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公开(公告)号：KR1020030081762A
公开(公告)日：2003-10-22
申请号：KR1020020020136
申请日：2002-04-12
Applicant: 동화약품주식회사
IPC: C07D401/04
CPC classification number: Y02P20/55
Abstract: PURPOSE: A quinoline carboxylic acid derivative with fluoropyrrolidine substituents and a preparation process thereof are provided. The compound has no toxicity and improved antimicrobial activity to both gram positive and negative bacteria. CONSTITUTION: A quinoline carboxylic acid derivative represented by the formula 1 in which 4-aminomethyl-4-fluoro-3-(Z)-alkoxyiminopyrrolidine is substituted at the 7-site of the quinolone scaffold, pharmaceutically acceptable acid adding salt and solvates thereof are provided. In the formula, Q is C-H, C-F, C-Cl, C-OCH3, C-OCHF2, C-CH3 or N; R is hydrogen, methyl or NH2; R1 is ethyl, cyclopropyl, t-butyl, or at least one fluoro substituted phenyl; R2 is hydrogen, C1-C5 alkyl, cyclopropyl, cyclopropyl methyl, C3-C6 alkenyl, C3-C6 alkynyl, phenyl or benzyl; and R3 or R4 is independently hydrogen, or C1-C3 alkyl, or R3 or R4 is hydrogen or C1-C3 alkyl bound nitrogen containing C3-C5 hetero ring compound. A process for preparing the quinoline carboxylic acid derivative represented by the formula 1 comprises the steps of: (1) reacting a quinolone scaffold compound of the formula 2 with a fluoro containing compound of the formula 3 in the presence of a solvent and a base to prepare a compound of the formula 4; and (2) deprotecting the compound of formula 4 with HX, wherein R3 or R4 is hydrogen; P is hydrogen or amine-protecting group; and X is F or Cl.
Abstract translation: 目的：提供具有氟吡咯烷取代基的喹啉羧酸衍生物及其制备方法。 该化合物对革兰氏阳性菌和阴性菌均无毒性和改善的抗微生物活性。 构成：在喹诺酮支架的7-位取代有4-氨基甲基-4-氟-3-（Z） - 烷氧基亚氨基吡咯烷的式1所示的喹啉羧酸衍生物，其药学上可接受的酸加成盐及其溶剂合物是 提供。 在该式中，Q为C-H，C-F，C-Cl，C-OCH 3，C-OCHF 2，C-CH 3或N; R是氢，甲基或NH 2; R 1是乙基，环丙基，叔丁基或至少一个氟取代的苯基; R 2是氢，C 1 -C 5烷基，环丙基，环丙基甲基，C 3 -C 6烯基，C 3 -C 6炔基，苯基或苄基; 并且R 3或R 4独立地是氢或C 1 -C 3烷基，或者R 3或R 4是氢或C 1 -C 3烷基键合的含有C 3 -C 5杂环化合物的氮。 制备由式1表示的喹啉羧酸衍生物的方法包括以下步骤：（1）在溶剂和碱的存在下使式2的喹诺酮支架化合物与式3的含氟化合物反应， 制备式4的化合物; 和（2）用HX使式4的化合物脱保护，其中R3或R4是氢; P是氢或胺保护基; X为F或Cl。
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2.发明公开
公开(公告)号：KR1020020002461A
公开(公告)日：2002-01-09
申请号：KR1020017014647
申请日：2000-05-18
Applicant: 동화약품주식회사
IPC: C07D471/04
CPC classification number: C07D401/04 , C07D471/04 , C07D487/10
Abstract: PURPOSE: Provided are optically active quinoline carboxylic acid derivatives, pharmaceutically acceptable salts thereof, solvates thereof, and a process for preparation thereof, which are useful for an antibacterial agent. CONSTITUTION: The optically active quinoline carboxylic acid derivatives are represented by the following formula(1), and contains optical activity-causing 4-aminomethyl-4-methyl-3 (Z)-alkoxyiminopyrrolidine substituents at the 7-position of the quinolone nuclei, their pharmaceutically acceptable salts, and their solvates. In the formula(1), Q is C-H, C-F, C-Cl or N; Y is H or NH2; R is a straight or branched alkyl group of Cl-C, an allyl group or a benzyl group, and * represents optically pure chiral carbon atom. Their preparation process comprises the steps of: condensing the quinolone nuclei-containing compound of formula(3), with the ketal compound of formula(2a), in the presence of an acid acceptor to give the optically active quinoline carboxylic acid derivative of formula(4); deketalizing the optically active quinoline carboxylic acid derivative of formula(4) to give the pyrrolidinone compound of formula(5); and reacting the pyrrolidinone compound of formula(5) with an alkoxylamine in the presence of a base to obtain the desired compound of formula(1).
Abstract translation: 目的：提供可用于抗菌剂的光学活性喹啉羧酸衍生物，其药学上可接受的盐，溶剂合物及其制备方法。 构成：光学活性喹啉羧酸衍生物由下式（1）表示，并且在喹诺酮核的7-位含有光学活性的4-氨基甲基-4-甲基-3（Z） - 烷氧基亚氨基吡咯烷取代基， 其药学上可接受的盐及其溶剂合物。 在式（1）中，Q是C-H，C-F，C-Cl或N; Y为H或NH 2; R是Cl-C，烯丙基或苄基的直链或支链烷基，*表示光学上纯的手性碳原子。 它们的制备方法包括以下步骤：在酸受体存在下将式（3）的喹诺酮核含有化合物与式（2a）的缩酮化合物缩合，得到式（3）的光学活性喹啉羧酸衍生物 4）; 对式（4）的光学活性喹啉羧酸衍生物进行缩酮化，得到式（5）的吡咯烷酮化合物; 并在碱的存在下使式（5）的吡咯烷酮化合物与烷氧基胺反应，得到所需的式（1）化合物。
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3.发明授权
公开(公告)号：KR100497942B1
公开(公告)日：2005-06-29
申请号：KR1020017014647
申请日：2000-05-18
Applicant: 동화약품주식회사
IPC: C07D471/04
CPC classification number: C07D401/04 , C07D471/04 , C07D487/10
Abstract: 본 발명은 광학활성의 퀴놀린 카르복실산 유도체, 이의 약학적으로 허용되는 염, 이의 용매화물 및 이의 제조방법에 관한 것으로, 구체적으로 본 발명은 퀴놀론 모핵의 7-위치에 광학활성을 유발하는 4-아미노메틸-4-메틸-3-(Z)-알콕시이미노피롤리딘 치환체를 갖는 광학활성의 퀴놀린 카르복실산 유도체에 관한 것으로, 본 발명의 화합물은 그의 거울상 이성질체, 라세믹 혼합물 및 기존의 항균제에 비하여 항균 효과가 매우 우수하고 약동력학적 특성이 우수할 뿐만 아니라 광독성도 거의 나타내지 않기 때문에 항균제로서 효과적으로 사용될 수 있다.
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Patent Agency Ranking
公开(公告)号：KR100273765B1
公开(公告)日：2000-12-15
申请号：KR1019980039547
申请日：1998-09-24
IPC: C07D211/58
Abstract: 본 발명은 위장계통을 자극하는 생리활성을 가지는 다음 일반식(Ⅰ)의 N-(4-피페리딘)벤즈아미드 및 그 약제학적으로 허용되는 부가염의 새로운 제조방법에 관한 것이다. 보다 바람직하게는 다음 일반식(Ⅰ)에서 L이 3-(4-플루오로펜옥시)프로필이고, R이 메틸인 위장 연동운동 촉진제로 사용되는 시사프라이드의 새로운 제조방법에 관한 것이다.
또한 본 발명은 일반식(Ⅰ)의 N-(4-피페리딘)벤즈아미드 제조에 유용한 구조식(Ⅲ)의 새로운“활성티오에스테르”및 그 제조방법에 관한 것이다.
즉, 본 발명은 구조식(Ⅶ)의 카르복실산 유도체와 일반식(Ⅵ)의 알킬클로로포르메이트를 반응시켜 일반식(Ⅴ)의 중간체를 생성시킨 후 일반식(Ⅴ)의 중간체와 구조식(Ⅳ)의 2-머캅토벤즈이미다졸을 반응시켜 구조식(Ⅲ)의 새로운“활성티오에스테르”를 제조한 다음, 일반식(Ⅱ)의 시스-피페리딘아민 유도체와 반응시켜 목적화합물인 일반식(Ⅰ)의 시스프라이드를 포함하는 벤즈아미드 유도체를 제조하는 방법에 관한 것이다.
상기 식에서 L은 아르알킬 또는 아릴옥시알킬인데, 이때 알킬부분은 C
1 -C
6 의 알킬이고, 아릴부분은 할로, C
1 -C
6 의 저급알킬 또는C
1 -C
6 의 저급알콕시로부터 독립적으로 선택된 3개까지의 치환체로 임의치환된 것이고； R은 C
1 -C
6 의 저급알킬이며; R
1 은 에틸, 이소프로필 또는 이소부틸이다.-
公开(公告)号：KR1020000013029A
公开(公告)日：2000-03-06
申请号：KR1019980031662
申请日：1998-08-04
Applicant: 동화약품주식회사
IPC: C07D211/58
Abstract: PURPOSE: An N-(4-piperidine)benzamide has a physiological activity for the stimulating gastrointestinal system and a pharmaceutically accepted additional salt thereof. CONSTITUTION: An N-(4-piperidine)benzamide represented by the formula (1) having a physiological activity for the stimulating gastrointestinal system and a pharmaceutically accepted additional salt thereof: wherein L is aralkyl or aryloxyalkyl, wherein the alkyl moiety is C1-C6 alkyl and the aryl moieties are up to three substituents each independently selected from the group consisting of halo, C1-C6 low alkyl and C1-C6 low alkoxy; and R is C1-C6 low alkyl.
Abstract translation: 目的：N-（4-哌啶）苯甲酰胺具有刺激胃肠系统的生理活性和药学上可接受的另外的盐。 构成：由式（1）表示的具有刺激胃肠系统的生理活性的N-（4-哌啶）苯甲酰胺及其药学上可接受的另外的盐：其中L是芳烷基或芳氧基烷基，其中烷基部分是C1-C6 烷基和芳基部分是至多三个独立地选自卤素，C 1 -C 6低级烷基和C 1 -C 6低级烷氧基的取代基; 且R为C1-C6低级烷基。
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6.发明公开
公开(公告)号：KR1020010029698A
公开(公告)日：2001-04-06
申请号：KR1020000024657
申请日：2000-05-09
Applicant: 동화약품주식회사
IPC: C07D403/04
Abstract: PURPOSE: Provided is a method for manufacturing 4-aminomethyl-4-methyl-3-(Z)-alkoxyamino derivative which has antibacterial effects on both gram positive and negative bacteria so that the derivative is useful for medical purposes. And Its pharmaceutically acceptable salt and its solvate are also provided. CONSTITUTION: A method for producing 4-aminomethyl-4-methyl-3-(Z)-alkoxyamino derivative comprises the following steps of: i) reacting the compound of the formula (3) with ketal compound of the formula (2a) in the presence of acid receptor, for 1-24 hours at 0-150 deg.C, preferably from room temperature to 90 deg.C, to manufacture optically active quinoline carboxylic acid derivative of the formula (4); ii) deketalizing the quinoline carboxylic acid derivative to manufacture pyrrolidinone of the formula (5) at from room temperature to 100 deg.C; and iii) reacting the pyrrolidinone with alkoxylamine in the presence of base at 0-90 deg.C. In the formula (1), Q is C-H, C-F, C-CL, or N. Y is H or NH2. R is a C1-C4 linear or branched alkyl, aryl, or benzyl group. * is an optically pure asymmetric carbon.
Abstract translation: 目的：提供对革兰氏阳性细菌和阴性细菌都具有抗菌作用的4-氨基甲基-4-甲基-3-（Z） - 烷氧基氨基衍生物的制备方法，因此该衍生物可用于医疗目的。 还提供其药学上可接受的盐及其溶剂合物。 构成：4-氨基甲基-4-甲基-3-（Z） - 烷氧基氨基衍生物的制备方法包括以下步骤：i）使式（3）的化合物与式（2a）的缩酮化合物反应于 存在酸受体，在0-150℃，优选室温至90℃下进行1-24小时，以制备式（4）的光学活性喹啉羧酸衍生物; ii）将喹啉羧酸衍生物缩酮化，制备式（5）的吡咯烷酮，室温至100℃; 和iii）在0-90℃下，在碱的存在下使吡咯烷酮与烷氧基胺反应。 在式（1）中，Q是C-H，C-F，C-CL或N.Y是H或NH 2。 R是C1-C4直链或支链烷基，芳基或苄基。 *是光学纯的不对称碳。
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公开(公告)号：KR1020000020793A
公开(公告)日：2000-04-15
申请号：KR1019980039547
申请日：1998-09-24
IPC: C07D211/58
Abstract: PURPOSE: An N-(4-piperidine) benzamide is prepared by the reaction of thioester and is-piperidine amine derivatives which has gastroenteric irritative physiological activities. CONSTITUTION: Carboxylic derivatives and alkyl chloroformate are reacted to give an intermediate(formula 5), and reacted with 2-mercaptobenzimidazole to give the novel active thioester(formula 3). Active thioester and is-piperidine amine derivatives(formula 2) are reacted to give benzamide derivatives(formula 1; R is C1-C6 lower alkyl; L is an alkyl or aryloxyalkyl). Thus, 376 mg of triethyl amine and 280 mg of ethyl chloroformate are drop in 500 mg of 4-amino-5-chloro-2-methoxybenzoic acid and reacted at 0-10°C for 1.5 hours, adding 396 mg of 2-mercaptobenzimidazole at room temperature for 6 hour. A mixed solution of 630 mg of is-4-amino-3-method-1-£3-(4-fluorophenoxy) propyl|piperidine and 1 ml of N,N-dimethyl form amide is drop at room temperature for 5 hours in the reactant to give 963 mg of is-2-method-4-amino-5-chloro-N-£1-£3-(4- fluorophenoxy)propyl|-3-method-4-piperidinyl|benzamide1 hydrate.
Abstract translation: 目的：通过具有胃肠刺激性生理活性的硫酯和异哌啶胺衍生物的反应制备N-（4-哌啶）苯甲酰胺。 组成：羧酸衍生物和氯甲酸烷基酯反应得到中间体（式5），并与2-巯基苯并咪唑反应得到新的活性硫酯（式3）。 使活性硫酯和哌啶胺衍生物（式2）反应得到苯甲酰胺衍生物（式1; R是C 1 -C 6低级烷基; L是烷基或芳氧基烷基）。 因此，将376mg三乙胺和280mg氯甲酸乙酯滴加到500mg 4-氨基-5-氯-2-甲氧基苯甲酸中，并在0-10℃下反应1.5小时，加入396mg 2-巯基苯并咪唑 在室温下放置6小时。 将630mg的is-4-氨基-3-方法1-（3-氟苯氧基）丙基|哌啶和1ml N，N-二甲基甲酰胺的混合溶液在室温下滴加5小时， 反应物得到963mg的is-2-方法-4-氨基-5-氯-N- {3-（4-氟苯氧基）丙基| 3-方法-4-哌啶基|苯甲酰胺1水合物。
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公开(公告)号：KR1020000008471A
公开(公告)日：2000-02-07
申请号：KR1019980028294
申请日：1998-07-14
Applicant: 동화약품주식회사
IPC: C07D211/58
Abstract: PURPOSE: A method for preparing N-(4-piperidine)benzamide is provided in which high purity of compound can be obtained in high yield and a side reaction product is easily separated from an object product. CONSTITUTION: A benzamide derivatives of formula I is obtained by reacting an active ester compound of formula II and a piperidine amine compound of formula III. The active ester compound of formula II is obtained by reacting a compound of formula VI and a compound of formula IV and the piperidine amine compound of formula III is obtained by using a ketone compound of formula VII. The compound of formula VI is obtained by reacting a carboxylic acid compound of formula II` and an ethylchloroformate or an isobytylchloroformate of formula V.
Abstract translation: 目的：提供一种制备N-（4-哌啶）苯甲酰胺的方法，其中可以高产率获得高纯度的化合物，并且副反应产物容易与目标产物分离。 构成：式I的苯甲酰胺衍生物通过使式II的活性酯化合物与式III的哌啶胺化合物反应获得。 式Ⅱ的活性酯化合物是通过使式Ⅵ化合物与式Ⅳ化合物反应得到的，通过使用式Ⅶ的酮化合物得到式Ⅲ的哌啶胺化合物。 式VI化合物通过使式II'的羧酸化合物与氯甲酸乙酯或式V的氯代甲酸异丁酯反应而得到。
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