KR870001693B1 - Process for preparing 1,4-dihydro-4-oxo-naphthyridine derivatives - Google Patents

Process for preparing 1,4-dihydro-4-oxo-naphthyridine derivatives Download PDF

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KR870001693B1
KR870001693B1 KR8502822A KR850002822A KR870001693B1 KR 870001693 B1 KR870001693 B1 KR 870001693B1 KR 8502822 A KR8502822 A KR 8502822A KR 850002822 A KR850002822 A KR 850002822A KR 870001693 B1 KR870001693 B1 KR 870001693B1
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oxo
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dihydro
naphthyridine
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히로가주 나리따
요시노리 고니시
준 니따
히데요시 나가끼
이사오 기따야마
요리꼬 고바야시
미가꼬 시나가와
야수오 와따나베
아끼라 요쭈지
신자부로 미나미
이사무 사이가와
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나까노 다다오
도야마 가가꾸 고오교오 가부시끼 가이샤
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with heteroatoms or with carbon atoms having three bonds to hetero atoms, with at the most one to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61Halogen atoms or nitro radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with heteroatoms or with carbon atoms having three bonds to hetero atoms, with at the most one to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72Nitrogen atoms
    • C07D213/74Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic 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
    • C07D471/02Heterocyclic 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
    • C07D471/04Ortho-condensed systems
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of products other than chlorine, adipic acid, caprolactam, or chlorodifluoromethane, e.g. bulk or fine chemicals or pharmaceuticals
    • Y02P20/55Synthetic design, e.g. reducing the use of auxiliary or protecting groups

Abstract

The title compds. (I; R1=H; R2=F, C1-4 alkyl-substd. ph; R3=1 - pyrrolidinyl or 1-piperazinyl; R1a=carboxyl-protecting gp.; R2a= substd. ph; R3a=C1-4 alkyl or C1-4 alkylamino gp.-substd. 1pyrrolidinyl or 1-piperazinyl) are prepd. by decycling (II), followed by eliminating its protecting gp.. Antibacterials with good activity against-positive and gram-negative organisms, particularly antibiotic-resistant strains. Results in vitro tests are given in the specification.

Description

1,4-디하이드로-4-옥소나프티리딘 유도체의 제조방법 Production method of 1,4-dihydro-4-oxo-naphthyridine derivative

본 발명은 일반식(Ⅰ)의 1,4-디하이드로-4-옥소나프티리딘 유도체 및 그의 염의 제조방법에 관한 것이다. The present invention relates to 1,4-dihydro-4-oxo-naphthyridine derivative represented by the general formula (Ⅰ), and a method of producing a salt.

Figure kpo00001

상기식에서, R 1 은 수소원자 또는 카복실-보호 그룹을 나타내고, Wherein, R 1 is a hydrogen atom or a carboxyl-protecting group represents,

R 2 는 치환된 또는 비치환된 아릴 그룹을 나타내며, R 2 represents a substituted or unsubstituted aryl group,

R 3 는 할로겐 원자 또는 치환된 또는 비치환된 환상의 아미노 그룹을 나타낸다. R 3 represents an amino group, a halogen atom or a substituted or unsubstituted cyclic.

본 발명은 1위치에 치환된 또는 비치환된 아릴그룹을 갖고 7위치에 할로겐원자 또는 치환된 또는 비치환된 환상의 아미노 그룹을 갖는 신규한 1, 4-디하이드로-4-옥소-나프티리딘 유도체, 그의 제조방법및 그의 살균제로서의 용도에 관한 것이다. The present invention has a substituted or unsubstituted aryl group in the 1 position to a new position 7 with an amino group, a halogen atom or a substituted or unsubstituted cyclic 1, 4-dihydro-4-oxo-naphthyridine derivative relates to a method of manufacturing the same, and their use as fungicides.

날리딕스산, 피로미드산, 피페미드산등은 이제까지 합성 살균제로서 광범위하게 사용되어 왔다. Throwing away Dix acid, fatigue acid imide, l Mead acid, and the like have been so far widely used as synthetic fungicides. 그러나 이들 제제의 어느 것도 난치성 질환인 녹농균 및 그람양성 세균의 감염에는 만족할만한 치료적 효과를 가져오지 못했다. However, it did not get a satisfactory therapeutic effects none incurable disease and Pseudomonas aeruginosa infections of gram-positive bacteria of these agents. 그러므로, 종래의 합성 살균제의 대체제로서 여러가지의 피리돈 카복실산 유형의 화합물, 예를들어, 1-에틸-6-플루오로-1, 4-디하이드로-4-옥소-7-(1-피페라지닐)-3-퀴놀린카복실산(노르플록사신)등이 개발되고 있다. Thus, the compounds of the various pyridone carboxylic acid type as a substitute for conventional synthetic fungicides, for example, 1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-7- (1-piperazinyl ) it has been developed, such as 3-quinolinecarboxylic acid (Nord floc reaper). 이들 화합물은 녹농균을 포함한 여러 종류의 그람음성 세균에 대해서는 살균력이 뛰어나지만, 그람 양성 세균에 대해서는 살균력이 신통하지 않다. These compounds while very sterilization for several types of Gram-negative bacteria, including Pseudomonas aeruginosa, which is not germicidal the sintong for gram-positive bacteria. 따라서, 그람음성 세균뿐 아니라 그람양성 세균에도 유효한 광범위한 살균력을 지닌 합성살균제의 개발이 요구되어 왔다. Therefore, even in Gram-positive bacteria as well as Gram-negative bacteria it has been desired the development of synthetic fungicides with a broad range of effective sterilization.

이러한 상황하에서, 본 발명의 발명가들은, 광범위한 연구끝에, 신규의 1, 4-디하이드로-4-옥소-나프티리딘 유도체 및 그의 염이 상기에 기술한 문제들을 해결할 수 있음을 발견하였다. Under these circumstances, the inventors of the present invention, extensive studies at the end, 1,4-dihydro-4-oxo-a new-found that the naphthyridine derivatives and salts thereof that can solve the problems described above.

본 발명의 목적은 우수한 특성, 예를들면, 그람 양성 및 그람음성 세균, 특히 항생제 내성 세균에 대해서 강력한 살균 활성을 지니고, 경구 또는 비경구적으로 투여하였을때 혈액중에서 고 농도로 유지되며, 높은 안전성을 지닌 신규의 1, 4-디하이드로-4-옥소나프티리딘 유도체 및 그의 염을 제공하는데 있다. Object of the present invention can be maintained in excellent properties, for example, Gram-positive and Gram-negative bacteria, in particular, have a strong bactericidal activity against antibiotic-resistant bacteria, the concentration and in blood when administered orally or parenterally, a high level of safety having to provide a 1, 4-dihydro-4-oxo-naphthyridine derivative and its salt of the novel.

본 발명의 다른 목적은 신규의 1, 4-디하이드로-4-옥소나프티리딘 유도체 및 그의 염을 제조하는 방법을 제공하는데 있다. Another object of the present invention to provide a process for preparing a 1, 4-dihydro-4-oxo-naphthyridine derivative and its salt of the novel.

본 발명의 또 다른 복적은 세균등의 감염을 치료하는데 유용하고 신규의 1, 4-디하이드로-4-옥소나프티리딘 유도체 또는 그의 염을 함유하는 살균제를 제공하는데 있다. Another recursively of the present invention is to provide a fungicide which is useful to contain 1, 4-dihydro-4-oxo-naphthyridine derivative or a salt of a novel in the treatment of infections, such as bacteria. 본 발명은 아래에 상세히 설명된다. The invention is described in detail below.

일반식(Ⅰ)의 화합물 또는 그의 염에 있어서, R 1 의 카복실-보호 그룹에는, 예를들어, 촉매적 환원, 화학적 환원 또는 온화한 조건하에서의 다른 처리에 의해 제거될 수 있는 에스테르-형성 그룹 ; In the compounds of formula (Ⅰ), R 1 of the carboxyl-protecting group includes, for example, catalytic reduction, chemical reduction, or an ester which can be removed by different treatment under mild conditions-forming group; 생체내에서 쉽게 제거될 수 있는 에스테르-형성 그룹 ; Ester, which may be easily removed in a living body-forming group; 물 또는 알코올 처리에 의해 쉽게 제거될 수 있는 유기 실릴함유 그룹, 유기인-함유 그룹 및 유기 주석-함유 그룹 ; In an organic or water can be easily removed by alcohol treatment silyl group-containing, organophosphorus-containing groups and organic tin-containing group; 및 다른 여러가지 공지 에스테르 형성 그룹이 포함된다. And it will include various other well-known ester forming groups.

이들 카복실-보호 그룹중에서, 바람직한 보호그룹에는, 예를들어, 일본국 특허원 공개공보 제80,665/84에 기술된 카복실-보호 그룹이 포함된다. In the protection group, the preferred protecting group, for example, Japanese Laid-carboxylated described in Patent Application Publication No. 80 665/84 - - These include carboxyl protecting group.

R 2 의 아릴 그룹에는, 예를들어, 페닐, 나프틸등이 포함된다. Is an aryl group of R 2, for example, and the like phenyl, naphthyl. 아릴 그룹은 할로겐원자(예, 불소, 염소, 브롬, 요오드등) ; Aryl groups are halogen atoms (e.g., fluorine, chlorine, bromine, iodine and the like); 알킬 그룹(예, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, 2급-부틸, 3급-부틸, 펜틸, 헥실, 헵틸, 옥틸 등과 같은 직쇄 또는 축쇄 C 1 -C 10 알킬그룹) ; Alkyl group (e.g., methyl, ethyl, n- propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, such as linear or chukswae, pentyl, hexyl, heptyl, octyl, C 1 -C 10 alkyl group); 알콕시그룹, (예, 메톡시, 에톡시, n-프로폭시, 이소프로폭시, n-부톡시, 이소 부톡시, 2급-부톡시, 3급-부톡시, 펜틸옥시, 헥실옥시, 헵틸옥시, 옥틸옥시등과 같은 직쇄 또는 분지된 C 1 -C 10 알콕시그룹) ; Alkoxy group (e.g., methoxy, ethoxy, n- propoxy, isopropoxy, n- butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy oxy, octyl, straight-chain or branched C 1 -C 10 alkoxy groups, such as oxy, etc.); 시아노 그룹 ; Cyano group; 아미노 그룹 ; Amino group; 아실아미노 그룹(예, 포르밀아미노, 아세틸아미노, 프로피오닐아미노, 부티릴아미노등과 같은 C 1 -C 4 아실아미노) ; Acylamino group (e.g., formylamino, acetylamino, propionylamino, C 1 -C 4 acylamino, such as butyrylamino, etc.); 및 트리할로게노알킬그룹(예, 트리플루오로메틸, 트리클로로메틸등과 같은 트리할로게노-C 1 -C 4 -알킬그룹)으로 이루어진 그룹으로부터 선택된 하나이상의 치환체에 의해 치환될 수 있다. It may be substituted by one or more substituents selected from the group consisting of - (alkyl group methyl, trichloromethyl trihaloalkyl such as methyl halogeno -C 1 -C 4 as example, trifluoromethyl), and a halogeno-alkyl group to the tree.

또한, R 3 의 할로겐에는, 예를들어, 불소, 염소 및 브롬이 포함된다. Further, R 3 of a halogen, for instance, include fluorine, chlorine and bromine. R 3 의 환상 아미노 그룹은 적어도 하나의 질소원자를 가지며 추가로 환을 이루는 헤테로 원자로서 하나이상의 산소 원자를 가질 수 있고, 1-피롤리디닐, 피페리디노, 1-피페라지닐, 모폴리노등과 같은 5-또는 6-원 환의 아미노 그룹이 포함된다. Cyclic amino group in R 3 may have one or more oxygen atoms as the hetero atom forming the ring further having at least one nitrogen atom, 1-pyrrolidinyl, piperidino, 1-piperazinyl, morpholino include 5- or 6-membered ring, such as amino groups. 이 환상의 아미노 그룹은 알킬그룹(예, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, 2급-부틸 및 3급-부틸과 같은 직쇄 또는 측쇄된 C 2 -C 4 알킬그룹) ; Amino group of a cyclic alkyl group (e.g., methyl, ethyl, n- propyl, isopropyl, n- butyl, isobutyl, sec-butyl and tert-butyl and like straight or branched chain with C 2 -C 4 alkyl group) ; 아미노 그룹 ; Amino group; 아미노알킬그룹(예, 아미노메틸, 2-아미노에틸, 3-아미노프로필 등과 같은 아미노-C 1 -C 4 알킬그룹) ; Aminoalkyl group (e.g., amino -C 1 -C 4 alkyl group such as aminomethyl, 2-aminoethyl, 3-aminopropyl); 하이드록시알킬 그룹(예, 하이드록시메틸, 2-하이드록시메틸, 3-하이드록시프로필등과 같은 하이드록시-C 1 -C 4 알킬그룹) ; Hydroxyalkyl group (e.g., hydroxymethyl, hydroxy -C 1 -C 4 alkyl groups such as, 2-hydroxymethyl-3-hydroxy-propyl); 하이드록실그룹 ; A hydroxyl group; 알케닐 그룹(예, 비닐, 알릴등과 같은 C 2 -C 4 알케닐 그룹) ; Alkenyl group (C 2 -C 4 alkenyl group, such as for example, vinyl, allyl and the like); 아실 그룹(예, 포르밀, 아세틸, 프로피오닐, 부티릴등과 같은 C 1 -C 4 아실그룹) ; Acyl group (e.g., formyl, acetyl, propionyl, C 1 -C 4 acyl groups such as butyryl, and the like); 알킬아미노 그룹(예, 메틸아미노, 에틸아미노, n-프로필아미노, 이소프로필아미노등과 같은 C 1 -C 4 알킬아미노 그룹) ; Alkylamino group (e.g., methylamino, ethylamino, n- propylamino, isopropyl-C 1 -C 4 alkyl-amino groups such as amino, etc.); 디알킬아미노, 그룹(예 : 디메틸아미노, 디에틸아미노, 디-n-프로필아미노, 메틸에틸아미노등과 같은 디-C 1 -C 4 알킬아미노 그룹) ; A dialkylamino group (e.g., dimethylamino, diethylamino, di -n- propylamino, di -C 1 -C 4 alkylamino groups, such as methyl-ethyl-amino); 시아노 그룹 ; Cyano group; 옥소 그룹 ; Oxo group; 아르알킬아미노그룹(예, 벤질아미노, 펜에틸아미노등과 같은 아르-C 1 -C 4 알킬아미노 그룹) ; Aralkyl-amino group (e.g., benzylamino, are -C 1 -C 4 alkylamino groups, such as such as phenethyl-amino); 아실아미노 그룹(예, 아세틸아미노, 프로피오닐아미노, 부티릴아미노등과 같은 C 1 -C 4 아실아미노 그룹) ; Acylamino group (e.g., acetylamino, propionylamino, C 1 -C 4 acylamino group, such as a butyrylamino, etc.); 알콕시카보닐 그룹(예, 메톡시 카보닐, 아톡시가보닐, n-프로폭시카보닐, 이소프로폭시 카보닐과 같은 C 1 -C 4 알콕시카보닐 그룹) ; Alkoxycarbonyl group (for example, methoxycarbonyl, ethoxy ah go carbonyl, n- propoxy carbonyl, isopropoxy-carbonyl, such as carbonyl C 1 -C 4 alkoxycarbonyl group); 및 N-아실-N-알킬아미노 그룹, (예, 알킬아미노 그룹 부위의 질소 원자가 아세틸, 프로피오닐, 부티릴등과 같은 C 1 -C 4 아실그룹에 의해 치환된 N-아실-N-알킬아미노그룹)으로 이루어진 그룹으로부터 선택된 하나이상의 치환체에 의해 치환될 수 있다. And N- acyl -N- alkylamino groups, (e.g., alkyl-amino group site of the nitrogen atoms are acetyl, propionyl, butyryl, etc., and C 1 -C 4 alkyl-substituted N- acyl -N- by an acyl amino group such as It may be substituted by one or more substituents selected from the group consisting of a group).

일반식(Ⅰ)의 화합물중에서, R 2 가 불소-치환된 페닐 그룹을 나타내고 R 3 는 치환된 또는 비치환된 1-피롤리디닐 또는 1-피페라지닐 그룹을 나타내는 화합물이 바람직하며, R 2 가 2, 4-디플루오로페닐 그룹이고 R 3 가 3-아미노-1-피롤리디닐 그룹인 화합물이 더 바람직하다. Among the compounds represented by the general formula (Ⅰ), R 2 is a fluorine-represents a substituted phenyl group, R 3 is preferably a substituted or unsubstituted 1-pyrrolidinyl group or compound that possess 1-piperazinyl, and, R 2 2, the 4-difluorophenyl group and R 3 is 3-amino-1-pyrrolidinyl group, the compound is more preferred.

일반식(Ⅰ)의 화합물의 염에는 아미노 그룹등과 같은 염기성 그룹, 및 카복실 그룹등과 같은 산성 그룹에서의 통상의 염이 포함된다. The salts of the compounds of general formula (Ⅰ) include conventional salts at acidic groups such as such as a basic group, and carboxyl group, such as such as an amino group. 염기성 그룹에서의 염에는, 예를들어, 염산, 황산등과 같은 무기산과의 염 옥살산, 포름산, 트리클로로아세트산, 트리플루오로 아세트산등과 같은 유기 카복실산과의 염 ; Salts in the basic groups include, for example, salts with an organic acid such as hydrochloric acid, a salt with an inorganic acid such as sulfuric acid, oxalic acid, formic acid, trichloroacetic acid, and trifluoroacetic acid; 메탄 설폰산, P-톨루엔설폰산, 나프탈렌설폰산등과 같은 설폰산과의 염이 포함된다. Methanesulfonic acid, include salts of sulfonic acid such as P- toluenesulfonic acid, naphthalenesulfonic acid. 산성 그룹에서의 염에는, 예를들어, 나트륨, 칼륨 등과 같은 알카리 금속과의 염 ; Salts at acidic groups include, for example, salts with alkali metals such as sodium, potassium; 칼슘, 마그네슘등과 같은 알카리 토금속과의 염 ; Salts with alkaline earth metals such as calcium, magnesium and the like; 암모늄 염 ; Ammonium salt; 및 프로카인, 디벤질아민, N-벤질-β-펜에틸아민, 1-에펜아민, N, N-디벤질에틸렌디아민, 트리에틸아민, 트리메틸아민, 트리부틸아민, 피리딘, N,N-디메틸-아닐린, N-메틸피페리딘, N-메틸모폴린, 디에틸아민, 디사이클로헥실아민등과 같은 질소-함유염기와의 염이 포함된다. And procaine, dibenzylamine, N- benzyl -β- phenethylamine, 1-Epen amine, N, N- dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, N, N- dimethyl - it includes a salt with a base containing - aniline, N- methylpiperidine, N- methylmorpholine, diethylamine, di-cyclohexylamine, such as nitrogen or the like.

일반식(Ⅰ)의 화합물 및 그의 염이 이성체(예, 광학 이성체, 기하 이성체, 토오토머등)를 가지면, 본 발명에는 그의 이성체, 결정형 및 수화물 모두가 포함된다. The compound and its salt represented by the general formula (Ⅰ) Having an isomer (e.g., optical isomers, and geometric isomers, tautomers), the present invention includes all their isomers, crystal forms and hydrates thereof.

살균활성 및 급성 독성은 본 발명의 통상의 화합물을 참고하여 설명한다. Fungicidal activity and acute toxicity will be described with reference to the normal of the compounds of the present invention.

[표 1] TABLE 1

Figure kpo00002

Figure kpo00003

Figure kpo00004

1. 살균 활성 1. fungicidal activity

[실험 방법] [Experimental method]

일본국의 화학요법[(chemotherapy, 29(1), 76-79(1981)]의 표준방법에 따라, 37℃의 하트 인퓨전 육즙(Heart Infusion broth)(아이껜 가가꾸제품)에서 20시간동안 배양하여 얻은 세균용액을 약품을 함유하는 하트 인퓨전 한천상에 접종하고 37℃에서 20시간동안 배양시킨 후에, 세균의 증식을 관찰하여 세균의 증식이 억제되는 최소 농도를 MIC(㎍/ml)로서 측정한다. 접종된 세균의 양은 10 4 세포수/평판(10 6 세포수/ml)이었다. 다음 실험 화합물의 MIC값을 표 1에 나타낸다. Cultured for 20 hours in the chemotherapy of Japan [(chemotherapy, 29 (1), 76-79 (1981)], Heart Infusion broth (Heart Infusion broth for 37 ℃) according to standard procedures of (a child kken Chemical Industries, Ltd.) and measures the minimum concentration that is inoculated into a Heart Infusion agar containing a drug a bacterial solution obtained, and after incubation at 37 ℃ for 20 hours, by observing the growth of bacteria the bacterial growth inhibited as MIC (㎍ / ml) the amount of the inoculated bacterium 10 4 cells / plate was (10 6 cells / ml). shows the MIC values of the compound are shown in Table 1. the following experiments.

표 1에 쓰여진 기호는 다음 의미를 갖는다 : Written symbols in Table 1 have the following meanings:

* 1 : 페니실리나제-생성 세균, * 1: Penicillium xylanase-producing bacteria,

* 2 : 세파로스포리나제-생성 세균, * 2: The Sepharose sports Lena-producing bacteria,

* 3 : 접종 크기 : 10 8 세포수/ml * 3: Vaccination Size: 10 8 cells can / ml

Me : 메틸 그룹, Me: methyl group,

Et : 에틸 그룹, Et: ethyl group,

n-Pr : n-프로필 그룹 n-Pr: n- propyl group

i-Pr : 이소프로필 그룹 i-Pr: isopropyl group,

2. 급성 독성 2. Acute toxicity

마우스(ICR균종, 수컷, 체중 : 18내지 24g)에 상기에 언급한 바와같이 제5, 6및 12번의 실험화합물을 정맥주사하여 얻어지는 LD 50 값은 200mg/kg이상이었다. Mouse (ICR species, male, weight: 18 to 24g) in a claim 5, 6, and LD 50 values obtained by a single intravenous injection of test compound 12, as referred to above was more than 200mg / kg.

본 발명 화합물을 제조하는 방법은 아래에 설명되어 있다. Process for preparing a compound of the present invention is described below.

본 발명의 화합물은, 예를들어, 다음 제조 루트에 따라 제조될 수 있다 : The compounds of the present invention, for example, be prepared according to the following production route:

Figure kpo00005

Figure kpo00006

상기식에서, Wherein

R 1a 는 R 1 에서와 같은 카복시-보호 그룹을 나타내며 ; R 1a is a carboxy, such as in R 1 - represents a protecting group;

R 3a 는 R 3 에서와 같은 할로겐 원자를 나타내고 ; R 3a represents a halogen atom, such as in R 3;

R 3b 는 R 3 에서와 같은 치환된 또는 비치환된 환상의 아미노 그룹을 나타내며 ; R 3b represents a substituted or unsubstituted amino group of a cyclic ring as in R 3;

R 1 및 R 2 는 상기에서와 같이 정의된다. R 1 and R 2 are defined as above.

일반식(Ⅰa), (Ⅰb), (Ⅲ), (Ⅳ) 및 (Ⅴ)의 화합물의 염에는 일반식(Ⅰ)화합물의 염과 동일한 염들이 포함된다. The salts of the compounds of general formula (Ⅰa), (Ⅰb), (Ⅲ), (Ⅳ) and (Ⅴ) includes, the same salt with a salt of formula (Ⅰ) compound.

(ⅰ) 일반식(Ⅲ)의 화합물 또는 그의 염 또는 일반식(Ⅴ)의 화합물 또는 그의 염은, 각각, 일반식(Ⅱ)의 화합물 또는 일반식(Ⅳ)의 화합물 또는 그의 염을 N, N-디메틸포름아미도-디메틸아세탈, N, N-디메틸포름아미도-디에틸아세탈 등과 같은 아세탈과 반응시키고 이어서 일반식 R 2 -NH 2 (이때, R 2 는 상기에서와 같이 정의된다)의 아민과 반응시킴으로써 얻어진다. (Ⅰ) Compounds of the general formula (Ⅲ) Compounds or formula (Ⅴ) of, respectively, a compound of formula (Ⅱ) compound or Formula (Ⅳ) of N, N -dimethyl formamido-dimethyl acetal, N, N- dimethyl-formamido-diethyl acetal and the acetal reaction and the like followed by the general formula R 2 -NH 2 amine, (wherein, R 2 is defined as above) and it is obtained by the reaction.

상기 반응에 사용되는 용매는 반응에 불활성인 용매일 수 있고, 한정되어 있는 것은 아니지만, 벤젠, 톨루엔, 크실렌등과 같은 방향족 탄화수소 ; The solvent used in this reaction may be every day for as it is inactive in this reaction, it is limited, but aromatic hydrocarbons such as benzene, toluene, xylene and the like; 디옥산, 테트라하이드로푸란, 아니솔, 디에틸렌 글리콜 디메틸 에테르등과 같은 에테르 ; Dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether and like ethers; 메틸렌클로라이드, 클로로포름, 디클로로에탄등과 같은 할로겐화 탄화수소 ; Halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; N, N-디메틸포름아미드, N, N-디메틸아세트 아미드 등과 같은 아민 ; Amines such as N, N- dimethylformamide, N, N- dimethylacetamide; 디메틸설폭사이드 등과 같은 설폭사이드 등이 포함되고, 이들 용매는 단독으로 또는 두개이상이 혼합되어 사용될 수 있다. Dimethyl sulfoxide and the like, such as sulfoxide, and these solvents can be used alone or in mixture of two or more. 사용되는 아세탈의 양은 일반식(Ⅱ)의 화합물 또는 일반식(Ⅳ)의 화합물 또는 그의 염의 몰당 1몰 이상, 특히 약 1.0내지 1.3몰이 바람직하다. The compounds of the amount of the used acetal formula (Ⅱ) compound or Formula (Ⅳ) or a salt thereof per mole of at least 1 mol, and particularly preferably about 1.0 to 1.3 moles. 이 반응은 통상적으로는 0내지 100℃, 바람직하게는 50내지 80℃에서, 통상적으로는 20분 내지 50시간, 바람직하게는 1내지 3시간동안 수행한다. This reaction is typically from 0 to 100 ℃, preferably from 50 to 80 ℃, typically is carried out for 20 minutes to 50 hours, preferably 1 to 3 hours. 아민은 일반식(Ⅱ)의 화합물 또는 일반식(Ⅳ)이 화합물 또는 그의 염의 몰당 1몰 이상의 양이 사용된다. Amine is a compound or a positive formula (Ⅳ) The compound or a salt thereof per mole of at least one mole of the formula (Ⅱ) is used. 이 반응은 통상적으로는 0°내지 100℃, 바람직하게는 10°내지 60℃에서, 통상적으로는 20분 내지 30시간, 바람직하게는 1내지 5시간동안 수행한다. This reaction is usually carried out at 0 ° to 100 ℃, preferably from 10 ° to 60 ℃, typically for 20 minutes to 30 hours, preferably 1 to 5 hours.

다른 방법으로서, 일반식(Ⅱ)의 화합물 또는 일반식(Ⅳ)의 화합물 또는 그의 염을 아세트산 무수물의 존재하에서 에틸 오르토포르메이트 또는 메틸 오르토 포르메이트와 반응시키고, 이어서 일반식 R 2 -NH 2 의 아민 또는 그의 염과 반응시킴으로써 각각 일반식(Ⅲ)의 화합물 또는 그의 염 또는 일반식(Ⅴ)의 화합물 또는 그의 염을 수득 할 수 있다. Alternatively, compounds of general formula (Ⅱ) compound or Formula (Ⅳ) in the presence of acetic anhydride, ethyl orthoformate or methyl orthoformate and the reaction was followed by the general formula R 2 -NH 2 by reaction with an amine or a salt thereof can be obtained compounds of general formula (ⅲ) compounds or formula (ⅴ), respectively.

(ⅱ) 일반식(Ⅲ)의 화합물 또는 그의 염 또는 일반식(Ⅴ)의 화합물 또는 그의 염을 염기의 존재하에 또는 염기의 부재하에서 폐환화시켜(바람직하게는 가열시켜), 일반식(Ⅰa)의 화합물 또는 그의 염 또는 일반식(Ⅰb)의 화합물 또는 그의 염을, 각각 수득한다. (Ⅱ) to cyclize the compounds of the general formula (Ⅲ) Compounds or formula (Ⅴ) of under or absence of a base in the presence of a base (preferably by heating), the general formula (Ⅰa) the yield of the compound or compounds of the general formula or a salt thereof (ⅰb), respectively.

이 반응에 사용되는 용매는 반응에 불활성인 용매일 수 있고, 한정되어 있지는 않지만, 예를들어, N, N-디메틸 포름아마이드, N, N-디메틸아세트 아마이드등과 같은 아마이드 ; The solvent used in this reaction may be every day for as it is inactive in this reaction, although not limited, for example, amides such as N, N- dimethylformamide, N, N- dimethyl-acetamide; 디옥산, 아니솔, 디에틸렌 글리콜 디메틸 에테르등과 같은 에테르 ; Dioxane, anisole, diethylene glycol dimethyl ether and like ethers; 디메틸설폭사이드등과 같은 설폭사이드등이 포함된다. And the like sulfoxides, such as dimethyl sulfoxide. 이들 용매는 단독으로 또는 두개 이상이 혼합되어 사용될 수 있다. These solvents may be used alone or in combinations of two or more of a mixture. 염기에는, 예를들어, 탄산 수소 나트륨, 탄산칼륨, 칼륨 3급-부톡사이드, 수소화나트륨 등이 포함된다. Bases include, for example, sodium bicarbonate, potassium carbonate, potassium tert-butoxide, and the like, and sodium hydride. 사용되는 염기의 양은 일반식(Ⅲ) 또는 (Ⅴ)의 화합물 또는 그의 염의 몰당 0.5내지 5몰이 바람직하다. The amount of the base to be used is preferably the general formula (Ⅲ), or a compound or a salt thereof per mole of from 0.5 to 5 moles of (Ⅴ). 반응은 통상적으로는 20내지 160℃, 바람직하게는 100내지 150℃에서, 통상으로는 5분 내지 30시간, 바람직하게는 5분내지 1시간동안 수행한다 The reaction is typically carried out at from 20 to 160 ℃, preferably 100 to 150 ℃, as is conventional for 5 minutes to 30 hours, preferably 5 minutes to 1 hour

(ⅲ) 일반식(Ⅱ)의 화합물, 일반식(Ⅲ)의 화합물 또는 그의 염, 또는 일반식(Ⅰa)의 화합물 또는 그의 염, 일반식, R 3b -H(이때, R 3b 는 상기와 같이 정의된다)의 환상 아민 또는 그의 염과 반응시킴으로써, 일반식(Ⅳ)의 화합물 또는 그의 염, 일반식(Ⅴ)의 화합물 또는 그의 염, 일반식(Ⅰb)의 화합물 또는 그의 염을 각각 수독한다. (Ⅲ) compound represented by the general formula (Ⅱ), formula (Ⅲ) Compounds of the, or the general formula or a salt thereof of (Ⅰa), the general formula, R 3b -H (wherein, R 3b are as described above by definition it is) of the cyclic amine or a salt thereof and a reaction, sudok compounds of general formula (ⅳ) or a salt thereof, a compound represented by the general formula (ⅴ) or a salt thereof represented by the general formula (ⅰb), respectively.

이 반응에 사용되는 용매는 반응에 불활성인 용매일 수 있고, 한정되어 있지는 않지만, 벤젠, 톨루엔, 크실렌 등과 같은 방향족 탄화수소 ; The solvent used in this reaction may be every day for as it is inactive in this reaction, although not limited to, aromatic hydrocarbons such as benzene, toluene and xylene; 디옥산, 테트라 하이드로푸란, 아니솔, 디에틸렌 글리콜 디에틸 에테르등과 같은 에테르 ; Dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, ethers such as; 메틸렌클로라이드, 콜로로포름, 디클로로 에탄등과 같은 할로겐화 탄화수소 ; Halogenated hydrocarbons such as methylene chloride, to form Colonna, dichloroethane and the like; N, N-디메틸포름 아마이드, N, N-디메틸아세트아마이드등과 같은 니트릴등이 포함되며, 이들 용매는 단독으로 또는 두개이상이 혼합되어 사용될 수 있다. N, N- dimethylformamide, and the like containing a nitrile, such as such as N, N- dimethyl acetamide, these solvents can be used alone or in mixture of two or more. 사용되는 환상 아민 또는 그의 염의 양은 일반식(Ⅱ)의 화합물, 일반식(Ⅲ)의 화합물 또는 그의 염, 또는 일반식(Ⅰa)의 화합물 또는 그의 염 1몰당 바람직하게는 과량, 더 바람직하게는 2내지 5몰이다. Use cyclic amines or compounds of the amount of a salt thereof formula (Ⅱ), formula (Ⅲ) Compounds of the, or the general formula (Ⅰa) or a salt thereof per mole and preferably an excess of, and more preferably being 2 to 5 mol. 사용되는 환상의 아민의 양이 약 1내지 1.3몰이면, 산 결합제는 일반식(Ⅱ)의 화합물, 일반식(Ⅲ)의 화합물 또는 그의 염, 또는 일반식(Ⅰa)의 화합물 또는 그의 염, 몰당 1몰을 사용하면 충분하다. When the amount of the amine used cyclic about 1 to 1.3 mol, an acid binder is a compound represented by the general formula (Ⅱ), formula (Ⅲ) Compounds of the, or the general formula or a salt thereof of (Ⅰa), per mole of it is sufficient to use one mole. 산 결합제에는 트리에틸아민, 1, 8-디아자비 사이클로 [5, 4, 0]운덱-7-엔(DBU), 칼륨 3급-부톡사이드, 탄산칼륨, 탄산나트륨, 수소화나트륨 등과 같은 유기 또는 무기 염기가 포함된다. Acid binding agent is triethylamine, 1, 8-diazabicyclo [5, 4, 0] undec-7-ene (DBU), potassium tert-butoxide, an organic or inorganic base such as potassium carbonate, sodium carbonate, sodium hydride It is included.

R 3b -H의 염에는 일반식(Ⅰ)화합물의 염기 그룹에서의 염과 동일한 염이 포함된다. Salt of R 3b -H includes the same salt with a salt of the base group represented by the general formula (Ⅰ) compound.

이 반응은 통상으로는 0내지 150℃, 바람직하게는 50내지 100℃에서, 통상으로는 5분 내지 30시간, 바람직하게는 30분 내지 3시간동안 수행한다. This reaction is usually carried out at 0 to 150 as is ℃, preferably from 50 to 100 ℃, as is conventional for 5 minutes to 30 hours, preferably 30 minutes to 3 hours.

R 1 이 카복실-보호 그룹을 나타내는 일반식 (Ⅰa), (Ⅰb), (Ⅲ) 또는 (Ⅴ)의 화합물 또는 그의 염을, 경우에 따라, 통상적으로 0내지 100℃, 바람직하게는 20내지 100℃에서 5분내지 50시간, 바람직하게는 5분내지 4시간동안 통상의 산 또는 알카리의 존재하에서 가수분해시킴으로써 상응하는 유리 카복실산으로 전환시킬 수 있다. R 1 is a carboxyl-in some cases the Formula (Ⅰa), compounds of (Ⅰb), (Ⅲ), or (Ⅴ) represents a protective group, usually from 0 to 100 ℃, preferably from 20 to 100 5 minutes to 50 hours in ℃, preferably, can be converted to free carboxylic acid by hydrolysis in the presence of a corresponding conventional acid or alkali for 5 minutes to 4 hours. 또한 일반식(Ⅰa), (Ⅰb), (Ⅲ) 또는 (Ⅴ)의 화합물 또는 그의 염을, 경우에 따라, 그 분야에 공지된 염-생성 반응화 또는 에스테르화시킴으로써 상응하는 화합물의 염 또는 에스테르로 전환시킬 수 있다. In addition, formula (Ⅰa), (Ⅰb), (Ⅲ), or (Ⅴ) compound or in some cases a salt thereof, a known salt in the field of - generating reaction Chemistry or a salt or ester of the corresponding compound by esterification a it can be converted. 일반식(Ⅰa), (Ⅲ), (Ⅳ) 또는 (Ⅴ)의 화합물 또는 그의 염이 반응부위 이외의 위치에 활성 그룹(예, 하이드록실 그룹, 아미노 그룹등)을 가지면, 통상의 방법으로 그 호라성 그룹을 미리 보호하였다가 반응이 끝난후에 보호그룹을 제거할 수도 있다. Has the general formula (Ⅰa), (Ⅲ), (Ⅳ) or (Ⅴ) an active group (for example, such as hydroxyl group, amino group) in the compound or a non-salt thereof, the reaction area position, and in a conventional manner No. is the Castle group was protected in advance may be a reaction to remove the protecting group after the end.

수득된 화합물을 칼럼 크로마토그라피, 재결정화, 추출등과 같은 통상의 분리 및 정제 공정에 적용시킬 수 있다. It can be applied to the compound obtained in a usual separation and purification process such as column chromatography, recrystallization, extraction or the like.

R 3 가 할로겐 원자를 나타내는 일반식(Ⅰ)의 화합물 또는 그의 염(일반식(Ⅰa)의 화합물에 상응하는)은 또한 R 3 가 치환된 또는 비치환된 환상의 아미노 그룹을 나타내는 화합물(일반식(Ⅰb)화합물에 상응하는)을 수득하기 위한 중간체로서 유용하다. R 3 is (corresponding to compounds of general formula (Ⅰa)) Formula (Ⅰ) compounds of represents a halogen atom are also the compounds represented by the amino group of R 3 is a substituted or unsubstituted cyclic (Formula (ⅰb) it is useful as intermediates for obtaining the corresponding) to the compound.

본 발명의 화합물이 약품 또는 의약품으로서 쓰일 경우에는, 적절하게는 통상의 약제학적 제제에서 사용되는 담체와 혼합하여 통상의 방법으로 정제, 캅셀제, 산제, 시럽제, 과립제, 좌제, 연고, 주사제 등으로 제조한다. When the compound of the present invention is used as a drug or drugs, it is suitably prepared by mixing the carrier to be used in the normal pharmaceutical preparation of purified by a conventional method, capsules, powders, syrups, granules, suppositories, ointments, injections, etc. do. 투여 경로, 용량, 투여횟수는 적절하게는 환자의 증상에 따라 달라질 수 있으며, 통상적으로는 성인에게 0.1내지 100mg/kg/day량을 1회 내지 수회 분복하여 경구 또는 비경구적으로(예, 주사, 적주, 항문투여)투여할 수 있다. The route of administration, dose, administration frequency may be suitably vary depending on the symptom of the patient, and usually 0.1 to the amount of 100mg / kg / day to an adult in one to several bunbok orally or parenterally (e.g., by injection, jeokju may be administered anal administration).

본 발명은 다음의 참조 실시예, 실시예 및 제조 실시예에서 더욱 설명된다. The invention is further described in the following Reference Examples, Examples and Preparation Examples.

참조 실시예 및 실시예에서 사용되는 기호는 다음 의미를 갖는다 ; Symbols used in Reference Examples and Examples has the following meaning;

Me : 메틸 그룹, Me: methyl group,

Et : 에틸 그룹, Et: ethyl group,

n-Pr : n-프로필 그룹, n-Pr: propyl group, n-,

i-Pr : 이소프로필 그룹, i-Pr: isopropyl group,

Ac : 아세틸 그룹, Ac: acetyl group,

Figure kpo00007
: 알릴 그룹 Allyl group,

Figure kpo00008
: 에틸렌 그룹. Ethylene group.

[참조 실시예 1] [Reference Example 1]

210ml의 클로로포름중에 21g의 2, 6-디클로로-5-플루오로니코틴산, 및 23.8g의 티오닐클로라이드를 용해시키고, 생성된 용액에 0.1g의 N, N-디메틸포름아마이드를 가한다. In 210ml of chloroform was dissolved in thionyl chloride of nicotinic acid, and 23.8g of 2, 6-dichloro-5-fluoro and 21g, there is a 0.1g of N, N- dimethylformamide in the resulting solution. 생성된 혼합물을 70℃에서 2시간동안 반응시킨다. The resulting mixture is allowed to react for 2 hours at 70 ℃. 용매 및 과량의 염화 티오닐을 감압하에 증류로 제거하고, 수득된 잔사를 21ml의 테트라 하이드로푸란중에 용해시킨다. The solvent and excess is removed by distillation and the obtained residue was purified thionyl chloride under reduced pressure, dissolved in tetrahydrofuran 21ml. 110ml의 테트라 하이드로푸란중에 25.1g의 디에틸 에톡시마그네슘 말로네이트를 용해시키고, 그 용액을 -40°내지 -30℃로 냉각시킨다. 110ml of tetrahydrofuran was dissolved in ethoxy magnesium malonate to 25.1g of diethyl and cool the solution to -40 ° to -30 ℃. 미리 동일 온도에서 30분에 걸쳐 준비하였던 2, 6-디클로로-5-플루오로-니코티닐 클로라이드의 테트라 하이드로푸란 용액을 이 용액으로 적가한다. Was added dropwise a tetrahydrofuran solution of nicotinyl chloride in a solution-pre-2, 6-dichloro-5-fluoro who prepared over a period of 30 minutes at the same temperature. 이 혼합 용액을 동일 온도에서 1시간동안 교반하고, 이어서 용액의 온도를 단계적으로 실온으로 높힌다. This mixed solution was stirred at the same temperature for 1 hour, and is then gradually nophin to room temperature the temperature of the solution. 감압하에 증류하여 용매를 제거하고, 얻어진 잔사에 200ml의 클로로포름 및 100ml의 물을 가한다. It was evaporated under reduced pressure to remove the solvent, and that the chloroform 100ml and 200ml of water to the obtained residue. 6N염산으로 pH를 1로 맞춘다. Set the pH to 1 with 6N hydrochloric acid. 유기층을 분리하고, 연속적으로 50ml의 물, 50ml의 5%탄산수소나트륨 수용액 및 50ml의 염화 나트륨 포화 수용액으로 세척한 후, 무수황산 마그네슘상에서 건조시킨다. After the organic layer was separated, successively washed with water, 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride in 50ml of 50ml of 50ml, and then dried over anhydrous magnesium sulfate. 감압하에 증류하여 용매를 제거하고, 수득된 오일성 생성물에 50ml의 물 및 0.15g의 P-톨루엔 설폰산을 가한 후, 생성된 혼합물을 격렬히 교반하면서 100℃에서 2시간동안 반응시킨다. It was evaporated under reduced pressure to remove the solvent, and after adding water and P- toluenesulfonic acid in 0.15g of oily product was obtained 50ml of a, with vigorous stirring and the resulting mixture is allowed to react for 2 hours at 100 ℃. 반응 혼합물을 100ml의 콜로로포름으로 추출한다. The reaction mixture was extracted with formaldehyde in colo of 100ml. 유기층을 50ml의 염화 나트륨 포화 수용액으로 세척하고 무수 황산 마그네슘 상에서 건조시킨 후에, 감압하에 증류하여 용매를 제거한다. The organic layer was washed with a sodium chloride saturated aqueous solution of 50ml, and removes that, the solvent was evaporated under reduced pressure after dried over anhydrous magnesium sulfate. 수득된 잔사를 칼럼 크로마토그라피(WAKO SILICA GEL C-200, 용출제 : 톨루엔)로 정제하여 융점이 64-65℃인 23.5g의 에틸(2, 6-디클로로-5-플루오로니코티노일)-아세테이트를 수독한다. The resulting residue was purified by column chromatography (WAKO SILICA GEL C-200, eluent: toluene) to give 23.5g of ethyl a melting point of 64-65 ℃ to (2, 6-dichloro-5-fluoro-nicotinoyl) the sudok acetate.

IR(KBr)cm -1 : ν c=0 1650, 1630, 1620 IR (KBr) cm -1: ν c = 0 1650, 1630, 1620

NMR(CDCl 3 )δ값 : 1.25(1.29H, t, J=7Hz), 1.33(1.71H, t, J=7Hz), 4.07(1.14H, s), 4.28(2H, q, J=7Hz), 5.82(0.43H, s), 7.80(1H, d, J=7Hz), 12.62(0.43H, s) NMR (CDCl 3) δ value: 1.25 (1.29H, t, J = 7Hz), 1.33 (1.71H, t, J = 7Hz), 4.07 (1.14H, s), 4.28 (2H, q, J = 7Hz) , 5.82 (0.43H, s), 7.80 (1H, d, J = 7Hz), 12.62 (0.43H, s)

[참조 실시예 2] [Reference Example 2]

40ml의 벤젠중에 8.8g의 에틸(2, 6-디클로로-5-플루오로니코티노일)아세테이트를 용해시키고, 여기에 4.5g의 N, N-디메틸포름아미도디메틸아세탈을 가한 후에, 생성된 혼합물을 70℃에서 1.5시간동안 반응시킨다. The dissolved ethyl (2, 6-dichloro-5-fluoro-nicotinoyl) acetate in 8.8g in 40ml of benzene and, after adding this to the Fig dimethylacetal N, N- dimethyl formamido of 4.5g, the resulting mixture to react for 1.5 hours at 70 ℃. 이어서, 4.1g의 2, 4-디플루오로아닐린을 가하고 생성된 혼합물을 실온에서 4시간동안 반응시킨다. Subsequently, it was reacted for 4 hours to 2, the mixture was added to 4-fluoro-aniline, and yielded 4.1g of generating at room temperature. 감압하에 여과하여 용매를 제거한다. Filtered under a reduced pressure to remove the solvent. 수득된 잔사를 칼럼 크로마토그라피(WAKO SILICA GEL C-200, 용출제 : 클로로포름)로 정제하여 융점이 138내지 139℃인 9.0g의 에틸 2-(2, 6-디클로로-5-플루오로니코티노일)-3-(2, 4-디플루오로페닐아미노) 아크릴레이트를 수득한다. The resulting residue was purified by column chromatography (WAKO SILICA GEL C-200, eluant: chloroform) to give a melting point of 138 to 139 ℃ of 9.0g of ethyl 2- (2, 6-dichloro-5-fluoro-nicotinoyl ) -3- (2, affords the 4-difluoro-phenylamino) acrylate.

IR(KBr)cm -1 : ν c=0 1690 IR (KBr) cm -1: ν c = 0 1690

NMR(CDCl 3 )δ값 : 1.08(3H, t, J=7Hz), 4.10(2H, q, J=7Hz), 6.77-7.40(4H, m), 8.50(1H, d, J=13Hz), 12.70(1H, d, J=13Hz) NMR (CDCl 3) δ value: 1.08 (3H, t, J = 7Hz), 4.10 (2H, q, J = 7Hz), 6.77-7.40 (4H, m), 8.50 (1H, d, J = 13Hz), 12.70 (1H, d, J = 13Hz)

유사한 방법으로, 표 2의 화합물을 수득한다. In a similar manner, to give the compounds of Table 2.

[표 2] TABLE 2

Figure kpo00009

Figure kpo00010

Figure kpo00011

참고 : * KBr법 대신에 니이트법(neat method)을 이용하였다. Note: * used a kneader teubeop (neat method) instead of the KBr method.

[참조 실시예 3] [Reference Example 3]

(1) 55ml의 클로로포름중에 5.5g의 에틸(2, 6-디클로로-5-플루오로니코티노일) 아세테이트, 2.37g의 N-메틸피페라진 및 2.37g의 트리에틸아민을 용해시키고, 생성된 용액을 60℃내지 65℃에서 2시간동안 반응시킨다. (1) 5.5g of ethyl (2, 6-dichloro-5-fluoro-nicotinoyl) in 55ml of chloroform the acetate, dissolved in N- methyl piperazine and 2.37g of triethylamine and 2.37g of the resulting solution to react for 2 hours at 60 ℃ to 65 ℃. 반응 혼합물을 30ml의 물로 세척하고, 무수황산 마그네슘상에서 건조시킨다. The reaction mixture was washed with water 30ml, and dried over anhydrous magnesium sulfate. 감압하에 증류하여 용매를 제거하고, 수득된 잔사를 칼럼 크로마토그라피(WAKO SILICA GEL C-200, 용출제 클로로포름)로 정제하여 5.4g의 오일성 에틸 [2-클로로-5-플루오로-6-(4-메틸-1-피페라지닐)니코티노일] 아세티이트를 수득한다. Was evaporated under reduced pressure to remove the solvent, to give the oily ethyl 5.4g of the obtained residue was subjected to column chromatography (WAKO SILICA GEL C-200, eluent chloroform for) [6-chloro-5-fluoro-2- (4 -methyl-1-piperazinyl) nicotinoyl] to obtain the Oh setiyi agent.

IR(Neat)cm -1 : ν c=0 1750, 1695 IR (Neat) cm -1: ν c = 0 1750, 1695

NMR(CDCl 3 )δ값 : 1.25(3H, t, J=7Hz), 2.32(3H, s), 2,12-2.70(4H, m), 3.55-3.96(4H, m), 4.03(2H, s), 4.20(2H, d, J=7Hz), 7.78(1H, d, J=13Hz) NMR (CDCl 3) δ value: 1.25 (3H, t, J = 7Hz), 2.32 (3H, s), 2,12-2.70 (4H, m), 3.55-3.96 (4H, m), 4.03 (2H, s), 4.20 (2H, d, J = 7Hz), 7.78 (1H, d, J = 13Hz)

유사한 방법으로, 표 3의 화합물을 수득한다. In a similar manner, to give the compounds of Table 3.

[표 3] TABLE 3

Figure kpo00012

(2) 22.5ml의 벤젠중에 4.5g의 에틸 [2-클로로-5-플루오로-6-(4-메틸-1-피페라지닐)니코니노일] 아세테이트를 용해시키고, 여기에 1.87g의 N, N-디메틸포름아미도디메틸아세탈을 가한 후에, 생성된 혼합물을 70℃에서 2시간동안 반응시킨다. (2) [2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) Nikko Nino yl] 4.5g of the ethyl benzene was dissolved in 22.5ml acetate and 1.87g of the herein N , N- dimethyl formamido after adding the dimethyl acetal, and the resulting mixture is allowed to react for 2 hours at 70 ℃. 이어서, 1.8g의 4-메톡시-2-메틸아닐린을 가하고 생성된 혼합물을 실온에서 4시간동안 반응시킨다. Subsequently, it was reacted for 4 hours the mixture was added 4-methoxy-2-methyl-aniline of 1.8g generated at room temperature. 이어서 감압하에 증류하여 용매를 제거하고 수득된 잔사를 칼럼 크로마토그라피 [WAKO SILICA GEL C-200, 용출제 : 클로로포름 : 에탄올=100 : 1(용적비)]로 정제시킨다. Then the solvent is removed by distillation under reduced pressure and the obtained residue was subjected to column chromatography then purified by [WAKO SILICA GEL C-200, eluant: 1 (by volume) chloroform: ethanol = 100]. 수득된 결정성물질을 10ml의 디에틸 에테르로 세척하여 융점이 141내지 142℃인 5.0g의 에틸 2-[2-클로로-5-플루오로-6-(4-메틸-1-피페라지닐)-니코티노일]-3-(4-메톡시-2-메틸페닐아미노)아크릴레이트를 수득한다. Ethyl 2 of washing the resulting crystalline material with diethyl ether, 10ml of a melting point of 141 to 142 ℃ 5.0g [2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) -nicotinoyl] to give a 3- (4-methoxy-2-methylphenylamino) acrylate.

IR(KBr)cm -1 : ν c=0 1710(Sh), 1695 IR (KBr) cm -1: ν c = 0 1710 (Sh), 1695

NMR(CDCl 3 )δ값 : 1.08(3H, t, J=7Hz), 2.32(3H, s), 2.40(3H, s), 2.23-2.68(4H, m), 3.47-3.83(4H, m), 3.75(3H, s), 4.07(2H, q, J=7Hz), 6.65-7.25(3H, m), 7.20(1H, d, J=13Hz), 8.48(1H, d, J=13Hz), 12.82(1H, d, J=13Hz) NMR (CDCl 3) δ value: 1.08 (3H, t, J = 7Hz), 2.32 (3H, s), 2.40 (3H, s), 2.23-2.68 (4H, m), 3.47-3.83 (4H, m) , 3.75 (3H, s), 4.07 (2H, q, J = 7Hz), 6.65-7.25 (3H, m), 7.20 (1H, d, J = 13Hz), 8.48 (1H, d, J = 13Hz), 12.82 (1H, d, J = 13Hz)

유사한 방법으로, 표 4의 화합물을 수득한다. In a similar manner, to give the compounds of Table 4.

[표 4] TABLE 4

Figure kpo00013

Figure kpo00014

참고 : * 1 : KBr Note: * 1: KBr

* 2 : 니이트(Neat) * 2: kneader agent (Neat)

[실시예 1] Example 1

90ml의 N, N-디메틸포름 아마이드중에 9.0g의 에틸 2-(2, 6-디클로로-5-플루오로니코티노일)-3-(2, 4-디플루오로페닐아미노) 아크릴레이트를 용해시키고, 여기에 3.6g의 탄산수소 나트륨을 가한 후에 120℃에서 20분간 반응시킨다. 90ml of N, N- dimethylformamide (2, 6-dichloro-5-fluoro-nicotinoyl) 9.0g of ethyl 2 of the amide-3- (2, 4-difluoro-phenylamino) dissolved in an acrylate and , excites the reaction for 20 minutes at 120 ℃ after adding 3.6g of sodium bicarbonate to. 이어서, 감압하에 증류하여 용매를 제거하고, 수득된 잔사를 50ml의 클로로포름 중에 용해시킨다. Subsequently, it was evaporated under reduced pressure to remove the solvent, dissolving the obtained residue in chloroform 50ml. 생성된 용액을 연속적으로 30ml의 물 및 30ml의 염화 나트륨 포화수용액으로 세척하고, 이어서 무수 황산 마그네슘상에서 건조시킨다. Sequentially and the resulting solution washed with water and sodium chloride saturated aqueous solution of 30ml of 30ml and then dried over anhydrous magnesium sulfate. 감압하에 증류하여 용매를 제거하고, 수득된 결정성물질을 30ml의 디에틸에테르로 세척하여 융점이 220내지 222℃인 7.0g의 에틸 7-클로로-6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실레이트를 수득한다. Was evaporated under reduced pressure to remove the solvent, and the 1-crystalline material obtained with diethyl ether and washed with 7.0g of a melting point of 220 to 222 ℃ ethyl 7-chloro-6-fluoro-30ml (2, 4- difluorophenyl) -1, to give a 1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylate.

IR(KBr)cm -1 : ν c=0 1730, 1690 IR (KBr) cm -1: ν c = 0 1730, 1690

NMR(CDCl 3 )δ값 : 1.36(3H, t, J=7Hz), 4.30(2H, q, J=7Hz), 6.80-7.60(3H, m), 8.27(1H, d, J=7H), 8.42(1H, s) NMR (CDCl 3) δ value: 1.36 (3H, t, J = 7Hz), 4.30 (2H, q, J = 7Hz), 6.80-7.60 (3H, m), 8.27 (1H, d, J = 7H), 8.42 (1H, s)

유사한 방법으로, 표 5의 화합물을 수득한다. In a similar manner, to give the compounds of Table 5.

[표 5] Table 5

Figure kpo00015

Figure kpo00016

Figure kpo00017

Figure kpo00018

[실시예 2] Example 2

(1) 35ml의 클로로포름중에 3.5g의 에틸 7-클로로-6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실레이트를 용해시키고1.5g의 N-아사텔 피페라진 및 1.6g의 트리에틸아민을 가한후에, 생성된 용액을 60℃에서 1시간동안 반응시킨다. (1) 1- (2, 4-difluorophenyl) ethyl 7-chloro-6-fluoro 3.5g in 35ml of chloroform, 1, 4-dihydro-4-oxo-1, 8-naphthyridin after dissolving the 3-carboxylate was added to 1.5g of N- necked Tel piperazine and 1.6g of triethylamine, and the resulting solution is allowed to react for one hour at 60 ℃. 이어서 감압하에 증류하여 용매를 제거하고, 수득된 잔사를 칼럼 크로마토그라피 [WAKO SILICA GEL C-200, 용출제 클로로포름 : 에탄올=30 : 1(용적비)]로 정제하여 융점이 207내지 209℃인 3.5g의 에틸 7-(4-아세틸-1-피페라지닐)-6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디클로로-4-옥소 1, 8-나프티리딘-3-카복실레이트를 수득한다. Then the solvent is removed by distillation under reduced pressure, the obtained residue was subjected to column chromatography [eluent WAKO SILICA GEL C-200, chloroform: ethanol = 30: 1 (volume ratio)], and purification by a melting point of 207 to 209 ℃ to 3.5g of ethyl 7- (4-acetyl-1-piperazinyl) -6-fluoro-1- (2, 4-difluorophenyl) -1, 4-dichloro-4-oxo-1, 8-naphthyridin- to give a 3-carboxylate.

IR(KBr)cm -1 : ν c=0 1730, 1695 IR (KBr) cm -1: ν c = 0 1730, 1695

NMR(CDCl 3 )δ값 : 1.38(3H, t, J=7Hz), 2.05(3H, s), 3.53(8H, bs), 4.30(2H, q, J=7Hz), 6.80-7.75(3H, m), 8.00(1H, d, J=13Hz), 8.30(1H, s) NMR (CDCl 3) δ value: 1.38 (3H, t, J = 7Hz), 2.05 (3H, s), 3.53 (8H, bs), 4.30 (2H, q, J = 7Hz), 6.80-7.75 (3H, m), 8.00 (1H, d, J = 13Hz), 8.30 (1H, s)

유사한 방법으로, 표 6의 화합물을 수득한다. In a similar manner, to give the compounds of Table 6.

[표 6] TABLE 6

Figure kpo00019

Figure kpo00020

Figure kpo00021

Figure kpo00022

Figure kpo00023

Figure kpo00024

Figure kpo00025

(2) 25ml의 6N염산중에 2.5g의 에틸 7-(4-아세틸-1-피페라지닐)-6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실레이트를 용해시키고, 생성된 용액을 환류하에서 2시간동안 가열한다. (2) (possess 4-acetyl-l-piperazinyl) ethyl 7- 2.5g in 25ml of 6N yeomsanjung-6-fluoro-1- (2, 4-difluorophenyl) -1, 4-dihydro- 4-oxo-1, 8-naphthyridine-3-carboxylate was dissolved naphthyridine is heated for 2 hours and the resulting solution under reflux. 이어서, 반응혼합물을 실온으로 냉각시키고, 그의 pH를 1N수산화나트륨 수용액으로 12로 맞춘다음 아세트산으로 6.5로 조절한다. Then, the reaction mixture was cooled to room temperature, adjusted its pH to 6.5 with acetic acid and then adjusted to 12 with 1N aqueous sodium hydroxide solution. 침전된 결정을 여과로 모아서 30ml의 물로 세척하고, 이어서 건조시켜서 1.8g의 6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-4-옥소-7-(1-피페라지닐)-1, 8-나프티리딘-3-카복실산을 수득한다. Washed in 30ml collecting the precipitated crystals by filtration with water, then dried 6-Fluoro of 1.8g -1- (2, 4-difluorophenyl) -1, 4-dihydro-4-oxo-7- to afford (1-piperazinyl) -1, 8-naphthyridine-3-carboxylic acid.

NMR(TFA-d 1 )δ값 : 3.30-4.50(8H, m), 7.00-7.85(3H, m), 8.33(1H, d, J=13Hz), 9.21(1H, s) NMR (TFA-d 1) δ value: 3.30-4.50 (8H, m), 7.00-7.85 (3H, m), 8.33 (1H, d, J = 13Hz), 9.21 (1H, s)

유사한 방법으로, 표 7의 화합물을 수득한다. In a similar manner, to give the compounds of Table 7.

[표 7] Table 7

Figure kpo00026

Figure kpo00027

Figure kpo00028

참고 : * KBr법 대신에 누졸법(nujol method)를 이용하였다. Note: To use the press jolbeop (nujol method) instead of * KBr method.

[실시예 3] Example 3

(1) 5ml의 클로로포름중에 0.50g의 에틸 7-클로로-6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실레이트를 용해시키고, 0.20g의 3-아세틸아미노피롤리딘 및 0.15g의 트리에틸아민을 가한후에, 생성된 용액을 60℃에서 1시간동안 반응시킨다. (1) to 0.50g of ethyl 7-chloro-6-fluoro-in chloroform of 5ml -1- (2, 4-difluorophenyl) -1, 4-dihydro-4-oxo-1, 8-naphthyridin after dissolving the 3-carboxylate and, added to 3-acetyl aminopyrrolidine and triethylamine 0.15g of 0.20g, and the resulting solution is allowed to react for one hour at 60 ℃. 이어서 감압하에 증류하여 용매를 제거하고, 수득된 잔사를 칼럼 크로마토그라피 [WAKO SILICA GEL C-200, 용출제 : 클로로포름 : 에탄올=30 : 1(용적비)]로 정제하여 융점이 233내지 235℃인 0.5g의 에틸 7-(3-아세틸아미노-1-피롤리디닐)-6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디클로로-4-옥소-1, 8-나프티리딘-3-카복실레이트를 수득한다. Then the solvent is removed by distillation under reduced pressure, and the obtained residue was subjected to column chromatography [eluent WAKO SILICA GEL C-200,: chloroform: ethanol = 30: 1 (volume ratio)] to 0.5 to give a melting point of 233 to 235 ℃ g of ethyl 7- (3-acetylamino-1-pyrrolidinyl) -6-fluoro-1- (2, 4-difluorophenyl) -1, 4-dichloro-4-oxo-1, 8- to obtain a 6-naphthyridin-3-carboxylate.

IR(KBr)cm -1 : ν c=0 1725, 1700 IR (KBr) cm -1: ν c = 0 1725, 1700

NMR(CDCl 3 )δ값 : NMR (CDCl 3) δ value:

Figure kpo00029

유사한 방법으로, 표 8의 화합물을 수득한다. In a similar manner, to give the compounds of Table 8.

[표 8] Table 8

Figure kpo00030

Figure kpo00031

(2) 2.5ml의 6N염산중에 0.25g의 에틸 7-(3-아세틸아미노-1-피롤리디닐)-6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-4-옥소-1, 8-나프디리딘-3-카복실레이트를 용해시키고, 생성된 용액을 환류하에서 2시간동안 가열한다. (2) 0.25g of a 6N yeomsanjung 2.5ml of ethyl 7- (3-acetylamino-1-pyrrolidinyl) -6-fluoro-1- (2, 4-difluorophenyl) -1, 4 dihydro-4-oxo-1, 8-naphthyl di-naphthyridine-3-carboxylate were dissolved, and heated for 2 hours and the resulting solution under reflux. 이어서 반응혼합물을 실온으로 냉각시ㅋ고, 그의 pH를 1N수산화나트륨 수용액으로 12로 맞춘다음 아세트산으로 6.5로 조절한다. Then blah and when the reaction mixture was cooled to room temperature, adjusted its pH to 6.5 with acetic acid and then adjusted to 12 with 1N aqueous sodium hydroxide solution. 침전된 결정을 여과로 모아서 2ml의 물로 세척하고, 이어서 건조시켜서 0.18g의 7-(3-아미노-1-피롤리디닐)-6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실산을 수득한다. By collecting the precipitated crystal was filtered, washed with 2ml of water and then dried with 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1-of 0.18g (2, 4-difluorophenyl) 1, to give the 1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid.

NMR(TFA-d 1 )δ값 : 2.25-2.85(2H,m), 3.37-4.69(5H, m), 6.93-7.81(3H, m), 8.22(1H, d, J=11Hz), 9.16(1H, s) NMR (TFA-d 1) δ value: 2.25-2.85 (2H, m), 3.37-4.69 (5H, m), 6.93-7.81 (3H, m), 8.22 (1H, d, J = 11Hz), 9.16 ( 1H, s)

유사한 방법으로, 표 9의 화합물을 수득한다. In a similar manner, to give the compounds of Table 9.

[표 9] Table 9

Figure kpo00032

Figure kpo00033

[실시예 4] Example 4

(1) 20ml의 클로로포름중에 2.0g의 에틸 2, 6-디클로로-5-플루오로니코티노일아세테이트, 0.96g의 3-아세틸아미노피롤리딘 및 0.8g의 트리에틸아민을 용해시키고, 생성된 용액을 60내지 65℃에서 2시간동안 반응시킨다. (1) 2.0g in 20ml of chloroform, ethyl 2, 6-dichloro-5-fluoro-nicotinoyl acetate, was dissolved in 3-acetyl aminopyrrolidine and 0.8g of triethylamine and 0.96g of, and the resulting solution to react for 2 hours at 60 to 65 ℃. 반응 혼합물을 30ml의 물로 세척하고, 무수 황산 마그네슘상에서 건조시킨다. The reaction mixture was washed with water 30ml, and dried over anhydrous magnesium sulfate. 감압하에 증류하여 용매를 제거하고, 수득된 잔사를 칼럼 크로마토그래피 [WAKO SILICA GEL C-200, 용출제 벤제 : 에틸 아세테이트=1 : 1(용적비)]로 정제하여 1.8g의 오일성 에틸 [2-클로로-5-플루오로-6-(3-아세틸아미노-1-피롤리디닐)니코티노일] 아세테이트를 수득한다. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified by column chromatography [WAKO SILICA GEL C-200, eluent benje for: ethyl acetate = 1: 1 (volume ratio)] to give oily ethyl 1.8g of [2-chloro 5-fluoro to give the 6- (3-acetylamino-1-pyrrolidinyl) nicotinoyl] acetate.

IR(Neat)cm -1 : ν c=0 1740, 1650 IR (Neat) cm -1: ν c = 0 1740, 1650

NMR(CDCl 3 )δ값 : 1.28(3H, t, J=7Hz), 1.97(3H, s), 1.90-2.62(2H, m), 4.02(2H, s), 4.15(2H, s), 4.15(2H, q, J=7Hz), 3.50-4.70(5H, m), 7.06(1H, d, J=6Hz), 7.57(1H, d, J=13Hz) NMR (CDCl 3) δ value: 1.28 (3H, t, J = 7Hz), 1.97 (3H, s), 1.90-2.62 (2H, m), 4.02 (2H, s), 4.15 (2H, s), 4.15 (2H, q, J = 7Hz), 3.50-4.70 (5H, m), 7.06 (1H, d, J = 6Hz), 7.57 (1H, d, J = 13Hz)

(2) 10ml의 벤젠중에 0.7g의 에틸 2-클로로-5-플루오로-6-(3-아세틸아미노-1-피롤리디닐)니코티노일 아세테이트를 용해시키고, 여기에 0.235g의 N, N-디메틸포름아미도디메틸아세탈을 가한 후에, 생성된 혼합물을 70℃에서 2시간동안 반응시킨다. (2) 0.7g of ethyl 2-chloro-5-fluoro-benzene in 10ml -6- (3- acetylamino-1-pyrrolidinyl) was dissolved nicotinoyl acetate, here 0.235g of N, the N -dimethyl after formamido added to dimethyl acetal, and the resulting mixture is allowed to react for 2 hours at 70 ℃. 이어서, 0.243g의 2, 4-디플루오로아닐린을 가하고 생성된 혼합물을 실온에서 8시간동안 반응시킨다. Subsequently, it was reacted with 2, the mixture was added to 4-fluoro aniline in the generation of 0.243g at room temperature for 8 hours. 그후에, 감압하에 증류하여 용매를 제거하고, 수득된 잔사를 칼럼크로마토그라피 [WAKO SILICA GEL C-200, 용출제 : 벤젠 : 에틸아세테이트=1 : 1(용적비)]로 정제하여 융점이 82내지 85℃인 0.25g의 에틸 2-[2-클로로-5-플루오로-6-(3-아세틸아미노-1-피롤리디닐)니코티노일]-3-(2, 4-디플루오로페닐 아미노) 아크릴레이트를 수득한다. Thereafter, distilled under the reduced pressure to remove the solvent, the obtained residue was subjected to column chromatography [WAKO SILICA GEL C-200, eluant: benzene: ethyl acetate = 1: 1 (volume ratio)] to give a melting point of 82 to to 85 ℃ [6- (3-acetylamino-1-pyrrolidinyl) 2-chloro-5-fluoro-nicotinoyl] ethyl 2 of 0.25g -3- (2, 4-difluoro-phenylamino) acrylate to obtain the rate.

IR(KBr)cm -1 : ν c=0 1695(Sh), 1660 IR (KBr) cm -1: ν c = 0 1695 (Sh), 1660

NMR(CDCl 3 )δ값 : 1.25(3H, t, J=7Hz), 2.07(3H, s), 1.90-2.30(2H, m), 4.19(2H, q, J=7Hz), 3.60-4.70(5H, m), 6.49(1H, d, J=6Hz), 6.80-7.50(4H, m), 8.53(1H, d, J=13Hz), 12.46(1H, d, J=13Hz) NMR (CDCl 3) δ value: 1.25 (3H, t, J = 7Hz), 2.07 (3H, s), 1.90-2.30 (2H, m), 4.19 (2H, q, J = 7Hz), 3.60-4.70 ( 5H, m), 6.49 (1H, d, J = 6Hz), 6.80-7.50 (4H, m), 8.53 (1H, d, J = 13Hz), 12.46 (1H, d, J = 13Hz)

(3) 3ml의 N, N-디메틸포름아마이드중에 0.2g의 에틸 2-[2-플로로-5-플루오로-6-(3-아세틸아미노-1-피롤리디닐)니코티노일]-3-(2, 4-디플루오로 페닐아미노) 아크릴레이트를 용해시키고, 여기에 0.04g의 탄산수소 나트륨을 가한 후에, 120℃에서 1시간동안 반응시킨다. (3) -3 [6- (3-acetylamino-1-pyrrolidinyl) nicotinoyl-5-fluoro-2-Flo] ethyl 2 0.2g of the N, N- dimethylformamide, 3ml of - dissolving the (2, 4-difluoro-phenylamino) acrylate and, here in after adding 0.04g of sodium bicarbonate, and reacted for 1 hour at 120 ℃. 그후에 감압하에 증류하여 용매를 제거하고, 수득된 잔사를 10ml의 클로로포름중에 용해시킨다. Thereafter distilled to remove the solvent under reduced pressure, dissolving the obtained residue in chloroform 10ml. 생성된 용액을 연속적으로 10ml의 물 및 10ml의 염화 나트륨 포화수용액으로 세척하그, 이어서 무수 황산 마그네슘상에서 건조시킨다. Sequentially and the resulting solution washed with water and a sodium chloride saturated aqueous solution Hague in 10ml of 10ml, then dried over anhydrous magnesium sulfate. 감압하에 증류하여 용매를 제거하고, 수득된 결정성 물질을 5ml의 디에틸 에테르로 세척하여 융점이 233 내지 235℃인 0.13g의 에틸 7-(3-아세틸아미노-1-피롤리디닐)-6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실레이트를 수득한다. It was evaporated under reduced pressure to remove the solvent, and the crystalline material washed with diethyl ether and ethyl 0.13g of a melting point of 233 to 235 ℃ 7- (3- acetylamino-1-pyrrolidinyl) in 5ml obtained -6 - to give the l- (2, 4-difluorophenyl) -1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylate fluoro.

유사한 방법으로, 에틸 7-(3-아세틸아미노-1-피롤리디닐)-6-플루오로-1-(4-플루오로페닐)-1, 4-디하이드로-4-옥소ㅡ1, 8-나프티리딘-3-카복실레이트를 수득한다. In a similar manner, ethyl 7- (3-acetylamino-1-pyrrolidinyl) -6-fluoro-1- (4-fluorophenyl) -1, 4-dihydro-4-oxo-sul 1, 8 to obtain a 6-naphthyridin-3-carboxylate. 이 생성물의 물리적 성질은 실시예 3-(1)에서 수득된 생성물의 성질과 동일하다. Physical properties of this product are the same as the properties of the product obtained in Example 3- (1).

[실시예 5] Example 5

(1) 15ml의 6N염산중에 0.50g의 에틸 7-클로로-6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실레이트를 현탁시키고, 생성된 현탁액을 환류하에서 3시간동안 가열한다. (1) in 15ml of a 6N yeomsanjung with ethyl 7-chloro-6-fluoro 0.50g -1- (2, 4-difluorophenyl) -1, 4-dihydro-4-oxo-1, 8-naphthyridin naphthyridin-3-carboxylate was suspended, and heated for 3 hours to the resulting suspension under reflux. 이어서, 반응혼합물을 50ml의 물로 희석하고 50ml씩의 클로로포름으로 3회 추출한다. Then, the reaction mixture was diluted with water and extracted three times with chloroform 50ml of 50ml each. 추출물을 합하여 100ml의 염화 나트륨 포화수용액으로 세척하고, 무수 황산마그네슘상에서 건조시킨다. The combined extracts were washed with sodium chloride saturated aqueous solution of 100ml and dried over anhydrous magnesium sulfate. 감압하에 증류로 용매를 제거한다. The solvent was removed under reduced pressure by distillation. 수득된 결정성 물질을 15ml의 디에틸 에테르로 세척하여 융점이 244내지 248℃인 0.40g의 7-클로로-6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실산을 수득한다. The crystalline material obtained from 7-chloro-6-fluoro-washed with diethyl ether, 0.40g of a melting point of 244 to 248 ℃ 15ml -1- (2, 4-difluorophenyl) -1, 4 dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid to give a naphthyridine.

IR(KBr)cm -1 : ν c=0 1720 IR (KBr) cm -1: ν c = 0 1720

NMR(d 6 -DMSO)δ값 : 7.26-8.56(3H, m), 8.86(1H, d, J=7Hz), 9.18(1H, s). NMR (d 6 -DMSO) δ values: 7.26-8.56 (3H, m), 8.86 (1H, d, J = 7Hz), 9.18 (1H, s).

(2) 3ml의 디메틸설폭사이드중에 0.30g의 7-클로로-6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실산을 현탁시키고, 이어서 0.25g의 N-메틸피페라진을 가한후에, 생성된 현탁액을 60℃에서 30분간 반응시킨다. (2) -1 in dimethylsulfoxide 0.30g of 7- chloro-6-fluoro-in side of 3ml (2, 4-difluorophenyl) -1, 4-dihydro-4-oxo-1, 8-naphthyridin naphthyridine-3-carboxylic acid were suspended, and then later added to N- methylpiperazine of 0.25g, and the resulting suspension was reacted at 60 ℃ 30 minutes. 이어서, 감압하에 증류하여 용매를 제거하고, 얻어진 잔사에 30ml의 물을 가한다. Then, distillation under reduced pressure to remove the solvent, and that the 30ml of water to the obtained residue. 생성된 혼합물의 pH를 10% 수산화나트륨 수용액으로 12로 맞추고, 이어서 아세트산으로 7로 조절한다. Align to 12. The pH of the resulting mixture with 10% aqueous sodium hydroxide solution, and was then adjusted to 7 with acetic acid. 침전된 결정성 물질을 여과로 모아서 5ml의 물로 세척하여 융점이 208내지 209℃인 0.24g의 6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-7-(4-메틸-1-피페라지닐)-4-옥소-1, 8-나프티리딘-3-카복실산을 수득한다. The crystalline substance precipitated collected by filtration and washed with 5ml water and 0.24g of 6-fluoro-a melting point of 208 to 209 ℃ -1- (2, 4-difluorophenyl) -1, 4-dihydro -7 - to obtain a 4-oxo-1, 8-naphthyridine-3-carboxylic acid (4-methyl-1-piperazinyl).

IR(KBr)cm -1 : ν c=0 1730 IR (KBr) cm -1: ν c = 0 1730

NMR(TFA-d 1 )δ값 : 3.30(3H, s), 3.45-5.25(8H, m), 7.12-8.10(3H, m), 8.49(1H, d, J=13Hz), 9.38(1H, s). NMR (TFA-d 1) δ value: 3.30 (3H, s), 3.45-5.25 (8H, m), 7.12-8.10 (3H, m), 8.49 (1H, d, J = 13Hz), 9.38 (1H, s).

[실시예 6] Example 6

50ml의 N, N-디메틸포름아마이드중에 5.0g의 에틸 2-[2-클로로-5-플루오로-6-(4-메틸-1-피페라지닐)니코티노일]-3-(4-메톡시-2-메틸페닐아미노) 아크릴레이트를 용해시키고, 여기에 1.03g의 탄산수소 나트륨을 가한후에, 120℃에서 3시간동안 반응시킨다. 5.0g of the N, N- dimethylformamide, 50ml of ethyl 2- [2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) nicotinoyl] -3- (4-methoxy amino-2-methylphenyl) was dissolved in an acrylate, here in after adding 1.03g of sodium bicarbonate, and reacted at 120 ℃ for 3 hours. 이어서, 감압하에 증류하여 용매를 제거하고, 수득된 잔사를 50ml의 클로로포름중에 용해시킨다. Subsequently, it was evaporated under reduced pressure to remove the solvent, dissolving the obtained residue in chloroform 50ml. 생성된 용액을 연속적으로 30ml의 물 및 30ml의 염화나트륨 포화수용액을 세척하고, 이어서 무수황산 마그네슘상에서 건조시킨다. Sequentially and the resulting solution washed with water and saturated sodium chloride aqueous solution in 30ml of 30ml and then dried over anhydrous magnesium sulfate. 감압하에 증류하여 용매를 제거하고, 수득된 결정성 물질을 30ml의 디에틸에테르로 세척하여 융점이 144내지 145℃인 2.38g의 에틸-6-플루오로-1, 4-디하이드로-1-(4-메톡시-2-메틸 페닐)-7-(4-메틸-1-피페라지닐)-4-옥소-1, 8-나프티리딘-3-카복실레이트를 수득한다. The crystals was evaporated under reduced pressure to remove the solvent, and the obtained material with ethyl-6-fluoro 2.38g of a melting point of 144 to 145 ℃ and washed with diethyl ether 30ml -1, 4- dihydro-1 ( 4-methoxy-2-methyl-phenyl) -7- (4-methyl-1-piperazinyl) -4-oxo-1, 8-naphthyridine-3-carboxylate was obtained.

IR(KBr)cm -1 : ν c=0 1730, 1690 IR (KBr) cm -1: ν c = 0 1730, 1690

NMR(CDCl 3 )δ값 : 1.33(3H, t, J=7Hz), 1.95(3H, s), 2.20(3H, s), 2.05-2.62(4H, m), 3.32-3.63(4H, m), 3.82(3H, s), 4.32(2H, q, J=7Hz), 6.60-7.15(3H, m), 8.02(1H, d, J=13Hz), 8.23(1H, s). NMR (CDCl 3) δ value: 1.33 (3H, t, J = 7Hz), 1.95 (3H, s), 2.20 (3H, s), 2.05-2.62 (4H, m), 3.32-3.63 (4H, m) , 3.82 (3H, s), 4.32 (2H, q, J = 7Hz), 6.60-7.15 (3H, m), 8.02 (1H, d, J = 13Hz), 8.23 ​​(1H, s).

유사한 방법으로, 표 10의 화합물을 수득한다. In a similar manner, to give the compounds of Table 10.

[표 10] [Table 10]

Figure kpo00034

Figure kpo00035

[실시예 7] Example 7

5ml의 47% 브롬산중에 2.0g의 에틸 6-플루오로-1, 4-디하이드로-1-(4-메톡시-2-메틸페닐)-7-(4-메틸-1-피페라지닐)-4-옥소-1, 8-나프티리딘-3-카복실레이트를 용해시키고, 생성된 용액을 120내지 125℃에서 2시간동안 반응시킨다. To 47% of ethyl 6-fluoro bromine 2.0g of the mountains of 5ml -1, 4-dihydro-1- (4-methoxy-2-methylphenyl) -7- (4-methyl-1-piperazinyl possess) 4-oxo-1, 8-naphthyridin and reacted for 2 hours was dissolved naphthyridine-3-carboxylate, 120 to 125 ℃ the resulting solution. 반응혼합물의 pH를 10% 수산화 나트륨 수용액으로 13으로 맞추고, 이어서 아세트산으로 6.5로 맞춘다. The pH of the reaction mixture with 10% aqueous sodium hydroxide solution in 13 align, then adjusted to 6.5 with acetic acid. 침전된 결정을 여과로 모으고 10ml의 물로 세척하여 융점이 280℃보다 높은 1.8g의 6-플루오로-1, 4-디하이드로-1-(4-하이드록시-2-메틸페닐)-7-(4-메틸-1-피페라지닐)-4-옥소-1, 8-나프티리딘-3-카복실산을 수득한다. The precipitated crystals were collected by filtration and washed in 10ml of a 6-fluoro-water having a melting point higher than 280 ℃ 1.8g -1, 4- dihydro-1- (4-hydroxy-2-methylphenyl) -7- (4 - possess methyl-1-piperazinyl) to give the 4-oxo-1, 8-naphthyridine-3-carboxylic acid.

IR(KBr)cm -1 : ν c=0 1725, 1700(sh) IR (KBr) cm -1: ν c = 0 1725, 1700 (sh)

NMR(TFA-d 1 )δ값 : 2.08(3H, s), 3.12(3H, s), 2.88-5.12(8H, m), 6.93-7.62(3H, m), 9.25(1H, s), 9.43(1H, d, J=13Hz) NMR (TFA-d 1) δ value: 2.08 (3H, s), 3.12 (3H, s), 2.88-5.12 (8H, m), 6.93-7.62 (3H, m), 9.25 (1H, s), 9.43 (1H, d, J = 13Hz)

유사한 방법으로 표 11의 화합물을 수득한다. In a similar manner to give the compounds shown in Table 11.

[표 11] [Table 11]

Figure kpo00036

Figure kpo00037

Figure kpo00038

[실시예 8] Example 8

10ml의 47% 브롬산중에 0.40g의 에틸 6-플루오로-1, 4-디하이드로-1-(4-메톡시페닐)-7-(1-피롤리디닐)-4-옥소-1, 8-나프티리딘-3-카복실레이트를 용해시키고, 생성된 용액을 120내지 125℃에서 2시간동안 반응시킨다. -1 with ethyl 6-fluoro 0.40g of 47% bromine in the mountains of 10ml, 4-dihydro-1- (4-methoxyphenyl) -7- (1-pyrrolidinyl) -4-oxo-1, 8 -naphthyridine-3-carboxylate was dissolved naphthyridine, and reacted for 2 hours, the resulting solution at 120 to 125 ℃. 반응혼합물의 pH를 10%수산화 나트륨 수용액으로 13으로 맞추고 이어서 아세트산으로 6.5로 맞춘다. Align the pH of the reaction mixture to 13 with 10% sodium hydroxide aqueous solution was then adjusted to 6.5 with acetic acid. 침전된 결정을 여과로 모으고 4ml의 물로 세척하여 융점이 263내지 265℃인 0.30g의 6-플루오로-1, 4-디하이드로-1-(4-하이드록시페닐)-7-(1-피롤리디닐)-4-옥소-1, 8-나프티리딘-3-카복실산을 수득한다. The precipitated crystals were collected by filtration and washed with water, 4ml of 0.30g of 6-fluoro-a melting point of 263 to 265 ℃ -1, 4-dihydro-1- (4-hydroxyphenyl) -7- (1-P a pyrrolidinyl) -4-oxo-1, 8-naphthyridine-3-carboxylic acid was obtained.

IR(KBr)cm -1 : ν c=0 1725, 1705 IR (KBr) cm -1: ν c = 0 1725, 1705

NMR(TFA-d 1 )δ값 : 1.54-2.40(4H, m), 3.14-4.14(4H, m), 6.95-7.69(4H, m), 8.09(1H, d, J=12Hz), 9.14(1H, s). NMR (TFA-d 1) δ value: 1.54-2.40 (4H, m), 3.14-4.14 (4H, m), 6.95-7.69 (4H, m), 8.09 (1H, d, J = 12Hz), 9.14 ( 1H, s).

유사한 방법으로, 다음 화합물을 수득한다 : In a similar manner, to give the following compounds:

6-플루오로-1, 4-디하이드로-1-(4-하이드록시페닐)-7-(3-하이드록시-1-피롤리디닐)-4-옥소-1, 8-나프티리딘-3-카복실산. 6-fluoro-1, 4-dihydro-1- (4-hydroxyphenyl) -7- (3-hydroxy-1-pyrrolidinyl) -4-oxo-1, 8-naphthyridin-3 carboxylic acid.

융점 : 180내지 183℃ Melting point: 180 to 183 ℃

IR(KBr)cm -1 : ν c=0 1725, 1705 IR (KBr) cm -1: ν c = 0 1725, 1705

[실시예 9] Example 9

0.1g의 에틸 7-(4-아세틸-1-피페라지닐)-6-플루오로-1-(4-플루오로페닐)-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실레이트에 2ml의 1N수산화 나트륨 수용액 및 2ml의 에탄올을 가하고, 생성된 용액을 40°내지 50℃에서 10분간 반응시킨다. 1- (4-fluorophenyl) ethyl-6-fluoro-7- (4-acetyl-1-piperazinyl) 0.1g of 1, 4-dihydro-4-oxo-1, 8-naphthyridin ethanol was added a 1N aqueous solution of sodium hydroxide and 2ml 2ml of a 3-carboxylate, and the resulting solution is allowed to react for 10 minutes at 40 ° to 50 ℃. 그 후에 아세트산을 가하여 pH를 6.5로 조절한다. After addition of acetic acid to adjust the pH to 6.5. 이어서 5ml씩의 클로로포름으로 2회 추출한다. Then extracted twice with chloroform in each 5ml. 추출물을 합하여 연속적으로 5ml의 물 및 5ml의 염화나트륨 포화수용액으로 세척한 다음 황산 마그네슘상에서 건조시킨다. After washing the combined extracts successively with water and a saturated sodium chloride aqueous solution of 5ml of 5ml, and then dried over magnesium sulfate. 감압하에 증류하여 용매를 제거하고, 얻어진 결정성 물질을 2ml의 디에틸 에테르로 세척하여 융점이 280℃보다 높은 0.08g의 7-(4-아세틸-1-피페라지닐)-6-플루오로-1-(4-플루오로페닐)-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실산을 수득한다. Was evaporated under reduced pressure to remove the solvent, the resulting crystalline material to the washed with diethyl ether, 2ml of a melting point (possess 4-acetyl-l-piperazinyl) 7 0.08g of higher than 280 ℃ -6-fluoro- 1- (4-fluorophenyl) -1, to obtain a 1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid.

IR(KBr)cm -1 : ν c=0 1725, 1700(sh) IR (KBr) cm -1: ν c = 0 1725, 1700 (sh)

NMR(d 6 -DMSO)δ값 : 2.05(3H, s), 3.57(8H, bs), 7.13-7.80(4H, m), 8.13(1H, d, J=13Hz), 8.70(1H, s). NMR (d 6 -DMSO) δ values: 2.05 (3H, s), 3.57 (8H, bs), 7.13-7.80 (4H, m), 8.13 (1H, d, J = 13Hz), 8.70 (1H, s) .

유사한 방법으로, 표 12의 화합물을 수득한다. In a similar manner, to give the compounds of Table 12.

[표 12] [Table 12]

Figure kpo00039

Figure kpo00040

Figure kpo00041

[실시예 10] Example 10

0.10g의 에틸 6-플루오로-1-(4-플루오로페닐)-1, 4-디하이드로-7-(3-하이드록시-1-피롤리디닐)-4-옥소-1, 8-나프티리딘-3-카복실레이트에 2ml에 1N수산화 나트륨 수용액 및 2ml의 에탄올을 가하고, 생성된 용액을 40°내지 50℃에서 10분간 반응시킨다. 1- (4-fluorophenyl) ethyl 6-fluoro 0.10g of 1, 4-dihydro-7- (3-hydroxy-1-pyrrolidinyl) -4-oxo-1, 8-naphthyridin in 2ml in naphthyridine-3-carboxylate was added to ethanol in 1N aqueous sodium hydroxide solution and 2ml, the resulting solution at 40 ° to 50 ℃ and reacted for 10 minutes. 그 후에, 아세트산을 가하여 pH를 6.5로 조절한다. Thereafter, the pH is adjusted to 6.5 by adding acetic acid. 이어서 5ml씩의 클로로포름으로 2회 추출한다. Then extracted twice with chloroform in each 5ml. 추출물을 합하여 연속적으로 5ml의 물 및 5ml의 염화 나트륨 포화수용액으로 세척한 다음 황산 마그네슘상에서 건조시킨다. The combined extracts were washed successively with water and a sodium chloride saturated aqueous solution of 5ml of 5ml, and then dried over magnesium sulfate. 감압하에 증류하여 용매를 제거하고, 얻어진 결정성 물질을 2ml의 디에틸 에테르로 세척하여 융점이 280℃보다 높은 0.08g의 6-플루오로-1(4-플루오로페닐)-1, 4-디하이드로-7-(3-하이드록시-1-피롤리디닐)-4-옥소-1, 8-나프티리딘-3-카복실산을 수득한다. By distillation under the reduced pressure to remove the solvent, the resulting crystalline material with diethyl ether, washed with fluoro 0.08g of a melting point of higher than 280 ℃ 6- to the 2ml -1 (4-fluorophenyl) -1, 4- the dihydro-7- (3-hydroxy-1-pyrrolidinyl) -4-oxo-1, 8-naphthyridine-3-carboxylic acid was obtained.

IR(KBr)cm -1 : ν c=0 1730 IR (KBr) cm -1: ν c = 0 1730

NMR(d 6 -DMSO)δ값 : 1.92-2.52(2H, m), 3.22-5.00(5H, m), 6.97-7.60(4H, m), 8.01(1H, d, J=11Hz), 9.00(1H, s). NMR (d 6 -DMSO) δ value: 1.92-2.52 (2H, m), 3.22-5.00 (5H, m), 6.97-7.60 (4H, m), 8.01 (1H, d, J = 11Hz), 9.00 ( 1H, s).

유사한 방법으로, 표 13의 화합물을 수득한다. In a similar manner, to give the compounds of Table 13.

[표 13] [Table 13]

Figure kpo00042

[실시예 11] Example 11

2.5ml의 진한 염산에 0.25g의 6-플루오로-1, 4-디하이드로-1-(4-하이드록시-2-메틸페닐)-4-옥소-7-(1-피페라지닐)-1, 8-나프티리딘-3-카복실산을 용해시키고, 이어서 20ml의 에탄올을 가한후에, 생성된 혼합물을 실온에서 15분간 교반한다. 6-Fluoro of 0.25g in 2.5ml concentrated hydrochloric acid in 1, 4-dihydro-1- (4-hydroxy-2-methyl-phenyl) -4-oxo-7- (1-piperazinyl) -1, 8-naphthyridin-naphthyridine-3-carboxylic acid was dissolved, followed by stirring for 15 minutes after adding 20ml of ethanol, and the resulting mixture at room temperature. 침전된 결정을 여과로 모으고 5ml의 에탄올로 세척하여 융점이 280℃보다 높은 0.2g의 6-플루오로-1, 4-디하이드로-1-(4-하이드록시-2-메틸페닐)-4-옥소-7-(1-피페라지닐)-1, 8-나프티리딘-3-카복실산의 염산염을 수득한다. To collect precipitated crystals by filtration, washed with 5ml of ethanol, 6-fluoro 0.2g of a melting point of higher than 280 ℃ -1, 4-dihydro-1- (4-hydroxy-2-methyl-phenyl) -4-oxo 7- (1-piperazinyl) -1, 8-naphthyridine-3-carboxylic acid, to obtain the hydrochloride of the naphthyridine.

IR(KBr)cm -1 : ν c=0 1725(sh), 1705 IR (KBr) cm -1: ν c = 0 1725 (sh), 1705

유사한 방법으로 표 14의 화합물을 수득한다. In a similar manner to give the compounds of Table 14.

[표 14] [Table 14]

Figure kpo00043

Figure kpo00044

[실시예 12] Example 12

20ml의 진한 염산에 2.0g의 7-(3-아미노-1-피롤리디닐)-6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실산을 용해시키고, 이어서 실온에서 200ml의 에탄올을 가한후에, 생성된 혼합물을 15분간 교반한다. Of 2.0g of concentrated hydrochloric acid in 20ml 7- (3- amino-1-pyrrolidinyl) -6-fluoro-1- (2, 4-difluorophenyl) -1, 4-dihydro-4-oxo 1, 8-naphthyridin-naphthyridine-3-carboxylic acid was dissolved, and then stirred after adding 200ml of ethanol at room temperature, the resulting mixture for 15 minutes. 침전된 결정을 여과로 모으고 40ml의 에탄올로 세척하여 융점이 247내지 250℃(분해)인 1.4g의 7-(3-아미노-1-피롤리디닐)-6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실산의 염산염을 수득한다. 1- (2, and the precipitated crystals collected by filtration and washed with a 40ml of ethanol, 1.4g of a melting point of 247 to 250 ℃ (decomposition) 7- (3-amino-1-pyrrolidinyl) -6-fluoro, 4-difluorophenyl) - 1, to obtain the hydrochloride salt of 1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid.

IR(KBr)cm -1 : ν c=0 1730 IR (KBr) cm -1: ν c = 0 1730

[실시예 13] Example 13

(1) 25ml의 클로로포름중에 0.5g의 에틸 2-(2, 6-디클로로-5-플루오로니코티노일)-3-(2, 4-디플루오로페닐아미노)아크릴레이트, 0.143g의 N-메틸피페라진 및 0.145g의 트리에틸 아민을 용해시키고, 생성된 용액을 환류하에 3.5시간동안 가열한다. (1) (2, 6-dichloro-5-fluoro-nicotinoyl) 0.5g of ethyl 2 in chloroform in 25ml -3- (2, 4-difluoro-phenylamino) acrylate, 0.143g of N- methyl piperazine and dissolved in 0.145g of triethylamine, and heated for 3.5 hours and the resulting solution under reflux. 이어서, 반응혼합물을 연속적으로 3ml의 물 및 3ml의 염화나트륨 포화수용액으로 세척한 다음 무수황산 마그네슘상에서 건조시킨다. Then, the reaction mixture was washed successively with water and a saturated sodium chloride aqueous solution in 3ml of 3ml then dried over anhydrous magnesium sulfate. 감압하에 증류하여 용매를 제거하고, 얻어진 잔사를 칼럼 크로마토그라피 [WAKO SILICA GEL C-200, 용출제 : 클로로포름 : 에탄올=50 : 1(용적비)]로 정제하여 0.294g의 오일성 에틸 2-[2-클로로-5-플루오로-6-(4-메틸-1-피페라지닐)니코티노일]-3-(2, 4-디플루오로페닐아미노)아크릴레이트를 수득한다. Was evaporated under reduced pressure to remove the solvent, the residue thus obtained was purified by column chromatography [eluent WAKO SILICA GEL C-200,: chloroform: ethanol = 50: 1 (volume ratio)] to give oily ethyl 0.294g of 2- [2- chloro-5-fluoro-6- (4-methyl-1-piperazinyl) nicotinoyl] -3, to obtain the (2, 4-difluoro-phenylamino) acrylate.

IR(Neat)cm -1 : ν c=0 1735, 1700 IR (Neat) cm -1: ν c = 0 1735, 1700

NMR(CDCl 3 )δ값 : 1.13(3H, t, J=7Hz), 2.36(3H, s), 2.55(4H, t, J=5Hz), 3.70(4H, t, J=5Hz), 4.15(2H, q, J=7Hz),6.77-7.90(4H, m), 8.51(1H, d, J=13Hz), 12.50(1H, d, J=13Hz). NMR (CDCl 3) δ value: 1.13 (3H, t, J = 7Hz), 2.36 (3H, s), 2.55 (4H, t, J = 5Hz), 3.70 (4H, t, J = 5Hz), 4.15 ( 2H, q, J = 7Hz), 6.77-7.90 (4H, m), 8.51 (1H, d, J = 13Hz), 12.50 (1H, d, J = 13Hz).

(2) 실시예 6및 9와 동일한 방법으로 0.2g의 에틸 2-[2-클로로-5-플루오로-6-(4-메틸-1-피페라지닐)니코티노일]-3-(2, 4-디플루오로페닐-아미노)아크릴 레이트를 처리함으로써, 융점이 208내지 209℃인 0.12g의 6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-7-(4-메틸-1-피페라지닐)-4-옥소-1, 8-나프티리딘-3-카복실산을 수득한다. (2) Examples 6 and [2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) nicotinoyl] 0.2g of 2-ethyl-3-9 in the same manner as (2 , 4-fluoro-phenyl-amino) by treatment with an acrylate, a melting point of 1 - (2, 4-difluorophenyl 6-fluoro of 208 to 209 ℃ 0.12g) -1, 4-dihydro- the 7- (4-methyl-1-piperazinyl) -4-oxo-1, 8-naphthyridine-3-carboxylic acid was obtained.

[실시예 14] Example 14

0.3g의 에틸 7-(4-에톡시카보닐-2-메틸-1-피페라지닐)-6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실레이트에 5ml의 1n수산화 나트륨 수용액 및 5ml의 에탄올을 가하고, 생성된 용액을 90℃에서 2시간 동안 반응시킨다. Ethyl 7- 0.3g of (4-ethoxy-carbonyl-2-methyl-1-piperazinyl) -6-fluoro-1- (2, 4-difluorophenyl) -1, 4-dihydro- 4-oxo-1, 8-naphthyridin-ethanol was added to 1n of the aqueous solution of sodium hydroxide, 5ml and 5ml of a 3-carboxylate, and the resulting solution is allowed to react for 2 hours at 90 ℃. 그후에, 아세트산을 가하여 pH를 6.5로 조절한다. Thereafter, the pH is adjusted to 6.5 by adding acetic acid. 침전된 결정을 여과로 모아서, 물로 세척하고 이어서 건조시켜 융점이 230내지 239℃인 0.2g의 디에틸 에테르로 세척하여 0.08g의 6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-7-(2-메틸-1-피페라지닐)-4-옥소-1, 8-나프티리딘-3-카복실산을 수득한다. Collecting the precipitated crystals by filtration, washed and then dried to give the 1-6-fluoro-of 0.08g was washed with diethyl ether, 0.2g of 230 to 239 ℃ (2, 4-difluorophenyl) Melting point of water 1, to give the 1,4-dihydro-7- (2-methyl-1-piperazinyl) -4-oxo-1, 8-naphthyridine-3-carboxylic acid.

IR(KBr)cm -1 : ν c=0 1730 IR (KBr) cm -1: ν c = 0 1730

NMR(TFA-d 1 )δ값 : 1.50(3H, s), 3.20-5.15(7H, m), 7.00-7.90(3H, m), 8.35(1H, d, J=13Hz), 9.20(1H, s). NMR (TFA-d 1) δ value: 1.50 (3H, s), 3.20-5.15 (7H, m), 7.00-7.90 (3H, m), 8.35 (1H, d, J = 13Hz), 9.20 (1H, s).

[실시예 15] Example 15

20ml의 에탄올중에 1.0g의 3-아미노 피롤리딘의 중염산 염을 현탁시키고, 여기에 2.06g의 트리에틸아민을 가하여 용액을 만든다. Suspending the hydrochloride salt of the 1.0g of 3- aminopyrrolidine in ethanol of 20ml was to make the solution was added 2.06g of triethylamine here. 이어서, 이 용액에 2.0g의 에틸 7-클로로-6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실레이트를 30℃에서 15분에 걸쳐 가한다음, 생성된 혼합물을 동일 온도에서 3시간동안 반응시킨다. Then, with ethyl 7-chloro-6-fluoro 2.0g To this solution was added 1- (2,4-difluorophenyl) -1, 4-dihydro-4-oxo-1, 8-naphthyridine -3 - adding the carboxylate in 30 ℃ over 15 minutes and then, the resulting mixture is allowed to react for 3 hours at the same temperature. 반응이 끝난 후에, 30ml의 물을 가하고, 침전되는 결정을 여과로 모아서 4ml의 물로 세척한다. After the reaction was over, it added to 30ml of water, and washed the crystals that precipitate collected by filtration with water in 4ml. 얻어진 결정성 물질은 13ml의 6N염산중에 현탁시키고, 생성된 현탁액을 환류하에 2시간동안 가열한다. Crystalline material thus obtained is heated for 2 hours under suspended in 6N yeomsanjung of 13ml, reflux the resulting suspension. 그후에, 반응 혼합물을 냉각시키고, 침전된 결정을 여과로 모아서 2ml씩의 물로 2회 세척하여 1.97g의 7-(3-아미노-1-피롤리디닐)-6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실산의 염산염을 수득한다. Thereafter, the reaction mixture was allowed to cool, 1-precipitated crystals collected by filtration and washed twice with water by 2ml of a 7- (3-amino-1-pyrrolidinyl) -6- fluoro 1.97g of (2, 4-difluorophenyl) - 1, to obtain the hydrochloride salt of 1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid.

IR(KBr)cm -1 : ν c=0 1730 IR (KBr) cm -1: ν c = 0 1730

[실시예 16] Example 16

75ml의 에탄올 및 75ml의 물중에 10.0g의 7-(3-아미노-1-피롤리디닐)-6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실산을 현탁시킨다. From 7 10.0g of (3- amino-1-pyrrolidinyl) -6-fluoro-in 75ml of ethanol and 75ml of water, 1 - (2, 4-difluorophenyl) -1, 4-dihydro- 4-oxo-1, 8-naphthyridine is suspended a naphthyridine-3-carboxylic acid. 생성된 현탁액에 5.2g의 P-톨루엔설폰산 일수화물을 40℃에서 가하고, 생성된 혼합물을 같은 온도에서 30분간 교반한다. The P- toluenesulfonic acid monohydrate 5.2g of the resulting suspension was added at 40 ℃, and the mixture was stirred for 30 minutes at the same temperature and the resulting mixture. 그후에, 반응 혼합물을 15℃로 냉각시키고, 침전된 결정을 여과로 모아서 5ml의 에탄올 및 5ml의 물의 혼합 용매로 세척하여 융점이 258내지 260℃인 12.8g의 7-(3-아미노-1-피롤리디닐)-6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실산의 P-톨루엔설폰산 일수화물염을 수득한다. Thereafter, the reaction mixture was cooled to 15 ℃, of water and washed with a mixed solvent of ethanol and 5ml of 5ml collecting the precipitated crystal by filtration having a melting point of 258 to 260 ℃ 12.8g 7- (3- amino-1-P pyrrolidinyl) -6-fluoro-1- (2, 4-difluorophenyl) -1, 4-dihydro-4-oxo-1, 8-naphthyridin-naphthyridine-3-carboxylic acid of the P- toluenesulfonic acid days to give the monohydrate salt.

IR(KBr)cm -1 : ν c=0 1735 IR (KBr) cm -1: ν c = 0 1735

Figure kpo00045

유사한 방법으로 다음 화합물을 수득한다. In a similar way, to obtain the following compound.

7-(3-아미노-1-피롤리디닐)-6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실산의 옥살산염 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2, 4-difluorophenyl) -1, 4-dihydro-4-oxo-1, 8-naphthyridin- oxalate of 3-carboxylic acid

융점(℃) : 250-253 Melting point (℃): 250-253

IR(KBr)cm -1 : ν c=0 1730 IR (KBr) cm -1: ν c = 0 1730

[실시예 17] Example 17

1.6g의 메탄설폰산 및 25ml의 아세트산 용액에 5.00g의 7-(3-아미노-1-피롤리디닐)-6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실산을 가한 후에, 생성된 현탁액을 실온에서 교반하여 용액을 만든다. In acetic acid a solution of methane sulfonic acid and 25ml of a 1.6g of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1-of 5.00g (2, 4-difluorophenyl) -1, 4 -dihydro-4-oxo-1, 8-naphthyridin after adding the naphthyridin-3-carboxylic acid, followed by stirring the resulting suspension at room temperature to make the solution. 그 용액에 100ml의 에탄올을 40내지 45℃에서 30분에 걸쳐 가한다. From 40 to 45 ℃ 100ml of ethanol in the solution it is added over 30 minutes. 그 후에 반응혼합물을 실온으로 냉각시키고, 30분간 교반한다. Thereafter the reaction mixture was cooled to room temperature, the mixture was stirred for 30 minutes. 침전된 결정을 여과하여 모으고 20ml씩의 에탄올로 3회 세척하여 융점이 300℃보다 높은 3.12g의 7-(3-아미노-1-피롤리디닐)-6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실산의 메탄설폰산을 수득한다. To collect by filtration of the precipitated crystals were washed three times with 20ml of ethanol by a melting point higher than 300 ℃ 3.12g 7- (3- amino-1-pyrrolidinyl) -6-fluoro-1- (2, 4 -difluorophenyl) -1, 4-dihydro-4-oxo-1, 8-naphthyridine to give the methane sulfonate of the naphthyridine-3-carboxylic acid.

IR(KBr)cm -1 : ν c=0 1735 IR (KBr) cm -1: ν c = 0 1735

유사한 방법으로 다음 화합물을 수득한다 : To give the following compounds in a similar manner:

7-(3-아미노-1-피롤리디닐)-6-플루오로-1-(2, 4-디플루오로페닐)-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실산의 황산염. 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2, 4-difluorophenyl) -1, 4-dihydro-4-oxo-1, 8-naphthyridin- sulfates of the 3-carboxylic acid.

융점(℃) : 220-230 Melting point (℃): 220-230

IR(KBr)cm -1 : ν c=0 1735 IR (KBr) cm -1: ν c = 0 1735

[제조 실시예 1] [Preparation Example 1 embodiment;

50g의 6-플루오로-1-(2, 4-디플루오로페닐-1, 4-디하이드로-4-옥소-7-(1-피페라지닐)-1, 8-나프티리딘-3-카복실산을 49g의 결정성 셀룰로즈, 50g의 옥수수전분 및 1g의 마그테슘 스테아레이트와 혼합하고, 그 혼합물을 압축하여 1000개의 납작한 정제를 제조한다. 1 - (2 6-Fluoro of 50g, 4-difluoro-phenyl-1, 4-dihydro-4-oxo-7- (1-piperazinyl) -1, 8-naphthyridine-3-carboxylic acid to the cellulose of 49g, mixed with the mug potassium stearate, corn starch, and 50g of 1g and compressing the mixture to produce a 1000 flat tablets.

[제조 실시예 2] [Preparation Example 2]

100g의 6-플루오로-1-(2, 4-디플루오로페닐-1, 4-디하이드로-4-옥소-7-(1-피페라지닐)-1, 8 나프티리딘-3-카복실산을 50g의 옥수수전분과 혼합하고, 이 혼합물을 1000개의 캅셀에 충진시켜서 캅셀제를 제조한다. 6-Fluoro of 100g -1- (2, 4-difluorophenyl-1, 4-dihydro-4-oxo-7- (1-piperazinyl) -1, 8-naphthyridine-3-carboxylic acid mixed with 50g of corn starch, and by filling the mixture in 1000 capsules to prepare the capsule.

[제조 실시예 3] [Preparation Example 3]

50g의 7-(3-아미노-1-피롤리디닐)-1-(2, 4-디플루오로페닐)-6-플루오로-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실산을 49g의 결정성 셀룰로즈, 50g의 옥수수 전분 및 1g의 마그네슘 스테아레이트와 혼합하고, 그 혼합물을 압축하여 1000개의 납작한 정제를 제조한다. 50g 7- (3- amino-1-pyrrolidinyl) -1-fluoro-1 (2, 4-difluorophenyl), 4-dihydro-4-oxo-1, 8-naphthyridin naphthyridine-3-carboxylic acid mixed with the crystal of 49g cellulose, magnesium stearate, corn starch, and 50g of 1g and compresses the mixture to produce a 1000 flat tablets.

[제조 실시예 4] [Preparation Example 4]

100g의 7-(3-아미노-1-피롤리디닐)-1-(2, 4-디플루오로페닐)-6-플루오로-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실산과 50g의 옥수수전분을 혼합하고, 그 혼합물을 1000개의 캅셀에 충진시켜 캅셀제를 제조한다. 100g 7- (3- amino-1-pyrrolidinyl) -1-fluoro-1 (2, 4-difluorophenyl), 4-dihydro-4-oxo-1, 8-naphthyridin mixture of corn starch and 50g of a naphthyridine-3-carboxylic acid, which was filled with the mixture in 1000 capsules to prepare the capsule.

Claims (12)

  1. 일반식(V')의 화합물 또는 그의 염을 폐환시킨 다음, 보호그룹을 제거함을 특징으로 하여, 일반식(Ⅰ)의 1, 4-디하이드로-4-옥소나프티리딘 유도체 또는 그의 염을 제조하는 방법. Which ring closing a compound of formula (V ') to the next, characterized by removing the protecting group, one of the general formula (Ⅰ), 4- dihydro-4-oxo-naphthyridine derivative or a salt thereof for preparing a Way.
    Figure kpo00046
    상기식에서, R 1 은 수소원자이고, R 2 는 불소원자, C 1-4 알킬그룹 및 하이드록실 그룹으로 이루어진 그룹으로부터 선택된 적어도 하나의 치환체에 의해 치환될 수 있는 페닐그룹이며, R 3 는 C 1-4 알킬그룹, 아미노그룹, 하이드록시그룹 및 C 1-4 알킬아미노그룹으로 이루어진 그룹으로부터 선택된 치환체에 의해 치환될 수 있는 1-피롤리디닐 또는 1-피페라지닐 그룹이고, R 1a 는 카복실-보호그룹이며, R 2a 는 불소원자, C 1-4 알킬그룹 및 임의로 보호될 수 있는 하이드록실그룹으로 이루어진 그룹으로부터 선택된 적어도 하나의 치환체에 의해 치환될 수 있는 페닐그룹이고, R 3a 는 C 1-4 알킬그룹 및 C 1-4 알킬아미노그룹 및 임의로 보호될 수 있는 아미노 및 하이드록시 그룹으로 이루어진 그룹으로부터 선택된 치환체에 의해 치환될 수 있는 1-피롤리디닐 또는 Wherein, R 1 is a hydrogen atom, R 2 is a phenyl group which may be substituted by at least one substituent selected from the group consisting of a fluorine atom, C 1-4 alkyl group and a hydroxyl group, R 3 is C 1 -4 alkyl group, amino group, hydroxy group and C 1-4 is 1-pyrrolidinyl or 1-piperazinyl group which may be substituted by a substituent selected from the group consisting of an alkylamino group, R 1a is a carboxyl- the protecting group, R 2a is a phenyl group which may be substituted by at least one substituent selected from the group consisting of a hydroxyl group which may be protected with a fluorine atom, C 1-4 alkyl groups, and optionally, R 3a is a C 1- 4 alkyl groups and C 1-4 alkylamino groups, and which optionally may be substituted by a substituent selected from the group consisting of amino and hydroxy groups which may be protected with 1-pyrrolidinyl, or 1-피페라지닐그룹이다. 1-P is the piperazinyl group.
  2. 제1항에 있어서, 7-(3-아미노-1-피롤리디닐)-1-(2, 4-디플루오로페닐)-6-플루오로-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실산 또는 그의 염을 제조하는 방법. The method of claim 1, wherein 7- (3-amino-1-pyrrolidinyl) -1- (2, 4-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo -1 , 8-naphthyridine process for preparing 3-carboxylic acid or a salt thereof.
  3. 제1항에 있어서, 1-(2, 4-디플루오로페닐)-6-플루오로-1, 4-디하이드로-4-옥소-7-(1-피페라지닐)-1, 8-나프티리딘-3-카복실산 또는 그의 염을 제조하는 방법. In accordance with claim 1, 1- (2, 4-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo-7- (1-piperazinyl) -1, 8-naphthyridin naphthyridine-3-carboxylic acid or the method for producing a salt.
  4. 일반식(Ⅰ'a)의 호합물 또는 그의 염을 일반식 R 3a H(여기서, R 3a 는 하기 정의하는 바와같다)의 화합물 또는 그의 염과 반응시킨 다음 보호그룹을 제거함을 특징으로 하여, 일반식(Ⅰ)의 1, 4-디하이드로-4-옥소-나프티리딘 유도체 또는 그의 염을 제조하는 방법. Hohap the water or the salt thereof represented by the general formula (Ⅰ'a) the formula R 3a H and characterized by the removal of the protecting group and then reaction of that compound, or a salt thereof, and (wherein, R 3a is as defined below), Common 1 of the formula (ⅰ), 4- dihydro-4-oxo-process for preparing a naphthyridine derivative or a salt thereof.
    Figure kpo00047
    상기식에서, R 1 은 수소원자이고, R 2 는 불소원자, C 1-4 알킬그룹 및 하이드록실 그룹으로 이루어진 그룹으로부터 선택된 적어도 하나의 치환체에 의해 치환될 수 있는 페닐그룹이며, R 3 는 C 1-4 알킬그룹, 아미노그룹, 하이드록시그룹 및 C 1-4 알킬아미노그룹으로 이루어진 그룹으로부터 선택된 치환체에 의해 치환될 수 있는 1-피롤리디닐 또는 1-피페라지닐 그룹이고, R 1a 는 카복실-보호그룹이며, R 2a 는 불소원자, C 1-4 알킬그룹 및 임의로 보호될 수 있는 하이드록실 그룹으로 이루어진 그룹으로부터 선택된 적어도 하나의 치환체에 의해 치환될 수 있는 페닐그룹이고, R 3b 는 할로겐 원자이며, R 3a 는 C 1-4 알킬그룹 및 C 1-4 알킬아미노그룹 및 임의로 보호될 수 있는 아미노 및 하이드록시 그룹으로부터 선택된 치환체에 의해 치환될 수 있는 1-피롤리디닐 Wherein, R 1 is a hydrogen atom, R 2 is a phenyl group which may be substituted by at least one substituent selected from the group consisting of a fluorine atom, C 1-4 alkyl group and a hydroxyl group, R 3 is C 1 -4 alkyl group, amino group, hydroxy group and C 1-4 is 1-pyrrolidinyl or 1-piperazinyl group which may be substituted by a substituent selected from the group consisting of an alkylamino group, R 1a is a carboxyl- the protecting group, R 2a is a phenyl group which may be substituted by at least one substituent selected from the group consisting of a hydroxyl group which may be protected with a fluorine atom, C 1-4 alkyl groups, and optionally, R 3b is a halogen atom , R 3a is C 1-4 alkyl groups and C 1-4 alkylamino groups, and which optionally may be substituted by a substituent selected from amino and hydroxy groups that may be protected 1-pyrrolidinyl 또는 1-피페라지닐그룹이다. Or 1-piperazinyl group is blood.
    Figure kpo00047
  5. 제4항에 있어서, 7-(3-아미노-1-피롤리디닐)-1-(2, 4-디플루오로페닐)-6-플루오로-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실산 또는 그의 염을 제조하는 방법. 4 wherein, 7- (3-amino-1-pyrrolidinyl) -1- (2, 4-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo -1 , 8-naphthyridine process for preparing 3-carboxylic acid or a salt thereof.
  6. 제4항에 있어서, 1-(2, 4-디플로오로페닐)-6-플루오로-1, 4-디하이드로-4-옥소-7-(1-피페라지닐)-1, 8-나프티리딘-3-카복실산 또는 그의 염을 제조하는 방법. 4 wherein 1- (2,4-deployment by oro-phenyl) -6-fluoro-1, 4-dihydro-4-oxo-7- (1-piperazinyl) -1, 8-naphthyridin in naphthyridine-3-carboxylic acid or the method for producing a salt.
  7. 일반식(1a)의 화합물 또는 그의 염을 일반식 R 3 H(여기서, R 3 은 하기 정의하는 바와같다)의 화합물 또는 그의 염과 반응시킴을 특징으로 하여, 일반식(Ⅰ)의 1, 4-디하이드로-4-옥소-나프티리딘 유도체 또는 그의 염을 제조하는 방법. A compound of Formula (1a) Formula R 3 H to characterized the compounds or Sikkim salts thereof as the reaction of (wherein, R 3 is to the same as that defined), 1, 4 in the formula (Ⅰ) -dihydro-4-oxo-naphthyridine derivative or a method for producing a salt.
    Figure kpo00048
    상기식에서, R 1 은 수소원자이고, R 2 는 불소원자, C 1-4 알킬그룹 및 하이드록실 그룹으로 이루어진 그룹으로부터 선택된 적어도 하나의 치환체에 의해 치환될 수 있는 페닐그룹이며, R 3 는 C 1-4 알킬그룹, 아미노그룹, 하이드록시 그룹 및 C 1-4 알킬아미노그룹으로 이루어진 그룹으로부터 선택된 치환체에 의해 치환될 수 있는 1-피롤리디닐 또는 1-피페라지닐 그룹이고, R 3b 는 할로겐 원자이다. Wherein, R 1 is a hydrogen atom, R 2 is a phenyl group which may be substituted by at least one substituent selected from the group consisting of a fluorine atom, C 1-4 alkyl group and a hydroxyl group, R 3 is C 1 -4 alkyl group, amino group, hydroxy group and C 1-4 is 1-pyrrolidinyl or 1-piperazinyl group which may be substituted by a substituent selected from the group consisting of an alkylamino group, R 3b represents a halogen atom to be.
  8. 제7항에 있어서, 7-(3-아미노-1-피롤리디닐)-1-(2, 4-디플루오로페닐)-6-플루오로-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실산 또는 그의 염을 제조하는 방법. Claim 7, 7- (3-amino-1-pyrrolidinyl) -1- (2, 4-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo -1 , 8-naphthyridine process for preparing 3-carboxylic acid or a salt thereof.
  9. 제7항에 있어서, 1-(2, 4-디플루오로페닐)-6-플루오로-1, 4-디하이드로-4-옥소-7-(1-피페라지닐)-1, 8-나프티리딘-3-카복실산 또는 그의 염을 제조하는 방법. According to claim 7 wherein 1- (2, 4-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo-7- (1-piperazinyl) -1, 8-naphthyridin naphthyridine-3-carboxylic acid or the method for producing a salt.
  10. 일반식(Ⅰa˝)의 화합물 또는 그의 염을 일반식 R 3c H(여기서, R 3c 는 보호된 아미노그룹 및 보호된 하이드록실그룹으로 이루어진 그룹으로부터 선택된 치환체에 의해 치환될 수 있는 1-피롤리디닐 또는 1-피페라지닐 그룹이다)의 화합물 또는 그의 염과 반응시킨 다음 보호그룹을 제거함을 특징으로 하여, 일반식(Ⅰ)의 1, 4-디하이드로-4-옥소-나프티리딘 유도체 또는 그의 염을 제조하는 방법. A compound of formula (Ⅰa˝) the formula R 3c H (wherein, R 3c is 1-P which may be substituted by a substituent selected from the group consisting of a protected amino group and a protected hydroxyl group, pyrrolidinyl or 1-piperazinyl which possess a group) or a salt thereof and reaction of the features and then removing the protecting group, one of the general formula (ⅰ), 4- dihydro-4-oxo-naphthyridine derivative or a salt thereof, method for manufacturing.
    Figure kpo00049
    상기식에서, R 1 은 수소원자이고, R 2 는 불소원자, C 1-4 알킬그룹 및 하이드록실 그룹으로 이루어진 그룹으로부터 선택된 적어도 하나의 치환체에 의해 치환될 수 있는 페닐그룹이며, R 3 는 C 1-4 알킬그룹, 아미노그룹, 하이드록시 그룹 및 C 1-4 알킬아미노그룹으로 이루어진 그룹으로부터 선택된 치환체에 의해 치환될 수 있는 1-피롤리디닐 또는 1-피페라지닐 그룹이고, R 2a 는 불소원자, C 1-4 알킬그룹 및 임의로 보호될 수 있는 하이드록실 그룹으로 이루어진 그룹으로부터 선택된 적어도 하나의 치환체에 의해 치환될 수 있는 페닐그룹이며, R 3b 는 할로겐 원자이다. Wherein, R 1 is a hydrogen atom, R 2 is a phenyl group which may be substituted by at least one substituent selected from the group consisting of a fluorine atom, C 1-4 alkyl group and a hydroxyl group, R 3 is C 1 -4 alkyl group, amino group, hydroxy group and C 1-4 is 1-pyrrolidinyl or 1-piperazinyl group which may be substituted by a substituent selected from the group consisting of an alkylamino group, R 2a is fluorine atom , a phenyl group which may be substituted by at least one substituent selected from the group consisting of a C 1-4 alkyl group and optionally a hydroxyl group which may be protected, R 3b represents a halogen atom.
  11. 제10항에 있어서, 7-(3-아미노-1-피롤리디닐)-1-(2, 4-디플루오로페닐)-6-플루오로-1, 4-디하이드로-4-옥소-1, 8-나프티리딘-3-카복실산 또는 그의 염을 제조하는 방법. Claim 10 wherein, 7- (3-amino-1-pyrrolidinyl) -1- (2, 4-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo -1 , 8-naphthyridine process for preparing 3-carboxylic acid or a salt thereof.
  12. 제10항에 있어서, 1-(2, 4-디플루오로페닐)-6-플루오로-1, 4-디하 이드로-4-옥소-7-(1-피페라지닐)-1, 8-나프티리딘-3-카복실산 또는 그의 염을 제조하는 방법. According to claim 10, wherein the fluoro-1- (2, 4-difluorophenyl) -1, 4 diha Jethro-4-oxo-7- (1-piperazinyl) -1, 8-naphthyridin naphthyridine-3-carboxylic acid or the method for producing a salt.
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AR223983A1 (en) * 1978-08-25 1981-10-15 Dainippon Pharmaceutical Co A process for preparing derivatives of acid-6-halogeno-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid
DE3033157A1 (en) * 1980-09-03 1982-04-01 Bayer Ag 7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-naphthyridine-3-carboxylic acids, process for their preparation and antibacterial agents containing
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Publication number Priority date Publication date Assignee Title
KR100981351B1 (en) * 2003-10-29 2010-09-10 주식회사 엘지생명과학 Process for preparing 7-chloro-1-cyclopropyl-6- fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid

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