WO1993003026A1 - Novel quinolone carboxylic acid derivatives - Google Patents

Novel quinolone carboxylic acid derivatives Download PDF

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Publication number
WO1993003026A1
WO1993003026A1 PCT/KR1992/000035 KR9200035W WO9303026A1 WO 1993003026 A1 WO1993003026 A1 WO 1993003026A1 KR 9200035 W KR9200035 W KR 9200035W WO 9303026 A1 WO9303026 A1 WO 9303026A1
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carbon atoms
oxo
dihydro
carboxylic acid
hydrogen
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PCT/KR1992/000035
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French (fr)
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Dae Young Kim
Jae Wook Lee
Kyeu Sam Lee
Ho Jung Son
Tae Choong Kang
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Daewoong Pharmaceutical Co., Ltd.
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Publication of WO1993003026A1 publication Critical patent/WO1993003026A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel quinolone carboxylic acid derivatives of the following structural formula(I) and pharmaceutically acceptable salts thereof.
  • R 1 is hydrogen or alkyl group having one to six carbon atoms
  • R 2 is alkyl group having one to four carbon atoms, haloalkylgroup having one to four caibon atoms, cycloalkyl group having three to six carbon atoms, alkenyl group having two to four carbon atoms, or phenyl group which is optionally mono or disubstituted by fluorine atoms
  • X is hydrogen, halogen, alkyl gorup having one to four carbon atoms, alkenyl group having two to four carbon atoms, cycloalkyl group having three to six carbon atoms, or amino,
  • A is N or C-Y
  • Y is hydrogen, halogen, hydroxy, methoxy, or methyl
  • Q is SR 3 or OR 4 when m is O and n is 0 or 1
  • Q is SR 3 , OR 4 , or NR 5 R 6 when m is 1 and n is 0 or 1.
  • R 3 is hydrogen, alkyl group having one to four caibon atoms, haloalkylgroup having one to three carbon atoms, acyl group, cycloalkyl group having three to six carbon atoms, aryl, or heteroaryl group
  • R 4 is hydrogen or alkyl group having one to three carbon atoms
  • R 5 and R 6 are each independently hydrogen or alkyl group having one to three carbon atoms includes straight chain or branched chain).
  • the antibacterial activity of quinolone depends greatly upon the kinds of substituent groups at the 7 position.
  • Quinolone antibacterial compounds are known with a 7-aminopy ⁇ rolidine or a 7-aminomethylpyrrolidine substituent group(European Patent Application No. 183129, No.207497, No.208210). These compounds show a very excellent antibacterial activites.
  • the present invention relates to a novel quinolone carboxylic acid derivatives having 3,4-disubstituted pyrrolidines containing thio or thiomethyl group at the C-7 position.
  • the purpose of the present invention is to provide a novel quinolone carboxylic acid derivatives and pharmaceutically salts thereof having excellent properties, for example, potent antibacterial activities against Gram-positive enginea • including S. aureus as well as against Gram-negative bacteria and high safety.
  • Another the purpose of the present invention is to provide a process for producing a novel quinolone carboxylic acid derivatives and pharmaceutically acceptable salts thereof. 5
  • the present invention relates to a novel quinolone carboxylic acid derivatives of the described structural formula(I).
  • Also preferred group of compounds of this invention is compounds of the above formula® wherein R 1 is hydrogen, methyl, or ethyl, and R 2 is ethyl, fluoroethyl, cyclopropyl, tert-butyl, 2,4-di_luo_ophenyl, or 4-fluorophenyl radical.
  • X is hydrogen, l Q methyl, or amino
  • A is nitrogen or C-Y
  • Y is hydrogen, fluorine, chlorine, hydroxy, methoxy, or methyl radical.
  • the compounds of the formula(I) of the present invention can be prepared by reacting a quinolone carboxylic acid of the following structural formula(II) with an amine of the following structural formula(HI) in an inert solvent or a basic solvent.
  • R 1, R 2 , R 3 , X, A, Y, m, n, and Q are as defined above, W is halogen(preferabIy, fluorine or chlorine),
  • HA is an inorganic or organic acid capable of forming a salt with amines
  • K is 0, 1, 2, or 3.
  • Convenient solvents for this reaction are non-reactive solvents such as tetrahydrofuran, pyridine, ethanol, propanol, butanol, chloroform, dimethylsulfoxide, dimethylformamide, water, acetonitrile, dioxane, and the like.
  • Solvent mixtures may also be utilized.
  • the reaction is preferably carried out in the presence of an acid acceptor such as an alkali metal, or alkaline earth metal carbonate, alkali metal or alkaline earth metal bicarbonate, or a tertiary amine such as triethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene(DBU), pyridine, and the like.
  • an acid acceptor such as an alkali metal, or alkaline earth metal carbonate, alkali metal or alkaline earth metal bicarbonate, or a tertiary amine such as triethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene(DBU), pyridine, and the like.
  • the preferred solvent is acetonitrile and the preferred base is l,8-diazabicyclo[5.4.0]undec-7-ene(DBU), triethylamine, and mixture thereof.
  • the reaction temperature ranges from 50 TJ to 190 TJ, preferably from 50T ⁇ 120 " at atomospheric pressure.
  • the reaction is usually carried out for about lhour to about 48 hours.
  • the starting compounds having structural formula(II) are known in the articIe(U.S. Pat. No.4398029, No.4616019, No. 4663457, No. 4670444, No.4730000, No.4795751, No. 4840954, No. 4885386, No. 4935420, No. 4980470, No. 5013841, and European Patent Application No. 319906, No. 387802).
  • the amine compound of the above-described structural formula(III) can be prepared through the following sequence from the known starting materials, for example, 3-pyrroline(Aldrich's reagent), N-benzyl-3-hydroxy-4-hydroxymethylpyrro- lidine (J. Org. Chem., V. 30, 740 (1965)), N-benzylpyrrolidine-3,4-dimethanol (Chem. Pharm. Bull., V. 35(6), 2266(1987)) : [ Scheme I ]
  • R 3 is hydrogen, alkyl group having one to four carbon atoms, haloalkyl group having one to three carbon atoms, acyl group, cycloalkyl group having three to six carbon atoms, aryl or heteroaryl group,
  • R 7 is amine protecting group
  • R 8 is alkylsulfonyloxy group, arylsulfonyloxy group, or halide
  • HA is organic acid or inorganic acid
  • Compound (A) may be prepared from the known starting materials by the well- known method of debenzylation(for example, catalytic hydrogenation with 10% Pd-C). Thus compound (A) may be converted to compound (B) by treatment with an appropriate amine protection reagent.
  • amine protection reagent preferably, acetic anhydride, alkoxycarbonyl anhydride, acetyl halide, or alkoxycarbonyl halide may be utilized.
  • the hydroxyl function of the compound (B) may next be converted to an appropriate leaving group of compound (C) by treatment with convinient reagents, for example, methanesulfonyl chloride or p-toluenesulfonyl chloride in the presence of a base (for example, triethylamine, pyridine) or thionyl chloride or phosphorus trihalide, etc.
  • convinient reagents for example, methanesulfonyl chloride or p-toluenesulfonyl chloride in the presence of a base (for example, triethylamine, pyridine) or thionyl chloride or phosphorus trihalide, etc.
  • Compound (C) may also be converted to compound (D) by treatment with thioalkoxide or mercapto compound in the presence of an appropriate base(for example, sodium hydride, potassium tert-butoxide).
  • an appropriate base for example, sodium hydride, potassium tert-butoxide
  • compound (D) may be deprotected to produce compound of the above described structural fromula (E) in the state of an acid salt or a free base by various well known reagents, for example, hydrochloric acid, trifluoroacetic acid, methanesulfonic acid, iodotrimethylsilane, sodium hydroxide, etc.
  • R 3 , R 7 , R 8 , HA, and n are as defined above [Scheme I],
  • R 5 and R 6 are each independently hydrogen or alkylgroup having one to three carbon atoms includes straight chain or branched chain,
  • K is 0, 1, 2, or 3.
  • Compound( F) may be prepared by reacting compound (C) with thioalkoxide or mercapto compound in the presence of an appropriate base(for example, sodium hydride, potassium tert-butoxide). Compound (F) may also be converted to compound (G) by treatment with various methods.
  • an appropriate base for example, sodium hydride, potassium tert-butoxide
  • amine and secondary amine for example, ammonia, methylamine, dimethylamine, ethylamine, cyclopropylamine, benzylamine, etc.
  • reducing of azido compounds which are formed by treatment with sodium azide or deprotectmg of intermediates which are formed by treatment with amide and imide (for example, acetamide, phthalimide) in the presence of strong bases, or reacting compound (G) with alkyl halide.
  • amide and imide for example, acetamide, phthalimide
  • compound (G) may be deprotected to produce compound of the above described structural formula (H) in the state of an acid salt or a free base by various well known methods.
  • R 3 , R 7 , R 8 , HA and n are as defined above [Scheme I],
  • K is O or l
  • R 4 is hydrogen or alkylgroup having one to three carbon atoms.
  • Compound (B) may be converted to compound (I) under the similar reaction l c condition as employed in the reaction of the compound (B) and the compound (C) in the above described reaction [Scheme I] .
  • compound (I) may be converted to compound (J) under the similiar reaction condition as employed in the reaction of the compound (C) and the compound (D) in the above described reaction [Scheme T .
  • Compound (J) may be converted to compound (K) by treatment with alkyl halide, dialkyl sulfate in the presence of a base (for example, sodium hydride, potassium tert-butoxide, etc).
  • a base for example, sodium hydride, potassium tert-butoxide, etc.
  • 3-Pyrroline may be converted to compound (N) under the similiar reaction condition as employed in the reaction of the compound (A) and the compound (B) in the above described reaction [Scheme I ⁇ .
  • Compound (N) may be converted to compound (O) by treatment with epoxidation reagents (for example, m-chloroperoxybenzoic acid, hydrogenperoxide).
  • Compound (O) and (Q) may be converted to compound (P) and (R) under the similiar reaction condition as employed in the reaction of the compound (C) and the compound (D) in the above described reaction [Scheme I]. Also, compound (P) may be converted to compound (Q) under the similiar reaction condition as employed in the reaction of the compound (B) and the compound (C) in the above described reaction [Scheme I].
  • compound (P), (T), and (R) may be deprotected to produce compound of the above described structural formala (U), (V), and (S) in the state of an acid salt or a free base by various well known methods.
  • acids for salt formation are acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, methanesulfonic acid, cinnamic acid, fumaric acid, phosphoric acid, hydrochloric acid, hydroiodic acid, sulfuric acid, and the like.
  • the salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce either a mono or di, etc. salt in the conventional manner.
  • Pharmaceutically acceptable base salts of the above-described structrual formula (I) are formed with metals such as alkali and alkaline earth metals, or amines including ammonia and organic amines.
  • Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like.
  • Examples of suitable amines are diethanolamine, N- methylglucamine, arginine, and the like.
  • the compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms.
  • inert and pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersable granules, capsules, cachets, suppositories, and ointments.
  • a solid carriers can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablets disintegrating agents . ; it can also be an encapsulating material.
  • Suitable solid carriers are magnesium carbonate, magnesium sterate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, and the like.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Such solutions are prepared so as to be acceptable to biological systems(isotonicity, pH, etc.). Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.
  • reaction mixture was poured into 30ml of water and extracted with diethyl ether over several times.
  • reaction mixture was poured into 20ml of water and extracted with ethyl acetate over several times.
  • the resulting solution was treated with 20ml of water and extracted with diethyl ether over several times.
  • the tide compound was prepared according to example 1 by reacting 1- cyclopropyl-6,7-difluoro-8-chloro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid with 3-amino-4-methylthiomethylpyrrolidine tritrifluoroacetate.
  • m.p 206 - 21013 (decompose) ⁇ NMR (ppm, NaOD/D 2 0) : 0.80 - 1.43(m, 4H), 2.14(s, 3H),
  • the tide compound was prepared according to example 1 by reacting l-(2,4- difluorophenyl)-6,7,8-trifluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid with 3- amino-4-methylthiomethylpyrrolidine tritrifluoroacetate.
  • m.p 232 - 23613 (decompose) 0 1 H NMR (ppm, NaOD/D 2 O) : 2.00(s, 3H), 2.08 - 2.72(m, 3H),
  • the tide compound was prepared according to example 1 by reacting l-(2,4- difluorophenyl)-6,7-difiuoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid with 3- amino-4-methylthiomethylpyrrolidine tritrifluoroacetate.
  • m.p 218 - 222TJ (decompose)
  • C 1 HNMR (ppm, NaOD D 2 O) : 2.05(s, 3H), 2.10 - 2.64(m, 3H),
  • the tide compound was prepared according to example 1 by reacting l-(2,4- difluorophenyl)-6-fluoro-7-chloro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid with 3-amino-4-methylthiomethylpyrrolidine tritrifluoroacetate.
  • m.p 16013 (decompose)
  • the tide compound was prepared according to example 1 by reacting l-(2,4- difluoroph enyl)-6-f luoro-7-chloro- 1 ,4-dihydro-4-oxo - 1 , 8-naphthyri dine-3-carb oxylic acid with 3-hydroxy-4-methylthiomethylpyrrolidine trifluoroacetate.
  • m.p 199 - 20013 (decompose)
  • 1 HNMR (ppm, DMSO-d 6 /D 2 O) : 2.09(s, 3H), 2.2 - 3.0(m, 3H),
  • the tide compound was prepared according to example 1 by reacting 1- cyclopropyl-6,7,8-trifluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid with 3-methoxy-4-methylthiomethylpyrrolidine trifluoroacetate.
  • 1 HNMR ppm, DMSO-d 6 D 2 O
  • the tide compound was prepared according to example 1 by reacting 1- cyclopropy-5-amino-6,7,8-trifluoro-l ,4-dihydro-4-oxo-3-quinolineca ⁇ boxylic acid with 3-methoxy-4-methylthiopyrrolidine trifluoroacetate.
  • m.p 154 - 15513 (decompose) ⁇ vIR t ⁇ pm ⁇ MSO-c D-O) : 0.8 - 1.4(m, 4H), 2.1(s, 3H), 3.45(s, 3H),
  • the numerals in the table 1 show minimum inhibitory concentration (MIC in «g /ml).
  • the compound of example 1 was orally administered to determine the LD 50 for a group of male mice.

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Abstract

The present invention relates to novel quinolone carboxylic acid derivatives of structural formula (I) and pharmaceutically acceptable salts thereof. These compounds also have a potent activity against both Gram-positive bacteria and Gram-negative bacteria, wherein R1 is hydrogen or alkyl group having one to six carbon atoms, R2 is alkyl group having one to four carbon atoms, haloalkylgroup having one to four carbon atoms, cycloalkylgroup having three to six carbon atoms, alkenyl group having two to four carbon atoms, or phenyl group which is optionally mono or disubstituted by fluorine atoms, X is hydrogen, halogen, alkyl group having one to four carbon atoms, alkenyl group having two to four carbon atoms, cycloalkyl group having three to six carbon atoms, or amino, A is N or C-Y, Y is hydrogen, halogen, hydroxy, methoxy, or methyl, Z is formula (a), wherein Q, R3, m and n are respectively defined as the above.

Description

A NOVEL QUINOLONE CARBOXYLIC ACID DERIVATIVES
BACKGROUND OF THE INVENTION
The present invention relates to a novel quinolone carboxylic acid derivatives of the following structural formula(I) and pharmaceutically acceptable salts thereof.
These compounds also have a potent activity against both Gram positive bacteria and Gram-negative bacteria.
Figure imgf000003_0001
wherein,
R1 is hydrogen or alkyl group having one to six carbon atoms,
R2 is alkyl group having one to four carbon atoms, haloalkylgroup having one to four caibon atoms, cycloalkyl group having three to six carbon atoms, alkenyl group having two to four carbon atoms, or phenyl group which is optionally mono or disubstituted by fluorine atoms, X is hydrogen, halogen, alkyl gorup having one to four carbon atoms, alkenyl group having two to four carbon atoms, cycloalkyl group having three to six carbon atoms, or amino,
A is N or C-Y,
Y is hydrogen, halogen, hydroxy, methoxy, or methyl,
Z is
(wherein, Q is SR3 or OR4 when m is O and n is 0 or 1, Q is SR3, OR4, or NR5R6 when m is 1 and n is 0 or 1.
R3 is hydrogen, alkyl group having one to four caibon atoms, haloalkylgroup having one to three carbon atoms, acyl group, cycloalkyl group having three to six carbon atoms, aryl, or heteroaryl group, R4 is hydrogen or alkyl group having one to three carbon atoms, R5 and R6 are each independently hydrogen or alkyl group having one to three carbon atoms includes straight chain or branched chain). In general, the antibacterial activity of quinolone depends greatly upon the kinds of substituent groups at the 7 position.
Quinolone antibacterial compounds are known with a 7-aminopyιrolidine or a 7-aminomethylpyrrolidine substituent group(European Patent Application No. 183129, No.207497, No.208210). These compounds show a very excellent antibacterial activites.
Also, quinolone antibacterial compounds are known with a 7-thiomorpholine substituent group having antibacterial properties(J. Med. Chem., V. 29, 394(1986)). But, there is no report on clinical use thereof yet.
SUMMARY OF THE INVENTION
The present invention relates to a novel quinolone carboxylic acid derivatives having 3,4-disubstituted pyrrolidines containing thio or thiomethyl group at the C-7 position.
These compounds show a very excellent activity against Gram-positive bacteria including S. aureus as well as against Gram-negative bacteria and a low toxicity.
Therefore, the purpose of the present invention is to provide a novel quinolone carboxylic acid derivatives and pharmaceutically salts thereof having excellent properties, for example, potent antibacterial activities against Gram-positive bacteriia • including S. aureus as well as against Gram-negative bacteria and high safety. Another the purpose of the present invention is to provide a process for producing a novel quinolone carboxylic acid derivatives and pharmaceutically acceptable salts thereof. 5
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a novel quinolone carboxylic acid derivatives of the described structural formula(I).
The preferred examples of the group represented by Z in the above described i o structural formula(I) are as follows ;
3-amino-4-methylthiomethylpyrrolidinyl,
3-methylamino-4-methylthiomethylpyrrolidinyl,
3-ethylamino-4-methylthiomethylpyrrolidinyl,
3-dimethylamino-4-methylthiomethylpyrrolidinyl, 5 3-hydroxy-4-methylthiomethylpyrrolidinyl,
3-methoxy-4-methylthiomethylpyxrolidinyl,
3-amino-4-ethylthiomethylpyrrolidinyl,
3-methylamino-4-ethylthiomethylpyrrolidinyl,
3-ethylamino-4-ethylthiomethylpyrrolidinyl, 0 3-dimethylamino-4-ethylthiomethylpyrrolidinyl,
3-hydroxy-4-ethylthiomethylpyrrolidinyl,
3-methoxy-4-ethylthiomethylpyrτolidinyl,
3-methylthio-4-methylthiomethylpyrrolidinyl,
3-ethylthio-4-methylthiomethylpyrrolidinyl, 5 3-ethylthio-4-ethylthiomethylpyrrolidinyl,
3-methylthio-4-hydroxymethylpyrrolidinyl,
3-methylthio-4-methoxymethylpyrrolidinyl,
3-ethylthio-4-hydroxymethylpyrrolidinyl,
3-ethylthio-4-methoxymethylpyrrolidinyl, 3-cyclopropyIamino-4-methylthiomethyIpyrrolidinyl, 3-cyclopropyIamino-4-ethylthiomethylpyrrolidinyl, 3-hydroxy-4-methylthiopy_rolidinyl, 5 3-methoxy-4-methylthiomethylpyrrolidinyl.
Also preferred group of compounds of this invention is compounds of the above formula® wherein R1 is hydrogen, methyl, or ethyl, and R2 is ethyl, fluoroethyl, cyclopropyl, tert-butyl, 2,4-di_luo_ophenyl, or 4-fluorophenyl radical.
Other preferred compounds of this invention are those wherein X is hydrogen, l Q methyl, or amino, A is nitrogen or C-Y, and Y is hydrogen, fluorine, chlorine, hydroxy, methoxy, or methyl radical.
Representative examples of the novel compound of the structural formula© according to the present invention can be given as follows, but the present invention is not limited to the examples given as follows : 5 l-cyclopropyl-6,8-difIuoro-7-(3-amino-4-methylthiomethyl)pyrrolidinyl-l,4-dihydro-4- oxo-3-quinoline carboxylic acid, l-cyclopropyI-6-fluoro-7-(3-amino-4-methylthiomethyl)pyrrolidinyl-l,4-dihydro-4- oxo-3-quinoline carboxylic acid, l-cyclopropyl-5-amino-6,8-difluoro-7-(3-amino-4-methylthiomethyl)pyrrolidinyl-l,4- 0 dihydro-4-oxo-3-quinoline carboxylic acid, l-cyclopropyI-6-fluoro-8-chloro-7-(3-amino-4-methylthiomethyl)pyrrolidinyl-l,4- dihydro-4-oxo-3-quinoline carboxylic acid, l-(2,4-difluorophenyl)- 6,8-difluoro-7-(3-amino-4-m ethylthiomethyl)pyrrolidinyl- 1 ,4- dihydro-4-oxo-3-quinoline carboxylic acid, l-(2,4-difluorophenyl)-6-fluoro-7-(3-amino-4-methylthϊomethyl)pyrrolidinyl-l,4- dihydro-4-oxo-3-quinoline carboxylic acid, l-cyclopropyl-6,8-difluoro-7-(3-methylamino-4-methylthiomethyl)pyrrolidinyl-l,4- dihydro-4-oxo-3-quinoline carboxylic acid, l-cyclopropyl-6,8-di_luoro-7-(3-methylthio-4-methylthiomethyl)pyrτolidinyl-l,4- dihydro-4-oxo-3-quinoline carboxylic acid, l-cyclopropyl-6,8-di_luoro-7-(3-hydroxy-4-methylthiomethyl)pyrrolidinyl-l,4-dihydro-
4-oxo-3-quinohne carboxylic acid, l-cyclopropyl-6-fluoro-7-(3-amino-4-methylthiomethyl)pyrrolidinyl-l,4-dihydro-4- oxo- 1 ,8-naphthyridine-3-carboxylic acid, l-(2,4-difluorophenyl)-6-fluoro-7-(3-amino-4-methylthiomethyl)pyrrolidiny 1-1,4- dihydro-4-oxo- 1 , 8-naphthyridine-3-carboxylic acid, l-cyclopropyl-5-amino-6,8-difluoro-7-(3-hydroxy-4-methylthiomethyl)pyrrolidinyl- l,4-dihydro-4-oxo-3-quinoline carboxylic acid, l-cyclopropyl-6-fluoro-7-(3-hydroxy-4-methylthiomethyl)pyrrolidinyl-l ,4-dihydro-4- oxo- 1 ,8-naphthyridine-3-carboxylic acid, l-(2,4-difluorophenyl)-6-fluoro-7-(3-hydroxy-4-methylthiomethyl)pyrrolidinyl-l,4- dihydro-4-oxo- 1 ,8-naphthyridine-3-carboxylic acid, l-cyclopropyl-6-fluo_O-8-methoxy-7-(3-hydroxy-4-methylthiomethyl)py_τolidinyl-l,4- dihydro-4-oxo-3-quinoline carboxylic acid, l-cyclopropyl-6,8-difluoro-7-(3-methoxy-4-methylthiomethyl)pyrrolidinyl-l,4- dihydro-4-oxo-3-quinoline carboxylic acid, l-cyclopropyl-6,8-difluoro-7-(3-hydroxy-4-methylthio)pyrrolidinyl-l,4-dihydro-4-oxo- 3-quinoline carboxylic acid, l-cyclopropyl-5-amino-6,8-difluoro-7-(3-hydroxy-4-methylthio)pyrrolidinyl-l,4- dihydro-4-oxo-3-quinoline carboxylic acid, l-cyclopropyl-6,8-di_luoro-7-(3-methoxy-4-methylthio)pyrrolidinyl-l,4-dihydro-4-oxo-
3-quinoline carboxylic acid, l-cyclopropyl-5-amino-6,8-difluoro-7-(3-methoxy-4-methylthio)pyrrolidinyl- l,4- dihydro-4-oxo-3-quinoline carboxylic acid.
The compounds of the formula(I) of the present invention can be prepared by reacting a quinolone carboxylic acid of the following structural formula(II) with an amine of the following structural formula(HI) in an inert solvent or a basic solvent. ( π )
Figure imgf000008_0002
wherein,
R1, R2, R3, X, A, Y, m, n, and Q are are as defined above, W is halogen(preferabIy, fluorine or chlorine),
HA is an inorganic or organic acid capable of forming a salt with amines, K is 0, 1, 2, or 3.
Convenient solvents for this reaction are non-reactive solvents such as tetrahydrofuran, pyridine, ethanol, propanol, butanol, chloroform, dimethylsulfoxide, dimethylformamide, water, acetonitrile, dioxane, and the like.
Solvent mixtures may also be utilized. The reaction is preferably carried out in the presence of an acid acceptor such as an alkali metal, or alkaline earth metal carbonate, alkali metal or alkaline earth metal bicarbonate, or a tertiary amine such as triethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene(DBU), pyridine, and the like. According to the present invention, the preferred solvent is acetonitrile and the preferred base is l,8-diazabicyclo[5.4.0]undec-7-ene(DBU), triethylamine, and mixture thereof.
The reaction temperature ranges from 50 TJ to 190 TJ, preferably from 50T ~ 120 " at atomospheric pressure. The reaction is usually carried out for about lhour to about 48 hours.
The starting compounds having structural formula(II) are known in the articIe(U.S. Pat. No.4398029, No.4616019, No. 4663457, No. 4670444, No.4730000, No.4795751, No. 4840954, No. 4885386, No. 4935420, No. 4980470, No. 5013841, and European Patent Application No. 319906, No. 387802). The amine compound of the above-described structural formula(III) can be prepared through the following sequence from the known starting materials, for example, 3-pyrroline(Aldrich's reagent), N-benzyl-3-hydroxy-4-hydroxymethylpyrro- lidine (J. Org. Chem., V. 30, 740 (1965)), N-benzylpyrrolidine-3,4-dimethanol (Chem. Pharm. Bull., V. 35(6), 2266(1987)) : [ Scheme I ]
Figure imgf000009_0001
( B ) ( C )
Figure imgf000009_0002
( D ) ( E )
wherein,
R3 is hydrogen, alkyl group having one to four carbon atoms, haloalkyl group having one to three carbon atoms, acyl group, cycloalkyl group having three to six carbon atoms, aryl or heteroaryl group,
R7 is amine protecting group,
R8 is alkylsulfonyloxy group, arylsulfonyloxy group, or halide,
HA is organic acid or inorganic acid,
K is 0 or 1, n is O or l. Compound (A) may be prepared from the known starting materials by the well- known method of debenzylation(for example, catalytic hydrogenation with 10% Pd-C). Thus compound (A) may be converted to compound (B) by treatment with an appropriate amine protection reagent.
For example, a known amine protection reagent, preferably, acetic anhydride, alkoxycarbonyl anhydride, acetyl halide, or alkoxycarbonyl halide may be utilized.
The hydroxyl function of the compound (B) may next be converted to an appropriate leaving group of compound (C) by treatment with convinient reagents, for example, methanesulfonyl chloride or p-toluenesulfonyl chloride in the presence of a base (for example, triethylamine, pyridine) or thionyl chloride or phosphorus trihalide, etc.
Compound (C) may also be converted to compound (D) by treatment with thioalkoxide or mercapto compound in the presence of an appropriate base(for example, sodium hydride, potassium tert-butoxide).
Finally compound (D) may be deprotected to produce compound of the above described structural fromula (E) in the state of an acid salt or a free base by various well known reagents, for example, hydrochloric acid, trifluoroacetic acid, methanesulfonic acid, iodotrimethylsilane, sodium hydroxide, etc. [ Scheme II]
Figure imgf000010_0001
( C ) ( F )
Figure imgf000010_0002
( G ) ( H ) wherein,
R3, R7, R8, HA, and n are as defined above [Scheme I],
R5 and R6 are each independently hydrogen or alkylgroup having one to three carbon atoms includes straight chain or branched chain,
K is 0, 1, 2, or 3.
Compound( F) may be prepared by reacting compound (C) with thioalkoxide or mercapto compound in the presence of an appropriate base(for example, sodium hydride, potassium tert-butoxide). Compound (F) may also be converted to compound (G) by treatment with various methods.
For example, reacting with appropriate primary amine and secondary amine (for example, ammonia, methylamine, dimethylamine, ethylamine, cyclopropylamine, benzylamine, etc.), or reducing of azido compounds which are formed by treatment with sodium azide, or deprotectmg of intermediates which are formed by treatment with amide and imide (for example, acetamide, phthalimide) in the presence of strong bases, or reacting compound (G) with alkyl halide.
And then, compound (G) may be deprotected to produce compound of the above described structural formula (H) in the state of an acid salt or a free base by various well known methods.
[ Scheme HI ]
Figure imgf000012_0001
( B )
Figure imgf000012_0002
( I )
Figure imgf000012_0003
5 wherein,
R3, R7, R8, HA and n are as defined above [Scheme I],
K is O or l,
R4 is hydrogen or alkylgroup having one to three carbon atoms.
Compound (B) may be converted to compound (I) under the similar reaction l c condition as employed in the reaction of the compound (B) and the compound (C) in the above described reaction [Scheme I] .
Also, compound (I) may be converted to compound (J) under the similiar reaction condition as employed in the reaction of the compound (C) and the compound (D) in the above described reaction [Scheme T .
Compound (J) may be converted to compound (K) by treatment with alkyl halide, dialkyl sulfate in the presence of a base (for example, sodium hydride, potassium tert-butoxide, etc).
Finally, compound (J) and compound (K) may be deprotected to produce compound of the structural formula (L) and (M) in the state of an acid salt or a free base by various well known methods. [ Scheme IV ]
Figure imgf000013_0001
( U ) ( V )
t t
Figure imgf000013_0002
t
Figure imgf000013_0003
( Q ) ( R ) ( S ) wherein, R3, R4 , R7, R8, HA, and K are as defined above [Scheme III]. 3-Pyrroline may be converted to compound (N) under the similiar reaction condition as employed in the reaction of the compound (A) and the compound (B) in the above described reaction [Scheme I\. Compound (N) may be converted to compound (O) by treatment with epoxidation reagents (for example, m-chloroperoxybenzoic acid, hydrogenperoxide).
Compound (O) and (Q) may be converted to compound (P) and (R) under the similiar reaction condition as employed in the reaction of the compound (C) and the compound (D) in the above described reaction [Scheme I]. Also, compound (P) may be converted to compound (Q) under the similiar reaction condition as employed in the reaction of the compound (B) and the compound (C) in the above described reaction [Scheme I].
Finally, compound (P), (T), and (R) may be deprotected to produce compound of the above described structural formala (U), (V), and (S) in the state of an acid salt or a free base by various well known methods.
On the other hand, pharmaceutically acceptable acid addition salts of the above- described structural formula (I) are formed with organic acid or inorganic acids.
Examples of suitable acids for salt formation are acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, methanesulfonic acid, cinnamic acid, fumaric acid, phosphoric acid, hydrochloric acid, hydroiodic acid, sulfuric acid, and the like.
The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce either a mono or di, etc. salt in the conventional manner. Pharmaceutically acceptable base salts of the above-described structrual formula (I) are formed with metals such as alkali and alkaline earth metals, or amines including ammonia and organic amines.
Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are diethanolamine, N- methylglucamine, arginine, and the like. The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms.
For preparing pharmaceutical compositions from the compounds described by this invention, inert and pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersable granules, capsules, cachets, suppositories, and ointments. A solid carriers can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablets disintegrating agents . ; it can also be an encapsulating material.
Suitable solid carriers are magnesium carbonate, magnesium sterate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, and the like.
Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Such solutions are prepared so as to be acceptable to biological systems(isotonicity, pH, etc.). Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.
The following nonlimiting examples illustrate the inventor's preferred methods for preparing the compounds of the invention. Reference Example 1 Preparation of 3-hydroxymethyl-4-hydroxypyrrolidine
A solution of 6.6g(0.03 mol) of N-benzyl-3-hydroxymethyl-4-hydroxy pyrrolidine in 50 ml of methanol with 0.4g of 5% palladium on carbon catalyst was hydrogenated at room temperature for 15 hours.
After filtration, the filtrate was evaporated under reduced pressure to afford 3.3g(yield = 89.8%) of the title compound as yellowish brown oil. Reference Example 2 Preparation of N-tert-butoxycarbonyl-3-hydroxymethyl-4-hydroxypyrrolidine A mixture of 3.3g (0.03 mole) of 3-hydroxymethyl-4-hydroxy pyrrolidine in 30 ml dioxane, 10ml of lN-NaOH, and 10ml of water was cooled to 0 TJ .
To this solution was added dropwise with a solution of 8.28g(0.038 mole) of di-tert-butyldicarbonate in 5ml of dioxane, and warmed to room temperature.
The resulting solution was stirred for 15 hours and extracted with ethyl acetate over several times.
The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to afford 4.5g(yield = 72.3%) of the title compound as yellowish brown oil. Reference Example 3
Preparation of N-tert-butoxycarbonyl-3-[(methylsulfonyl)-oxymethyl]-4- methylsulfonyloxypyrrolidine
A solution of 4.0g(0.019 mole) of N-tert-butoxycarbonyl-3-hydroxymethyl-4- hydroxypyrrolidine in 30ml of dichloromethane was treated with 7.84πzZ(0.057mole) of triethylamine and cooled to 0 t .
A solution of 4.4ml (0.057mole) of methanesulfonyl chloride in 15ml of dichloromethane was added dropwise to the reaction mixture, stirred for 15 hours at room temperature, and then treated with 40ml of water. After 30 minutes, the organic layer was seperated which was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to afford 6.46g(y_eld = 93%) of the title compound as yellowish brown oil. IHNMR (ppm, CDCl3) : L46(s, 9H), 2.8 ~ 3.0(m, 1H), 3.15(d, 6H),
3.20 ~ 3.84(m, 4H), 4.18 ~ 4.30(m, 2H), 5.10 ~5.32(m, 1H)
Reference Example 4
Preparation of N-tert-butoxycarbonyl-3-methylthiomethyl-4-methylsulfonyloxy- pyrrolidine
A solution of 4.1g (0.011 mole) of N-tert-butoxycarbonyl-3-[(methylsulfonyl)- oxymethyl]-4-methylsulfonyloxypyrrolidine and 1.17g(0.017 mole) of sodium thiomethoxide in 25 ml of anhydrous dimethylformamide was stirred for 15 hours at room temperature. The reaction mixture was poured into 20ml of water and extracted with ethyl acetate over several times. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give the crude product. This was purified by column chromatography using diethyl ether : n-hexane (1 : 1) as an eluent to afford 2.56g(yield = 72%) of the title compound as yellowish brown oil. 1H NMR (ppm, CDCl3) : 1.46(s, 9H), 2.14(s, 3H), 2.30 ~ 2.81 (m, 3H), 3.09(s, 3H), 3.20 ~ 3.92(m, 4H), 5.06 ~ 5.21 (m, 1H)
Reference Example 5 Preparation of N-tert-butoxycarbonyl-3-methylthiomethyl-4-azidopyrrolidine
A mixture of 2.56g (7.97 mmole) of N-tert-butoxycarbonyl-3-methylthio- methyl-4-methylsulfonyloxypyrrolidine, 0.77g(0.012 mole) fo sodium azide, 30JRZ of dimethylformamide, and 6ml of water was stirred for 5 hours at 8013 and cooled to room temperature.
The reaction mixture was poured into 30ml of water and extracted with diethyl ether over several times.
The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to afford 2.08g(yield = 96%) of the title compound as yellowish brown oil. Η NMR (ppm, CDC13) : 1.46(s, 9H), 2.14(s, 3H), 2.20 ~ 2.64(m, 3H),
3.14 ~ 3.84(m, 4H), 4.10 ~ 4.32(m, 1H) Reference Example 6 Preparation of N-tert-butoxycarbonyl-3-methylthiomethyl-4-aminopyrrolidine
A solution of 2.08 g (7.64 mmole) of N-tert-butoxycarbonyl-3-methylthio- methyl-4-azidopyrrolidine in 40ml of methanol with 0.3g of 5% palladium on carbon catalyst was hydrogenated at room temperature for 15 hours.
After filtration, the filtrate was evaporated under reduced pressure to afford 1.61g(yield = 85.6%) of the title compound as yellowish brown oil. 1HNMR (ppm, CDCl3/D20) : 1.45(s, 9H), 2.13(s, 3H), 2.20 ~ 2.80(m, 3H),
2.85 ~ 3.81(m, 4H), 4.0 ~ 4.18(m, 1H) Reference Example 7
Preparation of 3-methyIthiomethyl-4-aminopyrroIidine tritrifluoroacetate
To a mixture of 0.3ml of anisole and 0.6g(2.44 mmole) of N-tert-butoxy- caιbonyI-3-methylthiomethyl-4-aminopyrrolidine was added 2ml of trifluoroacetic acid at 013. The mixture was stirred for 1 hours at room temperature. The reaction mixture was evaporated under reduced pressure followed by washing with 20raZ of n-hexane over twice.
This was concentrated under reduced pressure to afford 1.15g(yield = 96.7%) of the title compound as yellowish brown oil. IHNMR (ppm, DMSO-d6/D2O) : 2.12(s, 3H), 2.46 ~ 2.98(m, 3H),
3.0 ~ 3.84(m, 4H), 3.98 ~ 4.20(m, 1H) Reference Example 8 I^pajation ofN-tert-butoxycarbonyl-3-methylthiomethyl-4-methylthiopyrrolidine
A solution of lg (2.71 mmole) of N-tert-butoxycarbonyl-3-[(methylsulfonyl)- oxymethyl]-4-methylsulfonylpyrrolidine and 0.56g (8.1 mmole) of sodium thiomethoxide in 25ml of anhydrous dimethylformamide was stirred for 15 hours at room temperature. The reaction mixture was poured into 25ml water and extracted with diethyl ether over several times. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to afford 0.66g (yield = 89%) of the title compound as yellowish brown oil.
1HNMR (ppm, CDCl3) : L47(s, 9H), 2.14(s, 6H), 2.20 ~ 2.89(m, 3H),
3.10 ~ 3.84(m, 5H) Reference Example 9 Preparation of 3-methylthiomethyI-4-methylthiopyrrolidine trifluoroacetate In the same manner as described in Reference Example 7, except that N-tert- butoxycarbonyl-3-methylthiomethyl-4-methylthiopyrrolidine was used in place of N- tert-butoxycarbonyl-3-methylthiomethyl-4-aminopyrrolidine, the title compound was prepared as yellowish brown oil.
1H NMR (ppm, CDCl3 D20) : 2.19(s, 6H), 2.40 ~ 2.95(m, 3H),
3.06 ~ 3.90(m, 5H) Reference Example 10
Preparation of N-tert-butoxycarbonyl-3-hydroxy-4-methylsulfonyloxypyrrolidine A solution of 4.48g (0.02 mole) of N-tert-butoxycarbony 1-3- hydroxy- 4- hydroxymethylpyrrolidine in 25 ml of dichloromethane was treated with 3.07 ml (0.022 mole) of triethylamine and cooled to OtJ . A solution of 1.71 ml (0.022 mole) of methanesulfonyl chloride in 15ml of dichloromethane was added dropwise to the reaction mixture, stirred for 15 hours at room temperature, and then treated with 40ml of water.
After 30 minutes, the organic layer was seperated which was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to afford 4.1g (yield = 67%) of the title compound as yellowish brown oil. 1H NMR (ppm, CDCl3 D2O) : 1.46(s, 9H), 3.0(s, 3H), 3.2 ~ 4.0(m, 6H), 4.2 ~ 4.4(m, 2H)
Reference Example 11 Preparation of N-tert-butoxycarbonyl-3-hydroxy-4-methylthiomethylpyrrolidine
A solution of 4g(0.013 mole) of N-teιt-butoxycarbonyl-3-hydroxy-4- methylsulfonyloxypyrrolidine and 1.15g(0.016 mole) of sodium thiomethoxide in 25ml of anhydrous dimethylformamide was stirred for 15 hours at room temperature.
The reaction mixture was poured into 20ml of water and extracted with ethyl acetate over several times.
The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to afford 2.9g(yield = 87%) of the title compound as yellowish brown oil.
ΗNMR (ppm, CDCl3/D2O) : 1.47(s, 9H), 2.1(s, 3H), 2.2 ~ 2.6(m, 3H),
2.8 ~ 3.4(m, 2H), 3.5 ~ 3.85(m, 2H), 4.0 ~4.3(m, 1H)
Reference Example 12 Preparation of 3-hydroxy-4-methylthiomethylpyrrolidine trifluoroacetate
In the same manner as described in Reference Example 7, except that N-teit- butoxycarbonyl-3-hydroxy-4-methylthiomethylpyτrolidine was used in place of N-tert- butoxycarbonyl-3-methylthiomethyl-4-aminopyrrolidine, the title compound was preapred as yellowish brown oil. Η NMR (ppm, DMSO-dg/D ) : 2.0 ~ 2.1 l(s, 3H), 2.2 ~ 2.7(m, 3H),
2.76 ~ 3.24(m, 2H), 3.24 ~ 3.65(m, 2H), 4.05 ~4.3(m, 1H) Reference Example 13
Preparation of N-tert-butoxycarbonyl-3-methoxy-4-methylthiomethylpyrrolidine
To a solution of 0.5g(2.05 mmole) of N-tert-butoxycaτbonyl-3-hydroxy-4- methylthiomethylpyrrolidine in 20ml of dimethylsulfoxide was added O.lg (2.67 mmole) of sodium hydroxide at 0 3 and stirred for 2 hours at room temperature. To this solution was added dropwise with 0.25ml (2.67 mmole) of dimethylsulfate at 0TJ and stirred for 15 hours at room temperature.
The resulting solution was treated with 20ml of water and extracted with diethyl ether over several times.
The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to afford 0.48 g (yield = 92%) of the title compound as yellowish brown oil.
IHNMR (ppm, CDCl3) : 1.47(s, 9H), 2.2 ~ 2.5(m, 3H), 3.35(s, 3H),
3.1 ~ 3.9(m, 5H) Reference Example 14
Preparation of 3-methoxy-4-methylthiomethylpy_TO_idine trifluoroacetate
In the same manner as described in Reference Example 7, except that N-tert- butoxycarbonyl-3-methoxy-4-methylthiomethylpyrrolidine was used in place of N-tert- butoxycarbonyl-3-methylthiomethyl-4-aminopyrrolidine, the title compound was prepared as yellowish brown oil.
Η NMR (ppm, CDα,/D2O) : 2.13(s, 3H), 2.2 - 2.7(m, 3H),
3.36(s, 3H), 3.1 ~ 4.1(m, 5H) Reference Example 15
Preparation of N-teιt-butoxycarbonyl-3-pyrroline
In the same manner as described in Reference Example 2, except that 3- pyrroline was used in place of 3-hydroxymethyl-4-hydroxypyrrolidine, the title compound was prepared as yellowish brown oil. 1H NMR (ppm, CDCl3) : 1.47(s, 9H), 4.10(s, 4H), 5.76(s, 2H) Reference Example 16 Preparation of N-tert-butoxycarbonyl-3,4-epoxypyrrolidine
A solution of 12g(0.071 mole) of N-tert-butoxycarbonyl-3-pyrroline in 50nzZ of dichloromethane was cooled to 01 . A solution of 24.4g (0.14 mole) of 3-chloroperoxybenzoic acid in 50ml of dichloromethane was added dropwise to the above solution, stirred for 15 hours at room temperature, and then treated with 200mZ of water. The resulting solution was stirred for 30 minutes and extracted with ethyl acetate over several times.
The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to afford 10.9g (yield = 83%) of the title compound as yellowish brown oil.
Η NMR (ppm, CDC13) : 1.47(s, 9H), 3.0 ~ 4.0(m, 6H) Reference Example 17 Preparation of N-tert-butoxycarbonyl-3-hydroxy-4-methylthiopyrrolidine i the same manner as described in Reference Example 11, except that N-tert- butoxycarbonyl-3,4-epoxypyrrolidine was used in place of N-tert-butoxycarbonyl-3- hydroxy-4-methylsulfonyloxypyrrolidine, the title compound was prepared as yellowish brown oil.
1HNMR (ppm, CDα3/D2O) : 1.47(s, 9H), 2.15(s, 3H), 3.0 ~ 4.2(m, 5H),
4.2~ 4.4(m, 1H) Reference Example 18
Preparation of 3-hydroxy-4-methylfhiopyrrolidine trifluoroacetate In the same manner as described in Reference Example 7, except that N-tert- butoxycarbonyl-3-hydroxy-4-methylthiopyrrolidine was used in place of N-tert- butoxycarbonyl-3-methyIthiomethyl-4-aminopyrrolidine, the title compound was prepared as yellowish brown oil.
Η NMR (ppm, CDCl^O) : 2.19(s, 3H), 3.0 ~ 4.2(m, 5H), 4.2 ~ 4.45(m, 1H) Reference Example 19
Preparation of N-tert-butoxycarbonyl-3-methoxy-4-methylthiopyrroIidine
In the same manner as described in Reference Example 13, except that N-tert- butoxycaιbonyl-3-hydroxy-4-methylthiopyrrolidine was used in place of N-tert- butoxycarbonyl-3-hydroxy-4-methylthiomethylpyrrolidine, the title compound was prepared as yellowish brown oil.
1HNMR (ppm, CDCl3) : 1.47(s, 9H), 2.1(s, 3H), 3.38(s, 3H), 3.1 ~4.0(m, 6H)
Reference Example 20
Preparation of 3-methoxy-4-methylthiopyπOlidine trifluoroacetate
In the same manner as described in Reference Example 7, except that N-tert- butoxycarbonyl-3-methoxy-4-methylthiopyrrolidine was used in place of N-tert- butoxycarbonyl-3-methylthiomethyl-4-aminopyrrolidine, the title compound was prepared as yellowish brown oil. ΗNMR (ppm, CDCl3/D20) : 2.19(s, 3H), 3.4(s, 3H), 3.1 - 4.1(m, 6H) Example 1
Preparation of l-cyclopropyl-6,8-difluoro-7-(3-amino-4-methylthiomethyl)pyrrolidinyl - 1 ,4-dihydro-4-oxo- 3-quinolinecarboxylic acid A mixture of 0.2g (0.71 mmole) of l-cyclopropyl-6,7,8-trifluoro-l,4-dihydro-4- oxo-3-quinolinecaιboxylic acid, 0.1g(0.72 mmole) of l,8-diazabicyclo[5.4.0]undec-7- ene, and 5ml of acetonitrile was stirred for 20minutes.
To this mixture was added 0.37g (0.76 mmole) of 3-amino-4-methylthio- methylpyrrolidine tritrifluoroacetate and O.l (0.99 mmole) of triethylamine. The resulting solution was stirred for 8 hours at 6013 and cooled to room temperature.
The precipitate was filtered, washed with acetonitrile and diethyl ether, and dried to afford 0.2g(yield = 70%) of the title compound as pale yellow solid, m.p : 210 - 21413 (decompose) Η NMR (ppm, DMSO-dg) : 1.01 - 1.32(m, 4H), 2.11 (s, 3H),
2.21 - 2.83(m, 3H), 3.08 ~ 4.21 (m, 6H), 6.40(br, 2H), 7.70(dd, 1H), 8.59(s, 1H) Example 2
Preparation of l-cyclopropyl-6-fluoro-7-(3-amino-4-methylthiomethyl)pyrrolidinyl- l,4-dihydro-4-oxo-3-quinolinecarboxylic acid
The title compound was prepared according to example 1 by reacting 1- cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid with 3-amino- 4-methylthiomethylpyrrolidine tritrifluoroacetate. m.p : 222 - 226 3 (decompose) Η NMR (ppm, DMSO-cU • 1-01 ~ 1.43(m, 4H), 2.15(s, 3H),
2.30 - 3.01 (m, 3H), 3.12 ~ 4.12(m, 6H), 6.75(br, 2H), 7.04(d, 1H), 7.76(d, 1H), 8.58(s, 1H) Example 3 Preparation of 1 -cyclopropyl-5-amino-6,8-difluoro-7-(3-amino-4-methylthiomethyl) pyrrolidinyl-1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid
The title compound was prepared according to example 1 by reacting 1- cyclopropyl-5-amino-6,7,8-trifluoro- 1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid with 3-amino-4-methylthiomethylpyrrolidine tritrifluoroacetate. m.p : 218 - 22013 (decompose) Η NMR (ppm, NaOD/D2O) : 0.8 - 1.41 (m, 4H), 2.14(s, 3H),
2.20 - 2.82(m, 3H), 3.10 - 4.14(m, 6H), 8.22(s, 1H) Example 4
Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-amino-4-methylthiomethyl) pyrroIidinyl-1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid
The tide compound was prepared according to example 1 by reacting 1- cyclopropyl-6,7-difluoro-8-chloro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid with 3-amino-4-methylthiomethylpyrrolidine tritrifluoroacetate. m.p : 206 - 21013 (decompose) Η NMR (ppm, NaOD/D20) : 0.80 - 1.43(m, 4H), 2.14(s, 3H),
2.20 - 2.98(m, 3H), 3.14 - 4.20(m, 6H), 7.46(d, 1H), 8.39(s, 1H) Example 5
Preparation of l-cyclopropyl-6,8-difluoro-7-(3-methylthio-4-methylthiomethyl) pyπolidinyl -l,4-dihydro-4-oxo-3-quinolinecarboxylic acid
The title compound was prepared according to example 1 by reacting 1- cyclopropyl-6,7,8-trifluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid with 3- methylthio-4-methylthiomethylpyrrolidine trifluoroacetate. m.p : 214-21813 (decompose)
1HNMR (ppm, CDCI3) : 1.01 - 1.36(m, 4H), 2.17(s, 3H), 2.20(s, 3H),
2.31 - 3.01(m, 3H), 3.30 - 3.54(m, 1H), 3.60 - 4.3 l(m, 5H), 7.80(dd, 1H), 8.70(s, 1H), 14.75(br, 1H) Example 6
Preparation of 1 -(2 ,4-difluorophenyl)-6,8-difluoro-7-(3-amino-4-methylthiomethyl) 5 pyrrolidinyl- l,4-dihydro-4-oxo-3-quinolinecarboxylic acid
The tide compound was prepared according to example 1 by reacting l-(2,4- difluorophenyl)-6,7,8-trifluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid with 3- amino-4-methylthiomethylpyrrolidine tritrifluoroacetate. m.p : 232 - 23613 (decompose) 0 1H NMR (ppm, NaOD/D2O) : 2.00(s, 3H), 2.08 - 2.72(m, 3H),
2.98 - 3.96(m, 5H), 6.95 - 7.90(m, 4H), 8.16(s, 1H) Example 7
Preparation of l-(2,4-difluorophenyl)-6-fluoro-7-(3-amino-4-methylthiomethyl) 5 pyrrolidinyl- 1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid
The tide compound was prepared according to example 1 by reacting l-(2,4- difluorophenyl)-6,7-difiuoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid with 3- amino-4-methylthiomethylpyrrolidine tritrifluoroacetate. m.p : 218 - 222TJ (decompose) C 1HNMR (ppm, NaOD D2O) : 2.05(s, 3H), 2.10 - 2.64(m, 3H),
2.70 - 3.74(m, 5H), 5.73(d, 1H), 7.01 ~ 7.94(m, 5H), 8.24(s, 1H) Example 8
Preparation of 1 -cyclopropyl-6,8-difluoro-7-(3-methylamino-4-methylthiomethyl) 5 pyrrolidinyl- l,4-dihydro-4-oxo-3-quinolinecarboxylic acid
The title compound was prepared according to example 1 by reacting 1- cyclopropyl-6,7,8-trifluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid with 3- methylamino-4-methylthiomethylpyιrolidine ditrifluoroacetate. m.p : 220 - 22413 (decompose) :HNMR (ppm, NaOD/D2O) : 0.90 - 1.34(m, 4H), 2.10(s, 3H),
2.20 - 2.80(m, 3H), 2.30(s, 3H), 3.13 ~4.12(m, 6H), 7.55(dd, 1H), 8.40(s, 1H)
Example 9
Preparation of l-cyclopropyl-6,8-difluoro-7-(3-hydroxy-4-memylthiomethyl) pyrrolidinyl-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid
The title compound was prepared according to example 1 by reacting 1- cyclopropyl-6,7,8-trifluoro-l,4-dihydro-4-oxo-3-quinohnecarboxylic acid with 3- hydroxy-4-methylthiomethyIpy_rolidine trifluoroacetate. Η NMR (ppm, NaOD/D2O) : 1.01 - 1.30(m, 4H), 2.1 l(s, 3H),
2.20 - 2.84(m, 3H), 3.02 - 4.20(m, 5H), 4.30 ~ 4.52(m, lH), 7.56(dd, 1H), 8.40(s, 1H) Example 10
Prparation of l-cyclopropyl-6-fluoro-7-(3-amino-4-methyIthiomethyl)pyrrolidinyl-l,4- dihydro-4-oxo-l ,8-naphthyridine-3-carboxylic acid
The title compound was prepared according to -example 1 by reacting 1- cyclopropyl-6-fluoro-7-chloro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid with 3-amino-4-methylthiomethylpyrrolidine tritrifluoroacetate. m.p : 17813 (decompose) 1HNMR (ppm, DMSO-d6/D2O) : 0.80 - 1.44(m, 4H), 2.12(s, 3H),
2.2 - 2.90(m, 3H), 3.1 - 4.2(m, 6H), 7.8 - 8.1(d, 1H), 8.54(s, 1H) Example 11
Preparation of l-(2,4-difluorophenyl)-6-fluoro-7-(3-amino-4-methylthiomethyl) pyrrolidinyl-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid
The tide compound was prepared according to example 1 by reacting l-(2,4- difluorophenyl)-6-fluoro-7-chloro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid with 3-amino-4-methylthiomethylpyrrolidine tritrifluoroacetate. m.p : 16013 (decompose)
1H NMR (ppm, DMSO-d6/D2O) : 2.10(s, 3H), 2.2 - 2.85(m, 3H), 3.0 ~ 4.2(m, 5H), 7.2 - 8.0(m, 3H),
7.9 ~ 8.1(d, 1H), 8.7(s, 1H)
Example 12
Preparation of l-cyclopropyl-5-amino-6,8-difluoro-7-(3-hydroxy-4-methylthiomethyl) pyrrolidinyl- 1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid The title compound was prepared according to example 1 by reacting 1- cyclopropyl-5-amino-6,7,8-trifluoro- 1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid with
3-hydroxy-4-methylthiomethylpyrrolidine trifluoroacetate. m.p : 19813 (decompose)
Η NMR (ppm, DMSO-α^/Dp) : 0.9 - 1.39(m, 4H), 2.11 (s, 3H), 2.23 - 2.9(m, 3H), 3.2 - 4.4(m, 5H),
5.2 - 5.4(m, 1H), 8.7(s, 1H)
Example 13
Preparation of l-cyclopropyl-6-fluoro-7-(3-hydroxy-4-methylthiomemyl)pyrrolidinyl-
1 ,4-dihydro-4-oxo- 1 ,8-naphthyridine-3-carboxylic acid The title compound was prepared according to example 1 by reacting 1- cyclopropyl-6-fluoro-7-chloro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid with 3-hydroxy-4-memylthiomethylpyrrolidine trifluoroacetate. m.p : 218 - 21913 (decompose)
Η NMR φpm. DMSO-dg/Dp) : 0.9 - 1.4(m, 4H), 2.1(s, 3H), 2.2 - 3.0(m, 3H), 3.2 - 4.4(m, 6H),
5.2 ~ 5.4(m, 1H), 7.8 - 8.1(d, 1H), 8.5(s, 1H)
Example 14
Preparation of 1 -(2,4-difluorophenyl)-6-fluoro-7-(3-hydroxy-4-methylmiomethyl) pyιxolidinyI-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid
The tide compound was prepared according to example 1 by reacting l-(2,4- difluoroph enyl)-6-f luoro-7-chloro- 1 ,4-dihydro-4-oxo - 1 , 8-naphthyri dine-3-carb oxylic acid with 3-hydroxy-4-methylthiomethylpyrrolidine trifluoroacetate. m.p : 199 - 20013 (decompose) 1HNMR (ppm, DMSO-d6/D2O) : 2.09(s, 3H), 2.2 - 3.0(m, 3H),
3.2 - 4.4(m, 5H), 7.2 - 7.95((m, 3H), 7.96 - 8.13(d, 1H), 8.76(s, 1H) Example 15
Preparation of I -cyclopropyI-6-fluoro-8-methoxy-7-(3-hydroxy-4-methylthiomethyl) pyrrolidinyl-1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid
The title compound was prepared according to example 1 by reacting 1- cyclopropyl-6,7-difluoro-8-methoxy-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid with 3-hydroxy-4-methylthiomethylpyrrolidine trifluoroacetate. m.p : 220 - 22213 (decompose)
1HNMR (ppm,DMSO-d6/D2O) : 0.8 - 1.32(m, 4H), 2.1(s, 3H),
2.3 - 2.7(m, 3H), 3.48(m, 3H), 3.3 - 4.45(m, 6H), 7.5 - 7.7(d, 1H), 8.6(s, 1H)
Example 16
Preparation of l-cyclopropyl-6,8-difluoro-7-(3-methoxy-4-methylthiomethyl) pyrrolidinyl-1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid
The tide compound was prepared according to example 1 by reacting 1- cyclopropyl-6,7,8-trifluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid with 3-methoxy-4-methylthiomethylpyrrolidine trifluoroacetate. 1HNMR (ppm, DMSO-d6 D2O) : 0.8 - l_4(m, 4H), 2.1(s, 3H),
2.2 ~ 2.9(m, 3H), 3.4(s, 3H), 3.2 - 4.2(m, 6H), 7.7 - 7.96(dd, 1H), 8.7(s, 1H) Example 17
Preparation of l-cyclopropyl-6,8-difluoro-7-(3-hydroxy-4-memylthio)pyrrolidinyl-l,4- dihydro-4-oxo-3-quinolinecarboxylic acid
The title compound was prepared according to example 1 by reacting 1- cyclopropyl-6,7,8-trifluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid witii 3- hydroxy-4-methylthiopyrrolidine trifluoroacetate. m.p : 218 - 21913 (decompose) Η NMR (ppm, DMSO-cyD-O) : 0.82 - 1.4(m, 4H), 2.15(s, 3H),
3.0 - 4.3(m, 7H), 7.6 - 7.8(dd, 1H), 8.6(s, 1H) Example 18
Preparation of l-cyclopropyl-5-amino-6,8-difluoro-7-(3-hydroxy-4-methylthio) pyrrolidinyl- 1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid
The title compound was prepared according to example 1 by reacting 1- cyclopropyl-5-amino-6,7,8-trifluoro- 1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid with 3-hydroxy-4-methylthiopyrrolidine trifluoroacetate. m.p : 23013 (decompose) 1H NMR (ppm, DMSO-d6/D2O) : 0.8 - 1.4(m, 4H), 2.1(s, 3H),
3.0~ 4.3(m, 7H), 8.4(s, 1H) Example 19
Preparation of 1 -c yclopropy 1 -6, 8-difluoro-7- (3-m ethoxy-4-methylthio)pyrrolidinyl- 1 ,4- dihydro-4-oxo-3-quinolinecarboxylic acid The tide compound was prepared according to example 1 by reacting l-cyclopropyl-6,7,8-trifluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid with 3- methoxy-4-methylthiopyrτolidine trifluoroacetate . m.p : 220 - 22213 (decompose)
!H NMR (ppm, DMSO-dg/D ) : 0.8 - 1.4(m, 4H), 2.1(s, 3H), 3.45(s, 3H), 3.1 - 4.5(m, 7H), 7.7 - 7.9(dd, 1H), 8.7(s, 1H) Example 20
Preparation of l-cyclopropyl-5-amino-6,8-difluoro-7-(3-methoxy-4-methylthio) pyrrolidinyl-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid
The tide compound was prepared according to example 1 by reacting 1- cyclopropy-5-amino-6,7,8-trifluoro-l ,4-dihydro-4-oxo-3-quinolinecaιboxylic acid with 3-methoxy-4-methylthiopyrrolidine trifluoroacetate. m.p : 154 - 15513 (decompose) Ηϊ^πvIR tøpm^MSO-c D-O) : 0.8 - 1.4(m, 4H), 2.1(s, 3H), 3.45(s, 3H),
3.1 ~4.4(m, 7H), 8.5(s, 1H) The typical examples of the present compounds were tested for antimicrobial activity in vitro against 13 strains of Gram-positive and Gram-negative microorganisms. The antibacterial activity in vitro is shown in Table 1.
The numerals in the table 1 show minimum inhibitory concentration (MIC in «g /ml).
The minimum inhibitory concentrations were determined according to the agar dilution metiiod recommended by Japan Society of Chemotherapy [Chemotherapy., 29, 76(1986)].
The compound of example 1 was orally administered to determine the LD50for a group of male mice.
The result was proved to be LD50 > 3000 mg/kg. Table 1. In vitro Antibacterial Activity, MIC (μg/ml)
Figure imgf000031_0001
Figure imgf000032_0001
= Ciprofloxacin

Claims

WHAT IS CLAIMED IS ;
1. A compound of following structural formula(I) or pharmaceutically acceptable salts thereof.
Figure imgf000033_0003
Figure imgf000033_0001
wherein,
R1 is hydrogen or alkyl group having one to six carbon atoms, R2 is alkyl group having one to four carbon atoms, haloalkylgroup having one to four carbon atoms, cycloalkylgroup having three to six carbon atoms, alkenyl group having two to four carbon atoms, or phenyl group which is optionally mono or disubstituted by fluorine atoms, X is hydrogen, halogen, alkyl gorup having one to four carbon atoms, alkenyl group having two to four carbon atoms, cycloalkyl group having three to six carbon atoms, or amino, A is N or C-Y
Y is hydrogen, halogen, hydroxy, methoxy, or methyl, Z is
Figure imgf000033_0002
(wherein,
Q is SR3 or OR4 when m is 0 and n is 0 or 1 Q is SR3, OR4, or NR5R6 when m is 1 and n is 0 or 1.
R3 is hydrogen, alkyl group having one to four carbon atoms, haloalkylgroup having one to three carbon atoms, acyl group, cycloalkyl group having three to six carbon atoms, aryl, or heteroaryl group, R4 is hydrogen or alkyl group having one to three carbon atoms, R5 andR6 are each independentiy hydrogen or alkyl group having one to three 5 carbon atoms includes straight chain or branched chain).
2. A compound according to claim 1, wherein R1 is hydrogen.
3. A compound according to claim 1, wherein R2 is cyclopropyl, or 2,4- o difluorophenyl.
4. A compound according to claim 1, wherein X is hydrogen, methyl, or amino.
5. A compound according to claim 1, wherein A is N or C-Y.
6. A compound according to claim 5, wherein Y is hydrogen, fluorine, chlorine, ormethoxy.
7. A compound according to claim 1, wherein Z is
Figure imgf000034_0001
(wherein, R3 is hydrogen, alkylgroup having one to four carbon atoms, haloalkylgroup having one to three carbon atoms, acryl group, cycloalkylgroup having three to six carbon atoms, aryl or heteroarylgroup, R4 is hydrogen or alkyl group having one to three carbon atoms, R5 and R6 are each independentiy hydrogen or alkyl roup having one to three carbon atoms includes straight chain or branched chain, n is 0 or 1).
8. A compound according to claim 7, wherein R3 is methyl or ethyl.
9. A compound according to claim 7, wherein R4 is hydrogen or metiiyl.
10. A compound according to claim 7, wherein R5 and R6 are each independently hydrogen, methyl, cyclopropyl, or ethyl.
11. A compound to according to claim 1 and selected from the groups consisting of : l-cyclopropyl-6,8-difluoro-7-(3-amino-4-methylthiomethyl)pyrrolidinyl- l,4-dihydro-4-oxo-3-quinoline carboxylic acid, l-cyclopropyl-6-fluoro-7-(3-amino-4-methylthiomethyl)pyrrolidinyl-l ,4- dihydro-4-oxo-3-quinoline carboxylic acid, l-cyclopropyl-5-amino-6,8-difluoro-7-(3-amino-4-m ethyl thiomethyl) pyrrolidinyl- l,4-dihydro-4-oxo-3-quinoline carboxylic acid, 1 -eye lop ropyl-6-flu oro-8-chloro-7-(3- am ino-4- methyl thiomethyl) pyrrolidinyl- l,4-dihydro-4-oxo-3-quinoline carboxylic acid, l-(2,4-difluorophenyl)-6,8-difluoro-7-(3-amino-4-methylthiomethyl) pyrrolidinyl-l,4-dihydro-4-oxo-3-quinoline carboxylic acid, l -(2,4-diflu orophenyl)-6-flu oro-7 -(3-amino-4-meth ylthiometh yl) pyrrolidinyl- l,4-dihydro-4-oxo-3-quinoline carboxylic acid, 1 -cyclopropyl -6, 8-difluoro-7- (3-m ethyl ami no-4-methylthiomethyl) pyrrolidinyl- l,4-dihydro-4-oxo-3-quinoline carboxylic acid, 1 -cyclopropyl -6, 8- difluoro-7- (3-m ethyl thio-4-m ethyl thiomethyl) pyrrolidinyl-l,4-dihydro-4-oxo-3-quinoline carboxylic acid, l-cyclopropyl-6,8-difluoro-7-(3-hydroxy-4-methylthiomethyl)pyrrolidinyl- l,4-di__ydro-4-oxo-3-quinoline carboxylic acid,
1-cy cloprop yl- 6-fluoro-7 -(3- amino-4- methylthiometh yl)pyrrolidiny 1-1 ,4 - dihydro-4-oxo-l,8-naphthyridine-3- carboxylic acid, l-(2,4-difluorophenyl)-6-fluoro-7 -(3-amino-4-methylthiomethyl) pyrroIidinyl-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid, l-cyclopropyl-5-amino-6,8-difluoro-7-(3-hydroxy-4-methylthiomethyl) py_τo__d_nyl-l,4-dihydro-4-oxo-3-quino_ine carboxylic acid, l-cyclopropyl-6-fluoro-7-(3-hydroxy-4-methylthiomethyl)pyrrolidinyl-l,4- dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid, l-(2,4-difIuorophenyl)-6-fluoro-7-(3-hydroxy-4-methylthiomethyl) pyrrolidinyl- 1 ,4-dihydro-4-oxo-l ,8-naphthyridine-3-carboxylic acid, l-cyclopropyl-6-fluoro-8-methoxy-7-(3-hydroxy-4-methylthiomethyl) pyrrolidinyl-l,4-dihydro-4-oxo-3-quinoline carboxylic acid, l-cyclopropyl-6, 8-difluoro-7-(3-methoxy-4-methylthiomethyl)pyrrolidinyl- l,4-dihydro-4-oxo-3-quinoline carboxylic acid, l-cyclopropyI-6,8-difluoro-7-(3-hydroxy-4-methyIthio)pyrrolidiny 1-1,4- dihydro-4-oxo-3-quinoline carboxylic acid, l-cycIopropyl-5-amino-6 ,8-difluoro-7- (3-h ydroxy-4-methylthio) pyrrolidinyl- 1 ,4-dihydro-4-oxo-3-quinoline carboxylic acid, l-cyclopropyl-6,8-difluoro-7-(3-methoxy-4-methylthio)pyrrolidinyl-l,4- dihydro-4-oxo-3-quinoline carboxylic acid,
1-cy clopropyl-5-amino- 6, 8-difluoro-7-(3-methoxy-4-m ethyl thio) pyrrolidinyl-l,4-dihydro-4-oxo-3-quinoline carboxylic acid.
12. A compound of following structural formula(III)
Figure imgf000036_0001
wherein,
Q is SR3 or OR4 when m is 0 and n is 0 or 1 Q is SR3, OR4 , or NRSR6 when m is 1 and n is 0 or 1 5 HA is organic acid or inorganic acid,
K is 0, 1, 2 or 3 (R3 is hydrogen, alkyl group having one to four carbon atoms, haloalkylgroup having one to three carbon atoms, acyl group, cycloalkyl group having three to six carbon atoms, aryl, or heteroaryl group, i o R4 is hydrogen or alkylgroup having one to three carbon atoms,
R5 and R 6 are each independently hydrogen or alkyl group having one to three carbon atoms includes straight chain or branched chain).
13. A pharmaceutical composition comprising an antibacterially effective amount 5 of compound according to claim 1 together with a pharmaceutically acceptable carrier.
Figure imgf000037_0001
wherein, 0 R1 is hydrogen or alkyl group having one to six carbon atoms,
R2 is alkyl group having one to four carbon atoms, haloalkylgroup having one to four carbon atoms, cycloalkylgroup having three to six carbon atoms, alkenyl group having two to four carbon atoms, or phenyl group which is optionally mono or disubstituted by fluorine atoms, 5 X is hydrogen, halogen, alkyl gorup having one to four carbon atoms, alkenyl group having two to four carbon atoms, cycloalkyl group having three to six carbon atoms, or amino, A is N or C-Y
Y is hydrogen, halogen, hydroxy, methoxy, or methyl, Z is
Figure imgf000038_0001
(wherein,
Q is SR3 or OR4 when m is 0 and n is 0 or 1 Q is SR3, OR4, or NR5R6 when m is 1 and n is 0 or 1. R3 is hydrogen, alkyl group having one to four carbon atoms, haloalkylgroup having one to three carbon atoms, acyl group, cycloalkyl group having three to six carbon atoms, aryl, or heteroaryl group, R4 is hydrogen or alkyl group having one to three carbon atoms, R5 and R6 are each independently hydrogen or alkyl group having one to three carbon atoms includes straight chain or branched chain).
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DE3906365A1 (en) * 1988-07-15 1990-01-18 Bayer Ag 7- (1-PYRROLIDINYL) -3-CHINOLONE AND NAPHTHYRIDONE CARBOXYLIC ACID DERIVATIVES, METHOD AND SUBSTITUTED (OXA) DIAZABICYCLOOCTANES AND NONANESE AS INTERMEDIATE PRODUCTS, AND ANTIBACTERIAL AGENTS AND FOOD ADDITIVES CONTAINING THEM

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EP0641793A1 (en) * 1993-08-27 1995-03-08 Hokuriku Seiyaku Co., Ltd. 5-Amino-8-methyl-7-pyrrolidinylquinoline-3-carboxylic acid derivative
US5547962A (en) * 1993-08-27 1996-08-20 Horuriku Seiyaku Co., Ltd. 5-amino-8-methyl-7-pyrrolidinylquinoline-3-carboxylic acid derivative
WO1996022988A1 (en) * 1995-01-24 1996-08-01 Hokuriku Seiyaku Co., Ltd. Quinolinecarboxylic acid derivatives
US5859026A (en) * 1995-01-24 1999-01-12 Hokuriku Seiyaku Co., Ltd. Quinoline carboxylic acid
EP1258478A1 (en) * 2000-02-25 2002-11-20 Daiichi Pharmaceutical Co., Ltd. Process for producing quinolonecarboxylic acids and intermediates thereof
EP1258478A4 (en) * 2000-02-25 2006-03-15 Daiichi Seiyaku Co Process for producing quinolonecarboxylic acids and intermediates thereof
KR20030030075A (en) * 2001-10-06 2003-04-18 조한주 A Centrifugal force use portable and airball Soft contact lens clean machine
US8217029B2 (en) 2007-04-11 2012-07-10 Actelion Pharmaceuticals Ltd Oxazolidinone antibiotics
EP2905283A1 (en) 2007-04-11 2015-08-12 Actelion Pharmaceuticals Ltd. Oxazolidinone antibiotics
EP2915813A1 (en) 2007-04-11 2015-09-09 Actelion Pharmaceuticals Ltd. Oxazolidinone antibiotics

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AU2391192A (en) 1993-03-02
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