CN101910153B - 作为激酶抑制剂的嘧啶类 - Google Patents
作为激酶抑制剂的嘧啶类 Download PDFInfo
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- CN101910153B CN101910153B CN200980101839.1A CN200980101839A CN101910153B CN 101910153 B CN101910153 B CN 101910153B CN 200980101839 A CN200980101839 A CN 200980101839A CN 101910153 B CN101910153 B CN 101910153B
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- Prior art keywords
- pyridin
- phenyl
- pyrimidin
- methyl
- piperazin
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Abstract
游离或盐或溶剂化物形式的式(I)化合物,其中T1、T2和T3具有本说明书所指出的含义,其可用于治疗炎性或阻塞性气道、肺动脉高压、肺纤维化、肝纤维化、肌肉疾病以及全身性骨骼障碍。还描述了包含此类化合物的药物组合物以及用于制备此类化合物的方法。
Description
本发明涉及有机化合物及其作为药物、特别是用于治疗炎性或阻塞性气道疾病、肺动脉高压、肺纤维化、肝纤维化;癌症;肌肉疾病如肌萎缩和肌营养不良以及全身性骨骼障碍如骨质疏松症的用途。
一方面,本发明提供了游离或可药用盐或溶剂化物形式的式I化合物:
其中,
T1是包含1-3个N杂原子的4-14元杂环基团或C4-C15-环烯基,其各自任选地在一个、两个或三个位置被以下基团取代:R1、C1-C8-烷氧基、C3-C5-环烷基、C1-C8-烷硫基、卤素、卤代C1-C8-烷基、氨基、C1-C8-烷基氨基、二(C1-C8-烷基)氨基、氰基、氧代、羟基、羧基或硝基;
T2是4-14元杂环基团,其任选地在一个、两个或三个位置被以下基团取代:R1、R2、R5、C1-C8-烷氧基、C1-C8-烷氧基羰基、C1-C8-烷硫基、卤素、卤代C1-C8-烷基、氨基、C1-C8-烷基氨基、二(C1-C8-烷基)氨基、氰基、氧代、羟基、羧基或硝基;
T3是-H、-OH、卤素、C1-C8-烷基、-C(O)Rx、-CH2ORy、-ORz、-SRp、CH(OH)R1、C(OH)R1R1a或CH(NHR8)R1,其中所述烷基基团任选地被一个或多个选自以下基团所取代:羟基、氰基、卤素、R5、-C(=O)-R5、氨基、C1-C8-烷基氨基、二(C1-C8-烷基)氨基、C1-C8-烷酰基氨基、C1-C8-烷氧基、-C(=O)NR6R7、-NH(C=O)-C1-C8-烷基和-SO2NR6R7;
R1和R1a各自独立地选自C1-C8-烷基、C2-C8-链烯基、C3-C8-环烷基和C2-C8-炔基,各自任选地在一个、两个或三个位置被以下基团取代:羟基、氰基、氨基、卤素、R5、-C(=O)-R5、C1-C8-烷基氨基、二(C1-C8-烷基)氨基、C1-C8-烷酰基氨基、C1-C8-烷氧基、-C(=O)NR6R7、-NH(C=O)-C1-C8-烷基或-SO2NR6R7;
R2是C6-C15-芳基或C4-C15-环烯基,其各自任选地在一个、两个或三个位置被以下基团取代:卤素、羟基、R1、R5、C1-C8-烷硫基、氰基、COOH、CHO、硝基、-O-C6-C15-芳基、卤代C1-C8-烷基、-NR6R7、-C1-C8-烷基-NR6R7、-O-C1-C8-烷基-NR6R7、-C1-C8-烷基-R5、任选被NR6R7取代的-O-R1、-O-R5、-C(=O)-R5、-C(=O)-NH2、-C(=O)NR6R7、-C(=O)-O-R1、-O-C(=O)-R1、-SO2-NH2、-SO2-R1、-NH-SO2-C1-C8-烷基、-C(=O)-NH-R1、-C(=O)-NH-R5、-SO2-C6-C15-芳基、-SO2-R5或-SO2NR6R7;
R5是4-14元杂环基团,其任选地在一个、两个或三个位置被以下基团取代:氧代、氨基、卤素、C1-C8-烷基氨基、二(C1-C8-烷基)氨基、氰基、羟基、羧基、硝基、-R1、C1-C8-烷氧基、C1-C8-烷硫基、卤代C1-C8-烷基、-C(=O)-NH2或-SO2-NH2;
R6和R7独立地是氢、-R1、C6-C15-芳基、-C1-C8-烷基-C6-C15-芳基、-R5或-C1-C8-烷基-R5;
R8是H或R1;
Rp、Rx和Ry独立地是C1-C8-烷基、C2-C8-链烯基、C3-C8-环烷基或C2-C8-炔基,其各自任选地在一个、两个或三个位置被以下基团取代:羟基、氰基、氨基或卤素;
Rz是C1-C8-烷基、C1-C8-烷基-C6-C15-芳基、C1-C8-烷基-Het,其中所述烷基和芳基基团各自任选地被至少一个选自以下的取代基所取代:氧代、氨基、卤素、C1-C8-烷基氨基、二(C1-C8-烷基)氨基、氰基、羟基、羧基、硝基、-R1、C1-C8-烷氧基、C1-C8-烷硫基、卤代C1-C8-烷基、-C(=O)-NH2或-SO2-NH2,且
Het是4-14元杂环基团,其任选地在一个、两个或三个位置被以下基团取代:氧代、氨基、卤素、C1-C8-烷基氨基、二(C1-C8-烷基)氨基、氰基、羟基、羧基、硝基、-R1、C1-C8-烷氧基、C1-C8-烷硫基、卤代C1-C8-烷基、-C(=O)-NH2或-SO2-NH2。
本说明书中所用的术语具有以下含义:
本文所用的“任选地在一个、两个或三个位置被取代”的含义是所指的基团可以在一个、两个或三个位置被下文所列出基团的任何一个或任何组合所取代。因此,在存在两个或多个取代基时,其可以是相同或者不同的。
本文所用的“卤素”是指属于元素周期表中第17族(以前的第VII族)的元素,其可以是例如氟、氯、溴或碘。
本文所用的“C1-C8-烷基”是指包含1-8个碳原子的直链或支链烷基。当具体描述碳原子的不同数量时,例如C6或C4,该定义应当相应地进行解释。
本文所用的“C2-C8-链烯基”是指包含2-8个碳原子和一个或多个碳碳双键的直链或支链的烃链。当具体描述碳原子的不同数量时,例如C6或C4,该定义应当相应地进行解释。
本文所用的“C2-C8-炔基”是指包含2-8个碳原子和一个或多个碳碳叁键的直链或支链的烃链。当具体描述碳原子的不同数量时,例如C6或C4,该定义应当相应地进行解释。
本文所用的“C6-C15-芳基”是指具有6-15个环碳原子的芳香基团。C6-C15-芳基基团的实例包括但不限于苯基、亚苯基、苯三基(benzenetriyl)、茚满基、萘基、亚萘基、萘三基(naphthalenetriyl)和亚蒽基。
本文所用的“4-14元杂环基团”是指包含至少一个选自氮、氧和硫的环杂原子的4-14元杂环,其可以是饱和、部分饱和或不饱和的。4-14元杂环基团的实例包括但不限于呋喃、吖丁啶、吡咯、吡咯烷、吡唑、咪唑、三唑、异三唑、四唑、噻二唑、异噻唑、噁二唑、吡啶、哌啶、吡嗪、噁唑、异噁唑、吡嗪、哒嗪、嘧啶、哌嗪、吡咯烷、吡咯烷酮、吗啉、三嗪、噁嗪、四氢呋喃、四氢噻吩、四氢噻喃、四氢呋喃、1,4-二噁烷、1,4-氧杂硫杂环己烷、吲唑、喹啉、吲哚、噻唑、异喹啉、苯并噻吩、苯并噁唑、苯并异噁唑、苯并噻唑、苯并异噻唑、苯并呋喃、二氢苯并呋喃、苯并间二氧杂环戊烯、苯并咪唑、四氢萘啶、吡咯并吡啶、四氢咔唑、苯并三唑和四氢噻喃并吲哚。所述4-14元杂环基团可以是未取代或被取代的。
本文所用的“N-杂环基团”是指杂环基团,其中至少一个环原子是氮原子。所述N-杂环基团可以是未取代或被取代的。
“C3-C10-环烷基”是指具有3-10个环碳原子的全饱和碳环,例如单环基团如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基,或者二环基团如二环庚基或二环辛基。当具体描述碳原子的不同数量时,例如C6,该定义应当相应地进行解释。
“C4-C15-环烯基”是部分不饱和的碳环,带有至少一个双键的单-、二-或三环,例如环丁烯基、环戊烯基如环戊烯-2-或-3-基、环己烯基如环己烯-2-或-3-基、环庚烯基如环庚烯-2-、-3-或-4-基、环辛烯基、环壬烯基或环癸烯基,或者二环基团例如二环庚烯基或二环辛烯基,且可以是未取代或被取代的。
本文所用的“卤代C1-C8-烷基”是指被一个或多个卤素原子、优选一个、两个或三个卤素原子取代的如上文所定义的C1-C8-烷基。
本文所用的“C1-C8-烷基氨基”和“二(C1-C8-烷基)氨基”是指分别被一个或两个如上文所定义的C1-C8-烷基基团取代的氨基,所述烷基基团可以是相同或者不同的。
本文所用的“C1-C8-烷硫基”是指包含1-8个碳原子的直链或支链烷硫基。当具体描述碳原子的不同数量时,例如C6或C4,该定义应当相应地进行解释。
本文所用的“C1-C8-烷氧基”是指包含1-8个碳原子的直链或支链烷氧基。当具体描述碳原子的不同数量时,例如C6或C4,该定义应当相应地进行解释。
本文所用的“C1-C8-烷氧基羰基”是指通过氧原子与羰基基团相连的如上文所定义的C1-C8-烷氧基。
当变量是根据其它变量来定义时,例如R2是任选地被R1或R5取代的C6-C15芳基,其含义是R2基团是任选地被一个或多个各自独立地选自R1和/或R5定义的取代基取代。当化合物包含超过一个选自特定变量(例如R1)定义的取代基时,各个取代基是相同或不同的。
在说明书及下文的权利要求书全文中,除非上下文另外需要,否则应当理解词语“包含”或其变体如“包括”是指包含所述整体或步骤或者整体或步骤的组,但不排除任何其它整体或步骤或者整体或步骤的组。
合适的式I化合物包括游离的或盐或溶剂化物形式的化合物,其中:
T1是包含一个或两个N-杂原子的5-7元杂环基团,任选地在一个或两个位置被R1、C1-C4-烷氧基、C3-C5-环烷基、卤素、羟基或硝基取代;
T2是包含一个或两个N-杂原子的5-7元杂环基团,任选地在一个或两个位置被R1、R2、R5、C1-C8-烷氧基、C1-C8-烷氧基羰基或氰基取代;
T3是-H;-OH;卤素;任选被羟基、卤素或氨基取代的C1-C8-烷基;或-ORz,
R1是C1-C4-烷基;
R2是C6-C10-芳基,其任选地在一个或两个位置被卤素、COOH、CHO、R1、O-R1、R5、-C1-C8-烷基-R5、-C(=O)-R5、-SO2-NH2、-SO2-R1、-NH-SO2-C1-C8-烷基、-C(=O)-NH-R1、-C(=O)-NH-R5取代,或者被任选地在一个位置被二(C1-C8-烷基)氨基取代的C1-C8-烷氧基取代;
R5是4-14元杂环基团,其任选地在一个、两个或三个位置被C1-C8-烷基基团取代;
Rz是C1-C4-烷基、C1-C4-烷基-C6-C10-芳基、C1-C4-烷基-Het,其中Het是5-10元杂环环系,包含一个或两个N杂原子,其中所述烷基、芳基和Het基团各自任选地被至少一个选自以下的取代基取代:氧代、氨基、卤素、C1-C8-烷基氨基、二(C1-C8-烷基)氨基、氰基、羟基、羧基、硝基、-R1、C1-C8-烷氧基、C1-C8-烷硫基、卤代C1-C8-烷基、-C(=O)-NH2或-SO2-NH2。
其它合适的式I化合物包含游离或盐或溶剂化物形式的化合物,其中:
T1是包含一个或两个N-杂原子的5-6元杂环基团,任选地在一个位置被R1或C1-C4-烷氧基取代;
T2是5-6元N-杂环基团,任选地在一个或两个位置被R1、R2、R5、C1-C4-烷氧基、C1-C4-烷氧基羰基或氰基取代;
T3是-H;-OH;Cl;任选地被卤素、氨基或羟基取代的C1-C6-烷基;或-ORz;
R1是C1-C4-烷基;
R2是苯基,其任选地在一个或两个位置被以下基团取代:卤素、COOH、CHO、R1、O-R1、R5、-C1-C8-烷基-R5、-C(=O)-R5、-SO2-NH2、-SO2-R1、-NH-SO2-C1-C8-烷基、-C(=O)-NH-R1、-C(=O)-NH-R5,或者被任选地在一个位置被二(C1-C8-烷基)氨基取代的C1-C8-烷氧基取代;
R5是任选地在一个或两个位置被C1-C4-烷基取代的4-14元杂环基团;且
Rz是C1-C3-烷基、C1-C3-烷基-C6-C10-芳基、C1-C3-烷基-Het,其中Het是6-9元杂环环系,包含一个或两个N-杂原子,其中所述烷基、芳基和Het基团各自任选地被至少一个选自以下的取代基取代:氧代、氨基、卤素、C1-C8-烷基氨基、二(C1-C8-烷基)氨基、氰基、羟基、羧基、硝基、-R1、C1-C8-烷氧基、C1-C8-烷硫基、卤代C1-C8-烷基、-C(=O)-NH2或-SO2-NH2。
根据式I,本发明的多种实施方案可以独立地、全体地或以任何组合合并。因此,一项实施方案中变量的定义可以与本文所述不同实施方案中独立变量的定义相结合。因此,本发明意图涵盖实施方案或实施方案的部分的组合,所以术语“本发明的实施方案”应作为“本文任何地方所述或所定义的本发明的实施方案或方面”进行解释。
T1适当地是包含1-3个N-杂原子的4-14元杂环基团,其任选地在一个、两个或三个位置被以下基团取代:R1、C1-C8-烷氧基、C3-C5-环烷基、C1-C8-烷硫基、卤素、卤代C1-C8-烷基、氨基、C1-C8-烷基氨基、二(C1-C8-烷基)氨基、氰基、氧代、羟基、羧基或硝基。任选地,T1是6元N-杂环基团,包含一个N-杂原子,其任选地在一个位置被C1-C4-烷基(例如甲基、乙基、异丙基、正丙基、异丁基、正丁基、叔丁基,但优选甲基)取代。例如,T1可以是未取代的吡啶基,尤其是吡啶-2-基或被C1-C4-烷基(尤其是甲基)取代的吡啶-2-基,例如6-甲基-吡啶-2-基。
T2适当地是包含一个N杂原子的6元N-杂环基团,其任选地在一个位置被C1-C4-烷氧基或被C6-C15-芳基(尤其是苯基)取代,其中所述芳基基团任选地被卤素、C1-C4-烷氧基(尤其是甲氧基)、R5、C1-C4-烷基-R5或-C(=O)-R5取代。例如,T2是未取代的吡啶基,尤其是未取代的吡啶-3-基,或者T2是吡啶基,尤其是吡啶-3-基,其被在一个位置被以下基团取代的苯基取代:C1-C4-烷氧基(例如甲氧基、乙氧基、异丙氧基、正丙氧基、异丁氧基、正丁氧基、叔丁氧基,但优选甲氧基)、C(O)R5或CH2-R5。本文优选的T2基团选自未取代的吡啶-3-基和在5-位被以下基团取代的吡啶-3-基基团:3-甲氧基苯基、(4-异丙基-哌嗪-1-基)甲酮取代的苯基或被(4-异丙基-哌嗪-1-基)甲基取代的苯基。
T3适当地是H;Cl;OH;任选被OH、NH2或卤素取代的C1-C6-烷基;或-Orz,其中Rz是C1-C3-烷基(尤其是甲基或异丙基)、C1-C2-烷基苯基、C1-C2-烷基Het。例如T3是H、Cl、OH、叔丁基、苄氧基、-氧基-乙基-1H-吲哚、甲氧基或异丙氧基;
R1适当地是任选地在一个位置被羟基或卤素取代的C1-C4-烷基。
R2适当地是任选在一个、两个或三个位置被以下基团取代的C6-C15-芳基:卤素、羟基、R1、R5、C1-C8-烷硫基、氰基、COOH、CHO、硝基、-O-C6-C15-芳基、卤代C1-C8-烷基、-NR6R7、-C1-C8-烷基-NR6R7、-O-C1-C8-烷基-NR6R7、-C1-C8-烷基-R5、任选被NR6R7取代的-O-R1、-O-R5、-C(=O)-R5、-C(=O)-NH2、-C(=O)NR6R7、-C(=O)-O-R1、-O-C(=O)-R1、-SO2-NH2、-SO2-R1、-NH-SO2-C1-C8-烷基、-C(=O)-NH-R1、-C(=O)-NH-R5、-SO2-C6-C15-芳基、-SO2-R5或-SO2NR6R7。任选地,R2是C6-C10-芳基,尤其是苯基,其任选地在一个或两个位置被以下基团取代:卤素、-R1、-C1-C4-烷基-R5、-C(=O)-R5、-SO2-NH2、-SO2-C1-C4-烷基、-NH-SO2-C1-C4-烷基、-C(=O)-NH-R5或任选地在一个位置被二(C1-C4-烷基)氨基取代的C1-C4-烷氧基。
R5适当地是4-10元杂环基团(尤其是5或6元杂环基团),其任选地在一个或两个位置被氧代或C1-C4-烷基取代。例如R5是哌嗪-2-酮、哌嗪基(尤其是哌嗪-1-基)、吗啉基、吡唑基、吡咯烷基、哌嗪基(尤其是哌嗪-1-基)或四氢吡喃基。
根据其它实施方案,本发明涉及如本文示例的式I化合物,其独立地选自以下化合物:
4-苄氧基-6-[5-(3-甲氧基-苯基)-吡啶-3-基]-2-吡啶-2-基-嘧啶,
(4-异丙基-哌嗪-1-基)-{4-[5-(2-吡啶-2-基-嘧啶-4-基)-吡啶-3-基]-苯基}-甲酮,
4-{5-[4-(4-异丙基-哌嗪-1-基甲基)-苯基]-吡啶-3-基}-2-吡啶-2-基-嘧啶,
3-[2-(6-吡啶-3-基-2-吡啶-2-基-嘧啶-4-基氧基)-乙基]-1H-吲哚,
3-{2-[2-(6-甲基-吡啶-2-基)-6-吡啶-3-基-嘧啶-4-基氧基]-乙基}-1H-吲哚,
(4-{5-[6-氯-2-(6-甲基-吡啶-2-基)-嘧啶-4-基]-吡啶-3-基}-苯基)-(4-异丙基-哌嗪-1-基)-甲酮,
(4-{5-[6-苄氧基-2-(6-甲基-吡啶-2-基)-嘧啶-4-基]-吡啶-3-基}-苯基)-(4-异丙基-哌嗪-1-基)-甲酮,
(4-异丙基-哌嗪-1-基)-(4-{5-[6-甲氧基-2-(6-甲基-吡啶-2-基)-嘧啶-4-基]-吡啶-3-基}-苯基)-甲酮,
(4-{5-[6-羟基-2-(6-甲基-吡啶-2-基)-嘧啶-4-基]-吡啶-3-基}-苯基)-(4-异丙基-哌嗪-1-基)-甲酮,
{4-[5-(6-氯-2-吡啶-2-基-嘧啶-4-基)-吡啶-3-基]-苯基}-(4-异丙基-哌嗪-1-基)-甲酮,
{4-[5-(6-苄氧基-2-吡啶-2-基-嘧啶-4-基)-吡啶-3-基]-苯基}-(4-异丙基-哌嗪-1-基)-甲酮,
{4-[5-(6-异丙氧基-2-吡啶-2-基-嘧啶-4-基)-吡啶-3-基]-苯基}-(4-异丙基-哌嗪-1-基)-甲酮,
4-叔丁基-6-{5-[4-(4-甲基-哌嗪-1-基甲基)-苯基]-吡啶-3-基}-2-吡啶-2-基-嘧啶,
二甲基-((R)-1-{4-[5-(2-吡啶-2-基-嘧啶-4-基)-吡啶-3-基]-苄基}-吡咯烷-3-基)-胺,
二甲基-((R)-1-{3-[5-(2-吡啶-2-基-嘧啶-4-基)-吡啶-3-基]-苄基}-吡咯烷-3-基)-胺,
(4-{5-[6-氯-2-(6-甲基-吡啶-2-基)-嘧啶-4-基]-吡啶-3-基}-苯基)-(3-二甲基氨基-吡咯烷-1-基)-甲酮,
(1-{4-[5-(6-甲氧基-2-吡啶-2-基-嘧啶-4-基)-吡啶-3-基]-苄基}-吡咯烷-3-基)-二甲基-胺,
(4-{5-[6-苄氧基-2-(6-甲基-吡啶-2-基)-嘧啶-4-基]-吡啶-3-基}-苯基)-(3-二甲基氨基-吡咯烷-1-基)-甲酮,
4-叔丁基-6-{5-[4-(4-甲基-哌嗪-1-基甲基)-苯基]-吡啶-3-基}-2-(6-甲基-吡啶-2-基)-嘧啶,
及其游离或盐或溶剂化物形式。
含有碱性中心的式I化合物能够形成酸加成盐、特别是可药用的酸加成盐。式I化合物的可药用酸加成盐包括无机酸和有机酸的那些,所述无机酸例如氢卤酸如氢氟酸、盐酸、氢溴酸、氢碘酸、硝酸、硫酸、磷酸;所述有机酸例如脂肪族一元羧酸如甲酸、乙酸、三氟乙酸、丙酸和丁酸、辛酸、二氯乙酸、马尿酸,脂肪族羟酸如乳酸、柠檬酸、酒石酸或苹果酸、葡糖酸、扁桃酸,二元羧酸如马来酸或琥珀酸、己二酸、天冬氨酸、富马酸、谷氨酸、丙二酸、癸二酸,芳族羧酸如苯甲酸、对氯苯甲酸、烟酸、二苯基乙酸或三苯基乙酸,芳族羟酸如邻羟基苯甲酸、对羟基苯甲酸、1-羟基萘-2-甲酸或3-羟基萘-2-甲酸,以及磺酸如甲磺酸或苯磺酸、乙磺酸、乙烷-1,2-二磺酸、2-羟基-乙磺酸、(+)樟脑-10-磺酸、萘-2-磺酸、萘-1,5-二磺酸或对甲苯磺酸。这些盐可以由式I化合物通过已知的成盐方法制备。可药用的溶剂化物通常是水合物。
含有酸性基团如羧基的式I化合物也能够与碱、特别是可药用碱、例如本领域众所周知的那些碱形成盐。适宜的盐包括金属盐、特别是碱金属或碱土金属盐如钠、钾、镁或钙盐,或者与氨或可药用有机胺或杂环碱的盐,例如乙醇胺、苄胺或吡啶、精氨酸、苯乙苄胺、苄星盐(benzathine)、二乙醇胺、4-(2-羟基乙基)吗啉、1-(2-羟基乙基)吡咯烷、N-甲基葡糖胺、哌嗪、三乙醇胺或氨丁三醇的盐。这些盐可以由式I化合物通过已知的成盐方法制备。含有酸性基团如羧基的式I化合物还可以作为具有季铵中心的两性离子而存在。
可以以常规方式将游离形式的式I化合物转化为盐形式,反之亦然。游离或盐形式的化合物可以以水合物或含有用于结晶的溶剂的溶剂化物形式而得到。式I化合物可以从反应混合物中回收并以常规方式纯化。异构体、例如对映异构体可以以常规方式、例如通过分步结晶或由相应不对称取代的、例如具有旋光活性的原料经不对称合成得到。
许多本发明的某些化合物含有至少一个不对称碳原子,因此它们以单一的旋光活性的异构形式或作为其混合物、例如作为外消旋混合物而存在。在其中存在另外的不对称中心的情况中,本发明还包括单一的旋光活性的异构体以及其混合物、例如非对映异构混合物。
本发明包括所有这类形式、特别是纯异构形式。可以通过常规方法使不同的异构形式相互分离或拆分,或者可以通过常规合成方法或者通过立体特异性或不对称合成来得到任意给定的异构体。因为本发明的化合物用于药物组合物,所以应当容易理解,它们各自优选以基本上纯的形式、例如至少60%纯、更适宜地至少75%纯、优选至少85%纯、尤其是至少98%纯(%根据重量计算)来提供。化合物的不纯制备物可以用于制备用于药物组合物的更纯形式;化合物的这些较不纯的制备物应当含有至少1%、更适宜地至少5%、优选10至59%的本发明化合物。
本发明包括全部可药用的同位素标记的式I化合物,其中一个或多个原子被具有相同原子序数但原子质量或质量数不同于自然界中通常所见原子质量或质量数的原子置换。适于包含在本发明化合物中的同位素的实例包括氢的同位素,例如2H和3H,碳例如11C、13C和14C,氯例如36Cl,氟例如18F,碘例如123I和125I,氮例如13N和15N,氧例如15O、17O和18O,和硫例如35S。
某些同位素标记的式I化合物,例如掺入放射性同位素的那些,可用于药物和/或底物的组织分布研究。放射性同位素氚(3H)和碳-14(14C)由于其易于加入和检测方法容易,特别可用于此目的。较重同位素例如氘(2H)的取代可提供某些治疗优点,这是由于其有更好的代谢稳定性,例如延长的体内半衰期或降低的剂量需要,因此可在某些情况下优选。正电子发射同位素取代,如11C、18F、15O和13N可用于检查底物受体占有率的正电子发射断层显像(PET)研究。
同位素标记的式I化合物通常可使用适宜的同位素标记试剂替换从前使用的非标记试剂,通过本领域技术人员已知的常规技术或与所附实施例中描述的那些相似的方法而制备。
本发明的可药用溶剂化物包括其中结晶的溶剂可被同位素取代的那些,例如D2O、d6-丙酮或d6-DMSO。
本发明特别优选的化合物是那些在下文实施例中所述的化合物。
本发明还提供了式I化合物的制备方法,其包括:
(i)(A)将式II化合物
其中T1和T2如上文所定义且X是卤素,与式III化合物反应,
T3-L (III),
其中T3如上文所定义且L是离去基团或者在某些反应条件下(例如T3是亲核基团)时L可以不存在;或者
(B)将式IV化合物
其中T1和T3如上文所定义且X是卤素,与式V化合物反应
其中T2如上文所定义;和
(ii)回收游离或盐或溶剂化物形式的产物。
方法变体(A)可以使用将卤代杂环基团与亲核体反应的已知方法或者类似于下文实施例中所述的方法实现。该反应在有机溶剂如DMF中,任选地在碱如叔丁醇钾存在下方便地进行。合适的反应温度是室温。
方法变体(B)可以使用将卤代杂环基团与杂环硼酸在合适的催化剂如四(三苯基膦)钯存在下反应的已知方法或者类似于下文实施例中所述的方法实现。反应在有机溶剂如乙腈、四氢呋喃(THF)或二甲基乙二醇(DME)中,任选地在无机碱如碳酸钠存在下进行。合适的反应温度是较高的温度,例如60℃-150℃,优选在微波下于约90℃进行。
通过将式VI化合物与卤化剂反应来制备式II化合物,
其中T1和T2如上文所定义。其可以使用卤化羟基化合物的已知方法或者类似下文实施例中所述方法实现。所述卤化剂优选地是强Lewis酸的组合,例如POCl3和PCl5。合适的反应温度是较高的温度,例如回流温度。
式III化合物是已知的或者可以通过已知方法制备。
通过将式VII化合物与式III化合物反应来制备式IV化合物,
其中T1如上文所定义且X是卤素。
其可以使用已知用于将卤代杂环基团与亲核体反应的方法或者如下文实施例中所述类似的方法实现。该反应在有机溶剂例如异丙醇中,在合适的碱例如N,N-二异丙基乙胺(DIPEA)的存在下方便地进行。合适的反应温度是较高的温度,例如100℃-150℃,优选在微波下于约130℃进行。
式V化合物是已知的或者可以通过已知方法制备。
通过将式VIII化合物,其中T1如上文所定义,
与式IX化合物
反应来制备式VI化合物,其中T2如上文所定义。
其可以使用已知用于将脒与β-酮酯反应的方法或如下文实施例中所述类似的方法实现。该反应在有机溶剂例如乙醇中,优选在无机碱氢氧化钠的存在下方便地进行。合适的反应温度是0℃-50℃,方便地在室温下进行。
通过使用已知用于卤化羟基化合物的方法或如下文实施例中所述的方法,将式X化合物,其中T1如上文所定义,
反应来形成式VII化合物。所述卤化剂优选地是强Lewis酸的组合,例如POCl3和PCl5。合适的反应温度是较高的温度,例如回流温度。
式VIII或IX化合物是已知的或者可以通过已知方法制备。
通过将式VIII化合物,其中T1如上文所定义,
与式XI化合物反应来制备式X化合物
其可以使用已知用于将脒与β-酮酯反应的方法或如下文实施例中所述类似的方法实现。该反应在有机溶剂例如甲醇中,优选在无机碱例如甲醇钠的存在下,并优选地在惰性气体中(例如在氩气中)方便地进行。合适的反应温度是10℃-70℃,但优选在约55℃下进行。
式XI化合物是已知的并且可以通过已知方法制备。
式I化合物或其可药用盐在下文中也称为“本发明活性剂”,可用作药物。因此,本发明还提供了用作药物的式I化合物或其可药用盐。本发明活性剂用作活化素样激酶(“ALK”)-5抑制剂。至少一些本发明的活性剂也用作ALK-4抑制剂。
TGF-β1是细胞因子家族的原型成员,所述细胞因子家族包括TGF-β、活化素、抑制素(inhibitins)、骨形态发生蛋白和苗勒(Mullerian)抑制物质,其通过单跨膜丝氨酸/苏氨酸激酶受体家族进行信号传导。这些受体可以分成两类:I型或活化素样激酶(ALK)受体和II型受体。ALK受体与II型受体的区别在于:ALK受体(a)没有富含丝氨酸/苏氨酸的胞内尾区,(b)具有在I型受体之间非常同源的丝氨酸/苏氨酸激酶结构域,和(c)共享共同的称为GS结构域的序列基元,该GS结构域由富含甘氨酸和丝氨酸残基的区域组成。GS结构域位于细胞内激酶结构域的氨基末端,它对于由II型受体激活而言是关键的。数项研究已经表明:TGF-β信号传导既需要ALK也需要II型受体。特别地,在TGF-β的存在下,II型受体使TGF-β的I型受体ALK5的GS结构域磷酸化。ALK5继而使在两个羧基末端丝氨酸处的胞质蛋白Smad2和Smad3磷酸化。磷酸化的Smad蛋白易位到核中并激活促使产生细胞外基质的基因。因此,本发明的优选化合物是选择性的,因为它们抑制I型受体。
活化素以类似于TGF-β的方式转导信号。活化素与丝氨酸/苏氨酸激酶—活化素II型受体(ActRIIB)结合,激活的II型受体使ALK4的GS区域中的丝氨酸/苏氨酸残基超磷酸化。激活的ALK4继而使Smad2和Smad3磷酸化。随后形成含有Smad4的杂Smad复合物,导致活化素诱发的基因转录的调节。
TGF-β1轴的激活和细胞外基质的扩张是慢性肾脏疾病和血管疾病发生和进展的早期和持续性的贡献者。Border W.A.等人,N.Engl.J.Med.,1994;331(19),1286-92。此外,TGF-β1还通过TGF-β1受体ALK5引起的Smad3磷酸化的作用而在纤连蛋白和纤溶酶原激活物抑制剂-1(硬化沉积物的组分)的形成中起作用。Zhang Y.等人,Nature,1998;394(6696),909-13;Usui T.等人,Invest.Ophthalmol.Vis.Sci.,1998;39(11),1981-9。
肾和心血管系统中的进行性纤维化是患病和死亡的主要原因,并且是卫生保健费用的重要因素。TGF-β1已经牵涉于多种肾脏纤维化障碍。Border W.A.等人,N.Engl.J.Med.,1994;331(19),1286-92。TGF-β1在急性和慢性肾小球肾炎(Yoshioka K.等人,Lab.Invest.,1993;68(2),154-63)、糖尿病性肾病(Yamamoto,T.等人,1993,PNAS 90,1814-1818)、同种异体移植物排斥、HIV肾病和血管紧张素引起的肾病(Border W.A.等人,N.Engl.5 J.Med.,1994;331(19),1286-92)中升高。在这些疾病中,TGF-β1表达的水平与细胞外基质的产生一致。三条证据提示:TGF-β1与基质产生之间具有因果关系。第一条,外源TGF-β1可以在体外引起正常肾小球、肾小球膜细胞和非肾细胞产生细胞外基质蛋白并抑制蛋白酶活性。第二条,抗TGF-β1的中和抗体可以阻止肾炎大鼠的细胞外基质聚积。第三条,TGF-β1转基因小鼠或TGF-β1基因向正常大鼠肾脏中的体内转染,导致肾小球硬化症迅速发展。Kopp J.B.等人,Lab.Invest.,1996;74(6),991 1003。因此,抑制TGF-β1活性表明可作为慢性肾脏疾病的治疗介入。
TGF-β1及其受体在受损的血管中增加并且在气囊血管成形术后的新内膜形成中显示(Saltis J.等人,Clin.Exp.Pharmacol.Physiol.,1996;23(3),193-200)。此外,TGF-β1还是平滑肌细胞(“SMC”)体外迁移的有效刺激物,SMC在动脉壁中的迁移是动脉粥样硬化和再狭窄发病的促进因素。而且,在抗总胆固醇的内皮细胞产物的多变量分析中,TGF-β受体ALK5与总胆固醇相关(P<0.001)(Blann A.D.等人,Atherosclerosis,1996;120(1-2),221-6)。此外,来自人动脉粥样硬化病变的SMC所具有的ALK5/TGF-βII型受体的比例增加。因为TGF-β1在纤维增殖性血管性损伤中被过度表达,所以受体-I变体细胞将被允许以缓慢但失控的方式生长,而同时超量产生细胞外基质组分(McCaffrey T.A.等人,Jr.,J.Clin.;Invest.,1995;96(6),2667-75)。TGF-β1被免疫定位到其中发生活性基质合成的动脉粥样硬化病变中的非泡沫状巨噬细胞,这提示非泡沫状巨噬细胞可以通过TGF-β-依赖性机制参与调节动脉粥样硬化重塑中基质基因表达。因此,抑制TGF-β1对ALK5的作用也表明可用于动脉粥样硬化和再狭窄。
肝纤维化是响应于由许多物质如乙型肝炎和丙型肝炎病毒、酒精或药物以及自身免疫性疾病引发的慢性肝损伤的失衡的创伤愈合响应的结果。最终,肝纤维化可导致威胁生命的肝硬化和肝癌(参见Gressner等人(2006)J.Cell.Mol.Med.2006,10(1):76-99的综述文章)。
已知有数条细胞信号传导途径在慢性肝损伤中被改变。有许多文件证明TGF-β信号传导、其受体和相关的Smad信号传导蛋白存在于参与纤维形成的细胞类型中。已经发现TGF-β的循环水平在包括肝纤维化在内的纤维化疾病的多种动物模型中升高。具有TGF-β1过度表达的转基因小鼠在包括肝、肾、肺和心脏在内的多个器官中发展为纤维化。显然,升高的TGF-β信号传导参与包括肝纤维化在内的所有类型的纤维化疾病。该观点已经在使用TGFβ抑制剂的数项研究中在纤维化模型中被进一步证实。TGF-β通过与两种ser/thr激酶受体—TGFβRII和ALK5结合而介导其信号。表达显性负相TGFβRII在二甲基亚硝胺引起的肝纤维化的大鼠模型中显示出有益作用(参见Qi等人(1999)Proc.Natl.Acad.Sci.96:2345-9和Nakamura等人(2000)Hepatology 32:247-55)。使用反义方法抑制TGF-β表达也减少了由胆道结扎引起的肝纤维化(参见Arias等人(2003)BMCGastroenterol.3:29)。近来,ALK5的小分子抑制剂GW6604当治疗性地给予大鼠时,在治疗二甲基亚硝胺引起的肝纤维化中具有显著的作用。相当显著的是,GW6604防止了40%的死亡率并且抑制了60%的细胞外基质沉积,这是纤维化的关键量度。重要的是,在用GW6604进行的3周治疗过程中没有发现明显的副作用(参见De Gouville等人(2005)Br.J.Pharmacol.145:166-77)。总而言之,这些研究表明抑制TGFβ信号传导可以是对肝纤维化疾病的有效治疗。
TGF-β1还适用于创伤修复。已经在多种模型中使用了TGF-β1的中和抗体,证明TGF-β1信号传导的抑制通过在愈合过程中限制过多瘢痕形成而有益于损伤后的功能恢复。例如,在大鼠中,TGF-β1和TGF-β2的中和抗体通过减少单核细胞和巨噬细胞的数量以及减少皮肤纤连蛋白和胶原沉积而减少了瘢痕形成并改善了新真皮的细胞结构(Shah M.,J.Cell.Sci.,1995,108,985-1002)。而且,TGF-β抗体还可改善兔角膜创伤的愈合(Moller-Pedersen T.,Curr Eye Res.,1998,17,736-747)和加速大鼠胃溃疡的创伤愈合(Ernst H.,Gut,1996,39,172-175)。这些数据有力地表明:限制TGF-β的活性将有益于多种组织,并表明:具有TGF-β长期升高的任何疾病将受益于抑制Smad2和Smad3信号传导途径。
TGF-β还参与腹膜粘连(Sand G.M.等人,Wound Repair Regeneration,1999年11-12月,7(6),504-510)。因此,ALK5的抑制剂将有益于防止手术操作后腹膜与真皮下纤维化粘连。
TGF-β还参与皮肤的光老化(参见Fisher等人,“光老化和时间皮肤老化的机制”,Archives of Dermatology,138(11):1462-1470,2002年11月和Schwartz E.Sapadin AN.Kligman LH.“UItraviolet B radiationincreases steady state mRNA levels for cytokines and integrins in hairlessmouse skin-modulation by 25 topical tretinoin”,Archives of DermatologicalResearch,290(3):137-144,1998年3月)。
TGF-β信号传导还参与肺障碍、特别是肺动脉高压和肺纤维化的发生(参见Morrell NW等人,“来自原发性肺动脉高压患者的肺动脉平滑肌细胞对转化生长因子-β(1)和骨形态发生蛋白的改变的生长应答”,Circulation.2001年8月14日;104(7):790-5和Bhatt N等人,“在治疗肺纤维化中有希望的药理学创新”,Curr Opin Pharmacol.2006年4月28日)。
TGF-β1水平在肺动脉高压动物模型中增加(Mata-Greenwood E等人,“具有肺血流增加和肺动脉高压的羔羊中TGF-β1表达的变化”,Am.J.Physiol.Lung Cell Mol.Physiol.2003年7月;285(1):L209-21)。其它研究已经表明,肺内皮细胞衍生的TGF-β1可以刺激肺血管平滑肌细胞的生长,这可以成为在患有肺动脉高压个体的肺血管系统中观察到肌型化增强的原因(Sakao S等人,“肺微血管内皮细胞的细胞凋亡刺激血管平滑肌细胞生长”,Am.J.Physiol.Lung Cell Mol.Physiol.2006年4月14日)。因此,抑制TGF-β1对ALK5的作用适合于作为肺动脉高压的治疗介入。
此外,失调的TGF-β信号传导还已经参与了特发性肺纤维化的发生。ALK5的激活可导致Smad3激活,以及牵涉于纤维化过程的基因如纤溶酶原激活物抑制剂-1、原胶原3A1和结缔组织生长因子的表达的下游调节。已经证明:TGF-β1及其下游促纤维化介体的水平在取自特发性肺纤维化患者的支气管肺泡灌洗液中(Hiwatari N等人,“来自特发性肺纤维化患者的支气管肺泡灌洗液的原胶原-III-肽和转化生长因子-β水平升高的重要性”,Tohoku J.Exp.Med.1997年2月;181(2):285-95)和在特发性肺纤维化动物模型中(Westergren-Thorsson G等人,“大鼠发生博来霉素诱发的肺纤维化中小蛋白聚糖、胶原和转化生长因子-β1的表达改变”,J.Clin.Invest.1993年8月,92(2):632-7)被上调。
使用腺病毒载体介导的基因转移,使鼠肺中活性TGF-β1瞬时过表达,在野生型小鼠中导致了进行性肺纤维化,而在Smad3敲除小鼠的肺中直至TGF-β1攻击后28天都没有观察到纤维化(Khalil N等人,“博来霉素诱发的肺损伤中肺细胞的转化生长因子βI型和II型受体的差异表达:与修复和纤维化的相关性”,Exp.Lung.Res.2002年4-5月;28(3):233-50)。因此,抑制ALK5的TGF-β1激活还可用于肺纤维化。
TGF-β1还可参与肿瘤,因此本发明的活性剂可用于治疗癌症,包括前列腺癌、乳腺癌、胃癌、血管生成、瘤转移、肿瘤,例如治疗和/或预防肿瘤进展。
活化素信号传导和活化素的过表达与病理性障碍相关,其涉及如下:细胞外基质聚积和纤维化(例如Matsuse,T.等人,Am.J.Respir Cell Mol.Biol.13:17-24(1995);Inoue,S.等人,Biochem.Biophys.Res.Comn.205:441-448(1994);Matsuse,T.等人,Am.J.Pathol.148:707-713(1996);De Bleser等人,Hepatology 26:905-912(1997);Pawlowski,J.E.等人,J.Clin.Invest.100:639-648(1997);Sugiyama,M.等人,Gastroenterology114:550-558(1998);Munz,B.等人,EMBO J.18:5205-5215(1999))、炎症应答(例如Rosendahl,A.等人,Am.J.Respir.Cell Mol.Biol.25:60-68(2001)、恶病质或消耗(Matzuk7 M.M.等人,Proc.Natl.Acad.Sci.USA 91:8817-8821(1994);Coerver,K.A.等人,Mol.Endocrinol.10:531543(1996);Cipriano,S.C.等人,Endocrinology 141:2319-2327(2000))、中枢神经系统疾病或病理性应答(例如Logan,A.等人,Eur.J.Neurosci.11:2367-2374(1999);Logan,A.等人,Exp.Neurol.159:504-510(1999);Masliah,E.等人,Neurochem.Int.39:393-400(2001);De Groot,C.J.A.等人,J.Neuropathol.Exp.Neural.58:174-187(1999);John,G.R.等人,Nat.Med.8:1115-1121(2002))和高血压(例如Dahly,A.J.等人,Am.J.Physiol.Regul.Integr Comp.Physiol.283:R757-767(2002))。研究已经表明:TGF-β和活化素可以协同作用以诱导细胞外基质产生(例如Sugiyama,M.等人,Gastroerterology 114;550-558(1998))。
因此,由此得出结论,通过本发明化合物抑制Smad2和Smad3的ALK5和/或ALK4磷酸化,可以用于治疗和预防涉及这些信号传导途径的病症。
活化素信号传导还参与肺障碍、特别是肺动脉高压和肺纤维化的发生。例如,活化素A在来自间质性肺纤维化患者的肺样品中的表达证明了活化素A在化生性上皮、增生性平滑肌细胞、脱屑细胞和肺泡巨噬细胞上有强表达。来自原发性或继发性肺动脉高压患者的肺动脉表明在平滑肌细胞上有大量的免疫反应性活化素A。这些发现表明,这种生长因子活化素A在与间质性肺纤维化和肺动脉高压有关的肺组织重塑的发病机理中具有潜在作用(Matsuse T等人,“免疫反应性活化素A蛋白在与间质性肺纤维化有关的重塑损伤中的表达”,Am.J.Pathol.1996 Mar;148(3):707-13)。成纤维细胞和相关结缔组织的增加是肺纤维化和肺动脉高压的特征。已经证明:活化素A可调节人肺成纤维细胞(HFL1)活性、特别是在增殖及分化为肌成纤维细胞方面,因此活化素A对肺成纤维细胞的增殖及分化为肌成纤维细胞具有潜在作用,它可以促使在肺纤维化和肺动脉高压中观察到的结构重塑(Ohga E等人,“活化素A对人肺成纤维细胞的增殖和分化的作用”,Biochem.Biophys.Res.Commun.1996年11月12日;228(2):391-6)。在大鼠中由博来霉素攻击介导的肺纤维化的引起,可使肺中浸润的巨噬细胞中的活化素A的表达上调,并且在聚积于纤维化区域中的成纤维细胞中被检测到。将滤泡抑素-活化素信号传导拮抗剂-施用于博来霉素处理的大鼠,显著减少了支气管肺泡灌洗液中巨噬细胞和嗜中性粒细胞的数量,并降低了蛋白质含量。滤泡抑素显著减少了浸润细胞的数量、改善了肺结构的破坏并减弱了肺纤维化(Aoki F等人,“滤泡抑素减弱博来霉素诱发的肺纤维化”,Am.J.Respir.Crit.Care Med.2005年9月15日;172(6):713-20)。因此,通过ALK4抑制来抑制活化素信号传导,也可以有益于治疗肺纤维化和肺动脉高压。
近来已经证明,通过其效应物Smad3而减少TGF-β信号传导,可提高骨基质的机械性能和矿物浓度以及骨量,使骨能够更好地抵抗骨折。这些结果表明:TGF-β信号传导的减少,可以被认为是治疗骨障碍的治疗靶标。(Balooch G等人Proc.Natl.Acad.Sci.USA.2005年12月27日;102(52):18813-8)。因此,抑制ALK5的TGF-β1激活还可用于增加骨的矿物密度强度和含量,并且可以用于治疗多种病症,例如包括骨质减少、骨质疏松症、骨折和其中低骨矿物密度是疾病特征的其它障碍。
考虑到它们对ALK-5和/或ALK-4受体的抑制,本发明的活性剂可用于治疗由ALK-5和/或ALK-4受体介导的病症。本发明的治疗可以是对症治疗或预防性治疗。
因此,根据另外的方面,本发明提供了第一个方面所定义的化合物在制备治疗或预防由ALK-5抑制或ALK-4抑制介导的疾病或病症的药物中的用途。
由ALK-5抑制或ALK-4抑制介导的疾病或病症包括肾小球肾炎、糖尿病性肾病、狼疮性肾炎、高血压诱发的肾病、肾间质性纤维化、由药物接触的并发症引起的肾纤维化、与HIV有关的肾病、移植肾病、由所有病因引起的肝纤维化、归因于感染引起的肝功能障碍、酒精诱发的肝炎、胆系障碍、肺纤维化、肺动脉高压、急性肺损伤、成人呼吸窘迫综合征、特发性肺纤维化、慢性阻塞性肺病、由传染物或毒性物引起的肺部疾病、梗塞后心纤维化、充血性心力衰竭、扩张型心肌病、心肌炎、血管狭窄、再狭窄、动脉粥样硬化、眼瘢痕形成、角膜瘢痕形成、增殖性玻璃体视网膜病变、在由创伤或外科伤口引起的创伤愈合过程中发生的真皮中过多或肥厚性瘢痕或者瘢痕疙瘩形成、腹膜和皮下粘连、硬皮病、纤维硬化、进行性全身性硬化症、皮肌炎、多发性肌炎、关节炎、溃疡、神经系统功能受损、男性勃起机能障碍、阿尔茨海默病、雷诺综合征、纤维化癌、肿瘤转移生长、辐射诱发的纤维化、血栓形成,以及与钙耗竭或再吸收增加有关或者其中需要刺激骨形成和骨中钙固定的骨病症,如骨质减少和骨质疏松症。
由ALK-5抑制介导的疾病或病症特别包括慢性肾脏疾病、急性肾脏疾病、创伤愈合、关节炎、骨质疏松症、肾脏疾病、充血性心力衰竭、炎性或阻塞性气道疾病、肺动脉高压、溃疡(包括糖尿病性溃疡、慢性溃疡、胃溃疡和十二指肠溃疡)、眼疾病、角膜创伤、糖尿病性肾病、神经系统功能受损、阿尔茨海默病、动脉粥样硬化、腹膜和皮下粘连、其中纤维化是主要组分的任意疾病,包括但不限于肾纤维化、肺纤维化和肝纤维化,例如乙型肝炎病毒(HBV)、丙型肝炎病毒(HCV)、酒精诱发的肝炎、血色素沉着病、原发性胆汁性肝硬化、再狭窄、腹膜后纤维化、肠系膜纤维化、子宫内膜异位症、瘢痕疙瘩、癌症、骨功能异常、炎性障碍、皮肤瘢痕形成和光老化。
本发明适用的炎性或阻塞性气道疾病包括任何类型或起因的哮喘,包括内源性(非过敏性)哮喘和外源性(过敏性)哮喘。哮喘的治疗还应当理解为包含对显示喘鸣(wheezing)症状并被诊断为或可诊断为“喘鸣幼儿”的个体,例如小于4或5岁的个体的治疗,这是一种受到主要医学关注的已建立的患者类别,现在通常定义为初期或早期哮喘患者。(为方便起见,这种特定的哮喘病症被称为“喘鸣幼儿综合征”)。
在哮喘治疗中的预防有效性由以下效果来证明:症状发作如急性哮喘或支气管收缩发作的频率或严重度降低、肺功能改善或者气道高反应性改善。其还可通过对其它对症治疗的需求减少来证明,所谓对症治疗即当症状发作时用于或意欲对其进行限制或使其中止的治疗,例如抗炎性(例如皮质类固醇)或支气管扩张性治疗。哮喘的预防益处对易发生“晨降(morningdipping)”的个体尤其明显。“晨降”是公认的哮喘症状,常见于很大百分比的哮喘者,特征是例如在凌晨约4-6点间,即在与任何以前所施用的对症哮喘治疗通常间隔较长的时间内哮喘发作。
适用本发明的其它炎性或阻塞性气道疾病和病症包括成人/急性呼吸窘迫综合征(ARDS)、慢性阻塞性肺或气道疾病(COPD或COAD),包括慢性支气管炎或与之相关的呼吸困难、气肿,以及因其它药物治疗、尤其是其它吸入的药物治疗导致的气道高反应性的恶化。本发明还适用于治疗任何类型或病因的支气管炎,包括例如急性、花生仁吸入性、卡他性、格鲁布性、慢性或结核性支气管炎。本发明适用的其它炎性或阻塞性气道疾病包括任何类型或病因的尘肺病(一种炎性的、通常是职业性的肺病,无论是慢性或还是急性都常伴有气道阻塞,由反复吸入粉尘引起),包括例如肺矾土沉着病、碳末沉着病、石棉沉着病、石末沉着病、鸵鸟毛尘肺、肺铁末沉着病、矽肺、烟草尘肺和棉屑沉着病。
优选由ALK-5抑制或ALK-4抑制介导的疾病或病症是肺动脉高压、肺纤维化、肝纤维化或骨质疏松症。
根据本发明所治疗的肺动脉高压包括:原发性肺动脉高压(PPH);继发性肺动脉高压(SPH);家族性PPH;散发性PPH;毛细血管前肺动脉高压;肺动脉高血压(PAH);肺动脉血压过高;特发性肺动脉高压;血栓性肺动脉病(TPA);丛原性肺动脉病(plexogenic pulmonary arteriopathy);功能性I至IV级肺动脉高压;以及与如下状况相关、相联系或继发于如下状况的肺动脉高压:左心室功能障碍、二尖瓣瓣膜病、缩窄性心包炎、主动脉狭窄、心肌病、纵隔纤维化、异常肺静脉引流、肺静脉闭塞性疾病、胶原血管病、先天性心脏病、HIV病毒感染、药物和毒素如芬氟拉明、先天性心脏病、肺静脉高压、慢性阻塞性肺病、间质性肺病、睡眠障碍性呼吸、肺泡换气不足障碍、长期暴露于高海拔、新生儿肺病、肺泡毛细血管发育不良、镰状细胞病、其它凝血障碍、慢性血栓栓塞、结缔组织疾病、狼疮、血吸虫病、结节病或肺毛细血管血管瘤病。
根据本发明所治疗的肺动脉高压最特别是与呼吸系统障碍和/或低氧血相关的肺动脉高压,包括慢性阻塞性肺病、间质性肺病、睡眠障碍性呼吸、肺泡换气不足障碍、长期暴露于高海拔、新生儿肺病和肺泡毛细血管发育不良,但尤其是慢性阻塞性肺病。
肺纤维化特别包括特发性肺纤维化。
本发明的化合物还可以用于治疗肌肉疾病,包括肌萎缩(例如废用)、肌营养不良(例如Duchenne肌营养不良、Becker肌营养不良、Limb-Gordle肌营养不良、面-肩-肱型肌营养不良)、少肌症和恶病质。
肌肉疾病如肌肉萎缩和营养不良的治疗是很大程度上未满足的医学需要。只有很少的化合物被批准用于各种肌肉障碍、主要用于癌症引起的和HIV肌肉废用或恶病质的范围,少数其他药物在药品核准标示外(off-label)用于这些适应症。此外,这些药物中的大部分仅解决重量减轻而不特定地影响肌肉的生长和功能。因此,需要有效的疗法来治疗与恶病质(例如在癌症、HIV和COPD中)、废用性萎缩、少肌症和营养不良相关的肌肉疾病有关的功能缺损。
肌肉生长抑制因子(myostatin)是转化生长因子β(TGF-β)家族的成员,它是骨骼肌量的关键负调节物。在双肌牛和具有骨骼肌肥厚的人体中检测到在肌肉生长抑制因子基因中的不同突变(McPherron等人(1997)Nature387:83-90;Schuelke等人(2004)N.Engl.J.Med.350:2682-2688)。在多项体内和体外研究中证实了肌肉生长抑制因子对骨骼肌生长和障碍的重要作用。例如,小鼠中肌肉生长抑制因子的肌肉特异性过表达可引起肌肉量损失(Reisz-Porszasz等人(2003)AJP-Endo.285:876-888),而没有肌肉生长抑制因子的小鼠的骨骼肌量增加并且体脂肪减少(Lin等人(2002)Biochem.Biophys.Res.Comm.291:701-706)。相应地,全身性施用肌肉生长抑制因子可引起恶病质(Zimmers等人(2002)Science 296:1486-1488),而抑制肌肉生长抑制因子、例如通过肌肉生长抑制因子中和抗体JA16抑制肌肉生长抑制因子,可增加野生型和营养不良的mdx小鼠的肌肉量和强度(Bogdanovich等人(2002)Nature 420:418-421.2002;Wagner等人(2002)Ann.Neurol.52:832-836;Wolfman等人(2003)Proc.Natl.Acad.Sci.100(26):15842-15846)。此外,还已经在实验和临床肌肉萎缩中如在患有人免疫缺陷病毒(HIV)、癌症或肝硬化的患者中以及在老年和处于糖皮质激素治疗下的少肌症中,观察到了肌肉生长抑制因子水平升高(Ma等人(2003)Am.J.Physiol.Endocrinol.Metab.285:E363-371;Gonzales-Cadavid等人(1998)Proc.Natl.Acad.Sci.95:14938-14943;还参见Reisz-Porszasz等人(2003)AJP-Endo.285:876-888和Jespersen等人(2006)Scand.J.Med.Sci.Sports.16:74-82)。这些发现表明:肌肉生长抑制因子抑制剂作为对肌萎缩和营养不良的治疗具有高潜力。
肌肉生长抑制因子的作用方式仍然在研究中。相对充分认可的是:肌肉生长抑制因子通过Smad2/3进行信号传导(Lee S.J.(2004)Ann.Rev.Dev.Biol.20:61-86)。此外,已显示:成熟的肌肉生长抑制因子通过脂肪细胞中的活化素IIb型和活化素受体样激酶(ALK)受体起作用(Rebbarpragada等人(2003)Mol.Cell.Biol.23:7230-7242)。但是,没有描述骨骼肌细胞中的各个发现。据信,肌肉生长抑制因子通过ALK信号传导而抑制分化和引起萎缩。此外,ALK信号传导的抑制可促进skMC分化并引起skMC肥厚。
骨质疏松症是以低骨量和骨组织微结构劣化、随后骨脆性和骨折危险性增加为特征的全身性骨骼障碍。骨质疏松综合征是多面性的,包括原发性障碍如绝经后或与年龄有关的骨质疏松症,以及伴随疾病状态或给药出现的继发性病症。骨基质的机械性能和组成以及骨量和结构是骨抵抗骨折能力的关键决定因素。
因此在另一方面,本发明包括预防或治疗与钙耗竭或再吸收增加有关或者其中需要刺激骨形成和骨中钙固定的骨病症的方法,其中将有效量的如上文所定义的式I化合物或其可药用的和药学上可裂解的酯或酸加成盐施用于需要该治疗的患者。
在另一方面,本发明包括用于预防或治疗与钙耗竭或再吸收增加有关或者其中需要刺激骨形成和骨中钙固定的骨病症的药物组合物,其包含如上文所定义的式I化合物或其可药用的和药学上可裂解的酯或酸加成盐以及可药用的赋形剂、稀释剂或载体。
下文实施例的化合物通常具有低于2μM、且多数低于1μM的IC50值。例如实施例1、3、6、8和11的化合物分别具有0.335、0.592、0.261、0.265和0.024μM的IC50值。
ALK5的激酶活性通过测定掺入通用底物酪蛋白中的放射标记的磷酸盐[33P]来评价。将人ALK5的激酶结构域(氨基酸200-503)与N-末端组氨酸标记融合。通过在氨基酸204位的点突变(苏氨酸转变为天冬氨酸,ALK5T204D)使得ALK5的激酶活性为组成型,激酶构建体被改造以从昆虫细胞中的杆状病毒表达构建体中被表达。将纯化的、重组表达的、组氨酸标记的ALK5T204D蛋白以5.4mg/ml溶解在50mM Tris-HCl pH 8.0、150mMNaCl、5mM DTT中。在使用当天将ALK5 T204D用测定缓冲液(测定缓冲液:20mM Tris-HCl pH 7.4、10mM MgCl2、2mM MnCl2)溶解至2.5μg/ml。
将测试化合物和参考化合物溶解于不含DTT而含5%(v/v)DMSO的测定缓冲液中。将测试和参考化合物的储备液用含DTT(1.25mM)且含有4.5%(v/v)DMSO的测定缓冲液稀释。将10μl测试或参考化合物加入到U形底的96孔板的适宜孔中。通过在没有ALK5激酶抑制剂参考化合物的存在下测定ALK5 T204D活性来测定总酶活性。通过在ALK5激酶抑制剂参考化合物的存在下测定ALK5 T204D的活性来确定非特异性结合(NSB)。每孔加入10μl脱磷酸化的酪蛋白储备液(将脱磷酸化的酪蛋白以20mg/ml溶解在ddH2O中)(200μg/孔最终测定浓度)。每孔加入20μl ALK5T204D(2.5μg/ml溶液)(50ng/孔最终测定浓度)。将板于室温孵育10分钟。
将10μl ATP混合物加入到孔中以引发反应(0.66nM[33P]ATP/1μM未标记的ATP/孔最终测定浓度)。ATP混合物制备如下:将未标记的ATP(3mM)溶解在ddH2O中,将pH调至7.4。[33P]ATP的储备浓度为10μCi/μl。将适宜体积的[33P]ATP加入到未标记的ATP溶液中,以使每孔的最终测定浓度为0.1μCi。加入ATP混合物后,将板于室温孵育50分钟。加入50μL终止缓冲液(20mM Tris-HCl pH 7.4、10mM EDTA)使激酶反应终止。
将75μl/孔从反应板中转移至Multiscreen-IP板(MultiScreen-IP板如下制备:每孔加入50μL 70%(v/v)乙醇并于室温孵育5分钟。通过MultiScreenHTS真空歧管部件(Millipore,目录号MSVMHT500)抽吸移去乙醇。通过加入200μl/孔ddH2O将板洗涤2次)。将MultiScreen-IP板于室温孵育30分钟以使酪蛋白与板结合。通过加入200μl/孔100mM磷酸溶液将MultiScreen-IP板洗涤3次,从MultiScreen-IP板的背部将衬垫小心取出,将板在烘箱中干燥30分钟。将MultiScreen-IP板进行背部密封,加入50μLMicroscintTM20,然后将板进行顶部密封,在TopCountTM读板器上使用33P闪烁方法对放射标记的酪蛋白进行检测和定量。
本发明的活性剂还可用作与其它药物如抗炎药物、支气管扩张药物、抗组胺药物、解充血药物或镇咳药物组合使用的共同治疗活性剂,特别是在治疗阻塞性或炎性气道疾病、例如上文提到的那些疾病中,例如作为这类药物的治疗活性的增强剂或者作为减少这类药物的所需剂量或潜在副作用的手段。本发明的活性剂可以与一种或多种其它药物混合在固定的药物组合物中,或者它可以单独地在其它药物之前、与之同时或在其它药物之后施用。
这类抗炎药包括:类固醇,特别是糖皮质激素如布地奈德、倍氯米松、氟替卡松、环索奈德或莫米松,或者在WO 02/88167、WO 02/12266、WO02/100879或WO 02/00679(尤其是实施例3、11、14、17、19、26、34、37、39、51、60、67、72、73、90、99和101的那些)描述的甾类,以及非甾体类激动剂,如在WO 00/00531、WO 02/10143、WO 03/82280、WO03/82787、WO 03/104195、WO 04/05229中描述的那些;LTB4拮抗剂,如BIIL 284、CP-195543、DPC11870、LTB4乙醇酰胺、LY 293111、LY255283、CGS025019C、CP-195543、ONO-4057、SB 209247和SC-53228,以及在US 5451700和WO 04/108720中描述的那些;LTD4拮抗剂,如孟鲁司特、普仑司特、扎鲁司特、安可来、SR2640、Wy-48,252、ICI 198615、MK-571、LY-171883、Ro 24-5913和L-648051;多巴胺受体激动剂,如卡麦角林、溴隐亭、罗匹尼罗和4-羟基-7-[2-[[2-[[3-(2-苯基乙氧基)-丙基]磺酰基]乙基]氨基]乙基]-2(3H)-苯并噻唑酮及其可药用盐(盐酸盐是Viozan-阿斯利康公司);PDE4抑制剂,如西洛司特(Ariflo葛兰素史克公司)、罗氟司特(Byk Gulden)、V-11294A(Napp)、BAY19-8004(拜耳公司)、SCH-351591(先灵葆雅公司)、阿罗茶碱(Almirall Prodesfarma)、PD189659/PD168787(Parke-Davis)、AWD-12-281(Asta Medica)、CDC-801(Celgene)、SelCID(TM)CC-10004(Celgene)、VM554/UM565(Vernalis)、T-440(Tanabe)、KW-4490(Kyowa HakkoKogyo)和GRC 3886(Oglemilast,Glenmark),以及那些在WO 92/19594、WO 93/19749、WO 93/19750、WO 93/19751、WO 98/18796、WO 99/16766、WO 01/13953、WO 03/39544、WO 03/104204、WO 03/104205、WO04/00814、WO 04/00839和WO 04/05258(默克公司)、WO 04/18450、WO04/18451、WO 04/18457、WO 04/18465、WO 04/18431、WO 04/18449、WO 04/18450、WO 04/18451、WO 04/18457、WO 04/18465、WO 04/019944、WO 04/19945、WO 04/45607、WO 04/37805、WO 04/63197、WO 04/103998、WO 04/111044、WO 05/12252、WO 05/12253、WO 05/13995、WO 05/30212、WO 05/30725、WO 05/87744、WO 05/87745、WO 05/87749和WO 05/90345中描述的那些;A2a激动剂,例如在EP 409595A2、EP 1052264、EP1241176、WO 94/17090、WO 96/02543、WO 96/02553、WO 98/28319、WO 99/24449、WO 99/24450、WO 99/24451、WO 99/38877、WO 99/41267、WO 99/67263、WO 99/67264、WO 99/67265、WO 99/67266、WO 00/23457、WO 00/77018、WO 00/78774、WO 01/23399、WO 01/27130、WO 01/27131、WO 01/60835、WO 01/94368、WO 02/00676、WO 02/22630、WO 02/96462、WO 03/86408、WO 04/39762、WO 04/39766、WO 04/45618和WO 04/46083中描述的那些;以及A2b拮抗剂,例如在WO 02/42298和WO 03/42214中描述的那些。
这类支气管扩张药包括β-2肾上腺素受体激动剂。适宜的β-2肾上腺素受体激动剂包括:舒喘灵(沙丁胺醇)、奥西那林、特布他林、沙美特罗、非诺特罗、丙卡特罗和尤其是福莫特罗、卡莫特罗(carmoterol)及其可药用盐,以及引入本文作为参考的WO 00/75114的式I化合物(游离或盐或溶剂化物形式)、优选其实施例的化合物、尤其是下式化合物及其可药用盐,
以及WO 04/16601的式I化合物(游离或盐或溶剂化物形式)以及下列的化合物:EP 147719、EP 1440966、EP 1460064、EP 1477167、EP 1574501、JP 05025045、JP 2005187357、US 2002/0055651、US 2004/0242622、US2004/0229904、US 2005/0133417、US 2005/5159448、US 2005/5159448、US 2005/171147、US 2005/182091、US 2005/182092、US 2005/209227、US2005/256115、US 2005/277632、US 2005/272769、US 2005/239778、US2005/215542、US 2005/215590、US 2006/19991、US 2006/58530、WO93/18007、WO 99/64035、WO 01/42193、WO 01/83462、WO 02/66422、WO 02/70490、WO 02/76933、WO 03/24439、WO 03/42160、WO 03/42164、WO 03/72539、WO 03/91204、WO 03/99764、WO 04/16578、WO 04/22547、WO 04/32921、WO 04/33412、WO 04/37768、WO 04/37773、WO 04/37807、WO 04/39762、WO 04/39766、WO 04/45618 WO 04/46083、WO04/80964、WO 04/087142、WO 04/89892、WO 04/108675、WO 04/108676、WO 05/33121、WO 05/40103、WO 05/44787、WO 05/58867、WO 05/65650、WO 05/66140、WO 05/70908、WO 05/74924、WO 05/77361、WO 05/90288、WO 05/92860、WO 05/92887、WO 05/90287、WO 05/95328、WO 05/102350、WO 06/56471、WO 06/74897或WO 06/8173。
这类支气管扩张药还包括:其它抗胆碱能或抗毒蕈碱剂,特别是福莫特罗、卡莫特罗(carmoterol)、异丙托溴铵、氧托溴铵、噻托铵盐(tiotropiumsalts)、格隆溴铵、CHF 4226(Chiesi)和SVT-40776,以及在EP 424021、US 3714357、US 5171744、US 2005/171147、US 2005/182091、WO 01/04118、WO 02/00652、WO 02/51841、WO 02/53564、WO 03/00840、WO 03/33495、WO 03/53966、WO 03/87094、WO 04/18422、WO 04/05285、WO 04/96800、WO 05/77361和WO 06/48225中描述的那些。
适宜的双重抗炎和支气管扩张药包括双重β-2肾上腺素受体激动剂/毒蕈碱拮抗剂,例如在US 2004/0167167、US 2004/0242622、US 2005/182092、WO 04/74246和WO 04/74812中公开的那些。
适宜的抗组胺/抗过敏药物包括:扑热息痛、阿伐斯汀、阿司咪唑、氮卓斯汀、巴米品、盐酸西替立嗪、右氯苯那敏(cexchloropheniramine)、氯苯沙明、富马酸氯马斯汀、地氯雷他定、茶苯海明、二甲茚定、苯海拉明、多西拉敏、依巴斯汀、依美斯汀、依匹斯汀、盐酸非索非那定、酮替芬、左卡巴斯汀、氯雷他定、氯苯甲嗪、咪唑斯汀、非尼拉敏、异丙嗪和特芬那定(tefenadine),以及在JP 2004107299、WO 03/099807和WO 04/026841中公开的那些(包括任何可能存在的其可药用的酸加成盐)。
根据本发明的另外的实施方案,本发明的活性剂可以用作其它治疗的辅助剂或佐剂,所述的其它治疗例如使用骨再吸收抑制剂的治疗、例如在骨质疏松症治疗中,特别是采用如下药物的治疗:钙、降钙素或其类似物或衍生物、例如鲑鱼、鳗鱼或人降钙素,类固醇激素、例如雌激素、部分雌激素激动剂或雌激素-孕激素联合,SERM(选择性雌激素受体调节剂)、例如雷洛昔芬、拉索昔芬、TSE-424、FC1271、替勃龙(Livial A)、维生素D或其类似物,或者PTH、PTH片段或PTH衍生物、例如PTH(1-84)、PTH(1-34)、PTH(1-36)、PTH(1-38)、PTH(1-31)NH2或PTS 893。
根据上文,本发明还提供了治疗阻塞性或炎性气道疾病的方法,该方法包括向需要其的个体、特别是人类个体施用如上文所述的式I化合物或者其可药用盐或溶剂化物。在另一方面,本发明提供了用于制备治疗阻塞性或炎性气道疾病的药物的如上文所述的式I化合物或者其可药用盐或溶剂化物。
本发明的活性剂可以通过任意适宜的途径施用,例如经口服、例如以片剂或胶囊的形式;经胃肠外、例如经静脉内;局部施用于皮肤,例如用于治疗银屑病;经鼻内,例如用于治疗枯草热;或者优选经吸入,特别是用于治疗阻塞性或炎性气道疾病。特别地,本发明的活性剂可以作为用于治疗COPD和哮喘的可吸入制剂进行递送。
另一方面,本发明还提供了药物组合物,其包含游离形式或者其可药用盐或溶剂化物形式的式I化合物以及任选的可药用稀释剂或载体。这类组合物可以使用常规的稀释剂或赋形剂以及制剂领域中已知的技术制备。因此,口服剂型可以包括片剂和胶囊剂。用于局部施用的制剂可以采取乳膏剂、软膏剂、凝胶剂或透皮传递系统如贴剂的形式。用于吸入的组合物可以包含气溶胶或者其它可雾化的制剂或干粉制剂。
当活性成分的可吸入形式是气溶胶组合物时,吸入装置可以是设置有适于传递定量、例如10至100μl、如25至50μl组合物的阀的气溶胶小瓶,即称为定量吸入器的装置。适宜的这类气溶胶小瓶和用于在其中包含处于压力下的气雾剂组合物的方法是吸入治疗领域技术人员众所周知的。例如,气雾剂组合物可以从例如EP-A-0642992中描述的包被罐(coated can)中施用。当活性成分的可吸入形式是可雾化的水性、有机或水性/有机分散液时,吸入装置可以是已知的喷雾器、例如常规的气动喷雾器如空气喷射喷雾器或超声喷雾器,它们可以例如含有1至50ml、通常为1至10ml的分散液;或者是手提式喷雾器、有时称为软雾或软喷雾吸入器,例如电子控制装置如AERx(Aradigm,US)或Aerodose(Aerogen),或机械装置、例如允许有比常规喷雾器小得多的喷雾体积如10至100μl的RESPIMAT(Boehringer Ingelheim)喷雾器。当活性成分的可吸入形式是精细粉碎的颗粒形式时,吸入装置可以例如是适于从含有干粉、包含剂量单位的(A)和/或(B)的胶囊或泡罩中递送干粉的干粉吸入装置,或者适合于每喷传递例如3-25mg干粉、包含剂量单位的(A)和/或(B)的多剂量干粉吸入(MDPI)装置。干粉组合物优选含有稀释剂或载体如乳糖,以及帮助防止由水分引起产品性能变坏的化合物如硬脂酸镁。适宜的这类干粉吸入装置包括在US3991761(包括AEROLIZERTM装置)、WO 05/113042、WO 97/20589(包括CERTIHALERTM装置)、WO 97/30743(包括TWISTHALERTM装置)和WO05/37353(包括GYROHALERTM装置)中公开的装置。
本发明还包括:(A)可吸入形式的游离或者可药用盐或溶剂化物形式的如上文所述的式I化合物;(B)包含可吸入形式的此类化合物以及可吸入形式的可药用载体的可吸入药物;(C)包含可吸入形式的此类化合物以及可吸入装置的药物产品;和(D)包含可吸入形式的此类化合物的可吸入装置。
用于实施本发明的本发明活性剂的剂量当然将根据例如待治疗的具体病症、所需效果和施用方式而变化。一般而言,用于吸入施用的适宜的日剂量约为每位患者0.0001至30mg/kg、通常为0.01至10mg,而对于口服施用,适宜的日剂量约为0.01至100mg/kg。
本发明通过以下实施例说明。
实施例
本发明特别优选的化合物包括下表1中所示的化合物,制备方法在下文中描述。
表1
一般条件:
使用电喷射离子化在LCMS系统上进行质谱分析。这些是Agilent1100 HPLC/Micromass Platform Mass Spectrometer组合或者WatersAcquity UPLC与SQD Mass Spectrometer。[M+H]+是指单同位素分子重量。
1H-NMR:使用ICON-NMR在Bruker UltrashieldTM 400(400MHz)波谱仪或在Bruker AVANCE 400NMR波谱仪上进行。在298K下进行波谱检测,并使用以ppm表示的溶剂峰、化学位移(δ值)作为参数,偶合常数(J)用Hz表示,波谱裂分模式表示为单峰(s)、双峰(d)、三重峰(t)、四重峰(q)、多重峰或多个交叠信号(m),宽信号(br),溶剂在括号内给出。
所用缩写具有以下含义:
AcOH是乙酸,DCM是二氯甲烷,DME是二甲基乙二醇,DMF是二甲基甲酰胺,TEA是三乙胺,Et2O是乙醚,EtOAc是乙酸乙酯,EtOH是乙醇,HATU是2-(3H-[1,2,3]三唑并[4,5-b]吡啶-3-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(V),h是小时,HPLC是高效色谱,MeCN是乙腈,MgSO4是硫酸镁,NaBH(OAc)3是三乙酰氧基硼氢化钠,NaOMe是甲醇钠,NMP是N-甲基-2-吡咯烷酮,PdCl2(dppf).DCM是[1,1-二(二苯基膦基)-二茂铁]二氯化钯(II)与二氯甲烷复合物,PdCl2(PPh3)2是二氯二(三苯基膦)-钯(II),PS是支撑聚合物,RT是室温,SCX-2是强阳离子交换柱(例如得自Biotage的IsoluteSCX-2柱),TFA是三氟乙酸且THF是四氢呋喃。
最终化合物的制备
实施例1
{4-[5-(6-氯-2-吡啶-2-基-嘧啶-4-基)-吡啶-3-基]-苯基}-(4-异丙基-哌嗪-1-基)-甲酮
将(4-异丙基哌嗪-1-基)(4-(5-(4,4,5,5-四甲基-[1,3,2]-二氧杂硼杂环戊烷-2-基)吡啶-3-基)-苯基)-甲酮(中间体I)(1.5当量,402mg)在DME(1ml)和2M碳酸钠(0.62ml)中的溶液用4,6-二氯-2-吡啶-2-基-嘧啶(中间体C)(1当量,139mg)处理,并放置在氩气中。加入PdCl2(dppf).DCM(0.1当量,45mg),并将该反应混合物用微波辐射在90℃下加热90分钟。冷却至室温后,将该混合物在DCM/水之间分配,并分离有机部分,用盐水洗涤,干燥(MgSO4)并真空浓缩。将粗的残余物在硅胶色谱上用0-10%MeOH在DCM中的溶液洗脱纯化,得到标题化合物[M+H]+=499/501,为固体。
实施例2
4-苄氧基-6-[5-(3-甲氧基-苯基)-吡啶-3-基]-2-吡啶-2-基-嘧啶
步骤1:4-氯-6-[5-(3-甲氧基-苯基)-吡啶-3-基]-2-吡啶-2-基-嘧啶
将5-(3-甲氧基-苯基)-吡啶硼酸盐酸化物(中间体D)(1当量,59mg)在DME(1ml)和2M碳酸钠(0.4ml)中的溶液用4,6-二氯-2-吡啶-2-基-嘧啶(中间体C)(1当量,50mg)处理,并放置在氩气中。加入PdCl2(dppf).DCM(0.1当量,16mg),并将该反应混合物用微波辐射在90℃下加热1h。冷却至室温后,将该混合物在EtOAc/水之间分配,分离有机部分,用盐水洗涤,干燥(MgSO4)并真空浓缩。将粗的残余物用反相柱色谱(IsoluteTM C18,0-100%乙腈的水溶液-0.1%TFA)纯化,将合适的流份合并并真空浓缩。将残余物装入SCX-2柱,用MeOH、随后用2M NH3的MeOH溶液洗脱。将氨的甲醇溶液流分真空浓缩,并真空干燥过夜,得到标题化合物[M+H]+=375/377。
步骤2:4-苄氧基-6-[5-(3-甲氧基-苯基)-吡啶-3-基]-2-吡啶-2-基-嘧啶
在惰性气体氩气中向叔丁醇钾(2当量,18.6mg)在DMF(1ml)的混悬液中加入苄基醇(2当量,7.2μl)。在室温下搅拌15分钟后,将该混合物用4-氯-6-[5-(3-甲氧基-苯基)-吡啶-3-基]-2-吡啶-2-基-嘧啶(1当量,31mg)溶液逐滴进行处理,并随后在室温下搅拌5小时。将该反应物用水(4ml)猝灭,并将该混合物用EtOAc萃取。合并有机萃取物,用盐水洗涤,干燥(MgSO4)并真空浓缩。将残余物装入SCX-2柱(1g)上用MeOH,随后用2M NH3的MeOH溶液洗脱,真空浓缩该氨的甲醇溶液流分并真空干燥过夜,得到标题化合物[M+H]+=447,为油状物。
实施例3
(4-异丙基-哌嗪-1-基)-{4-[5-(2-吡啶-2-基-嘧啶-4-基)-吡啶-3-基]-苯基}-甲酮
将搅拌过的4-(4-异丙基哌嗪-1-羰基)苯基硼酸(中间体E)(1.2当量,53mg)和2M碳酸钠溶液(2当量,2ml)在DME(1ml)中的溶液在N2中用4-(5-溴-吡啶-3-基)-2-吡啶-2-基-嘧啶(中间体H)(1当量,50mg)处理,随后用PdCl2(dppf).DCM(0.1当量,13mg)处理。将该混合物用微波辐射在90℃下加热90分钟,并随后冷却至室温。将该混合物用DCM萃取,并将有机萃取物用水洗涤。真空除去溶剂,并将粗的产物用反相柱色谱(IsoluteTMC18,0-80%乙腈的水溶液-0.1%TFA)纯化,将合适的流份合并,并真空浓缩。将残余物装入SCX-2柱上,用MeOH,随后用2M NH3的MeOH溶液洗脱。将该氨的甲醇溶液流分真空浓缩,并真空干燥过夜,得到标题化合物[M+H]+=465,为黄色固体。
实施例4
4-{5-[4-(4-异丙基-哌嗪-1-基甲基)-苯基]-吡啶-3-基}-2-吡啶-2-基-嘧啶
按照与实施例3类似的方法,用4-((4-异丙基哌嗪-1-基)甲基)苯基硼酸(中间体F)代替4-(4-异丙基哌嗪-1-羰基)苯基硼酸(中间体E)来制备该化合物。[M+H]+=451,为黄色固体。
实施例5
3-[2-(6-吡啶-3-基-2-吡啶-2-基-嘧啶-4-基氧基)-乙基]-1H-吲哚
步骤1:3-[2-(6-吡啶-3-基-2-吡啶-2-基-嘧啶-4-基氧基)-乙基]-1H-吲哚
和2-[1-(6-吡啶-3-基-2-吡啶-2-基-嘧啶-4-基)-1H-吲哚-3-基]-乙醇的混合物
按照与实施例2类似的方法,从4-氯-6-吡啶-3-基-2-吡啶-2-基-嘧啶(中间体A)和3-(2-羟基乙基)吲哚制备标题化合物。
步骤2:3-[2-(6-吡啶-3-基-2-吡啶-2-基-嘧啶-4-基氧基)-乙基]-1H-吲哚
将步骤1中的混合物(1当量,111.7mg)在DCM(8ml)中的溶液用PS-甲苯磺酰氯(8当量,1.44g),随后用吡啶(16ml)处理。将该混合物在室温下振荡48小时,随后过滤并用DCM(3x)和THF(3x)洗涤。真空浓缩滤液并将所得粗的残余物经反相柱色谱(C18,0-100%乙腈的水溶液-0.1%TFA)纯化,将合适的流份合并并真空浓缩。将残余物装入SCX-2柱上用MeOH,随后用2M NH3的MeOH溶液洗脱。合并该氨的甲醇溶液流分并真空浓缩,真空干燥过夜得到标题化合物[M+H]+=394,为胶状物。
实施例6
3-{2-[2-(6-甲基-吡啶-2-基)-6-吡啶-3-基-嘧啶-4-基氧基]-乙基}-1H-吲哚
按照与实施例5类似的方法,从4-氯-2-(3-甲基-吡啶-2-基)-6-吡啶-3-基-嘧啶(中间体G)制备该化合物:[M+H]+=408,为油状物。
实施例7
(4-{5-[6-氯-2-(6-甲基-吡啶-2-基)-嘧啶-4-基]-吡啶-3-基}-苯基)-(4-异丙基-哌嗪-1-基)-甲酮
按照与实施例1类似的方法,从4,6-二氯-2-(6-甲基-吡啶-2-基)-嘧啶(中间体B)和(4-异丙基哌嗪-1-基)(4-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-3-基)苯基)甲酮(中间体I)制备该化合物:[M+H]+=513/515,为褐色固体。
实施例8
(4-{5-[6-苄氧基-2-(6-甲基-吡啶-2-基)-嘧啶-4-基]-吡啶-3-基}-苯基)-(4-异丙基-哌嗪-1-基)-甲酮
按照与实施例2类似的方法,从(4-{5-[6-氯-2-(6-甲基-吡啶-2-基)-嘧啶-4-基]-吡啶-3-基}-苯基)-(4-异丙基-哌嗪-1-基)-甲酮(实施例7)制备该化合物:[M+H]+=585,为黄色固体。
实施例9
(4-异丙基-哌嗪-1-基)-(4-{5-[6-甲氧基-2-(6-甲基-吡啶-2-基)-嘧啶-4-基]-吡啶-3-基}-苯基)-甲酮
按照与实施例2类似的方法,从(4-{5-[6-氯-2-(6-甲基-吡啶-2-基)-嘧啶-4-基]-吡啶-3-基}-苯基)-(4-异丙基-哌嗪-1-基)-甲酮(实施例7)和甲醇制备该化合物:[M+H]+=509,为白色固体。
实施例10
(4-{5-[6-羟基-2-(6-甲基-吡啶-2-基)-嘧啶-4-基]-吡啶-3-基}-苯基)-(4-异丙基-哌嗪-1-基)-甲酮
将(4-{5-[6-苄氧基-2-(6-甲基-吡啶-2-基)-嘧啶-4-基]-吡啶-3-基}-苯基)-(4-异丙基-哌嗪-1-基)-甲酮(实施例8)(1当量,30mg)在无水DCM(0.6ml)中的溶液在N2中用三甲基硅烷基碘化物(12当量,83.6μl)处理。在室温下搅拌过夜后,将该反应物通过加入MeOH(5ml)猝灭,并继续搅拌45分钟。真空除去溶剂,并将残余物装入SCX-2柱(1g)上用MeOH,随后用2M NH3的MeOH溶液洗脱。将该氨的甲醇溶液流分合并,真空浓缩并真空干燥过夜得到标题化合物[M+H]+=495,为白色固体。
实施例11
{4-[5-(6-苄氧基-2-吡啶-2-基-嘧啶-4-基)-吡啶-3-基]-苯基}-(4-异丙基-哌嗪-1-基)-甲酮
按照与实施例2类似的方法,从{4-[5-(6-氯-2-吡啶-2-基-嘧啶-4-基)-吡啶-3-基]-苯基}-(4-异丙基-哌嗪-1-基)-甲酮(实施例1)制备该化合物:[M+H]+=571,为黄色固体。
1H NMR(400MHz,MeOD-d4)9.39(d,2.04Hz,1H),9.06(m,1H),8.98(d,2.20Hz,1H),8.78(m,1H),8.64(m,1H),8.05(t,1H),7.97(d,8.36Hz,2H),7.66-7.55(m,5H),7.42-7.39(m,4H),5.70(s,2H),4.59(br,1H),3.60(br hump,4H),3.00(br hump,4H),1.25(d,6.44Hz,6H)。
实施例12
{4-[5-(6-异丙氧基-2-吡啶-2-基-嘧啶-4-基)-吡啶-3-基]-苯基}-(4-异丙基-哌嗪-1-基)-甲酮
按照与实施例2类似的方法,从{4-[5-(6-氯-2-吡啶-2-基-嘧啶-4-基)-吡啶-3-基]-苯基}-(4-异丙基-哌嗪-1-基)-甲酮(实施例1)和异丙醇制备该化合物:[M+H]+=523,为浅黄色固体。
实施例13
4-叔丁基-6-{5-[4-(4-甲基-哌嗪-1-基甲基)-苯基]-吡啶-3-基}-2-吡啶-2-基-嘧啶
步骤A:3-溴-5-三甲基硅烷基乙炔基-吡啶:
在惰性气体氮气中向3,5-二溴吡啶(1.0当量,5.0g,20.9mmol)在TEA(100ml)的溶液中加入碘化亚铜(I)(0.1当量,406mg,2.09mmol)和PdCl2(PPh3)2(0.1当量,1.5g,2.09mmol)。加入三甲基硅烷基乙炔(1.2当量,3.6ml,25mmol),并将所得混合物在室温下搅拌2小时。真空除去溶剂,并将残余物在水和DCM之间分配。分离有机部分,并用饱和NaHCO3水溶液洗涤,干燥(MgSO4)并真空浓缩。经柱色谱(己烷/DCM)纯化,得到标题化合物;[M+H]+=254/256。
步骤B:1-(5-溴-吡啶-3-基)-4,4-二甲基-戊-1-炔-3-酮:
将3-溴-5-三甲基硅烷基乙炔基-吡啶(1.0当量,1.22g,4.78mmol)、特戊酰氯(1.1.当量,0.647ml,5.26mmol)和碘化亚铜(I)(0.2当量,95mg,0.96mmol)溶于DMF(8ml)中。将所得混合物用微波辐射在120℃下加热30分钟。过滤该混合物并用EtOAc洗涤。真空浓缩滤液并在饱和NaHCO3水溶液和EtOAc之间分配。分离有机部分,干燥(MgSO4)并真空浓缩,得到标题化合物;[M+H]+=266/268。
步骤C:4-(5-溴-吡啶-3-基)-6-叔丁基-2-吡啶-2-基-嘧啶:
向1-(5-溴-吡啶-3-基)-4,4-二甲基-戊-1-炔-3-酮(1当量,770mg,2.89mmol)在THF(12ml)的溶液中加入吡啶-2-甲脒(1.5当量,684mg,4.34mmol)和Na2CO3(2.4当量,736mg,6.94mmol)。将所得混合物用微波辐射在150℃下加热1h。真空除去溶剂并将残余物在饱和NaHCO3水溶液和DCM之间分配。将有机部分干燥(MgSO4)并真空浓缩。将所得残余物用柱色谱(DCM/MeOH)纯化得到标题化合物;[M+H]+=369/371。
步骤D:4-叔丁基-6-{5-[4-(4-甲基-哌嗪-1-基甲基)-苯基]-吡啶-3-基}-2- 吡啶-2-基-嘧啶:
向4-(5-溴-吡啶-3-基)-6-叔丁基-2-吡啶-2-基-嘧啶(1当量,200mg,0.542mmol)在EtOH/DME(2ml,1∶1)的溶液中加入4-(4-甲基-哌嗪-1-基甲基)-苯基-硼酸(1.1当量,174mg,0.596mmol)、Na2CO3水溶液(2M,3当量,0.812ml,1.63mmol)和Pd(PPh3)4(0.05当量,31mg,0.027mmol)。将所得混合物用微波辐射在140℃下加热20分钟。过滤该混合物,用DCM洗涤并真空浓缩。将残余物在饱和NaHCO3水溶液和DCM之间分配,用盐水洗涤有机层,干燥(MgSO4)并减压浓缩。将所得残余物用反相色谱纯化得到标题化合物;[M+H]+=479。1H NMR(CDCl3,400MHz):9.26(d,1H),8.95(d,1H),8.87(m,1H),8.66(t,1H),8.62(m,1H),7.88(td,1H),7.77(s,1H),7.64(d,2H),7.47(d,2H),7.41(ddd,1H),3.58(s,2H),2.60-2.43(m,8H),2.32(s,3H),1.51(s,9H)。
实施例14-15
按照类似于实施例4的方法,使用合适的硼酸来制备二甲基-((R)-1-{4-[5-(2-吡啶-2-基-嘧啶-4-基)-吡啶-3-基]-苄基}-吡咯烷-3-基)-胺(实施例14)和二甲基-((R)-1-{3-[5-(2-吡啶-2-基-嘧啶-4-基)-吡啶-3-基]-苄基}-吡咯烷-3-基)-胺(实施例15)的化合物。这些硼酸可以按照类似于中间体F的方法,使用合适的市售的起始化合物来制备。
实施例16
(4-{5-[6-氯-2-(6-甲基-吡啶-2-基)-嘧啶-4-基]-吡啶-3-基}-苯基)-(3-二甲基氨基-吡咯烷-1-基)-甲酮
按照类似于实施例7的方法,用合适的硼酸酯代替4-异丙基哌嗪-1-基)(4-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-3-基)苯基)甲酮(中间体I)来制备该化合物。所述硼酸酯按照类似于中间体I的方法,用合适的胺制备。[M+H]+=499。
实施例17
(1-{4-[5-(6-甲氧基-2-吡啶-2-基-嘧啶-4-基)-吡啶-3-基]-苄基}-吡咯烷-3-基)-二甲基-胺
按照类似于实施例9的方法,用合适的硼酸代替4-(4-异丙基哌嗪-1-羰基)苯基硼酸(中间体E)且用吡啶-2-甲脒代替6-甲基-吡啶-2-甲脒来制备该化合物。所述硼酸按照类似于中间体F的方法,用合适的胺制备;[M+H]+=467.
实施例18
(4-{5-[6-苄氧基-2-(6-甲基-吡啶-2-基)-嘧啶-4-基]-吡啶-3-基}-苯基)-(3-二甲基氨基-吡咯烷-1-基)-甲酮
按照与实施例8类似的方法,从(4-{5-[6-氯-2-(6-甲基-吡啶-2-基)-嘧啶-4-基]-吡啶-3-基}-苯基)-(3-二甲基氨基-吡咯烷-1-基)-甲酮(实施例16)和苄基醇制备该化合物;[M+H]+=571。
实施例19
4-叔丁基-6-{5-[4-(4-甲基-哌嗪-1-基甲基)-苯基]-吡啶-3-基}-2-(6-甲基-吡啶-2-基)-嘧啶
按照与实施例13类似的方法,用6-甲基-吡啶-2-甲脒(中间体B,步骤2)代替吡啶-2-甲脒(步骤C)来制备该化合物;[M+H]+=493。
中间体化合物的制备
中间体A
4-氯-6-吡啶-3-基-2-吡啶-2-基-嘧啶
步骤1:6-吡啶-3-基-2-吡啶-2-基-3H-嘧啶-4-酮:
将吡啶-2-甲酰胺(1.2当量,3.76g)在水(13ml)中的溶液用NaOH(1.5当量,1.6g)在水(5ml)中的溶液缓慢处理。随后缓慢加入3-吡啶甲酰乙酸乙酯(1当量,3.76g)在EtOH(5ml)中的溶液,并将所得混合物在室温下搅拌过夜。通过过滤收集所得混悬液,并用最少体积的水(约5ml)洗涤。在真空炉中干燥该固体,得到标题化合物[M+H]+=251。
步骤2:4-氯-6-吡啶-3-基-2-吡啶-2-基-嘧啶:
在惰性气体中向6-吡啶-3-基-2-吡啶-2-基-3H-嘧啶-4-酮(1当量,0.26mmol,0.035g)中逐滴加入磷酰氯(15当量,3.9mmol,0.36ml),随后小心加入五氯化磷(1当量,0.26mmol,0.054g)。在100℃下4小时后,将该反应混合物缓慢加入冰/水中。用NaHCO3将pH调至pH7,并将水部分用EtOAc萃取。分离合并的有机萃取物,用盐水洗涤,干燥(MgSO4)并真空浓缩。将粗的产物经快速色谱法用0-100%MeOH在DCM中的溶液洗脱纯化,得到4-氯-6-吡啶-3-基-2-吡啶-2-基-嘧啶,为白色固体。[M+H]+=269/271。
中间体B
4,6-二氯-2-(6-甲基-吡啶-2-基)-嘧啶
步骤1:N-甲氧基-6-甲基-吡啶-2-甲脒
在惰性气体氩气中向6-甲基-2-吡啶甲腈(1当量,42.3mmol,5.00g)在无水MeOH(20ml)的溶液中加入0.5M甲醇钠在MeOH中的溶液(1.1当量,46.6mmol,93.1ml)。将该反应混合物在室温下搅拌过夜,并随后真空浓缩。将残余物溶于DCM中并用水洗涤。将有机部分干燥(MgSO4)并真空浓缩,得到标题化合物,为橙色固体。[M+H]+=151。
步骤2:6-甲基-吡啶-2-甲脒
在室温下向N-甲氧基-6-甲基-吡啶-2-甲脒(1当量,32.9mmol,4.94g)在EtOH(40ml)和水(10ml)的溶液中加入氯化铵(1当量,32.9mmol,1.76g)。将所得混合物加热至80℃持续4小时,并随后冷却至室温过夜。真空除去溶剂,得到标题化合物,其不经进一步纯化用于随后步骤。[2M+H]+=271。
步骤3:2-(6-甲基-吡啶-2-基)-嘧啶-4,6-二醇
在惰性气体氩气中将6-甲基-吡啶-2-甲脒(步骤2)(1.2当量,8.23mmol,1.41g)在MeOH(5ml)中的溶液在室温下用丙二酸二甲酯(1当量,6.86mmol,1.04ml)和0.5M甲醇钠在MeOH中的溶液(3当量,20.6mmol,41.2ml)处理。将所得混合物加热回流过夜,并随后冷却至室温。将该混合物干燥装入硅胶上,并经快速色谱法用0-5%MeOH在DCM中的溶液洗脱纯化,得到标题化合物,为浅黄色固体。[M+H]+=204。
步骤4:4,6-二氯-2-(6-甲基-吡啶-2-基)-嘧啶
在惰性气体氩气中用磷酰氯(10当量,42.3mmol,3.87ml),随后用五氯化磷(1当量,4.23mmol,879mg)在室温下处理2-(6-甲基-吡啶-2-基)-嘧啶-4,6-二醇(1当量,4.23mmol,859mg)。将所得黄色混悬液在105℃加热6小时,并随后冷却至室温。冷却后,将该混合物逐滴加入冰水中。用NaHCO3将pH调至pH7,并将水部分用EtOAc萃取。将合并的有机萃取物用盐水洗涤,干燥(MgSO4)并真空浓缩。将粗的残余物干燥装入硅胶上,并经快速色谱法用100%的DCM洗脱纯化,得到标题化合物,为褐色固体。[M+H]+=240/242。
中间体C
4,6-二氯-2-吡啶-2-基-嘧啶
按照类似于中间体B的方法,从吡啶-2-甲脒制备该化合物。
中间体D
5-(3-甲氧基-苯基)-吡啶硼酸
步骤1:3-溴-5-(3-甲氧基-苯基)-吡啶
在惰性气体氩气中将3-甲氧基-苯基硼酸(1.0当量,300mg,1.27mmol)在DME(3ml)中的溶液和2M碳酸钠溶液(1.2ml)用3,5-二溴吡啶(300mg,1.27mmol),随后用PdCl2(dppf).DCM(0.1当量,93mg)处理,并随后在微波辐射下在90℃加热30分钟。将该混合物用DCM萃取,并用水洗涤该有机萃取物。真空除去溶剂,并将粗产物经硅胶色谱用0-30%EtOAc在异己烷中的溶液洗脱纯化,得到标题化合物。[M+H]+=265。
步骤2:5-(3-甲氧基-苯基)-吡啶硼酸盐酸化物
在惰性气体氩气中将3-溴-5-(3-甲氧基-苯基)-吡啶(180mg,0.68mmol)在无水THF(3ml)的溶液中用三异丙基硼酸酯处理,并随后冷却至-78℃。将该反应混合物用正丁基锂(2.5M的己烷溶液)逐滴进行处理,并随后历经2小时加温至室温。通过缓慢加入2M HCl猝灭该反应。将水部分用EtOAc洗涤,并随后真空浓缩,直至固体沉淀。过滤固体并用水(1ml)洗涤,得到标题化合物[M+H]+=230。
中间体E
4-(4-异丙基哌嗪-1-羰基)苯基硼酸
将4-羧基苯基硼酸(1当量,213mg)在DMF(5ml)中的溶液用1-异丙基哌嗪(1当量,155mg)处理,并将该反应混合物在室温下搅拌10分钟。加入TEA(1.2当量,0.202ml)和HATU(2.4当量,1.104g),并将所得混合物在室温下搅拌过夜。通过加入水猝灭该反应,并将该混合物用DCM(2x)萃取。将合并的有机部分用盐水洗涤,干燥(MgSO4)并真空浓缩。将残余物在50℃下真空干燥过夜,得到标题化合物,其不经进一步纯化直接使用。[M+H]+=277。
中间体F
4-((4-异丙基哌嗪-1-基)甲基)苯基硼酸
将4-甲醛苯基硼酸(1当量,1g)在DCM(25ml)中的冷却(0℃)溶液用异丙基哌嗪(1.2当量,1.03g),随后用AcOH(1.2当量,0.48ml)和NaBH(OAc)3(1.6当量,2.27g)处理。将反应混合物加温至室温并搅拌4小时。随后将该混合物冷却(0℃)并用水(约25ml)猝灭。将水部分用DCM(2x)洗涤,并真空浓缩得到黄色油状物。在40℃下将该油状物真空干燥过夜,并随后用DME(约50ml)研磨得到固体,将其过滤并干燥,得到标题化合物[M+H]+=263。
本文所述实施例合成所需的其它硼酸可以按照类似于中间体D、E和F的方法,使用合适的市售的起始化合物来制备。
中间体G
4-氯-2-(6-甲基-吡啶-2-基)-6-吡啶-3-基-嘧啶
按照类似于中间体A的方法,用6-甲基-吡啶-2-甲脒(中间体B,步骤2)代替吡啶-2-甲酰胺(步骤1)来制备该化合物。
中间体H
4-(5-溴-吡啶-3-基)-2-吡啶-2-基-嘧啶
步骤1:(E)-1-(5-溴-吡啶-3-基)-3-二甲基氨基-丙烯酮
将3-乙酰基-5-溴吡啶(1当量,0.2g)和二甲氧基甲基-二甲基-胺(2.5当量,133μl)在100℃下加热1小时。冷却至室温后,加入Et2O/异己烷(10ml的1∶1混合物),其导致黄色沉淀形成。过滤固体并用Et2O/异己烷(20ml的1∶1混合物)洗涤。将所得固体在室温下真空干燥3小时,得到标题化合物,为浅褐色固体。[M+H]+=255/257。
步骤2:4-(5-溴-吡啶-3-基)-2-吡啶-2-基-嘧啶
在N2中将NaOMe(2.6当量,56mg)在无水MeOH(3ml)中的溶液于室温下搅拌10分钟,并随后用吡啶-2-甲脒(1当量,63mg)处理。在室温下搅拌20分钟后,加入(E)-1-(5-溴-吡啶-3-基)-3-二甲基氨基-丙烯酮(步骤1)(1当量,0.1g),并将该混合物回流加热过夜。将该反应混合物冷却至室温,并随后真空除去溶剂。将残余物用Et2O(约10ml)研磨,过滤所得浅褐色固体并用Et2O洗涤,得到标题化合物[M+H]+=313/315。
中间体I
(4-异丙基哌嗪-1-基)-(4-(5-(4,4,5,5-四甲基-[1,3,2]-二氧杂硼杂环戊烷-2-基)吡啶-3-基)苯基)-甲酮
步骤1:(4-异丙基哌嗪-1-基)-(4-(4,4,5,5-四甲基-[1,3,2]-二氧杂硼杂环
戊烷-2-基)苯基)-甲酮
将4-羧基苯基硼酸酯(1当量,0.5g)在DMF(5ml)中的溶液用HATU(2.4当量,1.82g)、TEA(1.2当量,334μl)和N-异丙基哌嗪(1.2当量,343μl)处理,并在室温下搅拌90分钟。将所得混合物在水和DCM之间分配,并分离有机部分。将水部分用DCM(3x)萃取,并将合并的有机萃取物用盐水洗涤,干燥(MgSO4)并真空浓缩。将残余物在40℃下真空干燥过夜,得到标题化合物,为褐色固体[M+H]+=359。
步骤2:(4-(5-溴吡啶-3-基)苯基)-(4-异丙基哌嗪-1-基)-甲酮
将(4-异丙基哌嗪-1-基)-(4-(4,4,5,5-四甲基-[1,3,2]-二氧杂硼杂环戊烷-2-基)苯基)-甲酮(步骤1)(1.0当量,778mg)在DME(4ml)中的溶液和2M碳酸钠溶液(2当量,2.2ml)用3,5-二溴吡啶(1当量,514mg),随后用PdCl2(dppf).DCM(0.1当量,159mg)处理。将所得混合物用微波辐射在90℃下加热1h。将该混合物用DCM萃取,并将有机萃取物用水洗涤。真空除去溶剂,并将粗产物经硅胶色谱用0-100%EtOAc的异己烷溶液,随后用0-5%MeOH的DCM溶液洗脱纯化,得到标题化合物[M+H]+=388/390。
步骤3:(4-异丙基哌嗪-1-基)-(4-(5-(4,4,5,5-四甲基-[1,3,2]-二氧杂硼杂
环戊烷-2-基)吡啶-3-基)苯基)-甲酮
Claims (13)
1.化合物,其独立地选自以下化合物:
4-苄氧基-6-[5-(3-甲氧基-苯基)-吡啶-3-基]-2-吡啶-2-基-嘧啶,
(4-异丙基-哌嗪-1-基)-{4-[5-(2-吡啶-2-基-嘧啶-4-基)-吡啶-3-基]-苯基}-甲酮,
4-{5-[4-(4-异丙基-哌嗪-1-基甲基)-苯基]-吡啶-3-基}-2-吡啶-2-基-嘧啶,
3-[2-(6-吡啶-3-基-2-吡啶-2-基-嘧啶-4-基氧基)-乙基]-1H-吲哚,
3-{2-[2-(6-甲基-吡啶-2-基)-6-吡啶-3-基-嘧啶-4-基氧基]-乙基}-1H-吲哚,
(4-{5-[6-氯-2-(6-甲基-吡啶-2-基)-嘧啶-4-基]-吡啶-3-基}-苯基)-(4-异丙基-哌嗪-1-基)-甲酮,
(4-{5-[6-苄氧基-2-(6-甲基-吡啶-2-基)-嘧啶-4-基]-吡啶-3-基}-苯基)-(4-异丙基-哌嗪-1-基)-甲酮,
(4-异丙基-哌嗪-1-基)-(4-{5-[6-甲氧基-2-(6-甲基-吡啶-2-基)-嘧啶-4-基]-吡啶-3-基}-苯基)-甲酮,
(4-{5-[6-羟基-2-(6-甲基-吡啶-2-基)-嘧啶-4-基]-吡啶-3-基}-苯基)-(4-异丙基-哌嗪-1-基)-甲酮,
{4-[5-(6-氯-2-吡啶-2-基-嘧啶-4-基)-吡啶-3-基]-苯基}-(4-异丙基-哌嗪-1-基)-甲酮,
{4-[5-(6-苄氧基-2-吡啶-2-基-嘧啶-4-基)-吡啶-3-基]-苯基}-(4-异丙基-哌嗪-1-基)-甲酮,
{4-[5-(6-异丙氧基-2-吡啶-2-基-嘧啶-4-基)-吡啶-3-基]-苯基}-(4-异丙基-哌嗪-1-基)-甲酮,
4-叔丁基-6-{5-[4-(4-甲基-哌嗪-1-基甲基)-苯基]-吡啶-3-基}-2-吡啶-2-基-嘧啶,
二甲基-((R)-1-{4-[5-(2-吡啶-2-基-嘧啶-4-基)-吡啶-3-基]-苄基}-吡咯烷-3-基)-胺,
二甲基-((R)-1-{3-[5-(2-吡啶-2-基-嘧啶-4-基)-吡啶-3-基]-苄基}-吡咯烷-3-基)-胺,
(4-{5-[6-氯-2-(6-甲基-吡啶-2-基)-嘧啶-4-基]-吡啶-3-基}-苯基)-(3-二甲基氨基-吡咯烷-1-基)-甲酮,
(1-{4-[5-(6-甲氧基-2-吡啶-2-基-嘧啶-4-基)-吡啶-3-基]-苄基}-吡咯烷-3-基)-二甲基-胺,
(4-{5-[6-苄氧基-2-(6-甲基-吡啶-2-基)-嘧啶-4-基]-吡啶-3-基}-苯基)-(3-二甲基氨基-吡咯烷-1-基)-甲酮,
4-叔丁基-6-{5-[4-(4-甲基-哌嗪-1-基甲基)-苯基]-吡啶-3-基}-2-(6-甲基-吡啶-2-基)-嘧啶,
及其盐。
2.药物组合物,其包含权利要求1的化合物和其它药物,所述其它药物为抗炎药物、支气管扩张药物、抗组胺药物、解充血药物或镇咳药物。
3.药物组合物,其包含作为活性成分的权利要求1的化合物和合适的可药用赋形剂。
4.权利要求1的化合物在制备治疗由ALK-5受体所介导的病症的药物中的用途。
5.权利要求4的用途,其中所述病症选自肺动脉高压、创伤愈合、骨质疏松症、肾脏疾病、充血性心力衰竭、溃疡、眼疾病、糖尿病性肾病、神经系统功能受损、阿尔茨海默病、动脉粥样硬化、腹膜和皮下粘连、肺纤维化和肝纤维化、乙型肝炎、丙型肝炎、酒精诱发的肝炎、血色素沉着病、原发性胆汁性肝硬化、再狭窄、腹膜后纤维化、肠系膜纤维化、子宫内膜异位症、瘢痕疙瘩、癌症、骨功能异常、炎性障碍和光老化。
6.权利要求4的用途,其中所述病症是肺动脉高压。
7.权利要求4的用途,其中所述病症是肺纤维化或肝纤维化。
8.权利要求4的用途,其中所述病症是骨质疏松症。
9.权利要求4的用途,其中所述病症是慢性肾脏疾病或急性肾脏疾病。
10.权利要求4的用途,其中所述病症是肾纤维化。
11.权利要求4的用途,其中所述病症是角膜创伤。
12.权利要求4的用途,其中所述病症是皮肤瘢痕形成。
13.权利要求4的用途,其中所述病症是关节炎。
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- 2009-01-09 WO PCT/EP2009/050222 patent/WO2009087224A1/en active Application Filing
- 2009-01-09 EP EP09700452.7A patent/EP2231642B1/en not_active Not-in-force
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JP2011509278A (ja) | 2011-03-24 |
EA201001129A1 (ru) | 2011-02-28 |
EP2231642A1 (en) | 2010-09-29 |
EP2231642B1 (en) | 2013-10-23 |
CN101910153A (zh) | 2010-12-08 |
AU2009203693B2 (en) | 2012-06-07 |
US8431578B2 (en) | 2013-04-30 |
AU2009203693A1 (en) | 2009-07-16 |
MX2010007604A (es) | 2010-08-02 |
BRPI0906838A2 (pt) | 2015-07-14 |
CA2711637A1 (en) | 2009-07-16 |
JP5584138B2 (ja) | 2014-09-03 |
WO2009087224A1 (en) | 2009-07-16 |
PT2231642E (pt) | 2014-03-12 |
PL2231642T3 (pl) | 2014-04-30 |
ES2442930T3 (es) | 2014-02-14 |
KR20100113557A (ko) | 2010-10-21 |
US20100298337A1 (en) | 2010-11-25 |
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