CN1314904A - 用作抗癌剂的炔基取代的喹啉-2-酮衍生物 - Google Patents
用作抗癌剂的炔基取代的喹啉-2-酮衍生物 Download PDFInfo
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- CN1314904A CN1314904A CN99810204A CN99810204A CN1314904A CN 1314904 A CN1314904 A CN 1314904A CN 99810204 A CN99810204 A CN 99810204A CN 99810204 A CN99810204 A CN 99810204A CN 1314904 A CN1314904 A CN 1314904A
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Classifications
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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
- C07D401/02—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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- 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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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
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Abstract
本发明涉及式1化合物及其药学上可接受的盐、药物前体和溶剂化物,其中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10和R11是如本文所定义的。上述式1化合物可用于治疗哺乳动物过度增殖性疾病,例如癌症。本发明也涉及含有式1化合物的药物组合物,涉及抑制哺乳动物包括癌症在内的异常细胞生长的方法,该方法是将式1化合物对需要这种治疗的哺乳动物给药。
Description
发明背景
本发明涉及一系列炔基取代的喹啉-2-酮衍生物,它们用于治疗哺乳动物过度增殖性疾病,例如癌症。本发明也涉及在哺乳动物、尤其是人的过度增殖性疾病的治疗中使用该化合物的方法,还涉及含有该化合物的药物组合物。
癌基因经常编码导致刺激细胞生长和有丝分裂期发生的信号转导途径的蛋白质组分。癌基因在培养细胞内的表达引起细胞转化,其特征是细胞在软琼脂中的生长能力和细胞生长为密集病灶,缺乏由非转化细胞所表现的接触抑制。某些癌基因的突变和/或过度表达经常与人的癌症有关。
为了获得转化的可能性,Ras癌蛋白必须经历位于羧基末端四肽中的半胱氨酸残基的法呢基化。因此有人已经提出用催化这种修饰的酶--法呢基蛋白转移酶--的抑制剂对抗Ras有助于转化的肿瘤。在很多人癌症中经常发现突变后的癌基因形式的Ras,特别是在50%以上的结肠和胰腺癌中(Kohl等《科学》260,1834-1837,1993)。本发明化合物表现出法呢基蛋白转移酶抑制剂活性,因此据信可用作抗癌剂和抗肿瘤剂。此外,本发明化合物可以对任何借助于法呢基蛋白转移酶而增殖的肿瘤都具有活性。
发明概述
本发明涉及式1化合物及其药学上可接受的盐、药物前体和溶剂化物,其中:
虚线表示喹啉-2-酮环的C-3与C-4之间的键是单键或双键;
R1选自H、C1-C10烷基、-(CR13R14)qC(O)R12、-(CR13R14)qC(O)OR15、-(CR13R14)qOR12、-(CR13R14)qSO2R15、-(CR13R14)t(C3-C10环烷基)、-(CR13R14)t(C6-C10芳基)和-(CR13R14)t(4-10元杂环),其中t是0至5的整数,q是1至5的整数,所述环烷基、芳基和杂环R1基团任选地与C6-C10芳基、C5-C8饱和环基或4-10元杂环基稠合;除H以外但包括上述任何任选的稠合环在内的前述R1基团任选地被1至4个R6基团取代;
R2是卤、氰基、-C(O)OR15或选自由R12定义所提供的取代基的基团;
每个R3、R4、R5、R6和R7独立地选自H、C1-C10烷基、C2-C10烯基、卤、氰基、硝基、巯基、三氟甲基、三氟甲氧基、叠氮基、-OR12、-C(O)R12、-C(O)OR12、-NR13C(O)OR15、-OC(O)R12、-NR13SO2R15、-SO2NR12R13、-NR13C(O)R12、-C(O)NR12R13、-NR12R13、-CH=NOR12、-S(O)jR12--其中j是0至2的整数--、-(CR13R14)t(C6-C10芳基)、-(CR13R14)t(4-10元杂环)、-(CR13R14)t(C3-C10环烷基)和-(CR13R14)tC≡CR16,其中在前述R3、R4、R5、R6和R7基团中,t是0至5的整数;前述基团的环烷基、芳基和杂环部分任选地与C6-C10芳基、C5-C8饱和环基或4-10元杂环基稠合;所述烷基、烯基、环烷基、芳基和杂环基任选地被1至3个取代基取代,取代基独立地选自卤、氰基、硝基、三氟甲基、三氟甲氧基、叠氮基、-NR13SO2R15、-SO2NR12R13、-C(O)R12、-C(O)OR12、-OC(O)R12、-NR13C(O)OR15、-NR13C(O)R12、-C(O)NR12R13、-NR12R13、-OR12、C1-C10烷基、C2-C10烯基、C2-C10炔基、-(CR13R14)t(C6-C10芳基)和-(CR13R14)t(4-10元杂环),其中t是0至5的整数;
R8是H、-OR12、-NR12R13、-NR12C(O)R13、氰基、-C(O)OR13、-SR12、-(CR13R14)t(4-10元杂环)--其中t是0至5的整数--,或C1-C6烷基,其中所述杂环和烷基部分任选地被1至3个R6取代基取代;
R9是-(CR13R14)t(咪唑基),其中t是0至5的整数,所述咪唑基部分任选地被1或2个R6取代基取代;
每个R10和R11独立地选自由R6定义所提供的取代基;
每个R12独立地选自H、C1-C10烷基、-(CR13R14)t(C3-C10环烷基)、-(CR13R14)t(C6-C10芳基)和-(CR13R14)t(4-10元杂环),其中t是0至5的整数;所述环烷基、芳基和杂环R12基团任选地与C6-C10芳基、C5-C8饱和环基或4-10元杂环基稠合;除H以外的前述R12取代基任选地被1至3个取代基取代,取代基独立地选自卤、氰基、硝基、三氟甲基、三氟甲氧基、叠氮基、-C(O)R13、-C(O)OR13、-OC(O)R13、-NR13C(O)R14、-C(O)NR13R14、-NR13R14、羟基、C1-C6烷基和C1-C6烷氧基;
每个R13和R14独立地是H或C1-C6烷基,其中若R13和R14是-(CR13R14)q或(CR13R14)t的形式,则对于每个超过1的q或t的迭代,各自被独立地定义;
R15选自由R12定义所提供的取代基,但R15不是H;
R16选自R12定义所提供的取代基和-SiR17R18R19;
R17、R18和R19各自独立地选自由R12定义所提供的取代基,但R17、R18和R19不是H;和
其前提条件是R3、R4和R5至少有一个是-(CR13R14)tC≡CR16,其中t是0至5的整数,R13、R14和R16是如上所定义的。
优选的式1化合物包括这些,其中R1是H、C1-C6烷基或环丙基甲基;R2是H;R3是-C≡CR16;R8是-NR12R13、-OR12、或选自三唑基、咪唑基、吡唑基和哌啶基的杂环基,其中所述杂环基任选地被R6基团取代。更优选的化合物包括这些,其中R9是任选被C1-C6烷基取代的咪唑基;R8是羟基、氨基或三唑基;R4、R5、R10和R11各自独立地选自H和卤。
其它优选的式1化合物包括这些,其中R1是-(CR13R14)t(C3-C10环烷基),其中t是0至3的整数;R2是H;R3是-C≡CR16;R8是-NR12R13、-OR12、或选自三唑基、咪唑基、吡唑基和哌啶基的杂环基,其中所述杂环基任选地被R6基团取代。更优选的化合物包括这些,其中R9是任选被C1-C6烷基取代的咪唑基;R8是羟基、氨基或三唑基;R4、R5、R10和R11各自独立地选自H和卤;R1是环丙基甲基。
其它优选的式1化合物包括这些,其中R3是乙炔基,其它取代基是如上所定义的。
具体的优选化合物包括如下:
6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-4-(3-乙炔基-苯基)-1-甲基-1H-喹啉-2-酮(对映体A);
6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-4-(3-乙炔基-苯基)-1-甲基-1H-喹啉-2-酮(对映体B);
6-[氨基-(4-氯-苯基)-(3-甲基-3H-咪唑-4-基)-甲基]-4-(3-乙炔基-苯基)-1-甲基-1H-喹啉-2-酮(对映体A);
6-[氨基-(4-氯-苯基)-(3-甲基-3H-咪唑-4-基)-甲基]-4-(3-乙炔基-苯基)-1-甲基-1H-喹啉-2-酮(对映体B);
6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-4-(3-乙炔基-4-氟-苯基)-1-甲基-1H-喹啉-2-酮;
和前述化合物的药学上可接受的盐、药物前体和溶剂化物,以及前述化合物的立体异构体。
其中R1、R2、R3、R4、R5、R6、R7、R10和R11是如上所定义的。
本发明也涉及下列具体的中间体,它们可用于本发明化合物的制备:
6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-1-甲基-4-(3-三甲基硅烷基乙炔基-苯基)-1H-喹啉-2-酮;
6-[(4-氯-苯基)-羟基-(2-巯基-3-甲基-3H-咪唑-4-基)-甲基]-1-甲基-4-(3-三甲基硅烷基乙炔基-苯基)-1H-喹啉-2-酮;
6-(4-氯-苯甲酰基)-1-甲基-4-(3-三甲基硅烷基乙炔基-苯基)-1H-喹啉-2-酮;
6-(4-氯-苯甲酰基)-1-甲基-4-[3-(4-三苯甲氧基-丁-1-炔基)-苯基]-1H-喹啉-2-酮;
6-(4-氯-苯甲酰基)-1-环丙基甲基-4-(3-三甲基硅烷基乙炔基-苯基)-1H-喹啉-2-酮。
本发明也涉及制备其中R3是乙炔基的式1化合物的方法,包括将式29化合物
其中R1、R2、R4、R5、R5、R7、R8、R9、R10和R11是如上所定义的,用氟化四丁铵处理。
本发明也涉及包括人在内的哺乳动物异常细胞生长的治疗方法,包括将一定量的如上所定义的式1化合物或其药学上可接受的盐、药物前体或溶剂化物对所述哺乳动物给药,给药量对抑制法呢基蛋白转移酶是有效的。在该方法的一种实施方式中,异常细胞生长是癌症,包括但不限于肺癌、骨癌、胰腺癌、皮肤癌、头或颈癌、皮或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛区癌、胃癌、结肠癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、何杰金氏病、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、慢性或急性白血病、淋巴细胞淋巴瘤、膀胱癌、肾或输尿管癌、肾细胞癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、脊柱枢椎肿瘤、脑干神经胶质瘤、垂体腺瘤、或一种或多种前述癌症的组合。在所述方法的另一种实施方式中,所述异常细胞生长是良性增殖性疾病,包括但不限于牛皮癣、良性前列腺肥大或再狭窄。
本发明也涉及包括人在内的哺乳动物异常细胞生长的治疗方法,包括将一定量的如上所定义的式1化合物或其药学上可接受的盐、药物前体或溶剂化物对所述哺乳动物给药,给药量对治疗异常细胞生长是有效的。
本发明也涉及哺乳动物异常细胞生长的治疗方法,包括将治疗学上有效量的式1化合物或其药学上可接受的盐、药物前体或溶剂化物结合抗肿瘤剂对所述哺乳动物给药,该抗肿瘤剂选自由有丝分裂抑制剂、烷化剂、抗代谢剂、嵌入性抗生素(intercalating antibiotics)、生长因子抑制剂、细胞周期抑制剂、酶、拓扑异构酶抑制剂、生物反应调节剂、抗激素物质和抗雄激素物质组成的组。
本发明也涉及包括人在内的哺乳动物感染的治疗方法,该感染受到法呢基蛋白转移酶的促进作用,例如丁型肝炎病毒或疟疾,该方法包括将治疗学上有效量的式1化合物或其药学上可接受的盐、药物前体或溶剂化物对所述哺乳动物给药。
本发明也涉及用于包括人在内的哺乳动物异常细胞生长治疗的药物组合物,包含一定量的如上所定义的式1化合物或其药学上可接受的盐、药物前体或溶剂化物,含量对抑制法呢基蛋白转移酶是有效的,和药学上可接受的载体。在所述组合物的一种实施方式中,所述异常细胞生长是癌症,包括但不限于肺癌、骨癌、胰腺癌、皮肤癌、头或颈癌、皮或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛区癌、胃癌、结肠癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、何杰金氏病、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、慢性或急性白血病、淋巴细胞淋巴瘤、膀胱癌、肾或输尿管癌、肾细胞癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、脊柱枢椎肿瘤、脑干神经胶质瘤、垂体腺瘤、或一种或多种前述癌症的组合。在所述方法的另一种实施方式中,所述异常细胞生长是良性增殖性疾病,包括但不限于牛皮癣、良性前列腺肥大或再狭窄。
本发明也涉及用于包括人在内的哺乳动物异常细胞生长治疗的药物组合物,包含一定量的如上所定义的式1化合物或其药学上可接受的盐、药物前体或溶剂化物,含量对治疗异常细胞生长是有效的,和药学上可接受的载体。
本发明也涉及用于包括人在内的哺乳动物异常细胞生长治疗的药物组合物,包含治疗学上有效量的如上所定义的式1化合物或其药学上可接受的盐、药物前体或溶剂化物与药学上可接受的载体和抗肿瘤剂的组合,该抗肿瘤剂选自由有丝分裂抑制剂、烷化剂、抗代谢剂、嵌入性抗生素、生长因子抑制剂、细胞周期抑制剂、酶、拓朴异构酶抑制剂、生物反应调节剂、抗激素物质和抗雄激素物质组成的组。
本发明也涉及用于包括人在内的哺乳动物感染治疗的药物组合物,该感染受到法呢基蛋白转移酶的促进作用,例如疟疾或丁型肝炎病毒,该组合物包含一定量的如上所定义的式1化合物或其药学上可接受的盐、药物前体或溶剂化物,含量对治疗异常细胞生长是有效的,和药学上可接受的载体。
本文所用的“异常细胞生长”除非另有指定,涉及与正常的有规则的机理无关的细胞生长(例如接触抑制的丧失)。这包括下列异常生长:(1)表达活化的Ras癌基因的肿瘤细胞(肿瘤);(2)由于另一个基因内的癌基因突变而使Ras蛋白活化的肿瘤细胞;(3)其它发生异常Ras活化的增殖性疾病的良性和恶性细胞;和(4)任何凭借法呢基蛋白转移酶而增殖的肿瘤。
本文所用的动词“治疗”除非另有指定,表示逆转、缓解、抑制疾患或疾病的进展或预防疾患或疾病,或该疾患或疾病的一种或多种症状。本文所用的名词“治疗”除非另有指定,涉及刚才所定义的动词“治疗”的行为。
本文所用的术语“卤”除非另有指定,表示氟、氯、溴或碘。优选的卤代基团是氟、氯和溴。
本文所用的术语“烷基”除非另有指定,包括具有直链或支链部分的饱和一价烃基。
本文所用的术语“环烷基”除非另有指定,包括环状烷基部分,其中烷基是如上所定义的。
本文所用的术语“烯基”除非另有指定,包括具有至少一条碳-碳双键的烷基部分,其中烷基是如上所定义的。
本文所用的术语“炔基”除非另有指定,包括具有至少一条碳-碳叁键的烷基部分,其中烷基是如上所定义的。
本文所用的术语“烷氧基”除非另有指定,包括O-烷基,其中烷基是如上所定义的。
本文所用的术语“芳基”除非另有指定,包括通过除去一个氢而从芳烃衍生的有机基团,例如苯基或萘基。
本文所用的术语“4-10元杂环”除非另有指定,包括含有一个或多个、通常为1至4个杂原子的芳族和非芳族杂环基,杂原子各自选自O、S和N,其中每个杂环基在其环系内具有4-10个原子。非芳族杂环基包括在其环系内仅具有4个原子的基团,但是芳族杂环基必须在其环系内具有至少5个原子。杂环基包括苯并-稠合环系和用一个或多个氧代部分取代的环系。4元杂环基的例子是氮杂环丁烷基(从氮杂环丁烷衍生)。5元杂环基的例子是噻唑基,10元杂环基的例子是喹啉基。非芳族杂环基的例子是吡咯烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶子基、吗啉代、硫吗啉代、噻噁烷基、哌嗪基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、1,2,3,6-四氢吡啶基、2-吡咯烷基、3-吡咯烷基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二噁烷基、1,3-二氧杂环戊基、吡唑啉基、二噻烷基、二硫杂环戊基、二氢吡喃基、二氢噻吩基、二氢呋喃基、吡唑烷基、咪唑啉基、咪唑烷基、3-氮杂二环[3.1.0]己烷基、3-氮杂二环[4.1.0]庚烷基、3H-吲哚基和喹嗪基。芳族杂环基的例子是吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、噌啉基、吲唑基、吲嗪基、酞嗪基、哒嗪基、三嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、噻二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、喹喔啉基、萘啶基和呋吡啶基。如果可能的话,上述从所列举的化合物衍生的基团可以是C-连接的或N-连接的。例如,从吡咯衍生的基团可以是吡咯-1-基(N-连接的)或吡咯-3-基(C-连接的)。
若R13和R14是(CR13R14)q或(CR13R14)t的形式,则对于每个超过1的q或t的迭代,各自被独立地定义。也就是说,例如若q或t是2,则包括-CH2CH(CH3)-类型的亚烷基部分和其它不对称地分支链基团。
本文所用的术语“药学上可接受的盐”除非另有指定,包括可以存在于式1化合物中的酸性或碱性基团的盐。例如,药学上可接受的盐包括羧酸根的钠、钙和钾盐,和氨基的盐酸盐。氨基的其它药学上可接受的盐是氢溴化物、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、磷酸二氢盐、乙酸盐、琥珀酸盐、柠檬酸盐、酒石酸盐、乳酸盐、扁桃酸盐、甲磺酸盐和对甲苯磺酸盐(甲苯磺酸盐)。盐的制备如下所述。
本发明也包括同位素标记的化合物及其药学上可接受的盐,它们等同于式1所列举的那些,但是事实上一个或多个原子被原子质量或质量数不同于通常在自然中所发现的原子质量或质量数的原子所代替。可以结合在本发明化合物中的同位素的例子包括氢、碳、氮、氧、磷、氟和氯的同位素,分别例如2H、3H、13C、14C、15N、18O、17O、35S、18F和36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其药物前体和所述化合物或所述药物前体的药学上可接受的盐也在本发明的范围内。本发明的某些同位素标记化合物在药物和/或底物组织分布测定法中是有用的,例如在其中结合了3H和14C等放射性同位素的那些。基于制备的简易性和检测能力,氚(即3H)和碳-14(即14C)同位素是特别优选的。此外,用较重的同位素取代,例如氘(即2H),由于代谢稳定性更高而能够赋予某些治疗上的优点,例如体内半衰期延长或剂量需要减少,因此在某些情况下可以是优选的。本发明的式1同位素标记化合物及其药物前体通常能够按照下列流程和/或实施例和制备例所公开的程序加以制备,用易于获得的同位素标记试剂代替非同位素标记试剂。
本发明也涵盖含有式1化合物药物前体的药物组合物和通过式1化合物药物前体给药来治疗细菌感染的方法。具有游离氨基、酰氨基、羟基或羧基的式1化合物能够转化为药物前体。药物前体包括这样的化合物,其中氨基酸残基、或两个或多个(例如两个、三个或四个)氨基酸残基的多肽链通过酰胺或酯键共价结合到式1化合物的游离氨基、羟基或羧酸根上。氨基酸残基包括但不限于20种天然来源的氨基酸,常用三个字母的符号表示,也包括4-羟基脯氨酸、羟基赖氨酸、demosine、isodemosine、3-甲基组氨酸、正缬氨酸、β-丙氨酸、γ-氨基丁酸、瓜氨酸、高半胱氨酸、高丝氨酸、鸟氨酸和甲硫氨酸砜。
其它类型药物前体也涵盖其中。例如,游离羧基能够衍生为酰胺或烷基酯。酰胺和酯部分可以结合这样的基团,包括但不限于醚、胺和羧酸官能度。游离羟基可以利用这样的基团加以衍生,包括但不限于半琥珀酸酯、磷酸酯、二甲氨基乙酸酯和磷酰氧基甲氧基羰基化合物,见D.F1eisher,R.Bong,B.H.Stewart,Advanced Drug DeliveryReview(1996)19,115。羟基和氨基的氨基甲酸酯药物前体也包括在内,羟基的碳酸酯药物前体和硫酸酯也是如此。还有,羟基衍生为(酰氧基)甲基和(酰氧基)乙基醚,其中酰基可以是烷基酯,并任选地被这样的基团取代,包括但不限于醚、胺和羧酸官能度,或者该酰基是如上所述的氨基酸酯。这种类型的药物前体描述在R.P.Robinson等《医药化学杂志》(J.Medicinal Chemistry)(1996)39,10。
某些式1化合物可以具有不对称中心,因此以不同的对映形存在。式1化合物的全部旋光异构体和立体异构体及其混合物被视为在本发明的范围内。关于式1化合物,本发明包括外消旋物、一种或多种对映形、一种或多种非对映形或其混合物的使用。尤其,R8和R9基团所连接的碳代表潜在的手性中心;本发明涵盖基于该手性中心的全部立体异构体。式1化合物也可以以互变体存在。本发明涉及全部这些互变体及其混合物的使用。某些式1化合物也可以包括肟部分,例如R3、R4、R5、R6或R7是-CH=NOR12,它以E或Z构型存在。本发明包括式1化合物的外消旋混合物,该式1化合物包括该化合物的肟部分或具体的E或Z异构体。
发明的详细说明
式1化合物可以如下所述加以制备。
根据下列流程1,式1化合物可以这样制备,按照本领域技术人员所熟悉的方法,水解其中R是C1-C6烷基的式2中间体醚,例如在酸水溶液中搅拌式2中间体。适当的酸例如氢氯酸。所得其中R1是氢的式1喹啉酮可以按照本领域技术人员所熟悉的N-烷基化方法,转化为其中R1具有如上所定义的除氢以外含义的喹啉酮。
根据下列流程2,式1(b)化合物、即其中R8是羟基的式1化合物可以这样制备,使式3中间体酮与式H-R9中间体反应,其中R9是如上所定义的,其中在所述R9基团的咪唑基部分中,游离的氮原子可以被任选的保护基团保护起来,例如磺酰基(例如二甲氨基磺酰基),保护基团能够在加成反应后除去。所述反应要求适当强碱的存在,例如仲丁基锂,在适当溶剂中,例如四氢呋喃,和适当硅烷衍生物的存在,例如氯-叔丁基二甲基硅烷。甲硅烷基能够用氟化物除去,例如氟化四丁铵。也可以采用带有类似于硅烷衍生物的保护基团的其它程序。
流程2
按照下列流程3,式1(b-1)化合物、即其中虚线是一条键且R1是氢的式1化合物能够这样制备,使式21中间体与式H-R9中间体反应,其中R9如上所述。所得中间体22经历异噁唑部分的开环作用如下,在水的存在下,将其与酸搅拌,例如TiCl3。所得式23中间体随后用适当试剂处理,例如R2CH2COCl或R2CH2COOC2H5,其中R2是如上所定义的,直接得到式1(b-1)化合物或中间体,将该中间体用碱处理,例如叔丁醇钾,能够转化为式1(b-1)化合物。
流程3
式21中间体能够这样制备,在酸性条件下处理式16中间体,见下流程9。
根据下列流程4,其中R8是式-NR12R13基团--其中R12和R13如上所述--的式1化合物(所述化合物由下式1(g)代表)可以这样制备,使式13中间体与式14试剂反应,式13中W是适当的离去基团,例如卤。所述反应可以这样进行,将反应物在适当溶剂中搅拌,例如四氢呋喃。
流程4
按照本领域技术人员所熟悉的氢化方法,其中虚线代表一条键的式1(g)化合物或式1的其它实施方式能够转化为其中虚线不代表一条键的化合物。按照本领域技术人员所熟悉的氧化方法,其中虚线不代表一条键的化合物可以转化为其中虚线代表一条键的化合物。
根据下列流程5,按照本领域技术人员已知的方法,包括O-烷基化或O-酰基化反应,其中R8是羟基的式1化合物(所述化合物由式1(b)代表)可以转化为式1(c)化合物,其中R12具有上述含义,但它不是氢;例如在碱的存在下,例如氢化钠,在适当条件下,例如在偶极非质子溶剂中,例如DMF,使式1(b)化合物与烷化剂反应,例如R12-W,其中R12如上所述。W是适当的离去基团,例如卤基或磺酰基。
作为上述反应程序的替代选择,式1(c)化合物也可以这样制备,在酸性介质中,使式1(b)化合物与式R12-OH试剂反应,其中R12如上所述。
式1(b)化合物也可以转化为其中R12是氢且R13被C1-C6烷基羰基代替的式1(g)化合物如下,在酸性介质中,例如硫酸,使式1(b)化合物与C1-C6烷基-CN进行里特反应(Ritter-type reaction)。此外,式1(b)化合物也可以转化为其中R12和R13是氢的式1(g)化合物如下,使式1(b)化合物与乙酸铵反应,随后用NH3(含水)处理。
根据下列流程6,上述式1(b)化合物也可以转化为其中R8是氢的式1(d)化合物如下,使式1(b)化合物受到适当还原条件的作用,例如在适当还原剂的存在下,例如硼氢化钠,在三氟乙酸中搅拌,或者在甲酰胺的存在下,在乙酸中搅拌式1(b)化合物。此外,其中R8是氢的式1(d)化合物可以转化为其中R12是C1-C10烷基的式1(e)化合物如下,在碱的存在下,例如叔丁醇钾,在适当溶剂中,例如二甘醇二甲醚,使式1(d)化合物与其中W是适当离去基团的式5试剂反应。
根据下列流程7,式1化合物可以这样制备,使式6硝酮与羧酸的酸酐反应,例如乙酸酐,在喹啉部分的2-位上生成相应的酯。利用碱,例如碳酸钾,所述喹啉酯能够就地水解为相应的喹啉酮。
或者,式1化合物可以这样制备,在碱的存在下,例如含水碳酸钾,使式6硝酮与含有磺酰基的亲电试剂反应,例如对甲苯磺酰氯。反应最初涉及2-羟基-喹啉衍生物的生成,随后互变异构为所需的喹啉酮衍生物。采用本领域技术人员所熟悉的相转移催化条件,可以提高反应速率。
式1化合物也可以通过上述式6化合物的分子内光化学重排加以制备。所述重排可以这样进行,将试剂溶于反应惰性溶剂,在366nm波长下照射。有利的是采用脱气溶液,在惰性气氛下进行反应,例如无氧的氩或氮气,目的是最小化所不需要的副反应或减少量子产额。
经过本领域技术人员所熟悉的反应或官能团转化,式1化合物的取代基可以转化为其它式1范围内的取代基。上文已经描述了大量这样的转化作用。其它例子是羧酸酯水解为相应的羧酸或醇;酰胺水解为相应的羧酸或胺;腈水解为相应的酰胺;咪唑或苯基部分上的氨基可以通过本领域技术人员所熟悉的重氮化反应被氢代替,随后重氮基被氢代替;醇可以转化为酯和醚;伯胺可以转化为仲胺或叔胺;双键可以氢化为相应的单键。
根据下列流程8,上述式3中间体可以这样制备,在适当条件下,例如在强酸(例如多磷酸)的存在下,在适当溶剂中,使式8喹啉酮衍生物与式9中间体或其官能衍生物反应。式8中间体可以这样生成,在强酸的存在下,例如多磷酸,搅拌环化式7中间体。任选地,所述环化反应可以后接氧化步骤,氧化步骤可以这样进行,在氧化剂的存在下,例如溴或碘,在适当溶剂中,例如卤代芳族溶剂(例如溴苯),搅拌环化后所生成的中间体。在该阶段,通过本领域技术人员所熟悉的官能团转化反应,R1取代基可以变为不同的部分。
根据下列流程9,式3(a-1)中间体、即其中虚线是一条键且R1和R2是氢的式3中间体能够从式17中间体制备,后者适宜通过保护相应的酮加以制备。在适当溶剂中,例如醇(例如甲醇),在碱的存在下,例如氢氧化钠,将所述式17中间体与式18中间体搅拌。在水的存在下,将所得式16中间体与酸搅拌,例如TiCl3,式16中间体将经历酮缩醇的水解和异噁唑部分的开环。随后,可以利用乙酸酐制备式15中间体,在碱的存在下,例如叔丁醇钾,式15中间体将经历闭环作用。
利用本领域技术人员所熟悉的N-烷基化程序,式3(a-1)中间体能够转化为式3(a)中间体,后者是这样的式3中间体,其中虚线代表一条键,R2是氢,R1是如上所定义的,但不是氢。
流程9
根据下列流程10,制备其中R1是氢的式3(a-1)中间体的替代方法开始于式16中间体,在反应惰性溶剂中,例如四氢呋喃(THF),利用催化氢化条件,例如利用氢气和碳上的钯,式16中间体能够转化为式19中间体。式19中间体能够转化为式20中间体如下,使式19中间体进行乙酰化反应,例如在反应惰性溶剂中,例如甲苯,用羧酸的酸酐(例如乙酸酐)处理,随后在反应惰性溶剂中,例如1,2-二甲氧基乙烷,用碱处理,例如叔丁醇钾。使式20中间体受到酸性条件的作用,能够得到式3(a-1)中间体。
流程10
根据下列流程11,上述式2中间体可以这样制备,使其中W是卤等适当离去基团的式10中间体与式11中间体酮反应。该反应进行如下,通过与强碱搅拌,例如丁基锂,使式10中间体转化为有机金属化合物,随后加入式11中间体酮。尽管该反应主要得到羟基衍生物(R8是羟基),不过通过进行本领域技术人员所熟悉的官能团转化,所述羟基衍生物能够转化为其中R8具有另外定义的其它中间体。
根据下列流程12,式6中间体硝酮(nitrones)能够这样制备,在适当溶剂中,例如二氯甲烷,将式12喹啉衍生物用适当氧化剂进行N-氧化,例如间氯过苯甲酸或H2O2。
流程12
所述N-氧化也可以对式12喹啉的前体进行。
式12中间体可以经式6中间体体内代谢为式1化合物。因此,式12和6中间体可以充当式1化合物的药物前体。这样的药物前体也在本发明的范围内。
根据下列流程13,其中Y是溴、碘或三氟甲磺酰氧基的式24化合物能够这样反应,在0℃至100℃的温度下,在胺溶剂中,例如二乙胺,在铜(Ⅰ)盐的存在下,例如碘化铜(Ⅰ),利用钯催化条件(钯试剂,例如双(三苯膦)-氯化钯(Ⅱ)),加入式-C≡CR16的R3、R4或R5基团(以R3的加入为例),特别是末端的炔,例如(三甲基甲硅烷基)乙炔。可以加入助溶剂,例如DMF(N,N-二甲基甲酰胺),有助于溶解试剂。其它进行这类炔加成反应的方法参见美国专利5747498。
根据下列流程14,式26化合物能够这样制备,使式25化合物与其中R12是H或苯基的式27中间体反应。该反应要求适当碱的存在,例如叔丁基锂(当R12=H时)或2,2,6,6-四甲基哌啶锂(当R12=苯基时),在适当溶剂中,例如THF。-SR12基团能够用阮内TM镍通过还原方法从式26化合物中除去,或者在乙酸中用硝酸或含水过氧化氢通过氧化方法除去。
式1化合物和上述有些中间体可以在其结构中具有一个或多个立体形成中心。这样的立体形成中心可以以R或S构型存在。肟部分可以以E或Z构型存在,例如其中的R3、R4、R5、R6或R7是-CH=NOR12。
上述过程中所制备的式1化合物通常是对映体的外消旋混合物,按照本领域技术人员所熟悉的拆分程序能够彼此分离各对映体。通过与适当手性酸的反应,式1外消旋化合物可以转化为相应的非对映盐。所述非对映盐随后例如通过选择或分级结晶加以分离,借助碱的作用从中释放出对映体。分离式1化合物的对映形的替代方式涉及使用手性固定相的液相色谱。所述立体化学纯的异构形也可以从适当原料的相应的立体化学纯的异构形衍生而来,只要立体有择地进行反应即可。优选地,如果需要特殊的立体异构体,那么所述化合物将按照立体有择性制备方法加以合成。这些方法将有利地采用对映体纯的原料。
碱性式1化合物能够与不同的无机和有机酸形成各种不同的盐。尽管这样的盐为了对动物给药而必须是药学上可接受的,不过在实践中常常需要最初从反应混合物中分离式1化合物的药学上不可接受的盐,然后通过碱性试剂的处理,将后者简单地转化为游离的碱化合物,随后将后者游离的碱转化为药学上可接受的酸加成盐。本发明碱化合物的酸加成盐易于制备如下,在含水溶剂介质或适当的有机溶剂中,例如甲醇或乙醇,将碱化合物用基本上等量的选定的无机或有机酸处理。一旦蒸发溶剂,易于得到所需的固体盐。通过向游离碱在有机溶剂中的溶液中加入适当的无机或有机酸,所需酸加成盐也能够从该溶液中沉淀出来。式1化合物的阳离子盐按相似方法制备,但是羧基与适当的阳离子盐试剂反应,例如钠、钾、钙、镁、铵、N,N’-二苄基乙二胺、N-甲基葡糖胺(葡甲胺)、乙醇胺、氨基丁三醇或二乙醇胺。
式1化合物及其药学上可接受的盐和溶剂化物(以下统称为“治疗化合物”)能够口服、透皮(例如通过贴剂的使用)、肠胃外或局部给药。口服给药是优选的。一般来说,式1化合物及其药学上可接受的盐和溶剂化物最需要的给药剂量为约1.0mg至约500mg每天,优选为约1至约100mg每天,是为一次或分次(即多次)剂量。治疗化合物的每日给药剂量一般为约0.01至约10mg每kg体重每天,是为一次或分次剂量。可以根据所治疗个人的体重和状况和所选择的特定给药途径进行调整。在有些情况下,低于上述范围下限的剂量水平可能是更恰当的,而在其它情况下,采用更大的剂量也不会导致有害的副作用,只要这种更大的剂量首先分为若干小剂量在当天内给药即可。
治疗化合物可以单独或与药学上可接受的载体或稀释剂结合给药,给药途径为前述两种之一,给药可以分一次或多次剂量进行。确切地说,本发明的新治疗化合物能够以各种不同的剂型给药,也就是说,它们可以与各种药学上可接受的惰性载体结合成为片剂、胶囊剂、锭剂、糖锭剂、硬糖剂、散剂、喷雾剂、霜剂、油膏剂、栓剂、胶冻剂、凝胶剂、糊剂、洗剂、软膏剂、酏剂、糖浆剂等。这样的载体包括固体稀释剂或填充剂、无菌含水介质和各种无毒的有机溶剂等。此外,口服药物组合物可以适当加入甜味剂和/或矫味剂。
关于口服给药,可以采用含有各种赋形剂的片剂,例如微晶纤维素、柠檬酸钠、碳酸钙、磷酸二钙和甘氨酸,以及各种崩解剂,例如淀粉(优选为玉米、马铃薯或木薯淀粉)、海藻酸和某些复合硅酸盐,以及造粒粘合剂,如聚乙烯吡咯烷酮、蔗糖、明胶和阿拉伯胶。另外,润滑剂对压片目的来说常常是非常有用的,例如硬脂酸镁、月桂基硫酸钠和滑石。也可以采用相似类型的固体组合物作为胶囊中的填充剂;这方面优选的原料也包括乳糖或奶糖以及高分子聚乙二醇。当口服给药需要含水悬浮液和/或酏剂时,活性成分可以结合各种甜味剂或矫味剂、着色剂或染剂、(如果需要的话)乳化和/或悬浮剂,以及稀释剂,例如水、乙醇、丙二醇、甘油,和它们的组合。
关于肠胃外给药,可以采用治疗化合物在芝麻油或花生油中的溶液或在含水丙二醇中的溶液。如果必要的话,含水溶液应当加以适当缓冲,首先赋予液体稀释剂等渗性。这些含水溶液适合于静脉内注射目的。油性溶液适合于动脉内、肌内和皮下注射目的。按照本领域技术人员熟知的标准药学技术,所有这些溶液在无菌条件下的制备是易于实现的。
另外,也可能将治疗化合物局部给药,按照标准药学实践,可以优选地凭藉霜剂、胶冻剂、凝胶剂、糊剂、软膏剂等进行给药。
治疗化合物也可以对除人以外的哺乳动物给药。对哺乳动物给药的剂量将取决于动物种类和所治疗的疾病或疾患。治疗化合物可以以胶囊剂、大丸剂、片剂或液体兽用顿服药的剂型对动物给药。治疗化合物也可以通过注射或作为植入物对动物给药。按照标准兽医实践,这样的制剂是以常规方式制备的。作为替代选择,治疗化合物可以与动物饲料一起给药,为此可以制备浓缩的饲料添加剂或预混合物,与正常的动物饲料混合。
式1化合物表现出作为Ras法呢基化作用抑制剂的活性,可用于包括人在内的哺乳动物癌症的治疗和异常细胞生长的抑制。式1化合物作为Ras法呢基化作用抑制剂的活性可以通过它们相对于对照的体外抑制Ras法呢基转移酶的能力加以测定。该程序描述如下。
使用包含匀化脑组织胞质部分的人法呢基转移酶(FTase)粗制剂,在96孔测定皿中筛选化合物。细胞溶质部分是这样制备的,在100ml蔗糖/MgCl2/EDTA缓冲液中匀化大约40克新鲜组织(利用Dounce匀化器;10-15冲程),在4G下,以1000克离心组织匀浆10分钟,在4G下,以17000克再离心上清液15分钟,然后收集所得上清液。稀释该上清液至含有最终浓度如下,50mM Tris HCl(pH7.5)、5mN DTT、0.2M KCl、20mM ZnCl2、1mM PMSF,在4G下,以178000克再离心90分钟。上清液称为“粗FTase”,测定其蛋白质浓度,制备等分试样,在-70℃下贮藏。
用于测量体外人Ftase抑制作用的测定法是AmershamLifeScience所述方法的改进,该方法使用他们的法呢基转移酶(3H)闪烁亲近测定(SPA)试剂盒(TRKQ 7010)。FTase酶活性是在100ml溶液中测定的,其中含有50mM N-(2-羟基乙基)哌嗪-N-(2-乙磺酸)(HEPES),pH7.5、30mM MgCl2、20μM KCl、5mM Na2HPO4、5mM二硫苏糖醇(DTT)、0.01%Triton X-100、5%二甲基亚砜(DMSO)、20mg粗FTase、0.12mM[3H]-法呢基焦磷酸酯([3H]-FPP;36000dpm/pmole,Amersham LifeScience)和0.2mM生物素化Ras肽KTKCVIS(Bt-KTKCVIS),后者在其α-氨基上被N-末端生物素化,通过HPLC合成和纯化。加入酶引发反应,在37℃下恒温45分钟后加入EDTA(TRKQ7010试剂盒中的终止试剂)终止反应。向每孔内加入10ml链霉抗生物素包覆的SPA珠粒(TRKQ 7010)捕获异戊二烯基化和没有异戊二烯基化的Bt-KTKCVIS,反应混合物在室温下恒温30分钟。利用MicroBeta1450平板计数器测定与SPA珠粒结合的放射性的量。在这些测定条件下,酶活性与异戊二烯基受体、Bt-KTKCVIS和粗FTase的浓度线性相关,但是关于异戊二烯基供体、FPP是饱和的。测定反应时间也在线性范围内。
按常规做法将供试化合物溶于100%二甲基亚砜(DMSO)。通过计算在供试化合物存在下的含氚法呢基相对于对照孔(不存在抑制剂)的百分掺入率,测定对法呢基转移酶活性的抑制作用。从所得剂量-反应测定IC50值,它是产生最大Bt-KTKCVIS法呢基化作用的一半所需浓度。
下列实施例进一步阐述本发明。下列实施例中,“Et”表示乙基,“Me”表示甲基,“Ac”表示乙酰基。
实施例1
6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-1-甲基-4-(3-三甲基硅烷基乙炔基-苯基)-1H-喹啉-2-酮
1A.5-[2-(4-氯-苯基)-[1,3]二氧戊环-2-基]-3-(3-碘-苯基)-苯并[c]异噁唑
在干燥N2气氛下,将2-(4-氯苯基)-2-(4-硝基苯基)-1,3-二氧戊环(38.7g,127mMol)悬浮在190mL甲醇(MeOH)中。向该溶液中加入(3-碘苯基)乙腈(46.3g,190mMol)和25.4g(625mMol)氢氧化钠(NaOH)。然后加热溶液至回流,在该温度下反应2小时。反应混合物冷却至环境温度,在真空下除去MeOH。使所得红色油在二氯甲烷(DCM)与0.1N含水NaOH之间分配。DCM层连续用0.1N含水NaOH、然后用盐水洗涤。DCM层经MgSO4干燥,过滤,在真空下浓缩,得到暗红色油。将该油在MeOH中搅拌,标题化合物沉淀出来,为黄色固体。该黄色固体用MeOH洗涤,在真空下干燥,得到52.4g标题化合物,使用时无需进-步纯化。
1B.[6-氨基-3-(4-氯-苯甲酰基)-环己-2,4-二烯基]-(3-碘-苯基)-甲酮
将5-[2-(4-氯-苯基)-[1,3]二氧戊环-2-基]-3-(3-碘-苯基)-苯并[c]异噁唑(65.4g,130mMol)溶于四氢呋喃(THF)(500mL)与DCM(100mL)的溶液。向该溶液中加入500mL氯化钛(Ⅲ)(10wt%溶液,溶剂为20-30wt%氢氯酸(HCl)),反应混合物搅拌1小时。另向反应混合物中加入100mL氯化钛(Ⅲ)(10wt%溶液,溶剂为20-30wt%氢氯酸(HCl)),反应混合物搅拌2.5小时。然后将反应混合物倒入冰水中,所得不均匀溶液用DCM萃取。DCM层连续用含水饱和NaHCO3和盐水洗涤。DCM层经MgSO4干燥,过滤,在真空下浓缩,得到标题化合物,为橙色的油(60g)。该油使用时无需进一步纯化。
1C.6-(4-氯-苯甲酰基)-4-(3-碘-苯基)-1H-喹啉-2-酮
在干燥N2气氛下,将[6-氨基-3-(4-氯-苯甲酰基)-环己-2,4-二烯基]-(3-碘-苯基)-甲酮(60g,130mMol)溶于无水甲苯(450mL)。向该溶液中加入180mL三乙胺(NEt3)、50ml乙酸酐(Ac2O)和1.60g(13.0mMol)4-二甲氨基吡啶(DMAP)。然后加热反应混合物至回流,在该温度下搅拌20小时。反应混合物冷却至环境温度,用吸滤法收集沉淀。固体用乙醚(Et2O)洗涤,在真空下干燥,得到标题化合物(63g),使用时无需进一步纯化。
1D.6-(4-氯-苯甲酰基)-4-(3-碘-苯基)-1-甲基-1H-喹啉-2-酮
在干燥N2气氛下,将6-(4-氯-苯甲酰基)-4-(3-碘-苯基)-1H-喹啉-2-酮(63g,130mMol)溶于THF(500mL)。向该溶液中加入10N含水NaOH(550mL)、苄基三乙基氯化铵(13.8g,60.5mMol)和甲基碘(13.5mL,212.0mMol)。反应混合物在环境温度下搅拌15小时,然后使其在DCM与水之间分配。DCM层连续用水(4次)、然后用盐水洗涤。有机层经MgSO4干燥,过滤,在真空下浓缩,得到51.2g黄色固体,为标题化合物,使用时无需进一步纯化。
1E.6-(4-氯-苯甲酰基)-1-甲基-4-(3-三甲基硅烷基乙炔基-苯基)-1H-喹啉-2-酮
将6-(4-氯-苯甲酰基)-4-(3-碘-苯基)-1-甲基-1H-喹啉-2-酮(9.98g,20.0mMol)悬浮在二乙胺(300mL)中。向该溶液中加入50mL无水N,N-二甲基甲酰胺(DMF)、(三甲基甲硅烷基)乙炔(8.5mL)和双(三苯膦)-氯化钯(Ⅱ)(1.40g,2.00mMol)。将烧瓶用铝箔覆盖,然后加入碘化铜(Ⅰ)(780mg,4.09mMol),导致反应混合物放热。在环境温度下、在干燥N2气氛下搅拌过夜后,反应混合物在真空下浓缩,残余物经过硅胶快速色谱,用DCM至MeOH/DCM(2∶98)梯度洗脱,得到8.55g标题产物,为固体。
1F.6-[(4-氯-苯基)-羟基-(2-巯基-3-甲基-3H-咪唑-4-基)-甲基]-1-甲基-4-(3-三甲基硅烷基乙炔基-苯基)-1H-喹啉-2-酮
在干燥N2气氛下,将2-巯基-1-甲基咪唑(2.08g,18.2mMol)溶于无水THF(200mL)。溶液冷却至-78℃,加入叔丁基锂溶液(1.7M戊烷溶液,22mL,37mMol)。然后将溶液加热至0℃。有黄色沉淀生成后,溶液冷却至-78℃,加入6-(4-氯-苯甲酰基)-1-甲基-4-(3-三甲基硅烷基乙炔基-苯基)-1H-喹啉-2-酮(8.55g,18.2mMol)的无水THF(25mL)溶液。30分钟后,溶液加热至0℃,在该温度下搅拌1小时。然后将反应混合物加热至环境温度,搅拌过夜。用20mL饱和含水氯化铵(NH4Cl)终止反应,然后在DCM与水之间分配。DCM层经硫酸钠(Na2SO4)干燥,过滤,在真空下浓缩。残余物经过硅胶快速色谱,用DCM至MeOH/DCM(3∶97)梯度洗脱,得到5.0g标题化合物,为固体。
1G.6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-1-甲基-4-(3-三甲基硅烷基乙炔基-苯基)-1H-喹啉-2-酮
将6-[(4-氯-苯基)-羟基-(2-巯基-3-甲基-3H-咪唑-4-基)-甲基]-1-基-4-(3-三甲基硅烷基乙炔基-苯基)-1H-喹啉-2-酮(5.0g,8.6mMol)溶于乙醇(40mL),向其中加入阮内TM镍(约10g),加热反应物至回流。每20分钟加入更多的阮内TM镍,直到反应物的质谱分析显示原料已被消耗为止。反应混合物冷却至环境温度,通过CELITETM(硅藻土)过滤。CELITETM用大量乙醇洗涤。合并滤液,在真空下浓缩,得到3.88g标题化合物。
C.l.m/z 552[M+1];1H NMR(CD3OD)δ7.64-7.75(m,3H),7.17-7.48(m,9H),6.59(s,1H),6.17(s,1H),3.79(s,3H),3.42(s,3H),0.23(s,9H).
实施例2
6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-4-(3-乙炔基-苯基)-1-甲基-1H-喹啉-2-酮
在干燥N2气氛下,将6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-1-甲基-4-(3-三甲基硅烷基乙炔基-苯基)-1H-喹啉-2-酮(3.88g,7.03mMol)溶于THF(10mL)。向该溶液中加入1.0N氟化四丁铵的THF溶液(20mL,20mMol)。反应混合物在环境温度下搅拌过夜,然后在真空下浓缩。使残余物在4-(二氰基亚甲基)-2-甲基-6-(4-二甲氨基-苯乙烯基)-4H-吡喃(DCM)与水之间分配。保留DCM层,用水洗涤3次以上,然后用盐水洗涤。DCM层经Na2SO4干燥,过滤,在真空下浓缩。残余物经过闪式硅胶色谱,用DCM至MeOH/DCM(4∶96)梯度洗脱,得到3.01g标题化合物。
C.l.m/z 480[M+1];1H NMR(CD3OD)δ7.75(dd,J=2.1,8.9Hz,1H),7.69(s,1H),7.66(d,8.5Hz,1H),7.52(d,J=7.9Hz,1H),7.41(t,J=7.7Hz,1H),7.38(s,1H),7.29(m,3H),7.23(d,J=1.7Hz,1H),7.17(d,J=8.5Hz,2H),6.59(s,1H),6.16(s,1H),3.79(s,3H),3.60(s,1H),3.42(s,3H).
6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-4-(3-乙炔基-苯基)-1-甲基-1H-喹啉-2-酮的对映体的分离
将6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-4-(3-乙炔基-苯基)-1-甲基-1H-喹啉-2-酮(4.96g)分离为它的对映体,在CHIRALPAKTMAD(由Daicel Chemical Industries,LTD,Osaka,Japan制造)上用高效液相色谱法纯化(20μm;洗脱剂:己烷/异丙醇/二乙胺85/15/0.1;30℃)。在这些条件下,得到1.73g快速洗脱的对映体A({α}D 20=-25.1(c=50.0mg/5mL))和2.07g慢速运动的对映体B({α}D 20=+24.2(c=27.7mg/5mL))。两种对映体都是>97%光学纯的。
实施例3
6-[氨基-(4-氯-苯基)-(3-甲基-3H-咪唑-4-基)-甲基]-4-(3-乙炔基-苯基)-1-甲基-1H-喹啉-2-酮
将6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-4-(3-乙炔基-苯基)-1-甲基-1H-喹啉-2-酮(1.75mg,3.65mMol)溶于5.0mL亚硫酰氯(SOCl2),在室温下、在干燥N2气氛下搅拌2小时。然后将反应混合物在减压下浓缩,将所得固体溶于甲苯,在真空下浓缩。将所得固体溶于THF(15mL),向该混合物中加入浓氢氧化铵(20mL)。反应混合物在环境温度下搅拌1小时,然后在DCM与1.0N含水NaOH之间分配。含水层再次用DCM萃取,然后合并有机层,经Na2SO4干燥,过滤,在真空下浓缩,得到棕色固体。残余物经过硅胶快速色谱,用MeOH/乙酸乙酯(EtOAc)/氢氧化铵(NH4OH)(5∶95∶0.1)至MeOH/EtOAc/NH4OH(10∶90∶0.1)梯度洗脱,得到643mg标题化合物。
C.l.m/z479[M+1];1H NMR(CD3OD)δ7.84(dd,J=2.3,9.1Hz,1H),7.70(d,8.9Hz,1H),7.57(s,1H),7.51(m,1H),7.37(t,J=7.7Hz,1H),7.33(s,1H),7.28(m,2H),7.21(dd,J=1.0,7.7Hz,1H),7.10(d,J=8.5Hz,2H),6.96(d,J=1.3Hz,1H),6.57(s,1H),6.10(s,1H),3.78(s,3H),3.60(s,1H),3.41(s,3H).
6-[氨基-(4-氯-苯基)-(3-甲基-3H-咪唑-4-基)-甲基]-4-(3-乙炔基-苯基)-1-甲基-1H-喹啉-2-酮的对映体的分离
将6-[氨基-(4-氯-苯基)-(3-甲基-3H-咪唑-4-基)-甲基]-4-(3-乙炔基-苯基)-1-甲基-1H-喹啉-2-酮(5.25g)分离为它的对映体,在CHIRALCELTMOD(由Daicel Chemical Industries,LTD,Osaka,Japan制造)上用高效液相色谱法纯化(20um;洗脱剂:己烷/异丙醇/二乙胺67/33/0.1;25℃)。在这些条件下,得到2.29g快速洗脱的对映体A和1.60g慢速运动的对映体B。两种对映体都是>97%光学纯的。
实施例4
6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-1-甲基-4-[3-(3-甲基-丁-1-炔基)-苯基]-1H-喹啉-2-酮
采用与实施例1所述相同的程序,但是在步骤1E中用3-甲基-1-丁炔代替(三甲基甲硅烷基)乙炔,得到标题化合物。
C.l.m/z 522[M+1];1H NMR(CDCl3)δ7.60(m,2H),7.42(d,J=7.9Hz,1H),7.37(d,J=7.9Hz,1H),7.25-7.29(m,5H),7.17(d,J=8.7Hz,2H),7.03(d,J=8.1Hz,1H),6.60(s,1H),6.31(brs,1H),3.70(s,3H),3.43(s,3H),2.79(m,J=6.9Hz,1H),1.26(d,J=6.9Hz,6H).
实施例5
6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-4-[3-(3,3-二甲基-丁-1-炔基)-苯基]-1-甲基-1H-喹啉-2-酮
采用与实施例1所述相同的程序,但是在步骤1E中用3,3-二甲基-1-丁炔代替(三甲基甲硅烷基)乙炔,得到标题化合物。
C.l.m/z 536[M+1];1H NMR(CDCl3)δ7.84(brs,1H),7.60(m,1H),7.40(m,3H),7.21-7.27(m,4H),7.15(d,J=8.5Hz,2H),7.02(d,J=7.3Hz,1H),6.61(s,1H),6.34(brs,1H),3.70(s,3H),3.48(s,3H),1.30(s,9H).
实施例6
6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-1-甲基-4-[3-(4-甲基-戊-1-炔基)-苯基]-1H-喹啉-2-酮
采用与实施例1所述相同的程序,但是在步骤1E中用4-甲基-1-戊炔代替(三甲基甲硅烷基)乙炔,得到标题化合物。
C.l.m/z 536[M+1];1H NMR(CDCl3)δ7.84(brs,1H),7.62(d,J=8.1Hz,1H),7.39-7.44(m,2H),7.25-7.30(m,5H),7.17(d,J=8.3Hz,2H),7.05(d,J=7.2Hz,1H),6.63(s,1H),6.36(brs,1H),3.72(s,3H),3.49(s,3H),2.31(d,J=6.4Hz,2H),1.91(m,1H),1.03(d,J=6.6Hz,6H).
实施例7
6-[(4-氯-苯基)-(3-甲基-3H-咪唑-4-基)-[1,2,4]三唑-1-基-甲基]-4-[3-(3,3-二甲基-丁-1-炔基)-苯基]-1-甲基-1H-喹啉-2-酮
将6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-4-[3-(3,3-二甲基-丁-1-炔基)-苯基]-1-甲基-1H-喹啉-2-酮(330mg,0.633mMol)溶于4mL亚硫酰氯,在环境温度下、在干燥N2气流下搅拌2小时。然后将反应混合物在真空下浓缩,向反应混合物中加入甲苯(5mL),随后在真空下浓缩,得到黄色固体。在干燥N2气氛下,将210mg黄色固体溶于5.0mL无水DMF。向该溶液中加入800mg碳酸钾和300mg 1,2,4-三唑,随后将反应混合物加热至80℃,在该温度下搅拌过夜。然后将反应混合物在真空下浓缩,在EtOAc与水之间分配。EtOAc层用水洗涤3次以上,然后用盐水洗涤。EtOAc层然后经Na2SO4干燥,过滤,在真空下浓缩,得到黄色固体。该固体经过硅胶快速色谱,用MeOH/DCM/NH4OH(2∶98∶0.1)至MeOH/DCM/NH4OH(7∶93∶0.1)梯度洗脱,得到150mg标题产物,为白色固体。
1H NMR(CDCl3)δ8.06(s,1H),7.89(s,1H),7.59(brs,1H),7.41(d,J=8.7Hz,2H),1H),7.22-7.27(m,5H),7.00-7.05(m,2H),6.89(d,J=8.7Hz,2H),6.67(s,1H),6,54(brs,1H),3.75(s,3H),3.08(s,3H),1.31(s,9H).
实施例8
6-[(4-氯-苯基)-(3-甲基-3H-咪唑-4-基)-[1,2,4]三唑-1-基-甲基]-1-甲基-4-[3-(3-甲基-丁-1-炔基)-苯基]-1H-喹啉-2-酮
采用与实施例7所述相同的程序,但是用6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-1-甲基-4-[3-(3-甲基-丁-1-炔基)-苯基]-1H-喹啉-2-酮代替6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-4-[3-(3,3-二甲基-丁-1-炔基)-苯基]-1-甲基-1H-喹啉-2-酮,得到标题化合物。
1H NMR(CDCl3)δ8.06(s,1H),7.90(s,1H),7.43-7.48(m,2H),7.20-7.34(m,6H),7.01(d,J=8.1Hz,1H),6.98(s,1H),6.79(m,3H),6.70(s,1H),3.77(s,3H),3.28(s,3H),2.80(m,1H),1.26(d,J=6.9Hz,6H).
实施例9
6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-4-(3-乙炔基-4-氟-苯基)-1-甲基-1H-喹啉-2-酮
9A.4-溴甲基-1-氟-2-碘-苯
在干燥N2气氛下,将4-氟-3-碘甲苯(50g,210mMol)、N-溴琥珀酰亚胺(37.7g,212mMol)和2,2’-偶氮双(2-甲基丙腈)(348mg,2.12mMol)溶于四氯化碳(300mL)。将混合物加热至回流4小时,然后冷却至环境温度。将混合物在真空下浓缩,用Et2O研制。滤液连续用水、含水饱和NaHCO3和盐水洗涤。醚层经MgSO4干燥,过滤,在真空下浓缩,得到红色的油。该油经过硅胶快速色谱,用己烷洗脱,得到33.8g标题化合物,为白色固体。
9B.(4-氟-3-碘-苯基)-乙腈
将4-溴甲基-1-氟-2-碘-苯(33.8g,107mMol)加入到240mL 0.5M氰化锂的DMF溶液中。在干燥N2气氛下将反应混合物加热至80℃,在该温度下搅拌过夜。然后将混合物冷却至环境温度,在Et2O与0.1N含水NaOH之间分配。醚层然后用0.1N含水NaOH洗涤4次以上。醚层然后经MgSO4干燥,过滤,在真空下浓缩,得到24.7g标题化合物,为红色固体,使用时无需进一步纯化。
9C.6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-4-(3-乙炔基-4-氟-苯基)-1-甲基-1H-喹啉-2-酮
采用实施例1和2的程序,但是在步骤1A中用(4-氟-3-碘-苯基)-乙腈代替(3-碘苯基)乙腈,得到标题化合物。
C.l.m/z 498[M+1];1H NMR(CDCl3)δ7.61(d,J=8.1Hz,1H),7.53(brs,1H),7.36(d,9.0Hz,1H),7.04-7.33(m,8H),6.52(s,1H),6.21(brs,1H),3.67(s,3H),3.38(s,3H),3.36(s,1H).
实施例10
6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-1-甲基-4-(3-苯乙炔基-苯基)-1H-喹啉-2-酮
采用实施例1的程序,但是在步骤1E中用苯乙炔代替(三甲基甲硅烷基)乙炔,得到标题化合物。
C.l.m/z 556[M+1];1H NMR(CDCl3)δ7.60(dd,J=2.1,8.8Hz,1H),7.50(m,3H),7.43(brs,1H),7.21-7.37(m,9H),7.17(d,J=8.5Hz,2H),7.08(d,J=7.5Hz.1H),6.61(s,1H),6.26(brs,1H),3.69(s,3H),3.38(s,3H).
实施例11
6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-4-[3-(4-羟基-丁-1-炔基)-苯基]-1-甲基-1H-喹啉-2-酮
11A.6-(4-氯-苯甲酰基)-1-甲基-4-[3-(4-三苯甲氧基-丁-1-炔基)-苯基]-1H-喹啉-2-酮
在实施例1步骤1E中用3-丁炔-1-醇代替(三甲基甲硅烷基)乙炔,制得6-(4-氯-苯甲酰基)-4-[3-(4-羟基-丁-1-炔基)-苯基]-1-甲基-1H-喹啉-2-酮,在干燥N2气氛下,将其(1.41g,3.20mMol)和三乙胺(900mL,6.40mMol)溶于DCM(15ml)。向该溶液中加入三苯甲基氯(980mg,3.50mMol),混合物在环境温度下搅拌4小时。然后使反应混合物在Et2O/EtOAc与水之间分配。有机层再次用水洗涤,然后用饱和含水NaHCO3洗涤,经MgSO4干燥,过滤,在真空下浓缩,得到白色泡沫,为标题化合物,使用时无需进一步纯化。
11B.6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-4-[3-(4-羟基-丁-1-炔基)-苯基]-1-甲基-1H-喹啉-2-酮
在干燥N2气流下,将2-巯基-1-甲基咪唑(400mg,3.50mMol)溶于无水THF(7.0mL)。然后将溶液冷却至-78℃,然后加入2.8mL 2.5M正丁基锂的己烷溶液。加入完成后,将反应混合物加热至环境温度,在该温度下搅拌1小时。然后将反应混合物冷却至-78℃,向混合物中加入6-(4-氯-苯甲酰基)-1-甲基-4-[3-(4-三苯甲氧基-丁-1-炔基)-苯基]-1H-喹啉-2-酮的THF(7.0mL)溶液。将反应物加热至环境温度,搅拌过夜。用饱和含水NH4Cl(25mL)终止反应,在DCM与水之间分配。DCM层经Na2SO4干燥,过滤,在真空下浓缩,得到绿色固体。将该绿色固体溶于30mL乙酸(AcOH),溶液冷却至约5℃。向该溶液中滴加2.0mL30%含水过氧化氢(H2O2)。加入完成后,反应混合物在环境温度下搅拌30分钟。然后将反应混合物冷却至0℃,加入200mL水,缓慢加入NaOH使反应物碱化至pH=10。分次加入亚硫酸钠,直到用淀粉-碘试纸测试没有H2O2剩下时为止。使反应混合物在DCM与水之间分配。DCM层经Na2SO4干燥,过滤,在真空下浓缩,得到绿色固体。将该绿色固体溶于MeOH/DCM(25∶3)溶液,向其中加入3N含水HCl(3.0mL)。然后将溶液加热至68℃,在该温度下反应2小时。将溶液在真空下浓缩至粘稠淤渣,然后在DCM与0.01N含水NaOH之间分配。DCM层在真空下浓缩,经过硅胶快速色谱,用MeOH/EtOAc/NH4OH(5∶95∶0.1)至MeOH/EtOAc/NH4OH(10∶90∶0.1)梯度洗脱,得到标题化合物。
C.l.m/z 524[M+1];1H NMR(CDCl3)δ7.53(m,1H),7.43(brs,1H),7.34(d,J=7.9Hz,1H),7.16-7.26(m,8H),7.03(d,J=7.5Hz,1H),6.38(s,1H),6.28(s,1H),3.73(m,2H),3.52(s,3H),2.39(s,3H),2.61(m,2H).
实施例12
6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-1-环丙基甲基-4-(3-乙炔基-苯基)-1H-喹啉-2-酮
12A.6-(4-氯-苯甲酰基)-1-环丙基甲基-4-(3-碘-苯基)-1H-喹啉-2-酮
将如PCT国际专利申请公开号WO 97/21701(1997年6月19日公开)制备的6-(4-氯-苯甲酰基)-4-(3-碘-苯基)-1H-喹啉-2-酮(9.68g,19.9mmol)(3.10g,7.87mmol)的DMF(70mL)溶液用碳酸铯(23.1g,19.9mmol)和(溴甲基)环丙烷(5.37g,39.8mmol)处理。反应混合物在室温下搅拌12小时,用二氯甲烷(75ml)稀释,用1N HCl(2×50mL)和盐水(100mL)洗涤。合并后的有机萃取液干燥(MgSO4),过滤,在真空中浓缩,得到黑色残余物。用快速柱色谱法纯化(硅胶,乙酸乙酯∶石油醚1∶9-3∶7)得到6-(4-氯-苯甲酰基)-1-环丙基甲基-4-(3-碘-苯基)-1H-喹啉-2-酮(6.79g,63%),为黄色固体。
C.l.m/z 540[M+1];1H NMR(CDCl3):δ=8.05(dd,J=9.0,2.0Hz,1H),7.92(d,J=2.0Hz,1H),7.80-7.77(m,2H),7.71-7.64(m,3H),7.50-7.46(m,2H),7.37(dd,J=7.8,1.2Hz,1H),7.22-7.17(m,1H),6.68(s,1H),4.32(d,J=6.8Hz,2H),1.34-1.23(m.1H),0.64-0.56(m,4H).
12B.6-(4-氯-苯甲酰基)-1-环丙基甲基-4-(3-三甲基硅烷基乙炔基-苯基)-1H-喹啉-2-酮
将6-(4-氯-苯甲酰基)-1-环丙基甲基-4-(3-碘-苯基)-1H-喹啉-2-酮(4.0g,7.41mmol)的DMF/二乙胺(1∶1,80mL)溶液用双(三苯基)膦氯化钯(Ⅱ)(0.26g,0.37mmol)、三甲基甲硅烷基乙炔(1.09g,11.1mmol)和碘化铜(Ⅰ)(0.21g,1.09mmol)处理。反应混合物在室温下搅拌3小时,在真空中浓缩,倒入H2O(450mL)中,过滤,得到粗的棕色泡沫。用快速柱色谱法纯化(硅胶,乙醚∶石油醚1∶1)得到6-(4-氯-苯甲酰基)-1-环丙基甲基-4-(3-三甲基硅烷基乙炔基-苯基)-1H-喹啉-2-酮(3.47g,92%),为黄色固体。
C.l.m/z 510[M+1];1H NMR(CDCl3):δ=8.08(dd,J=8.9,1.9Hz,1H),7.92(d,J=1.7Hz,1H),7.72-7.65(m,3H),7.58-7.29(m,6H),6.69(s,1H),4.33(d,J=7.1Hz,2H),1.34-1.25(m,1H),0.63-0.55(m,4H),0.26(s,9H).
12C.6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-1-环丙基甲基-4-(3-乙炔基-苯基)-1H-喹啉-2-酮
在-78℃下,将2-(叔丁基-二甲基-硅烷基)-1-甲基-1H-咪唑(1.71g,8.7mmol)的THF(40mL)溶液用仲丁基锂(1.3M环己烷溶液,8.4mL,10.9mmol)处理。将反应混合物加热至0℃,搅拌3小时,冷却至-78℃。用套管向反应混合物中加入6-(4-氯-苯甲酰基)-1-环丙基甲基-4-(3-三甲基硅烷基乙炔基-苯基)-1H-喹啉-2-酮(3.47g,6.8mmol)(2.87g,6.4mmol)的THF(20mL)溶液,缓慢加热至室温,搅拌过夜。用氯化铵(12mL)终止反应,用乙醚(200mL)稀释,用H2O(200mL)和盐水(200mL)洗涤。有机层干燥(Na2SO4),过滤,在真空中浓缩,得到6-[[2-(叔丁基-二甲基-硅烷基)-3-甲基-3H-咪唑-4-基]-(4-氯-苯基)-羟基-甲基]-1-环丙基甲基-4-(3-三甲基硅烷基乙炔基-苯基)-1H-喹啉-2-酮(4.50g),为黄色泡沫。粗物料无需任何进一步纯化即可用在下面的步骤中。
将6-[[2-(叔丁基-二甲基-硅烷基)-3-甲基-3H-咪唑-4-基]-(4-氯-苯基)-羟基-甲基]-1-环丙基甲基-4-(3-三甲基硅烷基乙炔基-苯基)-1H-喹啉-2-酮(4.50g粗品)的THF(100mL)溶液用四丁基氯化铵(1M THF溶液,10.0mmol)处理。反应混合物在室温下搅拌12小时,倒入H2O(200mL)中,用乙酸乙酯萃取(3×100mL)。合并后的有机萃取液用1N HCl(100mL)、含水NaHCO3(100mL)和盐水(100mL)洗涤,干燥(MgSO4),过滤,在真空中浓缩,得到浅绿色泡沫。用快速柱色谱法纯化(硅胶,EtOAc∶石油醚∶NH4OH1∶1∶0.01)得到6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-1-环丙基甲基-4-(3-乙炔基-苯基)-1H-喹啉-2-酮(1.82g,51%),为黄色粉末。
C.l.m/z 520[M+1];1H NMR(CDCl3):δ=7.59(dd,J=9.1,2.1Hz,1H),7.53-7.51(m,2H),7.35-7.25(m,6H),7.18-7.15(m,3H),6.60(s,1H),6.30(s,1H),4.25(d,J=7.1Hz,2H),3.37(s,3H),3.13(s,1H),1.76(br.s,1H),1.39-1.25(m,1H),0.59-0.51(m,4H).
6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-1-环丙基甲基-4-(3-乙炔基-苯基)-1H-喹啉-2-酮的对映体的分离
将6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-1-环丙基甲基-4-(3-乙炔基-苯基)-1H-喹啉-2-酮(1.02g)分离为它的对映体,在CHIRALCELTMOD(由Daicel Chemical Industries,LTD,Osaka,Japan制造)上用高效液相色谱法纯化(20μm;洗脱剂:己烷/异丙醇/二乙胺65/35/0.1;25℃)。在这些条件下,得到0.42g快速洗脱的对映体A和0.43g慢速洗脱的对映体B。两种对映体都是>97%光学纯的。
实施例13
6-[氨基-(4-氯-苯基)-(3-甲基-3H-咪唑-4-基)-甲基]-1-环丙基甲基-4-(3-乙炔基-苯基)-1H-喹啉-2-酮
遵循与实施例3所用相同的程序,但是用6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-1-环丙基甲基-4-(3-乙炔基-苯基)-1H-喹啉-2-酮(1.80g,3.5mmol)代替6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-4-(3-乙炔基-苯基)-1-甲基-1H-喹啉-2-酮,得到6-[氨基-(4-氯-苯基)-(3-甲基-3H-咪唑-4-基)-甲基]-1-环丙基甲基-4-(3-乙炔基-苯基)-1H-喹啉-2-酮(1.12g,62%),为黄色泡沫。
C.l.m/z 519[M+1];1H NMR(CDCl3):δ=7.57-7.51(m.3H),7.43(s,1H),7.36-7.31(m,2H),7.26-7.22(m,2H),7.18(d,J=7.7Hz,1H),7.09-7.05(m,3H),6.63(s,1H),6.32(s,1H),4.28(d,J=7.1Hz,2H),3.39(s,3H),3.13(s,1H),2.11(br.s,2H),1,31-1.27(m,1H).0.61-0.52(m,4H).
实施例14
6-[(4-氯-苯基)-(3-甲基-3H-咪唑-4-基)-[1,2,4]三唑-1-基-甲基]-1-环丙基甲基-4-(3-乙炔基-苯基)-1H-喹啉-2-酮
遵循与实施例7所用相同的程序,但是用6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-1-环丙基甲基-4-(3-乙炔基-苯基)-1H-喹啉-2-酮代替6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-4-[3-(3,3-二甲基-丁-1-炔基)-苯基]-甲基-1H-喹啉-2-酮,得到6-[(4-氯-苯基)-(3-甲基-3H-咪唑-4-基)-[1,2,4]三唑-1-基-甲基]-1-环丙基甲基-4-(3-乙炔基-苯基)-1H-喹啉-2-酮(21.0mg,55%),为黄色的膜。
C.l.m/z 571[M+1];1H NMR(CDCl3):δ=8.06(s,1H),7.89(s,1H),7.56-7.52(m,3H),7.34-7.25(m,5H),7.14(dd,J=7.8,1.4Hz,1H),7.04(d,J=2.1Hz,1H),6.95-6.91(m,2H),6.66(s,1H),6.55(s,1H),4.26(d,J=6.9Hz,2H),3.14(s,1H),3.06(s,3H),1.30-1.23(m,1H),0.61-0.52(m,4H);IR:vmar=3500,1650.1500,1325,1275,1125,1100,1025 cm-1.
Claims (29)
或其药学上可接受的盐、药物前体或溶剂化物,其中:
虚线表示喹啉-2-酮环的C-3与C-4之间的键是单键或双键;
R1选自H、C1-C10烷基、-(CR13R14)qC(O)R12、-(CR13R14)qC(O)OR15、-(CR13R14)qOR12、-(CR13R14)qSO2R15、-(CR13R14)t(C3-C10环烷基)、-(CR13R14)t(C6-C10芳基)和-(CR13R14)t(4-10元杂环),其中t是0至5的整数,q是1至5的整数,所述环烷基、芳基和杂环R1基团任选地与C6-C10芳基、C5-C8饱和环基或4-10元杂环基稠合;除H以外但包括上述任何任选的稠合环在内的前述R1基团任选地被1至4个R6基团取代;
R2是卤、氰基、-C(O)OR15或选自由R12定义所提供的取代基的基团;
每个R3、R4、R5、R6和R7独立地选自H、C1-C10烷基、C2-C10烯基、卤、氰基、硝基、三氟甲基、三氟甲氧基、叠氮基、-OR12、-C(O)R12、-C(O)OR12、-NR13C(O)OR15、-OC(O)R12、-NR13SO2R15、-SO2NR12R13、-NR13C(O)R12、-C(O)NR12R13、-NR12R13、-CH=NOR12、-S(O)jR12--其中j是0至2的整数--、-(CR13R14)t(C6-C10芳基)、-(CR13R14)t(4-10元杂环)、-(CR13R14)t(C3-C10环烷基)和-(CR13R14)tC≡CR16,其中在前述R3、R4、R5、R6和R7基团中,t是0至5的整数;前述基团的环烷基、芳基和杂环部分任选地与C6-C10芳基、C5-C8饱和环基或4-10元杂环基稠合;所述烷基、烯基、环烷基、芳基和杂环基任选地被1至3个取代基取代,该取代基独立地选自卤、氰基、硝基、三氟甲基、三氟甲氧基、叠氮基、-NR13SO2R15、-SO2NR12R13、-C(O)R12、-C(O)OR12、-OC(O)R12、-NR13C(O)OR15、-NR13C(O)R12、-C(O)NR12R13、-NR12R13、-OR12、C1-C10烷基、C2-C10烯基、C2-C10炔基、-(CR13R14)t(C6-C10芳基)和-(CR13R14)t(4-10元杂环),其中t是0至5的整数;
R8是H、-OR12、-NR12R13、-NR12C(O)R13、氰基、-C(O)OR13、-SR12、-(CR13R14)t(4-10元杂环)--其中t是0至5的整数--,或C1-C6烷基,其中所述杂环和烷基部分任选地被1至3个R6取代基取代;
R9是-(CR13R14)t(咪唑基),其中t是0至5的整数,所述咪唑基部分任选地被1或2个R6取代基取代;
每个R10和R11独立地选自由R6定义所提供的取代基;
每个R12独立地选自H、C1-C10烷基、-(CR13R14)t(C3-C10环烷基)、-(CR13R14)t(C6-C10芳基)和-(CR13R14)t(4-10元杂环),其中t是0至5的整数;所述环烷基、芳基和杂环R12基团任选地与C6-C10芳基、C5-C8饱和环基或4-10元杂环基稠合;除H以外的前述R12取代基任选地被1至3个取代基取代,该取代基独立地选自卤、氰基、硝基、三氟甲基、三氟甲氧基、叠氮基、-C(O)R13、-C(O)OR13、-OC(O)R13、-NR13C(O)R14、-C(O)NR13R14、-NR13R14、羟基、C1-C6烷基和C1-C6烷氧基;
每个R13和R14独立地是H或C1-C6烷基,且若R13和R14是-(CR13R14)q或(CR13R14)t的形式,则对于每个超过1的q或t的迭代,各自被独立地定义;
R15选自由R12定义所提供的取代基,但R15不是H;
R16选自R12定义所提供的取代基和-SiR17R18R19;
R17、R18和R19各自独立地选自由R12定义所提供的取代基,但R17、R18和R19不是H;和
其前提条件是R3、R4和R5至少有一个是-(CR13R14)tC≡CR16,其中t是0至5的整数,R13、R14和R16是如上所定义的。
2、根据权利要求1的化合物,其中R1是H、C1-C6烷基或环丙基甲基;R2是H;R3是-C≡CR16;R8是-NR12R13、-OR12、或选自三唑基、咪唑基、吡唑基和哌啶基的杂环基,其中所述杂环基任选地被R6基团取代。
3、根据权利要求2的化合物,其中R9是任选被C1-C6烷基取代的咪唑基;R8是羟基、氨基或三唑基;R4、R5、R10和R11各自独立地选自H和卤。
4、根据权利要求1的化合物,其中R1是-(CR13R14)t(C3-C10环烷基),其中t是0至3的整数;R2是H;R8是-NR12R13、-OR12、或选自三唑基、咪唑基、吡唑基和哌啶基的杂环基,其中所述杂环基任选地被R6基团取代。
5、根据权利要求4的化合物,其中R9是任选被C1-C6烷基取代的咪唑基;R8是羟基、氨基或三唑基;R3是-C≡CR16;R4、R5、R10和R11各自独立地选自H和卤;和R1是环丙基甲基。
6、根据权利要求5的化合物,其中R3是乙炔基。
7、根据权利要求2的化合物,其中R3是乙炔基。
8、根据权利要求1的化合物,其中所述化合物选自由下列化合物组成的组:
6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-4-(3-乙炔基-苯基)-1-甲基-1H-喹啉-2-酮(对映体A);
6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-4-(3-乙炔基-苯基)-1-甲基-1H-喹啉-2-酮(对映体B);
6-[氨基-(4-氯-苯基)-(3-甲基-3H-咪唑-4-基)-甲基]-4-(3-乙炔基-苯基)-1-甲基-1H-喹啉-2-酮(对映体A);
6-[氨基-(4-氯-苯基)-(3-甲基-3H-咪唑-4-基)-甲基]-4-(3-乙炔基-苯基)-1-甲基-1H-喹啉-2-酮(对映体B);
6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-4-(3-乙炔基-4-氟-苯基)-1-甲基-1H-喹啉-2-酮;
和前述化合物的药学上可接受的盐、药物前体和溶剂化物。
9、哺乳动物异常细胞生长的治疗方法,包括将一定量的根据权利要求1的化合物对所述哺乳动物给药,该给药量对抑制法呢基蛋白转移酶是有效的。
10、根据权利要求9的方法,其中所述异常细胞生长是癌症。
11、根据权利要求10的方法,其中所述癌症包括肺癌、骨癌、胰腺癌、皮肤癌、头或颈癌、皮或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛区癌、胃癌、结肠癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、何杰金氏病、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、慢性或急性白血病、淋巴细胞淋巴瘤、膀胱癌、肾或输尿管癌、肾细胞癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、脊柱枢椎肿瘤、脑干神经胶质瘤、垂体腺瘤、或两种或多种前述癌症的组合。
12、根据权利要求9的方法,其中所述异常细胞生长是良性增殖性疾病。
13、根据权利要求12的方法,其中所述良性增殖性疾病包括牛皮癣、良性前列腺肥大或再狭窄。
14、哺乳动物异常细胞生长的治疗方法,包括将治疗有效量的根据权利要求1的化合物联合抗肿瘤剂对所述哺乳动物给药,该抗肿瘤剂选自由有丝分裂抑制剂、烷化剂、抗代谢物、嵌入性抗生素、生长因子抑制剂、细胞周期抑制剂、酶、拓朴异构酶抑制剂、生物反应调节剂、抗激素物质和抗雄激素物质组成的组。
15、哺乳动物异常细胞生长的治疗方法,包括将一定量的根据权利要求1的化合物对所述哺乳动物给药,该给药量对治疗异常细胞生长是有效的。
16、用于哺乳动物异常细胞生长的治疗的药物组合物,包含对抑制法呢基蛋白转移酶是有效的量的根据权利要求1的化合物,和药学上可接受的载体。
17、根据权利要求16的药物组合物,其中所述异常细胞生长是癌症。
18、根据权利要求17的药物组合物,其中所述癌症包括肺癌、骨癌、胰腺癌、皮肤癌、头或颈癌、皮或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛区癌、胃癌、结肠癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、何杰金氏病、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、慢性或急性白血病、淋巴细胞淋巴瘤、膀胱癌、肾或输尿管癌、肾细胞癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、脊柱枢椎肿瘤、脑干神经胶质瘤、垂体腺瘤、或一种或多种前述癌症的组合。
19、根据权利要求16的药物组合物,其中所述异常细胞生长是良性增殖性疾病。
20、根据权利要求19的药物组合物,其中所述良性增殖性疾病包括牛皮癣、良性前列腺肥大或再狭窄。
21、用于哺乳动物异常细胞生长的治疗的药物组合物,包含对治疗异常细胞生长是有效的量的根据权利要求1的化合物,和药学上可接受的载体。
22、用于哺乳动物异常细胞生长的治疗的药物组合物,包含治疗有效量的权利要求1化合物以及药学上可接受的载体和抗肿瘤剂,该抗肿瘤剂选自由有丝分裂抑制剂、烷化剂、抗代谢物、嵌入性抗生素、生长因子抑制剂、细胞周期抑制剂、酶、拓朴异构酶抑制剂、生物反应调节剂、抗激素物质和抗雄激素物质组成的组。
23、哺乳动物感染的治疗方法,其中所述感染受到法呢基蛋白转移酶的促进作用,该方法包括将治疗有效量的权利要求1化合物对所述哺乳动物给药。
24、权利要求23的方法,其中所述感染是丁型肝炎病毒或疟疾。
25、用于哺乳动物感染的治疗的药物组合物,其中所述感染受到法呢基蛋白转移酶的促进作用,该组合物包含治疗学上有效量的权利要求1化合物和药学上可接受的载体。
26、权利要求25的药物组合物,其中所述感染是丁型肝炎病毒或疟疾。
其中
R1选自H、C1-C10烷基、-(CR13R14)qC(O)R12、-(CR13R14)qC(O)OR15、-(CR13R14)qOR12、-(CR13R14)qSO2R15、-(CR13R14)t(C3-C10环烷基)、-(CR13R14)t(C6-C10芳基)和-(CR13R14)t(4-10元杂环),其中t是0至5的整数,q是1至5的整数,所述环烷基、芳基和杂环R1基团任选地与C6-C10芳基、C5-C8饱和环基或4-10元杂环基稠合;除H以外但包括上述任何任选的稠合环在内的前述R1基团任选地被1至4个R6基团取代;
R2是卤、氰基、-C(O)OR15或选自由R12定义所提供的取代基的基团;
每个R3、R4、R5、R6和R7独立地选自H、C1-C10烷基、C2-C10烯基、卤、氰基、硝基、三氟甲基、三氟甲氧基、叠氮基、-OR12、-C(O)R12、-C(O)OR12、-NR13C(O)OR15、-OC(O)R12、-NR13SO2R15、-SO2NR12R13、-NR13C(O)R12、-C(O)NR12R13、-NR12R13、-CH=NOR12、-S(O)jR12--其中j是0至2的整数--、-(CR13R14)t(C6-C10芳基)、-(CR13R14)t(4-10元杂环)、-(CR13R14)t(C3-C10环烷基)和-(CR13R14)tC≡CR16,其中在前述R3、R4、R5、R6和R7基团中,t是0至5的整数;前述基团的环烷基、芳基和杂环部分任选地与C6-C10芳基、C5-C8饱和环基或4-10元杂环基稠合;所述烷基、烯基、环烷基、芳基和杂环基任选地被1至3个取代基取代,该取代基独立地选自卤、氰基、硝基、三氟甲基、三氟甲氧基、叠氮基、-NR13SO2R15、-SO2NR12R13、-C(O)R12、-C(O)OR12、-OC(O)R12、-NR13C(O)OR15、-NR13C(O)R12、-C(O)NR12R13、-NR12R13、-OR12、C1-C10烷基、C2-C10烯基、C2-C10炔基、-(CR13R14)t(C6-C10芳基)和-(CR13R14)t(4-10元杂环),其中t是0至5的整数;
每个R10和R11独立地选自由R6定义所提供的取代基;
每个R12独立地选自H、C1-C10烷基、-(CR13R14)t(C3-C10环烷基)、-(CR13R14)t(C6-C10芳基)和-(CR13R14)t(4-10元杂环),其中t是0至5的整数;所述环烷基、芳基和杂环R12基团任选地与C6-C10芳基、C5-C8饱和环基或4-10元杂环基稠合;除H以外的前述R12取代基任选地被1至3个取代基取代,该取代基独立地选自卤、氰基、硝基、三氟甲基、三氟甲氧基、叠氮基、-C(O)R13、-C(O)OR13、-OC(O)R13、-NR13C(O)R14、-C(O)NR13R14、-NR13R14、羟基、C1-C6烷基和C1-C6烷氧基;
每个R13和R14独立地是H或C1-C6烷基,且若R13和R14是-(CR13R14)q或(CR13R14)t的形式,则对于每个超过1的q或t的迭代,各自被独立地定义;
R15选自在R12定义中所提供的取代基,但R15不是H;
R16选自在R12定义中所提供的取代基的名单和-SiR17R18R19;
R17、R18和R19各自独立地选自由R12定义所提供的取代基,但R17、R18和R19不是H;和
其前提条件是R3、R4和R5的至少一个是-(CR13R14)tC≡CR16,其中t是0至5的整数,和R13、R14和R16是如上所定义的。
28、选自下组的化合物:
6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-1-甲基-4-(3-三甲基硅烷基乙炔基-苯基)-1H-喹啉-2-酮;
6-[(4-氯-苯基)-羟基-(2-巯基-3-甲基-3H-咪唑-4-基)-甲基]-1-甲基-4-(3-三甲基硅烷基乙炔基-苯基)-1H-喹啉-2-酮;
6-(4-氯-苯甲酰基)-1-甲基-4-(3-三甲基硅烷基乙炔基-苯基)-1H-喹啉-2-酮;
6-(4-氯-苯甲酰基)-1-甲基-4-[3-(4-三苯甲氧基-丁-1-炔基)-苯基]-1H-喹啉-2-酮;
6-(4-氯-苯甲酰基)-1-环丙基甲基-4-(3-三甲基硅烷基乙炔基-苯基)-1H-喹啉-2-酮。
29、制备其中R3是乙炔基的权利要求1化合物的方法,包括将式29化合物
其中R1、R2、R4、R5、R6、R7、R8、R9、R10和R11是如权利要求1所定义的,
用氟化四丁铵处理。
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