CN104136428A - 用于抑制bcl2与结合配偶体相互作用的化合物 - Google Patents
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- CN104136428A CN104136428A CN201280070470.4A CN201280070470A CN104136428A CN 104136428 A CN104136428 A CN 104136428A CN 201280070470 A CN201280070470 A CN 201280070470A CN 104136428 A CN104136428 A CN 104136428A
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及其中R1、R2、R3和R4如发明概述中所定义的式I化合物。式I的化合物能破坏BCL-2与包含BH3结构域的蛋白的相互作用。破坏这种相互作用可恢复表达BCL-2的癌细胞和肿瘤组织中BCL-2的抗细胞凋亡功能。本发明进一步提供了一种制备本发明化合物的方法、包含该类化合物的药物制剂和用该类化合物治疗癌性疾病的方法。
Description
相关申请的交叉参考
本申请要求于2011年12月23日申请的临时专利申请号为61/579740的美国专利申请的优先权。该申请的全部公开内容都被引入本文作为参考且用于所有目的。
背景
发明领域
本发明涉及能破坏BCL-2与包含BH3结构域的蛋白的相互作用的化合物。破坏这种相互作用有可能恢复表达BCL-2的癌细胞和肿瘤组织中BCL-2的抗细胞凋亡功能。本发明进一步提供了一种制备本发明化合物的方法、包含该类化合物的药物制剂以及用该类化合物来治疗癌症的方法。
发明背景
细胞凋亡或编程性细胞死亡对于正常胚胎学或解剖学上的发育、宿主防御以及肿瘤生成的抑制都很重要。在癌症和由细胞分裂和细胞死亡过程间的失衡导致的许多其它人类疾病中,都涉及细胞凋亡的错误调节。BCL-2属于调控细胞凋亡的蛋白家族。BCL-2通过阻止由生理性细胞死亡机理造成的正常细胞更新来促进癌细胞发展。
BCL-2蛋白的表达水平与对广谱化疗药和γ-放疗的耐受性相关。已经在许多形式的癌症中观察到了BCL-2的过度表达。已经在癌症中观察到了下面的过度表达百分比:在前列腺癌中20-40%;在激素耐受性前列腺癌中80-100%;在乳癌中60-80%;在非小细胞肺癌中20-40%;在小细胞肺癌中60-80%;在直肠结肠癌中50-100%;在黑素瘤中65%;在头颈癌中13%;在胰腺癌中23%。
已经证实用反义寡核苷酸或单链抗体调节Bcl-2功能的生物学方法增强了肿瘤细胞的化学敏感性。在使用反义寡核苷酸(G3139)和多西紫杉醇的联合治疗中,已经在体内观察到协同作用和完全的肿瘤消退。因此,对于治疗许多形式癌症的新治疗的研究而言,BCL-2代表了一种十分有吸引力的靶点。特别是需要一些与BCL-2结合和阻断其在癌症中的抗细胞凋亡功能且促进肿瘤中的细胞死亡的小分子。本发明满足了这种需求。
发明概述
在一个方面,本发明提供了式I的化合物及其N-氧化物衍生物、前药衍生物、被保护的衍生物、单个异构体和异构体混合物;以及该类化合物可药用的盐和溶剂化物(例如水合物):
其中:
R1选自氢和卤素;
R2选自氢和C1-4烷基;其中相对于吡唑环而言,R2位于间位上且R3位于对位上,或者相对于吡唑环而言,R2位于对位上且R3位于间位上;
R3是R5;
R4选自氢、羟基、-X3NR8R9、-X3C(O)OR8、-X3OR8、-X3C(O)NR8R9和-X3NR8C(O)R9;其中X3选自键和C1-4亚烷基;且R8和R9独立地选自氢、C1-4烷基和苯基;或者R8和R9连同R8和R9与之相连的氮一起形成一种包含1至3个独立地选自C(O)、NR10、O和S(O)0-2的基团或杂原子的5至7元饱和环;其中R10选自氢和C1-4烷基;
R5选自环丙基、3-氧代吗啉代、咪唑并[1,2-a]嘧啶基、2-氧代-4-苯基哌嗪-1-基、4-(2-氯苄基)-3-氧代哌嗪-1-基、咪唑并[1,2-a]吡啶基、苯并[d]异唑基、萘并[2,1-d][1,2,3]二唑-5-基、1H-吡咯并[2,3-b]吡啶基、咪唑并[2,1-b]噻唑基、1H-吡唑并[3,4-b]吡啶基、苯并[c][1,2,5]噻二唑基、4-氧代-4,5,6,7-四氢苯并呋喃基、2-氧代-1,2,3,6-四氢嘧啶基、1,2,4-二唑基、2,3-二氢苯并[b][1,4]二恶英-2-基、萘并[2,3-d][1,3]间二氧杂环戊烯-2-基、3,4-二氢-2H-苯并[b][1,4]嗪-7-基、2,3-二氢苯并呋喃-3-基、色满-8-基、3-氧代-3H-吡唑基、6-氧代-1,6-二氢哒嗪基、苯并[b]噻吩基、苯并[b]呋喃基、2-氧代-1,2-二氢吡啶基、2-氧代-1,2,5,6,7,8-六氢喹啉基、4-氧代-1,4-二氢-1,8-萘啶基、4-氧代-4H-吡喃并[2,3-b]吡啶基、10,10-二氧化-9-氧代-9H-噻吨-3-基、5-氧代吡咯烷-3-基、苯基、喹啉基、异喹啉基、苯氧基、苯硫基、苄氧基、苯基-磺酰基、呋喃基、噻唑基、唑基、异唑基、噻吩基、吡咯基、喹啉-8-基氧基、嘧啶基、吡啶基、吡咯烷基、吡咯烷酮基、咪唑烷-2,4-二酮基、哌啶基、哌嗪基、吡嗪基、吡唑基、吗啉代、氧代吗啉代、吲哚基、苯并[b]噻吩基、苯并[b]呋喃基、苯并[d][1,2,3]三唑和氧代哌嗪基;其中所述R5的环丙基、咪唑并[1,2-a]嘧啶基、苯并[d]异唑基、咪唑并[1,2-a]吡啶基、4-氧代-4,5,6,7-四氢苯并呋喃基、2-氧代-1,2,3,6-四氢嘧啶基、咪唑并[2,1-b]噻唑基、1H-吡咯并[2,3-b]吡啶基、1H-吡唑并[3,4-b]吡啶基、1,2,4-二唑基、苯并[c][1,2,5]噻二唑基、2,3-二氢苯并[b][1,4]二恶英-2-基、萘并[2,3-d][1,3]间二氧杂环戊烯-2-基、3,4-二氢-2H-苯并[b][1,4]嗪-7-基、2,3-二氢苯并呋喃-3-基、色满-8-基、3-氧代-3H-吡唑基、6-氧代-1,6-二氢哒嗪基、2-氧代-1,2-二氢吡啶基、2-氧代-1,2,5,6,7,8-六氢喹啉基、4-氧代-1,4-二氢-1,8-萘啶基、4-氧代-4H-吡喃并[2,3-b]吡啶基、10,10-二氧化-9-氧代-9H-噻吨-3-基、5-氧代吡咯烷-3-基、苯基、喹啉基、异喹啉基、苯氧基、苄氧基、苯氧基-甲基、苯硫基、苯基-磺酰基、呋喃基、噻唑基、唑基、异唑基、噻吩基、吡啶基、吡咯基、喹啉-8-基氧基、吡咯烷基、嘧啶基、吡咯烷酮基、哌嗪基、哌啶基、吡嗪基、吡唑基、吗啉代、氧代吗啉代、吲哚基、苯并[d][1,2,3]三唑或氧代哌嗪基是未取代的或者被1至3个独立地选自卤素、氰基、硝基、-NR6R7、C1-4烷基、卤代-C1-4烷基、C1-4烷氧基、卤代-C1-4烷氧基、卤代-C1-4烷硫基、-C(O)OR6、-X3OR6、-C(O)R6、-C(O)NR6R7、-NR6S(O)2X3R7、-X3NR6C(O)R7、-S(O)0-2R6、-S(O)0-2NR6R7、苯基、苄基、哌啶基、吡咯烷基、吗啉代、吗啉代-甲基、1,2,4-二唑基、吡唑基、苯氧基、吲哚基、(1H-1,2,4-三唑基)甲基和苄氧基的基团取代;其中R6和R7独立地选自氢、C1-4烷基、C3-8环烷基、吡啶基、苯基、苄基和萘基;其中所述R5的苯基、吡啶基、苄基、吗啉代、吗啉代-甲基、1,3-二氧代异二氢吲哚基、1,2,4-二唑基、吡唑基、吲哚基和苄氧基取代基或所述R6的吡啶基和苯基可以是未取代的或者进一步被选自卤素、硝基、氨基-磺酰基、C1-4烷基、C1-4烷氧基和卤代-C1-4烷基的基团取代;其中X3选自键和C1-4亚烷基。
在第二个方面,本发明提供了一种包含式I化合物或其N-氧化物衍生物、单个异构体和异构体混合物;或其可药用盐以及与其混合的一种或多种适宜赋形剂的药物组合物。
在第三个方面,本发明提供了一种在动物中治疗其中BCL-2活性的调节可以阻止、抑制或改善该疾病的病理学和/或症状的疾病的方法,该方法包括向动物施用治疗有效量式I的化合物或其N-氧化物衍生物、单个异构体和异构体混合物或其可药用盐。
在第四个方面,本发明提供了式I化合物在制备用于在动物中治疗其中BCL-2活性有助于该疾病的病理学和/或症状的疾病的药物中的用途。
在第五个方面,本发明提供了一种制备式I化合物及其N-氧化物衍生物、前药衍生物、被保护的衍生物、单个异构体和异构体混合物及其可药用的盐的方法。
定义
除非另外说明,否则上下文所用的一般性术语在本公开物背景中优选地具有下面的含义,其中任何地方使用的更一般性的术语可彼此独立地被更具体的定义替代或者保留,从而定义了本发明更详细的实施方案:
作为一种基团或其它基团,例如卤代-烷基和烷氧基的结构元素的“烷基”可以是直链或支链的。C1-4-烷氧基包括甲氧基、乙氧基等。卤代烷基包括二氟甲基、三氟甲基、五氟乙基等。
“芳基”意指包含6至10个环碳原子的单环或稠合的二环芳族环系。例如,芳基可以是苯基或萘基,优选地是苯基。“亚芳基”意指一种得自芳基的二价基团。
“杂芳基”被定义为其中一个或多个环成员是杂原子的上述芳基。例如,C5-10杂芳基如碳原子所示最少为5元环,但是,这些碳原子可以被杂原子代替。因此,C5-10杂芳基包括吡啶基、吲哚基、吲唑基、喹喔啉基、喹啉基、苯并呋喃基、苯并吡喃基、苯并噻喃基、苯并[1,3]间二氧杂环戊烯、咪唑基、苯并-咪唑基、嘧啶基、呋喃基、唑基、异唑基、三唑基、四唑基、吡唑基、噻吩基等。
“环烷基”意指包含所示环原子数的饱和或部分不饱和的单环、稠合的二环或桥连的多环环系。例如,C3-10环烷基包括环丙基、环丁基、环戊基、环己基等。
“杂环烷基”意指如本申请所定义的环烷基,条件是一个或多个所示的环碳原子被选自-O-、-N=、-NR-、-C(O)-、-S-、-S(O)-或-S(O)2-的部分代替,其中R是氢、C1-4烷基或氮保护基团。例如,在本申请中用于描述本发明化合物的C3-8杂环烷基包括吗啉代、吡咯烷基、吡咯烷基-2-酮、哌嗪基、哌啶基、哌啶基酮、1,4-二氧杂-8-氮杂-螺[4.5]癸-8-基、硫代吗啉代、亚磺基(sulfano)吗啉代、磺酰(sulfono)吗啉代等。
“卤素”(或卤代)优选表示氯或氟,但是也可以是溴或碘。
式I的化合物可以具有不同的异构体形式。例如,任何不对称碳原子都可以以(R)-、(S)-、或(R,S)-构型存在,优选地以(R)-或(S)-构型存在。位于双键或者尤其是位于环上的取代基可以以顺式(=Z-)或反式(=E-)形式存在。因此,该化合物可以以异构体混合物形式或者优选地以纯异构体的形式存在,优选地以纯非对映异构体或纯对映异构体的形式存在。
在使用复数(例如,多种化合物,多种盐)的情况中,其也包括单数(例如,单个化合物,单个盐)。“一种化合物”并不排除存在一种以上式I的化合物(或其盐)(例如,在一种药物制剂中),“一种”仅仅表示不定冠词。因此,“一种”优选被解读为“一种或多种”,次优选被解读为“一种”。
在提及式I化合物时,其也旨在包括该类化合物的N-氧化物和/或其互变异构体。
术语“和/或其N-氧化物、其互变异构体和/或其(优选可药用的)盐”尤其是指式I的化合物可以以本身形式或与其N-氧化物的混合物的形式、以互变异构体(例如由于酮-烯醇、内酰胺-内酰亚胺、酰胺-亚胺酸或烯胺-亚胺互变异构现象)形式或者与其互变异构体的混合物(例如由均等的反应造成的)、或者式I化合物的盐和/或任何这些形式或两种或多种该类形式的混合物的形式存在。
本发明还包括本发明化合物所有适宜的同位素变型或其可药用盐。本发明化合物或其可药用盐的同位素变型被定义为一种其中至少一个原子被具有相同原子数,但是具有与自然界中常见的原子质量不同的原子质量的原子替换的物质。可被混入到本发明化合物及其可药用盐中的同位素的实例非限制性地包括氢、碳、氮和氧的同位素如2H、3H、11C、13C、14C、15N、17O、18O、35S、18F、36Cl和123I。本发明化合物及其可药用盐的某些同位素变型,例如其中混入放射性同位素如3H或14C的那些物质可用于药物和/或底物组织分布研究。在一些特定的实例中,因易于制备和检测,可使用3H和14C同位素。在另一些实例中,用同位素如2H取代可提供一些因代谢稳定性更高、如体内半衰期增加或剂量需求降低导致的治疗优点。本发明化合物或其可药用盐的同位素变型通常可通过使用适宜试剂的同位素变型的常规操作来进行制备。
优选实施方案说明
本发明涉及能抑制BCL-2和BH3之间的相互作用的式I化合物的发现。在式I化合物的一个实施方案中,其是式Ia的化合物或其可药用盐:
其中:
R1选自氢和卤素;
R4选自氢、羟基、-X3NR8R9、-X3C(O)OR8、-X3OR8、-X3C(O)NR8R9和-X3NR8C(O)R9;其中X3选自键和C1-4亚烷基;且R8和R9独立地选自氢、C1-4烷基和苯基;或者R8和R9连同R8和R9与之相连的氮一起形成一种包含1至3个独立地选自C(O)、NR10、O和S(O)0-2的基团或杂原子的5至7元饱和环;其中R10选自氢和C1-4烷基;
R5选自3-氧代吗啉代、2-氧代哌嗪基、苯基、吗啉代、哌啶基、吡啶基、哌嗪基、喹啉基、异喹啉基、萘基、1,3,4-二唑基、异唑基和吡唑基;其中所述R5的吡唑基、2-氧代哌嗪基、哌嗪基、1,3,4-二唑基、哌啶基、吡啶基、喹啉基、异喹啉基、萘基、异唑基或苯基是未取代的或者被1至3个独立地选自苯基、苄基、甲基、甲氧基、乙氧基、叔-丁氧基-羰基、1,3,4-二唑基、卤素、氰基、异丙氧基、甲基-羰基-氨基、吗啉代-磺酰基、哌啶基-磺酰基、吡咯烷基-羰基、甲基-氨基-羰基、二甲基-氨基、二甲基-氨基-羰基、氨基-羰基、三氟甲氧基、甲基-磺酰基、二甲基-氨基-羰基和羧基的基团取代;其中所述R5的苄基或1,3,4-二唑基取代基是未取代的或者进一步被选自卤素和甲基的基团取代。
在另一个实施方案中,这些化合物选自:
药理学和效用
本发明使得可获得能抑制BCL-2和包含BH3结构域的蛋白之间的相互作用的方法和化合物。本发明的一个方面涉及一种治疗BCL-2介导的病症的方法,其包括给需要其的患者施用治疗有效量的如本发明概述部分所定义的式I化合物。
已经表明BCL-2抑制剂作为单一活性剂对许多癌细胞系具有活性,所述癌细胞系包括但不限于乳癌(US 2003/0119894,公开的PCT申请WO02/097053和WO 02/13833)、淋巴瘤(Nature(2005)435,677-681)、小细胞肺癌(Nature(2005)435,677-681)、头颈癌(公开的PCT申请WO 02/097053)和白血病(公开的PCT申请WO 02/13833)。
BCL-2最初是在携带t(14;18)的B-细胞淋巴瘤的染色体断裂点上被鉴定出来的,并且属于逐步壮大的调节细胞凋亡的蛋白家族。(Gross,A;McDonnell,JM;Korsmeyer,S.J.BCL-2族成员和细胞凋亡中的线粒体。Genes&Development 1999,13,1899-1911,Cory,S.;Huang,D.C.S.;Adams,J.M.BCL-2族:在细胞存活和肿瘤生成中的作用。Oncogene,2003 22,8590-8607。Danial,N.N.;Korsmeyer,S.J.细胞死亡:关键的控制点。Cell2004,116,205-218。Chao,D.T.;Korsmeyer,S.J.BCL-2族:细胞死亡的调节剂。Annu.Rev.Immunol.1998,16,395-419)。Apoptosis,ChristopherPotten,James Wilson,Cambridge University Press,2004)。蛋白的BCL-2族同时包括抗细胞凋亡分子如BCL-2和BCL-XL以及促细胞凋亡分子如BAX、BAK、BID和BAD。BCL-2通过阻止由生理学细胞死亡机理造成的正常细胞更新来促进癌细胞发展。已经在70%的乳癌和许多其它形式的癌症中观察到了BCL-2的过度表达(Buolaniwini,J.K.新的抗癌药物发现。Curr.Opin.Chem.Biol.1999,3,500-509)。BCL-2蛋白的表达水平还与对化疗药物和γ-放疗的广谱耐受性有关(Reed,J.C.;Miyashita,T.;Takayama,S.;Wang,H.-G.;Sato,T.;Krajewski,S.;Aime-Sempe,C.;Bodrug,S.;Kitada,S.;Hanada,M.BCL-2族蛋白:在癌症发病机理和对治疗的耐受性中涉及的细胞死亡的调节剂。J.Cell.Biochem.1996,60,23-32;Reed,J.C.BCL-2族蛋白:克服癌症化学抗性的策略。Advances inPharmocology 1997,41,501-553;Strasser,A.;Huang,D.C.S.;Vaux,D.L.BCL-2/ced-9基因族在癌症中的作用和在对于肿瘤形成和化疗耐受性的细胞死亡控制中的缺陷中的普遍牵涉。Biochem.Biophys.Acta 1997,1333,F151-F189;DiPaola,R.S.;Aisner,J.克服BCL-2-和p53-介导的前列腺癌中的耐受性。Semin.Oncol.1999,26,112-116)。
具有促细胞凋亡(例如,BAX、BAK、BID、BIM、NOXA、PUMA)和抗细胞凋亡(例如,BCL-2、BCL-XL、MCL-1))功能的蛋白BCL-2族的成员代表了细胞凋亡的关键调节剂。该族的促-和抗细胞凋亡成员之间的选择性和竞争性二聚作用决定了被给予促细胞凋亡刺激的细胞的命运。虽然还不完全了解BCL-2和BCL-XL在癌症中的精确作用,但是,有一些证据线索表明,BCL-2和BCL-XL不仅通过阻止正常细胞更新来促进癌症发展,而且也在癌细胞对目前癌症治疗的耐受性中起一定作用。BCL-2(BCL-XL)的实验性过度表达使得癌细胞对许多化疗剂和辐射有耐受性(BCL-2族蛋白:在癌症发病机理和对治疗的耐受性中涉及的细胞死亡的调节剂。J.Cell.Biochem.1996,60,23-32;Reed,J.C)。BCL-2和/或BCL-XL在如下所示的所有肿瘤的50%以上中过度表达(得自Wang,S.;Yang,D.;Lippman,M.E.用非肽小分子拮抗剂靶向BCL-2和BCL-XL。Seminars in Oncology,2003,5,133-142)。
已经证实用反义寡核苷酸或单链抗体来调节BCL-2功能的生物学方法增强了肿瘤细胞的化学敏感性(Ziegler,A.;Luedke,G.H.;Fabbro,D.;Altmann,K.H.;Stahel,R.A.;Zangemeister-Wittke,U.用靶向于BCL-2编码序列的反义寡脱氧核苷酸在小细胞肺癌细胞中诱导细胞凋亡。J.Natl.Cancer.Inst.1997,89,1027-1036;Webb,A.;Cunningham,D.;Cotter,F.;Clarke,P.A.;Di Stefano,F.;Ross,P.;Corpo,M.;Dziewanowska,Z.患有非何杰金淋巴瘤患者的BCL-2反义疗法。Lancet1997,349,1137-1141;Cotter,F.E.患有非何杰金淋巴瘤患者的BCL-2反义寡核苷酸疗法的I期临床和药动学研究。J.Clin.Oncol.2000,18,1812-1823;Piche,A.;Grim,J.;Rancourt,C.;Gomez-Navarro,J.;Reed,J.C.;Curiel,D.T.用细胞内抗BCL-2单链抗体调节BCL-2蛋白水平在乳癌细胞系MCF-7中增加了药物诱导的细胞毒性。Cancer Res.1998,58,2134-2140)。
已经表明,被设计用于与BCL-2mRNA中的序列杂交的反义寡核苷酸(G3139)(Raynaud,F.I.;Orr,R.M.;Goddard,P.M.;Lacey,H.A.;Lancashire,H.;Judson,I.R.;Beck,T.;Bryan,B.;Cotter,F.E.在静脉给药或连续皮下输入给小鼠后,G3139,一种BCL-2的反义磷硫酰寡脱氧核苷酸的药动学。J.Pharmacol.Exp.Ther.1997,281,420-427)在具有BCL-2过度表达的人乳癌细胞中抑制了BCL-2表达、诱导了细胞凋亡并抑制了细胞生长(Chen,H.X.,Marchall,J.L.,Trocky,N.,Baidas,S.,Rizvi,N.,Ling,Y.,Bhagava,P.,Lippman,M.E.,Yang,D.,and Hayes,D.F.在每周使用一次多西紫杉醇的患有晚期乳癌和其它实体瘤的患者中BCL-2反义G3139(Genta)的I期研究。Proceedings of American Society ofClinical Oncology,2000)。重要的是,在G3139和多西紫杉醇的联合治疗中,在体内观察到了协同作用和完全的肿瘤消退。因此,BCL-2是开发用于治疗多种形式的癌症的新疗法的十分有吸引力的靶点。
在某些实施方案中,本发明涉及上述方法,其中所述BCL-2介导的病症是癌症。
在某些实施方案中,本发明涉及上述方法,其中所述癌症选自急性白血病、急性淋巴细胞性白血病、急性髓细胞性白血病、成髓细胞性白血病、前髓细胞性白血病、骨髓单核细胞(myelomonocytic)白血病、单核细胞性白血病、红白血病、慢性白血病、慢性髓细胞性(粒细胞性)白血病、慢性淋巴细胞性白血病、真红细胞增多症、何杰金病、非-何杰金病;多发性骨髓瘤、瓦尔登斯特伦巨球蛋白血症、重链病、纤维肉瘤、粘液肉瘤、脂肉瘤、软骨肉瘤、骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤因氏瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌(stadenocarcinoma)、髓样癌、支气管癌、肾细胞癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎癌、维尔姆斯氏肿瘤、宫颈癌、子宫癌、睾丸肿瘤、肺癌、小细胞肺癌、膀胱癌、上皮癌、神经胶质瘤、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血管细胞瘤、听神经瘤、少突神经胶质瘤、脑脊膜瘤、黑素瘤、成神经细胞瘤、视网膜成神经细胞瘤和子宫内膜癌。
在某些实施方案中,本发明涉及上述方法,其中所述癌症是滤泡性淋巴瘤、弥漫性大B-细胞淋巴瘤、套细胞淋巴瘤、慢性淋巴细胞性白血病、前列腺癌、乳癌、成神经细胞瘤、直肠结肠癌、子宫内膜癌、卵巢癌、肺癌、肝细胞癌、多发性骨髓瘤、头颈癌或睾丸癌。
在某些实施方案中,本发明涉及上述方法,其中所述癌症过度表达BCL-2。
在某些实施方案中,本发明涉及上述方法,其中所述癌症的生长和存活依赖BCL-2。
在某些实施方案中,本发明涉及上述方法,其中所述化合物被胃肠外施用。
在某些实施方案中,本发明涉及上述方法,其中所述化合物被肌内、静脉内、皮下、口服、肺、鞘内、局部或鼻内施用。
在某些实施方案中,本发明涉及上述方法,其中所述化合物被全身施用。
在某些实施方案中,本发明涉及上述方法,其中所述患者是哺乳动物。
在某些实施方案中,本发明涉及上述方法,其中所述患者是灵长类动物。
在某些实施方案中,本发明涉及上述方法,其中所述患者是人。
在另一个方面,本发明涉及一种治疗Bcl-介导的病症的方法,其包括如下步骤:给需要其的患者联合施用治疗有效量的化疗剂与治疗有效量的如发明概述中所定义的式I化合物。
药物组合物
在另一个方面,本发明提供了包含与一种或多种可药用的载体(添加剂)和/或稀释剂一起配制的治疗有效量的一种或多种如上所述的化合物的可药用组合物。如下面详细描述的那样,本发明的药物组合物尤其是可以被配制为用于以固体或液体形式进行施用,包括适用于下面施用的那些形式:(1)口服施用,例如,兽用顿服药(水性或非水性溶液或混悬液)、片剂,例如,靶向于颊、舌下和全身吸收的那些片剂、大丸剂、散剂、颗粒剂、用于应用于舌的糊剂;(2)胃肠外施用,例如,通过皮下、肌内、静脉内或硬膜外注射进行施用,以例如无菌溶液或混悬液、或缓释制剂形式进行施用;(3)局部应用,例如,以霜剂、软膏或控释贴剂或应用于皮肤的喷雾的形式进行应用;(4)阴道内或直肠内施用,例如,以阴道栓、霜剂或泡沫形式进行应用;(5)舌下施用;(6)眼用;(7)经皮;(8)鼻;(9)肺;或(10)鞘内。
本文所用的短语“治疗有效量”意指在对任何医学治疗适用的合理的获益/风险比下,在动物细胞的至少一种亚群中可有效产生一些所需的治疗作用的化合物、材料或包含本发明化合物的组合物的数量。
本文所用的短语“可药用的”是指在合理医学判断范围内,适于与人类的组织和动物接触,没有过度毒性、刺激性、变态反应,或者其它问题或并发症,具有合理的获益/风险比的那些化合物、材料、组合物和/或剂型。
本文所用的短语“可药用的载体”意指在将各化合物由一个器官或机体的一部分携带到或转运到另一个器官或机体的另一部分时涉及的可药用的材料、组合物或基质,如液体或固体填充剂、稀释剂、赋形剂、制造助剂(例如润滑剂、滑石粉、硬脂酸镁、钙或锌、或硬脂酸)、或溶剂包封材料。各载体在能与该制剂的其它成分可相容的意义上是“可接受的”并且对患者无害。可作为可药用载体的材料的一些实例包括:(1)糖类,如乳糖、葡萄糖和蔗糖;(2)淀粉类,如玉米淀粉和马铃薯淀粉;(3)纤维素以及其衍生物,如羧甲基纤维素钠、乙基纤维素和醋酸纤维素;(4)西黄蓍胶粉;(5)麦芽糖糊精(malt);(6)明胶;(7)滑石粉;(8)赋形剂,如可可豆脂和栓剂蜡;(9)油类,如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和豆油;(10)二醇类,如丙二醇;(11)多元醇,如甘油、山梨醇、甘露醇和聚乙二醇;(12)酯类,如油酸乙酯和月桂酸乙酯;(13)琼脂;(14)缓冲剂,如氢氧化镁和氢氧化铝;(15)海藻酸;(16)无热源的水;(17)等渗的盐水;(18)林格氏溶液;(19)乙醇;(20)pH缓冲溶液;(21)聚酯、聚碳酸酯和/或聚酐;和(22)药物制剂所用的其它无毒的可相容物质。
如上所述,本发明化合物的某些实施方案可包含碱性官能团,如氨基或烷基氨基,因此,能与可药用的酸一起形成可药用的盐。在这一方面,术语“可药用的盐”是指本发明化合物相对无毒的无机和有机酸加成盐。这些盐可以在给药载体或剂型的生产过程中原位制备,或者可以通过单独使游离碱形式的纯化了的本发明化合物与适宜的有机或无机酸反应,并在随后的纯化过程中分离由此形成的盐来进行制备。典型的盐包括氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、磷酸盐、硝酸盐、醋酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、枸橼酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、萘酸盐(napthylate)、甲磺酸盐、葡庚糖酸盐、乳糖醛酸盐和月桂基硫酸盐等。(见,例如,Berge等(1977)“药用盐”,J.Pharm.Sci.66:1-19)。
本发明化合物的可药用盐包括该化合物常规的无毒盐或季铵盐,例如,得自无毒的有机酸或无机酸的盐。例如,该类常规的无毒盐包括得自无机酸如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐;以及由有机酸制备的盐,所述有机酸如醋酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、枸橼酸、抗坏血酸、棕榈酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基苯甲酸、富马酸、苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸(isothionic acid)等。
在另一些情况中,本发明的化合物可能包含一个或多个酸性官能团,因此,能与可药用的碱形成可药用的盐。在这些情况中,术语“可药用的盐”是指本发明化合物相对无毒的无机和有机碱加成盐。这些盐同样可以在给药载体或剂型的生产过程中原位制备,或者可以通过单独使游离酸形式的纯化的化合物与适宜的碱,如可药用金属阳离子的氢氧化物、碳酸盐或碳酸氢盐、与氨、与可药用的有机伯、仲或叔胺反应来进行制备。代表性的碱金属或碱土金属盐包括锂、钠、钾、钙、镁和铝盐等。用于形成碱加成盐的代表性有机胺包括乙胺、二乙胺、乙二胺、乙醇胺、二乙醇胺、哌嗪等。(见,例如,Berge等,同上)
在该组合物中也可以存在润湿剂、乳化剂和润滑剂如月桂基硫酸钠和硬脂酸镁以及着色剂、释放剂、包衣剂、甜味剂、矫味剂和芳香剂、防腐剂和抗氧剂。
可药用抗氧剂的实例包括:(1)水溶性抗氧剂,如抗坏血酸、盐酸半胱氨酸、硫酸氢钠、焦亚硫酸钠、亚硫酸钠等;(2)油溶性抗氧剂,如抗坏血酸棕榈酸酯、丁羟基茴香醚(BHA)、丁羟基甲苯(BHT)、卵磷脂、没食子酸丙酯、α-生育酚等;和(3)金属螯合剂,如枸橼酸、乙二胺四乙酸(EDTA)、山梨醇、酒石酸、磷酸等。
本发明的制剂包括适用于口服、鼻、局部(包括颊和舌下)、直肠、阴道和/或胃肠外施用的那些制剂。该制剂可方便地以单位剂型形式存在,并且可以用药学领域众所周知的任何方法来进行制备。可与载体物质结合从而产生一种单个剂型的活性成分的量将根据所治疗的主体、特定的施用方式而变化。可与载体物质结合从而产生一种单个剂型的活性成分的量通常是产生一种治疗作用的化合物的量。一般而言,自百分之一百开始,这一数量为约0.1%至约99%的活性成分,优选地为约5%至约70%,最优选约10%至约30%。
在某些实施方案中,本发明的制剂包含选自环糊精、纤维素、脂质体、成胶束剂,例如胆汁酸、和聚合性载体,例如聚酯和聚酐的赋形剂;以及本发明化合物。在某些实施方案中,上述制剂提供了可口服生物利用的本发明化合物。
制备这些制剂或组合物的方法包括使本发明化合物与载体和任选的一种或多种助剂缔合的步骤。一般而言,该制剂是通过使本发明化合物与液体载体或细分的固体载体或二者均匀、紧密地混合,然后如果需要的话,将产品成型来进行制备的。
适于口服给药的本发明制剂可以为胶囊、扁囊剂、丸剂、片剂、锭剂(使用进行了矫味的基质,通常为蔗糖和阿拉伯胶或西黄蓍胶)、散剂、颗粒的形式,或者可以为位于水性或非水性液体中的溶液或混悬液形式,或者可以为水包油或油包水液体乳剂,或者为酏剂或糖浆、或软锭剂(使用一种惰性基质,如明胶和甘油,或蔗糖和阿拉伯胶)和/或漱口剂等形式,其各自包含预定量的作为活性成分的本发明化合物。本发明化合物也可以以大丸剂、药糖剂或糊剂的形式进行施用。
在用于口服施用的本发明固体剂型(胶囊、片剂、丸剂、糖锭剂、散剂、颗粒剂、锭剂等)中,将活性成分与一种或多种可药用载体,如枸橼酸钠或磷酸二钙,和/或任何下面的物质混合:(1)填充剂或增量剂,如淀粉类、乳糖、蔗糖、葡萄糖、甘露醇和/或硅酸;(2)粘合剂,例如,羧甲基纤维素、藻酸盐类、明胶、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯胶;(3)湿润剂,如甘油;(4)崩解剂,如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠;(5)溶液阻滞剂,如石蜡;(6)吸收促进剂,如季铵化合物和表面活性剂,如泊洛沙姆和月桂基硫酸钠;(7)润湿剂,例如鲸蜡醇、甘油单硬脂酸酯、和非离子表面活性剂;(8)吸收剂,如高岭土和皂土;(9)润滑剂,如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇类、月桂基硫酸钠、硬脂酸锌、硬脂酸钠、硬脂酸、及其混合物;(10)着色剂;和(11)控释剂如交联聚维酮或乙基纤维素。在胶囊、片剂和丸剂的情况中,该药物组合物还可包含缓冲剂。类似类型的固体组合物也可以用作软和硬壳明胶胶囊中的填充物,并使用诸如乳糖之类的赋形剂以及高分子量聚乙二醇类等。
片剂可以通过压缩或模塑来进行制备,任选地使用一种或多种辅助成分。压缩片可以用粘合剂(例如,明胶或羟丙基甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如,羟乙酸淀粉钠或交联羧甲基纤维素钠)、表面活性剂或分散剂来制备。模塑片可以通过在适宜的机器中对用惰性液体稀释剂润湿的粉状化合物混合物进行模塑来进行制备。
片剂和本发明药物组合物的其它固体剂型,如糖锭剂、胶囊、丸剂和颗粒剂,可任选地被刻痕或用包衣和壳,如肠溶包衣或药物制剂领域众所周知的其它包衣来进行制备。还可以用例如用于提供所需释放性质的各种比例的羟丙基甲基纤维素、其它聚合物基质、脂质体和/或微球将其配制为用于提供其中活性成分的缓慢或受控释放。其可被配制为用于快速释放,例如被冷冻-干燥。例如,可以用截留细菌的滤器过滤或者通过掺入灭菌剂以无菌固体组合物的形式进行灭菌,所述无菌固体组合物可在临用前溶解于无菌水或其它可注射无菌介质中。这些组合物还可任选地包含遮光剂,并且可以为仅在或者优选在胃肠道中的某一部分释放(任选地以延迟方式释放)活性成分的组合物。可用的包埋组合物的实例包括聚合物和蜡类。如果适宜的话,也可使用一种或多种上述赋形剂将活性成分制成微胶囊形式。
用于口服施用本发明化合物的液体剂型包括可药用的乳剂、微乳、溶液、混悬液、糖浆和酏剂。除活性成分外,该液体剂型还可包含本领域常用的惰性稀释剂,例如,水或其它溶剂、增溶剂和乳化剂,如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、油类(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢呋喃醇、聚乙二醇类和脱水山梨醇的脂肪酸酯,以及它们的混合物。
除惰性稀释剂外,该口服组合物还可包含助剂如润湿剂、乳化剂和混悬剂、甜味剂、矫味剂、着色剂、芳香剂和防腐剂。
除活性化合物外,混悬液还可包含助悬剂例如,乙氧基化异硬脂醇、聚氧乙烯山梨醇和脱水山梨醇酯类、微晶纤维素、偏铝酸(aluminummetahydroxide)、皂土、琼脂和西黄蓍胶,以及它们的混合物。
用于直肠或阴道施用的本发明药物组合物的制剂可以以栓剂形式呈现,其可以通过将一种或多种本发明化合物与一种或多种适宜的非刺激性赋形剂或载体混合来进行制备,所述赋形剂或载体包括例如,可可豆脂、聚乙二醇、栓剂蜡或水杨酸酯,所述栓剂在室温下是固体,但是在体温下是液体,并因此可在直肠或阴道腔中熔化和释放活性化合物。
适于阴道施用的本发明制剂还包括包含本领域已知为适宜的该类载体的阴道栓剂、塞、霜剂、凝胶、糊剂、泡沫或喷雾制剂。
用于本发明化合物局部或经皮施用的剂型包括粉剂、喷雾、软膏、糊剂、霜剂、洗剂、凝胶、溶液、贴剂和吸入剂。可以将活性成分在无菌条件下与可药用的载体和可能需要的任何防腐剂、缓冲剂或推进剂进行混合。
除本发明的活性化合物外,该软膏、糊剂、霜剂和凝胶还可包含赋形剂,如动物和植物脂类、油类、蜡类、石蜡、淀粉、西黄蓍胶、纤维素衍生物、聚乙二醇类、硅酮类、皂土类、硅酸、滑石粉和氧化锌、或它们的混合物。
除本发明的化合物外,粉剂和喷雾还可包含赋形剂如乳糖、滑石粉、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末、或这些物质的混合物。喷雾还可包含常规推进剂,如氯氟烃类和未被取代的挥发性烃类,如丁烷和丙烷。
经皮贴剂具有提供本发明化合物向机体的受控传递的附加优点。该类剂型可以通过将化合物溶解或分散于适宜的介质中来进行制备。也可以用吸收增强剂来增加通过皮肤的化合物流量。可以通过提供一种控速膜或将化合物分散于聚合物基质或凝胶中来控制流速。
本发明范围内也考虑眼用制剂、眼用软膏、粉末、溶液等。
适用于胃肠外施用的本发明药物组合物包含一种或多种本发明化合物以及一种或多种可药用的等渗的无菌的水性或非水性溶液、分散体、混悬液或乳剂,或可在临用前被重组成无菌的可注射溶液或分散体的无菌粉末,其可包含糖类、醇类、抗氧剂、缓冲剂、制菌剂、使得制剂与预期使用者的血液等渗的溶质或助悬剂或增稠剂。
可用于本发明药物组合物中的适宜水性和非水性载体的实例包括水、乙醇、多元醇(如甘油、丙二醇、聚乙二醇等)、以及它们的适宜混合物、植物油,如橄榄油,和可注射的有机酯类,如油酸乙酯。可以通过例如使用包衣材料,如卵磷脂、通过维持所需的粒度(在分散体的情况中)、和通过使用表面活性剂来维持适宜的流动性。
这些组合物还可包含助剂如防腐剂、润湿剂、乳化剂和分散剂。可以通过包含各种抗细菌剂和抗真菌剂,例如尼泊金酯、氯丁醇、苯酚、山梨酸等来阻止微生物对主题化合物的作用。还可能希望在该组合物中包含等渗剂,如糖类、氯化钠等。此外,可通过包含延迟吸收的物质如单硬脂酸铝和明胶来延长可注射药物形式的吸收。
在一些情况中,为了延长药物的作用,希望减缓皮下或肌内注射的药物的吸收。其可通过使用水溶性差的结晶或无定型物质的液体混悬液来实现。此时,药物的吸收速率将取决于其溶解速率,其溶解速率又取决于晶粒大小和晶型。或者,可以通过将药物溶解或混悬于油性基质中来延迟胃肠外施用药物形式的吸收。
可以通过形成主题化合物在生物可降解聚合物如聚丙交酯-聚乙醇酸交酯中的微包封的基质来制备可注射的储库形式。根据药物与聚合物的比例和所用特定聚合物的性质,可以控制药物释放速率。其它可生物降解的聚合物的实例包括聚(原酸酯)类和聚(酐)类。也可以通过将药物捕获到可与机体组织相容的脂质体或微乳中来制备可注射的储库制剂。
当本发明的化合物以药物形式施用于人和动物时,其可以以本身形式或者以药物组合物形式被给予,所述药物组合物包含例如0.1至99%(更优选10至30%)的活性成分和可药用的载体。
本发明的制剂可被口服、胃肠外、局部或直肠给予。它们当然是以适于各施用途径的形式被给予的。例如,它们可以以片剂或胶囊的形式进行施用、通过注射、吸入、洗眼剂、软膏、栓剂等形式施用,通过注射、输注或吸入施用;通过洗剂或软膏局部施用;以及通过栓剂直肠施用。优选口服施用。
本文所用的短语“胃肠外施用”和“被胃肠外施用”意指除肠施用和局部施用之外的施用方式,通常为通过注射进行的施用,并且非限制性地包括静脉内、肌内、动脉内、鞘内、囊内、眼眶内、心内、真皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、椎管内和胸骨内注射和输入。
本文所用的短语“全身施用”、“被全身施用”、“外周施用”和“被外周施用”意指不是将化合物、药物或其它物质直接施用到中枢神经系统中,从而使得其进入到患者的系统中并因此遭受代谢和其它类似过程,例如皮下施用。
这些化合物可通过任何适宜的施用途径被施用给人和其它动物用于治疗,所述途径包括口服、鼻(例如通过喷雾来进行施用)、直肠、阴道内、胃肠外、脑池内和局部(如通过粉剂、软膏或滴剂来进行),包括颊和舌下。
无论选择何种施用途径,都可以用本领域技术人员已知的常规方法将可以以适宜的水合形式使用的本发明化合物和/或本发明的药物组合物配制成可药用的剂型。
可以改变本发明药物组合物中活性成分的实际剂量水平以获得对于特定患者、组合物和施用方式而言,可有效获得所需治疗响应,同时对该患者无毒的活性成分量。
所选择的剂量水平将取决于许多因素,包括所用的本发明特定化合物、或其酯、盐或酰胺的活性、施用途径、施用时间、所用特定化合物的排泄或代谢速率、吸收速度和程度、治疗的持续时间、与所用特定化合物联用的其它药物、化合物和/或材料、所治疗患者的年龄、性别、体重、情况、一般健康和之前的药物史、和医学领域众所周知的类似因素。
具有本领域普通技能的医师或兽医可容易地确定和处方所需药物组合物的有效量。例如,医师或兽医可以从低于获得所需治疗作用所需水平的药物组合物中所用本发明化合物的剂量开始,并逐渐增加其剂量直至获得所需的作用。
一般而言,本发明化合物适宜的日剂量将是可有效产生治疗作用所需的最低剂量的化合物数量。该类有效剂量将取决于上述因素。当用于所示镇痛作用时,本发明化合物用于患者的口服、静脉内、脑室内和皮下剂量的范围将为每天每公斤体重月0.0001至约100mg。
如果需要,活性化合物的有效日剂量可以在一天中以适宜的时间间隔单独施用的两个、三个、四个、五个、六个或多个亚剂量的形式进行施用,任选地,以单位剂型形式进行施用。优选的给药为每天施用一次。
虽然本发明的化合物可单独施用,但是,该化合物优选地以药物制剂(组合物)的形式进行施用。
与其它药物一样,本发明的化合物可以被配制为用于以任何方便的方式施用以用于人或兽医药物。
在另一个方面,本发明提供了包含与一种或多种可药用载体(添加剂)和/或稀释剂一起配制的治疗有效量的一种或多种如上所述的主题化合物的可药用组合物。如下面详细描述的那样,本发明的药物组合物尤其是可以被配制为用于以固体或液体形式进行施用,包括适用于下面施用的那些形式:(1)口服施用,例如,兽用顿服药(水性或非水性溶液或混悬液)、片剂、大药丸、散剂、颗粒剂、用于应用于舌的糊剂;(2)胃肠外施用,例如,通过皮下、肌内或静脉内注射进行施用,例如无菌的溶液或混悬液;(3)局部应用,例如以霜剂、软膏或应用于皮肤、肺、或粘膜的喷雾的形式进行应用;或(4)阴道内或直肠内施用,例如,以阴道栓、霜剂或泡沫形式进行应用;(5)舌下或颊;(6)眼用;(7)经皮;或(8)经鼻。
术语“治疗”还意指包括预防、治疗和治愈。
接受这种治疗的患者是有此需要的任何动物,包括灵长类动物,特别是人类,和其它哺乳动物,如马、牛、猪和绵羊;以及通常的家禽和宠物。
本发明的化合物可以就以自身形式进行施用,或者可以与可药用载体混合施用,并且也可以与抗菌剂如青霉素类、头孢菌素类、氨基糖苷类和糖肽类联合施用。因此,联合治疗包括以在施用随后的活性化合物时,首先施用的活性化合物的治疗作用未完全消失的方式将活性化合物顺序、同时和独立施用。
微乳化技术可改善一些亲脂性(水不溶性)药学活性剂的生物利用度。实例包括Trimetrine(Dordunoo,S.K.等,Drug Development andIndustrial Pharmacy,17(12),1685-1713,1991和REV 5901(Sheen,P.C.等,J Pharm Sci 80(7),712-714,1991)。其中,微乳化通过优先将吸收定向于淋巴系统而非循环系统,从而绕过肝并阻止了化合物在肝胆循环中的破坏而增强了生物利用度。
虽然考虑所有适宜的两亲性载体,但本发明优选的载体通常是具有一般认为安全(GRAS)的身份,且可同时溶解本发明化合物并在随后当该溶液与复杂的水相(如人胃肠道中的水相)接触时将该化合物微乳化的那些载体。满足这些要求的两亲性成分通常具有2-20的HLB(亲水-亲油平衡)值,且其结构包含C-6至C-20直链脂族基团。实例有聚乙烯-乙二醇化的(glycolized)脂族甘油酯和聚乙二醇类。
特别是考虑可商业获得的两亲性载体,包括Gelucire-系列、Labrafil、Labrasol或Lauroglycol(都由Gattefosse Corporation,Saint Priest,法国制造和派送)、PEG-单-油酸酯、PEG-二-油酸酯、PEG-单-月桂酸酯和二-月桂酸酯、卵磷脂、聚山梨醇酯80等(由USA和全世界许多公司制备和派送)。
适用于本发明的亲水聚合物是易溶于水、可与成囊泡的脂质共价连接并且可在体内被耐受而没有毒性(即,可生物相容)的那些聚合物。适宜的聚合物包括聚乙二醇(PEG)、聚乳酸(也被称为聚丙交酯)、聚乙醇酸(也被称为聚乙交酯)、聚乳酸-聚乙醇酸共聚物和聚乙烯醇。优选的聚合物是那些具有约100或120道尔顿至高至约5,000或10,000道尔顿,更优选约300道尔顿至约5,000道尔顿的分子量的聚合物。在一个特别优选的实施方案中,该聚合物是具有约100至约5,000道尔顿的分子量,更优选具有约300至约5,000道尔顿的分子量的聚乙二醇。在一个特别优选的实施方案中,该聚合物是750道尔顿的聚乙二醇(PEG(750))。还可以用其中的单体数来对聚合物进行定义;本发明的一个优选实施方案利用至少约三个单体的聚合物,如由三个单体组成的PEG聚合物(约150道尔顿)。
可适用于本发明的其它亲水聚合物包括聚乙烯吡咯烷酮、聚甲基唑啉(polymethoxazoline)、聚乙基唑啉、聚羟基丙基甲基丙烯酰胺、聚甲基丙烯酰胺、聚二甲基丙烯酰胺、及衍生化纤维素如羟甲基纤维素或羟乙基纤维素。
在某些实施方案中,本发明的制剂包含选自聚酰胺类、聚碳酸酯类、聚亚烷基类、丙烯酸酯和甲基丙烯酸酯的聚合物、聚乙烯基聚合物、聚乙交酯类、聚硅氧烷类、聚氨酯及其共聚物、纤维素、聚丙烯、聚乙烯、聚苯乙烯、乳酸和乙醇酸的聚合物、聚酐、聚(原)酸酯、聚(丁酸)、聚(戊酸)、聚(丙交酯-共-己内酯)、多糖、蛋白、聚透明质酸、聚氰基丙烯酸酯、以及它们的掺合物、混合物或共聚物的生物可相容性聚合物。
环糊精是由6、7或8个葡萄糖单位组成的(分别用希腊字母α、β或γ表示)环状低聚糖。已知不存在具有低于6个葡萄糖单元的环糊精。其葡萄糖单元通过α-1,4-糖苷键进行连接。因为糖单元的椅式构象,所有的仲羟基(在C-2,C-3上)都位于环的一侧,而所有位于C-6上的伯羟基位于另一侧。结果,其外表面是亲水性的,使得环糊精是水溶性的。相反,因为环糊精的腔通过C-3和C-5原子的氢和醚样氧排列而成,因此,环糊精的腔是疏水性的。这些矩阵使得其可以与各种相对疏水的化合物络合,所述化合物包括例如甾族化合物,如17.β-雌二醇(见,例如,van Uden等Plant Cell Tiss.Org.Cult.38:1-3-113(1994))。通过范德华力相互作用和通过形成氢键来发生络合。关于环糊精化学的一般性综述参见Wenz,Agnew.Chem.Int.Ed.Engl.,33:803-822(1994)。
环糊精衍生物的物理-化学性质强烈依赖于取代的种类和程度。例如,它们在水中的溶解度范围从不溶(例如,三乙酰基-β-环糊精)至147%可溶(w/v)(G-2-β-环糊精)。此外,它们也可溶解于许多有机溶剂中。环糊精的性质使得可以通过增加或降低其溶解度来控制各种制剂组分的溶解度。
已经对许多环糊精及其制备方法进行了描述。例如,Parmeter(I)等(US专利号3,453,259)和Gramera等(US专利号3,459,731)描述了电中性的环糊精。其它衍生物包括具有阳离子特性的环糊精[Parmeter(II),US专利号3,453,257]、不溶性的交联环糊精(Solms,US专利号3,420,788)和具有阴离子特性的环糊精[Parmeter(III),US专利号3,426,011]。在具有阴离子特性的环糊精衍生物中,已经将羧酸、亚磷酸、三价膦酸、膦酸、磷酸、硫代磷酸、硫代亚磺酸和磺酸悬挂到母体环糊精上[见,Parmeter(III),同上]。此外,Stella等(US专利号5,134,127)对磺基烷基醚环糊精衍生物进行了描述。
脂质体由至少一种包封着一种水性内室的脂质双层膜组成。可以用膜的类型和大小对脂质体进行表征。小的单层囊泡(SUV)具有单层膜并通常具有0.02至0.05μm的直径;大的单层囊泡(LUV)通常大于0.05μm。寡层大囊泡和多层囊泡具有多层(通常为同心的)膜层,并且通常大于0.1μm。具有一些非同心膜的脂质体,即被包含于一个较大囊泡中的多个较小囊泡被定义为多泡囊泡。
本发明一方面涉及包含含有本发明化合物的脂质体的制剂,其中该脂质体膜被配制成用于提供携带能力增加的脂质体。二者择一或另外地,本发明的化合物还可以被包含于脂质体的脂质双层中或者被吸附到脂质体的脂质双层上。本发明的化合物可以与脂质表面活性剂一起聚集和被携带到脂质体内部空间中;在这些情况中,该脂质体膜被配制为耐受该活性剂-表面活性剂聚集体的破坏作用。
根据本发明的一个实施方案,脂质体的脂质双层包含用聚乙二醇(PEG)衍生的脂质,从而使得PEG链从脂质双层的内表面延伸到由该脂质体包封的内部空间中,以及由该脂质双层的外表面延伸到周围环境中。
被包含于本发明脂质体中的活性剂为溶解形式。表面活性剂和活性剂的聚集体(如包含感兴趣的活性剂的乳剂或胶束)可以被捕获到本发明脂质体的内部空间中。表面活性剂起分散和溶解活性剂的作用,并且可选自任何适宜的脂族、脂环族或芳族表面活性剂,包括但不限于各种链长(例如,从约C14-至约C20)的可生物相容的溶血磷脂酰胆碱(LPC)。也可以用聚合物衍生的脂质如PEG-脂质来形成胶束,因为其将发挥抑制胶束/膜融合的作用,并且向表面活性剂分子中加入聚合物降低了表面活性剂的CMC并有助于胶束形成。优选CMC在微摩尔范围内的表面活性剂;可以用更高CMC的表面活性剂来制备被捕获在本发明脂质体中的胶束,但是,胶束表面活性剂单体可能会影响脂质体双层的稳定性并且将是设计具有所需稳定性的脂质体的一个因素。
本发明的脂质体可以用本领域已知的各种技术中的任意一种来制备。见,例如,US专利号4,235,871;公开的PCT申请WO 96/14057;新RRC,脂质体:一种实用的方法,IRL Press,Oxford(1990),第33-104页;LasicDD,脂质体,从物理学到应用,Elsevier Science Publishers BV,Amsterdam,1993。
例如,本发明的脂质体可以通过将用亲水聚合物衍生的脂质扩散到预先形成的脂质体中来进行制备,如通过在与脂质体所需的衍生化脂质的最终摩尔百分比相当的脂质浓度下,使预先形成的脂质体与由脂质-接枝聚合物组成的胶束接触来进行制备。如本领域已知的那样,包含亲水聚合物的脂质体也可以通过均化、脂质域水合或挤出技术来形成。
在本发明的一个方面,该脂质体被制备成在所选择的尺寸范围内具有基本均匀的尺寸。一种有效的筛选方法包括挤压该脂质体的水性混悬液通过一系列具有所选择的均匀孔径的聚碳酸酯膜;该膜的孔径将大致等于通过经由该膜进行挤出制得的脂质体的最大粒度。见,例如,US专利号4,737,323(1988年4月12日)。
本发明制剂的释放特性取决于包封材料、被包封药物的浓度、以及释放改性剂的存在。例如,可以将释放处理成pH依赖性的,例如,使用仅在低pH如在胃中的pH下释放、或仅在较高pH如在小肠中的pH下释放的pH敏感包衣。可以用肠溶包衣使得直到通过胃后才发生释放。可以用多层包衣或被包封于不同材料中的氨腈混合物来获得在胃中开始释放,然后稍后在小肠中释放。也可以通过包含盐或致孔剂来控制释放,所述盐或致孔剂可增加吸水性和通过由胶囊中扩散来增加药物释放。还可以用改变药物溶解度的赋形剂来控制释放速率。也可以混入增加基质降解或由基质释放的物质。可以将其加入到药物中,取决于化合物,可将其以独立相形式(即,以微粒形式)加入,或者可以将其共同溶解于聚合物相中。在所有的情况中,其数量都应为0.1至30%(w/w聚合物)。降解增强剂的类型包括无机盐如硫酸铵和氯化铵、有机酸如枸橼酸、苯甲酸和抗坏血酸、无机碱如碳酸钠、碳酸钾、碳酸钙、碳酸锌和氢氧化锌、和有机碱如硫酸鱼精蛋白、精胺、胆碱、乙醇胺、二乙醇胺和三乙醇胺,以及表面活性剂如和。给基质增加微观结构的致孔剂(即水溶性化合物如无机盐和糖类)以微粒形式被加入。其范围为1至30%(w/w聚合物)。
还可以通过改变颗粒在肠中的驻留时间来控制吸收。其例如可以通过将颗粒用一种粘膜粘附性聚合物包衣或选择粘膜粘附性聚合物作为包封材料来实现。实例包括大部分具有游离羧基的聚合物,如壳聚糖、纤维素,并且尤其是聚丙烯酸酯(本文所用聚丙烯酸酯是指包括丙烯酸酯基团和改性的丙烯酸酯基团如氰基丙烯酸酯和甲基丙烯酸酯的聚合物)。
药物组合
本发明尤其是涉及式I的化合物(或包含式I化合物的药物组合物)在治疗一种或多种本文所述疾病中的用途;其中对治疗的响应被证实是有益的,例如,部分或完全消除该疾病的一种或多种症状至完全治愈或缓解。
已经表明Bcl-2抑制剂与其它抗癌剂和放疗联合可有效对抗许多癌细胞系,包括但不限于乳癌(与多西紫杉醇联合,公开的PCT申请WO02/097053)、前列腺癌(与多西紫杉醇联合,公开的PCT申请WO02/097053)、头颈癌(与多西紫杉醇联合,公开的PCT申请WO 02/097053)和非小细胞肺癌(与紫杉醇联合,Nature(2005)435,677-681)。除上述联合化学疗法外,Bcl-2蛋白的小分子抑制剂也与其它抗癌剂表现出协同作用,所述其它抗癌剂非限制性地包括依托泊苷、阿霉素、顺铂、紫杉醇和放疗(Nature(2005)435,677-681)。
式(I)的化合物也可以与其它抗增殖化合物联合。该类抗增殖化合物非限制性地包括芳香酶抑制剂;抗雌激素药;拓扑异构酶I抑制剂;拓扑异构酶II抑制剂;微管活性化合物;烷化化合物;组蛋白脱乙酰基酶抑制剂;诱导细胞分化过程的化合物;环氧合酶抑制剂;MMP抑制剂;mTOR抑制剂,如RAD001;抗增殖的抗代谢物;铂化合物;靶向/降低蛋白或脂质激酶活性的化合物和另外的抗血管生成的化合物;靶向、降低或抑制蛋白或脂质磷酸酶活性的化合物;促性腺激素释放激素激动剂;抗雄激素药;蛋氨酸氨基肽酶抑制剂;二膦酸盐;生物学反应调节剂;抗增殖的抗体,如HCD122;类肝素酶抑制剂;Ras致癌亚型的抑制剂;端粒末端转移酶抑制剂;蛋白酶体抑制剂;用于治疗血液学恶性肿瘤的化合物,如FLUDARABINE;靶向、降低或抑制Flt-3活性的化合物,如PKC412;Hsp90抑制剂如17-AAG(17-烯丙基氨基格尔德霉素,NSC330507)、17-DMAG(17-二甲基氨基乙基氨基-17-脱甲氧基-格尔德霉素,NSC707545)、IPI-504、CNF1010、CNF2024、得自Conforma Therapeutics的CNF1010和AUY922;替莫唑胺驱动蛋白纺锤体蛋白抑制剂,如得自GlaxoSmithKline的SB715992或SB743921,或得自CombinatoRx的喷他脒/氯丙嗪;PI3K抑制剂,如BEZ235;RAF抑制剂,如LGX818或RAF265;MEK抑制剂如得自Array PioPharma的ARRY142886、得自AstraZeneca的AZD6244、得自Pfizer的PD181461、亚叶酸、EDG结合剂、抗白血病化合物、核苷酸还原酶抑制剂、S-腺苷基蛋氨酸脱羧酶抑制剂、抗增殖的抗体或其它化疗化合物。二者择一或另外地,其还可以与其它抗肿瘤治疗方法联合,包括手术、电离辐射、光动力疗法、植入剂,如与皮质激素、激素联合,或者其还可以用作放射致敏剂。在抗炎和/或抗增殖治疗中,还包括与抗炎药的联合。还可以与抗组胺药、支气管扩张药、NSAID或趋化因子受体拮抗剂联合。
本文所用的“芳香酶抑制剂”涉及抑制雌激素产生,即分别抑制底物雄甾烯二酮和睾酮向雌酮和雌二醇的转化的化合物。该术语非限制性地包括甾族化合物,尤其是阿美他坦、依西美坦和福美坦,并且特别是非甾族化合物,尤其是氨鲁米特、洛太米特、吡格鲁米特、曲洛司坦、睾内酯、酮康唑、伏氯唑、法倔唑、阿那曲唑和来曲唑。依西美坦例如可以以其市售形式,例如以商标AROMASIN市售的形式施用。福美坦例如可以以其市售形式,例如以商标LENTARON市售的形式施用。法倔唑例如可以以其市售形式,例如以商标AFEMA市售的形式施用。阿那曲唑例如可以以其市售形式,例如以商标ARIMIDEX市售的形式施用。来曲唑例如可以以其市售形式,例如以商标FEMARA或FEMAR市售的形式施用。氨格鲁米特例如可以以其市售形式,例如以商标ORIMETEN市售的形式施用。包含芳香酶抑制剂化疗剂的本发明组合特别是可用于治疗激素受体阳性肿瘤,例如,乳腺肿瘤。
本文所用的术语“抗雌激素药”涉及在雌激素受体水平拮抗雌激素作用的化合物。该术语非限制性地包括他莫昔芬、氟维司群、雷洛昔芬和盐酸雷洛昔芬。他莫昔芬例如可以以其市售形式,例如以商标NOLVADEX市售的形式施用。盐酸雷洛昔芬例如可以以其市售形式,例如以商标EVISTA市售的形式施用。氟维司群可以如US 4,659,516中所公开的那样来进行配制或者其例如可以以其市售形式,例如以商标FASLODEX市售的形式施用。包含是抗雌激素药的化疗剂的本发明的组合特别是可用于治疗雌激素受体阳性肿瘤,例如乳腺肿瘤。
本文所用的术语“抗雄激素药”涉及能抑制雄激素的生物学作用的任何物质并且非限制性地包括比卡鲁胺(CASODEX),其例如可以如US4,636,505中所公开的那样来进行配制。
本文所用的术语“促性腺激素释放激素激动剂”非限制性地包括阿巴瑞克、戈舍瑞林和醋酸戈舍瑞林。戈舍瑞林在US 4,100,274中被公开并且例如可以以其市售形式,例如以商标ZOLADEX市售的形式施用。阿巴瑞克例如可以如US 5,843,901中所公开的那样来进行配制。
本文所用的术语“拓扑异构酶I抑制剂”非限制性地包括托泊替康、吉马替康、伊立替康、喜树碱及其类似物、9-硝基喜树碱和大分子喜树碱轭合物PNU-166148(WO99/17804中的化合物A1)。伊立替康例如可以以其市售形式,例如以商标CAMPTOSAR市售的形式施用。托泊替康例如可以以其市售形式,例如以商标HYCAMTIN市售的形式施用。
本文所用的术语“拓扑异构酶II抑制剂”非限制性地包括蒽环类抗生素如阿霉素(包括脂质体制剂,例如CAELYX)、柔红霉素、表柔比星、伊达比星和奈莫柔比星、蒽醌类米托蒽醌和洛索蒽醌、和鬼臼毒素类(podophillotoxines)依托泊苷和替尼泊苷。依托泊苷例如可以以其市售的形式,例如以商标ETOPOPHOS市售的形式施用。替尼泊苷例如可以以其市售的形式,例如以商标VM 26-BRISTOL市售的形式施用。阿霉素例如可以以其市售的形式,例如以商标ADRIBLASTIN或ADRIAMYCIN市售的形式施用。表柔比星例如可以以其市售的形式,例如以商标FARMORUBICIN市售的形式施用。伊达比星例如可以以其市售的形式,例如以商标ZAVEDOS市售的形式施用。米托蒽醌例如可以以其市售的形式,例如以商标NOVANTRON市售的形式施用。
术语“微管活性化合物”涉及微管稳定化合物、微管去稳定化合物和微管聚合抑制剂,非限制性地包括紫杉烷类,例如紫杉醇和多西紫杉醇、长春花属生物碱,例如,长春碱,尤其是硫酸长春碱、长春新碱,尤其是硫酸长春新碱和长春瑞滨、discodermolides、秋水仙碱和埃坡霉素类(epothilones)及其衍生物,例如埃坡霉素B或D或其衍生物。紫杉醇例如可以以其市售形式,例如TAXOL的形式施用。多西紫杉醇例如可以以其市售形式,例如以商标TAXOTERE市售的形式施用。硫酸长春碱例如可以以其市售形式,例如以商标VINBLASTIN R.P市售的形式施用。硫酸长春新碱例如可以以其市售形式,例如以商标FARMISTIN市售的形式施用。Discodermolide例如可以如US 5,010,099中所公开的那样获得。还包括在WO 98/10121、US 6,194,181、WO 98/25929、WO 98/08849、WO 99/43653、WO 98/22461和WO 00/31247中公开的埃坡霉素衍生物。尤其优选的是埃坡霉素A和/或B。
本文所用的术语“烷化化合物”非限制性地包括环磷酰胺、异环磷酰胺、美法仑或亚硝基脲(BCNU或Gliadel)。环磷酰胺例如可以以其市售形式,例如以商标CYCLOSTIN市售的形式施用。异环磷酰胺例如可以以其市售形式,例如以商标HOLOXAN市售的形式施用。
术语“组蛋白脱乙酰基酶抑制剂”或“HDAC抑制剂”涉及抑制组蛋白脱乙酰基酶并具有抗增殖活性的化合物。这包括化合物如在WO 02/22577中公开的LDH589,尤其是N-羟基-3-[4-[[(2-羟基乙基)[2-(1H-吲哚-3-基)乙基]-氨基]甲基]苯基]-2E-2-丙烯酰胺、N-羟基-3-[4-[[[2-(2-甲基-1H-吲哚-3-基)-乙基]-氨基]甲基]苯基]-2E-2-丙烯酰胺及其可药用盐。还尤其包括辛二酰基苯胺异羟肟酸(SAHA)。
术语“抗肿瘤的抗代谢物”非限制性地包括5-氟尿嘧啶或5-FU、卡培他滨、吉西他滨、DNA脱甲基化合物,如5-氮杂胞苷和地西他滨、甲氨蝶呤和依达曲沙、和叶酸拮抗剂如培美曲塞。卡培他滨例如可以以其市售形式,例如以商标XELODA市售的形式施用。吉西他滨例如可以以其市售形式,例如以商标GEMZAR市售的形式施用。
本文所用的术语“铂化合物”非限制性地包括卡铂、顺铂(cis-platin)、顺铂(cisplatinum)和奥沙利铂。卡铂例如可以以其市售形式,例如以商标CARBOPLAT市售的形式施用。奥沙利铂例如可以以其市售形式,例如以商标ELOXATIN市售的形式施用。
本文所用的术语“靶向/降低蛋白或脂质激酶活性的化合物”;或“蛋白或脂质磷酸酶活性”;或“其它抗血管生成化合物”非限制性地包括蛋白酪氨酸激酶和/或丝氨酸和/或苏氨酸激酶抑制剂或脂质激酶抑制剂,例如:
a)靶向、降低或抑制血小板衍生生长因子受体(PDGFR)活性的化合物,如靶向、降低或抑制PDGFR活性的化合物,尤其是抑制PDGF受体的化合物,例如,N-苯基-2-嘧啶-胺衍生物,例如,伊马替尼、SU101、SU6668和GFB-111;
b)靶向、降低或抑制成纤维细胞生长因子受体(FGFR)活性的化合物;
c)靶向、降低或抑制胰岛素样生长因子受体I(IGF-IR)活性的化合物,如靶向、降低或抑制IGF-IR活性的化合物,尤其是抑制IGF-I受体的激酶活性的化合物,如在WO 02/092599中所公开的那些化合物,或靶向于IGF-1受体或其生长因子的细胞结构域的抗体;
d)靶向、降低或抑制Trk受体酪氨酸激酶族活性的化合物,或ephrin B4抑制剂;
e)靶向、降低或抑制Axl受体酪氨酸激酶族活性的化合物;
f)靶向、降低或抑制Ret受体酪氨酸激酶活性的化合物;
g)靶向、降低或抑制Kit/SCFR受体酪氨酸激酶,即C-kit受体酪氨酸激酶-(PDGFR族的一部分)的化合物,如靶向、降低或抑制c-Kit受体酪氨酸激酶族活性的化合物,尤其是抑制c-Kit受体的化合物,例如伊马替尼;
h)靶向、降低或抑制c-Abl族成员、其基因融合产物(例如BCR-Abl激酶)和突变型活性的化合物,如靶向、降低或抑制c-Abl族成员以及其基因融合产物活性的化合物,例如N-苯基-2-嘧啶-胺衍生物,例如伊马替尼或尼洛替尼(AMN107);PD180970;AG957;NSC 680410;或得自ParkeDavis的PD173955;或达沙替尼(BMS-354825)
i)靶向、降低或抑制蛋白激酶C(PKC)成员和丝氨酸/苏氨酸激酶的Raf族、MEK、SRC、JAK、FAK、PDK1、PKB/Akt和Ras/MAPK族成员和/或细胞周期蛋白-依赖性激酶族(CDK)成员的活性的化合物并且尤其是在US 5,093,330中所公开的那些十字孢碱衍生物,例如米哚妥林;其它化合物的实例包括例如UCN-01、沙芬戈、BAY 43-9006、苔藓抑素1、哌立福辛;依莫福新;RO 318220和RO 320432;GO 6976;Isis 3521;LY333531/LY379196;异喹啉化合物如在WO 00/09495中公开的那些化合物;FTIs;BEZ235(一种P13K抑制剂)或AT7519(CDK抑制剂);
j)靶向、降低或抑制蛋白-酪氨酸激酶抑制剂活性的化合物,如靶向、降低或抑制蛋白-酪氨酸激酶抑制剂活性的化合物包括甲磺酸伊马替尼(GLEEVEC)或酪氨酸磷酸化抑制剂(tyrphostin)。酪氨酸磷酸化抑制剂优选地是一种低分子量(mw<1500)化合物或其可药用盐,尤其是选自亚苄基丙二腈类或S-芳基苯丙二腈或双底物(bisubstrate)喹啉类化合物,更尤其是任何选自Tyrphostin A23/RG-50810;AG 99;Tyrphostin AG213;Tyrphostin AG 1748;Tyrphostin AG 490;Tyrphostin B44;Tyrphostin B44(+)对映异构体;Tyrphostin AG 555;AG 494;Tyrphostin AG 556、AG957和adaphostin(4-{[(2,5-二羟基苯基)甲基]氨基}-苯甲酸金刚烷酯;NSC 680410,adaphostin)的化合物;
k)靶向、降低或抑制受体酪氨酸激酶的表皮生长因子族(均-或杂二聚体形式的EGFR、ErbB2、ErbB3、ErbB4)及其突变体的活性的化合物,如靶向、降低或抑制表皮生长因子受体族活性的化合物尤其是抑制EGF受体酪氨酸激酶族成员例如EGF受体、ErbB2、ErbB3和ErbB4或者与EGF或EGF相关配体结合的化合物、蛋白或抗体,并且特别是在WO 97/02266中一般和具体公开的那些化合物、蛋白或单克隆抗体,例如实施例39的化合物,或者是在EP 0 564 409、WO 99/03854、EP0520722、EP 0 566 226、EP 0 787 722、EP 0 837 063、US 5,747,498、WO 98/10767、WO 97/30034、WO 97/49688、WO 97/38983并且尤其是在WO 96/30347(例如被称为CP 358774的化合物)、WO 96/33980(例如化合物ZD 1839)和WO 95/03283(例如化合物ZM105180)中所公开的化合物、蛋白或单克隆抗体;例如曲妥单抗(HerceptinTM)、西妥昔单抗(ErbituxTM)、Iressa、Tarceva、OSI-774、CI-1033、EKB-569、GW-2016、E1.1、E2.4、E2.5、E6.2、E6.4、E2.11、E6.3或E7.6.3,和在WO 03/013541中公开的7H-吡咯并-[2,3-d]嘧啶衍生物;以及
l)靶向、降低或抑制c-Met受体活性的化合物,如靶向、降低或抑制c-Met活性的化合物,尤其是抑制c-Met受体的激酶活性的化合物,或靶向于c-Met的细胞结构域或者与HGF结合的抗体。
其它抗血管生成的化合物包括其活性具有其它机理例如与蛋白或脂质激酶的抑制无关的机理的化合物,例如沙利度胺(THALOMID)和TNP-470。
靶向、降低或抑制蛋白或脂质磷酸酶活性的化合物有例如磷酸酶1、磷酸酶2A、或CDC25的抑制剂,例如冈田酸或其衍生物。
诱导细胞分化过程的化合物有例如视黄酸、α-γ-或δ-生育酚或α-γ-或δ-生育三烯酸。
本文所用的术语环氧合酶抑制剂非限制性地包括例如Cox-2抑制剂、5-烷基取代的2-芳基氨基苯基乙酸和衍生物,如塞来考昔(CELEBREX)、罗非考昔(VIOXX)、艾托考昔、伐地考昔或5-烷基-2-芳基氨基苯基乙酸,例如5-甲基-2-(2’-氯-6’-氟苯氨基)苯基乙酸、鲁米考昔。
本文所用的术语“二膦酸盐”非限制性地包括依替膦酸(etridonic)、氯膦酸、替鲁膦酸、帕米膦酸、阿仑膦酸、伊班膦酸、利塞膦酸和唑来膦酸。“依替膦酸”例如可以以其市售形式,例如以商标DIDRONEL市售的形式施用。“氯膦酸”例如可以以其市售形式,例如以商标BONEFOS市售的形式施用。“替鲁膦酸”例如可以以其市售形式,例如以商标SKELID市售的形式施用。“帕米膦酸”例如可以以其市售形式,例如以商标标AREDIATM市售的形式施用。“阿仑膦酸”例如可以以其市售形式,例如以商标FOSAMAX市售的形式施用。“伊班膦酸”例如可以以其市售形式,例如以商标BONDRANAT市售的形式施用。“利塞膦酸”例如可以以其市售形式,例如以商标ACTONEL市售的形式施用。“唑来膦酸”例如可以以其市售形式,例如以商标ZOMETA市售的形式施用。
术语“mTOR抑制剂”涉及抑制哺乳动物雷帕霉素(mTOR)靶点并具有抗增殖活性的化合物如西罗莫司依维莫司CCI-779和ABT578。
本文所用的术语“类肝素酶抑制剂”是指靶向、降低或抑制硫酸肝素降解的化合物。该术语非限制性地包括PI-88。
本文所用的术语“生物学响应改性剂”涉及淋巴因子或干扰素类物质,例如干扰素γ。
本文所用的术语“Ras致癌亚型的抑制剂”,例如H-Ras、K-Ras、或N-Ras是指靶向、降低或抑制Ras的致癌活性的化合物例如“法尼基转移酶抑制剂”例如L-744832、DK8G557或R115777(Zarnestra)。
本文所用的术语“端粒末端转移酶抑制剂”是指靶向、降低或抑制端粒末端转移酶活性的化合物。靶向、降低或抑制端粒末端转移酶活性的化合物尤其是抑制端粒末端转移酶受体的化合物,例如telomestatin。
本文所用的术语“蛋氨酸氨基肽酶抑制剂”指的是靶向、降低或抑制蛋氨酸氨基肽酶活性的化合物。靶向、降低或抑制蛋氨酸氨基肽酶活性的化合物例如是bengamide或其衍生物。
本文所用的术语“蛋白酶体抑制剂”指的是靶向、降低或抑制蛋白酶体活性的化合物。靶向、降低或抑制蛋白酶体活性的化合物包括例如硼替佐米(Velcade)和MLN 341。
本文所用的术语“基质金属蛋白酶抑制剂”或(“MMP抑制剂”)非限制性地包括胶原拟肽和非拟肽抑制剂、四环素衍生物,例如异羟肟酸盐拟肽抑制剂巴马司他以及其可口服利用的类似物马立马司他(BB-2516)、普啉司他(AG3340)、metastat(NSC 683551)BMS-279251、BAY 12-9566、TAA211、MMI270B或AAJ996。
本文所用的术语“用于治疗血液学恶性肿瘤的化合物”非限制性地包括FMS-样酪氨酸激酶抑制剂例如靶向、降低或抑制FMS-样酪氨酸激酶受体(Flt-3R)活性的化合物;干扰素、1-b-D-阿糖呋喃基胞嘧啶(ara-c)和bisulfan;以及ALK抑制剂例如靶向、降低或抑制间变性淋巴瘤激酶的化合物。
靶向、降低或抑制FMS-样酪氨酸激酶受体(Flt-3R)活性的化合物尤其是抑制Flt-3R受体激酶族成员的化合物、蛋白或抗体,例如PKC412、TKI258、米哚妥林、十字孢碱衍生物、SU11248和MLN518。
本文所用的术语“HSP90抑制剂”非限制性地包括靶向、降低或抑制HSP90的固有ATP酶活性的化合物;通过泛素蛋白酶体途径降解、靶向、降低或抑制HSP90客户蛋白的化合物。靶向、降低或抑制HSP90的固有ATP酶活性的化合物尤其是抑制HSP90的ATP酶活性的化合物、蛋白或抗体例如,17-烯丙基氨基、17-脱甲氧基格尔德霉素(17AAG)、格尔德霉素衍生物;其它与格尔德霉素有关的化合物;根赤壳菌素和HDAC抑制剂。一个HSP90抑制剂的实例是AUY922。
本文所用的术语“抗增殖的抗体”非限制性地包括曲妥单抗(HerceptinTM)、曲妥单抗-DM1、爱必妥、贝伐单抗(AvastinTM)、利妥昔单抗PRO64553(抗-CD40)、2C4抗体和HCD122抗体(抗-CD40)。抗体指的是例如完整的单克隆抗体、多克隆抗体、由至少2个完整的抗体形成的多特异性抗体、和抗体片段,只要其表现出所需的生物学活性即可。
对于急性髓细胞性白血病(AML)的治疗而言,可以将式I的化合物与标准的白血病疗法联合使用,尤其是与用于治疗AML的治疗联用。式I的化合物特别是可以与例如法尼基转移酶抑制剂和/或用于治疗AML的其它药物如柔红霉素、阿霉素、Ara-C、VP-16、替尼泊苷、米托蒽醌、伊达比星、碳铂和PKC412联合施用。
术语“抗白血病的化合物”包括例如Ara-C,一种嘧啶类似物,其是脱氧胞苷酸的2-α-羟基核糖(阿糖胞苷)衍生物。还包括次黄嘌呤的嘌呤类似物、6-巯基嘌呤(6-MP)和磷酸氟达拉滨。
靶向、降低或抑制组蛋白脱乙酰基酶(HDAC)抑制剂活性的化合物如丁酸钠和辛二酰基苯胺异羟肟酸(SAHA)抑制了被称为组蛋白脱乙酰基酶的酶的活性。特定的HDAC抑制剂包括MS275、SAHA、FK228(以前称为FR901228)、曲古抑菌素A和在US 6,552,065中公开的化合物,特别是N-羟基-3-[4-[[[2-(2-甲基-1H-吲哚-3-基)-乙基]-氨基]甲基]苯基]-2E-2-丙烯酰胺或其可药用盐和N-羟基-3-[4-[(2-羟基乙基){2-(1H-吲哚-3-基)乙基]-氨基]甲基]苯基]-2E-2-丙烯酰胺或其可药用盐,尤其是其乳酸盐。
本文所用的生长抑素受体拮抗剂是指靶向、治疗或抑制生长抑素受体的化合物如奥曲肽和SOM230(pasireotide)。
损害肿瘤细胞的方法是指诸如电离辐射之类的方法。上面和下文所涉及的术语“电离辐射”是指以电磁射线(如X-射线和γ射线)或粒子(如α和β粒子)形式存在的电离辐射。电离辐射在例如、但不限于放疗中被提供并且在现有技术中是已知的。见Hellman,放疗原则,癌症(Principles ofRadiation Therapy,Cancer),肿瘤学中的原则和实践(Principles andPractice of Oncology),Devita等人编辑,第4版,第1卷,第248-275页(1993)。
本文所用的术语“EDG结合剂”是指一类调节淋巴细胞再循环的免疫抑制剂如FTY720。
术语“核苷酸还原酶抑制剂”是指嘧啶或嘌呤核苷类似物,非限制性地包括氟达拉滨和/或阿糖胞苷(ara-C)、6-硫鸟嘌呤、5-氟尿嘧啶、克拉屈滨、6-巯基嘌呤(尤其是与ara-C激动剂ALL联合)和/或喷司他丁。核苷酸还原酶抑制剂尤其是羟基脲或2-羟基-1H-异吲哚-1,3-二酮衍生物,如在Nandy等人,Acta Oncologica,第33卷,第8期,第953-961页(1994)中提及的PL-1、PL-2、PL-3、PL-4、PL-5、PL-6、PL-7或PL-8。
本文所用的术语“S-腺苷基甲硫氨酸脱羧酶抑制剂”非限制性地包括在US 5,461,076中公开的化合物。
还包括特别是在WO 98/35958中公开的那些化合物、蛋白或VEGF的单克隆抗体,例如1-(4-氯苯胺基)-4-(4-吡啶基甲基)酞嗪或其可药用盐,例如其琥珀酸盐,或在WO 00/09495、WO 00/27820、WO00/59509、WO 98/11223、WO 00/27819和EP 0 769 947中公开的那些物质;如Prewett等人,Cancer Res,第59卷,第5209-5218页(1999);Yuan等人,Proc Natl Acad Sci U S A,第93卷,第14765-14770页(1996);Zhu等人,Cancer Res,第58卷,第3209-3214页(1998);和Mordenti等人,Toxicol Pathol,第27卷,第1期,第14-21页(1999)所述的那些物质;在WO 00/37502和WO 94/10202中公开的那些物质;O’Reilly等人,Cell,第79卷,第315-328页(1994)所述的血管他丁(ANGIOSTATIN);O’Reilly等人,Cell,第88卷,第277-285页(1997)所述的内皮他丁(ENDOSTATIN);
邻氨基苯甲酰胺类;ZD4190;ZD6474;SU5416;SU6668;贝伐单抗;
或抗-VEGF抗体或抗-VEGF受体抗体,例如rhuMAb和RHUFab、VEGF适体例如Macugon;FLT-4抑制剂、FLT-3抑制剂、VEGFR-2IgG1抗体、Angiozyme(RPI 4610)和贝伐单抗(AvastinTM)。
本文所用的光动力学疗法是指使用某些被称为光致敏化合物的化学品来治疗或预防癌症的疗法。光动力学疗法的实例包括用化合物例如VISUDYNE和卟吩姆钠进行的治疗。
本文所用的抗血管生成的(angiostatic)甾族化合物是指阻断或抑制血管生成的化合物,例如,阿奈可他、曲安西龙、氢化可的松、11-α-表氢可的松、11-脱氧皮甾醇、17-α-羟基黄体酮、皮质酮、去氧皮质酮、睾酮、雌酮和地塞米松。
包含皮质激素的植入物是指化合物,例如氟轻松、地塞米松。
“其它化疗化合物”非限制性地包括植物生物碱类、激素化合物和拮抗剂;生物学反应调节剂,优选淋巴因子类或干扰素类;反义寡核苷酸或寡核苷酸衍生物;shRNA或siRNA;或具有其它或未知作用机理的各种化合物。
用代码、属名或商品名确定的活性化合物的结构可以得自标准纲要“默克索引(The Merck Index)”的现行版本或数据库,例如PatentsInternational(例如IMS World Publications)。
本公开物引用的任何参考资料都不应被看作是承认所引用的参考资料是将对本发明专利性有负面影响的现有技术。
本发明化合物的制备方法
本发明还包括制备本发明化合物的方法。在所述反应中,当终产物中需要有反应性官能团,例如羟基、氨基、亚胺基、巯基或羧基的情况中,可能需要对这些官能团进行保护,以避免其在反应中不必要的参与。可以根据标准操作使用常规保护基团,例如,参见T.W.Greene和P.G.M.Wuts,“有机化学中的保护基团(Protective Groups in Organic Chemistry)”,John Wiley和Sons,1991。
其中R3通过非氮原子与苯基环相连的式I化合物可以用如下反应流程I中的方法来制备:
反应流程I:
其中R1、R2和R4如发明概述中式I所定义且R3是任选地被取代的芳基或杂芳基。式I的化合物可以通过使化合物(4)与式(5)的化合物任选地在存在适宜催化剂(例如,二(三苯基膦)-氯化钯(II)等)、适宜的碱(如碳酸钠等)和适宜的溶剂(如DME等)的情况下反应来进行制备。该反应在约120℃下进行并且进行最长约2小时以反应完全。对于反应流程III而言,化合物4苯基环上R2和Br的位置可互换。
可以在下面的实施例中找到式I化合物合成的详细实例。
另一些制备本发明化合物的方法
可以通过使化合物的游离碱形式与可药用的无机酸或有机酸反应来将本发明化合物制备为可药用酸加成盐的形式。或者,可以通过使化合物的游离酸形式与可药用的无机碱或有机碱反应来制备本发明化合物可药用的碱加成盐。
也可以通过附加适宜的官能团来对式I化合物进行修饰以增强选择性生物学性质。这类修饰在现有技术中是已知的,并且包括下面那些修饰:增加向给定生物系统(例如血液、淋巴系统、中枢神经系统、睾丸)中的渗透、增加生物利用度、增加溶解度以使得可以进行胃肠外施用(例如注射、输入)、改变代谢和/或改变分泌速率的修饰。这类修饰的实例非限制性地包括酯化,例如用聚乙二醇类进行酯化、用新戊酰氧基或脂肪酸取代基进行衍生、转化成氨基甲酸酯类、芳族环的羟基化和在芳族环中进行杂原子取代。在提及式I化合物和/或其N-氧化物、互变异构体和/或盐(优选药用的盐)的情况中,其包含该类进行了修饰的结构式,优选意指式I的分子、其N-氧化物、其互变异构体和/或其盐。
或者,可以用起始材料或中间体的盐来制备本发明化合物的盐形式。由于游离形式的新式I化合物和其盐形式(包括可用作中间体的那些盐,例如在该新化合物的纯化或鉴定中用作中间体的那些盐)的那些化合物之间的紧密关系,在上下文中任何时候涉及到式I的化合物时均应理解为涉及游离形式的化合物和/或在适宜和有利时,也涉及其一种或多种盐,以及一种或多种溶剂化物,例如水合物。
由具有碱性氮原子的式I化合物形成例如酸加成盐形式的盐,优选地用有机酸或无机酸来形成盐,尤其是可药用的盐。适宜的无机酸有例如氢卤酸,如盐酸、硫酸或磷酸。适宜的有机酸有例如羧酸、膦酸、磺酸或氨基磺酸,例如醋酸、丙酸、辛酸、癸酸、十二烷酸、乙醇酸、乳酸、富马酸、琥珀酸、丙二酸、己二酸、庚二酸、辛二酸、壬二酸、苹果酸、酒石酸、枸橼酸、氨基酸,如谷氨酸或天门冬氨酸、马来酸、羟基马来酸、甲基马来酸、环己烷甲酸、金刚烷甲酸、苯甲酸、水杨酸、4-氨水杨酸、酞酸、苯乙酸、扁桃酸、肉桂酸、甲磺酸或乙磺酸、2-羟基乙磺酸、乙烷-1,2-二磺酸、苯磺酸、4-甲苯磺酸、2-萘磺酸、1,5-萘-二磺酸、2-或3-甲基苯磺酸、甲基硫酸、乙基硫酸、十二烷基硫酸、N-环己基氨基磺酸、N-甲基、N-乙基或N-丙基-氨基磺酸、或其它有机质子酸,如抗坏血酸。
对于分离或纯化目的而言,也可使用不可药用的盐,例如苦味酸盐或高氯酸盐。对于治疗应用而言,仅使用可药用的盐或游离化合物(在适宜的情况中可以使用药物制剂形式),并且因此优选这些形式的物质。
本发明化合物的游离酸或游离碱形式可以分别由相应的碱加成盐或酸加成盐形式来制备。例如,可以通过用适宜的碱(例如氢氧化铵溶液、氢氧化钠等)处理来将酸加成盐形式的本发明化合物转化成相应的游离碱。可以通过用适宜的酸(例如盐酸等)处理来将碱加成盐形式的本发明化合物转化成相应的游离酸。
未氧化形式的本发明化合物可以由本发明化合物的N-氧化物,通过用还原剂(例如硫、二氧化硫、三苯基膦、硼氢化锂、硼氢化钠、三氯化磷、三溴化磷等)在适宜的惰性有机溶剂(例如乙腈、乙醇、含水二恶烷等)中在0至80℃下处理来进行制备。
本发明化合物的前药衍生物可以用本领域普通技术人员已知的方法来制备(例如,对于进一步的细节而言,参见Saulnier等,(1994),Bioorganicand Medicinal Chemistry Letters,第4卷,第1985页)。例如,可以通过使未被衍生化的本发明化合物与适宜的氨基甲酰化试剂(例如,1,1-酰氧基烷基羰基氯(carbanochloridate)、对-硝基苯基碳酸酯等)反应来制备适宜的前药。
本发明化合物被保护的衍生物可以通过本领域技术人员已知的方法制备。用于产生保护基团和除去它们的技术的详述可以参见T.W.Greene,“有机化学中的保护基团(Protecting Groups in Organic Chemistry)”,第三版,John Wiley和Sons,Inc.,1999。
本发明化合物可以在本发明的工艺过程中方便地被制备或形成为溶剂化物(例如,水合物)形式。本发明化合物的水合物可以方便地通过由使用有机溶剂如二噁英、四氢呋喃或甲醇的水性/有机溶剂混合物重结晶来进行制备。
通过使化合物的外消旋混合物与光学活性的拆分试剂反应形成非对映异构体化合物对,分离非对映异构体并回收光学纯的对映体,可以将本发明化合物制备为其各个立体异构体形式。虽然对映体的拆分可以用本发明化合物的共价非对映异构体衍生物进行,但是优选可解离的复合物(如,结晶性非对映异构的盐)。非对映异构体具有不同的物理性质(如,熔点、沸点、溶解度、反应性等),利用这些不同点可以容易地对其进行分离。可通过色谱技术来对非对映异构体进行分离,或者优选地根据溶解性的差异,通过分离/拆分技术来进行分离。然后,用不会导致消旋化的任何实用的方法回收获得光学纯的对映异构体以及拆分剂。用于由其外消旋混合物拆分化合物的立体异构体的技术的更详细描述可参见Jean Jacques,AndreCollet,Samuel H.Wilen,“对映异构体、外消旋体和拆分”,John Wiley和Sons,Inc.,1981。
总之,式I化合物可通过下述方法制备,该方法包括:
(a)反应流程I;和
(b)任选地将本发明化合物转化为可药用的盐;
(c)任选地将本发明化合物的盐形式转化为非盐形式;
(d)任选地将本发明化合物的未氧化形式转化为可药用的N-氧化物;
(e)任选地将本发明化合物的N-氧化物形式转化为其未被氧化的形式;
(f)任选地由异构体混合物拆分出本发明化合物的各个异构体;
(g)任选地将本发明化合物的未衍生化形式转化成可药用的前药衍生物;以及
(h)任选地将本发明化合物的前药衍生物转化成其未衍生化的形式。
当未对起始材料的制备进行特别描述时,该化合物是已知的或者可用本领域已知的方法类似地制备或如下文实施例所述那样进行制备。
本领域技术人员将意识到上述转化仅仅是制备本发明化合物方法的代表,并可类似地使用其它众所周知的方法。
实施例
以下中间体和实施例用来对本发明进行说明但不会对其范围构成限制。在实施例的描述中使用下面的缩写和方法:
缩写:
aq.(水性);AcOH(醋酸);DCM(二氯甲烷);DIPEA(二异丙基乙基胺);DME(1,2-二甲氧基乙烷);DMSO(二甲基亚砜);EDC(1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐);eq(当量);Et3N(三乙胺);EtOAc(乙酸乙酯);EtOH(乙醇);h(小时);HOBt(1-羟基-苯并三唑);MeOH(甲醇);min(分钟);MS(质谱);N(当量浓度);NMR(核磁共振光谱);Rf(保留因子);RT(室温);TBDMS(叔丁基二甲基甲硅烷基);THF(四氢呋喃);TLC(薄层色谱)。
HPLC条件:
方法A:柱:Inertsil ODS3V(250X 4.6)mm,5μm;流动相:A:0.01MKH2PO4/0.01M KH2PO4pH调至6.5;B:ACN;梯度信息:(T/%B):0/30,2/30,6/85,16/85,17/30,18/30);流速:1.0ml/min;UV检测210.0nm。
方法B:柱:Inertsil ODS3V(250X 4.6)mm,5μm;流动相:A:0.01MKH2PO4/0.01M KH2PO4pH调至6.5;B:ACN;梯度信息:(T/%B):0/30,2/30,6/80,13/80,14/30,15/30);流速:1.0ml/min;UV检测210.0nm。
方法C:柱:XTerra RP18(250X 4.6)mm,5μm;流动相:A:0.01MKH2PO4/0.01M KH2PO4pH调至6.5;B:ACN;梯度信息:(T/%B):0/30,2/30,6/85,16/85,17/30,18/30);流速:1.0ml/min;UV检测210.0nm。
方法D:柱:XTerra RP18(250X 4.6)mm,5μm;流动相:A:0.01MKH2PO4/0.01M KH2PO4pH调至6.5;B:ACN;梯度信息:(T/%B):0/30,2/30,6/80,13/80,14/30,15/30);流速:1.0ml/min;UV检测210.0nm。
方法E:柱:Hypersil BDS C18(250X 4.6)mm,5μm;流动相:A:0.01M KH2PO4/0.01M KH2PO4pH调至6.5;B:ACN;梯度信息:(T/%B):0/30,15/50,18/90,28/90,28.10/30);流速:0.8ml/min;UV检测260.0nm。
方法F:柱:Hypersil BDS C18(250X 4.6)mm,5μm;流动相:A:0.01M醋酸铵;B:ACN;梯度信息:(T/%B):0/30,15/50,18/90,28/90,28.10/30);流速:0.8ml/min;UV检测260.0nm。
方法G:柱:XTerra RP18(250X 4.0)mm,5μm;流动相:A:0.01MKH2PO4(pH 6.5);B:ACN;梯度信息:(T/%B):0/30,2/30,6/80,13/80,14/30,15/30;流速:1.0ml/min;UV检测210.0nm。
方法H:柱:Inertsil ODS3V(250X 4.6)mm,5μm;流动相:A:0.01MKH2PO4(pH调至6.5);B:ACN;梯度信息:(T/%B):0/70,1.5/70,5/85,13/85,14/70,15/70;流速:1.0ml/min;UV检测210.0nm。
方法I:柱:XTerra RP18(250X 4.6)mm,5μm;流动相:A:0.01MKH2PO4;B:ACN;梯度信息:(T/%B):0/30,2/30,6/80,16/80,17/30,18/30;流速:1.0ml/min;UV检测210.0nm。
方法J:柱:ACE5C18(250X 4.6)mm,5μm;流动相:A:0.01MKH2PO4;B:ACN;梯度信息:(T/%B):0/30,2/30,6/85,16/85,17/30,18/30;流速:1.0ml/min;UV检测210.0nm。
方法K:柱:Inertsil ODS3V;流动相:A:0.01M KH2PO4;B:ACN;梯度信息:(T/%B):0/50,1.5/50,5/80,13/80,14/50,15/50;流速:1.0ml/min;UV检测210.0nm。
方法L:柱:XTerra RP18(250X 4.6)mm,5μm;流动相:A:0.01MKH2PO4(pH 6.5);B:ACN;梯度信息:(T/%B):0/50,2/50,9/85,16/85,17/50,18/50;流速:1.0ml/min;UV检测210.0nm。
方法M:柱:Symmetry Shield RP18(150mm x 4.6mm),5μm;流动相:A:0.01%TFA(aq.);B:ACN;梯度信息:(T/%B):0/20,2/20,6/85,13/85,14/20,15/20;流速:1.0ml/min;UV检测210.0nm。
NMR光谱:
1H NMR光谱是在Varian 400MHz(Varian Mercury Plus)或500MHz(Unity INOVA)光谱仪上进行记录的,用DMSO-d6或CDCl3作为溶剂。化学位移是以δ值来进行报告的,用四甲基甲硅烷(TMS,d 0.00)作为内标,偶合常数(J)以Hz为单位进行报告。分别用标准缩写s、d、t、q、dd、dt和m来表征单峰、双峰、三重峰、四重峰、双二重峰、双三重峰和多重峰。
质谱:
LC-MS和ES-MS谱是在Perkin-Elmer Sciex,API 3000型上进行的。
LC-MS条件:
方法A:在甲酸(FA)中的常规方法;柱:Cynergi 2.5μm Max-RP100A(20x4.0)mm;流动相:A:0.1%FA(aq.);B:ACN;T/%B:0/20,0.5/20,2.5/95,4.5/95,5.0/20;流速:1.5mL/min。
方法B:在醋酸铵(AA)中的常规方法;柱:Cynergi 2.5μmMax-RP100A(20x 4.0)mm;流动相:A:0.01M醋酸铵(aq.);B:ACN;T%B:0/20,1.0/20,2.5/85,4.0/95,4.5/20,5.0/20;流速:1.0mL/min。
中间体A
(S)-1-(4-氨基-2-(3-(羟基甲基)-1,2,3,4-四氢异喹啉-2-羰基)苯基)-N,N-二丁
基-5-甲基-1H-吡唑-3-甲酰胺
步骤1:2-肼基-5-硝基苯甲酸盐酸盐的制备。向冰冷的2-氨基-5-硝基苯甲酸(50.0g,274.5mmol)在水(350mL)中的溶液中加入浓HCl(404mL)。将反应混合物搅拌至盐沉淀完全。在0℃下缓慢加入亚硝酸钠(29.0g,411.8mmol)在水(300mL)中的溶液,同时将其搅拌15min。将反应混合物缓慢加入到冰冷的亚硫酸(2.5L)中,然后在室温下搅拌12小时。将反应混合物再次冷却至0℃,加入浓HCl直至固体分离出来。将该固体滤出,用冷HCl洗涤并真空干燥,从而得到黄色固体状的标题化合物60g(93%),将其在不进行进一步纯化的情况下使用。Rf=0.10(10%MeOH的DCM溶液)。
步骤2:2-(3-(乙氧基羰基)-5-甲基-1H-吡唑-1-基)-5-硝基苯甲酸的制备。向2-肼基-5-硝基苯甲酸盐酸盐(59.4g,255.1mmol)在AcOH(500mL)中的溶液中加入乙基-2,4-二氧代戊酸酯(31.0g,196.2mmol)。将反应混合物回流2小时。真空蒸发掉AcOH并将残余物与甲苯(100mL)一起共馏两次。将残余物溶解于EtOAc中并用水洗涤至水层变为中性。将有机层用硫酸钠干燥并真空浓缩。将树胶状物质用乙醚研磨得到白色固体状标题化合物35g(56%)。Rf=0.30(10%MeOH的DCM溶液);1H NMR(400MHz,DMSO-d6):δ13.90-13.60(brs,1H),8.62(d,J=2.5Hz,1H),8.54(dd,J=2.6&8.5Hz,1H),7.90(d,J=8.3Hz,1H),6.76(s,1H),4.27(q,J=7.0Hz,2H),2.19(s,3H),1.28(t,J=7.1Hz,3H);LC-MS:m/z 320.1(M+H)。
步骤3:(S)-1-(2-(3-(羟基甲基)-1,2,3,4-四氢异喹啉-2-羰基)-4-硝基苯基)-5-甲基-1H-吡唑-3-甲酸乙酯的制备。向冰冷的2-(3-(乙氧基羰基)-5-甲基-1H-吡唑-1-基)-5-硝基苯甲酸(25.0g,78.4mmol)在DMF(250mL)中的溶液中加入(S)-(1,2,3,4-四氢异喹啉-3-基)甲醇(31.0g,62.7mmol)、EDC.HCl(23.0g,117.5mmol)、HOBT(13.75g,101.9mmol),然后在室温下搅拌12小时。将反应混合物用水稀释,用EtOAc萃取两次(500mL X 2)。将所合并的有机层用水(500mL)、盐水(100mL)洗涤,用硫酸钠干燥并真空浓缩。将残余物在硅胶(100-200目)上进行纯化得到’米白色’标题化合物18g(49%)。Rf=0.45(25%EtOAc的己烷溶液);1H NMR(400MHz,DMSO-d6):δ8.70-8.35(m,2H),8.15-7.98(m,1H),7.25-6.95(m,4H),6.82-6.58(m,1H),5.20-3.80(m,8H),3.40-2.40(m,2H),2.38-2.10(m,3H),1.30-0.80(m,3H);ES-MS:m/z 465.3(M+H)。
步骤4:(S)-1-(2-(3-(羟基甲基)-1,2,3,4-四氢异喹啉-2-羰基)-4-硝基苯基)-5-甲基-1H-吡唑-3-甲酸的制备。向(S)-1-(2-(3-(羟基甲基)-1,2,3,4-四氢异喹啉-2-羰基)-4-硝基苯基)-5-甲基-1H-吡唑-3-甲酸乙酯(18.0g,38.8mmol)在THF(30mL)和水(20mL)中的溶液中加入氢氧化锂单水合物(5.0g,116.8mmol),然后在室温下搅拌6小时。将反应混合物真空浓缩,用水(80mL)稀释并用乙醚(100mL)萃取。将水层冷却至0℃,用3N HCl酸化至pH~4并用EtOAc(200mL X 2)萃取两次。将所合并的有机层用水(200mL)、盐水(100mL)洗涤,用硫酸钠干燥并真空浓缩。将残余物在硅胶(100-200目)上进行纯化得到白色固体状标题化合物14g(82%)。Rf=0.25(70%EtOAc的己烷溶液);1H NMR(400MHz,DMSO-d6):δ12.90-12.50(brs,1H),8.64-8.30(m,2H),8.06-7.72(m,1H),7.24-6.82(m,4H),6.80-6.42(m,1H),5.20-3.80(m,6H),3.40-2.40(m,2H),2.40-2.10(m,3H);ES-MS:m/z 437.2(M+H)。
步骤5:(S)-N,N-二丁基-1-(2-(3-(羟基甲基)-1,2,3,4-四氢异喹啉-2-羰基)-4-硝基苯基)-5-甲基-1H-吡唑-3-甲酰胺的制备。向(S)-1-(2-(3-(羟基甲基)-1,2,3,4-四氢异喹啉-2-羰基)-4-硝基苯基)-5-甲基-1H-吡唑-3-甲酸(14.0g,32.1mmol)在DMF(150mL)中的溶液中加入二丁基胺(8.6mL,48.2mmol)、EDC.HCl(9.2g,48.2mmol)、HOBT(5.63g,41.7mmol),然后在室温下搅拌12小时。将反应混合物用水稀释并用EtOAc萃取两次(300mLX 2)。将所合并的有机层用水(300mL)、盐水(100mL)洗涤,用硫酸钠干燥并真空浓缩。将残余物在硅胶(100-200目)上进行纯化得到‘米白色’固体状标题化合物9g(51%)。Rf=0.47(25%EtOAc的己烷溶液);1H NMR(400MHz,DMSO-d6):δ8.62-8.22(m,2H),8.00-7.80(m,1H),7.30-6.84(m,4H),6.60-6.35(m,1H),5.20-3.80(m,3H),3.79-2.40(m,9H),2.38-2.20(m,3H),1.60-0.50(m,14H);LC-MS:m/z 548.0(M+H)。
步骤6:(S)-1-(4-氨基-2-(3-(羟基甲基)-1,2,3,4-四氢异喹啉-2-羰基)苯基)-N,N-二丁基-5-甲基-1H-吡唑-3-甲酰胺的制备。向(S)-N,N-二丁基-1-(2-(3-(羟基甲基)-1,2,3,4-四氢异喹啉-2-羰基)-4-硝基苯基)-5-甲基-1H-吡唑-3-甲酰胺(1.1g,2.0mmol)在EtOH(10mL)中的溶液中加入10%Pd-C(0.04g),然后在H2囊压下在室温下搅拌5小时。将反应混合物用硅藻土过滤,将滤床用EtOH(20mL)洗涤并将滤液真空浓缩。将残余物在硅胶(100-200目)上进行纯化得到‘米白色’固体状标题化合物0.8g(77%)。Rf=0.33(40%EtOAc的己烷溶液);1H NMR(400MHz,DMSO-d6):δ7.30-6.82(m,5H),6.80-6.15(m,3H),5.72-5.50(m,2H,D2O可交换的),5.20-4.78(m,1H,D2O可交换的),4.90-4.00(m,2H),4.00-2.22(m,9H),2.20-2.00(m,3H),1.60-0.60(m,14H);LC-MS:m/z 518.3(M+H);HPLC:98.64%(RT=5.997min.,方法B)。
中间体B
(S)-1-(4-氨基-2-(3-(((叔-丁基二甲基甲硅烷基)氧基)甲基)-1,2,3,4-四氢异喹
啉-2-羰基)苯基)-N,N-二丁基-5-甲基-1H-吡唑-3-甲酰胺
(S)-N,N-二丁基-1-(2-(3-(((叔-丁基二甲基甲硅烷基)-氧基)甲基)-1,2,3,4-四氢异喹啉-2-羰基)-4-硝基苯基)-5-甲基-1H-吡唑-3-甲酰胺的制备。向(S)-N,N-二丁基-1-(2-(3-(羟基甲基)-1,2,3,4-四氢异喹啉-2-羰基)-4-硝基苯基)-5-甲基-1H-吡唑-3-甲酰胺(9.0g,16.4mmol)在DCM(150mL)中的溶液中加入TBDMS-氯化物(2.98g,19.7mmol)、咪唑(2.23g,32.9mmol),然后在室温下搅拌12小时。将反应混合物用水稀释并用EtOAc萃取两次(300mL X 2)。将所合并的有机层用水(300mL)、盐水(100mL)洗涤,用硫酸钠干燥并真空浓缩。将残余物在硅胶(100-200目)上进行纯化得到液体状标题化合物7g(64%)。Rf=0.74(25%EtOAc的己烷溶液);1H NMR(400MHz,DMSO-d6):δ8.60-8.20(m,2H),8.05-7.80(m,1H),7.40-6.80(m,4H),6.60-6.30(m,1H),5.10-3.84(m,4H),3.82-2.40(m,7H),2.40-2.20(m,3H),1.60-0.55(m,23H),0.05-0.40(m,6H);LC-MS:m/z 662.4(M+H)。
步骤2:(S)-1-(4-氨基-2-(3-(((叔-丁基二甲基甲硅烷基)-氧基)甲基)-1,2,3,4-四氢异喹啉-2-羰基)苯基)-N,N-二丁基-5-甲基-1H-吡唑-3-甲酰胺的制备。向(S)-N,N-二丁基-1-(2-(3-(((叔-丁基二甲基甲硅烷基)-氧基)甲基)-1,2,3,4-四氢异喹啉-2-羰基)-4-硝基苯基)-5-甲基-1H-吡唑-3-甲酰胺(3.0g,4.5mmol)在EtOH(50mL)中的溶液中加入10%Pd-C(0.3g),然后在H2囊压下在室温下搅拌3小时。将反应混合物用硅藻土过滤,将滤床用EtOH(150mL)洗涤并将滤液真空浓缩。将残余物在硅胶(100-200目)上进行纯化得到‘米白色’固体状标题化合物2.0g(69%)。Rf=0.45(25%EtOAc的己烷溶液);1H NMR(400MHz,DMSO-d6):δ7.40-6.82(m,5H),6.80-6.20(m,3H),5.74-5.50(m,2H),5.10-4.00(m,2H),3.99-2.20(m,9H),2.20-2.00(m,3H),1.60-0.58(m,23H),0.00--0.04(m,6H);LC-MS:m/z 632.6(M+H)。
中间体C
(S)-1-(4-溴-2-(3-(((叔-丁基二甲基甲硅烷基)氧基)甲基)-1,2,3,4-四氢-异喹啉
-2-羰基)苯基)-N,N-二丁基-5-甲基-1H-吡唑-3-甲酰胺
步骤1:5-溴-2-肼基苯甲酸盐酸盐的制备。在-10℃下,向2-氨基-5-溴苯甲酸(50.0g,231.5mmol)在浓HCl(250mL)中的混悬液中缓慢加入亚硝酸钠(23.92g,347.2mmol)在水(250mL)中的溶液,然后搅拌2小时。向该反应混合物中缓慢加入氯化亚锡(130.50g,225.6mmol)在浓HCl(125mL)中的溶液,同时将其在室温下继续搅拌12小时。将反应混合物过滤,将残余物用少量水洗涤并真空干燥得到‘米白色’固体状标题化合物61g(100%),将其在不进行进一步纯化的情况下用于下一步。Rf=0.10(乙酸乙酯);1H NMR(400MHz,DMSO-d6):δ11.60-9.60(brs,3H),7.93(d,J=2.4Hz,1H),7.72(dd,J=2.4&8.8Hz,1H),7.12(d,J=8.8Hz,1H);ES-MS:m/z 229.1(M-H)。
步骤2:5-溴-2-(3-(乙氧基羰基)-5-甲基-1H-吡唑-1-基)苯甲酸的制备。向5-溴-2-肼基苯甲酸盐酸盐(60.0g,225.6mmol)在AcOH(600mL)中的溶液中加入乙基-2,4-二氧代戊酸酯(35.67g,225.6mmol),然后回流3小时。真空蒸发掉AcOH并将残余物与甲苯(100mL)一起共馏两次。将残余物溶解于EtOAc中并用水洗涤至水层变为中性。将有机层用硫酸钠干燥并真空浓缩。将树胶状物质用乙醚研磨,从而以棕色油状物形式得到标题化合物80g(100%),将其在不进行进一步纯化的情况下用于下一步。Rf=0.23(10%MeOH的DCM溶液);1H NMR(400MHz,DMSO-d6):δ13.80-12.80(brs,1H),8.08(d,J=1.9Hz,1H),7.96(dd,J=2.4&8.3Hz,1H),7.53(d,J=8.3Hz,1H),6.70(s,1H),4.26(q,J=7.2Hz,2H),2.13(s,3H),1.28(t,J=7.1Hz,3H);ES-MS:m/z 353.1(M+H)。
步骤3:(S)-1-(4-溴-2-(3-(羟基甲基)-1,2,3,4-四氢异喹啉-2-羰基)苯基)-5-甲基-1H-吡唑-3-甲酸乙酯的制备。向冰冷的5-溴-2-(3-(乙氧基羰基)-5-甲基-1H-吡唑-1-基)苯甲酸(45.0g,127.8mmol)在DCM(450mL)中的溶液中加入(S)-(1,2,3,4-四氢异喹啉-3-基)甲醇(20.8g,102.27mmol)、HATU(72.7g,191.2mmol)、DIPEA(55.7mL,319.6mmol),然后在室温下搅拌12小时。将反应混合物用DCM(750mL)稀释,用水(500mL)、盐水(100mL)洗涤,用硫酸钠干燥并真空浓缩。将残余物在硅胶(100-200目)上进行纯化得到液体状标题化合物50g(79%)。Rf=0.44(55%EtOAc的己烷溶液);1H NMR(400MHz,DMSO-d6):δ8.00-7.40(m,3H),7.30-7.00(m,4H),6.80-6.40(m,1H),5.10-3.80(m,7H),3.50-2.40(m,3H),2.40-2.10(m,3H),1.30-1.00(m,3H);ES-MS:m/z 498.2(M+H)。
步骤4:(S)-1-(4-溴-2-(3-(羟基甲基)-1,2,3,4-四氢异喹啉-2-羰基)苯基)-5-甲基-1H-吡唑-3-甲酸的制备。向(S)-1-(4-溴-2-(3-(羟基甲基)-1,2,3,4-四氢异喹啉-2-羰基)苯基)-5-甲基-1H-吡唑-3-甲酸乙酯(50.0g,100.6mmol)在THF(80mL)和水(20mL)中的溶液中加入氢氧化锂单水合物(21.1g,503.0mmol),然后在室温下搅拌12小时。将反应混合物真空浓缩,用水(80mL)稀释并用乙醚(100mL)萃取。将水层冷却至0℃,用3N HCl酸化至pH~4并用EtOAc萃取两次(200mL X 2)。将所合并的有机层用水(200mL)、盐水(100mL)洗涤,用硫酸钠干燥并真空浓缩。将残余物在硅胶(100-200目)上进行纯化得到浅黄色固体状标题化合物,40g(粗品)。Rf=0.10(30%EtOAc的己烷溶液);1H NMR(400MHz,DMSO-d6):δ12.80-11.80(m,1H),8.15-7.40(m,3H),7.30-6.90(m,4H),6.70-6.30(m,1H),5.10-3.70(m,5H),3.50-2.40(m,3H),2.38-2.10(m,3H);ES-MS:m/z470.5(M+H)。
步骤5:(S)-1-(4-溴-2-(3-(羟基甲基)-1,2,3,4-四氢异喹啉-2-羰基)苯基)-N,N-二丁基-5-甲基-1H-吡唑-3-甲酰胺的制备。向(S)-1-(4-溴-2-(3-(羟基甲基)-1,2,3,4-四氢异喹啉-2-羰基)苯基)-5-甲基-1H-吡唑-3-甲酸(10.0g,21.3mmol)在DMF(100mL)中的溶液中加入二丁基胺(3.7mL,21.3mmol)、EDC.HCl(6.1g,31.9mmol)、HOBT(3.3g,21.3mmol),然后在室温下搅拌12小时。将反应混合物用水稀释,用EtOAc萃取两次(100mL X 2)。将所合并的有机层用水(100mL)、盐水(50mL)洗涤,用硫酸钠干燥并真空浓缩。将残余物在硅胶(100-200目)上进行纯化得到吸湿性固体状标题化合物,4.5g(36%)。Rf=0.44(55%EtOAc的己烷溶液);1H NMR(400MHz,DMSO-d6):δ8.00-7.40(m,3H),7.30-6.80(m,4H),6.50-6.20(m,1H),5.10-4.00(m,3H),4.00-2.40(m,9H),2.40-2.00(m,3H),1.60-0.50(m,14H);LC-MS:m/z 581.4(M+H);HPLC:90.74%(RT=9.216min.,方法C)。
步骤6:(S)-1-(4-溴-2-(3-(((叔-丁基二甲基甲硅烷基)-氧基)甲基)-1,2,3,4-四氢-异喹啉-2-羰基)苯基)-N,N-二丁基-5-甲基-1H-吡唑-3-甲酰胺的制备。向(S)-1-(4-溴-2-(3-(羟基甲基)-1,2,3,4-四氢异喹啉-2-羰基)苯基)-N,N-二丁基-5-甲基-1H-吡唑-3-甲酰胺(3.0g,5.2mmol)在DCM(30mL)中的溶液中加入TBDMS-氯化物(0.93g,6.2mmol)、咪唑(0.70g,10.3mmol),然后在室温下搅拌5小时。将反应混合物用水稀释,用EtOAc萃取两次(100mL X 2)。将所合并的有机层用水(100mL)、盐水(50mL)洗涤,用硫酸钠干燥并真空浓缩。将残余物在硅胶(100-200目)上进行纯化得到液体状标题化合物3.0g(83%)。Rf=0.66(50%EtOAc的己烷溶液);1HNMR(400MHz,DMSO-d6):δ8.00-7.40(m,3H),7.30-6.60(m,4H),6.55-6.20(m,1H),5.00-4.10(m,2H),4.10-2.40(m,6H),2.40-2.00(m,6H),1.60-0.50(m,23H),0.20--0.40(m,6H);LC-MS:m/z 695.3(M+H)。
中间体D
4-氯-1-[4-羟基-2-((S)-3-羟基甲基-3,4-二氢-1H-异喹啉-2-羰基)-苯基]-5-甲
基-1H-吡唑-3-甲酸二丁基酰胺
步骤1:4-氯-5-甲基-1H-吡唑-3-甲酸乙酯的制备。将5-甲基-1H-吡唑-3-甲酸乙酯(4.45g,28.9mmol)和N-氯琥珀酰亚胺(5.01g,37.5mmol)在二甲基甲酰胺(60mL)中的混合物在环境温度下搅拌24小时。然后,将该反应浓缩并通过经由硅胶柱进行洗脱来进行纯化,用0至100%乙酸乙酯/庚烷梯度洗脱得到白色固体状标题化合物(5.2g,96%的收率)。MS(ESI)[m/e,(M+H)+]=189.3。1H NMR(400MHz,氯仿-d)δppm 9.39(br.s.,1H),4.44(q,J=7.1Hz,2H),2.35(s,3H),1.43(t,J=7.1Hz,3H)。
步骤2:4-氯-5-甲基-1H-吡唑-3-甲酸二丁基酰胺的制备。在氮气气氛下,向进行着搅拌的二丁基胺(13mL,76mmol)在二氯甲烷(250mL)中的溶液中加入三甲基铝(38mL,2M甲苯溶液,76mmol)。将该混合物在环境温度下搅拌30分钟。向该混合物中滴加位于二氯甲烷(30mL)中的(4-氯-5-甲基-1H-吡唑-3-甲酸乙酯(4.8g,25mmol)。将该反应在氮气气氛下搅拌12小时。将该混合物缓慢倾倒到饱和罗谢尔盐溶液中并在环境温度下搅拌2小时。收集有机层。将水层用二氯甲烷萃取并将其与有机层合并。将有机相用盐水洗涤,用硫酸钠干燥,过滤,浓缩,干燥。通过经由硅胶柱洗脱来对残余物进行纯化,用0至100%乙酸乙酯/庚烷梯度洗脱得到澄清油状的标题化合物(4.7g,68%的收率)。MS(ESI)[m/e,(M+H)+]=272.4。1H NMR(400MHz,氯仿-d)δppm 3.50(t,J=7.5Hz,2H),3.37(t,J=7.5Hz,2H),2.28(s,3H),1.64(quin,J=7.5Hz,2H),1.44-1.55(m,2H),1.30-1.43(m,2H),1.10-1.22(m,2H),0.97(t,J=8.0Hz,3H),0.82(t,J=7.3Hz,3H)。
步骤3:4-氯-1-(2-氰基-4-甲氧基-苯基)-5-甲基-1H-吡唑-3-甲酸二丁基酰胺的制备。将4-氯-5-甲基-1H-吡唑-3-甲酸二丁基酰胺(1.5g,5.5mmol)、2-氟-5-甲氧基苄腈(1.1g,7.2mmol)和碳酸铯(1.8g,5.5mmol)在二甲基甲酰胺(5mL)中的混合物在130℃下微波30分钟。真空除去溶剂。使该粗品物质通过硅胶柱进行洗脱,用0至70%乙酸乙酯/庚烷梯度洗脱得到白色固体状标题化合物(1.3g,59%的收率)。MS(ESI)[m/e,(M+H)+]=403.5。1HNMR(400MHz,氯仿-d)δppm 7.32(d,J=8.5Hz,1H),7.18-7.22(m,1H),7.12-7.18(m,1H),3.84(s,3H),3.41-3.51(m,2H),3.32-3.41(m,2H),2.15(s,3H),1.54-1.66(m,2H),1.48(qd,J=7.7,7.5Hz,2H),1.26-1.40(m,2H),1.17(ddd,J=14.9,7.4,7.3Hz,2H),0.89(t,J=7.3Hz,3H),0.77(t,J=7.3Hz,3H)。
步骤4:2-(4-氯-3-二丁基氨基甲酰基-5-甲基-吡唑-1-基)-5-甲氧基-苯甲酸的制备。将4-氯-1-(2-氰基-4-甲氧基-苯基)-5-甲基-1H-吡唑-3-甲酸二丁基酰胺(1.3g,3.2mmol)和氢氧化钾(1.2g,21mmol)在乙醇(5mL)和水(5mL)中的混合物在150℃下微波90分钟。用HCl水溶液(15N)将其pH调至约5。真空除去溶剂。使该粗品物质通过硅胶柱进行洗脱,用10至100%乙酸乙酯/庚烷,然后用1至20%甲醇/二氯甲烷梯度洗脱得到白色固体状标题化合物(0.53g,39%的收率)。MS(ESI)[m/e,(M+H)+]=422.4。
步骤5:4-氯-1-[2-((S)-3-羟基甲基-3,4-二氢-1H-异喹啉-2-羰基)-4-甲氧基-苯基]-5-甲基-1H-吡唑-3-甲酸二丁基酰胺的制备。在氮气气氛下,向进行着搅拌的2-(4-氯-3-二丁基氨基甲酰基-5-甲基-吡唑-1-基)-5-甲氧基-苯甲酸(0.35g,0.82mmol)和(S)-(1,2,3,4-四氢异喹啉-3-基)甲醇(0.13g,0.82mmol)在二氯甲烷(8mL)中的溶液中加入1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(0.16g,0.82mmol)和羟基苯并三唑(0.13g,0.82mmol)。将该混合物在环境温度下搅拌5分钟。向该混合物中加入三乙胺(0.34mL,2.5mmol)。将该反应在环境温度下搅拌60小时。将该混合物用水洗涤并通过经由硅胶柱进行洗脱来进行纯化,用10至100%乙酸乙酯/庚烷梯度洗脱得到标题化合物(21mg,4.5%的收率)。MS(ESI)[m/e,(M+H)+]=567.3。1H NMR(400MHz,氯仿-d)δppm 6.75-7.36(m,7H),4.13-5.41(m,4H),3.80-3.96(m,3H),2.51-3.71(m,8H),2.17-2.32(m,3H),1.48-1.68(m,4H),1.19-1.44(m,4H),0.70-0.97(m,6H)。
步骤6:4-氯-1-[4-羟基-2-((S)-3-羟基甲基-3,4-二氢-1H-异喹啉-2-羰基)-苯基]-5-甲基-1H-吡唑-3-甲酸二丁基酰胺。将4-氯-1-[2-((S)-3-羟基甲基-3,4-二氢-1H-异喹啉-2-羰基)-4-甲氧基-苯基]-5-甲基-1H-吡唑-3-甲酸二丁基酰胺(40mg,0.071mmol)和氯化铝(75mg,0.56mmol)的混合物在乙硫醇(0.052mL,0.71mmol)和二氯甲烷(0.5mL)中在环境温度下在氮气气氛下搅拌12小时。向混合物中加入水并用1:4的甲醇:二氯甲烷进行萃取。真空除去有机层。在通过短硅胶柱垫和C18柱洗脱后,用HPLC对该粗品物质进行纯化得到标题化合物(9mg,33%的收率)。MS(ESI)[m/e,(M+H)+]=553.5。1H NMR(400MHz,DMSO-d6)δppm 6.66-7.50(m,7H),2.03-5.08(m,14H),0.53-1.62(m,14H)。
中间体E
1-[5-羟基-2-((S)-3-羟基甲基-3,4-二氢-1H-异喹啉-2-羰基)-苯基]-5-甲基-1H-
吡唑-3-甲酸二丁基酰胺
步骤1:5-甲基-1H-吡唑-3-甲酸二丁基酰胺的制备。按照中间体D/步骤2的制备,由5-甲基-1H-吡唑-3-甲酸乙酯制得标题化合物(6g,65%)。MS(ESI)[m/e,(M+H)+]=238.1。1H NMR(400MHz,氯仿-d)δppm 6.29(s,1H),3.59(t,J=7.5Hz,2H),3.38-3.51(m,2H),2.32(s,3H),1.47-1.74(m,4H),1.17-1.47(m,4H),0.76-1.03(m,6H)。
步骤2:2-(3-二丁基氨基甲酰基-5-甲基-吡唑-1-基)-4-甲氧基-苯甲酸。将5-甲基-1H-吡唑-3-甲酸二丁基酰胺(0.85g,3.6mmol)、2-碘-4-甲氧基苯甲酸(1.0g,3.6mmol)、碘化亚铜(0.14g,0.72mmol)、碳酸铯(1.2g,3.6mmol)和反式-二甲基胺环己烷(0.23mL,1.44mmol)在二恶烷(5mL)中的混合物在120℃下微波15分钟。用乙酸乙酯稀释,使该粗品物质通过硅胶柱进行洗脱,用0至100%乙酸乙酯/庚烷,然后用0至20%甲醇/二氯甲烷梯度洗脱得到标题化合物(0.43g,31%的收率)。MS(ESI)[m/e,(M+H)+]=388.5。
步骤3:1-[2-((S)-3-羟基甲基-3,4-二氢-1H-异喹啉-2-羰基)-5-甲氧基-苯基]-5-甲基-1H-吡唑-3-甲酸二丁基酰胺。按照中间体D/步骤5的制备,由2-(3-二丁基氨基甲酰基-5-甲基-吡唑-1-基)-4-甲氧基-苯甲酸制得标题化合物(610mg,29%)。MS(ESI)[m/e,(M+H)+]=533.3。1H NMR(400MHz,氯仿-d)δppm 6.81-7.33(m,7H),5.95-6.40(m,1H),4.28-5.62(m,4H),3.83-3.96(m,3H),2.66-3.81(m,7H),2.01-2.38(m,3H),1.10-1.65(m,8H),0.76-1.01(m,6H)。
实施例1
(S)-N,N-二丁基-1-(2-(3-(羟基甲基)-1,2,3,4-四氢异喹啉-2-羰基)-4-吗啉代苯
基)-5-甲基-1H-吡唑-3-甲酰胺
将(S)-1-(4-溴-2-(3-(羟基甲基)-1,2,3,4-四氢-异喹啉-2-羰基)苯基)-N,N-二丁基-5-甲基-1H-吡唑-3-甲酰胺(中间体C的步骤1~5,0.08g,0.138mmol)、吗啉(0.013g,0.150mmol)、L-脯氨酸(0.003g,0.002mmol)、CuI(0.002g,0.001mmol)、K2CO3(0.038g,0.27mmol)在DMSO(2mL)中的混合物在110℃下加热12小时。将反应混合物用硅藻土过滤并将滤床用乙酸乙酯(20mL)洗涤。将滤液用EtOAc(30mL)稀释,用水(30mL)、盐水(20mL)洗涤,用硫酸钠干燥并真空浓缩。将残余物在硅胶(100-200目)上进行纯化得到吸湿性固体状标题化合物,0.013g(16%)。Rf=0.13(75%EtOAc的己烷溶液);1H NMR(400MHz,DMSO-d6):δ7.40-6.85(m,7H),6.50-6.20(m,1H),5.16-3.60(m,6H),3.60-2.40(m,14H),2.30-2.00(m,3H),1.60-0.50(m,14H);LC-MS:m/z 588.2(M+H),HPLC:99.43%(RT=8.375min.,方法K)。
实施例2
(S)-N,N-二丁基-1-(2-(3-(羟基甲基)-1,2,3,4-四氢异喹啉-2-羰基)-4-(2-氧代
-4-苯基哌嗪-1-基)苯基)-5-甲基-1H-吡唑-3-甲酰胺
将2-酮基哌嗪(0.20g,2.00mmol)、溴代苯(0.31g,2.00mmol)、Cs2CO3(0.65g,2.00mmol)在二恶烷(5mL)中的混合物脱气20分钟,然后加入xanthphos(0.11g,0.20mmol)、三(二亚苄基丙酮)二钯(0)(0.09g,0.1mmol)并在110℃下加热4小时。将反应混合物冷却至室温,用EtOAc(100mL)稀释。将有机层用水(50mL)、盐水(20mL)洗涤,用硫酸钠干燥并真空浓缩。将残余物在硅胶(100-200目)上进行纯化得到米白色固体状4-苯基哌嗪-2-酮,0.030g(8%)。Rf=0.22(EtOAc);1H NMR(400MHz,DMSO-d6):δ8.15-8.00(brs,1H),7.23(dd,J=7.4Hz&8.2Hz,2H),6.91(d,J=7.6Hz,2H),6.78(t,J=7.4Hz,1H),3.69(s,2H),3.40-3.33(m,2H),3.31-3.28(m,2H),1.60-0.50(m,14H);ES-MS:m/z 177.3(M+H)。
将(S)-1-(4-溴-2-(3-(羟基甲基)-1,2,3,4-四氢-异喹啉-2-羰基)苯基)-N,N-二丁基-5-甲基-1H-吡唑-3-甲酰胺(0.10g,0.172mmol)、4-苯基哌嗪-2-酮(0.03g,0.172mmol)、Cs2CO3(0.056g,0.172mmol)在二恶烷(2mL)中的混合物脱气20分钟,然后加入xanthphos(0.01g,0.017mmol)、三(二亚苄基丙酮)二钯(0)(0.008g,0.008mmol)并在110℃下加热4小时。将反应混合物冷却至室温,用EtOAc(100mL)稀释。将有机层用水(50mL)、盐水(20mL)洗涤,用硫酸钠干燥并真空浓缩。将残余物在硅胶(100-200目)上进行纯化得到吸湿性固体状标题化合物,0.018g(16%)。Rf=0.33(EtOAc);1HNMR(400MHz,DMSO-d6):δ7.80-6.70(m,12H),6.50-6.20(m,1H),5.18-3.80(m,8H),3.80-2.40(m,10H),2.30-2.00(m,3H),1.60-0.50(m,14H);LC-MS:m/z 677.2(M+H),HPLC:97.85%(RT=7.611min.,方法L)。
实施例3
(S)-N,N-二丁基-1-(4-(4-(4-氯苄基)-3-氧代哌嗪-1-基)-2-(3-(羟基甲
基)-1,2,3,4-四氢异喹啉-2-羰基)苯基)-5-甲基-1H-吡唑-3-甲酰胺
将(S)-1-(4-溴-2-(3-(((叔-丁基二甲基甲硅烷基)氧基)甲基)-1,2,3,4-四氢-异喹啉-2-羰基)苯基)-N,N-二丁基-5-甲基-1H-吡唑-3-甲酰胺(中间体C,0.43g,4.32mmol)、Cs2CO3(1.40g,4.32mmol)在二恶烷(10mL)中的混合物脱气20分钟,然后加入xanthphos(0.25g,0.43mmol)、三(二亚苄基丙酮)二钯(0)(0.20g,0.22mmol)并在110℃下加热5小时。将反应混合物冷却至室温,用EtOAc(100mL)稀释。将有机层用水(50mL)、盐水(20mL)洗涤,用硫酸钠干燥并真空浓缩。将残余物在硅胶(100-200目)上进行纯化得到吸湿性固体状(S)-N,N-二丁基-1-(2-(3-(((叔-丁基二甲基甲硅烷基)氧基)甲基)-1,2,3,4-四氢异喹啉-2-羰基)-4-(3-氧代哌嗪-1-基)苯基)-5-甲基-1H-吡唑-3-甲酰胺,0.5g(13%),Rf=0.20(EtOAc),同时还得到(S)-N,N-二丁基-1-(2-(3-(((叔-丁基二甲基甲硅烷基)氧基)甲基)-1,2,3,4-四氢异喹啉-2-羰基)-4-(2-氧代哌嗪-1-基)苯基)-5-甲基-1H-吡唑-3-甲酰胺0.7g(19%),Rf=0.52(EtOAc);1H NMR(400MHz,DMSO-d6):δ8.42-8.22(brs,1H),7.90-7.00(m,7H),6.65-6.40(m,1H),5.30-2.60(m,17H),2.60-2.20(m,3H),1.80-0.85(m,23H),0.25--0.08(m,6H);ES-MS:m/z 715.6(M+H)。
向冰冷却的(S)-N,N-二丁基-1-(2-(3-(((叔-丁基二甲基甲硅烷基)-氧基)甲基)-1,2,3,4-四氢异喹啉-2-羰基)-4-(3-氧代哌嗪-1-基)苯基)-5-甲基-1H-吡唑-3-甲酰胺(0.13g,0.18mmol)在THF(5mL)中的溶液中加入NaH(0.009g,0.36mmol),然后加入1-(溴甲基)-4-氯苯(0.037g,0.18mmol)并用EtOAc(50mL)进行萃取。将有机层用水(30mL)、盐水(20mL)洗涤,用硫酸钠干燥并真空浓缩。将残余物在硅胶(100-200目)上进行纯化得到液体状(S)-N,N-二丁基-1-(2-(3-(((叔-丁基二甲基甲硅烷基)氧基)甲基)-1,2,3,4-四氢异喹啉-2-羰基)-4-(4-(4-氯苄基)-3-氧代哌嗪-1-基)苯基)-5-甲基-1H-吡唑-3-甲酰胺,0.080g(53%)。Rf=0.58(乙酸乙酯);LC-MS:m/z 839.7(M+H)。
向(S)-N,N-二丁基-1-(2-(3-(((叔-丁基二甲基甲硅烷基)氧基)-甲基)-1,2,3,4-四氢异喹啉-2-羰基)-4-(4-(4-氯苄基)-3-氧代哌嗪-1-基)苯基)-5-甲基-1H-吡唑-3-甲酰胺(0.08g,0.095mmol)在THF(5mL)中的溶液中加入3N HCl(0.5mL),然后在室温下搅拌1小时。将反应混合物用水(20mL)稀释,然后用NaHCO3水溶液将其pH调至约8并用EtOAc(50mL)萃取。将有机层用水(30mL)、盐水(20mL)洗涤,用硫酸钠干燥并真空浓缩。将残余物在硅胶(100-200目)上进行纯化得到液体状标题化合物,0.012g(17%)。Rf=0.29(2%MeOH的DCM溶液);1H NMR(400MHz,DMSO-d6):δ7.60-6.78(m,11H),6.50-6.20(m,1H),5.20-3.80(m,6H),3.80-2.40(m,14H),2.40-2.00(m,3H),1.60-0.58(m,14H);LC-MS:m/z725.3(M+H),HPLC:96.64%(RT=8.518min.,方法M)。
实施例4
(S)-4'-(3-(二丁基氨基甲酰基)-5-甲基-1H-吡唑-1-基)-3'-(3-(羟基甲
基)-1,2,3,4-四氢异喹啉-2-羰基)-[1,1'-联苯]-3-甲酸
向(S)-1-(4-溴-2-(3-(羟基甲基)-1,2,3,4-四氢异喹啉-2-羰基)苯基)-N,N-二丁基-5-甲基-1H-吡唑-3-甲酰胺(0.12g,0.206mmol)在DME(1.2mL)中的溶液中加入3-羧基苯硼酸(0.034g,0.206mmol)、2M碳酸钠水溶液(0.6mL)。将反应混合物脱气30分钟。加入二(三苯基膦)氯化钯(II)(0.015mg,0.021mmol)并将反应混合物在120℃下加热1小时。将反应混合物用水(50mL)稀释并用EtOAc(75mL)萃取两次。将所合并的有机层用水(50mL)、盐水(30mL)洗涤,用硫酸钠干燥并真空浓缩。将残余物在硅胶(100-200目)上进行纯化得到米白色固体状标题化合物0.044g(34%)。Rf=0.18(10%MeOH的DCM溶液);1H NMR(400MHz,DMSO-d6):δ14.00-11.00(brs,1H,D2O可交换的),8.35-8.24(m,1H),8.10-7.84(m,4H),7.82-7.58(m,2H),7.22-6.82(m,4H),6.54-6.25(m,1H),5.20-3.86(m,3H),3.84-2.40(m,1H),2.38-2.10(m,3H),1.70-0.55(m,14H);LC-MS:m/z 623.3(M+H),HPLC:98.10%(RT=8.684min.,方法D)。
通过重复上面实施例所述的操作,用适宜的起始材料和HPLC方法,得到如表1中所鉴定的下面的式I化合物。
表1
可以用各种已知方法来测定BCL-2结合。一种该类测定是使用荧光偏振(FP)的灵敏和定量的体外结合试验,该试验记载于Wang,J.-L.;Zhang,Z-J.;Choksi,S.;Sjam.S.;Lu,Z.;Croce,C.M.;Alnemri,E.S.;Komgold,R.;Huang,Z.细胞可渗透的BCL-2结合肽:一种在肿瘤细胞中诱导细胞凋亡的化学方法。Cancer Res.2000,60,1498-1502。
IC
50
测定方法
本方法包括利用一种以表面等离子体共振(SPR)为基础的生物传感器(BiacoreTM GE Healthcare,Uppsala,瑞典)来对BCL-2抑制剂进行定性。
BiacoreTM利用表面等离子体共振(SPR)现象来探测和测量结合相互作用。在一个典型的Biacore实验中,将相互作用的分子之一(配体)固定在一种柔韧的葡聚糖基质上,同时使相互作用的伴侣(分析物)流动通过该表面。结合相互作用使得该传感器表面上的质量增加和相应的该传感器表面附近的介质折射率的直接变化。在共振单元(R.U.)中记录折射率或信号的变化。以一种非侵入性的方式,连续和实时监测由于复合物的缔合和解离产生的信号变化,以传感图谱的形式报告该信号变化结果。
该SPR试验被构建为用于检查BCL-2与肽衍生的传感器表面结合的溶液抑制作用,从而产生了作为抑制功效量度的IC50值。
溶液抑制试验格式:
用BiacoreTM A100(GE Healthcare,Uppsala,瑞典)来进行本文所报告的所有实验。传感器表面制备和所有的相互作用分析实验都是在25℃下进行的。试剂购自GE Healthcare。在所有的分析期间,都使用包含10mMHepes,pH7.4、150mM氯化钠、1.25mM二硫苏糖醇、3%二甲基亚砜和0.05%聚山梨醇酯20的运行缓冲液。
用运行缓冲液将生物素化的BAK、BAD和NOXA肽稀释至10nM并将其捕获到一个用链霉抗生素蛋白预衍生化的传感器表面至50-100R.U.的肽表面密度。用500μM PEO2-生物素阻断捕获了肽的表面。类似地用PEO2-生物素阻断各流通池中的空白探测点并将其作为竞争试验中的参照点。
相互作用分析按如下进行:在仪器启动操作期间,首先将16μM至0.004nM范围内的6点三倍系列稀释化合物的各样品与56nM BCL-2平衡1小时。然后,将蛋白化合物混合物以30μL/min的流速注射到平行的各肽表面上达60秒。还制备56nM BCL-2对照样品并在试验期间以规则的间隔运行。在各分析循环结束时,通过两次30秒注射10mM甘氨酸,pH2.5、1M氯化钠、0.05%聚山梨醇酯20来进行表面再生。一式两份地运行样品和对照化合物样品,并且在试验期间也以规则的间隔运行对照以监测表面和试验性能。
用BiacoreTM A100评价软件v1.1进行数据分析以确认试验质量。使用相对于BCL-2对照样品的结合水平报告点来计算各化合物蛋白混合物的%抑制值。然后,用这些数据对化合物浓度作图并通过对数回归在 v2.1中对其进行分析以计算各化合物的IC50值。表1中所示的数据范围表示由多个实验获得的高和低IC50值。
半胱天冬酶活化试验方法
在依赖BCL2而存活的癌细胞系如Caki-2肾透明细胞癌细胞系中,BCL2的抑制诱导了特征为半胱天冬酶活化的细胞凋亡。如下那样对本发明化合物在Caki-2细胞系中诱导半胱天冬酶活化的能力进行试验。在第1天,将2500个Caki-2细胞涂镀到384孔组织培养板中。在第2天,在包含1%胎牛血清的Opti-MEM培养基(Invtrogen)中用一定剂量范围的本发明化合物将这些细胞处理4小时。在处理4小时后,用得自Promega的Caspase-glo试剂对相对于基质处理的细胞中的基准水平而言的半胱天冬酶活化的相对水平进行评估。
细胞增殖试验方法
如下那样对本发明化合物影响Caki-2细胞系中的细胞增殖和/或存活的能力进行测试。在第1天,将2500个Caki-2细胞涂镀到384孔组织培养板中。在第2天,在包含1%胎牛血清的Opti-MEM培养基(Invtrogen)中用一定剂量范围的本发明化合物将这些细胞处理24小时。在处理24小时后,用得自Perkin Elmer的ATPLite试剂对相对于基质处理细胞而言的细胞活力进行评估。
应当清楚的是,本文所述的实施例和实施方案仅用于说明目的,将建议本领域技术人员根据其进行各种修改或变化,这些修改和变化都被包括在本申请和所附权利要求书的主旨和范围内。本文所引用的所有公开物、专利和专利申请都被引入本文作为参考用于所有目的。
Claims (9)
1.式I的化合物或其可药用盐:
其中:
R1选自氢和卤素;
R2选自氢和C1-4烷基;其中相对于吡唑环而言,R2位于间位上且R3位于对位上,或者相对于吡唑环而言,R2位于对位上且R3位于间位上;
R3是R5;
R4选自氢、羟基、-X3NR8R9、-X3C(O)OR8、-X3OR8、-X3C(O)NR8R9和-X3NR8C(O)R9;其中X3选自键和C1-4亚烷基;且R8和R9独立地选自氢、C1-4烷基和苯基;或者R8和R9连同R8和R9与之相连的氮一起形成一种包含1至3个独立地选自C(O)、NR10、O和S(O)0-2的基团或杂原子的5至7元饱和环;其中R10选自氢和C1-4烷基;
R5选自环丙基、3-氧代吗啉代、咪唑并[1,2-a]嘧啶基、2-氧代-4-苯基哌嗪-1-基、4-(2-氯苄基)-3-氧代哌嗪-1-基、咪唑并[1,2-a]吡啶基、苯并[d]异唑基、萘并[2,1-d][1,2,3]二唑-5-基、1H-吡咯并[2,3-b]吡啶基、咪唑并[2,1-b]噻唑基、1H-吡唑并[3,4-b]吡啶基、苯并[c][1,2,5]噻二唑基、4-氧代-4,5,6,7-四氢苯并呋喃基、2-氧代-1,2,3,6-四氢嘧啶基、1,2,4-二唑基、2,3-二氢苯并[b][1,4]二恶英-2-基、萘并[2,3-d][1,3]间二氧杂环戊烯-2-基、3,4-二氢-2H-苯并[b][1,4]嗪-7-基、2,3-二氢苯并呋喃-3-基、色满-8-基、3-氧代-3H-吡唑基、6-氧代-1,6-二氢哒嗪基、苯并[b]噻吩基、苯并[b]呋喃基、2-氧代-1,2-二氢吡啶基、2-氧代-1,2,5,6,7,8-六氢喹啉基、4-氧代-1,4-二氢-1,8-萘啶基、4-氧代-4H-吡喃并[2,3-b]吡啶基、10,10-二氧化-9-氧代-9H-噻吨-3-基、5-氧代吡咯烷-3-基、苯基、喹啉基、异喹啉基、苯氧基、苯硫基、苄氧基、苯基-磺酰基、呋喃基、噻唑基、唑基、异唑基、噻吩基、吡咯基、喹啉-8-基氧基、嘧啶基、吡啶基、吡咯烷基、吡咯烷酮基、咪唑烷-2,4-二酮基、哌啶基、哌嗪基、吡嗪基、吡唑基、吗啉代、氧代吗啉代、吲哚基、苯并[b]噻吩基、苯并[b]呋喃基、苯并[d][1,2,3]三唑和氧代哌嗪基;其中所述R5的环丙基、咪唑并[1,2-a]嘧啶基、苯并[d]异唑基、咪唑并[1,2-a]吡啶基、4-氧代-4,5,6,7-四氢苯并呋喃基、2-氧代-1,2,3,6-四氢嘧啶基、咪唑并[2,1-b]噻唑基、1H-吡咯并[2,3-b]吡啶基、1H-吡唑并[3,4-b]吡啶基、1,2,4-二唑基、苯并[c][1,2,5]噻二唑基、2,3-二氢苯并[b][1,4]二恶英-2-基、萘并[2,3-d][1,3]间二氧杂环戊烯-2-基、3,4-二氢-2H-苯并[b][1,4]嗪-7-基、2,3-二氢苯并呋喃-3-基、色满-8-基、3-氧代-3H-吡唑基、6-氧代-1,6-二氢哒嗪基、2-氧代-1,2-二氢吡啶基、2-氧代-1,2,5,6,7,8-六氢喹啉基、4-氧代-1,4-二氢-1,8-萘啶基、4-氧代-4H-吡喃并[2,3-b]吡啶基、10,10-二氧化-9-氧代-9H-噻吨-3-基、5-氧代吡咯烷-3-基、苯基、喹啉基、异喹啉基、苯氧基、苄氧基、苯氧基-甲基、苯硫基、苯基-磺酰基、呋喃基、噻唑基、唑基、异唑基、噻吩基、吡啶基、吡咯基、喹啉-8-基氧基、吡咯烷基、嘧啶基、吡咯烷酮基、哌嗪基、哌啶基、吡嗪基、吡唑基、吗啉代、氧代吗啉代、吲哚基、苯并[d][1,2,3]三唑或氧代哌嗪基是未取代的或者被1至3个独立地选自卤素、氰基、硝基、-NR6R7、C1-4烷基、卤代-C1-4烷基、C1-4烷氧基、卤代-C1-4烷氧基、卤代-C1-4烷硫基、-C(O)OR6、-X3OR6、-C(O)R6、-C(O)NR6R7、-NR6S(O)2X3R7、-X3NR6C(O)R7、-S(O)0-2R6、-S(O)0-2NR6R7、苯基、苄基、哌啶基、吡咯烷基、吗啉代、吗啉代-甲基、1,2,4-二唑基、吡唑基、苯氧基、吲哚基、(1H-1,2,4-三唑基)甲基和苄氧基的基团取代;其中R6和R7独立地选自氢、C1-4烷基、C3-8环烷基、吡啶基、苯基、苄基和萘基;其中所述R5的苯基、吡啶基、苄基、吗啉代、吗啉代-甲基、1,3-二氧代异二氢吲哚基、1,2,4-二唑基、吡唑基、吲哚基和苄氧基取代基或所述R6的吡啶基和苯基可以是未取代的或者进一步被选自卤素、硝基、氨基-磺酰基、C1-4烷基、C1-4烷氧基和卤代-C1-4烷基的基团取代;其中X3选自键和C1-4亚烷基。
2.式Ie的权利要求1的化合物:
其中:
R1选自氢和卤素;
R4选自氢、羟基、-X3NR8R9、-X3C(O)OR8、-X3OR8、-X3C(O)NR8R9和-X3NR8C(O)R9;其中X3选自键和C1-4亚烷基;且R8和R9独立地选自氢、C1-4烷基和苯基;或者R8和R9连同R8和R9与之相连的氮一起形成一种包含1至3个独立地选自C(O)、NR10、O和S(O)0-2的基团或杂原子的5至7元饱和环;其中R10选自氢和C1-4烷基;
R5选自3-氧代吗啉代、2-氧代哌嗪基、苯基、吗啉代、哌啶基、吡啶基、哌嗪基、喹啉基、异喹啉基、萘基、1,3,4-二唑基、异唑基和吡唑基;其中所述R5的吡唑基、2-氧代哌嗪基、哌嗪基、1,3,4-二唑基、哌啶基、吡啶基、喹啉基、异喹啉基、萘基、异唑基或苯基是未取代的或者被1至3个独立地选自苯基、苄基、甲基、甲氧基、乙氧基、叔-丁氧基-羰基、1,3,4-二唑基、卤素、氰基、异丙氧基、甲基-羰基-氨基、吗啉代-磺酰基、哌啶基-磺酰基、吡咯烷基-羰基、甲基-氨基-羰基、二甲基-氨基、二甲基-氨基-羰基、氨基-羰基、三氟甲氧基、甲基-磺酰基、二甲基-氨基-羰基和羧基的基团取代;其中所述R5的苄基或1,3,4-二唑基取代基是未取代的或者进一步被选自卤素和甲基的基团取代。
3.权利要求2的化合物,其选自:
4.包含权利要求1的化合物或其可药用盐和至少一种可药用载体的药物组合物。
5.一种治疗方法,其包括给需要该类治疗的人以可有效预防或治疗由BCL-2的活性介导的疾病或病症的数量施用权利要求1的化合物或其可药用盐。
6.权利要求5的方法,其中所述由BCL-2的活性介导的疾病或病症是选自前列腺癌、激素耐受性的前列腺癌、乳癌、非小细胞肺癌、小细胞肺癌、直肠结肠癌、黑素瘤、头癌、颈癌和胰腺癌的癌症。
7.用于治疗由BCL-2的活性介导的病症或疾病的权利要求1的化合物或其盐。
8.权利要求1的化合物或其盐在制备用于治疗个体由BCL-2的活性介导的病症或疾病的药物中的用途。
9.与一种或多种治疗活性剂联合的权利要求1的化合物或其盐。
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- 2012-12-12 KR KR1020147020534A patent/KR20140107578A/ko not_active Application Discontinuation
- 2012-12-12 CN CN201280070470.4A patent/CN104136428A/zh active Pending
- 2012-12-12 US US14/366,860 patent/US20140350014A1/en not_active Abandoned
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- 2012-12-12 AU AU2012355615A patent/AU2012355615A1/en not_active Abandoned
- 2012-12-12 EP EP12805894.8A patent/EP2794589A1/en not_active Withdrawn
- 2012-12-12 BR BR112014015442A patent/BR112014015442A8/pt not_active Application Discontinuation
- 2012-12-12 JP JP2014549135A patent/JP2015503516A/ja active Pending
- 2012-12-12 MX MX2014007725A patent/MX2014007725A/es unknown
- 2012-12-12 WO PCT/US2012/069191 patent/WO2013096051A1/en active Application Filing
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MX2014007725A (es) | 2015-01-12 |
CA2859873A1 (en) | 2013-06-27 |
US20140350014A1 (en) | 2014-11-27 |
BR112014015442A2 (pt) | 2017-06-13 |
EP2794589A1 (en) | 2014-10-29 |
BR112014015442A8 (pt) | 2017-07-04 |
AU2012355615A1 (en) | 2014-07-10 |
KR20140107578A (ko) | 2014-09-04 |
WO2013096051A1 (en) | 2013-06-27 |
EA201491259A1 (ru) | 2014-11-28 |
JP2015503516A (ja) | 2015-02-02 |
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