CN110938094A - 一种甲状腺激素受体β亚型激动剂衍生物的制备方法和用途 - Google Patents
一种甲状腺激素受体β亚型激动剂衍生物的制备方法和用途 Download PDFInfo
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- CN110938094A CN110938094A CN201910748473.2A CN201910748473A CN110938094A CN 110938094 A CN110938094 A CN 110938094A CN 201910748473 A CN201910748473 A CN 201910748473A CN 110938094 A CN110938094 A CN 110938094A
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Abstract
本发明涉及一种通式(I)所述甲状腺激素受体β亚型激动剂衍生物及其制备方法,以及在制备治疗相关疾病(肥胖、高脂血症、高胆固醇血症、糖尿病等相关病症和疾病以及酒精性脂肪性肝炎、动脉粥样硬化、心血管疾病、甲状腺功能减退等相关病症和疾病)药物中的用途。
Description
技术领域
本发明涉及一种甲状腺激素受体β亚型激动剂衍生物及其制备方法,以及在制备治疗相关疾病(肥胖、高脂血症、高胆固醇血症、糖尿病等相关病症和疾病以及酒精性脂肪性肝炎、动脉粥样硬化、心血管疾病、甲状腺功能减退等相关病症和疾病)药物中的用途。
背景技术
MGL-3196是第一原创(first-in-class)口服给药的小分子肝脏甲状腺激素受体β亚型(THR-β)的选择性激动剂。临床前毒理学和临床1期数据表明,作为非酒精性脂肪性肝炎(NASH)和血脂异常的潜在治疗方法,MGL-3196能够显著降低LDL胆固醇、甘油三酯和脂蛋白(Journal of Hepatology,2018,vol.68,S37–S64),使其成为降低NASH患者心血管风险和中度他汀类药物剂量或对他汀类药物不耐受的血脂异常患者的理想候选药物(EuropeanHeart Journal,Volume 39,Issue suppl_1,1August 2018,ehy566.P5387)。临床2期数据表明,不良反应(AEs)主要是轻度(85%)及中度(15%),出现了3例与治疗无关的严重AEs(Journal of Hepatology,2018,vol.68,S37–S64)。
甲状腺激素的生理作用几乎影响到每个器官系统。临床上,这些影响表现为代谢率的变化,脂质代谢改变和对心血管发育的特征效应。甲状腺受体分为α1,β1,β2三个亚型,最新研究表明,TRβ1在肝中调节TRH(促甲状腺激素释放激素)和调节甲状腺激素的作用中起重要作用。TRβ2在肝中调节TSH(甲状腺刺激激素)方面起主要作用(J.Clin.invest,1999,Vol 104,291-300)。如果能将甲状腺激素过量的有害影响与对降低胆固醇和血脂等潜在有益作用分开,我们就可能获得强效的新型药物。
因此需要开发新的技术,以达到改善药物在体内的吸收、分布、转运与代谢过程、提高生物利用度、提高药物对靶部位作用的选择性、降低药物的毒副作用、延长作用时间、降低食物影响等的技术效果,造福更多患者。
发明内容
本发明人经过大量创造性劳动,令人惊讶的得到了一种THR-β激动剂(MGL-3196)的衍生物,显著改善了MGL-3196的药代动力学特征。
具体的,本发明涉及一种通式(I)所示化合物及其立体异构体或药学上可接受的盐,及其氘代化合物,
其中,
R1a、R1a’、R1c、R1c’、R1e、R1e’各自独立的选自H、C1-6烷基或C3-8碳环基,所述的C1-6烷基或C3-8碳环基任选进一步被0至4个选自H、F、Cl、Br、I、C1-4烷基或C1-6烷氧基的取代基所取代;
R1b、R1d、R1f各自独立的选自C1-6烷基、苄基或C3-8碳环基,所述的C1-6烷基、苄基或C3-8碳环基任选进一步被0至4个选自H、F、Cl、Br、I、C1-6烷基或C1-6烷氧基的取代基所取代;
R1g选自C1-6烷基、C3-8碳环基或C5-10杂环基,所述的C1-6烷基、C3-8碳环基或C5-10杂环基任选进一步被0至4个选自H、F、Cl、Br、I、苯基、C1-6烷基或C1-6烷氧基的取代基所取代;
R2选自H或C1-6烷基;
n选自0或1。
本发明的一些实施例中,R1a、R1a’、R1c、R1c’、R1e、R1e’各自独立的选自H或C1-4烷基;R1b、R1d、R1f各自独立的选自C1-4烷基或苄基;R1g选自C1-4烷基、苯基或苄基;
R2选自H;n选自1。
本发明的一些实施例中,R1a、R1c、R1e各自独立的选自H、甲基、乙基、丙基或异丙基;R1a’、R1c’、R1e’选自H;R1b、R1d、R1f各自独立的选自甲基、乙基、丙基、异丙基或苄基;R1g选自甲基、乙基、丙基、异丙基、苯基或苄基。
本发明的一些实施例中,R1a、R1a’、R1c、R1c’、R1e、R1e’各自独立的选自H或C1-4烷基,优选H、甲基、乙基、丙基或异丙基;R1b、R1d、R1f各自独立的选自C1-4烷基或苄基,优选甲基、乙基、丙基、异丙基或苄基;R1g选自C1-4烷基、苯基或苄基,优选甲基、乙基、丙基、异丙基、苯基或苄基;
R2选自H;n选自1。
本发明所述的化合物及其立体异构体或药学上可接受的盐,及其氘代化合物,选自如下结构之一:
本发明还涉及一种药物组合物,所述药物组合物含有治疗有效剂量的本发明所述化合物的及其立体异构体或药学上可接受的盐,及其氘代化合物,以及药学上可接受的载体和赋形剂。
本发明还涉及本发明所述化合物及其立体异构体或药学上可接受的盐,及其氘代化合物,或本发明所述的药物组合物在制备用于治疗NAFLD药物中的应用。
为了完成本发明的目的,本发明化合物可以由以下方案制备而得:
苄醇与三氯氧磷(或甲氧基甲基二氯化磷或二氯磷酸R1g酯)反应,再与相应的氨基酸酯(例如)反应得到通式IA的化合物,经过氢氧化钯或钯碳脱苄得到通式IB的化合物,再与化合物MGL3196-Cl(合成详见CN101801960A)在氧化银的作用下生成通式I的化合物。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明中,C3-8碳环基表示C3-8的环烷基或C6-8芳基,C3-8的环烷基表示碳原子数为3-8的环状烷基,例如环丙基、环丁基、环戊基、环己基;C6-8芳基表示碳原子数是为6-8的芳香族环状基团,例如苯基、苄基。C1-6烷基表示碳原子数1-6的支链或直链烷基,例如甲基、乙基、丙基、异丙基、丁基、叔丁基。C1-6烷氧基表示氧原子与C1-6烷基结合形成的基团,例如甲氧基、乙氧基。C3-6环烷基表示碳原子数为3-6的环状烷基,例如环丙基、环丁基、环戊基。C5-10杂环基表示环的原子数为5-10的芳香族或非芳香族杂环基团,环的原子种类包括一个或以上的杂原子(例如N、O、S),例如吗啉基、氮杂环丁烷、哌啶基、哌嗪基、吡咯烷基。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又称为重氢)、氚(T,又称为超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生,该说明包括该事件或环境发生或不发生的场合。如:“任选被F取代的烷基”指烷基可以但不必须被F取代,说明包括烷基被F取代的情形和烷基不被F取代的情形。
“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐与其他组成成分的混合物,其中其它组分包含生理学/药学上可接受的载体和赋形剂。
“载体”指的是不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的载体或稀释剂。
“赋形剂”指的是加入到药物组合物中以进一步依赖于化合物给药的惰性物质。赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖和不同类型的淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“有效剂量”指引起组织、系统或受试者生理或医学反应的化合物的量,此量是所寻求的,包括在受治疗者身上施用时足以预防受治疗的疾患或病症的一种或几种症状发生或使其减轻至某种程度的化合物的量。
具体实施方式
以下通过具体实施例详细说明本发明的实施过程和产生的有益效果,旨在帮助阅读者更好地理解本发明的实质和特点,不作为对本案可实施范围的限定。
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的,超临界流体色谱法(SFC)拆分手性结构。
NMR位移(δ)以10-6(ppm)的单位给出。
NMR的测定是用(Bruker ADVANCE III 400)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS),1HNMR信息以下列格式来列表:化学位移(多重峰(s,单峰;d,双重峰;t,三重峰;q,四重峰;m,多重峰),质子数)。
MS的测定用(Agilent 6120B(ESI))。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorba x SB-C18 100x 4.6mm)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.20mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成,或购买于成都科龙化工,成都西陇化工,成都效佳,安耐吉化学,成都叮当化学,爱斯特(成都)医药技术有限公司,韶远化学科技(上海)有限公司,国药集团药业股份有限公司,百灵威科技有限公司等公司。
实施例1
异丙基(2S)-2-[[[3-[2,6-二氯-4-(6-氰基-3,5-二氧代-1,2,4-三嗪-2-基)苯氧基]-5-异丙基-6-氧代-哒嗪-1-基]甲氧基-(甲氧基甲基)磷酰基]氨基]丙酸酯(化合物1);
isopropyl
(2S)-2-[[[3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-1,2,4-triazin-2-yl)phenoxy]-5-isopropyl-6-oxo-pyrid azin-1-yl]methoxy-(methoxymethyl)phosphoryl]amino]propanoate
第一步:
异丙基(2S)-2-[[苄氧基(甲氧基甲基)磷酰基]氨基]丙酸酯(1B)
Isopropyl(2S)-2-[[benzyloxy(methoxymethyl)phosphoryl]amino]propanoate
将(甲氧基甲基)膦酰二氯((23.0g,141.2mmol)溶于二氯甲烷(400mL)中。在氮气保护下,-30℃左右滴加L-丙氨酸异丙脂(18.5g,141.2mmol)和三乙胺(57.1g,564.6mmol)的二氯甲烷溶液(200mL),保温搅拌1小时。并在此温度下加入1A(15.2g,141.2mmol),让其自然恢复到室温,并搅拌1小时。加入饱和磷酸二氢钠水溶液(300mL),并用二氯甲烷(500ml×2)萃取,分液,无水硫酸钠干燥有机相,浓缩,残留物用硅胶柱层析分离提纯(乙酸乙酯/石油醚=(v/v)1/20到1/1),得黄色油状物(1B)(15.0g,产率32.7%)。
1H NMR(400MHz,CDCl3)δ7.39-7.36(m,5H),5.11-4.99(m,3H),4.03-.4.0(m,1H),3.69(t,2H),3.43-3.34(m,4H),1.39-1.32(m,3H),1.26-1.22(m,6H)
第二步:
N-[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]-(甲氧基甲基)磷酰胺酸(1C)
N-[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]-(methoxymethyl)phosphonamidic acid
将异丙基(2S)-2-(((苯氧基)(甲氧甲基)磷酰基)氨基)丙酸酯(1B)(600mg,1.82mmol)溶于甲醇(10mL)中,依次加入三乙胺(202mg,1.99mmol)和钯碳(600mg,10%)。在氢气(1atm)条件下搅拌2小时。过滤,浓缩得类白色固体1C(650mg),直接用于下一步反应。
MS m/z(ESI):240.2[M+1]+.
第三步:
异丙基(2S)-2-[[[3-[2,6-二氯-4-(6-氰基-3,5-二氧代-1,2,4-三嗪-2-基)苯氧基]-5-异丙基-6-氧代-哒嗪-1-基]甲氧基-(甲氧基甲基)磷酰基]氨基]丙酸酯(化合物1);
isopropyl
(2S)-2-[[[3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-1,2,4-triazin-2-yl)phenoxy]-5-isopropyl-6-oxo-pyrid azin-1-yl]methoxy-(methoxymethyl)phosphoryl]amino]propanoate.
将化合物MGL3196-Cl(300mg,0.62mmol)溶于15mL乙腈中,依次加入1C(0.8g,2.35mmol)和氧化银(0.43g,1.86mmol),将反应混合物在黑暗中于室温下搅拌16h。将此混合液过滤后,滤液减压浓缩,残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇=(v/v)100/1-20/1),得到化合物1,黄色固体(80mg,19%yield)。
MS m/z(ESI):708.1[M+Na]+
1H NMR(400MHz,DMSO-d6)δ7.79(s,2H),7.51(d,1H),5.65-5.40(m,2H),5.33-5.15(m,1H),4.91-4.76(m,1H),3.80-3.62(m,1H),3.58-3.45(m,2H),3.22(d,3H),3.14-3.05(m,1H),1.26-1.18(m,9H),1.17-1.13(m,6H).
实施例2:
异丙基(2S)-2-[[[3-[2,6-二氯-4-(6-氰基-3,5-二氧代-1,2,4-三嗪-2-基)苯氧基]-5-异丙基-6-氧代-哒嗪-1-基]甲氧基-苯氧基-磷酰基]氨基]丙酸酯(化合物2);
isopropyl
(2S)-2-[[[3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-1,2,4-triazin-2-yl)phenoxy]-5-isopropyl-6-oxo-pyrid azin-1-yl]methoxy-phenoxy-phosphoryl]amino]propanoate.
第一步:
异丙基(2S)-2-[[苄氧基(苯氧基)磷酰基]氨基]丙酸酯(4B);
isopropyl(2S)-2-[[benzyloxy(phenoxy)phosphoryl]amino]propanoate;
将二氯磷酸苯酯(5.7g,27.02mmol)溶于200mL二氯甲烷中,降温至-30℃,缓慢滴加1A(2.9g,26.82mmol)和三乙胺(2.7g,26.68mmol)的混合物,滴毕,此温度下搅拌30min后,依次加入L-丙氨酸异丙酯盐酸盐(4.5g,26.84mmol)和三乙胺(5.5g,54.34mmol),加毕,升温至室温继续搅拌2h。加入饱和磷酸二氢钠水溶液(200mL),分液,有机层用饱和食盐水(200mL)洗涤,无水硫酸钠干燥,减压浓缩,残留物用硅胶柱层析分离提纯(乙酸乙酯/石油醚=(v/v)1/3-1/1),得到化合物4B,淡黄色油状物(5g,49%yield)。
MS m/z(ESI):378.2[M+H]+
第二步:
N-[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]-苯氧基-膦酰胺酸(4C);
N-[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]-phenoxy-phosphonamidicacid.
将化合物4B(1g,2.65mmol)溶于10mL甲醇中,加入氢氧化钯(0.1g,20wt%),在氢气(1atm)条件下搅拌2小时。过滤,减压浓缩得化合物4C,淡黄色油状物(0.75g,100%yield),直接用于下一步。
MS m/z(ESI):288.1[M+H]+
第三步:
异丙基(2S)-2-[[[3-[2,6-二氯-4-(6-氰基-3,5-二氧代-1,2,4-三嗪-2-基)苯氧基]-5-异丙基-6-氧代-哒嗪-1-基]甲氧基-苯氧基-磷酰基]氨基]丙酸酯(化合物4);
isopropyl
(2S)-2-[[[3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-1,2,4-triazin-2-yl)phenoxy]-5-isopropyl-6-oxo-pyrid azin-1-yl]methoxy-phenoxy-phosphoryl]amino]propanoate.
将化合物MGL3196-Cl(300mg,0.62mmol)溶于15mL乙腈中,依次加入4C(0.75g,2.60mmol)和氧化银(0.43g,1.86mmol),将反应混合物在黑暗中于室温下搅拌16h。将此混合液过滤后,滤液减压浓缩,残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇=(v/v)100/1-20/1),得到化合物4,淡黄色固体(60mg,13%yield)。
MS m/z(ESI):734.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ7.83-7.78(m,2H),7.55-7.47(m,1H),7.37-7.27(m,2H),7.20-7.03(m,3H),6.02-5.85(m,1H),5.69-5.52(m,2H),4.90-4.73(m,1H),3.78-3.62(m,1H),3.14-3.07(m,1H),1.23-1.15(m,9H),1.14-1.10(m,6H).
实施例3:
(2S)-2-[[[3-[2,6-二氯-4-(6-氰基-3,5-二氧代-1,2,4-三嗪-2-基)苯氧基]-5-异丙基-6-氧代-哒嗪-1-基]甲氧基-[[(1S)-2-乙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基]氨基]丙酸乙酯(化合物5);
ethyl
(2S)-2-[[[3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-1,2,4-triazin-2-yl)phenoxy]-5-isopropyl-6-oxo-pyrid azin-1-yl]methoxy-[[(1S)-2-ethoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]amino]propanoate.
第一步:
(2S)-2-[[苄氧基-[[(1S)-2-乙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基]氨基]丙酸乙酯(5B)ethyl
(2S)-2-[[benzyloxy-[[(1S)-2-ethoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]amino]propanoate;
将三氯氧磷(3.54g,23.12mmol)溶于200mL二氯甲烷中,降温至-30℃,缓慢滴加1A(2.5g,23.12mmol)和三乙胺(2.4g,23.72mmol)的混合物,滴毕,此温度下搅拌30min后,依次加入L-丙氨酸乙酯盐酸盐(7.1g,46.24mmol)和三乙胺(9.6g,94.86mmol),加毕,升温至室温继续搅拌2h。加入饱和磷酸二氢钠水溶液(200mL),分液,有机层用饱和食盐水(200mL)洗涤,无水硫酸钠干燥,减压浓缩,残留物用硅胶柱层析分离提纯(乙酸乙酯/石油醚=(v/v)1/3-1/1),得到化合物5B,淡黄色油状物(5g,56%yield)。
MS m/z(ESI):387.2[M+H]+
第二步:
双[[(1S)-2-乙氧基-1-甲基-2-氧代-乙基]氨基]次膦酸(5C);
bis[[(1S)-2-ethoxy-1-methyl-2-oxo-ethyl]amino]phosphinic acid.
将化合物3B(1g,2.59mmol)溶于10mL甲醇中,加入氢氧化钯(0.1g,20wt%),在氢气(1atm)条件下搅拌2小时。过滤,减压浓缩得化合物5C,淡黄色油状物(0.75g,98%yield),直接用于下一步。
MS m/z(ESI):297.2[M+H]+
第三步:
(2S)-2-[[[3-[2,6-二氯-4-(6-氰基-3,5-二氧代-1,2,4-三嗪-2-基)苯氧基]-5-异丙基乙酯-6-氧代-哒嗪-1-基]甲氧基-[[(1S)-2-乙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基]氨基]丙酸乙酯(化合物5);
ethyl
(2S)-2-[[[3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-1,2,4-triazin-2-yl)phenoxy]-5-isopropyl-6-oxo-pyrid azin-1-yl]methoxy-[[(1S)-2-ethoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]amino]propanoate.
将化合物MGL3196-Cl(300mg,0.62mmol)溶于15mL乙腈中,依次加入5C(0.75g,2.52mmol)和氧化银(0.43g,1.86mmol),将反应混合物在黑暗中于室温下搅拌16h。将此混合液过滤后,滤液减压浓缩,残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇=(v/v)100/1-20/1),得到化合物5,黄棕色固体。
MS m/z(ESI):743.1[M+H]+
生物测试例
实施例4
大鼠组织分布实验
1.试验材料
(1)试验动物:
雄性SD大鼠,200g左右,6~8周龄,共24只。购于成都达硕实验动物有限公司。
(2)受试化合物
准确称取一定量受试化合物,用75%PEG400+25%水溶解。
2.试验方法
受试化合物灌胃给药剂量(以游离碱计)为5.0mg/kg,给药体积灌胃为10ml/kg。每只动物在给药前及给药后异氟烷麻醉经眼眶取血0.5ml,置于EDTAK2离心管中并放置冰浴上。5000rpm,4℃离心10min,收集血浆。动物安乐死放血后取肝组织,清洗干净后用冰的50%甲醇水溶液按照1:1(m/v)匀浆获取组织匀浆液。采集时间点:给药后0.5,2,6,24h;所有样品存于-80℃用于检测。用HPLC-MS/MS对样品进行检测,检测内容为MGL3196。肝血比=AUC0-t(肝)/AUC0-t(血浆)。
表1大鼠组织分布参数
*注:i.g.(灌胃)给予化合物1,检测原药MGL3196
结论:运用本发明技术所合成的MGL3196前药在大鼠组织分布中显示出更好的肝靶向性,将具有减毒增效的作用。
Claims (6)
1.一种通式(I)所示化合物及其立体异构体或药学上可接受的盐,及其氘代化合物,
其中,
R1a、R1a’、R1c、R1c’、R1e、R1e’各自独立的选自H、C1-6烷基或C3-8碳环基,所述的C1-6烷基或C3-8碳环基任选进一步被0至4个选自H、F、Cl、Br、I、C1-4烷基或C1-6烷氧基的取代基所取代;
R1b、R1d、R1f各自独立的选自C1-6烷基、苄基或C3-8碳环基,所述的C1-6烷基、苄基或C3-8碳环基任选进一步被0至4个选自H、F、Cl、Br、I、C1-6烷基或C1-6烷氧基的取代基所取代;
R1g选自C1-6烷基、C3-8碳环基或C5-10杂环基,所述的C1-6烷基、C3-8碳环基或C5-10杂环基任选进一步被0至4个选自H、F、Cl、Br、I、苯基、C1-6烷基或C1-6烷氧基的取代基所取代;
R2选自H或C1-6烷基;
n选自0或1。
2.根据权利要求1所述的化合物及其立体异构体或药学上可接受的盐,及其氘代化合物,其中
R1a、R1a’、R1c、R1c’、R1e、R1e’各自独立的选自H或C1-4烷基;
R1b、R1d、R1f各自独立的选自C1-4烷基或苄基;R1g选自C1-4烷基、苯基或苄基;
R2选自H;n选自1。
3.根据权利要求2所述的化合物及其立体异构体或药学上可接受的盐,及其氘代化合物,其中
R1a、R1c、R1e各自独立的选自H、甲基、乙基、丙基或异丙基;R1a’、R1c’、R1e’选自H;
R1b、R1d、R1f各自独立的选自甲基、乙基、丙基、异丙基或苄基;
R1g选自甲基、乙基、丙基、异丙基、苯基或苄基。
5.一种药物组合物,所述药物组合物含有治疗有效剂量的权利要求1至4中任意一项所述的化合物及其立体异构体或药学上可接受的盐,及其氘代化合物,以及药学上可接受的载体和赋形剂。
6.权利要求1至4中任意一项所述的化合物及其立体异构体或药学上可接受的盐,及其氘代化合物,或权利要求5中所述药物组合物在制备用于治疗NAFLD药物中的应用。
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WO2022037617A1 (zh) | 2020-08-19 | 2022-02-24 | 成都凡诺西生物医药科技有限公司 | 腈代三嗪类衍生物及其制备方法和应用 |
WO2022127699A1 (zh) * | 2020-12-15 | 2022-06-23 | 中国科学院上海药物研究所 | 甲状腺素受体β选择性激动剂化合物、其药物组合物和用途 |
WO2022143574A1 (zh) | 2020-12-30 | 2022-07-07 | 昆药集团股份有限公司 | 2-吡啶酮类衍生物及其制备方法和在医药上的应用 |
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WO2022037617A1 (zh) | 2020-08-19 | 2022-02-24 | 成都凡诺西生物医药科技有限公司 | 腈代三嗪类衍生物及其制备方法和应用 |
WO2022127699A1 (zh) * | 2020-12-15 | 2022-06-23 | 中国科学院上海药物研究所 | 甲状腺素受体β选择性激动剂化合物、其药物组合物和用途 |
WO2022143574A1 (zh) | 2020-12-30 | 2022-07-07 | 昆药集团股份有限公司 | 2-吡啶酮类衍生物及其制备方法和在医药上的应用 |
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