CN109661231A - 用于非酒精性脂肪性肝炎和纤维化的新治疗 - Google Patents
用于非酒精性脂肪性肝炎和纤维化的新治疗 Download PDFInfo
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- CN109661231A CN109661231A CN201780053972.9A CN201780053972A CN109661231A CN 109661231 A CN109661231 A CN 109661231A CN 201780053972 A CN201780053972 A CN 201780053972A CN 109661231 A CN109661231 A CN 109661231A
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
式(I)的化合物
Description
本发明涉及用于非酒精性脂肪性肝炎(NASH)和纤维化的新治疗。
非酒精性脂肪性肝炎(NASH)是一种肝脏疾病,特征在于肝脏中的:(1)脂肪变性(脂肪堆积),(2)小叶炎症,和(3)肝细胞破坏(气球样变)。其为非酒精性脂肪性肝病(NAFLD)组的一部分,所述非酒精性脂肪性肝病由良性肝脏脂肪变性开始,但可以发展为NASH、纤维化、具有永久性肝损伤的肝硬化、肝细胞癌和死亡。
NAFLD通常与肥胖症和2型糖尿病有关,其在全世界的发病率极高且持续升高。
在USA,据估计NASH出现在12%的成年群体和22%的糖尿病患者中。还估计15-25%的患有NASH的患者将发展为肝硬化(肝纤维化,即纤维组织在器官中的过量沉积)。NASH也相当大地增加了心血管意外事件的风险。
目前,对于治疗NASH不存在任何有效的药物,健康监管机构(FDA,EMA)认为NASH流行病的控制是优先考虑的事情。
因此,需要提供NASH的有效治疗。
本发明的一个目的是提供适用于预防和/或治疗NASH的化合物。
本发明的还一个目的是提供也可适用于预防和/或治疗纤维化,优选肝纤维化的化合物。
而且,通过阅读下述发明说明书将实现其它目的。
本发明涉及式(I)的化合物
其中
R1代表∶
-基团–C(O)CR4R5CR6R7C(O)OH;
-基团–C(OH)(H)CR4R5CR6R7C(O)OH;
-基团
-–(CH2)4C(O)OH基团;
m代表0至8的整数;
R2代表∶
-任选取代的C6至C10芳基基团;或
-任选取代的5至10-元杂芳基基团;
R3相同或不同,代表:
-直链或支链的、C1至C5优选地C1至C4烷基;例如,甲基、乙基、丙基、异丙基、丁基、叔丁基;任选地被碳环基团或杂环基团取代,所述碳环为5至10元、饱和的、部分不饱和的或芳香族的、取代的或非取代的碳环,所述杂环包括5至10元、取代的或非取代的、饱和的、部分不饱和的或芳香族的杂环且其可以包括1、2或3个杂原子,所述杂原子相同或不同,特别地选自氮、氧或硫,
R4、R5、R6和R7相同或不同,代表:
-氢原子;
-直链或支链的、C1至C5优选地C1至C4的烷基;
-5、6或7-元饱和的、部分不饱和的或芳香族的、非取代的或取代的碳环基团;或
R4和R5与它们键合的碳原子一起形成具有5、6或7元、取代的或非取代的、优选饱和的碳环;例如环戊基或环己基;或
R6和R7与它们键合的碳原子一起形成具有5、6或7元、取代的或非取代的、优选饱和的碳环;例如环戊基或环己基;
或其对映异构体、其非对映异构体及其与可药用碱或酸的加成盐,
用于预防或治疗,优选地治疗NASH。
在本发明中,“用于治疗Y的化合物X”等同于“在治疗Y的方法中使用的化合物X”或“在治疗Y中使用的化合物X”。
术语杂芳基指包括至少一个相同或不同的选自O、N、S,优选N的杂原子的5至10元杂芳基。杂芳基可以包括1、2、3或4个相同或不同的选自O、N、S,优选N的杂原子,优选地1、2或3个相同或不同的杂原子。
所述碳环、杂环、芳基、杂芳基为非取代的或被一个或多个相同或不同的取代基取代,所述取代基特别地选自:
-直链或支链的C1至C6烷氧基,例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基或叔丁氧基;
-卤素原子;
-直链或支链的烃基,优选地C1至C5优选地C1至C4烷基,例如,甲基、乙基、丙基、丁基、异丙基、叔丁基;
-直链或支链的烃基,优选地C1至C5优选地C1至C4烷基,特别地被一个或多个卤素原子取代;
-氰基(-CN)基团;或
-磺酰基烷基(-S(O)2-烷基)基团,其中所述烷基为直链或支链的、C1至C5优选地C1至C4烷基,例如甲基、乙基、丙基、丁基、异丙基或叔丁基;
-具有5、6或7元、饱和的、部分不饱和的或芳香族优选苯基的、取代的或非取代的碳环基团,特别地被一个或多个相同或不同的选自下述的取代基取代:卤素原子,直链或支链的C1至C6烷氧基,例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基或叔丁氧基;C1至C5烷基,优选地C1至C4烷基,例如甲基、乙基、丙基、丁基、异丙基或叔丁基。
优选地,在本发明的化合物中,m为0。
优选地,在本发明的化合物中,R1为–C(O)CH2CH2C(O)OH或–(CH2)4C(O)OH。
优选地,在本发明的化合物中,R1为–C(O)CH2CH2C(O)OH。
优选地,在本发明的化合物中,R2代表∶
-C6至C10芳基基团,任选地被至少一个选自下述的取代基取代:直链或支链的C1-C6烷基,或直链或支链的O-(C1-C6)-烷基,优选地直链或支链的O-(C1-C3)-烷基;或
-5至10-元杂芳基基团。
优选地,在本发明的化合物中,R2代表:
-5至10-元杂芳基基团。
优选地,在本发明的化合物中,R1为–C(O)CH2CH2C(O)OH和m为0。
优选地,在本发明的化合物中,
m为0;和
R2代表∶
-C6至C10芳基基团,任选地被至少一个选自下述的取代基取代:直链或支链的C1-C6烷基,或直链或支链的O-(C1-C6)-烷基,优选地直链或支链的O-(C1-C3)-烷基;或
-5至10-元杂芳基基团。
优选地,在本发明的化合物中,
m为0;和
R2代表∶
-5至10-元杂芳基基团。
优选地,在本发明的化合物中,
R1为–C(O)CH2CH2C(O)OH,和
R2代表∶
-C6至C10芳基基团,任选地被至少一个选自下述的取代基取代:直链或支链的C1-C6烷基,或直链或支链的O-(C1-C6)-烷基,优选地直链或支链的O-(C1-C3)-烷基;或
-5至10-元杂芳基基团。
优选地,在本发明的化合物中,
R1为–C(O)CH2CH2C(O)OH,和
R2代表:
-5至10-元杂芳基基团。
优选地,在本发明的化合物中,
R1为–C(O)CH2CH2C(O)OH
m为0,和
R2代表:
-C6至C10芳基基团,任选地被至少一个选自下述的取代基取代:直链或支链的C1-C6烷基,或直链或支链的O-(C1-C6)-烷基,优选地直链或支链的O-(C1-C3)-烷基;或
-5至10-元杂芳基基团。
优选地,在本发明的化合物中,
R1为–C(O)CH2CH2C(O)OH
m为0,和
-5至10-元杂芳基基团。
优选地,在本发明的化合物中,R2代表∶
-苯基基团,任选地被至少一个选自下述的取代基取代:直链或支链的C1-C6烷基,或直链或支链的O-(C1-C6)-烷基,优选地直链或支链的O-(C1-C3)-烷基;或
-6-元杂芳基基团,优选地包括至少一个氮,优选吡啶。
优选地,在本发明的化合物中,R2代表:
-6-元杂芳基基团,优选地包括至少一个氮,优选吡啶。
优选地,在本发明的化合物中,
m为0;和
R2代表:
-苯基基团,任选地被至少一个选自下述的取代基取代:直链或支链的C1-C6烷基,或直链或支链的O-(C1-C6)-烷基,优选地直链或支链的O-(C1-C3)-烷基;或
-6-元杂芳基基团,优选地包括至少一个氮,优选吡啶。
优选地,在本发明的化合物中,
m为0;和
R2代表:
-6-元杂芳基基团,优选地包括至少一个氮,优选吡啶。
优选地,在本发明的化合物中,
R1为–C(O)CH2CH2C(O)OH;和
R2代表:
-苯基基团,任选地被至少一个选自下述的取代基取代:直链或支链的C1-C6烷基,或直链或支链的O-(C1-C6)-烷基,优选地直链或支链的O-(C1-C3)-烷基;或
-6-元杂芳基基团,优选地包括至少一个氮,优选吡啶。
优选地,在本发明的化合物中,
R1为–C(O)CH2CH2C(O)OH;和
R2代表∶
-6-元杂芳基基团,优选地包括至少一个氮,优选吡啶。
优选地,在本发明的化合物中,
R1为–C(O)CH2CH2C(O)OH;
m为0,和
R2代表∶
-苯基基团,任选地被至少一个选自下述的取代基取代:直链或支链的C1-C6烷基,或直链或支链的O-(C1-C6)-烷基,优选地直链或支链的O-(C1-C3)-烷基;或
-6-元杂芳基基团,优选地包括至少一个氮,优选吡啶。
优选地,在本发明的化合物中,
R1为–C(O)CH2CH2C(O)OH;
m为0,和
R2代表∶
-6-元杂芳基基团,优选地包括至少一个氮,优选吡啶。
根据本发明的化合物可以如在WO2012/17515和WO2012/175707(将其通过援引并入本文中)中提及的合成。
式(I)的化合物具有羧基官能团,且可以成盐。然后,它们可以是与有机碱或无机碱的加成盐形式。与碱的加成盐为例如可药用盐,比如钠盐、钾盐或钙盐,其是使用相应的碱金属和碱土金属氢氧化物作为碱获得的。作为与可药用碱的加成盐的另外的形式,可以提及与胺且特别是葡糖胺、N-甲基葡糖胺、N,N-二甲基葡糖胺、乙醇胺、吗啉、N-甲基吗啉或赖氨酸的盐。
式(I)的化合物也可以与无机酸或有机酸成盐,且优选地与药用酸成盐,所述药用酸比如盐酸、磷酸、富马酸、柠檬酸、草酸、硫酸、抗坏血酸、酒石酸(tartric acid)、马来酸、扁桃酸、甲烷基磺酸、乳糖酸、葡糖酸、葡糖二酸、琥珀酸、磺酸或羟基丙烷磺酸。
本发明的化合物用于治疗或预防优选地治疗NASH。
本发明还涉及药物组合物,包括作为有效成分的至少一种根据本发明的化合物,用于预防或治疗,优选地治疗NASH。这些组合物也可包括可药用媒介物和/或赋形剂。
药物组合物可以是本领域技术人员已知的任何形式,特别是预期用于肠胃外、口服、直肠、经粘膜(permucosal)或经皮方法优选地口服给药的形式。
根据本发明的组合物将以下述形式存在:可注射的溶质或悬浮液或多剂量烧瓶的形式,素片(bare tablets)或包衣片、丸剂、胶囊、粉剂、栓剂或直肠胶囊、溶液或悬浮液的形式,用于经皮用途(在极性溶剂中),或经粘膜(permucosal)用途。
对于固体形式,适用于这种给药的赋形剂为纤维素或微晶纤维素的衍生物、碱土碳酸盐、磷酸镁、淀粉、改性淀粉或乳糖。
对于直肠使用,可可脂或硬脂酸聚乙二醇酯是优选的赋形剂。
对于肠胃外使用,水、水性溶质、生理学血清和等渗溶质是最方便使用的媒介物。
剂量学可以根据治疗适应症和给药方法、以及受试者的年龄和体重在很大限度之内变化。
本发明还涉及一种预防或治疗,优选地治疗NASH的方法,包括向如此需要的患者给药足够量的至少一种根据本发明的化合物与可药用媒介物或赋形剂。
如上所述需要治疗的患者的鉴别由本领域技术人员定义。兽医或医生可以利用临床试验、身体检查、生物检验或诊断和通过家庭和/或病史鉴别需要这种治疗的受试者。
足够量指有效地预防或治疗病理学病症的根据本发明的化合物的量。足够量可以由本领域技术人员利用常规技术和通过观察在类似情形中得到的结果确定。为了确定足够量,本领域技术人员必须考虑各种因素,特别地且不限于此:受试者、其尺码、其年龄、其整体健康状况、涉及的疾病及其严重程度;受试者的反应、化合物的类型、给药方法、给药组合物的生物利用度、剂量、同时使用的其它药物等。优选地,以一个或多个剂量,优选地以一个剂量向患者给药5至500mg/天的根据本发明的化合物。
本发明还涉及一种预防或治疗,优选地治疗NASH的方法,包括向需要其的患者给药足量的至少一种根据本发明的组合物。
本发明还涉及式(I)的化合物在制备用于预防或治疗,优选地治疗NASH的药物中的用途。
本发明还涉及根据本发明的组合物在制备用于预防或治疗,优选地治疗NASH的药物中的用途。
除了治疗NASH之外,根据本发明的化合物还用于治疗纤维化,优选肝纤维化。实际上,本发明还涉及用于预防或治疗,优选地治疗纤维化优选肝纤维化的根据本发明的化合物。本发明还涉及用于预防或治疗,优选地治疗纤维化优选肝纤维化的根据本发明的组合物。
本发明还涉及一种预防或治疗,优选地治疗纤维化优选肝纤维化的方法,包括向如此需要的患者给药足量的至少一种根据本发明的化合物或组合物与可药用媒介物或赋形剂。
本发明还涉及根据本发明的化合物或组合物在制备用于预防或治疗,优选地治疗纤维化优选肝纤维化的药物中的用途。
本发明还涉及用于预防或治疗,优选地治疗NASH和纤维化优选肝纤维化的根据本发明的化合物。本发明还涉及用于预防或治疗,优选地治疗NASH和纤维化优选肝纤维化的根据本发明的组合物。
本发明还涉及一种预防或治疗,优选地治疗NASH和纤维化优选肝纤维化的方法,包括向如此需要的患者给药足量的至少一种根据本发明的化合物或组合物与可药用媒介物或赋形剂。
本发明还涉及根据本发明的化合物或组合物在制备用于预防或治疗,优选地治疗NASH和纤维化优选肝纤维化的药物中的用途。
现在,本发明将借助于非限制性实施例进行描述。
已经测试了下述式(I)的化合物(1)∶
如WO 2012/175715中描述的获得该化合物。
该研究在STAM模型上进行。
从日本SLC,Inc.(日本)获得无病原体的十四天妊娠C57BL/6小鼠。通过产后单次皮下注射链脲佐菌素(Sigma,USA)和在四周龄(28±2天)之后不限量饲喂高脂肪饮食(CLEA日本,日本)在雄性小鼠中建立NASH。在开始治疗之前的数天中,将六周龄(42±2天)的小鼠随机分成三组,每组10只,并且将九周龄(63±2天)的小鼠分成三组,每组10只。在治疗期间,每日测量个体体重。在治疗期间,每周两次测量食物消耗。每日监测小鼠的存活、临床征兆和行为。
评价对于NASH作用的体内研究1
NASH体内研究具有3组(arms):
第1组(媒介物)∶向10只NASH小鼠口服给药与接受化合物(1)的小鼠相同的媒介物(0.5%甲基纤维素水溶液)。
第2组(替米沙坦)∶从第六至第九(6至9)周龄,每日一次向五只小鼠给药补充有100mg/kg剂量的替米沙坦的相同媒介物(0.5%甲基纤维素水溶液)。替米沙坦,一种血管紧张素受体阻断剂,是参考化合物,其已被证明在STAM动物模型中治疗NASH和纤维化是有活性的。
第3组(化合物(1))∶从第六至第九(6至9)周龄,每日一次向十只NASH小鼠口服给药补充有100mg/kg剂量的化合物(1)的相同媒介物(0.5%甲基纤维素水溶液)。评价的参数和组织学结果测量方法描述如下。
评价对于纤维化作用的体内研究2
纤维化体内研究具有3组:
第1组(媒介物)∶向10只NASH小鼠口服给药与接受化合物(1)的小鼠相同的媒介物(0.5%甲基纤维素水溶液)。
第2组(替米沙坦)∶从第九至第十二(9至12)周龄,每日一次向五只小鼠给药补充有100mg/kg剂量的替米沙坦的相同媒介物(0.5%甲基纤维素水溶液)。
第3组(化合物(1))∶从第九至第十二(9至12)周龄,每日一次向十只NASH小鼠口服给药补充有100mg/kg剂量的化合物(1)的相同媒介物(0.5%甲基纤维素水溶液)。评价的参数和组织学结果测量方法描述如下。
研究测量方法、分析物、结果和分析
对于两个体内研究,进行下述测量:
·个体肝重
·个体体重
·通过FUJI DRI-CHEM(Fujifilm,日本)测量血浆ALT(丙氨酸氨基转移酶),AST(天门冬氨酸氨基转移酶),甘油三酯和总胆固醇。
·通过甘油三酯E-试验试剂盒(Wako,日本)定量肝甘油三酯。
·组织学分析肝部分(根据常规方法)
·HE(苏木精伊红)染色和NAFLD活性评分(NAS)的评估
NAS的定义和计算
NASH临床研究网络(Clinical Research Network)提议的NAFLD活性评分(NAS)是NAFLD/NASH研究领域中最广泛使用的评分系统(Kleiner,DE.,等人,(2005).Design andvalidation of a histological scoring system for nonalcoholic fatty liverdisease.Hepatology,41,1313-21)。
NAS定义为对于代表活化肝损伤(active liver injury)的脂肪变性(0-3)、小叶炎症(0-3)和肝细胞气球样变(0-2)的组织学评分的未加权总和(见表)。在临床和非临床试验中,NAS得到0至8的总分,并且能够详细分析比较研究和相关研究的组织学变化。
NAS最初被研究用于评价而非诊断NAFLD/NASH。然而,所述评分通常被用于NASH诊断,NAS 5被认为是阈值。尽管NAS显示出与诊断的良好相关性,但是必须需要仔细的解释。存在的情形是,其中非NASH肝可评分为总NAS≥5,或者相反地,具有NAS≤4的肝可得到NASH的诊断(Brunt,EM.,等人,(2011)。Nonalcoholic fatty liver disease(NAFLD)activityscore and the histopathologic diagnosis in NAFLD:distinct clinicopathologicmeanings.Hepatology,53,810-20and Hjelkrem,M.,等人,(2011).Validation of thenon-alcoholic fatty liver disease activity score.Aliment.Pharmacol.Ther.,34,214-8)。
在评价药物功效的情况下,当严格地应用于组织学证实的NASH患者时,NAS是有用的。从非临床研究的方面来看,当应用于NASH病理学的不稳定发病(uneven onset)的动物模型时,应当小心地使用NAS。
由于Stelic的专有NASH-HCC模型(STAM模型)具有均一且可再现的[100%]疾病进程,STAM模型对于使用NAS进行比较研究是有利的。
·2002年由国家糖尿病消化与肾病研究所(National Institute of Diabetesand Digestive and Kidney Diseases)(NIDDK)建立了研究成人和儿童脂肪性肝病的自然病史(natural history)和进行临床试验的网络。
NAS构成的定义
表1NAFLD活性评分的构成(Kleiner等人,2005)
结果以附图给出。
图1表示研究1和2中各个组1(媒介物)、2(替米沙坦)和3(根据本发明的化合物)的NAS评分。
图2显示研究1和2中各个组1(媒介物)、2(替米沙坦)和3(根据本发明的化合物)的肝中甘油三酯的量。
图3显示研究1和2中各个组1(媒介物)、2(替米沙坦)和3(根据本发明的化合物)的血浆中甘油三酯的量。
与媒介物和替米沙坦相比,在研究1和2中,根据本发明的化合物(1)显示NAFLD活性评分(NAS)显著降低。
根据本发明的化合物(1)显示肝甘油三酯(TG)的量减少。
根据本发明的化合物(1)显示血浆甘油三酯(TG)的量减少,特别是在研究2中。
Claims (12)
1.式(I)的化合物:
其中
R1代表:
-基团–C(O)CR4R5CR6R7C(O)OH;
-基团–C(OH)(H)CR4R5CR6R7C(O)OH;
-基团或
-–(CH2)4C(O)OH基团;
m代表0至8的整数;
R2代表:
-任选取代的C6至C10芳基基团;或
-任选取代的5至10-元杂芳基基团;
R3相同或不同,代表:
-直链或支链的、C1至C5优选地C1至C4烷基;例如,甲基、乙基、丙基、异丙基、丁基、叔丁基;任选地被碳环基团或杂环基团取代,所述碳环为5至10元、饱和的、部分不饱和的或芳香族的、取代的或非取代的碳环,所述杂环包括5至10元、取代的或非取代的、饱和的、部分不饱和的或芳香族的杂环且其可以包括1、2或3个杂原子,所述杂原子相同或不同,特别地选自氮、氧或硫,
R4、R5、R6和R7相同或不同,代表:
-氢原子;
-直链或支链的、C1至C5优选地C1至C4烷基;
-5、6或7-元饱和的、部分不饱和的或芳香族的、非取代的或取代的碳环基团;或
R4和R5与它们键合的碳原子一起形成具有5、6或7元、取代的或非取代的、优选饱和的碳环;例如环戊基或环己基;或
R6和R7与它们键合的碳原子一起形成具有5、6或7元、取代的或非取代的、优选饱和的碳环;例如环戊基或环己基;
或其对映异构体、其非对映异构体及其与可药用碱或酸的加成盐,
用于预防或治疗,优选地治疗NASH。
2.根据权利要求1的用途的化合物,其中m为0。
3.根据权利要求1或2的用途的化合物,其中R1为–C(O)CH2CH2C(O)OH或–(CH2)4C(O)OH。
4.根据权利要求1至3的用途的化合物,其中R1为–C(O)CH2CH2C(O)OH。
5.根据权利要求1至4中任一项的用途的化合物,其中R2代表∶-C6至C10芳基基团,任选地被至少一个选自下述的取代基取代:直链或支链的C1-C6烷基,或直链或支链的O-(C1-C6)-烷基,优选地直链或支链的O-(C1-C3)-烷基;或
-5至10-元杂芳基基团。
6.根据权利要求1至5中任一项的用途的化合物,其中R2代表5至10-元杂芳基基团。
7.根据权利要求1至6中任一项的用途的化合物,其中R2代表6-元杂芳基基团,优选地包括至少一个氮,优选吡啶。
8.用于预防或治疗NASH的组合物,包括根据权利要求1至7中任一项的化合物。
9.根据权利要求1至7中任一项的化合物,用于预防或治疗纤维化,优选地肝纤维化。
10.根据权利要求1至7中任一项的化合物,用于预防或治疗NASH和纤维化,优选地肝纤维化。
11.组合物,包括根据权利要求1至7中任一项的化合物,用于预防或治疗纤维化,优选地肝纤维化。
12.组合物,包括根据权利要求1至7中任一项的化合物,用于预防或治疗NASH和纤维化,优选地肝纤维化。
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