CN109384785B - 吡咯并吡啶酮类衍生物、其制备方法及其在医药上的用途 - Google Patents
吡咯并吡啶酮类衍生物、其制备方法及其在医药上的用途 Download PDFInfo
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- CN109384785B CN109384785B CN201710680316.3A CN201710680316A CN109384785B CN 109384785 B CN109384785 B CN 109384785B CN 201710680316 A CN201710680316 A CN 201710680316A CN 109384785 B CN109384785 B CN 109384785B
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- C—CHEMISTRY; METALLURGY
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明涉及吡咯并吡啶酮类衍生物及其制备方法和医药用途。具体而言,本发明涉及一种通式(I)所示的吡咯并吡啶酮类衍生物、其制备方法及其可药用的盐,以及它们作为治疗剂,特别是作为溴结构域蛋白抑制剂的用途,其中通式(I)中的各取代基的定义与说明书中的定义相同。
Description
发明领域
本发明属于医药领域,具体涉及一种新的吡咯并吡啶酮类衍生物、其制备方法及含有该衍生物的药物组合物,以及它们作为治疗剂,特别是作为溴结构域蛋白抑制剂的用途。
背景技术
近年来,肿瘤成为全球范围内导致人类死亡的主要原因之一。肿瘤普遍具有总体治愈率低且复发率高等特点,因此预防、治疗以及抑制肿瘤复发具有重要的科研价值,实现肿瘤的预防和治愈具有相当的紧迫性和挑战性。表观遗传调控的异常是导致肿瘤发生的重要因素之一。
溴结构域(bromodomain)是一种能识别N-乙酰化赖氨酸残基的蛋白结构域。含溴结构域的蛋白质的BET家族包括四个成员(BRD2、BRD3、BRD4和BRDt)。BET家族的每个成员都使用两个溴结构域来识别,主要(但并非排外地)在组蛋白蛋白质的氨基末端尾巴(amino-terminal tail)发现N-乙酰化的赖氨酸残基。通过将转录因子募集至染色质内的具体基因组位置来调节基因表达。例如,组蛋白连接的BRD4将转录因子P-TEFb募集至启动子,导致表达涉及细胞周期进程的基因子集(Yang et al.,Mol.Cell.Biol.28:967-976(2008))。BRD2和BRD3还起生长促进基因的转录调节剂的作用。近来的研究已经证实以BET溴结构域为靶点来治疗多种癌症((Zuber et al.,Nature 478:524-528(2011);Mertz et al.,Proc.Natl.Acad.Sci.108:16669-16674(2011);Delmore et al.,Cell 146:1-14,(2011);Dawson et al.,Nature 478:529-533(2011))、动脉粥样硬化、炎症(Huang et al.,Mol.Cell.Biol.29:1375-1387(2009))和HIV感染。
最新研究发现,BRD4蛋白介导的表观遗传异常与癌基因的过表达密切相关,并与癌细胞的生长增殖关系密切。BRD4是含溴结构域和额外终端域家族蛋白(Bromo and extraC-terminal domain,BET)蛋白家族的一员,由于在抗肿瘤方面的潜在价值,引起了各大制药公司和科研机构的极大关注。近期还发现BRD4在病毒基因的转录调控中也扮演了重要角色,并且与病毒瘤的发病机制存在一定联系。这些研究结果说明BRD4与多种肿瘤存在密切联系,尤其在一些至今难以治愈或者尚无有效治疗手段的肿瘤中具有重要作用,其与肿瘤关系的研究为肿瘤治疗提供了新的策略。通过作用于BRD4蛋白溴结构域的小分子化合物,干扰溴结构域与乙酰化赖氨酸的特异性结合,影响肿瘤细胞内的转录调节和其它细胞过程,可以实现对肿瘤的靶向治疗。因此,BRD4蛋白是一个非常有前景的表观遗传新靶点,而作用于BRD4蛋白溴结构域的小分子抑制剂在肿瘤研究中也有着广阔的应用前景,而且有可能从中开发出新型抗肿瘤药物。
目前已经公开了一系列的溴结构域蛋白抑制剂专利,其中包括WO2011054846、WO2008092231、WO2012075383和WO2016139292等,其中WO2016139292公开了实施例1化合物。目前处于临床III期的药物为Apabetalone,处于临床II期的药物包括GSK-525762A、INCB-54329和BMS-986158等,处于临床I期的药物包括mivebresib等。但这些对于抗肿瘤的研究是远远不够的,仍有必要研究和开发新的溴结构域蛋白抑制剂。
发明内容
本发明提供一种通式(I)所示的吡咯并吡啶酮类化合物或其立体异构体、互变异构体或其可药用的盐:
其中:
R1选自芳基或杂芳基,优选为苯基,其中所述的芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、环烷基、杂环基、芳基、杂芳基、-NR6R7、-C(O)NR6R7、-OR8、-C(O)R8、-C(O)OR8或-NR6C(O)R7的取代基所取代;
R2和R3各自独立地选自氢原子、烷基、氰基、卤素、环烷基、杂环基、芳基、杂芳基、-NR6R7、-C(O)NR6R7、-OR8、-C(O)R8、-C(O)OR8或-NR6C(O)R7,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、环烷基、杂环基、芳基、杂芳基、-NR6R7、-C(O)NR6R7、-OR8、-C(O)R8、-C(O)OR8或-NR6C(O)R7的取代基所取代;
R4选自氢原子或烷基;优选为甲基或乙基;
R5选自氢原子、烷氧基或卤素;优选为氢原子;
R6、R7和R8各自独立地选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR9R10、-C(O)NR9R10、-C(O)R11、-C(O)OR11或-NR9C(O)R10的取代基所取代;
或者,R6和R7与相连接的N原子一起形成一个4~8元杂环基,其中4~8元杂环内含有一个或多个N、O、S(O)m原子,并且4~8元杂环上任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-NR9R10、-C(O)NR9R10、-C(O)R11、-C(O)OR11或-NR9C(O)R10的取代基所取代;
R9、R10和R11各自独立地选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代;且
m为0、1或2。
本发明的优选方案,一种通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中R1为苯基,所述的苯基进一步被一个或多个卤素所取代;其中所述的卤素优选为氟。
本发明的优选方案,一种通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中R2和R3各自独立地选自氢原子或-OR8;且R8选自烷基,优选为甲基。
本发明的典型化合物包括,但不限于:
或其立体异构体、互变异构体或其可药用的盐。
进一步,本发明提供一种通式(I)化合物的制备方法,该方法包括:
通式(Ie)化合物脱去N的保护基PG,得到通式(I)化合物;
其中:
PG为N的保护基团,优选为三取代的硅基;更优选为二甲基叔丁基硅基;
R4选自烷基;且
R1~R3和R5的定义如通式(I)中所述。
本发明提供一种通式(Ie)所示的化合物或其立体异构体、互变异构体或其可药用的盐,
其中:
PG为N的保护基团,优选为三取代的硅基;更优选为二甲基叔丁基硅基;且
R1~R5的定义如通式(I)中所述。
通式(Ie)的典型化合物包括,但不限于:
或其立体异构体、互变异构体或其可药用的盐。
进一步,本发明提供一种通式(Ie)化合物的制备方法,该方法包括:
通式(Ic)化合物与通式(Id)化合物进行缩合反应,得到通式(Ie)化合物;
其中:
X选自卤素原子,优选为氯或溴;
PG为N的保护基团,优选为三取代的硅基;更优选为二甲基叔丁基硅基;
R4选自烷基;且
R1~R3和R5的定义如通式(I)中所述。
更近一步,本发明提供一种药物组合物,所述的药物组合物含有有效剂量的通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐,及可药用的载体、赋形剂或它们的组合。
本发明提供一种抑制溴结构域蛋白的方法,其中包括将所述的受体与通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物相接触,其中所述的溴结构域蛋白优选为BRD2、BRD3和BRD4,更优选为BRD4。
本发明提供一种通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制备溴结构域蛋白抑制剂的药物中的用途,其中所述的溴结构域蛋白优选为BRD2、BRD3和BRD4,更优选为BRD4。
本发明提供一种通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制备治疗与溴结构域蛋白相关的疾病的药物中的用途,其中所述的疾病优选为癌症或炎症;其中所述的炎症优选为类风湿性关节炎、克隆恩病、湿疹、巨细胞性动脉炎、肝炎、炎性肠病、骨关节炎、胰腺炎、肺炎、银屑病、银屑病性关节炎、***性红斑狼疮、肾小球性肾炎、狼疮性肾炎、膜性肾小球肾炎或心肌炎;所述的炎症更优选为类风湿性关节炎;其中所述的癌症优选为小细胞肺癌、非小细胞肺癌、乳腺癌、结直肠癌、***癌、黑色素瘤、胰腺癌、神经胶质瘤、脑瘤、***、卵巢癌、胰腺癌、***癌、肾细胞癌、胃癌、膀胱癌、肝癌、睾丸核蛋白中线癌、多发性骨髓瘤、急性髓性白血病、急性淋巴细胞性白血病、慢性淋巴细胞性白血病、慢性髓细胞性白血病或慢性骨髓性白血病。
本发明提供一种通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制备治疗糖尿病性肾病、高血压性肾病、HIV-相关的肾病、多囊性肾病、肥胖、血脂异常、高胆固醇血症、阿尔茨海默病、代谢综合征、脂肪肝、II型糖尿病、胰岛素抵抗、糖尿病性视网膜病或糖尿病性神经病的药物中的用途。
发明的详细说明
除非有相反陈述,否则本发明在说明书和权利要求书中所使用的部分术语定义如下:
“烷基”当作一基团或一基团的一部分时是指包括C1-C20直链或者带有支链的脂肪烃基团。优选为C1-C10烷基,更优选为C1-C6烷基。烷基基团的实施例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代或未取代的。
“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上定义的烷基,代表性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-,2-或3-丁烯基等。烯基可以是任选取代的或未取代的。
“炔基”作为一基团或一基团的一部分时是指含有一个碳碳三键的脂肪烃基团,可为直链也可以带有支链。优先选择的是C2-C10的炔基,更优选C2-C6炔基,最优选C2-C4炔基。炔基基团的实施例包括,但不限于乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。炔基可以是取代或未取代的。
“环烷基”是指饱和或部分饱和的单环、稠环、桥环和螺环的碳环。优选为C3-C12环烷基,更优选为C3-C8环烷基,最优选为C3-C6环烷基。单环环烷基的实施例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等,优选环丙基、环己烯基。
“螺环烷基”指5至18元,两个或两个以上环状结构,且单环之间彼此共用一个碳原子(称螺原子)的多环基团,环内含有1个或多个双键,但没有一个环具有完全共轭的π电子的芳香***。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺、双螺或多螺环烷基,优选为单螺和双螺环烷基,优选为4元/5元、4元/6元、5元/5元或5元/6元。“螺环烷基”的非限制性实施例包括但不限于:螺[4.5]癸基、螺[4.4]壬基、螺[3.5]壬基、螺[2.4]庚基。
“稠环烷基”指5至18元,含有两个或两个以上环状结构彼此公用一对碳原子的全碳多环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子的芳香***,优选为6至12元,更优选为7至10元。根据组成环的数目可以分为双环、三环、吡啶酮或多环稠环烷基,优选为双环或三环,更优选为5元/5元或5元/6元双环烷基。“稠环烷基”的非限制性实施例包括但不限于:二环[3.1.0]己基、二环[3.2.0]庚-1-烯基、二环[3.2.0]庚基、十氢化萘基或十四氢菲基。
“桥环烷基”指5至18元,含有两个或两个以上环状结构,彼此共用两个不直接相连接碳原子的全碳多环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子的芳香***,优选为6至12元,更优选为7至10元。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、吡啶酮或多环桥环烷基,优选为双环、三环或吡啶酮,更有选为双环或三环。“桥环烷基”的非限制性实施例包括但不限于:(1s,4s)-二环[2.2.1]庚基、二环[3.2.1]辛基、(1s,5s)-二环o[3.3.1]壬基、二环[2.2.2]辛基、(1r,5r)-二环[3.3.2]癸基。
所述环烷基环可以稠合于芳基、杂芳基或杂环基环上,其中与母体结构连接在一起的环为环烷基,非限制性实施例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或未取代的。
“杂环基”、“杂环”或“杂环的”在本申请中可交换使用,都是指非芳香性杂环基,其中一个或多个成环的原子是杂原子,如氧、氮、硫原子等,包括单环、稠环、桥环和螺环。优选具有5至7元单环或7至10元双-或三环,其可以包含1,2或3个选自氮、氧和/或硫中的原子。“杂环基”的实例包括但不限于吗啉基,氧杂环丁烷基,硫代吗啉基,四氢吡喃基,1,1-二氧代-硫代吗啉基,哌啶基,2-氧代-哌啶基,吡咯烷基,2-氧代-吡咯烷基,哌嗪-2-酮,8-氧杂-3-氮杂-双环[3.2.1]辛基和哌嗪基。杂环基可以是取代或未取代的。
“螺杂环基”指5至18元,两个或两个以上环状结构,且单环之间彼此共用一个原子的多环基团,环内含有1个或多个双键,但没有一个环具有完全共轭的π电子的芳香***,其中一个或多个环原子选自氮、氧或S(O)m(其中m选自0、1或2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺杂环基、双螺杂环基或多螺杂环基,优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。“螺杂环基”的非限制性实施例包括但不限于:1,7-二氧杂螺[4.5]癸基、2-氧杂-7-氮杂螺[4.4]壬基、7-氧杂螺[3.5]壬基和5-氧杂螺[2.4]庚基。
“稠杂环基”指含有两个或两个以上环状结构彼此共用一对原子的全碳多环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子的芳香***,其中一个或多个环原子选自氮、氧或S(O)m(其中m选自0、1或2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、吡啶酮或多环稠杂环基,优选为双环或三环,更优选为5元/5元或5元/6元双环稠杂环基。“稠杂环基”的非限制性实施例包括但不限于:八氢吡咯并[3,4-c]吡咯基、八氢-1H-异吲哚基,3-氮杂二环[3.1.0]己基,八氢苯并[b][1,4]二噁英(dioxine)。
“桥杂环基”指5至14元,5至18元,含有两个或两个以上环状结构,彼此共用两个不直接相连接的原子的多环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子的芳香***,其中一个或多个环原子选自氮、氧或S(O)m(其中m选自0、1或2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、吡啶酮或多环桥杂环基,优选为双环、三环或吡啶酮,更有选为双环或三环。“稠杂环基”的非限制性实施例包括但不限于:2-氮杂二环[2.2.1]庚基,2-氮杂二环[2.2.2]辛基和2-氮杂二环[3.3.2]癸基。所述杂环基环可以稠合于芳基、杂芳基或环烷基环上,其中与母体结构连接在一起的环为杂环基。杂环基可以是任选取代的或未取代的。
“芳基”是指含有一个或者两个环的碳环芳香***,其中所述环可以以稠合的方式连接在一起。术语“芳基”包括比如苯基、萘基、四氢萘基的芳香基团。优选芳基为C6-C10芳基,更优选芳基为苯基和萘基,最优选为苯基。芳基可以是取代或未取代的。所述“芳基”可与杂芳基、杂环基或环烷基稠合,其中与母体结构连接在一起的为芳基环,非限制性实施例包括但不限于:
“杂芳基”是指芳香族5至6元单环或9至10元双环,其可以包含1至4个选自氮、氧和/或硫中的原子。“杂芳基”的实施例包括但不限于呋喃基,吡啶基,2-氧代-1,2-二氢吡啶基,哒嗪基,嘧啶基,吡嗪基,噻吩基,异噁唑基,噁唑基,噁二唑基,咪唑基,吡咯基,吡唑基,***基,四氮唑基,噻唑基,异噻唑基,1,2,3-噻二唑基,苯并间二氧杂环戊烯基,苯并咪唑基,吲哚基,异吲哚基,1,3-二氧代-异吲哚基,喹啉基,吲唑基,苯并异噻唑基,苯并噁唑基和苯并异噁唑基。杂芳基可以是取代或未取代的。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环,非限制性实施例包括但不限于:
“烷氧基”是指(烷基-O-)的基团。其中,烷基见本文有关定义。C1-C6的烷氧基为优先选择。其实例包括,但不限于:甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。
“羟基”指-OH基团。
“卤素”是指氟、氯、溴和碘,优选氯、溴和碘。
“氨基”指-NH2。
“氰基”指-CN。
“硝基”指-NO2。
“苄基”指-CH2-苯基。
“羧基”指-C(O)OH。
“羧酸酯基”指-C(O)O(烷基)或(环烷基),其中烷基、环烷基的定义如上所述。
“DMSO”指二甲基亚砜。
“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1~3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本说明书所述的“取代”或“取代的”,如无特别指出,均是指基团可被一个或多个选自以下的基团取代:烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、疏基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、=O、-NR6R7、-C(O)NR6R7、-OR8、-C(O)R8、-C(O)OR8或-NR6C(O)R7;
R6、R7和R8各自独立地选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基,其中所述烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-NR9R10、-C(O)NR8R10、-C(O)R11、-C(O)OR11或-NR9C(O)R10的取代基所取代;
或者,R6和R7与相连接的N原子一起形成一个4~8元杂环基,其中4~8元杂环内含有一个或多个N、O、S(O)m原子,并且4~8元杂环上进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-NR9R10、-C(O)NR8R10、-C(O)R11、-C(O)OR11或-NR9C(O)R10的取代基所取代;
R9、R10和R11各自独立地选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基,其中所述烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代;且
m为0、1或2。
“可药用的盐”是指上述化合物能保持原有生物活性并且适合于医药用途的某些盐类。式(I)所表示的化合物的可药用的盐可以为金属盐、与合适的酸形成的胺盐。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
本发明化合物的合成方法
为了完成本发明的目的,本发明采用如下技术方案:
本发明通式(I)所述的化合物或其立体异构体、互变异构体或其可药用盐的制备方法,包括以下步骤:
通式(Ia)化合物在碱性条件下,与N的保护试剂反应,得到通式(Ib)化合物;通式(Ib)化合物与PPh3X2反应,得到通式(Ic)化合物;通式(Ic)化合物与通式(Id)化合物反应,得到通式(Ie)化合物;通式(Ie)化合物进一步脱去N的保护基,得到通式(I)化合物;
其中:
X选自卤素原子,优选为氯或溴;
PG为N的保护基团,优选为三取代的硅基;更优选为二甲基叔丁基硅基;
R4选自烷基;且
R1~R3和R5的定义如通式(I)中所述;
上述制备方法中,碱性条件由有机碱或无机碱提供,有机碱优选自二异丙基乙胺、二异丙胺、吡啶、三乙胺、哌啶、N-甲基哌嗪、4-二甲氨吡啶,更优选为二异丙胺和三乙胺;无机碱优选自氢化钾、氢化钠、碳酸钠、碳酸钾、碳酸铯、氢氧化钠、氢氧化钾,更优选为氢化钠。
具体实施方式
以下结合实施例用于进一步描述本发明,但这些实施例并非限制着本发明的范围。
实施例
实施例给出了式(I)所表示的代表性化合物的制备及相关结构鉴定数据。必须说明,下述实施例是用于说明本发明而不是对本发明的限制。1H NMR图谱是用Bruker仪器(400MHz)测定而得,化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。1H NMR的表示方法:s=单峰,d=双重峰,t=三重峰,m=多重峰,br=变宽的,dd=双重峰的双重峰,dt=三重峰的双重峰。若提供偶合常数时,其单位为Hz。
质谱是用LC/MS仪测定得到,离子化方式可为ESI或APCI。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.2mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
在下列实施例中,除非另有指明,所有温度为摄氏温度,除非另有指明,各种起始原料和试剂来自市售或者是根据已知的方法合成,市售原料和试剂均不经进一步纯化直接使用,除非另有指明,市售厂家包括但不限于Aldrich Chemical Company,ABCR GmbH&Co.KG,Acros Organics,广赞化工科技有限公司和景颜化工科技有限公司等处购买。
CD3OD:氘代甲醇。
CDCl3:氘代氯仿。
DMSO-d6:氘代二甲基亚砜。
氩气氛是指反应瓶连接一个约1L容积的氩气气球。
实施例中无特殊说明,反应中的溶液是指水溶液。
对化合物进行纯化,采用硅胶柱层析洗脱剂体系和薄层色谱法,其中洗脱剂体系选自:A:石油醚和乙酸乙酯体系;B:二氯甲烷和甲醇体系;C:二氯甲烷:乙酸乙酯;其中溶剂的体积比根据化合物的极性不同而不同,也可以加入少量的酸性或碱性试剂进行调节,如醋酸或三乙胺等。
实施例1
N-(4-(2,4-二氟苯氧基)-3-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)乙烷亚胺基磺酰胺
第一步
二氯三苯基膦
氩气保护下,将三苯基膦1a(2.62g,10mmol)和六氯乙烷(2.37mmol,10mmol)溶于10mL氯仿中,70℃下反应6小时,得到二氯三苯基膦1b(10mL,1mol/L),反应液不需要处理直接用于下一步。
第二步
N-(叔丁基二甲基硅基)乙磺酰胺
氩气保护下,将乙磺酰胺1c(545.7mg,5mmol)溶于10mL干燥四氢呋喃中,0℃下加入氢化钠(300mg,7.5mmol),0℃下搅拌0.5小时。将叔丁基二甲基氯硅烷(979mg,6.5mmol)溶于2mL四氢呋喃中,0℃下滴加到上述反应液中,室温下反应1小时。将反应液降温至0℃,滴加10mL饱和氯化铵溶液,以乙酸乙酯(20mL×2)萃取,合并有机相,以无水硫酸钠干燥,减压浓缩,得到N-(叔丁基二甲基硅基)乙磺酰胺1d(1.12g,棕色油状),产率:100%。
第三步
N’-(叔丁基二甲基硅基)-N-(4-(2,4-二氟苯氧基)-3-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)乙烷亚胺基磺酰胺
氩气保护下,在二氯三苯基膦1b(1.5mL,1.5mmol)中,加入三乙胺(252mg,2.5mmol),室温下搅拌10分钟。降温至0℃,加入N-(叔丁基二甲基硅基)乙磺酰胺1d(112mg,0.5mmol)的氯仿(1mL)溶液,0℃下继续反应0.5小时,然后加4-(5-氨基-2-(2,4-二氟苯氧基)苯基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮1e(183.5mg,0.5mmol,根据WO2013097601制得)的氯仿(1mL)溶液,室温下反应3小时。加入10mL二氯甲烷稀释反应液,以饱和氯化钠溶液(10mL)洗涤,分去水层,有机相以无水硫酸钠干燥,减压浓缩,得到粗品N’-(叔丁基二甲基硅基)-N-(4-(2,4-二氟苯氧基)-3-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)乙烷亚胺基磺酰胺1f(100mg,棕色油状),产率:34.9%。
MS m/z(ESI):458.8[M-115]
第四步
N-(4-(2,4-二氟苯氧基)-3-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)乙烷亚胺基磺酰胺
将N’-(叔丁基二甲基硅基)-N-(4-(2,4-二氟苯氧基)-3-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)乙烷亚胺基磺酰胺1f(100mg,0.175mmol)溶于2mL的甲酸中,室温下反应1小时。将反应液减压浓缩,除去溶剂,加入100mL乙酸乙酯稀释,依次以饱和碳酸氢钠溶液(100mL)和饱和氯化钠溶液(100mL)洗涤,分去水层,有机相以无水硫酸钠干燥,减压浓缩,得到的残留物用薄层色谱法(展开剂:B体系)纯化,得到N-(4-(2,4-二氟苯氧基)-3-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)乙烷亚胺基磺酰胺1(22mg,白色固体),产率:27.5%。
MS m/z(ESI):458.8[M+1]
1H NMR(400MHz,DMSO-d6):δ12.01(s,1H),7.33-7.21(m,4H),6.97-6.92(m,3H),6.83-6.81(d,J=8.0Hz,1H),6.64(s,2H),6.26(s,1H),3.52(s,3H),3.19-3.13(m,2H),1.33-1.30(t,J=6.0Hz,3H).
生物学评价
测试例1、本发明化合物对BRD4蛋白活性测定
本发明优选化合物通过以下方法测试其针对BRD4蛋白的生物活性。
本测试方法采用Cisbio Assays公司的EPIGENEOUSTMBROMODOMAIN ASSAY在体外条件下,测试化合物对重组人源BRD4蛋白与乙酰化组蛋白多肽底物之间基于FRET(荧光能量共振转移)的相互作用的影响来表述化合物针对BRD4的生物活性。其中GST标记的重组人源BRD4(1/2)蛋白来源于BPS Bioscience,乙酰化组蛋白多肽底物[Lys(5,8,12,16)Ac]H4(1-21)-biotin peptide购于AnaSpec。
具体实验方法和流程可参考EPIGENEOUSTMBROMODOMAIN ASSAY试剂盒说明书,实验流程简述如下:
本发明中的化合物先溶解于DMSO中,随后以试剂盒中提供的缓冲液将其稀释至测试所需浓度(终浓度范围10μM-0.1nM)。将2μL化合物加入到384孔微孔板中,随后分别加入4uL以缓冲液稀释的GST标记的重组人源BRD4(1/2)蛋白和4μL乙酰化组蛋白多肽底物,最后向孔中加入偶联有铕系元素化合物的抗GST抗体和偶联有链酶亲和素的FRET受体d2各5uL,振荡混匀后以封板膜密封,并在室温下振荡孵育3~5小时。化合物每个浓度设复孔对照,对照孔和空白孔中加入2μL DMSO。随后在兼容TF-FRET模式的酶标仪上测定读取各孔在对应铕系元素激发波长下,发射波长为620nM和665nM下的荧光强度。通过与对照组的荧光强度数值进行比较计算化合物在各浓度点下的抑制率,进而通过GraphPad Prism 5软件中以化合物浓度对数-抑制率进行非线性回归分析并得到化合物抑制BRD4蛋白与乙酰化组蛋白多肽底物相互作用的IC50值。
表1本发明优选化合物对BRD4蛋白活性抑制的IC50数据
化合物 | IC<sub>50</sub>(nM)/BRD4(1/2) |
mivebresib | 23 |
实施例1 | 7.8 |
结论:本发明的优选化合物对于BRD4蛋白具有较好的抑制作用。
备注:mivebresib的结构式如下式所示,其制备方法参见WO2013097601。
测试例2、本发明化合物对***癌细胞(LNCaP)增殖抑制测定
本发明优选化合物的细胞水平活性通过CCK-8(Dojindo,东仁化学科技)以吸光度方法来检测化合物对细胞增殖的抑制作用。将处于对数生长期的***癌细胞LNCaP(购于中国科学院上海生命科学研究院细胞资源中心)以4000个每孔的密度接种至96孔培养板中,培养过夜后,加入不同浓度的测试化合物(终浓度浓度范围30μM~0.1nM)。在37℃,5%CO2条件下培养细胞72小时。培养结束后,向每孔加入适宜体积的CCK-8试剂(购于东仁化学科技(上海)有限公司,货号CK04)并在37℃下继续培养1~5小时,随后在酶标仪上读取各孔的在450nM下的吸光度数值。通过与对照组的吸光度数值进行比较计算化合物在各浓度点下的抑制率,进而通过GraphPad Prism 5软件中以化合物浓度对数-抑制率进行非线性回归分析并得到化合物抑制细胞增殖的IC50值。
表2本发明优选化合物对LNCaP细胞活性抑制的IC50值。
化合物 | IC<sub>50</sub>(nM)/LNCaP |
mivebresib | 4 |
实施例1 | 1.15 |
结论:本发明的优选化合物对于***癌细胞LNCaP增殖具有较好的抑制作用。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (11)
2.一种药物组合物,所述的药物组合物含有有效剂量的根据权利要求1所述的化合物或其可药用的盐,及可药用的载体、赋形剂或它们的组合。
3.根据权利要求1所述的化合物或其可药用的盐,或根据权利要求2所述的药物组合物在制备溴结构域蛋白抑制剂的药物中的用途。
4.根据权利要求3所述的用途,其中所述的溴结构域蛋白选自BRD2、BRD3和BRD4。
5.根据权利要求3所述的用途,其中所述的溴结构域蛋白为BRD4。
6.根据权利要求1所述的化合物或其可药用的盐,或根据权利要求2所述的药物组合物在制备治疗与溴结构域蛋白相关的疾病的药物中的用途。
7.根据权利要求6所述的用途,其中所述的疾病为癌症或炎症。
8.根据权利要求7所述的用途,其中所述的炎症选自类风湿性关节炎、克隆恩病、湿疹、巨细胞性动脉炎、肝炎、炎性肠病、骨关节炎、胰腺炎、肺炎、银屑病、银屑病性关节炎、***性红斑狼疮、肾小球性肾炎、狼疮性肾炎、膜性肾小球肾炎或心肌炎。
9.根据权利要求8所述的用途,其中所述的炎症为类风湿性关节炎。
10.根据权利要求7所述的用途,其中所述的癌症为小细胞肺癌、非小细胞肺癌、乳腺癌、结直肠癌、***癌、黑色素瘤、胰腺癌、神经胶质瘤、脑瘤、***、卵巢癌、胰腺癌、***癌、肾细胞癌、胃癌、膀胱癌、肝癌、睾丸核蛋白中线癌、多发性骨髓瘤、急性髓性白血病、急性淋巴细胞性白血病、慢性淋巴细胞性白血病、慢性髓细胞性白血病或慢性骨髓性白血病。
11.根据权利要求1所述的化合物或其可药用的盐,或根据权利要求2所述的药物组合物在制备治疗糖尿病性肾病、高血压性肾病、HIV-相关的肾病、多囊性肾病、肥胖、血脂异常、高胆固醇血症、阿尔茨海默病、代谢综合征、脂肪肝、II型糖尿病、胰岛素抵抗、糖尿病性视网膜病或糖尿病性神经病的药物中的用途。
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