CN106539790A - 一种治疗子宫内膜异位症的药物组合物 - Google Patents
一种治疗子宫内膜异位症的药物组合物 Download PDFInfo
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- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
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Abstract
本发明涉及一种治疗子宫内膜异位症的药物组合物，所述药物组合物包含下式的化合物或其药学上可接受的盐、和药学上可以接受的载体：
Description
技术领域
本发明涉及医药领域，具体的说，本发明涉及一种治疗子宫内膜异位症的药物组合物。
背景技术
子宫内膜异位症是指有生长功能的子宫内膜组织出现在子宫腔被覆粘膜及子宫肌层以外的身体其他部位而引起的以痛经进行性加重、性交痛、不孕、月经异常等为主要症状的疾病。本病多发生在25-45岁的育龄妇女，发病率大约在10％-15％左右，其中80％的患者有痛经症状，近50％的患者导致不孕。在慢性盆腔疼痛而又不孕的妇女中，经腹腔镜检查证实患有子宫内膜异位症的高达40％-60％。
子宫内膜异位症的发病机制尚未完全阐明，随着对子宫内膜异位症的深入研究，发现盆腹腔内环境如免疫功能异常及内分泌功能紊乱在发病过程中，起着重要的作用。子宫内膜异位症合并多种内分泌因素的异常，这些异常最终通过影响卵泡的发育、成熟、及排卵和黄体功能，导致不孕。免疫功能紊乱在子宫内膜异位症的发生、发展过程中起着重要作用。免疫系统包括细胞免疫和体液免疫，机体发挥细胞免疫和体液免疫功能有赖于免疫系统中细胞间的相互作用，包括细胞间直接接触和通过分泌细胞因子或其他活性分子介导的作用。细胞因子可通过干扰精子的活力、影响卵泡的发育及成熟、抑制精卵的结合、抑制早期胚胎的发育、影响输卵管对卵子的捕获及孕卵的输送等途径导致不孕。现代研究表明，内异症引起不孕涉及机械性、腹腔内环境、卵巢功能、子宫内膜容受性等免疫内分泌因素的复杂疾病。
发明内容
本发明的目的在于提供一种治疗子宫内膜异位症的药物组合物。
为了实现本发明的目的，本发明提供一种治疗子宫内膜异位症的药物组合物，所述药物组合物包含下式的化合物或其药学上可接受的盐、和药学上可以接受的载体：
其中
R1独立地选自：H或C1-C3烷基；
R2独立地选自：H、-OH、卤素、-CN或-C1-C6烷基。
优选地，R1为H。
优选地，R2为H。
本发明还提供化合物在制备治疗子宫内膜异位症的药物中的用途，所述化合物具有下列结构：
其中
R1独立地选自：H或C1-C3烷基；
R2独立地选自：H、-OH、卤素、-CN或-C1-C6烷基。
优选地，R1为H。
优选地，R2为H。
药学上可接受的盐
本发明还涉及药学上可接受的盐。所述药学上可接受的盐包括如从无毒无机酸或有机酸形成的常见的苯并咪唑衍生物无毒盐。例如，此类常见的无毒盐包括源自诸如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的无机酸的那些盐，和从以下有机酸制备的盐，诸如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、双羟萘酸、马来酸、羟基马来酸、苯基乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基-苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟基乙磺酸、三氟乙酸等。
本发明的药学上可接受的盐可通过常见化学方法从含有碱性部分的本发明的化合物合成。通常，所述盐通过离子交换色谱或通过使游离碱与化学计量量或过量的所需成盐的无机酸或有机酸在合适的溶剂或各种溶剂的组合中反应来制备。
本发明的药物改善盆腔局部血液循环，缓解盆腔粘连，调节其紊乱的细胞免疫功能，改善自身免疫反应的存在和异常，从而防止异位内膜粘附、侵袭、血管形成。
具体实施方式
为了说明和描述目前本发明的最佳模式的目的，以下示出了实施例。本发明的范围不以任何方式限于本文所示的实施例。
实验例1本发明化合物的表征
mp 196-197℃；1H NMR(500MHz,甲醇-d4)δ2.00-2.26(m,3H),2.34-2.45(m,2H),2.46-2.55(m,1H),2.60(dt,J＝12.97,3.28Hz,2H),2.81(d,J＝13.12Hz,2H),3.48(s,6H),3.58-3.67(m,1H),8.20(t,J＝8.85Hz,2H),8.82(dd,J＝8.85,5.49Hz,2H),9.07(br.s,1H),10.50(br.s,1H),12.80(s,1H)；13C NMR(126MHz,甲醇-d4)δ35.1,35.2,40.9,47.3,54.9,111.6,112.1,119.5,121.1,125.3,125.5,136.7,137.5,139.2,139.3,140.3,141.1,141.1,149.3,150.7,168.8,172.7,174.7；HPLC(1)：t＝11.4min,纯度>99％。
实验例2本发明药物对于子宫内膜异位症的治疗效果
选择性成熟雌性SD大鼠，数量为50只，体质量(200±20)g，清洁级。饲养室保持恒温、恒湿。在饮水、进食正常的情况下，适应性喂养1周，进行实验。将大鼠按体质量随机分为5组，每组10只，分别为空白组、模型组、实施例1化合物高剂量组、实施例1化合物低剂量组、阳性对照(达那唑)组。
采用给药统一达到动情周期的方法，适应性饲养1周后，给予己烯雌酚灌服5d，剂量为0.02mg/kg。手术在无菌环境下进行，按照Vernon M,Wilson A.Study on thesurgical induction of endometriosis in the rats[J].Fertil Steri1,1985,44:782-786的方法进行自体移植法手术建模。以2％戊巴比妥钠(30mg/kg，腹腔注射)麻醉，然后将大鼠腹部剃毛后固定于手术板上，常规碘酒、酒精消毒腹部切口，在尿道口上约lcm处切长2～3cm的纵形切口，逐层进入进腹。结扎局部子宫血管以及需切除的子宫上下端，切下左侧子宫角长约1cm，立即放入PBS溶液中，修剪去子宫浆膜外的脂肪组织，纵向切开子宫腔，切取5mm长的片段，内膜层反向对着种植部位，用5～0号丝线缝在右侧腹壁血运丰富处，令其内膜而紧贴腹壁，固定位置尽量远离切口以减少粘连，并防止再次开腹取材时损伤种植的异位内膜。剩余组织进行组织学检查，以证实移植物为子宫组织。向腹腔注入青霉素钠水溶液，0号丝线分层缝合腹壁和皮肤。动物分笼单放，让其自然苏醒。常规饲养。术后给予青霉素钠水溶液肌注，每天一次，连续5d。术后第10日予以己烯雌酚灌服，剂量为0.02mg/kg，连续5d。造模结束。
各组均于造模后1周给药：高剂量组给予0.04mg/1000g灌胃；低剂量组给予0.02mg/1000g灌胃；阳性对照组给予0.03mg/1000g灌胃；空白组和模型组均给予生理盐水灌胃。一天一次，连续给药3w。
停止给药后次日，各组动物给予腹主动脉采血，采血1mL取血清备检，1mL肝素抗凝，用淋巴细胞分离液常规分离制备单个核细胞(PBMC)，洗涤，用10％的小牛血清PRML-1640营养液悬浮并调至所需细胞浓度备检。
采用间接免疫荧光法检测子宫内膜异位症大鼠血液中CD3、CD、CD8。首先制备PBMC悬液并将其调整至l×106·mL-1，选取48孔培养板，用移液枪在实验孔和对照孔各加PBMC悬液100μL，于各孔中分别加入20μL鼠抗人CD3、CD4、CD8单克隆抗体(购于北京赛泰克公司)，4℃静置1h后用0.1％NaN3-PBS洗涤1次，把游离的单克隆抗体洗去。然后，在各孔中加入20μLFITC标记羊抗鼠IgG荧光抗体(购于北京赛泰克公司)，4℃静置30～45min后用0.1％NaN3-PBS洗净多余的FITC标记抗体，最后在荧光显微镜下计数，每个标本计数200个细胞，计算荧光阳性细胞百分率。放免法测定E2、P、PRL，按试剂盒说明严格进行操作。
实验结果用SPSS 17.0统计软件进行分析。实验结果以表示，计数资料用卡方检验，计量资料用方差检验。P<0.05为差异有统计学意义。
对子宫内膜异位症大鼠免疫功能的影响见表1和2。
表1对子宫内膜异位症大鼠免疫功能的影响
注：与空白组比较P<0.05；与模型组比较△P<0.05。
表2温对子宫内膜异位症大鼠内分泌的影响
注：与空自组比较：P<0.05，P<0.01；与模型组比较：ΔP<0.05。
Claims (6)
1.一种治疗子宫内膜异位症的药物组合物，其特征在于，所述药物组合物包含下式的化合物或其药学上可接受的盐、和药学上可以接受的载体：
其中
R1独立地选自：H或C1-C3烷基；
R2独立地选自：H、-OH、卤素、-CN或-C1-C6烷基。
2.根据权利要求1所述的治疗子宫内膜异位症的药物组合物，其特征在于，R1为H。
3.根据权利要求2所述的治疗子宫内膜异位症的药物组合物，其特征在于，R2为H。
4.化合物在制备治疗子宫内膜异位症的药物中的用途，其特征在于，所述化合物具有下列结构：
其中
R1独立地选自：H或C1-C3烷基；
R2独立地选自：H、-OH、卤素、-CN或-C1-C6烷基。
5.根据权利要求4所述的用途，其特征在于，R1为H。
6.根据权利要求5所述的用途，其特征在于，R2为H。
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