CN101006999A - 异黄酮化合物的制药用途以及含有它们的组合物 - Google Patents
异黄酮化合物的制药用途以及含有它们的组合物 Download PDFInfo
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- CN101006999A CN101006999A CNA2007100016743A CN200710001674A CN101006999A CN 101006999 A CN101006999 A CN 101006999A CN A2007100016743 A CNA2007100016743 A CN A2007100016743A CN 200710001674 A CN200710001674 A CN 200710001674A CN 101006999 A CN101006999 A CN 101006999A
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Abstract
本发明是关于异黄酮化合物的制药用途以及含有它们的组合物，包含和/或包括一定的异黄酮化合物的治疗用途、方法、化合物、制剂、饮料和食品。所述异黄酮化合物用通式I表示，其中各个基团如说明中所述。
Description
本发明是1997年8月29日递交的申请号为97198690.8、发明名称为“使用异黄酮的治疗方法和含有异黄酮的组合物”的中国专利申请的分案申请。
本发明是关于涉及、含有、包含和/或包括一定的异黄酮化合物的治疗用途、方法、化合物、制剂、饮料和食品。
本发明中的异黄酮化合物用通式I表示。
其中
Z代表H，
R1代表H、或RACO，其中RA代表C1-10烷基或一种氨基酸，
R2代表H、OH、或ORB，其中RB代表一种氨基酸或CORA，这里RA同前面所定义，
W代表H，A代表H或OH，B选自如下3个基团，
或W代表H，A和B一起形成选自下面结构的六元环，
或W、A和B与其所相连的基团一起形成如下结构式，
或W和A与其所相连的基团一起形成如下结构式，
并且B是
其中
R3代表H；CORA，其中RA同前所定义；CO2RC，其中RC是C1-10烷基；或CORB，其中RB同前所定义，
R4代表H；CORD，其中RD代表H、OH、C1-10烷基或氨基酸；CO2RC，其中RC同前所定义；CORE，其中RE代表H、C1-10烷基或氨基酸；COOH；CORC，其中RC同前所定义；或CONHRE，其中RE同前所定义，
R5代表H；CO2RC，其中RC同前所定义；或CORCORE，其中RC和RE同前所定义，并且当两个R5基团连接在同一基团上时，它们可以是相同或不同的基团，
R6代表H或羟基C1-10烷基，
X优选为0，但是可以为N或S，
Y是
其中R7代表H或C1-10烷基。
假如在通式I化合物中
R1、W和Z代表H
R2代表H或OH
A和B一起形成一个六元环
Y同前所定义
并且R7代表H或OCH3，
那么这些化合物是特定排除的，
并且假如方法是治疗或预防绝经综合症或经前紧张综合症的方法时，那么在通式I化合物中
当R1代表H，W和Z代表H，并且R2代表H或OH，
A和B一起形成一个六元环
或A代表OH并且B是
Y同前所定义，R7代表H时，这些化合物是特定排除的，假如方法是治疗癌症或类风湿性关节炎的方法时，那么在通式I化合物中
当R1和W代表H，Z代表H或OCH3，并且R2代表H或OH，
A和B一起形成一个六元环
Y同前所定义，R4代表CO2H或CO2CH2CH3，并且R7代表H时，这些化合物是特定排除的。
优选的通式I化合物选自具有以下结构的化合物：
其中
R8代表CORD，其中RD同前所定义，
R9代表CO2RC或CORE，其中RC和RE同前所定义，
R10代表CORC或CORCORE，其中RC和RE同前所定义，
R11代表H或OH，
R12代表H；COOH；CO2RC，其中RC同前所定义；或CONHRE，其中RE同前所定义，
R13代表OH；ORB，其中RB同前所定义；或CORA，其中RA同前所定义，
R14代表H或CORA，其中RA同前所定义，
R15代表CORA，其中RA同前所定义，
R16代表H、CORB或CO2RC，其中RB和RC同前所定义，
R17代表H或羟基C1-10烷基，
R18代表H或C1-10烷基，
“”表示一个单键或双键。
烷基可以是直链或支链烷基。C1-10烷基优选含有1-5个碳原子，更优选甲基、乙基或丙基。
一些上述的化合物可以通过名称查阅，二氢黄豆苷原(化合物1，其中R8是H)、二氢金雀异黄素(化合物2和5)、去氢-O-去甲安哥拉紫檀素(化合物11)、四氢黄豆苷原(化合物8)、牛尿酚和去氢牛尿酚(化合物10)、O-去甲安哥拉紫檀素(ODMA，化合物13)和6-羟基-O-去甲安哥拉紫檀素(6-羟基-ODMA，化合物14)。
本发明人惊奇地发现，通式I的化合物，特别是结构式1-19所表示的化合物在治疗、预防、改善、防御、和/或防治绝经综合症包括热潮红、焦虑、和抑郁症、情绪不稳、盗汗、头痛、和尿失禁；骨质疏松症；经前期综合症包括流质潴留、周期性乳腺痛、和痛经；雷纳德(Reynaud)综合症；Reynaud现象；伯格氏病；冠状动脉痉挛；偏头痛；高血压；良性前列腺肥大；乳癌；子宫癌；卵巢癌；睾丸癌；大肠癌；子宫内膜癌；前列腺癌；子宫癌；动脉粥样硬化；阿耳茨海默氏病；炎症包括炎性肠病、溃疡性结膜炎、克罗恩氏病；风湿病包括类风湿性关节炎；痤疮；脱发包括男性脱发(遗传性脱发)；牛皮癣和与氧化剂反应有关的疾病包括癌、心肌梗塞、中风、关节炎、阳光诱导的皮肤损伤或白内障方面具有特别的作用和效力。
一方面，本发明提供了治疗、预防、改善、防御、和/或防治绝经综合症包括热潮红、焦虑、和抑郁症、情绪不稳、盗汗、头痛、和尿失禁；骨质疏松症；经前期综合症包括流质潴留、周期性乳腺痛、和痛经；Reynaud综合症；Reynaud现象；伯格氏病；冠状动脉痉挛；偏头痛；高血压；良性前列腺肥大；乳癌；子宫癌；卵巢癌；睾丸癌；大肠癌；子宫内膜癌；前列腺癌；子宫癌；动脉粥样硬化；阿耳茨海默氏病；炎症包括炎性肠病、溃疡性结膜炎、克罗恩氏病；风湿病包括类风湿性关节炎；痤疮；脱发包括男性脱发(遗传性脱发)；牛皮癣和与氧化剂反应有关的疾病包括癌、心肌梗塞、中风、关节炎、阳光诱导的皮肤损伤或白内障的方法，其中包括将有效治疗剂量的一种或多种通式I的化合物，可单独或与一种或多种可药用载体和/或赋形剂一起对受治疗者给药。
其中R1、R2、Z、W、A和B同前所定义。
优选一种或多种结构式1-19的化合物用于治疗、预防、改善绝经综合症包括热潮红、焦虑、和抑郁症、情绪不稳、盗汗、头痛、和尿失禁；骨质疏松症；经前期综合症包括流质潴留、周期性乳腺痛、和痛经；Reynaud综合症；Reynaud现象；伯格氏病；冠状动脉痉挛；偏头痛；高血压；良性前列腺肥大；乳癌；子宫癌；卵巢癌；睾丸癌；大肠癌；子宫内膜癌；前列腺癌；子宫癌；动脉粥样硬化；阿耳茨海默氏病；炎症包括炎性肠病、溃疡性结膜炎、克罗恩氏病；风湿病包括类风湿性关节炎；痤疮；脱发包括男性脱发(遗传性脱发)；牛皮癣和与氧化剂反应有关的疾病包括癌、心肌梗塞、中风、关节炎、阳光诱导的皮肤损伤或白内障(为方便起见，下文称为“适应症”)。癌、心肌梗塞、中风、关节炎、阳光诱导的皮肤损伤或白内障通常被认为与氧化剂应激反应有关。本发明包括治疗与氧化剂应激反应有关的疾病。
本发明的第二个方面是通式I的化合物在制造用于治疗、改善、防御、预防、和/或防治一种或多种所说的适应症的药物中的用途。特别优选的是，使用一种或多种结构式1-19的化合物来治疗、预防、改善、防御、和/或防治所说的适应症。
本发明的第三个方面是一种或多种通式I的化合物在治疗、改善、防御、预防、和/或防治一种或多种这些适应症中的用途。结构式1-19的化合物是特别优选的。
本发明的第四个方面包括一种用于治疗、预防、改善、防御和/或防治所说的适应症的治疗剂，其中既可以仅含有一种或多种通式I的化合物，也可以同时含有一种或多种载体或赋形剂。结构式1-19的化合物是特别优选的。
本发明的第五个方面涉及一种治疗组合物，其中含有一种或多种通式I的化合物和一种或多种药用载体和/或赋形剂。组合物优选含有一种或多种结构式1-19的化合物。
本发明的第六个方面涉及一种饮料或食品，其中含有一种或多种通式I的化合物。优选食品中含有一种或多种结构式1-19的化合物。
本发明的第七个方面涉及一种微生物培养物或含有一种或多种微生物株的食品，其中的微生物能产生一种或多种通式I的化合物。所说的微生物优选能产生一种或多种结构式1-19的化合物。
本发明的第八个方面涉及一种或多种微生物，其能产生一种或多种通式I的化合物。微生物优选是一种纯培养物，所述的培养物可以与其它能产生通式I化合物的一种或多种培养物混合和/或用其接种。通式I的化合物优选选自一种或多种结构式1-19的化合物。
本发明进一步涉及通式I的化合物。所说的化合物优选包含结构式1-19的化合物。
本发明中的化合物特别适用于治疗与雌激素作用、雄激素作用、血管舒张(vasolidatory)和痉挛作用、炎性作用和氧化作用有关或由其导致的疾病。
在本发明中，通式I的化合物进行治疗所需的剂量与许多因素有关，包括具体应用、所用化合物的性质、进行治疗的疾病的状态、给药方式和病人的状况。通常，每个病人给药的日剂量是0.1mg-2g；典型的日剂量是0.5mg-1g；优选50mg-200mg。
通式I的化合物可以以常规方式和剂量使用。例如，见Goodman andGilman，治疗的药理学基础(The Pharmacological Basis of Therapeutics，1299)(第7版，1985)。所用的具体剂量与进行治疗的疾病的状态、受治疗者的状况、给药途径以及其它如上所述的已知因素有关。
制备用于治疗所说的适应症的药物组合物，是将通式I的化合物(为方便起见，下文称为“活性化合物”)与一种或多种本领域所熟知的可药用或可兽药用载体和/或赋形剂混合。
当然，载体必须是药物可接受的，也就是与制剂中的其它任何成份都相配伍，并且必须对受治疗者无害。载体或赋形剂可以是固体或液体，或两者都是，并且优选制成化合物为一个单位剂量的制剂，例如，一种片剂，其中可以含有0.5％-59％重量比的活性化合物，或高达100％重量比的活性化合物。本发明中的制剂可以含有一种或多种活性化合物，可以使用任何熟知的药学技术来制备，基本上包括将组分混合，可选择地包括一种或多种辅助成分。
本发明中的制剂包括适于口服、直肠、眼内、口腔(例如舌下)、肠胃外(例如皮下、肌内、真皮内、静脉内)和透皮给药的制剂，虽然在任何具体的病例中，最适合的给药途径与所治疗的疾病的特性和严重程度以及所用特定活性化合物的性质有关。
适于口服给药的制剂可以制成单个的单位，例如胶囊、扁囊剂、锭剂、或片剂，其中每一单位中含有预定剂量的活性化合物；粉剂或粒剂；在水或非水液体中的溶液或悬浮液；水包油乳液或油包水乳液。这些制剂可以用合适的药物学方法制备，其中包括将活性化合物与合适的载体(可能含有一种或多种如上所述的辅助成分)混合这一步骤。通常，本发明中的制剂是这样制备的，将活性化合物与液体或分散的很细的固体载体或既与液体又与固体载体均匀而紧密地混合，然后，如果需要的话，将得到的混合物定形，例如制成一个单位剂量形式的制剂。例如，片剂可以通过将含有活性化合物的粉末或颗粒压片或铸模制备到，其中所述的粉末或颗粒中可选择地含有一种或多种辅助成分。压片可以通过将自由流动的化合物例如粉末或颗粒在合适的机器中压制而成，其中所述的粉末或颗粒中可选择地混有粘合剂、润滑剂、惰性稀释剂和/或表面活性剂/分散剂。模制片可以通过将用惰性液体粘合剂润湿的粉末状化合物在合适的机器中铸模来制备。
适于口腔(舌下)给药的制剂包括活性化合物存在于调味基质中的锭剂，调味基质通常是蔗糖和阿拉伯胶或西黄蓍胶；活性化合物存在于惰性基质例如明胶和甘油或蔗糖和阿拉伯胶中的软锭剂。
本发明中适于肠胃外给药的组合物通常包含活性化合物的无菌含水制剂，制剂优选与打算接受给药者的血液等渗。虽然也可以通过皮下、肌内、或真皮内注射来达到给药效果，但是这些制剂优选静脉给药。通常，可以通过将活性化合物与水或甘氨酸缓冲液混合，然后将得到的溶液灭菌并且调到与血液等渗来制备这些制剂。根据本发明的注射制剂通常含有0.1％-60％w/w的活性化合物，并且以0.1ml/min/kg的速度给药。
适于直肠给药的制剂优选制成含有单位剂量的栓剂。这些栓剂可以通过将活性化合物与一种或几种常规固体载体，例如椰子油混合，然后将得到的混合物定形来制备。
适于对皮肤局部给药的制剂或组合物优选制成软膏、乳膏、洗剂、糊剂、凝胶、喷雾剂、气溶胶、或油剂。可使用的载体包括凡士林、羊毛脂、聚乙二醇、乙醇、和其两种或多种的组合物。活性化合物的浓度通常是0.1％-0.5％w/w，例如0.5％-2％w/w。这些组合物的实例包括皮肤用化妆品乳膏。
适于透皮给药的制剂可以制成单个的贴剂，其适于与受药者的表皮长时间紧密地接触。这种贴剂可适当地含有作为缓冲水溶液的活性化合物，例如，所说的活性化合物在这种缓冲水溶液中的浓度是0.1M-0.2M。
适于透皮给药的制剂也可以通过离子电渗疗法释放活性化合物(见，例如，药理学研究(Pharmaceutical Research)3(6)，318(1986))，并且典型的使用形式是活性化合物任选的缓冲水溶液。合适的制剂中包含柠檬酸盐或bis/tris缓冲液(PH 6)或乙醇/水，并且含有0.1M-0.2M的活性成份。
活性化合物可以以食品的形式提供，例如以加入、混合、包衣、结合或其它途径加到食品中去。术语食品是指从最广义上讲，包括液体食品，例如包括乳制品在内的饮料，和其它食品，例如健康条状食品、甜点等。含有本发明化合物的食品能依据标准方法容易地制备。
本发明的化合物具有有效的抗氧化剂活性，因此能广泛地应用于药学和兽药学、化妆品例如能防止皮肤衰老的护肤乳膏、防晒剂、食品、健康饮料、洗发剂以及类似物中。
我们惊奇地发现，通式I的化合物与维生素E能互相协同作用以保护脂质、蛋白质和其它生物分子不被氧化。相应地，本发明进一步提供了一种组合物，其中含有一种或多种通式I的化合物、维生素E、和可选择地含有药物、兽药或化妆品可接受载体和/或赋形剂。
治疗方法、用途和组合物可以是对人或动物进行给药，所说的动物是，例如宠物和家养动物(例如狗和猫)、鸟(例如小鸡、火鸡、鸭子)、家畜(例如牛、绵羊、猪和山羊)等。
通式I的化合物可以按照下面的步骤制备：
A.将黄豆苷原、金雀异黄素或其衍生物用吸附在碳酸钙上的钯氢化，反应式如下
其中A’代表H或R1，R1、R8、R11和X同前所定义。化合物2、3、4、5、6和7可以用这种方法制备。化合物5-7是化合物2-4的烯醇式。
B.将黄豆苷原和黄豆苷原衍生物用氢硼化钠还原，反应式如下
其中R9和X同前所定义。化合物8可以用这种方法制备。
C.将黄豆苷原和黄豆苷原衍生物用吸附在炭上的钯作为催化剂氢化。
其中R11和R12同前所定义。化合物10可以用这种方法制备。
D.将间苯二酚或其衍生物酰化，然后用溴化锂脱氢
化合物11和14可以用这种方法制备。化合物12可以用相似的方法制备。
E.将1、3和5三取代苯用4-羟基苯基异丙酸或其衍生物酰化。
其中R13和R15同前所定义。化合物15和16可以用这种方法制备。
F.结构式17、18和19的化合物可以依据下面的反应方案制备。
其中R11、R17和R18同前所定义。
G.将人尿用高效液相色谱法分离/尿的高效液相色谱馏份/将细菌培养物的上清液用气液色谱法分离以得到纯的结构式1-19的化合物。产物用质谱法鉴定。结构式1-19的化合物可以使用Joannou et al(1995)甾体化合物生物化学分子生物学杂志(J.Steroid.Biochem.Molec.Biol.)54，167-184中的方法纯化，在此引入作为参考。
本发明者惊奇地发现，异黄酮在身体分泌物中的存在，更具体地说，异黄酮代谢物在受治疗者尿中的存在，与特定的治疗反应、医疗状态、或缺乏特定的医疗状态有关。确定由人体分泌的不同异黄酮的特定生物指纹，可使治疗方法能够被执行。
下面将用非限制性的实施例来描述本发明的实施方案。
实施例1
黄豆苷原和金雀异黄素
依据Wahala的方法(芬兰化学通讯(Finnish Chem.Lett.)1989，16，79)，用三氟化硼合乙醚作为催化剂，使间苯二酚和4-羟基-苯乙酸发生Friedel-Crafts酰化反应能得到黄豆苷原，然后用DMF和甲磺酰氯处理，得到72％的产率。虽然金雀异黄素从商业上可得到，但是非常昂贵。然而，它能用与制备黄豆苷原相同的方法合成，其中用1，3，5-三羟基苯代替间苯二酚。
其中当R代表H时，产物是黄豆苷原，当R代表OH时，产物是金雀异黄素。
二氢黄豆苷原和二氢金雀异黄素(各自为化合物2和3)
用吸附在碳酸钙上的钯作为催化剂来氢化黄豆苷原和金雀异黄素，以很好的产率得到了二氢黄豆苷原和二氢金雀异黄素。
其中当R代表H时，产物是二氢黄豆苷原，当R代表OH时，产物是二氢金雀异黄素。
四氢黄豆苷原(化合物8)
用硼氢化钠还原黄豆苷原，得到了四氢黄豆苷原。
牛尿酚衍生物(化合物10)
牛尿酚衍生物是通过用吸附在炭上的钯作为催化剂来氢化黄豆苷原衍生物得到的(芬兰化学通讯(Finnish Chem.Lett.)1989，16，79)。
6-羟基-O-去甲安哥拉紫檀素(化合物14)
将4-羟基苯基异丙酸用1，3，5-三羟基苯酰化，得到了6-羟基-O-去甲安哥拉紫檀素。
2-去氢-O-去甲安哥拉紫檀素(化合物11)
如下面的反应式所示，将间苯二酚酰化，然后氢化就得到了去氢-O-去甲安哥拉紫檀素。
结构式17、18和19的化合物用如下的方法制备：
化合物17
结构式17的化合物是依据下面的反应方案制备的：
其中R11、R17和R18同前所定义。
如上所示，吲哚I-2是依据Black等人(澳大利亚化学杂志(Aust.J.Chem.)
33(1980)343-350页)的方法制备的，在此引入作为参考。
吲哚I-4是通过Vilsmeier反应制备的。当3-位C上具有吸电子基团时，与2-位C相比，亲电性攻击优选发生在7-位C上。吲哚I-4的醛基通过与格氏试剂I-3进行亲核加成而生成仲醇，然后被MnO2氧化成酮I-5，再在弱碱中生成结构式17的化合物。
化合物18
结构式18的化合物是依据下面的反应方案制备的：
其中R24、R25和R26同前所定义。
吲哚I-4中的7-醛基与格氏试剂I-5进行亲核加成生成醇I-6，醇I-6被MnO2氧化生成结构式18的化合物。
化合物19
结构式19的化合物是依据下面的反应方案制备的：
其中R11、R17和R18同前所定义。
实施例2
包含氮和硫原子的杂环系统是依据下面的反应方案合成的：
其中R’代表H或-OC1-10烷基，R”代表OH或-OC1-10烷基，R代表H或-OC1-10烷基。
其中R’、R”和R同前所定义。
实施例3
1：合成ODMA(O-去甲安哥拉紫檀素2，4，4’-三羟苯基-α-甲基二苯乙酮)。化合物13。
1.1：2-(对甲氧苯基)丙酸
将对甲氧苯基乙基酮(2.39g，14.5mmol)、90％醋酸铅(IV)(6.45g，14.5mmol)、原甲酸三乙酯(15ml)和70％高氯酸(1.2ml，29mmol)的混合物在55℃加热18小时。把混合物冷却，在减压条件下将原甲酸三乙酯除去。将剩余物溶解在CHCl3中，剩余沉淀过滤除去。然后用水洗涤CHCl3溶液，再蒸发得到粗制的酯。将粗制的酯产物溶解在10％KOH1∶1水∶甲醇溶液中，然后加热回流3小时。冷却后，将甲醇通过减压蒸发除去，然后用乙醚(3×25ml)洗涤水溶液。把水溶液用2N H2SO4酸化，再用乙醚(3×25ml)洗涤。将第二次乙醚洗涤级份合并，干燥(Na2SO4)，蒸发得到丙酸(1.66g，63％)。
1.2：2，4，4’-三甲氧基-α-甲基二苯乙酮
将2-(对甲氧苯基)丙酸(0.39g，4mmol)和1，3-二甲氧基苯(0.5g，0.5ml，4mmol)在多磷酸(PPA)(10g)中混合，反应混合物在75℃、机械搅拌条件下加热5小时。将反应混合物冷却至室温，再进一步机械搅拌12小时。用冰水结束反应，用CHCl3(3×25ml)萃取产物。将CHCl3层干燥(Na2SO4)，然后在减压条件下除去溶剂。得到的粗产物用硅胶柱层析法(洗脱剂7∶2 CH2Cl2∶Et OAc)纯化，得到纯的2，4，4’-三甲氧基-(α-甲基二苯乙酮(0.68g，58％)。
1.3：2，4，4’-三羟苯基-α-甲基二苯乙酮(O-去甲安哥拉紫檀素或ODMA)
将2，4，4’-三甲氧基-α-甲基二苯乙酮(0.312g，1.04mmol)溶于干燥的CH2Cl2(10ml)中。向此溶液中缓慢地加入5当量的1.0M BBr3己烷溶液(1.3g，5.2ml，5.2mmol)，反应混合物在通入氮气、室温条件下搅拌6天。用冰水结束反应，搅拌1小时后用乙醚(3×25ml)萃取产物。将乙醚层干燥(Na2SO4)，然后在减压条件下除去溶剂。得到的粗产物用硅胶柱层析法(洗脱剂7∶1 CH2Cl2∶EtOAc)纯化，得到纯的2，4，4’-三羟苯基-α-甲基二苯乙酮(0.68g，58％)。
2：合成4’甲氧基6-OH-ODMA(4’甲氧基6-OH-O-去甲安哥拉紫檀素2，4，6，4’-四羟苯基-α-甲基二苯乙酮)
2.1：用POCl3与间苯三酚和对甲氧基苯丙酸合成
将2-(对甲氧苯基)丙酸(0.1g，0.55mmol)和1.1当量的1，3，5-三羟基苯(间苯三酚)(0.077g，0.61mmol)溶于干燥的四氢呋喃(THF)(2ml)中。把新蒸馏的POCl3(1.0ml)加入到此溶液中，反应混合物在室温下搅拌4天。用冰水结束反应，用乙醚(3×10ml)萃取产物。将乙醚层干燥(Na2SO4)，然后在减压条件下除去溶剂。得到的粗产物用硅胶柱层析法(洗脱剂7∶2 CH2Cl2∶EtOAc)纯化，得到两种产物，即酯(1)和所要的4’甲氧基6-OH-ODMA(2)。
3：二氢黄豆苷原(化合物1)的合成
3.1黄豆苷原(Daidzein)的合成
在通入氮气条件下，将间苯二酚(29mmol)和4-羟基苯乙酸(29mmol)溶于新蒸馏的三氟化硼合乙醚(20mol当量)中。得到的混合物在70℃、搅拌状态下加热过夜。反应用TLC(80％Et2O/己烷)监视。将得到的混合物冷却至室温，然后滴加N，N-二甲基甲酰胺(46.2ml)。将混合物再加热至50℃30分钟。然后滴加甲磺酰氯(7ml溶于10mlDMF)，把得到的混合物在60℃-70℃加热，直到LC(80％Et2O/己烷)表明反应已经结束，约需10小时。冷却至室温后，将混合物倒入400ml冰水中。把沉淀过滤。收集滤液并且干燥。将粗产物在94％乙醇(含水)中重结晶，得到了相当纯的黄豆苷原(3g)，产率为44％。
3.2二氢黄豆苷原的合成
将10％Pd/C(0.657g)小心地加入黄豆苷原(0.657g，2.58mmol)甲醇溶液(60ml)中，然后加入甲酸铵(0.652g，10.3mmol)。把混合物加热到50℃-60℃并且在此温度下搅拌1小时。反应用TLC(CH2Cl2/EtOAc＝7∶2或70％Et2O/己烷)和GC监视。反应完全后，将Pd/C过滤除去并且把滤液浓缩，得到的主产物是二氢黄豆苷原的粗产物(0.558g)，副产物是四氢黄豆苷原的反/顺式异构体。用标准方法将二氢黄豆苷原纯化。
也可以使用其它制备二氢黄豆苷原的方法，例如Jain，A.C.和Mehta美国化学会志(A.，J.Chem.Soc.)Perkin Trans.1，1986，215中的方法。
4：四氢黄豆苷原反/顺式异构体(化合物8)的合成
4-1氢黄豆苷原反/顺式异构体的合成
黄豆苷原 四氢黄豆苷原 四氢黄豆苷原
4-2氢黄豆苷原反/顺式异构体的合成
二氢黄豆苷原 四氢黄豆苷原 四氢黄豆苷原
将二氢黄豆苷原(0.001g，0.004mmol)溶于200L二烷和40L水中。加入硼氢化钠(0.002g，0.053mmol)，将得到的混合物在室温下搅拌2小时。用一滴醋酸中和过量的硼氢化钠，混合物通入氮气蒸发至干燥。将剩余物用EtOAc提取，有机层用水洗涤并且蒸发至干燥。气相色谱表明大多数二氢黄豆苷原已经转化成通过GC-MS[M+384.(G.E.Joannou，G.E.Kelly，A.Y.Reeder，M.Waring和C.Nelson.甾体生物化学分子生物学杂志(J.Steroid. Biochem.Molec.Biol.)Vol.54，No3/4，167-184页，1995)]所证实的四氢黄豆苷原。也可以用硼氢化钠二烷/水(5∶1)将二氢黄豆苷原还原来合成四氢黄豆苷原(参见：G.E.Joannou，G.E.Kelly，A.Y.Reeder，M.Waring和C.Nelson.甾体生物化学分子生物学杂志(J.Steroid.Biochem.Molec.Biol.)Vol.54，No3/4，167-184页，1995)。
5：去氢牛尿酚的合成(化合物10)
将四氢黄豆苷原混合物(0.02336g)悬浮在干燥的苯(5ml)中，加入对甲苯磺酸(0.0487g)。将得到的混合物在95℃加热35分钟，然后将苯蒸发掉，用HPLC(MeOH/H2O＝60∶40)纯化粗产物，得到了去氢牛尿酚和牛尿酚。用H NMR、GS-MS和高分辨率MS证实了去氢牛尿酚的生成。
6：二氢金雀异黄素(化合物2和5)的合成
二氢金雀异黄素
将金雀异黄素(Genistein)(Sigma公司，0.0023g，0.0085mmol)溶于EtOH(2ml)中，在搅拌状态下加入10％Pd/C(0.0023g)和甲酸铵(0.0027g，0.043mmol)。把得到的混合物搅拌过夜。GC表明所有的起始原料都已转化成通过GC、GC-MS和NMR数据所确认的二氢金雀异黄素。还原产物用HPLC纯化。
实施例4
如Kelly等人在临床化学动态(Clinica Chemica Act)(1993)9-22中所描述的方法那样，将志愿者的尿用气相色谱-质谱法(GC-MS)法筛析，在此引入此文献以作参考。选择那些尿中含有超过0.5μm并且通常为2.5-50μm或更多的个体来进行进一步的实验。从那些个体中获得粪便样本，使用标准的粪便培养条件来得到微生物培养物。使用GC-MS检测能分泌感兴趣化合物的生物体。分离能分泌每一种结构式1-19化合物至少50μg的生物体。将这些生物体进行微生物发酵以生产结构式1-19的化合物。当生物体是选自乳酸杆菌属、产气荚膜梭菌、拟杆菌属、白色念珠菌和其它酵母、厌氧球菌、瘤胃球菌属、真细菌、消化链球菌属、梭状芽胞杆菌属、双歧杆菌、消化球菌属、链球菌属和/或厌氧链球菌属、格兰氏阴性兼性菌、梭形杆菌属时，它们可直接用于食品组合物例如乳制品中以生产结构式1-19的化合物。
实施例5
将结构式1-19的化合物与大豆粉基质(可从可食用加强蛋白StMarys，Australia获得的脱脂大豆粉)混合以制备治疗制剂。
制备含有40mg-200mg活性化合物的一系列药物制剂。
为了实现本实施例的目的，以上面提到的大豆粉或不含胆固醇的酸乳为基质，制备含有200mg每一种结构式1-19的活性化合物的明胶胶囊和片剂。
实施例6
A.治疗血管疾病-绝经综合症、热潮红、高血压、动脉粥样硬化和男性阳萎
用大鼠主动脉环进行的血管反应性实验通常被认为能直接预测候选化合物治疗上述血管疾病的生物学效果(Karapapanis，S.等人(1994)Heptology)。根据Karapapanis的方法(如上)，在血管收缩剂去甲肾上腺素存在的情况下，测定在主动脉环中对限制剂反应的抑制作用。二氢黄豆苷原(化合物1)、二氢金雀异黄素(化合物2和5)、四氢黄豆苷原(化合物8)、ODMA(化合物13)和牛尿酚(化合物10)都表现出了有效的对去甲肾上腺素反应的抑制作用，也就是说，它们能抑制血管收缩剂的反应。
接下来的临床实验是用来证实这些化合物在治疗上述疾病方面的治疗价值。
B：治疗激素应答癌-治疗与激素有关的癌，包括乳房癌、卵巢癌、睾丸癌、子宫癌、子宫内膜癌和前列腺癌
使用特征很明确的人应答癌细胞系K562和HL60测定本发明中的化合物抑制激素应答癌细胞生长的活性。抗癌筛分试验测定了对细胞增殖的抑制，这种抑制导致终未分化细胞的死亡。细胞死亡是由于编程性细胞死亡或坏死，ODMA(化合物13)和牛尿酚(化合物10)或有效的抑制剂抑制了细胞系K563和HL60的生长，因此从此结果中能直接预测出这些化合物能抑制与激素有关的癌例如上面提及的癌的生长。四氢黄豆苷原(化合物8)表现出很强的抑制细胞系HL60的作用。
接下来的临床实验是用来证实这些化合物在治疗上述疾病方面的治疗价值。
C：与癌症治疗有关的抗氧化剂实验；与胆固醇氧化有关的疾病，例如动脉粥样硬化血管病；心肌梗塞、中风、心脏病；关节炎和白内障
已经有许多研究表明，具有抗氧化剂活性的化合物能用于治疗上面所述的疾病(见例如McLaughlan等人(1995)生物化学协会会报(Biochem.Soc.Trans.)23(2)2575；和van’t Veer等人(1996)癌症流行病生物标记物进展(Cander Epidemiol Biomarkers Prev.)5(6)441-7)。
根据本发明的化合物具有抗氧化剂活性。
四氢黄豆苷原(化合物8)和去氢牛尿酚(化合物10)是非常有效的抗氧化剂。下面进行与这些化合物有关的测试：
1.LDL抗氧化测试-此项测试是测定化合物直接清除自由基或螯合过渡金属元素的能力。在同样条件下，与作为阳性对照的抗坏血酸盐相比，滞后时间越长，化合物抗氧化活性就越强。这些测试是依据Esterbauer等人Free.Rad.Res.Coms.(1989)6，67-75中的方法进行的。简言之，将LDL(0.25 mg/ml)与10μm活性化合物以及4μm Cu++一起培养，通过HPLC分析来测定LDL的氧化情况。测定结果如下：
样本 滞后时间-分钟 比对照增加的％
对照 20
抗坏血酸盐 50 150
四氢黄豆苷原 ＞140 ＞600
去氢牛尿酚 ＞140 ＞600
这项重要发现表明，四氢黄豆苷原和去氢牛尿酚是非常有效的抗氧化剂，并且因此被认为可以有效地治疗癌、心肌梗塞、中风、关节炎、阳光诱导的皮肤损伤或白内障、以及其它由氧化性损伤导致的疾病。
2.氧化还原测试-此项测试是测定在存在维生素E的条件下，化合物防止LDL脂质氧化的能力。本项测试是一种生理测试，维生素E(α-生育酚)与LDL一起存在于血流中，并且LDL氧化被认为是造成动脉粥样硬化的主要因素之一。测得值越小，氧化还原活性就越高。高的氧化还原活性表示化合物能与α-生育酚在LDL中相互作用，也许是通过还原α-生育酚自由基而相互作用的。本项测试间接地测定了化合物与α-生育酚在正经受缓和而化学控制的氧化作用的人LDL中协同作用的能力。氧化作用是通过当内源性α-生育酚消耗了20％时，测定胆甾醇酯氢过氧化物的积聚量来评价的。使用丁基羟基甲苯(BHT 10μm)作为阳性对照。氧化还原指标是这样测定的：存在测试样本时LDL的相对氧化程度除以测试化合物不存在时LDL的相对氧化程度。活性化合物使氧化还原指标降低。测试是依据Bowry，V.W.等人(1995)生化杂志(J.Bio.Chem.)270(11)5756-5763中的方法进行的。这些测试表明化合物1-19能与维生素E协同作用以防止脂质、蛋白和其它生物物质的氧化。
与作为阳性对照的抗氧化剂(BHT)相比，测试结果表明，作为实例的去氢牛尿酚(化合物10)是特别优秀的抗氧化剂，去氢牛尿酚的氧化还原指标是4.5±1.2，BHT的是6.3。
上面的测试结果表明，化合物1-19，特别是去氢牛尿酚能与维生素E协同作用以阻止氧化反应。这是一项重要的发现，因为在以前维生素E已经被认为具有与促进氧化相反的活性并且能减少脂质和蛋白质的氧化。含有一种或多种化合物1-19和维生素E的组合物可以用来治疗癌、心肌梗塞、中风、关节炎、阳光诱导的皮肤损伤或白内障、以及其它能用抗氧化剂治疗的适应症。
3.与α-生育酚(TRAA)的协同作用-本项测试直接评定了测试样本在氯化十六烷基三甲铵(HTAC)或SDS分子团中减少α-生育酚自由基的能力。使用抗坏血酸盐作为阳性对照。以存在测试样本时α-生育酚自由基的相对衰减速度常数除以不存在测试样本时α-生育酚自由基的相对衰减速度常数来表示测定结果。TRAA接近单体被认为具有很差的协同活性，而活性化合物的测定值很高，这是因为它们与α-生育酚混合后能立即将其自由基清除掉。
测试是依据Witting等人(1996)脂质研究杂志(J.Lipid Res.，)37，853-867中的方法进行的。这些测试结果表明化合物1-19，特别是去氢牛尿酚(化合物10)，二氢黄豆苷原和二氢金雀异黄素能与α-生育酚相互协同作用。
4.LDL受体实验-治疗动脉粥样硬化、心肌梗塞、中风和高血压。本项实验将证实向上调节LDL受体的化合物能使循环中的LDL减少，并且因此能减少动脉粥样硬化、心肌梗塞、中风和高血压的发病可能。依据Stephan Z.F.和Yurachek，E.C.(1993)脂质研究杂志(J,LipidRes.，)34，325-330中的方法进行测定，结果表明结构式1-19的化合物能有效地增加肝细胞对LDL的摄取，这直接预示着人血流中循环的LDL会减少。ODMA和牛尿酚在这方面表现出了特别好的活性。
实施例7
治疗痤疮
一个自青春期以来就生长痤疮的18岁女孩，对避孕药丸或局部用乳膏没有任何反应，并且出于安全原因拒绝使用异维生素A酸(Roacutane)，用大豆异黄酮提取物对她给药，所述的提取物中含有金雀异黄素、黄豆苷原、芒柄花黄素和鸡豆黄素A，如通过尿分析所证实的那样，它们转变成其代谢物，即化合物1、2、5、8、10、11、13和14。每天给药40mg，每天给药2次，2周内痤疮症状、颜色和一般外观有了显著的改善。
一个自青春期以来就生长痤疮的40岁男子，对局部用乳膏没有任何反应，并且出于安全原因拒绝使用异维生素A酸，用如前面所描述的大豆异黄酮提取物给药。如通过尿分析所证实的那样，这些异黄酮转变成其代谢物，即化合物1、2、5、8、10、11、13和14。出乎意料的是，他报告说在2周内他的痤疮有了戏剧性的改善，起了在约20年中从来没有观察到的变化。
随后的临床实验已经证实了上述化合物在治疗痤疮方面的治疗价值。
接下来的临床实验是用来证实上述化合物在治疗上述疾病方面的治疗价值。
实施例8
将异黄酮提取物以16mg的日剂量对一个患有前列腺癌的67岁老年男子给药，所述的异黄酮提取物是从红花草中提取的，其中含有金雀异黄素、黄豆苷原、芒柄花黄素和鸡豆黄素A。接下来进行前列腺癌手术以后，针对提取的前列腺组织的病理报告表明，编程性细胞死亡发生率增加了(Stephens，F.O.(1997)澳大利亚医学联盟杂志(J.Aus.Med.Assoc.167，3，138-140))。对此病人的尿样进行的分析表明其中含有前面提及的代谢物，这表示这些化合物与此病人的病情改善有关，因为前列腺切除部分有变性变化，尤其编程性细胞死亡作用表示雄激素丧失和对雌激素治疗有反应。
实施例9
用一组病人进行实验，其中包括具有乳癌病史的妇女(已经进行过手术或辐射治疗，或两种治疗都已进行过)和具有很强的乳癌家族连续性的妇女，也就是说，她们的母亲或同胞已经患过乳癌。这项实验是测定将化合物1-19每天通过皮肤贴剂透皮给药是否能防止乳癌发生或能防止接受癌治疗后的癌转移。
制备的贴剂中含有能迅速透皮吸收的亲脂性载体乳膏。这种乳膏包括一种含有甘油和花生油的甘油冷膏。将从结构式1-19的任一个化合物中选择的活性化合物与亲脂性乳膏混合，使每一片贴剂中包含10mg-100mg活性化合物。每天将这种贴剂贴在皮肤上，并且能快速吸收。两个小时后拿掉贴剂。非彼即此，这种贴剂也可以每天贴很长时间。
经过一年的实验周期后，发现这组高危病人没有表现出任何乳癌或其它癌转移的迹象。
在另外相似的一组高危病人中也显示了这种治疗的有效性。将化合物11、13和14用与上面相同的方式和剂量对病人透皮给药。经过6个月的实验周期后观察到了相同的有益结果。
实施例10
用一组正患有良性前列腺肥大(BPH)和不同程度前列腺癌的病人进行实验来测定结构式1-19的化合物给药的效果。给药方案与实施例3相同，包括每天服用一粒含有200mg活性化合物的明胶胶囊。实验发现相关的癌标记物(PAS，前列腺特异抗原)生成的速度有了显著下降。癌肿块又一次表现出退化，或表现为没有进一步生长。在另一个实验中，一个患有BPH的45岁男子具有尿路梗阻和尿频症状。每日服用40mg红花草异黄酮提取物后，症状消失。尿样分析表明尿中含有上述的代谢物。
给一个患有晚期肠癌的病人每日静脉注射2g溶于无菌生理盐水的结构式14的化合物，治疗3周。病人的疼痛和不适显著降低，并且也观察到了癌标记物的减少。在治疗期间癌肿块的生长也被抑制。
用与治疗上面的病人相同的手段治疗另一个患有相同疾病的病人，只是2g的活性化合物是通过快速浓注的方式给药。得到的结果与上面一段中描述的一样。
在另外的一系列实验中，患有晚期肠癌的病人每日快速浓注(静脉内或肌内)2g一种选自结构式1-19的化合物。实验周期过后，结果表明疼痛和不适有显著降低。血液分析表明癌肿块标记物(癌胚胎抗原(CEA))减少了，并且癌肿块生长速度下降了。
实施例11
用患有男性脱发的病人进行实验。每一受试者每天在头皮上涂有含有50mg活性化合物的惰性药用凝胶。一个月的实验周期过后，在治疗区域观察到浅色的短绒毛或头发残茬。本项实验表明这些化合物能有效地治疗脱发，并且通过长期敷用可以使头发再生。
在本说明书中，除非上下文需要，否则术语“包含”，或其变化例如“含有”或术语“包括”或其变化，是指其包含规定的成份或组分或成份或组分的组合，但不排除任何其它成份或组分或成份或组分的组合。从这方面考虑，在对权利要求保护范围的解释上，将一个或多个技术特征加入到任一权利要求中的实施方案应被认为在本发明的保护范围内，因为本发明所要求保护的必要技术特征包含在这些实施方案中。
本领域普通技术人员能认识到，除了那些特别描述的实施方案以外，本发明容许作出变化和更改。需要知道的是，本发明包括所有不超出其宗旨和保护范围的变化和更改。本发明也包括所有在说明书所提到或指出的步骤、特征、组合物和化合物，单独地或共同地，和两个或多个所说的步骤或特征的所有组合。
Claims (13)
1.一种药物组合物，包含具有下列结构的化合物：
其中
R11代表H或OH，
R12代表H；COOH；CO2RC，其中RC为C1-10烷基；或CONHRE，其中RE为H，C1-10烷基或氨基酸；
以及可药用载体和/或赋形剂。
2.根据权利要求1的药物组合物，其中所述化合物具有下列结构：
3.根据权利要求1或2的药物组合物，其中所述组合物为单位剂量形式的可注射性组合物或可输注性组合物。
4.一种药物组合物，包含具有下列结构的化合物：
其中
R11代表H或OH，
R12代表H；COOH；CO2RC，其中RC为C1-10烷基；或CONHRE，其中RE为H，C1-10烷基或氨基酸；
以及可药用载体和/或赋形剂；
其中所述化合物存在的量在0.1mg-2g的范围。
5.根据权利要求4的药物组合物，其中所述化合物存在的量在0.5mg-1g的范围。
6.根据权利要求5的药物组合物，其中所述化合物存在的量在50mg-200mg的范围。
7.根据权利要求4的药物组合物，其中所述化合物具有下列结构：
8.根据权利要求4的药物组合物，其中所述组合物为单位剂量形式的注射性组合物或可输注性组合物。
9.一种用于局部给药的药物组合物，包含具有下列结构的化合物：
其中
R11代表H或OH，
R12代表H；COOH；CO2RC，其中RC为C1-10烷基；或CONHRE，其中RE为H，C1-10烷基或氨基酸；
以及可药用载体和/或赋形剂；
其中所述化合物存在的量在0.1-5％重量/重量的范围。
10.根据权利要求9的药物组合物，其中所述化合物存在的量在0.5-2％重量/重量的范围。
11.根据权利要求9的药物组合物，其中所述化合物具有下列结构：
12一种可注射的药物组合物，包含具有下列结构的化合物：
其中
R11代表H或OH，
R12代表H；COOH；CO2RC，其中RC为C1-10烷基；或CONHRE，其中RE为H，C1-10烷基或氨基酸；
以及可药用载体和/或赋形剂；
其中所述化合物存在的量在0.1-60％重量/体积的范围。
13.根据权利要求12的药物组合物，其中所述化合物具有下列结构：
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101716135B (zh) * | 2010-01-08 | 2012-11-14 | 山西医科大学 | 大豆异黄酮固体分散体栓剂及其制备方法 |
| CN102503922A (zh) * | 2011-11-07 | 2012-06-20 | 吉首大学 | 黄烷醇（异黄烷醇）类尿素酶抑制剂及其合成和用途 |
| CN105777693A (zh) * | 2014-12-22 | 2016-07-20 | 王靖林 | 一种雌马酚的合成方法 |
| CN110590727A (zh) * | 2019-09-16 | 2019-12-20 | 西安联泽生物科技有限公司 | 一种雌马酚的制备方法 |
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