CN1082029A - 联苯甲基取代的吡啶酮 - Google Patents
联苯甲基取代的吡啶酮 Download PDFInfo
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- CN1082029A CN1082029A CN93105751A CN93105751A CN1082029A CN 1082029 A CN1082029 A CN 1082029A CN 93105751 A CN93105751 A CN 93105751A CN 93105751 A CN93105751 A CN 93105751A CN 1082029 A CN1082029 A CN 1082029A
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- C07D421/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings
- C07D421/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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Abstract
用吡啶酮与适宜的联苯甲基化合物反应制备联
苯甲基取代的吡啶酮。
联苯甲基取代的吡啶酮能作为活性化合物用于
药剂中,尤其是用于治疗高动脉压和动脉粥样硬化。
Description
本发明涉及联苯甲基取代的吡啶酮,它们的制备方法以及作为药物,具体来说是降压和抗动脉粥样硬化药物的用途。
人们知道,肾素这种蛋白水解酶在体内能从血管紧张素原清除十肽-血管紧张素Ⅰ,血管紧张素Ⅰ在肺、肾或其它组织又降解为高血压病人的八肽-血管紧张素Ⅱ。血管紧张素Ⅱ的各种效应,例如血管收缩、肾钠潴留、肾上腺释放醛酮以及使交感神经系统紧张的协同作用使血压增高。
另外,血管紧张素Ⅱ具有促进细胞生长和繁殖的特性,所述细胞有:例如心肌细胞和平滑肌细胞,在各种疾病状态下(例如高血压、动脉粥样硬化和心机能不全)这些细胞以递增的方式生长和繁殖。
除抑制肾素活性外,干预肾素-血管紧张素系统(RAS)的可能途径是抑制血管紧张素-转化酶(ACE)的活性以及阻断备管紧张素Ⅱ受体。
本发明涉及通式(Ⅰ)的联苯甲基取代的吡啶酮及其盐:
式中:
R1和R2相同或不同,代表氢,氰基,卤素或代表各自具有不超过8个碳原子并可为下述基团取代的直链或支链烷基、链烯基或炔基:具3-6个碳原子的环烷基、羟基或具不超过6个碳原子的直链或支链烷氧基或苯基;或代表具3-6碳原子的环烷基;或代表各自具不超过8个碳原子的直链或支链酰基或烷氧基羰基,苄氧基羰基或羧基;或代表可为下述基团中相同或不同和取代基取代不超过3次的苯基:包括卤素、硝基、氰基、羟基、羟甲基、三氟甲基和三氟甲氧基,或代表可被各自具不超过6个碳原子的直链或支链烷基或烷氧基取代不超过3次的苯基,或代表-CO-NR8R9、B-R10或-NR11R12基团,
式中:
R8和R9相同或不同,表示氢、苯基、具不超过6个碳原子的直链或支链烷基或苄基,
B表示氧或硫原子,
R10表示具不超过8个碳原子的直链或支链烷基,
R11和R12相同或不同,其定义同上述R8和R9,或者
R11或R12表示-SO2R13基团,
式中;
R13表示具不超过6个碳原子的直链或支链烷基、可为甲基取代的苄基或苯基;
R3和R4,包括该双键形成一个苯环或吡啶环,该环可为下述基团中相同或不同的取代基取代不超过3次;包括羟基、甲酰基、羧基、卤素各自具不超过8个碳原子的直链或支链酰基或烷氧基羰基和具不超过6个碳原子的直链或支链全氟烃基,或该环可为具不超过8个碳原子的直链或支链烷基取代不超过3次,该烷基又可被羟基或具不超过6个碳原子的直链或支链烷氧基取代,或该环可被式-CONR8R9基团取代,
式中;
R8和R9定义同上;
R5和R6相同或不同,代表氢,卤素或具不超过8个碳原子的直链或支链烷基,或代表具不超过6个碳原子的直链或支链全氟烃基;
式中:
R14表示氢、具不超过6个碳原子的直链或支链烷基或三苯甲基,和
R15表示羟基、具不超过8个碳原子的直链或支链烷氧基、苯氧基或式-NR16R17基团,
式中:
R16和R17相同或不同,表示氢或具不超过6个碳原子的直链或支链烷基或苯基。
按照本发明的联苯甲基取代的吡啶酮也可以其盐的形式存在。一般说来,本文所述的是有机或无机碱或酸的盐。
就本发明而言,优选生理上可接受的盐。联苯甲基取代的吡啶酮的生理上可接受的盐可以是本发明化合物的无机酸盐、羧酸盐或磺酸盐。
特别优选的盐是,例如下述的酸的盐:盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、洒石酸、柠檬酸、富马酸、马来酸或苯甲酸。
生理上可接受的盐也可以是具游离羧基的本发明化合物的金属盐或铵盐。特别优选的盐是,例如钠盐、钾盐、镁盐或钙盐,以及由诸如下述氨或有机胺衍生的铵盐:例如乙胺、二乙胺或三乙胺、二乙醇胺或三乙醇胺、二环己胺、二甲氨基甲醇、精氨酸、赖氨酸或乙二胺。
优选的通式(Ⅰ)化合物为下述通式(Ⅰ)化合物及其盐,其式中:
R1和R2相同或不同,代表氢,氰基,氯或代表各自具不超过6个碳原子并可为下述基团取代的直链或支链烷基、链烯基或炔基:环丙基、环戊基、环己基或羟基,或具不超过4个碳原子的直链或支链烷氧基或苯基,或代表环丙基,环戊基或环己基,代表各自具不超过6个碳原子的直链或支链酰基或烷氧基羰基,苄氧基羰基或羧基,或代表可为下述基团中相同或不同的取代基取代不超过2次的苯基:氟、氯、溴、三氟甲基、三氟甲氧基和羟甲基,或可为各自具不超过4个碳原子的直链或支链烷基或烷氧基取代不超过2次的苯基,或代表式-CO-NR8R9、B-R10或-NR11R12基团,
式中:
R8和R9相同或不同,表示氢、苯基、具不超过4个碳原子的直链或支链烷基,或苄基,
B表示氧或硫原子,
R10表示具不超过6个碳原子的直链或支链烷基,
R11和R12相同或不同,其定义同上述R8和R9,或者
R11或R12表示-SO2R13基团,
式中:
R13表示具不超过4个碳原子的直链或支链烷基、苯基或甲苯基;
R3和R4一起包括该双键形成一个苯环或吡啶环,该环所为下述基团相同或不同的取代基取代不超过2次;包括羟基、甲酰基、羧基、氟、氯、溴、各自具不超过6个碳原子的直链或支链酰基或烷氧基羰基和具不超过4个碳原子的直链或支链全氟烃基,或该环可为具不超过6个碳原子的直链或支链烷基取代不超过2次,该烷基又可被羟基或具不超过4个碳原子的直链或支链烷氧基取代,或该环可被式-CONR8R9基团取代,
式中:
R8和R9定义同上;
R5和R6相同或不同,代表氢,氟、氯、溴或具不超过6个碳原子的直链或支链烷基,或代表具不超过4个碳原子的直链或支链全氟烃基;
式中:
R14表示氢、具不超过4个碳原子的直链或支链烷基或三苯甲基,和
R15表示羟基、具不超过6个碳原子的直链或支链烷氧基、苯氧基或式-NR16R17基团,
式中:
R16和R17相同或不同,表示氢或具不超过4个碳原子的直链或支链烷基。
特别优选的通式(Ⅰ)化合物是下述通式(Ⅰ)化合物及其盐,其式中:
R1和R2相同或不同,代表氢、氰基、氯或代表各自具不超过4个碳原子并可为环丙基取代的直链或支链烷基,或代表环丙基,或代表各自具不超过4个碳原子的直链或支链酰基或烷氧基羰基,苄氧基羰基或羧基,或代表可为下述基团中相同或不同的取代基取代不超过2次的苯基:氟、氯、溴、三氟甲基、三氟甲氧基和羟甲基,或可为各自具不超过4个碳原子的直链或支链烷基或烷氧基取代不超过2次的苯基,或代表式-CO-NR8R9、B-R10或-NR11R12基团,
式中:
R8和R9相同或不同,表示氢、苯基、乙基或苄基,
B表示氧或硫原子,
R10表示具不超过4个碳原子的直链或支链烷基,
R11和R12相同或不同,其定义同上述R8和R9或者
R11或R12表示-SO2R13基团,
式中;
R13表示甲基、苯基或甲苯基;
R3和R4一起包括该双键形成一个稠合苯环或吡啶环,该环可为下述基团相同或不同的取代基取代不超过2次:包括羟基、羧基、氟、氯、各自具不超过4个碳原子的直链或支链酰基或烷氧基羰基和具不超过3个碳原子的直链或支链全氟烃基,或该环可为具不超过4个碳原子的直链或支链烷基取代不超过2次,该烷基又可被羟基或具不超过3个碳原子的直链或支链烷氧基取代,或该环可被式-CONR8R9基团取代,
式中:
R8和R9定义同上;
R5和R6相同或不同,代表氢,氟、氯或具不超过4个碳原子的直链或支链烷基,或代表具不超过3个碳原子的直链或支链全氟烃基;
式中:
R14表示氢、甲基、乙基或三苯甲基,和
R15表示羟基、具不超过4个碳原子的直链或支链烷氧基、苯氧基或式-NR16R17基团,
式中:
R16和R17相同或不同,,表示氢或具不超过3个碳原子的直链或支链烷基。
另外,提供按照本发明通式(Ⅰ)化合物的制备方法,其特征在于:
[A]通式(Ⅱ)吡啶酮与通式Ⅲ化合物反应,通式(Ⅱ)结构如下:
式中R1、R2、R3和R4的定义同前,
通式(Ⅲ)结构如下:
式中R5和R6定义同前,D代表囟素,最好是溴,和
[B]当R3和R4与该双键一起形成一个可被取代的吡啶环(R3′、R4′)时,由通式(Ⅳ)代合物与通式(Ⅲa)化合物反应,通式(Ⅳ)化合物如下:
式中R1、R2、R3′和R4′的定义同上,
通式(Ⅲa)化合物如下:
式中R5、R6和R7′的定义同上,和
D′代表NH2基团;
上述[A]和[B]两反应均在惰性溶剂中进行,如果合适,在碱存在下进行,三苯甲基基团随后可用酸除去;当R7不是氢时,可按常规方法烷基化或水解;取代基R1、R2、R5、R6和R7可按常规方法衍生。
按本发明的方法可用以下反应方案举例说明:
适宜于该方法各步反应的溶剂为在该反应条件下不发生变化的常规有机溶剂,最好包括醚类,例如乙醚、二噁烷、四氢呋喃、乙二醇二甲醚,或烃类,例如苯、甲苯、二甲苯、己烷、环己烷或矿物油馏分,或卤代烃类,例如二氯甲烷、三氯甲烷、四氯甲烷、二氯乙烷、三氯乙烷或氯苯,或乙酸乙酯,三乙胺,吡啶,二甲亚砜,二甲基甲酰胺,六甲基磷酰胺,乙腈,丙酮,硝基甲烷,或二甲氧基乙烷;也可以使用上述溶剂的混合物。优选的溶剂有;四氢呋喃、乙醚、己烷、乙酸乙酯、二噁烷、乙腈和二甲氧基乙烷。
可用的碱一般是无机碱或有机碱,最好包括诸如碱金属氢氧化物,例如氢氧化钠或氢氧化钾;碱土金属氢氧化物,例如氢氧化钡;碱金属碳酸盐,例如碳酸钠,碳酸钾或碳酸铯;碱土金属碳酸盐,例如碳酸钙;或碱金属或碱土金属醇盐或氨化物,例如甲醇钠或甲醇钾,乙醇钠或乙醇钾,叔丁醇钾或氨化钾;或有机胺类(三烷基(C1-C6)胺),例如三乙按;或杂环类,例如1,4-二氮杂二环[2.2.2]-辛烷(DABCO),1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU),吡啶,二氨基吡啶,甲基哌啶或吗啉。也可以使用碱金属,例如钠或其氢化物如氢化钠作为该碱。优选的碱有;三乙胺,氨化钾,氢氧化钠,碳酸钠和碳酸铯。
一般来说,碱的用量为每摩尔式(Ⅲ)化合物0.05-10mol,最好为1-2mol。
按本发明方法制备一般在-30-+100℃温度范围内进行,-10℃-+60℃为最好。
按本发明的各步反应一般在常压下进行。但也可以在减压或加压条件下(例如在0.5-5巴范围内)进行。
用以除去三苯甲基基团的适宜的酸一般为有机酸,可以是卤代的C1-C6羧酸或质子酸。盐酸、冰乙酸或三氟乙酸是优选。
该除去反应一般在0℃-+120℃温度范围内进行,+20℃-+100℃为最好。反应在常压下进行。
水解用的适宜的碱为常规无机碱,最好包括诸如碱金属氢氧化物或碱土金属氢氧化物,例如氢氧化钠、氢氧化钾或氢氧化钡;或碱金属碳酸盐,例如碳酸钠或碳酸钾或碳酸氢钠;或碱金属醇盐,例如甲醇钠,乙醇钠,甲醇钾,乙醇钾或叔丁醇钾。氢氧化钠或氢氧化钾特别优选。
适于水解用的溶剂为水或通常用于水解的有机溶剂,最好包括醇类,例如甲醇,乙醇,丙醇,异丙醇或丁醇;或醚类,例如四氢呋喃或二噁烷;或二甲基甲酰胺;或二甲亚砜。醇类象甲醇、乙醇、丙醇或异丙醇特别优先选用。也可以使用上述溶剂的混合物。
水解亦可以使用诸如下述的酸类来完成;例如三氟乙酸、乙酸、盐酸、氢溴酸、甲磺酸,硫酸或高氯酸,最好使用三氟乙酸。
水解一般在0℃-+100℃温度范围内进行,最好为+20℃-+80℃。
水解一般在常压下进行,但亦可以在减压或加压条件下(例如0.5-5巴)进行。
进行水解时,碱的一般用量为每摩尔酯1-3mol,优选1-1.5mol,特别优先选用等当量的反应剂。
当进行反应时,第一步反应生成本发明化合物的羧酸酯,该酯为中间体,可分离出来。用常规无机酸处理该羧酸酯得到本发明的酸。所用无机酸最好包括例如盐酸、氢溴酸、硫酸或磷酸。业已证明,在第二步反应中不分离出酯,酸化水解产生的碱性反应混合物,有利于该羧酸的制备。然后可按常规方法分离该羧酸。对于碱性的杂环来说,用上述酸处理该羧酸酯溶液也可得到该杂环的无机酸盐。
烷基化一般使用诸如下述烷基化试剂来完成:(C1-C6)-烷基卤化物、磺酸酯或取代的或未取代的硫酸(C1-C6)-二烷基酯或硫酸(C1-C6)-二芳基酯。优选碘甲烷或硫酸二甲酯。
烷基化一般在上述的一种溶剂中进行,最好是在二甲基甲酰胺中,0℃-+70℃温度范围内,最好为0℃-+30℃,常压下进行。
通式(Ⅱ)的吡啶酮是新化合物,可用下述方法来制备:
[A]R3和R4形成一个苯环时可通过转化通式(Ⅴ)化合物来制备,例如,将通式(Ⅴ)化合物先在保护性气氛和一种上述溶剂中并且在一种上述碱,最好是氨化钾的氨液存在下与通式(Ⅵ)化合物反应,生成通式(Ⅶ)化合物,然后在醇中用酸环合,最好是在乙醇中用硫酸环合;当R1不是烷基、链烯基或炔基基团时,可按常规方法通过衍生取代基R1来制备;通式(Ⅴ)化合物结构如下:
式中:
R18和R19形成一个可被取代的苯环,
通式(Ⅵ)化合物结构如下:
式中:
R1′代表烷基、链烯基或炔基基团,和
E代表C1-C4-烷基,最好是甲基,
通式(Ⅶ)化合物结构如下:
式中:
R1′,R18和R19的定义同上。
[B]R3和R4一起形成一个吡啶环时,可通过转化式(Ⅷ)的吡啶来制备,例如将通式(Ⅷ)的吡啶化合物置高压釜中,在保护性气氛及催化剂/辅助剂存在下,最好是在双-(三苯膦)氯化钯(Ⅱ)/碘化亚铜(Ⅰ)体系存在下,先与通式(Ⅸ)化合物反应,生成通式(Ⅹ)化合物,然后即可以按[A]中所述方法直接环合,也可以经通式(Ⅳa)阶段先环合,然后再与氨反应;当R2不是氢时,可按常规方法通过衍生来制备,也可以通过改变R3/R4中给出的苯基取代基和吡啶基取代基来制备。
通式(Ⅷ)化合物结构如下:
式中;
R3′和R4′形成一个可被取代的吡啶环,
通式(Ⅸ)化合物结构如下:
式中R1′的定义同上,
通式(Ⅹ)化合物结构如下:
式中R1,R3′和R4′的定义同上,
通式(Ⅳa)化合物结构如下:
式中R1,R3′和R4′的定义同上。
所述反应中催化剂/辅助剂的用量一般为每摩尔通式(Ⅴ)化合物和每摩尔通式(Ⅶ)化合物使用0.001-0.5mol,0.01-0.3mol为最好。
碱的用量一般为每摩尔通式(Ⅴ)化合物用1-5mol,1-3mol为最好。
各步反应的反应温度在0℃-180℃之间,20℃-150℃为最好。
反应既可在常压下也可减压或加压条件下,例如0.5-5巴,而且可以在保护性气氛中进行,这依各步反应而定。
通式(Ⅴ)、(Ⅵ)和(Ⅶ)化合物绝大部分是已知的,或可以按常规方法(例如,参见J.Org.Chem.1966,31卷,3807页)制备。
通式(Ⅷ)化合物有些是新的,可以按例如下述方法制备:第一步将相应的3-溴-取代吡啶与过氧化氢在乙酸中进行转化反应,得到对应的N-氧化吡啶;第二步再按常规方法引入氰基基团,例如用三甲基甲硅烷基氰在乙腈中及三乙胺存在下,于20℃-120℃,最好20℃-100℃引入氰基基团(参见J.Org.Chem.1958,23卷,1616页;Chem.Pharm.Bull.1985,33卷,565页)。
通式(Ⅸ)化合物本身是已知的,或可按常规方法制备。
通式(Ⅳ)和(Ⅵa)化合物有些是已知的,或是新的,可以按例如上述或以下已发表的方法制备(例如,参见Chem.Pharm.Bull.34卷(第7期),2760-5页;33卷(第2期),626-33页;Heterocycles 32卷(第5期),1310-16页;Indian J.Chem.Sect.B,20B卷(第5期),376-9;页Chem.Pharm.Bull.1988,36卷,1890页)。
通式(Ⅲ)化合物绝大部分是已知的。
通式(Ⅲa)化合物有些是已知的,或者是新的,可以按例如下述方法制备;将通式(Ⅲ)化合物先在一种上述的溶剂,最好是二甲基甲酰胺中于70℃与叠氮化锂反应,然后再于宝温与三氯化磷/四氢呋喃/水反应。
本发明通式(Ⅰ)化合物出人意料地显示出有用的药理作用谱。
本发明化合物具有特异的拮抗AⅡ的作用,这是因为它们能够抑制血管紧张素Ⅱ与AⅡ受体的结合。它们抑制血管紧张素Ⅱ的血管收缩和刺激醛固酮分泌的效应。此外,它们还抑制平滑肌细胞的增生。
固此它们可以用作药物来治疗高动脉压和动脉粥样硬化。此外,它们还可以用来治疗冠状心脏疾病,心肌能不全,脑功能失调,局部缺血性大脑疾病,外周循环障碍,肾和肾上腺功能失调,具血管因素的支气管痉挛病和呼吸道疾病,钠潴留和水肿。
对促效剂所致收缩的抑制作用的研究
将兔(雌雄均可)在脑后一击致昏并放血,或在某些情况下用戊巴比妥(约60-80mg/kg静注)麻醉,开胸杀死。分出胸主动脉,去除粘连的结缔组织,分成1.5mm宽的环节,在最初负重约3.5g时,将它们转移至含克-汉二氏(Krebs-Henseleit)营养液的器官浴中,该浴的温度控制在37℃并充有95%O2/5%CO2气体,并含有下列成分:119mmol/升NaCl;2.5mmol/升CaCl2X2H2O;1.2mmol/升KH2PO4;10mmol/升葡萄糖;4.8mmol/升KCl;1.4mmol/升MgSO4X7H2O和25mmol/升NaHCO3。
用Statham UC2池通过桥放大器(bridge amplifiers)(ifd M 1heim或DSM Aalen)来检测等轴收缩,并用A/D变换器(系统570,Keithley Munich)来数字化并评价收缩。促效剂剂量响应曲线(DRC)按时间(小时)标绘。对于每个DRC,都是向该器官浴中加入3或4种浓度,时间间隔为4分钟。标绘DRC的测定结束和其后的冲洗循环(在每种情况下用上述营养液约5秒/分钟冲洗16次)之后,随后是休息或保温期28分钟,在这期间,一般规律是再次达到开始的值。
在正常情况下,第3个DRC的高度在以后的标作中被用作参比变数来评价所要研究的试验物,将该物质按下列各DRC加到该器官浴中,在每一个的保温期开始的时候加入,并采用递增剂量。在此情况下,每个主动脉环被用同一种促效剂兴奋一整天。
促效剂及其标准浓度(每单个剂量应用体积=100μl):
KCl 22.7;32.7;42.7;52.7 mmol/l
1-去甲肾上腺素 3×10-9;3×10-8;
3×10-7;3×10-6g/ml
5-羟色胺 10-8;10-7;10-6;10-5g/ml
B-HT920 10-7;10-6;10-5; g/ml
美沙明 10-7;10-6;10-5; g/ml
血管紧张素II 3×10-9;10-8;
3×10-8;10-7g/ml
在计算IC50(所研究物质产生50%抑制作用的浓长度)时,在每种情况下,效应都是以第三个浓度为基础的,该浓度=次最大促效剂浓度。
本发明化合物以依赖剂量的方式抑制由血管紧张素Ⅱ所致离体兔主动脉的收缩,对由钾去极化作用或其它促效剂所致收缩无抑制作用或仅在高浓度时产生弱的抑制作用。
表A:
体外对离体兔主动脉环血管收缩的抑制作用
IC50(g/ml)抑制诱导收缩:
实例号: AⅡ
2 2.3×10-7
4 8.4×10-7
6 >10-6
对输注血管紧张素Ⅱ的大鼠的血压测定
雄性Wistar大鼠(Moellegaard,哥本哈根,丹麦),体重300-350g,用硫喷妥钠麻醉(100mg/kg,腹腔给药)。施行气管造口术后,在股动脉内插入一个插管用于血压测量,在股静脉内插入两个插管分别用于输注血管紧张素Ⅱ和给药。将神经节阻断剂安血定(5mg/kg静注)给药后,开始输注血管紧张素Ⅱ(0.3μg/kg/分)。当血压值达到一个稳定的平稳状态时,开始将试验物质给药,既可以静脉注射,也可以口服,使用试验物质在0.5%纤基乙酸钠的悬浮液或溶液。在该物质作用下的血压变化的平均值±SEM列在表中。
在清醒的患高血压的大鼠身上测定抗高血压活性
本发明化合物的口服抗高血压活性是在手术所致一侧肾动脉狭窄的清醒的大鼠身上试验的。为此,用一个内宽0.18mm的银夹将右肾动脉阻塞。在此后的头六星期内,这种形式的高血压者中血浆肾素活性增高。用“尾胶管管头”(“tail cuff”)给药后,以不出血(blood-free)的方式在规定的时间间隔内测量这些大鼠的动脉血压。将待试验物质混悬在纤基乙酸钠中制成混悬剂,用胃管按各种不同的剂量进行胃内(“口服”)给药。本发明化合物在与临床上相应的剂量条件下能降低高血压大鼠的动脉血压。
此外,本发明化合物以依赖浓度的方式抑制放射性血管紧张素Ⅱ的特异性结合。
本发明化合物与肾上腺皮质(牛的)膜部分的血管紧张素Ⅱ受体的相互作用
将刚分离出且仔细去除了腺髓质的牛肾上腺皮质(AGC)于蔗糖溶液(0.32M)中用Ultra-Turrax(Janke&Kunkel,Stanfen i.B)粉碎,得到粗的膜均浆,经两次离心部分纯化得到膜部分。对于牛AGC部分纯化的膜部分用放射性血管紧张素Ⅱ进行受体结合研究,测定体积为0.25ml,其中特定地含有该部分纯化的膜(50-80μg),3H-血管紧张素Ⅱ(3-5nM),试验缓冲溶液(50mM Tris,pH7.2,5mM MgCl2),以及待测试物质。室温培养60分钟后,样品的未结合的放射性物用湿的玻璃纤维滤纸(Whatman GF/C)分出,结合的放射性物经用冰冷的缓冲液(50mM Tris/HCl,pH7.4,5%PEG 6000)冲洗蛋白质后在一种闪烁合剂(scintillation cocktail)中用分光光度法测定。用计算机程序分析原始数据得出Ki值或IC50值(Ki:对于所作放射性物的IC50校正值;IC50值:所测试物质对放射性配体的特异性结合的抑制率为50%时的浓度)。
实施例2 Ki=42nM
实施例4 Ki=750nM
实施例6 Ki=2000nM
本发明化合物对平滑肌细胞增生的抑制作用的研究
本发明化合物的抗增生作用用平滑肌细胞来测定。用血管中层移植技术(the media explant technigue)[R.Ross,J.Cell.Biol.50卷,172页,1971]从大鼠或猪的主动脉获得平滑肌细胞。将该细胞移至合适的培养皿,一般为24孔平皿中于37℃在培养基中培养2-3天,该培养基中加有血清,2mmol L-谷氨酰胺和15mmol HEPES,在5%CO2pH7.4。然后通过撤出血清,用2-3天使这些细胞同步。然后用AⅡ,血清或其它要素刺激细胞生长,同时加入试验化合物。16小时后加入1μCi3H-胸苷,再过4小时后测定该物质与该细胞能沉淀TCA的DNA的结合。
实施例 在10-6M时的抑制百分数
6 70%
该种新的活性化合物可按已知方法用惰性、无毒、药学上适宜的赋形剂或溶剂加工成常规制剂,例如片剂,包衣片剂,丸剂,粒剂,气雾剂,糖浆,乳剂,混悬剂和溶液。这样,当用于治疗时,每种制剂中活性化合物的浓度应约为总混合物重量的0.5-90%,即活性化合物的量应足以达到所需的剂量范围。
制剂可通过例如将活性化合物搀进溶剂和/或赋形剂中来制备,如果合适,可以使用乳化剂和/或分散剂,例如在用水作稀释剂的情况下,有机溶剂可以作为辅助溶剂。
给药可以按常规方式,最好是口服或肠道外给药,尤其是舌下给药或静注。
往肠道外给药时,可利用适宜的液体赋形物质使用该活性化合物的溶液。
一般来说,下述给药方式证明是有利的:静脉内给药,给药量约0.001-1mg/kg体重,最好约为0.01-0.5mg/kg体重以取得有效的结果;口服给药,剂量约为0.01-20mg/kg体重,最好约为0.1-10mg/kg体重。
尽管如此,有时还是需要偏离上述剂量的,这取决于体重或应用途径的类型,对药物的个体反应,制剂的形式和给药的时间或间隔。因此,在某些情况下使用剂量低于上述最低剂量是合适的,而在另些情况下则必须使用高于上述最高限的剂量。在给药量相对大的情况下,可取的办法是:将一天的药量分成若干单剂。
原料
实施例Ⅰ
2-(2-氧代-己基)-苄腈
通氩气条件下,将钾(3.8g,0.10mol)溶于氨(150ml)中,用一刮勺尖量的硝酸铁(Ⅲ)处理,混合物回流搅拌15分钟,滴加2-甲苯基氰(12ml;0.10mol)的乙醚(25ml)溶液,10分钟后再加入戊酸甲酯(6.6ml;0.050mol)的乙醚(25ml)溶液。1小时后加入氯化铵(6.1g,0.12mol)和乙醚(25ml),将氨蒸发过夜。混悬液经短时加热,用6N盐酸调成酸性,用二氯甲烷提取,有机相用无水硫酸钠干燥,浓缩及硅胶层析(己烷∶乙酸乙酯=5∶1),得3.1g黄色油(收率为31%)。
Rf=0.52(己烷∶乙酸乙酯=3∶1)。
实施例Ⅱ
3-丁基-异喹啉-1(2H)-酮
在冰冷却下,将浓硫酸(60ml)加到实施例Ⅰ产物(3.1g;15mmol)的乙醇/水(19∶1;600ml)溶液中,加热回流7小时后,将反应液倒在冰上并浓缩,吸滤,将从己烷中沉淀析出的产物重结晶,得1.8g白色固体(收率为57%)。
m.p.137℃
Rf=0.28(己烷∶乙酸乙酯=3∶1)。
实施例Ⅲ
2-(2-氧代丁基)-苄腈
用与实施例Ⅰ类似的方法,通过用丙酸甲酯(4.8ml;50mmol)酰化2-甲苯基氰(1ml;0.10mol),得3.1g黄色油(收率为36%)。
Rf=0.46(己烷∶乙酸乙酯=3∶1)。
实施例Ⅳ
3-乙基-异喹啉-1(2H)-酮
用与实施例Ⅱ类似的方法,以实施例Ⅲ产物(3.1g;18mmol)为原料,得1.6g白色固体(收率为52%)。
m.p.136℃
Rf=0.13(己烷∶乙酸乙酯=3∶1)。
实施例Ⅴ
2-(苯甲酰基甲基)-苄腈
用与实施例Ⅰ类似的方法,通过用苯甲酸甲酯(6.3ml;50mmol)酰化2-甲苯基氰(12ml;0.10mol),得3.1g白色固体(收率为50%)。
m.p.109℃
Rf=0.42(己烷∶乙酸乙酯=3∶1)。
实施例Ⅵ
3-苯基-异喹啉-1(2H)-酮
用与实施例Ⅱ类似的方法,以实施例Ⅴ产物(4.3g;19mmol)为原料,得2.0g固体(收率为46%)。
m.p.105℃
Rf=0.15(己烷∶乙酸乙酯=3∶1)。
实施例Ⅶ
3-溴吡啶N-氧化物
用过氧化氢:水(30∶70;50ml)处理3-溴吡啶(3ml;0.32mol)的冰乙酸(250ml)溶液,于100℃搅拌3小时和19小时后,再加过氧化氢;水(30∶70;每次25ml),混合物于100℃再加热4小时。将反应液浓缩至原体积的1/3,再用水补充至原体积,浓缩至干,将残留物溶于二氯甲烷,用碳酸钠溶液洗涤,水相用氯化钠饱和,用二氯甲烷提取,干燥,浓缩合并的有机相,得43g油(收率为77%),
Rf=0.37(二氯甲烷∶甲醇=20∶1)。
实施例Ⅷ
3-溴-2-氰基吡啶
将实施例Ⅶ的产物(22g;0.12mol),三甲基甲硅烷基氰(45ml;0.36mmol)和三乙胺(22ml;0.24mol)的乙腈(120ml)溶液加热回流4小时,浓缩并倒入3N碳酸钠溶液中,用二氯甲烷提取,干燥,浓缩有机相,用己烷/乙酸乙酯重结晶,得17g固体(收率:79%)。
m.p.92℃
Rf=0.31(己烷∶乙酸乙酯=3∶1)。
实施例Ⅸ
2-氰基-3-己-1-炔基吡啶
将实施例Ⅷ化合物(4.8g,26mmol)、1-己炔(3.6ml;31mmol),双-(三苯膦)-氯化钯(Ⅱ)(0.42g;0.60mmol)和碘化亚铜(Ⅰ)(0.21g;1.1mmol)置高压釜中用氮气吹扫,于120℃加热5小时。将反应混合物在水和乙醚中分配。有机相经干燥、浓缩及硅胶层析(己烷∶乙酸乙酯=4∶1)后,得0.76g油(收率:16%)。
Rf=0.60(己烷∶乙酸乙酯=3∶1)。
实施例Ⅹ
6-丁基-吡喃并[3,4-b]吡啶-8-酮
将实施例Ⅸ化合物(100mg;0.490mmol)在丙膦酸酐(2g)中于130℃加热3小时。将反应混合物加到冰水中并用碳酸钾调至碱性,水层用氯仿提取,有机相用无水硫酸钠干燥,浓缩及硅胶层析(二氯甲烷∶甲醇=50∶1-40∶1),得76mg树脂状物(收率为76%)。
Rf=0.58(二氯甲烷∶甲醇=20∶1)。
实施例Ⅺ
[2′-(N-三苯甲基-四唑-5-基)-联苯-4-基]-甲基叠氮
[2′-(N-三苯甲基-四唑-5-基)-联苯-4-基]甲基溴(5g;9mmol)的二甲基甲酰胺(40ml)溶液用叠氮化锂(0.88g;18mmol)处理,在预热的油浴中于70℃搅拌15分钟,真空除去溶剂,将残留物在水和乙酸乙酯中分配,有机相用水和氯化钠饱和溶液洗涤并用无水硫酸钠干燥,浓缩,得4.5g淡黄色固体(收率为96%)。
Rf=0.86(己烷∶乙酸乙酯=5∶1,TLC展开二次)。
实施例Ⅻ
[2′-(N-三苯甲基-四唑-5-基)-联苯-4-基]-甲胺
实施例Ⅺ化合物(2.0g;3.8mmol)的四氢呋喃(100ml)溶液用三苯膦(1.2g;4.6mmol)和水(0.10ml;5.8mmol)处理并于室温搅拌4小时,浓缩,残留物经硅胶层析(二氯甲烷∶甲醇=20∶1),得0.78g淡黄色树脂状物(收率为41%)。
Rf=0.16(二氯甲烷∶甲醇=20∶1)。
制备实施例
实施例1
3-丁基-2-{[2′-(N-三苯甲基-四唑-5-基)-联苯-4-基]甲基}-异喹啉-(2H)-酮
实施例Ⅱ产物(1.0g;5.0mmol)的二甲亚砜(20ml)溶液用[2′-(N-三苯甲基-四唑-5-基)-联苯-4-基]甲基溴(3.1g;5.5mmol)和碳酸铯(1.4g;2.5mmol)处理并于80℃搅拌3小时,再加入上述溴化物(1.4g;2.5mmol)和碳酸铯(0.82g;2.5mmol)并于80℃搅拌4小时,将反应液在乙酸乙酯和水中分配,有机相用水洗涤,干燥,浓缩,经硅胶层析(己烷∶乙酸乙酯=4∶1)后,得0.89g产物(收率26%)。
Rf=0.31(己烷∶乙酸乙酯=3∶1)。
实施例2
3-丁基-2-{[2′-(四唑-5-基)-联苯-4-基]甲基}-异喹啉-1(2H)-酮
将0.18g(0.27mmol)得自实施例1的化合物用4N HCl/二噁烷溶解,搅拌2小时。该反应液用浓氢氧化钠溶液碱化后,浓缩,用乙醚提取,将水相酸化至pH2,用氯化钠饱和并用乙酸乙酯提取,有机相经干燥,浓缩,得70mg粘稠油(收率:59%)。
Rf=0.20(二氯甲烷∶甲醇=20∶1)。
实施例3
3-乙基-2-{[2′-三苯甲基-四唑-5-基)-联苯-4-基]甲基}-异喹啉-1(2H)-酮
用与实施例1类似的方法,以实施例Ⅳ产物(1.0g;5.8mmol)为原料,得1.18g固体(收率为31%)。
Rf=0.27(己烷∶乙酸乙酯=3∶1)。
实施例4
3-乙基-2-{[2′-(四唑-5-基)-联苯-4-基]甲基}-异喹啉-1(2H)-酮
用与实施例2类似的方法,以实施例3产物(0.26g,0.38mmol)为原料,得95mg树脂状物(收率:61%)。
Rf=0.19(二氯甲烷∶甲醇=20∶1)。
实施例5
3-苯基-2-{[2′-三苯甲基-四唑-5-基)-联苯-4-基]甲基}-异喹啉-1(2H)-酮
用与实施例1类似的方法,以实施例Ⅵ产物(1.0g;4.5mmol)为原料,得0.56g固体(收率:14%)。
Rf=0.25(己烷∶乙酸乙酯=3∶1)。
实施例6
3-苯基2-{[2′-(四唑-5-基)-联苯-4-基]甲基}-异喹啉-1(2H)-酮
用与实施例2类似的方法,以实施例5产物(0.53g,0.76mmol)为原料,得0.16g树脂状物(收率:45%)。
Rf=0.35(二氯甲烷∶甲醇=20∶1)。
实施例7
3-氯-5,8-二甲基-2-{[2′-(N-三苯甲基-四唑-5-基)-联苯-4-基]甲基}-异喹啉-1(2H)-酮
用与实施例1类似的方法,以3-氯-5,8-二甲基-异喹啉-1(2H)-酮(1.9g;9.0mmol)为原料,得0.32g固体(收率为24%)。
Rf=0.60(己烷∶乙酸乙酯=3∶1)。
实施例8
3-氯-5,8-二甲基-2-{[2′-(四唑-5-基)-联苯-4-基]甲基}-异喹啉-1(2H)-酮
用与实施例2类似的方法,以实施例9(0.20g;0.29mmo)为原料,得76mg树脂状物(收率为59%)。
Rf=0.57(二氯甲烷∶甲醇=20∶1)。
实施例9
6-丁基-7-{[2′-(N-三苯甲基-四唑-5-基)-联苯-4-基]甲基}-1,7-二氮杂萘-8[7H]-酮
用实施例Ⅻ化合物(469mg;0.950mmol)处理实施例Ⅹ化合物(161mg;0.792mmol)的THF(5ml)溶液并加热回流2小时,浓缩反应混合物,将残留物在乙酸乙酯和1M硫酸氢钾溶液中分配,有机相用无水硫酸钠干燥,浓缩及硅胶层析(己烷∶乙酸乙酯=3∶1),得101mg白色固体(收率:19%)。
Rf=0.40(己烷∶乙酸乙酯=2∶1)。
实施例10
6-丁基-7-{[2′-四唑-5-基)-联苯-4-基]甲基}-1,7-二氮杂萘-8(7H)-酮
用与实施例2类似的方法,以实施例9化合物(70mg;0.10mmol)为原料,得34mg固体(收率:77%)。
Rf=0.20(二氯甲烷∶甲醇∶乙酸=100∶10∶1)。
Claims (10)
1、通式(Ⅰ)的联苯甲基取代的吡啶酮及其盐,通式(Ⅰ)结构如下:
式中:
R1和R2相同或不同,代表氢,氰基,卤素或代表各自具不超过8个碳原子并可为下述基团取代的直链或支链烷基、链烯基或炔基:具3-6个碳原子的环烷基、羟基或具不超过6个碳原子的直链或支链烷氧基或苯基,或代表具3-6个碳原子的环烷基,或代表各自具不超过8个碳原子的直链或支链酰基或烷氧基羰基、苄氧基羰基或羧基,或代表可为下述基团中相同或不同的取代基取代不超过3次的苯基:包括卤素、硝基、氰基、羟基、羟甲基、三氟甲基和三氟甲氧基或代表可被各自具不超过6个碳原子的直链或支链烷基或烷氧基取代不超过3次的苯基,或代表式-CO-NR8R9、B-R10或-NR11R12基团,
式中:
R8和R9相同或不同,表示氢、苯基,具不超过6个碳原子的直链或支链烷基或苄基,
B表示氧或硫原子,
R10表示具不超过8个碳原子的直链或支链烷基,
R11和R12相同或不同,其定义同上述R8和R9,或R11或R12表示-SO2R13基团,
式中:
R13表示具不超过6个碳原子的直链或支链烷基,可为甲基取代的苄基或苯基;
R3和R4包括该双键形成一个苯环或吡啶环,该环可为下述基团中相同或不同的取代基取代不超过3次:包括羟基、甲酰基、羧基、卤素、各自具不超过8个碳原子的直链或支链酰基或烷氧基羰基和具不超过6个碳原子的直链或支链全氟烃基,或该环可为具不超过8个碳原子的直链或支链烷基取代不超过3次,该烷基又可被羟基或具不超过6个碳原子的直链或支链烷氧基取代,或该环可被式-CONR8R9基团取代,
式中:
R8和R9定义同上;
R5和R6相同或不同,代表氢,卤素或具不超过8个碳原子的直链或支链烷基,或代表具不超过6个碳原子的直链或支链全氟烃基;
式中:
R14表示氢、具不超过6个碳原子的直链或支链烷基或三苯甲基,和
R15表示羟基,具不超过8个碳原子的直链或支链烷氧基、苯氧基或式-NR16R17基团,
式中:
R16和R17相同或不同,表示氢或具不超过6个碳原子的直链或支链烷基或苯基。
2、按照权利要求1的联苯甲基-取代的吡啶酮及其盐,其中
R1和R2相同或不同,代表氢、氰基、氯或代表各自具不超过6个碳原子并可为下述基团取代的直链或支链烷基、链烯基或炔基:环丙基、环戊基、环己基或羟基,或具不超过4个碳原子的直链或支链烷氧基或苯基,或代表环丙基,环戊基或环己基,代表各自具不超过6个碳原子的直链或支链酰基或烷氧基羰基,苄氧基羰基或羧基,或代表可以为下述基团中相同或不同的取代基取代不超过2次的苯基:氟、氯、溴、三氟甲基、三氟甲氧基和羟甲基,或可为各自具不超过4个碳原子的直链或支链烷基或烷氧基取代不超过2次的苯基,或代表式-CO-NR8R9、B-R10或-NR11R12基团,
式中:
R8和R9相同或不同,表示氢、苯基,具不超过4个碳原子的直链或支链烷基或苄基,
B表示氧或硫原子,
R10表示具不超过6个碳原子的直链或支链烷基,
R11和R12相同或不同,其定义同上述R8和R9,或R11或R12表示-SO2R13基团,
式中:
R13表示具不超过4个碳原子的直链或支链烷基、苯基或甲苯基;
R3和R4一起包括该双键形成一个苯环或吡啶环,该环可为下述基团中相同或不同的取代基取代不超过2次:包括羟基、甲酰基、羧基、氟、氯、溴,各自具不超过6个碳原子的直链或支链酰基或烷氧基羰基和具不超过4个碳原子的直链或支链全氟烃基,或该环可为具不超过6个碳原子的直链或支链烷基取代不超过2次,该烷基又可被羟基或具不超过4个碳原子的直链或支链烷氧基取代,或该环可被式-CONR8R9基团取代,
式中:
R8和R9定义同上;
R5和R6相同或不同,代表氢、氟、氯、溴或具不超过6个碳原子的直链或支链烷基,或代表具不超过4个碳原子的直链或支链全氟烃基;
式中:
R14表示氢,具不超过4个碳原子的直链或支链烷基或三苯甲基,和
R15表示羟基,具不超过6个碳原子的直链或支链烷氧基、苯氧基或式-NR16R17基团,
式中:
R16和R17相同或不同,表示氢或具不超过4个碳原子的直链或支链烷基。
3、按照权利要求1的联苯甲基取代的吡啶酮及其盐,其中
R1和R2相同或不同,代表氢、氰基、氯或代表各自具不超过4个碳原子并可为环丙基取代的直链或支链烷基,或代表环丙基,或代表各自具不超过4个碳原子的直链或支链酰基或烷氧基羰基,苄氧基羰基或羧基,或代表可为下述基团中相同或不同的取代基取代不超过2次的苯基:氟、氯、溴、三氟甲基、三氟甲氧基和羟甲基或可为各自具不超过4个碳原子的直链或支链烷基或烷氧取代不超过2次的苯基,或代表式-CO-NR8R9、B-R10或-NR11R12基团,
式中:
R8和R9相同或不同,表示氢、苯基、乙基或苄基,
B表示氧或硫原子,
R10表示具不超过4个碳原子的直链或支链烷基,
R11和R12相同或不同,其定义同上述R8和R9,或R11或R12表示-SO2R13基团,
式中:
R13表示甲基、苯基或甲苯基;
R3和R4一起包括该双键形成一个稠合苯环或吡啶环,该环可为下述基团中相同或不同的取代基取代不超过2次:包括羟基、甲酰基、羧基、氟、氯,各自具不超过4个碳原子的直链或支链酰基或烷氧基羰基和具不超过3个碳原子的直链或支链全氟烃基,或该环可为具不超过4个碳原子的直链或支链烷基取代不超过2次,该烷基又可被羟基或具不超过3个碳原子的直链或支链烷氧基取代,或该环可被式-CONR8R9基团取代,
式中:
R8和R9定义同上;
R5和R6相同或不同,代表氢、氟、氯或具不超过4个碳原子的直链或支链烷基,或代表具不超过3个碳原子的直链或支链全氟烃基;
式中:
R14表示氢、甲基、乙基或三苯甲基,和
R15表示羟基,具不超过4个碳原子的直链或支链烷氧基、苯氧基或式-NR16R17基团,
式中:
R16和R17相同或不同,表示氢或具不超过3个碳原子的直链或支链烷基。
4、按照权利要求1的联苯甲基取代的吡啶酮在治疗方面的用途。
5、按照权利要求1的联苯甲基取代的吡啶酮的制备方法,其特征在于:
[A]通式(Ⅱ)的吡啶酮与通式Ⅲ的化合物反应,通式(Ⅱ)结构如下:
式中R1、R2、R3和R4的定义同前,通式(Ⅲ)结构如下:
式中R5和R6定义同前,D代表卤素,最好是溴,和
R7′代表式
基团,或
[B]当R3和R4与该双键一起形成一个可被取代的吡啶环(R3′、R4′)时,使通式(Ⅳ)化合物与通式(Ⅲa)化合物反应,通式(Ⅳ)化合物如下:
式中R1、R2、R3′和R4′的定义同上,
通式(Ⅲa)化合物如下:
式中R5、R6和R7′的定义同上,和
D′代表NH2基团;
上述[A]和[B]两反应均在惰性溶剂中进行,如果合适,在碱存在下进行,三苯甲基基团随后可用酸除去;当R7不是氢时,可按常规方法衍生。
6、按照权利要求5的方法,其特征在于,该反应在-30℃-+100℃温度范围内进行。
7、含有至少一种按照权利要求1的联苯甲基取代的吡啶酮的药物。
8、按照权利要求7用于治疗高动脉压和动脉粥样硬化的药物。
9、权利要求1的联苯甲基取代的吡啶酮在药物生产中的用途。
10、按照权利要求9的用途,用于生产治疗高动脉压和动脉粥样硬化的药物。
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DEP4215588.6 | 1992-05-12 | ||
DE4215588A DE4215588A1 (de) | 1992-05-12 | 1992-05-12 | Biphenylmethyl-substituierte Pyridone |
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EP (1) | EP0569794A1 (zh) |
JP (1) | JPH0656783A (zh) |
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CN (1) | CN1082029A (zh) |
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CA (1) | CA2095802A1 (zh) |
CZ (1) | CZ72193A3 (zh) |
DE (1) | DE4215588A1 (zh) |
FI (1) | FI932106A (zh) |
HU (1) | HU9301365D0 (zh) |
IL (1) | IL105647A0 (zh) |
MX (1) | MX9302487A (zh) |
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CN111662228A (zh) * | 2019-03-07 | 2020-09-15 | 中国医学科学院药物研究所 | 吡啶酮酰联芳基胺类化合物及其用途 |
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TW263498B (zh) * | 1993-11-10 | 1995-11-21 | Takeda Pharm Industry Co Ltd | |
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AU2006275514B2 (en) | 2005-07-29 | 2012-04-05 | Resverlogix Corp. | Pharmaceutical compositions for the prevention and treatment of complex diseases and their delivery by insertable medical devices |
PT2118074E (pt) | 2007-02-01 | 2014-03-20 | Resverlogix Corp | Compostos para a prevenção e tratamento de doenças cardiovasculares |
CA2711103C (en) | 2008-06-26 | 2016-08-09 | Resverlogix Corp. | Methods of preparing quinazolinone derivatives |
CA2747417C (en) | 2009-01-08 | 2017-01-03 | Resverlogix Corp. | Compounds for the prevention and treatment of cardiovascular disease |
CA3146333A1 (en) | 2009-03-18 | 2010-09-23 | Resverlogix Corp. | Phenyl-quinazolin-4(3h)-one and phenyl-pyrido[2,3-d]pyrimidin-4(3h)-one derivatives and compositions thereof useful as anti-inflammatory agents |
LT2421533T (lt) | 2009-04-22 | 2018-12-27 | Resverlogix Corp. | Nauji priešuždegiminiai agentai |
JP5992049B2 (ja) | 2011-11-01 | 2016-09-14 | レスバーロジックス コーポレイション | 置換されたキナゾリノンのための経口速放性製剤 |
US9073878B2 (en) | 2012-11-21 | 2015-07-07 | Zenith Epigenetics Corp. | Cyclic amines as bromodomain inhibitors |
WO2014080291A2 (en) | 2012-11-21 | 2014-05-30 | Rvx Therapeutics Inc. | Biaryl derivatives as bromodomain inhibitors |
AU2013365926B9 (en) | 2012-12-21 | 2019-01-17 | Zenith Epigenetics Ltd. | Novel heterocyclic compounds as bromodomain inhibitors |
WO2016147053A1 (en) | 2015-03-13 | 2016-09-22 | Resverlogix Corp. | Compositions and therapeutic methods for the treatment of complement-associated diseases |
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DE3406329A1 (de) * | 1984-02-22 | 1985-08-22 | Merck Patent Gmbh, 6100 Darmstadt | Pyridone |
DE3800785A1 (de) * | 1988-01-09 | 1989-07-20 | Hoechst Ag | Substituierte 7-(pyridazin-5-yl)-3,5-dihydroxyheptan(en)- saeuren, ihre entsprechenden (delta)-lactone bzw. derivate, verfahren zu ihrer herstellung, ihre verwendung als arzneimittel, pharmazeutische praeparate und zwischenprodukte |
GB8911854D0 (en) * | 1989-05-23 | 1989-07-12 | Ici Plc | Heterocyclic compounds |
IE64514B1 (en) * | 1989-05-23 | 1995-08-09 | Zeneca Ltd | Azaindenes |
EP0955294B1 (en) * | 1989-06-14 | 2003-09-24 | Smithkline Beecham Corporation | Imidazolyl-alkenoic acid |
CA2018443A1 (en) * | 1989-06-14 | 1990-12-14 | Joseph A. Finkelstein | Imidazolyl-alkenoic acids |
US5164407A (en) * | 1989-07-03 | 1992-11-17 | Merck & Co., Inc. | Substituted imidazo-fused 5-membered ring heterocycles and their use as angiotensin ii antagonsists |
EP0485410A1 (en) * | 1989-07-06 | 1992-05-20 | The Secretary Of State For Defence In Her Britannic Majesty's Government Of The United Kingdom Of Great Britain And Northern | A detector for monitoring low molecular weight compounds |
CA2027937A1 (en) * | 1989-10-25 | 1991-04-26 | Richard M. Keenan | Substituted 5-¬ (tetrazolyl)alkenyl|imidazoles |
CA2051705A1 (en) * | 1990-06-19 | 1991-12-20 | Kiyoaki Katano | Pyridine derivatives having angiotensin ii antagonism |
IL100917A0 (en) * | 1991-02-16 | 1992-11-15 | Fisons Plc | Pyridinone and pyrimidinone derivatives,their preparation and pharmaceutical compositions containing them |
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-
1992
- 1992-05-12 DE DE4215588A patent/DE4215588A1/de not_active Withdrawn
-
1993
- 1993-04-22 AU AU37109/93A patent/AU3710993A/en not_active Abandoned
- 1993-04-23 CZ CZ93721A patent/CZ72193A3/cs unknown
- 1993-04-27 NO NO93931535A patent/NO931535L/no unknown
- 1993-04-28 MX MX9302487A patent/MX9302487A/es unknown
- 1993-04-29 EP EP93106987A patent/EP0569794A1/de not_active Ceased
- 1993-05-05 US US08/058,550 patent/US5407942A/en not_active Expired - Fee Related
- 1993-05-06 JP JP5129946A patent/JPH0656783A/ja active Pending
- 1993-05-07 CA CA002095802A patent/CA2095802A1/en not_active Abandoned
- 1993-05-10 FI FI932106A patent/FI932106A/fi not_active Application Discontinuation
- 1993-05-10 IL IL105647A patent/IL105647A0/xx unknown
- 1993-05-11 KR KR1019930008038A patent/KR930023364A/ko not_active Application Discontinuation
- 1993-05-11 ZA ZA933274A patent/ZA933274B/xx unknown
- 1993-05-11 HU HU9301365A patent/HU9301365D0/hu unknown
- 1993-05-12 CN CN93105751A patent/CN1082029A/zh active Pending
- 1993-05-12 SK SK467-93A patent/SK46793A3/sk unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111662228A (zh) * | 2019-03-07 | 2020-09-15 | 中国医学科学院药物研究所 | 吡啶酮酰联芳基胺类化合物及其用途 |
CN111662228B (zh) * | 2019-03-07 | 2023-07-28 | 中国医学科学院药物研究所 | 吡啶酮酰联芳基胺类化合物及其用途 |
Also Published As
Publication number | Publication date |
---|---|
KR930023364A (ko) | 1993-12-18 |
CA2095802A1 (en) | 1993-11-13 |
SK46793A3 (en) | 1994-02-02 |
HU9301365D0 (en) | 1993-09-28 |
MX9302487A (es) | 1993-11-01 |
JPH0656783A (ja) | 1994-03-01 |
IL105647A0 (en) | 1993-09-22 |
CZ72193A3 (en) | 1994-01-19 |
EP0569794A1 (de) | 1993-11-18 |
DE4215588A1 (de) | 1993-11-18 |
NO931535D0 (no) | 1993-04-27 |
ZA933274B (en) | 1993-11-29 |
FI932106A0 (fi) | 1993-05-10 |
US5407942A (en) | 1995-04-18 |
FI932106A (fi) | 1993-11-13 |
NO931535L (no) | 1993-11-15 |
AU3710993A (en) | 1993-11-18 |
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