KR950018002A - Novel quinolone derivatives and preparation methods thereof - Google Patents

Abstract

The present invention relates to a quinolone derivative represented by the following general formula (I) and a pharmaceutically acceptable acid addition salt thereof.

Wherein R ₁ is a chain or cyclic lower alkyl group having 1-3 carbon atoms, a substituted or halogen group having 1 to 3 carbon atoms substituted with a halogen, a phenyl group or 1-2 halogen substituted Phenyl group; R ₂ is a hydrogen atom, a lower alkyl group or an amino group; R ₃ is a heteroatom compound containing at least one nitrogen atom in the ring with a halogen atom or a substituted or unsubstituted heteroatom, having the general formula (A)

Wherein R ₆ , R ₇ , R ₈ and R ₉ are each hydrogen atoms or lower alkyl groups, two of which may form a bond with each other, m and n are from 0 to 1 and Ca-Cb forms a bond Or a single bond or a double bond), or the following general formula (B):

(Wherein R ₁₀ is a hydrogen atom or a lower alkyl group or aminoprotecting group such as methyl, ethyl or butoxycarbonyl, R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ are the same or different and each is hydrogen or an amino group, A lower alkyl group, such as methyl or ethyl, optionally substituted with a hydroxy group or a halogen; X represents a nitrogen atom or CR ₄ , wherein R ₄ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group; R ₄ and R ₁ together form a ring -CH ₂ CH ₂ CH ₂ -,-CH ₂ CH ₂ CH (CH ₃ )-, OCH ₂ CH ₂ , -OCH ₂ CH (CH ₃ )-,-SCH ₂ CH ₂ -or -SCH ₂ CH (CH ₃ )-; Y is a residue of a 5-7 membered carboxyl or heterocyclic ring having an acidic proton [p <α <14].

The present invention also relates to an antimicrobial agent containing as an active ingredient of the compound of formula (I).

Description

Novel quinolone derivatives and preparation methods thereof

Since this is an open matter, no full text was included.

Claims (10)

The novel quinolone derivatives represented by the following general formula (I) and pharmaceutically acceptable acid addition salts thereof. Wherein R ₁ is a chain or cyclic lower alkyl group having 1-3 carbon atoms, a substituted or halogen group having 1 to 3 carbon atoms substituted with a halogen, a phenyl group or 1-2 halogen substituted Phenyl group; R ₂ is a hydrogen atom, a lower alkyl group or an amino group; R ₃ is a heteroatom compound containing at least one nitrogen atom in the ring with a halogen atom or a substituted or unsubstituted heteroatom, having the general formula (A) Wherein R ₆ , R ₇ , R ₈ and R ₉ are each hydrogen atoms or lower alkyl groups, two of which may form a bond with each other, m and n are from 0 to 1 and Ca-Cb forms a bond Or a single bond or a double bond), or the following general formula (B): (Wherein R ₁₀ is a hydrogen atom or a lower alkyl group or aminoprotecting group such as methyl, ethyl or butoxycarbonyl, R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ are the same or different and each is hydrogen or an amino group, A lower alkyl group, such as methyl or ethyl, optionally substituted with a hydroxy group or a halogen; X represents a nitrogen atom or CR ₄ , wherein R ₄ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group; R ₄ and R ₁ together form a ring -CH ₂ CH ₂ CH ₂ -,-CH ₂ CH ₂ CH (CH ₃ )-, OCH ₂ CH ₂ , -OCH ₂ CH (CH ₃ )-,-SCH ₂ CH ₂ -or -SCH ₂ CH (CH ₃ )-; Y is a residue of a 5-7 membered carboxyl or heterocyclic ring having an acidic proton [p <α <14]. The compound of claim 1, wherein R ₁ is a cyclopropyl group and R ₃ is a substituted or unsubstituted 3-aminopyrrolidine group or a 2,8-diazabicyclo [4,3,0] non-5,6-ene group. compound. The compound of claim 1, wherein Y is selected from the group consisting of the following general formulas (Ya) (Yb) and (Yc). Wherein A ₁ completes a saturated or unsaturated 5-7 membered ring, consisting of 0,1 or 2 oxygen atoms, the remainder being carbon substituted with 1 or 2 C _1-4 alkyl groups, A ₂ completes a 5 to 7 membered ring, optionally containing one nitrogen atom, the remainder consisting of carbon (which may optionally be a carbonyl group), n is 0.1 or 2, and A ₃ is C _{2- 4} polymethylene group, m and n are each 0.1 or 2, and both cannot be 0 at the same time. The compound according to claim 1, wherein the compound of general formula (I) is one of the following compounds or acid addition salts thereof: 1-cyclopropyl-6-fluoro-8-methoxy-7- ( 3-methylaminopyrrolidin-1-yl) -3- (2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl) carbonyl-4-oxo-1,4- Dihydroquinoline hydrochloride; 1-cyclopropyl-6-fluoro-8-methoxy-7- (3-aminopyrrolidin-1-yl) -3- (6-methyl-2, 4-dioxo-oxan-3-yl) Carbonyl-4-oxo-1,4-dihydroquinoline hydrochloride; 1-cyclopropyl-6-fluoro-8-methoxy-7- (3-aminopyrrolidin-1-yl) -3- (6,6-dimethyl-2,4-dioxo-oxan-3- I) carbonyl-4-oxo-1, -4-dihydroquinoline hydrochloride; 1-cyclopropyl-6-fluoro-8-methoxy-7- (3-aminopyrrolidin-1-yl) -3- (2,4-dioxo-oxan-3-yl) carbonyl-4 Oxo-1, -4-dihydroquinoline hydrochloride; 1-cyclopropyl-6-fluoro-8-methoxy-7- (3-aminopyrrolidin-1-yl) -3- (2,5-dioxocyclopentyl) carbonyl-4-oxo-1 , -4-dihydroquinoline hydrochloride; 1-cyclopropyl-6-fluoro-8-methoxy-7- (3-aminopyrrolidin-1-yl) -3- (1,1,3, -tetraoxo-`-1,3-diti An-2-yl) carbonyl-4-oxo-1,4-dihydroquinoline hydrochloride; 1-cyclopropyl-6-fluoro-8-methoxy-7-3 (3-aminopyrrolidine-1- Yl) -3- (1,1,3-trioxothiolan-2-yl) carbonyl-4-oxo-1,4-dihydroquinoline hydrochloride; 1-cyclopropyl-6-fluoro-8-methoxy-7- (2,8-diazabicyclo [4,3,0] non-5-en-8-yl) -3- (2,2- Dimethyl-4,6-dioxo-1,3-dioxan 5-yl) carbonyl-4-oxo-1, 4-dihydroquinoline hydrochloride; 1cyclopropyl-6-fluoro-8-methoxy-7- (2,8-diazabicyclo [4,3,0] non-5-en-8-yl) -3- (6-methyl-2 , 4-dioxo-oxo-3-yl) carbonyl-4-oxo-1,4-dihydroquinoline hydrochloride; 1-cyclopropyl-6-fluoro-8-methoxy-7- (2,8- Diazabicyclo [4,3,0] non-5-en-8-yl) -3- (6,6-dimethyl-2,4-dioxo-oxan-3-yl) carbonyl-4-oxo- 1,4-dihydroquinoline hydrochloride; 1-cyclopropyl-6-fluoro-8-methoxy-7- (2,8-diazabicyclo [4,3,0] non-5-en-8-yl) -3- (2,5- Dioxocyclopentyl) carbonyl-4-oxo-1,4-dihydroquinoline hydrochloride; 1-cyclopropyl-6-fluoro-8-methoxy-7- (2,8-diazabicyclo [4,3 , 0] non-5-en-8-yl) -3- (2,6-dioxocyclohexyl) carbonyl-4-oxo-1,4-dihydroquinoline hydrochloride; 1-cyclopropyl-6-fluoro-8-methoxy-7- (2,8-diazabicyclo [4,3,0] non-5-en-8-yl) -3- (1,1, 3,3-tetraoxo-1,3-dithia-2-yl) carbonyl-4-oxo-1,4dihydroquinoline hydrochloride; or 1-cyclopropyl-6-fluoro-8-methoxy-7 -(2,8-diazabicyclo [4,3,0] non-5-en-8-yl) -3- (1,1,3-trioxothiolan-2-yl) carbonyl-4-oxo -1,4-dihydroquinoline hydrochloride. An antimicrobial agent containing the compound of claim 1 as an active ingredient. (a) activating the compound of formula (II) using a carboxyl active reagent to prepare a compound of formula (III); (b) reacting a compound of formula (III) with a compound represented by M ^{n +} Y to prepare a compound of formula (IV); And (c) deprotecting the compound of general formula (IV) to produce a compound of general formula (I). Act, Act ₁ and M ^{n +} in the above schemes represent carboxylic acid active reagents, activated carboxyl groups, alkyl groups or alkyl earth metal ions, etc., and R ₁ , R ₂ , R ₃ , X, Y and Z are As defined in claim 1, R ₁₅ is R ₃ in an amine group protected state. The method of claim 6, wherein the deprotection reaction is carried out at a reaction temperature of 0 ° C. to 80 ° C. under 1-10% HCl-methanol solution and CF ₃ CO ₂ H or 1-10% HCl-ethylacetate solution. . The method of claim 6, wherein the salt of the compound of formula (I) is dissolved in water to adjust the pH to about 7, and the resulting solid is filtered and dried to dissolve it in a lower alcohol, haloalkane or a mixed solvent thereof. A method of preparing an acid addition salt of a compound of formula (I), further comprising the step of adding a scientifically acceptable organic or inorganic acid. The method of claim 8, wherein the lower alcohol is ethanol or methanol and the haloalkanes are chloroform, dichloromethane or 1,2-dichloroethane. The organic acid of claim 8, wherein the organic acid is selected from the group consisting of lactic acid, ascorbic acid, maleic acid, malonic acid, glutamic acid, citric acid, fumaric acid, paratoluene sulfonic acid, acetic acid, trifluoro acetic acid, propionic acid, tartaric acid, succinic acid, methanesulfonic acid, and the like. The selected acid and the inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid or nitric acid ※ Note: The disclosure is based on the initial application.