CN111040015B - 19-去甲-c21取代类固醇衍生物 - Google Patents
19-去甲-c21取代类固醇衍生物 Download PDFInfo
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- CN111040015B CN111040015B CN201811194851.9A CN201811194851A CN111040015B CN 111040015 B CN111040015 B CN 111040015B CN 201811194851 A CN201811194851 A CN 201811194851A CN 111040015 B CN111040015 B CN 111040015B
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Abstract
本发明涉及19‑去甲‑C21取代类固醇衍生物及其药物组合物，以及上述19‑去甲‑C21取代类固醇衍生物或其药物组合物在制备用于预防或治疗中枢神经系统紊乱疾病药物中的用途。
Description
技术领域
本发明涉及药物化学领域，具体涉及式(I)的19-去甲-C21取代类固醇衍生物及其在制备用于预防或治疗中枢神经系统紊乱疾病药物中的用途。
背景技术
脑兴奋性(excitability)被定义为动物的唤醒水平，是范围从昏迷到惊厥的连续体，并通过各种神经递质调节。通常，神经递质负责调节离子跨越神经元膜的传导性。在静止时，神经元膜具有约-70mV的电势(或膜电压)，细胞内部相对于细胞外部是负的。电势(电压)是跨越神经元半透膜的离子(K+、Na+、Cl-、有机阴离子)平衡的结果。神经递质存储在突触前泡囊中，并且在神经元动作电位的影响下释放。当释放到突触间隙中时，兴奋性化学递质(例如，乙酰胆碱)将引起膜去极化(电势从-70mV到-50mV的变化)。这种作用是通过突触后的烟碱受体介导的，所述突触后的烟碱受体由乙酰胆碱刺激以增加膜对Na+离子的渗透性。降低的膜电势以突触后动作电位的形式刺激神经元兴奋性。
在GABA受体复合物(GRC)存在的情况下，对脑兴奋性的作用通过GABA神经递质介导。GABA对总的脑兴奋性具有深度的影响，这是因为脑中的高达40％的神经元利用GABA作为神经递质。GABA通过调节氯离子跨越神经元膜的传导来调节单独的神经元的兴奋性。GABA与其在GRC上的识别位点相互作用，促进氯离子沿着GRC的电化学梯度流入到细胞中。该阴离子水平的细胞内增加导致跨膜电位的超极化，使神经元对于兴奋性输入不太敏感(即，神经元兴奋性的降低)。换句话说，神经元中的氯离子浓度越高，脑兴奋性(唤醒水平)越低。
有许多文献证明，GRC负责焦虑、发作行为和镇静的介导。因此，GABA和像GABA一样起作用或促进GABA的作用的药物(例如，治疗上使用的巴比妥酸盐和苯并二氮
(BZ)，例如Valium)，通过与GRC上的特异性调节位点相互作用，产生其治疗上有用的效果。研究表明，除苯并二氮
和巴比妥酸盐结合位点之外，GRC还包含针对神经活性类固醇的独特的位点。
神经活性类固醇是神经组织中具有活性的类固醇，是极为重要的神经和行为的内源性调质。最有效的神经活性类固醇为3α-羟基-5-还原孕甾烷-20-酮和3α-21-二羟基-5-还原孕甾烷-20-酮，其分别为激素类固醇孕酮和脱氧皮质酮的代谢物。1986年时，研究发现这些类固醇代谢物具有改变脑兴奋性的能力。
研究还发现孕酮及其代谢物的水平可以随着月经周期的阶段而改变。已有许多文献证明，孕酮及其代谢物的水平在月经开始之前降低，同时每月一次重现的在月经开始之前身体会出一些症状，这些症状包括应激(紧张)、焦虑和偏头痛，上述症状统称为经前综合症。此外，孕酮的减少也与女性癫痫患者即月经性癫痫的发作频率的增加有关。对于具有原发性全身性小发作癫痫的受试者，癫痫发作的发生率与经前综合征(PMS)症状的发生率有关。产后抑郁症(PND)也与低的孕酮水平有关。在分娩之后，孕酮水平立即急剧降低，导致PND的发作。PND的症状范围是从轻度抑郁症到需要住院治疗的精神病。PND也与重度焦虑和应激性有关。PND有关的抑郁症不能通过经典的抗抑郁药治疗，且经历PND的女性显示具有增加的经前综合症的发生率。
综上所述，已有研究结果表明孕酮和脱氧皮质酮及其代谢物在脑兴奋性的稳态调节中起到关键作用，表现为上述调节物质水平异常与月经性癫痫，PMS和PND的发作行为或症状的增加有关。因发现了低孕酮水平与月经性癫痫，PMS和PND有关，已开始尝试将孕酮用于上述症状的治疗。然而，使用孕酮治疗上述症状时，孕酮存在不能有效治疗的现象(Maddocks等,Obstet.Gynecol.154:573-581(1986)；Dennerstein等,Brit.Med J 290:16-17(1986))。
SAGE-217是由Sage Therapeutics研发的一种GABA调节剂，目前处于临床研究中，可适用于重度抑郁症，产后抑郁症，失眠症，抑郁狂躁型忧郁症等多种中枢神经系统紊乱疾病。文献记载，SAGE-217对GABAa受体α1β2γ2亚型具有较强的调节作用，EC50在375nM左右。但本发明人研究发现，SAGE-217溶解性能较差，在磷酸盐缓冲体系中几乎不溶，在磺丁基类环糊精体系中的饱和溶解度只有2mg/mL，为了达到起效剂量，需要较大体积的药物制剂才能达到药效，成药性较差，且降低了患者依从性。
因此，需要开发一类新的类固醇衍生物，可以通过调节GABA而发挥脑兴奋性调节剂的作用，进而用于中枢神经系统紊乱疾病的预防或治疗，还具有改善的溶解性能，利于药物制剂的制备。
发明内容
本发明的目的在于提供了一种19-去甲-C21取代类固醇衍生物；本发明的目的还在于提供了一种包含19-去甲-C21取代类固醇衍生物的药物组合物；本发明的另一目的在于提供一种制备19-去甲-C21取代类固醇衍生物的方法；本发明的又一目的在于提供该类化合物在制备用于治疗中枢神经系统异常引起的疾病中的药物的应用。
本发明的目的是由以下技术方案来达到的，本发明涉及式(I)的19-去甲-C21取代类固醇衍生物，
或其可药用盐；
其中：
R1，R2各自独立地选自氢，卤素，氰基，硝基；
R3选自卤素，氰基，硝基，羧基，醛基，酰胺基，磺酸基。
在一实施例中，所述化合物选自式(Ⅰ-A)的化合物：
在一优选实施例中，所述化合物选自式(Ⅰ-A1)的化合物：
在一更优选实施例中，R1，R2各自独立地选自氢，卤素。
在一最优选实施例中，R1，R2各自独立地选自氢，氟，氯，溴，碘。
在一更优选实施例中，R3选自氰基。
在一优选实施例中，所述化合物选自式(Ⅰ-A2)的化合物：
在一更优选实施例中，R1，R2各自独立地选自氢，卤素。
在一最优选实施例中，R1，R2各自独立地选自氢，氟，氯，溴，碘。
在一更优选实施例中，R3选自氰基。
根据本发明，通式为式(I)的化合物，其优选化合物包括：
本发明还提供了所述的化合物在制备用于治疗由中枢神经系统异常引起的疾病的药物中的用途。所述的疾病包括震颤，癫痫，抑郁症或焦虑障碍。更详细地，所述中枢神经系统紊乱疾病包括特发性震颤，癫痫，临床抑郁，分娩后或产后抑郁，非典型抑郁，精神病性严重抑郁症，紧张型抑郁，季节性情绪失调症，心境恶劣，双重抑郁，抑郁性人格障碍，复发性短暂抑郁，轻度抑郁障碍，双向性精神障碍或躁狂抑郁性障碍，创伤后应激障碍，因慢性医学病状引起的抑郁，耐治疗性抑郁，难治性抑郁，自杀倾向，自杀观念或自杀行为。
本发明还提供了一种药用组合物，包括本发明提供的上述式(I)化合物和，以及可药用赋形剂。
本发明进一步提供了上述所述的药物组合物在制备用于治疗由中枢神经系统异常引起的疾病的药物中的用途。所述的疾病包括震颤，癫痫，抑郁症或焦虑障碍。更详细地，所述中枢神经系统紊乱疾病包括特发性震颤，癫痫，临床抑郁，分娩后或产后抑郁，非典型抑郁，精神病性严重抑郁症，紧张型抑郁，季节性情绪失调症，心境恶劣，双重抑郁，抑郁性人格障碍，复发性短暂抑郁，轻度抑郁障碍，双向性精神障碍或躁狂抑郁性障碍，创伤后应激障碍，因慢性医学病状引起的抑郁，耐治疗性抑郁，难治性抑郁，自杀倾向，自杀观念或自杀行为。
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素，任选地进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又称为重氢)、氚(T，又称为超重氢)，氧的同位素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S，氮的同位素包括14N和15N，氟的同位素包括19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。
本发明描述的化合物可包括一个或多个不对称中心，且因此可以存在多种异构体形式，例如，对映异构体和/或非对映异构体形式。例如，本发明描述的化合物可为单独的对映异构体、非对映异构体或几何异构体，或者可为立体异构体的混合物的形式，包括外消旋混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离，所述方法包括：手性高压液相色谱法(HPLC)以及手性盐的形成和结晶；或者优选的异构体可通过不对称合成来制备。本发明另外包括作为基本上不含其它异构体的单独异构体、或者作为多种异构体的混合物的本文描述的化合物。
“羧基”是指基团-C(O)OH。
“醛基”是指基团-C(O)H。
“氰基”是指基团-CN。
“卤代”或“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。在一些实施方案中，卤素基团是氟或氯。
“硝基”是指基团-NO2。
“可药用盐”是指，在可靠的医学判断范围内，适合与人和低等动物的组织接触而没有过度毒性、刺激性、变态反应等等，并且与合理的益处/危险比例相称的那些盐。可药用盐在本领域是众所周知的。例如，Berge等人在J.Pharmaceutical Sciences(1977)66:1-19中详细描述的可药用盐。本发明化合物的可药用盐包括衍生自合适无机和有机酸和碱的盐。可药用无毒酸加成盐的例子是氨基与无机酸形成的盐，例如盐酸、氢溴酸、磷酸、硫酸和高氯酸，或与有机酸形成的盐，例如乙酸、草酸、马来酸、酒石酸、枸橼酸、琥珀酸或丙二酸，或使用本领域使用的方法形成的盐，例如，离子交换方法。其它可药用盐包括：已二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡萄糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酯酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐、戊酸盐，等等。衍生自合适的碱的可药用盐包括碱金属、碱土金属、铵和N+(C1-4烷基)4盐。代表性的碱金属或碱土金属盐包括钠、锂、钾、钙、镁盐，等等。如果合适的话，进一步的可药用盐包括使用反离子形成的无毒的铵盐、季铵盐和胺阳离子，反离子例如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、低级烷基磺酸根和芳基磺酸根。
附图说明
图1显示了化合物1在多浓度对GABAa受体电流的正向调节拟合曲线
图2显示了化合物2在多浓度对GABAa受体电流的正向调节拟合曲线
图3显示了化合物3在多浓度对GABAa受体电流的正向调节拟合曲线
具体实施方式
以下通过实施例形式的具体实施方式，对本发明的上述发明内容做进一步详细说明，但不应理解为本发明的内容仅限于以下实施例，凡基于本发明上述内容所做出的发明均属于本发明的范围。
实施例1化合物1和化合物3的制备
中间体B的制备：
氮气保护下，向200mL三口反应瓶中加入物质A(4.2g，10.57mmol)，DCM(42mL)，Et3N(3.21g，31.71mmol)和TMSCl，随后室温搅拌3h。停止反应，反应液用饱和NaCl水溶液洗，合并有机层，减压浓缩，粗产品柱层析(PE/EtOAc＝10:1)得4.15g中间体B，无色油状物，收率85％。
1H NMR(400MHz,CDCl3)δ4.14–3.86(m,2H),2.89–2.67(m,1H),2.26–2.11(m,1H),1.98–0.97(m,25H),0.64(s,3H),0.13(s,9H).
中间体C的制备：
氮气保护下，向250mL单口反应瓶中加入中间体B(4.00g，8.51mmol)，DCM(40mL)，随后加入4-氰基吡唑(0.937g，10.06mmol)和Et3N(1.94g，19.17mmol)，室温搅拌过夜。停止反应，反应液用饱和NaCl水溶液洗，合并有机层，减压浓缩，粗产品柱层析(PE/EtOAc＝15:1)得3.73g中间体C，白色固体，收率82％。
1H NMR(400MHz,CDCl3)δ7.86(s,1H),7.81(s,1H),5.68–4.69(m,2H),2.62(t,J＝8.9Hz,1H),2.33–2.09(m,1H),2.13–1.98(m,1H),1.93–1.01(m,22H),0.93–0.81(m,3H),0.67(s,3H),0.13(s,9H).
化合物1和化合物3：
氮气保护下，向250mL三口反应瓶中加入中间体C(3.60g，7.47mmol)，THF(36mL)和LHMDS(9.00ml，9.00mmol)，随后在干冰乙醇浴下搅1h。加入TMSCl，继续在室温下搅拌2h。停止反应，减压浓缩，加DCM适量溶解，过滤，浓缩得4.03g烯醇硅醚粗产品。
氮气保护下，向250mL单口反应瓶中加入上步所得烯醇硅醚粗产品(4.03g)，MeCN(40mL)，Selectfluor(3.97g，11.20mmol)，室温下搅拌1.5h。停止反应，反应液中加入适量EtOAc，过滤，浓缩，粗产品柱层析(PE/Acetone 15:1)分别得到1.05g白色固体(化合物1)，收率33％，0.35g白色固体(化合物3)，收率11％。
化合物1：
1H NMR(400MHz,CDCl3)δ8.08(s,1H),7.90(s,1H),6.27(d,J＝49.1Hz,1H),3.23–3.10(m,1H),2.28–2.11(m,1H),2.00–0.98(m,27H),0.67(s,3H).19F NMR(377MHz,CDCl3)δ-144.62.
MS:m/z calcd for C25H34FN3O2[M+Na]+450.205,found 450.2.
化合物3：
1H NMR(400MHz,CDCl3)δ8.08(s,1H),7.90(s,1H),6.27(d,J＝49.1Hz,1H),3.23–3.10(m,1H),2.28–2.11(m,1H),2.00–0.98(m,27H),0.67(s,3H).
19F NMR(377MHz,CDCl3)δ-144.62.
MS:m/z calcd for C25H34FN3O2[M+Na]+450.25,found 450.2.
实施例2化合物2的制备
中间体D的制备:
氮气保护下，向250mL三口反应瓶中加入中间体C(3.60g，7.47mmol)，THF(36mL)，LHMDS(9.00mL，9.00mmol)，随后在干冰乙醇浴下搅拌1h。加入TMSCl(1.62g，14.94mmol)，继续在室温下搅拌2h。停止反应，减压浓缩，加DCM适量溶解，过滤，浓缩得4.03g烯醇硅醚粗产品。
氮气保护下，向250mL单口反应瓶中加入上步所得烯醇硅醚粗产品(4.03g)，MeCN(40mL)，Selectfluor(3.97g，11.20mmol)，室温下搅拌1.5h。停止反应，反应液中加入适量EtOAc，过滤，浓缩，粗产品柱层析(PE/Acetone＝15:1)得1.12g白色固体，收率35％。中间体E的制备：
氮气保护下，向20mL两口反应瓶中加入中间体D(200mg，0.50mmol)，DCM(2mL)，Et3N(152mg，1.50mmol)，TMSCl(136mg，1.25mmol)，随后室温搅拌3h。停止反应，反应液用饱和NaCl水溶液洗，合并有机相，减压浓缩，粗品柱层析(PE/EtOAc＝10:1)得216mg中间体E，无色油状物，收率92％。
化合物2的制备：
氮气保护下，向25mL两口反应瓶中加入中间体E(200mg，0.40mmol)，THF(2mL)，LHMDS(0.50mL，0.50mmol)，随后在干冰乙醇浴下搅拌1h。加入TMSCl(87mg，0.80mmol)，继续室温下搅拌2h。停止反应，减压浓缩，加入DCM适量溶解，浓缩得235mg烯醇硅醚粗产品。
氮气保护下，向10mL单口反应瓶中加入上步所得烯醇硅醚粗品(200mg)，MeCN(2.5mL)，Selectfluor(213mg，0.60mmol)，室温下搅拌1.5h。停止反应，加入EtOAc适量，过滤，浓缩，粗产品柱层析(PE/Acetone＝15:1)得63mg白色固体，收率35％。
1H NMR(400MHz,CDCl3)δ8.28(s,1H),7.93(s,1H),3.09(t,J＝9.2Hz,2H),2.17–2.07(m,1H),1.98–1.20(m,24H),1.19–0.99(m,3H),0.92–0.82(m,1H),0.86(s,1H),0.77(s,3H).19F NMR(377MHz,CDCl3)δ-82.94–-97.49(m,2F).
MS.m/z calcd for C25H33F2N3O2[M+Na]+468.24,found 468.2.
实施例3本发明化合物的体外药效学研究
测试方法：
实验使用转染有人类GABAa受体α1,β2及γ2亚基cDNA后稳定表达正常GABAa受体功能的HEK293T细胞系，研究化合物对GABAa受体α1β2γ2亚型的作用，测试个别化合物之半最大效应浓度(EC50)数值。实验采用手动膜片钳系统HEKA EPC10USB信号放大器及数字转换系统作全细胞电流记录，记录GABAa通道的氯离子电流。实验都是在常规室温下进行(～25℃)。1μM的GABA通过药物灌流系统作用于细胞上诱导出GABAa通道的氯离子电流，作用时间大约为4秒，其电流大小作为初始对照值。随后灌流孵育测试浓度化合物3分钟，再给予1μM GABA和相应测试浓度的本发明化合物的混合溶液作用于细胞诱导电流，以观察测试化合物对1μM的GABA所诱导电流的增强效果。当细胞状态稳定时，测试化合物由低到高浓度作用于同一细胞，每个浓度数据点n＝3。本发明化合物测试的浓度范围为0.03-10μM。Diazepam(地西泮)作为已知的GABAa受体正向调节剂在本实验中作阳性对照以保证所使用的HEK293T GABAa细胞功能正常。
测试结果：
本发明化合物对于GABAa受体的正向调节作用(与1μM GABA所诱导的GABAa受体反应比较)半最大效应浓度(EC50)值，最大增强幅度Emax及对应的化合物浓度列于表1，个别化合物在多浓度对GABAa受体电流的正向调节拟合曲线列于附图1-3。
表1化合物对细胞GABAa受体(氯离子通道)电流的正向调节作用的数据分析结果
结论：由试验结果可知，本发明化合物对GABA具有较强的正向调节作用。文献记载SAGE-217作用与GABAa受体α1β2γ2亚型的EC50大概为375nM，本发明化合物测得的受体调节活性，与SAGE-217相当，或高于SAGE-217的调节能力。
实施例4本发明化合物的溶解性能测试
测试方法：
1)环糊精溶液的配制：称取磺丁基-β-环糊精1.25g，纯化水3.75g，加入西林瓶中，电磁搅拌下溶解；
2)对照品的配制：精密称定5mg待测样品，置于50mL量瓶中，加入10mlACN溶解，再用20％CAN稀释定容至刻度。平行配制两份，一份5、10、13μL进样作标曲，一份10μL进样作回收率；
3)测试样品的配制：称取适量待测样品，电磁搅拌24h，得过饱和溶液(搅拌后有样品未完全溶解)，过滤取适量体积的上层清液，将其用20％CAN稀释至约0.1mg/ml。
上述对照品及测试样品使用HPLC检测，检测条件如下所示：
色谱柱：Agilent Pursuit 3C18,4.6*150mm
流动相：A相-0.1％甲酸，B相-乙腈
梯度：
表-2
| T(min) | 0 | 14 | 14.1 | 20 |
| A(％) | 60 | 21.5 | 60 | 60 |
| B(％) | 40 | 78.5 | 40 | 40 |
流速：1mL/min，柱温35℃，进样体积：10μL
CAD参数：Flow ratio-Normal，Ion Trap-20.3V，Evaporation Temp-On 35℃，Charger Voltage-2.63kv，Charger Current-1.00μA
测试结果：
计算公式：
其中，C为测试样品饱和溶解度，
A为测试样品溶液中主峰面积，
a，b分别为对照品以浓度为y峰面积为x所得标曲y＝ax+b中的a，b。
依照计算公式，测试样品的稀释倍数，HPLC检测到的主峰面积，及对照品标曲中a,b的数值，测试样品的饱和溶解度如下所示：
表-3测试样品饱和溶解度
结论：由试验结果可知，本发明化合物具有显著改善的溶解性能，特别地，优于SAGE-217的溶解能力，其在磺丁基环糊精中的溶解能力是SAGE-217的至少4倍以上。
以上所述仅是本发明的优选实施方式，应当指出，对于本领域技术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 (6)
1.式(Ⅰ)的化合物:
或其可药用盐，
其中，所述式(Ⅰ)的化合物选自：
2.药物组合物，包含权利要求1中所述的化合物或其可药用盐，以及可药用赋形剂。
3.权利要求1中所述的化合物或其可药用盐在制备用于预防或治疗中枢神经系统紊乱疾病药物中的用途。
4.权利要求2中所述的药物组合物在制备用于预防或治疗中枢神经系统紊乱疾病药物中的用途。
5.如权利要求3或4所述的用途，其中，中枢神经系统紊乱疾病选自震颤，癫痫，抑郁症或焦虑障碍。
6.如权利要求3或4所述的用途，其中，中枢神经系统紊乱疾病选自特发性震颤，癫痫，临床抑郁，分娩后或产后抑郁，非典型抑郁，精神病性严重抑郁症，紧张型抑郁，季节性情绪失调症，心境恶劣，双重抑郁，抑郁性人格障碍，复发性短暂抑郁，轻度抑郁障碍，双向性精神障碍或躁狂抑郁性障碍，创伤后应激障碍，因慢性医学病状引起的抑郁，耐治疗性抑郁，难治性抑郁，自杀倾向，自杀观念或自杀行为。
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| CN (1) | CN111040015B (zh) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998005337A1 (en) * | 1996-08-01 | 1998-02-12 | Cocensys, Inc. | Use of gaba and nmda receptor ligands for the treatment of migraine headache |
| CN105339381A (zh) * | 2013-04-17 | 2016-02-17 | 萨奇治疗股份有限公司 | 19-去甲c3,3-二取代的c21-n-吡唑基类固醇及其使用方法 |
| WO2018013615A1 (en) * | 2016-07-11 | 2018-01-18 | Sage Therapeutics, Inc. | C7, c12, and c16 substituted neuroactive steroids and their methods of use |
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2018
- 2018-10-15 CN CN201811194851.9A patent/CN111040015B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998005337A1 (en) * | 1996-08-01 | 1998-02-12 | Cocensys, Inc. | Use of gaba and nmda receptor ligands for the treatment of migraine headache |
| CN105339381A (zh) * | 2013-04-17 | 2016-02-17 | 萨奇治疗股份有限公司 | 19-去甲c3,3-二取代的c21-n-吡唑基类固醇及其使用方法 |
| WO2018013615A1 (en) * | 2016-07-11 | 2018-01-18 | Sage Therapeutics, Inc. | C7, c12, and c16 substituted neuroactive steroids and their methods of use |
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