CN113712970A - 芒柄花素衍生物在制备治疗或预防围绝经期综合征的药物中的应用 - Google Patents
芒柄花素衍生物在制备治疗或预防围绝经期综合征的药物中的应用 Download PDFInfo
- Publication number
- CN113712970A CN113712970A CN202111068314.1A CN202111068314A CN113712970A CN 113712970 A CN113712970 A CN 113712970A CN 202111068314 A CN202111068314 A CN 202111068314A CN 113712970 A CN113712970 A CN 113712970A
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- Prior art keywords
- formononetin
- formula
- derivative
- alkyl
- groups
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- HKQYGTCOTHHOMP-UHFFFAOYSA-N formononetin Chemical class C1=CC(OC)=CC=C1C1=COC2=CC(O)=CC=C2C1=O HKQYGTCOTHHOMP-UHFFFAOYSA-N 0.000 title claims abstract description 101
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- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical group N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 claims description 3
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Abstract
本发明涉及药物制备技术领域,提供了芒柄花素衍生物在制备治疗或预防围绝经期综合征的药物中的应用。芒柄花素衍生物可以调节雌激素失衡个体的体内雌激素平衡,减轻围绝经期综合征,增加子宫萎缩个体中的子宫内膜厚度或子宫重量,调节骨组织中破骨细胞异常个体的成骨和破骨的平衡,进而改善围绝经期综合症引起的骨质疏松等症状。同时,芒柄花素衍生物具备稳定性好、适于成药、生物活性好、低毒性的优点,本发明将其应用于抗围绝经期综合征药物的开发中,或用于制备研究围绝经期综合征病理机制以及评价围绝经期综合征疗效的试剂中,具有广阔的应用前景。
Description
技术领域
本发明涉及药物合成技术领域,尤其涉及芒柄花素衍生物制备治疗或预防围绝经期综合征的药物中的应用。
背景技术
围绝经期综合征(Perimenopausal syndrome)是指妇女在围绝经期或其后,由于卵巢功能逐渐衰退或丧失,雌激素水平下降所引起的植物神经功能紊乱,以代谢障碍为主的一系列症候群。当女性进入绝经期后,体内雌激素水平显著下降,进而导致神经、精神、心理、内分泌和代谢等系统失衡,出现围绝经期综合征,具体表现为潮热、失眠、烦躁、骨质疏松、子宫内膜萎缩、心脑血管疾病、代谢综合征、乳腺癌和子宫内膜癌等。
医学研究发现,雌激素替代疗法可有效缓解低雌激素引起的绝经期症状和泌尿生殖道症状,提高绝经后妇女的生活质量。但长期应用雌激素易产生高血凝状态、高血压、水肿、痴呆等副作用,并增加乳腺癌及子宫内膜癌等妇科肿瘤的发病危险。鉴于雌激素替代疗法的风险性,人们一直致力于寻求雌激素替代物,期望这种替代物既能缓解更年期综合症,发挥雌激素对各个系统的保护作用,同时又能避免上述副作用。大豆异黄酮类化合物是典型的植物雌激素,包括豆黄素、芒柄花素、依普黄酮、染料木素、黄豆黄苷。目前植物雌激素类化合物在抗围绝经期综合征药物中的应用较少,因此,基于现有药物,发现新的化合物对围绝经期综合征的诊断和治疗具有重要意义。
发明内容
有鉴于此,本发明提供了芒柄花素衍生物在制备治疗或预防围绝经期综合征的药物中的应用。本发明基于具有天然植物雌激素,提供了一类以芒柄花素(Formonoetin)为母核的衍生物,其在治疗或预防围绝经期综合征的中具有广阔的前景。
为了实现上述发明目的,本发明提供以下技术方案:
芒柄花素衍生物在制备治疗或预防围绝经期综合征的药物中的应用,所述芒柄花素衍生物具有式I所示结构:
式I中:
R1为氢、羟基、乙酰氧基、C1-12烷基或C1-12烷氧基;
R2为氢、羟基、乙酰氧基、C1-12烷基或C1-12烷氧基;
R3为1-吡咯烷基、(3-甲基)吡啶烷基、C1-3烷基-吡啶基、(4-乙酰基)-哌嗪基、C1-3烷基-哌嗪基、C1-3烷基-4-(乙酰基)哌嗪基、2-(吲哚-3-基)乙胺基、甲酰基、C1-3烷基-苯乙胺基、C1-3烷基-苄胺基、C1-3烷基-氨基酸残基、氨基酸残基、N,N′-双(3-氨基丙基)-1,4-丁二胺基、3,4-二羟基苄胺基、苯胺基、苄胺基、4-氟-苄胺基、4-三氟甲基苯胺基、2-(3,4-二羟基苯基)乙胺基、异丙胺基、环己胺基、正己胺基、2-呋喃甲胺基、正丁基氨基、2-羟基乙胺基、3-羧基丙胺基、2-氨基-4-甲酸苯胺基、2-氯-4-硝基苯胺基、1,4-丁二胺基、脲基、N-(3-氨基丙基)-1,4-丁二胺基或C1-3烷基-二(C1-12烷基)-氨基;其中所述C1-3烷基-氨基酸残基中的氨基酸残基通过N-C键与母核连接;
或,R2和R3连接形成恶嗪环状结构,此时所述芒柄花素衍生物具有式II所示结构:
式II中:R4为C1-3烷基-苄基、苄基、苯基、C1-3烷基-苯乙基、4-氟苄基、3,4-二羟基苄基、2-(吲哚-3-基)乙基、2-(3,4-二羟基苯基)乙基、环己基、2-呋喃甲基、异丙基、2-氨基-4-甲酸苯基、2-吡啶基、4-硝基-2-氯苯基、4-(三氟甲基)苯基、3-羧基丙基、正丙基、正丁基、2-羟基乙基、C1-3烷基-二(C1-12烷基)、1-氨基-4,9-二氮十二烷基或1-氨基-5-氮辛烷。
优选的,所述药物包括芒柄花素衍生物以及至少一种药用载体或助剂。
优选的,所述药物为片剂、粉剂、胶囊剂、颗粒剂、混悬剂、膏滋剂、糖浆、酏剂、搽剂或注射剂。
优选的,所述芒柄花素衍生物的日剂量为0.2~150mg/kg体重。
优选的,所述R1为氢、羟基、甲氧基或乙酰氧基。
优选的,所述R2为氢、羟基、甲氧基或乙酰氧基。
优选的,所述芒柄花素衍生物具有式I-1、I-2、II-1或II-2所示结构:
式I-1和式I-2中,R3的种类和权利要求1中相同;式II-1和式II-2中,R4的种类和权利要求1中相同。
优选的,当所述芒柄花素衍生物具有式I所示结构时,所述芒柄花素衍生物的制备方法包括以下步骤:
将具有式a所示结构的化合物、甲醛和第一氨基化合物混合进行反应,得到具有式I所示结构的化合物;所述具有式a所示结构的化合物、甲醛和第一胺类化合物的摩尔比为1:1:1;所述第一胺类化合物的结构中包括伯胺基团或仲胺基团以及R3基团;
当所述芒柄花素衍生物具有式II所示结构时,所述芒柄花素衍生物的制备方法包括以下步骤:
将具有式b所示结构的化合物、甲醛和第二氨基化合物混合进行反应,得到具有式II所示结构的芒柄花素衍生物;所述具有式b所示结构的化合物、甲醛和第二氨基化合物的摩尔比为1:2:1;所述第二氨基化合物中的结构中包括伯胺基团以及R4基团;
所述式a、式b中的R1、R2基团与式I中一致。
本发明还提供了芒柄花素衍生物在制备研究围绝经期综合征理机制的试剂、制备评价围绝经期综合征的试剂中的应用,所述芒柄花素衍生物具有上述方案所述的式I或式II所示结构。
本发明提供了芒柄花素衍生物在制备治疗或预防围绝经期综合征的药物中的应用,所述芒柄花素衍生物具有式I或式II所示结构。芒柄花素衍生物可以调节雌激素失衡个体的体内雌激素平衡,减轻围绝经期综合征,增加子宫萎缩个体中的子宫内膜厚度或子宫重量,调节骨组织中破骨细胞异常个体的成骨和破骨的平衡,进而改善围绝经期综合症引起的骨质疏松等症状。同时,芒柄花素衍生物具备稳定性好、适于成药、生物活性好、低毒性的优点,将其应用于抗围绝经期综合征药物的开发中,或用于制备研究围绝经期综合征病理机制以及评价围绝经期综合征疗效的试剂中,具有广阔的应用前景。
本发明选择切除卵巢致骨质疏松模型小鼠观察芒柄花素衍生物对骨质疏松的改善情况,结果表明,F11和F13均能明显增加骨密度,提高骨表面积和组织体积之比、相对骨体积和骨体积分数;本发明还观察了芒柄花素衍生物对切除卵巢致小鼠激素失衡模型的影响,结果显示,F11和F13能明显纠正小鼠的激素缺乏;进一步的对切除卵巢所致小鼠子宫萎缩模型进行病理组织学观察,发现F11和F13均能明显对抗模型小鼠子宫内膜萎缩,增加子宫内膜厚度。以上实验结果表明,芒柄花素衍生物可安全用于制备治疗围绝经期综合征,干预围绝经期综合症引起的骨质疏松和子宫萎缩的发生。
附图说明
图1为实施例7中芒柄花素衍生物对切除卵巢小鼠骨密度的影响;
图2为实施例8中芒柄花素衍生物对切除卵巢小鼠骨体积分数的影响;
图3为实施例9中芒柄花素衍生物对切除卵巢小鼠骨表面积与骨体积比值的影响;
图4为实施例10中芒柄花素衍生物对切除卵巢小鼠子宫系数的影响;
图5为实施例11中芒柄花素衍生物对切除卵巢小鼠子宫内厚度的影响;
图6为实施例12中芒柄花素衍生物对切除卵巢小鼠血清中雌激素水平的的影响。
具体实施方式
本发明提供了芒柄花素衍生物在制备治疗或预防围绝经期综合征的药物中的应用,所述芒柄花素衍生物具有式I所示结构:
式II中:
R1为氢、羟基、乙酰氧基、C1-12烷基或C1-12烷氧基;所述C1-12烷氧基优选为甲氧基,所述C1-12烷基优选为异丙基;
R2为氢、羟基、乙酰氧基、C1-12烷基或C1-12烷氧基;所述C1-12烷氧基优选为甲氧基,所述C1-12烷基优选为异丙基;
R3为1-吡咯烷基、(3-甲基)吡啶烷基、C1-3烷基-吡啶基、(4-乙酰基)-哌嗪基、C1-3烷基-哌嗪基、C1-3烷基-4-(乙酰基)哌嗪基、2-(吲哚-3-基)乙胺基、甲酰基、C1-3烷基-苯乙胺基、C1-3烷基-苄胺基、C1-3烷基-氨基酸残基、氨基酸残基、N,N′-双(3-氨基丙基)-1,4-丁二胺基、3,4-二羟基苄胺基、苯胺基、苄胺基、4-氟-苄胺基、4-三氟甲基苯胺基、2-(3,4-二羟基苯基)乙胺基、异丙胺基、环己胺基、2-呋喃甲胺基、正丁基氨基、2-羟基乙胺基、3-羧基丙胺基、2-氨基-4-甲酸苯胺基、2-氯-4-硝基苯胺基、1,4-丁二胺基、脲基、N-(3-氨基丙基)-1,4-丁二胺基或C1-3烷基-二(C1-12烷基)-氨基;其中所述C1-3烷基-氨基酸残基中的氨基酸残基通过N-C键与母核连;
或,R2和R3连接形成恶嗪环状结构,此时所述芒柄花素衍生物具有式II所示结构:
式II中:R4为C1-3烷基-苄基、苄基、苯基、C1-3烷基-苯乙基、4-氟苄基、3,4-二羟基苄基、2-(吲哚-3-基)乙基、2-(3,4-二羟基苯基)乙基、环己基、2-呋喃甲基、异丙基、2-氨基-4-甲酸苯基、2-吡啶基、4-硝基-2-氯苯基、4-(三氟甲基)苯基、3-羧基丙基、正丙基、正丁基、2-羟基乙基、C1-3烷基-二(C1-12烷基)、1-氨基-4,9-二氮十二烷基或1-氨基-5-氮辛烷。
在本发明中,所述芒柄花素衍生物优选具有式I-1、I-2、II-1或II-2所示结构:
式I-1、式I-2、式II-1和式II-2中:R3和R4的种类和上述方案相同。
在本发明中,按照不同的取代基对式I-1、式I-2、式II-1或式II-2中的衍生物进行编号,具体如表1所示:
表1芒柄花素衍生物结构和编号
在本发明中,所述芒柄花素衍生物的制备方法优选包括以下步骤:
当所述芒柄花素衍生物具有式I所示结构时,所述制备方法包括以下步骤:
将具有式a所示结构的化合物、甲醛和第一氨基化合物混合进行反应,得到具有式I所示结构的化合物;所述具有式a所示结构的化合物、甲醛和第一胺类化合物的摩尔比为1:1:1;所述第一胺类化合物的结构中包括伯胺基团或仲胺基团以及R3基团;
所述式a中的R1、R2基团与式I中一致。
在本发明中,所述具有式a所示结构的化合物具体优选为芒柄花素(结构式如式a-1所示)或豆黄素(结构式如式a-2所示)。
在本发明中,所述第一氨基化合物具体根据R3基团的种类进行选择,具体的,当所述R3为甲酰胺时,所述第一氨基化合物为六亚甲基四胺,当所述R3为1-吡咯烷基时,所述第一氨基化合物为吡咯烷;当所述R3为(3-甲基)-吡啶烷基时,所述第一氨基化合物为(3-甲基)-吡啶烷;当所述R3为(4-乙酰基)-哌嗪基时,所述第一氨基化合物为(4-乙酰基)-哌嗪;当所述R3为2-呋喃甲基时,所述第一氨基化合物为2-呋喃甲胺;当所述R3为正丁基氨基时,所述第一氨基化合物为正丁胺;其余不再一一列举,根据本领域技术人员的公知常识进行选择即可。
在本发明中,所述反应用溶剂优选为冰乙酸或二甲基亚砜-甲醇混合溶剂,所述二甲基亚砜-甲醇混合溶剂中二甲基亚砜和甲醇的体积比优选为1:4;所述甲醛优选以甲醛水溶液的形式使用,所述甲醛水溶液的质量分数优选为36%;本发明对所述甲醛水溶液的来源没有特殊要求,采用本领域技术人员熟知的市售甲醛水溶液即可;在本发明的具体实施例中,优选在制备F1时使用冰乙酸为溶剂,制备其他化合物时使用二甲基亚砜-甲醇混合溶剂为溶剂。
在本发明中,所述反应优选在加热回流条件下进行,所述反应的时间优选为6~12h;在本发明的具体实施例中,当采用二甲基亚砜-甲醇混合溶剂为反应溶剂时,优选先将具有式a所示结构的化合物溶解于二甲基亚砜中,将甲醇、甲醛水溶液和第一氨基化合物的混合溶液滴加到式a化合物的溶液中,室温下搅拌混合均匀,然后升温至回流温度进行反应。
在本发明中,制备具有式I所示结构的芒柄花素衍生物的反应式如下:
反应完成后,本发明优选将所得产物料液进行后处理,得到具有式I所示结构的化合物。在本发明中,当使用冰乙酸为溶剂时,所述后处理优选包括以下步骤:向所得产物料液中加入盐酸后搅拌5min,然后冷却至室温,加入水,得到沉淀,收集沉淀,得到粗产物,将所述粗产物进行硅胶柱层析分离,得到具有式I所示结构的化合物。
当以二甲基亚砜-甲醇混合溶剂为溶剂时,所述后处理优选包括以下步骤:将所得产物料液减压蒸去溶剂,有固体析出,将剩余产物过滤后得到粗产物,将所述粗产物进行硅胶柱层析分离,得到具有式I所示结构的化合物;所述硅胶柱层析分离采用的试剂为石油醚-乙酸乙酯混合试剂或石油醚-甲醇-乙酸乙酯混合试剂,所述石油醚-乙酸乙酯混合试剂中石油醚和乙酸乙酯的体积比优选为2:1,所述石油醚-甲醇-乙酸乙酯混合试剂中石油醚、甲醇和乙酸乙酯的体积比优选为2:1:1。
在本发明中,当所述芒柄花素衍生物具有式II所示结构时,所述制备方法包括以下步骤:
将具有式b所示结构的化合物、甲醛和第二氨基化合物混合进行反应,得到具有式II所示结构的芒柄花素衍生物;所述具有式b所示结构的化合物、甲醛和第二氨基化合物的摩尔比为1:2:1;所述第二氨基化合物中的结构中包括伯胺基团以及R4基团;
所述式b中的R1基团与式I中一致。
在本发明中,所述具有式b所示结构的化合物具体优选为芒柄花素或豆黄素,结构式如上文所示。
在本发明中,所述第二氨基化合物具体根据R4基团的种类进行选择,具体的,当所述R4为2-呋喃甲基时,所述第二氨基化合物为2-呋喃甲胺,当所述R4为正丁基时,所述第二氨基化合物为正丁胺;当所述R4为苄基时,所述第二氨基化合物为苄胺;当所述R4为2-(吲哚-3-基)乙基时,所述第二氨基化合物为色胺;其余不再一一列举,根据本领域技术人员的公知常识进行选择即可。
在本发明中,制备具有式II所示结构的芒柄花素衍生物的反应式如下:
在本发明中,当所述芒柄花素衍生物具有式II所示结构时,反应用溶剂、具体操作方法以及反应条件均和制备具有式I所示结构的芒柄花素衍生物时一致,仅是其中甲醛的摩尔量不同,具体条件不再赘述。
下面以F11和F13为例说明本发明的反应原理:
制备F11和F13时,具有式b所示结构的化合物为芒柄花素,结构式如式a-1所示,F11和F13的结构如下:
反应过程中,芒柄花素A环8-C位的活性H与脂肪族伯/仲胺或芳香族伯/仲胺在甲醛水溶液中进行Mannich反应,合成得到Mannich碱衍生物;在伯胺的Mannich反应中,例如苄胺或对甲基苯胺与甲醛的摩尔配比为1:2时,反应产物Mannich碱进一步与甲醛反应生成N-取代羟甲基化合物,再脱水环合,得含六元环的二氢苯并噁嗪衍生物。根据不同取代基团,生成具有直链烷基或取代的直链烷基、环烷基、五元或六元杂环、苯环或含取代基的苯环、氨基的芒柄花素衍生物。
在本发明中,所述药物包括芒柄花素衍生物以及至少一种药用载体或助剂。在本发明中,所述药用载体具体是指药学上可接受的载体、药学领域常规的药物载体,例如:稀释剂、赋形剂、填充剂、黏合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂;具体的,所述赋形剂优选为水;所述填充剂优选为淀粉和/或蔗糖;所述黏合剂优选为纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮中的一种或几种;所述润湿剂优选为甘油;所述崩解剂优选为琼脂、碳酸钙和碳酸氢钠中的一种或几种;所述吸收促进剂优选为季铵化合物;所述表面活性剂优选为十六烷醇;所述吸附载体优选为高岭土和/或皂黏土;所述润滑剂优选为滑石粉、硬脂酸钙、硬脂酸镁和聚乙二醇中的一种或几种。
本发明对所述助剂没有特殊要求,采用本领域技术人员熟知的药用助剂即可,具体如香味剂、甜味剂。
本发明所述的芒柄花素衍生物的药物可通过口服、鼻吸入、直肠或肠胃外给药的方式施用于需要治疗的患者。用于口服时,可将其制成常规的固体制剂如片剂、粉剂、胶囊剂、颗粒剂、混悬剂、膏滋剂、搽剂或注射剂等,制成液体制剂如水、油悬浮剂、糖浆、酏剂等;用于肠胃外给药时,可将其制成注射用的溶液、水或油性悬浮剂等;在本发明的具体实施例中,所述药物的形式形式优选为片剂、胶囊和注射剂。
本发明对上述各种衍生物的剂型的制备方法没有特殊要求,按照药学领域的常规生产方法制备即可,如将活性成分与一种或多种载体混合,然后将其制成所需的剂型。
在本发明的具体实施例中,所述芒柄花素衍生物的施用量可根据用药途径、患者的年龄、体重、所治疗的疾病的类型和严重程度等进行确定,具体的,所述芒柄花素衍生物的日剂量优选为0.2~150mg/kg体重,更优选0.5~100mg/kg体重,可以一次或多次施用。
本发明还提供了上述方案所述芒柄花素衍生物在制备研究围绝经期综合征理机制的试剂、制备评价围绝经期综合征的试剂中的应用,所述试剂具体用于:
a)研究大豆异黄酮Mannich反应的机理和药物活性机制;
b)研究围绝经期综合征病理机制;
c)评价对抗围绝经期综合征的效果。
下面将结合本发明中的实施例,对本发明中的技术方案进行清楚、完整地描述。
实施例1:F1的制备
将芒柄花素134.130mg(0.5mmol)和六亚甲基四胺70mg(0.5mmol)溶解于6mL冰乙酸中,室温搅拌至完全溶解,加热回流反应6h,保持100℃,迅速加入2ml 20%的盐酸,搅拌5min,冷却至室温,加入10mL水,得到褐黄色沉淀,收集褐黄色沉淀,得到粗产物,硅胶柱层析分离,采用的试剂为石油醚-乙酸乙酯,石油醚和乙酸乙酯的体积比为2:1,Rf为0.11,得到产物F163.5 mg,产率47.31%。
产物的核磁氢谱、碳谱和质谱数据为:
1H-NMR(400MHz,DMSO-D6)δ10.48(s,1H),8.48(s,1H),8.23(d,1H),7.52(dd,2H),7.12(dd,2H),7.01(d,1H),3.88(s,3H).
13C-NMR(400MHz,DMSO-D6)δ190.32,174.39,166.36,159.66,157.26,153.51,134.05,130.55,124.60,123.95,116.95,116.38,114.15,112.00,55.46.
质谱(M+H+):297.1
分子式:C17H13O5
实施例2:F2的制备
将芒柄花素67.065mg(0.25mmol)完全溶解于1mL DMSO中,缓慢滴加配置好的混合液[4mL甲醇、22.5μL 36%甲醛(0.25mmol)和0.042mL吡咯烷(0.25mmol)],室温搅拌2h,回流反应10h,减压蒸出溶剂,得到淡红色固体,收集淡红色固体,得到粗产物,硅胶柱层析分离,采用的试剂为石油醚-甲醇-乙酸乙酯,石油醚、甲醇和乙酸乙酯的体积比为2:1:1,Rf为0.108,得到产物F2,产率7.25%。
产物的核磁氢谱、碳谱和质谱数据为:
1H-NMR(400MHz,DMSO-D6)δ8.35(s,1H),7.91(d,1H),7.49(d,2H),7.00(d,2H),6.85(d,1H),4.11(s,3H),3.78(s,2H),2.71(m,4H),1.80(m,4H).
13C-NMR(400MHz,DMSO-D6)δ23.65,49.86,53.51,55.61,109.16,114.06,115.84,116.13,123.40,124.73,126.14,130.56,153.18,155.32,159.41,164.51,175.16.
质谱(M+H+):352.1579
分子式:C22H24NO4
实施例3:F3的制备
将芒柄花素67.065mg(0.25mmol)完全溶解于1mL DMSO中,缓慢滴加配置好的混合液[4mL甲醇、22.5μL 36%甲醛(0.25mmol)和24.75mg 3-甲基吡啶烷(0.25mmol)]室温搅拌2h,回流反应10h,减压蒸出溶剂,得到淡黄色固体,收集淡黄色固体,得到粗产物,硅胶柱层析分离,得到产物F3,产率23.58%。
产物的核磁氢谱、碳谱和质谱数据为:
1H-NMR(400MHz,DMSO-D6)δ8.37(s,1H),7.90(d,1H),7.52(d,2H),7.01(d,1H),6.88(d,2H),3.79(s,3H),3.62(s,2H),2.19-2.51(dm,4H),1.69(dm,4H),1.53(m,1H),0.87(d,3H).
13C-NMR(400MHz,DMSO-D6)δ19.65,25.01,49.06,53.09,55.61,60.50,108.24,109.59,114.07,115.71,123.46,124.65,126.20,130.56,153.29,159.41,164.25,164.92,175.20.
质谱(M+H+):380.1346
分子式:C23H26NO4
实施例4:F4的制备
将芒柄花素67.065mg(0.25mmol)完全溶解于1mL DMSO中,缓慢滴加配置好的混合液[4mL甲醇、22.5μl 36%甲醛(0.25mmol)和32mg(4-乙酰基)-哌嗪(0.25mmol)]室温搅拌2h,回流反应10h,减压蒸出溶剂,得到淡黄色固体,收集淡黄色固体,得到粗产物,硅胶柱层析分离,得到产物F4,产率28.37%。
产物的核磁氢谱、碳谱和质谱数据为:
1H-NMR(400MHz,DMSO-D6)δ8.38(s,1H),7.92(d,1H),7.52(d,2H),6.99(d,1H),6.97(d,2H),3.88(s,2H),3.78(s,3H),3.44(m,4H),2.47-2.54(m,4H),1.98(s,3H).
13C-NMR(400MHz,DMSO-D6)δ21.61,50.91,52.52,52.91,55.60,109.71,114.07,115.33,116.88,123.40,124.64,126.34,130.53,153.45,156.06,159.42,162.70,168.61,175.28.
质谱(M+H+):409.1720
分子式:C23H25N2O5
实施例5:F11的制备
将芒柄花素67.065mg(0.25mmol)完全溶解于1mL DMSO中,缓慢滴加配置好的混合液[4mL甲醇、45μL 36%甲醛(0.5mmol)和24.25mg2-呋喃甲胺(0.25mmol)]室温搅拌2h,回流反应10h,减压蒸出溶剂,得到褐色固体,收集褐色固体,得到粗产物,硅胶柱层析分离,得到产物F11,产率18.55%。
产物的核磁氢谱、碳谱和质谱数据为:
1H-NMR(400MHz,CDCl3)δ8.05(s,1H),7.53(d,1H),7.13(dd,2H),6.64(d,2H),6.60(d,1H),6.06(m,1H),6.01(d,1H),4.66(s,2H),3.78(s,2H),3.54(s,2H),3.42(s,3H).
13C-NMR(400MHz,DMSO-D6)δ43.87,48.22,55.61,82.86,108.17,109.47,110.96,114.10,115.55,117.77,123.91,124.47,124.88,130.56,143.35,151.88,153.58,154.62,158.56,159.50,175.30.
质谱(M+H+):390.0816
分子式:C23H19NO5
实施例6:F13的制备
将芒柄花素67.065mg(0.25mmol)完全溶解于1mL DMSO中,缓慢滴加配置好的混合液[4mL甲醇、45μL 36%甲醛(0.5mmol)和18.25mg正丁胺(0.25mmol)]室温搅拌2h,回流反应10h,减压蒸出溶剂,得到淡褐色固体,收集淡褐色固体,得到粗产物,硅胶柱层析分离,得到产物F13,产率36.82%。
产物的核磁氢谱、碳谱和质谱数据为:
1H-NMR(400MHz,CDCl3)δ8.08(s,1H),7.91(d,1H),7.50(d,2H),6.97(d,2H),6.87(d,1H),4.96(s,2H),4.17(s,2H),3.83(s,3H),2.75(t,2H),1.58(m,2H),1.38(m,2H),0.94(t,3H).
13C-NMR(400MHz,CDCl3)δ13.96,20.30,30.23,45.01,51.51,55.34,83.21,107.73,113.97,115.21,117.96,124.21,124.93,125.24,130.15,151.60,154.69,158.67,159.59.
质谱(M+H+):366.1420
分子式:C22H23NO4
实施例7:对切除卵巢小鼠骨密度(BMD/BV)的影响
选择来源于昆明医科大学的SPF级雌性ICR鼠,对其进行麻醉,而后将其固定在手术台上,对腹部皮肤进行消毒,在腹白线处侧作一切口,充分暴露子宫,切除双侧卵巢,用缝合线逐层缝合。假手术组在卵巢周围切除与卵巢同样大小的脂肪组织。术后恢复饲养7天,选择状态良好的动物进行分组;将F11和F13混悬于0.5%羧甲基纤维素钠中进行腹腔注射和灌胃给药,腹腔注射F11和F13的剂量为10mg/kg,灌胃给予的剂量为20mg/kg,连续12周,到期后处死小鼠,取股骨进行显微CT扫描分析。
同时设置模型组、雌二醇组和依普黄酮组进行对照,均为对切除卵巢的小鼠进行给药,模型组为灌胃给予0.5%羧甲基纤维素钠,灌胃体积为10mL/kg,雌二醇组采用灌胃给药,给药量为1.5mg/kg,依普黄酮采用腹腔注射和灌胃给药,给药量和上述F11与F13的给药量一致。
本发明的芒柄花素衍生物对切除卵巢小鼠骨密度的影响见图1,图1中Sham表示假手术组,Model表示模型,E2表示雌二醇,IP表示依普黄酮,ip表示腹腔注射,ig表示灌胃给药。
图1中的实验结果表明:经过F11和F13连续12周腹腔注射或灌胃给药后,小鼠骨密度明显增加,效果优于依普黄酮组和雌二醇组,说明本发明的芒柄花素衍生物可通过增加小鼠骨密度来抑制围绝经期综合征中骨质疏松的形成,进而改善围绝经期综合征。
实施例8:对切除卵巢小鼠骨体积分数(BV/TV)的影响
选择来源于昆明医科大学的SPF级雌性ICR鼠,对其进行麻醉,而后将其固定在手术台上,对腹部皮肤进行消毒,在腹白线处侧作一切口,充分暴露子宫,切除双侧卵巢,用缝合线逐层缝合。假手术组在卵巢周围切除与卵巢同样大小的脂肪组织。术后恢复饲养7天,选择状态良好的动物进行分组,将F11和F13溶解于0.5%羧甲基纤维素钠中进行腹腔注射和灌胃给药,腹腔注射F11和F13的剂量为10mg/kg,灌胃给药的剂量为20mg/kg,连续12周,到期后处死小鼠,取股骨进行显微CT扫描分析骨密度。
同时设置模型组、雌二醇组和依普黄酮组进行对照,均为对切除卵巢的小鼠进行给药,模型组为灌胃给予0.5%羧甲基纤维素钠,灌胃体积为10mL/kg,雌二醇组采用灌胃给药,给药量为1.5mg/kg,依普黄酮采用腹腔注射和灌胃给药,给药量和上述F11与F13的给药量一致。
本发明的芒柄花素衍生物对切除卵巢小鼠骨体积分数的影响见图2,图2中Sham表示假手术组,Model表示模型,E2表示雌二醇,IP表示依普黄酮,ip表示腹腔注射,ig表示灌胃给药。
图2中的实验结果表明:经过F11和F13连续12周腹腔注射和灌胃给药后,小鼠骨体积分数明显增加,说明本发明的芒柄花素衍生物可通过骨体积分数来抑制围绝经期综合征中骨质疏松的形成,从而改善围绝经期综合征。
实施例9:对切除卵巢小鼠骨表面积与骨体积比值(BS/BV)的影响
选择来源于昆明医科大学的SPF级雌性ICR鼠,对其进行麻醉,而后将其固定在手术台上,对腹部皮肤进行消毒,在腹白线处侧作一切口,充分暴露子宫,切除双侧卵巢,用缝合线逐层缝合。假手术组在卵巢周围切除与卵巢同样大小的脂肪组织。术后恢复饲养7天,选择状态良好的动物进行分组,将F11和F13溶解于0.5%羧甲基纤维素钠中进行腹腔注射和灌胃给药,腹腔注射F11和F13的剂量为10mg/kg,灌胃给予的剂量为20mg/kg,连续12周,到期后处死小鼠,取股骨进行显微CT扫描分析骨密度。
同时设置模型组、雌二醇组和依普黄酮组进行对照,均为对切除卵巢的小鼠进行给药,模型组为灌胃给予0.5%羧甲基纤维素钠,灌胃体积为10mL/kg,雌二醇组采用灌胃给药,给药量为1.5mg/kg,依普黄酮采用腹腔注射和灌胃给药,给药量和上述F11与F13的给药量一致。
本发明的芒柄花素衍生物对切除卵巢小鼠骨表面积与骨体积比值的影响见图3,图3中Sham表示假手术组,Model表示模型,E2表示雌二醇,IP表示依普黄酮,ip表示腹腔注射,ig表示灌胃给药。
图3中的实验结果表明:经过F11和F13连续12周腹腔注射和灌胃给药后,小鼠骨表面积与骨体积比值明显上升,说明本发明的芒柄花素衍生物可通过增加小鼠骨表面积与骨体积比值来减轻骨质疏松的形成,从而改善围绝经期综合征。
实施例10:对切除卵巢小鼠子宫系数的影响
选择来源于昆明医科大学的SPF级雌性ICR鼠,对其进行麻醉,而后将其固定在手术台上,对腹部皮肤进行消毒,在腹白线处侧作一切口,充分暴露子宫,切除双侧卵巢,用缝合线逐层缝合。假手术组在卵巢周围切除与卵巢同样大小的脂肪组织。术后恢复饲养7天,选择状态良好的动物进行分组,将F11和F13溶解于0.5%羧甲基纤维素钠中进行腹腔注射和灌胃给药,腹腔注射F11和F13的剂量为10mg/kg,灌胃给予的剂量为20mg/kg,连续12周,到期后处死小鼠,取子宫称重。
同时设置模型组、雌二醇组和依普黄酮组进行对照,均为对切除卵巢的小鼠进行给药,模型组为灌胃给予0.5%羧甲基纤维素钠,灌胃体积为10mL/kg,雌二醇组采用灌胃给药,给药量为1.5mg/kg,依普黄酮采用腹腔注射和灌胃给药,给药量和上述F11与F13的给药量一致。
本发明的芒柄花素衍生物对切除卵巢小鼠子宫系数的影响见图4,图4中Sham表示假手术组,Model表示模型,E2表示雌二醇,IP表示依普黄酮,ip表示腹腔注射,ig表示灌胃给药。
图4中的实验结果表明:经过F11和F13连续12周腹腔注射和灌胃给药后,小鼠子宫系数明显增加,说明本发明的芒柄花素衍生物可通过增加小鼠子宫重量来围绝经期子宫的萎缩,从而改善围绝经期综合征。
实施例11:对切除卵巢小鼠子宫内膜的影响
选择来源于昆明医科大学的SPF级雌性ICR鼠,对其进行麻醉,而后将其固定在手术台上,对腹部皮肤进行消毒,在腹白线处侧作一切口,充分暴露子宫,切除双侧卵巢,用缝合线逐层缝合。假手术组在卵巢周围切除与卵巢同样大小的脂肪组织。术后恢复饲养7天,选择状态良好的动物进行分组,将F11和F13溶解于0.5%羧甲基纤维素钠中进行腹腔注射和灌胃给药,腹腔注射F11和F13的剂量为10mg/kg,灌胃给予的剂量为20mg/kg,连续12周,到期后处死小鼠,取子宫进行病理组织学切片分析。
同时设置模型组、雌二醇组和依普黄酮组进行对照,均为对切除卵巢的小鼠进行给药,模型组为灌胃给予0.5%羧甲基纤维素钠,灌胃体积为10mL/kg,雌二醇组采用灌胃给药,给药量为1.5mg/kg,依普黄酮采用腹腔注射和灌胃给药,给药量和上述F11与F13的给药量一致。
本发明的芒柄花素衍生物对切除卵巢小鼠子宫内厚度的影响见图5,图4中Sham表示假手术组,Model表示模型,E2表示雌二醇,IP表示依普黄酮,ip表示腹腔注射,ig表示灌胃给药。
图5中的实验结果表明:经过F11和F13连续12周腹腔注射和灌胃给药后,小鼠的子宫内膜腺体数目明显增多,腺腔较大,子宫内膜明显增厚恢复至正常水平,腺体数量增多且腺腔扩大,细胞间隙增大,间质细胞多以圆形为主,少部分为梭形,间质细胞血管丰富,腺上皮细胞呈单层柱状,说明本发明的芒柄花素衍生物可通过增加小鼠子宫内膜的厚度来围绝经期子宫的萎缩,从而改善围绝经期综合征。
实施例12:对切除卵巢小鼠血清中雌激素(E)水平的影响
选择来源于昆明医科大学的SPF级雌性ICR鼠,对其进行麻醉,而后将其固定在手术台上,对腹部皮肤进行消毒,在腹白线处侧作一切口,充分暴露子宫,切除双侧卵巢,用缝合线逐层缝合。假手术组在卵巢周围切除与卵巢同样大小的脂肪组织。术后恢复饲养7天,选择状态良好的动物进行分组,将F11和F13溶解于0.5%羧甲基纤维素钠中进行腹腔注射和灌胃给药,腹腔注射F11和F13的剂量为10mg/kg,灌胃给予的剂量为20mg/kg,连续12周,到期后取小鼠血,并分离血清,测定血清中雌激素含量。
同时设置模型组、雌二醇组和依普黄酮组进行对照,均为对切除卵巢的小鼠进行给药,模型组为灌胃给予0.5%羧甲基纤维素钠,灌胃体积为10mL/kg,雌二醇组采用灌胃给药,给药量为1.5mg/kg,依普黄酮采用腹腔注射和灌胃给药,给药量和上述F11与F13的给药量一致。
本发明的芒柄花素衍生物对切除卵巢小鼠血清中雌激素水平的的影响见图6,图6中Sham表示假手术组,Model表示模型,E2表示雌二醇,IP表示依普黄酮,ip表示腹腔注射,ig表示灌胃给药。
图6中的实验结果表明:经过F11和F13连续12周腹腔注射和灌胃给药后,小鼠的血清中雌激素含量明显升高,说明本发明的芒柄花素衍生物可通过调节小鼠体内雌激素水平来改善围绝经期引起的激素失衡,从而改善围绝经期综合征。
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来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (9)
1.芒柄花素衍生物在制备治疗或预防围绝经期综合征的药物中的应用,所述芒柄花素衍生物具有式I所示结构:
式I中:
R1为氢、羟基、乙酰氧基、C1-12烷基或C1-12烷氧基;
R2为氢、羟基、乙酰氧基、C1-12烷基或C1-12烷氧基;
R3为1-吡咯烷基、(3-甲基)吡啶烷基、C1-3烷基-吡啶基、(4-乙酰基)-哌嗪基、C1-3烷基-哌嗪基、C1-3烷基-4-(乙酰基)哌嗪基、2-(吲哚-3-基)乙胺基、甲酰基、C1-3烷基-苯乙胺基、C1-3烷基-苄胺基、C1-3烷基-氨基酸残基、氨基酸残基、N,N′-双(3-氨基丙基)-1,4-丁二胺基、3,4-二羟基苄胺基、苯胺基、苄胺基、4-氟-苄胺基、4-三氟甲基苯胺基、2-(3,4-二羟基苯基)乙胺基、异丙胺基、环己胺基、正己胺基、2-呋喃甲胺基、正丁基氨基、2-羟基乙胺基、3-羧基丙胺基、2-氨基-4-甲酸苯胺基、2-氯-4-硝基苯胺基、1,4-丁二胺基、脲基、N-(3-氨基丙基)-1,4-丁二胺基或C1-3烷基-二(C1-12烷基)-氨基;其中所述C1-3烷基-氨基酸残基中的氨基酸残基通过N-C键与母核连接;
或,R2和R3连接形成恶嗪环状结构,此时所述芒柄花素衍生物具有式II所示结构:
式II中:R4为C1-3烷基-苄基、苄基、苯基、C1-3烷基-苯乙基、4-氟苄基、3,4-二羟基苄基、2-(吲哚-3-基)乙基、2-(3,4-二羟基苯基)乙基、环己基、2-呋喃甲基、异丙基、2-氨基-4-甲酸苯基、2-吡啶基、4-硝基-2-氯苯基、4-(三氟甲基)苯基、3-羧基丙基、正丙基、正丁基、2-羟基乙基、C1-3烷基-二(C1-12烷基)、1-氨基-4,9-二氮十二烷基或1-氨基-5-氮辛烷。
2.根据权利要求1所述的应用,其特征在于,所述药物包括芒柄花素衍生物以及至少一种药用载体或助剂。
3.根据权利要求1所述的应用,其特征在于,所述药物为片剂、粉剂、胶囊剂、颗粒剂、混悬剂、膏滋剂、糖浆、酏剂、搽剂或注射剂。
4.根据权利要求1、2或3所述的应用,其特征在于,所述芒柄花素衍生物的日剂量为0.2~150mg/kg体重。
5.根据权利要求1所述的应用,其特征在于,所述R1为氢、羟基、甲氧基或乙酰氧基。
6.根据权利要求1所述的应用,其特征在于,所述R2为氢、羟基、甲氧基或乙酰氧基。
8.根据权利要求1所述的应用,其特征在于,当所述芒柄花素衍生物具有式I所示结构时,所述芒柄花素衍生物的制备方法包括以下步骤:
将具有式a所示结构的化合物、甲醛和第一氨基化合物混合进行反应,得到具有式I所示结构的化合物;所述具有式a所示结构的化合物、甲醛和第一胺类化合物的摩尔比为1:1:1;所述第一胺类化合物的结构中包括伯胺基团或仲胺基团以及R3基团;
当所述芒柄花素衍生物具有式II所示结构时,所述芒柄花素衍生物的制备方法包括以下步骤:
将具有式b所示结构的化合物、甲醛和第二氨基化合物混合进行反应,得到具有式II所示结构的芒柄花素衍生物;所述具有式b所示结构的化合物、甲醛和第二氨基化合物的摩尔比为1:2:1;所述第二氨基化合物中的结构中包括伯胺基团以及R4基团;
所述式a、式b中的R1、R2基团与式I中一致。
9.芒柄花素衍生物在制备研究围绝经期综合征理机制的试剂、制备评价围绝经期综合征的试剂中的应用,所述芒柄花素衍生物具有权利要求1所述的式I或式II所示结构。
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