CN1188760A - 联苯磺酰基取代的五元杂环、其制备方法、其药用和组合物 - Google Patents
联苯磺酰基取代的五元杂环、其制备方法、其药用和组合物 Download PDFInfo
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- CN1188760A CN1188760A CN98104298A CN98104298A CN1188760A CN 1188760 A CN1188760 A CN 1188760A CN 98104298 A CN98104298 A CN 98104298A CN 98104298 A CN98104298 A CN 98104298A CN 1188760 A CN1188760 A CN 1188760A
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- Prior art keywords
- alkyl
- methyl
- group
- hydrogen
- phenyl
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- 125000000623 heterocyclic group Chemical group 0.000 title description 3
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 86
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 77
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- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 2
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Classifications
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- 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
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- 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
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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
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Abstract
式Ⅰ化合物,其中的符号具有权利要求中指出的意义,具有杰出的抗心律失常性质并显示心脏保护功能。它们在局部缺血引起的损伤形成,尤其是局部缺血引起的心律失常的发生中,可以预防性地抑制或大大减少病理过程。而且,它们对于细胞增生具有很强的抑制作用。
Description
它是未取代的或被1-3个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(8)R(9)的取代基取代;
R(8)和R(9)
相互独立地是H或(C1-C4)烷基;
a是零,1或2;或R1是-CbH2b-(C1-C9)杂芳基,
它是未取代的或被1-3个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(10)R(11)的取代基取代;R(10)和R(11)
相互独立地是H或(C1-C4)烷基;
b是零,1或2;或R1是-CdH2d-(C3-C7)环烷基;
d是零,1或2;R2和R3
相互独立地是氢,F,Cl,Br,I,CF3,-C≡N,-NO2,CH2OR17,CO-R6或O-R7;
R17是氢,具有1,2,3,4,5,6,7或8个碳原子的烷基
R6是氢,具有1,2,3,4,5,6,7或8个碳原子的烷基,OR30或苯基,
它是未取代的或被1-3个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(31)R(32)的取代基取代;
R(31)和R(32)
相互独立地是H或(C1-C4)烷基;
R30是氢或具有1,2,3,4,5,6,7或8个碳原子的烷基;R7是氢,具有1,2,3,4,5,6,7或8个碳原子的烷基,苯基,
它是未取代的或被1-3个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(12)R(13)的取代基取代;
R(12)和R(13)
相互独立地是H或(C1-C4)烷基;或R7是(C1-C9)杂芳基,
它是未取代的或被1-3个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(14)R(15)的取代基取代;
R(14)和R(15)
相互独立地是H或(C1-C4)烷基;或R2和R3
相互独立地是具有1,2,3,4,5,6,7或8个碳原子的烷基,具有3,4,5,6或7个碳原子的环烷基或-CgH2g-苯基,
它是未取代的或被1-3个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(18)R(19)的取代基取代;
R(18)和R(19)
相互独立地是H或(C1-C4)烷基;g是零,1或2;或R2和R3
是-CIH2I-(C1-C9)杂芳基,
它是未取代的或被1-3个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(20)R(21)的取代基取代;
R(20)和R(21)
相互独立地是H或(C1-C4)烷基;I是零,1或2;或R2和R3
是SOn-R22;
n是零,1或2;
R22是具有1,2,3,4,5,6,7或8个碳原子的烷基,具有3,4,5,6或7个碳原子的环烷基或-CsH2s-苯基,
它是未取代的或被1-3个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(34)R(35)的取代基取代;
R(34)和R(35)
相互独立地是H或(C1-C4)烷基;s是零,1或2;R4和R5
相互独立地是氢,具有1,2,3,4,5,6,7或8个碳原子的烷基,F,Cl,Br,I,CF3,-C≡N,-NO2,SOp-R16,CO-R23或O-R24;
p是零,1或2;
R16是具有1,2,3,4,5,6,7或8个碳原子的烷基或苯基,
它是未取代的或被1-3个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(26)R(27)的取代基取代;
R(26)和R(27)
相互独立地是H或(C1-C4)烷基;R23是氢,具有1,2,3,4,5,6,7或8个碳原子的烷基或OR25;
R25氢,具有1,2,3,4,5,6,7或8个碳原子的烷基;R24是氢,具有1,2,3,4,5,6,7或8个碳原子的烷基或苯基,
它是未取代的或被1-3个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(28)R(29)的取代基取代;
R(28)和R(29)
相互独立地是H或(C1-C4)烷基。
优选的式I化合物是这样的化合物,其中:R1是氢,具有1,2,3或4个碳原子的烷基或-CaH2a-苯基,
它是未取代的或被1-2个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(8)R(9)的取代基取代;
R(8)和R(9)
相互独立地是H或甲基;
a是零或1;或R1是(C1-C9)杂芳基,
它是未取代的或被1个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(10)R(11)的取代基取代;
R(10)和R(11)
相互独立地是H或甲基;或R1是-CdH2d-(C3-C7)环烷基;
d是零或1;R2或R3
相互独立地是氢,F,Cl,Br,I,CF3,-C≡N,-NO2,CH2OR17,CO-R6或O-R7;
R17是氢,具有1,2,3或4个碳原子的烷基
R6是氢,具有1,2,3或4个碳原子的烷基,OR30或苯基,
它是未取代的或被1-2个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(31)R(32)的取代基取代;
R(31)和R(32)
相互独立地是H或甲基;
R30是氢或具有1,2,3或4个碳原子的烷基;R7是氢,具有1,2,3或4个碳原子的烷基,苯基,
它是未取代的或被1-2个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(12)R(13)的取代基取代;
R(12)和R(13)
相互独立地是H或甲基;或R7是(C1-C9)杂芳基,
它是未取代的或被1个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(14)R(15)的取代基取代;
R(14)和R(15)
相互独立地是H或甲基;或R2和R3
相互独立地是具有1,2,3或4个碳原子的烷基,具有3,4,5,6或7个碳原子的环烷基或-CgH2g-苯基,
它是未取代的或被1-2个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(18)R(19)的取代基取代;
R(18)和R(19)
相互独立地是H或甲基;g是零或1;或R2和R3
是(C1-C9)杂芳基,
它是未取代的或被1个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(20)R(21)的取代基取代;
R(20)和R(21)
相互独立地是H或甲基;或R2和R3
是SOn-R22;
n是零,1或2;
R22是具有1,2,3或4个碳原子的烷基,具有3,4,5,6或7个碳原子的环烷基或-CsH2s-苯基,
它是未取代的或被1-2个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(34)R(35)的取代基取代;
R(34)和R(35)
相互独立地是H或甲基;s是零或1;R4和R5
相互独立地是氢,具有1,2,3或4个碳原子的烷基,F,Cl,Br,I,CF3,-C≡N,-NO2,SOp-R16,CO-R23或O-R24;
p是零,1或2;
R16是具有1,2,3或4个碳原子的烷基或苯基,
它是未取代的或被1-2个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(26)R(27)的取代基取代;
R(26)和R(27)
相互独立地是H或甲基;R23是氢,具有1,2,3或4个碳原子的烷基或OR25;
R25是氢,具有1,2,3或4个碳原子的烷基;R24是氢,具有1,2,3或4个碳原子的烷基或苯基,
它是未取代的或被1-2个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(28)R(29)的取代基取代;
R(28)和R(29)
相互独立地是H或甲基;和其生理上耐受的盐。
特别优选的式I化合物是这样的化合物,其中:R1是氢,具有1,2,3或4个碳原子的烷基或苯基,
它是未取代的或被1个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(8)R(9)的取代基取代;
R(8)和R(9)
相互独立地是H或甲基;或R1是(C1-C9)杂芳基,
它是未取代的或被1个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(10)R(11)的取代基取代;R(10)和R(11)
相互独立地是H或甲基;或R1是(C3-C7)环烷基;R2或R3
相互独立地是氢,F,Cl,Br,I,CF3,-C≡N,-NO2,CO-R6或O-R7;
R6是氢,具有1,2,3或4个碳原子的烷基,OR30或苯基,
它是未取代的或被1-2个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(31)R(32)的取代基取代;
R(31)和R(32)
相互独立地是H或甲基;
R30是氢或具有1,2或3个碳原子的烷基;R7是氢,具有1,2,3或4个碳原子的烷基,苯基,
它是未取代的或被1个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(12)R(13)的取代基取代;
R(12)和R(13)
相互独立地是H或甲基;或R7是(C1-C9)杂芳基,
它是未取代的或被1个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(14)R(15)的取代基取代;
R(14)和R(15)
相互独立地是H或甲基;或R2和R3
相互独立地是具有1,2,3或4个碳原子的烷基,具有3,4,5,6或7个碳原子的环烷基或苯基,
它是未取代的或被1个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(18)R(19)的取代基取代;
R(18)和R(19)
相互独立地是H或甲基;或R2和R3
是(C1-C9)杂芳基,
它是未取代的或被1个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(20)R(21)的取代基取代;
R(20)和R(21)
相互独立地是H或甲基;或R2和R3
是SOn-R22;
n是零或2;
R22是具有1,2,3或4个碳原子的烷基,具有3,4,5,6或7个碳原子的环烷基或苯基,
它是未取代的或被1-2个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(34)R(35)的取代基取代;
R(34)和R(35)
相互独立地是H或甲基;R4和R5
相互独立地是氢,具有1,2,3或4个碳原子的烷基,F,Cl,CF3,-C≡N,-NO2,SOp-R16,CO-R23或O-R24;
p是零或2;R23是氢,具有1,2,3或4个碳原子的烷基或OR25;
R25是氢,具有1,2或3个碳原子的烷基;R24是氢,具有1,2,3或4个碳原子的烷基或苯基,
它是未取代的或被1个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(28)R(29)的取代基取代;
R(28)和R(29)
相互独立地是H或甲基;R16是具有1,2,3或4个碳原子的烷基或苯基,
它是未取代的或被1个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(26)R(27)的取代基取代;
R(26)和R(27)
相互独立地是H或甲基;和其生理上耐受的盐。
非常优选的式I化合物是这样的化合物,其中:R1是具有1,2,3或4个碳原子的烷基或苯基,
它是未取代的或被1个选自F,Cl,CF3,甲基,甲氧基的取代基取代;或R1是(C1-C9)杂芳基,
它是未取代的或被1个选自F,Cl,CF3,甲基,甲氧基的取代基取代;或R1是(C3-C7)环烷基;R2或R3
相互独立地是氢,F,Cl,CF3,-C≡N,CO-R6或O-R7;
R6是氢,具有1,2,3或4个碳原子的烷基,OR30或苯基,
它是未取代的或被1-2个选自F,Cl,CF3,甲基,甲氧基的取代基取代;
R30是氢,甲基或乙基;R7是氢,具有1,2,3或4个碳原子的烷基或苯基,
它是未取代的或被1个选自F,Cl,CF3,甲基,甲氧基的取代基取代;或R7是(C1-C9)杂芳基,
它是未取代的或被1个选自F,Cl,CF3,甲基,甲氧基的取代基取代;或R2和R3
相互独立地是具有1,2,3或4个碳原子的烷基,具有3,4,5,6或7个碳原子的环烷基或苯基,
它是未取代的或被1个选自F,Cl,CF3,甲基,甲氧基的取代基取代;或R2和R3
是(C1-C9)杂芳基,
它是未取代的或被1个选自F,Cl,CF3,甲基,甲氧基的取代基取代;或R2和R3
是SOn-R22;
n是零或2;
R22是具有1,2,3或4个碳原子的烷基或苯基,
它是未取代的或被1-2个选自F,Cl,CF3,甲基,甲氧基的取代基取代;R4和R5
相互独立地是氢,甲基,F,Cl,CF3,-C≡N,SO2-R16,CO-R23或O-R24;R16是具有1,2,3或4个碳原子的烷基或苯基,
它是未取代的或被1个选自F,Cl,CF3,甲基,甲氧基的取代基取代;R23是氢,甲基或OR25;
R25是氢,甲基或乙基;R24是氢,具有1,2,3或4个碳原子的烷基或苯基,
它是未取代的或被1个选自F,Cl,CF3,甲基,甲氧基的取代基取代;和其生理上耐受的盐。
另外,优选的式I化合物是其中基团R1,R2,R3,R4和R5如上定义,而R4和R5不同时为氢的化合物。
烷基可以是直链或支链的。
环烷基也理解为烷基-取代的环。
(C1-C9)杂芳基被理解为尤其是从苯基或萘基衍生的,其中一个或多个CH基团被N置换和/或其中至少两个相邻的CH基团(形成五-员芳香环的情况)被S,NH或O置换的基团。另外,双环基团(如中氮茚基)缩合位点的一个或两个原子也可以是氮原子。
杂芳基具体地是呋喃基,噻吩基,吡咯基,咪唑基,三唑基,四唑基,恶唑基,异恶唑基,噻唑基,异噻唑基,吡啶基,吡嗪基,嘧啶基,哒嗪基,吲哚基,喹啉基,异喹啉基,2,3-二氮杂萘基,喹喔啉基,喹唑啉基,噌啉基。
如果存在,立体中心具有或者(R)或者(S)构型。
式I化合物的生理上耐受的盐被理解为其有机和无机盐,如在Reminton的药物科学[17版1418页(1985)]中所述的。考虑到物理和化学稳定性和溶解性,对于酸性基团,特别地,钠,钾,钙和铵盐是优选的;对于碱性基团,特别地,盐酸,硫酸,磷酸或羧酸或磺酸,如,乙酸,柠檬酸,苯甲酸,马来酸,富马酸,酒石酸和对甲苯磺酸酯的盐是优选的。
本发明也涉及制备式I化合物和其生理上耐受的盐的方法,该方法包括,使式II的化合物其中的基团如上面定义,并且要么是在药物化学杂志1995,38,2357页中已知的,要么类似地制备,与溴化氰反应。反应在对溴化氰稳定的偶极非质子性溶剂例如乙腈,DMA,TMU或NMP中,用不非常亲核的强辅助碱例如,K2CO3或Cs2CO3进行。合适的反应温度是0℃至所用溶剂沸点之间的温度;60℃至120℃的温度是优选的。
本发明进一步涉及下式化合物和其生理上耐受的盐的用途其中:a)X,Y和Z相同或不同,是N或CR(102)b)R(1)是
1.(C1-C10)烷基,2.(C3-C10)烯基,3.(C3-C10)炔基,4.-OR(103),5.(C3-C8)环烷基,6.(C4-C10)环烷基烷基,7.(C5-C10)环烷基烯基,8.(C5-C10)环烷基炔基,9.-(CH2)m-B-(CH2)n-R(104),10.-苄基,11.如在b)项1.,2.,3.或9.中定义的基团,它被CO2R(103)单取代,12.如在b)项1.,2.,3.或9.中定义的基团,其中1个至所有的氢原子被氟取代,或13.如在b)项10.中定义的基团,它在苯基上被1或2个选自卤素,(C1-C4)烷氧基和硝基的相同或不同的基团取代,c)R(102)是
1.氢,2.卤素,3.硝基,4.CvH2v+1,5.五氟苯基,6.氰基,7.-O-R(106),8.苯基,9.苯基(C1-C3)烷基,10.(C1-C10)烷基,11.(C3-C10)烯基,12.苯基(C2-C6)烯基,13.1-咪唑基(CH2)m-,14.1,2,3-三唑基-(CH2)n-,15.四唑基-(CH2)m-,16.-(CH2)o-1-CHR(107)-OR(105),17.-(CH2)o-O-CO-R(103),18.-(CH2)o-S-R(106),19.-S(O)r-R(119),20.-CH=CH-(CH2)m-CHR(103)-OR(106),21.-CH=CH-(CH2)m-CO-R(108),22.-CO-R(108),23.-CH=CH-(CH2)m-O-CO-R(107),24.-(CH2)m-CH(CH3)-CO-R(108),25.-(CH2)o-CO-R(108),26.-(CH2)o-O-[C=W]-NH-R(109),27,-(CH2)o-NR(107)-[C=W]-OR(109),28.-(CH2)o-NR(107)-CO-NHR(109),29.-(CH2)o-NR(107)-SO2R(109),30.-(CH2)o-NR(107)-[C=W]-R(109),31.-(CH2)nF,32.-(CH2)n-O-NO2,33.-CH2-N3,34.-(CH2)n-NO2,35.-CH=N-NR(105)R(107),36.邻苯二甲酰亚胺基(CH2)n-,37.38.39.40.
41.phenyl-SO2-NH-N=CH-,
4243.-(CH2)n-SO2-NR(107)-CS-NR(106)R(109),44.-(CH2)n-SO2-NR(107)-CO-NR(106)R(109),45.-(CH2)o-SO2R(109),46.如在c)项8.或9.中定义的基团,在苯基上被1或2个选自卤素,羟基,甲氧基,三氟甲基,CO2R(103)和苯基的相同或不同基团取代,47.如在c)项10.,11.或19中定义的基团,其中一个至所有的氢原子被氟取代,48.如在c)项14.中定义的基团,被1或2个选自甲氧羰基和(C1-C4)烷基的相同或不同基团取代,49.-(CH2)n-SO2-NR(107)-CO-R(106),50.-(CH2)n-SO2-NR(107)-CS-R(106),d)R(103)是
1.氢,2.(C1-C8)烷基,3.(C3-C8)环烷基,4.苯基,5.苄基,6.如在d)项2.中定义的基团,其中一个至所有的氢原子被氟取代;e)R(104)是
1.氢,2.(C1-C6)烷基,3.(C3-C8)环烷基,4.(C2-C4)烯基或5.(C2-C4)炔基;f)R(105)是
1.氢,2.(C1-C6)烷基,3.(C3-C8)环烷基,4.苯基或5.苄基;g)R(106)和R(109)是
相同或不同地为1.氢,2.(C1-C6)烷基,它未取代或被1-3个选自(C1-C6)烷氧基,该烷氧基自身可被1-3个选自羟基,(C1-C6)烷氧基,氨基,单(C1-C6)烷基氨基,二(C1-C6)烷基氨基取代,(C2-C10)烯基,羟基,氨基,单(C1-C6)烷基氨基,二(C1-C6)烷基氨基,(C1-C6)烷氧基羰基氨基,(C6-C12)芳基(C1-C4)烷氧羰基氨基,(C6-C10)芳基,(C6-C10)芳基-(C1-C3)烷基,(C1-C9)杂芳基,羧基和(C1-C4)烷氧羰基的取代基取代;3.(C3-C8)环烷基,其中环烷基部分是未取代的或被1-3个选自(C1-C4)烷基和(C2-C4)烯基的取代基取代;4.(C3-C8)环烷基-(C1-C3)烷基,5.(C6-C12)芳基,优选苯基,6.(C6-C10)-芳基-(C1-C4)烷基,7.(C1-C9)杂芳基,它部分或完全被氢化,8.如在g)项5.,6.,7.,9.,15.,16.,17.,19.,20.或21.中定义的基团,被1或2个选自卤素,羟基,(C1-C4)烷基,甲氧基,硝基,氰基,CO2R(103),三氟甲基,NR(11 1)R(112)和的相同或不同基团取代,9.(C1-C9)-杂芳基-(C1-C3)烷基,
其中杂芳基部分可以部分或完全氢化,10.(C1-C6)烷基,其中1至所有的H原子被氟取代,11.(C2-C10)烯基,(C2-C10)烯酰基或(C2-C10)二烯基,12.(C3-C8)环烯基,13.(C3-C8)环烯基-(C1-C3)-烷基,14.二-或三环(C4-C10)-环烯基-(C1-C4)烷基,
它也可以被1-3个(C1-C4)-烷基取代;15.(C6-C10)芳基(C1-C4)烷基,16.(C6-C10)芳基(C3-C6)烯基,17.(C1-C9)杂芳基(C3-C6)烯基,18.(C3-C6)炔基,19.(C6-C10)芳基(C3-C6)炔基,20.(C1-C9)杂芳基(C3-C6)炔基,21.R(106)和R(109)与带有它们的氮原子一起形成一个杂芳基,
它也可以部分或完全氢化;h)R(107)是
1.氢,2.(C1-C6)烷基,3.(C3-C8)环烷基,4.(C6-C12)芳基(C1-C6)烷基,优选苄基,5.苯基或6.(C1-C9)杂芳基;i)R(108)是
氰基,硝基或CO2R(107);k)R(111)和R(112)
相同或不同地是1.氢,2.(C1-C4)烷基,3.苯基,4.苄基,或5.α-甲基苄基;l)D是NR(113),O或CH2;m)R(113)是
氢,(C1-C4)烷基或苯基;n)A是联苯基,
它是未取代的或被1-4个、优选1或2个相同或不同的取代基R(114)或R(115)取代;o)R(114)是
1.卤素,2.亚硝基,3.硝基,4.氨基,5.氰基,6.羟基,7.(C1-C6)烷基,8.(C1-C4)烷酰基,9.(C1-C4)烷酰氧基,10.CO2R(103),11.甲磺酰胺基,12.三氟甲磺酰胺基,13.-CO-NH-OR(109),14.-SO2-NR(106)R(107),15.-CH2-OR(107),16,(C1- C9)杂芳基-(CH2)q-,优选1-四唑基,17.(C7-C13)芳酰基,18.19.或20.(C6-C12)芳基;p)R(115)是
1.氢,2.(C1-C6)烷基,3.(C3-C8)环烷基,4.(C6-C12)芳基,5.(C7-C13)芳酰基,6.(C1-C4)烷氧基,7.(C1-C4)烷酰氧基,8.(C1-C9)杂芳基,9.CO2R(103);10.卤素,11.氰基,12,硝基,13.NR(106)R(107),14.羟基,15.-CO-NH-CHR(105)-CO2R(103),16.磺基,17.-SO3R(103),18.-SO2-NR(107)-CO-NR(106)R(109)或-SO2-NR(107)-CS-NR(106)R(109),19.-NR(107)-CO-NR(106)-SO2-CH2-R(105),20.-C(CF3)2OH,21.膦酰氧基,22.-PO3H2,23.-NH-PO(OH)2,24.-S(O)rR(106),25.-CO-R(108),26.-COR(106)R(109),27.-CR(120)(OH)-PO(OH) 2 ,28.在o)项20.中定义的基团,29.30.31.32. 5-四唑基-NH-CO-,33.-CO-NH-NH-SO2-CF3,34.35.36.37.38.39.40.-CO-NH-SO2-R(119),41.-SO2-NH-CO-R(106)或42.在p)项4.中定义的基团,被1或2个选自卤素,氰基,硝基,NR(106)R(107)和羟基的相同或不同基团取代;43.R(115)与R(114)一起是-CO-NH-SO2-,44.-SO2-NH-CO-O-R(106),45.-SO2-NH-SO2-NR(106)R(109),46.-SO2-NH-SO2-R(106);q)B是O,NR(107)或S;r)W是O或S;s)L是(C1-C3)烷二基;t)R(116)是
CO2R(103)或CH2CO2R(103);u)R(117)是
氢,卤素,(C1-C4)烷基或(C1-C4)烷氧基;v)R(118)是
氢,(C1-C4)烷基或苯基;w)R(119)是
1.(C1-C6)烷基,2.(C3-C8)环烷基,3.苯基,4.苄基或5.在w)项1.中定义的基团,其中1至所有的H原子被氟取代,x)T是1.一个单键,2.-CO-,3.-CH2-,4.-O-,5.-S-,6.-NR(121)-,7.-CO-NR(121),8.-NR(121)-CO-,9.-O-CH2-,10.-CH2-O-,11.-S-CH2-,12.-CH2-S,13.-NH-CR(120)R(122),14.-NR(121)-SO2,15.SO2-NR(121)-,16.-CR(120)R(122)-NH,17.-CH=CH-,18.-CF=CF-,19.-CH=CF-,20.-CF=CH-,21.-CH2-CH2-,22.-CF2-CF2-,23.-CH[OR(103)]-,24.-CH(OCOR(105))-,25.-C[N=R(123)]-或26.-[R(124)O]-C-[OR(125)]-y)R(120)和R(122)是
相同或不同,为氢,(C1-C5)烷基,苯基,烯丙基或苄基;z)R(121)是
氢,(C1-C6)烷基,苄基或烯丙基;a’)R(123)是
1.NR(120)R(121),2.脲基,3.硫脲基,4.甲苯-4-磺酰基或5.苯磺酰氨基;b’)R(124)和R(125)是,
相同或不同,为(C1-C4)烷基或一起为-(CH2)q-;c’)Q是CH2,NH,O或S;d’)m是1,2,3,4或5;e’)n是1,2,3,4或5;f’)o是1,2,3,4,5,6,7,8,9或10;g’)q是零或1;h’)r是零,1或2;i’)v是1,2,3,4,5或6;用于生产治疗或预防由局部缺血状况引起的疾病的医药,也用于生产治疗损害的呼吸动力的医药。
另外,本发明也涉及式I化合物的用途,用于生产治疗或预防由局部缺血状况引起的疾病的医药;以及式I化合物用于生产治疗或预防心肌梗塞的医药的用途;还有式I化合物用于生产治疗或预防心绞痛的医药的用途;还有式I化合物用于生产治疗或预防心脏局部缺血的医药的用途;还有式I化合物用于生产治疗或预防末梢和中枢神经系统局部缺血和中风的医药的用途;还有式I化合物用于生产治疗或预防外周器官和肢体局部缺血的医药的用途;还有式I化合物用于生产治疗休克状态的医药的用途;还有式I化合物用于生产用于外科手术和器官移植的医药的用途;还有式I化合物用于生产用于外科测量的移植物的防腐和储存的医药的用途;还有式I化合物用于生产治疗其中细胞增生是第一或第二原因的疾病的医药的用途;和其用于生产抗动脉粥样硬化剂或抗糖尿病后期并发症,癌症,纤维性疾病如肺纤维变性,肝纤维变性或肾纤维变性,或前列腺增生的组合物的用途;还有式I化合物用于生产治疗损害的呼吸动力的医药的用途;以及包含有效量式I化合物的药物。
类似于本发明式I化合物的化合物披露于美国专利5482957和5604251。然而,它们没有在本发明中总是存在的磺酰基氰酰胺侧链。作为血管紧张肽II拮抗剂的咪唑衍生物也在WO9523792,WO9523791,US5391732,EP-A648763中描述。另外,在US5281614中已将三唑衍生物、在WO9220662和药物化学杂志(1994),37(17),2808-2824中已将三唑啉酮衍生物描述为血管紧张肽II受体拮抗剂。该已知化合物是亚类AT1的血管紧张肽II受体拮抗剂,它在本发明的化合物I中的作用不存在或者只以很小的程度存在。
本发明的式I化合物具有良好的抗心律失常性质,例如很重要的用于治疗在缺氧症状的情况下发生的疾病。由于其药理性质,化合物I特别适合作为用于梗塞预防和梗塞治疗,也用于治疗心绞痛的具有心脏保护成分的抗心律失常药物,其中它们也在局部缺血引起的损伤的形成,尤其是在局部缺血引起的心律失常的发生中,保护性地抑制或大大减少病理过程。
由于其对病理性低氧和局部缺血状况的保护作用,本发明的式I化合物可以被,作为抑制细胞内Na+-依赖的Cl-/HCO3 -交换机理或钠/碳酸氢盐同向转运剂的结果,用作治疗所有由局部缺血引起的急性或慢性损伤或其作为第一或第二诱因的疾病的药物。它们通过降低或防止化学诱导的损伤而保护氧急性或慢性供应不足的器官,因而适合作为,例如血栓形成,血管痉挛,动脉粥样硬化或在外科排解(例如在肾或肝脏器官移植中,其中该化合物既可以在取出之前在供体内保护器官,或取出期间例如在用其治疗或将其储存在生理浴液中的期间、也可以在移植到接受者身体时用于保护取出的器官)或急性肾衰竭中的药物。式I化合物当例如在心脏或者在外周血管上进行血管形成术外科排解时也是具有保护作用的有用药物。对应于其对局部缺血引起的损伤的保护作用,该化合物也适合作为用于治疗神经系统,尤其是中枢神经系统局部缺血的药物,其中它们适合,例如,用于治疗中风或脑水肿。进一步地,本发明的式I化合物也适合用于治疗休克,例如,变应性,心原性,血容量减少性和细菌性休克的形成。进一步地,本发明的式I化合物由于其对于细胞增生,例如纤维变性细胞增生和血管平滑肌细胞增生的强烈抑制作用而卓越。因此,式I化合物适合作为其中细胞增生是第一或第二起因的疾病的有价值的治疗剂,因此可以用作抗动脉粥样硬化剂,抗糖尿病后期并发症,癌症,纤维性疾病如肺纤维变性,肝纤维变性或肾纤维变性,器官肥大和增生,尤其是前列腺增生或前列腺肥大的药剂。
已经发现,Na+-依赖的Cl-/HCO3 -交换机理或钠/碳酸氢盐同向转运剂的抑制剂可以通过增加呼吸器官的化学受体的化学敏感性而刺激呼吸道。这些化学受体在一定程度上对保持有序的呼吸道活性负责。它们在身体内被低氧,pH降低和二氧化碳升高(高碳酸血)活化并导致呼吸瞬间体积的调节。在睡眠期间,呼吸对于障隘特别敏感并在很大程度上依赖于化学受体的活性。
通过用抑制Na+-依赖的Cl-/HCO3 -交换的物质刺激化学受体改进呼吸动力,导致呼吸道在如下临床症状和疾病中的改进:障隘的中心呼吸动力(例如中心睡眠呼吸暂停,卧床死亡,手术后的低氧),肌肉-相关的呼吸道疾病,长期换气后的呼吸道疾病,在适应高山地区期间的呼吸道疾病,梗塞性和混合形式的睡眠呼吸暂停,低氧和高碳酸血的急性和慢性肺病。
含有式I化合物的药物在这种情况下可以被口服,非肠胃,静脉内,直肠或吸入给药,优选的给药方式取决于具体的病症。式I化合物在这种情况下可以单独或与药用辅助剂一起使用,并可以用作兽药和人药。
对于所需的药物制剂合适的辅助剂对于本专业熟练的技术人员以其专业知识为基础是熟悉的。除了溶剂,凝胶-形成剂,栓剂基质,片剂辅助剂,和其它载体之外,还可以用,例如,抗氧化剂,分散剂,乳化剂,消泡剂,矫味剂,防腐剂,增溶剂或着色剂。
对于口服给药形式,活性化合物与合适的添加剂,如赋形剂,稳定剂或惰性稀释剂混合,通过常规方法制成合适的给药形式,如片剂,包衣片剂,硬胶囊,水,醇或油溶液。可被使用的惰性赋形剂有,例如,阿拉伯胶,苦土,碳酸镁,磷酸钾,乳糖,葡萄糖或淀粉,尤其是玉米淀粉。在这种情况下,制备既可以以干的也可以以湿的颗粒的方式进行。合适的油状赋形剂或溶剂有,例如,植物或动物油,如葵花籽油或鱼肝油。
对于皮下或静脉内给药,活性化合物,如果需要,与常用物质如增溶剂,乳化剂或其它辅助剂被制成溶液,悬浮液或乳化液。可能的溶剂有,例如:水,生理食盐溶液或醇,如乙醇,丙醇,甘油,还有糖溶液如葡萄糖或甘露糖醇溶液,以及各种提到的溶剂的混合物。
用于以气雾剂或喷雾剂形式给药的合适的药物制剂有,例如,式I的活性化合物在药用溶剂如,尤其是,乙醇或水,或这类溶剂的混合物中的溶液,悬浮液或乳化液。
如果需要,制剂也可以含有其它药用辅助剂如表面活性剂,乳化剂和稳定剂以及推进气体。这类制剂一般以大约0.1至10、尤其是大约0.3至3重量%含有活性化合物。
被给药的式I化合物的剂量和给药的频率取决于所用化合物的效能和作用周期;另外,也取决于被治疗的疾病的性质和严重程度,还有患者的性别,年龄,体重和被治疗的各个哺乳动物的响应。
平均起来,在患者体重大约75kg的情况下,式I化合物的日剂量为至少0.001mg/kg,优选0.01mg/kg,至多10mg/kg。优选1mg/kg体重。在疾病急性发作的情况下,例如在患有心肌梗塞时,也需要更高尤其是更频繁的剂量,例如高达每天4个单剂量。尤其是在i.v.给药的情况下,例如在梗塞患者急性发作的情况下需要高达每天200mg。
式I化合物可以作为单独的活性化合物或与其它药理活性化合物结合。
式I化合物和/或其生理上耐受的盐可被用于实现有利的治疗作用,与其它药理活性化合物一起,用于治疗或预防上述病症,尤其是用于治疗心血管疾病。与钠/氢交换剂(NHE)抑制剂和/或与其它类型的心血管活性化合物结合是优选的。
本发明还非常一般地涉及a)NCBE抑制剂和/或其生理上耐受的盐与NHE抑制剂和/或其生理上耐受的盐组合;b)NCBE抑制剂和/或其生理上耐受的盐与其它类型的心血管活性化合物的活性物质和/或其生理上耐受的盐组合;还有c)NCBE抑制剂和/或其生理上耐受的盐与NHE抑制剂和/或其生理上耐受的盐与其它类型的心血管活性化合物和/或其生理上耐受的盐的活性物质组合。优选使用的组合是其中式I的NCBE抑制剂和/或其生理上耐受的盐。
已知的并且被认作NHE抑制剂的活性化合物是胍衍生物,优选酰基胍,如在Edward J.Cragoe,Jr.,“利尿剂,化学,药理学和药物”,J.Wiley&Sons(1983),303-341中所述的,或在DE19737224.4中提到的NHE抑制剂。合适的NHE抑制剂有,例如,苯甲酰基胍如下列文献所述的:US5292755,US5373024,US5364868,US5591754,US5516805,US5559153,US5571842,US5641792,US5631293,EP-A577024,EP-A602522,EP-A602523,EP-A603650,EP-A604852,EP-A612723,EP-A627413,EP-A628543,EP-A640593,EP-A640588,EP-A702001,EP-A713864,EP-A723956,EP-A754680,EP-A765868,EP-A774459,EP-A794171,DE19624178.2,DE19713427.0。如在EP-A556673,EP-A791577,EP-A794172,DE19624178.2中所述的邻位-取代的苯甲酰基胍;如在EP-A690048中所述的邻位-氨基-取代的胍;如在EP-A590455中所述的异喹啉;如在EP-A639573中所述的苯并-稠合的5-员杂环;如在EP-A640587中所述的二酰基-取代的胍;如在US5547953中所述的酰基胍;如在US5567734,EP-A688766中所述的带有全氟烷基的苯基取代的烷基-或烯基羧酸;如在EP-A676395中所述的杂芳酰基胍;如在EP-A682017中所述的双环杂芳酰基胍;如在EP-A738712中所述的茚酰基胍;如在EP-A748795中所述的苄氧羰基胍;如在EP-A744397中所述的带有氟苯基的苯基取代的烯基羧酸胍;如在EP-A755919中所述的取代的肉桂酰基胍;如在EP-A771788中所述的磺酰基脒;如在EP-A774458,EP-A774457中所述的苯二羧酸二胍;如在EP-A787717中所述的二芳基羧酸二胍;如在EP-A790245中所述的取代的苯硫基烯基羧酸胍;如在DE19621319.3中所述的二邻位取代的苯甲酰基胍;如在DE19621482.3和DE19621483.1中所述的取代的2-萘基胍;如在EP-96112275.1中所述的1,2-二氢化茚亚基乙酰基胍;如在DE19633966.9中所述的苯基取代的烯基羧酸胍;如在EP667341中所述的氨基哌啶基苯甲酰基胍;如在EP694537中所述的杂环氧基苄基胍;如在EP704431中所述的邻位取代的苯甲酰基胍;如在EP-A699660中所述的邻位取代的烷基苄基胍;如在EP-A699666中所述的邻位取代的杂环基苯甲酰基胍;如在EP-A708088中所述的邻位取代的5-甲基磺酰基苯甲酰基胍;如在EP-A723963中所述的具有4-氨基取代基的邻位取代的5-烷基磺酰基苯甲酰基胍;如在EP-A743301中所述的具有4-巯基取代基的邻位取代的5-烷基磺酰基苯甲酰基胍;如在EP-A758644中所述的4-磺酰基或4-亚磺酰基苄基胍;如在EP-A760365中所述的烯基苯甲酰基胍;如在DE19548708中所述的具有稠合的,环状砜的苯甲酰基胍;如在WO9426709中所述的苯甲酰基-,多环芳酰基-和杂芳酰基胍;如在WO9604241中所述的3-芳基/杂芳基苯甲酰基胍;如在WO9725310中所述的在5-位具有碱性酰氨基的3-苯基苯甲酰基胍;如在WO9727183中所述的在5-位具有碱性取代基的3-二卤代噻吩基-或3-二卤代苯基苯甲酰基胍;如在WO9512584中所述的在4-位具有某些氨基取代基的3-甲基磺酰基苯甲酰基胍;如在WO9512592中所述的氨氯吡脒衍生物;如在WO9726253中所述的,在4-位具有某些氨基取代基的3-甲基磺酰基苯甲酰基胍;如在EP-A622356和EP-A708091中所述的吲哚酰基胍;如在EP787728中所述的具有稠合的附加环系的吲哚酰基胍;如在WO9504052中所述的甲基胍衍生物;如在EP-A719766中所述的1,4-苯并恶嗪酰基胍;如在JP8225513中所述的5-溴-2-萘甲酰基胍;如在EP-A726254中所述的,在2-位具有苯基的喹啉-4-羰基胍;如在JP09059245中所述的肉桂酰基胍;如在JP9067332中所述的具有萘取代基的丙烯酰基胍;如在JP9067340中所述的具有吲哚取代基的丙烯酰基胍;或如在WO9711055中所述的杂芳基-取代的丙烯酰基胍,和其生理上耐受的盐。
优选的NHE抑制剂是在上面的文献中强调为优选的化合物。非常优选的化合物是cariporide(HOE642),HOE694,EMD96785,FR168888,FR183998,SM-20550,KBR-9032,和其生理上耐受的盐。最优选的是cariporide或其生理上耐受的盐。
一类具有心血管活性、可以与NCBE抑制剂治疗上有益地组合或可以另外与NCBE抑制剂和NHE抑制剂的结合物组合的活性化合物的例子有β-受体阻断剂,钙拮抗剂,血管紧张肽-转化酶抑制剂,血管紧张肽受体阻断剂,环利尿剂,噻嗪类利尿剂,钾-贫乏利尿剂,醛甾酮拮抗剂,如在,例如,降低血压中应用,还有强心苷或其它在治疗心脏机能不全和充血性心衰竭中用于增加收缩力的药剂,还有类型I-IV的抗心律失常药,硝酸酯,KATP开通剂,KATP阻断剂,藜芦次碱-可活化的钠通道抑制剂,等等。例如下列药物是合适的:萘心安,氨酰心安,美多心安;钙拮抗剂盐酸硫氮卓酮,盐酸戊脉安,硝苯吡啶;ACE抑制剂羟甲丙脯酸,enalapril,ramipril;trandolapril,quinapril,spirapril,优选ramipril或trandolapril;血管紧张肽II受体拮抗剂losartan,valsartan,telmisartan,eprosartan,tasosartan,candesartan,irbesartan;环利尿剂速尿灵,苯吡磺苯酸,胺吡磺异丙脲;噻嗪类利尿剂双氢氯噻嗪,甲苯喹唑酮,茚磺苯酰胺;钾-贫乏利尿剂氨氯吡脒,氨苯喋啶,螺内酯;强心苷地高辛,洋地黄毒甙,毒毛旋花甙K;抗心律失常药乙胺碘呋酮,甲磺胺心定,溴苄铵,哌氟酰胺;硝酸酯甘油三硝酸酯;K+(ATP)开通剂cromakalim,lemakalim,nocorandil,pinacidil,长压定;藜芦次碱-可活化的Na+通道抑制剂。
这类特别有益的成分与NCBE抑制剂的组合的例子有非-灭活的钠通道(藜芦次碱-可活化的钠通道)的阻断剂。NCBE抑制剂与有非-灭活的钠通道(藜芦次碱-可活化的钠通道)的阻断剂的组合是适合用于梗塞和再梗塞预防和梗塞治疗,也用于治疗心绞痛并抑制局部缺血引起的心律失常,心动过速和室纤维性颤动的形成和维持,NCBE抑制剂与有非-灭活的钠通道阻断剂的组合也预防性地抑制或大大降低在局部缺血引起的损伤形成中的病理过程。由于其对病理性低氧和局部缺血状况的增强的保护作用,根据本发明NCBE抑制剂与有非-灭活的钠通道阻断剂的组合,作为强烈抑制Na+流入细胞内的结果,被用作用于治疗所有由局部缺血引起的急性或慢性损伤或其作为第一或第二起因的疾病的药物。这涉及其用作在外科排解,例如,例如在器官移植中,其中NCBE抑制剂与有非-灭活的钠通道阻断剂的组合既可以在取出之前在供体内保护器官,或取出期间例如在用其治疗或将其储存在生理浴液中期间、也可以在移植到接受者身体时用于保护取出的器官。NCBE抑制剂与有非-灭活的钠通道阻断剂的组合当进行血管形成术外科排解,例如在心脏上,以及外周血管上时,是有价值的,保护作用的药物。根据其对局部缺血引起的损伤的保护作用,NCBE抑制剂与有非-灭活的钠通道阻断剂的组合也适合作为用于治疗神经系统,尤其是中枢神经系统局部缺血的药物,其中它们适合,例如,用于治疗中风或脑水肿。进一步地,根据本发明的NCBE抑制剂与有非-灭活的钠通道阻断剂的组合也适合用于治疗休克,例如,变应性,心原性,血容量减少性和细菌性休克的形成。
除了作为固定组合给药外,本发明也涉及NCBE抑制剂与NHE抑制剂和/或其它类型的用于治疗上述疾病的心血管活性化合物的同时,分开或连续给药。
本发明还涉及包含a)NCBE抑制剂和NHE抑制剂和/或其生理上耐受的盐;或b)NCBE抑制剂和其它类型的心血管活性化合物的活性物质和/或其生理上耐受的盐;或c)NCBE抑制剂和NHE抑制剂和/或其生理上耐受的盐与其它类型的心血管活性化合物和/或其生理上耐受的盐的活性物质的药物制剂。
优选的药物制剂是其中含有式I化合物和/或其生理上耐受的盐作为NCBE抑制剂的制剂。
通过组合给药,一个组合成分的效果可以通过各个其它成分增强,即根据本发明的组合物或制剂的作用和/或作用周期比各个单个成分的作用和/或作用周期更强或更持久(协同作用)。在组合给药的情况下,这导致与单个给药相比,降低各个组合成分的剂量。根据本发明的组合物或制剂具有被给药的活性化合物的量可以明显降低,而不希望有的副作用可以被消除或大大降低的优点。
本发明进一步涉及商品药包,包含作为药物活性的化合物a)NCBE抑制剂和NHE抑制剂和/或其生理上耐受的盐;或b)NCBE抑制剂和其它类型的心血管活性化合物的活性物质和/或其生理上耐受的盐;或c)NCBE抑制剂,NHE抑制剂和/或其生理上耐受的盐和其它类型的心血管活性化合物和/或其生理上耐受的盐的活性物质,在各种情况下与在治疗或预防上述病症,尤其是治疗心血管疾病时,以同时,分开或连续给药的组合使用这些活性化合物的器械一起。
优选的商品药包是含有式I化合物作为NCBE抑制剂的。
根据本发明的药物制剂可以,例如,通过强烈混合粉末状单个成分,或通过将单个成分溶于合适的溶剂,例如,低级醇中,然后除去溶剂而制得。
在根据本发明的组合物和制剂中,NCBE抑制剂与NHE抑制剂或具有心血管活性的物质的重量比有利地是1∶0.01至1∶100,优选地1∶0.1至1∶10。
根据本发明的组合物和制剂含有总量优选地为0.5-99.5重量%,特别是4-99重量%的这些活性化合物。
当根据本发明用于哺乳动物,优选地用于人时,各种活性化合物成分的剂量例如在0.001至100mg/kg/天的范围内变化。缩写如下:Bn 苄基CH2Cl2 二氯甲烷DCl 解吸-化学离子化DIP 二异丙基醚DMA 二甲基乙酰胺DME 二甲氧基乙烷DMF N,N-二甲基甲酰胺EA 乙酸乙酯(EtOAc)EI 电子撞击eq 当量ES 电子喷射离子化Et 乙基FAB 快速原子轰击HEP 正庚烷HOAc 乙酸Me 甲基MeOH 甲醇mp 熔点MTB 甲基叔丁基醚NCBE 钠-依赖的氯化物/碳酸氢盐交换剂NHE 钠/氢交换剂NMP N-甲基吡咯烷酮RT 室温THF 四氢呋喃TMU N,N,N’,N’-四甲基脲Tol 甲苯CNS 中枢神经系统
从磺酰胺制备磺酰基氰胺的一般操作
将磺酰胺原料溶于10ml/mmol无水乙腈中,滴加3摩尔当量K2CO3和1摩尔当量BrCN在乙腈中的5N溶液,混合物被加热回流直到转换完全(典型的反应时间1-6小时)。然后将反应混合物用硅胶层析而不进一步处理。实施例1:2-丁基-5-甲硫基-3-(2’-氰基氨基磺酰基-联苯-4-基甲基)-3H-咪唑-4-羧酸乙酯
将975mg1-[[2’-(氨基磺酰基)(1,1’-联苯)-4-基]甲基]-2-丁基-4-(甲硫基)-1H-咪唑-5-羧酸乙酯(药物化学杂志,1995,38,2357页)溶于10ml无水乙腈中,然后加入276mg碳酸钾和2ml溴化氰在乙腈中的1N溶液,混合物加热回流4小时。将反应混合物用硅胶层析,用EA/MeOH 10∶1洗脱,结晶后,得到780mg无色无定形固体,分解。mp111℃分解,Rf(EA/MeOH 10∶1)=0.2 MS(FAB):513(M+H)+实施例2:2-丁基-5-甲硫基-3-(3’-氰基氨基磺酰基-联苯-4-基甲基)-3H-咪唑-4-羧酸乙酯a)3-溴-N-二甲基氨基亚乙基苯磺酰胺
将20.3g 3-溴苯磺酰胺溶于120ml DMF,并在室温下滴加57ml二甲基甲酰胺二甲基缩酮。混合物在室温下搅拌5小时,在室温下放置3天。然后将反应混合物倒入1.2L水中并搅拌90分钟,滤出白色沉淀。产物在50℃真空干燥,得到20.5g白色晶体,mp122℃。Rf(EA)=0.59 MS(DCI):291(M+H)+b)4’-甲基联苯-3-磺酸二甲基氨基亚甲基酰胺
将2.9g 3-溴-N-二甲基氨基亚乙基苯磺酰胺,1.5g对甲苯基硼酸,112mg乙酸Pd(II)和224mg三苯膦溶于60ml甲苯和17ml乙醇中,加入10ml 2N碳酸钠水溶液,混合物回流7小时。将反应混合物溶于150ml饱和碳酸钠水溶液和150ml水中,每次用200ml EA萃取3次。萃取液用硫酸钠干燥,真空除去溶剂。用MTB硅胶层析给出1.8g无色泡沫体。Rf(EA/HEP2∶1)=0.22 MS(DCI):302(M+H)+c)4’-溴甲基联苯-3-磺酸二甲基氨基亚甲基酰胺
将1.7g 4’-甲基联苯-3-磺酸二甲基氨基亚甲基酰胺溶于30ml氯苯中,在130℃加入1.0gN-溴代琥珀酰亚胺和10mg过氧化苯甲酰,将混合物回流30分钟。反应混合物用150ml EA溶解并每次用150ml饱和碳酸钠水溶液和饱和亚硫酸钠的8∶1混合物洗两次。水相然后每次用150ml EA萃取两次。合并的有机相用硫酸钠干燥,真空除去溶剂。用MTB硅胶层析给出1.6g浅黄色油状物。Rf(EA)=0.59 MS(DCI):291(M+H)+d)2-丁基-3-[3’-(二甲基氨基亚甲基氨基磺酰基)联苯-4-基甲基]-5-(甲基甲硫基)-3H-咪唑-4-羧酸乙酯
将1.6g 4’-溴甲基联苯-3-磺酸二甲基氨基亚甲基胺,990mg 2-丁基-5-甲基甲硫基-3H-咪唑-4-羧酸乙酯(药物化学杂志,1995,38,2357页)和碳酸钾在室温下在12ml DMF中搅拌4小时,然后放置过夜。然后将反应混合物在室温下再搅拌6小时,倒入125ml饱和碳酸氢钠水溶液和125ml水中,每次用200ml EA萃取3次。萃取液用硫酸钠干燥,真空除去溶剂。在硅胶上用EA/HEP2∶1层析,给出1.1g无色油状物。Rf(EA/HEP1∶1)=0.10MS(ES):543(M+H)+e)2-丁基-5-甲基甲硫基-3-(3’-氨基磺酰基联苯-4-基甲基)-3H-咪唑-4-羧酸乙酯
将1.1g 2-丁基-3-[3’-(二甲基氨基亚甲基氨基磺酰基)联苯-4-基甲基]-5-(甲基甲硫基)-3H-咪唑-4-羧酸乙酯溶于20ml甲醇中,加入10ml饱和盐酸水溶液。将混合物加热回流4小时,然后用6N氢氧化钠水溶液调节至pH=5-6,用50ml水稀释,每次用150ml EA萃取3次。萃取液用硫酸钠干燥,真空除去溶剂。在硅胶上用EA/HEP1∶1层析,给出950mg无色泡沫体。Rf(EA/HEP 1∶1)=0.38 MS(ES):488(M+H)+f)2-丁基-5-甲基甲硫基-3-(3’-氰基氨基磺酰基-联苯-4-基甲基)-3H-咪唑-4-羧酸乙酯
720mg 2-丁基-5-甲硫基-3-(3’-氨基磺酰基联苯-4-基甲基)-3H-咪唑-4-羧酸乙酯根据从磺酰胺制备磺酰基氰胺的一般操作反应,得到550mg无定形固体。Rf(EA/MeOH 10∶1)=0.38 MS(ES):513(M+H)+类似于实施例2合成实施例3-9的标题化合物:实施例3:2-丁基-5-甲基甲硫基-3-(4’-氰基氨基磺酰基-联苯-4-基甲基)-3H-咪唑-4-羧酸乙酯mp244℃分解Rf(EA/MeOH 10∶1)=0.17 MS(ES):513(M+H)+实施例4:2-丁基-5-甲基甲硫基-3-(2’-氰基氨基磺酰基-联苯-3-基甲基)-3H-咪唑-4-羧酸乙酯mp188℃分解Rf(EA/MeOH 10∶1)=0.19 MS(ES):513(M+H)+实施例5:2-丁基-5-甲基甲硫基-3-(3’-氰基氨基磺酰基-联苯-3-基甲基)-3H-咪唑-4-羧酸乙酯mp112℃分解Rf(EA/MeOH 10∶1)=0.15 MS(ES):513(M+H)+实施例6:2-丁基-5-甲基甲硫基-3-(4’-氰基氨基磺酰基-联苯-3-基甲基)-3H-咪唑-4-羧酸乙酯Rf(EA/MeOH 10∶1)=0.36 MS(ES):513(M+H)+实施例7:2-丁基-5-甲基甲硫基-3(2’-氰基氨基磺酰基-联苯-2-基甲基)-3H-咪唑-4-羧酸乙酯mp105℃分解Rf(EA/MeOH 10∶1)=0.23 MS(ES):513(M+H)+实施例8:2-丁基-5-甲基甲硫基-3-(3’-氰基氨基磺酰基-联苯-2-基甲基)-3H-咪唑-4-羧酸乙酯实施例9:2-丁基-5-甲基甲硫基-3-(4’-氰基氨基磺酰基-联苯-2-基甲基)-3H-咪唑-4-羧酸乙酯mp116℃分解Rf(EA/MeOH 10∶1)=0.23 MS(ES):513(M+H)+
从2-环丙基-5-甲基甲硫基-3-(4’-氨基磺酰基-联苯-2-基甲基)-3H-咪唑-4-羧酸乙酯(药物化学杂志,1995,38,2357页)类似于实施例2合成实施例10的标题化合物:实施例10:2-环丙基-5-甲基甲硫基-3-(2’-氰基氨基磺酰基-联苯-2-基甲基)-3H-咪唑-4-羧酸乙酯mp>260℃Rf(EA/MeOH 10∶1)=0.30 MS(ES):497(M+H)+实施例11:4’-(4-氯-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酰基氰酰胺a)4’-(4-氯-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酸二甲基氨基亚甲基酰胺
将2.1g 4-氯-5-甲酰基-2-苯基咪唑(化学药物公报1976,24(5),960),3.8g 4’-溴甲基联苯-2-磺酸二甲基氨基亚甲基胺(药物化学杂志,1995,38,2357页)和2.8g碳酸钾在室温下、在50ml DMF中搅拌30小时。将反应混合物倒入500ml水中,每次用250ml EA萃取2次。然后将有机相用100ml水洗涤并用硫酸镁干燥,真空除去溶剂。在硅胶上用MTB层析给出1.9g白色晶种粉末,mp193℃。Rf(MTB)=0.19 MS(ES):507(M+H)+b)4’-(4-氯-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酰胺
将1.9g 4’-(4-氯-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酸二甲基氨基亚甲基酰胺溶于20ml乙醇中,加入20ml饱和盐酸溶液。将混合物加热回流2小时,然后真空除去挥发成分,残余物溶于200ml水中,溶液用氢氧化钠水溶液调节至pH-7并搅拌1小时,抽滤出沉淀。真空干燥产物,得到1.7g无色固体,mp215℃分解。Rf(MTB)=0.57 MS(FAB):452(M+H)+c)4’-(4-氯-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酰基氰酰胺
800mg 4’-(4-氯-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酰胺根据从磺酰胺制备磺酰基氰酰胺的一般操作反应,得到650mg无定形固体。Rf(EA/MeOH 10∶1)=0.18 MS(ES):477(M+H)+实施例12:4’-(4-甲氧基-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酰基氰酰胺a)4’-(4-甲氧基-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酰胺
将700mg 4’-(4-氯-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酰胺(实施例11b)和620mg氢氧化钠溶于10ml甲醇,加热回流1小时。真空除去溶剂,剩余物溶于20ml水中,溶液用盐酸水溶液调节至pH=7,滤出沉淀。将其真空干燥,得到650mg无色固体,mp188℃。Rf(DIP/MTB1∶1)=0.26 MS(FAB):488(M+H)+b)4’-(4-甲氧基-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酰基氰酰胺
650mg 4’-(4-甲氧基-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酰胺根据从磺酰胺制备磺酰基氰酰胺的一般操作反应,得到600mg无定形固体。Rf(EA/MeOH 10∶1)=0.18 MS(ES):472(M+H)+实施例13:2-丁基-3-(2’-氰基氨基磺酰基联苯-4-基甲基)-3H-咪唑-4-羧酸乙酯a)1-[[2’-(氨基磺酰基)(1,1’-联苯)-4-基]甲基]-2-丁基-1H-咪唑-5-基羧酸乙酯
将244mg1-[[2’-(氨基磺酰基)(1,1’-联苯)-4-基]甲基]-2-丁基-4-(甲硫基)-1H-咪唑-5-基羧酸乙酯(药物化学杂志,1995,38,2357)溶于10ml乙醇中,加入200mg阮内镍。然后将混合物回流6小时,再加入200mg阮内镍并再次回流3小时。滤出残余物,真空除去溶剂。得到200mg无色油状物。Rf(DIP/MTB1∶1)=0.12 MS(FAB):442(M+H)+b)2-丁基-3-(2’-氰基氨基磺酰基联苯-4-基甲基)-3H-咪唑-4-羧酸乙酯
140mg 1-[[2’-(氨基磺酰基)(1,1’-联苯)-4-基]甲基]-2-丁基-1H-咪唑-5-基羧酸乙酯根据从磺酰胺制备磺酰基氰酰胺的一般操作反应(反应时间1小时)得到90mg白色晶体,mp 121℃分解。Rf(EA/MeOH5∶1)=0.20 IR(C≡N):2174.7cm-1MS(ES):467(M+H)+实施例14:4’-(2-丁基-5-氰基-4-甲氧基咪唑-1-基甲基)联苯-2-磺酰基氰酰胺a)4’-[2-丁基-5-(羟基亚氨基甲基)-4-甲氧基咪唑-1-基甲基]联苯-2-磺酰胺
将4.1g 4’-(4-甲氧基-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酰胺(实施例12a)溶于500ml甲醇,加入3.3g盐酸羟胺和1.2g1,4-二氮杂双环[2.2.2]辛烷。混合物在室温下搅拌11小时,然后用200ml饱和碳酸氢钠水溶液和200ml水处理,每次用400ml EA萃取6次。萃取液用硫酸钠干燥并真空除去溶剂。得到4.5g无色油状物。Rf(MTB/甲苯1∶1)=0.32b)4’-(2-丁基-5-氰基-4-甲氧基咪唑-1-基甲基)联苯-2-磺酸乙酰胺
将210mg 4’-[2-丁基-5-(羟基亚氨基甲基)-4-甲氧基咪唑-1-基甲基]联苯-2-磺酰胺溶于4ml吡啶中并加入4ml乙酸酐。将混合物回流170分钟,然后倒入200ml冰冷却的饱和碳酸氢钠水溶液中,每次用80ml EA萃取3次。萃取液用硫酸钠干燥,真空除去溶剂。得到230mg无色油状物。Rf(MTB/甲苯1∶1)=0.32 MS(FAB):467(M+H)+c)4’-(2-丁基-5-氰基-4-甲氧基咪唑-1-基甲基)联苯-2-磺酰胺
将2.1g4’-(2-丁基-5-氰基-4-甲氧基咪唑-1-基甲基)联苯-2-磺酸乙酰胺悬浮于40ml 20%硫酸水溶液中,混合物被回流3小时。将反应混合物滴加到400ml KH2PO4的2/3M水溶液中,并每次用300ml EA萃取3次。萃取液用硫酸钠干燥,真空除去溶剂。在硅胶上用MTB层析给出1.6g无色油状物。Rf(MTB)=0.48d)4’-(2-丁基-5-氰基-4-甲氧基咪唑-1-基甲基)联苯-2-磺酰基氰酰胺
360mg4’-(2-丁基-5-氰基-4-甲氧基咪唑-1-基甲基)联苯-2-磺酰胺根据从磺酰胺制备磺酰基氰酰胺的一般操作反应(反应时间1小时),得到300mg白色晶体,mp 160℃分解。Rf(EA/MeOH5∶1)=0.27 IR(C≡N):2177.2cm-1MS(ES):450(M+H)+实施例15:4’-(2-丁基-4-氯-5-甲酰基咪唑-1-基甲基)联苯-2-磺酰基氰酰胺a)4’-(2-丁基-4-氯-5-甲酰基咪唑-1-基甲基)联苯-2-磺酰胺
将10.6g4’-(2-丁基-4-氯-5-甲酰基咪唑-1-基甲基)联苯-2-磺酸二甲基氨基亚甲基酰胺(药物化学杂志,1995,38,2357)溶于200ml甲醇中并加入100ml饱和盐酸水溶液。混合物被回流2小时,冷却后用2N氢氧化钠水溶液调节至pH=5-6并每次用200ml EA萃取4次。萃取液用硫酸钠干燥并真空除去溶剂。得到9.2g无色油状物。Rf(EA/HEP2∶1)=0.46b)4’-(2-丁基-4-氯-5-甲酰基咪唑-1-基甲基)联苯-2-磺酰基氰酰胺
将160mg 4’-(2-丁基-4-氯-5-甲酰基咪唑-1-基甲基)联苯-2-磺酰胺根据从磺酰胺制备磺酰基氰酰胺的一般操作反应(反应时间75分钟),得到110mg白色晶体,mp135℃分解。Rf(EA/MeOH5∶1)=0.28 IR(C≡N):2176.9cm-1MS(ESI):457(M+H)+类似于实施例1合成实施例16-19的标题化合物:实施例16:5-甲基甲硫基-2-丙基-3-(2’-氨基磺酰基联苯-4-基甲基)-3H-咪唑-4-羧酸乙酯mp165℃(分解) Rf(EA/MeOH5∶1)=0.42 IR(C≡N):2178.6cm-1MS(ES):499(M+H)+实施例17:2-乙基-5-甲基甲硫基-3-(2’-氰基氨基磺酰基联苯-4-基甲基)-3H-咪唑-4-羧酸乙酯mp94℃(分解) Rf(EA/MeOH5∶1)=0.38 IR(C≡N):2173.3cm-1MS(ES):485(M+H)+实施例18:2-甲基-5-甲基甲硫基-3-(2’-氰基氨基磺酰基联苯-4-基甲基)-3H-咪唑-4-羧酸乙酯mp169℃(分解) Rf(EA/MeOH5∶1)=0.29 IR(C≡N):2173.3cm-1MS(ES):471(M+H)+实施例19:2-异丙基-5-甲基甲硫基-3-(2’-氰基氨基磺酰基联苯-4-基甲基)-3H-咪唑-4-羧酸乙酯mp276℃(分解) Rf(EA/MeOH5∶1)=0.28 IR(C≡N):2178.8cm-1MS(ES):499(M+H)+实施例20:2-丁基-5-甲基甲硫基-3-(2’-氰基氨基磺酰基联苯-4-基甲基)-3H-咪唑-4-羧酸异丙基酯a)2-丁基-5-甲基甲硫基-3-(2’-氨基磺酰基联苯-4-基甲基)-3H-咪唑-4-羧酸异丙基酯
将980mg2-丁基-5-甲基甲硫基-3-(2’-氨基磺酰基联苯-4-基甲基)-3H-咪唑-4-羧酸乙酯溶于10ml异丙醇中然后加入590μl异丙醇钛(IV)。将混合物回流8小时,再加入1.2ml异丙醇钛(IV)。再回流11小时之后,将混合物倒入200ml饱和碳酸氢钠水溶液中并用200ml水稀释。每次用150ml EA萃取3次,萃取液用硫酸钠干燥,真空除去溶剂。在硅胶上用EA/HEP1∶2层析给出420mg无色油状物。Rf(MTB/HEP/CHCl3 2∶1∶1)=0.36b)2-丁基-5-甲基甲硫基-3-(2’-氰基氨基磺酰基联苯-4-基甲基)-3H-咪唑-4-羧酸异丙基酯
410mg 2-丁基-5-甲基甲硫基-3-(2’-氨基磺酰基联苯-4-基甲基)-3H-咪唑-4-羧酸异丙基酯根据从磺酰胺制备磺酰基氰酰胺的一般操作反应(反应时间2小时),得到310mg白色晶体,mp113℃分解。Rf(EA/MeOH5∶1)=0.16 IR(C≡N):2178.2cm-1MS(ES):527(M+H)+实施例21:2-丁基-3-(2’-甲基-5’-氰基氨基磺酰基联苯-4-基甲基)-5-甲基甲硫基-3H-咪唑-4-羧酸乙酯a)4,4,5,5-四甲基-2-对甲苯并[1.3.2]二氧杂硼杂环戊烷(dioxaborolane)
将1.4g对甲苯基硼酸,1.2g频哪醇和催化量(大约2mg)对甲苯磺酸分3次每次40ml悬浮于甲苯中,在每种情况下都真空除去挥发性成分。然后将混合物在高真空中干燥,得到2.0g浅黄色油状物。Rf(EA/HEP)=0.86b)2-(4-溴甲基苯基)-4,4,5,5-四甲基-2-对甲苯并[1.3.2]二氧杂硼杂环戊烷
将2.0g4,4,5,5-四甲基-2-对甲苯并[1.3.2]二氧杂硼杂环戊烷溶于50ml氯苯中,在沸腾的温度下分批加入1.7gN-溴代琥珀酰亚胺和5mg过氧化苯甲酰。将混合物回流4小时,冷却后用200ml EA稀释。每次用100ml饱和碳酸氢钠水溶液和饱和硫酸钠水溶液的8∶1混合物洗涤两次,然后水相每次用100ml EA萃取2次,合并的有机相用硫酸钠干燥。真空除去溶剂,在硅胶上用EA/HEP1∶4层析给出1.6g浅黄色油状物。Rf(EA/HEP1∶4)=0.55 MS(DCI):297(M+H)+c)2-丁基-5-甲基甲硫基-3-[4-(4,4,5,5-四甲基[1.3.2]二氧杂硼杂环戊烷-2-基)苄基]-3H-咪唑-4-羧酸乙酯
将1.5g 2-(4-溴甲基苯基)-4,4,5,5-四甲基-2-对甲苯并[1.3.2]二氧杂硼杂环戊烷,1.2g 2-丁基-5-甲基甲硫基-3H-咪唑-4-羧酸乙酯(药物化学杂志,1995,38,2357)和700mg碳酸钾在室温下于15mlDMF中搅拌14小时。将反应混合物倒入200ml饱和碳酸氢钠水溶液中,用200ml水稀释,每次用150ml EA萃取3次。萃取液用硫酸钠干燥并真空除去溶剂。在硅胶上用EA/HEP1∶4层析给出1.4g无色油状物。Rf(EA/HEP 1∶2)=0.29 MS(FAB):459(M+H)+d)2-丁基-5-甲基甲硫基-3-[4-(二羟基硼烷基)苄基]-3H-咪唑-4-羧酸乙酯
将1.2g 2-丁基-5-甲基甲硫基-3-[4-(4,4,5,5-四甲基[1.3.2]二氧杂硼杂环戊烷-2-基)苄基]-3H-咪唑-4-羧酸乙酯溶于50ml EA中,加入260μl二乙醇胺。混合物在室温下在超声波清洗浴中搅拌4小时。然后加入260μl二乙醇胺,混合物在超声波清洗浴中再处理2小时。然后在室温下搅拌14小时,滤出沉淀。将此沉淀溶于50ml半浓的硫酸氢钠水溶液中并在室温下搅拌2小时。然后每次用150ml EA萃取3次,萃取液用硫酸钠干燥,真空除去溶剂。得到390mg无定形固体。Rf(EA)=0.62 MS(FAB,+甘油):433(M+H)+e)3-溴-4-甲基苯磺酰胺
将10g 3-溴-4-甲基苯胺悬浮于22ml水中并滴加22ml饱和盐酸水溶液。将混合物在室温下搅拌5分钟然后冷却至-10℃,在此温度下滴加4.1g亚硝酸钠在15ml水中的溶液。混合物在-15℃搅拌45分钟,并在室温下分批加到916mg CuCl2×2H2O和92mg CuI在SO2于冰醋酸中的饱和溶液中的悬浮液内。将反应混合物在水浴中温热直到氮气逸出完全。然后每次用250ml乙醚萃取3次,有机相每次用80ml水洗涤两次,硫酸钠干燥。真空除去溶剂,剩余物溶于75ml丙酮中,溶液被冷却至0℃,在此温度下慢慢滴加饱和氨水溶液直到pH达到10。在此期间有沉淀出现,将其滤出并用MTB重结晶得到2.5g白色晶体,mp 156℃。Rf(DIP)=0.30 MS(DCI):250(M+H)+f)3-溴-N-二甲基氨基亚甲基-4-甲基苯磺酰胺
将7.7g 3-溴-4-甲苯磺酰胺溶于50ml DMF并在室温下滴加20.5ml二甲基甲酰胺二甲基缩酮。将混合物在室温下搅拌4.5小时,然后抽滤出产物,真空干燥。得到9.0g浅黄色晶体,mp162℃。Rf(EA)=0.48 MS(ES):305(M+H)+g)2-丁基-3-[5’-(二甲基氨基亚乙基氨基磺酰基)-2’-甲基联苯-4-基甲基]-5-甲基甲硫基-3H-咪唑-4-羧酸乙酯
将390mg 2-丁基-5-甲基甲硫基-3-[4-(二羟基硼烷基)苄基]-3H-咪唑-4-羧酸乙酯,288mg 3-溴-N-二甲基氨基亚甲基-4-甲基苯磺酰胺,11mg乙酸Pd(II)和28mg三苯膦悬浮于6ml甲苯中,加入1.6ml乙醇和940μl 2M碳酸钠水溶液。混合物被回流5.5小时,将反应混合物倒入200ml半浓的碳酸氢钠水溶液中,每次用150ml EA萃取3次。萃取液用硫酸钠干燥并真空除去溶剂。在硅胶上层析给出150mg无色油状物。Rf(EA/HEP2∶1)=0.19 MS(ES):557(M+H)+h)2-丁基-3-[5’-氨基磺酰基-2’-甲基联苯-4-基甲基]-5-甲基甲硫基-3H-咪唑-4-羧酸乙酯
将140mg2-丁基-3-[5’-(二甲基氨基亚乙基氨基磺酰基)-2’-甲基联苯-4-基甲基]-5-甲基甲硫基-3H-咪唑-4-羧酸乙酯溶于2.5ml甲醇中,滴加1.3ml饱和盐酸水溶液。然后将反应混合物回流75分钟,用6N氢氧化钠水溶液调节至pH=6并用50ml水稀释。将其每次用50ml EA萃取5次,萃取液用硫酸钠干燥,真空除去溶剂。得到110mg无定形固体。Rf(EA/HEP2∶1)=0.44 MS(ES):502(M+H)+i)2-丁基-3-(2’-甲基-5’-氰基氨基磺酰基联苯-4-基甲基)-5-甲基甲硫基-3H-咪唑-4-羧酸乙酯
将100mg 2-丁基-3-[5’-氨基磺酰基-2’-甲基联苯-4-基甲基]-5-甲基甲硫基-3H-咪唑-4-羧酸乙酯根据从磺酰胺制备磺酰基氰酰胺的一般操作反应(反应时间13/4小时),得到63mg白色晶体,mp127℃分解。Rf(EA/MeOH5∶1)=0.09 IR(C≡N):2179.3cm-1MS(ES):527(M+H)+类似于实施例21合成实施例22-26的标题化合物:实施例22:2-丁基-3-(2’-甲基-4’-氰基氨基磺酰基联苯-4-基甲基)-5-甲基甲硫基-3H-咪唑-4-羧酸乙酯mp211℃ Rf(EA/MeOH5∶1)=0.20 IR(C≡N):2182.9cm-1MS(ES):527(M+H)+实施例23:2-丁基-5-甲基甲硫基-3-(4’-氰基氨基磺酰基-2’-三氟甲基联苯-4-基甲基)-3H-咪唑-4-羧酸乙酯(无定形) Rf(EA/MeOH10∶1)=0.20 IR(C≡N):2184.9cm-1MS(ES):581(M+H)+实施例24:2-丁基-3-(2’-甲基-5’-氰基氨基磺酰基联苯-3-基甲基)-5-甲基甲硫基-3H-咪唑-4-羧酸乙酯mp160℃(分解) Rf(EA/MeOH10∶1)=0.18 IR(C≡N):2181.3cm-1MS(ES):527(M+H)+实施例25:2-丁基-3-(2’-甲基-4’-氰基氨基磺酰基联苯-3-基甲基)-5-甲基甲硫基-3H-咪唑-4-羧酸乙酯mp115℃(分解) Rf(EA/MeOH10∶1)=0.18 IR(C≡N):2182.2cm-1MS(ES):527(M+H)+实施例26:2-丁基-5-甲基甲硫基-3-(4’-氰基氨基磺酰基-2’-三氟甲基联苯-3-基甲基)-3H-咪唑-4-羧酸乙酯mp122℃(分解) Rf(EA/MeOH 10∶1)=0.27 IR(C≡N):2186.1cm-1MS(ES):581(M+H)+实施例27:4’-(2-丁基-4-甲基甲硫基咪唑-1-基甲基)联苯-2-磺酰基氰酰胺a)4’-(2-丁基-4-甲基甲硫基咪唑-1-基甲基)联苯-2-磺酰胺
将460mg 2-丁基-5-甲基甲硫基-3-(2’-氨基磺酰基联苯-4-基甲基)-3H-咪唑-4-羧酸溶于异丙醇中,注射加入220μl氯化亚砜,混合物被回流4小时。混合物用6N氢氧化钠水溶液调节至pH=6,用100ml水稀释,每次用100ml EA萃取3次。萃取液用硫酸钠干燥并真空除去溶剂。在硅胶上用EA/HEP1∶1层析,给出300mg无色油状物。Rf(EA)=0.58 MS(FAB):416(M+H)+b)4’-(2-丁基-4-甲基甲硫基咪唑-1-基甲基)联苯-2-磺酰基氰酰胺
将260mg4’-(2-丁基-4-甲硫基咪唑-1-基甲基)联苯-2-磺酰胺根据从磺酰胺制备磺酰基氰酰胺的一般操作反应(反应时间2小时20分钟)得到50mg无定形粉末。Rf(EA/MeOH5∶1)=0.19 IR(C≡N):2171.8cm-1MS(ES):441(M+H)+实施例28:4’-(4-氯-2-苯基咪唑-1-基甲基)联苯-2-磺酰基氰酰胺a) 4’-(4-氯-2-苯基咪唑-1-基甲基)联苯-2-磺酰胺
将9.2g 4’-(4-氯-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酸二甲基氨基亚甲基酰胺(实施例11a),95ml饱和盐酸水溶液和95ml乙醇回流2小时。冷却后,混合物用500ml水稀释,每次用500ml EA萃取2次,有机相每次用100ml饱和氯化钠水溶液洗涤两次。萃取液用硫酸钠干燥,真空除去溶剂。产品混合物用200ml EA重结晶,得到6.2g4’-(4-氯-2-苯基咪唑-1-基甲基)联苯-2-磺酰胺。真空除去母液的溶剂,剩余物在硅胶上用MTB/DIP1∶1层析。得到40mg无色油状物。Rf(MTB/DIP)=0.22 MS(ES):424(M+H)+b)4’-(4-氯-2-苯基咪唑-1-基甲基)联苯-2-磺酰基氰酰胺
将30mg4’-(4-氯-2-苯基咪唑-1-基甲基)联苯-2-磺酰胺根据从磺酰胺制备磺酰基氰酰胺的一般操作反应(反应时间2小时)得到15mg无定形粉末。Rf(EA/MeOH10∶1)=0.09 MS(ES-):447(M-H)-ES-:电子喷射,负电模式实施例29:4’-(5-乙酰基-4-氯-2-苯基咪唑-1-基甲基)联苯-2-磺酰基氰酰胺a)3-(4-溴苄基)-5-氯-2-苯基-3H-咪唑-4-甲醛
将3.0g 4-氯-5-甲酰基-2-苯基咪唑(化学药物公报1976,24(5),960),7.0g4-溴苄基溴和11.7g碳酸钾在室温下在200ml DMF中搅拌20小时。然后将反应混合物倒入500ml水中,抽滤出沉淀并在硅胶上用DIP层析。得到3.9g无定形泡沫体。Rf(DIP)=0.36 MS(ES):375(M+H)+b)1-[3-(4-溴代苄基)-5-氯-2-苯基-3H-咪唑-4-基]乙醇
将3.8g 3-(4-溴苄基)-5-氯-2-苯基-3H-咪唑-4-甲醛溶于50ml THF中,在室温下慢慢注射加入由385mg镁屑和990μl甲基碘在50ml乙醚中制备的Grignard溶液。混合物在室温下搅拌3天,然后加入200ml 5%硫酸氢钠水溶液,混合物每次用200ml EA萃取两次。萃取液用硫酸钠干燥,真空除去溶剂。得到3.7g无色油状物。Rf(DIP)=0.13 MS(DCI):391(M+H)+c)1-[3-(4-溴代苄基)-5-氯-2-苯基-3H-咪唑-4-基]乙酮
将3.7g 1-[3-(4-溴代苄基)-5-氯-2-苯基-3H-咪唑-4-基]乙醇溶于20ml乙酸中,在15℃慢慢地用15.6g(NH4)2Ce(NO3)6在30ml水中的溶液处理。混合物在10℃搅拌30分钟,然后温热至室温。将其用200ml水稀释,并用碳酸氢钠调节至pH=5,抽滤出产物。用DIP和MTB层析给出2.0g无色油状物。Rf(DIP)=0.42 MS(DCI):389(M+H)+d)4’-(5-乙酰基-4-氯-2-苯基咪唑-1-基甲基)联苯-2-磺酸叔丁基酰胺
将21.0g 1-[3-(4-溴代苄基)-5-氯-2-苯基-3H-咪唑-4-基]乙酮,2.0g N-叔丁基-2-二羟基硼烷-2-基苯磺酰胺,135mg三苯膦,58mg乙酸Pd(II)和1.1g碳酸钠在50ml甲苯和10ml水中回流6小时。混合物用200ml EA稀释,用50ml饱和碳酸氢钠水溶液洗涤两次,硫酸钠干燥,真空除去溶剂。在硅胶上用DIP层析给出1.4g无色油状物。MS(ES):522(M+H)+e)4’-(5-乙酰基-4-氯-2-苯基咪唑-1-基甲基)联苯-2-磺酰胺
将1.0g 4’-(5-乙酰基-4-氯-2-苯基咪唑-1-基甲基)联苯-2-磺酸叔丁基酰胺和230μl茴香醚溶于5ml三氟乙酸,在室温下放置24小时。然后真空除去挥发性成分,剩余物用庚烷蒸煮。得到870mg无定形固体。Rf(MTB)=0.66 MS(ES):466(M+H)+f)4’-(5-乙酰基-4-氯-2-苯基咪唑-1-基甲基)联苯-2-磺酰基氰酰胺
将100mg4’-(5-乙酰基-4-氯-2-苯基咪唑-1-基甲基)联苯-2-磺酰胺根据从磺酰胺制备磺酰基氰酰胺的一般操作反应(反应时间2小时)得到30mg无定形粉末。Rf(EA/MeOH 10∶1)=0.20 IR(C≡N):2182.0cm-1MS(ES-):489(M-H)-实施例30:4’-(5-乙酰基-4-甲氧基-2-苯基咪唑-1-基甲基)联苯-2-磺酰基氰酰胺a)4’-(5-乙酰基-4-甲氧基-2-苯基咪唑-1-基甲基)联苯-2-磺酰胺
将760mg4’-(5-乙酰基-4-氯-2-苯基咪唑-1-基甲基)联苯-2-磺酰胺和650mg氢氧化钠在10ml甲醇中回流22小时。然后真空除去溶剂,剩余物溶于20ml水中,溶液用10%盐酸水溶液调节至pH=6,每次用50ml EA萃取3次。萃取液用硫酸钠干燥,真空除去溶剂。在硅胶上用MTB/DIP 1∶1层析,给出230mg粘性油状物。Rf(MTB/DIP1∶1)=0.31 MS(ES):462(M+H)+b)4’-(5-乙酰基-4-甲氧基-2-苯基咪唑-1-基甲基)联苯-2-磺酰基氰酰胺
将210mg 4’-(5-乙酰基-4-甲氧基-2-苯基咪唑-1-基甲基)联苯-2-磺酰胺据从磺酰胺制备磺酰基氰酰胺的一般操作反应(反应时间2小时)得到181mg无定形粉末。Rf(EA/MeOH10∶1)=0.14 IR(C≡N):2179.7cm-1MS(ES-):485(M-H)-实施例31:4’-(2,4,5-三苯基咪唑-1-基甲基)联苯-2-磺酰基氰酰胺a)4’-(2,4,5-三苯基咪唑-1-基甲基)联苯-2-磺酸二甲基氨基亚甲基酰胺
将1.5g 2,4,5-三苯基咪唑,1.9g 4’-溴甲基联苯-2-磺酸二甲基氨基亚甲基酰胺(药物化学杂志,1995,38,2357)和2.1g碳酸钾在室温下在50ml DMF中搅拌6天。将反应混合物倒入300ml水中并用500ml EA萃取。有机相每次用250ml饱和氯化钠水溶液洗涤3次,用硫酸钠干燥,真空除去溶剂。得到2.8g粘性油状物。MS(ES):579(M+H)+b)4’-(2,4,5-三苯基咪唑-1-基甲基)联苯-2-磺酰胺
将1.9g 4’-(2,4,5-三苯基咪唑-1-基甲基)联苯-2-磺酸二甲基氨基亚甲基酰胺在20ml乙醇和20ml饱和盐酸水溶液中回流3小时。真空除去挥发性成分,剩余物与100ml水搅拌,滤出产物。得到1.0g无定形粉末。Rf(MTB)=0.47 MS(ES):542(M+H)+c)4’-(2,4,5-三苯基咪唑-1-基甲基)联苯-2-磺酰基氰酰胺
将1.0g 4’-(2,4,5-三苯基咪唑-1-基甲基)联苯-2-磺酰胺根据从磺酰胺制备磺酰基氰酰胺的一般操作反应(反应时间2小时)得到970mg无定形粉末。Rf(EA/MeOH10∶1)=0.26 IR(C≡N):2173.5cm-1MS(FAB):576(M+H)+实施例32:3’-氯-4’-(4-氯-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酰基氰酰胺a)4-溴-1-溴甲基-2-氯苯
将7.1ml 4-溴-2-氯甲苯溶于20ml氯苯中,混合物在130℃分批用9.4gN-溴代琥珀酰亚胺和200mg过氧化苯甲酰处理。将其回流30分钟,冷却后用100ml二氯甲烷稀释,分别用50ml饱和亚硫酸钠水溶液和100ml饱和碳酸氢钠水溶液洗涤一次。萃取液用硫酸钠干燥,真空除去溶剂。得到11.0g浅黄色油状物。Rf(EA/HEP1∶8)=0.49 MS(DCI):238(M+H)+b)3-(4-溴-2-氯苄基)-5-氯-2-苯基-3H-咪唑-4-甲醛
将1.5g 4-氯-5-甲酰基-2-苯基咪唑(化学药物公报1976,24(5),960),5.8g碳酸钾和8.0g4-溴-1-溴甲基-2-氯苯在室温下在50ml DMF中搅拌24小时。然后将混合物用250ml EA稀释,每次用100ml水洗涤两次并用100ml饱和氯化钠水溶液洗涤一次。萃取液用硫酸钠干燥,真空除去溶剂。在硅胶上用EA/HEP1∶4层析给出2.2g无色油状物。Rf(EA/HEP1∶4)=0.47 MS(ES):411(M+H)+c)3’-氯-4’-(4-氯-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酸叔丁基酰胺
将2.2g 3-(4-溴-2-氯苄基)-5-氯-2-苯基-3H-咪唑-4-甲醛,2.0g N-叔丁基-2-二羟基硼烷-2-基苯磺酰胺(药物化学杂志1997,40,547),140三苯膦,64mg乙酸Pd(II)和1.2g碳酸钠溶于30ml甲苯,10ml乙醇和10ml水中,溶液被回流3小时。冷却后,加入200ml饱和碳酸氢钠水溶液,混合物每次用200mlEA萃取3次。萃取液用硫酸镁干燥,真空除去溶剂。在硅胶上层析给出1.5g无色泡沫体。Rf(DIP)=0.25 MS(ES):542(M+H)+d)3’-氯-4’-(4-氯-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酰胺
将1.5g 3’-氯-4’-(4-氯-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酸叔丁基酰胺和340μl茴香醚溶于10ml三氟乙酸,溶液在室温下搅拌24小时。然后真空除去挥发性成分,剩余物每次用50ml甲苯处理两次,再次真空除去挥发性成分。得到1.5g无色泡沫体。Rf(DIP)=0.15 MS(ES):486(M+H)+e)3’-氯-4’-(4-氯-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酰基氰酰胺
将400mg 3’-氯-4’-(4-氯-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酰胺根据从磺酰胺制备磺酰基氰酰胺的一般操作反应(反应时间2小时)得到970mg无定形粉末。Rf(EA/MeOH10∶1)=0.23 IR(C≡N):2179.2cm-1MS(FAB):511(M+H)+类似于实施例32合成实施例33的标题化合物。实施例33:3’-氟-4’-(4-氯-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酰基氰酰胺Rf(EA/MeOH10∶1)=0.28 IR(C≡N):2177.7cm-1MS(ES-):493(M-H)-类似于实施例12,用3’-氯-4’-(4-氯-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酰胺(实施例32d)作原料,合成实施例34的标题化合物:实施例34:3’-氯-4’-(4-甲氧基-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酰基氰酰胺Rf(EA/MeOH10∶1)=0.26 IR(C≡N):2177.4cm-1MS(ES-):505(M-H)-实施例35:3’-氯-4’-(4-苯氧基-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酰基氰酰胺a)3’-氯-4’-(4-苯氧基-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酰胺
将500mg3’-氯-4’-(4-氯-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酰胺(实施例32d),116苯酚和426mg碳酸钾在10ml DMF中在100℃搅拌8小时。混合物然后冷却至室温,加入100ml饱和碳酸氢钠水溶液,每次用300ml EA萃取3次。有机相每次用50ml水洗涤3次,硫酸钠干燥并真空除去溶剂。在硅胶上用EA/HEP1∶1层析,给出150mg树脂状化合物。Rf(甲苯/EA2∶1)=0.39 MS(ES+):544(M+H)+b)3’-氯-4’-(4-苯氧基-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酰基氰酰胺
将145mg3’-氯-4’-(4-苯氧基-5-甲酰基-2-苯基咪唑-1-基甲基)联苯-2-磺酰胺根据从磺酰胺制备磺酰基氰酰胺的一般操作反应(反应时间2小时)得到99mg泡沫体。Rf(EA/MeOH10∶1)=0.35 IR(C≡N):2180.4cm-1MS(ES-):567(M-H)-类似于实施例11合成实施例36-38的标题化合物:实施例36:4’-[4-氯-5-甲酰基-2-(4-氯苯基)咪唑-1-基甲基]联苯-2-磺酰基氰酰胺Rf(EA/MeOH10∶1)=0.28 mp 160-187℃ MS(ES):511(M+H)+实施例37:4’-[4-氯-5-甲酰基-2-(4-甲氧基苯基)咪唑-1-基甲基]联苯-2-磺酰基氰酰胺Rf(EA/MeOH10∶1)=0.31 mp110-126℃ MS(ES):507(M+H)+实施例38:4’-[4-氯-5-甲酰基-2-(2,6-二氟苯基)咪唑-1-基甲基]联苯-2-磺酰基氰酰胺Rf(EA/MeOH 10∶1)=0.25 mp164-178℃ MS(ES):513(M+H)+药理数据:在人内皮细胞中抑制Na+-依赖的Cl-/HCO3 -交换剂(NCBE)
人内皮细胞(ECV-304)在胰蛋白酶/EDTA缓冲液(0.05/0.02%于磷酸缓冲液中)的帮助下从培养瓶中分离,离心(100g,5分钟)后,溶于缓冲的盐溶液(mmol/l:115 NaCl,20NH4Cl,5KCl,1CaCl2,1MgCl2,20N-(2-羟基乙基)哌嗪-N’-2-乙磺酸(HEPES),5葡萄糖和1g/l牛血清白蛋白;pH7.4)。此细胞悬浮液在37℃用5μM BCECF-乙酰氧基甲基酯温育20分钟。然后洗涤细胞并悬浮于无钠和碳酸氢盐的缓冲液(5HEPES,133.8氯化胆碱,4.7KCl,1.25MgCl2,0.97K2HPO4,0.23KH2PO4,5葡萄糖;pH7.4)。
为了随后的在FLIPR(荧光成像板读数计)上的荧光测量,在每种情况下具有20000个细胞的细胞悬浮液被移液到96-孔微滴板的每个孔内,并将此微滴板离心(100g,5分钟)。
在FLIPR中,在每种情况下,将100μl缓冲液从进一步预处理的微滴板中除去,并移液到96孔测量板的每个孔中。含有50μM HOE642的含碳酸氢盐和钠的缓冲液(mmol/l:5HEPES,93.8NaCl,40NaHCO3,4.7KCl,1.25CaCl2,1.25MgCl2,0.97Na2HPO4,0.23NaH2PO4,5葡萄糖;pH7.4)被用作100%对照,即通过NCBE恢复细胞内pH(pHi)。对于0%对照,即没有任何pHi恢复,无碳酸氢盐,含钠缓冲液(mmol/l:5HEPES,133.8NaCl,4.7KCl,1.25CaCl2,1.25MgCl2,0.97Na2HPO4,0.23NaH2PO4,5葡萄糖;pH7.4)被应用,往其中同样加入50μM HOE642。以各种浓度将本发明化合物加入含有钠和碳酸氢盐的溶液。将缓冲液加入在测量板中的带染料、酸化的细胞中后,测量在每个孔中对应于pHi升高的荧光强度的增加。在此情况下在35℃2分钟的周期记录动力学。
对于不同浓度的本发明化合物,荧光强度的增加涉及两个对照,由此测定物质的抑制作用。结果在10μM抑制剂浓度下NCBE的残留活性实施例 以%计的残留活性1 17.72 39.63 74.14 39.75 43.26 58.67 72.18 60.89 31.610 21.611 15.012 20.813 89.514 47.315 55.716 11.517 39.118 45.819 21.520 19.521 42.622 34.223 31.624 29.225 70.826 65.327 50.028 30.529 39.630 48.831 36.532 7.833 7.634 5.535 3.236 7.837 16.838 8.6
Claims (20)
1.式I化合物和其生理上耐受的盐其中的符号具有如下意义:R1是氢,具有1,2,3,4,5,6,7或8个碳原子的烷基或-CaH2a-苯基,
它是未取代的或被1-3个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(8)R(9)的取代基取代;
R(8)和R(9)
相互独立地是H或(C1-C4)烷基;
a是零,1或2;或R1是-CbH2b-(C1-C9)杂芳基,
它是未取代的或被1-3个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(10)R(11)的取代基取代;R(10)和R(11)
相互独立地是H或(C1-C4)烷基;
b是零,1或2;或R1是-CdH2d-(C3-C7)环烷基;
d是零,1或2;R2和R3
相互独立地是氢,F,Cl,Br,I,CF3,-C≡N,-NO2,CH2OR17,CO-R6或O-R7;
R17是氢,具有1,2,3,4,5,6,7或8个碳原子的烷基
R6是氢,具有1,2,3,4,5,6,7或8个碳原子的烷基,OR30或苯基,
它是未取代的或被1-3个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(31)R(32)的取代基取代;
R(31)和R(32)
相互独立地是H或(C1-C4)烷基;
R30是氢或具有1,2,3,4,5,6,7或8个碳原子的烷基;R7是氢,具有1,2,3,4,5,6,7或8个碳原子的烷基,苯基,
它是未取代的或被1-3个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(12)R(13)的取代基取代;
R(12)和R(13)
相互独立地是H或(C1-C4)烷基;或R7是(C1-C9)杂芳基,
它是未取代的或被1-3个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(14)R(15)的取代基取代;
R(14)和R(15)
相互独立地是H或(C1-C4)烷基;或R2和R3
相互独立地是具有1,2,3,4,5,6,7或8个碳原子的烷基,具有3,4,5,6或7个碳原子的环烷基或-CgH2g-苯基,
它是未取代的或被1-3个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(18)R(19)的取代基取代;
R(18)和R(19)
相互独立地是H或(C1-C4)烷基;g是零,1或2;或R2和R3
是-CIH2I-(C1-C9)杂芳基,
它是未取代的或被1-3个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和
NR(20)R(21)的取代基取代;
R(20)和R(21)
相互独立地是H或(C1-C4)烷基;I是零,1或2;或R2和R3
是SOn-R22;
n是零,1或2;
R22是具有1,2,3,4,5,6,7或8个碳原子的烷基,具有3,4,5,6或7个碳原子的环烷基或-CsH2s-苯基,
它是未取代的或被1-3个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(34)R(35)的取代基取代;
R(34)和R(35)
相互独立地是H或(C1-C4)烷基;s是零,1或2;R4和R5
相互独立地是氢,具有1,2,3,4,5,6,7或8个碳原子的烷基,F,Cl,Br,I,CF3,-C≡N,-NO2,SOp-R16,CO-R23或O-R24;
p是零,1或2;
R16是具有1,2,3,4,5,6,7或8个碳原子的烷基或苯基,
它是未取代的或被1-3个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(26)R(27)的取代基取代;
R(26)和R(27)
相互独立地是H或(C1-C4)烷基;R23是氢,具有1,2,3,4,5,6,7或8个碳原子的烷基或OR25;
R25氢,具有1,2,3,4,5,6,7或8个碳原子的烷基;R24是氢,具有1,2,3,4,5,6,7或8个碳原子的烷基或苯基,
它是未取代的或被1-3个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(28)R(29)的取代基取代;
R(28)和R(29)
相互独立地是H或(C1-C4)烷基。
2.如权利要求1的式I化合物,其中:R1是氢,具有1,2,3或4个碳原子的烷基或-CaH2a-苯基,
它是未取代的或被1-2个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(8)R(9)的取代基取代;
R(8)和R(9)
相互独立地是H或甲基;
a是零或1;或R1是(C1-C9)杂芳基,
它是未取代的或被1个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(10)R(11)的取代基取代;
R(10)和R(11)
相互独立地是H或甲基;或R1是-CdH2d-(C3-C7)环烷基;
d是零或1;R2或R3
相互独立地是氢,F,Cl,Br,I,CF3,-C≡N,-NO2,CH2OR17,CO-R6或O-R7;
R17是氢,具有1,2,3或4个碳原子的烷基
R6是氢,具有1,2,3或4个碳原子的烷基,OR30或苯基,
它是未取代的或被1-2个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(31)R(32)的取代基取代;
R(31)和R(32)
相互独立地是H或甲基;
R30是氢或具有1,2,3或4个碳原子的烷基;R7是氢,具有1,2,3或4个碳原子的烷基,苯基,
它是未取代的或被1-2个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(12)R(13)的取代基取代;
R(12)和R(13)
相互独立地是H或甲基;或R7是(C1-C9)杂芳基,
它是未取代的或被1个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(14)R(15)的取代基取代;
R(14)和R(15)
相互独立地是H或甲基;或R2和R3
相互独立地是具有1,2,3或4个碳原子的烷基,具有3,4,5,6或7个碳原子的环烷基或-CgH2g-苯基,
它是未取代的或被1-2个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(18)R(19)的取代基取代;
R(18)和R(19)
相互独立地是H或甲基;g是零或1;或R2和R3
是(C1-C9)杂芳基,
它是未取代的或被1个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(20)R(21)的取代基取代;
R(20)和R(21)
相互独立地是H或甲基;或R2和R3
是SOn-R22;
n是零,1或2;
R22是具有1,2,3或4个碳原子的烷基,具有3,4,5,6或7个碳原子的环烷基或-CsH2s-苯基,
它是未取代的或被1-2个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(34)R(35)的取代基取代;
R(34)和R(35)
相互独立地是H或甲基;s是零或1;R4和R5
相互独立地是氢,具有1,2,3或4个碳原子的烷基,F,Cl,Br,I,CF3,-C≡N,-NO2,SOp-R16,CO-R23或O-R24;
p是零,1或2;
R16是具有1,2,3或4个碳原子的烷基或苯基,
它是未取代的或被1-2个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(26)R(27)的取代基取代;
R(26)和R(27)
相互独立地是H或甲基;R23是氢,具有1,2,3或4个碳原子的烷基或OR25;
R25是氢,具有1,2,3或4个碳原子的烷基;R24是氢,具有1,2,3或4个碳原子的烷基或苯基,
它是未取代的或被1-2个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(28)R(29)的取代基取代;
R(28)和R(29)
相互独立地是H或甲基;和其生理上耐受的盐。
3.如权利要求1的式I化合物,其中:R1是氢,具有1,2,3或4个碳原子的烷基或苯基,
它是未取代的或被1个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(8)R(9)的取代基取代;
R(8)和R(9)
相互独立地是H或甲基;或R1是(C1-C9)杂芳基,
它是未取代的或被1个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(10)R(11)的取代基取代;R(10)和R(11)
相互独立地是H或甲基;或R1是(C3-C7)环烷基;R2或R3
相互独立地是氢,F,Cl,Br,I,CF3,-C≡N,-NO2,CO-R6或O-R7;
R6是氢,具有1,2,3或4个碳原子的烷基,OR30或苯基,
它是未取代的或被1-2个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(31)R(32)的取代基取代;
R(31)和R(32)
相互独立地是H或甲基;
R30是氢或具有1,2或3个碳原子的烷基;R7是氢,具有1,2,3或4个碳原子的烷基,苯基,
它是未取代的或被1个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(12)R(13)的取代基取代;
R(12)和R(13)
相互独立地是H或甲基;或R7是(C1-C9)杂芳基,
它是未取代的或被1个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(14)R(15)的取代基取代;
R(14)和R(15)
相互独立地是H或甲基;或R2和R3
相互独立地是具有1,2,3或4个碳原子的烷基,具有3,4,5,6或7个碳原子的环烷基或苯基,
它是未取代的或被1个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(18)R(19)的取代基取代;
R(18)和R(19)
相互独立地是H或甲基;或R2和R3
是(C1-C9)杂芳基,
它是未取代的或被1个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(20)R(21)的取代基取代;
R(20)和R(21)
相互独立地是H或甲基;或R2和R3
是SOn-R22;
n是零或2;
R22是具有1,2,3或4个碳原子的烷基,具有3,4,5,6或7个碳原子的环烷基或苯基,
它是未取代的或被1-2个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(34)R(35)的取代基取代;
R(34)和R(35)
相互独立地是H或甲基;R4和R5
相互独立地是氢,具有1,2,3或4个碳原子的烷基,F,Cl,CF3,-C≡N,-NO2,SOp-R16,CO-R23或O-R24;
p是零或2;R23是氢,具有1,2,3或4个碳原子的烷基或OR25;
R25是氢,具有1,2或3个碳原子的烷基;R24是氢,具有1,2,3或4个碳原子的烷基或苯基,
它是未取代的或被1个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(28)R(29)的取代基取代;
R(28)和R(29)
相互独立地是H或甲基;R16是具有1,2,3或4个碳原子的烷基或苯基,
它是未取代的或被1个选自F,Cl,Br,I,CF3,甲基,甲氧基,羟基和NR(26)R(27)的取代基取代;
R(26)和R(27)
相互独立地是H或甲基;和其生理上耐受的盐。
4.如权利要求1的式I化合物,其中:R1是具有1,2,3或4个碳原子的烷基或苯基,
它是未取代的或被1个选自F,Cl,CF3,甲基,甲氧基的取代基取代;或R1是(C1-C9)杂芳基,
它是未取代的或被1个选自F,Cl,CF3,甲基,甲氧基的取代基取代;或R1是(C3-C7)环烷基;R2或R3
相互独立地是氢,F,Cl,CF3,-C≡N,CO-R6或O-R7;
R6是氢,具有1,2,3或4个碳原子的烷基,OR30或苯基,
它是未取代的或被1-2个选自F,Cl,CF3,甲基,甲氧基,的取代基取代;
R30是氢,甲基或乙基;R7是氢,具有1,2,3或4个碳原子的烷基或苯基,
它是未取代的或被1个选自F,Cl,CF3,甲基,甲氧基的取代基取代;或R7是(C1-C9)杂芳基,
它是未取代的或被1个选自F,Cl,CF3,甲基,甲氧基的取代基取代;或R2和R3
相互独立地是具有1,2,3或4个碳原子的烷基,具有3,4,5,6或7个碳原子的环烷基或苯基,
它是未取代的或被1个选自F,Cl,CF3,甲基,甲氧基的取代基取代;或R2和R3
是(C1-C9)杂芳基,
它是未取代的或被1个选自F,Cl,CF3,甲基,甲氧基的取代基取代;或R2和R3
是SOn-R22;
n是零或2;
R22是具有1,2,3或4个碳原子的烷基或苯基,
它是未取代的或被1-2个选自F,Cl,CF3,甲基,甲氧基的取代基取代;R4和R5
相互独立地是氢,甲基,F,Cl,CF3,-C≡N,SO2-R16,CO-R23或O-R24;R16是具有1,2,3或4个碳原子的烷基或苯基,
它是未取代的或被1个选自F,Cl,CF3,甲基,甲氧基的取代基取代;R23是氢,甲基或OR25;
R25是氢,甲基或乙基;R24是氢,具有1,2,3或4个碳原子的烷基或苯基,
它是未取代的或被1个选自F,Cl,CF3,甲基,甲氧基的取代基取代;和其生理上耐受的盐。
6.下式化合物和其生理上耐受的盐的用途其中:a)X,Y和Z相同或不同,是N或CR(102)b)R(1)是
1.(C1-C10)烷基,2.(C3-C10)烯基,3.(C3-C10)炔基,4.-OR(103),5.(C3-C8)环烷基,6.(C4-C10)环烷基烷基,7.(C5-C10)环烷基烯基,8.(C5-C10)环烷基炔基,9.-(CH2)m-B-(CH2)n-R(104),10.-苄基,11.如在b)项1.,2.,3.或9.中定义的基团,它被CO2R(103)单取代,12.如在b)项1.,2.,3.或9.中定义的基团,其中1个至所有的氢原子被氟取代,或13.如在b)项10.中定义的基团,它在苯基上被1或2个选自卤素,(C1-C4)烷氧基和硝基的相同或不同的基团取代,c)R(102)是
1.氢,2.卤素,3.硝基,4.CvH2v+1,5.五氟苯基,6.氰基,7.-O-R(106),8.苯基,9.苯基(C1-C3)烷基,10.(C1-C10)烷基,11.(C3-C10)烯基,12.苯基(C2-C6)烯基,13.1-咪唑基-(CH2)m-,14.1,2,3-三唑基-(CH2)n-,15.四唑基-(CH2)m-,16.-(CH2)o-1-CHR(107)-OR(105),17.-(CH2)o-O-CO-R(103),18.-(CH2)o-S-R(106),19.-S(O)r-R(119),20.-CH=CH-(CH2)m-CHR(103)-OR(106),21.-CH=CH-(CH2)m-CO-R(108),22.-CO-R(108),23.-CH=CH-(CH2)m-O-CO-R(107),24.-(CH2)m-CH(CH3)-CO-R(108),25.-(CH2)o-CO-R(108),26.-(CH2)o-O-[C=W]-NH-R(109),27,-(CH2)o-NR(107)-[C=W]-OR(109),28.-(CH2)o-NR(107)-CO-NHR(109),29.-(CH2)o-NR(107)-SO2R(109),30.-(CH2)o-NR(107)-[C=W]-R(109),31.-(CH2)nF,32.-(CH2)n-O-NO2,33.-CH2-N3,34.-(CH2)n-NO2,35.-CH=N-NR(105)R(107),36.邻苯二甲酰亚胺基(CH2)n-,37.
38.
39.
40.
41.苯基-SO2-NH=NH-,
43.-(CH2)n-SO2-NR(107)-CS-NR(106)R(109),44.-(CH2)n-SO2-NR(107)-CO-NR(106)R(109),45.-(CH2)o-SO2R(109),46.如在c)项8.或9.中定义的基团,在苯基上被1或2个选自卤素,羟基,甲氧基,三氟甲基,CO2R(103)和苯基的相同或不同基团取代,47.如在c)项10.,11.或19中定义的基团,其中一个至所有的氢原子被氟取代,48.如在c)项14.中定义的基团,被1或2个选自甲氧羰基和(C1-C4)烷基组成的相同或不同基团取代,49.-(CH2)n-SO2-NR(107)-CO-R(106),50.-(CH2)n-SO2-NR(107)-CS-R(106),d)R(103)是
1.氢,2.(C1-C8)烷基,3.(C3-C8)环烷基,4.苯基,5.苄基,6.如在d)项2.中定义的基团,其中一个至所有的氢原子被氟取代;e)R(104)是
1.氢,2.(C1-C6)烷基,3.(C3-C8)环烷基,4.(C2-C4)烯基或5.(C2-C4)炔基;f)R(105)是
1.氢,2.(C1-C6)烷基,3.(C3-C8)环烷基,4.苯基或5.苄基;g)R(106)和R(109)是
相同或不同,为1.氢,2.(C1-C6)烷基,它未取代或被1-3个选自(C1-C6)烷氧基,该烷氧基自身可被1-3个选自羟基,(C1-C6)烷氧基,氨基,单(C1-C6)烷基氨基,二(C1-C6)烷基氨基取代,(C2-C10)烯基,羟基,氨基,单(C1-C6)烷基氨基,二(C1-C6)烷基氨基,(C1-C6)烷氧基羰基氨基,(C6-C12)芳基(C1-C4)烷氧羰基氨基,(C6-C10)芳基,(C6-C10)-芳基-(C1-C3)烷基,(C1-C9)杂芳基,羧基和(C1-C4)烷氧羰基的取代基取代;3.(C3-C8)环烷基,其中环烷基部分是未取代的或被1-3个选自(C1-C4)烷基和(C2-C4)烯基的取代基取代;4.(C3-C8)环烷基-(C1-C3)烷基,5.(C6-C12)芳基,优选苯基,6.(C6-C10)-芳基-(C1-C4)烷基,7.(C1-C9)杂芳基,它部分或完全被氢化,8.如在g)项5.,6.,7.,9.,15.,16.,17.,19.,20.或21.中定义的基团,被1或2个选自卤素,羟基,(C1-C4)烷基,甲氧基,硝基,氰基,CO2R(103),三氟甲基,NR(111)R(112)和的相同或不同基团取代,9.(C1-C9)杂芳基(C1-C3)烷基,
其中杂芳基部分可以部分或完全氢化,10.(C1-C6)烷基,其中1至所有的H原子被氟取代,11.(C2-C10)烯基,(C2-C10)烯酰基或(C2-C10)二烯基,12.(C3-C8)环烯基,13.(C3-C8)环烯基(C1-C3)烷基,14.二-或三环(C4-C10)环烯基(C1-C4)烷基,
它也可以被1-3个(C1-C4)烷基取代;15.(C6-C10)芳基(C1-C4)烷基,16.(C6-C10)芳基(C3-C6)烯基,17.(C1-C9)杂芳基(C3-C6)烯基,18.(C3-C6)炔基,19.(C6-C10)芳基(C3-C6)炔基,20.(C1-C9)杂芳基(C3-C6)炔基,21.R(106)和R(109)与带有它们的氮原子一起形成一个杂芳基,
它也可以部分或完全氢化;h)R(107)是
1.氢,2.(C1-C6)烷基,3.(C3-C8)环烷基,4.(C6-C12)芳基(C1-C6)烷基,优选苄基,5.苯基或6.(C1-C9)杂芳基;i)R(108)是
氰基,硝基或CO2R(107);k)R(111)和R(112)
相同或不同,为1.氢,2.(C1-C4)烷基,3.苯基,4.苄基,或5.α-甲基苄基;l)D是NR(113),O或CH2;m)R(113)是
氢,(C1-C4)烷基或苯基;n)A是联苯基,
它是未取代的或被1-4个、优选1或2个、相同或不同的取代基R(114)或R(115)取代;o)R(114)是
1.卤素,2.亚硝基,3.硝基,4.氨基,5.氰基,6.羟基,7.(C1-C6)烷基,8.(C1-C4)烷酰基,9.(C1-C4)烷酰氧基,10.CO2R(103),11.甲磺酰胺基,12.三氟甲磺酰胺基,13.-CO-NH-OR(109),14.-SO2-NR(106)R(107),15.-CH2-OR(107),16,(C1-C9)杂芳基-(CH2)q-,优选1-四唑基,17.(C7-C13)芳酰基,18.19.或20.(C6-C12)芳基;p)R(115)是
1.氢,2.(C1-C6)烷基,3.(C3-C8)环烷基,4.(C6-C12)芳基,5.(C7-C13)芳酰基,6.(C1-C4)烷氧基,7.(C1-C4)烷酰氧基,8.(C1-C9)杂芳基,9.CO2R(103);10.卤素,11.氰基,12,硝基,13.NR(106)R(107),14.羟基,15.-CO-NH-CHR(105)-CO2R(103),16.磺基,17.-SO3R(103),18.-SO2-NR(107)-CO-NR(106)R(109)或-SO2-NR(107)-CS-NR(106)R(109),19.-NR(107)-CO-NR(106)-SO2-CH2-R(105),20.-C(CF3)2OH,21.膦酰氧基,22.-PO3H2,23.-NH-PO(OH)2,24.-S(O)rR(106),25.-CO-R(108),26.-COR(106)R(109),27.-CR(120)(OH)-PO(OH)2.28.在o)项20.中定义的基团,29.30.31.32. 5-四唑基-NH-CO-,33.-CO-NH-NH-SO2-CF3,34.35.36.37.38.
39.40.-CO-NH-SO2-R(119),41.-SO2-NH-CO-R(106)或42.在p)项4.中定义的基团,被1或2个选自卤素,氰基,硝基,NR(106)R(107)和羟基的相同或不同基团取代;43.R(115)与 R(114)一起是-CO-NH-SO2-,44.-SO2-NH-CO-O-R(106),45.-SO2-NH-SO2-NR(106)R(109),46.-SO2-NH-SO2-R(106);q)B是O,NR(107)或S;r)W是O或S;s)L是(C1-C3)烷二基;t)R(116)是
CO2R(103)或CH2CO2R(103);u)R(117)是
氢,卤素,(C1-C4)烷基或(C1-C4)烷氧基;v)R(118)是
氢,(C1-C4)烷基或苯基;w)R(119)是
1.(C1-C6)烷基,2.(C3-C8)环烷基,3.苯基,4.苄基或5.在w)项1.中定义的基团,其中1至所有的H原子被氟取代,x)T是1.一个单键,2.-CO-,3.-CH2-,4.-O-,5.-S-,6.-NR(121)-,7.-CO-NR(121),8.-NR(121)-CO-,9.-O-CH2-,10.-CH2-O-,11.-S-CH2-,12.-CH2-S,13.-NH-CR(120)R(122),14.-NR(121)-SO2,15.SO2-NR(121)-,16.-CR(120)R(122)-NH,17.-CH=CH-,18.-CF=CF-,19.-CH=CF-,20.-CF=CH-,21.-CH2-CH2-,22.-CF2-CF2-,23.-CH[OR(103)]-,24.-CH(OCOR(105))-,25.-C[N=R(123)]-或26.-[R(124)O]-C-[OR(125)]-y)R(120)和R(122)是
相同或不同,氢,(C1-C5)烷基,苯基,烯丙基或苄基;z)R(121)是
氢,(C1-C6)烷基,苄基或烯丙基;a’)R(123)是
1.NR(120)R(121),2.脲基,3.硫脲基,4.甲苯-4-磺酰基或5.苯磺酰氨基;b’)R(124)和R(125)
相同或不同,为(C1-C4)烷基或一起为-(CH2)q-;c’)Q是CH2,NH,O或S;d’)m是1,2,3,4或5;e’)n是1,2,3,4或5;f’)o是1,2,3,4,5,6,7,8,9或10;g’)q是零或1;h’)r是零,1或2;i’)v是1,2,3,4,5或6;用于生产治疗或预防由局部缺血状况引起的疾病的医药,也用于生产治疗损害的呼吸动力的医药。
7.如权利要求1要求的式I化合物或其生理上耐受的盐的用途,用于生产治疗或预防由局部缺血状况引起的疾病的医药或用于生产治疗损害的呼吸动力的医药。
8.如权利要求1要求的式I化合物用于生产治疗或预防由局部缺血状况引起的疾病的医药的用途。
9.如权利要求1要求的式I化合物用于生产治疗或预防心肌梗塞的医药的用途。
10.如权利要求1要求的式I化合物用于生产治疗或预防心绞痛的医药的用途。
11.如权利要求1要求的式I化合物用于生产治疗或预防心脏局部缺血的医药的用途。
12.如权利要求1要求的式I化合物用于生产治疗或预防末梢和中枢神经系统局部缺血和中风的医药的用途。
13.如权利要求1要求的式I化合物用于生产治疗或预防外周器官和肢体局部缺血的医药的用途。
14.如权利要求1要求的式I化合物用于生产治疗休克状态的医药的用途。
15.如权利要求1要求的式I化合物用于生产用于外科手术和器官移植的医药的用途。
16.如权利要求1要求的式I化合物用于生产用于外科测量的移植物的防腐和储存的医药的用途。
17.如权利要求1要求的式I化合物用于生产治疗其中细胞增生是第一或第二原因的疾病的医药的用途。
18.如权利要求1要求的式I化合物用于生产治疗损害的呼吸动力的医药的用途。
19.包含有效量的、如权利要求1至5中一项或多项要求的一种式I化合物的药物。
20.如权利要求19的医药,其中另外还含有有效量的NHE抑制剂和/或其它类型的心血管活性物质,或其生理上耐受的盐。
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DE19702045A DE19702045A1 (de) | 1997-01-22 | 1997-01-22 | Imidazol-Derivae mit Biphenylsulfonylcyanamid-Seitenkette, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
DE19702045.3 | 1997-01-22 | ||
DE19731328A DE19731328A1 (de) | 1997-07-22 | 1997-07-22 | Imidazol-Derivate mit Biphenylsulfonylcyanamid-Seitenkette, Verfahren zu ihrer Herstellung und ihre Verwendung als Medikament |
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DE19741636.5 | 1997-09-22 | ||
DE1997141636 DE19741636A1 (de) | 1997-09-22 | 1997-09-22 | Fünfgliedrige Heterocyclen mit Biphenylsulfonylsubstitution, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
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US9943509B2 (en) | 2013-03-15 | 2018-04-17 | University Of Southern California | Methods, compounds, and compositions for the treatment of musculoskeletal diseases |
WO2018002673A1 (en) | 2016-07-01 | 2018-01-04 | N4 Pharma Uk Limited | Novel formulations of angiotensin ii receptor antagonists |
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JPH0819110B2 (ja) * | 1986-06-04 | 1996-02-28 | 富山化学工業株式会社 | 新規なイミダゾール誘導体もしくはその塩およびそれらを含有する抗炎症剤、解熱鎮痛剤または抗関節炎剤 |
IL98319A (en) | 1990-07-05 | 1997-04-15 | Roussel Uclaf | Sulphurous derivatives of imidazole, their preparation process, and pharmaceutical compositions containing them |
US5126342A (en) * | 1990-10-01 | 1992-06-30 | Merck & Co., Inc. | Imidazole angiotensin ii antagonists incorporating acidic functional groups |
CA2058198A1 (en) | 1991-01-04 | 1992-07-05 | Adalbert Wagner | Azole derivatives, process for their preparation, and their use |
EP0586513A1 (en) | 1991-05-10 | 1994-03-16 | Merck & Co. Inc. | Acidic aralkyl triazole derivatives active as angiotensin ii antagonists |
TW215434B (zh) | 1992-03-07 | 1993-11-01 | Hoechst Ag | |
JPH0625229A (ja) * | 1992-03-09 | 1994-02-01 | Japan Tobacco Inc | 新規なイミダゾール誘導体 |
FR2711367B1 (fr) | 1993-10-19 | 1995-12-01 | Roussel Uclaf | Nouveau procédé de préparation de dérivés soufrés de l'imidazole et les nouveaux intermédiaires obtenus. |
FR2711368B1 (fr) | 1993-09-16 | 1996-01-05 | Roussel Uclaf | Nouveau procédé de préparation de dérivés soufrés de l'imidazole et les nouveaux intermédiaires obtenus. |
FR2716883B1 (fr) * | 1994-03-04 | 1996-04-26 | Roussel Uclaf | Nouveaux dérivés tétrasubstitués de l'imidazole, leur préparation, nouveaux intermédiaires obtenus, leur application à titre de médicaments, compositions pharmaceutiques les renfermant. |
FR2716882B1 (fr) * | 1994-03-04 | 1996-04-05 | Roussel Uclaf | Utilisation de dérivés de l'imidazole au traitement d'affections impliquant les récepteurs AT1 et AT2 de l'Angiotensine, certains de ces produits, leur préparation, compositions pharmaceutiques. |
DK0853477T3 (da) * | 1995-10-06 | 2003-02-10 | Novartis Ag | AT1-receptor-antagonister til forebyggelse og behandling af postiskæmisk nyresvigt og til beskyttelse af iskæmiske nyrer |
JP2000501736A (ja) * | 1995-12-12 | 2000-02-15 | メルク エンド カンパニー インコーポレーテッド | ロサルタンの新用途 |
EP0855392A3 (de) | 1997-01-22 | 2000-01-05 | Hoechst Aktiengesellschaft | Fünfgliedrige Heterocyclen mit Biphenylsulfonylsubstitution, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101193886B (zh) * | 2005-04-12 | 2014-08-27 | 维科尔药物公司 | 三环的血管紧张素ii激动剂 |
CN103992276A (zh) * | 2014-06-03 | 2014-08-20 | 吉林省药物研究院 | 4’-{[(2,4,5-三取代苯基)-1h-咪唑-1-基]甲基}联苯-2-甲酸衍生物 |
CN103992276B (zh) * | 2014-06-03 | 2016-08-24 | 吉林省药物研究院 | 4’-{[(2,4,5-三取代苯基)-1h-咪唑-1-基]甲基}联苯-2-甲酸衍生物 |
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