KR960022519A - Novel pyridone-carboxylic acid derivatives and preparation methods thereof - Google Patents

Abstract

Novel pyridonecarboxylic acid derivatives having the formula: and pharmaceutically acceptable salts thereof.

Wherein R ₁ is a C ₁ -C ₄ alkyl group, a lower haloalkyl group, a cyclopropyl group, or the like, R ₂ is hydrogen, lower alkyl, X is hydrogen, halogen, A is nitrogen or CY (Y is hydrogen, halogen , Methyl, etc.), R ₃ is hydrogen, lower alkyl and the like, R ₄ is hydrogen, lower alkylthio and the like, R ₅ is hydrogen and an alkylthio group of C _1-3 .

The compound of the present invention exhibits a wide range of excellent antimicrobial effects against gram positive and negative bacteria.

Description

Novel pyridone-carboxylic acid derivatives and preparation methods thereof

As this is a public information case, the full text was not included.

Claims (9)

A pyridone carboxylic acid derivative represented by the following structural formula (I) and a pharmaceutically acceptable salt thereof. Wherein R ₁ represents a lower alkyl group having 1 to 4 carbon atoms, a lower haloalkyl group having 1 to 4 carbon atoms, a cyclopropyl group substituted or unsubstituted with a halogen atom, a 2 to 4 alkenyl group having 1 or 2 fluorine atoms R ₂ is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, X is a hydrogen atom, a halogen, an amino group, a hydroxy group or a methyl group, A is a nitrogen atom or CY and Y is a hydrogen atom, a halogen group , -O-CH ₂ -CH (CH ₃ )-, -O-CH ₂ -N (CH) together with the nitrogen atom in the pyridone ring substituted or unsubstituted with a halogen atom or R ¹ is substituted ₃ )-, -S-CH ₂ -CH (CH ₃ )-, -S-CH ₂ -CH ₂ or -CH ₂ -CH ₂ -CH (CH ₃ )-form a ring, R ₃ is hydrogen Atom, lower alkyl group having 1 to 4 carbon atoms, benzyl group, p-toluenesulfonyl group, acyl group, 1-butoxycarbonyl Or an alkoxycarbonyl group and, R ₄ is coming hydrogen atom, a C 1 -C 3 alkyl group, an aryl tea is coming or a hetero arylthio group, R ₅ is a hydrogen atom, coming having 1 to 3 alkyl group or an alkylthio group, an aryl Thio group, heteroarylthio group, hydroxy group, alkoxy group having 1 to 3 carbon atoms, hydroxy, methyl group, amino group, amino group substituted with one or two alkyl groups of 1 to 3 carbon atoms, aminomethyl group, halogen, acyloxy group, acyl It is an amino group, an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, or an arylsulfinyl group, n shows the integer of 0, 1, or 2, but R < ₄ > R < ₅ > H is not. The compound of formula (I) according to claim 1, wherein A represents a nitrogen atom or C-Y, and Y represents a hydrogen atom, a halogen, a methyl or methoxy group substituted or unsubstituted with a halogen atom, and a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein A is together with the nitrogen atom in the pyridone ring substituted with R _1. , CO-CH ₂ -N (CH ₃ ), , CS-CH ₂ -CH _2- , or (* Represents an S-form, R-form, or SR mixture as an extra stereoisomer) A compound of formula (I) and a pharmaceutically acceptable salt thereof, which form a ring of the structure. The compound of formula (I) according to claim 1, wherein the compound of formula (I) is 1-cyclopropyl-6,8-difluoro-7- (3-methylthio-2,6-diazabicyclo [2.3.0] hept-6- Yl) -1,4-dihydro-4-oxo-quinolone-3-carboxylic acid, 1-cyclopropyl-6-fluoro-7- (3-methylthio-2,6-diazabicyclo [2.3. 0] hept-6-yl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 1- (2,4-difluorophenyl) -6-fluoro -7- (3-methylthio-2,6-diazabicyclo [2.3.0] hept-6-yl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxyl Acid, 1-cyclopropyn-6-fluoro-8-chloro-7- (3-methylthio-2,6-diazabicyclo [2.3.0] hept-6-yl) -1,4-dihydro 4-oxoquinolin-3-carboxylic acid, 1-cyclopropyl-6,8-difluoro-7- (1-methylthio-4,7-diazabicyclo [3.3.0] oct-7-yl ) -1,4-Dihydro-4-oxoquinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-8-chloro-7- (1-methylthio-4,7-diazabicycle [3.3.0] Oct-7-yl) -1,4-dihydro-4-oxoquinolin-3-carboxylic acid, 1-cyclopropyl-5-amino-6,8-difluoro-7- ( 1-Methylthio-4,7-diazabicyclo [3.3.0] oct-7-yl) -1,4-dihydro-4-oxoquinolin-3-carboxylic acid, 1-cyclopropyl-6-fluoro Rho-7- (1-methylthio-4,7-diazabicyclo [3.3.0] oct-7-yl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-car Acid, 1-cyclopropyl-6-fluoro-8-methoxy-7- (1-methylthio-4,7-diazabicyclo [3.3.0] oct-7-yl) -1,4-di Hydro-4-oxoquinoline-3-carboxylic acid, 1-cyclopropyl-6,8-difluoro-7- (1-methylthio-4-methyl-4,7-diazabicyclo [3.3.0] Butt-7-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-cyflopropyl-6-fluoro-8-chloro-7- (1-methylthio-4- Methyl-4,7-diazabicyclo [3.3.0] oct-7-yl) -1,4-dihydro-4-oxoquinolin-3-carboxylic acid, 1-cyclopropyl-6-fluoro- 8-methoxy-7- (1-methylthio-4-methyl-4,7-diazabicyclo [3.3.0] oct-7-yl) -1,4-dihydro-4-oxoquinoline-3- Carboxylic acid, 9-fluoro-3- (S) -methyl-10- (1-methylthio-4,7-diazabicyclo [3.3.0] oct-7-yl) -7-oxo-2, 3-dihydro-7H-pyrido [1,2,3-dec] [1,4] -benzoxazine-6-carboxylic acid, 9-fluoro-3- (S) -methyl-10- ( 1-methylthio-4-methyl-4,7-diazabicyclo [3.3.0] oct-7-yl) -7-oxo-2,3-dihydro-7H-pyrido [1,2,3- D] [1,4] -benzoxazine-6-carboxylic acid, 9-fluoro-3- (RS) -methyl-10- (1-methylthio-4,7-diazabicyclo [3.3.0] Oct-7-yl) -7-oxo-2,3-dihydro-7H-pyrido [1,2,3-dec] [1,4] -benzoxazine-6-carboxylic acid, 9- Fluoro-3- (RS) -methyl-10- (1-methylthio-4-methyl-4,7-diazabicyclo [3.3.0] oct-7-yl) -7-oxo-2,3- Dihydro-7H-pyrido [1,2,3-dec] [1,4) -benzoxazine-6-carboxylic acid, 1-cyclopropyl-6-fluoro-7- (1-meth Methylthio-4-methyl-4,7-diazabicyclo [3.3.0] oct-7-yl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 1-cyclopropyl-5-amino-6,8-difluoro-7- (1-methylthio-4-methyl-4,7-diazabicyclo [3.3.0] oct-7-yl) -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, 1- (2,4-difluorophenyl) -6-fluoro-7- (1-methylthio-4,7-diazabicyclo [ 3.3.0] butt-7-yl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 1- (2,4-difluorophenyl) -6- Fluoro-7- (1-methylthio-4-methyl-4,7-diazabicyclo [3.3.0] oct-7-yl) -1,4-dihydro-4-oxo-1,8-naphthy Lidin-3-carboxylic acid, 1-cyclopropyl-6,8-difluoro-7- (4-methylthio-2,7-diazabicyclo [3.3.0] oct-7-yl) -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-cyclopropyl-6-pululo-8-chloro-7- (4-methylthio-2,7-diazabicyclo [3.3.0 Oct-7-yl) -1,4-dihydro-4- Soquinoline-3-carboxylic acid, 1-cyclopropyl-5-amino-6,8-difluoro-7- (4-methylthio-2,7-diazabicyclo [3.3.0] oct-7- Yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-8-methoxy-7- (4-methylthio-2,7-diazabi Cyclo [3.3.0] oct-7-yl) -1,4-dihydro-4-oxoquinolin-3-carboxylic acid, 1-cyclopropyl-6-fluoro-5-methyl-7- (4- Methylthio-2,7-diazabicyclo [3.3.0] oct-7-yl) -1,4-dihydro-4-oxoquinolin-3-carboxylic acid, 1-cyclopropyl-6-fluoro- 7- (4-Methylthio-2,7-diazabicyclo [3.3.0] oct-7-yl) -1,4-dihydro-4-oxo-1.8-naphthyrinin-3-carboxylic acid, 1 -(2,4-difluorophenyl-6-fluoro-7- (4-methylthio-2,7-diazabicyclo [3.3.0] oct-7-yl) -1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid, 9-fluor-3- (S) -methyl-10- (4-methylthio-2,7-diazabicyclo [3.3.0] oct -7- ) -7-oxo-2,3-dihydro-7H-pyrido [1,2,3-dec] [1,4] -benzoxazine-6-carboxylic acid, 9-fluoro-3- ( RS) -methyl-10- (4-methylthio-2,7-diazabicyclo [3.3.0] oct-7-yl) -7-oxo-2,3-dihydro-7H-pyrido [1, 2,3-dec] [1,4] -benzoxazine-6-carboxylic acid, 1-ethyl-6,8-difluoro-7- (4-methylthio-2,7-diazabicyclo [ 3.3.0] oct-7-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-8-chloro-7- (4-hydroxy -2,7-diazabicyclo [3.3.0] oct-7-yl) -1,4-dihydro-4-oxoquinolin-3-carboxylic acid, 1-cyclopropyl-6-fluoro-8- Chloro-7- (4-fluoro-2,7-diazabicyclo [3.3.0] oct-7-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-cyclo Propyl-6-fluoro-8-methoxy-7- (4-fluoro-2,7-diazabicyclo [3.3.0] oct-7-yl) -1,4-dihydro-4-oxoquinoline 3-carboxylic acid, 1-cyclopropyl- 6-fluoro-7- (4-fluoro-2,7-diazabicyclo [3.3.0] oct-7-yl) -1,4-dihydro-4-oxo-1,8-naphthyridine- 3-carboxylic acid, 1- (2,4-diflurophenyl) -6-fluoro-7- (4-fluoro-2,7-diazabicyclo [3.3.0] oct-7-yl) -1,4-Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 9-fluoro-3- (S) -methyl-10- (4-fluoro-2,7- Diazabicyclo [3.3.0] oct-7-yl) -7-oxo-2,3-dihydro-7H-pyrido [1,2,3-dec] [1,4] -benzoxazine-6 -Carboxylic acid, 9-fluoro-3- (RS) -methyl-10- (4-fluoro-2,7-diazabicyclo [3.3.0] oct-7-yl) -7-oxo-2 , 3-dihydro-7H-pyrido [1,2,3-dec] [1,4] -benzoxazine-6-carboxylic acid, 1-cyclopropyl-6-fluoro-8-chloro-7 -(4-amino-2,7-diazabicyclo [3.3.0] oct-7-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-cyclopropyl-6- Fluoro-8-methoxy-7- (4-methylamino-2,7-diazabicyclo [3.3. 0] oct-7-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-cyclopropyl-6,8-difluoro-7- (5-methylthio-2, 8-diazabicyclo [4.3.0] non-8-yl) -1,4-dihydro-4-oxoquinolin-3-carboxylic acid, 1-cyclopropyl-6-fluoro-8-chloro-7 -(5-methylthio-2,8-diazabicyclo [4.3.0] non-8-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-cyclopropyl-6 -Fluoro-8-chloro-7- (5-fluoro-2,8-diazabicyclo [4.3.0] non-8-yl) -1,4-dihydro-4-oxoquinoline-3-car Acids, 1-cyclopropyne-6-fluoro-8-methoxy-7- (5-fluoro-2,8-diazabicyclo [4.3.0] non-8-yl) -1,4- Dihydro-4-oxoquinoline-3-carboxylic acid, 9-fluoro-3- (S) -methyl-10-5-fluoro-2,8-diazabicyclo [4.3.0] non-8- Yl) -7-oxo-1,3-dihydro-7H-pyrido [1,2,3-dec] [1,4] -benzoxazine-6-carboxylic acid, 9-fluoro-3- (RS) -methyl-10- (5-fluoro-2,8-dia Xavicyclo [4.3.0] non-8-yl) -7-oxo-2,3-dihydro-7H-pyrido [1,2,3-dec] [1,4] -benzoxazine-6- A compound of formula (I) and any other pharmaceutically acceptable salt that is any compound selected from carboxylic acids. The salt of claim 1, wherein the pharmaceutically acceptable salt is hydrochloride, sulfate, acetate, glycolate, lactate, succinate, citrate, tartarate, methanesulfonate, p-toluenesulfonate, galacturonate, gluconate Salts of the compound of formula (I) wherein those selected from acid salts, glutarates, ascorbates or aspartic acid salts. A method for producing a compound of formula (I) and a salt thereof by reacting a compound represented by formula (II) with a compound represented by formula (III). Wherein R ₁ , R ₂ , X, A, R ₃ , R ₄ , R ₅ and n are as defined in claim 1, W is a leaving group, HA is hydrochloric acid, bromic acid, trifluoroacetic acid Acid and m is an integer from 2 to o. A method for preparing a salt of the compound of formula (I) by reacting a compound represented by the following formula (Ia) with a metal cation or an organic cation donor. Wherein R ₁ , X, R ₃ , R ₄ , R ₅ A and n are as defined in claim 1. 8. The compound of formula (I) according to claim 7, wherein the metal cation donor is sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, silver nitrate, and the organic cation donor is a tertiary or quaternary C ₁ -C ₄ alkylammonium. How to prepare a salt of. An antimicrobial composition comprising the pyridonecarboxylic acid derivative according to any one of claims 1 to 5 as an active ingredient. ※ Note: The disclosure is based on the initial application.