CN1372555A - 涉及异黄酮及其类似物的组合物和治疗方法 - Google Patents
涉及异黄酮及其类似物的组合物和治疗方法 Download PDFInfo
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- CN1372555A CN1372555A CN00812500A CN00812500A CN1372555A CN 1372555 A CN1372555 A CN 1372555A CN 00812500 A CN00812500 A CN 00812500A CN 00812500 A CN00812500 A CN 00812500A CN 1372555 A CN1372555 A CN 1372555A
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Abstract
描述了异黄酮化合物,推荐其作为治疗剂。例证与优选的化合物是(a)。预示这些化合物对雌激素受体具有良好的竞争结合性。这是例证性的。
Description
本发明有关涉及、含有、包含、包括和/或用于制备某些异黄酮化合物及其类似物的化合物、制剂、饮料、食品、方法和治疗用途。
按照本发明的一个方面,提供了通式I的异黄酮化合物及其类似物:其中R1和R2独立地是氢、羟基、OR9、OC(O)R10、OS(O)R10、CHO、C(O)R10、COOH、CO2R10、CONR3R4、烷基、卤代烷基、芳基、芳烷基、硫代、烷硫基、氨基、烷基氨基、二烷基氨基、硝基或卤代,Z是氢,W是R1,A是氢、羟基、NR3R4或硫代,B选自或者W是R1,A和B与它们所连接的碳原子一起构成六元环,所述六元环选自 或者W、A和B与它们所缔合的基团一起构成或者W和A与它们所缔合的基团一起构成且B是其中R3是氢、烷基、芳基、芳烷基、氨基酸、C(O)R11或CO2R12,其中R11是氢、烷基、芳基、芳烷基或氨基酸,R12是氢、烷基、卤代烷基、芳基或芳烷基,R4是氢、烷基或芳基,或者R3和R4与它们所连接的氮一起构成吡咯烷基或哌啶基,R5是氢、C(O)R11或CO2R12,其中R11和R12是如前文所定义的,R6是氢、羟基、烷基、芳基、氨基、硫代、NR3R4、C(O)R11、CO2R12或CONR3R4,其中R11和R12是如前文所定义的,R7是氢、C(O)R11、烷基、卤代烷基、芳基、芳烷基或Si(R13)3,其中R11是如前文所定义的,每个R13独立地是氢、烷基或芳基,R8是氢、羟基、烷氧基或烷基,R9是烷基、卤代烷基、芳基、芳烷基、C(O)R11或Si(R13)3,其中R11和R13是如前文所定义的,R10是氢、烷基、卤代烷基、氨基、芳基、芳烷基、氨基酸、烷基氨基或二烷基氨基,图
代表单键或双键,X是O、NR4或S,Y是其中R14、R15和R16独立地是氢、羟基、OR9、OC(O)R10、OS(O)R10、CHO、C(O)R10、COOH、CO2R10、CONR3R4、烷基、卤代烷基、芳基、芳烷基、硫代、烷硫基、氨基、烷基氨基、二烷基氨基、硝基或卤代,其条件是若R1是羟基或OC(O)RA,其中RA是烷基或氨基酸,R2是氢、羟基、ORB或OC(O)RA,其中RB是氨基酸,RA是如前文所定义的,W是氢,则Y不是4-羟基苯基或4-烷基苯基;若R1是羟基或OC(O)RA,其中RA是烷基或氨基酸,R2是氢、羟基、ORB或OC(O)RA,其中RB是氨基酸,RA是如前文所定义的,Y是4-羟基苯基或4-烷基苯基,则W不是氢;若R1是羟基或OC(O)RA,其中RA是烷基或氨基酸,Y是4-羟基苯基或4-烷基苯基,W是氢,则R2不是氢、羟基、ORB或OC(O)RA,其中RB是氨基酸,RA是如前文所定义的;若R2是氢、羟基、ORB或OC(O)RA,其中RB是氨基酸,RA是如前文所定义的,Y是4-羟基苯基或4-烷基苯基,W是氢,则R1不是羟基或OC(O)RA,其中RA是烷基或氨基酸。
按照本发明的另一方面,提供了通式II的异黄酮化合物及其类似物:其中R1和R2独立地是氢、羟基、OR9、OC(O)R10、OS(O)R10、CHO、C(O)R10、COOH、CO2R10、CONR3R4、烷基、卤代烷基、芳基、芳烷基、硫代、烷硫基、氨基、烷基氨基、二烷基氨基、硝基或卤代,ZA是OR9、OC(O)R10、OS(O)R10、CHO、C(O)R10、COOH、CO2R10、CONR3R4、烷基、卤代烷基、芳基、芳烷基、硫代、烷硫基、氨基、烷基氨基、二烷基氨基、硝基或卤代,W是R1,A是氢、羟基、NR3R4或硫代,B选自或者,W是R1,A和B与它们所连接的碳原子一起构成六元环,所述六元环选自或者,W、A和B与它们所缔合的基团一起构成或者W和A与它们所缔合的基团一起构成其中R3是氢、烷基、芳基、芳烷基、氨基酸、C(O)R11或CO2R12,其中R11是氢、烷基、芳基、芳烷基或氨基酸,R12是氢、烷基、卤代烷基、芳基或芳烷基,R4是氢、烷基或芳基,或者R3和R4与它们所连接的氮一起构成吡咯烷基或哌啶基,R5是氢、C(O)R11或CO2R12,其中R11和R12是如前文所定义的,R6是氢、羟基、烷基、芳基、氨基、硫代、NR3R4、COR11、CO2R12或CONR3R4,其中R11和R12是如前文所定义的,R7是氢、C(O)R11、烷基、卤代烷基、芳基、芳烷基或Si(R13)3,其中R11是如前文所定义的,每个R13独立地是氢、烷基或芳基,R8是氢、羟基、烷氧基或烷基,R9是烷基、卤代烷基、芳基、芳烷基、C(O)R11或Si(R13)3,其中R11和R13是如前文所定义的,R10是氢、烷基、卤代烷基、氨基、芳基、芳烷基、氨基酸、烷基氨基或二烷基氨基,图
代表单键或双键,X是O、NR4或S,Y是其中R14、R15和R16独立地是氢、羟基、OR9、OC(O)R10、OS(O)R10、CHO、C(O)R10、COOH、CO2R10、CONR3R4、烷基、卤代烷基、芳基、芳烷基、硫代、烷硫基、氨基、烷基氨基、二烷基氨基、硝基或卤代。
本发明人已经惊人地发现,通式I和II化合物:其中R1、R2、W、A、B、Z和ZA是如上所定义的,在下列疾病的治疗、预防、改善、防卫和/或防止中具有特有的实用性和有效性:绝经期综合征,包括热潮红、焦虑、抑郁、情绪摇摆、盗汗、头痛和尿失禁;骨质疏松;经前期综合征,包括液潴留、周期性乳腺痛和痛经;雷诺氏综合征;雷诺氏现象;伯格氏病;冠状动脉痉挛;偏头痛;高血压;良性前列腺肥大;各种形式的癌症,包括乳腺癌、子宫癌、卵巢癌、睾丸癌、大肠癌、子宫内膜癌、前列腺癌;动脉粥样硬化;阿尔茨海默氏病;炎性疾病,包括炎性肠疾病、溃疡性结肠炎、克罗恩氏病;风湿性疾病,包括类风湿性关节炎;痤疮;秃发,包括男性秃发(遗传性脱发);牛皮癣;与氧化剂应激反应有关的疾病,包括癌症;心肌梗塞;中风;关节炎;日光诱发的皮肤损伤或白内障。
按照本发明的另一方面,提供了用于下列疾病的治疗、预防、改善、防卫和/或防止的方法:绝经期综合征,包括热潮红、焦虑、抑郁、情绪摇摆、盗汗、头痛和尿失禁;骨质疏松;经前期综合征,包括液潴留、周期性乳腺痛和痛经;雷诺氏综合征;雷诺氏现象;伯格氏病;冠状动脉痉挛;偏头痛;高血压;良性前列腺肥大;各种形式的癌症,包括乳腺癌、子宫癌、卵巢癌、睾丸癌、大肠癌、子宫内膜癌、前列腺癌;动脉粥样硬化;阿尔茨海默氏病;炎性疾病,包括炎性肠疾病、溃疡性结肠炎、克罗恩氏病;风湿性疾病,包括类风湿性关节炎;痤疮;秃发,包括男性秃发(遗传性脱发);牛皮癣;与氧化剂应激反应有关的疾病,包括癌症;心肌梗塞;中风;关节炎;日光诱发的皮肤损伤或白内障(为方便起见,以下称为“治疗适应征”),该方法包括对受治疗者给以治疗学上有效量的一种或多种如上所定义的式I与II化合物。
本发明的另一方面是式I与II化合物的用途,用于制备治疗、改善、防卫、预防和/或防止一种或多种治疗适应征的药物。
本发明的另一方面是一种或多种式I与II化合物的用途,用于治疗、改善、防卫、预防和/或防止一种或多种治疗适应征。
本发明的另一方面包含治疗、预防、改善、防卫和/或防止治疗适应征的试剂,它包含单独的一种或多种式I与II化合物,或者所述化合物与一种或多种载体或赋形剂组合。
本发明的进一步方面是治疗组合物,它包含一种或多种式I与II化合物以及一种或多种药物载体和/或赋形剂。
本发明的更进一步方面是饮料或食品,它含有一种或多种式I与II化合物。
本发明的另外一方面是含有一种或多种微生物菌株的微生物培养物或食品,该微生物产生一种或多种式I与II化合物。
本发明还有另外一方面涉及一种或多种微生物,该微生物产生一种或多种式I与II化合物。优选地,该微生物是纯净的培养物,它可以与一种或多种其他产生式I与II化合物的培养物一起混合和/或给药。
本说明书和下列权利要求书全文中,除非另有需要,措辞“包含”及其变例将被理解为意味着包括所述一个整体或步骤或者一组整体或步骤,但是不排除任何其他整体或步骤或者一组整体或步骤。
术语“烷基”用来表示直链和支链烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基等。烷基具有1至10个碳原子,优选为1至6个碳原子,更优选为甲基、乙基、丙基或异丙基。烷基可以可选地被一个或多个氟、氯、溴、碘、羧基、C1-C4-烷氧羰基、C1-C4-烷基氨基-羰基、二-(C1-C4-烷基)-氨基-羰基、羟基、C1-C4-烷氧基、甲酰氧基、C1-C4-烷基-羰基氧基、C1-C4-烷硫基、C3-C6-环烷基或苯基取代。
术语“芳基”用来包括苯基和萘基,可以可选地被一个或多个C1-C4-烷基、羟基、C1-C4-烷氧基、羰基、C1-C4-烷氧羰基、C1-C4-烷基羰基氧基或卤代取代。
术语“卤代”用来包括氟代、氯代、溴代和碘代,优选为氟代和氯代,更优选为氟代。例如关于“卤代烷基”,将包括单卤代的、二卤代的、乃至全卤代的烷基。优选的卤代烷基是三氟甲基和五氟乙基。
本发明的化合物在与下列效应有关或由下列效应导致的疾病的治疗中具有特有的实用性:雌激素效应、雄激素效应、血管舒张与痉挛效应、炎性效应和氧化效应。
根据本发明的治疗对一种或多种式I与II化合物的需要量将取决于多种因素,包括具体应用、所用特定化合物的性质、所治疗的疾病、给药的方式和患者的条件。式I与II化合物可以按常规方式和常规量给药。例如参见Goodman和Gilman《治疗剂的药理学基础)》1299(第7版,1985)。所用具体剂量将取决于所治疗的疾病、受治疗者的状态、给药的途径和上述其他熟知因素。一般地,每名患者的每日剂量可以在0.1mg至2g的范围内;通常从0.5mg至1g;优选从50mg至200mg。
本文所述用于治疗适应征治疗的药物组合物通常是这样制备的,将本发明的化合物(为方便起见,以下称为“活性化合物”)与一种或多种药学上或兽医上可接受的载体和/或赋形剂混合,这些是本领域所熟知的。
当然,载体在与制剂中的任何其他成分可相容的意义上必须是可接受的,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,或二者皆可,优选地与化合物配制成单位剂量,例如片剂,可以含有0.05至59重量%的活性化合物,或高达100重量%的活性化合物。可以在本发明的制剂中结合一种或多种活性化合物,制剂可以按照任何熟知的药学工艺加以制备,主要包括混合各组分,可选地包括一种或多种助剂。
本发明的制剂包括适合于口服、直肠、局部、经颊(例如舌下)、肠胃外(例如皮下、肌内、真皮内或静脉内)和透皮给药的那些,不过在任意给定的情况下,最适合的途径将取决于所治疗疾病的性质与严重性和所用特定活性化合物的性质。
适合于口服给药的制剂可以是不连续的单位,例如是胶囊剂、扁囊剂、锭剂或片剂,各自含有预定量的活性化合物;例如是粉剂或颗粒剂;例如是在水性或非水性液体中的溶液或悬浮液;或者例如是水包油或油包水型乳剂。这类制剂可以按照任意适合的药学方法加以制备,包括使活性化合物与适合的载体(如上所述它可以含有一种或多种助剂)缔合的步骤。一般地,本发明的制剂是这样制备的,将活性化合物与液体或微细粉碎的固体载体(或二者)均匀一致地混合,然后如果必要的话,使所得混合物成型,例如形成单位剂型。例如,片剂可以是这样制备的,压制或模制含有活性化合物、可选地与一种或多种助剂的粉末或颗粒。压制片可以这样制备,在适合的机械中压制自由流动的化合物,例如粉末或颗粒,化合物可选地与粘合剂、润滑剂、惰性稀释剂和/或表面活性剂/分散剂混合。模制片可以这样制备,在适合的机械中模制已用惰性液体粘合剂湿润过的粉状化合物。
适合于经颊(舌下)给药的制剂包括锭剂,在经过矫味的基质中包含活性化合物,例如蔗糖和阿拉伯胶或黄蓍胶;和软锭剂,在惰性基质中包含化合物,例如明胶和甘油或蔗糖和阿拉伯胶。
适合于肠胃外给药的本发明组合物适宜包含活性化合物的无菌水性制剂,该制剂优选地与预期接受者的血液是等渗的。这些制剂优选地是静脉内给药的,不过给药也可以借助皮下、肌内或真皮内注射的方式进行。这类制剂可以适宜这样制备,将化合物与水或甘氨酸缓冲液混合,赋予所得溶液以无菌性和与血液等渗性。根据本发明的可注射制剂一般含有0.1至60%w/v的活性化合物,按0.1ml/分钟/kg的速率给药。
适合于直肠给药的制剂优选地是单位剂量的栓剂形式。它们可以这样制备,将活性化合物与一种或多种常规的固体载体混合,例如可可脂,然后使所得混合物成型。
适合于对皮肤局部给药的制剂或组合物优选地采取软膏剂、霜剂、洗剂、糊剂、凝胶剂、喷雾剂、气雾剂或油剂的形式。可以使用的载体包括凡士林、羊毛脂、聚乙二醇、醇类和其两种或多种的组合。活性化合物的浓度一般是从0.1至0.5%w/w,例如从0.5至2%w/w。这类组合物的实例包括化妆品用皮肤霜剂。
适合于透皮给药的制剂可以是不连续贴剂的形式,贴剂适合于长期与受者表皮紧密接触。这类贴剂适合含有活性化合物的可选被缓冲的水溶液,例如所述活性化合物的浓度为0.1M至0.2M。
适合于透皮给药的制剂还可以按照离子电渗疗法加以释放(例如参见《药学研究》3(6):318(1986)),通常采取活性化合物的可选被缓冲的水溶液形式。适合的制剂包含柠檬酸盐或bis/tris缓冲液(pH6)或乙醇/水,含有0.1M至0.2M活性成分。
还可以提供活性化合物的食品形式,例如加入、混合、包裹或结合(或添入)在食品中。术语食品使用其最广泛的含义,包括液体制剂,例如饮料,包括乳制品,和其他食品,例如保健条(health bar)、甜点等。按照标准实践能够容易地制备含有本发明化合物的食品制剂。
本发明化合物具有强抗氧化活性,因而在下列领域中具有广泛的实用性:药物与兽医,化妆品、例如防止皮肤衰老的皮肤霜剂,防晒剂,食品,保健饮料,香波等。
已经惊人地发现,式I或II化合物与维生素E协同作用,防止脂质、蛋白质和其他生物分子氧化。
因此,本发明的进一步方面提供组合物,包含一种或多种式I或II化合物、维生素E,和可选的在药学、兽医学或化妆品学上可接受的载体和/或赋形剂。
治疗方法、用途和组合物可以施用于人或动物,例如宠物(例如狗和猫)、鸟(例如鸡、火鸡、鸭)、牲畜(例如牛、绵羊、猪和山羊)等。
式I与II化合物可以按照本领域技术人员已知的标准方法加以制备。适合的方法例如可以参见国际专利申请WO 98/08503,全文引用在此作为参考文献。化学合成领域技术人员可以用来构建式I与II所述母环结构的方法描绘在下列流程1-8中。在本发明化合物的合成中可以酌情使用本领域技术人员已知的化学官能团的保护、去保护、合成子和其他工艺。在下列流程所描绘的结构式中,R1、R2、R6、R8、R14、R15、R16、W和X是如上所定义的。T部分是如上式I或II所定义的Z或ZA。异黄酮衍生物的还原可以按照本领域技术人员熟知的操作进行,包括硼氢化钠还原,和金属催化剂的氢化,例如Pd/C、Pd/CaCO3和氧化铂(IV)(亚当氏催化剂),反应在质子或质子惰性溶剂中进行。终产物和异构体比例可以因所选择的催化剂/溶剂系统而异。下述流程不被视为对本文所述发明范围的限制。
实施例1
取代的异黄酮的通用合成
6-氯-4’,7-二羟基异黄酮是这样合成的,4-氯雷琐酚与4-羟基苯乙酸缩合,得到5-氯-2,4,4’-三羟基脱氧苯偶姻。在三氟化硼醚合物的存在下用二甲基甲酰胺和甲磺酰氯处理,完成中间体脱氧苯偶姻的环化。
通过改变雷琐酚或苯乙酸上的取代模式,按相似方式还可以合成大量其他取代的异黄酮。例如从5-甲基雷琐酚开始得到4’,7-二羟基-5-甲基异黄酮,在通用合成方法中使用3-羟基苯乙酸得到3’-羟基异黄酮衍生物。
异黄烷-4-酮
实施例2
6-氯-4’,7-二乙酰氧基异黄酮的合成
将6-氯-4’,7-二羟基异黄酮(1.25g,4.3mmo1)、乙酸酐(7.5ml)与吡啶(1.4ml)的混合物在105-110℃油浴中加热1小时。冷却混合物至室温后,进一步搅拌30分钟,在此期间二乙酸酯从溶液中结晶出来。将产物过滤,用含水甲醇(50%)充分洗涤,干燥,得到6-氯-4’,7-二乙酰氧基异黄酮(1.2g,75%),为无色棱晶。
1H NMR(CDCl3):δ2.32(s,3H,OCOCH3),2.41(s,3H,OCOCH3),7.16(d,2H,J8.6Hz,ArH),7.36(s,1H,H8),7.57(d,2H,J8.6Hz,ArH),8.00(s,1H,H5),8.37(s,1H,H2).
实施例3
6-氯-4’,7-二乙酰氧基异黄烷-4-酮的合成
将亚当氏催化剂(0.045g)加入到6-氯-4’,7-二乙酰氧基异黄酮(0.25g,0.7mmol)的乙酸乙酯(30ml)溶液中,将混合物在室温氢气氛下搅拌24小时。通过C盐过滤除去催化剂,在真空中蒸发所得滤液。残余物从乙醇中重结晶,得到6-氯-4’,7-二乙酰氧基异黄烷-4-酮(0.15g,60%),为无色板状物。
1H NMR(CDCl3):δ2.29(s,3H,OCOCH3),2.37(s,3H,OCOCH3),3.98(dd,1H,J6.0Hz,7.5Hz,H3),4.68(m,2H,H2),6.87(s,1H,H8),7.07(d,2H,J8.6Hz,ArH),7.27(d,2H,J8.6Hz,ArH),8.01(s,1H,H5).
实施例4
6-氯-4’,7-二羟基异黄烷-4-酮的合成
将咪唑(0.60g)加入到6-氯-4’,7-二乙酰氧基异黄烷-4-酮(0.24g,0.06mmol)的无水乙醇(5.0ml)悬液中,将混合物在氩下回流45分钟。在减压下浓缩溶液,向残余物中加入蒸馏水(10ml)。将混合物在冰箱内放置过夜,将所得沉淀过滤,用水洗涤,得到6-氯-4’,7-二羟基异黄烷-4-酮(0.14g,75%),为白色粉末。
1H NMR(d6-丙酮):δ3.87(t,1H,J7.2Hz,H3),4.64(d,2H,J6.2Hz,H2),6.59(s,1H,H8),6.78(d,2H,J8.7Hz,ArH),7.10(d,2H,J8.7Hz,ArH),7.70(bs,1H,OH),7.77(s,1H,H5).
实施例5
4’,7-二乙酰氧基-5-甲基异黄酮的合成
将4’,7-二羟基-5-甲基异黄酮(1.51g,5.6mmol)、乙酸酐(9ml)与吡啶(1.7ml)的混合物在105-110℃油浴中加热1小时。冷却混合物至室温后,进一步搅拌30分钟,在此期间二乙酸酯从溶液中结晶出来。将产物过滤,用水充分洗涤,从甲醇中重结晶,得到4’,7-二乙酰氧基-5-甲基异黄酮(1.8g,91%),为无色棱晶。
m.p.195-97℃,1H NMR(CDCl3):δ2.32(s,3H,OCOCH3),2.35(s,3H,OCOCH3),2.87(s,3H,Me),6.92(bs,1H,H8),7.12(bs,1H,H5),7.16(d,2H,J8.7Hz,ArH),7.55(d,2H,J8.7Hz,ArH),7.89(s,1H,H2).
实施例6
4’,7-二乙酰氧基-5-甲基异黄烷-4-酮的合成
将披钯硫酸钡(5%,0.06g)加入到4’,7-二乙酰氧基-5-甲基异黄酮(0.30g,0.8mmol)的乙酸乙酯(50ml)溶液中,将混合物在室温氢气氛下搅拌24小时。通过C盐过滤除去催化剂,在真空中蒸发所得滤液。残余物从乙醇中重结晶,得到4’,7-二乙酰氧基-5-甲基异黄烷-4-酮(0.20g,67%),为无色板状物。
m.p.143-45℃,1H NMR(CDCl3):δ2.29(s,3H,OCOCH3),2.30(s,3H,OCOCH3),2.62(s,3H,Me),3.95(t,1H,J7.2Hz,H3),4.62(d,2H,J6.8Hz,H2),6.59(d,1H,J2.2Hz,H8),6.66(d,1H,J2.2Hz,H5),7.07(d,2H,J8.3Hz,ArH),7.28(d,2H,J8.3Hz,ArH).
实施例7
4’,7-二羟基-5-甲基异黄烷-4-酮的合成
将咪唑(0.63g)加入到4’,7-二乙酰氧基-5-甲基异黄烷-4-酮(0.50g,1.4mmol)的无水乙醇(20.0ml)悬液中,将混合物在氩下回流45分钟。在减压下浓缩溶液,向残余物中加入蒸馏水(10ml)。将混合物在冰箱内放置过夜,将所得沉淀过滤,用水洗涤,得到4’,7-二羟基-5-甲基异黄烷-4-酮(0.25g,66%),为白色粉末。
1H NMR(d6-丙酮):δ2.51(s,3H,Me),3.76(t,1H,J5.7Hz,H3),4.57(d,2H,J7.1Hz,H2),6.26(d,1H,J2.2Hz,H8),6.35(d,1H,J2.2Hz,H5),6.78(d,2H,J8.7Hz,ArH),7.11(d,2H,J8.7Hz,ArH).
异黄烷-4-醇和异黄-3-烯
实施例8
4’,7-二乙酰氧基-5-甲基异黄烷-4-醇的合成
4’,7-二乙酰氧基-5-甲基异黄烷-4-醇是这样制备的,在氢气氛下,在乙酸乙酯(30ml)中,用亚当氏催化剂进行4’,7-二乙酰氧基-5-甲基异黄酮(0.25g)的还原达72小时。通过C盐垫过滤溶液,主要得到顺式-4’,7-二乙酰氧基-5-甲基异黄烷-4-醇。1H NMR(CDCl3):δ2.26(s,3H,OCOCH3),2.30(s,H,OCOCH3),2.62(s,3H,Me),3.24(dt,1H,J3.4Hz,J11.8Hz,H3),4.31(ddd,1H,J1.4Hz,3.6Hz,10.5Hz,H2);4.57(dd,1H,J10.5Hz,11.8Hz,H2),4.82(bs,1H,H4),6.51(d,1H,J2.1Hz,H8),6.59(d,1H,J2.1Hz,H6),7.06(d,2H,J8.6Hz,ArH),7.29(d,2H,J8.6Hz ArH).
实施例9
4’,7-二乙酰氧基-5-甲基异黄-3-烯
4’,7-二乙酰氧基-5-甲基异黄-3-烯是这样制备的,在无水二氯甲烷(20ml)中,用五氧化磷(2.0g)进行顺式-与反式-4’,7-二乙酰氧基-5-甲基异黄烷-4-醇(0.2g)的脱水。粗产物经过硅胶柱色谱纯化,用二氯甲烷作为洗脱剂。1H NMR(CDCl3):δ2.28(s,3H,OCOCH3),2.31(s,3H,OCOCH3),2.36(s,3H,Me),5.08(s,2H,H2),6.49(d,1H,J2.0Hz,H8),6.52(d,1H,J2.2Hz,H5),6.89(s,1H,H4),7.14(d,2H,J8.6Hz,ArH),7.44(d,2H,J8.6Hz,ArH).
实施例10
4’,7-二羟基-5-甲基异黄-3-烯
在标准条件下,通过水解作用除去乙酰氧基,从4’,7-二乙酰氧基-5-甲基异黄-3-烯制备4’,7-二羟基-5-甲基异黄-3-烯。
实施例11
3’,5,7-三羟基异黄鎓氯(Trihydroxyisoflavyliumchloride)
将磷酰氯(1.75ml)加入到单醛(0.95g)与藤黄酚二水合物(1.6g)在乙腈(10ml)中的混合物中。将混合物在30℃下搅拌20分钟,然后在室温下搅拌3小时。过滤橙色沉淀,用乙酸洗涤,得到异黄鎓盐。
实施例12
异黄-3-烯-3’,5,7-三醇的合成
异黄-3-烯-3’,5,7-三醇是这样制备的,在乙酸乙酯(11ml)与乙酸(3ml)中用氰基硼氢化钠(0.33g)进行3’,5,7-三羟基异黄鎓氯(0.5g)的还原,用色谱法分离所得异黄-3-烯与异黄-2-烯的混合物。
1H NMR(d6-丙酮):δ4.99(s,2H,H2),5.92(d,1H,J2.0Hz,ArH),6.04(d,1H,J2.2Hz,ArH),6.78-7.18(m,5H,ArH).
异黄烷
实施例13
异黄烷-5,7-二醇的合成
异黄烷-5,7-二醇是这样制备的,在氢气氛下,在含有乙酸乙酯(2.5ml)的乙酸(15ml)中,用披钯碳(5%,0.1g)进行5,7-二羟基异黄鎓氯(0.5g)悬液的还原。粗产物从1,2-二氯甲烷中重结晶,得到异黄烷,为无色针晶,m.p.76-78℃(文献m.p.77-79℃)
实施例14
4’,5,7-三乙酰氧基异黄烷的合成
4’,5,7-三乙酰氧基异黄烷是这样制备的,在氢气氛下,在乙酸酐(2.0ml)与乙酸乙酯(10ml)的混合物中,用氧化铂(0.04g)进行4’,5,7-三羟基异黄鎓氯(0.31g)悬液的还原。除去催化剂后,将粗产物用吡啶(0.5ml)回流,蒸发溶剂,结晶残余物,分离所得三乙酸盐。m.p.126-28℃
实施例15
异黄烷-4’,5,7-三醇的合成
通过水解作用除去三乙酰基,从4’,5,7-三乙酰氧基异黄烷制备异黄烷-4’,5,7-三醇。m.p.206-8℃
实施例16
利用由Panvera Corporation供应的“雌激素受体α或β竞争体测定法核心HTS试剂盒”(产品编号P2614/2615)测定各种本发明化合物对两种亚型雌激素受体的结合亲合性。6-氯-4’,7-二羟基异黄烷-4-酮对雌激素受体显示良好的竞争性结合,结果如下:
ERα受体=37.82μM
ERβ受体=32.14μM
结果显示,本发明的化合物在与下列效应有关或由下列效应导致的疾病的治疗中具有特有的实用性:雌激素效应、雄激素效应、血管舒张与痉挛效应、炎性效应和氧化效应。
本领域技术人员将认识到,本文所述发明容易变换和修改为除具体描述以外的其他方式。不言而喻的是,本发明包括所有这类变换和修改。本发明还单独或共同包括在说明书中涉及或指出的所有步骤、特征、组合物和化合物,以及任意两种或多种所述步骤或特征的任意与所有组合。
Claims (11)
1、通式I的异黄酮化合物或其类似物:其中R1和R2独立地是氢、羟基、OR9、OC(O)R10、OS(O)R10、CHO、C(O)R10、COOH、CO2R10、CONR3R4、烷基、卤代烷基、芳基、芳烷基、硫代、烷硫基、氨基、烷基氨基、二烷基氨基、硝基或卤代,Z是氢,W是R1,A是氢、羟基、NR3R4或硫代,B选自或者,W是R1,A和B与它们所连接的碳原子一起构成六元环,所述六元环选自或者,W、A和B与它们所缔合的基团一起构成或者W和A与它们所缔合的基团一起构成B是其中R3是氢、烷基、芳基、芳烷基、氨基酸、C(O)R11或CO2R12,其中R11是氢、烷基、芳基、芳烷基或氨基酸,R12是氢、烷基、卤代烷基、芳基或芳烷基,R4是氢、烷基或芳基,或者R3和R4与它们所连接的氮一起构成吡咯烷基或哌啶基,R5是氢、C(O)R11或CO2R12,其中R11和R12是如前文所定义的,R6是氢、羟基、烷基、芳基、氨基、硫代、NR3R4、COR11、CO2R12或CONR3R4,其中R11和R12是如前文所定义的,R7是氢、C(O)R11烷基、卤代烷基、芳基、芳烷基或Si(R13)3,其中R11是如前文所定义的,每个R13独立地是氢、烷基或芳基,R8是氢、羟基、烷氧基或烷基,R9是烷基、卤代烷基、芳基、芳烷基、C(O)R11或Si(R13)3,其中R11和R13是如前文所定义的,R10是氢、烷基、卤代烷基、氨基、芳基、芳烷基、氨基酸、烷基氨基或二烷基氨基,图
代表单键或双键,X是O、NR4或S,Y是其中R14、R15和R16独立地是氢、羟基、OR9、OC(O)R10、OS(O)R10、CHO、C(O)R10、COOH、CO2R10、CONR3R4、烷基、卤代烷基、芳基、芳烷基、硫代、烷硫基、氨基、烷基氨基、二烷基氨基、硝基或卤代,其条件是若R1是羟基或OC(O)RA,其中RA是烷基或氨基酸,R2是氢、羟基、ORB或OC(O)RA,其中RB是氨基酸,RA是如前文所定义的,W是氢,则Y不是4-羟基苯基或4-烷基苯基;若R1是羟基或OC(O)RA,其中RA是烷基或氨基酸,R2是氢、羟基、ORB或OC(O)RA,其中RB是氨基酸,RA是如前文所定义的,Y是4-羟基苯基或4-烷基苯基,则W不是氢;若R1是羟基或OC(O)RA,其中RA是烷基或氨基酸,Y是4-羟基苯基或4-烷基苯基,W是氢,则R2不是氢、羟基、ORB或OC(O)RA,其中RB是氨基酸,RA是如前文所定义的;若R2是氢、羟基、ORB或OC(O)RA,其中RB是氨基酸,RA是如前文所定义的,Y是4-羟基苯基或4-烷基苯基,W是氢,则R1不是羟基或OC(O)RA,其中RA是烷基或氨基酸。
2、通式II的异黄酮化合物或其类似物:其中R1和R2独立地是氢、羟基、OR9、OC(O)R10、OS(O)R10、CHO、C(O)R10、COOH、CO2R10、CONR3R4、烷基、卤代烷基、芳基、芳烷基、硫代、烷硫基、氨基、烷基氨基、二烷基氨基、硝基或卤代,ZA是OR9、OC(O)R10、OS(O)R10、CHO、C(O)R10、COOH、CO2R10、CONR3R4、烷基、卤代烷基、芳基、芳烷基、硫代、烷硫基、氨基、烷基氨基、二烷基氨基、硝基或卤代,W是R1,A是氢、羟基、NR3R4或硫代,B选自或者W是R1,A和B与它们所连接的碳原子一起构成六元环,所述六元环选自或者W、A和B与它们所缔合的基团一起构成或者W和A与它们所缔合的基团一起构成B是其中R3是氢、烷基、芳基、芳烷基、氨基酸、C(O)R11或CO2R12,其中R11是氢、烷基、芳基、芳烷基或氨基酸,R12是氢、烷基、卤代烷基、芳 基或芳烷基,R4是氢、烷基或芳基,或者R3和R4与它们所连接的氮一起构成吡咯烷基或哌啶基,R5是氢、C(O)R11或CO2R12,其中R11和R12是如前文所定义的,R6是氢、羟基、烷基、芳基、氨基、硫代、NR3R4、COR11、CO2R12或CONR3R4,其中R11和R12是如前文所定义的,R7是氢、C(O)R11、烷基、卤代烷基、芳基、芳烷基或Si(R13)3,其中R11是如前文所定义的,每个R13独立地是氢、烷基或芳基,R8是氢、羟基、烷氧基或烷基,R9是烷基、卤代烷基、芳基、芳烷基、C(O)R11或Si(R13)3,其中R11和R13是如前文所定义的,R10是氢、烷基、卤代烷基、氨基、芳基、芳烷基、氨基酸、烷基氨基或二烷基氨基,图
代表单键或双键,X是O、NR4或S,Y是其中R14、R15和R16独立地是氢、羟基、OR9、OC(O)R10、OS(O)R10、CHO、C(O)R10、COOH、CO2R10、CONR3R4、烷基、卤代烷基、芳基、芳烷基、硫代、烷硫基、氨基、烷基氨基、二烷基氨基、硝基或卤代。
4、用于下列疾病的治疗、预防、改善、防卫和/或防止的方法:绝经期综合征,包括热潮红、焦虑、抑郁、情绪摇摆、盗汗、头痛和尿失禁;骨质疏松;经前期综合征,包括液潴留、周期性乳腺痛和痛经;雷诺氏综合征;雷诺氏现象;伯格氏病;冠状动脉痉挛;偏头痛;高血压;良性前列腺肥大;各种形式的癌症,包括乳腺癌、子宫癌、卵巢癌、睾丸癌、大肠癌、子宫内膜癌、前列腺癌;动脉粥样硬化;阿尔茨海默氏病;炎性疾病,包括炎性肠疾病、溃疡性结肠炎、克罗恩氏病;风湿性疾病,包括类风湿性关节炎;痤疮;秃发,包括男性秃发(遗传性脱发);牛皮癣;与氧化剂应激反应有关的疾病,包括癌症;心肌梗塞;中风;关节炎;日光诱发的皮肤损伤或白内障(“治疗适应征”),该方法包括对受治疗者给以治疗学上有效量的一种或多种选自式I与II的化合物。
5、一种或多种选自式I与II的化合物的用途,用于制备治疗、改善、防卫、预防和/或防止一种或多种根据权利要求4的治疗适应征的药物。
6、一种或多种选自式I与II的化合物的用途,用于治疗、改善、防卫、预防和/或防止一种或多种根据权利要求4的治疗适应征。
7、用于治疗、预防、改善、防卫和/或防止根据权利要求4的治疗适应征的试剂,它包含单独的或者与一种或多种载体或赋形剂组合的一种或多种选自式I与II的化合物。
8、治疗组合物,它包含一种或多种选自式I与II的化合物以及一种或多种药物载体和/或赋形剂。
9、饮料或食品,它含有一种或多种选自式I与II的化合物。
10、含有一种或多种微生物菌株的微生物培养物或食品,该微生物产生一种或多种选自式I与II的化合物。
11、一种或多种微生物,该微生物产生一种或多种选自式I与II的化合物。
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CNA2005100558841A Pending CN1680358A (zh) | 1999-09-06 | 2000-09-06 | 涉及异黄酮及其类似物的组合物和治疗方法 |
CN00812500A Pending CN1372555A (zh) | 1999-09-06 | 2000-09-06 | 涉及异黄酮及其类似物的组合物和治疗方法 |
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EP (2) | EP1721903A1 (zh) |
JP (1) | JP2003508526A (zh) |
CN (2) | CN1680358A (zh) |
AT (1) | ATE334978T1 (zh) |
AU (2) | AUPQ266199A0 (zh) |
BR (1) | BR0013777A (zh) |
CA (1) | CA2384099A1 (zh) |
CZ (1) | CZ20021077A3 (zh) |
DE (1) | DE60029797D1 (zh) |
HK (1) | HK1048993A1 (zh) |
HU (1) | HUP0202570A3 (zh) |
IL (2) | IL148061A0 (zh) |
NO (1) | NO20021122L (zh) |
NZ (2) | NZ529085A (zh) |
TR (1) | TR200200581T2 (zh) |
WO (1) | WO2001017986A1 (zh) |
ZA (1) | ZA200200835B (zh) |
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2000
- 2000-09-06 WO PCT/AU2000/001056 patent/WO2001017986A1/en active Application Filing
- 2000-09-06 EP EP06015974A patent/EP1721903A1/en not_active Ceased
- 2000-09-06 JP JP2001522209A patent/JP2003508526A/ja active Pending
- 2000-09-06 DE DE60029797T patent/DE60029797D1/de not_active Expired - Lifetime
- 2000-09-06 TR TR2002/00581T patent/TR200200581T2/xx unknown
- 2000-09-06 AT AT00960231T patent/ATE334978T1/de not_active IP Right Cessation
- 2000-09-06 AU AU72617/00A patent/AU7261700A/en not_active Abandoned
- 2000-09-06 CA CA002384099A patent/CA2384099A1/en not_active Abandoned
- 2000-09-06 HU HU0202570A patent/HUP0202570A3/hu unknown
- 2000-09-06 NZ NZ529085A patent/NZ529085A/en unknown
- 2000-09-06 CN CNA2005100558841A patent/CN1680358A/zh active Pending
- 2000-09-06 CZ CZ20021077A patent/CZ20021077A3/cs unknown
- 2000-09-06 NZ NZ539819A patent/NZ539819A/en unknown
- 2000-09-06 CN CN00812500A patent/CN1372555A/zh active Pending
- 2000-09-06 EP EP00960231A patent/EP1210341B1/en not_active Expired - Lifetime
- 2000-09-06 BR BR0013777-4A patent/BR0013777A/pt not_active Application Discontinuation
- 2000-09-06 IL IL14806100A patent/IL148061A0/xx unknown
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2002
- 2002-01-30 ZA ZA200200835A patent/ZA200200835B/en unknown
- 2002-03-06 NO NO20021122A patent/NO20021122L/no not_active Application Discontinuation
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2003
- 2003-02-18 HK HK03101155.6A patent/HK1048993A1/zh unknown
- 2003-11-07 US US10/704,385 patent/US7488494B2/en not_active Expired - Fee Related
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2005
- 2005-12-14 US US11/300,976 patent/US20060106220A1/en not_active Abandoned
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2007
- 2007-09-17 US US11/901,724 patent/US20080014249A1/en not_active Abandoned
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NO20021122L (no) | 2002-03-26 |
EP1721903A1 (en) | 2006-11-15 |
ATE334978T1 (de) | 2006-08-15 |
US7488494B2 (en) | 2009-02-10 |
NO20021122D0 (no) | 2002-03-06 |
US20040147551A1 (en) | 2004-07-29 |
EP1210341A1 (en) | 2002-06-05 |
IL193332A0 (en) | 2009-05-04 |
EP1210341B1 (en) | 2006-08-02 |
HK1048993A1 (zh) | 2003-04-25 |
DE60029797D1 (de) | 2006-09-14 |
US20060106220A1 (en) | 2006-05-18 |
NZ539819A (en) | 2006-12-22 |
AU7261700A (en) | 2001-04-10 |
WO2001017986A1 (en) | 2001-03-15 |
IL148061A0 (en) | 2002-09-12 |
CA2384099A1 (en) | 2001-03-15 |
JP2003508526A (ja) | 2003-03-04 |
EP1210341A4 (en) | 2003-06-11 |
BR0013777A (pt) | 2002-05-07 |
ZA200200835B (en) | 2003-03-26 |
CN1680358A (zh) | 2005-10-12 |
AUPQ266199A0 (en) | 1999-09-30 |
TR200200581T2 (tr) | 2002-06-21 |
CZ20021077A3 (cs) | 2002-08-14 |
HUP0202570A3 (en) | 2005-01-28 |
US20080014249A1 (en) | 2008-01-17 |
HUP0202570A1 (hu) | 2002-11-28 |
NZ529085A (en) | 2005-08-26 |
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