KR960001919B1 - Novel quinolone carboxylic acid derivatives and its - Google Patents

Novel quinolone carboxylic acid derivatives and its Download PDF

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KR960001919B1
KR960001919B1 KR1019930002572A KR930002572A KR960001919B1 KR 960001919 B1 KR960001919 B1 KR 960001919B1 KR 1019930002572 A KR1019930002572 A KR 1019930002572A KR 930002572 A KR930002572 A KR 930002572A KR 960001919 B1 KR960001919 B1 KR 960001919B1
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carboxylic acid
amino
fluorophenyl
oxo
dihydro
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KR940019690A (en
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김성진
정점양
김남기
이상용
김백중
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제일약품주식회사
한승수
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    • 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The quinolone carboxylic acid derivs. of formula(I) are prepd. by reacting an ethyl-(2,3,4,5-tetrafluorobenzoyl)-3-ethoxy acrylate of formula (II) or an ethyl-(5-fluoro-2,4-dihalobenzoyl)-3-ethoxy acrylate of formula(III) with a 2-nitro-4-fluoroaniline in the alcohol solvent, reacting the reactant with a potassium carbonate in the dimethyl formamide solvent at 40-60deg. C, acid-hydrolyzing the reactant, and reducing it with a tin chloride or a tin. In the formulas, R1 is 2-amino-4-fluorophenyl; R2 is F, piperazine, piperidine, pyrrolidine or morphorine; R3 is H or halogen; X is halogen. The derivs. (I) have a good antibacterial activity against gram positive and negative bacteria.

Description

신규한 퀴놀론 카르복실산 유도체와 그의 제조방법Novel quinolone carboxylic acid derivatives and preparation method thereof

본 발명은 다음 일반식(I)로 표시되는 신규한 퀴놀론 카르복실산 유도체와 그의 제조방법에 관한 것으로서, 더욱 상세하게는 그람 양성균과 음성균에 대하여 우수한 항균력을 가지며, 특히 그람 양성균에 대하여는 기존의 약제보다 우수한 항균작용을 갖는 신규한 퀴놀론 카르복실산 유도체와 그염 및 그의 제조방법에 관한 것이다.The present invention relates to a novel quinolone carboxylic acid derivative represented by the following general formula (I) and a method for preparing the same, and more particularly, has an excellent antimicrobial activity against Gram-positive bacteria and negative bacteria, and in particular, existing drugs for Gram-positive bacteria. Novel quinolone carboxylic acid derivatives having better antibacterial activity, salts thereof, and methods for preparing the same.

상기식에서 R1은 2-아미노-4-플루오로페닐기이고, R2는 할로겐 원자, 또는 질소나 산소를 함유하는 헤테로 싸이크릭 화합불이고, R3는 수소 또는 할로겐 원자이다.In the above formula, R 1 is a 2-amino-4-fluorophenyl group, R 2 is a halogen atom or a hetero cyclic compound containing nitrogen or oxygen, and R 3 is hydrogen or a halogen atom.

퀴놀론계 항균제로는 1963년 날리딕식산이 개발된 이래 많은 연구가 진행되어 광범위하고 우수한 항균 스팩트럼을 갖는 노플록사신, 오플록사신 등의 퀴놀론계 항균제가 개발되어 널리 사용되어 왔다. 그러나 이들은 그람 음성균에 대한 항균력은 우수한데 비하여 그람 양성균에 대한 항균력을 떨어지는 결점이 있다. 또한 퀴놀론계 항균제로 N1위치 치환기가 2,4-디플루오르페닐인 테마플록사신은 항균력이 우수한 반면 임상시험중 용혈작용과 혈소판 감소등 여러 장기기판에 대한 부작용으로 시판이 중단되고 있다.Since the development of nalidic acid in 1963, as a quinolone antimicrobial agent, many researches have been conducted, and a quinolone antibacterial agent such as nofloxacin and oploxacin having a broad and excellent antibacterial spectrum has been developed and widely used. However, they have a disadvantage in that the antimicrobial activity against gram-negative bacteria is superior to that of the gram-positive bacteria. Temofloxacin, an N 1 -substituted 2,4-difluorophenyl as a quinolone antimicrobial agent, has excellent antimicrobial activity, but its commercialization has been discontinued due to side effects on various organ substrates such as hemolysis and platelet reduction during clinical trials.

또한, 국내특허 제58124호에는 N1치환기가 2,4-디아미노페닐인 퀴놀론 카르복실산이 개시되어 있는데 이는 그람 양성균에 대하여는 좋은 항균력을 보이나 그람 음성균에 대하여는 기존의 약제보다 항균력이 떨어지는 문제가 있어 바람직하지 않다.In addition, Korean Patent No. 58124 discloses a quinolone carboxylic acid having a N 1 substituent of 2,4-diaminophenyl, which shows a good antibacterial activity against gram-positive bacteria but a lower antibacterial activity against gram negative bacteria. Not desirable

따라서, 본 발명자들은 상기와 같은 종래기술의 문제점을 해결하고자 노력한 결과 퀴놀론 카르복실산 N1위치에 아미노기와 플루오르기를 동시에 갖는 페닐기를 도입하여 그람 음성균에 대한 항균작용은 기존의 퀴놀론계 항균제와 비슷하고 그람 양성균에 대해서는 더욱 우수한 항균력을 나타낼 뿐 아니라 독성이 적은 신규한 퀴놀론 카르복실산을 개발함으로써 본 발명을 완성하였다.Therefore, the present inventors have attempted to solve the problems of the prior art as described above, by introducing a phenyl group having both an amino group and a fluorine group at the quinolone carboxylic acid N 1 position, the antimicrobial activity against Gram-negative bacteria is similar to that of a conventional quinolone antimicrobial agent. The present invention has been completed by developing a novel quinolone carboxylic acid which not only shows better antimicrobial activity against Gram-positive bacteria but also has low toxicity.

본 발명은 독성이 적고 그람 양성균에 대하여 우수한 항균력을 갖는 새로운 퀴놀론 카르복실산 유도체와 그의 제조방법을 제공하는데 그 목적이 있다.It is an object of the present invention to provide a novel quinolone carboxylic acid derivative having a low toxicity and excellent antimicrobial activity against Gram-positive bacteria and a method for preparing the same.

이하, 본 발명을 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail.

본 발명은 다음 일반식(I)로 표시되는 신규한 퀴놀론 카르복실산 유도체 및 그 염에 관한 것이다.The present invention relates to novel quinolone carboxylic acid derivatives represented by the following general formula (I) and salts thereof.

상기식에서 R1은 2-아마노-4-플루오로페닐기이고, R2는 할로겐 원자, 또는 질소나 산소를 함유하는 헤테로 싸이크릭 화합물이고, R3는 수소 또는 할로겐 원자이다.In the above formula, R 1 is a 2-amano-4-fluorophenyl group, R 2 is a halogen atom or a hetero cyclic compound containing nitrogen or oxygen, and R 3 is hydrogen or a halogen atom.

본 발명에 따른 상기 일반식(I)의 화합물은 다음 일반식(II)로 표시되는 에틸-(2,3,4,5-테트라 플루오로벨조일)-3-에톡시 아크릴레이트 또는 다음 일반식(III)으로 표시되는 에틸-(5-플루오로-2,4-디할로벤조일)-3-에톡시 아크릴레이트에 2-니트로-4-플루오로아닐린을 알콜 용매하에서 반응시킨 후 다시 디메틸프름아미드(이하, DMF라 함) 용매하에서 탄산칼륨과 반응시켜 폐환하고 이를 산가수분해한 후 철, 염화주석 또는 주석으로 환원하여 상기 일반기(I)로 표시되는 신규한 퀴놀론 카르복실산 모액을 제조할 수 있다.The compound of general formula (I) according to the present invention is ethyl- (2,3,4,5-tetrafluorobelzoyl) -3-ethoxy acrylate represented by the following general formula (II) or 2-nitro-4-fluoroaniline is reacted with ethyl- (5-fluoro-2,4-dihalobenzoyl) -3-ethoxy acrylate represented by III) in an alcoholic solvent, and then dimethylpramide ( Hereinafter, a new quinolone carboxylic acid mother liquor represented by the general group (I) may be prepared by reacting with potassium carbonate in a solvent and ring-closing and ring-closing and acid-hydrolyzing it and then reducing it with iron, tin chloride or tin. have.

상기식에서, X는 할로겐 원자이다.Wherein X is a halogen atom.

이와 같은 본 발명을 더욱 상세히 설명하면 다음과 같다.Referring to the present invention in more detail as follows.

본 발명은 그람 음성균과 특히 그람 양성균에 우수한 항균력을 가지고 상기 일반식(1)로 표시되는 신규한 퀴놀론 카르복실산 유도체에 관한 것으로, 본 발명의 상기 일반식(I)의 화합물은 상기 일반식(II) 또는 (III)으로 표시되는 화화물 1몰에 2-니트로-4-플루오르아닐린 1.2∼2몰을 알콜용매하에서 반응시키고 탄산칼슘 1∼1.4몰과 DMF 용매하에서 40∼60℃로 반응시켜 폐환하고, 이소프로필 알콜용매 하에서 18% 염산 5∼12배몰을 가하고 가온하여 산가수분해 하여 얻은 일반식(IV)로 표시되는 화합물을 산성조건하에 2∼4 배몰의 철, 주석 또는 염화주석을 사용하여 환원시켜 제조할 수 있다.The present invention relates to a novel quinolone carboxylic acid derivative represented by the general formula (1) having excellent antimicrobial activity against Gram-negative bacteria and in particular Gram-positive bacteria, wherein the compound of the general formula (I) To 1 mole of the compound represented by II) or (III), 1.2 to 2 moles of 2-nitro-4-fluoroaniline are reacted in an alcoholic solvent, and 1 to 1.4 moles of calcium carbonate are reacted at 40 to 60 ° C. under DMF solvent to close the ring. 5 to 12 times mole of 18% hydrochloric acid in an isopropyl alcohol solvent and heated to acid hydrolysis to obtain a compound represented by formula (IV) under acid conditions of 2 to 4 times mole of iron, tin or tin chloride. It can be prepared by reduction.

상기식에서, X는 할로겐 원자이고, Y는 플루오르원자 또는 수소원자이다.Wherein X is a halogen atom and Y is a fluorine atom or a hydrogen atom.

또한, 상기 일반식(I)의 화합물은 6,7,8-트리플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산, 또는 6-플루오로-7-할로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산의 N1위치에 2-아미노-4-플루오르 페닐이 치환된 화합물과 C7위치에 할로겐 원자 대신 피페라진, 피롤리딘, 피페리딘, 모포린 등과 같이 질소를 함유하는 헤테로싸이클릭 화합물을 도입한 신규한 퀴놀론 카르복신산 유도체로써, 이들은 상기 일반식(I)의 R2가 할로겐인 화합물과 질소를 함유하는 헤테로 싸이클릭 화합물을 반응시켜 얻을 수 있다.In addition, the compound of formula (I) is 6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, or 6-fluoro-7-halo-1 Compound substituted with 2-amino-4-fluorophenyl at the N 1 position of 4-4-dihydro-4-oxo-3-quinoline carboxylic acid and piperazine, pyrrolidine, piperi instead of halogen atom at position C 7 Novel quinolone carboxylic acid derivatives incorporating nitrogen-containing heterocyclic compounds such as dean, morpholine, and the like, which are compounds in which R 2 in Formula (I) is halogen and heterocyclic compounds containing nitrogen It can be obtained by reacting.

예를들면, 다음 일반식(I-a)에 포함되는 화합물 1-(2-아미노-4-플루오로페닐)-678-트리플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산 및 다음 일반식(I-b)에 포함되는 1-(2-아미노-4-플루오로페닐)-6,8-디플루오르-1,4-디하이드로-4-옥소-7-피페라지닐-3-퀴놀린 카르복실산은 다음과 같은 반응식으로 나타낼 수 있으며, 여기서 기본 모핵이 되는 일반식(1-a)와 그들의 유도체인 일반식(I-b)화합물은 다음의 반응식과 같은 과정을 거쳐 제조할 수 있다.For example, compound 1- (2-amino-4-fluorophenyl) -678-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxyl contained in the following general formula (Ia) 1- (2-amino-4-fluorophenyl) -6,8-difluoro-1,4-dihydro-4-oxo-7-piperazinyl-3 included in the acid and in formula (lb) -Quinoline carboxylic acid can be represented by the following reaction formula, wherein the general formula (1-a) and the derivatives of the general formula (Ib) compounds that can be prepared by the same process as the following reaction scheme.

상기식에서, X는 할로겐 원자이고, Y는 플루오르원자 또는 수소원자이다.Wherein X is a halogen atom and Y is a fluorine atom or a hydrogen atom.

즉, 화합물(I-a)와 (I-b)는 현재까지 잘 알려진 공지의 방법에 따라 상기 일반식(II')의 화합물을 합성하고, 여기에 2-니트로-4-플루오로아닐린을 에탄올 용매하에서 치환한 후 탄산칼륨과 DMF 용매에서 폐환하고 산가수분해 하여 상기 일반식(IV')을 얻고 이를 예컨대 염산의 산성조건에서 철이나 주석 또는 염화주석을 사용하여 환원시키면 기본모핵이 되는 상기 일반식(I-a)의 화합물을 얻고 여기에 피페라진을 반응시키면 상기 일반식(I-b)의 화합물을 제조할 수 있다.That is, the compounds (Ia) and (Ib) synthesize the compounds of the general formula (II ') according to well-known methods known to date, and are substituted with 2-nitro-4-fluoroaniline in an ethanol solvent. After ring closure in potassium carbonate and DMF solvent and acid hydrolysis to obtain the above general formula (IV ′), which is reduced by using iron, tin, or tin chloride under acidic conditions of hydrochloric acid. Compound of Formula (Ib) can be prepared by obtaining a compound of and reacting piperazine with it.

본 발명에 의하면 상기 구조식(I-a)와 (I-b) 모두 우수한 항균활성이 있는 것으로 밝혀졌다.According to the present invention, both the structural formulas (I-a) and (I-b) were found to have excellent antimicrobial activity.

한편, 상기 구조식(I)의 화합물은 유기 또는 무기산과의 염으로 전환시킬 수 있고, 염을 만들기 위한 산으로는 예켠대, 할로겐화 수소산, 황산, 아세트산, 시트르산 등을 들 수 있으며 금속염 및 알카리토금속 염으로는 나트륨염, 칼륨염, 마그네슘염 등이 있다.On the other hand, the compound of formula (I) can be converted into a salt with an organic or inorganic acid, and the acid for making the salt, for example, a halogenated acid, sulfuric acid, sulfuric acid, acetic acid, citric acid and the like, metal salts and alkaline metal salts Examples thereof include sodium salts, potassium salts and magnesium salts.

이와 같이 본 발명에 따른 상기 구조식(I)의 화합물들과 그 약제학적으로 유용한 산부가염, 알칼리 금속염, 수화물 등은 그람 음성균은 물론 그람 양성균에 대해 우수한 항균력을 나타내며, 이들 화합물들의 구체적인 예로는 7-플루오로-1-(2-아미노-4-플루오로페닐)-6-플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산, 7-피페라지닐-1-(2-아미노-4-플루오로페닐)-6-플루오로-1,4-디하이드로-4-옥소-3-퀴놀린카르복실산, 7-(4-메틸피레라진)-1-(2-아미노-4-플루오로페닐)-6-플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산, 7-(3-메칠-1-피페라지닐)-1-(2-아미노-4-플루오로페닐)-6-플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산, 7-피페리디닐-1-(2-아미노-4-플루오로페닐)-6-플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산, 7-(4-메틸피페라디닐)-1-(2-아미노-4-플루오로페닐)-6-플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산, 7-모포리닐-1-(2-아미노-4-플루오로페닐)-6-플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산, 7-아지리디닐-1-(2-아미노-4-플루오로페닐)-6-플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산, 7-(3-하이드록시피롤리디닐)-1-(2-아미노-4-플루오로페닐)-6-플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산, 7-(1,2,3,6-테트라하이드로피리디닐)-1-(2-아미노-4-플루오로페닐)-6-플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산, 7-피롤리디닐-1-(2-아미노-4-플루오로페닐)-6-플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산, 7-플루오로-1-(2-아미노-4-플루오로페닐)-6,8-디플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산, 7-피페라지닐-1-(2-아미노-4-플루오로페닐)-6,8-플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산, 7-(4-메틸피페라진)-1-(2-아미노-4-플루오로페닐)-6,8-디플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산, 7-(3-메칠-1-피페라지닐)-1-(2-아미노-4-플루오로페닐)-6,8-디플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산, 7-피페리디닐-1-(2-아미노-4-플루오로페닐)-6,8-디플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산, 7-(4-메틸피페리디닐)-1-(2-아미노-4-플루오로페닐)-6,8-디플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산, 7-모포리닐-1-(2-아미노-4-플루오로페닐)-6,8-디플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산, 7-아지리디닐-1-(2-아미노-4-플루오로페닐)-6,8-디플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산, 7-(3-하이드록시피롤리디닐)-1-(2-아미노-4-플루오로페닐)-6,8-디플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산, 7-(1,2,3,6-테트라하이드로피리디닐)-1-(2-아미노-4-플루오로페닐)-6,8-디플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산 또는 7-피롤리디닐-1-(2-아미노-4-플루오로페닐)-6,8-디플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산 등이 있다.As described above, the compounds of the formula (I) according to the present invention and pharmaceutically useful acid addition salts, alkali metal salts, and hydrates thereof exhibit excellent antimicrobial activity against Gram-negative bacteria as well as Gram-positive bacteria. Fluoro-1- (2-amino-4-fluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 7-piperazinyl-1- (2 -Amino-4-fluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7- (4-methylpyrazine) -1- (2-amino- 4-fluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 7- (3-methyl-1-piperazinyl) -1- (2-amino 4-fluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 7-piperidinyl-1- (2-amino-4-fluorophenyl) -6-Fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 7- (4-methylpiperidinyl) -1- (2-amino-4-ple Fluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 7-morpholinyl-1- (2-amino-4-fluorophenyl) -6-fluoro Rho-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 7-aziridinyl-1- (2-amino-4-fluorophenyl) -6-fluoro-1,4-di Hydro-4-oxo-3-quinoline carboxylic acid, 7- (3-hydroxypyrrolidinyl) -1- (2-amino-4-fluorophenyl) -6-fluoro-1,4-dihydro -4-oxo-3-quinoline carboxylic acid, 7- (1,2,3,6-tetrahydropyridinyl) -1- (2-amino-4-fluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo-3-quinoline carboxylic acid, 7-pyrrolidinyl-1- (2-amino-4-fluorophenyl) -6-fluoro-1,4-dihydro-4- Oxo-3-quinoline carboxylic acid, 7-fluoro-1- (2-amino-4-fluorophenyl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline Carboxylic acid, 7-piperazinyl-1- (2-amino-4-fluorophenyl) -6,8-fluoro-1,4-dihydro-4- So-3-quinoline carboxylic acid, 7- (4-methylpiperazin) -1- (2-amino-4-fluorophenyl) -6,8-difluoro-1,4-dihydro-4- Oxo-3-quinoline carboxylic acid, 7- (3-methyl-1-piperazinyl) -1- (2-amino-4-fluorophenyl) -6,8-difluoro-1,4-di Hydro-4-oxo-3-quinoline carboxylic acid, 7-piperidinyl-1- (2-amino-4-fluorophenyl) -6,8-difluoro-1,4-dihydro-4- Oxo-3-quinoline carboxylic acid, 7- (4-methylpiperidinyl) -1- (2-amino-4-fluorophenyl) -6,8-difluoro-1,4-dihydro-4 Oxo-3-quinoline carboxylic acid, 7-morpholinyl-1- (2-amino-4-fluorophenyl) -6,8-difluoro-1,4-dihydro-4-oxo-3- Quinoline carboxylic acid, 7-aziridinyl-1- (2-amino-4-fluorophenyl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid , 7- (3-hydroxypyrrolidinyl) -1- (2-amino-4-fluorophenyl) -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarr Acid, 7- (1,2,3,6-tetrahydropyridinyl) -1- (2-amino-4-fluorophenyl) -6,8-difluoro-1,4-dihydro-4 Oxo-3-quinoline carboxylic acid or 7-pyrrolidinyl-1- (2-amino-4-fluorophenyl) -6,8-difluoro-1,4-dihydro-4-oxo-3 -Quinoline carboxylic acid and the like.

또한, 그 염으로서는 이들 화합물의 산 및 알칼리금속 부가 염을 예로 들 수 있다.Examples of the salts include acid and alkali metal addition salts of these compounds.

이하, 본 발명을 실시예에 의거 상세히 설명하면 다음과 같은 바, 본 발명이 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited by the Examples.

[실시예 1]Example 1

[1-(2-니트로-4-플루오로페닐)-6,7-디플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산의 제조][Preparation of 1- (2-nitro-4-fluorophenyl) -6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid]

에틸-(2,4,5-트리플루오로벤조일)-3-에톡시아크릴레이트 10g을 에탄올 20ml에 용해하고, 2-니트로-4-플루오로아닐린 5.5g을 에탄올 50ml에 용해한 액을 10℃에서 서서히 적가한 후 4시간 반응시킨 다음 여과하여 연황색의 결정 12g을 얻고 이 결정 10g을 DMF 40ml에 용해하고 탄산칼륨 4g을 가하여 50∼80℃에서 4시간 반응시킨 후 증류수 500ml에 분산하고 아세톤으로 세척 후 건조하면 융점 222∼224℃의 결정 8g을 얻고 이를 1 : 1 염산 30ml와 이소프로필알콜 35ml에서 50시간 환류시키고 냉각하여 여과한후 증류수로 세척한 다음 건조하여 융점 257∼262℃의 목적 화합물 6.2g을 얻었다(수율 : 61.9%).10 g of ethyl- (2,4,5-trifluorobenzoyl) -3-ethoxyacrylate was dissolved in 20 ml of ethanol, and 5.5 g of 2-nitro-4-fluoroaniline in 50 ml of ethanol was dissolved at 10 ° C. After slowly added dropwise, the mixture was reacted for 4 hours, filtered to obtain 12 g of pale yellow crystals. 10 g of the crystals were dissolved in 40 ml of DMF, 4 g of potassium carbonate was added and reacted at 50 to 80 ° C. for 4 hours, and then dispersed in 500 ml of distilled water and washed with acetone. After drying, 8 g of crystals having a melting point of 222 to 224 ° C. were obtained, which was refluxed in 30 ml of 1: 1 hydrochloric acid and 35 ml of isopropyl alcohol for 50 hours, cooled, filtered, washed with distilled water, and dried to give the desired compound at a melting point of 257 to 262 ° C. 6.2 g was obtained (yield: 61.9%).

1HNMR(DMSO-D6, TMS) : 7.25∼7.7(m, 1H), 7.75∼8.6(m, 4H), 9.1(s, 1H). 1 HNMR (DMSO-D 6 , TMS): 7.25 to 7.7 (m, 1H), 7.75 to 8.6 (m, 4H), 9.1 (s, 1H).

IR(KBr) : 3550∼3280(O-H), 3060(arom. C-H), 1730(C=O), 1530, 1340(NO2).IR (KBr): 3550-3280 (OH), 3060 (arom. CH), 1730 (C = O), 1530, 1340 (NO 2 ).

[실시예 2]Example 2

[1-(2-니트로-4-플루오로페닐)-6,7,8-트리플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산의 제조][Preparation of 1- (2-nitro-4-fluorophenyl) -6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid]

화합물 에틸-(2,3,4,5-테트라플루오로벤조일)-3-에톡시아크릴레이트 10g을 출발물질로 하여 상기 실시예 1과 동일한 방법으로 합성하여 융점 238∼240℃의 목적화합물 7.2g을 얻었다(수율 : 64.7%).Compound 10 g of compound ethyl- (2,3,4,5-tetrafluorobenzoyl) -3-ethoxyacrylate as a starting material was synthesized in the same manner as in Example 1, 7.2 g of the target compound at a melting point of 238 to 240 ° C. Obtained (yield: 64.7%).

1HNMR(DMSO-D6, TMS) : 7.7∼8.5(m, 4H), 9.0(s, 1H). 1 HNMR (DMSO-D 6 , TMS): 7.7 to 8.5 (m, 4H), 9.0 (s, 1H).

IR(KBr) : 3500∼3320(O-H), 3070(arom. C-H), 1720(C=O), 1540, 1360(NO2).IR (KBr): 3500 to 3320 (OH), 3070 (arom. CH), 1720 (C = O), 1540, 1360 (NO 2 ).

[실시예 3]Example 3

[1-(2-아미노-4-플루오로페닐)-6,7-플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산 및 1-(2-아미노-4-플루오로페닐)-6,7,8-트리플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산의 제조][1- (2-Amino-4-fluorophenyl) -6,7-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid and 1- (2-amino-4-fluoro Preparation of Rophenyl) -6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid]

1-(2-니트로-4-플루오로페닐)-6,7-디플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산 또는 1-(2-니트로-4-플루오로페닐)-6,7,8-트리플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산 10.0g을 진한 염산 45ml에 넣고 염화주석 33g을 가하여 상온에서 3시간 반응시킨 다음 증류수 500ml을 가하고 가성소다 용액으로 중화시킨 다음 여과하고 아세톤으로 세척한 후 DMF에 녹인다. 이 액에 적당량의 활성탄을 가하여 탈색한 후 여과하고 감압으로 DMF를 유리한 후 증류수에 분산시켜 여과한다. 결정을 에탄올로 세척한 수 건조하여 융점 228∼256℃의 목적화합물(I-a) 7.0∼7.4g을 얻었다(수율 : 78∼82%).1- (2-nitro-4-fluorophenyl) -6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid or 1- (2-nitro-4-fluoro 10.0 g of phenyl) -6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid was added to 45 ml of concentrated hydrochloric acid, and 33 g of tin chloride was added thereto to react at room temperature for 3 hours. Next, 500 ml of distilled water is added, neutralized with caustic soda solution, filtered, washed with acetone, and dissolved in DMF. An appropriate amount of activated carbon is added to this solution to decolorize the filtrate, and the resulting mixture is filtered under reduced pressure, and then dispersed in distilled water. The crystals were washed with ethanol and dried to obtain 7.0 to 7.4 g of the target compound (I-a) having a melting point of 228 to 256 占 폚 (yield: 78 to 82%).

i) 1-(2-아미노-4-플루오로페닐)-6,7-디플루오로-1,4-디하이드롤-4-옥소-3-퀴놀린 카르복실산i) 1- (2-amino-4-fluorophenyl) -6,7-difluoro-1,4-dihydrool-4-oxo-3-quinoline carboxylic acid

1HNMR(DMSO-D6, TMS) : 5.6∼5.95(bs, 2H), 6.3∼7.6(m, 4H), 8.1∼8.5(m, 1H), 8.6(s, 1H). 1 HNMR (DMSO-D 6 , TMS): 5.6 to 5.95 (bs, 2H), 6.3 to 7.6 (m, 4H), 8.1 to 8.5 (m, 1H), and 8.6 (s, 1H).

IR(KBr) : 3440∼3360(N-H), 3060(N-H), 3060(arom. C-H), 1718(C=O).IR (KBr): 3440-3360 (N-H), 3060 (N-H), 3060 (arom. C-H), 1718 (C = O).

ii) 1-(2-아미노-4-플루오로페닐)-6,7,8-트리플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산ii) 1- (2-amino-4-fluorophenyl) -6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid

1HNMR(DMSO-D6, TMS) : 5.6∼5.95(bs, 2H), 6.1∼6.8(m, 2H), 7.2∼7.6(m, 1H), 7.95∼8.05(m, 1H), 8.44(s, 1H). 1 HNMR (DMSO-D 6 , TMS): 5.6 to 5.95 (bs, 2H), 6.1 to 6.8 (m, 2H), 7.2 to 7.6 (m, 1H), 7.95 to 8.05 (m, 1H), 8.44 (s , 1H).

IR(KBr) : 3450, 3360(N-H), 3060(arom. C-H), 1720(C=O).IR (KBr): 3450, 3360 (N-H), 3060 (arom. C-H), 1720 (C = O).

[실시예 4]Example 4

[1-(2-아미노-4-플루오로페닐)-6-플루오로-7-피페라지닐-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산의 제조][Preparation of 1- (2-Amino-4-fluorophenyl) -6-fluoro-7-piperazinyl-1,4-dihydro-4-oxo-3-quinoline carboxylic acid]

화합물 1-(2-아미노-4-플루오로페닐)-6,7-디플루오로-1,4-디하이드로-4-옥소-3-퀴놀린 카르복실산 2g에 피리딘 15ml와 피페라진 8g을 가하여 60∼120℃으로 2∼4시간 반응 후 아세톤 30ml를 가하여 여과하고 결정을 소량의 DMF에 용해한 후 증류수에 분산하고 HCL로 중화하고 여과한 다음 메탄올과 에탄올로 세척하여 건조하여 융점 261∼264℃의 목적화합물 0.92g을 얻었다(수율 : 38.3%).To 2 g of compound 1- (2-amino-4-fluorophenyl) -6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 15 ml of pyridine and 8 g of piperazine were added. After reaction for 2 to 4 hours at 60-120 ° C, 30 ml of acetone was added and filtered. The crystals were dissolved in a small amount of DMF, dispersed in distilled water, neutralized with HCL, filtered, washed with methanol and ethanol and dried to obtain a melting point of 261-264 ° C. 0.92 g of the target compound was obtained (yield: 38.3%).

1HNMR(DMSO-D6, TMS) : 2.6∼3.1(m, 8H), 5.5∼5.8(bs, 2H), 6.2∼6.8(m, 3H), 7.1∼7.5(m, 1H), 7.7∼8.0(d, 1H), 8.4(s, 1H). 1 HNMR (DMSO-D 6 , TMS): 2.6 to 3.1 (m, 8H), 5.5 to 5.8 (bs, 2H), 6.2 to 6.8 (m, 3H), 7.1 to 7.5 (m, 1H), 7.7 to 8.0 (d, 1 H), 8.4 (s, 1 H).

IR(KBr) : 3440, 3365(N-H), 3065(arom. C-H), 1720(C=O).IR (KBr): 3440, 3365 (N-H), 3065 (arom. C-H), 1720 (C = O).

[실시예 5∼20][Examples 5-20]

실시예 5에서 20의 퀴놀린 카르볼실산 유도체들을 상기 실시예 4와 동일한 방법으로 제조하여 그 결과를 다음 표 1에 나타내었다.In Example 5, quinoline carbosilic acid derivatives of 20 were prepared in the same manner as in Example 4, and the results are shown in Table 1 below.

[표 1]TABLE 1

[실험예 1 : 최소억제농도(MIC)의 측정]Experimental Example 1 Measurement of Minimum Inhibition Concentration (MIC)

상기 실시예에서 제조한 화합물을 일본 화학요법확회 표준방법[Chemotherapy, 29(1), 976-77(1981)]에 따라 한천평판 희석법으로 최소억제농도(MIC)를 측정한 결과를 다음 표 2에 나타내었는바 그람 음성균을 물론 특히 그람 양성균에 대하여 우수한 항균력을나타내었다.The results of the measurement of the minimum inhibitory concentration (MIC) by the agar plate dilution method according to the standard method of chemotherapy expansion [Chemotherapy, 29 (1), 976-77 (1981)] of the compound prepared in Example It showed good antimicrobial activity against Gram-negative bacteria as well as Gram-positive bacteria.

[표 2-1]TABLE 2-1

* (주) Ofl : 오플록사신, C8=H : 일반식(I) 모핵의 8번 위치가 H인 경우.* Ofl: Ofloxacin, C 8 = H: Formula (I) When the 8th position of the parent nucleus is H.

[표 2-2]Table 2-2

* (주) C8=F : 일반식(I) 모핵의 8번 위치가 F인 경우.* (Note) C 8 = F: When position 8 of parent formula (I) is F.

(주)＜사용균주＞(Note) <used strain>

① 에스케리키아 콜라이(Escherichia Coli) BE 1186① Escherichia coli BE 1186

② 살모넬라 티피무리엄(Salmonella Typhimurium) ATCC 19430② Salmonella Typhimurium ATCC 19430

③ 스태필로코커스 에피더미디스(Staphylococcus Epidermidis) ATCC 12228③ Staphylococcus Epidermidis ATCC 12228

④ 스태필로코커스 아우레우스(Staphylococcus Aureus) ATCC 6538P④ Staphylococcus Aureus ATCC 6538P

⑤ 바실러스 섭틸리스(Bacillus Subitlis) ATCC 6633⑤ Bacillus Subitlis ATCC 6633

⑥ 바실러스 섭틸리스(Bacillus Subtilis) IFO 3158⑥ Bacillus Subtilis IFO 3158

[실험예 2 : 독성시험]Experimental Example 2: Toxicity Test

리치필드-윌콕슨(Litchfild-Wilcoxon)법에 따라 이들 화합물중 몇개의 화합물에 대하여 마우스를 대상으로 경구투여 하여 급성독성 실험을 한 결과 다음 표 3과 같이 독성이 매우 낮게 나타났다. 참고적으로 오플록사신의 경우는 5, 290㎎/㎏이며 노르플록사신의 경우는 4, 000㎎/㎏이므로 본 발명의 화합물 보다 독성이 높다.According to the Litchfild-Wilcoxon method, some of these compounds were orally administered to mice. As a result of the acute toxicity test, the toxicity was very low as shown in Table 3 below. For reference, 5,290 mg / kg in the case of oploxacin and 4,000 mg / kg in the case of norfloxacin is higher than the compound of the present invention.

[표 3]TABLE 3

Claims (2)

다음 일반식(I)로 표시되는 신규한 퀴놀론 카르복실산 유도체와 그 염.The novel quinolone carboxylic acid derivative represented by the following general formula (I) and its salt. 상기식에서, R1은 2-아미노-4-플루오로페닐기이고, R2는 플루오로원자, 피페라진, 3-메틸피페라진, 4-메틸피페라진, 모포린, 피롤리딘, 3-하리드록시피롤리딘, 피페리딘, 1,2,3,6-테트라하이드로피리딘 또는 4-메틸피페리딘이고, R3는 수소 또는 할로겐 원자이다.Wherein R 1 is a 2-amino-4-fluorophenyl group, R 2 is a fluoro atom, piperazine, 3-methylpiperazine, 4-methylpiperazine, morpholine, pyrrolidine, 3-haridlock Cypyrrolidine, piperidine, 1,2,3,6-tetrahydropyridine or 4-methylpiperidine, and R 3 is hydrogen or a halogen atom. 다음 일반식(II)로 표시되는 에틸-(2,3,4,5-테트라플루오로벤조일)-3-에톡시아크릴레이트 또는 다음 일반식(III)으로 표시되는 에틸-(5-플루오로-2,4-디할로벤조일)-3-에톡시아크릴레이트에 2-니트로-4-플루오로아닐린을 알콜 용매하에서 반응시킨 후 다시 디메틸포름아미드 용매하에서 탄산칼륨과 반응시켜 폐환하고 이를 산가수분해한 후 염화주석 또는 주석으로 환원하여 다음 일반식(I)로 표시되는 신규한 퀴놀론 카르복실산 유도체를 제조하는 방법.Ethyl- (2,3,4,5-tetrafluorobenzoyl) -3-ethoxyacrylate represented by the following general formula (II) or ethyl- (5-fluoro- represented by the following general formula (III) 2-nitro-4-fluoroaniline was reacted with 2,4-dihalobenzoyl) -3-ethoxyacrylate in an alcoholic solvent, and then reacted with potassium carbonate in a dimethylformamide solvent to ring-close and acid hydrolyzed it. After the reduction to tin chloride or tin to prepare a novel quinolone carboxylic acid derivative represented by the following general formula (I). 상기식에서, X는 할로겐원자이고, R1, R2및 R3는 상기 청구범위 제1항에서 정의한 바와 같다.Wherein X is a halogen atom and R 1 , R 2 and R 3 are as defined in claim 1 above.
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KR100589429B1 (en) * 2004-08-31 2006-06-14 한국화학연구원 Process for preparation of quinolone derivatives substituted by aminopyridyl moieties at n-1 site

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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