CN105189529B - 孕烯醇酮的3‑(4’‑取代的)‑苄基‑醚衍生物 - Google Patents
孕烯醇酮的3‑(4’‑取代的)‑苄基‑醚衍生物 Download PDFInfo
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- CN105189529B CN105189529B CN201380062354.2A CN201380062354A CN105189529B CN 105189529 B CN105189529 B CN 105189529B CN 201380062354 A CN201380062354 A CN 201380062354A CN 105189529 B CN105189529 B CN 105189529B
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- Prior art keywords
- pregnenolone
- benzyloxy
- methyl
- epoxide
- alkyl
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Abstract
本发明涉及式I化合物或其药学上可接受的盐,其中R1是C1‑8烷基、C1‑8烷氧基、CN、NO2、氨基、COOH、COOCH3、OH、N3或卤素和R2是H、OH、C1‑8烷基、C1‑8烷氧基、C2‑C6烯基、卤素、Bn‑O‑、Bn‑任选被取代或Ph‑任选被取代。
Description
技术领域
本发明涉及合成的刺激神经组织的类固醇,更具体地,涉及合成的孕烯醇酮衍生物及其在治疗人体或动物体的方法中的用途。
背景技术
在肾上腺和性腺中合成的各种类固醇能够调节CNS中的神经元兴奋性。对于这些化合物,已产生术语“刺激神经组织的类固醇”(Majewska等,1986),或脑可以重新合成的“神经类固醇”(Baulieu,1991)。
很久之前就已公认类固醇激素在动物和人类中具有镇静、麻醉和抗咬合的性质(Aird,1944;Aird和Gordan,1951;Gyermek等,1967;Green等,1978)。过去二十年间的研究揭示黄体酮和去氧皮质酮分别充当内源性神经类固醇别孕烯醇酮(5α-孕烷-3α-ol-20-酮)和THDOC(5α-孕烷-3α,21-二醇-20-酮)的前体(Reddy,2003;2009a)。睾丸激素衍生的雄激素例如二氢雄甾酮(5α-雄甾烷-3α,17β-二醇)和雌二醇可以被认为是神经类固醇(Reddy,2008)。通常,神经类固醇的急性效应与和传统的调节基因转录的类固醇激素受体的相互作用无关。此外,神经类固醇本身在胞内类固醇受体中无活性。它们主要通过与神经元的膜受体(主要是GABA-A受体)和离子通道的相互作用调节脑兴奋性(Lambert等,2003;Reddy,2003;Akk等,2009)。
除其刺激神经组织的性质已被描述的内源性类固醇例如孕烯醇酮硫酸酯、DHEA-S、雌二醇或黄体酮之外(Paul和Purdy,1992;Rupprecht,1997),最近已经开发合成类固醇,其具有与它们的内源性对应物相同的调节各种G蛋白偶联受体和配体门控离子通道的特征(Gasior等,1999)。
评估了一些显示出较好的药代动力学和功效的合成神经类固醇的镇静和抗焦虑(米那索龙)、麻醉(alphaxolone)和抗癫病(加奈索酮)的作用。
然而,刺激神经组织的类固醇的不同体内作用是由于天然和合成类固醇缺乏特异性,它们不能只结合一个神经递质受体,而是结合几个神经递质受体。刺激神经组织的类固醇的代谢以及较之其前体显示出不同的药理学特性的代谢物也是造成单个类固醇的多样作用的原因。由于其代谢,至今没有开发出显示出唯一的受体特异性或避免副作用的天然存在或合成的类固醇的衍生物。
发明简述
在天然存在的类固醇中,描述孕烯醇酮体内作用的研究非常少,但是它们提出这种类固醇有有益的作用。已表明施用孕烯醇酮降低大鼠大脑皮层和海马中尖锐损害后神经胶组织的形成(Garcia-Estrada等,1999)。在海马细胞系(HT-22)培养物中显示孕烯醇酮防止谷氨酸和蛋白质β淀粉状蛋白引起的毒性(Gursoy等,2001)。此外,也提出孕烯醇酮能增强记忆性能(Mathis等,1994)。然而,通常将孕烯醇酮的这些作用归因于孕烯醇酮的下游代谢物,其本身被认为是下游的活性类固醇的无活性前体。因此,孕烯醇酮对作为GABA和兴奋性氨基酸受体的刺激神经组织的类固醇的主要目标没有作用。
最近,本发明人表明孕烯醇酮充当具有不同于邻位拮抗剂(orthostericantagonist)和不同于其他刺激神经组织的类固醇的药理学特征的人CB1受体抑制剂,其表明孕烯醇酮的非特异性和不期望的作用小于CB1的邻位拮抗剂和其他刺激神经组织的类固醇(专利申请PCT/EP2012/059310,以WO2012/160006公开;Vallée等,2013)
考虑到孕烯醇酮是脑和其他器官中类固醇合成的第一步骤,孕烯醇酮被认为不是用来衍生合成的刺激神经组织的类固醇的良好目标。
事实上,这种孕烯醇酮衍生物具有被代谢的高风险。产生的代谢物可以显示出较之其前体不同的药理学特征并产生副作用。
本发明人发现,由孕烯醇酮衍生的包含3-苄氧基基团(取代或非取代)的分子不能转化为具有促妊娠、产生雄性征、雌激素和糖皮质激素的活性的代谢物。因此,利用不转化为或基本上不转化为孕烯醇酮代谢物的这些孕烯醇酮衍生物来避免副作用。
因此,本发明涉及式I化合物或其药学上可接受的盐,
其中:
R1是:
C1-8烷基,
C1-8烷氧基,
CN,
NO2,
氨基,
COOH,
COOCH3
OH,
N3,
或
卤素
和
R2是:
H,
OH,
C1-8烷基,
C1-8烷氧基,
C2-C6烯基,
卤素,
Bn-O-
Bn-任选被C1-8烷基、C1-8烷氧基、CN、NO2、氨基、COOH或卤素取代,或
Ph-任选被C1-8烷基、C1-8烷氧基、CN、NO2、氨基、COOH或卤素取代。
发明详述
定义
术语“激动剂”是指增强另一种化合物或受体位点的活性的化合物。
术语“拮抗剂”和“抑制剂”是指减低或阻止受体位点处另一种化合物的活性的化合物,通常是指减低或阻止受体的活化和/或活性的化合物。
术语“治疗(treatment)或治疗(treating)”是指治疗性治疗和预防性(prophylactic)或预防性(preventive)措施,其中目的是预防或减缓目标病理性病症或疾病。需要治疗的那些包括已经患有疾病的那些以及倾向于患有疾病的那些或其中疾病将被预防的那些。因此,本文待治疗的受试者可能已经被诊断为患有所述疾病或可能对所述疾病易感或敏感。
如本文所使用,术语“受试者”表示哺乳动物,例如啮齿动物、猫科动物、狗和灵长类动物。优选地,根据本发明的受试者是人。
“治疗有效量”意欲指将治疗性或预防性效益赋予受试者所必需的最少量的活性剂。例如,哺乳动物的“治疗有效量”是这种量:其诱导、改进或者引起与疾病有关或抵抗从而不屈服于疾病的病理性症状、疾病进展或生理性病症的改善。
“烷基”表示仅由碳和氢原子组成的一价直链或支链的饱和烃部分。C1-8烷基表示具有一到八个碳原子的直链或支链烷基。
“烷氧基”表示式-OR部分,其中R是如本文所定义的烷基部分。
本文所使用的术语“烯基”描述具有至少一个碳碳双键的不饱和、直链或支链的脂族烃。“C2-6烯基”表示具有至少一个双键的2到6个碳原子的直链或支链。
单独或与其他基团结合的术语“卤素”表示氯(Cl)、碘(I)、氟(F)和溴(Br)。
单独或与其他基团结合的术语“氰基”表示基团-CN。
单独或与其他基团结合的术语“羟基”表示基团-OH。
单独或与其他基团结合的术语“硝基”表示基团-NO2。
单独或与其他基团结合的术语“羧基”表示基团-COOH。
“氨基”表示式-NRR'部分,其中R和R'各自独立地是氢或如本文所定义的烷基。
缩写Bn是指苄基。
缩写Ph是指苯基。
术语“药学上可接受的盐”是指适用于和人和动物的组织接触而无过度毒性、刺激性、过敏反应等的盐。适合的盐的实例包括碱金属例如钾、钠、锂的盐,碱土金属例如钙、镁的盐和酸加成盐,其中无机酸和有机酸是但不限于盐酸、硝酸、硫酸、磷酸、硫酸、柠檬酸、甲酸、富马酸、马来酸、乳酸、苹果酸、乙酸、琥珀酸、半琥珀酸、酒石酸、甲磺酸、对甲苯磺酸、三氟乙酸等。
分子平面上的取代基显示为实线且描述为β;平面下的那些通过虚线显示且描述为α。
本发明化合物
通式:
本发明涉及式I化合物或其药学上可接受的盐:
其中:
R1是:
C1-8烷基,
C1-8烷氧基,
CN,
NO2,
氨基,
COOH,
COOCH3
OH,
N3,
或
卤素
和
R2是:
H,
OH,
C1-8烷基,
C1-8烷氧基,
C2-C6烯基,
卤素,
Bn-O-
Bn-任选被C1-8烷基、C1-8烷氧基、CN、NO2、氨基、COOH或卤素取代,
或
Ph-任选被C1-8烷基、C1-8烷氧基、CN、NO2、氨基、COOH或卤素取代。
在一个优选的实施方式中,R2位于α位。
在该实施方式中,本发明化合物具有式II:
其中:
R1是:
C1-8烷基,
C1-8烷氧基,
CN,
NO2,
氨基,
COOH,
COOCH3
OH,
N3,
或
卤素
和
R2是:
H,
OH,
C1-8烷基,
C1-8烷氧基,
C2-C6烯基,
卤素,
Bn-O-
Bn-任选被C1-8烷基、C1-8烷氧基、CN、NO2、氨基、COOH或卤素取代,
或
Ph-任选被C1-8烷基、C1-8烷氧基、CN、NO2、氨基、COOH或卤素取代。
在一个优选的实施方式中,R1是OH、C1-8烷基、C1-8烷氧基或卤素、更优选地R1是OH、甲基、乙基、甲氧基、乙氧基、甲基羧基、Cl、Br、F或氰基。
在一个优选的实施方式中,R2是H、OH、C1-8烷基、C1-8烷氧基、C2-6烯基或Bn,更优选地R2是H、OH、甲基、乙基、甲氧基、乙氧基、烯丙基或Bn。
更优选地,本发明化合物是:
3-(对羟基苄氧基)-孕烯醇酮、
3-(对甲基苄氧基)-孕烯醇酮、
3-(对乙基苄氧基)-孕烯醇酮、
3-(对甲氧基苄氧基)-孕烯醇酮、
3-(对乙氧基苄氧基)-孕烯醇酮、
3-(对甲基羧基苄氧基)-孕烯醇酮、
3-(对氟代苄氧基)-孕烯醇酮、
3-(对氯代苄氧基)-孕烯醇酮、
3-(对溴代苄氧基)-孕烯醇酮、
3-(对氰基苄氧基)-孕烯醇酮、
17-羟基-3-(对羟基苄氧基)-孕烯醇酮、
17-羟基-3-(对甲基苄氧基)-孕烯醇酮、
3-(对乙基苄氧基)-17-羟基-孕烯醇酮、
17-羟基-3-(对甲氧基苄氧基)-孕烯醇酮、
3-(对乙氧基苄氧基)-17-羟基-孕烯醇酮、
17-羟基-3-(对甲基羧基苄氧基)-孕烯醇酮、
3-(对氟代苄氧基)-17-羟基-孕烯醇酮、
3-(对氯代苄氧基)-17-羟基-孕烯醇酮、
3-(对溴代苄氧基)-17-羟基-孕烯醇酮、
3-(对氰基苄氧基)-17-羟基-孕烯醇酮、
3-(对羟基苄氧基)-17-甲基-孕烯醇酮、
17-甲基-3-(对甲基苄氧基)-孕烯醇酮、
3-(对乙基苄氧基)-17-甲基-孕烯醇酮、
3-(对甲氧基苄氧基)-17-甲基-孕烯醇酮、
3-(对乙氧基苄氧基)-17-甲基-孕烯醇酮、
17-甲基-3-(对甲基羧基苄氧基)-孕烯醇酮、
3-(对氟代苄氧基)-17-甲基-孕烯醇酮、
3-(对氯代苄氧基)-17-甲基-孕烯醇酮、
3-(对溴代苄氧基)-17-甲基-孕烯醇酮、
3-(对氰基苄氧基)-17-甲基-孕烯醇酮、
17-乙基-3-(对羟基苄氧基)-孕烯醇酮、
17-乙基-3-(对甲基苄氧基)-孕烯醇酮、
17-乙基-3-(对乙基苄氧基)-孕烯醇酮、
17-乙基-3-(对甲氧基苄氧基)-孕烯醇酮、
3-(对乙氧基苄氧基)-17-乙基-孕烯醇酮、
17-乙基-3-(对甲基羧基苄氧基)-孕烯醇酮、
17-乙基-3-(对氟代苄氧基)-孕烯醇酮、
3-(对氯代苄氧基)-17-乙基-孕烯醇酮、
3-(对溴代苄氧基)-17-乙基-孕烯醇酮、
3-(对氰基苄氧基)-17-乙基-孕烯醇酮、
3-(对羟基苄氧基)-17-甲氧基-孕烯醇酮、
17-甲氧基-3-(对甲基苄氧基)-孕烯醇酮、
3-(对乙基苄氧基)-17-甲氧基-孕烯醇酮、
17-甲氧基-3-(对甲氧基苄氧基)-孕烯醇酮、
3-(对乙氧基苄氧基)-17-甲氧基-孕烯醇酮、
17-甲氧基-3-(对甲基羧基苄氧基)-孕烯醇酮、
3-(对氟代苄氧基)-17-甲氧基-孕烯醇酮、
3-(对氯代苄氧基)-17-甲氧基-孕烯醇酮、
3-(对溴代苄氧基)-17-甲氧基-孕烯醇酮、
3-(对氰基苄氧基)-17-甲氧基-孕烯醇酮、
17-乙氧基-3-(对羟基苄氧基)-孕烯醇酮、
17-乙氧基-3-(对甲基苄氧基)-孕烯醇酮、
17-乙氧基-3-(对乙基苄氧基)-孕烯醇酮、
17-乙氧基-3-(对甲氧基苄氧基)-孕烯醇酮、
17-乙氧基-3-(对乙氧基苄氧基)-孕烯醇酮、
17-乙氧基-3-(对甲基羧基苄氧基)-孕烯醇酮、
17-乙氧基-3-(对氟代苄氧基)-孕烯醇酮、
3-(对氯代苄氧基)-17-乙氧基-孕烯醇酮、
3-(对溴代苄氧基)-17-乙氧基-孕烯醇酮、
3-(对氰基苄氧基)-17-乙氧基-孕烯醇酮、
17-烯丙基-3-(对羟基苄氧基)-孕烯醇酮、
17-烯丙基-3-(对甲基苄氧基)-孕烯醇酮、
17-烯丙基-3-(对乙基苄氧基)-孕烯醇酮、
17-烯丙基-3-(对甲氧基苄氧基)-孕烯醇酮、
17-烯丙基-3-(对乙氧基苄氧基)-孕烯醇酮、
17-烯丙基-3-(对甲基羧基苄氧基)-孕烯醇酮、
17-烯丙基-3-(对氟代苄氧基)-孕烯醇酮、
17-烯丙基-3-(对氯代苄氧基)-孕烯醇酮、
17-烯丙基-3-(对溴代苄氧基)-孕烯醇酮、
17-烯丙基-3-(对氰基苄氧基)-孕烯醇酮、
17-苄基-3-(对羟基苄氧基)-孕烯醇酮、
17-苄基-3-(对甲基苄氧基)-孕烯醇酮、
17-苄基-3-(对乙基苄氧基)-孕烯醇酮、
17-苄基-3-(对甲氧基苄氧基)-孕烯醇酮、
17-苄基-3-(对乙氧基苄氧基)-孕烯醇酮、
17-苄基-3-(对甲基羧基苄氧基)-孕烯醇酮、
17-苄基-3-(对氟代苄氧基)-孕烯醇酮
17-苄基-3-(对氯代苄氧基)-孕烯醇酮
17-苄基-3-(对溴代苄氧基)-孕烯醇酮或
17-苄基-3-(对氰基苄氧基)-孕烯醇酮。
优选的本发明化合物选自下组:3β-(对甲氧基苄氧基)-17α-甲基-孕烯醇酮、17-苄基-3-(对甲氧基苄氧基)-孕烯醇酮、3-(对甲氧基苄氧基)-孕烯醇酮、3-(对溴代苄氧基)-孕烯醇酮、3-(对甲基羧基苄氧基)-孕烯醇酮、3-(对甲基苄氧基)-孕烯醇酮、3-(对氟代苄氧基)-孕烯醇酮和3-(对氰基苄氧基)-孕烯醇酮。
优选的本发明化合物是3β-(对甲氧基苄氧基)-17α-甲基-孕烯醇酮。
本发明还涉及包含本发明化合物或其药学上可接受的盐和药学上可接受的载体的药物组合物。
制备方法
本发明还涉及制备本发明化合物的方法,其包括使式III化合物:
其中R2如上所定义,
在非均质除酸剂和三氟甲磺酸甲酯(methyl triflate)存在下与式IV化合物反应:
其中R1如上所定义,
或
在非均质除酸剂存在下与式V化合物反应:
其中R1如上所定义。
在式V化合物情况下,由于OTf基团而不需要存在三氟甲磺酸甲酯。
在一个实施方式中,制备本发明化合物的方法包括使式III化合物:
其中R2如上所定义,
在非均质除酸剂和三氟甲磺酸甲酯存在下与式IV化合物反应:
其中R1如上所定义。
在另一个实施方式中,制备本发明化合物的方法包括使式III化合物:
其中R2如上所定义,
在非均质除酸剂存在下与式V化合物反应:
其中R1如上所定义。
优选地,用于该反应的溶剂是芳族溶剂例如三氟甲苯或甲苯。
优选地,非均质除酸剂是碳酸钾或氧化镁。
合成式III化合物的方法在现有技术(Glazier E.R.,1962,Marshall等,1948,Jones等,1965)中有详细描述。
例如,其中R2是烷基、烯丙基、苄基或芳基的式III化合物的合成可通过使孕烯醇酮与Ac2O反应形成烯醇乙酸酯(enol acetate)来进行。然后,烯醇乙酸酯与格氏试剂反应生成烯醇化物,随后用卤代-R2捕获。
此外,例如,其中R2是烷氧基、苄氧基或芳氧基的式III化合物的合成可通过使孕烯醇酮与相应的醇在Cu2+存在下反应来进行。
治疗方法
本发明还涉及如上所定义的本发明化合物或其药学上可接受的盐用于治疗人体或动物体的方法。
本发明还涉及在需要治疗的受试者中治疗病理性病症或疾病的方法,包括向所述受试者施用有效量的如上所定义的本发明化合物或其药学上可接受的盐。
可用本发明化合物治疗的病理是可通过孕烯醇酮治疗的那些,例如由于孕烯醇酮充当CB1受体抑制剂而可通过其治疗的病理。
这种病理的实例是精神病和神经系统疾病;神经退化性疾病;代谢疾病;成瘾性;依赖性;滥用复发和相关疾病;膀胱和胃肠疾病;肝病例如脂肪变性;非酒精性脂肪性肝炎(NASH)、肝硬化;酒精性脂肪变性;炎性疾病;心血管疾病;肾病;青光眼;痉挛;癌症;骨质疏松症;肥胖;自身免疫性肝炎和脑炎;疼痛或生殖疾病和皮肤炎症和纤维变性疾病。
本发明还涉及本发明化合物或其药学上可接受的盐在制备用于治疗上述病理之一的药物中的用途。
本发明将通过以下附图和实施例进一步说明。然而,这些实施例和附图不应解释为以任何方式限制本发明的范围。
具体实施方式
A.孕烯醇酮衍生物的合成实施例
孕烯醇酮是众所周知和可商购的类固醇(CAS号145-13-1)。
如下文所示,孕烯醇酮可用作合成其衍生物的前体。
1.C17取代的孕烯醇酮衍生物的合成
首先,孕烯醇酮的C17被取代。
C17被R取代的孕烯醇酮衍生物的合成实施例:
如下所示,为合成C17位被烷基、烯丙基或芳基取代的孕烯醇酮,在第一步骤,通过使孕烯醇酮与Ac2O反应形成相应的烯醇乙酸酯。然后,将烯醇乙酸酯与THF中的格氏试剂例如MeMgBr反应生成烯醇化物,其随后用亲电子试剂捕获。所述亲电子试剂将优选R-碘代-或R-溴代,其中R是烷基、烯丙基、苄基或芳基。
烯醇乙酸酯中间体的合成实施例
如下所示,将对甲苯磺酸一水化物(1.12g;5.9mmol;0.93eq.)加入孕烯醇酮(2g;6.3mmol;1eq.)的乙酸酐(230ml)溶液中。将反应介质在回流下搅拌5h,并将乙酸酐缓慢馏出。冷却到20℃后,将反应介质倒入碎冰,然后用二乙醚萃取混合物。将有机层用饱和Na2CO3水溶液洗涤,经Na2SO4干燥,然后在减压下蒸发。将残余物通过色谱法在硅胶上纯化(洗脱液:环己烷/AcOEt,100/0-90/10)获得白色固体状孕烯醇酮烯醇乙酸酯(2.2g;85%)。
17α-甲基-孕烯醇酮的合成实施例
如下所示,将MeMgBr2(3M在Et2O中;25ml;75mmol;10eq.)加入孕烯醇酮烯醇乙酸酯(3g;7.5mmol;1eq.)的无水THF(65ml)溶液中。将反应介质在回流下搅拌1h,然后冷却到20℃。加入CH3I(4.6ml;75mmol;10eq.)且将反应介质在回流下搅拌。每45分钟重复加入CH3I,直到40当量。冷却到20℃后,加入NH4Cl水溶液,然后用乙酸乙酯萃取混合物。将有机层用盐水洗涤,经Na2SO4干燥,然后在减压下蒸发。将残余物通过色谱法在硅胶上纯化(洗脱液:环己烷/AcOEt 75/25)获得白色固体状17α-甲基-孕烯醇酮(600mg;25%)。
C17被OR取代的孕烯醇酮衍生物的合成实施例:
为合成C17位被烷氧基、苄氧基或芳氧基取代的孕烯醇酮,在Cu2+存在下使孕烯醇酮与相应的醇R-OH反应。
17-甲氧基-孕烯醇酮的合成实施例:
如下所示,将CuBr2(4.05g;18.13mmol;1.9eq.)加入孕烯醇酮(3g;9.48mmol;1eq.)在甲醇(360ml)中的悬浮液。将反应介质在回流下搅拌24h,然后在减压下蒸发。将残余物溶于二氯甲烷和水中。将有机层用盐水洗涤,经Na2SO4干燥,然后在减压下浓缩。将残余物通过色谱法在硅胶上纯化(洗脱液:环己烷/AcOEt 80/20)然后再结晶(丙酮)以获得白色固体状17-甲氧基-孕烯醇酮(510mg;15%)。
2.式IV化合物的合成
一些式IV化合物是可商购的,例如2-(4-甲氧基苄氧基)-4-甲基喹啉
式IV化合物也可以根据如下流程通过在18-冠-6和KOH的存在下使2-氯代-4-甲基喹啉和对-取代的苯甲醇反应来合成。
2-(对甲基苄氧基)-4-甲基喹啉的合成实施例
如下所示,向2-氯代-4-甲基喹啉-(500mg;2.8mmol;1eq.)的无水甲苯(10mL)溶液中连续添加4-甲基苄基乙醇(409mg,3.35mmol;1.25eq)、KOH(630mg;11.2mmol;4.0eq.),以及18-冠-6(45mg,0.16mmol,0.06eq)。利用迪安-斯达克分水器(Dean-Stark trap)将反应介质在回流下加热1.5h。然后将反应介质冷却到室温,然后添加水,将产物用AcOEt萃取。将有机相干燥(Na2SO4)然后在真空下蒸发。将残余物通过色谱法在硅胶上纯化(洗脱液:环己烷/AcOEt 95/5)以获得无色油状的2-(对甲基苄氧基)-4-甲基喹啉(660mg;89%)。
3.式V化合物的合成
式V化合物可以两步法合成:根据以下流程,首先在18-冠-6和KOH或t-BuOK的存在下使2-氯吡啶和对-取代的苯甲醇反应;其次使所得产物与三氟甲磺酸甲酯反应以形成盐。
2-(对溴代苄氧基)-1-三氟甲磺酸甲基吡啶的合成实施例
如下所示,向2-氯吡啶(0.9mL;9.6mmol;1.2eq.)的无水甲苯(16mL)溶液中连续添加4-溴代苄基乙醇(1.5g,8.0mmol;1eq)、KOH(1.35g;24mmol;3.0eq.)以及18-冠-6(105mg,0.4mmol,0.05eq)。利用迪安-斯达克分水器将反应介质在回流下搅拌1h。然后将反应介质冷却到室温,然后添加水,将产物用AcOEt萃取。将有机相干燥(Na2SO4)然后在真空下蒸发。将残余物通过色谱法在硅胶上纯化(洗脱液:环己烷/AcOEt 9/1)以获得无色油状的2-(对溴代苄氧基)-吡啶(2g;78%)。
对于第二步骤,将三氟甲磺酸甲酯、MeOTf(450μL;3.97mmol;1.05eq)加入2-(对溴代苄氧基)-吡啶(1g;.3.7mmol;1eq)的冷溶液中。将反应介质在室温下搅拌2小时,然后在真空下蒸发以获得定量的白色固体状2-(对溴代苄氧基)-1-三氟甲磺酸甲基吡啶(1.6g)。
2-(对甲基羧基苄氧基)-1-三氟甲磺酸甲基吡啶的合成实施例
如下所示,向2-氯吡啶(1.13mL;12.0mmol;1.0eq.)的无水甲苯(48mL)溶液中连续添加4-甲基羧基-苯甲醇(1.5g,8.0mmol;1eq)和t-BuOK(2g;18mmol;1.5eq.)。将反应介质在回流下加热16h。然后将反应介质冷却到室温,然后添加水,将产物用AcOEt萃取。将有机相干燥(Na2SO4)然后在真空下蒸发。将残余物通过色谱法在硅胶上纯化(洗脱液:环己烷/AcOEt 96/4)以获得无色油状的2-(对甲基羧基苄氧基)-吡啶(1.13g;39%)。
对于第二步骤,将MeOTf(293μL;2.59mmol;1.05eq)加入2-(对甲基羧基苄氧基)-吡啶(600mg;2.46mmol;1eq)的冷溶液中。将反应介质在室温下搅拌2小时,然后在真空下蒸发以获得定量的白色固体状2-(对甲基羧基苄氧基)-1-三氟甲磺酸甲基吡啶(0.9g)。
4.C3被对-取代的苄氧基取代的孕烯醇酮衍生物的合成
根据已知的乙醇的苄基化方法(Poon KWC等.2006,Giannis等,2009,Nwoye,E.O等,2007),从在C17具有适合基团的孕烯醇酮或孕烯醇酮衍生物开始,将孕烯醇酮或孕烯醇酮衍生物的C3用基团OBn-R1取代,如下所示。
或
孕烯醇酮的苄基化实施例
如下所示,将MgO(46mg;1.14mmol;2eq.)和2-苄氧基-1-三氟甲磺酸甲基吡啶(400mg;1.14mmol;2.0eq.)加入孕烯醇酮(181mg;0.57mmol;1eq.)的三氟甲苯(4ml)溶液中。将反应介质在85℃下搅拌一夜,然后在硅藻土上过滤并在减压下蒸发。将残余物通过色谱法在硅胶上纯化(洗脱液:环己烷/AcOEt 95/5)获得白色固体状3β-苄氧基-孕烯醇酮(0.16g;70%)。
17α-苄基孕烯醇酮的苄基化实施例
如下所示,将MgO(116mg;2.42mmol;2.0eq.)和2-苄氧基三氟甲磺酸甲基吡啶(1g;2.86mmol;2.0eq.)加入17α-苄基孕烯醇酮(580mg;1.43mmol;1eq.)的三氟甲苯(15ml)溶液中。将反应介质在85℃下搅拌一夜,然后在硅藻土上过滤并在减压下蒸发。将残余物通过色谱法在硅胶上纯化(洗脱液:环己烷/AcOEt 95/5)获得白色固体状3β-苄氧基-17α-苄基-孕烯醇酮(300mg;42%)。
3β-(对溴代苄氧基)-孕烯醇酮的合成实施例
如下所示,向孕烯醇酮(477mg;1.51mmol;1eq.)的无水α,α,α-三氟甲苯(9mL)溶液中添加MgO(121mg;3.02mmol;2.0eq.)然后添加2-(对溴代苄氧基)-1-三氟甲磺酸甲基吡啶(1.29g;3.02mmol;2.0eq.)。将反应介质在100℃下搅拌20h,然后在硅藻土上过滤。添加水,将产物AcOEt萃取。将有机相干燥(Na2SO4)然后在真空下蒸发。将残余物通过色谱法在硅胶上纯化(洗脱液:环己烷/AcOEt 96/4)然后用丙酮研磨以获得白色固体状3β-(对溴代苄氧基)-孕烯醇酮(375mg;49%)。
3β-(对甲氧基苄氧基)-孕烯醇酮的合成实施例
如下所示,向孕烯醇酮(250mg;0.79mmol;1eq.)的无水甲苯溶液中连续添加MgO(63mg;1.58mmol;2.0eq.)、2-(4-甲氧基苄氧基)-4-甲基喹啉(441mg;1.58mmol;2.0eq.)和三氟甲磺酸甲酯(MeOTf)(180μl;1.58mmol;2eq)。将反应介质在60℃下搅拌20h,然后在硅藻土上过滤。添加水,将产物用AcOEt萃取。将有机相干燥(Na2SO4)然后在真空下蒸发。将残余物通过色谱法在硅胶上纯化(洗脱液:环己烷/AcOEt 9/1)然后用丙酮研磨以获得白色固体状3β-(对甲氧基苄氧基)-孕烯醇酮(160mg;43%)。
3β-(对甲氧基苄氧基)-17α-甲基-孕烯醇酮的合成实施例
17α-甲基-孕烯醇酮按如上所述合成。
向17α-甲基-孕烯醇酮(170mg;0.5mmol;1eq.)的无水甲苯溶液中连续添加MgO(40mg;1mmol;2eq.)、2-(4-甲氧基苄氧基)-4-甲基喹啉(290mg;1mmol;2eq)和三氟甲磺酸甲酯(MeOTf)(0.11ml;1mmol;2eq)。将反应介质在85℃下搅拌一夜,然后在硅藻土上过滤。添加水,将产物用AcOEt萃取。将有机相干燥(Na2SO4)然后在真空下蒸发。将残余物通过色谱法在硅胶上纯化(洗脱液:环己烷/AcOEt1/0-95/5)然后用丙酮研磨以获得白色固体状3β-(对甲氧基苄氧基)-17α-甲基-孕烯醇酮(80mg;35%)。
3β-(对甲氧基苄氧基)-17α-苄基-孕烯醇酮的合成实施例
17α-苄基-孕烯醇酮按如上所述合成。
向17α-苄基-孕烯醇酮(1.9g;4.66mmol;1eq.)的无水甲苯(45ml)溶液中连续添加MgO(373mg;9.3mmol;2eq.)、2-(4-甲氧基苄氧基)-4-甲基喹啉(2.6g;9.33mmol;2eq)和三氟甲磺酸甲酯(MeOTf)(1.06ml;9.33mmol;2eq)。将反应介质在40℃下搅拌一夜,然后在硅藻土上过滤。添加水,将产物用AcOEt萃取。将有机相干燥(Na2SO4)然后在真空下蒸发。将残余物通过色谱法在硅胶上纯化(洗脱液:环己烷/AcOEt 9/1)然后用丙酮研磨以获得白色固体状3β-(对甲氧基苄氧基)-17α-苄基-孕烯醇酮(1.18g;49%)。
B.孕烯醇酮衍生物不被转化为衍生自孕烯醇酮的其他活性类固醇的能力
材料和方法
代谢的体外测试
可选择地,可向表达代谢培养物中的孕烯醇酮的酶的任何细胞系施用所述化合物,然后在细胞内或细胞培养基上通过GC/MS测量孕烯醇酮代谢物的含量并将这些浓度与仅接受载体或孕烯醇酮的细胞培养物中代谢物的浓度进行比较。
在该实施例中,使用CHO细胞系。这些细胞源自具有需要在下游类固醇中代谢孕烯醇酮的所有酶的卵巢。
通过GC/MS测量CHO培养基中别孕烯醇酮(ALLO)、表别孕烯醇酮(EPIALLO)、孕烯醇酮(PREG)、DHEA和睾酮(TESTO)的含量。
结果
下游活性类固醇中的体外转化被限制的孕烯醇酮衍生物。
本发明人利用CHO细胞中的体外测试分析了孕烯醇酮衍生物的代谢。
向这些细胞施用孕烯醇酮(1μM)48小时在培养基中产生了别孕烯醇酮和表别孕烯醇酮的明显增加(表1)。
表1
利用CHO细胞中的体外测试来测试C3被苄氧基取代的孕烯醇酮衍生物。
结果显示于下表2。结果表示为由用孕烯醇酮处理的CHO细胞的变化百分比或表示为pg/ml(0=浓度低于检测极限)。
表2
如表2所示,化合物68,3β-(对甲氧基苄氧基)-17α-甲基-孕烯醇酮,不在孕烯醇酮中代谢,和化合物63和41不在孕烯醇酮中明显代谢(代谢<1%)。包含3-苄氧基功能(取代或非取代)的孕烯醇酮衍生物不显示可检测的孕烯醇酮衍生物DHEA和睾酮的代谢以及显示别孕烯醇酮和表别孕烯醇酮的极低代谢。这些结果表明C3中OBn-R基团的存在避免了孕烯醇酮衍生物转化为孕烯醇酮和孕烯醇酮衍生物,特别是其孕烯醇酮是前体且具有促妊娠、产生雄性征、雌激素、糖皮质激素的活性或神经调节性质的代谢物。
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Claims (13)
1.式I化合物或其药学上可接受的盐,
其中:
R1是:
C1-8烷基,
C1-8烷氧基,
CN,
NO2,
氨基,
COOH,
COOCH3,
OH,
N3,
或
卤素
和
R2是:
H,
OH,
C1-8烷基,
C1-8烷氧基,
C2-C6烯基,
卤素,
Bn-O-,
Bn-任选被C1-8烷基、C1-8烷氧基、CN、NO2、氨基、COOH或卤素取代,或
Ph-任选被C1-8烷基、C1-8烷氧基、CN、NO2、氨基、COOH或卤素取代。
2.根据权利要求1所述的化合物,其中R2位于α位。
3.根据权利要求1或2所述的化合物,其中R1是OH、C1-8烷基、C1-8烷氧基、甲基羧基、氰基或卤素。
4.根据权利要求3所述的化合物,其中R1是OH、甲基、乙基、甲氧基、乙氧基、甲基羧基、Cl、Br、F或氰基。
5.根据权利要求1或2所述的化合物,其中R2是H、OH、C1-8烷基、C1-8烷氧基、C2-6烯基或Bn。
6.根据权利要求5所述的化合物,其中R2是H、OH、甲基、乙基、甲氧基、乙氧基、烯丙基或Bn。
7.根据权利要求1或2所述的化合物,其是:
3-(对羟基苄氧基)-孕烯醇酮、
3-(对甲基苄氧基)-孕烯醇酮、
3-(对乙基苄氧基)-孕烯醇酮、
3-(对甲氧基苄氧基)-孕烯醇酮、
3-(对乙氧基苄氧基)-孕烯醇酮、
3-(对甲基羧基苄氧基)-孕烯醇酮、
3-(对氟代苄氧基)-孕烯醇酮、
3-(对氯代苄氧基)-孕烯醇酮、
3-(对溴代苄氧基)-孕烯醇酮、
3-(对氰基苄氧基)-孕烯醇酮、
17-羟基-3-(对羟基苄氧基)-孕烯醇酮、
17-羟基-3-(对甲基苄氧基)-孕烯醇酮、
3-(对乙基苄氧基)-17-羟基-孕烯醇酮、
17-羟基-3-(对甲氧基苄氧基)-孕烯醇酮、
3-(对乙氧基苄氧基)-17-羟基-孕烯醇酮、
17-羟基-3-(对甲基羧基苄氧基)-孕烯醇酮、
3-(对氟代苄氧基)-17-羟基-孕烯醇酮、
3-(对氯代苄氧基)-17-羟基-孕烯醇酮、
3-(对溴代苄氧基)-17-羟基-孕烯醇酮、
3-(对氰基苄氧基)-17-羟基-孕烯醇酮、
3-(对羟基苄氧基)-17-甲基-孕烯醇酮、
17-甲基-3-(对甲基苄氧基)-孕烯醇酮、
3-(对乙基苄氧基)-17-甲基-孕烯醇酮、
3-(对甲氧基苄氧基)-17-甲基-孕烯醇酮、
3-(对乙氧基苄氧基)-17-甲基-孕烯醇酮、
17-甲基-3-(对甲基羧基苄氧基)-孕烯醇酮、
3-(对氟代苄氧基)-17-甲基-孕烯醇酮、
3-(对氯代苄氧基)-17-甲基-孕烯醇酮、
3-(对溴代苄氧基)-17-甲基-孕烯醇酮、
3-(对氰基苄氧基)-17-甲基-孕烯醇酮、
17-乙基-3-(对羟基苄氧基)-孕烯醇酮、
17-乙基-3-(对甲基苄氧基)-孕烯醇酮、
17-乙基-3-(对乙基苄氧基)-孕烯醇酮、
17-乙基-3-(对甲氧基苄氧基)-孕烯醇酮、
3-(对乙氧基苄氧基)-17-乙基-孕烯醇酮、
17-乙基-3-(对甲基羧基苄氧基)-孕烯醇酮、
17-乙基-3-(对氟代苄氧基)-孕烯醇酮、
3-(对氯代苄氧基)-17-乙基-孕烯醇酮、
3-(对溴代苄氧基)-17-乙基-孕烯醇酮、
3-(对氰基苄氧基)-17-乙基-孕烯醇酮、
3-(对羟基苄氧基)-17-甲氧基-孕烯醇酮、
17-甲氧基-3-(对甲基苄氧基)-孕烯醇酮、
3-(对乙基苄氧基)-17-甲氧基-孕烯醇酮、
17-甲氧基-3-(对甲氧基苄氧基)-孕烯醇酮、
3-(对乙氧基苄氧基)-17-甲氧基-孕烯醇酮、
17-甲氧基-3-(对甲基羧基苄氧基)-孕烯醇酮、
3-(对氟代苄氧基)-17-甲氧基-孕烯醇酮、
3-(对氯代苄氧基)-17-甲氧基-孕烯醇酮、
3-(对溴代苄氧基)-17-甲氧基-孕烯醇酮、
3-(对氰基苄氧基)-17-甲氧基-孕烯醇酮、
17-乙氧基-3-(对羟基苄氧基)-孕烯醇酮、
17-乙氧基-3-(对甲基苄氧基)-孕烯醇酮、
17-乙氧基-3-(对乙基苄氧基)-孕烯醇酮、
17-乙氧基-3-(对甲氧基苄氧基)-孕烯醇酮、
17-乙氧基-3-(对乙氧基苄氧基)-孕烯醇酮、
17-乙氧基-3-(对甲基羧基苄氧基)-孕烯醇酮、
17-乙氧基-3-(对氟代苄氧基)-孕烯醇酮、
3-(对氯代苄氧基)-17-乙氧基-孕烯醇酮、
3-(对溴代苄氧基)-17-乙氧基-孕烯醇酮、
3-(对氰基苄氧基)-17-乙氧基-孕烯醇酮、
17-烯丙基-3-(对羟基苄氧基)-孕烯醇酮、
17-烯丙基-3-(对甲基苄氧基)-孕烯醇酮、
17-烯丙基-3-(对乙基苄氧基)-孕烯醇酮、
17-烯丙基-3-(对甲氧基苄氧基)-孕烯醇酮、
17-烯丙基-3-(对乙氧基苄氧基)-孕烯醇酮、
17-烯丙基-3-(对甲基羧基苄氧基)-孕烯醇酮、
17-烯丙基-3-(对氟代苄氧基)-孕烯醇酮、
17-烯丙基-3-(对氯代苄氧基)-孕烯醇酮、
17-烯丙基-3-(对溴代苄氧基)-孕烯醇酮、
17-烯丙基-3-(对氰基苄氧基)-孕烯醇酮、
17-苄基-3-(对羟基苄氧基)-孕烯醇酮、
17-苄基-3-(对甲基苄氧基)-孕烯醇酮、
17-苄基-3-(对乙基苄氧基)-孕烯醇酮、
17-苄基-3-(对甲氧基苄氧基)-孕烯醇酮、
17-苄基-3-(对乙氧基苄氧基)-孕烯醇酮、
17-苄基-3-(对甲基羧基苄氧基)-孕烯醇酮、
17-苄基-3-(对氟代苄氧基)-孕烯醇酮
17-苄基-3-(对氯代苄氧基)-孕烯醇酮
17-苄基-3-(对溴代苄氧基)-孕烯醇酮或
17-苄基-3-(对氰基苄氧基)-孕烯醇酮。
8.根据权利要求1或2所述的化合物,其选自下组:3β-(对甲氧基苄氧基)-17α-甲基-孕烯醇酮、17-苄基-3-(对甲氧基苄氧基)-孕烯醇酮、3-(对甲氧基苄氧基)-孕烯醇酮、3-(对溴代苄氧基)-孕烯醇酮、3-(对甲基羧基苄氧基)-孕烯醇酮、3-(对甲基苄氧基)-孕烯醇酮、3-(对氟代苄氧基)-孕烯醇酮和3-(对氰基苄氧基)-孕烯醇酮。
9.药物组合物,其包含根据权利要求1-8任一项所述的化合物或其药学上可接受的盐和药学上可接受的载体。
10.制备根据权利要求1-8任一项所述的式I化合物的方法,其包括使式III化合物:
其中R2是:
H,
OH,
C1-8烷基,
C1-8烷氧基,
C2-C6烯基,
卤素,
Bn-O-,
Bn-任选被C1-8烷基、C1-8烷氧基、CN、NO2、氨基、COOH或卤素取代,或
Ph-任选被C1-8烷基、C1-8烷氧基、CN、NO2、氨基、COOH或卤素取代,
在三氟甲磺酸甲酯和非均质除酸剂存在下与式IV化合物反应:
其中R1是:
C1-8烷基,
C1-8烷氧基,
CN,
NO2,
氨基,
COOH,
COOCH3,
OH,
N3,
或
卤素,
或
在非均质除酸剂存在下与式V化合物反应:
其中R1是:
C1-8烷基,
C1-8烷氧基,
CN,
NO2,
氨基,
COOH,
COOCH3,
OH,
N3,
或
卤素。
11.根据权利要求1-8任一项所述的化合物或其药学上可接受的盐在制备用于治疗人体或动物体的病理的药物中的用途,其中所述病理选自下组:精神病和神经系统疾病;代谢疾病;成瘾性;依赖性;滥用复发和相关疾病;膀胱和胃肠疾病;肝病;炎性疾病;心血管疾病;肾病;青光眼;痉挛;癌症;骨质疏松症;肥胖;自身免疫性脑炎;疼痛或生殖疾病和皮肤炎症和纤维变性疾病。
12.根据权利要求11所述的用途,其中所述神经系统疾病是神经退化性疾病。
13.根据权利要求11所述的用途,其中所述肝病选自脂肪变性、非酒精性脂肪性肝炎(NASH)、肝硬化、酒精性脂肪变性和自身免疫性肝炎。
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- 2013-11-27 CA CA2892347A patent/CA2892347C/en active Active
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2015
- 2015-05-13 ZA ZA2015/03326A patent/ZA201503326B/en unknown
- 2015-05-27 CL CL2015001438A patent/CL2015001438A1/es unknown
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2017
- 2017-03-28 HR HRP20170503TT patent/HRP20170503T1/hr unknown
- 2017-04-06 CY CY20171100408T patent/CY1118825T1/el unknown
- 2017-04-25 US US15/496,160 patent/US20170226148A1/en not_active Abandoned
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2019
- 2019-03-11 US US16/298,060 patent/US20190202857A1/en not_active Abandoned
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2020
- 2020-12-01 US US17/108,163 patent/US20210230211A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4933157A (en) * | 1988-06-27 | 1990-06-12 | The University Of Michigan | Radioiodinated arylaliphatic ether analogues of cholesterol |
WO2004067010A1 (fr) * | 2003-01-17 | 2004-08-12 | Mapreg | Utilisation de la 3-methoxy-pregnenolone pour la preparation d’un medicament destine a traiter les maladies neurodegeneratives |
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