CN1498206A - 二尿烷衍生物 - Google Patents
二尿烷衍生物 Download PDFInfo
- Publication number
- CN1498206A CN1498206A CNA028067584A CN02806758A CN1498206A CN 1498206 A CN1498206 A CN 1498206A CN A028067584 A CNA028067584 A CN A028067584A CN 02806758 A CN02806758 A CN 02806758A CN 1498206 A CN1498206 A CN 1498206A
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- CN
- China
- Prior art keywords
- oxo
- compound
- phenyl
- base
- aminocarboxyl
- Prior art date
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Abstract
式I的新化合物,其中X、Y、Z、R、R1、R2和R3如专利要求1所定义,是凝血因子Xa的抑制剂,它可用于预防和/或治疗血栓栓塞疾病和治疗肿瘤。
Description
本发明涉及式I化合物及其药学上有用的衍生物、溶剂合物和立体异构体,包括它们呈各种比例的混合物。
其中
R为H、Hal或CN,
R1为H、A或(CH2)n-Ar,
R2为H或Hal,
R3为H、未被取代或被SO2A、SO2NHA或SO2NH2一取代的苯基,
或Het,
X为(CH2)n,
Y不存在或为哌啶-1,4-二基,
Z为CH或N,
Ar为未取代或被以下基团一取代或二取代的苯基:Hal、苯基、A、OH、OA、NH2、NHA、NA2、NO2、CN、COOH、COOA、CONH2、CONHA、CONA2、NHCHO、NACHO、NHCOA、NACOA、NHSO2A、NASO2A、CHO、COA、SO2NH2、SO2NHA或SO2NA2,
Het为有1-4个N、O和/或S原子的单环饱和、不饱和或芳族杂环基,它可未被取代或可被羰基氧、Hal、A、OH、OA、NH2、NHA、NA2、NO2、CN、COOH、COOA、CONH2、CONHA、CONA2、NHCHO、NACHO、NHCOA、NACOA、NHSO2A、NASO2A、CHO、COA、SO2NH2、SO2NHA或SO2NA2一取代或二取代,
A为有1-6个碳原子的直链或支链烷基,其中一或两个CH2基可被O或S原子和/或被-CH=CH-基团取代,和/或另外1-7个H原子可被F取代,
Hal为F、Cl、Br或I,
n为0、1或2。
本发明的目的是寻找具有有价值的性质的新化合物,尤其是可用于制备药物的那些化合物。
已发现式I化合物及其盐具有极有价值的药理学性质并有好的耐受性。特别是它们表现出抑制Xa因子的性质,因而可用于治疗或预防血栓栓塞疾病,例如,血栓形成、心肌梗死、动脉硬化、炎症、中风、心绞痛、血管成形术的术后再狭窄和间歇性跛行。
根据本发明的式I化合物还可作为血液凝血级联系统中的凝血因子VIIa、因子IXa和凝血酶的抑制剂。
有抗血栓形成作用的芳族脒衍生物已公开于,例如,EP0 540 051B1、WO98/28269、WO00/71508、WO00/71511、WO00/71493、WO00/71507、WO00/71509、WO00/71512、WO00/71515或WO00/71516中。例如,治疗血栓栓塞疾病的环胍描述于WO97/08165中。例如,具有凝血因子Xa-抑制活性的芳族杂环化合物公开于WO96/10022中。作为凝血因子Xa抑制剂的被取代的N-[(氨基亚氨基甲基)苯基烷基]氮杂杂环酰胺类描述于WO96/40679中。
根据本发明的化合物的抗血栓栓塞和抗凝作用归因于这些化合物对称作激活凝血蛋白酶(已知为因子Xa)的抑制作用,或归因于对其它激活的丝氨酸蛋白酶如因子VIIa、因子IXa或凝血酶的抑制作用。
因子Xa是涉及血液凝固的复杂过程的蛋白酶之一。因子Xa催化凝血酶原转化为凝血酶。凝血酶使纤维蛋白原裂解为纤维蛋白单体,所述纤维蛋白单体交联后,对血栓形成起基本的促进作用。凝血酶的激活会导致血栓栓塞性疾病的发生。因此,抑制凝血酶可抑制涉及血栓形成的纤维蛋白的生成。可以例如通过G.F.Cousins等在Circulation 1996,94,1705-1712中所述的方法,测定对凝血酶的抑制作用。
因此,抑制因子Xa可防止凝血酶的生成。
因而,本发明的式I化合物及其盐通过抑制因子Xa而参与血液的凝固过程,从而抑制血栓形成。
通过常规体外或体内方法,可以测定本发明化合物对因子Xa的抑制作用以及测定抗凝剂和抗血栓药物的活性。合适的方法如由J.Hauptmann等在Thrombosis和Haemostasis 1990,63,220-223中所述。
例如可以采用T.Hara等在Thromb Haemostas 1994,71,314-319中所述的方法,测定对因子Xa的抑制作用。
在与组织因子结合后,凝血因子VIIa启动凝血级联系统的外在部分并促使因子X激活成为因子Xa。因此,抑制因子VIIa可以防止因子Xa的形成以及随后的凝血酶形成。
通过常规体外或体内方法,可以测定本发明化合物对因子VIIa的抑制作用以及测定抗凝剂和抗血栓药物的活性。例如由H.F.Ronning等在Thrombosis Research 1996,84,73-81中叙述了用于测定对因子VIIa的抑制作用的常规方法。
血液凝固因子IXa是在内源性凝血级联系统中产生的,同样,该因子涉及因子X激活成为因子Xa。因此抑制因子IXa可以以不同方式防止形成因子Xa。
通过常规体外或体内方法,可以测定本发明化合物对因子IXa的抑制作用以及测定抗凝剂和抗血栓药物的活性。合适的方法如J.Chang等在Journal of Biological Chemistry 1998,273,12089-12094中所述。
此外,本发明的化合物可以用于治疗肿瘤、肿瘤性疾病和/或肿瘤转移。T.Taniguchi和N.R.Lemoine在Biomed.Health Res.(2000),41(Molecular Pathogenesis of Pancreatic Cancer),57-59中已经阐述了组织因子TF/因子VIIa与各种类型的癌症发生之间的相关关系。
下列出版物描述了TF-VII和凝血因子Xa抑制剂对各种肿瘤的抗肿瘤作用;
K.M.Donnelly等,Thromb.Haemost.1998;79:1041-1047;
E.G.Fischer等,J.Clin.Invest.104:1213-1221(1999);
B.M.Mueller等,J.Clin.Invest.101:1372-1378(1998);
M.E.Bromberg等,Thromb.Haemost.1999;82:88-92。
式I的化合物可以在人类医学和兽医中用作药物活性成分,尤其是用于治疗和预防血栓栓塞性疾病,如血栓形成、心肌梗死、动脉硬化、炎症、中风、心绞痛、血管成形术后的再狭窄、间歇性跛行、静脉血栓形成、肺栓塞、动脉血栓形成、心肌缺血、不稳定型心绞痛和血栓形成性中风。
本发明的化合物也可以用于治疗或预防动脉粥样硬化疾病,如冠状动脉疾病、脑动脉疾病或外周动脉疾病。
所述化合物也与其它血栓溶解剂联合用于心肌梗死,此外还用于预防血栓形成、经皮经腔血管成形术(PTCA)以及冠状动脉分流术后的再闭塞。
本发明的化合物还可以用于防止显微外科手术中的再次血栓形成,还可以在人造器官或血液透析中作为抗凝剂。
所述化合物还可以用于清洁病人体内的导管和医用辅助器,或者作为抗凝剂用于体外血液、血浆和其它血液制品的保存。本发明的化合物还可以用于其中血液凝固对疾病过程起关键作用或者血液凝固是继发性病理改变的原因的疾病,如癌症(包括转移)、炎性疾病(包括关节炎)以及糖尿病。
在所述疾病的治疗中,本发明的化合物也与其它具有血栓溶解活性的化合物如与“组织纤溶酶原激活剂”t-PA、修饰的t-PA、链激酶或尿激酶联合使用。本发明的化合物可以与上述的其它物质同时或在其前或其后给药。
为了防止发生血栓形成的复发,特别优选与阿斯匹林同时给药。
本发明的化合物也与抑制血小板聚集的血小板糖蛋白受体(IIb/IIIa)拮抗剂联合使用。
本发明涉及式I化合物及其盐,涉及根据权利要求1的式I化合物及其盐的制备方法,其特征在于
式II化合物
其中
R和R1如权利要求1所定义,
与式III化合物反应
其中R2、R3、X、Y和Z如权利要求1所定义,
和/或
式I的碱或酸被转化为它的一种盐。
本发明还涉及这些化合物的光学活性形式(立体异构体),对映体、外消旋体、非对映异构体和水合物及溶剂合物。术语所述化合物的溶剂合物是指惰性溶剂分子对所述化合物的加成,其生成归因于它们相互间的吸引力。例如,溶剂合物有一水合物或二水合物或醇化物。
术语药学上有用的衍生物是指,例如,根据本发明的化合物的盐,也是所谓的前药化合物。
术语前药衍生物是指,例如,已被例如,烷基、酰基、糖或低聚肽修饰的式I化合物,且其在有机体中快速裂解,生成根据本发明的有效化合物。
这些化合物也包括根据本发明的可生物降解的聚合物衍生物,例如,如Int.J.Pharm.
115,61-67(1995)中所述。
本发明还涉及根据本发明的式I化合物的混合物,例如,两种非对映异构体,例如,呈1∶1、1∶2、1∶3、1∶4、1∶5、1∶10、1∶100或1∶1000的比例的混合物。
这些是特别优选的立体异构化合物的混合物。
对所有出现不止一次的基团而言,例如,A,它们的意义相互独立。
上下文中,基团或参数R、X、Y、R1、R2和R3如式I所定义,除非另有说明。
A为无支链(直链)或支链的烷基,且有1、2、3、4、5、6、7、8、9或10个碳原子。A优选为甲基,此外还有乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基,此外还有戊基、1-、2-或3-甲基丁基、1,1-、1,2-或2,2-二甲基丙基、1-乙基丙基、己基、1-、2-、3-或4-甲基戊基、1,1-、1,2-、1,3-、2,2-、2,3-或3,3-二甲基丁基、1-或2-乙基丁基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基、1,1,2-或1,2,2-三甲基丙基,此外还优选,例如,三氟甲基。
A特别优选为有1-6个碳原子的烷基,优选甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、己基、三氟甲基、五氟代乙基或1,1,1-三氟代乙基。
环烷基优选,例如,环丙基、环丁基、环戊基、环己基或环庚基。
亚烷基优选亚甲基、亚乙基、亚丙基、亚丁基、亚戊基或亚己基,还有支链亚烷基。
-COA(酰基)优选乙酰基、丙酰基,还有丁酰基、戊酰基、己酰基或例如,苯甲酰基。
Ph为苯基,Me为甲基,Et为乙基,
Hal优选为F、Cl或Br,还有I。
R1优选H,有1、2、3、4、5或6个碳原子的烷基、苯基或苄基。
R2优选H、F或Cl。
R3优选单-SO2A-取代的苯基或Het。
Ar为例如,未取代苯基、萘基或联苯基,此外还优选例如被A、氟、氯、溴、碘、羟基、甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基、硝基、氰基、甲酰基、乙酰基、丙酰基、三氟甲基、氨基、甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、苄氧基、亚磺酰氨基、甲基亚磺酰氨基、乙基亚磺酰氨基、丙基亚磺酰氨基、丁基亚磺酰氨基、二甲基亚磺酰氨基、苯基亚磺酰氨基、羧基、甲氧基羰基、乙氧基羰基或氨基羰基一取代、二取代或三取代的苯基、萘基或联苯基。
Ar特别优选为,例如,未取代或被Hal、A、OH或甲氧基一取代或二取代的苯基。
Het为例如2-或3-呋喃基、2-或3-噻吩基、1-、2-或3-吡咯基、1-、2-、4-或5-咪唑基、1-、3-、4-或5-吡唑基、2-、4-或5-噁唑基、3-、4-或5-异噁唑基、2-、4-或5-噻唑基、3-、4-或5-异噻唑基、2-、3-或4-吡啶基、2-、4-、5-或6-嘧啶基,还优选1,2,3-三唑-1-、-4-或-5-基、1,2,4-三唑-1-、-3-或-5-基、1-或5-四唑基、1,2,3-噁二唑-4-或-5-基、1,2,4-噁二唑-3-或-5-基、1,3,4-噻二唑-2-或-5-基、1,2,4-噻二唑-3-或-5-基、1,2,3-噻二唑-4-或-5-基、3-或4-哒嗪基、吡嗪基、1-、2-、3-、4-、5-、6-或7-吲哚基、4-或5-异吲哚基、1-、2-、4-或5-苯并咪唑基、1-、3-、4-、5-、6-或7-苯并吡唑基、2-、4-、5-、6-或7-苯并噁唑基、3-、4-、5-、6-或7-苯并异噁唑基、2-、4-、5-、6-或7-苯并噻唑基、2-、4-、5-、6-或7-苯并异噻唑基、4-、5-、6-或7-苯并-2,1,3-噁二唑基、2-、3-、4-、5-、6-、7-或8-喹啉基、1-、3-、4-、5-、6-、7-或8-异喹啉基、3-、4-、5-、6-、7-或8-喹啉基、2-、4-、5-、6-、7-或8-喹唑啉基、5-或6-喹喔啉基、2-、3-、5-、6-、7-或8-2H-苯并-1,4-噁嗪基,还优选1,3-苯并二氧杂环戊-5-基、1,4-苯并二噁烷-6-基、2,1,3-苯并噻二唑-4-或-5-基或2,1,3-苯并噁二唑-5-基。
所述杂环基团也可以部分或全部氢化。
因此,Het也可以是例如2,3-二氢-2-、-3-、-4-或-5-呋喃基、2,5-二氢-2-、-3-、-4-或-5-呋喃基、四氢-2-或-3-呋喃基、1,3-二氧戊环-4-基、四氢-2-或-3-噻吩基、2,3-二氢-1-、-2-、-3-、-4-或-5-吡咯基、2,5-二氢-1-、-2-、-3-、-4-或-5-吡咯基、1-、2-或3-吡咯烷基、四氢-1-、-2-或-4-咪唑基、2,3-二氢-1-、-2-、-3-、-4-或-5-吡唑基、四氢-1-、-3-或-4-吡唑基、1,4-二氢-1-、-2-、-3-或-4-吡啶基、1,2,3,4-四氢-1-、-2-、-3-、-4-、-5-或-6-吡啶基、1-、2-、3-或4-哌啶基、2-、3-或4-吗啉基、四氢-2-、3-或4-吡喃基、1,4-二噁烷基、1,3-二噁烷-2-、-4-或-5-基、六氢-1-、-3-或-4-哒嗪基、六氢-1-、-2-、-4-或-5-嘧啶基、1-、2-或3-哌嗪基、1,2,3,4-四氢-1-、-2-、-3-、-4-、-5-、-6-、-7-或-8-喹啉基、1,2,3,4-四氢-1-、-2-、-3-、-4-、-5-、-6-、-7-或-8-异喹啉基、2-、3-、5-、6-、7-或8-3,4-二氢-2H-苯并-1,4-噁嗪基,还优选2,3-亚甲二氧基苯基、3,4-亚甲二氧基苯基、2,3-亚乙二氧基苯基、3,4-亚乙二氧基苯基、3,4-(二氟亚甲二氧基)苯基、2,3-二氢苯并呋喃-5-或-6-基、2,3-(2-氧代亚甲二氧基)-苯基或者3,4-二氢-2H-1,5-苯并二氧杂庚英(dioxepin)-6-或-7-基、还优选2,3-二氢苯并呋喃基或2,3-二氢-2-氧代呋喃基。
Het优选有1-2个N和/或O原子的单环饱和或不饱和杂环基,它可以是未取代的或被羰基氧、OH或OA一取代或二取代。
Het尤其是有1-2个N和/或O原子的、被羰基氧一取代或二取代的单环饱和、未饱和或芳族杂环基。Het特别优选例如吡啶基、2-氧代哌啶-1-基、2-氧代吡咯烷-1-基、2-氧代-1H-吡啶-1-基、3-氧代吗啉-4-基、4-氧代-1H-吡啶-1-基、2,6-二氧代哌啶-1-基、2-氧代哌嗪-1-基、2,6-二氧代哌嗪-1-基、2,5-二氧代吡咯烷-1-基、2-氧代-1,3-噁唑烷-3-基、3-氧代-2H-哒嗪-2-基、2-己内酰胺-1-基(=2-氧氮杂环庚烷-1-基)、2-羟基-6-氧代哌嗪-1-基或2-甲氧基-6-氧代哌嗪-1-基。
式I化合物可有一或多个手性中心并因此产生各种立体异构形式。式I包括所有这些形式。
因此,本发明特别涉及式I的化合物,其中至少一个所述的基团具有以上所述优选的定义之一。一些优选的化合物组可以由与式I相符的以下亚式Ia-Ig表示,并且其中的没有详细说明的基团具有如在式I中所定义的意义,但是其中
在Ia中 R1是(CH2)nAr;
在Ib中 R1是(CH2)nAr和
Ar为未取代或被Hal一取代的苯基;
在Ic中 R1是(CH2)nAr,
Ar为未取代或被Hal一取代的苯基;
R2是H;
在Id中 R1是(CH2)nAr,
Ar为未取代或被Hal一取代的苯基;
R2是H;
R3是被SO2A或SO2NH2或Het一取代的苯基;
在Ie中 R1是(CH2)nAr,
Ar为未取代或被Hal一取代的苯基;
R2是H;
R3是被SO2A或SO2NH2或Het一取代的苯基;
Het为有1-2个N和/或O原子的单环、饱和或不饱和
杂环基,它可以未被取代或被羰基氧、OH或OA一取代
或二取代;
在If中 R1是(CH2)nAr,
Ar为未取代或被Hal一取代的苯基;
R2是H;
R3是被SO2A或SO2NH2或Het一取代的苯基;
Het为吡啶基、2-氧代哌啶-1-基、2-氧代吡咯烷-1-基、2-
氧代-1H-吡啶-1-基、3-氧代吗啉-4-基、4-氧代-1H-吡啶-1-
基、2,6-二氧代哌啶-1-基、2-氧代哌嗪-1-基、2,6-二氧代
哌嗪-1-基、2,5-二氧代吡咯烷-1-基、2-氧代-1,3-噁唑烷-3-
基、3-氧代-2H-哒嗪-2-基、2-己内酰胺-1-基、2-羟基-6-氧
代哌嗪-1-基或2-甲氧基-6-氧代哌嗪-1-基;
在Ig中 Het为有1-2个N和/或O原子的单环、饱和或不饱和
杂环基,它可未被取代或被羰基氧、OH或OA一取代或
二取代;
另外,通过已知的方法,如在文献(例如在标准教科书如Houben-Weyl,Methoden der organischen Chemie[Methods of OrganicChemistry],Georg-Thieme-Verlag,Stuttgart)中所述的方法,在已知的和适合所述反应的反应条件下,制备式I的化合物及其原料。也可以使用已知方法的变通方法,但本文没有详细叙述。
如果需要,也可以在现场生产原料从而它们不用从反应混合物中分离,而是立即进一步转化为式I的化合物
式I化合物的可优选经式II化合物与式III化合物的反应得到。
所述反应一般在惰性溶剂中进行。根据所用条件,所述反应的时间在几分钟至14天内,反应温度在0-150℃,一般在20-130℃。
合适的惰性溶剂的实例是水、烃如己烷、石油醚、苯、甲苯或二甲苯;氯代烃如三氯乙烯、1,2-二氯乙烷、四氯甲烷、氯仿或二氯甲烷;醇如甲醇、乙醇、异丙醇、正-丙醇、正-丁醇或叔-丁醇;醚如乙醚、二异丙醚、四氢呋喃(THF)或二噁烷;乙二醇醚如乙二醇一甲醚或一乙醚或乙二醇二甲醚(二甘醇二甲醚);酮,如丙酮或丁酮;酰胺,如乙酰胺、二甲基乙酰胺或二甲基甲酰胺(DMF);腈,如乙腈;亚砜,如二甲基亚砜(DMSO);二硫化碳;羧酸,如甲酸或乙酸;硝基化合物,如硝基甲烷或硝基苯;酯,如乙酸乙酯,或者所述溶剂的混合物。
式II和III的起始化合物往往是已知的。如其是新的,可通过本身已知的方法制备。
例如,用乙酸或用溶于水的NaOH或KOH、水/THF或水/二噁烷于0-100℃的温度下可皂化酯。
用常规方法,在惰性溶剂,例如二氯甲烷或THF和/或在碱例如三乙胺或吡啶的存在下,于-60至+30℃下,用酰氯或酐可进一步使游离氨基酰化或用未取代或取代的烷基卤或与CH3-C(=NH)-OEt可使其烷基化。
用酸可以将式I的碱转化为相关的酸加成盐,例如通过等量的碱和酸在惰性溶剂如乙醇中反应,随后蒸发。用于该反应的合适的酸特别是那些可以得到生理上可接受的盐的酸。因此,可以使用无机酸如硫酸、硝酸、氢卤酸如盐酸或氢溴酸、磷酸如正磷酸或氨基磺酸,还包括有机酸,特别是脂族、脂环、芳脂族、芳族或杂环一元或多元羧酸、磺酸或硫酸,如甲酸、乙酸、丙酸、新戊酸、二乙基乙酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、乳酸、酒石酸、苹果酸、柠檬酸、葡糖酸、抗坏血酸、烟酸、异烟酸、甲-或乙磺酸、乙二磺酸、2-羟基乙磺酸、苯磺酸、对-甲苯磺酸、萘一-和二磺酸以及月桂基硫酸。与生理上不能接受的酸形成的盐(如苦味酸盐)可以用于分离和/或纯化式I化合物。
另一方面,用碱(如氢氧化钠、氢氧化钾、碳酸钠或碳酸钾)可以将式I的化合物转化为相应的金属盐,特别是碱金属盐或碱土金属盐,或转化为相应的铵盐。也可以使用生理上可接受的有机碱如乙醇胺。
由于它们分子的结构,本发明的式I的化合物可以是手性的并相应可以以多种对映体形式存在。因此,它们可以以外消旋或以旋光活性形式存在。
由于本发明化合物的外消旋物或立体异构体的药物活性不同,可能需要使用对映体。在这些情况下,通过本领域技术人员已知的或者在所述合成中所使用的化学或物理方法,可以将终产物或者中间体分离为对映体化合物。
在外消旋胺的情况下,通过与旋光活性拆分试剂反应,由混合物中形成非对映异构体。合适的拆分试剂的实例是旋光活性的酸如R和S形式的酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、扁桃酸、苹果酸、乳酸、合适N-保护的氨基酸(例如N-苯甲酰基脯氨酸或N-苯磺酰基脯氨酸),或者不同旋光活性的樟脑磺酸。利用旋光活性的拆分试剂(例如二硝基苯甲酰基苯基甘氨酸、三乙酸纤维素或其它碳水化合物的衍生物或固定在硅胶上的手性衍生的异丁烯酸酯聚合物)有利于色谱对映体拆分。用于此目的合适的洗脱剂的实例是含水或醇溶剂的混合物,例如比率为82∶15∶3的己烷/异丙醇/乙腈。
本发明还涉及式I化合物和/或它们的生理上可接受的盐在制备药物制剂,特别是通过非化学方法制备的药物制剂中的用途。可以将它们与至少一种固体、液体和/或半液体赋形剂或辅助剂一起以及,如果需要,与一种或更多种其它活性成分组合,转变为合适的剂型。
本发明也涉及含有至少一种式I和/或药学上有用的衍生物、其溶剂合物和立体异构体,包括它们呈各种比例的混合物,和任选的赋形剂和/或辅助剂的药剂。
本发明还涉及药物制剂,它包括至少一种式I化合物和/或一种其药理学上可接受的盐。
这些制剂可以用作在人类医学或兽医中的药物。合适的赋形剂是有机或无机物质,这些物质适合肠内(如口服)、胃肠外或局部给药并且不与所述新化合物反应,例如水、植物油、苄醇、烷撑二醇、聚乙二醇、甘油三乙酸酯、明胶、碳水化合物如乳糖或淀粉、硬脂酸镁、滑石或凡士林。适合口服给药的特别是片剂、丸剂、包衣片、胶囊、散剂、颗粒剂、糖浆、汁液或滴剂,适合直肠给药的是栓剂,适合胃肠外给药的是溶液,优选油基溶液或水溶液,另外还有悬浮剂、乳剂或植入剂,适合局部使用的是软膏剂、乳膏剂、散剂或者还有滴鼻剂。所述新的化合物也可以被冻干以及使用所获得的冻干产品制备例如注射制剂。所述制剂可以是无菌的和/或含有辅辅助剂如润滑剂、防腐剂、稳定剂和/或润湿剂、乳化剂、用于改变渗透压的盐、缓冲物质、着色剂以及调味剂和/或一些其它活性成分如一种或更多种维生素。
因此式I化合物及其生理上可接受的盐可用于治疗血栓栓塞性疾病如血栓形成、心肌梗死、动脉硬化、炎症、中风、心绞痛、血管成形术后再狭窄、间歇性跛行、肿瘤、肿瘤性疾病和/或肿瘤转移。
通常,本发明的物质以大约每剂量单位优选1和500mg之间,特别是5和100mg之间的剂量给药。日剂量优选在大约0.02和10mg/kg体重之间。但是,对于每一个病人的具体剂量取决于多种因素,如所使用的具体化合物的功效、患者的年龄、体重、一般健康状况、性别、饮食、给药的次数和方法、排泄率、药物的联合使用情况以及所治疗的具体疾病的严重性。优选口服给药。
本发明还涉及药物,它包括至少一种式I化合物和/或药学上可用的衍生物、其溶剂合物和立体异构体,包括它们呈各种比例的混合物和至少一种其它药物活性成分。
本发明也涉及由分开包装的以下药物组成的套装药剂(药剂盒)
(a)有效量的式I化合物和/或其药学上有用的衍生物、溶剂合物和立体异构体,包括它们呈各种比例的混合物,
和
(b)有效量的其它药物活性成分。
所述套装药剂包括适用容器,例如盒、单独的瓶、袋或安瓿。
例如,所述套装药剂可包括分开的各装有有效量的式I化合物和/或其药学上有用的衍生物、溶剂合物和立体异构体,包括它们呈各种比例的混合物的安瓿,
和呈溶解或冻干形式的有效量的其它药物活性成分。
本发明还涉及式I和/或药学上可用的衍生物、其溶剂合物和立体异构体,包括它们呈各种比例的混合物,与至少一种其它药物活性成分组合在制备治疗血栓栓塞性疾病如血栓形成、心肌梗死、动脉硬化、炎症、中风、心绞痛、血管成形术后再狭窄、间歇性跛行、肿瘤、肿瘤性疾病和/或肿瘤转移的药物中的用途。
在上下文中,所有温度以℃表示。在以下的实施例中,“常规后处理”表示如果需要则加入水,如果需要则根据终产物的组成将pH调至2-10,用乙酸乙酯或二氯甲烷萃取该混合物,分离各相,经硫酸钠干燥有机相并蒸发,将产物经硅胶层析和/或重结晶纯化。在硅胶上测定Rf值;洗脱剂:乙酸乙酯/甲醇9∶1。
质谱(MS): EI(电子电离)M+
FAB(快速原子轰击)(M+H)+
ESI(电雾化电离)(M+H)+(除非另有
说明)
实施例
式I化合物
表1
编号 | R | R1 | X | Y | Z | R3 | m.p.[℃] |
1 | 4-Cl | Ph | - | - | CH | 2-氧代-哌啶-1-基 | 165-170 |
2 | 4-Cl | 4-Cl-Ph | - | - | CH | 2-氧代-哌啶-1-基 | 170-175 |
3 | 4-Cl | Ph | - | - | CH | 2-甲基-磺酰基苯基 | >250 |
4 | 4-Cl | Ph | - | - | CH | 2,6-二氧代-哌嗪-1-基 | |
5 | 4-Cl | Ph | - | - | CH | 2-氧代-哌嗪-1-基 | |
6 | 4-Cl | Ph | - | - | CH | 2-氧代-1H-吡啶-1-基 | |
7 | 4-Cl | Ph | - | - | CH | 2-羟基-6-氧代-哌嗪-1-基 | |
8 | 4-Cl | Ph | - | - | CH | 2-甲氧基-6-氧代-哌嗪-1-基 | |
9 | 4-CN | Ph | - | - | CH | 2-氧代-哌嗪-1-基 | |
10 | 4-CN | Ph | - | - | CH | 2-氧代-哌啶-1-基 | |
11 | 4-CN | Ph | - | - | CH | 3-氧代-吗啉-4-基 | |
12 | 4-Cl | Ph | - | - | CH | 3-氧代-吗啉-4-基 | |
13 | 4-Cl | Ph | CH2 | - | CH | 2-氧代-1H-吡啶-1-基 | |
14 | 4-Cl | Ph | CH2 | - | CH | 2-氧代-哌啶-1-基 | |
15 | 4-Cl | Ph | CH2 | “1” | N | H | |
16 | 4-Cl | Ph | - | - | CH | 2-氧代-氮杂环庚烷-1-基 |
Ph=苯基;R2=H
实施例1
1号化合物的制备
N-(4-氯代苯基氨基羰基)-N’-[4-(2-氧代-1-哌啶基)苯基氨基羰基]-N’-苯肼
1.1氮气下,将50ml THF中的15.35g异氰酸4-氯代苯酯溶液加到100ml THF中的9.83g苯肼溶液中,使该混合物回流2小时。常规后处理得到25.1g N-(4-氯代苯基氨基羰基)-N’-苯肼(“AA”),EI 277,m.p.187-189。
1.2氮气下,将0.032ml氯甲酸三氯甲基酯加入5ml THF中的50mg 1-(4-氨基苯基)哌啶-2-酮(用阮内镍作为催化剂从1-(4-硝基苯基)哌啶-2-酮经氢化制得)溶液,接着使该混合物回流1.5小时,生成1-(4-异氰酸基(isocyanato)苯基)哌啶-2-酮(“AB”)。
1.3将78.4mg“AA”加入含“AB”的溶液中,回流该混合物2小时,再常规后处理,生成105mg N-(4-氯代苯基氨基羰基)-N’-[4-(2-氧代-1-哌啶基)苯基氨基羰基]-N’-苯肼,EI478,m.p.165-170°(分解)。
类似地制备表1中所示的化合物。
药理学数据
对受体的亲和力
表2
编号 | m.P.[℃] | Fxa-IC50[nM/L] | TF/FVIIa-IC50[nM/L] |
1 | 165-170 | 180.0 | 91.0 |
2 | 170-175 | 670.0 | 340.0 |
3 | >250 | 390.0 | 190.0 |
以下实施例涉及药物制剂的制备:
实施例A:注射小瓶
用2N盐酸将100g式I的活性成分和5g磷酸氢二钠的3L双蒸馏水溶液调至pH6.5,无菌过滤,转移至注射小瓶中,在无菌条件下冻干并在无菌条件下密封。每个注射小瓶内含有5mg活性成分。
实施例B:栓剂
将20g所述式I的活性成分与100g大豆卵磷酯以及1400g可可脂的混合物熔化,倒入模型中并使其冷却。每粒栓剂含有20mg活性成分。
实施例C:溶液
由1g式I的活性成分、9.38g NaH2PO4·2H2O、28.48g Na2HPO4·12H2O和0.1g苯扎氯铵在940ml双蒸馏水中制备溶液。将pH调至6.8并将所述溶液加到1L,经辐照灭菌。该溶液可以以滴眼液的形式使用。
实施例D:软膏
将500mg式I的活性成分与99.5g凡士林在无菌条件下混合。
实施例E:片剂
以常规方法,将1kg式I的活性成分、4kg乳糖、1.2kg马铃薯淀粉、0.2kg滑石和0.1kg硬脂酸镁的混合物压片得到片剂,此方法得到的每个片剂含有10mg活性成分。
实施例F:包衣片剂
以类似于实施例E的方法压制成片剂,随后以常规方法用蔗糖、马铃薯淀粉、滑石、黄蓍胶和染料包衣。
实施例G:胶囊
以常规方法将2kg式I的活性成分装入硬明胶胶囊中,此方法得到的每粒胶囊含有20mg所述活性成分。
实施例H:安瓿
将1kg式I活性成分的60L双蒸馏水溶液无菌过滤,转移至安瓿中,在无菌条件下冻干并在无菌条件下密封。每个安瓿含有10mg活性成分。
Claims (18)
1.式I化合物及其药学上有用的衍生物、溶剂合物和立体异构体,包括它们呈各种比例的混合物
其中
R为H、Hal或CN,
R1为H、A或(CH2)n-Ar,
R2为H或Hal,
R3为H、未被取代或被SO2A、SO2NHA或SO2NH2一取代的苯基,或Het,
X为(CH2)n,
Y不存在或为哌啶-1,4-二基,
Z为CH或N,
Ar为未取代或被以下基团一取代或二取代的苯基:Hal、苯基、A、OH、OA、NH2、NHA、NA2、NO2、CN、COOH、COOA、CONH2、CONHA、CONA2、NHCHO、NACHO、NHCOA、NACOA、NHSO2A、NASO2A、CHO、COA、SO2NH2、SO2NHA或SO2NA2,
Het为有1-4个N、O和/或S原子的单环饱和、不饱和或芳族杂环基,它可未被取代或被羰基氧、Hal、A、OH、OA、NH2、NHA、NA2、NO2、CN、COOH、COOA、CONH2、CONHA、CONA2、NHCHO、NACHO、NHCOA、NACOA、NHSO2A、NASO2A、CHO、COA、SO2NH2、SO2NHA或SO2NA2一取代或二取代,
A为有1-6个碳原子的直链或支链烷基,其中一或两个CH2基可被O或S原子和/或被-CH=CH-基团取代,和/或1-7个H原子可被F取代,
Hal为F、Cl、Br或I,
n为0、1或2。
2.权利要求1的化合物及其药学上有用的衍生物、溶剂合物和立体异构体,包括它们呈各种比例的混合物,其中
R2为H。
3.权利要求1或2的化合物及其药学上有用的衍生物、溶剂合物和立体异构体,包括它们呈各种比例的混合物,其中
R1为(CH2)nAr。
4.权利要求1或2的化合物及其药学上有用的衍生物、溶剂合物和立体异构体,包括它们呈各种比例的混合物,其中
R1为(CH2)nAr和
Ar为未取代或被Hal一取代的苯基。
5.权利要求1的化合物及其药学上有用的衍生物、溶剂合物和立体异构体,包括它们呈各种比例的混合物,其中
R1为(CH2)nAr,
Ar为未取代或被Hal一取代的苯基,
R2为H。
6.权利要求1的化合物及其药学上有用的衍生物、溶剂合物和立体异构体,包括它们呈各种比例的混合物,其中
R1为(CH2)nAr,
Ar为未取代或被Hal一取代的苯基,
R2为H,
R3为被SO2A或SO2NH2一取代的苯基,或Het。
7.权利要求1的化合物及其药学上有用的衍生物、溶剂合物和立体异构体,包括它们呈各种比例的混合物,其中
R1为(CH2)nAr,
Ar为未取代或被Hal一取代的苯基,
R2为H,
R3为被SO2A或SO2NH2一取代的苯基,或Het,
Het为有1-2个N和/或O原子的单环、饱和或不饱和杂环基,它可未被取代或被羰基氧、OH或OA一取代或二取代。
8.权利要求1的化合物及其药学上有用的衍生物、溶剂合物和立体异构体,包括它们呈各种比例的混合物,其中
R1为(CH2)nAr,
Ar为未取代或被Hal一取代的苯基,
R2为H,
R3为被SO2A或SO2NH2一取代的苯基,或Het,
Het为吡啶基、2-氧代哌啶-1-基、2-氧代吡咯烷-1-基、2-氧代-1H-吡啶-1-基、3-氧代吗啉-4-基、4-氧代-1H-吡啶-1-基、2,6-二氧代哌啶-1-基、2-氧代哌嗪-1-基、2,6-二氧代哌嗪-1-基、2,5-二氧代吡咯烷-1-基、2-氧代-1,3-噁唑烷-3-基、3-氧代-2H-哒嗪-2-基、2-己内酰胺-1-基、2-羟基-6-氧代哌嗪-1-基或2-甲氧基-6-氧代哌嗪-1-基。
9.权利要求1-5的化合物及其药学上有用的衍生物、溶剂合物和立体异构体,包括它们呈各种比例的混合物,其中
Het为有1-2个N和/或O原子的单环、饱和或不饱和杂环基,它可未被取代或被羰基氧、OH或OA一取代或二取代。
10.权利要求1的化合物,选自下列化合物:
N-(4-氯代苯基氨基羰基)-N’-[4-(2-氧代-1-哌啶基)苯基氨基羰基]-N’-苯肼,
N-(4-氯代苯基氨基羰基)-N’-[4-(2-氧代-1-哌啶基)苯基氨基羰基]-N’-4-氯代苯肼,
N-(4-氯代苯基氨基羰基)-N’-[4-(2-甲磺酰基苯基)苯基氨基羰基]-N’-苯肼,
N-(4-氯代苯基氨基羰基)-N’-[4-(2,6-二氧代-1-哌嗪基)苯基氨基羰基]-N’-苯肼,
N-(4-氯代苯基氨基羰基)-N’-[4-(2-氧代-1-哌嗪基)苯基氨基羰基]-N’-苯肼,
N-(4-氯代苯基氨基羰基)-N’-[4-(2-氧代-1H-吡啶-1-基)苯基氨基羰基]-N’-苯肼,
N-(4-氯代苯基氨基羰基)-N’-[4-(2-羟基-6-氧代-1-哌嗪基)苯基氨基羰基]-N’-苯肼,
N-(4-氯代苯基氨基羰基)-N’-[4-(2-甲氧基-6-氧代-1-哌嗪基)苯基氨基羰基]-N’-苯肼,
N-(4-氰基苯基氨基羰基)-N’-[4-(2-氧代-1-哌嗪基)苯基氨基羰基]-N’-苯肼,
N-(4-氰基苯基氨基羰基)-N’-[4-(2-氧代-1-哌啶基)苯基氨基羰基]-N’-苯肼,
N-(4-氰基苯基氨基羰基)-N’-[4-(3-氧代吗啉-4-基)苯基氨基羰基]-N’-苯肼,
N-(4-氯代苯基氨基羰基)-N’-[4-(3-氧代吗啉-4-基)苯基氨基羰基]-N’-苯肼,
N-(4-氯代苯基氨基羰基)-N’-[4-(2-氧代-1H-吡啶-1-基)苯基甲基氨基羰基]-N’-苯肼,
N-(4-氯代苯基氨基羰基)-N’-[4-(2-氧代-1-哌啶基)苯基甲基氨基羰基]-N’-苯肼,
N-(4-氯代苯基氨基羰基)-N’-[1-(吡啶-4-基)哌啶-4-基氨基羰基]-N’-苯肼,
及其药学上有用的衍生物、溶剂合物和立体异构体,包括它们呈各种比例的混合物。
12.作为凝血因子Xa的抑制剂的权利要求1-10中一项或多项的式I化合物。
13.作为凝血因子VIIa的抑制剂的权利要求1-10中一项或多项的式I化合物。
14.药物,它包括至少一种权利要求1-10中的一项或多项的式I化合物和/或药学上有用的衍生物、其溶剂合物和立体异构体,包括它们呈各种比例的混合物,和任选的赋形剂和/或辅助剂。
15.药物,它包括至少一种权利要求1-10中的一项或多项的式I化合物和/或药学上有用的衍生物、其溶剂合物和立体异构体,包括它们呈各种比例的混合物,和至少一种其它药物活性成分。
16.权利要求1-10中的一项或多项的化合物和/或其生理学上可接受的盐和溶剂合物在制备治疗血栓形成、心肌梗死、动脉硬化、炎症、中风、心绞痛、血管成形术后再狭窄、间歇性跛行、肿瘤、肿瘤性疾病和/或肿瘤转移的药物中的用途。
17.套装药剂(药剂盒),它由下列分开包装的药物组成:
(a)有效量的权利要求1-10的一或多项的式I化合物和/或其药学上有用的衍生物、溶剂合物和立体异构体,包括它们呈各种比例的混合物,
和
(b)有效量的其它药物活性成分。
18.权利要求1-10的一或多项的式I化合物和/或其药学上有用的衍生物、溶剂合物和立体异构体,包括它们呈各种比例的混合物,与至少一种其它药物活性成分组合,在制备治疗血栓形成、心肌梗死、动脉硬化、炎症、中风、心绞痛、血管成形术后再狭窄、间歇性跛行、肿瘤、肿瘤性疾病和/或肿瘤转移的药物中的用途。
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DE10302500A1 (de) | 2003-01-23 | 2004-07-29 | Merck Patent Gmbh | Carbonsäureamidderivate |
US7205318B2 (en) * | 2003-03-18 | 2007-04-17 | Bristol-Myers Squibb Company | Lactam-containing cyclic diamines and derivatives as a factor Xa inhibitors |
WO2004087646A2 (de) * | 2003-04-03 | 2004-10-14 | Merck Patent Gmbh | Pyrrolidin -1,2-dicarbonsäure-1-(phenylamid) -2- (4-(3-oxo-morpholin-4-yl)-phenylamid) derivate und verwandte verbindungen als inhibitoren des koagulationsfaktors xa zur behandlung von thromboembolischen erkrankungen |
DE502004003688D1 (de) | 2003-04-03 | 2007-06-14 | Merck Patent Gmbh | Pyrazolidin-1,2-dicarbonsäure-1-((phenyl)-amid)-2-((phenyl)-amid) derivate als koagulationsfaktor xa inhibitoren zur behandlung von thrombosen |
US7820673B2 (en) | 2003-12-17 | 2010-10-26 | Takeda Pharmaceutical Company Limited | Urea derivative, process for producing the same, and use |
DE102004004731A1 (de) * | 2004-01-30 | 2005-08-18 | Merck Patent Gmbh | Harnstoffderivate |
US7371743B2 (en) * | 2004-02-28 | 2008-05-13 | Boehringer Ingelheim International Gmbh | Carboxylic acid amides, the preparation thereof and their use as medicaments |
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MXPA03008394A (es) | 2004-01-29 |
DE10113402A1 (de) | 2002-09-26 |
EP1385818A2 (de) | 2004-02-04 |
HUP0303512A2 (hu) | 2004-01-28 |
CA2441427A1 (en) | 2002-09-26 |
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