CN101938902B - 苄基苯基环己烷衍生物及使用方法 - Google Patents
苄基苯基环己烷衍生物及使用方法 Download PDFInfo
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- CN101938902B CN101938902B CN200880126441.9A CN200880126441A CN101938902B CN 101938902 B CN101938902 B CN 101938902B CN 200880126441 A CN200880126441 A CN 200880126441A CN 101938902 B CN101938902 B CN 101938902B
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- compound
- chloro
- phenyl
- methylol
- alkyl
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- 238000000034 method Methods 0.000 title abstract description 53
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- 150000001875 compounds Chemical class 0.000 claims abstract description 149
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- 201000010099 disease Diseases 0.000 claims abstract description 34
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- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 claims abstract description 17
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- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 5
- 230000005764 inhibitory process Effects 0.000 claims abstract description 4
- -1 2-((1R, 2S, 3R, 4R, 5S, 6R)-2,3,4,6-tetrahydroxy-5-(methylol) cyclohexyl) benzyl Chemical group 0.000 claims description 149
- 238000002360 preparation method Methods 0.000 claims description 96
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 90
- 229910052760 oxygen Inorganic materials 0.000 claims description 50
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 42
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- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 26
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Abstract
本发明提供对钠依赖性葡萄糖共转运体SGLT具有抑制作用的化合物。本发明还提供药物组合物、制备所述化合物的方法、合成中间体及独立地使用或与其他治疗剂联用所述化合物以治疗受SGLT抑制影响的疾病和病症的方法。
Description
相关申请的交叉引用
本申请要求2007年12月13日提交的美国临时申请序号61/013,517的权益,其公开内容通过引用结合到本文中。
关于按联邦资助的研究与开发取得发明的权利的声明
不适用
发明背景
根据世界卫生组织的数据,全世界大约15000万人患有糖尿病。糖尿病的两种主要形式是1型糖尿病和2型糖尿病,在1型糖尿病中胰腺不能产生胰岛素,而在2型糖尿病中身体不能对所产生的胰岛素作出正确应答(胰岛素抵抗)。2型糖尿病最普遍,占所有糖尿病病例的约90%。在这两种类型的糖尿病中,胰岛素作用的缺乏或对胰岛素的正确应答的缺乏导致血清葡萄糖水平升高(高血糖症)。与糖尿病相关的严重并发症包括视网膜病(导致视觉缺陷或失明)、心血管疾病、肾病、神经病、溃疡和糖尿病足病。
患1型糖尿病的个体目前需要胰岛素疗法。虽然在许多情况下2型糖尿病可通过饮食和锻炼加以控制,但常常也需要药物干预。除胰岛素(约三分之一的2型糖尿病患者需要)外,当前的抗糖尿病疗法包括双胍类(其减少肝脏内葡萄糖的产生并提高对胰岛素的敏感性)、磺酰脲类和氯茴苯酸类(其刺激胰岛素的产生)、α-葡糖苷酶抑制剂(其减慢对淀粉的吸收和葡萄糖的产生)和噻唑烷二酮类(其提高胰岛素敏感性)。这些药物常常联用,尽管这样仍不能提供适当的血糖控制或可能产生不希望的副作用。这类副作用包括乳酸酸中毒(双胍类)、低血糖(磺酰脲类)及浮肿和体重增加(噻唑烷二酮类)。因此,非常希望提供改进的血糖控制并且没有这些不利作用的新型抗糖尿病药剂。
糖尿病及相关紊乱的治疗干预的一个有前景的目标是肾的葡萄糖转运系统。细胞葡萄糖转运通过易化性(“被动的”)葡萄糖转运体(GLUT) 或钠依赖性(“主动的”)葡萄糖共转运体(SGLT)进行。SGLT1主要存在于肠刷状缘中,而SGLT2位于肾近端小管中并据报道负责肾的绝大部分葡萄糖再摄取。最近的研究表明,抑制肾的SGLT可以是通过增加排泄到尿中的葡萄糖的量来治疗高血糖症的有用方法(Arakawa K,et al.,Br J Pharmacol 132:578-86,2001;Oku A,et al.,Diabetes 48:1794-1800,1999)。该治疗方法的潜力得到家族性肾性糖尿情况SGLT2基因发生突变的最近发现的进一步支持,家族性肾性糖尿是一种明显良性的综合征,其特征为正常血清葡萄糖水平下且没有肾功能不全或其他疾病存在下的尿葡萄糖排泄(Santer R,et al.,J Am Soc Nephrol 14:2873-82,2003)。因此,抑制SGLT、特别是SGLT2的化合物是用作抗糖尿病药物的有前景的候选化合物。前述可用于抑制SGLT的化合物包括环己烷衍生物(如WO2006011469中描述的那些)、C-糖苷衍生物(如US6414126、US20040138439、US20050209166、US20050233988、WO2005085237、US7094763、US20060009400、US20060019948、US20060035841、US20060122126和WO2006108842中描述的那些)、O-糖苷衍生物(如US6683056、US20050187168、US20060166899、US20060234954、US20060247179和US20070185197中描述的那些)、螺缩酮-糖苷衍生物(WO2006080421中描述的那些)和硫代吡喃葡萄糖苷衍生物(如US20050209309和WO2006073197中描述的那些)。
发明简述
本发明提供对钠依赖性葡萄糖共转运体SGLT具有抑制作用的化合物。本发明还提供药物组合物、制备所述化合物的方法、合成中间体及单独地或与其他治疗剂一起使用所述化合物以治疗受SGLT抑制影响的疾病和病症的方法。
附图简述
图1-2提供本发明化合物的一般合成方案。
图3-8提供针对下面实施例中的化合物的更具体合成方案。
发明详述
定义
本文中所用的术语“卤素”指选自氟、氯、溴和碘的一价卤素基团或原子。优选的卤素基团有氟、氯和溴。
本文中所用的术语“合适的取代基”指化学和药学上可接受的基团,即不显著干扰本发明化合物的制备或不会使本发明化合物的功效不起作用的部分。这类合适的取代基可由本领域技术人员按常规选择。合适的取代基可选自卤素、C1-C6烷基、C2-C6烯基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C2-C6炔基、C3-C8环烯基、(C3-C8环烷基)C1-C6烷基、(C3-C8环烷基)C2-C6烯基、(C3-C8环烷基)C1-C6烷氧基、C3-C7杂环烷基、(C3-C7杂环烷基)C1-C6烷基、(C3-C7杂环烷基)C2-C6烯基、(C3-C7杂环烷基)C1-C6烷氧基、羟基、羧基、氧代、硫醇基、C1-C6烷基硫醇基、芳基、杂芳基、芳氧基、杂芳氧基、芳烷基、杂芳烷基、芳烷氧基、杂芳烷氧基、硝基、氰基、氨基、C1-C6烷基氨基、二-(C1-C6烷基)氨基、氨甲酰基、(C1-C6烷基)羰基、(C1-C6烷氧基)羰基、(C1-C6烷基)氨基羰基、二-(C1-C6烷基)氨基羰基、芳基羰基、芳氧基羰基、(C1-C6烷基)磺酰基和芳基磺酰基。上面作为合适的取代基所列出的基团的定义同下文,不同之处是合适的取代基可以不再被任选地取代。
除非另有指出,否则本文中所用的术语“烷基”单独或联用指具有指定碳原子数的一价饱和脂族烃基。所述基团可以是直链或带支链的,在指出时任选被一到三个如上所定义的合适的取代基取代。烷基的示意性实例包括但不限于甲基、乙基、正丙基、正丁基、正戊基、正己基、异丙基、异丁基、异戊基、戊基、仲丁基、叔丁基、叔戊基、正庚基、正辛基、正壬基、正癸基、正十二烷基、正十四烷基、正十六烷基、正十八烷基、正二十烷基等。优选的烷基包括甲基、乙基、正丙基和异丙基。优选的任选合适的取代基包括卤素、甲氧基、乙氧基、氰基、硝基和氨基。
除非另有指出,否则本文中所用的术语“烯基”单独或联用指具有指定碳原子数和至少一个碳-碳双键的一价脂族烃基。所述基团可以是直链或带支链的,具有E型或Z型,在指出时任选被一到三个如上所定义的合适的取代基取代。烯基的示意性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、异丁烯基、2-甲基-1-丙烯基、1-戊烯基、2-戊烯基、4-甲基-2-戊烯基、1,3-戊二烯基、2,4-戊二烯基、1,3-丁二烯基等。优选的烯基包括乙烯基、1-丙烯基和2-丙烯基。优选的任选合适 的取代基包括卤素、甲氧基、乙氧基、氰基、硝基和氨基。
除非另有指出,否则本文中所用的术语“炔基”单独或联用指具有指定碳原子数和至少一个碳-碳三键的一价脂族烃基。所述基团可以是直链或带支链的,在指出时任选被一到三个如上所定义的合适的取代基取代。炔基的示意性实例包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、3-甲基-1-戊炔基、3-戊炔基、1-己炔基、2-己炔基、3-己炔基等。优选的炔基包括乙炔基、1-丙炔基和2-丙炔基。优选的任选合适的取代基包括卤素、甲氧基、乙氧基、氰基、硝基和氨基。
除非另有指出,否则本文中所用的术语“环烷基”单独或联用指具有三个或更多个碳形成碳环的一价脂环族饱和烃基,在指出时任选被一到三个如上所定义的合适的取代基取代。环烷基的示意性实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基等。优选的任选合适的取代基包括卤素、甲基、乙基、甲氧基、乙氧基、氰基、硝基和氨基。
除非另有指出,否则本文中所用的术语“环烯基”单独或联用指具有三个或更多个碳形成碳环和至少一个碳-碳双键的一价脂环族烃基,在指出时任选被一到三个如上所定义的合适的取代基取代。环烯基的示意性实例包括但不限于环戊烯基、环己烯基等。优选的任选合适的取代基包括卤素、甲基、乙基、甲氧基、乙氧基、氰基、硝基和氨基。
除非另有指出,否则本文中所用的术语“亚烷基”、“亚烯基”、“亚环烷基”和“亚环烯基”分别指通过从如上所定义的烷基、烯基、环烷基或环烯基上除去一个氢原子所形成的二价烃基。
本文中所用的术语“(C3-C10亚环烷基)(C1-C6亚烷基)”指通过键合如上所定义的C3-C10亚环烷基与C1-C6亚烷基所形成的二价烃基。
除非另有指出,否则本文中所用的术语“芳基”单独或联用指具有六到十个碳原子形成碳环的一价芳族烃基,在指出时任选被一到三个如上所定义的合适的取代基取代。芳基的示意性实例包括但不限于苯基、萘基、四氢萘基、茚满基等。优选的芳基为任选被选自卤素、氰基、C1-C3烷基、C3-C6环烷基、二氟甲基、三氟甲基、C1-C3烷氧基、二氟甲氧基和三氟甲 氧基的相同或不同的合适的取代基单-或二取代的苯基和萘基。
除非另有指出,否则本文中所用的术语“杂环烷基”单独或联用指其中环的一个或多个碳被选自N、S和O的杂原子替代的如上所定义的环烷基。杂环烷基的示意性实例包括但不限于吡咯烷基、四氢呋喃基、哌嗪基、四氢吡喃基等。
除非另有指出,否则本文中所用的术语“杂芳基”单独或联用指具有二到九个碳和一到四个选自N、S和O的杂原子形成五元到十元单环或稠合双环的一价芳族杂环基,在指出时任选被一到三个如上所定义的合适的取代基取代。杂芳基的示意性实例包括但不限于吡啶基、哒嗪基、吡嗪基、嘧啶基、三嗪基、喹啉基、异喹啉基、喹 啉基、喹唑啉基、苯并三嗪基、苯并咪唑基、苯并吡唑基、苯并三唑基、苯并异 唑基、异苯并呋喃基、异吲哚基、吲哚嗪基、噻吩并吡啶基、噻吩并嘧啶基、吡唑并嘧啶基、咪唑并吡啶基、苯并噻唑基、苯并呋喃基、苯并噻吩基、吲哚基、异噻唑基、吡唑基、吲唑基、咪唑基、三唑基、四唑基、 唑基、异 唑基、 二唑基、噻二唑基、吡咯基、噻唑基、呋喃基、噻吩基等。五-或六-元单环杂芳环包括:吡啶基、哒嗪基、吡嗪基、嘧啶基、三嗪基、异噻唑基、吡唑基、咪唑基、三唑基、四唑基、 唑基、异 唑基、 二唑基、噻二唑基、吡咯基、噻唑基、呋喃基、噻吩基等。具有一到四个杂原子的八-到十-元双环杂芳环包括:喹啉基、异喹啉基、喹 啉基、喹唑啉基、苯并三嗪基、苯并咪唑基、苯并吡唑基、苯并三唑基、苯并异 唑基、异苯并呋喃基、异吲哚基、吲哚嗪基、噻吩并吡啶基、噻吩并嘧啶基、吡唑并嘧啶基、咪唑并吡啶基、苯并噻唑基、苯并呋喃基、苯并噻吩基、吲哚基、吲唑基等。优选的任选合适的取代基包括选自卤素、氰基、C1-C3烷基、C3-C6环烷基、二氟甲基、三氟甲基、C1-C3烷氧基、二氟甲氧基和三氟甲氧基的一个或两个相同或不同的取代基。
除非另有指出,否则本文中所用的术语“烷氧基”和单独或联用指烷基-O-形式的脂族基团,其中烷基的定义同上。烷氧基的示意性实例包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基、戊氧基、异戊氧基、新戊氧基、叔戊氧基、己氧基、异己氧基、庚氧基、辛氧基等。优选的烷氧基包括甲氧基和乙氧基。
除非另有指出,否则本文中所用的术语“卤代烷基”指被一个或多个卤 素取代的上述烷基。卤代烷基的示意性实例包括但不限于氯甲基、二氯甲基、氟甲基、二氟甲基、三氟甲基、2,2,2-三氯乙基等。
除非另有指出,否则本文中所用的术语“卤代烷氧基”指被一个或多个卤素取代的上述烷氧基。卤代烷氧基的示意性实例包括但不限于三氟甲氧基、二氟甲氧基等。
除非另有指出,否则本文中所用的术语“芳烷基”指被上述芳基取代的上述具有一到六个碳的烷基。
除非另有指出,否则本文中所用的术语“杂芳烷基”指被上述杂芳基取代的上述具有一到六个碳的烷基。
除非另有指出,否则本文中所用的术语“芳烷氧基”指被上述芳基取代的上述具有一到六个碳的烷氧基。
除非另有指出,否则本文中所用的术语“杂芳烷氧基”指被上述杂芳基取代的上述具有一到六个碳的烷氧基。
除非另有指出,否则本文中所用的术语“氨甲酰基”指-C(O)NH(R)形式的一价基团,其中R为氢、如上所定义的C1-C6烷基、C2-C6烯基、C3-C6环烷基或芳基。
除非另有指出,否则本文中所用的术语“二-(C1-C3烷基)氨基”和“二-(C1-C6烷基)氨基”单独或联用分别指被独立地选自C1-C3烷基或C1-C6烷基的两个基团所取代的氨基。
本文中所用的术语“治疗”指所述术语适用的疾病或病症,或这类疾病或病症的一种或多种症状的出现延迟,发展减慢或逆转,或被减轻或预防。
本文中所用的术语“给药”指口服给药、栓剂给药、局部接触给药、静脉内给药、腹膜内给药、肌内给药、病灶部位内给药、鼻内给药或皮下给药、或为患者植入缓释装置如微型渗透泵。给药通过任何途径进行,包括肠胃外和透粘膜(如经口、经鼻、经阴道、经直肠或透皮)。肠胃外给药包括例如静脉内、肌内、小动脉内、皮内、皮下、腹膜内、心室内和颅内给药。其他递送方式包括但不限于使用脂质体制剂、静脉输注、透皮贴剂等。
本文中所用的术语“前药”指给药后经由某种化学或生理过程在体内释放生物活性化合物的前体化合物(例如在达到生理pH时或通过酶作用前药转化为生物活性化合物)。前药自身可以没有或具有所需的生物活性。
本文中所用的术语“化合物”指通过任何途径,包括但不限于体外合成或原位或体内生成产生的分子。
术语“控制释放”、“持续释放”、“延长释放”和“定时释放”意在可互换地指任何含药物的制剂其中的药物不是立即释放,即采用“控制释放”制剂时,口服给药不会导致药物立即释放到吸收池中。这些术语与Remington:The Science and Practice of Pharmacy,21st Ed.,Gennaro,Ed.,Lippencott Williams & Wilkins(2003)中定义的“非立即释放”可互换地使用。如其中所讨论的,立即释放和非立即释放动力学上可参照下式定义:
“吸收池”代表所施用药物在特定吸收部位的溶液,kr、ka和ke分别是药物(1)从制剂中释放、(2)吸收和(3)消除的一级速率常数。对于立即释放剂型,药物释放速率常数kr远大于吸收速率常数ka。对于控制释放制剂,情况相反,即kr<<ka,以致于药物从剂型中释放的速率为药物向靶区递送中的速率限制步骤。
术语“持续释放”和“延长释放”常规上用来指药物制剂在延长时间例如12小时或更长时间内逐步释放药物,而且虽然不是必须的但优选导致在延长时间内基本恒定的血药水平。
本文中所用的术语“延迟释放”指药物制剂完好地通过胃并在小肠中溶解。
概述
本发明提供对钠依赖性葡萄糖共转运体SGLT、优选SGLT2具有抑制作用的化合物。根据本发明的一些化合物也对钠依赖性葡萄糖共转运体SGLT1具有抑制作用。由于其抑制SGLT的能力,因此本发明的化合物适 于治疗和/或预防任何受SGLT活性、特别是SGLT2活性抑制影响的病症和疾病。因此,本发明的化合物适于预防和治疗特别是代谢紊乱的疾病和病症,包括但不限于1型和2型糖尿病、高血糖症、糖尿病并发症(如视网膜病、肾病[如进行性肾病]、神经病、溃疡、微血管和大血管病变和糖尿病足病)、胰岛素抵抗、代谢综合征(综合征X)、高胰岛素血症、高血压、高尿酸血症、肥胖症、浮肿、异常脂肪血症、慢性心力衰竭、动脉粥样硬化和相关疾病。
本发明还提供根据本发明化合物的药学上可接受的盐和前药。
本发明还提供在药学上可接受的载体中包含有效量的根据本发明的化合物或化合物的混合物或其药学上可接受的盐或前药的药物组合物。
本发明还提供合成中间体及制备本发明的化合物的方法。
本发明还提供单独地或与其他治疗剂一起使用根据本发明的化合物治疗可以受SGLT抑制影响的疾病和病症的方法。
本发明还提供使用根据本发明的化合物制备用于治疗可以受SGLT抑制影响的疾病和病症的药剂的方法。
详细的实施方案
化合物和制备方法
在一个方面,本发明提供式I的化合物:
其中
A代表氧、NH、亚甲基或单键;
Q选自下式Q1到Q4中的一个:
其中波浪线表示与该分子其余部分的连接位置;
Z代表氧、硫、SO、SO2、1,1-亚环丙基、羰基或任选被一到两个独立地选自卤素、羟基、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基和C3-C6环烷氧基的取代基所取代的亚甲基;
R1、R2和R3各自独立地代表氢、卤素、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C5-C10环烯基、C1-C6烷氧基、C3-C10环烷氧基、氰基、氨基或硝基,其中烷基、烯基、炔基、环烷基和环烯基基团或部分任选可被部分或完全氟化并可被选自氯、羟基、C1-C3烷氧基和C1-C3烷基的相同或不同取代基单-或二取代,在环烷基和环烯基基团或部分中,一个或两个亚甲基任选彼此独立地被NRa、O、S、CO、SO或SO2所代替,并且一个或两个亚甲基任选可被N所代替,或
在R1和R2与苯环的两个相邻C原子相连的情况下,R1和R2可连接在一起,使得R1和R2一起形成C3-C5亚烷基、C3-C5亚烯基或亚丁二烯基桥,其可被部分或完全氟化并可被选自氯、羟基、C1-C3烷氧基和C1-C3烷基的相同或不同取代基单-或二取代,其中一个或两个亚甲基任选彼此独立地被O、S、CO、SO、SO2或NRa所代替,其中一个或两个亚甲基任选可被N所代替。
R4独立地代表氢、卤素、氰基、硝基、氨基、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C5-C10环烯基、C1-C6烷氧基、C3-C10环烷氧基、(C1-C6烷氧基)C1-C6烷氧基、C5-C7环烯氧基、芳基、杂芳基、 芳氧基、杂芳氧基、(C2-C4烯基)C1-C3烷氧基、(C2-C4炔基)C1-C3烷氧基、(芳基)C1-C3烷氧基、(杂芳基)C1-C3烷氧基、(C3-C10环烷基)C1-C3烷基、(C3-C10环烷基)C1-C3烷氧基、(C5-C10环烯基)C1-C3烷基、(C5-C10环烯基)C1-C3烷氧基、(C1-C4烷氧基)C1-C3烷基、(C3-C7环烷氧基)C1-C3烷基、(C3-C7环烷氧基)C2-C4烯基、(C3-C7环烷氧基)C2-C4炔基、(C3-C7环烷氧基)C1-C3烷氧基、(C1-C4烷基氨基)C1-C3烷基、二-(C1-C3烷基氨基)C1-C3烷基、三-(C1-C4烷基)甲硅烷基-C1-C6烷基、三-(C1-C4烷基)甲硅烷基-C2-C6烯基、三-(C1-C4烷基)甲硅烷基-C2-C6炔基、三-(C1-C4烷基)甲硅烷基-C1-C6烷氧基、(C3-C7环烷基)C2-C5烯基、(C3-C7环烷基)C3-C5烯氧基、(C3-C7环烷基)C3-C5炔氧基、(C5-C8环烯基)C3-C5烯氧基、(C5-C8环烯基)C3-C5炔氧基、C3-C6亚环烷基甲基、(C1-C4烷基)羰基、芳基羰基、杂芳基羰基、氨基羰基、(C1-C4烷基)氨基羰基、二-(C1-C3烷基)氨基羰基、羟基羰基、(C1-C4烷氧基)羰基、C1-C4烷基氨基、二-(C1-C3烷基)氨基、(C1-C4烷基)羰基氨基、芳基羰基氨基、杂芳基羰基氨基、C1-C4烷基磺酰氨基、芳基磺酰氨基、C1-C4烷基硫醇基、C1-C4烷基亚磺酰基、C1-C4烷基磺酰基、C3-C10环烷基硫醇基、C3-C10环烷基亚磺酰基、C3-C10环烷基磺酰基、C5-C10环烯基硫醇基、C5-C10环烯基亚磺酰基、C5-C10环烯基磺酰基、芳基硫醇基、芳基亚磺酰基或芳基磺酰基,其中烷基、烯基、炔基、环烷基和环烯基基团或部分任选可被部分或完全氟化并可被选自氯、羟基、C1-C3烷氧基和C1-C3烷基的相同或不同取代基单-或二取代,在环烷基和环烯基基团或部分中,一个或两个亚甲基任选彼此独立地被NRa、O、S、CO、SO或SO2所代替,一个或两个亚甲基任选可被N所代替;
R5和R6各自独立地代表氢、卤素、氰基、硝基、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C1-C3烷氧基或C3-C10环烷氧基,其中烷基、烯基、炔基、环烷基和环烯基基团或部分任选可被部分或完全氟化并可被选自氯、羟基、C1-C3烷氧基和C1-C3烷基的相同或不同取代基单-或二取代,在环烷基和环烯基基团或部分中,一个或两个亚甲基任选彼此独立地被NRa、O、S、CO、SO或SO2所代替,一个或两个亚甲基任选可被N所代替,或
如果R5和R6与苯环的两个相邻C原子相连,则R5和R6任选可连接在一起使得R5和R6一起形成C3-C5亚烷基、C3-C5亚烯基或亚丁二烯基桥,其可被部分或完全氟化并可被选自氯、羟基、C1-C3烷氧基和C1-C3烷基的 相同或不同取代基单-或二取代,其中一个或两个亚甲基任选彼此独立地被O、S、CO、SO、SO2或NRa所代替,一个或两个亚甲基可被N所代替;
R7、R8、R9和R10各自独立地代表羟基、(C1-C18烷基)羰氧基、(C1-C18烷基)氧羰氧基、芳基羰氧基、芳基-(C1-C3烷基)羰氧基、(C3-C10环烷基)羰氧基、氢、卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、(C3-C10环烷基)C1-C3烷基、(C5-C7环烯基)C1-C3烷基、(芳基)C1-C3烷基、(杂芳基)C1-C3烷基、C1-C6烷氧基、C2-C6烯氧基、C2-C6炔氧基、C3-C7环烷氧基、C5-C7环烯氧基、芳氧基、杂芳氧基、(C3-C7环烷基)C1-C3烷氧基、(C5-C7环烯基)C1-C3烷氧基、(芳基)C1-C3烷氧基、(杂芳基)C1-C3烷氧基、氨基羰基、羟基羰基、(C1-C4烷基)氨基羰基、二-(C1-C3烷基)氨基羰基、(C1-C4烷氧基)羰基、(氨基羰基)C1-C3烷基、(C1-C4烷基)氨基羰基-(C1-C3)烷基、二-(C1-C3烷基)氨基羰基-(C1-C3)烷基、(羟基羰基)C1-C3烷基、(C1-C4烷氧基)羰基-(C1-C3)烷基、(C3-C7环烷氧基)C1-C3烷基、(C5-C7环烯氧基)C1-C3烷基、(芳氧基)C1-C3烷基、(杂芳氧基)C1-C3烷基、C1-C4烷基磺酰氧基、芳基磺酰氧基、(芳基)C1-C3烷基磺酰氧基、三甲基甲硅烷氧基、叔丁基二甲基甲硅烷氧基或氰基;其中烷基、烯基、炔基、环烷基和环烯基基团或部分任选可被部分或完全氟化并可被选自氯、羟基、C1-C3烷氧基和C1-C3烷基的相同或不同取代基单-或二取代,在环烷基和环烯基基团或部分中,一个或两个亚甲基任选彼此独立地被NRa、O、S、CO、SO或SO2所代替;
任选地,R10和R11可与其各自相连的碳原子结合形成五-到七-元稠合环烷烃或环烯烃环,所述环任选被部分或完全氟化并可被选自氯、羟基、C1-C3烷氧基和C1-C3烷基的相同或不同取代基单-或二取代,其中在环烷基和环烯基环中,一个或两个亚甲基任选彼此独立地被NRa、O、S、CO、SO或SO2所代替;
R11和R12各自独立地代表氢、羟基、卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C1-C6烷氧基、C2-C6烯氧基、C2-C6炔氧基或C3-C6环烷氧基,其中烷基、烯基、炔基和环烷基基团或部分任选可被部分或完全氟化,或
R11和R12任选连接在一起使得R11和R12与其相连的碳原子一起形成C3-C7螺环烷烃环,所述环任选可被部分或完全氟化并且可被选自氯、羟基、C1-C3烷氧基和C1-C3烷基的相同或不同取代基单-或二取代;
其中当Q为Q1且R11和R12均为氢时,则R10或R14中的至少一个为卤素,或R13不为氢,或R4为C2-C6炔基、C3-C10环烷氧基、C5-C7环烯氧基、(C3-C10环烷基)C1-C3烷氧基、(C3-C7环烷基)C3-C5烯氧基、(C3-C7环烷基)C3-C5炔氧基、(C5-C10环烯基)C1-C3烷氧基、(C5-C8环烯基)C3-C5烯氧基或(C5-C8环烯基)C3-C5炔氧基,或
当Q为Q2且R11为氢时,则至少R10为卤素,或R4为C2-C6炔基、C3-C10环烷氧基、C5-C7环烯氧基、(C3-C10环烷基)C1-C3烷氧基、(C3-C7环烷基)C3-C5烯氧基、(C3-C7环烷基)C3-C5炔氧基、(C5-C10环烯基)C1-C3烷氧基、(C5-C8环烯基)C3-C5烯氧基或(C5-C8环烯基)C3-C5炔氧基,或
当Q为Q4且R11为氢时,则至少R10为卤素,或R13不为氢,或R4为C2-C6炔基、C3-C10环烷氧基、C5-C7环烯氧基、(C3-C10环烷基)C1-C3烷氧基、(C3-C7环烷基)C3-C5烯氧基、(C3-C7环烷基)C3-C5炔氧基、(C5-C10环烯基)C1-C3烷氧基、(C5-C8环烯基)C3-C5烯氧基或(C5-C8环烯基)C3-C5炔氧基;
R13和R14各自独立地代表氢、羟基、卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C1-C6烷氧基、C2-C6烯氧基、C2-C6炔氧基或C3-C6环烷氧基,其中烷基、烯基、炔基和环烷基基团或部分任选可被部分或完全氟化;
R15独立地代表氧或CRbRc;
Ra独立地代表氢、C1-C4烷基或(C1-C4烷基)羰基,其中烷基基团或部分任选可被部分或完全氟化;和
Rb和Rc各自独立地代表氢、卤素或C1-C4烷基,其中烷基基团任选可被部分或完全氟化。
除非另有指出,否则上文及下文所用的其中苯基上取代基的键示为终止于苯环中心附近的表达方式表示该取代基可连接到苯基具有氢原子的任何自由位置。
本发明涵盖混合物或纯或基本纯形式的式I化合物的所有互变异构体和立体异构体。本发明的化合物可在碳原子处具有不对称中心,因此式I 化合物可以以非对映体或对映体形式或其混合物存在。所有构型异构体(如顺反异构体)和所有光学异构体(如对映体和非对映体)、这类异构体的外消旋混合物、非对映体混合物及其他混合物以及溶剂化物、水合物、类质同晶型体、多晶型和互变异构体均在本发明的范围内。根据本发明的化合物可利用非对映体、对映体或外消旋混合物作为原料制备。此外,非对映体和对映体产物可通过色谱、分级结晶或本领域技术人员熟知的其他方法分离。
本发明还提供式I化合物的前药。本发明化合物的前药包括但不限于羧酸酯、碳酸酯、半酯、磷酯、硝基酯、硫酸酯、亚砜、酰胺、氨基甲酸酯、偶氮化合物、磷酰胺、糖苷、醚、缩醛和缩酮。前药酯和碳酸酯可例如通过采用本领域技术人员熟知的方法使式I化合物的一个或多个羟基与烷基、烷氧基或芳基取代的酰化试剂反应以生成甲基碳酸酯、乙酸酯、苯甲酸酯、特戊酸酯等而形成。本发明化合物的前药酯的示意性实例包括但不限于具有羧基部分的式I化合物,其中游离氢被C1-C4烷基、C1-C7烷酰氧基甲基、1-((C1-C5)烷酰氧基)乙基、1-甲基-1-((C1-C5)烷酰氧基)-乙基、C1-C5烷氧基羰氧基甲基、1-((C1-C5)烷氧基羰氧基)乙基、1-甲基-1-((C1-C5)烷氧基羰氧基)乙基、N-((C1-C5)烷氧基羰基)氨基甲基、1-(N-((C1-C5)烷氧基羰基)氨基)乙基、3-酞基、4-巴豆酰内酯基、γ-丁内酯-4-基、二-N,N-(C1-C2)烷基氨基(C2-C3)烷基(如β-二甲基氨基乙基)、氨甲酰基-(C1-C2)烷基、N,N-二(C1-C2)烷基氨甲酰基-(C1-C2)烷基和哌啶基-、吡咯烷基-或吗啉代(C2-C3)烷基所代替。寡肽修饰物及生物可降解聚合物衍生物(如Int.J.Pharm.115,61-67,1995中所述)在本发明的范围内。选择和制备合适前药的方法在例如如下文献中给出:T.Higuchi and V.Stella,“Prodrugs as Novel Delivery Systems,”Vol.14,ACS Symposium Series,1975;H.Bundgaard,“Design of Prodrugs,”Elsevier,1985;和“Bioreversible Carriers in Drug Design,”ed.Edward Roche,American Pharmaceutical Association and Pergamon Press,1987。
本发明还提供式I化合物的药学上可接受的盐及其前药。可用作试剂制备本发明碱性化合物的药学上可接受的酸加成盐的酸为形成无毒酸加成盐,即含药学上可接受的阴离子的盐(如盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、乙酸盐、乳酸盐、柠檬酸盐、酸式柠檬酸盐、酒石酸盐、酒石酸氢盐、琥珀酸盐、马来酸盐、 富马酸盐、葡糖酸盐、糖二酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对-甲苯磺酸盐和双羟萘酸盐(1,1’-亚甲基-双-2-羟基-3-萘甲酸盐))的那些。可用作试剂制备本发明酸性化合物的药学上可接受的碱盐的碱为与这类化合物形成无毒碱盐的那些,包括但不限于由药理学上可接受的阳离子如碱金属阳离子(如钾、锂和钠)和碱土金属阳离子(如钙和镁)得到的那些、铵或水溶性胺加成盐如N-甲基葡糖胺(葡甲胺),以及低级链烷醇铵和药学上可接受的有机胺(如甲胺、乙胺、丙胺、二甲胺、三乙醇胺、二乙胺、叔丁胺、叔辛胺、三甲胺、三乙胺、乙二胺、羟基乙胺、吗啉、哌嗪、脱氢枞胺、赖氨酸和胍)的其他碱盐的那些。
本发明还包括同位素标记的式I化合物,其中一个或多个原子被具有特定原子质量或质量数的一个或多个原子所代替。可引入本发明化合物中的同位素的实例包括但不限于氢、碳、氮、氧、氟、硫和氯的同位素(如2H、 3H、13C、14C、15N、18O、17O、18F、35S和36Cl)。同位素标记的式I化合物及其前药以及同位素标记的式I化合物的药学上可接受的盐及其前药在本发明的范围内。本发明的同位素标记化合物可用于化合物及它们的前药和代谢物的组织分布的测定中;对于这类测定优选的同位素包括3H和14C。此外,在某些情况下,用较重的同位素如氘(2H)取代可提供增加的代谢稳定性,这带来治疗方面的优点如体内半衰期增长或剂量需要减少。本发明的同位素标记化合物及其前药通常可通过用同位素标记的试剂代替没有用同位素标记的试剂按本文中描述的方法来制备。
在优选的实施方案中,A代表氧或单键。在特别优选的实施方案中,A代表单键。
在优选的实施方案中,Z代表氧、硫或任选被独立地选自卤素、羟基、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基和C3-C6环烷氧基的一到两个取代基所取代的亚甲基。在特别优选的实施方案中,Z代表亚甲基。
在优选的实施方案中,R1、R2和R3各自独立地代表氢、卤素、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C1-C6烷氧基或氰基。在特别优选的实施方案中,R1、R2和R3各自独立地代表氢、卤素或C1-C6烷基。在更特别优选的实施方案中,R1代表氢、卤素或C1-C6烷基,R2和R3均代表氢。
在优选的实施方案中,R4代表C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C1-C6烷氧基、C3-C10环烷氧基、(C3-C10环烷基)C1-C3烷氧基、(C3-C7环烷基)C3-C5烯氧基或(C3-C7环烷基)C3-C5炔氧基。
在优选的实施方案中,R5和R6各自独立地代表氢、卤素、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C1-C6烷氧基或氰基。在特别优选的实施方案中,R5和R6各自独立地代表氢、卤素或C1-C6烷基。在更特别优选的实施方案中,R5和R6均代表氢。
在优选的实施方案中,R7、R8、R9和R10各自独立地代表羟基、卤素、C1-C6烷基、C1-C6烷氧基、(C3-C7)环烷氧基、芳氧基或(C3-C7)环烷基-(C1-C3)烷氧基,其中烷基和环烷基基团或部分可被部分或完全氟化。在特别优选的实施方案中,R7、R8、R9和R10各自代表羟基。
在优选的实施方案中,R11代表氢或羟基。
在优选的实施方案中,R12、R13和R14代表氢。
在优选的实施方案中,R15代表氧或CRbRc,其中Rb和Rc各自独立地代表氢或卤素。
如上所述,式IA代表其他优选的实施方案:
其中R1代表氢、卤素或C1-C6烷基;R4代表C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C1-C6烷氧基、C3-C10环烷氧基、(C3-C10环烷基)C1-C3烷氧基、(C3-C7环烷基)C3-C5烯氧基或(C3-C7环烷基)C3-C5炔氧基;Q选自下式Q1A到Q4A:
其中R11代表氢或羟基;R15代表氧或CRbRc,其中Rb和Rc各自独立地代表氢或卤素;其中当R11为氢时,R4为C2-C6炔基、C3-C10环烷氧基、(C3-C10环烷基)C1-C3烷氧基、(C3-C7环烷基)C3-C5烯氧基或(C3-C7环烷基)C3-C5炔氧基。在一些实施方案中,Q选自式Q1A到Q3A。
在特别优选的实施方案中,本发明的化合物选自:
(1R,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-乙基苄基)苯基)-6-(羟甲基)环己烷-1,2,3,5-四醇
(1R,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-乙氧基苄基)苯基)-6-(羟甲基)环己烷-1,2,3,5-四醇
(1R,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-环丙基苄基)苯基)-6-(羟甲基)环己烷-1,2,3,5-四醇
(1R,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-丙基苄基)苯基)-6-(羟甲基)环己烷-1,2,3,5-四醇
(1R,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-环己基苄基)苯基)-6-(羟甲基)环己烷-1,2,3,5-四醇
(1R,2S,3S,6R)-4-(4-氯-3-(4-(3-环丙基丙-2-炔氧基)苄基)苯基)-6-(羟甲基)环己-4-烯-1,2,3-三醇
(1S,2R,3R,4S,5R,6R)-3-(4-氯-3-(4-乙基苄基)苯基)-2,4,5,6-四羟基环己基)乙酸甲酯
(1R,2S,3R,4R,5S,6R)-4-(2-(4-乙基苄基)苯氧基)-6-(羟甲基)环己烷-1,2,3,5-四醇
(1R,2R,3S,4S,6R)-4-(4-氯-3-(4-乙基苄基)苯基)-6-(羟甲基)-5-亚甲基环己烷-1,2,3-三醇
(4S,5S,6R,7R,8R)-4-(4-氯-3-(4-乙基苄基)苯基)-8-(羟甲基)螺[2.5]辛烷-5,6,7-三醇
1-(4-(2-氯-5-((1R,2S,3R,4R,5S,6R)-2,3,4,6-四羟基-5-(羟甲基)环己基)苄基)苯基)乙酮和
(1R,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-(1-羟乙基)苄基)苯基)-6-(羟甲基)环己烷-1,2,3,5-四醇
在另一方面,本发明涉及式I化合物及其药学上可接受的盐、前药和/或同位素标记化合物,其中烷基、烯基、炔基、环烷基、环烯基、芳基和杂芳基基团或部分任选被一到三个如上所定义的合适的取代基取代。
在其他方面,本发明提供中间体和可用于制备下面的中间体以及式I化合物及其药学上可接受的盐和前药的方法。
这类方法概括为如下图1和2的方案中示出的通用制备方法,更详细的具体实施例在以下描述实际实施例的实验部分中给出(图3-8)。按照下面讨论的通用制备方法或采用变化方案或替代方法,通过采用本领域技术人员熟知的化学反应和过程可容易地制得本发明的化合物。除非另有指出,否则下面描述的通用方法中表示基团的变量(如R基团)具有上文所定义的含义。
本领域技术人员将认识到,一般通过采用下述通用方法的轻微方案可制备具有各所述官能团的本发明化合物。在各方法的范围内,使用适合反应条件的官能团。必要时,可能干扰某些反应的官能团以被保护的形式给出,这类保护基的移除在适当的阶段通过本领域技术人员熟知的方法完成。
在某些情况下,本发明的化合物可由本发明的其他化合物通过所存在的官能团的精制、转化、交换等制备。这类精制包括但不限于水解、还原、氧化、烷基化、酰化、酯化、酰胺化和脱水。这类转化在某些情况下可以按T.W.Greene and P.G.M.Wuts,Protective Groups in Organic Synthesis,4th Edition;Wiley:New York,(2007)和P.J.Kocienski,Protecting Groups,3rd Edition;Georg Thieme Verlag:Stuttgart,(2005)中公开的方法需要使用保护基,所述两篇文献均通过引用结合到本文中。这类方法在合成所需的化合物之后或在合成路线中的另一位置处起动,这对于本领域技术人员来说是很明显的。
在其他方面,本发明提供可用于按下面讨论的一般制备方法及本领域技术人员熟知的其他方法制备式I化合物及其药学上可接受的盐和前药的合成中间体。
整篇公开内容中使用的如下缩略语和简称具有如下含义:Ac2O,乙酸酐;AcOEt,乙酸乙酯;AcOH,乙酸;AlBr3,溴化铝;AlCl3,氯化铝;BBr3,三溴化硼;BF3.Et2O,三氟化硼合乙醚;n-BuLi,正丁基锂;s-BuLi,仲丁基锂;t-BuLi,叔丁基锂;t-BuOK,叔丁醇钾;CaCl2,氯化钙;calc.,计算值;CD3OD,甲醇-d4;CDCl3,氯仿-d;CF3SO3H,三氟甲烷磺酸; CH2Cl2,二氯甲烷;CH2I2,二碘甲烷;CH3CN,乙腈;(COCl)2,草酰氯;DAST,(二乙基氨基)三氟化硫;DCM,二氯甲烷;DIAD,偶氮二甲酸二异丙酯;DMAP,4-二甲基氨基吡啶;DMEM,Dulbecco改性的Eagle培养基;DMF,N,N-二甲基甲酰胺;DMP,戴斯-马丁氧化剂;DMSO,二甲亚砜;EA,乙酸乙酯;eq,当量;ESI,电喷雾电离;Et,乙基;Et3SiH,三乙基甲硅烷;EtOAc,乙酸乙酯;EtOH,乙醇;FBS,胎牛血清;h,小时;H2,氢气;H2SO4,硫酸;Hepes,4-(2-羟乙基)-1-哌嗪乙磺酸;1HNMR,质子核磁共振;HPLC,高效液相色谱;K2CO3,碳酸钾;K2CrO7,重铬酸钾;KOH,氢氧化钾;LC-ESI-MS,液相色谱-电喷雾电离-质谱;LC-MS,液相色谱-质谱;Me,甲基;MeOH,甲醇;MeSO3H,甲磺酸;Mg,镁;MgCl2,氯化镁;min,分钟;MS,质谱;MsOH,甲磺酸;NaH,氢化钠;NaHCO3,碳酸氢钠;NaOAc,醋酸钠;NaOH,氢氧化钠;Na2SO4,硫酸钠;NH4Cl,氯化铵;Pd/C,钯碳;PE,石油醚;Ph,苯基;POCl3,三氯氧化磷;PPh3,三苯基膦;Rf,保持系数;rt,室温;SOCl2,亚硫酰二氯;TBAI,四丁基碘化铵;TFA,三氟乙酸;THF,四氢呋喃;TLC,薄层色谱;TMS,三甲基甲硅烷基;Tris,三羟甲基氨基甲烷(或2-氨基-2-(羟甲基)丙烷-1,3-二醇)。
方案I的一般合成方法
本发明的式I化合物可按如方案I(图1)所示的反应顺序方便地制备。
如方案I所示,通过酰化剂如草酰氯、SOCl2或POCl3等将酸A1(商购或按标准文献方法制得)转化为酰氯A2。使酰氯A2与取代的苯A3在路易斯酸如AlCl3或AlBr3的存在下反应得到酮A4。在路易斯酸如BF3·Et2O或TFA的存在下用还原剂如Et3SiH将中间体A4的酮基团选择性地还原为亚甲基。在合适的温度下于溶剂如THF中用活化剂如n-BuLi、s-BuLi或t-BuLi或Mg处理A5,然后加入到中间体A6中,得到中间体A7。在路易斯酸如BF3·Et2O或TFA的存在下用还原剂如Et3SiH处理A7,获得中间体A8。然后将A8氧化形成中间体A9,对其去保护得到本发明的化合物A10。或者,也可通过氧化中间体A9制备A11。
方案II的一般合成方法
本发明的式I化合物也可按如方案II(图2)所示的反应顺序常规地制 备。
如方案II所示,通过酰化剂如草酰氯、SOCl2或POCl3等将酸A12(商购或按标准文献方法制得)转化为酰氯A13。使酰氯A13与取代的苯A3在路易斯酸如AlCl3或AlBr3的存在下反应得到酮A14。在路易斯酸如BF3·Et2O或TFA的存在下用还原剂如Et3SiH将中间体A14的酮基团选择性地还原为亚甲基,然后去保护得到中间体A15。使A15与A16偶联,得到中间体A17。氧化A17得到中间体A18,然后对其去保护得到本发明的化合物A19。
药物组合物及使用方法
本发明还提供在药学上可接受的载体中包含有效量的式I化合物或式I化合物的混合物或其药学上可接受的盐或前药的药物组合物。
本发明的化合物可被引入到多种用于治疗性施用的制剂中。更特别地,本发明的化合物可一起或单独地通过与合适的药学上可接受的载体或稀释剂一起配制成药物组合物并可配制成固体、半固体、液体或气体形式的制剂如片剂、胶囊、丸剂、粉剂、颗粒、糖锭、凝胶、浆料、软膏、溶液、栓剂、注射剂、吸入剂和气雾剂。由此,本发明化合物的施用可以以多种方式实现,包括口服、经鼻、肠胃外、静脉内、皮内(如皮下、肌内)、透皮等施用。此外,所述化合物可以局部而非全身方式施用,例如以积存(depot)或持续释放制剂施用。
用于本发明的合适制剂见Remington:The Science and Practice of Pharmacy,21st Ed.,Gennaro,Ed.,Lippencott Williams & Wilkins(2003),其通过引用结合到本文中。本文中所述的药物组合物可以以本领域技术人员熟知的方式制备,即通过常规的混合、溶解、制粒、包糖衣、研磨、乳化、包封、截留(entrapping)或冻干工艺制备。下面的方法和赋形剂仅是示意性的而绝非限制性的。
在一个优选的实施方案中,本发明的化合物制备为以持续释放、控制释放、延长释放、定时释放或延迟释放制剂递送例如在固体疏水聚合物的半透性基体中包含治疗剂的制剂。各种类型的持续释放材料已确定并为本领域技术人员所熟知。目前的延长释放制剂包括包膜片剂、多微粒或丸粒 体系、采用亲水或亲脂材料的基体技术和含成孔赋形剂的蜡基片剂(参见例如Huang,et al.Drug Dev.Ind.Pharm.29:79(2003);Pearnchob,et al.Drug Dev.Ind.Pharm.29:925(2003);Maggi,et al.Eur.J.Pharm.Biopharm.55:99(2003);Khanvilkar,et al.,Drug Dev.Ind.Pharm.228:601(2002);和Schmidt,et al.,Int.J.Pharm.216:9(2001))。根据设计,持续释放递送体系可在数小时或数天的时间内释放化合物,例如在4、6、8、10、12、16、20、24小时或更长时间内。通常,持续释放制剂可使用天然或合成的聚合物来制备,所述聚合物例如为乙烯基吡咯烷酮类聚合物如聚乙烯基吡咯烷酮(PVP);羧乙烯基亲水聚合物;疏水和/或亲水水胶体如甲基纤维素、乙基纤维素、羟丙基纤维素和羟丙基甲基纤维素;和聚羧乙烯。
持续或延长释放制剂也可利用天然成分如矿物质来制备,所述矿物质包括二氧化钛、二氧化硅、氧化锌和粘土(参见美国专利6,638,521,通过引用结合到本文中)。可用于递送本发明化合物的示例性延长释放制剂包括美国专利6,635,680、6,624,200、6,613,361、6,613,358、6,596,308、6,589,563、6,562,375、6,548,084、6,541,020、6,537,579、6,528,080和6,524,621中描述的那些,这些专利各自通过引用结合到本文中。特别受关注的控制释放制剂包括美国专利6,607,751、6,599,529、6,569,463、6,565,883、6,482,440、6,403,597、6,319,919、6,150,354、6,080,736、5,672,356、5,472,704、5,445,829、5,312,817和5,296,483中描述的那些,这些专利各自通过引用结合到本文中。本领域技术人员将容易地想到其他适用的持续释放制剂。
对于口服给药,可通过结合本发明的化合物与本领域熟知的药学上可接受的载体容易地配制。这类载体使得所述化合物能够配制成片剂、丸剂、糖锭、胶囊、乳剂、亲脂和亲水混悬剂、液体、凝胶、糖浆、浆料、混悬剂等,以便待治疗的患者口服摄入。口服用的药物制剂可通过混合所述化合物与固体赋形剂,任选地研磨所得混合物并在根据需要加入合适的辅料后加工颗粒混合物以得到片剂或糖锭芯而获得。特别地,合适的赋形剂为填充剂如糖,包括乳糖、蔗糖、甘露糖醇或山梨糖醇;纤维素制剂如玉米淀粉、小麦淀粉、稻米淀粉、马铃薯淀粉、明胶、黄蓍树胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和/或聚乙烯基吡咯烷酮(PVP)。如果需要,可添加崩解剂如交联的聚乙烯基吡咯烷酮、琼脂或藻酸或其盐如藻酸钠。
可口服用的药物制剂包括由明胶制成的推入配合(push-fit)胶囊以及由明胶和增塑剂如甘油或山梨糖醇制成的密封软胶囊。推入配合胶囊可包含与填充剂如乳糖、粘合剂如淀粉和/或润滑剂如滑石或硬脂酸镁和任选的稳定剂混合的活性成分。在软胶囊中,活性化合物可溶解或悬浮在合适的液体如脂肪油、液体链烷烃或液体聚乙二醇中。此外,可添加稳定剂。所有用于口服给药的制剂均应具有适于这样给药的剂量。
糖锭芯具有适合的包衣。为此,可使用糖的浓溶液,其可任选包含阿拉伯树胶、滑石、聚乙烯基吡咯烷酮、卡波凝胶、聚乙二醇和/或二氧化钛、漆溶液和合适的有机溶剂或溶剂混合物。可向片剂或糖锭剂包衣中添加染料或颜料以识别或表征不同的活性化合物剂量组合。
该化合物可配制为通过注射如通过推注或连续输注来肠胃外给药。对于注射,可通过将化合物溶解、混悬或乳化在水性溶剂或非性水溶剂如植物油或其他类似的油、合成脂族酸甘油酯、高级脂族酸或丙二醇的酯中而将化合物配制成制剂,并且如果需要,可添加常规添加剂如增溶剂、等渗剂、悬浮剂、乳化剂、稳定剂和防腐剂。优选地,可以在水溶液中,优选在生理学相容的缓冲液如Hanks溶液、Ringer溶液或生理学盐水缓冲液中配制本发明的化合物。注射用制剂可以单位剂量形式提供,例如在安瓿中或在多剂量容器中,并添加防腐剂。组合物可采取例如在油性或水性载体中的混悬体、溶液或乳剂的形式,并可包含配方剂如悬浮剂、稳定剂和/或分散剂。
用于肠胃外给药的药物制剂包括水溶性形式的活性化合物的水溶液。此外,活性化合物的混悬体可制备为合适的油性注射混悬体。合适的亲脂性溶剂或载体包括脂肪油(如芝麻油)或合成脂肪酸酯(如油酸乙酯或甘油三酯)或脂质体。水性注射混悬体可包含提高混悬体粘度的物质如羧甲基纤维素钠、山梨糖醇或右旋糖苷。任选地,混悬体还可包含合适的稳定剂或提高化合物溶解度的试剂以制备高浓溶液。作为替代方案,活性成分可呈粉末形式以便在使用前用合适的载体如无菌无热原水配制。
也可通过透粘膜或透皮方式全身给药。对于透粘膜或透皮给药,制剂中使用适合待渗透的屏障的渗透剂。对于局部给药,试剂被配制成软膏、乳膏、药膏、粉末和凝胶。在一个实施方案中,透皮递送剂可为DMSO。透皮递送体系可包括例如贴剂。对于透粘膜给药,制剂中使用适合待渗透 的屏障的渗透剂。这样的渗透剂通常是本领域熟知的。可用于本发明中的示例性透皮递送制剂包括美国专利6,589,549、6,544,548、6,517,864、6,512,010、6,465,006、6,379,696、6,312,717和6,310,177中描述的那些,这些专利各自通过引用结合到本文中。
对于口腔给药,组合物可采取常规方式配制的片剂或锭剂的形式。
除前面描述的制剂之外,本发明的化合物还可配制为积存制剂。这样的长效制剂可通过植入(例如皮下或肌内)或通过肌内注射施用。因此,例如所述化合物可与合适的聚合物或疏水材料(例如以可接受油中的乳剂)或离子交换树脂一起配制或配制为微溶的衍生物例如微溶的盐。
药物组合物还可包含合适的固体或凝胶相载体或赋形剂。这类载体或赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖、淀粉、纤维素衍生物、明胶和聚合物如聚乙二醇。
适用于本发明的药物组合物包括其中包含治疗有效量的活性成分的组合物。本发明还涵盖包含式I化合物与有效量的作为联用药的其他治疗剂的药物组合物,其中所述其他治疗剂特别是用于治疗可能受SGLT抑制影响的疾病和病症的那些,例如抗糖尿病剂、降脂/调脂剂、用于治疗糖尿病并发症的试剂、减肥剂、抗高血压剂、抗高尿酸血症剂及用于治疗慢性心力衰竭、动脉粥样硬化或相关病症的试剂。所述化合物和/或联用药的有效量当然应取决于被治疗的对象、痛苦程度及给药方式。有效量的确定完全在本领域技术人员能力范围内,尤其是按照本文提供的详细公开内容。通常,化合物的有效量通过首先低剂量或少量施用、然后逐渐增加所施用的剂量直至从被治疗的对象身上观察到所希望的治疗效果并且毒副作用极小或无毒副作用来确定。为本发明的给药确定合适剂量及给药时间表的适用方法在例如Goodman and Gilman’s The Pharmacological Basis of Therapeutics,11th Ed.,Brunton,Lazo and Parker,Eds.,McGraw-Hill(2006)和Remington:The Science and Practice of Pharmacy,21st Ed.,Gennaro,Ed.,Lippencott Williams & Wilkins(2003)中描述,其二者均通过引用结合到本文中。
本发明还提供使用式I化合物预防和治疗疾病的方法。在一个实施方案中,本发明提供治疗1型和2型糖尿病、高血糖症、糖尿病并发症(如 视网膜病、肾病、神经病、溃疡、微血管和大血管病变、痛风及糖尿病足病)、胰岛素抵抗、代谢综合征(综合征X)、高胰岛素血症、高血压、高尿酸血症、肥胖症、浮肿、异常脂肪血症、慢性心力衰竭、动脉粥样硬化和相关疾病的方法,所述方法包括对需要其的对象施用有效量的式I化合物或式I化合物的混合物或其药学上可接受的盐或前药。在另一实施方案中,本发明提供使用式I化合物或式I化合物的混合物或其药学上可接受的盐或前药制备用于治疗1型和2型糖尿病、高血脂症、糖尿病并发症、胰岛素抵抗、代谢综合征、高胰岛素血症、高血压、高尿酸血症、肥胖症、浮肿、异常脂肪血症、慢性心力衰竭、动脉粥样硬化和相关疾病的药剂的方法。
本发明还涵盖式I化合物或其药学上可接受的盐或前药与其他治疗剂的联用,其中所述其他治疗剂特别是用于治疗上面提到的疾病和病症的那些,例如抗糖尿病剂、降脂/调脂剂、用于治疗糖尿病并发症的药剂、减肥剂、抗高血压剂、抗高尿酸血症剂及用于治疗慢性心力衰竭、动脉粥样硬化或相关病症的药剂。本领域技术人员会认识到,下面讨论的其他治疗剂可具有多种治疗用途,而且将药剂罗列在一个特定类别中不应被理解为以任何方式限制其在与本发明化合物的联合疗法中的有用性。
适于与本发明的化合物联用的抗糖尿病剂的实例包括胰岛素和胰岛素模拟物、磺酰脲(如醋磺己脲、氨磺丁脲、氯磺丙脲、格列本脲、格列波脲、格列齐特、谷胱甘肽、格列甲嗪、格列喹酮、格列派特、格列本脲、格列吡脲、妥拉磺脲、甲磺环己脲、甲苯磺丁脲等)、胰岛素分泌促进剂(如JTT-608、格列丁唑等)、双胍(如二甲双胍、丁双胍、苯乙双胍等)、磺酰脲/双胍组合(如格列本脲/二甲双胍等)、氯茴苯酸(如瑞格列奈、那格列奈、米格列奈等)、噻唑烷二酮(如罗格列酮、吡格列酮、伊沙列酮、萘格列酮、利格列酮、巴格列酮、达格列酮、CLX-0921等)、噻唑烷二酮/双胍组合(如吡格列酮/二甲双胍等)、 二唑烷二酮(如YM440等)、过氧化物酶体增殖物激活受体(PPAR)-γ激动剂(如法格列酮、metaglidasen、MBX-2044、GI262570、GW1929、GW7845等)、PPAR-α/γ双重激动剂(如莫格列扎(muraglitazar)、那格列扎(naveglitazar)、替格列扎(tesaglitazar)、培利格列扎(peliglitazar)、JTT-501、GW-409544、GW-501516等)、PPAR-α/γ/δ泛激动剂(如PLX204、GlaxoSmithKline 625019、GlaxoSmithKline 677954等)、类维生素A X受体激动剂(如ALRT-268、AGN-4204、MX-6054、 AGN-194204、LG-100754、蓓萨罗丁等)、α-葡糖苷酶抑制剂(如阿卡波糖、米格列醇等)、胰岛素受体酪氨酸激酶兴奋剂(如TER-17411、L-783281、KRX-613等)、三肽基肽酶II抑制剂(如UCL-1397等)、二肽基肽酶IV抑制剂(如西他列汀、维达列汀、地那列汀、沙格列汀、NVP-DPP728、P93/01、P32/98、FE 99901、TS-021、TSL-225、GRC8200、美国专利6,869,947、6,727,261、6,710,040、6,432,969、6,172,081、6,011,155中描述的化合物等)、蛋白酪氨酸磷酸酶-1B抑制剂(如KR61639、IDD-3、PTP-3848、PTP-112、OC-86839、PNU-177496、Vats,R.K.,et al.,Current Science,Vol.88,No.2,2005年1月25日,第241-249页中描述的化合物等)、糖原磷酸化酶抑制剂(如NN-4201、CP-368296等)、葡萄糖-6-磷酸酶抑制剂、果糖1,6-二磷酸酶抑制剂(如CS-917、MB05032等)、丙酮酸脱氢酶抑制剂(如AZD-7545等)、咪唑啉衍生物(如BL11282等)、肝糖异生抑制剂(如FR-225659等)、D-手性肌醇、糖原合成酶激酶-3抑制剂(如Vats,R.K.,et al.,Current Science,Vol.88,No.2,2005年1月25日,第241-249页中描述的化合物等)、肠降血糖模拟物(如艾塞那肽(exenatide)等)、胰高血糖素受体拮抗剂(如BAY-27-9955、NN-2501、NNC-92-1687等)、胰高血糖素样肽-1(GLP-1)、GLP-1类似物(如利拉鲁肽、CJC-1131、AVE-0100等)、GLP-1受体激动剂(如AZM-134、LY-315902、GlaxoSmithKline 716155等)、amylin、amylin类似物和激动剂(如普兰林肽等)、脂肪酸结合蛋白(aP2)抑制剂(如美国专利6,984,645、6,919,323、6,670,380、6,649,622、6,548,529中描述的化合物等)、β-3肾上腺素能受体激动剂(如索拉勃隆(solabegron)、CL-316243、L-771047、FR-149175等)和其他胰岛素增敏剂(如reglixane、ONO-5816,MBX-102,CRE-1625,FK-614,CLX-0901,CRE-1633,NN-2344,BM-13125,BM-501050,HQL-975,CLX-0900,MBX-668,MBX-675,S-15261,GW-544,AZ-242,LY-510929,AR-H049020,GW-501516等)。
适于与本发明的化合物联用以治疗糖尿病并发症的试剂的实例包括醛糖还原酶抑制剂(如依帕司他、咪瑞司他、托瑞司他、米那司他、泊那司他、唑泊司他、非达司他、维C加莫酯、ADN-138、BAL-ARI8、ZD-5522、ADN-311、GP-1447、IDD-598、利沙司他、折那司他、甲索比尼尔、AL-1567、M-16209、TAT、AD-5467、AS-3201、NZ-314、SG-210、JTT-811、lindolrestat、索比尼尔等)、晚期糖基化终产物(AGE)形成抑制剂(如吡哆胺、OPB-9195、ALT-946、ALT-711、匹马吉定等)、AGE裂解剂(如ALT-711等)、舒洛地 特、5-羟基-1-甲基海因、胰岛素样生长因子-I、血小板衍生生长因子、血小板衍生生长因子类似物、表皮生长因子、神经生长因子、尿核苷、蛋白激酶C抑制剂(如鲁伯斯格(ruboxistaurin)、米哚妥林(midostaurin)等)、钠通道拮抗剂(如美西律、奥卡西平等)、核因子-kappaB(NF-kappaB)抑制剂(如dexlipotam等)、脂质过氧化物酶抑制剂(如甲磺酸替拉扎特等)、N-乙酰化-α-连接-酸二肽酶抑制剂(如GPI-5232、GPI-5693等)和肉碱衍生物(如肉碱、乙酰左旋肉碱、左旋肉碱、ST-261等)。
适于与本发明的化合物联用的抗高尿酸血症剂的实例包括尿酸合成抑制剂(如别嘌呤醇、奥昔嘌醇等)、促尿酸尿剂(如丙磺舒、磺吡酮、苯溴马隆等)和尿碱化剂(如碳酸氢钠、柠檬酸钾、柠檬酸钠等)。
适于与本发明的化合物联用的降脂/调脂剂的实例包括羟甲基戊二酰辅酶A还原酶抑制剂(如阿昔替酯、阿伐他汀、柏伐他汀、carvastatin、西伐他汀、考来酮、克伐他汀、达伐他汀、氟伐他汀、格仑伐他汀、洛伐他汀、美伐他汀、尼伐他汀、匹伐他汀、普伐他汀、利托那韦、瑞舒伐他汀、沙喹那韦、辛伐他汀、visastatin、SC-45355、SQ-33600、CP-83101、BB-476、L-669262、S-2468、DMP-565、U-20685、BMS-180431、BMY-21950、美国专利5,753,675、5,691,322、5,506,219、4,686,237、4,647,576、4,613,610、4,499,289中描述的化合物等)、纤维酸衍生物(如吉非罗齐、非诺贝特、苯扎贝特、苄氯贝特、比尼贝特、环丙贝特、克利贝特、氯贝特、依托贝特、尼可贝特、吡贝特、氯烟贝特、双贝特、羟乙茶碱安妥明、AHL-157等)、PPAR-α激动剂(如GlaxoSmithKline 590735等)、PPAR-δ激动剂(如GlaxoSmithKline 501516等)、酰基-辅酶A:胆固醇酰基转移酶抑制剂(如阿伐麦布、依鲁麦布、依达麦布、来西贝特、NTE-122、MCC-147、PD-132301-2、C1-1011、DUP-129、U-73482、U-76807、TS-962、RP-70676、P-06139、CP-113818、RP-73163、FR-129169、FY-038、EAB-309、KY-455、LS-3115、FR-145237、T-2591、J-104127、R-755、FCE-27677、FCE-28654、YIC-C8-434、CI-976、RP-64477、F-1394、CS-505、CL-283546、YM-17E、447C88、YM-750、E-5324、KW-3033、HL-004等)、普罗布可、甲状腺激素受体激动剂(如碘塞罗宁、左甲状腺素、KB-2611、GC-1等)、胆固醇吸收抑制剂(如依折麦布、SCH48461等)、脂蛋白相关磷脂酶A2抑制剂(如瑞拉帕地(rilapladib)、darapladib等)、微粒体甘油三酯转移蛋白抑制剂(如CP-346086、BMS-201038、美国专利5,595,872、5,739,135、5,712,279、 5,760,246、5,827,875、5,885,983、5,962,440、6,197,798、6,617,325、6,821,967、6,878,707中描述的化合物等)、低密度脂蛋白受体活化剂(如LY295427、MD-700等)、脂氧合酶抑制剂(如WO 97/12615、WO 97/12613、WO96/38144中描述的化合物等)、肉碱棕榈酰转移酶抑制剂(如乙莫克舍等)、角鲨烯合成酶抑制剂(如YM-53601、TAK-475、SDZ-268-198、BMS-188494、A-87049、RPR-101821、ZD-9720、RPR-107393、ER-27856、美国专利5,712,396、4,924,024、4,871,721中描述的化合物等)、烟酸衍生物(如阿西莫司、尼克酸、烟酰胺、尼可莫尔、戊四烟酯、尼可地尔等)、胆汁酸螯合剂(如考来替泼、消胆胺、考来替兰、考来维仑、GT-102-279等)、钠/胆汁酸共转运体抑制剂(如264W94、S-8921、SD-5613等)和胆固醇酯转移蛋白抑制剂(如托塞匹布(torcetrapib)、JTT-705、PNU-107368E、SC-795、CP-529414等)。
适于与本发明的化合物联用的减肥剂的实例包括五羟色胺-去甲肾上腺素再摄取抑制剂(如西布曲明、米那普伦、米氮平、文拉法辛、度洛西汀、去甲文拉法辛等)、去甲肾上腺素-多巴胺再摄取抑制剂(如radafaxine、安非他酮、阿米庚酸等)、五羟色胺-去甲肾上腺素-多巴胺再摄取抑制剂(如特索芬辛等)、选择性五羟色胺再摄取抑制剂(如西酞普兰、艾司西酞普兰、氟西汀、氟伏沙明、帕罗西汀、舍曲林等)、选择性去甲肾上腺素再摄取抑制剂(如瑞波西汀、托莫西汀等)、去甲肾上腺素释放兴奋剂(如咯利普兰、YM-992等)、食欲抑制剂(如安非他明、甲基安非他明、右旋安非他明、芬特明、苄非他明、苯甲曲秦、芬美曲秦、安非拉酮、氯苯咪吲哚、芬氟拉明、右芬氟拉明、苯丙醇胺等)、多巴胺激动剂(如ER-230、doprexin、甲磺酸溴隐亭等)、H3-组胺拮抗剂(如impentamine、硫丙咪胺、ciproxifan、clobenpropit、GT-2331、GT-2394、A-331440等)、5-HT2c受体激动剂(如1-(间-氯苯基)哌嗪(m-CPP)、米氮平、APD-356(绿卡色林(lorcaserin))、SCA-136(戊卡色林)、ORG-12962、ORG-37684、ORG-36262、ORG-8484、Ro-60-175、Ro-60-0332、VER-3323、VER-5593、VER-5384、VER-8775、LY-448100、WAY-161503、WAY-470、WAY-163909、MK-212、BVT.933、YM-348、IL-639,IK-264、ATH-88651、ATHX-105等(参见例如Nilsson BM,J.Med.Chem.2006,49:4023-4034))、β-3肾上腺素能受体激动剂(如L-796568、CGP 12177、BRL-28410、SR-58611A、ICI-198157、ZD-2079、BMS-194449、BRL-37344、CP-331679、CP-331648、CP-114271、L-750355、 BMS-187413、SR-59062A、BMS-210285、LY-377604、SWR-0342SA、AZ-40140、SB-226552、D-7114、BRL-35135、FR-149175、BRL-26830A、CL-316243、AJ-9677、GW-427353、N-5984、GW-2696等)、胆囊收缩素激动剂(如SR-146131、SSR-125180、BP-3.200、A-71623、A-71378、FPL-15849、GI-248573、GW-7178、GI-181771、GW-7854、GW-5823等)、抗抑郁剂/乙酰胆碱酯酶抑制剂组合(如文拉法新/卡巴拉汀、舍曲林/加兰他敏等)、脂肪酶抑制剂(如奥利司他、ATL-962等)、抗癫痫剂(如托吡酯、唑尼沙胺等)、瘦素、瘦素类似物和瘦素受体激动剂(如LY-355101等)、神经肽Y(NPY)受体拮抗剂和调节剂(如SR-120819-A、PD-160170、NGD-95-1、BIBP-3226、1229-U-91、CGP-71683、BIBO-3304、CP-671906-01、J-115814等)、睫状神经营养因子(如阿索开(Axokine)等)、甲状腺激素受体-β激动剂(如KB-141、GC-1、GC-24、GB98/284425等)、大麻素CB1受体拮抗剂(如利莫那班、SR147778、SLV 319等(参见例如Antel J et al.,J.Med.Chem.2006,49:4008-4016))、黑色素浓集激素受体拮抗剂(如GlaxoSmithKline 803430X、GlaxoSmithKline 856464、SNAP-7941、T-226296等(参见例如Handlon AL and Zhou H,J.Med.Chem.2006,49:4017-4022))、黑素皮质素-4受体激动剂(包括PT-15、Ro27-3225、THIQ、NBI 55886、NBI 56297、NBI 56453、NBI 58702、NBI 58704、MB243等(参见例如Nargund RP et al.,J.Med.Chem.2006,49:4035-4043))、选择性毒蕈碱型受体M1拮抗剂(如替仑西平、哌仑西平等)、阿片受体拮抗剂(如纳曲酮、甲基纳曲酮、纳美芬、纳洛酮、爱维莫潘、norbinaltorphimine、纳洛芬等)及其组合。
适于与本发明的化合物联用的抗高血压剂和治疗慢性心力衰竭、动脉粥样硬化或相关疾病的试剂的实例包括氯吡哌醇、血管紧张素转化酶抑制剂(如卡托普利、依那普利、福辛普利、赖诺普利、培哚普利、喹那普利、雷米普利等)、中性内肽酶抑制剂(如塞奥芬(thiorphan)、奥帕曲拉(omapatrilat)、MDL-100240、法西多曲、山帕曲拉、GW-660511、mixanpril、SA-7060、E-4030、SLV-306、依卡曲尔等)、血管紧缩素II受体拮抗剂(如坎地沙坦西来替昔酯、依普沙坦、厄贝沙坦、洛沙坦、奥美沙坦酯、替米沙坦、缬沙坦、他索沙坦、enoltasosartan等)、内皮素转换酶抑制剂(如CGS 35066、CGS 26303、CGS-31447、SM-19712等)、内皮素受体拮抗剂(如全可利、西他生坦、安贝生坦、L-749805、TBC-3214、BMS-182874、BQ-610、TA-0201、SB-215355、PD-180988、BMS-193884、达卢生坦、 TBC-3711、波生坦、替唑生坦、J-104132、YM-598、S-0139、SB-234551、RPR-118031A、ATZ-1993、RO-61-1790、ABT-546、恩拉生坦、BMS-207940等)、利尿剂(如双氢氯噻嗪、苄氟噻嗪、三氯噻嗪、吲达帕胺、美托拉宗、呋喃苯胺酸、布美他尼、托拉塞米、氯噻酮、美托拉宗、环戊噻嗪、氢氟甲噻嗪、曲帕胺、美夫西特、苄氢氯噻嗪、戊氟噻嗪、甲氯噻嗪、阿佐酰胺、依他尼酸、托拉塞米、吡咯他尼、美替克仑、坎利酸钾、螺内酯、氨苯蝶啶、氨茶碱、西氯他宁、LLU-α、PNU-80873A、异山梨醇、D-甘露醇、D-山梨糖醇、果糖、甘油、乙酰唑胺、醋甲唑胺、FR-179544、OPC-31260、利昔伐坦、考尼伐坦等)、钙通道拮抗剂(如氨氯地平、苄普地尔、地尔硫卓、非洛地平、依拉地平、尼卡地平、尼莫地平、维拉帕米、S-维拉帕米、阿雷地平、依福地平、巴尼地平、贝尼地平、马尼地平、西尼地平、尼索地平、尼群地平、硝苯地平、尼伐地平、费乐地平、普拉地平、乐卡地平、依拉地平、依高地平、阿折地平、拉西地平、伐尼地平、来米地平、地尔硫卓、克仑硫卓、法舒地尔、苄普地尔、戈洛帕米等)、引起血管舒张的抗高血压剂(如吲达帕胺、托屈嗪、肼屈嗪、卡屈嗪、布屈嗪等)、β阻断剂(如醋丁洛尔、比索洛尔、艾司洛尔、普萘洛尔、阿替洛尔、拉贝洛尔、卡维地洛、美托洛尔等)、交感神经阻断剂(如氨磺洛尔、特拉唑嗪、布那唑嗪、哌唑嗪、多沙唑嗪、普萘洛尔、阿替洛尔、美托洛尔、卡维地洛、尼普洛尔、塞利洛尔、奈比洛尔、倍他洛尔、吲哚洛尔、特他洛尔、贝凡洛尔、噻吗洛尔、卡替洛尔、比索洛尔、波吲洛尔、尼普洛尔、喷布洛尔、醋丁洛尔、替利洛尔、纳多洛尔、乌拉地尔、吲哚拉明等)、α-2-肾上腺素受体激动剂(如可乐定、甲基多巴、CHF-1035、醋酸胍那苄、胍法辛、莫索尼定、洛非西定、他利克索等)、作用于中枢的抗高血压剂(如利血平等)、血小板聚集抑制剂(如华法林、双香豆素、苯丙香豆素、醋硝香豆素、茴茚二酮、苯茚二酮、希美加群等)和抗血小板剂(如阿司匹林、氯吡格雷、氯苄匹啶、双嘧达莫、西咯他唑、二十碳五烯酸乙酯、沙格雷酯、地拉齐普、曲匹地尔、贝前列素等)。
此外,在另一方面,本发明提供在药学上可接受的载体中包含有效量的式I化合物或式I化合物的混合物或其药学上可接受的盐或前药和选自上文作为联用药所列治疗剂中的至少一种的药物组合物。
本发明的治疗法可预防性地施用以预防或延迟疾病或病症(如高血糖症)的开始或发展或治疗性地施用以持续获得所需效果(如所需的血清葡 萄糖水平)较长时间。
本发明的化合物可单独地或与联用药一起作为其药学上可接受的盐或前药或作为药物组合物以治疗有效量施用给对象如患者、家养动物如猫或狗,其中所述化合物和/或联用药与合适的载体或赋形剂混合。因此,式I化合物或式I化合物的混合物或其药学上可接受的盐或前药和待与之联用的其他活性剂可存在于单种制剂如胶囊或片剂中或存在于两种单独的制剂中,所述两种单独的制剂可相同或不同,例如以包含选定剂量的各试剂的试剂盒的形式。
化合物的合适剂量将根据所选的给药途径、组合物的配方及其他因素如患者的应答而变化。可根据个体患者的需要随时间增减剂量。最初可给予患者低剂量,然后增至患者可耐受的有效剂量。通常,当通过口服途径给药时,成人的适用剂量可以为1-2000mg、优选1-200mg,当通过静脉内途径给药时,为0.1-100mg、优选1-30mg,每种情况下均每天施用1-4次。当本发明的化合物与另一治疗剂联合给药时,联用药的适用剂量可以为通常推荐剂量的20%到100%。
剂量和时间间隔可根据个体加以调节以提供足以保持治疗效果的血浆的活性化合物水平。优选通过每日单剂量给药达到治疗有效的血清水平,但有效的每日多剂量方案也涵盖在本发明中。在局部给药或选择性摄取的情况下,药物的有效局部浓度可以与血浆浓度无关。本领域技术人员无需过度实验即能优化治疗有效的局部剂量。
本说明书中引用的所有公开和专利申请均通过引用结合到本文中,如同将每一个别公开或专利申请特定且个别地通过引用结合到本文中一样。本文中引用的任何参考文献与本说明书的公开内容之间存在任何冲突时,以后者为准。同样,在字词或术语的业内公认定义与本说明书中提供的字词或术语定义之间存在任何冲突时,以后者为准。虽然为清晰理解的目的通过示意和实施例的方式相当详细地描述了本发明,但可对其作某些改变和修改而不偏离所随的权利要求书的精神或范围,这对于本领域技术人员来说将是显而易见的。下面通过特定实施例更详细地描述本发明。
实施例
下面的实施例为示意的目的提供,而非意在以任何方式限制本发明。本领域技术人员将容易地找出多个非关键参数,这些参数可被改变或修改但产生基本相同的结果。
下面的实施例中所示化合物的名称根据ChemDraw Ultra 10.0版本中所采用的CambridgeSoft Struct=Name算法所示的结构得到。除非另有指出,否则下面实施例中合成的化合物的结构用如下程序确认:
(1)利用装配有Agilent 6890气相色谱仪和HP-5MS柱(0.25μm涂层;30m×0.25mm)的Agilent 5973N质谱仪得到气相色谱-电喷雾电离质谱(MS ESI)。离子源保持在230℃下,按3.09秒每次扫描从25-500amu扫描谱图。
(2)利用装配有四元泵、设置在254nm的可变波长检测器、XB-C18柱(4.6×50mm,5μm)和Finnigan LCQ电喷雾电离离子阱质谱仪的Finnigan Surveyor HPLC得到高压液相色谱质谱(LC-MS)。根据源中的离子数采用可变离子时间从80-2000amu扫描谱图。洗脱剂为B:乙腈和D:水。以1.0mL/min的流量实施10%到90%的B梯度洗脱达8分钟,最后在90%的B下保持7分钟。总运行时间为15分钟。
(3)在400MHz或300MHz Varian Mercury-Plus光谱仪上进行常规一维NMR谱。将样品溶解在得自Qingdao Tenglong Weibo Technology Co.,Ltd.的氘代溶剂中并转移至5mm ID的NMR管中。在293K下获得谱图。以ppm记录化学位移并以合适的溶剂信号为基准,例如对于1H谱图DMSO-d6为2.49ppm、CD3CN为1.93ppm、CD3OD为3.30ppm、CD2Cl2为5.32ppm、CDCl3为7.26ppm。
实施例1
本实施例示意按图3中给出的方法制备化合物5(R=Et)。化合物编号与图中给出的那些相对应。该一般方法适用于本发明的其他化合物。
(1R,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-乙基苄基)苯基)-6-(羟甲基)环己烷-1,2,3,5-四醇的制备
(1)格氏试剂的制备
在氩气中向三颈烧瓶中装入Mg粉(0.216g,8.98mmol,1.2eq),然后加入一部分4-溴-1-氯-2-(4-乙基苄基)苯8(0.769g,2.49mmol)在无水THF(6mL)中的溶液和1,2-二溴乙烷(10%摩尔)。将混合物加热至回流。反应开始(放热并消耗Mg)后,逐滴加入剩余的2-(4-乙基苄基)-4-溴-1-氯苯8(1.539g,4.99mmol)在无水THF(14mL)中的溶液。然后使混合物在温和回流下再反应一小时直至大多数Mg被消耗。
(2)2的制备
在室温(约25℃)和氩气下向(4R,5S,6R)-4,5,6-三(苄氧基)-3-(苄氧基甲基)环己-2-烯酮1(2g,3.74mmol,1eq)/无水THF(20mL)溶液中逐滴加入上面的格氏试剂,然后使其反应3小时。向混合物中加入NH4Cl(饱和水溶液)以终止反应。用乙酸乙酯(20mL×3)萃取混合物,用盐水洗涤有机层,用Na2SO4干燥,过滤,将滤液蒸发至干。用硅胶色谱(洗脱剂为石油醚∶乙酸乙酯=20∶1)纯化残余物,得到目标化合物2的黄色油(2.428g,3.17mmol,产率84.8%)。1H-NMR(400MHz,CDCl3):δ7.42(1H,s),7.28-7.41(17H,m),7.04-7.254(8H,m),5.83(1H,s),4.74(1H,d,J=11.2Hz),4.39-4.64(7H,m),4.33(1H,d,J=12.4Hz),4.23(1H,s),4.08(2H,s),4.03(1H,d,J=12.8Hz),3.70-3.73(2H,m),2.93(1H,s),2.58(2H,q,J=7.6Hz),1.19(3H,t,J=7.6Hz);MS(ESI+):765[M+H]+,782[M+H2O]+,787[M+Na]+。
(3)3(R=Et)的制备
于氩气和-20℃下向2(1.9g,2.48mmol,1eq)在CH2Cl2中的溶液中依次加入三乙基甲硅烷(1mL,7.44mmol,3eq)和三氟化硼合乙醚(0.44mL,4.96mmol,2eq),然后使其保持-20℃的温度反应4小时。加入NaCl(饱和水溶液)以终止反应。用CH2Cl2(20mL×3)萃取混合物,用盐水洗涤有机层,用Na2SO4干燥,过滤,将滤液蒸发至干。用硅胶色谱(洗脱剂为石油醚∶乙酸乙酯=20∶1)纯化残余物,得到目标化合物的黄色油(1.67g,2.23mmol,89.9%)。1H-NMR(400MHz,CDCl3):δ7.26-7.40(16H,m),7.15-7.25(7H,m),7.04-7.06(4H,m),6.85-6.87(2H,m),5.89(1H,s),4.85-4.98(3H,m),4.75-4.77(1H,m),4.45-4.56(4H,m),4.32(1H,d,J=10.8Hz),3.97-4.09(4H,m),3.74(1H,t,J=10.4Hz),3.62-3.65(1H,m),3.54-3.57(1H,m),2.63-2.71(1H,m),2.59(2H,q,J=7.6Hz),1.21(3H,t,J=7.6Hz);MS(ESI+)749[M+H]+,766[M+H2O]+。
(4)4(R=Et)的制备
于氩气和0℃下向3(250mg,0.334mmol,1eq)在无水THF(10mL)中的溶液中加入硼烷-二甲硫醚配合物(在THF中的2M溶液)(1.678mL,3.34mmol,10eq),然后温热回流1小时。在0℃下用NaOH(3M水溶液,1mL,3.34mmol,10eq)处理混合物,然后在室温(高于30℃)下用30%的H2O2(0.11mL,3.34mmol,10eq)处理,并使其在室温(~25℃)下反应过夜。向混合物中加入NH4Cl(饱和水溶液)以终止反应。用乙酸乙酯(10mL×3)萃取混合 物,用盐水洗涤有机层,用Na2SO4干燥,过滤,将滤液蒸发至干。用制备TLC纯化残余物,得到目标化合物4的白色固体(108.8mg,0.142mmol,42.5%)。1H-NMR(400MHz,CDCl3)δ7.29-7.40(15H,m),7.12-7.24(7H,m),7.03-7.07(4H,m),6.74(2H,d,J=6.8Hz),4.94(1H,d,J=10.8Hz),4.91(2H,s),4.46-4.58(4H,m),4.01-4.13(2H,m),3.83-3.93(3H,m),3.68-3.73(2H,m),3.52-3.62(2H,m),2.74(1H,t,J=10.8Hz),2.59(2H,q,J=7.6Hz),1.89-1.96(1H,m),1.19(3H,t,J=7.6Hz);MS(ESI+)767[M+H]+,784[M+H2O]+,789[M+Na]+。
(5)5(R=Et)的制备
将4(12mg,1.57×10-2mmol,1eq)/THF∶CH3OH=2∶1(9mL)溶液用1,2-二氯苯(1%摩尔)和Pd/C(含量10%,12mg,100%质量级)处理并在H2气氛和室温(高于30℃)下搅拌2小时。用LC-MS监测反应以确认反应完成。过滤混合物,将滤液蒸发至干。用制备HPLC纯化残余物,得到呈白色固体的目标化合物5(2.82mg,0.69×10-2mmol,产率43.9%)。1H-NMR(400MHz,CD3OD)δ7.33(1H,d,J=8.0Hz),7.07-7.17(6H,m),4.05(2H,s),3.91(2H,d,J=3.2Hz),3.65(1H,t,J=10.4Hz),3.39-3.49(2H,m),3.31(1H,t,J=8.8Hz),2.51-2.62(3H,m),2.53(1H,m),1.19(3H,t,J=8.0Hz);MS(ESI+):407[M+H]+,424[M+NH4]+,448[M+H+CH3CN]+,813[2M+H]+,(ESI-):405[M-H]-,451[M+HCOO]-。
下面的工艺由US 2006/0063722 A1中公开的程序修改而来。
(6)(5-溴-2-氯苯基)(4-乙基苯基)甲酮7的制备
向含有磁力搅拌下的市售5-溴-2-氯苯甲酸(410g,1.74mol)/700mLCH2Cl2混悬体的2L圆底烧瓶中加入草酰氯(235g,1.85mol),然后加入1.5mL的DMF。为截留所产生的HCl,为该烧瓶装配管以便气体在搅拌着的KOH水溶液的表面上方排出。当两小时后气体的急剧放出停止时,将均匀反应混合物搅拌过夜,然后用旋转蒸发器真空移除挥发物。所得的油在随后的抽空过程中凝固。在将粗5-溴-2-氯苯甲酰氯溶解在530mL乙苯中后,将黄色溶液冷却至-3℃,然后以约30g为一份逐份加入AlCl3(257g,1.93mol),60分钟加完,以确保温度不超过10℃。在加入60%的AlCl3后开始放出的大量HCl气体因通入搅拌着的浓NaOH溶液中而被截留。如果反应混合物更浓缩,则磁力搅拌可能已不能保持搅拌到完成AlCl3的加入。搅拌1小时(同时浴温热至~15℃)后,将浴移开。在20℃下4小时后,将稠浆倒到冰(1.5kg)上。随后,在搅拌着的混悬体冷却后加入H2O(1L),然后用1N HCl萃取四次、用1M KOH萃取三次并用盐水萃取两次,再用Na2SO4干燥。先用旋转蒸发器、再通过在1托下于60℃加热来移除挥发物。所得深色油的1H-NMR分析表明,残余物为邻位/对位异构体的1∶14混合物。溶解在己烷中并随后通过硅胶垫过滤即去除大部分颜色。浓缩洗脱液得到560g产物((5-溴-2-氯苯基)(4-乙基苯基)甲酮/(5-溴-2-氯苯基)(2-乙基苯基)甲酮的14∶1混合物的99%)。
(7)4-溴-1-氯-2-(4-乙基苄基)苯8的制备
在30℃下向搅拌着的Et3SiH(400g,3.45mol)和含~7%异构酮的(5-溴-2-氯苯基)(4-乙基苯基)甲酮(534g,1.65mol)在300mL TFA的溶液中加入CF3SO3H(1.5g,0.01mol)。数分钟内温度升高,致使溶液剧烈回流。注意: 此中等放热需要用外部冰浴冷却。1小时后,HPLC表明反应完成90%。加入另外的Et3SiH(20g)并于70℃加热过夜后,HPLC分析表明反应完成>95%。冷却后通过减压球-球蒸馏除去挥发物。将所得~1L浅灰色油倒入1L H2O中。混合物用己烷萃取三次,用H2O洗涤合并的有机层三次、用Na2CO3水溶液洗涤两次、用盐水洗涤两次,再用Na2SO4干燥。使用旋转蒸发器浓缩后,留下~1L澄清的亮琥珀色油。该物质经进一步浓缩,蒸馏除去(Et3Si)2O(450mL)直至蒸馏头温度达到75℃,使残余物冷却。残余物的1H NMR分析表明其含二芳基甲烷与(Et3Si)2O的~8∶1混合物。将产物倒到剧烈搅拌着的85%EtOH∶H2O(1.2L)的冷(10℃)混合物中使该混合物结晶。搅拌数小时后,过滤收集晶体,用冷的1∶1的EtOH/H2O洗涤并真空干燥。得到含~1%(Et3Si)2O的低熔点固体4-溴-1-氯-2-(4-乙基苄基)苯(500g),其在使用前不经进一步纯化。
实施例2
本实施例示意(1R,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-乙氧基苄基)苯基)-6-(羟甲基)环己烷-1,2,3,5-四醇(9)的制备。
化合物9按与实施例1中所述类似的方法制备:H1-NMR(400MHz,CD3OD):δ7.32(1H,d,J=8.0),7.11-7.16(4H,m),6.79(2H,d,J=6.8Hz),3.96-4.02(4H,m),3.91(1H,d,J=3.2Hz),3.63(1H,t,J=10.4Hz),3.39-3.47(2H,m),3.32(1H,t,J=8.8Hz),2.54(1H,t,J=10.4Hz),1.53(1H,tt,J=3.2,10.4Hz),1.36(3H,t,J=7.2Hz);MS(ESI+):423[M+H]+,440[M+NH4]+,845[2M+H]+,862[2M+NH4]+,(ESI-):467[M+HCOO]-。
实施例3
本实施例示意(1R,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-环丙基苄基)苯基)-6-(羟甲基)环己烷-1,2,3,5-四醇(10)的制备。
化合物10按与实施例1中所述类似的方法制备:1H NMR(400MHz,CDCl3):δ7.33(1H,d,J=8.0Hz),7.16-7.12(2H,m),7.09(2H,d,J=8.0Hz),6.96(2H,d,J=8.0Hz),4.04(2H,s),3.91(2H,d,J=3.2Hz),3.65(1H,t,J=10.6Hz),3.48(1H,t,J=10.0Hz),3.42(1H,t,J=10.0Hz),3.32(1H,t,J=9.0Hz),2.54(1H,t,J=10.8Hz),1.87-1.82(1H,m),1.57-1.51(1H,m,),0.94-0.89(2H,m),0.64-0.60(2H,m);MS(ESI+):419[M+H]+,436[M+NH4]+。
实施例4
本实施例示意(1R,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-丙基苄基)苯基)-6-(羟甲基)环己烷-1,2,3,5-四醇(11)的制备。
化合物11按与实施例1中所述类似的方法制备:1H NMR(400MHz,CDCl3):δ7.35(1H,d,J=8.4Hz),7.20(1H,d,J=1.6Hz),7.16-7.13(3H,m),7.08(2H,d,J=8.0Hz),4.07(2H,s),3.93(2H,d,J=3.2Hz),3.67(1H,t,J=10.4Hz),3.49(1H,t,J=10.4Hz),3.43(1H,t,J=10.4Hz),3.33(1H,t,J=9.0Hz),2.58-2.53(3H,m),1.67-1.58(2H,m),1.58-1.52(1H,m),0.94(3H,t,J=7.2Hz);MS(ESI+):438[M+NH4]+。
实施例5
本实施例示意(1R,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-环己基苄基)苯基)-6-(羟甲基)环己烷-1,2,3,5-四醇(12)的制备。
化合物12按与实施例1中所述类似的方法制备:1H NMR(400MHz,CDCl3):δ7.34(1H,d,J=8.0Hz),7.19(1H,d,J=2.0Hz),7.15-7.12(3H,m),7.09(2H,d,J=8.4Hz),4.05(2H,s),3.92(2H,d,J=3.2Hz),3.66(1H,t,J=10.6Hz),3.48(1H,t,J=10.0Hz),3.43(1H,t,J=10.2Hz),3.32(1H,t,J=9.0Hz),2.55(1H,t,J=10.6Hz),2.48-2.42(1H,m),1.84-1.81(4H,m),1.76-1.73(1H,m),1.57-1.50(1H,m),1.47-1.36(4H,m),1.34-1.22(1H,m);MS(ESI+):478[M+NH4]+。
实施例6
本实施例示意(1R,2S,3S,6R)-4-(4-氯-3-(4-(3-环丙基丙-2-炔氧基)苄基)苯基)-6-(羟甲基)环己-4-烯-1,2,3-三醇(13)的制备。
1H-NMR(400MHz,CD3OD):δ7.27-7.31(2H,m),7.20-7.23(1H,m),7.09(2H,d,J=8.8Hz),6.82-6.84(2H,m),5.83-5.84(1H,m),4.02(2H,dd,J=14.8Hz),3.83-3.86(1H,m),3.48-3.65(3H,m),2.36(1H,b),0.72-0.77(2H,m),0.57-0.60(2H,m);MS(ESI+):472[M+NH4]+,479[M+Na]+,(ESI-):499[M+HCOO]-。
实施例7
本实施例说明采用图4中概述的合成方法制备(2S,3S,4R,5R,6R)-2-(4-氯-3-(4-乙基苄基)苯基)-3,4,5-三羟基-6-(羟甲基)环己酮(15)。
0℃下向(1R,2S,3R,4R,5S,6R)-3,4,5-三(苄氧基)-2-(苄氧基甲基)-6-(4-氯-3-(4-乙基苄基)苯基)环己醇(4,R=Et)(1.0g,1.3mmol)在无水CH2Cl2(20mL)中的溶液中加入戴斯-马丁氧化剂(MW 424.5,白色粉末,1.5eq),然后将混合物在室温下搅拌过夜。用1N NaOH终止反应,分离,并用CH2Cl2萃取水层。合并有机层,用Na2SO4干燥,并过滤。将滤液蒸发至干,残余物用制备TLC纯化,得到化合物14(0.92g,白色固体,纯度95%,产率92.3%)。1H-NMR(400MHz,CDCl3):δ7.29-7.37(14H,m),7.13-7.23(5H,m),7.03-7.08(4H,dd,J=8.4Hz),6.97-6.99(2H,m),6.76(2H,d,J=7.6Hz),4.91-4.95(3H,m),4.64(1H,d,J=10.8Hz),4.50-4.57(3H,m),3.91-4.14(6H,m),3.74-3.76(3H,m),2.80(1H,d,J=8.4Hz),2.58(2H,dd,J=7.6Hz),1.20(3H,t,J=7.6);MS(ESI+):765[M+H]+,782[M+H2O]+,787[M+Na]+。
用1,2-二氯苯(0.354g,0.3mL,2.41mmol,2eq)和Pd/C(10%,74mg,8重量%)处理14(0.92g,纯度95%,1.20mmol,1eq)在THF∶CH3OH(2∶1)(12mL)中的溶液并在H2气氛和室温(约25℃)下搅拌4小时。用LC-MS监测反应直至完成。过滤混合物,并将滤液蒸发至干。残余物(黄色油)用制备HPLC纯化,得到化合物15(450mg,白色固体,纯度98%,产率92.6%)。1H-NMR(400HMz,CD3OD):δ7.34(1H,d,J=8.0Hz),6.99-7.12(6H,m),4.05(2H,s),3.98(1H,dd,J=2.8,10.8Hz),3.88(1H,dd,J=5.6,11Hz),3.77-3.81(2H,m),3.57-3.67(2H,m),2.65-2.79(1H,m),2.59(2H,d,J=7.6,15.2Hz),1.20(3H,t,J=7.6Hz);MS(ESI+):405[M+H]+,422[M+NH4]+,(ESI-):403[M-H]-,449[M+HCOO]-。
实施例8
(1R,2R,3S,4S,5R,6R)-4-(4-氯-3-(4-乙基苄基)苯基)-6-(羟甲基)-5-甲氧基环己烷-1,2,3-三醇(16)的制备。
(1)4-((1R,2S,3R,4R,5S,6R)-2,3,4-三(苄氧基)-5-(苄氧基甲基)-6-甲氧基环己基)-2-(4-乙基苄基)-1-氯苯的制备:
0℃下向(1R,2S,3R,4R,5S,6R)-3,4,5-三(苄氧基)-2-(苄氧基甲基)-6-(4-氯-3-(4-乙基苄基)苯基)环己醇(4,R=Et,2g,2.61mmol)在无水THF(10mL)中的溶液中加入NaH(157g,1.5eq,60%含在油中)。在相同温度下搅拌1小时后向反应混合物中加入TBAI(0.1eq)和CH3I(760mg,2eq),反应混合物于室温搅拌过夜。加入NH4Cl饱和水溶液以终止反应,所得混合物用EtOAc萃取。用Na2SO4干燥合并的有机层,过滤,并将滤液蒸发至干。将残余物(黄色油,2.05g)溶解在THF∶CH3OH=2∶1中,用1,2-二氯苯(1%摩尔比)和Pd/C(10%,1/1重量比)处理,并在H2气氛和室温下搅拌2小时。用LC-MS监测反应直至完成。过滤混合物,将滤液蒸发至干并用制备HPLC纯化,得到目标化合物16(987mg,白色固体,产率90.0%)。1H-NMR(400MHz,CD3COCD3):δ7.32-7.34(2H,m),7.22(1H,dd,J=2.4,8.0Hz),7.12(4H,dd,J=8.4Hz),4.15(2H,s),3.93-3.98(1H,m),3.70-.3.75(1H,m),3.65-3.67(1H,m),3.54-3.60(2H,m),3.37(1H,t,J=10.4Hz),3.30(1H,t,J=8.8Hz),2.84(3H,s),2.52-2.65(3H,m),1.51-1.58(1H,m),1.17(3H,t,J=7.2Hz);MS(ESI+):421[M+H]+,438[M+NH4]+,841[2M+H]+,858[2M+NH4]+,(ESI-):465[M+HCOO]-。
实施例9
((1S,2R,3R,4S,5R,6R)-3-(4-氯-3-(4-乙基苄基)苯基)-2,4,5,6-四羟基环己基)乙酸甲酯(17)的制备。
0℃下向(1R,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-乙基苄基)苯基)-6-(羟甲基)环己烷-1,2,3,5-四醇(5,R=Et,1g,2.46mmol)和DMAP(催化剂)在CH2Cl2(10mL)中的溶液中逐滴加入Ac2O(377mg,1.5eq),然后加入吡啶(292mg,1.5eq),混合物于室温下搅拌过夜。用3N HCl洗涤反应混合物,合并有机层,用Na2SO4干燥,过滤,并将滤液蒸发至干。用制备HPLC纯化残余物,得到目标化合物(566mg,白色固体,产率50.4%)。1H-NMR(400MHz,CD3OD):δ7.32(1H,d,J=8.4Hz),7.06-7.14(6H,m),4.37(2H,ddd,J=2.0,10.8,16.8Hz),4.04(2H,s),3.57(1H,t,J=10.8Hz),3.40-3.47(1H,m),2.49-2.60(3H,m),2.04(3H,s),1.60-1.66(1H,m),1.18(3H,t,J=8.0Hz);MS(ESI+):449[M+H]+,466[M+NH4]+,897[2M+H]+,(ESI-):492[M+HCOO]-,941[2M+HCOO]-。
实施例10
(4aR,5R,6R,7S,8S,8aR)-8-(4-氯-3-(4-乙基苄基)苯基)-2,2-二甲基六氢-4H-苯并[d][1,3]二 英-5,6,7-三醇(18)的制备。
向(1R,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-乙基苄基)苯基)-6-(羟甲基)环己烷-1,2,3,5-四醇(5,R=Et,1g,2.46mmol)在MeOH(80mL)和丙酮(20mL)中的溶液中逐滴加入1N HCl(5mL)并搅拌过夜,然后将混合物蒸发至干。用制备HPLC纯化残余物,得到目标化合物(864mg,白色固体,产率75.3%)。 1H-NMR(400MHz,CD3COCD3):δ7.26-7.29(2H,m),7.10-7.16(5H,m),3.74-4.21(6H,m),3.46-3.51(1H,m),3.35-3.37(1H,m),2.56-2.66(3H,m), 1.72-1.75(1H,m),1.28(3H,s),1.18(3H,t,J=7.6Hz),1.13(3H,s);MS(ESI+):447[M+H]+,488[M+H+CH3CN]+,910[2M+NH4]+,491[M+HCOO]-,937[2M+HCOO]-。
实施例11
(1S,2R,3R,4S,5R,6R)-4-(乙酰氧基甲基)-6-(4-氯-3-(4-乙基苄基)苯基)环己烷-1,2,3,5-四基四乙酸酯(19)的制备。
化合物19由化合物5(R=Et)按实施例20中所述制备。1H-NMR(400MHz,CDCl3):δ7.29(1H,d,J=8.4Hz),7.30-7.12(6H,m),5.27-5.38(3H,m),5.20(1H,t,J=9.6Hz),4.03-4.06(3H,m),3.93-3.96(1H,m),2.98(1H,t,J=11.6),2.61(2H,q,J=7.6Hz),2.14-2.20(1H,m),2.08(3H,s),2.06(3H,s),2.00(3H,s),1.66(6H,s),1.21(3H,t,J=7.6Hz);MS(ESI+):617(M+H)+,934[M_NH4]+,(ESI-):661[M+HCOO]-。
实施例12
本实施例采用图5中概述的合成方法制备(1R,2R,3R,4S,5S)-1-(4-氯-3-(4-乙基苄基)苯基)-5-(羟甲基)环己烷-1,2,3,4,5-五醇(22,R=Et)。
化合物22按与实施例1中所述类似的方法制备。1H-NMR(400MHz, CD3OD):δ7.45(1H,s),7.32-7.33(2H,m),7.05-7.10(4H,m),4.05(2H,s),3.86(1H,t,J=9.6Hz),3.67(1H,d,J=9.2Hz),3.54-3.57(2H,m),3.31-3.35(2H,m),2.57(2H,q,J=8.0Hz),2.00(1H,d,J=15.2Hz),1.81(1H,d,J=15.2Hz),1.18(3H,t,J=8.0Hz)。
实施例13
(1R,2R,3R,4S,5S)-1-(3-(4-乙基苄基)苯基)-5-(羟甲基)环己烷-1,2,3,4,5-五醇(23)的制备。
化合物23按与实施例12中所述类似的方法制备。1H-NMR(400MHz,CD3OD):δ7.39(1H,s),7.29-7.31(1H,m),7.21-7.25(1H,m),7.03-7.11(5H,m),3.92(2H,s),3.88(1H,t,J=9.2Hz),3.72(1H,d,J=9.6Hz),3.56(1H,d,J=10.4Hz),3.32-3.35(1H,m),2.58(2H,q,J=7.6Hz),2.02(1H,d,J=15.2Hz),1.82(1H,d,J=15.2Hz),1.18(3H,t,J=7.6Hz)。
实施例14
本实施例说明如图6中所概述(1R,2S,3R,4R,5S,6R)-4-(4-氯-2-(4-乙基苄基)苯氧基)-6-(羟甲基)环己烷-1,2,3,5-四醇(29)的制备。
(5-氯-2-羟苯基)(4-乙基苯基)甲酮
在室温和氩气下搅拌2-甲氧基-5-氯苯甲酸(2.0g,10.5mmol)在无水CH2Cl2(10mL)中的溶液。向反应混合物中逐滴加入草酰氯(2.0g,15.8mmol),然后加入DMF(0.04mL)。搅拌过夜后,用旋转蒸发器蒸发出挥发物并在室温和氩气下将残余物溶解在无水CH2Cl2(10mL)中。冷却到-5℃后,加入乙苯(2.57mL,21mmol),然后逐份加入AlCl3(2.80g,21mmol),同时使反应温度保持在-5℃到0℃之间。反应混合物于室温下搅拌4小时,然后倒入冰水中并用CH2Cl2(50mL×2)萃取。然后用1N HCl(50mL)、1NNaOH(50mL)、水(50mL)和盐水(50mL)洗涤有机层并用无水Na2SO4干燥。浓缩滤液,粗产物用柱色谱(PE∶EA=10∶1)纯化,得到目标化合物(1.944g)。
4-氯-2-(4-乙基苄基)苯酚
向Et3SiH(2.26ml,14.2mmol)和(5-氯-2-羟苯基)(4-乙基苯基)甲酮(1.944g,7.08mmol)在10mL TFA中的搅拌着的0℃溶液中以使温度保持在约0℃下的速率加入CF3SO3H(30μL)。加入完成后,将混合物温热至室温并在室温下搅拌过夜。减压蒸发出挥发物后,使残余物在乙酸乙酯和水中分配。分离有机层,用水、Na2CO3水溶液、盐水洗涤,然后用Na2SO4干燥并浓缩。粗产物用柱色谱(PE∶EA=10∶1)纯化,得到目标化合物(1.659g)。
((1S,2S,3R,6R)-4-(苄氧基甲基)-6-(4-氯-2-(4-乙基苄基)苯氧基)环己-4-烯-1,2,3-三基)三(氧)三(亚甲基)三苯(27)
在氩气流中于室温下向4-氯-2-(4-乙基苄基)苯酚(345mg,1.400mmol)的THF(6mL)溶液中加入(1S,4R,5S,6S)-4,5,6-三(苄氧基)-3-(苄氧基甲基)环己-2-烯醇(0.5g,0.933mmol)和三苯基膦(367mg,1.400mmol)。于相同温度下向其中加入DIAD(0.276mL,1.400mmol)。反应混合物搅拌48小时。减压浓缩反应混合物,所得残余物用制备LC-MS纯化,得到157mg((1S,2S,3R,6R)-4-(苄氧基甲基)-6-(4-氯-2-(4-乙基苄基)苯氧基)环己-4-烯-,2,3-三基)三(氧)三(亚甲基)三苯(27)。
(1S,2S,3R,4S,5R,6R)-3,4,5-三(苄氧基)-2-(苄氧基甲基)-6-(4-氯-2-(4-乙基苄基)苯氧基)环己醇(28)
向((1S,2S,3R,6R)-4-(苄氧基甲基)-6-(4-氯-2-(4-乙基苄基)苯氧基)环己-4-烯-1,2,3-三基)三(氧)三(亚甲基)三苯(27,150mg,0.196mmol)的搅拌着的0℃THF溶液中逐滴加入BH3OEt2(2M,0.98mL,1.962mmol)。于0℃搅拌2小时后,将混合物温热至25℃并搅拌过夜。加入H2O2(30%,4.2mL),然后在0℃下向反应混合物中加入NaOH水溶液(1M,3.93mL,3.93mmol)。加入完成后,将反应混合物温热至25℃并搅拌3小时。加入稀HCl(1N,10mL)终止反应并用乙酸乙酯(3×30mL)萃取。用水和盐水洗涤有机层,然 后用无水Na2SO4干燥。残余物用制备TLC(EA∶PE=1∶8v/v)纯化,得到59mg(1S,2S,3R,4S,5R,6R)-3,4,5-三(苄氧基)-2-(苄氧基甲基)-6-(4-氯-2-(4-乙基苄基)苯氧基)环己醇(28)。
(1R,2S,3R,4R,5S,6R)-4-(4-氯-2-(4-乙基苄基)苯氧基)-6-(羟甲基)环己烷-1,2,3,5-四醇(29)
向含有(1S,2S,3R,4S,5R,6R)-3,4,5-三(苄氧基)-2-(苄氧基甲基)-6-(4-氯-2-(4-乙基苄基)苯氧基)环己醇(28,55mg,0.070mmol)的烧瓶中加入14mLTHF和甲醇(1∶1)。向反应混合物中一次性加入55mg Pd/C(10%)。混合物用H2脱气五次,将所得混悬体在H2气氛和环境温度下搅拌3小时。过滤反应混合物并浓缩,残余物用制备LC-MS纯化,得到25mg(1R,2S,3R,4R,5S,6R)-4-(4-氯-2-(4-乙基苄基)苯氧基)-6-(羟甲基)环己烷-1,2,3,5-四醇(29)。1H-NMR(D2O):δ7.22~7.2(1H,d,J=9.2Hz),7.17~7.11(4H,q),7.08~7.06(1H,dd),6.92~6.91(1H,d,J=3.2Hz),4.11~4.08(1H,tJ=9.2Hz),4.01(2H,s),3.92~3.91(2H,m),3.69~3.665(1H,dd,J=10.8,8.8Hz),3.46~3.39(2H,m),3.35~3.30(1H,m),2.66~2.58(2H,q),1.52~1.46(1H,tt),1.24~1.19(3H,t)。
实施例15
(1R,2S,3R,4R,5S,6R)-4-(2-(4-乙基苄基)苯氧基)-6-(羟甲基)环己烷-1,2,3,5-四醇(30)的制备。
化合物30按与实施例14中所述类似的方法制备。1H-NMR(D2O):δ7.24~7.22(1H,d,J=8Hz),7.17~7.08(5H,m),7.02~6.99(1H,d,J=7.2Hz),6.83~6.79(1H,t,J=7.2Hz),4.14~4.09(1H,t,J=9.2Hz),4.03(2H,s),3.94~3.87(2H,m),3.68~3.63(1H,dd,J=10.8,9.2Hz),3.46~3.38(2H,m),3.34~3.30(1H,m),2.62~2.56(2H,q),1.53~1.46(1H,tt),1.22~1.18(3H,t)。
实施例16
(1R,2S,3R,4R,6R)-4-(3-(4-乙基苄基)苯基)-4-氟-6-(羟甲基)环己烷-1,2,3-三醇(31)的制备。
在-78℃和Ar气氛下向2(30mg)在CH2Cl2(1mL)中的溶液中加入DAST(7μL)。2小时后向混合物中加入MeOH(0.5mL),然后将混合物温热至室温。向残余物中加入饱和NaCl水溶液(5mL),混合物用乙酸乙酯萃取(3×10mL)。蒸发合并的有机萃取物,将残余物溶解在MeOH/THF(1∶1,5mL)中,然后在H2气氛下用10%的Pd/C(10mg)处理。4小时后通过制备HPLC分离化合物31(1.4mg)。1H-NMR(300MHz):δ7.18-7.01(8H,m),3.90-3.86(3H,m),3.77-3.72(1H,m),3.61-3.31(3H,m),2.62-2.54(2H,q,J=7.5Hz),2.45-2.60(2H,m),1.53(1H,m),1.20-1.17(3H,t,J=7.6Hz);MS(ESI+):375[M+H]+,392[M+H2O]+,416[M+CH3CN+H]+。
实施例17
(1R,2S,3S,6S)-4-(4-氯-3-(4-乙基苄基)苯基)-6-(氟甲基)环己-4-烯-1,2,3-三醇(33)的制备。
在-78℃和Ar下向3(R=Et)(122mg)在CH2Cl2(5mL)中的溶液中逐滴加入BBr3(0.33mL)。搅拌2小时后向混合物中加入饱和NaHCO3水溶液(1mL),然后将混合物温热至室温并用乙酸乙酯(3×10mL)萃取。用Na2SO4干燥合并的有机萃取物,浓缩并用制备HPLC纯化,得到18mg化合物32。1H-NMR(400MHz):δ7.33-7.30(2H,m),7.25-7.23(1H,m),7.10(4H,s),5.85(1H,d),4.58(2H,s),4.51-4.49(1H,m),4.12-4.01(2H,q,J=15.2Hz),3.89-3.85(1H,dd,J=4,10.4Hz),3.68-3.53(3H,m),2.63-2.57(2H,q,J=7.6Hz),1.23-1.19(3H,t,J=7.6Hz);MS(ESI+):406[M+H2O]+。
在-78℃和Ar下用DAST(3eq,0.02mL)处理32(11mg)在CH2Cl2(2mL)中的溶液。2小时后向混合物中加入MeOH(0.5mL),然后温热至室温。向残余物中加入饱和NaCl水溶液(5mL),水相用乙酸乙酯(3×10mL)萃取。蒸发合并的有机萃取物,用制备HPLC纯化残余物,得到1.8mg化合物33。1H-NMR(400MHz)δ7.30-7.08(7H,m),5.85(1H,m),4.59-4.57(1H,m),4.54(2H,s),4.13-4.03(2H,q,J=15.2Hz),3.90-3.86(1H,dd,J=4,10.4Hz),3.70-3.58(3H,m),2.60-2.55(2H,q,J=7.6Hz),1.22-1.18(3H,t,J=7.6Hz);MS(ESI+):391[M+H]+;408[M+H2O]+。
实施例18
本实施例说明如图7中所概述(1R,2R,3S,4S,6R)-4-(4-氯-3-(4-乙基苄 基)苯基)-6-(羟甲基)-5-亚甲基环己烷-1,2,3-三醇(35)的制备。
实施例18和19中所合成的化合物的结构用如下程序确认:1H NMR数据在Varian Mercury 300光谱仪上在300MHz下获得,化学位移以内标TMS为基准。液相色谱电喷雾电离质谱(LC-ESI-MS)分析在由Shimadzu LC-10AD vp系列HPLC泵和双波长UV检测器、Gilson 215自动取样器、Sedex 75c蒸发光散射(ELS)检测器和PE/Sciex API 150EX质谱仪组成的仪器上进行。ELS检测器设置为温度40℃、增益调整定值7、N2压力3.3atm。API 150上采用Turbo IonSpray源,离子喷雾电压为5kV,温度为300℃,孔和环电压分别为5V和175V。在Q1中从160到650m/z扫描正离子。在Phenomenex Gemini 5μm C18柱上注射各样品5.0μL。流动相由0.05%的甲酸/(HPLC级水(A)+HPLC级乙腈(B))组成,流量为2mL/min,并使用如下梯度:0.00min,95%A,5%B;4.00min,0%A,100%B;5.80min,0%A,100%B;6.00min,95%A,5%B;7.00min,95%A,5%B。
(2R,3R,4R,5S,6S)-3,4,5-三(苄氧基)-2-(苄氧基甲基)-6-(4-氯-3-(4-乙基苄基)苯基)环己酮(14)的制备:
向叔丁醇(28.2μL,296μMol)在二氯甲烷(4mL)中的溶液中加入戴斯-马丁氧化剂[1,1,1-三(乙酰氧基)-1,1-二氢-1,2-苯碘酰-3-(1H)-酮](116mg,274μMol),所得混合物在室温和氩气下搅拌10分钟。向混合物中加入醇4(R=Et,异构体混合物)在二氯甲烷(2mL)中的溶液并在室温下搅拌3小时。混合物用4mL乙酸乙酯稀释并与1.5∶1∶1的饱和亚硫酸钠∶饱和碳酸氢钠∶盐水水溶液(3.5mL)一起剧烈搅拌1小时。分离相,水相用乙酸乙酯(3mL)再次萃取。用盐水(2mL)洗涤合并的有机物,干燥(无水Na2SO4),过滤,并蒸发。使用二氯甲烷作为展开溶剂实施制备TLC,得到91mg(52%)呈白色固体的化合物14。1H NMR(300MHz,CDCl3)δ7.35-6.90(m,25H),6.80(m,2H),4.96(m,3H),4.55(m,4H),4.11(m,3H),3.94(m,2H),3.79(m,3H),3.47(s,1H),2.83(m,1H),2.62(q,J=7.8Hz,2H),1.16(t,J=7.5Hz,3H)。LC-ESI-MS m/z 766(M+H),788(M+Na)。
((1S,2R,3R,4R,6S)-4-(苄氧基甲基)-6-(4-氯-3-(4-乙基苄基)苯基)-5-亚甲基环己烷-1,2,3-三基)三(氧)三(亚甲基)三苯(34):
向氮气氛下的小瓶中的0.5ml无水THF中加入环-二溴二-μ-亚甲基[μ-(四氢呋喃)]三锌[Nysted试剂](179mg,151μL,78μmol,悬浮在THF中的20重量%混悬体),将所得混合物冷却至-78℃。以逐滴方式向该混合物中加入(2R,3R,4R,5S,6S)-3,4,5-三(苄氧基)-2-(苄氧基甲基)-6-(4-氯-3-(4-乙基苄基)苯基)环己酮(14,40mg,52μmol)/0.5mL无水THF,然后加入TiCl4(78μL,78μmol,在DCM中的1M溶液)。混合物于-78℃搅拌20分钟,然后移走冷却浴,并将混合物在室温下搅拌3小时。加入饱和碳酸氢钠水溶液(2mL),所得混合物搅拌30分钟。用乙酸乙酯(2×4mL)萃取混合物,有机层用盐水(2mL)洗涤,用Na2SO4干燥,过滤,并蒸发。制备TLC(8∶1H/EtOAc)给出25mg(63%)化合物34。1H NMR(300MHz,CDCl3)δ7.34-6.99(m,25H),6.63(m,2H),5.14(s,1H),4.90(m,1H),4.53(m,5H),4.2(m,3H),3.78(m,3H),3.60(m,2H),3.47(s,1H),3.35(m,1H),2.56(q,J=7.8Hz,2H),2.42(m,1H),1.16(t,J=7.5Hz,3H)。LC-ESI-MS m/z 764(M+H),786(M+Na)。
(1R,2R,3S,4S,6R)-4-(4-氯-3-(4-乙基苄基)苯基)-6-(羟甲基)-5-亚甲基环己烷-1,2,3-三醇(35):
向-78℃且氮气氛下的小瓶中的((1S,2R,3R,4R,6S)-4-(苄氧基甲基)-6-(4-氯-3-(4-乙基苄基)苯基)-5-亚甲基环己烷-1,2,3-三基)三(氧)三(亚甲基)三苯(34,24mg,31.4mmol)/无水DCM(0.8mL)溶液中逐滴加入BCl3(在DCM中的1M溶液,0.25mL),15分钟加完。所得混合物于-78℃搅拌30分钟并逐步温热至-20℃。所得混合物于-20℃再搅拌30分钟。此时,LC-MS表明反应完成。将溶液冷却至-78℃并缓慢加入甲醇(1mL)。将所得溶液温热至室温并减压浓缩。将残余物溶解在0.5mL 1∶1的DCM∶MeOH中并装载在制备TLC板上,将其在15∶1(DCM∶MeOH)中展开,得到9mg(71%)呈白色固体的化合物35。1H NMR(300MHz,CDCl3)δ7.29-6.89(m,7H),4.80(s,1H),4.28(s,1H),3.95(m,4H),3.64(m,2H),3.51(m,3H),3.22(m,1H),2.58(q,J=7.2Hz,2H),2.25(m,1H),1.18(t,J=7.5Hz,3H)。LC-E SI-MS m/z 425(M+Na)。
实施例19
本实施例说明如图8中所概述(4S,5S,6R,7R,8R)-4-(4-氯-3-(4-乙基苄基)苯基)-8-(羟甲基)螺[2.5]辛烷-5,6,7-三醇(37)的制备。
(4R,5R,6R,7S,8S)-5,6,7-三(苄氧基)-4-(苄氧基甲基)-8-(4-氯-3-(4-乙基苄基)苯基)螺[2.5]辛烷(36):
在氮气和-10℃下向剧烈搅拌着的((1S,2R,3R,4R,6S)-4-(苄氧基甲基)-6-(4-氯-3-(4-乙基苄基)苯基)-5-亚甲基环己烷-1,2,3-三基)三(氧)三(亚甲基)-三苯(34,25mg,32.7μmol)/无水甲苯(2mL)溶液中逐滴加入2M的二甲基锌溶液(146μL,291μmol)并搅拌15分钟。逐滴加入二碘甲烷(47μL,583μmol),所得混合物搅拌过夜。观察到生成40%的产物。加入更多二甲基锌(另外18当量,分两批加入,48小时加完)和二碘甲烷(35当量,分两批加入,48小时加完),反应96小时后反应完成80%。加入饱和NH4Cl溶液(1mL),混合物搅拌30分钟。用水(1mL)稀释混合物并用乙酸乙酯(3×1mL)萃取。用10%的硫酸(1.5mL)、饱和NaHCO3(1.5mL)和盐水(1.5mL)洗涤合并的有机萃取物,干燥(Na2SO4),过滤并蒸发。制备TLC(9∶1的己烷∶乙酸乙酯)给出85%的化合物36,其在接下来的反应中直接使用。
(4S,5S,6R,7R,8R)-4-(4-氯-3-(4-乙基苄基)苯基)-8-(羟甲基)螺[2.5]辛烷-5,6,7-三醇(37):
向(4R,5R,6R,7S,8S)-5,6,7-三(苄氧基)-4-(苄氧基甲基)-8-(4-氯-3-(4-乙基苄基)苯基)螺[2.5]辛烷(36,20mg,25.7μmol)在THF(0.2mL)和甲醇(0.8mL)的混合物中的溶液中加入1,2-二氯苯(58μL,515μmol),然后加入14mg钯碳催化剂(10%)。混合物在1个大气压的氢气下搅拌40分钟。通过在6mL注射器中的硅藻土小垫过滤混合物并用甲醇(1mL)洗涤。减压蒸发出溶剂,残余物在制备TLC板(8∶1的DCM∶EtOH)上纯化该硅藻土垫,得到4mg(37%)呈白色固体的化合物37。1H NMR(300MHz,CDCl3)δ7.27-6.85(m,7H),4.01(s,2H),3.80(m,2H),3.63(m,H),3.35(d,J=5.1Hz,2H),3.02(d,J=11.1hz,1H),2.62(q,J=7.5Hz,2H),2.06(m,1H),1.21(t,J=7.5Hz,3H),0.40(m,1H),0.29(m,1H),0.076(m,1H),-0.326(m,1H)。LC-ESI-MS m/z 418(M+H),440(M+Na)。
实施例20
本实施例说明化合物5(R=Et)的大规模制备。
(1R,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-乙基苄基)苯基)-6-(羟甲基)环己烷 -1,2,3,5-四醇的制备
(1)(4R,5S,6R)-4,5,6-三(苄氧基)-3-(苄氧基甲基)环己-2-烯酮的制备
在室温和氩气下向(3S,4S,5S,2R)-5-羟基-5-[(苯基甲氧基)甲基]-2,3,4-三(苯基甲氧基)环己-1-酮(580.0g,1.051mol)/无水二氯甲烷(3.6L)溶液中加入三氟乙酸酐(331.1g,222mL,1.577mol),然后加入吡啶(149.7g,153mL,1.892mol)。混合物在室温下搅拌24小时后加入冰水(1.0L)终止反应。分离有机层,水层用二氯甲烷(3×2L)萃取。用碳酸氢钠(饱和水溶液,3×0.5L)、盐水(饱和水溶液,3×1.0L)洗涤合并的有机层,用硫酸钠干燥,过滤并浓缩,得到黄色油(476.7g,纯度90%,产率85%)。1H NMR(CDCl3,400MHz):δ7.26-7.48(m,20H),6.26(s,1H),5.15(d,J=11.2Hz,1H),5.05(d,J=10.8Hz,1H),4.95(d,J=10.8Hz,1H),4.77-4.81(m,2H),4.72(d,J=11.2Hz),4.55(S,2H),4.40-4.42(m,1H),4.31(d,J=16Hz,1H),4.03-4.13(m,3H)。
(2)(4-氯-3-(4-乙基苄基)苯基)溴化镁的制备
在氩气下向三颈烧瓶中装入镁粉(34.7g,1.446mol),然后加入一部分2-(4-乙基苄基)-4-溴-1-氯苯(122.5g,0.398mol)在无水四氢呋喃(0.4L)和1,2-二溴乙烷(2.89g,1.34mL,0.015mol)中的溶液。将混合物加热至回流,反应开始(放热并消耗镁)后,逐滴加入剩余的2-(4-乙基苄基)-4-溴-1-氯苯(245.0g,0.796mol)在无水四氢呋喃(0.81L)中的溶液。然后使混合物在温和的回流下再反应一小时直至大多数镁被消耗。
(3)(1R,4R,5S,6R)-4,5,6-三(苄氧基)-3-(苄氧基甲基)-1-(4-氯-3-(4-乙基苄基)苯基)环己-2-烯醇的制备
在氩气和室温(约25℃)下向(4R,5S,6R)-4,5,6-三(苄氧基)-3-(苄氧基甲基)环己-2-烯酮(476.7g,纯度90%,0.893mol)/无水四氢呋喃(1.0L)溶液中逐滴加入来自上一步骤的格氏试剂,混合物搅拌3小时。加入氯化铵(饱和水溶液,100mL),混合物用乙酸乙酯萃取(3×1L)。有机层用盐水(3×0.5L)洗涤,用Na2SO4干燥,过滤并浓缩,得到黄色油(614g,产率90%)。该粗(1R,4R,5S,6R)-4,5,6-三(苄氧基)-3-(苄氧基甲基)-1-(4-氯-3-(4-乙基苄基)苯基)环己-2-烯醇在下一步中直接使用。MS(ESI+)(m/z):782(M+18)+,787(M+23)+。
(4)((1R,2S,3S,6R)-6-苄氧基甲基)-4-(4-氯-3-(4-乙基苄基)苯基)环己-4-烯-1,2,3-三基)三(氧)三(亚甲基)三苯的制备
于氩气和-20℃下向(1R,4R,5S,6R)-4,5,6-三(苄氧基)-3-(苄氧基甲基)-1-(4-氯-3-(4-乙基苄基)苯基)环己-2-烯醇(614.0g,粗,~0.723mol,1eq)在二氯甲烷(2.6L)中的溶液中依次加入三乙基甲硅烷(167.9g,229.7mL,1.446mol,2eq)和三氟化硼合乙醚(205.2g,204.1mL,1.446mol,2eq),混合物于-20℃搅拌1小时。加入氯化铵(饱和水溶液,100mL),混合物用二氯甲烷萃取(3×1L),有机层用盐水(3×0.5L)洗涤,用硫酸钠干燥,过滤并浓缩。残余物通过在回流的无水乙醇/异丙醚中重结晶纯化,得到白色固体(513g,纯度95%,产率95%)。
(5)(1R,2S,3R,4R,5S,6R)-3,4,5-三(苄氧基)-2-(苄氧基甲基)-6-(4-氯 -3-(4-乙基苄基)苯基)环己醇的制备
在高压不锈钢反应容器中于氩气和0℃下向((1R,2S,3S,6R)-6-苄氧基甲基)-4-(4-氯-3-(4-乙基苄基)苯基)环己-4-烯-1,2,3-三基)三(氧)三(亚甲基)三苯(513g,纯度95%,0.651mol,1eq)和硼氢化锂(7.1g,在四氢呋喃中的2M溶液,0.326mol,0.5eq)在无水四氢呋喃(5L)中的溶液中加入硼烷-四氢呋喃络合物(在四氢呋喃中的1M溶液)(1.31L,1.302mol,2eq.),将混合物加热至约70-80℃,由此反应器中的压力达到约2-2.5atm。混合物在此温度下搅拌40分钟。将反应容器冷却至室温,将内容物转移至三颈烧瓶中并冷却至-20℃。加入冷的(0℃)氢氧化钠溶液(78.1g,在水中的3M溶液,1.953mol,3eq),然后加入30%的过氧化氢(442.8g,438.4mL,1.953mol,20eq),将混合物温热至室温过夜。用1N盐酸酸化反应混合物至pH 6并减压除去溶剂。向残余物中加入水(5L)并用乙酸乙酯(3×2L)萃取。有机层用盐水(3×1L)洗涤,用硫酸钠干燥,过滤并浓缩。残余物通过在乙醚/正己烷(v/v=1∶10,10mL/g(粗))中重结晶纯化,得到白色固体(314.7g,纯度95%,产率60%)。
(6)粗(1R,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-乙基苄基)苯基)-6-(羟甲基)环己烷-1,2,3,5-四醇的制备
向(1R,2S,3R,4R,5S,6R)-3,4,5-三(苄氧基)-2-(苄氧基甲基)-6-(4-氯-3-(4-乙基苄基)苯基)环己醇(60g,纯度98%,0.077mol,1eq)在四氢呋喃∶甲醇(v/v=2∶1)(600mL)中的溶液中加入1,2-二氯苯(21.5g,16.54mL,0.82mol,2eq)和钯碳(10%,4.8g)并在室温(约25℃)和一个大气压力的氢气下搅拌4 小时。过滤混合物并将滤液蒸发至干,得到黄色油(纯度80%)。
(7)(1S,2R,3R,4S,5R,6R)-4-(乙酰氧基甲基)-6-(4-氯-3-(4-乙基苄基)苯基)环己烷-1,2,3,5-四基四乙酸酯(19)的制备
于0℃下向上述粗油(1R,2R,3S,4R,5R,6S)-4-(3-(4-乙基苄基)-4-氯苯基)-6-(羟甲基)环己烷-1,2,3,5-四醇(0.077mol,纯度80%)在二氯甲烷(300mL)中的溶液中缓慢加入乙酸酐(78.8g,72.9mL,0.77mol,10eq)、N,N-二异丙基乙胺(99.5g,134.1mL,0.77mol,10eq)和4-二甲基氨基吡啶(DMAP,0.47g,3.85mmol,0.05eq),混合物在室温下搅拌过夜。用1N盐酸酸化混合物至pH 6,有机层用1N盐酸(3×200mL)洗涤,用硫酸钠干燥,过滤并浓缩。残余物在沸腾的乙醇/乙酸乙酯(v/v=3∶1,15mL/g(粗))中重结晶。第一固体在~58℃出现,混合物于58℃搅拌2小时。将混合物冷却至室温,用时2小时,得到白色固体(42.2g,纯度99.4%,两步产率88.7%)。
(8)(1R,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-乙基苄基)苯基)-6-(羟甲基)环己烷-1,2,3,5-四醇的制备
向搅拌着的(1S,2R,3R,4S,5R,6R)-4-(乙酰氧基甲基)-6-(4-氯-3-(4-乙基苄基)苯基)环己烷-1,2,3,5-四基四乙酸酯(98g,>99%,0.158mol,1eq)/甲醇(1L)溶液中加入氢氧化钠(粉末,12.6g,0.315mol,2eq),混合物回流过夜。用1N盐酸酸化混合物至pH 6并减压除去挥发物。将残余物溶解在乙酸乙酯(3L)中,用水(1L)、然后用盐水(1L)洗涤,用硫酸钠干燥,过滤并浓缩,得到白色泡沫。将此泡沫在回流的乙醇/水(v/v=1∶3,20mL/g(粗))中重结晶 两次,得到白色固体(58g,纯度99.3%,产率90%)。
实施例21
本实施例说明1-(4-(2-氯-5-((1R,2S,3R,4R,5S,6R)-2,3,4,6-四羟基-5-(羟甲基)环己基)苄基)苯基)乙酮(39)的制备。
(1S,2R,3R,4S,5R,6R)-4-(乙酰氧基甲基)-6-(3-(4-乙酰基苄基)-4-氯苯基)环己烷-1,2,3,5-四基四乙酸酯(38)的制备
向剧烈搅拌着的(1S,2R,3R,4S,5R,6R)-4-(乙酰氧基甲基)-6-(4-氯-3-(4-乙基苄基)苯基)环己烷-1,2,3,5-四基四乙酸酯(19)(300mg,48.7μmol)/乙酸(5mL)溶液中加入K2Cr2O7(172mg,0.58mmol),混合物于125℃搅拌22小时。将混合物冷却至室温,用水(20mL)稀释并用乙酸乙酯(3×20mL)萃取。用饱和NaHCO3(3×10mL)、然后用盐水(20mL)洗涤合并的有机萃取物,干燥(Na2SO4),过滤并浓缩。制备TLC(2∶1的己烷∶乙酸乙酯)给出100mg所需化合物。MS(ESI+):631[M+H]+,648[M+H2O]+。
1-(4-(2-氯-5-((1R,2S,3R,4R,5S,6R)-2,3,4,6-四羟基-5-(羟甲基)环己基)苄基)苯基)乙酮(39)的制备
向(1S,2R,3R,4S,5R,6R)-4-(乙酰氧基甲基)-6-(3-(4-乙酰基苄基)-4-氯苯基)环己烷-1,2,3,5-四基四乙酸酯(38)(300mg,47.6μmol)/MeOH(5mL)溶液中加入氢氧化钠(29mg,72μmol)并在回流下搅拌1.5小时。用1N盐酸 酸化混合物至pH 6并减压除去溶剂。用制备HPLC纯化残余物,得到30mg所需化合物。1H-NMR(400MHz,CD3OD):δ7.90(2H,d,J=8.4Hz),7.35(3H,m),7.22(H,d,J=1.6Hz),7.18(1H,d,J=8.4,1.6Hz),4.17(2H,s),3.91(2H,d,J=3.2Hz),3.66(1H,t,J=10.4Hz),3.49-3.40(2H,m),3.30(1H,m),2.57-2.52(4H,m),1.55-1.50(1H,m);MS(ESI+):421[M+H]+,443[M+Na]+,(ESI-):465[M+HCOO]-。
实施例22
(1R,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-(1-羟乙基)苄基)苯基)-6-(羟甲基)环己烷-1,2,3,5-四醇(40)的制备
化合物40通过用过量硼氢化钠还原(1S,2R,3R,4S,5R,6R)-4-(乙酰氧基甲基)-6-(3-(4-乙酰基苄基)-4-氯苯基)环己烷-1,2,3,5-四基四乙酸酯(38)制备并通过制备HPLC纯化,得到0.6mg澄清膜。MS(ESI+):445[M+Na]+,(ESI-):467[M+HCOO]-。
实施例23
本发明的化合物的SGLT抑制作用通过下面的程序验证。
人SGLT2表达载体的制备
将表达人SGLT2的全长cDNA克隆(GenScript Corporation)亚克隆成pEAK15表达载体的Hind III和Not I位点。含cDNA插入片段的克隆通过限制性分析识别。
稳定表达人SGLT2的细胞系的制备
含人SGLT2的质粒用Nsi I线性化并通过琼脂糖凝胶电泳纯化。使用Lipofectamine 2000转染试剂(Invitrogen Corporation)将DNA转染到HEK293.ETN细胞中并在含10%胎牛血清(FBS)的Dulbecco改性的Eagle 培养基(DMEM)中于37℃和5%CO2下培养24小时。在添加有嘌呤霉素(Invitrogen Corporation)两周的相同生长培养基中筛选转染子。回收抗嘌呤霉素的细胞,接种在新鲜的96孔板上(每孔一个细胞),并在嘌呤霉素的存在下培养直至细胞汇合。在下面描述的甲基-α-D-[U-14C]吡喃葡萄糖苷吸收试验中评价抗嘌呤霉素的克隆的SGLT2活性。使用具有最高信号背景比的克隆进行甲基-α-D-[U-14C]吡喃葡萄糖苷吸收试验。
人SGLT1表达细胞的制备
从GenScript Corporation获得在pDream2.1表达载体上的全长人SGLT1 cDNA并使用含氨苄西林的Luria-Bertani(LB)培养基在大肠杆菌菌株DH5α中增殖。用QIAGEN质粒中提试剂盒(QIAGEN Inc.)分离质粒DNA。用Lipofectamine 2000转染试剂按生产商建议的程序将人SGLT1表达质粒DNA转染到COS-7细胞(美国模式培养物保藏所)中。将转染细胞贮存在-80℃的含10%二甲亚砜(DMSO)的DMEM中。
甲基-α-D-[U-14C]吡喃葡萄糖苷吸收试验
试验前将表达SGLT1或SGLT2的细胞接种在96孔ScintiPlate闪烁板(PerkinElmer,Inc.)上含有10%FBS的DMEM中(每孔100μl培养基中1×105个细胞)并在37℃和5%CO2下培养48小时。用150μl钠缓冲液(137mM NaCl,5.4mM KCl,2.8mM CaCl2,1.2mM MgCl2,10mM三(羟甲基)氨基甲烷/N-2-羟乙基哌嗪-N′-乙磺酸[Tris/Hepes],pH 7.2)或无钠缓冲液(137mM N-甲基-葡糖胺,5.4mM KCl,2.8mM CaCl2,1.2mM MgCl2,10mM Tris/Hepes,pH 7.2)洗涤细胞两次。向96孔板的每个孔中加入各自包含在50μl含有40μCi/ml甲基-α-D-[U-14C]吡喃葡萄糖苷(AmershamBiosciences/GE Healthcare)和25%人血清的钠或无钠缓冲液中的试验化合物并在振摇的同时于37℃下培养2小时(SGLT1试验)或1.5小时(SGLT2试验)。用150μl洗涤缓冲液(137mM N-甲基葡糖胺,10mM Tris/Hepes,pH7.2)洗涤细胞两次并用TopCount闪烁计数器(PerkinElmer,Inc.)测定甲基-α-D-[U-14C]吡喃葡萄糖苷吸收量。钠依赖性吡喃葡萄糖苷吸收量用使用钠缓冲液所获得的值减去用无钠缓冲液所获得的值量度(三次测定的平均值)。
表1
Claims (16)
2.权利要求1的化合物,其中Q选自Q1A和Q3A。
3.一种化合物,所述化合物选自
(1R,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-乙基苄基)苯基)-6-(羟甲基)环己烷-1,2,3,5-四醇;
(1R,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-乙氧基苄基)苯基)-6-(羟甲基)环己烷-1,2,3,5-四醇;
(1R,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-环丙基苄基)苯基)-6-(羟甲基)环己烷-1,2,3,5-四醇;
(1R,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-丙基苄基)苯基)-6-(羟甲基)环己烷-1,2,3,5-四醇;
(1R,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-环己基苄基)苯基)-6-(羟甲基)环己烷-1,2,3,5-四醇;
(1R,2S,3R,4R,5S,6R)-4-(2-(4-乙基苄基)苯氧基)-6-(羟甲基)环己烷-1,2,3,5-四醇;
(1R,2R,3S,4S,6R)-4-(4-氯-3-(4-乙基苄基)苯基)-6-(羟甲基)-5-亚甲基环己烷-1,2,3-三醇;
(4S,5S,6R,7R,8R)-4-(4-氯-3-(4-乙基苄基)苯基)-8-(羟甲基)螺[2.5]辛烷-5,6,7-三醇;
1-(4-(2-氯-5-((1R,2S,3R,4R,5S,6R)-2,3,4,6-四羟基-5-(羟甲基)环己基)苄基)苯基)乙酮;和
(1R,2R,3S,4R,5R,6S)-4-(4-氯-3-(4-(1-羟乙基)苄基)苯基)-6-(羟甲基)环己烷-1,2,3,5-四醇。
6.一种权利要求1的化合物的前药羧酸酯。
7.一种药物组合物,其包含药学上可接受的载体和权利要求1的化合物。
8.权利要求1的化合物用于制备治疗与SGLT的抑制相关的疾病或病症的药物的用途。
9.权利要求1的化合物用于制备治疗糖尿病的药物的用途。
10.根据权利要求9的用途,其中所述糖尿病为1型糖尿病。
11.根据权利要求9的用途,其中所述糖尿病为2型糖尿病。
12.根据权利要求9的用途,其中所述化合物与选自以下的治疗剂联合给药:抗糖尿病剂、降脂/调脂剂、用于治疗糖尿病并发症的药剂、减肥剂、抗高血压剂和抗高尿酸血症剂。
13.根据权利要求8的用途,其中所述疾病或病症选自1型糖尿病、2型糖尿病、高血糖症、糖尿病并发症、胰岛素抵抗、代谢综合征、高胰岛素血症、高血压、高尿酸血症、肥胖症、浮肿和异常脂肪血症。
14.权利要求4的化合物用于制备治疗与SGLT的抑制相关的疾病或病症的药物的用途,其中所述疾病或病症选自1型糖尿病、2型糖尿病、高血糖症、糖尿病并发症、胰岛素抵抗、代谢综合征、高胰岛素血症、高血压、高尿酸血症、肥胖症、浮肿和异常脂肪血症。
15.权利要求4的化合物用于制备治疗糖尿病的药物的用途。
16.一种药物组合物,其包含药学上可接受的载体和权利要求4的化合物。
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CN104909997B (zh) * | 2011-05-26 | 2017-04-12 | Tf化学公司 | 芳基、杂芳基、o‑芳基和o‑杂芳基碳环糖家族 |
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CN105611920B (zh) | 2013-10-12 | 2021-07-16 | 泰拉科斯萨普有限责任公司 | 羟基-二苯甲烷衍生物的制备 |
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CN116785268A (zh) * | 2022-03-14 | 2023-09-22 | 江苏万邦生化医药集团有限责任公司 | 一种sglt-2抑制剂的药物组合物 |
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CN101010276A (zh) * | 2004-07-26 | 2007-08-01 | 中外制药株式会社 | 新的环己烷衍生物、其前体药物及其盐、以及含有它的糖尿病治疗药 |
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KR20100098690A (ko) | 2010-09-08 |
TWI426081B (zh) | 2014-02-11 |
AU2008335080A1 (en) | 2009-06-18 |
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UA101004C2 (en) | 2013-02-25 |
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AR071268A1 (es) | 2010-06-09 |
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AU2008335080B2 (en) | 2014-06-05 |
US8129434B2 (en) | 2012-03-06 |
KR101567969B1 (ko) | 2015-11-10 |
TW200932755A (en) | 2009-08-01 |
AR113211A2 (es) | 2020-02-19 |
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