off the solvent, and the precipitated crystals are counted to obtain 0.220 of 2-nitro-5-(4-acetylamino-1-piperidyl)benzaldehyde.

NMR (CDC93) δppm: 1.21-1.75 (2H, m>, 1.92-2.22 (21-1, m), 1.99 (
3H,s>, 2.97-3.28 (2H,m), 3.85-4.31 (3H,m), 5.39 (IH,d, J=7Hz>, 6.95 (1
H, dd, J=9Hz, 3Hz>, 7.14 (1H,
d, J=3Hz>, 8.11 (1H, d, J=9Hz
>, 10.52 (1H, s> Reference Example 3 2-nitro-5-(4-acetylamino-1-piperidyl)benzaldehyde 0.22 g, malonic acid 0.16 g
, pyridine 21TIQ, and 2 drops of piperidine are heated and stirred at 80'C for 4 hours, then at 90'C for 1 hour. After the reaction, the solvent was distilled off and the resulting residue was mixed with 0.5H salt M10.
Add ITIQ and extract with dichloromethane. After washing with water and saturated saline in that order, drying with sodium sulfate. The solvent was distilled off, recrystallized from methanol-chloroform,
0.19 g of 2-nitro-5-(4-acetylamino-1-piperidyl)]uccinic acid is obtained.

Melting point 265-268°C (decomposition), yellow powder Example 1 3 g of 6-carboxy-3,4-dihydrocarbostyryl
and 4-methylamino-1-benzylpiperidine 3.5
g is dispersed in 40 mQ of dimethylformamide, and a solution of 2.61 mQ of diethyl cyanophosphate and 2.39 nB2 of triethylamine in 10 n+Q of dimethylformamide is added dropwise under water cooling. Stir for 1 hour under water cooling, then further stir for 2 hours at room temperature.
After stirring for an hour, the reaction mixture is poured into ice water. After extraction with chloroform and drying with sodium carbonate, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography and recrystallized from acetonitrile to give 6-
(N-methylamino(1-benzyl-4-piperidyl)
3 g of [amine]carbonyl-3,4-dihydrocarbostyryl 1/2 hydrate were obtained.

The compounds shown in Table 1 below are obtained in the same manner as in Example 1 using appropriate starting materials having a melting point of 186i and 88°C (decomposed) and a white powder.

= 97- Table 1 100-1 113--115,--1''16--117 Example 53 3-(4-(N-methylacetylamino)-1-beridylcou-6-nitrocinnamic acid Dissolve 1.25 g of methyl ester in 50 mQ of ethanol, add 10% palladium-carbon o, 4.c+, and stir at room temperature and normal pressure until hydrogen absorption stops. After distilling off the catalyst, concentrate the solvent, The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol-50:1), and recrystallized from methanol-diethyl ether.
0.820 of (4-(N-methylacetylamino)-1-piperidyl)-3,4-dihydrocarbostyryl is obtained.

The compounds of Examples 1 to 52 and the compounds shown in Table 2 below are obtained in the same manner as in Example 53 using appropriate starting materials having a melting point of 195-197 DEG C. and a pale yellow needle shape.

Table 2 R Example 65 6-(4-amino-1-piperidyl)carbonyl-3,
4-dihydrocarbostyryl 1 g, 98% @ acid 1 mQ
and 35% formalin 0.7n+Q at 100°C.
After stirring for 3 hours, the solvent was concentrated under reduced pressure. The resulting residue is dispersed in water and made basic by adding sodium carbonate. After extraction with chloroform and drying with sodium carbonate, the solvent was distilled off.

The obtained residue was subjected to medium pressure liquid chromatography (eluent;
Purified from chloroform:methanol-100:1),
The product was converted into citric acid and recrystallized from ethanol-diethyl ether to obtain 0.8 (j) of 6-(4-dimethylamino-1-piperidyl)carbonyl-3,4-dihydrocarbostyryl 2citrate.

Melting point 115-120°C, white powder Example 66 6-(4-oxo-1-piperidyl)carbonyl 3,
0.8Ω of 4-dihydrocarbostyryl, 1.6IQ of benzylamine, and 1g of Molecular Sieve 3A are dispersed in 15mQ of chloroform and heated under reflux for 6 hours. After washing Molecular Sieve 3A, the furnace solution was concentrated, and the resulting residue was washed several times with diethyl ether, and then purified using silica gel column chroma 1 to graphite to obtain 6-(4-benzylimino-1-piperidyl). 〉Carbonyl-3,4-
Dihydrocarbostyryl 6-(4-Benzylimino-1-piperidyl)carbonyl-3,4-dihydrocarbostyryl obtained above was dissolved in 30 mQ of methanol, and sodium borohydride 1
Gradually add g and stir overnight at room temperature. The reaction mixture is poured into ice-dilute hydrochloric acid and made basic by adding carbonate. After extraction with chloroform and drying with sodium carbonate, the solvent was distilled off. The obtained residue was subjected to thin layer chromatography (developing solution: chloroform:methanol-10
D) Purification is performed in 1) to obtain 0.2 CI of 6-(4-benzylamino-1-piperidyl)carbonyl-3,4-dihydrocarbostyryl 1/2 hydrate.

NMR (200MHz, CDC(173)δppm
: 1, 16-2.03 (6H, m), 2, 50-3.08 (7f-(, m), 3, 61
(2H, s>, 4, 1 7-4.58 (1H, brs), 8, 82
(1H, d.J=7.7Hz), 7, 14-7.38
(7H, m), 9, 32 (1H, brs) Example 67 Palladium-black 200mc+ was dispersed in a 4.4% @acid methanol 101+112 solution, and 6-(1-
Add 200 mc+ of benzyl-4-piperidylamide)-3.1-dihydrocarbostyryl and stir for 30 minutes at room temperature in an argon stream. After the reaction was completed, the catalyst was removed, the reaction solution was concentrated, and the resulting residue was subjected to silica glu column chromatography (eluent: dichloromethane: methanol-10
:1) and recrystallized from ethanol-diethyl ether to give 6-(1-formyl-4-piperidylamide)-3.

150 mg of 4-dihydrocarbostyryl are obtained.

Melting point 2 4. 6-2 4. 8°C (decomposition), white powder Example 68 6-(1-benzyl-4-piperidylamide)-3,4
-dihydrocarbostyryl 1.90 and platinum oxide 150
mCI is dispersed in 40 mQ of acetic acid and hydrogenated at 80-100°C. After the reaction is complete, the catalyst is filtered off and the filtrate is concentrated. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol - 5:1), which was neutralized with sodium hydrogen carbonate, and recrystallized from methanol to give 6-(4-piperidylamide).
-3,4-dihydrocarbostyryl 1/2 permanent product 0.
8C] is obtained.

Melting point 265-268°C (decomposed), white powder Example 6
9 1.12 mG of 6-(4-piperidylamide)-3,4-dihydrocarbostyrane was dissolved in 20 mQ of acetonitrile, and p-me]-xybenzyl chloride o. Add asmc and stir overnight at room temperature. The reaction mixture was poured into water and extracted with chloroform. After drying over sodium carbonate and then concentrating the solvent, the resulting residue was recrystallized from methanol to give 6-(1-(4-methoxybenzyl)-4).
-Piperidylamide)-3,4-dihydrocarbostyryl 1/2 hydrate is obtained (1.2 g).

Examples 1 to 3 were prepared in the same manner as in Example 69 using appropriate starting materials in the form of white powder with a melting point of 209-210°C (decomposition).
, 7-11, 14-21, 23-29, 31-46 and 55 are obtained.

Example 70 6-(4-amino-1-goberidylcarbonyl)-3,
2 g of 4-dihydrocarbostyryl and 3.06 ml of triethylamine were dispersed in 40 mG of methylene chloride, and 0.78n+Q of acetyl chloride was added dropwise to this under water cooling.
Stir at room temperature for 4 hours.

The reaction mixture was poured into saturated brine and extracted with chloroform. After drying with sodium carbonate, the solvent is distilled off. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethannimethanol-10:1) and recrystallized from methanol-diethyl ether to give 6
-(4-acetylamino-1-piperidylcarminyl L
-3,4-dididrocarbostyryl 1/4 hydrate 0.
Get 39.

Examples 4 to 70 were prepared in the same manner as in Example 70 using appropriate starting materials in the form of white powder with a melting point of 228-229°C (decomposition).
Compounds 6, 12, 53-54 and 56-64 are obtained.

- 128 = Example 71 (a) p-C4-(N-methylacetylamino) = 1-
piperidylguanyline 16C] was dissolved in 150 mG of toluene, and 9.12 mQ of triethylamine was added. Next, 11g of β-bromopropionyl chloride and 30g of toluene
111i2 solution is added dropwise at 80° C. with stirring. followed by 30
After reacting for a minute, the colored substance was removed, washed with water, dried, and the solvent was distilled off to form an oily product of N-(β-bromopropionyl)-p-(4-(N-methylacetylamino)).
-18 g of 1-piperidylguanyline is obtained.

(b) N=(β-bromopropionyl)-p-(4-(
2.7 g of N-methylacetylamino)-1-piperidylguaniline and pulverized anhydrous aluminum chloride 28Q are suspended in carbon disulfide 501110 and heated under reflux for 4 hours. The reaction solution was poured into ice water, the precipitate was counted, washed with water and ether, converted into a hydrobromide salt, and recrystallized from methanol-diethylnithyl to give 6- (4- (N-methylacetylamino)). 0.8 g of -1-piperidyl)-3.4=dihydrocarbostyryl is obtained.

Pale yellow needle crystals having a melting point of 195-197 DEG C. The compounds of Examples 1 to 9, 11 to 52 and 54 to 64 are obtained in the same manner as in Example 71 using appropriate starting materials.

Example 72 (a) p-(4-(N-methyl-N-benzylamino)-1-piperidylcarbonylcyaniline 10,4C
7 was dissolved in 100 ml of benzene, and 4.56 ml of triethylamine was added. Next, a solution of 3.94 CI of β-methoxyacrylic acid in 20 mQ of benzene was added dropwise under reflux. Reflux for 1 hour after addition. After the reaction is completed, the reaction solution is washed with water, dried, and the solvent is distilled off. The residue was purified by silica gel column chromatography to give N-(β-methoxyacryloyl)-p-(4-(N-methyl-N-benzylamino)-1-piperidylcarbonylcoaniline 8
Get Ω.

(b) N-(β-methoxyacryloyl)-p-(4,
iN-methyl-N-benzylamino)-1-piperidylcarbonylcoaniline 4.790% W under stirring at room temperature
Gradually add to 50 mQ of L acid. Continue the reaction for 2 hours. The reaction solution was neutralized with a 1ON aqueous sodium hydroxide solution, the precipitated crystals were counted, washed with water, and recrystallized with ethanol to give 6- (4-
200 mg of (N-methyl-N-benzylamino)-1-pipe-1wozylcarbonyl]carbostyril is obtained.

Melting point 198-200'C1 white powder Example 73 6-bromo-3,4-dihydrocarbostyryl 5.6q
, 1.8Q of 4-(N-methylacetylamino)-1-piperidine', 1.80Q of potassium carbonate, and 0.2Q of copper powder are mixed in 60mQ of 3-methoxybutanol, and the mixture is rapidly flowed for 5 hours. The reaction solution was filtered, the mother liquor was concentrated to dryness under reduced pressure, and the residue was extracted with methanol-chloroform. The chloroform layer is distilled off, and the resulting residue is purified by preparative silica gel thin layer chromatography. Recrystallization from methanol-diethyl ether gives 450 mg of 6-(4-(N=methylacetylamino)-1-piperidyl]-3°4-dihydrocarbostyryl.

Melting point: 195-197°C, pale yellow needle-shaped crystals.Prepared in the same manner as in Example 73, using appropriate starting materials.
The compound is obtained.

Example 74 0-(N-(1-benzoylmethyl-4-piperidyl L-N-methylamide)-3,4-dihydrocarbostyrylformamide (1:1) suspended in 150 mQ, and added to sodium borohydride at room temperature. Add 0.26Q and stir for 1 hour. Excess sodium borohydride is decomposed with 2 molar hydrochloric acid, and the solvent is distilled off. The residue is partitioned between water and ethyl acetate, and the organic layer is washed with water and dried. The solvent was then distilled off. The residue was made into a hydrochloride with ethanol and concentrated hydrochloric acid, and recrystallized from ethanol and water to give 6-(N-(1-(2-phenyl-2-
Hydroxyethyl)-4-piperidylco-N-methylamide)-3,4-dihydrocarbostyryl monohydrochloride.
0.8 g of quarter hydrate is obtained.

Melting point 275-278°C (decomposition), colorless needles Example 75 N-methyl of 6-(1-piperazinylcarbonyl 13.4-dihydrocarbostyryl 4.2 g and 2-7 enyl eboxide 1.79 CI) 1 30mQ solution of pyrrolidone
Heat and stir at 00 to 110°C for 11 hours. After the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol - 25:1), and purified with ethanol-concentrated hydrochloric acid, 133-hydrochloric acid. Salt and recrystallize from ethanol-water to give 6-(N-
(1-(2-hydroxy-2-phenylethyl)-4
2.9 g of -piperidyl>N-methylamide)-3,4-dihydrocarbostyryl monohydrochloride 1/4 hydrate are obtained.

Melting point 275-278°C (decomposed), colorless needles Example 76 6-(4-oxo-1-piperidylcarbonyl-3,4
-Dihydrocarbostyryloxylamine hydrochloride 30.3CI and sodium acetate 83.5g were mixed with ethanol 600 mQ and water 3
00 mQ and stirred at room temperature overnight. The precipitated crystals were counted and recrystallized from ethanol to obtain 16 g of 6-(4-didroximino-1-piperidylcarbonyl)-3,4-dihydrocarbostyryl.

NMR (90MHz.DMSO-d6) δppm:
2, 20-2.63 (6H, m>, 2, 79-3.02 (2H, m>, 3.20-3.68 (5H, m), 6.88 (IH, d, J=9Hz >, 7.13-7.
30 (21-1, m>, 10.22 (1H, brs
) Example 77 6-(4-hydroxyimino-1-piperidylcarbonyl)-3,4-dihydrocarbostyryl 15Q, acetic anhydride 11.4 m2 and 1-ethylamine 31.8 m (2
A solution of 300 mQ of methylene chloride is stirred at room temperature overnight. The reaction mixture was poured into ice water and extracted with chloroform. After drying with sodium carbonate, the solvent was distilled off to give 6-
(4-acetyloxyimino-1-piperidylcarbonyl 13.4-dihydrocarbostyryl 16.5CI is obtained.

NMR (200MH7, CDC93) δppm: 2.1
8 (3H,s), 2.50-2.80 (6H,m>, 3.01 (1H,t, J=8.1Hz>, 3,77(
4H, m), 6.80 (1H, d, J=8.0Hz), 7.25-
7.32 (2H, m>, 8.18 (1H, brs) Example 78 10 g of 6-(4-acetyloxyimino-1-piperidylcarbonyl)-3,4-dihydrocarbostyryl and 0.5Q of platinum oxide Dispersed in acetic acid 1501TI12,
Perform non-contact reduction at room temperature and pressure. After removing the catalyst, the furnace liquid was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (eluent dichloromethane:methanol-1).
0:1) to obtain 6-(4-amino-1-piperidylcarbonyl)-3,4-dihydrocarbostyryl 3q.

NMR (250MHz, DMSO-ds) δppm:
1.26 (2H, m>, 1.82 (2H, m),
2.43-2.53 (2H, m), 2,89-3,10 (3H, m>, 4.37 (6H, m), 6.90 (1H, d, J=8.0f-1z ), 7.1
6-7.22 (2H, m>, 10.27 (IH, brs) Example 79 6-(4,4'-ethylenedioxy-1-piperidylcarbonyl)-3,4-dihydrocarbostyryl 46
Q was dispersed in 400 mf2 of dioxane and 150 mQ of water, 115 mG of salt was added, and the mixture was heated and stirred at 100°C for 7 hours. After the reaction mixture is allowed to cool, sodium carbonate is added to make it alkaline, and the solvent is distilled off. The obtained residue was extracted with chloroborm, dried over sodium carbonate, and then the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (eluent; dichloromethane:methanol-1
0:1) to give 6-(4-oxo-1-piperidylcarbonyl)-3,4-dihydrocarposti-”13
7 - Obtain 37.6 g of Ru.

NMR (200MHz, CDCQ3) δppm: 2.
37-2.49 (4H, m), 2.55+-2,63 (2H, m>, 2.89-2.98 (2H, m>, 3.77-3.92 (4H, m>, 6.87 (1H, d, J=8.0Hz>, 7.21-
7.29 (2H, m>, 9.87 (1H, brs) Blood perfusion extracted pre-papillary specimen Adult male and female hybrids weighing 8-13 kg were anesthetized by intravenously administering bendoparbital sodium salt at a rate of 30 mg/kq. Pour 1000U of heparin sodium salt onto
After intravenous administration, the animals were sacrificed and the heart was removed. The specimen mainly consists of papillary muscles and ventricular septum, and is perfused with blood led from the blood donor hole at a constant pressure of 100 mmHg through a cannula inserted into the anterior septal artery. Blood donor hole weighs 1
For 8 to 27 kg -'138 - Bendoparbital sodium salt 30m (If/
KQ is administered intravenously for anesthesia, and heparin sodium salt '100OU/kc+ is administered intravenously. Using bipolar N pole, voltage 1.5 times the threshold (0.5 to 3 V), 5
The papillary muscles are stimulated with a square wave with a stimulation width of m5ec and a stimulation frequency of 120 times per minute. The resting tension of the papillary muscles is 1.5 g, and the generated tension of the papillary muscles is measured via a force displacement exchanger. The blood flow in the anterior septal artery is measured using an electromagnetic flowmeter. The generated tension and blood flow rate were recorded using an ink recorder. Details of this method have been previously reported by Endo and Hashimoto (Am, J. Physiol, 218.1459-14
63°1970>.

The test compound was intra-arterially administered in a volume of 10-30 μQ for 4 seconds. The inotropic effect of the test compound was expressed as a % change in the tension developed before drug administration. The effect on coronary blood flow was expressed as the change in absolute value (m01 min) from before administration. The results are shown in Table 3 below.

Test compound 1.614-benzylamino-1-piperidyl)-3,
4-dihydrocarbostyryl dihydrochloride hydrate 2.6-(4-ethoxycarbonylamino-1-piperidyl)-3,4-dihydrocarbostyryl 3.6-(4-amino-1-piperidyl)- 3゜4-Dididrocarbostyryl dihydrochloride 1/2 hydrate 4.6-(4-methylamino-1-piperidyl)-3
, 4-dihydrocarbostyryl dihydrochloride hydrate 5.6-(4-dimethylamino-1-piperidylcarbonyl)-3,4-dihydrocarbostyryl dicitrate 6.6- (4 -(N-(2-phenoxyethyl)-N
-Methylamine]-1-piperidylcarbonyl 13.4
-Dihydrocarbostyryl salt r! i salt 3/2 hydrate 7.6- (4-(N-benzyl-N-methylamine)
-1-piperidylcarbonyl]carbostyryl 8.6-(1-(2-phenylthioethyl)-4-piperidylamide)-3,4-dihydrocarbostyryl 9.6-(1-(2-(N-methyl -N-phenyl)ethyl]-4-piperidylamide)-3゜4-dihydrocarbostyryl 1/2 hydrate 10.6- (1-(4-
methoxybenzyl)-4-piperidylamide)-3,4
-dihydrocarbostyryl 1/2 hydrate 11.6-(1-(2,6-dichlorobenzyl)-4-
piperidylamide)-3,4-dihydrocarbostyryl hemihydrate 12,6-(N-(1-benzyl-4-piperidyl)-
N-methylamide L-3,4-dihydrocarbostyryl hemihydrate 13,6- (N-(1-(2-phenylthioethyl)
-4-piperidyl)-N-methylamide)-3,4-dihydrocarbostyryl hydrochloride 14.6- (N-(1
-(2-(N-methyl-N-phenyl)ethyl)-4-
15.6- (N-(1-benzoylmethyl-4-piperidyl)-N-methylamide)-3,4-dihydrocarbostyryl hydrochloride Hydrochloride 16,6-(N-(1-(2-hydroxy-2-]technylethyl)-4-piperidyl)-N-methylamide)-
3,4-dihydrocarbostyryl hydrochloride quarter hydrate 17.6- (N-(1-benzyl-4-piperidyl)
-N-ethylamide)-3,4-dihydrocarbostyryl hydrochloride 18.6-(4-(N-ethyl-N-benzylamino)
-1-Piperidylcarbonyl)-3,4-dihydrocarbostyryl 19.6- (N-(1-isobutyl-4-piperidylmiN-methylamide)-3,4-dihydrocarbostyryl hydrochloride 1/4 hydrate Product 20.6-(4-(N-benzyl-N-methylamino)-1-piperidylcarbonyl-dihydrocarbostyryl21,6-(N-(1-cinnamyl-4-piperidyl)-N-ethylamide)-3 .4-dihydrocarbostyryl hydrochloride 22, 6-(N-(1-(2-phenoxyethyl)=
4-Piperidylco-N-ethylamide)-3,4-dihydrocarbostyryl hydrochloride Table 3 Test Dose Ventricular myocardial coronary artery blood flow Compound
Shrinkage change Amount change NO. (mol) (%) (m+2/min)1
1μ 21 1.42 1μ 27
1.33 1μ 66 - 4 1μ 54 - 5 1μ 24.6 2.16 1μ
21 3.17 1μ 43.5
1.38 1μ 27.0 1.09
1μ 38.7 2.510 1μ
29 -11 1μ 31 2
．． 612 1μ 57 2.313
1μ 73 6 14 1μ 28 4.3 Test Dose Coronary artery blood flow Compound contraction change in ventricular muscle Amount change No. (mol) (%) (mQ/min)1
5 1μ 33 4.616 1μ
21 5.417 1μ 37
4.318 1μ 44 4.8
19 1μ 16.5 2.120
1μ 40.7 2.321 1μ 35
4.122 1μ 206.3 4
．． 1 Formulation Example 1 6-(4- (N-benzyl-N- 5+++c
+Methylamine)-1-piperidylco-3,4-dihydrocarbostyryl starch 132 mCI magnesium stearate 18 mCI lactose
45...Q meter
200mg by conventional method 1
Tablets of the above composition were prepared.

Formulation Example 2 6-(4-(N-benzyl=N-500mCI methylamimethylaminoperidylcarbonyl)carbostyryl polyethylene glycol 0.3g (molecular weight:
4000) Sodium chloride 0.9g Polyoxyethylene sorbitan 0.4Q monooleate Sodium metabisulfite 0.1C] Methyl-
Paraben 0.18Q Propyl-Paraben 0.02g Distilled water for injection
, 100 mQ The above parabens, sodium metabisulfite and sodium chloride are dissolved in the above distilled water at 80°C with stirring. The resulting solution was cooled to 40°C, the compound of the present invention, polyethylene 1-nocol, and polyoxyethylene sorbitan monooleate were sequentially dissolved, and then distilled water for injection was added to the solution to adjust the final volume. , sterilize by sterile filtration using a suitable filter paper, and dispense into 1 mQ ampoules.
Prepare injections.

(Above) Procedural amendment (disputed) September 20, 1988 1 Indication of the case 1988 Patent Application No. 156887 2 Name of the invention Relationship to the case Patent applicant Otsuka Pharmaceutical Co., Ltd. 4 Agent Higashi Ward, Osaka City Hirano-cho 2-10 Sawanotsuru Building Sponsored 6 Contents of amendment in the "Detailed Description of the Invention" section of the specification to be amended 1 Page 22 of the specification, line 13 "Number of carbons 1 to 12" is changed to 1 carbon Numbers 2 to 12,” he corrected.

2. Page 58, line 4 of the specification “For the compound (1)”
Correct the statement "for compounds of r (12>)."

3. The words ``dihydrocarbostyril'' on page 133, line 7 and page 134, line 4 of the specification are respectively corrected to ``dihydrocarbostyril.''

4 Specification, page 133, lines 11-12 r6- (1-piperazinyl... Carbostyryl 4.2 g
Correct the following.

r6-(N-(4-piperidyl)-N-methylamide)
-3,4-dihydrocarbostyryl 4.7 gJ (or more)

Claims (1)

[Claims] 1. General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R represents a group▲There are mathematical formulas, chemical formulas, tables, etc.▼or groups▲There are mathematical formulas, chemical formulas, tables, etc.▼. Here R^
1 is lower alkylenedioxy group, oxo group, hydroxyimino group, lower alkanoyloxyimino group, group =NA(
A represents a lower alkyl group, a phenyl lower alkyl group, a lower alkylsulfonyl group or a phenoxy lower alkyl group. ) or the group -NR^4R^5 (R^4 and R^5 are
The same or different hydrogen atoms, lower alkyl groups, lower alkanoyl groups, phenyl lower alkyl groups, lower alkoxycarbonyl groups, lower alkylsulfonyl groups, lower alkoxy groups as substituents on the phenyl ring, and halogen atoms. It represents a benzoyl group, a phenyl lower alkanoyl group, which may have 1 to 3 groups, a phenyl lower alkenylcarbonyl group, or a phenoxy lower alkyl group, which may have a lower alkoxy group as a substituent on the phenyl ring. ) is shown. l represents 0 or 1. R
^2 represents a hydrogen atom or a lower alkyl group. R^3 may have 1 to 3 groups selected from the group consisting of a hydrogen atom, a lower alkyl group, a lower alkanoyl group, and a lower alkoxy group, a halogen atom, and a nitro group as substituents on the phenyl ring, In addition, a phenyl lower alkyl group, a benzoyl lower alkyl group, a phenyl lower alkenyl group, an alkenyl group, a phenoxy lower alkyl group, a phenylthio lower alkyl group, or an amine may be substituted with a halogen atom, cyano group, or hydroxyl group as a substituent on the alkyl moiety. Indicates an anilino lower alkyl group which may have a lower alkyl group as a substituent. Furthermore, the carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton represent a single bond or a double bond. However, when l is 0 and R^4 represents a hydrogen atom, a lower alkyl group, or a phenyl lower alkyl group, R^
5 must not be a hydrogen atom, a lower alkyl group, or a phenyl lower alkyl group. ] A carbostyril derivative or a salt thereof represented by: