CN106511350A - 6‑羟基‑7‑芳甲酰基喹啉酮类化合物在治疗溃疡性结肠炎中的应用 - Google Patents
6‑羟基‑7‑芳甲酰基喹啉酮类化合物在治疗溃疡性结肠炎中的应用 Download PDFInfo
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Abstract
本发明公开了一种6‑羟基‑7‑芳甲酰基喹啉酮类化合物在治疗溃疡性结肠炎中的应用，其中的6‑羟基‑7‑芳甲酰基喹啉酮类化合物为6‑羟基‑7‑{4‑[2‑氧代‑4‑(4‑氯苯基)‑1‑哌嗪基]乙氧基}苯甲酰基}‑3，4‑二氢‑1H‑喹啉‑2‑酮。本发明可以改善微循环，抑制炎症反应，修复溃疡，从而达到治疗溃疡性结肠炎的效果，且安全可靠，无毒副作用，更适用于溃疡性结肠炎的维持治疗。
Description
技术领域
本发明属于化合物的生物活性应用技术领域，具体而言，涉及一种6-羟基-7-芳甲酰基喹啉酮类化合物的制药新用途，尤其涉及6-羟基-7-芳甲酰基喹啉酮类化合物在制备治疗溃疡性结肠炎的药物中的应用。
背景技术
溃疡性结肠炎是一种病因尚不十分清楚的结肠和直肠慢性非特异性炎症性疾病，病变局限于大肠黏膜及黏膜下层。病变多位于乙状结肠和直肠，也可延伸至降结肠，甚至整个结肠。该病见于任何年龄，但以20～45岁多见。临床表现：除少数患者起病急骤外，一般起病缓慢，病情轻重不一。症状以腹泻为主，排出含有血、脓和黏液的粪便，常伴有阵发性结肠痉挛性疼痛，并里急后重，排便后可获缓解。轻型患者症状较轻微，每日腹泻不足5次。重型每日腹泻在5次以上，为水泻或血便，腹痛较重，有发热症状，体温可超过38.5℃，脉率大于90次/分；起病急骤，病情发展迅速，腹泻量大，经常便血。体温升高可达40℃，严重者出现全身中毒症状；疾病日久不愈，可出现消瘦、贫血、营养障碍、衰弱等；部分患者有肠道外表现，如结节性红斑、虹膜炎、慢性活动性肝炎及小胆管周围炎等。
目前，临床上溃疡性结肠炎治疗的药物主要分为以下几类：糖皮质激素类、氨基水杨酸类、免疫抑制剂、抗生素以及一些生物制剂如英夫利西单抗，阿达木单抗等，但是有不同程度的毒副作用，如：糖皮质激素易引起肥胖，TNF-a单抗可引起患者皮肤不适应症状等，同时药物价格高，患者难以长期维持治疗。柳氮磺胺吡啶是目前临床最常用的西药，适用于中度、轻度和慢性溃疡性结肠炎患者，口服后在肠内分解为磺胺吡啶及5-氨基水杨酸，对结肠肠壁组织有特别亲和力，起到抗炎作用。然而，按指导剂量口服美沙拉嗪后有10％～40％的患者出现恶心、消化不良、头痛、白细胞下降等不良反应，偶有引起关节痛、皮疹、蛋白尿及胰腺炎等反应，随着病程以及治疗时间的延长，一半以上的患者不得不因副作用停止治疗或者寻求新的治疗药物，因此该药临床应用受限。美沙拉嗪的副作用小，但是其疗效一般，只能作为溃疡性结肠炎的辅助治疗药物。因此，研究并开发一种毒副作用小、对溃疡性结肠炎具有良好治疗作用的药物，这具有重要的经济意义和社会意义。
CN105237474A公开了6-羟基-7-芳甲酰基喹啉酮类化合物及其应用，该类化合物可用于治疗或预防与雌激素功能相关的各种疾病，如：骨质疏松，癌症，尤其是乳腺癌，卵巢癌，骨肉瘤和子宫内膜癌。目前，尚没有文献报道这类化合物具有防治溃疡性结肠炎方面的生物活性。
发明内容
本发明的目的在于提供一种6-羟基-7-芳甲酰基喹啉酮类化合物在制备治疗溃疡性结肠炎的药物中的应用。
为了实现本发明的目的，发明人通过大量的动物实验研究及不懈探索后发现，6-羟基-7-{4-[2-氧代-4-(4-氯苯基)-1-哌嗪基]乙氧基}苯甲酰基}-3，4-二氢-1H-喹啉-2-酮防治溃疡性结肠炎的疗效显著，可以明显改善大鼠一般情况，增加大鼠体质量，改善微循环，抑制炎症反应，修复溃疡，从而证实了该化合物具有防治溃疡性结肠炎的生物活性。因此，本发明提供的技术方案概况为：6-羟基-7-{4-[2-氧代-4-(4-氯苯基)-1-哌嗪基]乙氧基}苯甲酰基}-3，4-二氢-1H-喹啉-2-酮在制备防治溃疡性结肠炎的药物中的应用。
本发明所述防治溃疡性结肠炎的药物，其中6-羟基-7-{4-[2-氧代-4-(4-氯苯基)-1-哌嗪基]乙氧基}苯甲酰基}-3，4-二氢-1H-喹啉-2-酮作为活性成分以灌胃方式进行了相关动物试验，结果药物经胃肠吸收显著，因此本发明所述的药物可以为口服制剂。其中所述的口服制剂包括片剂、胶囊剂、颗粒剂。需要说明的是，按照制剂领域的常规工艺，本领域的技术人员很容易将6-羟基-7-{4-[2-氧代-4-(4-氯苯基)-1-哌嗪基]乙氧基}苯甲酰基}-3，4-二氢-1H-喹啉-2-酮与药剂学上可接受的辅料制备成常用的口服制剂，如颗粒剂、片剂、胶囊剂。其中，药剂学上可接受的辅料包括填充剂、崩解剂、粘合剂、矫味剂、润滑剂等等。所述的填充剂选自以下的一种或多种：预胶化淀粉、乳糖、甘露醇和微晶纤维素；所述的崩解剂选自以下的一种或多种：羧甲基淀粉钠、交联聚维酮、交联羧甲基纤维素钠和低取代羟丙基纤维素；所述的粘合剂选自以下的一种或多种：淀粉浆、羟丙基纤维素溶液、聚维酮溶液；所述的润滑剂选自以下的一种或两种：硬脂酸镁、滑石粉。
与现有技术相比，6-羟基-7-{4-[2-氧代-4-(4-氯苯基)-1-哌嗪基]乙氧基}苯甲酰基}-3，4-二氢-1H-喹啉-2-酮防治溃疡性结肠炎的疗效显著，可以明显改善大鼠一般情况，增加大鼠体质量，改善微循环，抑制炎症反应，修复溃疡，从而达到治疗溃疡性结肠炎的效果，且安全可靠，无毒副作用，更适用于溃疡性结肠炎的维持治疗。
附图说明
图1为实施例1各组小鼠的6日DAI评分结果，其中系列1为正常对照组，系列2为模型对照组，系列3为化合物低剂量组，系列4为化合物高剂量组。
具体实施方式
以下实施例进一步描述本发明的效果试验例和制备实施例，实施例仅用于例证的目的，不限制本发明的范围，同时本领域普通技术人员根据本发明所做的显而易见的改变也包含在本发明范围之内。
实施例1：6-羟基-7-{4-[2-氧代-4-(4-氯苯基)-1-哌嗪基]乙氧基}苯甲酰基}-3，4-二氢-1H-喹啉-2-酮对小鼠溃疡性结肠炎模型的影响试验
健康成年KM小鼠32只，雄性，体质量22±2g，随机分成如下四组：正常对照组、模型对照组、化合物低剂量组、药物高剂量组。正常对照组自由饮用蒸馏水，其余各组自由饮用5％葡聚糖硫酸钠水溶液6d，制造小鼠结肠炎模型。造模期间，正常对照组和模型对照组每日灌胃生理盐水；化合物低、高剂量组每日灌胃36、72mg/kg/d的6-羟基-7-{4-[2-氧代-4-(4-氯苯基)-1-哌嗪基]乙氧基}苯甲酰基}-3，4-二氢-1H-喹啉-2-酮，早中晚各一次。
试验期间，每日观察小鼠的精神状态、活动度、毛发等表现，称量小鼠体质量，采集大便，判断大便性状，采用邻联甲苯胺法检测大便隐血。按表1的标准进行疾病活动指数评分，以评估疾病活动情况。疾病活动指数(DAI)＝(体质量减轻率分数+粪便性状分数+隐血程度分数)/3。
表1：疾病活动指数(DAI)评分标准
大便形状的判断标准：①正常：成形颗粒样便；②半稀便：糊状或半成形，不黏附于肛门；③稀便：可黏附于肛门的稀水样便。各组小鼠DAI评分结果见图1。正常对照组小鼠活泼好动、毛发有光泽、大便基本正常、体质量缓慢增长；其他各组小鼠逐渐出现体质量下降、稀便、血便、少动、精神萎靡、毛发散乱等症状，模型对照组最为显著，且症状出现较早。随着治疗时间的推移，本发明化合物治疗组小鼠的大便情况明显缓解，体重下降程度明显轻。同模型对照组相比，各给药组评分明显降低，没有明显的剂量依耐性，且更接近于正常对照组。
实施例2：6-羟基-7-{4-[2-氧代-4-(4-氯苯基)-1-哌嗪基]乙氧基}苯甲酰基}-3，4-二氢-1H-喹啉-2-酮的制备
将3.26g(0.02mol)6-羟基喹啉酮，150mL二氯甲烷，2.24g(0.024mol)三乙胺加入250mL圆底烧瓶中，室温下搅拌均匀。搅拌下滴加含有对甲氧基苯甲酰氯的二氯甲烷溶液(对甲氧基苯甲酰氯3.74g，0.022mol；二氯甲烷40mL)，匀速滴入反应液中，20min内滴加完毕。室温搅拌5h，TLC监测至反应完全，将反应液缓慢倒入50mL1mol/L的盐酸中，抽滤，水30mL洗涤滤饼3次，干燥。将滤液转移至分液漏斗中，分出有机层，水100mL洗涤2次，无水MgSO4干燥，过滤除去干燥剂，滤液减压蒸去有机溶剂，得白色固体，产量5.86g，收率98.7％。m.p.257-259℃；ESI-MS：m/z297.1([M+H]+)。
在100mL圆底烧瓶中，加入6-(4-甲氧基苯甲酰氧基)-3，4-二氢-1H-喹啉-2-酮2.98g(0.012mol)，无水三氯化铝(4.4g，0034mol)，安装空气冷凝管，装有无水CaCl2的球形干燥管，180℃油浴反应6h，TLC监测至反应完全，冷却至室温。加入适量冰水及1mol/L的盐酸溶液调节pH至2～3，浸泡过夜，打浆，抽滤并水洗产物至中性，得淡黄色固体6-羟基-7-(4-羟基苯甲酰基)-3，4-二氢-1H-喹啉-2-酮，产量2.91g，收率97.7％。m.p.281-283℃；1H-NMR(600MHz，DMSO-d6)δ(ppm)10.38(s，1H)，10.15(s，1H)，9.90(s，1H)，7.61(d，J＝6.0Hz，2H)，6.87-6.79(m，4H)，2.88(t，J＝12.0Hz，2H)，2.43(t，J＝12.0Hz，2H)；ESI-MS：m/z283.1([M+H]+)。
将6-羟基-7-(4-羟基苯甲酰基)-3，4-二氢-1H-喹啉-2-酮(3mmol)，4-(4-氯苯基)-1-氯乙酰哌嗪(3.5mmol)，碳酸钾(6.2g，45mmol)和碘化钾(0.1g，0.6mmol)和30mL丙酮加于圆底烧瓶中，加热回流12h后，TLC监测至反应完毕。抽滤，经柱层析[V(石油醚)∶V(乙酸乙酯)＝1∶3]分离得到亮黄色固体6-羟基-7-{4-[2-氧代-4-(4-氯苯基)-1-哌嗪基]乙氧基}苯甲酰基}-3，4-二氢-1H-喹啉-2-酮0.60g，收率30.13％。1H-NMR(600MHz，DMSO-d6)δ(ppm)10.05(s，1H)，9.93(s，1H)，7.66(d，J＝7.8Hz，2H)，7.44(d，J＝7.8Hz，4H)，6.99(d，J＝8.4Hz，2H)，3.56(t，J＝8.4Hz，4H)，3.48(t，J＝8.4Hz，4H)，2.88(t，J＝15Hz，2H)，243(t，J＝9Hz，2H)，2.32(d，J＝29.4Hz，4H)；MS(m/z)：520.2([M+H]+)。
Claims (3)
1.6-羟基-7-芳甲酰基喹啉酮类化合物在制备防治溃疡性结肠炎的药物中的应用，所述的6-羟基-7-芳甲酰基喹啉酮类化合物为6-羟基-7-{4-[2-氧代-4-(4-氯苯基)-1-哌嗪基]乙氧基}苯甲酰基}-3，4-二氢-1H-喹啉-2-酮。
2.根据权利要求1所述的应用，其特征在于，所述的药物为口服制剂。
3.根据权利要求1所述的应用，其特征在于，所述的口服制剂包括片剂、胶囊剂、颗粒剂。
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