CN1078468A - 磺酰苄基取代的吡啶酮 - Google Patents
磺酰苄基取代的吡啶酮 Download PDFInfo
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- CN1078468A CN1078468A CN 93102232 CN93102232A CN1078468A CN 1078468 A CN1078468 A CN 1078468A CN 93102232 CN93102232 CN 93102232 CN 93102232 A CN93102232 A CN 93102232A CN 1078468 A CN1078468 A CN 1078468A
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- -1 Sulphonylbenzyl Chemical group 0.000 title claims abstract description 40
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 96
- 125000000217 alkyl group Chemical group 0.000 claims description 66
- 239000001257 hydrogen Substances 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 44
- 150000002431 hydrogen Chemical class 0.000 claims description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
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- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
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Abstract
磺酰苄基取代的吡啶酮可通过吡啶酮与磺酰苄
基化合物反应制备。磺酰苄基取代的吡啶酮可用作
药物中的活性化合物,特别是用于治疗动脉高血压和
动脉粥样硬化。
Description
本发明涉及磺酰苄基取代的吡啶酮,它们的制备方法以及它们作为药物,特别是作为降压药和抗动脉粥样硬化剂的应用。
众所周知,肾素,一种蛋白水解酶,在体内从血管紧张素原中降解出十肽血管紧张素Ⅰ,而血管紧张素Ⅰ再在肺、肾或其它组织中降解为高血压八肽血管紧张素Ⅱ。在提高血压的意义上,血管紧张素Ⅱ的各种作用,例如血管收缩、肾中Na+保留、肾上腺醛甾酮释放和交感神经系统紧张性增加具有协同作用。
此外,血管紧张素Ⅱ具有促进细胞(如心肌细胞和平滑肌细胞)生长和复制的作用,不同病态(如高血压,动脉粥样硬化和心肌能不全)中这些细胞以增加的方式生长和增殖。
除了抑制肾素活性之外,在肾素-血管紧张素系统(RAS)中介入的可能的起点是抑制血管紧张素转化酶(ACE)的活性和阻断血管紧张素Ⅱ受体。
本发明涉及通式(Ⅰ)的磺酰苄基取代的吡啶酮及其盐:
式中
R1代表最多有8个碳原子的直链或支链烷基,该烷基任意地被有3-6碳原子的环烷基、羟基或被最多有6个碳原子的直链或支链的烷氧基取代,或
代表有3-6个碳原子的环烷基,
R2、R3和R4可相同或不同,代表氢、氰基或最多有8个碳原子的直链或支链全氟烷基,或
代表最多有8个碳原子的直链或支链烷基,该烷基任意地被相同或不同的选自羟基、囟素、羧基和各最多有6个碳原子的直链或支链烷氧基或烷氧羰基的取代基或被苯基、苯氧基或被最多有三个杂原子的5-7元饱和或不饱和的杂环单取代或双取代,其中的各环系又可以被相同的或不同的选自三氟甲基、三氟甲氧基、囟素、硝基、氰基、羟基和羟甲基的取代基或被各最多有6个碳原子的直链或支链烷基或烷氧基单取代或二取代,或
代表各最多有8个碳原子的直链或支链酰基或烷氧羰基、苄氧羰基或羧基,或
代表苯基,该苯基任意地被相同的或不同的选自囟素、硝基、氰基、羟基、羟甲基、三氟甲基和三氟甲氧基的取代基或被各最多有6个碳原子的直链或支链烷基或烷氧基单取代至三取代,或
代表式-CO-NR6R7基团,其中
R6和R7相同或不同,代表氢、最多有8个碳原子的直链或支链烷基或各有6-10个碳原子的芳基或芳烷基,
R5代表氢、囟素或最多有8个碳原子的直链或支链烷基,或
代表最多有6个碳原子的直链或支链全氟烷基,或
代表式-OX基团,其中
X代表氢、苄基、羟基保护基,或
代表最多有8个碳原子的直链或支链烷基,
A代表3-8元饱和杂环,该杂环通过氮原子键接,另外最多含有2个选自S、N和O的杂原子,它任意地被相同或不同的选自最多有5个碳原子的全氟烷基和下列各式基团的取代基单取代或二取代:
式中
R8代表氢、最多有6个碳原子的直链或支链烷基或三苯甲基,
R9代表羟基、最多有8个碳原子的直链或支链烷氧基、苯氧基、苄氧基或式-NR12R13基团,其中
R12和R13相同或不同,代表氢或最多有6个碳原子的直链或支链烷基或苯基,
R10和R11相同或不同,代表氢、最多有8个碳原子的直链或支链烷基或苯基。
本发明的磺酰苄基取代的吡啶酮也可以其盐形式存在,通常,在此可提及的是与有机或无机碱或酸形成的盐。
在本发明的上下文中,优选生理上可接受的盐。磺酰苄基取代的吡啶酮的生理上可接受的盐可以是本发明的物质与无机酸、羧酸或磺酸形成的盐。举例来说,特别优选的盐是与盐酸、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、三氟乙酸、丙酸、乳酸、酒石酸、柠檬酸、富马酸、马来酸或苯甲酸形成的盐。
生理上可接受的盐也可以是具有游离羧基的本发明的化合物的金属盐或铵盐。举例来说,特别优选的盐是钠、钾、镁或钙盐以及由氨或有机胺例如乙胺、二-或三-乙胺、二-或三-乙醇胺、二环己胺、二甲氨基乙醇、精氨酸、赖氨酸或乙二胺得到的铵盐。
本发明的化合物可作为对映体或非对映异构体以立体异构的形式存在。本发明涉及这些对映体或非对映异构体及其特定的混合物。跟非对映异构体一样,外消旋形式可按公知方法分离成立体异构均一的组分[参见E.L.Eliel著的《碳化合物的立体化学》,Mc Graw Hill,1962]。
在R2、R3和R4的定义中的杂环通常代表可以最多含有2个氧、硫和/或氮原子作为杂原子的5-7元、优选5-6元的饱和或不饱和的环。优选具有1个氧、硫和/或最多2个氮原子的5和6元环。下述是可以优选提及的:噻吩基、呋喃基、吡咯基、吡唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、噻唑基、噁唑基、咪唑基、吡咯烷基、哌啶基、哌嗪基或四唑基。
经由氮原子键连的可另外含有最多2个氧、硫和/或氮原子作为杂原子的3-8元饱和杂环一般代表氮杂环丁烷基、哌啶基、吗啉基、哌嗪基或吡咯烷基。优选的是具有1个氧和/或最多2个原子的5和6元环如哌啶基、吗啉基或吡咯烷基。特别优选的是哌啶基和吡咯烷基。
优选的式(Ⅰ)化合物是各基团如下的那些化合物及其盐,其中
R1代表各最多有6个碳原子的直链或支链烷基,该烷基任意地被环丙基、环戊基、环己基、羟基或被最多有4个碳原子的直链或支链烷氧基取代,或
代表环丙基、环戊基或环己基,
R2、R3和R4可相同或不同,代表氢、氰基或最多有6个碳原子的直链或支链全氟烷基,或
代表最多有6个碳原子的直链或支链烷基,该烷基被羟基、氟、氯、溴、羧基和各最多有4个碳原子的直链或支链烷氧基或烷氧羰基或被苯基、苯氧基或噻吩基取代,其中的各环系又可以被三氟甲氧基、三氟甲基、羟甲基、氟、氯、溴或被各最多有6个碳原子的直链或支链烷基或烷氧基取代,或
代表各最多有6个碳原子的直链或支链酰基或烷氧羰基、苄氧羰基或羧基,或
代表任意地被相同或不同的选自氟、氯、溴、三氟甲基、三氟甲氧基和羟甲基的取代基或被各最多有4个碳原子的直链或支链烷基或烷氧基单取代或二取代的苯基,或
代表或-CONR6R7基团,其中
R6和R7相同或不同,代表氢、最多有6个碳原子的直链或支链烷基、苯基或苄基,
R5代表氢、氟、氯、溴或最多有6个碳原子的直链或支链烷基,或代表最多有4个碳原子的直链或支链全氟烷基,或
代表式-OX基团,其中
X代表氢、苄基或乙酰基,或
代表最多有6个碳原子的直链或支链烷基,
A代表经由氮原子键连的哌啶基、吡咯烷基或吗啉基,这些基团中的每一个都可任意地被三氟甲基或被下列各式基团取代,
式中
R8代表氢、最多有4个碳原子的直链或支链烷基或三苯甲基,
R9代表羟基、最多有6个碳原子的直链或支链烷氧基、苯氧基、苄氧基或式-NR12R13基团,其中
R12和R13相同或不同,代表氢或最多有4个碳原子的直链或支链烷基,及
R10和R11相同或不同,代表氢、最多有6个碳原子的直链或支链烷基或苯基。
特别优选的通式(Ⅰ)化合物是下列化合物及其盐,其中
R1代表最多有4个碳原子的直链或支链烷基,该烷基可任意地被环丙基取代,或
代表环丙基,
R2、R3和R4相同或不同,代表氢、氰基或最多有4个碳原子的直链或支链全氟烷基,或
代表最多有4个碳原子的直链或支链烷基,该烷基被羟基或各最多有3个碳原子的直链或支链烷氧基或烷氧羰基取代,或
代表各最多有4个碳原子的直链或支链酰基或烷氧羰基、苄氧羰基或羧基,或
代表式-CONR6R7基团,其中
R6和R7相同或不同,代表氢、最多有4个碳原子的直链或支链烷基、苯基或苄基,
R5代表氢、氟、氯、最多有4个碳原子的直链或支链烷基,或
代表最多有3个碳原子的直链或支链全氟烷基,或
代表式-OX基团,其中
X代表氢、苄基或乙酰基,或
代表最多有6个碳原子的直链或支链烷基,
A代表经由氮原子键连的哌啶基或吡咯烷基,这些基团中的每一个都可任意地被三氟甲基或被下列各式基团取代,
式中
R8代表氢、甲基、乙基或三苯甲基,
R9代表羟基、最多有4个碳原子的直链或支链烷氧基、苯氧基、苄氧基或式-NR12R13基团,其中
R12和R13相同或不同,代表氢或最多有3个碳原子的直链或支链烷基,
R10和R11相同或不同,代表氢、最多有4个碳原子的直链或支链烷基或苯基。
此外,已找到了本发明的式(Ⅰ)化合物的制备方法,其特征在于
在有机溶剂中,在碱和适当时催化剂存在下使式(Ⅱ)的吡啶酮与式(Ⅲ)化合物反应,
式中R1、R2、R3和R4具有上述意义,
式中R5和A具有上述意义,B代表囟素,优选溴,
并且在R8≠氢的情况下,还进行烷基化,而在酸的情况(R9=OH)下对相应的酯进行水解,
并且在酯或酰胺的情况下,适当时经由活化的羧酸步骤进行酯化或酰胺化,
并且按常规方法改变取代基R2、R3、R4和R5。
本发明的方法可以通过举例方式用下列反应式说明:
该方法所用的合适的溶剂是在反应条件下不变化的常用有机溶剂。这些溶剂优选包括醚类,例如乙醚、二噁烷、四氢呋喃或乙二醇二甲醚、1,2-二甲氧基乙烷,或烃类,例如苯、甲苯、二甲苯、己烷、环己烷或矿物油馏分,或囟代烃类,例如,二氯甲烷、三氯甲烷、四氯化碳、二氯乙烯、三氯乙烯或氯苯,或乙酸乙酸、三乙胺、吡啶、二甲基亚砜、二甲基甲酰胺、六甲基磷酸三酰胺、乙腈、丙酮或硝基甲烷。同样,也可以使用所述溶剂的混合物。优选四氢呋喃和1,2-二甲氧基乙烷。
一般来说,无机或有机碱可用作本发明方法的碱。这些碱优选包括碱金属氢氧化物或碱土金属氢氧化物,例如氢氧化钠、氢氧化钾或氢氧化锂、氢氧化钡、碱金属或碱土金属碳酸盐如碳酸钠、碳酸钾、碳酸钙或碳酸铯,或碱金属或碱土金属醇盐,例如甲醇钠或甲醇钾或叔丁醇钾,或二异丙基氨基锂(LDA),或有机胺(三烷基(C1-C6)胺),例如三乙胺,或杂环化合物,例如,1,4-二氮杂双环[2.2.2]辛烷(DABCO)、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、吡啶、二氨基吡啶、甲基哌啶或吗啉。也可以把碱金属例如钠或其氢化物例如氢化钠用作碱。优选碳酸钾、氢化钠、叔丁醇钾和碳酸铯。
一般来说,碱的用量为每摩尔式(Ⅲ)化合物0.05-10摩尔、优选1-2摩尔。
一般来说,本发明的方法是在-100℃-+100℃、优选0℃-40℃下进行的。
一般来说,本发明的方法是在常压下进行的。但是,也可以在加压或减压下(例如0.5-5巴)实施该方法。
三苯甲基的除去是用乙酸或三氟乙酸和水或上述醇之一或在两酮存在下或也在醇存在下用盐酸水溶液进行。
该脱除反应通常在0℃-150℃、优选20℃-100℃的温度范围内在常压下进行。
合适的催化剂是碘化钾或碘化钠,优选碘化钠。
烷基化一般用烷基化剂进行,该烷基化剂的例子有(C1-C6)烷基囟化物、磺酸酯或取代或未取代的(C1-C6)二烷基-或(C1-C6)二芳基磺酸酯,优选甲基碘或硫酸二甲酯。
烷基化一般在上述溶剂之一中进行,优选二甲基甲酰胺,所用的温度为0℃-+70℃、优选0℃-+30℃,所用的压力为常压。
适用于水解的碱是常用的无机碱。这些碱优选包括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,或碱金属醇化物,例如甲醇钠、乙醇钠、甲醇钾、乙醇钾或叔丁醇钾。特别优选使用氢氧化钠、氢氧化钾或氢氧化锂。
适用于水解的溶剂是水或常用于水解的有机溶剂。这些溶剂优选包括醇,例如甲醇、乙醇、丙醇、异丙醇或丁醇,或醚,例如四氢呋喃或二噁烷,或二甲基甲酰胺或二甲亚砜。特别优选使用醇,例如甲醇、乙醇、丙醇或异丙醇,也可以使用所述溶剂的混合物。优选四氢呋喃和甲醇。
水解也可用酸进行,酸的例子有三氟乙酸、乙酸、盐酸、氢溴酸、甲磺酸、硫酸或高氯酸,优选三氟乙酸。
水解一般在0℃-+100℃、优选+20℃-+80℃进行。
水解一般在常压下进行。但是,也可以在减压或加压(如0.5-5巴)下进行水解。
在进行水解时,碱的用量一般为每摩尔酯1-3摩尔、优选1-1.5摩尔。采用反应物的摩尔量特别优选。
叔丁酯的水解一般在上述溶剂之一和/或水或它们的混合物存在下用酸如盐酸或三氟乙酸进行,优选使用二噁烷或四氢呋喃。
酰胺化和磺酰胺化反应一般在上述溶剂之一中、优选在四氢呋喃或二氯甲烷中进行。
酰胺化和磺酰胺化反应可任意地经由酰囟的活化阶段进行,后者可以通过相应的酸与亚硫酰氯、三氯化磷、五氯化磷、三溴化磷或草酰氯反应而从相应的酸制得。
酰胺化和磺酰胺化反应通常在-20℃-+80℃、优选-10℃-+30℃的温度范围内在常压下进行。
除了上述碱之外,用于此目的的合适的碱优选为三乙胺和/或二甲氨基吡啶、DBU或DABCO。
相对于1mol相应的酸或酯,碱的用量为0.5-10mol,优选1-2mol。
对于磺酰胺化反应来说可用的酸结合剂是碱金属或碱土金属的碳酸盐如碳酸钠、碳酸钾,碱金属或碱土金属的氢氧化物例如氢氧化钠或氢氧化钾,或有机碱如吡啶、三乙胺,N-甲基哌啶,或双环脒如1,5-二氮杂双环[3.4.0]壬-5-烯(DBN)或1,5-二氮杂双环[3.4.0]+--5-烯(DBU)。优选碳酸钾。
合适的脱水剂是碳化二亚胺类如二异丙基碳化二亚胺、二环己基碳化二亚胺或N-(3-二甲氨基丙基)-N′-乙基碳化二亚胺盐酸盐或羰基化合物如羰基二咪唑或1,2-噁唑鎓化合物如2-乙基-5-苯基-1,2-噁唑鎓-3-磺酸盐或丙烷膦酸酐或氯甲酸异丁酯或苯并三唑氧基-三(二甲氨基)鏻六氟磷酸盐或氨基磷酸二苯酯或甲磺酰氯,适当时在碱如三乙胺或N-乙基吗啉或N-甲基哌啶或二环己基碳化二亚胺和羟基琥珀酰亚胺存在下使用[参见J.C.Sheehan,S.L.LEdis,J.Am.Chem.Soc.,95,875(1973);F.E.Frerman等人,J.Biol.Chem.,225,507(1982)和N.B.Benoton,K.Kluroda,Int.Pept.Prot.Res.,13,403(1979),17,187(1981)]。
酸结合剂和脱水剂的用量相对于1mol相应的羧酸通常为0.5-3mol,优选1-1.5mol。
通式(Ⅱ)化合物在一些情况下是已知的[参见,例如,DE3,406,329 Al,R.P.Mariella,R.Stansfield,J.Am.Chem.Soc.,731368(1951)和O.Isler等人,Helv.Chim.Acta 38,1033(1955)Bull.Soc.Chim.Fr.,687(1958)],或是新的,那么,它们可以按与上述所引用的公开物中所述方法相似的方法制备。
通式(Ⅲ)化合物是新的,可以通过在上述溶剂之一和碱中,优选在二氯甲烷中用三乙胺,使通式(Ⅳ)的取代的苄基磺酰氯与通式(Ⅴ)化合物反应进行制备,
式中B和R5具有上述意义,
H-A (Ⅴ),
式中A具有上述意义。
通常,该反应在常压下进行。然而,也可以在减压或加压下(例如0.5-5巴)进行。
当实施该反应时,相对于1mol通式(Ⅳ)化合物来说,碱的用量通常为1-3mol,优选1-1.5mol。特别优选使用反应物的摩尔量。
该反应通常在-40℃-+40℃、优选在-30℃-0℃的温度范围内在常压下进行。
通式(Ⅳ)和(Ⅴ)化合物是已知的,或者可以用常规方法制备。
本发明的通式(Ⅰ)化合物显示了出乎意料的有用的药理活性谱。
由于本发明的化合物能抑制血管紧张素Ⅱ结合到AⅡ受体上,因此具有特异性的AⅡ拮抗活性。它们抑制血管紧张素Ⅱ的血管收缩和醛甾酮分泌刺激作用。此外,它们还抑制平滑肌细胞的增殖。
因此,本发明的化合物可用作用于治疗动脉高血压和动脉粥样硬化的药物。此外,它们还可用于治疗冠心病、心肌能不全、大脑功能障碍、大脑局部缺血、外周循环障碍、肾和肾上腺功能性障碍、支气管疾病和脉管源的呼吸道疾病、钠滞留和浮肿。
此外,这类物质具有促尿钠排泄和利尿作用。在心源和非心源的病理流体增加期间,这种作用本身表明在水肿液体的流动性中。
激动剂引起的收缩抑制试验
往两种性别的兔的颈部猛击并放血,或在某些情况下用Nembutal(约60-80mg/kg i.v.)麻醉并开胸处死。取出胸主动脉,剔除粘连组织,并分成1.5mm宽的环形切片。在约3.5g的初始负荷之下,把诸切片分别放入10ml含95% O2/5% CO2充气的Krebs-Henseleit营养液的器官浴中,所述营养液恒温控制在37℃,并具有以下组成:119mmol/l NaCl;2.5mmol/l CaCl2·2H2O;1.2mmol/l KH2PO4;10mmol/l葡萄糖;4.8mmol/l KCl;1.4mmol/l MgSO4·7H2O和25mmol/l NaHCO3。
借助于桥接放大器(ifd Mulheim或DSM Aalen),用Statham UC2细胞等长地记录收缩情况,并利用A/D变换器(System 570,Keithley Munich)数字化和分析。按小时绘制激动剂剂量/响应曲线(DRC)。对于每条DRC来说,是以4分钟间隔将3或4个单个浓度加到浴中。DEC和随后清洗循环(用上述营养液清洗16次,每次约5秒/分钟)结束后,经过28分钟静置或保温期,一般在此期间内收缩再次达到起始值。
在正常情况下,第三DRC的高度用作评估以后待测试验物的参比量,该试验物在保温时间开始时以增加的剂量加到进行后面DRC的浴中。在整个一天中总是用相同的激动剂刺激每一主动脉环。
激动剂及其标准浓度(每单个剂量所加体积=100μl):
KCl 22.7;32.7;42.7;52.7 mmol/l
5-羟色胺 10-8;10-7;10-6;10-5g/ml
B-HT920 10-7;10-6;10-5g/ml
甲氧胺 10-7;10-6;10-5g/ml
血管紧张素II 3×10-9;10-8;3×10-8;10-7g/ml
为了计算IC50(被测物产生50%抑制率的浓度),在每种情况下,效果都是基于第三(次最大)激动剂浓度。
本发明的化合物以依赖于剂量的方式抑制血管紧张素Ⅱ引起的离体兔主动脉收缩。在高浓度下,因钾去极化或其它激动剂引起的收缩未被抑制或仅被稍微抑制。
表A
在体外对离体兔动脉环的血管收缩的体外抑制
抑制由以下物质引起的收缩的IC50[nM]:
实施例编号 AII
6 280
对输注了血管紧张素Ⅱ输液的大鼠的血压测定
体重300-350g的雄性Wistar大鼠(Moellegaard,Copenhagen,Denmark)用硫喷妥钠麻醉(100mg/kg i.p.)。气管切开术之后,把测定血压用的导管插入股动脉,并将输注血管紧张素Ⅱ用的插管和给待测物用的插管插入股静脉,在给予封阻神经节用的戊双吡铵(5mg/kg,i.v.)之后,开始输注血管紧张素Ⅱ(0.3μg/kg/分钟)。一旦血压值达到一稳定的平台,则静脉注射试验化合物,或以0.5%纤基醋酸钠的悬浮液或溶液给予试验物质。受该物化合物影响的血压的变化情况在表中以平均值±SEM给出。
对清醒的高血压大鼠的抗高血压活性的测定
对外科术诱发的单测肾动脉狭窄的清醒的大鼠测定本发明化合物的口服抗高血压活性。为此,用内径0.18mm的银钳止住右肾动脉。对于这种类型的高血压,术后头一个六星期中血浆肾素活性增加。在给予该物质之后,以一定时间间隔用“尾套”以无血方式测定这些动物的动脉血压。待试的物质以在纤基乙酸钠悬浮液中悬浮的不同剂量,通过胃管胃内给药(“口服”)。本发明的化合物以临床相关剂量降低高血压大鼠的动脉血压。
此外,本发明的化合物以依赖浓度的方式抑制放射性的血管紧张素Ⅱ的特异结合。
在肾上腺皮质的膜级分(牛)上本发明化合物与血管紧张素Ⅱ受体的相互作用
新取出的并仔细去除了囊髓的牛肾上腺皮质(AGC)借助于Ultra-Turrax(Janke & Kunkel,Staufen i.B.)细分成在蔗糖溶液(0.32M)中的粗膜组织均浆,并将均浆两步离心,部分纯化成膜级分。用放射性的血管紧张素Ⅱ对部分纯化的牛AGC膜级分进行受体结合分析,所用的试验液体积为0.25ml,具体含有部分纯化的膜(50-80μg)、3H-血管紧张素Ⅱ(3-5nM)、试验缓冲液(50mM Tris,pH 7.2)、5mM MgCl2和被测物。在室温60分钟保温时间之后,利用湿润过的玻璃纤维滤器(Whatman GF/C)分离样品的非结合放射性,并在蛋白质用冰冷缓冲液(50mM Tris/HCl,pH7.4,5% PEG 6000)清洗之后,在闪烁鸡尾酒状液中用分光光度测定法测定结合的放射性。利用计算机程序分析原始数据得到Ki和IC50值(Ki:所用放射性的校正IC50值;IC50值:被测物质引起放射性配位体特异结合的50%抑制率的浓度)。
本发明的化合物抑制平滑肌细胞增殖的试验
将通过培养基外殖技术[R.Ross,J.Cell.Biol.50,172,1971]由大鼠或猪主动脉得到的平滑肌细胞用于测定化合物的抗增殖活性。
将细胞分布在一般24孔板的合适的培养皿中,在含有7.5%FCS和7.5%NCS、2mM L-谷氨酰胺和15mM HEPES(pH7.4)的培养基199中,于37℃ 5%CO2中培养2-3天。然后,通过取出清液的方法将细胞同步培养2-3天,而后用AⅡ、血清或其它因素刺激生长。同时,加入试验化合物。16-20小时之后,加1μCi3H-胸苷,再4小时后测定该物质结合到细胞的TCA-可沉淀的DNA中的结合率。
促尿钠排泄活性试验
用口服试验物(悬浮在纤基乙酸钠溶液中)的方法处理禁食Wister大鼠。然后,在利尿笼中收集排泄出的尿6小时。利用火焰光度计法测定尿中的钠和钾的浓度。
按已知方法,使用惰性、无毒的适宜药用的赋形剂或溶剂,可将该新的活性化合物加工成常用制剂,例如片剂、包衣片剂、丸剂、粒剂、气溶胶、糖浆、乳剂、混悬液和溶液。在每种情况下,治疗活性化合物以占混合物总重约0.5-90%的浓度存在,这就是说,其含量足以达到规定剂量范围。
举例来说,制剂的制备方法是把活性化合物与溶剂和/或赋形剂掺混,合适的话,使用乳化剂和/或分散剂,例如在使用水作为溶剂的情况下,可任意地使用有机溶剂作为助溶剂。
活性化合物以传统方式给药,优选口服或肠胃外给药,特别是经舌给药或静脉注射。
就肠胃外给药而言,可以使用合适的液体赋形剂物质的活性化合物溶液。
一般来说,已证明以下给药量比较有利:就静脉注射而言,给药量为约0.001-1mg/kg、优选约0.01-0.5mg/kg体重,以取得有效的结果;就口服给药而言,给药剂量为约0.01-20mg/kg、优选0.1-10mg/kg体重。
不仅如此,有时必须背离上述用量,特别是随体重或给药途径的类型、个体对药物的反应,其制剂的性质和给药的时间或间隔而变化时,更是如此。因此,在某些情况下,不到上述最低用量便可足以解决问题;而在另一些情况下,必须超过上述上限。在较大给药量的情况下,将药物在一天内分成几个单个剂量给药比较有利。
溶剂:
a=CH2Cl2/CH3/OH=10∶1
b=CH2Cl2/CH3OH/CH3CO2H=10∶1∶0.5
c=CH2Cl2/CH3OH=5∶1
起始化合物
实施例Ⅰ
6-丁基-4-甲氧羰基-2-氧代-1,2-二氢吡啶
在冰冷却下,将12.5ml(0.17mol)亚硫酰氯滴加到29.25g(0.15mol)6-丁基-2-氧代-1,2-二氢异烟酸在200ml甲醇中的悬浮液中,并将混合物在室温下搅拌过液。浓缩至干,残留物在硅胶(450g,230-400目)上用二氯甲烷→二氯甲烷/甲醇10∶1洗脱进行层析,经二氯甲烷、乙醚和石油醚结晶后,得到29.6g(94%)无色晶体,m.p.106℃。
实施例Ⅱ
6-丁基-吡啶-2(1H)-酮
将4.9g(25mmol)6-丁基-2-氧代-1,2-二氢-异烟酸与1.79g(12.5mmol)氧化铜(Ⅰ)在50ml的喹啉中于237℃回流1.5小时。过滤后,真空蒸馏(在17mbar下110℃,然后在9mbar下67℃)除去挥发性组分。残馏物在硅胶上用二氯甲烷/甲醇(40∶1)→(20∶1)洗脱层析两次,产物在石油醚中搅拌。收率1.95g(52%),棕色晶体,m.p.68℃。
实施例Ⅲ
4-(溴甲基)苯-磺酰氯
将38.1g(0.2mol)4-甲基苯磺酰氯溶于300ml四氯化碳中,用35.6g(0.2mol)N-溴代琥珀酰亚胺处理,加入0.2g(1.2mmol)偶氮双异丁腈(ABU)后,将混合物加热回流4小时。冷却后,滤出固体物,除去滤液中的溶剂。闪式层析(石油醚/甲苯4∶1,50μm粒度)后,用100ml环己烷重结晶,得到24.0g(理论量的45%)标题化合物。Rf=0.75(甲苯)。
实施例Ⅳ
4-(溴甲基)-3-氯苯磺酰氯
将45.9g(0.2mol)3-氯-4-甲基苯磺酸钠与83.3g(0.4mol)五氯化磷混合,在140℃的油浴温度下加热30分钟。用500ml甲苯处理热混合物,将所得溶液加热至沸,冷却后倒到冰上。分出有机相,用水(2×200ml)洗涤,用MgSO4干燥,过滤,真空下汽提掉所有挥发物。所得残留物经闪式层析(石油醚/甲苯4∶1,50μm粒度)纯化,得到24.9g产物,直接进一步反应。
将所得产物溶于200ml四氯化碳中,加入19.6g(0.11mol)N-溴代琥珀酰亚胺和0.1g(0.6mmol)ABN后,加热回流6小时。冷却后,滤除固体物,除去滤液中的溶剂。闪式层析(石油醚/甲苯4∶1,50μm粒度)后,得到21.2g(35%)标题化合物。Rf=0.32(石油醚/二氯甲烷4∶1)。
实施例Ⅴ
N-[4-(溴甲基)苯磺酰基]吡咯烷
将5.3g(0.02mol)实施例Ⅲ化合物溶于200ml二氯甲烷和4.0g(0.04mol)三乙胺中,加入1.4g(0.02mol)吡咯烷后,将混合物在50ml二氯甲烷中于0℃下搅拌1小时。将混合物用2N HCl(2×100ml)、H2O(2×100ml)萃取,用MgSO4干燥后过滤,真空下蒸发掉所有挥发性组分。收率:5.4g(理论量的89%)。Rf=0.09(甲苯)。
实施例Ⅵ
N-[4-(溴甲基)-苯磺酰基]哌啶
按照与实施例Ⅴ相似的步骤,从1.1g(4mmol)实施例Ⅲ的化合物和0.34g(4mmol)哌啶得到1.0g(理论量的81%)标题化合物。Rf=0.14(甲苯)。
实施例Ⅶ
(S)-N-[4-(溴甲基)苯磺酰基]-2-(叔丁氧羰基)吡咯烷
按照与实施例Ⅴ相似的步骤,从7.25g(27mmol)实施例Ⅲ的化合物和4.6g(27mmol)S-脯氨酸叔丁酯得到9.1g(理论量的84%)标题化合物。Rf=0.66(石油醚/乙酸乙酯7∶3)。
实施例Ⅷ
外消旋-N-[4-(溴甲基)-苯磺酰基]-2-(叔丁氧羰基)哌啶
按照与实施例Ⅴ相似的步骤,从8.0g(30mmol)实施例Ⅲ的化合物和5.5g(30mmol)外消旋-哌啶甲酸叔丁酯得到7.4g(理论量的59%)标题化合物。Rf=0.53(石油醚/乙酸乙酯5∶1)。
实施例Ⅸ
(S)-N-[4-(溴甲基)-3-氯苯磺酰基]-2-(叔丁氧羰基)吡咯烷
按照与实施例5相似的步骤,从10.0g(33mmol)实施例Ⅳ的化合物和5.7g(33mmol)的S-脯氨酸叔丁酯得到13.9g(理论量的96%)标题化合物。Rf=0.55(石油醚/乙酸乙酯7∶3)。
实施例Ⅹ
外消旋-N-[4-(溴甲基)-3-氯苯磺酰基]-2-(叔丁氧羰基)哌啶
按照与实施例5相似的步骤,从10.0g(33mmol)实施例Ⅳ化合物和6.1g(33mmol)外消旋-哌啶甲酸叔丁酯得到14.6g(理论量的98%)的标题化合物。Rf=0.6(石油醚/乙酸乙酯7∶3)。
实施例Ⅺ
6-丁基-4-苄氧羰基-2-氧代-1,2-二氢吡啶
将13.3g(123mmol)苄醇和4.7g(31mmol)的羟基苯并三唑加到6.0g(31mmol)6-丁基-2-氧代-1,2-二氢-异烟酸在100ml DMF中的溶液中。将所得的透明溶液冷却至0℃,接着加入7.0g(34mmol)二环己基碳化二亚胺和4.2ml(31mmol)三乙胺。允许混合物升至20℃,再搅拌2小时,进行水相后处理,得到6.8g(理论量的77%)的标题化合物。m.p.139℃。
实施例Ⅻ
4-甲氧羰基-2-氧代-6-丙基-1,2-二氢吡啶
按照与实施例Ⅰ相似的步骤,从14.5g(80mmol)2-氧代-6-丙基-1,2-二氢-异烟酸和甲酸得到了13.7g(理论量的88%)标题化合物。m.p.144℃。
实施例ⅫⅠ
N-三氟乙酰基-L-脯氨酰胺
在保护性气体下,先将30g(0.142mol)三氟乙酰基脯氨酸引入150ml DMF中。在-20℃,加入在乙酸乙酯中的142.6ml(0.1704mol)的38%浓度的PPA。引入氨气,使混合物饱和,30分钟后沉出白色沉淀。在轻轻的氨气流下使该批产物缓和,然后将整个反应混合物加到600ml H2O中,用浓乙酸酸化至pH4,通过与200ml二氯甲烷振摇,提取4次,再用200ml乙醚振摇提取3次。合并有机相,用MgSO4干燥,汽提掉溶剂。残留物一起在硅胶60F 254上用二氯甲烷/甲醇(10∶1)洗脱层析。在旋转蒸发器上除去含产物的级分中的溶剂。得到17.12g标题化合物(理论量的57%);Rf=0.345(T/EA/CH3COOH)20∶20∶1。
实施例ⅪⅤ
2-氰基-N-三氟乙酰基-吡咯烷
在保护性气体下,先将40g(0.19mol)实施例ⅩⅢ的产物和45g(=46ml,0.57mol)吡啶引入300ml THF中。在0℃,加入48g(=32.25ml,0.228mol)三氟乙酸酐。将反应混合物在0℃下搅拌30分钟,然后在室温下搅拌90分钟。将该批反应物加入1升1N盐酸中,通过与200ml二氯甲烷振摇提取3次。合并有机相,通过用200ml饱和氯化钠溶液振摇提取,用MgSO4干燥。汽提掉溶剂,残留物在硅胶60 F254上层析,用石油醚/乙酸乙酯/乙酸(1600∶200∶5)洗脱。浓缩含产物的级分,得到32.4g标题化合物(理论量的88%)。Rf=0.57(PE/EA 7∶3)。
实施例ⅩⅤ
2-四唑基-N-三氟乙酰基-吡咯烷
在保护性气体下,将31.35g=32.6ml(0.26mol)氯化二乙基铝先引入到65ml甲苯中。在室温下加入29.95g=34.04ml(0.26mol)三甲基硅基叠氮,并在室温下将混合物搅拌10分钟。在0℃下加入溶解在65ml甲苯中的25g(0.13mol)的实施例ⅪⅤ的产物。将反应混合物在0℃搅拌30分钟,在室温下搅拌120分钟,然后在40℃下搅拌60分钟。冷却后,将该批反应物用饱和氟化钾溶液处理,直接不再能检测到气体放出。
将反应混合物加到600ml H2O中,酸化至pH4,用3×100ml乙酸乙酯提取。合并有机相,用50ml正己烷处理。为了除去叠氮化物,用不带冷却的蒸馏桥蒸馏除去约1/3的溶剂。残留物用硫酸镁干燥,在旋转蒸发器上除去溶剂,得到18.54g标题化合物(60.6%理论量)。Rf=0.4(甲苯/乙酸乙酯1∶1)。
实施例ⅩⅥ
N-三氟乙酰基-2-[N-三苯甲基四唑基]吡咯烷
先将16.23g(0.069mol)实施例ⅩⅤ的产物和10.47g=14.35ml(0.1035mol)的三乙胺引入70ml二氟甲烷中。然后加入19.83g(0.069mol)三苯甲基氯。将反应混合物在室温下搅拌1.5小时。用二氯甲烷稀释,用pH5的缓冲液(3×50ml)提取。用硫酸镁干燥有机用。在旋转蒸发器上汽提掉溶剂。残留物与乙醚一起搅拌。抽滤出产生的晶体,干燥。得到24.65g标题化合物(75%理论量)。Rf=0.53(石油醚/乙酸乙酯7∶3)。
实施例ⅩⅤⅡ
2-(N-三苯甲基-四唑基)吡咯烷
在保护性气体下,先将24g(0.05mol)实施例ⅩⅤⅠ的产物引入100ml乙醇中。在0℃下分批加入2.84g(0.075mol)硼氢化钠。使该批反应物缓和并在室温下搅拌1小时。用6ml乙酸处理,将整个反应混合物加到500ml缓冲液pH9中。用3×75ml二氯甲烷提取该批反应物。合并有机相,用硫酸镁干燥,在旋转蒸发器上除去溶剂。残留物在硅胶60 F254上层析,用石油醚/乙酸乙酯7∶3洗脱。浓缩相应的级分,干燥。得到7.16g标题化合物(37.5%理论量)。Rf=0.22(乙酸乙酯)。
实施例ⅩⅤⅢ
N-[4-溴甲基-3-氯-苯磺酰基]-2-[三苯甲基四唑基]吡咯烷
按照与实施例Ⅲ相似的步骤,从3.19g(10.5mmol)实施例Ⅳ化合物和4g(10.5mmol)实施例ⅩⅤⅡ化合物得到6.49g标题化合物(95%理论量)。Rf=0.53(石油醚/乙酸乙酯7∶3)。
实施例ⅪⅩ
4-(溴甲基)-3-氟苯磺酰氯
将20.9g(0.1mol)3-氟-4-甲基苯磺酰氯溶于200ml四氯化碳中,加入19.6g(0.11mol)N-溴代琥珀酰亚胺和0.3g过氧化二苯甲酰物后,将混合物加热回流5小时。冷却后,滤出固体物,除去滤液中的溶剂。闪式层析(石油醚/甲苯(4∶1),50μm粒度)后,得到12.4g(理论量的44%)。标题化合物。Rf=0.42(石油醚/甲苯3∶1)。
实施例ⅩⅩ
4-(溴甲基)-3-三氟甲基苯磺酰氯
将64.6g(0.25mol)3-三氟甲基-4-甲基苯磺酰氯溶于500ml四氯化碳中,加入44.5g(0.25mol)N-溴代琥珀酰亚胺和0.4g ABN后,将混合物加热回流24小时。冷却后,滤出固体物,除去滤液中的溶剂。闪式层析(石油醚/甲苯(4∶1),50μm粒度)后,得到33.9g(理论量的40%)标题化合物。Rf=0.41(石油醚/甲苯3∶1)。
实施例ⅩⅩⅠ
(S)-N-[4-(溴甲基)-3-氟苯磺酰基]-2-(叔丁氧羰基)吡咯烷
按照与实施例Ⅲ相似的步骤,从8.6g(30mmol)实施例ⅪⅩ化合物和5.1g(30mmol)的S-脯氨酸叔丁酯得到12.7g(理论量的100%)的标题化合物。Rf=0.57(石油醚/乙酸乙酯7∶3)。
实施例ⅩⅩⅡ
(S)-N-[4-(溴甲基)-3-三氟甲基苯磺酰基]-2-(叔丁氧羰基)吡咯烷
按照与实施例Ⅲ相似的步骤,从16.9g(50mmol)实施例ⅩⅩ化合物和8.6g(50mmol)S-脯氨酸叔丁酯得到23.6g(100%理论量)的标题化合物。Rf=0.63(石油醚/乙酸乙酯7∶3)。
实施例ⅩⅩⅢ
(S)-N-[4-羧基-3-羟基苯磺酰基]-(2-叔丁氧羰基)吡咯烷
按照与实施例Ⅴ相似的方法,从23.7g4-羧基-3-羟基苯磺酰氯(100mmol)和17.1g(100mmol)S-脯氨酸叔丁酯得到30.0g(理论量的81%)标题化合物。Rf=0.18(丙酮)。
实施例ⅩⅩⅣ
(S)-N-[4-苄氧羰基-3-苄氧基苯磺酰]-2-(叔丁氧羰基)吡咯烷
将28.3gK2CO3(204mmol)和25.7g(150mmol)苄基溴加到25.3g(68mmol)溶解在200ml DMF中的实施例ⅩⅩⅢ化合物中。将反应混合物再在75℃下搅拌2小时,冷却。然后加入1升水,用乙酸乙酯(3×400ml)提取混合物,提取液用水(5×400ml)洗涤,用MgSO4干燥,过滤,真空下汽提掉所有挥发性组分。通过闪式层析(石油醚/CH2Cl25∶1和石油醚/乙酸乙酯(6∶1,粒度50μ)纯化产物,再通过用600ml混合溶剂(石油醚/乙酸乙酯6∶1)重结晶进一步纯化,得到35.5g(理论量的95%)标题化合物。Rf=0.53(石油醚/乙酸乙酯7∶3)。
实施例ⅩⅩⅤ
(S)-N-[4-(羟甲基)-3-苄氧基苯磺酰]-2-(叔丁氧羰基)吡咯烷
将11.0g(20mmol)实施例ⅩⅩⅣ的化合物溶解于100ml二甘醇二甲醚中,加入1.51g(40mmol)硼氢化钠和1.68g(40mmol)LiCl,将混合物在70℃下搅拌4小时。冷却后,向反应混合物中加入500ml水,然后用INHCl酸化至pH3。用乙醚(3×300ml)提取混合物,提取液用水(6×300ml)洗涤,用MgSO4干燥,除去滤液中的溶剂。残留物在硅胶60F 254上层析(石油醚/乙酸乙酯(7∶3))。蒸发浓缩相应的级分,干燥,得到5.0g(理论量的56%)标题化合物。Rf=0.36(石油醚/乙酸乙酯7∶3)。
实施例ⅩⅩⅥ
(S)-N-[4-(溴甲基)-3-苄氧基苯磺酰]-2-(叔丁氧羰基)吡咯烷
先在惰性气体下,将2.24g(5mmol)实施例ⅩⅩⅤ化合物引入20ml无水DMF中。在0℃下加入2.53g(6mmol)三苯膦二溴化物。将反应混合物在室温下搅拌1小时。加入200ml水。用乙酸乙酯(3×80ml)提取混合物,提取液用水(5×60ml)洗涤,用MgSO4干燥。过滤,真空下汽提掉所有挥发性组分。产物用闪式层析纯化(CH2Cl2,粒度50μ),得到2.55g(理论量的100%)标题化合物。Rf=0.56(石油醚/乙酸乙酯7∶3)。
制备实施例
实施例1
外消旋-N-[4-[4-苄氧羰基-6-丁基-2-氧代-1,2-二氢吡啶-1-基]甲基-3-氯-苯磺酰基]-(2-叔丁氧羰基)哌啶
将500mg(1.75mmol)实施例Ⅹ产物和570mg(1.75mmol)Cs2CO3悬浮在10ml无水1,2-二甲氧基乙烷中,在20℃下搅拌10分钟。加入溶解在10ml 1,2-二甲氧基乙烷中的790mg(1.75mmol)实施例ⅤⅡ产物,将混合物在20℃搅拌5小时。冷却反应混合物,加到100ml水中,用乙酸乙酯(4×60ml)提取,用MgSO4干燥,真空下汽提掉溶剂。粗产物在硅胶上纯化(50μ粒度,洗脱剂石油醚/乙酸乙酯10∶1→7∶3)。得到78mg(8%理论量)的标题化合物。Rf=0.09(石油醚/乙酸乙酯5∶1)。
实施例2
外消旋-N-〔4-[4-苄氧羰基-6-丁基-2-氧代-1,2-二氢吡啶-1-基]甲基-3-氯苯磺酰基]-(2-羧基)哌啶
将400ml三氟乙酸加到76mg(126μmol)实施例1化合物在2ml二氯甲烷中的溶液中,将混合物在20℃搅拌5小时。用10ml二氯甲烷稀释,用水(4×20ml)洗涤,再用饱和氯化钠溶液(1×20ml)洗涤,MgSO4干燥,真空下汽提掉溶剂。残留物在20g硅胶上进行闪式层析(50μ粒度,洗脱剂:甲苯/乙酸乙酯/三氟乙酸10∶40∶1),得到63mg(理论量的83%)标题化合物。Rf=0.66(二氯甲烷/甲醇10∶1)。
实施例3
外消旋-N-[4-[6-丁基-4-羧基-2-氧代-1,2-二氢吡啶-1-基]甲基-3-氯苯磺酰基]-(2-羧基)哌啶
将58mg(96μmol)实施例1化合物溶于0.5ml THF、0.5ml水和0.1ml CH3OH中。加入12mg(129μmol)LiOH,将该溶液在室温下搅拌2.5小时。浓缩溶液,用水和乙酸乙酯处理,用乙酸酸化至pH=3。分相,水相再用乙酸乙酯提取三次。合并有机相,用水(7×20ml)洗涤,再用饱和NaCl溶液(1×20ml)洗涤,用MgSO4干燥,浓缩。得到36mg(74%)标题化合物。Rf=0.16(二氯甲烷/甲醇10∶1)。
表1 所示的化合物按照与制备实施例1-3相似的步骤制备:
实施例15
外消旋-N-[4-[6-丁基-4-羧基-2-氧代-1,2-二氢吡啶-1-基]-4-甲基苯磺酰基]-(2-羧基)哌啶二钠
将120mg(0.25mmol)实施例11的化合物在5ml THF和2.5ml水中于室温下用0.25ml 1N氢氧化钠溶液处理1小时,浓缩反应液,在高真空中用P2O5干燥残留物。收率115mg(91%理论量)。Rf=0.286,。
表2 所示的化合物按照与实施例14相似的步骤用1摩尔当量的NaOH制备。
表2
Claims (10)
1、式(Ⅰ)的磺酰苄基取代的吡啶酮及其盐:
式中
R1代表最多有8个碳原子的直链或支链烷基,该烷基任意地被有3-6碳原子的环烷基、羟基或被最多有6个碳原子的直链或支链的烷氧基取代,或
代表有3-6个碳原子的环烷基,
R2、R3和R4可相同或不同,代表氢、氰基或最多有8个碳原子的直链或支链全氟烷基,或
代表最多有8个碳原子的直链或支链烷基,该烷基任意地被相同或不同的选自羟基、卤素、羧基和各最多有6个碳原子的直链或支链烷氧基或烷氧羰基的取代基或被苯基、苯氧基或被最多有三个杂原子的5-7元饱和或不饱和的杂环单取代或双取代,其中的各环系又可以被相同的或不同的选自三氟甲基、三氟甲氧基、卤素、硝基、氰基、羟基和羟甲基的取代基或被各最多有6个碳原子的直链或支链烷基或烷氧基单取代或二取代,或
代表各最多有8个碳原子的直链或支链酰基或烷氧羰基、苄氧羰基或羧基,或
代表苯基,该苯基任意地被相同的或不同的选自卤素、硝基、氰基、羟基、羟甲基、三氟甲基和三氟甲氧基的取代基或被各最多有6个碳原子的直链或支链烷基或烷氧基单取代至三取代,或
代表式-CO-NR6R7基团,其中
R6和R7相同或不同,代表氢、最多有8个碳原子的直链或支链烷基或各有6-10个碳原子的芳基或芳烷基,
R5代表氢、卤素或最多有8个碳原子的直链或支链烷基,或
代表最多有6个碳原子的直链或支链全氟烷基,或
代表式-OX基团,其中
X代表氢、苄基、羟基保护基,或
代表最多有8个碳原子的直链或支链烷基,
A代表3-8元饱和杂环,该杂环通过氮原子键接,另外最多含有2个选自S、N和O的杂原子,它任意地被相同或不同的选自最多有5个碳原子的全氟烷基和下列各式基团的取代基单取代或二取代:
式中
R8代表氢、最多有6个碳原子的直链或支链烷基或三苯甲基,
R9代表羟基、最多有8个碳原子的直链或支链烷氧基、苯氧基、苄氧基或式-NR12R13基团,其中
R12和R13相同或不同,代表氢或最多有6个碳原子的直链或支链烷基或苯基,
R10和R11相同或不同,代表氢、最多有8个碳原子的直链或支链烷基或苯基。
2、根据权利要求1的磺酰苄基取代的吡啶酮及其盐,其中
R1代表各最多有6个碳原子的直链或支链烷基,该烷基任意地被环丙基、环戊基、环己基、羟基或被最多有4个碳原子的直链或支链烷氧基取代,或
代表环丙基、环戊基或环己基,
R2、R3和R4可相同或不同,代表氢、氰基或最多有6个碳原子的直链或支链全氟烷基,或
代表最多有6个碳原子的直链或支链烷基,该烷基被羟基、氟、氯、溴、羧基和各最多有4个碳原子的直链或支链烷氧基或烷氧羰基或被苯基、苯氧基或噻吩基取代,其中的各环系又可以被三氟甲氧基、三氟甲基、羟甲基、氟、氯、溴或被各最多有6个碳原子的直链或支链烷基或烷氧基取代,或
代表各最多有6个碳原子的直链或支链酰基或烷氧羰基、苄氧羰基或羧基,或
代表任意地被相同或不同的选自氟、氯、溴、三氟甲基、三氟甲氧基和羟甲基的取代基或被各最多有4个碳原子的直链或支链烷基或烷氧基单取代或二取代的苯基,或
代表或-CONR6R7基团,其中
R6和R7相同或不同,代表氢、最多有6个碳原子的直链或支链烷基、苯基或苄基,
R5代表氢、氟、氯、溴或最多有6个碳原子的直链或支链烷基,或代表最多有4个碳原子的直链或支链全氟烷基,或
代表式-OX基团,其中
X代表氢、苄基或乙酰基,或
代表最多有6个碳原子的直链或支链烷基,
A代表经由氮原子键连的哌啶基、吡咯烷基或吗啉基,这些基团中的每一个都可任意地被三氟甲基或被下列各式基团取代,
式中
R8代表氢、最多有4个碳原子的直链或支链烷基或三苯甲基,
R9代表羟基、最多有6个碳原子的直链或支链烷氧基、苯氧基、苄氧基或式-NR12R13基团,其中
R12和R13相同或不同,代表氢或最多有4个碳原子的直链或支链烷基,及
R10和R11相同或不同,代表氢、最多有6个碳原子的直链或支链烷基或苯基。
3、根据权利要求1的磺酰苄基取代的吡啶酮及其盐,其中
R1代表最多有4个碳原子的直链或支链烷基,该烷基可任意地被环丙基取代,或
代表环丙基,
R2、R3和R4相同或不同,代表氢、氰基或最多有4个碳原子的直链或支链全氟烷基,或
代表最多有4个碳原子的直链或支链烷基,该烷基被羟基或各最多有3个碳原子的直链或支链烷氧基或烷氧羰基取代,或
代表各最多有4个碳原子的直链或支链酰基或烷氧羰基、苄氧羰基或羧基,或
代表式-CONR6R7基团,其中
R6和R7相同或不同,代表氢、最多有4个碳原子的直链或支链烷基、苯基或苄基,
R5代表氢、氟、氯、最多有4个碳原子的直链或支链烷基,或
代表最多有3个碳原子的直链或支链全氟烷基,或
代表式-OX基团,其中
X代表氢、苄基或乙酰基,或
代表最多有6个碳原子的直链或支链烷基,
A代表经由氮原子键连的哌啶基或吡咯烷基,这些基团中的每一个都可任意地被三氟甲基或被下列各式基团取代,
式中
R8代表氢、甲基、乙基或三苯甲基,
R9代表羟基、最多有4个碳原子的直链或支链烷氧基、苯氧基、苄氧基或式-NR12R13基团,其中
R12和R13相同或不同,代表氢或最多有3个碳原子的直链或支链烷基,及
R10和R11相同或不同,代表氢、最多有4个碳原子的直链或支链烷基或苯基。
4、用于治疗应用的权利要求1的磺酰苄基取代的吡啶酮。
6、根据权利要求5的方法,其特征在于,反应在-100℃-+100℃的温度范围内进行。
7、含有至少一种权利要求1的磺酰苄基取代的吡啶酮的药物。
8、用于治疗动脉高血压和动脉粥样硬化的权利要求7的药物。
9、权利要求1的磺酰苄基取代的吡啶酮在生产药物中的应用。
10、权利要求1的磺酰苄基取代的吡啶酮在生产用于治疗动脉高血压和动脉粥样硬化的药物中的应用。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DE4206045A DE4206045A1 (de) | 1992-02-27 | 1992-02-27 | Sulfonylbenzyl substituierte pyridone |
DEP4206045.1 | 1992-02-27 |
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CN1078468A true CN1078468A (zh) | 1993-11-17 |
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CN 93102232 Pending CN1078468A (zh) | 1992-02-27 | 1993-02-27 | 磺酰苄基取代的吡啶酮 |
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US (1) | US5254543A (zh) |
EP (1) | EP0557843A3 (zh) |
JP (1) | JPH0641081A (zh) |
KR (1) | KR930017898A (zh) |
CN (1) | CN1078468A (zh) |
AU (1) | AU653288B2 (zh) |
CA (1) | CA2090267A1 (zh) |
CZ (1) | CZ15793A3 (zh) |
DE (1) | DE4206045A1 (zh) |
HU (1) | HUT64057A (zh) |
IL (1) | IL104843A0 (zh) |
MX (1) | MX9300766A (zh) |
MY (1) | MY129973A (zh) |
NZ (1) | NZ245999A (zh) |
PL (1) | PL297870A1 (zh) |
SK (1) | SK14593A3 (zh) |
TW (1) | TW230206B (zh) |
ZA (1) | ZA931370B (zh) |
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DE4215587A1 (de) * | 1992-05-12 | 1993-11-18 | Bayer Ag | Sulfonylbenzyl-substituierte Benzo- und Pyridopyridone |
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GB0316546D0 (en) * | 2003-07-15 | 2003-08-20 | Novartis Ag | Process for the manufacture of organic compounds |
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GB0514686D0 (en) * | 2005-07-18 | 2005-08-24 | Novartis Ag | Organic compounds |
TWI417095B (zh) * | 2006-03-15 | 2013-12-01 | Janssen Pharmaceuticals Inc | 1,4-二取代之3-氰基-吡啶酮衍生物及其作為mGluR2-受體之正向異位性調節劑之用途 |
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SI2203439T1 (sl) | 2007-09-14 | 2011-05-31 | Ortho Mcneil Janssen Pharm | 1',3'-disubstituirani 4-fenil-3,4,5,6-tetrahidro-2H-1'H-(1,4')bipiridinil-2'-oni |
KR20100065191A (ko) | 2007-09-14 | 2010-06-15 | 오르토-맥닐-얀센 파마슈티칼스 인코포레이티드 | 1,3-이치환된 4-(아릴-x-페닐)-1h-피리딘-2-온 |
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US8785486B2 (en) * | 2007-11-14 | 2014-07-22 | Janssen Pharmaceuticals, Inc. | Imidazo[1,2-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors |
RU2510396C2 (ru) | 2008-09-02 | 2014-03-27 | Янссен Фармасьютикалз, Инк. | 3-азабицикло[3.1.0]гексильные производные в качестве модуляторов метаботропных глутаматных рецепторов |
ES2466341T3 (es) | 2008-10-16 | 2014-06-10 | Janssen Pharmaceuticals, Inc. | Derivados de indol y benzomorfolina como moduladores de receptores de glutamato metabotrópicos |
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WO2010072599A1 (en) | 2008-12-23 | 2010-07-01 | F. Hoffmann-La Roche Ag | Dihydropyridone ureas as p2x7 modulators |
MX2011006843A (es) | 2008-12-23 | 2011-08-04 | Hoffmann La Roche | Dihidropiridona-amidas como moduladores de p2x7. |
SG172336A1 (en) | 2008-12-23 | 2011-07-28 | Hoffmann La Roche | Dihydropyridone amides as p2x7 modulators |
KR101370130B1 (ko) | 2008-12-23 | 2014-03-05 | 에프. 호프만-라 로슈 아게 | P2x7 조절제로서의 디히드로피리돈 아미드 |
US8153808B2 (en) | 2008-12-23 | 2012-04-10 | Roche Palo Alto Llc | Dihydropyridone amides as P2X7 modulators |
CA2760741C (en) | 2009-05-12 | 2018-05-01 | Addex Pharma S.A. | 1,2,4-triazolo [4,3-a] pyridine derivatives and their use for the treatment or prevention of neurological and psychiatric disorders |
EA020671B1 (ru) | 2009-05-12 | 2014-12-30 | Янссен Фармасьютикалз, Инк. | ПРОИЗВОДНЫЕ 1,2,4-ТРИАЗОЛО[4,3-a]ПИРИДИНА И ИХ ПРИМЕНЕНИЕ В КАЧЕСТВЕ ПОЛОЖИТЕЛЬНЫХ АЛЛОСТЕРИЧЕСКИХ МОДУЛЯТОРОВ РЕЦЕПТОРОВ mGluR2 |
MY153913A (en) | 2009-05-12 | 2015-04-15 | Janssen Pharmaceuticals Inc | 7-aryl-1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors |
JP5852666B2 (ja) | 2010-11-08 | 2016-02-03 | ジヤンセン・フアーマシユーチカルズ・インコーポレーテツド | 1,2,4−トリアゾロ[4,3−a]ピリジン誘導体およびmGluR2受容体のポジティブアロステリックモジュレーターとしてのそれらの使用 |
PT2649069E (pt) | 2010-11-08 | 2015-11-20 | Janssen Pharmaceuticals Inc | Derivados de 1,2,4-triazolo[4,3-a]piridina e sua utilização como moduladores alostéricos positivos de recetores mglur2 |
CA2814998C (en) | 2010-11-08 | 2019-10-29 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors |
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DE3406329A1 (de) * | 1984-02-22 | 1985-08-22 | Merck Patent Gmbh, 6100 Darmstadt | Pyridone |
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CA2018443A1 (en) * | 1989-06-14 | 1990-12-14 | Joseph A. Finkelstein | Imidazolyl-alkenoic acids |
DE69034103T2 (de) * | 1989-06-14 | 2004-07-15 | Smithkline Beecham Corp. | Imidazoalkensäure |
SG50669A1 (en) * | 1989-06-30 | 1998-07-20 | Du Pont | Fused-ring aryl subtituted imidazoles |
CA2027937A1 (en) * | 1989-10-25 | 1991-04-26 | Richard M. Keenan | Substituted 5-¬ (tetrazolyl)alkenyl|imidazoles |
NZ238624A (en) * | 1990-06-19 | 1994-08-26 | Meiji Seika Co | Pyridine derivatives, compositions, preparations and use thereof |
-
1992
- 1992-02-27 DE DE4206045A patent/DE4206045A1/de not_active Withdrawn
-
1993
- 1993-02-06 TW TW082100802A patent/TW230206B/zh active
- 1993-02-09 CZ CZ93157A patent/CZ15793A3/cs unknown
- 1993-02-12 MX MX9300766A patent/MX9300766A/es unknown
- 1993-02-15 EP EP19930102326 patent/EP0557843A3/de not_active Withdrawn
- 1993-02-18 US US08/019,000 patent/US5254543A/en not_active Expired - Fee Related
- 1993-02-24 AU AU33770/93A patent/AU653288B2/en not_active Ceased
- 1993-02-24 IL IL104843A patent/IL104843A0/xx unknown
- 1993-02-24 CA CA002090267A patent/CA2090267A1/en not_active Abandoned
- 1993-02-25 NZ NZ245999A patent/NZ245999A/en unknown
- 1993-02-25 JP JP5061017A patent/JPH0641081A/ja active Pending
- 1993-02-25 PL PL29787093A patent/PL297870A1/xx unknown
- 1993-02-26 KR KR1019930002728A patent/KR930017898A/ko not_active Application Discontinuation
- 1993-02-26 HU HU9300545A patent/HUT64057A/hu unknown
- 1993-02-26 MY MYPI93000350A patent/MY129973A/en unknown
- 1993-02-26 SK SK14593A patent/SK14593A3/sk unknown
- 1993-02-26 ZA ZA931370A patent/ZA931370B/xx unknown
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1985878B (zh) * | 2005-12-20 | 2011-06-22 | 广州王老吉药业股份有限公司 | 一种治疗消化性溃疡的药物组合物及其制备方法 |
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Publication number | Publication date |
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CZ15793A3 (en) | 1993-12-15 |
AU653288B2 (en) | 1994-09-22 |
ZA931370B (en) | 1993-03-23 |
US5254543A (en) | 1993-10-19 |
JPH0641081A (ja) | 1994-02-15 |
NZ245999A (en) | 1995-10-26 |
MX9300766A (es) | 1993-08-01 |
MY129973A (en) | 2007-05-31 |
IL104843A0 (en) | 1993-06-10 |
HUT64057A (en) | 1993-11-29 |
EP0557843A2 (de) | 1993-09-01 |
EP0557843A3 (en) | 1993-12-01 |
DE4206045A1 (de) | 1993-09-02 |
PL297870A1 (en) | 1993-10-04 |
AU3377093A (en) | 1993-09-02 |
HU9300545D0 (en) | 1993-05-28 |
TW230206B (zh) | 1994-09-11 |
CA2090267A1 (en) | 1993-08-28 |
KR930017898A (ko) | 1993-09-20 |
SK14593A3 (en) | 1993-10-06 |
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