CN116947756A - 环丁烯二酮基喹啉类化合物及其制备方法、药物组合物和应用 - Google Patents
环丁烯二酮基喹啉类化合物及其制备方法、药物组合物和应用 Download PDFInfo
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- CN116947756A CN116947756A CN202310963192.5A CN202310963192A CN116947756A CN 116947756 A CN116947756 A CN 116947756A CN 202310963192 A CN202310963192 A CN 202310963192A CN 116947756 A CN116947756 A CN 116947756A
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- cyclobutenedione
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Classifications
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
Abstract
本发明公开了一种环丁烯二酮基喹啉类化合物及其制备方法、药物组合物和应用。该类化合物结构如式(I),还包含其药学上可接受的盐,其可有效抑制P2Y14受体,进而发挥对肝纤维化、药物性肝损伤、溃疡性结肠炎的疗效;体内外活性显著,应用广泛;制备方法简便易行,对目标化学结构的通用性强。
Description
技术领域
本发明涉及一种环丁烯二酮基喹啉类化合物及制备方法、药物组合物和应用,尤其涉及一种具有P2Y14受体抑制活性的环丁烯二酮基喹啉类化合物及其制备方法、药物组合物和应用。
背景技术
P2Y14受体(P2Y14R)是P2Y受体的成员之一,其被尿苷5'-二磷酸葡萄糖(UDPG)和其他内源性UDP-糖类特异性激活后,可通过Gi/o蛋白抑制腺苷酸环化酶(AC),从而减少细胞内3',5'-环腺苷单磷酸(cAMP)的产生。P2Y14R在心脏,胎盘,脂肪组织,胃肠道,骨髓,胸腺等组织和器官中广泛表达,在免疫系统中尤其明显。
当P2Y14R激活时,能够促进肥大细胞释放介质和肾闰细胞炎症,提高小神经胶质细胞的超敏性和中性粒细胞的趋动性;并且能够抑制星形胶质细胞释放金属蛋白酶和肿瘤坏死因子。因此,在炎症环境中,P2Y14R的高水平表达表明其可能发挥着免疫调节的重要作用。
P2Y14R激活与细胞内cAMP含量密切相关,而cAMP能阻止NLRP3炎性小体的活化,因此P2Y14R可能通过NLRP3炎性小体对炎症反应进行调控。在慢性肝病中,纤维化是决定预后的主要因素,但缺乏有效的抗纤维化治疗。研究表明,P2Y14R诱导的ERK的激活是肝星状细胞的促纤维化作用的主要原因。
目前已报道的P2Y14R受体抑制剂结构存在着溶解性差、代谢稳定性不理想等缺点,限制了其后续的成药性研究。
发明内容
发明目的:本发明的第一目的是提供一种环丁烯二酮基喹啉类化合物,第二目的是提供一种所述化合物的制备方法,第三目的是提供一种包含所述化合物的药物组合物,第四目的是提供一种所述化合物及其药物组合物在制备P2Y14受体抑制剂药物中的应用。
技术方案:本发明所述的环丁烯二酮基喹啉类化合物具有式(I)的结构,还包含其药学上可接受的盐:
其中:
R选自3-6元环烷基、5-8元桥环烷基、苯环、4-6元含有1-2个N、O、S杂原子的杂环基、5-6元含有1-3个N、O、S杂原子的杂芳基;所述苯环被选自以下任一的取代基取代:氢、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、C1-C4烷氨基、卤素、羟基、硝基、氰基、氨基、巯基。
优选,所述结构中:
R选自3-5元环烷基、苯环、5-6元含有1-2个N、O杂原子的杂环基、5-6元含有1-2个N、O、S杂原子的杂芳基;所述苯环被选自以下任一的取代基取代:氢、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、卤素、羟基、硝基、氰基。
优选,所述结构中:
R选自环丙烷、环丁烷、环戊烷、环己烷、吡咯环、吡唑环、咪唑环、噻吩环、噻唑环、恶唑环、呋喃环、吡喃环、哌啶环、哌嗪环、吡啶环、吡嗪环、苯环,更优选自环丙烷、环丁烷、环戊烷、环己烷、苯环;所述苯环被选自以下任一的取代基取代:氢、甲基、乙基、丙基、异丙基、丁基、叔丁基、异丁基、甲氧基、氟、氯、硝基、三氟甲基、三氟甲氧基,更优选自氢、甲基、乙基、甲氧基。
优选,所述结构中:
苯环上的取代基与亚氨基处于对位或间位,更优选自对甲苯基、间甲苯基、对甲氧苯基、间甲氧苯基、对乙苯基、间乙苯基。
具体地,本发明所述的环丁烯二酮基喹啉类化合物优选自以下任一化合物:
环丁烯二酮基喹啉是现代药物发现中的重要药效团,其具有低毒性,高生物利用度,良好生物相容性和疗效,因此在化学、医学、生物学和材料科学等众多领域得到了广泛应用。利用活性叠加原理,在小分子药物中引入环丁烯二酮基喹啉基团后,其活性得到显著提升。
本发明的化合物设计时以提高成药性为导向,通过引入环丁烯二酮基喹啉的全新结构,进一步了增强抑制剂的活性,且化合物的溶解性和代谢稳定性得到提高。
进一步地,所述药学上可接受的盐为所述环丁烯二酮基喹啉类化合物与选自以下任一的酸所形成的盐:盐酸、氢溴酸、硫酸、磷酸、碳酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸、阿魏酸。
本发明所述的环丁烯二酮基喹啉类化合物的制备方法,包含以下步骤:
将化合物(II)与化合物(III)进行缩合反应,得到化合物(I);
更具体的方法如下:
其中,R的定义如前所述;
将相应的酸与以上方法制备的化合物(I)成盐,即得所述化合物的药学上可接受的盐。
本发明所述的环丁烯二酮基喹啉类化合物以及药学上可接受的载体构成本发明所述的药物组合物。具体通过添加香料、甜味剂、液体/固体填料、稀释剂等常用药用辅料制成常见的药用制剂,如片剂、胶囊、糖浆、悬浮剂或注射剂。
本发明所述的环丁烯二酮基喹啉类化合物或其药物组合物应用于P2Y14受体抑制剂药物的制备,所述药物具体为治疗肝纤维化、药物性肝损伤、溃疡性结肠炎的药物。
有益效果:与现有技术相比,本发明具有如下显著优点:
该类化合物可有效抑制P2Y14受体(抑制IC50值达到纳摩尔浓度水平,最优小于5nM),进而发挥对肝纤维化、药物性肝损伤、溃疡性结肠炎的疗效;体内外活性显著,应用广泛;制备方法简便易行,对目标化学结构的通用性强。
附图说明
图1化合物HDB-18对P2Y14R的抑制IC50值;
图2为总胆管结扎术后14天小鼠血清ALT、AST水平结果图;
图3为总胆管结扎术后14天小鼠肝组织HE染色图;
图4为总胆管结扎术后14天小鼠肝组织Masson染色图。
图5为对乙酰氨基酚腹腔注射后24h小鼠血清ALT、AST水平结果图;
图6为对乙酰氨基酚腹腔注射后24h小鼠肝组织HE染色图;
图7为HDB-18干预对DSS诱导的溃疡性结肠炎小鼠疾病活动指数影响结果图;
图8为HDB-18干预对DSS诱导的溃疡性结肠炎小鼠结肠长度影响结果图;
图9为HDB-18干预对DSS诱导的溃疡性结肠炎小鼠结肠长度影响的代表性图像;
图10为HDB-18干预对DSS诱导的溃疡性结肠炎小鼠结肠组织病理学影响结果图。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
实施例1:3-(喹啉-6-氨基)-4-(对甲苯氨基)环丁-3-烯-1,2-二酮的合成
将1.34g喹啉-6-胺溶于甲醇中,加入1.42g 3,4-二甲氧基环丁烷-3-烯-1,2-二酮,并将混合物室温搅拌24h。当反应完成时,用水和乙酸乙酯萃取粗产物。有机相用无水硫酸钠干燥并在减压下旋干。产物通过硅胶柱色谱法纯化,用二氯甲烷:甲醇(50:1)洗脱,得到3-(喹啉-6-基氨基)-4-甲氧基环丁-3-烯-1,2-二酮。
将0.642g对甲苯胺溶于甲醇中,加入0.642g 3-(喹啉-6-基氨基)-4-甲氧基环丁-3-烯-1,2-二酮,4.28g 1-羟基苯并三唑,并将混合物65℃搅拌24小时。当反应完成时,用水和乙酸乙酯萃取粗产物。有机相用无水硫酸钠干燥并在减压下旋干。产物通过硅胶柱色谱法纯化,用二氯甲烷:甲醇(100:1)洗脱,得到3-(喹啉-6-氨基)-4-(对甲苯氨基)环丁-3-烯-1,2-二酮。
核磁数据如下:
1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),9.91(s,1H),8.81(s,1H),8.31(s,1H),7.97(t,J=19.0Hz,3H),7.53(s,1H),7.37(s,2H),7.18(s,2H),2.27(s,3H).
13C NMR(101MHz,DMSO-d6)δ166.63,149.26,144.46,137.33,136.41,136.28,133.18,130.24,129.03,123.33,122.63,119.25,114.57,20.83.
实施例2:3-(喹啉-6-氨基)-4-(间甲苯氨基)环丁-3-烯-1,2-酮的合成
以间甲基苯胺为原料,合成方法参见实施例1。
核磁数据如下:
1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),9.91(s,1H),8.79(s,1H),8.27(d,J=8.2Hz,1H),8.01(d,J=8.6Hz,1H),7.98-7.86(m,2H),7.53-7.43(m,1H),7.26(d,J=16.3Hz,3H),6.90(s,1H),2.30(s,3H).
13C NMR(101MHz,DMSO-d6)δ166.61,165.80,149.42,144.74,139.23,138.83,137.21,136.01,130.54,129.69,128.98,124.68,123.18,122.60,119.65,116.31,114.62,21.62.
实施例3:3-((4-甲氧基苯基)氨基)-4-(喹啉-6-氨基)环丁-3-烯-1,2-二酮的合成
以对甲氧基苯胺为原料,合成方法参见实施例1。
核磁数据如下:
1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),9.86(s,1H),8.77(s,1H),8.25(s,1H),8.05-7.83(m,3H),7.43(d,J=59.7Hz,3H),6.93(s,2H),3.71(s,3H).
13C NMR(101MHz,DMSO-d6)δ181.67,166.49,165.24,156.24,149.37,137.25,135.84,131.99,130.57,128.95,123.07,122.54,120.80,114.98,114.43,55.75.
实施例4:3-(3-甲氧基苯基)氨基)-4-(喹啉-6-氨基)环丁-3-烯-1,2-酮的合成
以间甲氧基苯胺为原料,合成方法参见实施例1。
核磁数据如下:
1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.96(s,1H),8.25(s,1H),8.01(s,1H),7.92(d,J=26.4Hz,2H),7.49(s,1H),7.25(s,2H),6.98(s,1H),6.65(s,1H),3.77(s,3H).
13C NMR(101MHz,DMSO-d6)δ182.12,166.41,165.88,160.61,149.57,145.03,140.10,137.02,135.67,130.74,130.67,128.89,122.97,122.54,114.61,111.13,109.57,104.74,55.56.
实施例5:3-(喹啉-6-氨基)-4-(对甲苯氨基)环丁-3-烯-1,2-二酮的合成
以邻乙基苯胺为原料,合成方法参见实施例1。
核磁数据如下:
1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.94(s,1H),8.83-8.74(m,1H),8.28(d,J=8.3Hz,1H),8.02(d,J=9.0Hz,1H),7.97-7.88(m,2H),7.51(s,1H),7.39(d,J=7.8Hz,2H),7.20(d,J=7.9Hz,2H),2.56(d,J=7.6Hz,2H),1.15(s,3H).
13C NMR(101MHz,DMSO-d6)δ182.57,166.55,165.54,149.30,144.61,139.53,137.24,136.55,136.02,130.44,129.01,123.16,122.56,119.25,114.51,27.95,16.08.
实施例6:3-(喹啉-6-氨基)-4-(间乙苯氨基)环丁-3-烯-1,2-二酮的合成
以间乙基苯胺为原料,合成方法参见实施例1。
核磁数据如下:
1H NMR(400MHz,DMSO-d6)δ10.16(s,1H),9.95(s,1H),8.78(s,1H),8.26(d,J=8.1Hz,1H),8.04-7.86(m,3H),7.49(s,1H),7.32(d,J=31.8Hz,3H),6.94(s,1H),2.61(s,2H),1.20(s,3H).
13C NMR(101MHz,DMSO-d6)δ182.47,182.15,166.58,165.75,149.55,145.52,145.02,138.85,137.10,135.66,130.74,129.69,128.91,123.48,122.97,122.54,118.43,116.49,114.55,28.60,15.74.
实施例7:3-(喹啉-6-氨基)-4-(环丁基氨基)环丁-3-烯-1,2-酮的合成
以环丁烷胺为原料,合成方法参见实施例1。
核磁数据如下:
1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),8.75(dd,J=4.1,1.6Hz,1H),8.22(dd,J=8.4,1.6Hz,1H),7.99(s,1H),7.97(s,1H),7.92-7.79(m,2H),7.47(dd,J=8.3,4.1Hz,1H),4.56(q,J=8.4Hz,1H),2.32(d,J=8.9Hz,2H),2.07(pd,J=9.4,2.7Hz,2H),1.73-1.62(m,2H).
13C NMR(101MHz,DMSO-d6)δ184.47,180.82,168.81,163.58,149.25,144.80,137.47,135.52,130.70,129.02,122.77,122.48,113.73,49.25,32.08,14.43.
实施例8:3-(喹啉-6-氨基)-4-(环戊基氨基)环丁-3-烯-1,2-酮的合成
以环戊烷胺为原料,合成方法参见实施例1。
核磁数据如下:
1H NMR(400MHz,DMSO-d6)δ9.80(s,1H),8.74(dd,J=4.2,1.7Hz,1H),8.20(d,J=7.6Hz,1H),7.96(d,J=9.0Hz,1H),7.88(s,1H),7.83(dd,J=9.0,2.5Hz,1H),7.77(d,J=8.1Hz,1H),7.45(dd,J=8.3,4.1Hz,1H),4.41(p,J=6.6Hz,1H),1.96(dt,J=12.2,6.7Hz,2H),1.73-1.66(m,2H),1.63-1.52(m,4H).
13C NMR(101MHz,DMSO-d6)δ180.59,169.31,163.67,149.23,144.76,137.54,135.51,130.71,129.04,122.73,122.50,113.64,56.06,34.18,23.62.
实施例9:3-(环丙基氨基)-4-(喹啉-6-氨基)环丁-3-烯-1,2-酮的合成
以环丙烷胺为原料,合成方法参见实施例1。
核磁数据如下:
1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.75(dd,J=4.2,1.6Hz,1H),8.21(d,J=8.2Hz,1H),7.97(d,J=9.0Hz,1H),7.86(d,J=2.5Hz,1H),7.82(dd,J=9.0,2.6Hz,1H),7.47(dd,J=8.3,4.1Hz,1H),3.13(tt,J=7.1,3.7Hz,1H),0.79(h,J=5.0Hz,2H),0.68(q,J=5.2,4.2Hz,2H).
13C NMR(101MHz,DMSO-d6)δ181.25,171.03,164.11,149.24,144.79,137.49,135.52,130.62,128.98,122.81,122.47,113.72,26.54,7.50.
实施例10:3-(双环[1.1.1]戊-1-基氨基)-4-(喹啉-6-基氨基)环丁-3-烯-1,2-二酮的合成
以双环[1.1.1]戊烷-1-胺为原料,合成方法参见实施例1。
核磁数据如下:
1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),8.85(dd,J=7.5,1.5Hz,1H),8.53(dd,J=7.6,1.4Hz,1H),8.22(dt,J=7.5,1.5Hz,1H),7.72(d,J=7.5Hz,1H),7.38(t,J=7.5Hz,1H),6.93(t,J=1.5Hz,1H),2.46(hept,J=7.0Hz,1H),2.02(dd,J=13.0,7.0Hz,3H),1.89(dd,J=13.0,7.0Hz,3H).
13C NMR(101MHz,DMSO-d6)δ184.59,183.43,150.12,149.48,147.77,142.16,134.72,133.40,129.84,128.17,124.24,121.24,116.21,61.95,52.59,26.34.
实施例11:3-(环己基氨基)-4-(喹啉-6-氨基)环丁-3-烯-1,2-酮的合成
以环戊烷胺为原料,合成方法参见实施例1。
核磁数据如下:
1H NMR(400MHz,DMSO-d6)δ9.85(s,1H),8.73(dd,J=4.1,1.7Hz,1H),8.19(d,J=8.2Hz,1H),7.96(d,J=8.9Hz,1H),7.88(s,1H),7.84(d,J=8.7Hz,1H),7.75(d,J=8.0Hz,1H),7.45(dd,J=8.3,4.2Hz,1H),3.86(s,1H),1.97-1.89(m,2H),1.70(dd,J=9.3,4.4Hz,2H),1.55(d,J=11.9Hz,1H),1.33(p,J=12.1Hz,4H),1.19(d,J=9.6Hz,1H).
13C NMR(101MHz,DMSO-d6)δ184.40,180.54,169.14,163.69,149.22,144.76,137.55,135.50,130.71,129.04,122.73,122.49,113.65,53.14,34.03,25.16,24.47.
实施例12:化合物对P2Y14受体的抑制活性评价
稳定表达P2Y14R的HEK293细胞株(购自Keygen Biotech公司)培养于DMEM高糖培养基中(含10%胎牛血清),实验前约24h接种至384孔培养板,接种密度为1×104个细胞/孔,细胞于37℃、95%O2、5%CO2湿度条件下培养。实验前弃去培养基,改用无血清DMEM高糖培养基,加入IBMX(500μM)和Ro 20-1724(100μM)抑制PDEs活性,以保证cAMP在较高水平。采用AC激动剂Forskolin(10μM)刺激细胞cAMP的产生,预先加入不同浓度的环丁烯二酮基喹啉类化合物(0.01、0.1、1、10、100nM),以PPTN(CAS号:1160271-30-6)作为阳性对照。同时加入10μM的P2Y14受体激动剂UDPG,30min后根据cAMP GloTMAssay试剂盒(PROMEGACo.Ltd,美国)说明书步骤检测细胞内cAMP的含量。根据cAMP含量计算IC50值和抑制率,结果见表1和图1。
表1化合物对P2Y14受体的抑制活性
ND:Not Detected
结果显示,(3)号化合物(以下命名为HDB-18)抑制率为120.90%,IC50值为2.304nM。
实施例13:化合物对缓解肝纤维化的研究
雄性C57BL/6小鼠,6-8周,体重20-25g,自由水食,每天12h照明,环境温度为25±2℃。将小鼠随机分为5组:对照组、模型组、阳性药组(异甘草酸镁20mg/kg)、HDB-18低剂量组(HDB-18,10mg/kg)、HDB-18高剂量组(HDB-18,20mg/kg),每组8只。利用胆总管结扎术构建小鼠肝纤维化模型,开腹后分离胆总管,用5-0丝线结扎两次,除假手术组不结扎外,其他步骤与模型组相同;在胆管结扎后第2天时,治疗组每天腹腔注射给药1次,假手术组注射同等剂量生理盐水,直到造模结束;14天后摘眼球取血用ALT、AST试剂盒测定血清ALT、AST水平,处死小鼠以获取肝组织固定用于HE染色和Masson染色。
结果如图2所示,HDB-18治疗后可显著改善肝纤维化小鼠肝功能。###P<0.001,与对照组比较;***P<0.001,与模型组比较。如图3、4显示,HDB-18治疗后可显著减轻肝纤维化小鼠的肝细胞坏死程度和炎性细胞的浸润,且可显著减轻肝纤维化小鼠的肝纤维化程度(蓝色为胶原纤维)。
实施例14:化合物对缓解药物性肝损伤的研究
雄性C57BL/6小鼠,6-8周,体重20-25g,自由水食,每天12h照明,环境温度为25±2℃。将小鼠随机分为5组:对照组,模型组,阳性药组(异甘草酸镁20mg/kg),HDB-18低剂量组(HDB-18,10mg/kg)、HDB-18高剂量组(HDB-18,20mg/kg),每组8只。小鼠禁食16h后利用对乙酰氨基酚(350mg/kg)一次性腹腔注射构建药物性肝损伤模型,注射后观察动物状态。对乙酰氨基酚腹腔注射前1h治疗组给予治疗药物,正常对照组注射同等剂量生理盐水。对乙酰氨基酚腹腔注射后24h摘眼球取血,测定血清ALT、AST水平,处死小鼠以获取肝组织固定用于HE染色。
结果如图5、6显示,HDB-18治疗后可显著改善药源性肝损伤小鼠肝功能。###P<0.001,与对照组比较;**P<0.01,***P<0.001,与模型组比较。HDB-18治疗后可显著减轻药源性肝损伤小鼠的肝细胞坏死程度和炎性细胞的浸润。
实施例15:化合物对缓解DSS诱导的溃疡性结肠炎的研究
雄性C57BL/6小鼠,6-8周,体重20-25g,自由水食,每天12h照明,环境温度为25±2℃。将小鼠随机分为5组:对照组、模型组、阳性药组(美沙拉嗪50mg/kg)、HDB-18低剂量组(HDB-18,50μM)、HDB-18高剂量组(HDB-18,100μM),每组8只。除对照组小鼠自由饮用蒸馏水外,模型组及各给药组小鼠自由饮用3.5%DSS溶液7天,且每隔2天更换一次新配制的DSS溶液。造模期间,阳性对照组采用灌胃给药,HDB-18组采用直肠给药,每日记录各组小鼠体重、粪便硬度及直肠出血情况,对各组小鼠进行疾病活动指数评分。第8天处死小鼠取肛门至盲肠末端的整段结肠,测量结肠长度,收集远端结肠组织固定进行病理学检测。
结果如图7所示,HDB-18治疗后可显著降低小鼠疾病活动指数。如图8、9所示,HDB-18治疗后显著抑制小鼠结肠长度缩短。##P<0.01,###P<0.001,与对照组比较;**P<0.01,***P<0.001,与模型组比较。图10所示,HDB-18治疗后小鼠结肠组织隐窝结构相对完整。
Claims (10)
1.一种环丁烯二酮基喹啉类化合物,其特征在于,具有式(I)的结构,还包含其药学上可接受的盐:
其中:
R选自3-6元环烷基、5-8元桥环烷基、苯环、4-6元含有1-2个N、O、S杂原子的杂环基、5-6元含有1-3个N、O、S杂原子的杂芳基;所述苯环被选自以下任一的取代基取代:氢、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、C1-C4烷氨基、卤素、羟基、硝基、氰基、氨基、巯基。
2.根据权利要求1所述的环丁烯二酮基喹啉类化合物,其特征在于,所述结构中:
R选自3-5元环烷基、苯环、5-6元含有1-2个N、O杂原子的杂环基、5-6元含有1-2个N、O、S杂原子的杂芳基;所述苯环被选自以下任一的取代基取代:氢、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、卤素、羟基、硝基、氰基。
3.根据权利要求1所述的环丁烯二酮基喹啉类化合物,其特征在于,所述结构中:
R选自环丙烷、环丁烷、环戊烷、环己烷、吡咯环、吡唑环、咪唑环、噻吩环、噻唑环、恶唑环、呋喃环、吡喃环、哌啶环、哌嗪环、吡啶环、吡嗪环、苯环;所述苯环被选自以下任一的取代基取代:氢、甲基、乙基、丙基、异丙基、丁基、叔丁基、异丁基、甲氧基、氟、氯、硝基、三氟甲基、三氟甲氧基。
4.根据权利要求1所述的环丁烯二酮基喹啉类化合物,其特征在于,所述结构中:
苯环上的取代基与亚氨基处于对位或间位。
5.根据权利要求1所述的环丁烯二酮基喹啉类化合物,其特征在于,选自以下任一化合物:
6.根据权利要求1所述的环丁烯二酮基喹啉类化合物,其特征在于,所述药学上可接受的盐为所述化合物与选自以下任一的酸所形成的盐:盐酸、氢溴酸、硫酸、磷酸、碳酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸、阿魏酸。
7.一种权利要求1所述的环丁烯二酮基喹啉类化合物的制备方法,其特征在于,包含以下步骤:
将化合物(II)与化合物(III)进行缩合反应,得到化合物(I);
其中,R的定义如权利要求1所述;
将相应的酸与以上方法制备的化合物(I)成盐,即得所述化合物的药学上可接受的盐。
8.一种药物组合物,其特征在于,包含权利要求1所述的环丁烯二酮基喹啉类化合物以及药学上可接受的载体。
9.一种权利要求1所述的环丁烯二酮基喹啉类化合物或权利要求8所述的药物组合物在制备P2Y14受体抑制剂药物中的应用。
10.根据权利要9所述的应用,其特征在于,所述药物为治疗肝纤维化、药物性肝损伤、溃疡性结肠炎的药物。
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