CN1077711A - 环烷基和杂环基取代的咪唑基丙烯酸衍生物 - Google Patents
环烷基和杂环基取代的咪唑基丙烯酸衍生物 Download PDFInfo
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- CN1077711A CN1077711A CN93103421A CN93103421A CN1077711A CN 1077711 A CN1077711 A CN 1077711A CN 93103421 A CN93103421 A CN 93103421A CN 93103421 A CN93103421 A CN 93103421A CN 1077711 A CN1077711 A CN 1077711A
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- 125000000753 cycloalkyl group Chemical group 0.000 title claims abstract description 21
- ZLSNPZVGNMESDB-UHFFFAOYSA-N 2-(1h-imidazol-2-yl)prop-2-enoic acid Chemical class OC(=O)C(=C)C1=NC=CN1 ZLSNPZVGNMESDB-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 87
- -1 imidazolyl aldehyde Chemical class 0.000 claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
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- 206010020772 Hypertension Diseases 0.000 claims abstract description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 38
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
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- 238000002360 preparation method Methods 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 13
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- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
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- 239000002585 base Substances 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- IMLSAISZLJGWPP-UHFFFAOYSA-N 1,3-dithiolane Chemical compound C1CSCS1 IMLSAISZLJGWPP-UHFFFAOYSA-N 0.000 claims description 4
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- 239000012442 inert solvent Substances 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
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- 125000005842 heteroatom Chemical group 0.000 claims description 3
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- 125000001424 substituent group Chemical group 0.000 claims description 2
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
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Abstract
环烷基和杂环基取代的咪唑基丙烯酸衍生物可
以通过咪唑基醛与相应的羧酸衍生物反应,然后脱氢
来制备。这类化合物可用作药物、特别是用于治疗高
血压和动脉硬化药物的活性化合物。
Description
本发明涉及环烷基和杂环基取代的咪唑基丙烯酸衍生物,其制备方法及其在药物中的用途,特别是用作抗高血压剂和抗动脉粥样硬化剂。
已知血管紧张肽原酶即一种蛋白水解酶在体内由血管紧张肽原切下十肽血管紧张肽Ⅰ,而后该十肽本身在肺、肾或其他组织中降解为抗高血压的八肽血管紧张肽Ⅱ。就升高血压而言,血管紧张肽Ⅱ的各种效应,例如,血管收缩、肾中Na+潴留、肾上腺中醛甾酮的分泌及交感神经系统的紧张性增强具有协同效应。
此外,血管紧张肽Ⅱ具有促进细胞生长和繁殖的性质,例如,心肌细胞和平滑肌细胞,这些细胞在各种疾病(如高血压、动脉粥样硬化和心机能不全)中的生长与繁殖速度加快。
介入血管紧张肽原酶-血管紧张肽体系(RAS)的可能的方法除了抑制血管紧张原酶活性外,还有抑制血管紧张肽转化酶(ACE)活性及阻断血管紧张肽Ⅱ受体。
对血管紧张肽Ⅱ受体具有阻断作用的咪唑基衍生物公开在EP403,159A2和EP 425,211A1公开文本中。
本发明涉及通式(Ⅰ)的环烷基和杂环基取代的咪唑基丙烯酸衍生物及其盐
其中
R1代表各自具有至多8个碳原子的直链或支链烷基或链烯基,它们是未取代的或被具有3至6个碳原子的环烷基取代,或者代表具有3至8个碳原子的环烷基,
R2代表氢、卤素、羟基、硝基、氰基、三氟甲基、三氟甲氧基或五氟乙基,或代表具有至多6个碳原子的直链或支链烷基,或代表具有6至10个碳原子的芳基,
R3代表具有3至8个碳原子的环烷基、或具有3至8个碳原子和至多3个杂原子的杂环基,这些杂原子为S、O或N-A,其中,
A代表氢或具有至多6个碳原子的直链或支链烷基,
n代表整数0、1、2、3或4,
R4代表氢、具有至多8个碳原子的直链或支链烷基,或代表苯基,
R5代表下式基团:
其中
R6代表氢、卤素、氰基、硝基、三氟甲基、羟基、三氟甲氧基、各自具有至多6个碳原子的直链或支链烷基,
R7代表羧基、或具有至多6个碳原子的直链或支链烷氧羰基、或被C1-C4烷基化的四唑基。
本发明化合物也可以以其盐的形式存在。通常,本文所说的是与有机或无机碱或酸形成的盐。
在本发明范围内,优选生理学上无害的盐。环烷基和杂环烷基取代的咪唑基丙烯酸衍生物的生理上无害的盐可以是本发明化合物与无机酸、羧酸或磺酸的盐。特别优选例如与下列酸的盐;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、酒石酸、柠檬酸、富马酸、马来酸或苯甲酸。
生理上无害的盐还可以是带有游离羧基的本发明化合物的金属盐或铵盐。特别优选例如钠盐、钾盐、镁盐或钙盐、及由氨或有机胺衍生的铵盐,所述有机胺如乙胺、二或三乙胺、二或三乙醇胺、二环己胺、二甲氨基乙醇、精氨酸、赖氨酸或乙二酸。
本发明化合物可以立体异构形式存在,它们之间的关系或者是互为镜像(对映体)或者不互为镜像(非对映体)。本发明涉及对映体及非对映体或其各自的混合物。外消旋形式正象非对映体一样可以按照已知方法拆分为立体异构的单一组分[参见E.L.Eliel,Stereochemistry of Carbon Compounds,McGraw Hi ll,1962]。
通常,杂环烷基代表具有至多2个杂原子的5至6员环,杂原子选自N、S、O或NH基或N-C1-C6-烷基,例如,二硫戊环基、吡喃基或哌啶基。优选二硫戊环基或吡喃基。
优选的通式(Ⅰ)化合物及其盐是,
其中:
R1代表各自具有至多6个碳原子的直链或支链烷基或链烯基,它们是未取代的或被环丙基、环丁基、环戊基或环己基取代,或代表环丙基、环戊基或环己基,
R2代表氢、氟、氯、溴、碘、三氟甲基、三氟甲氧基、五氟乙基或具有至多6个碳原子的直链或支链烷基,
R3代表环丙基、环戊基、环己基、环庚基、二硫戊环基或吡喃基,
n代表整数0、1、2或3,
R4代表氢或具有至多6个碳原子的直链或支链烷基,
R5代表下式的基团:
其中,
R6代表氢、氟、氯、溴、三氟甲基、三氟甲氧基或具有至多4个碳原子的直链或支链烷基,
R7代表羧基、具有至多3个碳原子的直链或支链烷氧羰基,或代表四唑基。
特别优选的通式(Ⅰ)化合物及其盐是,
其中:
R1代表各自具有至多4个碳原子的直链或支链烷基或链烯基,或代表环丙基,
R2代表氢、氟、氯、溴、碘、三氟甲基、五氟乙基、三氟甲氧基或具有至多4个碳原子的直链或支链烷基,
R3代表环丙基、环戊基或环己基,
n代表整数0、1、或2,
R4代表氢或具有至多4个碳原子的直链或支链烷基,
R5代表下式的基团:
其中,
R6代表氢、氟、氯或溴,
R7代表羧基、具有至多3个碳原子的直链或支链烷氧羰基,或代表四唑基,
此外,已经发现制备本发明通式(Ⅰ)化合物的方法,该方法的特征在于,
在惰性溶剂中在碱存在下,使通式(Ⅱ)的醛与通式(Ⅲ)化合物反应,先将其转化为通式(Ⅳ)化合物,
(其中,R1、R2和R5具有上述定义)
(其中,R3和n具有上述定义,T代表具有至多8个碳原子的直链或支链烷基,或代表苯基),
(其中,R1、R2、R3、n和T具有上述定义),
然后,通过引入保护基团将游离羟基保护起来,在最后一步,在惰性溶剂中在碱存在下进行消除反应,
在酸的情况下(R4/R7=H),将酯水解,
如果需要,通过常规方法例如氢化或烷基化,将取代基R1和R2转化,
在R7代表烷基化的四唑基的情况下,将基团-NH烷基化。
本发明的方法可以通过下列反应式来举例说明:
在上述定义范围内,羟基保护基通常代表下列保护基:苄氧羰基、甲磺酰基、甲苯磺酰基、2-硝基苄基、4-硝基苄基、2-硝基苄氧羰基、4-硝基苄氧羰基、叔丁氧羰基、烯丙氧羰基、4-甲氧羰基、乙酰基、三氟乙酰基、2,2,2-三氟乙氧羰基、2,4-二甲氧基苄氧羰基、2-(甲硫甲氧基)乙氧羰基、苯甲酰基、4-甲基苯甲酰基、4-硝基苯甲酰基、4-氟苯甲酰基、4-氯苯甲酰基或4-甲氧基苯甲酰基。优选乙酰基、甲磺酰基和甲苯磺酰基。
对该方法适宜的溶剂是在该反应条件下保持不变的常用的有机溶剂。优选包括醚,如乙醚、二恶烷、四氢呋喃、二甘醇二甲醚,或烃,如苯、甲苯、二甲苯、己烷、环己烷或石油馏份,或卤代烃,如二氯甲烷、三氟甲烷、四氯化碳、二氯乙烯、三氯乙烯或氯苯,或乙酸乙酯、三乙胺、吡啶、二甲亚砜、二甲基甲酰胺、六甲基磷三酰胺、乙腈、丙酮或硝基甲烷。也可以使用上述溶剂的混合物。对于各步骤优选四氢呋喃、二氯甲烷和甲苯。
可用于本发明方法的碱通常为无机或有机碱。优选包括碱金属氢氧化物,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,如碳酸钠或碳酸钾,碱土金属碳酸盐,如碳酸钙,或碱金属醇盐或碱土金属醇盐,如甲醇钠或甲醇钾,乙醇钠或乙醇钾或叔丁醇钾,或有机胺(三烷基(C1-C6)胺),如三乙胺,或杂环化合物,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。所用的碱还可以是碱金属,如钠或其氢化物,如氢化钠。优选二异丙基氨基锂和DBU。
通常,相对于1mol式(Ⅲ)化合物碱的用量为0.05mol至10mol,优选1mol至2mol。
本发明方法通常在-100℃至+100℃,优选-78℃的温度下进行。
本发明方法通常在大气压下进行。然而,也可以在高于大气压或在减压下(例如在0.5至5bar)进行该方法。
通常是在一种上述溶剂和碱中,优选在含有二甲氨基吡啶的二氯甲烷中引入保护基。
引入保护基反应一般在0℃至+60℃的温度范围内,优选在室温大气压下进行。
消除反应通常在一种上述溶剂,优选甲苯中,在一种上述碱,优选DBU的存在下进行。
消除反应一般在+30℃至+130℃,优选+50℃至+100℃的温度下及大气压下进行。
合适的碱为常用于水解反应的无机碱。优选包括碱金属氢氧化物或碱土金属氢氧化物,如氢氧化钠、氢氧化钾或氢氧化钡,或碱金属碳酸盐,如碳酸钠或碳酸钾或碳酸氢钠,或碱金属醇盐,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或氢氧化钾。
水解反应的适宜溶剂是水或常用于水解反应的有机溶剂。优选包括醇,如甲醇、乙醇、丙醇、异丙醇或丁醇、或醚、如四氢呋喃或二恶烷,或二甲基甲酰胺,或二甲亚砜。特别优选使用醇,如甲醇、乙醇、丙醇或异丙醇。还可以使用上述溶剂的混合物。
水解反应还可以用酸进行,如三氟乙酸、乙酸、盐酸、氢溴酸、甲磺酸、磺酸或高氯酸,优选用三氟乙酸。
水解反应一般在0℃至+100℃,优选+20℃至+80℃的温度下进行。
通常,水解反应在大气压下进行。然而,也可以在减压或在高于大气压下(例如0.5至5bar)进行。
当进行水解时,碱的用量一般为1mol酯1至3mol,优选1至1.5mol,特别优选使用反应物的等摩尔量。
当进行反应时,在第一步生成本发明化合物的羧酸盐中间体,可将其分离。用常用的无机酸处理该羧酸盐,得到本发明的酸。所用无机酸优选包括矿物酸,如盐酸、氢溴酸、硫酸或磷酸。当制备羧酸时,已证实最好是在第二步不分离羧酸盐而将碱性水解反应混合物酸化。然后按常规方法分离出酸。在有碱性杂环的情况下,用上述酸处理羧酸盐溶液可以得到无机酸与杂环的盐。
烷基化反应通常用烷基化剂进行,如(C1-C6)烷基卤化物,硫酸酯或取代或未取代的(C1-C6)二烷基或(C1-C6)二芳基磺酸酯,优选碘甲烷或硫酸二甲酯。
烷基化反应通常在一种上述溶剂中,优选在二甲基甲酰胺中,在0℃至+70℃,优选在0℃至+30℃的温度下,在大气压下进行。
氢化反应通常在一种上述溶剂中,优选在甲醇中,在乙酸钠存在下,用氢气和Pd/C按常规方法进行。
通常,氢化反应在升压下(约2至3bar)进行。但也可以在减压或在大气压下进行。
氢化反应一般在0℃至+40℃的温度范围内,优选在室温下进行。
通式(Ⅱ)化合物部分为已知的(R5=苯基,参见EP425,211),或者可以通过通式(Ⅴ)化合物与通式(Ⅵ)化合物反应来制备,
(其中,R1和R2具有上述定义),
(其中,R5具有上述定义,M代表卤素,优选溴),
该反应在一种上述溶剂,优选二甲基甲酰胺中,在一种上述碱,优选碳酸钾或叔丁醇钾的存在下进行。
通式(Ⅴ)和(Ⅵ)化合物是已知的。
通式(Ⅲ)化合物是已知的,或者可以按照常规方法将可买到的酸酯化来制备[参见,如MSD Book 2,1593D]。
通式(Ⅳ)化合物作为这类化合物特定的代表是新的,它们可以通过如上述方法来制备。
上面给出的制备方法只是用于说明。本发明的通式(Ⅰ)化合物的制备并不限于这些方法,这些方法的任何变化都可同样地用于该制备。
环烷基和杂环基取代的咪唑基丙烯酸衍生物具有意想不到的有用的药理作用谱。
本发明化合物具有特异性AⅡ拮抗作用,因为它们竞争性地抑制血管紧张肽Ⅱ与受体的结合。它们抑制了血管紧张肽Ⅱ的血管收缩使用和醛甾酮分泌刺激作用。此外,它们还抑制平滑肌细胞的繁殖。
因此,本发明化合物可用于药物中以治疗动脉高血压和动脉硬化。此外,它们还可用于治疗冠心病、心机能不全、大脑功能紊乱、大脑局部缺血疾病、外周循环紊乱、肾和肾上腺机能障碍、呼吸道的支气管痉挛及血管疾病、钠潴留及浮肿。制兴奋剂诱导的收缩试验
将两种性别的家兔在颈背击昏并放血,或者在某些情况下用戊巴比妥(约60-80mg/kg,静脉注射)麻醉,并开胸将其处死。取出胸主动脉,去掉粘连的结缔组织,将其分割成1.5毫米宽的环形小段,并在约3.5g的起始负载下将其分别转移到10ml器官浴中,该器管浴含有Krebs-Henseleit营养液,该营养液的温度控制在37℃,并充有5%二氧化碳-95%氧气,其组成如下: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。
通过桥式放大器(ifd Miilheim或DSM Aalen)借助Statham UC2传感器等长测定收缩,通过模拟/数字转换器(System 570,Keithley Munich)使其数字化并进行评价。以小时记录兴奋剂剂量应答曲线(DRC)。对每个DRC以4分钟间隔对器官浴施用3或4个不同的浓度。在DRC结束和随后的洗涤循环(在每种情况下以约5秒/分用上述营养液洗涤16次)之后是28分钟的静止或保温阶段,此过程中收缩通常恢复到初始值。
在通常情况下,用第3条DRC的最大值作为在进一步的操作循环中评价待试验化合物的参照值,在后面的每个DRC中在保温时间开始时,向器官浴中加入剂量递增的试验化合物。每个主动脉环全天用同样的兴奋剂刺激。
兴奋剂及其标准浓度(每单剂量的使用体积=100μl):
KCI 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;3×10-6;g/ml
5-羟色胺 10-8;10-7;10-6;10-5; g/ml
B-HT 920 10-7;10-6;10-5; g/ml
甲氧胺 10-7;10-6;10-5; g/ml
血管紧张肽Ⅱ 3×10-9;3×10-8;3×10-8;3×10-7; g/ml
为计算IC50(试验化合物引起50%抑制率的浓度),在每种情况下以第3个兴奋剂浓度(即次最大浓度)下测定的效率作为基准。
本发明化合物对血管紧张肽Ⅱ诱导的离体家兔主动脉收缩的抑制率是剂量的函数。由钾去极化或其他兴奋剂诱导的收缩并未被抑制,或只在使用浓度高时略有抑制。
对输注血管紧张肽Ⅱ的大鼠血压的测定
将体重300-350g的雄性Wistar大鼠(Moellegard,Copenhagen,Denmark)用戊硫巴比胺钠(100mg/kg,腹膜注射)麻醉。进行气管造口术之后,将导管插入股动脉以测量血压,将输注血管紧张肽Ⅱ的导管和施加化合物的导管插入股静脉。在施用神经节阻断剂安血定(5mg/kg,静脉注射)之后,开始输注血管紧张肽Ⅱ(0.3μg/kg/分)。血压值达到稳定水平后立即施用试验化合物,或者静脉内给药,或者以在0.5% Tylose中的悬浮液或溶液形式口服给药。在化合物作用下血压的变化列于表中,以平均值上标准偏差表示。
在清醒高血压大鼠中抗高血压效率的测定
用由手术诱发了单侧肾动脉狭窄的清醒大鼠来试验本发明化合物的口服抗高血压效率。为此目的,用内径为0.18mm的银钳将右肾动脉缩紧。在这种类型的高血压中,手术后前六星期内血浆血管紧张肽原酶活性增加。用“尾套”施用化合物后,在指定的间隔内对这些动物的动脉血压进行无血测量。通过胃管以各种剂量胃内(口服)施用悬浮于Tylose悬浮液中的化合物。在临床上适用的剂量下,本发明化合物降低了高血压大鼠的动脉血压。
此外,本发明化合物对放射性血管紧张肽Ⅱ特异性结合的抑制率取决于浓度。
本发明化合物与牛肾上腺皮质的膜部分上血管紧张肽Ⅱ受体的相互作用
借助于Ultra-Turrax(Janke & Kunkel,Staufen i.B.)将新摘出的仔细去掉了髓质和被膜的牛肾上腺皮质(AC)在蔗糖溶液(0.32M)中捣碎,得到粗膜匀浆液,以两次离心步骤将其部分纯化,得到膜部分。用放射性血管紧张肽Ⅱ在0.25ml的试验溶液中对部分纯化的牛AC膜部分进行受体结合试验,试验溶液含有部分纯化的膜(50-80μg)、H3-血管紧张肽Ⅱ(3-5nM)、试验缓冲液(50mM Tris,pH7.2,5mM MgCl2,0.25% BSA)以及试验化合物。在室温保温60分钟后,通过润湿的玻璃纤维滤膜(Whatman GF/C)分离未结合放射性的样品,将蛋白用冰冷的缓冲液(50mM Tris/HCl,pH7.4,5% PEG 6000)洗涤后,通过分光光度法在闪烁液中测定结合的放射性。用计算机程序对原始数据进行分析得到Ki和IC50值(Ki:对所用放射性校正后的IC50值;IC50值:试验化合物对放射配体的总结合产生50%抑制率时的浓度)。
本发明化合物抑制平滑肌细胞繁殖的试验
为测定化合物的抗繁殖作用,使用通过介质移出技术[R.Ross,J.Cell.Biol.50,172,1971]由大鼠主动脉得到的平滑肌细胞。对细胞接种在适当的培养皿(一般为96孔板)中,在培养基199中在5%CO2中于37℃培养2-3天,该培养基含有7.5% FCS和7.5% NCS,2mM L-谷氨酰胺和15mM HEPES,pH7.4。然后通过血清缺乏使细胞同步化2-3天,再用血清或其他因子刺激其生长。同时加入试验化合物。16-20小时后加入1μCi3H-胸苷。再过4小时后测定该物质结合到细胞中可用TCA沉淀的DNA的量。
为了测定由加入10% FCS引起的胸苷结合量的半数最大抑制率(IC50),对化合物依次稀释到10-6M至10-9M。
可以按照已知方法,用惰性无毒的适于药用的载体或溶剂,将新的活性化合物转化为常用的制剂,如片剂、糖衣片剂、丸剂、粒剂、气雾剂、糖浆剂、乳剂、悬浮液和溶液。其中,每一制剂中治疗活性化合物的浓度是混合物总重量的约0.5%至90%,即足以达到指定剂量范围的量。
这些制剂是通过例如用固体和/或载体使活性化合物分散来制备的,如果需要,可以使用乳化剂和/或分散剂,例如在用水作稀释剂时可以使用有机溶剂作加溶剂。
按常规方法给药,优选口服或肠胃外给药,特别是经舌给药或静脉内给药。
在肠胃外给药的情况下,可以使用活性化合物在适当液体赋形剂中的溶液。
通常,已证实在静脉内给药的情况下,为达到有效的结果,最好以每千克体重约0.001至1mg,优选约0.01至0.5mg的剂量给药,而在口服给药的情况下,剂量为每千克体重约0.01至20mg,优选0.1至10mg。
然而,在某些情况下可能必需偏离上述剂量,即剂量要随着体重或施药方法、对药物的个体反应、制剂的类型以及给药时间或间隔而变化。因此,在某些情况下,用低于上述最小剂量的剂量可能就足够了,而在另一些情况下,必须超过上述剂量的上限。在使用较大剂量的情况下,可以将其分成一天之内的几个单剂量。
起始化合物
实施例Ⅰ
4-溴甲基苯甲酸甲酯
将45g(0.3mol)对甲基苯甲酸甲酯和53.4g(0.3mol)N-溴丁二酰亚胺与1.97g偶氮二异丁腈在375ml四氯化碳中加热至沸腾1小时,然后将混合物冷却至0℃,滤掉琥珀酰亚胺。残余物经硅胶(60柱)色谱纯化,用乙酸乙酯/石油醚(1∶10)洗脱。
产量:55.7g(为理论量的81%)
Rf=0.58(乙酸乙酯/石油醚=1∶10)
实施例Ⅱ
4-溴甲基-3-氯苯甲酸甲酯
用与实施例Ⅰ类似的方法,由9.0g(48.8mmol)3-氯-4-甲基苯甲酸甲酯制备标题化合物。
产量:7.3g(为理论产量的57%)
Rf=0.62(乙酸乙酯/石油醚=1∶5)
实施例Ⅲ
5-溴甲基噻吩-2-羧酸甲酯
用类似于实施例Ⅰ的方法,由20g(0.13mol)5-甲基噻吩-2-羧酸甲酯制备标题化合物。
产量:22g(为理论产量的73%)
Rf=0.43(二氯甲烷/甲醇=10∶1)
实施例Ⅳ
4-[(2-正丁基-4-氯-5-甲酰基咪唑-1-基)甲基]苯甲酸甲酯
在惰性气体气氛下于DMF中,将20g(0.107mol)2-正丁基-4-氯-5-甲酰基咪唑(按EP324,377的方法制备)与13g(0.107mol)叔丁醇钾在25℃搅拌30分钟,然后滴加在DMF中的36g(0.157mol)实施例Ⅰ化合物,将混合物在25℃搅拌20小时。浓缩后,粗产物经硅胶(60)柱色谱纯化,用乙酸乙酯/石油醚(1∶2)洗脱。
产量:25.5g(为理论量的69%)
Rf=0.7(乙酸乙酯/石油醚=1∶2)
实施例Ⅴ
4-[(2-正丁基-4-氯-5-甲酰基咪唑-1-基)甲基]-3-氯苯甲酸甲酯
用类似于实施例Ⅳ的方法,由3.16g(12mmol)实施例Ⅱ化合物制备标题化合物。
产量:2.3g(为理论量的78%)
Rf=0.38(乙酸乙酯/石油醚=1∶5)
实施例Ⅵ
5-[(2-正丁基-4-氯-5-甲酰基咪唑-1-基)甲基]噻吩-2-羧酸甲酯
将14.4g(77mmol)2-正丁基-4-氯-5-甲酰基咪唑、20g(85mmol)实施例Ⅲ化合物及21.3g(154mmol)碳酸钾在300ml DMF中于25℃下搅拌20小时。浓缩后,将残余物溶于300ml二氯甲烷和250ml水中,分出有机层,经硫酸钠干燥并浓缩。所得产物通过硅胶(60)柱色谱纯化,用乙酸乙酯/石油醚(1∶3)洗脱。产量:14.9g(为理论量的57%)
Rf=0.54(乙酸乙酯/石油醚=1∶3)。
实施例Ⅶ
4-[(2-正丁基-5-甲酰基咪唑-1-基)甲基]苯甲酸甲酯
在2g 5%披钯活性炭和8.6g(63mmol)乙酸钠三水合物的存在下,将在300ml甲醇中的20g(63mmol)实施例Ⅳ化合物在25℃及约3bar氢气压下氢化3小时。然后将溶液过滤除去催化剂并浓缩,残余物通过硅胶色谱纯化,用乙酸乙酯/石油醚(3∶1)洗脱。
产量:13.4g(为理论量的75%)
Rf=0.48(乙酸乙酯/石油醚=3∶1)
实施例Ⅷ
4-[(2-正丁基-5-甲酰基咪唑-1-基)甲基]-3-氯苯甲酸甲酯
用类似于实施例Ⅶ的方法,由3.1g(8.4mmol)实施例Ⅱ的化合物制备标题化合物。
产量:2g(为理论量的71%)
Rf=0.54(乙酸乙酯/石油醚=5∶1)
实施例Ⅸ
5-[(2-正丁基-4-氯-5-甲酰基咪唑-1-基)甲基]呋喃-2-羧酸乙酯
用类似于实施例Ⅵ的方法,由18.7g(0.1mmol)2-正丁基-4-氯-5-甲酰基咪唑和24.1g(0.103mol)5-溴甲基呋喃-2-羧酸乙酯制备标题化合物。
产量:22.8g(为理论量的65%)
Rf=0.38(乙酸乙酯/石油醚=1∶2)
实施例Ⅹ
5-[(2-正丁基-5-甲酰基咪唑-1-基)甲基]呋喃-2-羧酸乙酯
用类似于实施例Ⅶ的方法,由14.51g(42mmol)实施例Ⅸ的化合物制备标题化合物。
产量:7.31g(为理论量的57%)
Rf=0.39(乙酸乙酯/石油醚=1∶1)
实施例Ⅺ
5-[(2-正丁基-5-甲酰基咪唑-1-基)甲基]噻吩-2-羧酸乙酯
用类似于实施例Ⅶ的方法,由6.5g(19.1mmol)实施例Ⅵ的化合物制备标题化合物。
产量:4g(为理论量的68%)
RF=0.21(乙酸乙酯/石油醚=1∶1)
实施例Ⅻ
3-[(2-正丁基-1-{(2-乙氧羰基呋喃-5-基)甲基}-1H-咪唑-5-基]-2-环戊基甲基-3-羟基-丙酸甲酯
在-78℃惰性气体气氛下,将5.16ml(8.25mmol)1.6N正丁基锂的正己烷溶液加到0.89g(8.75mmol)N,N-二异丙基胺的10ml THF溶液中。然后,将反应溶液温热至0℃很短的一段时间,再将其冷却到-78℃,加入1.17g(7.5mmol)的3-环戊基丙酸甲酯的5ml THF溶液。混合在-78℃搅拌30分钟,加入1.52g(5mmol)实施例Ⅹ化合物的15ml THF溶液,并在-78℃继续搅拌45分钟。然后将混合物慢慢温热至25℃,加入20ml饱和氯化铵溶液,混合物用乙酸乙酯(3×50ml)萃取。有机层经硫酸钠干燥,浓缩,残余物通过硅胶柱色谱纯化,用乙酸乙酯/石油醚(2∶1)洗脱。
产量:1.1g(为理论量的48%)
Rf=0.09(乙酸乙酯/石油醚=2∶1,非对映体混合物)。
实施例ⅩⅢ
3-[2-正丁基-{(4-甲氧羰基苯基)甲基}-1H-咪唑-5-基]-2-环戊基甲基-3-羟基丙酸甲酯
用类似于实施例Ⅻ的方法,由885mg(8.75mmol)实施例Ⅶ的化合物制备标题化合物,并且不经纯化使其进一步反应。
Rf=0.17(乙酸乙酯/石油醚=4∶1,非对映体混合物)。
实施例ⅩⅣ
3-[2-正丁基-1-{(2-甲氧羰基噻吩-5-基)甲基}-1H-咪唑-5-基]-2-环戊基甲基-3-羟基丙酸甲酯
用类似于实施例Ⅻ的方法,由1.53mg(5mmol)实施例Ⅺ的化合物制备标题化合物。
产量:1.25g(为理论量的54%)
Rf=0.12(乙酸乙酯/石油醚=2∶1,非对映体混合物)。
实施例ⅩⅤ
3-乙酰氧基-3-[2-正丁基-1-{(2-乙氧羰基呋喃-5-基)甲基}-1H-咪唑-5-基]-2-环戊基甲基丙酸酯
将2.45g(5.36mmol)实施例Ⅻ化合物溶于50ml二氯甲烷中,加入264mg(2.16mmol)N,N-二甲氨基吡啶(DMAP)和0.76ml(8.04mmol)乙酸酐,混合物在25℃搅拌16小时。用乙醚稀释,用水(1×40ml)和饱和碳酸氢钠溶液洗涤,有机层经硫酸钠干燥并浓缩。所得粗产物通过硅胶柱色谱纯化,用乙酸乙酯/石油醚(3∶2)洗脱。
产量:1.93g(为理论量的72%)
Rf=0.65(乙酸乙酯/石油醚=3∶2)。
实施例ⅩⅥ
3-乙酰氧基-3-[2-正丁基-1-{(4-甲氧羰基苯基)甲基}-1H-咪唑-5-基]-2-环戊基甲基丙酸甲酯
用类似于实施例ⅩⅤ的方法,由实施例ⅩⅢ的粗产物制备标题化合物。
产量:1.7g(为理论量的66%)
Rf=0.63(乙酸乙酯/石油醚=4∶1,非对映体混合物)。
实施例ⅩⅦ
3-乙酰氧基-3-[2-正丁基-1-{(2-甲氧羰基噻吩-5-基)甲基}-1H-咪唑-5-基]-2-环戊基甲基丙酸甲酯
用类似于实施例ⅩⅤ的方法,由1.2g(2.6mmol)实施例ⅩⅣ的化合物制备标题化合物。
产量:1.23g(为理论量的94%)
Rf=0.67(乙酸乙酯/石油醚=2∶1,非对映体混合物)。
制备实施例
实施例1
3-[2-正丁基-1-{(2-乙氧羰基呋喃-5-基)甲基}-1H-咪唑-5-基]-2-环戊基甲基-2-丙烯酸甲酯
将1.9g(3.78mmol)实施例ⅩⅤ的化合物溶于60ml甲苯中,加入1.13ml(7.56mmol)1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU),混合物在80℃搅拌6小时。然后再加入1.13ml(7.56mmol)DBU,将烧瓶内的反应物在80℃搅拌16小时。冷却后,将混合物用饱和氯化钠溶液(1×30ml)洗涤,有机层经硫酸钠干燥、过滤并浓缩。残余物通过硅胶柱色谱纯化,用乙酸乙酯/石油醚(1∶2)洗脱。
产量:1.16g(为理论量的69%)
Rf=0.68(乙酸乙酯/石油醚=1∶1)。
实施例2
3-[2-正丁基-1-{(4-甲氧羰基苯基)甲基}-1H-咪唑-5-基]-2-环戊基甲基-2-丙烯酸甲酯
用类似于实施例1的方法,由1.6g(3.2mmol)实施例ⅩⅥ的化合物制备标题化合物。
产量:0.61g(为理论量的43%)
Rf=0.63(乙酸乙酯/石油醚=2∶1)。
实施例3
3-[2-正丁基-1-{(4-甲氧羰基噻吩-5-基)甲基}-1H-咪唑-5-基]-2-环戊基甲基-2-丙烯酸甲酯
用类似于实施例1的方法,由1.2g(2.38mmol)实施例ⅩⅦ的化合物制备标题化合物。
产量:0.5g(为理论量的47%)
Rf=0.55(乙酸乙酯/石油醚=1∶1)。
实施例4
3-[2-正丁基-1-{(4-羧基苯基)甲基}-1H-咪唑-5-基]-2-环戊基甲基-2-丙烯酸
将1g氢氧化钠的20ml甲醇/水(1∶1)溶液加到1.26g(2.88mmol)实施例2化合物的30ml甲醇溶液中。混合物在50℃搅拌16小时,然后用稀盐酸酸化,倾入300ml水中,用二氯甲烷(3×75ml)萃取,用乙酸乙酯(3×40ml)萃取。有机层经硫酸钠干燥、过滤并除去溶剂。粗产物通过硅胶柱色谱纯化(甲苯/乙酸乙酯/冰醋酸10∶30∶0.2→甲苯/甲醇/冰醋酸35∶5∶0.2),得到342mg产物(为理论量的29%)。Rf=0.25(甲苯/甲醇/冰醋酸=35∶5∶1)。
实施例5
3-[2-正丁基-1-{(2-羧基噻吩-5-基)甲基}-1H-咪唑-5-基]-2-环戊基甲基-2-丙烯酸
用类似于实施例4的方法,由500mg(1.13mmol)实施例3化合物制备标题化合物。
产量:101mg(为理论量的21%)
Rf=0.13(甲苯/乙酸乙酯/冰醋酸=10∶30∶0.2)。
实施例6
3-[2-正丁基-1-{(2-羧基呋喃-5-基)甲基}-1H-咪唑-5-基]-2-环戊基甲基-2-丙烯酸
用类似于实施例4的方法,由1.11g(1.13mmol)实施例1化合物制备标题化合物。
产量:380mg(为理论量的39%)
Rf=0.07(甲苯/乙酸乙酯/冰醋酸=10∶30∶1)。
实施例7
3-[2-正丁基-1-{(4-羧基苯基)甲基}-1H-咪唑-5-基]-2-环戊基甲基-2-丙烯酸二钠盐
将340mg(0.83mmol)实施例4化合物溶于甲醇/水中,加入1.66ml 1N氢氧化钠溶液,然后由混合物除去溶剂。得到376mg产物(为理论量的100%)。
实施例8
3-[2-正丁基-1-{(2-羧基噻吩-5-基)甲基}-1H-咪唑-5-基]-2-环戊基甲基-2-丙烯酸二钠盐
用类似于实施例7的方法,由330mg(0.79mmol)实施例5化合物制备标题化合物。
实施例9
3-[2-正丁基-1-{(2-羧基呋喃-5-基)甲基}-1H-咪唑-5-基]-2-环戊基甲基-2-丙烯酸二钠盐
用类似于实施例7的方法,由376mg(0.94mmol)实施例6化合物制备标题化合物。
Claims (10)
1、通式(Ⅰ)的环烷基和杂环基取代的咪唑基丙烯酸衍生物及其盐:
其中:
R1代表各自具有至多8个碳原子的直链或支链烷基或链烯基,它们是未取代的或被具有3至6个碳原子的环烷基取代,或者代表具有3至8个碳原子的环烷基,
R2代表氢、卤素、羟基、硝基、氰基、三氟甲基、三氟甲氧基或五氟乙基,或代表具有至多6个碳原子的直链或支链烷基,或代表具有6至10个碳原子的芳基,
R3代表具有3至8个碳原子的环烷基、或具有3至8个碳原子和至多3个杂原子的杂环基,这些杂原子为S、O或N-A,其中,
A代表氢或具有至多6个碳原子的直链或支链烷基,
n代表整数0、1、2、3或4,
R4代表氢、具有至多8个碳原子的直链或支链烷基,或代表苯基,
R5代表下式基团:
其中
R6代表氢、卤素、氰基、硝基、三氟甲基、羟基、三氟甲氧基、各自具有至多6个碳原子的直链或支链烷基,
R7代表羧基、或具有至多6个碳原子的直链或支链烷氧羰基、或被C1-C4烷基化的四唑基。
2、权利要求1的环烷基和杂环基取代的咪唑基丙烯酸衍生物及其盐,
其中:
R1代表各自具有至多6个碳原子的直链或支链烷基或链烯基,它们是未取代的或被环丙基、环丁基、环戊基或环己基取代,或代表环丙基、环戊基或环己基,
R2代表氢、氟、氯、溴、碘、三氟甲基、三氟甲氧基、五氟乙基或具有至多6个碳原子的直链或支链烷基,
R3代表环丙基、环戊基、环己基、环庚基、二硫戊环基或吡喃基,
n代表整数0、1、2或3,
R4代表氢或具有至多6个碳原子的直链或支链烷基,
R5代表下式的基团:
其中,
R6代表氢、氟、氯、溴、三氟甲基、三氟甲氧基或具有至多4个碳原子的直链或支链烷基,
R7代表羧基、具有至多3个碳原子的直链或支链烷氧羰基,或代表四唑基。
4、权利要求1的环烷基和杂环基取代的咪唑基丙烯酸衍生物用于治疗的用途。
5、权利要求1的环烷基和杂环基取代的咪唑基丙烯酸衍生物的制备方法,其特征在于:
在惰性溶剂中在碱存在下,使通式(Ⅱ)的醛与通式(Ⅲ)化合物反应,先将其转化为通式(Ⅳ)化合物,
(其中,R1、R2和R5具有上述定义),
(其中,R3和n具有上述定义,T代表具有至多8个碳原子的直链或支链烷基,或代表苯基),
(其中,R1、R2、R3、n和T具有权利要求1中给定的定义),
然后,通过引入保护基团将游离羟基保护起来,在最后一步,在惰性溶剂中在碱存在下进行消除反应,
如果制备(R4/R7=H),将酯水解,
如果需要,通过常规方法例如氢化或烷基化,将取代基R1和R2转化,
在R7代表烷基化的四唑基的情况下,将基团-NH烷基化。
6、根据权利要求5的方法,其特征在于反应在-100℃至+100℃的温度范围内进行。
7、含有至少一种权利要求1的环烷基或杂环基取代的咪唑基丙烯基衍生物的药物。
8、权利要求7的药物用于治疗高血压和动脉硬化。
9、权利要求7的药物的制备方法,其特征在于,如果需要,用常规的助剂和载体将环烷基或杂环基取代的咪唑基丙烯酸衍生物转化为适宜的应用形式。
10、权利要求1的环烷基和杂环基取代的咪唑基丙烯酸衍生物用于制备药物的用途。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DEP4210787.3 | 1992-04-01 | ||
DE4210787A DE4210787A1 (de) | 1992-04-01 | 1992-04-01 | Cycloalkyl- und Heterocyclyl substituierte Imidazolylpropensäurederivate |
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Publication Number | Publication Date |
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CN1077711A true CN1077711A (zh) | 1993-10-27 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CN93103421A Pending CN1077711A (zh) | 1992-04-01 | 1993-04-01 | 环烷基和杂环基取代的咪唑基丙烯酸衍生物 |
Country Status (16)
Country | Link |
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EP (1) | EP0563705A2 (zh) |
JP (1) | JPH0625179A (zh) |
KR (1) | KR930021623A (zh) |
CN (1) | CN1077711A (zh) |
AU (1) | AU3562093A (zh) |
CA (1) | CA2092886A1 (zh) |
CZ (1) | CZ34993A3 (zh) |
DE (1) | DE4210787A1 (zh) |
FI (1) | FI931424A (zh) |
HU (1) | HUT64037A (zh) |
IL (1) | IL105189A0 (zh) |
MX (1) | MX9301651A (zh) |
NO (1) | NO930947L (zh) |
SK (1) | SK27593A3 (zh) |
TW (1) | TW228000B (zh) |
ZA (1) | ZA932301B (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1276724A (zh) * | 1997-08-06 | 2000-12-13 | 史密丝克莱恩比彻姆公司 | 依普沙坦精氨酰电荷中和复合体及其制备过程和制剂 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CA2018438C (en) * | 1989-06-14 | 2000-08-08 | Joseph Alan Finkelstein | Imidazolyl-alkenoic acids |
EP0403158A3 (en) * | 1989-06-14 | 1991-12-18 | Smithkline Beecham Corporation | Imidazolyl-alkenoic acids |
AU640417B2 (en) * | 1989-10-25 | 1993-08-26 | Smithkline Beecham Corporation | Substituted 5-((tetrazolyl)alkenyl)imidazoles |
-
1992
- 1992-04-01 DE DE4210787A patent/DE4210787A1/de not_active Withdrawn
-
1993
- 1993-03-05 CZ CZ93349A patent/CZ34993A3/cs unknown
- 1993-03-06 TW TW082101659A patent/TW228000B/zh active
- 1993-03-16 NO NO93930947A patent/NO930947L/no unknown
- 1993-03-19 EP EP93104552A patent/EP0563705A2/de not_active Withdrawn
- 1993-03-23 KR KR1019930004471A patent/KR930021623A/ko not_active Application Discontinuation
- 1993-03-24 MX MX9301651A patent/MX9301651A/es unknown
- 1993-03-29 IL IL105189A patent/IL105189A0/xx unknown
- 1993-03-29 CA CA002092886A patent/CA2092886A1/en not_active Abandoned
- 1993-03-30 FI FI931424A patent/FI931424A/fi unknown
- 1993-03-31 JP JP5094937A patent/JPH0625179A/ja active Pending
- 1993-03-31 ZA ZA932301A patent/ZA932301B/xx unknown
- 1993-03-31 AU AU35620/93A patent/AU3562093A/en not_active Abandoned
- 1993-04-01 CN CN93103421A patent/CN1077711A/zh active Pending
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- 1993-04-01 SK SK275-93A patent/SK27593A3/sk unknown
Also Published As
Publication number | Publication date |
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EP0563705A2 (de) | 1993-10-06 |
CA2092886A1 (en) | 1993-10-02 |
HU9300954D0 (en) | 1993-06-28 |
FI931424A0 (fi) | 1993-03-30 |
KR930021623A (ko) | 1993-11-22 |
HUT64037A (en) | 1993-11-29 |
FI931424A (fi) | 1993-10-02 |
DE4210787A1 (de) | 1993-10-07 |
TW228000B (zh) | 1994-08-11 |
MX9301651A (es) | 1993-10-01 |
CZ34993A3 (en) | 1994-01-19 |
NO930947L (no) | 1993-10-04 |
IL105189A0 (en) | 1993-07-08 |
AU3562093A (en) | 1993-10-07 |
EP0563705A3 (zh) | 1994-04-20 |
SK27593A3 (en) | 1994-04-06 |
NO930947D0 (no) | 1993-03-16 |
ZA932301B (en) | 1993-10-25 |
JPH0625179A (ja) | 1994-02-01 |
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