CN107949557A - 作为mIDH1抑制剂的2‑芳基‑和2‑芳烷基‑苯并咪唑类 - Google Patents
作为mIDH1抑制剂的2‑芳基‑和2‑芳烷基‑苯并咪唑类 Download PDFInfo
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- CN107949557A CN107949557A CN201680051707.2A CN201680051707A CN107949557A CN 107949557 A CN107949557 A CN 107949557A CN 201680051707 A CN201680051707 A CN 201680051707A CN 107949557 A CN107949557 A CN 107949557A
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- Prior art keywords
- trimethylcyclohexyls
- methyl
- benzimidazole
- benzyl
- trifluoromethoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
本发明涉及通式(I)的2‑芳基‑和2‑芳烷基‑苯并咪唑类化合物:其中A、R1、R4、R5、R6、R7、R8、R9、R10和R11如本文所定义,还涉及制备所述化合物的方法、用于制备所述化合物的中间体化合物、含有所述化合物的药物组合物和联用药,以及所述化合物用于制备药物组合物的用途,以单一药剂或与其它活性组分的联用药形式用于治疗或预防疾病,尤其是肿瘤。
Description
本发明涉及本文所描述和所定义的通式(I)的2-芳基-和2-芳烷基-苯并咪唑化合物、制备所述化合物的方法、用于制备所述化合物的中间体化合物、含有所述化合物的药物组合物和联用药,以及所述化合物用于制备药物组合物的用途,所述药物组合物以单一药剂或与其它活性组分的联用药形式用于治疗或预防疾病,尤其是肿瘤。
发明背景
本发明涉及抑制突变的异柠檬酸脱氢酶1(mIDH1 R132H)的化合物、制备所述化合物的方法、含有所述化合物的药物组合物和联用药、所述化合物用于制备用于治疗或预防疾病的药物组合物的用途以及制备所述化合物使用的中间体化合物。
异柠檬酸脱氢酶(IDH)是细胞代谢中的关键酶,它使异柠檬酸转化为α-酮戊二酸,并且属于2个亚组,通过使用不同的电子受体来限定。它们中的两个,异柠檬酸脱氢酶1和2使用NADP(+)作为电子受体。IDH1位于细胞质和过氧化物酶体中,而IDH2位于线粒体中,作为TCA循环的组成部分,例如,在下面的反应中∶
异柠檬酸+ NADP+→ α-酮戊二酸 + CO2 + NADPH + H+
两种酶都起到同源二聚体的作用。
在各种肿瘤实体中,包括神经胶质瘤、急性骨髓性白血病(AML)、软骨肉瘤、胆管细胞癌、黑素瘤、前列腺癌、血管免疫母细胞的T细胞淋巴瘤等等,IDH1或IDH2在独立的氨基酸位置发生突变(Balss J. Acta Neuropathol. 2008 Dec; 116(6):597-602, Mardis ER,N Engl J Med. 2009 Sep 10; 361(11):1058-66, Amary MF, J Pathol. 2011 Jul;224(3):334-43, Borger DR, Oncologist. 2012;17(1):72-9, Shibata T, Am J Pathol.2011 Mar;178(3):1395-402, Ghiam AF, Oncogene. 2012 Aug 16; 31(33):3826,Cairns RA, Blood. 2012 Feb 23;119(8):1901-3)。这种突变始终是杂合的,并且互相排斥。已经在酶的催化域(负责2-酮戊二酸配位)的关键位置发现这些点突变的大部分,例如,IDH1R100、IDH1R132、IDH1G97和IDH2R140、IDH2R172(Dang L., Nature, 2009 Dec 10;462(7274):739-44)。在神经胶质瘤中,所有非原发性恶性胶质瘤的70%以上是IDH1突变的,并且在92.7%的IDH1突变的肿瘤当中,精氨酸被组氨酸替代(IDH1R132H)(Hartmann C, ActaNeuropathol. 2009 Oct; 118(4):469-74)。
在那些催化残基上替代野生型氨基酸,会引起酶的新生活性,使α-酮戊二酸转化为R-2-羟基戊二酸(2-HG)。2-HG是代谢废物,但也是肿瘤代谢物(oncometabolite),且被认为有助于肿瘤生成(Dang L., Nature, 2009 Dec 10;462(7274):739-44)。2-HG在正常细胞中仅以极低的水平生成,但隐藏IDH突变的细胞产生高水平的2-HG。在具有IDH突变的肿瘤中也发现了高数量的2-HG。在具有高2-HG水平的其它病症的患者中也描述了IDH突变,例如,在罕有的神经代谢病中,其特征在于超生理水平的2-HG(2-HG酸尿)(Kranendijk M,Science. 2010 Oct 15;330(6002):336)。
由此,抑制IDH突变和它的新生活性是肿瘤及其它IDH突变相关的病症的潜在治疗方案。
WO02/04425A2尤其涉及作为RNA依赖性RNA聚合酶的抑制剂的苯并咪唑衍生物。
WO05/014543A1涉及稠环化合物和其作为HCV聚合酶抑制剂的用途。
WO03/007945A1尤其涉及作为RNA依赖性RNA聚合酶的抑制剂的苯并咪唑甲酰胺类。
WO01/47883A1涉及用作丙型肝炎的治疗剂的苯并咪唑化合物。
EP0531883A1尤其涉及具有抑制聚集作用的脒基取代的苯并咪唑化合物。
WO2004064925尤其涉及作为RNA依赖性RNA聚合酶的抑制剂的酰基磺酰胺化合物。
WO2007043653公开了可以抑制sEH活性、提高EETs的苯并咪唑-5-甲酰胺衍生物。
然而,上述现有技术没有描述本文所定义的本发明的通式(I)的特定取代的苯并咪唑化合物,或本文所描述和所定义的其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐,或它们的混合物(以下简称为“本发明的化合物”),或它们的药理学活性。
现在已经发现,并且这构成了本发明的基础:所述本发明的化合物具有令人惊讶的和有利的性能。
尤其是,已经发现,所述本发明的化合物有效地抑制突变的异柠檬酸脱氢酶1(mIDH1 R132H),并因此可以用于治疗或预防无控的细胞生长、增殖和/或存活、不合适的细胞免疫响应或不合适的细胞炎性响应的疾病,或伴有无控的细胞生长、增殖和/或存活、不合适的细胞免疫响应或不合适的细胞炎性响应的疾病,例如:血液肿瘤、实体肿瘤和/或其转移病变,例如:白血病和脊髓发育不良综合征、恶性淋巴瘤(包括血管免疫母细胞的T细胞淋巴瘤)、头和颈部肿瘤,包括脑瘤和大脑转移病变(例如间变性星形细胞瘤、扩散性星形细胞瘤、恶性胶质瘤、寡枝神经胶质细胞瘤、继发性的多形性胶质母细胞瘤)、胸部肿瘤(包括非小细胞和小细胞肺肿瘤)、胃肠肿瘤(包括胆管细胞癌)、内分泌腺肿瘤、乳腺肿瘤及其它妇科肿瘤、泌尿系统肿瘤(包括肾、膀胱和前列腺肿瘤)、皮肤肿瘤和肉瘤(包括软骨肉瘤,和/或其转移病变)。
发明描述
按照第一个方面,本发明包括通式(I)的化合物∶
其中∶
A代表键或-CH2-或-(CH2)2-基团,
和
R5代表选自下列的基团∶
-C(O)OH、-C(=O)OR12、HOC(=O)-(C1-C6-烷基)-、R12OC(=O)-(C1-C6-烷基)-、HOC(=O)-(C2-C6-烯基)-、R12OC(=O)-(C2-C6-烯基)-、HOC(=O)-(C1-C6-烷氧基)-、R12OC(=O)-(C1-C6-烷氧基)-、-C(=O)N(R13)R14、R13(R14)NC(=O)-(C1-C6-烷基)-、R13(R14)NC(=O)-(C2-C6-烯基)-、R13(R14)NC(=O)-(C1-C6-烷氧基)-和氰基;
或
A代表-CH(CH3)-或-C(CH3)2-基团,
R5代表选自下列的基团∶
-C(=O)OH、HOC(=O)-(C1-C6-烷基)-、R12OC(=O)-(C1-C6-烷基)-、HOC(=O)-(C2-C6-烯基)-、R12OC(=O)-(C2-C6-烯基)-、HOC(=O)-(C1-C6-烷氧基)-、R12OC(=O)-(C1-C6-烷氧基)-、-C(=O)N(R13)R14、R13(R14)NC(=O)-(C1-C6-烷基)-、R13(R14)NC(=O)-(C2-C6-烯基)-、R13(R14)NC(=O)-(C1-C6-烷氧基)-和氰基;
R1代表苯基或5、6或9元杂芳基,
其中苯基任选被一个、两个或三个取代基取代,所述取代基彼此独立地是卤素原子或选自下列的基团∶C1-C6-烷基、C3-C6-环烷基、C1-C6-烷氧基、C3-C6-环烷基氧基、C1-C6-卤代烷基、C1-C6-卤代烷氧基和氰基;
且其中杂芳基任选被一个、两个或三个取代基取代,所述取代基彼此独立地是卤素原子或选自下列的基团∶C1-C3-烷基和苯基;
R4代表氢原子或卤素原子;
R6代表氢原子或卤素原子或选自下列的基团∶
C1-C6-烷基、C1-C6-烷氧基、C3-C6-环烷基、C3-C6-环烷基氧基、C1-C6-卤代烷基、C1-C6-卤代烷氧基和氰基;
R7代表氢原子;
R8代表C1-C3-烷基;
R9、R10和R11彼此独立地选自∶氢和C1-C3-烷基;
R12代表选自下列的基团∶C1-C6-烷基和C3-C6-环烷基;
R13和R14彼此独立地选自∶氢和C1-C6-烷基;
或
R13和R14与它们连接的氮原子一起形成4至6元杂环烷基;
所述4至6元杂环烷基任选被一个选自下列的取代基取代∶C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、氨基、羟基、卤素和氰基;
或所述4至6元杂环烷基任选被两个卤素原子取代;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐,或它们的混合物。
术语“取代的”意思是指定的原子或基团上的一个或多个氢被选择的指定基团代替,条件是,在现有情况下,不超过所指定原子的正常化合价。取代基和/或变量可以组合。
当在本说明书中使用时,术语“包含”包括“由...组成”。
如果说明书提到了“本文所述”,指的是说明书中的任何前页所提到的任何公开内容。
在本文中提到的术语优选具有下列含义∶
术语“卤素原子”是指氟、氯、溴或碘原子,优选氟、氯或溴原子。
术语“C1-C6-烷基”是指具有1、2、3、4、5或6个碳原子的直链或支链的饱和单价烃基团,例如,甲基、乙基、丙基、异丙基、丁基、仲丁基、异丁基、叔丁基、戊基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1-乙基丁基、2-乙基丁基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基、2,3-二甲基丁基、1,2-二甲基丁基或1,3-二甲基丁基,或其异构体。尤其是,所述基团具有1、2、3或4个碳原子(“C1-C4-烷基”),例如,甲基、乙基、丙基、异丙基、丁基、仲丁基、异丁基或叔丁基,更尤其是1、2或3个碳原子(“C1-C3-烷基”),例如,甲基、乙基、正丙基或异丙基。
术语“C1-C6-卤代烷基”是指直链或支链的饱和单价烃基团,其中,术语“C1-C6-烷基”如上所述,且其中,一个或多个氢原子被相同或不同的卤素原子替代。尤其是,所述卤素原子是氟。尤其是,所述基团具有1、2或3个碳原子(“C1-C3-卤代烷基”),例如,氟甲基、二氟甲基、三氟甲基、2-氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、五氟乙基、3,3,3-三氟丙基或1,3-二氟丙-2-基。
术语“C1-C6-烷氧基”是指式(C1-C6-烷基)-O-的直链或支链的饱和单价基团,其中,术语“C1-C6-烷基”如上所述,例如,甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、异丁氧基、叔丁氧基、戊氧基、异戊氧基或正己氧基,或其异构体。尤其是,所述基团具有1、2或3个碳原子(“C1-C3-烷氧基”),例如,甲氧基、乙氧基、正丙氧基或异丙氧基。
术语“C1-C6-卤代烷氧基”是指如上所述的直链或支链的饱和单价C1-C6-烷氧基,其中,一个或多个氢原子被相同或不同的卤素原子替代。尤其是,所述卤素原子是氟。尤其是,所述基团具有1、2或3个碳原子(“C1-C3-卤代烷氧基”),例如,氟甲氧基、二氟甲氧基、三氟甲氧基、2,2,2-三氟乙氧基、五氟乙氧基或3,3,3-三氟丙氧基。
术语“C3-C6-环烷基”是指含有3、4、5或6个碳原子的饱和单价的单环烃环(“C3-C6-环烷基”)。所述C3-C6-环烷基是,例如,单环烃环,例如,环丙基、环丁基、环戊基或环己基。
术语“C3-C6-环烷氧基”是指式(C3-C6-环烷基)-O-的饱和的单价单环基团,其含有3、4、5或6个碳原子(“C3-C6-环烷基氧基”),其中,术语“C3-C6-环烷基”如上所述,例如,环丙基氧基、环丁基氧基、环戊基氧基或环己基氧基。
术语“C2-C6-烯基”是指含有一个双键的直链或支链的单价烃基团,且其具有2、3、4、5或6个碳原子,尤其是2或3个碳原子(“C2-C3-烯基”)。所述烯基是,例如,乙烯基(或“乙烯基”)、丙-2-烯-1-基(或“烯丙基”)、丙-1-烯-1-基、丁-3-烯基、丁-2-烯基、丁-1-烯基、戊-4-烯基、戊-3-烯基、戊-2-烯基、戊-1-烯基、己-5-烯基、己-4-烯基、己-3-烯基、己-2-烯基、己-1-烯基、丙-1-烯-2-基(或“异丙烯基”)、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、2-甲基丁-2-烯基、1-甲基丁-2-烯基、3-甲基丁-1-烯基、2-甲基丁-1-烯基、1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-异丙基乙烯基、4-甲基戊-4-烯基、3-甲基戊-4-烯基、2-甲基戊-4-烯基、1-甲基戊-4-烯基、4-甲基戊-3-烯基、3-甲基戊-3-烯基、2-甲基戊-3-烯基、1-甲基戊-3-烯基、4-甲基戊-2-烯基、3-甲基戊-2-烯基、2-甲基戊-2-烯基、1-甲基戊-2-烯基、4-甲基戊-1-烯基、3-甲基戊-1-烯基、2-甲基戊-1-烯基、1-甲基戊-1-烯基、3-乙基丁-3-烯基、2-乙基丁-3-烯基、1-乙基丁-3-烯基、3-乙基丁-2-烯基、2-乙基丁-2-烯基、1-乙基丁-2-烯基、3-乙基丁-1-烯基、2-乙基丁-1-烯基、1-乙基丁-1-烯基、2-丙基丙-2-烯基、1-丙基丙-2-烯基、2-异丙基丙-2-烯基、1-异丙基丙-2-烯基、2-丙基丙-1-烯基、1-丙基丙-1-烯基、2-异丙基丙-1-烯基、1-异丙基丙-1-烯基、3,3-二甲基丙-1-烯基或1-(1,1-二甲基乙基)乙烯基。尤其是,所述基团具有2或3个碳原子(“C2-C3-烯基”),例如,乙烯基或烯丙基。
术语“4至6元杂环烷基”是指总计具有4至6个环原子的单环的饱和杂环,其含有一个环氮原子,以及任选一个选自N、O或S的其它环杂原子。
所述杂环烷基(不受其限制)可以是4元环,例如,氮杂环丁烷基;或5元环,例如,吡咯烷基、咪唑烷基、吡唑烷基、1,2-噁唑烷基、1,3-噁唑烷基或1,3-噻唑烷基;或6元环,例如,哌啶基、吗啉基、硫吗啉基、哌嗪基或1,2-噁嗪烷基。
术语“杂芳基”被理解为是指具有5、6或9个环原子的单价的单环或双环芳香环系统(“5、6或9元杂芳基”),其含有至少一个环杂原子,以及任选一个、两个或三个选自N、O和/或S的其它环杂原子,并且通过环碳原子键合,或任选通过环氮原子键合(当化合价允许时)。
所述杂芳基可以是5元杂芳基,例如,噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基或四唑基;或6元杂芳基基团,例如,吡啶基、哒嗪基、嘧啶基、吡嗪基或三嗪基;或三环杂芳基,例如,咔唑基、吖啶基或吩嗪基;或9元杂芳基,例如,苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并噻唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基、吲哚嗪基或嘌呤基。
除非另作说明,否则,通常杂芳香或杂亚芳香的基团通常包括其所有合适的异构形式,例如,相对于与分子的其余部分的连接位点的互变异构体和位置异构体。由此,对于一些说明性的非限制性实例,术语吡啶基包括吡啶-2-基、吡啶-3-基和吡啶-4-基;或术语噻吩基包括噻吩-2-基和噻吩-3-基。
贯穿本文使用的术语“C1-C6”,例如,在“C1-C6-烷基”、“C1-C6-卤代烷基”、“C1-C6-烷氧基”或“C1-C6-卤代烷氧基”的定义的背景下,是指具有1至6个有限数量的碳原子的烷基,即1、2、3、4、5或6个碳原子。
进一步的,贯穿本文使用的术语“C3-C6”,例如,在“C3-C6-环烷基”的定义的背景下,是指具有3至6个有限数量的碳原子的环烷基,即3、4、5或6个碳原子。
当列出数值范围时,是指包括每个数值和该范围内的子区间。
例如,“C1-C6”意在包括C1、C2、C3、C4、C5、C6、C1-C6、C1-C5、C1-C4、C1-C3、C1-C2、C2-C6、C2-C5、C2-C4、C2-C3、C3-C6、C3-C5、C3-C4、C4-C6、C4-C5和C5-C6。
例如,“C1-C3”意在包括C1、C2、C3、C1-C3、C1-C2和C2-C3。
例如,“C3-C6”意在包括C3、C4、C5、C6、C3-C6、C3-C5、C3-C4、C4-C6、C4-C5和C5-C6。
通式(I)的化合物可以存在为同位素变体。本发明因此包括通式(I)的化合物的一个或多个同位素变体,尤其是含有氘的通式(I)化合物。
化合物或试剂的术语“同位素变体”定义为具有构成这种化合物的非自然比例的一或多种同位素的化合物。
术语“通式(I)化合物的同位素变体”定义为具有构成这种化合物的非自然比例的一或多种同位素的通式(I)化合物。
术语“非自然比例”理解为是指这种同位素的比例高于它的天然丰度。在这方面,所使用的同位素的天然丰度描述在下列文献中: “Isotopic Compositions of theElements 1997”, Pure Appl. Chem., 70(1), 217-235, 1998。
这种同位素的例子包括氢、碳、氮、氧、磷、硫、氟、氯、溴和碘的稳定和放射性同位素,分别例如,2H(氘)、3H(氚)、11C、13C、14C、15N、17O、18O、32P、33P、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、125I、129I和131I。
关于治疗和/或预防本文列举的病症,优选,通式(I)化合物的同位素变体含有氘(“含有氘的通式(I)的化合物”)。其中结合了一或多种放射性同位素(例如,3H或14C)的通式(I)化合物的同位素变体用于例如药物和/或底物组织分配研究。由于它们容易结合并且容易检测,尤其优选这些同位素。正电子发射同位素,例如,18F或11C,可以结合进通式(I)的化合物中。通式(I)化合物的这些同位素变体可用于体内成像应用。在临床前或临床研究的背景下,含氘和含13C的通式(I)的化合物可以用于质谱分析(H. J. Leis等人,Curr. Org.Chem., 1998, 2, 131)。
通式(I)化合物的同位素变体一般可以通过本领域技术人员已知的方法制备,例如,本文反应路线和/或实施例所描述的方法,用所述试剂的同位素变体来替代试剂,优选,使用含有氘的试剂。根据氘化的目标位点,在某些情况下,D2O中的氘可以直接结合到所述化合物中,或结合到用于合成这种化合物的试剂中(Esaki等人,Tetrahedron, 2006, 62,10954; Esaki等人,Chem. Eur. J., 2007, 13, 4052)。氘气也是将氘结合到分子中的有用试剂。烯键(H. J. Leis等人,Curr. Org. Chem.,1998,2,131;J. R. Morandi等人,J.Org. Chem.,1969,34(6),1889)和炔键(N. H. Khan,J. Am. Chem. Soc.,1952,74(12),3018;S. Chandrasekhar等人,Tetrahedron,2011,52,3865)的催化氘化是结合氘的快速途径。在氘气的存在下,金属催化剂(即,Pd、Pt和Rh)可用于直接氘交换含有官能团的烃中的氢(J. G. Atkinson等人,美国专利3966781)。各种氘化试剂与合成结构单元可从公司商购,例如, C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc.,Andover, MA, USA;以及CombiPhos Catalysts, Inc., Princeton, NJ, USA。在下列文献中可以得到关于氘-氢交换的现有技术的其它信息,例如:Hanzlik等人,J. Org. Chem.55, 3992-3997, 1990; R. P. Hanzlik等人,Biochem. Biophys. Res. Commun. 160,844, 1989; P. J. Reider等人,J. Org. Chem. 52, 3326-3334, 1987; M. Jarman等人,Carcinogenesis 16(4), 683-688, 1993; J. Atzrodt等人,Angew. Chem., Int. Ed.2007, 46, 7744; K. Matoishi等人,J. Chem. Soc, Chem. Commun. 2000, 1519-1520;K. Kassahun等人,WO2012/112363。
术语“含氘的通式(I)化合物”定义为:其中一个或多个氢原子被一个或多个氘原子替代的通式(I)的化合物,其中,通式(I)化合物的每个氘化位置上的氘的丰度比氘的天然丰度高,其为大约0.015%。尤其是,在含有氘的通式(I)化合物中,通式(I)化合物的每个氘化位置上的氘的丰度在所述位置高出10%、20%、30%、40%、50%、60%、70%或80%,优选高出90%、95%、96%或97%,甚至更优选高出98%或99%。应当理解,每个氘化位置上的氘的丰度与其它氘化位置上的氘的丰度无关。
使一个或多个氘原子选择性地结合到通式(I)的化合物中,可以改变所述分子的物理化学性能(例如,酸性[A. Streitwieser等人,J. Am. Chem. Soc.,1963,85,2759;C.L. Perrin等人,J. Am. Chem. Soc.,2007,129,4490]、碱性[C. L. Perrin等人,J. Am.Chem. Soc.,2003,125,15008;C. L. Perrin,Advances in Physical OrganicChemistry,44,144;C. L. Perrin等人,J. Am. Chem. Soc.,2005,127,9641]、亲油性[B.Testa等人,Int. J. Pharm.,1984,19(3),271])和/或代谢特性,并且可以引起母体化合物与代谢物的比例或所形成的代谢物的量的变化。这种变化可以产生某些治疗优势,并由此可以在一些情况下优选。已经报道了代谢和代谢转换率降低,其中,改变了代谢物的比例(D. J. Kushner等人,Can. J. Physiol. Pharmacol., 1999, 77, 79; A. E. Mutlib等人,Toxicol. Appl. Pharmacol., 2000, 169, 102)。在接触母体药物和代谢物方面的这些变化,对于含氘的通式(I)化合物的药效学、耐受性和效果具有重要影响。在某些情况下,氘取代减少或消除不希望有的或毒性代谢物的形成,并且增加目标代谢物的形成(例如,Nevirapine: A. M. Sharma等人,Chem. Res. Toxicol., 2013, 26, 410; Uetrecht等人,Chemical Research in Toxicology, 2008, 21, 9, 1862; Efavirenz: A. E.Mutlib等人,Toxicol. Appl. Pharmacol., 2000, 169, 102)。在其它情况下,氘化作用的主要影响是:降低系统的廓清速率。因此,提高了所述化合物的生物半衰期。潜在临床益处包括:保持类似的系统接触的能力,同时降低峰值水平,提高波谷水平。根据具体化合物的药物动力学/药效学关系,这可以导致更低的副作用和提高的疗效。茚地普隆(Indiplon)(A. J. Morales等人,Abstract 285,The 15th North American Meeting of theInternational Society of Xenobiotics,San Diego,CA,2008年10月12-16日)、ML-337(C. J. Wenthur等人,J. Med. Chem.,2013,56,5208)和Odanacatib(K. Kassahun等人,WO2012/112363)是这种氘效果的实例。还报道了其它实例:其中代谢率的降低导致与药物的接触量增加,同时不会改变系统的廓清率(例如, Rofecoxib: F. Schneider等人,Arzneim. Forsch. Drug. Res., 2006, 56, 295; Telaprevir: F. Maltais等人,J.Med. Chem., 2009, 52, 7993)。显示这种效果的氘化药物可以具有降低的剂量要求(例如,更低的剂量数、或达到预期效果的更低剂量),和/或,可以产生更低的代谢物载荷。
通式(I)的化合物对于代谢可以具有多个潜在的作用位点。为了使对于物理化学性能和代谢特性的上述效果最佳化,可以选择具有一个或多个氘-氢交换的某些模式的含氘的通式(I)化合物。尤其是,含有氘的通式(I)化合物的氘原子连接到碳原子上,和/或位于通式(I)化合物的那些位置,它们对于代谢酶(例如,细胞色素P450)是作用的位点。
在另一个实施方案中,本发明涉及具有1、2、3或4个氘原子的含有氘的通式(I)化合物,尤其是具有1、2或3个氘原子。
在另一个实施方案中,本发明涉及含有氘的通式(I)化合物,其含有一个或多个选自CD3、OCD3和苄型CD2的基团。
在本文使用词化合物、盐、多晶型物、水合物、溶剂化物等等的复数形式的情况下,也是指单一化合物、盐、多晶型物、异构体、水合物、溶剂化物,等等。
“稳定化合物”或“稳定结构”是指充分稳固的化合物,能够从反应混合物中分离至有用的纯度,并且可以配制成为有效的治疗剂。
根据各个目标取代基的位置和性质,本发明的化合物可以任选包含一个或多个非对称中心。不对称碳原子可以存在(R)或(S)构型,在单一非对称中心的情况下,可以形成外消旋混合物,在多个非对称中心的情况下,形成非对映体的混合物。在某些情况下,由于围绕所给定的键的阻旋作用,例如,连接具体化合物的两个取代的芳香环的中心键,也可以存在不对称性。
环上的取代基也可以以顺式或反式存在。所有这种构型(包括对映异构体和非对映异构体)意图包括在本发明范围内。
优选的化合物是得到更合乎需要的生物活性的那些化合物。本发明化合物的分离、纯化或部分纯化的异构体和立体异构体或外消旋的或非对映体的混合物,也包括在本发明范围内。这种材料的纯化和分离可以通过本领域已知的标准技术实现。
按照常规方法,例如,使用光学活性的酸或碱,形成非对映异构体的盐,或形成共价非对映体,将外消旋混合物拆分,可以获得光学异构体。合适的酸的例子是酒石酸、二乙酰基酒石酸、二甲苯酰酒石酸和樟脑磺酸。利用本领域技术人员熟知的方法,例如,色谱或分级结晶,基于它们的物理和/或化学差异,可以将非对映异构体的混合物分离为它们的单一非对映异构体。然后,从分离的非对映体的盐中释放出光学活性的碱或酸。分离光学异构体的不同方法包括:在进行或不进行常规衍生化的条件下,使用手性色谱(例如,手性HPLC柱),最好选择最大化分离对映异构体。合适的手性HPLC柱由Daicel生产,例如,ChiracelOD和Chiracel OJ,还有许多其它的手性HPLC柱,都是通常可选择的柱。在进行或不进行衍生化的条件下,也使用酶分离。使用光学活性的起始原料,通过手性合成,也可以获得本发明的光学活性的化合物。
为了限制彼此类型不同的异构体,参考IUPAC Rules Section E(Pure Appl Chem45, 11-30, 1976)。
本发明包括本发明化合物的所有可能的立体异构体,可以是单一立体异构体,或任何比例的所述立体异构体的任何混合物,例如R-或S-异构体,或E-或Z-异构体。利用任何合适的本领域说明的方法,例如,色谱,尤其是手性色谱,可以实现本发明化合物的单一立体异构体的分离,例如,单一对映异构体或单一非对映异构体的分离。
进一步的,本发明的化合物可以以互变异构体形态存在。例如,含有吡唑部分作为杂芳基的任何本发明的化合物,例如,可以存在1H互变异构体或2H互变异构体,或甚至任何数量的两种互变异构体的混合物,也就是∶
。
本发明包括本发明化合物的所有可能的互变异构体,可以是单一互变异构体,或所述互变异构体的任何比例的任何混合物。
进一步的,本发明的化合物可以以N-氧化物形态存在,其定义为:本发明化合物的至少一个氮被氧化。本发明包括所有这种可能的N-氧化物。
本发明还涉及本文公开的化合物的有用形式,例如,代谢物、水合物、溶剂化物、前体药物、盐,尤其是可药用盐,以及共沉淀。
本发明的化合物可以以水合物或溶剂化物形态存在,其中本发明的化合物含有极性溶剂,尤其是水、甲醇或乙醇,例如作为化合物的晶格的结构要素。极性溶剂的量,尤其是水,可以以化学计量或非化学计量的比例存在。在化学计量的溶剂化物的情况下,例如,水合物,可以分别是半(部分)、一、一又二分之一、二、三、四、五溶剂化物或水合物,等等。本发明包括所有这种水合物或溶剂化物。
进一步的,本发明的化合物可以以游离形式存在,例如游离碱或游离酸或两性离子,或可以以盐形式存在。所述盐可以是药学通常使用的任何盐,有机或无机加成盐,尤其是任何可药用有机或无机加成盐。
术语“可药用盐”是指本发明化合物的相对无毒的无机或有机酸加成盐。例如,参见 S. M. Berge等人,“Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19。
本发明化合物的合适的可药用盐可以是,例如,链或环中携带氮原子的本发明化合物(例如,充分碱性的本发明化合物)的酸加成盐,例如,与无机酸形成的酸加成盐,所述无机酸例如盐酸、氢溴酸、氢碘酸、硫酸、一碱基硫酸(bisulfuric)、磷酸或硝酸,或与有机酸形成的酸加成盐,所述有机酸例如甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)-苯甲酸、樟脑酸、肉桂酸、环戊丙酸、二葡糖酸、3-羟基-2-萘酸、烟酸、双羟萘酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、新戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸。
进一步的,充分酸性的本发明化合物的另一合适的可药用盐是碱金属盐(例如钠或钾盐)、碱土金属盐(例如钙或镁盐)、铵盐、或与能够提供生理学可接受的阳离子的有机碱形成的盐,例如,与下列有机碱形成的盐:N-甲基-葡糖胺、二甲基-葡糖胺、乙基-葡糖胺、赖氨酸、二环己基胺、1,6-己二胺、乙醇胺、氨基葡糖、肌氨酸、丝氨醇、三羟基-甲基-甲胺、氨基丙二醇、sovak碱、1-氨基-2,3,4-丁三醇。此外,可以用如低级卤化烃试剂(例如甲基、乙基、丙基和丁基的氯、溴和碘化物)、硫酸二烷基酯(例如硫酸二甲基、二乙基、二丁基和二戊基酯)、长链卤化物(例如癸基、月桂基、十四烷基和硬脂基的氯、溴和碘化物)、芳烷基卤化物(例如苄基和苯乙基溴)等等,将含有碱性氮的基团季铵化。
本领域技术人员将会进一步认识到,请求保护的化合物的酸加成盐,可以通过许多已知的方法中的任何方法,通过所述化合物与合适的无机或有机酸的反应来制备。或者,通过各种已知的方法,通过本发明的化合物与合适的碱的反应,制备本发明酸性化合物的碱金属和碱土金属盐。
本发明包括本发明化合物所有可能的盐,可以是单一盐,或所述盐的任何比例的任何混合物。
在本文中,尤其是在实验部分中,对于本发明的中间体和实施例的合成,当提及化合物是用相应的碱或酸形成的盐形式时,通过相应的制备和/或提纯方法获得的所述盐形式的确切化学计量组成在大多数情况下是未知的。
除非另外说明,否则,化学名称或结构式的后缀,例如“盐酸盐”、“三氟乙酸盐”、“钠盐”或“xHCl”、“xCF3COOH”、“xNa+”,应理解为不是化学计量标准,仅仅是盐形式。
这可以类似地应用于已经通过所描述的制备和/或提纯方法获得溶剂化物形式的合成中间体或实施例化合物或其盐的情况,例如,化学计量组成未知的水合物(如果定义的话)。
本文使用的术语“体内可水解的酯”理解为是指含有羧基或羟基的本发明化合物的体内可水解的酯,例如,在人类或动物体中水解产生母体酸或醇的可药用酯。羧基的合适的可药用酯包括,例如烷基、环烷基和任选取代的苯基烷基酯,尤其是苄基酯、C1-C6烷氧基甲基酯(例如甲氧基甲基酯)、C1-C6烷酰氧基甲基酯(例如新戊酰氧基甲基)、酞基酯、C3-C8环烷氧基-羰基氧基-C1-C6烷基酯(例如1-环己基羰基氧基乙基酯)、1,3-二氧杂环戊烯-2-酮基甲酯(例如5-甲基-1,3-二氧杂环戊烯-2-酮基甲基酯)、以及C1-C6-烷氧羰基氧基乙酯(例如1-甲氧羰基氧基乙基酯),并且可以在本发明化合物的任何羧基上形成。
含有羟基的本发明化合物的体内可水解的酯包括无机酯,例如磷酸酯和[alpha]-酰氧烷基醚,以及由于酯的体内水解而分解得到母体羟基的相关化合物。[alpha]-酰氧烷基醚的例子包括乙酰氧基甲氧基和2,2-二甲基丙酰氧基甲氧基。对于羟基的体内可水解的酯形成基团的选择包括烷酰基、苯甲酰基、苯乙酰基和取代的苯甲酰基和苯乙酰基、烷氧羰基(得到碳酸烷基酯)、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(得到氨基甲酸酯)、二烷基氨基乙酰基和羧基乙酰基。本发明包括所有这种酯。
此外,本发明包括本发明化合物的所有可能的结晶形式,或多晶型物,可以是单一多晶型物,或任何比例的一个以上的多晶型物的混合物。
在一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中∶
A代表键或-CH2-或-(CH2)2-基团,
和
R5代表选自下列的基团∶
-C(O)OH、-C(=O)OR12、HOC(=O)-(C1-C6-烷基)-、R12OC(=O)-(C1-C6-烷基)-、HOC(=O)-(C2-C6-烯基)-、R12OC(=O)-(C2-C6-烯基)-、HOC(=O)-(C1-C6-烷氧基)-、R12OC(=O)-(C1-C6-烷氧基)-和氰基;
或
A代表-CH(CH3)-或-C(CH3)2-基团,
R5代表选自下列的基团∶
-C(=O)OH、HOC(=O)-(C1-C6-烷基)-、R12OC(=O)-(C1-C6-烷基)-、HOC(=O)-(C2-C6-烯基)-、R12OC(=O)-(C2-C6-烯基)-、HOC(=O)-(C1-C6-烷氧基)-、R12OC(=O)-(C1-C6-烷氧基)-和氰基;
R1代表苯基或5、6或9元杂芳基,
其中苯基任选被一个、两个或三个取代基取代,所述取代基彼此独立地是卤素原子或选自下列的基团∶C1-C6-烷基、C3-C6-环烷基、C1-C6-烷氧基、C3-C6-环烷基氧基、C1-C6-卤代烷基、C1-C6-卤代烷氧基和氰基;
其中的杂芳基任选被一个、两个或三个取代基取代,所述取代基彼此独立地是卤素原子或选自下列的基团∶C1-C3-烷基和苯基;
R4代表氢原子或卤素原子;
R6代表氢原子或卤素原子或选自下列的基团∶
C1-C6-烷基、C1-C6-烷氧基、C3-C6-环烷基、C3-C6-环烷基氧基、C1-C6-卤代烷基、C1-C6-卤代烷氧基和氰基;
R7代表氢原子;
R8代表C1-C3-烷基;
R9、R10和R11彼此独立地选自∶氢和C1-C3-烷基;
R12代表选自下列的基团∶C1-C6-烷基和C3-C6-环烷基;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐,或它们的混合物。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中∶
A代表键或-CH2-或-(CH2)2-基团,
和
R5代表选自下列的基团∶
-C(O)OH、-C(=O)OR12、HOC(=O)-(C1-C3-烷基)-、R12OC(=O)-(C1-C3-烷基)-、HOC(=O)-(C2-C3-烯基)-、R12OC(=O)-(C2-C3-烯基)-、HOC(=O)-(C1-C3-烷氧基)-、R12OC(=O)-(C1-C3-烷氧基)-和氰基;
或
A代表-CH(CH3)-或-C(CH3)2-基团,
和
R5代表选自下列的基团∶
-C(=O)OH、HOC(=O)-(C1-C3-烷基)-、R12OC(=O)-(C1-C3-烷基)-、HOC(=O)-(C2-C3-烯基)-、R12OC(=O)-(C2-C3-烯基)-、HOC(=O)-(C1-C3-烷氧基)-、R12OC(=O)-(C1-C3-烷氧基)-和氰基;
R1代表苯基或5、6或9元杂芳基,
其中,苯基任选被一个、两个或三个取代基取代,所述取代基彼此独立地是卤素原子或选自下列的基团∶C1-C6-烷基、C3-C6-环烷基、C1-C6-烷氧基、C3-C6-环烷基氧基、C1-C3-卤代烷基、C1-C3-卤代烷氧基和氰基;
且其中的杂芳基任选被一个、两个或三个取代基取代,所述取代基彼此独立地是卤素原子或选自下列的基团∶C1-C3-烷基和苯基;
R4代表氢原子或卤素原子;
R6代表氢原子或卤素原子或选自下列的基团∶
C1-C3-烷基、C1-C6-烷氧基、C3-C6-环烷基、C3-C6-环烷基氧基、C1-C3-卤代烷基、C1-C3-卤代烷氧基和氰基;
R7代表氢原子;
R8代表C1-C3-烷基;
R9、R10和R11彼此独立地选自∶氢和C1-C3-烷基;
R12代表C1-C3-烷基;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐,或它们的混合物。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中∶
A代表键或-CH2-基团,
和
R5代表选自下列的基团∶
-C(O)OH、-C(=O)OR12、HOC(=O)-(C1-C2-烷基)-、R12OC(=O)-(C1-C2-烷基)-和氰基;
或
A代表-CH(CH3)-或-C(CH3)2-基团,
和
R5代表-C(=O)OH基团;
R1代表苯基或5或9元杂芳基,
其中苯基任选被一或两个取代基取代,所述取代基彼此独立地是卤素原子或选自下列的基团∶
C1-C6-烷基、C1-C6-烷氧基、C1-C3-卤代烷基和C1-C3-卤代烷氧基;
且其中杂芳基任选被一或两个取代基取代,所述取代基彼此独立地是卤素原子或选自下列的基团∶C1-C3-烷基和苯基;
R4代表氢原子或卤素原子;
R6代表氢原子或选自下列的基团∶
C1-C3-烷基、C1-C6-烷氧基和C1-C3-卤代烷氧基;
R7代表氢原子;
R8代表甲基;
R9、R10和R11彼此独立地选自∶氢和甲基;
R12代表C1-C3-烷基;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐,或它们的混合物。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中∶
A代表键或-CH2-基团,
和
R5代表选自下列的基团∶
-C(O)OH、-C(=O)OR12、HOC(=O)-(CH2)2-、R12OC(=O)-(CH2)2-和氰基;
或
A代表-CH(CH3)-或-C(CH3)2-基团,
和
R5代表-C(=O)OH基团;
R1代表苯基或5或9元杂芳基,
其中苯基任选被氟原子或选自下列的基团取代∶甲基、异丙基、叔丁基、异丙氧基、三氟甲基和三氟甲氧基;
且其中杂芳基任选被一或两个取代基取代,所述取代基彼此独立地是氟原子或选自下列的基团∶甲基和苯基;
R4代表氢原子或氟原子;
R6代表氢原子或选自下列的基团∶
甲基、甲氧基、异丙氧基和2,2,2-三氟乙氧基;
R7代表氢原子;
R8代表甲基;
R9选自∶氢和甲基;
R10和R11都代表甲基;
R12代表甲基;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐,或它们的混合物。
应该理解,本发明涉及上述通式(I)化合物的本发明的任何实施方案或方面范围内的任何子组合。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中∶
A代表键或-CH2-或-(CH2)2-基团,和
R5代表选自下列的基团:
-C(O)OH、-C(=O)OR12、HOC(=O)-(C1-C6-烷基)-、R12OC(=O)-(C1-C6-烷基)-、HOC(=O)-(C2-C6-烯基)-、R12OC(=O)-(C2-C6-烯基)-、HOC(=O)-(C1-C6-烷氧基)-、R12OC(=O)-(C1-C6-烷氧基)-、-C(=O)N(R13)R14、R13(R14)NC(=O)-(C1-C6-烷基)-、R13(R14)NC(=O)-(C2-C6-烯基)-、R13(R14)NC(=O)-(C1-C6-烷氧基)-和氰基。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中∶
A代表键或-CH2-或-(CH2)2-基团,
R5代表选自下列的基团:
-C(O)OH、-C(=O)OR12、HOC(=O)-(C1-C6-烷基)-、R12OC(=O)-(C1-C6-烷基)-、HOC(=O)-(C2-C6-烯基)-、R12OC(=O)-(C2-C6-烯基)-、HOC(=O)-(C1-C6-烷氧基)-、R12OC(=O)-(C1-C6-烷氧基)-和氰基。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中∶
A代表键或-CH2-或-(CH2)2-基团,和
R5代表选自下列的基团:
-C(O)OH、-C(=O)OR12、HOC(=O)-(C1-C3-烷基)-、R12OC(=O)-(C1-C3-烷基)-、HOC(=O)-(C2-C3-烯基)-、R12OC(=O)-(C2-C3-烯基)-、HOC(=O)-(C1-C3-烷氧基)-、R12OC(=O)-(C1-C3-烷氧基)-和氰基。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中∶
A代表键或-CH2-基团,和
R5代表选自下列的基团:-C(O)OH、-C(=O)OR12、HOC(=O)-(C1-C2-烷基)-、R12OC(=O)-(C1-C2-烷基)-和氰基。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中∶
A代表键或-CH2-基团,和
R5代表选自下列的基团:-C(O)OH、-C(=O)OR12、HOC(=O)-(CH2)2-、R12OC(=O)-(CH2)2-和氰基。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中∶
A代表-CH(CH3)-或-C(CH3)2-基团,和
R5代表选自下列的基团:
-C(=O)OH、HOC(=O)-(C1-C6-烷基)-、R12OC(=O)-(C1-C6-烷基)-、HOC(=O)-(C2-C6-烯基)-、R12OC(=O)-(C2-C6-烯基)-、HOC(=O)-(C1-C6-烷氧基)-、R12OC(=O)-(C1-C6-烷氧基)-、-C(=O)N(R13)R14、R13(R14)NC(=O)-(C1-C6-烷基)-、R13(R14)NC(=O)-(C2-C6-烯基)-、R13(R14)NC(=O)-(C1-C6-烷氧基)-和氰基。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中∶
A代表-CH(CH3)-或-C(CH3)2-基团,和
R5代表选自下列的基团:
-C(=O)OH、HOC(=O)-(C1-C6-烷基)-、R12OC(=O)-(C1-C6-烷基)-、HOC(=O)-(C2-C6-烯基)-、R12OC(=O)-(C2-C6-烯基)-、HOC(=O)-(C1-C6-烷氧基)-、R12OC(=O)-(C1-C6-烷氧基)-和氰基。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中∶
A代表-CH(CH3)-或-C(CH3)2-基团,和
R5代表选自下列的基团:
-C(=O)OH、HOC(=O)-(C1-C3-烷基)-、R12OC(=O)-(C1-C3-烷基)-、HOC(=O)-(C2-C3-烯基)-、R12OC(=O)-(C2-C3-烯基)-、HOC(=O)-(C1-C3-烷氧基)-、R12OC(=O)-(C1-C3-烷氧基)-和氰基。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中A代表-CH(CH3)-或-C(CH3)2-基团,和R5代表-C(=O)OH基团。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中A代表键或-CH2-或-(CH2)2-基团。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中A代表键或-CH2-基团。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中A代表键。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中A代表-CH2-基团。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中A代表-CH(CH3)-或-C(CH3)2-基团。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中∶
R1代表苯基或5、6或9元杂芳基,
其中苯基任选被一个、两个或三个取代基取代,所述取代基彼此独立地是卤素原子或选自下列的基团∶C1-C6-烷基、C3-C6-环烷基、C1-C6-烷氧基、C3-C6-环烷基氧基、C1-C6-卤代烷基、C1-C6-卤代烷氧基和氰基;其中杂芳基任选被一个、两个或三个取代基取代,所述取代基彼此独立地是卤素原子或选自下列的基团∶C1-C3-烷基和苯基。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中∶
R1代表苯基或5、6或9元杂芳基,
其中苯基任选被一个、两个或三个取代基取代,所述取代基彼此独立地是卤素原子或选自下列的基团∶
C1-C6-烷基、C3-C6-环烷基、C1-C6-烷氧基、C3-C6-环烷基氧基、C1-C3-卤代烷基、C1-C3-卤代烷氧基和氰基;且其中杂芳基任选被一个、两个或三个取代基取代,所述取代基彼此独立地是卤素原子或选自下列的基团∶C1-C3-烷基和苯基。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中∶
R1代表苯基或5或9元杂芳基,
其中苯基任选被一或两个取代基取代,所述取代基彼此独立地是卤素原子或选自下列的基团∶C1-C6-烷基、C1-C6-烷氧基、C1-C3-卤代烷基和C1-C3-卤代烷氧基。且其中杂芳基任选被一或两个取代基取代,所述取代基彼此独立地是卤素原子或选自下列的基团∶C1-C3-烷基和苯基。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中∶
R1代表苯基或5或9元杂芳基,
其中苯基任选被氟原子或选自下列的基团取代∶甲基、异丙基、叔丁基、异丙氧基、三氟甲基和三氟甲氧基;
且其中杂芳基任选被一或两个取代基取代,所述取代基彼此独立地是氟原子或选自下列的基团∶甲基和苯基。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中R4代表氢原子或卤素原子。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中R4代表氢原子或氟原子。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中∶
R6代表氢原子或卤素原子或选自下列的基团:
C1-C6-烷基、C1-C6-烷氧基、C3-C6-环烷基、C3-C6-环烷基氧基、C1-C6-卤代烷基、C1-C6-卤代烷氧基和氰基。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中∶
R6代表氢原子或卤素原子或选自下列的基团:
C1-C3-烷基、C1-C6-烷氧基、C3-C6-环烷基、C3-C6-环烷基氧基、C1-C3-卤代烷基、C1-C3-卤代烷氧基和氰基。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中∶
R6代表氢原子或选自下列的基团:
C1-C3-烷基、C1-C6-烷氧基和C1-C3-卤代烷氧基。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中∶
R6代表氢原子或选自下列的基团:
甲基、甲氧基、异丙氧基和2,2,2-三氟乙氧基。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中R8代表C1-C3-烷基。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中R8代表甲基。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中R9、R10和R11彼此独立地选自氢和C1-C3-烷基。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中R9、R10和R11彼此独立地选自∶氢和甲基。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中R12代表选自下列的基团∶C1-C6-烷基和C3-C6-环烷基。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中R12代表选自C1-C6-烷基的基团。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中R12代表选自C1-C3-烷基的基团。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中R12代表甲基。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中∶
R13和R14彼此独立地选自∶氢和C1-C6-烷基;
或
R13和R14与它们连接的氮原子一起形成4至6元杂环烷基,所述4至6元杂环烷基任选被一个选自下列的取代基取代:
C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、氨基、羟基、卤素和氰基;或所述4至6元杂环烷基任选被两个卤素原子取代。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中R13和R14彼此独立地选自∶氢和C1-C6-烷基。
在另一个优选实施方案中,本发明涉及上述通式(I)的化合物,其中∶
R13和R14与它们连接的氮原子一起形成4至6元杂环烷基,所述4至6元杂环烷基任选被一个选自下列的取代基取代:
C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、氨基、羟基、卤素和氰基;或所述4至6元杂环烷基任选被两个卤素原子取代。
应该理解,本发明还涉及上述优选实施方案的任何组合形式。
更尤其是,本发明包括公开在下文的实施例部分中的通式(I)的实施例化合物。
按照另一个方面,本发明包括制备本发明的化合物的方法,所述方法包括本文实验部分中描述的步骤。
按照进一步的方面,本发明包括用于制备上述通式(I)化合物的中间体化合物。
尤其是,本发明包括通式(II)的中间体化合物∶
其中,R4、R5、R6、R7、R8、R9、R10和R11如上述通式(I)的化合物所定义。
更尤其是,本发明包括公开在下文的实施例部分中的中间体化合物。
按照进一步的方面,本发明包括通式(II)的中间体化合物,
其中R4、R5、R6、R7、R8、R9、R10和R11如上述通式(I)的化合物所定义,用于制备上述通式(I)化合物的用途。
按照进一步的方面,本发明涉及上述通式(I)的化合物,或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐,尤其是其可药用盐,或它们的混合物,用于治疗或预防疾病。
按照进一步的方面,本发明涉及含有上述通式(I)的化合物或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐(尤其是其可药用盐)或它们的混合物和可药用稀释剂或载体的药物组合物。
尤其是,所述药物联用药含有∶
- 一或多种选自上述通式(I)化合物的第一活性组分,以及
- 一或多种选自化学治疗的抗癌药剂的第二活性组分(参见下文)。
按照进一步的方面,本发明涉及上述通式(I)化合物或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐(尤其是其可药用盐)或它们的混合物,用于预防或治疗疾病的用途。
按照进一步的方面,本发明涉及上述通式(I)化合物或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐(尤其是其可药用盐)或它们的混合物,用于制备预防或治疗疾病的药物的用途。
前面所述的疾病尤其是无控的细胞生长、增殖和/或存活、不合适的细胞免疫响应或不合适的细胞炎性响应的疾病,尤其是,其中所述无控的细胞生长、增殖和/或存活、不合适的细胞免疫响应或不合适的细胞炎性响应的疾病是血液肿瘤、实体肿瘤和/或其转移病变,例如,白血病和脊髓发育不良综合征、恶性淋巴瘤、头和颈部肿瘤(包括脑瘤和大脑转移病变)、胸部肿瘤(包括非小细胞和小细胞肺肿瘤)、胃肠肿瘤、内分泌腺肿瘤、乳腺及其它妇科肿瘤、泌尿系统肿瘤(包括肾、膀胱和前列腺肿瘤)、皮肤肿瘤、以及肉瘤,和/或其转移病变。
实验部分
下面表1列出了该段落和中间体实施例以及实施例部分中使用的缩写,在正文内没有对它们进行解释。NMR峰形按照它们在光谱中出现的情形指明,没有考虑可能的更高级别的效果。使用ACD labs的ICS命名法,形成化学名称。在某些情况下,使用商购试剂的普遍接受的名称,代替ICS命名法形成的名称。
表1∶缩写
缩写 | 含义 |
br. | NMR中的宽峰信号 |
br. s. | 宽单峰 |
CDCl3 | 氘化三氯甲烷 |
DCM | 二氯甲烷 |
DMF | N,N-二甲基甲酰胺 |
D | 双峰 |
Dd | 双二重峰 |
DMSO | 二甲亚砜 |
DMSO-d6 | 氘化二甲亚砜 |
ESI | 电喷雾离子化 |
EtOH | 乙醇 |
H | 小时 |
HCl | 盐酸 |
HClO4 | 高氯酸 |
HPLC, LC | 高效液相色谱 |
M | 多重峰 |
Min | 分钟 |
MS | 质谱 |
MeOH | 甲醇 |
NH4Cl | 氯化铵 |
NMR | 核磁共振 |
Rt | 保留时间 |
Rt | 室温 |
S | 单峰 |
Sept | 七重峰 |
T | 三重峰 |
THF | 四氢呋喃 |
UPLC | 超高效液相色谱 |
对于技术人员来说,其它缩写具有它们本身的常规含义。
利用不以任何方式限制本发明的下列实施例,举例说明该申请所描述的本发明的各个方面。
合成化合物(概述)
下列反应路线和一般方法举例说明了本发明的通式(I)化合物的常规合成路线,但并不受其限制。本领域技术人员很清楚,可以用多种方式来改变反应路线1至3举例说明的转化顺序。因此,反应路线1至3所说明的转化顺序不具有限制性。另外,可以在示范性转化之前和/或之后,使取代基(例如,残基R1、R4、R5、R6、R7和A)相互转化。这些改变可以是,例如引入保护基、保护基的断裂、官能团的还原或氧化、卤化、金属化、取代或本领域技术人员已知的其它反应。这些转化包括引入能够使取代基进一步相互转化的官能团的那些转化。本领域技术人员熟知合适的保护基以及它们的引入和断裂方法(参见,例如, T.W. Greene 和P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley1999)。
反应路线1∶
其中R1、R4、R5、R6、R7、R8、R9、R10、R11和A如上文所定义,且X代表卤素原子。
在酰胺偶合/脱水试剂的存在下,可以使合适功能化的通式(II)的二胺与通式(III)的羧酸反应。对于酰胺偶合/脱水来说,可以使用本领域技术人员已知的所有方法。在合适的溶剂(例如乙酸乙酯或DMF)中,在例如2,4,6-三丙基-1,3,5,2,4,6-三氧杂三膦烷(phosphinane)2,4,6-三氧化物的存在下,在压力管瓶中,在0℃和150℃之间,典型地在100℃下,可以使通式(II)的二胺与通式(III)的羧酸反应。还可以分为两个单独的步骤进行偶合以及随后的脱水。例如,可以使用1,1'-羰基二咪唑,使通式(III)的羧酸活化,而后与通式(II)的二胺反应,得到相应的酰胺中间体。在室温和溶剂的沸点之间的温度,典型地在110℃,可以使用酸(例如,乙酸),将这些酰胺中间体脱水(环化)。
通过还原,可以由通式3的硝基苯胺获得通式(II)的二胺。对于还原来说,可以使用本领域技术人员已知的所有方法。在氢气氛围中,在1 bar至100 bar的压力下,在合适的溶剂(例如乙酸乙酯、四氢呋喃、甲醇或乙醇)中,在金属催化剂(例如钯/炭)的存在下,在0℃和溶剂的沸点之间的温度下,典型地在室温下,可以将通式3的硝基苯胺氢化。可能需要加入合适的酸,例如盐酸或乙酸。或者,在合适的溶剂(例如水、甲醇或乙醇或其混合物)中,在室温和溶剂沸点之间的温度下,典型地在70℃下,通式3的硝基苯胺可以被铁/氯化铵或氯化锡(II)还原。
在合适的溶剂(例如四氢呋喃)中,和在合适的碱(例如碳酸钾或三乙胺)的存在下,在室温和溶剂沸点之间的温度下,典型地在50-70℃下,通过与通式2的胺进行亲核取代,可以由通式1的硝基芳烃获得通式3的硝基苯胺。也可以使用它们的相应的铵盐,代替通式2的胺。
通式1的硝基芳烃和通式2的胺或它们的相应的铵盐是可以商购、已知的化合物,或可以通过本领域技术人员已知的方法、由已知的化合物形成。
反应路线2∶
其中,R1、R4、R5、R6、R7、R8、R9、R10、R11和A如上文所定义。
反应路线2描述了合成通式(I)的化合物的另一个方法。
在合适的溶剂(例如四氢呋喃或水或其混合物)中,在亚硫酸盐源(例如亚硫酸钠)的存在下,在0℃和溶剂沸点之间的温度下,典型地在65℃下,可以使合适功能化的通式(II)的二胺与通式(IV)的醛反应。
通式(II)的二胺和通式(IV)的醛是可以商购、已知的化合物,或可以通过本领域技术人员已知的方法、由已知的化合物形成。
反应路线3∶
其中,R4、R5、R6、R7、R8、R9、R10和R11如上文所定义。
反应路线3列出了通过还原胺化得到通式3的硝基苯胺的另一个途径。在合适的溶剂(例如二氯甲烷或二氯乙烷)中,在还原剂(例如硼氢化钠或三乙酰氧基硼氢化钠)的存在下,在0℃和溶剂沸点之间的温度下,典型地在室温下,可以使通式5的环己酮与通式4的硝基苯胺反应。可能需要向反应混合物中加入酸,例如三氟乙酸。
通式4的硝基苯胺和通式5的环己酮是可以商购、已知的化合物,或可以通过本领域技术人员已知的方法、由已知的化合物形成。
按照一个实施方案,本发明还涉及制备上述通式(I)化合物的方法,所述方法包括下列步骤∶使通式(II)的中间体化合物,
其中,R4、R5、R6、R7、R8、R9、R10和R11如上述通式(I)的化合物所定义,
与通式(III)的化合物反应,
其中R1和A如上述通式(I)的化合物所定义,
由此得到通式(I)的化合物∶
其中R1、R4、R5、R6、R7、R8、R9、R10、R11和A如上述通式(I)的化合物所定义。
按照另一个实施方案,本发明还涉及制备上述通式(I)化合物的方法,所述方法包括下列步骤∶使通式(II)的中间体化合物,
其中R4、R5、R6、R7、R8、R9、R10和R11如上述通式(I)的化合物所定义,
与通式(IV)的化合物反应,
其中R1和A如上述通式(I)的化合物所定义,
由此得到通式(I)的化合物∶
其中R1、R4、R5、R6、R7、R8、R9、R10、R11和A如上述通式(I)的化合物所定义。
通用部分
实验部分中没有描述的其合成方法的所有试剂是可商购的试剂,或是已知的化合物,或可以利用本领域技术人员已知的方法、由已知的化合物形成。
按照本发明的方法制备的化合物和中间体可能需要纯化。有机化合物的纯化为本领域技术人员所熟知,并且可以有若干途径来纯化同一化合物。在某些情况下,不需要纯化。在某些情况下,可以通过结晶来纯化化合物。在某些情况下,可以使用合适的溶剂来搅拌除去杂质。在某些情况下,可以通过色谱纯化化合物,尤其是快速柱色谱,例如,使用预先填充的硅胶柱,例如,与Biotage自动净化系统(SP4®或Isolera Four®)结合的BiotageSNAP cartidges KP-Sil®或KP-NH®,洗脱液为:例如,己烷/乙酸乙酯或DCM/甲醇的梯度。在某些情况下,可以通过制备HPLC纯化化合物,例如,使用配备有二极管阵列检测器的Waters自动净化器,和/或,与合适的预先填充的反相柱结合的在线电喷雾离子化质谱仪,洗脱液:水和乙腈的梯度,可以含有添加剂,例如三氟乙酸、甲酸或氨水。
在某些情况下,上述纯化方法可以提供具有充分碱性或酸性官能团的盐形式的本发明的化合物,例如,在本发明的化合物是充分碱性的情况下,提供三氟乙酸盐或甲酸盐,或在本发明的化合物是充分酸性的情况下,提供铵盐。利用本领域技术人员已知的各种方法,这种类型的盐可以分别转变成它的游离碱或游离酸形式,或在后续的生物试验中以盐的形式使用。应该理解,按照本文所描述的、分离的本发明化合物的具体形式(例如盐、游离碱等等)不一定是为了定量具体生物活性而可以用于生物试验的所述化合物的唯一形式。
UPLC-MS标准方法
如下所述,进行分析UPLC-MS。用正离子电喷雾电离模式报道质量(m/z),除非指定负离子模式(ES-)。
在大多数情况下,使用方法A。否则,会予以指明。
UPLC-MS 方法A
仪器∶Waters Acquity UPLC-MS SQD 3001;柱∶Acquity UPLC BEH C18 1.750x2.1mm;洗脱液A∶水+0.1%甲酸,洗脱液B∶乙腈;梯度∶0-1.6分钟1-99% B;1.6-2.0分钟99% B;流速∶0.8 mL/min;温度∶60℃;注射∶2µL;DAD扫描∶210-400 nm。
UPLC-MS 方法B
仪器∶Waters Acquity UPLC-MS SQD 3001;柱∶Acquity UPLC BEH C18 1.750x2.1mm;洗脱液A∶水+0.2%氨,洗脱液B∶乙腈;梯度∶0-1.6分钟1-99% B;1.6-2.0分钟99%B;流速∶0.8 mL/min;温度∶60℃;注射∶2µL;DAD扫描∶210-400 nm; ELSD。
UPLC-MS 方法D
仪器∶Waters Acquity UPLC-MS ZQ4000;柱∶Acquity UPLC BEH C18 1.7 50x2.1mm;洗脱液A∶水+0.2%氨,洗脱液B∶乙腈;梯度∶0-1.6分钟1-99% B;1.6-2.0分钟99% B;流速∶0.8 mL/min;温度∶60℃;注射∶2µL;DAD扫描∶210-400 nm;ELSD。
UPLC-MS 方法E
仪器∶Waters Acquity UPLC-MS ZQ2000;柱∶Acquity UPLC BEH C18 1.7 50x2.1mm;洗脱液A∶水+0.1%甲酸,洗脱液B∶乙腈;梯度∶0-1.6分钟1-99% B;1.6-2.0分钟99% B;流速∶0.8 mL/min;温度∶60℃;注射∶1µL;DAD扫描∶210-400 nm;ELSD。
UPLC-MS 方法F
仪器∶Waters Acquity UPLC-MS ZQ2000;柱∶Acquity UPLC BEH C18 1.7 50x2.1mm;洗脱液A∶水+0.2%氨,洗脱液B∶乙腈;梯度∶0-1.6分钟1-99% B;1.6-2.0分钟99% B;流速∶0.8 mL/min;温度∶60℃;注射∶1µL;DAD扫描∶210-400 nm;ELSD。
UPLC-MS 方法G
仪器∶Waters Acquity UPLC-MS;柱∶XBridge BEH C18 2.5µm 2.1x50mm;洗脱液A∶10mM碳酸氢铵,pH10,洗脱液B∶乙腈;梯度∶2-98% B在0.80分钟内,保持98% B至1.30分钟;流速∶0.8 mL/min;检测∶Waters Acquity自动进样器(UPLC LG 500 nm)。
UPLC-MS 方法H
仪器∶Waters Acquity UPLC-MS;柱∶XBridge BEH C18 2.5µm 2.1x50mm;洗脱液A∶10mM碳酸氢铵,pH10,洗脱液B∶乙腈;梯度∶2-98% B,在4.00分钟内,保持98% B至4.70分钟;流速∶0.8 mL/min;检测∶Waters Acquity自动进样器(UPLC LG 500 nm)。
NMR峰形按照它们在光谱中出现的峰形指出,没有考虑可能的更高级别的效果。
获得的通式(I)的苯并咪唑可能是手性的,并且可以通过手性HPLC,分离为它们的非对映异构体和/或对映异构体。
中间体
中间体1-1
(±)3-氨基-4-{[(反式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯和
(±)3-氨基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯
步骤1∶
3-硝基-4-[(3,3,5-三甲基环己基)氨基]苯甲酸甲酯
将22.7 g(114 mmol)4-氟-3-硝基苯甲酸甲酯(可商购)和16.1 g(114 mmol)3,3,5-三甲基环己胺(立体异构体的混合物,可商购)加入到460 mL四氢呋喃中。加入17.34 g(125mmol)碳酸钾之后,将该反应混合物在50℃下加热45小时。通过玻璃纤维过滤器滤出固体,用乙酸乙酯洗涤,并弃置。将滤液用水(200 mL)和乙酸乙酯(450 mL)稀释。剧烈搅拌15分钟之后,分离有机相。用乙酸乙酯(250 mL)洗涤水相。将合并的有机提取物用水(150 mL)和盐水(150 mL)洗涤。干燥(硫酸钠)之后,蒸发溶剂,得到35.9 g(93%)橙黄色固体(立体异构体的混合物),其没有进一步纯化,直接在下一步使用。
步骤2∶
3-氨基-4-{[(反式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯和3-氨基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯
将15 g(46.8 mmol)3-硝基-4-[(3,3,5-三甲基环己基)氨基]苯甲酸甲酯溶于乙酸乙酯(706 mL)中。加入0.98 g(9.2 mmol)钯/碳之后,将该反应混合物在室温下、在氢气氛围中搅拌七个小时。通过玻璃纤维过滤器滤出催化剂,并用乙酸乙酯洗涤。蒸发溶剂之后,用柱色谱纯化残余物(Biotage,洗脱液∶己烷/乙酸乙酯),得到0.6 g(4.2%)反式非对映异构体(外消旋体)和9.99 g(70%)顺式非对映异构体(外消旋体)。
中间体1-2
(±)5-氨基-2-甲基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯
步骤1∶
(±)2-甲基-5-硝基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯和(±)2-甲基-5-硝基-4-{[(反式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯
类似于中间体1-1的步骤1,使4-氟-2-甲基-5-硝基苯甲酸甲酯(CAS编号[1163287-01-1];5.14 g,24.1 mmol)与碳酸钾(1.10 eq,3.67 g,26.5 mmol)和3,3,5-三甲基环己胺(立体异构体的混合物,可商购;1.00 eq,3.41 g,24.1 mmol)在THF(154 mL)中、在室温下反应20小时,得到标题化合物(8.51 g,定量)的顺式非对映异构体和反式非对映异构体(大约7:1)的外消旋混合物,没有进一步纯化。
步骤2∶
(±)5-氨基-2-甲基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯
类似于中间体1-1的步骤2,使用钯/碳(10wt%;0.25 eq,643 mg,6.04 mmol)和氢气,将步骤1的(±)2-甲基-5-硝基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯和(±)2-甲基-5-硝基-4-{[(反式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯(大约7:1;8.51 g,24.2 mmol)的混合物在乙酸乙酯(400 mL)中、在室温下氢化过夜,通过快速色谱(SiO2-己烷/乙酸乙酯)纯化之后,得到标题化合物(3.7 g,50%)的外消旋顺式非对映异构体。
中间体1-3
3-氨基-2-氟-4-[(3,3,5,5-四甲基环己基)氨基]苯甲酸甲酯
步骤1∶
4-溴-3-氟-2-硝基-N-(3,3,5,5-四甲基环己基)苯胺
将4-溴-3-氟-2-硝基苯胺(CAS编号[886762-75-0];5.80 g,24.7 mmol)和3,3,5,5-四甲基环己酮(CAS编号[14376-79-5];1.00 eq,3.81 g,24.7 mmol)在二氯甲烷(60 mL)中的混合物用三氟乙酸(20 mL)逐滴处理,在室温下搅拌5分钟,此时将三乙酰氧基硼氢化钠([56553-60-7];1.5 eq,7.85 g,37.0 mmol)分批加入到该澄清溶液中,并在室温下继续搅拌2天。将冰冷却的反应混合物用氨水溶液(25%,22 mL)淬灭,并在水和二氯甲烷之间分配。分离各相,并用二氯甲烷提取水相两次。将合并的有机层用硫酸镁干燥,并真空浓缩。用快速色谱(SiO2-己烷/乙酸乙酯)纯化所获得的物质,得到标题化合物(4.7 g,48%)以及再次分离的4-溴-3-氟-2-硝基苯胺(2.7 g,47%)。
步骤2∶
3-氨基-2-氟-4-[(3,3,5,5-四甲基环己基)氨基]苯甲酸甲酯
在氩气氛中,将步骤1的4-溴-3-氟-2-硝基-N-(3,3,5,5-四甲基环己基)苯胺(2.08 g,5.57 mmol)的甲醇(56 mL)溶液放入钢制的反应釜中。加入1,1'-二(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷复合物(CAS编号[95464-05-4];0.200 eq,910 mg,1.11 mmol)和乙酸钾(4.00 eq,2.19 g,22.3 mmol),并将该混合物用一氧化碳吹扫3次。在20℃,在大约12.6 bar的一氧化碳压力下,将该混合物搅拌30分钟。将反应釜再次放置在真空条件下,然后,使用大约12 bar的一氧化碳压力,并将该混合物加热到100℃下,保持21小时,得到大约13.3 bar的最大压力。将该反应冷却到室温,释放压力,并将该反应混合物真空浓缩。用快速色谱法(SiO2-己烷/乙酸乙酯)纯化所获得的粗品,得到目标酯(805 mg,44%)。
中间体1-4
(±)5-氨基-2-甲氧基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯
步骤1∶
(±)2-氟-5-硝基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯和(±)4-氟-5-硝基-2-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯
将2,4-二氟-5-硝基苯甲酸甲酯(CAS编号[125568-71-0];15.7 g,72.3 mmol)的乙腈(360 mL)溶液用三乙胺(1.30 eq,13.1 mL,94.0 mmol)和3,3,5-三甲基环己胺(立体异构体的混合物,可商购;1.40 eq,14.3 g,101 mmol)处理,并在室温下搅拌过夜。将该反应混合物用水(300 mL)稀释,并通过加入盐酸水溶液(2M),将该混合物的pH值调节至pH3。用乙酸乙酯提取该反应混合物,并将合并的有机层用水、盐水洗涤,用硫酸钠干燥,并真空浓缩,得到(±)2-氟-5-硝基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯和(±)4-氟-5-硝基-2-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯的混合物(大约78:22,33.5g,定量)。该物质(含有少量的相应的反式产物)不用进一步纯化,在下一步直接使用。
步骤2∶
(±)2-甲氧基-5-硝基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯
将步骤1的冰冷却的(±)2-氟-5-硝基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯和(±)4-氟-5-硝基-2-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯(大约78:22;7.00 g,16.5 mmol)的混合物在甲醇(15 mL)中慢慢地用甲醇钠的甲醇溶液(CAS编号[124-41-4];10 eq,38 mL,30wt%溶液)处理,并在0℃下搅拌1小时。将该悬浮液吸收在乙酸乙酯中,并用水洗涤。分离各相,用硫酸钠干燥有机层,并真空浓缩。用快速色谱法(SiO2-己烷/乙酸乙酯)纯化所获得的物质,得到标题化合物(2.9 g,50%)的外消旋顺式非对映异构体。
步骤3∶
(±)5-氨基-2-甲氧基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯
类似于中间体1-1的步骤2,在室温下,将步骤2的(±)2-甲氧基-5-硝基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯(2.07 g,5.26 mmol)在乙酸乙酯(80 mL)中用钯/碳(10wt%;0.250 eq,140 mg,1.31 mmol)和氢气氢化过夜,得到标题化合物(1.9 g,定量),其没有进一步纯化,在下一步中直接使用。
中间体1-5
(±)3-(5-氨基-2-甲氧基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯基)丙酸甲酯
步骤1∶
1-溴-4-氟-2-甲氧基-5-硝基苯
将1-溴-4-氟-2-甲氧基苯(CAS编号[450-88-4];10.0 g,48.8 mmol)在浓硫酸(50 mL)中的混合物冷却到0℃,并用新制备的发烟硝酸(1.05 eq,2.1 mL,51 mmol)和浓硫酸(1.85eq,4.8 mL,90 mmol)的混合物逐滴处理。将该反应混合物在0℃下搅拌30分钟,并以小份形式倾倒在冰水上。滤出形成的沉淀,用冷水洗涤,并保持。用乙酸乙酯提取滤液,并将有机层与分离的沉淀合并。将有机层用硫酸钠干燥,并真空浓缩。用快速色谱法(SiO2-己烷/乙酸乙酯)纯化所获得的物质,得到标题化合物(5.88 g,44%)。
步骤2∶(±)4-溴-5-甲氧基-2-硝基-N-[(顺式)-3,3,5-三甲基环己基]苯胺
将步骤1的1-溴-4-氟-2-甲氧基-5-硝基苯(2.90 g,11.6 mmol)的THF(87 mL)溶液用碳酸钾(1.10 eq,1.76 g,12.8 mmol)和3,3,5-三甲基环己胺(立体异构体的混合物,可商购;1.00 eq,1.64 g,11.6 mmol)处理,并在70℃下搅拌过夜。过滤该反应混合物,在水和乙酸乙酯之间分配滤液,并用乙酸乙酯提取。将合并的有机层用水、盐水洗涤,用硫酸钠干燥,并真空浓缩,得到标题化合物(4.39 g,97%)的顺式非对映异构体(大约92-94%)和反式非对映异构体(大约6-8%)的外消旋混合物,其没有进一步纯化。
步骤3∶
(±)(2E)-3-(2-甲氧基-5-硝基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯基)丙-2-烯酸甲酯
向步骤2的(±)4-溴-5-甲氧基-2-硝基-N-[(顺式)-3,3,5-三甲基环己基]苯胺(6.79g,17.4 mmol)的DMF(129 mL)溶液中加入丙-2-烯酸甲酯(CAS编号[96-33-3];3.00 eq,4.69 mL,52.1 mmol)和三乙胺(2.00 eq,4.84 mL,34.7 mmol)。将该混合物用氩气吹扫若干次,并在室温下搅拌10分钟。加入四(三苯基膦)钯(0.150 eq,3.01 g,2.61 mmol),用氩气再次吹扫该混合物,并加热到110℃下过夜。将该反应混合物冷却至室温,并用水稀释。用乙酸乙酯提取(3次),并将合并的有机层用盐水洗涤,用硫酸钠干燥,并真空浓缩。用快速色谱法(SiO2-己烷/乙酸乙酯)纯化所获得的物质,得到标题化合物(3.9 g,55%)的外消旋顺式非对映异构体。
步骤4∶
(±)3-(5-氨基-2-甲氧基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯基)丙酸甲酯
将步骤3的(±)(2E)-3-(2-甲氧基-5-硝基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯基)丙-2-烯酸甲酯(2.70 g,7.17 mmol)的乙酸乙酯(190 mL)溶液用钯/碳(10wt%;1.50eq,1.15 g,10.8 mmol)处理,并在氢气氛围中、在室温下搅拌过夜。由于不完全转化,加入额外数量的钯/碳(10wt%;0.50 eq,382 mg,3.59 mmol),并在氢气氛围中、在室温下继续搅拌一天。用硅藻土过滤该反应混合物,用乙酸乙酯洗涤,并真空浓缩滤液,得到标题化合物(2.34 g,84%)的外消旋顺式非对映异构体,其没有进一步纯化。
中间体1-6
(±)3-(5-氨基-2-甲基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯基)丙酸甲酯
步骤1∶
(±)4-溴-5-甲基-2-硝基-N-[(顺式)-3,3,5-三甲基环己基]苯胺
类似于中间体1-1的步骤1,在室温下,使1-溴-4-氟-2-甲基-5-硝基苯(CAS编号[170098-98-3];1.00 eq,3.60 g,15.4 mmol)与碳酸钾(1.10 eq,2.34 g,16.9 mmol)和3,3,5-三甲基环己胺(立体异构体的混合物,可商购;1.00 eq,2.17 g,15.4 mmol)在THF(110mL)中反应7天,在40℃下反应3小时,用快速色谱(SiO2-己烷/乙酸乙酯)纯化之后,得到标题化合物(5.1 g,84%)的顺式非对映异构体(大约90%)和反式非对映异构体(大约7%)的外消旋混合物。
步骤2∶
(±)(2E)-3-(2-甲基-5-硝基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯基)丙-2-烯酸甲酯
类似于中间体1-5的步骤3,使步骤1的(±)4-溴-5-甲基-2-硝基-N-[(顺式)-3,3,5-三甲基环己基]苯胺(2.41 g,6.78 mmol)与丙-2-烯酸甲酯(CAS编号[96-33-3];3.00 eq,1.83 mL,20.4 mmol)、三乙胺(2.00 eq,1.89 mL,13.6 mmol)和四(三苯基膦)钯(0.150eq,1.18 g,1.02 mmol)在DMF(48 mL)中、在110℃下反应过夜,用快速色谱法(SiO2-己烷/乙酸乙酯)纯化之后,得到标题化合物(1.81 g,73%)的外消旋顺式非对映异构体。
步骤3∶
(±)3-(5-氨基-2-甲基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯基)丙酸甲酯
类似于中间体1-5的步骤4,将步骤2的(±)(2E)-3-(2-甲基-5-硝基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯基)丙-2-烯酸甲酯(1.81 g,5.02 mmol) 在乙醇(100 mL)和乙酸乙酯(30 mL)的混合物中的溶液用钯/碳(10wt%;1.50 eq,801 mg,7.53 mmol)处理,并在氢气氛围中、在室温下搅拌过夜。用硅藻土过滤该反应混合物,用乙酸乙酯洗涤,并真空浓缩滤液,得到标题化合物(1.76 g,79%)的外消旋顺式非对映异构体,其没有进一步纯化。
中间体1-7
(±)5-氨基-2-(丙-2-基氧基)-4-{[(反式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯和(±)5-氨基-2-(丙-2-基氧基)-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯
步骤1∶
(±)5-硝基-2-(丙-2-基氧基)-4-{[(反式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯和(±)5-硝基-2-(丙-2-基氧基)-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯
将丙-2-醇化钠(2.11 g,25.7 mmol)在丙-2-醇(25 mL)中、在室温下搅拌15分钟,而后冷却到-10℃。向该混合物中逐滴加入中间体1-4的步骤1的(±)2-氟-5-硝基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯和(±)4-氟-5-硝基-2-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯(大约78:22;8.70 g,25.7 mmol)(含有少量的相应的反式产物)的丙-2-醇(25 mL)溶液,并在-10℃下继续搅拌30分钟。将该反应混合物倒入水中,并用乙酸乙酯提取两次。将合并的有机层用硫酸钠干燥,并真空浓缩。用快速色谱法(SiO2-己烷/乙酸乙酯)纯化所获得的物质,得到标题化合物(1.22 g,11%)的顺式和反式(大约87:13)非对映异构体的外消旋混合物。
步骤2∶
(±)5-氨基-2-(丙-2-基氧基)-4-{[(反式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯和(±)5-氨基-2-(丙-2-基氧基)-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯
类似于中间体1-5的步骤4,将步骤1的(±)5-硝基-2-(丙-2-基氧基)-4-{[(反式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯和(±)5-硝基-2-(丙-2-基氧基)-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯(1.22 g,2.80 mmol)的乙酸乙酯(56 mL)溶液用钯/碳(10wt%;1.50 eq,448 mg,4.21 mmol)处理,并在氢气氛围中、在室温下搅拌过夜。用硅藻土过滤该反应混合物,用乙酸乙酯洗涤,并真空浓缩滤液,得到标题化合物(1.08 g,97%)的顺式和反式(大约88:12)非对映异构体的外消旋混合物,其没有进一步纯化。
中间体1-8
(±)5-氨基-2-(2,2,2-三氟乙氧基)-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯
步骤1∶
(±)5-硝基-2-(2,2,2-三氟乙氧基)-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯
将2,2,2-三氟乙醇(355 mg,3.55 mmol)的THF(8 mL)溶液用2-甲基丙-2-醇化钾处理,在室温下搅拌10分钟,而后在冰浴中冷却。向该混合物是中逐滴加入中间体1-4的步骤1的(±)2-氟-5-硝基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯和(±)4-氟-5-硝基-2-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯(大约78:22;1.00 g,2.96 mmol)(含有少量的相应的反式产物)的THF(8 mL)溶液,并在冰浴冷却下继续搅拌1小时。将该反应混合物倒入水中,并用乙酸乙酯提取两次。将合并的有机层用硫酸钠干燥,并真空浓缩。用快速色谱法(SiO2-己烷/乙酸乙酯)纯化所获得的物质,得到标题化合物(515 mg,41%)的外消旋顺式非对映异构体。
步骤2∶
(±)5-氨基-2-(2,2,2-三氟乙氧基)-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯
类似于中间体1-5的步骤4,将步骤1的(±)5-硝基-2-(2,2,2-三氟乙氧基)-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯(510 mg,1.22 mmol)的乙酸乙酯(36 mL)溶液用钯/碳(10wt%;1.50 eq,195 mg,1.83 mmol)处理,并在氢气氛围中、在室温下搅拌过夜。用硅藻土过滤该反应混合物,用乙醇洗涤,并真空浓缩滤液,得到标题化合物(440 mg,60%)的外消旋顺式非对映异构体,其没有进一步纯化。
中间体1-9
(±)3-氨基-4-{[(反式)-3,3,5-三甲基环己基]氨基}苄腈和(±)3-氨基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苄腈
步骤1∶
(±)3-硝基-4-{[(反式)-3,3,5-三甲基环己基]氨基}苄腈和(±)3-硝基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苄腈
类似于中间体1-1的步骤1,使4-氟-3-硝基苯甲腈(1.00 eq,5.00 g,30.1 mmol)与碳酸钾(2.00 eq,8.32 g,60.2 mmol)和3,3,5-三甲基环己胺(立体异构体的混合物,可商购;1.00 eq,4.25 g,30.1 mmol)在THF(195 mL)中、在50℃下反应过夜,得到标题化合物(9.83g,定量)的顺式非对映异构体(大约93%)和反式非对映异构体(大约7%)的外消旋混合物。
步骤2∶
(±)3-氨基-4-{[(反式)-3,3,5-三甲基环己基]氨基}苄腈和(±)3-氨基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苄腈
类似于中间体1-5的步骤4,将步骤1的(±)3-硝基-4-{[(反式)-3,3,5-三甲基环己基]氨基}苄腈和(±)3-硝基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苄腈(9.83 g,32.5mmol)的乙酸乙酯(200 mL)溶液用钯/碳(10wt%;0.20 eq,692 mg,6.50 mmol)处理,并在氢气氛围中、在室温下搅拌18小时。用硅藻土过滤该反应混合物,用乙酸乙酯洗涤,并真空浓缩滤液,得到标题化合物(7.78 g,79%)的顺式和反式(大约90:10)非对映异构体的外消旋混合物,其没有进一步纯化。
中间体1-10
3-{3-氨基-2-氟-4-[(3,3,5,5-四甲基环己基)氨基]苯基}丙酸甲酯
步骤1∶
(2E)-3-{2-氟-3-硝基-4-[(3,3,5,5-四甲基环己基)氨基]苯基}丙烯酸甲酯
将4-溴-3-氟-2-硝基-N-(3,3,5,5-四甲基环己基)苯胺(在中间体1-3的步骤1中制备;2.20 g,5.89 mmol)溶于N,N-二甲基甲酰胺(73 mL)中,而后加入丙烯酸甲酯(1.59 mL,17.68 mmol)和三乙胺(1.64 mL,11.79 mmol)。将该混合物用氩气脱气15分钟,然后加入四(三苯基膦)钯(681 mg,0.59 mmol),并将该反应在120℃下加热18小时。冷却该反应,并加入盐水(50 mL)和乙酸乙酯(50 mL)。分离各层,并将水层用乙酸乙酯(3 x 50 mL)提取。将合并的有机层用固体硫酸钠干燥,并真空浓缩。用快速色谱法(SiO2-庚烷/乙酸乙酯)纯化粗品,得到标题化合物(0.88 mg,39%)的橙色固体。
步骤2∶
3-{3-氨基-2-氟-4-[(3,3,5,5-四甲基环己基)氨基]苯基}丙酸甲酯
向步骤1的(2E)-3-{2-氟-3-硝基-4-[(3,3,5,5-四甲基环己基)氨基]苯基}丙-2-烯酸甲酯(880 mg,2.32 mmol)的四氢呋喃(44 mL)溶液中加入5%钯/碳(494 mg,0.23 mmol),并将该反应在氢气氛围中(1 atm)搅拌18小时。通过硅藻土过滤反应物,使用乙酸乙酯,并将滤液浓缩。用快速色谱法纯化残余物(SiO2-庚烷/乙酸乙酯),得到标题化合物(858 mg,定量)的棕色油。
实施例
实施例2-1
(±)2-[4-(三氟甲氧基)苯基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯
将亚硫酸钠(2.25 eq,150 mg,1.19 mmol)水(1 mL)溶液在室温下搅拌30分钟,此时在室温下逐滴加入4-(三氟甲氧基)苯甲醛(CAS编号[659-28-9];1.00 eq,101 mg,0.530mmol)的THF(1 mL)溶液,并在室温下继续搅拌1小时。逐滴加入(±)3-氨基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯(中间体1-1;1.30 eq,200 mg,0.689 mmol)的THF(1mL)溶液,将该反应混合物加热到65℃,并在此温度下继续搅拌过夜。加入额外数量的4-(三氟甲氧基)苯甲醛(0.80 eq,81 mg,0.42 mmol),并将该混合物在65℃下再搅拌3小时。将该反应混合物用水稀释,并用乙酸乙酯提取。用饱和碳酸氢钠水溶液和盐水洗涤有机层,用硫酸钠干燥,并真空浓缩,得到标题化合物(333 mg,定量),其没有进一步纯化。
利用手性制备HPLC(系统∶Agilent∶Prep 1200,2xPrep泵,DLA,MWD,Gilson∶液体处理器215;柱∶Chiralpak IC 5µm 250x30 mm;溶剂∶己烷/乙醇,70:30(v/v);流速∶50 mL/min;温度∶室温;溶液∶261 mg/5.5 mL DCM/MeOH;注射∶10 x 0.55 mL;检测∶UV 254 nm),将实施例2-1的外消旋物质的对映异构体分离,并利用手性HPLC(系统∶Waters∶Alliance2695,DAD 996,ESA∶Corona;柱∶Chiralpak IC 5µm 150x4.6 mm;溶剂∶己烷/乙醇,70:30(v/v);流速∶1.0 mL/min;温度∶25℃;溶液∶1.0 mg/mL EtOH/MeOH,1:1;注射∶5.0µL;检测∶DAD 254 nm),进行分析性表征∶
实施例2-1-1
2-[4-(三氟甲氧基)苯基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,对映异构体A
Rt=4.56 min。
实施例2-1-2
2-[4-(三氟甲氧基)苯基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,对映异构体B
Rt=5.08 min。
实施例2-2
(±)2-[4-(三氟甲氧基)苯基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸
将(±)2-[4-(三氟甲氧基)苯基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯(实施例2-1;32.5 mg,0.0706 mmol)在THF/水(1:1,2 mL)的混合物中的溶液用氢氧化锂(5.0 eq,8.5 mg,0.35 mmol)处理,并在70℃下搅拌23小时。将该反应混合物用2M盐酸水溶液(pH4-5)酸化,并用乙酸乙酯稀释。分离各层,并用乙酸乙酯提取水层两次。用水和盐水洗涤合并的有机层,用硫酸钠干燥,并真空浓缩。所获得的粗品(13 mg,40%)不用进一步纯化。
实施例2-2-1
2-[4-(三氟甲氧基)苯基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,对映异构体A
类似于实施例2-2,在THF/水(1:1,4 mL)的混合物中,使2-[4-(三氟甲氧基)苯基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯对映异构体A(实施例2-1-1;108mg,0.235 mmol)与氢氧化锂(5.0 eq,28 mg,1.2 mmol)在70℃下反应过夜,得到粗品标题化合物(87.5 mg,79%),其没有进一步纯化。
实施例2-2-2
2-[4-(三氟甲氧基)苯基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,对映异构体B
类似于实施例2-2,在THF/水(1:1,4 mL)的混合物中,使2-[4-(三氟甲氧基)苯基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯对映异构体B (实施例2-1-2;115 mg,0.250 mmol)与氢氧化锂(5.0 eq,30 mg,1.2 mmol)在70℃下反应过夜,得到粗品标题化合物(78 mg,67%),其没有进一步纯化。
实施例2-3
(±)2-[4-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯
在压力管中,将(±)3-氨基-4-{[(顺式)-3,3,5-三甲基环己基]氨基}苯甲酸甲酯(中间体1-1;200 mg,0.689 mmol)和[4-(三氟甲氧基)苯基]乙酸(CAS编号[4315-07-5];1.20eq,182 mg,0.826 mmol)在乙酸乙酯(2 mL)中的混合物用吡啶(25 eq,1.4 mL,17 mmol)和2,4,6-三丙基-1,3,5,2,4,6-三氧杂三磷烷(phosphinane)2,4,6-三氧化物(CAS编号[68957-94-8];50wt.%溶液,在DMF中,5.0 eq,2.2 g,2.0 mL,3.4 mmol)处理,将管密封,并在100℃下搅拌过夜。一旦冷却至室温,将该反应混合物在水和乙酸乙酯之间分配,并分离各层。用盐水洗涤有机层,用硫酸钠干燥,并真空浓缩。将所获得的物质用制备HPLC纯化,得到标题化合物(165 mg,50%)。
利用手性制备HPLC(系统∶Agilent∶Prep 1200,2xPrep泵,DLA,MWD,Prep FC;柱∶Chiralpak IA 5µm 250x30 mm;溶剂∶己烷/2-丙醇,70:30(v/v);流速∶50 mL/min;温度∶室温;溶液∶130 mg/1.8 mL DCM;注射∶3 x 0.6 mL;检测∶UV 254 nm),将实施例2-3的外消旋物质的对映异构体分离,并利用手性HPLC(系统∶Waters∶Alliance 2695,DAD 996,ESA∶Corona;柱∶Chiralpak IA 3µm 100x4.6 mm;溶剂∶己烷/2-丙醇,70:30(v/v);流速∶1.0mL/min;温度∶25℃;溶液∶1.0 mg/mL EtOH/MeOH,1:1;注射∶5.0µL;检测∶DAD 254 nm),进行分析性表征∶
实施例2-3-1
2-[4-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,对映异构体A
Rt=3.68 min。
实施例2-3-2
2-[4-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,对映异构体B
Rt=5.09 min。
类似于实施例2-3的方式,从给出的中间体和相应的商购的羧酸衍生物起始,制备表2中的参考化合物。分离对映异构体/非对映异构体,并按照给出的方法,进行分析。
类似于实施例2-3的方式,从给出的中间体和相应的商购的羧酸衍生物起始,制备表3中的实施例。分离对映异构体/非对映异构体,并按照给出的方法,进行分析。
实施例2-29
(±)2-[4-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸
将(±)2-[4-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯(实施例2-3;35 mg,0.0738 mmol)的溶液(在THF/水的混合物(1:1,2 mL)中)用氢氧化锂(5.0 eq,8.8 mg,0.37 mmol)处理,并在70℃下搅拌过夜。将该反应混合物用2M盐酸水溶液酸化(pH3-4),并用乙酸乙酯稀释。分离各层,并用乙酸乙酯提取水层两次。用水和盐水洗涤合并的有机层,用硫酸钠干燥,并真空浓缩。所获得的粗品(34 mg,定量)不用进一步纯化。
实施例2-29-1
2-[4-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,对映异构体A
类似于实施例2-29,在THF/水的混合物(1:1,2 mL)中,使2-[4-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯对映异构体A(实施例2-3-1;48mg,0.10 mmol)与氢氧化锂(5.0 eq,12 mg,0.51 mmol)在70℃下反应过夜,得到粗品标题化合物(44 mg,85%),其没有进一步纯化。
实施例2-29-2
2-[4-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,对映异构体B
类似于实施例2-29,在THF/水的混合物(1:1,2 mL)中,使2-[4-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯对映异构体B (实施例2-3-2;51mg,0.11 mmol)与氢氧化锂(5.0 eq,13 mg,0.54 mmol)在70℃下反应过夜,得到粗品标题化合物(41 mg,75%),其没有进一步纯化。
类似于实施例2-29的方式,从给出的酯前体物起始,制备表4中的实施例。
实施例2-51
3-{4-氟-1-(3,3,5,5-四甲基环己基)-2-[4-(三氟甲氧基)苄基]-1H-苯并咪唑-5-基}丙酸甲酯
在室温下,将4-三氟甲氧基苯乙酸(CAS-编号[4315-07-5];1.00 eq,126 mg,0.571mmol)的四氢呋喃(13 mL)溶液用1,1'-羰基二咪唑(1.0 eq,93 mg,0.57 mmol)处理,随后在75℃下加热1小时。加入3-{3-氨基-2-氟-4-[(3,3,5,5-四甲基环己基)氨基]苯基}丙酸甲酯(中间体1-10;1.00 eq,200 mg,0.571 mmol)的四氢呋喃(3 mL)溶液,并将该反应在75℃下加热18小时。除去挥发物,将深红色残余物吸收在乙酸(6 mL)中,并在110℃下加热2小时。用乙酸乙酯(20 mL)稀释该反应混合物,并用2M氢氧化钠水溶液洗涤,直到洗液呈碱性为止。将有机层用固体硫酸钠干燥,并真空浓缩。用快速色谱法纯化粗品(SiO2-庚烷/乙酸乙酯),得到标题化合物(159 mg,52%)的褐色胶质。
实施例2-52
3-{4-氟-1-(3,3,5,5-四甲基环己基)-2-[4-(三氟甲氧基)苄基]-1H-苯并咪唑-5-基}丙酸
将3-{4-氟-1-(3,3,5,5-四甲基环己基)-2-[4-(三氟甲氧基)苄基]-1H-苯并咪唑-5-基}丙酸甲酯(实施例2-51;159 mg,0.297 mmol)的四氢呋喃(30 mL)和水(7.5 mL)溶液用氢氧化锂一水合物(4.0 eq,50 mg,1.2 mmol)处理,并将该反应在室温下搅拌66小时。加入饱和氯化铵溶液(达到pH5),并将该混合物用乙酸乙酯(3 x 30mL)提取。将合并的有机层用固体硫酸钠干燥,并真空浓缩。研磨(乙醚)纯化,得到标题化合物(132 mg,85%)的淡粉红色固体。
进一步的,利用本领域技术人员已知的方法,本发明的式(I)的化合物可以转变为本文所描述的任何盐。类似地,利用本领域技术人员已知的任何方法,本发明的式(I)化合物的任何盐可以转变为游离化合物。
本发明的化合物的药物组合物
本发明还涉及含有一或多种本发明化合物的药物组合物。可以使用这些组合物,通过给予需要其的患者,获得目标药理学效果。对本发明来说,患者是需要治疗具体病症或疾病的哺乳动物,包括人。因此,本发明包括由可药用载体和药学有效量的本发明化合物或其盐组成的药物组合物。优选,可药用载体是在与活性组分的有效活性一致的浓度下对患者相对无毒和无害的载体,使得由于载体所引起的任何副作用不会损害活性组分的有益效果。优选,化合物的药学有效量是对所治疗的具体病症产生效果或产生影响的数量。本发明的化合物可以与本领域众所周知的可药用载体一起给予,使用任何有效的常规剂量单位形式,包括立即、缓慢和定时释放制剂,可以口服、肠胃外、局部、鼻部、眼部(ophthalmically)、眼睛(optically)、舌下、直肠、阴道给药,等等。
对于口服给药,可以将所述化合物配制为固体或液体制剂,例如胶囊剂、丸剂、片剂、锭剂、糖锭剂、融化物、粉剂、溶液剂、混悬剂或乳剂,并且可以按照药物组合物的制备领域已知的方法来制备。固体单位剂型可以是胶囊剂,这种胶囊剂可以是普通的硬或软壳明胶类型,例如,其包含表面活性剂、润滑剂和惰性填料,例如乳糖、蔗糖、磷酸钙和玉米淀粉。
在另一个实施方案中,本发明的化合物可以与常规片剂基质(例如乳糖、蔗糖和玉米淀粉)、且结合粘合剂(例如阿拉伯胶、玉米淀粉或明胶)、意在给药之后帮助片剂崩裂和溶出的崩解剂(例如马铃薯淀粉、藻酸、玉米淀粉和瓜尔豆胶、黄芪胶、阿拉伯胶)、意在改善制片颗粒的流动性和防止压片材料与压片模具和冲头的表面粘附的润滑剂(例如滑石粉、硬脂酸或硬脂酸镁、硬脂酸钙或硬脂酸锌)、意在增加片剂的美观性和使它们更易被患者接受的染料、着色剂和调味剂(例如薄荷、冬青油或樱桃香精)一起压片。用于口服液体剂型的合适的赋形剂包括:磷酸氢钙和稀释剂,例如水和醇(例如乙醇、苯甲醇和聚乙烯醇),可以加入或不加入可药用表面活性剂、悬浮剂或乳化剂。各种其它物质可以以包衣形式存在,或另外用以改变剂量单位的物理形式。例如片剂、丸剂或胶囊剂可以涂有虫胶、糖或两者。
可分散性粉剂和颗粒剂适合于制备水性混悬剂。它们与分散剂或湿润剂、悬浮剂和一或多种防腐剂的混合提供活性组分。合适的分散或湿润剂和悬浮剂通过前文中已经提到的那些进行了举例。还可以存在其它赋形剂,例如前文所述那些甜味剂、调味剂和着色剂。
本发明的药物组合物还可以是水包油乳剂形式。油相可以是植物油,例如液体石蜡或植物油的混合物。合适的乳化剂可以是:(1)天然存在的树胶,例如阿拉伯胶和黄芪胶,(2)天然存在的磷脂,例如大豆和卵磷脂,(3)衍生自脂肪酸和己糖醇酸酐的酯或偏酯,例如山梨糖醇酐单油酸酯,(4)所述偏酯与氧化乙烯的缩合产物,例如聚氧化乙烯山梨糖醇酐单油酸酯。该乳剂还可以含有甜味剂和调味剂。
油状混悬剂可以通过将活性组分悬浮在植物油(例如花生油、橄榄油、芝麻油或椰子油)或矿物油(例如液体石蜡)中来配制。油状混悬剂可以含有增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。混悬剂还可以含有一或多种防腐剂,例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯;一或多种着色剂;一或多种调味剂;和一或多种甜味剂,例如蔗糖或糖精。
糖浆剂和酏剂可以与甜味剂(例如丙三醇、丙二醇、山梨糖醇或蔗糖)一起配制。这种制剂还可以含有缓和剂和防腐剂,例如对羟苯甲酸甲酯和对羟苯甲酸丙酯,以及调味剂和着色剂。
还可以肠胃外给予本发明的化合物,也就是皮下、静脉内、眼内、滑膜内、肌内或腹膜间给药,作为所述化合物优选地在生理学可接受的稀释剂与药物载体中的可注射剂型进行肠胃外给予,所述生理学可接受的稀释剂与药物载体可以是无菌的液体或液体的混合物,所述液体例如水、盐水、葡萄糖和相关的糖的水溶液、醇(例如乙醇、异丙醇或十六醇)、二醇(例如丙二醇或聚乙二醇)、甘油酮缩醇(例如2,2-二甲基-1,1-二氧戊环-4-甲醇)、醚(例如聚(乙二醇)400)、油、脂肪酸、脂肪酸酯或脂肪酸甘油酯,或乙酰化的脂肪酸甘油酯,加入或不加入可药用表面活性剂,例如皂或洗涤剂,悬浮剂例如果胶、卡波姆、甲基纤维素、羟丙基甲基纤维素或羧甲纤维素,或乳化剂及其它药物佐剂。
可以在本发明的肠胃外制剂中使用的油的例子是石油产品、动物、植物或合成源的那些油,例如花生油、大豆油、芝麻油、棉籽油、玉米油、橄榄油、矿脂和矿物油。合适的脂肪酸包括油酸、硬脂酸、异硬脂酸和肉豆蔻酸。合适的脂肪酸酯是,例如油酸乙酯和十四烷酸异丙酯。合适的皂类包括:碱金属脂肪酸、铵和三乙醇胺盐,合适的洗涤剂包括阳离子型洗涤剂,例如二甲基二烷基卤化铵、烷基卤化吡啶鎓和乙酸烷基胺;阴离子型洗涤剂,例如烷基、芳基和烯属磺酸盐,烷基、烯烃、醚和甘油一酯硫酸盐和磺基丁二酸盐;非离子型洗涤剂,例如脂肪胺氧化物、脂肪酸烷醇酰胺和聚(环氧乙烷-氧化丙烯)或氧化乙烯或氧化丙烯共聚物;和两性洗涤剂,例如烷基-β-氨基丙酸盐和2-烷基咪唑啉季胺盐,以及混合物。
本发明的肠胃外组合物在溶液中典型地含有大约0.5%至大约25%重量的活性组分。还可以有利地使用防腐剂和缓冲剂。为了最小化或消除在注射位点的刺激性,这种组合物可以含有亲水亲油平衡值(HLB)优选为大约12至大约17的非离子型表面活性剂。优选,在这种制剂中,表面活性剂的数量在大约5%至大约15%重量的范围。表面活性剂可以是具有上述HLB的单一组分,或可以是两种或多种具有目标HLB的组分的混合物。
在肠胃外制剂中使用的表面活性剂的例子是聚乙烯山梨糖醇酐脂肪酸酯类,例如山梨糖醇酐单油酸酯,以及氧化乙烯与疏水性基质(由氧化丙烯与丙二醇缩合形成)的高分子量加合物。
药物组合物可以是无菌的可注射水性混悬剂形式。可以按照已知的方法配制这种混悬剂,使用合适的分散剂或润湿剂和悬浮剂,例如羧甲基纤维素钠、甲基纤维素、羟基丙基甲基-纤维素、海藻酸钠、聚乙烯吡咯烷酮、黄芪胶和阿拉伯胶;分散剂或润湿剂,其可以是天然存在的磷脂(例如卵磷脂)、氧化烯与脂肪酸的缩合产物(例如聚氧乙烯硬脂酸脂)、氧化乙烯与长链脂族醇的缩合产物(例如十七-乙烯氧基鲸蜡醇)、氧化乙烯与衍生自脂肪酸和己糖醇的偏酯的缩合产物(例如聚氧乙烯山梨糖醇单油酸酯)、或氧化乙烯与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物(例如聚氧乙烯山梨糖醇酐单油酸酯)。
无菌可注射制剂还可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液剂或混悬剂。可以使用的稀释剂和溶剂是,例如水、Ringer's溶液、等渗氯化钠溶液和等渗葡萄糖溶液。另外,无菌的不挥发油通常用作溶剂或悬浮介质。对于这种目的,可以使用任何柔和的不挥发油,包括合成的甘油单或二酯。此外,可以在可注射制剂中使用脂肪酸,例如油酸。
本发明的组合物还可以以直肠给药的栓剂形式来给药。这些组合物可以通过将药物与合适的无刺激性赋形剂混合来制备,这种赋形剂在常温下是固体,但在直肠温度下是液体,并因此在直肠中溶解,释放药物。这种材料是,例如,可可脂和聚乙二醇。
本发明的方法所采用的另一种制剂使用透皮递送装置(“贴片”)。这种透皮贴片可以以可控数量连续或不连续地输注本发明的化合物。递送药剂的透皮贴片的组成和使用在本领域是众所周知的(参见,例如,美国专利5,023,252,1991年6月11日颁发,本文在此引入作为参考)。可以将这种贴片构造成为连续、脉动或按要求递送药剂的形式。
肠胃外给药的控释制剂包括本领域已知的脂质体、聚合微球体和聚合凝胶制剂。
可能希望或需要通过机械递送装置,为患者输入药物组合物。递送药剂的机械递送装置的构成和使用在本领域是众所周知的。直接给药技术,例如,直接给予药物至脑部,通常包括:将给药导管放置到患者的脑室系统中,避开血脑屏障。用于将药剂送至身体的特定解剖学区域的一种这样的可植入递送系统描述在美国专利No.5,011,472(1991年4月30日颁发)中。
根据需要或要求,本发明的组合物还可以含有其它常规可药用配料组分,通常指载体或稀释剂。可以使用制备这种合适剂型的组合物的常规方法。
这种组分和方法包括下列参考文献所描述的那些组分和方法,本文结合每个参考文献作为参考∶Powell, M.F.等人, "Compendium of Excipients for ParenteralFormulations" PDA Journal of Pharmaceutical Science & Technology 1998, 52(5),238-311; Strickley, R.G "Parenteral Formulations of Small MoleculeTherapeutics Marketed in the United States(1999)-Part-1" PDA Journal ofPharmaceutical Science & Technology 1999, 53(6), 324-349; 以及Nema, S.等人, "Excipients and Their Use in Injectable Products" PDA Journal ofPharmaceutical Science & Technology 1997, 51(4), 166-171。
为了配制预定给药途径的组合物,可以酌情使用的普通药用组分包括∶
酸化剂(实例包括但不局限于乙酸、柠檬酸、富马酸、盐酸、硝酸);
碱化剂(实例包括但不局限于:氨水、碳酸铵、二乙醇胺、单乙醇胺、氢氧化钾、硼酸钠、碳酸钠、氢氧化钠、三羟乙基胺、三乙醇胺(trolamine));
吸附剂(实例包括但不局限于:粉末纤维素和活性炭);
气雾发射剂(实例包括但不局限于:二氧化碳、CCl2F2、F2ClC-CClF2和CClF3);
排空气剂(实例包括但不局限于:氮气和氩气);
抗真菌的防腐剂(实例包括但不局限于:苯甲酸、羟苯丁酯、羟苯乙酯、对羟基苯甲酸甲酯、对羟苯甲酸丙酯、苯甲酸钠);
抗菌防腐剂(实例包括但不局限于:苯扎氯铵、苄索氯铵、苯甲醇、氯化十六烷基吡啶、氯丁醇、苯酚、苯乙醇、硝酸苯汞和硫汞撒);
抗氧化剂(实例包括但不局限于:抗坏血酸、抗坏血酸棕榈酸酯、丁羟茴醚、丁羟甲苯、次磷酸、单硫代甘油、没食子酸丙酯、抗坏血酸钠、亚硫酸氢钠、甲醛合次硫酸氢钠、焦亚硫酸钠);
粘合物质(实例包括但不局限于:嵌段共聚物、天然与合成橡胶、聚丙烯酸酯、聚氨酯、硅氧烷、聚硅氧烷和苯乙烯-丁二烯共聚物);
缓冲剂(实例包括但不局限于:偏磷酸钾、磷酸二钾、乙酸钠、无水柠檬酸钠和柠檬酸钠二水合物);
载体(实例包括但不局限于:阿拉伯胶糖浆、芳香糖浆剂、香药酒、樱桃糖浆、可可糖浆剂、橙皮糖浆、糖浆剂、玉米油、矿物油、花生油、芝麻油、抑菌的氯化钠注射液和抑菌的注射用水);
螯合剂(实例包括但不局限于:依地酸二钠和依地酸);
着色剂(实例包括但不局限于:FD & C红3号、FD & C红20号、FD & C黄6号、FD & C蓝2号、D & C绿5号、D & C橙5号、D & C红8号、焦糖和氧化铁红);
澄清剂(实例包括但不局限于:膨润土);
乳化剂(实例包括但不局限于:阿拉伯胶、聚西托醇(cetomacrogol)、鲸蜡醇、单硬脂酸甘油酯、卵磷脂、山梨糖醇酐单油酸酯、聚氧乙烯50一硬脂酸酯);
包封剂(实例包括但不局限于:明胶和邻苯二甲酸醋酸纤维素);
香料(实例包括但不局限于:茴香油、肉桂油、可可、薄荷醇、橙油、薄荷油和香草醛);
保湿剂(实例包括但不局限于:甘油、丙二醇和山梨糖醇);
研和剂(实例包括但不局限于:矿物油和丙三醇);
油(实例包括但不局限于:花生油、矿物油、橄榄油、花生油、芝麻油和植物油);
软膏基质(实例包括但不局限于:羊毛脂、亲水性软膏、聚乙二醇软膏剂、凡士林、亲水性的凡士林、白色软膏剂、黄色软膏剂和玫瑰水软膏剂);
渗透增强剂(透皮递送)(实例包括但不局限于:单羟基或多羟基醇、单或多元醇、饱和或不饱和脂肪醇、饱和或不饱和脂肪酸酯、饱和或不饱和二羧酸、精油、磷脂酰基衍生物、脑磷脂、萜类、酰胺、醚、酮和脲);
增塑剂(实例包括但不局限于:邻苯二甲酸二乙酯和甘油);
溶剂(实例包括但不局限于:乙醇、玉米油、棉子油、甘油、异丙醇、矿物油、油酸、花生油、净化水、注射用水、灭菌注射水和用于冲洗的无菌水);
硬化剂(实例包括但不局限于:鲸蜡醇、鲸蜡基酯蜡、微晶蜡、石蜡烃、十八醇、白蜡和黄石蜡);
栓剂基质(实例包括但不局限于:可可脂和聚乙二醇(混合物));
表面活性剂(实例包括但不局限于:苯扎氯铵、壬苯醇醚10、oxtoxynol 9、聚山梨醇酯80、月桂基磺酸钠和脱水山梨糖醇单棕榈酸酯);
悬浮剂(实例包括但不局限于:琼脂、膨润土、卡波姆、羧甲基纤维素钠、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、高岭土、甲基纤维素、黄芪胶和硅酸镁铝);
甜味剂(实例包括但不局限于:阿斯巴甜、葡萄糖、甘油、甘露糖醇、丙二醇、糖精钠、山梨糖醇和蔗糖);
片剂防粘剂(实例包括但不局限于:硬脂酸镁和滑石粉);
片剂粘合剂(实例包括但不局限于:阿拉伯胶、藻酸、羧甲基纤维素钠、可压缩糖、乙基纤维素、明胶、液状葡萄糖、甲基纤维素、非交联的聚乙烯吡咯烷酮和预胶凝淀粉);
片剂和胶囊稀释剂(实例包括但不局限于:磷酸氢钙、高岭土、乳糖、甘露糖醇、微晶纤维素、粉末纤维素、沉淀碳酸钙、碳酸钠、磷酸钠、山梨糖醇和淀粉);
片剂包衣剂(实例包括但不局限于:液状葡萄糖、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素、乙基纤维素、邻苯二甲酸醋酸纤维素和虫胶);
片剂直接压缩赋形剂(实例包括但不局限于:磷酸氢钙);
片剂崩解剂(实例包括但不局限于:藻酸、羧甲纤维素钙、微晶纤维素、聚克利林钾、交联的聚乙烯吡咯烷酮、海藻酸钠、淀粉乙醇酸钠和淀粉);
片剂助流剂(实例包括但不局限于:胶态二氧化硅、玉米淀粉和滑石粉);
片剂润滑剂(实例包括但不局限于:硬脂酸钙、硬脂酸镁、矿物油、硬脂酸和硬脂酸锌);
片剂/胶囊剂遮光剂(实例包括但不局限于:二氧化钛);
片剂抛光剂(实例包括但不局限于:棕榈蜡(carnuba wax)和白蜡);
增稠剂(实例包括但不局限于:蜂蜡、鲸蜡醇和石蜡烃);
渗透剂(实例包括但不局限于:葡萄糖和氯化钠);
增粘剂(实例包括但不局限于:藻酸、膨润土、卡波姆、羧甲基纤维素钠、甲基纤维素、聚乙烯吡咯烷酮、海藻酸钠和黄芪胶);和
润湿剂(实例包括但不局限于:十七亚乙基氧基鲸蜡醇、卵磷脂、山梨糖醇单油酸酯、聚氧乙烯山梨糖醇单油酸酯和聚氧乙烯硬脂酸脂)。
按照本发明的药物组合物可以举例说明如下∶
无菌IV溶液剂∶
可以使用无菌的注射用水来制备本发明目标化合物的5 mg/ml溶液,如有必要,调节pH值。用无菌的5%葡萄糖稀释该溶液,达到给药浓度1-2 mg/ml,并用大约60分钟进行IV输注给药。
用于IV给药的冷冻干燥粉剂∶
可以用下列来制备无菌制剂:(i)100-1000 mg冷冻干燥粉剂形式的本发明的目标化合物,(ii)32-327 mg/ml柠檬酸钠,和(iii)300-3000 mg葡聚糖40。用无菌注射用盐水或5%葡萄糖将该制剂重组至10至20 mg/ml的浓度,将其用盐水或5%葡萄糖进一步稀释至0.2至0.4mg/ml,以IV推注或IV输注(15-60分钟)形式给药。
肌内混悬剂∶
可以制备下列肌内注射用的溶液剂或混悬剂∶
50 mg/mL不溶于水的本发明的目标化合物
5 mg/ml羧甲基纤维素钠
4 mg/ml TWEEN 80
9 mg/ml氯化钠
9 mg/ml苯甲醇。
硬壳胶囊∶
如下制备大量单位胶囊:装填标准两段硬肉冻胶囊,每个胶囊装填100 mg粉末活性组分、150 mg乳糖、50 mg纤维素和6 mg硬脂酸镁。
软明胶胶囊∶
在易消化的油例如大豆油、棉子油或橄榄油中制备活性组分的混合物,并利用正排量泵注射到熔融凝胶中,形成含有100 mg活性组分的软明胶胶囊。将胶囊洗涤并干燥。可以将活性组分溶于聚乙二醇、丙三醇和山梨糖醇的混合物中,制备水可混溶性的药物混合物。
片剂∶
利用常规方法制备大量片剂,使得剂量单位是100 mg活性组分、0.2 mg胶体二氧化硅、5 mg硬脂酸镁、275 mg微晶纤维素、11 mg淀粉和98.8 mg乳糖。为了提高适口性、提高精致性和稳定性或延迟吸收,可以使用合适的水性和非水性包衣。
立即释放片剂/胶囊∶
这些是利用常规方法和新方法制备的固体口服剂型。为了快速溶解和递送药物,在没有水的情况下,口服这些单位。将活性组分在含有组分例如糖、明胶、果胶和甜味剂的液体中混合。通过冷冻干燥和固态提取技术,将这些液体固化为固体片剂或囊片。可以将药物化合物与粘弹性和热弹性的糖和聚合物或发泡组分一起挤压,制备意欲立即释放的多孔基体(不需要水)。
联合治疗
在本发明中,术语“联用药(combination)”是如本领域技术人员已知的那样使用的,并且可以以固定联用药、非固定联用药或组件的试剂盒的形式提供。
“固定联用药”如本领域技术人员已知的那样在本发明中使用,并且定义为:所述第一活性组分和所述第二活性组分一起存在于一个单位剂量或单一实体中的联用药。“固定联用药”的一个例子是药物组合物,其中所述第一活性组分和所述第二活性组分存在于同时给药的混合物中,例如在制剂中。“固定联用药”的另一个例子是药物联用药,其中所述第一活性组分和所述第二活性组分存在于一个单元,但不是混合物。
在本发明中,非固定联用药或“组件的试剂盒”如本领域技术人员已知的那样使用,并且定义为:所述第一活性组分和所述第二活性组分存在于一个以上的单元中的联用药。非固定联用药或组件的试剂盒的一个例子是其中所述第一活性组分和所述第二活性组分独立存在的联用药。可以单独、顺序、同时、并行或按时间顺序交错给予非固定联用药或组件的试剂盒的组分。
本发明的化合物可以以单一药剂形式给予,或在联用药不会引起无法接受的副作用的情况下,与一或多种其它药剂联合给药。本发明还涉及这种联用药。例如,本发明的化合物可以与已知的化学治疗剂或抗癌症药剂联用,例如抗高增殖或其它适应症的药剂,等等,以及与其混合物和联用药结合。其它适应症药剂包括但不局限于:抗血管生成的药剂、有丝分裂抑制剂、烷化剂、抗代谢药、DNA-插入抗生素、生长因子抑制剂、细胞周期抑制剂、酶抑制剂、拓扑异构酶抑制剂、生物反应调节剂或抗激素。
化学治疗剂和抗癌症药剂的例子包括∶
131I-chTNT、阿倍瑞克(Abarelix)、阿比特龙、阿柔比星、ado-trastuzumabemtansine、阿法替尼(afatinib)、阿柏西普(aflibercept)、阿地白介素、阿仑单抗(alemtuzumab)、阿仑膦酸、阿利维A酸(alitretinoin)、六甲蜜胺、氨磷汀、氨鲁米特、己基氨基酮戊酸盐、氨柔比星、安吖啶、阿那曲唑、安西司亭(ancestim)、茴香脑二硫杂环戊二烯硫酮(anethole dithiolethione)、血管紧张素II、抗凝血酶III、阿瑞匹坦、阿西莫单抗、arglabin、三氧化二砷、门冬酰胺酶、阿西替尼(axitinib)、阿扎胞苷、巴利昔单抗(basiliximab)、贝洛替康(belotecan)、苯达莫司汀、贝利司他(belinostat)、贝伐单抗(bevacizumab)、贝沙罗汀(bexarotene)、比卡鲁胺、比生群、博来霉素、硼替佐米(Bortezomib)、布舍瑞林、博舒替尼(bosutinib)、brentuximab vedotin、白消安、卡巴他赛(cabazitaxel)、卡博替尼(Cabozantinib)、亚叶酸钙、左亚叶酸钙、卡培他滨、卡罗单抗、卡铂、卡非佐米(carfilzomib)、卡莫氟、卡莫司汀、卡妥索单抗(catumaxomab)、西乐葆、西莫白介素、色瑞替尼(ceritinib)、西妥昔单抗(cetuximab)、苯丁酸氮芥、氯地孕酮、氮芥、西多福韦、西那卡塞(cinacalcet)、顺铂、克拉屈滨、氯膦酸、氯法拉滨(clofarabine)、copanlisib、克立他酶(crisantaspase)、环磷酰胺、环丙孕酮、阿糖胞苷、达卡巴嗪、放线菌素、达依泊汀α(darbepoetin alfa)、达拉非尼(dabrafenib)、达沙替尼、柔红霉素、地西他滨、地盖瑞利(degarelix)、地尼白介素(denileukin diftitox)、地诺塞麦(denosumab)、地普奥肽(depreotide)、地洛瑞林、右雷佐生、二溴螺氯铵、1-2-5-6-双脱水卫矛醇、双氯芬酸、多西他赛、多拉司琼、去氧氟尿苷、多柔比星、多柔比星+雌酮、屈大麻酚、依库珠单抗(eculizumab)、依决洛单抗(edrecolomab)、依利醋铵、伊屈泼帕(eltrombopag)、血管内皮抑素、依诺他滨、恩杂鲁胺(enzalutamide)、表柔比星、环硫雄醇、阿法依伯汀、倍他依泊汀、阿法依伯汀(epoetin)zeta、依他铂、艾日布林(eribulin)、埃洛替尼、埃索美拉唑、雌二醇、雌莫司汀、依托泊苷、依维莫司、依西美坦、法屈唑、芬太尼、非格司亭、氟甲睾酮、氮尿苷、氟达拉滨、氟尿嘧啶、氟他胺、亚叶酸、福美坦、福沙吡坦(fosaprepitant)、福莫司汀、氟维司群、钆布醇(gadobutrol)、加多利道(gadoteridol)、钆特酸(gadoteric acid)葡甲胺、钆弗塞胺(gadoversetamide)、钆塞酸(gadoxetic acid)、硝酸镓、加尼瑞克、吉非替尼、吉西他滨、吉妥单抗(gemtuzumab)、羧肽酶(Glucarpidase)、谷胱甘肽(glutoxim)、GM-CSF、戈舍瑞林、格拉司琼、粒细胞集落刺激因子、二盐酸组胺、组氨瑞林(histrelin)、羟基脲、I-125seeds、兰索拉唑、依班膦酸、替伊莫单抗(ibritumomab tiuxetan)、依鲁替尼(ibrutinib)、伊达比星、异环磷酰胺、伊马替尼、咪喹莫特、英丙舒凡(Improsulfan)、吲地司琼(indisetron)、英卡膦酸(incadronic acid)、巨大戟醇甲基丁烯酸酯(ingenolmebutate)、干扰素alfa、干扰素beta、干扰素gamma、碘比醇(iobitridol)、硫酸碘苄胍(123I)、碘美普尔(iomeprol)、易普利姆玛(ipilimumab)、依立替康、伊曲康唑、伊沙匹隆(ixabepilone)、兰瑞肽、拉帕替尼(lapatinib)、iasocholine、来那度胺(lenalidomide)、来格司亭、蘑菇多糖、来曲唑、亮丙瑞林、左旋四咪唑、左炔诺孕酮、左旋甲状腺素钠、麦角乙脲、乐铂、环己亚硝脲、氯尼达明、马索罗酚、甲羟基孕酮、甲地孕酮、米拉索普、苯丙氨酸氮芥、美雄烷、巯基嘌呤、巯乙磺酸钠、美沙酮、氨甲喋呤、甲氧呋豆素、甲酯氨基酮戊酸(methylaminolevulinate)、甲基强的松龙、甲基睾甾酮、甲酪氨酸(metirosine)、米伐木肽(mifamurtide)、米特福辛、米铂(miriplatin)、二溴甘露醇、丙脒腙、二溴卫矛醇、丝裂霉素、米托坦、米托蒽醌、mogamulizumab、莫拉司亭、莫哌达醇、盐酸吗啡、硫酸吗啡、大麻隆(nabilone)、nabiximols、那法瑞林、纳洛酮+镇痛新、纳曲酮、那托司亭、奈达铂、奈拉滨(nelarabine)、奈立膦酸、nivolumabpentetreotide、尼洛替尼(nilotinib)、尼鲁米特、尼莫唑(nimorazole)、尼妥珠单抗(nimotuzumab)、嘧啶亚硝脲、二胺硝吖啶(nitraerine)、nivolumab、obinutuzumab、奥曲肽、奥法木单抗(ofatumumab)、高三尖杉酯碱(omacetaxinemepesuccinate)、奥美拉唑、昂丹司琼、奥普瑞白介素(oprelvekin)、铜锌协同质(orgotein)、orilotimod、奥沙利铂、氧可酮、康复龙、奥佐米星(ozogamicine)、p53基因治疗、太平洋紫杉醇、帕利夫明(palifermin)、钯-103 seed、帕洛诺司琼(Palonosetron)、帕米膦酸、帕尼单抗(panitumumab)、泮托拉唑、帕唑帕尼(pazopanib)、培加帕酶、PEG-倍他依泊汀(甲氧基PEG-倍他依泊汀)、派姆单抗(pembrolizumab)、聚乙二醇非格司亭(pegfilgrastim)、聚乙二醇化干扰素alfa-2b、培美曲唑(Pemetrexed)、镇痛新、喷司他丁、硫酸培洛霉素、全氟丁烷(Perflubutane)、培磷酰胺、帕妥珠单抗(Pertuzumab)、溶链菌制剂(picibanil)、毛果碱、吡柔比星、匹杉琼(pixantrone)、普乐沙福(plerixafor)、普卡霉素、聚氨葡糖(poliglusam)、磷酸聚雌二醇、聚乙烯吡咯烷酮+透明质酸钠、多糖-K、泊马度胺(Pomalidomide)、普纳替尼(ponatinib)、卟吩姆钠、普拉曲沙(pralatrexate)、松龙苯芥、脱氢可的松、普鲁苄肼、苯咪唑丙酸(procodazole)、普奈洛尔、喹高利特(quinagolide)、雷贝拉唑、racotumomab、镭-223氯化物、拉多替尼(radotinib)、雷诺昔酚、雷替曲塞(raltitrexed)、雷莫司琼、雷莫芦单抗(ramucirumab)、雷莫司汀(Ranimustine)、拉布立酶(rasburicase)、丙亚胺、refametinib、瑞戈非尼(regorafenib)、利塞膦酸、铼-186依替膦酸盐、利妥昔单抗(rituximab)、罗米地辛(romidepsin)、罗米司亭(romiplostim)、罗莫肽、roniciclib、来昔屈南(lexidronam)钐(153Sm)、沙格司亭、沙妥莫单抗(satumomab)、促胰液素、sipuleucel-T、西佐喃、索布佐生、甘氨双唑钠(sodiumglycididazole)、索拉非尼(sorafenib)、康力龙、链脲霉素、舒尼替尼(Sunitinib)、他拉泊芬(talaporfin)、他米巴罗汀(tamibarotene)、三苯氧胺、他喷他多(tapentadol)、他索纳明(tasonermin)、替西白介素(technetium)、锝(99mTc)巯诺莫单抗(nofetumomabmerpentan)、99mTc-HYNIC-[Tyr3]-奥曲肽、替加氟、替加氟+吉美嘧啶(gimeracil)+奥替拉西(oteracil)、替莫卟吩、替莫唑胺、西罗莫司(temsirolimus)、表鬼臼毒噻吩糖苷、睾酮、替曲膦(tetrofosmin)、反应停、硫替派、胸腺法新(thymalfasin)、促甲状腺激素alfa、硫鸟嘌呤(tioguanine)、托珠单抗(tocilizumab)、托泊替康、柠檬酸托瑞米芬、托西莫单抗(tositumomab)、曲贝替定(trabectedin)、反胺苯环醇、曲妥珠单抗(trastuzumab)、trastuzumab emtansine、曲奥舒凡(treosulfan)、维甲酸、三氟胸苷(trifluridine)+tipiracil、曲洛司坦、曲普瑞林、曲美替尼(Trametinib)、氯乙环磷酰胺、促血小板生成素(thrombopoietin)、色氨酸、乌苯美司、瓦他拉尼(valatinib)、戊柔比星(valrubicin)、凡德他尼(vandetanib)、伐普肽、维罗非尼(vemurafenib)、长春碱、长春花新碱、去乙酰长春酰胺、长春氟宁、长春瑞宾、维莫德吉(vismodegib)、伏立诺他(vorinostat)、伏氯唑、钇-90玻璃微球体、净司他丁、净司他丁斯酯、唑来膦酸、佐柔比星。
本发明的化合物还可以与蛋白治疗联合给予。适合于治疗癌症或其它血管生成的病症并且与本发明的组合物一起使用的这种蛋白治疗包括但不局限于:干扰素(例如,干扰素α、β或γ)超兴奋(supraagonistic)单克隆抗体、Tuebingen、 TRP-1蛋白疫苗、Colostrinin、抗FAP抗体、YH-16、吉妥单抗(gemtuzumab)、因福利美、西妥昔单抗(cetuximab)、曲妥珠单抗(trastuzumab)、地尼白介素(denileukin diftitox)、利妥昔单抗(rituximab)、胸腺素α1、贝伐单抗(bevacizumab)、 美卡舍明(mecasermin)、 美卡舍明-林菲培(mecasermin rinfabate)、奥普瑞白介素(oprelvekin)、那他珠单抗(natalizumab)、rhMBL、MFE-CP1 + ZD-2767-P、ABT-828、ErbB2-特异性免疫毒素、SGN-35、MT-103、林菲培(rinfabate)、AS-1402、B43-染料木素(genistein)、基于L-19的放射免疫治疗、AC-9301、NY-ESO-1疫苗、IMC-1C11、CT-322、rhCC10、r(m)CRP、MORAb-009、aviscumine、MDX-1307、Her-2疫苗、APC-8024、NGR-hTNF、rhH1.3、IGN-311、血管内皮抑素、volociximab、PRO-1762、来沙木单抗(lexatumumab)、SGN-40、帕妥珠单抗(Pertuzumab)、EMD-273063、L19-IL-2融合蛋白、PRX-321、CNTO-328、MDX-214、替加泊肽(tigapotide)、CAT-3888、拉贝珠单抗(labetuzumab)、α粒-发射放射性同位素结合的林妥珠单抗、EM-1421、HyperAcute疫苗、tucotuzumab celmoleukin、galiximab、HPV-16-E7、Javelin-前列腺癌症、Javelin-黑素瘤、NY-ESO-疫苗、EGF疫苗、CYT-004-MelQbG10、WT1肽、奥戈伏单抗(oregovomab)、奥法木单抗(ofatumumab)、扎芦木单抗(zalutumumab)、贝辛白介素(cintredekin besudotox)、WX-G250、Albuferon、阿柏西普(aflibercept)、地诺塞麦(denosumab)、疫苗、CTP-37、依夫单抗(Efungumab)或131I-chTNT-1/B。用作蛋白治疗剂的单克隆抗体包括但不局限于:鼠单克隆抗体(muromonab)-CD3、阿昔单抗(abciximab)、依决洛单抗(edrecolomab)、达(克)珠单抗(daclizumab)、吉姆单抗(gentuzumab)、阿仑单抗(alemtuzumab)、替伊莫单抗(ibritumomab)、西妥昔单抗(cetuximab)、贝伐珠单抗(bevicizumab)、依法利珠(efalizumab)、阿达木单抗(adalimumab)、奥马珠单抗(omalizumab)、muromomab-CD3、利妥昔单抗(rituximab)、达(克)珠单抗(daclizumab)、曲妥珠单抗(trastuzumab)、帕利珠单抗(palivizumab)、巴利昔单抗(basiliximab)和因福利美。
本文所定义的通式(I)化合物可以任选与一或多种下列药物联合给药∶ARRY-162、ARRY-300、ARRY-704、AS-703026、AZD-5363、AZD-8055、BEZ-235、BGT-226、BKM-120、BYL-719、CAL-101、CC-223、CH-5132799、deforolimus、E-6201、enzastaurin、GDC-0032、GDC-0068、GDC-0623、GDC-0941、GDC-0973、GDC-0980、GSK-2110183、GSK-2126458、GSK-2141795、MK-2206、novolimus、OSI-027、哌立福新(perifosine)、PF-04691502、PF-05212384、PX-866、雷帕霉素、RG-7167、RO-4987655、RO-5126766、司美替尼(selumetinib)、TAK-733、曲美替尼(Trametinib)、曲西立滨、 UCN-01、WX-554、XL-147、XL-765、佐他莫司、ZSTK-474。
通常,在与本发明的化合物或组合物的联用药中使用细胞毒素和/或细胞生长抑制剂,用于∶
(1) 与任一单独药剂给药相比较,在降低肿瘤生长方面得到更好效能,或甚至消除肿瘤,
(2) 使得所给予的化学治疗剂的给药量更少,
(3) 提供化学疗法,与单一药剂化疗和某些其它联合治疗所观察到的结果相比,这种化学疗法能够使患者的耐受性更好,同时,不利的药理学并发症更少,
(4) 为哺乳动物(尤其是人)提供更广谱的不同癌症类型的治疗方法,
(5) 在所治疗的患者中产生更高的响应率,
(6) 相比于标准化疗治疗,使所治疗的患者的存活时间更长,
(7) 提供更长的肿瘤进展时间,和/或
(8) 相比于其它癌症联用药产生拮抗效应的已知案例,产生效能和耐受性结果至少与单独使用的药剂的效能和耐受性同样好。
使细胞对于辐射敏感的方法
在本发明的一个独特的实施方案中,本发明的化合物可用以使细胞对于辐射敏感。也就是说,相比于没有使用本发明的化合物进行任何处理的细胞,在辐射治疗细胞之前,用本发明的化合物处理细胞使得细胞对DNA损伤和细胞死亡更敏感。在一方面,用至少一种本发明的化合物处理细胞。
由此,本发明还提供了杀死细胞的方法,在这种方法中,给予细胞一或多种本发明的化合物与常规放射疗法的联用形式。
本发明还提供了使细胞对细胞死亡更敏感的方法,在这种方法中,在治疗细胞以导致或诱导细胞死亡之前,用一或多种本发明的化合物处理细胞。在一方面,用一或多种本发明的化合物处理细胞之后,用至少一种化合物或至少一种方法或其联用形式来治疗细胞,以便导致DNA损伤,目的是抑制正常细胞的功能或杀死细胞。
在一个实施方案中,用至少一种DNA损伤剂来治疗细胞,从而杀死细胞。也就是说,用一或多种本发明的化合物处理该细胞、使细胞对于细胞死亡敏感之后,用至少一种DNA损伤剂来治疗细胞,从而杀死细胞。在本发明中使用的DNA损伤剂包括但不局限于:化学治疗剂(例如,顺铂)、电离辐射(X射线、紫外辐射)、致癌剂和诱变剂。
在另一个实施方案中,用至少一种方法治疗细胞,导致或诱导DNA损伤,从而杀死细胞。这种方法包括但不局限于:使细胞信号途径活化,当所述途径被活化时,引起DNA损伤,使细胞信号途径受到抑制,当所述途径受到抑制时,引起DNA损伤,和诱导细胞的生物化学变化,其中,这种变化导致DNA损伤。作为非限制性实例,可以抑制细胞的DNA修复途径,由此防止DNA损伤的修复,并导致细胞的DNA损伤的异常积累。
在本发明的一方面,在辐射细胞或其它诱导细胞DNA损伤之前,给予细胞本发明的化合物。在本发明的另一个方面,给予细胞本发明的化合物,同时伴随辐射细胞或其它诱导细胞DNA损伤的方式。在本发明的又一个方面,在辐射细胞或其它诱导细胞DNA损伤的方式开始之后,立即给予细胞本发明的化合物。
在另一个方面,细胞是体外的。在另一个实施方案中,细胞是体内的。
如上所述,意外地发现,本发明的化合物有效地抑制突变的异柠檬酸氢化酶1(mIDH1 R132H),并可以因此用于治疗或预防下列疾病:无控的细胞生长、增殖和/或存活、不合适的细胞免疫响应或不合适的细胞炎性响应的疾病,或伴有无控的细胞生长、增殖和/或存活、不合适的细胞免疫响应或不合适的细胞炎性响应的疾病,尤其是,其中无控的细胞生长、增殖和/或存活、不合适的细胞免疫响应或不合适的细胞炎性响应受到抑制突变的异柠檬酸氢化酶1(mIDH1 R132H)影响的疾病,例如血液肿瘤、实体肿瘤和/或其转移病变,例如白血病和脊髓发育不良综合征、恶性淋巴瘤、头和颈部肿瘤(包括脑瘤和脑转移病变)、胸部肿瘤(包括非小细胞和小细胞肺肿瘤)、胃肠肿瘤、内分泌腺肿瘤、乳腺及其它妇科肿瘤、泌尿系统肿瘤(包括肾、膀胱和前列腺肿瘤)、皮肤肿瘤和肉瘤、和/或其转移病变。
因此,按照另一个方面,本发明包括本文所描述和所定义的通式(I)的化合物或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐,尤其是其可药用盐,或它们的混合物,用于治疗或预防上文提到的疾病。
因此,本发明的另一个具体方面是上文所描述的通式(I)的化合物,或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐,尤其是其可药用盐,或它们的混合物,用于预防或治疗疾病的用途。
因此,本发明的另一个具体方面是上文所描述的通式(I)的化合物用于制备药物组合物的用途,所述药物组合物用于治疗或预防疾病。
前述两个段落中提到的疾病是无控的细胞生长、增殖和/或存活、不合适的细胞免疫响应或不合适的细胞的炎症性响应的疾病,或伴有无控的细胞生长、增殖和/或存活、不合适的细胞免疫响应或不合适的细胞炎症性响应的疾病,例如血液肿瘤、实体肿瘤和/或其转移病变,例如白血病和脊髓发育不良综合征、恶性淋巴瘤、头和颈部肿瘤(包括脑瘤和脑转移病变)、胸部肿瘤(包括非小细胞和小细胞肺肿瘤)、胃肠肿瘤、内分泌腺肿瘤、乳腺及其它妇科肿瘤、泌尿系统肿瘤(包括肾、膀胱和前列腺肿瘤)、皮肤肿瘤和肉瘤、和/或其转移病变。
在本发明的上下文中,尤其是在“不合适的细胞免疫响应或不合适的细胞炎性响应”的背景下,本文使用的术语“不合适的”理解为是指低于或高于正常响应的响应,这种响应与所述疾病的病变有关、对所述疾病的病变负责或导致所述疾病的病变。
优选,用途是在治疗或预防疾病中的用途,其中所述疾病是血液肿瘤、实体肿瘤和/或其转移病变。
治疗高增殖病症的方法
本发明涉及使用本发明化合物和其组合物来治疗哺乳动物的高增殖病症的方法。化合物可用于使细胞增殖和/或细胞分裂得到抑制、阻碍、减少、降低等等,和/或使细胞程序死亡。该方法包括:给予需要这种方法的哺乳动物(包括人)有效治疗病症数量的本发明的化合物,或其可药用盐、异构体、多晶型物、代谢物、水合物、溶剂化物或酯,等等。高增殖病症包括但不局限于,例如牛皮癣、瘢痕瘤及影响皮肤的其它增生、良性前列腺增生(BPH),实质固态瘤例如乳腺、呼吸道、脑、生殖器官、消化道、尿路、眼睛、肝、皮肤、头和颈、甲状腺、甲状旁腺的癌症,以及它们的远端转移病变。那些病症还包括淋巴瘤、肉瘤和白血病。
乳腺癌的例子包括但不局限于:侵入性导管癌,侵入性小叶癌,导管原位癌和小叶原位癌。
呼吸道癌症的例子包括但不局限于:小细胞和非小细胞肺癌,以及支气管腺瘤和胸膜肺的胚细胞瘤。
脑癌的例子包括但不局限于:脑干和下丘脑胶质瘤、小脑和大脑的星形细胞瘤、成髓细胞瘤、室管膜瘤、间变性星形细胞瘤、扩散性星形细胞瘤、恶性胶质瘤、寡枝神经胶质细胞瘤、继发性的多形性胶质母细胞瘤以及神经外胚层和松果体肿瘤。
男性生殖器官的肿瘤包括但不局限于前列腺和睾丸癌。女性生殖器官的肿瘤包括但不局限于:子宫内膜、子宫颈、卵巢、阴道和外阴癌,以及子宫的肉瘤。
消化道的肿瘤包括但不局限于:肛门、结肠、结肠直肠、食道、胆囊、胃、胰腺、直肠、小肠和唾液腺癌。
尿路的肿瘤包括但不局限于:膀胱、阴茎、肾脏、肾盂、输尿管、尿道癌和人类乳突状的肾癌。
眼癌包括但不局限于眼内黑素瘤和成视网膜细胞瘤。
肝癌的例子包括但不局限于:肝细胞癌(有或者没有纤维板层变体的肝细胞癌)、胆管细胞癌(肝内胆管癌)和混合的肝细胞胆管细胞癌。
皮肤癌包括但不局限于:鳞状细胞癌、卡波济氏肉瘤、恶性黑色素瘤、Merkel细胞皮肤癌和非黑素瘤皮肤癌。
头和颈癌包括但不局限于:喉、下咽、鼻咽、口咽、唇和口腔癌和鳞状细胞癌。淋巴瘤包括但不局限于:AIDS相关的淋巴瘤、非霍奇金氏淋巴瘤、皮肤T细胞淋巴瘤、伯基特淋巴瘤、霍奇金氏病和中枢神经系统的淋巴瘤。
肉瘤包括但不局限于:软组织的肉瘤、骨肉瘤、恶性纤维组织细胞瘤、淋巴肉瘤和横纹肌肉瘤。
白血病包括但不局限于:急性骨髓性白血病、急性淋巴母细胞性白血病、慢性淋巴细胞性白血病、慢性粒性白血病和毛细胞白血病。
这些病症已经在人类中进行了很好的表征,但在其它哺乳动物中也存在类似的病源,并且可以通过给予本发明的药物组合物来治疗它们。
贯穿本文陈述的术语“治疗”是通常使用的术语,例如为了抵御、缓和、降低、减轻疾病或失调(例如,癌瘤),或改善其症状等,而管理或护理患者。
治疗血管生成的病症的方法
本发明还提供了治疗与过量的和/或异常血管生成相关的病症和疾病的方法。
血管生成的不合适的和异位表达可能对有机体有害。大量病理性的病症与额外的血管生长有关。这些包括,例如,糖尿病性视网膜病、缺血性的视网膜静脉堵塞和早熟性的视网膜病[Aiello等人,New Engl. J. Med. 1994,331,1480;Peer等人,Lab. Invest.1995,72,638]、年龄相关的黄斑变性[AMD;参见Lopez等人,Invest. Opththalmol. Vis.Sci. 1996,37,855]、新生血管性青光眼、牛皮癣、晶状体后纤维增生、血管纤维瘤、炎症、类风湿性关节炎(RA)、再狭窄、支架再狭窄、血管移植再狭窄,等等。另外,与癌性和瘤组织相关的血液供给增加,能够促进生长,导致肿瘤快速增大和转移病变。此外,肿瘤中的新血管和淋巴管的生长,为变异细胞提供逃生路线,促进转移病变,和癌症扩散的结果。由此,可以使用本发明的化合物来治疗和/或预防任何上述血管生成病症,例如通过抑制和/或减少血管形成;通过抑制、阻碍、减少、降低内皮细胞增殖或涉及血管生成的其它类型,以及引起细胞死亡,或者,这种细胞类型的细胞程序死亡。
剂量和给药
基于评价用于治疗高增殖病症和血管生成病症的化合物的已知的标准实验室技术,通过确定哺乳动物上述病症的治疗的标准毒性检验和标准药理学试验,并且通过将这些结果与用于治疗这些病症的已知药物的结果相比较,可以容易地确定本发明化合物的治疗各个目标适应症的有效剂量。在治疗这些病症中的一种病症的过程中,根据所使用的具体化合物和剂量单位、给药模式、疗程、所治疗患者的年龄和性别以及所治疗病症的性质和程度等等考虑因素,所给予的活性成分的量会在很大范围内改变。
所给予的活性组分的总量通常在每天大约0.001 mg/kg至大约200 mg/kg体重的范围内,优选每天大约0.01 mg/kg至大约20 mg/kg体重。临床上使用的剂量计划在每天给药一至三次至每四周给药一次的范围内。另外,某一时段内不给患者药物的“休药期”,可以有益于药理学效果和耐受性之间的综合平衡。单位剂量可以含有大约0.5 mg至大约1500mg活性组分,并且可以每天给药一或多次,或每天少于一次。注射给药(包括静脉内、肌内、皮下和肠胃外注射以及使用输注技术)的平均日剂量,优选为0.01至200 mg/kg总体重。优选,平均每天直肠给药方案为0.01至200 mg/kg总体重。优选,平均每天阴道给药方案为0.01至200 mg/kg总体重。优选,平均每天局部给药方案为0.1至200 mg,每天给药一至四次。优选,透皮浓度符合保持0.01至200 mg/kg日剂量的要求。优选,平均每天吸入给药方案为0.01至100 mg/kg总体重。
当然,对于每个患者来说,具体的初始和连续给药方案根据诊断医生所确定的病症的性质和严重程度、使用的具体化合物的活性、患者的年龄和常规状况、给药时间、给药途径、药物的排泄率、联用药等等而变化。治疗的目标模式和本发明化合物或其可药用盐或酯或组合物的剂量数,可以使用常规治疗试验、由本领域技术人员来确定。
优选,所述方法的疾病是血液肿瘤、实体肿瘤和/或其转移病变。
可以使用本发明的化合物,尤其用于治疗和预防,即,预防肿瘤生长和转移病变,特别是所有适应症和阶段的实体肿瘤,不论有或者没有预先治疗肿瘤生长。
检验具体药理学或药物性能的方法对于本领域技术人员来说是众所周知的。
本文所描述的实施例测试实验用来举例说明本发明,本发明不局限于所给定的实施例。
生物试验∶
在选择的生物学试验中,对实施例检验一或多次。当检验一次以上时,以平均值或中值形式报道数据,其中,
• 平均值,还称为算术平均值,表示所获得的数值总和除以检验次数,和
• 中值表示以升序或降序排列时的数值组的中间值。如果数据组中的数值数量是奇数,则中值是中间数值。如果数据组中的数值数量是偶数,则中值是两个中间数值的算术平均值。
实施例合成一或多次。当合成一次以上时,从生物学试验获得的数据表示使用检验一或多个合成批料获得的数据组所计算的平均值或中值。
突变体IDH1 R132H生化试验
mIDH1催化α-酮戊二酸(α-KG)向(2R)-2-羟基戊二酸(2-HG)的NADPH依赖性还原。通过荧光读数,测定NADPH消耗状况。
在32℃,在384孔板中,进行生物化学反应,使用41µL的反应体积以及下列试验缓冲条件∶50 mM Tris pH7.5,100 mM NaCl,20 mM MgCl2,0.05% BSA,0.01% Brij,1µMNADPH和250µM α-KG。使用IDH1 R132H酶,最后浓度为1.5 nM。使用0.002和10µM之间的浓度范围的试验化合物。DMSO的最终浓度是2.4%。
将反应培养30分钟,然后加入40µL的检测混合物(0.75µg/mL荧光素酶,0.02 U/mL氧化还原酶,4µg/mL FMN,2µL/mL癸醛/乙醇,50 mM Tris pH7.5,0.5%丙三醇,0.01%Tween-20,0.05% BSA)。在荧光读数器上测定荧光(10秒钟测定时间,1秒钟积分时间,30%灵敏度)。荧光降低与mIDH1活性成正比例。利用内推法,由相对荧光相对于抑制剂浓度的图,测定IC50值。
表5∶
所选择的实施例在突变体IDH1 R132H生化试验中的IC50值
n.d.∶没有测定。
突变体IDH1细胞试验
在超表达突变的异柠檬酸脱氢酶(mIDH)蛋白的细胞系的培养基中,测定(2R)-2-羟基戊二酸(2HG)的水平。mIDH催化α-酮戊二酸向2-HG的NADPH依赖性还原。使细胞(LN229R132H,Mohrenz等人,Apoptosis(2013)18:1416-1425)生长在含有10% FCS的DMEM中。通过胰蛋白酶采集它们,并播种到96孔板中。将细胞在37℃、在5% CO2条件下培养过夜。第二天,将试验化合物加入到每个细胞孔中。DMSO的最后浓度是0.1%,并且包括DMSO对照物。然后,将板放入培养箱中24小时。
按照Balss等人(Acta Neuropathol(2012)124∶883-891)所述,测定2-HG。简单地,将HClO4加入到每个孔中,并将板离心。取出等分试样,并用羟基戊二酸脱氢酶(HGDH)、黄递酶、NAD+和刃天青培养。通过Ex 540 nm、Em 600 nm的荧光光谱,对于刃天青转化为试卤灵进行检测。荧光提高与2-HG的产生成正比例。利用内推法,由相对荧光对抑制剂浓度的图,测定IC50值。
表6∶
所选择的实施例在突变体IDH1细胞试验中的IC50值
Claims (15)
1.式(I)的化合物
其中∶
A代表键或-CH2-或-(CH2)2-基团,和
R5代表选自下列的基团∶
-C(O)OH、-C(=O)OR12、HOC(=O)-(C1-C6-烷基)-、R12OC(=O)-(C1-C6-烷基)-、HOC(=O)-(C2-C6-烯基)-、R12OC(=O)-(C2-C6-烯基)-、HOC(=O)-(C1-C6-烷氧基)-、R12OC(=O)-(C1-C6-烷氧基)-、-C(=O)N(R13)R14、R13(R14)NC(=O)-(C1-C6-烷基)-、R13(R14)NC(=O)-(C2-C6-烯基)-、R13(R14)NC(=O)-(C1-C6-烷氧基)-和氰基;
或
A代表-CH(CH3)-或-C(CH3)2-基团,和
R5代表选自下列的基团∶
-C(=O)OH、HOC(=O)-(C1-C6-烷基)-、R12OC(=O)-(C1-C6-烷基)-、HOC(=O)-(C2-C6-烯基)-、R12OC(=O)-(C2-C6-烯基)-、HOC(=O)-(C1-C6-烷氧基)-、R12OC(=O)-(C1-C6-烷氧基)-、-C(=O)N(R13)R14、R13(R14)NC(=O)-(C1-C6-烷基)-、R13(R14)NC(=O)-(C2-C6-烯基)-、R13(R14)NC(=O)-(C1-C6-烷氧基)-和氰基;
R1代表苯基或5、6或9元杂芳基,
其中,苯基任选被一个、两个或三个取代基取代,所述取代基彼此独立地是卤素原子或选自下列的基团∶
C1-C6-烷基、C3-C6-环烷基、C1-C6-烷氧基、C3-C6-环烷基氧基、C1-C6-卤代烷基、C1-C6-
卤代烷氧基和氰基;
和
其中杂芳基任选被一个、两个或三个取代基取代,所述取代基彼此独立地是卤素原子或选自下列的基团∶
C1-C3-烷基和苯基;
R4代表氢原子或卤素原子;
R6代表氢原子或卤素原子或选自下列的基团∶
C1-C6-烷基、C1-C6-烷氧基、C3-C6-环烷基、C3-C6-环烷基氧基、C1-C6-卤代烷基、C1-C6-卤代烷氧基和氰基;
R7代表氢原子;
R8代表C1-C3-烷基;
R9、R10和R11彼此独立地选自∶氢和C1-C3-烷基;
R12代表选自下列的基团∶C1-C6-烷基和C3-C6-环烷基;
R13和R14彼此独立地选自∶氢和C1-C6-烷基;或
R13和R14与它们连接的氮原子一起形成4至6元杂环烷基;
所述4至6元杂环烷基任选被一个选自下列的取代基取代∶C1-C3-烷基、C1-C3-卤代烷基、C1-C3-烷氧基、C1-C3-卤代烷氧基、氨基、羟基、卤素和氰基;或
所述4至6元杂环烷基任选被两个卤素原子取代;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐,或它们的混合物。
2.按照权利要求1的化合物,其中∶
A代表键或-CH2-或-(CH2)2-基团,和
R5代表选自下列的基团∶
-C(O)OH、-C(=O)OR12、HOC(=O)-(C1-C6-烷基)-、R12OC(=O)-(C1-C6-烷基)-、HOC(=O)-(C2-C6-烯基)-、R12OC(=O)-(C2-C6-烯基)-、HOC(=O)-(C1-C6-烷氧基)-、R12OC(=O)-(C1-C6-烷氧基)-和氰基;
或
A代表-CH(CH3)-或-C(CH3)2-基团,和
R5代表选自下列的基团∶
-C(=O)OH、HOC(=O)-(C1-C6-烷基)-、R12OC(=O)-(C1-C6-烷基)-、HOC(=O)-(C2-C6-烯基)-、R12OC(=O)-(C2-C6-烯基)-、HOC(=O)-(C1-C6-烷氧基)-、R12OC(=O)-(C1-C6-烷氧基)-和氰基;
R1代表苯基或5、6或9元杂芳基,
其中苯基任选被一个、两个或三个取代基取代,所述取代基彼此独立地是卤素原子或选自下列的基团∶
C1-C6-烷基、C3-C6-环烷基、C1-C6-烷氧基、C3-C6-环烷基氧基、C1-C6-卤代烷基、C1-C6-卤代烷氧基和氰基;
和
其中杂芳基任选被一个、两个或三个取代基取代,所述取代基彼此独立地是卤素原子或选自下列的基团∶C1-C3-烷基和苯基;
R4代表氢原子或卤素原子;
R6代表氢原子或卤素原子或选自下列的基团∶
C1-C6-烷基、C1-C6-烷氧基、C3-C6-环烷基、C3-C6-环烷基氧基、C1-C6-卤代烷基、C1-C6-卤代烷氧基和氰基;
R7代表氢原子;
R8代表C1-C3-烷基;
R9、R10和R11彼此独立地选自∶氢和C1-C3-烷基;
R12代表选自下列的基团∶C1-C6-烷基和C3-C6-环烷基;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐,或它们的混合物。
3.按照权利要求1的化合物,其中∶
A代表键或-CH2-或-(CH2)2-基团,和
R5代表选自下列的基团∶
-C(O)OH、-C(=O)OR12、HOC(=O)-(C1-C3-烷基)-、R12OC(=O)-(C1-C3-烷基)-、HOC(=O)-(C2-C3-烯基)-、R12OC(=O)-(C2-C3-烯基)-、HOC(=O)-(C1-C3-烷氧基)-、R12OC(=O)-(C1-C3-烷氧基)-和氰基;
或
A代表-CH(CH3)-或-C(CH3)2-基团,和
R5代表选自下列的基团∶
-C(=O)OH、HOC(=O)-(C1-C3-烷基)-、R12OC(=O)-(C1-C3-烷基)-、HOC(=O)-(C2-C3-烯基)-、R12OC(=O)-(C2-C3-烯基)-、HOC(=O)-(C1-C3-烷氧基)-、R12OC(=O)-(C1-C3-烷氧基)-和氰基;
R1代表苯基或5、6或9元杂芳基,
其中苯基任选被一个、两个或三个取代基取代,所述取代基彼此独立地是卤素原子或选自下列的基团∶
C1-C6-烷基、C3-C6-环烷基、C1-C6-烷氧基、C3-C6-环烷基氧基、C1-C3-卤代烷基、C1-C3-卤代烷氧基和氰基;
和
其中杂芳基任选被一个、两个或三个取代基取代,所述取代基彼此独立地是卤素原子或选自下列的基团∶C1-C3-烷基和苯基;
R4代表氢原子或卤素原子;
R6代表氢原子或卤素原子或选自下列的基团∶
C1-C3-烷基、C1-C6-烷氧基、C3-C6-环烷基、C3-C6-环烷基氧基、C1-C3-卤代烷基、C1-C3-卤代烷氧基和氰基;
R7代表氢原子;
R8代表C1-C3-烷基;
R9、R10和R11彼此独立地选自∶氢和C1-C3-烷基;
R12代表C1-C3-烷基;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐,或它们的混合物。
4.按照权利要求1的化合物,其中∶
A代表键或-CH2-基团,和
R5代表选自下列的基团∶
-C(O)OH、-C(=O)OR12、HOC(=O)-(C1-C2-烷基)-、R12OC(=O)-(C1-C2-烷基)-和氰基;
或
A代表-CH(CH3)-或-C(CH3)2-基团,和
R5代表-C(=O)OH基团;
R1代表苯基或5或9元杂芳基,
其中苯基任选被一或两个取代基取代,所述取代基彼此独立地是卤素原子或选自下列的基团∶
C1-C6-烷基、C1-C6-烷氧基、C1-C3-卤代烷基和C1-C3-卤代烷氧基;
和
其中杂芳基任选被一或两个取代基取代,所述取代基彼此独立地是卤素原子或选自下列的基团∶C1-C3-烷基和苯基;
R4代表氢原子或卤素原子;
R6代表氢原子或选自下列的基团∶
C1-C3-烷基、C1-C6-烷氧基和C1-C3-卤代烷氧基;
R7代表氢原子;
R8代表甲基;
R9、R10和R11彼此独立地选自∶氢和甲基;
R12代表C1-C3-烷基;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐,或它们的混合物。
5.按照权利要求1的化合物,其中∶
A代表键或-CH2-基团,和
R5代表选自下列的基团∶
-C(O)OH、-C(=O)OR12、HOC(=O)-(CH2)2-、R12OC(=O)-(CH2)2-和氰基;
或
A代表-CH(CH3)-或-C(CH3)2-基团,和
R5代表-C(=O)OH基团;
R1代表苯基或5或9元杂芳基,
其中苯基任选被氟原子或选自下列的基团取代∶
甲基、异丙基、叔丁基、异丙氧基、三氟甲基和三氟甲氧基;
和
其中杂芳基任选被一或两个取代基取代,所述取代基彼此独立地是氟原子或选自下列的基团∶甲基和苯基;
R4代表氢原子或氟原子;
R6代表氢原子或选自下列的基团∶
甲基、甲氧基、异丙氧基和2,2,2-三氟乙氧基;
R7代表氢原子;
R8代表甲基;
R9选自∶氢和甲基;
R10和R11都代表甲基;
R12代表甲基;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐,或它们的混合物。
6.按照权利要求1的化合物,选自:
(±)2-[4-(三氟甲氧基)苯基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-[4-(三氟甲氧基)苯基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-[4-(三氟甲氧基)苯基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
(±)2-[4-(三氟甲氧基)苯基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-[4-(三氟甲氧基)苯基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-[4-(三氟甲氧基)苯基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
(±)2-[4-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-[4-(三氟甲氧基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-[4-(三氟甲氧基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
(±)2-[4-(丙-2-基氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-[4-(丙-2-基氧基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-[4-(丙-2-基氧基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
(±)2-[4-(丙-2-基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-[4-(丙-2-基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-[4-(丙-2-基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
(±)2-[4-(三氟甲基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-[4-(三氟甲基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-[4-(三氟甲基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
(±)2-(4-氟苄基)-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-(4-氟苄基)-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-(4-氟苄基)-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
(±)2-(4-甲基苄基)-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-(4-甲基苄基)-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-(4-甲基苄基)-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
(±)2-(4-叔丁基苄基)-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-(4-叔丁基苄基)-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-(4-叔丁基苄基)-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
(±)2-苄基-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-苄基-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-苄基-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
(±)2-[2-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-[2-(三氟甲氧基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-[2-(三氟甲氧基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
(±)2-[3-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-[3-(三氟甲氧基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-[3-(三氟甲氧基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
(±)2-[(4-甲基-2-苯基-1,3-噻唑-5-基)甲基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-[(4-甲基-2-苯基-1,3-噻唑-5-基)甲基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-[(4-甲基-2-苯基-1,3-噻唑-5-基)甲基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
(±)2-[(5-氟-2-甲基-1H-吲哚-3-基)甲基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-[(5-氟-2-甲基-1H-吲哚-3-基)甲基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-[(5-氟-2-甲基-1H-吲哚-3-基)甲基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
(±)2-[(1-甲基-1H-吲哚-3-基)甲基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-[(1-甲基-1H-吲哚-3-基)甲基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
2-[(1-甲基-1H-吲哚-3-基)甲基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
(±)6-甲基-2-[4-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
6-甲基-2-[4-(三氟甲氧基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
6-甲基-2-[4-(三氟甲氧基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
(±)6-甲氧基-2-[4-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
6-甲氧基-2-[4-(三氟甲氧基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
6-甲氧基-2-[4-(三氟甲氧基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
(±)6-(丙-2-基氧基)-2-[4-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
6-(丙-2-基氧基)-2-[4-(三氟甲氧基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
6-(丙-2-基氧基)-2-[4-(三氟甲氧基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
(±)6-(2,2,2-三氟乙氧基)-2-[4-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
6-(2,2,2-三氟乙氧基)-2-[4-(三氟甲氧基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
6-(2,2,2-三氟乙氧基)-2-[4-(三氟甲氧基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸甲酯,
4-氟-1-(3,3,5,5-四甲基环己基)-2-[4-(三氟甲氧基)苄基]-1H-苯并咪唑-5-甲酸甲酯,
(±)2-[4-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲腈,
2-[4-(三氟甲氧基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲腈,
2-[4-(三氟甲氧基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲腈,
(±)2-[4-(丙-2-基氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲腈,
2-[4-(丙-2-基氧基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲腈,
2-[4-(丙-2-基氧基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲腈,
(±)2-[4-(丙-2-基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲腈,
2-[4-(丙-2-基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲腈,
2-[4-(丙-2-基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲腈,
(±)2-[4-(三氟甲基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲腈,
2-[4-(三氟甲基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲腈,
2-[4-(三氟甲基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲腈,
(±)3-{6-甲基-2-[4-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-基}丙酸甲酯,
3-{6-甲基-2-[4-(三氟甲氧基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-基}丙酸甲酯,
3-{6-甲基-2-[4-(三氟甲氧基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-基}丙酸甲酯,
(±)3-{6-甲氧基-2-[4-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-基}丙酸甲酯,
3-{6-甲氧基-2-[4-(三氟甲氧基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-基}丙酸甲酯,
3-{6-甲氧基-2-[4-(三氟甲氧基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-基}丙酸甲酯,
(±)2-[4-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-[4-(三氟甲氧基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-[4-(三氟甲氧基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-{1-[4-(三氟甲氧基)苯基]乙基}-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-{(1R)-1-[4-(三氟甲氧基)苯基]乙基}-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-{(1S)-1-[4-(三氟甲氧基)苯基]乙基}-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-{(1R)-1-[4-(三氟甲氧基)苯基]乙基}-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-{(1S)-1-[4-(三氟甲氧基)苯基]乙基}-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
(±)2-{2-[4-(三氟甲氧基)苯基]丙-2-基}-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-{2-[4-(三氟甲氧基)苯基]丙-2-基}-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-{2-[4-(三氟甲氧基)苯基]丙-2-基}-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
(±)2-[4-(丙-2-基氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-[4-(丙-2-基氧基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-[4-(丙-2-基氧基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
(±)2-[4-(丙-2-基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-[4-(丙-2-基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-[4-(丙-2-基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
(±)2-[4-(三氟甲基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-[4-(三氟甲基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-[4-(三氟甲基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
(±)2-(4-氟苄基)-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-(4-氟苄基)-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-(4-氟苄基)-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
(±)2-(4-甲基苄基)-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-(4-甲基苄基)-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-(4-甲基苄基)-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
(±)2-(4-叔丁基苄基)-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-(4-叔丁基苄基)-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-(4-叔丁基苄基)-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
(±)2-苄基-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-苄基-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-苄基-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
(±)2-[2-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-[2-(三氟甲氧基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-[2-(三氟甲氧基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
(±)2-[3-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-[3-(三氟甲氧基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-[3-(三氟甲氧基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
(±)2-[(4-甲基-2-苯基-1,3-噻唑-5-基)甲基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-[(4-甲基-2-苯基-1,3-噻唑-5-基)甲基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-[(4-甲基-2-苯基-1,3-噻唑-5-基)甲基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
(±)2-[(5-氟-2-甲基-1H-吲哚-3-基)甲基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-[(5-氟-2-甲基-1H-吲哚-3-基)甲基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-[(5-氟-2-甲基-1H-吲哚-3-基)甲基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
(±)2-[(1-甲基-1H-吲哚-3-基)甲基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-[(1-甲基-1H-吲哚-3-基)甲基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
2-[(1-甲基-1H-吲哚-3-基)甲基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
(±)6-甲基-2-[4-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
6-甲基-2-[4-(三氟甲氧基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
6-甲基-2-[4-(三氟甲氧基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
(±)6-甲氧基-2-[4-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
6-甲氧基-2-[4-(三氟甲氧基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
6-甲氧基-2-[4-(三氟甲氧基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
(±)6-(丙-2-基氧基)-2-[4-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
6-(丙-2-基氧基)-2-[4-(三氟甲氧基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
6-(丙-2-基氧基)-2-[4-(三氟甲氧基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
(±)6-(2,2,2-三氟乙氧基)-2-[4-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
6-(2,2,2-三氟乙氧基)-2-[4-(三氟甲氧基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
6-(2,2,2-三氟乙氧基)-2-[4-(三氟甲氧基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-甲酸,
4-氟-1-(3,3,5,5-四甲基环己基)-2-[4-(三氟甲氧基)苄基]-1H-苯并咪唑-5-甲酸,
(±)3-{6-甲基-2-[4-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-基}丙酸,
3-{6-甲基-2-[4-(三氟甲氧基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-基}丙酸,
3-{6-甲基-2-[4-(三氟甲氧基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-基}丙酸,
(±)3-{6-甲氧基-2-[4-(三氟甲氧基)苄基]-1-[(顺式)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-基}丙酸,
3-{6-甲氧基-2-[4-(三氟甲氧基)苄基]-1-[(1R,5R)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-基}丙酸,
3-{6-甲氧基-2-[4-(三氟甲氧基)苄基]-1-[(1S,5S)-3,3,5-三甲基环己基]-1H-苯并咪唑-5-基}丙酸,
3-{4-氟-1-(3,3,5,5-四甲基环己基)-2-[4-(三氟甲氧基)苄基]-1H-苯并咪唑-5-基}丙酸甲酯,和
3-{4-氟-1-(3,3,5,5-四甲基环己基)-2-[4-(三氟甲氧基)苄基]-1H-苯并咪唑-5-基}丙酸,
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐,或它们的混合物。
7.制备按照权利要求1至6的任一项的通式(I)的化合物的方法,所述方法包括下列步骤:使通式(II)的中间体化合物:
其中R4、R5、R6、R7、R8、R9、R10和R11如按照权利要求1至6的任一项的通式(I)化合物所定义,
与通式(III)的化合物反应:
其中R1和A如按照权利要求1至6的任一项的通式(I)化合物所定义,
由此得到通式(I)的化合物∶
其中R1、R4、R5、R6、R7、R8、R9、R10、R11和A如按照权利要求1至6的任一项的通式(I)化合物所定义。
8.制备按照权利要求1至6的任一项的通式(I)的化合物的方法,所述方法包括下列步骤:使通式(II)的中间体化合物:
其中R4、R5、R6、R7、R8、R9、R10和R11如按照权利要求1至6的任一项的通式(I)化合物所定义,
与通式(IV)的化合物反应:
其中R1和A如按照权利要求1至6的任一项的通式(I)化合物所定义,
由此得到通式(I)的化合物∶
其中R1、R4、R5、R6、R7、R8、R9、R10、R11和A如按照权利要求1至6的任一项的通式(I)化合物所定义。
9.按照权利要求1至6的任一项的通式(I)的化合物,或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐,尤其是其可药用盐,或它们的混合物,用于治疗或预防疾病。
10.药物组合物,其含有按照权利要求1至6的任一项的通式(I)的化合物,或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐,尤其是其可药用盐,或它们的混合物,以及可药用稀释剂或载体。
11.联用药,其含有∶
- 一或多种选自按照权利要求1至6的任一项的通式(I)化合物的第一活性组分,以及
- 一或多种选自化学治疗的抗癌药剂的第二活性组分。
12.按照权利要求1至6的任一项的通式(I)的化合物,或其立体异构体、N-氧化物、水合物、溶剂化物或盐,尤其是其可药用盐,或它们的混合物,用于预防或治疗疾病的用途。
13.按照权利要求1至6的任一项的通式(I)化合物,或其立体异构体、N-氧化物、水合物、溶剂化物或盐,尤其是其可药用盐,或它们的混合物,用于制备预防或治疗疾病的药物的用途。
14.按照权利要求9、12或13的用途,其中所述疾病是无控的细胞生长、增殖和/或存活、不合适的细胞免疫响应或不合适的细胞炎性响应的疾病,尤其是,其中所述无控的细胞生长、增殖和/或存活、不合适的细胞免疫响应或不合适的细胞炎性响应的疾病是血液肿瘤、实体肿瘤和/或其转移病变,例如白血病和脊髓发育不良综合征、恶性淋巴瘤、包括脑瘤和脑转移病变的头和颈部肿瘤、包括非小细胞和小细胞肺肿瘤的胸部肿瘤、胃肠肿瘤、内分泌腺肿瘤、乳腺及其它妇科肿瘤、包括肾、膀胱和前列腺肿瘤的泌尿系统肿瘤、皮肤肿瘤和肉瘤,和/或其转移病变。
15.通式(II)的化合物:
其中R4、R5、R6、R7、R8、R9、R10和R11如按照权利要求1至6的任一项的通式(I)化合物所定义,
用于制备按照权利要求1至6的任一项的通式(I)的化合物的用途。
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EP3319945A1 (en) | 2018-05-16 |
ES2877424T3 (es) | 2021-11-16 |
US20180207137A1 (en) | 2018-07-26 |
CA2991360A1 (en) | 2017-01-12 |
CN107949557B (zh) | 2021-11-02 |
WO2017005674A1 (en) | 2017-01-12 |
EP3319945B1 (en) | 2021-04-28 |
US10179123B2 (en) | 2019-01-15 |
JP2018522886A (ja) | 2018-08-16 |
JP6824952B2 (ja) | 2021-02-03 |
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