CN114075173A - 腈代三嗪类衍生物及其制备方法和应用 - Google Patents
腈代三嗪类衍生物及其制备方法和应用 Download PDFInfo
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- CN114075173A CN114075173A CN202110953070.9A CN202110953070A CN114075173A CN 114075173 A CN114075173 A CN 114075173A CN 202110953070 A CN202110953070 A CN 202110953070A CN 114075173 A CN114075173 A CN 114075173A
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- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 230000006016 thyroid dysfunction Effects 0.000 description 1
- 108091008763 thyroid hormone receptors α Proteins 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 239000012137 tryptone Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000002525 ultrasonication Methods 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical class CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical class CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
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Abstract
Description
技术领域
本发明涉及一种甲状腺激素受体-β(THR-β)亚型激动剂衍生物、制备方法及其在医学上的应用。本发明衍生物或者含有本发明衍生物的药物组合,可以用于治疗相关疾病。例如可以用于肥胖、高脂血症、高胆固醇血症、糖尿病等;也可用于其它病症的治疗,这些疾病包括NASH(nonalcoholic steatohepatitis,非酒精性的脂肪肝)、肝脂肪变性、动脉粥样硬化、心血管疾病、甲状腺功能减退、甲状腺癌和相关病症等。
背景技术
甲状腺激素对于正常生长和发育以及维持代谢平衡起到关键的作用(Physiological Reviews,2001,81(3),1097-1042;Biochimica et Biophysica Acta1812(2011)929-937)。甲状腺激素的循环水平由下丘脑/垂体/甲状腺轴中的反馈机制紧密调节。甲状腺功能紊乱可能会导致甲状腺功能减退或者甲状腺机能亢进。此外,甲状腺激素对心脏功能、体重、代谢、代谢率、体温、胆固醇、骨骼、肌肉和行为也有十分重要的影响。
甲状腺激素由甲状腺产生,以两种不同的形式分泌到循环系统中:3,5,3’,5’-四-碘-L-甲状腺原氨酸(T4)和3,5,3’-三-碘-L-甲状腺原氨酸(T3)。T4是由甲状腺分泌的主要形式。T3则是生理上更活跃的存在形式。T4通过组织特异性脱碘酶可以转化成T3。这种组织特异性脱碘酶存在于所有组织中,但是主要在肝和肾中。甲状腺激素的生物活性由甲状腺激素受体(THRs)介导产生(Endocrine Reviews,1993,348-399)。THR属于已知为核受体的超家族。主要的甲状腺受体亚类包括:α1、α2、β1和β2。甲状腺激素受体α1、β1和β2可以与甲状腺激素T3直接结合,而α2可以与非T3相互作用(Advances in DevelopmentalBiology.2006,16,1-31)。研究表明,甲状腺激素受体亚型在它们对于特殊生理响应的贡献方面可以不同。例如,THR-β1在肝中在调节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。THR-β2在调节TH(甲状腺刺激激素)方面起主要作用。THR-β1在调节心率方面起重要作用。例如,甲状腺激素增加代谢率、氧消耗和放热。从而降低体重。降低体重将通过改善与肥胖有关的共发病而对肥胖患者具有有益效果,并且还可以对于患有2型糖尿病的肥胖患者的血糖控制具有有益效果(J.Clin.Invest.,1999,104:291-300)。
显然,通过激活THR-β1,可以改变相应的生物功能,从而达到某种预期的治疗目的。鉴于肥胖及其引发的疾病病包括但不限于糖尿病、代谢综合征和动脉粥样硬化血管病等的发病率呈流行趋势上升,社会迫切需要能够治疗这些疾病的化合物。因此,具有增加的甲状腺激素受体β选择性和/或组织选择作用的甲状腺激素类似物,正受到广泛关注。这种THR-β选择性激动剂,可以产生体重、脂类、胆固醇和某些脂蛋白的适当下降,对心血管功能或下丘脑/垂体/甲状腺轴的正常功能具有降低的影响(J.Med.Chem.2014,57,3912-3923;Expert Opin Investig Drugs.2004,13(5):489-500)。
Madrigal Pharmaceuticals的MGL-3196(I)选择性作用于THR-β,非酒精性脂肪性肝炎(NASH)患者中效果明显,对肝脏副作用很小,是一款安全的降脂(LDL,LDL-C和TG)药,目前处于临床试验关键开发阶段(J.Med.Chem.2014,57,3912-3923)。F.Hoffmam-La Roche公司在pyridazinone的2-位上引入取代基,得到系列化合物II。化合物II不仅具有治疗NASH的作用,还具有抗甲状腺癌的功能(WO2009037172A1)。四川海思科制药有限公司在pyridazinone的2-位上引入的取代基为醚取代基,相应的衍生物III可以用于肥胖、高脂血症、高胆固醇血症、糖尿病等相关病症的治疗(CN110938094A)。嘉兴特科罗生物科技有限公司发明了IV,可以用治疗男性激素遗传型脱发或者脂溢性脱发或者化疗引起的脱发(CN108727344A)。
以MGL-3196为代表的THR-β的选择性激动剂能够显著降低NASH患者的肝脏脂肪和纤维化程度,同时也能够显著降低LDL胆固醇、甘油三酯和脂蛋白等。因此,THR-β的选择性激动剂成为了降低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(European Heart Journal,Volume 39,Issue suppl_1,1August 2018,566.P5387)。
由于甲状腺激素的生理作用几乎影响到每个器官系统,仍然需要进一步改善药物在体内的吸收、分布、转运与代谢过程,以及提高生物利用度、提高药物对靶部位作用的选择性等,以期增强疗效、减少降低药物的毒副作用、延长作用时间,以便满足社会需求、更好地造福人类。
发明内容
一种结构通式(I)的化合物,或其药学上可接受的盐、多晶型、互变异构体、立体异构体、水合物、溶剂化合物或任何同位素衍生物:
结构通式(I)
其中,
R1选自:H、-CN、-NO2、-CF3、-OCF3、-CO2H、-OH、乙炔基、卤素、氨基、烷基、链烯基、卤代烷基、卤代烯基、杂烷基、杂环烷基、芳基烷基、环烷基、芳基、杂环芳基、杂环芳基烷基、杂环烷基、杂环烯基、烷氧基、烷氧烷基、烯氧基、-炔基、-烷基炔基、-炔氧基、-烷基炔氧基、炔氧基、氨基、烷基氨基、氨基烷基、烷基氨基羰基、磺酰基、烷基磺酰基、烷基亚磺酰基、氨基磺酰基、酰基;在以上基团中,各自可不被取代或被一个或多个取代基取代,这些取代基包括:卤素、-CF3、烷基、链烯基、链炔基、羟基、羟烷基、烷氧基、烷氧烷基、氨基、烷基氨基、环烷基氨基。
R2选自:H、烷基、链烯基、卤代烷基、卤代烯基、杂烷基、杂环烷基、芳基烷基、环烷基、芳基、杂环芳基、杂环芳基烷基、杂环烷基、杂环烯基、烷氧基、烷氧烷基、烷基氨基、烷基氨基羰基、-炔基、-烷基炔基、-炔氧基、-烷基炔氧基、磺酰基、烷基磺酰基、烷基亚磺酰基、氨基磺酰基;在以上基团中,各自可不被取代或被一个或多个取代基取代,这些取代基包括:卤素、-CF3、烷基、链烯基、链炔基、羟基、羟烷基、烷氧基、烷氧烷基、氨基、烷基氨基、环烷基氨基。
R3选自:H、-CN、-NO2、-CF3、-OCF3、-CO2H、OH、-SR7、卤素、氨基、烷基、烷氧基、烷氧烷基、杂烷基、杂环烷基、芳基烷基、环烷基、杂环芳基烷基、杂环烷基、杂环烯基、烯氧基、-炔基、-烷基炔基、-炔氧基、-烷基炔氧基、烷基氨基、氨基烷基、烷基氨基羰基;在以上基团中,各自可不被取代或被一个或多个取代基取代,这些取代基包括:卤素、-CF3、烷基、链烯基、链炔基、羟基、羟烷基、烷氧基、烷氧烷基、氨基、烷基氨基、环烷基氨基。
R4和R5各自选自:H、卤素、烷基、烷氧基、烷氧烷基。
R6选自:H、-CN、-NO2、-CF3、-OCF3、-CO2H、-OH、烷基、卤素、羧基、酯基、酰胺。
X选自:共价键、-O-、-S-、-NH-、-SO2-、-CONH-或(CH2)q,X-连接到苯并咪唑环的C4-、C5-、C6-和C7-位碳原子上,q是1、2或3。
在某些的具体实施方案中,优先选择的R1为:H、卤素、C1-C4烷基。
在另一具体实施方案中,优先选择的R2为:H、C1-C4烷基。
在另一具体实施方案中,优先选择的R3为:H、卤素、C1-C6烷基。
在另一具体实施方案中,优先选择的X为:-O-。
在另一具体实施方案中,优先选择的R4和R5各自是Br,其中R4和R5分别连接到相应苯环上的C3-和C5-位上。
在另一具体实施方案中,优先选择的R4和R5各自是Cl,其中R4和R5分别连接到相应苯环上的C3-和C5-位上。
在另一具体实施方案中,优先选择的R6为:-CN。
除结构通式(I)所表示的所表示的化合物以外,本发明还包括这些化合物的药学上可接受的盐、多晶型、互变异构体、立体异构体、水合物、溶剂化合物或同位素衍生物、药学上可接受的前药和医药活性代谢物,和这些代谢物在药学上可接受的盐。
本发明包含了结构通式(I)所表示的所表示的化合物与药学上可接受的稀释剂、赋形剂或载体所形成的任何一种药物剂型。
本发明还涉及制备这些化合物的方法。这些化合物可以用作为甲状腺激素受体B选择性和/或组织选择性激动剂,从而可以产生体重、脂类、胆固醇和脂蛋白的适宜下降,对心血管功能或下丘脑/垂体/甲状腺轴的正常功能具有降低的影响。这些化合物可用于治疗代谢疾病如肥胖,高脂血症,高胆固醇血症,糖尿病和其它病症和疾病如肝脂肪变性和NASH,动脉粥样硬化,心血管疾病,甲状腺功能减退,甲状腺癌,甲状腺疾病,以及相关病症和疾病。
在另一具体实施方案中,结构通式(I)所代表的化合物可以治疗的疾病为:各种脂质异常症、代谢综合症、肥胖、动脉粥样硬化症或糖尿病。
在另一具体实施方案中,结构通式(I)所代表的化合物可以治疗的疾病为:NASH和杜氏肌营养不良综合症。
在另一具体实施方案中,结构通式(I)所代表的化合物可以治疗的疾病为:原发性胆汁肝硬化和胆管炎,包括老年痴呆和肿瘤。
在另一具体实施方案中,结构通式(I)所代表的化合物可以治疗的疾病为:增加T淋巴细胞的能量和活化性能而增强免疫功能,还有可转化肿瘤细胞为脂肪细胞,降低癌症转移等。
在另一具体实施方案中,结构通式(I)所代表的化合物可以治疗内脏脂肪型肥胖。
在另一具体实施方案中,结构通式(I)所代表的化合物可以治疗甲状腺疾病,包括甲状腺癌。
本申请的一个或多个实施方式还提供了治疗和/或预防性治疗由甲状腺激素调节的疾病的方法,其包括将本申请的化合物施用于有需要的对象。
本申请的一个或多个实施方式还提供了治疗和/或预防性治疗由甲状腺激素调节的肥胖、糖尿病、NASH、心血管疾病、甲状腺功能减退、或甲状腺癌的方法,其包括将本申请的化合物施用于有需要的对象。
本申请的一个或多个实施方式还提供了治疗和/或预防性治疗由甲状腺激素调节的高脂血症或动脉粥样硬化的方法,其包括将本申请的化合物施用于有需要的对象。
本申请的一个或多个实施方式还提供了治疗和/或预防性治疗由甲状腺激素调节的高胆固醇血症的方法,其包括将本申请的化合物施用于有需要的对象。
本申请的一个或多个实施方式还提供了用于治疗和/或预防性治疗由甲状腺激素调节的疾病的化合物。
本申请的一个或多个实施方式还提供了用于治疗和/或预防性治疗由甲状腺激素调节的肥胖、糖尿病、NASH、心血管疾病、甲状腺功能减退、或甲状腺癌的化合物。
本申请的一个或多个实施方式还提供了用于治疗和/或预防性治疗由甲状腺激素调节的高脂血症或动脉粥样硬化的化合物。
本申请的一个或多个实施方式还提供了用于治疗和/或预防性治疗由甲状腺激素调节的高胆固醇血症的化合物。
附图说明
图1表示体内药效试验中血液TG(甘油三酯)指标的试验结果。
图2表示体内药效试验中食物利用率的试验结果。
具体实施方式
定义
如本文所用,术语“本发明化合物”指式结构通式(I)所示的化合物。该术语还包括及式(I)化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
本发明所使用的术语“不被取代”是指无取代基或仅被氢取代。
本发明所使用的部分术语定义如下:
“卤素”是指氟、氯、溴和碘。
“烷基”当作一基团或一基团的部分时是指直链或者带有支链的脂肪烃基团。优先选择烷基为C1-C14的烷基;更优先选择为:C1-C10烷基;最优先选择为C1-C6,除非另有指明。直链或和带有支链的C1-C6烷基的实例包括,但不限于:甲基、乙基、正丙基、2-丙基、正丁基、异丁基、特丁基、己基等。
“烷基氨基”包括单烷基氨基和二烷基氨基两种,除非另有指明。“单烷基氨基”是指:(烷基-NH)-的基团;“二烷基氨基”是指:((烷基)2N)-的基团。其中,烷基见本文有关定义。该烷基基团优先选择C1-C6的烷基基团。实例包括,但不限于:N-甲胺基、N-乙胺基、N-异丙胺基、N,N-(二乙基)胺基等。
“氨基烷基”是指:(氨基-烷基)-的基团。其中,烷基见本文有关定义。实例包括,但不限于:氨基乙基、1-氨基丙基、1-氨基丙基等。
“芳基氨基”包括单-芳基氨基和二-芳基氨基两种,除非另有说明。单-芳基氨基是指:(芳基-)NH-的基团;二-芳基氨基是指式(芳基)2N-的基团;芳基的定义见本文相关部分。
“酰基“包括(烷基-CO)-的基团和(芳基-CO)-的基团,除非另有说明。其中烷基或芳基均见本文中的有关定义。酰基的实例包括,但不限于:乙酰基、丙酰基、异丁酰基、苯甲酰基等。
“酰胺基“包括(烷基-CONH)-的基团和(芳基-CONH)-的基团,除非另有说明。其中,烷基或芳基均见本文中的有关定义。酰胺基的实例包括,但不限于:乙酰胺基、丙酰胺基、丁酰胺基、异丁酰胺基、苯甲酰胺基等。
“烯基”作为一基团或一基团的一部分时是指至少含有一个碳-碳双键的脂肪烃基团,可为直链也可以带有支链。优先选择具有C2-C14的烯基。C2-C12则更好;最为优先选择的是C2-C6的烯基。该基团可在其主链中含有多个双键且其构象可各自为E或Z。烯基基团的例子包括,但不限于:乙烯基、丙烯基等。
“烷氧基”是指(烷基-O)-的基团。其中,烷基见本文有关定义。C1-C6的烷氧基为优先选择。其实例包括,但不限于:甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基等。
“烯氧基”是指(烯基-O)-的基团。其中烯基见本文有关定义。C1-C6的烯氧基为优先选择。
“炔氧基”是指(炔基-O)-的基团。其中炔基见本文有关定义。C1-C6的炔氧基为优先选择。
“烷氧羰基”是指(烷基-O-C(O))-的基团。其中,烷基见本文有关定义。优先选择的烷基基团为C1-C6烷基。其实例包括,但不限于:甲氧羰基、乙氧羰基等。
“烷基亚磺酰基”是指(烷基-S(O))-的基团。其中烷基见本文有关定义。优先选择的烷基为C1-C6烷基基团。烷基亚磺酰基基团包括,但不限于:甲基亚磺酰基、乙基亚磺酰基等。
“烷基磺酰基”是指(烷基-S(O)2-O)-的基团。其中烷基见本文有关定义。该优先选择的烷基为C1-C6烷基基团。其实例包括,但不限于:甲磺酰基、乙磺酰基等。
“烷基氨基羰基”是指烷基氨基-羰基基团。其中,烷基氨基见本文有关定义。
“环烷基”是指饱和或部分饱和的单环、稠环或螺环之碳环。以3-9个碳原子组成的环为优先选择。实例包括,但不限于:环丙基、环丁基、环戊基、环己基等。
“环烷基烷基”是指环烷基-烷基基团。其中,环烷基和烷基部分见本文有关定义。单环烷基烷基基团包括,但不限于:环丙基甲基,环戊基甲基,环己基甲基、环庚基甲基等。
“杂环烷基”是指至少含有至少一个选自N,S,O的杂原子的环烷基。优选含有1-3个(1、2或3个)杂原子。优选的环为3-14员环,更优先选择的环为4-7员环。杂环烷基包括,但不限于:吡咯烷基、二氢吡咯基、四氢吡咯基、二氢吡唑基、哌啶基、吗啉四氢呋喃基、四氢硫代呋喃基、四氢吡喃基等。
“杂环烯基”是指至少含有一个双键的杂环烷基。杂环烷基见本文有关定义。
“杂环烷基烷基”是指:(杂环烷基-烷基)-的基团。其中,杂环烷基和烷基部分见本文有关定义。杂环烷基烷基基团包括,但不限于:(2-四氢呋喃基)甲基、(2-四氢硫代呋喃基)甲基等。
“杂烷基”是指直链或含有支链烷基的基团,并且在主链中,至少含有一个或多个(例如1、2或3个)选自S,O和N的杂原子。优先选择含有2-14个原子链。杂烷基包括,但不限于:醚类、硫醚类、烷基酯类,第二或第三烷基胺类、烷基亚磺酸类等。
“芳基”作为一基团或一基团的部分是指:(1)芳香性的单环或稠环;优先选择具有5-12个碳原子的芳香性碳环(环原子均为碳的环状构造)。芳基的实例包括,但不限于:苯基,萘基;(2)可以连接部分饱和的碳环,例如:苯基和C5-7环烷基或C5-7环烯基基团系互相稠合而形成一环状结构。实例包括,但不限于:四氢萘基、茚基或氢茚基等。芳基基团可被一个或多个取代基取代。
“芳基烯基”是指:(芳基-烯基)-的基团。其中芳基和烯基见本文有关定义。示例性的芳基烯基基团包括,但不限于:苯基丙烯基等。
“芳烷基”是指:(芳基-烷基)-的基团。其中,芳基和烷基部分见本文有关定义。示例性的芳烷基基团包括,但不限于:苯甲基,苯乙基、1-萘甲基等。
“环烯基”是指非芳香性单环或多环环系。其至少含有一个碳-碳双键且每环优选具有5-10个碳原子。示例性的单环状环烯基环包括,但不限于:环戊烯、环己烯或环庚烯。环烯基团可被一个或多个取代基取代。
“杂芳基”是指单环性或稠合的多环芳香杂环。优先选择含有一个或多个(例如1、2或3个)选自N,O或/和S的杂原子的5-7员芳香环。典型的杂芳基取代基包括实例,但不限于:呋喃基,噻吩基,吡咯,吡唑,三唑,噻唑,吡啶,嘧啶,吡嗪,吲哚,苯并咪唑等。
“杂芳烷基”是指:(杂芳基-烷基)-的基团。其中,杂芳基和烷基部分见本文有关定义。示例性的杂芳烷基基团包括,但不限于:2-呋喃甲基、3-呋喃甲基、2-吡啶甲基等。
本发明包括结构通式(I)所表示的化合物及其可能的各种异构型式。包括:非镜像异构体、镜像异构体、互变异构体和“E”或“Z”构型异构体的几何异构体等。任何具有一定基础的化学工作者均可以分离出上述光学纯或者立体异构纯的化合物。
本发明包括结构通式(I)所表示的化合物及其可能的消旋体或/和镜像异构物/或/和非镜像异构物的混合物。
此外,结构通式(I)所表示的化合物在应用上也涵盖该化合物的溶剂化及非溶剂化型式。因此,各式均包括具有所指明结构的化合物,包括其水合物、溶剂化物及无水化合物的各种形式。
本发明结构通式(I)所表示的化合物在应用上也涵盖该化合物的各种晶型及无定形。因此,上述各种晶型包括但不限于:各种水合物晶型、各种溶剂化物晶型及各种无水化合物晶型等。
如本文所用,术语“药学上可接受的盐”是指,在可靠的医学判断范围内,适合与人和低等动物的组织接触而没有过度毒性、刺激性、变态反应等等,并且与合理的益处/危险比例相称的那些盐。药学上可接受的盐在本领域是众所周知的。例如,Berge等人在J.Pharmaceutical Sciences (1977)66:1-19中详细描述的药学上可接受的盐。本发明化合物的药学上可接受的盐包括衍生自合适的无机和有机酸和无机和有机碱的盐。药学上可接受的无毒的酸加成盐的实例是与无机酸形成的盐,例如盐酸、氢溴酸、磷酸、硫酸和高氯酸,或与有机酸形成的盐,例如乙酸、草酸、马来酸、酒石酸、枸橼酸、琥珀酸或丙二酸。也包括使用本领域常规方法形成的盐,例如,离子交换方法。其它药学上可接受的盐包括:已二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡萄糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酯酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐、戊酸盐,等等。衍生自合适的碱的药学上可接受的盐包括碱金属、碱土金属、铵和N+(C1-4烷基)4盐。代表性的碱金属或碱土金属盐包括钠、锂、钾、钙、镁盐,等等。如果合适的话,其它的药学上可接受的盐包括与反离子形成的无毒的铵盐、季铵盐和胺阳离子,反离子例如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、低级烷基磺酸根和芳基磺酸根。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”指本发明化合物与水进行配位形成的配合物。
本发明化合物可包括一个或多个不对称中心,且因此可以存在多种“立体异构体”形式,例如,对映异构体和/或非对映异构体形式。例如,本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺式和反式异构体),或者可为立体异构体的混合物的形式,包括外消旋混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离,所述方法包括:手性高压液相色谱法(HPLC)以及手性盐的形成和结晶;或者优选的异构体可通过不对称合成来制备。
药理效果可以用以下但不限于以下描述来体现。
将THR-β的配体结合结构域(氨基酸148-410)(H6-THR-β)和THR-α的配体结合结构域(氨基酸202-461)(H6-TRα)克隆到E.coli表达载体pET28a(Novagen,Milwaukee,WI)中,该载体含N-末端的六个His序列。将得到的重组六His标记的蛋白在E.coli BL21(DE3)细胞中生产。将细胞在Terrific Broth(自用的自制Bacto胰蛋白胨(3.3%,w/v)、Difico酵母抽提物(2.0%,w/c)和NaCl(0.5%,w/v)的培养基)中生长,使用摇瓶,在0.2mM IPTG中于25℃温育24小时,收获或者用5体积的缓冲液A(0.05M Tris,0.3M NaCL,1%W/V甜菜碱,0.01M咪唑,0.02M b-巯基乙醇,pH8.0)溶解。向浆液中加入溶菌酶(1.0mg/ml,Sigma)和CompleteProtease Inhibitor Cocktail(Roche Diagnostics Gmbh),并且将溶液超声一分钟,在4℃进行5次。将悬浮液在Ti45贝克曼转子中以127,300RCF离心2小时,并且将上清液装到NI NTAAgarose(Quigen 30210)柱上。在用缓冲液A洗涤后,H6-THR-β或H6-THR-α被含有0.25M咪唑的缓冲液A洗脱。
将30微升的在50mM Hepes,pH7.0,1mM DTT,0.05%NP40和0.2mg/ml BSA(结合缓冲液)中的H6-THR-β(50nM)或者H6-THR-α与等体积的在结合缓冲液中的EE-RxRα(50nM)混合。然后加入6微升的在DMSO中的T3(0-14.8uM)或测试化合物(0-1.2mM),并且将溶液在37℃温育30min。然后加入在30ul的结合缓冲液加5%DMSO中的30微升生物素-GRIP肽(生物素-Aca-HGTSLKEKHKILHRLLQDSSSPVDL-CONH2)(100nM),并且将溶液在37℃温育30min。加入30微升的在50mM Tris,pH7.4,100mM NaCl和0.2mg/ml BSA中含有12nM铕-共轭的抗-六His抗体和160nMAPC-共轭的链菌抗生物素的溶液,并且将溶液在4℃温育过夜。将等分试样(35ul/样品)转移到384孔黑微量滴定板上。在Victor5读数器(PerkinElmer LifeandAnalytical Sciences)上读取HTRF信号。计算出EC50。
术语“前药”包括其本身可以是具有生物活性的或非活性的,当用适当的方法服用后,其在人体内进行代谢或化学反应而转变成式(I)的一类化合物,或式(I)的一个化合物所组成的盐或溶液。所述的前药包括(但不限于)所属化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
如本文所用,术语“受试者”包括但不限于:人(即,任何年龄组的男性或女性,例如,儿科受试者(例如,婴儿、儿童、青少年)或成人受试者(例如,年轻的成人、中年的成人或年长的成人))和/或非人的动物,例如,哺乳动物,例如,灵长类(例如,食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在一些实施方案中,受试者是人。在另一些实施方案中,受试者是非人动物。
除非另作说明,否则,本文使用的术语“治疗”包括受试者患有具体疾病、障碍或病症时所发生的作用,它降低疾病、障碍或病症的严重程度,或延迟或减缓疾病、障碍或病症的发展(“治疗性治疗”),还包括受试者开始患有具体疾病、障碍或疾病之前发生的作用(“预防性治疗”)。
“组合”以及相关术语是指同时或依次给药本发明的治疗剂。例如,本发明化合物可以与另一治疗剂以分开的单位剂型同时或依次给药,或与另一治疗剂一起呈单一单位剂型同时给药。
“药学上可接受的赋形剂”是指不会破坏一起调配的化合物的药理学活性的无毒载体、佐剂或媒剂。可以用于本发明组合物中的药学上可接受的载体、佐剂或媒剂包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人类血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、十二指肠、直肠、肠胃外(静脉内、肌肉内或皮下)和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增溶剂,例如,淀粉、乳糖、蔗糖、葡萄糖、干露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如,石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如,鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其他本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性释放剂,如水或其他溶剂,增溶剂和乳化剂,例如,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物。
本发明提供了在需要其的受试者中治疗THR-β导致的疾病相关病症的方法,它包括步骤:给需要治疗的受试者给药本发明化合物,或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素衍生物,或给药本发明所述的药物组合物。
本发明化合物可用于治疗THR-β导致的疾病为:涉及肝脏细胞的病理破坏、炎症、退化和/或增殖的任何急性或慢性肝病,各种脂质异常症、代谢综合症。
本发明还涉及制备这些化合物的方法,这些化合物可以用作为THR-β选择性和/或组织选择性激动剂,从而可以产生体重、脂类、胆固醇和脂蛋白的适宜下降,对心血管功能或下丘脑/垂体/甲状腺轴的正常功能具有降低的影响。这些化合物可用于治疗代谢疾病如肥胖,高脂血症,高胆固醇血症,糖尿病和其它病症和疾病如肝脂肪变性和NASH、动脉粥样硬化、心血管疾病、甲状腺功能减退、甲状腺癌、甲状腺疾病、糖尿病NASH、杜氏肌营养不良综合症、以及相关病症和疾病。
腈代三嗪类衍生物的制备
结构通式(I)所表示的化合物可以用下面讨论的合成路线和合成方法来合成。所用原材料方便易得。但是,本发明所用的合成路线和合成方法,可以广泛应用于类似物的合成,只需要变换起始原材料即可。例如,在本文实例中没有详细描述的化合物的合成,只要把始原材料更换成相应目标化合物的起始原材料,依据化学常识,在有必要时稍为改变一下反应条件即可合成出所需要的目标化合物。
本发明所用的合成路线也可适用于制备不同于具体实施方案中的中间体或者目标化合物。所用试剂或者和中间体可以加保护基团也可以不加保护基团。在有机合成中的适当保护基团的列表可参见G.M.Peter的Protective Groups in Organic Synthesis,Wiley,2007。或者,本文中揭示或此项技艺中已知的其他反应。
可用以合成目标化合物的试剂可根据已知的技术加以取得或制备。
在下列实例中,除非另有指明,所有温度为摄氏度。
各种起始原料和试剂均来自市售。供应商包括但不限于:Aldrich ChemicalCompany、Lancaster Synthesis Ltd等等。市售原料和试剂均不经进一步纯化直接使用,除非另有指明。
玻璃器皿用烘箱干燥和/或加热干燥。反应用玻璃硅胶-60F254平板(0.25mm)(TLC)上进行跟踪。分析性薄层层析并以适当的溶剂比例(v/v)加以展开。以TLC上起始物质耗尽时为反应终点(J.Org.Chem.,Vol.43,No.14,19782923-2925)。
通常,后续处理是用反应所用的溶剂将反应液的体积增大一倍,然后用总体积的25%萃取溶剂来进行萃取三次,除非另有指明。将含产物萃取经无水硫酸钠脱水,在加以过滤于旋转蒸发器上,于减压之下将溶剂蒸发并注意溶剂于真空中的去除。最后,用快速柱层析分离得到目标化合物。
1H NMR图谱是用Bruker仪器(200-400MHz)测定而得,化学位移用ppm表示。使用氯仿作为参照标准(7.25ppm)或四甲基硅烷内标准(0.00ppm)。视需要,也可以使用其它NMR常用的溶剂。1H NMR的表示方法:s=单峰,d=双重峰,t=三重峰,m=多重峰,br=变宽的,dd=双重峰的双重峰,dt=三重峰的双重峰。若提供偶合常数时,其单位为Hz。
质谱是用LC/MS仪测定得到,离子化方式可为ESI或APCI。所有熔点均未经修正。
下面的实例仅仅是用来说明所发明的具体化合物的合成方法。但在合成方法上并没有任何限制。在下面未列出的化合物,也可以用与下面同样的合成路线与合成方法,选择适当的起始原材料、在有必要的地方稍加适当的常识性的反应条件调整即可加以制备。
合成
在结构通式(I)中的目标化合物可以用合成路_1所示的方法来合成。取代邻氟硝基苯衍生物V经过胺化、还原后后得到的VII。中间体VII与合适的酸或者醛环合得到VIII。将后者脱去甲基所得的相应的醇或者巯基衍生物IX与氟代衍生物反应,从而得到关键中间体XI。XI经还原、重氮和环合即得到如结构通式(I)所示的目标化合物。
合成路线_1
在结构通式(I)中,当R1、R3=H,R2=甲基时,相应的化合物明白化合物XXIII可以用合成路_2所示的方法来合成。
合成路线_2
具体来说,当R1、R2=H,R3=甲基,而X=O、S时,结构通式(I)中所示的化合物XXIII可以用合适的邻氟硝基苯衍生物XV为原料,在三乙胺作用下,得到化合物XVI。在合适的催化剂(例如钯羰)的催化下还原得XVII。然后,中间体XVII与甲酸加热发生环合反应,得到XVIII。在三溴化硼作用下,XVIII脱去甲基得相应的醇或者巯基衍生物XIX。后者与合适的化合物X碱性缩合,生成相应的XX。XX经过还原(例如铁粉下还原)、重氮化,然后与XIII反应,得到XXII,在醋酸-醋酸钠的作用下,环合即得到目标化合物XXIII。
合成路线_3
在结构通式(I)中,当R1、R2=H,R3=甲基,而X=CH2时,相应的目标化合物XXV可以用合成路线_3所示的方法来合成。具体来说,结构通式(I)中所示的化合物可以用合适的邻氟硝基甲苯衍生物XVI为原料,在三乙胺作用下,得到化合物XVII。在合适的催化剂(例如钯羰)的催化下还原得XVIII。然后,中间体XVIII与甲酸加热发生环合反应,得到相应的XIX。在NBS的作用下,XIX转化为溴取代衍生物XX。后者与合适的硼酸衍生物XXI发生缩合反应,得到XXII。XXII经过还原(例如铁粉下还原)、重氮化,然后与XIII反应,得到XXIV,在醋酸-醋酸钠的作用下,环合即得到目标化合物XXV。
下面结合实例进一步阐明本发明的内容。目的在于让具备有本领域相关的基本知识的技术人员更加清楚的了解并实践本发明的具体内容。但是,本发明的保护范围并不仅仅局限于这些实例。
实施例1
2-(3,5-二溴-4-((1-甲基--1H-苯并[d]咪唑-6-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈(1)的制备。
实施例1的化合物(化合物1)可以用上述合成路线_1的方法来实施。具体来说,只要选择需要的原料,可用下式表示的具体路来合成。
步骤_1 5-甲氧苯-N-甲基-2-硝基苯胺(VI-1)的合成
在封管中,依次加入V-1(5.13g,30.0mmol)、四氢呋喃(5mL)、三乙胺(9.10g,90.0mmol)和2M甲胺的呋喃溶液(30mL,60mmol)(40.0g,0.2mol)。在60℃下加热过夜。然后冷却至室温,减压除去溶剂。加入100mL乙酸乙酯,水洗两次,每次(50mL);盐水洗1次(50mL),再用Na2SO4干燥。减压除去溶剂后,再石油醚-乙酸乙酯(石油醚/乙酸乙酯,1/1,15mL)中重结晶,得到标题化合物VI-1(白色固体;3.95g;产率:72%)。1H NMR(400MHz,CDCl3):δ8.28(br s,1H),8.13(d,J=9.2Hz,1H),6.23(dd,J=9.6,2.4Hz,1H),6.12(d,J=2.4Hz,1H),3.88(m,3H),3.00(d,J=5.2Hz,3H)。
步骤_2 5-甲氧基-N1-甲基-1,2-苯二胺(VII-1)的合成
在盛有VI-1(3.95g,21.7mmol)的甲醇溶液(50mL)中加入Pd/C(10%,800mg)。在反应物在搅拌下通入氢气(1 atm),在50℃下加热6小时。反应物冷却至室温,过滤,浓缩即得到VII-1(棕色固体;3.25g;产率:98%)。1H NMR(400MHz,CDCl3):δ6.34(d,J=8.0Hz,1H),6.25(d,J=2.4Hz,1H),6.18(dd,J=8.4,2.8Hz,1H),3.76(s,3H),2.84(s,3H)。
步骤_3 6-甲氧基-1-甲基-1H-苯并[d]咪唑(VIII-1)的合成
VII-1(3.25g,21.4mmol)溶解于甲酸溶液(20 mL)中,加热至50℃过夜。冷却、减压浓缩。用过量饱和碳酸氢钠溶液中和,搅拌10分钟。用二氯甲烷-甲醇(20/1,200mL)洗两次。合并洗液,然后氧饱和盐水洗,Na2SO4干燥后过滤。滤液浓缩后得油状物,即标题化合物VIII-1(3.4g,严率:94%)。1H NMR(400MHz,CDCl3):67.75(s,1H),7.67(d,J=8.8Hz,1H),6.62(dd,J=8.4,2.4Hz,1H),6.82(d,J=2.8Hz,1H),3.88(s,3H),3.78(s,3H)。
步骤_4 1-甲基-1H-苯并[d]咪唑-6-醇(IX-1)的合成
在-78℃通氮的情况下,往盛有三溴化硼的二氯甲烷溶液(1M,80mL,80mmol)的反应瓶中加入VIII-1(3.24g,20.0mmol)。然后,自然升温至室温,搅拌下反应过夜。浓缩,用饱和碳酸氢钠溶液中和至pH=8。用二氯甲烷-甲醇溶液(10/1,200mL)萃取三次。萃取液水洗后用Na2SO4干燥。过滤,浓缩后得到标题化合物IX-1(棕色固体,2.0g,产率:68%)。1H NMR(400MHz,CDCl3):δ9.29(s,1H),7.94(s,1H),7.41(d,J=8.4Hz,1H),6.82(d,J=2.0Hz,1H),6.71(q,J=2.4Hz,1H),3.72(s,3H)。
步骤_5 6-(2,6-二溴-4-硝基苯氧基)-1-甲基-1H-苯并[d]咪唑(XI-1)的合成
在反应瓶中,依次加入IX-1(430mg,2.90mmol)、二甲亚砜(10mL)、碳酸钠(802mg,5.81mmol)和X-1(890 mg,3.0mmol)。反应物在50℃下搅拌2小时。冷却至室温,加入乙酸乙酯(100mL)。水洗有机相3次,每次30mL。饱和盐水洗(30mL),Na2SO4干燥,过滤。滤液浓缩,石油醚-乙酸乙酯(1/1,15mL)中结晶,得标题化合物XI-1(白色固体,1.1g,严率:89%)。1HNMR(400MHz,DMSO-d6):δ8.66(s,2H),8.13(s,1H),7.61(d,J=9.2Hz,1H),7.05(d,J=2.4Hz,1H),6.80(dd,J=9.2,2.8Hz,1H),3.75(s,3H)。
步骤_6 3,5-二溴-4-(1-甲基-1H-苯并[d]咪唑-6-基)氧-苯胺(XII-1)的合成
在反应瓶中,依次加入XI-1(1.00g,2.34mmol),乙醇(50mL),铁粉(1.31g,23.4mmol).在搅拌下,加热至75℃。然后滴加浓盐酸(2mL)。继续在75℃下反应30分钟。冷却至室温,过滤。浓缩,用饱和碳酸钠水溶液(50mL)中和。二氯甲烷-甲醇溶液(10/1,150mL)萃取三次。萃取液水洗后用Na2SO4干燥。过滤,浓缩后得到标题化合物XII-1(白色固体,830mg,产率:89%)。1H NMR(400MHz,CDCl3):δ8.08(s,1H),7.55(d,J=8.4Hz,1H),6.92(s,2H),6.86(d,J=2.8Hz,1H),6.69(dd,J=8.8,2.4Hz,1H),5.61(br s,2H),3.73(s,3H)。
步骤_7 (E)-乙基-(2-氰基-2-(2-(3,5-二溴斗((1-甲基-1H-苯并[d]咪唑-6-基)氧)苯)肼)乙酰氨基甲酸酯(XIV-1)的合成
在盛有XII-1(300mg,0.76mmol)的水溶液(7.5mL)加入浓盐酸(0.15mL)。在室温下搅拌,得到澄清溶液。冷却至0℃.在搅拌下滴加NaNO2(62mg,0.76mmo1)水(1.2mL)溶液,反应悬浮液的温度维持在5℃以下。滴加完毕后,继续在0℃下搅拌1个小时。将反应液滴加到XIII-1(142mg,0.910mmol)的吡啶-水溶液(8mL-3.6mL)中,反应温度维持不超过5℃。所得反应液在5℃下继续搅拌1小时。将反应液倒入饱和碳酸氢钠溶液(20mL)中,二氯甲烷-甲醇溶液(10/1,100mL)萃取三次。萃取液水洗后用Na2SO4干燥。过滤,浓缩。C18柱分离(展开系统:5-95%CH3CN水溶液,25min)后得到标题化合物XIV-1(白色固体,(240mg,严率:56%)。1HNMR(400MHz,DMSO-d6):δ10.76(s,1H),8.18(s,1H),8.16(s,2H),7.60(d,J=8.8Hz,1H),6.95(d,J=2.4Hz,1H),6.76(dd,J=8.8,2.8Hz,1H),4.19(q,J=6.8Hz,2H),3.75(s,3H),1.27(t,J=6.8Hz,3H)。
步骤_8 2-(3,5-二溴-4-((1-甲基--1H-苯并[d]咪唑-6-基)氧基)-苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈(1)的制备。
在盛有XIV-1(310mg,0.550mmol)乙酸(10mL)悬浮液中加入乙酸钠的(179mg,2.19mmol),所得反应悬浮液在120℃下搅拌2小时.反应物冷却至室温,浓缩。C18柱分离(展开系统:5-95%CH3CN水溶液,25min)后得到标题化合物XIV-1(白色固体,100mg,产率:35%)。1H NMR(400MHz,DMSO-d6):δ8.16(s,1H),7.97(s,2H),7.61(d,J=8.8Hz,1H),7.05(d,J=2.4Hz,1H),6.75(dd,J=8.8,2.4Hz,1H),3.77(s,3H).LC-MS[流动相:6.5min内,从80%水(0.02%NH4OAc)和20%CH3CN至30%水(0.02%NH4OAc)和70%CH3CN],Rt=2.732min;纯度:96.19%(254nm),MS计算:515.9;MS实测:516.9[M+H]+。
实施例2-12
根据实施例1的方法,只要变换适当的起始原材料,即可以合成出相应的各种各样的衍生物。实施例2-12是其中的一些代表性的例子(见表1)。
表1
另外,可以选择合成路线_1或者合成路线_2,参考实施例1的方法,只要适当选择起始原材料,还可以合成出更加广泛的各种各样的衍生物,例如表2所列的化合物就是其中的一些例子。
表2
药理试验
I.采用以下方法测定试验化合物(实施例化合物1、2、4、5、6、7、8、9)的THR-α/β激活作用。
试验方法1
THR/RXR/GRIP1检测
将表达THR-β(H6-THR-β)的配体结合域(氨基酸148-410)和THR-α(H6-THR-α)的配体结合域(氨基酸202-461)基因克隆插入到大肠杆菌表达载体pET28a中,该表达载体包含一个N-末端六组His序列。将其导入大肠杆菌BL21(DE3)菌株中,产生带有His标记的重组蛋白。将菌株接种于TB培养基中(培养基配方:胰蛋白酶3.3%、酵母菌提取物2.%、NaCl0.5%)加入终浓度为0.2mM的IPTG,并在25℃环境下摇瓶中培养24h,培养结束后收集培养中细菌,用5倍体积裂解液(0.05M Tris,0.3MNaCL,1%W/V甜菜碱,0.01M咪唑,0.02Mβ-巯基乙醇,pH 8.0)将收集的细菌重悬,同时加入溶菌酶和蛋白酶抑制剂,冰浴条件下(4℃)进行超声裂菌(1分钟5次)。裂解后的悬液127300RCF离心2小时,将上清液加载到NI_NTA琼脂糖(Quigen 30210)柱上,经缓冲液A洗涤后,用含有0.25M咪唑的缓冲液A洗脱H6-TRβ或H6-TRα蛋白。
将人类视黄醇X受体(氨基酸225-462)(RxRα)进行工程改造,使其用N端具有His6和EE(EFMPME)标签,将其克隆到pACYC载体中,并在大肠杆菌中产生His6 EEtagged蛋白。培养基中加入终浓度为0.1mM IPTG进行诱导,并在在18℃环境下使用摇瓶培养18h,培养结束后收集培养中细菌,用5倍体积裂解液(0.05M Tris,0.3MNaCL,1%W/V甜菜碱,0.01M咪唑,0.02M β-巯基乙醇,pH 8.0)将收集的细菌重悬,同时加入溶菌酶和蛋白酶抑制剂,4℃下搅拌30分钟,随后将悬浮液在4℃下超声处理30s,5次。收集悬浮液,12000RCF离心20min。收集上清液,采用0.45μm孔径的膜过滤上清液,随后加入0.5%NP-40。将带有His6标签的蛋白质与NiNTA金属亲和树脂结合并洗脱、浓缩蛋白质并透析。通过凝血酶消化,从EE-RxRα蛋白中中去除了His6标签(每毫克蛋白质加入10单位凝血酶,25℃孵育2h)。再使用苯甲醚琼脂糖凝胶6B分批除去凝血酶,浓缩蛋白质并透析。此蛋白用于共激活肽募集试验。
THR-β/RXR/GRIP1共激活肽招募试验
将50mM Hepes,pH7.0、1mM DTT,0.05%NP40和0.2mg/mL BSA(结合缓冲液)配置成30μL H6-THR-β(50nM),然后与等体积的EE-RxRα(50nM)缓冲液混合。然后加入6μL T3(0-14.8μM)或测试化合物(0-1.2mM)到DMSO中,并将溶液在37℃下孵育30分钟。然后加入30μL结合缓冲液和5%DMSO中的30μL生物素-GRIP1肽(100nM),并将溶液在37℃下孵育30分钟。加入包含12nM缀合物-偶联的抗六组氨酸His抗体和160nM APC-偶联的抗生蛋白链菌素溶液,30μL(50mM Tris,pH 7.4、100mM NaCl和0.2mg/mL BSA),4℃孵育过夜。将等分试样(35μL/样品)转移至384孔黑色微量滴定板。在Victor 5阅读器(PerkinElmer Life andAnalytical Sciences)上读取HTRF信号。
THR-α/RXR/GRIP1共激活肽招募试验
除使用125nMH6-THR-α,125nMEE-RxRα和250nM生物素-GRIP1之外,该测定方法与上述THR-β/RXR/GRIP1共激活肽回收技术基本相同。
试验方法2
体外细胞水平测试化合物对THR-α/β激活活性的方法:
采用ECHO液体工作站将化合物转移到384孔板,每个化合物10个梯度浓度,3倍稀释,三复孔。铺1.5×104个DMEM培养的细胞(TR beta-UAS-bla HEK 293T Cell)或1.0×104个TR alpha-UAS-bla HEK 293T Cell于384孔板中。HEK 293T-TR beta在培养箱中孵育16小时,HEK 293T-TR alpha在培养箱中孵育24小时,LiveBLAzerTM-FRET B/G(CCF4-AM)底物加入细胞板中用于检测细胞内β-内酰胺酶表达,产物在409nm激发作用下,产生447nm波长的荧光,如果没有表达β-内酰胺酶,在409nm激发作用下,直接通过FRET产生520nm波长的荧光,通过检测两荧光比值(蓝/绿,460nm/530nm)来判定化合物与蛋白的结合情况,从而计算化合物的EC50。在每次实验中,参考化合物三碘甲状腺原氨酸(T3)和MGL3196将作为阳性对照品用于实验。Z因子的计算(大于0.5)将用于监控每次实验的稳定性。
II.试验结果
应用前述方法,部分试验结果综述如表3所示。
表3
体内药效试验
I.试验方法:
本实验采用高脂肪饲料喂养金黄地鼠(80-110g,5-6周龄,雄性,北京维通利华,许可证号SCXK(京)2016-0011)产生高血脂模型,然后口服给予化合物1及MGL3196阳性对照药物,用全自动生化仪测定血浆中TG(甘油三酯)含量,并根据测定结果对化合物1治疗非酒精性脂肪肝(NASH)进行药效评价。
模型建立成功后,实验动物根据血脂水平将其平均分为5组,即:
组1:空白对照组,6只,普通饲料,同时给予溶媒,10mL/kg。
组2:模型对照组,8只,高脂饲料,同时给予溶媒,10mL/kg。
组3:低剂量组,8只,高脂饲料,剂量5mg/kg,10mL/kg。
组4:高剂量组,8只,高脂饲料,剂量15mg/kg,10mL/kg。
组5:阳性对照组(MGL3196),8只,高脂饲料,剂量15mg/kg,10mL/kg。
给药方式:口服给药,每天给药1次,时间间隔24h,连续给药4周,实验期间动物每周称重2次,每次采血检测前记录饲料剩余量及添加量,用来计算给药期间各组动物的摄食量。
II.试验结果:
1.血液TG(甘油三酯)指标:参见图1;
2.食物利用率:参见图2。
食物利用率代表动物每摄入100g饲料所增加的体重克数,食物利用率=体重增加量(g)/摄食量(100g)×100%。化合物1在给药4周期间,较模型组显著降低了血液中甘油三酯水平。
对于食物利用率,化合物1(Cpd1)有显著降低,MGL3196有一定的增加。说明在摄入同等食物尤其是脂肪的情况下,化合物1能通过增加能量消耗而降低食物中的脂肪转化为体重,这个正好印证了化合物1的TRβ激动剂的作用机制。
说明于本发明的特定实例的细节并非用以被推断为其限制。可不离本发明的本质及范围进行各种同义及修饰,且已知这些同义具体实施方案是本发明之一部份。
Claims (19)
1.具有通式(I)结构的化合物,或其药学上可接受的盐、多晶型、互变异构体、立体异构体、水合物、溶剂化合物或同位素衍生物:
结构通式(I)
其中,
R1选自:H、-CN、-NO2、-CF3、-OCF3、-CO2H、-OH、乙炔基、卤素、氨基、烷基、链烯基、卤代烷基、卤代烯基、杂烷基、杂环烷基、芳基烷基、环烷基、芳基、杂环芳基、杂环芳基烷基、杂环烷基、杂环烯基、烷氧基、烷氧烷基、烯氧基、-炔基、-烷基炔基、-炔氧基、-烷基炔氧基、炔氧基、氨基、烷基氨基、氨基烷基、烷基氨基羰基、磺酰基、烷基磺酰基、烷基亚磺酰基、氨基磺酰基、酰基;在以上基团中,各自可不被取代或被一个或多个取代基取代,这些取代基包括:卤素、-CF3、烷基、链烯基、链炔基、羟基、羟烷基、烷氧基、烷氧烷基、氨基、烷基氨基、环烷基氨基;
R2选自:H、烷基、链烯基、卤代烷基、卤代烯基、杂烷基、杂环烷基、芳基烷基、环烷基、芳基、杂环芳基、杂环芳基烷基、杂环烷基、杂环烯基、烷氧基、烷氧烷基、烷基氨基、烷基氨基羰基、-炔基、-烷基炔基、-炔氧基、-烷基炔氧基、磺酰基、烷基磺酰基、烷基亚磺酰基、氨基磺酰基;在以上基团中,各自可不被取代或被一个或多个取代基取代,这些取代基包括:卤素、-CF3、烷基、链烯基、链炔基、羟基、羟烷基、烷氧基、烷氧烷基、氨基、烷基氨基、环烷基氨基;
R3选自:H、-CN、-NO2、-CF3、-OCF3、-CO2H、OH、-SR7、卤素、氨基、烷基、烷氧基、烷氧烷基、杂烷基、杂环烷基、芳基烷基、环烷基、杂环芳基烷基、杂环烷基、杂环烯基、烯氧基、-炔基、-烷基炔基、-炔氧基、-烷基炔氧基、烷基氨基、氨基烷基、烷基氨基羰基;在以上基团中,各自可不被取代或被一个或多个取代基取代,这些取代基包括:卤素、-CF3、烷基、链烯基、链炔基、羟基、羟烷基、烷氧基、烷氧烷基、氨基、烷基氨基、环烷基氨基;
R4和R5各自选自:H、卤素、烷基、烷氧基、烷氧烷基;
R6选自:H、-CN、-NO2、-CF3、-OCF3、-CO2H、-OH、烷基、卤素、羧基、酯基、酰胺;
X选自:共价键、-O-、-S-、-NH-、-SO2-、-CONH-或-(CH2)q-、X-连接到苯并咪唑环的C4-、C5-、C6-和C7-位碳原子上,q是0、1、2、3。
2.根据权利要求1的化合物,其中R1、R2和R3各自是H。
3.根据权利要求1的化合物,其中R2为甲基。
4.根据权利要求1的化合物,其中R4和R5各自是Br,R4和R5分别连接到相应苯环上的C3-和C5-位上。
5.根据权利要求1的化合物,其中R4和R5各自是Cl,R4和R5分别连接到相应苯环上的C3-和C5-位上。
6.根据权利要求1的化合物,其中R4和R5各自是F,R4和R5分别连接到相应苯环上的C3-和C5-位上。
7.根据权利要求1的化合物,其中R4和R5各自是I,R4和R5分别连接到相应苯环上的C2′-和C6′-位上。
8.根据权利要求1的化合物,其中R4和R5各自是甲基,R4和R5分别连接到相应苯环上的C3-和C5-位上。
9.根据权利要求1的化合物,其中R4和R5各自是二氟甲基,R4和R5分别连接到相应苯环上的C3-和C5-位上。
10.根据权利要求1的化合物,其中R4和R5各自是三氟甲基,R4和R5分别连接到相应苯环上的C3-和C5-位上。
11.根据权利要求1的化合物,其中R6是H。
12.根据权利要求1的化合物,其中R6是是CN。
13.根据权利要求1的化合物,其中R6是含有1到3个C原子的低级烷基。
15.根据权利要求1-14中任一项的化合物,或者与其它药物组成的组合药物,用于治疗和/或预防性治疗由甲状腺激素调节的疾病的药物。
16.根据权利要求1-14中任一项的化合物,或者与其它药物组成的组合药物,用于治疗和/或预防性治疗由甲状腺激素调节的代谢疾病。
17.根据权利要求1-14中任一项的化合物,或者与其它药物组成的组合药物,用于治疗和/或预防性治疗由甲状腺激素调节的肥胖、糖尿病、NASH(nonalcoholicsteatohepatitis,非酒精性的脂肪肝)、心血管疾病、甲状腺功能减退、或甲状腺癌。
18.根据权利要求1-14中任一项的化合物,或者与其它药物组成的组合药物,用于治疗和/或预防性治疗由甲状腺激素调节的高脂血症或动脉粥样硬化。
19.根据权利要求1-14中任一项的化合物的应用,或者与其它药物组成的组合药物,用于治疗和/或预防性治疗由甲状腺激素调节的高胆固醇血症。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6787652B1 (en) * | 1999-09-30 | 2004-09-07 | Pfizer, Inc. | 6-Azauracil derivatives as thyroid receptor ligands |
CN113474335A (zh) * | 2019-02-21 | 2021-10-01 | 南京瑞捷医药科技有限公司 | 新型化合物及其作为甲状腺激素受体激动剂的用途 |
CN114430743A (zh) * | 2019-08-23 | 2022-05-03 | 拓臻制药公司 | 甲状腺激素受体β激动剂化合物 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PT1262177E (pt) * | 2001-05-31 | 2006-12-29 | Pfizer Prod Inc | Utilização medicinal de compostos tiromimético para tratamento da queda de cabelo e composições |
US8076334B2 (en) | 2007-09-20 | 2011-12-13 | Hoffmann-La Roche Inc. | Prodrugs of thyroid hormone analogs |
CN108727344A (zh) | 2018-05-14 | 2018-11-02 | 嘉兴特科罗生物科技有限公司 | 一种化合物及其合成方法和应用 |
CN110938094A (zh) | 2018-09-21 | 2020-03-31 | 四川海思科制药有限公司 | 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 |
AU2019359141A1 (en) * | 2018-10-12 | 2021-04-22 | InventisBio Co., Ltd. | Thyroid hormone receptor agonists |
AU2022228569A1 (en) * | 2021-03-03 | 2023-10-12 | Terns Pharmaceuticals, Inc. | Thyroid hormone receptor beta agonist compounds |
-
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6787652B1 (en) * | 1999-09-30 | 2004-09-07 | Pfizer, Inc. | 6-Azauracil derivatives as thyroid receptor ligands |
CN113474335A (zh) * | 2019-02-21 | 2021-10-01 | 南京瑞捷医药科技有限公司 | 新型化合物及其作为甲状腺激素受体激动剂的用途 |
CN114430743A (zh) * | 2019-08-23 | 2022-05-03 | 拓臻制药公司 | 甲状腺激素受体β激动剂化合物 |
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