CN1322001C - 抑制因子Xa活性的新化合物 - Google Patents
抑制因子Xa活性的新化合物 Download PDFInfo
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- CN1322001C CN1322001C CNB038031558A CN03803155A CN1322001C CN 1322001 C CN1322001 C CN 1322001C CN B038031558 A CNB038031558 A CN B038031558A CN 03803155 A CN03803155 A CN 03803155A CN 1322001 C CN1322001 C CN 1322001C
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- phenyl
- alkyl
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Abstract
本发明涉及式(I)的化合物:或其药物学上可接受的盐、溶剂化物、水合物或药物学上可接受的制剂。这些化合物可用于抑制因子Xa以及预防和/或治疗血栓栓塞病症。
Description
技术领域
本发明涉及对血液凝固具有抑制作用的新化合物(所谓的抗凝血药)以及它们的药物学上可接受的盐和溶剂化物及水合物。本发明还涉及所述化合物作为活性成分的药物组合物,制备这些化合物、盐和组合物的方法,以及它们在预防和/或治疗血栓栓塞病症中的应用。这些化合物、盐和组合物是非常有效的因子Xa抑制剂。本发明还涉及这些化合物及盐的前药、旋光体、外消旋体和非对映异构体。
背景技术
血栓栓塞病症是具有风险因素的患者中血液凝固趋势增加所导致的,所述风险因素例如是相对较大的手术、长期不动、下肢骨折、肥胖、血液脂肪代谢紊乱、格兰氏阴性菌的感染、癌症和老年化。
静脉血栓形成可由于受损血管的引流导致水肿和组织的炎症。更深静脉的血栓形成(所谓的深静脉血栓形成)可导致严重的并发症,例如肺栓塞。动脉血栓形成可导致通过受损动脉供血的组织的缺血性坏死,例如在冠状动脉受损时导致心肌梗塞。其他的血栓栓塞病症例如是动脉硬化、脑中风(脑卒中)、心绞痛、间歇性跛行。
在正常的生理条件下,自然的血液凝固防止大量的血液从破损血管中流失。在血液凝固期间,液态血液转化为血液凝块,其是一种明胶状物质,通过形成栓塞密封受损的血管。在该过程中,血浆中存在的可溶性纤维蛋白原在多级过程(即、所谓的凝血级联)中被转化为纤维-明胶状的凝块物质纤维蛋白。
在两个不同的凝血激活途径之间有明显的区别。当血液与非生理性表面接触时,引发内因性凝血途径。血管损伤时则引发外因性凝血途径。这两个凝血途径都参与一个共同的途径,在该共同途径中,凝血因子X(一种丝氨酸蛋白酶)被转化为其活性形式(因子Xa)。因子Xa与所谓凝血酶原酶复合物中的因子Va和Ca2+一起使凝血酶原转化为凝血酶,而该凝血酶又通过从纤维蛋白原上断裂肽而释放纤维蛋白单体,该纤维蛋白单体能够凝集形成纤维蛋白纤维。最后,因子XIII产生交联并由此使纤维蛋白纤维稳定。
抗凝血药是用于预防和治疗血栓栓塞病症。在涉及狭义的抗凝血药时,需要区别肝素和维生素K拮抗剂(例如香豆素衍生物),前者立即有效而且直接抑制某些血液凝固因子,而后者抑制某些依赖于维生素K的存在的凝血因子在肝脏中的产生,并仅是缓慢地开始产生效果。其他抗凝血药是对血纤维蛋白溶解系统产生直接或间接的活化作用的血纤维蛋白溶解药,以及血小板凝集抑制剂如乙酰水杨酸。更较少使用的一种方法是用酶——安克洛酶降低血液中的纤维蛋白原水平。使用抗凝血药的目的是防止有可能堵塞血管的血凝块的发展或者是在其已经形成时将其溶解。
上述狭义的抗凝血药,即、肝素和维生素K拮抗剂,仍具有缺点。对于肝素而言,在完整的肝素(UFH)和低分子量肝素(LMWH)之间有明显的差别。使用UFH的缺陷是其通常不得不通过静脉途径给药,具有变化的抗凝血作用,而且因此必须经常对患者以及所采用的剂量进行监测。虽然LMWH可以皮下给药恒定的、无需监测的剂量,但其效果与UFH的相比大大降低,这是因为其具有短的链长。
维生素K拮抗剂如华法林在不同的患者之间表现出不同的活性程度,有可能是因为遗传因素。除上述缓慢开始发生作用外,与之有关的缺陷是必须监测患者以及需要采用单独的剂量。
其他已知的抗凝血药属于凝血酶抑制剂类。在该领域中相关研究活动的最新综述可例如参见以下文献:Jules A.Shafer,Current Opinion inChemical Biology,1988,2:458-485;Joseph P.Vacca,Current Opinion inChemical Biology,2000,4:394-400;以及Fahad Al-Obeidi和James A.Ostrem,DDT,Vol.3,No.5,May 1998:223-231。
凝血酶抑制剂的关键性缺陷是为了得到所希望的作用,必须在体内很大程度地抑制凝血酶活性,使得有可能增加出血倾向,这使得给药剂量难以控制。
相反地,因子Xa抑制剂对由凝血酶原新形成凝血酶产生抑制作用,但它们并不破坏现存凝血酶活性,而后者对于初期淤血是必须的。
这些因子Xa抑制剂中的一些的作用谱以及副作用都尚未得到完全的研究。
发明内容
本发明的目的是提供一种具有有用的性质、特别是抗凝血作用的新化合物。
更具体而言,本发明的目的是提供具有更高效力、更少副作用和/或更高选择性的新因子Xa抑制剂。另外,还提供合适的药物组合物。这些化合物及组合物优选通过非胃肠道途径或者经口给药,特别是经口给药。
本发明的另一个目的是提供制备这些新化合物的方法。
这些新化合物还适用于预防和/或治疗血栓栓塞病症。
本发明涉及抗凝血化合物及其药物学上可接受的盐、溶剂化物和水合物以及制剂,它们具有高活性和选择性并且可以特别是经口给药。本发明进一步涉及这些化合物及其盐的前药、旋光体、外消旋体和非对映异构体。所述化合物和盐本身也有可能是仅通过代谢得以活化的前药。本发明还涉及包含所述化合物或盐等作为活性成分的药物组合物。
本发明涉及以下通式(I)的化合物或其药物学上可接受的盐、溶剂化物、水合物或药物学上可接受的制剂:
其中
A是氢原子;式-NHC(=NR4)NH2或-C(=NR4)NH2的基团,其中R4是氢原子、杂烷基、杂芳烷基、杂环烷基、杂烷基环烷基、羟基或烷氧基,或者R4与基团R1中的一个构成5-或6-元杂芳基或杂环烷基环的一部分;或者A具有以下结构之一:
或
Ar1是芳基、芳烷基、杂芳基或杂芳烷基,
Ar2是芳基、芳烷基、杂芳基或杂芳烷基,
基团R1相互独立地是氢原子,羟基,C1-、C2-、C3-或C4-烷氧基,氨基,C1-、C2-、C3-或C4-烷基氨基,C1-、C2-、C3-或C4-二烷基氨基,氰基或卤原子;
基团R2相互独立地是氢原子,羟基,C1-、C2-、C3-或C4-烷氧基,氨基,C1-、C2-、C3-或C4-烷基氨基,C1-、C2-、C3-或C4-二烷基氨基,氰基或卤原子;
R3是烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基;
G是糖基;
X是以下式的基团:NR5、O、CONR5、NR5CO、CH2NR5、S、SO、SO2、SO2NH、NHSO2、PO2NH、NHPO2、CH2、CHMe或CO,其中R5是氢原子,C1-、C2-、C3-或C4-烷基,C1-、C2-、C3-或C4-杂烷基,C7-、C8-、C9-、C10-、C11-或C12-芳烷基或C6-、C7-、C8-、C9-、C10-、C11-或C12-杂芳烷基;
Y是以下式的基团:CONR6、COCONR6、NR6、O、NR6CO、S、SO、SO2、SO2NH、NHSO2、PO2NH、NHPO2、CH2、CHMe或CO,其中R6是氢原子,C1-、C2-、C3-或C4-烷基,C1-、C2-、C3-或C4-杂烷基或C7-、C8-、C9-、C10-、C11-或C12-、芳烷基;
n是0、1、2、3或4,以及
m是0、1、2、3或4。
以下定义涉及整个说明书,特别是权利要求书:
术语“烷基”是指具有1-20个碳原子、优选1-12个碳原子、特别是1、2、3、4、5或6个碳原子的饱和、直链或支链烃基,例如甲基、乙基、丙基、异丙基、异丁基、叔丁基、n-己基、2,2-二甲基丁基或n-辛基。
术语“烯基”是指包含至少一个双键并具有2-20个碳原子、优选2-12个碳原子、特别是2、3、4、5或6个碳原子的直链或支链烃基,例如乙烯基、烯丙基、异丙烯基或己-2-烯基。它们优选具有一个或者二个(特别是一个)双键。
术语“炔基”是指包含至少一个叁键并具有2-20个碳原子、优选2-12个碳原子、特别是2、3、4、5或6个碳原子的直链或支链烃基,例如乙炔基或丙炔基。它们优选具有一个或者二个(特别是一个)叁键。
另外,术语烷基、烯基和炔基也可以指其中一个、二个、三个或者更多个氢原子被卤原子(优选F或Cl)取代的基团,例如2,2,2-三氯乙基或三氟甲基。
术语“杂烷基”是指其中1个或多个(优选1、2或3个)碳原子相互独立地被氧、氮、磷、硼、硒、硅和/或硫原子(优选氧、硫或氮)替代的烷基、烯基或炔基。术语杂烷基还指羧酸或由羧酸衍生的基团,例如酰基、酰基烷基、烷氧基羰基、酰氧基、酰氧基烷基、羧基烷基酰胺或烷氧基羰基氧基。
杂烷基的例子是以下式的基团:Ra-O-Ya、Ra-S-Ya-、Ra-N(Rb)-Ya-、Ra-CO-Ya-、Ra-O-CO-Ya-、Ra-CO-O-Ya-、Ra-CO-N(Rb)-Ya-、Ra-N(Rb)-CO-Ya-、Ra-O-CO-N(Rb)-Ya-、Ra-N(Rb)-CO-O-Ya-、Ra-N(Rb)-CO-N(Rc)-Ya-、Ra-O-CO-O-Ya-、Ra-N(Rb)-C(=NRd)-N(Rc)-Ya-、Ra-CS-Ya-、Ra-O-CS-Ya-、Ra-CS-O-Ya-、Ra-CS-N(Rb)-Ya-、Ra-N(Rb)-CS-Ya-、Ra-O-CS-N(Rb)-Ya-、Ra-N(Rb)-CS-O-Ya-、Ra-N(Rb)-CS-N(Rc)-Ya-、Ra-O-CS-O-Ya-、Ra-S-CO-Ya-、Ra-CO-S-Ya-、Ra-S-CO-N(Rb)-Ya-、Ra-N(Rb)-CO-S-Ya-、Ra-S-CO-O-Ya-、Ra-O-CO-S-Ya-、Ra-S-CO-S-Ya-、Ra-S-CS-Ya-、Ra-CS-S-Ya-、Ra-S-CS-N(Rb)-Ya-、Ra-N(Rb)-CS-S-Ya-、Ra-S-CS-O-Ya-、Ra-O-CS-S-Ya-,其中Ra是氢原子,C1-、C2-、C3-、C4-、C5-或C6-烷基,C2-、C3-、C4-、C5-或C6-烯基或C2-、C3-、C4-、C5-或C6炔基;Rb是氢原子,C1-、C2-、C3-、C4-、C5-或C6-烷基,C2-、C3-、C4-、C5-或C6-烯基或者C2-、C3-、C4-、C5-或C6炔基;Rc是氢原子,C1-、C2-、C3-、C4-、C5-或C6-烷基,C2-、C3-、C4-、C5-或C6-烯基或C2-、C3-、C4-、C5-或C6炔基;Rd是氢原子,C1-、C2-、C3-、C4-、C5-或C6-烷基,C2-、C3-、C4-、C5-或C6-烯基或者C2-、C3-、C4-、C5-或C6炔基;以及Ya是一个键,C1-、C2-、C3-、C4-、C5-或C6-亚烷基,C2-、C3-、C4-、C5-或C6-亚烯基或者C2-、C3-、C4-、C5-或C6-亚炔基,每个杂烷基包含至少一个碳原子,而且1、2、3或更多个氢原子有可能已被卤原子(特别是氟或氯原子)取代。杂烷基的具体例子是甲氧基、三氟甲氧基、乙氧基、n-丙基氧基、异丙基氧基、叔丁基氧基、甲氧基甲基、乙氧基甲基、甲氧基乙基、甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、异丙基乙基氨基、甲基氨基甲基、乙基氨基甲基、二异丙基氨基乙基、烯醇醚、二甲基氨基甲基、二甲基氨基乙基、乙酰基、丙酰基、丁酰氧基、乙酰氧基、甲氧基羰基、乙氧基羰基、N-乙基-N-甲基氨甲酰基和N-甲基氨甲酰基。杂烷基的进一步例子是腈、异腈、氰酸酯、硫氰酸酯、异氰酸酯、异硫氰酸酯、羰基和烷基腈。
术语“环烷基”是指饱和或部分不饱和(例如环烯基、环炔基)的、具有1个或者多个环(优选1或2个,特别是1个)并包含总共3-14个环碳原子、优选3-10个(特别是3、4、5、6或7)个环碳原子的环基。术语环烷基还指其中一个或者多个氢原子分别独立地被氟、氯、溴或碘原子或者被OH、=O、SH、=S、NH2、=NH或NO2基团取代的相应基团,也就是说例如环酮如环己酮、2-环己烯酮或环戊酮。环烷基的进一步例子是环丙基、环丁基、环戊基、螺[4,5]癸基、降冰片基、环己基、环戊烯基、环己二烯基、萘烷基、立方烷基、二环[4.3.0]壬基、1,2,3,4-四氢萘基、环戊基环己基、氟环己基或环己-2-烯基。
术语“杂环烷基”是指其中1个或多个(优选1、2或3)个环碳原子已相互独立地被氧、氮、硅、硒、磷或硫原子(优选氧、疏或氮)替换的如上所述的环烷基(例如饱和或单不饱和或多不饱和的环烷基,如环烯基)。杂环烷基优选具有1或2个(特别是1个)包含3-10个(特别是3、4、5、6或7个)环原子的环。术语杂环烷基还指其中一个或者多个氢原子分别独立地被氟、氯、溴或碘原子或者被OH、=O、SH、=S、NH2、=NH或NO2基团取代的相应基团。其例子是哌啶基、吗啉基、乌洛托品基、吡咯烷基、四氢硫苯基、四氢吡喃基、四氢呋喃基、氧杂环丙基、氮杂环丙基或2-吡唑啉基以及内酰胺、内酯、环酰胺和环酐。
术语“烷基环烷基”是指包含如上所定义的环烷基以及烷基、烯基或炔基的基团。烷基环烷基优选包含1或2(特别是1)个分别包含3-10(特别是3、4、5、6或7)个环碳原子的环烷基以及1或2个分别包含1或2-6个碳原子的烷基、烯基或炔基。
此等基团的例子是:烷基环烷基、烷基二环烷基、二烷基环烷基、烷基环烯基、烷基二环烯基、二烷基环烯基、烯基环烷基、烯基二环烷基、二烷基二环烷基、烯基环烯基、烯基二环烯基、二烷基二环烷基、二烯基环烷基、二烯基环烯基、炔基环烷基、炔基二环烷基、二烯基二环烷基、炔基环烯基、炔基二环烯基、二烯基二环烯基.
术语“杂烷基环烷基”是指其中1个或多个(优选1、2或3)个碳原子已相互独立地被氧、氮、硅、硒、磷或硫原子(优选氧、硫或氮)替换的如上所述的烷基环烷基。杂烷基环烷基优选包含1或2(特别是1)个分别包含3-10(特别是3、4、5、6或7)个环原子的环以及1或2个分别包含1或2-6个碳原子的烷基、烯基或炔基。该基团可以被烷基、烯基、炔基和/或杂烷基取代,而其例子如下:
杂烷基环烷基、杂烷基二环烷基、二杂-烷基环烷基、杂烷基环烯基、杂烷基二环烯基、二杂烷基环烯基、杂烯基环烷基、杂烯基二环烷基、二杂烷基二环烷基、杂烯基环烯基、杂烯基二环烯基、二杂烷基二环烷基、二杂烯基环烷基、二杂烯基环烯基、杂炔基环烷基、杂炔基二环烷基、二杂烯基二环烷基、杂炔基环烯基、杂炔基二环烯基、二杂烯基二环烯基、烷基杂环烷基、烷基二杂环烷基、二烷基杂环烷基、烷基杂环烯基、烷基二杂环烯基、二烷基杂环烯基、烯基杂环烷基、烯基二杂环烷基、二烷基二杂环烷基、烯基杂环烯基、烯基二杂环烯基、二烷基二杂环烷基、二烯基杂环烷基、二烯基杂环烯基、炔基杂环烷基、炔基二杂环烷基、二烯基二杂环烷基、炔基杂环烯基、炔基二杂环烯基、二烯基二杂环烯基、杂烷基杂环烷基、杂烷基二杂环烷基、二杂烷基杂环烷基、杂烷基杂环烯基、杂烷基二杂环烯基、二杂烷基杂环烯基、杂烯基杂环烷基、杂烯基二杂环烷基、二杂烷基二杂环烷基、杂烯基杂环烯基、杂烯基二杂环烯基、二杂烷基二杂环烷基、二杂烯基杂环烷基、二杂烯基杂环烯基、杂炔基杂环烷基、杂炔基二杂环烷基、二杂烯基二杂环烷基、杂炔基杂环烯基、杂炔基二杂环烯基、二杂烯基二杂环烯基。
特别优选的是:烷基杂环烷基、烷基杂环烯基、烯基杂环烷基、炔基杂环烷基、杂烷基环烷基、杂烷基杂环烷基和杂烷基杂环烯基,其中所述环基可以是饱和或者单、二或三不饱和的。
术语“芳基”或Ar是指具有1个或多个环、优选1个环并包含6-14个环碳原子、优选6-10个(特别是6个)环碳原子的芳香基团。术语芳基(或Ar)还指其中一个或者多个氢原子已相互独立地被氟、氯、溴或碘原子或者被OH、SH、NH2或NO2基团取代的相应基团。其例子有苯基、萘基、联苯基、2-氟苯基、苯胺基、3-硝基苯基或4-羟基苯基。
术语“杂芳基”是指具有1个或者更多个环、优选1个环,包含5-14个环原子、优选5、6、7、8、9或10个(特别是5或6个)环原子,1或多个(优选1、2、3或4个)环原子被置换为氧、氮、磷或硫环原子(优选O、S或N)的芳基。术语杂芳基还指其中一个或者多个氢原子已相互独立地被氟、氯、溴或碘原子或者被OH、SH、NH2或NO2基团取代的相应基团。其例子是4-吡啶基、2-咪唑基、3-苯基吡咯基、噻唑基、噁唑基、三唑基、四唑基、异噁唑基、吲唑基、吲哚基(例如6-吲哚基)、苯并咪唑基、哒嗪基、喹啉基、嘌呤基、咔唑基、吖啶基、嘧啶基、2,3′-联呋喃基、3-吡唑基和异喹啉基。
术语“芳烷基”是指包含如上定义的芳基以及烷基、烯基、炔基和/或环烷基的基团,例如芳基烷基、芳基烯基、芳基炔基、芳基环烷基、芳基环烯基、芳基环炔基、烷基芳基环烷基、烷基芳基环烯基、烷基芳基环炔基、烷基芳基烷基、烷基芳基烯基、烷基芳基炔基、烯基芳基烯基、炔基芳基烯基、炔基芳基炔基和芳基烷基环烷基。芳烷基的具体例子是甲苯基、三苯甲基、二甲苯基、1,3,5-三甲基苯基、苯乙烯、苄基氯、o-氟甲苯、1H-茚基、1,2,3,4-四氢萘基、二氢萘基、2,3-二氢-1-茚酮、苯基环戊基、枯烯、环己基苯基、芴和茚满。芳烷基优选包含具有6-10碳原子的芳香环系(1或2个环) (例如苯基或萘基)以及1或2个分别包含1或2-6碳原子的烷基、烯基和/或炔基和/或包含5或6个环碳原子的环烷基。
术语“杂芳烷基”是指其中1或多个(优选1、2、3或4个)碳原子已分别独立地被氧、氮、硅、硒、磷或硫原子(优选氧、硫或氮)替换的如上所述的芳烷基,也就是说该基团包含根据以上定义的芳基或杂芳基以及烷基、烯基或炔基和/或杂烷基和/或环烷基或环烯基和/或杂环烷基或杂环烯基。杂芳烷基优选包含1或2个分别具有5、6、7、8、9或10个环碳原子的芳香环系(分别包含1或2个环),以及1或2个分别包含1或2、3、4、5或6个碳原子的烷基、烯基和/或炔基和/或包含5或6个环碳原子的环烷基,而且这些碳原子和/或环碳原子中的1、2、3或4个已相互独立地被氧、硫或氮原子置换。
例子是芳基-杂烷基、芳基-杂环烷基、芳基-杂环烯基、芳基-烷基-杂环烷基、芳基-烯基-杂环烷基、芳基-炔基-杂环烷基、芳基-烷基-杂环烯基、芳基-杂烷基-杂环烷基、杂芳基-烷基、杂芳基-烯基、杂芳基-炔基、杂芳基-杂烷基、杂芳基-环烷基、杂芳基-环烯基、杂芳基-杂环烷基、杂芳基-杂环烯基、杂芳基-烷基-环烷基、杂芳基-杂烷基-环烷基、杂芳基-烷基-杂环烯基、杂芳基-杂烷基-环烯基和杂芳基-杂烷基-杂环烷基,该环基是饱和或者单、二或三不饱和的。具体的例子是四氢异喹啉基、苯甲酰基、2-或3-乙基-吲哚基、4-甲基吡啶基、2-、3-或4-甲氧基苯基、4-乙氧基苯基、2-、3-或4-羧基苯基烷基。
术语环烷基、芳基、杂环烷基、烷基环烷基、杂烷基环烷基、杂芳基、芳烷基和杂芳烷基还指其中一个或者多个氢原子分别独立地被氟、氯、溴或碘原子或者被OH、=O、SH、=S、NH2、=NH或NO2基团(其中=O、=S和=NH基团分别替换2个氢原子)取代的基团。
术语“任选取代的”是指其中一个或者多个氢原子分别独立地被氟、氯、溴或碘原子或者被OH、=O、SH、=S、NH2、=NH或NO2基团取代的基团。该术语还指其中1、2或更多个氢原子相互独立地被未取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6杂烷基、C3-C10环烷基、C2-C9杂环烷基、C6-C10芳基、C1-C9杂芳基、C7-C12芳烷基或C2-C11杂芳烷基取代的基团。
在本发明中,术语“糖基”是指通过α-或β-O-、-S-、-N-或-C-糖苷键(优选O-糖苷键)连接的糖(单或寡糖,包括氨基糖和N-乙酰基氨基糖),其中OH基团可任选地用乙酰基或苯甲酰基保护,特别是指单糖(例如葡萄糖、半乳糖、果糖、岩藻糖、核糖、葡糖胺、N-乙酰基葡糖胺、半乳糖胺、N-乙酰基半乳糖胺或甘露糖),优选-D-葡萄糖。
优选的通式(I)化合物是:其中Y是式CONR6的基团,而R3不是式-CHR7-CO-NR8R9的基团,R7、R8和R9相互独立地是氢原子、烷基、烯基、炔基、杂烷基、杂芳烷基、杂芳基、芳烷基、环烷基、杂环烷基、烷基环烷基、杂烷基环烷基或芳基,或者R8和R9一起是杂环烷基或杂芳基环系的一部分。
进一步优选的式(I)化合物是:其中Y是式CO的基团,而R3不是式-NR10-CHR7-CO-NR8R9的基团,R7、R8、R9和R10分别相互独立地是氢原子、烷基、烯基、炔基、杂烷基、杂芳烷基、杂芳基、烷基环烷基、杂烷基-环烷基、芳烷基、环烷基、杂环烷基或芳基,或者R8和R9和/或R7和R10一起是杂环烷基或杂芳基环系的一部分。具体排除的是其中基团-Y-R3具有以下结构的化合物:-C(=O)-NR-CR′R″-C(=O)-N(R)RIV,其中基团R、R′、R″、R和RIV根据希望进行定义或者定义为任意所希望的化学基团。
还优选的是,当A为式-C(=NR4)NH2(特别是-C(=NH)NH2)的基团时,Ar1不是其中A和X相互对位连接的苯基环。
进一步优选的是,A为式-C(=NR4)NH2的基团。
更优选的是,A为氢原子。
还优选的是,R4是氢原子、羟基或C1-、C2-、C3-或C4-烷氧基;特别优选的是,R4为氢原子。
进一步优选的是,Ar1为苯基或包含5、6、7、8、9或10个环原子以及1、2、3或4个选自于O、S和N的杂原子的杂芳基;特别优选的是,Ar1为苯基,特别是其中A和X相互为间位的苯基。
更优选的是,Ar2为苯基或包含5或6个环原子和1、2或3个选自于O、S和N的杂原子的杂芳基;特别优选的是,Ar2为苯基。
还优选的是,X为式NH、NMe或NAc的基团;特别优选的是,X为NH基团。
更优选的是,n为0、1或2,特别是0或1。
进一步优选的是,R1为羟基,在Ar1是苯基时,该羟基特别是连接在与A为对位的位置上。
还优选的是,m为0或1,基团R2和G优选相互为对位;特别优选的是,m为0。
进一步优选的是,Y为式CONH的基团。
更优选的是,R3为式-U-V-W的基团,其中U为任选取代的包含6-10或12个环碳原子的亚芳基或者任选取代的包含5、6、7、8、9或10个环碳原子以及1、2、3或4个(优选1或2个)选自于O、S和N的杂原子的亚杂芳基;V是一个键、氧原子、硫原子、式NR11(其中R11是氢原子,C1-、C2-、C3-或C4-烷基,C1-、C2-、C3-或C4-杂烷基,C7-、C8-、C9-、C10-、C11-或C12-芳烷基或C6-、C7-、C8-、C9-、C10-、C11-或C12-杂芳烷基)、CO、SO、SO2或SO2NH的基团;而W是氢原子、烷基、烯基、炔基、杂烷基、芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基。
特别优选的是,U为任选取代的亚苯基,特别是对亚苯基。
特别更优选的是,V是一个键或者羰基。
特别还优选的是,W为C1-、C2-、C3-或C4-烷基,包含1或2个O、N或S原子的C1-、C2-、C3-或C4-杂烷基,任选取代的苯基,任选取代的C3-、C4-、C5-、C6-或C7-环烷基,任选取代的包含3-7个(优选5或6个)环碳原子以及1、2或3个环杂原子(分别独立地选自于O、S和N)的杂环烷基,或者任选取代的包含5或6个环碳原子以及1、2、3或4个选自于O、S和N的环杂原子的杂芳基。
优选的通式I化合物是,其中Y为式CONR6的基团,而R3不是式-CHR7-CO-NR8R9的基团,R7、R8和R9与Morphochem AG于2002年2月22日的PCT申请PCT/EP02/01934(WO02/068390)中R5、R6和R7或者Morphochem AG于2001年8月23日的PCT申请PCT/EP01/09753(WO02/16312)中的R7、R8和R9的定义相同。
特别优选的是以下式(II)的化合物:
其中E是氢、氟、氯或溴原子,基团R1、R2、G、V和W与以上的定义相同,o是0或1,p是0或1,而q是0、1或2。特别优选的是,R1为羟基,R2为甲氧基或乙氧基,G为-D-葡糖基氧基,而V是一个键或羰基(C=O)。
特别优选的是,W为式-N(CH2CH2)2Q的环基,其中Q是氧原子或式NR12的基团,R12为氢原子,C1-、C2-、C3-或C4-烷基或C1-、C2-、C3-或C4-杂烷基(例如式-C(=N)NH2或-C(=N)CH3的基团)。
进一步优选的是,在式(I)(其中U=苯基)或式(II)的化合物中,V是一个键,W是在相对于V是对位的位置处被SO2NH2或SO2烷基取代的亚苯基。
更优选的是,在式(I)的化合物中,A和Ar1一起代表吲哚基,其中基团X优选连接在6-位处。
还优选的是,在式(I)的化合物中,n是0,A和Ar1一起代表6-吲哚基,X是CONH,m是0,Ar2是苯基,Y是CO,而R3是杂环烷基或杂烷基环烷基(特别是式-N(CH2CH2)2CH-CH(CH2CH2)2NMe的基团),在此情况下特别优选的是,苯基甘氨酸单位处的立体化学是(R)。
由于具有取代基,式(I)或(II)的化合物可包含1个或者多个手性中心。因此,本发明还涉及所有纯的对映体和所有纯的非对映异构体,以及它们以任意混合比的混合物。另外,本发明还包括式(I)或(II)化合物的所有cis/trans异构体以及它们的混合物。本发明还包括式(I)或(II)化合物的所有互变异构体形式。
式(I)或(II)化合物之药物学上可接受的盐的例子是生理学上可接受的无机酸的盐,所述无机酸例如是盐酸、硫酸和磷酸;或者是有机酸的盐,该有机酸例如是甲磺酸、p-甲苯磺酸、乳酸、甲酸、乙酸、三氟乙酸、柠檬酸、琥珀酸、富马酸、马来酸、和水杨酸。式(I)或(II)的化合物可以是溶剂化的,特别是水合的。水合作用可例如在制备过程中发生,或者作为初始无水的式(I)或(II)化合物吸湿性质的结果。
根据本发明的药物组合物包含至少一种式(I)或(II)化合物作为活性成分以及任选的载体物质和/或辅剂。
本发明所涉及的前药(例如B.R.B.Silverman,MedizinischeChemie,VCH Weinheim,1995,Chapter8,p.361ff)由式(I)或(II)的化合物以及至少一个药物学上可接受的保护基组成,该保护基可在生理条件下脱除,例如是羟基、烷氧基、芳烷氧基、酰基或酰氧基,如甲氧基、乙氧基、苄氧基、乙酰基或乙酰氧基。
在此描述的式(I)和(II)化合物可根据本领域技术人员已知的方法来制备。根据本发明的式(I)和(II)化合物可例如如下制备:通过多组分反应使式(III) (如果合适,可为盐酸盐的形式或者类似盐的形式)、(IV)和(V)的化合物反应(A.Dmling,I.Ugi,Angew.Chem.2000,112,3300-3344),其中各基团如上定义。在该方法中,式(III)的化合物优选与式(IV)的化合物一起溶解在合适的溶剂(优选乙腈和水的混合物)中,然后如果需要,进行搅拌(优选在室温下搅拌30分钟)。接着添加式(V)的化合物,如果需要,进一步进行搅拌(优选在室温下搅拌15小时)。优选真空除去任选存在的溶剂。在该方法中制得的化合物例如通过HPLC法进行纯制,并分离为单独的立体异构体。如果需要,可优选在Lewis酸(例如三氯化铟、三氟化硼醚合物、三甲基铝、氯化锂、三氯化铝、三氟甲磺酸钪、氯化锌、三氟甲磺酸镱、三氟甲磺酸镁、溴化镁、氯化锆、氯化钛(IV)或者四氯化锡)或者Brnsted酸存在下进行反应。如果化合物是以此方式得到的,发现在苯基甘氨酸单位处具有(R)构型的式(I)和(II)化合物以及相应的(S)构型的化合物都是非常优选的因子Xa抑制剂,而且当取代相同时,(S)构型的化合物具有略微更好的抑制性质。因此,优选式(I)和(II)化合物具有(S)构型,而具有(R)构型的化合物以及它们任意混合比的化合物也具有非常好的抑制性质,本发明也涉及它们。
或者,式(II)或(III)的化合物可例如类似于以下文献中的方法来制备:WO0230880、WO02057236、WO0112600、WO0071493、WO0071508、WO0071507、WO0035858、WO02068390、WO0216312以及WO0190051。
3-氨基苄脒可市售得到;3-氨基-4-羟基苄脒可如下制备:市售得到的4-羟基-3-硝基苄腈通过Pinner反应(A.Pinner,F.Klein,Ber.10,1889(1877);11,4,1475(1878);16,352,1643(1883))产生4-羟基-3-硝基-苄脒,随后用H2-Pd/C还原。其他的苄脒化合物(例如3-氨基-4-氯-苄脒)也可类似地制备。
糖基化的芳基化合物(例如糖基化的苯甲醛类化合物)例如可以通过以下文献中描述的方法来制备:Kleine等人,Carbo水合物Research1985,142,333-337,以及Brewster等人,Tetrahedron Letters 1979,5051-5054。
水杨醛葡糖苷(水杨醛-β-D-葡糖苷)可市售得到。
本发明的化合物或药物组合物可用于抑制因子Xa的活性,用于预防和/或治疗血栓栓塞病症、动脉再狭窄、败血症、癌症、急性炎症或因子Xa活性介导的其他病症,特别是静脉血栓形成、水肿或炎症、深静脉血栓形成、肺栓塞,较大手术、血管手术、长期不动、下肢骨折等之后的血栓栓塞并发症,动脉血栓形成、特别是心肌梗塞时冠状动脉的血栓形成,以及动脉硬化、脑卒中、心绞痛、间歇性跛行。
通常情况下,如开始时所述,根据本发明的活性成分对因子Xa具有尽可能大的抑制作用,并同时具有尽可能高的选择性。在此情况下,选择性是通过对比对因子Xa以及类胰蛋白酶、胰蛋白酶、血纤维蛋白溶酶、凝血酶和其他丝氨酸蛋白酶的抑制作用而进行评估的。另外令人感兴趣的是,根据本发明的化合物可用作凝血级联(外因和内因性)的其他酶如因子II、因子VII、因子VIIa、因子IX、因子IXa和因子X的抑制剂。
如上所述,式(I)或(II)化合物的治疗应用、其药物学上可接受的盐、溶剂化物和水合物以及制剂和药物组合物也在本发明的范围之内。
本发明还涉及这些活性成分在制备用于预防和/或治疗血栓栓塞病症的药物中的应用。通常情况下,式(I)或(II)的化合物可使用已知和可接受的方法单独或者与其他所希望的治疗剂联合给药。可通过以下途径之一来实施给药:口服,例如为锭剂、包衣片剂、丸剂、半固体物质、软或硬胶囊、溶液、乳液或混悬剂的形式;非胃肠道途径,例如为注射液的形式;直肠途径,以栓剂的形式;吸入给药,例如为粉末制剂或喷雾剂,透皮或鼻内给药。在制备所述片剂、丸剂、半固体物质、包衣片、锭剂和硬明胶胶囊时,治疗有用的产物可与制药惰性的无机或有机载体物质混合,如乳糖、蔗糖、葡萄糖、明胶、麦芽、硅胶、淀粉或其衍生物、滑石、硬脂酸或其盐、脱脂奶粉等。在制备软胶囊时,可以使用药物载体物质如植物油、矿物和动物或合成油、蜡、脂肪和多元醇。在制备液体溶液和糖浆时,可以使用药物载体如水、醇、盐水溶液、葡萄糖水溶液、多元醇、甘油、植物油、矿物和动物或合成油。对于栓剂,可以使用诸如植物油、矿物、动物或合成油、蜡、脂肪和多元醇。对于气雾剂,可以使用对此合适的压缩其他,如氧气、氮气和二氧化碳。药物学上可接受的物质还可包括用于防腐和稳定的添加剂、乳化剂、甜味剂、调味剂、用于改变渗透压的盐、缓冲剂、包胶添加剂和抗氧剂。
与其他治疗级的组合可包括其他通常用于预防和/或治疗血栓栓塞病症时的活性成分,例如华法林等。
为预防和/或治疗上述病症,根据本发明的生物活性化合物的剂量可在宽的范围内变化,并可根据个体需要进行调整。通常情况下,在每日0.1μg-10mg/kg体重范围内的剂量是合适的,该剂量优选为0.1-4mg/kg每日。在合适的情况下,该剂量也可以低于或者高于上述值。
日剂量可例如以1、2、3或4个单独剂量给药。还可以例如1周内以一个单剂量给药。
以下实施例是用于说明本发明。3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基的立体化学相应于β-D-葡萄糖的立体化学,而且实施例58、59和60的立体化学相应于β-D-半乳糖的立体化学。
实施例
总的制备方法
1mmol的胺(III)和1mmol的醛(IV)在20ml的乙腈/水(混合比为1∶0-1∶1)中于室温下搅拌30分钟。接着添加1mmol的异腈(V),并继续搅拌15小时。真空除去溶剂,而残留物通过HPLC进行纯制。
实施例1:2-(3-脒基-苯基氨基)-N-(2-三氟甲基-苄基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C29H31F3N4O7(604.5882)
ESI-TOF MS:605[M+H]
实施例2:2-(3-脒基-苯基氨基)-N-(2,3-二氢-苯并[1,4]二噁烯-6-基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C29H32N4O9(580.5998)
ESI-TOF MS:581[M+H]
实施例3:2-(3-脒基-苯基氨基)-N-[3-(2-氧代-吡咯烷-1-基)-丙基]-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C28H37N5O8(571.6358)
ESI-TOF MS:572[M+H]
实施例4:2-(3-脒基-苯基氨基)-N-(4-苯氧基-苯基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C33H34N4O8(614.6609)
ESI-TOF MS:615[M+H]
实施例5:2-(3-脒基-苯基氨基)-N-(3,3-二苯基-丙基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C36H40N4O7(640.7428)
ESI-TOF MS:641[M+H]
实施例6:2-(3-脒基-苯基氨基)-N-(3-苯氧基-苯基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C33H34N4O8(614.6609)
ESI-TOF MS:615[M+H]
实施例7:2-(3-脒基-苯基氨基)-N-(4-甲氧基-联苯基-3-基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C34H36N4O8(628.6880)
ESI-TOF MS:629[M+H]
实施例8:2-(3-脒基-苯基氨基)-N-(4-吗啉-4-基-苯基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C31H37N5O8(607.6692)
ESI-TOF MS:608[M+H]
实施例9:2-(3-脒基-苯基氨基)-N-(4-苯甲酰基-苯基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C34H34N4O8(626.6721)
ESI-TOF MS:627[M+H]
实施例10:2-(3-脒基-苯基氨基)-N-(3-苯甲酰基-苯基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C34H34N4O8(626.6721)
ESI-TOF MS:627[M+H]
实施例11:2-(3-脒基-苯基氨基)-N-(4-叔丁基-苄基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C32H40N4O7(592.6982)
ESI-TOF MS:593[M+H]
实施例12:2-(2-羟基-5-脒基-苯基氨基)-N-(4-吗啉-4-基-苯基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C31H37N5O9(623.6686)
ESI-TOF MS:624[M+H]
实施例13:2-(3-脒基-苯基氨基)-N-(3-甲氧基-苄基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C29H34N4O8(566.6163)
ESI-TOF MS:567[M+H]
实施例14:N-(4-乙酰基-苯基)-2-(3-脒基-苯基氨基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C29H32N4O8(564.6004)
ESI-TOF MS:565[M+H]
实施例15:2-(3-脒基-苯基氨基)-N-(3-三氟甲基-苄基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C29H31F3N4O7(604.5882)
ESI-TOF MS:605[M+H]
实施例16:2-(3-脒基-苯基氨基)-N-(2-环己-1-烯基-乙基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C29H38N4O7(554.6488)
ESI-TOF MS:555[M+H]
实施例17:2-(3-脒基-苯基氨基)-N-[2-(3,4-二甲氧基-苯基)-乙基]-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C31H38N4O9(610.6699)
ESI-TOF MS:611[M+H]
实施例18:2-(3-脒基-苯基氨基)-N-(3-吗啉-4-基-丙基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C28H39N5O8(573.6517)
ESI-TOF MS:574[M+H]
实施例19:2-(3-脒基-苯基氨基)-N-(4-三氟甲基-苄基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C29H31F3N4O7(604.5882)
ESI-TOF MS:605[M+H]
实施例20:N-[1-(4-溴-苯基)-乙基]-2-(3-脒基-苯基氨基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C29H33BrN4O7(629.5130)
ESI-TOF MS:630[M+H]
实施例21:N-苯并[1,3]间二氧杂环戊烯-5-基甲基-2-(3-脒基-苯基氨基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C29H32N4O9(580.5998)
ESI-TOF MS:581[M+H]
实施例22:2-(3-脒基-苯基氨基)-N-(3-苯基-丙基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C30H36N4O7(564.6440)
ESI-TOF MS:565[M+H]
实施例23:2-(3-脒基-苯基氨基)-N-(3,5-二甲基-苄基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C30H36N4O7(564.6440)
ESI-TOF MS:565[M+H]
实施例24:2-(3-脒基-苯基氨基)-N-(3-氰基-苯基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C28H29N5O7(547.5726)
ESI-TOF MS:548[M+H]
实施例25:2-(3-脒基-苯基氨基)-N-(3,4-二氯-苄基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C28H30C12N4O7(605.4799)
ESI-TOF MS:606[M+H]
实施例26:N-(3-乙酰基-苯基)-2-(3-脒基-苯基氨基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C29H32N4O8(564.6004)
ESI-TOF MS:565[M+H]
实施例27:2-(3-脒基-苯基氨基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-N-(1,2,2-三甲基-丙基)-乙酰胺
C27H38N4O7(530.6265)
ESI-TOF MS:531[M+H]
实施例28:N-烯丙基-2-(3-脒基-苯基氨基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C24H30N4O7(486.5293)
ESI-TOF MS:487[M+H]
实施例29:N-(3-丁氧基-丙基)-2-(3-脒基-苯基氨基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C28H40N4O8(560.6530)
ESI-TOF MS:561[M+H]
实施例30:2-(3-脒基-苯基氨基)-N-(3,7-二甲基-辛-2,6-二烯基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C31H42N4O7(582.7030)
ESI-TOF MS:583[M+H]
实施例31:2-(3-脒基-苯基氨基)-N-呋喃-2-基甲基-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C26H30N4O8(526.5510)
ESI-TOF MS:527[M+H]
实施例32:2-(3-脒基-苯基氨基)-N-(3-异丙氧基-丙基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C27H38N4O8(546.6259)
ESI-TOF MS:547[M+H]
实施例33:3-{2-(3-脒基-苯基氨基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰基氨基}-丙酸乙酯
C26H34N4O9(546.5823)
ESI-TOF MS:547[M+H]
实施例34:N-叔丁基-2-(3-脒基-苯基氨基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C25H34N4O7(502.5723)
ESI-TOF MS:503[M+H]
实施例35:2-(3-脒基-苯基氨基)-N-吡啶-4-基甲基-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C27H31N5O7(537.5774)
ESI-TOF MS:538[M+H]
实施例36:2-(3-脒基-苯基氨基)-N-甲基-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C22H28N4O7(460.4911)
ESI-TOF MS:461[M+H]
实施例37:2-(3-脒基-苯基氨基)-N-(1,3-二甲基-丁基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C27H38N4O7(530.6265)
ESI-TOF MS:531[M+H]
实施例38:N-(4-苯甲酰基-苯基)-2-(3-脒基-苯基氨基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C34H34N4O8(626.6721)
ESI-TOF MS:627[M+H]
实施例39:2-(5-脒基-2-羟基-苯基氨基)-N-(4-吗啉-4-基-苯基)-2-[2-(3,4,5-三羟基-6-羟基-甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C31H37N5O9(623.6686)
ESI-TOF MS:624[M+H]
实施例40:2-(3-脒基-苯基氨基)-N-(2,6-二甲基-苯基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C29H34N4O7(550.6169)
ESI-TOF MS:551[M+H]
实施例41:2-(3-脒基-苯基氨基)-N-(4-硝基-苯基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C27H29N5O9(567.5603)
ESI-TOF MS:568[M+H]
实施例42:N-(4-氨基-苯基)-2-(3-脒基-苯基氨基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C27H31N5O7(537.5774)
ESI-TOF MS:538[M+H]
实施例43:2-{2-(3-脒基-苯基氨基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰基氨基}-苯甲酸甲酯
C29H32N4O9(580.5998)
ESI-TOF MS:581[M+H]
实施例44:2-(5-脒基-2-氯-苯基氨基)-N-(4-吗啉-4-基-苯基)-2-[2-(3,4,5-三羟基-6-羟基-甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C31H36ClN5O8(642.1143)
ESI-TOF MS:643[M+H]
实施例45:2-(3-脒基-苯基氨基)-N-[4-(吗啉-4-羰基)-苯基]-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C32H37N5O9(635.6798)
ESI-TOF MS:636[M+H]
实施例46:2-(5-脒基-2-甲基氨基-苯基氨基)-N-(4-吗啉-4-基-苯基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C32H40N6O8(636.7110)
ESI-TOF MS:637[M+H]
实施例47:N-(2-溴-苯基)-2-(3-脒基-苯基-氨基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C27H29BrN4O7(601.4588)
ESI-TOF MS:602[M+H]
实施例48:2-{2-(3-脒基-苯基氨基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰基氨基}-苯甲酸
C28H30N4O9(566.5727)
ESI-TOF MS:567[M+H]
实施例49:2-(3-脒基-苯基氨基)-N-喹啉-6-基-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C30H31N5O7(573.6109)
ESI-TOF MS:574[M+H]
实施例50:2-{2-{3-[N-(3-氟-苄基)-脒基]-苯基氨基}-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰基氨基}-苯甲酸甲酯
C36H37FN4O9(688.7161)
ESI-TOF MS:689[M+H]
实施例51:N-(2-苯甲酰基-4-氯-苯基)-2-(3-脒基-苯基氨基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C34H33ClN4O8(661.1171)
ESI-TOF MS:662[M+H]
实施例52:2-(3-脒基-苯基氨基)-N-[3-氯-4-(吗啉-4-羰基)-苯基]-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C32H36ClN5O9(670.1248)
ESI-TOF MS:671[M+H]
实施例53:2-(3-脒基-苯基氨基)-N-[2-甲基-4-(吗啉-4-羰基)-苯基]-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C33H39N5O9(649.7069)
ESI-TOF MS:650[M+H]
实施例54:2-(5-脒基-2-羟基-苯基氨基)-N-[4-(吗啉-4-羰基)-苯基]-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C32H37N5O10(651.6792)
ESI-TOF MS:652 [M+H]
实施例55:2-(3-脒基-苯基氨基)-N-(3,4-二氟-苯基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C27H28F2N4O7(558.5436)
ESI-TOF MS:559[M+H]
实施例56:4-{2-(3-脒基-苯基氨基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰基氨基}-苯甲酸甲酯
C29H32N4O9(580.5998)
ESI-TOF MS:581[M+H]
实施例57:2-(3-脒基-苯基氨基)-N-(3,4-二甲氧基-苯基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C29H34N4O9(582.6157)
ESI-TOF MS:583[M+H]
实施例58:乙酸3,4,5-三乙酰氧基-6-{2-[(5-脒基-2-羟基-苯基氨基)-(4-吗啉-4-基-苯基氨甲酰基)-甲基]-苯氧基}-四氢吡喃-2-基甲基酯
C39H45N5O13(791.8192)
ESI-TOF MS:792[M+H]
实施例59:2-(3-脒基-苯基氨基)-N-(4-吗啉-4-基-苯基)-2-[2-(3,4,5-三羟基-6-羟基-甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C31H37N5O8(607.6692)
ESI-TOF MS:608[M+H]
实施例60:2-(5-脒基-2-羟基-苯基氨基)-N-(4-吗啉-4-基-苯基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C31H37N5O9(623.6686)
ESI-TOF MS:624[M+H]
实施例61:2-(3-脒基-苯基氨基)-N-(4-甲氧基-苯基)-2-[2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-乙酰胺
C28H32N4O8(552.5892)
ESI-TOF MS:553[M+H]
实施例62:2-(3-脒基-苯基氨基)-2-[3-乙氧基-2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-N-[4-(吗啉e-4-羰基)-苯基]-乙酰胺
C34H41N5O10(679.7334)
ESI-TOF MS:680[M+H]
实施例63:2-(3-脒基-苯基氨基)-2-[3-乙氧基-2-(3,4,5-三羟基-6-羟甲基-四氢吡喃-2-基氧基)-苯基]-N-(4-吗啉-4-基-苯基)-乙酰胺
C33H41N5O9(651.7228)
ESI-TOF MS:652[M+H]
为证实对因子Xa活性的抑制作用,使用生色肽底物。如下证实上述化合物对因子Xa的酰胺分解活性的抑制作用。在室温下于微量滴定板上进行测量。将化合物溶解在二甲基亚砜中,并将5μl的该溶液(1mM、100μM、10μM、1μM)添加至35μl的2.15nM人重组因子Xa(Enzyme Research Laboratories,South Bend,IN,美国)在缓冲液(pH:8.0,并使用50mM Tris-HCl、100mM NaCl,0.1%PEG 6000和0.05%Tween 80)中的溶液内。最后,添加在缓冲液中的10μl的25μMMeSO2-D-CHA-Gly-Arg-AMC乙酸盐溶液(“Spectrozym fXa”,American Diagnostica,Pfungstadt,德国),然后在以下波长用SpectraFluor Plus分光光度计(Tecan,Crailsheim,德国)在20分钟的时间内监测底物的水解:激发:360nm,发射:465nm。用Erithacus SoftwareLtd.(Staines,Middlesex,UK)公司的“GraFit4”程序计算IC50值。假设动力学包括竞争性抑制作用,则可通过以下的Cheng-Prusoff方程确定Ki值:Ki=IC50/(1+[S]/Km))(Cheng和Prusoff BiochemicalPharmacology 1973,22:3099-3108)。使用相同的方法,但使用甲苯磺酰基-甘氨酰基-脯氨酰基-赖氨酸-4-苯基重氮酸乙酸盐作为在肝素缓冲液(pH7.8)中的底物,以测定所述化合物对重组人类胰蛋白酶(Promega,Madison,WI,美国)的解蛋白活性的抑制作用。
上述实施例中的化合物的IC50值都在0.1nM-1μM的范围内。
Claims (8)
1、式(I)的化合物:
其中
A是式-C(=NH)NH2的基团;
Ar1是苯基;
Ar2是苯基;
基团R1相互独立地是羟基、C1-C4烷氧基、C1-C4烷基氨基、或卤原子;
基团R2相互独立地是羟基、或C1-C4-烷氧基;
R3是任选取代的苯基;任选取代的喹啉基;任选取代的芳烷基,其包含C1-6烷基以及一个或者两个苯环;任选取代的烷基环烷基,其包含C1-6烷基以及包含5或6个环原子且其中一个或者两个碳原子任选地被氧原子或者氮原子替代的环烷基;任选取代的烷基杂芳基,其包含C1-6烷基以及包含5或6个环原子的杂芳基,所述环原子中包括一个或者两个氮原子、硫原子和/或氧原子;任选取代的烷基芳基杂环烷基,其包含C1-6烷基、苯基、以及5或者6元包含两个氧原子的杂环烷基;任选取代的芳基杂环烷基,其包含苯基、以及5或者6元包含两个氧原子的杂环烷基,其中一个或者两个碳原子任选地被氧原子替代的C1-12烷基;其中一个或者多个碳原子任选地被氧原子替代的C2-12烯基;或者式U-V-W的基团,其中U是任选取代的苯基;V是直接键、氧原子、或羰基;而W是C1-4烷基、C1-4杂烷基、任选取代的苯基、任选取代的C3-7环烷基、任选取代的包含3-7个环原子以及1、2或3个选自于O、S和N的杂原子的杂环烷基或者任选取代的包含5或6个环原子以及1、2、3或4个选自于O、S和N的杂原子的杂芳基;其中术语“任选取代的”是指其中一个、两个或者多个氢原子任选地被F、Cl、Br、NH2、NO2、=O、C1-6烷基、甲氧基、CN或者COOH取代的基团;
G是糖基;
X是NH;
Y是CONH;
n是0或者1,以及
m是0或者1;
或其药物学上可接受的盐、或水合物。
2、如权利要求1所述的化合物,其中Ar1是A和X相互之间为间位连接的苯基。
3、如权利要求1或2所述的化合物,其中R1是羟基。
4、如权利要求1、2或3所述的化合物,其中R3是式-U-V-W的基团,其中U、V和W如权利要求1中所定义。
5、药物组合物,其包含如权利要求1、2、3或4所述的化合物以及任选的载体物质和/或辅剂。
6、如权利要求1、2、3、4或5所述的化合物或药物组合物在制备用于抑制因子Xa的药物中的应用。
7、如权利要求1、2、3、4或5所述的化合物或药物组合物在制备用于治疗和/或预防血栓栓塞病症、动脉再狭窄、败血症、癌症、急性炎症或者因子Xa活性介导的其他病症的药物中的应用。
8、如权利要求1、2、3、4或5所述的化合物或药物组合物在制备用于血管手术的药物中的应用。
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DE10204072.9 | 2002-01-31 | ||
DE10204072A DE10204072A1 (de) | 2002-01-31 | 2002-01-31 | Neue Verbindungen, die Faktor Xa-Aktivität inhibieren |
DE10300049.6 | 2003-01-03 | ||
DE10300049A DE10300049A1 (de) | 2003-01-03 | 2003-01-03 | Neue Verbindungen, die Faktor VIIa inhibieren |
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CN1322001C true CN1322001C (zh) | 2007-06-20 |
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KR (1) | KR20040096541A (zh) |
CN (1) | CN1322001C (zh) |
AT (1) | ATE377017T1 (zh) |
BR (1) | BR0307266A (zh) |
CA (1) | CA2473169A1 (zh) |
DE (1) | DE50308492D1 (zh) |
MX (1) | MXPA04007461A (zh) |
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EP2283833A3 (en) * | 2004-02-25 | 2013-07-10 | La Jolla Pharmaceutical Co. | Amines and amides for the treatment of diseases |
ES2365815T3 (es) * | 2005-12-14 | 2011-10-11 | Bristol-Myers Squibb Company | Análogos de arilpropionamida, arilacrilamida, arilpropinamida o arilmetilurea como inhibidores del factor xia. |
WO2007070826A1 (en) * | 2005-12-14 | 2007-06-21 | Bristol-Myers Squibb Company | Arylpropionamide, arylacrylamide, arylpropynamide, or arylmethylurea analogs as factor xia inhibitors |
WO2017156071A1 (en) | 2016-03-09 | 2017-09-14 | Blade Therapeutics, Inc. | Cyclic keto-amide compounds as calpain modulators and methods of production and use thereof |
US11292801B2 (en) | 2016-07-05 | 2022-04-05 | Blade Therapeutics, Inc. | Calpain modulators and therapeutic uses thereof |
AU2017336523B2 (en) | 2016-09-28 | 2022-07-21 | Blade Therapeutics, Inc. | Calpain modulators and therapeutic uses thereof |
Citations (5)
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EP0290321A1 (fr) * | 1987-05-04 | 1988-11-09 | Fournier Industrie Et Sante | Nouveaux beta-D-phényl-thioxylosides, leur procédé de préparation et leur application en thérapeutique |
EP0560568A2 (en) * | 1992-03-13 | 1993-09-15 | Takeda Chemical Industries, Ltd. | Hydroquinone derivatives and intermediates for production thereof |
EP0921116A1 (de) * | 1997-12-04 | 1999-06-09 | F. Hoffmann-La Roche Ag | N-(4-carbamimido-phenyl)-glycinamidderivate |
WO1999065934A1 (en) * | 1998-06-17 | 1999-12-23 | Akzo Nobel N.V. | Antithrombotic compounds |
EP1078917A1 (en) * | 1998-02-17 | 2001-02-28 | Ono Pharmaceutical Co., Ltd. | Amidino derivatives and drugs containing the same as the active ingredient |
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DE10041402A1 (de) * | 2000-08-23 | 2002-03-14 | Morphochem Ag | Neue Verbindungen, die Faktor Xa-Aktivität inhibieren |
ATE323071T1 (de) * | 2000-11-22 | 2006-04-15 | Astellas Pharma Inc | Substituierte phenolderivate und deren salze als hemmstoffe von koagulations faktor x |
-
2003
- 2003-01-31 AT AT03734605T patent/ATE377017T1/de not_active IP Right Cessation
- 2003-01-31 PL PL03369772A patent/PL369772A1/xx not_active Application Discontinuation
- 2003-01-31 CA CA002473169A patent/CA2473169A1/en not_active Abandoned
- 2003-01-31 CN CNB038031558A patent/CN1322001C/zh not_active Expired - Fee Related
- 2003-01-31 BR BR0307266-5A patent/BR0307266A/pt not_active IP Right Cessation
- 2003-01-31 KR KR10-2004-7011732A patent/KR20040096541A/ko not_active Application Discontinuation
- 2003-01-31 DE DE50308492T patent/DE50308492D1/de not_active Expired - Fee Related
- 2003-01-31 MX MXPA04007461A patent/MXPA04007461A/es active IP Right Grant
- 2003-01-31 JP JP2003564060A patent/JP2005525325A/ja active Pending
- 2003-01-31 US US10/501,932 patent/US20050049283A1/en not_active Abandoned
- 2003-01-31 WO PCT/EP2003/001011 patent/WO2003064440A1/de active IP Right Grant
- 2003-01-31 EP EP03734605A patent/EP1470143B1/de not_active Expired - Lifetime
- 2003-01-31 NZ NZ534238A patent/NZ534238A/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0290321A1 (fr) * | 1987-05-04 | 1988-11-09 | Fournier Industrie Et Sante | Nouveaux beta-D-phényl-thioxylosides, leur procédé de préparation et leur application en thérapeutique |
EP0560568A2 (en) * | 1992-03-13 | 1993-09-15 | Takeda Chemical Industries, Ltd. | Hydroquinone derivatives and intermediates for production thereof |
EP0921116A1 (de) * | 1997-12-04 | 1999-06-09 | F. Hoffmann-La Roche Ag | N-(4-carbamimido-phenyl)-glycinamidderivate |
EP1078917A1 (en) * | 1998-02-17 | 2001-02-28 | Ono Pharmaceutical Co., Ltd. | Amidino derivatives and drugs containing the same as the active ingredient |
WO1999065934A1 (en) * | 1998-06-17 | 1999-12-23 | Akzo Nobel N.V. | Antithrombotic compounds |
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NZ534238A (en) | 2006-09-29 |
ATE377017T1 (de) | 2007-11-15 |
BR0307266A (pt) | 2004-12-07 |
MXPA04007461A (es) | 2005-07-13 |
CN1625559A (zh) | 2005-06-08 |
PL369772A1 (en) | 2005-05-02 |
JP2005525325A (ja) | 2005-08-25 |
EP1470143B1 (de) | 2007-10-31 |
CA2473169A1 (en) | 2003-08-07 |
US20050049283A1 (en) | 2005-03-03 |
WO2003064440A1 (de) | 2003-08-07 |
KR20040096541A (ko) | 2004-11-16 |
EP1470143A1 (de) | 2004-10-27 |
DE50308492D1 (de) | 2007-12-13 |
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