CN1349530A - 作为血管紧张肽(1-7)受体兴奋剂的1-(p-噻吩基苄基)咪唑,其制备方法,其用途和含有它们的药物制剂 - Google Patents
作为血管紧张肽(1-7)受体兴奋剂的1-(p-噻吩基苄基)咪唑,其制备方法,其用途和含有它们的药物制剂 Download PDFInfo
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- CN1349530A CN1349530A CN00806799A CN00806799A CN1349530A CN 1349530 A CN1349530 A CN 1349530A CN 00806799 A CN00806799 A CN 00806799A CN 00806799 A CN00806799 A CN 00806799A CN 1349530 A CN1349530 A CN 1349530A
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- imidazoles
- thienyl
- methyl
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- 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
- C07D409/10—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 aromatic rings
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Abstract
本发明涉及新的式(I)的1-(p-噻吩基苄基)咪唑,其中基团R(1)-R(6),X和Y具有说明书中给出的意义。所说的化合物是血管紧张肽(1-7)受体的强力兴奋剂,并由于其产生和释放与在内皮细胞上这些受体的刺激有关的血管舒张剂,抗血栓形成和心脏保护信使环状3’,5’-鸟甘一磷酸酯(cGMP)和一氧化氮(NO),这些化合物可用作治疗和预防高血压,心脏肥大,心脏机能不全,冠状心脏病如心绞痛,心肌梗塞,血管成型术后的再狭窄,心肌病,内皮功能失调或内皮损伤,例如动脉粥样硬化或糖尿病引起的结果,和动脉和静脉血栓形成引起的结果的有效药物。
Description
本发明涉及新的式(I)的1-(p-噻吩基苄基)咪唑,该化合物是血管紧张肽(1-7)受体的强力兴奋剂,并由于其产生和释放与在内皮细胞上这些受体的刺激有关的血管舒张剂,抗血栓形成和心脏保护信使环状3’,5’-鸟甘一磷酸酯(cGMP)和一氧化氮(NO),这些化合物可用作治疗和预防高血压,心脏肥大,心脏机能不全,冠状心脏病如心绞痛,心肌梗塞,血管成型术后的再狭窄,心肌病,内皮功能失调或内皮损伤,例如动脉粥样硬化或糖尿病引起的结果,和动脉和静脉血栓形成引起的结果。
EP-A 512675和WO 94/27597描述了作为血管紧张肽II受体拮抗剂的噻吩基苄基取代的咪唑和其用于治疗高血压,心脏机能不全,偏头痛,Alzheimer’s病和作为抗抑郁剂的用途。而且,在EP-A 513979中公开了噻吩基苄基取代的咪唑并吡啶作为血管紧张肽II受体拮抗剂,和其治疗高血压,心脏机能不全,偏头痛和Alzheimer’s病的用途,而在US-5444067中作为血管紧张肽II兴奋剂和其治疗高血压和醛甾酮过少症的用途。另外,在EP-A 534706中公开了噻吩基苄基取代的喹唑啉酮和吡啶并嘧啶酮,而在EP-A 510812中公开了噻吩基苄基取代的三唑作为血管紧张肽II受体拮抗剂。
本文所述的式(I)的1-(p-噻吩基苄基)咪唑和其作为血管紧张肽(1-7)受体兴奋剂的用途既没有在上述专利申请中描述,也没有预期或建议。
出人意料地已经发现式(I)的1-(p-噻吩基苄基)咪唑对血管紧张肽(1-7)受体具有显著作用,并酷似效应子激素血管紧张肽(1-7)的生物作用。
2.羟基;
3.(C1-C4)-烷氧基;
4.(C1-C8)-烷氧基,其中1至6个碳原子被杂原子O,S或NH,优选O代替;
5.(C1-C4)-烷氧基,被饱和环状醚如四氢吡喃或四氢呋喃取代;
6.O-(C1-C4)-烯基;
7.O-(C1-C4)-烷基芳基;和
8.芳氧基,未取代或被由卤素,(C1-C3)-烷基,(C1-C3)-烷氧基或三氟甲基组成的组中的取代基取代;R(2) 1.CHO;
2.COOH;和
3.CO-O-(C1-C4)-烷基;R(3) 1.(C1-C4)-烷基;和
2.芳基;R(4) 1.氢;
2.卤素,和
3.(C1-C4)-烷基;X 1.氧;
2.硫;Y 1.氧;和
2.-NH-;R(5) 1.氢;
2.(C1-C6)-烷基;和
3.(C1-C4)-烷基芳基;
其中如果Y具有2给出的意义,则R(5)只能是氢;R(6) 1.(C1-C5)-烷基;其所有的非对映体形式和其所有比例的混合物,和其生理耐受盐;排除其中R(1)是氢,并且R(2)具有2.和3.意义的式(I)化合物。
如果不另外说明,术语烷基指直链或支链的饱和烃基。这也适用于从其衍生的取代基如烷氧基或S(O)m-烷基。烷基的例子有甲基,乙基,正丙基,异丙基,异丁基,仲丁基,叔丁基,正戊基,正己基。烷氧基的例子有甲氧基,乙氧基,正丙氧基,异丙氧基。芳氧基的例子有苯氧基或萘氧基。苯氧基是优选的。
烯基表示其中双键可以在任何需要的位置的一-或多不饱和烃基。烯基的例子有乙烯基,丙烯基和丁烯基。
卤素表示氟,氯,溴或碘,优选氯或氟。
芳基表示苯基或萘基,优选苯基。
在取代的芳基中,取代基可以在任何需要的相互位置。
芳基烷基的例子有苯基甲基(苄基),苯乙基,苯丙基,苯丁基,萘甲基,萘乙基,萘丙基,萘丁基。
如果式(I)化合物含有一个或多个酸性或碱性基团,则本发明也涉及相应的生理耐受的盐,尤其是生理耐受盐。带有酸性基团,例如一个或多个COOH基团的式(I)化合物可以以例如,碱金属盐,优选钠或钾盐,或碱土金属盐,例如钙或镁盐,或铵盐,例如与氨或有机胺或氨基酸的盐使用。带有一个或多个碱性基团,即可质子化的基团的式(I)化合物也可以以其与无机或有机酸的生理耐受的酸加成盐,例如盐酸盐,磷酸盐,硫酸盐,甲磺酸盐,醋酸盐,乳酸盐,马来酸盐,富马酸盐,苹果酸盐,葡糖酸盐等使用。如果式(I)化合物在分子内同时含有酸性和碱性基团,则本发明除上述盐形式外,还包括内盐,即所谓的甜菜碱。可以通过常规方法,例如通过与酸或碱在溶剂或分散剂化合而从式(I)化合物获得,或者从其它盐通过离子交换获得。
式(I)化合物的生理耐受盐应该理解为,例如,有机和无机盐,如在Remington’s Pharmaceutical Sciences(17th Edition,p.1418(1985))中所述的盐。考虑到物理和化学稳定性和溶解性,优选的酸性基团有钠,钾,钙和铵盐;优选的碱性基团有盐酸,硫酸,磷酸或羧酸或磺酸的盐,例如,醋酸,柠檬酸,苯甲酸,马来酸,富马酸,酒石酸和对甲苯磺酸的盐。
本发明还包括式(I)化合物的溶剂化物,例如水合物或与醇的加合物,和式(I)化合物的衍生物,例如酯,和前药和活性代谢物。
优选的式(I)化合物是这样的化合物,其中R(1) 1.氯;
2.羟基;
3.甲氧基,乙氧基,丙氧基;
4.甲氧基乙氧基,甲氧基丙氧基;
5.烯丙氧基;
6.苯氧基;R(4) 1.氢;和
2.氯;R(5) 1.氢;和
2.(C1-C4)-烷基;R(6) 正丙基和2-异丁基;其它基团如上定义,其所有的非对映体形式和其混合物,和其生理耐受盐。
更优选的化合物(I)是这样的化合物,其中R(1) 是卤素,优选氯;(C1-C4)-烷氧基;优选甲氧基,乙氧基,丙氧基,特别优选甲氧基;或(C1-C8)-烷氧基,其中1至6个碳原子被杂原子O,S或NH,优选O代替,优选甲氧基乙氧基,甲氧基丙氧基;R(2) 是CHO;R(3) 是芳基,优选苯基;R(4) 是卤素,优选氯,或氢;R(5) 是(C1-C6)-烷基,优选甲基,乙基,丙基,丁基;R(6) 是(C1-C5)-烷基,优选乙基,丙基或丁基;X 是氧;Y 是氧或-NH-;其所有的非对映体形式和其混合物,和其生理耐受盐。
优选的式(I)化合物也是其中R(1)是(C1-C4)-烷氧基或(C1-C8)-烷氧基,其中1至6个碳原子被杂原子O,S或NH,优选O代替,其它基团如上定义的化合物;其所有的非对映体形式和其混合物,和其生理耐受盐。
特别优选的式(I)化合物是其中R(2)是CHO,而其它基团如上定义的化合物,其所有的非对映体形式和其混合物,和其生理耐受盐。
优选的式(I)化合物是其中X是O,其它基团如上定义的化合物,其所有的非对映体形式和其混合物,和其生理耐受盐。
可被提到的特别优选的式(I)化合物有:4-氯-5-甲酰基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(正丙氧羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(乙氧羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(甲氧羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(正丁基氨基羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(乙基氨基羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(乙基氨基羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑钠盐;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(乙基氨基羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑L-赖氨酸盐;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(乙基氨基羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑三(羟甲基)氨基甲烷盐;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(甲基氨基羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑;5-甲酰基-4-甲氧基乙氧基-2-苯基-1-[[4-[2-(正丙氧羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-异丁基-3-噻吩基-2-氯苯基]甲基]咪唑;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-异丁基-3-噻吩基]-2-氯苯基]甲基]咪唑;4-氯-5-甲酰基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-正丙基-3-噻吩基]苯基]甲基]咪唑;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-正丙基-3-噻吩基]-苯基]甲基]咪唑;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(甲氧羰基磺酰胺基)-5-正丙基-3-噻吩基]-苯基]甲基]咪唑;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(正丁基氨基羰基磺酰胺基)-5-正丙基-3-噻吩基]苯基]甲基]咪唑;或5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(甲基氨基羰基磺酰胺基)-5-正丙基-3-噻吩基]苯基]甲基]咪唑;和其生理耐受盐。
本发明还涉及制备式(I)化合物的方法,该方法包括如下所示的反应步骤:a) 式(III)的4-氯-5-甲酰基咪唑衍生物其中R(3)具有上述意义,其制备在例如Chem.Pharm.Bull.24,1976,960-969中所述,与式(IV)的p-溴苄基溴反应其中R(4)如上定义,给出式(V)化合物其中R(3)和R(4)具有上述意义,其中烷基化可以在有机或无机碱,例如三乙胺,碳酸钾或碳酸铯存在下,在惰性溶剂,例如DMF中进行。式(IV)化合物可以购买或者通过已知方法制备。b)式(V)化合物可以与式(VI)的噻吩-3-硼酸反应其中R(6)如上定义,其制备在EP-A 512675中公开,给出式(VII)的1-(p-噻吩基)咪唑其中R(3),R(4)和R(6)如上定义。该Suzuki型交叉偶合反应优选地用醋酸钯(II)和三苯膦或四三苯膦钯作催化剂,在碱如碳酸铯或碳酸钾存在下,例如在乙醇和甲苯的溶剂混合物中,在最高为溶剂沸点的温度下进行;相应的反应在例如Synthetic Commun.11(1981)513,J.Med.Chem.38(1995)2357-2377和Liebigs Ann.1995,1253-1257中描述。c)可以通过脱去叔丁基保护基将式(VII)化合物转化为式(VIII)的磺酰胺其中R(3),R(4)和R(6)如上定义。该脱去反应优选地通过用有机酸,例如浓缩的三氟乙酸在茴香醚存在下处理式(VII)化合物而进行。d)式(VIII)化合物可以通过咪唑环4位的氯原子的取代而转化为式(IX)化合物其中R(3),R(4)和R(6)如上定义,而R(1)’表示2.至8.所述的基团。氯原子的取代在这种情况下可以,例如,通过用醇盐处理式(VIII)化合物而进行,该醇盐通过碱如氢氧化钠或氢化钠与一般也用作溶剂的醇,例如甲醇,乙醇或乙二醇一甲基醚在50℃至醇的沸点的温度下作用而就地形成。
另外,其中R(1)’是(C1-C4)-烷氧基的式(IX)化合物可以通过优选地用浓酸如HI和HBr或用Lewis酸如BF3,BCl3,BBr3,AlCl3或其醚加合物,优选用BBr3在惰性溶剂,例如二氯甲烷中处理式(IX)的甲氧基醚,经醚的裂解而转化为相应的酚,然后可以通过已知的方法与合适取代的卤化物如2-溴乙基甲基醚或苄基溴在碱存在下,在惰性溶剂中,在最高为溶剂沸点的温度下反应。
相应的二苯基醚化合物可以从式(IX)的酚与硼酸,例如苯基硼酸或4-甲氧基苯基硼酸在铜催化剂,例如Cu(OAc)2存在下反应而获得;合适的反应在例如,Tetrahedron Lett.39(1998),2937-2940中描述。e)从式(IX)的磺酰胺开始,能够与R(5)-取代的氯甲酸酯反应制备式(Ia)的磺酰基尿烷其中R(1),R(2),R(3),R(4),R(6)如上定义,而R(5)仅具有2.和3.中提到的意义。该反应可以在碱,例如吡啶和酰化促进剂如4-吡咯烷基吡啶存在下,在RT至150℃,但优选RT的温度下进行。f)从式(IX)的磺酰胺开始,能够通过用R(5)-取代的异氰酸酯或异硫代氰酸酯处理而得到式(Ib)的磺酰基脲其中R(1),R(2),R(3),R(4),R(6)和X如上定义,而R(5)仅具有2.和3.中提到的意义。与R(5)-取代的异氰酸酯或异硫代氰酸酯的反应可以在碱存在下,在惰性溶剂中,在RT至150℃的温度下进行。
合适的碱有,例如,碱金属或碱土金属氢氧化物,氢化物,氨化物或醇盐,如氢氧化钠,氢氧化钾,氢氧化钙,氢化钠,氢化钾,氢化钙,氨化钠,氨化钾,甲醇钠,乙醇钠或叔丁醇钾。合适的惰性溶剂是醚类如THF,二恶烷,乙二醇二甲醚或甘醇二甲醚,酮类如丙酮或丁酮,腈类如乙腈,硝基化合物如硝基甲烷,酯类如乙酸乙酯,酰胺类如DMF或N-甲基吡咯烷酮,六甲基磷酰胺,砜类如DMSO和烃类如苯,甲苯或二甲苯。而且,这些溶剂相互的混合物也是合适的。
式(Ib)的磺酰基脲也可以通过胺R(5)-NH2与磺酰基异氰酸酯反应而制备,后者通过例如用光气或光气代替物如三光气处理,从式(IX)的磺酰胺产生。
式(Ib)的磺酰基脲也可以通过式(IX)的磺酰胺与合适的胺R(5)-NH2的2,2,2-三氯乙酰胺衍生物在碱存在下,在惰性高沸点溶剂,例如DMSO中反应而制备,或从通过与氯甲酸乙酯反应得到的相应的式(Ia)的磺酰基尿烷,通过相应的胺R(5)-NH2在惰性高沸点溶剂,例如甲苯中,在最高为各溶剂沸点的温度下的作用而制备,该反应在例如,J.Med.Chem.,38(1995)2357-2377和Bioorg.Med.Chem.5(1997)673-678中所述的。
其中R(5)是氢的式(Ib)N-未取代的磺酰基脲可以通过磺酰胺基腈与硫酸在-10至0℃的温度下的水解而制备,磺酰胺基腈在式(IX)的磺酰胺与溴化氰在碳酸钾存在下在乙腈中反应后产生。
通过已知方法,如在文献中所述的方法(例如在经典著作如Houben-Weyl,Methoden der Organischen Chemie[有机化学方法],Georg Thieme Verlag,Stuttgart,Organic Reactions,John Wiley& Sons,Inc.,New York或Larock,Comprehensive OrganicTransformations,VCH,Weinheim中所述的),可以通过式(I)化合物中醛基的氧化来制备相应的式(I)羧酸或羧酸酯。
本发明也涉及式(X)化合物其中R是氢或合适的保护基,例如(C1-C6)-烷基,优选叔丁基,而基团R(1),R(2),R(3),R(4),R(6)如上定义,其所有的立体异构形式和其混合物,和其生理耐受盐。
式(X)的化合物是用于制备本发明式(I)化合物的有价值的中间体。另外,式(X)化合物对血管紧张肽(1-7)受体具有高亲和力,并可用作血管紧张肽(1-7)受体兴奋剂,因而作为治疗和/或预防由血管舒张剂,抗血栓形成和心脏保护信使环状3’,5’-鸟甘一磷酸酯(cGMP)和一氧化氮(NO)产生和/或释放的减少而直接或间接或至少部分引起的疾病,例如治疗和/或预防高血压,心脏肥大,心脏机能不全,冠状心脏病如心绞痛,心肌梗塞,血管成型术后的再狭窄,心肌病,内皮功能失调或内皮损伤,例如动脉粥样硬化或糖尿病引起的结果,和动脉和静脉血栓形成引起的结果。
血管内皮是具有大量调节功能的代谢活性器官,能够合成和释放血管活性物质。作为血管衬里的内皮层的功能失调与各种血管病如动脉粥样硬化和高血压的病理有关(Eur.J.Clin.Invest.1993,23,670-685)。内皮功能失调的特征在于血管舒张剂,心脏保护,抗血栓形成和抗增生活性信使NO和cGMP的合成和/或释放减少,而这些信使在预防和遏制血管重构和动脉高血压中扮演重要角色。因此,能够刺激这些信使合成和释放的物质是用于治疗与内皮功能失调为特征的所有疾病的有价值的药物。
大量的实验证实,肾素-血管紧张肽体系,七肽血管紧张肽(1-7)的降解产物是肾素-血管紧张肽体系的强力内源效应激素(Hypertension 1991,18[Suppl III]:III-126-III133),其生物作用由优选结合血管紧张肽(1-7)的特异性受体的刺激引起(Peptide1993,14,679-684,Hypertension 1997,29[part 2]:388-393))。该作用在许多情况下针对血管收缩激素血管紧张肽II,或以反向调节方式对抗(Hypertension 1997,30[part 2]:535-541,RegulatoryPeptides 1998,78,13-18)。在Hypertension 1992,19[Suppl II]:II-49-II-55和Am.J.Cardiol.1998,82,17S-19S中显示,血管紧张肽(1-7)刺激NO/cGMP和前列腺素E2和I2的产生和/或释放,而不被AT1和AT2受体拮抗剂预治疗阻断。狗和猪完整冠状动脉的内皮依赖性舒张在Hypertension 1996,27[part 2]:523-528中描述,而不受AT1受体拮抗剂影响的由血管紧张肽(1-7)引起的完整,KCl-预收缩的大鼠动脉的内皮-依赖性舒张在J.Cardiovasc.Pharmacol.1997,30,676-682中描述。在通过渗透微泵的手段连续灌注的自发高血压大鼠体内血管紧张肽(1-7)的高血压作用在Peptides 1993,14,679-684和Am.J.Physiol.1995,269:H313-H319中给出,以相同剂量,血管紧张肽(1-7)在血压正常的大鼠体内对血压没有影响。作为对这些研究的补充,在Hypertension 1998,31:699-705中证明,血管紧张肽(1-7)抗体的灌注在已经用lisinopril和losartan预先治疗过的清醒,自发性高血压大鼠体内增加平均动脉血压。
在Am.J.Hypertension 1998,11:137-146中证明,在具有自发性高血压的人体内,可以检测到的血管紧张肽(1-7)的血浆水平比正常血压的人明显地低。
血管紧张肽(1-7)对血管平滑肌细胞的抗增生作用在Hypertension 1996,28,104-108中证实,而血管组织损伤后的平滑肌细胞增生的抑制作用在Hypertension 1999,33[part II]:207-211中证实。
而且,血管紧张肽(1-7)在氯化钠-负载,麻醉的正常血压的Wistar大鼠体内也显示对肾的作用,如增加尿钠排泄和利尿(Am.J.Physiol.1996,270,F141-F147)。
本文所述的式(I)化合物是优选地位于血管(包括内皮),肾脏,CNS和心脏中的假说的血管紧张肽(1-7)受体的强力非肽兴奋剂。它们摹仿如上所述针对血管紧张肽II的肽激素血管紧张肽(1-7)的生物作用,它对从内皮生产和/或释放cGMP和NO有贡献,在这种情况下没有该激素的迅速代谢降解。由于刺激这些血管舒张剂,抗血栓形成和心脏保护信使的合成和/或释放,所以所述的式(I)的血管紧张肽(1-7)受体兴奋剂是用于治疗和/或预防由血管舒张剂,抗血栓形成和心脏保护信使环状3’,5’-鸟甘一磷酸酯(cGMP)和一氧化氮(NO)产生和/或释放的减少而直接或间接或至少部分引起的疾病,因而可以用于治疗和/或预防高血压,心脏肥大,心脏机能不全,冠状心脏病如心绞痛,心肌梗塞,血管成型术后的再狭窄,心肌病,内皮功能失调或内皮损伤,例如动脉粥样硬化或糖尿病引起的结果,和动脉和静脉血栓形成引起的结果。
由式(I)兴奋剂刺激内皮血管紧张肽(1-7)引起血管舒张和器官保护自体有效物质的释放。该机理与由通过要么避免降低组织血管紧张肽II(在ACE抑制剂的情况下)或目前尚不能评价的作用,与ANG II血浆值增加有关(在AT1受体拮抗剂的情况下),ACE抑制和AT1受体阻断不同。
因此,式(I)化合物和其生理耐受盐以其本身,与另一种的混合物,或与其它活性化合物一起,尤其是以药物制剂形式,可以用于动物,优选哺乳动物,尤其是人类。因此,本发明涉及式(I)化合物和/或其生理耐受盐在生产用于治疗或预防上述综合征的医药中的用途,并涉及含有有效量的至少一种式(I)化合物和/或其生理耐受盐作为活性成分,外加普通的药用无害载体和/或赋形剂的药物制剂。该药物制剂可以肠内或肠胃外使用,并一般含有0.5至90%重量的式(I)化合物和/或其生理耐受盐。在药物制剂中式(I)活性化合物和/或其生理耐受盐的量一般为0.2至500mg,优选1至300mg。
可以用于本发明并含有式(I)化合物和/或其生理耐受盐的药物可以肠内给药,例如口服或直肠内给药,例如以丸剂,片剂,包膜片剂,糖衣片剂,颗粒剂,硬和软胶囊,溶液如水溶液,醇溶液或油溶液,果汁,滴加,糖浆,乳液或悬浮液。给药也可以肠胃外进行,例如皮下,肌内或静脉内以注射液或灌注液形式给药。其它可能的给药形式有,例如,经皮或局部给药,例如以乳剂,软膏,糊剂,洗剂,凝胶,喷雾剂,粉剂,泡沫剂,气雾剂或溶液使用,或以植入的形式使用。
可以用于本发明的药物制剂可以通过生产药物制剂的已知标准方法制备。为此,将一种或多种式(I)化合物和/或其生理耐受盐与一种或多种固体或液体药用载体和/或添加剂或赋形剂混合在一起,如果需要,与具有治疗或预防作用的其它药物活性化合物,例如心血管活性药物,例如,钙拮抗剂,ACE抑制剂,AT1受体拮抗剂,NO供体,内皮肽受体拮抗剂,K通道开启剂,磷酸二酯酶抑制剂,利尿剂或α-和β-阻断剂结合成适合于给药形式或剂型,然后用作人药或兽药。
可能的载体是适合于肠内(例如口服)或肠胃外(例如静脉内)给药,或局部施用,并且不与式(I)的活性化合物反应的有机或无机物,例如水,植物油,醇如乙醇,异丙醇或苄基醇,1,2-丙二醇,聚乙二醇,甘油三乙酸酯,明胶,碳水化合物如乳糖或淀粉,硬脂酸镁,滑石,羊毛脂,凡士林,乙腈,二甲基甲酰胺和二甲基乙酰胺。特别是药物形式如片剂,糖衣片剂,胶囊,溶液,优选油溶液或水溶液,糖浆,果汁或滴剂,以及悬浮液或乳液,被用于口服或直肠给药。两种或多种载体也可以应用,例如两种或多种溶剂的混合物,尤其是一种或多种有机溶剂与水的混合物。作为添加剂或赋形剂,药物制剂可以含有例如稳定剂和/或润湿剂,乳化剂,盐,例如影响渗透压的盐,润滑剂,防腐剂,着色剂和调味剂和/或芳香剂和缓冲物质。如果需要,它们也可以含有一种或多种其它活性化合物,例如一种或多种维生素。式(I)化合物和/或其生理耐受盐也可以被冻干,所得的冻干物可以被用于,例如生产注射制剂。脂质体制剂也特别适合于局部施用。
被给药的式(I)活性化合物和/或其生理耐受盐的剂量在根据本发明使用的情况下,取决于各种情况,并根据个体条件配制,使其达到最佳作用。因此,剂量取决于被治疗疾病的性质和严重性,并依赖于被治疗的人或动物的性别,年龄,体重和个体反应,依赖于所用的化合物的效力和作用周期,依赖于该治疗是急性的还是慢性的,或者是预防性的,或者取决于除式(I)化合物外是否有其它活性化合物被给药。一般说来,用于治疗人的上述综合征的剂量范围是,对于体重约75kg的成人为大约0.1mg至大约100mg每kg每天,即足以实现所需的作用。每kg每天(在各种情况下每kg体重)1至20mg的剂量是优选的。日剂量这里可以作为单个剂量给药,或者可以被分为多个,例如,1,2,3或4个单剂量给药。也可以连续给药。如果需要,根据个体行为,可以上调或下调所标明的日剂量。药物制剂一般含有0.2至500mg,优选1至300mg式(I)的活性化合物和/或其生理耐受盐。
本发明也非常一般地包括优选非肽化合物作为药物的用途,该非肽化合物带来分布在例如血管(包括内皮),肾,CNS和心脏内的血管紧张肽(1-7)的刺激,优选口服给药或用作刺激血管舒张剂,血栓形成和心脏保护信使cGMP和NO,并用作治疗和/或预防由血管舒张剂,抗血栓形成和心脏保护信使环状3’,5-鸟甘一磷酸酯(cGMP)和一氧化氮(NO)产生的减少而直接或间接引起,或至少部分引起的疾病的药物,尤其是治疗或预防高血压,心脏肥大,心脏机能不全,冠状心脏病如心绞痛,心肌梗塞,血管成型术后的再狭窄,心肌病,内皮功能失调或内皮损伤,例如动脉粥样硬化或糖尿病引起的结果,和动脉和静脉血栓形成引起的结果。缩写如下:abs. 绝对cGMP 环状3’,5’-鸟甘一磷酸酯CH2Cl2 二氯甲烷DCl 解吸化学离子化DMF N,N-二甲基甲酰胺EA 乙酸乙酯ESI 电子喷雾离子化FAB 快速原子轰击m.p. 熔点satd 饱和h 小时min 分NO 一氧化氮RT 室温THF 氢呋喃
本发明由下列实施例举例说明,而不受其限制。
实施例:
将8.0g(32.0mmol)4-氯-5-甲酰基-2-苯基咪唑(根据Chem.Pharm.Bull.24,1976,960-969制备)和5.3g(32.0mmol)碳酸钾在200ML绝对DMF中的溶液在室温搅拌20分钟。然后滴加9.6g(32.0mmol)4-溴苄基溴在200ML绝对DMF中的溶液,反应溶液在室温搅拌6小时。将其真空浓缩,所得的残余物被溶于EA,用水,10%硫酸氢钾,10%碳酸氢钠和饱和氯化钠溶液洗涤,硫酸钠干燥。除去EA后的残余物用EA/庚烷(1∶4)作洗脱剂在硅胶上色谱纯化,给出11.5g米色固体形式的标题化合物。M.p.:92-95℃Rf(SiO2,EA/庚烷 1∶4)=0.24MS(ESI):m/e=375/377[M+H]+b) 4-氯-5-甲酰基-2-苯基-1-[[4-[2-(N-叔丁基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑
将7.2g(22.6mmol)5-异丁基-2-[(N-叔丁基)磺酰胺基]噻吩-3-硼酸(在EP-A 512675中公开)在125ML乙醇中的溶液在室温下滴加到8.5g(22.6mmol)实施例1a)的化合物和800mg四三苯膦钯(0)在100ML甲苯中的溶液。加入26ML 2M碳酸铯溶液,产生的反应溶液被回流搅拌5小时。将其浓缩至干,残余物被溶于EA/水(1∶1)。分出有机相,用水洗涤,硫酸钠干燥并浓缩。残余物在硅胶上用EA/庚烷(1∶4)作洗脱剂色谱纯化,给出6.7g标题化合物白色固体。 M.p.:104-105℃Rf(SiO2,EA/庚烷 1∶2)=0.26MS(ESI):m/e=570[M+H]+c) 4-氯-5-甲酰基-2-苯基-1-[[4-[2-磺酰胺基-5-异丁基-3-噻吩基]苯基]甲基]咪唑
将3.3g(5.96mmol)实施例1b)的化合物和3.5ML(5.96mmol)茴香醚在33ML三氟乙酸中的溶液在室温下搅拌48小时。真空浓缩至干,残余物被溶于EA。该EA溶液用水洗涤,硫酸钠干燥并浓缩。残余物在硅胶上用EA/庚烷(1∶1)作洗脱剂色谱纯化后,给出1.52g所需的化合物,为慢结晶的固体形式。M.p.:118-120℃Rf(SiO2,EA/庚烷 1∶1)=0.32MS(ESI):m/e=515[M+H]+d) 4-氯-5-甲酰基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑
将100mg(0.19mmol)实施例1c)的化合物在1.7ML绝对吡啶中的溶液在氩气氛中依次用3mg(0.02mmol)4-吡咯烷基吡啶和252μl(0.19mmol)氯甲酸丁基酯处理。反应溶液在室温搅拌24小时。然后加入0.7ML甲醇,将溶液浓缩至干,残余物溶于EA。然后将EA溶液用10%柠檬酸溶液,水和饱和氯化钠溶液洗涤,硫酸钠干燥并浓缩,除去溶剂后的残余物在硅胶上用EA/庚烷(1∶1)色谱纯化,最终给出85mg非晶型固体标题化合物。Rf(SiO2,EA/庚烷 1∶1)=0.15MS(FAB):m/e=614[M+H]+
实施例25-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑a) 5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-磺酰胺基-5-异丁基-3-噻吩基]苯基]甲基]咪唑
将850mg(1.65mmol)实施例1c)的化合物在25ML甲醇中的溶液用665mg(16.53mmol)氢氧化钠处理,并回流搅拌20小时。反应溶液被浓缩,残余物溶于60ML EA/庚烷(1∶1),通过加入1N盐酸将溶液的pH调节至6,分出有机层。水相用EA萃取2次,合并的有机相用硫酸钠干燥。除去EA后所得的残余物在硅胶上用EA/庚烷(1∶1)作洗脱剂色谱纯化,给出690mg黄色非晶型泡沫标题化合物。Rf(SiO2,EA/庚烷 1∶1)=0.23MS(FAB):m/e=510[M+H]+b) 5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑
通过实施例2a)的化合物与氯甲酸丁基酯根据实施例1d)所说的方法反应来制备标题化合物。在此情况下,从在硅胶上用EA/庚烷(1∶1)作洗脱剂色谱纯化后的106mg(0.21mmol)实施例2a)化合物开始,给出75mg非晶型泡沫状所需的化合物。Rf(SiO2,EA/庚烷 1∶1)=0.18MS(ESI):m/e=610[M+H]+实施例35-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(正丙氧羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑
通过实施例2a)的化合物与氯甲酸丙基酯根据实施例1d)所说的方法反应来制备标题化合物。在此情况下,从在硅胶上用EA/庚烷(1∶1)作洗脱剂色谱纯化后的60mg(0.12mmol)实施例2a)化合物开始,给出61mg非晶型泡沫状所需的化合物。Rf(SiO2,EA/庚烷 1∶1)=0.13MS(ESI):m/e=596[M+H]+
通过实施例2a)的化合物与氯甲酸乙基酯根据实施例1d)所说的方法反应来制备标题化合物。在此情况下,从60mg(0.12mmol)实施例2a)化合物开始在硅胶上用EA/庚烷(1∶1)作洗脱剂色谱纯化后,给出55mg非晶型泡沫状所需的化合物。Rf(SiO2,EA/庚烷 1∶1)=0.10MS(ESI):m/e=582[M+H]+
将80mg(0.16mmol)实施例2a)化合物,43.3mg(0.32mmol)碳酸钾和8.3mg二甲基氨基吡啶在6ML二甘醇二甲基醚中的溶液用16.8μl(0.16mmol)重碳酸二甲基酯处理,然后回流搅拌1.5小时。反应溶液被浓缩至干,残余物被溶于EA和10%磷酸二氢钾溶液(1∶1)的溶液。分出有机相,用10%磷酸二氢钾溶液洗涤2次,硫酸钠干燥并浓缩。残余物在硅胶上用EA/庚烷(2∶1)色谱纯化,给出55mg非晶型泡沫标题化合物。Rf(SiO2,EA/庚烷 4∶1)=0.23MS(ESI):m/e=568[M+H]+
将60mg(0.12mmol)实施例2a)化合物在2ML绝对DMF中的溶液依次用48mg(0.35mmol)碳酸钾和13.2μl(0.12mmol)异氰酸正丁基酯处理,然后回流搅拌3小时。冷却后,往反应溶液中加入15ML 10%磷酸二氢钾溶液。所得的溶液用EA萃取几次。合并的有机相用硫酸钠干燥并浓缩。所得的残余物在硅胶上用EA/二异丙基醚处理,抽滤产生的沉淀。将沉淀真空干燥,给出55mg标题化合物。M.p.:131-133℃Rf(SiO2,EA/庚烷 4∶1)=0.30MS(FAB):m/e=609[M+H]+
实施例75-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(乙基氨基羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑
通过实施例2a)的化合物与异氰酸乙酯根据实施例6)所述的方法反应来制备标题化合物。在此情况下,从60mg(0.12mmol)实施例2a)的化合物开始,得到46mg标题化合物。M.p.:105-106℃Rf(SiO2,EA/庚烷 4∶1)=0.30MS(ESI):m/e=581[M+H]+
将80mg(0.16mmol)实施例2a)的化合物在1.5ML DMSO中的溶液用30.4mg(0.17mmol)N-甲基-2,2,2-三氯乙酰胺和19.1mg(0.47mmol)粉状氢氧化钠处理,并在80℃搅拌1小时。将反应溶液冷却,用冰处理,通过加入2N盐酸将pH调节至4。抽滤出在此过程中沉积的沉淀,用水洗涤,干燥并在硅胶上用EA/庚烷(2∶1)作洗脱剂色谱纯化。得到62mg白色固体形式的标题化合物。M.p.:102-103℃Rf(SiO2,EA/庚烷 4∶1)=0.14MS(ESI):m/e=567[M+H]+实施例95-甲酰基-4-甲氧基乙氧基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑a) 5-甲酰基-4-甲氧基乙氧基-2-苯基-1-[[4-[2-磺酰胺基-5-异丁基-3-噻吩基]苯基]甲基]咪唑
将200mg(0.38mmol)实施例1c)的化合物在7.8ML乙二醇一甲基醚中的溶液用155mg(3.89mmol)粉状氢氧化钠在氩气氛中处理,然后在80℃搅拌5小时。将其浓缩至干,所得的残余物被溶于饱和碳酸氢钠溶液和EA。分出EA相,水相用EA萃取几次。合并有机相,硫酸钠干燥并浓缩。残余物在硅胶上用EA/庚烷(1∶1)色谱纯化,给出140mg浅黄色固体标题化合物。M.p.:91-92℃Rf(SiO2,EA/庚烷 1∶1)=0.12MS(FAB):m/e=554[M+H]+b)5-甲酰基-4-甲氧基乙氧基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑
将实施例9a)的化合物与氯甲酸丁基酯根据实施例1d)所述的方法反应来制备标题化合物。在此情况下,从70mg(0.13mmol)实施例9a)化合物开始在硅胶上用EA/庚烷(1∶1)作洗脱剂色谱纯化后,给出78mg非晶型泡沫状标题化合物。Rf(SiO2,EA/庚烷 1∶1)=0.07MS(ESI):m/e=654[M+H]+
实施例105-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-异丁基-3-噻吩基]-2-氯苯基]甲基]咪唑a) 4-氯-1-[(4-溴-2-氯苯基)甲基]5-甲酰基-2-苯基咪唑
通过4-氯-5-甲酰基-2-苯基咪唑与4-溴-2-氯苄基溴根据实施例1a)所述的方法反应来制备标题化合物。在此情况下,从2.0g(9.68mmol)4-氯-5-甲酰基-2-苯基咪唑开始,得到2.6g标题化合物。Rf(SiO2,EA/庚烷 1∶2)=0.56MS(DCI):m/e=409/411[M+H]+b) 4-氯-5-甲酰基-2-苯基-1-[[4-[2-(N-叔丁基磺酰胺基)-5-异丁基-3-噻吩基]-2-氯苯基]甲基]咪唑
通过实施例10a)的化合物和5-异丁基-2-[(N-叔丁基)磺酰胺基]噻吩-3-硼酸根据实施例1b)所述的方法反应来制备标题化合物。在此情况下,从2.0g(4.88mmol)实施例10a)的化合物开始,得到1.2g标题化合物浅褐色油状物。 Rf(SiO2,EA/庚烷 1∶2)=0.47MS(FAB):m/e=604[M+H]+c) 4-氯-5-甲酰基-2-苯基-1-[[4-[2-磺酰胺基-5-异丁基-3-噻吩基]-2-氯苯基]甲基]咪唑
从实施例10b)的化合物根据实施例1c)所述的方法来制备标题化合物。从1.2g(1.99mmol)实施例10b)的化合物开始,得到606mg标题化合物非晶型黄色泡沫。Rf(SiO2,EA/庚烷 1∶2)=0.32MS(FAB):m/e=548[M+H]+d) 5-甲酰基-2-甲氧基-2-苯基-1-[[4-[2-磺酰胺基-5-异丁基-3-噻吩基]-2-氯苯基]甲基]咪唑
从实施例10c)的化合物根据实施例2a)所述的方法来制备标题化合物。在此情况下,从400mg(0.73mmol)实施例10c)的化合物开始,得到280mg标题化合物非晶型黄色泡沫。M.p.:60℃(软化)Rf(SiO2,EA/庚烷 1∶2)=0.20MS(ESI):m/e=544[M+H]+e) 5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-异丁基-3-噻吩基]-2-氯苯基]甲基]咪唑
从实施例10d)的化合物与氯甲酸丁基酯根据实施例1d)所述的方法反应来制备标题化合物。从200mg(0.37mmol)实施例10d)的化合物开始,以米色固体形式得到167mg所需的化合物。M.p.:58℃(软化)Rf(SiO2,EA/庚烷 1∶1)=0.45MS(ESI):m/e=644[M+H]+实施例115-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-异丁基-3-噻吩基]-2-氯苯基]甲基]咪唑
从实施例10d)与异氰酸乙酯根据实施例7)所述的方法反应来制备标题化合物。在此情况下,从74mg(0.14mmol)实施例10d)的化合物开始在硅胶上用二氯甲烷/甲醇(20∶1)色谱纯化后,给出35mg白色固体形式的标题化合物。M.p.:83℃(软化)Rf(SiO2,EA/庚烷 1∶1)=0.30MS(ESI):m/e=614[M+H]+
实施例124-氯-5-甲酰基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-正丙基-3-噻吩基]苯基]甲基]咪唑a) 4-氯-5-甲酰基-2-苯基-1-[[4-[2-(N-叔丁基磺酰胺基)-5-正丙基-3-噻吩基]苯基]甲基]咪唑
通过实施例1a)的化合物与5-正丙基-2-[(N-叔丁基)磺酰胺基]噻吩-3-硼酸(在EP-A 512675中公开)根据实施例1b)的方法反应来制备标题化合物。在此情况下,从4.8g(13.1mmol)实施例1a)的化合物开始在硅胶上用EA/庚烷(1∶3)色谱纯化后,给出白色固体形式的2.9g标题化合物。M.p.:140℃Rf(SiO2,EA/庚烷 1∶2)=0.30MS(FAB):m/e=556[M+H]+b) 4-氯-5-甲酰基-2-苯基-1-[[4-[2-磺酰胺基-5-正丙基-3-噻吩基]苯基]甲基]咪唑
从实施例12a)的化合物根据实施例1c)的方法制备标题化合物。从1.9g(3.56mmol)实施例12a)的化合物开始,在硅胶上用EA/庚烷(1∶2)作洗脱剂色谱纯化后,给出1.1g白色固体形式的标题化合物。M.p.:93-95℃Rf(SiO2,EA/庚烷 1∶2)=0.18MS(ESI):m/e=500[M+H]+c) 4-氯-5-甲酰基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-正丙基-3-噻吩基]苯基]甲基]咪唑
通过实施例12b)的化合物与氯甲酸丁基酯根据实施例1d)的方法反应来制备标题化合物。在此情况下,从100mg(0.20mmol)实施例12b)的化合物开始,在硅胶上用EA/庚烷(1∶1)作洗脱剂色谱纯化后,给出90mg标题化合物。Rf(SiO2,EA/庚烷 1∶1)=0.14MS(ESI):m/e=600[M+H]+实施例135-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-正丙基-3-噻吩基]苯基]甲基]咪唑a) 5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-磺酰胺基-5-正丙基-3-噻吩基]苯基]甲基]咪唑
通过实施例12b)的化合物根据实施例2a)所述的方法反应来制备标题化合物。在此情况下,从850mg(1.70mmol)实施例12b)的化合物开始,在硅胶上用EA/庚烷(1∶2)色谱纯化后,给出460mg白色固体形式的标题化合物。M.p.:85-86℃Rf(SiO2,EA/庚烷 1∶1)=0.22MS(ESI):m/e=496[M+H]+b) 5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-正丙基-3-噻吩基]苯基]甲基]咪唑
通过实施例13a)的化合物与氯甲酸丁基酯根据实施例1d)所述的方法反应来制备标题化合物。在此情况下,从60mg(0.12mmol)实施例13a)的化合物开始,在硅胶上用EA/庚烷(1∶1)作洗脱剂色谱纯化后,得到52mg标题化合物。Rf(SiO2,EA/庚烷 1∶1)=0.18MS(ESI):m/e=596[M+H]+实施例145-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(甲氧羰基磺酰胺基)-5-正丙基-3-噻吩基]苯基]甲基]咪唑
通过实施例13b)的化合物与重碳酸二甲基酯根据实施例5)所述的方法反应来制备标题化合物。从75mg(0.15mmol)实施例13b)的化合物开始,在硅胶上用EA/庚烷(2∶1)作洗脱剂色谱纯化后,得到66mg非晶型固体标题化合物。Rf(SiO2,EA/庚烷 4∶1)=0.18MS(ESI):m/e=554[M+H]+
通过实施例13b)的化合物与异氰酸正丁基酯根据实施例6)所述的方法反应来制备标题化合物。从59mg(0.12mmol)实施例13b)的化合物开始,在硅胶上用EA/庚烷(1∶1)作洗脱剂色谱纯化后,得到54mg非晶型固体标题化合物。Rf(SiO2,EA/庚烷 4∶1)=0.25MS(ESI):m/e=595[M+H]+
通过实施例13b)的化合物与N-甲基-2,2,2-三氯乙酰胺根据实施例8)所述的方法反应来制备标题化合物。从70mg(0.14mmol)实施例13b)的化合物开始,在硅胶上用EA/庚烷(1∶1)作洗脱剂色谱纯化后,得到54mg非晶型固体标题化合物。Rf(SiO2,EA/庚烷 4∶1)=0.15MS(ESI):m/e=553[M+H]+
实施例175-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(乙基氨基羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑钠盐
220mg(0.38mmol)实施例7的化合物用3.7ML新制备的0.1M甲醇钠溶液处理,产生的溶液在室温下搅拌1小时。将反应溶液浓缩至干,所得的残余物在微温下溶于4ML乙酸正丁基酯。抽滤在冰箱中贮存3天后结晶出的沉淀,并用少量冷乙酸正丁基酯洗涤。高真空干燥后,最终给出120mg所需的钠盐。M.p.:170℃MS(ESI):m/e=603[M+H]+
500mg(0.86mmol)实施例7的化合物和125.8mg(0.86mmol)L-赖氨酸在100ML乙醇和25ML水中的溶液在室温下搅拌2小时。然后浓缩至干,所得的残余物溶于30ML水,所得的溶液被冻干。将所得的200mg非晶型残余物溶于10ML热甲苯。在冰箱中贮存几天后,滤出结晶的沉淀并高真空干燥。给出68mg标题化合物浅黄色晶体。M.p.:180℃MS(ESI):m/e=727[M+H]+
实施例195-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(乙基氨基羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑三(羟甲基)氨基甲烷盐
300mg(0.516mmol)实施例7的化合物和62.6mg(0.516mmol)三(羟甲基)氨基甲烷在75ML乙醇和15ML水中的溶液在室温下搅拌2小时。然后浓缩至干,所得的残余物溶于水并被冻干。将所得的非晶型残余物在加热下溶于30ML乙酸正丁基酯。在冰箱中贮存几天后,抽滤出结晶的沉淀并高真空干燥。给出120mg标题化合物浅黄色晶体。M.p.:144-145℃MS(ESI):m/e=702[M+H]+
式(I)化合物对于血管紧张肽(1-7)结合位点的亲和力,和其对内皮细胞的兴奋性质在下列试验(试验1和2)中证实:试验1:结合试验:
式(I)化合物对于血管紧张肽(1-7)受体的亲和力通过牛动脉内皮细胞的膜制剂上的配位代替实验测量,例如在Hypertension,1997;29[part 2]:388-393中所述的。a) 膜制剂:
从牛动脉(试验1,a)获得内皮细胞后,将该细胞在75cm2培养瓶(Becton Dickinson,Heidelberg)中培养,直至其铺满。然后将该细胞用冰冷的磷酸/氯化钠/EDTA缓冲液(50mmol/l NaHPO4,0.15mol/lNaCl,5mmol/l EDTA,pH 7.2)处理,用橡皮刮板分离并离心(1500×g,5min)。产生的细胞沉淀被冷冻(-80℃),用于后面的膜制剂。熔融的细胞沉淀在冰冷的磷酸/氯化钠/EDTA缓冲液中匀浆(玻璃/特氟龙锅,1000rpm,10冲程)。随后通过将细胞匀浆物离心(30000×g,20min)进行膜分离。所得的细胞沉淀悬浮于修饰过的HEPES缓冲液(10nmol/l HEPES,0.1mol/l NaCl,5mmol/l MgCl2,pH 7.4),加入0.2%牛血清白蛋白和蛋白酶抑制剂鸡尾酒(CompleteTM,BoehringerMannheim)。膜悬浮液的蛋白测定(根据Lowry的方法)后,将其立即用于配位结合试验。b) 结合实验
试验在配有Durapore滤纸(0.65μm孔径;Millipore,Eschborn)的96-孔不透明板上进行。试验开始之前,滤纸用1%牛血清白蛋白预处理30分钟,以使放射活性配体和冷物质对滤纸材料的非特异性结合最小化。温育在200μl总体积中进行:50μl 125I-ANG(1-7),20μl冷的非放射活性ANG(1-7)或式(I)的试验物质,30μl缓冲液和100μl膜(20μg蛋白质)。通过加入放射活性配体开始结合反应。样品的温育通过在室温连续摇动45分钟而进行。通过真空过滤(-20kPa真空;多筛过滤系统,Millipore,Eschborn)终止结合反应。为了完全除去非膜结合,自由放射活性,将滤纸用250μl冰冷的磷酸/氯化钠/EDTA缓冲液(50mmol/l NaHPO4,0.15mol/l NaCl,5mmol/l EDTA,pH 7.2)在真空洗涤2次,然后干燥。干燥的滤纸上的放射含量通过γ计数器测定。对于竞争实验(“个体值”或IC50值的测定),使用7.5至10nmol/l浓度的125I-ANG(1-7)(特异性活性1500-2100mCi/mg),而不增加式(I)的试验物质的浓度。在各种情况下非特异性结合都在10nmol/l非放射活性的ANG(1-7)存在下测量。c) 结果:实施例 IC50值[nM]2a 202b 304 57 20
该结果证实了式(I)化合物对于内皮细胞上的血管紧张肽受体的高亲和力。而对于AT1和AT2型的ANGII受体,在各种情况下式(I)化合物都没有亲和力或仅有可忽略(>10-6M)的亲和力。试验2:功能试验
作为在内皮细胞中NO生产或释放的标志,如J.Pharmacol.Exp.Ther.1992,262,729-733中所述在牛动脉的原代培养内皮细胞上测量式(I)化合物对细胞内cGMP生产的刺激作用。a) 细胞培养:
酶消化牛动脉内皮细胞后(Dispase II;Boehringer,Mannheim),将内皮细胞在培养基(Dulbecco’s修饰过的Eagle’s Ham’s F 12培养基1∶1带有青霉素(10U/l),链霉素(10μg/1),L-谷胺酰胺(1mmol/l),谷胱甘肽和L-(+)-抗坏血酸(各5mg/l)和加热失活的胎牛血清(20%))中处理,洗涤一次(在170×g,10min离心),并再悬浮于培养基中。所得的细胞悬浮液在6-孔板(Nunc Intermed,Wiesbaden)中用培养基温育(-250μg蛋白质或每孔3×10-5细胞),并在湿润和用95%O2/5%CO2充气的温育箱中于37℃保持。b) cGMP测定:
铺满后(温育后6-8天),除去培养基,细胞单层用温热的HEPES/Tyrode’s溶液洗涤两次。然后将细胞在37℃,在含有IBMX(3-异丁基-1-甲基黄嘌呤,10-4mol/l,Serva,heidelberg)的HEPES/Tyrode’s溶液中于37℃预温育15分钟。通过加入SOD(从牛红细胞得到的超氧化物歧化酶,3×10-7mol/l,Serva,heidelberg)和给定的浓度的式(I)物质开始温育。在适当的温育时间后,温育培养基被吸出,残留的细胞立即萃取到1N甲酸-丙酮(v/v,15∶85)中,并被刮出。适当的悬浮液被超声(10秒)然后离心(3000×g,10min)。为了通过放射免疫试验的手段(New England Nuclear,Bosten,MA)测定cGMP,将上清液冻干,并溶于醋酸钠缓冲液(0.05mol/l;pH 6.2)。细胞内cGMP的含量与细胞蛋白的mg相关。c) 结果:实施例 IC50值[nM]2a 0.52b 0.34 0.17 0.5
该结果证实了式(I)化合物对血管紧张肽(1-7)受体的兴奋作用。
本发明化合物对作为NO合成和释放标志的cGMP的生产在这里不受用AT1亚型如EXP3174或AT2亚型如PD 123319的血管紧张肽II受体拮抗剂预温育的影响。与此相反,本发明化合物对cGMP所述的刺激作用被用选择性的血管紧张肽(1-7)受体,[D-Ala7]-血管紧张肽(1-7)预温育的抑制,例如在Brain Res.Bull.1994,35,293-298中所述,它证实该功能作用的专一性。
式(I)化合物对心脏的作用在例如J.Cardiovasc.Pharmacol.1986,8[Suppl.10]:S91-S99中所述的分离的,工作的大鼠心脏(试验3)模型中证明。试验3:分离的,工作的大鼠心脏a) 方法:
分离的Wistar-Kyoto大鼠(280-300g体重)心脏用60mmHg的恒定灌注压,根据Langendorff的方法用氧气饱和(95%O2,5%CO2),非再循环,修饰过的Krebs-Henseleit缓冲溶液(118mmol/l NaCl,4.7mmol/l Kcl,2.5mmol/l CaCl2,1.6mmol/l MgCl2,24.9mmol/lNaHCO3,1.2mmol/l KH2PO4,5.5mmol/l葡萄糖和2.0mmol/l丙酮酸钠)灌注。为了测定冠状流,使用放在肺动脉中的具有电磁测量头的导管。平衡15分钟后,心脏被转为工作模式,其中设定15mmHg的前负载和60mmHg的后负载。心脏的工作负载在整个90分钟的试验时间保持恒定。用于分析的流量和压力信号通过PLUGSYS测量系统(HugoSachs Elektronik)记录。数据的分析以500Hz的频率,平均每2秒,用软件Aquire Plus VI.21f(PO-NE-MAH)收集。b) 结果:
以10-6mol/l浓度的实施例2化合物灌注心脏,与对照心脏相比,测得如下冠状流量(n=4):1. 处理过的心脏:冠状流量[ml/min] 时间[min]8.92±0.68 011.29±0.90 512.17±0.74 1012.22±0.10 152. 对照心脏:冠状流量[ml/min] 时间[min]8.98±0.59 08.94±0.52 59.04±0.70 108.91±0.44 15
在整个实验期间,在两组中都保持心律不变。
在分离的,工作的大鼠心脏中冠状流量的明显增加证实了式(I)化合物的心脏保护作用。
式(I)化合物对胶原-诱导的血小板凝聚的作用在人血小板富集的血浆中研究,如G.V.Born et al.,Nature 1962中所述。试验4:a) 方法:
从6个血液供体所得的人血小板富集的血浆(RPR)与试验化合物在37℃温育20分钟,然后用胶原活化,经光透射以%定量测定血小板的最大凝聚。b) 结果:
用30μM实施例2的化合物温育血小板富集的血浆,测得如下血小板凝聚(n=6):胶原(=最大凝聚):92±2.7%凝聚胶原+30μM实施例2的化合物:52±5.7%凝聚
人血小板富集血浆的血小板凝聚的明显抑制证实了式(I)化合物的抗血小板凝聚作用。
Claims (18)
2.羟基;
3.(C1-C4)-烷氧基;
4.(C1-C8)-烷氧基,其中1至6个碳原子被杂原子O,S或NH代替;
5.(C1-C4)-烷氧基,被饱和环状醚取代;
6.O-(C1-C4)-烯基;
7.O-(C1-C4)-烷基芳基;和
8.芳氧基,未取代或被由卤素,(C1-C3)-烷基,(C1-C3)-烷氧基或三氟甲基组成的组中的取代基取代;R(2) 1.CHO;
2.COOH;和
3.CO-O-(C1-C4)-烷基;R(3) 1.(C1-C4)-烷基;和
2.芳基;R(4) 1.氢;
2.卤素,和
3.(C1-C4)-烷基;X 1.氧;
2.硫;Y 1.氧;和
2.-NH-;R(5) 1.氢;
2.(C1-C6)-烷基;和
3.(C1-C4)-烷基芳基;
其中如果Y具有2中给出的意义,则R(5)只能是氢;R(6) 1.(C1-C5)-烷基;其所有的非对映体形式和其所有比例的混合物,和其生理耐受盐;排除其中R(1)是氢,并且R(2)具有2.和3.意义的式(I)化合物。
2.如权利要求1的式(I)化合物,其中:R(1) 1.氯;
2.羟基;
3.甲氧基,乙氧基,丙氧基;
4.甲氧基乙氧基,甲氧基丙氧基;
5.烯丙氧基;
6.苯氧基;R(4) 1.氢;和
2.氯;R(5) 1.氢;和
2.(C1-C4)-烷基;R(6) 正丙基和2-异丁基;其它基团如权利要求1中定义,其所有的非对映体形式和其混合物,和其生理耐受盐。
3.如权利要求1或2的化合物,其中:R(1) 是卤素;(C1-C4)-烷氧基;或(C1-C8)-烷氧基,其中1至6个碳原子被杂原子O,S或NH代替;R(2) 是CHO;R(3) 是芳基;R(4) 是卤素或氢;R(5) 是(C1-C6)-烷基;R(6) 是(C1-C5)-烷基;X 是氧;Y 是氧或-NH-;其所有的非对映体形式和其混合物,和其生理耐受盐。
5.如权利要求1至4的一项或多项的式(I)化合物,其中R(1)是(C1-C4)-烷氧基或(C1-C8)-烷氧基,其中1至6个碳原子被杂原子O,S或NH代替,其它基团如权利要求1至4一项或多项所定义;其所有的非对映体形式和其混合物,和其生理耐受盐。
6.如权利要求1至5的一项或多项的式(I)化合物,其中R(2)是CHO,而其它基团如权利要求1至5一项或多项所定义,其所有的非对映体形式和其混合物,和其生理耐受盐。
7.如权利要求1至6的一项或多项的式(I)化合物,其中X是O,其它基团如权利要求1至6一项或多项所定义,其所有的非对映体形式和其混合物,和其生理耐受盐。
8.如权利要求1至7的一项或多项的式(I)化合物,是4-氯-5-甲酰基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(正丙氧羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(乙氧羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(甲氧羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(正丁基氨基羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(乙基氨基羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(乙基氨基羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑钠盐;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(乙基氨基羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑L-赖氨酸盐;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(乙基氨基羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑三(羟甲基)氨基甲烷盐;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(甲基氨基羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑;5-甲酰基-4-甲氧基乙氧基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-异丁基-3-噻吩基]苯基]甲基]咪唑;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-异丁基-3-噻吩基]-2-氯苯基]甲基]咪唑;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-异丁基-3-噻吩基]-2-氯苯基]甲基]咪唑;4-氯-5-甲酰基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-正丙基-3-噻吩基]苯基]甲基]咪唑;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(正丁氧羰基磺酰胺基)-5-正丙基-3-噻吩基]苯基]甲基]咪唑;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(甲氧羰基磺酰胺基)-5-正丙基-3-噻吩基]苯基]甲基]咪唑;5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(正丁基氨基羰基磺酰胺基)-5-正丙基-3-噻吩基]苯基]甲基]咪唑;或5-甲酰基-4-甲氧基-2-苯基-1-[[4-[2-(甲基氨基羰基磺酰胺基)-5-正丙基-3-噻吩基]苯基]甲基]咪唑;和其生理耐受盐。
10.如权利要求1至9的一项或多项的式(I)或(X)的化合物,用作药物。
11.一种药物制剂,具有有效量的如权利要求1至9的一项或多项的式(I)或(X)的化合物和/或其生理耐受盐。
12.式(I)化合物和其所有的非对映体形式和其所有比例的混合物,和其生理耐受盐在生产用于治疗和/或预防由血管舒张剂,抗血栓形成和心脏保护信使环状3’,5’-鸟甘一磷酸酯(cGMP)和一氧化氮(NO)产生和/或释放的减少而直接或间接或至少部分引起的疾病的药物中的用途其中所述取代基具有下列意义:R(1) 1.卤素;
2.羟基;
3.(C1-C4)-烷氧基;
4.(C1-C8)-烷氧基,其中1至6个碳原子被杂原子O,S或NH代替;
5.(C1-C4)-烷氧基,被饱和环状醚取代;
6.O-(C1-C4)-烯基;
7.O-(C1-C4)-烷基芳基;和
8.芳氧基,未取代或被由卤素,(C1-C3)-烷基,(C1-C3)-烷氧基或三氟甲基组成的组中的取代基取代;R(2) 1.CHO;
2.COOH;和
3.CO-O-(C1-C4)-烷基;R(3) 1.(C1-C4)-烷基;和
2.芳基;R(4) 1.氢;
2.卤素,和
3.(C1-C4)-烷基;X 1.氧;
2.硫;Y 1.氧;和
2.-NH-;R(5) 1.氢;
2.(C1-C6)-烷基;和
3.(C1-C4)-烷基芳基;
其中如果Y具有2中给出的意义,则R(5)只能是氢;R(6) 1.(C1-C5)-烷基。
13.如权利要求12的式(I)化合物的用途,用于生产用于治疗和/或预防高血压,心脏肥大,心脏机能不全,冠状心脏病如心绞痛,心肌梗塞,血管成型术后的再狭窄,心肌病,内皮功能失调或内皮损伤,例如动脉粥样硬化或糖尿病引起的结果,和动脉和静脉栓形成引起的结果的药物。
14.血管紧张肽(1-7)受体兴奋剂在生产用于治疗和/或预防由血管舒张剂,抗血栓形成和心脏保护信使环状3’,5’-鸟甘一磷酸酯(cGMP)和一氧化氮(NO)产生和/或释放的减少而直接或间接或至少部分引起的疾病的药物中的用途。
15.血管紧张肽(1-7)受体兴奋剂在生产用于治疗和/或预防高血压,心脏肥大,心脏机能不全,冠状心脏病如心绞痛,心肌梗塞,血管成型术后的再狭窄,心肌病,内皮功能失调或内皮损伤,例如动脉粥样硬化或糖尿病引起的结果,和动脉和静脉血栓形成引起的结果的药物中的用途。
16.如权利要求1至9的一项或多项的式(I)或(X)的化合物,用作血管紧张肽(1-7)受体兴奋剂。
17.如权利要求1至9的一项或多项的式(I)或(X)的化合物,用于治疗和/或预防由血管舒张剂,抗血栓形成和心脏保护信使环状3’,5’-鸟甘一磷酸酯(cGMP)和一氧化氮(NO)产生和/或释放的减少而直接或间接或至少部分引起的疾病。
18.如权利要求1至9的一项或多项的式(I)或(X)的化合物,用于治疗和/或预防高血压,心脏肥大,心脏机能不全,冠状心脏病如心绞痛,心肌梗塞,血管成型术后的再狭窄,心肌病,内皮功能失调或内皮损伤,例如动脉粥样硬化或糖尿病引起的结果,和动脉和静脉血栓形成引起的结果。
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DE1999120815 DE19920815A1 (de) | 1999-05-05 | 1999-05-05 | 1-(p-Thienylbenzyl)-Imidazole als Agonisten von Angiotensin-(1-7)-Rezeptoren, Verfahren zu ihrer Herstellung, ihre Verwendung und sie enthaltende pharmazeutische Präparate |
DE19920815.8 | 1999-05-05 | ||
DE19961686.8 | 1999-12-21 | ||
DE1999161686 DE19961686A1 (de) | 1999-12-21 | 1999-12-21 | 1-(p-Thienylbenzyl)-Imidazole als Agonisten von Angiotensin-1(1-7)-Rezeptoren, Verfahren zu ihrer Herstellung, ihre Verwendung und sie enthaltende pharmazeutische Präparate |
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CN101247818A (zh) * | 2005-06-28 | 2008-08-20 | 米纳斯吉拉斯联合大学 | Mas g-蛋白偶联受体激动剂和拮抗剂作为凋亡活性调节剂用于预防和治疗疾病的用途 |
CN104302305A (zh) * | 2011-12-16 | 2015-01-21 | 塔瑞克斯制药有限公司 | 用于治疗纤维化的血管紧张素 |
CN104394878A (zh) * | 2012-02-10 | 2015-03-04 | 塔瑞克斯制药有限公司 | 用于治疗周围血管疾病的组合物和方法 |
US9333233B2 (en) | 2014-02-25 | 2016-05-10 | Tarix Pharmaceuticals Ltd. | Methods and compositions for the delayed treatment of stroke |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101247818A (zh) * | 2005-06-28 | 2008-08-20 | 米纳斯吉拉斯联合大学 | Mas g-蛋白偶联受体激动剂和拮抗剂作为凋亡活性调节剂用于预防和治疗疾病的用途 |
CN104302305A (zh) * | 2011-12-16 | 2015-01-21 | 塔瑞克斯制药有限公司 | 用于治疗纤维化的血管紧张素 |
CN104394878A (zh) * | 2012-02-10 | 2015-03-04 | 塔瑞克斯制药有限公司 | 用于治疗周围血管疾病的组合物和方法 |
US9511055B2 (en) | 2012-10-02 | 2016-12-06 | Tarix Pharmaceuticals Ltd. | Angiotensin in treating brain conditions |
US9333233B2 (en) | 2014-02-25 | 2016-05-10 | Tarix Pharmaceuticals Ltd. | Methods and compositions for the delayed treatment of stroke |
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HRP20010814A2 (en) | 2003-02-28 |
HUP0201311A3 (en) | 2003-03-28 |
AR023837A1 (es) | 2002-09-04 |
WO2000068226A1 (de) | 2000-11-16 |
EP1185527A1 (de) | 2002-03-13 |
HK1045519A1 (en) | 2002-11-29 |
KR20020012207A (ko) | 2002-02-15 |
IL146198A0 (en) | 2002-07-25 |
US20010018449A1 (en) | 2001-08-30 |
ATE300535T1 (de) | 2005-08-15 |
US6235766B1 (en) | 2001-05-22 |
RU2247121C2 (ru) | 2005-02-27 |
HK1045519B (zh) | 2005-04-22 |
JP2002544130A (ja) | 2002-12-24 |
TR200103171T2 (tr) | 2002-06-21 |
US20020077344A1 (en) | 2002-06-20 |
AU775244B2 (en) | 2004-07-22 |
EE200100572A (et) | 2003-02-17 |
NO20015309D0 (no) | 2001-10-30 |
AU4753600A (en) | 2000-11-21 |
DE50010835D1 (de) | 2005-09-01 |
NZ515242A (en) | 2003-11-28 |
US6429222B2 (en) | 2002-08-06 |
BR0010248A (pt) | 2002-02-13 |
HUP0201311A2 (en) | 2002-10-28 |
YU78601A (sh) | 2005-07-19 |
PL351609A1 (en) | 2003-05-05 |
CN1158279C (zh) | 2004-07-21 |
SK15942001A3 (sk) | 2002-04-04 |
NO20015309L (no) | 2001-12-28 |
CZ20013907A3 (cs) | 2002-02-13 |
EP1185527B1 (de) | 2005-07-27 |
CA2373010A1 (en) | 2000-11-16 |
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