CN116925015B - 用于抑制卵巢早衰的活性物质及其制备方法 - Google Patents
用于抑制卵巢早衰的活性物质及其制备方法 Download PDFInfo
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- CN116925015B CN116925015B CN202310714421.XA CN202310714421A CN116925015B CN 116925015 B CN116925015 B CN 116925015B CN 202310714421 A CN202310714421 A CN 202310714421A CN 116925015 B CN116925015 B CN 116925015B
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- curcumin derivative
- alkyl
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Abstract
本发明提供了一种用于抑制卵巢早衰的活性物质及其制备方法，所述活性物质具有式I所示的结构。所述化合物具有抑制卵巢早衰、提高卵巢功能方面的作用，且所述作用优于姜黄素，预期可应用于卵巢早衰的治疗。
Description
技术领域
本发明涉及医药领域，具体来说，本发明涉及一种用于抑制卵巢早衰的活性物质及其制备方法。
背景技术
受到社会环境和疾病等因素的影响，女性卵巢功能水平下降，生育能力受到极大影响，卵巢早衰(POF)、多囊卵巢综合征(PCOS)等与女性卵巢相关的疾病受到越来越多的关注。
卵巢早衰是指卵巢中卵泡数量不断减少，使生殖和分泌激素功能丧失，造成卵泡刺激素(follicle-stimulating hormone,FSH)、黄体生成激素(luteinizing hormone,LH)水平升高，雌二醇(estradiol,E2)水平降低并伴随相应围绝经期症状的妇科内分泌疾病。近年来，卵巢早衰发病率逐年增长，不孕症患者不断增加，严重影响育龄期妇女的生活和对生育的要求。
卵巢早衰患者的临床特征多表现为更年期样症状，如潮热，盗汗以及阴道、皮肤及黏膜干燥等，大多数卵巢早衰患者同时伴有生育能力的丧失。患者体内的激素水平多为异常状态，主要表现为低雌二醇水平、高黄体生成激素水平、高卵泡刺激素水平，以及低抗穆勒氏激素(Anti-Muller hormone,AMH)水平等。目前公认的卵巢早衰诊断为：年龄<40岁，继发性闭经4个月以上，且绝经后FSH水平>40IU/L。已知雄激素会导致POF和卵巢的永久性损伤，除此之外，化疗、放疗和/或手术，自身免疫病症，X染色体异常和常染色体遗传病症等均可导致POF的发生。
目前，西医对卵巢早衰主要采用激素补充治疗，虽疗效良好，但其无法恢复卵巢功能，且长时间使用激素容易增加患子宫内膜癌、乳腺癌等疾病的风险。近年来越来越多的研究发现，中药治疗POF的毒副作用较少，且效果显著。中药单体是中药中的活性成分，且化学结构确定，已报道多种中药单体如淫羊藿苷、葛根素、槲皮素、白藜芦醇、姜黄素等具有改善POF的作用。然而，中药单体往往存在活性不佳、治疗效果不够显著的问题，因此亟待提供具有更佳治疗活性的化合物。
发明内容
为了克服现有技术存在的上述问题，本发明从姜黄素出发，提供了一种具有改善的卵巢早衰治疗效果的活性物质。
在本发明的一个方面，本发明提供了一种式I所示的姜黄素衍生物或其药学上可接受的盐、溶剂合物、前药：
其中：
R1、R2各自独立地表示任选经取代的(C1-6)烷基；
R3表示氢、任选经取代的(C1-6)烷基；
L表示-(CR4R5)s-，其中R4、R5各自独立地选自氢或(C1-4)烷基；
s表示1、2、3或4；
Het表示任选经取代的5-10元杂芳基。
在一个实施方案中，R1、R2各自独立地表示(C1-4)烷基；优选的，R1、R2各自独立地表示甲基。
在一个实施方案中，R3表示氢、(C1-4)烷基；优选的，R3表示氢。
在一个实施方案中，在一个实施方案中，L表示-(CH2)s-，s表示1、2或3或4；优选的，L表示-(CH2)s-，s表示1或2。
在一个实施方案中，所述Het表示吡咯基、咪唑基、吡唑基、噻吩基、呋喃基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、嘧啶基，其任选被选自以下基团中的一个或多个取代或未取代：卤素、(C1-4)烷基、羟基、(C1-4)烷氧基、(C1-4)烷氨基、(C1-4)烷氧羰基。
在一个实施方案中，所述化合物选自：
在本发明中，卤素表示氟、氯、溴或碘。
在本发明中，烷基表示优选含有1-6个碳原子的直链或支链饱和烃基。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基或己基等。
在本发明中，杂芳基表示优选包含1-5个选自O、S和N的杂原子的5-12元单环或二环芳族基团。可提到的单环杂芳基包括咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、呋喃基、噻吩基、噻二唑基、三唑基、四唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基和三嗪基。可提到的双环杂芳基包括吲哚基、异吲哚基、苯并呋喃基、苯并噻吩基、苯并咪唑基、吲唑基、异苯并呋喃基、异苯并噻唑基、喹啉基、异喹啉基、噌啉基、喹唑啉基、喹喔啉基。
在一个实施方案中，本发明化合物的药学上可接受的盐是指药学上可接受的酸加成盐，所述酸包括：盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、过氯酸盐、富马酸盐、马来酸盐、磷酸盐、乙醇酸盐、乳酸盐、水杨酸盐、琥珀酸盐、甲苯对硫酸盐、酒石酸盐、乙酸盐、柠檬酸盐、甲磺酸盐、甲酸盐、苯甲酸盐、丙二酸盐与苯磺酸盐。
在本发明中，本发明化合物的溶剂合物是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水、甲醇、乙醇、异丙醇、二甲亚砜、乙酸乙酯、乙酸、氨基乙醇。
在本发明中，对本发明化合物的前药没有具体限制，只要其在生物体内能够代谢成本发明化合物即可，非限制性地包括酯等，例如甲酸酯、乙酸酯等。
本发明另一方面提供一种制备式I所示的姜黄素衍生物的方法，其包括以下步骤：
将式a所示的化合物与式b所示的化合物在碱的存在下反应以生成式I所示的姜黄素衍生物；
其中R1-R3、L、Het如上文所述，X表示氯或溴；
所述碱选自氢氧化物、碳酸盐、碳酸氢盐或醋酸盐，优选氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、醋酸钠或醋酸钾，最优选碳酸钾或醋酸钾。
本发明另一方面提供了一种药物组合物，其包含至少一种式I所示的姜黄素衍生物或其药学上可接受的盐、溶剂合物、前药以及一种或更多种药学上可接受的载体。考虑所有的给药方式，例如口服、直肠、肠胃外、局部、或通过静脉内、肌内、胸骨内或皮下注射、或以适于吸入的形式。只要合适，制剂可以方便地以个别剂量单位存在并可通过药学领域中熟知的任何方法进行制备。根据已知的和已确定的实践，所述化合物一般将与一种或多种药学上可接受的成分一起配制。因此，药物组合物可被配制成片剂、丸剂、胶囊剂、散剂、颗粒剂、混悬剂、口服液体剂等。
术语“药学上可接受的载体”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些载体，包括但不限于任何和所有溶剂、分散介质、涂层、抗细菌和抗真菌剂、等渗和吸收延迟剂、一个或多个合适的稀释剂、填料、盐、崩解剂、粘合剂、润滑剂、助流剂、润湿剂、控制释放基质、色素/调味剂、载体、赋形剂、缓冲剂、稳定剂、增溶剂或其组合。
本发明的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等等。药学上本发明化合物的含量应在整个组合物的0.05重量％至90重量％、优选0.1重量％至50重量％范围内。
对于成人患者，本发明化合物能够以口服或非口服的方式将作为1次的给予量的0.001～500mg、1天1次或分为数次来给予。应予说明，该给予量可根据治疗对象的疾病的种类、患者的年龄、体重、症状等适当增减。
本发明另一方面提供了式I所示的姜黄素衍生物或其药学上可接受的盐、溶剂合物、前药在制备药物中的应用，所述药物用于：1)预防和/或治疗卵巢早衰；或者2)提高卵巢功能；或者3)预防和/或治疗卵巢损伤。
有益效果
本发明提供了一种由姜黄素衍生的具有抑制卵巢早衰作用的活性物质。本发明还提供了所述活性物质的制备方法，并通过大鼠实验证实了其在抑制卵巢早衰、提高卵巢功能方面的作用，所述作用优于姜黄素，预期可应用于卵巢早衰的治疗。
具体实施方式
在下文中更详细地描述了本发明以有助于对本发明的理解。
下面实施例中的实验方法，如无特殊说明，均为常规方法。实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件，或者按照产品说明书进行。
实施例1：
在反应瓶中依次加入姜黄素3.68g(10mmol)、(E)-1-溴-4-(呋喃-2-基)丁-3-烯-2-酮2.15g(11mmol)、无水K2CO31.66g(12mmol)和丙酮100ml，回流搅拌反应10h。反应结束后，过滤，滤液减压蒸除溶剂，残余物溶于氯仿60ml中，依次用饱和NaCl水溶液、去离子水洗涤，有机层经无水硫酸钠干燥，过滤，减压蒸除溶剂，得到粗产物；粗产物用柱层析纯化(环己烷∶甲醇＝20∶1～10∶1)，得到3.93g的白色固体状产物化合物1，产率78.2％。ESI-MS：503.20[M+H]+；元素分析：理论值，C,69.31；H,5.22；O,25.47；实测值，C,69.35；H,5.14；O,25.49。
实施例2：
在反应瓶中依次加入姜黄素3.68g(10mmol)、(E)-1-溴-4-(噻吩-2-基)丁-3-烯-2-酮2.30g(11mmol)、无水K2CO31.66g(12mmol)和丙酮100ml，回流搅拌反应12h。反应结束后，过滤，滤液减压蒸除溶剂，残余物溶于氯仿60ml中，依次用饱和NaCl水溶液、去离子水洗涤，有机层经无水硫酸钠干燥，过滤，减压蒸除溶剂，得到粗产物；粗产物用柱层析纯化(环己烷∶甲醇＝20∶1～5∶1)，得到4.22g的灰白色固体状产物化合物2，产率81.3％。ESI-MS：519.15[M+H]+；元素分析：理论值，C,67.17；H,5.05；O,21.60；S,6.18；实测值，C,67.12；H,5.08；O,21.67；S,6.10。
实施例3：
在反应瓶中依次加入姜黄素3.68g(10mmol)、(E)-1-溴-4-(吡啶-2-基)丁-3-烯-2-酮2.30g(11mmol)、无水K2CO31.66g(12mmol)和丙酮100ml，回流搅拌反应12h。反应结束后，过滤，滤液减压蒸除溶剂，残余物溶于氯仿80ml中，依次用饱和NaCl水溶液、去离子水洗涤，有机层经无水硫酸钠干燥，过滤，减压蒸除溶剂，得到粗产物；粗产物用柱层析纯化(石油醚∶甲醇＝20∶1～8∶1)，得到3.97g的灰白色固体状产物化合物3，产率77.4％。ESI-MS：514.19[M+H]+；元素分析：理论值，C,70.17；H,5.30；N,2.73；O,21.81；实测值，C,70.20；H,5.32；N,2.77；O,21.78。
试验例：
1实验方法
取SPF雌性SD大鼠(年龄12周；无出生；体重200±15g)，阴道涂片观察动情周期，取动情周期正常的大鼠进行实验。按照体重随机分为6组:正常组、模型组、姜黄素组、化合物1组、化合物2组、化合物3组。除正常组外，其他5组于每天上午给予雷公藤多苷(75mg·kg-1·d-1)灌胃，连续30d，建立POF模型；于每天下午，4个给药组给予相应药物，用药量均为100mg·kg-1·d-1，均连续给药30d。正常组和模型组灌胃等量0.9％NaCl。
2结果采集
第30天给药结束后，乙醚吸入麻醉大鼠，心脏取血，收集血清。用ELISA法检测各组大鼠血清AMH(抗穆勒氏激素)、E2(雌二醇)、FSH(卵泡刺激素)和LH(黄体生成激素)的水平，根据试剂盒(武汉华美公司)说明书进行操作。用全波长酶标仪于波长450nm处检测光密度(OD)值，绘制标准化曲线，计算AMH、E2、FSH、LH浓度。称重后处死大鼠，分离大鼠的卵巢、子宫并称重，计算单侧卵巢指数(单侧卵巢重量mg/大鼠体重g)、子宫指数(子宫重量mg/大鼠体重g)。统计学分析采用SPSS 26.0软件行统计学分析，数据用均值±标准差表示，多组间比较采用单因素方差分析，组间均数比较采用t检验，检验水准α＝0.05。以P＜0.05表示差异性显著。
结果如下表1和表2所示：
表1：各组大鼠体重、卵巢指数、子宫指数的比较(n＝8)
注：与正常组相比，*P＜0.05，**P＜0.01；与模型组相比，#P＜0.05，##P＜0.01；与姜黄素组相比，&P＜0.05
表1的结果表明，模型组与正常组比较，体重、卵巢指数显著降低，差异均有统计学意义；姜黄素和化合物1-3均能够在一定程度上缓解体重、卵巢指数降低的情况，并且化合物1-3的效果优于姜黄素，差异均有统计学意义。
表2：各组大鼠血清抗苗勒氏管激素和性激素水平的比较(n＝8)
注：与正常组相比，**P＜0.01；与模型组相比，#P＜0.05，##P＜0.01；与姜黄素组相比，&P＜0.05
表2的结果表明，与正常组比较，模型组大鼠FSH和LH水平增加，E2和AMH水平降低，差异均有统计学意义；姜黄素和化合物1-3均能够在一定程度上改善FSH和LH水平增加、E2和AMH水平降低的情况，并且化合物1-3的效果优于姜黄素，差异均有统计学意义。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员，在不脱离本发明方法的前提下，还可以做出若干改进和补充，这些改进和补充也应视为本发明的保护范围。
Claims (7)
1.一种式I所示的姜黄素衍生物或其药学上可接受的盐：
其中：
R1、R2各自独立地表示(C1-6)烷基；
R3表示氢、(C1-6)烷基；
L表示-(CH2)s-，s表示1、2或3；
s表示1、2、3或4；
Het表示吡咯基、咪唑基、吡唑基、噻吩基、呋喃基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、嘧啶基，其任选被选自以下基团中的一个或多个取代或未取代：卤素、(C1-4)烷基、羟基、(C1-4)烷氧基、(C1-4)烷氨基、(C1-4)烷氧羰基。
2.根据权利要求1所述的式I所示的姜黄素衍生物或其药学上可接受的盐，其特征在于，R1、R2各自独立地表示(C1-4)烷基。
3.根据权利要求1所述的式I所示的姜黄素衍生物或其药学上可接受的盐，其特征在于，R3表示氢、(C1-4)烷基。
4.根据权利要求1所述的式I所示的姜黄素衍生物或其药学上可接受的盐，其特征在于，所述化合物选自：
5.一种制备权利要求1中所述的式I所示的姜黄素衍生物的方法，其包括以下步骤：
将式a所示的化合物与式b所示的化合物在碱的存在下反应以生成式I所示的姜黄素衍生物；
其中R1-R3、L、Het如权利要求1中所述，X表示氯或溴；
所述碱选自氢氧化物、碳酸盐、碳酸氢盐或醋酸盐。
6.一种药物组合物，其包含至少一种权利要求1-4任一项所述的式I所示的姜黄素衍生物或其药学上可接受的盐以及一种或更多种药学上可接受的载体。
7.权利要求1-4任一项所述的式I所示的姜黄素衍生物或其药学上可接受的盐在制备药物中的应用，所述药物用于：1)预防和/或治疗卵巢早衰；或者2)提高卵巢功能；或者3)预防和/或治疗卵巢损伤。
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