KR970010762A - Novel quinoline carboxylic acid derivatives having 7- (4-aminomethyl-3-fluoroalkyloxime) pyrrolidine substituents and methods for their preparation - Google Patents

Novel quinoline carboxylic acid derivatives having 7- (4-aminomethyl-3-fluoroalkyloxime) pyrrolidine substituents and methods for their preparation Download PDF

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KR970010762A
KR970010762A KR1019950024000A KR19950024000A KR970010762A KR 970010762 A KR970010762 A KR 970010762A KR 1019950024000 A KR1019950024000 A KR 1019950024000A KR 19950024000 A KR19950024000 A KR 19950024000A KR 970010762 A KR970010762 A KR 970010762A
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compound
hydrogen
formula
methyl
general formula
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KR1019950024000A
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KR0174372B1 (en
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홍창용
김미리
김영관
남두현
오정인
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성재갑
주식회사 Lg 화학
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—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
    • C07D207/10—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
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • 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

Abstract

본 발명은 탁월한 항균력을 나타내는 퀴놀론계 화합물 특히, 퀴놀론 모핵의 7-번 위치에 4-아미노메틸-3-플루오로알킬옥심피롤리딘 치환체를 갖는 화합물로서, 우수한 항균작용과 광범위한 항균스펙트럼을 가질 뿐만 아니라 기존의 퀴놀론계 항생제보다 월등히 뛰어난 흡수 및 약물동력학적 특성을 갖는 다음 일반식(Ⅰ)로 표시되는 신규한 퀴놀린(나프티리딘) 카르복실산 유도체, 약제학적으로 허용되는 그의 무독성염, 생리학적으로 가수분해 가능한 그의 에스테르, 용매화물 및 이성체에 관한 것이다.The present invention is a quinolone compound exhibiting excellent antimicrobial activity, in particular, a compound having a 4-aminomethyl-3-fluoroalkyloximepyrrolidine substituent at the 7-position of the quinolone mother nucleus, which has excellent antibacterial activity and broad antibacterial spectrum. But also a novel quinoline (naphthyridine) carboxylic acid derivative represented by the following general formula (I), which has superior absorption and pharmacokinetic properties than conventional quinolone antibiotics, pharmaceutically acceptable non-toxic salts thereof, physiologically Hydrolyzable esters, solvates and isomers thereof.

상기 식에서, Q, R, R1, R2, R3, R4, R5, R6및 R7은 명세서중에 정의된 바와 같다.Wherein Q, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined in the specification.

Description

7-(4-아미노메틸-3-플루오로알킬옥심)피롤리딘 치환체를 갖는 신규 퀴놀린 카르복실산 유도체 및 그의 제조방법Novel quinoline carboxylic acid derivatives having 7- (4-aminomethyl-3-fluoroalkyloxime) pyrrolidine substituents and preparation methods thereof

본 내용은 요부공개 건이므로 전문내용을 수록하지 않았음As this is a public information case, the full text was not included.

Claims (13)

하기 일반식(Ⅰ)로 표시되는 퀴놀린 카르복실산 유도체, 약제학적으로 허용되는 그의 염, 생리학적으로 가수분해 가능한 에스테르, 용매화물 및 이성체.Quinoline carboxylic acid derivatives represented by the following general formula (I), pharmaceutically acceptable salts thereof, physiologically hydrolysable esters, solvates and isomers. 상기 식에서, Q는 C-H, C-F, C-Cl, C-CH3, C-O-CH3또는 N을 나타내고; R은 수소, 메틸 또는 아미노를 나타내며; R1은 사이클로프로필, 에틸 또는 1개 이상의 불소원자로 치환된 페닐을 나타내고; R2는 1개 이상의 불소원자에 의해 치환된 C1-C4알킬을 나타내며; R3및 R4는 각각 독립적으로 수소 또는 C1-C3알킬을 나타내거나, 그들이 부착되어 있는 질소원자와 함께 탄소원자 3 내지 5원 환을 형성할 수 있고; R5는 수소, C1-C3알킬 또는 할로알킬을 나타내며; R6및 R7은 각각 독립적으로 수소, C1-C3알킬 또는 할로알킬을 나타내거나, 이들이 서로 연결되어 사이클로알킬 그룹을 형성할 수 있다.Wherein Q represents CH, CF, C-Cl, C-CH 3 , CO-CH 3 or N; R represents hydrogen, methyl or amino; R 1 represents cyclopropyl, ethyl or phenyl substituted with one or more fluorine atoms; R 2 represents C 1 -C 4 alkyl substituted by one or more fluorine atoms; R 3 and R 4 each independently represent hydrogen or C 1 -C 3 alkyl or together with the nitrogen atom to which they are attached may form a 3 to 5 membered carbon ring; R 5 represents hydrogen, C 1 -C 3 alkyl or haloalkyl; R 6 and R 7 each independently represent hydrogen, C 1 -C 3 alkyl or haloalkyl, or they may be linked to each other to form a cycloalkyl group. 제1항에 있어서, Q는 C-H, C-F, C-Cl 또는 N이고; R은 수소이며; R1은 시클로프로필 똔느 2,4-디플루오로페닐이고; R2는 2-플루오로에틸 또는 플루오로메틸이며; R3및 R4는 수소이고; R5는 수소 또는 메틸이며; R6및 R7은 각각 독립적으로 수소 또는 메틸이거나 이들이 서로 연결되어 형성된 사이클로프로필인 화합물.The compound of claim 1, wherein Q is CH, CF, C-Cl, or N; R is hydrogen; R 1 is cyclopropyl quinine 2,4-difluorophenyl; R 2 is 2-fluoroethyl or fluoromethyl; R 3 and R 4 are hydrogen; R 5 is hydrogen or methyl; R 6 and R 7 are each independently hydrogen or methyl or cyclopropyl formed by linking with each other. 제2항에 있어서, Q는 C-H, C-F, C-Cl 또는 N이고; R은 수소이며; R1은 사이클로프로필이고; R2는 2-플루오로에틸이며; R3및 R4는 수소이고; R5는 수소 또는 메틸이며; R6및 R7은 각각 독립적으로 수소 또는 메틸인 화합물.The compound of claim 2, wherein Q is CH, CF, C-Cl, or N; R is hydrogen; R 1 is cyclopropyl; R 2 is 2-fluoroethyl; R 3 and R 4 are hydrogen; R 5 is hydrogen or methyl; R 6 and R 7 are each independently hydrogen or methyl. 하기 일반식(Ⅱ)의 화합물을 용매중에서 염기의 존재하에 하기 일반식(Ⅲ)의 화합물과 반응시킴을 특징으로 하여 일반식(Ⅰ)의 화합물을 제조하는 방법.A process for preparing a compound of formula (I), wherein the compound of formula (II) is reacted with a compound of formula (III) in the presence of a base in a solvent. 상기 식에서, Q, R, R1, R2, R3, R4, R5, R6및 R7는 제1항에 정의한 바와 같고; X는 할로겐이다.Wherein Q, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined in claim 1; X is halogen. 제4항에 있어서, 일반식(Ⅲ)의 화합물이 염산, 브롬화수소산 또는 트리플루오로아세트산과의 염 형태로 사용되는 방법.The process according to claim 4, wherein the compound of general formula (III) is used in the form of a salt with hydrochloric acid, hydrobromic acid or trifluoroacetic acid. 제4항에 있어서, 일반식(Ⅲ)의 화합물을 일반식(Ⅱ)의 화합물에 대해 동몰량 내지 10몰배량 사용하는 방법.The method according to claim 4, wherein the compound of general formula (III) is used in an amount of 10 to 10 molar times with respect to the compound of general formula (II). 제4항에 있어서, 용매가 아세토니트릴, 디메틸포름아미드(DMF), 디메틸설폭사이드(DMSO), 피리딘 및 헥사메틸포스포아미드(HMPA) 중에서 선택되는 방법.The process of claim 4 wherein the solvent is selected from acetonitrile, dimethylformamide (DMF), dimethylsulfoxide (DMSO), pyridine and hexamethylphosphoamide (HMPA). 제4항에 있어서, 염기가 무기염기로서 탄산수소나트륨, 탄산칼륨 또는 유기염기로서 트리에틸아민, 디이소프로필에틸아민, 피리딘, N,N-디메틸아닐린, N,N-디메틸아미노피리딘, 1,8-디아자비사이클로[5.4.0]운데세-7-엔(DBU) 및 1,4-디아자비사이클로[2.2.0]옥탄(DABCO) 중에서 선택되는 방법.The method according to claim 4, wherein the base is sodium hydrogencarbonate, potassium carbonate as the inorganic base or triethylamine, diisopropylethylamine, pyridine, N, N-dimethylaniline, N, N-dimethylaminopyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) and 1,4-diazabicyclo [2.2.0] octane (DABCO). 제4항에 있어서, 반응 온도가 실온 내지 200℃인 방법.The process of claim 4 wherein the reaction temperature is from room temperature to 200 ° C. 6. 하기 일반식(Ⅲ′)의 화합물을 상기 일반식(Ⅱ)의 화합물과 염기 존재하에 반응시키고, 계속하여 아미노 보호기를 제거시킴을 특징으로 하여 일반식(Ⅰ)의 화합물을 제조하는 방법.A method of preparing a compound of formula (I), wherein the compound of formula (III ′) is reacted with a compound of formula (II) in the presence of a base, followed by removal of an amino protecting group. 상기 식에서, R2, R5, R6및 R7은 제1항에서 정의한 바와 같고; P는 아미노보호기를 나타낸다.Wherein R 2 , R 5 , R 6 and R 7 are as defined in claim 1; P represents an aminoprotecting group. 제10항에 있어서, 상기 아미노보호기는 포르밀, 아세틸, 트리플루오로아세틸, 벤조일, 파라-니트로벤조일, 파라-톨루엔설포닐, 메톡시카르보닐, 에톡시카르보닐, t-부톡시카르보닐, 벤질옥시카르보닐, 파라-메톡시벤질옥시카르보닐, 트리클로로에톡시카르보닐, 베타-요오드에톡시카르보닐, 벤질, 파라메톡시벤질, 트리틸 및 테트라하이드로피라닐 중에서 선택되는 방법.The method of claim 10, wherein the amino protecting group is formyl, acetyl, trifluoroacetyl, benzoyl, para-nitrobenzoyl, para-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, Benzyloxycarbonyl, para-methoxybenzyloxycarbonyl, trichloroethoxycarbonyl, beta-iodineethoxycarbonyl, benzyl, paramethoxybenzyl, trityl and tetrahydropyranyl. 제1항에 따른 일반식(Ⅰ)의 화합물을 유효 성분으로 함유하는 항균제 조성물.An antimicrobial composition comprising the compound of formula (I) according to claim 1 as an active ingredient. 제12항에 있어서, 일반식(Ⅰ)의 화합물을 단위 투약량 내에 1 내지 100㎎ 함유하는 조성물.The composition according to claim 12, which contains 1 to 100 mg of a compound of formula (I) in a unit dose. ※ 참고사항 : 최초출원 내용에 의하여 공개하는 것임.※ Note: The disclosure is based on the initial application.
KR1019950024000A 1995-08-03 1995-08-03 Novel quinoline carboxylic acid derivatives having 7-(4-aminomethyl-3-fluoroalkyloxime)pyrrolidine substituent and process for preparing thereof KR0174372B1 (en)

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