CN103501790B - 用于神经轴突的髓鞘再生的6-取代的雌二醇衍生物 - Google Patents
用于神经轴突的髓鞘再生的6-取代的雌二醇衍生物 Download PDFInfo
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- CN103501790B CN103501790B CN201280014512.2A CN201280014512A CN103501790B CN 103501790 B CN103501790 B CN 103501790B CN 201280014512 A CN201280014512 A CN 201280014512A CN 103501790 B CN103501790 B CN 103501790B
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Abstract
本文公开了用下式的6-取代的雌二醇化合物使轴突髓鞘再生的方法,所述方法可以用于治疗多种脱髓鞘性疾病。
Description
本申请要求2011年3月21日提交的临时申请系列号61/454,873的优先权,其全部引入本文作为参考。
发明领域
本发明涉及使用6-取代的雌二醇化合物和它们的可药用盐或前药使轴突髓鞘再生的方法。该方法可用于治疗脱髓鞘性疾病、例如多发性硬化。
发明背景
髓磷脂是包裹神经元的轴突的电绝缘材料,形成称为髓鞘的层。髓磷脂的主要目的是增加神经冲动向下传导至神经轴突的速度。通过增加穿过细胞膜的电阻,髓磷脂帮助防止电流离开轴突。
神经脱髓鞘是特征为神经系统中髓磷脂蛋白减少的病症,且是多种神经变性自身免疫疾病的基础,所述神经变性自身免疫疾病为例如多发性硬化、实验性自身免疫性脑脊髓炎、慢性炎症性脱髓鞘性多神经病、进行性多灶性白质脑病、横贯性脊髓炎、吉兰巴雷综合征、脑桥中央髓鞘溶解症、阿尔茨海默病、进行性核上麻痹(progressive supenuclearpalsy)、多灶性运动神经病(multifocual motor neuropathy),和脑白质营养不良例如肾上腺脑白质营养不良(ALD)、亚历山大病、卡纳范病(Canavan disease)、克拉伯病、异染性脑白质营养不良(MLD)、佩利措伊斯-梅茨巴赫病、雷弗素姆病、科克因综合征(Cockaynesyndrome)、Van der Knapp综合征和泽尔韦格综合征。
特别地,多发性硬化是最普通的脱髓鞘性疾病,在许多年轻的成年人中造成残疾。由于脱髓鞘和瘢痕形成,多发性硬化影响脑和脊髓中的神经细胞相互传导的能力。因此,罹患多发性硬化的人可以表现多种神经病学症状,包括知觉的变化例如敏感度或麻刺感的损失、肌无力、协调障碍和麻痹。疾病发生通常有两个阶段,复发期和慢性进行期。
多发性硬化目前的治疗包括抗炎和免疫调节方法。然而,这两种方法只在疾病复发期部分有效,且在疾病的继发进行期只有一点效果乃至无效。最近,雌激素受体-β调节剂已显示减缓此类神经变性。Carswell,H.V.O.等,AJP-Heart Circ.Physiol.,2004,第287卷,1501-04;Crawford,D.K.等,Brain,2010,第133卷,2999-3016;Donzelli,A.等,J.Pharmacol.Sci.,2010,第114卷,158-167。
因此,用于脱髓鞘性疾病的有效治疗的需要仍然存在。尤其是优选刺激内源性髓鞘形成和使轴突免于变性的化合物。
发明领域
根据上文,本发明的一个目的是提供预防神经细胞的轴突的脱髓鞘和/或增强神经细胞的轴突的髓鞘再生的方法,所述方法包括将神经细胞与有效量的6-取代的雌二醇衍生物接触。本领域技术人员会明白本发明的一个或多个方面可以满足某些目的,而一个或多个其它的方面可以满足某些其他目的。每个目的可能不在其所有角度中同样应用于本发明的每一个方面。因此,就本发明任何一个方面而言,以下的目的可以以备选的方式考虑。
因此,在本发明的一个方面中,本文公开的方法中使用的6-取代的雌二醇衍生物为式I化合物:
其中"a"环选自
R1、R2、R3和R4独立地是氢、C1-C6烷基、卤代、硫酸酯、葡糖苷酸(glucuronide)、-OH、大体积基团、芳基、环烷基、杂芳基、杂环烷基、-N(CH2)n;磷酸酯基团和次膦酸酯基团;R11选自H、C1-C6烷基、卤素、硫酸酯、葡糖苷酸、-SO2NH2、-COOH、-CN、-CH2CN-、-NHCN-、-CHO、=CHOCH3、-COO盐、-OSO2烷基、-NH2和-NHCO(CH2)n;X选自C1-C12烷基、C2-C12烯基、C2-C12炔基、卤素、葡糖苷酸、-NH2、-SO2NH2、-COOH、-CN、-CH2CN、-NHCN、-CHO、-COO盐、-OSO2烷基、-SH、-SCH3、-CH[(CH2)nCH3]COOCH3、-(CH2)mCOOCH3、-(CH2)m-O-CH3、-(CH2)m-O-(CH2)nCH3、(CH2)m-S-CH3、-(CH2)m-S-(CH2)nCH3、-(CH2)m-NH-(CH2)nCH3、-C2-C8烯基-O-(CH2)nCH3、-C2-C8烯基-S-(CH2)nCH3、-C2-C8烯基-N-(CH2)nCH3、-C2-C8炔基-O-(CH2)nCH3、-C2-C8炔基-S-(CH2)nCH3、-C2-C8炔基-N-(CH2)nCH3、-(CH2)m-OH、-(CH2)m-NH2、-(CH2)m-O-NH2、-(CH2)m-S-NH2、-NH(CH2)mCH3、-NH(CH2)mOCH3、-NH(CH2)mCHOH-COOH、-N(CH3)2、-(CH2)m(NH)CH2OH、-NHCOOH、-(CH2)mNHCOOH、-NO2、-SCN、-SO2烷基、-B(OH)2、-(CH2)mN(CH3)-SO2-NH3、-(CH2)m-NH-SO2-NH2、-NHC(=S)CH3和-NHNH2;Y选自氢、=O、-OCO(C1-C20烷基)和-OH;且Z是H或甲基;其中m是0-20的整数,n是0-8的整数,----符号表示能在3和/或17位形成酮基的单键或双键;且符号表示任何类型的键,而不论立体化学如何;
及所述化合物的相应的对映异构体、其它的立体化学异构体、水合物、溶剂化物、互变异构体和可药用盐。
在本发明的另一个方面,所述方法具体地提供了结合于雌激素受体-α(ER-α)和雌激素受体-β(ER-β)之一或二者的化合物。该方法可以包括启动、增强或增加涉及用于前体或祖细胞分化为形成髓磷脂的细胞的关键信号传导途径的RNA编码基因的基因转录。
根据该概述和以下的某些实施方案的描述,本发明的其它目的、特征、益处和优势将是明显的,且其对于具有各种甾体化合物和相关的治疗方法知识的本领域技术人员将是显而易见的。根据上文,所述目的、特征、益处和优势将是明显的,正如将其与所附的实施例、数据、附图一起考虑或考虑并入本文的参考文献一样。
附图简述
图1显示用多种6-取代的雌二醇衍生物处理96小时后在小鼠培养物中分化的少突胶质细胞前体细胞(OPCs)的总数。
图2描述了用10μM化合物21处理96小时后在小鼠培养物中的少突胶质细胞成熟;a)用阴性对照(DMSO)处理;b)用阳性对照(MEKi)处理;c)用化合物21处理。
图3给出多种6-取代的雌二醇衍生物使OPCs分化为成熟的少突胶质细胞的能力与对照药物T3、CNTF和MEKi使OPCs分化为成熟的少突胶质细胞的能力的对比。
图4描述了用化合物8处理后少突胶质细胞的代表性的过程延长。
发明详述
除非另外定义,否则本文所用的所有技术术语和科学术语具有本发明所属技术领域的普通技术人员通常所理解的相同的含义并且应理解为具有下述含义。将本文涉及的所有公开文献和专利完整地引入本文作为参考。除非另有限定,否则涉及的具体化合物包括所有这类化合物的异构体形式,包括其外消旋和其它混合物。除非另有限定,否则涉及的具体化合物还包括例如本文所述的其离子、盐、溶剂化物(例如水合物)、被保护形式、前药和其它立体异构体。
制备、纯化和/或处理活性化合物的相应盐,例如可药用盐是方便或令人期望的。可药用盐的实例描述在Berge等,1977,"Pharmaceutically Acceptable Salts,"J.Pharm.Sci.,第66卷,第1-19页中,并且在本文中讨论。
本文在治疗病症的上下文中所用的术语"治疗"或"疗法"一般涉及哺乳动物受试者的治疗和疗法,无论是人还是非人的动物(例如在兽医应用中),其中实现某些所需的治疗作用,例如抑制病症发展,并且包括减缓进展速率,使进展速度停止,改善病症和/或治愈病症。还包括作为预防性措施的治疗。治疗包括组合治疗和疗法,其中合并有两种或两种以上治疗或疗法,例如相继或同时进行。治疗和疗法的实例包括但不限于化学疗法(施用活性剂,包括,例如药物、抗体(例如作为在免疫疗法中)、抗炎药、前药(例如使用保护基,包括在适合位置,诸如3位或17位上的磷酸衍生物和次磷酸酯,其它用于光动力疗法、GDEPT、ADEPT等的化合物)、手术、放射疗法和基因疗法。优选的组合治疗包括本发明的方法结合用于肌肉硬化症的现有疗法、例如抗炎疗法或免疫调节疗法。
本文所用的术语“立体化学异构体”是指彼此仅在原子空间定向方面不同的异构体。在本发明中具有特别重要性的两种立体异构体为对映异构体和非对映异构体,这取决于两种异构体彼此是否为镜像。在优选的实施方案中,要求保护的制剂包含分离的、拆分的此类化合物,且“基本上不含其它异构体”。
本文所用的术语"治疗有效量"涉及以具有相当的合理的利益/风险比且有效产生某些所需的治疗作用的活性化合物或材料、包含活性化合物的组合物或剂型的量。术语"有效量"一般意指可以带来可检测的作用的量。
术语"患者"或"受试者"意指动物,包括哺乳动物,优选人类。
术语"组织"一般意指可以执行特定功能的专用细胞。术语"组织"可以意指单个细胞或多个细胞或细胞聚集物,例如膜、血液或器官。术语"组织"还包括涉及的异常细胞或多个异常细胞。示例性的组织包括乳腺组织(包括乳腺细胞)、膜组织(包括内皮和上皮)、层、结缔组织(包括间质组织和肿瘤)。
本发明中"烷基"意指具有1-20个,且优选1-12个碳原子的直链或支链烷基。实例包括但不限于甲基、乙基、丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、2-戊基、异戊基、新戊基、己基、2-己基、3-己基和3-甲基戊基。各烷基可以任选地被1个、2个或3个例如卤代、环烷基、芳基、烯基或烷氧基等的取代基取代。
"芳基"意指具有单环(例如苯基)、多个环(例如联苯)或其中至少一个环是芳族的多个稠合环(例如1,2,3,4-四氢萘基)的芳族碳环基团。芳基还可以任选地被例如卤代、烷基、烯基、环烷基或烷氧基等单、双或三取代。
"杂芳基"意指含有选自氮、氧或硫的至少一个和至多4个杂原子的5-、6-或7-元环的一个或多个稠合芳环系统。实例包括但不限于呋喃基、噻吩基、吡啶基、嘧啶基、苯并咪唑基和苯并噁唑基。杂芳基还可以任选地被例如卤代、烷基、烯基、环烷基或烷氧基等单、双或三取代。
"环烷基"意指具有单环(例如环己基)、多个环(例如双环己基)或多个稠合环(例如)的碳环基团。环烷基可以任选地含有1-4个杂原子。此外,环烷基可以具有一个或多个双键。环烷基还可以任选地被例如卤代、烷基、烯基、芳基或烷氧基等单、双或三取代。
"烷氧基"意指具有烷基部分的含氧的基团。实例包括,但是不限于,甲氧基、乙氧基、丙氧基、丁氧基和叔丁氧基。烷氧基还可以任选地被例如,卤代、芳基、环烷基或烷氧基等单、双或三取代。
"烯基"意指具有2-20个且优选2-6个碳原子,以及1-3个双键的直链或支链链烃基团,包括例如,乙烯基、丙烯基、1-丁-3-烯基、1-戊-3-烯基、1-己-5-烯基。烯基还可以任选地被例如卤代、芳基、环烷基或烷氧基等单、双或三取代。
"卤代"或"卤素"是氟、氯、溴或碘的卤素基团。
"葡糖苷酸"意指葡糖醛酸的苷基团。
术语"硫酸酯"是指具有通式–OS(O)2-OR'的基团,其中R'是氢、金属或烷基。
术语"磷酸酯"是指具有通式–OP(O)(OR')2的基团,其中R'各自独立地是氢、金属或烷基。
术语"次膦酸酯"是指具有通式–OP(O)(R')2的基团,其中R'各自独立地是氢、金属或烷基。
"大体积基团"意指在其连接空间周围产生位阻的取代基,例如叔丁基。
如本文使用的术语“氨基烷基”意指在其上具有氨基的烷基,例如H2N-CH2-、H2N-CH2CH2-、Me2NCH2-等,其中连接点是烷基链的碳;如本文使用的术语“烷基氨基”意指具有连接于氮原子的烷基的氨基,例如CH3NH-、EtNH-、iPr-NH-等,其中连接点通过氨基的氮原子。其中采用连续基团的所有其它术语都将遵循类似规则。
在本发明的一个实施方案中,描述了预防脱髓鞘和/或增强/刺激神经细胞的轴突的髓鞘再生的方法,所述方法包括将神经细胞与有效量的式I的6-取代的雌二醇衍生物接触。优选地,使用刺激内源性髓鞘形成(生成髓鞘)和使轴突免于变性的化合物。在一个非限制性的实例中,通过前体细胞分化为神经胶质细胞刺激髓鞘形成,例如施万细胞前体或少突胶质细胞祖细胞(OPCs)分别分化为例如施万细胞或少突神经胶质细胞。
响应脱髓鞘,前体/祖细胞必须经历基本上静止状态向再生表型的转变。这种活化是髓鞘再生过程的第一步,且涉及几种基因的向上调节的关键步骤,所述基因中的多种与例如发展期间的少突胶质细胞的产生有关。用于少突胶质细胞分化的关键信号传导途径内的差异表达基因(p<0.0001)的某些非限制性实例包括δ-notch-样EFG重复片段(DNER)、少突胶质细胞系转录因子2(OLIG2)、髓磷脂碱性蛋白(MBP)、髓磷脂少突胶质细胞糖蛋白(MOG)、白介素23受体(IL23R)、跨膜蛋白108(TMEM108)、连接蛋白(AF251047)、白介素20受体α(IL20RA)、白介素28A(IL28A)、同源异型框蛋白(NKX2.2)、髓磷脂转录因子1-样蛋白(MYT1)和性别决定区Y-框2(SOX2)等。分化阶段包括三个不同的步骤:与待髓鞘再生的轴突建立接触,表达髓磷脂基因并生成髓磷脂膜,最后包裹和并使该膜紧密以形成髓鞘。式I的6-取代的雌二醇衍生物正调节涉及OPCs的增殖和分化的信号传导途径中的这些基因,使得髓鞘再生可以发生。因此,式I化合物可以用于治疗病症,其防止脱髓鞘和/或增强/刺激髓鞘再生。该方法还可以包括监测髓鞘再生。
因此,可以通过式I化合物治疗的脱髓鞘性障碍包括但不限于,例如多发性硬化(例如,复发/缓解型多发性硬化、继发性进展型多发性硬化、进行性复发性多发性硬化、原发性进展型多发性硬化和急性暴发性多发性硬化)、脑桥中央髓鞘溶解症、实验性自身免疫性脑脊髓炎、急性播散性脑脊髓炎、横贯性脊髓炎、进行性多灶性白质脑病;阿尔茨海默病、亚急性硬化性全脑炎、感染后脑脊髓炎、慢性炎症性脱髓鞘性多神经病、进行性核上性麻痹、多灶性运动神经病、吉兰巴雷综合征、进行性多灶性白质脑病、德维克病、Balo同心性硬化,脑白质营养不良例如异染性脑白质营养不良、克拉伯病、肾上腺脑白质营养不良(ALD)、佩利措伊斯-梅茨巴赫病、卡纳范病、儿童共济失调伴中枢神经系统髓鞘形成不良(centralhypomyelination)、亚历山大病、科克因综合征、Van der Knapp综合征、泽尔韦格综合征和雷弗素姆病。具有脱髓鞘性障碍的人类患者可以具有脱髓鞘性障碍的一种或多种症状,诸如但不限于视觉损伤、麻木、四肢无力、震颤或痉挛状态、热耐受不良、言语障碍、失禁、头晕或受损的本体感受(例如,平衡、协调、肢体位置感)。为所述方法的目的,具有脱髓鞘性障碍家族史(例如,脱髓鞘性障碍遗传倾向)或者显示上文所述的脱髓鞘性障碍的缓和或不频发的症状的人(例如人类患者)可以被认为有发展脱髓鞘性障碍(例如,多发性硬化)的风险。可以对所述人进行监测以获得以下结果:例如,脱髓鞘性障碍的一个或多个症状(例如,本文描述的脱髓鞘性障碍的任何症状)的改善(例如增加的髓鞘再生)。
在本发明的一个实施方案中,所述方法的化合物具有以下式(Ia)中所示的通用结构:
其中R2、R3、R4、X和Y如上文为式(I)所定义。甚至更优选地,Y选自=O和–OH;R4选自氢、卤代和C1-C6烷基;R2选自氢、-OH和卤代;R3选自氢、卤代和–OH;且X选自C1-C12烷基、C2-C12烯基、-(CH2)mCOOCH3、-(CH2)m-O-CH3、-(CH2)m-O-(CH2)nCH3、(CH2)m-S-CH3、-(CH2)m-S-(CH2)nCH3、-(CH2)m-N-(CH2)nCH3、-C2-C8烯基-O-(CH2)nCH3、-C2-C8烯基-S-(CH2)nCH3、-C2-C8烯基-N-(CH2)nCH3、-C2-C8炔基-O-(CH2)nCH3、-C2-C8炔基-S-(CH2)nCH3、-C2-C8炔基-N-(CH2)nCH3、-(CH2)m-OH、-(CH2)m-O-NH2、-(CH2)m-S-NH2、-NH(CH2)mCH3、-NH(CH2)mOCH3、-NH(CH2)mCHOH-COOH、-(CH2)m(NH)CH2OH、-(CH2)mNHCOOH、-(CH2)mN(CH3)-SO2-NH3和-(CH2)m-NH-SO2-NH2;m是1-20的整数;n是0-8的整数;且----符号表示单键或双键。还更优选地,Y是(S)-OH;R4选自氢或烷基;R2是氢;R3是氢;且X选自C1-C12烷基、C2-C12烯基、-(CH2)m-O-CH3、-(CH2)m-O-(CH2)nCH3、(CH2)m-S-CH3和-(CH2)m-S-(CH2)nCH3;m是1-12的整数;n是0-4的整数;且C-13甲基是(S)构型。
本发明的又一个实施方案涉及使用式(Ib)化合物的方法:
其中R1R2、R3、R4和X如上文为式(I)所定义。甚至更优选地,R1选自氢、-OH和卤代;R4选自氢、卤代和C1-C6烷基;R2选自氢和卤代;R3选自氢、卤代和–OH;且X选自C1-C12烷基、C2-C12烯基、-(CH2)mCOOCH3、-(CH2)m-O-CH3、-(CH2)m-O-(CH2)nCH3、(CH2)m-S-CH3、-(CH2)m-S-(CH2)nCH3、-(CH2)m-N-(CH2)nCH3、-C2-C8烯基-O-(CH2)nCH3、-C2-C8烯基-S-(CH2)nCH3、-C2-C8烯基-N-(CH2)nCH3、-C2-C8炔基-O-(CH2)nCH3、-C2-C8炔基-S-(CH2)nCH3、-C2-C8炔基-N-(CH2)nCH3、-(CH2)m-OH、-(CH2)m-O-NH2、-(CH2)m-S-NH2、-NH(CH2)mCH3、NH(CH2)mOCH3、-NH(CH2)mCHOH-COOH、-(CH2)m(NH)CH2OH、-(CH2)mNHCOOH、-(CH2)mN(CH3)-SO2-NH3和-(CH2)m-NH-SO2-NH2;m是1-20的整数;且n是0-8的整数。还甚至更优选地,R1是氢;R4选自氢或烷基;R2是氢;R3是氢;且X选自C1-C12烷基、C2-C12烯基、-(CH2)m-O-CH3、-(CH2)m-O-(CH2)nCH3、(CH2)m-S-CH3和-(CH2)m-S-(CH2)nCH3;m是1-12的整数;n是0-4的整数;且C-13甲基和C-17羟基均为(S)构型。
本发明的又一个实施方案涉及使用式(Ic)化合物的方法:
其中R11、R2、R3、R4和X如上文为式(I)所定义。甚至更优选地,R11是氢或C1-C6烷基;R4选自氢、卤代和C1-C6烷基;R2选自氢和卤代;R3选自氢、卤代和–OH;且X选自C1-C12烷基、C2-C12烯基、-(CH2)mCOOCH3、-(CH2)m-O-CH3、-(CH2)m-O-(CH2)nCH3、(CH2)m-S-CH3、-(CH2)m-S-(CH2)nCH3、-(CH2)m-N-(CH2)nCH3、-C2-C8烯基-O-(CH2)nCH3、-C2-C8烯基-S-(CH2)nCH3、-C2-C8烯基-N-(CH2)nCH3、-C2-C8炔基-O-(CH2)nCH3、-C2-C8炔基-S-(CH2)nCH3、-C2-C8炔基-N-(CH2)nCH3、-(CH2)m-OH、-(CH2)m-O-NH2、-(CH2)m-S-NH2、-NH(CH2)mCH3、NH(CH2)mOCH3、-NH(CH2)mCHOH-COOH、-(CH2)m(NH)CH2OH、-(CH2)mNHCOOH、-(CH2)mN(CH3)-SO2-NH3和-(CH2)m-NH-SO2-NH2;m是1-20的整数;且n是0-8的整数。还甚至更优选地,R11是氢;R4选自氢或烷基;R2是氢;R3是氢;且X选自C1-C12烷基、C2-C12烯基、-(CH2)m-O-CH3、-(CH2)m-O-(CH2)nCH3、(CH2)m-S-CH3和-(CH2)m-S-(CH2)nCH3;m是1-12的整数;n是0-4的整数;且C-13甲基和C-17羟基均为(S)构型。
本发明的又一个实施方案涉及使用式(Id)化合物的方法:
其中R1、R2和X如上文为式(I)所定义。甚至更优选地,R1选自氢、-OH和卤代;R2选自氢和卤代;且X选自C1-C12烷基、C2-C12烯基、-(CH2)mCOOCH3、-(CH2)m-O-CH3、-(CH2)m-O-(CH2)nCH3、(CH2)m-S-CH3、-(CH2)m-S-(CH2)nCH3、-(CH2)m-N-(CH2)nCH3、-C2-C8烯基-O-(CH2)nCH3、-C2-C8烯基-S-(CH2)nCH3、-C2-C8烯基-N-(CH2)nCH3、-C2-C8炔基-O-(CH2)nCH3、-C2-C8炔基-S-(CH2)nCH3、-C2-C8炔基-N-(CH2)nCH3、-(CH2)m-OH、-(CH2)m-O-NH2、-(CH2)m-S-NH2、-NH(CH2)mCH3、NH(CH2)mOCH3、-NH(CH2)mCHOH-COOH、-(CH2)m(NH)CH2OH、-(CH2)mNHCOOH、-(CH2)mN(CH3)-SO2-NH3和-(CH2)m-NH-SO2-NH2;X选自C1-C12烷基、C2-C12烯基、-(CH2)m-O-CH3、-(CH2)m-O-(CH2)nCH3、(CH2)m-S-CH3和-(CH2)m-S-(CH2)nCH3;m是1-20的整数;且n是0-8的整数。仍然甚至更优选地,R1和R2是氢;m是1-12的整数;n是0-4的整数;且C-13甲基和C-17羟基均为(S)构型。
本发明的又一个实施方案涉及使用式(Ie)化合物的方法:
其中m、n、R1、R2、R3和R4如上文为式(I)所定义,且Z选自–O-、-S-和–NH-。甚至更优选地,m是1-12,n是0-4,R1选自氢、-OH和卤代;R4选自氢、卤代和C1-C6烷基;R2选自氢和卤代;R3选自氢、卤代和–OH;Z选自–O-和–S-;且C-13甲基和C-17羟基均为(S)构型。
本发明的又一个实施方案涉及使用式(If)化合物的方法:
其中R1、R2、R3、R4和X如上文为式(I)所定义。甚至更优选地,R1选自氢、-OH和卤代;R4选自氢、卤代和C1-C6烷基;R2选自氢和卤代;R3选自氢、卤代和–OH;且X选自C1-C12烷基、C2-C12烯基、-(CH2)mCOOCH3、-(CH2)m-O-CH3、-(CH2)m-O-(CH2)nCH3、(CH2)m-S-CH3、-(CH2)m-S-(CH2)nCH3、-(CH2)m-N-(CH2)nCH3、-C2-C8烯基-O-(CH2)nCH3、-C2-C8烯基-S-(CH2)nCH3、-C2-C8烯基-N-(CH2)nCH3、-C2-C8炔基-O-(CH2)nCH3、-C2-C8炔基-S-(CH2)nCH3、-C2-C8炔基-N-(CH2)nCH3、-(CH2)m-OH、-(CH2)m-O-NH2、-(CH2)m-S-NH2、-NH(CH2)mCH3、NH(CH2)mOCH3、-NH(CH2)mCHOH-COOH、-(CH2)m(NH)CH2OH、-(CH2)mNHCOOH、-(CH2)mN(CH3)-SO2-NH3和-(CH2)m-NH-SO2-NH2;X选自C1-C12烷基、C2-C12烯基、-(CH2)m-O-CH3、-(CH2)m-O-(CH2)nCH3、(CH2)m-S-CH3和-(CH2)m-S-(CH2)nCH3;m是1-20的整数;且n是0-8的整数。更优选地,R1、R2、R3和R4是氢;m是1-12的整数;且n是0-4的整数。
本发明的又一个实施方案涉及使用式(Ig)化合物的方法:
其中R1、R2、R3、R4、R11和X如上文为式(I)所定义。甚至更优选地,R1选自氢、-OH和卤代;R4选自氢、卤代和C1-C6烷基;R2选自氢和卤代;R3选自氢、卤代和–OH;且X选自C1-C12烷基、C2-C12烯基、-(CH2)mCOOCH3、-(CH2)m-O-CH3、-(CH2)m-O-(CH2)nCH3、(CH2)m-S-CH3、-(CH2)m-S-(CH2)nCH3、-(CH2)m-N-(CH2)nCH3、-C2-C8烯基-O-(CH2)nCH3、-C2-C8烯基-S-(CH2)nCH3、-C2-C8烯基-N-(CH2)nCH3、-C2-C8炔基-O-(CH2)nCH3、-C2-C8炔基-S-(CH2)nCH3、-C2-C8炔基-N-(CH2)nCH3、-(CH2)m-OH、-(CH2)m-O-NH2、-(CH2)m-S-NH2、-NH(CH2)mCH3、NH(CH2)mOCH3、-NH(CH2)mCHOH-COOH、-(CH2)m(NH)CH2OH、-(CH2)mNHCOOH、-(CH2)mN(CH3)-SO2-NH3和-(CH2)m-NH-SO2-NH2;X选自C1-C12烷基、C2-C12烯基、-(CH2)m-O-CH3、-(CH2)m-O-(CH2)nCH3、(CH2)m-S-CH3和-(CH2)m-S-(CH2)nCH3;m是1-20的整数;---OR11是=O或-OH;且n是0-8的整数。仍然甚至更优选地,R1、R2、R3和R4是氢;m是1-12的整数;且n是0-4的整数。
式(I)和(Ia)-(If)的化合物的具体实例如下文所示:
本发明的实施方案化合物可以用于药物组合物。此类组合物可以含有一种或多种选自上文讨论过的化合物,下列所示的化合物或在本文中以其它方式推知的化合物,及其组合。在某些实施方案中,此类组合物可以含有可药用的载体组分。此类组合物可以无限制地含有化合物的外消旋混合物。在某些实施方案中,此类化合物可以以S和R对映异构体的形式存在,优选其基本上不含其它异构体的分离和纯化的形式。
本发明化合物可具有不对称中心,且可以以外消旋体、外消旋混合物或以单个的和纯化的非对映异构体或对映异构体的形式出现,例如(通过ChemDraw Ultra,11.0(3)或12.0版命名)(6S,8R,9S,13S,14S)-3-羟基-6-(甲氧基甲基)-13-甲基-7,8,9,11,12,13,15,16-八氢-6H-环戊二烯并[a]菲-17(14H)-酮(化合物1);(6R,8R,9S,13S,14S)-3-羟基-6-(甲氧基甲基)-13-甲基-7,8,9,11,12,13,15,16-八氢-6H-环戊二烯并[a]菲-17(14H)-酮(化合物2);(6S,8R,9S,13S,14S)-6-(甲氧基甲基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇(化合物3);(6R,8R,9S,13S,14S)-6-(甲氧基甲基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇(化合物4);(6S,8R,9S,10R,13S,14S)-17-羟基-6-(甲氧基甲基)-10,13-二甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-3H-环戊二烯并[a]菲-3-酮(化合物5);(6R,8R,9S,10R,13S,14S)-17-羟基-6-(甲氧基甲基)-10,13-二甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-3H-环戊二烯并[a]菲-3-酮(化合物6);(6S,8R,9S,13S,14S)-6-(羟基甲基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇(化合物7);(6R,8R,9S,13S,14S)-6-(羟基甲基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇(化合物8);(6R,8R,9S,10R,13S,14S)-6-(甲氧基甲基)-10,13-二甲基十六氢-1H-环戊二烯并[a]菲-3,17-二醇(化合物9);(6R,8R,9S,13S,14S)-6-((氨基氧基)甲基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇(化合物10);(6S,8R,9S,13S,14S)-6-((氨基氧基)甲基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇(化合物11);(6R,8R,9S,13S,14S)-6-((氨基氧基)甲基)-17-羟基-13-甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-3H-环戊二烯并[a]菲-3-酮(化合物12);(6S,8R,9S,13S,14S)-6-((氨基氧基)甲基)-17-羟基-13-甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-3H-环戊二烯并[a]菲-3-酮(化合物13);(6R,8R,9S,13S,14S)-6-(((甲氧基甲基)氨基)甲基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇(化合物14);(6S,8R,9S,13S,14S)-6-(((甲氧基甲基)氨基)甲基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇(化合物15);1-((((6R,8R,9S,13S,14S)-3,17-二羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-基)甲基)氨基)丙-2-酮(化合物16);1-((((6S,8R,9S,13S,14S)-3,17-二羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-基)甲基)氨基)丙-2-酮(化合物17);(6R,8R,9S,13S,14S)-6-甲氧基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇(化合物18);(6S,8R,9S,13S,14S)-6-(2-甲氧基乙基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇(化合物19);(6R,8R,9S,13S,14S)-6-(4-甲氧基丁基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇(化合物20);(6R,8R,9S,13S,14S)-6-(6-甲氧基己基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇(化合物21);(6R,8R,9S,13S,14S)-6-(6-甲氧基辛基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇(化合物22);(6R,8R,9S,13S,14S)-3-羟基-6-(甲氧基甲基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-17-基硬脂酸酯(化合物23);(6R,8R,9S,10R,13S,14S)-6-(甲氧基甲基)-10,13-二甲基-7,8,9,10,11,12,13,14,15,16-十氢-3H-环戊二烯并[a]菲-3,17(6H)-二酮(化合物24);(6S,8R,9S,10R,13S,14S)-6-(甲氧基甲基)-10,13-二甲基-7,8,9,10,11,12,13,14,15,16-十氢-3H-环戊二烯并[a]菲-3,17(6H)-二酮(化合物25);(6R,8R,9S,10R,13S,14S)-6-(甲氧基甲基)-10,13-二甲基-4,5,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-3H-环戊二烯并[a]菲-3,17-二醇(化合物26);(6S,8R,9S,10R,13S,14S)-6-(甲氧基甲基)-10,13-二甲基-4,5,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-3H-环戊二烯并[a]菲-3,17-二醇(化合物27);(6S,8R,9S,13S,14S)-6-(甲氧基甲基)-13-甲基-17-氧代-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3-基硫酸氢酯(化合物28);(6R,8R,9S,13S,14S)-6-(甲氧基甲基)-13-甲基-17-氧代-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3-基硫酸氢酯(化合物29);(6R,8R,9S,13S,14S)-13-甲基-6-(4-丙氧基丁基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇(化合物30);(6R,8R,9S,13S,14S)-13-甲基-6-(5-乙氧基戊基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇(化合物31);
(6R,8R,9S,10R,13S,14S)-6-(甲氧基甲基)-10,13-二甲基十六氢-1H-环戊二烯并[a]菲-3,17-二醇(化合物32);和
(6R,8S,9S,14S,17S)-6-(甲氧基甲基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇(化合物33)。
本发明方法的化合物如U.S.S.N.12/627,874(引入本文作为参考)中所述制备,且涉及制备雌二醇的6-羟基甲基、6-烷氧基烷基、6-烷基烷硫基、6-氨基甲氧基、6-甲基氨基甲氧基或6-甲氧基胺衍生物的方法。以下流程1-3给出制备雌二醇衍生物的反应流程。所述方法可以包括将雌二醇的叔丁基二甲基硅烷基衍生物与LIDAKOR/THF/甲醛反应,得到6–羟基化的化合物,随后进行以下步骤:(i)水解得到雌二醇的6-羟基甲基衍生物;和/或(ii)用硫酸二甲酯处理,随后水解,得到雌二醇的6-甲基氧基甲基衍生物。通过在C-17羟基位进一步氧化化合物3可以得到化合物1。化合物33和其它的二甲基化合物可以根据U.S.S.N.13/232,798(引入本文作为参考)进行制备。
在供选择的途径中,本发明化合物还可以通过包含以下步骤的方法制备:(i)对雌二醇化合物进行保护,(ii)用LIDAKOR/丁基-锂/二异丙胺/叔戊醇钾在苄型的6-位酰化受保护的雌二醇化合物,(iii)用氢化铝锂还原6位的醛,(iv)将雌二醇化合物的受保护区域脱保护。以下流程2中给出制备雌二醇衍生物的反应流程。
本发明化合物可以通过如以下流程中所述的以下方法来合成。
流程1
流程2
本发明的多种烷基氧基烷基衍生物涉及烷化剂的选择。此类衍生物会被了解本发明的本领域技术人员所理解,且可通过本文所述的该类合成方法而获得。因此,多种C1至C6烷基和取代的烷基试剂可以无限制地如本文所述用于制备相应的烷基氧基烷基衍生物。
在本发明的另一个方面,制备雌二醇的6-氨基衍生物的方法在以下反应流程中公开。因此使用流程1-2中描述的6-甲氧基化的雌二醇,并将其转化为它们的各自的氨基衍生物。
流程3
提供了预防脱髓鞘和/或增强髓鞘再生的方法和化合物。在本发明的一个方面中,提供了启动、增强或增加细胞中RNA编码髓磷脂碱性蛋白基因和/或髓磷脂少突胶质细胞糖蛋白基因的基因转录的方法,所述方法包括将所述细胞与有效量的选自式(I)和(Ia)至(If)的6-取代的雌二醇衍生物进行接触。应理解此类基因转录的启动、增强或增加可以发生于这些基因中的一种或多种。
如本文所述,本发明化合物的盐是指无毒性的"可药用盐"。然而,其它的盐可以用于制备本发明的化合物或其可药用盐。当本发明的化合物含有碱性基团时,术语"可药用盐"中包括的盐是指一般通过使游离碱与适合的有机或无机酸反应制备的无毒性盐。代表性的盐包括本领域中已知的任何这类盐。如果本发明的化合物携带酸性部分,那么其适合的可药用盐可以包括碱金属盐,例如钠或钾盐;碱土金属盐,例如钙或镁盐;和与适合的有机配体形成的盐,例如季铵盐。
如本文所述,本发明的化合物可以与其它药剂或其它会增强哺乳动物受试者的治疗方案的药剂组合。例如,所述方法的化合物可以用于与其它的雌激素受体-β调节剂组合。这类组合中的单个组分可以在疗法过程期间在不同时间单独地、或以分开的或单一的组合形式同时地施用于需要这类疗法的患者或这类患者的部位。因此,应将本发明理解为包括所有同时或交替治疗的这类方案,并且由此解释术语"施用"。可以理解本发明化合物与其它用于治疗靶向脱髓鞘性疾病的药剂的组合的范围主要包括与用于治疗涉及雌激素起作用的障碍的任何药物组合物的任何组合。
以下的非限制性实例和数据阐述涉及本发明的化合物、组合物和/或方法的多个方面和特征,包括6-取代的雌二醇衍生物的合成,其如通过本文描述的方法可获得。与现有技术相比,本发明化合物和方法提供了令人惊讶的、意想不到的和结果和与之对立的数据。虽然通过若干化合物、基团和/或其取代基的制备和使用阐述了本发明的实用性,但本领域技术人员会理解使用多种其它化合物、基团和/或取代基可获得相当的结果,其与本发明的范围是相匹配的。
如上文所述,根据U.S.S.N.12/627,874和U.S.S.N.13/232,798中公开的操作制备所述方法的化合物。为例证上文描述的和U.S.S.N.12/627,874中详述的合成流程,在实施例1中提供了化合物21的制备。
实施例1
制备化合物21的方法
a)(8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-将氯甲基甲醚(7.0mL,92.0mmol)加入β-雌二醇(5g,18.4mmol)和二异丙基乙胺(16.0mL92mmol)在100mL的THF中的溶液中。将该反应混合物加热至回流,并搅拌18小时。将THF在真空下除去,并将该黄色/棕色油状物在水和CH2Cl2之间分配。将有机层分离,用盐水洗涤,干燥(Na2SO4),过滤,并在真空下蒸发,得到金色油状物。经硅胶柱色谱纯化(10%EtOAc/Hex),得到标题化合物,为粘稠的、澄清的油状物(5.7g,86%)。
b)(8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-醇-向叔丁醇钾(8.87g,79.0mmol)和二异丙胺(11.2mL,79.0mmol)在氩气下冷却至-78℃的80mL的无水THF中的溶液中滴加正丁基锂(49.4mL,79.0mmol,1.6M在己烷中)。将该反应混合物在-78℃搅拌30-45分钟。然后滴加来自a)的化合物(5.7g,15.8mmol)在45mL的THF中的溶液,并将该反应混合物在-78℃搅拌3小时。在来自a)的化合物的添加期间,该反应转变为深红色。然后缓慢加入硼酸三甲酯(10.6mL,94.8mmol),并将该混合物升温至0℃,并搅拌2小时。然后加入过氧化氢(24mL30%水溶液),并将该反应混合物升温至室温,并再搅拌1小时。将该反应混合物冷却回0℃,并小心地用10%Na2S2O3水溶液(70ml)淬灭。将得到的混合物用EtOAc萃取(2x),并将合并的有机萃取物干燥(Na2SO4),过滤,并在真空下蒸发,得到黄色/棕色油状物。经硅胶柱色谱纯化(25%EtOAc/Hex),得到标题化合物,为白色固体(3.5g,59%)。
c)(8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-酮-将戴斯-马丁氧化剂(Dess-MartinPeriodinane)(9.46g,22.3mmol)分批加入来自b)的化合物(7.0g,18.6mmol)在300mLCH2Cl2中的溶液中。将得到的反应混合物在室温搅拌3小时。将该混合物倾入水中,并将各层分离。将水层用CH2Cl2萃取,并将合并的有机萃取物用盐水洗涤,干燥(Na2SO4),过滤,并在真空下蒸发,得到胶粘性的棕色固体。经硅胶柱色谱纯化(15%EtOAc/Hex),得到标题化合物,为浅黄色、粘稠的油状物(6.0g,86%)。
d)2-(((8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-亚基)乙酸乙酯-在室温将膦酰乙酸三乙酯(4.1mL,20.8mmol)加入氢化钠(832mg,20.8mmol)在25mL的THF中的混合物中。约10分钟后,滴加来自c)的化合物(3.9g,10.4mmol)在10mL的THF中的溶液。将得到的反应混合物在密封管中加热至回流达72小时。将该混合物在真空下浓缩,并经硅胶柱色谱纯化(5%EtOAc/Hex至40%EtOAc/Hex的梯度),得到标题化合物,为澄清的、粘稠的油状物(3.4g,74%)。
e)2-((8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-亚基)乙醇-在0℃将来自d)的化合物(3.1g,6.97mmol)在65mL的THF中的溶液用氢化铝锂(5.2mL,10.46mmol,2M在THF中)滴加处理。除去冷却浴,并将该反应混合物在室温搅拌15分钟。将该反应混合物冷却回0℃,并通过小心地加入1.3mL水、随后加入2.6mL2N NaOH、然后加入1.3mL水进行淬灭。将该混合物剧烈搅拌直至形成白色固体。将该混合物过滤,并将滤液在真空下浓缩,得到标题化合物,为澄清的油状物(2.8g,99%)。
f)2-((6S,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-基)乙醛–在室温将来自e)的化合物(3.09g,7.68mmol)和10%Pd/C(500mg)在100mL乙酸乙酯中的混合物在40psi的H2(g)下搅拌5小时。将该混合物经Celite过滤,并将Celite用乙酸乙酯充分洗涤。将滤液在真空下浓缩,得到浅黄色油状物(3.1g)。将该油状物溶于100mL二氯甲烷中,并分批加入戴斯-马丁氧化剂(3.9g,9.22mmol)。将得到的反应混合物在室温搅拌30分钟。将该混合物倾入水中,并用CH2Cl2萃取。将合并的有机萃取物用盐水洗涤,干燥(Na2SO4),过滤,并在真空下蒸发,得到棕色固体。经硅胶柱色谱纯化(15%EtOAc/Hex),得到标题化合物,为澄清的油状物(2.0g,65%)。
g)4-((6R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-基)丁-2-烯-1-醇–在0℃将双(三甲基硅烷基)氨基锂(18.4mL,18.4mmol,1.0M在THF中)滴加至(2-羟基乙基)三苯基溴化鏻(3.37g,8.70mmol)在60mL的THF中的混悬液中。1小时后,将该金褐色溶液用来自f)的化合物(1.4g,3.48mmol)在10mL THF中的溶液滴加处理。将得到的反应混合物在0℃搅拌40分钟,然后用饱和的NH4Cl水溶液淬灭。将得到的混合物用EtOAc萃取(2x),并将合并的有机萃取物干燥(Na2SO4),过滤,并蒸发,得到棕色油状物。经硅胶柱色谱纯化(从20%EtOAc/Hex至75%EtOAc/Hex的梯度),得到标题化合物,为黄色粘稠的油状物(680mg,45%)。
h)4-((6R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-基)丁-2-烯醛-在室温将戴斯-马丁氧化剂(437mg,1.03mmol)加入来自g)的化合物(370mg,0.86mmol)在15mL CH2Cl2中的溶液中。将得到的反应混合物搅拌10分钟,然后倾入水中。将各层分离,并将水层用CH2Cl2萃取(2x)。将合并的有机萃取物用盐水洗涤,干燥(Na2SO4),过滤,并在真空下蒸发,得到棕色油状物。经硅胶柱色谱纯化(从5%EtOAc/CH2Cl2至10%EtOAc/CH2Cl2的梯度),得到标题化合物,为浅黄色粘稠的油状物(358mg,86%)。
i)6-((6R,8R,9S,13S,14S,17S)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-6-基)己-2,4-二烯-1-醇–在0℃将双(三甲基硅烷基)氨基锂(4.3mL,4.29mmol,1.0M在THF中)滴加至(2-羟基乙基)三苯基溴化鏻(786mg,2.03mmol)在14mL THF中的混悬液中。30分钟后,将该金褐色溶液用来自h)的化合物(345mg,0.81mmol)在2mL的THF中的溶液滴加处理。将得到的反应混合物在0℃搅拌20分钟,并用饱和的NH4Cl水溶液淬灭。将得到的混合物用EtOAc萃取(2x),并将合并的有机萃取物干燥(Na2SO4),过滤,并蒸发,得到棕色油状物。经硅胶柱色谱纯化(从5%EtOAc/CH2Cl2至40%EtOAc/CH2Cl2的梯度),得到标题化合物,为黄色粘稠的油状物(140mg,38%)。
j)(6R,8R,9S,13S,14S,17S)-6-(6-甲氧基己-2,4-二烯-1-基)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲–将i)中的化合物(135mg,0.3mmol)的溶液冷却至0℃,并分批加入氢化钠(120mg,3.0mmol)。5-10分钟后,滴加碘代甲烷(0.19mL,3.0mmol),并将得到的反应混合物升温至室温,并搅拌4小时。加入EtOAc,并将该反应用水小心地淬灭。将各层分离,并将有机层干燥(Na2SO4),过滤,并蒸发,得到棕色油性残余物。经硅胶柱色谱纯化(从5%EtOAc/Hex至20%EtOAc/Hex的梯度),得到标题化合物,为澄清的油状物(92mg,65%)。
k)(6R,8R,9S,13S,14S,17S)-6-(6-甲氧基己基)-3,17-双(甲氧基甲氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲–将j)中的化合物(90mg,0.19mmol)和10%Pd/C(100mg)在5-10mL乙酸乙酯中的混合物在室温在H2(g)气球下搅拌16小时。将该混合物经Celite过滤,并将Celite用乙酸乙酯充分洗涤。将滤液在真空下浓缩,得到标题化合物,为澄清的油状物(90mg,99%)。
l)(6R,8R,9S,13S,14S)-6-(6-甲氧基己基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇(化合物21)–在室温将来自k)的化合物(90mg,0.19mmol)在各1.5mL的6N HCl和THF中的溶液搅拌5小时。将该反应混合物用水稀释,并用EtOAc萃取(2x)。将合并的有机萃取物干燥(Na2SO4),过滤,并在真空下蒸发,得到澄清的、油性残余物。经硅胶柱色谱纯化(从CH2Cl2至30%EtOAc/CH2Cl2的梯度),得到化合物21,为白色固体泡沫(38mg,52%)。
实施例2
制备化合物3和4的方法
如在流程2中概述的,雌二醇衍生物化合物3和4以如下方式合成。通过将β-雌二醇与二氢吡喃在THF中反应、使用甲苯磺酸或樟脑磺酸作为催化剂制备受保护的雌二醇化合物。如本领域普通技术人员可以理解的,该反应是平衡反应,且在所述条件下不反应完全。因此,可以在该反应混合物中找到两种单保护的雌二醇。该粗制的反应混合物经历与乙腈的研磨步骤,引起所需的双-THP雌二醇结晶,收率约70%。
如流程2中所示,通过使用称为LiDAKOR:丁基锂、二异丙胺和叔戊醇钾的强碱混合物在苄6-位酰化得到关键中间体。在该条件下、在-70℃,本领域普通技术人员可以理解在苄位夺取一个质子。然后将中间体经柱色谱纯化,得到浆体(收率约50%),其仍包含较少的杂质和柱溶剂。使用过量的氢化铝锂将醛还原,得到高收率的消旋的羟基甲基雌二醇化合物。
为制备化合物3和4的目的,通过用氢化钠和碘代甲烷将羟基甲基雌二醇化合物甲基化制备甲氧基甲基化合物。将所述甲氧基甲基化合物经柱色谱纯化,得到玻璃状泡沫。将受保护的基团脱保护,得到外消旋的6-甲氧基甲基雌二醇化合物。使用手性制备型HPLC进行对映异构体的分离,得到化合物3和4。对于化合物4,实现了>95:5R:S的手性纯度。对于化合物3,实现了86:14S:R的手性纯度。使用NMR确定6-位的绝对立体化学完全在本领域技术人员所具有水平之内,其中4-和6-位质子具有诊断特征。
实施例3
化合物在肺、胰和卵巢肿瘤细胞系中的表达谱
本研究包括三种人肿瘤细胞系:A549、Panc-1和SK-OV-3。使所述细胞系各自在两个烧瓶中生长,将其培养至大致40%融合。通过将不同浓度(即10μM、20μM、50μM、100μM或200μM)化合物加入培养基而对其中一个烧瓶进行处理。将另一个模拟处理烧瓶仅用用于溶解和递送所述药物的介质进行处理。将提取自经处理的和未处理的样品对的RNA在AgilentWhole Human Genome Microarrays(G4112F)上进行微阵列分析。每个分析报告了对于阵列上41,000个特异性mRNA检测器中每一个而言的信使RNA丰度的差异。对于每个细胞系,该经处理的与未处理的样品的直接比较提供了对于由于所述药物处理产生的mRNA丰度的变化的极其敏感的检测。由于每个细胞系的比较是自身标准化的,获得的结果可以在样品中进行具有高置信度的比较。
细胞准备
使三种人肿瘤细胞系A549、Panc-1和SK-OV-3各自在两个烧瓶中生长,将其培养至大致40%融合。通过将浓度为10μM、50μM和100μM的化合物加入培养基而对其中一个烧瓶进行处理。将另一个模拟处理烧瓶仅用用于溶解和递送所述药物的介质进行处理。将所有烧瓶再培养24小时,然后自由刮取所述细胞并用冰冷的PBS洗涤,然后通过离心收集。将所获取的细胞立即冷冻并在-80℃或更低温度保存。
RNA纯化
使用基Trizol的细胞溶解、然后用65℃热苯酚萃取以及RNeasy色谱纯化,由冷冻的组织样品制备了总RNA。将纯化的RNA样品经分光光度计分析。通过测定260nm(A260)处的吸光度确定RNA的浓度。当在pH11测定时,在260nm的1单位的吸光度相当于35μg RNA/ml。
RNA质量评价-A260/A280吸光度比例
在260nm和280nm(A260/A280)的读数的比例提供了相对于吸收UV的杂质(例如蛋白质)的RNA的纯度的评价。RNA具有约2.1的理论A260/A280比例(10mM Tris·Cl,pH7.5)。在该试验中,具有1.8或更高的A260/A280比例的提取的RNA提供了优良的结果。
RNA质量评价–毛细管电泳
使用毛细管电泳(Agilent BioAnalyzer),通过确定完整的28S和18S核糖体RNA的比例,测试RNA的相对完整性。完全完整的RNA具有的28S/18S比例为2.2。对于阵列分析而言所接受的所有RNA具有超过1的比例,该比例是可靠的有重现性的微阵列结果的最小28S/18S比例,如通过回顾具有不同28S/18S比例的样品中的内部重现性所确定。
探针产生和芯片杂交
使用1mg RNA作为Agilent Low Input Labeling反应的用量,将所有的RNA进行标记。
将测试RNA使用Cy5(650nm发射源)标记,将参比RNA使用Cy3(550nm发射源)核苷酸进行标记。标记、杂交和随后的洗涤在Agilent H1Av2人表达芯片上进行。将得到的杂交芯片在Agilent微阵列扫描仪上进行扫描,使用Agilent特征抽提软件(Agilent featureextraction software)从扫描的图像中提取每个检测器点的强度信息。
杂交质量的最显著的测试是来自打印在这些芯片上的基因的大量副本的报告的比例中的差异水平。将一套基因探针在阵列的随机位置各自打印十次。将所有的各套的log2比例的标准偏差的中位值用作整个阵列的总标准偏差的评价物。
数据和分析
将所有三次杂交的关键数据收集至FileMaker Pro关系数据库,以允许容易地配置检索,所述检索能鉴别显示特定转录模式的基因。所报告的数据是红色(经处理的)和绿色(未经处理的)背景扣减的信号。这是数据的最少修改形式。基于与人DNA不互补的大量探针,评价所述的片的背景“面”。这些作为标记的cRNA与阵列表面的非特异性结合和标记的cRNA与固定的DNA低聚物的非特异性结合评价物。使用该信息,评价了每个探针周围的局部噪音,并且,对于阵列上的每个特定的探针特征,将其从在寡核苷酸沉积区域发现的信号中扣减(gBGSubSignal、rBGSubSignal)。将来自经处理的细胞的RNA和未经处理的细胞的RNA的信号的比例作为直接的比例和作为log2比例(比例,Log2比例)报道。以标准化每个通道中的强度的迭代的方法确定比例,因而发现了最大化大量基因的强度的相似性的标量,所述基因具有几乎相同的转录水平,因而应当具有非常接近1的比例。
在对标准化的数据计算了比例后,对各个对照和副本样品进行分析,以建立关于结果的重现性如何和该重现性如何根据信号的强度和噪音变化的模型。使用这些参数形成了关于以下的可能性的评价:如果从产生强度的相同分布的单一方法中随机抽取所述红色和绿色强度,可能已经出现每个比例。报告了每个样品的这种可能性,其为关于所述比例指示经处理和未处理的信号强度之间的差异的可能性的量度(PValLogRatio)。该可能性可以用于将结果归类为改变的和未改变的基因的阈值。在该数据库中,将阈值p≤0.001用作经处理的和未处理的样品之间的mRNA丰度中的显著变化的割点(Sig0.001)。鉴于在每个试验中考察的~40,000的比例,该阈值将预期的假阳性数量降低至合理的水平。表示相对于未处理的样品的显著变化和变化的方向的场将所述试验的结果简化至三个范围;1,相对于为处理组上调,0,相对于为处理组无变化,以及-1,相对于为处理组下调(Tri)。使用该表示法,容易构建鉴别已经在任何单一或多套试验中改变的基因的检索。
下表1所示的所述基因表达数据显示化合物4和化合物21在涉及OPCs增殖和分化的信号传导通路中上调基因,并最终上调神经轴突的髓鞘的合成。表1中所示的基因表达值是从三种人肿瘤细胞系(SKOV-3、A549和Panc-1)中获得的数据的log2值和平均值。基因表达中的显著性变化是p≤0.0001。基因ID与National Center for BiotechnologyInformation(NCBI)开发的Entrez基因数据库的标准一致。
表1
实施例4
少突胶质细胞分化试验
如Pedraza,C.E.等,Glia56(12),1339-52(2008)(引入本文作为参考)所述制备OPC培养物。从E14.5C57Bl6/J(表达PLP-EGFP)小鼠(Mallon,B.S.等,J.Neurosci22(3),876-85(2002))去除大脑,净化,并分离皮质半球。然后将组织研磨并以每个烧瓶一个大脑(2个皮质半球)的密度接种于T-25cm2烧瓶。三天后神经球传代一次。将来自2代的细胞用于准备用于初筛选的2个96孔板。在OPC培养基中孵育最初的48小时后,用以下物质处理所述OPC:10μM的17β-雌二醇、化合物4和化合物21,以及介质对照DMSO和阳性对照化合物,包括10μM睫状神经营养因子(CNTF)和1μM胞外信号调节(ERK)激酶抑制剂(MEKi)。将细胞处理总计4天,在48小时时用新鲜化合物替换培养基。在4天的处理后,将细胞用4%低聚甲醛固定,并用Hoechst33342染色,以使细胞核可见。还将细胞用抗-GFAP(GFAP=胶质细胞原纤维酸性蛋白)抗体染色,以鉴别星形细胞。将细胞用3%标准山羊血清阻断,随后孵育抗-兔GFAP抗体(1:500)过夜。将细胞用1:1000浓度的二级山羊抗-兔Alexa647荧光染料抗体进行标记。使用Cellomics Arrayscan VTI获得图像。在10x放大时每孔获得20个视野,并通过神经元描绘算法评价表达EGFP(增强的绿色荧光蛋白;成熟的少突胶质细胞)和GFAP(星形细胞)的细胞。
少突胶质细胞成熟的程度通过PLP-EGFP报告蛋白信号以及形成过程(processformation)的程度测定(图1-4;图1和3的图例见以下表2)。将蛋白质脂蛋白质(PLP)用作生物标记,原因是已知其在成熟的少突胶质细胞中表达且是髓鞘的组分。如图1和3所示,化合物4和21均是强效的6-取代的类似物,其中化合物21具有分别比DMSO强3-倍的分化少突胶质细胞的活性以及比阳性对照CNTF(Stankoff,B.等,J Neurosci22(21),9221-27(2002))和MEKi(Younes-Rapozo,V.等,Int J Dev Neurosci,27(8),757-68(2009))强1.5至2.0-倍的活性。与DMSO和所有其他测试化合物、包括CNTF相比,对于化合物21而言的形成过程的程度也最大(图2和4)。
表2–图1和3的图例
图1和3中的字母 | 化合物# |
A | 24 |
B,O | 4 |
C | 8 |
D | 雌二醇 |
E,M | 21 |
F | 32 |
G | 23 |
H | 雌三醇 |
I | 10 |
J | 18 |
K | 20 |
L | 依西美坦 |
N | 33 |
所有论文及参考文献、包括专利的公开内容被引入本文作为参考。目前将本发明以及制备和使用其的方式和过程以如此充分、清楚、简要和准确的术语进行描述,以使得任何本领域技术人员能够制造和使用本发明。在本说明书中引用的所有参考文献被引入本文作为参考。应当理解的是上文描述了本发明的优选的实施方案,可以在不背离本发明的主旨和范围的情况下对其进行修改。
Claims (16)
1.下式的6-取代的雌二醇衍生物在制备用于预防神经细胞的轴突的脱髓鞘和/或增强神经细胞的轴突的髓鞘再生的药物中的用途:
其中"a"环为
R1、R2、R3和R4为H;
R11为H;
X选自-(CH2)m-O-CH3和-(CH2)m-O-NH2;
Y选自=O、-OCO(C1-C20烷基)和-OH;
Z选自H和甲基;
m是0-20的整数;
符号各自独立地表示能在17位形成酮基的单键或双键;且
符号表示任何类型的键,而不论立体化学如何;
及所述化合物的可药用盐。
2.根据权利要求1的用途,其中
Y是–OH;
Z是甲基;
R11是H;
m是1-12的整数。
3.根据权利要求2的用途,其中
X为-(CH2)m-O-CH3。
4.根据权利要求1的用途,其中化合物选自
(6R,8R,9S,13S,14S)-6-(甲氧基甲基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇;
(6R,8R,9S,13S,14S)-6-(羟基甲基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇;
(6R,8R,9S,13S,14S)-6-((氨基氧基)甲基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇;
(6R,8R,9S,13S,14S)-6-甲氧基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇;
(6R,8R,9S,13S,14S)-6-(4-甲氧基丁基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇;
(6R,8R,9S,13S,14S)-6-(6-甲氧基己基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇;
(6R,8R,9S,13S,14S)-3-羟基-6-(甲氧基甲基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-17-基硬脂酸酯;
(6R,8R,9S,10R,13S,14S)-6-(甲氧基甲基)-10,13-二甲基-7,8,9,10,11,12,13,14,15,16-十氢-3H-环戊二烯并[a]菲-3,17(6H)-二酮;和
(6R,8S,9S,14S,17S)-6-(甲氧基甲基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇。
5.根据权利要求4的用途,其中化合物选自
(6R,8R,9S,13S,14S)-6-(甲氧基甲基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇和
(6R,8R,9S,13S,14S)-6-(6-甲氧基己基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇。
6.下式的6-取代的雌二醇衍生物在制备药物中的用途,所述药物用于在受试者中治疗脱髓鞘性障碍:
其中"a"环为
R1、R2、R3和R4为H;
R11为H;
X选自-(CH2)m-O-CH3和-(CH2)m-O-NH2;
Y选自=O、-OCO(C1-C20烷基)和-OH;
Z选自H和甲基;
m是0-20的整数;
符号各自独立地表示能在17位形成酮基的单键或双键;且
符号表示任何类型的键,而不论立体化学如何;
及所述化合物的可药用盐。
7.根据权利要求6的用途,其中
Y是–OH;
Z是甲基;
R11是H;
m是1-12的整数。
8.根据权利要求7的用途,其中
X为-(CH2)m-O-CH3。
9.根据权利要求6的用途,其中所述化合物选自
(6R,8R,9S,13S,14S)-6-(甲氧基甲基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇;
(6R,8R,9S,13S,14S)-6-(羟基甲基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇;
(6R,8R,9S,13S,14S)-6-((氨基氧基)甲基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇;
(6R,8R,9S,13S,14S)-6-甲氧基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇;
(6R,8R,9S,13S,14S)-6-(4-甲氧基丁基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇;
(6R,8R,9S,13S,14S)-6-(6-甲氧基己基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇;
(6R,8R,9S,13S,14S)-3-羟基-6-(甲氧基甲基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-17-基硬脂酸酯;
(6R,8R,9S,10R,13S,14S)-6-(甲氧基甲基)-10,13-二甲基-7,8,9,10,11,12,13,14,15,16-十氢-3H-环戊二烯并[a]菲-3,17(6H)-二酮;和
(6R,8S,9S,14S,17S)-6-(甲氧基甲基)-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇。
10.根据权利要求9的用途,其中所述化合物选自
(6R,8R,9S,13S,14S)-6-(甲氧基甲基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇和
(6R,8R,9S,13S,14S)-6-(6-甲氧基己基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-3,17-二醇。
11.根据权利要求10的用途,其中所述障碍选自多发性硬化、脑桥中央髓鞘溶解症、实验性自身免疫性脑脊髓炎、急性播散性脑脊髓炎、横贯性脊髓炎、进行性多灶性白质脑病;阿尔茨海默病、亚急性硬化性全脑炎、感染后脑脊髓炎、慢性炎症性脱髓鞘性多神经病、进行性核上性麻痹、多灶性运动神经病、吉兰巴雷综合征、进行性多灶性白质脑病、德维克病、Balo同心性硬化、克拉伯病、肾上腺脑白质营养不良(ALD)、佩利措伊斯-梅茨巴赫病、卡纳范病、儿童共济失调伴中枢神经系统髓鞘形成不良、亚历山大病、科克因综合征、Van derKnapp综合征、泽尔韦格综合征和雷弗素姆病。
12.根据权利要求11的用途,其中所述障碍是多发性硬化。
13.根据权利要求12的用途,其中通过脱髓鞘性障碍的症状的改善监测髓鞘再生。
14.根据权利要求13的用途,其中将所述化合物与抗炎药或免疫调节剂组合施用。
15.(6R,8R,9S,10R,13S,14S)-6-(甲氧基甲基)-10,13-二甲基十六氢-1H-环戊二烯并[a]菲-3,17-二醇在制备药物中的用途,所述药物用于预防神经细胞的轴突的脱髓鞘和/或增强神经细胞的轴突的髓鞘再生。
16.(6R,8R,9S,10R,13S,14S)-6-(甲氧基甲基)-10,13-二甲基十六氢-1H-环戊二烯并[a]菲-3,17-二醇在制备药物中的用途,所述药物用于在受试者中治疗脱髓鞘性障碍。
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Non-Patent Citations (1)
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Oestrogen receptor ligand: a novel treatment to enhance endogenous functional remyelination;D.K.CRAWFORD等;《BRAIN》;20100921;第133卷(第10期);2999-3016 * |
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DK2688570T3 (en) | 2015-12-21 |
ES2561536T3 (es) | 2016-02-26 |
US9364486B2 (en) | 2016-06-14 |
KR102080151B1 (ko) | 2020-02-21 |
US20160279144A1 (en) | 2016-09-29 |
CN106420767A (zh) | 2017-02-22 |
EP2688570B1 (en) | 2015-11-18 |
CN103501790A (zh) | 2014-01-08 |
US9636348B2 (en) | 2017-05-02 |
WO2012129324A2 (en) | 2012-09-27 |
WO2012129324A9 (en) | 2012-11-15 |
CA2830515C (en) | 2015-09-15 |
EP2688570A2 (en) | 2014-01-29 |
CA2830515A1 (en) | 2012-09-27 |
EP2688570A4 (en) | 2014-09-10 |
KR20140074253A (ko) | 2014-06-17 |
MX2013010650A (es) | 2013-10-07 |
AU2012230974A1 (en) | 2013-09-26 |
SG193380A1 (en) | 2013-10-30 |
AU2012230974B2 (en) | 2016-05-12 |
MX354409B (es) | 2018-03-05 |
JP6174563B2 (ja) | 2017-08-02 |
BR112013024168A2 (pt) | 2017-07-11 |
US20120245131A1 (en) | 2012-09-27 |
JP2014508807A (ja) | 2014-04-10 |
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