KR19990023074A - New pyridonecarboxylic acid derivatives - Google Patents
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Abstract
본 발명은 AIDS(Acquired Immunodeficiency Syndrome)를 유발하는 HIV(Human Immunodeficiency Virus)의 증식에 필수효소인 역전사효소를 저해하는 작용이 우수한 신규 피리돈 카르복실산 유도체에 관한 것으로서, 더욱 상세하기로는 다음 화학식 1로 표시되는 피리돈 카르복실산 유도체, 그의 약제학적으로 허용가능한 염 및 그의 제조방법에 관한 것이다.The present invention relates to a novel pyridone carboxylic acid derivative having excellent action of inhibiting reverse transcriptase which is an essential enzyme for proliferation of HIV (Human Immunodeficiency Virus), which induces AIDS (Acquired Immunodeficiency Syndrome). It relates to a pyridone carboxylic acid derivative, a pharmaceutically acceptable salt thereof, and a preparation method thereof.
상기 화학식에서In the above formula
X는 CH 또는 질소원자이고, A는 3-아미노피롤리딘, C1-3의 저급알킬기가 1-3개 치환 또는 비치환된 피페라진이고, B는 나프틸기 또는 퀴놀릴기이다.X is CH or a nitrogen atom, A is 3-aminopyrrolidine, piperazine in which a lower alkyl group of C 1-3 is substituted or unsubstituted, and B is a naphthyl group or a quinolyl group.
Description
본 발명은 AIDS(Acquired Immunodeficiency Syndrome)를 유발하는 HIV(Human Immunodeficiency Virus)의 증식에 필수효소인 역전사효소를 저해하는 작용이 우수한 신규 피리돈 카르복실산 유도체에 관한 것으로서, 더욱 상세하기로는 다음 화학식 1로 표시되는 피리돈 카르복실산 유도체, 그의 약제학적으로 허용가능한 염 및 그의 제조방법에 관한 것이다.The present invention relates to a novel pyridone carboxylic acid derivative having excellent action of inhibiting reverse transcriptase which is an essential enzyme for proliferation of HIV (Human Immunodeficiency Virus), which induces AIDS (Acquired Immunodeficiency Syndrome). It relates to a pyridone carboxylic acid derivative, a pharmaceutically acceptable salt thereof, and a preparation method thereof.
화학식 1Formula 1
상기 화학식에서In the above formula
X는 CH 또는 질소원자이고, A는 3-아미노피롤리딘, C1-3의 저급알킬기가 1-3개 치환 또는 비치환된 피페라진이고, B는 나프틸기 또는 퀴놀릴기이다.X is CH or a nitrogen atom, A is 3-aminopyrrolidine, piperazine in which a lower alkyl group of C 1-3 is substituted or unsubstituted, and B is a naphthyl group or a quinolyl group.
20세기 인류의 재앙이라 불리워지는 후천성 면역 결핍 증후군(AIDS)을 발생시키는 HIV는 인체의 면역작용을 조절하는 림프구내의 T4세포에 흡착하여 T4세포를 죽이거나 무력화 시킴으로써 인체의 면역기능을 저하시키는 역할을 한다. 이러한 면역기능 저하는 기회감염과 종양(neoplasia)을 유발함으로써 치명적인 병으로 발전시킨다. 불행히도 이러한 HIV감염에 의한 환자는 국내외적으로 이미 상당수 보고되어 있고 그 감염의 확산 속도가 빠른 것을 감안한다면 AIDS치료제의 개발이 긴급하게 절실히 요구되고 있다. AIDS 치료의 방법에는 크게 기회감염의 예방, 면역 체계의 증강, 항바이러스 화학요법제 및 백신개발 등으로 나눌 수 있다.HIV, which causes acquired immune deficiency syndrome (AIDS), which is called the plague of humans in the twentieth century, absorbs T4 cells in lymphocytes that control the body's immune function, kills or neutralizes T4 cells, and lowers the body's immune function. do. This decrease in immune function leads to fatal disease by causing opportunistic infections and neoplasia. Unfortunately, many HIV-infected patients have been reported both at home and abroad, and the development of AIDS treatments is urgently needed in view of the rapid spread of the infection. The methods of AIDS treatment can be broadly divided into prevention of opportunistic infection, strengthening of immune system, development of antiviral chemotherapeutic agents and vaccines.
AIDS 치료제의 개발은 1981년 AIDS환자가 처음 보고된 후, 1984년경에 AIDS를 일으키는 병원균이 HIV라는 것이 알려지게 되면서 활기를 띠게 되었다. 그 후 세계적으로 AIDS문제가 확대되면서 그 치료제 개발이 시급하게 되었고 이를 해결하기위한 연구의 중요한 한 분야로 역전사효소(reverse transcriptase, RT)저해제들이 집중적으로 개발되어 왔다. 이 과정에서 HIV-RT의 강력한 저해제인 AZT가 개발되었고, 이것을 선도물질로 하여 많은 뉴클레오사이드유도체들이 합성되었다. 이들중에 항HIV활성이 우수한 화합물들이 많이 개발되었으나, 이들은 대부분 항HIV활성은 우수하지만 세포독성, 내성균의 발현, 생체내이용율의 미흡 등의 많은 문제점을 가지고 있다. 최근에 피리돈카르복실산 골격을 가진 오플로삭신이 HIV억제 효과가 있다고 보고되었고(J. Nozaki, Renard et al., AIDS 4, 1283(1990)), 그 외에도 바이엘사와 우베사등에서 다양한 피리돈 카르복실산 유도체들의 HIV억제 효과를 입증하였지만(WO9602512, WO9602532, WO9602533, WO9602539 등) 아직까지 완전한 HIV억제제의 개발은 이루어지지 않고 있다.The development of AIDS treatments came to life after the first reports of AIDS patients in 1981 and the discovery of HIV as the pathogen causing AIDS around 1984. Since then, as the AIDS problem has expanded worldwide, the development of therapeutics is urgent, and reverse transcriptase (RT) inhibitors have been intensively developed as an important field of research to solve this problem. In the process, AZT, a potent inhibitor of HIV-RT, was developed, and many nucleoside derivatives were synthesized using this as a precursor. Among them, many compounds with excellent anti-HIV activity have been developed, but most of them have excellent problems such as cytotoxicity, expression of resistant bacteria, and insufficient bioavailability. Ofloxacin with a pyridonecarboxylic acid backbone has recently been reported to have an HIV inhibitory effect (J. Nozaki, Renard et al., AIDS 4, 1283 (1990)), as well as various pyridones in Bayer and Ubesa. Although the HIV inhibitory effects of the carboxylic acid derivatives have been demonstrated (WO9602512, WO9602532, WO9602533, WO9602539, etc.), the development of a complete HIV inhibitor is not made yet.
본 발명자들은 부작용 및 독성문제를 해결하고, 농도에 따른 활성도 변화가 적은 우수한 항HIV활성를 가지는 화합물들을 개발하고자 지속적인 연구를 수행하였으며, 그 결과 N-1위치에 나프틸기 또는 퀴놀릴기를 갖는 피리돈 카르복실산 유도체들이 HIV 증식에 필수효소인 역전사효소를 저해하는 효과가 우수함을 확인함으로써 본 발명을 완성하게 되었다.The present inventors conducted a continuous study to solve the side effects and toxicity problems, and to develop compounds having excellent anti-HIV activity with a small change in activity according to the concentration, as a result, pyridonecar having a naphthyl group or quinolyl group at the N-1 position The present invention was completed by confirming that acid derivatives have an excellent effect of inhibiting reverse transcriptase, an essential enzyme for HIV proliferation.
따라서, 본 발명은 항HIV-RT활성이 우수한 신규 피리돈카르복실산 유도체, 그의 약제학적으로 허용 가능한 염, 그리고 그의 제조방법 및 중간체에 관한 것이다.Accordingly, the present invention relates to novel pyridonecarboxylic acid derivatives having excellent anti-HIV-RT activity, pharmaceutically acceptable salts thereof, and methods for preparing and intermediates thereof.
본 발명은 다음 화학식 1로 표시되는 피리돈 카르복실산 유도체와 그의 약제학적으로 허용되는 염을 그 특징으로 한다.The present invention is characterized by a pyridone carboxylic acid derivative represented by the following formula (1) and a pharmaceutically acceptable salt thereof.
화학식 1Formula 1
상기 화학식에서In the above formula
X는 CH 또는 질소원자이고, A 는 3-아미노피롤리딘, C1-3의 저급알킬기가 1-3개 치환 또는 비치환된 피페라진이고, B 는 나프틸 또는 퀴놀릴기이다.X is CH or a nitrogen atom, A is 3-aminopyrrolidine, C 1-3 lower alkyl group substituted or unsubstituted piperazine, and B is a naphthyl or quinolyl group.
이와같은 본 발명을 더욱 상세히 설명하면 다음과 같다.Referring to the present invention in more detail as follows.
본 발명에 따르는 상기 화학식 1로 표시되는 신규 피리돈카르복실산 유도체에 있어서, 바람직하기로는 X는 CH 또는 N이고, A가 치환된 피페라진 또는 3-아미노피롤리딘이며, B가 2-나프틸 또는 3-퀴놀릴인 경우이다.In the novel pyridonecarboxylic acid derivative represented by Formula 1 according to the present invention, preferably X is CH or N, A is substituted piperazine or 3-aminopyrrolidine, and B is 2-naph. In the case of butyl or 3-quinolyl.
본 발명에 따른 상기 화학식 1로 표시되는 피리돈카르복실산 유도체의 대표적인 예는 다음과 같다.Representative examples of the pyridonecarboxylic acid derivative represented by Formula 1 according to the present invention are as follows.
또한, 본 발명에 따르는 상기 화학식 1로 표시되는 피리돈카르복실산 유도체또는 그의 에스테르는 당해기술분야에서 통상적인 방법에 따라 약제학적으로 허용되는 산 부가염을 형성할 수 있다. 그 예로는 염산, 인산, 아세트산, 옥살산, 숙신산, 메탄설폰산, 파라톨루엔설폰산, 말레인산, 말론산, 글루콘산과 같은 무기, 유기산과의 염 또는 칼슘, 아연 등과의 금속염일 수 있다.In addition, the pyridonecarboxylic acid derivative represented by the formula (1) or the ester thereof according to the present invention may form a pharmaceutically acceptable acid addition salt according to a conventional method in the art. Examples may be inorganic acids such as hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, succinic acid, methanesulfonic acid, paratoluenesulfonic acid, maleic acid, malonic acid, gluconic acid, salts with organic acids or metal salts with calcium, zinc and the like.
상기 화학식 1로 표시되는 화합물의 에스테르로는 치환 또는 비치환된 탄소수 1∼5의 저급 알킬에스테르이다. 본 발명은 또한 상기화학식 1로 표시되는 화합물의 수화물도 포함한다.The ester of the compound represented by Formula 1 is a substituted or unsubstituted lower alkyl ester having 1 to 5 carbon atoms. The present invention also includes a hydrate of the compound represented by the formula (1).
또한 본 발명은 상기 화학식 1로 표시되는 피리돈카르복실산유도체의 제조방법을 포함하는 바, 본 발명에 따른 상기 화학식1로 표시되는 피리돈카르복실산 유도체의 제조과정은 다음 반응식 1, 2로 나타낼수 있다.In addition, the present invention includes a method for preparing a pyridonecarboxylic acid derivative represented by Chemical Formula 1, the process of preparing a pyridonecarboxylic acid derivative represented by Chemical Formula 1 according to the present invention is represented by the following schemes 1, 2 Can be represented.
다음 반응식 1은 본 발명에 따른 상기 화학식 1로 표시되는 피리돈카르복실산 유도체를 합성하기 위한 핵심 중간체인 다음 화학식 2의 제조과정을 나타낸 것이다.The following scheme 1 shows the preparation of the following formula (2) which is a key intermediate for synthesizing the pyridonecarboxylic acid derivative represented by the formula (1) according to the present invention.
상기 반응식에서 Y는 불소 또는 염소원자이고, R은 치환 또는 비치환된 C1-5의 저급알킬기를 나태내며, X, B 는 앞에서 정의한 바와 같다.In the above scheme, Y is a fluorine or chlorine atom, R represents a substituted or unsubstituted C 1-5 lower alkyl group, and X and B are as defined above.
상기 반응식을 중심으로 하여, 본 발명에 따른 피리돈카르복실산 유도체를 합성하기 위한 핵심 중간체인 상기 화학식 2의 제조과정을 보다 구체적으로 설명하면 다음과 같다.Based on the above reaction scheme, the manufacturing process of Chemical Formula 2, which is a key intermediate for synthesizing a pyridonecarboxylic acid derivative according to the present invention, will be described in more detail.
상기 화학식 3의 화합물은 기존의 방법 [Ger. Offen. DE 3,142,854 : Ger. Offen. DE 3,318,145 : J. Med. Chem., 29, 2363(1986)]으로 제조하여 얻고, 이 화합물을 -30o∼50oC 에서 알코올(메틸알코올, 에틸알코올, 이소프로필알코올 등) 또는 할로포름(디클로로메탄, 클로로포름 등) 용매중에서 시중에서 판매되고 있는 화학식 4의 화합물 1-아미노나프탈렌, 2-아미노나프탈렌, 3-아미노퀴놀린, 5-아미노퀴놀린 또는 6-아미노퀴놀린(Aldrich회사 제품)과 반응시켜 화학식 5의 화합물을 얻는다. 수득된 화학식 5의 화합물을 아세토니트릴, N,N-디메틸포름아미드 또는 테트라하이드로퓨란과 같은 용매중에서 염기(탄산칼륨, 수산화칼륨 등)를 사용하여 폐환반응을 시켜 화학식 6의 화합물을 얻는다. 이때, 반응온도는 0oC∼환류온도이며 필요하면 18-크라운-6와 같은 촉매를 사용하여 반응의 효율을 높일 수도 있다. 화학식 6의 화합물을 산성하에서 가수분해하여 화학식 2의 화합물을 얻었다.Compound of Formula 3 is a conventional method [Ger. Offen. DE 3,142,854: Ger. Offen. DE 3,318,145: J. Med. Chem., 29, 2363 (1986)], and the compound was prepared at -30 o to 50 o C in alcohol (methyl alcohol, ethyl alcohol, isopropyl alcohol, etc.) or haloform (dichloromethane, chloroform, etc.) solvent. A compound of formula 5 is obtained by reacting with a commercially available compound 1-aminonaphthalene, 2-aminonaphthalene, 3-aminoquinoline, 5-aminoquinoline or 6-aminoquinoline (manufactured by Aldrich). The obtained compound of formula (5) is subjected to cyclization using a base (potassium carbonate, potassium hydroxide, etc.) in a solvent such as acetonitrile, N, N-dimethylformamide or tetrahydrofuran to obtain a compound of formula (6). At this time, the reaction temperature is from 0 o C to reflux temperature, if necessary, it is possible to increase the efficiency of the reaction by using a catalyst such as 18-crown-6. The compound of formula 6 was hydrolyzed under acidic acid to obtain a compound of formula 2.
이때, 사용되는 산으로는 염산, 황산 등을 들 수 있고, 산은 수용액 또는 에탄올, 메탄올등의 알콜성수용액 형태로 가수분해에 사용된다.At this time, examples of the acid used may include hydrochloric acid and sulfuric acid, and the acid is used for hydrolysis in the form of an aqueous solution or an alcoholic aqueous solution such as ethanol or methanol.
상기 화학식 2로 표시되는 중간체로부터, 본 발명에 따른 화학식 1로 표시되는 피리돈카르복실산 유도체를 제조하는 과정은 다음 반응식 2로 나타낼 수 있다.From the intermediate represented by the formula (2), the process for preparing a pyridonecarboxylic acid derivative represented by the formula (1) according to the present invention can be represented by the following scheme 2.
상기 반응식 2에서 X, Y, A, B는 상기에서 정의한 바와 같다.In Scheme 2, X, Y, A, and B are as defined above.
화학식 1의 화합물은 화학식 2의 화합물의 X 와 Y 의 종류에 관계없이 반응온도를 제외하고는 거의 동일한 방법으로 제조된다.The compound of Formula 1 is prepared in almost the same manner except for the reaction temperature regardless of the kind of X and Y of the compound of Formula 2.
상기 반응은 메탄올, 에탄올과 같은 알콜류, 테트라하이드로푸란, 디옥산, 1,2-디메톡시에탄과 같은 에테르류, 벤젠, 톨루엔, 크실렌등의 방향족 고리 화합물, 아세토니트릴, N,N-디메틸포름아미드, 디메틸술폭시드, 피리딘 등의 불활성 용매 내에서 모핵의 종류에 따라 0o∼150oC 온도에서 상기 화학식 2와 화학식 7을 1∼24시간 동안 서로 반응시킴으로써 수행된다. 또한 상기반응은 산수용체 존재하에서 일반적으로 수행되는데 화학식 2에 대해 산수용체를 1.5∼8당량 사용하는 것이 바람직하고 또는 화학식 7을 과량 사용하여 산수용체의 역할을 하게 할 수도 있다. 산수용체로는 피리딘, 트리에틸아민 또는 1,8-디아자비시클로[5.4.0]운덱-7-엔 등의 3급 아민 또는 탄산칼륨 등의 알칼리 금속 탄산염일 수 있다.The reaction includes alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane, aromatic ring compounds such as benzene, toluene and xylene, acetonitrile, N, N-dimethylformamide , it is carried out by dimethylsulfoxide, pyridine, and the like react with each other for the formula 2 and formula 71-24 hours at ~150 0 o o C temperature according to the type of mohaek in an inert solvent. In addition, the reaction is generally carried out in the presence of an acid acceptor, it is preferable to use 1.5 to 8 equivalents of the acid acceptor relative to the formula (2), or may be used as an acid acceptor by using an excess of the formula (7). The acid acceptor may be a pyridine, triethylamine or an alkali metal carbonate such as potassium carbonate or a tertiary amine such as 1,8-diazabicyclo [5.4.0] undec-7-ene.
이와 같은 본 발명은 다음의 제조예 및 실시예에 의거하여 더욱 상세히 설명하겠는 바, 본 발명이 이에 한정되는 것은 아니다.Such the present invention will be described in more detail based on the following Preparation Examples and Examples, but the present invention is not limited thereto.
제조예 1 : 에틸 3-(2-나프틸아미노)-2-(2,4,5-트리플루오로벤조일)-2-프로페노에이트의 제조Preparation Example 1 Preparation of Ethyl 3- (2-naphthylamino) -2- (2,4,5-trifluorobenzoyl) -2-propenoate
에틸 3-옥소-3-(2,4,5-트리플루오로페닐)프로파노에이트 5g에 트리에틸 오르소포르메이트 5.7ml(1.7eq.) 와 아세트산무수화물 5.7ml(3.0eq.) 를 넣고 4시간 동안 환류시킨 다음 감압증류한다. 잔사를 디클로로메탄 100ml 로 묽히고 -10℃ 이하로 냉각하여 2-아미노나프탈렌 2.97g(1.02eq.) 을 가한 다음 반응용액을 서서히 실온까지 올려서 3시간 동안 교반한다. 감압농축하여 용매를 대부분 제거한 후 에탄올 150ml 를 가하여 생성된 고체를 여과, 건조하여 목적화합물 7.38g을 얻었다.To 5 g of ethyl 3-oxo-3- (2,4,5-trifluorophenyl) propanoate, add 5.7 ml (1.7 eq.) Of triethyl orthoformate and 5.7 ml (3.0 eq.) Of acetic anhydride. It was refluxed for 4 hours and then distilled under reduced pressure. The residue was diluted with 100 ml of dichloromethane and cooled to -10 ° C. or lower, 2.97 g (1.02 eq.) Of 2-aminonaphthalene was added, and the reaction solution was gradually raised to room temperature and stirred for 3 hours. Concentrated under reduced pressure to remove most of the solvent, ethanol 150ml was added and the resulting solid was filtered and dried to give the title compound 7.38g.
수율: 91 %Yield: 91%
m.p. : 120 ℃m.p. : 120 ℃
1H-NMR(CDCl3, ppm) : 0.99, 1.12(한쌍의 t, J=7.07Hz, 3H), 4.12(m, 2H), 6.89(m, 1H), 7.24∼7.65(m, 5H), 7.88(m, 3H), 8.69(m, 1H) 1 H-NMR (CDCl 3 , ppm): 0.99, 1.12 (pair of t, J = 7.07 Hz, 3H), 4.12 (m, 2H), 6.89 (m, 1H), 7.24-7.57 (m, 5H), 7.88 (m, 3 H), 8.69 (m, 1 H)
제조예 2 : 에틸 3-(5-퀴놀릴아미노)-2-(2,4,5-트리플루오로벤조일)-2-프로페 노에이트의 제조Preparation Example 2 Preparation of Ethyl 3- (5-quinolylamino) -2- (2,4,5-trifluorobenzoyl) -2-propenoate
제조예 1과 유사한 방법에 의하여 2-아미노나프탈렌대신에 5-아미노퀴놀린을 사용하여 제조하였다.Prepared using 5-aminoquinoline instead of 2-aminonaphthalene by a method similar to Preparation Example 1.
수율: 92 %Yield: 92%
m.p. : 155∼158 ℃m.p. : 155-158 ° C
1H-NMR(CDCl3, ppm) : 1.03, 1.14(한 쌍의 t, J=7.07Hz, 3H) 4.15(m, 2H) 6.92(m, 1H) 7.36(m, 1H) 7.60(m, 2H) 7.83(m, 1H) 8.16(m, 1H) 8.58(m, 1H) 8.70(m, 1H) 9.05(m, 1H) 1 H-NMR (CDCl 3 , ppm): 1.03, 1.14 (pair of t, J = 7.07 Hz, 3H) 4.15 (m, 2H) 6.92 (m, 1H) 7.36 (m, 1H) 7.60 (m, 2H ) 7.83 (m, 1H) 8.16 (m, 1H) 8.58 (m, 1H) 8.70 (m, 1H) 9.05 (m, 1H)
제조예 3: 에틸 6,7-디플루오로-1-(2-나프틸)-4-옥소-1,4-디하이드로-3-퀴놀린 카르복실레이트의 제조Preparation Example 3: Preparation of ethyl 6,7-difluoro-1- (2-naphthyl) -4-oxo-1,4-dihydro-3-quinoline carboxylate
상기 제조예 1에서 수득한 에틸 3-(2-나프틸아미노)-2-(2,4,5-트리플루오로벤조일)-2-프로페노에이트 7.3g, 탄산칼륨 5.05g(2.0eq.), 18-크라운-6 1.45g(0.3eq.)을 아세토니트릴 100ml 에 넣고 1시간 동안 환류시킨 다음 냉각하여 물 100ml 를 실온에서 가한다. 이렇게하여 석출된 고체를 여과 건조하여 목적화합물 6.81g을 얻었다.7.3 g of ethyl 3- (2-naphthylamino) -2- (2,4,5-trifluorobenzoyl) -2-propenoate obtained in Preparation Example 1, 5.05 g (2.0 eq.) Of potassium carbonate , 1.45 g (0.3 eq.) Of 18-crown-6 was added to 100 ml of acetonitrile, refluxed for 1 hour, cooled, and 100 ml of water was added at room temperature. The precipitated solid was filtered and dried to obtain 6.81 g of the target compound.
수율 : 98 %Yield: 98%
m.p. : 200 ℃m.p. : 200 ℃
1H-NMR(CDCl3, ppm) : 1.37(t, J=7.35Hz, 3H), 4.37(q, J=7.35Hz, 2H), 6.81(m, 1H), 7.45(m, 1H), 7.66(m, 2H), 7.93(m, 2H), 8.00(m, 1H), 8.09(m, 1H), 8.31(m, 1H), 8.57(s, 1H) 1 H-NMR (CDCl 3 , ppm): 1.37 (t, J = 7.35 Hz, 3H), 4.37 (q, J = 7.35 Hz, 2H), 6.81 (m, 1H), 7.45 (m, 1H), 7.66 (m, 2H), 7.93 (m, 2H), 8.00 (m, 1H), 8.09 (m, 1H), 8.31 (m, 1H), 8.57 (s, 1H)
제조예 4 : 에틸 6,7-디플루오로-1-(5-퀴놀릴)-4-옥소-1,4-디하이드로-3-퀴놀린 카르복실레이트의 제조 Preparation Example 4 Preparation of Ethyl 6,7-Difluoro-1- (5-quinolyl) -4-oxo-1,4-dihydro- 3-quinoline carboxylate
상기 제조예 2에서 제조한 에틸 3-(5-퀴놀릴아미노)-2-(2,4,5-트리플루오로벤조일)-2-프로페노에이트를 이용하여 제조예 3과 유사한 방법으로 제조할수 있다.The ethyl 3- (5-quinolylamino) -2- (2,4,5-trifluorobenzoyl) -2-propenoate prepared in Preparation Example 2 may be prepared in a similar manner to Preparation Example 3. have.
수율 : 96 %Yield: 96%
m.p. : 297∼298 ℃m.p. : 297-298 ° C
1H-NMR(CDCl3, ppm) : 1.33(t, J=7.07Hz, 3H) 4.35(q, J=7.07Hz, 2H) 6.42(m, 1H) 7.48(m, 1H) 7.67(m, 1H) 7.73(m, 1H) 7.95(m, 1H) 8.31(m, 1H) 8.43(m, 1H) 8.49(s, 1H) 9.06(m, 1H) 1 H-NMR (CDCl 3 , ppm): 1.33 (t, J = 7.07 Hz, 3H) 4.35 (q, J = 7.07 Hz, 2H) 6.42 (m, 1H) 7.48 (m, 1H) 7.67 (m, 1H ) 7.73 (m, 1H) 7.95 (m, 1H) 8.31 (m, 1H) 8.43 (m, 1H) 8.49 (s, 1H) 9.06 (m, 1H)
제조예 5 : 6,7-디플루오로-1-(2-나프틸)-4-옥소-1,4-디하이드로-3-퀴놀린 카르복실산의 제조Preparation Example 5 Preparation of 6,7-Difluoro-1- (2-naphthyl) -4-oxo-1,4-dihydro-3-quinoline carboxylic acid
상기 제조예 3에서 수득한 에틸 6,7-디플루오로-1-(2-나프틸)-4-옥소-1,4-디하이드로-3-퀴놀린 카르복실레이트6.8g 을 에탄올 60ml 와 물 30ml 에 넣고 진한 염산 28ml(15eq.) 를 가한다음 18 시간 동안 환류시킨다. 반응 용액을 실온까지 냉각한 후 여과, 건조하여 목적화합물 6.23g을 얻었다.6.8 g of ethyl 6,7-difluoro-1- (2-naphthyl) -4-oxo-1,4-dihydro-3-quinoline carboxylate was obtained in Preparation Example 3, 60 ml of ethanol and 30 ml of water. Add 28 ml (15 eq.) Of concentrated hydrochloric acid and reflux for 18 hours. The reaction solution was cooled to room temperature, filtered and dried to give 6.23 g of the target compound.
수율 : 99 %Yield: 99%
m.p. : 281 ℃m.p. : 281 ℃
1H-NMR(CF3COOD, ppm) : 7.58(m, 2H), 7.85(m, 2H), 8.06(m, 1H), 8.16(m, 2H) 8.32(m, 1H), 8.63(m, 1H), 9.59(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 7.58 (m, 2H), 7.85 (m, 2H), 8.06 (m, 1H), 8.16 (m, 2H) 8.32 (m, 1H), 8.63 (m, 1H), 9.59 (s, 1H)
제조예 6 : 6,7-디플루오로-1-(5-퀴놀릴)-4-옥소-1,4-디하이드로-3-퀴놀린 카르복실산.염산의 제조Preparation Example 6 Preparation of 6,7-difluoro-1- (5-quinolyl) -4-oxo-1,4-dihydro-3-quinoline carboxylic acid.
상기 제조예 4에서 수득한 에틸 6,7-디플루오로-1-(5-퀴놀릴)-4-옥소-1,4-디하이드로-3-퀴놀린 카르복실레이트을 이용하여 제조예 5와 유사한 방법으로 제조하였다.Method similar to Preparation Example 5 using ethyl 6,7-difluoro-1- (5-quinolyl) -4-oxo-1,4-dihydro-3-quinoline carboxylate obtained in Preparation Example 4 above It was prepared by.
수율 : 97 %Yield: 97%
m.p. : 300 ℃m.p. : 300 ℃
1H-NMR(CF3COOD, ppm) : 7.17(m, 1H) 8.23(m, 1H) 8.47(m, 1H) 8.55(m, 1H) 8.62(m, 1H) 8.71(m, 1H) 8.93(m, 1H) 9.46(m, 1H) 9.61(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 7.17 (m, 1H) 8.23 (m, 1H) 8.47 (m, 1H) 8.55 (m, 1H) 8.62 (m, 1H) 8.71 (m, 1H) 8.93 ( m, 1H) 9.46 (m, 1H) 9.61 (s, 1H)
실시예 1 : 메탄설폰산Example 1 Methanesulfonic Acid
6,7-디플루오로-1-(1-나프틸)-4-옥소-1,4-디하이드로-3-퀴놀린카르복실산 300mg, 피페라진 184mg(2.5eq.)을 무수 아세토니트릴 15ml에 넣고 6시간 동안 환류시킨 다음 용매를 감압농축하여 제거한다. 잔사에 소량의 물과 이소프로필알코올을 가하여 석출시킨 결정을 여과하여 분리한다. 이렇게 하여 얻은 고체를 에탄올 10ml와 물 0.5ml의 혼합용매에 넣고 1 노르말 메탄설폰산 에탄올 용액 4.3ml(5.0eq.)를 가한 다음 실온에서 3시간 동안 교반한다. 그 후 용매를 감압농축하여 대부분 제거한 다음 이소프로필알코올과 에틸에테르로써 고체를 석출시킨 후 여과, 건조하여 목적화합물 350mg을 얻었다.300 mg of 6,7-difluoro-1- (1-naphthyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid and 184 mg (2.5eq.) Of piperazine were added to 15 ml of anhydrous acetonitrile. After refluxing for 6 hours, the solvent was concentrated under reduced pressure. A small amount of water and isopropyl alcohol were added to the residue, and the precipitated crystals were separated by filtration. The solid thus obtained was added to a mixed solvent of 10 ml of ethanol and 0.5 ml of water, and 4.3 ml (5.0 eq.) Of 1 normal methanesulfonic acid ethanol solution was added thereto, followed by stirring at room temperature for 3 hours. Thereafter, the solvent was concentrated under reduced pressure, and most of them were removed. Then, a solid was precipitated with isopropyl alcohol and ethyl ether, filtered, and dried to obtain 350 mg of the target compound.
수율 : 80 %Yield: 80%
m.p. : 230 ℃m.p. : 230 ℃
1H-NMR(CF3COOD, ppm) : 3.13(s, 3H), 3.53(m, 2H), 3.67(m, 6H), 6.70(m, 1H) 7.12(m, 1H), 7.65(m, 1H), 7.79∼7.91(m, 3H), 8.24(m, 1H), 8.41∼8.48(m, 2H), 9.39(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 3.13 (s, 3H), 3.53 (m, 2H), 3.67 (m, 6H), 6.70 (m, 1H) 7.12 (m, 1H), 7.65 (m, 1H), 7.79-7.91 (m, 3H), 8.24 (m, 1H), 8.41-8.48 (m, 2H), 9.39 (s, 1H)
실시예 2 : 메탄설폰산Example 2 Methanesulfonic Acid
상기 실시예 1과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 1.
수율 : 68 %Yield: 68%
m.p. : 286 ℃ (분해)m.p. : 286 ℃ (decomposition)
1H-NMR(CF3COOD, ppm) : 1.59(m, 3H), 3.27(s, 3H), 3.24∼3.70(m, 4H), 4.02(m, 3H), 6.78(m, 1H),7.20(m, 1H),7.75(m, 1H),7.88∼ 8.02(m, 3H), 8.33(m, 1H), 8.50∼8.54(m, 2H), 9.47(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 1.59 (m, 3H), 3.27 (s, 3H), 3.24 to 3.70 (m, 4H), 4.02 (m, 3H), 6.78 (m, 1H), 7.20 (m, 1H), 7.75 (m, 1H), 7.88-8.02 (m, 3H), 8.33 (m, 1H), 8.50-8.54 (m, 2H), 9.47 (s, 1H)
실시예 3 : 메탄설폰산Example 3 Methanesulfonic Acid
상기 실시예 1과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 1.
수율 : 73 %Yield: 73%
m.p. : 286 ℃ (분해)m.p. : 286 ℃ (decomposition)
1H-NMR(CF3COOD, ppm) : 3.18(s, 3H), 3.20(s, 3H), 3.43(m, 4H), 3.75∼3.84(m, 3H), 4.00(m, 1H), 6.77(m, 1H), 7.15(m, 1H), 7.70 (m, 1H), 7.83∼7.95(m, 3H),8.28(m, 1H),8.45∼8.53(m, 2H), 9.43(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 3.18 (s, 3H), 3.20 (s, 3H), 3.43 (m, 4H), 3.75 ~ 3.84 (m, 3H), 4.00 (m, 1H), 6.77 (m, 1H), 7.15 (m, 1H), 7.70 (m, 1H), 7.83-7.95 (m, 3H), 8.28 (m, 1H), 8.45-8.53 (m, 2H), 9.43 (s, 1H) )
실시예 4 : 메탄설폰산Example 4 Methanesulfonic Acid
상기 실시예 1과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 1.
수율 : 74 %Yield: 74%
m.p. : 271 ℃ (분해)m.p. : 271 ℃ (decomposition)
1H-NMR(CF3COOD+DMSO-D6, ppm) : 0.83(m, 3H), 0.91(m, 3H), 2.49∼2.65(m, 5H), 3.10∼3.34(m, 4H), 6.10(m, 1H), 6.63(m, 1H), 7.12(m, 1H), 7.25∼7.35(m, 3H),7.72(m, 1H), 7.88∼7.91(m, 2H), 8.84(m, 1H) 1 H-NMR (CF 3 COOD + DMSO-D 6 , ppm): 0.83 (m, 3H), 0.91 (m, 3H), 2.49 to 2.65 (m, 5H), 3.10 to 3.34 (m, 4H), 6.10 (m, 1H), 6.63 (m, 1H), 7.12 (m, 1H), 7.25-7.35 (m, 3H), 7.72 (m, 1H), 7.88-7.91 (m, 2H), 8.84 (m, 1H) )
실시예 5 : 메탄설폰산Example 5 Methanesulfonic Acid
6,7-디플루오로-1-(1-나프틸)-4-옥소-1,4-디하이드로-3-퀴놀린카르복실산 300mg, (3S)-3-아미노-1-피롤리딘.이염산염 340mg(2.5eq.) 1,8-디아자비시클로[5.4.0] 운덱-7-엔 910mg(7eq.)을 무수 아세토니트릴 15ml 에 넣고 6시간 동안 환류시킨 다음 용매를 감압농축하여 제거한다. 잔사에 소량의 물과 이소프로필알코올을 가하여 석출시킨 결정을 여과하여 분리한다. 이렇게 하여 얻은 고체를 에탄올 10ml와 물 0.5ml의 혼합용매에 넣고 1 노르말 메탄설폰산 에탄올 용액 4.3ml(5.0eq.)를 가한 다음 실온에서 3시간 동안 교반한다. 반응용액에 에틸 에테르 과량을 가하여 고체를 충분히 석출시킨 다음 여과, 건조하여 목적화합물 268mg을 얻었다.300 mg of 6,7-difluoro-1- (1-naphthyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, (3S) -3-amino-1-pyrrolidine. 340 mg (2.5 eq.) Of dihydrochloride, 910 mg (7 eq.) Of 1,8-diazabicyclo [5.4.0] undec-7-ene, was added to 15 ml of anhydrous acetonitrile, refluxed for 6 hours, and the solvent was concentrated under reduced pressure. . A small amount of water and isopropyl alcohol were added to the residue, and the precipitated crystals were separated by filtration. The solid thus obtained was added to a mixed solvent of 10 ml of ethanol and 0.5 ml of water, and 4.3 ml (5.0 eq.) Of 1 normal methanesulfonic acid ethanol solution was added thereto, followed by stirring at room temperature for 3 hours. Excess ethyl ether was added to the reaction solution to sufficiently precipitate a solid, followed by filtration and drying to obtain 268 mg of the target compound.
수율 : 61 %Yield: 61%
m.p. : 212 ℃m.p. : 212 ℃
1H-NMR(CF3COOD, ppm) : 2.56(m, 2H), 3.19(s, 3H), 3.38∼3.72(m, 2H), 3.90∼ 4.20(m, 2H), 4.42(m, 1H), 6.24(m, 1H), 7.20(m, 1H), 7.70(m, 1H), 7.84(m, 2H), 7.91(m, 1H), 8.27(m, 1H), 8.36(m, 1H), 8.43(m, 1H), 9.27(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 2.56 (m, 2H), 3.19 (s, 3H), 3.38-3.72 (m, 2H), 3.90-4.20 (m, 2H), 4.42 (m, 1H) , 6.24 (m, 1H), 7.20 (m, 1H), 7.70 (m, 1H), 7.84 (m, 2H), 7.91 (m, 1H), 8.27 (m, 1H), 8.36 (m, 1H), 8.43 (m, 1H), 9.27 (s, 1H)
실시예 6 : 메탄설폰산Example 6 Methanesulfonic Acid
상기 실시예 1과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 1.
수율 : 73 %Yield: 73%
m.p. : 280 ℃ (분해)m.p. : 280 ℃ (decomposition)
1H-NMR(CF3COOD, ppm) : 3.21(s, 3H), 3.22∼3.61(m, 4H),, 4.04∼4.19(m, 4H) 7.21(m, 1H), 7.67(m, 1H), 7.76∼7.82(m, 2H), 7.86(m, 1H), 8.23(m, 1H), 8.36(m, 1H), 8.50(m, 1H), 9.51(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 3.21 (s, 3H), 3.22-3.61 (m, 4H), 4.04-4.19 (m, 4H) 7.21 (m, 1H), 7.67 (m, 1H) , 7.76 to 7.82 (m, 2H), 7.86 (m, 1H), 8.23 (m, 1H), 8.36 (m, 1H), 8.50 (m, 1H), 9.51 (s, 1H)
실시예 7 : 메탄설폰산Example 7 Methanesulfonic Acid
상기 실시예 1과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 1.
수율 : 71 %Yield: 71%
m.p. : 226 ℃m.p. : 226 ℃
1H-NMR(CF3COOD+DMSO-D6, ppm) : 0.46∼0.70(m, 3H), 2.49(s, 3H), 2.65(m, 1H), 2.79(m, 2H), 3.05(m, 1H), 3.28(m, 1H), 3.52(m, 1H), 4.10(m, 1H), 6.86(m, 1H), 7.19(m, 1H), 7.25∼7.48(m, 3H), 7.79(m, 1H), 7.80∼8.01(m, 2H), 9.03(s, 1H) 1 H-NMR (CF 3 COOD + DMSO-D 6 , ppm): 0.46 to 0.70 (m, 3H), 2.49 (s, 3H), 2.65 (m, 1H), 2.79 (m, 2H), 3.05 (m , 1H), 3.28 (m, 1H), 3.52 (m, 1H), 4.10 (m, 1H), 6.86 (m, 1H), 7.19 (m, 1H), 7.25-7.48 (m, 3H), 7.79 ( m, 1H), 7.80 to 8.01 (m, 2H), 9.03 (s, 1H)
실시예 8 :Example 8:
6,7-디플루오로-1-(1-나프틸)-4-옥소-1,4-디하이드로-1,8-나프티리딘-3-카르복실산 300mg, N-메틸 피페라진 204mg(2.5eq.)을 무수 아세토니트릴 15ml에 넣고 4시간 동안 환류시킨 다음 용매를 감압농축하여 제거한다. 잔사에 소량의 물과 이소프로필알코올을 가하여 결정을 석출시킨 다음 여과, 건조하여 목적화합물 303mg을 얻었다.300 mg 6,7-difluoro-1- (1-naphthyl) -4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, 204 mg N-methyl piperazine (2.5 mg) eq.) was added to 15 ml of anhydrous acetonitrile and refluxed for 4 hours, and then the solvent was concentrated under reduced pressure. A small amount of water and isopropyl alcohol were added to the residue to precipitate a crystal, followed by filtration and drying to obtain 303 mg of the target compound.
수율 : 86 %Yield: 86%
m.p. : 255 ℃m.p. : 255 ℃
1H-NMR(CF3COOD, ppm) : 3.16(s, 3H), 3.00∼3.42(m, 2H), 3.68∼3.80(m, 4H), 4.5 0∼4.87(m, 2H), 7.31(m, 1H), 7.77∼7.98(m, 4H),8.33(m, 1H), 8.46(m, 1H), 8.60(m, 1H), 9.61(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 3.16 (s, 3H), 3.00-3.42 (m, 2H), 3.68-3.80 (m, 4H), 4.5 0-4.87 (m, 2H), 7.31 (m , 1H), 7.77-7.98 (m, 4H), 8.33 (m, 1H), 8.46 (m, 1H), 8.60 (m, 1H), 9.61 (s, 1H)
실시예 9 :Example 9:
상기 실시예 8과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 8.
수율 : 71 %Yield: 71%
m.p. : 272 ℃ (분해)m.p. : 272 ℃ (decomposition)
1H-NMR(CF3COOD+DMSO-D6, ppm) : 0.54(m, 3H), 0.84(m, 3H), 2.40∼2.90(m, 4H), 3.63∼3.88(m, 2H), 6.92(m, 1H), 7.21(m, 1H), 7.35∼7.45(m, 3H), 7.81(m, 1H), 7.93(m, 1H), 8.00(m, 1H), 9.04(s, 1H) 1 H-NMR (CF 3 COOD + DMSO-D 6 , ppm): 0.54 (m, 3H), 0.84 (m, 3H), 2.40-2.90 (m, 4H), 3.63-3.88 (m, 2H), 6.92 (m, 1H), 7.21 (m, 1H), 7.35-7.45 (m, 3H), 7.81 (m, 1H), 7.93 (m, 1H), 8.00 (m, 1H), 9.04 (s, 1H)
실시예 10 : 메탄설폰산Example 10 Methanesulfonic Acid
상기 실시예 1과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 1.
수율 : 70 %Yield: 70%
m.p. : 194 ℃m.p. : 194 ℃
1H-NMR(CF3COOD, ppm) : 2.40(m, 1H), 2.66(m, 1H), 3.24(s, 3H), 3.20(m, 1H), 3.55(m, 1H), 4.21∼4.73(m, 3H), 7.23(m, 1H), 7.70∼ 7.90(m, 4H), 8.27(m, 1H), 8.38∼8.43(m, 2H), 9.44(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 2.40 (m, 1H), 2.66 (m, 1H), 3.24 (s, 3H), 3.20 (m, 1H), 3.55 (m, 1H), 4.21-4.73 (m, 3H), 7.23 (m, 1H), 7.70-7.90 (m, 4H), 8.27 (m, 1H), 8.38-8.43 (m, 2H), 9.44 (s, 1H)
실시예 11 : 메탄설폰산Example 11 Methanesulfonic Acid
상기 실시예 1과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 1.
수율 : 78 %Yield: 78%
m.p. : 297 ℃ (분해)m.p. : 297 ℃ (decomposition)
1H-NMR(CF3COOD, ppm) : 3.17(s, 3H), 3.72(m, 4H), 3.76(m, 4H), 7.04(m, 1H), 7.63(m, 1H), 7.87(m, 2H), 8.09(m, 1H), 8.18(m, 2H), 8.33(m, 1H), 8.45(m, 1H), 9.43(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 3.17 (s, 3H), 3.72 (m, 4H), 3.76 (m, 4H), 7.04 (m, 1H), 7.63 (m, 1H), 7.87 (m , 2H), 8.09 (m, 1H), 8.18 (m, 2H), 8.33 (m, 1H), 8.45 (m, 1H), 9.43 (s, 1H)
실시예 12 : 메탄설폰산Example 12 Methanesulfonic Acid
상기 실시예 1과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 1.
수율 : 68 %Yield: 68%
m.p. : 294 ℃ (분해)m.p. : 294 ℃ (decomposition)
1H-NMR(CF3COOD, ppm) : 1.57(m, 3H), 3.19(s, 3H), 3.40(m, 1H), 3.50∼3.63(m, 2H), 3.77∼3.92(m, 3H), 4.04(m, 1H), 7.06(m, 1H), 7.65(m, 1H), 7.85∼7.92(m, 2H), 8.10(m, 1H), 8.19(m, 2H), 8.34(m, 1H), 8.45(m, 1H), 9.43(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 1.57 (m, 3H), 3.19 (s, 3H), 3.40 (m, 1H), 3.50-3.63 (m, 2H), 3.77-3.92 (m, 3H) , 4.04 (m, 1H), 7.06 (m, 1H), 7.65 (m, 1H), 7.85 ~ 7.92 (m, 2H), 8.10 (m, 1H), 8.19 (m, 2H), 8.34 (m, 1H ), 8.45 (m, 1 H), 9.43 (s, 1 H)
실시예 13 : 메탄설폰산Example 13: Methanesulfonic Acid
상기 실시예 1과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 1.
수율 : 80 %Yield: 80%
m.p. : 185 ℃m.p. : 185 ℃
1H-NMR(CF3COOD, ppm) : 3.16(s, 3H), 3.22(s, 3H), 3.46∼3.59(m, 4H), 3.88(m, 2H), 4.05(m, 2H), 7.09(m, 1H), 7.66(m, 1H), 7.86∼ 7.94(m, 2H), 8.12(m, 1H), 8.20(m, 2H), 8.35(m, 1H), 8.48(m, 1H), 9.45(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 3.16 (s, 3H), 3.22 (s, 3H), 3.46-3.59 (m, 4H), 3.88 (m, 2H), 4.05 (m, 2H), 7.09 (m, 1H), 7.66 (m, 1H), 7.86-7.94 (m, 2H), 8.12 (m, 1H), 8.20 (m, 2H), 8.35 (m, 1H), 8.48 (m, 1H), 9.45 (s, 1 H)
실시예 14 : 메탄설폰산Example 14 Methanesulfonic Acid
상기 실시예 1과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 1.
수율 : 72 %Yield: 72%
m.p. : 198 ℃m.p. : 198 ℃
1H-NMR(CF3COOD, ppm) : 1.49∼1.54(m, 6H), 3.22(s, 3H), 3.27∼3.33(m, 2H), 3.89(m, 2H), 4.02(m, 2H), 7.10(m, 1H), 7.69(m, 1H), 7.91(m, 2H), 8.13(m, 1H), 8.22(m, 2H), 8.36(m, 1H), 8.48(m, 1H), 9.44(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 1.49 to 1.54 (m, 6H), 3.22 (s, 3H), 3.27 to 3.33 (m, 2H), 3.89 (m, 2H), 4.02 (m, 2H) , 7.10 (m, 1H), 7.69 (m, 1H), 7.91 (m, 2H), 8.13 (m, 1H), 8.22 (m, 2H), 8.36 (m, 1H), 8.48 (m, 1H), 9.44 (s, 1 H)
실시예 15 : 메탄설폰산Example 15 Methanesulfonic Acid
상기 실시예 5와 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 5.
수율 : 52 %Yield: 52%
m.p. : 200 ℃ (분해)m.p. : 200 ℃ (decomposition)
1H-NMR(CF3COOD, ppm) : 2.49∼2.60(m, 2H), 3.17(s, 3H), 3.71(m, 1H), 3.86(m, 1H), 4.18(m, 2H), 4.46(m, 1H), 6.55(m, 1H), 7.63(m, 1H), 7.84∼7.91(m, 2H), 8.10(m, 1H), 8.16∼8.20(m, 2H), 8.31∼ 8.35(m, 2H), 9.29(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 2.49 to 2.60 (m, 2H), 3.17 (s, 3H), 3.71 (m, 1H), 3.86 (m, 1H), 4.18 (m, 2H), 4.46 (m, 1H), 6.55 (m, 1H), 7.63 (m, 1H), 7.84-7.91 (m, 2H), 8.10 (m, 1H), 8.16-8.20 (m, 2H), 8.31-8.35 (m , 2H), 9.29 (s, 1H)
실시예 16 : 메탄설폰산Example 16 Methanesulfonic Acid
상기 실시예 1과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 1.
수율 : 65 %Yield: 65%
m.p. : 137 ℃m.p. : 137 ℃
1H-NMR(CF3COOD, ppm) : 2.77(s, 3H), 3.18(m, 4H), 3.87(m, 4H), 7.21(m, 1H), 7.3 5∼7.43(m, 2H), 7.62∼7.71(m, 3H), 7.80(m, 1H) 8.04(m, 1H), 9.05(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 2.77 (s, 3H), 3.18 (m, 4H), 3.87 (m, 4H), 7.21 (m, 1H), 7.3 5-7.43 (m, 2H), 7.62 to 7.71 (m, 3H), 7.80 (m, 1H) 8.04 (m, 1H), 9.05 (s, 1H)
실시예 17 : 메탄설폰산Example 17 Methanesulfonic Acid
상기 실시예 1과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 1.
수율 : 82 %Yield: 82%
m.p. : 263 ℃m.p. : 263 ℃
1H-NMR(CF3COOD, ppm) : 1.18(m, 3H), 3.13(s, 3H), 3.46(m, 2H), 3.63(m, 2H), 3.83(m, 1H), 4.55(m, 1H), 4.72(m, 1H), 7.58(m, 1H), 7.73∼7.80(m, 2H), 8.00∼8.09(m, 3H), 8.18(m, 1H), 8.38(m, 1H), 9.44(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 1.18 (m, 3H), 3.13 (s, 3H), 3.46 (m, 2H), 3.63 (m, 2H), 3.83 (m, 1H), 4.55 (m , 1H), 4.72 (m, 1H), 7.58 (m, 1H), 7.73-7.80 (m, 2H), 8.00-8.09 (m, 3H), 8.18 (m, 1H), 8.38 (m, 1H), 9.44 (s, 1 H)
실시예 18 : 메탄설폰산Example 18 Methanesulfonic Acid
상기 실시예 1과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 1.
수율 : 81 %Yield: 81%
m.p. : 267 ℃m.p. : 267 ℃
1H-NMR(CF3COOD, ppm) : 3.08(s, 3H) 3.14(s, 3H), 3.27(m, 2H), 3.72(m, 4H), 4.76(m, 2H), 7.59(m, 1H), 7.76(m, 2H), 8.00(m, 1H), 8.05(m, 2H), 8.18(m, 1H), 8.42(m, 1H), 9.44(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 3.08 (s, 3H) 3.14 (s, 3H), 3.27 (m, 2H), 3.72 (m, 4H), 4.76 (m, 2H), 7.59 (m, 1H), 7.76 (m, 2H), 8.00 (m, 1H), 8.05 (m, 2H), 8.18 (m, 1H), 8.42 (m, 1H), 9.44 (s, 1H)
실시예 19 :Example 19:
상기 실시예 8과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 8.
수율 : 78 %Yield: 78%
m.p. : 288 ℃ (분해)m.p. : 288 ℃ (decomposition)
1H-NMR(CF3COOD, ppm) : 1.33 (m, 6H), 3.65(m, 4H), 4.73(m, 2H), 7.65(m, 1H), 7.85(m, 2H), 8.09∼8.18(m, 3H), 8.28(m, 1H), 8.46(m, 1H), 9.53(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 1.33 (m, 6H), 3.65 (m, 4H), 4.73 (m, 2H), 7.65 (m, 1H), 7.85 (m, 2H), 8.09-8.18 (m, 3H), 8.28 (m, 1H), 8.46 (m, 1H), 9.53 (s, 1H)
실시예 20 : 메탄설폰산Example 20 Methanesulfonic Acid
상기 실시예 1과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 1.
수율 : 63 %Yield: 63%
m.p. : 232 ℃m.p. : 232 ℃
1H-NMR(CF3COOD, ppm) : 2.32(m, 1H), 2.59(m, 1H), 3.06(s, 3H), 3.61(m, 1H), 3.77(m, 1H), 4.22∼4.52(m, 3H), 7.55(m, 1H), 7.71(m, 2H), 7.96(m, 2H), 8.03(m, 1H), 8.12(m, 1H), 8.24(m, 1H), 9.31(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 2.32 (m, 1H), 2.59 (m, 1H), 3.06 (s, 3H), 3.61 (m, 1H), 3.77 (m, 1H), 4.22-4.52 (m, 3H), 7.55 (m, 1H), 7.71 (m, 2H), 7.96 (m, 2H), 8.03 (m, 1H), 8.12 (m, 1H), 8.24 (m, 1H), 9.31 ( s, 1 H)
실시예 21 : 2 메탄설폰산Example 21 2 Methanesulfonic Acid
6,7-디플루오로-1-(5-퀴놀릴)-4-옥소-1,4-디하이드로-3-퀴놀린카르복실산.염산 350mg, 피페라진 271mg(3.5eq.)을 무수 아세토니트릴 15ml에 넣고 6시간 동안 환류시킨 다음 용매를 감압농축하여 제거한다. 잔사에 소량의 물과 이소프로필알코올 또는 에틸에테르를 가하여 석출시킨 결정을 여과하여 분리한다. 이렇게 하여 얻은 고체를 에탄올 10ml와 물 0.5ml의 혼합용매에 넣고 1 노르말 메탄설폰산 에탄올 용액 6.3ml(7.0eq.)를 가한 다음 실온에서 3시간 동안 교반한다. 그 후 용매를 감압농축하여 대부분 제거한 다음 이소프로필알코올과 에틸에테르로써 고체를 석출시킨 후 여과, 건조하여 목적화합물 369mg을 얻었다.6,7-difluoro-1- (5-quinolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid. 350 mg hydrochloric acid, piperazine 271 mg (3.5 eq.) Anhydrous acetonitrile The solution was added to 15 ml and refluxed for 6 hours, and then the solvent was concentrated under reduced pressure. A small amount of water and isopropyl alcohol or ethyl ether were added to the residue, and the precipitated crystals were separated by filtration. The solid thus obtained was added to a mixed solvent of 10 ml of ethanol and 0.5 ml of water, and 6.3 ml (7.0 eq.) Of 1 normal methanesulfonic acid ethanol solution was added thereto, followed by stirring at room temperature for 3 hours. Thereafter, the solvent was concentrated under reduced pressure to remove most of the solvent. A solid was precipitated with isopropyl alcohol and ethyl ether, and then filtered and dried to obtain 369 mg of the target compound.
수율 : 67 %Yield: 67%
m.p. : 196∼199 ℃m.p. 196 to 199 ° C
1H-NMR(CF3COOD, ppm) : 3.21(s, 6H) 3.70∼3.81(m, 8H) 6.68(m, 1H) 8.38(m, 1H) 8.53∼8.60(m, 2H) 8.68(m, 1H) 8.82(m, 1H) 8.99(m, 1H) 9.49(s, 1H) 9.60(m, 1H) 1 H-NMR (CF 3 COOD, ppm): 3.21 (s, 6H) 3.70 to 3.81 (m, 8H) 6.68 (m, 1H) 8.38 (m, 1H) 8.53 to 8.60 (m, 2H) 8.68 (m, 1H) 8.82 (m, 1H) 8.99 (m, 1H) 9.49 (s, 1H) 9.60 (m, 1H)
실시예 22 : 2 메탄슬폰산Example 22 2 Methanesulfonic Acid
상기 실시예 21과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 21.
수율 : 72 %Yield: 72%
m.p. : 274∼277 ℃m.p. : 274-277 ° C
1H-NMR(CF3COOD, ppm) : 1.57(m, 3H) 3.20(s, 6H) 3.36∼3.77(m, 3H) 3.81∼ 3.85(m, 2H) 3.92(m, 1H) 4.05(m, 1H) 6.70(m, 1H) 8.37(m, 1H) 8.53(m, 1H) 8.59(m, 1H) 8.66(m, 1H) 8.82(m, 1H) 8.98(m, 1H) 9.47(s, 1H) 9.59(m, 1H) 1 H-NMR (CF 3 COOD, ppm): 1.57 (m, 3H) 3.20 (s, 6H) 3.36-3.77 (m, 3H) 3.81-3.85 (m, 2H) 3.92 (m, 1H) 4.05 (m, 1H) 6.70 (m, 1H) 8.37 (m, 1H) 8.53 (m, 1H) 8.59 (m, 1H) 8.66 (m, 1H) 8.82 (m, 1H) 8.98 (m, 1H) 9.47 (s, 1H) 9.59 (m, 1 H)
실시예 23 :Example 23:
6,7-디플루오로-1-(5-퀴놀릴)-4-옥소-1,4-디하이드로-3-퀴놀린카르복실산.염산 350mg, N-메틸피페라진 316mg(3.5eq.)을 무수 아세토니트릴 15ml에 넣고 6시간 동안 환류시킨 다음 용매를 감압농축하여 제거한다. 잔사에 소량의 물과 이소프로필알코올 또는 에틸에테르를 가하여 석출시킨 결정을 여과, 건조하여 목적화합물 302mg을 얻었다.6,7-difluoro-1- (5-quinolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid. 350 mg of hydrochloric acid, 316 mg (3.5 eq.) Of N-methylpiperazine The solution was added to 15 ml of anhydrous acetonitrile and refluxed for 6 hours, followed by concentration under reduced pressure. A small amount of water, isopropyl alcohol or ethyl ether was added to the residue, and the precipitated crystals were filtered and dried to obtain 302 mg of the target compound.
수율 : 78 %Yield: 78%
m.p. : 275∼279 ℃m.p. : 275-279 ℃
1H-NMR(CF3COOD, ppm) : 3.21(s, 3H) 3.48(m, 4H) 3.82(m, 2H) 3.97∼4.06(m, 2H) 6.70(m, 1H) 8.36(m, 1H) 8.53∼8.61(m, 2H) 8.67(m,1H) 8.83(m, 1H) 8.96(m, 1H) 9.46(m, 1H) 9.53(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 3.21 (s, 3H) 3.48 (m, 4H) 3.82 (m, 2H) 3.97 to 4.06 (m, 2H) 6.70 (m, 1H) 8.36 (m, 1H) 8.53 to 8.61 (m, 2H) 8.67 (m, 1H) 8.83 (m, 1H) 8.96 (m, 1H) 9.46 (m, 1H) 9.53 (s, 1H)
실시예 24 : 2 메탄설폰산Example 24 2 Methanesulfonic Acid
상기 실시예 21과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 21.
수율 : 71 %Yield: 71%
m.p. : 247∼250 ℃m.p. : 247-250 ℃
1H-NMR(CF3COOD, ppm) : 1.52∼1.56(m, 6H) 3.24(s, 6H) 3.28(m, 2H) 3.91∼ 4.01(m, 4H) 6.79(m, 1H) 8.42(m, 1H) 8.56∼8.73(m, 3H) 8.86(m, 1H) 9.01(m, 1H) 9.49(s, 1H) 9.63(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 1.52 to 1.56 (m, 6H) 3.24 (s, 6H) 3.28 (m, 2H) 3.91 to 4.01 (m, 4H) 6.79 (m, 1H) 8.42 (m, 1H) 8.56 to 8.73 (m, 3H) 8.86 (m, 1H) 9.01 (m, 1H) 9.49 (s, 1H) 9.63 (s, 1H)
실시예 25 :Example 25
6,7-디플루오로-1-(5-퀴놀릴)-4-옥소-1,4-디하이드로-3-퀴놀린카르복실산 350mg, (3S)-3-아미노-1-피롤리딘.이염산염 358mg(2.5eq.) 1,8-디아자비시클로[5.4.0] 운덱-7-엔 1.234g(9eq.)을 무수 아세토니트릴 15ml 에 넣고 6시간 동안 환류시킨 다음 용매를 감압농축하여 제거한다. 잔사에 소량의 물과 이소프로필알코올 또는 에틸에테르를 가하여 석출시킨 결정을 여과, 건조하여 목적화합물 193mg을 얻었다.350 mg of 6,7-difluoro-1- (5-quinolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, (3S) -3-amino-1-pyrrolidine. 1.358 g (9 eq.) Of 1,8-diazabicyclo [5.4.0] undec-7-ene dihydrochloride 358 mg (2.5 eq.) Was added to 15 ml of anhydrous acetonitrile, refluxed for 6 hours, and the solvent was concentrated under reduced pressure. do. A small amount of water, isopropyl alcohol or ethyl ether was added to the residue, and the precipitated crystals were filtered and dried to obtain 193 mg of the target compound.
수율 : 53 %Yield: 53%
m.p. : 219∼222 ℃m.p. : 219 ~ 222 ℃
1H-NMR(CF3COOD, ppm) : 2.37∼2.60(m, 2H) 3.45∼3.80(m, 2H) 4.20(m, 2H) 4.43(m, 1H) 6.07(m, 1H) 8.39(m, 2H) 8.54(m, 1H) 8.67(m, 1H) 8.81(m, 1H) 8.95(m, 1H) 9.32(s, 1H) 9.53(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 2.37 to 2.60 (m, 2H) 3.45 to 3.80 (m, 2H) 4.20 (m, 2H) 4.43 (m, 1H) 6.07 (m, 1H) 8.39 (m, 2H) 8.54 (m, 1H) 8.67 (m, 1H) 8.81 (m, 1H) 8.95 (m, 1H) 9.32 (s, 1H) 9.53 (s, 1H)
실시예 26 :Example 26:
상기 실시예 23과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained in the same manner as in Example 23.
수율 : 71 %Yield: 71%
m.p. : 281∼282 ℃m.p. : 281 to 282 ° C
1H-NMR(CF3COOD, ppm) : 3.57(m, 4H) 4.14(m, 4H) 8.34(m, 1H) 8.45(m, 1H) 8.52(m, 1H) 8.61(m, 1H) 8.89(m, 2H) 9.52(m, 2H) 1 H-NMR (CF 3 COOD, ppm): 3.57 (m, 4H) 4.14 (m, 4H) 8.34 (m, 1H) 8.45 (m, 1H) 8.52 (m, 1H) 8.61 (m, 1H) 8.89 ( m, 2H) 9.52 (m, 2H)
실시예 27 : 2 메탄설폰산Example 27 2 Methanesulfonic Acid
상기 실시예 21과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 21.
수율 : 71 %Yield: 71%
m.p. : 286∼287 ℃m.p. 286-287 ° C
1H-NMR(CF3COOD, ppm) : 1.38(m, 3H) 3.16(s, 6H) 3.40(m, 2H) 3.42∼3.59(m, 3H) 4.30(m, 2H) 8.32(m, 1H) 8.41(m, 1H) 8.47(m, 1H) 8.57(m, 1H) 8.85(m, 2H) 9.50(m, 2H) 1 H-NMR (CF 3 COOD, ppm): 1.38 (m, 3H) 3.16 (s, 6H) 3.40 (m, 2H) 3.42-3.59 (m, 3H) 4.30 (m, 2H) 8.32 (m, 1H) 8.41 (m, 1H) 8.47 (m, 1H) 8.57 (m, 1H) 8.85 (m, 2H) 9.50 (m, 2H)
실시예 28 :Example 28:
상기 실시예 23과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained in the same manner as in Example 23.
수율 : 69 %Yield: 69%
m.p. : 274∼276 ℃m.p. : 274-276 ℃
1H-NMR(CF3COOD, ppm) : 3.14(s, 3H) 3.32(m, 2H) 3.48(m, 1H) 3.71∼3.79(m, 3H) 4.48(m, 1H) 4.63(m, 1H) 8.30(m, 1H) 8.44(m, 1H) 8.58(m, 1H) 8.62(m, 1H) 8.86(m, 2H) 9.49(m, 2H) 1 H-NMR (CF 3 COOD, ppm): 3.14 (s, 3H) 3.32 (m, 2H) 3.48 (m, 1H) 3.71-3.79 (m, 3H) 4.48 (m, 1H) 4.63 (m, 1H) 8.30 (m, 1H) 8.44 (m, 1H) 8.58 (m, 1H) 8.62 (m, 1H) 8.86 (m, 2H) 9.49 (m, 2H)
실시예 29 :Example 29:
상기 실시예 23과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained in the same manner as in Example 23.
수율 : 82 %Yield: 82%
m.p. : 241∼244 ℃m.p. : 241-244 ° C
1H-NMR(CF3COOD, ppm) : 1.33(m, 6H) 3.14(m, 1H) 3.43(m, 1H) 3.62(m, 2H) 4.24(m, 1H) 4.66(m, 1H) 8.32(m, 1H) 8.44∼8.52(m, 2H) 8.62(m, 1H) 8.87(m, 2H) 9.50(m, 2H) 1 H-NMR (CF 3 COOD, ppm): 1.33 (m, 6H) 3.14 (m, 1H) 3.43 (m, 1H) 3.62 (m, 2H) 4.24 (m, 1H) 4.66 (m, 1H) 8.32 ( m, 1H) 8.44 to 8.52 (m, 2H) 8.62 (m, 1H) 8.87 (m, 2H) 9.50 (m, 2H)
실시예 30 :Example 30:
상기 실시예 25와 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained in the same manner as in Example 25.
수율 : 51 %Yield: 51%
m.p. : 296 ℃ (분해)m.p. : 296 ℃ (decomposition)
1H-NMR(CF3COOD, ppm) : 2.35(m, 1H) 2.64(m, 1H) 3.33∼3.60(m, 2H) 4.19∼ 4.65(m, 3H) 8.33∼8.40(m, 3H) 8.60(m, 1H) 8.88(m, 2H) 9.48(m, 2H) 1 H-NMR (CF 3 COOD, ppm): 2.35 (m, 1H) 2.64 (m, 1H) 3.33-3.60 (m, 2H) 4.19-4.65 (m, 3H) 8.33-8.40 (m, 3H) 8.60 ( m, 1H) 8.88 (m, 2H) 9.48 (m, 2H)
실시예 31 :Example 31:
상기 실시예 23과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained in the same manner as in Example 23.
수율 : 78 %Yield: 78%
m.p. : 232∼235 ℃m.p. : 232 ~ 235 ℃
1H-NMR(CF3COOD, ppm) : 3.76(m, 4H) 3.93(m, 4H) 7.04(m, 1H) 8.42(m, 1H) 8.55(m, 1H) 8.63∼8.76(m, 3H) 9.59(s, 1H) 9.90(s, 1H) 10.03(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 3.76 (m, 4H) 3.93 (m, 4H) 7.04 (m, 1H) 8.42 (m, 1H) 8.55 (m, 1H) 8.63-8.76 (m, 3H) 9.59 (s, 1 H) 9.90 (s, 1 H) 10.03 (s, 1 H)
실시예 32 :Example 32:
상기 실시예 23과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained in the same manner as in Example 23.
수율 : 82 %Yield: 82%
m.p. : 252∼254 ℃m.p. : 252 to 254 ° C
1H-NMR(CF3COOD, ppm) : 1.58(m, 3H) 3.43(m, 1H) 3.60(m, 2H) 3.75(m, 1H) 3.99(m, 2H) 4.14(m, 1H) 7.01(m, 1H) 8.40(m, 1H) 8.54(m, 1H) 8.61∼8.70(m, 3H) 9.54(m, 1H) 9.83(m, 1H) 9.93(m, 1H) 1 H-NMR (CF 3 COOD, ppm): 1.58 (m, 3H) 3.43 (m, 1H) 3.60 (m, 2H) 3.75 (m, 1H) 3.99 (m, 2H) 4.14 (m, 1H) 7.01 ( m, 1H) 8.40 (m, 1H) 8.54 (m, 1H) 8.61-8.70 (m, 3H) 9.54 (m, 1H) 9.83 (m, 1H) 9.93 (m, 1H)
실시예 33 : 2 메탄설폰산Example 33 2 Methanesulfonic Acid
상기 실시예 21과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 21.
수율 : 71 %Yield: 71%
m.p. : 234∼237 ℃m.p. : 234 ~ 237 ℃
1H-NMR(CF3COOD, ppm) : 1.62(s, 6H) 1.65(s, 3H) 1.98(m, 4H) 2.29(m, 2H) 2.55(m, 2H) 5.41(m, 1H) 6.84(m, 1H) 6.93(m, 1H) 7.07(m, 2H) 7.19(m, 1H) 7.91(m, 1H) 8.23(m, 1H) 8.42(m, 1H) 1 H-NMR (CF 3 COOD, ppm): 1.62 (s, 6H) 1.65 (s, 3H) 1.98 (m, 4H) 2.29 (m, 2H) 2.55 (m, 2H) 5.41 (m, 1H) 6.84 ( m, 1H) 6.93 (m, 1H) 7.07 (m, 2H) 7.19 (m, 1H) 7.91 (m, 1H) 8.23 (m, 1H) 8.42 (m, 1H)
실시예 34 :Example 34:
상기 실시예 23과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained in the same manner as in Example 23.
수율 : 75 %Yield: 75%
m.p. : 292∼296 ℃m.p. : 292-296 ° C
1H-NMR(CF3COOD, ppm) : 1.46(m, 6H) 3.27(m, 2H) 4.04(m, 2H) 4.12(m, 2H) 7.04(m, 1H) 8.36(m, 1H) 8.50(m, 1H) 8.56∼8.66(m, 3H) 9.49(m, 1H) 9.79(m, 1H) 9.88(m, 1H) 1 H-NMR (CF 3 COOD, ppm): 1.46 (m, 6H) 3.27 (m, 2H) 4.04 (m, 2H) 4.12 (m, 2H) 7.04 (m, 1H) 8.36 (m, 1H) 8.50 ( m, 1H) 8.56-8.66 (m, 3H) 9.49 (m, 1H) 9.79 (m, 1H) 9.88 (m, 1H)
실시예 35 :Example 35:
상기 실시예 25와 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained in the same manner as in Example 25.
수율 : 62 %Yield: 62%
m.p. : 271 ℃ (분해)m.p. : 271 ℃ (decomposition)
1H-NMR(CF3COOD, ppm) : 2.51(m, 1H) 2.62(m, 1H) 3.72(m, 2H) 4.18(m, 1H) 4.35(m, 1H) 4.47(m, 1H) 6.37(m, 1H) 8.37(m, 2H) 8.59∼8.70(m, 3H) 9.37(s, 1H) 9.77(m, 1H) 9.88(m, 1H) 1 H-NMR (CF 3 COOD, ppm): 2.51 (m, 1H) 2.62 (m, 1H) 3.72 (m, 2H) 4.18 (m, 1H) 4.35 (m, 1H) 4.47 (m, 1H) 6.37 ( m, 1H) 8.37 (m, 2H) 8.59 to 8.70 (m, 3H) 9.37 (s, 1H) 9.77 (m, 1H) 9.88 (m, 1H)
실시예 36 : 2 메탄설폰산Example 36 2 Methanesulfonic Acid
상기 실시예 21과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 21.
수율 : 62 %Yield: 62%
m.p. : 298 ℃ (분해)m.p. : 298 ℃ (decomposition)
1H-NMR(CF3COOD+DMSO-D6, ppm) : 2.18(s, 6H) 2.65(m, 4H) 3.28(m, 4H) 7.33(m, 1H) 7.47∼7.64(m, 4H) 8.57(m, 1H) 8.68(s, 1H) 8.90(s, 1H) 1 H-NMR (CF 3 COOD + DMSO-D 6 , ppm): 2.18 (s, 6H) 2.65 (m, 4H) 3.28 (m, 4H) 7.33 (m, 1H) 7.47∼7.64 (m, 4H) 8.57 (m, 1H) 8.68 (s, 1H) 8.90 (s, 1H)
실시예 37 : 메탄설폰산Example 37 Methanesulfonic Acid
상기 실시예 21과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 21.
수율 : 63 %Yield: 63%
m.p. : 271∼274 ℃m.p. : 271-274 ° C
1H-NMR(CF3COOD+DMSO-D6, ppm) : 0.93(m, 3H) 2.61(s, 6H) 2.93∼3.04(m, 2H) 3.12∼3.28(m, 3H) 3.97∼4.07(m, 2H) 7.84(m, 1H) 7.9 9∼8.06(m, 2H) 8.16(m, 1H) 8.22(m, 1H) 8.95(m, 1H) 9.16(s, 1H) 9.39(s, 1H) 1 H-NMR (CF 3 COOD + DMSO-D 6 , ppm): 0.93 (m, 3H) 2.61 (s, 6H) 2.93 to 3.04 (m, 2H) 3.12 to 3.28 (m, 3H) 3.97 to 4.07 (m , 2H) 7.84 (m, 1H) 7.9 9 to 8.06 (m, 2H) 8.16 (m, 1H) 8.22 (m, 1H) 8.95 (m, 1H) 9.16 (s, 1H) 9.39 (s, 1H)
실시예 38 :Example 38:
상기 실시예 23과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained in the same manner as in Example 23.
수율 : 61 %Yield: 61%
m.p. : 270 ℃(분해)m.p. : 270 ° C (decomposition)
1H-NMR(CF3COOD, ppm) : 3.19(s, 3H) 3.49(m, 2H) 3.88(m, 4H) 4.86(m, 2H) 8.36(m, 1H) 8.56(m, 2H) 8.67(m, 2H) 9.70(s, 1H) 9.82(s, 1H) 10.07(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 3.19 (s, 3H) 3.49 (m, 2H) 3.88 (m, 4H) 4.86 (m, 2H) 8.36 (m, 1H) 8.56 (m, 2H) 8.67 ( m, 2H) 9.70 (s, 1H) 9.82 (s, 1H) 10.07 (s, 1H)
실시예 39 :Example 39:
상기 실시예 23과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained in the same manner as in Example 23.
수율 : 74 %Yield: 74%
m.p. : 300 ℃m.p. : 300 ℃
1H-NMR(CF3COOD, ppm) : 1.43(m, 6H) 3.47(m, 2H) 3.79(m, 2H) 4.77(m, 2H) 8.38(m, 1H) 8.52(m, 1H) 8.60(m, 1H) 8.67(m, 2H) 9.68(s, 1H) 9.79(s, 1H) 9.95(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 1.43 (m, 6H) 3.47 (m, 2H) 3.79 (m, 2H) 4.77 (m, 2H) 8.38 (m, 1H) 8.52 (m, 1H) 8.60 ( m, 1H) 8.67 (m, 2H) 9.68 (s, 1H) 9.79 (s, 1H) 9.95 (s, 1H)
실시예 40 : 2 메탄설폰산Example 40 2 Methanesulfonic Acid
상기 실시예 5와 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 5.
수율 : 56 %Yield: 56%
m.p. : 292∼295 ℃m.p. : 292-295 degreeC
1H-NMR(CF3COOD, ppm) : 2.50(m, 1H) 2.73(m, 1H) 3.23(s, 6H) 3.85(m, 1H) 4.08(m, 1H) 4.41∼4.68(m, 3H) 8.36(m, 2H) 8.57(m, 1H) 8.64(m, 2H) 9.62(s, 1H) 9.70(s, 1H) 10.04(s, 1H) 1 H-NMR (CF 3 COOD, ppm): 2.50 (m, 1H) 2.73 (m, 1H) 3.23 (s, 6H) 3.85 (m, 1H) 4.08 (m, 1H) 4.41 ~ 4.68 (m, 3H) 8.36 (m, 2H) 8.57 (m, 1H) 8.64 (m, 2H) 9.62 (s, 1H) 9.70 (s, 1H) 10.04 (s, 1H)
실시예 41 :Example 41:
상기 실시예 23과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained in the same manner as in Example 23.
수율 : 72 %Yield: 72%
m.p. : 300 ℃m.p. : 300 ℃
1H-NMR(CF3COOD, ppm) : 3.76(m, 4H) 3.88(m, 4H) 6.93(m, 1H) 8.51(m, 2H) 8.59(m, 1H) 9.00(m, 2H) 9.49(s, 1H) 9.58(m, 2H) 1 H-NMR (CF 3 COOD, ppm): 3.76 (m, 4H) 3.88 (m, 4H) 6.93 (m, 1H) 8.51 (m, 2H) 8.59 (m, 1H) 9.00 (m, 2H) 9.49 ( s, 1H) 9.58 (m, 2H)
실시예 42 : 2 메탄설폰산Example 42 2 Methanesulfonic Acid
상기 실시예 21과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 21.
수율 : 63 %Yield: 63%
m.p. : 297 ℃(분해)m.p. : 297 ° C (decomposition)
1H-NMR(CF3COOD, ppm) : 1.56(m, 3H) 3.17(s, 6H) 3.43(m, 1H) 3.60(m, 2H) 3.76(m, 1H) 3.91(m, 2H) 4.13(m, 1H) 6.90(m, 1H) 8.44(m, 2H) 8.54(m, 1H) 8.95(m, 2H) 9.41(s, 1H) 9.52(m, 2H) 1 H-NMR (CF 3 COOD, ppm): 1.56 (m, 3H) 3.17 (s, 6H) 3.43 (m, 1H) 3.60 (m, 2H) 3.76 (m, 1H) 3.91 (m, 2H) 4.13 ( m, 1H) 6.90 (m, 1H) 8.44 (m, 2H) 8.54 (m, 1H) 8.95 (m, 2H) 9.41 (s, 1H) 9.52 (m, 2H)
실시예 43 :Example 43:
상기 실시예 23과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained in the same manner as in Example 23.
수율 : 68 %Yield: 68%
m.p. : 295 ℃(분해)m.p. : 295 ° C (decomposition)
1H-NMR(CF3COOD, ppm) : 3.20(s, 3H) 3.53(m, 4H) 3.84(m, 2H) 4.11(m, 2H) 6.88(m, 1H) 8.46∼8.55(m, 3H) 8.89(m, 1H) 8.95(s, 1H) 9.34(s, 1H) 9.52(m, 2H) 1 H-NMR (CF 3 COOD, ppm): 3.20 (s, 3H) 3.53 (m, 4H) 3.84 (m, 2H) 4.11 (m, 2H) 6.88 (m, 1H) 8.46 ~ 8.55 (m, 3H) 8.89 (m, 1H) 8.95 (s, 1H) 9.34 (s, 1H) 9.52 (m, 2H)
실시예 44 :Example 44:
상기 실시예 23과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained in the same manner as in Example 23.
수율 : 69 %Yield: 69%
m.p. : 273 ℃(분해)m.p. : 273 ° C (decomposition)
1H-NMR(CF3COOD, ppm) : 1.54(m, 6H) 3.34(m, 2H) 3.91∼4.20(m, 4H) 6.98(m, 1H) 8.49∼8.57(m, 3H) 8.93(m, 1H) 9.00(m, 1H) 9.43(m,1H) 9.55(m, 2H) 1 H-NMR (CF 3 COOD, ppm): 1.54 (m, 6H) 3.34 (m, 2H) 3.91-4.20 (m, 4H) 6.98 (m, 1H) 8.49-8.57 (m, 3H) 8.93 (m, 1H) 9.00 (m, 1H) 9.43 (m, 1H) 9.55 (m, 2H)
실시예 45 :Example 45:
상기 실시예 25과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained in the same manner as in Example 25.
수율 : 56 %Yield: 56%
m.p. : 260 ℃(분해)m.p. : 260 ° C (decomposition)
1H-NMR(CF3COOD, ppm) : 2.32(m, 1H) 2.50(m, 1H) 3.74∼3.97(m, 2H) 4.18(m, 1H) 4.26(m, 1H) 4.46(m, 1H) 6.33(m, 1H) 8.36(m, 1H) 8.50(m, 2H) 8.92(m, 2H) 9.30(s, 1H) 9.54(m, 2H) 1 H-NMR (CF 3 COOD, ppm): 2.32 (m, 1H) 2.50 (m, 1H) 3.74-3.97 (m, 2H) 4.18 (m, 1H) 4.26 (m, 1H) 4.46 (m, 1H) 6.33 (m, 1H) 8.36 (m, 1H) 8.50 (m, 2H) 8.92 (m, 2H) 9.30 (s, 1H) 9.54 (m, 2H)
실시예 46 :Example 46:
상기 실시예 23과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained in the same manner as in Example 23.
수율 : 69 %Yield: 69%
m.p. : 275∼278 ℃m.p. : 275 to 278 ° C
1H-NMR(CF3COOD+DMSO-D6, ppm) : 3.00(m, 4H) 3.63(m, 4H) 8.03∼8.13(m, 2H) 8.26(m, 1H) 8.35(m, 1H) 8.54(m, 1H) 8.82(m, 1H) 9.16(m, 1H) 9.33(m, 1H) 1 H-NMR (CF 3 COOD + DMSO-D 6 , ppm): 3.00 (m, 4H) 3.63 (m, 4H) 8.03-8.13 (m, 2H) 8.26 (m, 1H) 8.35 (m, 1H) 8.54 (m, 1H) 8.82 (m, 1H) 9.16 (m, 1H) 9.33 (m, 1H)
실시예 47 : 2 메탄설폰산Example 47 2 Methanesulfonic Acid
상기 실시예 21과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 21.
수율 : 68 %Yield: 68%
m.p. : 300 ℃m.p. : 300 ℃
1H-NMR(CF3COOD+DMSO-D6, ppm) : 0.93(m, 3H) 2.49(s, 6H + DMSO) 2.95(m, 2H) 3.07∼3.30(m, 3H) 3.95∼4.07(m, 2H) 8.06∼8.16(m, 2H) 8.27(m, 1H) 8.39(m, 1H) 8.58(m, 1H) 8.86(m, 1H) 9.18(m, 1H) 9.34(m, 1H) 1 H-NMR (CF 3 COOD + DMSO-D 6 , ppm): 0.93 (m, 3H) 2.49 (s, 6H + DMSO) 2.95 (m, 2H) 3.07 to 3.30 (m, 3H) 3.95 to 4.07 (m , 2H) 8.06-8.16 (m, 2H) 8.27 (m, 1H) 8.39 (m, 1H) 8.58 (m, 1H) 8.86 (m, 1H) 9.18 (m, 1H) 9.34 (m, 1H)
실시예 48 :Example 48:
상기 실시예 23과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained in the same manner as in Example 23.
수율 : 71 %Yield: 71%
m.p. : 296 ℃(분해)m.p. : 296 ° C (decomposition)
1H-NMR(CF3COOD, ppm) : 3.17(s, 3H) 3.45(m, 2H) 3.85(m, 4H) 4.83(m, 2H) 8.43(m, 1H) 8.50(m, 1H) 8.63(m, 1H) 8.89(m, 2H) 9.4 9∼9.53(m, 3H) 1 H-NMR (CF 3 COOD, ppm): 3.17 (s, 3H) 3.45 (m, 2H) 3.85 (m, 4H) 4.83 (m, 2H) 8.43 (m, 1H) 8.50 (m, 1H) 8.63 ( m, 1H) 8.89 (m, 2H) 9.4 9-9.53 (m, 3H)
실시예 49 : 메탄설폰산Example 49 Methanesulfonic Acid
상기 실시예 21과 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained by the same preparation method as in Example 21.
수율 : 66 %Yield: 66%
m.p. : 220∼222 ℃m.p. : 220 ~ 222 ℃
1H-NMR(CF3COOD+DMSO-D6, ppm) : 0.91(m, 3H) 0.98(m, 3H) 2.49(s, 6H + DMSO) 2.88(m, 2H) 3.13(m, 2H) 4.05(m, 2H) 8.02∼ 8.12(m, 2H) 8.24(m, 1H) 8.36(m, 1H) 8.51(m, 1H) 8.84(m, 1H) 9.16(m, 1H) 9.27(m, 1H) 1 H-NMR (CF 3 COOD + DMSO-D 6 , ppm): 0.91 (m, 3H) 0.98 (m, 3H) 2.49 (s, 6H + DMSO) 2.88 (m, 2H) 3.13 (m, 2H) 4.05 (m, 2H) 8.02 to 8.12 (m, 2H) 8.24 (m, 1H) 8.36 (m, 1H) 8.51 (m, 1H) 8.84 (m, 1H) 9.16 (m, 1H) 9.27 (m, 1H)
실시예 50 :Example 50:
상기 실시예 25와 동일한 제조방법으로 실시하여 목적화합물을 얻었다.The target compound was obtained in the same manner as in Example 25.
수율 : 55 %Yield: 55%
m.p. : 246 ℃(분해)m.p. : 246 ° C (decomposition)
1H-NMR(CF3COOD+DMSO-D6, ppm) : 1.90∼2.12(m, 2H) 3.05∼4.01(m, 5H) 8.00∼ 8.17(m, 2H) 8.28∼8.44(m, 2H) 8.60(m, 1H) 8.83(m, 1H) 9.22(m, 1H) 9.40(m, 1H) 1 H-NMR (CF 3 COOD + DMSO-D 6 , ppm): 1.90 to 2.12 (m, 2H) 3.05 to 4.01 (m, 5H) 8.00 to 8.17 (m, 2H) 8.28 to 8.44 (m, 2H) 8.60 (m, 1H) 8.83 (m, 1H) 9.22 (m, 1H) 9.40 (m, 1H)
실험예 1 : 인체면역결핍바이러스 역전사효소(HIV-RT)의 생체외(Experimental Example 1 In Vitro of Human Immunodeficiency Virus Reverse Transcriptase (HIV-RT) in vitroin vitro ) 저해활성 테스트Inhibitory Activity Test
비방사성 역전사효소 분석기(Non-radioactive Reverse transcriptase assay Kit, Boehringer Mannheim)를 사용하여 생체외 저해활성을 측정하였다.In vitro inhibitory activity was measured using a non-radioactive reverse transcriptase assay kit (Boehringer Mannheim).
먼저, HIV-RT 20 ㎕(40 ng)을 스트렙타비딘(streptavidin)으로 코팅된 웰(well)에 넣고, template/primer hybrid poly(A)·oligo(dT)15와 DIG-(디그옥시게닌)-dUTP, 비오틴-dUTP, TTP가 포함된 반응혼합액(reaction mixture) 20 ㎕를 가한 다음, 활성을 측정하고자 하는 시료를 20 ㎕ 가하여 1시간동안 37℃에서 반응하였다. 시료를 넣지 않은 것을 대조군으로 하여 활성을 비교하였다. 이때, HIV-RT의 작용에 의하여 DNA가 만들어지며 디그옥시게닌(digoxigenin)과 비오틴이 표지된 뉴클레오티드가 함께 포함되므로, 웰의 바닥에 코팅되어 있는 스트렙타비딘과 결합하게 된다. 반응이 끝나면 남아있는 불순물 등을 제거하기 위하여 각 웰 당 250 ㎕의 세척용 완충용액(pH 7.0)을 가하여 30초간 5회 세척하고, 항-DIG-POD 항체를 200 ㎕씩 가하여 37℃에서 1시간동안 반응시킨 다음, 다시 불순물 제거를 위해 세척용 완충용액으로 씻어준 후, POD(peroxidase)의 기질(substrate)인 ABTS™을 각각 200 ㎕씩 가하여 30분간 상온에서 반응시킨 후, ELISA 판독기를 이용하여 405 nm에서 흡광도를 측정하여 역전사 효소활성 및 저해활성을 정량화하였다.First, 20 μl (40 ng) of HIV-RT were placed in a well coated with streptavidin, template / primer hybrid poly (A) oligo (dT) 15 and DIG- (digoxygenin). 20 μl of a reaction mixture containing -dUTP, biotin-dUTP, and TTP was added, and then 20 μl of the sample to measure activity was added and reacted at 37 ° C. for 1 hour. The activity was compared as a control without the sample. At this time, the DNA is produced by the action of HIV-RT and because digoxigenin and biotin-labeled nucleotides are included together, it binds to streptavidin coated on the bottom of the well. After the reaction was completed, 250 μl of washing buffer solution (pH 7.0) was added to each well to remove remaining impurities, and washed five times for 30 seconds. 200 μl of anti-DIG-POD antibody was added thereto for 1 hour at 37 ° C. After reacting for a while, washed again with a washing buffer to remove impurities, and then reacted at room temperature for 30 minutes by adding 200 μl of ABTS ™, a substrate of POD (peroxidase), and then using an ELISA reader. Absorbance was measured at 405 nm to quantify reverse transcriptase activity and inhibitory activity.
각 시료의 저해활성결과는 다음 표 1에 나타내었다.The inhibitory activity results of each sample are shown in Table 1 below.
[표 1]TABLE 1
인체면역결핍 바이러스 역전사효소(HIV-RT)의 생체외(in vitro) 저해활성도In vitro Inhibitory Activity of Human Immunodeficiency Virus Reverse Transcriptase (HIV-RT)
표1 (계속)Table 1 (continued)
표1 (계속)Table 1 (continued)
표1 (계속)Table 1 (continued)
표1 (계속)Table 1 (continued)
표 1에서 보는 바와 같이 1㎍/㎖ 농도에서 현재 업죤에서 개발중인 아테버딘(Atevirdine)(임상 3상)과 비슷한 HIV-RT 저해효과를 나타내며, 특히 본 발명의 화합물은 10배 낮은 농도인 0.1㎍/㎖에서의 HIV-RT 저해효과가 아테버딘에 비해 훨씬 우수하다. 즉, 아테버딘은 낮은 농도인 0.1㎍/㎖에서의 활성(25%)은 1㎍/㎖에서의 활성(64%)의 39%수준으로 급격히 떨어진 것에 비해, 본 발명의 화합물은 1㎍/㎖에서의 활성에 비해 0.1㎍/㎖의 낮은 농도에서 약 75-84%의 높은 수준으로 유지됨을 알 수 있다.As shown in Table 1, at a concentration of 1 µg / ml, HIV-RT inhibitory effect similar to that of Atevirdine (clinical phase 3), which is currently being developed in Upzon, is especially high, 0.1 µg. HIV-RT inhibitory effect at / ml is much better than ataverin. In other words, the compound of the present invention is 1 μg / ml, whereas atherodine has a sharp drop in activity (25%) at a low concentration of 0.1 μg / ml to 39% of activity (64%) at 1 μg / ml. It can be seen that it is maintained at a high level of about 75-84% at a low concentration of 0.1 μg / ml compared to the activity at.
실험예2. 급성독성시험Experimental Example 2. Acute Toxicity Test
본 발명에 따른 피리돈카르복실산 유도체의 급성독성실험에서는 무게가 20내지 25g인 암수 ICR마우스를 실험동물로 사용하였다. ICR마우스를 암수 각각 5마리씩 5투여 용량군으로 분주하여 시험약물의 투여량을 1% 카르복시메틸셀루로즈(CMC) 용액에 현탁시켜서 각 마리당 10㎎/㎏씩 경구투여하고, 72시간동안 행동의 이상유무와 사망여부를 관찰한 결과 LD50(㎎/㎏)가 1500이상이었다.In the acute toxicity test of the pyridonecarboxylic acid derivative according to the present invention, male and female ICR mice having a weight of 20 to 25 g were used as experimental animals. ICR mice were divided into 5 dose dose groups of 5 males and 5 females, and the dose of test drug was suspended in 1% carboxymethyl cellulose (CMC) solution and orally administered at 10 mg / kg for each animal, followed by abnormal behavior for 72 hours. LD 50 (mg / kg) was above 1500.
본 발명에 따른 퀴론론카르복실산 유도체는 독성 및 농도에 따른 활성도 변화가 적으며, 항 HIV-RT효과가 우수하여 에이즈치료에 유용하게 사용될 수 있다.The quyrononecarboxylic acid derivative according to the present invention has little change in activity according to toxicity and concentration, and has an excellent anti-HIV-RT effect, which can be usefully used for AIDS treatment.
Claims (4)
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|---|---|---|---|
| KR1019970040811A KR19990024314A (en) | 1997-08-26 | 1997-08-26 | New Quinolone Carboxylic Acid Derivatives |
| KR1019980006042A KR19990023074A (en) | 1997-08-26 | 1998-02-26 | New pyridonecarboxylic acid derivatives |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019970040811A KR19990024314A (en) | 1997-08-26 | 1997-08-26 | New Quinolone Carboxylic Acid Derivatives |
Country Status (1)
| Country | Link |
|---|---|
| KR (2) | KR19990024314A (en) |
-
1997
- 1997-08-26 KR KR1019970040811A patent/KR19990024314A/en unknown
-
1998
- 1998-02-26 KR KR1019980006042A patent/KR19990023074A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| KR19990024314A (en) | 1999-04-06 |
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| WITN | Withdrawal due to no request for examination |