CN109666055A - 调节中枢神经治疗抑郁症的化合物及其用途 - Google Patents
调节中枢神经治疗抑郁症的化合物及其用途 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
- C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
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- Organic Chemistry (AREA)
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Abstract
本发明提供式(I)化合物，其立体异构体、互变异构体或药学上可接受的盐，其作为调节中枢神经系统，治疗有抑郁症，具有广泛的应用前景。
Description
技术领域
本发明涉及新颖的结构式(I)化合物或其可药用盐、互变异构体或体内可水解的前体、它们的组合物和它们的使用方法。这些新颖的化合物及其在医学上的用途。
背景技术
产后抑郁症是女性精神障碍中最为常见的类型，是女性生产之后，由于性激素、社会角色及心理变化所带来的身体、情绪、心理等一系列变化，症状包括显著的功能性障碍、情绪低落以及对新生儿冷漠、食欲减退、难以入睡、注意力不集中、乏力、行动不便和丧失自信等众多抑郁症相关症状。典型的产后抑郁症是产后6周内发生，可持续整个产褥期，有的甚至持续至幼儿上学前。产后抑郁症的发病率在15％～30％。产后抑郁症通常在6周内发病，可在3～6个月自行恢复，但严重的也可持续1～2年，再次妊娠则有20％～30％的复发率。
部分女性产后抑郁症病情严重，甚至恶化到生活不能自理或情绪崩溃，需要住院治疗，在安全稳定的环境实现康复。在现代社会，自杀是分娩后产妇死亡的首要原因之一。
可选用选择性5-羟色胺再摄取抑制，具有毒副作用小，服用简便等特点。为当今很多发达国家治疗抑郁的一线用药。代表药物有氟西汀、帕罗西汀、舍曲林、氟伏沙明、西酞普兰。或选择服用其他递质机制的新型抗抑郁药：曲唑酮：是弱抗抑郁药，对严重抑郁效果相差。对抗焦虑、失眠的轻中度抑郁是最佳适应证。度洛西汀、文拉法辛：适用于各种抑郁状态，起效快，无特殊禁忌证，但肝肾患者慎用。米氮平：本药的耐受性好，副作用少，是一种新型抗抑郁剂。吗氯贝胺：它可以治疗各种类型的抑郁，对焦虑抑郁混合状态效果也较好。
根据美国疾病控制和预防中心(CDC)统计，美国2014年大约有400万例新生儿，其中10％～15％的产妇遭遇产后抑郁症的困扰，部分患者严重到需要住院治疗。目前尚无专门针对产后抑郁症的药物获批，重度产后抑郁症患者的治疗选择非常有限，对于治疗该疾病的药物需求十分迫切。
γ-氨基丁酸(简称GABA)是一种天然存在的非蛋白质氨基酸，是哺乳动物中枢神经系统中重要的抑制性神经传达物质，约30％的中枢神经突触部位以GABA为递质。在人体大脑皮质、海马、丘脑、基底神经节和小脑中起重要作用，并对机体的多种功能具有调节作用。研究发现(Neuron.2008；59(2):207-13)，P源性神经甾体于妊娠期间的大幅增加并于分娩后的迅速下降，可对脑内GABA(A)R产生较大影响从而引起抑郁症状产生。
GABA的A受体，又称作γ-氨基丁酸A型受体，是一种离子型受体，而且是一类配体门控型离子通道。此通道的内源性配体是一种被称为GABA的神经递质。GABA是中枢神经系统里的一种主要的递质，虽然GABA在神经递质的释放过程中产生的是抑制性效应，但GABA本身并非一种抑制性而是一种刺激性递质，因为GABA激活GABA受体的开放。在GABAA受体被激活后，可以选择性的让Cl-通过，引起神经元的超极化。
药物导致GABAA受体对神经元活动的中度抑制可使患者消除焦虑感(抗焦虑作用)，而更强的抑制作用则会产生全身麻醉。药物的严重过量鲜有出现，而产生的反应是延长麻醉时间，甚至出现死亡。[1]苯二氮卓类药物和苯二氮卓受体结合，可以增强GABA与GABA受体的亲和力，使cl离子内流增加，因而可以增加GABA能神经的抑制效应。
目前临床阶段的用于产后抑郁的GABA的A受体调节剂仅有两个，SAGETherapeutics的SAGE-547和SAGE-217，分别处于Ph3和Ph2阶段。SAGE-547在产后抑郁的二期临床显示了显著的疗法，但其生物利用度低，只能肠道外给药。SAGE-217治疗产后抑郁的临床数据还没有公开。
急需开发安全有效、给药方便的新型GABA的A受体调节剂。
发明内容
本发明提供一种式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐，
其中，R1为C1～C6碳酰基；
R2选自烷基，烷氧基，芳基，环烷基，杂芳基，杂环基，杂环基烷基。
本发明所述的式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐，其中包括下列化合物，
本发明所述化合物，其立体异构体，互变异构体或药学上可接受的盐，作为药物或药物组合物，在抑郁症治疗中的应用。
具体实施方式：
下面用实施例来进一步说明本发明，但本发明并不受其限制。
实施例1：
本发明按照文献WO2016134301提供类似试验方案，制备到化合物4，ESI-MS：m/z：359.6[M+H]+。
生物测试结果：根据文献WO2016134301提供的生物测试方案，TBPS结合试验测试结果表明化合物4的活性为0.1nM(IC50值)。
Claims (3)
1.一种式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐，
其中，R1为C1～C6碳酰基；
R2选自烷基，烷氧基，芳基，环烷基，杂芳基，杂环基，杂环基烷基。
2.如权利要求1所述的式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐，其中包括下列化合物，
3.如权利要求1至2中任一项所述化合物，其立体异构体，互变异构体或药学上可接受的盐，作为药物或药物组合物，在抑郁症治疗中的应用。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019211668A3 (en) * | 2018-05-04 | 2019-12-12 | Acerus Pharmaceuticals Corporation | Neurosteroid derivatives and uses thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005000869A1 (en) * | 2003-05-29 | 2005-01-06 | Washington University | Neuroactive 13,24-cyclo-18,21-dinorcholanes and structurally-related pentacyclic steroids |
| WO2016134301A2 (en) * | 2015-02-20 | 2016-08-25 | Sage Therapeutics, Inc. | Neuroactive steroids, compositions, and uses thereof |
-
2017
- 2017-10-16 CN CN201710956304.9A patent/CN109666055A/zh active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005000869A1 (en) * | 2003-05-29 | 2005-01-06 | Washington University | Neuroactive 13,24-cyclo-18,21-dinorcholanes and structurally-related pentacyclic steroids |
| WO2016134301A2 (en) * | 2015-02-20 | 2016-08-25 | Sage Therapeutics, Inc. | Neuroactive steroids, compositions, and uses thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019211668A3 (en) * | 2018-05-04 | 2019-12-12 | Acerus Pharmaceuticals Corporation | Neurosteroid derivatives and uses thereof |
| CN112823164A (zh) * | 2018-05-04 | 2021-05-18 | 阿克罗斯制药公司 | 神经甾体衍生物和其用途 |
| JP2021523938A (ja) * | 2018-05-04 | 2021-09-09 | アセラス ファーマシュウティカルズ コーポレーション | 神経ステロイド誘導体およびその使用 |
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Application publication date: 20190423 |