CN103957919B - RORγ调节剂 - Google Patents
RORγ调节剂 Download PDFInfo
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- CN103957919B CN103957919B CN201280045611.7A CN201280045611A CN103957919B CN 103957919 B CN103957919 B CN 103957919B CN 201280045611 A CN201280045611 A CN 201280045611A CN 103957919 B CN103957919 B CN 103957919B
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Abstract
本发明涉及用于治疗或预防、抑制或改善需要其的受试者的由RORγ受体介导的疾病、尤其是糖尿病及糖尿病相关病症、特别是II型糖尿病的式I化合物或其药学上可接受的盐,它们的制备方法以及治疗或预防所述疾病的方法。
Description
发明领域
本发明涉及用于治疗或预防、抑制或改善需要其的受试者的由RORγ受体介导的疾病、尤其是糖尿病及糖尿病相关病症、特别是II型糖尿病的化合物、制备所述化合物的方法以及治疗或预防所述疾病的方法。
背景
全世界约有两亿五千万人患糖尿病(I型和II型)且在接下来的二十年将突破该数目的两倍。1型糖尿病基于缺乏由胰腺生成的胰岛素。虽然尚未完全了解这些病因,但是1型糖尿病是由在胰腺中生成胰岛素的β-细胞的特异性和渐进性破坏引起的多因素自身免疫疾病。1型糖尿病的典型治疗包括(多次)施用胰岛素,然而,其并不治愈糖尿病或预防其最后作用,诸如肾衰竭、失明、神经损伤、截肢、心脏病发作和中风。即使在胰岛素治疗的情况下,1型糖尿病通常导致生活质量大幅度降低且使平均寿命缩短15年。2型糖尿病(也称作非胰岛素依赖型糖尿病)是以碳水化合物和脂肪代谢异常为特征的异质性疾病。2型糖尿病的病因是多因素的且包括在诸如肌肉、肝脏、胰腺和脂肪组织的组织中影响β-细胞功能和胰岛素敏感性的遗传要素和环境要素两者。因此,观察到损伤的胰岛素分泌且并行有β-细胞功能和慢性胰岛素抗性的渐进性下降。内分泌胰腺不能弥补周边胰岛素抗性导致高血糖症且临床2型糖尿病的发病以高血糖症、胰岛素抗性、绝对或相对胰岛素缺乏、高血糖素血症和增加的肝脏葡萄糖生成为特征。然而,对于该疾病仍然没有明确的治疗。
申请人现在已经惊奇地发现类视黄醇受体相关孤儿受体(ROR)可充当脂肪生成的中心调节因子。所述类视黄醇受体相关孤儿受体由三个家族成员组成,即RORα(Becker-Andree,Biochem.Biophys.Res.Commun.1993,194:1371)、RORβ(Andre等,Gene 1998,516:277)和RORγ(He等,Immunity 1998,9:797)且构成核受体超家族的NR1F(ROR/RZR)子群(Mangelsdorf等,Cell Mangelsdorf等,Cell 1995,83:835)。申请人已经表明,与免疫功能排他地相关的RORγ受体可允许抑制脂肪生成且可允许预防饮食或遗传诱发的胰岛素抗性。
因此,本发明提供本发明的化合物,尤其是基于多羟基化胆烷骨架的化合物,其能够充当ROR(γ)受体调节剂或配体,由此影响在由ROR(γ)控制的脂肪生成中的生物途径,且因此可以用于预防、治疗和改善糖尿病及糖尿病相关病症,尤其是II型糖尿病。
发明概述
本发明第一方面涉及用作ROR受体调节剂、尤其用作选择性RORγ受体配体的具有通式I的基于多羟基化胆烷骨架的化合物及其药学上可接受的盐或立体异构体(在下文中还称作本发明的化合物或本发明的RORγ受体配体或调节剂):
其中
R1、R2、R2’彼此独立地为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb,其中Ra和Rb彼此独立地为H或C(1-6)烷基,或者R1、R2与它们所连接的C-原子一起形成环氧基;
R3、R4、R5、R6彼此独立地为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb、氧代、硫代,其中Ra和Rb彼此独立地为H或C(1-6)烷基;
R7、R8、R9彼此独立地为H、C(1-10)烷基,其中一个或多个不相邻的CH2基团可被-O-、-S-、-CO-、-CO-O-、-O-CO-、-NRa-、-CO-NRa-、-NRa-CO-、-C=C-或-C≡C-置换,其中Ra为H或C(1-6)烷基;
L为连接基团,诸如直链或支化的C(1-12)烷基,其未被取代或被至少一个CN、卤素、OH、NRaRb、COORa、NO2取代,且其中所述不相邻的CH2基团中的一个或多个可独立地被选自-O-、-CO-、-CO-O-、-O-CO-、-NRa-、-NRa-CO-、-CO-NRa-、-CH=CH-、-C≡C-的基团置换,其中Ra和Rb彼此独立地为H或C(1-6)烷基,
X为H、-ORa、-SRa、-NRaRb、-COORc、-CONRaRc;其中Ra和Rb彼此独立地为H或C(1-6)烷基且Rc为-H、-C(1-6)烷基、-NH-(CH2)n-CO2Ra或-NH-(CH2)p-SO3Ra,其中n、p为1、2或3且Ra为-H或-C(1-6)烷基;
m为0-5。
在特定的实施方案中,本发明的化合物基于在C17处具有-L-X-取代基的多羟基化胆烷骨架,且其中所述羟基(或氧代-)取代基优选在一个或多个选自C1、C3、C6、C7、C12的位置,更优选其中所述羟基(或氧代-)取代基在总共三个或四个选自C1、C3、C6、C7、C12的位置,最优选其中所述羟基(或氧代-)取代基在总共三个或四个选自C1、C3、C6、C7、C12的位置,其中一个羟基(或氧代-取代基)在C1或C6位置。
本发明的优选化合物具有在位置C1、C3和C7;C1、C3和C12;C1、C7和C12;C3、C6和C7;C3、C6和C12;C6、C7和C12;C1、C3和C6;C1、C6和C7;及C1、C6和C12处的三个羟基(或氧代-取代基)。
本发明的其他优选化合物具有在位置C1、C3、C7和C12;C3、C6、C7和C12;C1、C3、C6和C7;C1、C3、C6和C12;及C1、C6、C7和C12处的四个羟基(或氧代-取代基)。
在一些实施方案中,本发明包括式II化合物及其药学上可接受的盐或立体异构体,优选其立体异构形式IIa:
其中
R1、R2彼此独立地为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb,其中Ra和Rb彼此独立地为H或C(1-6)烷基,或R1、R2与它们所连接的C-原子一起形成环氧基;
R3、R4、R5、R6彼此独立地为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb、氧代、硫代,其中Ra和Rb彼此独立地为H或C(1-6)烷基;
R2’为H或卤素;
L为连接基团,诸如直链或支化的C(1-12)烷基,其未被取代或被至少一个CN、卤素、OH、NRaRb、COORa、NO2取代,且其中不相邻的CH2基团中的一个或多个可独立地被选自-O-、-CO-、-CO-O-、-O-CO-、-NRa-、-NRa-CO-、-CO-NRa-、-CH=CH-、-C≡C-的基团置换,其中Ra和Rb彼此独立地为H或C(1-6)烷基;
X为H、-ORa、-SRa、-NRaRb、-COORc、-CONRaRc;其中Ra和Rb彼此独立地为H或C(1-6)烷基且Rc为-H、-C(1-6)烷基、-NH-(CH2)n-CO2Ra或-NH-(CH2)p-SO3Ra,其中n、p为1、2或3且Ra为-H或-C(1-6)烷基;
m为0-5。
在一个优选的实施方案中,至少三个、优选三个或四个选自R1、R3、R4、R5和R6的基团为-ORa或氧代,其中Ra为H或C(1-6)烷基。
在另一优选的实施方案中,R1和/或R4为-ORa或氧代。
更具体地讲,本发明的化合物以式I、II或IIa为特征,其中(i)R4和R6为-ORa,或(ii)R1和R6为-ORa,或(iii)R3为-ORa或氧代且R6为-ORa,或(iv)R5和R6为-OR,且在各所述化合物中的剩余基团具有以下意义(在适用的情况下):
R1为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb,优选为H、-ORa、-NRaRb,其中Ra和Rb彼此独立地为H或C(1-6)烷基,或R1与R2及与R1、R2连接的C-原子一起形成环氧基;
R2为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb,优选为H或卤素,其中Ra和Rb彼此独立地为H或C(1-6)烷基,或R2与R1及与R1、R2连接的C-原子一起形成环氧基;
R3、R4、R5彼此独立地为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb、氧代、硫代,优选为H、氧代、-ORa、-NRaRb,其中Ra和Rb彼此独立地为H或C(1-6)烷基;
R2’为H或卤素;
L为直链或支化的C(1-12)烷基,其未被取代且其中一个或多个不相邻的CH2基团可独立地被选自-O-、-CO-、-CO-O的基团置换;
X为H、-ORa、-SRa、-NRaRb、-COORc、-CONRaRc;其中Ra和Rb彼此独立地为H或C(1-6)烷基且Rc为-H、-C(1-6)烷基、-NH-(CH2)n-CO2Ra或-NH-(CH2)p-SO3Ra,其中n、p为1、2或3且Ra为-H或-C(1-6)烷基;
m为0-5。
在优选的实施方案中,本发明包括式IV和V的化合物(其中R3为-ORa或氧代)及其药学上可接受的盐或立体异构体,
其中
R1为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb,优选为H、-ORa、-NRaRb,其中Ra和Rb彼此独立地为H或C(1-6)烷基,或R1与R2及与R1、R2连接的C-原子一起形成环氧基;
R2为H或卤素,或R2与R1及与R1、R2连接的C-原子一起形成环氧基;
R2’为H或卤素;
R4为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb、氧代、硫代,优选为H、氧代、-ORa、-NRaRb,其中Ra和Rb彼此独立地为H或C(1-6)烷基;
L为直链或支化的C(1-12)烷基;
X为H、-ORa、-COORc、-CONRaRc,其中Ra为H或C(1-6)烷基且Rc为-H、-C(1-6)烷基、-NH-(CH2)n-CO2Ra或-NH-(CH2)p-SO3Ra,其中n、p为1、2或3且Ra为-H或-C(1-6)烷基;
Ra为H或C(1-6)烷基;且
m为0-5。
另一方面,本发明的方法还涉及合成本发明化合物的方便且高效的方法。
本发明在又一方面还涉及包含至少一种本发明的化合物和药学上可接受的载体及任选至少一种另外的治疗活性剂的药物组合物。
又一方面,本发明涉及通过给予至少一种本发明的化合物(或其药物组合物)治疗或预防需要其的哺乳动物的对RORγ受体的调节起应答的病症、疾病或病状,尤其是糖尿病及糖尿病相关病症,特别是II型糖尿病的方法。
又一方面,本发明涉及包含至少一种本发明的化合物(或其药物组合物)的药盒。
附图简述
图1:荧光素酶活性测定的示意图;
图2:RORγ活性的抑制(RI=相对抑制作用;Conc=1β,3α,7α,12α-四羟基-5β-胆烷-24-酸(四醇)的浓度(nM))。
图3:对在喂饲高脂饮食以及不同浓度的不同补充物的小鼠中的胰岛素敏感性的影响。y轴表示相对葡萄糖水平,x轴表示在胰岛素注射之后的时间,分钟。高脂饮食原样给予(E)或补充有四醇0.1%(A)或四醇0.01%(B)或胆酸0.1%(C)或胆酸0.01%(D)。
图4:随着时间的过去四醇化合物和作为对照化合物的胆酸对肥胖/胰岛素抗性小鼠中的葡萄糖水平的影响(x轴表示葡萄糖mM,y轴表示6周和12周的时间点,条纹条表示禁食小鼠,填充条表示喂饲小鼠)。
图5:随着时间的过去四醇化合物和作为对照化合物的胆酸对肥胖/胰岛素抗性小鼠中的胰岛素水平的影响(x轴表示pg/ml胰岛素,y轴表示6周和12周的时间点,条纹条表示禁食小鼠,填充条表示喂饲小鼠)。
发明详述
除非另外说明,否则以下术语具有所指出的意义:
术语“受试者”是指雄性或雌性的哺乳动物,诸如人类或动物,优选人类。
术语“配体”或“调节剂”是指结合受体分子以形成受体-配体复合物的天然或合成的化合物。术语配体可包括激动剂、拮抗剂和具有部分激动剂/拮抗剂作用的化合物。“激动剂”为结合受体以形成受体-激动剂复合物,由此活化所述受体,引发途径信号转导和另外的生物进程的天然或合成的化合物。“拮抗剂”是指具有与激动剂相反的生物作用的天然或合成的化合物。拮抗剂结合受体且阻断受体激动剂的作用。术语“配体”或“调节剂”在根据本发明并结合例如ROR(γ)受体使用时是指可与ROR(γ)受体相互作用并引发药理学或生化应答的(内源)化合物。
术语“结合亲和力”是指化合物结合其生物靶标的能力。对于本发明,其是指本发明化合物结合ROR(γ)受体的能力。
术语“功效”描述当与其受体结合时由化合物引发的应答的相对强度。最大应答取决于与受体结合的效率。
本文使用的术语“糖尿病”包括胰岛素依赖型糖尿病(即,IDDM,也称作I型糖尿病)和非胰岛素依赖型糖尿病(即,NIDDM,也称作II型糖尿病)两种。I型糖尿病即胰岛素依赖型糖尿病是绝对缺乏调节葡萄糖利用的激素-胰岛素的结果。II型糖尿病即非胰岛素依赖型糖尿病(insulin-independent diabete)(即,非胰岛素依赖型糖尿病(non-insulin-dependent diabetes mellitus))常以面临正常或甚至升高水平的胰岛素而出现,且似乎是组织不能对胰岛素作出适当反应的结果。本发明的化合物和组合物可用于治疗I型糖尿病和II型糖尿病两种,但可特别有效地治疗II型糖尿病(如在下文中所示)。
本文使用的术语“糖尿病相关病症”包括与1型和2型糖尿病相关的疾病、病症和病状,尤其是与2型糖尿病相关的疾病、病症和病状,因此可通过施用本发明的化合物和组合物来治疗、控制或在一些情况下预防。糖尿病相关病症例如包括高血糖症、低葡萄糖耐受、胰岛素抗性、肥胖症、脂质紊乱、血脂异常、高脂血症、高甘油三酯血症、高胆固醇血症、低HDL水平、高LDL水平、动脉粥样硬化、血管再狭窄、肠易激综合征、包括克罗恩氏病(Crohn′sdisease)和溃疡性结肠炎的炎性肠病、其他炎性病状、胰腺炎、腹部肥胖症、神经变性疾病、视网膜病、肾病、神经病、X综合征、卵巢雄激素过多症(多囊性卵巢症)及其中胰岛素抗性为贡献性成分的其他病症。
根据本发明糖尿病的“治疗”是指例如在需要其的受试者如糖尿病性受试者中给予至少一种本发明的化合物以治疗如本文定义的糖尿病及糖尿病相关病症。这类治疗的可能结果可降低在具有升高的葡萄糖水平的受试者中的葡萄糖水平和/或改进血糖控制和/或降低在具有升高的胰岛素水平的受试者中的胰岛素水平和/或降低升高的血糖浓度和/或降低增加的胰岛素浓度和/或降低增加的血液甘油三酯浓度和/或增加胰岛素敏感性和/或增强在具有葡萄糖耐受不良的受试者中的葡萄糖耐受和/或降低胰岛素抗性和/或降低血浆胰岛素水平和/或改进血糖控制,特别是改进2型糖尿病中的血糖控制。
根据本发明的糖尿病的“预防(Prevention)”(或“预防(prophylaxis)”)是指给予至少一种本发明的化合物以预防或治疗在需要其的受试者如前驱糖尿病受试者中的如本文定义的糖尿病和糖尿病相关病症的发病。
本文使用的术语“受试者”是指动物,优选哺乳动物,最优选人类。
术语“多羟基化胆烷骨架”尤其包括多羟基化胆甾烷且更具体地包括多羟基化胆汁酸。根据本发明的多羟基化胆烷或胆汁酸化合物包括但不限于三羟基化、四羟基化、五羟基化、六羟基化胆汁酸等至最大的羟基化水平,但优选(至少)三羟基化和(至少)四羟基化胆汁酸。术语“胆汁酸”涵盖所有天然存在(化学合成)的胆汁酸(不管是来自人还是另一动物),包括其缀合物(例如,尤其是与甘氨酸、牛磺酸和可能的其他氨基酸的缀合物)以及合成或半合成的类似物。大多数天然存在的胆汁酸的特征在于羟基在胆烷骨架的A、B和C环中,主要在位置C3、C7、C12中的一个或多个处,可能(但不太寻常)在位置C1、C6等处。在胆烷骨架中(和在胆汁酸中)的环A和B的连接以两种异构形式存在,即,C5-取代基和C8-取代基为构造的顺(5-β-胆烷)或反(5-α-胆烷)。对于本发明的化合物,如果没有说明不同之处,则涵盖A/B-环接点的α-异构体和β-异构体两者,优选β-异构体。
本发明在第一方面涉及用作ROR受体调节剂、尤其用作选择性RORγ受体配体的具有通式I的化合物或其药学上可接受的盐或立体异构体(编号根据IUPAC命名规则表明)
其中
R1、R2、R2’彼此独立地为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb,其中Ra和Rb彼此独立地为H或C(1-6)烷基,或R1、R2与它们所连接的C-原子一起形成环氧基;
R3、R4、R5、R6彼此独立地为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb、氧代、硫代,其中Ra和Rb彼此独立地为H或C(1-6)烷基;
R7、R8、R9彼此独立地为H、C(1-10)烷基,其中一个或多个不相邻的CH2基团可被-O-、-S-、-CO-、-CO-O-、-O-CO-、-NRa-、-CO-NRa-、-NRa-CO-、-C=C-或-C≡C-置换;其中Ra为H或C(1-6)烷基;
L为连接基团,诸如直链或支化的C(1-12)烷基,其未被取代或被至少一个CN、卤素、OH、NRaRb、COORa、NO2取代,且其中一个或多个不相邻的CH2基团可被选自-O-、-CO-、-CO-O-、-O-CO-、-NRa-、-NRa-CO-、-CO-NRa-、-CH=CH-、-C≡C-的基团独立地置换,其中Ra和Rb彼此独立地为H或C(1-6)烷基;
X为H、-ORa、-SRa、-NRaRb、-COORc、-CONRaRc;其中Ra和Rb彼此独立地为H或C(1-6)烷基且Rc为-H、-C(1-6)烷基、-NH-(CH2)n-CO2Ra或-NH-(CH2)p-SO3Ra,其中n、p为1、2或3且Ra为-H或-C(1-6)烷基;
m为0-5。
应当理解的是,(H)m表示在所指出的A-环上(即,在C1、C2、C3、C4、C5和C10上)的所有氢取代基。技术人员将知道对于在环A上的基团R1、R2、R2’、R3的特定取代型式存在多少H-取代基。例如,m=5可表示没有双键的完全饱和的环,m=3可表示例如具有一个双键(例如在C1-C2之间或在C4-C5之间)的环。m=2可表示例如具有一个双键(例如在C1-C2之间或在C4-C5之间)且R3为氧代的环,且m=0可表示例如具有在C1-C2之间和在C4-C5之间的双键且R3为氧代的完全不饱和的环。因此,饱和度和取代基的性质决定存在的H-原子的数目或反之亦然,H-原子的数目是指出环A的不饱和度的一种方式。
在特定的实施方案中,根据式I的本发明化合物基于在C17处具有-L-X-取代基的多羟基化胆烷骨架,且其中羟基(或氧代-)取代基优选在两个或更多个、优选至少三个选自C1、C3、C6、C7、C12的位置处(分别由基团R1、R3、R4、R5、R6表示),更优选其中羟基(或氧代-)取代基在总共三个或四个选自C1、C3、C6、C7、C12的位置处,最优选其中羟基(或氧代-)取代基在总共三个或四个选自C1、C3、C6、C7、C12的位置处,其中一个羟基(或氧代-)取代基在位置C1或C6处。
因此,在一些实施方案中,本发明的化合物具有三个羟基(或氧代-取代基)且羟基化型式包括(i)在C1处的羟基(或氧代-)取代基以及在位置C3和C7、C3和C12、C7和C12处的另外两个羟基(或氧代-)取代基的组合,和(ii)在C6处的羟基(或氧代-)取代基以及在位置C3和C7、C3和C12及C7和C12处的另外两个羟基(或氧代-)取代基的组合,和(iii)在C1和C6两者处的羟基(或氧代-)取代基以及在位置C3或C7或C12处的另一羟基(或氧代-)取代基。
在其他实施方案中,本发明的化合物具有四个羟基(或氧代-)取代基且羟基化型式包括(i)在C1处的羟基(或氧代-)取代基以及在位置C3、C7和C12处的另外三个羟基(或氧代-)取代基;(ii)在C6处的羟基(或氧代-)取代基以及在位置C3、C7和C12处的另外三个羟基(或氧代-)取代基;和(iii)在C1和C6两者处的羟基(和氧代-)取代基以及在位置C3和C7、C3和C12、C7和C12处的另外两个羟基(或氧代-)取代基的组合。
在一个优选的实施方案中,R7、R8、R9彼此独立地为H、C(1-10)烷基,更优选为甲基、乙基、丙基、丁基,最优选为甲基。
在一些实施方案中,R1、R2彼此独立地为H、卤素、-ORa、-COORa,其中Ra为H或C(1-6)烷基,或与它们所连接的C-原子一起形成环氧基。
优选R2为H或卤素,或与R1和与R1和R2连接的C-原子一起形成环氧基。
优选R2’为H或卤素,更优选为H或Cl、Br、I。
优选R3、R1、R5、R6彼此独立地为H、-ORa、-NRaRb、-COORa、-CONRaRb或氧代,其中Ra和Rb彼此独立地为H或C(1-6)烷基。
更优选R3为H、-ORa、-NRaRb或氧代,其中Ra和Rb彼此独立地为H或C(1-6)烷基;R4、R5、R6彼此独立地为H、-ORa或-NRaRb,其中Ra和Rb彼此独立地为H或C(1-6)烷基;且R7、R8、R9彼此独立地为H、C(1-10)烷基,更优选为甲基、乙基、丙基、丁基,最优选为甲基。
因此,优选本发明包括式II化合物及其药学上可接受的盐或立体异构体,优选其优选其立体异构形式IIa,
其中
R1、R2彼此独立地为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb,其中Ra和Rb彼此独立地为H或C(1-6)烷基,或R1、R2与它们所连接的C-原子一起形成环氧基;
R3、R4、R5、R6彼此独立地为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb、氧代、硫代,其中Ra和Rb彼此独立地为H或C(1-6)烷基;
R2’为H或卤素,
L为连接基团,诸如直链或支化的C(1-12)烷基,其未被取代或被至少一个CN、卤素、OH、NRaRb、COORa、NO2取代,且其中一个或多个不相邻的CH2基团可被选自-O-、-CO-、-CO-O-、-O-CO-、-NRa-、-NRa-CO-、-CO-NRa-、-CH=CH-、-C≡C-的基团独立地置换,其中Ra和Rb彼此独立地为H或C(1-6)烷基;
X为H、-ORa、-SRa、-NRaRb、-COORc、-CONRaRc;其中Ra和Rb彼此独立地为H或C(1-6)烷基,且Rc为-H、-C(1-6)烷基、-NH-(CH2)n-CO2Ra或-NH-(CH2)p-SO3Ra,其中n、p为1、2或3且Ra为-H或-C(1-6)烷基;
m为0-5。
在一个优选的实施方案中,至少三个、优选三个或四个选自R1、R3、R4、R5和R6的基团为-ORa或氧代,其中Ra为H或C(1-6)烷基。
在另一优选的实施方案中,R1和/或R4为-ORa或氧代。
更优选至少三个、优选三个或四个选自R1、R3、R4、R5和R6的基团为-ORa或氧代,其限制条件为R1和/或R4为-ORa或氧代,其中Ra为H或C(1-6)烷基。
在特定的实施方案中,L(在本文公开的所有式中)为直链或支化的C(1-12)烷基,其未被取代且其中一个或多个不相邻的CH2基团可被选自-O-、-CO-、-CO-O-的基团独立地置换。优选L为直链或支化的C(1-12)烷基,更优选为如本文定义的直链或支化的C(1-6)烷基。
优选X(在本文公开的所有式中)为H、-ORa、-COORc、-CONRaRc,其中Ra为H或C(1-6)烷基且Rc为-H、-C(1-6)烷基、-NH-(CH2)n-CO2Ra或-NH-(CH2)p-SO3Ra,其中n、p为1、2或3且Ra为-H或-C(1-6)烷基。优选Rc为-H、-C(1-6)烷基、-NH-CH2-CO2Ra或-NH-(CH2)2-SO3Ra,其中Ra为-H或-C(1-6)烷基。
在优选的实施方案中,基团-L-X(在本文公开的所有式中)为-C(1-6)烷基-COORa,更优选为-(CH2)2-COORa,其中Ra为-H或-C(1-6)烷基。
优选R2为H或卤素,或与R1和与R1和R2连接的C-原子一起形成环氧基。
在特定的实施方案中,R4、R6为-ORa,因此本发明特别包括式IIIa化合物及其所有药学上可接受的盐或立体异构体,优选其立体异构形式IIIb,
其中
R1为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb,优选为H、-ORa、-NRaRb,其中Ra和Rb彼此独立地为H或C(1-6)烷基,或R1与R2和与R1、R2连接的C-原子一起形成环氧基;
R2为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb,优选为H或卤素,其中Ra和Rb彼此独立地为H或C(1-6)烷基,或R2与R1和与R1、R2连接的C-原子一起形成环氧基;R3、R5彼此独立地为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb、氧代、硫代,优选为H、氧代、-ORa、-NRaRb,其中Ra和Rb彼此独立地为H或C(1-6)烷基;
R2’为H或卤素,
L为直链或支化的C(1-12)烷基,其未被取代且其中一个或多个不相邻的CH2基团可被选自-O-、-CO-、-CO-O的基团独立地置换;
X为H、-ORa、-SRa、-NRaRb、-COORc、-CONRaRc;其中Ra和Rb彼此独立地为H或-C(1-6)烷基且Rc为-H、-C(1-6)烷基、-NH-(CH2)n-CO2Ra或-NH-(CH2)p-SO3Ra,其中n、p为1、2或3且Ra为-H或-C(1-6)烷基;
Ra为H或C(1-6)烷基;
m为0-5。
在其他特定的实施方案中,R6为-ORa且R1为-ORa或与R2形成环氧化物,且因此本发明特别包括式IIIc和IIId的化合物及其所有药学上可接受的盐或立体异构体,优选为其立体异构形式IIIe1/IIIe2和IIIf1/IIIf2,
其中
R2为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb,优选为H或卤素,其中Ra和Rb彼此独立地为H或C(1-6)烷基;
R3、R4、R5彼此独立地为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb、氧代、硫代,优选为H、氧代、-ORa、-NRaRb,其中Ra和Rb彼此独立地为H或C(1-6)烷基;
R2’为H或卤素,
L为直链或支化的C(1-12)烷基,其未被取代且其中一个或多个不相邻的CH2基团可被选自-O-、-CO-、-CO-O的基团独立地置换;
X为H、-ORa、-SRa、-NRaRb、-COORc、-CONRaRc;其中Ra和Rb彼此独立地为H或C(1-6)烷基且Rc为-H、-C(1-6)烷基、-NH-(CH2)n-CO2Ra或-NH-(CH2)p-SO3Ra,其中n、p为1、2或3且Ra为-H或-C(1-6)烷基;
Ra为H或C(1-6)烷基,
m为0-5。
在特定的实施方案中,R3为-ORa且R6为-ORa或氧代,且因此本发明特别包括式IIIg和IIIh的化合物及其所有药学上可接受的盐或立体异构体,优选为其立体异构形式IIIi1、IIIi2,
其中
R1为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb,优选为H、-ORa、-NRaRb,其中Ra和Rb彼此独立地为H或C(1-6)烷基,或R1与R2和与R1、R2连接的C-原子一起形成环氧基;
R2为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb,优选为H或卤素,其中Ra和Rb彼此独立地为H或C(1-6)烷基,或R2与R1和与R1、R2连接的C-原子一起形成环氧基;R4、R5彼此独立地为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb、氧代、硫代,优选为H、氧代、-ORa、-NRaRb,其中Ra和Rb彼此独立地为H或C(1-6)烷基;
R2’为H或卤素,
L为直链或支化的C(1-12)烷基,其未被取代且其中一个或多个不相邻的CH2基团可被选自-O-、-CO-、-CO-O的基团独立地置换;
X为H、-ORa、-SRa、-NRaRb、-COORc、-CONRaRc;其中Ra和Rb彼此独立地为H或C(1-6)烷基且Rc为-H、-C(1-6)烷基、-NH-(CH2)n-CO2Ra或-NH-(CH2)p-SO3Ra,其中n、p为1、2或3且Ra为-H或-C(1-6)烷基;
Ra为H或C(1-6)烷基;
m为0-5。
在特定的实施方案中,R5、R6为-ORa,因此,本发明特别包括式IIIj化合物及其所有药学上可接受的盐或立体异构体,优选为基立体异构形式IIIk,
其中
R1为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb,优选为H、-ORa、-NRaRb,其中Ra和Rb彼此独立地为H或C(1-6)烷基,或R1与R2和与R1、R2连接的C-原子一起形成环氧基;
R2为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb,优选为H或卤素,其中Ra和Rb彼此独立地为H或C(1-6)烷基,或R2与R1和与R1、R2连接的C-原子一起形成环氧基;R3、R4彼此独立地为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb、氧代、硫代,优选为H、氧代、-ORa、-NRaRb,其中Ra和Rb彼此独立地为H或C(1-6)烷基;
R2’为H或卤素,
L为直链或支化的C(1-12)烷基,其未被取代且其中一个或多个不相邻的CH2基团可被选自-O-、-CO-、-CO-O的基团独立地置换;
X为H、-ORa、-SRa、-NRaRb、-COORc、-CONRaRc;其中Ra和Rb彼此独立地为H或C(1-6)烷基且Rc为-H、-C(1-6)烷基、-NH-(CH2)n-CO2Ra或-NH-(CH2)p-SO3Ra,其中n、p为1、2或3且Ra为-H或-C(1-6)烷基;
Ra为H或C(1-6)烷基;
m为0-5。
在特定的实施方案中,在式IIIa化合物(及其立体异构形式)中,R1为-ORa,或者在式IIIc和IIId化合物(及其立体异构形式)中,R4为-ORa,或者在式IIIg、IIIh和IIIk的化合物(及其立体异构形式)中,R1和R4皆为-ORa,其中Ra为H或C(1-6)烷基。
在优选的实施方案中,本发明包括式IV化合物(其中R3为氧代)及其所有药学上可接受的盐或立体异构体,
其中
R1为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb,优选为H、-ORa、-NRaRb,其中Ra和Rb彼此独立地为H或C(1-6)烷基,或R1与R2和与R1、R2连接的C-原子一起形成环氧基;
R2为H或卤素,或R2与R1和与R1、R2连接的C-原子一起形成环氧基;
R2’为H或卤素,
R4为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb、氧代、硫代,优选为H、氧代、-ORa、-NRaRb,其中Ra和Rb彼此独立地为H或C(1-6)烷基;
L为直链或支化的C(1-12)烷基;
X为H、-ORa、-COORc、-CONRaRc,其中Ra为H或C(1-6)烷基且Rc为-H、-C(1-6)烷基、-NH-(CH2)n-CO2Ra或-NH-(CH2)p-SO3Ra,其中n、p为1、2或3且Ra为-H或-C(1-6)烷基;
Ra为H或C(1-6)烷基;且
m为1、2、3或4。
优选如果环A完全饱和,则m为4,且如果环A部分(一个双键)或完全(两个双键)不饱和,则m为0或2。
在一个优选的实施方案中,在化合物IV中,R1或R4或R1和R4两者为-ORa,其中Ra为H或C(1-6)烷基。
在其他优选的实施方案中,本发明包括式V化合物(其中R3为-ORa)及其所有的药学上可接受的盐或立体异构体,优选为其立体异构形式Va和Vb,
其中
R1为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb,优选为H、-ORa、-NRaRb,其中Ra和Rb彼此独立地为H或C(1-6)烷基,或R1与R2和与R1、R2连接的C-原子一起形成环氧基;
R2为H或卤素,或R2与R1和与R1、R2连接的C-原子一起形成环氧基;
R2’为H或卤素;
R4为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb、氧代、硫代,优选为H、氧代、-ORa、-NRaRb,其中Ra和Rb彼此独立地为H或C(1-6)烷基;
L为直链或支化的C(1-12)烷基;
X为H、-ORa、-COORc、-CONRaRc,其中Ra为H或C(1-6)烷基且Rc为-H、-C(1-6)烷基、-NH-(CH2)n-CO2Ra或-NH-(CH2)p-SO3Ra,其中n、p为1、2或3且Ra为-H或-C(1-6)烷基;
Ra为H或C(1-6)烷基;且
m为1、2、3、4或5。
优选如果环A完全饱和,则m为5,且如果环A部分(一个双键)或完全(两个双键)不饱和,则m为1或3。
在一个优选的实施方案中,在式V、Va和Vb的任何化合物中R1或R4或R1和R4两者为-ORa,其中Ra为H或C(1-6)烷基。
一些优选的实例例如包括式VIa的化合物及其所有药学上可接受的盐或立体异构体,其中R3=-ORa,R1=R2=R2’=H且R4为-ORa,其包括C3α-立体异构体和C3β-立体异构体(VIa1、VIa2);或
式VIb的化合物及其所有药学上可接受的盐或立体异构体,其中R3为-ORa,R4=R2′=R2’=H且R1为-ORa,其包括C1α/C3α-、C1α/C3β-、C1β/C3α-、C1β/C3β-立体异构体(VIb1、VIb2、VIb3、VIb4);或
式VIc的化合物,其中R3为-ORa,R2′=R2’=H且R1和R4为-ORa,其包括C1α/C3α-、C1α/C3β-、C1β/C3α-、C1β/C3β-立体异构体,它们各自具有在α位或在β位的C6。
VIa
其中L为直链或支化的C(1-12)烷基,其未被取代且其中一个或多个不相邻的CH2基团可被选自-O-、-CO-、-CO-O-的基团独立地置换,优选直链或支化的C(1-6)烷基,
Ra为H或C(1-6)烷基,
X为H、-ORa、-SRa、-NRaRb、-COORc、-CONRaRc;其中Ra和Rb彼此独立地为H或C(1-6)烷基且Rc为-H、-C(1-6)烷基、-NH-(CH2)n-CO2Ra或-NH-(CH2)p-SO3Ra,其中n、p为1、2或3且Ra为-H或-C(1-6)烷基,优选为H、-ORa、-COORc、-CONRaRc。
其他优选的实例例如包括式VIIa、VIIb的化合物及其所有药学上可接受的盐或立体异构体,其中R3-氧代,R1-R2-R2’-H且R4为-ORa并且环A部分不饱和,其包括C6α-或C6β-立体异构体;
式VIIc、VIId的化合物及其所有药学上可接受的盐或立体异构体,其中R3=氧代,R4=R2′,且R1为-ORa且R2为H或者R1和R2形成环氧化物,其包括C1α-或C1β-立体异构体(环氧化物或-ORa);和
式VIIe、VIIf的化合物及其所有药学上可接受的盐或立体异构体,其中R3=氧代,R2′=H,R1和R4皆为-ORa或氧代且环A饱和或部分不饱和,其包括C1α/C6α-、C1α/C6β-、C1β/C6α-、C1β/C6β-立体异构体,
其中L为直链或支化的C(1-12)烷基,其未被取代且其中一个或多个不相邻的CH2基团可被选自-O-、-CO-、-CO-O-的基团独立地置换,优选直链或支化的C(1-6)烷基;
Ra为H或C(1-6)烷基;
X为H、-ORa、-SRa、-NRaRb、-COORc、-CONRaRc;其中Ra和Rb彼此独立地为H或C(1-6)烷基且Rc为-H、-C(1-6)烷基、-NH-(CH2)n-CO2Ra或-NH-(CH2)p-SO3Ra,其中n、p为1、2或3且Ra为-H或-C(1-6)烷基,优选为H、-ORa、-COORc、-CONRaRc。
术语“烷基”是指包含所规定数目的碳原子的直链或支化的碳链。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、1-甲基丙基、2-甲基丙基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、1,2-二甲基丙基、1,1-二甲基丙基、2,2-二甲基丙基、正己基、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、3-乙基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,2-二甲基丁基、2,3-二甲基丁基、3,3-二甲基丁基、正庚基、1-甲基己基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、1-乙基戊基、2-乙基戊基、3-乙基戊基、4-乙基戊基、1-丙基丁基、2-丙基丁基、3-丙基丁基、1,1-二甲基戊基、1,2-二甲基戊基、1,3-二甲基戊基、1,4-二甲基戊基、2,2-二甲基戊基、2,3-二甲基戊基、2,4-二甲基戊基、3,3-二甲基戊基、3,4-二甲基戊基、4,4-二甲基戊基、1-甲基-1-乙基丁基、1-甲基-2-乙基丁基、2-甲基-2-乙基丁基、1-乙基-2-甲基丁基、1-乙基-3-甲基丁基、1,1-二乙基丙基、正辛基、正壬基、正癸基等。
因此,本文使用的术语“C(1-6)烷基”是指支化或直链的烷基且包括“直链C(1-6)烷基”,诸如甲基、乙基、正丙基、正丁基、正戊基和正己基;和“支化C(3-6)烷基”,诸如异丙基、异丁基、叔丁基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、3-甲基-2-丁基、2,2-二甲基-丙基、2-己基、3-己基、3-甲基-2-戊基、3-甲基-3-戊基、2,2-二甲基-丁基、3,3-二甲基-丁基、2,3-二甲基-2-丁基、2,3-二甲基-3-丁基和3,3-二甲基-2-丁基。
术语“卤素”(或“卤素”)包括氟、氯、溴和碘,优选为氯和溴,更优选为溴。
术语“氧代”是指由双键连接的氧原子(=O)。
术语“硫代”是指由双键连接的硫原子(=S)。
指数“m”为1、2、3、4或5。
应理解的是,如果以上定义的术语中的一个或多个在式中出现不止一个(例如Ra、Rb、Rc),则各个术语彼此独立地定义。
本发明化合物可含有一个手性平面、一个或多个不对称或手性中心且可以不同立体异构型式存在,诸如外消旋物和外消旋混合物、光学纯对映异构体、对映异构混合物、光学纯非对映异构体和非对映异构混合物。本发明的中间体和化合物的所有立体异构形式以及包括外消旋混合物和非对映异构混合物的其混合物形成本发明的一部分,它们具有可用于治疗本文论述的病状的性质。
本发明的化合物可以通过本领域已知的标准技术分离成其单个对映异构体和非对映异构体,所述标准技术诸如为从例如甲醇或乙酸乙酯或其混合物的合适溶剂中分步结晶或使用光学活性固定相的手性色谱法。绝对立体化学可通过结晶产物或结晶中间体的X-射线晶体衍射法测定,如果需要,则所述结晶产物或结晶中间体用含有已知绝对构型的不对称中心的试剂衍生化。对映异构体和非对映异构体可通过使用手性HPLC柱或通过经由与适当的光学活性化合物(例如,手性助剂,诸如手性醇或Mosher′s酰基氯)反应将对映异构混合物转化成非对映异构混合物,分离所述非对映异构体并将单个非对映异构体转化(例如,水解)成对应的纯对映异构体来分离。或者,本发明化合物的任何立体异构体都可通过使用已知绝对构型的光学纯起始材料或试剂立体定向合成来获得。
如果对映异构体或非对映异构体的生物活性不同,则可能特别需要这类对映异构或非对映异构分离或立体定向合成。
本发明意欲包括本发明化合物的所有这样的异构形式,包括双键的E和Z几何异构体及其混合物。许多本发明化合物和中间体因此表现出互变异构现象,因此它们在一定条件下可以不同的互变异构形式存在。术语“互变异构体”或“互变异构形式”是指相同能量的结构异构体(50∶50混合物),或者不同能量的结构异构体,它们可经低能垒互相转化。例如,质子互变异构体包括经质子迁移互相转化,诸如酮-烯醇和亚胺-烯胺异构化。价键互变异构体包括通过重新组织一些成键电子进行的互相转化。所有这类互变异构形式都在本发明的范围内。在本文中的任何结构式中的任何特定的互变异构形式的描述并非想要对于该形式加以限制,而是想要表示全部互变异构组。
还应该理解,本发明的化合物包括本发明化合物的水合物、溶剂合物、多晶型物、结晶、水合结晶和无定形形式及其药学上可接受的盐。
例如,本发明的化合物和中间体可以非溶剂化形式以及用诸如水、乙醇、异丙醇等溶剂溶剂化的形式存在,且溶剂化形式和非溶剂化形式都包括在本发明的范围内。在本发明的方法方面使用的溶剂合物应该包括药学上可接受的溶剂。
术语“药学上可接受的盐”是指由包括无机或有机碱和无机或有机酸的药学上可接受的无毒碱或酸制备的盐。衍生自无机碱的盐包括铝、铵、钙、铜、铁、亚铁、钾、镁、锰盐、二价锰、钾、钠、锌等的盐。特别优选铵、钙、钾、镁、钾和钠盐。衍生自药学上可接受的有机无毒碱的盐包括以下的盐:伯胺、仲胺和叔胺、包括天然存在的被取代胺的被取代的胺、环胺和碱性离子交换树脂,诸如精氨酸、甜菜碱、咖啡因、胆碱、N,N’-二苄基乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、胺基葡萄糖、组氨酸、海巴明、异丙胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、TEA、三甲胺、三丙胺、氨基丁三醇等。
当本发明的化合物为碱性时,可由包括无机酸和有机酸的药学上可接受的无毒酸制备盐。所述酸包括乙酸、苯磺酸、安息香酸、樟脑磺酸、柠檬酸、乙磺酸、甲酸、反丁烯二酸、葡糖酸、谷氨酸、氢溴酸、盐酸、羟乙基磺酸、乳酸、顺丁烯二酸、苹果酸、扁桃酸、甲磺酸、丙二酸、粘液酸、硝酸、帕莫酸、泛酸、磷酸、丙酸、琥珀酸、硫酸、酒石酸、对甲苯磺酸、三氟乙酸等。特别优选柠檬酸、反丁烯二酸、氢溴酸、盐酸、顺丁烯二酸、磷酸、硫酸和酒石酸。应当理解的是,如本文所使用,提到本发明的化合物意欲还包括药学上可接受的盐,诸如盐酸盐。
另一方面,本发明还涉及制备本发明化合物的方法,该方法能够克服与已知现有技术方法相关的缺点(例如,产率低)。根据所报道的程序,1,3,7,12-四羟基化合物通过将适当保护的C3-氧代-胆酸衍生物转化成对应的烯酮,随后通过亲核环氧化使该烯酮官能化,接着打开环氧环以给出(在合适的去保护流程之后)所要的1,3,7,12-四羟基化合物来获得。
据发现,用于引入羟基官能团(例如,在C1处)的特别合适方法包括将基于硅的缀合物加成到关键中间体烯酮上且随后氧化除去硅基(在Tamao-Flcming条件下,如在例如Fleming,I.等,J.Chem.Soc.,Perkin TRans.1,1995,317-337中所述),其能够以高产率和立体选择性获得最终中间体。
或者,申请人已经发现,在特定条件下,如果关键中间体烯酮被保护为支化烷基酯如异丙基酯(在碱性条件下没有酯官能团的显著水解),则羟基官能基(例如,在C1处)的引入可以经由使关键中间体烯酮环氧化来以良好的产率实现。
另外,仅用溴化锂或与三乙酰氧基硼氢化钠(代替包括硒化物或碘化钐的供选试剂)组合的溴化锂进行环氧化物开环分别以高产率产生中间体二溴化酮或醇,其可使用无毒且廉价的试剂脱溴以提供最终关键化合物。另外,据发现在合成中使用的所有羟基酮的还原在用三乙酰氧基硼氢化钠进行时提供单一非对映异构体(即,反二醇(anti diol)),这与通过使用硼氢化钠或其他还原剂获得的差向异构混合物形成对比。
本发明的化合物可用作ROR受体且尤其是RORγ受体的有效配体或调节剂。因此,它们可用于治疗和/或预防对RORγ受体的调节起应答的病症,诸如糖尿病及糖尿病相关病症,且尤其是II型糖尿病。
因此,本发明还涉及至少一种本发明的化合物作为ROR受体且尤其是RORγ受体的有效配体或调节剂的用途。
具体地,本发明还涉及至少一种本发明的化合物用于治疗或预防、抑制或改善需要其的受试者的由RORγ受体介导的疾病的用途。
更具体地讲,本发明涉及治疗有效量的至少一种式I-VII的RORγ受体配体或其药学上可接受的盐或立体异构体用于治疗或预防、或抑制需要其的受试者的由RORγ受体介导的疾病的用途,其中所述疾病选自糖尿病及糖尿病相关病症,尤其是II型糖尿病。
更具体地讲,本发明涉及治疗有效量的至少一种式I-VII的化合物或其药学上可接受的盐或立体异构体用于治疗或预防、或抑制糖尿病和/或糖尿病相关病症、尤其是II型糖尿病的用途。
在一些实施方案中,本发明的化合物可单独使用,在其他实施方案中,本发明的化合物可与本发明的其他化合物组合或与其他治疗活性剂组合使用。可用于治疗和/或预防和/或改善可使用本发明化合物的疾病或病状(即,糖尿病和/或糖尿病相关病症,尤其是II型糖尿病)的其他治疗活性成分(与一种或多种本发明的组合物组合给予)的实例包括但不限于抗糖尿病剂、降脂剂、抗高血压剂和抗肥胖剂,诸如以下:
(a)抗糖尿病剂,例如(1)格列酮类(glitazones)(例如,环格列酮(ciglitazone)、达格列酮(darglitazonc)、恩格列酮(cnglitazonc)、isaglitazon、吡格列酮(pioglitazonc)、罗格列酮(rosiglitazone)、曲格列酮(troglitazone)、图拉里克(tularik)、BRL49653、CLX-0921、5-BTZD)和PPAR配体,诸如GW-0207、LG-100641和LY-300512;(2)双胍类,诸如丁福明(buformin)、二甲双胍(metformin)和苯乙双胍(phenformin);(3)蛋白质酪氨酸磷酸酶-1B(PTP-1B)抑制剂;(4)磺酰脲类,诸如醋磺己脲(acetohexamide)、氯磺丙脲(chlorpropamide)、氯磺丙脲(diabinese)、格列本脲(glibenclamide)、格列吡嗪(glipizide)、格列本脲(glyburide)、格列美脲(glimepiride)、格列齐特(gliclazide)、格列太特(glipentide)、格列喹酮(gliquidone)、格列索脲(glisolamide)、妥拉磺脲(tolazamide)和甲苯磺丁脲(tolbutamide);(5)美格替耐德(meglitinides),诸如瑞格列奈(repaglinide)、那格列奈(nateglinide)等;(6)α-葡糖苷酶抑制剂,诸如阿卡波糖(acarbosc)、脂解素(adiposinc)、卡格列波糖(camiglibosc)、乙格列酯(emiglitate)、米格列醇(miglitol)、伏格列波糖(voglibose)、帕地霉素(pradimicin)-Q、萨保菌素(salbostatin)、CKD-711、MDL-25,637、MDL-73,945和MOR14;(7)α-淀粉酶抑制剂,诸如淀粉酶抑肽(tendamistat)、萃他丁(trestatin)和Al-3688;(8)胰岛素促分泌素,诸如利诺格列(linogliride)、A-4166等;(9)脂肪酸氧化抑制剂,诸如氯莫克舍(clomoxir)和乙莫克舍(etomoxir);(10)α-2拮抗剂,诸如咪格列唑(midaglizole)、伊格列哚(isaglidole)、德格列哚(deriglidole)、咪唑克生(idazoxan)、衣罗杉(earoxan)和氟洛克生(fluparoxan);(11)胰岛素和胰岛素模拟物,诸如biota、LP-100、诺和锐(novarapid)、地特胰岛素(insulin detemir)、赖脯胰岛素、甘精胰岛素(insulin glargine)、胰岛素锌混悬液(长效和超长效)、Lys-Pro胰岛素、GLP-1(73-7)(促胰岛素激素(insulintropin))和GLP-1(7-36)-NH2;(12)非噻唑烷二酮类,诸如JT-501、法格列他扎(farglitazar)(GW-2570/GI-262579)和莫格列他(muraglitazar);PPAR拮抗剂,诸如莫格列他(muraglitazar)和在US 6,414,002中公开的化合物;(13)PPAR双重激动剂,诸如MK-0767/KRP-297、CLX-0940、GW-1536、GW-1929、GW-2433、L-796449、LR-90和SB219994;(14)其他胰岛素增敏剂;(15)VPAC2受体激动剂;(16)葡糖激酶激活剂;和(17)DPP-4抑制剂,诸如佳糖维(sitagliptin)、异亮氨酸噻唑烷(isoleucinethiazolidide)(P32/98)、NVP-DPP-728、维格列汀(vildagliptin)(LAF 237)、P93/01、地那列汀(denagliptin)(GSK 823093)、SYR322、RO 0730699、TA-6666和沙格列汀(saxagliptin)(BMS477118);
(b)降脂剂,例如(1)胆汁酸螯合剂,诸如考来烯胺(cholestyramine)、考来维仑(colesevelam)、考来替泊(colestipol)、交联葡聚糖的二烷基氨基烷基衍生物、Colestid(R)、LoCholest(R)和降胆敏(Questran)(R)等;(2)HMG-CoA还原酶抑制剂,诸如阿托伐他汀(atorvastatin)、伊托伐他汀(itavastatin)、氟伐他汀(fluvastatin)、洛伐他汀(lovastatin)、匹伐他汀(pitavastatin)、普伐他汀(pravastatin)、瑞伐他汀(rivastatin)、罗苏伐他汀(rosuvastatin)和辛伐他汀(simvastatin)、ZD-4522等;(3)HMG-CoA合酶抑制剂;(4)胆甾醇吸收抑制剂,诸如甾烷醇酯、β-谷甾醇、植物甾醇苷如替奎安(tiqueside)和氮杂环丁烷-3-酮(azetidinones)如依泽替米贝(ezetimibe);(5)酰基辅酶A-胆甾醇酰基-转移酶(ACAT)抑制剂,诸如阿伐麦布(avasimibe)、依鲁麦布(eflucimibe)、KY505和SMP797等;(6)CETP抑制剂,诸如JTT705、托彻普(torcetrapib)、CP532632、BAY63-2149、SC591和SC795等;(7)鲨烯合成酶抑制剂;(8)抗氧化剂,诸如普罗布考(probucol);(9)PPAR-a拮抗剂,诸如苄氯贝特(beclofibrate)、苯扎贝特(benzafibrate)、环丙贝特(ciprofibrate)、氯贝丁酯(clofibrate)、依托贝特(ctofibratc)、非诺贝特(fcnofibratc)、盖可滨(gcmcabcnc)、吉非贝齐(gcmfibrozil)及其他苯氧酸衍生物,例如GW7647、BM170744、LY518674、Atromid(R)、Lopid(R)和Tricor(R)及在WO 97/36579中描述的化合物等;(10)FXR受体调节剂,诸如GW4064、SR103912等;(11)LXR受体配体,诸如GW3965、T9013137和XTCO179628等;(12)脂蛋白合成抑制剂,诸如烟酸;(13)肾素/血管紧缩素***抑制剂;(14)PPAR-d部分激动剂;(15)胆汁酸重吸收抑制剂,诸如BARI1453、SC435、PHA384640、S8921、AZD7706等;(16)PPAR-d激动剂,诸如GW501516、GW590735和在WO97/28149中描述的化合物等;(17)甘油三酯合成抑制剂;(18)微粒体甘油三酯转移(MTTP)抑制剂,诸如inplitapide、LAB687和CP346086;(19)转录调节剂;(20)角鲨烯环氧酶抑制剂;(21)低密度脂蛋白(LDL)受体诱导剂;(22)血小板凝聚抑制剂;(23)5-LO或FLAP抑制剂;和(24)烟酸受体激动剂;和
(c)抗高血压剂,例如(1)利尿剂,诸如噻嗪类(thiazides),包括氯噻酮(chlorthalidone)、***(chlorothiazide)、双氯非那胺(dichlorphenamide)、氢氟甲噻嗪(hydroflumethiazide)、吲达帕胺(indapamide)和氢***(hydrochlorothiazide);髓袢利尿剂(loop diuretics),诸如布美他尼(bumetanide)、利尿酸(ethacrynic acid)、利尿磺胺(furosemide)和托拉塞米(torsemide);保钾剂(potassium sparing agent),诸如氨氯吡咪(amiloride)、氨苯蝶啶(triamterene);醛甾酮(aldosterone)拮抗剂,诸如螺内酯(spironolactone)和依普利酮(epirenone)等;(2)β-肾上腺素阻断剂,诸如醋丁洛尔(acebutolol)、阿替洛尔(atenolol)、倍他洛尔(betaxolol)、贝凡洛尔(bevantolol)、比索洛尔(bisoprolol)、波吲洛尔(bopindolol)、卡替洛尔(carteolol)、卡维地洛(carvedilol)、塞利洛尔(celiprolol)、艾司洛尔(esmolol)、茚诺洛尔(indenolol)、美托洛尔(metaprolol)、纳多洛尔(nadolol)、奈必洛尔(nebivolol)、喷布洛尔(penbutolol)、吲哚洛尔(pindolol)、心得安(propanolol)、索他洛尔(sotalol)、特他洛尔(tertatolol)、替利洛尔(tilisolol)和噻吗洛尔(timolol)等;(3)钙通道阻断剂,诸如氨氯地平(amlodipinc)、阿雷地平(aranidipine)、阿折地平(azelnidipine)、巴尼地平(barnidipine)、贝尼地平(benidipine)、苄普地尔(bepridil)、西尼地平(cinaldipine)、氯维地平(clevidipine)、硫氮酮(diltiazem)、依福地平(efonidipine)、非洛地平(felodipine)、戈洛帕米(gallopamil)、伊拉地平(isradipine)、拉西地平(lacidipine)、来米地平(lemildipine)、乐卡地平(lercanidipine)、尼卡地平(nicardipine)、硝苯地平(nifedipine)、尼伐地平(nilvadipine)、尼莫地平(nimodipine)、尼索地平(nisoldipine)、尼群地平(nitrendipine)、马尼地平(manidipine)、普拉地平(pranidipine)和维拉帕米(verapamil)等;(4)血管紧张素转化酶(ACE)抑制剂,诸如贝那普利(benazepril)、卡托普利(captopril)、西拉普利(cilazapril)、地拉普利(delapril)、依那普利(enalapril)、福辛普利(fosinopril)、咪达普利(imidapril)、赖诺普利(lisinopril)、莫西普利(mocxipril)、喹那普利(quinapril)、喹普利拉(quinaprilat)、雷米普利(ramipril)、培哚普利(perindopril)、培哚普利(perindropril)、全尼普利(quanipril)、螺普利(spirapril)、替莫普利(tenocapril)、群多普利(trandolapril)和佐芬普利(zofenopril)等;(5)中性肽链内切酶抑制剂,诸如奥马趋拉(omapatrilat)、次沙曲(cadoxatril)、依卡曲尔(ecadotril)、福森普利(fosidotril)、由帕曲拉(sampatrilat)、AVE7688、ER4030等;(6)内皮素拮抗剂,诸如波生坦(bosentan)、替唑生坦(tezosentan)、A308165和YM62899等;(7)血管扩张剂,诸如肼屈嗪(hydralazine)、可乐定(clonidine)、长压定(minoxidil)和烟醇;(8)血管紧张素II受体拮抗剂,诸如坎地沙坦西酯(candesartan)、依普罗沙坦(eprosartan)、厄贝沙坦(irbesartan)、洛沙坦(losartan)、洛沙坦(losartan)和氢***(hydrochlorothiazidc)、普拉沙坦(pratosartan)、他索沙坦(tasosartan)、替米沙坦(tclmisartan)、缬沙坦(valsartan)、EXP-3137、FI6828K和RNH6270等;(9)α/β-肾上腺素阻断剂,诸如尼普地洛(nipradilol)、阿罗洛尔(arotinolol)和胺磺洛尔(amosulalol);(10)a1阻断剂,诸如特拉唑嗪(terazosin)、乌拉地尔(urapidil)、哌唑嗪(prazosin)、布那唑嗪(bunazosin)、曲马唑嗪(trimazosin)、多沙唑嗪(doxazosin)、萘哌地尔(naftopidil)、吲哚哌胺(indoramin)、WHIP164和XEN010;(11)a2激动剂,诸如洛非西定(lofexidine)、噻美尼定(tiamenidine)、莫索尼定(moxonidine)、利美尼定(rilmenidine)和胍那本(guanobenz);(12)醛甾酮抑制剂;和(d)抗肥胖剂,诸如(1)生长激素促分泌素、生长激素促分泌素受体激动剂/拮抗剂,诸如NN703、海沙瑞林(hexarelin)、MK-0677、SM-130686、CP-424,391、L-692,429和L-163,255;(2)蛋白质酪氨酸磷酸酶-1B(PTP-1B)抑制剂;(3)***素受体配体,诸如***素CB1受体拮抗剂或反向激动剂,诸如利莫纳班(rimonabant)(Sanofi Synthelabo)、AMT-251和SR-14778及SR 141716A(Sanofi Synthelabo)、SLV-319(Solvay)、BAY 65-2520(Bayer);(4)抗肥胖血清素作用剂,诸如芬氟拉明(fcnfluraminc)、右芬氟拉明(dcxfcnfluraminc)、芬特明(phentermine)和***(sibutramine);(5)β3-肾上腺素受体激动剂,诸如AD9677/TAK677(Dainippon/Takeda)、CL-316,243、SB 418790、BRL-37344、L-796568、BMS-196085、BRL-35135A、CGP12177A、BTA-243、曲卡君(Trecadrine)、Zeneca D7114、SR 59119A;(6)胰脂酶抑制剂,诸如奥利司他(orlistat)(Xenical(R))、Triton WR1339、RHC80267、利普斯汀(lipstatin)、四氢利普斯汀(tetrahydrolipstatin)、茶皂素(teasaponin)、二乙基伞形酮磷酸酯(diethylumbelliferyl phosphate);(7)神经肽Y1拮抗剂,诸如BIBP3226、J-115814、BIBO3304、LY-357897、CP-671906、GI-264879A;(8)神经肽Y5拮抗剂,诸如GW-569180A、GW-594884A、GW-587081X、GW-548118X、FR226928、FR 240662、FR252384、1229U91、GI-264879A、CGP71683A、LY-377897、PD-160170、SR-120562A、SR-120819A和JCF-104;(9)黑色素浓集激素(MCH)受体拮抗剂,诸如在WO 01/21577和WO 01/21169中公开的那些;(10)黑色素浓集激素1受体(MCH1R)拮抗剂,诸如T-226296(Takeda);(11)黑色素浓集激素2受体(MCH2R)激动剂/拮抗剂;(12)阿立新(orexin)-1受体拮抗剂,诸如SB-334867-A及在WO 01/96302、WO 01/68609、WO 02/51232和WO 02/51838中公开的那些;(13)血清素再吸收抑制剂,诸如氟西汀(fluoxetine)、帕罗西汀(paroxetine)和舍曲林(sertraline);(14)黑素皮质素激动剂,诸如美拉诺坦II(Melanotan JI)、CHIR86036(Chiron)、ME-10142和ME-10145(Melacure)、CHIR86036(Chiron);PT-141和PT-14(Palatin);(15)其他MC4R(黑素皮质素4受体)激动剂;(16)5HT-2激动剂;(17)5HT2C(血清素受体2C)激动剂,诸如BVT933、DPCA37215、WAY161503、R-1065;(18)甘丙肽拮抗剂;(19)CCK激动剂;(20)CCK-1激动剂(缩胆囊肽-A)激动剂,诸如AR-R 15849、GI 181771、JMV-180、A-71378、A-71623和SR146131;(21)GLP-1激动剂;(22)促肾上腺皮质激素释放激素激动剂;(23)组胺受体-3(H3)调节剂;(24)组胺受体-3(H3)拮抗剂/反向激动剂,诸如hioperamide、N-(4-戊烯基)氨基甲酸3-(1H-咪唑-4-基)丙酯、clobenpropit、iodophenpropit、imoproxifan、GT2394(Gliatech)和O-[3-(1H-咪唑-4-基)丙醇]-氨基甲酸酯(Kiec-Kononowicz,K.等,Pharmazie,55:349-55(2000))、含哌啶的组胺H3-受体拮抗剂(Lazewska,D.等,Pharmazie,56:927-32(2001)、二苯甲酮衍生物及相关化合物(Sasse,A.等,Arch.Pharm.(Weinheim)334:45-52(2001))、被取代的N-苯基氨基甲酸酯(Reidemeister,S.等,Pharmazie,55:83-6(2000))和普罗昔番(proxifan)衍生物(Sasse,A.等,J.Med.Chem.43:3335-43(2000));(25)β-羟基类固醇脱氢酶-1抑制剂(β-HSD-1);26)PDE(磷酸二酯酶)抑制剂,诸如茶碱(theophylline)、己酮可可碱(pentoxifylline)、扎普司特(zaprinast)、喜地纳芬(sildenafil)、胺力农(amrinonc)、米力农(milrinonc)、西洛酰胺(cilostamidc)、咯利普兰(rolipram)和西洛司特(cilomilast);(27)磷酸二酯酶-3B(PDE3B)抑制剂;(28)NE(去甲肾上腺素)转移抑制剂,诸如GW 320659、地昔帕明(despiramine)、他舒普仑(talsupram)和诺米芬辛(nomifensine);(29)ghrelin受体拮抗剂;(30)瘦体素,包括重组人类瘦体素(PEG-OB,Hoffman La Roche)和重组甲硫氨酰基人类瘦体素(Amgen);(31)瘦体素衍生物;(32)其他BRS3(铃蟾肽受体亚型3)激动剂,诸如[D-Phe6,β-Ala11,Phe13,Nle14]Bn(6-14)和[D-Phe6,Phe13]Bn(6-13)丙基酰胺;(33)CNTF(睫状节神经细胞营养因子),诸如GI-181771(Glaxo-SmithKline)、SR146131(Sanofi Synthelabo)、butabindide、PD170,292和PD 149164(Pfizer);(34)CNTF衍生物,诸如阿索开(axokine)(Regeneron);(35)单胺再摄取抑制剂,诸如***;(36)UCP-1(去偶蛋白质-1)、2或3激活剂,诸如植烷酸、4-[(E)-2-(5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基)-1-丙烯基]苯甲酸(TTNPB)、视黄酸;(37)甲状腺激素β激动剂,诸如KB-2611(KaroBioBMS);(38)FAS(脂肪酸合酶)抑制剂,诸如浅蓝菌素(Cerulenin)和C75;(39)DGAT1(二酰基甘油酰基转移酶1)抑制剂;(40)DGAT2(二酰基甘油酰基转移酶2)抑制剂;(41)ACC2(乙酰辅酶A羧化酶-2)抑制剂;(42)糖皮质激素拮抗剂;(43)酰基-***;(44)二肽基肽酶IV(DP-IV)抑制剂,诸如异亮氨酸噻唑烷、缬氨酸吡咯烷、NVP-DPP728、LAF237、P93/01、TSL225、TMC-2A/2B/2C、FE 999011、P9310/K364、VIP 0177、SDZ 274-444和佳糖维;(46)二羧酸转运蛋白抑制剂;(47)葡萄糖转运蛋白抑制剂;(48)磷酸酯转运抑制剂;(49)二甲双胍(Glucophage(R));和(50)托吡酯(Topiramate)(Topimax(R));和(50)肽YY、PYY 3-36、肽YY类似物、衍生物和片段,诸如BIM-43073D、BIM-43004C(Olitvak,D.A.等,Dig.Dis.Sci.44(3):643-48(1999));(51)神经肽Y2(NPY2)受体激动剂,如NPY3-36、N乙酰基[Leu(28,31)]NPY 24-36、TASP-V和环-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY;(52)神经肽Y4(NPY4)激动剂,诸如胰腺肽(PP),如在Batterham等,J.Clin.Endocrinol.Metab.88:3989-3992(2003)中描述,和其他Y4激动剂,诸如1229U91;(54)环加氧酶-2抑制剂,诸如依托昔布(etoricoxib)、赛利克西(celecoxib)、伐地考昔(valdecoxib)、帕瑞昔布(parecoxib)、鲁米昔布(lumiracoxib)、BMS347070、依他昔布(tiracoxib)或JTE522、ABT963、CS502和GW406381,及其药学上可接受的盐;(55)神经肽Y1(NPY1)拮抗剂,诸如BIBP3226、J-115814、BIBO 3304、LY-357897、CP-671906、GI-264879A;(56)阿片拮抗剂,诸如纳美芬(nalmefene)(Revex(R))、3-甲氧基纳曲酮、纳洛酮(naloxone)、纳曲酮(naltrexone);(57)11βHSD-1(1型11-β羟基类固醇脱氢酶)抑制剂,诸如BVT 3498、BVT 2733;及其他化合物,诸如阿米雷司(aminorex)、amphechloral、***(amphetamine)、苄非他明(benzphetamine)、对氯苯丁胺(chlorphcntcrminc)、氯苄雷司(clobcnzorcx)、氯福雷司(cloforcx)、氯胺雷司(clominorex)、氯特胺(clortermine)、环己异丙甲胺(cyclexedrine)、右旋***(dextroamphetamine)、二苯甲哌啶乙醇(diphemethoxidine)、N-乙基苯内胺(N-ethylamphetamine)、芬布酯(fenbutrazate)、非尼雷司(fenisorex)、芬普雷司(fenproporex)、氟多雷司(fludorex)、氟胺雷司(fluminorex)、糠甲***(furfurylmethylamphetamine)、左***(levamfetamine)、左法哌酯(levophacetoperane)、美芬雷司(mefenorex)、甲胺苯丙酮(metamfepramone)、脱氧麻黄碱(methamphetamine)、去甲伪麻黄碱(norpseudoephedrine)、喷托雷司(pentorex)、苯甲曲嗪(phendimetrazine)、芬美曲秦(phenmetrazine)、匹西雷司(picilorex)、phytopharm57、唑尼沙胺(zonisamide)、神经调节素U及其类似物或衍生物、胃泌酸调节素(oxyntomodulin)及其类似物或衍生物、神经激素-1受体拮抗剂(NK-1拮抗剂);和Qnexa。
本发明的化合物可以药物组合物的形式使用。因此,另一方面,本发明提供包含至少一种本发明的化合物(其药学上可接受的盐)和药学上可接受的载体及任选至少一种另外的如上定义的治疗活性剂的药物组合物。术语“药学上可接受的盐”是指由包括如上文定义的无机碱或酸和有机碱或酸的药学上可接受的无毒碱或酸制备的盐。
常规上,本发明的化合物可根据常规制药技术与药物载体组合成均匀的混合物。所述载体可根据给药所希望的制剂形式(如在下文中定义)而采用各种形式。
本发明的化合物为ROR(γ)受体配体且已经表明可用于治疗、控制或预防对ROR(γ)受体的调节起应答的疾病、病症或病状,例如糖尿病及糖尿病相关病症,尤其是II型糖尿病。
因此,本发明在另一方面提供用于治疗或预防需要其的受试者的对RORγ受体的调节起应答的病症、疾病或病状的方法,其包括给予所述受试者治疗或预防有效量的至少一种本发明的化合物或其药学上可接受的盐以及任选至少一种另外的如上定义的治疗活性剂。
更具体地讲,本发明提供治疗或预防需要其的受试者的糖尿病及糖尿病相关病疗的方法,其包括给予所述受试者治疗或预防有效量的本发明的至少一种RORγ受体配体以及任选至少一种另外的如上定义的治疗活性剂。
具体地,本发明提供用于治疗或预防需要其的受试者的II型糖尿病的方法,其包括给予所述受试者治疗或预防有效量的至少一种本发明的化合物或其药学上可接受的盐以及任选至少一种另外的如上定义的治疗活性剂。
术语本发明化合物的“给予(administration of)”或“给予(administering)”本发明化合物应该理解为是指为需要治疗的受试者提供本发明化合物(或本发明化合物的前药)或其药物组合物。给予本发明化合物以实施本发明的治疗方法通过将治疗或预防有效量的本发明化合物(或组合物)以及任选治疗有效量的至少一种另外的治疗活性化合物给予需要所述治疗或预防的受试者来进行。
本文使用的术语“治疗有效量”是指将在组织、***或受试者中引起所要的生物或药物反应的本发明化合物的量,所要的生物或药物反应包括减轻所治疗病疗的症状。本文使用的术语“预防有效量”是指将在组织、***或受试者中引起所要的生物或药物反应以预防具有患病危险的受试者发病的本发明化合物的量。本发明的特定化合物的治疗或预防有效量或剂量由医师确定,但取决于诸如欲治疗的确切疾病、患者罹患的疾病及其他疾病或病状的严重程度、所选择的给药途径、患者可伴随需要的其他药物和治疗、患者的年龄和体质及医师判断中的其他因素的因素。
可采用任何合适的给药途径来为受试者、特别是人类提供治疗有效剂量的本发明化合物。例如,可采用口腔、直肠、局部、肠胃外(例如,皮下或静脉内输注和皮下或静脉内注射)、眼、肺、鼻等。剂型包括片剂、锭剂、分散剂、混悬剂、溶液剂、胶囊、乳膏剂、油膏剂、气雾剂等。优选本发明的化合物经口或肠胃外施用。
所采用的有效剂量的活性成分可根据选择的特定化合物、给药模式、治疗的病状和治疗的病状的严重程度而改变。所述剂量可由本领域技术人员容易地确定。
典型地,本发明化合物(或其组合)以约00001mg-约50mg/kg受试者体重的日剂量给予,优选以单次剂量或以一日二至六次分次给药,或以持续释放形式给予。例如,在70kg成人的情况下,总目剂量通常将为约0.07mg-约3500mg。可调节该给药方案以提供最佳治疗反应。在经口给药的情况下,合适的剂量范围为例如约0.01mg-约1500mg的本发明的一种或多种化合物/日,优选为约0.1mg-约600mg/日,更优选为约0.1mg-约100mg/日。对于经口给药,对于所治疗患者的症状调整剂量,所述组合物优选以含有0.01-1,000mg、优选为0.01、0.05、0.1、0.5、1、2.5、5、10、15、20、25、30、40、50、100、250、500、600、750、1000、1250或1500mg活性成分的片剂形式提供。在鼻内给药的情况下,合适的剂量范围例如为包含可使用0.001-10重量%的本发明的一种或多种化合物的溶液或悬浮液的制剂。在静脉内给药的情况下,合适的剂量范围为约0.001mg-约50mg,优选为0.01mg-约50mg,更优选为0.1mg-10mg的本发明的一种或多种化合物/kg体重/日。
可调节上述给药方案以提供最佳治疗应答。在一些情况下,可能需要使用在这些限制之外的剂量。本发明的一种或多种化合物的预防或治疗剂量的确切量当然将根据选择的一种或多种特定化合物、给药模式、治疗的病状和治疗的病状的严重程度而改变。其还将根据个体患者的年龄、体重和反应而改变。所述剂量可由本领域的技术人员容易地确定。
如上所指出,本发明还考虑到本发明的化合物以及至少一种另外的治疗活性化合物的用途。这类另外的治疗活性化合物可以常用的途径和量给予,且可单独地给予或与本发明的一种或多种化合物同时或顺序地联合(以单一药物组合物或单独的药物组合物)给予。在同时使用的情况下,可使用包含所述至少一种本发明的化合物和所述至少一种另外的治疗活性剂的药物组合物。因此,本发明还涉及给予包含至少一种RORγ受体配体以及至少一种另外的治疗活性剂的单一药物剂量制剂以及给予在其各自单独的药物剂量制剂中的各种活性剂。在使用单独的剂量制剂的情况下,所述组合物的各个组分可基本同时地给予,即同时给予,或者顺序地给予,及在给予所述组合物的另一组分之前或之后给予。应理解的是本发明包括同时或顺序治疗的所有这些方案,且将相应地解释术语“给予”。
可使用常用于药物制剂材料使用的各种有机或无机载体物质作为本发明化合物和所选择的给药途径的药学上可接受的载体。它们对于固体制剂作为赋形剂、润滑剂、粘结剂或崩解剂共混,且对于液体制剂,作为溶剂、增溶剂、悬浮剂、等渗剂、缓冲剂、安抚剂等共混。在需要时,可使用诸如防腐剂、抗氧化剂、着色剂、甜味剂等药物制剂添加剂。
赋形剂的典型实例包括乳糖、蔗糖、D-甘露糖醇、D-山梨糖醇、淀粉、预胶凝淀粉、糊精、结晶纤维素、低取代的羟丙基纤维素、羧甲基纤维素钠、***胶、支链淀粉、轻质无水硅酸、合成硅酸铝、铝酸镁、偏硅酸盐等。润滑剂的典型实例包括硬脂酸镁、硬脂酸钙、滑石粉、胶体二氧化硅等。粘结剂的典型实例包括预胶凝淀粉、蔗糖、明胶、***胶、甲基纤维素、羧甲基纤维素、羧甲基纤维素钠、结晶纤维素、蔗糖、D-甘露糖醇、海藻糖、糊精、支链淀粉、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮等。崩解剂的典型实例包括乳糖、蔗糖、淀粉、羧甲基纤维素、羧甲基纤维素钙、交联羧甲纤维素钠、羧甲基淀粉钠、轻质无水硅酸、低取代羟丙基纤维素等。溶剂的典型实例包括注射用水、生理盐水、林格氏溶液(Ringer′s solution)、乙醇、丙二醇、聚乙二醇、芝麻油、玉米油、橄榄油、棉籽油等。增溶剂的典型实例包括聚乙二醇、丙二醇、D-甘露糖醇、海藻糖、苯甲酸苄酯、乙醇、三羟甲基氨基甲烷(trisaminomethane)、胆甾醇、三乙醇胺、碳酸钠、柠檬酸钠、水杨酸钠、乙酸钠等。悬浮剂的典型实例包括表面活性剂,诸如硬脂酰基三乙醇胺、十二烷基硫酸钠、氨基丙酸十二烷基酯、卵磷脂、苯扎氯铵、苄索氯铵、单硬脂酸甘油酯等;亲水性聚合物,诸如聚乙烯醇、聚乙烯吡咯烷酮、羧甲基纤维素钠、甲基纤维素、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素等;聚山梨酸酯、聚氧乙烯氢化蓖麻油;等。等渗剂的典型实例包括氯化钠、甘油、D-甘露糖醇、D-山梨糖醇、葡萄糖等。缓冲剂的典型实例包括磷酸盐缓冲剂、乙酸盐缓冲剂、碳酸盐缓冲剂、柠檬酸盐缓冲剂等。安抚剂的典型实例包括苄醇等。防腐剂的典型实例包括对氧基苯甲酸酯、氯丁醇、苄醇、苯乙醇、脱氢乙酸、山梨酸等。抗氧化剂的典型实例包括亚硫酸酯、抗环血酸酯等。着色剂的典型实例包括水性可食用焦油颜料(例如,食品色素,诸如2和3号食品色素红、4和5号食品色素黄、1及2号食品色素蓝等)、水不溶性色淀颜料(例如,上述水性可食用焦油颜料的铝盐)、天然颜料(例如,β胡萝卜素、叶绿素、氧化铁红和黄色三氧化二铁)等。甜味剂的典型实例包括糖精钠、甘草酸二钾、阿斯巴特、甜菊等。
本发明化合物的合适剂型的实例包括口服制剂,诸如片剂(包括糖衣片剂、薄膜衣片剂、舌下片剂、口服崩解片剂)、胶囊(包括软胶囊、微胶囊)、颗粒剂、粉剂、锭剂、糖浆剂、乳剂、悬浮剂、膜剂(例如,口腔崩解膜)等;或肠胃外制剂,诸如注射剂(例如,皮下注射剂、静脉内注射剂、肌肉注射剂和腹膜内注射剂)、外用剂(例如,鼻给药制剂、经皮制剂和油膏剂)、栓剂(例如,直肠栓剂和***栓剂)、丸剂、滴剂、滴眼剂、肺部制剂(吸入剂)等。另外,这些制剂可为持续释放制剂(例如,持续释放微胶囊),诸如即时释放制剂或持续释放制剂。
本发明的药物组合物可根据在药物制剂领域中通常使用的方法来制备。所述至少一种本发明的化合物在药物组合物中的含量根据化合物的性质、给药途径(且因此药物制剂的性质)等改变,且例如为1-90重量%,优选为5-80重量%。
另一方面,本发明还涉及提供包含至少一种本发明的化合物和任选至少一种另外的治疗活性化合物的本发明药物组合物的药盒。在一个实施方案中,根据本发明的药盒可包含单一口服剂量制剂,该制剂在所述药盒的一个隔室中包含至少一种ROR(γ)受体配体和至少一种另外治疗活性成分两者。在另一实施方案中,根据本发明的药盒可包含在单独隔室中的至少两种单独的药物组合物,它们是在第一隔室中的包含预防或治疗有效量的至少一种ROR(γ)受体配体或其药学上可接受的盐或酯和药学上可接受的载体或稀释剂的第一单位剂型,和在第二隔室中的包含预防或治疗有效量的至少一种另外的活性成分或其药学上可接受的盐或酯和药学上可接受的载体或稀释剂的第二单位剂型。
本发明通过以下特定实施例进一步解释,这些实施例意欲说明本发明,而不应该将其理解为以任何方式限制本发明的范围。应理解的是,本领域技术人员可基于本文所述的程序容易地制备本发明的其他化合物。本领域的技术人员将容易地理解,可使用以下制备程序的条件和方法的已知变化来制备这些化合物。
实施例
材料和方法
所有化学品和溶剂均自ABCR、Acros、Aldrich、J.T.Baker、Fluka、MeRck、TCI或Lancaster购买且原样使用,例外之处如下:将THF和DMF在氩气氛下经无水中性A-2氧化铝的两个4”×36”管柱(Macherey und Nagel;在300℃下在N2流下活化过夜)干燥(H2O含量<30ppm,Karl-Fischer titration(卡尔-费希尔滴定))。除非另作说明,否则所有温度都是摄氏度。除非另有说明,否则所有非水反应都在火焰干燥的玻璃仪器中在氩/氮气氛下进行。TLC在Merck硅胶60 F254 TLC铝板上进行且用紫外荧光骤冷和p-Anysaldehyde-染色剂目视观察。除非另作说明,否则在减压下的浓缩通过在37℃下在适当压力下旋转蒸发来进行。柱层析纯化作为快速色谱用0.3-0.5巴压力在硅胶(,40-64μm)上进行。采用蒸馏工业级溶剂。所给出的产率是指纯化的产物。未校正的熔点在Büchi B-540熔点测定器上使用开口玻璃毛细管测量。NMR数据在VARIAN Mercury 300MHz、Gemini 300MHz、Bruker ARX300、Bruker AV 400、Bruker DRX 400光谱仪上记录。除非另作说明,否则测量在室温(约22℃)下进行。化学位移以ppm给出,其中剩余溶剂信号作为内标,分别对于1H-和13C,[d]-氯仿在7.26和77.00ppm下,d6-DMSO在2.50和39.52ppm下,[d]-甲醇在3.31和49.00ppm下。多重性缩写如下:单峰(s)、双重峰(d)、三重峰(t)、表观三重峰(at)、双重双峰(dd)、三重双峰(td)、双重双重双重峰(ddd)和多重峰(m),耦合常数(s)以Hz给出。13C-NMR光谱用1H-去耦记录。红外光谱在Perkin Elmer RXI FT-IR分光光度计用薄膜记录,吸收以波数(cm-1)给出。质谱分析通过由L.Bcrtschi和O.Grctcr在Dr.Zhang的指导下在ETH Zü rich由Laboratorium für Organische Chemie的mass spectrometry service进行。ESI和HRMS测量在Bruker Daltonics maxis和Varian IonSpec ESI FT-ICR在4.7Tesla下进行。EI测量在Waters Micromass AutoSpec Ultima上在70eV下进行。
已经充分记载了对于胺和羧酸官能团使用保护基团促进所要的反应并使不想要的反应减至最少。除去保护基团所需要的条件在标准教科书如Greene,T和Wuts,P.G.M.有机合成中的保护基团(Protective Groups in Organic Synthesis),John Wiley andSons,Inc.,New York,NY,1991中见到。CBZ和BOC是有机合成中的常用保护基团,且其去除条件为本领域技术人员所知。例如,CBZ可通过在存在贵金属或其氧化物如在活性碳上的钯的情况下在诸如甲醇或乙醇的质子溶剂中催化氢化来除去。如果催化氢化由于任何潜在的反应性官能团的存在而反应不当,则CBZ基团的去除也可以通过用溴化氢在乙酸中的溶液处理或通过用TFA和二甲基硫的混合物处理来实现。BOC保护基团的去除用诸如三氟乙酸、盐酸或氯化氢气体的强酸在诸如二氯甲烷、甲醇或乙酸乙酯的溶剂中进行。
荧光素酶活性测定.典型地,使3T3L1细胞在24孔盘中生长到60-70%融合并通过使用转染剂Fugene根据生产商方案(Invitrogen)用报道子基因(pMMP3-pGL3)(0.05μg)、pCMV-Renilla作为内参考(0.05μg)和用于RORγ的表达载体(0.1μg)转染。在转染之后让细胞再生长48小时。荧光素酶活性使用荧光素酶检测***遵循生产商方案(Promega)测量。
胰岛素耐量试验.典型地,对C57B6小鼠(6周龄)喂饲补充有0.1%或0.01%的1β,3α,7α,12α-四羟基-5β-胆烷-24-酸(即四醇化合物)或0.1%和0.01%的胆酸(即CA)的高脂饮食(60%的卡路里来源于脂肪,Kliba)。仅喂饲高脂饮食充当对照。在6周之后,通过腹腔注射0.5U/kg胰岛素测试小鼠的胰岛素敏感性。在注射之前和注射之后30分钟、60分钟、90分钟和120分钟测量血糖浓度。对于各个小鼠通过将时间点值除以起始血糖值来计算血糖的相对降低。
治疗效果.典型地,对C57B6小鼠(6周龄)喂饲高脂饮食(60%卡路里来源于脂肪,Kliba)6周以诱发肥胖相关的胰岛素抗性。随后将小鼠分成三组:第一组继续喂饲补充有0.01%四醇化合物的高脂饮食,第二组继续喂饲补充有0.01%胆酸的高脂饮食且最后一组喂饲高脂饮食作为对照。在相应的饮食6周和12周之后,使用Contour葡萄糖监测器(BayerAG,Diabetes Care,Switzerland)测量血糖且使用由Meso Scale Discovery(Gaithersburg,Maryland,USA)供应的大鼠/小鼠胰岛素测定来测定循环胰岛素浓度。
实施例1:合成1β,3α,7α,12α-四羟基-5β-胆烷-24-酸甲酯。
(a)3-氧代,7α,12α-二羟基-5β-胆烷-24-酸甲酯
根据文献程序将胆酸(50g,0.12mol)转化成相应的甲基酯(51g,98%)(RohacovaJ.等,Org.Biomol.Chem.,2009,7,4973-4980;Tohma M.等,Chem.Pharm.Bull.1986,34(7),2890-2899)。向所获得的甲基酯(23g,59mmol)在甲苯(400mL)中的溶液中加入Ag2CO3/(40g)。将混合物在150℃下在强烈搅拌下加热直至TLC表明起始材料(Rf=0.27,AcOEt 100%)完全转化成单一极性较小的产物(Rf=0.58,AcOEt 100%)。在9小时之后,将混合物冷却到室温且固体沉淀物通过经垫过滤而除去。在减压下除去溶剂以给出粗物质,将其用Et2O湿磨以给出作为白色固体的相应酮-二醇(19.7g,87%)。分析数据与所报道的值(Rohacova J.等,Org.Biomol.Chem.,2009,7,4973-4980;Tohma M.等,Chem.Pharm.Bull.1986,34(7),2890-2899)完全一致。
(b)3-氧代,7α,12α-二乙酰氧基-5β-胆烷-24-酸甲酯
向步骤(a)的酮-二醇(13g,31mmol)在乙酸酐和吡啶的混合物(50体积%,100mL)中的溶液中加入DMAP(380mg,3.1mmol)。将反应混合物在室温下搅拌1小时,在0℃下冷却并通过逐滴加入MeOH骤冷。将溶剂在减压下浓缩且将残余物溶解于EtOAc中并用1M HCl和NaHCO3(水溶液)洗涤。将有机相在减压下浓缩以给出固体残余物,将其从EtOAc/己烷中重结晶以提供双乙酰氧基固醇(14.8g,95%),且分析数据与所报道的值(Tohma M.等,Chem.Pharm.Bull.1986,34(7),2890-2899)完全一致。
(c)7α,12α-二乙酰氧基-2β,4β-二溴-3-氧代-5β-胆烷-24-酸甲酯
将步骤(b)的双乙酰氧基酮(11.47g,23mmol)溶解于CHCl3(20mL)和乙酸(40mL)的混合物中。逐滴加入Br2(2.34mL,46mmol)在乙酸(24mL)中的溶液。在室温下搅拌1小时之后,将混合物用NaHSO3(水溶液)猝灭且在减压下浓缩到其体积的1/4。将残余物溶解于EtOAc中并用NaHCO3水溶液洗涤。将有机相在减压下浓缩且将残余物用二异丙基醚湿磨以提供作为两种主要差向异构体的85∶15混合物的2,4-二溴衍生物(13.49g,90%),然而其适合按原样用于下一步骤。将粗物质的等分试样从CH2Cl2/Et2O中结晶两次以给出纯2,4-二溴衍生物(M.P.=196℃,Lit2=196-98℃),其分析数据和光谱数据与所描述的数据(TohmaM.等,Chem.Pharm.Bull.1986,34(7),2890-2899)相同。
(d)7α,12α-二乙酰氧基-3-氧代-5β-胆-1-烯-24酸甲酯
向步骤(c)的二溴酮(10.6g,16mmol)在DMF(85mL)中的溶液中加入Li2CO3(1.9g,24mmol)和LiBr(2.1g,24mmol)。在80℃下在氮气下搅拌8小时之后,TLC表明起始材料(Rf=0.53,己烷/EtOAc 80∶20)完全转化成单一极性更大的斑点(Rf=0.35,己烷/EtOAc 80∶20)。将混合物用EtOAc稀释并用1M HCl洗涤。将有机相在减压下浓缩以给出粗残余物,将该粗残余物用二异丙基醚湿磨以提供作为白色固体的中间体7α,12α-二乙酰氧基-4β-溴-3-氧代-5β-胆-1-烯-24酸甲酯(8.6g,92%),使其在不进一步纯化的情况下在下一步骤中反应。
向先前获得的1Δ-4-溴-烯酮在乙酸(80mL)中的溶液中加入细分散的Zn粉(4g,63mmol)。在室温下搅拌30分钟之后,在TLC上观察到起始材料完全转化成单一斑点(Rf=0.54,己烷/EtOAc 70∶30)。将固体经垫过滤且将所得溶液在减压下浓缩到其体积的1/5。随后将残余物加到含有500mL冰冷却的蒸馏水的烧瓶中以给出固体沉淀物,将该固体沉淀物滤出并通过快速色谱(己烷/EtOAc 70∶30)纯化以提供所要的烯酮(5.6g,76%),其分析数据与所报道的数据(Tohma M.等,Chem.Pharm.Bull.1986,34(7),2890-2899)完全一致。
(e)1β-二甲基苯基甲硅烷基-7α,12α-二乙酰氧基-3-氧代-5β-胆烷-24-酸甲酯
将金属锂(418mg,59.7mmol)悬浮在THF(20mL)中,在0℃下冷却且加入苯基二甲基氯硅烷(4.34mL,26.3mmol)。在0℃下持续搅拌1小时,随后所得***溶液经插管转移到先前在-30℃下冷却的CuI(2.5g,13.1mmol)在THF(20mL)中的悬浮液中。在30分钟之后,逐滴加入步骤(d)的7α,12α-二乙酰氧基-3-氧代-5β-胆-1-烯-24-酸甲酯(6g,11.9mmol)在THF(20mL)中的溶液。在-30℃下搅拌30分钟之后,反应通过加入0.1M HCl猝灭且将混合物用Et2O萃取。在减压下蒸发溶剂提供油性残余物,随后将其通过快速色谱纯化以给出甲硅烷基酮。白色固体m.p.=162℃; 1H NMR(400MHz,CDCl3):δ7.47-7.43(m,2H),7.36-7.32(m,3H),5.12(at,J=2.7Hz,1H),4.93(dd,J=5.6,3.4Hz,1H),3.65(s,3H),2.99(dd,J=15.6,12.7Hz,1H),2.44(dd,J=14.8,7.5Hz,1H),2.34(ddd,J=15.3,10.0,5.2Hz,1H),2.32-2.15(m,3H),2.10(s,3H),2.05(s,3H),2.00-1.75(m,6H),1.75-1.60(m,3H),1.60-1.47(m,3H),1.44-1.24(m,4H),1.15-1.04(m,1H),0.99(s,3H),0.81(d,J=6.4Hz,3H),0.71(s,3H),0.38(s,3H),0.33(s,3H);13C NMR(101MHz,CDCl3):δ212.2,174.4,170.5,170.1,139.3,133.8,133.8,129.0,127.9,127.9,75.2,70.3,51.5,47.3,45.0,44.5,43.5,40.3,38.4,38.2,37.5,34.6,32.3,30.9,30.7,30.7,30.5,27.2,25.8,22.7,22.1,21.5,21.3,17.5,12.2、-0.3、-0.4.;IR(薄膜):ν=2949,2870,1734,1435,1425,1376,1240,1110,1024cm-1;HRMS(ES+):m/z:C37H54O7NaSi(M++Na)计算值:661.3531,实验值:661.3525。
(f)1β,3α-二羟基-7α,12α-二乙酰氧基-5β-胆烷-24-酸甲酯
向步骤(e)的甲硅烷基-酮(2.5g,3.91mmol)在过氧乙酸(20mL,40%在乙酸中)和乙酸(10mL)的混合物中的溶液中加入Hg(OAc)2(1.5g,4.70mmol)。将混合物在室温下搅拌6小时,在0℃下冷却并通过缓慢加入NaHSO3(40%,水性)谨慎猝灭。将反应混合物在减压下浓缩,用AcOEt稀释且用NaHCO3和盐水洗涤。将溶剂在减压下蒸发以给出作为主要产物的粗中间羟基酮(Rf=0.29,己烷/EtOAc 4∶3),使其在不进一步纯化的情况下在下一步骤中反应。
将粗物质溶解于CH2Cl2/THF的混合物(1∶2,45mL)中且在0℃下加到通过向乙酸/THF的混合物(1∶1,10mL)中加入NaBH4(296mg,7.8mmol)获得的先前制备的Na(OAc)3BH溶液中。在0℃下搅拌30分钟之后,观察到起始材料完全转化成主要产物(Rf=0.25,EtOAc100%),而没有任何可检测量的相应3β差向异构体(Rf=0.48,EtOAc 100%)。将溶剂在减压下蒸发且将残余物溶解于AcOEt中并用盐水洗涤。在减压下蒸发溶剂且通过快速色谱(EtOAc/异丙醇10∶1)纯化残余物给出纯二醇(860mg,42%),其分析数据和光谱数据与所报道的数据(Tohma M.等,Chem.Pharm.Bull.1986,34(7),2890-2899)完全一致。
(g)1β,3α,7α,12α-四羟基-5β-胆烷-24-酸甲酯
使用无水碱(诸如在甲醇中的甲醇钠)选择性水解乙酸酯基产生四羟基-甲基酯。所述化合物的同一性经由相应游离酸1β,3α,7α,12α-四羟基-5β-胆烷-24-酸的甲基化证实。将游离酸(7mg,0.016mmol)加到含有乙酰氯(1μL,0.19mmol)的甲醇(1mL)的混合物中。将混合物在室温下搅拌4小时,蒸发溶剂以提供所要甲基酯(5mg,69%)。1H NMR(300MHz,CD3OD):δ3.93(at,J=2.8,1H),3.90-3.82(m,2H),3.80(dd,J=5.0,2.3Hz,1H),3.65(s,3H),2.45-2.28(m,4H),2.01(dd,J=12.0,4.8Hz,1H),1.92-1.48(m,12H),1.47-1.24(m,7H),1.19-1.02(m,2H),1.01(s,3H),1.00(d,J=6.2Hz,3H),0.72(s,3H)。
实施例2:合成1β,3α,7α,12α-四羟基-5β-胆烷-24-酸异丙酯
(a)3α,7α,12α-三乙酰氧基-5β-胆烷-24-酸甲酯
如在实施例1(a)中所报道,使胆酸(50g,0.12mol)转化成相应的甲基酯。向所获得的甲基酯(30g,71mmol)在乙酸酐和吡啶的混合物(50体积%,156mL)中的溶液中加入DMAP(860mg,7.1mmol)。将反应混合物在室温下搅拌1小时,在0℃下冷却,通过逐滴加入MeOH(60mL)猝灭且浓缩到几乎干燥。将残余物溶解于EtOAc中用1M HCl和NaHCO3水溶液洗涤。将有机相在减压下浓缩以给出相应的三乙酰氧基固醇(39g,100%),其分析性质与在文献(Opsenica D.等,J.Med.Chem.2000,43,3274-3282)中报道的性质相同。
(b)3α-羟基,7α,12α-二乙酰氧基-5β-胆烷-24-酸异丙酯。
向步骤(a)的固醇(29.5g,54mmol)在异丙醇(150mL)中的溶液中加入通过将细分散的Na(2.5g,108mmol)溶解于异丙醇(240mL)中获得的先前制备的异丙醇钠溶液。将混合物在室温下搅拌20分钟,且随后通过加入KHSO4(饱和水溶液)猝灭。将溶剂在减压下除去以给出粗物质,将该粗物质再溶解于EtOAc中且用盐水洗涤。蒸发溶剂且用二异丙醚湿磨粗残余物给出相应的醇(28.7g,100%)。1H NMR(400MHz,CDCl3):δ5.09-5.07(m,1H),4.99(sept.,J=6.3Hz,1H),4.90(dd,J=5.5,2.9Hz,1H),3.54-3.45(m,1H),2.29(ddd,J=15.6,10.3,5.1Hz,1H),2.18(dd,J=9.4,6.9Hz,1H),2.12(s,3H),2.08(s,3H),2.07-1.81(m,7H),1.81-1.49(m,8H),1.49-1.24(m,6H),1.22(d,J=6.3Hz,6H),1.17-0.95(m,2H),0.90(s,3H),0.81(d,J=6.8Hz,3H),0.72(s,3H)。
(c)3-氧代,7α,12α-二乙酰氧基-5β-胆烷-24-酸异丙酯。
向步骤(b)的醇(28.7g,54mmol)在乙酸(550mL)中的溶液中逐滴加入NaClO溶液(218mL,5%水溶液,268mmol)。将反应混合物在室温下搅拌1小时,用NaHSO3(饱和水溶液)猝灭且将溶剂在减压下浓缩。将残余物溶解于EtOAc中,用NaHCO3水溶液和盐水洗涤。将溶剂在减压下蒸发以给出固体残余物,该固体残余物通过快速色谱(己烷/EtOAc 4∶3)纯化以提供所要的酮(21.6g,76%)。1H NMR(400MHz,CDCl3):δ5.11(at,J=2.7Hz,1H),5.04-4.95(m,2H),2.98(dd,J=15.6,13.9Hz,1H),2.29(ddd,J=15.6,6.9,5.3Hz,1H),2.23-2.07(m,6H),2.11(s,3H),2.06(s,3H),1.99-1.74(m,5H),1.74-1.57(m,4H),1.49-1.24(m,6H),1.22(d,J=6.3Hz,6H),1.19-1.07(m,1H),1.01(s,3H),0.82(d,J=6.5Hz,3H),0.76(s,3H)。
(d)7α,12α-二乙酰氧基-2β,4β-二溴-3-氧代-5β-胆烷-24-酸异丙酯。
将步骤(c)的酮(10g,18.8mmol)溶解于乙酸(120mL)中。逐滴加入Br2(1.93mL,37.5mmol)在乙酸(100mL)中的溶液。在室温下搅拌1小时之后,将混合物倾入水中。将固体沉淀物过滤,干燥并用二异丙醚湿磨以提供2,4-二溴衍生物(9.2g,71%)。1H NMR(400MHz,CDCl3):δ5.35(d,J=11.9Hz,1H),5.18(at,J=2.7Hz,1H),5.06(dd,J=6.0,3.1Hz,1H),4.99(sept.,J=6.3Hz,1H),4.65(dd,J=14.2,4.9Hz,1H),2.62(dd,J=14.2,5.5Hz,1H),2.54(dat,J=15.7,2.0Hz,1H),2.30(ddd,J=14.9,9.4,5.6Hz,1H),2.21-2.10(m,2H),2.13(s,3H),2.12(s,3H),2.04-1.81(m,4H),1.80-1.62(m,6H),1.50-1.24(m,4H),1.21(d,J=5.7Hz,6H),1.18-1.12(m,1H),1.01(s,3H),0.82(d,J=6.4Hz,3H),0.76(s,3H)。
(e)7α,12α-二乙酰氧基-4β-溴-3-氧代-5β-胆-1-烯-24-酸异丙酯。
向步骤(d)的二溴丁酮(9.2g,13.3mmol)在DMF(60mL)中的溶液中加入Li2CO3(1.6g,20mmol)和LiBr(1.7g,20mmol)。在80℃下在氮气下搅拌8小时之后,将混合物倾入水中且将固体沉淀物过滤,干燥并用二异丙醚湿磨以提供所要的烯酮(6.8g,84%)。1H NMR(400MHz,CDCl3):δ6.77(d,J=10.3Hz,1H),6.05(d,J=10.3Hz,1H),5.34(d,J=13.4Hz,1H),5.09-5.06(m,2H),4.99(sept.,J=6.2Hz,1H),2.62(dat,J=16.0,2.0Hz,1H),2.29(ddd,J=15.3,9.6,5.7Hz,1H),2.24-2.10(m,2H),2.13(s,3H),2.08(s,3H),2.06-1.95(m,1H),1.94-1.74(m,6H),1.73-1.62(m,2H),1.52-1.29(m,4H),1,26(s,3H),1.22(d,J=6.1Hz,6H),1.18-1.11(m,1H),0.80(d,J=6.5Hz,3H),0.78(s,3H)。
(f)1-环氧基-7α,12α-二乙酰氧基-4β-溴-5β-胆烷-24-酸异丙酯。
向步骤(e)的溴-烯酮(6.8g,11.2mmol)在含有DBU(1.83mL,12.3mmol)的乙醇(450mL)中的溶液中经5小时的时间以三份加入脲-H2O2复合物(2.6g,27.6mmol),同时在室温下搅拌。将混合物用NaHSO3水溶液和KHSO4水溶液猝灭且将溶剂在减压下浓缩。将残余物溶解于EtOAc中且用1M HCl和盐水洗涤。在减压下蒸发溶剂且通过快速色谱(己烷/EtOAc 4∶2)纯化粗物质给出所要的环氧化物(4.2g,60%)。1H NMR(400MHz,CDCl3):δ5.09(at,J=2.9Hz,1H),5.06-5.04(m,1H),4.99(sept.,J=6.4Hz,1H),4.74(d,J=11.1Hz,1H),3.50(d,J=3.6Hz,1H),3.42(d,J-3.6Hz,1H),2.45-2.25(m,3H),2.18(dd,J-9.2,6.9Hz,1H),2.11(s,3H),2.10(s,3H),1.94-1.61(m,8H),1.49-1.35(m,3H),1,34(s,3H),1.32-1-24(m,3H),1.22(d,J=6.4Hz,6H),0.80(d,J=6.5Hz,3H),0.76(s,3H)。
(g)1β-羟基-2α,4β-二溴-7α,12α-二乙酰氧基-3-氧代-5β-胆烷-24-酸异丙酯。
向步骤(f)的环氧化物(300mg,0.48mmol)在乙酸(7mL)中的溶液中加入LiBr(104mg,1.2mmol)。在室温下搅拌30分钟之后,将反应混合物倾入水中且将白色沉淀物过滤并干燥以给出相应的羟基酮(283mg,86%)。1H NMR(400MHz,CDCl3):δ5.68(d,J=13.3Hz,1H),5.10(at,J=2.8Hz,1H),5.05(dd,J=5.6,2.7Hz,1H),4.99(sept.,J=6.0Hz,1H),4.48(d,J=4.6Hz,1H),4.13(at,J=4.5Hz,1H),2.72(td,J=11.7,3.9Hz,1H),2.61(dat,J=15.6,2.6Hz,1H),2.45(d,J=4.0Hz,1H),2.38(ddd,J=12.8,5.2,2.2Hz,1H),2.29(ddd,J=15.2,9.6,5.2Hz,1H),2.18(dd,J=9.2,7.0Hz,1H),2.16-2.09(m,2H),2.15(s,3H),2.03(s,3H),1.95-1.66(m,6H),1.51-1.25(m,4H),1.22(s,3H),1.22(d,J=6.4Hz,6H),1.15(m,1H),0.80(d,J=6.5Hz,3H),0.78(s,3H)。
(h)1β,3α-二羟基-2α,4β-二溴-7α,12α-二乙酰氧基-5β-胆烷-24-酸异丙酯。
向步骤(f)的环氧化物(420mg,0.67mmol)在乙酸(10mL)中的溶液中加入LiBr(117mg,1.3mmol)。向该反应混合物中加入三乙酰氧基硼氢化钠在乙酸中的先前制备的溶液(在0℃下通过将30.5mg NaBH4加到2mL乙酸中获得)。在室温下搅拌30分钟之后,蒸发溶剂且将残余物溶解于EtOAc中并用盐水洗涤。蒸发溶剂并用二异丙醚湿磨粗物质给出二溴-二醇衍生物(402mg,85%)。1H NMR(400MHz,CDCl3):δ5.04(at,J=2.4Hz,1H),4.98(sept.,J=6.5Hz,1H),5.00-4.95(m,1H),4.84(at,J=11.1Hz,1H),4.56(dd,J=4.2,3.1Hz,1H),4.19(br,1H),4.06(dat,J=10.4,4.4Hz,1H),2.79(d,J=4.5,1H),2.29(ddd,J=15.2,9.9,5.5Hz,1H),2.20-2.05(m,3H),2.15(s,3H),2.02(s,3H),1.95-1.82(m,2H),1.81-1.62(m,5H),1.53-1.25(m,5H),1.21(d,J=6.3Hz,6H),1.16-1.12(m,1H)1.14(s,3H),0.79(d,J=6.5Hz,3H),0.75(s,3H)。
(i)1β-羟基-7α,12α-二乙酰氧基-3-酮基-5β-胆烷-24-酸异丙酯。
将步骤(g)的二溴酮(100mg,0.14mmol)溶解于THF(5mL)中且在周围温度和压力下在5%Pd/C(15.0mg)上在存在乙酸钠(38mg,0.425mmol)的情况下氢化5小时。将催化剂经垫过滤且在减压下蒸发溶剂,残余物通过快速色谱(己烷/EtOAc 40∶60)纯化以提供羟基酮(35mg,45%)。1H NMR(400MHz,CDCl3):δ5.11(at,J=2.4Hz,1H),5.03-5.00(m,1H),4.99(sept.,J=6.3Hz,1H),4.09-4.04(m,1H),2.98(dd,J=15.5,13.0,1H),2.54(dd,J=14.8,2.0Hz,1H),2.39-2.29(m,3H),2.22-2.04(m,2H),2.11(s,3H),2.07(s,3H),1.94-1.64(m,10H),1.48-1.24(m,6H),1.22(d,J=6.3Hz,6H),1.14(s,3H),0.82(d,J=6.5Hz,3H),0.77(s,3H)。
(j)1β,3α-二羟基-7α,12α-二乙酰氧基-5β-胆烷-24-酸异丙酯。
将在含有NaOAc(11.5mg,0.14mmol)和乙酸(30μL)的乙醇(30mL)中的步骤(h)的二溴-二醇(50mg,0.71mmol)在雷内镍(raney Nickel)(8mg)上在180atm和室温下氢化72小时。经垫过滤催化剂,在减压下蒸发溶剂且通过硅胶快速色谱(AcOEt 100%)纯化粗物质给出所要的二醇(18mg,46%)。1H NMR(400MHz,CDCl3):δ5.06(at,J=2.5Hz,1H),4.99(sept.,J=6.3Hz,1H),4.92-4.89(m,1H),4.06-3.98(m,1H),3.88-3.85(m,1H)2.29(ddd,J=15.5,9.6,5.6,1H),2.18(dd,J=9.5,6.8Hz,1H),2.13(s,3H),2.09(s,3H),1.96-1.73(m,8H),1.73-1.36(m,13H),1.22(d,J=6.3Hz,6H),1.17-1.07(m,1H),1.03(s,3H),0.80(d,J=6.5Hz,3H),0.77(s,3H)。
类似于实施例1(g),使用无水碱(诸如在异丙醇中的异丙醇钠)选择性水解所述乙酸酯基产生四羟基-异丙基酯。
实施例3:合成1β,3α-二羟基-2α-溴-7α,12α-二乙酰氧基-5β-胆烷-24-酸异丙酯。
(a)1-环氧基-7α,12α-二乙酰氧基-5β-胆烷-24-酸异丙酯。
将在含有NaOAc(52mg,0.64mmol)的THF(5mL)中的在实施例2(f)中获得的溴化物(200mg,0.32mmol)在雷内镍(20mg)上在周围温度和压力下氢化30分钟。将催化剂在垫上过滤,在减压下蒸发溶剂且将残余物溶解于EtOAc中并用盐水洗涤。将有机萃取物在减压下蒸发且将粗残余物用二异丙醚湿磨以给出环氧基酮(141mg,81%)。1H NMR(400MHz,CDCl3):δ5.10-5.08(br,1H),5.03-4.96(m,2H),3.34(d,J=3.8Hz,1H),3.27(d,J=3.8Hz,1H),2.70(dd,J-19.3,11.9Hz,1H),2.34-2.25(m,2H),2.20-2.06(m,2H),2.11(s,3H),2.07(s,3H),1.92-1.73(m,7H),1.71-1.60(m,4H),1.47-1.34(m,2H),1.29(s,3H),1.21(d,J=6.3Hz,6H),1.34-1.25(m,2H),0.81(d,J=6.5Hz,3H),0.76(s,3H)。
(b)1β-羟基-2α-溴-7α,12α-二乙酰氧基-3-氧代-5β-胆烷-24-酸异丙酯。
向在步骤(a)中获得的环氧基酮(30mg,0.05mmol)在乙酸(0.7mL)中的溶液中加入LiBr(9.53mg,0.1mmol)。在室温下搅拌30分钟之后,将反应混合物倾入水中且加入NaHCO3直至中性pH。随后将混合物用EtOAc萃取且在减压下除去溶剂以给出羟基酮(33mg,96%)。1H NMR(400MHz,CDCl3):δ5.13-5.10(br,1H),5.03-4.93(m,2H),4.54(d,J=8.1Hz,1H),3.82(dd,J=7.7Hz,1H),3.20(dd,J=16.4,13.5Hz,1H),2.38-2.12(m,7H),2.10(s,3H),2.09(s,3H),1.96-1.61(m,8H),1.41-1.23(m,5H),1.22(d,J=6.2Hz,6H),1.15(s,3H),0.80(d,J=6.5Hz,3H),0.78(s,3H)。
(c)1β,3α-二羟基-2α-溴-7α,12α-二乙酰氧基-5β-胆烷-24-酸异丙酯。
向在步骤(a)中获得的环氧基酮(50mg,0.091mmol)在乙酸(1mL)中的溶液中加入LiBr(16mg,0.18mmol)。向反应混合物中加入三乙酰氧基硼氢化钠在乙酸中的先前制备的溶液(在0℃下通过将4.1mg NaBH4加到0.5mL乙酸中而获得)。在室温下搅拌30分钟之后,将反应混合物在减压下浓缩且将残余物溶解于EtOAc中并用盐水洗涤,在减压下蒸发溶剂以给出产物(43mg,75%)。1H NMR(400MHz,CDCl3):δ5.05(at.,J=2.6Hz,1H),4.99(sept.,J=6.2Hz,1H),4.94-4.87(m,1H),4.53-4.49(m,1H),4.15-4.09(m,1H),3.94-3.85(m,1H),2.34-2.10(m,6H),2.10(s,3H),2.04(s,3H),1.94-1.54(m,10H),1.54-1.24(m,5H),1.22(d,J=6.2Hz,6H),1.16-1.07(m,1H),1.05(s,3H),0.80(d,J=6.4Hz,3H),0.74(s,3H)。
随后还原产生相应的二醇化合物,其可分别经由部分或完全水解而转化成四羟基-酯或游离酸。
实施例4:合成1β,3α,7α,12α-四羟基-5β-胆烷-24-酸。
将在步骤1(f)中获得的二醇(1.5g,2.87mmol)加到含有NaOH(1.5g,28.7mmol)的MeOH/H2O混合物(3∶2,50mL)中。将混合物在120℃下加热且在13小时之后,TLC表明存在单一极性更大的斑点(Rf=0.48,CHCl3/MeOH/CH3COOH 5∶1∶0.5)。允许反应混合物在室温下冷却,且过量的碱通过加入阳离子交换树脂50WX2,50-100中和直至中性/微酸性的pH。将树脂滤出,用H2O/MeOH(50∶50)洗涤且在减压下除去溶剂以给出所要的游离酸-四醇(1.1g,90%)。白色固体:m.p.=288-290℃,Lit(Tohma M.等,Chem.Pharm.Bull.1986,34(7),2890-2899)=288-290℃。 1H NMR(400MHz,d6-DMSO):δ3.76(at,J=2.8Hz,1H),3.72-3.62(m,1H),3.62-3.57(m,2H),2.30-2.16(m,2H),2.14-2.04(m,2H),2.01-1.92(m,1H),1.81-1.57(m,7H),1.49-1.11(m,9H),1.01-0.92(m,1H),0.91(d,J=6.4Hz,3H),0.86(s,3H),0.58(s 3H);13C NMR(101MHz,d6-DMSO):δ175.0,71.4,70.9,66.1,64.7,46.1,45.5,41.3,39.9,39.2,38.7,37.6,35.2,35.1,34.6,31.0,30.9,28.6,27.7,27.2,22.9,17.3,16.9,12.4;IR(薄膜):v=3370,2922,2858,2359,2342,1705,1377,1184,1027,1033cm-1;HRMS(ES+):m/z:C24H39O6(M--H)计算值:423.2752,实验值:423.2734。
或者,在步骤2(j)中获得的二醇-二乙酸酯-异丙基酯(20mg,0.036mmol)可在上文报道的相同条件下水解以供给游离酸-四醇(13mg,84%),其分析数据与上文获得的化合物的数据重叠。
实施例5:合成3α-羟基-7α,12α-二乙酰氧基-5β-胆-1-烯-24-酸甲酯。
将实施例1(d)的烯酮(250mg,0.49mmol)和CeCl3(278mg,0.75mmol)在MeOH(8mL)中的悬浮液在-78℃下冷却且加入NaBH4(28mg,0.75mmol)。在-78℃下搅拌30分钟之后,将反应混合物用丙酮(0.5mL)猝灭且将溶剂在减压下蒸发。将残余物用EtOAc稀释且用盐水洗涤。将有机相在减压下浓缩以给出粗物质,将该粗物质用二异丙醚湿磨以给出所要的烯丙醇(244mg,97%)。1H NMR(400MHz,CDCl3):δ5.55(s,2H),5.06(at,J-2.8,1H),4.91(dd,J=5.9,3.1Hz,1H),4.26-4.18(m,1H),3.65(s,3H),2.34(ddd,J=15.9,10.6,5.1Hz,1H),2.22(dd,J=9.6,6.9Hz,1H),2.10(s,3H),2.08(s,3H),2.01-1.54(m,11H),1.53-1.22(m,6H),1.15-1.03(m,1H),1.00(s,3H),0.79(d,J=6.3Hz,3H),0.73(s,3H)。
实施例6:合成1β-环氧基-3α-羟基-7α,12α-二乙酰氧基-5β-胆烷-24-酸甲酯和1
α-环氧基-3α-羟基-7α,12α-二乙酰氧基-5β-胆烷-24-酸甲酯。
1α-环氧化物 1β-环氧化物
将在实施例4中获得的烯丙醇(100mg,0.39mmol)溶解于THF(3mL)和水(1mL)的混合物中,且加入NBS(89mg,0.39mmol)。将混合物在室温下搅拌24小时,此后可观察到起始材料完全转化成在TLC上对应于环氧化物的差向异构混合物的两个斑点(己烷/EtOAc 3∶4,分别Rf=0.38和Rf=0.42)。将混合物用NaHSO3猝灭且用EtOAc萃取。蒸发溶剂提供粗残余物,该粗残余物通过快速色谱(己烷/EtOAc 3∶4)纯化以给出1β-环氧化物(31mg,30%):1H NMR(400MHz,CDCl3):δ5.08(at,J=2.9,1H),4.86(dd,J=5.8,2.9Hz,1H),3.88(dd,J=10.8,6.3Hz,1H),3.65(s,3H),3.14(brd,J=3.6Hz,1H),3.05(brd,J=3.6Hz,1H),2.34(ddd,J=15.4,10.0,4.7Hz,1H),2.22(dd,J=9.9,7.0Hz,1H),2.15(s,3H),2.06(s,3H),1.98-1.54(m,12H),1.53-1.18(m,6H),1.18-1.02(m,1H),1.12(s,3H),0.79(d,J=6.3Hz,3H),0.75(s,3H)。
另外洗脱提供差向异构的1α-环氧化物(29mg,28%):1H NMR(400MHz,CDCl3):δ5.09(at,J=2.8,1H),4.85(dd,J=6.3,3.6Hz,1H),3.88(dd,J=10.8,6.3Hz,1H),3.66(s,3H),3.32(brd,J=4.1Hz,1H),2.93(d,J=4.1Hz,1H),2.35(ddd,J=15.5,10.3,5.6Hz,1H),2.21(dd,J=8.9,2.6Hz,1H),2.14(s,3H),2.06(s,3H),1.98-1.54(m,12H),1.53-1.18(m,7H),1.07(s,3H),0.82(d,J=6.3Hz,3H),0.75(s,3H)。
实施例6:合成1β,3β,7α,12α-四羟基-5β-胆烷-24-酸。
(a)1β,3β-二羟基-7α,12α-二乙酰氧基-5β-胆烷-24-酸甲酯。
在存在在THF(4mL)中的NaBH4(7.5mg,0.19mmol)的情况下在室温下还原根据Tohma M.等,Chem.Pharm.Bull.1986,34(7),2890-2899获得的羟基酮(100mg,0.19mmol)。在10分钟之后,将溶剂在减压下蒸发且将残余物用EtOAc稀释并用盐水洗涤以提供由在TLC上以约1∶1比率的对应于所要3β差向异构体(Rf=0.48,EtOAc 100%)和3α差向异构体(Rf=0.25,EtOAc 100%)的两个斑点组成的粗物质。通过快速色谱纯化(己烷/EtOAc 40∶60)提供所要的3β-二醇(40mg,39.8%)。1H NMR(400MHz,CDCl3):δ5.07(at,J=2.8,1H),4.94(dd,J=6.3,3.6Hz,1H),4.17-4.13(m,1H),3.78-3.74(m,1H),3.66(s,3H),2.40-2.14(m,2H),2.10(s,3H),2.08(s,3H),2.03-1.64(m,8H),1.63-1.54(m,6H),1.53-1.23(m,4H),1.18-1.00(m,2H),1.11(s,3H),0.81(d,J=6.3Hz,3H),0.75(s,3H)。
(b)1β,3β,7α,12α-四羟基-5β-胆烷-24-酸。
将在步骤(a)中获得的3β-二醇(40mg,0.077mmol)加到含有NaOH(31mg,0.77mmol)的MeOH/H2O混合物(3∶2,3mL)中。将混合物在120℃下加热且在13小时之后允许其在室温下冷却,且过量的碱通过加入阳离子交换树脂50WX2,50-100中和直至中性/微酸性的pH。将树脂滤出,用H2O/MeOH(50∶50)洗涤且在减压下除去溶剂以给出所要的1β,3β-四醇(27mg,83%)。1H NMR(300MHz,CD3OD):δ4.06(at,J=2.8,1H),3.94(at,J=2.4Hz,1H),3.82(dd,J=6.0,3.2Hz,1H),3.73-3.70(m,1H),2.64(at,J=14.2Hz,1H),2.33(ddd,J=14.8,9.9,4.8Hz,1H),2.20(dd,J=9.4,7.0Hz,1H),2.16-1.71(m,12H),1.71-1.22(m,6H),1.19-1.02(m,1H),1.07(s,3H),1.01(d,J=6.3Hz,3H),0.73(s,3H)。
实施例7:使用荧光素酶测定RORγ活性的抑制。
使用双重荧光素酶测定测试1β,3α,7α,12α-四羟基-5β-胆烷-24-酸(在本文中还称作四醇或四醇化合物)抑制RORγ的转译活性的能力(图1),其中作为RORγ的靶向基因的基质-金属蛋白酶3(MMP3)启动子由RORγ的活化在存在不同浓度的化合物1的情况下测试。将3T3L1前成脂肪细胞用报道基因RORγ的表达载体以及表达海肾(renilla)荧光素酶的标准化载体转染。在转染之后用1-25nM的不同量的RORγ处理细胞。在处理之后用该四醇化合物裂解细胞且测量萤火虫(firefly)以及Renilla荧光素酶活性。RORγ活性的抑制作用由萤火虫与Renilla荧光素酶的比率计算。在活性测定中该四醇化合物的分析表明RORγ活性的剂量依赖性降低。这在图2中说明,图2清晰地表明相对抑制作用(RI,y轴)随该四醇化合物的浓度升高(浓度,nM,x轴)而降低。
实施例8:体内预防功效。
为了测试所述四醇化合物的体内功效,对小鼠喂饲高脂饮食(60%卡路里来源于脂肪)6周。该饮食补充有0.1%或0.01%四醇化合物(在图3中,分别A和B)。仅接收高脂饮食的小鼠(在图3中,E)和接收补充有0.1%胆酸的高脂饮食的小鼠(在图3中,C)及接收补充有0.01%胆酸的高脂饮食的小鼠(在图3中,D)分别充当对照。
图3清晰地表明,通过胰岛素耐量试验测量,用该四醇化合物处理的小鼠在任意浓度下都引起胰岛素敏感性显著改善。
实施例9:体内治疗功效。
为了测试四醇化合物的体内治疗功效,对小鼠喂饲高脂饮食(60%卡路里来源于脂肪)6周。此后,对肥胖/胰岛素抗性小鼠施加补充有0.01%四醇或0.01%胆酸的饮食历时6周或12周(在图4和图5中,分别0.01%四醇和0.01%CA)。
图4和图5清晰地表明,通过循环葡萄糖(图4)和胰岛素水平(图5)测量,用四醇治疗肥胖胰岛素抗性小鼠随时间而引起胰岛素敏感性显著改善:gluc=葡萄糖水平,mM;ins=胰岛素水平,pg/ml。
Claims (16)
1.式V或式Va或Vb的具有多羟基化胆烷骨架的化合物或其所有的药学上可接受的盐或立体异构体在制备组合物中的用途,所述组合物用于治疗或预防有需要的个体的对RORγ受体的调节起应答的病症、疾病或病状,所述病症、疾病或病状是II型糖尿病以及与II型糖尿病有关的疾病、病症和病状,所述与II型糖尿病有关的疾病、病症和病状为低葡萄糖耐受、胰岛素抵抗和/或高血糖症,
V
Va Vb
其中
R1为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb,其中Ra和Rb彼此独立地为H或(C1-6)烷基,或R1与R2和与R1、R2连接的C-原子一起形成环氧基;
R2为H或卤素,或R2与R1和与R1、R2连接的C-原子一起形成环氧基;
R2’为H或卤素;
R4为H、卤素、-ORa、-SRa、-NRaRb、-COORa、-CONRaRb、氧代、硫代,其中Ra和Rb彼此独立地为H或(C1-6)烷基;
L为直链的C(1-12)烷基,其为未取代的,且其中一个或多个不相邻的CH2基团可被选自-O-、-CO-、-CO-O的基团独立地置换;
X为H、-ORa、-COORc、-CONRaRc,其中Ra为H或(C1-6)烷基且Rc为-H、-(C1-6)烷基、-NH-(CH2)n-CO2Ra或-NH-(CH2)p-SO3Ra,其中n、p为1、2或3且Ra为-H或-(C1-6)烷基;且
Ra为H或C(1-6)烷基;
m为0-5,且
其中R1或R4或R1和R4两者为-ORa,其中Ra为H或(C1-6)烷基。
2.权利要求1的化合物的用途,其中L为直链的C(1-12)烷基。
3.权利要求1或2的化合物的用途,其中R1是H、-ORa、-NRaRb,或其中R4是H、氧代、-ORa、-NRaRb,其中Ra和Rb彼此独立为H或(C1-6)烷基。
4.权利要求1或2的化合物的用途,其中X是H、-ORa、–COORc、-CONRaRc,其中Ra是H或(C1-6)烷基且Rc是-H、-(C1-6)烷基、-NH-CH2-CO2Ra或-NH-CH2-SO3Ra,其中Ra是-H或-(C1-6)烷基。
5.权利要求1或2的化合物的用途,其中-L-X是–(C1-6)烷基-COORa,其中Ra是-H或-(C1-6)烷基。
6.权利要求1或2的化合物的用途,其中R2是H或卤素。
7.权利要求1的化合物的用途,所述化合物具有式VIa或式VIa1和VIa2,
其中,
L为直链的C(1-12)烷基,其未被取代且其中一个或多个不相邻的CH2基团可被选自-O-、-CO-、-CO-O-的基团独立地置换;
Ra是H或C(1-6)烷基,
X为H、-ORa、-SRa、-NRaRb、-COORc、-CONRaRc;其中Ra和Rb彼此独立地为H或(C1-6)烷基且Rc为-H、-(C1-6)烷基、-NH-(CH2)n-CO2Ra或-NH-(CH2)p-SO3Ra,其中n、p为1、2或3且Ra为-H或-(C1-6)烷基。
8.权利要求7的化合物的用途,其中L为直链的C(1-12)烷基。
9.权利要求7或8的化合物的用途,其中X为H、-ORa、-COORc、-CONRaRc;其中Ra为H或(C1-6)烷基且Rc为-H、-(C1-6)烷基、-NH-(CH2)n-CO2Ra或-NH-(CH2)p-SO3Ra,其中n、p为1、2或3。
10.权利要求7或8的化合物的用途,其中-L-X是–(C1-6)烷基-COORa,其中Ra是-H或-(C1-6)烷基。
11.权利要求1的用途,其中所述化合物具有式VIb或式VIb1、VIb2、VIb3或VIb4或式VIc,
,
其中,
L为直链的C(1-12)烷基,其为未取代的,且其中一个或多个不相邻的CH2基团可被选自-O-、-CO-、-CO-O-的基团独立地置换,
Ra是H或C(1-6)烷基,
X为H、-ORa、-SRa、-NRaRb、-COORc、-CONRaRc;其中Ra和Rb彼此独立地为H或(C1-6)烷基且Rc为-H、-(C1-6)烷基、-NH-(CH2)n-CO2Ra或-NH-(CH2)p-SO3Ra,其中n、p为1、2或3且Ra为-H或-(C1-6)烷基。
12.权利要求11的化合物的用途,其中L为直链的C(1-12)烷基。
13.权利要求11或12的化合物的用途,其中X为H、-ORa、-COORc、-CONRaRc;其中Ra为H或(C1-6)烷基且Rc为-H、-(C1-6)烷基、-NH-(CH2)n-CO2Ra或-NH-(CH2)p-SO3Ra,其中n、p为1、2或3。
14.权利要求11或12的化合物的用途,其中-L-X是–(C1-6)烷基-COORa,其中Ra是-H或-(C1-6)烷基。
15.权利要求1、2、7、8、11或12的化合物的用途,其中所述化合物为药物组合物形式,该药物组合物包含至少一种药学上可接受的载体,任选包含至少一种另外的治疗活性剂。
16.权利要求1、2、7、8、11或12的化合物的用途,其中所述治疗或预防包括给予所述个体治疗或预防有效量的至少一种权利要求1、2、7、8、11或12中所述的化合物或其药学上可接受的盐或立体异构体、任选与至少一种另外的治疗活性剂联用。
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CN106132422A (zh) | 2014-02-27 | 2016-11-16 | 莱斯拉公司 | 使用视黄酸受体相关孤儿受体γ的激动剂的过继细胞疗法&相关治疗方法 |
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RU2014115796A (ru) | 2015-10-27 |
AU2012311599B2 (en) | 2017-07-06 |
EP2758060A1 (en) | 2014-07-30 |
RU2658013C2 (ru) | 2018-06-19 |
PL2758060T3 (pl) | 2018-04-30 |
KR102020923B1 (ko) | 2019-09-11 |
AU2012311599A1 (en) | 2014-02-20 |
BR112014003704A2 (pt) | 2017-03-07 |
KR20140079416A (ko) | 2014-06-26 |
US9777036B2 (en) | 2017-10-03 |
WO2013041519A1 (en) | 2013-03-28 |
NZ620485A (en) | 2016-04-29 |
WO2013041519A9 (en) | 2013-06-27 |
JP2018024651A (ja) | 2018-02-15 |
NO2758060T3 (zh) | 2018-04-28 |
PT2758060T (pt) | 2018-01-24 |
CN103957919A (zh) | 2014-07-30 |
JP6439206B2 (ja) | 2018-12-19 |
ES2659455T3 (es) | 2018-03-15 |
EP2758060B1 (en) | 2017-11-29 |
DK2758060T3 (en) | 2018-03-05 |
US20140343023A1 (en) | 2014-11-20 |
JP2014526494A (ja) | 2014-10-06 |
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