CN114315844B - 一类fxr调节剂及其制备方法和用途 - Google Patents
一类fxr调节剂及其制备方法和用途 Download PDFInfo
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- CN114315844B CN114315844B CN202210054163.2A CN202210054163A CN114315844B CN 114315844 B CN114315844 B CN 114315844B CN 202210054163 A CN202210054163 A CN 202210054163A CN 114315844 B CN114315844 B CN 114315844B
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- alkoxy
- pharmaceutically acceptable
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- halogenated
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- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- -1 isoxazole compound Chemical class 0.000 claims abstract description 48
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
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- 101000603876 Homo sapiens Bile acid receptor Proteins 0.000 claims abstract description 22
- 239000000203 mixture Substances 0.000 claims abstract description 19
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- 230000001404 mediated effect Effects 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims description 22
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 14
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
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- 229910052805 deuterium Inorganic materials 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
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- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 229910052722 tritium Inorganic materials 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
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- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
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- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 22
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- 239000000243 solution Substances 0.000 description 18
- 239000012043 crude product Substances 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 8
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000001270 agonistic effect Effects 0.000 description 6
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- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- XJLDYKIEURAVBW-UHFFFAOYSA-N 3-decanone Chemical compound CCCCCCCC(=O)CC XJLDYKIEURAVBW-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 229940095102 methyl benzoate Drugs 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- ZXERDUOLZKYMJM-ZWECCWDJSA-N obeticholic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCC(O)=O)CC[C@H]21 ZXERDUOLZKYMJM-ZWECCWDJSA-N 0.000 description 4
- 229960001601 obeticholic acid Drugs 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- LXWQVTNZUIURFE-UHFFFAOYSA-N 2,6-dichloro-n-hydroxybenzenecarboximidoyl chloride Chemical compound ON=C(Cl)C1=C(Cl)C=CC=C1Cl LXWQVTNZUIURFE-UHFFFAOYSA-N 0.000 description 3
- WVULOKZMQJKUIQ-UHFFFAOYSA-N 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbaldehyde Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)C=O WVULOKZMQJKUIQ-UHFFFAOYSA-N 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
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- KRGFOUGVZFEEBW-UHFFFAOYSA-N [5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methanol Chemical compound OCC1=C(C2CC2)ON=C1C1=C(Cl)C=CC=C1Cl KRGFOUGVZFEEBW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 208000019425 cirrhosis of liver Diseases 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
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- 230000002401 inhibitory effect Effects 0.000 description 3
- YBSXDWIAUZOFFV-UHFFFAOYSA-N n-[(2,6-dichlorophenyl)methylidene]hydroxylamine Chemical compound ON=CC1=C(Cl)C=CC=C1Cl YBSXDWIAUZOFFV-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
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- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 2
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- PNZIYSWKRBYITO-UHFFFAOYSA-N 4-(bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole Chemical compound ClC1=CC=CC(Cl)=C1C1=NOC(C2CC2)=C1CBr PNZIYSWKRBYITO-UHFFFAOYSA-N 0.000 description 2
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Abstract
本发明涉及一类FXR调节剂及其制备方法和用途,具体而言涉及一种式(I)的异噁唑类化合物,其制备方法,包含所述化合物的药物组合物,以及所述化合物及其组合物在制备治疗FXR介导的疾病的药物中的用途。
Description
技术领域
本发明涉及药物化学和药物治疗学领域,具体涉及一类下面式I所示的化合物,其制备方法,包含所述化合物的药物组合物,以及所述化合物及其组合物在制备治疗FXR介导的疾病的药物中的用途。
背景技术
非酒精性脂肪性肝病(NAFLD)是一种脂质在肝细胞之中异常沉积的疾病,流行病学调查显示NAFLD是全球范围内肝脏疾病的常见病因,发达国家有五分之一至四分之一的成年人患有NAFLD。NAFLD除可直接导致失代偿期肝硬化、肝细胞癌和移植肝复发外,还可影响其他慢性肝病的进展,并参与2型糖尿病和动脉粥样硬化的发病,被认为是全身代谢综合征的肝脏局部表现。
NAFLD主要包括单纯性脂肪肝(SFL)和非酒精性脂肪性肝炎(NASH),其中NASH是最主要的一种类型。目前,NASH治疗药物的研发主要包括:(1)选择性外周大麻素受体(CB)阻制剂;(2)过氧化物酶体增殖物激活受体(PPAR)激动剂;(3)半胱天冬酶(Caspase)抑制剂;(4)磷酸二脂酶4(PDE4)抑制剂;(5)法尼醇X受体(FXR)激动剂;(6)趋化因子受体-5/趋化因子受体-2(CCR5/CCR2)双靶点抑制剂;(7)凋亡信号调节激酶-1(ASK1)抑制剂等。药物研发中,法尼醇X受体FXR是热点的研究靶标。FXR生物学功能包括调节胆汁酸代谢、脂质代谢和葡萄糖代谢,对调控代谢综合征患者代谢紊乱发挥重要作用。
法尼醇X受体(farnesoid X receptor,FXR)是具有核受体超家族成员,最早于1995年在大鼠肝脏cDNA文库中筛选发现,因其转录活性可被超生理浓度的法尼酯衍生物增强而命名,在肝脏、肠、肾、肾上腺和脂肪组织中高度表达。FXR可以通过维持胆汁酸的内稳态,抑制肝细胞凋亡,减少组织的氧化应激反应,降低肝脏的纤维化水平,抑制炎症反应,促进肝细胞再生,抑制肝癌的发生及发展,改善胰岛素抵抗,减少脂肪的合成,从而减少肝脏脂肪的沉积等方式保护肝脏。
近年来,有多个FXR激动剂相继进入了临床研究,如Novatis发现的化合物tropifexor具有良好的生物活性和选择性,对FXR具有极高的激动活性,目前已经进入II期临床试验用于NASH和原发性胆汁性胆管炎(PBC)的治疗;由Metacrine公司开发的FXR激动剂MET-409、MET-642也进入到NASH的Ⅱ期临床试验当中。其中,奥贝胆酸(OCA)作为第一个FXR激动剂被批准上市,用于治疗PBC。尽管奥贝胆酸在减少肝脏纤维化方面发挥了积极作用,但是它却会升高低密度脂蛋白胆固醇(LDL)和降低高密度脂蛋白胆固醇(HDL),增加心血管风险,这可能会限制其使用。
在该背景下,本发明提供了一类新的化合物,其对FXR具有较好的激动活性,具备极佳的临床应用前景。
发明内容
本发明的目的之一是提供如下通式(I)所示的靶向FXR的小分子激动剂及其制备方法、药物组合物和用途。
本发明第一方面提供了一种式(I)的异噁唑类化合物或其对映异构体、非对映异构体、可药用盐,或它们的混合物:
n为1或2;
m为0或1;
A环为取代或未取代的5-12元杂环,所述的取代指基团上的氢原子被1、2、3或4个选自下组的取代基取代:氘、氚、卤素、氧代、C1-C6烷基、C1-C3烷基羰基;所述杂环含有1~4个选自氧、硫和氮中的杂原子;
R1为取代或未取代的C6-C10芳基,优选取代或未取代的苯基;其中,所述的取代指基团上的氢原子被1、2、3或4个选自下组的取代基取代:氘、氚、卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C8环烷基、卤代C3-C8环烷基、C3-C8环烷氧基、卤代C3-C8环烷氧基、氰基、硝基、-NRaRb、羟基、羟基C1-C6烷基、羧基、羧基C1-C6烷基、C6-C10芳基、C6-C10芳基氧基等;优选地,所述的取代指基团上的氢原子被1、2或3个选自下组的取代基取代:氘、氚、卤素、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷氧基、C3-C6环烷基、卤代C3-C6环烷基、C3-C6环烷氧基、卤代C3-C6环烷氧基、氰基、硝基、-NRaRb、羟基、羟基C1-C3烷基、羧基、羧基C1-C3烷基等;其中,Ra和Rb各自独立地选自氢、C1-C6烷基和卤代C1-C6烷基,优选各自独立地选自氢、C1-C3烷基和卤代C1-C3烷基;
优选地,R1为被羧基或羧基C1-C3烷基取代的苯基;其任选被1个选自下组的取代基进一步取代:氯、氟、C1-C6烷氧基、卤代C1-C6烷氧基、氰基;
R2选自取代或未取代的5-6元杂环基、取代或未取代的苯基、取代或未取代的5-6元杂芳基;其中,所述的取代指基团上的氢原子被1、2、3或4个选自下组的取代基取代:氘、氚、卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、氰基、硝基、氨基、羟基、羟基C1-C6烷基、羧基等,优选地,R2选自被氯取代的苯基;特别是二氯苯基。
在实施方式中,所述式(I)的异噁唑类化合物选自下列式(II)的化合物:
其中,
n为1或2;
m为0或1;
R11和R15各自独立地选自氢、氘、氚、卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、氰基、硝基;优选选自氢、氘、卤素、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基(例如甲氧基、乙氧基、异丙氧基)、卤代C1-C3烷氧基(例如卤代甲氧基,卤代乙氧基(包括2,2,2-三氟乙氧基))、氰基;优选R11和R15之一为H;
R12、R13、R14之一为羧基或羧基C1-C6烷基,优选为羧基或羧基C1-C3烷基,另外两个各自独立地选自氢、氘、氚、卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基;优选另外两个各自独立地选自氢、氘、卤素、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基(例如甲氧基、乙氧基、异丙氧基)、卤代C1-C3烷氧基(例如卤代甲氧基,卤代乙氧基(包括2,2,2-三氟乙氧基));
优选R11、R12、R13、R14、R15中至少三个为H。
在上述定义中,W作为连接基团的连接方向没有限定,即W可以以其基团的任何一端与两侧的基团之一连接,而另一端与两侧基团的另一个连接。
在实施方式中,所述式(II)的异噁唑类化合物选自下列化合物:
其中,n、R11、R12、R13、R14、R15的定义与式(II)相同。
在实施方式中,所述式(II)的异噁唑类化合物选自下列化合物:
本发明第二方面提供了一种药物组合物,其包含治疗有效量的选自上述含异噁唑类化合物、其对映异构体、非对映异构体、可药用盐中的一种或多种,以及任选地,药学上可接受的载体。
本发明第三方面提供了制备上述异噁唑类化合物的方法,所述方法为下列方法之一:
方法一:
步骤a:A1与A2发生亲核取代反应得到A3;
步骤b:A4的氧胺盐基团与A3的羰基反应生成酮肟醚键得到A5;
步骤c:A5脱保护基得到I-1;
方法二:
步骤d:B1的氧胺盐基团与B2的羰基反应生成酮肟醚键得到B3;
步骤e:B3与B4发生亲核取代反应得到B5;
步骤f:B5脱保护基得到I-2;
其中,m、n、L、R1、R2、A的定义与之前相同;R1’为R1中的官能团被保护的结构;X为氯或者溴。
本发明的式(I)化合物可能含有碱性或酸性基团,这类化合物可以与适宜的酸或碱形成药学上可接受的盐,这都将是属于本发明的一部分
具体地,本发明的部分化合物含有碱性官能团(例如但不仅限于当A为哌啶环时),因此可以与合适的酸形成药学上可接受的盐。所述合适的酸可以是无机酸,也可以是有机酸。药学上可接受的盐的代表性例子包括但不限于:盐酸盐、硫酸盐、氢溴酸盐、甲磺酸盐、硝酸、磷酸盐、乙酸盐、草酸盐、丁二酸盐、酒石酸盐、马来酸盐、精氨酸盐等。
本发明的部分化合物含有酸性官能团(例如但不仅限于当R1上的取代基有COOH时),因此可以与合适的碱形成药学上可接受的盐。所述合适的碱可以是无机碱,也可以是有机碱。药学上可接受的盐的代表性例子包括但不限于:与无机离子形成的盐,如钠盐、钾盐、锂盐、钙盐、铝盐、锌盐、铵盐等;与有机碱形成的盐,如甲胺盐、乙胺盐、三乙胺盐、葡甲胺盐、氨基丁三醇盐等。
本发明的部分化合物或其药学上可接受的盐是从水或有机溶剂中结晶或重结晶而来,晶体中可能包含所使用的溶剂分子。此外,不同的结晶条件可能导致化合物的晶型不同。因此,含有不同化学剂量的结晶溶剂以及所有晶型的式(I)所示的化合物或其药学上可接受的盐都在本发明的范围内。
本发明的部分化合物具有一个或多个手性中心(例如但不仅限于当A包含一个或多个手性碳剂时),因而可能存在外消旋体、外消旋混合物、对映异构体、非对映异构体、非对映异构混合物等多种形式。式(I)所示化合物的所有这些异构形式都在本发明的保护范围内。式(I)所示的化合物可能以顺反异构体的形式存在,因此某一种异构体以及两种顺反异构体的混合体都在本发明的保护范围内。
本发明提供了式(I)所示的化合物,其被证明对FXR具有较好的激动活性,具备极佳的临床应用前景。
因此,本发明第四方面提供了根据本发明的异噁唑类化合物或其对映异构体、非对映异构体、可药用盐,或它们的混合物的用途,所述用途选自:在制备FXR激动剂中的用途;在制备用于预防或治疗由FXR介导的疾病的药物中的用途。
所述由FXR介导的疾病包括,但不限于,非酒精性脂肪性肝病(NAFLD)和原发性胆汁性胆管炎(PBC)。
具体实施方式
定义
除非特别注明,本发明中所用的术语具有如下定义:
本发明中所述的“烷基”表示饱和的直链和支链烃基,具体地可列举如但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、叔戊基等。所述“C1-6烷基”表示碳原子数为1个到6个的饱和直链或支链烃基,具体地可列举如但不限于甲基、乙基、丙基、异丙基、丁基、异丁基等。
本发明所述的“5-12元杂环”代表具有6-12个成环原子、含有一到四个选自N、O、S的杂原子的饱和单环或多环(例如双环)体系。代表性的例子有但不限于:四氢呋喃、吡咯烷、哌啶、哌嗪、吗啉、氧杂环丁烷等。
本发明中所述的“环烷基”代表环原子仅为碳的饱和环状烃基。代表性的例子有但不限于:环丙基、环丁基、环戊基、环己基。
本发明所述的“烷氧基”表示RO-基团,其中,R为如上所述的烷基,具体地可列举如但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基等。
所述“卤素”表示氟、氯、溴、碘。
本发明中烷基或环烷基上的取代,如没有指明发生在特定的碳原子上,则表示可以发生在任何取代基个数尚未达到饱和的碳原子上。多个取代基从同一系列中选择时,它们可以相同,也可以不同。
本发明中苯环、芳杂环或者杂环上的取代,如没有指明发生在特定的原子上,则表示可以发生在任何未被除氢与外的其它原子取代的位置。多个取代基从同一系列中选择时,它们可以相同,也可以不同。
实施例
以下将以实施例进一步说明本发明。需要特别指出的是,这些实施例只用于举例说明本发明,而不以任何方式限制本发明。实例中的所有参数及其余说明,除另加说明外,都是以质量为依据的。柱层析分离所用填料若未说明均为硅胶。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明中。文中所述的较佳实施方法与材料仅作示范之用。
制备实施例
1)2,6-二氯苯甲醛肟的制备
在冰浴条件下,将氢氧化钠水溶液(1.656g,41.4mmol,溶于20ml水中)滴加入盐酸羟胺(3.94g,56.7mmol)的水(10ml)溶液中,搅拌半小时,再将2,6-二氯苯甲醛(10g,57.1mmol)溶于乙醇,滴加入反应体系中,然后升高温度到室温,搅拌过夜,减压浓缩得到粗品,过滤洗涤干燥得2,6-二氯苯甲醛肟(9.5g,产率89%)为白色固体。MS(ESI)m/e[M+H]+:189.9。
2)2,6-二氯苯甲酰氯肟的制备
向2,6-二氯苯甲醛肟(3g,15.87mmol)的N,N-二甲基甲酰胺(50ml)的溶液中分批加入N-氯代丁二酰亚胺(2.124g,15.9mmol)。加样完毕之后室温搅拌五个小时,再加入乙酸乙酯溶液稀释,用饱和食盐水洗涤有机相,干燥,减压浓缩得到粗品,粗品用正己烷重结晶得到2,6-二氯苯甲酰氯肟(3.478g,产率94%),为白色固体。
1H NMR(500MHz,DMSO-d6)δ7.71(d,J=1.7Hz,1H),7.69(d,J=0.7Hz,1H),7.64(dd,J=9.2,6.8Hz,1H).
3)5-环丙基-3-(2,6-二氯苯基)异噁唑-4-甲酸乙酯的制备
室温下,将三乙胺(1137mg,11.15mmol)滴加入3-环丙基-3-羰基-丙酸乙酯(2679mg,17.16mmol)的N,N-二甲基甲酰胺(30ml)溶液中,搅拌五个小时。再将2,6-二氯苯甲酰氯肟(2000mg,8.583mmol)溶于N,N-二甲基甲酰胺(10ml),滴加入反应体系中,搅拌过夜,加水(20ml)淬灭反应,用乙酸乙酯(50ml×3)萃取反应体系,合并有机相,干燥,浓缩并用硅胶柱层析(石油醚:乙酸乙酯=4:1)纯化得到5-环丙基-3-(2,6-二氯苯基)异噁唑-4-甲酸乙酯(1651mg,产率59%)为白色固体。MS(ESI)m/e[M+H]+:326.0;
1H NMR(400MHz,CDCl3)δ7.41(d,J=1.9Hz,1H),7.39(d,J=0.7Hz,1H),7.33(dd,J=9.3,6.6Hz,1H),4.12(q,J=7.1Hz,2H),2.93(tt,J=8.4,5.1Hz,1H),1.45-1.36(m,2H),1.36-1.23(m,2H),1.02(t,J=7.1Hz,3H).
4)(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲醇的制备
冰浴条件下,向5-环丙基-3-(2,6-二氯苯基)异噁唑-4-甲酸乙酯(1000mg,3.076mmol)的四氢呋喃的溶液(20ml)中滴加氢化锂铝(128.2mg,3.384mmol)的四氢呋喃溶液(1.41ml,2.5mol/L)滴加完毕之后,反应体系升高至室温,反应两个小时。加入饱和氯化铵溶液(30ml)淬灭反应,搅拌十分钟,减压过滤除去固体,减压浓缩滤液,再用乙酸乙酯(50ml×3)萃取滤液,有机相干燥,浓缩并用正己烷重结晶得到(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲醇(657mg,产率75%)为白色固体。MS(ESI)m/e[M+H]+:284.0;
1H NMR(400MHz,CDCl3)δ7.44(d,J=1.6Hz,1H),7.42(d,J=0.7Hz,1H),7.36(dd,J=9.2,6.8Hz,1H),4.41(d,J=5.8Hz,2H),2.19(tt,J=8.4,5.1Hz,1H),1.28(ddd,J=6.7,5.0,4.1Hz,2H),1.18-1.10(m,2H).
5)4-(溴甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑(中间体1.1)的制备
冰浴条件下,向(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲醇(400mg,1.414mmol)的二氯甲烷溶液(10ml)中加入三苯基膦(606.6mg,2.121mmol)搅拌十分钟后分批加入四溴化碳(693.5mg,2.121mmol),搅拌两个小时,将反应体系浓缩得到粗品,粗品用硅胶柱层析纯化(石油醚,乙酸乙酯=20:1),得到4-(溴甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑(420mg,86.2%)为白色固体。MS(ESI)m/e[M+H]+:345.9;
1H NMR(400MHz,CDCl3)δ7.46(d,J=1.9Hz,1H),7.44(d,J=0.7Hz,1H),7.38(dd,J=9.3,6.6Hz,1H),4.23(s,2H),2.13(tt,J=8.4,5.1Hz,1H),1.30(ddd,J=6.3,5.0,3.8Hz,2H),1.23-1.16(m,2H).
6)3-((1,3-二氧异吲哚啉-2-基)氧基)甲基)苯甲酸甲酯的制备
将3-溴甲基苯甲酸甲酯(2500mg,10.9mmol)和N-羟基邻苯二甲酰亚胺(2669mg,16.37mmol)溶于N,N-二甲基甲酰胺(50ml),氮气保护,加入N,N-二异丙基乙胺(4232mg,32.75mmol)70℃反应三个小时,冷却至室温,边搅拌边加入水,固体完全析出后用布氏漏斗过滤,用水洗涤固体至白色,烘干固体得到3-((1,3-二氧异吲哚啉-2-基)氧基)甲基)苯甲酸甲酯(3250mg,产率95.7%),为白色固体。MS(ESI)m/e[M+H]+:312.0;1H NMR(400MHz,CDCl3)δ8.17(d,J=1.8Hz,1H),8.06(dt,J=7.8,1.5Hz,1H),7.84-7.81(m,2H),7.81-7.76(m,1H),7.74(dd,J=5.5,3.1Hz,2H),7.49(t,J=7.7Hz,1H),5.25(s,2H),3.92(s,3H).
7)3-(氨基氧基)甲基苯甲酸甲酯盐酸盐的制备。
将3-((1,3-二氧异吲哚啉-2-基)氧基)甲基)苯甲酸甲酯(1000mg,3.21mmol)加入甲醇溶液(30ml)中,氮气保护,再加入正丁胺(236mg,3.21mmol)搅拌过夜。在冰浴条件下加入盐酸乙醇溶液(25ml,1mol/L)搅拌一个小时,常温旋干,得到粗品,再将粗品用甲基叔丁基醚(30ml×3)洗涤,过滤,常温烘干,得到3-(氨基氧基)甲基苯甲酸甲酯盐酸盐(521mg,产率75%)为白色固体。
1H NMR(400MHz,Methanol-d4)δ8.17-8.04(m,2H),7.72(dt,J=7.7,1.5Hz,1H),7.60(t,J=7.7Hz,1H),5.13(s,2H),3.95(s,3H).
类似的,可以利用同样的方法合成以下中间体
8)2-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)异吲哚-1,3-二酮的制备
将3-溴甲基苯甲酸甲酯(400mg,1.15mmol)和N-羟基邻苯二甲酰亚胺(300,1.84mmol)溶于N,N-二甲基甲酰胺(50ml),氮气保护,加入N,N-二异丙基乙胺(465mg,3.6mmol)70℃反应三个小时,冷却至室温,边搅拌边加入水,固体完全析出后用布氏漏斗过滤,用蒸馏水洗涤固体至白色,烘干固体得2-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)异吲哚-1,3-二酮(450mg,产率91.2%)。MS(ESI)m/e[M+H]+:429.0
9)4-(氨基氧基)-5-环丙基-3-(2,6-二氯苯基)异噁唑盐酸盐(中间体2.12)的制备
将2-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)异吲哚-1,3-二酮(450mg,1.04mmol)加入甲醇溶液(30ml)中,氮气保护,再加入正丁胺(77mg,1.04mmol)搅拌过夜。旋掉部分甲醇,在冰浴条件下加入盐酸乙醇溶液(5ml,1mol/L)搅拌一个小时,常温旋干,得到粗品,再将粗品用甲基叔丁基醚打浆过夜,过滤,常温烘干,得到3-(氨基氧基)甲基苯甲酸甲酯盐酸盐(200mg,产率60%),为白色固体。
10)8-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲基)-1-氧杂-8-氮杂螺环[4.5]癸-3-酮的制备
将2ml 4M的氯化氢二氧六环溶液滴加到3-氧代-1-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(1.0g,3.91mmol)的二氧六环溶液中,室温下搅拌过夜,旋干后加入2.0g无水碳酸钾和中间体1.1(1.4g,4.03mmol)及DMF,60℃搅拌反应过夜。加入乙酸乙酯萃取,用水洗有机相,无水硫酸钠干燥,旋干得到粗品,粗品用柱层析分离(乙酸乙酯:0-20%)),得到8-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲基)-1-氧杂-8-氮杂螺环[4.5]癸-3-酮,黄色固体(1100mg,产率67%)。LCMS:422.3[M+H]+
类似的,可以利用同样的方法合成以下中间体
11)5-环丙基-3-(2,6-二氯苯基)异噁唑-4-甲醛的制备
在0℃下,将dess-martin氧化剂(2.7g,6.36mmol)加入到5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲醇(1g,3.52mmol)的二氯甲烷溶液中,反应过夜,旋干直接柱层析分离,得到5-环丙基-3-(2,6-二氯苯基)异噁唑-4-甲醛(0.78g,78%),为白色固体。
1H NMR(500MHz,CDCl3)δ9.69(s,1H),7.48(d,J=8.1Hz,2H),7.46-7.38(m,1H),2.92-2.72(m,1H),1.58-1.48(m,2H),1.43-1.34(m,2H).
12)5-环丙基-3-(2,6-二氯苯基)-4-(2-甲氧基乙烯基)异噁唑的制备
0℃下在N2中向(甲氧基甲基)三苯基氯化膦(1.7g,4.95mmol)的THF溶液中滴加滴加双(三甲基硅烷基)酰胺钠溶液(在THF中2M,5mL,10mmol),搅拌30分钟,随后缓慢加入5-环丙基-3-(2,6-二氯苯基)异噁唑-4-甲醛(0.78g,2.76mmol)的THF溶液,反应过夜。旋干得到粗品,柱层析分离得到5-环丙基-3-(2,6-二氯苯基)-4-(2-甲氧基乙烯基)异噁唑(0.60g,70%)。
1H NMR(500MHz,CDCl3)δ7.40(m,4H),6.46(d,J=13.1Hz,1H),5.36(d,J=13.1Hz,1H),3.57(s,3H),2.14-2.05(m,1H),1.29-1.21(m,2H),1.17-1.08(m,2H).
13)2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙醛的制备
向5-环丙基-3-(2,6-二氯苯基)-4-(2-甲氧基乙烯基)异噁唑(0.60g,1.93mmol)的乙醇溶液中加入水和10ml 2M稀盐酸,加热回流反应4小时,浓缩后加入乙酸乙酯,用饱和食盐水洗涤有机层,无水硫酸钠干燥,旋干得到粗品约0.5g。
14)8-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙基)-1-氧杂-8-氮杂螺环[4.5]癸烷-3-醇的制备
将前一步的粗品和1-氧杂-8-氮杂螺环[4.5]癸烷-3-醇盐酸盐(0.33g,1.7mmol)溶于1,2-二氯乙烷中,搅拌半小时后加入三乙酰氧基硼氢化钠(1g,4.71mmol),反应过夜,直接浓缩后柱层析分离,得到淡黄色固体(0.70g,94%),即8-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙基)-1-氧杂-8-氮杂螺环[4.5]癸烷-3-醇。
15)8-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙基)-1-氧杂-8-氮杂螺环[4.5]癸烷-3-酮(中间体3.5)的制备
在0℃下,将dess-martin氧化剂(1.4g,3.3mmol)加入到5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲醇(0.7g,1.60mmol)的二氯甲烷溶液中,反应过夜,旋干直接柱层析分离,得到黄色固体,即8-(2-(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)乙基)-1-氧杂-8-氮杂螺环[4.5]癸烷-3-酮(0.43g,63%)。LCMS:435.1[M+H]+
16)3-甲氧基-5-((3-氧基-8-氮杂双环[3.2.1]辛基-8-基)甲基)苯甲酸甲酯的制备
将无水碳酸钾(1.38g,10mmol),3-(溴甲基)-5-甲氧基苯甲酸甲酯(1g,3.86mmol)加入去甲脱品酮盐酸盐(1g,6.20moml)的DMF溶液,60℃搅拌反应过夜。加入乙酸乙酯萃取,用水洗有机相,无水硫酸钠干燥,旋干得到粗品,粗品用柱层析分离,得到3-甲氧基-5-((3-氧基-8-氮杂双环[3.2.1]辛基-8-基)甲基)苯甲酸甲酯(1.03g,84%)。1H NMR(500MHz,CDCl3)δ7.64(s,1H),7.45(s,1H),7.22(s,1H),3.89(s,3H),3.84(s,3H),3.71(s,2H),3.45(d,J=6.6Hz,2H),2.72-2.59(m,2H),2.20(d,J=15.6Hz,2H),2.14-2.04(m,2H),1.66-1.55(m,2H).
类似的,可以利用同样的方法合成以下中间体
17)4-(1,4-二氧杂-8-氮杂螺环[4.5]癸-8-基)苯甲酸甲酯的制备
向两口瓶中加入4-哌啶酮缩乙二醇(200mg,1.39mmol)、对溴苯甲酸甲酯(200mg,0.93mmol)、Pd2(dba)3(50mg)、Xphos(50mg)和1,4-二氧六环,抽换氮气后,在115℃下反应6个小时,LC-MS监控反应,待冷却至室温过滤,浓缩得到粗品,柱层析分离得到4-(1,4-二氧杂-8-氮杂螺环[4.5]癸-8-基)苯甲酸甲酯,约320mg。1H NMR(500MHz,CDCl3)δ7.93(d,J=8.9Hz,2H),6.90(d,J=8.9Hz,2H),4.02(s,4H),3.89(s,3H),3.52(t,J=5.7Hz,4H),1.88-1.80(m,4H).LCMS:277.2[M+H]+
18)4-(4-氧哌啶-1-基)苯甲酸甲酯的制备
向4-(1,4-二氧杂-8-氮杂螺环[4.5]癸-8-基)苯甲酸甲酯乙醇溶液中加入水和10ml 2M稀盐酸,加热回流反应4小时,浓缩后加入乙酸乙酯,用饱和食盐水洗涤有机层,无水硫酸钠干燥,旋干得到粗品,柱层析分离得到4-(4-氧哌啶-1-基)苯甲酸甲酯,280mg。1HNMR(500MHz,CDCl3)δ7.95(dd,J=8.9,4.5Hz,2H),6.90(d,J=8.9Hz,2H),3.87(s,3H),3.74(t,J=6.1Hz,4H),2.56(t,J=6.1Hz,4H).
19)(E)-3-(((8-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲基)-1-氧-8-氮杂螺环[4.5]癸-3-亚基)氨基)氧基)甲基)-4-异丙氧基苯甲酸甲酯和(Z)-3-(((8-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲基)-1-氧-8-氮杂螺环[4.5]癸-3-亚基)氨基)氧基)甲基)-4-异丙氧基苯甲酸甲酯的制备
将中间体3.1(100mg,0.237mmol)和中间体2.5(80mg,0.308mmol)溶于甲醇中,搅拌过夜,固体全部溶解后,直接浓缩后用制备薄层色谱分离(EA:PE=1:4)分别得到(E)-3-(((8-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲基)-1-氧-8-氮杂螺环[4.5]癸-3-亚基)氨基)氧基)甲基)-4-异丙氧基苯甲酸甲酯(55mg,36.2%)和(Z)-3-(((8-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲基)-1-氧-8-氮杂螺环[4.5]癸-3-亚基)氨基)氧基)甲基)-4-异丙氧基苯甲酸甲酯(62mg,40.8%)
(E)-3-(((8-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲基)-1-氧-8-氮杂螺环[4.5]癸-3-亚基)氨基)氧基)甲基)-4-异丙氧基苯甲酸甲酯1H NMR(500MHz,CDCl3)δ8.02-7.94(m,2H),7.41(d,J=8.0Hz,2H),7.36-7.32(m,1H),6.90(d,J=8.6Hz,1H),5.15(s,2H),4.70-4.62(m,1H),4.36(s,2H),3.89(s,3H),3.29(s,2H),2.56(s,2H),2.47-2.28(m,4H),2.27-2.18(m,1H),1.70-1.61(m,2H),1.58-1.48(m,2H),1.38(d,J=6.0Hz,6H),1.27-1.22(m,2H),1.13-1.06(m,2H).LCMS:642.2[M+H]+
(Z)-3-(((8-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲基)-1-氧-8-氮杂螺环[4.5]癸-3-亚基)氨基)氧基)甲基)-4-异丙氧基苯甲酸甲酯1H NMR(500MHz,CDCl3)δ7.98-7.91(m,2H),7.41(d,J=8.0Hz,2H),7.37-7.30(m,1H),6.89(d,J=8.3Hz,1H),5.12(s,2H),4.72-4.59(m,1H),4.49(s,2H),3.88(s,3H),3.28(s,2H),2.44(s,2H),2.47-2.27(m,4H),2.26-2.18(m,1H),1.68-1.59(m,2H),1.57-1.48(m,2H),1.36(d,J=6.0Hz,6H),1.26-1.22(m,2H),1.14-1.06(m,2H).LCMS:642.2[M+H]+
20)(E)-3-(((8-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲基)-1-氧-8-氮杂螺环[4.5]癸-3-亚基)氨基)氧基)甲基)-4-异丙氧基苯甲酸的制备
将(E)-3-(((8-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲基)-1-氧-8-氮杂螺环[4.5]癸-3-亚基)氨基)氧基)甲基)-4-异丙氧基苯甲酸甲酯(55mg,0.086mmol)和一水合氢氧化锂(20mg,0.48mmol)加入混合溶剂10ml中(四氢呋喃:甲醇:水=3:3:1),40℃反应过夜。旋干溶剂,加入水(10ml)搅拌,用盐酸(1mmol/L)调节PH固体完全析出,过滤,减压干燥,得到(E)-3-(((8-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲基)-1-氧-8-氮杂螺环[4.5]癸-3-亚基)氨基)氧基)甲基)-4-异丙氧基苯甲酸,为白色固体。1H NMR(500MHz,CDCl3)δ8.01(dd,J=8.6,2.2Hz,1H),7.95(dd,J=5.8,2.1Hz,1H),7.53-7.47(m,2H),7.47-7.40(m,1H),6.91(d,J=8.7Hz,1H),5.16(s,2H),4.73-4.63(m,1H),4.32(s,2H),4.12(s,2H),3.24-3.08(m,2H),3.01-2.88(m,2H),2.70(s,2H),2.61-2.53(m,1H),2.47-2.30(m,2H),1.86(d,J=14.0Hz,2H),1.38(d,J=6.0Hz,6H),1.37-1.35(m,2H),1.33-1.26(m,2H).LCMS:628.2[M+H]+
21)(Z)-3-(((8-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲基)-1-氧-8-氮杂螺环[4.5]癸-3-亚基)氨基)氧基)甲基)-4-异丙氧基苯甲酸的制备
将(Z)-3-(((8-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲基)-1-氧-8-氮杂螺环[4.5]癸-3-亚基)氨基)氧基)甲基)-4-异丙氧基苯甲酸甲酯(60mg,0.093mmol)和一水合氢氧化锂(20mg,0.48mmol)加入混合溶剂10ml中(四氢呋喃:甲醇:水=3:3:1),40℃反应过夜。旋干溶剂,加入水(10ml)搅拌,用盐酸(1mmol/L)调节PH固体完全析出,过滤,减压干燥,得到(Z)-3-(((8-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲基)-1-氧-8-氮杂螺环[4.5]癸-3-亚基)氨基)氧基)甲基)-4-异丙氧基苯甲酸,为白色固体。1H NMR(500MHz,CDCl3)δ8.04-7.93(m,2H),7.45-7.38(m,2H),7.36-7.30(m,1H),6.90(d,J=8.6Hz,1H),5.14(s,2H),4.74-4.63(m,1H),4.50(s,2H),3.44(s,2H),2.68-2.39(m,4H),2.30-2.18(m,1H),1.80-1.59(m,4H),1.38(d,J=6.0Hz,6H),1.31-1.21(m,4H),1.15-1.06(m,2H).LCMS:628.2[M+H]+
类似的可以用对应的中间体合成以下的化合物
药理实施例
本发明化合物的FXR激动活性的体外测试
Huh7细胞培养于含10%FBS的DMEM培养液。细胞接种至10cm细胞培养皿。待增殖至约90%满时,以脂质体Lipofectamine 2000(40μl)共转染人FXR真核表达质粒EX-T0601-M02(1.6μg)以及含FXR应答序列驱动的报告基因质粒FXR-Luc(14.4μg)。操作步骤按照Lipofectamine 2000说明书进行。转染次日,以无酚红DMEM培养液(含5%Charcoaltreated FBS(活性碳处理FBS))接种至96孔细胞培养板,接种密度为每孔20000细胞,体积为每孔135μl。接种6h后细胞贴壁。溶解于DMSO中的化合物以无酚红DMEM培养液(含5%Charcoal treated FBS)稀释20倍至10倍终浓度后加入细胞孔,每孔15μl,即化合物再次被稀释10倍达到终浓度。设置阳性对照为OCA(10μM),空白对照为0.5%DMSO。完成加药后,细胞在37℃,5%CO2培养箱中过夜培养(16h)。孵育完成后,弃培养液,每孔加入无血清无酚红DMEM培养液35μl,每孔加入35μl,室温避光震荡10min后,用Flexstation检测化学发光值。
化合物的激动活性计算方法如下:效果%=(化合物-空白对照)/(阳性对照-空白对照)×100%。
化合物的EC50以GraphPad Prism 5.0拟合化合物的激动活性和化合物浓度的对数值获得。EC50值越低,说明活性越好。
化合物 | 活性 | 化合物 | 活性 |
1 | B | 20 | B |
2 | A | 21 | C |
3 | B | 22 | C |
4 | B | 23 | C |
5 | B | 24 | C |
6 | A | 25 | B |
7 | B | 26 | C |
8 | B | 27 | A |
9 | A | 28 | B |
10 | A | 29 | C |
11 | B | 30 | C |
12 | A | 31 | A |
13 | A | 32 | C |
14 | A | 33 | C |
15 | C | 34 | C |
16 | C | 35 | C |
17 | C | 36 | C |
18 | C | 37 | C |
19 | B | 38 | B |
注:A:<250nM;B:250-500nM:C:>500nM
从上述结果中可以看出,本发明的大多数化合物对FXR激动的EC50达到500nM以下,显示出了较好的FXR激动活性质,具备较佳的临床应用前景。
尽管已根据各种实施例/实施方案描述了所要求保护的主题,但本领域技术人员将认识到,可在不脱离本发明精神的情况下进行各种修改/修饰、替换、删减和改变/变化。因此,所要求保护的主题的范围仅由所附权利要求的范围限定,包括其等同物。
Claims (11)
2.根据权利要求1所述的化合物或其可药用盐,或它们的混合物,其中,R2是二氯苯基。
4.根据权利要求3所述的化合物或其可药用盐,或它们的混合物,其中,R11和R15各自独立地选自氢、氘、卤素、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷氧基、氰基。
5.根据权利要求3所述的化合物或其可药用盐,或它们的混合物,其中,
R11和R15之一为H;和/或
R12、R13、R14之一为羧基或羧基C1-C3烷基,另外两个各自独立地选自氢、氘、卤素、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷氧基;和/或
R11、R12、R13、R14、R15中至少三个为H。
8.一种药物组合物,其包含治疗有效量的选自根据权利要求1-7任一项中所述的化合物、其可药用盐中的一种或多种,以及任选地,药学上可接受的载体。
10.根据权利要求1-7任一项中所述的化合物或其可药用盐,或它们的混合物的用途,所述用途选自:在制备FXR激动剂中的用途;在制备用于预防或治疗由FXR介导的疾病的药物中的用途。
11.根据权利要求10所述的用途,其中,所述由FXR介导的疾病包括非酒精性脂肪性肝病和原发性胆汁性胆管炎。
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