CN1345312A - 用于治疗血栓形成、骨质疏松、动脉硬化的二苯并薁衍生物 - Google Patents
用于治疗血栓形成、骨质疏松、动脉硬化的二苯并薁衍生物 Download PDFInfo
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- CN1345312A CN1345312A CN00805748A CN00805748A CN1345312A CN 1345312 A CN1345312 A CN 1345312A CN 00805748 A CN00805748 A CN 00805748A CN 00805748 A CN00805748 A CN 00805748A CN 1345312 A CN1345312 A CN 1345312A
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Classifications
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- C07D213/02—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
- 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
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- C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
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- C—CHEMISTRY; METALLURGY
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- C07C2603/02—Ortho- or ortho- and peri-condensed systems
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Landscapes
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Abstract
本发明涉及式(I)的化合物及其生理可接受的盐和溶剂化物,其中R1、R2、R3、m和n定义如权利要求1。本发明物质用作整联蛋白抑制物质,特别是用于预防和治疗心血管疾病、血栓形成、心肌梗死、冠心病、动脉硬化、骨质疏松、由血管生成引起或蔓延的病症中以及肿瘤的治疗中。
Description
本发明涉及式I的化合物及其生理可接受盐和溶剂化物,
其中
R1是OR4、NHR4或NA″2,
R2是H、Hal、NO2、NHR4、NA″2、OR4、SO3R4、SO2R4或SR4,
R3是NH2、H2N-C(=NH)或H2N-(C=NH)-NH,其中伯胺基团也可以被常规氨基保护基保护,或R5-NH-,
R4是H、A、Ar或Aralk,
R5是具有1至4个氮、氧和/或硫原子的单或双核杂环,其可以未被取代或者被如下基团单、二或三取代:Hal、A″、CO-A′、OA′、CN、COOA′、CONH2、NO2、=NH或=O,
A是具有1-15个碳原子的烷基或者是具有3至15个碳原子的环烷基,其未被取代或者被R6单、二或三取代,且其中一个、两个或三个亚甲基可以被N、O和/或S代替,
R6是Hal、NO2、NHA′、NA″2、OA′、苯氧基、CO-A′、SO3A′、CN、NHCOA′、COOA′、CONA′2或SO2A′,
A′是H或具有1-6个碳原子的烷基,
A″是具有1-6个碳原子的烷基,
Ar是单或双核芳环系统,其未被取代或被具有1-6个碳原子的烷基单、二或三取代,和/或被R6取代的具有0、1、2、3或4个N、O和/或S的单或双核芳香环系统,
Aralk是具有7-14个碳原子的芳亚烷基,其未被取代或被R6一、二或三取代,且其中一个、两个或三个亚甲基被N、O和/或S代替,
Hal是F、Cl、Br或I,
m,n在各种情况下彼此独立地是0、1、2、3或4。
例如,类似的化合物公开于WO97/01540。
本发明的目的是发现有价值的新化合物,特别是可以用于制备药物的化合物。
现已发现式I的化合物及其盐和溶剂化物非常具有药用价值,同时具有良好的耐受性。它们特别作为整联蛋白抑制剂,其中它们特别抑制αv整联蛋白受体与配体的相互作用。这些化合物对于整联蛋白αvβ3和αvβ5显示了特别的活性。这些化合物作为玻连蛋白受体αvβ3的粘着受体拮抗剂具有非常特别的活性。
例如,按照J.W.Smith等在J.Bio1.Chem.265,11008-11013和12267-12271(1990)中描述的方法,可以说明此作用。
在Curr.Opin.Cell.Biol.5,864(1993)中,B.Felding-Habermann和D.A.Cheresh描述了整联蛋白作为粘着受体对于差别很大的现象和综合征的重要性,特别是与玻连蛋白受体αvβ3有关的。
血管生成的形成对血管整联蛋白和细胞外基质蛋白之间相互作用的依赖性,由P.C.Brooks,R.A.Clark和D.A.Cheresh描述于Science 264,569-71(1994)。
环肽对此相互作用进行抑制的可能性,并因此诱发的新血管细胞的编程性细胞死亡(程序性细胞死亡)的可能性由P.C.Brooks,A.M.Montgomerg,M.Rosenfeld,R.A.Reisfeld,T.-Hu,G.Klier和D.A.Cheresh描述于Cell,79,1157-64(1994)。
本发明化合物也防止活细胞与相应基质蛋白的联系,并因此也防止肿瘤细胞与基质蛋白的联系,其实验证据可以在细胞粘着实验中得到,该实验按照类似于F.Mitjans等,J.Cell Science,108,2825-2838(1995)的方法进行。
在J.Clin.Invest.96,1815-1822(1995)中,P.C.Brooks等描述了用于控制癌症和用于治疗肿瘤诱发的血管生成疾病的αvβ3拮抗剂。
本发明的式I化合物因此可以用作药物活性化合物,特别是用作用于治疗肿瘤病、骨质疏松、溶骨紊乱和用于抑制血管生成的化合物。
式I的化合物阻断整联蛋白受体和配体,如纤维蛋白原与纤维蛋白原受体(糖蛋白IIb/IIIa)之间的相互作用,其作为GPIIb/IIIa拮抗剂防止肿瘤细胞通过转移扩散。这可以通过下列观察得以证实:从局部肿瘤进入血管系统中的肿瘤细胞扩散,是通过肿瘤细胞与血小板相互作用形成微凝集物(微血栓)发生的。在此微凝集物中这些肿瘤细胞得到掩蔽保护,且不被免疫系统识别。这些微凝集物自身可以固定在血管壁上,结果有利于肿瘤细胞进一步穿透进入组织。由于纤维蛋白原结合纤维蛋白原受体形成微血栓是活化的血小板介导的,故GPIIa/IIIb可以被看作有效的转移抑制剂。
除了结合纤维蛋白原,纤连蛋白和von Willebrand因子结合血小板的纤维蛋白原受体,式I的化合物还抑制其它粘着蛋白如玻连蛋白、胶原和层粘连蛋白与不同类型细胞的表面上的相应受体的结合。具体地讲,它们防止血小板血栓的形成,并因此用于治疗血栓形成、中风、心肌梗死、炎症和动脉硬化。
这些化合物的性质也可以按照EP-A1-0462960描述的方法显示。对纤维蛋白原与纤维蛋白原受体结合的抑制可以通过EP-A1-0381033指出的方法检测。
血小板凝集-抑制作用可以按照Born的方法(Nature 4832,927-929,1962)在体外证明。
因此,本发明涉及权利要求1所述的式I化合物及其生理可接受的盐和溶剂化物,其作为GPIIb/IIIa拮抗剂用于控制血栓形成、心肌梗死、冠心病和动脉硬化。
本发明还涉及权利要求1所述的式I化合物及其生理可接受盐和溶剂化物在制备用作整联蛋白抑制剂的药物中的用途。
本发明具体地涉及权利要求1所述的式I化合物及其生理可接受盐和溶剂化物在制备控制病理性血管生成紊乱、肿瘤、骨质疏松、炎症和感染的药物中的用途。
在人和兽药中,式I的化合物可以用作药物活性化合物,用来预防和/或治疗血栓形成、心肌梗死、动脉硬化、炎症、中风、心绞痛、肿瘤病、溶骨疾病如骨质疏松、病理性血管生成病如炎症、眼病、糖尿病性视网膜病、黄斑变性、近视、眼组织胞浆菌病、类风湿性关节炎、骨关节炎、发红性青光眼(rubeotic glaucoma)、溃疡性结肠炎、克罗恩氏病、动脉硬化、牛皮癣、血管成形术后再狭窄、病毒感染、细菌感染、真菌感染、急性肾衰竭,并在伤口愈合中帮助愈合过程。
在使用生物材料、移植物、插管或心脏起博器的手术中,式I的化合物可以用作抗菌剂。此时它们具有抗菌作用。抗菌活性的效果可以通过P.Valentin-Weigund等在Infection and Immunity,2851-2855(1988)中描述的方法证明。
本发明进一步涉及制备权利要求1所述的式I化合物及其盐和溶剂化物的方法,其特征在于:
a)通过用溶剂分解或氢解试剂处理,将式I的化合物从其官能基衍生物中游离出,
或
b)通过,例如,以下方法将R1、R2和/或R3转变为另一种基团R1、R2和/或R3:
i)通过与脒化试剂反应将氨基转变为胍基,
ii)将酯水解,
iii)将羧酸还原为醇,
iv)通过氢化将羟基脒转变为脒,
和/或将式I的碱或酸转变为其一种盐。
式I的化合物具有至少一个手性中心并因此可以产生一定数量的立体异构形式。所有这些形式(如,D和L型)及其混合物(如DL型)包括在式I范围内。
在本发明的化合物中还包括所谓的前药衍生物,即用,例如,烷基或酰基、糖或低聚肽,修饰的式I的化合物,其在体内快速裂解得到本发明的活性化合物。
化合物的溶剂化物也包括在本发明的化合物中。这些被理解为与水(水合物)或醇如甲醇或乙醇的加成化合物。
上述及下述缩写表示:Ac 乙酰基BOC 叔丁氧羰基CBZ或Z 苄氧羰基DCCI 二环己基碳二亚胺DBU 1,8-二氮杂二环[5.4.0]十一碳-7-烯DMF 二甲基甲酰胺DOPA (3,4-二羟基苯基)丙氨酸DPFN 硝酸3,5-二甲基吡唑-1-甲脒DAMP 二甲基氨基吡啶EDCI N-乙基-N,N′-(二甲基氨基丙基)碳二亚胺Et 乙基Fmoc 9-芴基甲氧羰基HOBt 1-羟基苯并三唑Me 甲基MTB醚 甲基叔丁基醚Mtr 4-甲氧基-2,3,6-三甲基苯基磺酰基HONSu N-羟基琥珀酰亚胺Np 新戊基OBn 苄基酯OBut 叔丁基酯Oct 辛酰基OMe 甲酯OEt 乙酯Orn 鸟氨酸POA 苯氧基乙酰基TBTU 四氟硼酸O-(苯并三唑-1-基)-N,N,N,N-
四甲基脲鎓TFA 三氟乙酸pTSS盐 对甲苯磺酸盐Trt 三苯基甲基Z或CBZ 苄氧羰基
事实上,对于整个发明,出现若干次的所有基团可以相同或不同,即彼此独立。
即式I包括式I′和I″的化合物,在C-1和C-11a之间可以是单键或双键。
烷基优选甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基,另外还有戊基、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-乙基-1-甲基丙基、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-2-甲基丙基、1,1,2-、1,2,2-三甲基丙基、庚基、辛基、壬基或癸基,以及,例如,三氟甲基或五氟乙基。
A′优选H、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基或己基。
A″优选甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基或己基。
环烷基优选环丙基、环丁基、环戊基、环己基、环庚基、金刚烷基或3-薄荷基。
亚烷基优选亚甲基、亚乙基、亚丙基、亚丁基、亚戊基,此外还有亚己基、亚庚基、亚辛基、亚壬基或亚癸基。
Aralk是芳亚烷基并优选亚烷基苯基,例如,优选苄基或苯乙基。
A特别优选甲基、乙基、丙基、异丙基、丁基或叔丁基。
CO-A′是烷酰基或环烷酰基,并优选甲酰基、乙酰基、丙酰基、丁酰基、戊酰基、己酰基、庚酰基、辛酰基、壬酰基、癸酰基、十一烷酰基、十二烷酰基、十三烷酰基、十四烷酰基、十五烷酰基、十六烷酰基、十七烷酰基或十八烷酰基。
烷基、芳基、环烷基和Aralk的优选取代基R6优选,例如,Hal、NO2、NH2、NHA″,如甲基氨基、NA″2,如二甲基氨基、甲氧基、苯氧基、酰基,如甲酰基或乙酰基、CN、NHCOA′,如乙酰氨基、COOA′,如COOH或甲氧羰基、CONA′2或SO2A′,例如,特别是F、Cl、羟基、甲氧基、乙氧基、氨基、二甲基氨基、甲硫基、甲基亚磺酰基、甲基磺酰基或苯磺酰基。
在基团烷基、亚烷基和环烷基中,在各种情况下一个、两个或三个亚甲基可以被N、O和/或S代替。
Ar-CO是芳酰基并优选苯甲酰基或萘甲酰基。
Ar是未被取代的、如上所述优选一取代的苯基,特别优选苯基,邻、间或对-甲苯基,邻、间或对-乙基苯基,邻、间或对-丙基苯基,邻、间或对-异丙基苯基,邻、间或对-叔丁基苯基,邻、间或对-氰基苯基,邻、间或对-甲氧基苯基,邻、间或对-乙氧基苯基,邻、间或对-氟苯基,邻、间或对-溴代苯基,邻、间或对-氯苯基,邻、间或对-甲硫代苯基,邻、间或对-甲基亚磺酰基苯基,邻、间或对-甲基磺酰基苯基,邻、间或对-氨基苯基,邻、间或对-甲基氨基苯基,邻、间或对-二甲基氨基苯基,邻、间或对-硝基苯基,还优选2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二氟苯基,2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二氯苯基,2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二溴苯基,2-氯-3-甲基-、2-氯-4-甲基-、2-氯-5-甲基-、2-氯-6-甲基-、2-甲基-3-氯-、2-甲基-4-氯-、2-甲基-5-氯-、2-甲基-6-氯-、3-氯-4-甲基-、3-氯-5-甲基-或3-甲基-4-氯-苯基,2-溴-3-甲基-、2-溴-4-甲基-、2-溴-5-甲基-、2-溴-6-甲基-、2-甲基-3-溴-、2-甲基-4-溴-、2-甲基-5-溴-、2-甲基-6-溴-、3-溴-4-甲基-、3-溴-5-甲基-或3-甲基-4-溴-苯基,2,4-或2,5-二硝基苯基,2,5-或3,4-二甲氧基苯基,2,3,4-、2,3,5-、2,3,6-、2,4,6-或3,4,5-三氯苯基,2,4,6-三叔丁基苯基,2,5-二甲基苯基,对碘代苯基,4-氟-3-氯-苯基,4-氟-3,5-二甲基苯基,2-氟-4-溴-苯基,2,5-二氟-4-溴苯基,2,4-二氯-5-甲基苯基,3-溴-6-甲氧基苯基,3-氯-6-甲氧基苯基,2-甲氧基-5-甲基苯基,2,4,6-三异丙基苯基,萘基,1,3-苯并二氧杂环戊烯-5-基,1,4-苯并二氧杂环戊烷-6-基,苯并噻二唑-5-基或苯并噁二唑-5-基。
Ar进一步优选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,2-、3-、4-、5-或6-2H-噻喃基,2-、3-或4-4-H-噻喃基,3-或4-哒嗪基,吡嗪基,2-、3-、4-、5-、6-或7-苯并呋喃基,2-、3-、4-、5-、6-或7-苯并噻吩基,1-、2-、3-、4-、5-、6-或7-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-噌啉基,2-、4-、5-、6-、7-或8-喹唑啉基。
R5是单或双核杂环,优选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,2-、3-、4-、5-或6-2H-噻喃基,2-、3-或4-4-H-噻喃基,3-或4-哒嗪基,吡嗪基,2-、3-、4-、5-、6-或7-苯并呋喃基,2-、3-、4-、5-、6-或7-苯并噻吩基,1-、2-、3-、4-、5-、6-或7-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-噌啉基,2-、4-、5-、6-、7-或8-喹唑啉基。
此杂环基团也可以部分或完全氢化。
因此,R5还可以是,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,1,3-二氧杂环戊烷-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,1,4-二氧杂环戊烷基,1,3-二氧杂环戊烷-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。
所述杂环也可以被Hal、A、-CO-A、OH、CN、COOH、COOA、CONH2、NO2、=NH或=O一、二或三取代。
R5特别优选1H-咪唑-2-基、4,5-二氢-1H-咪唑-2-基、5-氧代-4,5-二氢-1H-咪唑-2-基、噻唑-2-基、1H-苯并咪唑-2-基、2H-吡唑-2-基、1H-四唑-5-基、2-亚氨基-咪唑烷-4-酮-5-基、1-烷基-1,5-二氢咪唑-4-酮-2-基、吡啶-2-基、嘧啶-2-基或1,4,5,6-四氢-嘧啶-2-基。
R1特别是,例如,羧基、甲氧羰基、乙氧羰基、CONH2、CONHMe、CONHEt、CONMe2或CONEt2。
R1特别优选羧基或乙氧羰基。
R2优选,例如,H、Hal、甲磺酰基、乙磺酰基、丙磺酰基、丁磺酰基、异丁基磺酰基、2,2-二甲基丙基磺酰基、苯磺酰基或苄基磺酰基。
R2特别优选H。
R3优选,例如,H2N-C(=NH)、H2N-(C=NH)-NH、1H-咪唑-2-基氨基、4,5-二氢-1H-咪唑-2-基氨基、5-氧代-4,5-二氢-1H-咪唑-2-基氨基、1H-苯并咪唑-2-基氨基、2H-吡唑-2-基氨基、2-亚氨基-咪唑烷-4-酮-5-基氨基、1-甲基-1,5-二氢咪唑-4-酮-2-基氨基、吡啶-2-基氨基、嘧啶-2-基氨基或1,4,5,6-四氢嘧啶-2-基氨基。
因此,本发明特别涉及式I的化合物,其中所述基团中至少一个具有上述优选的定义。化合物的一些优选类型可以通过下列亚结构式Ia至Ih表示,其相应于式I,其中没有详尽描述基团的定义与式I中的定义相同,而其中
在Ia)中,
R2是H;
在Ib)中,
R2是H,
而R1是COOH或COOA;
在Ic)中,
R2是H,
R1是COOH或COOA,而
R3是H2N-C(=NH)、H2N-(C=NH)-NH、1H-咪唑-2-基氨基、4,5-二氢-1H-咪唑-2-基氨基、5-氧代-4,5-二氢-1H-咪唑-2-基氨基、1H-苯并咪唑-2-基氨基、2H-吡唑-2-基氨基、2-亚氨基咪唑烷-4-酮-5-基氨基、1-甲基-1,5-二氢咪唑-4-酮-2-基氨基、吡啶-2-基氨基、嘧啶-2-基氨基或1,4,5,6-四氢嘧啶-2-基氨基;
在Id)中,
m是0或1;
在Ie)中,
m是0或1,且
R2是H;
在If)中,
R2是H;
R1是COOH或COOA,且
m是0或1;
在Ig)中,
R2是H,
R1是COOH或COOA,且
A是甲基、乙基、丙基、异丙基、丁基或叔丁基,且
m是0或1;
在Ih)中,
R2是H,
R1是COOH或COOA,
A是甲基、乙基、丙基、异丙基、丁基或叔丁基,
R3是H2N-C(=NH)、H2N-(C=NH)-NH、1H-咪唑-2-基氨基、4,5-二氢-1H-咪唑-2-基氨基、5-氧代-4,5-二氢-1H-咪唑-2-基氨基、1H-苯并咪唑-2-基氨基、2H-吡唑-2-基氨基、2-亚氨基咪唑烷-4-酮-5-基氨基、1-甲基-1,5-二氢咪唑-4-酮-2-基氨基、吡啶-2-基氨基、嘧啶-2-基氨基或1,4,5,6-四氢嘧啶-2-基氨基;
m是0或1,而
n是2、3或4;
及其生理可接受的盐和溶剂化物。
特别优选的化合物是分别说明的下式的化合物:
R2是H,
R1是COOH或COOA,
A是甲基、乙基、丙基、异丙基、丁基或叔丁基,
R3是H2N-C(=NH)、H2N-(C=NH)-NH、1H-咪唑-2-基氨基、4,5-二氢-1H-咪唑-2-基氨基、5-氧代-4,5-二氢-1H-咪唑-2-基氨基、1H-苯并咪唑-2-基氨基、2H-吡唑-2-基氨基、2-亚氨基咪唑烷-4-酮-5-基氨基、1-甲基-1,5-二氢咪唑-4-酮-2-基氨基、吡啶-2-基氨基、嘧啶-2-基氨基或1,4,5,6-四氢嘧啶-2-基氨基;
m是0或1,且
n是2、3或4;
R2是H,
R1是COOH或COOA,
A是甲基、乙基、丙基、异丙基、丁基或叔丁基,
R3是H2N-C(=NH)、H2N-(C=NH)-NH、1H-咪唑-2-基氨基、4,5-二氢-1H-咪唑-2-基氨基、5-氧代-4,5-二氢-1H-咪唑-2-基氨基、1H-苯并咪唑-2-基氨基、2H-吡唑-2-基氨基、2-亚氨基咪唑烷-4-酮-5-基氨基、1-甲基-1,5-二氢咪唑-4-酮-2-基氨基、吡啶-2-基氨基、嘧啶-2-基氨基或1,4,5,6-四氢嘧啶-2-基氨基;
m是0或1,且
n是2、3或4;
及其生理可接受的盐和溶剂化物。
式I的化合物及其制备过程中的起始物可通过本领域技术人员已知的方法制备,例如,描述于文献中的方法(例如,在标准著述中如Houben-Weyl,Methoden der organischen Chemie[有机化学方法],Georg-Thieme-Verlag,Stuttgart),即在已知的且适于上述反应的反应条件下。此种情况下,也可以使用本领域技术人员已知的变化形式,但不在此赘述。
如果需要,起始物也可以就地形成,即不从反应混合物中将它们分离,而是立即进一步反应得到式I的化合物。
可以优选通过用溶剂分解或氢解试剂处理从其一种官能基衍生物获得式I的化合物的游离形式,来制备式I的化合物。
溶剂分解或氢解使用的优选起始物为相应于式I,但是一个或多个游离的氨基和/或羟基含相应保护的氨基和/或羟基,优选将与N原子连接的氢原子用氨基保护基代替,特别是将HN基团用R′-N-基团代替,其中R′是氨基保护基,和/或将羟基的氢原子用羟基保护基代替,例如,相应于式I但将基团-COOH用基团-COOR″代替的化合物,其中R″是羟基保护基。
起始物分子中还可以存在一些相同或不同的被保护的氨基和/或羟基。如果存在的保护基彼此不同,在很多情况下它们可以被有所选择地除去。
术语“氨基保护基”是公知的并涉及适于在化学反应中保护(阻断)氨基,但在所需的化学反应在该分子的另一个位置已进行后易于除去的基团。此类典型基团特别是未被取代或被取代的酰基、芳基、芳烷氧基甲基或芳烷基。由于氨基保护基在所需反应(或系列反应)后除去,其性质和大小是不严格的;但是,优选具有1-20,特别是1-8个碳原子的。就本方法而言术语“酰基”含义广泛。其包括得自脂族、芳基脂族、芳族或杂环羧酸或磺酸的酰基,特别是烷氧羰基、芳氧羰基,并特别是芳烷氧羰基。此类酰基的实例为烷酰基如乙酰基、丙酰基、丁酰基;芳烷酰基如苯基乙酰基;芳酰基如苯甲酰基或甲苯酰基;芳氧基烷酰基如POA;烷氧羰基如甲氧羰基、乙氧羰基、2,2,2-三氯乙氧羰基、BOC、2-碘代乙氧羰基,芳烷氧基羰基如CBZ(“苄氧羰基”)、4-甲氧基苄氧羰基、FMOC;芳基磺酰基如Mtr。除了CBZ、Fmoc、苄基和乙酰基外,优选的氨基保护基为BOC和Mtr。
根据所用的保护基,除去氨基保护基,例如,用强酸,便利地用TFA或高氯酸,但也可以使用其它强无机酸如盐酸或硫酸,强有机羧酸如三氯乙酸或磺酸如苯-或对甲苯磺酸。可能存在其它惰性溶剂,但是不总是必需的。适宜的惰性溶剂优选为有机溶剂,如羧酸如乙酸,醚如四氢呋喃或二噁烷,酰胺如DMF,卤代烃如二氯甲烷,此外还有醇如甲醇、乙醇或异丙醇,也还有水。上述溶剂的混合物也是适宜的。TFA优选过量使用,不用再加入溶剂,乙酸和70%高氯酸9∶1形式的高氯酸。裂解的反应温度便利地为约0至约50℃;该反应优选在15至30℃(室温下)进行。
例如,用TFA在二氯甲烷中或者用约3至5N HCl在二噁烷中,在15-30℃下,可以优选除去基团BOC、OBut和Mtr,用二甲胺、二乙胺或哌啶在DMF中的约5至50%溶液在15至30℃下除去FMOC基团。
例如,通过在催化剂(如贵金属催化剂如钯,便利地在载体如碳上)存在下用氢气处理,可以除去可氢解除去的保护基(如CBZ或苄基)。此时,适宜的溶剂如上所述,特别是,例如,醇如甲醇或乙醇,或者酰胺如DMF。一般来说,氢解在约0至100℃温度下和约1至200巴压力下进行,优选在20-30℃和1-10巴下。例如,在20-30℃下,CBZ的氢解在5至10%钯碳上在甲醇中会容易地发生,或者用甲酸铵(代替氢气)在Pd/C上在甲醇/DMF中进行。
适宜的惰性溶剂为,例如,烃如己烷、石油醚、苯、甲苯或二甲苯;氯化烃如三氯乙烯、1,2-二氯乙烷、四氯化碳、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、二丙基醚、四氢呋喃(THF)或二噁烷;二醇醚如乙二醇单甲基或单乙基醚(甲基丙二醇或乙基丙二醇)、乙二醇二甲基醚(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,水或上述溶剂的混合物。
因此,水解式I的酯是可能的。这可通过如上所述的溶剂分解或氢解,例如,用氢氧化钠或氢氧化钾在二噁烷/水中,在0至60℃,优选在10至40℃的温度下便利地进行。
可以通过,例如,与羟基胺反应,并随后用氢气在催化剂如Pd/C的存在下还原N-羟基脒,将氰基转变为脒基。
通过如上所述的溶剂分解或氢解,还可以将常规氨基保护基用氢原子代替,或者通过溶剂分解或氢解将游离的氨基用常规保护基保护。
为了制备其中R3是H2N-C(=NH)-NH-的式I化合物,可以用脒化试剂处理适当的氨基化合物。优选的脒化试剂为1-脒基-3,5-二甲基吡唑(DPFN),其特别是以其硝酸盐的形式使用。在惰性溶剂或溶剂混合物如水/二噁烷中,在0至120℃,优选60至120℃温度下,加入碱如三乙胺或乙基二异丙基胺,该反应容易地进行。
为了制备式I的脒(R3=-C(=NH)-NH2)。试剂的加入优选以多步骤、本领域技术人员已知的方式进行,通过a)用H2S将腈转变为硫代酰胺,其用烷基化试剂如碘代甲烷转变为相应的S-烷基亚氨基硫代酸酯,此部分与NH3反应得到脒,b)用醇如乙醇在HCl的存在下将此腈转变为相应的酰氨基酯并将其用氨处理,或者c)将该腈与双(三甲基硅烷基)氨化锂反应,并再将此产物水解。
便利地在惰性溶剂如二氯甲烷或THF中,和/或碱如三乙胺或吡啶的存在下,在-60至+30℃下,游离的氨基可以再用酰氯或酸酐以常规方式酰化,或者用未被取代或被取代的烷基卤化物烷基化。
用酸,例如通过等当量的碱与等当量的酸在惰性溶剂如乙醇中反应并随后蒸发,式I的碱可以转变为相映的酸加成盐。此反应适用的酸特别是能得到生理可接受盐的那些。因此,可以使用无机酸,如硫酸、硝酸、氢卤酸如氢氯酸或氢溴酸、磷酸如正磷酸、氨基磺酸,此外可以使用有机酸,特别是脂族、脂环族、芳基脂族、芳族或杂环一元或多元羧酸、磺酸或硫酸,例如,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、酸,此外可以使用有机酸,特别是脂族、脂环族、芳基脂族、芳族或杂环一元或多元羧酸、磺酸或硫酸,例如,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-和二磺酸及十二烷基硫酸。与生理可接受的酸形成的盐如苦味酸盐,可以用来分离和/或纯化式I的化合物。
另一方面,通过与碱反应,式I的酸可以转变为其一种生理可接受的金属或铵盐。此处,可能的盐特别是钠、钾、镁、钙和铵盐,例如,二甲基-、二乙基-或二异丙基铵盐,单乙醇-、二乙醇或二异丙基铵盐,环己基-或二环己基铵盐,二苄基亚乙基二铵盐,此外,例如,与精氨酸或赖氨酸的盐。
式I的化合物含一个或多个手性中心并因此可以以外消旋或以光学活性形式存在。所得外消旋物可以通过本领域技术人员已知的方法用物理或化学手段拆分为对映异构体。优选,通过与光学活性拆分试剂反应由外消旋混合物形成非对映异构体。适宜的拆分试剂为,例如,光学活性酸,如D和L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、乳酸或者不同光学活性的樟脑磺酸如β-樟脑磺酸。借助填装了光学活性拆分试剂(如二硝基苯甲酰基苯基甘氨酸)的柱来分离对映异构体也是有利的;适宜的洗脱剂是,例如,己烷/异丙醇/乙腈的混合物,例如,其体积比为82∶15∶3。
当然,用光学活性的起始物按照上述方法,页可能获得式I的光学活性化合物。
本发明还涉及式I的化合物和/或其生理可接受盐制备药物的用途,特别是以非化学形式。在本文中,它们可以与至少一种固体、液体和/或半液体赋形剂或辅剂一起,并如果适当的话,与一种或多种其它活性化合物联合,制备成适当剂型。
本发明还涉及含有至少一种式I的化合物和/或一种其生理可接受盐的药物制剂。
在人或兽药中这些制剂可以用作药物。适宜的载体是有机或无机物质,其适于肠道(例如,口服)或非肠道给药、局部施用或以吸入喷雾剂的形式使用,且不与这些新的化合物反应,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、滑石和凡士林。片剂、丸剂、包衣片剂、胶囊、散剂、颗粒剂、糖浆、汁或滴剂特别用于口服给药,栓剂用于直肠给药,溶液剂,优选油或水溶液,还有混悬剂、乳剂或埋植剂用于非肠道给药,此外软膏、霜或粉用于局部使用。这些新的化合物也可以冻干并将所得冻干物用于,例如,制备注射剂。所述这些制剂可以是灭菌的和/或可以含有赋形剂如润滑剂、乳化剂、影响渗透压的盐、缓冲物质、着色剂、矫味剂和/或一种或多种其它活性化合物,例如,一种或多种维生素。
为了以吸入喷雾给药,可以使用含有活性化合物的喷雾剂,此活性化合物溶解于或悬浮于抛射剂或抛射剂混合物(如二氧化碳或氯氟烃)中。便利地,在此处以微粒化的形式使用此活性化合物,可以存在一种或多种其它生理可耐受的溶剂,例如,乙醇。吸入溶液可以借助常规吸入器给药。
本发明还涉及式I的化合物作为治疗活性化合物的用途。
在控制疾病,特别是在控制病理性血管生成紊乱、血栓形成、心肌梗死、冠心病、动脉硬化、肿瘤、炎症和感染中,式I的化合物及其生理可接受盐,可以用作整联蛋白抑制剂。
一般来说,本发明的物质可以以类似于其它已知的、商购的整联蛋白抑制剂的方式给药,但是特别是以类似于US-A-4472305所述化合物的方式,优选剂量为约0.05至500mg每剂量单位。日剂量优选约0.01至2mg/千克体重。然而,对每个患者特定的剂量依赖于各种因素,例如,所用特定化合物的效力、患者的年龄、体重、总的健康状况、性别及饮食、给药的时间和途径、以及排泄速度、药物联合及所治疗的特定疾病的严重性。优选非肠道给药。出有机相,用硫酸钠干燥并蒸发,并将此残余物在硅胶上通过色谱纯化和/或通过结晶纯化。
质谱(MS):
EI(电子碰撞电离)M+
FAB(快速原子轰击)(M+H)+
所示Rf值通过用TLC薄膜,硅胶60 F254的薄层色谱测定。
实施例1
8-[3-(吡啶-2-基氨基)丙氧基]-6,11-二氢-2H-二苯并[cd,g]薁-1-甲酸甲酯:
将3.5g(0.011mol)的(3-甲氧基-10,11-二氢-5H-二苯并[a,d]环庚烯-10-基)乙酸乙酯在50ml的1N HCl和80ml二噁烷中的溶液,室温下搅拌16小时。除去溶剂后,得到3.0g的(3-甲氧基-10,11-二氢-5H-二苯并[a,d]环庚烯-10-基)乙酸(“AB”),Rf0.68(乙酸乙酯)。
将3.0g的“AB”在50ml亚硫酰氯中的溶液,用几滴DMF处理并在80℃下搅拌1小时。除去溶剂后,将此残余物溶解于50ml二氯甲烷中,冷却至-10℃并加入1.61g氯化铝,并将此混合物随后在室温下搅拌2小时。将其以常规方式处理并在硅胶60上纯化(石油醚/乙酸乙酯4∶1)。得到1.7g的8-甲氧基-1,6,11,11a-四氢二苯并[cd,g]薁-2-酮(“AC”),Rf 0.51;EI 264。
在氩气氛下,将0.64g的NaH加入到2.1g的“AC”在30ml THF的溶液中。搅拌30分钟后,加入3.4ml的碳酸二甲酯,然后再将此混合物搅拌4小时。以常规方式处理,在硅胶60上纯化(石油醚/乙酸乙酯4∶1),得到了1.8g的8-甲氧基-2-氧代-1,6,11,11a-四氢-1H-二苯并[cd,g]薁-1-甲酸甲酯(“AD”),Rf 0.40;EI 322。
向1.0g的“AD”的155ml THF溶液中,加入9.3g离子交换树脂Amberlite I,然后加入0.59g的硼氢化钠。之后将此混合物室温下搅拌30分钟。除去离子交换树脂和溶剂后,得到8-甲氧基-2-羟基-1,6,11,11a-四氢-1H-二苯并[cd,g]薁-1-甲酸甲酯(“AE”),Rf0.69(石油醚/乙酸乙酯1∶1);EI 324。
将催化量的DMAP加入到0.3g的“AE”的18ml二氯甲烷和0.14ml三乙胺的溶液中。在冰浴中冷却此混合物,加入0.063ml甲磺酰氯并随后将此混合物室温下搅拌14小时。除去溶剂后,将此残余物溶解于50ml甲苯中,用0.179g的DBU处理并在80℃下搅拌16小时。除去溶剂后,将此混合物在硅胶60上纯化(石油醚/乙酸乙酯9∶1)。得到90mg的8-甲氧基-6,11-二氢-2H-二苯并[cd,g]薁-1-甲酸甲酯(“AF”),Rf 0.68(石油醚/乙酸乙酯4∶1)。
在冰浴中,将0.44g氯化铝和0.26g乙硫醇的悬浮液冷却。加入0.2g的“AF”的5ml二氯甲烷溶液。将此混合物室温下搅拌16小时,用2N HCl处理,并随后搅拌。常规处理后,得到181mg的8-甲氧基-6,11-二氢-2H-二苯并[cd,g]薁-1-甲酸甲酯(“AG”),Rf 0.368(石油醚/乙酸乙酯4∶1);EI 292。
在室温氩气氛下,将532mg的2-(3-羟基丙基氨基)-吡啶-N-氧化物和540mg的偶氮二甲酸二乙酯在10ml DMF中的溶液加入到440mg的“AG”和866mg的三苯基膦的20ml DMG溶液中。随后,将此混合物搅拌3天,分离出溶剂并将此混合物在硅胶60上纯化(乙酸乙酯/甲醇9∶1)。得到80mg的8-[3-(1-氧基吡啶-2-基氨基)丙氧基]-6,11-二氢-2H-二苯并[cd,g]薁-1-甲酸甲酯(“AH”),Rf0.42(乙酸乙酯/甲醇4∶1)。
将80mg的“AH”和0.063ml的三氯化磷的15ml氯仿溶液加热回流3小时。常规处理后,将此残余物通过制备HPLC纯化。得到7.6mg的8-[3-(吡啶-2-基氨基)丙氧基]-6,11-二氢-2H-二苯并[cd,g]薁-1-甲酸甲酯(“AI”),Rf 0.66(乙酸乙酯)。
实施例2
8-[3-(吡啶-2-基氨基)丙氧基]-6,11-二氢-2H-二苯并[cd,g]薁-1-甲酸盐:
将7.6mg的“AI”的1.5ml二噁烷溶液用2.0ml的1N HCl处理并在110℃下搅拌16小时。除去溶剂后,得到8-[3-(吡啶-2-基氨基)丙氧基]-6,11-二氢-2H-二苯并[cd,g]薁-1-甲酸氢氯酸盐,Rf0.62(乙酸乙酯/甲醇95∶5+1% TEA)。
类似于实施例1和2制备下列化合物:
8-[3-(1,4,5,6-四氢嘧啶-2-基氨基)丙氧基]-2,6,11,11a-四氢-1H-二苯并[cd,g]薁-1-甲酸
{8-[3-(1,4,5,6-四氢嘧啶-2-基氨基)丙氧基]-2,6,11,11a-四氢-1H-二苯并[cd,g]薁-2-基}-乙酸
下列实施例涉及药物制剂:
实施例A:注射小瓶
将100g的式I活性化合物和5g的磷酸氢二钠在3l双重蒸馏水中的溶液,用2N盐酸调节pH至6.5,除菌过滤,装入注射小瓶中,在无菌条件下冻干并无菌封装。每个注射小瓶装有5mg的活性化合物。
实施例B:栓剂
将20g的式I的活性化合物与100g大豆卵磷脂和1400g的可可脂的混合物熔化,倒入模具中并让其冷却。每个栓剂中含有20mg的活性化合物。
实施例C:溶液剂
用1g式I的活性化合物、9.38g的NaH2PO4·2H2O、28.48g的Na2HPO4·12H2O和0.1g的苯扎氯铵在940ml双蒸水中制备溶液。将此溶液调节至pH 6.8,加至1l并照射灭菌。此溶液可以以滴眼剂的形式使用。
实施例D:软膏
将500mg的式I活性化合物与99.5g的凡士林在无菌条件下混合。
实施例E:片剂
将1kg的式I活性化合物、4kg乳糖、1.2kg马铃薯淀粉、0.2kg滑石和0.1kg硬脂酸镁的混合物以常规方式压制,得到片剂,其中每片含10mg的活性化合物。
实施例F:包衣片剂
类似于实施例E压制片剂,然后用含蔗糖、马铃薯淀粉、滑石、黄蓍胶和着色剂的包衣以常规方式进行包衣。
实施例G:胶囊
将2kg的式I活性化合物以常规方式装入硬明胶胶囊中,使每个胶囊含20mg的活性化合物。
实施例H:安瓿
将1kg的式I的活性化合物在601双重蒸馏水中的溶液除菌过滤,装入安瓿中,在无菌条件下冻干并无菌密封。每只安瓿中装有10mg的活性化合物。
实施例I:吸入喷雾剂
将14g的式I的活性化合物溶解于10l的等渗氯化钠溶液中,并将此溶液装入商购的带有泵的喷雾容器中。此溶液可以喷雾到口腔和鼻内。启动一次的喷雾(约0.1ml)相对于约0.14mg的剂量。
Claims (10)
1、式I的化合物及其生理可接受盐和溶剂化物,
其中
R1是OR4、NHR4或NA″2,
R2是H、Hal、NO2、NHR4、NA″2、OR4、S03R4、SO2R4或SR4,
R3是NH2、H2N-C(=NH)或H2N-(C=NH)-NH,其中伯胺基团也可以被常规氨基保护基保护,或R5-NH-,
R4是H、A、Ar或Aralk,
R5是具有1至4个氮、氧和/或硫原子的单或双核杂环,其可以未被取代或者被如下基团单、二或三取代:Hal、A″、CO-A′、OA′、CN、COOA′、CONH2、NO2、=NH或=O,
A是具有1-15个碳原子的烷基或者是具有3至15个碳原子的环烷基,其未被取代或者被R6单、二或三取代,且其中一个、两个或三个亚甲基可以被N、O和/或S代替,
R6是Hal、NO2、NHA′、NA″2、OA′、苯氧基、CO-A′、SO3A′、CN、NHCOA′、COOA′、CONA′2或SO2A′,
A′是H或具有1-6个碳原子的烷基,
A″是具有1-6个碳原子的烷基,
Ar是单或双核芳环系统,其未被取代或被具有1-6个碳原子的烷基单、二或三取代,和/或被R6取代的具有0、1、2、3或4个N、O和/或S的单或双核芳香环系统,
Aralk是具有7-14个碳原子的芳亚烷基,其未被取代或被R6一、二或三取代,且其中一个、两个或三个亚甲基被N、O和/或S代替,
Hal是F、Cl、Br或I,
m,n在各种情况下彼此独立地是0、1、2、3或4。
2、权利要求1的式I化合物的对映异构体和非对映异构体。
3、权利要求1的化合物,它们是
a)8-[3-(吡啶-2-基氨基)丙氧基]-6,11-二氢-2H-二苯并[cd,g]薁-1-甲酸
b)8-[3-(1,4,5,6-四氢嘧啶-2-基氨基)丙氧基]-2,6,11,11a-四氢-1H-二苯并[cd,g]薁-1-甲酸
c){8-[3-(1,4,5,6-四氢嘧啶-2-基氨基)丙氧基]-2,6,11,11a-四氢-1H-二苯并[cd,g]薁-2-基}-乙酸
4、权利要求1的式I化合物及其盐和溶剂化物的制备方法,其特征在于
a)通过用溶剂分解或氢解试剂处理,将式I的化合物从其官能基衍生物中游离出,
或
b)通过,例如,以下方法将R1、R2和/或R3转变为另一种基团R1、R2和/或R3:
i)通过与脒化试剂反应将氨基转变为胍基,
ii)将酯水解,
iii)将羧酸还原为醇,
iv)通过氢化将羟基脒转变为脒,
和/或将式I的碱或酸转变为其一种盐。
5、作为GPIIb/IIIa拮抗剂用于控制血栓形成、心肌梗死、冠心病和动脉硬化的权利要求1的式I的化合物及其生理可接受的盐和溶剂化物。
6、权利要求1的式I化合物及其生理可接受盐和溶剂化物,作为αv整联蛋白抑制剂用于控制病理性血管生成紊乱、血栓形成、心肌梗死、冠心病、动脉硬化、肿瘤、骨质疏松和类风湿性关节炎。
7、药物制剂,其特征在于其中含有至少一种权利要求1所述的式I化合物和/或其一种生理可接受的盐或溶剂化物。
8、制备药物制剂的方法,其特征在于将权利要求1所述的式I化合物和/或其一种生理可接受的盐或溶剂化物与至少一种固体、液体或半液体载体或赋形剂混合制备为适宜的剂型。
9、权利要求1所述的式I化合物及其生理可接受的盐和溶剂化物作为治疗活性化合物的用途。
10、权利要求1所述的式I化合物及其生理可接受的盐和溶剂化物制备用作αv整联蛋白抑制剂的药物的用途。
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HUP0200643A3 (en) | 2003-10-28 |
NO20014976D0 (no) | 2001-10-12 |
SK14342001A3 (sk) | 2002-04-04 |
EP1169306A1 (de) | 2002-01-09 |
KR20010102570A (ko) | 2001-11-15 |
JP2002542231A (ja) | 2002-12-10 |
CZ20013704A3 (cs) | 2002-02-13 |
BR0009690A (pt) | 2002-01-08 |
AU3817400A (en) | 2000-11-02 |
US6521646B1 (en) | 2003-02-18 |
DE19916837A1 (de) | 2000-10-19 |
NO20014976L (no) | 2001-10-12 |
CA2367359A1 (en) | 2000-10-26 |
WO2000063178A1 (de) | 2000-10-26 |
MXPA01010294A (es) | 2002-05-06 |
ZA200109343B (en) | 2003-04-30 |
PL350354A1 (en) | 2002-12-02 |
AR023496A1 (es) | 2002-09-04 |
HUP0200643A2 (hu) | 2002-07-29 |
RU2001129708A (ru) | 2004-02-27 |
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