JPH059429B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel carbostyril derivatives, more specifically, the general formula [In the formula, R ¹ is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a phenyl lower alkyl group; R ² is a hydrogen atom, a halogen atom, a hydroxyl group, an unsubstituted or halogen-substituted benzoyloxy group, a lower alkyl group or a lower alkoxy group; R ³ is a hydroxyl group, an amino group, a cycloalkyl lower alkylamino group (the cycloalkyl ring may be substituted with a carboxyl group or a lower alkoxycarbonyl group), a lower alkoxy group, a lower alkoxycarbonyl lower alkoxy group, benzoyl lower alkoxy group or lower alkanoyloxy lower alkoxy group; R ⁴ is a hydrogen atom, phenylsulfonyl group, lower alkyl group, which may have a lower alkyl group or halogen atom as a substituent, as a substituent on the phenyl ring Phenyl lower alkyl group or group that may have a halogen atom -COR ⁶ (R ⁶ is a lower alkyl group that may have an amino group or phenyl lower alkoxycarbonylamino group as a substituent, an amino lower alkyl group or phenyl as a substituent) A cycloalkyl group that may have a lower alkoxycarbonylamino lower alkyl group, 1 to 3 groups selected from a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, a hydroxyl group, and an amino group as substituents on the phenyl ring. a phenyl group which may have a halogen atom as a substituent on the phenyl ring, a phenyl lower alkyl group which may have a halogen atom as a substituent on the phenyl ring, or a 5-membered or a 6-membered unsaturated heterocyclic group (the heterocycle may be substituted with a lower alkyl group); R ⁵ is a hydrogen atom or a phenylsulfonyl group that may have a lower alkyl group or a halogen atom as a substituent; A
is a lower alkylene group; n represents 0 or 1, and the formula of the substituent is

The dotted line in [Formula] means a single bond or a double bond, and the substitution position of this substituent is any of the 3, 4, 5, or 6 positions of the carbostyril bone core.
Furthermore, the bond between the 3rd and 4th positions of the carbostyril bone nucleus shows a single bond or a double bond. However, n=0
, R ¹ is a hydrogen atom, lower alkyl, lower alkenyl, lower alkynyl or phenyl lower alkyl; R ² is a hydrogen atom, hydroxyl group or lower alkoxy; R ³ is a hydroxyl group or lower alkoxy; R ⁴
is a group -COR ⁷ (R ⁷ is a lower alkyl, cycloalkyl, which may have an amino group or a phenyl lower alkoxycarbonylamino group as a substituent, or a halogen atom, lower alkyl, lower alkoxy, nitro as a substituent on the phenyl ring) and a phenyl group which may have 1 to 3 groups selected from amino); R ⁵ must not be a hydrogen atom] carbostyril derivatives and salts thereof,
Regarding. The compound of the present invention has an anti-ulcer effect and is useful, for example, as a therapeutic agent for gastrointestinal ulcers such as gastric ulcer and duodenal ulcer. The compounds of the present invention are particularly characterized in that they have remarkable preventive and therapeutic effects on chronic ulcer pathologies such as experimental acetic acid ulcers and burnt ulcers, have low toxicity and side effects, and are effective against chronic ulcers. It is a drug. The compound of the present invention also has the effect of increasing the amount of endogenous prostaglandin E ₂ and is useful as a medicinal effect derived from prostaglandin E ₂ , such as a prophylactic and therapeutic agent for ulcers. In this specification, lower alkyl includes straight chain or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc., and lower alkenyl includes carbon atoms. 2 to 6 linear or branched alkenyls, such as vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl, etc.
Further, as lower alkynyl, straight chain or branched chain alkynyl having 2 to 6 carbon atoms, such as ethynyl,
2-propynyl, 2-butynyl, 3-butynyl,
1-methyl-2-propynyl, 2-pentynyl,
Examples include 2-hexynyl. Examples of lower alkylene groups include methylene, ethylene, trimethylene, methylmethylene, ethylmethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-metaltrimethylene, tetramethylene, pentamethylene, hexamethylene, etc. Mention may be made of 1 to 6 straight or branched alkylene groups. Phenyl lower alkyl includes phenyl alkyl whose alkyl moiety is a straight chain or branched alkyl having 1 to 6 carbon atoms, such as benzyl, 2
-Phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-
Dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl-3
-phenylpropyl, etc., and the cycloalkyl includes cycloalkyl having 3 to 8 carbon atoms,
Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Lower alkoxy includes straight or branched alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,
Examples of the halogen atom include tert-butoxy, pentyloxy, and hexyloxy, and examples of the halogen atom include fluorine, chlorine, bromine, and iodine. Examples of phenyl lower alkoxycarbonylamino groups include phenylalkoxycarbonylamino in which the alkoxy moiety is straight-chain or branched-chain alkoxy having 1 to 6 carbon atoms, such as benzyloxycarbonylamino, 2-phenylethoxycarbonylamino , 1-phenylethoxycarbonylamino, 3-phenylpropoxycarbonylamino, 4-phenylbutoxycarbonylamino,
Examples include 1,1-dimethyl-2-phenylethoxycarbonylamino, 5-phenylpentyloxycarbonylamino, 6-phenylhexyloxycarbonylamino, and 2-methyl-3-phenylpropoxycarbonylamino. Therefore, examples of lower alkyl that may have an amino group or a phenyl lower alkoxycarbonylamino group include the above-mentioned lower alkyl when there is no substituent, and when it has a substituent, for example, aminomethyl , 2-aminoethyl, 2
- or 3-aminopropyl, 1-methyl-2-
Aminoethyl, 2-, 3- or 4-aminobutyl, 1,1-dimethyl-2-aminobutyl, 2-
or 3-aminopentyl, 4-aminohexyl, benzyloxycarbonylaminomethyl, 2
-benzyloxycarbonylaminoethyl, 2-
Benzyloxycarbonylaminopropyl, 3-
Benzyloxycarbonylaminopropyl, 4-
Benzyloxycarbonylaminobutyl, 3-benzyloxycarbonylaminobutyl, 5-benzyloxycarbonylaminopentyl, 6-benzyloxycarbonylaminohexyl, 2-phenylethoxycarbonylaminomethyl, 1-phenylethoxycarbonylaminomethyl, 2- (2
-phenylethoxycarbonylamino)ethyl,
3-(1-phenylethoxycarbonylamino)
Propyl, 2-(3-phenylpropoxycarbonylamino)ethyl, 4-(4-phenylbutoxycarbonylamino)butyl, 2-(5-phenylpentyloxycarbonylamino)ethyl, 2
An amino group such as -(6-phenylhexyloxycarbonylamino)ethyl, 1,1-dimethyl-2-(benzyloxycarbonylamino)ethyl, (1,1-dimethyl-2-phenylethoxycarbonylamino)methyl, or Examples include an alkyl group having 1 to 6 carbon atoms having a phenylalkoxycarbonylamino group having 1 to 6 carbon atoms in the alkoxy moiety. Examples of phenyl that may have 1 to 3 groups selected from halogen atoms, lower alkyl, lower alkoxy, hydroxyl, nitro, and amino as substituents on the phenyl ring include phenyl, 2
-, 3- or 4-chlorophenyl, 2-, 3-
or 4-fluorophenyl, 2-, 3- or 4-bromophenyl, 2-, 3- or 4-iodophenyl, 3,5-dichlorophenyl, 2,6
-dichlorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,5-dibromophenyl, 2-, 3- or 4-methylphenyl, 2-, 3- or 4-ethylphenyl, 4
-Propylphenyl, 3-isopropylphenyl, 2-butylphenyl, 4-hexylphenyl, 3-pentylphenyl, 4-tert-butylphenyl, 3,4-dimethylphenyl, 2,5-dimethylphenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 3-propoxyphenyl, 4-isopropoxyphenyl, 3-butoxyphenyl, 2-pentyloxyphenyl, 4-tert-butoxyphenyl , 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl,
2,5-dimethoxyphenyl, 2-, 3- or 4-nitrophenyl, 2,4-dinitrophenyl, 2-, 3- or 4-aminophenyl, 2,
4-diaminophenyl, 3-methyl-4-chlorophenyl, 2-chloro-6-methylphenyl, 2
-methoxy-3-chlorophenyl, 3,4,5-
trimethoxyphenyl, 3,4,5-trimethylphenyl, 3,4,5-trichlorophenyl, 2
-, 3- or 4-hydroxyphenyl, 3,4
- Substituents on the phenyl ring such as dihydroxyphenyl and 2,6-dihydroxyphenyl include halogen atoms, alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, hydroxyl groups, nitro groups, and amino groups. Examples include phenyl groups which may have 1 to 3 groups selected from the following groups. Examples of phenyl lower alkyl groups that may have a halogen atom on the phenyl ring include the above-mentioned phenyl lower alkyl groups when there is no substituent, and when there is a substituent, for example, 2-, 3- or 4- chlorobenzyl, 2-, 3- or 4-fluorobenzyl, 2-, 3- or 4-bromobenzyl, 2-, 3- or 4-iodobenzyl,
3,5-dichlorobenzyl, 2,6-dichlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl, 3,5-dibromobenzyl,
3,4,5-trichlorobenzyl, 2-(3-chlorophenyl)ethyl, 2-(3,4-dibromophenyl)ethyl, 2-(4-iodophenyl)
Ethyl, 1-(2-bromophenyl)ethyl, 1
-(3,5-dichlorophenyl)ethyl, 1-(4
-chlorophenyl)ethyl, 3-(2-fluorophenyl)propyl, 3-(3,4,5-trichlorophenyl)propyl, 4-(4-chlorophenyl)butyl, 1,1-dimethyl-2-(3 -bromophenyl)ethyl, 5-(2,4-dichlorophenyl)pentyl, 5-(2-iodophenyl)
pentyl, 6-(4-fluorophenyl)hexyl, 6-(2,6-dichlorophenyl)hexyl,
Having 1 to 3 halogen atoms as a substituent on the phenyl ring such as 2-methyl-3-(4-chlorophenyl)propyl, and having 1 carbon atom in the alkyl moiety
~6 phenylalkyl groups are mentioned. Examples of the cycloalkyl group that may have a phenyl lower alkoxycarbonylamino lower alkyl group or an amino lower alkyl group as a substituent on the cycloalkyl ring include the above-mentioned cycloalkyl groups when there is no substituent; For example, 2-benzyloxycarbonylaminomethylcyclopropyl, 3-(2-
Benzyloxycarbonylaminoethyl)cyclobutyl, 3-(2-benzyloxycarbonylaminopropyl)cyclopentyl, 3-(4-benzyloxycarbonylaminobutyl)cyclohexyl, 4-(3-benzyloxycarbonylaminobutyl)cyclohexyl, 2-( 5-benzyloxycarbonylaminopentyl)cyclohexyl, 3-(6-benzyloxycarbonylaminohexyl)cycloheptyl, 4-(6-benzyloxycarbonylaminohexyl)cycloheptyl, 5-(2-phenylethoxycarbonylaminomethyl) Cycloheptyl, 4-(1-phenylethoxycarbonylaminomethyl)cyclooctyl, 2-[2-(2-phenylethoxycarbonylamino)ethyl]cyclooctyl, 2-[3-(1
-Phenylethoxycarbonylamino)propyl]cyclopropyl, 3-[2-(3-phenylpropoxycarbonylamino)ethyl]cyclobutyl, 3-[4-(4-phenylbutoxycarbonylamino)butyl]cyclopentyl, 4- [2-(5
-Phenylpentyloxycarbonylamino)ethyl]hexyl, 2-[2-(6-phenylhexyloxycarbonylamino)ethyl]cyclohexyl, 3-[1,1-dimethyl-2-(benzyloxycarbonylamino)ethyl] Cyclohexyl, 4-[1,1-dimethyl-2-phenylethoxycarbonylamino]cyclohexyl, 2-benzyloxycarbonylmethylcyclooctyl,
4-benzyloxycarbonylmethylcyclohexyl, 3-aminomethylcyclopropyl, 3-
(2-aminoethyl)cyclobutyl, 4-(1-aminoethyl)cyclopentyl, 2-(3-aminopropyl)cyclohexyl, 3-(4-aminobutyl)cyclohexyl, 4-aminomethylcyclohexyl, 3-(5-amino A substituted alkyl group in which a lower alkyl having an amino group or a phenyl lower alkoxycarbonylamino group is substituted on a cycloalkyl ring having 3 to 8 carbon atoms, such as pentyl)cycloheptyl and 3-(6-aminohexyl)cyclooctyl groups. can be mentioned. Examples of lower alkoxycarbonyl groups include linear or branched alkoxycarbonyl groups in which the alkoxy moiety has 1 to 6 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, and pentyl. Examples include oxycarbonyl and hexyloxycarbonyl. The amino lower alkyl group includes aminoalkyl whose alkyl moiety is a straight or branched alkyl having 1 to 6 carbon atoms, such as aminomethyl,
2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 1,1-dimethyl-2-aminoethyl, 5-aminopentyl, 6
-aminohexyl, 2-methyl-3-aminopropyl, and the like. 5- or 6-membered compound having 1 or 2 heteroatoms selected from nitrogen, oxygen, and sulfur atoms
Examples of saturated or unsaturated heterocyclic groups that may be substituted with lower alkyl groups include pyridyl,
2-methylpyridyl, 3-ethylpyridyl, 4-
Butylpyridyl, thienyl, 2-methylthienyl, 3-propylthienyl, pyrimidinyl, 2-
pentylpyrimidinyl, tetrahydropyranyl,
2-hexyltetrahydropyranyl, pyrrolyl,
3-methylpyrrolyl, pyrrolidinyl, 3-ethylpyrodinyl, dihydropyridyl, 4-propyldihydropyridyl, 1-piperidinyl, 4-butyl-1-piperidinyl, 1-pyrazinyl, 4-pentyl-1-pyrazinyl, pyrazolyl, 3-methylpyrazolyl, 4-ethylpyrazolyl, imidazolyl, 2-propylimidazolyl, 4-pentylimidazolyl, imidazolidinyl, 4-hexylimidazolidinyl, pyridazinyl, 4-methylpyridazinyl, pyrazinyl, 2-ethylpyrazinyl,
1-piperazyl, 4-propyl-1-piperazyl, oxazolyl, 4-butyloxazolyl, isoxazolyl, 4H-1,4-oxazinyl,
1-morpholinyl, 3-hexylmorpholinyl,
Thiazolyl, 4-methylthiazolyl, 2-ethylthiazolyl, 5-propylthiazolyl, isothiazolyl, 3-methylisothiazolyl, 4H-1,
4-thiazinyl, 2-ethyl-4H-1,4-thiazinyl, furyl, 3-methylfuryl, 2-ethylfuryl, tetrahydrofuryl, 2-methyltetrahydrofuryl, 2H-pyran-2-yl, 2H-
Pyran-4-yl, 4H-pyran-4-yl, 4H
-pyran-3-yl, tetrahydrothienyl, 2
-butyltetrahydrothienyl, thianyl, 4-
Examples include methylthianyl, 1,4-dithian-2-yl, and the like. An amino group which may be substituted with a cycloalkyl lower alkyl group (the cycloalkyl group may be substituted with a carboxy group or a lower alkoxycarbonyl group as a substituent) is an amino group in which the alkyl moiety is a carbon A cycloalkyl having 1 to 6 straight or branched chain alkyl atoms, in which the cycloalkyl moiety has 3 to 8 carbon atoms (the cycloalkyl ring has a carboxyl or alkoxyl moiety as a substituent having 1 to 8 carbon atoms); 6 alkoxycarbonyl groups may be substituted),
For example, amino, cyclopropylmethylamino,
2-cyclobutylethylamino, 1-cyclopentylethylamino, 3-cyclohexylpropylamino, 4-cycloheptylbutylamino, 5-
Cyclooctylpentylamino, 6-cyclohexylhexylamino, cyclohexylmethylamino, 2-methyl-3-cyclohexylpropylamino, (2-carboxycyclopropyl)methylamino, 2-(3-carboxycyclobutyl)ethylamino, 1-( 3-carboxycyclopentyl)ethylamino, 3-(2-carboxycyclopentyl)propylamino, 4-(3-carboxycyclohexyl)butylamino, 5-(4-carboxycyclohexyl)pentylamino, 6-
(2-Carboxycyclohexyl)hexylamino, (3-carboxycycloheptyl)methylamino, 2-(4-carboxycycloheptyl)ethylamino, 1-(5-carboxycycloheptyl)ethylamino, 3-(4-carboxycycloheptyl)ethylamino octyl)propylamino, 4-(2-carboxycyclooctyl)butylamino, (4-carboxycyclohexyl)methylamino, 6-(2-
methoxycarbonylcyclopropyl)hexylamino, 5-(3-ethoxycarbonylcyclobutyl)pentylamino, 4-(3-propoxycarbonylcyclopentyl)butylamino, 3-(4
-methoxycarbonylcyclohexyl)propylamino, 2-(2-n-butoxycarbonylcyclohexyl)ethylamino, 1-(3-hexyloxycarbonylcyclohexyl)ethylamino, (3-ethoxycarbonylcyclohexyl)
Methylamino, 2-ethyl-3-(2-propoxycarbonylcycloheptyl)propylamino,
Examples include (5-methoxycarbonylcyclooctyl)methylamino and (4-methoxycarbonylcyclohexyl)methylamino. The lower alkoxycarbonyl lower alkoxy group is a straight or branched alkoxycarbonyl alkoxy group in which each alkoxy moiety has 1 to 6 carbon atoms, such as methoxycarbonylmethoxy, 2-methoxycarbonyl ethoxy, 1-methoxycarbonyl ethoxy. , 3-methoxycarbonylpropoxy, 4-methoxycarbonylbutoxy, 1,1-dimethyl-2-methoxycarbonylethoxy, 5-methoxycarbonylpentyloxy, 6-methoxycarbonylhexyloxy, 2
-methyl-3-methoxycarbonylpropoxy,
Ethoxycarbonylmethoxy, 3-ethoxycarbonylpropoxy, 6-ethoxycarbonylhexyloxy, 2-propoxycarbonylethoxy, 4-propoxycarbonylbutoxy, 5-butoxycarbonylpentyloxy, pentyloxycarbonylmethoxy, 1-pentyloxycarbonylethoxy, 1, Examples include 1-dimethyl-2-hexyloxycarbonyl ethoxy and 3-hexyloxycarbonylpropoxy. Examples of the benzoyl lower alkoxy group include benzoyl alkoxy whose alkoxy moiety is a straight-chain or branched alkoxy having 1 to 6 carbon atoms, such as benzoylmethoxy, 2-benzoylethoxy, 1-benzoylethoxy, 3- Benzoylpropoxy, 4-benzoylbutoxy,
1,1-dimethyl-2-benzoylethoxy, 5
-benzoylpentyloxy, 6-benzoylhexyloxy, 2-methyl-3-benzoylpropoxy and the like. The lower alkanoyloxy lower alkoxy group is an alkanoyloxyalkoxy whose alkoxy moiety is a linear or branched alkanoyloxy having 1 to 6 carbon atoms, such as acetyloxymethoxy, 2-acetyloxyethoxy, 1 -acetyloxyethoxy, 3-acetyloxypropoxy, 4-acetyloxybutoxy, 1,1-dimethyl-2-acetyloxyethoxy, 5-acetyloxypentyloxy, 6-
Acetyloxyhexyloxy, 2-methyl-3
-acetyloxypropoxy, propionyloxymethoxy, 3-propionyloxypropoxy, 6-propionyloxyhexyloxy, 2
-butyryloxyethoxy, 4-butyryloxybutoxy, 5-pentanoyloxypentyloxy, pentanoyloxymethoxy, t-butylcarbonyloxymethoxy, 2-(t-butylcarbonyloxy)ethoxy, 1-(t-butyl) carbonyloxy)ethoxy, 3-(t-butylcarbonyloxy)propoxy, 4-(t-butylcarbonyloxy)butoxy, 1,1-dimethyl-
2-(t-butylcarbonyloxy)ethoxy,
Examples include hexanoyloxymethoxy, 3-hexanoyloxypropoxy, 6-(t-butylcarbonyloxy)hexyloxy, and the like. Examples of the phenylsulfonyl group that may have a lower alkyl group or a halogen atom as a substituent include an alkyl group having 1 to 6 carbon atoms or a phenylsulfonyl group that may have a halogen atom as a substituent, e.g. , phenylsulfonyl, 4-methylphenylsulfonyl, 3
-methylphenylsulfonyl, 2-methylphenylsulfonyl, 2-ethylphenylsulfonyl,
3-Ethylphenylsulfonyl, 4-ethylphenylsulfonyl, 3-isopropylphenylsulfonyl, 4-hexylphenylsulfonyl, 2-
n-Butylphenylsulfonyl, 4-pentylphenylsulfonyl, 2-, 3- or 4-chlorophenylsulfonyl, 2-, 3- or 4-bromophenylsulfonyl, 2-, 3- or 4-iodophenyl Examples include sulfonyl. Examples of halogen atoms include fluorine atoms, chlorine atoms,
Examples include bromine atom and iodine atom. Examples of the benzoyloxy group that may have a halogen atom as a substituent include 2-, 3-,
- or 4-chlorobenzoyloxy, 2-, 3
- or 4-fluorobenzoyloxy, 2-,
3- or 4-bromobenzoyloxy, 2-,
Examples include 3- or 4-iodobenzoyloxy and benzoyloxy groups. In addition, lower alkanoyl has 1 to 6 carbon atoms.
straight-chain or branched-chain alkanoyl, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, hexanoyl, and the like. The compound of the present invention has optical isomers, and these are also included in the present invention. The compound of the present invention can be produced by various methods, for example, by the method shown in the reaction formula below. [In the formula, R ¹ , R ² , R ⁶ , A, n and the bond between the 3rd and 4th positions of the carbostyril bone nucleus are the same as above.
R ³ ′ is lower alkoxy, lower alkoxycarbonyl lower alkoxy, benzoyl lower alkoxy or lower alkanoyloxy lower alkoxy,
R ³ ″ is an amino group or a cycloalkyl lower alkylamino group (the cycloalkyl ring may be substituted with carboxy or lower alkoxycarbonyl), and R ⁴ ′ may have a lower alkyl or halogen atom as a substituent. Phenylsulfonyl, lower alkyl or phenyl lower alkyl which may have a halogen atom as a substituent on the phenyl ring, R ⁷ and R ⁹ each represent lower alkyl, R ⁸ represents lower alkanoyl] That is, the formula (2) The compound is hydrolyzed, and the product is optionally acylated, esterified, or a combination thereof to lead to the desired carbostyril derivative. This compound (2) is hydrolyzed to be one of the compounds of the present invention. The reaction leading to the compound of formula (1a) can be carried out using a suitable hydrolysis catalyst, such as a hydrohalic acid such as hydrochloric acid or hydrobromic acid, an inorganic acid such as sulfuric acid or phosphoric acid,
In the presence of an inorganic alkali compound such as an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, or an alkali metal carbonate or bicarbonate such as sodium carbonate, potassium carbonate, or sodium bicarbonate, without a solvent or with a suitable solvent. medium (e.g., water or a mixed solvent of water and a lower alcohol such as methanol or ethanol), 50 to 150°C, preferably
What is necessary is just to process at 70-100 degreeC for about 3-24 hours. By acylating compound (1a), (1c) or (1l) with the carboxylic acid of formula (3), it is possible to lead to the corresponding other target compound (1b), (1d) or (1m), respectively. However, this acylation is achieved by subjecting it to a conventional amide bond forming reaction. In this case, the carboxylic acid (3) may be an activated compound. The conditions for the amide bond forming reaction can be applied to the amide bond forming reaction. For example, (a) mixed acid anhydride method, that is, a method in which carboxylic acid (3) is reacted with an alkylhalocarboxylic acid to form a mixed acid anhydride, and this is reacted with compound (1a), (1c) or (1l); (b) Active ester method or active amide method, that is, carboxylic acid (3) is converted into an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, or benzoxazoline- A method of forming an active amide with 2-thione and reacting it with compound (1a), (1c) or (1l),
(c) Carbodiimide method, that is, a method in which compound (1a), (1c) or (1l) is dehydrated and bonded to carboxylic acid (3) in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole; (d) Carbodiimide method; Acid halide method, that is, a method of deriving carboxylic acid (3) into a halide compound and reacting this with compound (1a), (1c) or (1l), (e)
Another method is to convert carboxylic acid (3) into carboxylic acid anhydride using a dehydrating agent such as acetic anhydride,
A method in which compound (1a), (1c) or (1l) is reacted with this, and compound (1a), (1c) or (1l) is reacted with an ester of carboxylic acid (3) and, for example, a lower alcohol.
Examples include a method of reacting under high pressure and high temperature. In addition, carboxylic acid (3) is activated with a phosphorus compound such as triphenylphosphine or diethylchlorophosphate, and compounds (1a) and (1c) are added to this.
Alternatively, a method in which (1l) is applied may also be adopted. Examples of the alkylhalocarboxylic acids used in the mixed acid anhydride method include methyl chloroformate, methyl bromate, ethyl chloroformate, ethyl bromate, and isobutyl chloroformate. The mixed acid anhydride is obtained by the usual Schotten-Baumann reaction, and is reacted with the compound (1a), (1c) or (1l) without being isolated to produce the compound (1b), (1d) of the present invention. or (1m)
is manufactured. The Schotten-Baumann reaction is usually carried out in the presence of a basic compound. The basic compounds used are those commonly used in the Schotten-Baumann reaction, such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0 ] Nonene-5 (DBN), 1,5-diazabicyclo[5.4.0] Undecene-5-(DBU), 1,4
−Diazabicyclo[2.2.2]octane (DABCO)
and inorganic bases such as potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate. The reaction is carried out at -20 to 100℃
The reaction time is approximately 5 minutes to 10 hours, preferably 5 minutes to 2 hours.
It's time. The reaction between the obtained mixed acid anhydride and compound (1a), (1c) or (1l) is carried out at −20°C to 150°C.
C., preferably 10 to 50.degree. C., for about 5 minutes to 10 hours, preferably about 5 minutes to 5 hours. Although the mixed acid anhydride method does not require the use of a solvent,
Generally carried out in a solvent. Any solvent commonly used in the mixed acid anhydride method can be used, specifically halogenated carbons such as methylene chloride, chloroform, and dichloroethane, and aromatic hydrocarbons such as benzene, toluene, and xylene. , diethyl ether, tetrahydrofuran, ethers such as dimethoxyethane, methyl acetate,
Examples include esters such as ethyl acetate, aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, and the like. The ratio of carboxylic acid (3), alkylhalocarboxylic acid, and compound (1a), (1c), or (1l) in this method is usually at least the same molar amount, but the ratio of alkyl halocarboxylic acid to carboxylic acid (3) is It is preferable to use 1 to 2 moles of halocarboxylic acid and compound (1a), (1c) or (1l). For example, in the case of using benzoxazoline-2-thionamide, the active ester method or active amide method in (b) above can be carried out using an appropriate solvent that does not affect the reaction, such as the one used in the mixed acid anhydride method described above. In addition to the same solvent as above, 1-methyl-2-pyrrolidone or the like is used at 0 to 150°C, preferably at 10°C.
The reaction is carried out at ~100°C for 0.5 to 75 hours. In this case, the ratio of compound (1a), (1c) or (1l) and benzoxazoline-2-thionamide used is usually at least equimolar, preferably equimolar to twice molar, of the latter to the former. In addition, when N-hydroxysuccinimide ester is used, the reaction proceeds advantageously by using a suitable base, such as the same base used in the carboxylic acid halide method described below. In the carboxylic acid halide method (c) above, carboxylic acid
(3) is reacted with a halogenating agent to form a carboxylic acid halide, and the carboxylic acid halide is isolated and purified, or compound (1a), (1c) or (1l) is added thereto without isolation and purification. It is done by reacting. This carboxylic acid halide and compounds (1a) and (1c)
Alternatively, the reaction with (1l) is carried out in a suitable solvent in the presence of a dehydrohalogenating agent. Basic compounds are usually used as the dehydrohalogenating agent, and in addition to the basic compounds used in the Schotten-Baumann reaction described above, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, silver carbonate, sodium methylate, etc. , alkali metal alcoholates such as sodium ethylate, and the like. Note that an excess amount of the reaction compound (1a), (1c), or (1l) can also be used as a dehydrohalogenating agent. In addition to the solvents used in the Schotten-Baumann reaction, examples of solvents include water, alcohols such as methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, pyridine, acetone, acetonitrile, and the like. , or a mixed solvent of two or more thereof. Compound (1a), (1c) or (1l)
The proportion of the carboxylic acid halide and the carboxylic acid halide is not particularly limited and can be selected within a wide range, but the latter is usually used in at least an equimolar amount, preferably an equimolar to twice the molar amount of the former. The reaction temperature is usually around -30~180℃,
The reaction is preferably completed at a temperature of about 0 to 150°C, and generally within 5 minutes to 30 hours. The carboxylic acid halide used is carboxylic acid halide
It is produced by reacting (3) with a halogenating agent without a solvent or in a solvent. Any solvent can be used as long as it does not adversely affect the reaction, such as aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as chloroform, methylene chloride, and carbon tetrachloride, dioxane, and tetrahydrofuran. , ethers such as diethyl ether, dimethylformamide, dimethyl sulfoxide, and the like. As the halogenating agent, a normal halogenating agent that converts the hydroxyl group of a carboxy group into a halogen can be used, such as thionyl chloride,
Phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride,
Examples include phosphorus pentabromide. The ratio of the carboxylic acid (3) and the halogenating agent to be used is not particularly limited and is selected as appropriate, but when the reaction is carried out without a solvent, the latter is usually used in a large excess amount relative to the former, or in the solvent. When the reaction is carried out, 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 are also not particularly limited, but usually at room temperature to about 100°C, preferably 50 to 80°C, for 30
It takes about minutes to 6 hours. In addition, carboxylic acid (3) is activated with a phosphorus compound such as triphenylphosphine or diethylchlorophosphate, and compound (1a), (1c) or (1l) is reacted with this in an appropriate solvent. It will be done. Any solvent can be used as long as it does not affect the reaction, and specifically, halogenated carbons such as methylene chloride, chloroform, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, Examples include ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane, esters such as methyl acetate and ethyl acetate, and aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. In this reaction, since compound (1a), (1c) or (1l) itself acts as a basic compound, the reaction proceeds well by using it in excess of the theoretical amount.
If necessary, other basic compounds such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,5-diazabicyclo[5.4.0] undecene-5 (DBU), 1,4-
Organic bases such as diazabicyclo[2.2.2]octane (DABCO), potassium carbonate, sodium carbonate,
Inorganic bases such as potassium bicarbonate and sodium bicarbonate can also be used. The reaction is about 0~
This is achieved by carrying out the reaction at 150°C, preferably about 0 to 100°C, for about 1 to 30 hours. Compound (1a),
The ratio of the phosphorus compound and carboxylic acid (3) to (1c) or (1l) is usually at least equimolar, preferably 1 to 3 times the molar amount. In the reaction formula -, the corresponding target compound (1c) or (1d) can be obtained by esterifying the compound (1a) or (1b) with the alcohol of formula (4). This esterification reaction can be carried out under any of the usual reaction conditions for esterification reactions, such as (1) dehydration condensation in a solvent in the presence of a dehydrating agent, or (2) a suitable acidic or basic catalyst. React in a solvent. Examples of the solvent used in method (1) include halogenated carbons such as methylene chloride, chloroform, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, and ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane. Examples include aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. Examples of the dehydrating agent include dicyclohexylcarbodiimide and carbonyldiimidazole. The ratio of alcohol (4) to compound (1a) or (1b) is at least equimolar, preferably equimolar to 1.5 times molar. The proportion of the dehydrating agent used is at least equimolar, preferably equimolar to 1.5 times the molar amount of compound (1a) or (1b). The reaction temperature is usually room temperature to 150°C, preferably 50 to 100°C, and the reaction is generally completed in 1 to 10 hours. Examples of acidic catalysts used in method (2) include hydrochloric acid gas, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, boron trifluoride, inorganic acids such as perchloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and naphthalenesulfone. Examples include organic acids such as p-tosylic acid, benzenesulfonic acid and ethanesulfonic acid, acid anhydrides such as trichloromethanesulfonic anhydride and trifluoromethanesulfonic anhydride, thionyl chloride, and acetone dimethyl acetal. Furthermore, acidic ion exchange resins can also be used as catalysts in the present invention. A wide range of known basic catalysts can be used, such as sodium hydroxide,
Examples include inorganic bases such as potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, silver carbonate, and alcoholates such as sodium methylate and sodium ethylate. This reaction proceeds either without a solvent or in a solvent. As the solvent, those used in ordinary esterification reactions can be effectively used, and specifically, aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc. Examples include ethers such as halogenated hydrocarbons, diethyl ether, tetrahydrofuran, dioxane, and ethylene glycol monomethyl ether. Further, the above reaction is advantageously carried out by using a desiccant such as anhydrous calcium chloride, anhydrous copper sulfate, anhydrous calcium sulfate, phosphorus pentoxide, or the like. Compound (1a) or (1b) and alcohol in the reaction
The proportion of (4) to be used is not particularly limited and can be appropriately selected from a wide range; however, in the case of no solvent, the latter should be used in large excess relative to the former, and in the case of using a solvent, the latter should be used in equal molar proportions to the former. ~5 times the mole, preferably equimolar to 2 times the mole. The reaction temperature is not particularly limited, but is usually about -20 to 200°C, preferably 0 to 150°C.
℃, and the reaction time is usually about 1 to 20 hours. In addition, in the above reaction formula -, formula (1b),
Compounds (1c), (1d), (1n), (1l) or (1m) can also be hydrolyzed to lead to compounds of formula (1a), which hydrolysis is similar to the hydrolysis of compound (2). Can be adopted under the same conditions as in the case. The amidation reaction of compound (1a) or (1b) is
The reaction can be carried out under the same conditions as for the amide bond formation reaction of compound (1a), (1c) or (1l). The reaction between compound (1a), (1c) or (1l) and compound (5) is carried out without a solvent or in a common inert solvent under a temperature condition of room temperature to about 200°C, preferably room temperature to 120°C. It is carried out for about 24 hours. Examples of inert solvents include ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, and diethyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, lower alcohols such as methanol, ethanol, and isopropanol, dimethylformamide, and dimethyl. Polar solvents such as sulfoxide, hexamethylphosphoric triamide, acetone, and acetonitrile are used. The above reaction is more advantageously carried out using a basic compound as a deoxidizing agent. Examples of the basic compound include alkali metal compounds such as potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium amide, and sodium hydride, and tertiary amines such as triethylamine, tripropylamine, pyridine, and quinoline. is exemplified. The above reaction may be carried out by adding an alkali metal iodide compound such as potassium iodide or sodium iodide or hexamethylphosphoric acid triamide as a reaction promoter, if necessary. Compounds (1a) and (1c) in the above reaction
The ratio of (1l) and compound (5) to be used is not particularly limited, but the latter is usually used in an equimolar to excess amount, preferably equimolar to 5 times the molar amount of the former. The above compound (1a), (1c) or (1l) and the compound
The compound (1o), (1p) or (1q) obtained by reaction with (5) is further sulfonylated under similar conditions to give the general formula [In the formula, R ¹ , R ² , R ³ , R ⁴ ', A and n are the same as above. R ⁵ ' represents a phenylsulfonyl group which may have a lower alkyl group or a halogen atom as a substituent]. In addition, in the compound of formula (1), when R ⁴ is a lower alkyl group or a phenylsulfonyl group that may have a halogen atom as a substituent, the reaction similar to the reaction between compound (1a) and compound (3) can be performed. Acylated under conditions to give the general formula [In the formula, R ¹ , R ² , R ³ , R ⁵ ', R ⁶ , A and n are the same as above] This can lead to a compound represented by the following formula. Furthermore, the compound (1r) is prepared in water, lower alcohols such as methanol, ethanol, isopropanol, or a mixed solvent of water and lower alcohols in the presence of a mineral acid such as sulfuric acid, hydrochloric acid, or hydrobromic acid. , usually room temperature ~150℃, preferably 60~
A compound of general formula (1o) can also be obtained by reacting at 1120°C for about 30 minutes to 150 hours. The compound of the present invention can also be produced by the method shown in the following reaction formula. [In the formula, R ¹ , R ² , R ³ ′, R ³ ″, R ⁴ ′, R ⁶ , X,
The bonds between A, n and the 3rd and 4th positions of the carbostyril bone core are the same as above] That is, the compound of formula (6) and the compound of formula (7) are reacted, the resulting intermediate is hydrolyzed, and the desired The product is then hydrolyzed, acylated, esterified, or a combination thereof to give the desired carbostyryl derivative. The reaction between compound (6) and compound (7) can be carried out in a suitable solvent in the presence of a basic compound.
Examples of the basic compound used include organic bases such as triethylamine, trimethylamine, pyridine, piperidine, N-methylmorpholine, and 4-dimethylaminopyridine, potassium hydroxide,
Inorganic bases such as sodium hydroxide, sodium hydride, sodium amide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, alkali metal salts of aliphatic carboxylic acids such as sodium acetate, potassium acetate, sodium propionate, sodium Examples include alkali metal salts of lower alcohols such as methylate and sodium ethylate. Examples of solvents include alcohols such as methanol, ethanol, and isopropanol, hydrocarbons such as hexane and cyclohexane, ethers such as diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, and diethyl ether, esters such as ethyl acetate and methyl acetate, and benzene. , aromatic hydrocarbons such as toluene and xylene, water, acetic acid, acetic anhydride, and pyridine. The ratio of compound (7) to compound (6) to be used is at least equimolar, preferably equimolar to twice molar of the latter to the former. The reaction is usually carried out at 50 to 200°C,
Preferably, the temperature is 80 to 150°C, and the process is completed in about 30 minutes to 5 hours. By the reaction of the above compound (6) and compound (7), the formula [In the formula, R ¹ , R ² , R ⁶ , A, n and the bond between the 3rd and 4th positions of the carbostyril bone core are the same as above] - It is easily hydrolyzed by heating under reflux in acetone to obtain the compound of formula (1b'). This compound (1b') can be easily led to another target compound (1a') by hydrolysis under the same conditions as the hydrolysis of compound (2) in the above reaction formula. Furthermore, by esterifying compound (1b') or (1a') with the compound of formula (4) in the same manner as the esterification reaction in the above reaction scheme, compound (1d') or (1c ′). In addition, compounds (1a'), (1c'), or (1l') can be acylated using the compound of formula (3) in the same manner as the acylation reaction in the above reaction formula -, thereby producing compound (1b), respectively. ′), (1d′)
or (1m′). Further, compound (1a') or (1b') can be amidated in the same manner as the amidation reaction in the above reaction formula to lead to compound (1l') or (1n'), respectively. Compound (1a′), (1c′) or (1l′) and compound (5
)
The reaction with compound (1a), (1c) or (1l) can be carried out under the same conditions as the reaction of compound (5) with compound (1a), (1c) or (1l) in the reaction formula -. Furthermore, compounds (1c′), (1d′), (1l′), (1m′
) or (1n') can be hydrolyzed under the same conditions as the hydrolysis reaction of compound (2) in reaction formula - to lead to compound (1a'). The compound (1o'), (1p') or (1q') obtained by the reaction of the above compound (1a'), (1c') or (1l') with compound (5) is further treated with sulfonyl under the same conditions. and general formula [In the formula, R ¹ , R ² , R ³ , R ⁴ ′, R ⁵ ′ and n are the same as above] This can lead to a compound represented by the following formula. In addition, in the compound of general formula (1), when R ⁴ is a phenylsulfonyl group that may have a lower alkyl group or a halogen atom as a substituent, and the bond -CH〓〓CH- is a double bond, the compound Acylation was performed under the same conditions as the reaction of (1a) with compound (3),
general formula [In the formula, R ¹ , R ² , R ³ , R ⁵ ', R ⁶ , A and n are the same as above] This leads to a compound represented by the following formula. The above compound (1r') can also be treated under the same conditions as for the above (1r) to lead to the compound (1o'). Among the compounds of the present invention, substituents

[Reaction formula]

[In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , A, n and the bond between the 3rd and 4th positions of the carbostyril bone nucleus are the same as above] The above reduction reaction is usually carried out using an appropriate method. This is carried out by catalytic reduction in the presence of a suitable reduction catalyst. Examples of the reduction catalyst used include ordinary catalysts for catalytic reduction such as platinum, platinum oxide, palladium black, palladium carbon, and Raney nickel, and the amount used is usually about 0.2 to 0.5 times the amount of compound (1'). Weight range. This catalytic reduction can be carried out, for example, with water,
In a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, ethyl ether, etc., in a hydrogen atmosphere of 1 to 10 atm, preferably 1 to 3 atm, -30°C to the boiling point temperature of the solvent, preferably 0
This is done by shaking well at a temperature between ℃ and room temperature. Furthermore, the compound of the present invention can be expressed by the following reaction formula -
Other compounds of the present invention can also be derived by the method shown in . [Reaction formula] [In the formula, R ¹ , R ³ , R ⁴ , R ⁵ , A, n and the bond between the 3rd and 4th positions of the carbostyril bone nucleus are the same as above. R ² ′ represents lower alkoxy] The reaction of converting compound (1e) to compound (1f) shown in the above reaction formula is to react compound (1e) in an aqueous solution of hydrobromic acid at 50 to 150°C for 5 to 10 minutes. This is carried out by heat treatment for about an hour. [Reaction formula] [In the formula, R ² , R ³ , R ⁴ , R ⁵ , A, n and the bond between the 3rd and 4th positions of the carbostyril bone nucleus are the same as above. R ¹ ′ represents lower alkyl, lower alkenyl, lower alkynyl or phenyl lower alkyl] The alkylation reaction of the above compound (1g) can be carried out using, for example, sodium hydride, potassium hydride, metallic potassium, metallic sodium, sodium amide, potassium amide. The reaction is carried out in a suitable solvent in the presence of a basic compound such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate. Examples of solvents used include ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, Examples include aqueous ammonia and mixed solvents thereof. The alkylating agent has the general formula R ¹ 'X (R ¹ ' is the same as above,
alkyl halides (X is a halogen atom), dialkyl sulfates such as dimethyl sulfate and diethyl sulfate,
Benzyl p-toluenesulfonate, methyl p-
Examples include toluenesulfonates such as toluenesulfonate, and the proportion used thereof is not particularly limited, but is usually at least equimolar, preferably equimolar to 2 times mole, per 1 g of the compound. The reaction is usually carried out at about 0 to 70°C, preferably from 0°C to around room temperature, and is generally completed in about 30 minutes to 12 hours. [Reaction formula] [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , A and n are the same as above] Compound (1k) is obtained by dehydrogenating the above compound (1i).
The reaction leading to is carried out by treatment with a degreasing agent in a suitable solvent. As a dehydrogenating agent, for example, 2,3
-dichloro-5,6-dicyanobenzoquinone,
Benzoquinones such as 2,3,5,6-tetrachlorobenzoquinone (common name: chloranil), halogenating agents such as N-bromosuccinimide, N-chlorosuccinimide, bromine, cenone dioxide, palladium on carbon, palladium black, oxidation palladium,
Examples include dehydrogenation catalysts such as Raney nickel. The amount of the degreasing agent used is not particularly limited, but in the case of a halogenating agent, it is usually used in an amount of 1 to 5 times the mole, preferably 1 to 2 times the mole of compound (1i). In the case of catalysts, it is generally best to use an excess amount. In the case of other dehydrogenating agents as well, equimolar to excess amounts are usually used. As a solvent,
Ethers such as dioxane, tetrahydrofuran, methoxyethanol, dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, xylene, cumene, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, butanol, amyl alcohol , alcohols such as hexanol, polar protic solvents such as acetic acid, and aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. The reaction is usually carried out at room temperature to 300°C, preferably room temperature to 200°C.
Generally, it takes about 1 to 40 hours to complete. Further, compound (1k) can be reduced to lead to compound (1i), and this reduction reaction is carried out under the conditions of ordinary catalytic reduction, for example, in the presence of a metal catalyst in a suitable solvent. Examples of the catalyst include metal catalysts such as palladium, palladium on carbon, platinum, and Raney nickel, which are used in normal catalytic amounts. Examples of the solvent used include water, methanol, ethanol, isopropanol, dioxane, tetrahydrofuran, hexane, cyclohexane, ethyl acetate, or a mixed solvent thereof. The reaction can be carried out either at normal pressure or under elevated pressure, but usually at normal pressure to 20°C.
Kg/ ^cm2 , preferably at normal pressure to 10Kg/ ^cm2 , 0 to
It is carried out at 150°C, preferably between room temperature and 100°C. A compound of general formula (1) in which R ² is a hydroxyl group can be produced by dealkylating a compound in which R ² is a lower alkoxy group by heat treatment in an aqueous hydrobromic acid solution. It can also be produced by hydrolyzing a benzoyloxy compound in which R ² may have a halogen atom as a substituent. This hydrolysis is carried out in a suitable solvent in the presence of an acid or basic compound. Examples of solvents include water, lower alcohols such as methanol, ethanol, and isopropanol, dioxane,
Examples include ethers such as tetrahydrofuran, mixed solvents thereof, and the like. Examples of acids include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid.
Examples of the basic compound include metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide.
The reaction is usually carried out at room temperature to 150°C, preferably 80 to 120°C.
The process progresses suitably and is generally completed in about 1 to 15 hours. Further, a compound in which R ² is a lower alkoxy group can also be obtained by alkylating a corresponding compound in which R ² is a hydroxyl group. Examples of the alkylating agent used in this method include lower alkyl halides such as methyl iodide, ethyl chloride, and tert-butyl boromide, dimethyl sulfate, diethyl sulfate, and other alkylating agents such as diazomethane. You can also do it. This reaction is performed using ketones such as acetone and methyl ethyl ketone, ethers such as ether and dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, water, pyridine, dimethylformamide, dimethyl sulfoxide, and hexamethyl phosphoric triamide. Inert solvents such as
In addition to the basic compounds used in the acylation reaction described below, silver oxide or the like can be used as a catalyst. The reaction temperature is in the range of 0° C. to the boiling point of the solvent, and the ratio of the alkylating agent used is in the range of 1 to 3 times the molar amount of the compound in the general formula () in which R ² is a hydroxyl group. The reaction is completed in about 1 to 15 hours. Furthermore, a benzoyloxy group in which R ² may have a halogen atom as a substituent can also be produced by acylating (benzoylation) a corresponding compound in which R ² is a hydroxyl group. Examples of the acylating agent include benzoic acid halides such as p-chlorobenzoyl chloride, benzoyl chloride, and benzoyl bromide, benzoic anhydride, and benzoic acid. When an acid anhydride or an acid halide is used as the acylating agent, the acylation reaction is carried out in the presence of a basic compound. Examples of the basic compounds used include alkali metals such as sodium metal and potassium metal, hydroxides, carbonates, and bicarbonates of these alkali metals, and aromatic amine compounds such as pyridine and piperidine. Although this process can be carried out either without a solvent or in a solvent, it is usually carried out using a suitable solvent. Examples of the solvent include ketones such as acetone and methyl ethyl ketone, ethers such as ether and dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, water, and pyridine. The acylating agent is used in at least an equimolar amount relative to the raw material compound, but it is generally preferable to use an equimolar to large excess amount. The reaction proceeds at a temperature of 0 to 150°C, but is generally preferably carried out at a temperature of 0 to 80°C. The reaction time is completed in about 0.5 to 10 hours. Furthermore, when using an acid such as benzoic acid as an acylating agent, mineral acids such as sulfuric acid and hydrochloric acid and sulfonic acids such as para-toluenesulfonic acid, benzenesulfonic acid and ethanesulfonic acid are added as dehydrating agents to the reaction system. The acylation reaction proceeds advantageously by maintaining the reaction temperature, preferably between 50 and 120°C. Among the compounds (1) of the present invention, compounds in which R ¹ is a hydrogen atom and the bond between the 3- and 4-positions of the carbostyryl bone nucleus are double bonds are lactam- It can have lactim-type tautomerism. [In the formula, R ² , R ³ , R ⁴ , R ⁵ , A and n are the same as above] Among the compounds represented by general formula (1), the compound having an acidic group has a pharmacologically acceptable basicity. May form salts with compounds. Such basic compounds include, for example, sodium hydroxide, potassium hydroxide,
metal hydroxides such as calcium hydroxide, alkali metal carbonates or bicarbonates such as sodium carbonate, sodium bicarbonate, sodium methylate,
Examples include alkali metal alcoholates such as potassium ethylate. Furthermore, among the compounds represented by the general formula (1), those having a basic group can easily form a salt with a common pharmacologically acceptable acid. Examples of such acids include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, and hydrobromic acid, and organic acids such as acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, succinic acid, and benzoic acid. Can be mentioned. The compound of the present invention produced by the above method can be easily removed from the reaction system by conventional separation means such as distillation, recrystallization, column chromatography, preparative thin layer chromatography, solvent extraction, etc. Can be isolated and purified. The compound of formula (2) used as a starting material in the method of Reaction Scheme - above is a new compound, and can be produced, for example, by the method shown in Reaction Scheme - below. [Reaction formula] The desired compound (2) can be obtained by reacting compound (9) with compound (10). This reaction is carried out in a suitable inert solvent in the presence of a basic compound at room temperature to 200°C, preferably 60 to 120°C, for about 1 to 24 hours. Examples of the inert solvent used include ethers such as dioxane, tetrahydrofuran, ethylene glycol, and dimethyl ether;
Examples include aromatic hydrocarbons such as benzene, toluene, and xylene, lower alcohols such as methanol, ethanol, and isopropanol, and polar solvents such as dimethylformamide and dimethyl sulfoxide. Examples of basic compounds include inorganic bases such as calcium carbonate, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium amide, sodium hydride, potassium hydride, sodium methylate, and sodium ethylate. A wide variety of tertiary amines can be used, including tertiary amines such as , triethylamine, tripropylamine, pyridine, and quinoline. The above reaction may be carried out by adding an alkali metal iodide compound such as potassium iodide or sodium iodide as a reaction promoter, if necessary. The ratio of compound (9) and compound (10) to be used is not particularly limited, but the latter is usually used in an equimolar to excess amount, preferably equimolar to 5 times the molar amount, more preferably equimolar to 1.2 times the molar amount of the former. be. The compound of formula (2) can also be led to other compounds of formula (2) by the methods shown in the following reaction formulas and. [Reaction formula] [In the formula, R ² , R ⁷ , R ⁸ , R ⁹ , R ¹ ′, X, A, n and the bond between the 3-position and 4-position of the carbostyril bone nucleus are the same as above] The reaction between (2a) and the alkylating agent is carried out under the same reaction conditions as the alkylation reaction of compound (1g) in the reaction formula -. [Reaction formula] [In the formula, R ¹ , R ² , R ⁷ , R ⁹ , A and n are the same as above] The dehydrogenation reaction and the reduction reaction in the above reaction formula - are both the dehydrogenation reaction of compound (1i) in the above reaction formula - The reaction is carried out under the same reaction conditions as the reduction reaction of compound (1k). The compound of formula (6) as a starting material in the above reaction formula is partly known, but partly contains new compounds, and can be produced, for example, by the method shown in the following reaction formula. [Reaction formula] [In the formula, R ² is the same as above] In the above reaction formula, compound (11) is ring-closed to form compound (12).
The reaction leading to is carried out in the presence of an N,N-substituted formamide and an acid catalyst (commonly referred to as Willsmeier's reagent) in a suitable solvent or in the absence of a solvent. Examples of the N,N-substituted formamide used here include N,N-dimethylformamide, N,N-diethylformamide, N-ethyl-N-methylformamide, and N-methyl-N-phenylformamide. . Examples of acid catalysts include phosphorus oxychloride, thionyl clide, and phosgene. Solvents used include chloroform, 1,2-dichloroethane,
Examples include halogenated hydrocarbons such as 1,2-dichloroethylene, and aromatic hydrocarbons such as chlorobenzene and 1,2-dichlorobenzene.
The amounts of N,N-substituted formamide and acid catalyst used are:
The compound of general formula (11) is usually used in a large excess amount, preferably 2 to 5 times the mole of the former, and 5 to 10 times the mole of the latter. Reaction temperature is usually 150 days
C., preferably around 50 to 100.degree.
The reaction is completed in about 3 to 24 hours. The reaction to obtain compound (6a) from compound (12) is
Compound (12) can be used, for example, with hydrohalic acids such as hydrochloric acid and hydrobromic acid, inorganic acids such as sulfuric acid and phosphoric acid, alkali metal hydroxides such as potassium hydroxide and sodium hydroxide, sodium carbonate, potassium carbonate,
In the presence of an inorganic alkali compound such as potassium hydrogen carbonate or an organic acid such as acetic acid, at 50 to 150℃,
This is preferably achieved by heating at 70 to 120°C for about 0.5 to 24 hours. Compound (9) used as a starting material in the above reaction formula is produced by the method shown in the following reaction formula. [Reaction formula] [In the formula, R ¹ , R ² , A, n and the bond between the 3rd and 4th positions of the carbostyril bone nucleus are the same as above. ^R10
is lower alkyl or

[Reaction formula]

[In the formula, R ¹ , R ² , R ¹⁰ , X, A, n and the bond between the 3rd and 4th positions of the carbostyril bone nucleus are the same as above. R ¹² represents an aromatic amine residue] In the above reaction formula, the reaction between compound (21) and aromatic amine (22) is carried out in a suitable solvent or in the absence of a solvent. As a solvent, any inert solvent that does not adversely affect the reaction can be used, such as chloroform, methylene chloride, dichloromethane, halogenated hydrocarbons such as carbon tetrachloride, and ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane. , alcohols such as methanol, ethanol, isopropanol, and butanol, esters such as methyl acetate and ethyl acetate, aprotic polar solvents such as NN-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide, and acetonitrile. It will be done. Examples of aromatic amines include pyridine and quinoline. The amount of the aromatic amine to be used is at least equimolar to compound (21), preferably in large excess. The reaction temperature is
50-200℃, preferably 70-150℃, 3-10℃
The reaction completes in about an hour. The obtained compound (23) is hydrolyzed in water in the presence of an inorganic base such as sodium hydroxide or potassium hydroxide at room temperature to 150°C for about 1 to 10 hours. Further, esterification of compound (23) with compound (14) is carried out by reacting in the presence of a basic compound, in a solvent or without a solvent. Examples of the solvent used include halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, N, Examples include aprotic solvents such as N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. Basic catalysts used include, for example, triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0]
Organic bases such as nonene-5 (DBN), 1,5-diazabicyclo[5.4.0]undecene-5 (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO) and potassium carbonate, sodium carbonate, carbonic acid Examples include inorganic bases such as potassium hydrogen and sodium hydrogen carbonate. The proportion of the basic compound used here is at least equimolar, preferably 1 to 1 molar, relative to the compound of general formula (23).
It is best to use 1.5 times the molar amount. The compound of general formula (14) is preferably used in at least an equimolar amount, usually in large excess, relative to the compound of general formula (23). The reaction temperature is usually room temperature to 150°C, preferably around 50 to 100°C, and the reaction is generally
Finishes in 30 minutes to 10 hours. [Reaction formula] [In the formula, R ¹¹ and X are the same as above, and X' represents a hydrogen atom or a halogen atom] In the above reaction formula, compound (24) and compound (25)
The reaction with (26) is generally called Friedel-Crafts reaction, and is usually carried out in a suitable solvent in the presence of a Lewis acid. As the solvent used, those commonly used in this type of reaction are advantageously used, such as carbon disulfide, nitrobenzene, chlorobenzene, dichloromethane, dichloroethane, trichloroethane, carbon tetrachloride and the like. All commonly used Lewis acids are used, such as aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide,
Examples include boron trifluoride and concentrated sulfuric acid. The amount of Lewis acid to be used can be determined as appropriate, but is usually about 2 to 6 times the mole of compound (24), preferably 3 times
The amount of compound (25) or (26) used is usually at least equimolar, preferably equimolar to 3 times molar, relative to compound (24). The reaction temperature is usually about -50 to 120℃, preferably 0 to 70℃
Although the reaction time varies depending on the raw materials, catalyst, reaction temperature, etc. used, it is usually about 30 minutes to 24 hours. The nitration of the obtained compound (27) is carried out under the same conditions as those for ordinary nitration reactions of aromatic compounds, for example, by the action of a nitrating agent in a suitable inert catalyst or in the absence of a solvent. . Inert solvents include, for example, acetic acid, acetic anhydride, concentrated sulfuric acid, and nitrating agents include, for example, oleum nitric acid, concentrated nitric acid, nitric acid and other acids (sulfuric acid, oleum, phosphoric acid, acetic anhydride). and mixtures of alkali metal nitrates such as potassium nitrate and sodium nitrate with mineral acids such as sulfuric acid. The amount of the nitrating agent used is at least equimolar, usually in excess, relative to compound (27), the reaction temperature is preferably -10°C to around room temperature, and the reaction is carried out for 5 minutes to 4 hours. The obtained compound (28) is led to compound (13e) by reduction and ring closure. This reaction is expressed by the reaction formula -
The reduction reaction is carried out under the same conditions as those for compound (17) in (), but when using the catalytic reduction method in (), the reaction temperature is preferably 0 to 50°C, and there is no hydroxylation in the reaction system. The reaction proceeds advantageously in the presence of a basic compound such as sodium or potassium hydroxide. Furthermore, when using the method (), the reaction usually proceeds at -50 to 100°C and is completed in about 0.5 to 10 hours.
For example, when using stannous chloride and hydrochloric acid as reducing agents, the reaction is advantageously carried out at around -20 to 50°C. The amount of reducing agent used is at least equimolar to the raw material compound, usually equimolar to 3.
It is better to use twice the molar amount. By the above method, the ring is closed simultaneously with reduction of the nitro group to obtain compound (13e). However, when using the catalytic reduction catalyst (), the carbonyl group may also be reduced and converted to methylene, but such conversion can be avoided by appropriately selecting reaction conditions. [Reaction formula] [In the formula, R ² , R ¹¹ and X are the same as above. ^R13
represents lower alkyl] In the above reaction formula, the reaction between compound (29) and compound (30) is usually carried out in a suitable solvent in the presence or absence of a dehydrohalogenating agent. Basic compounds are usually used as the dehydrohalogenation agent, such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,
5-diazabicyclo[4.3.0]nonene-5 (DBN),
1,5-diazabicyclo[5.4.0]undecene-
5 (DBU), organic bases such as 1,4-diazabicyclo[2.2.2]octane (DABCO), potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, Examples include alkali metal alcoholates such as potassium hydride, silver carbonate, sodium methylate, and sodium ethylate. Note that the reaction compound Compound (30) can also be used as a dehydrohalogenation agent by using an excess amount. Examples of solvents include halogenated carbons such as methylene chloride, chloroform, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, diethyl ether, tetrahydrofuran,
Ethers such as dimethoxyethane, esters such as methyl acetate and ethyl acetate, aprotic polar solvents such as dimethyl formamide, dimethyl sulfoxide, and hexamethyl phosphoric triamide;
Alcohols such as pyridine, acetone, acetonitrile, methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, methyl cellosolve,
Examples include pyridine, acetone, acetonitrile, and a mixed solvent of two or more thereof. The ratio of compound (29) and compound (30) to be used is not particularly limited and can be selected within a wide range, but the latter is usually used in an amount of at least equimolar to the former, preferably equimolar to 5 times the molar amount. The reaction temperature is usually about -30 to 180°C, preferably about 0 to 150°C, and generally for 5 to 30 minutes.
The reaction completes in time. The ring-closing reaction of compound (31) is carried out in a suitable solvent or in the absence of a solvent in the presence of an acid. The acid is not particularly limited, and ordinary organic acids or inorganic acids are used, such as inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, Lewis acids such as aluminum chloride, boron trifluoride, and titanium tetrachloride, and formic acid. , acetic acid, ethanesulfonic acid, and p-toluenesulfonic acid. Among these, inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid are preferred. The amount of acid to be used is not particularly limited, and is usually at least the same weight, preferably 10 to 50 times the weight of compound (31).
In addition, ordinary inert solvents are used as solvents,
For example, water, lower alcohols such as methanol, ethanol, and propanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene, and xylene, and halogenated hydrocarbons such as methylene chloride, chloroform, and carbon tetrachloride. , aprotic polar solvents such as acetone, dimethylsulfoxide, dimethylformamide, and hexamethylphosphoric triamide. Among these, water-soluble solvents such as lower alcohols, ethers, acetone, dimethyl sulfoxide, dimethyl formamide, and hexamethyl phosphoric triamide are preferred. The reaction is usually carried out at 0 to 100°C, preferably at room temperature to 60°C,
It usually takes about 5 minutes to 6 hours to complete. The compounds (13) to (13f) and (15) can be prepared by the N-alkylation method shown in the above reaction formula - and, and the method using the dehydrogenation reaction or reduction reaction shown in the reaction formula - and. ,
Similarly, other corresponding compounds of formulas (13) to (13f) and (15) can also be derived. Furthermore, compounds (16) and compound (9) which are intermediates in the above reaction formula - and the above reaction formula -
The starting material, compound (21), etc., can also be produced by the method shown in the following reaction formula. [Reaction formula] [In the formula, R ¹ , X, X′ and the bond between the 3rd and 4th positions of the carbostyril bone nucleus are the same as above] Reaction of the above compound (32) with the compound (25) or (26) is carried out under the same conditions as the reaction between compound (24) and compound (25) or (26) in the reaction formula -. However, the reaction temperature is usually 20-120℃,
The temperature is preferably about 40 to 70°C, and the reaction time varies depending on the raw materials, catalyst, and reaction temperature, but is usually about 30 minutes to 24 hours. [Reaction formula] [In the formula, R ¹ , R ² , A, n and the bond between the 3rd and 4th positions of the carbostyril bone nucleus are the same as above. ^R14
is a hydrogen atom, lower alkyl or group

[Reaction formula]

[In the formula, R ² , A, n and X are the same as above] The ring-closing reaction of compound (35) in the above reaction formula is
The ring-closing reaction of compound (11) in the above reaction formula is carried out under the same conditions, and the reaction leading to compound (9b) from compound (36) is also carried out under the same conditions as the ring-closing reaction of compound (11) in the above reaction formula. It is carried out under the same conditions as the warping reaction. [Reaction formula] [In the formula, R ² and X are the same as above] In the above reaction formula, the halogenation reaction of compound (37) is carried out by treating compound (37) with a halogenating agent in an appropriate solvent. Examples of the halogenating agent used include halogen molecules such as chlorine and bromine;
Examples include N-halogenosuccinimides such as N-bromosuccinimide and N-chlorosuccinimide, copper halides such as sulfuryl chloride, copper chloride, and copper bromide. Examples of the solvent include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, ethers such as diethyl ether, tetrahydrofuran, and dioxane, and acetic acid. The amount of the halogenating agent used is from equimolar to excess, preferably equimolar to 1.2 times the molar amount of compound (37). The reaction is usually carried out at a temperature of 0°C to around the boiling point of the solvent, preferably room temperature to 40°C, and is usually completed in about 1 to 10 hours.
Note that a radical reaction initiator such as a peroxide such as benzoyl peroxide or hydrogen peroxide may be used in this reaction. The reaction of ring-closing compound (38) to lead to compound (9c) is carried out in a suitable solvent in the presence of a condensing agent.
Examples of condensing agents used include phosphorus pentoxide,
Examples include Lewis acids such as hydrogen fluoride, sulfuric acid, polyphosphoric acid, aluminum chloride, and zinc chloride.
Chloroform, dichloromethane,
Examples include halogenated hydrocarbons such as 1,2-dichloroethane, ethers such as diethyl ether and dioxane, and aromatic hydrocarbons such as nitrobenzene and chlorobenzene. Compound(38)
Although the ratio of the condensing agent and the former is not particularly limited, it is generally preferable to use the latter in an equimolar to 10-fold molar amount, preferably 3 to 6-fold molar to the former. This reaction is usually carried out at a temperature of 50 to 250°C, preferably 70 to 200°C.
It lasts about 20 minutes to 6 hours. [Reaction formula] [In the formula, R ¹ , R ² , X, A, n and the bond between the 3rd and 4th positions of the carbostyril bone nucleus are the same as above.
R ¹⁵ represents lower alkanoyl] The reaction between compound (9) and compound (39) in the above reaction formula preferably uses a basic compound as a dehydrohalogenation agent, and is carried out at room temperature to 200°C in an appropriate solvent.
It is preferably carried out at room temperature to 150°C for several hours to about 15 hours. Examples of solvents used include lower alcohols such as methanol, ethanol, and isopropanol; ethers such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol monomethyl ether, and diethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; Examples include ketones such as acetone and methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, hexamethyl, phosphoric acid triamide, and acetic anhydride. Examples of basic compounds include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and silver carbonate, alkali metals such as sodium and potassium, sodium amide, and sodium hydride. , alcoholates such as sodium methylate, sodium methylate, potassium ethylate, and tertiary amines such as triethylamine, tripropylamine, pyridine, quinoline, N,N-dimethylaniline, and N-methylmorpholine. In the above reaction, an alkali metal iodide such as potassium iodide or sodium iodide may be used as a reaction accelerator. The ratio of compound (9) and compound (39) to be used is not particularly limited, but is usually at least an equimolar amount of the latter to the former, preferably about 1 to 5 moles. Compound (16) can be obtained by hydrolyzing the compound (40) obtained.
guided by. This hydrolysis reaction can be carried out using, for example, hydrochloric acid,
Hydrohalic acids such as hydrobromic acid, mineral acids such as sulfuric acid and phosphoric acid, alkali metal hydroxides such as potassium hydroxide and sodium hydroxide, and alkali metal carbonates such as sodium carbonate, potassium carbonate, and sodium bicarbonate. Alternatively, the reaction is carried out by heating in the presence of bicarbonate or the like, usually at 50 to 150°C, preferably 70 to 100°C, for about 3 to 24 hours. In addition, these compounds (9) and (16) can be similarly prepared by the N-alkylation method shown in the above reaction formula - and, and the method using the dehydrogenation reaction or reduction reaction shown in the reaction formula - and. It is also possible to lead to other compounds of formula (9) or (16). Compound (13) of the above reaction formula can also be produced, for example, by the method of the following reaction formula. [Reaction formula] [In the formula, R ¹ , R ² , A and the bonds at the 3- and 4-positions of the carbostyril bone core are the same as above, R ¹⁶ is a lower alkyl group, and n' is 1] Compound (41) and compound ( The reaction with 42) is carried out under the same conditions as the reaction between compound (9) and compound (10) in the reaction formula -. The hydrolysis reaction of compound (43) is carried out under the same conditions as the hydrolysis reaction of compound (2) in the above reaction formula -. Examples of the compound (44) include potassium cyanide, sodium cyanide, silver cyanide, copper cyanide, and calcium cyanide. The reaction between compound (41) and compound (44) is carried out in a suitable solvent. Examples of the solvent used include water, lower alkanols such as methanol, ethanol, and isopropanol, or a mixed solvent of water and lower alkanols. Compound (4
The amount of 4) to be used is at least equimolar, preferably 1 to 1.5 times the molar amount of compound (41). The reaction is usually carried out at room temperature to 150°C, preferably around 50 to 120°C, for about 30 minutes to 10 hours. Moreover, the hydrolysis reaction of compound (45) is also similar to that of the above compound (2).
The hydrolysis reaction is carried out under similar conditions. In addition, the compound (13′) with the desired carbon number is
It can be obtained by appropriately combining and repeating the reaction of the reaction formula - and the carbon increase reaction of the reaction of the reaction formula -. Compound (1) of the present invention also has the following reaction formula -
It can also be manufactured by the method. [Reaction formula] [In the formula, R ¹ , R ² , R ⁴ ', R ¹⁶ , A, n', X,
The bonds at the 3- and 4-positions of carried out under similar conditions. The hydrolysis reaction of compound (47) is carried out under the same conditions as the hydrolysis reaction of compound (2) in the above reaction formula. The reaction between compound (48) and compound (49) is carried out in the presence of a basic compound in a solvent or without a solvent. The solvents used include ethers such as dioxane, tetrahydrofuran, ethylene glycol, dimethyl ether, and diethyl ether;
Examples include aromatic hydrocarbons such as benzene, toluene, and xylene, alcohols such as methanol, ethanol, and isopropanol, and polar solvents such as dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, and acetone. The basic catalysts used include inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium amide, sodium hydride, triethylamine, tripropylamine, pyridine, Examples include organic bases such as quinoline. The reaction is usually carried out at room temperature to 200°C, preferably room temperature to 150°C, for about 1 to 30 hours.
The reaction can also be easily progressed by adding an alkali metal iodide such as potassium iodide or sodium iodide, hexamethyl phosphoric acid triamide, etc. to the reaction system. Compound (49) in the above reaction
The proportion of the compound (48) to be used is usually an equimolar to a large excess, preferably an equimolar to 5 times the molar amount. The compounds of the present invention are useful as anti-ulcer agents and are usually used in the form of common pharmaceutical preparations. The formulation is prepared using commonly used diluents or excipients such as fillers, fillers, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and typical examples include tablets, pills, powders,
Examples include solutions, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions, suspensions, etc.). When forming tablets, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, anthene powder, laminaran powder , disintegrants such as sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc. class ammonium base,
Absorption enhancers such as sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol. Examples include brighteners. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets. When forming into a pill form, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, etc. ,
Examples include binders such as tragacanth powder, gelatin, and ethanol, and disintegrants such as laminaran and agar. When forming into a suppository, a wide variety of conventionally known carriers can be used, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin,
Examples include semi-synthetic glycerides.
When prepared as injections, solutions and suspensions are preferably sterile and isotonic with blood, and when formed into solutions, emulsions, and suspensions, diluents are used. All those commonly used in this field can be used, including water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, the anti-ulcer agent may contain a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution, and the anti-ulcer agent may also contain conventional solubilizing agents, buffers, soothing agents, etc.
Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, and other pharmaceutical agents may be included in the therapeutic agent, if necessary. The amount of the compound of the present invention to be contained in the anti-ulcer agent of the present invention is not particularly limited and can be selected within a wide range, but is usually 1 to 70% by weight, preferably 5 to 50% by weight based on the total composition. . There are no particular restrictions on the method of administering the anti-ulcer agent of the present invention, and it can be administered in a manner depending on various formulation forms, age, sex and other conditions of the patient, degree of disease, etc.
For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. In the case of injections, they are administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids, and if necessary, they can also be administered intramuscularly, intradermally, or
Administered subcutaneously or intraperitoneally. Suppositories are administered rectally. The dosage of the anti-ulcer agent of the present invention is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc., but the amount of the compound of the present invention is usually 0.6 to 50 mg/kg body weight per day. It is good, also,
The dosage unit form preferably contains 10 to 1000 mg of the active ingredient. Next, the present invention will be explained in more detail with reference to Reference Examples and Examples, but the present invention is not limited thereto. Reference Example 1 100 g of m-aminobenzoic acid is suspended in ether 1, and 44.6 g of β-ethoxyacrylic acid chloride is added dropwise to the suspension at room temperature with stirring. After reacting this mixture at 40°C for 5 hours, the precipitate was collected. The crystals were washed three times with water, dried, and recrystallized from methanol to obtain 60 g of m-carboxy-N-(β-ethoxyacryloyl)aniline as colorless flocculent crystals. Melting point 200.5~202.0
°C Reference Example 2 Methyl 3-phenylpropionate 50g, chloroacetyl chloride 51.6g and dichloromethane
Cool 250 ml of the mixture to 0°C. While stirring at 0-10°C, 122g of aluminum chloride is gradually added.
Then stir at room temperature for 2 hours. After standing overnight at room temperature, the reaction mixture is poured into ice-conc. hydrochloric acid and extracted with chloroform. The chloroform layer is washed with water, dried, and the chloroform is distilled off. The residue was crystallized by adding isopropyl ether, and the crystals were collected and recrystallized from ethanol to give colorless needle-like crystals of 3-(4-
Methyl chloroacetylphenyl)propionate
Get 53.4g. Melting point 90.0-92.0℃. Reference Example 3 36.26 g of methyl 3-(4-chloroacetylphenyl)propionate was dissolved in 300 ml of concentrated sulfuric acid, and 20.9 g of fuming nitric acid (d=1.52) was added dropwise with stirring under ice-water cooling. After stirring at room temperature for 3 hours, the reaction mixture is poured into ice water and extracted with chloroform. After washing the chloroform layer with water and drying, the chloroform is distilled off. The residue is purified by silica gel column chromatography and crystallized by adding ether. The crystals were collected and recrystallized from methanol to obtain 26.7 g of methyl 3-(4-carboxy-2-nitrophenyl)propionate in pale yellow prismatic crystals. melting point
120.0 to 122.0°C Reference Example 4 To a solution of 467 g of chloroacetyl chloride in 400 ml of dichloromethane, add 735 g of aluminum chloride in 1/3 portions at 30°C or below while stirring. Next, add 200g of carbostyril at the same temperature and stirring. After heating and refluxing the mixture for 6 hours, the reaction mixture was poured into ice-concentrated hydrochloric acid to collect precipitated crystals. This was washed with methanol and hot methanol to obtain 153 g of 6-chloroacetylcarbostyryl. The mother liquor was concentrated to dryness, the residue was purified by silica gel column chromatography, and recrystallized from methanol to give 35.41 g of 8-chloroacetylcarbostyryl in the form of pale yellow needles.
get. Melting point: 177.5-179.0°C Reference Example 5 30 g of 8-chloroacetylcarbostyryl and 300 ml of pyridine are mixed and heated and stirred at 80-90°C for 2.5 hours. The reaction solution was cooled with ice water, the precipitated crystals were collected, washed with ether, and recrystallized from methanol to obtain colorless needle-like crystals of 8-(α-pyridinium acetyl).
Obtain 40.85 g of carbostyryl chloride. melting point
261.5-264.0°C (decomposition) Reference Example 6 To a solution of 29.5 g of methyl m-aminobenzoate in 300 ml of diethyl ether is added dropwise 11.53 g of β-ethoxyacrylic acid chloride at 17-27°C with stirring. After dropping, the mixture was stirred at room temperature for 1 hour and the precipitated crystals were collected.
After washing with ether, the crude crystals are dissolved in chloroform and washed with 0.5N hydrochloric acid, saturated sodium bicarbonate, and saturated saline. After drying, chloroform was distilled off, the residue was purified by silica gel column chromatography, and then recrystallized from methanol to give 13.63 g of m-methoxycarbonyl-N-(β-methoxyacryloyl)aniline as colorless prismatic crystals. get. Melting point 108-110℃ Reference example 7 (a) 6-(α-chloroacetyl)carbostyryl
60g was suspended in 0.5Kg of pyridine, stirred at 80-90°C for 2 hours, and then stirred for 1 hour under ice cooling. The precipitated crystals were collected and recrystallized from methanol to obtain 70 g of 6-(α-pyridinium acetyl) carbostyryl chloride hemihydrate in the form of colorless needles.
Melting point: 300°C or higher (b) 69.7g of 6-(α-pyridinium acetyl)carbostyryl chloride and 65g of sodium hydroxide are dissolved in 0.6ml of water and stirred at 60-70°C for 3 hours. Under ice cooling, add concentrated hydrochloric acid to the reaction mixture to adjust the pH to 2. The precipitated crystals were collected and recrystallized from DMF to obtain 41.4 g of 6-carboxycarbostyryl in the form of light brown powder. Melting point: 300°C or higher Reference Example 8 The following compound is obtained in the same manner as in Reference Example 7 using appropriate starting materials. 6-carboxy-3,4-dihydrocarbostyryl, pale yellow powder crystal (dimethylformamide)
Melting point: 300℃ or higher 8-carboxycarbostyryl, colorless needle crystals (methanol-chloroform), melting point: 320℃ or higher,
NMR (DMSO) δ6.57 (d, J=9.5Hz.1H), 7.25
(t, J=8.0Hz, 1H), 7.94 (d, d, J=8.0Hz,
1.5Hz, 1H), 7.98 (d, J = 9.5Hz, 1H), 8.14
(d, d, J = 8.0 Hz, 1.5 Hz, 1H) Reference example 9 10 g of 6-carboxy-3,4-dihydrocarbostyryl and N-hydroxysuccinimide
Suspend 6.0 g in 200 ml of dioxane. Next, dicyclohexylcarbodiimide was added under ice-cooling and stirring.
Add 12.4 g of a 50 ml dioxane solution dropwise. The mixture was heated and stirred at 90°C for 4 hours. After the reaction is complete,
It was allowed to cool to room temperature, the precipitated crystals were removed, the liquid was concentrated to dryness, and the residue was recrystallized from dimethylformamide-ethanol to give colorless flaky crystals of succinimide 3,4-dihydrocarbostyryl-6-. 10.8 g of carboxylate are obtained. Melting point: 234.5-236°C Reference Example 10 8 g of m-carboxy-N-(β-ethoxyacryloyl)aniline is added to 80 ml of concentrated sulfuric acid, and the mixture is stirred at room temperature for 2 hours and then at 50°C for 1 hour. Pour the reaction solution into ice and adjust the pH to 3 with 10N aqueous sodium hydroxide solution.
Adjust to ~4. Remove the precipitated crystals and wash with water.
Recrystallization from DMF gives 4.26 g of 5-carboxycarbostyryl in the form of pale yellow powder. Melting point 320℃ or higher NMR (DMSO) δ6.58 (d, J = 9.5Hz, 1H),
7.40-7.80 (m, 3H), 8.69 (d, J = 9.5Hz, 1H) Reference example 11 3-(4-carboxy-2-nitrophenyl)
5 g of methyl propionate, 8.87 ml of 2.226N sodium hydroxide methanol solution, 100 ml of methanol and 1 g of 5% Pd-C (50% water content) are mixed and subjected to catalytic reduction at room temperature and pressure. Remove the catalyst, add concentrated hydrochloric acid to the mother liquor to adjust the pH to ≒1, collect the precipitated crystals,
Recrystallize colorless needle crystals from methanol to obtain 7-carboxy-3,4-dihydrocarbostyryl.
Get 3.62g. Melting point 320℃ or higher NMR (DMSO) δ2.33~2.60 (m, 2H), 2.77~
3.05 (m, 2H), 7.21 (d, J=8.5Hz, 1H), 7.38
~7.53 (m, 2H), 10.15 (s, 1H) Reference example 12 10g of m-methoxycarbonyl-N-(β-ethoxyacroyl)aniline was gradually added to 100ml of concentrated sulfuric acid, and the mixture was heated at room temperature for 2 hours at 45°C. Stir for 4 hours. Pour the reaction solution into ice, collect the precipitated crystals, and wash with water. The obtained crude crystals were recrystallized from methanol-chloroform to obtain 6.97 g of 5-methoxycarbonylcarbostyryl. Melting point: 277.5-279.0°C Reference Example 13 2 g of 5-carboxycarbostyryl is suspended in 30 ml of water, and a 10N aqueous sodium hydroxide solution is added thereto to dissolve the crystals. 500 mg of 10% Pt-C is added to the solution, and catalytic reduction is carried out at 70° C. under a hydrogen pressure of 3 to 4 kg/cm ² . After the reaction, the catalyst was removed, concentrated hydrochloric acid was added to the solution to make the pH≈1, the precipitated crystals were collected, and recrystallized from methanol to give colorless needle-like crystals of 5-carboxy-3,
820 mg of 4-dihydrocarbostyril are obtained. melting point
309-311°C Reference Example 14 2 g of 5-carboxycarbostyryl is suspended in 100 ml of methanol, saturated by bubbling hydrochloric acid gas, and then refluxed for 3 hours. Concentrate the reaction solution to half its volume and collect the precipitated crystals. Purified by silica gel column chromatography and then recrystallized from methanol-chlorohelm to give 230 mg of 5-methoxycarbonyl carbostyryl as colorless powder crystals.
get. Melting point 277.5-279℃ Reference example 15 Dissolve 2g of 8-(α-pyridinium acetyl)carbostyryl chloride in 20ml of methanol,
Add 1.01 g of DBU to this and reflux for 1 hour. The reaction solution was concentrated to dryness, and the residue was mixed with water, chloroform,
Add 1N hydrochloric acid. The chloroform layer is washed with water, saturated aqueous sodium bicarbonate solution, and saturated brine in this order, and then dried. Chloroform was distilled off, the resulting residue was purified by silica gel column chromatography, and then recrystallized from methanol to yield 130 mg of 8-methoxycarbonylcarbostyryl in the form of colorless needles.
get. Melting point 140-142℃ Reference example 16 34g of 3-formylcarbostyryl in methanol
Suspend in 800ml. Add 7.4 g of sodium borohydride little by little while stirring on ice. Stirring was performed for 3 hours under ice cooling. The precipitated crystals were collected and recrystallized from methanol to obtain 33.2 g of colorless prismatic 3-hydroxymethylcarbostyryl. Melting point 238~
239.5℃ Reference Example 17 Suspend 16g of lithium aluminum hydride in 200ml of dry tetrahydrofuran. 16 g of 3-methoxycarbonylcarbostyryl while stirring at room temperature.
Add. Stir at room temperature for 5 hours. Add ethyl acetate dropwise to decompose excess lithium aluminum hydride. After adding more water, the mixture is concentrated under reduced pressure. Dilute sulfuric acid was added to the residue, the precipitated crystals were collected, and 3.7 g of colorless prismatic 3-hydroxymethyl carbostyryl was recrystallized from methanol. melting point
238-239.5°C Reference Examples 18-22a The compounds shown in the following table are obtained in the same manner as in Reference Examples 16 and 17 using appropriate starting materials.

[Table] Reference example 23 47 for 5g of 3-hydroxymethylcarbostyryl
Add 50 ml of % hydrobromic acid and stir at 70-80°C for 3 hours. After cooling, the precipitated crystals were collected and recrystallized from methanol to obtain 6 g of colorless needle-like 3-bromomethylcarbostyryl. Melting point: 218.5-219°C (decomposed) Reference example 24 3 g of 3-hydroxymethyl carbostyryl is suspended in 100 ml of chloroform. A solution of 2 g of thionyl chloride in 20 ml of chloroform is added dropwise while stirring at room temperature. Stir for 1 hour at room temperature. Concentrate under reduced pressure, and recrystallize the residue from methanol to obtain 2.9 g of colorless needle-like 3-chloromethylcarbostyryl. melting point 204
~205°C Reference Example 25 2.8 g of 2-chloro-3-chloromethylquinoline was dissolved in 30 ml of acetic acid and refluxed for 2 hours. Pour the reaction solution into water and collect the precipitated crystals. Recrystallization from methanol yields 2.1 g of 3-chloromethylcarbostyryl in the form of colorless needles. Melting point: 204-205°C Reference Examples 26-39 The compounds shown in the following table are obtained in the same manner as in Reference Examples 23-25 using appropriate starting materials.

【table】

[Table] Reference example 40 Make sodium ethylate from 1.5g of sodium and 150ml of dry ethanol. To this was added 12 g of diethyl acetamidomalonate, and the mixture was stirred at room temperature for 1 hour. 4-bromomethylcarbostyryl 12g
was added and refluxed for 2 hours. Ethanol is distilled off, water is added to the residue, and the precipitated crystals are collected. Recrystallized from ethanol to form colorless prismatic ethyl
2-acetamido-2-carboethoxy-3-
(2-quinolon-4-yl)propionate 13g
get. Melting point: 224-226°C (decomposed) Reference Examples 41-58 In the same manner as in Reference Example 40, the compounds shown in the following table were obtained using appropriate starting materials.

【table】

[Table] Reference Example 59 Dissolve 5.6 g of ethyl 2-acetamido-2-carboethoxy-3-(2-quinolon-3-yl)propionate in 150 ml of tetrahydrofuran.
Add 0.8 g of 50% oily sodium hydrogen to this while stirring at room temperature. Add 4.5 g of methyl iodide dropwise and stir at room temperature for 3 hours. Concentrate under reduced pressure and pour the residue into water to collect precipitated crystals. Recrystallized from ethanol water to give colorless scales of ethyl 2-acetamide-2-
3.5 g of carboethoxy-3-(1-methyl-2-quinolon-3-yl)propionate are obtained. melting point
190.5-192°C Same as Reference Example 59, Reference Examples 45, 48,
Compounds 51, 52 and 57 are obtained. Reference Example 60 Suspend 1.9 g of lithium aluminum hydride in 100 ml of dry tetrahydrofuran. To this is added 1.9 g of 3-carboxycarbostyryl while stirring at room temperature. Stirring is carried out overnight at room temperature. Excess lithium aluminum hydride is decomposed by adding ethyl acetate dropwise. Add dilute sulfuric acid to make acidic. After distilling off tetrahydrofuran under reduced pressure, the precipitated crystals are collected. 0.5g of colorless prismatic 3-hydroxymethylcarbostyryl recrystallized from methanol
get. Melting point 238-239.5℃. Compounds of Reference Examples 18 to 22 are obtained in the same manner as in Reference Example 60 above using appropriate starting materials. Reference Example 61 Dissolve 30 g of acetoacetanilide in 30 ml of chloroform. A solution of 27 g of bromine in 30 ml of chloroform is added dropwise to this while stirring at room temperature. After dropping, reflux is performed for 30 minutes. Concentrate under reduced pressure and add the residue to 70 ml of concentrated sulfuric acid with stirring. Add while maintaining the internal temperature at 70-75°C, and stir at 95°C for 30 minutes. Pour the reaction solution into ice water and collect the precipitated crystals. Recrystallization from methanol-chloroform yields 20 g of 4-bromomethylcarbostyryl in the form of colorless needles. Melting point: 265-266°C Compounds of Reference Examples 23, 24, 26-28 and 30-37 are obtained in the same manner as in Reference Example 61 using appropriate starting materials. Reference Example 62 2.2 g of 3-chloromethyl-6-methoxycarbostyryl is dissolved in 20 ml of acetic anhydride. Add 12 g of potassium acetate to this and stir at 60-70°C for 3 hours. Pour the reaction solution into ice water and collect the precipitated crystals. Recrystallization from acetone yields 2 g of colorless prismatic 3-acetoxymethyl-6-methoxycarbostyryl. Melting point: 166-168°C Reference Example 63 2 g of 3-acetoxymethylcarbostyryl is dissolved in 30 ml of methanol containing 0.6 g of sodium hydroxide, and refluxed for 3 hours. After distilling off methanol,
Add water to the residue and collect the precipitated crystals. Recrystallization from acetone yields 1.3 g of pale yellow needle-like 3-hydroxymethyl-6-methoxycarbostyryl. melting point
196-197°C Compounds of Reference Examples 16 and 19-22 are obtained in the same manner as in Reference Example 63 above using appropriate starting materials. Reference Example 64 (a) Weigh 175 ml of water, 10.5 g of ferrous sulfate heptahydrate, 0.5 ml of concentrated hydrochloric acid, and 6 g of o-nitrobenzaldehyde into a four-necked flask, and heat to 90°C above the water solution. Add 25 ml of concentrated ammonia water all at once while stirring. 30ml of ammonia water every 2 minutes
Add in three parts. Immediately after the addition is complete, steam distillation is carried out. Collect 250 ml of distillate twice.
Cool the first distillate and collect the precipitated crystals. The mother liquor and the second distillate are combined, saturated with common salt, and extracted with ether. The ether solution is dried over sodium sulfate and the ether is distilled off. The residue and the previous crystals are combined and dried to obtain 2.9 g of o-aminobenzaldehyde in the form of yellow scales. melting point
38-39°C (b) Dissolve 2 g of malonic acid in 15 ml of pyridine. To this were added 1.2 g of o-aminobenzaldehyde and 2 ml of piperidine, and the mixture was stirred at 90°C for 5 hours. Pour the reaction solution into an aqueous hydrochloric acid solution to collect precipitated crystals.
Recrystallization from methanol-chloroform yields 1.2 g of 3-carboxycarbostyryl in the form of colorless needles. Melting point: 300°C or higher Reference Example 65 Add 140 ml of acetic anhydride to 60 g of isatin and reflux for 4 hours. After cooling, the precipitated crystals were collected and washed with ether to obtain 58 g of N-acetylisatin. Dissolve 30 g of sodium hydroxide in 1.5 g of water. To this was added 58 g of the above N-acetylisatin and refluxed for 1 hour. Cool slightly, add activated charcoal,
Reflux for 30 minutes. Remove the activated carbon when hot. Cool the mother liquor and adjust the pH to 3-4 with 6N hydrochloric acid. The precipitated crystals are collected, washed with water, and dried to obtain 45 g of 4-carboxycarbostyryl. Melting point 300℃
Reference Example 66 (a) 322 ml of phosphorus oxychloride is added dropwise to 96 ml of N,N-dimethylformamide while stirring under ice cooling. At the same temperature, add 67.5g of acetanilide, and at 75℃ it becomes 18.5g.
Stir for hours. Pour the reaction solution into ice to remove the precipitated crystals and dry. Recrystallization from ethyl acetate yields 55.2 g of 2-chloro-3-formylcarbostyryl in the form of yellow needles. Melting point 149-151℃ (b) 4 to 37g of 2-chloro-3-formylquinoline
Add 600 ml of normal hydrochloric acid and reflux for 1 hour. After cooling,
The precipitated crystals were collected and recrystallized from ethanol-chloroform to obtain 34 g of 3-formylcarbostyryl in the form of pale yellow needle-like crystals. Melting point: 308-309°C (c) 2.7 g of 3-formylcarbostyryl is dissolved in 150 ml of tetrahydrofuran, and 0.8 g of 50% oily sodium hydride is added to this with stirring at room temperature. Add 4.5 g of methyl iodide dropwise and stir at room temperature for 3 hours. Concentrate under reduced pressure and pour the residue into water to collect precipitated crystals. This was recrystallized from ethanol to obtain 1.7 g of 1-methyl-3-formylcarbostyril in the form of yellowish brown needles. Melting point: 211-214°C Reference Example 67 64.4ml of phosphorus oxychloride is added dropwise to 11.6ml of N,N-dimethylformamide at 0°C with stirring.
At the same temperature, 18.4 g of N-phenyl-3-chloropropionamide is added. Stir at 75-80°C for 10 hours.
Pour the reaction solution into ice water and collect the precipitated crystals. Recrystallization from ethanol yields 6.7 g of colorless prismatic 2-chloro-3-chloromethylquinoline. melting point
116-118℃ Reference Example 68 17g of 4-formylcarbostyryl, 18g of N-acetylglycine, 7g of sodium acetate anhydride and 100ml of acetic anhydride are heated at 110℃ to form a homogeneous solution,
Reflux for an additional 1.5 hours. After cooling, add to cold water,
Collect the precipitated crystals. Wash with cold water and ethanol-
Recrystallization from chloroform yields 10 g of 4-(1,2-dihydro-2-oxo-4-quinolylidene)-2-methyl-5-oxazolone.1/2H ₂ O.
Melting point: 275-277°C (decomposition) Reference Examples 69-70 In the same manner as in Reference Example 65, using appropriate starting materials, the compounds shown in the following table are obtained.

[Table] Reference example 71 Ethyl-2-acetamido-2-carboxy-
3-(2-quinolin-4-yl)propionate
Add 150 ml of 20% hydrochloric acid to 5 g and reflux for 9 hours. It was concentrated under reduced pressure, and the residue was recrystallized from ethanol-water to give colorless prismatic 2-amino-3-(2-
3.2 g of quinolin-4-yl)propionate hydrochloride monohydrate are obtained. Melting point 220-225℃ (decomposition) Reference example 72 2-amino-3-(2-quinolin-3-yl)
1.6 g of propionic hydrochloride and 2.4 g of potassium carbonate are dissolved in 60 ml of acetone and 30 ml of water. A solution of 1.2 g of p-chlorobenzoyl chloride in 10 ml of acetone is added dropwise to this while stirring on ice. Stir for 2 hours under ice cooling. After distilling off the acetone, water is added to the residue to remove insoluble materials. Acidify the solution with hydrochloric acid and collect the precipitated crystals. Recrystallized from ethanol-water to give 2-(4-chlorobenzoylamino)-3 as a white powder.
-(2-quinolon-3-yl)propionic acid 1.5g
get. Melting point: 270-271.5°C (decomposed) Reference Example 73 1.5 g of 2-amino-3-(6-methoxy-2-quinolon-3-yl) propionic acid hydrochloride is dissolved in a solution of 0.8 g of sodium hydroxide in 25 ml of water. Add 1 g of p-chlorobenzoyl chloride dropwise under ice cooling and stir. N-sodium hydroxide aqueous solution and acid chloride are added at appropriate times until the starting material disappears by thin layer chromatography. After the reaction is complete, acidify with hydrochloric acid and collect the precipitated crystals. After washing with ether, recrystallization from methanol-water yields a yellow powder of 2-
(4-Chlorbenzoylamino)-3-(6-methoxy-2-quinolon-3-yl)propionic acid
Get 0.7g. Melting point: 234.5-236℃ (decomposition) Reference example 74 2-amino-3-(6-hydroxy-2-quinolon-3-yl)propionic acid hydrochloride 2g was dissolved in 1-
Suspend in 50 ml of methyl-2-pyrrolidone and add 3-(4
-Chlorbenzoyl)benzoxazoline-2-
Add 2.2 g of thione and stir at room temperature for 3 days. Pour the reaction solution into ice water and collect the precipitated crystals. N crystal
- After dissolving in an aqueous sodium hydroxide solution, acidify with 10% hydrochloric acid and remove the precipitated crystals. After drying the crystals, wash them with chloroform. Recrystallization from methanol-water gives 1.5 g of 2-(4-chlorobenzoylamino)-3-(6-hydroxy-2-quinolon-3-yl)propionic acid as a pale yellow powder. melting point 223
~227°C (decomposition) Examples 1 to 5 In the same manner as in Example 1, using appropriate starting materials, the compounds shown in the following table are obtained.

[Table] Examples 6 to 27 The compounds shown in the following table are obtained in the same manner as in Reference Example 72 using appropriate starting materials.

【table】

【table】

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a phenyl lower alkyl group; R ² is a hydrogen atom, a halogen atom, a hydroxyl group, an unsubstituted or halogen-substituted benzoyloxy group, a lower alkyl group or a lower alkoxy group; R ³ is a hydroxyl group, an amino group, a cycloalkyl lower alkylamino group (the cycloalkyl ring may be substituted with a carboxyl group or a lower alkoxycarbonyl group), a lower alkoxy group, a lower alkoxycarbonyl lower alkoxy group, benzoyl lower alkoxy group or lower alkanoyloxy lower alkoxy group; R ⁴ is a hydrogen atom, phenylsulfonyl group, lower alkyl group, which may have a lower alkyl group or halogen atom as a substituent, as a substituent on the phenyl ring Phenyl lower alkyl group or group that may have a halogen atom -COR ⁶ (R ⁶ is a lower alkyl group that may have an amino group or phenyl lower alkoxycarbonylamino group as a substituent, an amino lower alkyl group or phenyl as a substituent) A cycloalkyl group that may have a lower alkoxycarbonylamino lower alkyl group, 1 to 3 groups selected from a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, a hydroxyl group, and an amino group as substituents on the phenyl ring. a phenyl group which may have a halogen atom as a substituent on the phenyl ring, a phenyl lower alkyl group which may have a halogen atom as a substituent on the phenyl ring, or a 5-membered or a 6-membered unsaturated heterocyclic group (the heterocycle may be substituted with a lower alkyl group); R ⁵ is a hydrogen atom or a phenylsulfonyl group that may have a lower alkyl group or a halogen atom as a substituent; A
is a lower alkylene group; n represents 0 or 1, the dotted line in the formula [Formula] of the substituent means a single bond or a double bond, and the substitution position of this substituent is 3, Either 4th, 5th or 6th place.
Further, the bond between the 3rd and 4th positions of the carbostyril skeleton represents a single bond or a double bond. However, when n=0, R ¹ is a hydrogen atom, lower alkyl, lower alkenyl, lower alkynyl, or phenyl lower alkyl; R ² is a hydrogen atom, hydroxyl group, or lower alkoxy; R ³ is a hydroxyl group or lower alkoxy; R ⁴ is a group - COR ⁷ (R ⁷ is lower alkyl, cycloalkyl, which may have an amino group or phenyl lower alkoxycarbonylamino group as a substituent,
or a phenyl group which may have 1 to 3 groups selected from halogen atoms, lower alkyl, lower alkoxy, nitro and amino as substituents on the phenyl ring); R ⁵ is a hydrogen atom; carbostyril derivatives and salts thereof.