CN1697655B - 使用免疫调节性化合物用于治疗和控制癌症和其它疾病的方法及组合物 - Google Patents
使用免疫调节性化合物用于治疗和控制癌症和其它疾病的方法及组合物 Download PDFInfo
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Abstract
本发明公开了治疗、预防和/或控制癌症以及与不希望的血管生成相关的、或以之为特征的疾病和病症的方法。特定的方法包括将免疫调节性化合物单独或与第二活性成分相联合给予。本发明进一步的涉及减轻或避免与化疗、放疗、激素疗法、生物学疗法或免疫疗法相关的副作用的方法,该方法包括给予免疫调节性化合物。本发明通式也公开了适用于本发明方法的药物组合物、单个单位剂型以及试剂盒。
Description
本申请要求享受分别于2002年5月17日提交的美国临时申请60/380,842和2002年11月6日提交的美国临时申请60/424,600的权利,这些申请的整体在此文中引入作为参考。
1.发明领域
本发明涉及通过单独、或与其它治疗剂联合给予一种或多种免疫调节性化合物以治疗、预防和/或控制特定的癌症、以及其它疾病包括,但不限于那些与不希望的血管生成相关的或以其为特征的疾病的方法。特别的,本发明包括药物和其它疗法(例如放射以治疗这些特定的癌症,应包括那些对常规疗法有抗性的癌症)的特定联合、或“鸡尾酒疗法”的应用。本发明还涉及药物组合物和给药方案。
2.发明背景
2.1癌症和其它疾病的病理学
癌症疾病的基本特征是来源于给定正常组织的异常细胞在数量上发生增长、邻近组织被这些异常细胞侵入、恶性细胞的淋巴性或血生性扩散到局部淋巴结和远处位点(转移)。临床数据和分子生物学研究显示,癌症是一种多级进程的疾病,其一开始是在某些形成瘤的条件下发生微小的肿瘤前变化。肿瘤性损伤可以无性系地演化,也可以在其侵入、生长、转移和异种性的能力上发展增强,尤其是在肿瘤细胞脱离了宿主免疫监督的情况下。Roitt,I.,Brostoff,J和Kale,D.,Immunology,17.1-17.12(3rd ed.,Mosby,St.Louis,Mo.,1993)。
在医学文献中详细记载了大量的各种癌症。癌症的例子可包括肺癌、结肠癌、直肠癌、前列腺癌、乳腺癌、脑癌和肠癌。由于总体上人口老化、新癌症产生的增加以及易患病人口(例如,感染了AIDS和过度暴露于阳光下的人群)的增加,导致癌症的发病率持续攀升。因此,对可用于治疗癌症患者的新方法和组合物存在着巨大的需求。
许多类型的癌症与新生血管形成,一种称之为血管生成的过程有关。某些涉及到肿瘤-诱导的血管生成的机理已经被阐明。这些机理最直接的原因是具有血管原性质的细胞因子由肿瘤细胞的分泌。这些细胞因子的例子包括酸性和碱性的成纤细胞生长因子(a、b-FGF)、血管生成素、血管内皮生长因子(VEGF)、以及TNF-α。另外的,肿瘤细胞还可通过产生蛋白酶然后接着储存着某些细胞因子(例如,b-FGF)的细胞外基质破裂而释放出血管生成性肽。血管生成也可通过补充炎症细胞(特别是巨噬细胞)然后它们释放出血管原细胞因子(例如,TNF-α、bFGF)的过程而直接诱导。
各种其它疾病和障碍也与人们所不希望的血管生成有关、或者以之为特征。例如,血管生成加强或不规则涉及到许多疾病和病况,这些疾病包括,但不限于眼部新生血管性疾病、脉络膜新生血管性疾病、视网膜新生血管性疾病、潮红(角新生血管形成)、病毒性疾病、遗传性疾病、炎性疾病、变应性疾病、以及自身免疫性疾病。这些疾病的例子和病况包括,但不限于:糖尿病性视网膜病;早产儿视网膜病;角膜移植排斥;新生血管性青光眼;晶状体后纤维组织增生;以及增殖性玻璃体视网膜病变。
相应的,可以控制血管生成或抑制某些细胞因子(包括TNF-α)生成的化合物可用于治疗和预防各种疾病和病况。
2.2治疗癌症的方法
现行癌症疗法可涉及到手术、化疗、激素疗法和/或放射治疗以消灭患者中的癌细胞(参见,例如,Stockdale,1998,Medicine,vol.3,Rubenstein和Federman,eds.,第12章,第IV节)。最近,癌症疗法也涉及了生物学疗法或免疫疗法。所有这些方法对患者而言都具有显著的缺点。对手术而言,例如,由于患者的健康状况,手术可能无法施行,或者可能对患者来说是不可接受的。此外,手术可能不能完全除去肿瘤组织。放射疗法只有在肿瘤组织比正常组织具有更高的放射敏感性时才是有效的。放射疗法也经常有可能引起严重的副作用。激素疗法几乎不以单一试剂的形式给予。尽管激素疗法是有效的,但是它通常用在其它治疗已经除去了大多数癌细胞以后,用于预防或延缓癌症的复发。生物学疗法和免疫疗法在数量上受限制,并且可能会引起副作用,诸如皮疹或肿胀、流感-样症状,包括发烧、寒战和疲劳、消化道问题或变应性反应。
就化疗而言,有很多化疗试剂可用于治疗癌症。大部分的癌症化疗是通过抑制脱氧核糖核苷三磷酸酯前体的生物合成,以阻止DNA复制和伴随的细胞分裂而直接或间接抑制DNA合成来起作用的。Gilman等,Goodman和Gilman′s:The Pharmacological Basis ofTherapeutics,第10版(McGraw Hill,New York)。
尽管有大量的化疗试剂存在,化疗还是具有很多缺点。Stockdale,Medicine,第3卷,Rubenstein and Federman,eds.,第12章,第10节,1998。几乎所有的化疗试剂都是有毒的,并且化疗可导致显著的且通常是危险的副作用,包括重度恶心、骨髓抑制和免疫抑制。此外,即使给予化疗试剂的联合体,很多肿瘤细胞对于化疗试剂都具有耐药性,或者能产生耐药性。事实上,对于治疗方案中特定化疗试剂具有耐药性的细胞通常被证明对于其它药物也是具有耐药性的,即便这些试剂和特定疗法中使用的药物是通过不同机理起作用的。这种现象被称为多效药物或多药耐药性。由于耐药性的存在,很多癌症被证实对与标准化疗治疗方案具有抵抗力。
其它与不希望的血管生成相关、或以之为特征的疾病也同样难以治疗。然而,某些化合物诸如鱼精蛋白、肝磷脂和甾族化合物被提议可用于治疗某些特定的疾病。Taylor等,Nature 297:307(1982);Folkman等,Science 221:719(1983);以及美国专利5,001,116和4,994,443。沙利度胺及其某些衍生物被提议可用于治疗这些疾病和病况。授予D′Amato的美国专利5,593,990、5,629,327、5,712,291、6,071,948和6,114,355。
现在,人们对在减少或避免常规疗法的毒性和/或副作用的同时能安全和有效的治疗、预防和控制癌症和其它疾病和病况,尤其是用于对标准疗法诸如手术、放射疗法、化疗和激素疗法具有抵抗力的疾病和病况的方法具有很强烈的需求。
2.3 IMIDs
TM
人们开展了很多以提供可安全和有效用于治疗与TNF-α异常增生相关的疾病的化合物为目的的试验。参见,例如,Marriott,J.B.,等,Expert Opin.Biol.Ther.1(4):1-8(2001);G.W.Muller,等,Journal of Medicinal Chemistry 39(17):3238-3240(1996);和G.W.Muller,等,Bioorganic & Medicinal Chemistry Letters8:2669-2674(1998)。某些研究聚焦在根据有效抑制LPS刺激的PBMC产生TNF-α的能力而选择的一组化合物上。L.G.Corral,等,Ann.Rheum.Dis.58:(Suppl I) 1107-1113(1999)。这些被称作IMiDsTM(Celgene公司)的化合物或免疫调节性药物,不仅显示了对TNF-α有效的抑制能力,还显示了对LPS诱导的单核细胞IL1β和IL12的生产的显著的抑制能力。免疫调节性化合物还可抑制LPS诱导的IL6,虽然是部分地。同样,这些化合物是LPS诱导的IL10.的有效的激动剂。特定的IMiDs的例子包括,但不限于,记载于授权给G.W.Muller,等的美国专利号6,281,230和6,316,471中的取代的2-(2,6-二氧代哌啶-3-基)酞酰亚胺类化合物和取代的2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚类化合物。
3.发明概述
本发明包括治疗和预防某些类型癌症,包括原发性和转移性癌症、以及对常规化疗具有抵抗性或耐药性的癌症的方法。该方法包括向有此治疗或预防需要的患者给予治疗或预防有效量的免疫调节性化合物或其可药用的盐、溶剂化物、水合物、立体异构体、包合物或前药。本发明还包括控制某些癌症的方法(例如,预防或推迟癌症的复发,或者延长缓解期的时间),该方法包括向有此控制需求的患者给予预防有效量的本发明免疫调节性化合物、或其可药用的盐、溶剂化物、水合物、立体异构体、包合物或前药。
在本发明特定的方法中,免疫调节性化合物与常用于治疗、防止或控制癌症的常规疗法相结合而给药。这些常规疗法的例子包括,但不限于:手术、化疗、放疗、激素疗法、生物疗法和免疫疗法。
本发明还包括癌症以外的、与不希望的血管生成相关的、或以之为特征的疾病和病症的治疗、控制或预防方法,该方法包括向有此治疗、控制或预防需要的患者给予治疗或预防有效量的免疫调节性化合物、或其可药用的盐、溶剂化物、水合物、立体异构体、包合物或前药。
在本发明的其它方法中,免疫调节性化合物与用于治疗、预防或控制与不希望的血管生成相关的或以之为特征的疾病或病症的常规疗法相结合给药。这些常规疗法的例子包括,但不限于,手术、化疗、放疗、激素疗法、生物疗法和免疫疗法。
本发明包括含有免疫调节性化合物或其可药用的盐、溶剂化物、水合物、立体异构体、包合物或前药,以及第二种、或附加的活性试剂的药物组合物、单个单位剂型、给药方案和试剂盒。第二活性成分包括药物的特定联合或“鸡尾酒”。
4.附图说明
图1显示了在体外试验中,3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(RevimidTM)和沙利度胺在抑制多发性骨髓瘤(MM)细胞系增殖效果上的比较。测定不同MM细胞系(MM.1S、HsSultan、U266和RPMI-8226)对[3H]-胸腺嘧啶核苷的摄取,以此作为衡量细胞增殖的指标。
5.发明详述
本发明第一个具体实施方案包括了治疗、控制或预防癌症的方法,该方法包括向有此治疗或预防需要的患者给予治疗或预防有效量的本发明免疫调节性化合物、或其可药用的盐、溶剂化物、水合物、立体异构体、包合物或前药。
在此实施方案中包含的特定的方法中,免疫调节性化合物与其它药物(“第二活性试剂”)或治疗、控制或预防癌症的方法相联合而给药。第二活性试剂包括小分子和大分子(例如,蛋白质和抗体),此文中将给出它们的示例,以及干细胞。可用于与免疫调节性化合物的给药相结合的方法或疗法包括,但不限于,手术、血液输注、免疫疗法、生物学疗法、放疗以及其它非-药物基础的现今用于治疗、预防或控制癌症的疗法。
本发明另一个实施方案包括了治疗、控制或预防癌症以外的并以不希望的血管生成为特征的疾病和病症的方法。这些方法包括给予治疗或预防有效量的免疫调节性化合物、或其可药用的盐、溶剂化物、水合物、立体异构体、包合物或前药。
与不希望的血管生成相关、或以之为特征的疾病和病症包括,但不限于,炎性疾病、自身免疫性疾病、病毒性疾病、遗传性疾病、变应性疾病、细菌性疾病、眼部新生血管性疾病、脉络膜新生血管性疾病、视网膜新生血管性疾病、和潮红(角新生血管形成)。
在此实施方案中所包括的特定方法中,免疫调节性化合物与第二活性试剂或治疗、控制或预防疾病或病况的方法相联合给予。第二活性试剂包括小分子和大分子(例如,蛋白质和抗体),此文中将给出它们的示例以及干细胞。与免疫调节性化合物的给药相联合的方法或疗法包括,但不限于手术、血液输注、免疫疗法、生物学疗法、放疗以及其它的非-药物基础的当前用于治疗、预防或控制与不希望的血管生成或以之为特征的疾病和病况的疗法。
本发明还包括可用于此文所公开的方法中的药物组合物(例如,单个单位剂型)。特定的药物组合物包括本发明的免疫调节性化合物、或其可药用的盐、溶剂化物、水合物、立体异构体、包合物或前药,以及第二活性剂。
5.1免疫调节性化合物
本发明中所使用的化合物包括消旋的、立体异构富含的或立体异构纯的免疫调节性化合物、及其可药用的盐、溶剂化物、水合物、立体异构体、包合物和前药。本发明中优选使用的化合物是分子量低于约1,000g/mol的有机小分子,并且不是蛋白质、肽、寡核苷酸、低聚糖或其它大分子。
如此文中所使用的,如果没有另外指出,术语“免疫调节性化合物”和“IMiDsTM”(Celgene公司)包括能显著抑制TNF-α、LPS诱导的单核细胞IL1β和IL12,并能部分的抑制IL6的产生的有机小分子。特定的免疫调节性化合物将在下文中进行讨论。
TNF-α是巨噬细胞和单核细胞在急性炎症期间产生的炎性细胞因子。TNF-α负责发生在细胞内的大量信号反应。TNF-α在癌症中可能具有病理学作用。在不被理论所束缚的情况下,本发明免疫调节性化合物所展现的一种生物学作用是减少TNF-α的合成。本发明免疫调节性化合物能增强TNF-αmRNA的降解。
进而,在不被理论所束缚的情况下,本发明中所使用的免疫调节性化合物也可能是T细胞的有效辅助刺激因子,并能以剂量依赖的方式显著的增加细胞增殖。本发明免疫调节性化合物对CD8+T细胞亚群而言,比对CD4+T细胞亚群具有更高的辅助刺激功能。此外,化合物优选的具有抗炎性质,并能有效地辅助-刺激T细胞。
本发明免疫调节性化合物的特定的例子包括,但不限于取代的苯乙烯的氰基和羧基衍生物,诸如那些公开于美国专利US 5,929,117中的化合物;1-氧代-2-(2,6-二氧代-3-氟哌啶-3基)异二氢吲哚和1,3-二氧代-2-(2,6-二氧代-3-氟哌啶-3-基)异二氢吲哚,诸如公开于美国专利号5,874,448中的化合物;记载于美国专利号5,798,368的四取代的2-(2,6-二氧代哌啶-3-基)-1-氧代-异二氢吲哚;1-氧代和1,3-二氧代-2-(2,6-二氧代哌啶-3-基)异二氢吲哚(例如,沙利度胺和EM-12的4-甲基衍生物),其包括,但不限于公开于美国专利号5,635,517中的化合物;以及公开于美国专利号5,698,579和5,877,200中的一类非-多肽环状酰胺;沙利度胺的类似物和衍生物,包括沙利度胺的水解产物、代谢物、衍生物和前体,诸如那些公开于授权给D′Amato的美国专利5,593,990、5,629,327和6,071,948中的化合物;氨基沙利度胺以及氨基沙利度胺的类似物、水解产物、代谢物、衍生物和前体,以及取代的2-(2,6-二氧代哌啶-3-基)酞酰亚胺类化合物和取代的2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚类化合物,诸如公开于美国专利号6,281,230和6,316,471中的化合物;异吲哚-酰亚胺化合物,诸如那些于2001年10月5日提交的美国申请专利09/972,487、于2001年12月21日提交的美国专利申请10/032,286以及国际申请PCT/US01/50401(国际公开号WO02/059106)中的化合物。每一专利或专利申请的整体作为参考引入此文。本发明免疫调节性化合物不包括沙利度胺。
其它特定的本发明免疫调节性化合物包括,但不限于在苯环上取代了氨基的1-氧代-和1,3-二氧代-2-(2,6-二氧代哌啶-3-基)异二氢吲哚,如美国专利5,635,517中所记载的,其在此处引入作为参考。
这些化合物具有结构式I:
其中,X和Y中有一个为C=O,另一个为C=O或CH2,R2是氢或低级烷基,特别是甲基。特定的免疫调节性化合物包括,但不限于:
1-氧代-2-(2,6-二氧代哌啶-3-基)-4-氨基异二氢吲哚;
1-氧代-2-(2,6-二氧代哌啶-3-基)-5-氨基异二氢吲哚;
1-氧代-2-(2,6-二氧代哌啶-3-基)-6-氨基异二氢吲哚;
1-氧代-2-(2,6-二氧代哌啶-3-基)-7-氨基异二氢吲哚;
1,3-二氧代-2-(2,6-二氧代哌啶-3-基)-4-氨基异二氢吲哚;以及
1,3-二氧代-2-(2,6-二氧代哌啶-3-基)-5-氨基异二氢吲哚。
其它特定的本发明免疫调节性化合物属于取代的2-(2,6-二氧代哌啶-3-基)酞酰亚胺类化合物和取代的2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚类化合物,诸如那些公开于美国专利号6,281,230;6,316,471;6,335,349和6,476,052以及国际专利申请号PCT/US 97/13375(国际公开号WO 98/03502)中的化合物,每一文献在此引入作为参考。此类中的代表性化合物为具有以下同式的化合物:
其中的R1是氢或甲基。在一个独立的实施方案中,本发明包括这些化合物的对映体纯(例如,任选的纯(R)或(S)对映体)的形式的用途。
本发明另外的特定的免疫调节性化合物属于公开于美国申请专利10/032,286、09/972,487和国际申请号PCT/US01/50401(国际公开号WO 02/059106)中的异吲哚-酰亚胺类化合物,这些文献在此引入作为参考。代表性的化合物为通式II的化合物:
及其可药用的盐、水合物、溶剂化物、包合物、对映体、非对映体、外消旋体和其立体异构体的混合物,其中:
X和Y的其中一个是C=O,另一个是CH2或C=O;
R1是H、(C1-C8)烷基、(C3-C7)环烷基、(C2-C8)链烯基、(C2-C8)炔基、苄基、芳基、(C0-C4)烷基-(C1-C6)杂环烷基、(C0-C4)烷基-(C2-C5)杂芳基、C(O)R3、C(S)R3、C(O)OR4、(C1-C8)烷基-N(R6)2、(C1-C8)烷基-OR5、(C1-C8)烷基-C(O)OR5、C(O)NHR3、C(S)NHR3、C(O)NR3R3、C(S)NR3R3′或(C1-C8)烷基-O(CO)R5;
R2是H、F、苄基、(C1-C8)烷基、(C2-C8)链烯基或(C2-C8)炔基;
R3和R3′各自独立的为(C1-C8)烷基、(C3-C7)环烷基、(C2-C8)链烯基、(C2-C8)炔基、苄基,芳基、(C0-C4)烷基-(C1-C6)杂环烷基、(C0-C4)烷基-(C2-C5)杂芳基、(C0-C8)烷基-N(R6)2、(C1-C8)烷基-OR5、(C1-C8)烷基-C(O)OR5、(C1-C8)烷基-O(CO)R5或C(O)OR5;
R4是(C1-C8)烷基、(C2-C8)链烯基、(C2-C8)炔基、(C1-C4)烷基-OR5、苄基、芳基、(C0-C4)烷基-(C1-C6)杂环烷基或(C0-C4)烷基-(C2-C5)杂芳基;
R5是(C1-C8)烷基、(C2-C8)链烯基、(C2-C8)炔基、苄基、芳基、或(C2-C5)杂芳基;
R6的每种情况独立的为H、(C1-C8)烷基、(C2-C8)链烯基、(C2-C8)炔基、苄基、芳基、(C2-C5)杂芳基或(C0-C8)烷基-C(O)O-R5,或者R6基团参与形成杂环烷基;
n是0或1;并且
*代表手性-碳中心。
在特定的通式II化合物中,其中当n是0时,R1是(C3-C7)环烷基、(C2-C8)链烯基、(C2-C8)炔基、苄基、芳基、(C0-C4)烷基-(C1-C6)杂环烷基、(C0-C4)烷基-(C2-C5)杂芳基、C(O)R3、C(O)OR4、(C1-C8)烷基-N(R6)2、(C1-C8)烷基-OR5、(C1-C8)烷基-C(O)OR5、C(S)NHR3或(C1-C8)烷基-O(CO)R5;
R2是H或(C1-C8)烷基;并且
R3是(C1-C8)烷基、(C3-C7)环烷基、(C2-C8)链烯基、(C2-C8)炔基、苄基、芳基、(C0-C4)烷基-(C1-C6)杂环烷基、(C0-C4)烷基-(C2-C5)杂芳基、(C5-C8)烷基-N(R6)2;(C0-C8)烷基-NH-C(O)O-R5;(C1-C8)烷基-OR5、(C1-C8)烷基-C(O)OR5、(C1-C8)烷基-O(CO)R5或C(O)OR5;以及其它的具有相同定义的变体。
在其它式II的具体化合物中,R2是H或(C1-C4)烷基。
在其它式II的具体化合物中,R1是(C1-C8)烷基或苄基。
在其它式II的具体化合物中,R1是H、(C1-C8)烷基、苄基、CH2OCH3、CH2CH2OCH3或
在式II化合物的另一个实施方案中,R1是
其中的Q是O或S,R7的每种情况独立的为H、(C1-C8)烷基、苄基、CH2OCH3或CH2CH2OCH3。
在其它式II的具体化合物中,R1是C(O)R3。
在其它式II的具体化合物中,R3是(C0-C4)烷基-(C2-C5)杂芳基、(C1-C8)烷基、芳基、或(C0-C4)烷基-OR5。
在其它式II的具体化合物中,杂芳基是吡啶基、呋喃基或噻吩基。
在其它式II的具体化合物中,R1是C(O)OR4。
在其它式II的具体化合物中,C(O)NHC(O)中的H可以被(C1-C4)烷基、芳基、或苄基所代替。
其它特定的本发明免疫调节性化合物属于公开于美国专利申请09/781,179、国际公开WO 98/54170以及美国专利号6,395,754中的异吲哚-酰亚胺类化合物,这些在此文中引入作为参考。代表性的化合物为通式III的化合物:
及其可药用的盐、水合物、溶剂化物、包含物、对映体、非对映体、外消旋体和立体异构体的混合,其中:
X和Y中的一个为C=O,另一个为CH2或C=O;
R是H或CH2OCOR′;
(i)每一R1、R2、R3或R4相互独立的为卤素、1-4个碳原子的烷基、1-4个碳原子的烷氧基或(ii)R1、R2、R3或R4的其中一个为硝基或-NHR5,其余的R1、R2、R3或R4为氢;
R5是氢或1-8个碳原子的烷基
R6是氢、1-8个碳原子的烷基、苯并、氯或氟;
R′是R7-CHR10-N(R8R9);
R7是间位-亚苯基或对位亚苯基或-(CnH2n)-,其中的n为0至4的值;R8和R9中的每一个相互独立的为氢或1-8个碳原子的烷基、或
R8和R9一起组成四亚甲基、五亚甲基、六亚甲基或-CH2CH2[X]X1CH2CH2-,其中的[X]X1是-O-、-S-或-NH-;
R10是氢、-8个碳原子的烷基、或苯基;并且
*代表手性-碳中心。
最为优选的本发明免疫调节性化合物是4-(氨基)-2-(2,6-二氧代(3-哌啶基))-异二氢吲哚-1,3-二酮和3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮。这些化合物可以通过标准的合成方法(参见例如,美国专利号5,635,517,在此引入作为参考)获得。这些化合物可以从Celgene公司(Warren,NJ.)获得。4-(氨基)-2-(2,6-二氧代(3-哌啶基))-异二氢吲哚-1,3-二酮(ACTIMIDTM)具有以下化学结构:
化合物3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(REVIMIDTM)具有以下化学结构:
本发明化合物可以商业购得,也可以是按照本文所引用的专利或专利公开物中记载的方法制备。进而,光学纯的化合物可以通过使用公知的拆分试剂或手性柱以及其它标准有机化学合成技术来而不对称的合成。
如此文中所使用的,除非另有说明,术语“可药用的盐”包括术语所指的化合物的非-毒性酸和碱的加成盐。可接受的非-毒性酸加成盐包括那些衍生自公知的有机酸或碱和无机酸或碱的盐,包括例如衍生自盐酸、氢溴酸、磷酸、硫酸、甲磺酸、醋酸、酒石酸、乳酸、琥珀酸、柠檬酸、苹果酸、马来酸、山梨酸、乌头酸、水杨酸、苯二甲酸、embolic acid、庚酸等等的盐。
本身为酸性的化合物可以与各种可药用的碱形成盐。可用于制备可药用的所述酸性化合物的碱加成盐的碱是那些能形成非-毒性碱加成盐(也即含可药用的阳离子:诸如但不限于碱金属或碱土金属并且特别是钙、镁、钠或钾的盐)的碱,适宜的有机碱包括,但不限于:N,N-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、甲葡胺(N-甲基葡糖胺)、赖氨酸和普鲁卡因。
如此文中所使用的,除非另有说明,术语“前药”指的是可以在生物学环境下(体外或体内)水解、氧化或其它反应以得到所述化合物的所述化合物的衍生物。前药的例子包括,但不限于:含有生物可水解的基团诸如生物可水解的酰胺、生物可水解的酯、,生物可水解的氨基甲酸酯、生物可水解的碳酸酯、生物可水解的酰脲以及生物可水解的磷酸酯类似物的本发明免疫调节性药物的衍生物。其它前药的例子包括含有-NO、-NO2、-ONO或-ONO2基团的本发明免疫调节性药物的衍生物。前药可以典型的使用公知的方法,诸如公开于1 Burger′sMedicinal Chemistry and Drug Discovery,172-178,949-982(Manfred E. Wolff ed.,5th ed.1995)以及Design ofProdrugs(H.Bundgaarded.,Elselvier,New York 1985)的方法制备。
如此文中所使用的,除非另有说明,术语“生物可水解的酰胺”、“生物可水解的酯”、“生物可水解的氨基甲酸酯”、“生物可水解的碳酸酯”、“生物可水解的酰脲”、“生物可水解的磷酸酯”分别指的是化合物中的酰胺、酯、氨基甲酸酯、碳酸酯、酰脲或磷酸酯可以:1)不会干扰化合物的生物学活性,但是能带来诸如化合物吸收、作用持续时间、作用引发方面有益的体内性质;或者可以2)生物学上没有活性,但是能在体内转化成生物学活性化合物。生物可水解的酯的例子包括,但不限于:低级烷基酯、低级酰氧基烷基酯(诸如乙酰氧基甲基、乙酰氧基乙基、氨基羰酰氧基甲基、新戊酰氧基甲基和新戊酰氧基乙基酯)、内酯(诸如酞基和硫代酞基酯)、低级烷氧基酰氧烷基酯(诸如甲氧基羰酰氧基甲基、乙氧基羰酰氧基乙基和异丙氧基羰酰氧基乙基酯)、烷氧基烷基酯、胆碱酯和酰氨基烷基酯(诸如乙酰氨基甲基酯)。生物可水解的酰胺的例子包括,但不限于:低级烷基酰胺、α-氨基酸酰胺、烷氧酰基酰胺以及烷氨基烷基羰酰胺。生物可水解的氨基甲酸酯的例子包括,但不限于:低级烷基胺、取代的乙二胺、氨基酸、羟基烷基胺、杂环性和杂芳环性胺以及聚醚胺。
各种本发明免疫抑制性药物含有一个或多个手性中心,并且可以对映体的外消旋混合物或非对映体的混合物的形式存在。本发明包括所述化合物的立体异构纯形式的用途,以及这些形式的混合物的用途。例如含有特定的本发明免疫调节性化合物的等量或非等量的对映体的混合物可用于本发明的方法和组合物之中。这此异构体可以不对称合成或使用标准技术如手性柱或手性拆分试剂来拆分。参见,诸如,Jacques,J.,等,Enantiomers,Racemates and Resolutions(Wiley-Interscience,New York,1981);Wilen,S.H.,等,Tetrahedron 33:2725(1977);Eliel,E.L.,Stereochemistry ofCarbon Compounds(Mc Graw-Hill,NY,1962);以及Wilen,S.H.,Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN,1972)。
如此文中所使用的,除非另有说明,术语“立体异构纯”指的是含有化合物的一种异构体并且基本上不含该化合物的其它异构体的组合物。例如,具有一个手性中心的化合物立体异构纯的组合物将基本上不含该化合物的对映异构体。具有两个手性中心的化合物的立体异构纯的组合物基本上不含该化合物的其它非对映体。典型的立体异构纯化合物含有大于约80重量%的化合物的一种立体异构体并且含有小于约20重量%的该化合物的其它立体异构体,更优选的含有大于约90重量%的化合物的一种立体异构体且含有小于约10重量%的化合物的其它立体异构体,更为优选的是含有大于约95重量%的化合物的一种立体异构体且含有小于约5重量%的该化合物的其它立体异构体,最为优选的是含有大于约97重量%的化合物的一种立体异构体且含少于约3重量%的该化合物的其它立体异构体。如此文中所使用的,除非另有说明,术语“立体异构富含的”指的是含有大于约60重量%的该化合物的一种立体异构体的组合物,优选大于约70重量%,更优选的大于约80重量%的该化合物的一种立体异构体。如此文中所使用的,除非另有说明,术语“对映体纯”指的是具有一个手性中心的该化合物的立体异构纯的组合物。相似的,术语“立体异构富含的”指的是具有一个手性中心的该化合物的立体异构富含的组合物。
必需注意的是,当所述结构和该结构的命名之间存在偏差时,所述结构更重要(accorded more weight)。此外,如果所述结构的立体化学或者结构的一部分没有用例如粗体或下划线标注,则该结构或该结构的部分应当理解成包含了所有它的异构体形式。
5.2第二活性试剂
在本发明方法和组合物之中,免疫调节性药物可与其它药理学活性化合物(“第二活性成分”)相联合。我们确信某些联合方式在治疗特定类型的癌症和某些与不希望的血管生长相关、或以之为特征的疾病和病况中能产生协同的作用。免疫调节性化合物也可用于减轻与某些第二活性试剂相关的副作用,而某些第二活性试剂也可用于减轻与免疫调节性药物相关的副作用。
一种或多种第二活性成分或试剂可与免疫调节性药物一起用于本发明的方法和组合物之中。第二活性成分可以是大分子(例如,蛋白质)或小分子(例如,合成的无机的、有机金属的、或有机的分子)。
大分子活性试剂的例子包括,但不限于:造血生长因子、细胞因子、以及单克隆和多克隆抗体。典型的大分子活性试剂是生物分子,诸如天然产生的或人工制备的蛋白质。在本发明中特别有用的蛋白质包括在体内和体外可刺激造血前体细胞和促免疫活性产生细胞存活和/或增殖的蛋白质。其它的蛋白质在体内和体外刺激细胞中红血球原祖细胞的分裂和分化。特定的蛋白质包括,但不限于:白介素,诸如IL-2(包括重组IL-II(“rIL2”)和金丝雀痘(canarypox)IL-2)、IL-10、IL-12和IL-18;干扰素,诸如干扰素α-2a、干扰素α-2b、干扰素α-n1、干扰素α-n3、干扰素β-Ia和干扰素γ-Ib;GM-CF和GM-CSF;以及EPO。
可用于本发明的方法和组合物的特定的蛋白质包括,但不限于:在美国以商品名Neupogent(Amgen,Thousand Oaks,CA)出售的非格司亭;在美国以商品名Leukine(Immunex,Seattle,WA)出售的沙莫司亭;以及在美国以商品名Epogen(Amgen,Thousand Oaks,CA)出售的重组EPO。
重组和突变型GM-CSF可根据美国专利5,391,485;5,393,870;和5,229,496的记载而制备,所有文献在此处引入作为参考。重组和突变型G-CSF可根据美国专利4,810,643;4,999,291;5,528,823和5,580,755的记载而制备,所有文献在此处引入作为参考。
本发明包括原生的、天然产生的和重组的蛋白质的使用。本发明进一步的包括天然产生的蛋白质的突变体以及衍生物(例如,修饰型),这些突变体在体内至少具有突变源蛋白质的某些药理学活性。突变体的例子包括,但不限于:具有一个或多个与天然产生型蛋白质的相应残基不同的氨基酸残基的蛋白质。术语“突变型”还包括缺少碳水化物部分的蛋白质,而该部分在天然产生型(例如,非糖基化型)中通常是存在的。衍生物的例子包括,但不限于:PEG化的衍生物和融合蛋白,诸如通过向目标蛋白或蛋白的活性部分融入IgG1或IgG3。参见,例如,Penichet,M.L.和Morrison,S.L.,J.Immunol.Methods248:91-101(2001)。
可用于与本发明化合物相联合的抗体包括单克隆和多克隆抗体。抗体的例子包括,但不限于:曲妥珠单抗(Herceptin)、美罗华(Rituxan)、贝伐单抗(AvastinTM)、pertuzumab(OmnitargTM)、托西莫单抗(Bexxar)、依决洛单抗(Panorex)和G250。本发明化合物还可以与抗-TNF-α抗体相结合或联合使用。
大分子活性试剂可以抗-癌疫苗的形式给药。例如分泌、或引起细胞因子(诸如IL-2、G-CSF和GM-CSF)分泌的疫苗可用于本发明的方法、药物组合物和试剂盒之中。参见,例如,Emens,L.A.,等,Curr.Opinion Mol.Ther.3(1):77-84(2001)。
在本发明的一个实施方案中,大分子活性试剂减少、消除或预防与免疫调节性药物的施用相关的副作用。根据特定的免疫调节性药物和需要治疗的疾病和病症,副作用可包括,但不限于:困倦和嗜睡、眩晕和体位性低血压、中性粒细胞减少、由中性粒细胞减少而导致的感染、HIV-病毒负荷增加、心动过缓、Stevens-Johnson综合征、毒性表皮坏死溶解、以及癫痫发作(例如,癫痫大发作惊厥)。特定的副作用是中性粒细胞减少。
小分子形式的第二活性试剂也可用于缓解与免疫调节性药物的给药相关的副作用。然而,与某些大分子相似,在与免疫调节性药物一同(例如,之前、之后或同时)给药时,很多小分子被认为能引起协同效果。小分子形式的第二活性试剂包括,但不限于:抗-癌剂、抗生素、免疫抑制剂和甾类化合物。
抗-癌剂的例子包括,但不限于:阿西维辛;阿柔比星;盐酸阿考达唑;阿克罗宁;阿多来新;阿地白介素;六甲蜜胺;安波霉素;醋酸阿美蒽醌;安吖啶;阿那曲唑;安曲霉素;天门冬酰胺酶;曲林霉素;阿扎胞苷;阿扎替派;阿佐霉素;巴马司他;苯佐替派;比卡鲁胺;盐酸比生群;二甲磺酸双奈法德;比折来新;硫酸博来霉素;布喹那钠;溴匹立明;白消安;放线菌素C;卡普睾酮;卡醋胺;卡贝替姆;卡铂;卡莫斯汀;盐酸卡柔比星;卡折来新;西地芬戈;塞来昔布(COX-2抑制剂);苯丁酸氮芥;西罗霉素;顺铂;克拉屈滨;甲磺酸克雷斯托;环磷酰胺;阿糖胞苷;达卡巴嗪;放线菌素D;盐酸柔红霉素;地西他滨;右奥马铂;地扎胍宁;地扎胍宁甲磺酸盐;地吖醌;多西紫杉醇;阿霉素;盐酸阿霉素;屈洛昔芬;柠檬酸屈洛昔芬;丙酸屈他雄酮;达佐霉素;依达曲沙;盐酸依氟鸟氨酸;依沙芦星;恩洛铂;恩普氨酯;依匹哌啶;盐酸表柔比星;厄布洛唑;盐酸依索比星;雌莫司汀;雌莫司汀磷酸钠;依地硝唑;依托泊苷;磷酸依托泊苷;氯苯乙嘧胺;盐酸法倔唑;法扎拉滨;芬维A胺;氮尿苷;磷酸氟达拉滨;氟尿嘧啶;氟西他滨;磷喹酮;福司曲星钠;吉西他滨;盐酸吉西他滨;羟基脲;盐酸伊达比星;异环磷酰胺;伊莫福新;异丙铂;伊立替康;盐酸伊立替康;醋酸兰瑞肽;来曲唑;醋酸亮丙瑞林;盐酸利阿唑;洛美曲索钠;环己亚硝脲;盐酸洛索蒽醌;马索罗酚;美登素;盐酸氮芥;醋酸甲地孕酮(megestrol acetate);醋酸美仑孕酮;美法仑;美诺立尔;巯嘌呤;甲氨喋呤;甲氨喋呤钠;氯苯氨啶;美妥替派;米丁度胺;mitocarcin;丝裂红素;米托洁林;米托马星;丝裂霉素;米托司培;米托坦;盐酸米托蒽醌;麦考酚酸;诺考达唑;诺拉霉素;奥马铂;奥昔舒仑;紫杉醇;培门冬酶;培利霉素;奈莫司汀;硫酸培洛霉素;培磷酰胺;派泊溴烷;哌泊舒凡;盐酸吡罗蒽醌;普卡霉素;普洛美坦;卟吩姆钠;泊非霉素;泼尼莫司汀;盐酸丙卡巴肼;嘌罗霉素;盐酸嘌呤霉素;吡唑霉素;利波腺苷;沙芬戈;盐酸沙芬戈;司莫司汀;辛曲嗪;磷乙酰天冬氨酸钠(sparfosate sodium);司帕霉素;盐酸锗螺胺;螺莫司汀;螺铂;链黑霉素;链佐星;磺氯苯脲;他利霉素;替可加兰钠(tecogalansodium);紫杉特尔;替加氟;盐酸替洛蒽醌;替莫泊芬;替尼泊苷;替罗昔隆;睾内酪;硫咪嘌呤;硫鸟嘌呤;塞替派;噻唑呋林;替拉扎明;柠檬酸托瑞米芬;醋酸曲托龙;磷酸曲西立滨;三甲曲沙;葡糖醛酸三甲曲沙;曲普瑞林;盐酸妥布氯唑;乌拉莫司汀;乌瑞替派;伐普肽;维替泊芬;硫酸长春碱;硫酸长春新碱;长春地辛;硫酸长春地辛;硫酸长春匹定;硫酸长春甘酯;硫酸环氧长春碱;酒石酸长春瑞滨;硫酸长春罗定;硫酸长春利定;伏氯唑;折尼铂;净司他丁;盐酸佐柔比星。
其它抗-癌药物包括,但不限于:20-epi-1,25-二羟基维生素D3;5-乙炔基尿嘧啶;阿比特龙;阿柔比星;羰酰富烯(acylfulvene);adecypenol;阿多来新;阿地白介素;ALL-TK拮抗剂;六甲蜜胺;氨莫司汀;amidox;氨磷定;氨基乙酰丙酸;氨柔比星;安吖啶;阿那格雷;阿纳托司唑;穿心莲内酯;血管生成抑制剂;拮抗剂D;拮抗剂G;安雷利克斯;anti-dorsalizing morphogeneticprotein-1;抗雄激素,前列腺癌;抗雌激素;抗瘤酮类;反义寡核苷酸;阿非迪霉素甘氨酸盐;凋亡基因调节剂;凋亡调节剂;无嘌呤核酸;ara-CDP-DL-PTBA;精氨酸脱氨基酶;asulacrine;阿他美坦;阿莫司汀;axinastatin 1;axinastatin 2;axinastatin 3;阿扎司琼;阿扎霉素(azatoxin);重氮酪氨酸;浆果赤霉素III衍生物;balanol;巴马司他;BCR/ABL拮抗剂;苯并二氢扑酚(benzochlorins);苯甲酰基星型包菌素;β-内酰胺衍生物;β-alethine;β-clamycin B;桦木酸;bFGF抑制剂;比卡鲁胺;比生群;双氮丙啶基精胺;双奈法德;bistratene A;比折来新;breflate;溴匹立明;布度钛;丁硫氨酸亚矾胺;卡泊三醇;calphostin C;喜树碱衍生物;卡培他滨;氨甲酰-氨基-三唑;羧甲酰胺基三唑;CaRestM3;CARN 700;衍生自软骨的抑制剂;卡折来新;酪蛋白激酶抑制剂(ICOS);粟精胺;天蚕抗菌肽B;西曲瑞克;chlorlns;氯代喹噁啉磺酰胺;西卡前列素;顺式-卟啉;克拉屈滨;氯米芬类似物;克霉唑;collismycin A;collismycin E;考布他汀A4(combretastatin A4)、考布他汀类似物;conagenin;crambescidin 816;克立那托(crisnatol);自念珠藻环肽8;自念珠藻环肽A衍生物;curacinA;环戊烷并蒽醌类;cycloplatam;cypemycin;阿糖胞苷ocfosfate;细胞溶解因子;磷酸己烷雌酚;达昔单抗;地西他滨;脱氢代代宁B;地洛瑞林;地塞米松;右异环磷酰胺;右雷佐生;右维拉帕米;地吖醌;代代宁B;didox;二乙基去甲精胺(diethylnorspermine);二氢-5-氮胞苷;二氢紫杉醇,9-;dioxamycin;二苯基螺莫司汀;多西他赛;二十二烷醇;多拉司琼;去氧氟尿苷;阿霉素;屈洛昔芬;屈大麻酚;duocarmycin SA;依布硒;依考莫司汀;依地福新;依决洛单抗;依氟鸟氨酸;榄香烯;乙嘧替氟;表柔比星;依立雄胺;雌莫可汀类似物;雌激素激动剂;雌激素拮抗剂;依他硝唑;磷酸依托泊苷;依西美坦;法倔唑;法扎拉滨;芬维A胺;非格司亭;非那雄胺;flavopiridol;氟卓斯汀(flezelastine);fluasterone;氟达拉滨;盐酸氟代柔红霉素;福酚美克;福美坦;福司曲星;福莫司汀;钆替沙林(gadolinium texaphynin);硝酸镓;加洛他滨;加尼瑞克;明胶酶抑制剂;吉西他滨;谷胱甘肽抑制剂;hepsulfam;heregulin;六甲撑二乙酰胺;金丝桃素;依班膦酸;伊达比星;艾多昔芬;依决孟酮;伊莫福新;伊洛马司他;imatinib(例如,Gleevec);咪喹莫特;免疫刺激肽;胰岛素-样生长因子-1受体抑制剂;干扰素激动剂;干扰素;白介素s;碘苄胍;碘代阿霉素;药薯,4-;伊罗普拉;伊索拉定;isobengazole;isohomohalicondrin B;伊他司琼;jasplakinolide;kahalalide F;lamellarin-N三醋酸酯;兰瑞肽;leinamycin;来格司亭;硫酸香菇多糖;leptolstatin;来曲唑;白血病抑制因子;白细胞α干扰素;亮丙瑞林+雌激素+黄体酮;亮丙瑞林;左旋咪唑;利阿唑;线性多胺类似物;亲脂性二糖肽;亲脂性铂化合物;lissoclinamide 7;洛铂;蚯蚓磷脂;洛美曲索;氯尼达明;洛索蒽醌;洛索立宾;勒托替康;lutetium texaphyrin;lysofylline;溶解肽;美坦新;mannostatin A;马立马司他;马索罗酚;maspin;基质溶解因子抑制剂;基质金属蛋白酶抑制剂;美诺立尔;merbarone;美替瑞林(meterelin);甲硫氨酸酶;甲氧氯普胺;MIF抑制剂;米非司酮;米替福新;米立司亭;米托胍腙;二溴卫矛醇;丝裂霉素类似物s;米托萘胺;mitotoxin纤维母细胞生长因子-皂草素(saporin);米托蒽醌;莫法罗汀;莫拉司亭;Erbitux、人绒毛膜促性腺激素;单磷酰基脂肪;A+肌菌体细胞壁sk(A+myobacterium cell wall sk);莫哌达醇;氟芥抗癌剂;mycaperoxide B;分枝杆菌细胞壁提取物;myriaporone;N-乙酰地那林;N-取代的苯甲酰胺类;那法瑞林;那瑞替喷(nagrestip);纳洛酮+喷他佐辛;napavin;naphterpin;那托司亭;奈达铂;奈莫柔比星;奈立磷酸;尼鲁米特;nisamycin;一氧化氮调节剂;硝基氧抗氧化剂;nitrullyn;oblimersen(Genasense);O6-苄基鸟嘌呤;奥曲肽;okicenone;寡核苷酸;奥那司酮;昂丹司琼;昂丹司琼;oracin;口服细胞因子诱导剂;奥马铂;奥沙特隆;奥沙利铂;oxaunomycin;紫杉醇;紫杉醇类似物;紫杉醇衍生物;palauamine;棕榈酰根霉素;帕米磷酸;人参萜三醇;帕诺米芬;副细菌素(parabactin);帕折普汀;培门冬酶;培得星(peldesine);木聚硫钠;喷司他丁;戊四唑;潘氟隆;培磷酰胺;紫苏乙醇;phenazinomycin;醋酸苯酯;磷酸酶抑制剂;溶链菌素;盐酸毛果芸香碱;吡柔比星;吡曲克李;placetin A;placetin B;纤溶酶原活化因子抑制剂;铂复合物;铂化合物;铂-三胺复合物;卟吩姆钠;泊非霉素;泼尼松;丙基双吖啶酮;前列腺素J2;蛋白酶体抑制剂;蛋白A-为基础的免疫调节剂;蛋白激酶C抑制剂;蛋白激酶C抑制剂,微海藻;蛋白酪氨酸磷酸酶抑制剂;嘌呤核苷磷酸化酶抑制剂;红紫素;吡唑并吖啶;吡醇羟乙酯血红蛋白聚氧乙烯共轭物;raf拮抗剂;雷替曲塞;雷莫司琼;ras法呢基蛋白转移酶抑制剂;ras抑制剂;ras-GAP抑制剂;去甲瑞替普汀;铼Re 186代替膦酸钠;根霉素;核酶;RII retinamide;rohitukine;罗莫肽;罗喹美克;rubiginone B1;ruboxyl;沙芬戈;saintopin;SarCNU;sarcophytol A;沙格司亭;Sdi 1模拟物;司莫司汀;老化衍生的抑制剂1;正义寡核苷酸;信号转导抑制剂;西佐喃;索布佐生;硼卡钠;醋酸苯酯钠;solverol;生长介素结合蛋白;索纳明;膦门冬酸(sparfosicacid);spicamycin D;螺莫司汀;splenopentin;海绵素1(spongistatin 1);角鲨胺;stipiamide;基质降解酶因子抑制剂;sulfinosine;强效肠道血管活性肽拮抗剂;suradista;苏拉明;八氢吲嗪三醇;他莫司汀;他莫昔芬甲碘化物;牛磺莫司汀;他扎罗汀;替可加兰钠(tecogalan sodium);替加氟;tellurapyrylium;端粒末端转移酶抑制剂;替莫泊芬;替尼泊苷;四氯decaoxide;tetrazomine;thaliblastine;噻可拉林(thiocorahne);促血小板生成素;促血小板生成素模拟物;胸腺法新;胸腺素受体激动剂;胸腺曲南;促甲状腺激素;tin本紫红素乙酯(tin ethyl etiopurpurin);替拉扎明;三氯环戊二烯肽;topsentin;托瑞米芬;转译抑制剂;维甲酸;三乙酰基尿苷;曲西立滨;三甲曲沙;曲普瑞林;托烷司琼;妥罗雄脲;酪氨酸激酶抑制剂;tyrphostins;UBC抑制剂;乌苯美司;泌尿生殖窦-衍生的生长抑制性因子;尿激酶受体拮抗剂;伐普肽;variolin B;维拉雷琐;藜芦明(veramine);verdins;维替泊芬;长春瑞滨;vinxaltine;整合蛋白抗体;伏氯唑;扎诺特隆;折尼泊;亚苄维C;和净司他丁苯马聚合物(stimalamer)。
特定的第二活性试剂包括,但不限于:oblimersen(Genasense)、remicade、多西他赛、塞来昔布、美法仑、地塞米松(Decadron)、类固醇、吉西他滨、顺铂、替莫唑胺、依托泊苷、环磷酰胺、替莫唑胺、卡铂、丙卡巴肼、卡莫斯汀、他莫昔芬、拓普替康、甲氨喋呤、Arisa、紫杉醇、紫杉特尔、氟尿嘧啶、亚叶酸、依立替康、希罗达(xeloda)、CPT-11、干扰素α、PEG化的干扰素α(例如,PEG INTRON-A)、卡培他滨、顺铂、塞替派、氟这拉滨、卡铂、脂质体柔红霉素、阿糖胞苷、doxetaxol、pacilitaxel、长春碱、IL-2、GM-CSF、达卡巴嗪、长春瑞滨、唑来磷酸、palmitronate、biaxin、白消安、泼尼松、双磷酸酯、arsenic trioxide、长春新碱、阿霉素(Doxil)、紫杉醇、更昔洛韦、阿霉素、雌莫司汀磷酸钠(Emcyt)、舒林酸和依托泊苷。
5.3治疗和预防方法
本发明的方法包括治疗、预防和/或控制各种类型的与不希望的血管生成相关、或以之为特征的癌症和疾病以及病症的方法。如此文中所使用的,除非另有指明,术语“治疗”指的是在某种特定疾病或病症发作后给予本发明化合物或其它附加的活性成分。如此文中所使用的,除非另有指明,术语“预防”指的是在症状、特别对于患有癌症和其它与不希望的血管形成有关、或以之为特征的疾病危险的患者的症状发生之前给药。术语“预防”包括抑制特定的疾病或病症的某种症状。具有与不希望的血管形成相关的、或以之为特征的癌症和疾病和病症的家族发病史的患者特别推荐使用预防性疗法。如此文中所使用的,除非另有说明,术语“控制”包括预防患特定疾病或病症的患者复发疾病,和/或延长患疾病或病症的病人的缓解期。
如此文中所使用的,术语“癌症”包括,但不限于:实体瘤和血液原肿瘤。术语“癌症”指的是皮肤组织、器官、血液和脉管的疾病,这些疾病包括,但不限于:膀胱癌、骨癌或血癌、脑癌、乳腺癌、宫颈癌、胸癌、结肠癌,子宫内膜癌、食道癌、眼睛癌、头癌、肾癌、肝癌、淋巴结癌、肺癌、口腔癌、颈癌、卵巢癌、胰腺癌、前列腺癌、直肠癌、胃癌、睾丸癌、咽喉癌和子宫癌。特定的癌症包括,但不限于:晚期恶性肿瘤、淀粉样病变、神经母细胞瘤、脑(脊)膜瘤、血管外皮细胞瘤、多发性脑转移肿瘤(multiple brain metastase)、多形性成神经胶质细胞瘤、成神经胶质细胞瘤、脑干神经胶质瘤、预后不良恶性脑肿瘤、恶性神经胶质瘤、再发性恶性神经胶质瘤、退行发育性星细胞瘤、退行发育性少突神经胶质瘤、神经内分泌肿瘤、直肠腺癌、Dukes C&D结肠直肠癌、不可切除直肠结肠癌、转移性肝细胞癌、卡波氏肉瘤、karo型急性成髓细胞白血病、何杰金氏淋巴瘤、非-何杰金氏淋巴瘤、表皮T细胞淋巴瘤、表皮B-Cell淋巴瘤、弥散性大B-Cell淋巴瘤、低度恶性囊泡淋巴瘤、恶性黑素瘤、恶性间皮瘤、恶性胸膜渗漏间皮瘤综合征、腹膜癌、乳头状浆液性癌、妇科肉瘤、软组织肉瘤、scelroderma、表皮脉管炎、郎格罕细胞组织细胞增生症、平滑肌肉瘤、进行性骨化性纤维发育不良、耐激素性前列腺癌、可切除的高危软组织肉瘤、不可切除的肝细胞癌、Waldenstrom’s巨球蛋白血症、郁积型骨髓瘤、无痛性骨髓瘤、输卵管癌、非雄激素依赖性前列腺癌、雄激素依赖型IV期非-转移性前列腺癌、激素-非敏感性前列腺癌、化疗-非敏感性前列腺癌、乳头状甲状腺癌、滤泡性甲状腺癌、甲状腺髓样癌以及平滑肌瘤。在-个特定的实施方案中,癌症是转移性的。在另-个实施方案中,癌症对化疗或放疗具有抵抗或耐药性的:特别的,对于沙利度胺具有抵抗力的。
如此文中所使用的,为了表示癌症以外的疾病和病症,术语“与不希望的血管生成相关、或以之为特征的疾病或病症”、“与不希望的血管生成相关的疾病或病症”以及“以不希望的血管生成为特征的疾病或病症”指的是由不希望的或无法控制的血管生成而导致的、介导的、或伴随的疾病、病症和病况,包括,但不限于:炎性疾病、自身免疫疾病、遗传疾病、变应性疾病、细菌性疾病、眼新生血管疾病、脉络膜新生血管疾病以及视网膜新生血管疾病。
与不希望的血管生成相关的疾病或病症的例子包括,但不限于,糖尿病性视网膜病、早产儿视网膜病、角膜移植排斥、新生血管性青光眼,晶状体后纤维组织增生、增殖性玻璃体视网膜病变、沙眼、近视、视窝、流行性角膜结膜炎、异位性角膜炎、上边缘角膜炎、翼状胬肉干性角膜炎、sjogrens、酒渣鼻、phylectenulosis、梅毒、脂质退化、细菌性溃疡、真菌性溃疡、单纯性疱疹感染、带状疱疹感染、原生动物性感染、卡波西肉瘤、蚕食性角膜溃疡、Terrien’s角膜边缘性变性、边缘性角质层分离、类风湿性关节炎、全身性红斑狼疮、多动脉炎、外伤、Wegeners肉状瘤病、巩膜炎、Steven′s Johnson疾病、periphigoid径向角膜切开、镰刀细胞贫血症、结节病、弹性假黄瘤、佩吉特病、静脉闭塞、动脉闭塞、颈动脉闭塞疾病、慢性眼葡萄膜炎、慢性玻璃体炎、莱姆病、视网膜静脉周围炎、Bechets疾病、视网膜炎、脉络膜炎、假眼组织胞浆菌病、Bests疾病、Stargarts疾病、扁平部睫状体炎、慢性视网膜剥离、高粘滞性综合征、弓形体病、潮红、sarcodisis、硬化症、soriatis、牛皮癣、原发性硬化性胆管炎、直肠炎、原发性胆汁srosis、特发性肺纤维化、和酒精性肝炎。
在本发明的特定的实施方案中,与不希望的血管生成相关的疾病或病症不包括充血性心力衰竭、心肌病、肺水肿、内毒素-介导的败血症性休克、急性病毒性心肌炎、心脏同种异体移植物排斥、心肌梗死、HIV、肝炎、成人呼吸窘迫综合征、骨再吸收疾病、慢性阻塞性肺疾病、慢性肺炎、皮炎、囊性纤维病、败血症性休克、败血症、内毒素性休克、血液动力休克、败血症综合征、后局部缺血再灌注损伤、脑膜炎、牛皮癣、纤维变性疾病、恶质病、移植排斥、类风湿性脊椎炎、骨质疏松症、克罗恩氏病、溃疡性结肠炎、炎症性肠病、多发性硬化症、全身性红斑狼疮、原红细胞增多症、结节性红斑、麻风病中leprosum放射损伤、哮喘、高含氧肺泡损伤、疟疾、分支杆菌感染、以及HIV导致的机会性感染。
本发明包括治疗那些曾经进行过癌症或与不希望的血管生成相关、或以之为特征的疾病或病症的治疗但对标准疗法不敏感的患者的方法,以及治疗那些以前未进行治疗的患者的方法。本发明还包括治疗患者的方法而不管患者的年龄如何,尽管某些疾病或病症在某一年龄段内比较普遍。本发明进一步的包括治疗那些经历了外科手术以试图治疗疾病或病况的患者的方法,以及治疗那些未曾有此经历的患者的方法。由于患病症和与不希望的血管生长相关的疾病和病症的患者具有不同种类的临床表现并且在临床结果上各有不同,因此给予患者的治疗方法可根据他/她的预后来进行变化。熟练的临床医生可以容易的而不需要不适当的试验就可确定可有效用于治疗患癌症和其它疾病或病症的单个患者的特定的第二试剂、手术类型、以及非-药物基础的标准疗法。
本发明包括的方法中包含向患有、或似乎患有癌症或由不希望的血管生成介导的疾病或病症的患者(例如,人类)给予一种或多种本发明免疫调节性化合物或其可药用的盐、溶剂化物、水合物、立体异构体、包合物或前药。
在本发明的一种实施方式中,本发明免疫调节性化合物可口服的以单个每日剂量或分开每日剂量,并以约0.10至约150mg/天的剂量给药。在一具体的实施方式中,4-(氨基)-2-(2,6-二氧代(3-哌啶基))-异二氢吲哚-1,3-二酮(ActimidTM)可以0.1至约1mg/天的剂量给药,或者可以选择每隔一天约0.1至约5mg的剂量给药。在一个优选的实施方案中,3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基-哌啶-2,6-二酮(RevimidTM)可以约5至25mg/天的剂量给药,或者可以选择每隔一天约10至约50mg的剂量给药。
在一特定的具体实施反式中,4-(氨基)-2-(2,6-二氧代(3-哌啶基))-异二氢吲哚-1,3-二酮(ActimidTM)可以约1、2或5mg/天的剂量向患有多发性骨髓瘤复发的患者给药。在一具体的实施方式中,3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(RevimidTM)可在最初以5mg/天的剂量给药,然后剂量可以每周增加至10、20、25、30和50mg/天。在一特定的具体实施反式中,RevimidTM可以高至30mg/天的量向患有实体瘤的患者给药。在一具体的实施方式中,RevimidTM可以高至约40mg/天的量向患神经胶质瘤的患者给药。
5.3.1含有第二活性试剂的联合疗法
本发明的特定方法包括与一种或多种第二活性试制相结合,和/或与放疗、血液输注或手术相结合,给予本发明的免疫调节性化合物或其可药用的盐、溶剂化物、水合物、立体异构体、包合物或前药。本发明免疫调节性化合物的例子公开于此文中(参见,例如,5.1章节)。第二活性试剂也公开于此文中(参见,例如,5.2章节)。
向患者给予免疫调节性化合物与第二活性试剂可以同时或顺次的通过相同或不同的给药途径而进行。对于患者而言,所使用的特定给药路径的适宜性取决于活性试剂本身(例如,是否可以口服给药而不会在进入血管之前降解)和所需治疗的疾病。本发明免疫调节性化合物的优选给药路径是口服。本发明第二活性试剂或成分的优选给药路径是对于本领域技术人员来说都是公知的。参见,例如,Physicians′DeskReference,1755-1760(56th ed.,2002)。
在本发明的一个实施方案中,第二活性成分以静脉内或皮下、每日一次或两次、以约1至约1000mg的量、约5至约500mg的量、约10至约350mg的量、或约50至约200mg的量给药。第二活性成分的具体量可根据使用的具体成分、所需治疗或控制的疾病类型、疾病的严重程度和发展阶段、本发明免疫调节性化合物的量、和任选的同时使用的附加活性试剂等因素而向患者给药。在一特定的实施方案中,第二活性成分是oblimersen(Genasense)、GM-CSF、G-CSF、EPO、紫杉特尔、依立替康、达卡巴嗪、反式视黄酸、拓普替康、己酮可可碱、环丙沙星、地塞米松、长春新碱、阿霉素、cox-2抑制剂、IL2、IL8、IL18、IFN、Ara-C、长春瑞宾或者它们的联合形式。
在一特定的实施方案中,GM-CSF、G-CS F或EPO皮下施用,在4或6周的循环内,在约5天时间内给药,以约1至约750mg/m2/天,优选约25至约500mg/m2/天,更优选约50至约250mg/m2/天,最优选约50至约200mg/m2/天的量给药。在某一实施方案中,GM-CSF可以约60至约500mcg/m2的量静脉给药2小时,或皮下给药约5至约12mcg/m2/天。在一个特定的实施方案中,G-CSF可在最初以约1mcg/kg/天的量皮下给药,然后可根据总粒细胞数的增加而进行剂量调整。G-CSF的维持剂量可以约300(在更小的患者中)或480mcg的量皮下给药。在某一实施方案中,EPO可以10,000单位的量每周3次皮下给药。
在另一个实施方案中,RevimidTM可以约25mg/d的量、达卡巴嗪可以约200至1,000mg/m2/d的量向患有转移性恶性黑素瘤的患者给药。在一个特定的实施方案中,RevimidTM可以约5至约25mg/d的量向患有转移性恶性黑素瘤的患者给药,这些患者还使用达卡巴嗪、IL-2或IFN进行治疗。在一个特定的实施方案中,RevimidTM与地塞米松相联合,可以约15mg/d的量一日两次或30mg/d的量一日四次向患有复发性或顽固性多发骨髓瘤的患者给药。
在另一个实施方案中,免疫调节性化合物与美法仑和地塞米松向患有淀粉样病变的患者给药。在一个特定的实施方案中,本发明免疫调节性化合物和甾类化合物一起,向患有淀粉样病变的患者给药。
在另一个实施方案中,免疫调节性化合物与吉西他滨和顺铂一起,向患局部发展或转移性移行细胞膀胱癌的患者给药。
在另一个实施方案中,免疫调节性化合物与第二活性组分替莫唑胺相联合给予患有复发性或进行性脑肿瘤或复发性神经母细胞瘤的儿科患者给药;与塞来昔布、依托泊苷和环磷酰胺相联合,向患有复发性或进行性CNS癌症的患者给药;与替莫唑胺相联合,向患有复发性或进行性脑(脊)膜瘤、恶性脑(脊)膜瘤、血管外皮细胞瘤、多发性脑转移、复发性脑肿瘤、或新诊断的多形性胶质母细胞瘤的患者给药;与依立替康相结合向患有复发性胶质母细胞瘤的患者给药;与卡铂相联合向患有脑干神经胶质瘤的儿童患者给药;与丙卡巴肼相联合,向患有进行性恶性神经胶质瘤的儿童患者给药;与环磷酰胺相结合与患有预后不良恶性脑肿瘤、新诊断的或复发的多形性胶质母细胞瘤的患者给药;与Gliadel相联合,向患有高度复发性恶性神经胶质瘤的患者给药;与替莫唑胺和他莫昔芬相联合,向患有退行发育性星细胞瘤的患者给药;或拓普替康相联合,向患有神经胶质瘤、胶质母细胞瘤、退行发育性星细胞瘤或退行发育性少突神经胶质瘤的患者给药。
在另一个实施方案中,免疫调节性化合物与甲氨喋呤和环磷酰胺一起,向患有转移性乳腺癌的患者给药。
在另一个实施方案中,免疫调节性化合物与替莫唑胺一起,向患有神经内分泌肿瘤的患者给药。
在另一个实施方案中,免疫调节性化合物与吉西他滨一起,向患有复发性或转移性头颈部癌的患者给药。在另一个实施方案中,免疫调节性化合物与吉西他滨一起,向患有胰腺癌的患者给药。
在另一个实施方案中,免疫调节性化合物与Arisa、紫杉醇和/或紫杉特尔相联合,向患有结肠癌的患者给药。
在另一个实施方案中,免疫调节性化合物与卡培他滨一起,向患有顽固性结肠直肠癌的患者、或在一线治疗中失败的患者、或在结肠或直肠腺癌中表现较差的患者给药。
在另一个实施方案中,免疫调节性化合物与氟尿嘧啶、亚叶酸和依立替康相联合向患有Dukes C & D结肠直肠癌的患者、或之前进行过转移性结肠直肠癌治疗的患者给药。
在另一个实施方案中,免疫调节性化合物与卡培他滨、xeloda和/或CPT-11相联合,向患有顽固性结肠直肠癌的患者给药。
在另一个实施方案中,本发明免疫调节性化合物与卡培他滨和依立替康一起,向患有顽固性结肠直肠癌的患者、或向患有不可切除性或转移性结肠直肠癌的患者给药。
在另一个实施方案中,免疫调节性化合物单独、或与干扰素α或卡培他滨相联合相患有不能切除的或转移性肝细胞癌的患者给药;或者与顺铂和塞替派相联合,向患有原发性或转移性肝癌的患者给药。
在另一个实施方案中,免疫调节性化合物与PEG化的干扰素α相联合,向患有卡波氏肉瘤的患者给药。
在另一个实施方案中,免疫调节性化合物与氟达拉滨、卡铂和/或拓普替康相联合,向患有顽固性或复发性或高危性急性骨髓性白血病的患者给药。
在另一个实施方案中,免疫调节性化合物与脂质体柔红霉素、拓普替康和/或阿糖胞苷相联合,向患有不利的karo型急性成髓细胞白血病的患者给药。
在另一个实施方案中,免疫调节性化合物与吉西他滨和依立替康相联合,向患有非-小细胞肺癌的患者给药。在一项实施方案中,免疫调节性化合物与卡铂和依立替康相联合,向患有非-小细胞肺癌的患者给药。在一项实施方案中,免疫调节性化合物与doxetaxol相联合,向患有非-小细胞肺癌并且之前用carbo/VP 16和放疗进行治疗的患者给药。
在另一个实施方案中,免疫调节性化合物与卡铂和/或紫杉特尔相联合,或者与卡铂、pacilitaxel和/或胸部放疗相联合,向患有非-小细胞肺癌的患者给药。在一个特定的实施方案中,免疫调节性化合物与紫杉特尔相联合,向患有IIIB或IV期非-小细胞肺癌的患者给药。
在另一个实施方案中,本发明免疫调节性化合物与oblimersen(Genasense)相联合,向患有小细胞肺癌的患者给药。
在另一个实施方案中,免疫调节性化合物单独、或与第二活性成分诸如长春碱或氟达拉滨相结合向患有各种淋巴瘤,包括,但不限于:何杰金氏淋巴瘤、非-何杰金氏淋巴瘤、表皮T-细胞淋巴瘤、表皮B-细胞淋巴瘤、弥散性大B-细胞淋巴瘤或复发性或顽固性低度恶性囊泡淋巴瘤的患者给药。
在另一个实施方案中,免疫调节性化合物与紫杉特尔、IL-2、IFN、GM-CSF和/或达卡巴嗪相联合,向患有各种类型或阶段的黑素瘤的患者给药。
在另一个实施方案中,免疫调节性化合物单独、或与长春瑞滨相联合,向患有恶性间皮瘤、或含胸膜移植物的IIIB期非-小细胞肺癌或恶性胸膜渗漏间皮瘤综合征的患者给药。
在另一个实施方案中,免疫调节性化合物与地塞米松、唑来磷酸、palmitronate、GM-CSF、biaxin、长春碱、美法仑、白消安、环磷酰胺、IFN、palmidronate、泼尼松、二膦酸盐、塞来昔布、三氧化砷、PEG INTRON-A、长春新碱或它们的联合形式相联合,向患有各种类型或阶段的多发性骨髓瘤的患者给药。
在另一个实施方案中,免疫调节性化合物与紫杉醇、卡铂、阿霉素、吉西他滨、顺铂、xeloda、紫杉醇、地塞米松或它们的联合形式相联合,向患有各种类型或阶段的卵巢癌诸如腹膜癌、乳头状浆液性癌、顽固性卵巢癌或复发性卵巢癌的患者给药。
在另一个实施方案中,免疫调节性化合物与xeloda、5 FU/LV、吉西他滨、依立替康+吉西他滨、环磷酰胺、长春新碱、地塞米松、GM-CSF、塞来昔布、紫杉特尔、更昔洛韦、紫杉醇、阿霉素、多西他赛、雌莫可汀、Emcyt或它们的联合形式相联合,向患有各种类型或阶段的前列腺癌的患者给药。
在另一个实施方案中,免疫调节性化合物与卡培他滨、IFN、他莫昔芬、IL-2、GM-CSF、Celebrex或它们的联合形式相联合,向患有各种类型或阶段肾细胞癌症的患者给药。
在另一个实施方案中,免疫调节性化合物与celebrex、依托泊苷、环磷酰胺、多西他赛、apecitabine、IFN、他莫昔芬、IL-2、GM-CSF或它们的联合形式相结合,向患有各种类型或阶段的实体瘤的患者给药。
在另一个实施方案中,免疫调节性化合物与celebrex、依托泊苷、环磷酰胺、多西他赛、apecitabine、IFN、他莫昔芬、IL-2、GM-CSF或它们的联合形式相联合,向患有硬皮病或表皮脉管炎的患者给药。
本发明还包括增加抗癌药物或试剂的剂量的方法,该试剂或药物可安全有效的向患者给药,该方法包括向患者(例如,人类)给予本发明免疫调节性化合物,或其可药用的衍生物、盐、溶剂化物、包合物、水合物或前药。可以从此方法中受益的患者是那些被副作用折磨的患者,这些患者的副作用是与治疗特定的皮肤癌、皮下组织癌、淋巴结癌、脑癌、肺癌、肝癌、骨癌、肠癌、结肠癌、心脏癌、胰脏癌、肾上腺癌、肾癌、前列腺癌、乳腺癌、结肠直肠癌或者它们的结合症的抗-癌药物相关联的。给予本发明免疫抑制性化合物能减缓或减轻严重的副作用,所述副作用是如此严重以致限制了抗癌药物的用量。
在一项实施方案中,本发明免疫调节性化合物可以约0.1至约150mg、优选约1至约50mg、更优选约2至约25mg的量在与抗-癌药物相关的副作用发生之前、之时或之后每日口服给予患者。在一特定的实施方案中,本发明免疫抑制性化合物与特定的试剂诸如肝素、阿司匹林、苄丙酮香豆素钠或G-CSF相结合,以避免与抗-癌药物相关的副作用,诸如,但不限于:中性粒细胞减少或血小板减少。
在一项实施方案中,本发明免疫调节性化合物可与附加的活性成分相结合,向患有与不希望的血管生长相关的、或以之为特征的疾病和病症的患者给药,附加的活性成分包括,但不限于:抗-癌药、抗-炎剂、抗组胺药、抗生素和甾类化合物。
在另一个实施方式中,本发明包括治疗、预防和/或控制癌症的方法,其包括与常规疗法相结合(例如,之间、之时或之后)给予本发明免疫调节性化合物或其可药用的盐、溶剂化物、水合物、立体异构体、包合物或前药;其中的常规疗法包括,但不限于:手术,免疫疗法,生物学疗法,放疗,或其它当前使用的用于治疗、预防或控制癌症的非-药物基础的疗法。本发明免疫调节性化合物和常规疗法的联合疗法可提供独特的、对于某些患者具有意想不到有效效果的治疗方案。在不被理论所束缚的情况下,我们相信本发明免疫调节性化合物当与常规疗法一同使用时,将可产生加成的和协同的效果。
如在此文中其它部分所讨论的,本发明包括减少、治疗和/或预防与常规疗法相关的不良的或不希望的作用的方法,这些常规疗法包括,但不限于:手术、化疗、放疗、激素疗法、生物学疗法和免疫疗法。一种或多种本发明免疫调节性化合物以及其它的活性成分可以在与常规疗法相关的副作用发生之前、之时或之后向患者给药。
在一项实施方式中,本发明免疫调节性化合物可以约0.1至约150mg、优选约1至约25mg、更优选约2至约10mg的量单独、或与此文中的第二活性试剂(参见,例如章节5.2)相结合,在常规疗法使用之前、之时或之后每日口服给药。
在一个特定的实施方式中,本发明免疫调节性化合物和doxetaxol向患有非-小细胞肺癌并接受过carbo/VP 16和放疗治疗的患者给药。
5.3.2与移植疗法的结合使用
本发明化合物可用于减少移植物对抗宿主疾病(GVHD)的危险。因此,本发明包括一种治疗、预防和/或控制癌症的方法,包括与移植疗法相结合,给予本发明免疫调节性化合物或其可药用的盐、溶剂化物、水合物、立体异构体、包合物或前药。
如本领域普通技术人员所熟知的,癌症的治疗通常以癌症的阶段和机理为基础而开展。例如在癌症的某一阶段,由于不可避免的白血病转化的发生,需要进行外周血液干细胞、造血干细胞制剂或骨髓的移植。本发明免疫调节性化合物和移植疗法的相联合的应用可提供独特的意想不到的协同作用。特别的,在患有癌症的患者中,本发明免疫调节性化合物与移植疗法一同使用时,具有加成的或协同的效果。
本发明免疫调节性化合物可与移植疗法联合作用,以减少与移植术侵入性操作相关的并发症和GVHD的发生危险。本发明包括一种治疗、预防和/或控制癌症的方法,该方法包括在脐带血、胎盘血、外周血液干细胞、造血干细胞制剂或骨髓移植之前、之时或之后,向患者(例如,人类)给予本发明免疫调节性化合物或其可药用的盐、溶剂化物、水合物、立体异构体、包合物或前药。适合本发明方法中使用的干细胞的例子公开于R.Hariri等人在2002年4月12日提交的美国临时专利申请60/372,348之中,其全部内容在此引入作为参考。
在此方法的一项实施方式中,在多发性骨髓瘤同源外周血祖细胞的移植之前、之时或之后,向患有实体瘤的患者给予本发明免疫调节性化合物。
在另一个实施方式中,干细胞移植之后,向患有复发性多发性骨髓瘤的患者给予免疫调节性化合物。
在另一个实施方式中,在同源干细胞的移植之后,向患有多发性骨髓瘤的患者给予作为维持疗法的免疫调节性化合物和泼尼松。
在另一个实施方式中,免疫调节性化合物和地塞米松作为低危险性移植后补救疗法,向患有多发性骨髓瘤的患者给药。
在另一个实施方式中,在同源骨髓移植之后,向患有多发性骨髓瘤的患者给予作为维持疗法的免疫调节性化合物和地塞米松。
在另一个实施方式中,在给予高剂量的美法仑和同源干细胞移植之后,向患有化疗敏感性多发性骨髓瘤的患者给予免疫调节性化合物。
在另一个实施方式中,在同源CD34-选择的外周干细胞移植之后,免疫调节性化合物和PEG INTRO-A作为维持疗法向患有多发性骨髓瘤的患者给药。
在另一个实施方式中,免疫调节性化合物与移植后突变化疗向患有新近诊断的多发性骨髓瘤的患者施用以评估抗-血管生成剂。
在另一个实施方式中,在高剂量的美法仑治疗和外周血液干细胞移植之后,作为DCEP实变之后的维持疗法,向患有多发性骨髓瘤的65岁或更老的老年患者给予免疫调节性化合物和地塞米松。
5.3.3循环疗法
在某些实施方案中,向患者循环给予本发明预防性或治疗性试剂。循环疗法涉及在一段时间内,在停止给药一段时间后再给予活性试剂,然后重复此给药顺序。循环疗法可减少对一种或多种疗法的耐药性的发展、避免或减少某种疗法的副作用、和/或提高治疗的功效。
因此,在本发明的一项实施方案中,本发明免疫抑制性化合物在4-6个星期(其中停止给药约1或2周)内,以单个或分开剂量每日给药。本发明进一步的允许增加频率、数量和给药循环时长。由此,当单独给药时,本发明另一个具体的实施方式包括比典型的更多次循环的给予本发明免疫抑制性化合物。在本发明另一项具体的实施方式中,本发明免疫抑制性化合物以可典型的引起患者剂量-限制性毒性的更多次的循环给药,且该患者没有给予第二活性成分。
在一项实施方案中,本发明免疫调节性化合物以约0.1至约150mg/d的量,每日且连续的给药3或4周随后中断1周或2周。ActimidTM优选的以最初剂量0.1-5mg/d的量每日且连续的给药,其中的剂量按1-10mg/d的比例(每周)上升至最大剂量为50mg/d,只要疗法是可耐受的。在一特定的实施方案中,RevimidTM在4或6周的循环中,以约5,10或25mg/天,优选以约10mg/天的量施用3-4周,随后停药1-2周。
在本发明的一个实施方案中,在4-6周的循环中,口服给予本发明免疫抑制性化合物和第二活性成分,其中,在给予第二活性成分之前30-60分钟,给予本发明免疫抑制性化合物。在本发明另一项实施方案中,本发明免疫抑制性化合物和第二活性成分的联合形式在每次循环内通过静脉输注而给药约90分钟。在一个特定的实施方案中,一个循环包括每日给予约10至约25mg/天的RevimidTM和约50至约200mg/m2/天的第二活性成分3-4周,然后停止给药1或2周。在另一项实施方案中,每个循环包括,给予约5至约10mg/天的Actimid TM和约50至约200mg/m2/天的第二活性成分3-4周,随后停药1-2周。典型的,给予患者联合疗法的循环数量为约1至约24个循环,更典型的为约2至约16个循环,更典型的为约4至约3个循环。
5.4药物组合物和剂型
药物组合物可用于制备个体的、单个单位剂量。本发明药物组合物和剂型包含本发明免疫调节性化合物或其可药用的盐、溶剂化物、水合物、立体异构体、包合物或前药。本发明药物组合物和剂型可进一步的包含一种或多种赋形剂。
本发明药物组合物和剂型也可含有一种或多种附加活性成分。因此,本发明药物组合物和剂型含有此文中所公开的活性成分(例如,免疫调节性化合物和第二活性成分)。任选的第二、或附加的活性成分的例子公开于此文中(参见,例如,5.2章节)。
本发明单个单位剂型适于口服、粘膜(例如、鼻部、舌下、阴道、颊腔或直肠)、肠胃外(例如,皮下、静脉内、快速浓注、肌内或动脉内)、局部(例如,滴眼剂或其它眼科制剂)、穿过表皮或经皮方式给予患者。剂型的例子包括,但不限于:片剂;囊片;胶囊,诸如软弹性明胶胶囊;扁囊剂;锭剂;糖锭剂;分散剂;栓剂;粉末;气溶剂(例如,鼻部喷雾剂或吸入剂);凝胶剂;适于口腔或粘膜给予患者的液体剂型,包括混悬液(例如,水性或非-水性液体混悬液、水包油乳液、或油包水液体乳液)、溶液剂和酏剂;适于向患者肠胃外给药的液体制剂;适于局部给药的滴眼剂或其它的眼科制剂;以及可重新配制以提供适于患者肠胃外给药的无菌固体(例如,结晶或无定型固体)。
本发明剂型的组成、形状和剂型类型典型的根据它们的用途而进行变化。例如,用于疾病的急性治疗的剂型与用于同种疾病慢性治疗的剂型相比,要含有更多量的一种或多种活性成分。相似的,肠胃外剂型与用于治疗相同疾病的口服疾病的剂型相比,要含更少量的一种或多种活性成分。将特定的剂型包含在本发明中的这些方法以及其它方法相互之间可以是不同的,这些技术对于本领域技术人员来说是显而易见的。参见,例如,Remington′s Pharmaceutical Sciences,18thed.,Mack Publishing,Easton PA(1990)。
典型的药物组合物和剂型含有一种或多种赋形剂。适宜的赋形剂对于药物领域的技术人员是公知的,在此给出了适宜赋形剂的非-限制性的例子。一个特定的赋形剂是否适合于掺入到药物组合物或剂型之中,取决于本领域公知的各种因素,这些因素包括,但不限于:剂型给予患者的途径;例如,口腔剂型,诸如片剂可含有不适于肠胃外剂型使用的赋形剂。特定赋形剂的适应性也可根据剂型中的特定活性成来确定。例如,某些活性成分可被赋形剂诸如乳糖、或被暴露于水分中而加速降解的进程。含有伯、仲胺的活性成分对于这些加速降解过程尤为敏感。因此,本发明所包括的药物组合物和剂型几乎不含、或者含极少量的乳糖和其它的单-或二-糖。如此文中所使用的,术语“不含乳糖”指的是如果含有乳糖,则所含乳糖的量基本不足以加速活性成分的降解速率。
本发明不含乳糖的组合物可含有本领域公知并列于例如美国药典(USP)25-NF20(2002)中的赋形剂。通常,不含乳糖的组合物含有药学可相容和可药用量的活性成分、粘合剂/填充剂、和润滑剂。优选的不含乳糖的剂型含有活性成分、微晶纤维素、预胶化淀粉和硬脂酸镁。
由于水可促进某些化合物的降解,本发明进一步的包括含活性成分的无水药物组合物和剂型。例如加入水(诸如,5%)在药物领域中被广泛的作为一种模拟长期储存的方法以测定制剂在一段时间内的一些性质,诸如贮存期和稳定性。参见,例如,Jens T.Carstensen,DrugStability:Principles & Practice,2d.Ed.,Marcel Dekker,NY,NY,1995,pp.379-80。事实上,水和热能加速某些化合物的降解。由此,水对制剂所产生的作用是非常重要的,因为水分和/或湿气在制剂的制造、操作、包装、储存、运输和使用中是经常会遇到的。
无水的本发明药物组合物和剂型可通过使用无水或低含水量的成分,在低含水量和低湿度的环境下而制备。如果预计到在制备、包装和/或贮存中会遇到水分和/或湿气,含有乳糖和至少一种含有伯胺或仲胺的活性成分的药物组合物和剂型优选是无水的。
无水药物组合物必需以保持其无水性质的方法制备和贮存。因此,无水的组合物优选的使用可预防药物暴露在水分中的材料包装,以使药物可置于适宜的试剂盒之中。适宜的包装的例子包括,但不限于:密封箔片、塑料、单剂量容器(例如,小瓶)、泡罩包装、以及管状包装。
本发明进一步的包含药物组合物和剂型,其中含有一种或多种可减慢其活性成分降解速率的化合物。所述化合物,指的是“稳定剂”包括,但不限于抗氧化剂诸如抗坏血酸、pH缓冲剂或缓冲盐。
和赋形剂的量和类型一样,剂型中的活性成分的量和特定类型根据一些因素而进行调整,这些因素诸如,但不限于:患者的给药途径。然而,本发明典型的剂型包括约0.10至约150mg的本发明免疫调节性化合物或其可药用的盐、溶剂化物、水合物、立体异构体、包合物或前药。典型的剂型包括约0.1、1、2、5、7.5、10、12.5、15、17.5、20、25、50、100、150或200mg的本发明免疫调节性化合物或可药用的盐、溶剂化物、水合物、立体异构体、包合物或前药。在一特定的实施方案中,一个优选的剂型含有约1、2、5、10、25或50mg的4-(氨基)-2-(2,6-二氧代(3-哌啶基))-异二氢吲哚-1,3-二酮(ActimidTM)。在一个特定的实施方案中,优选的剂型含有约5、10、25或50mg的3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(RevimidTM)。典型的剂型含有1至约1000mg、约5至约500mg、约10至约350mg、约50至约200mg的第二活性成分。当然,特定量的抗癌药物将根据所使用的特定试剂、所需治疗或控制的癌症的类型、本发明免疫调节性化合物的量、和任何任选的同时给予患者的附加活性试剂来确定。
5.4.1口服剂型
适于口腔给药的本发明药物组合物可以不连续的剂型形式诸如,但不限于片剂(诸如,咀嚼片)、囊片、胶囊和液体制剂(例如,矫味糖浆)的形式提供。所述剂型含有预定量的活性成分,并且可以按照本领域公知的药物方法制备。通常参见,Remington′s PharmaceuticalSciences,18th ed.,Mack Publishing,Easton PA(1990)。
本发明典型的口服剂型根据常规的药物化合物技术,通过在混合物中将活性成分与至少一种赋形剂相结合而制备。可根据所需给予的制剂的形式来确定赋形剂的各种广泛的形式。例如,适于口服液体或气溶剂剂型的赋形剂包括,但不限于:水、甘油、油、醇、矫味剂、防腐剂和着色剂。适用于固体口服剂型(例如,粉末、片剂、胶囊和囊片)的赋形剂包括,但不限于:淀粉,糖,微晶纤维素、稀释剂、制粒剂、润滑剂、粘合剂和崩解剂。
片剂和囊片由于其易于给药,因此它们是最有利的使用固体赋形剂的口服剂型单位形式的代表。如有需要,片剂可通过标准的水性或非-水性技术进行包衣。所述剂型可用通过任一药物方法来制备。通常,药物组合物和剂型可通过均匀、密切的将活性成分与液体载体、细碎分离的固体载体、或两者的结合一同混合,然后,如有需要,将产品塑成所需的制剂形式。
例如,片剂可以通过压制或铸形而制备。压制片剂可以通过在适宜机械中,将以随意流动的形式诸如粉末或颗粒存在的活性成分,任选的与赋形剂相混合后压片。铸形片剂可以通过在适宜的机械中,将粉末化的用惰性液体稀释剂湿润后的化合物进行塑形而制得。
可用于本发明口服剂型中的赋形剂的例子包括,但不限于:粘含剂、填充剂、崩解剂和润滑剂。适用于药物组合物和剂型的粘合剂包括,但不限于:玉米淀粉、土豆淀粉、或其它淀粉、明胶、天然和人工合成胶诸如阿拉伯胶、海藻酸钠、海藻酸、其它藻酸盐、粉末状黄蓍胶、瓜尔胶、纤维素及其衍生物(例如,乙基纤维素、纤维素醋酸酯、羧甲基纤维素钙、羧甲基纤维素钠)、聚乙烯吡咯烷酮、甲基纤维素、预胶化淀粉、羟丙甲基纤维素(例如,2208、2906、2910号)、微晶纤维素、以及它们的混合物。
适宜的微晶纤维素的类型包括,但不限于:以AVICEL-PH-101、AVICEL-PH-103 AVICEL RC-581、AVI CEL-PH-105(可购自FMC公司American Viscose Division,Avicel Sales,Marcus Hook,PA)销售的产品、以及它们的混合物。一种特定的粘合剂是微晶纤维素和羧甲基纤维素钠的混合物(以AVICEL RC-581出售)。适宜的无水的低水分的赋形剂或添加剂包括AVICEL-PH-103TM和淀粉1500LM。
此处所公开的适用于药物组合物和剂型的填充剂的例子包括,但不限于:滑石、碳酸钙(例如,颗粒或粉末)、微晶纤维素、粉末纤维素、dextrates、高岭土、甘露醇、硅酸、山梨醇、淀粉、预胶化淀粉、以及它们的混合物。本发明药物组合物中的粘合剂或填充剂典型的占药物组合物或剂型的约50至约99重量%。
在本发明组合物中使用崩解剂以使片剂在水性环境中崩解。含有太多崩解剂的片剂会在贮存期间发生崩解,而如果含太少的崩解剂,则在所需环境下无法按照所需的速度发生崩解。由此,可用于调整活性成分的释放的,不太多也不太少的有效量的崩解剂可用于本发明固体口服剂型的制备。崩解剂的量根据制剂的类型而改变,并且这种改变对于本领域普通技术人员来说是显而易见的。典型的药物组合物含有约0.5至约15重量%的崩解剂,优选约1至约5重量%的崩解剂。
可用于本发明药物组合物和剂型的崩解剂包括,但不限于:琼脂、褐藻酸、碳酸钙、微晶纤维素、交联羧甲基纤维素钠、交联聚维酮、polacrilin钾、羟乙酸淀粉钠、土豆或木薯淀粉、或其他的淀粉、预胶化淀粉、其它淀粉、粘土、其它的藻胶、其它的纤维素、胶类、以及它们的混合物。
可用于本发明药物组合物和剂型中润滑剂包括,但不限于:硬脂酸钙、硬脂酸镁,矿物油,轻质矿物油,甘油,山梨醇,甘露醇,聚乙二醇,其它二元醇,硬脂酸,月桂基硫酸钠,滑石,氢化植物油(例如,花生油,棉籽油,向日葵油,芝麻油,橄榄油,玉米油,和大豆油),硬脂酸锌,油酸乙酯,月桂酸乙酯,琼脂、以及它们的混合物。附加的润滑剂包括,例如硅酸盐硅胶(AEROSIL200,由W.R.Grace Co.of Baltimore,MD制造)、合成硅石的凝固气溶胶(由Degussa Co.of Plano,TX销售)、CAB-O-SIL(一种热解二氧化硅产品,由Cabot Co.of Boston,MA销售)、以及它们的混合物。如果使用,润滑剂的量低于含有它本身的药物组合物或剂型的约1重量%。
一种优选的本发明固体口服剂型含有本发明免疫抑制性化合物、无水的乳糖、微晶纤维素、聚乙烯吡咯烷酮、硬脂酸、无水胶体硅石和明胶。
5.4.2缓释剂型
本发明活性成分可以通过本领域普通技术人员非常公知的控释方式、或通给药系统来给予。这些例子包括,但不限于:记载于美国专利号US 3,845,770、3,916,899、3,536,809、3,598,123、和4,008,719、5,674,533、5,059,595、5,591,767、5,120,548、5,073,543、5,639,476、5,354,556和5,733,566中的内容,每一文献在此引入作为参考。所述剂型可用于提供慢速或控速释放一种或多种活性成分,使用例如羟丙基甲基纤维素、其它的聚合物基质、凝胶、渗透膜、渗透系统、多层包衣、微粒、脂质体、微球或它们的联合形式以不同的比例提供所需的释放性质。本领域普通技术人员公知的适宜的控释制剂,包括那些在此描述的制剂,可以容易选择以用于本发明活性成分。本发明因此包含适于口腔给药的单个单位剂型,诸如,但不限于:适于控制释放的片剂、胶囊、软胶囊和囊片。
所有控释药物产品的共同目标是比其非-控释的相应产品具有更为提高的药物疗效。理想的,最佳设计的控释制剂在医学治疗中的特点是:最小量的药物在最短的时间内用于治疗或控制病况。控释制剂的优点包括药物的活性时间延长、给药频率减少、患者顺应性增加。此外,控释制剂可用于影响发生作用的时间或其它性质,诸如药物的血液浓度,由此可影响副(如,不利的)作用的发生。
大部分控释制剂设计成具有最初的药物(活性成分)的释放量,以快速的产生所需的治疗效果,并逐渐连续的释放药物的其它量以在一段延长的时间内维持治疗性或预防性效果。为了维持药物在体内的恒定水平,药物必需以一定的速度从剂型中释放出来以替代药物在体内被代谢和排泌的量。活性成分的控制释放可以被各种不同的情况而受到刺激,这些情况包括,但不限于:pH、温度、酶、水、或其它的生理条件或化合物。
5.4.3肠胃外制剂
肠胃外剂型可以通过各种途径向患者给予,这些途径包括,但不限于:皮下、静脉内(包括快速浓注)、肌内和动脉内。由于这些给药方法典型的绕过了患者的天然对抗外物的屏障,因此肠胃外剂型优选的是无菌的,或者在向患者给药之前进行消毒。肠胃外剂型的例子包括,但不限于:可立即注射的溶液、可立即溶解或混悬在可药用的注射载体中的干燥产品、可立即注射的混悬液、和乳液。
可用于提供本发明肠胃外剂型的适宜的载体对于本领域技术人员是公知的。这些例子包括,但不限于:注射用水USP;水性载体诸如,但不限于:氯化钠注射液、Ringer′s注射液、葡萄糖注射液、葡萄糖和氯化钠注射液和乳酸化Ringer′s注射液;易于水混合的载体,诸如,但不限于:乙醇、聚乙二醇和聚丙二醇;和非-水性载体,诸如,但不限于:玉米油、棉籽油、花生油、芝麻油、油酸乙酯、肉豆蔻酸异丙酯和苯甲酸苄酯。
此文中所公开的,可增加一种或多种活性成分的溶解度的化合物可加入到本发明肠胃外剂型之中。这些化合物例如环糊精及其衍生物可用于增加本发明免疫调节性化合物及其衍生物的溶解度。参见,例如,美国专利号US 5,134,127,此文在此引入作为参考。
5.4.4局部和粘膜剂型
本发明局部和粘膜剂型包括,但不限于:喷雾剂、气溶剂、溶液、乳液、混悬液、滴眼剂或其他的眼科制剂、或其它本领域技术人员公知的形式。参见,例如,Remington′s Pharmaceutical Sciences,16thand 18th eds.,Mack Publishing,Easton PA(1980 & 1990);以及Introduction to Pharmaceutical dosage forms,4tb ed.,Lea &Febiger,Philadelphia(1985)。适于在口腔内治疗粘膜组织疾病的剂型可制成漱口剂或口腔凝胶的形式。
本发明中所包括的可用于提供局部和粘膜剂型的适宜的赋形剂(例如,载体和稀释剂)以及其它的物料对于药物领域技术人员是公知的,并且根据给定药物组合物或剂型所施用的特定组织来确定使用。根据这个概念,使用典型的赋形剂包括,但不限于:水、丙酮、乙醇、乙二醇、丙二醇、丁-1,3-二醇、肉豆蔻酸异丙酯、棕榈酸异并酯、矿物油、以及它们的混合物以制备形成无毒且可药用的溶液、乳液或凝胶剂。如有需要,也可向药物组合物和剂型中加入湿润剂或保湿剂。所述附加成分的例子在本领域是公知的。参见,例如,Remington′sPharmaceutical Sciences,16th and 18th eds.,MackPublishing,Easton PA(1980 & 1990)。
药物组合物或剂型的pH也可进行调节以改进一种或多种活性成分的转运。相似的,溶剂载体的极性、离子强度、或张力都可以进行调节以改进药物转运。化合物,诸如硬脂酸盐可加入到药物组合物或剂型之中以有利的改变一种或多种活性成分的亲水性或亲脂性,以改进药物转运。据此,硬脂酸盐可作为制剂的脂肪载体、乳化剂或表面活性剂使用,并作为一种转运-促进或渗透-促进剂使用。活性成分的不同的盐、水合物或溶剂化物可进一步的用于调节所得组合物的性质。
5.4.5试剂盒
典型的,本发明活性成分优选的不在相同的时间、和不以相同的途径给予患者。本发明因此包括一种试剂盒,当其被医生使用时,可以简化将适宜量的活性成分向患者给药的操作。
本发明典型的试剂盒包括本发明免疫调节性化合物或其可药用的盐、溶剂化物、水合物、立体异构体、前药或包合物的剂型。本发明所包括的试剂盒可进一步的含有附加的活性成分诸如oblimersen(Genasense)、美法仑、G-CSF、GM-CSF、EPO、拓普替康、达卡巴嗪、依立替康、紫杉特尔、IFN、COX-2抑制剂、己酮可可碱、环丙沙星、地塞米松、IL2、IL8、IL18、Ara-C、长春瑞滨、异维甲酸、13顺式维生素A酸、或它们的药理学活性变体或衍生物或它们的联合形式。附加活性成分的例子包括,但不限于公开于此文中的化合物(参见,例如,5.2章节)。
本发明的试剂盒可进一步的包含用于给予活性成分的装置。所述装置的例子包括,但不限于:注射器、滴注袋、贴片和吸入器。
本发明试剂盒可进一步的含有用于移植的细胞或血液,以及可用于一种或多种活性成分的给药的可药用的载体。例如,如果活性成分以可重新配制成肠胃外给药的固体剂型的形式提供,则该试剂盒中可含有适宜载体的密封容器,活性成分在该载体中溶解以形成适于肠胃外给药的、不含颗粒的无菌溶液。可药用的载体包括,但不限于:注射用水USP;水性载体诸如,但不限于:氯化钠注射液、Ringer’s注射液、葡萄糖注射液、葡萄糖和氯化钠注射液以及乳酸盐的Ringer′s注射液;可与水混溶的载体,诸如,但不限于:乙醇、聚乙二醇和聚丙二醇;以及非水性载体,诸如,但不限于:玉米油、棉籽油、花生油、芝麻油、油酸乙酯、肉豆蔻酸异丙酯和苯甲酸苄酯。
6.实施例
本发明的某项实施方案通过以下非-限制性实施例进行举例说明。
6.1细胞因子生产的调节
实施一系列的非-临床学药理学和毒理学研究以支持本发明免疫调节性化合物在人类对象中的临床评估。除非另有说明,这些研究根据国际公认的用于指导研究设计的指南、并且符合良好实验室操作规范(GLP)的要求而进行。
研究4-(氨基)-2-(2,6-二氧代(3-哌啶基))-异二氢吲哚-1,3-二酮(ActimidTM)、3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮和沙利度胺(RevimidTM)在体外对人PBMC和人类全血的LPS-刺激之后的TNF-α生成的抑制(Muller等,Bioorg.Med.Chem.Lett.9:1625-1630,1999)。4-(氨基)-2-(2,6-二氧代(3-哌啶基))-异二氢吲哚-1,3-二酮对PBMC和人类全血LPS-刺激之后的TNF-α生成的抑制的IC50分别为~24nM(6.55ng/mL)和~25nM(6.83ng/mL)。体外研究显示3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮的药理学活性与沙利度胺相似,但是至少为其的200倍更强。体外研究还证实浓度为2.73-27.3ng/mL(0.01-0.1uM)的4-(氨基)-2-(2,6-二氧代(3-哌啶基))-异二氢吲哚-1,3-二酮能对MM.1s和Hs Sultan细胞增殖的产生50%的抑制。
3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮对PBMC和人类全血LPS-刺激之后的TNF-α生成的抑制的IC50分别为~100nM(25.9ng/mL)和~480nM(103.6ng/mL)。相比之下,沙利度胺对在PBMC LPS-刺激之后的TNF-α生成的抑制IC50为~194μM(50.2μg/mL)。体外研究显示3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮的药理活性与沙利度胺相似,但是比沙利度胺高出50-2000倍。研究显示,对于通过T-细胞受体(TCR)活化初始诱导刺激的T-细胞的增殖,该化合物比沙利度胺高出约50-100倍。3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮对在PBMC(IL-2)或T-细胞(IFN-γ)的TCR活化之后的IL-2和IFN-γ增殖的扩大的作用,约为沙利度胺的50-100倍。此外,3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮显示了在增加抗-炎性细胞因子IL-10产生的情况下对LPS-刺激的由PBMC导致的前-炎性细胞因子TNF-α、IL-1β和IL-6的生成的剂量-依赖型的抑制。
6.2MM细胞增殖的抑制
在一项体外研究中研究3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(RevimidTM)和沙利度胺对多发性骨髓瘤(MM)细胞系增殖的的影响能力的比较。测定不同MM细胞系(MM.1S、Hs Sultan、U266和RPMI-8226)的[3H]-胸腺嘧啶脱氧核苷的摄取作为细胞增殖的指示。细胞在化合物存在的情况下温孵48小时;在温孵期的最后8小时,引入[3H]-胸腺嘧啶脱氧核苷。分别向MM.1S和Hs Sultan细胞中加入0.4μm和1μm的3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮可获得50%的对细胞增殖的抑制。作为对照,加入高至100μm的沙利度胺仅能得到MM.1S和Hs Sultan细胞分别为15%和20%的抑制。这些数据概括在图1之中。
6.3毒理学研究
在麻醉狗中观察3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(RevimidTM)对心血管和呼吸功能的作用。使用两组(2/性别/组)Beagle狗。一组只接受三种剂量的载体,另一组接受三种上升剂量的3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(2、10和20mg/kg)。在所有试验中,3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮或载体的剂量相继并间隔至少30分钟通过颈动脉输注而给予试验狗。
所有剂量的3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮对心血管和呼吸功能的影响,与载体对照组相比,差别都很小。载体组和给药组唯一显著的差别是:在给予了低剂量的3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮之后,动脉血压有微弱的上升(从94mmHg上升至101mmHg)。该现象持续了约15分钟;并且在较高剂量的给药中没有出现该现象。大腿血流、呼吸参数和Qtc间隔中的偏差对于对照组和治疗组来说都是普遍存在的,并且不被认为是与治疗-相关的。
6.4给予患者的循环疗法
在一个特定的实施方案中,本发明免疫调节性化合物循环给予患有癌症的患者。循环疗法涉及先在一段时间内给予第一试剂,然后停药一段时间,然后再次重复之前连续的给药。循环疗法可减少对一种或多种疗法的抗药性、避免或减少其中一种疗法的副作用、和/或改进治疗效果。
在一个特定的实施方案中,预防性或治疗性试剂以约4-6周的一个循环给药,约每日1或2次。一个循环可包含给予治疗性或预防性试剂3-4周、以及停药至少1或2周。给药循环可以是1个至24个循环,更典型的是约2个至至约16个循环,更为优选的是约4个至约8个循环。
例如,在一个4周的循环疗法中,第一天,给予25mg/d的3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮作为起始。在第22天停止给予化合物1周作为中断。在第29天,再开始给予25mg/d的3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮。
6.5患者的临床研究
6.5.1复发性多发性骨髓瘤的治疗
向患有复发性/顽固性多发性骨髓瘤的患者给药4-(氨基)-2-(2,6-二氧代(3-哌啶基))-异二氢吲哚-1,3-二酮(ActimidTM)。按照良好临床操作规范(GCP)要求进行研究。患者至少为18岁,并被诊断患有多发性骨髓瘤(血清和/或尿中有病变蛋白),并在至少两个循环治疗后被认为是有抗性的、或者在至少两个循环治疗后再次复发。
根据Southwest Oncology Group(SWOG)标准,在患者前期治疗之中仍发生进行性疾病的患者被认为是治疗顽固性(抵抗性)的。病情减缓后的复发被定义为:M组分从基线水平开始增加>25%;之前消失的M病变蛋白重新出现;在放射照片中所辨识到的溶解性骨损伤的大小和数量都有明显的增加。患者可在之前先用沙利度胺治疗,使得患者对治疗具有耐受性。所有患者需要具有0-2的Zubrod体力状态。
4-(氨基)-2-(2,6-二氧代(3-哌啶基))-异二氢吲哚-1,3-二酮以1、2、5或10mg/天的剂量给予患者,持续至多4周;在每种剂量水平中,最初都有3名患者参加;每天早晨大约相同的时间给药,所有的剂量都在患者禁食状态(在给药之前和之后至少2小时不吃东西)给予。4-(氨基)-2-(2,6-二氧代(3-哌啶基))-异二氢吲哚-1,3-二酮的各种剂量以上升模式给药,这样使得开始阶段的患者获得最低剂量的4-(氨基)-2-(2,6-二氧代(3-哌啶基))-异二氢吲哚-1,3-二酮(1mg/天),当现行剂量的安全性和耐受性确立之后再增加至下一个较高的剂量水平。如果三人中有一人在任何剂量水平下出现剂量最大容许毒性(DLT),那么另外的三个患者将被加入到所述剂量级别中。如果后来的三个人中没有人出现DLT,则再将剂量升至下一个较高的剂量;然后以相同的方式增加剂量直至到达MTD水平或达到最大每日剂量(10mg/天)。然而,如果三个后来的患者中出现了DLT,就认为是到达了MTD水平。如果另外三个患者中有两个或更多的人出现DLT,MTD被认为是过量,并将三个另外的患者参加到前一个剂量水平中以确定MTD的水平。一旦MTD被确定,4个另外的患者参加到该剂量水平中,这样,总共10位患者以MTD剂量进行治疗。
在第1和第8天,根据以下采血表采取血样用于分析药代动力学参数:给药前、给药后0.25、0.5、0.75、1、1.5、2、2.5、3、4、6、8、10、12、18和24小时。在每周收集附加血样用于确定4-(氨基)-2-(2,6-二氧代(3-哌啶基))-异二氢吲哚-1,3-二酮水平。根据以下给药后的时间间隔,用尿盒收集总尿液:0至4、4至8、8至12、和12至24小时。通过在研究期间的特定时间内监测副作用、生命征象、ECGs、临床试验评价(血液化学、血液学、淋巴细胞表现型和尿分析)和物理检查,确定试验的安全性。
向患有多发性骨髓瘤的患者给予单-和多-剂量的4-(氨基)-2-(2,6-二氧代(3-哌啶基))-异二氢吲哚-1,3-二酮之后得到的中间的药代动力学分析结果记录在表1和表2中。数据显示,4-(氨基)-2-(2,6-二氧代(3-哌啶基))~异二氢吲哚-1,3-二酮在复发性多发性骨髓瘤患者中在所有的剂量水平下都有稳定的吸收。在第1天的给药后2.5和2.8小时之间、以及在第4周给药后3-4小时之间的中值Tmax点处获得最大血浆浓度。在到达Cmax之后,所有的剂量、血浆浓度以单相方式下降。消除相分别开始于第1天和第4周的给药后3-10小时之间。
这些数据还表明,在给药4周之后,4-(氨基)-2-(2,6-二氧代(3-哌啶基))-异二氢吲哚-1,3-二酮蓄积到了一定的微小程度(Cmax的平均蓄积率为~1.02至1.52,AUC(0-t)的平均蓄积率为~0.94至1.62)。AUC(0-t)和Cmax随着剂量的增加,基本上成比例性的增加。给予5倍以上的4-(氨基)-2-(2,6-二氧代(3-哌啶基))-异二氢吲哚-1,3-二酮剂量可在第1天和第4周分别产生3.2~和2.2~倍的Cmax。相似的,剂量增加5倍,第1天和第4周的AUC(0-t)分别增加至3.6~和2.3~倍。
表1
t=24小时 N/A=不可得
表2
多剂量口服给药ActimidTM后(1、2和5mg/天)的复发性多发性骨髓瘤患者中的药代动力学参数
τ=24小时
N/A=不可得
*N=3个患者
6.5.2 T复发性多发性骨髓瘤的治疗
进行3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(RevimidTM)的二期1临床研究以确定患顽固性或复发性多发性骨髓瘤患者中的最大耐受剂量(MTD)。当口服给予上升性剂量的3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮长达4周时,这些研究还可确定3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮的安全特征。最初以5mg/天的剂量给予3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮的患者随后按比例将剂量上升至10、25和50mg/天。在28天内记录患者的指定剂量,那些疾病没有加深或者没有出现剂量最大容许毒性(DLT)的患者可选择扩大治疗。在每一观察点评估患者的副作用,并根据国立癌症研究院(NCI)通用毒性标准(National Cancer Institute(NCI)Common ToxicityCriteria)给这些副作用现象分级。如果患者出现DLT(3级或更高级别的非-血液性毒性、或4级血液性毒性),则需要终止治疗。
在此研究中,有27位患者参与。所有的患者患有复发性多发性骨髓瘤,且18(72%)位对补救疗法具有抗药性。在这些患者中,15位曾经接受了自体干细胞移植,16位曾接受沙利度胺的治疗。先前治疗方案的平均数为3(2至6种)。
在第1天和第28天,采集血样和尿样用于分析药代动力学参数。根据以下采样时间表,采集血样:给药前、给药后0.25、0.5、0.75、1、1.5、2、2.5、3、4、6、8、10、12、18和24小时。此外,在每周的临床访问时采取血样以确定3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮的水平。根据以下给药后的时间间隔采集并混合总尿液;0至4、4至8、8至12、12至24小时。通过对血清和24-小时收集的尿液的M-蛋白定量法(通过免疫电泳法),同时在筛选、基线、第2和4周、以及此后每月(或在早期的终止时期)计算肌酸肝清除率和24-小时的蛋白来测定患者对治疗的应答情况。以最佳应答标准为基础,如果患者异型蛋白的血清浓度或24-小时尿蛋白分泌降至下一个较低的水平,则还需在第3、6和12月实施骨髓穿刺和/或组织检查。28-天治疗期的初步结果概括如下。
基于上述两项研究的初步药代动力学分析显示,多发性骨髓瘤患者(如健康志愿者中所见的)的AUC和Cmax值随着单-和多-剂量发生比例性的增加。进而,在给予相同剂量的3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮之后,当单剂量的AUC(0-∞)和多剂量的AUC(0-τ)相比较时,没有证据显示多剂量给药中产生了蓄积现象。与健康志愿者的研究情况相似,研究中观察到了双峰。以Cmax和AUC值的为基础,多发性骨髓瘤患者的暴露要轻微的高于健康男性志愿者,而清除率则低于健康志愿者,这种现象也与患者的肾脏机能较差(也是患者年龄和疾病的结果)相-致。最后,3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮在患者体内的半衰期(平均8小时,最高范围17小时)要短于健康志愿者。
在此研究中,第一组3个患者以5mg/天的剂量治疗28天,而没有任何的剂量最大容许毒性(DLT)出现。第二组的3个患者随后以10mg/天的剂量开始治疗。在给予第二个10mg/天剂量的3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮的患者中,获得了很好的耐受性。
6.5.3实体瘤的治疗
在患有各种类型的实体瘤的患者中进行3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(RevimidTM)的研究,这些实体瘤包括恶性黑色素瘤(13)、胰腺癌(2)、未知原因的原发性良性肿瘤(1)、肾癌(1)、乳腺癌(1)和NSCLC(2)。患者接受5mg/天剂量的3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮共计7天,然后每7天增加至10mg/天、25mg/天和50mg/天,总共持续4周的治疗。如果患者获得了有利的临床效果,则允许其接着作为记名患者(Named Patients)进行治疗。
该研究起初招募到20位患者,随后增加16名附加患者(肾上腺癌、NSCLC、恶性间皮细胞癌、乳腺癌、恶性黑色素瘤(8)、肾细胞癌(4)),研究为高剂量。16名附加患者给予每周增加的剂量25mg/天、50mg/天、75mg/天、100mg/天、125mg/天和150mg/天持续6周的时间,并在之后再附加治疗6周。
1期研究被设计成确定3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮在顽固性实体瘤和/或淋巴瘤患者中的最大耐受剂量(MTD),同时确定3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮在患者中的药代动力学性质和副作用特性。研究设计显示,在患者接受下一个更高的剂量之前,必需有至少3名患者在该剂量下完成2 8天的治疗。第一组的患者3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮的起始剂量为5mg/天。只要没有毒性,患者的剂量将增加至10、20、25和30mg/天。
在此研究中,MTD被定义成这样一种最高剂量:在该剂量下,6名接受治疗的患者中有少于2名患者没有出现3级或更严重的非-血液性毒性、或4级或更严重的血液性毒性。如果在任一试验的任一给定剂量中,三名中有一名患者出现了毒性,则三名附加患者必需接受这一特定剂量的治疗。如果,6名中有2名患者出现了DLT,则认为该剂量超过了MTD。不再进一步增加剂量,附加的患者均加入到以前的剂量水平。3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮的剂量持续升高,直至到达MTD,或到达最高每日剂量。
在试验最初组的20位患者中,没有报告出现DLTs。在最初的20位试验患者中的13位患者,以及2位非-试验患者,接着作为记名患者以高至150mg/天的剂量接受治疗。
6.5.4神经胶质瘤的治疗
实施该试验以确定化合物对患复发性、重度神经胶质瘤患者的毒性。该试验被设计成患者被给予持续升高性剂量的3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮直至到达建立起最大耐受剂量(MTD)。该研究还将确定3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮的初期毒性信息和药代动力学数据,同时,使用体内机能性神经影像研究和体外血清血管形成肽测定建立与体内血管生成的替代末端(surrogate end point)相关的探索性数据。
第一组的患者接受2.5mg/m2/天的剂量,并持续4-周的循环。在每一个4-周的循环治疗中,3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮每天给药一次,持续3周,之后停药1周。如果符合以下两个标准,完成了1个治疗循环的患者可进行另一个3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮的治疗循环:首先,患者必需病况稳定,或者经历了部分或全部的应答,或者根据肿瘤-相关的症状诸如神经性损伤的减少的现象证实,患者从3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮的治疗中获得了有益的效果。其次,根据患者的毒性水平小于1级的证据显示,患者从最初的循环中所发生的与3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮相关的毒性中,经过42天或更短的时间(28-天循环+2周康复时间)就恢复过来。对于在最初的循环中出现了DLT的患者,必需调整他们的剂量。DLT被定义成:被认为需要进行研究治疗的非-血液性情况的级别>3级毒性或血液性情况的毒性位4级的情况。在第一个循环中出现DLT,并且对疗法没有产生应答的患者,必需取消他的试验。
3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮的剂量随后增加至5、8、11、15和20mg/m2/天,直至最高总每日剂量40mg。患者持续在每一剂量水平接受3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮的4-周循环治疗,直至满足了停止试验标准中的任一条标准。
在每组中招募到3位患者。如果只有一位出现了DLT,在该特定剂量水平下,向该组中加入3个后加的患者。如果两个患者出现了DLTs,MTD(被定义为:在此剂量下,每一剂量水平有少于1/3的患者出现了DLT)被超出,并且在先前的剂量下需要对4个以上的患者进行治疗。
在第一个4-周的循环治疗中,出现了DLT的患者必需停止试验,除非他们对治疗发生了应答效果。对于那些完成了第一个4-周治疗且没有出现DLT,但是随后出现了3级或4级血液性和/或非血液性毒性的患者,需要终止试验最少1周。如果在3周之内毒性缓解至<2级,患者以低于导致毒性的剂量两个水平的剂量(或者如果患者以第一或第二剂量水平进行治疗,剂量需减少50%)进行治疗。那些在3周之内,3级或4级毒性没有缓解至<1级的患者,或者那些在降低的剂量下产生其它的3级毒性的患者,必需停止试验。
在给予3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(1天)第一个剂量之前以及之后的0.5、1、2、4、6、8、24和48小时,采集药代动力学样本。采样也可在第7、21天的给药前和第21天给药后第0.5、1、2、4、6、8和24小时进行,以评估稳定-状态的3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮水平。
6.5.5转移性黑素瘤的治疗
患有转移性黑素瘤的患者开始以5mg/天的剂量给予3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(RevmidTM),持续7天。然后,剂量每7天分别增加至10mg/天、25mg/天和50mg/天,持续总共为4周的疗程。在此疗法下,在第一个4周的治疗中,13个黑素瘤患者中的5个显示了疾病的的稳定化,或显示了部分的应答。在表皮和皮下损伤(5位患者)、淋巴节(2位患者)和肝脏(1位患者)中观察到了肿瘤应答。应答的持续时间约为6个月。结果显示,本发明化合物是有希望的新抗癌试剂,并且同时具有抗血管生成和免疫调节性质。
6.5.6复发性或顽固性多发性骨髓瘤的治疗
曾接受至少三种疗法但都没有效果、并且身体状况很差、中性粒细胞减少或血小板减少的,患有复发性和顽固性Dune-Salmon III期多发性骨髓瘤的患者,每4-6个星期用美法仑(50mg静脉给药)、本发明免疫调节性化合物(约1-150mg每日口服给药)和地塞米松(40mg/天,在第1-4天口服给药)的联合形式进行给药治疗,至多4个循环。接下来给予由每日给予本发明免疫调节性化合物并口服地塞米松组成的维持疗法直至疾病被抑制。本发明免疫调节性化合物的给药与美法仑和地塞米松的给药相结合的疗法,活性很高且在预治疗的重症多发性骨髓瘤患者中得到了很好的耐受,如若不然,其预后结果将非常糟糕。
上文所述的本发明的实施方案仅为示例性的,任何本领域技术人员都可以认识到或者可以确定无数的特定化合物、材料和操作的等价物,而不需要进行超出常规的试验。所有这些等价物都是在本发明范围之内的,并且被权利要求所包含。
Claims (5)
1.化合物3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮或其可药用的盐、溶剂化物或立体异构体在制备用于和地塞米松联合治疗多发性骨髓瘤的药物或试剂盒中的用途。
2.权利要求1的用途,其中的化合物在给予地塞米松之前、期间或之后给予。
3.权利要求1的用途,其中的化合物以28天的循环在每循环的第1-21天每天给予25mg一次,地塞米松以28天的循环在开始的4个循环的每个循环的第1-4、9-12和17-20天每天给予40mg一次,然后在该开始的4个循环后,在28天的循环的每循环的第1-4天每天给予40mg一次。
4.权利要求1的用途,其中的化合物以28天的循环在每循环的第1-21天每天给予25mg一次,地塞米松以28天的循环在每个循环的第1、8、15和22天每天给予40mg一次。
5.权利要求1的用途,其中的化合物以15mg的量每天给予两次。
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