CN1436196A - 吡啶-2-基-氨烷基羰基甘氨酰基-β-丙氨酸及其衍生物 - Google Patents
吡啶-2-基-氨烷基羰基甘氨酰基-β-丙氨酸及其衍生物 Download PDFInfo
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- CN1436196A CN1436196A CN01811104A CN01811104A CN1436196A CN 1436196 A CN1436196 A CN 1436196A CN 01811104 A CN01811104 A CN 01811104A CN 01811104 A CN01811104 A CN 01811104A CN 1436196 A CN1436196 A CN 1436196A
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Abstract
本发明涉及通式(I)的化合物,其中:R1代表H,A,Ar,Hal,-OH,-O-A,-CF3或-OCF3;R2和R7代表H或A;R3,R4,R5和R6,彼此独立地,代表H,A,Hal,-OH,-O-A,-CF3,-OCF3,-CN,-NH2,-A-NH2;A代表C1-C6烷基;Ar代表由芳香化合物形成的取代基,其可选择性地被R5取代一次,两次或三次,并具有1-3个可选择性地与其它环状结构稠合形成稠环系的环状结构;Het代表由具有1-3个环状结构的杂环形成的取代基,各环状结构是饱和的,不饱和的或芳香的并可选择性地与其它环状结构稠合形成稠环系,且所述杂环的环状结构中总共具有1-4个N,O和/或S原子并可选择性地被R6取代;Hal代表F,Cl,Br或I,且;n等于2,3,4,5或6。本发明还涉及所述化合物的用途。
Description
本发明涉及通式I的化合物及其良好耐受的盐和溶剂化物,
其中
R1为H,A,Ar,Hal,-OH,-O-A,-CF3或-OCF3;
R2和R7为H或A;
R3为
R4和R6在各种情况中,彼此独立地为H,A,Hal,-OH,-O-A,-CF3,-OCF3,-CN,-NH2,-A-NH2;
R5在各种情况中,彼此独立地为H,A,Hal,-OH,-O-A,-CF3,-OCF3,-CN,-NO2;
A为C1-C6烷基;
Ar是由
芳基形成的取代基,其可选择性地被R5取代一次,两次或三次,并具有1-3个可选择性地与其它环状结构稠合形成稠环系的环状结构;
Het是由具有1-3个环状结构的
杂环形成的取代基,各环状结构可以是饱和的,不饱和的或芳香的并可选择性地与其它环状结构稠合形成稠环系,且所述杂环的环状结构中总共具有1-4个N,O和/或S原子并可选择性地被R6取代;
Hal为F,Cl,Br或I;
n为2,3,4,5或6。
WO97/26250和
WO97/24124涉及相关物质种类的化合物。
其中X,Y,m,n,R3,R4,R5和R6具有WO97/26250中给出的含义。X是5-元至6-元单环的芳环,其具有0-4个氮,氧或硫原子,并可选择性地被R1或R2取代,或X是9-元至10-元多环系,其中至少一个环是芳香的,且其具有0-4个氮,氧或硫原子并被选择性地取代。n和m是0-6的自然数。
其中的取代基具有WO97/24124中给出的含义。
本发明是以发现有价值的新化合物,特别是用于生产药物的那些化合物为目的的。
人们已经发现,由于通式I的化合物及其盐可被良好耐受,它们具有非常有价值的药理学性能。首先,它们可起整联蛋白抑制剂的作用,因此它们可抑制ανβ3或ανβ5整联蛋白的受体与配体的相互作用,如玻连蛋白与ανβ3整联蛋白受体的结合。整联蛋白是膜结合的异源二聚糖蛋白,它由一个α-亚单位和一个较小的β-亚单位组成。结合配体的相对亲和性和特异性是通过不同α-和β-亚单位的结合确定的。就整联蛋白ανβ1,ανβ3,ανβ5,αIIbβ3和ανβ6及ανβ8来说,特别是就ανβ3,ανβ5和ανβ6来说,本发明的化合物可显示出特别高的活性程度。特别是,人们已经发现了有效的ανβ3整联蛋白选择性抑制剂。ανβ3整联蛋白可在许多细胞,例如内皮细胞,血管如主动脉的平滑肌细胞,破坏骨基质的细胞(破骨细胞)和肿瘤细胞上表达。
本发明化合物的效果可使用J.W.Smith等在J.Biol.Chem.1990,265,12267-12271中描述的方法加以证实。
在Science 1994,264,569-571中,P.C.Brooks,R.A.Clark和D.A.Cheresh描述了血管生成的起源依赖于血管整联蛋白与细胞外基质蛋白间的相互作用。
在Cell 1994,79,1157-1164中,P.C.Brooks,A.M.Montgomery,M.Rosenfeld,R.A.Reisfeld,T.Hu,G.Klier和D.A.Cheresh描述了使用环肽抑制该相互作用,由此引发生血管细胞的编程性细胞死亡(细胞程序死亡)的可能性。该文章描述了,例如,ανβ3的拮抗剂或抗ανβ3的抗体,其通过引发编程性细胞死亡而使肿瘤缩小。
关于本发明化合物可防止活细胞与相应基质蛋白的粘附,从而防止肿瘤细胞与基质蛋白粘附的实验证据可在细胞粘附试验中提供,所述试验与F.Mitjans等在J.Cell Science 1995,108,2825-2838中描述的方法类似。
通式I的化合物能够抑制金属蛋白酶与整联蛋白的结合,从而防止细胞利用蛋白酶的酶活性。P.C.Brooks等在Cell 1996,85,683-693描述了环-RGD肽抑制MMP-2(基质金属蛋白酶2)与玻连蛋白受体ανβ3结合的能力。
可阻断整联蛋白受体与配体,如血纤蛋白原与血纤蛋白原受体(糖蛋白IIb/IIIa)结合的通式I化合物可作为拮抗剂防止肿瘤细胞通过转移而扩散,因此其可在外科手术除去肿瘤的操作过程中,被用作具有抗转移作用的物质。这是通过下列理由加以证实的:由于肿瘤细胞与血小板相互作用形成微团聚体(微血栓),肿瘤细胞从局部肿瘤扩散到血管系统中。肿瘤细胞被微团聚体提供的保护遮挡,因此不被免疫系统的细胞识别。所述微团聚体能够沉降在血管壁上,由此进一步促进肿瘤细胞侵入到组织中。由于微血栓的形成是由配体与相应整联蛋白受体,如ανβ3或αIIbβ3在活化血小板上的结合介导的,因此相应的拮抗剂可被看作是转移的有效抑制剂。
化合物对ανβ5整联蛋白受体的作用,及其所以被用作抑制剂的原因可以用J.W.Smith等,在J.Biol.Chem.1990,265,12267-12271中描述的方法加以证实。
通式I的化合物可被用作人和兽药中的药物活性化合物,特别可用于预防和/或治疗循环疾病,血栓形成,心肌梗塞形成,动脉硬化,中风,心绞痛,肿瘤疾病,如肿瘤的发展或转移,骨质溶解疾病,如骨质疏松症,病理性血管生成疾病,如炎症,眼科疾病,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(rubeotic)青光眼,溃疡性结膜炎,克罗恩氏病,动脉粥样硬化,牛皮癣,血管成形术后的再狭窄,多发性硬化,病毒感染,细菌感染和真菌感染,且其与急性肾衰竭和伤口愈合有关,可用于促进愈合过程。
ανβ6是一种相对较稀有的整联蛋白(Busk等,1992J.Biol.Chem.267(9),5790),其形成量的增加与上皮组织的修复过程有关,且它优选结合天然基质分子纤连蛋白和腱生蛋白(Wang等,1996,Am.J.Respir.Cell Mol.Biol 15(5),664)。目前还不能准确知道ανβ6的生理和病理功能:然而,人们猜测此整联蛋白在涉及上皮细胞的生理过程和疾病(例如,炎症,伤口愈合及肿瘤)中起着重要的作用。因此,ανβ6在伤口中的角质形成细胞上表达(Haapasalmi等,1996,J.Invest.Dermatol.106(1),42),由此假设它可作为所述整联蛋白的激动剂或拮抗剂除影响伤口愈合过程和炎症之外还能影响其它皮肤病理事件,如牛皮癣。此外,ανβ6在呼吸道上皮中发挥重要的作用(Weinacker等,1995,Am.J.Respir.CellMol.Biol.12(5),547),这意味着应该能使用此整联蛋白相应的激动剂/拮抗剂而成功治疗呼吸道疾病如支气管炎,哮喘,肺纤维组织形成及呼吸道肿瘤。最后,已知ανβ6还可在肠上皮中发挥重要的作用,这意味着相应的整联蛋白激动剂/拮抗剂应该可用于治疗炎症,肿瘤和胃/肠道的伤口。
化合物对ανβ6整联蛋白受体的作用,及其所以被用作抑制剂的原因是利用J.W.Smith等在J.Biol.Chem.1990,265,12267-12271中描述的方法加以证实的。
在使用生物材料,植入物,导管或心脏起博器的手术中,通式I的化合物可被用作具有抗菌作用的物质。
在本文中,它们的作用是抗菌。抗菌活性的功效可使用P.Valentin-Weigund等在Infection and Immunity,1988,2851-2855中描述的方法加以证实。
药物活性化合物摄取到生物体中的测量值是它的生物可利用率。
如果药物活性化合物是以注射溶液的形式静脉内给予到生物体中的,那么其不变形式的绝对生物可利用率,即,到达全身血液,即到达大循环的药物比例为100%。
当口服给予治疗活性的化合物时,通常活性化合物是作为固体存在于制剂中的,并因此首先将它溶解,以便能穿过进入屏障,例如胃肠道,口腔粘膜,鼻隔膜或皮肤,特别是角质层,或能被身体吸收。药动学数据,即生物可利用率可按照与J.Shaffer等在J.Pharm.Sciences,1999,88,313-318中描述的类似方法获得。通式I的化合物至少具有一个手性中心,因此能够以几个立体异构的形式存在。所有这些形式(例如D和L形式)及其混合物(例如,DL形式)均包括在通式中。
本发明的化合物还包括被认为是前体药物衍生物的那些。这些的例子是已经用烷基或酰基,糖或寡肽改性过的通式I化合物,且其在生物体中迅速裂解,形成本发明的活性化合物。如果忽略通常为最低限度的药动学差异,那么前体药物衍生物的效果与它们的活性分解产物相等,正是由于这个原因,而寻求这些化合物的保护。
此外,游离氨基或游离羟基,其是通式I化合物的取代基,可具有适宜的保护基团。
通式I化合物的溶剂化物是指将惰性溶剂分子加入到通式I的化合物中,这种加入是由于化合物与溶剂分子的相互吸引而形成的。溶剂化物的例子是一水合物,二水合物或与醇,例如与甲醇或乙醇的加合化合物。
上述定义的引申,取代基R1,R2,R3,R4,R5,R6,R7,A,Ar,Het,Hal和n的含义及优选含义在下面详细解释。
R1优选为H,A,Hal或-OH,特别是甲基。R1优选在吡啶氮的对位。
R2和R7优选为氢。
R4优选为H,A或Hal,特别是氢。
R5优选为甲基,乙基,-OCH3,-CF3,OH,氟,氯或溴。
A为直链或支链且具有1-6,优选1,2,3,4,5或6个碳原子的取代基。A优选甲基,和,另外还有,乙基,正-丙基,异丙基,正-丁基,仲-丁基或叔-丁基,和,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,1,1-,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,或1,1,2-或1,2,2-三甲基丙基。
A特别优选甲基,乙基,异丙基,正-丙基,正-丁基或叔-丁基。
Ar是由芳基形成的取代基,其可选择性地被R5取代一次,两次或三次,并具有1-3个可选择性地与其它环状结构稠合形成稠环系的环状结构。芳基中的环状结构数与理论上必须进行开环以便将芳基转化成无环化合物的开环数相等。Ar优选仅具有一个环状结构。
Ar优选为被R5选择性地取代一次,两次或三次的苯基,萘基,蒽基,联苯基,特别是被选择性地取代一次,两次或三次的苯基或萘基。因此Ar优选为苯基,邻-,间-或对-甲基苯基,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-羟基苯基,邻-,间-或对-甲氧基苯基,邻-,间-或对-乙氧基苯基,邻-,间-或对-三氟甲基苯基,邻-,间-或对-氟苯基,邻-,间-或对-氯苯基或邻-,间-或对-溴苯基,还优选2,3-,2,4-,2,5-,2,6-,3,4-或3,5-二甲基苯基,2,3-,2,4-,2,5-,2,6-,3,4-或3,5-二羟基苯基,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,2,3-,2,4-,2,5-,2,6-,3,4-或3,5-二甲氧基苯基或3-氯-4-氟苯基,4-氟-2-羟基苯基,萘-1-基,萘-2-基或2-,3-,4-,5-,6-,7-或8-甲基萘-1-基,2-,3-,4-,5-,6-,7-或8-乙基萘-1-基,2-,3-,4-,5-,6-,7-或8-氯萘-1-基,2-,3-,4-,5-,6-,7-或8-氟萘-1-基,2-,3-,4-,5-,6-,7-或8-溴萘-1-基,2-,3-,4-,5-,6-,7-或8-羟基萘-1-基,1-,3-,4-,5-,6-,7-或8-甲基萘-2-基,1-,3-,4-,5-,6-,7-或8-乙基萘-2-基,1-,3-,4-,5-,6-,7-或8-氯萘-2-基,1-,3-,4-,5-,6-,7-或8-氟萘-2-基,1-,3-,4-,5-,6-,7-或8-溴萘-2-基,1-,3-,4-,5-,6-,7-或8-羟基萘-2-基。Ar特别优选苯基,邻-,间-或对-氟苯基,间-或对-氯苯基,对-甲基苯基,对-三氟甲基苯基,3-氯-4-氟苯基,4-氯-2-羟基苯基,萘-1-基或萘-2-基。
Het是由选择性地取代的,具有1-3个环状结构的杂环形成的取代基;优选具有一个环状结构的杂环。杂环中的环状结构数与理论上必须进行开环以便将杂环转化成无环化合物的开环数相等。在化学可能的范围内,该环状结构彼此独立地可以是饱和的,不饱和的或芳香的。环状结构可选择性地与其它环状结构稠合形成稠环系。非芳香的饱和或不饱和环状结构可像稠环系那样相互连接,即彼此共用化学键,例如与甾族化合物或与苯并二氢吡喃。所述杂环共含有1-4个氮,氧和/或硫原子,其可替换环状结构中的碳原子。优选这些N,O和/或S原子不相邻。该杂环可选择性地被R6取代。Het优选吡啶基,喹啉基,噻吩基,苯并[b]噻吩基,吲哚基,特别是吡啶-3-基或吡啶-4-基,喹啉-8-基,苯硫-3-基,苯并[b]苯硫-6-基或吲哚-7-基。
Hal是F,Cl,溴或碘,特别是F,Cl或溴。
N是2,3,4,5或6,特别优选3,4或5,然而特别是3。
其中R7不是氢的通式I化合物及其溶剂化物被认为是前体药物,即,它们在体外实验中是非活性的,这是因为它们掩蔽了生物活性的羧基。然而,前体药物可在肌体中代谢转化成生物活性的形式。与R7=H的通式I化合物相对应的相应游离酸及其盐和溶剂化物在体外是活性的。
因此,本发明特别涉及通式I的那些化合物,其中所述基团至少有一个具有上述优选含义之一。
本发明还涉及一种制备通式I化合物及其盐和溶剂化物的方法,该方法包括
(a)通式II的化合物
其中R1和n具有上述含义,
与通式III的化合物反应
其中R2,R3和R7具有上述含义,且R7≠H的基团可被选择性地转化成R7=H的基团,
或包括
其中R1,R2和n具有上述含义,
其中R3和R7具有上述含义,且R7≠H的基团可被选择性地转化成R7=H的基团,或
(c)通式I化合物的一个或多个基团R1,R2,R3,R4,R5,R6和/或R7可通过
i)使羟基烷基化和/或
ii)水解酯基形成羧基和/或
iii)使羧基酯化和/或
iv)使氨基烷基化和/或
v)使氨基酰化和/或
vi)用酸或碱处理而使通式I的碱性或酸性化合物转化成其盐或溶剂化物,
而被转化成一个或多个基团R1,R2,R3,R4,R5,R6和/或R7。
通式I化合物及用于制备它们的起始化合物是按照本身已知且在文献中描述过的方法制备的(例如,在标准著作中,如Houben-Weyl,Methoden der organischen Chemie[有机化学方法],Georg-Thieme-Verlag,Stuttgart),特别是在适于所述反应的已知反应条件下制备。就此而论,也可使用本身已知,但未在此处详述的不同方法。
如果需要,也可就地形成起始化合物,这样就不用将它们从反应混合物中分离出来,而是立即经过进一步的反应,从而形成通式I的化合物。
一些相同或不同的被护氨基和/或羟基也可存在于起始化合物的分子中。如果存在的保护基彼此不相同,那么在大多数情况下,它们可被选择性地除去(就这一问题参看:T.W.Greene,P.G.M.Wuts,Protective Groups in Organic Chemistry,2nded.,Wiley,New York1991或P.J.Kocienski,Protecting Groups,1sted.,Georg ThiemeVerlag,Stuttgart-New York,1994,H.Kunz,H.Waldmann inComprehensive Organic Synthesis,Vol.6(ed.,B.M.Trost,I.Fleming,E.Winterfeldt),Pergamon,Oxford,1991,pp.631-701)。
术语“氨基保护基”为人们所熟知,它是指适于保护(封闭)化学反应中氨基的基团。特别是,未取代或取代的酰基,芳基,芳烷氧甲基或芳烷基是这种性质的典型基团。因为氨基保护基在预期的反应(或反应顺序)之后即被除去,因此它们的性质和大小不很重要;然而,具有1-20个,特别是1-8个C原子的那些是优选的。就本方法而论,术语“酰基”可以最广义的形式来解释。它包括来源于脂肪族,芳脂肪族,脂环族,芳香或杂环羧酸或磺酸的酰基,特别是烷氧羰基,烯氧羰基,芳氧羰基和,特别是,芳烷氧羰基。这种酰基的例子是烷酰基,如乙酰基,丙酰基或丁酰基;芳烷酰基,如苯乙酰基;芳酰基,如苯甲酰基或甲苯甲酰基;芳氧烷酰基,如苯氧乙酰基;烷氧羰基,如甲氧羰基,乙氧羰基,2,2,2-三氯乙氧羰基,BOC或2-碘乙氧羰基;烯氧羰基,如烯丙氧羰基(Aloc),芳烷氧羰基,如CBZ(与Z同义),4-甲氧苄氧羰基(MOZ),4-硝基-苄氧羰基或9-芴基甲氧羰基(Fmoc);2-(苯基磺酰基)乙氧羰基;三甲基甲硅烷基乙氧羰基(Teoc)或芳磺酰基,如4-甲氧-2,3,6-三甲基苯基磺酰基(Mtr)。优选的氨基保护基是BOC,Fmoc和Aloc,此外还有CBZ,苄基和乙酰基。
术语“羟基保护基”同样为人们所熟知,它是指适于保护化学反应中羟基的基团。上述未取代或取代的芳基,芳烷基,芳酰基或酰基是这种基团的典型基团,还有烷基,芳基或芳烷基甲硅烷基,或O,O-或O,S-缩醛。羟基保护基的性质和大小不很重要,这是因为它们在预期的化学反应或反应顺序后即被再一次除去;具有1-20个,特别是1-10个C原子的基团是优选的。羟基保护基的一些例子是芳烷基,如苄基,4-甲氧苄基或2,4-二甲氧苄基,芳酰基,如苯甲酰基或对-硝基苯甲酰基,酰基,如乙酰基或新戊酰基,对-甲苯磺酰基,烷基,如甲基或叔-丁基及烯丙基,烷基甲硅烷基,如三甲基甲硅烷基(TMS),三异丙基甲硅烷基(TIPS),叔-丁基二甲基甲硅烷基(TBS)或三乙基甲硅烷基,三甲基甲硅烷基乙基,芳烷基甲硅烷基,如叔-丁基二苯基甲硅烷基(TBDPS),环状缩醛,如异亚丙基缩醛,亚环戊基缩醛,亚环己基缩醛,亚苄基缩醛,对-甲氧亚苄基缩醛或邻,对-二甲氧亚苄基缩醛,无环缩醛,如四氢吡喃基(Thp),甲氧甲基(MOM),甲氧乙氧甲基(MEM),苄氧甲基(BOM)或甲基硫甲基(MTM)。特别优选的羟基保护基是苄基,乙酰基,叔-丁基或TBS。
对各种情况中所用的保护基而言,文献公开了如何将通式I的化合物从它们的官能衍生物中释放出来(例如,T.W.Greene,P.G.M.Wuts,Protective Groups in Organic Chemistry,2nded.,Wiley,New York1991或P.J.Kocienski,Protecting Groups,1sted.,Georg ThiemeVerlag,Stuttgart-New York,1994)。就这一问题,还可使用本身已知,但未在此处详述的不同方法。
例如,优选在15-30℃时,使用约3-5N HCl在二噁烷中,或使用TFA在二氯甲烷中除去BOC和O-叔-丁基,而在15-30℃时,使用二甲胺,二乙胺或哌啶的约5-50%溶液在DMF中除去Fmoc基团。Aloc基团是20-30℃时,在温和条件下,使用贵金属催化,在氯仿中裂解的。优选的催化剂是四(三苯基膦)钯(O)。
通常,通式II-V的起始化合物是已知的。然而如果它们是新的,可使用本身已知的方法制备它们。
通式II的化合物是在有碱存在的情况下,偶合相应的2-氨基吡啶衍生物与相应的正-溴羧酸酯(Br-[CH2]n-COOSG1,其中SG1是前述的羟基保护基),并随后在标准条件下除去保护基而得到的。
通式IV的化合物是在标准条件下,通过通式II化合物与甘氨酸衍生物H2N-CH2-COOSG2的肽-类似物的偶合得到的,其中SG2是前述的羟基保护基。
通式V的化合物(β-氨基酸)可按照与Skinner等,在J.Org.Chem.1960,25,1756中描述的类似方法制备。使相应的醛R3-CHO与丙二酸和醋酸铵在适宜溶剂中反应,溶剂优选为醇,如特别优选乙醇,产生通式V的β-氨基酸,其中R7是H。在标准条件下,酯化通式V的游离酸,可产生通式V的化合物,其中R7是A。
为了制备通式III的化合物,将酸功能受到保护的通式V的β-氨基酸(或者利用适宜的保护基保护该化合物或R7为A)与甘氨酸衍生物SG3-NH-CH2-COOH偶合。甘氨酸衍生物SG3-NH-CH2-COOH的取代基SG3是一种氨基保护基,如前所述,其随后被除去。在Houben-Weyl,1.c.,第15/II册,1974,1-806页中描述了肽合成的常规方法。
通式I的化合物可通过使通式II的化合物与通式III的化合物反应,随后除去保护基或使表示A的基团R7转化成基团R7=H而得到。
通式I的化合物同样可通过使通式IV的化合物与通式V的化合物反应,随后除去保护基或使表示A的基团R7转化成基团R7=H而得到。
所述偶合反应优选在有脱水剂,例如碳二亚胺,如二环己基碳二亚胺(DCC),N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺盐酸盐(EDC)或二异丙基碳二亚胺(DIC),或者,例如,丙烷膦酸酐(参见Angew.Chem.1980,92,129),二苯基磷酰基叠氮化物或2-乙氧基-N-乙氧羰基-1,2-二氢喹啉存在的情况下,在惰性溶剂,例如卤代烃,如二氯甲烷,醚,如四氢呋喃或二噁烷,酰胺,如DMF或二甲基乙酰胺,腈,如乙腈中,在二甲基亚砜中或在有这些溶剂存在的情况下,在大约-10-40℃,优选0-30℃的温度范围内完成。根据所用条件的不同,反应时间在几分钟到几天之间。
已经证实偶合试剂TBTU(O-(苯并三唑-1-基)-N,N,N’,N’-四甲基尿鎓四氟硼酸盐)或O-(苯并三唑-1-基)-N,N,N’,N’-四甲基尿鎓六氟磷酸盐的加入非常有利,这是因为在有这些化合物其中一种存在的情况下,仅有较小程度的外消旋作用发生,且没有细胞毒性的副产物形成。
代替通式II和/或IV的化合物,还可使用通式II和/或IV化合物的衍生物,优选预活化的羧酸,或羰基卤化物,对称或混合的酸酐或活性酯。文献描述了用于在典型酰化反应中活化羧基的基团(例如,在标准著作中,如Houben-Weyl,Methoden der organischen Chemie[有机化学方法],Georg-Thieme-Verlag,Stuttgart)。活化酯可很方便地就地形成,例如通过加入HOBt(1-羟苯并三唑)或N-羟基琥珀酰亚胺形成。
通常,所述反应在惰性溶剂中进行;当使用羰基卤化物时,它在有酸-结合剂,优选有机碱,如三乙胺,二甲基苯胺,吡啶或喹啉存在的情况下进行。
碱金属或碱土金属的氢氧化物,碳酸盐或碳酸氢盐的加入,或其它弱酸与碱金属或碱土金属,优选钾,钠,钙或铯的盐的加入也是有利的。
用酸可将通式I的碱转化成相关的酸加成盐,例如在惰性溶剂如乙醇中,使等量的碱和酸反应,然后蒸发浓缩。能够产生生理无害盐的酸特别适于此反应。因此可使用无机酸,例如硫酸,亚硫酸,连二硫酸,硝酸,氢卤酸,如盐酸,氢溴酸,磷酸,如正磷酸,或氨基磺酸,也可使用有机酸,特别是脂肪酸,脂环酸,芳脂肪酸,芳香或杂环的一元或多元羧酸,磺酸或硫酸,例如甲酸,乙酸,丙酸,己酸,辛酸,癸酸,十六酸,十八酸,新戊酸,二乙基乙酸,丙二酸,丁二酸,庚二酸,反丁烯二酸,顺丁烯二酸,乳酸,酒石酸,苹果酸,柠檬酸,葡萄糖酸,抗坏血酸,烟酸,异烟酸,甲磺酸或乙磺酸,苯磺酸,三甲氧基苯甲酸,金刚烷羧酸,对-甲苯磺酸,乙醇酸,扑酸,氯苯氧基乙酸,天门冬氨酸,谷氨酸,脯氨酸,乙醛酸,软脂酸,对氯-苯氧基异丁酸,环己烷羧酸,葡萄糖1-磷酸盐,萘一磺酸,萘二磺酸或月桂基硫酸。还可使用生理无害酸的盐,如苦味酸盐分离和/或纯化通式I的化合物。另一方面,可用碱(例如,钠或钾的氢氧化物或碳酸盐)将通式I的化合物转化成相应的金属盐,特别是碱金属盐或碱土金属盐,或转化成相应的铵盐。
本发明还涉及作为药物活性化合物的通式I化合物,及其生理上无害的盐或溶剂化物。
本发明还涉及作为整联蛋白抑制剂的通式I化合物,及其生理上无害的盐或溶剂化物。
本发明还涉及用于控制疾病的通式I化合物,及其生理上无害的盐或溶剂化物。
此外,本发明还涉及药物制剂,其至少含有一种通式I的化合物,和/或其生理上无害的盐或溶剂化物,其是通过非化学途径制备的。在这一点上,通式I的化合物可与至少一种固体,液体和/或半流体的赋形剂或辅剂和,适宜的,与一种或多种另外的活性化合物一起形成适宜的给药形式。
这些制剂可被用作人或兽药中的药物。适宜的赋形剂是有机或无机的物质,其适于肠内(例如口服),非肠道或局部给药,且其不与新化合物反应,如水,植物油,苄醇,烷撑二醇,聚乙二醇,三乙酸甘油酯,明胶,碳水化合物,如乳糖或淀粉,硬脂酸镁,滑石和凡士林。可使用片剂,丸剂,包衣片剂,胶囊剂,散剂,颗粒剂,糖浆剂,汁剂和滴剂,特别是口服使用;而栓剂可直肠使用;溶液,优选油溶液或水溶液,和,此外还有,混悬液,乳液和植入物可非肠道使用;软膏剂,乳膏或粉剂可局部使用。还可将所述新化合物冷冻干燥,并使用所得的冷冻干燥物,例如,用于生产注射制剂。上述制剂可被灭菌和/或含有辅剂如润滑剂,防腐剂,稳定剂,湿润剂,乳化剂,改变渗透压的盐,缓冲物质,染料,矫味剂和/或多种附加的活性化合物,例如一种或多种维生素。
对于吸入喷雾给药而言,可使用含有活性化合物的喷雾剂,该活性化合物溶解或混悬在推进剂气体或推进剂气体混合物(例如,CO2或氟氯化烃)中。在这一点上,所述活性化合物可很方便地以微粉化形式使用,且还可有一种或多种另外的生理耐受溶剂,例如,乙醇存在。可使用常规的吸入器给予吸入溶液。
通式I的化合物及其生理上无害的盐或溶剂化物可被用作整联蛋白抑制剂,用来控制疾病,特别是血栓形成,心肌梗塞形成,冠心病,动脉硬化,肿瘤,骨质疏松症,炎症和感染。
通式I的化合物和/或它们生理上无害的盐还可用于与由血管生成维持或传播的病变有关的疾病,特别是与肿瘤和类风湿性关节炎有关的疾病。
在这一点上,本发明的物质通常是按照与WO97/26250或WO97/24124中描述的化合物类似的方法给药,优选每个剂量单位约为0.05-500mg,特别是0.5-100mg。优选每日剂量约为0.01-2mg/kg体重。然而,各病人具体的给药剂量取决于各种因素,例如所用具体化合物的功效,年龄,体重,一般的健康状况,性别,日常饮食,给药的时间和途径,排泄的速率,药物的组合及所治疗的具体疾病的严重程度。优选非肠道给药。
此外,通式I的化合物可被用作整联蛋白的配体用于制备用于纯化整联蛋白的亲和色谱柱。
在这一点上,所述配体,即,通式I的化合物经由结合功能团,例如羧基与聚合载体共价偶合。
适宜的聚合载体材料是聚合的固相,其本身在肽化学中已知,且优选显示亲水性,例如交联聚合糖如纤维素,琼脂糖或交联葡聚糖R,丙烯酰胺,基于聚乙二醇的聚合物或Tentakel聚合物R。
用于纯化整联蛋白的亲和色谱材料是在通常用于缩合氨基酸且本身已知的条件下制备的。
通式I的化合物含有一个或多个手性中心,因此可以外消旋形式或旋光形式存在。使用本身已知的方法可将所得外消旋物机械或化学分离成对映异构体。优选通过使它与旋光分离剂反应而从外消旋混合物形成非对映异构体。适宜分离剂的例子是旋光酸,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,苦杏仁酸,苹果酸,乳酸或各种旋光樟脑磺酸,如β-樟脑磺酸。还可使用填充有旋光分离剂(例如,二硝基苯甲酰基苯基甘氨酸)的柱子进行对映异构体的分离;适宜洗脱剂的例子是己烷/异丙醇/乙腈混合物,例如体积比为82∶15∶3。
还可通过上述方法,使用已经旋光的起始化合物得到旋光的通式I化合物。
下面通过实施例更详细地说明本发明。
在上下文中,所有温度均是以℃给出的。在实施例中,“常规处理”表示:如果需要可加入水,且如果需要可根据终产品的组成调节pH值至2-10,用乙酸乙酯或二氯甲烷萃取混合物,进行相分离,在硫酸钠上干燥有机相并蒸发浓缩,通过硅胶色谱,制备型HPLC和/或通过结晶纯化残余物。适当的时候,冷冻干燥该纯化的化合物。
RT=下列系统中HPLC的保留时间(分钟):
柱:Lichrosorb RP-18(5μm)250×4mm;(分析型)
Lichrosorb RP-18(15μm)250×50mm;(制备型)
分析型HPLC
所用洗脱剂是由(A)0.1%TFA和(B)0.1%TFA在9份乙腈和1份水中组成的梯度洗脱剂。梯度是以乙腈的体积百分比给出的。该梯度洗脱是在20%B中跑5分钟,在90%B中跑50分钟。LichrosorbRP-18(5μm)250×4mm柱的保留时间是以分给出的。在强极性物质的情况下,使用另一个梯度洗脱:在5%B中5分钟,然后在75%B中50分钟。此梯度洗脱的保留时间用*表示。
在225nm处进行检测。
制备型HPLC:
使用Lichrosorb RP-18(15μm)250×50mm柱。分析检测并收集各部分。然后将该物质冷冻干燥。
通过制备型HPLC纯化的化合物以三氟醋酸盐的形式被分离。
通过使用FAB(快速原子轰击)质谱(MS)测定分子量:此后其被称为“MS-FAB(M+H)+”。
缩略语:
TBTU:(2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基尿鎓四氟硼酸盐)
HOBt:(1-羟基苯并三唑)
实施例1
制备4-喹啉-8-基苯甲醛:
将1g 8-溴喹啉,720mg 4-甲酰基苯基硼酸和166mg四(三苯基膦)钯(O)溶解在甲苯中,并将碳酸钠水溶液(1g/3ml)加入到此溶液中。使所述反应混合物沸腾回流过夜。
分离有机相,并用水洗两次。然后用无水硫酸钠干燥有机相,过滤,在旋转式蒸发仪上除去溶剂。为了进行纯化,在二氯甲烷/甲醇9/1中进行硅胶色谱。
用二乙醚研磨合所述产物的流分。得到450mg淡粉红色的结晶。
氯仿/甲醇/冰醋酸85/10/5的TLC:Rf=0.75。
实施例2
制备β-氨基酸:
β-氨基酸是按照引用的参考文献所述制备的。110mg β-氨基酸3-氨基-3-(4-喹啉-8-基苯基)丙酸是从450mg 4-喹啉-8-基苯甲醛,200mg丙二酸和300mg醋酸铵得到的。
其它β-氨基酸是按照类似的方法制备的。
对于随后的反应而言,乙醚是通过常规方法制备的(与亚硫酰氯/乙醇沸腾)。
参考文献:
Skinner等,;J.Org.Chem.25,1756(1960)
E.Profft,F.-J.Becker;Journal für Praktische Chemie[实用化学杂志],30,18-38(1965)
实施例3
合成3-{2-[4-(4-甲基吡啶-2-基氨基)丁酰氨基]乙酰氨基}-3-(4-喹啉-8-基苯基)丙酸:
将30mg乙基3-氨基-3-(4-喹啉-8-基苯基)丙酸盐的盐酸盐溶解在5ml DMF中,并将63mg[4-(4-甲基吡啶-2-基氨基)丁酰氨基]乙酸加入到此溶液中。将其全部冷却至大约0℃,并在此温度加入30mgTBTU和4.3mg HOBt。用大约0.4ml N-甲基吗啉中和该混合物。然后在室温搅拌过夜。
除去残余物得澄清溶液。然后将30ml乙酸乙酯加入到残余物中,用20ml半-浓缩的碳酸氢盐溶液萃取两次,并用30ml饱和氯化钠溶液洗一次。在硫酸钠上干燥有机相,过滤并浓缩。
将所得50mg粗物质溶解在4.5ml乙醇中,加入0.5mlNaOH(2mol/l)。室温搅拌该混合物过夜。在旋转式蒸发仪上蒸发该溶液,并通过制备型HPLC纯化残余物。得到22mg上述物质。
FAB MS(M+H+)526;保留时间(RT)13.88分钟
实施例4:
实施例5
测定
生成的肿瘤血管可显著显示出ανβ3整联蛋白,因此可使用ανβ3-特异性抑制剂追踪到它。
使用分析方法,可鉴定从人的肿瘤中分离出来的细胞系,该细胞系可提供整联蛋白ανβ6,但不提供整联蛋白ανβ3,例如Detroit562,HT-29和UCLA-P3,或提供两种整联蛋白ανβ3和ανβ6,例如Calu-3和Capan-2。(分析方法:免疫沉淀和荧光-活化细胞分类分析)。这些鉴定了的细胞系作为皮下肿瘤在免疫缺陷的啮齿类动物,例如nu/nu小鼠中生长。
就像已经描述过的那样,ανβ3整联蛋白受体的抑制剂可通过血管阻断肿瘤生长,所述血管因暴露于编程性细胞死亡信号中而长成肿瘤,并由于程序性细胞死亡(编程性细胞死亡)而死亡。(参考文献:P.C.Brooks,Eur.J.Cancer 1996,32A,2423-2426,P.C.Brooks等,Cell 1994,79,1157-1164或S.Stomblad等,J.Clin.Invest 1996,98,426-433)。
ανβ6整联蛋白抑制剂直接损害肿瘤的发展。本发明联合疗法的协同作用是通过下列一系列实验加以证实的,其按照与Mitjans等在J.Cell.Sci.1995,108,2825-2838中描述的试验系统相类似的方法进行:将ανβ6-表达肿瘤细胞皮下植入到例如nu/nu小鼠中。与Mitjans等所述的M21细胞系类似,在小鼠中观察到了整联蛋白抑制剂对这些肿瘤细胞生长的作用。
植入肿瘤细胞后,将这样处理的小鼠分成每10只一组。按照本发明每天对小鼠进行治疗,即腹膜内注射适宜的整联蛋白抑制剂,并观察到了肿瘤的生长。对照组注射无菌无热原的盐水。每周两次测量肿瘤大小,并计算相应的肿瘤体积。
下列实施例涉及药物制剂:
实施例A:注射瓶
将100g通式I的活性化合物和5g磷酸氢二钠溶解在3升双蒸馏水中,用2N盐酸调节该溶液的pH值至6.5,滤过灭菌,等分到注射瓶中,并在无菌条件下冷冻干燥;然后在无菌条件下密封该瓶。各注射瓶含5mg活性化合物。
实施例B:栓剂
熔化由20g通式I的活性化合物,100g大豆卵磷脂和1400g椰子油组成的混合物,并将其注入到模具中并使之冷却。各栓剂含20mg活性化合物。
实施例C:溶液剂
将1g通式I的活性化合物,9.38g NaH2PO4·2H2O,28.48gNa2HPO4·12H2O和0.1g苯扎氯铵溶解在940ml双蒸馏水中。调节该溶液的pH值至6.8,补足至1升,并通过辐照灭菌。此溶液剂可以滴眼剂的形式使用。
实施例D:软膏剂
将500mg通式I的活性化合物与99.5g凡士林在无菌条件下混合。
实施例E:片剂
按照常规方式,将1kg通式I的活性化合物,4kg乳糖,1.2kg马铃薯淀粉,0.2kg滑石粉和0.1kg硬脂酸镁的混合物压制成片剂,每片含10mg活性化合物。
实施例F:包衣片剂
按照与实施例E类似的方法压制片剂,然后以常规方式,用由蔗糖,马铃薯淀粉,滑石粉,黄芪胶和着色剂组成的糖衣包裹这些片剂。
实施例G:胶囊剂
按照常规方法,将2kg通式I的活性化合物等分到硬明胶胶囊中,每个胶囊含20mg活性化合物。
实施例H:安瓿剂
将1kg通式I的活性化合物溶解在60升双蒸馏水中,滤过灭菌该溶液,并将其等分到安瓿中,并在无菌条件下冷冻干燥;然后在无菌条件下密封该安瓿。各安瓿含10mg活性化合物。
实施例I:吸入喷雾剂
将14g通式I的活性化合物溶解在10升等渗的NaCl溶液中,将所得溶液等分到具有泵结构的市售喷雾容器中。该溶液可喷到口腔或鼻子中。喷一下(大约0.1ml)相当于大约0.14mg的给药剂量。
Claims (11)
其中
R1为H,A,Ar,Hal,-OH,-O-A,-CF3或-OCF3;
R2和R7为H或A;
R3为
R4,R5和R6在各种情况中,彼此独立地为H,A,Hal,-OH,-O-A,-CF3,-OCF3,-CN,-NH2,-A-NH2;
A为C1-C6烷基;
Ar是由芳基形成的取代基,其可选择性地被R5取代一次,两次或三次,并具有1-3个可选择性地与其它环状结构稠合形成稠环系的环状结构;
Het是由具有1-3个环状结构的杂环形成的取代基,各环状结构是饱和的,不饱和的或芳香的并可选择性地与其它环状结构稠合形成稠环系,且所述杂环的环状结构中总共具有1-4个N,O和/或S原子并可选择性地被R6取代;
Hal为F,Cl,Br或I;
n为2,3,4,5或6。
2.根据权利要求1所述的化合物,选自
a)3-{2-[4-(4-吡啶-2-基氨基)丁酰氨基]乙酰氨基}-3-(4-吡啶-4-基苯基)丙酸
b)3-{2-[4-(4-甲基吡啶-2-基氨基)丁酰氨基]乙酰氨基}-3-(4-吡啶-4-基苯基)丙酸
c)3-{2-[4-(吡啶-2-基氨基)丁酰氨基]乙酰氨基}-3-(4-吡啶-3-基苯基)丙酸
d)3-{2-[4-(4-甲基吡啶-2-基氨基)丁酰氨基]乙酰氨基}-3-(4-喹啉-8-基苯基)丙酸
e)3-{2-[4-(吡啶-2-基氨基)丁酰氨基]乙酰氨基}-3-(4-喹啉-8-基苯基)丙酸
f)3-[4-(1H-吲哚-7-基)-苯基]-3-{2-[4-(吡啶-2-基氨基)丁酰氨基]乙酰氨基}丙酸
g)3-{2-[4-(4-甲基吡啶-2-基氨基)丁酰氨基]乙酰氨基}-3-(4-苯硫-3-基苯基)丙酸
h)3-{2-[4-(吡啶-2-基氨基)丁酰氨基]乙酰氨基}-3-(4-苯硫-3-基苯基)丙酸
i)3-{2-[4-(4-甲基吡啶-2-基氨基)丁酰氨基]乙酰氨基}-3-(4-吡啶-3-基-3-(4-苯并[b!]苯硫-6-基苯基)-3-{2-[4-(吡啶-2-基氨基)-丁酰氨基]乙酰氨基}丙酸及其良好耐受的盐和溶剂化物。
3.一种制备权利要求1或2所述的通式I化合物及其盐和溶剂化物的方法,其中
其中R1和n具有权利要求1中给出的含义,
与通式III的化合物反应
其中R2,R3和R7具有权利要求1中给出的含义,且R6≠H的基团可被选择性地转化成R6=H的基团,适当的,
或
(b)通式IV的化合物
其中R1,R2和n具有权利要求1中给出的含义,
与通式V的化合物反应
其中R3和R7具有权利要求1中给出的含义,且R7≠H的基团可被转化成R7=H的基团,适当的,或
(c)在通式I的化合物中,一个或多个基团R1,R2,R3,R4,R5,R6和/或R7可通过
vii)使羟基烷基化和/或
viii)使酯基水解成羧基和/或
ix)使羧基酯化和/或
x)使氨基烷基化和/或
xi)使氨基酰化和/或
xii)用酸或碱处理而使通式I的碱性或酸性化合物转化成其盐或溶剂化物,
而被转化成一个或多个基团R1,R2,R3,R4,R5,R6和/或R7。
4.一种含有权利要求1或2所述的化合物的药物。
5.一种药物制剂,其含有至少一种权利要求1或2所述的化合物。
6.根据权利要求1或2所述的化合物用于生产药物的用途。
7.根据权利要求1或2所述的化合物作为整联蛋白抑制剂的用途。
8.根据权利要求1或2所述的化合物作为整联蛋白ανβ1,ανβ3,ανβ5,ανβ6和αIIbβ3抑制剂的用途。
9.根据权利要求1或2所述的化合物作为整联蛋白αν β3,ανβ5和ανβ6抑制剂的用途。
10.根据权利要求1或2所述的化合物用于治疗由血管生成维持或传播的病变的用途。
11.根据权利要求1或2所述的化合物用于生产控制血栓形成,心肌梗塞形成,冠心病,动脉硬化,炎症,肿瘤,骨质疏松症,感染和血管成形术后再狭窄的药物的用途。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10028402.7 | 2000-06-13 | ||
DE10028402A DE10028402A1 (de) | 2000-06-13 | 2000-06-13 | Pyridin-2-yl-aminoalkycarbonylglycyl-beta-alanin und Derivate |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1436196A true CN1436196A (zh) | 2003-08-13 |
Family
ID=7645128
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CN01811104A Pending CN1436196A (zh) | 2000-06-13 | 2001-06-12 | 吡啶-2-基-氨烷基羰基甘氨酰基-β-丙氨酸及其衍生物 |
Country Status (18)
Country | Link |
---|---|
US (1) | US20030171304A1 (zh) |
EP (1) | EP1290010A1 (zh) |
JP (1) | JP2004503562A (zh) |
KR (1) | KR20030022145A (zh) |
CN (1) | CN1436196A (zh) |
AR (1) | AR028714A1 (zh) |
AU (1) | AU6606301A (zh) |
BR (1) | BR0111555A (zh) |
CA (1) | CA2414000A1 (zh) |
CZ (1) | CZ20023952A3 (zh) |
DE (1) | DE10028402A1 (zh) |
HU (1) | HUP0303716A2 (zh) |
MX (1) | MXPA02012411A (zh) |
NO (1) | NO20025968D0 (zh) |
PL (1) | PL358671A1 (zh) |
SK (1) | SK17112002A3 (zh) |
WO (1) | WO2001096365A1 (zh) |
ZA (1) | ZA200209410B (zh) |
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US6455734B1 (en) * | 2000-08-09 | 2002-09-24 | Magnesium Diagnostics, Inc. | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
TR200103432T2 (tr) | 1999-06-01 | 2002-10-21 | Biogen, Inc. | Engelleyici monoklonal VLA-1 antikoru ve enflamasyonlu hastalıkların tedavisinde kullanımı. |
EA006705B1 (ru) | 2001-04-13 | 2006-02-24 | Байоджен Айдек Ма Инк. | Антитела против vla-1 |
US6908935B2 (en) | 2002-05-23 | 2005-06-21 | Amgen Inc. | Calcium receptor modulating agents |
US7176322B2 (en) | 2002-05-23 | 2007-02-13 | Amgen Inc. | Calcium receptor modulating agents |
WO2005090329A1 (en) | 2004-03-24 | 2005-09-29 | Jerini Ag | New compounds for the inhibition of angiogenesis and use of thereof |
US20090196912A1 (en) * | 2004-07-30 | 2009-08-06 | Gpc Botech Ag | Pyridinylamines |
DK2034830T3 (da) | 2006-05-25 | 2014-10-27 | Biogen Idec Inc | Anti-vla-1-antistof til behandling af slagtilfælde |
ES2400633T3 (es) * | 2008-11-24 | 2013-04-11 | Basf Se | Composición curable que comprende una base termolatente |
MX370199B (es) | 2012-02-16 | 2019-12-05 | Santarus Inc | Composiciones farmaceuticas de anticuerpo anti-antigeno muy tardio (cd49a). |
TN2020000059A1 (en) | 2017-11-01 | 2022-01-06 | Arrowhead Pharmaceuticals Inc | Integrin ligands and uses thereof |
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CN1209063A (zh) * | 1995-12-29 | 1999-02-24 | 史密丝克莱恩比彻姆公司 | 玻连蛋白受体拮抗剂 |
-
2000
- 2000-06-13 DE DE10028402A patent/DE10028402A1/de not_active Withdrawn
-
2001
- 2001-06-12 KR KR1020027016894A patent/KR20030022145A/ko not_active Application Discontinuation
- 2001-06-12 CN CN01811104A patent/CN1436196A/zh active Pending
- 2001-06-12 JP JP2002510506A patent/JP2004503562A/ja active Pending
- 2001-06-12 PL PL01358671A patent/PL358671A1/xx unknown
- 2001-06-12 EP EP01943499A patent/EP1290010A1/de not_active Withdrawn
- 2001-06-12 MX MXPA02012411A patent/MXPA02012411A/es unknown
- 2001-06-12 SK SK1711-2002A patent/SK17112002A3/sk unknown
- 2001-06-12 CA CA002414000A patent/CA2414000A1/en not_active Abandoned
- 2001-06-12 US US10/297,989 patent/US20030171304A1/en not_active Abandoned
- 2001-06-12 AU AU66063/01A patent/AU6606301A/en not_active Abandoned
- 2001-06-12 WO PCT/EP2001/006661 patent/WO2001096365A1/de not_active Application Discontinuation
- 2001-06-12 CZ CZ20023952A patent/CZ20023952A3/cs unknown
- 2001-06-12 BR BR0111555-3A patent/BR0111555A/pt not_active Application Discontinuation
- 2001-06-12 HU HU0303716A patent/HUP0303716A2/hu unknown
- 2001-06-13 AR ARP010102804A patent/AR028714A1/es unknown
-
2002
- 2002-11-19 ZA ZA200209410A patent/ZA200209410B/en unknown
- 2002-12-12 NO NO20025968A patent/NO20025968D0/no not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
HUP0303716A2 (hu) | 2004-03-01 |
MXPA02012411A (es) | 2003-04-25 |
CZ20023952A3 (cs) | 2003-03-12 |
DE10028402A1 (de) | 2001-12-20 |
AR028714A1 (es) | 2003-05-21 |
PL358671A1 (en) | 2004-08-09 |
NO20025968L (no) | 2002-12-12 |
JP2004503562A (ja) | 2004-02-05 |
ZA200209410B (en) | 2004-02-19 |
KR20030022145A (ko) | 2003-03-15 |
CA2414000A1 (en) | 2002-12-03 |
US20030171304A1 (en) | 2003-09-11 |
WO2001096365A1 (de) | 2001-12-20 |
SK17112002A3 (sk) | 2003-04-01 |
EP1290010A1 (de) | 2003-03-12 |
BR0111555A (pt) | 2003-07-08 |
NO20025968D0 (no) | 2002-12-12 |
AU6606301A (en) | 2001-12-24 |
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