CN1208347A - 取代的n-[(氨基亚氨基甲基和氨基甲基)苯基]丙基酰胺 - Google Patents
取代的n-[(氨基亚氨基甲基和氨基甲基)苯基]丙基酰胺 Download PDFInfo
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- CN1208347A CN1208347A CN96199894A CN96199894A CN1208347A CN 1208347 A CN1208347 A CN 1208347A CN 96199894 A CN96199894 A CN 96199894A CN 96199894 A CN96199894 A CN 96199894A CN 1208347 A CN1208347 A CN 1208347A
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- 0 C[C@]([C@@](Cc1cccc(C(N)=N)c1)C(OC)=O)N*(c(cc1)ccc1-c1ccncc1)=O Chemical compound C[C@]([C@@](Cc1cccc(C(N)=N)c1)C(OC)=O)N*(c(cc1)ccc1-c1ccncc1)=O 0.000 description 7
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- JZCHSDMDWRLIOG-OPAMFIHVSA-N C[C@H]([C@@H](Cc1cc(C(N)=N)ccc1)C(OC)=O)NC(c(cc1)ccc1-c1cccnc1)=O Chemical compound C[C@H]([C@@H](Cc1cc(C(N)=N)ccc1)C(OC)=O)NC(c(cc1)ccc1-c1cccnc1)=O JZCHSDMDWRLIOG-OPAMFIHVSA-N 0.000 description 2
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- GFQQDLITWJZKHD-UHFFFAOYSA-O CC(C(Cc1cccc(C(N)N)c1)C(OC)=O)NC(c(cc1)ccc1-c1cc(C[N+](C)(C)C)ccc1)=O Chemical compound CC(C(Cc1cccc(C(N)N)c1)C(OC)=O)NC(c(cc1)ccc1-c1cc(C[N+](C)(C)C)ccc1)=O GFQQDLITWJZKHD-UHFFFAOYSA-O 0.000 description 1
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- AXCHQMQEQBQLSQ-UHFFFAOYSA-N CC(NCc(cc1)ccc1-c(cc1)ccc1C(NC(Cc1ccccc1)C(Cc1cccc(C(N)=N)c1)CO)=O)=O Chemical compound CC(NCc(cc1)ccc1-c(cc1)ccc1C(NC(Cc1ccccc1)C(Cc1cccc(C(N)=N)c1)CO)=O)=O AXCHQMQEQBQLSQ-UHFFFAOYSA-N 0.000 description 1
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- KAEQYUSEVZVZNT-UHFFFAOYSA-N NC(c1cc(CC(CO)C(Cc2ccccc2)NC(c(cc2)ccc2-c(c(N)c2)ccc2N)=O)ccc1)=N Chemical compound NC(c1cc(CC(CO)C(Cc2ccccc2)NC(c(cc2)ccc2-c(c(N)c2)ccc2N)=O)ccc1)=N KAEQYUSEVZVZNT-UHFFFAOYSA-N 0.000 description 1
- VLKXMGWYOSOTBF-UHFFFAOYSA-N NC(c1cc(CC(CO)C(Cc2ccccc2)NC(c(cc2)ccc2-c(c([N+]([O-])=O)c2)ccc2[N+]([O-])=O)=O)ccc1)=N Chemical compound NC(c1cc(CC(CO)C(Cc2ccccc2)NC(c(cc2)ccc2-c(c([N+]([O-])=O)c2)ccc2[N+]([O-])=O)=O)ccc1)=N VLKXMGWYOSOTBF-UHFFFAOYSA-N 0.000 description 1
- RAIYHEMVMGBJSF-UHFFFAOYSA-N NC(c1cc(CC(CO)C(Cc2ccccc2)NC(c(cc2)ccc2-c(cc2)ccc2N)=O)ccc1)=N Chemical compound NC(c1cc(CC(CO)C(Cc2ccccc2)NC(c(cc2)ccc2-c(cc2)ccc2N)=O)ccc1)=N RAIYHEMVMGBJSF-UHFFFAOYSA-N 0.000 description 1
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- YHPXLIYZWSORLX-UHFFFAOYSA-N NC(c1cc(CC(CO)C(Cc2ccccc2)NC(c(cc2)ccc2-c2cccc(N)c2)=O)ccc1)=N Chemical compound NC(c1cc(CC(CO)C(Cc2ccccc2)NC(c(cc2)ccc2-c2cccc(N)c2)=O)ccc1)=N YHPXLIYZWSORLX-UHFFFAOYSA-N 0.000 description 1
- JOTHRAALGKEBKE-UHFFFAOYSA-N NC(c1cccc(CC(CO)C(Cc2ccccc2)NC(c(cc2)ccc2-c(cc2)ccc2O)=O)c1)=N Chemical compound NC(c1cccc(CC(CO)C(Cc2ccccc2)NC(c(cc2)ccc2-c(cc2)ccc2O)=O)c1)=N JOTHRAALGKEBKE-UHFFFAOYSA-N 0.000 description 1
- YWVHBVFOEYETSY-UHFFFAOYSA-N NC(c1cccc(CC(CO)C(Cc2ccccc2)NC(c(cc2)ccc2-c(cc2)ccc2[N+]([O-])=O)=O)c1)=N Chemical compound NC(c1cccc(CC(CO)C(Cc2ccccc2)NC(c(cc2)ccc2-c(cc2)ccc2[N+]([O-])=O)=O)c1)=N YWVHBVFOEYETSY-UHFFFAOYSA-N 0.000 description 1
- JVUNWPDTDNCCMI-UHFFFAOYSA-N NCc(cc1)ccc1-c(cc1)ccc1C(NC(Cc1ccccc1)C(Cc1cccc(C(N)=N)c1)CO)=O Chemical compound NCc(cc1)ccc1-c(cc1)ccc1C(NC(Cc1ccccc1)C(Cc1cccc(C(N)=N)c1)CO)=O JVUNWPDTDNCCMI-UHFFFAOYSA-N 0.000 description 1
- QRJFGWOXDCNDBD-QXPUDEPPSA-N NCc1cc(-c(cc2)ccc2C(NC([C@H](Cc2cc(C(N)=N)ccc2)CO)c2cnccc2)=O)ccc1 Chemical compound NCc1cc(-c(cc2)ccc2C(NC([C@H](Cc2cc(C(N)=N)ccc2)CO)c2cnccc2)=O)ccc1 QRJFGWOXDCNDBD-QXPUDEPPSA-N 0.000 description 1
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
- C07D207/327—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
- C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
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- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
- C07C259/18—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings
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- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
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- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
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- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
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Abstract
本发明化合物是式(Ⅰ)取代的N-[(氨基亚氨基甲基或氨基甲基)苯基]丙基酰胺,该化合物显示有益的药理活性,因此将其掺入药物组合物中用于治疗患有某种内科生理失调患者,更具体地说,它们是因子Xa的抑制剂,本发明的目的在于式(Ⅰ)化合物、含有式(Ⅰ)化合物的组合物、它们的制备方法及它们的用途,它们用于治疗患有通过给入因子Xa抑制剂能够改善的病症的患者。
Description
发明领域
式(Ⅰ)化合物显示有益的药理活性,因此将其掺入药物组合物中用于治疗患有某种内科生理失调的患者,更具体地说,它们是因子Xa的抑制剂,本发明的目的在于式(Ⅰ)化合物、含有式(Ⅰ)化合物的组合物及它们的用途,它们用于治疗患有通过给入因子Xa的抑制剂能够改善的病症的患者。
因子Xa是在凝固级联中的次末级酶,式(Ⅰ)化合物抑制前凝血酶复合物(因子Xa、因子Va、钙和磷脂)中的游离因子Xa和因子Xa,通过在抑制剂与酶之间直接形成复合物而抑制因子Xa,因此,因子Xa的抑制不取决于血浆辅因子抗凝血酶Ⅲ,通过口服、连续静脉输液、团块性静脉给药或任何其它肠胃外途径施用化合物以有效抑制因子Xa的作用从而防止因子Xa诱导凝血酶原形成凝血酶而达到所需的效果。
抗凝剂疗法是在于治疗和预防各种静脉和动脉脉管系统的血栓症状,在动脉系统中,异常血栓的形成最初与冠状、大脑和外周脉管系统的动脉有关,这些与血管的血栓闭合有关的疾病主要包括急性心肌梗塞(AMI)、不稳定心绞痛、血栓栓塞、与溶栓治疗和经皮冠状动脉成形术(PTCA)有关的急性血管闭合、暂时缺血性发作、中风、间歇性跛行综合症和冠状或外周动脉支路移植(CABG)。慢性抗凝疗法也有益于预防血管腔再狭窄(该血管腔再狭窄经常产生随后的PTCA和CABG)并有益于维持长期血液透析的患者脉管通路开放,就静脉脉管系统而言,病理性血栓形成经常发生于继腹、膝和胯外科手术之后的较低末端静脉(深静脉血栓形成,DVT),DVT进一步使患者易患高危肺血栓栓塞。全身、弥散性血管内凝血病(DIC)通常发生于脓毒性休克、某些病毒感染和癌期间的血管系统,该病症的特征在于凝血因子的迅速积累和它们的血浆抑制剂导致在某些器官系统的整个微脉管系统中形成威胁生命的凝决,上述讨论的适应症包括需要抗凝剂治疗的一些(但不是所有)可能的临床情况,本领域经验丰富人员很清楚需要急性或慢性定期抗凝剂疗法的详情。
本发明概述
本发明的目的在于下面式(Ⅰ)化合物的药物用途,用于在治疗患有与生理有害过量因子Xa有关的疾病的患者中抑制因子Xa的产生或生理效果,其中,式Ⅰ如下:R1和R2是氢或共同为=NR9;R3是-CO2R6,-C(O)R6,-CONR6R6,-CH2OR7或-CH2SR7;R4是式:或R4是氢、烷基、环烷基或环烷基烷基;R5是烷基、链烯基、任选取代的芳基或任选取代的杂芳基;R6是氢或低级烷基;R7是氢、低级烷基、低级酰基、芳酰基或杂芳基;R8是氢或低级烷基;R9是R10O2C-、R10O-、HO-、氰基、R10CO-、HCO-、低级烷基硝基或Y1Y2N-,其中R10是任选取代的烷基、任选取代的芳烷基或任选取代的杂芳烷基,和其中Y1和Y2独立地是氢或烷基;A和B是氢或共同为键;Ar是任选取代的芳基或任选取代的杂芳基;和n是0,1或2;其药用盐、其N-氧化物、其水合物或其溶剂化物。
本发明详述
如上所用的和本发明说明书全文中的下列术语除非另有注明应理解为具有下列意义:定义
“患者”包括人类和其它哺乳类动物。
“烷基”是指在链中具有大约1-大约15个碳原子的直链或支链的脂肪烃,优选在链中具有大约1-大约12个碳原子的烷基,支链是指一个或多个更低级的烷基(如甲基、乙基或丙基)结合到直链烷基链上。“低级烷基”是指在链中具有大约1-大约6个碳原子的可以是直链或支链的烷基,烷基可以被一个或多个卤素、环烷基或环烯基取代,烷基基团的实例包括甲基、氟甲基、二氟甲基、三氟甲基、环丙基甲基、环戊基甲基、乙基、正丙基、异丙基、正丁基、叔丁基、正戊基、3-戊基、庚基、辛基、壬基、癸基和十二烷基。
“链烯基”是指含有双键碳原子并在链中具有大约2-大约15个碳原子的可以是直链或支链的脂肪烃,优选在链中具有大约2-大约12个碳原子的链烯基,更优选在链中具有大约2-大约6个碳原子的链烯基,支链是指一个或更低级的烷基(如甲基、乙基或丙基)结合到直链烯基链上。“低级链烯基”是指在链中具有大约2-大约4个碳原子的可以是直链或支链的链烯基,链烯基可以被一个或多个卤素取代,链烯基基团的实例包括乙烯基、丙烯基、正丁烯基、异丁烯基、3-甲基丁-2-烯基、正戊烯基、庚烯基、辛烯基和癸烯基。
“环烷基”是指大约3-大约10个碳原子的非芳香族单或多环系统,单环环烷基环的实例包括环戊基、氟环戊基、环己基和环庚基。环烷基基团可以是被一个或多个卤素、亚甲基(H2C=)或烷基取代的。多环环烷基环的实例包括1-十氢化萘、金刚烷-(1-或2-)基和降冰片基。
“环烯基”是指含有碳碳双键和大约3-大约10个碳原子的非芳香族单或多环系统,单环环烯基环的实例包括环戊烯基、环己烯基和环庚烯基。多环环烯基环的实例是降冰片烯基。环烯基基团可以是被一个或多个卤素、亚甲基(H2C=)或烷基取代的。
“杂环基”是指大约3-大约10个碳原子的非芳香族单或多环系统,优选的环包括大约5-大约6个环原子,其中环原子之一是氧、氮或硫。杂环基可以任选被一个或多个卤素、取代。优选的单环杂环基环包括吡咯、四氢噻吩基和四氢噻喃基。杂环基的硫或氮部分也可以任选被氧化成相应的N-氧化物、S-氧化物或S,S-二氧化物。
“芳基”是指含有大约6-大约10个碳原子的芳香族碳环基,芳基实例包括任选被一个或多个可以是相同或不同的芳基取代基取代的苯基或萘基,其中芳基取代基包括氢、烷基、任选取代的芳基、任选取代的杂芳基、芳烷基、羟基、羟基烷基、烷氧基、芳氧基、芳烷氧基、羧基、酰基、芳酰基、卤素、硝基、氰基、烷氧羰基、芳基氧基羰基、芳烷氧基羰基、酰基氨基、芳酰基氨基、烷基磺酰基、芳基磺酰基、烷基亚磺酰基、芳基亚磺酰基、烷基硫基、芳基硫基、芳烷基硫基、Y1Y2N-、Y1Y2N-CO-、Y1Y2N-烷基-或Y1Y2NSO2-,其中Y1和Y2独立地是氢、烷基、芳基和芳烷基,优选的芳基取代基包括氢、烷基、任选取代的芳基、任选取代的杂芳基、羟基、酰基、芳酰基、卤素、硝基、氰基、烷氧基羰基、酰胺基、烷硫基、Y1Y2N-、Y1Y2N-CO-或Y1Y2NSO2-,其中的Y1和Y2独立地是氢和烷基。
“杂芳基”是指大约5-大约10元芳香单环或多环烃系,其中在环系中一个或多个碳原子是与碳不同的元素,例如氮、氧或硫,“杂芳基”也可以被一个或多个芳基取代基取代,杂芳基的实例包括吡嗪基、呋喃基、噻吩基、吡啶基、嘧啶基、异噁唑基、异噻唑、喹啉基、吲哚基和异喹啉基。
“芳烷基”是指芳基烷基基团,其中的芳基和烷基如前所述,优选的芳烷基含有低级烷基部分,芳烷基基团的实例包括苄基、2-苯乙基和萘甲基。
“羟基烷基”是指HO-烷基-基团,其中的烷基如前所述,优选的羟基烷基含有低级烷基,羟基烷基的实例包括羟基甲基和2-羟基乙基。
“酰基”是指H-CO-或烷基-CO-基团,其中的烷基如前所述,优选的酰基含有低级烷基,酰基的实例包括甲酰基、乙酰基、丙酰基、2-甲基丙酰基、丁酰基和棕榈酰基。
“芳酰基”是指芳基-CO-基团,其中的烷基如前所述,芳酰基的实例包括苯甲酰基和1-和2-萘酰基。
“烷氧基”是指烷基-O-基团,其中的烷基如前所述,烷氧基的实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基和庚氧基。
“芳氧基”是指芳基-O-基团,其中的芳基如前所述,芳氧基的实例包括苯氧基和萘氧基。
“芳烷氧基”是指芳烷基-O-基团,其中的芳烷基如前所述,芳烷氧基的实例包括苄氧基和1-或2-萘基甲氧基。
“烷硫基”是指烷基-S-基团,其中的烷基如前所述,烷硫基的实例包括甲硫基、乙硫基、异丙硫基和庚硫基。
“芳硫基”是指芳基-S-基团,其中的芳基如前所述,芳硫基的实例包括苯硫基和萘硫基。
“芳烷硫基”是指芳烷基-S-基团,其中的芳烷基如前所述,芳烷硫基的实例是苄硫基。
“Y1Y2N-”是指取代的或未取代的氨基,其中Y1和Y2如前所述,基团实例包括氨基(H2N-)、甲基氨基、乙基甲基氨基、二甲基氨基和二乙基氨基。
“烷氧基羰基”是指烷基-O-CO-基团,烷氧基羰基的实例包括甲氧基和乙氧基羰基。
“芳氧基羰基”是指芳基-O-CO-基团,芳氧基羰基的实例包括苯氧基-和萘氧基羰基。
“芳烷氧基羰基”是指芳烷基-O-CO-基团,芳烷氧基羰基的实例是苄氧基羰基。
“Y1Y2N-CO-”是指取代的或未取代的氨基甲酰基,其中Y1和Y2如前所述,基团实例是氨基甲酰基(H2NCO-)和二甲基氨基甲酰基(Me2NCO-)。
“Y1Y2NSO2-”是指取代的或未取代的氨磺酰基基团,其中Y1和Y2如前所述,基团实例是氨基氨磺酰基(H2NSO2-)和二甲基氨基氨磺酰基(Me2NSO2-)。
“酰基氨基”是指酰基-NH-基团,其中酰基如上定义。
“芳酰基氨基”是指芳酰基-NH-基团,其中芳酰基如上定义。
“烷基磺酰基”是指烷基-SO2-基团,优选的基团是其中烷基是低级烷基的基团。
“烷基亚磺酰基”是指烷基-SO-基团,优选的基团是其中烷基是低级烷基的基团。
“芳基磺酰基”是指芳基-SO2-基团。
“芳基亚磺酰基”是指芳基-SO-基团。
“卤素”是指氟、氯、溴或碘,优选氟、氯或溴,更优选氟或氯。
“前药”是指本身可能或不可能是生物活性的,但是可以通过代谢、溶剂离解作用或其它生物方式将其转化为生物活性的化学物质。优选的实施方案
本发明优选的实施方案是通过有效量的式Ⅰ化合物抑制患有所述疾病患者的因子Xa的产生来治疗疾病的方法。
本发明优选的化合物是其中R1和R2共同为=NH的式Ⅰ化合物。
本发明另一方面优选的化合物是其中R3是-CO2R6、-CH2R7O或-CH2SR7的式Ⅰ化合物。
本发明另一方面优选的化合物是其中n是1的式Ⅰ化合物。
本发明另一方面优选的化合物是其中R3是-CO2R6和R6是低级烷基的式Ⅰ化合物。
本发明另一方面优选的化合物是其中R3是-CH2OR7或-CH2SR7和R7是氢或低级烷基的式Ⅰ化合物。
本发明另一方面优选的化合物是其中R1和R2共同为=NH并在苯基部分(该苯基部分是在苯基与丙基连接位的间位)形成氨基亚氨基甲基的式Ⅰ化合物。
本发明另一方面优选的化合物是其中Ar是任选取代的芳基的式Ⅰ化合物。
本发明另一方面优选的化合物是其中Ar是苯基的式Ⅰ化合物。
本发明另一方面优选的化合物是其中R5是任选取代的苯基、任选取代的联苯基、任选取代的萘基或任选取代的杂联苯基的式Ⅰ化合物。
本发明另一方面优选的化合物是其中R10是低级烷基的式Ⅰ化合物。
包括在式Ⅰ范围内的化合物是其中R1和R2共同为=NR9,其中R9是R10O2C-、R10O-、氰基、R10CO-、任选取代的低级烷基、硝基或Y1Y2N-的化合物,该衍生物本身可以包括用于通过抑制患有所述疾病患者的因子Xa的产生来治疗疾病的生物活性化合物,或作为在生物条件下形成生物活性化合物的前药。
通过使用或采纳已知方法、即借助以前所用的方法或文献所述方法或根据本发明的方法制备式Ⅰ化合物。
反应路线图A说明了用于制备本发明式Ⅰ化合物的中间体的一般制备方法。
反应路线图A
反应路线图C说明了在本发明式Ⅰ化合物之间产生相互转化的一般方法。
此外,通过用烷基或芳基磺酰卤化物处理醇可以将其中R3是羟基甲基的式Ⅰ化合物转化为相应的硫基甲基化合物并用NaSH置换磺酸烷基酯或芳基酯,然后,可以将硫基甲基化合物烷基化或酰化,得到本发明范围内的其它化合物。
反应路线图D说明了将腈中间体转化为式Ⅰ化合物的一般方法和在本发明式Ⅰ化合物之间产生相互转化的另一种一般方法。
反应路线图E说明了在本发明式Ⅰ化合物之间产生相互转化的另一种一般方法。
反应路线图F说明了制备其中式Ⅰ中的R4是任选取代的苯乙基的本发明化合物的一般方法。
反应路线图G说明了制备其中式Ⅰ中的R4是甲基的本发明化合物的一般方法。
反应路线图G
本领域技术人员都清楚某些式Ⅰ化合物能够显示异构现象,例如几何异构(如E或Z异构)和光学异构(R或S构形),几何异构体包括顺式和反式具有链烯基部分的本发明化合物,式Ⅰ范围内的具体几何异构体和立体异构体和它们的混合物是在本发明范围内的。
通过使用或采纳已知方法(例如层析技术和重结晶)能够从异构体混合物中将其分离,或例如通过使用或修正在此描述的方法分别从它们中间体的适当的异构体中分别制备它们。
本发明化合物以游离碱或酸的形式或以其药用盐的形式使用,所有形式均在本发明范围内。
当本发明化合物被碱部分取代时,可以形成酸加成盐并且是更简单方便的使用形式;实际上,使用盐的形式本质上相当于使用游离碱的形式,能够用于制备酸加成盐的酸优选包括当与游离碱结合时产生药用盐的那些酸,就是说,盐的阴离子(以盐的药物剂量)对患者是无毒的,以使阴离子的副作用不损害游离碱固有的对因子Xa有益的抑制剂效果,虽然,优选所述碱化合物的药用盐,但是,所有酸加成盐均用作游离碱形式的来源,甚至仅需要具体盐本身作为中间体产物、像(例如)当仅是为了纯化和鉴定而形成的盐或当通过离子交换过程制备药用盐而用作中间体一样。
本发明领域范围内的药用盐是衍生于下列酸的盐:无机酸如盐酸、硫酸、磷酸和氨基磺酸;和有机酸如乙酸、柠檬酸、乳酸、酒石酸、丙二酸、甲基磺酸、乙基磺酸、苯磺酸、对甲苯磺酸、环己基氨基磺酸、金鸡纳酸等类似物。相应的酸加成盐分别包括:氢卤酸盐、例如盐酸盐和氢溴酸盐、硫酸盐、磷酸盐、硝酸盐、氨基磺酸盐、乙酸盐、柠檬酸盐、乳酸盐、酒石酸盐、丙二酸盐、草酸盐、水杨酸盐、丙酸盐、琥珀酸盐、延胡索酸盐、马来酸盐、亚甲基-双-B-羟基萘甲酸盐、龙胆酸盐、甲磺酸盐、羟乙基磺酸盐和二对甲苯基酒石酸甲磺酸盐、乙磺酸盐、苯基磺酸盐、对甲苯基磺酸盐、环己基氨基磺酸盐和奎尼酸盐。
根据本发明的进一步特征,通过使用或采纳已知方法,用适当的酸与游离碱反应制备本发明化合物的酸加成盐,例如,通过将游离碱溶解在水或含水醇或其它含有适当酸的合适的溶剂中并通过蒸发溶液分离盐制备本发明化合物的酸加成盐,或者通过在有机溶剂中使游离碱和酸反应、在该情形下直接分离盐或通过浓缩溶液能够得到盐制备本发明化合物的酸加成盐。
通过使用或采纳已知方法能够从盐中再生本发明化合物的酸加成盐,例如,通过用碱如碳酸氢钠水溶液或氨水溶液处理能够从它们的酸加成盐中再生本发明母体化合物。
当本发明化合物被酸部分取代时,可以形成碱加成盐并且是更简单方便的使用形式;实际上,使用盐的形式本质上相当于使用游离酸的形式,能够用于制备碱加成盐的碱优选包括当与游离酸结合时产生药用盐的那些碱,就是说,盐的阳离子(以盐的药物剂量)对动物机体是无毒的,以使阳离子的副作用不损害游离酸固有的对因子Xa有益的抑制剂效果,药用盐包括例如碱或碱土金属盐,本发明领域内的这些盐衍生于下列碱:氢化钠、氢氧化钠、氢氧化钾、氢氧化钙、氢氧化铝、氢氧化锂、氢氧化镁、氢氧化锌、氨、乙二胺、N-甲基-葡糖胺、赖氨酸、精氨酸、鸟氨酸、胆碱、N,N’-二苄基乙二胺、氯普鲁卡因、二乙醇胺、普鲁卡因、N-苄基苯乙胺、二乙胺、哌嗪、三(羟甲基)-氨基甲烷、羟化四甲基铵及其类似物。
通过在水或有机溶剂中使氢化物、氢氧化物、碳酸化物或所选择金属的同样活性化合物与游离酸形式的化合物接触可以得到本发明化合物的金属盐,所用的水溶剂可以是水或可以是水与有机溶剂(优选醇如甲醇或乙醇;酮如丙酮;脂族醚如四氢呋喃或酯如乙酸乙酯)的混合物,该反应通常在环境温度下进行,但是,如果需要,它们可以在加热下进行。
通过在水或有机溶剂中使胺与游离酸形式的化合物接触可以得到本发明化合物的胺盐,合适的含水溶剂包括水和水与醇如甲醇或乙醇、醚如四氢呋喃、腈如乙腈或酮如丙酮,类似该方法可以制备氨基酸盐。
通过使用或采纳已知方法能够从盐再生本发明化合物碱加成盐,例如通过用酸如盐酸处理,能够从它们的碱加成盐再生本发明母体化合物。
因为一些本发明化合物不形成稳定盐,这对本领域技术人员会是不言而喻的,但是,一般通过具有含氮杂芳基团的本发明化合物和/或其中含有氨基作为取代基的化合物形成酸加成盐,优选的本发明酸加成盐化合物是其中无酸不稳定基团的那些化合物。
本发明化合物的盐所用目的为例如通过本领域普通技术人员熟知的技术,利用盐与母体化合物、副产物和/或起始原料之间溶解度的差异纯化化合物,本发明的盐化合物本身又作为活性化合物。
通过使用或采纳已知方法例如参考例中所述的方法或它们明显的化学类似方法,或通过本发明方法制备起始原料和中间体。
通过下列举例说明本发明化合物制备方法的实施例进一步例证但不限制本发明。
在核磁共振谱(NMR)中,化学位移相对于四甲基硅烷表达为ppm,缩写具有下列意义:s=单峰;d=双重峰;t=三重峰;m=多重峰;dd=双重的双重峰;ddd=双重双重的双重峰;dt=双重的三重峰;b=宽峰。实施例1
化合物1
向室温下、N2气氛中和搅拌着的3-氰基安息香醛(20g;153mmol)的100ml无水THF中加入三苯基膦亚基乙酸甲酯(methyl(triphenylphosphoranylidene)(61.2g;183mmol),室温下搅拌混合物过夜,然后,真空下浓缩,粗产品经层析(40%乙酸乙酯∶己烷洗脱),得到27.3g(96%)丙烯酸酯1。1H NMR(CDCl3,d):7.43-7.8(m,5H),6.47(d,J=12Hz,1H),3.8(s,3H).实施例2化合物2
向搅拌着的化合物1(27.33g)的150ml EtOH溶液中加入2g10%pd/CaCO3,在室温下、45PSI H2气氛下、帕尔振荡器中氢化得到的混合物,然后,通过硅藻土塞过滤混合物,真空下浓缩滤液,得到26.93g(98%)澄清油状化合物2。1H NMR(CDCl3,d):7.33-7.72(m,4H),3.66(s,3H),2.97(t,J=7.8Hz,2H),2.62(t,J=7.8 Hz,2H).实施例3化合物3
向室温下、搅拌着的化合物2(16.8g;89mmol)的200ml THF∶MeOH(2∶1)溶液中滴加9ml 10N NaOH溶液,2小时后,真空下除去大部分溶剂,加入30ml 5N HCl,用乙酸乙酯萃取得到的混合物数次,干燥(MgSO4)合并的萃取液,将其过滤并浓缩,得到9.8g(63%)白色固体的纯酸3。1H NMR(CDCl3,d):7.35-7.55(m,4H),2.98(t,J=7.9Hz,2H),2.7(t,J=7.9Hz,2H).实施例4化合物4
向室温下、氮气氛中、搅拌着的羧酸3(8.2g;47mmol)、DMF(0.5ml)的无水CH2Cl2溶液中滴加草酰氯(6.1ml;70mmol),1小时后,产气停止,真空下除去溶剂和过量的草酰氯,将残渣再次溶解在100ml无水CH2Cl2中并冷却至0℃,加入巯基吡啶(5.6g;50mmol)相继加入三乙胺(7.9ml;56mmol),使混合物的温度升至室温并搅拌1小时。用CH2Cl2稀释、用1N NaOH洗涤混合物,干燥(MgSO4)、过滤和浓缩有机层,残渣经层析(50%乙酸乙酯∶己烷洗脱),得到5.12g(84%)黄色油状硫酯4。1H NMR(CDCl3,d):8.63(d,J=9Hz,1H),7.7-7.8(m,1H),7.27-7.62(m,6H),3.05(s,4H).实施例5化合物5
在0℃氮气氛中将MgSO4(19.55g;162mmol)加到搅拌着的肉桂醛(10.2ml;81mmol)和对茴香胺(10g;81mmol)的200ml CH2Cl2溶液中,4小时后,将混合物过滤,浓缩滤液,得到18.87g(98%)金色∶棕色固体亚胺化合物5。1H NMR(CDCl3,d):8.28(m,1H),7.52(m,2H),7.38(m,3H),7.2(m,2H),7.12(m,2H),6.93(m,2H),3.82(s,3H).实施例6化合物6
向-78℃下、氮气氛中、搅拌着的硫酯5(7g;26mmol)的无水CH2Cl2溶液中滴加TiCl4溶液(在CH2Cl2中26.1ml 1M溶液),15分钟后,滴加三乙胺(3.6ml;26mmol),使混合物在-78℃下搅拌1/2小时,然后滴加亚胺1溶液(在20ml CH2Cl2中4.42g;19mmol),然后使混合物温至0℃,在该温度下经过1.5小时后,用饱和NaHCO3溶液淬灭混合物并用水分配,有机层用1N NaOH洗涤、干燥(MgSO4)并真空浓缩,粗产品经层析(40%乙酸乙酯∶己烷洗脱),得到2.42g(32%)胶体5∶1反/顺b-内酰胺6a和6b混合物。
主要是反式异构体6a。1H NMR(CDCl3,d):7.2-7.6(m,11H),6.8(d,J=11Hz,2H),6.65(d,J=15.8Hz,1H),6.2(dd,J=15.8,7.9Hz,1H),4.32(m,1H),3.72(s,3H),3-3.42(m,3H).实施例7化合物7
在-20℃下,向搅拌着的6a、6b(1.5g;3.8mmol)的60mlTHF/CH3CN(1/3)溶液中加入硝酸高铈铵(在10ml水中的CAN,3.13g;5.7mmol)溶液,15分钟后,再加入在5ml水中的1.5g CAN,又过30分钟后,用饱和NaHCO3溶液猝灭混合物并使温度升至室温,通过一层硅藻土过滤得到的悬浮液,用CH2Cl2(共计200ml)洗涤硅藻土滤垫数次,滤液层分相,干燥有机层(MgSO4),过滤并真空浓缩,残渣经过层析(60%乙酸乙酯∶己烷洗脱)得到476mg(43%)纯反式异构体7a和与其在一起的85mg顺式7b和反式7a异构体的混合物。
主要是反式异构体7a1H NMR(CDCl3,d):7.17-7.65(m,9H),6.52(d,J=15.8 Hz,1H),6.25(s,1H),6.14(dd,J=15.8,7.9Hz,1H),3.97(m,1H),3-3.33(m,3H).次要的顺式异构体7b1H NMR(CDCl3,d):7.21-7.52(m,9H),6.62(d,J=15.8 Hz,1H),6.45(s,1H),6.1(dd,J=15.8,7.9Hz,1H),4.46(m,1H),3.7(m,1H),3.02-3.17(m,1H),2.6-2.93(m,1H).实施例8化合物8
在室温下、N2气氛中,向搅拌着的反式-b内酰胺7a的无水CH2Cl2溶液中滴加三乙胺(4.04ml;29mmol),然后加入联苯基碳酰氯(5.05g;23.2mmol)、再加入DMAP(50ml),30分钟后,混合物用CH2Cl2稀释并用1N HCl洗涤,干燥有机层(Na2SO4),过滤并浓缩,粗产品经过层析(30%乙酸乙酯∶己烷洗脱)得到2.19g(81%)固体产物8。1H NMR(CDCl3,d):8.06(m,2H),7.2-7.75(m,16H),6.67(d,J=15.8,Hz,1H),6.23(dd,J=15.8,7.9Hz,1H),4.63(m,1H),3.46(m,1H),3.1-3.3(m,2H).实施例9化合物9
在室温下,向搅拌着的b-内酰胺8(2.19g;4.7mmol)的50ml THF溶液中滴加1N NaOH溶液(13.6ml),2小时后,真空下除去大部分THF并加入20ml 1N HCl,用EtAc萃取得到的混合物,干燥萃取液(Na2SO4),过滤并真空浓缩,粗产品通过RPHPLC(CH3CN∶水,0.1%TFA,40-100梯度)纯化,冷冻干燥含产物的级分,得到1.1g(50%)白色固体羧酸9。1H NMR(CDCl3,d):7.18-7.97(m,18H),6.61(d,J=15.8 Hz,1H),6.2(dd,J=15.8,7.9Hz,1H),5.14(m,1H),3-3.22(m,3H).实施例10化合物10
在室温下,向搅拌着的羧酸9(105mg;0.22mmol)的3ml无水MeOH溶液中加入分子筛(大约50mg),导入HCl气大约2分钟,然后在室温下搅拌混合物过夜,在N2蒸汽下浓缩,将NH3的MeOH溶液(3ml 7N的溶液)加到残渣中,并使混合物回流1.5小时,使其冷却,真空下除去溶剂,残渣通过RPHPLC(CH3CN∶水,0.1%TFA,40-100梯度)纯化,冷冻干燥含产物的级分,得到73mg(53%)白色固体产物10。1H NMR(DMSO-d6,d):8.7(d,J=8.6Hz,1H),7.92(d,J=9Hz,2H),7.78(d,J=9Hz,2H),7.75-7.21(m,14H),6.67(d,J=16.1Hz,1H),6.4(dd,J=16.1,7.8Hz,1H),4.98(dd,J=16.1,7.8Hz,1H),3.46(s,3H),3.25-3.18(m,1H),3.05-2.88(m,2H).实施例11化合物11
用类似于上述化合物10的制备方法、从亚胺5和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用苯甲酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物11并将其冷冻干燥。1H NMR(MeOH-d4,d):8.61(d,J=11.3Hz,1H),7.83(d,J=7.5Hz,2H),7.15-7.67(m,14H),6.67(d,J=15.8Hz,1H),6.3(dd,J=15.8,7.9Hz,1H),4.98(m,1H),3.55(s,3H),3.27(m,1H),3.1(m,2H).实施例12化合物12
用类似于上述化合物10的制备方法、从亚胺5和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用邻甲苯酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物12并将其冷冻干燥。1H NMR(DMSO-d6,d):9.3(s,1H),9.15(s,1H),8.7(d,J=7.6Hz,1H),7.7(d,J=8Hz,2H),7.6(d,J=9Hz,2H),7.2-7.6(m,12H),6.9(d,J=8Hz,1H),6.6(d,J=15Hz,1H),6.35(dd,J=15,6Hz,1H),4.9(dd,J=15,6Hz,1H),3.55(s,3H),3.2-3.3(m,1H),2.8-3(m,1H),2.3(s,3H).实施例13化合物13
用类似于上述化合物10的制备方法、从亚胺5和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用间甲苯酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物13并将其冷冻干燥。1H NMR(DMSO-d6,d): 9.3(s,1H),9.2(s,1H),8.7(d,J=7.6 Hz,1H),7.7(d,J=8Hz,2H),7.6(d,J=9Hz,2H),7.2-7.6(m,12H),6.9(d,J=8Hz,1H),6.6(d,J=15Hz,1H),6.35(dd,J=15,6Hz,1H),4.9(dd,J=16,6 Hz,1H),3.6(s,3H),3.2-3.3(m,1H),2.8-3(m,1H),2.35(s,3H).实施例14化合物14
用类似于上述化合物10的制备方法、从亚胺5和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用4′-乙基-4-联苯基碳酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物14并将其冷冻干燥。1H NMR(DMSO-d6,d):9.3(s,1H),9.15(s,1H),8.9(d,J=7.6Hz,1H),8.2(d,J=8Hz,2H),8(d,J=9Hz,2H),7.4-7.9(m,12H),7,2(d,J=8Hz,1H),6.9(d,J=15Hz,1H),6.6(dd,J=15,6Hz,1H),5.2(dd,J=16,6Hz,1H),3.7(s,3H),3.4-3.5(m,1H),3.1-3.2(m,1H),2.85(q,2H),1.4(t,3H).实施例15化合物15
用类似于上述化合物10的制备方法、从亚胺5和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用3′,4′-二甲氧基-4-联苯基碳酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物15并将其冷冻干燥。1H NMR(DMSO-d6,d):9.5(s,1H),9.3(s,1H),8.9(d,J=7.6Hz,1H),8.1(d,J=8Hz,2H),7.9(d,J=9Hz,2H),7.8(s,2H),7.4-7.7(m,11H),7.25(d,J=8Hz,1H),6.6(d,J=15Hz,1H),6.4(dd,J=15,6Hz,1H),4(s,3H),3.9(s,3H),3.7(s,3H),3.4-3.5(m,1H),3.2-3.4(m,1H).实施例16化合物16
用类似于上述化合物10的制备方法、从亚胺5和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用4-(2′-吡啶)苯甲酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物16并将其冷冻干燥。1H NMR(DMSO-d6,d):9.5(s,1H),9.3(s,1H),8.9(d,J=7.6Hz,1H),8.8(s,1H),8.4(d,J=8Hz,2H),8.3(d,J=9Hz,1H),8.1(d,J=8Hz,2H),7.9(s,2H),7.4-7.8(m,10H),7.4(d,J=8Hz,1H),6.9(d,J=15Hz,1H),6.6(dd,J=15,6Hz,1H),5.2(dd,J=16,6Hz,1H),3.7(s,3H),3.4-3.5(m,1H),3.2-3.4(m,1H).实施例17化合物17
用类似于上述化合物10的制备方法、从亚胺5和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用4-(3′-吡啶)苯甲酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物17并将其冷冻干燥。1H NMR(DMSO-d6,d):9.5(s,1H),9.3(s,1H),8.9(d,J=7.6Hz,1H),8.5(s,1H),8.2(d,J=8Hz,2H),8.1(d,J=9Hz,2H),8(d,J=8Hz,1H),7.9(s,2H),7.4-7.8(m,9H),7.4(d,J=8Hz,1H),6.9(d,J=15Hz,1H),6.6(dd,J=15,6Hz,1H),5.2(dd,J=16,6Hz,1H),3.7(s,3H),3.4-3.5(m,1H),3.2-3.4(m,1H).实施例18化合物18
用类似于上述化合物10的制备方法、从亚胺5和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用4-(4′-吡啶)苯甲酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物18并将其冷冻干燥。1H NMR(DMSO-d6,d):9.5(s,1H),9.3(s,1H),9(d,J=7.6Hz,1H),8.2(s,4H),7.8(s,2H),7.5-7.8(m,11H),7.4(d,J=8Hz,1H),6.9(d,J=15Hz,1H),6.6(dd,J=15,6Hz,1H),5.2(dd,J=16,6Hz,1H),3.7(s,3H),3.4-3.5(m,1H),3.2-3.4(m,1H).实施例19化合物19
用类似于上述化合物10的制备方法、从亚胺5和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用2′-甲基-4-联苯基碳酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物19并将其冷冻干燥。1H NMR(DMSO-d6,d):9.25(s,1H),9.03(s,1H),8.71(d,J=8.7Hz,1H),7.86(d,J=8Hz,2H),7.61(d,J=8Hz,2H),7.6-7.12(m,13H),6.67(d,J=15.9Hz,1H),6.42(dd,J=15.9,7.8Hz,1H),5.0(dd,J=16,7.9Hz,1H),3.32(s,3H),3.3-3.15(m,1H),3.11-2.9(m,2H),2.21(s,3H).实施例20化合物20
用类似于上述化合物10的制备方法、从亚胺5和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用3′-甲基-4-联苯基碳酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物20并将其冷冻干燥。1H NMR(DMSO-d6,d):9.25(s,1H),8.99(s,1H),8.68(d,J=8.7Hz,1H),7.9(d,J=9Hz,1H),7.75(d,J=9Hz,1H),7.68-7.15(m,13H),6.68(d,J=15.9Hz,1H),6.4(dd,J=15.9,7.8Hz,1H),5.0(dd,J=16,7.9Hz,1H),3.46(s,3H),3.28-3.18(m,1H),3.1-2.9(m,2H),2.36(s,3H).实施例21化合物21
用类似于上述化合物10的制备方法、从亚胺5和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用2′-甲氧基-4-联苯基碳酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物21并将其冷冻干燥。1H NMR(DMSO-d6,d):9.25(s,1H),9.03(s,1H),8.76(d,J=8.7Hz,1H),7.83(d,J=9.5Hz,2H),7.65-6.95(m,15H),6.64(d,J=15.9Hz,1H),6.4(dd,J=15.9,7.8Hz,1H),4.99(dd,J=16,7.9Hz,1H),3.75(s,3H),3.46(s,3H),3.3-3.17(m,1H),3.1-2.9(m,2H).实施例22化合物22
用类似于上述化合物10的制备方法、从亚胺5和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用32′-甲氧基-4-联苯基碳酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物22并将其冷冻干燥。1H NMR(DMSO-d6,d):9.23(s,1H),8.96(s,1H),8.69(d,J=8.7Hz,1H),7.9(d,J=9.6Hz,2H),7.68-7.18(m,12H),6.96(dd,J=9.6,2Hz,1H),6.64(d,J=15.9Hz,1H),6.39(dd,J=15.9,7.8Hz,1H),4.98(dd,J=16,7.9Hz,1H),3.81(s,3H),3.47(s,3H),3.28-3.17(m,1H),3.08-2.86(m,2H).实施例23化合物23
用类似于上述化合物10的制备方法、从亚胺5和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用2-萘基碳酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物23并将其冷冻干燥。1H NMR(DMSO-d6,d):9.24(s,1H),9.02(s,1H),8.83(d,J=8.6Hz,1H),8.4(s,1H),8.08-7.85(m,4H),7.68-7.2(m,12H),6.68(d,J=15.8Hz,1H),6.43(dd,J=15.8,7.8Hz,1H),5.03(dd,J=15.8,7.8Hz,1H),3.46(s,3H),3.28-3.2(m,1H),3.13-2.95(m,2H).实施例24化合物24
用类似于上述化合物10的制备方法、从亚胺5和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用1-萘基碳酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物24并将其冷冻干燥。1H NMR(DMSO-d6,d):9.27(s,1H),9.11(s,1H),8.88(d,J=8.67Hz,1H),8.18-8.07(m,1H),8.05-7.9(m,2H),7.7-7.2(m,13H),6.73(d,J=15.9Hz,1H),6.4(dd,J=15.9,7.8Hz,1H),5.07(dd,J=16,7.9Hz,1H),3.52(s,3H),3.28-3.17(m,1H),3.12-2.95(m,2H).实施例25化合物25
用类似于上述化合物10的制备方法、从亚胺5和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用3′-乙基-4-联苯基碳酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物25并将其冷冻干燥。1H NMR(DMSO-d6,d):9.25(s,1H),9.05(s,1H),8.68(d,J=8.6Hz,1H),7.88(d,J=9Hz,2H),7.76(d,J=9Hz,2H),7.62(m,2H),7.55-7.15(m,11H),6.66(d,J=16Hz,1H),6.4(dd,J=16,7.8Hz,1H),4.96(dd,J=16,7.8Hz,1H),3.47(s,3H),3.3-3.18(m,1H),3.1-2.88(m,2H),2.67(q,J=8.5Hz,2H),1.22(t,J=8.5Hz,3H).实施例26化合物26
用类似于上述化合物10的制备方法、从亚胺5和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用4′-甲氧基-4-联苯基碳酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物26并将其冷冻干燥。
1H NMR(DMSO-d6,d):9.23(s,1H),8.96(s,1H),8.66(d,J=8.7Hz,1H),7.88(d,J=9.1Hz,2H),7.72-7.22(m,11H),7.03(d,J=8.7Hz,2H),6.64(d,J=16.1Hz,1H),6.4(dd,J=16.1,7.9Hz,1H),4.97(dd,J=16.1,7.9Hz,1H),3.77(s,3H),3.46(s,3H),3.28-3.15(m,1H),3.08-2.88(m,2H).实施例27化合物27
用类似于上述化合物10的制备方法、从亚胺5和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用2′,4′-二甲氧基-4-联苯基碳酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物27并将其冷冻干燥。1H NMR(DMSO-d6,d):9.23(s,1H),9.07(s,1H),8.63(d,J=9Hz,1H),7.81(d,J=8.9Hz,2H),7.68-7.15(m,14H),6.72-6.52(m,1H),6.45-6.3(m,1H),5.04-4.9(m,1H),3.78(s,3H),3.75(s,3H),3.51(s,3H),3.21-3.15(m,1H),3.08-2.85(m,2H).实施例28化合物28
用类似于上述化合物10的制备方法、从亚胺5和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用2′-乙基-4-联苯基碳酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物28并将其冷冻干燥。1H NMR(DMSO-d6,d):9.25(s,1H),8.92(s,1H),8.69(d,J=8.7Hz,1H),7.78(d,J=9Hz,2H),7.68-7.08(m,15H),6.65(d,J=15.9Hz,1H),6.38(dd,J=15.9,7.8Hz,1H),5.0(dd,J=16,7.9Hz,1H),3.46(s,3H),3.28-3.18(m,1H),2.52(q,J=9.6Hz,2H),0.98(t,J=9.6Hz,3H).实施例29化合物29
用类似于上述化合物10的制备方法、从亚胺5和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用4′-甲基-4-联苯基碳酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物29并将其冷冻干燥。1H NMR(DMSO-d6,d):9.22(s,1H),8.91(s,1H),8.68(d,J=8.7Hz,1H),7.85(d,J=9Hz,2H),7.75(d,J=9Hz,2H),7.65-7.2(m,13H),6.65(d,J=15.9Hz,1H),6.39(dd,J=15.9,7.8Hz,1H),4.99(dd,J=16,7.9Hz,1H),3.46(s,3H),3.28-3.18(m,1H),3.08-2.88(m,2H),2.35(s,3H).实施例30化合物30
用类似于上述化合物10的制备方法、从亚胺5和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用3′-甲氧基-4-联苯基碳酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物30并将其冷冻干燥。1H NMR(DMSO-d6,d):9.22(s,1H),9.05(s,1H),8.7(d,J=8.7Hz,1H),7.88(d,J=9Hz,2H),7.76(d,J=9Hz,2H),7.68-7.12(m,12H),6.98-6.85(m,1H),6.67(d,J=16Hz,1H),6.4(dd,J=16,7.8Hz,1H),5.01(dd,J=18,7.8Hz,1H),4.08(q,J=7.5Hz,2H),3.45(s,3H),3.25-3.15(m,1H),3.08-2.89(m,2H),1.32(t,J=7.5Hz,2H).实施例31化合物31
用类似于上述化合物10的制备方法、从亚胺5和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用4′-甲氧基-4-联苯基碳酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物31并将其冷冻干燥。1H NMR(DMSO-d6,d):9.26(s,1H),9.02(s,1H),8.64(d,J=8.7Hz,1H),7.86(d,J=9Hz,2H),7.72(d,J=9Hz,2H),7.7-7.22(m,11H),7.01(d,J=10.4Hz,2H),6.64(d,J=15.9Hz,1H),6.38(dd,J=15.9,7.8Hz,1H),4.98(dd,J=16,7.8Hz,1H),4.06(q,J=8.2Hz,2H),3.45(s,3H),3.3-3.18(m,1H),3.08-2.85(m,2H),1.32(t,J=8.2Hz,3H).实施例32化合物32
用类似于上述化合物10的制备方法、从亚胺5和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用2′-甲氧基-4-联苯基碳酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物32并将其冷冻干燥。1H NMR(DMSO-d6,d):9.24(s,1H),9.11(s,1H),8.68(d,J=8.7Hz,1H),7.85(d,J=9Hz,2H),7.6(d,J=9Hz,2H),7.59-6.95(m,13H),6.65(d,J=15.9Hz,1H),6.39(dd,J=15.9,7.8Hz,1H),4.98(dd,J=16,7.8Hz,1H),4.03(q,J=8.1Hz,2H),3.47(s,3H),3.28-3.18(m,1H),3.1-2.88(m,2H),1.24(t,J=8.1Hz,3H).实施例33化合物33
在室温下,向搅拌着的2-萘醛(20g;0.13mol)的200ml CH2Cl2溶液中加入对茴香胺(15.8g;0.13mol),接着加入无水硫酸镁(16.9g;0.14mol),3.5小时后,将混合物过滤,在真空下浓缩滤液,得到31.5g(92%)亚胺33。1H NMR(CDCl3,d):8.64(s,1H),8.19(m,2H),7.78-7.98(m,3H),7.43-7.56(m,2H),7.32(m,2H),6.96(m,2H),3.83(s,3H).实施例34化合物34
用反式-3-(2′-萘基)丙烯醛、对茴香胺和无水硫酸镁,如上面化合物33所述方法制备该化合物。1H NMR(CDCl3,d):8.35(d,J=9Hz,1H),7.78-7.9(m,4H),7.72(m,1H),7.5(m,2H),7.25(m,4H),6.93(m,2H),3.82(s,3H).实施例35化合物35
如上面化合物33所述方法,用反式-3-(4′-联苯基)丙烯醛、对茴香胺和无水硫酸镁制备该化合物。1H NMR(CDCl3,d):8.33(d,J=9Hz,1H),7.2-7.68(m,13H),6.9(m,2H),3.82(s,3H).实施例36化合物36
如上面化合物33所述方法,用4-联苯基羧醛、对茴香胺和无水硫酸镁制备该化合物。1H NMR(CDCl3,d):8.52(s,1H),7.97(m,2H),7.62-7.73(m,4H),7.35-7.52(m,3H),7.27(m,2H),6.95(m,2H),3.85(s,3H).实施例37化合物37
用类似于上述化合物10的制备方法、从亚胺33和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用苯甲酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物37并将其冷冻干燥。1H NMR(MeOH-d4,d):9.01(d,J=9.4Hz,1H),7.77-7.98(m,6H),7.43-7.67(m,9H),5.53(m,1H),3.56(m,1H),3.54(s,3H),3.1(m,1H),2.81(m,1H).实施例38化合物38
用类似于上述化合物10的制备方法、从亚胺34和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用苯甲酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物38并将其冷冻干燥。1H NMR(DMSO-d6,d):9.27(s,2H),9.1(s,2H),8.72(d,1H),7.4-7.95(m,16H),6.86(d,J=18Hz,1H),6.54(dd,J=10,6Hz,1H),5.03(m,1H),3.48(s,3H),3.32(m,1H),3.04(m,2H).实施例39化合物39
用类似于上述化合物10的制备方法、从亚胺35和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用苯甲酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物39并将其冷冻干燥。1H NMR(DMSO-d6,d):9.25(s,2H),9.11(s,2H),8,74(d,1H),7.30-8(m,22H),6.23(d,J=18Hz,1H),6.47(dd,J=18,6Hz,1H),5.04(m,1H),3.49(s,3H),3.3(m,1H),3.03(m,2H).实施例40化合物40
用类似于上述化合物10的制备方法、从亚胺36和硫酯4开始制备该化合物,在b-内酰胺酰化步骤中,用苯甲酰氯代替4-联苯基碳酰氯,通过反相HPLC(CH3CN∶水,0.1%TFA)纯化最终产物40并将其冷冻干燥。1H NMR(DMSO-d6,d):9.23(s,2H),9.05(s,2H),8.97(s,2H),7.28-7.8(m,18H),5.35(t,1H),3.42(s,3H),3.31(m,1H),2.89(dd,1H),2.6(dd,1H).实施例41化合物41
在0℃下、N2气氛中,向搅拌着的羧酸9(980mg;2mmol)和三乙胺(0.44ml;3.2mmol)的无水THF中滴加氯甲酸异丁酯(0.39ml;3mmol),15分钟后,滴加硼氢化钠溶液(153mg;4mmol的5ml水),将混合物的温度升至室温,1小时后,真空下除去大部分THF,然后加入水并用乙酸乙酯萃取混合物,将合并的萃取液干燥(MgSO4)、过滤和浓缩,粗产品通过色谱层析(用35%EtAc∶己烷洗脱)纯化,得到720mg(76%)醇41。1H NMR(CDCl3,d):7.92(d,J=9Hz,2H),7.2-7.72(m,16H),6.67(d,J=15.5Hz,1H),6.27(dd,J=15.5,7.8Hz,1H),4.94(m,1H),3.88(m,1H),3.5(m,1H),3.12(m,1H),2.82-3.03(m,2H),1.95(m,1H).实施例42化合物42
在室温下,向搅拌着的醇41(106mg;0.22mmol)的无水甲醇中加入分子筛(大约50mg),导入HCl气大约2分钟,然后在室温下搅拌混合物过夜,在N2蒸汽下浓缩混合物,将NH3的MeOH溶液(3ml 7N的溶液)加到残渣中,并使混合物回流1.5小时,使其冷却,真空下除去溶剂,残渣通过RPHPLC(CH3CN∶水,0.1%TFA,40-100梯度)纯化,冷冻干燥含产物的级分,得到29mg(22%)产物42的三氟乙酸盐。实施例43化合物43
在0℃下、N2气氛中,向搅拌着的醇化合物(88mg;0.2mmol)的2ml2∶1THF∶DMF溶液中加入NaH(15ml的60%的分散体;0.4mmol),15分钟后,加入碘甲烷(0.02ml;0.3mmol),将混合物的温度升至室温,2小时后,用饱和NaHCO3溶液猝灭混合物,真空下除去大部分THF,将残渣用水稀释并用CH2Cl2萃取,将合并的萃取液干燥(MgSO4)、过滤和浓缩,粗产品通过色谱层析(用35%EtAc∶己烷洗脱)纯化,得到21mg(23%)产物43和其在一起的34mg回收的醇41。1H NMR(CDCl3,d):7.93(d,J=9.3Hz,2H),7.15-7.83(m,16H),6.57(d,J=15.8Hz,1H),6.22(dd,J=15.8,6.8Hz,1H),5(m,1H),3.75(m,1H),3.42(s,3H),3.27(m,1H),2.87-3.03(m,2H),2.12(m,1H).实施例44化合物44
向搅拌着的化合物43(20mg;0.04mmol)的1.5ml 2∶1吡啶∶Et3N溶液中导入H2S大约1小时,室温下,使反应混合物搅拌过夜,氮蒸汽下将其浓缩,并将其溶解在2ml CH2Cl2中,加入碘甲烷(1ml),回流混合物1小时,真空下除去溶剂,将残渣溶解在2ml MeOH中,加入NH4OAc(30mg),将得到的混合物回流1小时,然后使其冷却,真空下除去溶剂,残渣通过RPHPLC(CH3CN∶水,0.1%TFA,40-100%CH3CN梯度)纯化,冷冻干燥含产物的级分,得到13mg(51%)产物44的三氟乙酸盐。1H NMR(MeOH-d4,d):8.47(d,J=7.9Hz,1H),7.95(d,J=8Hz,2H),7.78(d,J=8Hz,2H),7.17-7.73(m,14H),6.55(d,J=15.8Hz,1H),6.31(dd,J=15.8,7.9Hz,1H),4.77(m,1H),3.7(dd,J=9.5,3.1Hz,1H),3.47(dd,J=9.5,3.1Hz,1H),3(d,J=7.9Hz,2H),2.35(m,1H).实施例45化合物45
室温下,搅拌醇41(480mg;1mmol)、吡啶(0.40ml;4.9mmol)和乙酸酐(0.12ml;1.2mmol)的混合物过夜,次日,加入3滴吡啶和乙酸酐,次日,反应不完全,所以加入4mgDMAP,1小时后,通过薄层层析证明反应完全,混合物用CH2Cl2稀释、用0.1NHCl洗涤,将有机层干燥(MgSO4)、过滤和浓缩,得到520mg化合物45。1H NMR(CDCl3,d):7.98(d,J=8 Hz,2H),7.73(d,J=8Hz,2H),7.67(d,J=8Hz,2H),7.17-7.58(m,12H),6.94(d,1H),6.55(d,J=18Hz,1H),6.21(dd,J=18,5Hz,1H),5.1(m,1H),4.38(m,1H),4.08(m,1H),2.68-2.97(m,2H),2.51(m,1H).实施例46化合物46
按43转化为44所述的硫化氢/碘甲烷∶乙酸铵的顺序,将化合物45转化为相应的脒46,产物46通过RPHPLC纯化,分离到它的三氟乙酸盐。1H NMR(DMSO-d6,d):9.31(s,2H),8.97(s,2H),8.7(d,1H),7.18-8(m,18H),6.6(d,J=18Hz,1H),6.40(dd,J=18,6Hz,1H),4.83(m,1H),4.02(m,1H),3.84(m,2H),2.95(m,1H),2.57(m,1H),1.93(s,3H).实施例47化合物47
按43转化为44所述的硫化氢/碘甲烷∶乙酸铵的顺序,将羧酸9转化为相应的脒47,产物47通过RPHPLC分离,得到它的三氟乙酸盐。1H NMR(MeOH-d4,d):8(d,J=9Hz,2H),7.82(d,J=9Hz,2H),7.22-7.77(m,14H),6.73(d,J=15.8Hz,1H),6.4(dd,J=15.8,7.9Hz,1H), 4.95(m,1H),3.08-3.45(m,3H).实施例49化合物49
在室温下、N2气氛中,向搅拌着的羧酸48(120mg;0.29mmol)的5ml无水CH2Cl2溶液中加入三乙胺(0.05ml;0.38mmol),滴加氯甲酸异丙酯(在甲苯溶液中0.38ml、1M),30分钟后,加入DMAP(18mg;0.15mmol),室温下进一步搅拌混合物1.5小时,混合物用CH2Cl2稀释并用1N HCl洗涤,将有机层干燥(Na2SO4)、过滤并真空浓缩,粗产品经过层析(40%乙酸乙酯∶己烷洗脱)得到44mg(33%)相应的异丙酯,然后按43转化为44所述的硫化氢/碘甲烷∶乙酸铵的步骤,将该化合物转化为相应的脒49,产物49通过RPHPLC分离,得到它的三氟乙酸盐。1H NMR(MeOH-d4,d):8.6(d,J=7.9Hz,1H),7.85(d,J=8Hz,2H),7.16-7.7(m,12H),6.69(d,J=15.8Hz,1H),6.32(dd,J=15.8,7.9Hz,1H),4.98(m,1H),4.85(m,1H),3.23(m,1H),3.08(m,2H),1.07(d,J=6Hz,3H),0.97(d,J=6Hz,3H).实施例50化合物50
按43转化为44所述的硫化氢/碘甲烷∶乙酸铵的顺序,通过将48转化为相应的脒制备该化合物,产物50通过RPHPLC分离,得到它的三氟乙酸盐。1H NMR(MeOH-d4,d):8.6(d,J=7.9Hz,1H),7.85(d,J=8Hz,2H),7.16-7.7(m,12H),6.69(d,J=15.8Hz,1H),6.32(dd,J=15.8,7.9Hz,1H),4.98(m,1H),4.85(m,1H),3.23(m,1H),3.08(m,2H),1.07(d,J=6Hz,3H),0.97(d,J=6Hz,3H).实施例51化合物51
室温下,向搅拌着的羧酸50(96mg;0.18mmol)的3ml EtOH溶液中导入HCl大约3分钟,室温下将混合物搅拌7小时并贮存在冰箱中(0℃)过一周,真空下除去溶剂,残渣通过RPHPLC纯化,分离得到产物51的三氟乙酸盐。1H NMR(MeOH-d4,d):8.63(d,J=7.9Hz,1H),7.84(d,J=8Hz,2H),7.16-7.68(m,12H),6.68(d,J=15.8Hz,1H),6.32(dd,J=15.8,7.9Hz,1H),5(m,1H),4.02(q,2H),3.25(m,1H),3.07(d,J=7.9 Hz,2H),1.05(t,3H).实施例52化合物52
在室温下、45 PSI H2中,氢化化合物和10%Pb/C(25mg)在EtAc(2ml)∶EtOH(5ml)中的混合物19小时,混合物通过一层硅藻土过滤并浓缩滤液,粗品通过RPHPLC(CH3CN∶水,0.1%TFA,10-100%CH3CN梯度)纯化,冷冻干燥含产物的级分,得到21mg 52。1H NMR(MeOH-d4,d):8.27(d,J=9.3Hz,1H),7.83(m,2H),7.43-7.65(m,7H),7.09-7.27(m,5H),4.35(m,1H),3.58(s,3H),2.95-3.15(m,3H),2.54-2.75(m,2H),1.93(m,2H).化合物10的拆分
用制备性HPLC(Chiralpak AD柱,50mm ID×500mm,15微米)将外消旋体10(大约650mg,根据顺位立体化学的显示推定为单一的非对映异构体)拆分为它的两个对映体53(后洗脱下的异构体)和54(先洗脱下的异构体),流动相是带有0.1%TFA的庚烷(A)和带有0.1%TFA的异丙醇(B)、isocratic 20%A、80%B(流速=200ml:分钟),后洗脱异构体通过真空浓缩分离,产率:180mg,通过HPLC(ChiralpakAD)分析测定对映体53的百分率为100%,53和54的1H NMR谱是一致的。1H NMR(DMSO-d6,d):8.7(d,J=8.6Hz,1H),7.92(d,J=9Hz,2H),7.78(d,J=9Hz,2H),7.75-7.21(m,14H),6.67(d,J=16.1Hz,1H),6.4(dd,J=16.1,7.8Hz,1H),4.98(dd,J=16.1,7.8Hz,1H),3.46(s,3H),3.25-3.18(m,1H),3.05-2.88(m,2H).实施例55化合物55
除省略乙酸乙酯外,像上述化合物52那样进行化合物53(后洗脱下的对映体)的氢化,产品通过RPHPLC(CH3CN∶水,0.1%TFA,410-100%CH3CN)纯化,分离出产品55的三氟乙酸盐。1H NMR(MeOH-d4,d):8.3(d,J=9.3Hz,1H),7.84(m,2H),7.07-7.8(m,16H),4.37(m,1H),3.6(s,3H),2.97-3.17(m,3H),2.57-2.77(m,2H),1.95(m,2H).实施例56化合物56
在-20℃下,向N-α-Boc-D-苯基丙氨酸(38mmol)的80ml无水四氢呋喃溶液中一次性加入N-甲基吗啉(38mmol),以相同的方式,随后加入氯代甲酸异丁酯(38mmol),在-20℃下,搅拌该反应混合物10分钟,在0℃下,将其过滤进重氮甲烷(≈70mmol)的预制醚溶液中,在0℃下,使所得溶液静止20分钟,通过滴加冰醋酸使多余重氮甲烷分解并真空除去溶剂。
将得到的油溶解在150ml无水甲醇中,在室温下,伴随着搅拌缓慢加入苯甲酸银(8mmol)的17ml三乙胺溶液,室温下搅拌得到的黑色反应混合物45分钟,真空下除去甲醇,将残渣溶解在700ml乙酸乙酯中,混合物通过硅藻土过滤、用饱和碳酸氢钠(3×150ml)、水(1×150ml)、1N硫酸氢钾(3×150ml)和盐水(1×150ml)依次洗涤,有机层用硫酸镁干燥、过滤、真空下浓缩和通过快速色谱层析(3∶1己烷∶乙酸乙酯)纯化。实施例57化合物57
用化合物56中所述步骤制备化合物58,得到N-α-Boc-D-高苯基丙氨酸。实施例59化合物59
将化合物56(11mmol)的70ml无水四氢呋喃溶液冷却至-78℃,用注射器以使温度不超过-60℃以上的速度加入六甲基二硅氮烷锂的四氢呋喃溶液(33mmol),在40分钟内将反应混合物的温度升至-25℃并再冷却至-78℃,用注射器以使温度不超过-60℃以上的速度加入3-氰基苄基溴(27mmol)的四氢呋喃溶液20ml,使反应混合物的温度升至室温并在室温下搅拌1小时。
加入125ml饱和碳酸氢钠并在真空下除去四氢呋喃,残余物在500ml的乙酸乙酯和150ml的饱和碳酸氢钠中分配,进一步用饱和碳酸氢钠(2×100ml)和盐水洗涤有机层,有机层用硫酸镁干燥、过滤、真空下浓缩,用40ml 4∶1己烷∶乙酸乙酯研制残渣,固体被滤掉并弃去,真空下浓缩含有所需产物的滤液。实施例63化合物63
按照化合物62中所述方法制备化合物65,得到实施例59的取代产物。实施例66化合物66
在0℃下,向化合物62(5mmol)的60ml二氯甲烷溶液中滴加20ml三氟乙酸,在0℃下搅拌所得溶液2小时,真空下除去溶剂,残渣通过反相HPLC、用30%-70%在水中含有0.1%三氟乙酸的乙腈梯度洗脱。
溶液(A):在-78℃下通过注射器向11.8ml的正丁基锂在13ml四氢呋喃的己烷溶液中滴加1-溴-2-氟苯(19mmol)的2ml四氢呋喃溶液,在-78℃下将其连续搅拌1小时,在-78℃下、2分钟内加入氯化锌(19mmol)的38ml四氢呋喃溶液,在40分钟内将反应溶液的温度升至室温。
溶液(B):在室温下,向二氯双(三苯膦)钯(1mmol)的11ml四氢呋喃溶液中加入氢化二异丁基铝(1mmol)的己烷溶液,在室温下,随后一次性加入碘苯甲酸甲酯。
按照化合物74中所述方法、在溶液(A)制剂中代之以3,4-亚乙基二氧基溴苯制备化合物77。实施例78化合物78
将氨气导入化合物80(24mmol)的200ml甲醇悬浮液中5分钟,向该溶液中加入铑/铝土(5g),在氢气氛下振荡该悬浮液36小时,滤去催化剂,真空下除去甲醇,得到用醚研磨和过滤的油。实施例82化合物82
在室温下,将化合物81(15.4mmol)、三乙胺(17mmol)、碳酸二叔丁酯(15.4mmol)和4-二甲基氨基吡啶(1.5mmol)的60ml二甲基甲酰胺溶液搅拌过夜,溶液用800ml乙酸乙酯稀释并用1N盐酸(3×150ml)和盐水洗涤,有机层用硫酸镁干燥、过滤、真空下浓缩和通过快速色谱层析(3∶2己烷∶乙酸乙酯)纯化。实施例83化合物83
在室温下,将化合物81(2mmol)、乙酸酐(8mmol)、和二甲基氨基吡啶(0.2mmol)的20ml吡啶溶液搅拌过夜,将反应混合物倾入200ml 5%盐酸中,并用乙酸乙酯(3×200ml)萃取,合并的有机萃取液用硫酸镁干燥、过滤、真空下浓缩和通过快速色谱层析(3∶1己烷∶乙酸乙酯)纯化。实施例84化合物84
按照化合物83中所述方法制备化合物87,得到实施例85的取代产物。实施例88化合物88
向阔马酸甲酯(6.5mmol)和3-硝基苯乙烯(32.5mmol)的30ml间二甲苯溶液中一次性加入10%钯/碳(2.5g),在140℃下加热反应混合物过夜,冷却后,通过硅藻土过滤反应混合物,真空下浓缩滤液,用3∶1己烷∶乙酸乙酯研磨得到的淤浆,通过过滤得到所需的固体产物。实施例89化合物89
在室温下,向化合物74(1.6mmol)的10ml甲醇和20ml四氢呋喃悬浮液中滴加10ml 2N氢氧化钠,室温下搅拌所得溶液2小时,真空下除去有机溶剂,残渣用20ml水稀释,并用1N盐酸将其调节至pH2,滤出固体物质并真空干燥。实施例94化合物94
按照化合物93中所述方法制备化合物96,得到实施例77的取代产物。实施例97化合物97
按照化合物93中所述方法制备化合物101,得到实施例86的取代产物。实施例102化合物102
按照化合物93中所述方法制备化合物105,得到实施例91的取代产物。实施例106化合物106
按照化合物93中所述方法制备化合物106,得到实施例90的取代产物。实施例107化合物107
在室温下,向化合物96(2mmol)的10ml DMF溶液中一次性加入二异丙基乙基胺(2mmol),以相同的方式随后加入2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基
四氟硼酸盐(2mmol),室温下搅拌反应混合物2分钟并一次性加入化合物70(2mmol)的15ml二甲基甲酰胺,室温下继续搅拌过夜。
按照化合物107中所述的相同步骤、 用化合物 98代替96制备化合物113。实施例114化合物114
按照化合物107中所述的相同步骤、用化合物100代替96并用化合物68代替化合物70制备化合物115。实施例116化合物116
按照化合物107中所述的相同步骤、用化合物99代替96并用化合物73代替化合物70制备化合物124。实施例125化合物125
按照化合物107中所述的相同步骤、用吲哚-5-羧酸代替化合物96并用化合物69代替化合物70制备化合物128。实施例129化合物129
在0℃下,向化合物107(1.2mmol)的10ml甲醇和10ml四氢呋喃溶液中滴加10ml 2N氢氧化钠,使溶液升至室温并在室温下搅拌溶液2.5小时,将溶液冷却至0℃,加入1N盐酸至pH7,真空下除去有机溶剂,用25ml水稀释残渣,加入1N盐酸使pH降到2,用乙酸乙酯(3×75ml)萃取混合物,合并的有机萃取液用硫酸镁干燥、过滤、浓缩并在真空下干燥。
将酸(1.1mmol)溶解在15ml四氢呋喃中,并将其冷却至-20℃,用注射器一次性加入N-甲基吗啉(1.45mmol),随后加入氯甲酸异丁酯,将反应混合物在-20℃下搅拌20分钟,在0℃下,将反应混合物过滤到硼氢化钠(11mmol)的20ml水溶液中,在0℃下继续搅拌1.5小时,反应混合物用300ml乙酸乙酯稀释,用水(3×100ml)和盐水洗涤,有机层用硫酸镁干燥、过滤并浓缩,通过快速色谱层析(2∶3乙酸乙酯∶己烷)纯化得到的醇。实施例130化合物130
按照化合物129中 所述的步骤、 用化合物108代替107制备化合物130。实施例131化合物131
按照化合物129中所述的步骤、用化合物109代替107制备化合物131。实施例132化合物132
按照化合物129中所述的步骤、用化合物110代替107制备化合物132。实施例133化合物133
按照化合物129中所述的步骤、用化合物114代替107制备化合物135。实施例136化合物136
按照化合物129中所述的步骤、用化合物116代替107制备化合物137。实施例138化合物138
按照化合物129中所述的步骤、用化合物119代替107制备化合物140。实施例141化合物141
按照化合物129中所述的步骤、用化合物120代替107制备化合物141。实施例142化合物142
在0℃下,向化合物129(0.5mmol)的8ml二氯甲烷溶液中一次性加入吡啶(0.6mmol),一次性加入乙酸酐(0.6mmol),以同样的方式随后加入二甲基氨基吡啶,使反应混合物升至室温,继续搅拌过夜,反应混合物在10ml 0.1N盐酸和30ml二氯甲烷中分配,有机层用硫酸镁干燥、过滤并真空下浓缩。实施例149化合物149
按照化合物148中所述的方法、用化合物134代替129制备化合物153。实施例154化合物154
在0℃下,向化合物135(1.1mmol)的30ml二氯甲烷溶液中一次性加入10ml三氟乙酸,在0℃下,搅拌所得溶液3小时,真空下除去溶剂,残渣在10%碳酸氢钠水溶液和乙酸乙酯中分配,有机层用硫酸镁干燥、过滤并真空下浓缩,将游离胺(1.1mmol)溶解在10ml冰醋酸中,在室温下一次性加入仲甲醛(11mol),在室温下继续搅拌过夜。
将反应混合物倾入50ml冰冷的2N氢氧化钠中并用乙酸乙酯(3×100ml)萃取,合并的有机萃取液用水回洗、硫酸镁干燥、过滤并真空下浓缩,通过反相HPLC纯化所需产物(用0.1%三氟乙酸缓冲的20%-100%乙腈/水洗脱)。实施例155化合物155
在室温下,向化合物154(0.5mmol)的10ml无水丙酮溶液中一次性加入碘甲烷(大大超量,2ml),在室温下搅拌所得溶液过夜,真空下除去溶剂,得到所需的四甲基铵盐。实施例156化合物156
在0℃下,向化合物111(0.8mmol)的2ml二甲基甲酰胺和8ml四氢呋喃溶液中一次性加入氢化钠(1mmol),在0℃下,搅拌该溶液1小时,并一次性加入碘甲烷(大大超量),将溶液升至室温并搅拌过夜,将反应混合物倾入100ml冰水中,用乙酸乙酯(3×75ml)萃取,合并的有机萃取液用水回洗、硫酸镁干燥、过滤、真空下浓缩并通过快速色谱层析(1∶2乙酸乙酯∶己烷)纯化。实施例157化合物157
向化合物129(1mmol)的50ml无水甲醇溶液中加入碾碎的3分子筛(大约1g),在0℃下,搅拌混合物10分钟,在0℃下向混合物中导入氯化氢气,10分钟,使反应混合物的温度升至室温,并将其搅拌过夜,向反应混合物中导入氮气5分钟并真空下除去甲醇,残渣在真空下干燥以除去痕迹量的氯化氢,然后用75ml无水甲醇再次混合,将混合物冷却至0℃,向反应混合物中导入氨气10分钟,使反应混合物的温度升至室温,然后在60℃下加热3小时,冷却至室温后,向反应混合物中导入氮气5分钟,将混合物通过硅藻土过滤、真空下浓缩、通过反相HPLC纯化,用0.1%三氟乙酸缓冲的20%-80%乙腈/水梯度洗脱,真空下除去乙腈,将水相冷冻干燥,得到所需产物的三氟乙酸盐。实施例159b化合物159
1H NMR(300Mhz,d6 DMSO)d 9.21(s,2H),9.01(s,2H),8.22(d,1H,J=9.6Hz),7.85(d,2H,J=7.2Hz),7.70(d,2H,J=7.2Hz),7.62-7.38(m,4H),7.25-7.05(m,7H),6.93(d,1H,J=8.4Hz),4.90-4.65(m,1H),4.24(s,4H),4.18-4.05(m,2H),2.78-2.63(m,2H),2.65-2.45(m,2H),2.08-1.75(m,3H).MS,LRFAB,计算值591,实测值592(M+H)+。
在室温下,向化合物129(1mmol)的20ml吡啶和4ml三乙胺溶液中导入硫化氢气10分钟,室温下将其搅拌过夜,向反应混合物中导入氮气5分钟并真空下除去溶剂,残渣在真空下干燥,然后将其溶解在15ml无水丙酮中,向该溶液中加入5ml碘甲烷,然后将该溶液在50℃下加热1小时,真空下浓缩,将残渣溶解在20ml甲醇中,在室温下,一次性加入乙酸铵(2mmol),将反应混合物在65℃下加热2小时,冷却后,真空下除去甲醇并通过反相HPLC纯化残渣,用0.1%三氟乙酸缓冲的20%-80%乙腈/水梯度洗脱,真空下除去乙腈,将水相冷冻干燥,得到所需产物的三氟乙酸盐。
用适当的起始原料通过基本类似上面所述的步骤制备下列化合物。实施例161化合物1611H NMR(300MHz,d6 DMSO)d 9.23(s,2H),9.01(s,2H),8.27(d,1H,J=9.6Hz),7.93(d,2H,J=7.2Hz),7.72(d,2H,J=7.2Hz),7.65-7.55(m,2H),7.54-7.42(m,2H),7.28-7.08(m,7H),6.94(d,1H,J=8.4Hz),4.25(s,4H),4.24-4.11(m,1H),4.05-3.83(m,2H),2.86(dd,1H,J=6.0,15.6Hz),2.70-2.55(m,2H),2.53-2.43(m,1H),2.35-2.20(m,1H),1.98-1.90(m,2H),1.87(s,3H).MS,LRFAB,计算值591,实测值592(M+H)+。实施例162化合物1621H NMR(300Mhz,d6 DMSO)d 9.21(s,2H),9.01(s,2H),8.22(d,1H,J=9.6Hz),7.85(d,2H,J=7.2Hz),7.70(d,2H,J=7.2Hz),7.62-7.38(m,4H),7.25-7.05(m,7H),6.93(d,1H,J=8.4Hz),4.90-4.65(m,1H),4.24(s,4H),4.18-4.05(m,2H),2.78-2.63(m,2H),2.65-2.45(m,2H),2.08-1.75(m,3H).MS,LRFAB,计算值591,实测值592(M+H)+。实施例163化合物163NMR 300MHz,d6 DMSO,d 9.23(s,2H),9.09(s,2H),8.83(d,1H,J=9.6Hz),7.97(d,2H,J=7.2Hz),7.83(d,1H,J=7.2Hz),7.65-7.35(m,7H),7.28-7.05(m,6H),4.26-4.10(m,1H),4.05-3.83(m,2H),2.87(dd,1H,J=6.0Hz,15.6Hz),2.70-2.55(m,2H),2.32-2.18(m,1H),2.03-1.90(m,2H),1.87(s,3H).MS离子喷射:计算值551,实测值552(M+H)+。实施例164化合物164NMR 300MHz,d6 DMSO,d 9.22(s,2H),9.02(s,2H),8.32(d,1H,J=9.6Hz),7.96(d,2H,J=7.2Hz),7.81-7.65(m,4H),7.65-7.40(m,4H),7.38-7.05(m,7H),4.25-4.10(m,1H),4.05-3.85(m,2H),2.87(dd,1H,J=6.0,15.6Hz),2.70-2.55(m,2H),2.54-2.43(m,1H),2.35-2.20(m,1H,1.98-1.90(m,2H),1.89(s,3H).MS离子喷射:计算值551,实测值552(M+H)+。实施例165化合物165H1 NMR,300MHz,d6 DMSO,d 9.25(s,2H),9.18(s,2H),8.35(d,1H,J=9.6Hz),7.80(d,2H,7.2Hz),7.73(d,2H,J=7.2Hz),7.68(d,2H,J=6.0Hz),7.62(br.s,2H),7.55-7.31(m,5H),7.25-7.03(m,5H),4.65-4.45(m,1H),3.53(s,3H),3.20-2.82(m,5H).MS LRFAB:计算值505,实测值506(M+H)+。实施例166化合物166
1H NMR(300MHz,d6 DMSO)d 9.23(s,2H),8.99(s,2H),8.26(d,1H,J=9.6Hz),7.93(d,2H,J=7.2Hz),7.72(d,2H,J=7.2Hz),7.65-7.56(m,2H),7.54-7.42(m,2H),7.32(d,1H,J=2.4Hz),7.28-7.08(m,6H),7.02(d,1H,J=8.4 Hz),6.07(s,2H),4.25-4.12(m,1H),4.06-3.85(m,2H),2.85(dd,1H,J=6.0,15.6Hz),2.68-2.55(m,2H),2.53-2.43(m,1H),2.32-2.20(m,1H),2.01-1.90(m,2H),1.87(s,3H)MS LRFAB:计算值557,实测值558(M+H)+。实施例167化合物167NMR:9.5(s,1H),9.4(s,1H),8.4(d,1H J=9.0Hz),8.1(d,2H,J=8.0Hz),7.9(d,2H,J=8.0Hz),7.5-7.8(m,5H),7.1-7,4(m,7H),5.0(m,1H),4.0-4.1(m,1H),4.0(s,3H),3.(s,3H),3.6(m,1H),2.9-3.1(m,4H),2.1-2.3(m,2H),2.0(s,3H).M.S.计算值594.3,实测值594。实施例168化合物168
NMR:9.4(s,1H),9.0(s,1H),8.4(d,1H,J=9.0Hz),8.1(d,2H,J=7.0Hz),7.9(d,2H,J=7.0Hz),7.5-7.8(m,5H),7.1-7.4(m,7H),5.0(m,1H),4.0-4.1(m,1H),4.0(s,3H),3.(s,3H),3.6(m,H),2.9-3.1(m,4H),2.1-2.3(m,2H).M.S.计算值552.1,实测值552。实施例169化合物169
H1 NMR,300MHz,d6 DMSO,d 9.22(s,2H),9.11(s,2H),7.92(d,2H,J=7.2Hz),7.80-7.65(m,4H),7.62-7.40(m,4H),7.37-7.01(m,7H),4.85-4.65(m,1H),4.22-4.02(m,1H),3.55-3.36(m,2H),2.82-2.62(m,2H),2.60-2.45(m,1H),2.05-1.73(m,3H).MS LRFAB:计算值509,实测值510(M+H)。实施例170化合物170
NMR:8.5(d,1H,J=9.0Hz),7.8(d,2H,J=9.0Hz),7.7(d,2H,J=9.0Hz),7.1-7.6(m,11H),4.5(m,1H),4.4(s,2H),4.0(dd,1H,J=6.0Hz,10.0Hz),3.7(dd,1H,(J=6.0Hz,10.0Hz),3.0(d,2H,J=9.0Hz),2.9(d,2H,J=9.0Hz),2.0(d,1H,J=7.0Hz).质谱M+H:计算值549.2,实测值549(M+H)+。实施例171化合物171实施例171化合物171
NMR:8.5(d,1H,J=9.0Hz),7.75-7.9(m,6H),7.4-7.7(m,6H),7.0-7.2(m,5H),4.4(m,1H),4.2(s,2H),4.0(dd,1H,(J=6.0Hz,10.0Hz),3.7(dd,1H,J=6.0Hz,10.0Hz),3.0(d,2H,J=9.0Hz),2.9(d,1H,(J=9.0Hz),2.0(m,1H).质谱M+H:计算值507.3,实测值507。实施例172化合物172
NMR:8.5(d,1H,J=9.0Hz),7.8(d,2H,J=10.0Hz),7.7(d,2H,J=10.0Hz),7.6(d,1H,J=10.0Hz),7.5(m,3H),7.0-7.3(m,8H),6.8(d,1H,J=9.0Hz),4.5(m,3H),4.1(dd,1H,J=6.0Hz,10.0Hz),3.9(dd,H J=6.0Hz,10.0Hz),3.1(d,2H,J=9.0Hz)2.9(d,2H,J=9.Hz),2.0(m,1H).质谱M+H:计算值494.2,实测值494。实施例173化合物173
NMR:8.5(d,1H,J=9.0Hz),7.9(d,2H,J=10.0Hz),7.8(d,2H,J=10.0Hz),7.7(d,2H,J=10.0Hz),7.6(d,2H,J=10.0Hz),7.4(s,1H),7.0-7.2(m,3H),4.5(m,3H),4.1(dd,HJ=6.0Hz,10.0Hz),3.9(dd,1H J=6.0Hz,10.0Hz),3.1(d,2H,J=9.0Hz)2.9(d,2H,J=9.0Hz),2.1(d,3H,J=10.0Hz).质谱M+H:计算值549.3,实测值549。实施例174化合物174
NMR:8.5(d,1H,J=9.0Hz),7.8(d,2H,J=8.0Hz),7.6-7.8(m,4H),7.4-7.6(m,4H),7.17.3(m,4H),6.8(d,2H,J=9.0Hz),4.3(m,1H),4.0(dd,1H,J=6.0Hz,10.0Hz),3.7(dd1H,J=6.0Hz,10.0Hz),3.0(d,2H,J=4.0Hz),2.9(d,1H,J=9.0Hz),2.0(m,1H)质谱M+H:计算值507.3,实测值507。实施例175化合物175
质谱M+H:计算值494.2,实测值494。实施例176化合物176
NMR 300MHz,d6 DMSO d 9.23(s,2H),9.04(s,2H),8.57(d,1H,9.6Hz),8.42(s,1H),8.32(d,2H,7.2Hz),8.13(dd,1H,J=1.2,7.2Hz),7.75-7.40(m,7H),7.25-7.13(m,4H),7.12-7.05(m,2H),4.48-4.35(m,1H),3.58-3.42(m,2H),3.10-2.62(m,4H),2.15-1.95(m,1H).MS(LRFAB):计算值567,实测值568(M+H)+。实施例177化合物177NMR 300MHz,d6 DMSO d 9.23(s,2H),8.98(s,2H),8.37-8.22(m,3H),7.97(d,2H,J=7.2Hz),7.86(s,4H),7.65-7.40(m,4H),7.25-7.15(m,3H),7.13-7.05(m,2H),4.45-4.25(m,1H),3.62-3.48(m,2H),3.00-2.86(m,2H),2.85-2.65(m,2H),2.06-1.92(m,1H).MS(LRFAB):计算值522,实测值523(M+H)+。实施例178化合物178
Nmr 300MHz,d6 DMSO,9.23(d,4H,J=6Hz), 8.28(d,1H,J=10Hz),7.77(d,2H,J=10Hz),7.71-7.42(m,8H),7.22-7.12(m,4H),7.10-7.01(m,3H),4.45-4.25(m,1H),3.65-3.45(m,2H),3.05-2.87(m,2H),2.85-2.65(m,2H),2.05-1.95(m,1H).MS(LRFAB):计算值492,实测值493(M+H)+。实施例179化合物179Nmr 300MHz,d6 DMSO,9.38-9.21(m,4H),8.28(d,1H,J=10Hz),8.16(d,1H,J=10Hz),7.70-7.45(m,5H),7.42(d,2H,J=7Hz),7.23(s,1H),7.21-7.03(m,8H),4.48-4.23(m,1H),3.64-3.40(m,2H),3.10-2.85(m,2H),2.84-2.62(m,2H),2.03-1.87(m,1H).MS(LRFAB):计算值507,实测值508(M+H)+。实施例180化合物180
NMR 300MHz,d6 DMSO,9.23(s,2H),8.95(s,2H),8.45(s,1H),8.32(d,1H,J=8.4Hz),8.24(d,1H,J=8.4Hz),8.18(d,1H,J=7.2Hz),7.86(br.s,4H),7.83-7.73(m,1H),7.63-7.43(m,4H),7.25-7.16(m,4H),7.14-7.05(m,1H),4.45-4.30(m,1H),3.63-3.48(m,2H),3.02-2.88(m,2H),2.87-2.65(m,2H),2.08-1.93(m,1H).MS(LRFAB):计算值522,实测值523(M+H)+。实施例181化合物181
NMR 300MHz,d6 DMSO,9.25(s,2H),9.19(s,2H),8.30(d,1H,J=9.6Hz),7.82(s,1H),7.82(d,2H,J=7.2Hz),7.66(d,2H,J=7.2Hz),7.63-7.45(m,4H),7.38-7.27(m,1H),7.25-7.13(m,6H),7.13-7.05(m,1H),6.93(d,1H,J=8.4Hz),4.43-4.28(m,1H),3.65-3.45(m,2H),3.05-2.86(m,2H),2.83-2.68(m,2H),2.08-1.92(m,1H).MS(LRFAB):计算值492,实测值493(M+H)+。实施例182化合物182
Nmr 300MHz,d6 DMSO,9.22(s,2H),9.07(s,2H),8.38(d,1H,J=10Hz),7.93(s,1H),7.83(d,2H,J=7Hz),7.65(d,2H,J=7Hz),7.62-7.45(m,5H),7.42-7.28(m,2H),7.25-7.16(m,4H),7.13-7.07(m,1H),4.45-4.28(m,1H),3.63-3.53(m,2H),3.05-2.87(m,2H),2.85-2.68(m,2H),2.03(s,3H),2.02-1.93(m,1H).MS(LRFAB):计算值534,实测值535(M+H)+。实施例183化合物183
Nmr 300MHz,d6 DMSO,10.05(s,1H),9.23(s,2H),9.10(s,2H),8.25(d,1H,J=10Hz),7.78(d,2H,J=7Hz),7.73-7.40(m,10H),7.21-7.13(m,4H),7.13-7.05(m,1H),4.43-4.25(m,1H),3.63-3.45(m,2H),3.03-2.85(m,2H),2.83-2.68(m,2H),2.04(s,3H),2.01-1.93(m,1H).MS(LRFAB):计算值534,实测值535(M+H)+。实施例184化合物184
NMR:8.5(d,1H,J=7.0Hz),7.8-8.0(m,6H),7.4-7.7(M,6H),7.1-7.3(m,5H)4.6(m,3H),4.1(dd,1H,J=6.0Hz,10.0Hz),3.7(dd,1H,J=6.0Hz,10.0Hz),3.0(d,2H,J=9.0Hz),2.9(d,2H,J=9.0Hz),2.9(s,6H),2.0(m,1H).质谱M+H计算值535.3,实测值535。实施例185化合物185
NMR:8.5(d,1H,J=7.0Hz),7.8-8.0(m,6H),7.4-7.7(M,6H),7.1-7.3(m,5H)4.6(m,3H),4.0(dd,1H,J=6.0Hz,10.0Hz),3.6(dd,1H,J=6.0Hz,10.0Hz),3.2(s,9H),3.0(d,2H,J=9.0Hz),2.9(d,2H,J=9.0Hz),2.0(m,1H).质谱M+H计算值549.3,实测值549。实施例186化合物186
1H NMR(300MHz,d6 DMSO),d 9.30-9.11(m,3H),8.31(br.s,2H),8.15(d,1H,J=8.4Hz),7.93(d,2H,J=7.2Hz),7.86-7.68(m,2H),7.64-7.48(m,6H),4.30-4.15(m,1H),4.14-4.04(m,2H),2.75(d,2H,J=6.0Hz),1.95-1.82(m,1H),1.80-1.68(m,2H),1.65-1.46(m,5H),1.42-1.32(m,1H),1.31-1.15(m,1H),1.13-0.93(m,2H),0.92-0.65(m,4H).MS,LRFAB计算值512,实测值513。实施例187化合物187NMR:9.0(s,1H),8.5(d,1H,J=9.0Hz),7.9(d,2H,J=9.0Hz),7.6-7.8(m,4H),7.3-7.5(m,6H),7.2-7.1(m,6H),3.5(s,3H),3.1(s,3H),3.0(d,2H,J=8.0Hz),2.9(d,2H,J=8.1Hz).质谱M+H计算值520.1,实测值520。实施例188化合物188
NMR:9.4(d,1H,J=12.0Hz),8.6(d,1H,J=10.0Hz),8.1(d,2H,J=10.0Hz),7.9-8.1(m,4H),7.6-7.8(m,6H),4.7(m,1H)4,4(d,2H,J=9.0Hz),3.7(s,3H),3.1-3.4(m,4H),1.6(d,3H,J=9.0Hz).质谱M+H计算值459.2,实测值459。实施例189化合物189NMR:9.4(d,1H,J=12.0Hz),8.0(d,1H,J=10.0Hz),8.1(d,2H,J=10.0Hz),7.7-7.9(m,4H),7.4-7.6(m,6H),4.5(m,1H),4.2(d,2H,J=9.0Hz),3.6(s,3H),3.0-3.2(m,3H),1.6(d,3H,J=9.0Hz).质谱M+H计算值475.1,实测值475。实施例190化合物190
NMR:8.4(d,1H,J=9.0Hz),7.9(d,2H,J=10.0Hz),7.7-7.9(m,4H),7.4-7.6(m,6H),4.(m,H),4.5(s,2H),3.6(s,3H),3.1-3.2(m,3H),2.9(s,6H),1.3(d,3H,J=9.0Hz).质谱M+H计算值459.2,实测值459。实施例191化合物191
NMR:9.3(d,1H,J=9.0Hz),9.1(d,1H,J=9.0Hz),8.4(d,1H,J=10.0Hz),7.7-8.0(m,4H),7.3-7.6(m,5H),4.6(s,2H),4,4(m,1H),3.5(s,3H),3.1(s,9H),2.9-3.1(m,3H)1.6(d,3H,J=9.0Hz).质谱M+H计算值501.1,实测值501。实施例192化合物192
M.S.APCl计算值392,实测值393(M+H)+。实施例193化合物193
M.S.APCl计算值392,实测值393(M+H)+。实施例194化合物194
NMR:9.4(d,1H,J=12.0Hz),8.6(d,1H,J=10.0Hz),8.0(d,2H,J=9.0Hz),7.7(d,2HJ=9.0Hz),7.3-7.6(m,6H),7.0-7.2(m,2H),4.2(m,3H),4.0(dd,1H,(J=6.0Hz,10.0Hz),3.6(dd,1H,(J=6.0Hz,10.0Hz),3.0(d,2H,J=8.0Hz),2.0(m,1H),1,6(m,H)1.1-1.3(m,8H).质谱M+H计算值473.1,实测值473。实施例195化合物195
实施例196化合物196
实施例197化合物197
在室温下、氮气氛中,向搅拌着的(R)-3-氨基丁酸甲酯乙酸盐(8.9g;50mmol)和三乙胺(Et3N)(21ml;150mmol)的无水二氯甲烷(CH2Cl2)溶液中滴加二碳酸二叔丁酯(BOC2O)(21.8g;100mmol),然后加入4-二甲基氨基吡啶(DMAP)(大约50mg),室温下搅拌混合物过夜,此时,用饱和碳酸氢钠(NaHCO3)溶液洗涤混合物,有机层用硫酸钠(Na2SO4)干燥、过滤并浓缩,粗产物通过色谱层析(20%-40%乙酸乙酯(EtAc,或EtOAc)己烷溶液洗脱),得到化合物197。1H NMR(CDCl3,d):4.92(bs,1H),3.96(bm,1H),3.65(s,3H),2.45-2.37(m,2H),1.39(s,9H),1.16(d,J=7.9Hz,3H).实施例198化合物198
在-78℃下、氮气氛中,向搅拌着的化合物197(2.00g;9.21mmol)的无水四氢呋喃(THF)溶液中滴加六甲基二硅氮烷锂(LHMDS)溶液(在THF中25.8ml 1.0M溶液),使混合物温度升至-20至-25℃30分钟,然后冷却至-78℃,滴加3-氰基苄基溴(4.51g;23.0mmol)的无水THF溶液,使所得溶液的温度升至室温,室温下1小时后,用饱和NaHCO3溶液猝灭混合物,真空下除去大部分THF,将残渣溶解在CH2Cl2中并用水洗涤,将有机层干燥(Na2SO4)、过滤并浓缩,粗产物通过快速色谱层析(25%乙酸乙酯/己烷洗脱),用20%乙酸乙酯/己烷研磨半固体残渣并滤出白色固体,真空下浓缩滤液,得到化合物198。1H NMR(CDCl3,d):7.25-7.50(m,4H),5.21(bd,1H),3.88(m,1H),3.60(s,3H),3.07-2.73(m,3H),1.48(s,9H),1.14(d,J=7.9Hz,3H).实施例199化合物199
在室温下、氮气氛中,向搅拌着的化合物198(4.20g;12.7mmol)的10ml CH2Cl2溶液中加入20ml三氟乙酸,使混合物在室温下搅拌过夜,然后真空浓缩,得到化合物199的三氟乙酸(TFA)盐4.20g。1H NMR(DMSO-d6,d):8.07(bs,1H),7.73-7.43(M,4H),3.50(S,3H),3.51(M,1H),3.05-2.82(M,3H),1.23(D,J=7.9HZ,3H).实施例200化合物200
向搅拌着的D-3-氨基丁酸甲酯(6.98g;39.4mmol)乙酸盐的40ml CH2Cl2溶液中加入饱和NaHCO3溶液(40ml),然后滴加氯甲酸苄基酯(9.0ml;63mmol),室温下剧烈搅拌混合物,3小时后,分离有机相,用水洗涤有机相,将有机层干燥(Na2SO4)、过滤并浓缩。粗产物通过色谱层析(10%乙酸乙酯/CHCl3洗脱),得到化合物200。1H NMR(CDCl3,d):7.40-7.22(m,5H),5.25(m,1H),5.08(s,2H),4.11(m,1H),3.65(s,3H),2.53(d,J=7.0Hz,2H),1.23(d,J=7.9Hz,3H).实施例201化合物201
在-78℃下、氮气氛中,向搅拌着的化合物200(3.45g;13.71mmol)的20ml无水THF溶液中滴加LHMDS溶液(41.2ml 1.0M溶液),使混合物温度升至-20℃ 30分钟,然后冷却至-78℃,然后滴加3-氰基苄基溴(4.51g;23.0mmol)的无水THF溶液,使所得溶液的温度升至室温,室温下1小时后,用饱和NaHCO3溶液猝灭混合物,真空下除去大部分THF,将残渣溶解在CH2Cl2中并用水洗涤,将有机层干燥(Na2SO4)、过滤并浓缩,粗产物通过快速色谱层析(30%乙酸乙酯/己烷洗脱)纯化,用20%乙酸乙酯/己烷研磨半固体残渣,并滤出白色固体,真空下浓缩滤液,得到化合物201。1H NMR(CDCl3,d)7.20-7.65(m,9H),5.57(bd,1H),5.12(s,2H),3.97(m,1H),3.60(s,3H),3.07-2.75(m,3H),1.16(d,J=7.9Hz,3H).实施例202化合物202
向搅拌着的化合物201(2.6g;7.1mmol)的25ml乙醇(EtOH)溶液中加入520mg 10%Pd/C,在室温、1个大气压氢气氛下搅拌混合物3小时,然后用一层硅藻土过滤混合物并除去催化剂,真空下浓缩滤液,得到1.45g化合物201。实施例203化合物203
在室温下、氮气氛中,将3′-吡啶基-4-苯基碳酰氯(如实施例228所制备的化合物228)(384mg;1.8mmol)一次性加到化合物199 TFA盐(373mg;1.6mmol)和Et3N(0.67ml;4.8mmol)的5.0ml无水EtOH溶液中,室温下搅拌混合物过夜,真空下除去溶剂,粗产物通过硅胶色谱层析纯化(70%EtAc/己烷洗脱),得到化合物203。1H NMR(CDCl3,d):8.88(m,1H),8.63(m,1H),7.85-8.00(m,7.70(m,2H),7.57-7.33(m,6H),4.51(m,1H),3.65(s,3H),3.10-2.82(m,3H),1.28(d,J=7.9Hz,3H).实施例204化合物204
按照实施例203的步骤、用4′-吡啶基-4-苯基碳酰氯(实施例231所制备的化合物231)代替化合物228进行化合物199的酰化作用,操作并色谱层析后,得到化合物204。1H NMR(CDCl3,d):8.70(m,2H),8.02-7.65(m,4H),7.57-7.32(m,7H),4.50(m,1H),3.68(s,3H),3.10-2.83(M,3H),1.30(d,J=7.9Hz,3H).实施例205化合物205
按照实施例203的步骤、用CH2Cl2代替无水EtOH并用4-联苯基碳酰氯溶液代替3′-吡啶基-4-苯基碳酰氯进行化合物199的酰化作用,操作并色谱层析后,得到化合物205。1H NMR(CDCl3,d):7.93(m,2H),7.73-7.30(m,12H),4.50(m,1H),3.66(s,3H),3.10-2.83(m,3H),1.26(d,J=7.9Hz,3H).实施例206化合物206
按照实施例203的步骤、用2-亚联苯基碳酰氯溶液代替3′-吡啶基-4-苯基碳酰氯进行化合物199的酰化作用,操作并色谱层析后,得到化合物206。1H NMR(CDCl3,d):7.55-7.27(m,5H),7.07(m,2H),6.85-6.66(m,5H),4.44(m,1H),3.65(s,3H),3.05-2.80(m,3H),1.23(d,J=7.9Hz,3H).实施例207化合物207
室温下、氮气氛中,将邻氯过苯甲酸(mCPBA)(381mg;2.21mmol)加到化合物204(608mg;1.47mmol)的10ml CH2Cl2溶液中,室温下搅拌混合物过夜,此时,用CH2Cl2稀释并用5%Na2CO3溶液洗涤混合物,有机层用硫酸钠(Na2SO4)干燥、过滤并浓缩,得到化合物207。MS:M+.+H+(计算值)=430;实测值(FAB)=430实施例208化合物208
室温下、氮气氛中,将(mCPBA)(124mg;0.72mmol)加到化合物203(150mg;0.36mmol)的10ml CH2Cl2溶液中,室温下搅拌该混合物过夜,此时,用CH2Cl2稀释并用5%Na2CO3溶液洗涤混合物,有机层用硫酸钠(Na2SO4)干燥、过滤并浓缩,得到化合物208。1H NMR(CDCl3,d):8.57(m,1H),8.30(m,1H),7.95(m,2H),7.73-7.35(m,9H),4.50(m,1H),3.68(s,3H),3.07-2.85(m,3H),1.20(d,J=7.9Hz,3H).实施例209化合物209
在室温下,将氯化氢气(HCl(g))导入含有3分子筛(粒状、大约50mg)的化合物207(480mg)的5.0ml无水甲醇(MeOH)溶液中约2分钟,然后在室温下搅拌混合物过夜,在真空下浓缩,加入氨(NH3)的MeOH溶液(5.0ml 7N的溶液),并使混合物回流1小时,真空下除去溶剂,残渣通过RPHPLC(CH3CN∶水,0.1%TFA,10%-100%CH3CN梯度洗脱)纯化,冷冻干燥含产物的级分,得到化合物209。1H NMR(MeOH-d4,d):8.42(m,2H),8.00-7.85(m,6H),7.68-7.47(m,4H),4.47(m,1H),3.60(s,3H),3.18-3.00(m,3H),1.33(d,J=7.9Hz,3H).MS:M+.+H+(计算值)=447;实测值(FAB)=447。实施例210化合物210
用与实施例209相似方法处理化合物203,通过RPHPLC纯化后,得到化合物210。1H NMR(DMSO-d6,d):9.36(m,3H),8.50-8.27(m,2H),8.00-7.80(m,3H),7.80-7.40(m,4H),4.40(m,1H),3.49(s,3H),3.13-2.81(m,3H),1.25(d,J=7.9Hz,3H).MS:M+.+H+(计算值)=431;实测值(FAB)=431。实施例211化合物211
用与实施例209相似方法处理化合物205,通过RPHPLC纯化后,得到化合物216。1H NMR(DMSO-d6,d):9.30(s,1H),9.00(s,1H),8.40(m,1H),8.05-7.40(m,12H),4.46(m,1H),3.56(s,3H),3.20-2.97(m,3H),1.28(d,J=7.9Hz,3H).MS:M+.+H+(计算值)=430;实测值(FAB)=430。实施例217化合物217
用与实施例209相似方法处理化合物208,通过RPHPLC纯化后,得到化合物217。1H NMR(MeOH-d4,d):8.67(m,1H),8.50-8.35(m,2H),8.00-7.78(m,5H),7.72-7.48(m,5H),4.47(m,1H),3.60(s,3H),3.16-3.05(m,3H),1.32(d,J=7.9Hz,3H).MS:M+.+H+(计算值)=447;实测值(FAB)=447。实施例218化合物218
将硫化氢气(H2S)导入化合物203(498mg;1.21mmol)的5.0ml吡啶和1.0ml三乙胺溶液中约20分钟,室温下将所得混合物搅拌过夜,然后在氮气蒸汽下浓缩至干,将残余物溶于5ml CH2Cl2,并加入5ml碘甲烷。将混合物回流3小时,使其冷却至室温并在真空下浓缩,将残渣溶解在5ml无水甲醇中,加入NH4OAc(300mg),将该混合物回流3小时并在真空下浓缩,粗产物通过反相HPLC(CH3CN/水,0.1%TFA,10%-100%CH3CN梯度洗脱)纯化,冷冻干燥含产物的级分,得到化合物218。1H NMR(MeOH-d4,d):9.35(s,1H),8.92(m,2H),8.50(d,1H),8.17(m,1H),8.08-7.92(m,4H),7.66-7.50(m,4H),4.50(s,3H),4.50(m,1H),3.58(s,3H),3.15-3.02(m,3H),1.34(d,J=7.9Hz,3H).MS:M+.(计算值)=445;实测值(FAB)=445。实施例219化合物219
用与上述实施例218中处理化合物203的相似方法处理化合物204,通过RPHPLC纯化后,得到化合物219。1H NMR(DMSO-d6,d):9.05(m,1H),8.55(m,3H),8.20-7.97(m,5H),7.65-7.47(m,4H),4.33(s,3H),4.10(m,1H),3.13(s,3H),3.13-2.90(m,3H),1.27(d,J=7.9Hz,3H).MS:M+.(计算值)=445;实测值(FAB)=445。实施例220化合物220
用与上述实施例218中处理化合物203的相似方法处理化合物206,通过RPHPLC纯化后,得到化合物220。实施例221化合物221
向甲醇钠的MeOH的溶液(12.4ml 0.5M溶液)中加入盐酸羟胺,所用固体一旦溶解,便在室温下将该溶液加到化合物207(530mg;1.24mmol)的5ml MeOH溶液中,在室温下、氮气氛中将该混合物搅拌过夜,此时,真空下除去溶剂,通过快速色谱层析(10%MeOH/CH2Cl2洗脱)纯化产物,真空下浓缩含产物的级分,然后冷冻干燥水中的残渣,得到化合物221。1H NMR(CDCl3,d):9.60(s,1H),8.60-7.10(m,12H),5.80(bs,1H),4.40(m,1H),4.45(s,3H),3.15-2.80(m,3H),1.15(d,J=7.9Hz,3H).MS:M+.+H+(计算值)=463;实测值(FAB)=463。实施例222化合物222
用与上述实施例221中处理化合物207的相似方法处理化合物208,通过快速色谱层析纯化后,得到化合物222。1H NMR(MeOH-d4,d):8.69(m,1H),8.35(m,1H),8.00-7.75(m,5H),7.72-7.25(m,5H),4.47(m,1H),3.579s,3H),3.15-2.95(m,3H),1.33(d,J=-7.9Hz,3H).MS:M+.+H+(计算值)=463;实测值(离子喷射)=463。实施例223化合物223
向搅拌着的化合物204(319mg;0.77mmol)的4ml MeOH/THF(1/1)溶液中加入1N NaOH溶液(10ml),室温下搅拌该混合物2小时,然后用12ml1NHCl溶液酸化该混合物,过滤并真空干燥固体产物:化合物223。1H NMR(CDCl3,d):9.30(bs,1H),8.50(bs,1H),8.30-7.80(m,6H),7.65-7.28(m,5H),4.40(m,1H),3.20-2.85(m,3H),a.33(d,J=7.9Hz,3H).实施例224化合物224
在室温下、氮气氛中,将三乙胺(0.11ml;0.77mmol)滴加到化合物223的无水CH2Cl2(10ml)悬浮液中,10分钟后,滴加氯甲酸异丙酯(0.77ml;0.77mmol),30分钟后,加入DMAP(31mg),室温下搅拌混合物过夜,此时,混合物用CH2Cl2稀释并用1N盐酸洗涤,有机层干燥(Na2SO4)、过滤并浓缩,粗产物通过色谱层析(用40%EtOAc/己烷随后用70%EtOAc/己烷洗脱),得到化合物224。MS:M+.+H+(计算值)=442;实测值(离子喷射)=442实施例225化合物225
用与上述实施例218中处理化合物203的相似方法处理化合物224,通过RPHPLC纯化后,得到化合物225。1H NMR(DMSO-d6,d):9.28(m,1H),9.00(m,3H),8.53(m,1H),8.23-7.92(m,4H),7.32(s,1H),7.15(s,1H),7.00(s,1H),4.38(m,1H),4.32(s,3H),3.14-2.93(m,3H),1.25(m,3H),0.99(m,3H),0.87(m,3H).MS:M+.(计算值)=473;实测值(FAB)=473。实施例226化合物226
将4-溴苯甲酸乙酯(7.0g;31mmol)溶解在100mlTHF中,向该溶液中加入Pd(Ph3P)4(1.0g;1.0mmol)、四丁基溴化铵(592mg;1.8mmol)、氢氧化钾粉末(KOH)(3.4g;61mmol)和二乙基(3-吡啶基)硼烷(3.0g),使该混合物回流2.5小时,将其冷却至室温并真空浓缩,将粗产物溶解在MeOH中,通过色谱层析(50%乙酸乙酯/己烷至70%乙酸乙酯/己烷梯度洗脱),蒸发溶剂后,得到化合物226。1H NMR(CDCl3,d):8.83(s,1H),8.60(m,1H),8.10(m,2H),7.90-7.30(m,3H),4.34(m,2H),1.37(m,3H).实施例227化合物227
在室温下,将氢氧化钠溶液(25.5ml 1.0N的溶液)滴加到搅拌着的化合物226(2.7g;12mmol)的21ml 1/1 THF/MeOH溶液中,3小时后,加入25ml 1N HCl,滤出白色沉淀,真空干燥固体,得到化合物227。1H NMR(DMSO-d6,d):8.90(s,1H),8.60(s,1H),8.13(m,1H),8.05-7.80(m,4H),7.50(m,1H).实施例228化合物228
在200℃下,将阔马酸甲酯(10g;65mmol)、4-乙烯基吡啶(35ml;325mmol)和10%Pd/C(25g)的1,3,5-三甲基苯(300ml)的混合物加热30小时,此时,将混合物冷却并通过硅藻土过滤、用CHCl3洗涤,真空下除去大部分溶剂,剩余液体通过色谱层析(50%乙酸乙酯/己烷至70%乙酸乙酯/己烷梯度洗脱),得到化合物229。MS:M+.(计算值)=213;实测值(EI)=213。实施例230化合物230
如实施例227,用THF/MeOH中的氢氧化钠处理化合物229,得到化合物230。MS:M+.(计算值)=199;实测值(EI)=199。实施例231化合物231
如实施例228,用回流的亚硫酰氯处理化合物230,得到化合物231。MS:M+.(计算值)=217;实测值(EI)=217。实施例232化合物232
在-78℃下、氮气氛中,向搅拌着N-BOC高苯基丙氨酸甲酯(5.57g;18.1mmol)的30ml THF溶液中滴加LHMDS溶液(在THF中54.8ml 1N的溶液),使混合物温度升至0℃30分钟,然后回冷却至-78℃,滴加3-氰基苄基溴(7.46g;38.0mmol)的无水THF溶液,使所得溶液的温度升至室温,室温下1小时后,用饱和NaHCO3溶液猝灭混合物,真空下除去大部分THF,将残渣溶解在CH2Cl2中并用水洗涤,将有机层干燥(Na2SO4)、过滤并浓缩,粗产物通过快速色谱层析(25%乙酸乙酯/己烷洗脱),用20%乙酸乙酯/己烷研磨半固体残渣并滤出白色固体,真空下浓缩滤液,得到化合物232。1H NMR(CDCl3,d):7.82 -7.08((m,9H),5.32(bd,1H),3.84(m,1H),3.60(s,3H),3.06-2.57(m,5H), 1.70(m,2H),1.47(s,9H).实施例233化合物233
0℃下、氮气氛中,向搅拌着的化合物232(1.42g;3.35mmol)的5.0mlCH2Cl2溶液中加入3.5ml三氟乙酸,室温下搅拌混合物2小时,然后真空下浓缩,得到化合物233的TFA盐。MS:M+.(计算值)=322;实测值(EI)=322。实施例234化合物234
用上述实施例209的处理化合物207的相同方法用HCl/MeOH、然后用NH4OAc处理化合物234,通过RPHPLC纯化后,得到化合物235。MS:M+.+H+(计算值)=521;实测值(FAB)=521。实施例236化合物236
用上述实施例218处理化合物203的相同方法处理化合物234,通过RPHPLC纯化后,得到化合物236。1H NMR(MeOH-d4):9.35(s,1H),8.90(m,2H),8.45(m,1H),8.17(m,1H),8.11-7.92(m,4H),7.68-7.46(m,5H),7.27-7.10(m,6H),4.50(s,3H), 4.40(m,1H),3.57(s,3H),3.05(m,3H),2.67(m,2H),2.00(m,2H).实施例237化合物237
根据上述实施例227的步骤,用在THF/MeOH中的氢氧化钠进行化合物234的水解,操作完毕后,得到化合物237。MS:M+.+H+(计算值)=490;实测值(FAB)=490。实施例238化合物238
以上述实施例218处理化合物203的相同方法处理化合物237,通过RPHPLC纯化后,得到化合物238。1H NMR(MeOH-d4):9.38(s,1H),8.90(m,2H),8.47(m,1H),8.17(m,1H),8,11-7.92(m,4H),7.68-7.46(m,5H),7.26-7.10(m,6H),4.50(s,3H),4.38(m,1H),3.12-2.97(m,.3H),2.68(m,2H),2.03(m,2H).
本文所述分子依靠它们抑制凝固级联中次末级酶(因子Xa,而不是凝血酶)的能力抑制血液凝固,前凝血酶复合物(因子Xa、因子Va、钙和磷脂)中的游离因子Xa和因子Xa得到抑制,通过在抑制剂与酶之间直接形成复合物抑制因子Xa,因此,因子Xa的抑制不取决于血浆辅因子抗凝血酶Ⅲ,通过口服、连续静脉输液、团块性静脉给药或任何其它肠胃外途径施用化合物达到有效抑制因子Xa的作用以避免因子Xa诱导凝血酶原形成凝血酶所需的效果。
抗凝剂疗法是在于治疗和预防各种静脉和动脉脉管系统的血栓症状,在动脉系统中,异常血栓的形成最初与冠状、大脑和外周脉管系统的动脉有关,这些与血管的血栓闭合有关的疾病主要包括急性心肌梗塞(AMI)、不稳定心绞痛、血栓栓塞与溶栓治疗和经皮冠状动脉成形术(PTCA)有关的急性血管闭合、暂时缺血性发作、中风、间歇性跛行综合症和冠状或外周动脉支路移植(CABG)。慢性抗凝疗法也有益于预防血管腔再狭窄(该血管腔再狭窄经常产生随后的PTCA和CABG)并有益于维持长期血液透析的患者脉管通路开放,就静脉脉管系统而言,病理性血栓形成经常发生于继腹、膝和胯外科手术之后的较低末端静脉(深静脉血栓形成,DVT),DVT进一步使患者易患高危肺血栓栓塞。全身、弥散性血管内凝血病(DIC)通常发生于脓毒性休克、某些病毒感染和癌期间的血管系统,该病症的特征在于凝血因子的迅速积累和它们的血浆抑制剂导致在某些器官系统的整个微脉管系统中形成威胁生命的凝块,上述讨论的适应症包括需要抗凝剂治疗的一些(但不是所有)可能的临床情况,本领域经验丰富人员很清楚需要急性或慢性定期抗凝剂治疗的详情。
这些化合物可以单独或与其它诊断剂、抗凝剂、抗血小板剂或纤维蛋白溶解剂混合使用,例如,与标准肝素、低分子量肝素、直接凝血酶抑制剂(即、水蛭素)、阿司匹林、纤维蛋白原受体拮抗剂、链激酶、尿激酶和/或组织纤溶酶原激动剂一起联合施用因子Xa抑制剂可以产生较大抗凝或溶栓的效力或效率。可施用本文所述化合物以治疗各种动物(如包括人类的灵长类动物、羊、马、牛、猪、狗、大鼠和小鼠)血栓形成并发症。因子Xa抑制剂不仅用于具有血栓症状患者的抗凝治疗,而且用于需要血液凝聚的抑制以防止贮存的全血凝聚并防止试验或贮存的其它生物样品的凝聚,因此,可以将任何因子Xa抑制剂加到或接触任何含有或悬浮有因子Xa和其中需要抑制血液凝聚的介质中。
因子Xa抑制剂除了用于抗凝疗法外,还可以用于治疗或预防涉及起病理作用的并发凝血酶产生的其它疾病,例如,已证明通过细胞表面凝血酶受体的特殊分裂和活化、凝血酶凭借它调节许多不同细胞类型的能力在慢性和变性疾病(如关节炎、癌、动脉粥样硬化和阿尔茨默氏病)的发病率和死亡率中起作用,因子Xa抑制剂将有效地阻滞凝血酶的产生并因此中和凝血酶对各种细胞类型的任何病理作用。
本发明进一步的特征是提供治疗患病的人或动物的方法,所述病症(如上文所述病症)能够通过施用因子Xa抑制剂得到改善,其中包括将有效量的式(Ⅰ)化合物或含有式(Ⅰ)化合物的组合物施于患者,“有效量”是指能有效抑制因子Xa并因此而产生所述的治疗效果的本发明化合物用量。
本发明还包括在其范围内的药物制剂,该药物制剂含有至少一种与药用载体或涂层有关的式Ⅰ化合物。
实际上,本发明化合物一般可以肠胃外、静脉、皮下、肌内、结肠、鼻、腹膜内、直肠或口服给药。
本发明产物可以通过允许最佳途径给药的形式存在,本发明还涉及药物组合物,该药物组合物含有至少一种适合用于人类或兽类药物的本发明产物,这些组合物可以常规方法制备,用一种或多种药用辅助剂或赋形剂,辅助剂尤其包括稀释剂、消毒水介质和各种无毒有机溶剂。为了得到药用制剂,组合物可以片剂、丸剂、颗粒、粉末、水溶液或悬浮液、注射液、酏剂或糖浆的形式存在,并能够含有一种或多种选自含有甜味剂、调味品、色素或稳定剂物质中的试剂。
通常根据物质的溶解度和化学性质、具体的给药形式和药物常规中遵守的条款决定载体的选择和载体中活性物质的含量。例如,赋形剂(如乳糖、柠檬酸钠、碳酸钙、磷酸氢钙)和崩解剂(如淀粉、藻酸、和某些复合硅酸盐)与润滑剂(如硬脂酸镁、磷酸十二烷基硫酸钠和滑石)混合可以用于制备片剂。对于制备胶囊,用乳糖和高分子量聚乙二醇很有利,当使用水悬浮液时,它们能够含有乳化剂或利于悬浮的试剂。稀释剂如蔗糖、乙醇、聚乙二醇、丙二醇、甘油和氯仿或可以使用其混合物。
对于肠胃外给药,使用在植物油中的本发明产物的乳化剂、悬浮液或溶液,其中的植物油例如芝麻油、花生油或橄榄油,或水-有机溶液如水和丙二醇、注射用有机酯如油酸乙酯,还有药用盐的消毒液。本发明产物的盐的溶液特别用于肌内或皮下注射给药,也含有纯蒸馏水盐溶液的水溶液可以用于静脉给药,条件是适当地调节它们的pH;用足够量的葡萄糖或氯化钠适宜地使它们得到缓冲和等渗并通过加热、辐照或微量过滤使它们消毒。
含有本发明化合物的合适的组合物可以通过常规方法制备,例如,可以将本发明化合物溶解于或悬浮于的合适载体以用于喷雾剂或悬浮液或溶液气雾剂,或可以将其吸附于合适的固体载体上以用于干粉吸入剂。
直肠给药的固体组合物包括根据已知方法按配方制备的栓剂并含有至少一种式Ⅰ化合物。
本发明组合物中活性成分的百分比可以变化,但应当组成得到合适剂量的比例。显然,各种单位剂量形式可以大约相同时间给药,所用剂量将通过大夫根据所需治疗效果、给药途径和治疗持续时间以及患者的症状来决定。对于成年人,通过吸入法一般的剂量是大约0.01-大约100mg/kg体重/天,优选大约0.01-大约10mg/kg/天;通过口服一般的剂量是大约0.01-大约100mg/kg/天,优选大约0.1-大约70mg/kg/天,更优选大约0.5-大约10mg/kg/天;通过静脉内给药一般的剂量是大约0.01-大约50mg/kg/天,优选大约0.01-大约10mg/kg/天,在各自具体的病例中,将根据处理客体的差别因素如年龄、体重、健康状态和其它能够影响医药产品效果的性质来决定剂量。
为了得到所需治疗效果可以按需要决定用药次数施用本发明产品,一些患者可以对较高或较低剂量作出迅速反应并可以发现适当的更弱的维持剂量。根据各自具体患者的生理需要,对于其它患者以1-4剂量/天的量长期治疗是必要的,一般以口服1-4次/天施用活性产物,不言而喻,对于其它患者规定不多于一个或两个剂量/天是必要的。
根据文献所述试验和下列涉及人类和其它哺乳类动物的令人确信的药理活性试验结果显示本发明范围内的化合物具有明显的药理活性。酶试验:
通过测定得到使所用纯酶的50%酶活性(IC50)丧失的抑制剂浓度来评估作为因子Xa、凝血酶、胰蛋白酶、组织-纤溶酶原激动剂(t-PA)、尿激酶-纤溶酶原激动剂(t-PA)、纤溶酶和活性蛋白质C的抑制剂的本发明化合物的效果。
所有的酶试验均在室温下、用1nM的最终酶浓度在96孔微量滴定板上进行,因子Xa和凝血酶的浓度通过活性位点滴定法测定,所有其它酶的浓度均以厂商提供的蛋白质浓度为基础。将本发明化合物溶解在DMSO中,用它们各自的缓冲液稀释并在最大最终DMSO浓度1.25%下试验。将稀释的化合物加到含有缓冲液和酶的小孔中,并预平衡5-30分钟,通过加入底物启动酶反应,在V最大微量滴定板读数器(分子仪器)上、在405nm处连续监测肽-对硝酰苯胺底物水解产生的颜色达5分钟,在这些条件下,在所有试验中使用少于10%的底物,测定的初始速度用于计算使对照速度减少50%(IC50)的抑制剂的量,然后根据Cheng-Prusoff公式(IC50=Ki[1+[S]/Km])估算完全抑制的动力学来测定表观Ki值。
另一体外试验可以用于估计正常人血浆中本发明化合物的效力,活化的局部凝血酶原激酶凝血时间是依赖于就地产生因子Xa的基于血浆的凝血试验,它集群成凝血酶原酶复合物并相继产生凝血酶和最终得到作为试验终点的凝块形成的纤维蛋白,经过临床估计,该试验一般用于临床监测常用抗凝血药物肝素和直接抗凝血剂的活体外效果,因此,该体外活性试验被认为是体内抗凝血活性的替代标志。基于人血浆的凝集试验
用MLA Eletra 800仪一次两份测定活性局部凝血酶原激酶凝集时间,将100μl正常人柠檬酸钠血浆(George King Biomedical)加到含有100μl本发明化合物的Tris/NaCl缓冲液(pH7.5)的比色池中,并放于仪器中,接着,向温热3分种的仪器中自动加入100μl活性cephaloplastin(肌动蛋白,Date),相继加入100μl 0.035M CaCl2启动凝聚反应,用分光光度法测定凝块的形成并按秒测定,将化合物的效力定量为达到在无本发明化合物存在的情况下,用人血浆测定的对照凝聚时间的二倍所需的浓度。
也可以用两种已确定的急性血管血栓形成的动物试验模型估计本发明化合物的体内抗凝血的效力,用颈静脉血栓形成的兔模型和颈动脉血栓形成的大鼠模型说明在人静脉血栓形成和动脉血栓形成的分别不同的动物模型中这些化合物抗血栓形成的活性。兔静脉血栓形成模型的体内试验:
这是一个已确定的富含纤维蛋白静脉血栓形成的模型,该模型是在文献中证实的并显示对于包括肝素的各种抗凝药物敏感(在试验静脉血栓形成中,阻断组织因子通道抑制剂(TFPI 1-161)的重组体的抗血栓形成效果-与低分子量肝素对照,血栓形成和淤血J.Holst,B.
Lindblad,D.Bergqvist,O.Nordfang,P.B.Ostergaard,J.G.L.Petersen,G.
Nielsen和U.Hedner.Thrombosis and Haemostasis,71.214-219(1994).用该模型的目的是估测化合物防止在体内伤口处产生静脉血栓(凝块)形成和颈静脉中局部阻滞的能力。
用35mg/kg的氯胺酮和5mg/kg的甲苯噻嗪以1ml/kg(i.m.)的体积麻醉重1.5-2kg的雄性和雌性新西兰白兔,将套管插入右颈静脉以导入麻醉液(以大约0.5ml/hr的速率导入氯胺酮/甲苯噻嗪172.5mg/kg/hr)和给入试验物,将套管插入右颈动脉以记录动脉血压和收集血样,用GAYMAR T-PUMP使体温维持在39℃,隔离左外部颈静脉并沿暴露的2-3cm血管处绑住所有分支,将套管插入普通颈部双叉口上部右颈静脉并将套管推进至普通颈静脉的基部,用非创伤血管钳隔阻1cm静脉片段,在末端钳下面用18G针头绕静脉打结形成相对狭窄,这就在受伤处创造出一个减少流动和局部停滞的区域,在内部颈静脉中通过套管用盐水漂洗隔离片段2-3次,其后,用0.5ml 0.5%聚氧乙烯醚(W-1)充满隔离片段5分钟,W-1是使片段的内皮细胞衬里破裂的去垢剂,因此,提供了启动形成凝块的形成血栓表面,5分钟后,从片段中除去W-1,再次用盐水漂洗隔离片段2-3次,然后,除去血管钳,使血液流经该血管部分,在狭窄结下面割下静脉并监测血流(血流不存在记录为完全闭合)后,使凝块形成并生长30分钟,然后结扎静脉整个隔离片段,除去形成的凝块并称重(湿重),将对最后凝块重量的试验试剂效果作为初期终结点,维持动物生命30分钟以得到抗凝的最终药代动力学测定,在用W-1损伤血管前,给药15分钟,并继续通过凝块形成和发展成熟的阶段,得到估算止血参数的三个血样(3ml ea):一个为使用W-1之前的样品,第二个为除去血管钳后30分钟的样品,第三个为试验结束的样品。抗凝血形成效果表示为在用与处理空白动物赋形剂比较的本发明化合物处理的实验中最终凝块重量的减少。鼠动脉血栓形成模型的体内试验:
可以用已确定的鼠颈动脉FeCl2-诱导的血栓形成模型估计因子Xa抑制剂抑制富含血小板的动脉血栓形成的抗凝效率(在动脉和静脉血栓形成的鼠模型中,血栓素受体拮抗剂与阿司匹林对照的优异活性W.A.Schumacher,C.L.Heran,T.E.Steinbacher,S.Youssef和M.L.Ogletree.Journal of cardiovascular Pharmacology,22,526-533(1993);通过氯化铁诱导的动脉血栓形成的鼠模型,K.D.Kurtz,B.W.Main,和G.E.Sandusky.Thrombosis Research,60,269-280(1990);在鼠动脉血栓形成模型中的凝血酶抑制作用,R.J.Broersma,L.W.Kutcher和E.F.Heminger.Thrombosis Research,64,405-412(1991)),该模型广泛用于估测各种包括肝素的试剂抗血栓形成的能力并直接起凝血酶抑制剂的作用。
用戊巴比妥钠(50mg/kg i.p.)麻醉重量为375-450g的SpragueDawley鼠,根据反应出的麻醉接受水平,割下颈部腹面并准备无菌手术,连接心电图电极并通过试验监测导向器Ⅱ,用PE-50管材将套管插入右股骨静脉以分别给入本发明化合物和得到血样并监测血压,在颈部腹面沿中线切开,暴露气管并用PE-240管材插管以确保通气管开放,隔离右动脉并沿血管放置两根4-0丝线以利于仪器测定,沿血管放置电磁流探针(0.95-1.0mm)以测定血流,在血管下、探针末端放置4×4mm parafilm条以使其与周围的肌肉层隔离,制作基线流测量后,将2×5mm预先在35%FeCl2中饱和的滤纸条在探针处下游放置于血管顶部10分钟,然后将其除去,FeCl2扩散到动脉下侧片段上并产生导致急性血栓形成的去内皮化。接着在60分钟观察期间监测浸泡FeCl2滤纸的敷用、血压、动脉血流和心率,接着,闭合血管(定义为达到零血流)或如果维持效果,敷用滤纸后60分钟,结扎伤口近侧及远端的动脉,并切除血管,除去血栓并迅速称重,记录研究的初期终点。
用手术仪吸取对照血样(B1),从动脉导管采集所有血样并与防止凝血的柠檬酸钠混合,用0.5ml 0.9%盐水冲洗各样品、导管,在使用FeCl2前开始5分钟时静脉(i.v.)给入本发明化合物,记录使用FeCl2之间的时间而导管血流达到零的时间记录为闭合时间(TTO),对于60分钟内不闭合的血管而言,将TTO指定为60分钟的值,使用FeCl2后5分钟,吸取第二个血样(B2),FeCl2暴露10分钟后,从血管上除去滤纸并监测动物试验残余物,当达到零血流的血液,吸取第三个血样(B2),除去凝块并称重,对得到血样相同时间的前肢脚趾垫进行模板出血时间的测定,使所有血样具有活性局部凝血酶原激酶时间(APTT)和凝血酶原时间(PT)组成的凝固图形,在一些实例中,可以口服本发明化合物,用标准技术人工约束鼠,通过胃管饲法用18规格弯曲剂量针(5ml/kg的体积)给入化合物,胃饲后15分钟,如前所述麻醉动物并给其配备仪器,然后根据上述规定进行试验。
经由实施例,化合物184对因子Xa、胰蛋白酶和凝血酶试验分别显示Ki值为27.0nM,1.72μM和2.71μM,化合物45对因子Xa、胰蛋白酶和凝血酶试验分别显示Ki值为94.0nM,129nM和477nM,化合物167对因子Xa、胰蛋白酶和凝血酶试验分别显示Ki值为19.0nM,46nM和1.228μM。
可以其它具体形式使本发明具体化,而不背离本发明精神或其必要特性。
Claims (13)
1、下式化合物、其药用盐、其N-氧化物、其水合物和其溶剂化物:R1和R2是氢或共同为=NR9;R3是-CO2R6,-C(O)R6,-CONR6R6,-CH2OR7或-CH2SR7;R4是式:或R4是氢、烷基、环烷基或环烷基烷基;R5是烷基、链烯基、任选取代的芳基或任选取代的杂芳基;R6是氢或低级烷基;R7是氢、低级烷基、低级酰基、芳酰基或杂芳基;R8是氢或低级烷基;R9是R10O2C-、R10O-、HO-、氰基、R10CO-、HCO-、低级烷基、硝基或Y1Y2N-,其中R10是任选取代的烷基、任选取代的芳烷基或任选取代的杂芳烷基,和其中Y1和Y2独立地是氢或烷基;A和B是氢或共同为键;Ar是任选取代的芳基或任选取代的杂芳基;和n是0,1或2。
2、权利要求1所述化合物,其中R1和R2共同为=NH。
3、权利要求2所述化合物,其中R1和R2共同为=NH,并在苯基部分与丙基部分连接位置的间位在苯基部分上形成氨基亚氨基甲基。
4、权利要求1所述化合物,其中R3是-CO2R6,-CH2OR7或-CH2SR7。
5、权利要求4所述化合物,其中R3是-CO2R6和R6是低级烷基。
6、权利要求4所述化合物,其中R3是-CH2OR7或-CH2SR7和R7是氢或低级烷基。
7、权利要求1所述化合物,其中n是1。
8、权利要求1所述化合物,其中Ar是任选取代的芳基。
9、权利要求1所述化合物,其中Ar是苯基。
10、权利要求1所述化合物,其中R5是任选取代的苯基、任选取代的联苯基、任选取代的萘基或任选取代的杂联苯基;
12、一种药物组合物,该药物组合物含有药用量的根据权利要求1所述化合物和药用载体。
13、治疗疾病的方法,该方法通过有效量权利要求1所述化合物抑制患有所述疾病患者因子Xa的产生从而调节所治疗疾病的症状。
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EP (1) | EP0906094B1 (zh) |
JP (1) | JP4053597B2 (zh) |
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CL (1) | CL2004000376A1 (zh) |
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PT (1) | PT906094E (zh) |
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CN1293052C (zh) * | 1999-10-28 | 2007-01-03 | 三共株式会社 | 苯甲脒衍生物 |
CN103562183A (zh) * | 2011-03-29 | 2014-02-05 | 赛诺菲 | 奥米沙班的苯甲酸盐 |
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TW542822B (en) | 1997-01-17 | 2003-07-21 | Ajinomoto Kk | Benzamidine derivatives |
US6620961B1 (en) * | 1997-08-26 | 2003-09-16 | Kumiai Chemical Industry Co., Ltd. | Biarylalkylenecarbamic acid derivatives and bacteriocides for agricultural and horticultural use |
US6740682B2 (en) | 1997-08-29 | 2004-05-25 | Tularik Limited | Meta-benzamidine derivatives as serine protease inhibitors |
EP1080075B1 (en) * | 1998-03-23 | 2004-08-11 | Aventis Pharmaceuticals Inc. | Piperididinyl and n-amidinopiperidinyl derivatives |
AU758567B2 (en) * | 1998-06-08 | 2003-03-27 | Ajinomoto Co., Inc. | Benzamidine derivative |
WO2000039111A1 (en) | 1998-12-23 | 2000-07-06 | Eli Lilly And Company | Antithrombotic amides |
AU3127900A (en) | 1998-12-23 | 2000-07-31 | Du Pont Pharmaceuticals Company | Thrombin or factor xa inhibitors |
PL349267A1 (en) * | 1998-12-24 | 2002-07-01 | Aventis Pharm Prod Inc | Substituted (aminoiminomethyl or aminomethyl)benzoheteroaryl compounds |
BR9916733A (pt) | 1999-01-02 | 2001-09-25 | Aventis Pharma Gmbh | Derivados de arilalcanoìla, processos para sua preparação, seu uso e composições farmacêuticas que os contêm |
EP1022268A1 (en) * | 1999-01-02 | 2000-07-26 | Aventis Pharma Deutschland GmbH | Arylalkanoyl derivatives, processes for their preparation, their use and pharmaceutical compositions containing them |
US6794412B1 (en) * | 1999-03-11 | 2004-09-21 | Bristol-Myers Squibb Pharma Company | Treatment of thrombosis by combined use of a factor Xa inhibitor and aspirin |
JP2003502314A (ja) | 1999-06-14 | 2003-01-21 | イーライ・リリー・アンド・カンパニー | 化合物 |
WO2001033217A2 (en) | 1999-11-02 | 2001-05-10 | Aventis Pharma Deutschland Gmbh | Monitoring the activity of factor xa inhibitors |
DE10006601A1 (de) | 2000-02-15 | 2001-08-16 | Clariant Gmbh | Verfahren zur Herstellung von 4-(4'-Carboxyphenyl)pyridin |
GB0108903D0 (en) | 2000-10-05 | 2001-05-30 | Aventis Pharm Prod Inc | Novel crystalline forms of a factor Xa inhibitor |
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DE102006048300A1 (de) | 2006-01-26 | 2007-08-02 | Hellstern, Peter, Prof. Dr.med. | Inhibitoren des Blutgerinnungsfaktors Xa zur Verwendung als Antikoagulans |
TW201040130A (en) * | 2009-04-17 | 2010-11-16 | Merz Pharma Gmbh & Co Kgaa | Synthesis of 1-amino-1,3,3,5,5-pentamethylcyclohexane mesylate |
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EP4070658A1 (de) | 2021-04-06 | 2022-10-12 | BIORoxx GmbH | Verwendung von blutgerinnungshemmenden verbindungen als rodentizide |
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CN1273128C (zh) * | 1996-01-02 | 2006-09-06 | 阿温蒂斯药物公司 | 取代的n-[(氨基亚氨基甲基或氨基甲基)苯基]丙基酰胺 |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1293052C (zh) * | 1999-10-28 | 2007-01-03 | 三共株式会社 | 苯甲脒衍生物 |
CN103562183A (zh) * | 2011-03-29 | 2014-02-05 | 赛诺菲 | 奥米沙班的苯甲酸盐 |
CN103562183B (zh) * | 2011-03-29 | 2015-12-23 | 赛诺菲 | 奥米沙班的苯甲酸盐 |
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