CN101674828A - 用于治疗甲状腺癌的Raf抑制剂 - Google Patents
用于治疗甲状腺癌的Raf抑制剂 Download PDFInfo
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- CN101674828A CN101674828A CN200880014174A CN200880014174A CN101674828A CN 101674828 A CN101674828 A CN 101674828A CN 200880014174 A CN200880014174 A CN 200880014174A CN 200880014174 A CN200880014174 A CN 200880014174A CN 101674828 A CN101674828 A CN 101674828A
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- alkyl
- chemical compound
- trifluoromethyl
- alkoxyl
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- 239000003112 inhibitor Substances 0.000 title claims abstract description 27
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- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
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- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及Raf抑制剂在制备用于治疗甲状腺癌、特别是甲状腺***状癌(PTC)的药物组合物中的应用;Raf抑制剂在治疗甲状腺癌、特别是PTC中的应用;治疗患有甲状腺癌、特别是PTC的包括哺乳动物的温血动物、尤其是人类的方法,该方法通过向需要该治疗的所述动物施用对所述疾病有效剂量的Raf抑制剂来进行。本发明还涉及Raf抑制剂与铂化合物联合用于治疗甲状腺癌、特别是甲状腺***状癌的应用。
Description
发明领域
本发明涉及Raf抑制剂在制备用于治疗甲状腺癌、特别是甲状腺***状癌(PTC)的药物组合物中的应用;Raf抑制剂在治疗甲状腺癌、特别是PTC中的应用;治疗患有甲状腺癌、特别是PTC的包括哺乳动物的温血动物、尤其是人类的方法,该方法通过向需要该治疗的所述动物施用对所述疾病有效剂量的Raf抑制剂来进行。本发明还涉及Raf抑制剂与铂化合物联合用于治疗甲状腺癌、特别是甲状腺***状癌的应用。
发明背景
甲状腺癌是相对罕见的疾病,占每年所有新的癌症诊断的大约1%(在美国每年26,000例)。最普遍的亚型是PTC,占所有甲状腺癌的大约80%。虽然这些患者的大多数通过外科手术,接着辅以131I-放射性碘来治愈,但这对一些患者无效,并且对于这些患者来说很少有治疗选择。
PTC的基因特征显示有机会对该疾病采取靶向治疗,且令人特别感兴趣的是Ras/Raf/MAPK通路内的靶点。多至70%的PTC表达B-Raf的突变型(B-RafV600E){Chiloeches,2006#270;Cohen,2003#287}。B-Raf一般通过Ras活化,且通过MEK的磷酸化和活化在该通路中起作用,以自细胞表面受体传递增殖和存活信号。然而,B-RafV600E不需要通过Ras活化,并组成性激活该通路,从而促进增殖失调并抑制凋亡。
多至30%的这类肿瘤表达由基因重排引起并导致组成性活化受体酪氨酸激酶活性和MAPK通路的活化{Viglietto,1995#288}的受体的突变型,这一观察进一步验证了该通路在PTC中的重要性。因而,绝大多数PTC肿瘤显示通过B-Raf或RET突变来活化MAPK通路,且靶向于RET或B-Raf的物质有潜在的治疗利益。因此有需要研究新的治疗方法。
发明概述
现已惊奇地发现Raf抑制剂能治疗PTC。因此本发明涉及Raf抑制剂在制备用于治疗PTC的药物中的应用。本发明还涉及Raf抑制剂在PTC的治疗中的应用。本发明涉及治疗患有PTC的包括哺乳动物的温血动物、尤其是人类的方法,该治疗通过向需要该治疗的所述动物施用对所述疾病有效剂量的Raf抑制剂或其可药用盐来进行。
发明详述
Raf抑制剂是具有式(I)的被取代的苯并咪唑类化合物或其互变异构体、立体异构体、多晶型物、酯、代谢物或前体药物或所述化合物、互变异构体、立体异构体、多晶型物、酯、代谢物或前体药物的可药用盐:
其中:
各R1独立地选自羟基、卤素、C1-6烷基、C1-6烷氧基、(C1-6烷基)硫烷基、(C1-6烷基)磺酰基、环烷基、杂环烷基、苯基和杂芳基;
R2是C1-6烷基或卤代(C1-6烷基);
各R3独立地选自卤素、C1-6烷基和C1-6烷氧基;
各R4独立地选自羟基、C1-6烷基、C1-6烷氧基、卤素、杂环烷基羰基、羧基、(C1-6烷氧基)羰基、氨羰基、C1-6烷基氨羰基、氰基、环烷基、杂环烷基、苯基和杂芳基;
其中R1、R2、R3和R4可以任选地被一个或多个独立地选自以下的取代基所取代:羟基、卤素、C1-6烷基、卤代(C1-6烷基)、C1-6烷氧基和卤代(C1-6烷氧基);
a是1、2、3、4或5;
b是0、1、2或3;且
c是1或2。
在其他的实施方案中,提供了新的被取代的式(II)的苯并咪唑类化合物或其互变异构体、立体异构体、多晶型物、酯、代谢物或前体药物或所述化合物、互变异构体、立体异构体、多晶型物、酯、代谢物或前体药物的可药用盐:
其中:
各R1独立地选自C1-6烷基、C1-6烷氧基、羟基、卤素、(C1-6烷基)硫烷基、(C1-6烷基)磺酰基、环烷基、杂环烷基、苯基和杂芳基;
各R3独立地选自卤素、C1-6烷基和C1-6烷氧基;
各R4独立地选自羟基、C1-6烷基、C1-6烷氧基、卤素、羧基、(C1-6烷氧基)羰基、氨羰基、氰基、环烷基、杂环烷基、杂环烷基羰基、苯基和杂芳基;
其中R1、R2、R3和R4可以任选地被一个或多个独立地选自以下的取代基所取代:羟基、卤素、C1-6烷基和C1-6烷氧基;
a是1、2、3、4或5;
b是0、1、2或3;且
c是1或2。
在其他的实施方案中,提供了新的被取代的式(III)的苯并咪唑类化合物或其互变异构体、立体异构体、多晶型物、酯、代谢物或前体药物或所述化合物、互变异构体、立体异构体、多晶型物、酯、代谢物或前体药物的可药用盐:
其中:
各R1独立地选自C1-6烷基、C1-6烷氧基、羟基、卤素、(C1-6烷基)硫烷基、(C1-6烷基)磺酰基、环烷基、杂环烷基、苯基和杂芳基;
各R4独立地选自羟基、C1-6烷基、C1-6烷氧基、卤素、羧基、(C1-6烷氧基)羰基、氨羰基、氰基、环烷基、杂环烷基、杂环烷基羰基、苯基和杂芳基;
其中R1和R4可以任选地被一个或多个独立地选自以下的取代基所取代:羟基、卤素、C1-6烷基和C1-6烷氧基;
a是1、2、3、4或5;且
c是1或2。
还公开了具有下式(IV)的化合物或其互变异构体、立体异构体、多晶型物、酯、代谢物或前体药物或所述化合物、互变异构体、立体异构体、多晶型物、酯、代谢物或前体药物的可药用盐:
其中:
各R1独立地选自C1-6烷基、C1-6烷氧基、羟基、卤素、(C1-6烷基)硫烷基、(C1-6烷基)磺酰基、环烷基、杂环烷基、苯基和杂芳基;
R2是C1-6烷基或卤代(C1-6烷基);
各R3独立地选自卤素、C1-6烷基和C1-6烷氧基;
各R4独立地选自羟基、C1-6烷基、C1-6烷氧基、卤素、羧基、(C1-6烷氧基)羰基、氨羰基、C1-6烷基氨羰基、氰基、氰基(C1-6烷基)、环烷基、杂环烷基、杂环烷基(C1-6烷基)、杂环烷基羰基、苯基和杂芳基;
其中R1、R2、R3和R4可以任选地被一个或多个独立地选自以下的取代基所取代:羟基、卤素、C1-6烷基和C1-6烷氧基;
a是1、2、3、4或5;且
b是0、1、2或3。
在其他的实施方案中,提供了新的被取代的式(I)-(IV)的苯并咪唑类化合物,其中各R1独立地选自羟基、氯、氟、溴、甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基、丁氧基、三氟甲基、三氟乙基、三氟甲氧基、三氟乙氧基、三氟甲基硫烷基、哌啶基、C1-6烷基哌啶基、哌嗪基、C1-6烷基哌嗪基、四氢呋喃基、吡啶基和嘧啶基。在其他的实施方案中,提供了新的被取代的式(I)-(IV)的苯并咪唑类化合物,其中a是1或2,且至少一个R1是卤代(C1-6烷基)如三氟甲基。在其他的实施方案中,提供了新的被取代的式(I)和(IV)的苯并咪唑类化合物,其中R2是C1-6烷基,例如,甲基或乙基。在另外的实施方案中,提供了新的被取代的式(I)、(II)和(IV)的苯并咪唑类化合物,其中b是0,因而R3不存在。在作为选择的实施方案中,提供了新的被取代的式(I)-(IV)的苯并咪唑类化合物,其中b是1,且R3是C1-6烷氧基,例如,甲氧基。在另外的实施方案中,提供了新的被取代的式(I)-(III)的苯并咪唑类化合物,其中c是1或2,且至少一个R4是卤代(C1-6烷基),例如,三氟甲基。
“烷基”指不含杂原子的饱和烃基团且包括直链烷基如甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基等等。烷基还包括直链烷基的支链异构体,包括但不限于所提供的下列实例:-CH(CH3)2、-CH(CH3)(CH2CH3)、-CH(CH2CH3)2、-C(CH3)3、-C(CH2CH3)3、-CH2CH(CH3)2、-CH2CH(CH3)(CH2CH3)、-CH2CH(CH2CH3)2、-CH2C(CH3)3、-CH2C(CH2CH3)3、-CH(CH3)-CH(CH3)(CH2CH3)、-CH2CH2CH(CH3)2、-CH2CH2CH(CH3)(CH2CH3)、-CH2CH2CH(CH2CH3)2、-CH2CH2C(CH3)3、-CH2CH2C(CH2CH3)3、-CH(CH3)CH2CH(CH3)2、-CH(CH3)CH(CH3)CH(CH3)2、-CH(CH2CH3)CH(CH3)CH(CH3)(CH2CH3),以及其他实例。由此烷基包括伯烷基、仲烷基和叔烷基。术语“C1-12烷基”指具有一至十二个碳原子的烷基。术语“C1-6烷基”指具有一至六个碳原子的烷基。
“链烯基”指具有2-6个碳原子、优选2-4个碳原子且具有至少1个、优选1-2个乙烯基(>C=C<)不饱和位点的直链或支链烃基。这类基团例如是乙烯基、烯丙基和丁-3-烯-1-基。该术语包括顺式和反式异构体或这些异构体的混合物。
“烷氧基”指RO-,其中R是烷基。本文所用术语“C1-6烷氧基”指RO-,其中R是C1-6烷基。C1-6烷氧基的代表性的实例包括甲氧基、乙氧基、叔丁氧基等。
“(C1-6烷氧基)羰基”指的是酯-C(=O)-OR,其中R是C1-6烷基。
“脒基”指-C(=NH)NH2基团。“脒”指含有这类基团的化合物。
本文的“氨羰基”指-C(O)-NH2基团。
“C1-6烷基氨基羰基”指-C(O)-NRR′基团,其中R是C1-6烷基且R′选自氢和C1-6烷基。
“羰基”指二价基团-C(O)-。
“羧基”指-C(=O)-OH。
“氰基”、“甲腈”或“腈”指-CN。
“氰基(C1-6烷基)”指被-CN取代的C1-6烷基。
“环烷基”指单-或多环的烷基取代基。通常的环烷基具有3-8个碳环原子。代表性的环烷基包括环丙基、环丁基、环戊基、环己基、环庚基和环辛基。
“卤素”或“卤代”指氯、溴、氟和碘基团。
“卤代(C1-6烷基)”指被一个或多个卤素原子、优选1-5个卤素原子取代的C1-6烷基。更优选的卤代(C1-6烷基)是三氟甲基。
“卤代(C1-6烷基)苯基”指被卤代(C1-6烷基)取代的苯基。
“卤代(C1-6烷氧基)”指被一个或多个卤素原子、优选1-5个卤素原子取代的烷氧基。更优选的卤代(C1-6烷氧基)是三氟甲氧基。
“卤代(C1-6烷基)磺酰基”和“卤代(C1-6烷基)硫烷基”指被卤代(C1-6烷基)取代的磺酰基和硫烷基,其中磺酰基和硫烷基如本文所定义。
“杂芳基”指在芳环中具有1-4个杂原子作为环原子且剩余的环原子是碳原子的芳族基团。用于本发明化合物的合适的杂原子是氮、氧和硫,其中氮和硫原子可以任选地被氧化。示例性的杂芳基具有5-14个环原子并且包括例如苯并咪唑基、苯并噻唑基、苯并噁唑基、二氮杂基、呋喃基、吡嗪基、吡唑基、吡啶基、哒嗪基、嘧啶基、吡咯甲酰、噁唑基、异噁唑基、咪唑基、吲哚基、吲唑基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、噻唑基、噻吩基和***基。
本文的“杂环烷基”指在环结构中具有1-5个并且通常为1-2个杂原子的环烷基取代基。用于本发明化合物的合适的杂原子是氮、氧、和硫,其中氮和硫原子可以任选地被氧化。代表性的杂环烷基基团包括例如吗啉代、哌嗪基、哌啶基等等。
“(C1-6烷基)杂环烷基”指被C1-6烷基取代的杂环烷基。
“杂环烷基(C1-6烷基)”指被杂环烷基取代的C1-6烷基。
本文的“杂环烷基羰基”指-C(O)-R10基团,其中R10是杂环烷基。
“(C1-6烷基)杂环烷基羰基”指-C(O)-R11基团,其中R11是(C1-6烷基)杂环烷基。
“羟基”指-OH。
“羟基(C1-6烷基)”指被羟基取代的C1-6烷基。
“羟基(C1-6烷基氨基羰基)”指被羟基取代的C1-6烷基氨基羰基。
“亚氨酸酯”或指-C(=NH)O-基团或含有这类基团的化合物。亚氨酸酯包括例如亚氨酸甲酯-C(=NH)OCH3。
“硝基”指-NO2。
“磺酰基”本文指-SO2-基团。
“硫烷基”本文指-S-基团。“烷基磺酰基”指具有-SO2R12结构的被取代的磺酰基,其中R12是烷基。“烷基硫烷基”指具有-SR12结构的被取代的硫烷基,其中R12是烷基。用于本发明化合物的烷基磺酰基和烷基硫烷基包括(C1-6烷基)磺酰基和(C1-6烷基)硫烷基。因此,通常的基团包括例如甲基磺酰基和甲基硫烷基(即其中R12是甲基)、乙基磺酰基和乙基硫烷基(即其中R12是乙基)、丙基磺酰基和丙基硫烷基(即其中R12是丙基)等等。
“羟基保护基团”指对OH的保护基团。本文所用的该术语也指保护酸COOH的OH的基团。适合的羟基保护基团以及用于特定官能团的保护和脱保护的适宜条件在本领域是众所周知的。例如,在T.W.greene和P.G.M.Wuts,Protecting Groups in Organic Synthesis(有机合成中的保护基团),第三版,Wiley,纽约(1999)中描述了大量的这类保护基团。这类羟基保护基团包括C1-6烷基醚、苄基醚、p-甲氧基苄基醚、硅烷基醚等。
“任选地被取代”或“被取代”指用一价或二价基团替代一个或多个氢原子。
当被取代的取代基包括直链基团时,取代可以在链内(例如2-羟基丙基、2-氨基丁基等等)或链的末端(例如2-羟基乙基、3-氰基丙基等等)发生。被取代的取代基可以是直链、支链或环状排列的共价连接的碳原子或杂原子。
应当了解,上述定义不包括不允许的取代型式(例如,被五个氟取代的甲基或被另一个卤素原子取代的卤素原子)。这类不可能的取代型式对本领域的技术人员而言是公知的。
对于本领域的技术人员而言显而易见地是:本发明的化合物,包括式(I)、(II)、(III)或(IV)的化合物或它们的立体异构体和多晶型物,以及它们任意一个的可药用盐、酯、代谢产物和前体药物,可以发生互变异构化并因此可以以多种互变异构的形式存在,其中分子中一个原子上的质子转移到另一个原子上并且分子中原子间的化学键因此重排。参见,例如,March,A dvanced Organic Chemistry:Reactions,Mechanisms and Structures(高等有机化学:反应、机理和结构),第四版,John Wiley&Sons,69-74页(1992)。
本文所用的术语“可药用的盐”指(I)、(II)、(III)或(IV)的化合物、互变异构体、立体异构体、多晶型物、酯、代谢物或前体药物的无毒的酸或碱土金属盐。这些盐可以在最终分离和纯化式(I)、(II)、(III)或(IV)的化合物过程中在原位来制备或者单独地将酸或碱官能团各自与合适的有机或无机酸或碱反应而制备。代表性的盐非限制性地包括以下的盐:醋酸盐、己二酸盐、藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、环戊烷丙酸盐、十二烷基硫酸盐、乙磺酸盐、葡糖庚酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、富马酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、双羟萘酸盐、果胶酯酸盐、过硫酸盐、3-苯丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐和十一酸盐。而且,含氮的碱性基团可以被以下物质季铵化,如低级烷基卤化物,例如甲基、乙基、丙基和丁基氯化物、溴化物和碘化物;二烷基硫酸酯如二甲基、二乙基、二丁基和二戊基硫酸酯,长链卤化物例如癸基、十二烷基、十四烷基和十八烷基氯化物、溴化物和碘化物,苯基烷基卤化物如苄基和苯乙基溴化物,以及其他物质。由此得到水溶性或油溶性的或可分散的产物。
可应用于生成可药用的酸加成盐的酸的实例包括无机酸如盐酸、硫酸及磷酸和有机酸如草酸、马来酸、甲磺酸、琥珀酸和柠檬酸。碱加成盐可以在最终分离和纯化式(I)化合物期间在原位制备,或者单独地通过将羧酸部分与合适的碱如可药用的金属阳离子的氢氧化物、碳酸盐或碳酸氢盐,或者与氨或有机的伯、仲、叔胺反应来制备。可药用的盐包括但不限于,基于碱金属和碱土金属的阳离子如钠、锂、钾、钙、镁、铝盐等等,以及无毒的铵、季铵和胺阳离子,包括但不限于铵、四甲铵、四乙铵、甲胺、二甲胺、三甲胺、三乙胺、乙胺等等。用于生成碱加成盐的其他代表性有机胺包括二乙胺、乙二胺、乙醇胺、二乙醇胺、哌嗪等等。
在一个实施方案中,Raf抑制剂是具有以下化学式的1-甲基-5-[2-(5-三氟甲基-1H-咪唑-2-基)-吡啶-4-基氧基]-1H-苯并咪唑-2-基}-(4-三氟甲基苯基)-胺或其可药用盐:
在一个实施方案中,Raf抑制剂与铂化合物、特别是顺铂联合用于治疗PTC。Raf抑制剂的一个非限制性实例是具有以下化学式的1-甲基-5-[2-(5-三氟甲基-1H-咪唑-2-基)-吡啶-4-基氧基]-1H-苯并咪唑-2-基}-(4-三氟甲基苯基)-胺或其可药用盐:
本文所用的“Raf抑制剂”是指显示对Raf激酶活性的IC50不超过大约100μM、并且更典型地不超过大约50μM的化合物,其按照下文概述的Raf/Mek滤过实验进行测定。本发明化合物显示可抑制的Raf激酶优选的亚型包括A-Raf、B-Raf和C-Raf(Raf-1)。“IC50”是使酶(例如,Raf激酶)活性减至最大水平一半的抑制剂浓度。已发现本发明代表性的化合物对Raf显示出抑制活性。本发明化合物对Raf显示出的IC50优选地不超过大约10μM、更优选地不超过大约5μM、甚至更优选地不超过大约1μM,且最优选地不超过大约200nM,其按照本文所述的Raf激酶试验进行测定。
本发明化合物可以以包含所需要的常规无毒可药用载体、辅助剂和介质的单位剂量形式的制剂,经口服、经胃肠外、经舌下、通过气雾化或吸入喷雾、经直肠或局部地施用。局部施用还可以包括透皮施用的应用,如透皮贴剂或离子电泳装置。本文所使用的术语“胃肠外的”包括皮下注射、静脉内、肌肉内、胸骨内注射或输注技术。
有关领域的技术人员完全能够选择相关试验模型以证明本文所提及的对PTC的有益作用。所述化合物的药理学活性可以例如通过下文所述的实施例的方法、通过体外试验和体内试验或通过适合的临床研究来证明。适合的临床研究是例如对PTC患者的开放标记、非随机、剂量渐增研究。在这些研究中测定该治疗的效用,例如通过每四周与安慰剂对照组相比评价肿瘤尺寸。
实施例1对体外MAPK信号传导的作用
研究Raf抑制剂对体外MAPK信号传导的作用。测试了10种细胞系:5种具有BRAF突变和5种具有RET/PTC突变,以检测通过抑制MAPK磷酸酶来抵抗的潜能。
1)对生长、细胞周期和细胞凋亡的作用。
2)对异种移植瘤的作用:通过管饲法给药50、30和10mg/kg/天。
3)研究RAF265与顺铂联合在体外和在异种移植物中的作用。
实施例2
测试RAF265对4种甲状腺***状癌细胞系的抗增殖活性,所有的细胞系都表达萤光素酶转基因:BHP5-16、BHP14-9、BHP17-10和NPA87。将细胞接种于384孔板中并加入系列稀释的RAF265(例如,0.0002-4μM)。将板在37℃孵育2天。通过Bright-Glo(Promega)测量萤光素酶的表达以测定细胞增殖。
在体外测试了RAF265对BHP17-10异种移植物模型的抗肿瘤活性。将BHP17-10细胞皮下植入免疫低下的小鼠,且当肿瘤一旦达到大约70mm3的平均体积,就开始用RAF265以100、30和10mg/kg q3dx5处理。每周使用测径器测量肿瘤体积2-3次。与介质处理的对照组对比确定RAF265的抗肿瘤作用。
Claims (25)
1.Raf抑制剂在制备用于治疗甲状腺***状癌的药物中的应用。
2.依据权利要求1的应用,其中Raf抑制剂是式(III)的化合物或其互变异构体、立体异构体、多晶型物、酯、代谢物或前体药物或所述化合物、互变异构体、立体异构体、多晶型物、酯、代谢物或前体药物的可药用盐:
其中:
各R1独立地选自C1-6烷基、C1-6烷氧基、羟基、卤素、(C1-6烷基)硫烷基、(C1-6烷基)磺酰基、环烷基、杂环烷基、苯基和杂芳基;
各R4独立地选自羟基、C1-6烷基、C1-6烷氧基、卤素、羧基、(C1-6烷氧基)羰基、氨羰基、氰基、环烷基、杂环烷基、杂环烷基羰基、苯基和杂芳基;
其中R1和R4可以任选地被一个或多个独立地选自以下的取代基所取代:羟基、卤素、C1-6烷基和C1-6烷氧基;
a是1、2、3、4或5;且
c是1或2。
3.依据权利要求2的化合物,其中各R1独立地选自:羟基、氯、氟、溴、甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基、丁氧基、三氟甲基、三氟乙基、三氟甲氧基、三氟乙氧基、哌啶基、C1-6烷基哌啶基、哌嗪基、C1-6烷基哌嗪基、四氢呋喃基、吡啶基和嘧啶基。
4.依据权利要求3的化合物,其中a是1或2,且至少一个R1是卤代(C1-6烷基)。
5.依据权利要求4的化合物,其中至少一个R1是三氟甲基。
6.依据权利要求2的化合物,其中a是1。
7.依据权利要求6的化合物,其中R1是三氟甲基。
8.依据权利要求2的化合物,其中c是1或2,且至少一个R4是卤代(C1-6烷基)。
9.权利要求8的化合物,其中至少一个R4是三氟甲基。
10.权利要求9的化合物,其中c是1。
11.依据权利要求2的应用,其中式(I)化合物是1-甲基-5-[2-(5-三氟甲基-1H-咪唑-2-基)-吡啶-4-基氧基]-1H-苯并咪唑-2-基}-(4-三氟甲基苯基)-胺或其可药用盐。
12.依据权利要求1的应用,其中温血动物是人类。
13.治疗甲状腺***状癌的方法,其包括向有需要的温血动物施用治疗有效量的Raf抑制剂。
14.依据权利要求13的方法,其包括施用治疗有效量的式(III)化合物或其互变异构体、立体异构体、多晶型物、酯、代谢物或前体药物或所述化合物、互变异构体、立体异构体、多晶型物、酯、代谢物或前体药物的可药用盐:
其中:
各R1独立地选自C1-6烷基、C1-6烷氧基、羟基、卤素、(C1-6烷基)硫烷基、(C1-6烷基)磺酰基、环烷基、杂环烷基、苯基和杂芳基;
各R4独立地选自羟基、C1-6烷基、C1-6烷氧基、卤素、羧基、(C1-6烷氧基)羰基、氨羰基、氰基、环烷基、杂环烷基、杂环烷基羰基、苯基和杂芳基;
其中R1和R4可以任选地被一个或多个独立地选自以下的取代基所取代:羟基、卤素、C1-6烷基和C1-6烷氧基;
a是1、2、3、4或5;且
c是1或2。
15.依据权利要求14的化合物,其中各R1独立地选自:羟基、氯、氟、溴、甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基、丁氧基、三氟甲基、三氟乙基、三氟甲氧基、三氟乙氧基、哌啶基、C1-6烷基哌啶基、哌嗪基、C1-6烷基哌嗪基、四氢呋喃基、吡啶基和嘧啶基。
16.依据权利要求15的化合物,其中a是1或2,且至少一个R1是卤代(C1-6烷基)。
17.依据权利要求16的化合物,其中至少一个R1是三氟甲基。
18.依据权利要求14的化合物,其中a是1。
19.依据权利要求18的化合物,其中R1是三氟甲基。
20.依据权利要求14的化合物,其中c是1或2,且至少一个R4是卤代(C1-6烷基)。
21.依据权利要求14的化合物,其中至少一个R4是三氟甲基。
22.依据权利要求21的化合物,其中c是1。
23.依据权利要求13的方法,其中Raf抑制剂是1-甲基-5-[2-(5-三氟甲基-1H-咪唑-2-基)-吡啶-4-基氧基]-1H-苯并咪唑-2-基}-(4-三氟甲基苯基)-胺或其可药用盐。
24.依据权利要求13的方法,其中温血动物是人类。
25.治疗甲状腺***状癌的方法,其包括将治疗有效量的Raf抑制剂与顺铂联合施用于有需要的温血动物,其中Raf抑制剂是1-甲基-5-[2-(5-三氟甲基-1H-咪唑-2-基)-吡啶-4-基氧基]-1H-苯并咪唑-2-基}-(4-三氟甲基苯基)-胺或其可药用盐。
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US93962507P | 2007-05-23 | 2007-05-23 | |
US60/939,625 | 2007-05-23 | ||
PCT/US2008/064280 WO2008147782A1 (en) | 2007-05-23 | 2008-05-21 | Raf inhibitors for the treatment of thyroid cancer |
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EP (1) | EP2150252A1 (zh) |
JP (1) | JP2010528032A (zh) |
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CA3013342A1 (en) * | 2016-02-05 | 2017-08-10 | Evol Science LLC | Combinations to treat cancer |
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BRPI0808526A2 (pt) * | 2007-03-02 | 2014-08-19 | Novartis Ag | Formas sólidas de um inibidor de raf cinase |
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BRPI0811097A2 (pt) | 2014-12-09 |
CL2008001492A1 (es) | 2009-02-20 |
CA2686787A1 (en) | 2008-12-04 |
AU2008256922B2 (en) | 2011-07-28 |
WO2008147782A1 (en) | 2008-12-04 |
ZA200907250B (en) | 2010-07-28 |
US20120213867A1 (en) | 2012-08-23 |
JP2010528032A (ja) | 2010-08-19 |
IL201690A0 (en) | 2010-05-31 |
EP2150252A1 (en) | 2010-02-10 |
MA31446B1 (fr) | 2010-06-01 |
KR20100017894A (ko) | 2010-02-16 |
TN2009000486A1 (en) | 2011-03-31 |
AU2008256922A1 (en) | 2008-12-04 |
TW200914008A (en) | 2009-04-01 |
US20100160381A1 (en) | 2010-06-24 |
MX2009012626A (es) | 2009-12-07 |
RU2009147291A (ru) | 2011-06-27 |
NZ580592A (en) | 2012-02-24 |
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