CN1832761A - 硫代钨酸盐类似物及其用途 - Google Patents
硫代钨酸盐类似物及其用途 Download PDFInfo
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- CN1832761A CN1832761A CNA200480021514XA CN200480021514A CN1832761A CN 1832761 A CN1832761 A CN 1832761A CN A200480021514X A CNA200480021514X A CN A200480021514XA CN 200480021514 A CN200480021514 A CN 200480021514A CN 1832761 A CN1832761 A CN 1832761A
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Abstract
本发明提供新型四硫代钨酸盐衍生物,新型四硫代钨酸盐衍生物的制备方法,新型四硫代钨酸盐衍生物的药物组合物,使用新型四硫代钨酸盐衍生物治疗或预防与异常血管生成有关的疾病、铜代谢紊乱、神经变性疾病和肥胖症,以及使用四硫代钨酸盐衍生物的药物组合物治疗或预防与异常血管生成有关的疾病、铜代谢紊乱、神经变性疾病、肥胖症或NF-κB调节障碍的方法。
Description
1.发明领域
本发明通常涉及四硫代钨酸盐衍生物,新型四硫代钨酸盐衍生物的制备方法,新型四硫代钨酸盐衍生物的药物组合物,以及使用新型四硫代钨酸盐衍生物和四硫代钨酸盐衍生物的药物组合物治疗或预防与异常血管生成有关的疾病、铜代谢紊乱、神经变性疾病和肥胖症的方法。
2.发明背景
大多数形式的癌症源自于实体瘤(Shockley et al.,Ann.N.YAcad.Sci.1991,617:367-382),该实体瘤已证明其在临床上对治疗例如使用单克隆抗体和免疫毒素的治疗具有抗性。用于癌症治疗的抗血管生成疗法是根据实体瘤的持续生长需要血管生成(即,新的血管生成)这一认识发展起来的(Folkman,Ann.Surg.1972,175:409-416;Folkman,Mol.Med.1995,1(2):120-122;Folkman,Breast Cancer Res.Treat.1995,36(2):109-118;Hanahan et al.,Cell 1996,86(3):353-364)。抗血管生成疗法的效力在动物模型中已经得到证明(Millauer et al.,Cancer Res.1996,56:1615-1620;Borgstrom et al.,Prostrate 1998,35:1-10;Benjamin et al.,J..Clin.Invest.1999,103:159-165;Merajver et al.,Proceedings Of Special AACR Conference OnAngiogenesis and Cancer 1998,Abstract#B-11,January22-24)。在没有血管生成的情况下,实体瘤的内细胞层没有充分被滋养。此外,血管生成(即,异常血管生成)还与许多其它疾病有关(例如,眼新血管疾病、黄斑变性、风湿性关节炎等)。最近,在动物模型中,抑制血管生成与脂肪组织损失和体重减轻有着直接的关系,这表明抗血管生成疗法可以用于预防肥胖症(Rupnicket al.,Proc.Natl.Acad,Sci.2002,99:10730-10735)。
与此相反的是,除特殊情况外(例如,伤口修复,月经期间的子宫内壁增殖),正常组织不需要生成血管。因此,需要生成血管是肿瘤细胞与正常组织之间一种显著的差异。重要地是,肿瘤细胞与正常细胞相比在血管生成方面依赖性的差异,远远大于正常组织与肿瘤之间在细胞复制和细胞死亡方面的差异,这常常被利用在癌症治疗中。
血管生成需要铜,这一点已经被大量研究所证实(Parke et al.,Am.J.Pathol.1988,137:173-178;Raju et al.,Natl.Cancer lnst.1982,69:1183-1188;Ziche et al.,Natl.Cancer lnst.1982,69:475-482;Gullino,Anticancer Res.1986,6(2):153-158)。在本领域中,已经报道了通过降低体内铜的量,从而预防动物模型中的血管生成并因此减少肿瘤生长(Brem etal.,Neurosurgery 1990,26:391-396;Brem et al.,Am.J.Pathol.1990,137(5):1121-1142;Yoshida et al.,Neurosurgery 1995 37(2):287-295)。这些方法包括结合采用铜螯合剂和低铜饮食。最近,Brewer等人,在国际申请号PCT/US99/20374已经表明:铜螯合剂(例如,四硫代钼酸盐)可以有效地治疗需要血管生成的疾病(例如,实体瘤生长)。
除诱导血管生成之外,铜在肿瘤细胞生长和存活方面也具有直接的作用。在患有许多不同实体癌的患者的血浆和肿瘤组织中,存在高含量的铜(Chakravarty et al,J.Cancer Res.Clin.Oncol.1984,108:312-315)。最近,已经表明四硫代钼酸盐下调了NF-κB的表达并抑制了其移位至炎性乳腺癌细胞系SUM 149中的细胞核(Pan et al.,Cancer Res.2002,62:4854-4859)。NF-κB体系可能涉及在调节肿瘤细胞存活率过程中,并因此通过四硫代钼酸盐下调的其在肿瘤细胞中的表达,表示了铜的螯合在肿瘤存活方面的直接作用。
因此,在治疗和/或预防血管生成以及在减少肿瘤细胞成活率中,需要全面探索新型化合物四硫代钨酸盐化合物即铜螯合剂的潜在作用。这样的新型四硫代钨酸盐化合物可有效地治疗各种与血管生成有关的疾病比如癌症、伴随铜代谢紊乱的肥胖症、神经变性疾病、肥胖症以及治疗NF-κB途径调节障碍疾病比如炎症。
3.发明概述
通过提供新型四硫代钨酸盐衍生物,新型四硫代钨酸盐衍生物的制备方法,新型四硫代钨酸盐衍生物的药物组合物,使用新型四硫代钨酸盐衍生物治疗或预防与异常血管生成有关的疾病、铜代谢紊乱、神经变性疾病和肥胖症,以及使用四硫代钨酸盐衍生物的药物组合物治疗或预防与异常血管生成有关的疾病、铜代谢紊乱、神经变性疾病、肥胖症或NF-κB调节障碍的方法,本发明满足这些以及其它要求。
第一方面,本发明提供结构式(I)的化合物或其溶剂化物、水合物或N-氧化物:
其中:
R1、R2、R3、R5、R6和R7独立地是氢、烷基、取代烷基、芳基、取代芳基、芳烷基、取代芳烷基、环烷基、取代环烷基、环杂烷基、取代环杂烷基、杂芳基、取代杂芳基、杂芳基烷基、取代杂芳基烷基、杂烷基或取代杂烷基;
R4和R8独立地是氢、烷基、取代烷基、芳基、取代芳基、芳烷基、取代芳烷基、环烷基、取代环烷基、环杂烷基、取代环杂烷基、杂芳基、取代杂芳基、杂芳基烷基、取代杂芳基烷基、杂烷基或取代杂烷基、或者当N是芳环的一部分时则不存在;
任选地,R1和R2一起是烷二基、取代烷二基、杂烷二基或取代杂烷二基;
任选地,R5和R6一起是烷二基、取代烷二基、杂烷二基或取代杂烷二基;
任选地,R1和R2一起,R2和R3一起以及R2和R4一起是烷二基、取代烷二基、杂烷二基或取代杂烷二基;
任选地,R5和R6一起,R6和R7一起以及R6和R8一起是烷二基、取代烷二基、杂烷二基或取代杂烷二基;
任选地,R3和R7一起是烷二基、取代烷二基、杂烷二基或取代杂烷二基;以及
Y-2是(WS4)-2、(W2S12)-2、(W2S9)-2、(W2S7)-2、(W2S8)-2、(W2S11)-2、(W2S6)-2或(W2S13)-2。
第二方面,本发明提供本发明化合物的药物组合物。该药物组合物通常包含一种或多种本发明化合物、其水合物或溶剂化物以及可药用稀释剂、载体、赋形剂和助剂。稀释剂、载体、赋形剂和助剂的选择将取决于所需的给药方式以及其它因素。
第三方面,本发明提供治疗或预防以异常血管生成为特征的疾病、铜代谢紊乱、神经变性疾病、肥胖症或NF-κB调节障碍的方法。所述的方法通常包括向需要这种治疗或预防的患者给予治疗有效量的本发明化合物和/或药物组合物。
第四方面,本发明为需要治疗或预防的患者提供治疗或预防以异常血管生成、铜代谢紊乱、神经变性疾病、肥胖症或NF-κB调节障碍为特征的疾病或病症的药物组合物。
4.附图简介
附图1说明四硫代钨酸铵在Matrigel栓塞测定中抑制了血管生成。
5.发明的详细说明
5.1定义
“化合物”是指包括在此公开的结构式(I)的化合物以及任何在此公开的包括在该通式类之内的具体化合物。化合物可以通过它们的化学结构和/或化学名称进行确定。当化学结构和化学名称矛盾时,用化学结构来确定化合物。化合物可以含有一个或多个手性中心和/或双键,并因此可以存在立体异构体,例如双键异构体(即,几何异构体)、对映异构体或非对映异构体。因此,在此所示的化学结构图包括所示化合物的所有可能的对映异构体和立体异构体,其包括立体异构纯形式(例如,几何纯的,对映异构体纯的或非对映纯的)以及对映异构体和立体异构体的混合物。使用本领域技术人员公知的分离技术或手性合成技术,可将对映异构体和立体异构体混合物拆分成组成它们的各对映异构体或立体异构体。化合物还可以以若干互变异构比如烯醇形式、酮形式或其混合物存在。因此,在此描述的化学结构图包括所示化合物的所有可能的互变异构形式。化合物还包括同位素标记的化合物,其中一个或多个原子具有不同于通常在自然界中发现的原子量。可以包括在本发明化合物中的同位素的例子包括,但不局限于,2H、3H、13C、14C、15N、18O、17O和35S。化合物可以以未溶剂化的形式和溶剂化的形式存在,包括水合物形式和N-氧化物。通常,水合物、溶剂化物和N-氧化物形式包括在本发明的范围内。某些化合物可以以多晶或无定形的形式存在。通常,对本发明的用途来说,所有物理形式是等效的。此外,应当理解,当举例说明化合物的部分结构时,括号表示该分子的部分结构与其余部分的连结点。
“烷基”本身或作为另一取代基的一部分,是指饱和的或不饱和的、支链的、直链或环状一价烷基,是由母体烷烃、烯烃或炔烃的单个碳原子除去一个氢原子所衍生的。典型的烷基包括,但不局限于,甲基、乙基例如乙烷基、乙烯基、乙炔基;丙基例如丙烷-1-基、丙烷-2-基、环丙烷-1-基,丙-1-烯-1-基、丙-1-烯-2-基、丙-2-烯-1-基(烯丙基)、环丙-1-烯-1-基;环丙-2-烯-1-基、丙-1-炔-1-基、丙-2-炔-1-基等;丁基例如丁烷-1-基、丁烷-2-基、2-甲基-丙烷-1-基、2-甲基-丙烷-2-基、环丁烷-1-基、丁-1-烯-1-基、丁-1-烯-2-基、2-甲基-丙-1-烯-1-基、丁-2-烯-1-基、丁-2-烯-2-基、丁-1,3-二烯-1-基、丁-1,3-二烯-2-基、环丁-1-烯-1-基、环丁-1-烯-3-基、环丁-1,3-二烯-1-基、丁-1-炔-1-基、丁-1-炔-3-基、丁-3-炔-1-基等;诸如此类。
术语“烷基”具体的是指包括具有任何饱和度或饱和水平的基团,即仅具有碳-碳单键的基团,具有一个或多个碳-碳双键的基团,具有一个或多个碳-碳三键的基团,以及具有碳-碳单键、碳-碳双键和碳-碳三键混合的基团。当说明具体的饱和水平时,使用“烷基(alkanyl)”、“烯基(alkenyl)”和“炔基”这样表示。优选地,烷基包含1-20个碳原子,更优选包含1-10个碳原子,最优选包含1-6个碳原子。
“烷基”本身或作为另一取代基的一部分,是指饱和的、支链的、直链或环烷基基团,是由母体烷烃的单个碳原子除去一个氢原子所衍生的。典型的烷基基团包括,但不局限于,甲烷基;乙烷基;丙烷基例如丙烷-1-基、丙烷-2-基(异丙基)、环丙烷-1-基等;丁烷基例如丁烷-1-基、丁烷-2-基(仲丁基)、2-甲基-丙烷-1-基(异丁基)、2-甲基-丙烷-2-基(叔丁基)、环丁烷-1-基等;诸如此类。
“烯基”本身或作为另一取代基的一部分,是指具有至少一个碳-碳双键的不饱和的、支链的、直链或环烷基基团,是由母体烯烃的单个碳原子除去一个氢原子所衍生的。该基团可以以双键的顺式或反式构型存在。典型的烯基基团包括,但不局限于,乙烯基;丙烯基例如丙-1-烯-1-基、丙-1-烯-2-基、丙-2-烯-1-基(烯丙基)、丙-2-烯-2-基、环丙-1-烯-1-基、环丙-2-烯-1-基;丁烯基例如丁-1-烯-1-基、丁-1-烯-2-基、2-甲基-丙-1-烯-1-基、丁-2-烯-1-基、丁-2-烯-1-基、丁-2-烯-2-基、丁-1,3-二烯-1-基、丁-1,3-二烯-2-基、环丁-1-烯-1-基、环丁-1-烯-3-基、环丁-1,3-二烯-1-基等;诸如此类。
“炔基”本身或作为另一取代基的一部分,是指具有至少一个碳-碳三键的不饱和的、支链的、直链或环烷基基团,是由母体炔烃的单个碳原子除去一个氢原子所衍生的。典型的炔基基团包括,但不局限于,乙炔基;丙炔基例如丙-1-炔-1-基、丙-2-炔-1-基等;丁炔基例如丁-1-炔-1-基、丁-1-炔-3-基、丁-3-炔-1-基等;诸如此类。
“烷二基”本身或作为另一取代基团的一部分,是指饱和的或不饱和的、支链的、直链的或环状的二价烷基团,是由母体烷烃、烯烃或炔烃的两个不同碳原子各自除去一个氢原子或由母体烷烃、烯烃或炔烃的单个碳原子除去两个氢原子所衍生的。两个单价基团中心或二价基团中心的每个化合价可以与相同或不同的原子形成键。典型的烷二基基团包括,但不局限于甲烷二基;乙二基类例如乙烷-1,1-二基、乙烷-1,2-二基、乙烯-1,1-二基、乙烯-1,2-二基;丙二基类例如丙烷-1,1-二基、丙烷-1,2-二基、丙烷-2,2-二基、丙烷-1,3-二基、环丙烷-1,1-二基、环丙烷-1,2-二基、丙-1-烯-1,1-二基、丙-1-烯-1,2-二基、丙-2-烯-1,2-二基、丙-1-烯-1,3-二基、环丙-1-烯-1,2-二基、环丙-2-烯-1,2-二基、环丙-2-烯-1,1-二基、丙-1-炔-1,3-二基等;丁二基类例如丁烷-1,1-二基、丁烷-1,2-二基、丁烷-1,3-二基、丁烷-1,4-二基、丁烷-2,2-二基、2-甲基-丙烷-1,1-二基、2-甲基-丙烷-1,2-二基、环丁烷-1,1-二基;环丁烷-1,2-二基、环丁烷-1,3-二基、丁-1-烯-1,1-二基、丁-1-烯-1,2-二基、丁-1-烯-1,3-二基、丁-1-烯-1,4-二基、2-甲基-丙-1-烯-1,1-二基、2-亚甲烷基(methanylidene)-丙烷-1,1-二基、丁-1,3-二烯-1,1-二基、丁-1,3-二烯-1,2-二基、丁-1,3-二烯-1,3-二基、丁-1,3-二烯-1,4-二基、环丁-1-烯-1,2-二基、环丁-1-烯-1,3-二基、环丁-2-烯-1,2-二基、环丁-1,3-二烯-1,2-二基、环丁-1,3-二烯-1,3-二基、丁-1-炔-1,3-二基、丁-1-炔-1,4-二基、丁-1,3-二炔-1,4-二基等;诸如此类。当说明具体的饱和水平时,使用术语“烷基二基”、“烯基二基”和“炔基二基”。优选地,烷二基基团是(C1-C20)烷二基,更优选(C1-C10)烷二基,最优选(C1-C6)烷二基。优选的是饱和的非环状烷基二基基团,其中基团中心在未端碳原子上,例如,甲烷二基(亚甲基);乙烷-1,2-二基(亚乙基);丙烷-1,3-二基(亚丙基);丁烃-1,4-二基(亚丁基);诸如此类(也称为亚烷基,在下文进行定义)。
“亚烷基(alkyleno)”本身或作为另一取代基的一个部分,是指具有两个末端单价基团中心的直链烷二基基团,其由直链的母体烷烃、烯烃或炔烃的两个末端碳原子各自除去一个氢原子所衍生的。典型的亚烷基基团包括,但不局限于,亚甲基;亚乙基类例如亚乙烷基、亚乙烯基、亚乙炔基;亚丙基类例如亚丙烷基、亚丙[1]烯基、亚丙[1,2]二烯基、亚丙[1]炔基等;亚丁基类例如亚丁烷基、亚丁[1]烯基、亚丁[2]烯基、亚丁[1,3]二烯基、亚丁[1]炔基、亚丁[2]炔基、亚丁[1,3]二炔基等;诸如此类。当说明具体的饱和水平时,使用术语亚烷基、亚烯基和/或亚炔基。优选地,亚烷基基团是(C1-C20)亚烷基,更优选是(C1-C10)亚烷基,最优选是(C1-C6)亚烷基。优选的是直链饱和的亚烷基基团,例如亚甲基、亚乙基、亚丙基、亚丁基,诸如此类。
“酰基”本身或作为另一取代基的一个部分,是指基团-C(O)R30,其中R30是如在此所定义的氢、烷基、环烷基、环杂烷基、芳基、芳烷基、杂烷基、杂芳基、杂芳基烷基。代表性的例子包括,但不局限于,甲酰基、乙酰基、环己基羰基、环己基甲基羰基、苯甲酰基、苄基羰基诸如此类。
“酰胺基”本身或作为另一取代基的一个部分,是指基团-NR31C(O)R32,其中R31和R32各自独立地是如在此所定义的氢、烷基、环烷基、环杂烷基、芳基、芳烷基、杂烷基、杂芳基、杂芳基烷基。代表性的例子包括,但不局限于,甲酰氨基、乙酰氨基、环己基羰基氨基、环己基甲基-羰基氨基、苯甲酰基氨基、苄基羰基氨基诸如此类。
“烷氧基”本身或作为另一取代基的一个部分,是指基团-OR33,其中R33表示如在此定义的烷基或环烷基基团。代表性的例子包括,但不局限于,甲氧基、乙氧基、丙氧基、丁氧基、环己氧基等。
“烃氧羰基”本身或作为另一取代基的一个部分,是指基团-C(O)OR33其中R33如上述定义。
“芳基”本身或作为另一取代基的一部分,是指单价的芳香族烷基团,是由母体芳环体系的单个碳原子除去一个氢原子所衍生的。典型的芳基基团包括,但不局限于,来源于醋蒽烯、苊烯、acephenanthrylene、蒽、薁、苯、chrysene、六苯并苯、荧蒽、芴、并六苯、己芬、hexalene、as-indacene、s-indacene、茚满、茚、萘、octacene、octaphene、octalene、卵苯(ovalene)、戊-2,4-二烯、并五苯、并环戊二烯、戊芬、二萘嵌苯、phenalene、菲、苉(picene)、pleiadene、芘、皮蒽、玉红省、三亚苯、三亚萘等的基团。优选地,芳基包含6-20个碳原子,更优选包含6-12个碳原子。
“芳烷基”本身或作为另一取代基的一个部分,是指非环状的烷基基团,其中氢原子中的一个被芳基基团所代替,该氢原子中的一个是与一个碳原子(典型地是末端的或sp3碳原子)相连的。典型的芳烷基基团包括,但不局限于,苄基、2-苯基乙烷-1-基、2-苯基乙烯-1-基、萘甲基、2-萘乙烷-1-基、2-萘乙烯-1-基、萘并苄基、2-萘并苯基乙烷-1-基诸如此类。当举例说明具体的烷基部分时,可以使用术语芳基烷基、芳基烯基和/或芳基炔基。优选地,芳烷基基团是(C6-C30)芳烷基,例如芳烷基基团的烷基、烯基或炔基部分是(C1-C10)以及芳基部分是(C6-C20),更优选地,芳烷基基团是(C6-C20)芳烷基,例如,芳烷基基团的烷基、烯基或炔基部分是(C1-C8)以及芳基部分是(C6-C12)。
“环烷基”本身或作为另一取代基的一个部分,是指饱和的或不饱和的环烷基基团。当说明具体的饱和水平时,可以使用术语“环烷基”或“环烯基”。典型的环烷基基团包括,但不局限于,由环丙烷、环丁烷、环戊烷、环己烷等衍生的基团。优选地,环烷基基团是(C3-C10)环烷基,更优选是(C3-C7)环烷基。
“环杂烷基”本身或作为另一取代基的一个部分,是指饱和的或不饱和的环烷基基团,其中一个或多个碳原子(以及任何有关的氢原子)独立地被相同的或不同的杂原子所代替。代替碳原子的典型杂原子包括,但不局限于,N、P、O、S、Si等。当举例说明具体的饱和度时,可以使用术语“环杂烷基”或“环杂烯基”。典型的环杂烷基基团包括,但不局限于,由环氧化物、azirines、硫杂丙环(thiirane)、四氢咪唑、吗啉、哌嗪、哌啶、吡唑烷、吡咯烷、奎核碱诸如此类的基团。
“杂烷基、杂烷基、杂烯基、杂烷基、杂烷二基和杂亚烷基”本身或作为另一取代基的一个部分,分别是指烷基、烷基、烯基、炔基、烷二基和亚烷基基团,其中一个或多个碳原子(以及任何有关的氢原子)每个独立地被相同的或不同的杂原子基团所代替。可以包括在这些基团中的典型杂原子基团包括,但不局限于,-O-、-S-、-O-O-、-S-S-、-O-S-、-NR35R36-、=N-N=、-N=N-、-N=N-NR37R38、-PR39、-P(O)2、-POR39、-O-P(O)2-、-SO-、-SO2-、-SnR41R42-等,其中R35、R36、R37、R38、R39、R40、R41和R42独立地是氢、烷基、取代烷基、芳基、取代芳基、芳烷基、取代芳烷基、环烷基、取代环烷基、环杂烷基、取代环杂烷基、杂烷基、取代杂烷基、杂芳基、取代杂芳基、杂芳基烷基或取代杂芳基烷基。
“杂芳基”本身或作为另一取代基的一个部分,是指单价杂芳香族基团,其是通过从母体杂芳香族环体系的一个原子上除去一个氢所衍生的。典型的杂芳基基团包括,但不局限于,由吖啶、砷杂茚、咔唑、β-咔啉、色满、色烯、噌啉、呋喃、咪唑、吲唑、吲哚、二氢吲哚、吲嗪、异苯并呋喃、异色烯、异吲哚、异二氢吲哚、异喹啉、异噻唑、异噁唑、萘啶、噁二唑、噁唑、萘嵌间二氮苯、菲啶、菲咯啉、吩嗪、酞嗪、蝶啶、嘌呤、吡喃、吡嗪、吡唑、哒嗪、吡啶、嘧啶、吡咯、吡咯嗪(pyrrolizine)、喹唑啉、喹啉、喹嗪、喹噁啉、四唑、噻二唑、噻唑、噻吩、三唑、呫吨等衍生的基团。优选地,所述的杂芳基基团为5-20员杂芳基,更优选为5-10员杂芳基。优选的杂芳基基团是由噻吩、吡咯、苯并噻吩、苯并呋喃、吲哚、吡啶、喹啉、咪唑、噁唑和吡嗪衍生的。
“杂芳基烷基”本身或作为另一取代基的一个部分,是指一种非环状的烷基基团,其中与一个碳原子(典型地是末端碳原子或sp3碳原子)连接的氢原子中的一个被杂芳基基团代替。当举例说明具体的烷基部分时,可以使用术语杂芳基烷基、杂芳基烯基和/或杂芳基炔基。在优选实施方案中,杂芳基烷基基团是6-30员的杂芳基烷基,例如,杂芳基烷基的烷基、烯基或炔基部分是1-10员的以及杂芳基部分是5-20员的杂芳基,更优选是6-20员的杂芳基烷基,例如杂芳基烷基的烷基、烯基或炔基部分是1-8员的以及杂芳基部分是5-12员的杂芳基。
“母体芳环体系”本身或作为另一取代基的一个部分,是指不饱和的环状或多环的环系,所述的环系具有一个共轭π电子体系。包括在“母体芳环体系”定义中的具体例子是稠环系,其中一个或多个环是芳香族的以及一个或多个环是饱和的或不饱和的,例如芴、茚满、茚、phenalene等。典型的母体芳环体系包括,但不局限于,醋蒽烯、苊烯、acephenanthrylene、蒽、薁、苯、chrysene、六苯并苯、荧蒽、芴、并六苯、己芬、hexalene、as-indacene、s-indacene、茚满、茚、萘、octacene、octaphene、octalene、卵苯、戊-2,4-二烯、并五苯、并环戊二烯、戊芬、二萘嵌苯、phenalene、菲、苉、pleiadene、芘、皮蒽、玉红省、三亚苯、三亚萘等。
“母体杂芳环体系”本身或作为另一取代基的一个部分,是指一种母体芳环体系,其中一个或多个碳原子(以及任何有关的氢原子)独立地被相同的或不同的杂原子代替。代替碳原子的典型的杂原子包括,但不局限于,N、P、O、S、Si等。包括在”母体杂芳环体系”定义中的具体例子是稠环系,其中一个或多个环是芳香族的以及一个或多个环是饱和的或不饱和的,例如砷杂茚、苯并二噁烷、苯并呋喃、色满、色烯、吲哚、二氢吲哚、呫吨等。典型的母体杂芳环体系包括,但不局限于,砷杂茚、咔唑、β-咔啉、色满、色烯、噌啉、呋喃、咪唑、吲唑、吲哚、二氢吲哚、吲嗪、异苯并呋喃、异色烯、异吲哚、异二氢吲哚、异喹啉、异噻唑、异噁唑、萘啶、噁二唑、噁唑、萘嵌间二氮苯、菲啶、菲咯啉、吩嗪、酞嗪、蝶啶、嘌呤、吡喃、吡嗪、吡唑、哒嗪、吡啶、嘧啶、吡咯、吡咯嗪、喹唑啉、喹啉、喹嗪、喹噁啉、四唑、噻二唑、噻唑、噻吩、三唑、呫吨等。
“药物组合物”是指至少一种本发明化合物以及与所述化合物一起向患者给予的可药用媒介物。
“可药用盐”是指本发明化合物的一种盐,其具有母体化合物所需的药理学活性。这些盐包括:(1)酸加成盐,与无机酸例如盐酸、氢溴酸、硫酸、硝酸、磷酸等形成的;或与有机酸例如乙酸、丙酸、己酸、环戊烷丙酸(cyclopentanepropionic acid)、羟基乙酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙烷-二磺酸、2-羟基乙磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟脑磺酸、4-甲基双环[2.2.2]-辛-2-烯-1-羧酸、葡庚糖酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、月桂基硫酸、葡糖酸、谷氨酸、羟萘甲酸、水杨酸、硬脂酸、黏康酸等形成的;或者(2)当母体化合物中存在酸质子时,酸质子被金属离子例如碱金属离子、碱土金属离子或铝离子代替后形成的盐;或者是与有机碱例如乙醇胺、二乙醇胺、三乙醇胺、N-甲基葡糖胺等配位的盐。
“可药用媒介物”是指与本发明化合物一起服用的稀释剂、助剂、赋形剂或载体。
“患者”包括人。术语”人”和”患者”在此可互换使用。
“预防”是指减少患疾病或病症的危险(即,在易受疾病感染的、但还没有遭受或出现该疾病症状的患者中,将导致该疾病的至少一种临床症状无法发展)。
“前药”是指药物分子的一种衍生物,其需要在体内转化以释放出活性药物。在转化为母体药物之前,前药通常但不必需是药理学惰性的。例如,含羟基的药物可以转化成磺酸酯、酯或碳酸酯前药,其在体内可以水解形成羟基化合物。例如,含氨基的药物可以转化成氨基甲酸酯、酰胺、烯胺、亚胺、N-膦酰基、N-磷酰基或N-亚磺酰基前药,其在体内可以水解形成氨基化合物。羧酸药物可以转化成酯(包括甲硅烷基酯和硫代酸酯)、酰胺或酰肼前药,其在体内水解形成羧酸化合物。官能团不同于上面所列那些的药物的前药是本领域普通技术人员所公知的。
“前部分(promoiety)”是指一种保护基形式,当将其用于掩蔽药物分子内的官能团时可以将药物转化为前药。典型地,前部分通过键连接在药物上,通过体内酶催化方法或非酶催化方法裂解该键。
“保护基”是指由一些原子形成的基团,当所述原子附着于分子中的活性官能团时,能掩蔽、降低或防止官能团的活性。保护基的例子可以在Green等人“Protective Groups in Organic Chemistry”,(Wiley,第二版1991)和Harrison等人”Compendium Of Synthetic Organic Methods”,Vols.1-8(JohnWiley and Sons,1971-1996)中找到。代表性的氨基保护基包括,但不局限于,甲酰基、乙酰基、三氟乙酰基、苄基、苄氧羰基(“CBZ”)、叔丁氧羰基(“Boc”)、三甲基甲硅烷基(“TMS”)、2-三甲基甲硅烷基-乙磺酰基(“SES”)、三苯甲基和取代三苯甲基、烯丙氧羰基、9-芴甲氧羰基(“FMOC”)、硝基-藜芦氧羰基(“NVOC”)等。代表性的羟基保护基包括,但不局限于,其中羟基被酰化或烷基化的那些例如;苄基、三苯甲基醚和烷基醚、四氢吡喃基醚、三烷基甲硅烷基醚和烯丙基醚。
“取代”是指一个基团中一个或多个氢原子独立地被相同的或不同的取代基所代替。典型的取代基包括,但不局限于-M、-R60、-O-、=O、-OR60、-SR60、-S-、=S、-NR60R61、=NR60、-CF3、-CN、-OCN、-SCN、-NO、-NO2、=N2、-N3、-S(O)2O-、-S(O)2OH、-S(O)2R60、-OS(O2)O-、-OS(O)2R60、-P(O)(O-)2、-P(O)(OR60)(O-)、-OP(O)(OR60)(OR61)、-C(O)R60、-C(S)R60、-C(O)OR60、-C(O)NR60R61、-C(O)O-、-C(S)OR60、-NR62C(O)NR60R61、-NR62C(S)NR60R61、-NR62C(NR63)NR60R61和-C(NR62)NR60R61,其中M独立地是卤素;R60、R61、R62和R63独立地是氢、烷基、取代烷基、烷氧基、取代烷氧基、环烷基、取代环烷基、环杂烷基、取代环杂烷基、芳基、取代芳基、杂芳基或取代杂芳基,或任选R60和R61与其相连的氮原子一起形成环杂烷基环或取代环杂烷基环;以及R64和R65独立地是氢、烷基、取代烷基、芳基、环烷基、取代环烷基、环杂烷基、取代环杂烷基、芳基、取代芳基、杂芳基或取代杂芳基,或者任选地R64和R65与其相连的氮原子一起形成环杂烷基环或取代环杂烷基环。优选地,取代基包括-M、-R60、=O、-OR60、-SR60、-S-、=S、-NR60R61、=NR60、-CF3、-CN、-OCN、-SCN、-NO、-NO2、=N2、-N3、-S(O)2R60、-OS(O2)O-、-OS(O)2R60、-P(O)(O-)2、-P(O)(OR60)(O-)、-OP(O)(OR60)(OR61)、-C(O)R60、-C(S)R60、-C(O)OR60、-C(O)NR60R61、-C(O)O-、-NR62C(O)NR60R61,更优选-M、-R60、=O、-OR60、-SR60、-NR60R61、-CF3、-CN、-NO2、-S(O)2R60、-P(O)(OR60)(O-)、-OP(O)(OR60)(OR61)、-C(O)R60、-C(O)OR60、-C(O)NR60R61、-C(O)O-,最优选-M、-R60、=O、-OR60、-SR60、-NR60R61、-CF3、-CN、-NO2、-S(O)2R60、-OP(O)(OR60)(OR61)、-C(O)R60、-C(O)OR60、-C(O)O-,其中R60、R61和R62如上所定义。
在一种实施方案中,任何疾病或病症的“治疗”是指改善疾病或病症(即,阻止或降低疾病的发展或其至少一种临床症状的发展)。在另一种实施方案,“治疗”是指改善至少一种可能无法被患者识别的身体参数。在另一种实施方案中,“治疗”是指在身体上地(例如稳定一种可识别的症状)或在生理上地(例如稳定一种身体参数)、或同时地抑制疾病或病症。在另一种实施方案中,“治疗”是指推迟疾病或病症的发作。
“治疗有效量”是指一种化合物的数量,当向患者给予以治疗一种疾病时,该量足以对治疗的这种疾病产生作用。“治疗有效量”将随化合物、疾病以及其严重程度、以及所治疗患者的年龄、体重等而改变。
现在,将详细地说明本发明的优选实施方案。虽然本发明通过优选的实施方案进行说明,但是本发明并不意在限于那些优选实施方案。相反,它意在覆盖可以包括在所附权利要求所定义的本发明的构思和范围内的各种替换、修饰和同等物。
5.2结构式(I)的化合物
在第一实施方案中,本发明的化合物包括结构式(I)的化合物或其溶剂化物或水合物或N-氧化物,
其中:
R1、R2、R3、R5、R6和R7独立地是氢、烷基、取代烷基、芳基、取代芳基、芳烷基、取代芳烷基、环烷基、取代环烷基、环杂烷基、取代环杂烷基、杂芳基、取代杂芳基、杂芳基烷基、取代杂芳基烷基、杂烷基或取代杂烷基;
R4和R8独立地是氢、烷基、取代烷基、芳基、取代芳基、芳烷基、取代芳烷基、环烷基、取代环烷基、环杂烷基、取代环杂烷基、杂芳基、取代杂芳基、杂芳基烷基、取代杂芳基烷基、杂烷基或取代杂烷基、或者当N是芳环的一个部分时为不存在;
任选地,R1和R2一起是烷二基、取代烷二基、杂烷二基或取代杂烷二基;
任选地,R5和R6一起是烷二基、取代烷二基、杂烷二基或取代杂烷二基;
任选地,R1和R2一起,R2和R3一起以及R2和R4一起是烷二基、取代烷二基、杂烷二基或取代杂烷二基;
任选地,R5和R6一起,R6和R7一起以及R6和R8一起是烷二基、取代烷二基、杂烷二基或取代杂烷二基;
任选地,R3和R7一起是烷二基、取代烷二基、杂烷二基或取代杂烃二基;以及
Y-2是(WS4)-2、(W2S12)-2、(W2S9)-2、(W2S7)-2、(W2S8)-2、(W2S11)-2、(W2S6)-2或(W2S13)-2;
在一些实施方案中,Y是(WS4)-2且所有的R1、R2、R3、R4、R5、R6、R7和R8不是氢。在其它的实施方案中,Y是(WS4)-2且所有的R1、R2、R3、R4、R5、R6、R7和R8不是烷基。
在另一种实施方案中,
优选地,Y是(WS4)-2。
在一些实施方案中,R1、R2、R3和R4中至少一种不是烷基。在其它的 实施方案中,R1、R2和R4是氢、烷基或取代烷基。优选地,R1、R2和R4是氢、甲基或乙基。
在另一种实施方案中,R1和R2是烷基。优选地,R1和R2是甲基或乙基。
在另一种实施方案中,R1烷基、取代烷基、烯基、取代烯基、芳基、取代芳基、芳烷基、取代芳烷基、环烷基或取代环烷基。优选地,R1和R2一起是亚烷基、取代亚烷基、杂亚烷基或取代杂亚烷基。更优选地,R1和R2一起是亚烷基或杂亚烷基。
在另一种实施方案中,R1和R2一起,R2和R3一起以及R2和R4一起是亚烷基、取代亚烷基、杂亚烷基或取代杂亚烷基。优选地,R1和R2一起,R2和R3一起以及R2和R4一起是亚烷基。优选地,R1(R2)(R3)(R4)N具有结构:
在另一种实施方案中,R3和R7一起是亚烷基、取代亚烷基、杂亚烷基或取代杂亚烷基。优选地,R3和R7一起是亚烷基或杂亚烷基。
在另一种实施方案中,R1、R2和R4是氢、烷基或取代烷基,以及R3是烷基、取代烷基、烯基、芳基、芳烷基、环烷基,或者R3和R7一起是亚烷基、取代亚烷基、杂亚烷基或取代杂亚烷基。优选地,R1、R2和R4是甲基或乙基,以及R3是烷基、取代烷基、烯基、芳基、芳烷基、环烷基,或者R3和R7一起是亚烷基或杂亚烷基。优选地,R1、R2和R4是甲基或乙基,以及R3是烷基、取代烷基、烯基、芳基、芳烷基或环烷基。
在另一种实施方案中,R1(R2)(R3)(R4)N是
或
在另一种实施方案中,R1(R2)(R3)(R4)N是
在另一种实施方案中,R1(R2)(R3)(R4)N是
在另一种实施方案中,R1、R2和R4是甲基或乙基,以及R3和R7一起是亚烷基或杂亚烷基。优选地,R1(R2)(R3)(R4)N具有结构
在另一种实施方案中,R1、R2和R4是氢以及R3是取代烷基、环烷基或取代杂芳基,或者R3和R7一起是亚烷基。在另一种实施方案中,R1和R2是烷基以及R3和R4是烷基、取代烷基、芳基、芳烷基或亚烷基。优选地,R1和R2是甲基或乙基,以及R3和R4是烷基、取代烷基、芳基、芳烷基或亚烷基。
在另一种实施方案中,R1(R2)(R3)(R4)N是
其中R9是具有至少8个碳原子并且不超过18个碳原子的直链烷基基团的混合基团。
在另一种实施方案中,R1、R2和R4是氢,以及R3是取代烷基、取代杂芳基、环烷基或亚烷基。优选地,R1(R2)(R3)(R4)N具有结构:
在另一种实施方案中,R1和R2一起是亚烷基、取代亚烷基、杂亚烷基或取代杂亚烷基,R3是烷基或取代烷基,以及R4是氢或不存在。优选地,R1(R2)(R3)N或R1(R2)(R3)(R4)N具有结构:
5.3化合物的合成
本发明的化合物可以通过方案1和2中所示的常规合成方法获得。用于制备本发明化合物的原料及其中间体是市场上可买到的,或者它们可以通过众所周知的合成方法进行制备。取代铵盐(例如,氢氧化铵和卤化铵)可以从市场上购买得到,或者可以使用众所周知的合成方法很容易地进行合成(Harrison et al.,″Compendium of Synthetic Organic Methods″,Vols.1-8(John Wiley and Sons,1971-1996);″Beilstein Handbook of Organic Chemistry,″Beilstein Institute of Organic Chemistry,Frankfurt,Germany;Feiser etal.,″Reagents for Organic Synthesis,″Volumes 1-17,Wiley Interscience;Trost etal.,″Comprehensive Organic Synthesis,″Pergamon Press,1991;″Theilheimer′sSynthetic Methods of Organic Chemistry,″Volumes 1-45,Karger,1991;March,″Advanced Organic Chemistry,″Wiley Interscience,1991;Larock″Comprehensive Organic Transformations,″VCH Publishers,1989;Paquette,″Encyclopedia of Reagents for Organic Synthesis,″John Wiley &Sons,1995)。在此描述的化合物和/或原料的其它合成方法或者已经在本领域中进行了描述,或者对本领域技术人员而言是显而易见的。因此,此处方案1和2中所示的方法仅是举例说明而非全面综述。
方案1
如上所述,在方案1中,在水的存在下将氢氧化季铵加入到硫代钨酸盐中,引起阳离子交换(通过除去挥发性氨推动向产物的平衡),以获得所需的硫代钨酸盐衍生物。
方案2
如上所述,在方案2中,在乙腈的存在下,将卤化季铵加入到硫代钨酸盐中,引起阳离子交换(通过除去挥发性氨推动向产物的平衡),以获得所需的硫代钨酸盐衍生物。
应注意,当铵抗衡离子不同时,可通过使用一当量不同的铵抗衡离子处理化合物3制备钨酸盐衍生物。这样的反应预期将生成令人满意的混合产物。
此外,本领域技术人员将理解到,包括使用铵盐和硫化氢处理钨酸盐的常规方法可用于合成本文所述的许多化合物。
5.4测定法
本领域普通技术人员可以理解,在此所述的用于测定本发明化合物活性的体外和体内测定是举例而不是全面综述。
5.4.1内皮细胞迁移的测定
对于内皮细胞迁移,通过向每个跨孔(transwell)加入200μL的胶原蛋白溶液,用I型胶原蛋白(50μg/mL)涂铺跨孔,然后在37℃下培养过夜。将跨孔装配在一个24孔板中,将化学引诱物(例如,FGF-2)以总体积0.8mL培养基加入到下室(bottom chamber)中。用无血清培养基将内皮细胞例如人脐静脉内皮细胞(“HUVEC”),其已经用胰蛋白酶从单层培养中脱离,稀释至约106细胞/mL的最终浓度,然后将0.2mL这种细胞悬液加入到每个跨孔的上室(upper chamber)中。向上室和下室中均加入抑制剂,并在潮湿空气中在37℃下迁移5小时。从用DiffQuik染色的板中移去跨孔。通过用药棉拭子刮除,从所述的上室中除去没有迁移的细胞,然后将膜分离,安放在载玻片上,在高倍视野(400x)下计数,以测定细胞迁移的数目。
5.4.2抗侵袭活性的生物测定
对本发明的化合物和/或药物组合物进行抗侵袭能力测试。在一种测定中,即Matrgel侵袭测定中,测定细胞例如内皮细胞或肿瘤细胞(例如,PC-3人前列腺癌)细胞通过重组基膜(Matrgel)侵袭的能力(Kleinman et al,Biochemistry 1986,25:312-318;Parish et al.,Int.J.Cancer 1992,52:378-383)。Matrgel是一种含IV型胶原蛋白、层粘连蛋白、硫酸类肝素蛋白多糖例如基膜蛋白多糖的重组基膜,其与bFGP、玻璃粘连蛋白和转化生长因子-β(TGFβ,尿激酶型纤维蛋白酶原激活剂(uPA)、组织纤维蛋白溶酶原激活剂(tPA)和丝氨酸蛋白酶抑制剂即纤维蛋白溶酶原激活剂抑制剂1型(PAL-l))结合,并定位(Chambers et al.,Canc.Res.1995,55:1578-1585)。对于将细胞外受体或酶作为靶向的化合物,在本测定中获得的结果通常可以预测这些化合物在体内的效力(Rabbani et al,1995,Int.J.Cancer 63:840-845)。
这些测定使用跨孔组织培养插入物。侵袭细胞定义为能够通过Matrgel和聚碳酸酯膜的上部并与膜的底部粘连的细胞。含聚碳酸酯膜(8.0μm孔径)的跨孔(Costar)用Matrgel涂铺(Collaborative Reserach),其中Matrgel已经在无菌PBS中稀释至75μg/mL的最终浓度(每个插入物60μL的稀释Matrgel),然后将其放在24孔板的孔中。所述的膜在生物学安全工作橱中干燥过夜,然后通过加入100μL含抗生素的DMEM,在振动台上再水合1小时。通过抽吸从每个插入物中除去DMEM,将0.8mL DMEM/10%FBS/抗生素加入到24孔板的每个孔中,这样使它围绕在跨孔的外围(“下室”)。将新鲜的DMEM/抗生素(100μL)、人谷氨酸-纤维蛋白溶酶原(5μg/mL)以及任何测试抑制剂加入到上部,跨孔的内部(“上室”)。对测试细胞进行胰蛋白酶化,接着再悬浮在DMEM/抗生素中,然后以800,000细胞/mL的最终浓度将其加入到跨孔的上室中。将上室的最终体积调节至200μL。然后,将装配板在潮湿的5%CO2空气中培养72小时。培养后,固定细胞,用DiffQuik(吉姆沙染色剂)进行染色,然后使用药棉拭子刮擦上室以除去Matrigelt和任何没有侵袭通过膜的细胞。使用X-acto刀片将膜从跨孔中分离,将其安装在使用Permount和盖片的载玻片上,然后在高倍视野(400x)下进行计数。由5-10倍视野计数确定被侵袭细胞的平均值,并作为抑制剂浓度的函数进行绘图。
5.4.3抗血管生成活性的管形成测定
在两种不同的体外测定体系中,可以对本发明化合物进行抗血管生成活性的测试。
将可以制备得到或者从商业上购买得到的内皮细胞,如人脐静脉内皮细胞(“HMVEC”)或人微血管内皮细胞(“HMVEC”),以2×105细胞/mL的浓度与纤维蛋白原(5mg/mL在磷酸盐缓冲盐水(“PBS”)中)以1∶1(v/V)的比例混合。加入凝血酶(5单位/mL最终浓度),然后将混合物立即转入到24孔板中(每孔0.5mL)。使其生成血纤维蛋白凝胶,然后将VEGF和bFGF与测试化合物一起加入到所述的孔(每个孔的最终浓度为5ng/mL)。细胞在37℃下在5%CO2中培养4天,在此期间,对每个孔中的细胞进行计数,并将其分类为圆的、不带支链的长的、带支链的长的、或者带有两个或更多个支链的长的。结果用化合物每一浓度的5个不同孔的平均值来表示。典型地,在血管生成抑制剂存在下,细胞保持圆形的或形成未分化的管(例如,0或1个分枝)。这种测定法在本领域中被认为可以用于预测体内血管生成(或抗血管生成)的效力(Min et al.,Cancer Res.199656:2428-2433)。
在一种可供选择的测定法中,当内皮细胞在Matrigel中进行培养时,可以观察到内皮细胞管的形成(Schnaper et al.,J.Cell.Physiol.1995,165:107-118)。将内皮细胞(1×104细胞/孔)转移到涂敷有Matrigel的24孔板中,48小时后,确定管形成的数量。通过与内皮细胞同时加入或在其后的不同时间点上加入而测试抑制剂。也可以通过加入血管生成生长因子例如bFGF或VEGF、分化刺激剂(例如PMA)或其组合,来刺激管形成。
通过使特定类型的基膜出现在内皮细胞中,即迁移和分化内皮细胞的基质层将被预见为首先出现,这种测定法模拟血管生成。另外,在Matrigel(以及在基膜原位中)中发现的基质组分或其蛋白水解物也可能刺激内皮细胞的管形成,这使得这种模型对前面所述的血纤维蛋白凝胶血管生成模型构成互补(Blood et al.,Biochim.Biophys.Acta 1990,1032:89-118;Odedra et al.,Pharmac.Ther.1991,49:111-124)。在两种测定法中,本发明化合物抑制内皮细胞管形成,其表明所述的化合物还具有抗血管生成活性。
5.4.4抑制增殖的测定
本发明化合物抑制内皮细胞增殖能力可以在96孔板中进行测定。用I型胶原(明胶)涂铺所述板的孔(在PBS中0.1-1mg/mL,每孔0.1mL,在室温下30分钟)。将所述的板洗涤(3x w/PBS)后,每孔平铺3-6,000细胞,让其在内皮生长培养基(EGM;Clonetics)或含0.1-2% FBS的M199培养基中附着4小时(37℃/5% CO2)。4小时后,除去培养基与任何未附着的细胞,向每个孔中加入含bPGF(1-10ng/mL)或VEGF(1-10ng/ml)的新鲜培养基。最后加入测试化合物,将板培养(37℃/5% CO2)24-48小时。向每个孔中加入MTS(Promega),然后培养1-4小时。然后,测定490nm处的吸光度,其与细胞数目成正比,以确定在对照组孔和那些含测试化合物孔之间增殖的差异。用培养的粘附肿瘤细胞,可以建立类似的测定体系。但是,在这种情形中可以省略胶原。平铺肿瘤细胞(例如,3,000-10,000/孔),然后使其粘附过夜。然后,向孔中加入无血清培养基,细胞同步24小时。然后,向每个孔中加入含10%FBS的培养基,以刺激增殖。在一些孔中加入测试化合物。24小时后,将MTS加入到板中进行测试,然后如上所述那样进行读数。除了不使用VEGF和bFGF来刺激细胞生长之外,还可以使用相似的方法以评价本发明化合物对其它细胞类型(包括肿瘤细胞)增殖的作用。如果有证据表明抗增殖活性,可以使用TumorTACS(Genzyme)测定细胞凋亡的诱导。
5.4.5细胞毒性的测定
可以测定本发明化合物对各种细胞类型包括肿瘤细胞、内皮细胞、成纤维细胞和巨噬细胞的细胞毒性作用。
一种典型的测定法包括在96孔板中以5-10,000细胞每孔的密度平铺细胞。以各种浓度加入测试化合物,并与细胞培养24小时。细胞用培养基洗涤3次。对于细胞毒性测定(测定细胞溶解作用),使用Promega 96孔细胞毒性试剂盒。
5.4.6角膜的血管生成模型
所使用的方案基本上与Volpen等人,J.Clin.Invest.1996,98:671-679中所述的相同。简要地说,将雌性费希尔老鼠(Fischer rat)(120-140gms)麻醉,然后将由Hydron、bPGF(150nM)和测试化合物组成的小球(5μl)植入到很小的切口中,该切口在距离角膜边缘1.0-1.5mm处。移植后第5天和第7天,评价新血管生成。在第7天,将动物麻醉,灌输一种染料例如胶体碳,以对血管进行染色。然后,使动物安乐死,角膜用福尔马林固定,将角膜弄平,拍照,评价新血管生成的程度。通过对总的血管面积或长度进行成像,或者简单地通过对血管进行计数,可以确定新血管的数量。
5.4.7Matrigel栓塞测定
此测定法基本上如passaniti等人,Lab Invest.1992,67:519-528所述那样进行。将冰冷的Matrigel(例如,500μl)(Collaborative BiomedicalProducts,Inc.,Bedford,MA)与肝素(例如,50μg/ml)、FGF-2(例如,400ng/ml)和测试化合物混合。在某些测定中,bPGF可以被肿瘤细胞取代作为血管生成刺激物。将Matrigel混合物皮下注射到4-8周龄的无胸腺裸鼠,注射部位在腹部中线附近,优选每只老鼠进行三次注射。注入的Matrigel形成明显的固体凝胶。如此选择注射部位以致每只动物接受阳性对照栓塞(例如FGF-2+肝素)、阴性对照栓塞(例如,缓冲液+肝素)以及包括对血管生成起作用的测试化合物的栓塞(例如,FGF-2+肝素+化合物)。所有处理优选一式三份。在注射后约第7天或者在观察血管生成最佳的其它时间,通过颈部脱位处死动物。沿腹部中线剥离鼠皮,回收Matrigel栓塞,并立即在高分辨率下进行扫描。然后,将栓塞分散在水中并在37℃下培养过夜。根据厂商的指示使用德腊布金溶液(例如,从Sigma处获得),测定血红蛋白(Hb)含量。由于栓塞中Hb的数量反映样品中血液的数量,因此栓塞中Hb的数量是测定血管生成的一种间接方法。此外,另一种方法,在将动物处死前,向其注射0.1ml含与一个荧光基团共轭的高分子量右旋糖酐的缓冲液(优选PBS)。能通过荧光测定的在分散的栓塞中荧光的数量,也可以作为一种栓塞中血管生成的测定方法。使用mAb抗-CD31(CD31是血小板-内皮细胞粘附分子或“PECAM”)的染色也可以用来证实栓塞中新血管生成和微血管密度。
5.4.8鸡绒毛膜尿囊膜(CAM)血管生成测定
此测定法基本上如Nguyen等人,Microvascular Res.1994,47:31-40所述那样进行。将含血管生成因子(bFGF)或肿瘤细胞以及抑制剂的网眼放到8-天的鸡胚CAM上,在植入样品后第3-9天观察CAM。通过测定含血管的网眼中正方形的百分比,来确定血管生成的数量。
5.4.9使用采用肿瘤细胞的Matrigel栓塞测定法,进行抑制血管生成和抗肿瘤作用的体内评价
在此测定中,肿瘤细胞,例如将1-5×106个3LL路易士肺癌或老鼠前列腺细胞系MatLyLu的细胞与Matrigel混合,然后根据在上面4.4.7节中所述方案,将其注射到老鼠的侧腹中。约5-7天后,在栓塞中可以观察到大量的肿瘤细胞和大量的血管生成反应。在真实的肿瘤环境中,化合物的抗肿瘤和抗血管生成作用可以通过将所述的化合物包含在栓塞中进行评价。然后,测定形成的肿瘤重量、Hb水平或荧光水平(在处死前,注入右旋糖酐-荧光基团共轭物)。为了测定Hb或荧光,首先将所述的栓塞用组织匀浆器匀浆。
5.4.10皮下肿瘤生长的异种移植模型
在裸鼠的右侧腹皮下接种MDA-MB-231细胞(人乳癌)和Matrigel(1×106细胞,在0.2mL中)。肿瘤成长至200mm3,然后开始用测试化合物进行处理。每隔一天测量肿瘤的体积,处理2周后处死所述的动物。切除肿瘤,称重并埋入石蜡中。通过H和E、抗-CD31、Ki-67、TUNEL和CD68染色,分析肿瘤的组织切片。
其它人肿瘤细胞系,包括但不局限于PC-3、CWR22R、SK-OV-3、A2780、A549、HCT116、HT29也可以按类似方式用来测试本发明化合物的抗肿瘤活性。
5.4.11转移的异种移植模型
使用实验性转移模型(Crowley et al.,Proc.Natl.Acad.Sci.USA 1993,905021-5025),本发明的化合物还可以用来测试对晚期转移的抑制。晚期转移包括肿瘤细胞的附着和外渗、局部侵袭、接种、增殖和血管生成。将用报导基因转染,优选用绿色荧光蛋白(GFP)基因转染的人前列腺癌细胞(PC-3),但是作为一种可供选择的方法,用编码酶氯霉素乙酰转移酶(CAT)、荧光素酶或LacZ的基因进行转染的人前列腺癌细胞(PC-3)接种到裸鼠中。这种方法允许利用这些标记(GFP的荧光检测或酶活性的组织化学比色检测)中的任何一个以跟踪这些细胞的命运。注射细胞,优选静脉注射,约14天后确定转移,特别是在肺中,但也在局部淋巴结、股骨和大脑中。这模拟在人前列腺癌中天然存在的转移的器官趋向性。例如,将GFP-表达的PC-3细胞(每只老鼠1×106细胞)静脉内注射到裸(nu/nu)鼠的尾部静脉中。以100μg/动物/天的剂量每天通过IP给予动物测试组合物。观察单一转移性细胞和病灶,并且通过荧光显微术或光学显微镜组织化学,或者通过研磨组织并定量比色测定可测的标记,进行定量测定。
5.4.12通过HPRG和功能性衍生物抑制在体内的自发转移
大鼠同源乳腺癌系(Xing et al.,Int.J.Cancer 199667:423-429(1996)使用Mat BIII大鼠乳腺癌细胞。将肿瘤细胞,例如约106悬浮在0.1mL PBS中,接种到雌性费希尔大鼠乳房的脂肪垫中。在接种的时候,腹膜内植入一种14天的Alza渗透微泵以分散测试化合物。将化合物溶于PBS中(例如,200mM的储备液),过滤除菌,并将其放在微型泵中以获得约4mg/kg/天的释放速度。对照组动物仅仅接受在微型泵中的媒介物(PBS)或空白对照肽。在大约第14天的时候处死动物。
实验性转移的其它模型也可以用来评价本发明的化合物。这些模型利用上文所述的人肿瘤细胞系,对裸鼠的尾部静脉进行静脉。典型地,在接种肿瘤细胞28天后处死这些大鼠,在它们的肺中评价是否出现转移。
5.4.133LL路易士肺癌:原发肿瘤的生长
在1951年,这种肿瘤系在C57BL/6小鼠中作为肺癌的自发形成(CancerRes.1955,15:39.还可参见Malave et al.,J.Nat’l.Canc.Inst.1979,62:83,88)。通过皮下接种,在C57BL/6小鼠中通过传代进行繁殖,并且在半同种异源的C57BL/6×DBA/2F1小鼠中或在异源的C3H小鼠中进行测试。典型地,对于皮下植入每组使用六只动物,或者对于肌肉注射植入每组使用十只动物。肿瘤可以以2-4mm片段进行皮下接种,或者可以以约0.5-2×106细胞的悬浮细胞的接种物进行肌肉注射植入或皮下植入。植入24小时后开始进行治疗,或者直到获得具体大小的肿瘤(通常约400mg)后才开始进行治疗。每天腹膜内给予测试化合物,连续给药11天。
接着对动物进行称重、触诊并测定肿瘤大小。在未经治疗的对照组受试动物中,肌内接种12天后,典型的肿瘤重量为500-2500mg。典型的平均存活时间为18-28天。在第1-11天,使用阳性对照化合物,例如环磷酰胺以每天20mg/kg/注射。计算的结果包括平均动物体重、肿瘤大小、肿瘤重量、存活时间。为了证实治疗活性,应该在两种多剂量测定中对测试组合物进行测试。
5.4.143LL路易士肺癌:原发生长和自发转移模型
此模型已经被许多研究者使用(参见例如Gorelik et al.,1980,J..Nat’l.Canc.Inst.65:1257-1264;Gorelik et al.,Rec.Results Canc.Res.1980,75:20-28;Isakov et al.,Invasion Metas.1982,2:12-32;Talmadge et al.,J.Nat′l.Canc.Inst.1982,69:975-980;Hilgard et al.,Br.J.Cancer 1977,35:78-86)。测试小鼠是雄性C57BL/6小鼠,2-3月龄。皮下注射、肌内注射或足垫内植入后,此肿瘤发生转移,优选在肺中。对于某些肿瘤系,原发性肿瘤起抗转移作用,因此在进行转移阶段研究之前,首先必须切除原发性肿瘤(还参见O’Reilly et al.美国专利号5,639,725)。
通过用0.3%的胰蛋白酶溶液处理切碎的肿瘤组织,从实体瘤中制备得到单细胞悬浮液。细胞用PBS(pH7.4)洗涤3次,然后将其悬浮在PBS中。以这种方式制得的3LL细胞的成活力通常为约95-99%(由台盼蓝染料排除)。将悬浮在0.05ml PBS中的活肿瘤细胞(3×104-5×106)进行皮下注射,或者注射到C57BL/6小鼠的背部或后足的脚垫之一。背部皮下注射106细胞3-4天后,可以观察到肿瘤的出现。出现肿瘤的那天以及每隔一天用卡尺测量已确立的肿瘤的直径。
治疗为每周给予一个或两个剂量的化合物。在另一种实施方案中,所述的肽通过渗透微型泵给予。
在背部肿瘤切除的实验中,当肿瘤达到约1500mm3大小时,将小鼠随机分为两组:(1)彻底切除原发性肿瘤;或(2)进行假手术并原封不动的保留肿瘤。虽然500-3000mm3的肿瘤抑制转移的生长,但是1500mm3是最大尺寸的原发性肿瘤,其在高存活率和没有局部再生长的情况下可以安全地被切除。21天后,处死所有小鼠,并进行尸体解剖。
除去肺并称其重量。将肺固定在布安溶液中,记录可见转移的数目。还使用装有含千分尺的目镜的双目立体镜,在8X放大倍数下,测定转移的直径。在所记录直径的基础上,能够计算每个转移的体积。为了测定每个肺中转移的总体积,将可见转移的平均数乘以转移的平均体积。为了进一步测定转移性生长,可以测定125IdUrd与肺细胞的结合(Thakur et al.,J..Lab.Clin.Med.1977,89:217-228)。十天后切除肿瘤,将25μg氟脱氧尿嘧啶接种到带肿瘤的腹膜中(和,如果使用,切除肿瘤的小鼠)。30分钟后,向小鼠给予1μCi的125IdUrd(碘苷)。一天后,除去肺和脾并称重,然后使用γ计数器测定125IdUrd的结合度。
在带足垫肿瘤的小鼠中,当肿瘤达到约8-10mm直径时,将小鼠随机分为两组:(1)膝关节以上结扎后,将带肿瘤的腿截肢;或(2)小鼠保持原封不动,作为未截肢的带肿瘤对照组。(在带肿瘤的小鼠中,无肿瘤腿的截肢对随后的转移没有已知的影响,排除了麻醉、应激或手术的可能影响)。截肢后第10-14天杀死小鼠。如上所述那样对转移进行评价。
5.5治疗用途
向患有疾病的患者,优选为人,给予结构式(I)化合物和/或其药物组合物,其中疾病的特征在于异常血管生成。异常血管生成包括异常新血管生成例如形成新血管、血管变大、血管出现更多分枝以及任何其它机理,其导致有病组织或部位的血液承载能力增加。这些化合物及其药物组合物可用于治疗和/或预防异常血管生成。
优选地,疾病特征为异常血管生成的疾病包括,但不局限于,癌症(例如,任何血管化肿瘤,优选是一种实体瘤,包括但不局限于,肺癌、乳腺癌、卵巢癌、胃癌、胰腺癌、喉癌、食道癌、睾丸癌、肝癌、腮腺癌、胆道癌、结肠癌、直肠癌、子宫颈癌、子宫癌、子宫内膜癌、肾癌、膀胱癌、前列腺癌、甲状腺癌、鳞状细胞癌、腺癌、小细胞癌、黑色素瘤、神经胶质瘤、成神经细胞瘤、肉瘤(例如血管肉瘤、软骨肉瘤))、关节炎、糖尿病、动脉硬化、动静脉的畸形、角膜移植新血管生成、延迟伤口愈合、糖尿病性视网膜病、与年龄有关的黄斑变性、肉芽形成、烧伤、血友病性关节、类风湿性关节炎、肥厚性瘢痕、新生血管性青光眼、不结合性骨折、奥-韦二氏病(Osier Weber syndrome)、牛皮癣、肉芽肿、晶状体后纤维组织形成、翼状胬肉、硬皮病、沙眼、血管粘连、眼睛的新血管生成、寄生虫病、术后肥大、头发生长的抑制、黄斑变性(包括湿型和干型)、类风湿性关节炎和骨关节炎。特征在于异常血管生成的、优选给予结构式(I)的化合物和/或其药物组合物的疾病是癌症、黄斑变性和类风湿性关节炎。
此外,可以向患有与铜代谢紊乱有关的疾病(例如,威尔逊氏病)为特征的患者,优选为人,给予结构式(I)的化合物和/或其药物组合物,以治疗和/或预防这样的疾病。
更进一步,可以向患者,优选人,给予结构式(I)的化合物和/或其药物组合物以治疗和/或预防肥胖症。结构式(I)的化合物还可以用于降低炎性细胞因子的水平(例如,TNF-α、TNF-β、IL-8等),以及用作纤溶酶原激活物抑制剂,其可能与血管生成和肥胖症有关(Loskutoff et al.,Ann.N.Y.Acad.Sci.,2000,902:272-281;Pan et al.,Cancer Res.,2002,62:4854-4859;Hanadaet al.,Cytokine Growth Factor Rev.2002,13:413-421;Chen et al.,Science2002,296:1634-5;Miyake et al.,J.Neuropathol.Exp.Neurol.59:18-28;Kochet al.,Science 1992,258:1798-801;Osawa et al.,Infect.Immun.2002,70:6294-6301;Bajou et al.,Nat.Med.1998,4:923-8)。
更进一步,可以向患有神经变性疾病的患者(优选人)给予结构式(I)的化合物和/或其药物组合物以治疗和/或预防所述的神经变性疾病。在本领域中已经报道,铜含量的提高可以调节各种神经变性疾病包括阿尔茨海默氏病、肌萎缩性侧索硬化症(ALS)和朊病毒病的病理学(Llanos et al.,DNA Cell Biol.2002,21:259-270;Carri et al.,Funct.Neurol 2001,16:181-188;Perry et al.,CNS Drugs 2002,16:339-352;Kowalik-Jankowska et al.,Environ HealthPerspect,2002,5:869-870;Maynard et al.,J.Biol.Chem.2002,277,44670-44676;Gnjec et al.,Front Biosci.2002,16-23;Strausak et al.,Brain Res.Bull.2001,55:175-185;Brown,Brain Res.Bull.2001,55:165-173;Brown,Biochem.Soc.Trans 2002,30:742-745)。
更进一步,根据本发明,可以向患者(优选人)给予结构式(I)的化合物和/或其药物组合物以治疗疾病,所述疾病的特征在于NF-κB异常调节活性或者炎性反应的异常调节炎症。
此外,在某些实施方案中,向患者(优选人)给予结构式(I)的化合物和/或其药物组合物作为抵抗各种疾病或病症的预防措施,这些疾病的特征在于异常血管生成、铜代谢紊乱、神经变性病症、肥胖症或NF-κB调节障碍。因此,结构式(I)的化合物和/或其药物组合物可以用来预防一种疾病或病症并且同时用来治疗另一种疾病(例如,预防威尔逊氏病或阿尔茨海默氏病,同时治疗癌症)。
治疗性/预防性给药
结构式(I)的化合物和/或其药物组合物可以有利地在人类医学中使用。如上面第4.5节所述,结构式(I)的化合物和/或其药物组合物适用于治疗或预防各种疾病或病症,这些疾病或病症的特征在于异常血管生成、铜代谢紊乱、神经变性病症、肥胖症或NF-κB调节障碍。
当用于治疗和/或预防上述疾病或病症时,可以单独服用或使用结构式(I)化合物和/或其药物组合物,或者可以与其它药物一起服用或使用。结构式(I)化合物和/或其药物组合物可以单独服用或使用,还可以与其它药物活性剂(例如,其它抗癌药,其它抗血管生成药,其它螯合剂例如锌、青霉胺等以及其它抗肥胖药)一起服用或使用,其中所述的其它药物活性剂包括结构式(I)其它化合物。
本发明提供治疗和预防方法,包括向需要这种治疗的患者给予治疗有效量的结构式(I)化合物和/或其药物组合物。所述的患者可以是动物,更优选是哺乳动物,最优选是人。
本发明的结构式(I)化合物和/或其药物组合物优选为口服给药。结构式(I)化合物和/或其药物组合物还可以通过任何其它方便的途径给药,例如通过输注或弹丸注射,通过上皮粘膜或皮肤粘膜(例如,口腔粘膜、直肠粘膜和肠粘膜)吸收。可以全身或局部给药。可以用来施用本发明化合物和/或药物组合物的各种递送体系是已知的(例如,包封在脂质体、微粒、微胶囊、胶囊中等)。给药方法包括,但不局限于,皮内、肌内、腹膜内、静脉内、皮下、鼻内、硬膜外、口服、舌下、鼻内、脑内、阴道内、经皮、直肠、吸入,或者局部给药,特别是局部用于耳、鼻、眼睛或皮肤。优选的给药方式将由医师决定,并且部分取决于医疗病症的部位。在多数情况下,给药将使结构式(I)化合物和/或其药物组合物释放到血流中。
在具体实施方案中,可能希望将一种或多种结构式(I)化合物和/或其药物组合物局部地用于需要治疗的部位。例如,这可以通过手术期间的局部输注、局部施用例如手术后与创伤敷料一起使用、通过注射、通过导管、通过栓剂、或通过植入物而实现,但是并不受这些方法的限制,其中所述植入物是包括膜如sialastic膜、或纤维的多孔的、无孔的或凝胶状材料。在一种实施方案中,给药可以通过在异常血管生成(例如癌症或关节炎)的部位(或形成部位)进行直接注射。
在某些实施方案中,可能希望通过任何合适的途径,包括心室内、鞘内和硬膜外注射,将结构式(I)化合物和/或其药物组合物引入到中枢神经系统中。例如通过心室内导管与容器例如Ommaya容器相连,可以有助于进行心室内注射。
结构式(I)化合物和/或其药物组合物还可以直接吸入肺部。对于通过吸入法给药,结构式(I)化合物和/或其药物组合物可以方便地通过许多不同装置被释放到肺中。例如,可计量的“剂量吸入器”(“MDI”),其使用含有合适的低沸点推进剂(例如,二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或任何其它合适的气体)的罐,可以用来将结构式(I)化合物和/或其药物组合物直接给药到肺。
或者,可以使用干粉吸入(“DPI”)装置,将结构式(I)化合物和/或其药物组合物用于肺中。DPI装置采用在容器内由一股气体生成大量的干粉的给药机理,该干粉然后可以让患者吸入。DPI装置在本领域中也是公知的。有各种各样多剂量DPI(“MDDPI”)系统,可以释放一次以上的治疗剂量。例如,对于这些系统,可以配制用在吸入器或吹药器中的明胶的胶囊和药筒,其中含有结构式(I)化合物与用于这些系统的合适的粉末基质例如乳糖或淀粉的粉末混合物。
可以用来将结构式(I)化合物和/或其药物组合物给药至肺的另一种类型的装置是液体喷雾装置,例如由Aradigm公司,Hayward,CA提供。液体喷雾系统使用非常小的喷嘴孔使液体药物制剂雾化,该雾化后的药物制剂之后可以直接被肺吸入。
在一种实施方案中,使用喷雾器将结构式(I)化合物和/或其药物组合物用于肺中。例如通过使用超声波能量,喷雾器从液体药物制剂中生成气溶胶,以形成能够容易被吸入的微粒(例如参见,Verschoyle et al.,British J.Cancer,1999,80,Suppl.2,96)。喷雾器的例子包括由SheffieldPharmaceuticals,Inc提供的装置(参见,Armer et al.,美国专利号5,954,047;van der Linden et al.,美国专利号5,950,619;van der Linden et al.,美国专利号5,970,974),以及Batelle Pulmonary Therapeutics,Columbus,OH提供。
在另一种实施方案中,可以使用电流体动力学(“EHD”)气溶胶装置,将结构式(I)化合物和/或其药物组合物递送到肺中。EHD气溶胶装置使用电能将液体药物溶液或悬浮液雾化(例如参见,Noakes et al.,美国专利号4,765,539)。当使用EHD气溶胶装置将结构式(I)化合物和/或其药物组合物用于肺时,所述制剂的电化学性质是重要的优化参数,这样的优化通常由本领域普通技术人员进行。EHD气溶胶装置可以比现有的肺给药技术更有效。
在另一种实施方案中,结构式(I)化合物和/或其药物组合物可以以小囊泡(vesicle)的形式递送,特别是以脂质体的形式给予。(参见,Langer,1990,Science 249:1527-1533;Treat et al.,in“Liposomes in the Therapy of InfectiousDisease and Cancer,”Lopez-Berestein and Fidler(eds.),Liss,New York,pp.353-365(1989);通常参见“Liposomes in the Therapy of Infectious Disease andCancer”Lopez-Berestein and Fidler(eds.),Liss,New York,pp.353-365(1989))。
另一种实施方案中,结构式(I)化合物和/或其药物组合物可以通过持续释放系统递送,优选通过口服持续释放系统递送。在一种实施方案中,可以使用泵(参见,Langer,supra,Sefton,1987,CRC Crit.Ref.Biomed Eng.14:201;Saudek et al.,1989,N.Engl.J.Med.321:574)。
在另一种实施方案中,可以使用聚合材料(参见″Medical Applications ofControlled Release,″Langer and Wise(eds.),CRC Pres.,Boca Raton,Florida(1974);″Controlled Drug Bioavailability,″Drug Product Design andPerformance,Smolen and Ball(eds.),Wiley,New York(1984);Langer et al.,1983,J.Macromol.Sci.Rev.Macromol Chem.23:61;还可参见Levy et al.,1985,Science 228:190;During et al.,1989,Ann.Neurol.25:351;Howard etal.,1989,J.Neurosurg.71:105)。在另一种实施方案中,聚合材料用于口服的持续释放给药。优选的聚合物包括羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素和羟乙基纤维素(最优选羟丙基甲基纤维素)。其它优选的纤维素醚已经被描述(Alderman,Int.J Pharm.Tech.& Prod.Mfr.,1984,5(3)1-9)。影响药物释放的因素是本领域普通技术人员所公知的,并且已经在本领域中进行了描述(Bamba et al.,Int.J Pharm.,1979,2,307)。
在另一种实施方案中,包有肠溶衣的制剂可以用于口服持续释放给药。优选的包衣材料包括溶解度与pH有关的聚合物(即,pH-控制释放的),具有缓慢的或与pH有关的溶胀、溶解或侵蚀速率的聚合物(即,时间-控制释放的)、酶降解的聚合物(即,酶-控制释放的),以及形成坚固层(该坚固层在压力增加的情况下才破坏)的聚合物(即,压力-控制释放的)。
在另一种实施方案中,渗透性递送体系可以用于口服持续释放给药(Verma et al.,Drug Dev.Ind.Pharm.,2000,26:695-708)。在另一种实施方案中,OROSTM渗透装置可以用于口服持续释放装置。(Theeuwes et al,美国专利号3,845,770;Theeuwes et al.,美国专利号3,916,899)。
在另一种实施方案中,可以将控释系统放在本发明化合物和/或药物组合物的靶点附近,因此仅需要一部分的全身性剂量(例如参见,Goodson,in″Medical Applications of Controlled Release,″supra,vol.2,pp.115-138(1984))。还可使用在Langer,1990,Science 249:1527-1533中讨论的其它控释系统。
5.7药物组合物
本发明的药物组合物包含治疗有效量的一种或多种结构式(I)化合物,优选为纯化的形式,与合适量的可药用赋形剂一起,由此提供一种合适患者给药的形式。当给予患者时,结构式(I)化合物和可药用赋形剂优选是无菌的。当静脉内施用结构式(I)化合物时,水是优选的赋形剂。盐溶液和葡萄糖水溶液以及丙三醇溶液也可以用作液体赋形剂,具体是对于可注射溶液。合适的药物赋形剂还包括赋形剂例如淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石粉、氯化钠、干脱脂奶粉、丙三醇、丙二醇、乙二醇、水、乙醇等。本发明的药物组合物,如果需要,还可以含有少量的润湿剂或乳化剂或pH缓冲剂。此外,可以使用助剂、稳定剂、增稠剂、润滑剂和着色剂。
包含结构式(I)化合物的药物组合物可以通过常规的混合、溶解、造粒、制糖锭、研磨、乳化、封装、包埋或冷冻干燥方法进行制备。药物组合物可以以常规的方式使用一种或多种生理上可接受的载体、稀释剂、赋形剂或助剂进行制备,这些生理上可接受的载体、稀释剂、赋形剂或助剂有助于将结构式(I)化合物加工成药学上可使用的制剂。合适的制剂取决于所选择的给药途径。
本发明的药物组合物可以采取溶液、悬浮液、乳剂、片剂、药片、丸剂、胶囊、含液体的胶囊、粉末、持续释放制剂、栓剂、乳剂、气溶胶、喷雾剂、悬浮液或任何其它可使用形式。在一种实施方案中,可药用赋形剂是胶囊(例如参见,Grosswald et al.,美国专利号5,698,155)。合适的药物赋形剂的其它例子已经描述在本领域中(例如Remlngton:The Science andPractice of Pharmacy,Philadelphia College o Pharmacy and Science,20thEdition,2000)。
对于局部给药,可以将结构式(I)化合物配制成溶液、凝胶剂、膏剂、乳剂、悬浮液等这些在本领域中所公知的。
全身性制剂包括设计成通过注射给药的那些,例如皮下注射、静脉注射、肌内注射、鞘内注射或腹膜内注射,以及设计成经皮、转化粘液质(transmucosal)、经口或经肺给药的那些。全身性制剂可以与另一种活性剂一起制备,所述活性剂可以改善气道粘液的粘液纤毛清除率或减少粘液粘度。这些活性剂包括,但不局限于,钠通道阻滞剂、抗生素、N-乙酰半胱氨酸、高半胱氨酸和磷脂。
在一种实施方案中,根据常规方法,将结构式(I)化合物配制成适合于人静脉注射给药的药物组合物。典型地,静脉注射给药的本发明化合物是以无菌等渗含水缓冲液形式的溶液。对于注射,可以将结构式(I)化合物配制在水溶液中,优选配制在生理学相容的缓冲液中,例如汉克斯液、林格液或生理盐水缓冲液。所述溶液可以含有配制试剂例如悬浮剂、稳定剂和/或分散剂。必要时,所述药物组合物还可以包括一种增溶剂。用于静脉注射给药的药物组合物可以任选包括一种局部麻醉剂例如利多卡因以减轻注射部位的疼痛。通常,在单位剂型中,各组分或者单独提供或者混合在一起提供,例如,在密闭容器例如标明活性剂数量的安瓿或药囊中作为冷冻干燥粉末或无水浓缩物。当结构式(I)化合物经由输液给药时,例如,它可以用含无菌药物级水或盐水的输液瓶进行配制。当结构式(I)化合物通过注射给药时,提供安瓿的灭菌注射水或盐水,这样在给药前可以将所述组分混合。
对于转化粘液质给药,在该制剂中使用适合渗透过屏障的渗透剂。这样的渗透剂通常在本领域中是已知的。
用于口服给药的药物组合物例如可以以片剂、锭剂、水性或油性悬浮液、粒剂、粉末、乳剂、胶囊、糖浆剂或酏剂的形式存在。口服给药的药物组合物可以含有一种或多种任选试剂,例如甜味剂如果糖、阿司帕坦或糖精,调味剂如薄荷、冬青油,或樱桃着色剂以及防腐剂,以便获得一种可口的制剂。此外,当以片剂或丸剂形式存在时,所述的组合物可以进行包衣,以便延迟在胃肠道中的崩解和吸收,由此在延长期限内获得一种持续作用。包裹渗透性活性驱动化合物(driving compound)的选择性渗透膜同样适合于口服给药的结构式(I)化合物。在这些后者的平台中,包围胶囊的环境中的液体被驱动化合物吸收,该驱动化合物溶胀以通过孔隙替换出药物或药物组合物。与立即释放制剂的尖锋分布图不同,这些释放平台可以提供一种基本上零级的释放分布图。还可以使用时间延迟物质例如单硬脂酸甘油酯或硬脂酸甘油酯。口服组合物可以包括标准赋形剂甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。这些赋形剂优选是药物级的。
对于口服液体药剂例如,悬浮液、酏剂和溶液,合适的载体、赋形剂或稀释剂包括水、盐水、亚烷基二醇(例如,丙二醇)、聚(亚烷基)二醇(例如,聚乙二醇)油类、醇类、pH在4至6之间的略微酸性的缓冲液(例如,在约5.0mM至约50.0mM之间的乙酸盐、柠檬酸盐、抗坏血酸)等。此外,可以加入调味剂、防腐剂、着色剂、胆盐、酰基肉碱等。
对于含服给药,所述的药物组合物可以采取片剂、糖锭等的形式,以常规方式进行配制。
适合与喷雾器、液体喷雾装置和EHD气溶胶装置一起使用的液体药物制剂通常包括结构式(I)化合物和可药用赋形剂。优选地,所述的可药用赋形剂是液体例如醇、水、聚乙二醇或全氟化碳。任选地,可以加入另外的物质,以改变本发明化合物溶液或悬浮液的气溶胶性质。优选地,这种物质是液体例如醇、乙二醇、聚乙二醇或脂肪酸。适合在气溶胶装置中使用的配制液体药物溶液或悬浮液的其它方法是本领域普通技术人员所已知的(例如,参见Biesalski,美国专利号5,112,598;Biesalski,美国专利号5,556,611)。
结构式(I)化合物还可以配制成直肠或阴道的药物组合物例如栓剂或保留灌肠剂,例如含常规栓剂基质例如可可脂或其它甘油酯。
除前面所述的制剂外,结构式(I)化合物还可以配制成储存制剂。这些长效作用制剂可以通过植入给药(例如,皮下注射或肌内)或通过肌内注射给药。因此,例如,结构式(I)化合物可以与合适的聚合材料或疏水性材料(例如,以在可接受油中乳液的形式)或离子交换树脂,或以微溶衍生物的形式例如以微溶盐的形式,一起进行配制。
当结构式(I)化合物是酸性时,在上述任何制剂中包括游离酸、可药用盐、溶剂化物或水合物。基本上保持游离酸活性的可药用盐,可以通过与碱反应进行制备,并且可药用盐比相应的游离酸形式在含水和其它质子溶剂中更易溶解。
5.8治疗剂量
结构式(I)化合物和/或其药物组合物通常将以可有效地实现指定的目的的量使用。用于治疗或预防特征在于异常血管生成的疾病或病症、铜代谢紊乱、神经变性疾病和肥胖症时,结构式(I)化合物和/或其药物组合物将以治疗有效量给予或施用。
在治疗在此公开的具体疾病或病症中,结构式(I)化合物的量将取决于疾病或病症的性质,并且可以由之前所述的在本领域中已知的标准临床技术进行确定。此外,可以任选进行体外或体内测定,以确定最佳的剂量范围。当然,结构式(I)化合物的给药量将取决于所治疗的对象、所治疗对象的体重、疾病的严重程度、给药方式以及主治医生的判断等因素。
例如,在一种药物组合物中,剂量可以由单一给药、多次应用或控制释放递送。在一种实施方案中,结构式(I)化合物通过口服持续释放给药。优选地,在此实施方案中,结构式(I)化合物每天给药两次(更优选每天给药一次)。可以周期性地重复剂量给药,可以单独提供或与其它药物一起提供,并且如果需要有效治疗疾病状态或病症,可以持续给药。
口服给药的合适剂量范围取决于药效,但是相对于每公斤体重,通常给予约0.001mg至约200mg的本发明化合物。剂量范围可以很容易地由本领域普通普通技术人员根据已知方法进行确定。
静脉注射(i.v.)给药的合适剂量范围在约0.01mg至约100mg每公斤体重之间。鼻内给药的合适剂量范围在约0.01mg/kg体重至约1mg/kg体重之间。栓剂通常含有约0.01毫克至约50毫克的结构式(I)化合物每公斤体重,并且包含约0.5%至约10%重量的活性成分。对于皮内、肌内、腹膜内、皮下、硬膜外、舌下或脑内给药的情况,推荐的剂量为约0.001mg至约200mg每公斤体重。有效剂量可以从来源于体外或动物模型测试体系的剂量反应曲线外推知。这些动物模型和体系在本领域中是公知的。
在人体中使用之前,优选将结构式(I)化合物进行体外和体内测定,以获得所需的治疗活性或预防活性。例如,体外测定可以用于确定给予结构式(I)的具体化合物或结构式(I)化合物的组合是否优选用于治疗或预防特征在于异常血管形成、神经变性疾病和肥胖症的疾病或病症。使用动物模型体系还可以证明本发明的化合物是有效的和安全的。
优选地,在此所述的结构式(I)化合物的治疗活性剂量将提供治疗益处,但是不会引起显著的毒性。结构式(I)化合物的毒性可以使用标准药物方法进行确定,并且可以很容易地由本领域普通技术人员确定。毒性作用和治疗作用的剂量比是治疗指数。在治疗疾病和病症中,结构式(I)化合物优选表现出特别高的治疗指数。在此所述的结构式(I)化合物的剂量将优选在循环浓度的范围内,其包括很少或没有毒性的活性剂量。
5.9联合治疗
在本发明的某些实施方案中,结构式(I)化合物和/或药物组合物可以与至少一种其它治疗剂进行联合治疗。结构式(I)化合物和/或药物组合物与该治疗剂累加起作用,或更优选起协同作用。在一些优选实施方案中,结构式(I)化合物和/或药物组合物与其它药物同时给药,其中其它药物可以是与结构式(I)化合物部分相同的药物组合物或者是不同的药物组合物。在其它实施方案中,在给予其它药物的之前或之后,给予结构式(I)化合物的药物组合物。
在一些实施方案中,结构式(I)化合物和/或药物组合物可以与其它化学治疗剂进行联合治疗,例如烷基化试剂(例如,氮芥类(例如,环磷酰胺(cyclophosphamide)、异磷酰胺(ifosfamide)、双氯乙基甲胺(mechlorethamine)、美法仑(melphalen)、苯丁酸氮芥(chlorambucil)、六甲三聚氰胺(hexamethylmelamine)、硫替派(thiotepa)),磺酸烷基酯(例如,白消安(busulfan))、亚硝基脲(三嗪)抗代谢物(例如,叶酸类似物、嘧啶类似物(例如,氟尿嘧啶(fluorouracil)、5-氟脲嘧啶脱氧核苷(floxuridine)、阿糖胞苷(cytosinearabinoside)等),嘌呤类似物(例如,巯嘌呤(mercaptopurine)、thiogunaine、喷司他丁(pentostatin)等),天然产物(例如,长春碱(vinblastine)、长春新碱(vincristine)、依托泊苷(etoposide)、terdiposide、更生霉素(dactinomycin)、柔红霉素(daunorubicin)、doxurubicin、博来霉素(bleomycin)、mithrmycin、丝裂霉素C(mitomycin C)、左天冬酰胺酶(L-asparaginase)、干扰素α(interferonalpha)),铂配位络合物(例如,顺-铂(cis-platinum)、卡铂(carboplatin)等),米托蒽醌(mitoxantrone),羟基脲(hydroxyurea),丙卡巴肼(procarbazine),激素和拮抗剂(例如,泼尼松(prednisone)、己酸羟孕酮(hydroxyprogesteronecaproate)、醋酸甲羟孕酮(medroxyprogesterone acetate)、醋酸甲地孕酮(megestrol acetate)、己烯雌酚(diethylstilbestrol)、乙炔雌二醇(ethinylestradiol)、他莫昔芬(tamoxifen)、丙酸睾酮(testosterone propionate)、氟甲睾酮(fluoxymesterone)、氟他米特(flutamide)、醋酸亮丙瑞林(leuprolide)等),抗血管生成药或抑制剂(例如,血管他丁(angiostatin)、维甲酸(retinoic acids)和紫杉醇(paclitaxel)、雌二醇衍生物、噻唑嘧啶衍生物等),细胞凋亡诱导剂(例如,阻断抑制细胞凋亡的致癌基因的反义核苷酸、肿瘤抑制剂、TRAIL、TRAIL多肽、与Fas有关的因子1、白细胞介素-1β-转化酶、磷酸酪氨酸抑制剂、RXR类视色素受体激动剂、喹诺酮衍生物等),螯合剂(青霉胺(penicillamine)、锌、曲恩汀(trientine)等)以及其它减肥药。
5.10治疗试剂盒
本发明提供治疗试剂盒,其包含结构式(I)化合物和/或药物组合物。治疗试剂盒还可以含有其它化合物(例如,化学治疗剂、天然产物、激素或拮抗剂、抗血管生成药或抑制剂、细胞凋亡诱导药或螯合剂)和/或其药物组合物。
治疗试剂盒可以具有单个容器,其含有结构式(I)化合物和/或药物组合物,以及具有或者没有其它组分(例如,其它化合物或其药物组合物);或者对于每个组分可以有不同的容器。优选地,本发明的治疗试剂盒包括结构式(I)化合物和/或药物组合物,以及与第二种化合物或其药物组合物一起共同给药(第二种药物优选是化学治疗剂、天然产物、激素或拮抗剂、抗血管生成药或抑制剂、细胞凋亡诱导药或螯合剂)。试剂盒中的组分可以预先混合,或者在给予患者之前,将每种组分放在分开的容器中。
试剂盒中的组分可以以一种或多种液体溶液的形式提供,优选以水溶液,更优选以无菌水溶液的形式提供。试剂盒中的组分也可以以固体的形式提供,通过加入合适的溶剂(其优选放在另外的不同容器中)以转化为液体。
治疗试剂盒的容器可以是管瓶、试管、烧瓶、瓶、注射器或用来包封固体或液体的任何其它容器。通常,当存在多个组分时,所述的试剂盒含有第二个管瓶或其它容器,其可以将剂量分开。所述的试剂盒还可以含有用于可药用液体的另一个容器。
优选地,治疗试剂盒将含有一些器件(例如,一个或多个针头、注射器、滴眼管,吸管等),其使试剂盒中的组分能够施用。
6.实施例
本发明通过下列实施例进一步进行说明,其详细描述了本发明化合物的制备以及生物学活性测定的方法。显然,本领域普通技术人员可以在材料和方法方面进行不脱离本发明范围的许多修饰。
6.1实施例1:合成四硫代钨酸盐衍生物的一般方法
将市场上可买到的氢氧化季铵的水溶液(2当量)加入到四硫代钨酸铵(1当量)中,接着加入去离子水,直到所有固体物料溶解为止。将该溶液置于旋转蒸发仪上,在真空(约5-10托)中20℃浴中维持一小时,需要时,补入水以保持恒定的体积。然后允许该反应混合物蒸发至干并从离子水和异丙醇中重结晶所得的黄色固体。经过滤收集该固体,用异丙醇和乙醚洗涤,然后在真空干燥器中在P2O5存在下高真空干燥24小时。
6.2实施例2:合成四硫代钨酸盐衍生物的一般方法
将季铵卤化物(2当量)固体加入到四硫代钨酸铵(1当量)的干燥乙腈悬浮液(5mL每毫摩尔的四硫代钨酸盐)中并将所得混合物在室温下于氮气中搅拌18小时。如果该过程形成沉淀,经过滤收集固体,使用异丙醇和乙醚洗涤并从去离子水和异丙醇中重结晶。经过滤收集黄色结晶,用异丙醇和乙醚洗涤并在真空干燥器中在P2O5存在下高真空干燥24小时。如果溶液保持澄清,那么真空除去溶剂,将残留物置于二氯甲烷中,用水洗涤三次、盐水洗涤一次,干燥(Na2SO4),浓缩溶液。在真空干燥器中在P2O5存在下高真空干燥所得的油或固体24小时。
6.3实施例3:合成四硫代钨酸盐衍生物的一般方法
将季铵卤化物(2当量)的去离子水溶液(10mL每毫摩尔四硫代钨酸盐)加入到四硫代钨酸铵(1当量)的干燥乙腈悬浮液(20mL每毫摩尔的四硫代钨酸盐)中并将所得混合物在室温下于氮气中搅拌18小时。如果该过程形成沉淀,经过滤收集固体,使用水、异丙醇和乙醚洗涤,然后在真空干燥器中在P2O5存在下高真空干燥24小时。如果溶液保持澄清,那么首先过滤该反应混合物,并真空浓缩滤液。所得固体从离子水和异丙醇中重结晶,经过滤收集黄色结晶,用异丙醇和乙醚洗涤,然后在真空干燥器中在P2O5存在下高真空干燥24小时。
6.4实施例4:四硫代钨酸盐,二(胆碱)
根据实施例1的方法,由四硫代钨酸铵(158mg,0.454mmol)和50%重量份的氢氧化胆碱(222mg,0.916mmol)水溶液制备该化合物,得到151mg(64%)标题化合物,为亮黄色结晶:
IR(KBr,cm-1)3402,459;1H NMR(300MHz,DMSO-d6)δ5.21(t,J=4.8Hz,2H),3.88-3.81(m,4H),3.46-3.43(m,4H),3.14(s,18H);13C NMR(75MHz,DMSO-d6)δ66.8(2C),55.2(2C),53.1(6C);ES MS m/z(胆碱)+104.3;UV(H2O)393.5nm(ε=16730).C10H28N2O2S4W的计算值:C,23.08;H,5.42;N,5.38;S,24.65.测定值:C,23.17;H,5.28;N,5.43;S,24.87.
6.5实施例5:四硫代钨酸盐,二(三乙基甲基铵)
根据实施例1的方法,由四硫代钨酸铵(164mg,0.471mmol)和20%重量份的氢氧化三乙基甲基铵(627mg,0.941mmol)水溶液制备该化合物,得到147mg(61%)标题化合物,为亮黄色结晶:
IR(KBr,cm-1)460;1H NMR(300MHz,DMSO-d6)δ3.29(q,J=6.9Hz,12H),2.91(s,6H),1.21(t,J=6.9Hz,18H);13C NMR(75MHz,DMSO-d6)δ55.0(6C),46.0(2C),7.5(6C);ES MS m/z(三乙基甲基铵)+116.4;UV(H2O)393.5nm(ε=16730).C14H36N2S4W的计算值:C,30.88;H,6.66;N,5.14;S,23.55.测定值:C,30.87;H,6.33;N,5.18;S,23.77.
6.6实施例6:四硫代钨酸盐,二(三乙基苯基铵)
根据实施例1的方法,由四硫代钨酸铵(155mg,0.444mmol)和10%重量份的氢氧化三乙基苯基铵(1.74g,0.889mmol)水溶液制备该化合物,得到198mg(69%)标题化合物,为亮黄色结晶:
IR(KBr,cm-1)455;1H NMR(300MHz,DMSO-d6)δ7.92(d,J=8.4Hz,4H),7.71-7.57(m,6H),3.91(q,J=7.1Hz,12H),1.06(t,J=7.1Hz,18H);13C NMR(75MHz,DMSO-d6)δ141.7(2C),130.4(4C),130.0(2C),122.6(4C),55.3(6C),7.8(6C);ES MS m/z(三乙基苯基铵)+178.4;UV(H2O)393.5nm(ε=15600).C24H40N2S4W的计算值:C,43.11;H,6.03;N,4.19;S,19.18.测定值:C,42.99;H,5.73;N,4.25;S,19.31.
6.7实施例7:四硫代钨酸盐,二(1,4-二甲基吡啶鎓)
根据实施例2的方法,由四硫代钨酸铵(163mg,0.467mmol)和碘化1,4-二甲基吡啶鎓(221mg,0.940mmol)制备该化合物,得到143mg(58%)标题化合物,为亮黄色结晶:
IR(KBr,cm-1)458;1H NMR(300MHz,DMSO-d6)δ8.88(d,J=6.4Hz,4H),7.96(d,J=6.4Hz,4H),4.32(s,6H),2.60(s,6H);13C NMR(75MHz,DMSO-d6)δ158.1(2C),144.8(4C),128.0(4C),47.1(2C),21.4(2C);ES MS m/z(1,4-二甲基吡啶鎓)+108.3;UV(H2O)393.5nm(ε=16030).C14H20N2S4W的计算值:C,31.82;H,3.81;N,5.30;S,24.27.测定值:C,31.67;H,3.77;N,5.32;S,24.13.
6.8实施例8:四硫代钨酸盐,二(1,4-二甲基吡咯鎓)
根据实施例3的方法,由四硫代钨酸铵(300mg,0.861mmol)和碘化1,1-二甲基吡咯鎓(400mg,1.76mmol)制备该化合物,得到223mg(51%)标题化合物,为亮黄色结晶:
IR(KBr,cm-1)455;1H NMR(300MHz,DMSO-d6)δ3.53-3.47(m,8H),3.13(s,12H),2.14-2.08(m,8H);13C NMR(75MHz,DMSO-d6)δ64.8(4C),51.0(4C),21.5(4C);ES MS m/z(1,1-二甲基吡咯鎓)+100.3;UV(H2O)393.5nm(ε=16950).C12H28N2S4W的计算值:C,28.12;H,5.51;N,5.47;S,25.03.测定值:C,27.90;H,5.47;N,5.56;S,25.01.
6.9实施例9:四硫代钨酸盐,二(三甲基苯基铵)
根据实施例2的方法,由四硫代钨酸铵(167mg,0.479mmol)和氯化苯基三甲基铵(166mg,0.968mmol)制备该化合物,得到139mg(50%)标题化合物,为亮黄色结晶:
IR(KBr,cm-1)459;1H NMR(300MHz,DMSO-d6)δ7.99(d,J=8.2Hz,4H),7.68-7.55(m,6H),3.64(s,18H);13C NMR(75MHz,DMSO-d6)δ147.3(2C),130.1(4C),130.0(2C),120.5(4C),56.4(6C);ES MS m/z(三甲基苯基铵)+136.2;UV(H2O)394.0nm(ε=15630).C18H28N2S4W的计算值:C,36.99;H,4.83;N,4.79;S,21.94.测定值:C,36.88;H,4.72;N,4.90;S,21.92.
6.10实施例10:四硫代钨酸盐,二(乙酰胆碱)
根据实施例2的方法,由四硫代钨酸铵(171mg,0.491mmol)和氯化乙酰胆碱(179mg,0.987mmol)制备该化合物,得到163mg(55%)标题化合物,为亮黄色结晶:
IR(KBr,cm-1)1749,1729,473,456;1H NMR(300MHz,DMSO-d6)δ4.47-4.41(m,4H),3.72-3.69(m,4H),3.16(s,18H),2.07(s,6H);13C NMR(75MHz,DMSO-d6)δ169.9(2C),63.8(2C),57.9(2C),53.0(6C),20.7(2C);ES MS m/z(乙酰胆碱)+146.4;UV(H2O)393.5nm(ε=15400).C14H32N2O4S4W的计算值:C,27.82;H,5.34;N,4.63;S,21.22.测定值:C,27.62;H,5.12;N,4.68;S,20.71.
6.11实施例11:四硫代钨酸盐,二[烷基二甲基(苯甲基)铵]
根据实施例2的方法,由四硫代钨酸铵(320mg,0.920mmol)和氯化苯甲烃铵(664mg,1.84mmol)制备该化合物,得到651mg(74%)标题化合物,为稠的、红色油状物:
IR(膜,cm-1)466;1H NMR(300MHz,DMSO-d6)δ7.59-7.48(m,10H),4.56(s,4H),3.31-3.23(m,4H),2.97(s,12H),1.84-1.72(m,4H),1.32-1.22(m,40H),0.88-0.82(m,6H);ES MS m/z[十二烷基二甲基(苯甲基)铵]+304.7,[十四烷基二甲基(苯甲基)铵]+332.7;UV(DMSO)399.0nm(ε=10400).
6.12实施例12:四硫代钨酸盐,环庚基二胆碱
根据实施例2的方法,由四硫代钨酸铵(299mg,0.860mmol)和二碘化环庚基二胆碱(516mg,0.860mmol)制备该化合物,得到115mg(20%)标题化合物,为亮黄色结晶:
IR(KBr,cm-1)1733,1719,455;1H NMR(300MHz,DMSO-d6)δ4.48-4.42(m,4H),3.73-3.69(m,4H),3.17(s,18H),2.35(t,J=7.4Hz,4H),1.59-1.48(m,4H),1.32-1.26(m,4H);13C NMR(75MHz,DMSO-d6)δ172.3(2C),63.7(2C),57.7(2C),52.8(6C),33.2(2C),28.0(2C),23.9(2C);UV(H2O)394.0nm(ε=15570)
6.13实施例13:四硫代钨酸盐,戊烷-1,5-二(三甲基铵)
根据实施例3的方法,由四硫代钨酸铵(140mg,0.402mmol)和N,N-戊基亚甲基二(碘化三甲基铵)(195mg,0.442mmol)制备该化合物,得到109mg(54%)标题化合物,为亮黄色粉末:
IR(KBr,cm-1)456;1H NMR(300MHz,D2O)δ3.34-3.26(m,4H),3.07(s,18H),1.89-1.77(m,4H),1.45-1.34(m,2H);UV(H2O)394.0nm(ε=15950).C11H28N2S4W:的计算值C,26.40;H,5.64;N,5.60;S,25.63.测定值:C,26.60;H,5.26;N,5.75;S,24.64.
6.14实施例14:四硫代钨酸盐,丁烷-1,4-二(三甲基铵)
根据实施例3的方法,由四硫代钨酸铵(200mg,0.574mmol)和N,N-四亚甲基二(碘化三甲基铵)(271mg,0.632mmol)制备该化合物,得到185mg(66%)标题化合物,为亮黄色粉末:
IR(KBr,cm-1)456;1H NMR(300MHz,D2O)δ3.45-3.35(m,4H),3.11(s,18H),1.92-1.82(m,4H);UV(H2O)394.0nm(ε=15990).C10H26N2S4W的计算值:C,24.69;H,5.39;N,5.76;S,26.37.测定值:C,24.77;H,5.35;N,5.85;S,25.80.
6.15实施例15:四硫代钨酸盐,丙烷-1,3-二(三甲基铵)
根据实施例3的方法,由四硫代钨酸铵(201mg,0.578mmol)和N,N-三亚甲基二(碘化三甲基铵)(263mg,0.635mmol)制备该化合物,得到192mg(70%)标题化合物,为亮黄色粉末:
IR(KBr,cm-1)456;UV(H2O)393.5nm(ε=16190).C9H24N2S4W:的计算值C,22.88;H,5.12;N,5.93;S,27.15.测定值:C,22.94;H,5.01;N,6.01;S,26.79.
6.16实施例16:四硫代钨酸盐,亚乙基-二(三甲基铵)
根据实施例3的方法,由四硫代钨酸铵(200mg,0.573mmol)和亚乙基二(碘化三甲基铵)(249mg,0.623mmol)制备该化合物,得到171mg(65%)标题化合物,为亮黄色粉末:
IR(KBr,cm-1)459;UV(H2O)393.5nm(ε=15720).C8H22N2S4W的计算值:C,20.96;H,4.84;N,6.11;S,27.98.测定值:C,20.88;H,4.71;N,6.21;S,27.39.
6.17实施例17:四硫代钨酸盐,二(N-苄基-2-苯基乙基铵)
根据实施例3的方法,再添加6ml的去离子水,由四硫代钨酸铵(295mg,0.848mmol)和氯化N-苄基-2-苯基乙基铵(422mg,1.70mmol)制备该化合物,得到317mg(51%)标题化合物,为橙色固体:
IR(KBr,cm-1)455;1H NMR(300MHz,DMSO-d6)δ8.83(br s,4H),7.57-7.52(m,4H),7.48-7.40(m,6H),7.36-7.23(m,10H),4.22(s,4H),3.21-3.15(m,4H),3.03-2.95(m,4H);13C NMR(75MHz,DMSO-d6)δ137.4(2C),132.5(2C),130.0(4C),128.9(2C),128.72(8C),128.68(4C),126.8(2C),50.6(2C),48.1(2C),31.8(2C);ES MS m/z[N-苄基-2-苯基乙基铵]+212.4;UV(DMSO)399.5nm(ε=16270).
6.18实施例18:四硫代钨酸盐,二(1-乙基-3-甲基-1H-咪唑鎓)
根据实施例3的方法,由四硫代钨酸铵、二(铵)(0.400g,1.15mmol)和氯化1-乙基-3-甲基-1H-咪唑鎓(0.354g,2.41mmol)制备该化合物,得到(0.217g,35%)标题化合物,为亮黄色固体:
IR(KBr pellet,cm-1)3438,3068,1569,1560,1169,450;1H NMR(300MHz,DMSO-d6)δ9.22(s,1H),7.78(s,1H),7.70(s,1H),4.21(q,2H,J=7.3Hz),3.31(s,3H),1.42(t,3H,J=7.3Hz);13C NMR(75MHz,DMSO-d6)δ136.4,123.4,121.8,44.0,35.6,15.1;MS m/z(C6H11N2)+111.3;UV(H2O)394nm(ε=15,891);C12H22N4WS4的计算值:C,26.97;H,4.15;N,10.48;S,24.00.测定值:C,26.91,H,3.92,N,10.55;S,23.67.
6.19实施例19:四硫代钨酸盐,二(苄基三甲基铵)
根据实施例1的方法,由四硫代钨酸铵、二(铵)(0.200g,0.574mmol)和氢氧化苄基三甲基铵(0.48g的40%水溶液,1.15mmol)制备该化合物,得到(0.246g,70%)标题化合物,为亮黄色固体:
IR(KBr pellet,cm-1)3446,2999,1456,458;1H NMR(300MHz,DMSO-d6)δ7.53-7.55(m,10H),4.56(s,4H),3.05(s,18H);13C NMR(75MHz,DMSO-d6)δ132.7,130.2,128.8,128.3,67.7,51.7(t);MS m/z(C10H16N)+150.3;UV(H2O)394nm(ε=15,027);C20H32N2WS4的计算值:C,39.21;H,5.27;N,4.57;S,20.94.测定值:C,39.28,H,4.88,N,4.65;S,20.89.
6.20实施例20:四硫代钨酸盐,二(2-羟基亚胺甲基-1-甲基-吡啶鎓)
根据实施例3的方法,由四硫代钨酸铵、二(铵)(0.200g,0.574mmol)和2-吡啶醛肟甲基氯化物(2-pyridinealdoxime methochloride)(0.198g,1.15mmol)制备该化合物,得到(0.198g,59%)标题化合物,为亮黄色固体:
IR(KBr pellet,cm-1)3077,1508,1005,455;1H NMR(300MHz,DMSO-d6)δ9.04(d,1H,J=5.9Hz),8.68(s,1H),8.55(app t,1H),8.37(d,1H,J=8.0Hz),8.07(app t,1H),4.39(s,3H);13C NMR(75MHz,DMSO-d6)δ147.3,146.7,144.8,141.7,127.1,124.7,46.1;MS m/z(C7H9N2O)+137.2;UV(H2O)394nm(ε=15380);C14H18N4O2WS4的计算值:C,28.67;H,3.09;N,9.55;S,21.87.测定值:C,28.51,H,2.87,N,9.63;S,21.55.
6.21实施例21:四硫代钨酸盐,二(乙酰基-β-甲基胆碱)
根据实施例3的方法,由四硫代钨酸铵、二(铵)(0.200g,0.574mmol)和氯化乙酰基-β-甲基胆碱(0.235g,1.20mmol)制备该化合物,得到(0.115g,32%)标题化合物,为亮黄色固体:
IR(KBr pellet,cm-1)3452,3008,1735,1252,454;1H NMR(300MHz,DMSO-d6)δ5.27(m,1H),3.58-3.74(m,2H),3.13(s,9H),2.06(s,3H),1.24(d,3H,J=6.3Hz);13C NMR(75MHz,DMSO-d6)δ169.5,67.6,65.2,53.2,21.1,18.5;MS m/z(C8H18NO2)+160.3;UV(H2O)394nm(ε=15831);C16H36N2O4S4W的计算值:C,30.38;H,5.74;N,4.43;S,20.28.测定值:C,30.10,H,5.62,N,4.47;S,20.47.
6.22实施例22:四硫代钨酸盐,琥珀酰胆碱
根据实施例3的方法,由四硫代钨酸铵、二(铵)(0.400g,1.15mmol)和氯化琥珀酰胆碱二水合物(0.456g,1.15mmol)制备该化合物,得到(0.414g,60%)标题化合物,为亮黄色固体:
IR(KBr pellet,cm-1)3005,1732,1208,1150,455;1H NMR(300MHz,DMSO-d6)δ4.47(m,4H),3.68-3.72(m,4H),3.30(d,18H,J=4.2Hz),2.66(m,4H);13C NMR(75MHz,DMSO-d6)δ171.3,58.0,52.9,28.4;UV(H2O)394nm(ε=15513);C14H30N2O4S4W的计算值:C,27.91;H,5.02;N,4.65;S,21.29.测定值:C,27.84,H,4.80,N,4.66;S,21.06.
6.23实施例23:四硫代钨酸盐,(亚乙基-1,2-二铵)
根据实施例3的方法,由四硫代钨酸铵、二(铵)(0.300g,0.862mmol)、氯化铵(0.092g,1.72mmol)和乙二胺(57.61μl,0.862mmol)制备该化合物,得到(0.257g,80%)标题化合物,为亮黄色固体:
IR(KBr pellet,cm-1)3002,1435,1025,451;1H NMR(300MHz,DMSO-d6)δ7.89(bs,6H),3.09(s,4H);13C NMR(75MHz,DMSO-d6)δ36.8;UV(H2O)394nm(ε=13291);C2H10N2S4W的计算值:C,6.42;H,2.69;N,7.49;S,34.27.测定值:C,6.58,H,2.43,N,7.49;S,32.98.
6.24实施例24:四硫代钨酸盐的湿度稳定性
于室温、95%相对湿度的条件下,将四硫代钨酸盐置于丙烯酸室中两周。除了在493nm处监测吸光度且摩尔吸光率为15710M-1cm-1之外,根据先前报道的方法进行纯度分析(McDonald et.al.,Inorg.Chim.Acta 1983,72,205-210)。结果报道于下表1中。
表1
名称 | %降解 |
四硫代钨酸盐,二(三乙基苯基铵) | -0.12 |
四硫代钨酸盐,二(铵) | -0.46 |
四硫代钨酸盐,二(三甲基苯基铵) | -0.46 |
四硫代钨酸盐,二(苄基三甲基铵) | 0.41 |
四硫代钨酸盐,二(乙酰胆碱) | 2.4 |
四硫代钨酸盐,二(胆碱) | 3.0 |
四硫代钨酸盐,二(1-乙基-3-甲基-1H-咪唑鎓) | 1.3 |
四硫代钨酸盐,二(1,4-二甲基吡啶鎓) | 2.0 |
四硫代钨酸盐,二(乙酰基-β-甲基胆碱) | 4.2 |
四硫代钨酸盐,二(1,1-二甲基吡咯鎓) | 0.04 |
四硫代钨酸盐,二(2-羟基亚胺基甲基-1-甲基 | 5.6 |
-1H-吡啶鎓) | |
四硫代钨酸盐,戊烷-1,5-二(三甲基铵) | 19.8* |
四硫代钨酸盐,亚乙基二(三甲基铵) | 8.6* |
四硫代钨酸盐,丙烷-1,3-二(三甲基铵) | 23.8* |
四硫代钨酸盐,丁烷-1,4-二(三甲基铵) | 5.7* |
四硫代钨酸盐,(琥珀酰胆碱) | 23.3* |
四硫代钨酸盐,(环庚基二胆碱) | 18.4* |
四硫代钼酸盐,二(铵) | 56++±5 |
四硫代钼酸盐,二(胆碱) | 36++±2 |
*部分可溶
++2个数值点的平均
6.25实施例25:
四硫代钨酸盐的铜结合能力
根据四硫代钨酸盐抑制半胱氨酸自氧化的能力测定了四硫代钨酸盐的铜结合能力,如下表2所示。
表2
半胱氨酸自氧化的抑制(100μM Cys,100μM香豆素-3-羧酸,100μMCuSO4)
抑制剂 | 抑制剂浓度 | %抑制率 |
曲恩汀 | 50μM | 39.71% |
四硫代钨酸盐,二(铵) | 50μM | 95.94% |
四硫代钨酸盐,二(三乙基苯基铵) | 50μM | 91.32% |
四硫代钨酸盐,二(三甲基苯基铵) | 50μM | 91.53% |
四硫代钨酸盐,二(苄基三甲基铵) | 50μM | 94.62% |
四硫代钨酸盐,二(乙酰胆碱) | 50μM | 90.36% |
四硫代钨酸盐,二(胆碱) | 50μM | 92.54% |
四硫代钨酸盐,二(1-乙基-3-甲基-1H-咪唑鎓) | 50μM | 91.16% |
四硫代钨酸盐,二(1,4-二甲基吡啶鎓) | 50μM | 89.98% |
四硫代钨酸盐,二(乙酰基-β-甲基胆碱) | 50μM | 90.40% |
四硫代钨酸盐,二(1,4-二甲基吡啶鎓) | 50μM | 89.66% |
四硫代钨酸盐,二(2-羟基亚胺基甲基-1-甲基-1H-吡啶鎓) | 50μM | 91.15% |
四硫代钨酸盐,戊烷-1,5-二(三甲基铵) | 50μM | 90.69% |
四硫代钨酸盐,二(胆碱) | 50μM | 91.99% |
四硫代钼酸盐,二(铵) | 50μM | 94.24% |
四硫代钨酸盐,亚乙基二(三甲基铵) | 50μM | 89.60% |
四硫代钨酸盐,丙烷-1,3-二(三甲基铵) | 50μM | 92.95% |
四硫代钨酸盐,丁烷-1,4-二(三甲基铵) | 50μM | 91.75% |
曲恩汀 | 10μM | 4.27% |
四硫代钼酸盐,二(铵) | 10μM | 87.71% |
四硫代钨酸盐,亚乙基二(三甲基铵) | 10μM | 84.66% |
四硫代钨酸盐,丙烷-1,3-二(三甲基铵) | 10μM | 85.53% |
四硫代钨酸盐,丁烷-1,4-二(三甲基铵) | 10μM | 87.32% |
曲恩汀 | 10μM | 17.72% |
四硫代钼酸盐,二(铵) | 10μM | 76.69% |
四硫代钨酸盐,(琥珀酰胆碱) | 10μM | 81.38% |
四硫代钨酸盐,(环庚基二胆碱) | 10μM | 77.83% |
曲恩汀 | 1μM | 0.00% |
四硫代钼酸盐,二(铵) | 1μM | 68.48% |
四硫代钨酸盐,(琥珀酰胆碱) | 1μM | 66.06% |
四硫代钨酸盐,(环庚基二胆碱) | 1μM | 67.74% |
6.25实施例25:
Matrigel栓塞测定法中四硫代钨酸铵对于血管生成的 抑制
在如上5.4.7节描述的Matrigel栓塞测定法中测定四硫代钨酸铵。使用两种阳性对照,当治疗开始时植入五天后测量阳性对照1且在治疗结束时植入五天后测量阴性对照2。使用两种阴性对照,当治疗开始时植入五天后测量阴性对照1且在治疗结束时植入五天后测量阴性对照2。如附图1所示,使用四硫代钨酸铵治疗导致该测试约34%抑制。
最后,应该注意到实施本发明有几种可供选择的途径。因此,本发明的实施方案应当被认为是举例说明而不是限制性的,本发明并不受在此给出的这些细节的限制,而是可以在所附权利要求的范围和在同等物的范围内进行修饰。本文提到的所有公开的文献和专利文献均全部引入作为参考。
Claims (57)
1、结构式(I)化合物或其溶剂化物、水合物或N-氧化物,
其中:
R1、R2、R3、R5、R6和R7独立地是氢、烷基、取代烷基、芳基、取代芳基、芳烷基、取代芳烷基、环烷基、取代环烷基、环杂烷基、取代环杂烷基、杂芳基、取代杂芳基、杂芳基烷基、取代杂芳基烷基、杂烷基或取代杂烷基;
R4和R8独立地是氢、烷基、取代烷基、芳基、取代芳基、芳烷基、取代芳烷基、环烷基、取代环烷基、环杂烷基、取代环杂烷基、杂芳基、取代杂芳基、杂芳基烷基、取代杂芳基烷基、杂烷基或取代杂烷基、或者当N是芳环的一部分时则不存在;
任选地,R1和R2一起是烷二基、取代烷二基、杂烷二基或取代杂烷二基;
任选地,R5和R6一起是烷二基、取代烷二基、杂烷二基或取代杂烷二基;
任选地,R1和R2一起,R2和R3一起以及R2和R4一起是烷二基、取代烷二基、杂烷二基或取代杂烷二基;
任选地,R5和R6一起,R6和R7一起以及R6和R8一起是烷二基、取代烷二基、杂烷二基或取代杂烷二基;
任选地,R3和R7一起是烷二基、取代烷二基、杂烷二基或取代杂烷二基;以及
Y-2是(WS4)-2、(W2S12)-2、(W2S9)-2、(W2S7)-2、(W2S8)-2、(W2S11)-2、(W2S6)-2或(W2S13)-2。
2、权利要求1的化合物,其中Y是(WS4)-2。
3、权利要求1的化合物,其中
4、权利要求3的化合物,其中Y是(WS4)-2。
5、权利要求1的化合物,其中R1、R2、R3和R4中至少一个不是烷基。
6、权利要求1的化合物,其中R1、R2、R3、R4、R5、R6、R7和R8中至少一个不是烷基。
7、权利要求1的化合物,其中R1、R2和R4是氢、烷基或取代烷基。
8、权利要求1的化合物,其中R1、R2和R4是氢、甲基或乙基。
9、权利要求1的化合物,其中R1和R2是烷基。
10、权利要求1的化合物,其中R1和R2是甲基或乙基。
11、权利要求1的化合物,其中R1是烷基、取代烷基、烯基、取代烯基、芳基、取代芳基、芳烷基、取代芳烷基、环烷基或取代环烷基。
12、权利要求1的化合物,其中R1和R2一起是亚烷基、取代亚烷基、杂亚烷基或取代杂亚烷基。
13、权利要求1的化合物,其中R1和R2一起是亚烷基或杂亚烷基。
14、权利要求1的化合物,其中R1和R2一起,R2和R3一起以及R2和R4一起是亚烷基、取代亚烷基、杂亚烷基或取代杂亚烷基。
15、权利要求1的化合物,其中R1和R2一起,R2和R3一起以及R2和R4一起是亚烷基。
17、权利要求1的化合物,其中R3和R7一起是亚烷基、取代亚烷基、杂亚烷基或取代杂亚烷基。
18、权利要求1的化合物,其中R3和R7一起是亚烷基或杂亚烷基。
19、权利要求1的化合物,其中R1、R2和R4是氢、烷基或取代烷基,以及R3是烷基、取代烷基、烯基、芳基、芳烷基、环烷基,或者R3和R7一起是亚烷基、取代亚烷基、杂亚烷基或取代杂亚烷基。
20、权利要求1的化合物,其中R1、R2和R4是甲基或乙基,以及R3是烷基、取代烷基、烯基、芳基、芳烷基、环烷基,或者R3和R7一起是亚烷基或杂亚烷基。
21、权利要求1的化合物,其中R1、R2和R4是甲基或乙基,以及R3是烷基、取代烷基、烯基、芳基、芳烷基或环烷基。
24、权利要求1的化合物,其中R1(R2)(R3)(R4)N结构为
26、权利要求1的化合物,其中R1、R2和R4是甲基或乙基,以及R3和R7一起是亚烷基或杂亚烷基。
28、权利要求1的化合物,其中R1、R2和R4是氢,以及R3是取代烷基、环烷基或取代杂芳基,或者R3和R7一起是亚烷基。
29、权利要求1的化合物,其中R1和R2是烷基以及R3和R4是氢、烷基、取代烷基、芳基、芳烷基或亚烷基。
30、权利要求1的化合物,其中R1和R2是甲基或乙基以及R3和R4是氢、烷基、取代烷基、芳基、芳烷基或亚烷基。
32、权利要求1的化合物,其中R1、R2和R4是氢,以及R3是取代烷基、取代杂芳基、环烷基或亚烷基。
33、权利要求1的化合物,其中R1(R2)(R3)(R4)N结构为
或
34、权利要求1的化合物,其中R1和R2一起是亚烷基、取代亚烷基、杂亚烷基或取代杂亚烷基,R3是烷基或取代烷基以及R4是氢或不存在。
36、一种药物组合物,包含权利要求1的化合物以及可药用稀释剂、赋形剂或辅料。
37、一种治疗或预防患者癌症的方法,包括向需要该治疗的患者给予治疗有效量的权利要求1化合物。
38、一种治疗或预防患者癌症的方法,包括向需要该治疗的患者给予治疗有效量的权利要求36药物组合物。
39、权利要求36的方法,进一步包括向需要该治疗的患者给予治疗有效量的另一种抗癌药或包含另一种抗癌药和可药用稀释剂、赋形剂或辅料的药物组合物。
40.权利要求37的方法,进一步包括向需要该治疗的患者给予治疗有效量的另一种抗癌药或包含所述另一种抗癌药和可药用稀释剂、赋形剂或辅料的药物组合物。
41、权利要求36的方法,进一步包括向需要该治疗的患者给予治疗有效量的锌或锌的药物组合物。
42、权利要求37的方法,进一步包括向需要该治疗的患者给予治疗有效量的锌或包含锌和可药用稀释剂、赋形剂或辅料的药物组合物。
43、权利要求36的方法,其中癌症是乳腺癌、肾癌、脑癌、结肠癌、前列腺癌、软骨肉瘤或血管肉瘤。
44、一种治疗或预防患者湿型黄斑变性或类风湿性关节炎的方法,包括向需要该治疗的患者给予治疗有效量的权利要求1化合物。
45、一种治疗或预防患者湿型黄斑变性或类风湿性关节炎的方法,包括向需要该治疗的患者给予治疗有效量的权利要求36药物组合物。
46、一种治疗或预防患者异常血管生成的方法,包括向需要该治疗的患者给予治疗有效量的权利要求1化合物。
47、一种治疗或预防患者异常血管生成的方法,包括向需要该治疗的患者给予治疗有效量的权利要求36药物组合物。
48、一种治疗或预防患者铜水平过量的方法,包括向需要该治疗的患者给予治疗有效量的权利要求1化合物。
49、一种治疗或预防患者铜水平过量的方法,包括向需要该治疗的患者给予治疗有效量的权利要求36药物组合物。
50、一种治疗或预防患者肥胖症的方法,包括向需要该治疗的患者给予治疗有效量的权利要求1化合物。
51、一种治疗或预防患者肥胖症的方法,包括向需要该治疗的患者给予治疗有效量的权利要求36药物组合物。
52、权利要求50的方法,进一步包括向需要该治疗的患者给予治疗有效量的另一种抗肥胖药或包含另一种抗肥胖药和可药用稀释剂、赋形剂或辅料的药物组合物。
53、权利要求51的方法,进一步包括向需要该治疗的患者给予治疗有效量的另一种抗肥胖药或包含另一种抗肥胖药和可药用稀释剂、赋形剂或辅料的药物组合物。
54、一种治疗或预防患者神经变性疾病的方法,包括向需要该治疗的患者给予治疗有效量的权利要求1化合物。
55、一种治疗或预防患者神经变性疾病的方法,包括向需要该治疗的患者给予治疗有效量的权利要求36药物组合物。
56、权利要求55的方法,其中神经变性疾病为阿尔茨海默病、肌萎缩性侧索硬化症和朊病毒病。
57、权利要求56的方法,其中神经变性疾病为阿尔茨海默病、肌萎缩性侧索硬化症和朊病毒病。
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- 2004-05-27 JP JP2006533497A patent/JP2007516234A/ja active Pending
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- 2004-05-27 CA CA002527236A patent/CA2527236A1/en not_active Abandoned
- 2004-05-27 WO PCT/US2004/016948 patent/WO2004110364A2/en active Application Filing
- 2004-05-27 AU AU2004247059A patent/AU2004247059A1/en not_active Abandoned
- 2004-05-27 MX MXPA05012722A patent/MXPA05012722A/es not_active Application Discontinuation
- 2004-05-27 CN CNB200480021514XA patent/CN100558409C/zh not_active Expired - Fee Related
- 2004-05-27 EA EA200501865A patent/EA200501865A1/ru unknown
- 2004-05-27 BR BRPI0410651-2A patent/BRPI0410651A/pt not_active Application Discontinuation
-
2005
- 2005-11-24 IL IL172195A patent/IL172195A0/en unknown
- 2005-12-21 NO NO20056116A patent/NO20056116L/no not_active Application Discontinuation
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2010
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Also Published As
Publication number | Publication date |
---|---|
AU2004247059A1 (en) | 2004-12-23 |
CN100558409C (zh) | 2009-11-11 |
JP2007516234A (ja) | 2007-06-21 |
US20060160805A1 (en) | 2006-07-20 |
WO2004110364A9 (en) | 2005-04-07 |
EA200501865A1 (ru) | 2006-08-25 |
EP1633310A2 (en) | 2006-03-15 |
NO20056116L (no) | 2006-02-24 |
EP1633310A4 (en) | 2006-10-18 |
MXPA05012722A (es) | 2006-05-25 |
IL172195A0 (en) | 2009-02-11 |
PL218366B1 (pl) | 2014-11-28 |
US20110151022A1 (en) | 2011-06-23 |
CA2527236A1 (en) | 2004-12-23 |
WO2004110364A3 (en) | 2006-03-02 |
ZA200509719B (en) | 2007-03-28 |
WO2004110364A2 (en) | 2004-12-23 |
KR20060013561A (ko) | 2006-02-10 |
PL379262A1 (pl) | 2006-08-07 |
BRPI0410651A (pt) | 2006-07-04 |
US7851505B2 (en) | 2010-12-14 |
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