JPS6335623B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel carbostyril derivatives, more specifically, the general formula [Wherein, 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 hydrogen atom or lower alkyl;
R ⁴ is lower alkyl, cycloalkyl, which may have an amino group or phenyl lower alkoxycarbonylamino group as a substituent, or a group selected from halogen atom, lower alkyl, lower alkoxy, nitro, and amino as a substituent on the phenyl ring. Indicates a phenyl group that may have 1 to 3 of the substituent formula

The group -A in [Formula] means -CH ₂ -CH or -CH=C, and the substitution position of this substituent is any one of the 3, 4, 5, 6, 7, or 8 position of the carbostyril bone core. It is. Also, the bond between the 3rd and 4th positions of the carbostyril bone nucleus shows a single bond or a double bond]
The present invention relates to carbostyril derivatives and salts thereof. The compounds of the present invention have anti-ulcer effects and are useful as anti-ulcer agents. The compounds of the invention are, in particular,
It is characterized by having remarkable preventive and therapeutic effects on chronic ulcer conditions such as experimental acetic acid ulcers and burnt ulcers, and has low toxicity and side effects, making it an effective drug for chronic 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, 3-butynyl, 1-methyl-2
-propynyl, 2-pentynyl, 2-hexynyl, etc. 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 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
-(6-phenylhexyloxycarbonylamino)ethyl, 1,1-dimethyl-2-(benzyloxycarbonylamino)ethyl, (1,1-dimethyl-2-phenylethoxycarbonylamino)methyl, and the like. Examples of phenyl which may have 1 to 3 groups selected from halogen atoms, lower alkyl, lower alkoxy, nitro and amino as substituents on the phenyl ring include phenyl, 2-, 3- or 4-chlorophenyl, 2-chlorophenyl, 2-, 3- or 4-chlorophenyl, -, 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,
Examples include 4,5-trichlorophenyl. 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 ⁴ and the bond between the 3rd and 4th positions of the carbostyril bone nucleus are the same as above. R ³ ′, R ⁶
and R ⁸ each represent lower alkyl and R ⁷ represents lower alkanoyl] That is, the compound of formula (2) is hydrolyzed and, if desired, the product is acylated, esterified, or a combination thereof to form the desired carbostyryl. lead to derivatives. The reaction of hydrolyzing this compound (2) to lead to the compound of formula (1a), which is one of the compounds of the present invention, can be carried out using a suitable hydrolysis catalyst, such as a hydrohalic acid such as hydrochloric acid or hydrobromic acid, Inorganic acids such as sulfuric acid and 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) or compound (1c) with a carboxylic acid of formula (3), the corresponding other target compound (1b) or (1d), 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) or (1c);
(b) Active ester method or active amide method, that is, carboxylic acid (3) is converted into p-nitrophenyl ester, N-hydroxysuccinimide ester, 1
-Active ester such as hydroxybenzotriazole ester, or benzoxazoline-2-
As an active amide with thione, compound (1a) is added to this.
or a method of reacting (1c), (c) carbodiimide method, that is, a method of dehydrating compound (1a) or (1c) with carboxylic acid (3) in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole. (d) Carboxylic acid halide method, that is, a method in which carboxylic acid (3) is induced into a halide form and reacted with compound (1a) or (1c); (e) Other methods include carboxylic acid (3). For example, use a dehydrating agent such as acetic anhydride to form a carboxylic acid anhydride, and add compound (1a) or (1c) to this.
and a method of reacting compound (1a) or (1c) with an ester of carboxylic acid (3) and, for example, a lower alcohol under high pressure and high temperature. In addition, carboxylic acid (3) is activated with a phosphorus compound such as triphenylphosphine or diethylchlorophosphate, and compound (1a) is added to this.
Alternatively, a method of reacting (1c) may also be adopted.
Examples of the alkylhalocarboxylic acids used in the mixed acid anhydride method include methyl chloroformate,
Examples include methyl bromate, ethyl chloroformate, ethyl bromate, and isobutyl chloroformate. The mixed acid anhydride is obtained by the usual Schotten-Baumann reaction, and the compound (1b) or (1d) of the present invention is produced by reacting it with the compound (1a) or (1c) without isolation. . The Schotten-Baumann reaction is usually carried out in the presence of a basic compound. As the basic compound used, compounds commonly used in the Schotten-Baumann reaction are used, such as triethylamine,
Trimethylamine, pyridine, 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 other organic bases; and inorganic bases such as potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate. The reaction is carried out at about -20 to 100°C, preferably 0 to 50°C, and the reaction time is about 50°C.
The time is about 10 minutes to 10 hours, preferably 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and compound (1a) or (1c) is carried out at about -20 to 150°C, preferably 10 to 50°C, for about 5 minutes to 10 hours, preferably 5
It lasts for about 5 minutes to 5 hours. Although the mixed acid anhydride method does not require the use of a solvent, it is 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. , 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. The proportion of carboxylic acid (3), alkylhalocarboxylic acid, and compound (1a) or (1c) in this method is usually at least the equivalent molar amount;
It is preferable to use the alkylhalocarboxylic acid and compound (1a) or (1c) in moles of 1 to 2 times the amount of (3). For example, in the case of using benzoxazoline-2-thionamide, the active ester method or active amide method in (b) above is performed 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 and the like are used at 0 to 150°C, preferably at 10°C.
The reaction is carried out at ~100°C for 5 to 75 hours. In this case, the ratio of compound (1a) or (1c) and benzoxazoline-2-thionamide used is usually at least equimolar, preferably equimolar to twice molar, of the latter to the former. In the carboxylic acid halide method (c) above, carboxylic acid
(3) is reacted with a halogenating agent to form a carboxylic acid halide, and this carboxylic acid halide is isolated and purified, or is reacted with compound (1a) or (1c) without isolation and purification. It will be done. The reaction between the carboxylic acid halide and compound (1a) or (1c) is carried out in a suitable solvent in the presence of a dehydrohalogenating agent. Basic compounds are usually used as the dehydrohalogenation agent, and in addition to the basic compounds used in the above Schotten-Baumann reaction, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, silver carbonate, sodium methylate, etc. , alkali metal alcoholates such as sodium ethylate, and the like. Incidentally, the reaction compound compound (1a) or (1c) can also be used as a dehydrohalogenation agent by using an excess amount. In addition to the solvent used in the Schotten-Baumann reaction, examples of the solvent include water,
Alcohols such as methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, methyl cellosolve, pyridine, acetone, acetonitrile, etc.
Or a mixed solvent of two or more thereof can be mentioned. The ratio of compound (1a) or (1c) and carboxylic acid halide to be used is not particularly limited and can be selected over a wide range, but the latter is usually used in an amount of at least equimolar, preferably equimolar to twice the molar amount of the former. The reaction temperature is usually about -30 to 180°C, preferably about 0 to 150°C, and the reaction is generally completed in 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 diether 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. Further, the method of activating carboxylic acid (3) with a phosphorus compound such as triphenylphosphine or diethylchlorophosphate and reacting it with compound (1a) or (1c) is carried out in a suitable solvent.
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, Ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane; esters such as methyl acetate and ethyl acetate;
dimethylformamide, dimethyl sulfoxide,
Examples include aprotic polar solvents such as hexamethylphosphoric triamide. In this reaction, compound (1a) or (1c) itself acts as a basic compound, so the reaction proceeds well by using it in excess of the theoretical amount, but if necessary, other basic compounds may be added. , for example, triethylamine, trimethylamine, pyridine, dimethylaniline,
N-methylmorpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] nonene-5 (DBN), 1,5-diazabicyclo [5.4.0]
Organic bases such as undecene-5 (DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO), and inorganic bases such as potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate can also be used. The reaction is accomplished at a temperature of about 0 to 150°C, preferably about 0 to 100°C, for about 1 to 30 hours. Compound (1a) or (1c)
The proportions of the phosphorus compound and carboxylic acid (3) used are usually at least about equimolar amounts, respectively.
Preferably it is 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. The amount used is 5 to 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 -, the compound of formula (1b) can be hydrolyzed to lead to the compound of formula (1a), and the same conditions as in the case of hydrolysis of compound (2) are adopted for the hydrolysis. It can be done. 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 ⁴ and the bond between the 3rd and 4th positions of the carbostyril bone nucleus are the same as above] That is, the compound of formula (5) and the compound of formula (6) are reacted, the resulting intermediate is hydrolyzed, and the product is optionally guided to the desired carbostyryl derivative by hydrolysis, acylation, esterification, or a combination thereof. The reaction between compound (5) and compound (6) 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 (6) to compound (5) 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 (5) and compound (6), the formula [In the formula, R ¹ , R ² , R ⁴ 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 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 formula, compound (1d') or (1c ′). In addition, by acylating compound (1a') or (1c') with the compound of formula (3) in the same manner as the acylation reaction in the above reaction formula -, compound (1b') or (1d ′). Among the compounds of the present invention, substituents

[Formula] A compound in which group A is -CH ₂ -CH can be produced by reducing a compound having a corresponding double bond, as shown in the following reaction formula. [In the formula, R ¹ , R ² , R ³ , R ⁴ and the bond between the 3rd and 4th positions of the carbostyril bone core are the same as above] The above reduction reaction is usually carried out in the presence of an appropriate reduction catalyst. This is done by catalytic reduction. 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 solvents 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°C to
This is done by shaking well at around 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 . [In the formula, R ¹ , R ² , R ³ , R ⁴ 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 shown in the above reaction formula to lead compound (1e) to compound (1f) 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. [In the formula, R ² , R ³ , R ⁴ 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 reaction between the above compound (1g) and compound (8) can be performed using, for example, sodium hydride, potassium hydride, metallic potassium, metallic sodium, sodium amide. , in a suitable solvent in the presence of a basic compound such as potassium amide. Examples of the solvent used include ethers such as dioxane, tetrahydrofuran, diethyl ether, and diethylene glycol dimethyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. The ratio of compound (1 g) to compound (8) is not particularly limited, but usually the latter is at least equimolar to the former.
Preferably it is equimolar to twice the molar amount. 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. [In the formula, R ¹ , R ² , R ³ and R ⁴ are the same as above] The above reaction of dehydrogenating compound (1i) to lead to compound (1k) is carried out by treating with a dehydrogenating agent in an appropriate solvent. It is done. Examples of dehydrogenating agents include benzoquinones such as 2,3-dichloro-5,6-dicyanobenzoquinone and 2,3,5,6-tetrachlorobenzoquinone (common name chloranil), N
- Bromosuccinimide, N-chlorosuccinimide, halogenating agents such as bromine, selenium dioxide,
Examples include dehydrogenation catalysts such as palladium on carbon, palladium black, palladium oxide, and Raney nickel. The amount of the dehydrogenating agent to be 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.
It is generally completed in about 1 to 40 hours. Further, compound (1k) can be reduced to lead to compound (1i), and this reduction reaction is carried out under conditions for 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. 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 and R ⁴ are the same as above] Among the compounds represented by the general formula (1), the compound having an acidic group can form a salt with a pharmacologically acceptable basic compound. . 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 isolated from the reaction system by conventional separation methods such as distillation, recrystallization, column chromatography, preparative thin layer chromatography, and solvent extraction. Can be separated and purified. The compound of formula (2) used as a starting material in the method of the above reaction formula is a new compound, and can be produced, for example, by the method shown in the following reaction formula. [In the formula, R ¹ , R ² , R ⁶ , R ⁷ , R ⁸ and the bond between the 3rd and 4th positions of the carbostyril bone nucleus are the same as above.
R ⁹ is lower alkyl or

[Formula], X represents a halogen atom] In the above reaction formula, compound (9) and compound (10)
The reaction with compound (4) can be carried out under exactly the same reaction conditions as the esterification reaction of compound (1a) or (1b) with compound (4) in the above reaction formula. Compound (11) obtained by the esterification can be reduced to lead to the corresponding compound (12). Note that this compound (12) can be obtained by directly reducing compound (9).
These reduction reactions are usually performed using a hydrogenation reducing agent. Examples of the hydrogenation reducing agent include sodium borohydride, lithium aluminum hydride, diborane, etc., and the amount used is usually at least equimolar to compound (9) or (11), preferably The range is from equimolar to 3 times the molar amount. When lithium aluminum hydride is used as a hydrogenation reducing agent, it is convenient to use it in an equal weight to compound (9) or (11). This reduction reaction is
Usually, using a suitable solvent such as water, lower alcohols such as methanol, ethanol, and isopropanol, and ethers such as tetrahydrofuran, ethyl ether, and diglyme,
C., preferably at -30 to room temperature, for about 10 minutes to about 5 hours. Note that when lithium aluminum hydride or diborane is used as the reducing agent, it is preferable to use an anhydrous solvent such as ethyl ether, tetrahydrofuran, or diglyme. For the reaction of halogenating compound (12) to lead to compound (13), any reaction conditions for normal halogenation reactions of hydroxyl groups are adopted. For example, compound (12) is halogenated in an appropriate inert solvent or without a solvent. This is done by reacting with a halogenating agent. Examples of the halogenating agent used include hydrohalic acids such as hydrochloric acid and hydrobromic acid, N,N-diethyl-1,2,2-
Examples include trichlorvinylamide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, and thionyl chloride. Examples of the inert solvent include ethers such as dioxane and tetrahydrofuran, and halogenated hydrocarbons such as chloroform, methylene chloride, and carbon tetrachloride. The ratio of compound (12) and halogenating agent used is such that the latter is at least equimolar to the former, usually in excess. The reaction is usually carried out at room temperature to about 150°C, preferably at room temperature.
It is carried out at 80°C for about 1 to 6 hours. The desired compound (2) can be obtained by reacting compound (13) with compound (14). This reaction is carried out in a suitable inert solvent in the presence of a basic compound at room temperature to 200°C.
C., preferably 60 to 120.degree. C., for about 1 to 24 hours. Examples of inert solvents that can be used include ethers such as dioxane, tetrahydrofuran, ethylene glycol, and dimethyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, lower alcohols such as methanol, ethanol, and isopropanol, dimethylformamide, and dimethyl. Examples include polar solvents such as sulfoxide. Examples of basic compounds include calcium carbonate, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium amide, sodium hydride, potassium hydride, sodium methylate,
A wide variety of bases can be used, including inorganic bases such as sodium ethylate, 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 (13) and compound (14) 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 mole, more preferably equimolar to 1.2 times 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. [In the formula, R ² , R ⁶ , R ⁷ , R ⁸ , R ¹ ', The reaction with compound (8) is carried out under the same reaction conditions as the reaction between compound (1g) and compound (8) in the reaction formula -. [In the formula, R ¹ , R ² , R ⁶ , R ⁷ and R ⁸ 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 - and is carried out under the same reaction conditions as the reduction reaction of compound (1k). The compound of formula (5) 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 -X. [In the formula, R ² is the same as above] In the above reaction formula, the reaction that leads to compound (16) by ring-closing compound (15) is carried out using N,N-substituted formamide and an acid catalyst (generally called a Willsmeier reagent). ) in a suitable solvent or in the absence of a solvent. The N,N-substituted formamide used here includes N,N-dimethylformamide, N,N-diethylformamide, N-
Ethyl-N-methylformamide, N-methyl-
Examples include N-phenylformamide. Examples of acid catalysts include phosphorus oxychloride, thionyl chloride, and phosgene. Examples of the solvent used include halogenated hydrocarbons such as chloroform, 1,2-dichloroethane, and 1,2-dichloroethylene, and aromatic hydrocarbons such as chlorobenzene and 1,2-dichlorobenzene. The amount of N,N-substituted formamide and acid catalyst to be used is usually in large excess with respect to the compound of general formula (15), preferably 2 to 5 times the molar amount of the former and 5 to 10 times the molar amount of the latter. It is better to do so. The reaction temperature is usually 0 to 150°C, preferably around 50 to 100°C. The reaction is completed in about 3 to 24 hours. In addition, in the reaction to obtain compound (5a) from compound (16), compound (16) can be mixed with hydrohalic acids such as hydrochloric acid and hydrobromic acid, inorganic acids such as sulfuric acid and phosphoric acid, potassium hydroxide, sodium hydroxide, etc. In the presence of alkali metal hydroxides such as, inorganic alkali compounds such as sodium carbonate, potassium carbonate, potassium bicarbonate, or organic acids such as acetic acid,
0.5-24 at 50-150℃, preferably 70-120℃
This is achieved by heating for about an hour. The carboxylic acid compound (9) and its ester compound (11), which are the starting materials in the above reaction formula, are partially known and include new compounds, for example, the following reaction formula -XI~
It can be manufactured by the method shown below. [In the formula, R ² is the same as above, and R ¹⁰ represents a hydrogen atom or lower alkyl] In the above reaction formula, the reduction reaction of the nitro group of compound (17) can be carried out under any of the usual conditions for reduction of the nitro group. For example, (i) reduction using a catalytic reduction catalyst in a suitable solvent, or (ii) metal or metal salt and acid, or metal or metal salt and alkali metal hydroxide, sulfide, in a suitable inert solvent. It is carried out by reducing the compound or a mixture thereof with an ammonium salt or the like as a reducing agent. In the case of catalytic reduction (i), the solvents used include, for example, water, alcohols such as acetic acid, methanol, ethanol, isopropanol, butanol, and ethylene glycol, and ethers such as diethyl ether, dimethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme. Examples include hydrocarbons such as hexane and cyclohexane, esters such as methyl acetate and ethyl acetate, and aprotic polar solvents such as N,N-dimethylformamide. Examples of the catalytic reduction catalyst include palladium, palladium black, palladium carbon, platinum, platinum oxide, copper chromite,
Examples include Raney Nickel. The amount of these catalysts used is preferably 0.02 to 1.00 times (by weight) the amount of compound (17). The reaction is usually -20 to 150
℃, preferably from 0℃ to around room temperature, and under a hydrogen pressure of 1 to 10 atmospheres for about 30 minutes to 10 hours. When using method (ii), iron as a reducing agent,
combinations of zinc, tin or stannous chloride with mineral acids such as hydrochloric acid or sulfuric acid; alkali metal hydroxides such as iron, ferrous sulfate, zinc or tin and sodium hydroxide;
Sulfides such as ammonium sulfide, ammonia water,
Combinations with ammonium salts such as ammonium chloride are used. Examples of the inert solvent used include water, acetic acid, methanol, ethanol, dioxane, and the like. The reaction temperature and time are appropriately selected depending on the type of catalyst used,
For example, in the case of a combination of ferrous sulfate and aqueous ammonia, it is advantageously carried out at around 50 to 150°C for about 30 minutes to 10 hours. The amount of the reducing agent used is usually at least equimolar, preferably equimolar to 5 times the molar amount of compound (17). The reaction between compound (18) and compound (19) can be carried out in a suitable solvent in the presence of a basic compound. Examples of basic compounds include inorganic bases such as sodium hydroxide, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride, sodium methylate, and sodium ethylate, triethylamine, pyridine, α-picoline, and N,N-dimethyl. A wide range of amines can be used, including amines such as aniline, N-methylmorpholine, piperidine, and pyrrolidine. Solvents include ethers such as dioxane, tetrahydrofuran, glyme, and diclime, aromatic hydrocarbons such as toluene and xylene, lower alcohols such as methanol, ethanol, and isopropanol,
Examples include polar solvents such as dimethylformamide and dimethyl sulfoxide. The reaction takes place at room temperature to 150℃.
It is preferably carried out at 60 to 120°C for about 1 to 24 hours. The ratio of compound (18) and compound (19) 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. [In the formula, R ² is the same as above. R represents lower alkyl] The above reaction is carried out with the compound (20) RCOX or (RCO) ₂ O [in the formula, R is the same as above. X represents a halogen atom] to form a compound (20a),
Subsequent hydrolysis yields compound (9b)
can be obtained. The reaction between general formula (20) and RCOX or (RCO) ₂ O is carried out in the presence or absence 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. The reaction proceeds either without a solvent or in a solvent. Examples of solvents include ketones such as acetone and methyl ethyl ketone, ethers such as ether and dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, water,
Examples include pyridine. The amount of RCOX or (RCO ₂ )O compound used is determined by the general formula (20)
It is used in at least an equimolar amount with respect to the compound, but it is generally preferable to use an equimolar amount to a large excess amount. The reaction proceeds at a temperature of 0 to 200°C, but is generally preferably carried out at a temperature of 0 to 150°C. The reaction time is
It takes about 0.5 to 10 hours to complete. The hydrolysis reaction of general formula (20a) is carried out in an aqueous solution in the presence of a hydrolysis catalyst, such as an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide, or an inorganic alkali compound such as sodium carbonate, potassium carbonate, or sodium bicarbonate. , usually 50~150℃,
This is preferably carried out by heating at 70 to 100°C for about 0.5 to 10 hours. [In the formula, R ¹ , R ² , R ⁹ , X and the bond between the 3rd and 4th positions of the carbostyril bone nucleus are the same as above. ^R11
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 without a solvent. All inert solvents that do not adversely affect the reaction can be used as solvents, such as chloroform, methylene chloride, dichloromethane,
Halogenated hydrocarbons such as carbon tetrachloride, diethyl ether, tetrahydrofuran, dioxane,
Ethers such as dimethoxyethane, alcohols such as methanol, ethanol, isopropanol, butanol, esters such as methyl acetate and ethyl acetate, aprotons such as N,N-dimethylformamide, dimethyl sulfoxide, hexamethyl phosphoric triamide, etc. Examples include polar solvents, acetonitrile, and the like. Examples of aromatic amines include pyridine and quinoline. The amount of the aromatic amine to be used is at least equimolar, preferably in large excess, relative to compound (21). The reaction temperature is 50 to 200°C, preferably 70 to 150°C, and the reaction is completed in about 3 to 10 hours. 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, the esterification of compound (23) with compound (10) is carried out by reacting in the presence of a basic compound in a solvent or in the absence of a solvent. Examples of solvents 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-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, and other aprotic solvents. Examples of the basic catalysts used include 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-
Examples include organic bases such as diazabicyclo[2.2.2]octane (DABCO) and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate. The usage ratio of the basic compound used here is given by the general formula (23)
It is preferable to use at least an equimolar amount, preferably 1 to 1.5 times the molar amount of the compound. The compound of general formula (10) 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. [ ^wherein , The reaction is generally called a 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 can be used, including aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, boron trifluoride, concentrated sulfuric acid, and the like. The amount of Lewis acid to be used can be determined as appropriate, but is usually about 2 to 6 times the mole of compound (24), preferably 3 to 4 times the mole, and the amount of compound (25) or (26) to be used is The amount is usually at least equimolar, preferably equimolar to 3 times the molar amount of compound (24). The reaction temperature is usually about -50 to 120°C, preferably 0 to 70°C, and the reaction time varies depending on the raw materials used, the catalyst, the reaction temperature, etc.
Usually, it takes 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 solvent 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 to compound (27),
It is usually an excess amount, 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 (9e) by reduction and ring closure. This reaction is expressed by the reaction formula-XI
However, when using the catalytic reduction method (i), the reaction temperature is preferably 0 to 50°C, and there is no water in the reaction system. The reaction proceeds advantageously in the presence of a basic compound such as sodium oxide or potassium hydroxide. Furthermore, when method (ii) is used, 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 the reducing agent to be used is preferably at least equimolar, usually equimolar to 3 times the molar amount of the raw material compound. By the above method, the ring is closed simultaneously with reduction of the nitro group to obtain compound (9e). However, when using the catalytic reduction catalyst (i), carbonyl groups may also be reduced and converted to methylene, but such conversion can be avoided by appropriately selecting reaction conditions. [In the formula, R ² and X are the same as above. R ¹² is a hydrogen atom or lower alkyl, R ¹³ is lower alkyl] In the above reaction formula, the reaction between compound (29) and compound (30) is usually carried out in the presence or absence of a dehydrohalogenating agent. It is carried out in a suitable solvent. As the dehydrohalogenating agent, a basic compound is usually used, 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 other organic bases;
Examples include alkali metal alcoholates such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, silver carbonate, sodium methylate, and sodium ethylate. Note that the reaction compound compound (30) can also be used as a dehydrohalogenating agent by using an excess amount. Solvents include halogenated carbons such as methylene chloride, chloroform, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane, and esters such as methyl acetate and ethyl acetate. , aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide, pyridine, acetone, acetonitrile, and alcohols such as methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve. pyridine, acetone, acetonitrile, etc.
Or a mixed solvent of two or more thereof can be mentioned. 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, preferably equimolar to 5 times the molar amount of the former. The reaction temperature is usually -30
The reaction is completed at about 180 DEG C., preferably about 0 DEG to 150 DEG C., generally in 5 minutes to 30 hours. 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, p-toluenesulfonic acid and the like. Among these, inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid are preferred. The amount of acid 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 600°C,
It usually takes about 5 minutes to 6 hours to complete. In addition, the compound (9) can be prepared by the N-alkylation method shown in the above reaction formula - and the reaction formula -
Other compounds of formula (9) can also be derived in the same way by methods that utilize the dehydrogenation reaction or reduction reaction shown in and. Furthermore, compounds (12) and (13), which are intermediates in the above reaction formula, and compound (21), which is a starting material in the above reaction formula, can also be produced by the method shown in the following reaction formula. be done. [In the formula, R ¹ , The reaction is carried out under the same conditions as the reaction between compound (24) and compound (25) or (26) in the above reaction formula. However, the reaction temperature is usually 20 to 120℃, preferably about 40 to 70℃,
The reaction time varies depending on the raw materials, catalyst, and reaction temperature, but is usually about 30 minutes to 24 hours. [In the formula, R ¹ , R ² and the bond between the 3rd and 4th positions of the carbostyril bone nucleus are the same as above. R ¹⁴ is a hydrogen atom, lower alkyl or group

[Formula]] In the above reaction formula, the reaction of reducing compound (34) to lead to compound (5) is carried out under the same reduction conditions as in the case of reducing compound (9) to compound (12) in the above reaction formula. It is carried out under the same conditions as the catalytic reduction method in which compound (1') is led to compound (1'') in the following and the above reaction formula. Method for further reducing compound (5) to lead to compound (12) There are various methods for this, but for example, a reduction method using a hydrogenation reducing agent is preferably used. Examples of the hydrogenation reducing agent used include sodium aluminum hydride, lithium tri-tert-butoxyaluminum hydride, Diisobutylaluminum hydride, (1,1-dimethyl-1-diisopropylmethyl)boron hydride [(i-C ₃ H ₇ )
(CH ₃ ) ₂ CBH ₂ ], and the amount used is:
Usually, the weight is equal to that of compound (5). This reduction reaction is usually carried out in a suitable solvent such as diethyl ether, tetrahydrofuran, diglyme, etc.
It is carried out at about -60 to 50°C, preferably -30°C to room temperature, and is completed in 10 minutes to 5 hours. [In the formula, R ² and The reaction leading from compound (13a) from 36) is also the reaction from compound (16) to compound (5a) in the above reaction formula.
It is carried out under the same conditions as the reaction that yields. [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, N-halogenosuccinimides such as N-bromosuccinimide and N-chlorosuccinimide,
Examples include 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 amount, preferably from equimolar to 1.2 times mole, relative to 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 (13b) is carried out in a suitable solvent in the presence of a condensing agent. Examples of the condensing agent used include Lewis acids such as phosphorus pentoxide, hydrogen fluoride, sulfuric acid, polyphosphoric acid, aluminum chloride, and zinc chloride. Examples of the solvent include halogenated hydrocarbons such as chloroform, dichloromethane and 1,2-dichloroethane, ethers such as diethyl ether and dioxane, and aromatic hydrocarbons such as nitrobenzene and chlorobenzene. The ratio of the compound (38) and the condensing agent to be used is not particularly limited, but 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 50-250°C, preferably 70-200°C.
It is carried out at ℃ for about 20 minutes to 6 hours. [In the formula, R ¹ , R ² , X 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 (13) and compound (39) in the above reaction formula preferably uses a basic compound as a dehydrohalogenating agent, and is carried out at room temperature to 200°C in an appropriate solvent. Preferably at room temperature to 150℃ for several hours.
It will be held for 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 ethylate, 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 (13) 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. Hydrolysis of the resulting compound (40) leads to compound (12). This hydrolysis reaction is carried out using, for example, hydrohalic acids such as hydrochloric acid and hydrobromic acid, mineral 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 alkali metal carbonate or bicarbonate such as sodium hydrogen carbonate, usually at 50-150°C, preferably at 70-100°C.
The reaction is carried out by heating at a temperature of 3 to 24 hours. In addition, these compounds (12) and (13) can be prepared by the N-alkylation method shown in the above reaction formula and by a method utilizing the dehydrogenation reaction or reduction reaction shown in the reaction formula and, etc.
Similarly, other compounds of formula (12) or (13) can be derived. 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, agar 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, dissolution-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 alone.
Administered intradermally, 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 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 50 g of methyl 3-phenylpropionate, 51.6 g of chloroacetyl chloride 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 was poured into ice-concentrated hydrochloric acid and extracted with chloroform. The chloroform layer is washed with water, dried, and the chloroform is distilled off. Add isopropyl ether to the residue to crystallize it, collect the crystals,
Recrystallized from ethanol to give colorless needle crystals of 3-(4
-methyl chloroacetylphenyl)propionate
Obtain 53.4g. Melting point: 90.0-92.0°C Reference Example 3 36.26 g of methyl 3-(4-chloroacetylphenyl)propionate is dissolved in 300 ml of concentrated sulfuric acid, and 20.9 g of fuming nitric acid (d=1.52) is 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 a temperature below 30°C while stirring. Next, add 200 g 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-chloroacetylcarbostyril. The mother liquor was concentrated to dryness, the residue was purified by silica gel column chromatography, and recrystallized from methanol to give pale yellow needle-like crystals of 8-chloroacetylcarbostyryl.
get g. Melting point: 177.5-179.0°C Reference Example 5 Mix 30 g of 8-chloroacetylcarbostyryl and 300 ml of pyridine, and heat and stir at 80-90°C for 2.5 hours. The reaction solution was cooled with ice water, and the precipitated crystals were collected, washed with ether, and then recrystallized from methanol to obtain 40.85 g of 8-(α-pyridinium acetyl)carbostyryl chloride in the form of colorless needles.
Melting point: 261.5 to 264.0°C (decomposed) Reference Example 6 To a solution of 29.5 g of methyl m-aminobenzoate in 300 ml of diethyl ether, 11.53 g of β-ethoxyacrylic acid chloride is added dropwise at 17 to 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 obtain 13.63 g of m-methoxycarbonyl-N-(β-ethoxyacryloyl)aniline as colorless prismatic crystals. get. Melting point 108-110℃ Reference example 7 (a) 6-(α-chloroacetyl)carbostyryl
Suspend 60g in 0.5Kg of pyridine and heat at 80-90℃ for 2 hours.
Stir for 1 hour, then stir for 1 hour under ice cooling. The precipitated crystals are collected and recrystallized from methanol to obtain 70 g of 6-(α-pyridinium acetyl) carbostyryl chloride 1/2 hydrate in the form of colorless needles.
Melting point: 300°C or higher (b) Dissolve 69.7g of 6-(α-pyridinium acetyl)carbostyryl chloride and 65g of sodium hydroxide in 0.6ml of water and stir 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 (PMSO) 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 = 8.0Hz, 1.5Hz, 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, under ice-cooling and stirring, dicyclohexylcarbodiimide 12.4
g of 50 ml dioxane solution is added dropwise. The mixture was heated and stirred at 90°C for 4 hours. After the reaction was completed, 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 obtain colorless flaky crystals of succinimide 3,4-dihydrocarbohydrate. 10.8 g of styryl-6-carboxylate are obtained. Melting point: 234.5-236°C Reference example 10 Add 8 g of m-carboxy-N-(β-ethoxyacryloyl)aniline to 80 ml of concentrated sulfuric acid, stir at room temperature for 2 hours, then at 50°C for 1 hour. Place the reaction solution in ice. Pour and adjust the pH to 3 with 10N sodium hydroxide aqueous solution.
Adjust to ~4. Remove the precipitated crystals and wash with water.
Recrystallization from DMF gave 4.26 g of 5-carboxycarbostil as pale yellow powder crystals. Melting point over 320℃. 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, and recrystallize the colorless needle-like crystals from methanol.
3.62 g of 7-carboxy-3,4-dihydrocarbostyryl are obtained. 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 (n, 2H), 10.15 (s, 1H) Reference example 12 10 g of m-methoxycarbonyl-N-(β-ethoxyacroyl)aniline was gradually added to 100 ml 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 are recrystallized from methanol-chloroform to obtain 6.97 g of 5-methoxycarbonyl carbostyril. 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 adjust the pH to 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 is 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-chloroform to give 230 mg of 5-methoxycarbonyl carbostyril 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 obtain 130 mg of 8-methoxycarbonylcarbostyryl in the form of colorless needles.
get. Melting point: 140-142℃ Reference example 16 34g of 3-formylcarbostyryl was added to methanol.
Suspend in 800ml. Add 7.4 g of sodium borohydride little by little while stirring on ice. Under ice cooling, 3
Stir for hours. The precipitated crystals were collected and recrystallized from methanol to obtain 33.2 g of colorless prismatic 3-hydroxymethylcarbostyryl. Melting point 238~
239.5°C Reference Example 17 16 g of lithium aluminum hydride is suspended in 200 ml of dry tetrahydrofuran. 3-Methoxycarbonylcarbostyryl 16PH 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 is added to the residue, and the precipitated crystals are collected and recrystallized from methanol to obtain 3.7 g of colorless prismatic 3-hydroxymethylcarbostyryl. melting point
238-239.5°C Reference Examples 18-22 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 are collected and recrystallized from methanol to obtain 6 g of colorless needle-like 3-bromomethylcarbostyryl. Melting point: 218.5-219°C (decomposition) Reference example 24 3-hydroxymethyl carbostyril (3 g) is suspended in chloroform (100 ml). While stirring at room temperature, a solution of 2 g of thionyl chloride in 20 ml of chloroform is added dropwise. 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℃ Reference example 25 2-chloro-3-chloromethylquinoline 2.8g
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 colorless needle-like 3-chloromethylcarbostyryl. Melting point: 204-205°C Reference Examples 26-30 The compounds shown in the following table are obtained in the same manner as in Reference Examples 23-25 using appropriate starting materials.

[Table] Reference Example 31 Make sodium ethylate from 1.5 g of sodium and 150 ml of dry ethanol. To this was added 12 g of diethyl acetamidomalonate, and the mixture was stirred at room temperature for 1 hour. 4-Glomomethylcarbostyryl 12g
and reflux 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-quinolone-4-yl)propionate 13g
get. Melting point: 224-226°C (decomposition) Reference Examples 32-41 In the same manner as in Reference Example 31, using appropriate starting materials, the compounds shown in the following table are obtained.

【table】

[Table] Reference Example 42 Dissolve 5.6 g of ethyl 2-acetamido-2-carboethoxy-3-(2-quinolon-3-yl) propionate in 150 ml of tetrahydrofuran.
Add 50% oily sodium hydrogen 0.8PH to this while stirring at room temperature. Drop 4.5g of methyl iodide,
Stir at room temperature for 3 hours. Concentrate under reduced pressure and pour the residue into water to collect precipitated crystals. Ethyl 2-acetamide-2 recrystallized from ethanol water in the form of colorless scales.
3.5 g of -carboethoxy-3-(1-methyl-2-quinolon-3-yl)propionate are obtained.
Melting point: 190.5-192°C Compounds of Reference Examples 36-39 are obtained in the same manner as in Reference Example 42 above. Reference Example 43 1.9 g of lithium aluminum hydride is suspended in 100 ml of dry tetrahydrofuran. Add 1.9 3-carboxycarbostyryl to this while stirring at room temperature.
Add g. 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. Colorless prismatic 3-hydroxymethylcarbostyryl recrystallized from methanol
Obtain 0.5g. Melting point 238-239.5℃. Compounds of Reference Examples 18 to 22 are obtained in the same manner as in Reference Example 43 above using appropriate starting materials. Reference Example 44 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 are obtained in the same manner as in Reference Example 44 using appropriate starting materials. Reference Example 45 Dissolve 2.2 g of 3-chloromethyl-6-methoxycarbostyryl 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 46 2 g of 3-acetoxymethylcarbostyryl was dissolved in 30 ml of methanol containing 0.6 g of sodium hydroxide, and refluxed for 3 hours. After distilling off the methanol, water is added to the residue and the precipitated crystals are collected. Recrystallization from acetone yields 1.3 g of pale yellow needle-shaped 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 46 above using appropriate starting materials. Reference Example 47 (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-neck flask, and heat to 90°C above the water solution. Add 25 ml of concentrated ammonia water all at once while stirring. Furthermore, every 2 minutes, 30% of ammonia water is added.
Add ml in 3 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. Recrystallized from methanol-chloroform to give colorless needle-shaped 3-carboxycarbostyryl 1.2
get g. Melting point: 300°C or higher Reference Example 48 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.
Add 58g of the above N-acetylisatin to this and
Reflux for a period of time. Cool slightly, add activated carbon, and reflux for 30 minutes. Remove activated carbon when hot. Cool the mother liquor and adjust the pH to 3-4 with 6N hydrochloric acid. Take the precipitated crystals, dry them with water, and then dry them.
Obtain 45 g of 4-carboxycarbostyril. melting point
300°C or above Reference Example 49 (a) Add 322 ml of phosphorus oxychloride dropwise to 96 ml of N,N-dimethylformamide while stirring on ice. 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 yellow needle-like 2-chloro-3-formylcarbostyryl. 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 Reference Example 50 64.4ml of phosphorus oxychloride is added dropwise to 11.6ml of N,N-dimethylformamide at 0°C with stirring.
At the same temperature, add 18.4 g of N-phenyl-3-chloropropionamide. Stir at 75-80°C for 10 hours. Pour the reaction solution into ice water and collect the precipitated crystals.
Recrystallized from ethanol to form colorless prismatic 2-
6.7 g of chloro-3-chloromethylquinoline are obtained.
Melting point 116-118℃ Reference example 51 Ethyl 2-acetamido-2-carboxy-3
-(2-quinolone-4-yl)propionate 5
150 ml of 20% hydrochloric acid was added to the solution and refluxed for 9 hours.
Concentrate under reduced pressure, and recrystallize the residue from ethanol-water to obtain colorless prismatic 2-amino-3-(2-quinolon-4-yl)propionate hydrochloride hydrate.
Obtain 3.2g. Melting point: 220-225°C (decomposition) Example 1 2-Amino-3-(2-quinolon-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. Add 1.2 g of p-chlorobenzoyl chloride to this while stirring on ice.
Add 10 ml of acetone solution dropwise. 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. Ethanol - recrystallized from water to give white powder 2-(4-chlorobenzoylamino)
-3-(2-quinolon-3-yl)propionic acid
Obtain 1.5g. Melting point: 270-271.5°C (decomposition) Example 2 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 raw materials disappear 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-chlorobenzoylamino)-3-.
0.7 g of (6-methoxy-2-quinolon-3-yl)propionic acid is obtained. Melting point 234.5-236°C (decomposition) Example 3 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. After dissolving the crystals in an aqueous N-sodium hydroxide solution, acidify with 10% hydrochloric acid and collect the precipitated crystals. After drying the crystals,
Wash with chloroform. Recrystallization from methanol-water gives 1.5 g of 2-(4-chlorobenzoylamino)-3-(6-hydroxy-2-quinolon-3-yl)propionic acid in the form of a pale yellow powder. Melting point 223-227°C (decomposition) Example 4 2-Amino-3-(2-quinolon-3-yl)
Suspend 1.2 g of propionic acid, 1.3 g of DCC and 1.0 g of p-chlorobenzoic acid in 10 ml of dioxane,
Stir at 70°C for 5 hours. After the reaction is completed, the solvent is distilled off, and ether is added to remove the precipitated crystals. After concentrating the liquid, the residue is dissolved in chloroform and washed with water and saturated brine. After drying with sodium sulfate, the solvent is distilled off. Recrystallized from ethanol-water to give white powder 2-(4-chlorobenzoylamino)-3-(2-quinolon-3-yl)
Obtain 350 mg of propionic acid. Melting point 270-271.5℃
(Decomposition) Example 5 2-amino-3-(2-quinolon-3-yl)
1.2g propionic acid and 0.8ml triethylamine
was suspended in 10 ml of tetrahydrofuran, and while stirring at room temperature, a solution of 1.0 g of diethyl chlorophosphate in 10 ml of tetrahydrofuran was added dropwise, followed by stirring at room temperature for 3 hours. A solution of 1.0 g of p-chlorobenzoic acid in 10 ml of tetrahydrofuran was added dropwise to this mixture, and the mixture was further stirred at room temperature for 10 hours. After the reaction was completed, the precipitated crystals were removed, the liquid was concentrated, and saturated sodium chloride was poured into the residue.
Extract with chloroform. The organic layer is washed with water and saturated brine, dried over sodium sulfate, and then the solvent is distilled off. Ethanol - Recrystallized from water to give white powder 2-(4-chlorobenzoylamino)-
3-(2-quinolon-3-yl)propionic acid
Obtain 0.9g. Melting point: 270-271.5°C (decomposition) Example 6 A solution of 3.87 g of isobutyl chloroformate in 2 ml of dimethylformamide is added dropwise to a solution of 4.84 g of p-chlorobenzoic acid and 4 ml of triethylamine in 50 ml of dimethylformamide. After stirring at room temperature for 30 minutes, a solution of 6.03 g of 2-amino-3-(2-quinolon-3-yl)propionic acid in 3 ml of dimethylformamide was added dropwise, followed by stirring at room temperature for 30 minutes and then at 50-60°C.
Stir for 1 hour. The reaction mixture is poured into a large amount of saturated brine, extracted with chloroform, washed with water, and then dried. The crude crystals obtained by distilling off the solvent are recrystallized from ethanol-water to obtain 2-(4-
3.7 g of chlorobenzoylamino)-3-(2-quinolon-3-yl)propionic acid are obtained. melting point 270
~271.5℃ (decomposition) Example 7 Add 1.66 g of ethyl p-chlorobenzoate, 0.5 g of sodium ethylate, and 2.09 g of 2-amino-3-(2-quinolon-3-yl)propionic acid to 100 ml of ethanol in an autoclave. ,
React at 110 atm and 140-150°C for 6 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform.
After dissolving in 200 ml of water and washing sequentially with 1% potassium carbonate aqueous solution, dilute hydrochloric acid and water, drying over sodium sulfate, distilling off the solvent and recrystallizing from ethanol water, 2-(4-chlorobenzoyl) was obtained as a white powder. 300 mg of amino)-3-(2-quinolon-3-yl)propionic acid are obtained. Melting point: 270-271.5°C (decomposition) Reference Examples 52-66 In the same manner as in Reference Example 51, using appropriate starting materials, the compounds shown in the following table are obtained.

[Table] Examples 8 to 47 The compounds shown in the following table are obtained in the same manner as in Examples 2 and 5 to 8 using appropriate starting materials.

【table】

【table】

【table】

【table】

【table】

【table】

【table】

[Table] Examples 48 to 87 The compounds shown in the following table are obtained in the same manner as in Example 2 using appropriate starting materials.

【table】

【table】

【table】

【table】

【table】

【table】

【table】

[Table] Examples 88 to 127 The compounds shown in the following table are obtained in the same manner as in Example 3 using appropriate starting materials.

【table】

【table】

【table】

【table】

【table】

【table】

【table】

[Table] Example 128 5-formyl-8-methoxycarbostyryl 20
18 g of N-acetylglycine, 7 g of anhydrous sodium acetate, and 100 ml of acetic anhydride were heated at 110°C to form a homogeneous solution, and the mixture was further refluxed for 1.5 hours.
After cooling, add cold water and remove the precipitated crystals. Wash with cold water to obtain crude azlactone. Crude azlactone was added to 100 ml of water and 300 ml of acetone, and refluxed for 5 hours. Acetone is distilled off, cold water is added to the residue, and crude crystals are collected. The obtained crude crystals are dissolved in an aqueous sodium bicarbonate solution, and insoluble materials are removed. After the liquid is treated with activated carbon, it is made acidic with hydrochloric acid and the precipitated crystals are removed. Recrystallized from ethanol to form colorless needle-like 2-
10 g of acetylamino-3-(8-methoxy-2-quinolon-5-yl)acrylic acid are obtained. melting point
264-265℃ (decomposition) Reference example 67 Add 60 ml of 47% hydrobromic acid to 6 g of 2-amino-3-(6-methoxy-2-quinolon-3-yl) propionic acid hydrochloride and reflux for 7 hours. Let's do it. After cooling, the precipitated crystals were collected and recrystallized from water to give a yellow powder of 2-amino-3-(6-hydroxy-2-
Quinolon-3-yl)propionic acid hydrobromide
Obtain 1.8g. Reference example with melting point of 300℃ or higher 68 2-amino-3-(2-quinolon-4-yl)
Dissolve 5 g of propionic hydrochloride in 150 ml of water.
Add 1 g of 10% palladium on carbon and absorb hydrogen at 70°C and normal pressure. After removing the catalyst, the liquid is concentrated under reduced pressure. The residue was crystallized by adding acetone and recrystallized from ethanol-ether to obtain 2-amino-3-(3,4-dihydroquinoline-) as a white powder.
2-on-4-yl)propionate hydrochloride 3.6g
get. Melting point 237-238℃ (decomposition) Reference example 69 2-amino-3-(2-quinolon-4-yl)
Suspend 4 g of propionic hydrochloride in 50 ml of methanol. To this was added dropwise 5.3 g of thionyl chloride while stirring on ice, and the mixture was stirred overnight at room temperature. After distilling off methanol and thionyl chloride under reduced pressure, the residue was diluted with methanol.
Recrystallized from acetone to give methyl 2 as a white powder.
2.4 g of -amino-3-(2-quinolon-4-yl)propionate hydrochloride is obtained. Melting point 208-211℃
(Decomposition) Example 129 2-(4-methoxybenzoyl)amino-3-
Dissolve 1.8 g of (2-quinolon-3-yl)propionic acid in 100 ml of ethanol. This was mixed with ice-cooling and stirred.
After introducing hydrochloric acid gas and saturating it, refluxing was carried out for 5 hours. After the reaction was completed, the reaction was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate-ethanol to obtain ethyl 2-(4-methoxybenzoyl)amino-3 as a white powder.
-(2-quinolone-3-yl)propionate
Obtain 1.5g. Melting point: 206-208.5°C Compounds of Examples 34 and 78 are obtained in the same manner as in Example 196 above using appropriate starting materials. Reference example 70 2-acetylamino-3-(2-quinolone-4
Add 30 ml of 20% hydrochloric acid to 2.7 g of propionic acid and reflux for 3 hours. After concentrating to dryness under reduced pressure, recrystallization from ethanol-water yields colorless prismatic 2.
1.9 g of -amino-3-(2-quinolon-4-yl)propionate hydrochloride monohydrate is obtained. Melting point 220~
225°C (decomposition) Compounds of Reference Examples 52-66 are obtained in the same manner as in Reference Example 70 above using appropriate starting materials. Reference Example 71 Dissolve 6 g of 2-amino-3-(8-methoxy-2-quinolon-5-yl)acrylic acid hydrochloride in 100 ml of 1N aqueous sodium hydroxide solution. 2 g of Raney nickel was added to this, and hydrogenation was carried out at room temperature and 3 atm. After removing the catalyst, neutralize the mother liquor with acetic acid, leave it in the refrigerator, and collect the precipitated crystals. 2-Amino- is recrystallized from water as a colorless powder.
3-(8-methoxy-2-quinolon-5-yl)
2 g of propionic hydrochloride hydrate are obtained. melting point 257
~260°C (decomposition) In the same manner as in Reference Example 71 above, using appropriate starting materials, the compounds of Reference Examples 51 to 62 and 64 and Examples 1 and 8 to 47 are obtained. Example 130 2-(4-chlorobenzoyl)amino-3-
Dissolve 2.8 g of (2-quinolon-3-yl)propionic acid in 50 ml of N,N-dimethylformamide.
To this was added 1 g of 50% oily sodium hydride while stirring at room temperature, and the mixture was stirred for 30 minutes. While cooling with ice and stirring, 1.5 g of methyl iodide was added dropwise, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water. Acidify with concentrated hydrochloric acid and collect the precipitated crystals. Recrystallized from ethanol to form white powder 2-
(4-chlorobenzoyl)amino-3-(1-methyl-2-quinolon-3-yl)propionic acid
Obtain 0.5g. Melting point: 246-247.5°C (decomposition) In the same manner as in Example 130 above, using appropriate starting materials, the compounds of Examples 32-36 above are obtained. Pharmacological test Test compound: 1 2-(4-chlorobenzoylamino)-3-
(2-quinolon-3-yl)propionic acid 2 2-benzoylamino-3-(2-quinolon-3-yl)propionic acid 3 2-cyclohexylcarbonylamino-3-
(2-quinolon-3-yl)propionic acid 4 2-(4-chlorobenzoylamino)-3-
(1-Methyl-2-quinolon-3-yl)propionic acid 5 2-(4-chlorobenzoylamino)-3-
(2-quinolon-4-yl)propionic acid 6 2-benzoylamino-3-(2-quinolon-4-yl)propionic acid 7 Methyl 2-(4-chlorobenzoylamino)
-3-(2-quinolon-4-yl)propionate 8 2-(4-chlorobenzoylamine) -3-
(1-allyl-2-quinolon-4-yl)propionic acid 9 2-(4-chlorobenzoylamino)-3-
(1-propargyl-2-quinolone-4-yl)
Propionic acid 10 2-(4-chlorobenzoylamino)-3-
(1-benzyl-2-quinolon-4-yl)propionic acid 11 2-acetylamino-3-(2-quinolone-
3-yl)propionic acid. 12 2-(4-chlorobenzoylamino)-3-
(8-hydroxy-2-quinolon-5-yl)
Propionic acid. 13 2-(4-chlorobenzoylamino)-3-
(8-Methoxy-2-quinolon-5-yl)propionic acid. 14 2-acetylamino-3-(8-methoxy-
2-quinolon-5-yl)acrylic acid. 15 2-(3-chlorobenzoylamino)-3-
(2-quinolon-4-yl)propionic acid. 16 2-(2-chlorobenzoylamino)-3-
(2-quinolon-4-yl)propionic acid. 17 2-(4-chlorobenzoylamino)-3-
(3,4-dihydro-2-quinolon-4-yl)
Propionic acid. 18 2-(4-methoxybenzoylami)-3-
(2-quinolon-3-yl)propionic acid. 19 2-(3,4,5-trimethoxybenzoylamino)-3-(2-quinolon-4-yl)propionic acid. 20 2-(2,4-dimethylbenzoylamino)
-3-(2-quinolon-4-yl)propionic acid. 21 2-(4-nitrobenzoylamino)-2-
(2-quinolon-4-yl)propionic acid. 22 2-(4-aminobenzoylamino)3-
(2-quinolon-4-yl)propionic acid. 23 2-(3-aminopropionylamino)-3
-(2-quinolon-3-yl)propionic acid. 24 2-(3-benzyloxycarbonylaminopropionylamino)-3-(2-quinolone-
4-yl)propionic acid. 25 2-(4-methylbenzoylamino)-3-
(2-quinolon-4-yl)propionic acid. Experimental method: Rats are laparotomized under ether anesthesia, the stomach is removed, and 15 ml of 30% acetic acid is injected submucosally into the anterior wall of the gastric body and the bifurcation of the antrum using a microsyringe. and press it for a few seconds to prevent the liquid from leaking. After the abdominal incision was closed, the animals were fasted overnight, and from the next morning, 10 mg/Kg was orally administered twice in the morning and evening for 9 days. Animals were killed by cervical dislocation 4 hours after the final administration.
The stomach was removed, fixed with 10 ml of 1% formalin solution, then incised along the greater curvature, and the ulcer area (mm ² ) was measured under a stereomicroscope (10x magnification), which was determined as the ulcer index.
The treatment rate was calculated using the following formula. Treatment rate = Ulcer index of control group - Ulcer index of test drug group / Ulcer index of control group x 100% Distilled water or 0.5% CMC was orally administered to the control group. The results are shown in the table below.

【table】

【table】

[Table] Formulation example 1 2-(4-chlorobenzoylamino)-3-
(2-quinolon-3-yl)propionic acid 150g Avicel (trade name, manufactured by Asahi Kasei Corporation) 40g Cornstarch 30g Magnesium stearate 2g Hydroxypropylmethylcellulose 10g Polyethylene glycol-6000 3g Castor oil 40g Methanol 40g The compound of the present invention, Avicel, After mixing and polishing corn starch and magnesium stearate, sugar coating
Compress the tablets with an R10mm kine. The obtained tablets are coated with a film coating agent consisting of hydroxypropyl methylcellulose, polyethylene glycol-6000, castor oil, and methanol to produce film-coated tablets. Formulation example 2 2-(4-chlorobenzoylamino)-3-
(2-quinolon-4-yl)propionic acid 150g Citric acid 1.0g Lactose 33.5g Dicalcium phosphate 70.0g Pluronic F-68 30.0g Sodium lauryl sulfate 15.0 Polyvinylpyrrolidone 15.0g Polyethylene glycol (Carbovacs)
1500) 4.5g polyethylene glycol (Carbowax
6000) 45.0g Corn starch 30.0g Dry sodium lauryl sulfate 3.0g Dry magnesium stearate 3.0g Ethanol Appropriate amount The compound of the present invention, citric acid, lactose, dicalcium phosphate, Pluronic F-68, and sodium lauryl sulfate are mixed. The above mixture was sieved through a No. 60 screen, and polyvinylpyrrolidone, Carbowax 1500 and 6000 were added.
wet granulation in an alcoholic solution containing Add alcohol if necessary to make the powder into a pasty mass. Add cornstarch and continue mixing until uniform particles are formed. Pass it through a No. 10 screen, put it in a tray and put it in an oven at 100℃ for 12 hours.
Dry for ~14 hours. Sieve through a dry particle No. 16 screen, add and mix dry sodium lauryl sulfate and dry magnesium stearate, and compress into the desired shape with a tablet machine. The core is treated with varnish and sprinkled with talc to prevent moisture absorption. Cover the core with an undercoat layer. . Apply varnish enough times for internal use. Further subbing layers and smooth coatings are applied to make the tablet perfectly round and smooth. Pigmented coatings are applied until the desired shade is obtained. After drying,
Polish the coated tablet to give it a uniform luster. Formulation example 3 2-(4-chlorobenzoylamino)-3-
(1-methyl-2-quinolon-3-yl)propionic acid 5g polyethylene glycol (molecular weight: 4000)
0.3g Sodium chloride 0.9g Polyoxyethylene sorbitan monooleate
0.4g Sodium metabisulfite 0.1g Methyl-paraben 0.18g Propyl-paraben 0.02g Distilled water for injection 10.0ml Add the above parabens, sodium metabisulfite and sodium chloride to about half the amount of distilled water above at 80°C while stirring. dissolve. The resulting solution was cooled to 40°C, and the compound of the present invention, followed by polyethylene glycol and polyoxyethylene sorbitan monooleate, were dissolved in the solution. Next, distilled water for injection is added to the solution to adjust the final volume, and the solution is sterilized by sterilization using a suitable filter paper to prepare an injection.

Claims (1)

[Claims] 1. General formula [In the formula, 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 hydrogen atom or lower alkyl;
R ⁴ is lower alkyl, cycloalkyl, which may have an amino group or phenyl lower alkoxycarbonylamino group as a substituent, or a group selected from halogen atom, lower alkyl, lower alkoxy, nitro, and amino as a substituent on the phenyl ring. In the substituent formula [Formula], the group -A means -CH ₂ -CH or -CH=C, and the substitution position of this substituent is Either the 3rd, 4th, 5th, 6th, 7th or 8th position of the styril nucleus. Also, the bond between the 3rd and 4th positions of the carbostyril bone nucleus shows a single bond or a double bond]
Carbostyryl derivatives and salts thereof. 2 R ¹ is a hydrogen atom, R ² is a hydrogen atom, R ³ is a hydrogen atom, and R ⁴ is a substituent on the phenyl ring with 1 to 3 groups selected from halogen atoms, lower alkyl, lower alkoxy, nitro, and amino. The compound according to claim 1, which is a phenyl group which may have a phenyl group. 3 The group -A in the formula [formula] of the substituent represents -CH ₂ -CH, and the substitution position of this substituent is either the 3rd or 4th position of the carbostyril bone nucleus, and 3
3. The compound according to claim 2, wherein the bond between the position and the 4th position is a double bond. 4 2-(4-chlorobenzoylamino)-3-
The compound according to claim 3, which is (2-quinolon-4-yl)propionic acid.