CN112812052A - 一种治疗溃疡性结肠炎的化合物及其制备方法和用途 - Google Patents
一种治疗溃疡性结肠炎的化合物及其制备方法和用途 Download PDFInfo
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
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Abstract
本发明提供了一种治疗溃疡性结肠炎的化合物,具有式I所示结构。本发明提供的化合物能够显著抑制患结肠炎时结肠组织中TNF‑α、IL‑1β和IL‑6等促炎因子的异常分泌,抑制炎性细胞浸润,维持肠上皮和隐窝腺的完整,能够有效减轻炎症,改善结肠缩短和肠壁增厚症状,在制备治疗溃疡性结肠炎的药物中具有优异的潜在应用价值,为临床提供了新的选择。
Description
技术领域
本发明属于生物医药领域,具体涉及一种治疗溃疡性结肠炎的化合物及其制备方法和用途。
背景技术
溃疡性结肠炎(UC)是炎症性肠病的主要类型之一,是一种主要累及消化系统的慢性炎症性肠道疾病,临床表现为持续或反复发作的腹泻、黏液脓血便伴腹痛、里急后重和不同程度的全身症状。目前,中国溃疡性结肠炎患病率已超过11.6/10万,发病高峰年龄为20~49岁,存在着知晓率低、就诊率低、诊断和治疗水平差异较大、治疗不规范、患者治疗依从性差等诸多问题。
作为一种慢性疾病,溃疡性结肠炎复发率高、临床表现变异性大,患者的10年累积复发率高达70%~80%,近50%患者需要住院治疗,5年再住院率为50%4,确诊后5年和10年的结肠切除率为10%-15%。此外,随着溃疡性结肠炎病变的持续进展、病程迁延不愈,患者的不良预后风险也在不断增加,如结直肠癌风险明显增高5、6、结构性肠损伤7、8、更易抑郁焦虑等。
病程长、症状重、病情复杂反复,溃疡性结肠炎使得患者需要频繁就医和长期治疗,严重影响了患者的工作效率和生活质量,对患者家庭和社会造成了沉重的经济负担。
目前治疗溃疡性结肠炎方法除了一般的饮食生活习惯调整和特殊的手术治疗外,药物治疗主要包括氨基水杨酸类制剂、糖皮质激素和免疫治疗。药物治疗的安全性和有效性方面都有不尽如人意之处,存在如恶心呕吐、食欲减退、头痛、可逆性男性不育和过敏等不良反应,并且预后较差复发率高。随着免疫系统基础研究的不断深入,炎症发生机制相关治疗靶点被不断发现,多种新型靶向药物已经陆续开始应用于治疗,为治疗提供了新思路。
例如,目前已经进入三期临床的新药Etrasimod(APD334),结构为:
Etrasimod是一种口服、选择性的磷酸鞘氨醇受体1调节剂,根据已公布的2期临床研究(OASIS)数据显示,Etrasimod针对中重度活动性溃疡性结肠炎具有良好的有效性、安全性和耐受性。Etrasimod用药后快速起效,用药1周即观察到大便频率和便血症状的改善,治疗12周后除了临床症状的显著改善外,还观察到组织学的明显改善。但Etrasimod临床二期实验发现其临床缓解率仍不高,仅达24.5%~41.8%。因此,进一步研究开发新的、能够有效治疗溃疡性结肠炎的新化合物,具有重要的意义。
发明内容
本发明的目的在于提供一种新的治疗溃疡性结肠炎的化合物。
本发明提供了一种治疗溃疡性结肠炎的化合物,具有式I所示结构:
优选地,上述化合物具有如下所示结构:
本发明还提供了上述化合物的制备方法,包括如下步骤:
步骤(1):化合物1与化合物2在催化剂a和脱水剂的作用下缩合反应,加入催化剂b和缚酸剂进行关环反应,制得化合物3;
步骤(2):化合物3在碱和催化剂的作用下反应,制得化合物4;
步骤(3):化合物4与化合物5在缚酸剂的作用下反应,制得化合物6;
步骤(4):化合物6加碱水解得到式I所示化合物;
合成路线如下:
进一步地,上述步骤(1)所述催化剂a为4-甲基苯磺酸吡啶;所述脱水剂为四乙氧基硅烷;所述缚酸剂选自N,N-二异丙基乙胺、吡啶、三乙胺中的至少一种,优选为N,N-二异丙基乙胺;所述催化剂b选自醋酸钯、氯化钯中的至少一种,优选为醋酸钯;
所述化合物1、化合物2、脱水剂、缚酸剂、催化剂a和催化剂b的摩尔比为:(3~4):(4~5):(4~4.5):(9~10):(0.1~0.2):(0.05~0.1);
优选为3.14:4.72:4.08:9.42:0.13:0.09;
和/或步骤(2)所述碱选自碳酸氢铵、碳酸氢钠、醋酸钠、碳酸氢钾、醋酸钾中的至少一种,优选为碳酸氢铵;所述催化剂选自钯碳催化剂Pd/C;所述化合物3、碱和催化剂的摩尔比为:(0.5~1.5):(2~4):(0.04~0.06),优选为1:3:0.05;
和/或步骤(3)所述缚酸剂选自碳酸铯、碳酸钠、碳酸钾中的至少一种,优选为碳酸铯;所述化合物4、化合物5和缚酸剂的摩尔比为:(1~2):(0.5~1.5):(0.5~1.5);优选为1.2:1:1;
和/或步骤(4)所述碱为氢氧化锂、氢氧化钠、氢氧化钾中的至少一种,优选为氢氧化锂;所述化合物6和碱的摩尔比为:(0.5~1.5):(1~2);优选为1:1.2。
进一步地,上述步骤(1)所述缩合反应为:在有机溶剂中,125~145℃反应2~6小时;优选为:在DMF中,135℃反应4小时;所述关环反应为:在110~130℃反应至TLC监测反应完全;优选为:120℃反应至TLC监测反应完全;
和/或步骤(2)所述反应为:在溶剂中,30~50℃反应至TLC监测反应完全;优选为:在乙醇和水的混合溶剂中,40℃反应至TLC监测反应完全;
和/或步骤(3)所述反应为:在有机溶剂中,20~30℃反应3~4小时;优选为:在DMF中,25℃反应3~4小时;
和/或步骤(4)所述加碱水解为:在有机溶剂中,加入碱的水溶液,20~30℃反应2~4小时;优选为:在二氧六环中,加入氢氧化锂水溶液,25℃反应3小时。
更进一步地,上述步骤(1)还包括如下后处理步骤:冷却至25℃,加水淬灭反应,过滤,乙酸乙酯萃取得有机相,干燥,色谱柱分离纯化;
和/或步骤(2)还包括如下后处理步骤:浓缩除去乙醇,二氯甲烷萃取得有机相,干燥,色谱柱分离纯化;
和/或步骤(3)还包括如下后处理步骤:加水淬灭反应,乙酸乙酯萃取得有机相,饱和食盐水洗涤,浓缩;
和/或步骤(4)还包括如下后处理步骤:调节pH至酸性,浓缩,制备色谱分离纯化。
更进一步地,上述化合物6与甲醇钠反应包括如下步骤:在有机溶液中,加入化合物6的1~2倍摩尔比的甲醇钠,25~35℃反应12~24h;优选地,为在甲醇溶液中,加入化合物6等摩尔比的甲醇钠,30℃反应12~24h。
更进一步地,上述化合物6与甲醇钠反应还包括如下后处理步骤:浓缩,色谱柱分离纯化。
本发明还提供了上述化合物在制备治疗溃疡性结肠炎的药物中的用途,优选的,所述治疗溃疡性结肠炎的药物是减轻结肠炎炎症、改善结肠缩短和/或肠壁增厚的药物。
实验结果表明,本发明化合物能够显著抑制患结肠炎时结肠组织中TNF-α、IL-1β和IL-6等促炎因子的异常分泌,抑制炎性细胞浸润,维持肠上皮和隐窝腺的完整,能够有效改善结肠炎小鼠体重减轻、结肠缩短和肠壁增厚的现象,缓解结肠炎的症状,在制备治疗溃疡性结肠炎的药物中具有优异的潜在应用价值,为临床提供了新的选择。
本发明的术语解释:
DMF为N,N-二甲基甲酰胺;反应式中的Et基团是乙基-CH2CH3。
缚酸剂为:能够结合反应过程中所产生的酸性物质,从而避免酸性物质影响反应进行的化合物。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明所用原料与设备均为已知产品,通过购买市售产品所得。
实施例1、本发明化合物A的制备
合成路线:
制备方法:
将2,5-二氟-4-甲氧基苯胺(500mg,3.14mmol)与2-氧代环戊基乙酸乙酯(802mg,4.72mmol)加入有10mL DMF的圆底烧瓶中,依次加入脱水剂四乙氧基硅烷(850mg,4.08mmol)和催化剂4-甲基苯磺酸吡啶(31mg,0.13mmol),135℃反应4小时后,冷却至120℃,加入DIEA(1.22g,9.42mmol)作缚酸剂,以醋酸钯(20mg,0.09mmol)催化发生关环反应,TLC监测反应完全后,停止反应。冷却至25℃后,反应液加水(10mL)淬灭,经硅藻土过滤后,用乙酸乙酯(10mL*3)萃取3次,合并有机相,无水硫酸钠干燥后经柱色谱分离纯化得化合物3(694.7mg,76%),LCMS m/z=292.2[M+H]+。1H NMR(400MHz,DMSO-d6)δppm 1.22(t,J=7.2Hz,3H),2.01-2.12(m,1H),2.35(dd,J=16.0,8.8Hz,1H),2.52-2.71(m,4H),3.39-3.47(m,1H),3.82(s,3H),4.10-4.22(m,2H),7.09(d,J=8.4Hz,1H),7.20(d,J=2.3Hz,1H),10.35(s,1H)。
将化合物3(600mg,2.06mmol)加入含有乙醇/水(4mL/2mL)混合溶剂的圆底烧瓶中,加入碳酸氢铵(244mg,3.09mmol)和10%Pd/C(109mg,0.10mmol)催化,升温至40℃反应,TLC监测反应完成后,减压浓缩除去乙醇,残留物用二氯甲烷(5mL*3)萃取3次,合并有机相并用无水硫酸钠干燥,过滤,滤液浓缩柱色谱分离纯化得化合物4(182.6mg,32%)。LCMS m/z=278.2[M+H]+。1H NMR(400MHz,DMSO-d6)δppm 1.25(t,J=7.2Hz,3H),2.01-2.12(m,1H),2.35(dd,J=16.0,8.8Hz,1H),2.52-2.71(m,4H),3.39-3.47(m,1H),4.10-4.22(m,2H),7.09(d,J=8.4Hz,1H),7.20(d,J=2.4Hz,1H),8.45(s,1H),10.35(s,1H)。
取化合物4(400mg,1.44mmol),碳酸铯(563mg,1.73mmol)加入DMF(6mL),室温搅拌15~20分钟后将化合物5(453mg,1.73mmol)的DMF(2mL)溶液在0℃下滴加入上述反应液中,滴毕升至室温继续搅拌反应3~4小时。反应完成后用10mL水淬灭反应,乙酸乙酯(5mL*3)萃取3次,有机相用饱和食盐水洗涤2次,减压浓缩得化合物6粗品(782.6mg,108%),直接用于下一步反应。
将化合物6粗品(600mg,1.19mmol)溶于二氧六环(10mL)中,加入氢氧化锂(34mg,1.43mmol)水溶液,室温搅拌反应3小时后,TLC监测。反应完全后,用3mol/L稀盐酸调节pH至4.0,减压浓缩后采用制备色谱分离纯化得化合物A(486mg,收率86%,纯度97.62%)。LCMSm/z=476.2[M+H]+。1H NMR(400MHz,DMSO-d6)δppm 1.46-1.56(m,4H),1.67-1.89(m,4H),2.05-2.13(m,1H),2.29-2.42(dd,J=15.2,8.2Hz,1H),2.52-2.83(m,4H),2.76(m,1H),3.36-3.44(m,1H),5.02(s,2H),7.01(d,J=3.6Hz,1H),7.05(d,J=2.8Hz,1H),7.22(d,J=8.4Hz,1H),7.45(d,J=8.8Hz,1H),7.58(s,1H),10.60(s,1H),12.31(bs,1H).
实施例2本发明化合物B~G的制备
将实施例1中的化合物1’、5’分别替换为表1中对应的化合物,采用与实施例1相同的合成路线和方法,制得本发明得化合物B~G;其结构表征如下:
化合物B:收率78.0%,纯度96.85%。LCMS m/z=476.3[M+H]+。1H NMR(400MHz,DMSO-d6)δppm 1.44-1.52(m,4H),1.70-1.86(m,4H),2.01-2.15(m,1H),2.31-2.42(dd,J=15.6,8.4Hz,1H),2.48-2.82(m,4H),2.70(m,1H),3.38-3.46(m,1H),5.10(s,2H),6.82(dd,J=8.6Hz,2.4Hz,1H),7.01(d,J=3.6Hz,1H),7.25(d,J=8.4Hz,1H),7.38(d,J=8.8Hz,1H),7.54(s,1H),10.53(s,1H),12.32(bs,1H).
化合物C:收率68.5%,纯度97.94%。LCMS m/z=430.2[M+H]+。1H NMR(400MHz,DMSO-d6)δppm 2.03-2.19(m,1H),2.31-2.42(dd,J=15.6,8.4Hz,1H),2.48-2.82(m,4H),3.25(m,2H),3.38-3.46(m,1H),4.82-4.98(m,2H),5.15(s,2H),5.82-5.94(m,1H),6.82(dd,J=8.6,2.4Hz,1H),7.01(d,J=3.6Hz,1H),7.20(d,J=8.2Hz,1H),7.28(d,J=8.8Hz,1H),7.42(d,J=8.8Hz,1H),7.54(s,1H),10.53(s,1H),12.32(bs,1H).
化合物D:收率76.0%,纯度96.88%。LCMS m/z=448.2[M+H]+。1H NMR(400MHz,DMSO-d6)δppm 1.01-1.25(m,4H),1.78(m,1H),2.01-2.14(m,1H),2.24-2.40(dd,J=14.8,8.0Hz,1H),2.52-2.82(m,4H),3.36-3.44(m,1H),5.05(s,2H),7.04(d,J=3.2Hz,1H),7.05(d,J=3.0Hz,1H),7.22(d,J=8.6Hz,1H),7.46(d,J=8.4Hz,1H),7.60(s,1H),10.40(s,1H),12.25(bs,1H).
化合物E:收率70.5%,纯度98.06%。LCMS m/z=462.2[M+H]+。1H NMR(400MHz,DMSO-d6)δppm 1.85-2.02(m,2H),2.08-2.15(m,1H),2.17-2.29(m,4H),2.24-2.40(dd,J=15.2,8.2Hz,1H),2.52-2.82(m,4H),3.24-3.29(m,1H),3.36-3.44(m,1H),5.12(s,2H),7.08(d,J=3.6Hz,1H),7.12(d,J=3.2Hz,1H),7.24(d,J=8.4Hz,1H),7.48(d,J=8.4Hz,1H),7.62(s,1H),10.44(s,1H),12.27(bs,1H).
化合物F:收率81.0%,纯度97.80%。LCMS m/z=450.2[M+H]+。1H NMR(400MHz,DMSO-d6)δppm 1.50(d,J=3.8Hz,6H),2.08-2.15(m,1H),2.18-2.39(dd,J=15.2,8.2Hz,1H),2.50-2.84(m,4H),2.90-2.98(m,1H),3.38-3.46(m,1H),5.18(s,2H),7.12(d,J=3.40Hz,1H),7.15(d,J=3.4Hz,1H),7.18(d,J=8.2Hz,1H),7.50(d,J=8.8Hz,1H),7.64(s,1H),10.35(s,1H),12.16(bs,1H).
化合物G:收率79.5%,纯度98.20%。LCMS m/z=475.2[M+H]+。1H NMR(400MHz,DMSO-d6)δppm 2.01-2.17(m,1H),2.33-2.45(dd,J=15.2,8.2Hz,1H),2.50-2.78(m,4H),3.25-3.29(m,4H),3.36-3.42(m,1H),3.68-3.72(d,J=7.8Hz,4H),5.08(s,2H),6.84(dd,J=8.0,2.6Hz,1H),7.08(d,J=3.2Hz,1H),7.25(d,J=8.4Hz,1H),7.32(d,J=9.2Hz,1H),7.47(d,J=9.0Hz,1H),7.58(s,1H),10.49(s,1H),12.27(bs,1H).
表1化合物B~G的制备原料和结构
实施例3本发明化合物H的制备
以制备化合物A的中间体6’作为起始物料,与甲醇钠发生取代反应得化合物7’,再经水解反应即可得化合物H。合成路线如下:
化合物7’的合成:
取化合物6’(500mg,0.99mmol)于100mL圆底烧瓶中,加入10mL无水甲醇,室温下加入甲醇钠(53.5mg,0.99mmol)的甲醇溶液(2mL)。加入完成后,30℃反应过夜,减压浓缩,残留物硅胶柱色谱分离纯化得化合物7’(331.5mg,65%)。LCMS m/z=516.2[M+H]+。1H NMR(400MHz,DMSO-d6)δppm 1.25(t,J=7.6Hz,3H),1.44-1.52(m,4H),1.64-1.78(m,4H),2.08-2.14(m,1H),2.28-2.40(dd,J=15.4,8.4Hz,1H),2.50-2.76(m,4H),2.79(m,1H),3.37-3.45(m,1H),3.86(s,3H),4.12(q,J=4.4Hz,2H),5.06(s,2H),6.98(d,J=3.6Hz,1H),7.02(d,J=2.8Hz,1H),7.24(d,J=8.4Hz,1H),7.38(d,J=8.8Hz,1H),7.54(s,1H),10.52(s,1H).
化合物H的合成:
将化合物7’(500mg,0.97mmol)溶于二氧六环(10mL)中,加入氢氧化锂(28mg,1.16mmol)水溶液,室温搅拌反应3~4小时后,TLC监测。反应完全后,用3mol/L稀盐酸调节pH至4.0,减压浓缩后采用制备色谱分离纯化得化合物H(425mg,收率90.0%,纯度98.50%)。LCMS m/z=488.3[M+H]+。H NMR(400MHz,DMSO-d6)δppm 1.42-1.52(m,4H),1.66-1.79(m,4H),2.10-2.16(m,1H),2.26-2.41(dd,J=15.4,8.4Hz,1H),2.53-2.75(m,4H),2.81(m,1H),3.42-3.47(m,1H),3.89(s,3H),5.12(s,2H),7.05(d,J=3.6Hz,1H),7.10(d,J=2.8Hz,1H),7.25(d,J=8.4Hz,1H),7.42(d,J=8.8Hz,1H),7.57(s,1H),10.48(s,1H),12.32(bs,1H).
对比例1 Etrasimod的制备
Etrasimod参照化合物1的合成步骤自制,纯度98.49%。LCMS m/z=458.3[M+H]+。1H NMR(400MHz,DMSO-d6)δppm 1.48-1.59(m,4H),1.64-1.86(m,4H),2.01-2.11(m,1H),2.27-2.40(dd,J=15.4,8.0Hz,1H),2.56-2.80(m,4H),2.71(m,1H),3.35-3.46(m,1H),5.05(s,2H),6.49(dd,J=8.4,2.8Hz,1H),7.05(d,J=3.8Hz,1H),7.07(d,J=3.2Hz,1H),7.19(d,J=8.8Hz,1H),7.47(d,J=8.6Hz,1H),7.62(s,1H),10.54(s,1H),12.21(bs,1H).
以下通过实验例证明本发明制备的化合物的有益效果。
实验例1、本发明制备的化合物治疗溃疡性结肠炎
1、材料与方法
材料与动物:葡聚糖硫酸钠(DSS,分子量:36,000~50,000kDa)购自MPBiomedical公司(Solon,OH,USA);TNF-α、IL-1β和IL-6ELISA试剂盒(R&D system,Minneapolis,MN,USA);Etrasimod纯度99%,上海吉至生化科技有限公司;其他所有试剂均为国产分析级;实验动物:雄性C57BL/6J小鼠,6周龄,体重16-18g,共64只,由成都达硕生物科技有限公司提供。
分组造模与给药:所有小鼠随机分为正常组、模型组、本发明实施例1~3和对比例1所制得的化合物A组、化合物B组、化合物C组、化合物D组、化合物E组和Etrasimod组。共8组,每组8只。整个实验周期内正常组小鼠自由饮水,其余三组小鼠均予2%DSS溶液自由饮用诱导结肠炎7d诱导溃疡性结肠炎。模型组、化合物A组、化合物B组、化合物C组、化合物D组、化合物E组和Etrasimod组于第1~7d分别给予0.9%生理盐水、化合物A(16mg·kg-1)、化合物B(16mg·kg-1)、化合物C(16mg·kg-1)、化合物D(16mg·kg-1)、化合物E(16mg·kg-1)和Etrasimod(20mg·kg-1)灌胃。
动物疾病活动指数(DAI)评估:每日监测所有小鼠体重、粪便稠度和粪便隐血。评分标准如下:体重减失评分,体重未减轻:0分;减轻1%~5%:1分;减轻5%~10%:2分;减轻10%~20%:3分;减轻20%以上:4分。粪便稠度评分,正常:0分;稀便:2分;水样腹泻:4分。粪便隐血程度评分,隐血阴性:0分;隐血阳性:2分;隐血强阳性:4分。DAI分数的范围为0~12分。
结肠组织中TNF-α、IL-1β和IL-6水平的测定取结肠组织置于3mL PBS(0.1mol·L-1,pH7.4)在4℃环境下均化,离心(4℃,10000g,5min)。根据ELISA试剂盒说明书,分别测定结肠组织中TNF-α、IL-1β和IL-6水平。
数据以平均值±SD表示。使用Duncan's的多重范围测试,通过单因素方差分析评估各组之间平均值的差异,P<0.05表示统计学上有显著差异。SAS v9.1统计软件包(SASInstitute Inc.,Cary,NC,USA)用于分析实验中获得的数据。
2、实验结果
2.1本发明化合物对结肠炎小鼠症状的影响
DSS溶液诱导结肠炎模型是目前应用最为广泛的实验方法之一,临床症状、病理学表现和病变部位与人类UC最为相似,即出现典型的体重减轻,结肠短缩和肠壁增厚,并出现腹泻和血便等特点。与正常组小鼠相比,模型组能够显著引起结肠炎小鼠的体重减轻、结肠缩短、结肠重量/长度比以及总DAI指数明显升高(P<0.05)(表1)。表明自由饮用DSS溶液能引起小鼠出现相应的UC临床症状。经CME剂量组干预后,剂量组小鼠的各项指标较模型组小鼠均具有显著差异性。
表1本发明化合物对结肠炎小鼠最终体重、结肠长度、结肠重量长度比和总DAI指数的影响
注:*代表与正常组对比差异具有统计学意义(P<0.05),**代表与正常组对比差异具有统计学意义(P<0.01),&代表与模型组对比差异具有统计学意义(P<0.05),&&代表与模型组对比差异具有统计学意义(P<0.01),#代表与Etrasimod组对比差异具有统计学意义(P<0.05)。
根据以上试验结果可以得知:本发明化合物能有效改善结肠炎小鼠体重减轻症状,化合物A~D、F~H对小鼠体重减轻的改善程度显著优于Etrasimod组,化合物A~H对结肠长度增长、总DAI指数的评分结果都与Etrasimod组相当。
其中,尤其是化合物E的结肠重量/长度比显著低于Etrasimod组,DAI指数与模型组相比也具有统计学意义,说明其对肠壁增厚程度的改善以及对结肠炎症状的改善极为明显,且效果显著优于Etrasimod。
因此,本发明化合物能够显著改善结肠炎小鼠体重减轻、结肠缩短和肠壁增厚的现象,缓解结肠炎小鼠的症状,且效果与Etrasimod效果相当甚至显著优于Etrasimod,其中,化合物E的效果最佳。
2.2本发明化合物对结肠炎小鼠结肠组织中TNF-α、IL-1β和IL-6水平的影响TNF-α,IL-1β,IL-6和IL-8等促炎细胞因子分泌水平异常升高是导致结肠组织炎性损伤的主要原因之一。如表3所示,较正常组小鼠相比,模型组小鼠的结肠组织中TNF-α、IL-1β和IL-6分泌水平显著增多(P<0.05)。经化合物A~H和Etrasimod干预处理后,能显著抑制结肠炎小鼠结肠组织中TNF-α、IL-1β和IL-6的异常分泌(P<0.05)。表明化合物A~H能够抑制促炎因子的释放,减轻结肠炎的炎性反应。
表2本发明化合物对结肠炎小鼠结肠组织中TNF-α、IL-1β和IL-6水平的影响
注:*代表与正常组对比差异具有统计学意义(P<0.05),**代表与正常组对比差异具有统计学意义(P<0.01),&代表与模型组对比差异具有统计学意义(P<0.05),&&代表与模型组对比差异具有统计学意义(P<0.01),#代表与Etrasimod组对比差异具有统计学意义(P<0.05),##代表与Etrasimod组对比差异具有统计学意义(P<0.01)。
根据以上试验结果可以得知:本发明化合物能有效抑制结肠炎小鼠结肠组织中TNF-α、IL-1β和IL-6炎症因子的异常分泌,化合物E~G对IL-1β分泌的减少程度显著优于Etrasimod组。
其中,尤其是化合物E对IL-1β分泌的抑制作用和Etrasimod相比具有极显著的差异,且化合物E对IL-6分泌的抑制作用也显著优于Etrasimod。
因此,本发明化合物能够显著抑制结肠炎小鼠结肠组织中TNF-α、IL-1β和IL-6炎症因子的异常分泌,且效果与Etrasimod效果相当甚至显著优于Etrasimod。其中,化合物E的效果最佳。
综上,本发明提供了一种新的治疗溃疡性结肠炎的化合物,能够显著抑制患结肠炎时结肠组织中TNF-α、IL-1β和IL-6等促炎因子的异常分泌,抑制炎性细胞浸润,维持肠上皮和隐窝腺的完整,能够有效改善结肠炎小鼠体重减轻、结肠缩短和肠壁增厚的现象,缓解结肠炎的症状,在制备治疗溃疡性结肠炎的药物中具有优异的潜在应用价值,为临床提供了新的选择。
Claims (10)
6.如权利要求5所述的制备方法,其特征在于,
步骤(1)所述催化剂a为4-甲基苯磺酸吡啶;所述脱水剂为四乙氧基硅烷;所述缚酸剂选自N,N-二异丙基乙胺、吡啶、三乙胺中的至少一种,优选为N,N-二异丙基乙胺;所述催化剂b选自醋酸钯、氯化钯中的至少一种,优选为醋酸钯;所述化合物1、化合物2、脱水剂、缚酸剂、催化剂a和催化剂b的摩尔比为(3~4):(4~5):(4~4.5):(9~10):(0.1~0.2):(0.05~0.1),优选为3.14:4.72:4.08:9.42:0.13:0.09;
和/或步骤(2)所述碱选自碳酸氢铵、碳酸氢钠、醋酸钠、碳酸氢钾、醋酸钾中的至少一种,优选为碳酸氢铵;所述催化剂选自钯碳催化剂Pd/C;所述化合物3、碱和催化剂的摩尔比为:(0.5~1.5):(2~4):(0.04~0.06),优选为1:3:0.05;
和/或步骤(3)所述缚酸剂选自碳酸铯、碳酸钠、碳酸钾中的至少一种,优选为碳酸铯;所述化合物4、化合物5和缚酸剂的摩尔比为:(1~2):(0.5~1.5):(0.5~1.5);优选为1.2:1:1;
和/或步骤(4)所述碱为氢氧化锂、氢氧化钠、氢氧化钾中的至少一种,优选为氢氧化锂;所述化合物6和碱的摩尔比为:(0.5~1.5):(1~2);优选为1:1.2。
7.如权利要求5或6所述的制备方法,其特征在于,步骤(1)所述缩合反应为:在有机溶剂中,125~145℃反应2~6小时;优选为:在DMF中,135℃反应4小时;所述关环反应为:在110~130℃反应至TLC监测反应完全;优选为:120℃反应至TLC监测反应完全;
和/或步骤(2)所述反应为:在溶剂中,30~50℃反应至TLC监测反应完全;优选为:在乙醇和水的混合溶剂中,40℃反应至TLC监测反应完全;
和/或步骤(3)所述反应为:在有机溶剂中,20~30℃反应3~4小时;优选为:在DMF中,25℃反应3~4小时;
和/或步骤(4)所述加碱水解为:在有机溶剂中,加入碱的水溶液,20~30℃反应2~4小时;优选为:在二氧六环中,加入氢氧化锂水溶液,25℃反应3小时;
优选地,步骤(1)还包括如下后处理步骤:冷却至25℃,加水淬灭反应,过滤,乙酸乙酯萃取得有机相,干燥,色谱柱分离纯化;
和/或步骤(2)还包括如下后处理步骤:浓缩除去乙醇,二氯甲烷萃取得有机相,干燥,色谱柱分离纯化;
和/或步骤(3)还包括如下后处理步骤:加水淬灭反应,乙酸乙酯萃取得有机相,饱和食盐水洗涤,浓缩;
和/或步骤(4)还包括如下后处理步骤:调节pH至酸性,浓缩,制备色谱分离纯化。
9.如权利要求8所述的方法,其特征在于,所述化合物6与甲醇钠反应还包括如下后处理步骤:浓缩,色谱柱分离纯化。
10.权利要求1或2所述化合物在制备治疗溃疡性结肠炎的药物中的用途,优选的,所述治疗溃疡性结肠炎的药物是减轻结肠炎炎症、改善结肠缩短和/或肠壁增厚的药物。
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