CN111763173A - 苯乙基咪唑类衍生物及其用途 - Google Patents
苯乙基咪唑类衍生物及其用途 Download PDFInfo
- Publication number
- CN111763173A CN111763173A CN202010671930.5A CN202010671930A CN111763173A CN 111763173 A CN111763173 A CN 111763173A CN 202010671930 A CN202010671930 A CN 202010671930A CN 111763173 A CN111763173 A CN 111763173A
- Authority
- CN
- China
- Prior art keywords
- methanone
- imidazol
- alkyl
- phenylethyl
- cyclopropyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000004840 phenethylimidazoles Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 30
- 102100025353 G-protein coupled bile acid receptor 1 Human genes 0.000 claims abstract description 25
- 101000857733 Homo sapiens G-protein coupled bile acid receptor 1 Proteins 0.000 claims abstract description 25
- -1 phenylimidazole amide Chemical class 0.000 claims abstract description 22
- IGRCWJPBLWGNPX-UHFFFAOYSA-N 3-(2-chlorophenyl)-n-(4-chlorophenyl)-n,5-dimethyl-1,2-oxazole-4-carboxamide Chemical compound C=1C=C(Cl)C=CC=1N(C)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl IGRCWJPBLWGNPX-UHFFFAOYSA-N 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 239000000651 prodrug Substances 0.000 claims abstract description 13
- 229940002612 prodrug Drugs 0.000 claims abstract description 13
- 239000012453 solvate Substances 0.000 claims abstract description 11
- 150000004677 hydrates Chemical class 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- FUKYBSBCLLWVBB-UHFFFAOYSA-N (4-cyclopropyl-2,3-dihydroquinoxalin-1-yl)-[3-[(2,4-dichlorophenyl)methyl]imidazol-4-yl]methanone Chemical compound C1(CC1)N1CCN(C2=CC=CC=C12)C(=O)C1=CN=CN1CC1=C(C=C(C=C1)Cl)Cl FUKYBSBCLLWVBB-UHFFFAOYSA-N 0.000 claims description 3
- XZSMYYVGVXAOKM-UHFFFAOYSA-N (4-cyclopropyl-2,3-dihydroquinoxalin-1-yl)-[3-[(2,4-difluorophenyl)methyl]imidazol-4-yl]methanone Chemical compound C1(CC1)N1CCN(C2=CC=CC=C12)C(=O)C1=CN=CN1CC1=C(C=C(C=C1)F)F XZSMYYVGVXAOKM-UHFFFAOYSA-N 0.000 claims description 3
- UCUFXJBDIPVFGI-UHFFFAOYSA-N (4-cyclopropyl-2,3-dihydroquinoxalin-1-yl)-[3-[(2,5-dichlorophenyl)methyl]imidazol-4-yl]methanone Chemical compound C1(CC1)N1CCN(C2=CC=CC=C12)C(=O)C1=CN=CN1CC1=C(C=CC(=C1)Cl)Cl UCUFXJBDIPVFGI-UHFFFAOYSA-N 0.000 claims description 3
- YOYFGBZPWLVCSH-UHFFFAOYSA-N (4-cyclopropyl-2,3-dihydroquinoxalin-1-yl)-[3-[(4-fluorophenyl)methyl]imidazol-4-yl]methanone Chemical compound C1(CC1)N1CCN(C2=CC=CC=C12)C(=O)C1=CN=CN1CC1=CC=C(C=C1)F YOYFGBZPWLVCSH-UHFFFAOYSA-N 0.000 claims description 3
- OBUMDWCXRJHJOD-UHFFFAOYSA-N [3-[(2-chlorophenyl)methyl]imidazol-4-yl]-(4-cyclopropyl-2,3-dihydroquinoxalin-1-yl)methanone Chemical compound ClC1=C(CN2C=NC=C2C(=O)N2CCN(C3=CC=CC=C23)C2CC2)C=CC=C1 OBUMDWCXRJHJOD-UHFFFAOYSA-N 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
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- 206010019708 Hepatic steatosis Diseases 0.000 claims description 2
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- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 2
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 13
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Abstract
本发明属于医药技术领域，提供了如通式(Ι)新型苯基咪唑酰胺类衍生物及其几何异构体或其药学上可接受的盐、水合物、溶剂化物、前药和它们的制备方法。本发明的化合物能够激活TGR5活性，能够用于治疗或预防与TGR5活性调节有关的疾病。
Description
技术领域
本发明属药物技术领域，具体涉及一类新型苯基咪唑酰胺类衍生物，以及所述化合物的药学可接受的盐、水合物、溶剂化物或前药，它们的制备方法及其作为治疗TGR5参与的生物病理过程的疾病和病症的药物用途。
背景技术
TGR5受体为胆汁酸膜受体，与2002年Maruyama和Kawamata首次发现，由330个氨基酸组成，包含7个跨膜结构域，属于GPCR家族。TGR5主要分布在胆囊、肠道、脂肪组织、肌肉组织和胆囊中。TGR5在多种生理过程中发挥着重要的调节作用，比如能量代谢、免疫炎症反应、肝胆系统功能、胃肠道系统功能等。
TGR5受体目前在能量代谢的调控方面研究最为充分，肠道TGR5受体的激动可以促进肠道L细胞分泌GLP-1、GLP-2和PYY(peptide tyrosine-tyrosine,由回肠和结肠细胞分泌，能够促进饱腹感)。GLP-1可以促进血糖水平依赖的胰岛素分泌、抑制糖原分解、抑制食欲、减缓胃肠道排空并增加外周组织对于葡萄糖的摄取。PYY水平升高可以增加饱腹感、减少食物摄取。另外TGR5受体调节胰岛α和β细胞的功能，从而起到降糖的效果。胰岛β细胞上TGR5受体的激活可以直接促进胰岛素的分泌，而胰岛α细胞上TGR5受体的激活，通过Epac通路，促进GLP-1的分泌，从而间接地促进胰岛素的分泌。以上研究表明TGR5激动剂在治疗糖尿病、肥胖症等代谢性疾病方面具有潜在的治疗价值。
目前在研的TGR5激动剂，主要包括甾体类和非甾体类化合物。其中甾体类TGR5激动剂中INT-777为选择性的TGR5激动剂，能够在小鼠中增加能量代谢，减少体重的上升，减轻肝脏脂肪的含量，对血糖高及脂肪肝产生有益的治疗效果。但是，甾体类激动剂尚存在选择性较差，具有毒副作用较强等缺点。在研的非甾体类TGR5激动剂主要包括：双取代异噁唑甲酰胺类和氨甲基喹啉类。
本发明人在参考文献的基础上，设计并合成了一系列新型苯基咪唑类衍生物。该类化合物经体外活性测试表明具有较强的TGR5激动活性，且在小鼠试验中能够有效降低血糖水平。
发明内容
本发明的目的是针对现有技术的不足，提供一种新型苯基咪唑酰胺类衍生物，所述化合物的制备方法及其用途。
为实现上述目的，本发明采取的技术方案是：本发明提供一种通式(I)所示的新型苯基咪唑酰胺类衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药；
其中，X选自H、(C1-C6)烷基；
R1选自1-3个羟基、卤素、硝基、氨基、氰基、(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)烷氧基、(C1-C6)烷基硫基、任选被羟基、氨基或卤素取代的(C1-C6)烷基或(C1-C6)烷氧基或(C1-C6)烷基硫基、被单或二(C1-C6烷基)取代的氨基、(C1-C6)烷基酰氨基、游离的、成盐的、酯化的和酰胺化的羧基、(C1-C6)烷基亚磺酰基、(C1-C6)烷基磺酰基、(C1-C6)烷基酰基、氨基甲酰基、被单或二(C1-C6烷基)取代的氨基甲酰基、(C1-C3)亚烷基二氧基；
A环部分选自
R2选自1-3个羟基、卤素、硝基、氨基、氰基、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷基硫基。
本发明优选通式(I)所示的新型苯基咪唑酰胺类衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其中：
X选自H、CH3；
R1选自1-3个羟基、卤素、硝基、氨基、氰基、(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)烷氧基；
A环部分选自
R2选自1-3个羟基、卤素、硝基、氨基、(C1-C6)烷基、(C1-C6)烷氧基。
本发明通式(I)所示的化合物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，优选以下化合物，但这些化合物并不意味着对本发明的任何限制：
(R)-(1-(1-苯乙基)-1H-咪唑-5-基)(4-苯基哌嗪-1-基)甲酮
(R)-(4-(2-氟苯乙基)哌嗪-1-基)(1-(1-苯乙基)-1H-咪唑-5-基)甲酮
(R)-(4-(4-甲氧基苯乙基)哌嗪-1-基)(1-(1-苯乙基)-1H-咪唑-5-基)甲酮
(R)-(4-(2-甲氧基苯乙基)哌嗪-1-基)(1-(1-苯乙基)-1H-咪唑-5-基)甲酮
(R)-(4-环丙基-3,4-二氢喹喔啉-1(2H)-基)(1-(1-苯乙基)-1H-咪唑-5-基)甲酮
(R)-(3,4-二氢喹啉-1(2H)-基)(1-(1-苯乙基)-1H-咪唑-5-基)甲酮
(R)-(2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)(1-(1-苯乙基)-1H-咪唑-5-基)甲酮
(1-苄基-1H-咪唑-5-基)(4-环丙基-3,4-二氢喹喔啉-1(2H)-基)甲酮
(4-环丙基-3,4-二氢喹喔啉-1(2H)-基)(1-(4-氟苄基)-1H-咪唑-5-基)甲酮
(4-环丙基-3,4-二氢喹喔啉-1(2H)-基)(1-(2-氯苄基)-1H-咪唑-5-基)甲酮
(4-环丙基-3,4-二氢喹喔啉-1(2H)-基)(1-(2,4-二氯苄基)-1H-咪唑-5-基)甲酮
(4-环丙基-3,4-二氢喹喔啉-1(2H)-基)(1-(2,5-二氯苄基)-1H-咪唑-5-基)甲酮
(4-环丙基-3,4-二氢喹喔啉-1(2H)-基)(1-(2,4-二氟苄基)-1H-咪唑-5-基)甲酮
而且，按照本发明所属领域的一些通常方法，本发明中通式(I)的部分化合物具有碱性基团，可以与酸生成药学上可接受的盐。可药用加成盐包括无机酸和有机酸加成盐，与下列酸加成的盐是特别优选的：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。最优选为盐酸。
此外，本发明还包括本发明衍生物的前药。本发明衍生物的前药是通式(I)的衍生物，它们自身可能具有较弱的活性甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
通式(I)所示的化合物可以以非溶剂化形式和含有药学上可接受的溶剂(如水、乙醇等)的溶剂化形式。通式(I)所示的化合物可以含有不对称或手性中心，因此可以以不同立体异构形式存在。本发明的所有立体异构形式，包括但不限于非对映异构体、对映异构体和阻转异构体以及它们的混合物(如外消旋混合物)，均包括在本发明的范围内。
通式(I)所示的化合物可以以不同的互变异构体形式存在，所有这些形式均包括在本发明的范围内。术语“互变异构体”或“互变异构形式”是指经由低能垒互相转化的不同能量的结构异构体。
本发明中“卤素”是指氟、氯、溴或碘代；“烷基”是指直链或支链的烷基；吡咯烷基、吗啉基、哌啶基、四氢吡唑烷基、四氢咪唑烷基和四氢噻唑啉基等。
本发明可以含有通式(I)的衍生物，及其药学上可接受的盐、水合物、溶剂化物或前药作为活性成份，与药学上可接受的载体或赋型剂混合制备成组合物，并制备成临床上可接受的剂型，上述药学上可接受的赋型剂是指任何可用于药学领域的稀释剂、辅助剂和/或载体。本发明的衍生物可以与其他活性成份组合使用，只要它们不产生其他不利的作用，例如过敏反应。
本发明的药用组合物可配制成若干种剂型，其中含有药物领域中一些常用的赋形剂。如上所述的若干种剂型可以采用注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用搽剂、软膏剂等剂型药物。
用于本发明药物组合物的载体是药物领域中可得到的常见类型，包括：粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、无色素、矫味剂、防腐剂、加溶剂和基质等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药，如果某些药物在胃部条件下不稳定的，可将其配制成肠衣片剂。
本发明可以含有通式(I)的衍生物可以通过包括化学领域众所周知的方法来合成，尤其根据本发明的说明来合成。
原料一般可以从商业来源例如阿拉丁、达瑞等试剂公司获得或者使用本领域技术人员所熟知的方法来制备。
本发明中室温指环境温度，为10摄氏度至30摄氏度。
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解，下述实例和制备例的范围并不以任何方式限制本发明的范围。按照本发明的式I的化合物，可按照合成路线1-2的方法制备得到。
具体实施例中实施例1-7化合物按照路线1的合成路线进行合成，以依托咪酯1为起始原料，首先在碱性条件下水解得到中间体2，再与各种取代的N-苯基哌嗪或取代的四氢喹喔啉，在缩合剂HATU下，经缩合反应，得到实施例1-7化合物。
路线1.试剂和条件:(a)NaOH,MeOH/H2O,r.t.；(b)HATU,DIEA,DMF,r.t..
具体实施方式中实施例8-13化合物按照路线2的合成路线进行合成，以咪唑-4-甲酸乙酯3为起始原料，首先在碱性条件下与各种取代的溴苄进行亲核取代反应得到中间体4a-f，再在碱性条件下水解得到5a-f，最后再与各种取代的N-苯基哌嗪或取代的四氢喹喔啉，在缩合剂HATU下，经缩合反应，得到实施例8-13化合物。
路线2.试剂和条件:(a)K2CO3,Toluene,0℃；(b)NaOH,MeOH/H2O；(c)HATU,DIEA,DMF,r.t.
本发明的积极进步效果在于：本发明提供了一种新型苯基咪唑酰胺类衍生物，其制备方法、药物组合物和应用。本发明的苯基咪唑酰胺类化合物对TGR5具有较好的激动活性，可以用于治疗或预防与TGR5活性调节有关的疾病中的用途。
附图说明
图1 C57L/6J小鼠单次给药后的OGTT试验。
具体实施方式
不需进一步详细说明，认为本领域熟练技术人员借助于前面的描述，可以最大程度地利用本发明。因此下面提供的实施例旨在阐述而不是限制本发明的范围。
原料一般可以从商业来源获得或者使用本领域技术人员所熟知的方法来制备，或根据本发明所述的方法制备。未经特殊说明，所用试剂均为分析纯或化学纯。化合物结构确证所用质谱用Agilent 1100LC/MSD测定。柱层析纯化产物使用的是青岛海洋化工厂生产的100-200目或者200-300目硅胶。
实施例1：(R)-(1-(1-苯乙基)-1H-咪唑-5-基)(4-苯基哌嗪-1-基)甲酮
步骤1：(R)-1-(1-苯乙基)-1H-咪唑-5-甲酸的合成
将依托咪酯(2.0g,8.19mmol)溶于20mL甲醇中，然后加入5mL2N的氢氧化钠室温搅拌6h。TLC检测反应完成，减压蒸出甲醇，用1N的盐酸调节PH至5-6，析出白色固体，抽滤得(R)-1-(1-苯乙基)-1H-咪唑-5-甲酸1.61g，收率90.1％。
步骤2：(R)-(1-(1-苯乙基)-1H-咪唑-5-基)(4-苯基哌嗪-1-基)甲酮的合成
将(R)-1-(1-苯乙基)-1H-咪唑-5-甲酸(1.0g,4.62mmol)溶于DMF中，然后向溶液中依次加入HATU(2.11g,5.55mmol)、DIEA(1.20g,9.25mmol)和N-苯基哌嗪(0.75g,4.62mmol)，升温至70℃反应。6小时后TLC检测反应完成，将反应液倒入水中，析出固体，过滤得粗品，再经硅胶色谱柱纯化，得类白色粉末状固体0.95g,收率56.7％。1H NMR(400MHz,DMSO-d6)δ8.12(s,1H),7.28(t,J＝7.6Hz,2H),7.23–7.16(m,4H),7.10(d,J＝7.2Hz,2H),6.85(d,J＝8.0Hz,2H),6.80(t,J＝7.3Hz,1H),5.77(q,J＝7.1Hz,1H),3.39-3.34(m,4H),2.94-2.89(m,4H),1.83(d,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ160.42,150.65,142.60,137.66,130.71,128.97(2C),128.65(2C),127.64,126.09(2C),124.88,119.45,115.98(2C),56.04,54.77(2C),48.27(2C),21.20.HRMS calcd for C20H22N3O3SNa,[M+Na]+,383.1848；found383.1842.
按照实施例1的方法，以依托咪酯为原料，经水解后分别与取代的N-取代苯基哌嗪缩合得到实施例2-7
实施例2：(R)-(4-(2-氟苯乙基)哌嗪-1-基)(1-(1-苯乙基)-1H-咪唑-5-基)甲酮
1H NMR(400MHz,CDCl3)δ7.79(s,1H),7.22(dd,J＝13.2,5.5Hz,2H),7.15(t,J＝7.3Hz,1H),7.10(s,1H),7.04(d,J＝7.2Hz,2H),7.01–6.96(m,1H),6.97–6.85(m,2H),6.77–6.64(m,1H),5.86(q,J＝7.1Hz,1H),3.85–3.31(m,4H),2.72-2.70(m,4H),1.81(d,J＝7.1Hz,3H).13C NMR(100MHz,DMSO-d6)δ160.39,142.63,139.39,137.66,130.60,128.72(2C),127.68,126.14(2C),124.88,124.83,122.97,119.54,116.10,115.90,54.85,49.92(2C),49.90(2C),21.24.HRMS calcd for C22H24FN4O,[M+H]+,379.1934；found 379.1947.
实施例3：(R)-(4-(4-甲氧基苯乙基)哌嗪-1-基)(1-(1-苯乙基)-1H-咪唑-5-基)甲酮
1H NMR(400MHz,DMSO-d6)δ8.55(s,1H),7.44(s,1H),7.31(t,J＝7.5Hz,2H),7.21(t,J＝7.3Hz,1H),7.14(d,J＝7.2Hz,2H),6.85–6.77(m,4H),5.80(q,J＝7.0Hz,1H),3.68(s,3H),3.33(s,3H),2.71(d,J＝16.7Hz,4H),1.85(d,J＝7.1Hz,3H).13C NMR(100MHz,DMSO-d6)δ159.76,153.88,145.32,142.21,137.61,129.23(2C),128.39,128.16,126.72(2C),125.63,118.69(2C),114.70(2C),56.14(2C),55.62(2C),50.14(2C),21.64.HRMScalcd for C23H27N4O2,[M+H]+,391.2134；found 391.2127.
实施例4：(R)-(4-(2-甲氧基苯乙基)哌嗪-1-基)(1-(1-苯乙基)-1H-咪唑-5-基)甲酮
1H NMR(400MHz,DMSO-d6)δ8.12(s,1H),7.31(t,J＝7.0Hz,2H),7.22(t,J＝7.0Hz,1H),7.18(s,1H),7.11(d,J＝7.2Hz,2H),7.01–6.81(m,3H),6.73(d,J＝7.5Hz,1H),5.79(q,J＝6.5Hz,1H),3.75(s,3H),3.45–3.31(m,4H),2.76–2.65(m,4H),1.83(d,J＝6.8Hz,3H).13C NMR(100MHz,DMSO-d6)δ160.81,152.42,143.12,141.02,138.05,131.11,129.14(2C),128.10,126.56(2C),125.41,123.40,121.23,118.72,112.29,55.76(2C),55.25(2C),50.35(2C),21.70.HRMS calcd for C23H27N4O2,[M+H]+,391.2134；found 391.2134.
实施例5：(R)-(4-环丙基-3,4-二氢喹喔啉-1(2H)-基)(1-(1-苯乙基)-1H-咪唑-5-基)甲酮
1H NMR(300MHz,DMSO-d6)δ8.11(s,1H),7.38–7.25(m,3H),7.12(d,J＝7.0Hz,3H),6.98(dd,J＝12.0,4.9Hz,1H),6.90(s,1H),6.59(d,J＝7.5Hz,1H),6.43(t,J＝7.6Hz,1H),5.76(q,J＝7.1Hz,1H),4.06–3.90(m,1H),3.43-3.39(m,1H),3.28-3.23(m,1H),2.93-2.89(m,1H),2.44–2.33(m,1H),1.76(d,J＝7.1Hz,3H),0.84–0.78(m,2H),0.57–0.47(m,2H).13CNMR(100MHz,DMSO-d6)δ159.87,142.38,139.56,137.92,132.87,128.69(2C),127.78,126.01(2C),125.74,125.59,124.95,123.65,115.93,112.95,54.93,54.79,48.07,31.12,21.18,7.95,7.52.HRMS calcd for C23H25N4O,[M+H]+,373.2028；found 373.2021.
实施例6：(R)-(3,4-二氢喹啉-1(2H)-基)(1-(1-苯乙基)-1H-咪唑-5-基)甲酮
1H NMR(400MHz,DMSO-d6)δ8.11(s,1H),7.40–7.32(m,2H),7.32–7.26(m,1H),7.18(d,J＝7.2Hz,2H),7.14(d,J＝7.5Hz,1H),6.99(t,J＝7.1Hz,1H),6.86(t,J＝7.3Hz,1H),6.79(s,1H),6.47(d,J＝8.0Hz,1H),5.89(q,J＝7.1Hz,1H),3.84(dt,J＝12.4,6.1Hz,1H),3.41(ddd,J＝12.8,7.4,5.5Hz,1H),2.77–2.58(m,2H),1.83(d,J＝7.2Hz,3H),1.77–1.58(m,2H).13C NMR(100MHz,DMSO-d6)δ161.08,142.43,138.57,137.90,132.94,131.16,128.72(2C),128.55,127.84,126.20,126.16(2C),125.29,124.54,124.27,54.77,44.74,25.94,23.43,21.22.HRMS calcd for C21H22N3O,[M+H]+,332.1763；found 332.1760.
实施例7：(R)-(2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)(1-(1-苯乙基)-1H-咪唑-5-基)甲酮
1H NMR(400MHz,DMSO-d6)δ8.20(s,1H),7.33(t,J＝7.3Hz,2H),7.28(d,J＝7.1Hz,1H),7.24(s,1H),7.19(d,J＝8.0Hz,1H),7.14(d,J＝7.2Hz,2H),7.02–6.94(m,1H),6.87–6.81(m,1H),6.73(t,J＝7.7Hz,1H),5.86(q,J＝7.1Hz,1H),4.21–4.12(m,1H),3.92–3.83(m,1H),3.68–3.47(m,2H),1.85(d,J＝7.1Hz,3H).13C NMR(100MHz,DMSO-d6)δ160.25,145.91,142.56,138.78,133.56,128.73(2C),127.79,126.02(2C),125.40,125.15,125.13,123.68,119.60,116.97,65.38,54.94,44.10,21.30.HRMS calcd forC20H19N3O2Na,[M+Na]+,356.1375；found356.1381.
实施例8-13的合成方法
步骤1乙基1-苄基-1H-咪唑-5-甲酸乙酯的合成
将咪唑-4-甲酸乙酯(2.00g,14.27mmol)和溴苄(2.44g,14.27mmol)溶于30mL甲苯中，然后加入10％的氢氧化钠5mL和四丁基溴化铵(0.78g,2.85mmol)，在室温下反应8h。TLC检测反应完成，减压浓缩，蒸出溶剂。然后加入40mL水，30mL乙酸乙酯萃取，饱和食盐水洗涤有机层，Na2SO4干燥过夜。滤除干燥剂，减压蒸除溶剂，残余物经硅胶柱层析纯化，得g白色固体3.11g，收率82.32％。
步骤2和3按照实施例1的方法，以乙基1-苄基-1H-咪唑-5-甲酸乙酯为原料，经水解后与1-环丙基-1,2,3,4-四氢喹喔啉缩合得到实施例8-13。
实施例8：(1-苄基-1H-咪唑-5-基)(4-环丙基-3,4-二氢喹喔啉-1(2H)-基)甲酮
1H NMR(400MHz,DMSO-d6)δ7.98(s,1H),7.39–7.24(m,3H),7.13(d,J＝7.4Hz,3H),6.99(t,J＝7.7Hz,1H),6.88(s,1H),6.66(d,J＝7.6Hz,1H),6.45(t,J＝7.5Hz,1H),5.35(s,2H),3.74(t,J＝5.2Hz,2H),3.12(t,J＝5.3Hz,2H),2.40(ddd,J＝10.1,6.7,3.7Hz,1H),0.81(q,J＝6.5Hz,2H),0.59–0.46(m,2H).13C NMR(100MHz,DMSO-d6)δ159.77,140.93,139.54,137.51,133.51,128.66(2C),127.80,127.30(2C),125.62,125.01,124.92,123.73,115.90,112.96,48.55,48.06,43.02,31.16,7.73(2C).HRMS calcd for C22H23N4O,[M+H]+,359.1872；found 359.1872.
实施例9：(4-环丙基-3,4-二氢喹喔啉-1(2H)-基)(1-(4-氟苄基)-1H-咪唑-5-基)甲酮
1H NMR(400MHz,DMSO-d6)δ7.98(s,1H),7.27–7.10(m,5H),7.00(t,J＝7.8Hz,1H),6.88(s,1H),6.71–6.63(m,1H),6.46(t,J＝7.5Hz,1H),5.34(s,2H),3.75(t,J＝5.4Hz,2H),3.14(t,J＝5.3Hz,2H),2.43–2.36(m,1H),0.82(q,J＝6.4Hz,2H),0.60–0.49(m,2H).13C NMR(100MHz,DMSO-d6)δ159.76,140.87,139.59,133.76,133.72,133.56,129.70,129.62,125.67,124.94,124.87,123.76,115.93,115.58,115.36,113.00,48.11,47.86,43.04,31.17,7.71(2C).HRMS calcd for C22H22FN4O,[M+H]+,377.1778；found 377.1792.
实施例10：(4-环丙基-3,4-二氢喹喔啉-1(2H)-基)(1-(2-氯苄基)-1H-咪唑-5-基)甲酮
1H NMR(400MHz,DMSO-d6)δ7.98(s,1H),7.25–7.10(m,5H),7.04–6.96(m,1H),6.88(s,1H),6.67(d,J＝7.3Hz,1H),6.46(t,J＝7.3Hz,1H),5.34(s,2H),3.75(t,J＝5.4Hz,2H),3.14(t,J＝5.4Hz,2H),2.44–2.36(m,1H),0.85–0.78(m,2H),0.58–0.52(m,2H).13CNMR(100MHz,DMSO-d6)δ159.54,141.59,139.59,135.06,133.57,131.73,129.51,128.36,127.61,125.92,125.73,125.12,124.77,123.77,115.99,113.04,48.11,46.67,43.17,31.19,7.76(2C).HRMS calcd for C22H22ClN4O,[M+H]+,393.1482；found 393.1476.
实施例11：(4-环丙基-3,4-二氢喹喔啉-1(2H)-基)(1-(2,4-二氯苄基)-1H-咪唑-5-基)甲酮
1H NMR(400MHz,DMSO-d6)δ7.93(s,1H),7.67(d,J＝2.1Hz,1H),7.42(dd,J＝8.4,2.1Hz,1H),7.16(d,J＝8.2Hz,1H),7.01(dd,J＝11.3,4.2Hz,1H),6.96(s,1H),6.88(d,J＝7.9Hz,1H),6.82(d,J＝8.4Hz,1H),6.52(t,J＝7.6Hz,1H),5.47(s,2H),3.81(t,J＝5.3Hz,2H),3.20(t,J＝5.3Hz,2H),2.46–2.36(m,1H),0.88–0.78(m,2H),0.61–0.50(m,2H).13CNMR(100MHz,DMSO-d6)δ159.43,141.60,139.61,134.31,133.66,133.07,132.66,129.78,128.93,127.72,125.75,124.97,124.76,123.82,115.99,113.03,48.14,46.31,43.12,31.19,7.72(2C).HRMS calcd for C22H21Cl2N4O,[M+H]+,427.1092；found 427.1075.
实施例12：(4-环丙基-3,4-二氢喹喔啉-1(2H)-基)(1-(2,5-二氯苄基)-1H-咪唑-5-基)甲酮
1H NMR(400MHz,DMSO-d6)δ7.95(s,1H),7.55(d,J＝8.5Hz,1H),7.44(dd,J＝8.5,2.5Hz,1H),7.16(d,J＝7.9Hz,1H),7.03(t,J＝7.7Hz,1H),6.95(s,1H),6.87(d,J＝7.8Hz,1H),6.76(d,J＝2.4Hz,1H),6.52(t,J＝7.4Hz,1H),5.49(s,2H),3.82(t,J＝5.4Hz,2H),3.25(t,J＝5.4Hz,2H),2.46–2.36(m,1H),0.83(q,J＝6.5Hz,2H),0.62–0.51(m,2H).13CNMR(100MHz,DMSO-d6)δ159.36,141.65,139.68,137.35,133.70,132.11,131.23,130.42,129.26,127.92,125.85,124.95,124.79,123.80,115.94,113.06,48.16,46.48,42.99,31.17,7.71(2C).HRMS calcd for C22H21Cl2N4O,[M+H]+,427.1092；found 427.1082.
实施例13：(4-环丙基-3,4-二氢喹喔啉-1(2H)-基)(1-(2,4-二氟苄基)-1H-咪唑-5-基)甲酮
1H NMR(400MHz,DMSO-d6)δ7.92(s,1H),7.33–7.24(m,1H),7.19–6.98(m,4H),6.89(s,1H),6.76(d,J＝7.3Hz,1H),6.49(t,J＝7.6Hz,1H),5.41(s,2H),3.78(t,J＝5.4Hz,2H),3.19(t,J＝5.3Hz,2H),2.45–2.36(m,1H),0.82(q,J＝6.5Hz,2H),0.56(dd,J＝6.4,3.6Hz,2H).13C NMR(100MHz,DMSO-d6)δ159.51,141.24,139.62,133.25,131.09,130.99,125.74,124.98,124.84,123.71,120.94,120.83,115.96,113.04,111.82,104.17,56.04,48.10,42.53,31.18,7.72(2C).HRMS calcd for C22H21F2N4O,[M+H]+,395.1683；found395.1672.
本发明部分产物的药理研究
一、TGR5激动活性测试
HTRF均相时间分辨荧光技术：稳转细胞株的建立，用构建好的质粒HA-HGR5-pcDNA3.1在HEK293细胞中进行表达。在稳定表达TGR5的细胞株中加入IBMX，按4×103个细胞/孔/5μL细胞密度接种至384孔板，然后加入5μL含不同浓度(0-100μM)的待测化合物，INT-777为阳性对照药，混合均匀，室温下避光孵育30min。然后分别加入稀释好的5μLcAMP-D2和5μL anti-cAMP-Cryptate，离心混合均匀。室温避光反应1h，最后在酶标仪中进行读数，实施例化合物在10和40μM对TGR5的激动率及部分化合物EC50值见表1。
表1实施例化合物对TGR5的激动率及部分化合物EC50值。
如上表所示，本发明通式(I)中的化合物具有较强的TGR5激动活性，部分化合物对TGR5的激动活性明显优于对照药INT-777。
二、降糖活性测试(OGTT实验)
6-8周的C57L/6J小鼠实验前禁食12h，实验组口服30mg/kg的实施例11和12化合物，空白对照采用0.25％的CMC-Na溶液，每组8只小鼠。给药后60min口服葡萄糖(4g/kg)，分别在葡萄糖注射前0,15,30,60,120min后通过尾部取血，测定其血糖值，并计算0-120min内的曲线下面积(AUC0-120 min)。测试结果见图1，其中(A)血糖值随时间变化，(B)血糖AUC0-120min。给药剂量30mg/kg，给药60min后口服4g/kg的葡萄糖，在不同时间点取血测定血糖。*p<0.05.
结果显示：本发明通式(I)中的化合物实施例11和实施例12在OGTT试验中均表现出一定的降糖活性。
Claims (6)
1.一种通式(I)所示的苯基咪唑类衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其特征在于，所述的通式如下：
其中，
X选自H、(C1-C6)烷基；
R1选自1-3个氢、羟基、卤素、硝基、氨基、氰基、(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)烷氧基、(C1-C6)烷基硫基、任选被羟基、氨基或卤素取代的(C1-C6)烷基或(C1-C6)烷氧基或(C1-C6)烷基硫基、被单或二(C1-C6烷基)取代的氨基、(C1-C6)烷基酰氨基、游离的、成盐的、酯化的和酰胺化的羧基、(C1-C6)烷基亚磺酰基、(C1-C6)烷基磺酰基、(C1-C6)烷基酰基、氨基甲酰基、被单或二(C1-C6烷基)取代的氨基甲酰基、(C1-C3)亚烷基二氧基；
A环部分选自
R2选自1-3个氢、羟基、卤素、硝基、氨基、氰基、(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷基硫基。
2.如权利要求1通式(I)所示的苯基咪唑酰胺类衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其特征在于，其中
X选自H、CH3；
R1选自1-3个氢、羟基、卤素、硝基、氨基、氰基、(C1-C6)烷基、(C1-C6)烷氧基；
A环部分选自
R2选自1-3个氢、羟基、卤素、硝基、氨基、氰基、(C1-C6)烷基、(C1-C6)烷氧基。
3.如权利要求1通式(I)所示的苯基咪唑酰胺类衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其特征在于，
其中：
X选自H、CH3；
R1选自1-3个氢、卤素、氨基、(C1-C6)烷基、(C1-C6)烷氧基；
A环部分选自
R2选自1-3个卤素、(C1-C6)烷基、(C1-C6)烷氧基。
4.权利要求1-3任一所述的通式(I)所示的化合物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其特征在于，选自：
(R)-(1-(1-苯乙基)-1H-咪唑-5-基)(4-苯基哌嗪-1-基)甲酮
(R)-(4-(2-氟苯乙基)哌嗪-1-基)(1-(1-苯乙基)-1H-咪唑-5-基)甲酮
(R)-(4-(4-甲氧基苯乙基)哌嗪-1-基)(1-(1-苯乙基)-1H-咪唑-5-基)甲酮
(R)-(4-(2-甲氧基苯乙基)哌嗪-1-基)(1-(1-苯乙基)-1H-咪唑-5-基)甲酮
(R)-(4-环丙基-3,4-二氢喹喔啉-1(2H)-基)(1-(1-苯乙基)-1H-咪唑-5-基)甲酮
(R)-(3,4-二氢喹啉-1(2H)-基)(1-(1-苯乙基)-1H-咪唑-5-基)甲酮
(R)-(2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)(1-(1-苯乙基)-1H-咪唑-5-基)甲酮
(1-苄基-1H-咪唑-5-基)(4-环丙基-3,4-二氢喹喔啉-1(2H)-基)甲酮
(4-环丙基-3,4-二氢喹喔啉-1(2H)-基)(1-(4-氟苄基)-1H-咪唑-5-基)甲酮
(4-环丙基-3,4-二氢喹喔啉-1(2H)-基)(1-(2-氯苄基)-1H-咪唑-5-基)甲酮
(4-环丙基-3,4-二氢喹喔啉-1(2H)-基)(1-(2,4-二氯苄基)-1H-咪唑-5-基)甲酮
(4-环丙基-3,4-二氢喹喔啉-1(2H)-基)(1-(2,5-二氯苄基)-1H-咪唑-5-基)甲酮
(4-环丙基-3,4-二氢喹喔啉-1(2H)-基)(1-(2,4-二氟苄基)-1H-咪唑-5-基)甲酮。
5.如权利要求1-4任一通式(I)所示的苯基咪唑类衍生物在治疗TGR5参与的生物病理过程的疾病和病症中应用。
6.如权利要求5所述的治疗TGR5参与的生物病理过程的疾病和病症，其特征在于，具体为糖尿病、高血糖症、肥胖症、高胆固醇血症、脂质病症或脂肪肝。
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