CN1220684C - 用作抗肿瘤剂的2,4-二(杂-)芳基氨基(-氧基)-5-取代的嘧啶 - Google Patents
用作抗肿瘤剂的2,4-二(杂-)芳基氨基(-氧基)-5-取代的嘧啶 Download PDFInfo
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- CN1220684C CN1220684C CNB018058469A CN01805846A CN1220684C CN 1220684 C CN1220684 C CN 1220684C CN B018058469 A CNB018058469 A CN B018058469A CN 01805846 A CN01805846 A CN 01805846A CN 1220684 C CN1220684 C CN 1220684C
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- alkyl
- amino
- pyrimidine
- phenylamino
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- 229940034982 antineoplastic agent Drugs 0.000 title description 2
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- 238000000034 method Methods 0.000 claims abstract description 116
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- 238000001727 in vivo Methods 0.000 claims abstract description 33
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- 108010067715 Focal Adhesion Protein-Tyrosine Kinases Proteins 0.000 claims abstract description 32
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- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 29
- 229910052799 carbon Inorganic materials 0.000 claims description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 27
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- 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
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- 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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- C—CHEMISTRY; METALLURGY
- C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
- C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
- C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
- C04B35/622—Forming processes; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
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Abstract
本发明公开了式(I)嘧啶衍生物、或其可药用盐或其在体内可水解的酯,其中Q1、Q2、G和R1如说明书中所定义。本发明还公开了制备所述化合物的方法,含有它们的药物组合物,及其作为细胞周期蛋白依赖性丝氨酸/苏氨酸激酶(CDK)和粘着斑激酶(FAK)抑制剂的应用。
Description
本发明涉及嘧啶衍生物、或其可药用盐或其在体内可水解的酯,所述化合物具有细胞循环抑制活性,具有有用的抗癌(例如抗细胞增殖、抗细胞迁移和/或细胞程序死亡)活性,并因此可用于治疗温血动物例如人的方法中。本发明还涉及制备所述嘧啶衍生物的方法,含有它们的药物组合物,及其在制备药物中的应用或在温血动物例如人中产生抗癌作用(抗细胞增殖/转移和/或细胞程序死亡)的应用。
称为细胞周期蛋白的一族细胞内蛋白在细胞周期中起关键作用。细胞周期蛋白的合成和降解受到严格控制,这样它们的表达水平在细胞周期期间波动。细胞周期蛋白与细胞周期蛋白依赖性丝氨酸/苏氨酸激酶(CDKs)的结合和这种结合对于细胞内的CDK(例如CDK1、CDK2、CDK4和/或CDK6)活性是必需的。虽然对于这些因子各自是如何组合来调控CDK活性的细节了解很少,但是两个指令(是否细胞)之间的平衡贯穿整个细胞周期。
最近集中在原癌基因和肿瘤抑制基因的研究已经确定了进入细胞周期的调控是肿瘤有丝分裂发生的关键控制点。此外,CDK似乎在多种原癌基因信号传导途径的下游。由于细胞周期蛋白上调和/或缺失内源性抑制剂而导致的CDK活性失控似乎是肿瘤细胞致有丝分裂信号传导途径与增殖之间的重要枢纽。
因此,已经认识到,细胞周期激酶抑制剂,特别是CDK2、CDK4和/或CDK6抑制剂(分别在S-期、G1-S和G1-S期作用)应当具有用作细胞增殖选择性抑制剂例如哺乳动物癌细胞生长选择性抑制剂的价值。
此外,据信抑制参与信号传导途径的粘着斑激酶(FAK)会诱导细胞程序死亡(细胞死亡)和/或抑制细胞迁移,因此FAK抑制剂具有用作抗癌剂的价值。
本发明是基于下列发现,即一些2,4-嘧啶化合物令人惊奇地抑制细胞周期激酶的作用,表现出对CDK2、CDK4和CDK6的选择性,而且还抑制FAK,并因此具有抗癌(抗细胞迁移/增殖和/或细胞程序死亡)活性。预计这样的活性在下列方面有价值:治疗与异常细胞周期和细胞增殖有关的病症,例如癌症(实体瘤和白血病)、纤维增殖和分化病症、牛皮癣、类风湿性关节炎、Kaposi′s肉瘤、血管瘤病(haemangioma)、急性和慢性肾病、粉瘤、动脉粥样硬化、动脉再狭窄、自身免疫性疾病、急性和慢性炎症、骨疾病和具有视网膜血管增殖的眼疾病。
本发明提供了式(I)嘧啶衍生物、或其可药用盐或其在体内可水解的酯:
其中:
Q1和Q2独立地选自芳基或碳连接的杂芳基;Q1和Q2当中有一个或者Q1和Q2都在一个环碳原子上被一个选自下列的取代基取代:N-(C1-2烷基)氨基、N,N-二-(C1-2烷基)氨基、苯基、杂环基、苯氧基、杂环基-O-、取代的C1-2烷基、取代的C1-2烷氧基、取代的C1-2烷氧基羰基、取代的N-(C1-2烷基)氨基、取代的C1-2烷氧基C1-2烷基、取代的C2-4链烯基和取代的C2-4炔基;其中对于C1-2烷基、C1-2烷氧基、C1-2烷氧基羰基、N-(C1-2烷基)氨基、C1-2烷氧基C1-2烷基、C2-4链烯基和C2-4炔基,所述取代基选自卤素、羟基、巯基、硝基、甲酰基、甲酰胺基、羧基、氰基、氨基、脲基、氨基甲酰基、氨磺酰基、C1-4链烷酰基、C1-4烷氧基羰基、苯基、杂环基、苯甲酰基、杂环基-C(O)-、其中a是0-2的C1-4烷基S(O)a、N′-(C1-4烷基)脲基、N′,N′-二-(C1-4烷基)脲基、N′-(C1-4烷基)-N-(C1-4烷基)脲基、N′,N′-二-(C1-4烷基)-N-(C1-4烷基)脲基、N-C1-4烷基氨基、N,N-二-(C1-4烷基)氨基、N-(C1-4烷基)氨磺酰基、N,N-二-(C1-4烷基)氨磺酰基、N-C1-4烷基氨基甲酰基、N,N-二-(C1-4烷基)氨基甲酰基和C1-4链烷酰基氨基;其中任何苯基、苄基、苯甲酰基或杂环基任选在环碳原子上被一个或多个选自Ra的基团取代,并且如果杂环基含有-NH-部分,该氮可任选被一个选自Rb的基团取代;
G是-O-或-NR2-;
R2选自氢、C1-6烷基、C3-6链烯基和C1-6炔基;其中所述C1-6烷基、C3-6链烯基和C3-6炔基可任选被一个或多个选自Rc的基团取代;
R1选自氢、卤素、羟基、硝基、氨基、N-(C1-3烷基)氨基、N,N-二-(C1-3烷基)氨基、氰基、三氟甲基、三氯甲基、C1-3烷基[任选被1或2个独立地选自下列的取代基取代:卤素、氰基、氨基、N-(C1-3烷基)氨基、N,N-二-(C1-3烷基)氨基、羟基和三氟甲基]、C3-5链烯基[任选被最高达3个卤素取代、或者被一个三氟甲基取代]、C3-5炔基、C1-3烷氧基、巯基、C1-3烷硫基、羧基和C1-3烷氧基羰基;
Q1任选在环碳原子上被1-4个独立地选自下列的取代基取代:卤素、巯基、硝基、甲酰基、甲酰胺基、羧基、氰基、氨基、脲基、氨基甲酰基、氨磺酰基、C1-4烷基、C2-4链烯基、C2-4炔基[其中所述C1-4烷基、C2-4链烯基和C2-4炔基任选被一个或多个选自Rd的取代基取代]、C1-4链烷酰基、C1-4烷氧基羰基、杂环基、其中a是0-2的C1-4烷基S(O)a[任选被羟基取代]、N′-(C1-4烷基)脲基、N′,N′-二-(C1-4烷基)脲基、N′-(C1-4烷基)-N-(C1-4烷基)脲基、N′,N′-二-(C1-4烷基)-N-(C1-4烷基)脲基、N-C1-4烷基氨基、N,N-二-(C1-4烷基)氨基、N-(C1-4烷基)氨磺酰基、N,N-二-(C1-4烷基)氨磺酰基、N-C1-4烷基氨基甲酰基、N,N-二-(C1-4烷基)氨基甲酰基和C1-4链烷酰基氨基;
独立地,或者除了上述取代基以外,Q1可任选被1-2个独立地选自芳基、C3-8环烷基和杂环基的取代基取代;其中所述芳基、C3-8环烷基或杂环基可任选在环碳原子上被一个或多个选自Re的基团取代;并且如果杂环基含有-NH-部分,该氮可任选被一个选自Rf的基团取代;
Q2任选在环碳原子上被1-4个独立地选自下列的取代基取代:卤素、羟基、巯基、硝基、甲酰基、甲酰胺基、羧基、氰基、氨基、脲基、氨基甲酰基、氨磺酰基、C1-4烷基、C2-4链烯基、C2-4炔基、C1-4烷氧基[其中所述C1-4烷基、C2-4链烯基、C2-4炔基和C1-4烷氧基可任选被一个或多个选自Rg的基团取代]、C1-4链烷酰基、C1-4烷氧基羰基、杂环基、其中a是0-2的C1-4烷基S(O)a[任选被羟基取代]、N′-(C1-4烷基)脲基、N′,N′-二-(C1-4烷基)脲基、N′-(C1-4烷基)-N-(C1-4烷基)脲基、N′,N′-二-(C1-4烷基)-N-(C1-4烷基)脲基、N-C1-4烷基氨基、N,N-二-(C1-4烷基)氨基、N-(C1-4烷基)氨磺酰基、N,N-二-(C1-4烷基)氨磺酰基、N-C1-4烷基氨基甲酰基、N,N-二-(C1-4烷基)氨基甲酰基、C2-4链烯氧基、C2-4炔氧基、C1-4链烷酰基氨基;
独立地,或者除了上述取代基以外,Q2可任选被1-2个独立地选自芳基、C3-8环烷基和杂环基的取代基取代;其中所述芳基、C3-8环烷基或杂环基可任选在环碳原子上被一个或多个选自Rh的基团取代;并且如果杂环基含有-NH-部分,该氮可任选被一个选自Ri的基团取代;
Rc、Rd和Rg独立地选自羟基、卤素、氨基、氰基、甲酰基、甲酰胺基、羧基、硝基、巯基、氨基甲酰基、氨磺酰基、N-C1-4烷基氨基、N,N-二-(C1-4烷基)氨基、C1-4链烷酰基、C1-4链烷酰氧基、C1-4烷氧基、C1-4烷氧基羰基、N-C1-4烷基氨基甲酰基、N,N-二-(C1-4烷基)氨基甲酰基、C1-4链烷酰基氨基、其中a是0-2的C1-4烷基S(O)a、C1-4烷基磺酰基氨基、N-(C1-4烷基)氨磺酰基、N-(C1-4烷基)2氨磺酰基、N-(C1-4烷基)氨基甲酰基、N-(C1-4烷基)2氨基甲酰基、苯基、苯硫基、苯氧基、C3-8环烷基和杂环基;其中所述苯基、苯硫基、苯氧基、C3-8环烷基或杂环基可任选在环碳原子被一个或多个R5的基团取代;并且如果所述杂环基含有-NH-部分,该氮可任选被一个选自Rk的基团取代;
Ra、Re、Rh和Rj独立地选自羟基、卤素、氨基、氰基、甲酰基、甲酰胺基、羧基、硝基、巯基、氨基甲酰基、氨磺酰基、C1-4烷基[任选被一个或多个选自卤素、氰基、氨基、N-C1-4烷基氨基、N,N-二-(C1-4烷基)氨基或羟基取代]、C2-4链烯基[任选被一个或多个选自卤素的基团取代]、C2-4炔基、N-C1-4烷基氨基、N,N-二-(C1-4烷基)氨基、C1-4链烷酰基、C1-4链烷酰氧基、C1-4烷氧基[任选被一个或多个选自卤素的基团取代]、C1-4烷氧基羰基、N-C1-4烷基氨基甲酰基、N,N-二-(C1-4烷基)氨基甲酰基、C1-4链烷酰基氨基、其中a是0-2的C1-4烷基S(O)a、C1-4烷基磺酰基氨基、N-(C1-4烷基)氨磺酰基、N-(C1-4烷基)2氨磺酰基、苯基、C3-8环烷基和杂环基;且
Rb、Rf、Rl和Rk独立地选自C1-4烷基、C1-4链烷酰基、C1-4烷基磺酰基、氨基甲酰基、N-(C1-4烷基)氨基甲酰基、N,N-(C1-4烷基)氨基甲酰基、苄基、苄氧基羰基、苯甲酰基和苯基磺酰基。
“芳基”是含有4-12个原子的全不饱和或部分不饱和的单环或二环碳环。“芳基”优选为含有5或6个原子的单环或含有9或10个碳原子的二环。“芳基”更优选为苯基、萘基、四氢萘基或二氢茚基。“芳基”特别是苯基、萘基或二氢茚基。“芳基”更特别是苯基。
“碳连接的杂芳基”是全不饱和的5-元或6-元单环或9-元或10-元二环,其中至少一个原子选自氮、硫或氧。该环是经由碳原子连接在NH-(对于Q1)或G(对于Q2)上。“碳连接的杂芳基”优选为呋喃基、噻吩基、吡咯基、噁唑基、异噁唑基、噻唑基、异噻唑基、咪唑基、吡唑基、呋咱基、三唑基、噻二唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、吲哚基、喹啉基或苯并咪唑基。“碳连接的杂芳基”更优选为吡啶基、噻唑基或吡唑基。“碳连接的杂芳基”特别是吡啶基。
“杂环基”是含有4-12个原子的饱和、部分饱和或不饱和单环或二环,其中至少一个原子选自氮、硫或氧,除非另有说明,否则该基团是经由碳或氮连接的,其中-CH2-基可任选被-C(O)-代替,并且环硫原子可任选被氧化以形成S-氧化物。“杂环基”是吡咯烷基、吗啉代、哌啶基、奎宁环基、吡啶基、吡喃基、吡咯基、异噻唑基、吲哚基、喹啉基、噻吩基、呋喃基、1,3-苯并二氧杂环戊烯基、噻二唑基、哌嗪基、噻唑烷基、吡咯烷基、琥珀酰亚氨基、硫代吗啉代、吡唑基、吡咯啉基、高哌嗪基、四氢吡喃基、咪唑基、嘧啶基、吡嗪基、哒嗪基、异噁唑基、邻苯二甲酰亚氨基、4-吡啶酮、1-异喹诺酮、2-吡咯烷酮、4-噻唑烷酮、咪唑并[1,2-a]吡啶或3-氮杂-8-氧杂二环[3,2,1]己烷。“杂环基”更优选为吡咯烷基、吗啉代、哌啶基、奎宁环基、哌嗪基、琥珀酰亚氨基、咪唑基或邻苯二甲酰亚氨基。
在本说明书中,术语“烷基”包括直链或支链烷基,但是当提及单独的烷基例如“丙基”时,其仅特指直链型。类似约定适用于其它一般术语。“卤素”是氟、氯、溴和碘。
C2-4链烯基的实例是乙烯基和烯丙基;C2-6链烯基的实例是C3-5链烯基、乙烯基和烯丙基;C3-6链烯基的实例是烯丙基;C3-6炔基的实例是C3-5炔基和丙炔-2-基;C2-4炔基的实例是乙炔基和丙炔-2-基;C2-6炔基的实例是乙炔基和丙炔-2-基;C1-4链烷酰基的实例是乙酰基和丙酰基;C1-4烷氧基羰基的实例是C1-3烷氧基羰基、C1-2烷氧基羰基、甲氧基羰基、乙氧基羰基、丙氧基羰基和叔丁氧基羰基;C1-4亚烷基的实例是亚甲基、亚乙基和亚丙基;C1-4烷基的实例是C1-3烷基、C1-2烷基、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基;C1-6烷基的实例甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基和3-甲基丁基;C1-4烷氧基的实例是C1-3烷氧基、C1-2烷氧基、甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基;C2-4链烯氧基的实例是烯丙氧基;C2-4炔氧基的实例是丙炔氧基;其中a是0-2的C1-4烷基S(O)a的实例是C1-3烷硫基、甲硫基、乙硫基、丙硫基、甲基亚磺酰基、乙基亚磺酰基、丙基亚磺酰基、甲磺酰基、乙基磺酰基和丙基磺酰基;N-C1-4烷基氨基甲酰基的实例是N-甲基氨基甲酰基、N-乙基氨基甲酰基和N-丙基氨基甲酰基;N,N-二-(C1-4烷基)-氨基甲酰基是N,N-二甲基氨基甲酰基、N-乙基-N-甲基氨基甲酰基和N,N-二乙基氨基甲酰基;N-C1-4烷基氨基的实例是N-(C1-3烷基)氨基、N-(C1-2烷基)氨基、甲基氨基、乙基氨基和丙基氨基;N,N-二-(C1-4烷基)氨基的实例是N,N-二-(C1-3烷基)氨基、N,N-二-(C1-2烷基)氨基、二甲基氨基、N-乙基-N-甲基氨基、二乙基氨基、N-甲基-N-丙基氨基和二丙基氨基;C1-4链烷酰基氨基的实例是乙酰氨基、丙酰氨基和丁酰氨基;C3-8环烷基的实例是环丙基、环戊基和环己基;C1-4链烷酰基的实例是乙酰基和丙酰基;C1-4链烷酰氧基的实例是乙酰氧基和丙酰氧基;N′-(C1-4烷基)脲基的实例是N-甲基脲基和N-乙基脲基;N′,N′-二-(C1-4烷基)脲基的实例是N′,N′-二甲基脲基、N′,N′-二异丙基脲基和N′-甲基-N′-丙基脲基;N′-(C1-4烷基)-N-(C1-4烷基)脲基的实例是N-甲基-N-乙基脲基和N′-甲基-N-甲基脲基;N′,N′-二-(C1-4烷基)-N-(C1-4烷基)脲基的实例是N′,N′-二甲基-N-乙基脲基和N′-甲基-N′-丙基-N-丁基脲基;N-(C1-4烷基)氨磺酰基的实例是N-甲基氨磺酰基和N-异丙基氨磺酰基;N,N-二-(C1-4烷基)氨磺酰基的实例是N-甲基-N-乙基氨磺酰基和N,N-二丙基氨磺酰基;C1-4烷基磺酰基氨基的实例是甲磺酰基氨基、乙基磺酰基氨基和丙基磺酰基氨基;杂环基-O-的实例是哌啶基氧基、吡啶基氧基和嘧啶基氧基;C1-2烷氧基C1-2烷基的实例是甲氧基甲基和乙氧基乙基;杂环基-C(O)-的实例是哌嗪基羰基、吡啶基羰基和嘧啶基羰基。
本发明嘧啶衍生物的合适的可药用盐是例如具有充分碱性的本发明嘧啶衍生物的酸加成盐,例如与无机酸或有机酸如盐酸、氢溴酸、硫酸、磷酸、三氟乙酸、柠檬酸或马来酸形成的酸加成盐。此外,具有充分酸性的本发明嘧啶衍生物的合适的可药用盐是碱金属盐,例如钠盐或钾盐,和碱土金属盐例如钙盐或镁盐,铵盐或者与获得生理可接受阳离子的有机碱形成的盐,例如与甲基胺、二甲基胺、三甲基胺、哌啶、吗啉或三-(2-羟基乙基)胺形成的盐。
本发明式(I)化合物可以以前药的形式施用,所述前药在人或动物体内分解释放出式(I)化合物。前药的实例包括式(I)化合物的在体内可水解的酯。
含有羧基或羟基的式(I)化合物的在体内可水解的酯是例如在人或动物体内水解以生成母酸或醇的可药用酯。对于羧基,合适的可药用酯包括C1-6烷氧基甲基酯例如甲氧基甲酯,C1-6烷酰氧基甲酯例如新戊酰氧基甲酯、苯并呋喃酮酯,C3-8环烷氧基羰基氧基C1-6烷基酯例如1-环己基羰基氧基乙酯;1,3-二氧杂环戊烯-2-酮基甲基酯例如5-甲基-1,3-二氧杂环戊烯-2-酮基甲酯;和C1-6烷氧基羰基氧基乙基酯例如1-甲氧基羰基氧基乙酯,并且可在本发明化合物中的任何羧基上形成。
含有羟基的式(I)化合物的在体内可水解的酯包括无机酯例如磷酸酯和α-酰氧基烷基醚以及相关化合物,它们在体内通过酯水解释放出母羟基。α-酰氧基烷基醚的实例包括乙酰氧基甲氧基和2,2-二甲基丙酰氧基甲氧基。对于羟基,体内可水解的酯形成基团的选择包括链烷酰基、苯甲酰基、苯基乙酰基和取代的苯甲酰基和苯基乙酰基、烷氧基羰基(以生成烷基碳酸酯)、二烷基氨基甲酰基和N-(二烷基氨基乙基)-N-烷基氨基甲酰基(以生成氨基甲酸酯)、二烷基氨基乙酰基和羧基乙酰基。在苯甲酰基上的取代基的实例包括从环氮原子上经由亚甲基连接在苯甲酰基环的3-位或4-位上的吗啉代和哌嗪子基。
某些式(I)化合物可能具有手性中心和/或几何异构中心(E-和Z-异构体),并且应当理解,本发明包括具有CDK和/或FAK抑制活性的所有这样的旋光、非对映异构体和几何异构体。
本发明涉及具有CDK和/或FAK抑制活性的任何和所有互变异构形式的式(I)化合物。
还应当理解,一些式(I)化合物可以以溶剂化以及非溶剂化形式例如水合物形式存在。应当理解,本发明包括具有CDK和/或FAK抑制活性的所有这样的溶剂化形式。
特别优选的的本发明化合物包括式(I)嘧啶衍生物、或其可药用盐或在体内可水解的酯,其中R1、Q1、Q2、和G具有任何上文定义的含义,或者任何下列值。适当的话,任何定义、权利要求或上下文中的实施方案可使用这些值。
Q1和Q2优选独立地地选自苯基和吡啶基。
Q1优选为苯基。
Q2优选为苯基或吡啶基。
优选地,Q1是苯基,Q2选自苯基和吡啶基。
优选地,Q1和Q2当中有一个或者Q1和Q2都在环碳原子上被一个选自下列的取代基取代:N,N-二-(C1-2烷基)氨基、杂环基、杂环基-O-、取代的C1-2烷基、取代的C1-2烷氧基、取代的C1-2烷氧基羰基、取代的N-(C1-2烷基)氨基、取代的C1-2烷氧基C1-2烷基和取代的C2-4炔基;其中对于C1-2烷基、C1-2烷氧基、C1-2烷氧基羰基、N-(C1-2烷基)氨基、C1-2烷氧基C1-2烷基和C2-4炔基,所述取代基选自羟基、羧基、氨基、杂环基、杂环基-C(O)-、N-C1-4烷基氨基和N,N-二-(C1-4烷基)氨基;其中任何杂环基任选在环碳原子上被一个或多个选自Ra的基团取代,并且如果杂环基含有-NH-部分,该氮可任选被一个选自Rb的基团取代。
更优选地,Q1和Q2当中有一个或者Q1和Q2都在环碳原子上被一个选自下列的取代基取代:N,N-二-(C1-2烷基)氨基、哌嗪子基(任选在4-氮上被甲基取代)、哌啶-3-基氧基(任选在氮上被甲基取代)、哌啶-4-基氧基(任选在氮上被甲基取代)、取代的C1-2烷基、取代的C1-2烷氧基、取代的C1-2烷氧基羰基、取代的N-(C1-2烷基)氨基、取代的C1-2烷氧基C1-2烷基和取代的C2-4炔基;其中对于C1-2烷基、C1-2烷氧基、C1-2烷氧基羰基、N-(C1-2烷基)氨基、C1-2烷氧基C1-2烷基和C2-4炔基,所述取代基选自羟基、羧基、氨基、琥珀酰亚胺-1-基、哌啶-3-基(任选在氮上被甲基取代)、邻苯二甲酰亚胺-1-基、吗啉代、奎宁环-3-基(任选被羟基取代)、哌啶-4-基、吡咯烷-1-基、哌嗪子基(任选在氮上被甲基取代)、咪唑-1-基、哌啶子基、哌嗪子基羰基(任选在氮上被异丙基取代)、N-C1-4烷基氨基和N,N-二-(C1-4烷基)氨基。
特别地,Q1和Q2当中有一个或者Q1和Q2都在环碳原子上被一个选自下列的取代基取代:二甲基氨基、4-甲基哌嗪子基、氨基甲基、2-羟基乙氧基甲基、琥珀酰亚胺-1-基甲基、2-吡咯烷-1-基乙基、2-氨基乙基、哌啶-4-基氧基、1-甲基哌啶-4-基氧基、1-甲基哌啶-3-基氧基、羧基甲氧基、1-甲基哌啶-2-基甲氧基、1-甲基哌啶-3-基甲氧基、哌啶-4-基甲氧基、4-异丙基哌嗪子基羰基甲氧基、2-邻苯二甲酰亚胺-1-基乙氧基、2-吗啉代乙氧基、2二甲基氨基乙氧基、2-二乙基氨基乙氧基、2-(4-甲基哌嗪子基)乙氧基、2-咪唑-1-基乙氧基、2-吡咯烷-1-基乙氧基、2-氨基乙炔基、2-二甲基氨基乙炔基、2-甲基氨基乙炔基、2-(3-羟基奎宁环-3-基)乙炔基、2-吗啉代乙氧基甲基、2-二乙基氨基乙氧基甲基、2-吡咯烷-1-基乙氧基甲基、2-(4-甲基哌嗪子基)乙氧基甲基、2-二乙基氨基乙氧基羰基、2-哌啶子基乙基氨基或2-异丙基氨基乙基氨基。
更特别地,Q1和Q2当中有一个或者Q1和Q2都在环碳原子上被一个选自下列的取代基取代:1-甲基哌啶-4-基氧基、羧基甲氧基、2-二甲基氨基乙氧基、2-甲基氨基乙炔基、2-哌啶子基乙基氨基或2-异丙基氨基乙基氨基。
Q1优选在环碳原子上被一个选自下列的取代基取代:N-(C1-2烷基)氨基、N,N-二-(C1-2烷基)氨基、苯基、杂环基、苯氧基、杂环基-O-、取代的C1-2烷基、取代的C1-2烷氧基、取代的C1-2烷氧基羰基、取代的N-(C1-2烷基)氨基、取代的C1-2烷氧基C1-2烷基、取代的C2-4链烯基和取代的C2-4炔基;其中对于C1-2烷基、C1-2烷氧基、C1-2烷氧基羰基、N-(C1-2烷基)氨基、C1-2烷氧基C1-2烷基、C2-4链烯基和C2-4炔基,所述取代基选自卤素、羟基、巯基、硝基、甲酰基、甲酰胺基、羧基、氰基、氨基、脲基、氨基甲酰基、氨磺酰基、C1-4链烷酰基、C1-4烷氧基羰基、苯基、杂环基、苯甲酰基、杂环基-C(O)-、其中a是0-2的C1-4烷基S(O)a、N′-(C1-4烷基)脲基、N′,N′-二-(C1-4烷基)脲基、N′-(C1-4烷基)-N-(C1-4烷基)脲基、N′,N′-二-(C1-4烷基)-N-(C1-4烷基)脲基、N-C1-4烷基氨基、N,N-二-(C1-4烷基)氨基、N-(C1-4烷基)氨磺酰基、N,N-二-(C1-4烷基)氨磺酰基、N-C1-4烷基氨基甲酰基、N,N-二-(C1-4烷基)氨基甲酰基和C1-4链烷酰基氨基;其中任何苯基、苄基、苯甲酰基或杂环基任选在环碳原子上被一个或多个选自Ra的基团取代;并且如果杂环基含有-NH-部分,该氮可任选被一个选自Rb的基团取代,并且更优选地,除了选自上面列出的一个取代基以外,Q1是未取代的。
Q1更优选在-NH-的对位或间位被取代。
Q1特别优选在-NH-的对位被取代。
在本发明一个方面,G优选为-O-。
在本发明另一个方面,G优选为-NR2-。
在本发明一个方面,当G是-NR2-时,R2优选为氢。
在另一个本发明方面,当G是-NR2-时,R2优选不是氢。
R1优选为氢、氯或溴。
R1优选为溴。
Q2优选未取代或者被选自氟、溴、甲基、甲氧基和氰基的一个基团取代。
Q2更优选未取代或者被一个甲基取代。
Q2优选是苯基、2-氰基苯基、3-甲基苯基、4-氟苯基、4-溴苯基、4-甲氧基苯基或6-甲基吡啶-2-基。
Q2更优选为苯基或6-甲基吡啶-2-基。
因此,在一个优选的本发明方面,本发明提供了如上所述的式(I)嘧啶衍生物、或其可药用盐或在体内可水解的酯,其中:
Q1和Q2独立地选自苯基和吡啶基;且Q1在环碳上被一个选自下列的取代基取代:N,N-二-(C1-2烷基)氨基、杂环基、杂环基-O-、取代的C1-2烷基、取代的C1-2烷氧基、取代的C1-2烷氧基羰基、取代的N-(C1-2烷基)氨基、取代的C1-2烷氧基C1-2烷基和取代的C2-4炔基;其中对于C1-2烷基、C1-2烷氧基、C1-2烷氧基羰基、N-(C1-2烷基)氨基、C1-2烷氧基C1-2烷基和C2-4炔基,所述取代基选自羟基、羧基、氨基、杂环基、杂环基-C(O)-、N-C1-4烷基氨基和N,N-二-(C1-4烷基)氨基;其中任何杂环基任选在环碳原子上被一个或多个选自Ra的基团取代;并且如果杂环基含有-NH-部分,该氮可任选被一个选自Rb的基团取代;且Q2是未取代的或者被一个选自氟、溴、甲基、甲氧基和氰基的基团取代;
G是-NH-;且
R1是氢、氯或溴。
因此,在更优选的本发明方面中,本发明提供了如上所述的式(I)嘧啶衍生物、或其可药用盐或在体内可水解的酯,其中:
Q1是苯基,且Q2选自苯基和吡啶基;Q1在-NH-的对位或间位被一个选自下列的取代基取代:二甲基氨基、4-甲基哌嗪子基、氨基甲基、2-羟基乙氧基甲基、琥珀酰亚胺-1-基甲基、2-吡咯烷-1-基乙基、2-氨基乙基、哌啶-4-基氧基、1-甲基哌啶-4-基氧基、1-甲基哌啶-3-基氧基、羧基甲氧基、1-甲基哌啶-2-基甲氧基、1-甲基哌啶-3-基甲氧基、哌啶-4-基甲氧基、4-异丙基哌嗪子基羰基甲氧基、2-邻苯二甲酰亚胺-1-基乙氧基、2-吗啉代乙氧基、2-二甲基氨基乙氧基、2-二乙基氨基乙氧基、2-(4-甲基哌嗪子基)乙氧基、2-咪唑-1-基乙氧基、2-吡咯烷-1-基乙氧基、2-氨基乙炔基、2二甲基氨基乙炔基、2-甲基氨基乙炔基、2-(3-羟基奎宁环-3-基)乙炔基、2-吗啉代乙氧基甲基、2-二乙基氨基乙氧基甲基、2-吡咯烷-1-基乙氧基甲基、2-(4-甲基哌嗪子基)乙氧基甲基、2-二乙基氨基乙氧基羰基、2-哌啶子基乙基氨基或2-异丙基氨基乙基氨基;且Q2是未取代的或者被一个选自氟、溴、甲基、甲氧基和氰基的基团取代;
G是-NH-;且
R1是氢、氯或溴。
在本发明的一个方面中,优选的本发明化合物是实施例2、12、21、28、30或38的化合物或其可药用盐或在体内可水解的酯。
在本发明另一个方面,优选的本发明化合物包括任何实施例的化合物或其可药用盐或在体内可水解的酯。
优选的本发明方面是涉及本发明化合物或其可药用盐的那些。
式(I)嘧啶衍生物或其可药用盐或在体内可水解的酯可通过适于制备在化学上相关的化合物的任何已知方法制得。当用于制备式(I)嘧啶衍生物或其可药用盐或在体内可水解的酯时,这样的方法是作为本发明另外的特征提供的,并且可通过下述代表性实施例举例说明,其中除非另有说明,否则R1、Q1、Q2和G具有上文关于式(I)嘧啶衍生物所定义的任何含义,并且除非在环Q1或Q2上画出另一取代基,否则环可携带任何上述取代基(任选按照需要保护的)。当在环Q1上画出取代基时,这包括(除非另有说明)在环Q2上还携带取代基的可能性,或者环Q2上携带取代基以代替在环Q1上的取代基。必需原料可通过标准有机化学方法获得(参见例如Advanced Organic Chemistry(Wiley-Interscience),Jerry March-还用于反应条件和试剂的一般指导)。在随同的非限制性方法和实施例中描述了这样的原料的制备。另外,必需原料可通过在本领域技术人员知识范围内的类似于所举例说明的方法的方法制得。
因此,作为本发明另一特征,本发明提供了下列方法,包括:
a)对于其中G是-NR2-的式(I)化合物,将式(II)嘧啶化合物
其中L是如下所定义的可置换基团,
与式(III)化合物反应
其中G是-NR2-;
b)将式(IV)嘧啶化合物
其中L是如下所定义的可置换基团,
与式(V)化合物反应
然后如果需要的话:
i)将式(I)化合物转化成另一式(I)化合物;
ii)除去任何保护基;
iii)形成可药用盐或在体内可水解的酯。
L是可置换基团,L的合适的值是例如卤素、磺酰氧基或硫基,例如氯、溴、甲磺酰氧基、甲苯-4-磺酰氧基、甲磺酰基、甲硫基和甲基亚磺酰基。
上述反应的具体反应条件如下:
方法a)
式(II)嘧啶与式(III)化合物可以在下列条件下反应:
i)任选在合适的酸例如无机酸如盐酸或硫酸存在下,或者在有机酸例如乙酸或甲酸存在下进行反应。该反应优选在合适的惰性溶剂或稀释剂例如二氯甲烷(DCM)、乙腈、丁醇、环丁砜、四氢呋喃、1,2-二甲氧基乙烷、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或N-甲基吡咯烷-2-酮中于例如0℃-150℃温度下、方便起见在接近回流温度下进行;或者
ii)在标准Buchwald条件下(例如参见J.Am.Chem.Soc.,118,7215;J.Am.Chem.Soc.,119,8451;J.Org.Chem.,62,1568和6066),例如在乙酸钯存在下,在合适的溶剂例如芳族溶剂如甲苯、苯或二甲苯中,使用合适的碱例如无机碱如碳酸铯或有机碱例如叔丁氧基钾,在合适的配体例如2,2′-二(二苯基膦基)-1,1′-联萘存在下,在25-80℃温度下进行。
式(II)嘧啶可依据下述反应方案制得:
其中Ra是任选取代的烷基或芳基,且L是如上所定义的可置换基团。
Ra优选为甲基、乙基或对甲苯基。
式(III)化合物可商购获得,或者通过本领域已知方法制得。
方法b)
式(IV)嘧啶和式(V)苯胺可在下列条件下反应:
i)在合适的溶剂例如酮如丙酮或醇例如乙醇或丁醇或芳烃例如甲苯或N-甲基吡咯烷存在下,任选在合适的酸例如上文定义的酸(或合适的路易斯酸)存在下,在0℃-回流温度下、优选回流温度下进行反应;或者
ii)在如上所述的标准Buchwald条件下进行反应。
式(IV)嘧啶可依据下述反应方案制得
其中L是如上所定义的可置换基团。
式(V)苯胺可商购获得,或者可通过本领域已知方法制得。
式(IVA)嘧啶可商购获得,或者可通过例如将其中L是-OH的式(IVA)化合物(即尿嘧啶)与POCl3反应以生成其中L是-Cl的式(IVA)化合物来制得。
将一种式(I)化合物转化成另一种式(I)化合物的实例有:
i)当G是-NR2-时,将作为氢的R2转化成其它R2,例如:
其中L是可置换基团;
ii)当G是-NR2-时,将作为取代的侧链的R2转化成另一取代的侧链,例如:
其中Ms是甲磺酰基,且Nu是引入如式(I)中所定义的R2的任选取代基的亲核试剂(NB羟基部分无需在如上所示的末端碳上);
iii)使用标准技术将R1的一个值转化成R1的另一个值,例如将作为羟基的R1转化成C1-4烷氧基。
本发明优选方法是方法b)。
应当理解,在本发明化合物中的各个环取代基可在进行上述方法之前或者之后立即通过标准芳族取代反应引入或者通过常规官能团修饰来生成,并且这也包括在本发明方法中。这样的反应和修饰包括例如通过芳族取代反应引入取代基、将取代基还原、将取代基烷基化和将取代基氧化。用于这些方法的试剂和反应条件是化学领域众所周知的。芳族取代反应的特别实例包括使用浓硝酸引入硝基,在FriedelCrafts条件下使用例如酰卤和路易斯酸(例如三氯化铝)引入酰基;在Friedel Crafts条件下使用例如烷基卤和路易斯酸(例如三氯化铝)引入烷基;和引入卤素基团。修饰的特别实例包括通过例如用镍催化剂催化氢化或者在盐酸存在下、加热条件下用铁处理来将硝基还原成氨基;将烷硫基氧化成烷基亚磺酰基或烷基磺酰基。
还应当理解,在某些上述反应中,可能必需/最好将化合物中的任何敏感基团保护起来。需要或最好进行保护的情况以及合适的保护方法是本领域技术人员已知的。可依据标准实践使用常规保护基(参见例如T.W.Green,Protective Groups in Organic Synthesis,JohnWiley and Sons,1991)。因此,在某些本文所述的反应中,如果反应物包含基团例如氨基、羧基或羟基,可能最好将基团保护起来。
对于氨基或烷基氨基,合适的保护基是例如酰基,例如链烷酰基如乙酰基,烷氧基羰基例如甲氧基羰基、乙氧基羰基或叔丁氧基羰基,芳基甲氧基羰基例如苄氧基羰基,或芳酰基例如苯甲酰基。上述保护基的脱保护条件必需根据所选的保护基而变。因此,例如,酰基如链烷酰基或烷氧基羰基或芳酰基可通过例如用合适的碱如碱金属氢氧化物例如氢氧化锂或氢氧化钠水解来除去。或者,酰基例如叔丁氧基羰基可通过例如用合适的酸如盐酸、硫酸或磷酸或三氟乙酸处理来除去,芳基甲氧基羰基例如苄氧基羰基可通过例如用催化剂例如披钯碳氢化或者通过用路易斯酸例如三(三氟乙酸)硼处理来除去。对于伯氨基,另外合适的保护基是例如邻苯二甲酰基,其通过用烷基胺例如二甲基氨基丙基胺或肼处理来除去。
对于羟基,合适的保护基是例如酰基如链烷酰基例如乙酰基,芳酰基例如苯甲酰基,或芳基甲基例如苄基。上述保护基的脱保护条件必需根据所选的保护基而变。因此,例如,酰基如链烷酰基或芳酰基可通过例如用合适的碱如碱金属氢氧化物例如氢氧化锂或氢氧化钠水解来除去。或者,芳基甲基例如苄基可通过例如用催化剂例如披钯碳氢化来除去。
对于羧基,合适的保护基是例如酯化基团,例如可通过例如用碱如氢氧化钠水解来除去的甲基或乙基,或例如可通过例如用酸如有机酸例如三氟乙酸处理来除去的叔丁基,或例如可通过例如用催化剂如披钯碳氢化来除去的苄基。
可在合成中的任何适宜步骤使用化学领域众所周知的常规技术来除去保护基。
许多本文限定的中间体是新的,例如式II和IV中间体,它们作为本发明另外的特征。
测定
如上所述,在本发明中限定的嘧啶衍生物具有抗细胞增殖活性例如抗癌活性,据信这是由于它们的CDK和/或FAK抑制活性所致。这些性质可通过例如使用下列方法来评价:
CDK4抑制测定
使用下列缩写:-
HEPES是N-(2-羟基乙基)哌嗪-N′-(2-乙磺酸)
DTT是二硫苏糖醇
PMSF是苯基甲基磺酰氟
使用测定掺入到测试底物(GST-成视网膜细胞瘤)内的[γ-33-P]-三磷酸腺苷的闪烁近似测定法(SPA-得自Amersham),在96孔格式板中在体外激酶测定中测试化合物。将测试化合物(在DMSO和水中稀释至合适的浓度)置于每个孔中,将p16作为抑制剂对照或DMSO作为正对照置于对照孔中。
将在25μl培养缓冲液中稀释的大约0.5μl CDK4/细胞周期蛋白D1部分纯化酶(其量取决于酶活性)加到每个孔中,然后加入20μlGST-Rb/ATP/ATP33混合物(含有0.5μg GST-Rb和0.2μM ATP以及0.14μCi[γ-33-P]-三磷酸腺苷),并将所得混合物轻微振摇,然后在室温培养60分钟。
然后向每个孔中加入含有(0.8mg/孔蛋白A-PVT SPA珠子(Amersham))、20pM/孔抗-谷胱甘肽转移酶、兔子IgG(得自分子探针)、61mM EDTA和含0.05%叠氮化钠的50mM HEPES pH7.5的150μL终止溶液。
用Topseal-S板密封器将平板密封,放置2个小时,然后以2500rpm、1124×g旋转5分钟。将平板在Topcount上读取,每个孔读取30秒。
用于稀释酶和底物混合物的培养缓冲液含有50mM HEPES pH7.5、10mM MnCl2、1mM DTT、100pM钒酸钠、100μM NaF、10mM甘油磷酸钠BSA(1mg/ml终体积)。
可使用另一已知的CDK4抑制剂代替p16作为对照。
测试底物
在该测定中,仅使用一部分与GST尾融合的成视网膜细胞瘤(Science 1987 Mar 13;235(4794):1394-1399;Lee W.H.,Bookstein R.,Hong F.,Young L.J.,Shew J.Y.,Lee E.Y.)。进行成视网膜细胞瘤氨基酸379-928(得自成视网膜细胞瘤质粒ATCCpLRbRNL)的PCR,将该序列克隆到用于扩增氨基酸792-928的pGEX 2T融合载体内(Smith D.B.和Johnson,K.S.Gene 67,31(1988);该载体含有用于诱导表达的tac启动子、用于在任何大肠杆菌宿主中使用的内lac Iq基因、和用于凝血酶分裂的编码区域-得自PharmaciaBiotech)。再将该序列克隆到pGEX 2T内。
使用标准诱导表达技术将由此获得的成视网膜细胞瘤792-928序列在大肠杆菌(BL21(DE3)pLysS细胞)中表达,并如下所述纯化。
将大肠杆菌粘重悬在10ml/g NETN缓冲液(50mM Tris pH7.5,120mM NaCl,1mM EDTA,0.5%v/v NP-40,1mM PMSF,1ug/ml亮抑蛋白酶肽,1ug/ml抑肽酶和1ug/ml胃蛋白酶抑制剂)中,并超声2×45秒/100ml匀化物。离心后,将上清液负载到10ml谷胱甘肽琼脂糖柱(Pharmacia Biotech,Herts,UK)上,并用NETN缓冲液洗涤。用激酶缓冲液(50mM HEPES pH7.5,10mM MgCl2,1mM DTT,1mM PMSF,1ug/ml亮抑蛋白酶肽,1ug/ml抑肽酶和1ug/ml胃蛋白酶抑制剂)洗涤,用50mM还原谷胱甘肽在激酶缓冲液中的溶液将蛋白稀释。将含有GST-Rb(792-927)的级分汇集,并用激酶缓冲液透析过夜。通过使用8-16%Tris-甘氨酸凝胶(Novex,San Diego,USA)的十二烷基硫酸钠(SDS)PAGE(聚丙烯酰胺凝胶)分析终产物。
CDK4和细胞周期蛋白D1
按照下述方法将CDK4和细胞周期蛋白D1从RNA中克隆到MCF-7细胞系(得自ATCC号:HTB22,乳腺癌系)内。该RNA是由MCF-7细胞,然后用低聚dT引物逆转录制得的。使用PCR来扩增每个基因的完全编码序列[CDK4氨基酸1-303;Ref.Cell 1992 Oct 16;71(2):323-334;Matsushime H.,Ewen M.E.,Stron D.K.,Kato J.Y.,Hanks S.K.,Roussel M.F.,Sherr C.J.和细胞周期蛋白D1氨基酸1-296;Ref.Cold Spring Harb.Symp.Quant.Biol.,1991;56:93-97;ArnoldA.,Motokura T.,Bloom T.,Kronenburg,Ruderman J.,JuppnerH.,Kim H.G.]。
定序后,使用标准技术将PCR产物克隆到昆虫表达载体pVL1393(得自Invitrogen 1995编入目录号:V1392-20)。然后将PCR产物双重表达[使用标准病毒Baculogold共感染技术]到昆虫SF21细胞系统(Spodoptera Frugiperda细胞,得自Fall Army Worm的卵巢细胞—可商购获得)内。
下列实施例提供了在SF21细胞中(在TC100+10%FBS(TCS)+0.2%Pluronic)(对于每个细胞周期蛋白D1 & CDK4的病毒,具有双重感染MOI 3)制备细胞周期蛋白D1/CDK4的详细描述。
制备细胞周期蛋白CD1/CDK4的实施例
使用在滚式瓶培养物中生长至2.33×106个细胞/ml的SF21细胞以0.2×10E6个细胞/ml接种到滚式瓶中。将滚式瓶在滚柱装置上于28℃培养。
3天(72小时)后,得自2个瓶的平均值为1.86×10E6个细胞/ml(99%存活)。然后用双重病毒以MOI 3/每个病毒感染培养物。
感染10×500ml,JS303细胞周期蛋白D1病毒效价-9×10E7pfu/ml。JS304 CDK4病毒效价-1×10E8 pfu/ml。
细胞周期蛋白D1对于每个500ml瓶,1.86×10E6×500×3/0.9×108=31ml病毒。
CDK4对于每个500ml瓶,1.86×10E6×500×3/1×108=31ml病毒。
在加入培养物之前,将病毒混合在一起,并将培养物再置于滚柱装置上于28℃培养。
转染3天(72小时)后,收获5升培养物。收获物中的总细胞数目为1.58×10E6个细胞/ml(99%存活)。将细胞以250ml批量在Heraeus Omnifuge 2.0RS中以2500rpm于4℃旋转30分钟。弃去上清液,将20个沉降团(~4×10E8个细胞/沉降团)在液氮中迅速冷冻,并在CCRF冷室中于-80℃贮存。然后通过重悬在裂解缓冲液(50mMHEPES pH7.5,10mM氯化镁,1mM DTT,10mM甘油磷酸盐,0.1mM PMSF,0.1mM氟化钠,0.1mM原钒酸钠,5ug/ml抑肽酶,5ug/ml亮抑蛋白酶肽和20%w/v蔗糖)中、并加入冰冷的去离子水将SF21细胞进行低渗裂解。离心后,将上清液负载到Poros HQ/M 1.4/100阴离子交换柱(PE Biosystems,Hertford,UK)上。将CDK4和细胞周期蛋白D1用375mM NaCl在裂解缓冲液中的溶液共洗脱下来,通过蛋白质印迹法,使用合适的抗-CDK4和抗-细胞周期蛋白D1抗体(得自Santa CruzBiotechnology,California,US)检查其其存在。
p16对照(Nature 366.:704-707:1993:Serrano M.Hannon GJ.Beach
D)
将p16(CDK4/细胞周期蛋白D1的天然抑制剂)从HeLa cDNA(得自ATCC CCL2的Hela细胞,得自子宫颈的人上皮癌;Cancer Res.12:264,1952)中扩增,克隆到具有5′His尾的pTB 375 NBSE中,并用标准技术转化到BL21(DE3)pLysS细胞(得自Promega;Ref.Studier F.W.和Moffat B.A.,J.Mol.Biol.,189,113,1986)中。将1升培养物生长至适当OD,然后用IPTG诱导以过夜表达p16。然后通过在50mM磷酸钠,0.5M氯化钠,PMSF,0.5μg/ml亮抑蛋白酶肽和0.5μg/ml抑肽酶中超声来裂解细胞。将该混合物旋转,把上清液加到镍蝥合物珠子中,并混合1.5小时。将珠子在磷酸钠,NaCl pH6.0中洗涤,并将p16产物洗脱到具有200mM咪唑的磷酸钠,NaCl pH7.4。
按照下列方法用pTB375 NBPE构建pTB NBSE:-
pTB375
用于生成pTB375的背底载体是pZEN0042(参见UK专利2253852),并在pAT153衍生背底中含有得自质粒RP4的tetA/tetR诱导四环素抗性序列和得自质粒pKS492的cer稳定性序列。通过加入由T7基因10启动子、多克隆位点和T7基因10终止序列构成的表达试剂盒来生成pTB375。此外,设计用来减少从背底载体的转录读取的终止子序列包括在表达试剂盒的上游。
pTB375 NBPE
除去存在于pTB375中的独特的EcoRI限制位点。将含有关于限制酶NdeI、BamHI、PstI和EcoRI的识别序列的新的多克隆位点引入到pTB375内,其中是引入到位于破坏存在于pTB375中的初始BamHI位点的NdeI和BamHI位点之间。
pTB375 NBSE
将含有关于限制酶NdeI、BamHI、SmaI和EcoRI的识别序列的新的多克隆位点引入到pTB375 NBPE内NdeI和EcoRI位点之间。含有这些限制位点的低聚核苷酸在与存在于NdeI位点内的起始密码子(ATG)相同的阅读框架中还含有6个位于NdeI和BamHI之间的6个组氨酸密码子。
按照类似于上述的方法,可构建设计用来评价CDK2和CDK6抑制的测定。CDK2(EMBL登记号X62071)可以与细胞周期蛋白A或细胞周期蛋白E(见EMBL登记号M73812)一起使用,关于这些测定的进一步详细描述公开于PCT国际出版物WO99/21845,该文献的有关生物化学&生物学评价章节引入本发明以作参考。
如果使用具有细胞周期蛋白E部分的CDK2,可如下所述进行共纯化:将Sf21细胞重悬在裂解缓冲液(50mM Tris pH8.2,10mM MgCl2,1mM DTT,10mM甘油磷酸盐,0.1mM原钒酸钠,0.1mM NaF,1mM PMSF,1ug/ml亮抑蛋白酶肽和1ug/ml抑肽酶)中,并在10ml Dounce均化器中均化2分钟。离心后,将上清液负载到Poros HQ/M 1.4/100阴离子交换柱(PE Biosystems,Hertford,UK)上。在0-1M NaCl梯度(在没有蛋白酶抑制剂的裂解缓冲液中)将CDK2和细胞周期蛋白E共洗脱下来,洗脱20个柱体积。通过使用抗-CDK2和抗-细胞周期蛋白E抗体的蛋白质印迹法(Santa Cruz Biotechnology,California,US)来检查共洗脱。
FAK3激酶抑制测定
该测定法确定了测试化合物抑制人粘着斑激酶(FAK)活性的能力。
编码FAK的DNA是通过基因全合成获得的(Edwards M,International
Biotechnology Lab 5(3),19-25,1987)或者通过克隆获得的。然后在合适的表达系统中表达这些基因以获得具有酪氨酸激酶活性的多肽。例如,经发现,通过在昆虫细胞中表达重组蛋白而获得的FAK表现出内在的酪氨酸激酶活性。
将FAK(Andre等人描述的全长人cDNA(Biochemical andBiophysical Research Communications,1993,190(1):140-147;EMBL/GenBank登记号L05186))修饰,这样当翻译时,所得蛋白在紧挨着起始蛋氨酸的前面具有一个6-组氨酸尾。之前已经在使用类似的N-末端6-组氨酸tag的杆状病毒系统(Protein Expression AndPurification,1996,7:12-18)中表达了活性FAK蛋白。将人FAKcDNA克隆到杆状病毒置换型载体pFastbac 1(Life Technologies)内,将重组构建物与病毒RNA共转染到昆虫细胞(例如Spodopterafrugiperda 21(Sf21))中以制备重组杆状病毒(关于装配重组DNA分子的方法以及重组杆状病毒的制备和应用的详细描述可参见标准教科书例如Sambrook等人,1989,Molecular cloning-A LaboratoryManual,第2版,Cold Spring Harbour Laboratory Press和O′Reilly等人,1992,Baculovirus Expression Vectors-ALaboratory Manual,W.H.Freeman和Co,New York.pFastbac(′Bacto Bac′)系统的应用的专门详细描述参见Anderson等人,1995,FOCUS(Life Technologies Bulletin Magazine),17,p53)。
为了表达生物活性人FAK蛋白,用噬斑纯FAK重组病毒在感染复数3将Sf21细胞感染,48小时后收获。将收获的细胞用冰冷的磷酸盐缓冲盐水溶液(PBS)(10mM磷酸钠pH7.4,138mM氯化钠,2.7mM氯化钾)洗涤,然后重悬在冰冷的裂解缓冲液(50mM HEPES pH7.5,1mM二硫苏糖醇,100uM氟化钠,100uM原钒酸钠,10mM甘油磷酸盐,100uM苯基甲基磺酰氟(PMSF),5ug/ml抑肽酶,5ug/ml亮抑蛋白酶肽,1%吐温;PMSF是在临用前从新制备的100mM甲醇溶液中加入的),每一亿个细胞使用250μl裂解缓冲液。然后将悬浮液在冰上培养15分钟,并以13,000rpm于4℃离心10分钟。取出上清液(酶贮备物),分成等分试样,迅速在液氮中冷却,然后在-70℃贮存。对于典型的一批,用酶稀释液(100mM HEPES pH7.4,0.2mM二硫苏糖醇,200uM原钒酸钠,0.1%Triton X-100)将酶贮备物进行250倍的稀释,对于每个测定孔,使用50ml新稀释的酶(参见下文中的FAK3方案)。
FAK3:体外酶测定方案
由含有酪氨酸的无规共聚物例如聚(Glu,Ala,Tyr)6∶3∶1(Sigma P3899)制备底物贮备液,作为在PBS中的1mg/ml贮备液于-20℃贮存,并用PBS稀释500倍以用于铺平板。
在测定的前一天,将100μl稀释的底物溶液加到测定板(Maxisorp96孔免疫板Life technologies,Cat.No.439454A)的所有孔中,并平板密封器密封,并在4℃放置过夜。
在测定的当天,弃去底物溶液,将测定板用200μl PBST(含有0.05%v/v吐温20的PBS)洗涤一次,用200μl 50mM Hepes pH7.4洗涤一次。
将测试化合物在DMSO中制成10mM或30mM贮备液,然后在玻璃蒸馏水中进一步稀释至比最终的测定浓度高10倍的浓度。将10μl稀释的化合物转移到洗涤过的测定板的孔中。“无化合物”对照孔含有10μl玻璃蒸馏水以代替化合物。
将40微升含有6.25M腺苷-5′-三磷酸(ATP)的25mM氯化锰加到所有测试孔中。为了开始反应,将50μl新稀释的酶加到每个孔中,并将平板在23℃培养90分钟。然后通过加入含有20mM EDTA的100μl PBS来终止反应。弃去液体,并用PBST将孔洗涤2次。
将100微升在含有0.5%w/v胎牛血清白蛋白(BSA)的PBST中稀释1500倍的鼠HRP-连接的抗磷酸酪氨酸抗体(Santa Cruz,Product SC7020-HRP)加到每个孔中,将平板在室温培养1小时,然后弃去液体,并用200μl PBST将孔洗涤2次。向每个孔中加入100微升2,2′-连氮基-二(3-乙基苯并噻唑啉-6-磺酸)(ABTS)溶液,该溶液是用一个50mgABTS片(Boehringer 1204 521)在50ml新制备的50mM磷酸盐-柠檬酸盐缓冲液pH5.0+0.03%过硼酸钠(每100ml蒸馏水使用具有过硼酸钠(PCSB)胶囊(Sigma P4922)的1磷酸盐-柠檬酸盐缓冲液)新制备的。然后将平板在室温培养20-60分钟,直至使用平板读数分光光度计在405nm测定的“无化合物”对照孔的吸收度值大约为1.0。
使用Origin Software由吸收度读数生成剂量反应曲线。使用通过Origin Software分析确定的抑制浓度50(IC50)将化合物分级。
虽然式(I)化合物的药理性质随着结构的改变而变化,但是在上述测定中,可在250μM-1nM的IC50浓度或剂量证实式(I)化合物所具有的一般活性。
当在上述体外测定中测试时,所测定的实施例31的CDK4抑制活性为IC50=0.679μM。当在上述体外测定中测试时,所测定的实施例25的FAK抑制活性为lC50=0.218μM。
本发明化合物的体内活性可通过标准技术来评价,例如通过测定抑制细胞生长和评价细胞毒害作用来评价。例如,进一步的详细描述可参见下列参考文献:
a)在肿瘤细胞中减弱粘着斑激酶的表达会诱导细胞程序死亡.XuL-h等人.Cell Growth & Differentiation(1996)7,p413-418;
b)在人肿瘤细胞中粘着斑激酶的COOH-末端域引起粘着损失和细胞死亡.Xu L-h等人.Cell Growth & Differentiation(1998)9,p999-1005;
c)在培养的成纤维细胞中抑制pp125-FAK导致细胞程序死亡.Hungerford J.E等人.The Journal of Cell Biology(1996)135,p1383-1390;
d)抑制粘着斑中的粘着斑激酶(FAK)信号传导降低细胞能动性和增殖.Gilmore A.P和Romer L.H.Molecular Biology of the Cell(1996)7,p1209-1224。
细胞生长抑制可通过用Sulforhodamine B(SRB)将细胞染色来测定,SRB是一种荧光染料,其将蛋白染色,并因此给出孔中蛋白(即细胞)的估计量(参见Boyd,M.R.(1989)NCI临床前抗肿瘤药物开发筛选的状况.Prin.Prac Oncol 10:1-12)。因此,提供关于测定细胞生长抑制的下列详细描述:-
在96孔平板中,将细胞以100μl的体积铺在适当培养基中;培养基是用于MCF-7、SK-UT-1B和SK-UT-1的Dulbecco′s改性的Eagle培养基。将细胞过夜附着,然后将抑制剂化合物以最大浓度为1%DMSO(v/v)的不同浓度加入。测定对照平板以得到用药前的细胞的值。将细胞在37℃(5%CO2)培养3天。
在3天结束时,将TCA以16%(v/v)的终浓度加到平板中。然后将平板在4℃培养1小时,取出上清液,用自来水洗涤平板。干燥后,加入100μl SRB染料(0.4%SRB在1%乙酸中的溶液),在37℃培养30分钟。取出过量SRB,用1%乙酸洗涤平板。将与蛋白结合的SRB溶解在10mM Tris pH7.5中,并在室温振摇30分钟。在540nm读取OD,从抑制剂浓度对吸收度的半对数曲线确定出引起50%抑制的抑制剂浓度。将光密度降至低于当在开始实验时铺细胞所获得的光密度的化合物的浓度给出毒性的值。
当在SRB测定中测试时,本发明化合物的一般IC50值为1mM-1nM。
依据本发明的另一方面,本发明提供了包含如上所定义的式(I)嘧啶衍生物或其可药用盐或在体内可水解的酯和可药用稀释剂或载体的药物组合物。
本发明组合物可呈口服给药的形式,例如呈片剂或胶囊形式,适于非胃肠道注射(包括静脉内、皮下、肌内、血管内注射或输注)的形式,例如呈无菌溶液、悬浮液或乳液的形式,适于局部给药的形式,例如呈膏剂或霜剂的形式,或适于直肠给药的形式,例如呈栓剂形式。
上述组合物一般可用常用赋形剂以常规方式制得。
本发明嘧啶化合物通常以5-5000mg/平方米身体面积,即约0.1-100mg/kg的单位剂量施用给温血动物,并且这通常提供了治疗有效剂量。单位剂型例如片剂或胶囊通常含有例如1-250mg活性组分。优选使用1-50mg/kg的日剂量。然而,日剂量必须根据所治疗的宿主、特定的给药途径、和所治疗的疾病的严重程度而改变。因此,最佳剂量可由治疗任何特定患者的医师决定。
依据本发明另一方面,本发明提供了用于预防或治疗温血动物例如人的方法中的如上所定义的式(I)嘧啶衍生物或其可药用盐或在体内可水解的酯。
我们已经发现,本发明嘧啶衍生物或其可药用盐或在体内可水解的酯是有效的细胞周期抑制剂(抗细胞增殖剂),据信该特征(不想受缚于理论)是由于其CDK抑制性质所致。本发明化合物还是FAK的有效抑制剂。因此,预计本发明化合物可用于治疗仅由或部分由CDK和/或FAK酶介导的疾病或病症,即本发明化合物可用于在需要这样的治疗的温血动物中产生CDK和/或FAK抑制作用。因此,本发明化合物提供了通过抑制CDK和/或FAK酶来治疗恶性细胞增殖和/或迁移的方法,即化合物可用于产生仅由或部分由CDK和/或FAK抑制介导的抗增殖/迁移作用。通过诱导细胞死亡(细胞程序死亡),本发明化合物还可用作FAK抑制剂。预计本发明嘧啶衍生物具有宽范围的抗癌性质,这是因为CDK和/或FAK涉及多种常见的人癌症例如白血病和乳腺癌、肺癌、结肠癌、直肠癌、胃癌、前列腺癌、膀胱癌、胰腺癌和卵巢癌。因此,预计本发明嘧啶衍生物具有抗这些癌的抗癌活性。此外还预计本发明嘧啶衍生物具有抗一系列白血病、淋巴恶性肿瘤和实体瘤例如组织中例如肝脏、肾、前列腺和胰腺中的癌和肉瘤。特别是,预计本发明化合物能有利地减慢原发性或复发性实体瘤例如结肠、乳腺、前列腺、肺和皮肤肿瘤的生长。更特别地,依据本发明化合物或其可药用盐或在体内可水解的酯能抑制与CDK和/或FAK有关的这些原发性和复发性肿瘤的生长,尤其是其生长和扩散显著依赖于CDK和/或FAK的肿瘤,包括例如一些结肠、乳腺、肺、外阴和皮肤的肿瘤。
还预计,本发明嘧啶衍生物具有抗广泛的其它病症中的其它细胞增殖/迁移疾病的活性,这些其它病症包括白血病、纤维增殖和分化病症、牛皮癣、类风湿性关节炎、Kaposi′s肉瘤、血管瘤病(haemangioma)、急性和慢性肾病、粉瘤、动脉粥样硬化、动脉再狭窄、自身免疫性疾病、急性和慢性炎症、骨疾病和具有视网膜血管增殖的眼疾病。
因此,依据本发明的该方面,本发明提供了用作药物的如上所定义的式(I)嘧啶衍生物或其可药用盐或在体内可水解的酯;和如上所定义的式(I)嘧啶衍生物或其可药用盐或在体内可水解的酯在制备用于在温血动物例如人中产生抗癌、细胞周期抑制(抗细胞增殖)作用和/或FAK抑制(抗细胞迁移和/或细胞程序死亡诱导)作用的药物中的应用。特别是,通过抑制CDK2、CDK4和/或CDK6,尤其是CDK4和CDK6而在S或G1-S期产生细胞循环抑制作用。
依据本发明另一方面,本发明提供了在需要这样的治疗的温血动物例如人中产生抗癌、细胞周期抑制(抗细胞增殖)作用和/或FAK抑制(抗细胞迁移和/或细胞程序死亡诱导)作用的方法,包括给所述动物施用有效量的如上所定义的嘧啶衍生物。特别是,抑制作用是通过抑制CDK2、CDK4和/或CDK6,尤其是CDK4和CDK6而在S或G1-S期产生的。
预防或治疗特定细胞增殖疾病所需的上述剂量必须根据所治疗的宿主、给药途径和所治疗的疾病的严重程度而改变。可采用例如1-100mg/kg、优选1-50mg/kg的单位剂量。
上文所定义的CDK和/或FAK抑制活性可作为单独的治疗应用,或者除了本发明化合物以外,还包括一种或多种其它物质和/或治疗。这样的联合治疗可通过同时、依次或分别单独施用各组分来实现。在肿瘤医疗领域,联合使用不同形式的治疗来治疗各癌症患者是标准惯例。在肿瘤医疗领域,除了上文定义的细胞周期抑制治疗以外,这样的联合治疗的其它组分可以是:手术、放疗或化疗。这样的化疗可使用下列3类主要的治疗剂:
(i)通过与上文限定的机制相同或不同的机制起作用的其它细胞周期抑制剂;
(ii)细胞抑制剂例如抗雌激素(例如他莫昔芬、托米芬、雷洛昔芬、屈洛昔芬、iodoxyfene)、孕激素(例如乙酸甲地孕酮)、芳香酶抑制剂(例如anastrozole、来曲唑、伏氯唑、依西美)、抗孕激素、抗雄激素(例如氟他胺、尼鲁米特、比卡鲁胺、乙酸环丙孕酮)、LHRH激动剂和拮抗剂(例如乙酸性瑞林、luprolide)、睾酮5α-二氢还原酶抑制剂(例如芬甾酮)、抗侵袭剂(例如金属蛋白酶抑制剂如marimastat和尿激酶纤溶酶原激活剂受体功能抑制剂)以及生长因子功能抑制剂(这样的生长因子包括例如血小板衍生生长因子和肝细胞生长因子,这样的抑制剂包括生长因子抗体、生长因子受体抗体、酪氨酸激酶抑制剂和丝氨酸/苏氨酸激酶抑制剂);和
(iii)肿瘤治疗中使用的抗增殖/抗肿瘤药物及其组合例如抗代谢物(例如抗叶酸剂如甲氨蝶呤、氟代嘧啶例如5-氟尿嘧啶、嘌呤和腺苷类似物、阿糖胞苷);抗肿瘤抗体(例如蒽环例如阿霉素、柔红霉素、表阿霉素和去甲氧柔红霉素,丝裂霉素-C、更生霉素、光辉霉素);铂衍生物(例如顺铂、卡铂);烷化剂(例如氮芥、美法仑、苯丁酸氮芥、白消安、环磷酰胺、异环磷酰胺、亚硝脲、噻替派);抗有丝分裂剂(例如长春花生物碱例如长春新碱和taxoids例如紫杉醇、taxotere);拓扑异构酶抑制剂(例如表鬼臼毒素如依托泊苷和替尼泊苷、安吖啶、托泊替堪)。依据本发明的该方面,本发明提供了包含如上所定义的式(I)嘧啶衍生物或其可药用盐或在体内可水解的酯和如上所定义的用于癌症联合治疗的其它抗肿瘤物质的药物。还可以施用抗吐剂,例如当施用如上所述的联合治疗时施用抗吐剂。
除了治疗应用,式(I)化合物及其可药用盐还可用作开发和标准化体外和体内测试系统的药理工具,这样的测试系统是为了在实验动物例如猫、狗、兔子、猴子、大鼠和小鼠中评价细胞周期活性抑制剂的作用,这是开发新的治疗剂的一部分。
在上述其它药物组合物、加工、方法、应用以及药物制备特征中,也可以使用本文所述的本发明化合物的其它且优选的实施方案。
用下列非限制性实施例举例说明本发明,其中在适当时可使用化学技术人员已知的标准技术和类似于这些实施例中描述的技术,并且除非另有说明,否则:
(i)蒸发是通过在真空下旋转蒸发进行的,并且后处理操作是在通过过滤除去残余固体例如干燥剂后进行的;
(ii)除非另有说明,否则操作是在室温、一般是18-25℃在空气中进行的,或者本领域技术人员可在惰性气氛下例如氩气氛下进行的;
(iii)柱色谱(快速操作)和中等压力液相色谱(MPLC)是在得自E.Merck,Darmstadt,Germany的Merck Kieselgel二氧化硅(Art.9385)或Merck Lichroprep RP-18(Art.9303)反相二氧化硅上进行的;结合洗脱色谱是用得自Varian Sample Preparation Products,California,USA的Varian Mega Bond Elut柱(10g,指令码1225-6034)进行的;
(iv)给出产率仅是为了举例说明,并且不一定是可达到的最大产率;
(v)式(I)终产物的结构一般是通过核(一般是质子)磁共振(NMR)和质谱技术证实的;质子磁共振化学位移值是在氘化DMSOd6(除非另有说明)中以δ标度(距离四甲基甲硅烷的ppm低场)使用在300MHz场强度操作的Varian Gemini 2000或在250MHz场强度操作的BrukerAM250光谱计测定的;峰多重性如下所示:s,单峰;d,双峰;dd,双双峰;t,三重峰;tt,三三重峰;q,四重峰;tq,三四重峰;m,多重峰;br,宽的;质谱(MS)是通过电喷雾在VG平台上进行的;
(vi)除非在本文中具体给出进一步的详细说明,分析高效液相色谱(HPLC)是在Waters Spherisorb ODS1 25cm柱上进行的,流速为2ml/分钟,使用乙腈/水/三氟乙酸(60∶40∶0.1v/v)作为洗脱剂,在254nm波长检测,数据作为以分钟为单位的保留时间(RT)给出;
(vii)机器人合成是使用Zymate XP机器人进行的,其中溶液加入是经由Zymate Master Laboratory Station进行的,搅拌是经由Stem RS5000 Reacto-Station于25℃进行的;
(viii)得自机器人合成的反应混合物的后处理和纯化是如下所述进行的:蒸发是在真空下使用Savant AES 2000进行的;柱色谱是用Anachem Sympur MPLC或Jones Flashmaster MPLC系统在使用VarianMega Bond Elut柱的二氧化硅上进行的;终产物的结构是通过LCMS在使用下列的Micromass OpenLynx系统上证实的,并且作为以分钟为单位的保留时间(RT)给出;
柱: 4.6mm×10cm Hichrom RPB 100(系统A)
2.1mm×3cm Waters Symmetry C18 3.5μm(系统B)
溶剂: I=水+0.1%甲酸,
II=乙腈+0.1%甲酸
运行时间: 10分钟,其中6分钟5-95%II(系统A)的梯度
5分钟,其中4.5分钟5-95%II(系统B)的梯度
波长: 254nm,带宽10nm
质量检测器:平台LC
(ix)中间体的特征没有完全确定,并且纯度是通过薄层色谱(TLC)、HPLC、红外(IR)、MS或NMR分析评价的;
(x)当干燥溶液时,干燥剂是硫酸镁;
(xi)可在上下文中使用下列缩写:
DCM 二氯甲烷;
DMF N,N-二甲基甲酰胺;
DMSO 二甲亚砜;
NMP N-甲基吡咯烷-2-酮;
THF 四氢呋喃。
实施例1
4-苯氨基-5-溴-2-[4-(4-甲基哌嗪子基)苯氨基]嘧啶
将4-(4-甲基哌嗪子基)苯胺盐酸盐(按照在J.Med.Chem.1993,36,2716-25中描述的方法制得的;156mg,0.56mmol)在甲醇(1ml)中的溶液加到4-苯氨基-5-溴-2-氯嘧啶(方法1,250mg,0.90mmol)在正丁醇(2ml)内的溶液中。将该混合物在100℃加热5小时,收集不溶性固体,并用正丁醇(5ml)和乙醚(5ml)洗涤,获得了产物,为盐酸盐(50mg,14%)。
NMR:2.2(s,3H),2.4(m,4H),3.0(m,4H),6.8(m,2H),7.1(m,1H),7.3-7.5(m,4H),7.7(m,2H),8.2(s,1H),8.4(s,1H),9.0(s,1H);MS(MH+):438.9,440.9.
实施例2-6
下列化合物是通过类似于实施例1中描述的方法,由4-苯氨基-5-溴-2-氯嘧啶(方法1)和合适的苯胺盐酸盐(按照J.Med.Chem.,1993,36,2716-25;Eur.Pat.Appl.EP 487252;Eur.Pat.Appl.EP401358;J.Med.Chem.,1972,15,523-9;J.Med.Chem.,1985,28,1427中描述的方法制得的)制得的:
Ex | R | NMR | MS(MH+) |
21 | 二甲基氨基 | 2.19(s,6H),2.57(t,2H),3.96(t,2H),6.75(d,2H),7.11(t,1H),7.33 dd,2H),7.45(d,2H),7.60(d,2H),8.16(s,1H),8.46(s,1H),9.09(s,1H) | 428.3,430.3 |
31,2 | 邻苯二甲酰亚氨基 | 529.9,531.9 | |
43 | 吗啉代 | 3.1-3.25(m,2H),3.4-3.55(m,4H),3.8-4.0(m,4H),4.39(t,2H),6.85(d,2H),7.21(t,1H),7.35-7.45(m,4H),7.54(d,2H),8.31(s,1H),9.36(brs,1H),10.03(br s,1H) | 470,471.9 |
54 | 4-甲基哌嗪子基 | 2.81(s,3H),3.4-3.8(m,10H),4.38(t,2H),6.87(d,2H),7.23(t,1H),7.39(d,2H),7.41(dd,2H),7.55(d,2H),8.32(s,1H),9.38(br.s,1H),10.05(br s,1H) | 482.9,484.9 |
61 | 咪唑-1-基 | 4.18(t,2H),4.31(t,2H),6.72(d,2H),6.89(d,1H),7.12(t,1H),7.21(d,1H),7.33(dd,2H),7.45(d,2H),7.60(d,2H),7.66(s,1H),8.15(s,1H),8.47(s,1H),9.11(s,1H) | 450.8,452.8 |
1产物是作为游离碱通过结合洗脱色谱分离出来的,用0-4%2.0M氨甲醇溶液在DCM中的溶液洗脱
2HPLC(RT):6.33
3反应是在1.0M氯化氢乙醚溶液(2当量)中进行的,并且产物是作为二盐酸盐分离出来的
4反应是在1.0M氯化氢乙醚溶液(2当量)中进行的,并且产物是作为三盐酸盐分离出来的
实施例7-9
下列化合物是通过类似于实施例1中描述的方法,由合适的4-苯氨基-2-氯-5-卤代嘧啶(方法2-3,或者按照在PCT Int.Appl.WO 9719065中描述的方法制得的)和合适的苯胺盐酸盐(按照在Eur.Pa t.Appl.EP401358;J.Med.Chem.,1985,28,1427;Ger.Offen.DE 2315791中描述的方法制得的)制得的,并且产物是作为游离碱通过结合洗脱色谱分离出来的,用0-4%2.0M氨甲醇溶液在DCM中的溶液洗脱。
Ex | R1 | R2 | R3 | NMR | MS(MH+) |
7 | Cl | 2-CN | 吗啉代 | 2.44(t,4H),2.62(t,2H),3.57(t,4H),3.98(t,2H),6.63(d,2H),7.29(d,2H),7.44(t,1H),7.63(d,1H),7.75(dt,1H),7.89(d,1H),8.14(s,1H),9.13(s,1H),9.20(s,1H) | 451,453 |
8 | Br | 4-OMe | 咪唑-1-基 | 3.77(s,3H),4.15(t,2H),4.30(t,2H),6.70(d,2H),6.88(d,1H),6.91(d,2H),7.22(d,1H),7.4-7.45(m,4H),7.66(s,1H),8.10(s,1H),8.46(s,1H),9.08(s,1H) | 481.4,483.4 |
9 | H | H | 吡咯烷-1-基 | 1.85-1.95(m,2H),2.0-2.1(m,2H),3.1-3.2(m,2H),3.65-3.8(m,4H),4.3(t,2H),6.4(d,1H),7.05(d,2H),7.15-7.25(m,1H),7.3-7.4(m,2H),7.4-7.5(d,2H),7.6-7.7(m,2H),7.95(d,1H | 376 |
实施例10-12
下列化合物是通过类似于实施例1中描述的方法,由4-苯氨基-5-溴-2-氯嘧啶(方法1)和合适的苯胺盐酸盐(商购获得或者按照在Bioorg.Med.Chem.Lett.,1997,7,1921-1926;J.Med.Chem.,1984,27,967-78中描述的方法制得的)制得的,并且产物是作为游离碱通过结合洗脱色谱分离出来的,用0-4%2.0M氨甲醇溶液在DCM中的溶液洗脱。
Ex | R | NMR | MS(MH+) |
10 | 4(2,5-二氧代吡咯烷-1-基甲基) | 2.64(s,4H),4.64(s,2H),7.03(d,2H),7.2(t,1H),7.4(m,4H),7.55(d,2H),8.3(s,1H),9.2(br s,1H),9.82(bs,1H) | 452,454 |
111 | 3-二甲基氨基 | 384.0,386.0 | |
12 | 4-羧基甲氧基 | 4.6(s,2H),6.8(d,2H),7.2(t,1H),7.4(m,4H),7.6(m,2H),8.3(s,1H) | 414.8,416.8 |
1HPLC(RT):5.73
实施例13
4-苯氨基-5-溴-2-[4-(氨基甲基)苯氨基]嘧啶
将4-氨基苄基胺(122mg,1.0mmol)和氯化氢乙醚溶液(1.0M;1.0ml,1.0mmol)加到4-苯氨基-5-溴-2-氯嘧啶(256mg,0.9mmol)在正丁醇(4ml)内的溶液中,并将该混合物在100℃加热16小时。过滤出不溶性固体,并溶解在甲醇(5ml)中。加入二氧化硅(2g),通过蒸发除去挥发性材料。通过结合洗脱色谱纯化残余物,用0-4%2.0M氨甲醇溶液在DCM中的溶液洗脱,获得了产物(163mg,49%):LCMS(MH+):370,372;HPLC(RT,系统A):2.04。
实施例14-15
下列化合物是用Zymate XP机器人,通过类似于实施例13中描述的方法,由4-苯氨基-5-溴-2-氯嘧啶(方法1)和合适的苯胺制得的:
Ex | R | LCMS(MH+) | HPLC(RT)1 |
14 | 2-(二乙基氨基)乙氧基羰基 | 484,486 | 2.26 |
15 | 2-氨基乙基 | 384,386 | 5.78 |
1System B
实施例16-17
下列化合物是按照类似于实施例1中描述的方法,由4-苯氨基-5-溴-2-氯嘧啶(方法1)和合适的苯胺盐酸盐(按照J.Med.Chem.,1971,14,836-42;PCT Int.Appl.WO 9921846中描述的方法制得的)制得的,并且产物是作为游离碱通过结合洗脱色谱分离出来的,用0-4%2.0M氨甲醇溶液在DCM中的溶液洗脱。
Ex | R | NMR | MS(MH+) |
16 | 二乙基氨基 | 0.94(t,6H),2.51(q,4H),2.70(t,2H),3.85(t,2H),6.45(dd,1H),7.01(dd,1H),7.11(t,1H),7.18(d,1H),7.21(s,1H),7.34(dd,2H),7.62(d,2H),8.20(s,1H),8.51(s,1H),9.22(s,1H). | 456.4,458.4 |
17 | 吗啉代 | 2.4(m,4H),2.6(m,2H),3.6(m,4H),3.9(m,2H),6.5(m,1H),7.0-7.4(m,6H),7.6(m,2H),8.2(s,1H),8.5(s,1H),9.2(m,1H) | 470.2,472.2 |
实施例18-19
下列化合物是按照类似于实施例1中描述的方法,由合适的4-苯氨基-5-溴-2-氯嘧啶(方法1,4)和4-(4-异丙基哌嗪子基)甲氧羰基苯胺盐酸盐(方法13)制得的,并且产物是作为游离碱通过结合洗脱色谱分离出来的,用0-4%2.0M氨甲醇溶液在DCM中的溶液洗脱。
Ex | R | NMR | MS(MH+) |
18 | H | 1.2(d,6H),3.6-4.1(m,8H),4.4(m,1H),4.8(s,2H),6.8(d,2H),7.2(m,1H),7.4(m,4H),7.6(d,2H),8.2(s,1H),9.2(br s,1H),9.4(brs,1H) | 525.2,526.9 |
19 | F | 1.2(d,6H),2.8-3.1(m,2H),3.4(m,2H),3.6-4.0(m,2H),4.4(m,2H),4.8(s,2H),6.8(d,2H),7.2(m,2H),7.3(m,2H),7.5(m,2H),8.3(s,1H),9.4(br s,1H) | 543.4,545.3 |
实施例20-23
下列化合物是按照类似于实施例13中描述的方法,由4-苯氨基-5-溴-2-氯嘧啶(方法1)和合适的苯胺(方法15-17)制得的:
Ex | R | NMR | MS(MH+) |
201 | 哌啶-4-基 | 1.4(m,2H),1.9(m,2H),2.56(m,2H),2.95(m,2H),4.25(m,1H),6.76(d,2H),7.1(t,1H),7.35(t,2H),7.4(d,2H),7.6(d,2H),8.15(s,1H),8.45(s,1H),9.05(s,1H) | 440,442 |
21 | 1-甲基哌啶-4-基 | 1.5-1.7(m,2H),1.8-1.95(m,2H),2.15-2.3(m,5H),2.6-2.8(m,2H),6.75(d,2H),7.1(t,1H),7.3(dd,2H),7.45(d,2H),8.15(s,1H),8.5(s,1H),9.1(s,1H) | 454.3,456.3 |
22 | (1-甲基哌啶-2-基)甲基 | 1.2-1.6(m,4H),1.6-1.8(m,2H),2.0(m,1H),2.1-2.2(m,1H),2.2(s,3H),2.7-2.8(m,1H),3.8(m,1H),4.0(m,1H),6.75(d,2H),7.1(t,1H),7.3(dd,2H),7.45(d,2H),7.6(d,2H),8.15(s,1H),8.45(s,1H),9.1(s,1H) | 468.3,470.3 |
232 | 1-甲基哌啶-3-基 | 454.3,456.3 |
1直接从4-4-苯氨基-5-溴-2-氯嘧啶与4-[1-(叔丁氧基羰基)哌啶-4-基]苯胺(按照PCT Int.Appl.WO 9952895中描述的方法制得的)的反应分离出来的
2HPLC(RT):3.50
实施例24
4-苯氨-5-溴-2-[3-(1-甲基哌啶-3-基)甲氧基苯氨基]嘧啶
将碳酸钾(160mg,1.2mmol)、4-苯氨基-5-溴-2-(3-羟基苯氨基)嘧啶(方法10,200mg,0.6mmol)和3-氯甲基-1甲基哌啶(按照Eur.J.Med.Chem.1994,29,967-73中描述的方法制得的;0.11ml,0.62mmol)在DMSO(2ml)中的混合物在100℃加热18小时。加入二氧化硅(1g),通过蒸发除去挥发性物质。将残余物负载到Varian Mega Bond Elut柱上,并用0-10%2.0M氨甲醇溶液洗脱,获得了产物,为棕色固体(40mg,15%)。
NMR:1.0(m,1H),1.4(m,1H),1.6(m,3H),1.8(m,2H),2.1(s,3H),2.6-2.8(m,2H),3.6(m,2H),6.4(d,1H),7.0-7.4(m,6H),7.6(m,2H),8.2(s,1H),8.5(s,1H),9.2(s,1H);MS(MH+):468.5,470.5.
实施例25-26
下列化合物是按照类似于实施例24中描述的方法,由4-苯氨基-5-溴-2-(4-羟基苯氨基)嘧啶(方法9)和合适的2-(二烷基氨基)乙基氯化物制得的:
Ex | R | MS(MH+) | HPLC(RT) |
25 | 二乙基氨基 | 455.9,457.9 | 5.72 |
26 | 吡咯烷-1-基 | 453.9,455.9 | 5.52 |
实施例27-30
下列化合物是按照类似于实施例1中描述的方法,由合适的4-取代的5-溴-2-氯嘧啶(方法1,5-7)和合适的苯胺盐酸盐(方法21-22)制得的,并且产物是作为游离碱通过结合洗脱色谱分离出来的,用0-4%2.0M氨甲醇溶液在DCM中的溶液洗脱。
Ex | X | R1 | R2 | R3 | MS(MH+) | HPLC(RT) |
27 | CH | Me | H | 哌啶子基 | 481.0,483.0 | 7.45 |
28 | N | Me | H | 哌啶子基 | 482.0,484.0 | 6.65 |
29 | CH | H | Br | i-PrNH | 518.9,520.9 | 3.03 |
30 | CH | H | H | i-PrNH | 441.0,443.0 | 4.48 |
实施例31
4-苯氨基-5-溴-2-[4-(2-羟基乙氧基)甲基苯氨基]嘧啶
将4-苯氨基-5-溴-2-氯嘧啶(方法1,2.0g,7.03mmol)溶解在正丁醇(40ml)和甲醇(10ml)中。加入4-氨基苄基醇(778mg,6.33mmol)和氯化氢乙醚溶液(1.0M;6.33ml,6.33mmol),并将该溶液在100℃加热20小时。通过蒸发除去挥发性物质,将残余物溶解在乙二醇(20ml)中。将该溶液在100℃加热6小时,通过蒸发除去挥发性物质。通过柱色谱纯化残余物,用含有0.5%氨水溶液的0-4%甲醇在DCM中的溶液洗脱,获得了产物,为白色固体(550mg,19%)。
NMR:3.40(t,2H),3.50(dt,2H),4.37(s,2H),4.57(t,1H),7.09(d,2H),7.10(s,1H),7.15(t,1H),7.36(dd,2H),7.54(d,2H),7.60(d,2H),8.09(s,1H),8.54(s,1H),9.29(s,1H);MS(MH+):415.2,417.2.
实施例32
4-苯氨基-5-溴-2-{4-[2-(二乙基氨基)乙氧基甲基苯氨基}嘧啶
在0℃将三乙胺(33ml,0.241mmol)和甲磺酰氯(19ml,0.241mmol)加到4-苯氨基-5-溴-2-[4-(2-羟基乙氧基)甲基苯氨基]嘧啶(实施例31;100mg,0.241mmol)在DCM(5ml)内的溶液中。将该溶液温热至室温,并静置1小时。加入二乙胺(2ml),并将该混合物在50℃加热3小时。通过蒸发除去溶剂,通过柱色谱纯化残余物,用含有0.5%氨水溶液的0-2%甲醇在DCM中的溶液洗脱,获得了产物,为乳白色固体(38mg,34%)。
NMR(CDCl3):1.03(t,6H),2.58(q,4H),2.69(t,2H),3.54(t,2H),4.48(s,2H),7.06(d,2H),7.17(t,1H),7.22(s,1H),7.26(s,1H),7.38(dd,2H),7.49(d,2H),7.58(d,2H),8.15(s,1H);MS(MH+):470.4,472.4.
实施例33-35
下列化合物是按照类似于实施例32中描述的方法,由4-苯氨基-5-溴-2-[4-(2-羟基乙氧基)甲基苯氨基]嘧啶(实施例31)和合适的胺制得的,并且产物是作为二盐酸盐或三盐酸盐分离出来的。
Ex | R | NMR | MS(MH+) |
331 | 吗啉代 | 3.0-3.2(m,2H),3.3-3.45(m,4H),3.75-3.85(m,4H),3.9-4.0(m,2H),4.42(s,2H),7.17(d,2H),7.23(t,1H),7.40(dd,2H),7.48(d,2H),7.55(d,2H),834(s,1H),9.30(s,1H),10.09(s,1H) | 484.2,486.2 |
341 | 吡咯烷-1-基 | 1.8-2.05(m,4H),2.95-3.1(m,2H),3.33(t,2H),3.4-3.55(m,2H),3.70(t,2H),4.45(s,2H),7.17(d,2H),7.23(t,1H),7.40(dd,2H),7.49(d,2H),7.56(d,2H), 8.35(s,1H),9.30(s,1H),10.08(s,1H) | 467.9,469.9 |
352 | 4-甲基哌嗪子基 | 2.80(s,3H),3.35-3.75(m,10H),3.80(t,2H),4.44(s,2H),7.18(d,2H),7.26(t,1H),7.40(dd,2H),7.49(d,2H),7.56(d,2H),8.34(s,1H),9.30(s,1H),10.09(s,1H) | 497.0,499.0 |
1作为二盐酸盐分离出来的
2作为三盐酸盐分离出来的
实施例36
4-苯氨基-5-溴-2-[4-(2-吡咯烷-1-基乙基)苯氨基]嘧啶
使用类似于实施例32中描述的方法,但是由4-苯氨基-5-溴-2-[4-(2-羟基乙基)苯氨基]嘧啶(方法11)和吡咯烷合成,获得了产物。
MS(MH+):438.1,440.1;HPLC(RT):5.64。
实施例37
4-苯氨基-[溴-2-[4-(3-二甲基氨基-1-丙炔基)苯氨基]嘧啶
将4-苯氨基-5-溴-2-(4-碘苯氨基)嘧啶(方法12;200mg,0.40mmol)、N,N-二甲基炔丙基胺(0.09ml,0.85mmol)和四(三苯基膦)钯(O)(25mg,0.02mmol)在吡咯烷(3ml)中的溶液搅拌60小时,然后在80℃加热2小时。将该混合物用DCM(10ml)稀释,并加入二氧化硅(2g)。通过蒸发除去挥发性材料,将残余物负载到Varian MegaBond Elut柱上。用0-10%2.0M氨甲醇溶液在DCM中的溶液洗脱,获得了产物(30mg,17%)。
NMR:2.2(s,6H),3.4(s,2H),7.2(m,3H),7.4(m,2H),7.6(m,4H),8.2(s,1H),8.6(s,1H),9.5(s,1H);MS(MH+):422.3,424.3.
实施例38-39
下列化合物是按照类似于实施例37中描述的方法,由4-苯氨基-5-溴-2-(4-碘苯氨基)嘧啶(方法12)和合适的炔烃(商购获得或者按照PCT Int.Appl.WO 9425459中描述的方法制得)制得的:
实施例40
4-苯氨基-5-溴-2-[4-(3-氨基-1-丙炔基)苯氨基]嘧啶
将三氟乙酸(0.25ml)加到4-苯氨基-5-溴-2-{4-[3-(叔丁氧基羰基氨基)-1-丙炔基]苯氨基}嘧啶(方法25;30mg,0.06mmol)在DCM(1ml)内的溶液中。将该溶液静置3小时,通过蒸发除去挥发性物质。用乙醚研制残余物,获得了产物,为三氟乙酸盐(25mg,81%)。
NMR:4.0(m,2H),7.2(m,2H),7.4(m,2H),7.5-7.7(m,4H),7.8(m,1H),8.2(br s,2H),8.7(s,1H),9.6(s,1H);MS(MH+):394.3,396.3.
实施例41
4-苯氨-5-溴-2-[4-(哌啶-4-基)甲氧基苯氨基]嘧啶
使用类似于实施例40中描述的方法,但是由4-苯氨基-5-溴-2-{4-[1-(叔丁氧基羰基)哌啶-4-基]甲氧基苯氨基}嘧啶(方法26)来开始,获得了产物。
NMR:1.4-1.6(m,2H),1.8-2.0(m,3H),2.8-3.0(m,2H),3.2-3.3(m,2H),3.8(d,2H),6.8(d,2H),7.25(t,1H),7.3-7.4(m,4H),7.55(d,2H),8.35(s,1H),8.6-9.0(br d,1H),9.0-9.2(br s,1H),9.5(br s,1H);MS(MH+):453.9,455.9.
制备原料:
用于上述实施例的原料是商购获得的,或者易于通过标准方法由已知物质制得。例如,下列反应举例说明但不是限制了上述反应中所用的某些原料。
方法1
4-苯氨基-5-溴-2-氯嘧啶
将5-溴-2,4-二氯嘧啶(6.84g,30.0mmol)、苯胺(2.79g,30.0mmol)和N,N-二异丙基乙基胺(3.87g,30.0mmol)在正丁醇(75ml)中的溶液加热回流4小时。通过蒸发除去挥发性物质,并将残余物溶解在DCM(100ml)中。将该溶液用水(3×100ml)和饱和盐水(100ml)洗涤,并干燥。通过蒸发除去挥发性物质,通过柱色谱纯化残余物,用15%乙酸乙酯/异己烷洗脱,获得了产物,为油状物,其在静置时会固化(5.12g,60%)。
NMR:7.1(t,1H),7.4(t,2H),7.55(d,2H),8.4(s,1H),9.2(br s,1H);MS(MH+):284,286,288.
方法2-7
下列中间体是通过类似于方法1中描述的方法,使用合适的取代的苯胺和5-溴-2,4-二氯嘧啶或2,4,5-三氯嘧啶(方法8)制得的:
方法 | X | R1 | R2 | R3 | MS(MH+) |
2 | C.CN | Cl | H | H | 265.1,267.1,269.1 |
3 | CH | Br | H | OMe | 314,316 |
41 | CH | Br | H | F | |
5 | CH | Br | Me | H | 298,300,302 |
6 | N | Br | Me | H | 299,301 |
7 | CH | Br | H | Br | 360.0,362.0,364.0,366.0(MH-) |
1NMR:7.22(m,2H),7.55(m,2H),8.42(s,1H),9.32(s,1H)
方法8
2,4,5-三氯嘧啶
将5-氯尿嘧啶(10.0g,68.5mmol)溶解在三氯氧化磷(60ml)中,并加入五氯化磷(16.0g,77.0mmol)。将该混合物加热回流16小时,冷却,然后在剧烈搅拌下缓慢地倒入水(200ml)中。将该混合物搅拌1.5小时,然后加入乙酸乙酯(250ml)。分离出有机层,再用另部分乙酸乙酯(250ml)萃取水层。将合并的萃取液用饱和碳酸氢钠(200ml)和饱和氯化钠(200ml)洗涤,然后干燥。通过蒸发除去挥发性物质,通过柱色谱纯化残余物,用DCM洗脱,获得了产物,为黄色液体(6.37g,51%)。
NMR(CDCl3):8.62(s,1H);MS(MH+):182,184,186.
方法9
4-苯氨基-5-溴-2-(4-羟基苯氨基)嘧啶
将4-氨基苯酚(0.73g,7.8mmol)和浓盐酸(1.30ml,7.1mmol)加到在正丁醇(30ml)内的4-苯氨基-5-溴-2-氯嘧啶(方法1;3.0g,7.1mmol)中,并将该混合物在100℃加热12小时。过滤出在冷却后沉淀出的固体,用正丁醇和乙醚洗涤,获得了产物(0.80g,32%)。
MS(MH+):357,359。
方法10-12
下列中间体是通过类似于方法9中描述的方法,由4-苯氨基-5-溴-2-氯嘧啶(方法1)和合适的取代的苯胺制得的:
方法 | R | MS(MH+) |
10 | 3-OH | 357,359 |
11 | 4-CH2CH2OH | 383.3,385.3(MH-) |
12 | 4-I | 467.2,469.2 |
方法13
4-(4-异丙基哌嗪子基)甲氧羰基苯胺
将4-[(4-异丙基哌嗪子基)甲氧羰基]硝基苯(方法14,830mg,2.70mmol)在乙醇(25ml)中的溶液用10%披钯碳(60mg)氢化2小时。通过硅藻土过滤除去催化剂,并将滤液浓缩至5ml体积。加入氯化氢乙醚溶液(1.0M,3ml),通过过滤收集沉淀出的固体,获得了产物,为盐酸盐(613mg,82%)。
NMR:0.9(d,6H),2.4(m,4H),2.7(m,1H),3.4(m,2H),4.6(m,4H),6.4(d,2H),6.6(d,2H);MS(MH+):277.9.
方法14
4-[(4-异丙基哌嗪子基)甲氧羰基]硝基苯
在0℃,将1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(2.14g,11.0mmol)加到4-硝基苯氧基乙酸(按照J.Med.Chem.,1984,27,967-78中描述的方法制得的;2.0g,10.0mmol)、4-异丙基哌嗪(2.56g,20.0mmol)和1-羟基苯并三唑(2.06g,15.0mmol)在DMF(50ml)内的溶液中。将该混合物搅拌16小时,通过蒸发除去挥发性物质。加水(50ml),并用乙酸乙酯(3×100ml)萃取该混合物。将萃取液干燥,并通过蒸发浓缩,获得了产物,为黄色固体(600mg,22%)。
NMR:1.0(d,6H),2.4(m,4H),2.7(m,1H),3.4(m,4H),5.0(s,2H),7.1(d,2H),8.2(d,2H);MS(MH+):307.9.
方法15-17
下列中间体是按照类似于方法13中描述的方法由合适的取代的硝基苯(方法18-20)制得的:
方法 | R | MS(MH+) |
15 | 1-甲基哌啶-4-基 | 207.2 |
16 | (1-甲基哌啶-2-基)甲基 | 221.2 |
17 | 1-甲基哌啶-3-基 | 207.2 |
方法18
4-(1-甲基哌啶-4-基氧基)硝基苯
将三苯基膦(7.9g,30.0mmol)加到4-硝基苯酚(1.39g,10.0mmol)在DCM(100ml)内的搅拌溶液中,并将该溶液搅拌30分钟。加入4-羟基-1-甲基哌啶(1.15g,11.0mmol)在DCM(5ml)中的溶液,并将该溶液搅拌2分钟。滴加偶氮二甲酸二乙酯(4.9ml,30.0mmol),并将该混合物搅拌4小时。通过蒸发除去挥发性物质,将残余物溶解在乙酸乙酯(200ml)中。将该溶液用水(2×100ml)洗涤,然后用2M盐酸(2×50ml)萃取。将合并的酸性萃取液用乙醚(2×100ml)洗涤,然后通过加入0.88氨溶液来碱化。用乙醚(2×100ml)萃取该碱性溶液,将萃取液用水(2×100ml)和饱和氯化钠(100ml)洗涤,并干燥。通过蒸发除去挥发性物质,向残余物中加入饱和氯化氢甲醇溶液。通过蒸发除去挥发性物质,用乙醇和乙醚的混合物将残余物重结晶,获得了产物,为盐酸盐(350mg)。
NMR(373K):2.0-2.1(m,2H),2.2-2.3(m,2H),2.75(s,3H),2.8-3.0(m,2H),3.2-3.4(m,2H),4.9(br s,1H),7.2(d,2H),8.2(d,2H);MS(MH+):237.
方法19
4-(1-甲基哌啶-2-基)甲氧基]硝基苯
将氢化钠(60%油分散液;400mg,10.0mmol)加到2-羟基甲基-1-甲基哌啶(1.29g,10.0mmol)在DMF(20ml)内的溶液中,并将该混合物搅拌2小时。加入4-氟硝基苯(1.4g,10.0mmol),并将该混合物在80℃加热17小时。将该混合物倒入水(100ml)中,并用乙酸乙酯(2×100ml)萃取。将萃取液用水(2×100ml)洗涤,然后用2M盐酸(2×50ml)萃取。将合并的酸性萃取液用乙醚(2×100ml)洗涤,然后通过加入0.88氨溶液来碱化。用乙醚(2×100ml)萃取该碱性溶液,将萃取液用水(2×100ml)和饱和氯化钠(100ml)洗涤,并干燥。通过蒸发除去挥发性物质,向残余物中加入饱和氯化氢甲醇溶液。蒸发,获得了产物的盐酸盐,为油状物(2.4g)。NMR(星号是指构象异构形式):
1.4-1.6(m,1H),1.6-1.9(m,4H),1.9-2.0(m,1H),2.75(s,3H)*,2.8(s,3H)*,3.0-3.2(m,2H)*,3.3-3.4(m,2H)*,3.4-3.6(m,1H)*,3.7-3.9(m,1H)*,4.4(m,2H),7.2(d,2H),8.2(d,2H),10.6-10.8(br s,1H)*.11.0-11.1(br s,1H)*;MS(MH+):251.2.
方法20
4-(1-甲基哌啶-3-基氧基)硝基苯
使用类似于方法18中描述的方法,但是由4-硝基苯酚和3-羟基-1-甲基哌啶开始,获得了产物。MS(MH+):237。
方法21-22
下列中间体是按照类似于方法13中描述的方法,由合适的硝基苯(方法23-24)制得的:
方法 | R | MS(MH+) |
21 | i-PrNH | 194 |
22 | 哌啶子基 | 220 |
方法23
4-[2-(异丙基氨基)乙基氨基]硝基苯
将N-异丙基乙二胺(4.87ml,39.0mmol)和碳酸钾(6.37g,46.0mmol)加到4-氟硝基苯(5.0g,35.0mmol)在DMF(50ml)内的溶液中,并将该混合物在氮气氛下于70℃加热3小时。通过过滤除去不溶性物质,并将滤液浓缩。将残余物溶解在乙酸乙酯(300ml)中,并将该溶液用水(3×100ml)和饱和氯化钠(50ml)洗涤,并干燥。通过蒸发除去溶剂,获得了产物,为橙色油状物,其在静置时会结晶(7.55g,95%)。
NMR:1.0(d,6H),1.7(m,1H),2.7(m,3H),3.2(m,1H),6.6(m,2H),7.1(m,1H),8.0(m,2H);MS(MH+):224.
方法24
4-[2-(哌啶子基)乙基氨基]硝基苯
使用类似于方法23中描述的方法,但是由4-氟硝基苯和1-(2-氨基乙基)哌啶开始,获得了产物。
NMR:1.3(m,2H),1.5(m,4H),2.3(m,4H),2.4(t,2H),3.2(m,2H),6.6(d,2H),7.1(m,1H),8.0(d,2H);MS(MH+):250.
方法25
4-苯氨基-5-溴-2-{4-[3-(叔丁氧基羰基氨基-1-丙炔基]苯氨基}嘧
啶
使用类似于实施例37中描述的方法,由4-苯氨基-5-溴-2-(4-碘苯氨基)嘧啶(方法12)和3-(叔丁氧基羰基氨基)丙炔开始,获得了产物。
NMR:1.4(s,9H),3.9(d,2H),7.1-7.3(m,4H),7.4(m,2H),7.6(m,4H),8.2(s,1H),8.6(s,1H),9.5(s,1H);MS(MH+):494.3,496.3.
方法26
4-苯氨基-5-溴-2-{4-[1-(叔丁氧基羰基)哌啶-4-基]甲氧基苯氨基}
嘧啶
使用类似于实施例24中描述的方法,由4-苯氨基-5-溴-2-(4-羟基苯氨基)嘧啶(方法9)和1-(叔丁氧基羰基)-4-(4-甲苯磺酰氧基)甲基哌啶(按照在PCT Int.Appl.WO 9427965中描述的方法制得的),获得了产物。
实施例42
下面举例说明用于治疗或预防的含有式(I)化合物或其可药用盐或在体内可水解的酯(下文中称为化合物X)的代表性药物剂型:
(a):片剂I | mg/片 |
化合物X | 100 |
乳糖Ph.Eur | 182.75 |
交联羧甲基纤维素钠 | 12.0 |
玉米淀粉糊(5%w/v糊) | 2.25 |
硬脂酸镁 | 3.0 |
(b):片剂II | mg/片 |
化合物X | 50 |
乳糖Ph.Eur | 223.75 |
交联羧甲基纤维素钠 | 6.0 |
玉米淀粉 | 15.0 |
聚乙烯吡咯烷酮(5%w/v糊) | 2.25 |
硬脂酸镁 | 3.0 |
(c):片剂III | mg/片 |
化合物X | 1.0 |
乳糖Ph.Eur | 93.25 |
交联羧甲基纤维素钠 | 4.0 |
玉米淀粉糊(5%w/v糊) | 0.75 |
硬脂酸镁 | 1.0 |
(d):胶囊 | mg/胶囊 |
化合物X | 10 |
乳糖Ph.Eur | 488.5 |
硬脂酸镁 | 1.5 |
(e):注射剂I | (50mg/ml) |
化合物X | 5.0%w/v |
1M氢氧化钠溶液 | 15.0%w/v |
0.1M盐酸 | (将pH调节至7.6) |
聚乙二醇400 | 4.5%w/v |
注射用水 | 至100% |
(f):注射剂II | 10mg/ml |
化合物X | 1.0%w/v |
磷酸钠BP | 3.6%w/v |
0.1M氢氧化钠溶液 | 15.0%w/v |
注射用水 | 至100% |
(g):注射剂III | (1mg/ml,缓冲至pH6) |
化合物X | 0.1%w/v |
磷酸钠BP | 2.26%w/v |
柠檬酸 | 0.38%w/v |
聚乙二醇400 | 3.5%w/v |
注射用水 | 至100% |
注解
上述制剂可通过药物领域众所周知的常规方法制得。可通过常规方法将片剂(a)-(c)包衣,以例如提供邻苯二甲酸乙酸纤维素包衣。
Claims (10)
1.式(I)嘧啶衍生物、或其可药用盐或其在体内可水解的酯:
其中:
Q1是苯基和Q2选自苯基或吡啶基;Q1和Q2当中有一个在一个环碳原子上被一个选自下列的取代基取代:N,N-二-(C1-2烷基)氨基、杂环基、杂环基-O-、取代的C1-2烷基、取代的C1-2烷氧基、取代的C1-2烷氧基羰基、取代的N-(C1-2烷基)氨基、取代的C1-2烷氧基C1-2烷基、取代的C2-4链烯基和取代的C2-4炔基;其中对于C1-2烷基、C1-2烷氧基、C1-2烷氧基羰基、C1-2烷氧基C1-2烷基、C2-4链烯基和C2-4炔基,所述取代基选自羟基、羧基、氰基、氨基、杂环基、杂环基-C(O)-、N-C1-4烷基氨基、N,N-二-(C1-4烷基)氨基;并且如果杂环基含有-NH-部分,该氮未被取代或被一个选自Rb的基团取代;
G是-NH-;
R1选自氢、卤素;
Q1任选在环碳原子上被1-4个选自下列的取代基取代:氰基;
Q2任选在环碳原子上被1-4个独立地选自下列的取代基取代:卤素、氰基、C1-4烷基、C1-4烷氧基,其中所述C1-4烷基和C1-4烷氧基未被取代或被一个或多个选自R9的基团取代;
R9为氰基;
Rb是C1-4烷基。
2.权利要求1的嘧啶衍生物、或其可药用盐或其在体内可水解的酯,其中Q1和Q2当中有一个在环碳原子上被一个选自下列的取代基取代:二甲基氨基、4-甲基哌嗪子基、氨基甲基、2-羟基乙氧基甲基、琥珀酰亚胺-1-基甲基、2-吡咯烷-1-基乙基、2-氨基乙基、哌啶-4-基氧基、1-甲基哌啶-4-基氧基、1-甲基哌啶-3-基氧基、羧基甲氧基、1-甲基哌啶-2-基甲氧基、1-甲基哌啶-3-基甲氧基、哌啶-4-基甲氧基、4-异丙基哌嗪子基羰基甲氧基、2-邻苯二甲酰亚胺-1-基乙氧基、2-吗啉代乙氧基、2-二甲基氨基乙氧基、2-二乙基氨基乙氧基、2-(4-甲基哌嗪子基)乙氧基、2-咪唑-1-基乙氧基、2-吡咯烷-1-基乙氧基、2-氨基乙炔基、2-二甲基氨基乙炔基、2-甲基氨基乙炔基、2-(3-羟基奎宁环-3-基)乙炔基、2-吗啉代乙氧基甲基、2-二乙基氨基乙氧基甲基、2-吡咯烷-1-基乙氧基甲基、2-(4-甲基哌嗪子基)乙氧基甲基、2-二乙基氨基乙氧基羰基、2-哌啶子基乙基氨基或2-异丙基氨基乙基氨基。
3.权利要求1的嘧啶衍生物、或其可药用盐或其在体内可水解的酯,其中Q1在-NH-的对位或间位上被取代。
4.权利要求1的嘧啶衍生物、或其可药用盐或其在体内可水解的酯,其中R1是氢、氯或溴。
5.权利要求1-4任一项的嘧啶衍生物、或其可药用盐或其在体内可水解的酯,其中Q2未取代或者被一个选自氟、溴、甲基、甲氧基和氰基的基团取代。
6.权利要求1的嘧啶衍生物或其可药用盐或其在体内可水解的酯,其中所述化合物选自:
4-苯氨基-5-溴-2-[4-(2-二甲基氨基乙氧基)苯氨基]嘧啶;
4-苯氨基-5-溴-2-[4-(羧基甲氧基)苯氨基]嘧啶;
4-苯氨基-5-溴-2-[4-(1-甲基哌啶-4-基氧基)苯氨基]嘧啶;
4-(6-甲基吡啶-2-基)-5-溴-2-[4-(2-哌啶-1-基乙基氨基)苯氨基]嘧啶;
4-苯氨基-5-溴-2-[4-(2-异丙基氨基乙基氨基)苯氨基]嘧啶;或
4-苯氨基-5-溴-2-[4-(3-甲基氨基-1-丙炔基)苯氨基]嘧啶。
8.一种药物组合物,其中包含权利要求1-6任一项的式(I)嘧啶衍生物、或其可药用盐或其在体内可水解的酯和可药用稀释剂或载体。
9.权利要求1-6任一项的式(I)嘧啶衍生物、或其可药用盐或其在体内可水解的酯在制备用于在温血动物中产生抗癌、细胞周期抑制作用和/或粘着斑激酶抑制作用的药物中的应用。
10.权利要求9的应用,其中所述温血动物是人。
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