CN1902213B - 异黄酮类前药、其组合物和涉及它们的治疗方法 - Google Patents
异黄酮类前药、其组合物和涉及它们的治疗方法 Download PDFInfo
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- CN1902213B CN1902213B CN2004800402381A CN200480040238A CN1902213B CN 1902213 B CN1902213 B CN 1902213B CN 2004800402381 A CN2004800402381 A CN 2004800402381A CN 200480040238 A CN200480040238 A CN 200480040238A CN 1902213 B CN1902213 B CN 1902213B
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- Prior art keywords
- compound
- osajin
- phosphoric acid
- acid ester
- dhe
- 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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Abstract
制备了异黄酮类化合物的磷酸酯，其用作前药、药物，并在制剂、饮料和食物中使用。
Description
发明领域
本发明涉及化合物、制剂、饮料、食物、方法和治疗用途，涉及、含有、包含、包括和/或制备特定的异黄烯(isoflavene)前药及其类似物。特别地，本发明涉及异黄酮类及其衍生物的磷酸酯、包含其的药物及其治疗用途。
背景
异黄酮及其许多衍生物具有非常广泛的重要生物学特性，其中包括雌激素作用。异黄酮如染料木素和黄豆苷元表现出具有调节或降低体内的雌激素类固醇水平的作用。最近，异黄烯特别是脱氢雌马酚表现出具有强效的化学治疗特性。在一些生物活性领域，甚至有些矛盾，例如，一些异黄酮类为雌激素受体激动剂，而另一些为雌激素受体拮抗剂。人们相信降低体内雌激素类固醇水平和较低的癌症发病率如乳腺癌和许多其它疾病和病症之间有很大关系。
但是，异黄酮类在动物中的生物活性在异黄酮家族的谱系中并不是一成不变的(conserved)，因此无法预测，特别是涉及到生物利用度时。因此，基本异黄酮类分子的每种特定的结构改变在动物中会产生从无效到有效的高度个体化的生物学特性。此外，人们认为一些生物活性分子的缀合物如一些生物活性雌激素类固醇的磷酸酯，会在很大程度上失去活性。
现在迫切需要鉴别新型的、改良的、更好的和/或可选择的药用组合物和药物来治疗、改善和预防疾病、病症和机能紊乱。另外也需要提供新型的异黄酮类化合物和衍生物来改善制剂、生物利用度和这些化合物的传递。还需要内科医生和普通大众可用的新型和与众不同的疗法来与大量各种类型的影响人类健康的疾病和机能紊乱作斗争。
因此，需要提供治疗学上有益的可表现出改善的、可替代的或至少可比得上已知异黄酮类化合物的生物活性和生物利用特性的新型异黄酮类化合物及其衍生物。
发明概述
本发明的发明者惊讶地发现，异黄酮类化合物的磷酸酯表现出良好的水溶性和生物利用度，并显示出有益的生物学特性。特别地，当给予磷酸酯时，其会展现出广泛的治疗活性，包括调节(address)体内雌激素水平的能力。
虽然不想被理论限制，发明者相信异黄烯前药及其衍生物，特别是本发明的异黄酮类磷酸酯会导致雌激素类固醇供应减少，降低雌激素相关性疾病和病症的风险或严重性。发明者还认为本发明的异黄酮类磷酸酯会提供哺乳动物分子靶范围的调节。典型地，这些分子靶与信号传导过程紧密相关，所述信号传导过程为关键的细胞过程的基础，如细胞生长、分化、迁移和死亡。因此可以预见，这些令人惊讶的生化作用对包括人类在内的动物的健康具有广泛和重要的意义。本文描述了本发明的这些和其它优选的目标化合物。
因此，本发明的一个方面提供了具通式I的异黄酮类磷酸酯化合物或其药学可接受盐：
其中
R1、R2和Z独立为M2POx-、氢、羟基、OR9、OC(O)R10、OS(O)R10、CHO、C(O)R10、COOH、CO2R10、CONR3R4、烷基、卤代烷基、芳烷基、烯基、炔基、芳基、杂芳基、烷基芳基、烷氧基芳基、巯基(thio)、烷硫基、氨基、烷基氨基、二烷基氨基、硝基或卤素，或
R2如前定义，R1和Z与连接它们的碳原子一起形成选自下述基团的五元环，
R1如前定义，R2和Z与连接它们的碳原子一起形成选自下述基团的五元环
W为R1，A和B与连接它们的碳原子一起形成选自下述基团的六元环
其中
R3为氢、烷基、芳基、芳烷基、氨基酸、C(O)R11或CO2R12，其中R11为氢、烷基、芳基、芳烷基或氨基酸，R12为氢、烷基、卤代烷基、芳基、杂芳基或芳烷基，
R4为氢、烷基或芳基，
或R3和R4与连接它们的氮原子一起形成吡咯烷基或哌啶基，
R5为M2PO4-、氢、其中R11如前定义的COR11或其中R12如前定义的CO2R12，
R6为M2PO4-、氢、羟基、烷基、芳基、氨基、巯基、NR3R4、其中R11如前定义的COR11、其中R12如前定义的CO2R12或CONR3R4，
R7为氢、其中R11如前定义的COR11、烷基、卤代烷基、芳基、芳烷基或其中每个R13独立为氢、烷基或芳基的Si(R13)3，
R8为M2PO4-、氢、羟基、烷氧基或烷基，
R9为烷基、卤代烷基、芳基、芳烷基、其中R11如前定义的C(O)R11或其中R13如前定义的Si(R13)3，
R10为氢、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，
图形
代表单键或双键，
M独立为氢、直链或支链烷基、烯基、炔基、烷氧基烷基、烷硫基烷基或氨基烷基、取代或非取代的环烷基、芳基、芳烷基或烷基芳基，以及取代的环烷基，其中至少一个环包含一个或多个在该至少一个环上的氮、硫、氧、磷或硅杂原子；
T独立为氢、烷基或芳基，
X为O、NR4或S，优选为O，和
Y为
其中
R14、R15和R16独立为M2PO4-、氢、羟基、OR9、OC(O)R10、OS(O)R10、CHO、C(O)R10、COOH、CO2R10、CONR3R4、烷基、卤代烷基、芳烷基、烯基、炔基、芳基、杂芳基、烷基芳基、烷氧基芳基、巯基、烷硫基、氨基、烷基氨基、二烷基氨基、硝基或卤素，和
其中如果存在R1、R2、R5、R6、R8、R14、R15、R16、Z、W或A，至少一个独立为M2PO4-。
在一个优选的实施方案中，磷酸酯部分可为相应的盐-O-PO(OM)2，其中M为氢或药学可接受的抗衡离子，更优选为Na+、K+、Li+、Mg++或NH3 +，更优选为Na+。
发明者意外地发现具通式I的化合物：
其中
R1、R2、W、A、B和Z如上定义，所述化合物在治疗、预防、改善、防御和/或防止下列疾病和紊乱(为了方便在下文中提到时称为“治疗学适应症”)中具有特别的用途和作用：
(a)身体上所有组织中所有形式的癌症(恶变前的、良性的和恶性的)。在这方面，所述化合物可单独作为抗癌疗法使用，或与其它形式的包括但不限于放疗和化疗的抗癌疗法联合使用；
(b)与身体任何组织中的异常或过度性质的(prolonged nature)炎症反应相关的疾病和紊乱，包括但不限于类风湿性关节炎、腱炎、炎性肠病、溃疡性结肠炎、节段性回肠炎、硬化性胆管炎；
(c)丘疹结节的皮肤病损，包括但不限于肉样瘤病、血管肉瘤、卡波济肉瘤(Kaposi′s sarcome)、Fabry′s病；
(d)丘疹鳞屑性皮肤病损，包括但不限于银屑病、博温(氏)病(Bowen′s Disease)和莱特(氏)病(Reiter′s Disease)；
(e)以退化性变化为特征的皮肤光化性损伤，包括但不限于日光性角化病、光过敏病和皱纹；
(f)与影响体内任何组织的异常血管发生相关的疾病，包括但不限于血管瘤和毛细血管扩张；
(g)骨髓增生性疾病，包括但不限于巨幼红细胞病、骨髓增生异常综合征、真性红细胞增多症、血小板增多症和骨髓纤维化；
(h)以异常免疫应答为特征的自身免疫疾病，包括但不限于多发性硬化、1型糖尿病、全身性红斑狼疮和胆汁性肝硬变；
(i)以神经系统结构退化性变化为特征的神经变性疾病和病症，包括但不限于帕金森病、阿尔茨海默症、肌肉萎缩症、Lou-Gehrig病、运动神经元病；
(j)与血管壁退行性变化相关的疾病和病症，包括但不限于动脉粥样硬化、粉瘤、冠心病、中风、心肌梗塞、高血压性血管疾病、恶性高血压、血栓闭塞性脉管炎、纤维肌性发育异常；
(k)与异常免疫应答相关的疾病和病症，包括但不限于皮肌炎和硬皮病；
(l)与眼睛退行性变化相关的疾病和病症，包括但不限于白内障、黄斑变性、视网膜萎缩。
特别地，异黄烯化合物还被令人惊讶地发现对生殖激素如雌激素和雄激素的产生和功能具有强效的作用。因此，这些化合物可用于治疗和预防下列病症和疾病：
(a)与雌激素/雄激素失衡相关的女性病症，包括但不限于周期性乳腺痛、痤疮、痛经、子宫平滑肌瘤、子宫内膜异位、卵巢囊肿、月经前期综合征、急性更年期综合征、骨质疏松症、老年性痴呆、不育症；和
(b)与雌激素/雄激素失衡相关的男性病症，包括但不限于良性前列腺肥大、不育症、男子女性型乳房、遗传性秃发症各种其它形式的秃发症。
因此，根据本发明的另一发面提供了治疗、预防、改善、防御和/或防止一种或多种治疗学适应症的方法，所述方法包括给予患者治疗有效量的如上定义的一种或多种式I的化合物。
根据本发明的另一方面，本发明提供了式I化合物在生产用于治疗、改善、防御、预防和/或防止一种或多种治疗学适应症的药物的中的用途。
根据本发明的另一方面，本发明提供了式I化合物在治疗、改善、防御、预防和/或防止一种或多种治疗学适应症中的用途。
根据本发明的另一方面，本发明提供了治疗、预防、改善、防御和/或治疗一种或多种治疗学适应症的药物，所述药物包括单独的一种或多种式I的化合物或其与一种或多种载体或赋形剂的混合物。
根据本发明的另一方面，本发明提供了治疗用组合物，所述组合物包括一种或多种式I化合物和一种或多种药用载体和/或赋形剂。
根据本发明的另一方面，本发明提供了其中包含一种或多种式I化合物的饮料或食物。
根据本发明的另一方面，本发明提供了包含一种或多种微生物菌株的微生物培养物或食物，所述微生物产生一种或多种式I的化合物。
根据本发明的另一方面，本发明提供了一种或多种产生一种或多种式I化合物的微生物。优选的微生物为纯化的培养物，其可与一种或多种其它产生式I化合物的培养物混合和/或一起给予。
在本说明书和下面的权利要求中，除非本文需要，否则，单词“包括”及其变化形式如“包含”或“含有”应被理解为包括所述的整体或步骤或整体或步骤的组，而不是排除其它任何整体或步骤或整体或步骤的组。
附图筒述
图1描述了腹腔注射大剂量的在PBS中制备的DHE二磷酸酯后小鼠血清中游离和总脱氢雌马酚的浓度的药代动力学数据的比较，其中所注射的在PBS中制备的DHE二磷酸酯剂量为25mg/kg。
图2a和2b描述了腹腔注射大剂量的不同方法制备的脱氢雌马酚后小鼠血清中游离和总脱氢雌马酚浓度的药代动力学数据的比较。DHE二磷酸酯制剂在PBS中制备，剂量为25mg/kg。DHE PEG:PBS制剂在1∶1 PEG:PBS中制备，剂量为50mg/kg。DHE-HPBCD制剂在20％HPBCD(HPBCD在PBS中制备)中制备，剂量为50mg/kg(未显示总DHE水平)。
发明详述
术语“异黄酮类”一般是指在吡喃环上连有苯基的稠环苯并吡喃分子，以1，2-二苯基丙烷系统为基础。因此，在本文中通常称为异黄酮、异黄烯、异黄烷、异黄烷酮、异黄烷醇(isoflavano1s)等类型的化合物通常是指异黄酮类、异黄酮类化合物或异黄酮代谢物或其衍生物。
本发明优选的异黄酮类化合物为异黄烷-4-酮、异黄烯、异黄烷-4-醇和异黄烷，它们一般为基本异黄酮类的氢化产物，这些化合物可任选被取代。
术语“烷基”包括1-10个碳原子优选1-6个碳原子的直链、支链和环状(如5碳或更多)的饱和烷基，如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、环戊基等。所述烷基更优选为甲基、乙基、丙基或异丙基。所述烷基可任选被一个或多个氟、氯、溴、碘、羧基、C1-C4-烷氧基羰基、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“烯基”包括2-10个碳原予优选2-6个碳原子的直链、支链和环状(如5碳或更多)并具有至少一个双键的烃，如乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、2-甲基-1-丙烯基、2-甲基-2-丙烯基等。所述烯基更优选为乙烯基、1-丙烯基或2-丙烯基。所述烯基可任选被一个或多个氟、氯、溴、碘、羧基、C1-C4-烷氧基羰基、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“炔基”包括2-10个碳原子优选2-6个碳原子的直链和支链并具有至少一个三键的烃，如乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基等。所述炔基更优选为乙炔基、1-丙炔基和2-丙炔基。所述炔基可任选被一个或多个氟、氯、溴、碘、羧基、C1-C4-烷氧基羰基、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。
所述“芳基”包括苯基、联苯基和萘基，它们可任选被一个或多个C1-C4-烷基、羟基、C1-C4-烷氧基、羰基、C1-C4-烷氧基羰基、C1-C4-烷基羰基氧基或卤素取代。
术语“杂芳基”包括五元和六元环，所述环包括至少一个环上的氧、硫或氮，所述环可任选与其它芳基或杂芳基环稠合，所述芳基或杂芳基环包括但不限于呋喃基、吡啶基、嘧啶基、噻吩基、咪唑基、四唑基、吡嗪基、苯并呋喃基、苯并噻吩基(benzothiophenyl)、喹啉基、isopuinolyl、嘌呤基、吗啉基、噁唑基、噻唑基、吡咯基、黄嘌呤基、嘌呤、胸腺嘧啶、胞嘧啶、尿嘧啶和异噁唑基。所述杂芳基可任选被一个或多个氟、氯、溴、碘、羧基、C1-C4-烷氧基羰基、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。所述杂芳基可按照需要被部分或全部氢化。
术语“卤素”包括氟、氯、溴和碘，优选氟和氯，更优选氟。“卤代烷基”的例子包括单卤代、二卤代和直到全卤代的烷基。优选的卤代烷基为三氟甲基和五氟乙基。
术语“药学可接受盐”是指可与药物一起给药的带有电荷的有机或无机部分，如在盐中作为抗衡阳离子或抗衡阴离子。本领域中技术人员知道的包括M部分的药学可接受阳离子包括但不限于钠、钾、钙、锌和季胺。本领域中技术人员知道的药学可接受阴离子包括但不限于氯化物、乙酸盐、柠檬酸盐、碳酸氢盐和碳酸盐。
术语“药学可接受衍生物”或“前药”是指活性化合物的衍生物，其在给予受者后可直接或间接提供母体化合物或代谢物，或本身显示出活性。
本文所用的术语“治疗”、“预防”或“防止”、“改善”等应被认为是它们的广义。特别地，术语“治疗”不必指动物被治疗至完全恢复。因此，术语“治疗”包括症状或特定病症的严重性的改善或预防或在其它方面降低特定病症发展的风险。
本发明特别涉及具通式II的化合物及其用途：
其中
R1、R2、R5、R6、R14、R15、W和Z如上定义，图形
表示单键或双键，和
更优选其中图形表示双键。
在另一方面，本发明特别涉及具通式III的化合物及其用途：
其中
R1、R2、R5、R6、R14、R15、W和Z如上定义。
在另一方面，本发明特别涉及具通式IV的化合物及其用途：
其中
R1、R2、R5、R6、R14、R15、W和Z如上定义。
本发明的特别优选的化合物为如下的异黄酮类化合物：
异黄酮类-O-PO(OM)2
其中M独立为氢或抗衡阳离子，和
其中异黄烯化合物或衍生物为单-、二-或全-磷酸化的，它们可得自下面的含羟基的异黄烷酮、异黄烯、异黄烷醇和异黄烷化合物，和下面的衍生物1-22：
其中
R2、R16、W和Z独立为H、OH、Cl、Br、Me或Ome，和
R14为H、Ome、Me、Cl或Br。
在最优选的实施方案中异黄酮类化合物或衍生物为二氢黄豆苷元、二氢染料木素(dihydrogenestein)、四氢黄豆苷元、脱氢雌马酚或雌马酚的新型单-、二-或全磷酸酯，最优选为脱氢雌马酚的磷酸酯。
本发明的化合物在治疗与雌激素作用、雄性作用、血管扩张(vasodilatory)和痉挛作用、炎症作用和氧化作用相关或由这些作用引起的疾病方面具有特别的应用。
根据本发明，一种或多种式I化合物治疗时所需的量取决于许多因素，包括特定的用法、所用特定化合物的性质、被治疗的病症、给药方式和患者的情况。式I的化合物可用常规使用的方式和量给药。例如参见Goodman和Gilman，治疗法的药理学基础(ThePharmacological Basis of Therapeutics)，1299(第7版，1985)。所用的特定剂量取决于被治疗的病症、患者的情况、给药途径和其它上述众所周知的因素。一般来说，每个患者的日剂量可在0.1mg-2g范围内；典型地为0.5mg-1g；优选50mg-200mg。给药间隔可为单剂量每天或两天一次至根据需要在一周至许多月至许多年的疗程中给予一天两次或三次，这取决于被治疗和减轻的病症的严重性。还需要了解，对于特定的患者，要根据该患者的个体需要和专业判断管理或指导组合物的给药，随时调整特定的给药方案。
典型地，本文描述的治疗治疗学适应症的药用组合物是通过将本发明化合物(方便起见，下面提到时称为“活性化合物”)与一种或多种本领域中众所周知的药学或兽医学可接受载体和/或赋形剂混合制得。
当然，所述载体必须与制剂中其它成份相容，且对患者必须无害。所述载体或赋形剂可为固体或液体，或两者都有，优选以单位剂量与所述化合物按配方制造，如片剂，其可包含0.5％-59％重量百分比的活性化合物，或高至100％的活性化合物。在本发明的制剂中可混有一种或多种活性化合物，其可由药学上众所周知的任何技术制备，所述技术基本上都是由将任选包括一种或多种助剂的各成份混合组成。
虽然在任何给定的情况下，最合适的给药途径取决于被治疗病症的严重性和所用特定活性化合物的性质，但是本发明的制剂包括适合口服、直肠给药、眼部给药、口腔给药(如舌下给药)、胃肠外给药(如皮下给药、肌内给药、真皮给药或静脉给药)和经皮给药的制剂。
适于口服的制剂可以离散单元形式存在，如胶囊、囊剂、锭剂或片剂，每个都包含预定量的活性化合物；散剂或颗粒剂；水或非水液体溶液剂或混悬剂；或水包油或油包水型乳剂。这样的制剂可用药学上合适的方法制备，所述方法包括使活性化合物和合适的载体(如上所述，其可包含一种或多种助剂)结合的步骤。一般而言，本发明的制剂是通过将活性化合物和液体或细碎的固体载体或两者均匀而紧密地混合，然后，如果需要的话，将所得混合物成型得到单位剂型而制得的。例如，片剂可通过将含有任选与一种或多种助剂混合的活性成份的粉末或颗粒压片或用模具成型制得。压制的片剂可用合适的机器，由自由流动的化合物如任选与粘合剂、润滑剂、惰性稀释剂和/或表面活性/分散剂混合的粉末或颗粒压片制得。模制的片剂可用合适的机器，由惰性液体粘合剂湿润的粉末状化合物由成型制得。
适合口腔(舌下)给药的制剂包括在调味基质中含有活性化合物的锭剂(lozenges)，所述调味基质通常为蔗糖和阿拉伯胶或西黄芪树胶；和在惰性基质中含有活性化合物的软锭剂(pastilles)，所述惰性基质如明胶和丙三醇或蔗糖和阿拉伯胶。
适于胃肠外给药的本发明的组合物包括活性化合物的无菌水制剂，所述制剂优选与目标受者血液等渗的。虽然皮下注射、肌肉注射或皮内注射给药也可产生效果，但这些制剂优选静脉给药。这样的制剂可方便地通过将活性化合物与水或甘氨酸缓冲液混合，并使所得溶液无菌并与血液等渗。根据本发明，注射剂一般包含0.1％-60％w/v的活性化合物，以0.1ml/min/kg的速率给药。
适于直肠或阴道给药的制剂优选为单位剂量的栓剂。这些制剂可通过将活性化合物与一种或多种常规的固体载体如可可脂混合，然后将所得混合物成型制得。
适于皮肤局部给药的制剂或组合物优选为软膏、乳剂、洗剂、糊剂、凝胶剂、喷雾剂、气溶剂或油剂。可用的载体包括凡士林、羊毛脂、聚乙二醇、醇类及两种或多种这些物质的组合。活性化合物的浓度一般为0.1％-0.5％w/w，如0.5％-2％w/w。这样的组合物的实例包括化妆用皮肤乳剂。
适于经皮给药的制剂可为适合与受者的表皮在较长的时期内保持紧密接触离散的贴剂。这样的贴剂适当地包含活性化合物的任选缓冲水溶液，如所述活性化合物的浓度为0.1M-0.2M的缓冲水溶液。
适合经皮给药的制剂还可通过离子电渗透法递药(例如，参见Pharmaceutical Research 3(6)，(1986))，典型地，采用活性化合物的任选缓冲水溶液形式。合适的制剂包含柠檬酸盐或bis/tris缓冲 液(pH 6)或乙醇/水，并包含0.1M-0.2M的活性成份。
适合吸入给药的制剂可以溶液、混悬液或乳液形式的喷雾组合物递药。吸入喷雾组合物还可包含药学可接受喷射剂，如二氧化碳或氧化亚氮。
活性化合物可以食物形式提供，如加入、混合入、涂抹、结合或其它方式加入到食物中。所用的术语食物为其广义，包括液体制剂，如包括奶制品的饮料和其它食物，如健康棒(health bars)、点心等。含有本发明化合物的食物制剂很容易根据标准惯例制备。
本发明的化合物具有强效的抗氧化剂活性，因此，在以下方面发现了其广泛的用途，药学和兽医学应用、化妆品如防止皮肤老化的皮肤乳剂、屏蔽阳光、食物、健康饮料、洗发香波等。
令人惊讶地发现式I的化合物与维生素E在防止脂质、蛋白质和其它生物分子氧化方面具有相互促进的作用。
因此本发明的另一方面提供了一种组合物，所述组合物包含一种或多种式I化合物、维生素E和任选药学、兽医学或化妆品可接受载体和/或赋形剂。
治疗方法、用途和组合物可给予人类或动物，如宠物和家养动物(如狗和猫)、禽类(如小鸡、火鸡、鸭子)、家畜(如牛、绵羊、猪和山羊)，用于水产养殖等。
异黄酮类前药和衍生物还可与其它不损害所需作用的活性物质或可补充所需作用的物质联合给药，如抗生素、抗真菌药、抗炎药或抗病毒化合物。
活性药物可包含两种或更多以组合形式或协同作用混合物形式存在的(in combination或synergistic mixture)异黄酮或其衍生物。活性化合物还可与下列药物一起给药：降脂类药物如普罗布考和烟酸；血小板聚集抑制剂如阿司匹林；抗凝血药如香豆素；钙通道阻滞剂如维拉帕米、地尔硫卓和硝苯地平；血管紧张素转化酶(ACE)抑制剂如卡托普利和依那普利；和β-阻滞剂如心得安、特布他林和拉贝洛尔。所述化合物还可与非甾体类抗炎药联合给药，如布洛芬、吲哚美辛、阿司匹林、非诺洛芬、甲芬那酸、氯芬那酸和舒林酸。所述化合物还可与皮质激素一起给药。
联合给药可以是同时的或相继的。同时给药可能会受在同一单位剂型或在相同或相似的时间给药的个体或离散剂型中的化合物的影响。相继给药可以任何需要的次序进行，典型地，当给予第二种或后来的活性成份时需要第一种或开始的活性成份正在发生生理效应，特别是需要累积或协同效应的情况。
异黄酮化合物为合成式I的异黄酮类化合物的合适的起始原料，这些异黄酮起始原料可通过本领域技术人员知道的标准方法制得。例如，在国际专利申请WO 98/08503和WO 00/49009中可找到合适的方法，通过引用将它们全部结合到本文中。可在本发明化合物的合成中适当应用化学官能团保护、脱保护、合成元和其它本领域技术人员知道的技术。可用任何本领域技术人员知道的合适的方法对羟基取代的异黄酮衍生得到本发明的缀合物。
异黄酮起始原料也可从植物资源以浓缩物或提取物形式得到。此外，本领域技术人员很容易鉴别合适的植物物种，但是，例如，包括豆科植物的特别有用的植物。更优选地，所述异黄酮提取物可从鹰嘴豆、扁豆、大豆、红三叶草或地三叶种属等中获得。
异黄酮类的水溶性对它们配制成药物、食物、化妆品非常重要，它们中的许多都是以水为基础的系统。低溶解度在口服产品中也常常会妨碍有效的生物利用度。低溶解度在注射给药制剂中是特别严重的障碍，因为注射剂通常是以水性介质递药。本发明的异黄酮类磷酸酯比未修饰的化合物具有较高的生物利用度，特别是水溶性有所增加，同时还基本保持了这些未修饰化合物的活性特征。异黄酮类磷酸酯是具有极性(可溶性(solubilising))离去基团的有用的前药，其在生理条件下可容易地被水解产生相应的异黄酮类化合物。
在优选的实施方案中，异黄酮类的醇官能团被磷酸基团酯化得到磷酸酯。一般地，该酯化的异黄酮类可被胃肠道消化和吸收液、其它酸和各种酶水解，得到起始的异黄酮类。
所述磷酸酯优选为(OH)2PO2基团，由于两个极性基团的存在，其是良好的增溶剂并具有高度的生物相容性。当M2PO4-基团中M不为氢时，通常化合物的溶解度较小并因此不是特别有利。例如，其中M为烷基时，优选选择较小的非极性基团。
还考虑到用酯化异黄酮的金属盐复合物，特别是Li+、Na+、K+、Mg++和铵盐，包括NH4 +和低分子量的单-或多烷基铵抗衡离子。
下面的实施例不应被看作是对本发明的限制。
实施例
本发明的异黄酮类磷酸酯可通过本领域中技术人员知道的标准化学方法用有效的起始原料和直接的合成方法制得。本发明主题的几个实施方案可以以这种方式制备并以此为特征。这些实施例全在具有至少一个M2PO4-基团式I化合物的前化合物范围内。这些新型的磷酸酯都为水溶性的，且在体内很容易水解，但在体外在正常pH条件下，在室温或体温下一般在水溶液中相当稳定，固体更稳定。
实施例1
脱氢雌马酚磷酸酯
将脱氢雌马酚(120mg，0.5mmole)和氨基亚磷酸二叔丁基酯(di-butyl phosphoramidite)(330ul，1.0mmole)的DMF(1ml)溶液在氩气中搅拌下滴加1H-四唑(210mg的0.5ml DMF溶液；3.0mmole)。将该溶液冷至-20℃，然后滴加间氯过氧苯甲酸(260mg的0.5ml二氯甲烷溶液，1.5mmole)。升至室温后，将该混合物用3倍乙酸乙酯稀释，然后用10％焦亚硫酸钠和10％碳酸氢钠洗涤。
将包含脱氢磷酸雌马酚的丁基酯的乙酸乙酯溶液用1M HCl洗涤，用硫酸钠干燥。真空除去溶剂后，将残留物用30％TFA的乙酸溶液在室温下处理90分钟。真空除去溶剂，残留物用乙醇吸收，用氢氧化钠中和至pH 5.5。真空除去溶剂得到脱氢磷酸雌马酚的钠盐混合物，130mg。
对磷酸酯混合物的分析表明混合物中存在4′-磷酸酯、7-磷酸酯和4′，7-二磷酸酯衍生物。对本发明化合物的酯化得到磷酸酯混合物，其可通过标准技术被分离为单体成份，所述标准技术包括分步结晶法、柱层析法和HPLC。
由上述方法制备的异黄酮类磷酸酯包括：
同样，二氢黄豆苷元、四氢黄豆苷元和雌马酚的磷酸酯的合成可得到下述化合物及其药学可接受盐。
实施例2
脱氢雌马酚-7-磷酸酯
将脱氢雌马酚侧链苯基4′-位的羟基保护，按照实施例1的方法反应，得到相应的7-磷酸酯衍生物。任何合适的保护基团都可使用，包括MOM或MEM醚和苄基醚。磷酸化作用后，这些基团可任选被除去。其中所用的保护基团可按照此处提到的任何方法在合成异黄酮类起始原料时结合上，或者可利用目标羟基上或其附近的合成元(synthons)、化学反应性、极性、电子情况(electronic considerations)或立体条件在稍后的时间接上保护基团。
通过这些方法，可合成此处多描述的化合物1-22的单-、二-和全-磷酸化衍生物。因此制得其亚磷酸和药学可接受盐。用质子或碳磁共振光谱、IR和/或质谱来鉴定合成的化合物。
实施例3
本发明的异黄酮类磷酸酯的生物利用度通过用各种酶和生物介质对脱氢雌马酚磷酸酯体外水解作用检测。通过HPLC检测游离脱氢雌马酚的量来确定结果。所用血清和介质包括人血清、人全血、大鼠全血、碱性磷酸酶型VII-S(牛肠内粘液)和碱性磷酸酶型XXIV(人类胎盘)。
从酯得出的生物利用度和转换率取决于许多因素，这些因素包括磷酸酯和其上的取代的性质、介质、存在的酶、温度和pH。通过控制这些不同的参数，我们发现，通过改变酯类前药的半衰期可得到一定程度的调节或控制，更好地匹配所需的生物利用度比率。
实施例4
酯化的异黄酮类在生物介质如胃肠液和血液中容易转换为游离异黄酮类。在其中，胃肠液经常含有酶和足够高的pH来水解酯键，血液通常含有酶，如可水解磷酸酯键的磷酸酯酶。
药代动力学实验
用脱氢雌马酚(DHE)-二磷酸酯的PBS溶液通过腹腔注射(i.p.)和口服递药模式分别进行两组PK实验。每个时间点分配3只动物，共计5个时间点(15分钟、30分钟、1小时、4小时和24小时)(每项实验15只小鼠)。
该实验的目的是为了确定腹腔内注射和口服递药的PK曲线是否有可比性。
实验设计-腹腔注射给药
1.将雌性裸鼠保持异黄酮自由饮食(free diet)至少一周，除去血浆中的背景异黄酮水平。
2.实验之前一天，每个时间点指定3只小鼠并用独特的标识符标记。将每只小鼠称重，以确保每次腹腔注射所需的DHE-二磷酸酯的密度(density)达到每只小鼠50mg/kg剂量。
按配方制造稍微过量的DHE-二磷酸酯并相应调整粉末的质量。剩余的溶液在-20℃保存，用做QA分析。
3.在每只小鼠下腹部右侧或左侧四分之一处注射，确保注射针头不在血管内或肠袢(loop of bowel)中。一旦给予DHE-二磷酸酯，将小鼠置于笼子中，直到每个时间点(15分钟、30分钟、1小时、4小时、24小时)。
4.用颈脱位法处死每只小鼠，然后按照SOP BD-009用20号针头通过胸腔收集血液。
5.使血液凝结，然后用bench-top mini-microfuge在室温下将其以最高速度离心3分钟。
6.将血清吸入适当标记的微量离心管并在-20℃保存至被分析。动物血清与载体对照和按配方制造的DHE-二磷酸酯与200ul等分的载体和按配方制造的DHE-二磷酸酯一起在-20℃保存用做分析。
实验设计-口服给药
1.将雌性BALB/c小鼠保持异黄酮自由饮食至少一周，除去血浆中的背景异黄酮水平。
2.实验之前一天，每个时间点指定3只小鼠并用独特的标识符标记。将每只小鼠称重，以确保给予动物所需的DHE-二磷酸酯的密度为50mg/kg剂量。
3.限制并管饲每只小鼠适当体积的按配方制造的DHE-二磷酸酯，达到50mg/kg的剂量。一旦给予DHE-二磷酸酯，将小鼠置于笼子中，直到每个时间点(15分钟、30分钟、1小时、4小时、24小时)。对照动物管饲200μl 1％CMC对照物。对照动物在15分钟、30分钟、1小时、4小时、24小时时间点被处死。
4.在指定的时间点，用颈脱位法处死每只小鼠，然后按照SOPBD-009用20号针头通过胸腔收集血液。
5.使血液凝结，然后用bench-top mini-microfuge在室温下将其以最高速度离心3分钟。
6.将血清吸入适当标记的微量离心管并在-20℃保存至被分析。动物血清与载体对照和按配方制造的DHE-二磷酸酯与200ul等分的载体和按配方制造的DHE-二磷酸酯一起在-20℃保存用做分析。
7.在零时间点将剩余的3只动物用载体制剂管饲，在30分钟时处死。血清与其它样品一起保存。
结果
当给予小鼠25mg/kg剂量时，腹腔注射后15分钟，DHE-二磷酸酯代谢为游离形式的DHE，其在血液中的血清浓度平均为98.6μM。给药1小时后，药物以62μM/hr的速率迅速排泄，血清水平降至12μM。给药15分钟后，DHE总浓度(结合的+游离的)达到120μM，给药1小时后，药物排泄(120μM/hr)达到30.85的血清浓度。(表1和图1)。
表1：二磷酸酯∶游离量与总量的比较
对取自腹腔注射DHE-二磷酸酯和DHE-PEG:PBS制剂的小鼠的血清中游离和总脱氢雌马酚浓度的比较显示：给药15分钟后，要使血清中药物的游离形式达到大约相等的浓度(分别为74.4μM和62μM)，与DHE-PEG:PBS(50mg/kg)相比，只需一半剂量的DHE-二磷酸酯(25mg/kg)(表1、表2和图2a)。有趣的是，观察到的DHE-二磷酸酯和DHE-PEG:PBS制剂的游离∶总的比率为大约5倍的差异，注射DHE-PEG:PBS制剂15分钟后的大鼠血浆中的总DHE多于注射DHE-二磷酸酯制剂后的总DHE(120.8μM苯氧代二醇(phenoxodiol)，511.6μM脱氢雌马酚)。血浆中游离脱氢雌马酚的浓度为给予小鼠脱氢雌马酚的HPBCD制剂15分钟后所达到的血浆中游离脱氢雌马酚的浓度的约1/1.8(DHE-二磷酸酯)和1/2.2(DHE-PEG:PBS)(50mg/kg)(图2b；表3)。
表2.PEG:PBS游离量与总量的比较
表3：游离DHE HPBCD制剂
酯化异黄酮类的用途包括任何现在已知的或后来发现的用途，包括上面列出的或在文献中描述的异黄酮类或其衍生物的用途。酯化异黄酮类被发现可用于治疗骨质疏松症和绝经后女性雌激素缺乏的其它症状。本发明的化合物也可用于防止骨质疏松症和骨质疏松症引起的随后的骨折，其为老年人发病率和死亡率的重要因素。另外，酯化异黄酮的预防应用可提供防UV保护，在其它方面改善一般皮肤健康，刺激免疫系统，降低不希望的氧化作用(即，提供抗氧化剂的好处)。重要地，本发明的化合物可用于治疗癌症，包括乳腺癌、卵巢癌和前列腺(prostrate)癌。
本发明的异黄酮类磷酸酯相当出人意料地在被治疗的受试者中表现出一些有益的和/或显著的活性。这些比较表明本发明的缀合的异黄酮类化合物具有特定的作用和功效，特别是上述化合物1-34的缀合物。
与上面描述和示例的异黄酮类配对物相比，染料木素磷酸酯具有较差的药代动力学性质和曲线。
因此，已经公开了酯化的异黄酮类化合物特定的实施方案和申请。但是，本领域中技术人员应明白除了已经描述的之外还有更多的修饰可能也不偏离本发明的概念。因此，除了附加的权利要求的精神之外，本发明不应被限制。
本领域中技术人员会理解此处描述的本发明易于进行上述特定描述之外的变更和改动。不言而喻，本发明包括所有这样的变更和改动。本发明还包括本说明书中单独或一起提到或表明的所有步骤、特征、组合物和化合物，以及任何和所有任意两种或更多所述步骤或特征的组合。
本说明书中引用的任何先有技术不是，也不应被认为是对先有技术为本领域中普通知识的一部分的确认或任何形式的暗示。
Claims (5)
1.一种异黄酮类磷酸酯，其具有通式I：
其中R1为M2PO4-、羟基或OR9，
R2、W和Z为氢，
A和B与连接它们的碳原子一起形成选自下述的六元环
其中
R6和R7为氢，
R9为甲基，
图形
代表双键，
M独立为氢或药学可接受的阳离子；
X为O，和
Y为
其中R14为M2PO4-、羟基或OR9，和
R15和R16为氢，
其中R1和R14中至少一个是M2PO4-。
2.权利要求1的异黄酮类磷酸酯，其中M2PO4-是NaO(HO)P(O)O-。
3.权利要求1的异黄酮类磷酸酯，其选自化合物23至25：
4.权利要求1-3中任一项的一种或多种磷酸酯在制备用于治疗乳腺癌，卵巢癌或前列腺癌的药物中的用途。
5.一种药用组合物，其含有权利要求1-3中任一项的一种或多种磷酸酯以及一种或多种药用载体和/或赋形剂。
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| AU2003906353 | 2003-11-18 | ||
| AU2003906353A AU2003906353A0 (en) | 2003-11-18 | Isoflavene prodrugs, compositions thereof and therapeutic methods involving same | |
| PCT/AU2004/001602 WO2005049627A1 (en) | 2003-11-18 | 2004-11-18 | Isoflavonoid prodrugs, compositions thereof and therapeutic methods involving same |
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| EP (1) | EP1685140A4 (zh) |
| JP (1) | JP2007511542A (zh) |
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| AU2009287344A1 (en) * | 2008-08-29 | 2010-03-04 | Novogen Research Pty Ltd | Immunomodulating activities |
| US9617274B1 (en) | 2011-08-26 | 2017-04-11 | Demerx, Inc. | Synthetic noribogaine |
| WO2013085922A1 (en) * | 2011-12-09 | 2013-06-13 | Demerx, Inc. | Phosphate esters of noribogaine |
| JP2016508979A (ja) | 2012-12-20 | 2016-03-24 | デメレックス， インコーポレイテッド | 置換ノルイボガイン |
| JP6473321B2 (ja) * | 2014-11-20 | 2019-02-20 | 株式会社ダイセル | 酵素を用いたリン酸化エクオールの製造法 |
| ES2877712T3 (es) | 2015-02-02 | 2021-11-17 | Mei Pharma Inc | Terapias combinadas para su uso en el tratamiento del cáncer de mama |
| US20200354336A9 (en) * | 2017-08-11 | 2020-11-12 | Unity Biotechnology, Inc. | Treatment of Lung Diseases Using Pharmaceutical Agents that Eliminate Senescent Cells |
| US10881634B2 (en) * | 2017-12-07 | 2021-01-05 | Hughes Biotechnology Co., Ltd | Method for treatment or prevention of a disease associated with a decrease in bone mass and method of improving bone architecture and bio mechanical strength of bone |
| EP3781561B1 (en) | 2018-04-18 | 2024-03-13 | Constellation Pharmaceuticals, Inc. | Modulators of methyl modifying enzymes, compositions and uses thereof |
| US11919912B2 (en) | 2018-05-21 | 2024-03-05 | Constellation Pharmaceuticals, Inc. | Modulators of methyl modifying enzymes, compositions and uses thereof |
| CN109485675B (zh) * | 2018-11-30 | 2020-12-08 | 福州热方健康科技有限公司 | 葛根素衍生物及其制备方法以及应用 |
| JP6870011B2 (ja) * | 2019-01-25 | 2021-05-12 | 株式会社ダイセル | 酵素を用いたリン酸化エクオールの製造法 |
| JP2021080264A (ja) * | 2021-02-15 | 2021-05-27 | 株式会社ダイセル | 酵素を用いたリン酸化エクオールの製造法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3535344A (en) * | 1966-02-16 | 1970-10-20 | Merck Ag E | 3,4-cis-4-aryl-isoflavanes |
| WO1998008503A1 (en) * | 1996-08-30 | 1998-03-05 | Novogen Research Pty. Ltd. | Therapeutic methods and compositions involving isoflavones |
| US20030212009A1 (en) * | 2000-12-15 | 2003-11-13 | Hendler Sheldon S. | Isoflavone derivatives |
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| AU4435199A (en) * | 1998-06-12 | 1999-12-30 | Vyrex Corporation | Isoflavone derivatives |
| JP2002238594A (ja) * | 2001-02-19 | 2002-08-27 | Mitsukan Group Honsha:Kk | リン酸化イソフラボンの製造方法 |
| AUPR957001A0 (en) * | 2001-12-19 | 2002-01-24 | Novogen Research Pty Ltd | Isoflavone conjugates, derivatives thereof and therapeutic methods involving same |
| EP1503751A4 (en) * | 2002-04-09 | 2007-08-01 | Novogen Res Pty Ltd | THERAPEUTIC PROCESSES AND COMPOSITIONS WITH ISOFLAV-3-EN AND ISOFLAVAN STRUCTURES |
| JP2004024139A (ja) * | 2002-06-26 | 2004-01-29 | Mitsukan Group Honsha:Kk | 健康食品素材 |
-
2004
- 2004-11-18 US US10/579,789 patent/US20070244075A1/en not_active Abandoned
- 2004-11-18 EP EP04797050A patent/EP1685140A4/en not_active Withdrawn
- 2004-11-18 JP JP2006540079A patent/JP2007511542A/ja active Pending
- 2004-11-18 WO PCT/AU2004/001602 patent/WO2005049627A1/en active Application Filing
- 2004-11-18 CA CA002546643A patent/CA2546643A1/en not_active Abandoned
- 2004-11-18 CN CN2004800402381A patent/CN1902213B/zh not_active Expired - Fee Related
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3535344A (en) * | 1966-02-16 | 1970-10-20 | Merck Ag E | 3,4-cis-4-aryl-isoflavanes |
| WO1998008503A1 (en) * | 1996-08-30 | 1998-03-05 | Novogen Research Pty. Ltd. | Therapeutic methods and compositions involving isoflavones |
| US20030212009A1 (en) * | 2000-12-15 | 2003-11-13 | Hendler Sheldon S. | Isoflavone derivatives |
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| EP1685140A4 (en) | 2009-02-25 |
| CA2546643A1 (en) | 2005-06-02 |
| JP2007511542A (ja) | 2007-05-10 |
| CN1902213A (zh) | 2007-01-24 |
| NO20062878L (no) | 2006-06-19 |
| EP1685140A1 (en) | 2006-08-02 |
| US20070244075A1 (en) | 2007-10-18 |
| WO2005049627A1 (en) | 2005-06-02 |
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