CN105934433B - A3腺苷受体激动剂 - Google Patents
A3腺苷受体激动剂 Download PDFInfo
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- CN105934433B CN105934433B CN201480073564.6A CN201480073564A CN105934433B CN 105934433 B CN105934433 B CN 105934433B CN 201480073564 A CN201480073564 A CN 201480073564A CN 105934433 B CN105934433 B CN 105934433B
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Abstract
公开了作为A3腺苷受体激动剂的式(I)和(II)的化合物、包含这样的化合物的药物组合物和使用这些化合物的方法,其中X、Y、Z、R2‑R6和R103‑R106如说明书中所定义。这些化合物对于A3受体是选择性的,并且被考虑用于治疗或预防大量疾病或病症例如神经性疼痛。
Description
相关申请的交叉引用
本专利申请要求于2013年11月27日提交的美国临时专利申请号61/909,742和于2014年8月6日提交的申请号62/033,723的权益,将其通过引用结合于此。
发明背景
慢性神经性疼痛(neuropathic pain)(NP)是广泛分布的病症,其通常与糖尿病、癌症、损伤、暴露于毒性物质和多种其他疾病如AIDS和帕金森病(Parkinson’s disease)相关(Renfrey,S.等人,Nat.Rev.Drug Discov.2003,2:175-6;Farquhar-Smith,P.,Curr.Opin.Support Palliat.Care 2011,5:1-7)。当其在癌症化疗或放疗后发生时,其常常需要中断拯救生命的治疗。目前使用的对于NP的疗法效果差并且经受严重的副作用,范围从肝毒性到成瘾和性格改变(personality change)。在很多情况中,所述疗法牵涉开发用于不同病症而偶然发现降低NP的药物,例如生物胺再摄取抑制剂如抗抑郁药阿密曲替林(amitriptyline)或抗惊厥药物如加巴喷丁(gabapentin)。针对急性疼痛有效的阿片类(Opioids)不是对慢性NP的第一线治疗,都是因为成瘾易患性、低效力、发展出抗伤害感受耐受性和对热、冷和机械损害的超敏感型(Ossipov,M.H.等人,J.Neubiol.2004,61:126-48)。因此,对于以可以单独或作为阿片类的辅剂提供以允许经长期使用有效疼痛缓解而没有产生依赖性的不同机制操作的慢性神经性疼痛治疗存在未满足的需要。
发明概述
本发明提供式(I)的化合物:
其中X选自NHR1、CH3和CH=C(Ra)(Rb),其中Ra和Rb独立地选自氢、羟基、C1-C6烷基和C6-C14芳基,
R1选自C1-C6烷基、C1-C6烷氧基、羟基、C3-C8环烷基、C6-C14芳基C3-C8环烷基、C3-C8环烷基C1-C6烷基、C3-C8二环烷基C1-C6烷基(C3-C8双环烷基C1-C6烷基,C3-C8dicycloalkylC1-C6alkyl)、C7-C12双环烷基(C7-C12二环烷基,C7-C12bicycloalkyl)、C7-C12双环烷基C1-C6烷基、C7-C14三环烷基C1-C6烷基、C6-C14芳基、C6-C14芳基C1-C6烷基、C6-C14二芳基C1-C6烷基、C6-C14芳基C1-C6烷氧基、杂环基C1-C6烷基、杂环基、4-[[[4-[[[(2-氨基C1-C6烷基)氨基]-羰基]-C1-C6烷基]苯胺基]羰基]C1-C6烷基]C6-C14芳基和C6-C14芳基C3-C8环烷基,其中R1的所述芳基或杂环基部分任选地被一个或多个选自以下各项的取代基取代:卤代(卤素,halo)、氨基、羟基、羧基、烷氧基羰基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C6-C14芳氧基、羟基C1-C6烷基、羟基C2-C6烯基、羟基C2-C6炔基、羧基C1-C6烷基、羧基C2-C6烯基、羧基C2-C6炔基、氨基羰基C1-C6烷基、氨基羰基C2-C6烯基、氨基羰基C2-C6炔基及其任意组合;并且R1的所述烷基或环烷基部分任选地被一个或多个选自以下各项的取代基取代:卤代、氨基、烷基、烷氧基、芳氧基、羟基烷基、羟基烯基、羟基炔基、氨基羰基烷氧基和芳基烷氧基及其任意组合。
R2选自C6-C12芳基、C3-C8环烷基、杂芳基和茂金属基(金属茂基,metallocenyl),其中所述芳基基团任选地被一个或多个选自以下各项的取代基取代:卤代、三氟甲基、羟基烷基、烷氧基、磺酰基氧基、羧基烷基、磺酰基氧基烷基、芳基羰基及其任意组合,其中所述杂芳基基团任选地被一个或多个选自以下各项的取代基取代:卤代、三氟甲基、氨基、烷基、羟基烷基、芳基、烷氧基、羟基、羧基、磺酰基氧基、羧基烷基、磺酰基氧基烷基、烷基羰基、芳基羰基及其任意组合,
R3和R4独立地选自羟基、氨基、巯基(mercapto)、脲基(ureido)、C1-C6烷基羰基氨基、羟基C1-C6烷基和肼基(hydrazinyl);
R5选自氢、C1-C3烷基氨基羰基、二(C1-C3烷基)氨基羰基、C1-C3烷硫基C1-C3烷基、卤代C1-C3烷基、肼基、氨基C1-C3烷基、羟基C1-C3烷基、C3-C6环烷基氨基、羟基氨基和C2-C3烯基;并且
R6选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、杂芳基和C1-C6氨基烷基;
或其药用盐。
本发明还提供式(II)的化合物:
其中X选自NHR101、CH3和CH=C(Ra)(Rb),其中Ra和Rb独立地选自氢、羟基、C1-C6烷基和C6-C14芳基,
Y是N或CH,
R101选自C1-C6烷基、C1-C6烷氧基、羟基、C3-C8环烷基、C6-C14芳基C3-C8环烷基、C3-C8环烷基C1-C6烷基、C3-C8二环烷基C1-C6烷基、C7-C12双环烷基、C7-C12双环烷基C1-C6烷基、C7-C14三环烷基C1-C6烷基、C6-C14芳基、C6-C14芳基C1-C6烷基、C6-C14二芳基C1-C6烷基、C6-C14芳基C1-C6烷氧基、杂环基C1-C6烷基、杂环基、4-[[[4-[[[(2-氨基C1-C6烷基)氨基]-羰基]-C1-C6烷基]苯胺基]羰基]C1-C6烷基]C6-C14芳基和C6-C14芳基C3-C8环烷基,其中R1的所述芳基或杂环基部分任选地被一个或多个选自以下各项的取代基取代:卤代、氨基、羟基、羧基、烷氧基羰基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C6-C14芳氧基、羟基C1-C6烷基、羟基C2-C6烯基、羟基C2-C6炔基、羧基C1-C6烷基、羧基C2-C6烯基、羧基C2-C6炔基、氨基羰基C1-C6烷基、氨基羰基C2-C6烯基、氨基羰基C2-C6炔基及其任意组合;并且R101的所述烷基或环烷基部分任选地被一个或多个选自以下各项的取代基取代:卤代、氨基、烷基、烷氧基、芳氧基、羟基烷基、羟基烯基、羟基炔基、氨基羰基烷氧基和芳基烷氧基及其任意组合,
Z是卤代、叠氮基或式的基团,其中R102选自C6-C12芳基、C6-C12芳基-C1-C6烷基、C3-C8环烷基、杂芳基和茂金属基,其中所述芳基基团任选地被一个或多个选自以下各项的取代基取代:三氟甲基、羟基烷基、烷氧基、磺酰基氧基、羧基烷基、磺酰基氧基烷基、芳基羰基及其任意组合,其中所述杂芳基基团任选地被一个或多个选自以下各项的取代基取代:卤代、三氟甲基、氨基、烷基、羟基烷基、芳基、烷氧基、羟基、羧基、磺酰基氧基、羧基烷基、磺酰基氧基烷基、烷基羰基、芳基羰基及其任意组合,
R103和R104独立地选自氢、羟基、氨基、巯基、脲基、C1-C6烷基羰基氨基、羟基C1-C6烷基和肼基;
R105选自氢、C1-C3烷基氨基羰基、二(C1-C3烷基)氨基羰基、C1-C3烷硫基C1-C3烷基、卤代C1-C3烷基、肼基、氨基C1-C3烷基、羟基C1-C3烷基、C3-C6环烷基氨基、羟基氨基和C2-C3烯基;并且
R106选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、杂芳基和C1-C6氨基烷基;
或其药用盐。
本发明还提供药物组合物,所述药物组合物包含本发明的化合物或盐以及药用载体。
本发明另外提供用于激活哺乳动物中的A3腺苷受体的方法,所述方法包括向所述哺乳动物施用有效量的本发明的化合物或盐。
本发明还提供用于在有需要的哺乳动物中治疗或预防神经性疼痛的方法,所述方法包括向所述哺乳动物施用有效量的本发明的化合物或盐。
有利地,本发明的化合物表现出所需的药物样理化性质,这包括小于约500道尔顿的分子量,被预期赋予口服生物利用度。此外,存在对由A3AR激动剂表现出的针对神经性疼痛的保护的外周和中枢机械性组分。本发明的化合物具有对跨越血脑屏障有利的物化性质并且因此可以在脑内起作用。
附图的多视图简述
图1A-1C示出了在神经性疼痛的慢性缩窄性损伤模型(chronic constrictioninjury model)中,分别由化合物7(MRS5914)、8(MRS5917)和17(MRS5969)表现出的机械性痛觉超敏(mechano-allodynia)随时间的逆转(反转,reversal)。
图2示出了在神经性疼痛的慢性缩窄性损伤模型中,由化合物13(MRS5967)、16(MRS5968)、17(MRS5969)、14(MRS5970)和11(MRS5971)表现出的机械性痛觉超敏随时间的逆转。
图3示出了在神经性疼痛的慢性缩窄性损伤模型中,由化合物6(MRS5913)、7(MRS5914)、8(MRS5917)、9(MRS5921)和10(MRS5929)表现出的机械性痛觉超敏随时间的逆转。
图4示出了在神经性疼痛的慢性缩窄性损伤模型中,由化合物6(MRS5913)、7(MRS5914)、8(MRS5917)、9(MRS5921)和10(MRS5929)在对侧表现出的机械性痛觉超敏随时间的逆转。
图5示出了在神经性疼痛的慢性缩窄性损伤模型中,由化合物40(MRS5918)、41(MRS5919)、37(MRS5979)和32(MRS5980)表现出的机械性痛觉超敏随时间的逆转。
图6描绘了MRS5698和MRS5676的结构。
图7A-7F示出了化合物7、8、40、41、32和101分别在利用表达mA1AR的HEK293细胞的对毛喉素-刺激的cAMP积累的抑制的测定中的浓度效应曲线。
图8A-8C示出了在神经性疼痛的慢性缩窄性损伤模型中,由化合物7(图8A)、17(图8B)和32(图8C)以0.3mmol/kg、1mmol/kg和3mmol/kg的剂量表现出的机械性痛觉超敏随时间的逆转。
图9A和9B示出了化合物7(图9A)和8(图9B)在抑制人A1AR和A3AR处的环AMP形成方面的活性。
图10示出了在神经性疼痛的慢性缩窄性损伤模型中,由化合物8、16和100表现出的机械性痛觉超敏随时间的逆转。
图11示出了在神经性疼痛的慢性缩窄性损伤模型中,由化合物100(MRS7110)、105(MRS7113)、103(MRS7114)、101(MRS7115)和104(MRS7116)分别表现出的机械性痛觉超敏随时间的逆转。
图12示出了在神经性疼痛的慢性缩窄性损伤模型中,由化合物112(MRS7121)、102(MRS7117)、108(MRS7118)、111(MRS7119)、106(MRS7120)和110(MRS7126)分别表现出的机械性痛觉超敏随时间的逆转。
图13A和13B描绘了来自对照组(图13A)和化合物32-处理组(图13B)的肝样品的组织学分析。
图14示出了当与MRS5698或化合物32一起用药时由吗啡表现出的对机械性痛觉超敏随时间的逆转的维持。
图15描绘了在化合物32以1mg/kg静脉内用药后和在以1、3和10mg/kg口服用药后的雄性SD大鼠中作为时间的函数的血浆浓度。
图16示出了由化合物126(MRS7135)以0.3、1、2、10和30μmol/kg剂量口服给药时,表现出的机械性痛觉超敏随时间的逆转。
图17示出了在神经性疼痛的慢性缩窄性损伤模型中,由化合物125(MRS7137)、120(MRS7138)、121(MRS7139)和127(MRS7140)分别表现出的机械性痛觉超敏随时间的逆转。
发明详述
在一个实施方案中,本发明提供式(I)的化合物:
其中X选自NHR1、CH3和CH=C(Ra)(Rb),其中Ra和Rb独立地选自氢、羟基、C1-C6烷基和C6-C14芳基,
R1选自C1-C6烷基、C1-C6烷氧基、羟基、C3-C8环烷基、C6-C14芳基C3-C8环烷基、C3-C8环烷基C1-C6烷基、C3-C8二环烷基C1-C6烷基、C7-C12双环烷基、C7-C12双环烷基C1-C6烷基、C7-C14三环烷基C1-C6烷基、C6-C14芳基、C6-C14芳基C1-C6烷基、C6-C14二芳基C1-C6烷基、C6-C14芳基C1-C6烷氧基、杂环基C1-C6烷基、杂环基、4-[[[4-[[[(2-氨基C1-C6烷基)氨基]-羰基]-C1-C6烷基]苯胺基]羰基]C1-C6烷基]C6-C14芳基和C6-C14芳基C3-C8环烷基,其中R1的所述芳基或杂环基部分任选地被一个或多个选自以下各项的取代基取代:卤代、氨基、羟基、羧基、烷氧基羰基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C6-C14芳氧基、羟基C1-C6烷基、羟基C2-C6烯基、羟基C2-C6炔基、羧基C1-C6烷基、羧基C2-C6烯基、羧基C2-C6炔基、氨基羰基C1-C6烷基、氨基羰基C2-C6烯基、氨基羰基C2-C6炔基及其任意组合;并且R1的所述烷基或环烷基部分任选地被一个或多个选自以下各项的取代基取代:卤代、氨基、烷基、烷氧基、芳氧基、羟基烷基、羟基烯基、羟基炔基、氨基羰基烷氧基和芳基烷氧基及其任意组合。
R2选自C6-C12芳基、C3-C8环烷基、杂芳基和茂金属基、其中所述芳基基团任选地被一个或多个选自以下各项的取代基取代:卤代、三氟甲基、羟基烷基、烷氧基、磺酰基氧基、羧基烷基、磺酰基氧基烷基、芳基羰基及其任意组合,其中所述杂芳基基团任选地被一个或多个选自以下各项的取代基取代:卤代、三氟甲基、氨基、烷基、羟基烷基、芳基、苯并(苯并基,benzo)、烷氧基、羟基、羧基、磺酰基氧基、羧基烷基、磺酰基氧基烷基、烷基羰基、芳基羰基及其任意组合,
R3和R4独立地选自羟基、氨基、巯基、脲基、C1-C6烷基羰基氨基、羟基C1-C6烷基和肼基;
R5选自氢、C1-C3烷基氨基羰基、二(C1-C3烷基)氨基羰基、C1-C3烷硫基C1-C3烷基、卤代C1-C3烷基、肼基、氨基C1-C3烷基、羟基C1-C3烷基、C3-C6环烷基氨基、羟基氨基和C2-C3烯基;并且
R6选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、杂芳基和C1-C6氨基烷基;
或其药用盐。
在一个实施方案中,当R1是甲基,R3和R4都是羟基,R6是氢,并且R5是甲基氨基羰基时,R2不是2-吡啶基或苯基。
在一个实施方案中,R6是氢。
在某些实施方案中,Y是N。
在某些实施方案中,R5选自C1-C3烷基氨基羰基或二(C1-C3烷基)氨基羰基。
在一个实施方案中,R3和R4都是羟基。
在一个实施方案中,X是NHR1。在一个优选的实施方案中,R1是C1-C6烷基。
在某些实施方案中,R2是C6-C10芳基,其中所述芳基基团被一个或多个选自以下各项的取代基取代:卤代、三氟甲基、羟基烷基、烷氧基及其任意组合。
在某些其他实施方案中,R2是杂芳基,并且所述杂芳基基团任选地被一个或多个选自以下各项的取代基取代:羟基、卤代和烷基。
在某些优选的实施方案中,所述化合物选自:
在某些更优选的实施方案中,所述化合物选自:
在某一实施方案中,所述化合物是:
在某些优选的实施方案中,所述化合物选自:
在某些实施方案中,R1是C6-C14芳基C3-C8环烷基,其中所述芳基基团任选地被一个或多个选自以下各项的取代基取代:C1-C6烷基、甲基、F、Cl和Br。
在某些优选的实施方案中,所述化合物选自:
在某些实施方案中,X是CH3。
在一个特定实施方案中,所述化合物是:
在某些实施方案中,X是CH=C(Ra)(Rb)。
在特定实施方案中,所述化合物选自:
在某些实施方案中,Y是CH。
在某些实施方案中,R3和R4都是羟基。
在某些实施方案中,R5选自C1-C3烷基氨基羰基或二(C1-C3烷基)氨基羰基。
在某些实施方案中,X是NHR1。
在某些实施方案中,R1是C1-C6烷基。
在某些实施方案中,R2是C6-C10芳基,其中所述芳基基团被一个或多个选自以下各项的取代基取代:三氟甲基、羟基烷基、烷氧基及其任意组合。
在某些其他实施方案中,R2是杂芳基,并且所述杂芳基基团任选地被一个或多个选自以下各项的取代基取代:卤代、羟基和烷基。
在特定实施方案中,所书化合物选自:
在另一特定实施方案中,所述化合物是:
本发明还提供式(II)的化合物:
其中X选自NHR101、CH3和CH=C(Ra)(Rb),其中Ra和Rb独立地选自氢、羟基、C1-C6烷基和C6-C14芳基,
Y是N或CH,
R101选自C1-C6烷基、C1-C6烷氧基、羟基、C3-C8环烷基、C6-C14芳基C3-C8环烷基、C3-C8环烷基C1-C6烷基、C3-C8二环烷基C1-C6烷基、C7-C12双环烷基、C7-C12双环烷基C1-C6烷基、C7-C14三环烷基C1-C6烷基、C6-C14芳基、C6-C14芳基C1-C6烷基、C6-C14二芳基C1-C6烷基、C6-C14芳基C1-C6烷氧基、杂环基C1-C6烷基、杂环基、4-[[[4-[[[(2-氨基C1-C6烷基)氨基]-羰基]-C1-C6烷基]苯胺基]羰基]C1-C6烷基]C6-C14芳基和C6-C14芳基C3-C8环烷基,其中R1的所述芳基或杂环基部分任选地被一个或多个选自以下各项的取代基取代:卤代、氨基、羟基、羧基、烷氧基羰基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C6-C14芳氧基、羟基C1-C6烷基、羟基C2-C6烯基、羟基C2-C6炔基、羧基C1-C6烷基、羧基C2-C6烯基、羧基C2-C6炔基、氨基羰基C1-C6烷基、氨基羰基C2-C6烯基、氨基羰基C2-C6炔基及其任意组合;并且R101的所述烷基或环烷基部分任选地被一个或多个选自以下各项的取代基取代:卤代、氨基、烷基、烷氧基、芳氧基、羟基烷基、羟基烯基、羟基炔基、氨基羰基烷氧基和芳基烷氧基及其任意组合,
Z是卤代、叠氮基或式的基团,其中R102选自C6-C12芳基、C6-C12芳基-C1-C6烷基、C3-C8环烷基、杂芳基和茂金属基,其中所述芳基基团任选地被一个或多个选自以下各项的取代基取代:三氟甲基、羟基烷基、烷氧基、磺酰基氧基、羧基烷基、磺酰基氧基烷基、芳基羰基及其任意组合,其中所述杂芳基基团任选地被一个或多个选自以下各项的取代基取代:卤代、三氟甲基、氨基、烷基、羟基烷基、芳基、烷氧基、羟基、羧基、磺酰基氧基、羧基烷基、磺酰基氧基烷基、烷基羰基、芳基羰基及其任意组合,
R103和R104独立地选自氢、羟基、氨基、巯基、脲基、C1-C6烷基羰基氨基、羟基C1-C6烷基和肼基;
R105选自氢、C1-C3烷基氨基羰基、二(C1-C3烷基)氨基羰基、C1-C3烷硫基C1-C3烷基、卤代C1-C3烷基、肼基、氨基C1-C3烷基、羟基C1-C3烷基、C3-C6环烷基氨基、羟基氨基和C2-C3烯基;并且
R106选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、杂芳基和C1-C6氨基烷基;
或其药用盐,
条件是,当R103和R104都是羟基,R105是甲基氨基羰基,R106是氢,X是NHMe,并且Y是CH时,则Z不是碘(碘代,iodo)。
在一个实施方案中,R106是氢。
在某些实施方案中,Y是N。
在某些实施方案中,R105选自C1-C3烷基氨基羰基或二(C1-C3烷基)氨基羰基.
在一个实施方案中,R103和R104都是羟基。
在一个实施方案中,X是NHR101。在优选的实施方案中,R101是C1-C6烷基。
在某些实施方案中,Z是
在某些实施方案中,R102是C6-C10芳基,其中所述芳基基团被一个或多个选自以下各项的取代基取代:三氟甲基、羟基烷基、烷氧基及其任意组合。
在某些其他实施方案中,R102是杂芳基,并且所述杂芳基基团任选地被一个或多个选自以下各项的取代基取代:卤代、羟基和烷基。
在某些优选的实施方案中,所述化合物选自:
在某一实施方案中,所述化合物是:
在某些优选的实施方案中,所述化合物选自:
在某个这些实施方案中,R102是C6-C10芳基,其中所述芳基基团被一个或多个选自以下各项的取代基取代:三氟甲基、羟基烷基、烷氧基及其任意组合。
在某些其他实施方案中,R102是杂芳基,并且所述杂芳基基团任选地被一个或多个选自以下各项的取代基取代:卤代、羟基和烷基。
在某些优选的实施方案中,所述化合物选自:
现在提及本文中一般使用的术语,术语“烷基”意为含有例如1至约6个碳原子,优选为1至约4个碳原子,更优选为1至2个碳原子的直链或支链烷基取代基。这样的取代基的实例包括甲基、乙基、丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、戊基、异戊基、己基等。
如本文中使用的,术语“环烷基”意为含有例如约3至约8个碳原子,优选为约4至约7个碳原子,并且更优选为约4至约6个碳原子的环状烷基取代基。这样的取代基的实例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。环状烷基基团可以是未被取代的或进一步被烷基如甲基、乙基等取代。
如本文中使用的,术语“杂环基”是指含有一个或多个选自由O、N、S及其组合组成的组中的杂原子的单环或二环5-或6-元环体系。所述杂环基基团可以是任意合适的杂环基基团并且可以是脂肪族杂环基基团、芳族杂环基基团或其组合。杂环基基团可以是单环杂环基基团或二环杂环基基团。合适的杂环基包括吗啉、哌啶、四氢呋喃基、氧杂环丁烷基、吡咯烷基等。合适的二环杂环基基团包括与C6-C10芳基环稠和的单环杂环基环。当所述杂环基是二环杂环基基团时,两个环体系可以都是脂肪族的或芳族的,或一个环体系是芳族的而另一个环体系可以是脂肪族的,如在例如,二氢苯并呋喃中。术语“杂芳基”是指如本文所述的单环或二环5-或6-元环体系,其中所述杂芳基基团是不饱和的并且满足休克尔(Hückel)规则。合适的杂芳基的非限制性实例包括呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、1,2,3-三唑基、1,2,4-三唑基、异唑基、唑基、异噻唑基、噻唑基、1,3,4-二唑-2-基、1,2,4-二唑-2-基、5-甲基-1,3,4-二唑、3-甲基-1,2,4-二唑、吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、苯并呋喃基、苯并噻吩基、吲哚基、喹啉基、异喹啉基、苯并咪唑基、苯并唑啉基、苯并噻唑啉基和喹唑啉基。所述杂环基或杂芳基基团任选地被1、2、3、4或5个如本文所述的取代基取代,如被烷基如甲基、乙基等,卤代基团如氯或羟基基体取代,被芳基基团如苯基、萘基等取代,其中所述芳基可以进一步被例如卤代、二卤代烷基、三卤代烷基、硝基、羟基、烷氧基、芳氧基、氨基、取代的氨基、烷基羰基、烷氧基羰基、芳基羰基、芳氧基羰基、硫代、烷硫基、芳硫基等取代,其中所述任选的取代基可以存在于所述杂环基或杂芳基基体上的任何开放位置,或被苯并基团(benzo group)取代,以形成例如苯并呋喃的基团。
如本文中使用的,术语“烷基羰基”是指与羰基连接并且进一步通过羰基与分子连接的烷基,例如,烷基-C(=O)-。如本文中使用的,术语“烷氧基羰基”是指与羰基连接并且进一步通过羰基与分子连接的烷氧基,例如,烷基-O-C(=O)-。
如本文中使用的,术语“卤代”或“卤素”意为选自第VIIA族的取代基,如,例如,氟、溴、氯和碘。
术语“芳基”是指如本领域中通常理解的未取代的或取代的芳族碳环取代基,并且术语“C6-C10芳基”包括苯基和萘基。要理解,根据休克尔规则,术语芳基适用于是平面的并且包含4n+2冗电子的环状取代基。
术语“茂金属(metallocene)”是指通常由结合于在氧化状态II的金属中心(M)的两个环戊二烯基阴离子(Cp,其是C5H5 -)组成的化合物,具有得到的通式(C5H5)2M。金属中心可以是Ti、V、Nb、Mo或Fe。在优选的实施方案中,金属中心是Fe(II)。
不论何时指出结构中原子数的范围(例如,C1-C12、C1-C8、C1-C6、C1-C4,或C2-C12、C2-C8、C2-C6、C2-C4烷基、烯基、炔基等),具体考虑为也可以使用落在所指出的范围内的的任何子范围或单个碳原子数。因此,例如,如就本文中提及的任意化学基团(例如,烷基、烷基氨基等)而言使用的,1-8个碳原子(例如,C1-C8),1-6个碳原子(例如,C1-C6),1-4个碳原子(例如,C1-C4),1-3碳原子(例如,C1-C3)或2-8个碳原子(例如,C2-C8)的范围的陈述,在适当时,涵盖并且具体描述1、2、3、4、5、6、7、8、9、10、11和/或12个碳原子,以及其任意子范围(例如,在适当时,为1-2个碳原子,1-3个碳原子,1-4个碳原子,1-5个碳原子,1-6个碳原子,1-7个碳原子,1-8个碳原子,1-9个碳原子,1-10个碳原子,1-11个碳原子,1-12个碳原子,2-3个碳原子,2-4个碳原子,2-5个碳原子,2-6个碳原子,2-7个碳原子,2-8个碳原子,2-9个碳原子,2-10个碳原子,2-11个碳原子,2-12个碳原子,3-4个碳原子,3-5个碳原子,3-6个碳原子,3-7个碳原子,3-8个碳原子,3-9个碳原子,3-10个碳原子,3-11个碳原子,3-12个碳原子,4-5个碳原子,4-6个碳原子,4-7个碳原子,4-8个碳原子,4-9个碳原子,4-10个碳原子,4-11个碳原子,和/或4-12个碳原子等)。类似地,如就本文中提及的任意化学基团(例如,芳基)而言使用的6-10个碳原子(例如,C6-C10)的范围的陈述,在适当时,涵盖并且具体描述6、7、8、9和/或10个碳原子以及其任意子范围(例如,在适当时,为6-10个碳原子,6-9个碳原子,6-8个碳原子,6-7个碳原子,7-10个碳原子,7-9个碳原子,7-8个碳原子,8-10个碳原子,和/或8-9个碳原子等)。
术语“药用盐”意在包括通过常规化学方法从含有碱性或酸性部分的母体化合物合成的无毒盐。通常,这样的盐可以通过将这些化合物的游离酸或碱形式与化学计量量的适当碱或酸在水中或在有机溶剂中,或在二者的混合物中反应来制备。通常,非水介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈是优选的。合适的盐的列表在Remington’sPharmaceutical Sciences,第18版,Mack Publishing Company,Easton,PA,1990,p.1445和Journal of Pharmaceutical Science,66,2-19(1977)中找到。
合适的碱包括无机碱如碱金属和碱土金属碱,例如,含有金属阳离子如钠、钾、镁、钙等的那些。合适的碱的非限制性实例包括氢氧化钠、氢氧化钾、碳酸钠和碳酸钾。合适的酸包括无机酸如盐酸、氢溴酸、氢碘酸、硫酸、磷酸等,和有机酸如对甲苯磺酸、甲磺酸、苯磺酸、草酸、对溴苯磺酸、碳酸、琥珀酸、柠檬酸、苯甲酸、乙酸、马来酸、酒石酸、脂肪酸、长链脂肪酸等。具有酸性部分的本发明的化合物的优选的药用盐包括钠盐和钾盐。具有碱性部分(例如,二甲基氨基烷基基团)的本发明的化合物的优选的药用盐包括盐酸盐和氢溴酸盐。含有酸性或碱性部分的本发明的化合物以游离碱或酸的形式或其药用盐的形式是有用的。
应该认识到,形成本发明的任意盐的一部分的具体抗衡离子通常不具有关键性质,只要所述盐作为整体是药理学可接受的并且只要抗衡离子不对所述盐作为整体贡献不需要的品质即可。
还要理解,上述化合物和盐可以形成溶剂化物,或以基本上未复合的形式,如无水形式存在。如本文中使用的,术语″溶剂化物″是指分子复合物,其中所述溶剂分子,如结晶溶剂,结合到晶格中。当结合入溶剂化物中的溶剂是水时,所述分子复合物被称为水合物。药用溶剂化物包括水合物、醇合物如甲醇合物和乙醇合物、乙腈合物(acetonitrilate)等。这些化合物也可以以多晶形形式存在。
在上述实施方案任一个中,式(I)的化合物或盐可以具有至少一个不对称碳原子。当所述化合物或盐具有至少一个不对称碳原子时,所述化合物或盐可以以外消旋形式,以其纯的光学异构体形式,或以其中一种异构体相对于另一种富集的混合物的形式存在。特别地,根据本发明,当本发明的化合物具有单个不对称碳原子时,本发明的化合物可以作为外消旋物,即作为等量光学异构体,即等量的两种对映异构体的混合物,或以单个对映异构体的形式存在。如本文中使用的,″单个对映异构体″意在包括包含多于50%的单个对映异构体(即,对映异构过量直至100%的纯对映异构体)的化合物。
当化合物或盐具有多于一个手性中心时,所述化合物或盐可以因此作为非对映异构体的混合物或以单个非对映异构体的形式存在。如本文中使用的,“单个非对映异构体”意在是指包含多于50%的单个非对映异构体(即,非对映异构过量至100%纯的非对映异构体)的化合物。
本发明还提供包含如上所述化合物和药用载体的药物组合物。本发明提供包含药用载体和有效量的一种或多种本发明的上述化合物或其盐的药物组合物,所述有效量例如治疗有效量,包括预防有效量。
药用载体可以是常规使用的那些中的任一种并且仅由化学-物理考虑因素和给药途径所限制,所述考虑因素例如溶解度和与所述化合物缺乏反应性。本领域技术人员应当理解,除下面描述的药物组合物外,还可以将本发明的化合物配制成包合配合物,例如环糊精包合配合物,或脂质体。
本文描述的药用载体,例如,媒介物(vehicle)、辅剂、赋形剂或稀释剂是本领域技术人员公知的并且公众可容易获得。优选所述药用载体对活性化合物是化学惰性的载体并且在使用的条件下不具有有害副作用或毒性的载体。
载体的选择将部分由特定活性剂以及由用于施用组合物的特定方法确定。因此,存在多样的本发明的药物组合物的合适的制剂。以下用于口服、气雾剂、肠胃外、皮下、静脉内、动脉内、肌肉内、腹膜内、鞘内、直肠和阴道施用的制剂仅仅是示例性的并且不以任何方式限制。
适于口服施用的制剂可以由以下各项组成:(a)液体溶液,如溶解在稀释剂如水、盐水或橙汁中的有效量的化合物;(b)胶囊、小袋(sachet)、片剂、锭剂(lozenge)和糖锭(troche),其各自含有作为固体或颗粒的预定量的活性成分;(c)粉剂;(d)在适当液体中的混悬剂和(e)合适的乳剂。液体制剂可以包括稀释剂,如水和醇,例如,乙醇、苄醇和聚乙烯醇(polyethylene alcohol),加入或不加入药学上可接受的表面活性剂、悬浮剂或乳化剂。胶囊形式可以是普通的硬壳或软壳明胶类型,其含有,例如,表面活性剂、润滑剂和惰性填料,如乳糖、蔗糖、磷酸钙和玉米淀粉。片剂形式可以包括乳糖、蔗糖、甘露醇、玉米淀粉、马铃薯淀粉、藻酸、微晶纤维素、阿拉伯树胶、明胶、瓜尔胶、胶态二氧化硅、交联羧甲基纤维素钠(croscarmellose sodium)、滑石、硬脂酸镁、硬脂酸钙、硬脂酸锌、硬脂酸和其他赋形剂、着色剂、稀释剂、缓冲剂、崩解剂、润湿剂、防腐剂、芳香剂和药理学相容的载体中的一种或多种。锭剂形式可以包含香味形式的活性成分,通常是蔗糖和阿拉伯树胶或黄芪胶,还有包含惰性基形式的活性成分的锭剂,例如明胶和甘油,或除了所述活性成分外还含有本领域中已知的这类载体的蔗糖和阿拉伯树胶,乳状液,凝胶等。
可以将本发明的化合物,单独或与其它适合的组分组合,制成经由吸入施用的气雾剂剂型。可以将这些气雾剂剂型放置在加压可接受的推进剂中,例如二氯二氟甲烷、丙烷、氮气等。也可以将它们配制成常压制备用药物,例如在雾化器或喷雾器中。
适于肠胃外施用的制剂包括水和非水的等渗压的无菌注射溶液,所述溶液可以含有抗氧化剂、缓冲剂、杀菌剂、和使得所述制剂与预定接受者血液等渗压的溶质,以及水和非水的无菌混悬剂,所述混悬剂可以包括悬浮剂、增溶剂、增稠剂、稳定剂和防腐剂。可以将所述化合物在药物载体中的生理可接受的稀释剂中施用,如无菌液体或液体混合物,包括水,盐水,右旋糖和相关糖的水溶液,醇如乙醇、异丙醇或十六醇,二醇如丙二醇或聚乙二醇,甘油缩酮如2,2-二甲基-1,3-二氧戊环-4-甲醇,醚如聚(乙二醇)400、油、脂肪酸、脂肪酸酯或甘油酯,或者加入或没有加入药学上可接受的表面活性剂的乙酰化脂肪酸甘油酯如脂肪酸盐或清洁剂,悬浮剂,诸如果胶、卡波姆(carbomers)、甲基纤维素、羟丙基甲基纤维素或羧甲基纤维素,或乳化剂及其他药物辅剂。
可被用在胃肠外的制剂中的油包括石油、动物油、植物油或合成油。油的具体实例包括花生、大豆、芝麻、棉籽、玉米、橄榄、矿脂、和矿物油。供胃肠外制剂用的合适脂肪酸包括油酸、硬脂酸和异硬脂酸。油酸乙酯和十四烷酸异丙酯是适合的脂肪酸酯的实例。供胃肠外制剂用的合适脂肪酸盐包括脂肪碱金属、铵和三乙醇胺盐,并且合适的洗涤剂包括(a)阳离子洗涤剂例如二甲基二烷基卤化铵和烷基吡啶卤化物,(b)阴离子洗涤剂例如,烷基的、芳基的和烯烃的磺酸盐或酯,烷基、烯烃、醚和单酸甘油酯的硫酸盐或酯,和磺基丁二酸盐或酯,(c)非离子型洗涤剂例如,脂肪胺氧化物、脂肪酸链烷醇酰胺和聚氧乙烯-聚丙烯共聚物,(d)两性洗涤剂例如烷基-β-氨基丙酸盐或酯和2-烷基-咪唑啉季铵盐,和(3)其混合物。
所述胃肠外制剂将在溶液中典型含有约0.5至约25重量%的活性成分。合适的防腐剂和缓冲剂可用于这样的制剂。为了最小化或消除注射部位的刺激,这样的组合物可以含有一种或多种非离子型表面活性剂,所述非离子型表面活性剂具有的亲水-亲脂平衡(HLB)为约12至约17。这样的制剂中表面活性剂的量在约5至约15重量%的范围内。适合的表面活性剂包括聚乙烯脱水山梨糖醇脂肪酸酯,如单油酸脱水山梨糖醇酯和环氧乙烷与疏水性碱的高分子量加合物,由环氧丙烷与丙二醇的缩合形成。所述胃肠外制剂可以存在于单位-剂量或多-剂量密封容器中,如安瓿和小瓶,并且可以储存在冷冻-干燥(冻干的)状态,仅需要在使用之前立即加入无菌液体载体例如水用于注射。可以从上述种类的无菌粉剂、颗粒剂和片剂制备临时的注射液和混悬剂。
本发明的化合物可以制成可注射制剂。对于用于可注射组合物的有效药物载体的要求对于本领域技术人员是公知的。参见Pharmaceutics and Pharmacy Practice,J.B.Lippincott Co.,Philadelphia,Pa.,Banker and Chalmers,eds.,pages 238-250(1982),和ASHP Handbook on Injectable Drugs,Toissel,4th ed.,pages 622-630(1986)。
局部制剂(包括可用于透皮药物释放的那些)对于本领域技术人员是公知的并且在本发明的内容中适用于皮肤。局部施用的组合物通常是液体、霜剂、糊剂、洗剂和凝胶的形式。局部施用包括施用于口腔粘膜(其包括口腔)、口腔上皮、腭、齿龈和鼻粘膜。在一些实施方案中,所述组合物含有至少一种活性成分和合适的媒介物或载体。其还可以含有其它组分,如抗刺激剂。所述载体可以是液体、固体或半固体。在实施方案中,所述组合物是水溶液。备选地,所述组合物可以是用于各种组分的分散体、乳液、凝胶、洗剂或霜剂媒介物。在一个实施方案中,主要载体是水或生物相容性溶剂,其基本上是中性的或其基本上被赋予中性。液体媒介物可以包括其它材料,如缓冲液、醇、甘油和矿物油,与本领域已知的各种乳化剂或分散剂一起,以获得所需的pH、稠度和粘度。有可能的是,所述组合物可以制备为固体,如粉末或颗粒。所述固体可以直接施用或溶解于水或生物相容性溶剂,之后用于形成基本上中性或基本上被赋予中性然后可以用于目标部位的溶液。在本发明的实施方案中,用于局部施用至皮肤的媒介物可以包括水,缓冲液,各种醇,二醇类如甘油,脂质材料如脂肪酸,矿物油,磷酸甘油酯,胶原蛋白,明胶,有机硅(silicone)类材料。
另外,可以通过与多种基质例如乳化基质或水溶性基质混合将本发明的化合物制成栓剂。适于阴道给药的制剂可以存在为含有除所述活性成分之外如本领域已知的适当的这类载体的阴道栓、棉塞、乳膏、凝胶、糊剂、泡沫,或喷雾配方。
化学
以下描述对于本发明的化合物,例如,表1和2中列出的那些的代表性途径。方案1-4中描述的合成方法从6-氯5’-乙基酯中间体52开始,其如之前所述从L-核糖51制备(Paoletta,S.等人,J.Med.Chem.,2013,56:5949-5963;Tosh,D.K.等人,J.Med.Chem.2012,55:4847-4860;和Tosh,D.K.等人,Med.Chem.Comm.,2013,4:619-630)。在甲醇中在Et3N的存在下将6-氯5’-乙基酯中间体52用MeNH2·HCl处理并且将得到的化合物在室温用40%甲基胺溶液(水溶液)处理,得到用于N6-甲基衍生物的中间体53(方案1)。在N6-(2-苯基环丙基)衍生物的情况下,随后将52用适当的2-苯基环丙基胺处理,得到55a-f,接着用甲基胺处理,得到56a-f(方案2)。然后,在PdCl2(Ph3P)2、CuI和三乙胺的存在下将中间体53和56与适当的芳基-或环烷基乙炔进行Sonogashira偶联,分别得到受保护的中间体54和57。最后,亚异丙基保护基的水解,得到用于生物学测试的核苷目标化合物。
方案1.N6-甲基衍生物的合成。
(i)(a)MeNH2·HCl,Et3N,甲醇,室温(RT),(b)40%MeNH2,MeOH,室温;(ii)HC≡CR2,Pd(PPh3)2Cl2,CuI,Et3N,DMF,室温;(iii)10%TFA,MeOH,70℃。Ref.24:Tosh,D.K.等人,Med Chem.Comm.2013,4:619-630。
方案2.N6-苯基环丙基衍生物的合成。
(i)Xn-苯基环丙基-H2,Et3N,MeOH,室温;(ii)40%MeNH2,MeOH,室温;(iii)HC≡CR2,Pd(PPh3)2Cl2,CuI,Et3N,DMF,室温;(iv)10%TFA,MeOH,70℃。
本发明的含有2-芳基乙炔基基团以及6-烷基和苯乙烯基取代基的(N)-桥亚甲基甲(methanocarba)嘌呤5’-甲基糖酰胺的合成在方案3中显示。在PdCl2(Ph3P)2、CuI和三乙胺存在下2-碘衍生物52a与适当的芳基乙炔的Sonogashira偶联,得到双重取代的中间体58。在尝试5’-酯与甲基胺的选择性反应后,发现C6-炔基还与甲基胺反应,得到苯乙烯基加合物59。在尝试用10%TFA/水水解59的亚异丙基时,在一些情况下,与苯乙烯醇(styrenol)截短的C6-甲基化合物39和41一起获得苯乙烯醇衍生物38、40和42。经由意料之外的重排,形成这些副产物(显示具有其自身的生物活性)。类似地,通过涉及中间体52b、60和61的途径制备C2-氯系列中的羟基苯乙烯基衍生物43。
方案3.C6-甲基和C6-苯乙烯基衍生物的合成
本发明含有2-三唑基的(N)-桥亚甲基甲嘌呤5’-甲基糖酰胺的合成显示在方案4中。在Et3N的存在下在甲醇中用伯胺处理52a得到80。用甲基胺在甲醇中处理80得到酰胺81。用三氟乙酸在甲醇中水解81得到82。在抗坏血酸钠、CuSO4·5H2O、Na2CO3和L-脯氨酸的存在下在叔丁醇和水的混合物中将82与叠氮化钠反应,得到叠氮化物83。在抗坏血酸钠、CuSO4·5H2O、Na2CO3和L-脯氨酸的存在下,在叔丁醇和水的混合物中将83与适当的芳基炔烃反应,得到三唑84。
方案4.三唑的合成。
本发明的含有2-三唑基的(N)-桥亚甲基甲嘌呤5’-甲基糖酰胺的脱氮类似物的合成在方案5中显示。从相应氨基化合物85,在DMF中使用对甲氧基苄基氯,经由用对甲氧基苄基保护咪唑氮(imidazo nitrogen)得到86,将86与异戊腈、二碘甲烷和碘化亚铜在THF中反应得到87,以及用TFA将87脱保护得到88的顺序制备1-脱氮-6-氯-2-碘嘌呤88。将88与89(衍生自L-核糖)在三苯基膦和二异丙基偶氮二甲酸酯的存在下,在THF中反应,得到90。将5’-乙基酯化合物90用甲基胺水溶液处理得到酰胺91。在二异丙基乙胺的存在下在异丙醇中,在微波照射下用MeNH2·HCl处理91得到92。在PdCl2(Ph3P)2、CuI和Et3N的存在下在DMF中将92与5-氯-2-乙炔基噻吩进行Sonogashira偶联得到93,将其用TFA在甲醇中脱保护,得到化合物127。
方案5.脱氮类似物的合成。
在某些实施方案中,本发明提供在有需要的患者中治疗或预防疾病、状态(state)或病症的方法,所述方法包括向患者施用有效量的本发明的任一实施方案的化合物或其药用盐,其中所述疾病、状态或病症选自由以下各项组成的组:神经性疼痛、血管炎症(vascular inflammation)、关节炎(arthritis)、变态反应(allergies)、哮喘(asthma)、伤口愈合(wound healing)、卒中(stroke)、心力衰竭(cardiac failure)、急性脊髓损伤(acute spinal cord injury)、急性颅脑损伤或创伤(acute head injury or trauma)、癫痫(seizure)、新生儿缺氧(neonatal hypoxia)、大脑性瘫痪(cerebral palsy)、由于动静脉畸形(arteriovenous malformations)和闭塞性脑动脉病(occlusive cerebral arterydisease)导致的慢性缺氧(chronic hypoxia)、骨骼肌中的缺血(ischemia)和再灌注损伤(reperfusion injury)、与兴奋性毒性相关的严重神经障碍(severe neurologicaldisorders related to excitotoxicity)、帕金森病(Parkinson′s disease)、亨廷顿舞蹈症(Huntington′s chorea)、CNS疾病(diseases of the CNS)、心脏病(cardiac disease)、肾病(kidney disease)、青光眼(glaucoma)、癌症(cancer)、神经性疼痛、与糖尿病相关的神经性疼痛、短暂性脑缺血发作(transient ischemic attacks)、骨髓保护(myeloprotection)、干眼综合征(dry eye syndrome)、骨关节炎(osteoarthritis)、类风湿性关节炎(rheumatoid arthritis)、皮肤色素沉着的损失(loss of skinpigmentation)、炎性肠病(inflammatory bowel disease)、肺炎(pulmonaryinflammation)、葡萄膜炎(uveitis)和感染性休克(septic shock)。在优选的实施方案中,本发明提供在有需要的患者中治疗或预防神经性疼痛的方法。在另一优选的实施方案中,本发明提供在有需要的患者中治疗或预防术后痛(postoperative pain)的方法。
在一个实施方案中,本发明的化合物还可以用于治疗与由包含化疗药物作为治疗方案的一部分的一种或多种组合导致的化疗引起的外周神经病(chemotherapy-inducedperipheral neuropathy)(CIPN)相关的疼痛。合适的组合的非限制性实例包括CHOPP(环磷酰胺(cyclophosphamide)、阿霉素(doxorubicin)、长春新碱(vincristine)、强的松(prednisone)和甲基苄肼(procarbazine));CHOP(环磷酰胺、阿霉素、长春新碱和强的松);COP(环磷酰胺、长春新碱和强的松);CAP-BOP(环磷酰胺、阿霉素、甲基苄肼、博来霉素(bleomycin)、长春新碱和强的松);m-BACOD(甲氨蝶呤(methotrexate)、博来霉素、阿霉素、环磷酰胺、长春新碱、地塞米松(dexamethasone)和亚叶酸(leucovorin));ProMACE-MOPP(强的松、甲氨蝶呤、阿霉素、环磷酰胺、依托泊甙(etoposide)、亚叶酸、氮芥(mechloethamine)、长春新碱、强的松和甲基苄肼);ProMACE-CytaBOM(强的松、甲氨蝶呤、阿霉素、环磷酰胺、依托泊甙、亚叶酸、阿糖胞苷(cytarabine)、博来霉素和长春新碱);MACOP-B(甲氨蝶呤、阿霉素、环磷酰胺、长春新碱、强的松、博来霉素和亚叶酸);MOPP(氮芥、长春新碱、强的松和甲基苄肼);ABVD(亚德里亚霉素(adriamycin)/阿霉素、博来霉素、长春碱(vinblastine)和达卡巴嗪(dacarbazine));MOPP(氮芥、长春新碱、强的松和甲基苄肼),其与ABV(亚德里亚霉素/阿霉素、博来霉素和长春碱)交替;MOPP(氮芥、长春新碱、强的松和甲基苄肼),其与ABVD(亚德里亚霉素/阿霉素、博来霉素、长春碱和达卡巴嗪)交替;ChIVPP(苯丁酸氮芥(chlorambucil)、长春碱、甲基苄肼和强的松);IMVP-16(异环磷酰胺(ifosfamide)、甲氨蝶呤和依托泊甙);MIME(甲基-gag、异环磷酰胺、甲氨蝶呤和依托泊甙);DHAP(地塞米松、高剂量阿糖胞苷(high-dose cytaribine)和顺铂(cisplatin));ESHAP(依托泊甙、甲基泼尼松龙(methylpredisolone)、高剂量阿糖胞苷和顺铂);CEPP(B)(环磷酰胺、依托泊甙、甲基苄肼、强的松和博来霉素);CAMP(洛莫司汀(lomustine)、米托蒽醌(mitoxantrone)、阿糖胞苷和强的松);CVP-1(环磷酰胺、长春新碱和强的松)、ESHOP(依托泊甙、甲基泼尼松龙、高剂量阿糖胞苷、长春新碱和顺铂);EPOCH(依托泊甙、长春新碱和阿霉素达96小时,具有环磷酰胺和口服强的松的推注剂量)、ICE(异环磷酰胺、环磷酰胺和依托泊甙)、CEPP(B)(环磷酰胺、依托泊甙、甲基苄肼、强的松和博来霉素)、CHOP-B(环磷酰胺、阿霉素、长春新碱、强的松和博来霉素)、CEPP-B(环磷酰胺、依托泊甙、甲基苄肼和博来霉素)和P/DOCE(表柔比星(epirubicin)或阿霉素、长春新碱、环磷酰胺和强的松)。
在一个实施方案中,提供了在受试者中治疗神经性疼痛的方法,所述方法包括与止痛剂联合向受试者施用本发明的化合物。该实施方案基于这样的发现,即本发明的化合物和止痛剂表现出协同效应,增加止痛剂的效力。换句话说,这些化合物的施用表现出超过个体组分的仅仅加合的贡献的协同效应。因此,一起使用的本发明的化合物和止痛剂的协同有效量可以小于以单个治疗施用的本发明的化合物或止痛剂的有效量。
所述方法可以涉及向受试者施用与第二量的止痛剂联合的第一量的本发明的化合物,其中所述第一和第二量一起构成药学有效量。因为上述协同效应,所述第一量、第二量或者这二者可以小于作为单个治疗施用的各个化合物的有效量。本发明的化合物和止痛剂的治疗有效量共同施用给受试者,即,同时或分开地,以任意给定顺序并且通过相同或不同的施用途径施用给受试者。可能有利的是例如在开始施用止痛剂之前一天或几天或几周首先开始施用本发明的化合物。此外,可以提供另外的药物与上述联合治疗联合。
本实施方案的方法可以用于缓解神经性疼痛的症状(不论该疼痛的病因),例如,但不限于,脊髓损伤(spinal cord injury)、多发性硬化(multiple sclerosis)、卒中、糖尿病(diabetes)、带状疱疹感染(herpes zoster infection)、HIV相关神经病(HIV-related neuropathies)、营养缺乏(nutritional deficiencies)、毒素(toxins)、恶性肿瘤的远程表现(remote manifestations of malignancies)、遗传、免疫介导的病症(genetic,immune mediated disorders)或对神经干的物理创伤(physical trauma to anerve trunk)、癌症、化疗、放射损伤或外科手术(例如,术后痛)、外阴痛(vulvodynia)和口腔烧灼综合征(burning mouth syndrome)。在一个实施方案中,神经性疼痛与阿片类的长期使用相关。
与本发明的化合物联合施用的止痛剂可以根据所治疗的特定病症选择,并且优选为在治疗疼痛方面具有证实的效力而没有显著的成瘾的可能。目前已知的止痛剂包括,但不限于,阿片类、拟吗啡物质(morphinomimetics)、抗抑郁药、抗癫痫剂、NMDA受体拮抗剂、脂肪酸胺水解酶抑制剂、抗惊厥药、非甾体抗炎药(NSAID)、COX-2抑制剂、NOS抑制剂、醋氨酚(acetaminophen)和钙通道亚单位α2δ配体。
示例性阿片类包括任何天然或合成的阿片类止痛剂,如吗啡、芬太尼(fentanyl)、可待因(codeine)、蒂巴因(thebaine)、二乙酰基吗啡(海洛因)、二氢可待因、氢可酮(hydrocodone)、氢吗啡酮(hydromorphone)、尼可吗啡(nicomorphine)、氧可酮(oxycodone)、氧化吗啡酮(oxymorphone)、α甲基芬太尼、阿芬太尼(alfentanil)、舒芬太尼(sufentanil)、雷米芬太尼(remifentanil)、卡芬太尼(carfentanil)、羟甲芬太尼(ohmefentanil)、可卡因(nocaine)、哌替啶(pethidine)(盐酸麦佩里定(meperidine))、凯托米酮(ketobemidone)、MPPP、烯丙罗定(allylprodine)、普鲁丁(prodine)、PEPAP、丙氧芬(propoxyphene)、右旋丙氧芬(dextropropoxyphene)、右旋吗拉迈得(dextromoramide)、苯腈米特(bezitramide)、哌腈米特(piritramide)、美沙酮(methadone)、地匹哌酮(dipipanone)、左旋α乙酰地美庚醇(levoalphaacetylmethadol)(LAAM)、洛派丁胺(loperamide)、苯乙哌啶(diphenoxylate)、戊唑辛(pentazocine)、非那佐辛(phenazocine)、丁丙诺啡(buprenorphine)、埃托啡(etorphine)、布托啡诺(butorphanol)、纳布啡(nalbuphine)、羟甲左吗喃(levorphanol)、左美沙芬(levomethorphan)、地佐辛(dezocine)、利非他明(lefetamine)、替利定(tilidine)、曲马多(tramadol)、丙氧芬和氧可酮。如本文中意图的,阿片类还包括任何天然或合成的麻醉药拮抗剂如纳美芬(nalmefene)、纳洛酮(naloxone)或纳曲酮(naltrexone)以及任何天然或合成的混合类鸦片激动剂/拮抗剂如纳布啡(nalbuphine)、布托啡诺(butorphanol)、丁丙诺啡和戊唑辛(pentazocine)。
示例性非甾体抗炎药(NSAID)包括阿司匹林(aspirine)、布洛芬(ibuprofen)、醋氨酚(acetaminophen)、萘普生(naproxen)、非诺洛芬(fenoprofen)、酮洛芬(ketoprofen)、氟比洛芬(flurbiprofen)、丙嗪(oxaprozin)、吲哚美辛(indomethacin)、舒林酸(sulindac)、依托度酸(etodolac)、酮咯酸(ketorolac)、双氯芬酸(diclofenac)、萘布美酮(nabumetone)、吡罗昔康(piroxicam)、美洛昔康(meloxicam)、替诺昔康(tenoxicam)、哚昔康(droxicam)、氯诺昔康(lornoxicam)、伊索昔康(isoxicam)、甲灭酸(mefenamic acid)、甲氯灭酸(meclofenamic acid)、氟灭酸(flufenamic acid)、托芬那酸(tolfenamicacid)、塞来考昔(celecoxib)、罗非考昔(rofecoxib)、伐地考昔(valdecoxib)、帕瑞考昔(parecoxib)、鲁米考昔(1umiracoxib)、艾托考昔(etoricoxib)、非罗考昔(firocoxib)、尼美舒利(nimesulide)和利克飞龙(licofelone)。示例性抗抑郁药包括三环抗抑郁药如:阿密曲替林(amitriptyline)、氧阿米替林(amitriptylinoxide)、布替林(butriptyline)、氯米帕明(clomipramine)、地美替林(demexiptiline)、脱甲丙咪嗪(desipramine)、二苯西平(dibenzepin)、二甲他林(dimetacrine)、度硫平(dosulepin)、多虑平(doxepin)、丙咪嗪(imipramine)、氧米帕明(imipraminoxide)、洛非帕明(lofepramine)、美利蒽(melitracen)、美他帕明(metapramine)、硝沙西平(nitroxazepine)、去甲替林(nortriptyline)、诺昔替林(noxiptiline)、哌泊非嗪(pipofezine)、丙吡西林(propizepine)、普罗替林(protriptyline)和奎纽帕明(quinupramine);安咪奈丁(amineptine)、去甲肾上腺素(norepinephrine)、伊普吲哚(iprindole)、奥匹哌醇(opipramol)、噻萘普汀(tianeptine)、曲米帕明(trimipramine)、卡马西平(carbamezapine)和氟吡丁(flupirtine)。
还考虑的是,当与认为结合钙通道亚单位α2δ,即钙通道亚单位α2δ配体的阿片样物质、三环抗抑郁药或止痛剂共同施用时,本发明的化合物将特别适于治疗疼痛。这样的配体的实例包括GABA类似物,如加巴喷丁(gabapentin)(2-[1-(氨基甲基)环己基]乙酸)和普瑞巴林(pregabalin)((S)-3-(氨基甲基)-5-甲基己酸)。
可以选择化合物的相对量以提供协同的疼痛缓解。例如,本发明的化合物与加巴喷丁的合适的比例可以在约0.1重量份的化合物至约3至约30重量份的加巴喷丁的范围内。本发明的化合物与吗啡的合适的比例可以在约0.1重量份的化合物至约1至约5重量份的吗啡的范围内。尽管这些比例就游离化合物(非盐形式)而言计算的,但应该理解,对于药用盐或化合物的前药,也可以通过使用盐的分子量的比例容易地确定当量比。
在一些情况下,本发明的化合物和止痛剂的共同施用通过将化合物一起配制入组合组合物来实现。因此,在第三个方面,提供了用于治疗神经性疼痛的组合组合物。
可以根据治疗的特定病症选择以组合组合物施用的止痛剂,并且优选被证实在疼痛治疗中有效而没有显著的成瘾可能的止痛剂。目前己知的止痛剂包括,但不限于,阿片类、吗啡样物质、抗抑郁药、抗癫痫剂、NMDA受体拮抗剂、脂肪酸胺水解酶抑制剂、抗惊厥药、非甾体抗炎药(NSAID)、COX-2抑制剂、NOS抑制剂、钙通道亚单位α2δ配体、钠通道拮抗剂和大麻素。
在一些情况中,所述组合组合物包含含有第一量的本发明的化合物的第一药用组合物,和含有第二量的止痛剂的第二药用组合物,其中所述第一和第二量一起构成药学有效量。第一量、第二量或这二者可以小于作为单个治疗施用的各个化合物的有效量。
在其他情况中,所述组合组合物是包含第一量的本发明的化合物和第二量的止痛剂的药用组合物,其中所述第一和第二量一起构成药学有效量。所述第一量、第二量或这二者可以小于作为单个治疗施用的各个化合物的有效量。
在一个实施方案中,本发明提供减少接受鸦片制剂治疗以用于急性/严重和慢性神经性(恶性和非恶性)疼痛的受试者中的阿片样物质抗镇痛耐受性和/或超敏性的方法,所述方法包括向受试者施用足以减少阿片样物质抗镇痛耐受性的本发明的化合物的量。所述阿片样物质可以是吗啡、氧可酮或芬太尼。受试者可以是人或非人哺乳动物。伤害感受性疼痛可以是慢性疼痛或急性疼痛。伤害感受性疼痛可以是损伤如穿透伤、烧伤、冻伤或骨折的结果。伤害感受性疼痛可以是疾病,如糖尿病(例如,糖尿病性视网膜病(diabeticneuropathy))、术后疼痛(postsurgical pain)、骨癌疼痛(bone cancer pain)、乳腺癌疼痛(breast cancer pain)、外伤性疼痛(traumatic pain)、脊髓神经损伤(spinal nerveinjuries)、多发性硬化、关节炎、自身免疫病或感染的结果。
鸦片制剂和本发明的化合物可以同时递送,并且可以共同配制或不共同配制。备选地,鸦片制剂和本发明的化合物可以在不同时间递送,如阿片样物质在本发明的化合物之前,或本发明的化合物之后递送。鸦片制剂和本发明的化合物可以以交替施用递送。本发明的化合物和/或鸦片制剂可以在一周、两周、三周、四周、一个月、两个月、三个月、四个月、五个月、六个月、七个月、八个月、九个月、十个月、十一个月、一年、两年或三年的时期内递送。鸦片制剂和/或本发明的化合物可以通过连续输注,如通过植入的泵递送。
在另一实施方案中,预防或治疗阿片样物质依赖性(即在接受鸦片制剂的受试者中戒除(withdrawal))的方法,所述方法包括向受试者施用足以治疗阿片样物质戒除的一种或多种症状的本发明的化合物的量。所述阿片样物质可以是吗啡、氧可酮、芬太尼、可卡因、海洛因或鸦片。受试者可以是人或非人哺乳动物。患者可以接受对疼痛,如慢性或急性疼痛的治疗。所述急性疼痛可以是损伤,如穿透伤、烧伤、冻伤或骨折的结果。所述慢性疼痛是疾病,如关节炎、自身免疫病或感染的结果。
本发明的化合物可以在开始戒除之前或开始戒除之后递送。本发明的化合物可以与减少剂量的鸦片制剂共同施用。本发明的化合物可以在开始鸦片制剂治疗之前递送。本发明的化合物可以在不再向受试者施用鸦片制剂之后递送达一段时期。本发明的化合物可以在不再向受试者施用鸦片制剂之后的一周、两周、三周、四周、一个月、两个月、三个月、四个月、五个月或六个月的时期内递送。鸦片制剂和/或本发明的化合物可以通过连续输注,如通过植入的泵递送。
所述受试者可以是合法或非法获得的鸦片制剂的滥用者。所述一种或多种症状可以包括兴奋(agitation)、焦虑(anxiety)、肌肉疼痛(muscle ache)、增加流泪(increasedtearing)、失眠(insomnia)、流鼻水(runny nose)、出汗(sweating)和打哈欠(yawning),而戒除的晚期症状包括腹绞痛(abdominal cramping)、腹泻(diarrhea)、瞳孔散大(dilatedpupils)、鸡皮疙瘩(goose bumps)、恶心和/或呕吐。所述方法还可以包括将受试者进行药物治疗程序,如美沙酮治疗或丁丙诺啡治疗。
腺苷参与介导慢性阿片样物质施用的不希望的副作用如依赖性和奖赏(reward)。例如,已经报道,慢性施用阿片类减少脑干中腺苷的胞外水平和其在A1AR处的信号传导,一种与依赖性/成瘾相关的现象;因此,A1AR激动剂或AdK抑制剂削弱纳洛酮-引起的阿片样物质戒除的行为证据,而A1AR拮抗剂恶化阿片样物质戒除效应。其他成瘾药物如安非他明(amphetamine)和可卡因(cocaine),像阿片类一样,已知调节CNS中的腺苷水平,其促进成瘾相关的病症的病理生理学;值得注意的是,CNS中神经胶质活化在它们的奖赏和依赖性方面发挥作用。然而,在这样的情况下,现有文献和科学焦点在A1AR和A2AR信号传导方面;关于A3AR的作用是未知的。已经报道,A3AR激动剂如IB-MECA阻断阿片样物质依赖性(在吗啡依赖性大鼠中纳洛酮-促进的戒除,美国专利申请号14/496,030)。已经证明,A3AR激动剂,如MRS5980,阻断阿片样物质-引起的超敏性和止痛剂耐受性。这些发现十分有意义,因为它们确立了在与滥用物质的药物相关的神经生物学通路中腺苷对A3AR系统的贡献,同时提升这样的感兴趣的可能性,即靶向A3AR轴可以产生解决与药物滥用相关的关键问题的深远机会。
在其他实施方案中,本发明的化合物与以下试剂联合施用,所述试剂如TNF-α抑制剂、IL-1β抑制剂、p38激酶抑制剂、ERK抑制剂、JNK抑制剂、转录因子如NF-κB的调节剂、调节神经胶质细胞功能的试剂、阻断腺苷激酶的表达和/或活性的试剂、重组外核苷酸酶、ENT抑制剂等。p38激酶抑制剂的非限制性实例包括PH-797804、BIRB 796、VX-702、SB 239063、SB202190、SCIO 469和BMS 582949。ERK抑制剂的实例是索拉非尼(sorafenib)。JNK抑制剂的实例是AM-111。NF-κB调节剂的非限制性实例包括双硫仑(戒酒硫,disulfiram)、奥美沙坦(olmesartan)、二硫代氨基甲酸酯(盐)和安那他品(anatabine)。
所述化合物或其盐可以以任何合适的剂量使用。合适的剂量和配药方案可以由常规测距(range finding)技术确定。通常治疗以小于最优剂量的较小剂量开始。之后,剂量以小的增量增加,直到达到在该情况下的最优效果。为了方便,如果需要,可以将总的日剂量分开并且在每日期间分部分施用。以某些化合物的适当剂量并且利用其合适施用,本发明提供宽范围的响应。典型地,剂量范围为约0.001至约1000mg/kg治疗动物的体重/日。例如,在实施方案中,所述化合物或盐可以以约100mg/kg至约300mg/kg,约120mg/kg至约280mg/kg,约140mg/kg至约260mg/kg,约150mg/kg至约250mg/kg,约160mg/kg至约240mg/kg的受试者体重/天施用,一天一次或多次,以获得所需的疗效。
以下实施例进一步举例说明本发明,但当然不应该任何方式被解释为限制其范围。
实施例1
该实施例举例说明根据本发明的实施方案的化合物的一些生物性质。
[3H]R-N6-苯基异丙基腺苷(40,[3H]R-PIA,63Ci/mmol)、[3H](2-[对-(2-羧基乙基)苯基-乙基氨基]-5′-N-乙基甲酰胺基-腺苷)(41,[3H]CGS21680,40.5Ci/mmol)和[125I]N6-(4-氨基-3-碘苄基)腺苷-5′-N-甲基糖酰胺(42,[125I]I-AB-MECA,2200Ci/mmol)购自Perkin-Elmer Life和Analytical Science(Boston,MA)。将测试化合物制备为在DMSO中的5mM储液并且冷冻储存。药理学标准物1b(A3AR激动剂)、腺苷-5’-N-乙基甲酰胺(43,NECA,非选择性AR激动剂)和2-氯-N6-环戊基腺苷(44,CCPA,A1AR激动剂)购自Tocris R&DSystems(Minneapolis,MN)。
细胞培养和膜制备-将稳定表达重组hA1和hA3AR的CHO细胞和稳定表达hA2AAR的HEK293细胞在补充以10%胎牛血清、100单位/mL青霉素、100μg/mL链霉素和2μmol/mL谷氨酰胺的Dulbecco改良的Eagle培养基(DMEM)和F12(1∶1)中培养。此外,向A2A培养基中加入800μg/mL遗传霉素(geneticin),而向A1和A3培养基中加入500μg/mL潮霉素(hygromycin)。收获后,将细胞匀化并悬浮在PBS中。然后将细胞在240g离心5min,并将团粒重悬在50mM含有10mM MgCl2的Tris-HCl缓冲液(pH 7.5)中。将悬浮液匀化并随后在4℃在14,330g超离心30分钟。将得到的团粒重悬在Tris缓冲液中,在37℃用腺苷脱氨酶(3单位/mL)温育30分钟。悬浮液用电匀化器匀化10秒,移液至1mL小瓶中随后在-80℃储存直到进行结合实验。使用来自Pierce Biotechnology,Inc.(Rockford,IL)27的BCA蛋白测定试剂盒测量蛋白浓度。
结合测定:在结合测定中,向各个管中加入50μL在含有10mM MgCl2的Tris-HCl缓冲液(50mM,pH 7.5)中的增加浓度的测试配体、50μL的适当激动剂放射性配体,以及最后100μL的膜悬浮液。对于A1AR(22μg的蛋白/管),使用的放射性配体是[3H]40(终浓度为3.5nM)。对于A2AAR(20μg/管),使用的放射性配体是[3H]41(10nM)。对于A3AR(21μg/管),使用的放射性配体是[125I]42(0.34nM)。使用用缓冲液稀释的终浓度为10μM的43来确定非特异结合。在振荡水浴中将混合物在25℃温育60分钟。使用M-24孔收获机(Brandel,Gaithersburg,MD),通过在减压下的Brandel GF/B滤器过滤来终止结合反应。将滤器用3mL的50mM冰冷的Tris-HCl缓冲液(pH 7.5)洗涤三次。将用于A1和A2AAR结合的滤器置于含有5mL Hydrofluor闪烁缓冲液的闪烁瓶中并使用Perkin Elmer液体闪烁分析仪(Tri-Carb2810TR)计数。使用Packard Cobra IIγ-计数器计数用于A3AR结合的滤器。对于所有测定,使用GraphPad Prism确定Ki值。
使用表达mAR的HEK293细胞膜进行类似的竞争性结合测定,其中使用[125I]42标记A1或A3AR并且使用[3H]41标记A2AAR。如所述的28,将IC50值转变为Ki值。在100μM 43的存在下确定非特异结合。
结果在表1-5中提供。
表1.AR激动剂和两种参照化合物(400,401)的结构和结合亲和力。
X=NHMe,除非另有说明。
b早期报道了化合物6和7(如在Tosh等人,J.Med.Chem.,2012,55:4847-4860中的化合物9和10)。
c人,其中小鼠数据通过(m)示出。
表2.N6-苯基环丙基(N)-桥亚甲基甲A3AR激动剂的结构和结合亲和力
表3.N6-甲基和N6-羟基苯乙烯基化合物的结构和结合亲和力
表4.N2-三唑基化合物的结构和结合亲和力
a在从稳定表达三种hAR亚型中的一种的CHO或HEK293(仅A2A)细胞制备的膜中的结合。对于hA1、A2A和A3AR的结合亲和力表示为Ki值(n=3-4),其中分别使用激动剂放射性配体[3H]N6-R-苯基异丙基腺苷65、[3H]2-[对-(2-羧基乙基)苯基-乙基氨基]-5′-N-乙基甲酰胺基-腺苷66或[125I]N6-(4-氨基-3-碘苄基)腺苷-5′-N-甲基-脲酰胺67测量。斜体的百分数表示在10μM的结合的抑制。使用68(在hAR为10μM,在mAR为100μM)确定非特异结合。
表5.N2-叠氮基和N2-碘化合物的结构和结合亲和力
实施例2
该实施例表明根据本发明的实施方案制备化合物的方法。
(1S,2R,3S,4R,5S)-2,3-二羟基-N-甲基-4-(6-(甲基氨基)-2-(嘧啶-2-基乙炔基)-9H-嘌呤-9-基)双环[3.1.0]己烷-1-甲酰胺(6)
将PdCl2(PPh3)2(6.08mg,0.02mmol)、CuI(1.0mg,0.005mmol)、2-乙炔基嘧啶(27.1mg,0.26mmol)和三乙胺(0.06mL,0.43mmol)加入至化合物53(21mg,0.04mmol)在无水DMF(1mL)中的溶液中,并且将混合物在室温搅拌过夜。将溶剂在真空下蒸发,并且将残留物在急骤硅胶柱色谱上粗略地纯化。将得到的化合物溶解在MeOH(2mL)和10%三氟乙酸(2mL)中并在70℃加热5h。将溶剂在真空下蒸发,并且将残留物在急骤硅胶柱色谱(CH2Cl2∶MeOH=25∶1)上纯化,得到化合物6(12.2mg,67%),为浆液。1H NMR(CD3OD,400MHz)δ8.86(d,J=5.2Hz,2H),8.14(s,1H),7.53(t,J=5.2Hz,1H),5.17(d,J=6.8Hz,1H),4.92(s,1H),4.6(d,J=6.4Hz,1H),3.14(br s,3H),2.86(s,3H),2.11-2.07(m,1H),1.84(t,J=5.2Hz,1H),1.42-1.39(m,1H)。对于C20H21N8O3(M+H)+的HRMS:计算值421.1737;实测值(found)421.1732。
(1S,2R,3S,4R,5S)-2,3-二羟基-N-甲基-4-(6-(甲基氨基)-2-(吡嗪-2-基乙炔基)-9H-嘌呤-9-基)双环[3.1.0]己烷-1-甲酰胺(7)
按照对于化合物6相同的方法,从化合物53制备化合物7(65%)。1H NMR(CD3OD,400MHz)δ8.92(s,1H),8.69(d,J=2.4Hz,1H),8.64(d,J=2.4Hz,1H),8.14(s,1H),5.12(d,J=5.2Hz,1H),4.89(s,1H),4.05(d,J=6.4Hz,1H),3.15(br s,3H),2.85(s,3H),2.12-2.08(m,1H),1.86(t,J=5.2Hz,1H),1.42-1.40(m,1H)。对于C20H21N8O3(M+H)+的HRMS:计算值421.1737;实测值421.1725。
(1S,2R,3S,4R,5S)-2,3-二羟基-N-甲基-4-(6-(甲基氨基)-2-(噻吩-2-基乙炔基)-9H-嘌呤-9-基)双环[3.1.0]己烷-1-甲酰胺(8)
按照与化合物6对于相同的方法,从化合物53制备化合物8(61%)。1H NMR(CD3OD,400MHz)δ8.10(s,1H),7.57(dd,J1=1.2,J2=4.0Hz,1H),7.50(dd,J1=1.2,J2=4.0Hz,1H),7.13(dd,J1=1.6,J2=3.6Hz,1H),5.05(d,J=6.4Hz,1H),4.88(s,1H),4.02(d,J=6.4Hz,1H),3.14(br s,3H),2.86(s,3H),2.13-2.09(m,1H),1.88(t,J=5.2Hz,1H),1.41-1.39(m,1H)。对于C20H21N6O3S(M+H)+的HRMS:计算值425.1396;实测值425.1388。
(1S,2R,3S,4R,5S)-4-(2-((1H-吡唑-3-基)乙炔基)-6-(甲基氨基)-9H-嘌呤-9-基)-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-甲酰胺(9)
按照与对于化合物6相同的方法,从化合物53制备化合物9(64%)。1H NMR(CD3OD,400MHz)δ8.10(s,1H),7.73(s,1H),6.66(s,1H),5.12(d,J=6.8Hz,1H),4.87(s,1H),4.04(d,J=6.8Hz,1H),3.13(br s,3H),2.85(s,3H),2.10-2.07(m,1H),1.85(t,J=4.8Hz,1H),1.41-1.38(m,1H)。对于C19H21N8O3(M+H)+的HRMS:计算值409.1737;实测值409.1731。
(1S,2R,3S,4R,5S)-2,3-二羟基-N-甲基-4-(6-(甲基氨基)-2-(哒嗪-3-基乙炔基)-9H-嘌呤-9-基)双环[3.1.0]己烷-1-甲酰胺(10)
按照与对于化合物6相同的方法,从化合物53制备化合物10(65%)。1H NMR(CD3OD,400MHz)δ9.23(d,J=3.2Hz,1H),8.15(s,1H),8.03(d,J=6.8Hz,1H),7.83-7.81(m,1H),5.14(d,J=5.2Hz,1H),4.90(s,1H),4.07(d,J=5.2Hz,1H),3.15(br s,3H),2.84(s,3H),2.11-2.08(m,1H),1.86(t,J=4.8Hz,1H),1.42-1.39(m,1H)。对于C20H21N8O3(M+H)+的HRMS:计算值421.1737;实测值421.1734。
(1S,2R,3S,4R,5S)-2,3-二羟基-4-(2-((4-甲氧基苯基)乙炔基)-6-(甲基氨基)-9H-嘌呤-9-基)-N-甲基双环[3.1.0]己烷-1-甲酰胺(11)
按照与对于化合物6相同的方法,从化合物53制备化合物11(68%)。1H NMR(CD3OD,400MHz)δ8.08(s,1H),7.60(d,J=9.2Hz,1H),7.01(d,J=9.2Hz,1H),5.05(d,J=5.2Hz,1H),4.91(s,1H),4.02(d,J=6.0Hz,1H),3.86(s,3H),3.15(br s,3H),2.85(s,3H),2.13-2.09(m,1H),1.88(t,J=5.2Hz,1H),1.41-1.39(m,1H)。对于C23H25N6O4(M+H)+的HRMS:计算值449.1937;实测值449.1944。
(1S,2R,3S,4R,5S)-2,3-二羟基-4-(2-((3-甲氧基苯基)乙炔基)-6-(甲基氨基)-9H-嘌呤-9-基)-N-甲基双环[3.1.0]己烷-1-甲酰胺(12)
按照与对于化合物6相同的方法,从化合物53制备化合物12(69%)。1H NMR(CD3OD,400MIHz)δ8.10(s,1H),7.35(t,J=6.0Hz,1H),7.24-7.21(m,2H),7.02(d,J=8.4Hz,1H),5.06(d,J=6.8Hz,1H),4.92(s,1H),4.02(d,J=6.4Hz,1H),3.85(s,3H),3.15(br s,3H),2.84(s,3H),2.13-2.09(m,1H),1.88(t,J=4.4Hz,1H),1.41-1.38(m,1H)。对于C23H25N6O4(M+H)+的HRMS:计算值449.1937;实测值449.1944。
(1S,2R,3S,4R,5S)-2,3-二羟基-4-(2-((2-甲氧基苯基)乙炔基)-6-(甲基氨基)-9H-嘌呤-9-基)-N-甲基双环[3.1.0]己烷-1-甲酰胺(13)
按照与对于化合物6相同的方法,从化合物53制备化合物13(69%)。1H NMR(CD3OD,600MHz)δ8.10(s,1H),7.59(d,J=6.0Hz,1H),7.45(t,J=7.2Hz,1H),7.10(d,J=8.4Hz,1H),7.01(t,J=7.2Hz,1H),5.15(d,J=6.0Hz,1H),4.90(s,1H),4.04(d,J=6.0Hz,1H),3.96(s,3H),3.15(br s,3H),2.82(s,3H),2.09-2.07(m,1H),1.86(t,J=4.8Hz,1H),1.43-1.41(m,1H)。对于C23H25N6O4(M+H)+的HRMS:计算值449.1937;实测值449.1932。
(1S,2S,3R,4R,5S)-2,3-二羟基-N-甲基-4-(6-(甲基氨基)-2-((3-(三氟甲基)苯基)乙炔基)-9H-嘌呤-9-基)双环[3.1.0]己烷-1-甲酰胺(14)
按照与对于化合物6相同的方法,从化合物53制备化合物14(70%)。1H NMR(CD3OD,400MHz)δ8.14(s,1H),7.97(s,1H),7.92(d,J=7.6Hz,1H),7.78(d,J=7.6Hz,1H),7.68(t,J=8.0Hz,1H),5.08(d,J=4.8Hz,1H),4.90(s,1H),4.04(d,J=5.2Hz,1H),3.15(br s,3H),2.84(s,3H),2.13-2.10(m,1H),1.88(t,J=5.2Hz,1H),1.42-1.39(m,1H)。
对于C23H22N6O3F3(M+H)+的HRMS:计算值487.1705;实测值487.1716。
(1S,2R,3S,4R,5S)-2,3-二羟基-N-甲基-4-(6-(甲基氨基)-2-(吡啶-3-基乙炔基)-9H-嘌呤-9-基)双环[3.1.0]己烷-1-甲酰胺(15)
按照与对于化合物6相同的方法,从化合物53制备化合物15(60%)。1H NMR(CD3OD,400MHz)δ8.87(s,1H),8.64(s,1H),8.18(d,J=6.4Hz,1H),8.15(s,1H),7.61-7.58(m,1H),5.05(d,J=5.2Hz,1H),4.90(s,1H),4.02(d,J=5.2Hz,1H),3.13(br s,3H),2.82(s,3H),2.11-2.09(m,1H),1.87(t,J=4.0Hz,1H),1.40-1.37(m,1H)。对于C21H22N7O3(M+H)+的HRMS:计算值420.1784;实测值420.1785。
(1S,2R,3S,4R,5S)-2,3-二羟基-N-甲基-4-(6-(甲基氨基)-2-(噻吩-3-基乙炔基)-9H-嘌呤-9-基)双环[3.1.0]己烷-1-甲酰胺(16)
按照与对于化合物6相同的方法,从化合物53制备化合物16(59%)。1H NMR(CD3OD,400MHz)δ8.13(s,1H),7.88(dd,J1=1.2,J2=2.0Hz,1H),7.54(dd,J1=2.0,J2=3.2Hz,1H),7.33(dd,J1=1.2,J2=4.0Hz,1H),5.07(d,J=5.2Hz,1H),4.89(s,1H),4.04(d,J=5.2Hz,1H),3.15(br s,3H),2.85(s,3H),2.13-2.09(m,1H),1.87(t,J=4.8Hz,1H),1.42-1.39(m,1H)。对于C20H21N6O3S(M+H)+的HRMS:计算值425.1396;实测值425.1403。
(1S,2R,3S,4R,5S)-4-(2-(呋喃-2-基乙炔基)-6-(甲基氨基)-9H-嘌呤-9-基)-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-甲酰胺(17)
按照与对于化合物6相同的方法,从化合物53制备化合物17(58%)。1H NMR(CD3OD,400MHz)δ8.16(s,1H),7.66(d,J=1.2Hz,1H),6.95(d,J=2.8Hz,1H),6.58(dd,J1=1.6,J2=2.0Hz,1H),5.07(d,J=5.2Hz,1H),4.89(s,1H),4.03(d,J=6.4Hz,1H),3.14(br s,3H)2.87(s,3H),2.11-2.09(m,1H),1.86(t,J=4.8Hz,1H),1.41-1.40(m,1H)。对于C20H21N6O4(M+H)+的HRMS:计算值409.1624;实测值409.1611。
(1S,2R,3S,4R,5S)-2,3-二羟基-N-甲基-4-(2-((1-甲基-1H-吡唑-4-基)乙炔基)-6-(甲基氨基)-9H-嘌呤-9-基)双环[3.1.0]己烷-1-甲酰胺(18)
按照与对于化合物6相同的方法,从化合物53制备化合物18(63%)。1H NMR(CD3OD,400MHz)δ8.08(s,1H),7.98(s,1H),7.75(s,1H),5.05(d,J=5.6Hz,1H),4.88(s,1H),4.02(d,J=6.4Hz,1H),3.94(s,3H),3.13(br s,3H),2.86(d,J=4.4Hz,1H),2.12-2.08(m,1H),1.87(t,J=4.8Hz,1H),1.41-1.37(m,1H)。对于C20H23N8O3(M+H)+的HRMS:计算值423.1888;实测值423.1888。
(1S,2R,3S,4R,5S)-4-(2-(环己基乙炔基)-6-(甲基氨基)-9H-嘌呤-9-基)-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-甲酰胺(19)
按照与对于化合物6相同的方法,从化合物53制备化合物7(71%)。1H NMR(CD3OD,400MHz)δ8.06(s,1H),4.98(d,J=6.8Hz,1H),4.85(s,1H),3.95(d,J=6.4Hz,1H),3.11(brs,3H)2.86(s,3H),2.86-2.62(m,1H),2.11-2.08(m,1H),1.99-1.96(m,2H),1.89(t,J=4.8Hz,1H),1.84-1.80(m,2H),1.63-1.58(m,3H),1.43-1.39(m,4H)。对于C22H29N6O3(M+H)+的HRMS:计算值425.2301;实测值425.2308。
(1S,2R,3S,4R,5S)-4-(2-(环丙基乙炔基)-6-(甲基氨基)-9H-嘌呤-9-基)-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-甲酰胺(20)
按照与对于化合物6相同的方法,从化合物53制备化合物7(68%)。1H NMR(CD3OD,400MHz)δ8.06(s,1H),5.02(d,J=6.0Hz,1H),4.83(s,1H),3.97(d,J=6.4Hz,1H),3.10(brs,3H),2.88(s,3H),2.10-2.07(m,1H),1.86(t,J=4.8Hz,1H),1.59-1.52(m,1H),1.40-1.37(m,1H),1.00-0.98(m,2H),0.94-0.86(m,2H)。对于C19H23N6O3(M+H)+的HRMS:计算值383.1832;实测值383.1838。
(1S,2R,3S,4R,5S)-4-(2-((4,5-二甲基呋喃-2-基)乙炔基)-6-(甲基氨基)-9H-嘌呤-9-基)-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-甲酰胺(29)
按照与对于化合物37相同的方法,从化合物53制备化合物29(63%)。1H NMR(CD3OD,400MHz)δ8.09(s,1H),6.69(s,1H),5.06(d,J=6.4Hz,1H),4.85(s,1H),4.01(d,J=6.4Hz,1H),3.12(br s,3H),2.87(s,3H),2.26(s,3H),2.12-2.08(m,1H),1.99(s,3H),1.85(t,J=4.8Hz,1H),1.40-1.38(m,1H)。对于C22H25N6O4(M+H)+的HRMS:计算值437.1932;实测值437.1934。
(1S,2R,3S,4R,5S)-2,3-二羟基-N-甲基-4-(6-(甲基氨基)-2-(吡啶-4-基乙炔基)-9H-嘌呤-9-基)双环[3.1.0]己烷-1-甲酰胺(30)
按照与对于化合物6相同的方法,从化合物53制备化合物30(63%)。1H NMR(CD3OD,400MHz)δ8.63(d,J=6.0Hz,2H),8.14(s,1H),7.65(d,J=6.0Hz,1H),5.06(d,J=6.0Hz,1H),4.90(s,1H),4.03(d,J=6.8Hz,1H),3.14(br s,3H),2.13-2.10(m,1H),1.88(d,J=4.8Hz,1H),1.42-1.40(m,1H)。对于C21H22N7O3(M+H)+的HRMS:计算值420.1784;实测值420.1786。
(1S,2R,3S,4R,5S)-2,3-二羟基-4-(2-((4-(羟基甲基)苯基)乙炔基)-6-(甲基氨基)-9H-嘌呤-9-基)-N-甲基双环[3.1.0]己烷-1-甲酰胺(31)
按照与对于化合物6相同的方法,从化合物53制备化合物31(66%)。1H NMR(CD3OD,400MHz)δ8.13(s,1H),7.63(d,J=8.0Hz,2H),7.43(d,J=8.0Hz,2H),5.06(d,J=6.4Hz,1H),4.89(s,1H),4.67(s,2H),4.02(d,J=6.4Hz,1H),3.15(br s,3H),2.84(s,3H),2.13-2.09(m,1H),1.88(d,J=4.8Hz,1H),1.41-1.39(m,1H)。对于C23H25N6O4(M+H)+的HRMS:计算值449.1937;实测值449.1942。
(1S,2R,3S,4R,5S)-4-(2-((5-氯噻吩-2-基)乙炔基)-6-(甲基氨基)-9H-嘌呤-9-基)-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-甲酰胺(32)
按照与对于化合物6相同的方法,从化合物53制备化合物32(59%)。1H NMR(CD3OD,400MHz)δ8.11(s,1H),7.31(d,J=4.0Hz,1H),7.03(d,J=4.0Hz,1H),5.04(d,J=7.2Hz,1H),4.86(s,1H),4.01(d,J=6.8Hz,1H),3.13(br s,3H),2.86(s,3H),2.12-2.09(m,1H),1.88(d,J=4.8Hz,1H),1.41-1.38(m,1H)。对于C20H20N6O3SCl(M+H)+的HRMS:计算值459.1006;实测值459.1005。
(1S,2R,3S,4R,5S)-4-(2-(苯并呋喃-2-基乙炔基)-6-(甲基氨基)-9H-嘌呤-9-基)-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-甲酰胺(33)
按照与对于化合物6相同的方法,从化合物53制备化合物33(62%)。1H NMR(CD3OD,400MHz)δ8.12(s,1H),7.67(d,J=7.6Hz,1H),7.5(d,J=7.6Hz,1H),7.43(t,J=6.0Hz,1H),7.33-7.31(m,2H),5.11(d,J=5.2Hz,1H),4.89(s,1H),4.04(d,J=6.4Hz,1H),3.15(br s,3H),2.89(s,3H),2.13-2.10(m,1H),1.87(t,J=4.8Hz,1H),1.42-1.39(m,1H)。对于C24H23N6O4(M+H)+的HRMS:计算值459.1775;实测值459.1777。
(1S,2R,3S,4R,5S)-4-(2-((5-乙基呋喃-2-基)乙炔基)-6-(甲基氨基)-9H-嘌呤-9-基)-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-甲酰胺(34)
按照与对于化合物6相同的方法,从化合物53制备化合物34(53%)。1H NMR(CD3OD,400MHz)δ8.11(s,1H),6.82(d,J=7.2Hz,1H),6.18(d,J=7.6Hz,1H),5.08(d,J=6.4Hz,1H),4.93(s,1H),4.02(d,J=6.4Hz,1H),3.14(br s,3H),2.75-2.69(m,2H),2.11-2.08(m,1H),1.86(t,J=5.2Hz,1H),1.41-1.38(m,1H),1.29(t,J=7.6Hz,3H)。对于C22H25N6O4(M+H)+的HRMS:计算值437.1932;实测值437.1932。
(1S,2R,3S,4R,5S)-4-(2-((5-溴噻吩-2-基)乙炔基0-6-(甲基氨基)-9H-嘌呤-9-基)-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-甲酰胺(100)
按照与对于化合物6相同的方法,从化合物53制备化合物100(48%)。1H NMR(CD3OD,400MHz)δ8.10(s,1H),7.28(d,J=4.0Hz,1H),7.15(d,J=4.0Hz,1H),5.05(d,J=5.2Hz,1H),4.91(s,1H),4.02(d,J=5.6Hz,1H),3.14(br s,3H),2.86(s,3H),2.12-2.09(m,1H),1.88(t,J=4.8Hz,1H),1.41-1.37(m,1H)。对于C20H20N6O3SBr(M+H)+理论值HRMS;503.0495;实测值503.0498。
(1S,2S,3R,4R,5S)-2,3-二羟基-N-甲基-4-(6-(甲基氨基)-2-(噻唑-2-基乙炔基)-9H-嘌呤-9-基)双环[3.1.0]己烷-1-甲酰胺(101)
按照与对于化合物6相同的方法,从化合物53制备化合物101(64%)。1H NMR(CD3OD,400MHz)δ8.18(s,1H),7.97(d,J=3.2Hz,1H),7.82(d,J=3.2Hz,1H),5.12(d,J=5.2Hz,1H),4.90(s,1H),4.04(d,J=6.4Hz,1H),3.14(br s,3H),2.86(s,3H),2.11-2.07(m,1H),1.86(t,J=4.8Hz,1H),1.42-1.38(m,1H)。对于C19H20N7O3S(M+H)+理论值HRMS;426.1343;实测值426.1342。
(1S,2R,3S,4R,5S)-4-(2-((1H-吡咯-2-基)乙炔基)-6-(甲基氨基)-9H-嘌呤-9-基)-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-甲酰胺(35)
(1S,2R,3S,4R,5S)-2,3-二羟基-4-(2-((5-羟基吡啶-3-基)乙炔基)-6-(甲基氨基)-9H-嘌呤-9-基)-N-甲基双环[3.1.0]己烷-1-甲酰胺(36)
(1S,2R,3S,4R,5S)-4-(2-((二茂铁-基)乙炔基)-6-(甲基氨基)-9H-嘌呤-9-基)-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-甲酰胺(37)
将化合物53(31mg,0.06mmol)在甲醇(3mL)和10%三氟甲磺酸(2mL)中的溶液在70℃加热5h。将溶剂在真空下蒸发,并将残留物在急骤硅胶柱色谱(CH2Cl2∶MeOH=25∶1)上纯化,得到亚异丙基-脱封端衍生物(deblocked derivative)(27mg,95%),为浆液。将PdCl2(PPh3)2(8.5mg,0.012mmol)、CuI(1.1mg,0.006mmol)、乙炔基二茂铁(76.6mg,0.36mmol)和三乙胺(0.08mL,0.6mmol)加入至获得的化合物(27mg,0.06mmol)在无水DMF(1.2mL)中的溶液,并且将混合物在室温搅拌过夜。将溶剂在真空下蒸发,并且将残留物在急骤硅胶柱色谱(CH2Cl2∶MeOH=30∶1)上纯化,得到化合物37(29mg,86%),为浅黄色浆液。1H NMR(CD3OD,400MHz)δ8.10(s,1H),5.01(d,J=6.4Hz,1H),4.89(s,1H),4.63(s,2H),4.40(s,2H),4.31(s,6H),4.01(d,J=6.4Hz,1H),3.15(br s,3H),2.88(s,3H),2.13-2.10(m,1H),1.91(t,J=4.8Hz,1H),1.42-1.38(m,1H)。对于C26H27N6O3Fe(M+H)+的HRMS:计算值527.1489;实测值527.1489。
(3aS,3bS,4aS,5R,5aR)-5-(2-碘-6-((2-苯基环丙基)氨基)-9H-嘌呤-9-基)-2,2-二甲基四氢环丙基(dimethyltetrahydrocyclopropa)[3,4]环戊二烯并[1,2-d][1,3]间二氧杂环戊烯-3b(3aH)-甲酸乙酯(55a)
将2-苯基环丙烷-1-胺(152mg,0.90mmol)和三乙胺(0.35mL,1.8mmol)加入至化合物52(91mg,0.18mmol)在无水甲醇(3mL)中的溶液并且将混合物在室温搅拌过夜。将溶剂在真空下蒸发,并且将残留物在急骤硅胶柱色谱(己烷∶乙酸乙酯=1∶1)上纯化,得到化合物55a(82mg,76%),为浆液。1H NMR(CD3OD,400MHz)δ7.96(s,1H),7.36-7.28(m,3H),7.19(t,J=7.2Hz,2H),5.84(d,J=6.4Hz,1H),4.9(s,1H),4.81(d,J=6.4Hz,1H),4.31-4.27(m,2H),2.72-2.67(m,1H),2.26-2.22(m,1H),2.17-2.13(m,1H),1.65-1.61(m,1H),1.53-1.48(m,4H),1.36-1.33(m,3H),1.27(s,3H),0.85-0.84(m,1H)。对于C26H29N5O4I(M+H)+的HRMS:计算值602.1264;实测值602.1282。
(3aS,3bS,4aS,5R,5aR)-5-(2-碘-6-((2-(间甲苯基)环丙基)氨基)-9H-嘌呤-9-基)-2,2-二甲基四氢环丙基[3,4]环戊二烯并[1,2-d][1,3]间二氧杂环戊烯-3b(3aH)-甲酸乙酯(55b)
按照与对于化合物55a相同的方法,从化合物52制备化合物55b(73%)。1H NMR(CD3OD,400MHz)δ7.96(s,1H),7.24(s,1H),7.19-7.12(m,2H),7.02(d,J=7.2Hz,1H),5.84(d,J=7.2Hz,1H),4.95(s,1H),4.82(d,J=6.8Hz,1H),4.31-4.27(m,2H),2.36(s,3H),2.26-2.22(m,1H),2.16-2.05(m,1H),1.65-1.62(m,1H),1.53-1.50(m,4H),1.36-1.33(m,4H),1.29-1.23(m,4H)。对于C27H31N5O4I(M+H)+的HRMS:计算值616.1415;实测值616.1413。
(3aS,3bS,4aS,5R,5aR)-5-(6-((2-(3-氟苯基)环丙基)氨基)-2-碘-9H-嘌呤-9-基)-2,2-二甲基四氢环丙基[3,4]环戊二烯并[1,2-d][1,3]间二氧杂环戊烯-3b(3aH)-甲酸乙酯(55c)
按照与对于化合物55a相同的方法,从化合物52制备化合物55c(70%)。1H NMR(CD3OD,400MHz)δ7.97(s,1H),7.33-7.28(m,1H),7.19-7.18(m,2H),6.95-6.90(m,1H),5.84(d,J=6.8Hz,1H),4.95(s,1H),4.83-4.82(m,1H),4.29-4.26(m,2H),3.01(br s,1H),2.26-2.22(m,1H),2.18-2.12(m,1H),1.65-1.62(m,1H),1.53-1.49(m,4H),1.42-1.32(m,4H),1.31-1.23(m,4H)。对于C26H28N5O4IF(M+H)+的HRMS:计算值620.1170;实测值620.1184。
(3aS,3bS,4aS,5R,5aR)-5-(6-((2-(3-氯苯基)环丙基)氨基)-2-碘-9H-嘌呤-9-基)-2,2-二甲基四氢环丙基[3,4]环戊二烯并[1,2-d][1,3]间二氧杂环戊烯-3b(3aH)-甲酸乙酯(55d)
按照与化合物55a对于相同的方法,从化合物52制备化合物55d(79%)。1H NMR(CD3OD,400MHz)δ7.96(s,1H),7.43(s,1H),7.30-7.19(m,3H),5.84(d,J=6.4Hz,1H),4.95(s,1H),4.83-4.80(m,1H),4.34-4.33(m,2H),2.98(br s,1H),2.26-2.21(m,1H),2.15-2.11(m,1H),1.65-1.61(m,1H),1.53-1.48(m,4H),1.41-1.35(m,5H),1.29(s,3H)。对于C26H28N5O4ICl(M+H)+的HRMS:计算值636.087;实测值636.087。
(3aS,3bS,4aS,5R,5aR)-5-(6-((2-(3-溴苯基)环丙基)氨基)-2-碘-9H-嘌呤-9-基)-2,2-二甲基四氢环丙基[3,4]环戊二烯并[1,2-d][1,3]间二氧杂环戊烯-3b(3aH)-甲酸乙酯(55e)
按照与对于化合物55a相同的方法,从化合物52制备化合物55e(82%)。1H NMR(CD3OD,400MHz)δ7.97(s,1H),7.62(s,1H),7.36(d,J=7.6Hz,2H),7.22(d,J=7.6Hz,1H),5.84(d,J=7.2Hz,1H),4.95(s,1H),4.83-4.82(m,1H),4.34-4.25(m,2H),3.03(br s,1H),2.26-2.22(m,1H),2.13-2.11(m,1H),1.65-1.62(m,1H),1.53-1.50(m,4H),1.40-1.33(m,5H),1.28(s,3H)。对于C26H28N5O4IBr(M+H)+的HRMS:计算值680.0364;实测值680.0362。
(3aS,3bS,4aS,5R,5aR)-5-(6-((2-(3,4-二氟苯基)环丙基)氨基)-2-碘-9H-嘌呤-9-基)-2,2-二甲基四氢环丙基[3,4]环戊二烯并[1,2-d][1,3]间二氧杂环戊烯-3b(3aH)-甲酸乙酯(55f)
按照与对于化合物55a相同的方法,从化合物52制备化合物55f(73%)。1H NMR(CD3OD,400MHz)δ7.97(s,1H),7.41(s,1H),7.21-7.16(m,2H),5.84(d,J=7.2Hz,1H),4.96(s,1H),4.84-4.80(m,1H),4.34-4.31(m,2H),2.92(br s,1H),2.26-2.21(m,1H),2.15-2.06(m,1H),1.65-1.62(m,1H),1.53-1.50(m,4H),1.41-1.32(m,5H),1.29s,3H)。对于C26H27N5O4IF2(M+H)+的HRMS:计算值638.1116;实测值638.1100。
(3aS,3bS,4aS,5R,5aR)-5-(2-碘-6-((2-苯基环丙基)氨基)-9H-嘌呤-9-基)-N,2,2-三甲基四氢环丙基[3,4]环戊二烯并[1,2-d][1,3]间二氧杂环戊烯-3b(3aH)-甲酰胺(56a)
将甲基胺溶液(40%水溶液,2mL)加入至化合物55a(40mg,0.066mmol)在甲醇(2mL)中的溶液中并且将混合物在室温搅拌过夜。将溶剂在真空下蒸发,并且将残留物在急骤硅胶柱色谱(CH2Cl2∶MeOH=40∶1)上纯化,得到化合物56a(28mg,71%),为浆液。1H NMR(CD3OD,400MHz)δ7.98(s,1H),7.41-7.36(m,2H),7.30(t,J=7.2Hz,1H),7.19(t,J=7.2Hz,1H),5.73(d,J=6.8Hz,1H),4.94(s,1H),4.85-4.84(m,1H),3.03(br s,1H),2.91(s,3H),2.15-2.11(m,2H),1.54-1.50(m,4H),1.41-1.36(m,2H),1.35-1.26(m,4H)。对于C25H28N6O3I(M+H)+的HRMS:计算值587.1268;实测值587.1287。
(3aS,3bS,4aS,5R,5aR)-5-(2-碘-6-((2-(间甲苯基)环丙基)氨基)-9H-嘌呤-9-基)-N,2,2-三甲基四氢环丙基[3,4]环戊二烯并[1,2-d][1,3]间二氧杂环戊烯-3b(3aH)-甲酰胺(56b)
按照与对于化合物56a相同的方法,从化合物55b制备化合物56b(65%)。1HNMR(CD3OD,400MHz)δ7.98(s,1H),7.25(s,1H),7.18-7.11(m,2H),7.00(d,J=7.2Hz,1H),5.73(d,J=7.2Hz,1H),4.94(s,1H),4.84-4.83(m,1H),3.07(br s,1H),2.90(d,J=1.6Hz,1H),2.36(s,H),2.15-2.10(m,2H),1.54-1.50(m,4H),1.41-1.32(m,2H),1.30-1.28(m,4H)。对于C25H28N6O3I(M+H)+的HRMS:计算值601.1419;实测值601.1418。
(3aS,3bS,4aS,5R,5aR)-5-(6-((2-(3-氟苯基)环丙基)氨基)-2-碘-9H-嘌呤-9-基)-N,2,2-三甲基四氢环丙基[3,4]环戊二烯并[1,2-d][1,3]间二氧杂环戊烯-3b(3aH)-甲酰胺(56c)
按照与对于化合物56a相同的方法,从化合物55c制备化合物56c(73%)。1H NMR(CD3OD,400MHz)δ7.98(s,1H),7.33-7.27(m,1H),7.21-7.17(m,2H),6.94-6.89(m,1H),5.73(d,J=7.2Hz,1H),4.94(s,1H),4.86-4.84(m,1H),3.01(br s,1H),2.90(d,J=2.0Hz,3H),2.16-2.11(m,2H),1.54-1.50(m,4H),1.41-1.34(m,3H),1.29(s,3H)。对于C25H27N6O3IF(M+H)+的HRMS:计算值605.1168;实测值605.1169。
(3aS,3bS,4aS,5R,5aR)-5-(6-((2-(3-氯苯基)环丙基)氨基)-2-碘-9H-嘌呤-9-基)-N,2,2-三甲基四氢环丙基[3,4]环戊二烯并[1,2-d][1,3]间二氧杂环戊烯-3b(3aH)-甲酰胺(56d)
按照与对于化合物56a相同的方法,从化合物55d制备化合物56d(76%)。1H NMR(CD3OD,400MHz)δ7.98(s,1H),7.45(s,1H),7.29-7.18(m,3H),5.72(d,J=7.2Hz,1H),4.94(s,1H),4.87-4.83(m,1H),3.01(br s,1H),2.90(s,3H),2.15-2.11(m,2H),1.54-1.50(m,4H),1.41-1.37(m,3H),1.31(s,3H)。对于C25H27N6O3ICl(M+H)+的HRMS:计算值621.0870;实测值621.0872。
(3aS,3bS,4aS,5R,5aR)-5-(6-((2-(3-溴苯基)环丙基)氨基)-2-碘-9H-嘌呤-9-基)-N,2,2-三甲基四氢环丙基[3,4]环戊二烯并[1,2-d][1,3]间二氧杂环戊烯-3b(3aH)-甲酰胺(56e)
按照与对于化合物56a相同的方法,从化合物55e制备化合物56e(65%)。1H NMR(CD3OD,400MHz)δ7.98(s,1H),7.61(s,1H),7.36-7.34(m,2H),7.22(t,J=7.8Hz,1H),5.72(d,J=7.2Hz,1H),4.94(s,1H),4.85-4.83(m,1H),2.96(br s,1H),2.90(s,3H),2.14-2.12(m,2H),1.54-1.50(m,4H),1.41-1.34(m,3H),1.29(s,3H)。对于C25H27N6O3IBr(M+H)+的HRMS:计算值665.0373;实测值665.0366。
(3aS,3bS,4aS,5R,5aR)-5-(6-((2-(3,4-二氟苯基)环丙基)氨基)-2-碘-9H-嘌呤-9-基)-N,2,2-三甲基四氢环丙基[3,4]环戊二烯并[1,2-d][1,3]间二氧杂环戊烯-3b(3aH)-甲酰胺(56f)
按照与对于化合物56a相同的方法,从化合物55f制备化合物56f(65%)。1H NMR(CD3OD,400MHz)δ7.99(s,1H),7.41(s,1H),7.20-7.16(m,2H),5.73(d,J=7.2Hz,1H),4.94(s,1H),4.84(d,J=7.2Hz,1H),2.90(s,3H),2.17-2.10(m,2H),1.54-1.50(m,4H),1.41-1.33(m,3H),1.30(s,3H)。对于C25H26N6O3IF2(M+H)+的HRMS:计算值623.1119;实测值623.1100。
(3aS,3bS,4aS,5R,5aR)-N,2,2-三甲基-5-(6-((2-苯基环丙基)氨基)-2-(苯基乙炔基)-9H-嘌呤-9-基)四氢环丙基[3,4]环戊二烯并[1,2-d][1,3]间二氧杂环戊烯-3b(3aH)-甲酰胺(57a)
将PdCl2(PPh3)2(3.8mg,0.005mmol)、CuI(1.0mg,0.005mmol)、苯基乙炔(18μL,0.16mmol)和三乙胺(40μL,0.6mmol)加入至化合物56a(27mg,0.06mmol)在无水DMF(1.0mL)中的溶液中,并且将混合物在室温搅拌过夜。将溶剂在真空下蒸发,并且将残留物通过急骤硅胶柱色谱(CH2Cl2∶MeOH=35∶1)纯化,得到化合物57a(12mg,77%),为浆液。1H NMR(CD3OD,400MHz)δ8.01(s,1H),7.70-7.68(m,2H),7.49-7.45(m,4H),7.36-7.35(m,2H),7.31-7.25(m,2H),5.81(d,J=7.2Hz,1H),5.04(s,1H),2.80(s,3H),2.24-2.14(m,2H),1.57-1.54(m,4H),1.44-1.41(m,2H),1.38-1.27(m,4H)。对于C33H33N6O3(M+H)+的HRMS:计算值561.2614;实测值561.2615。
(3aS,3bS,4aS,5R,5aR)-5-(6-((2-(3-氯苯基)环丙基)氨基)-2-(苯基乙炔基)-9H-嘌呤-9-基)-N,2,2-三甲基四氢环丙基[3,4]环戊二烯并[1,2-d][1,3]间二氧杂环戊烯-3b(3aH)-甲酰胺(57d)
按照与对于化合物57a相同的方法,从化合物56d制备化合物57d(80%)。1H NMR(CD3OD,400MHz)δ8.02(s,1H),7.76-7.65(m,2H),7.67-7.44(m,4H),7.32-7.18(m,3H),5.80(d,J=7.2Hz,1H),5.05(s,1H),3.19(br s,1H),2.78(s,3H),2.29-2.13(m,2H),1.61-1.54(m,4H),1.44-1.37(m,3H),1.31(s,3H)。对于C33H32N6O3Cl(M+H)+的HRMS:计算值595.2224;实测值595.2227。
(3aS,3bS,4aS,5R,5aR)-5-(6-((2-(3-溴苯基)环丙基)氨基)-2-(苯基乙炔基)-9H-嘌呤-9-基)-N,2,2-三甲基四氢环丙基[3,4]环戊二烯并[1,2-d][1,3]间二氧杂环戊烯-3b(3aH)-甲酰胺(57e)
按照与对于化合物57a相同的方法,从化合物56e制备化合物57e(78%)。1H NMR(CD3OD,400MHz)δ8.17(s,1H),7.70-7.67(m,2H),7.54(s,1H),7.46-7.44(m,3H),7.36-7.33(m,2H),7.22-7.17(m,1H),5.81(d,J=7.2Hz,1H),5.04(s,1H),3.20(br s,1H),2.78(s,3H),2.21-2.14(m,2H),1.57-1.46(m,4H),1.46-1.36(m,3H),1.31(s,1H)。对于C33H32N6O3Br(M+H)+的HRMS:计算值639.1719;实测值639.1730。
(3aS,3bS,4aS,5R,5aR)-5-(6-((2-(3,4-二氟苯基)环丙基)氨基)-2-(苯基乙炔基)-9H-嘌呤-9-基)-N,2,2-三甲基四氢环丙基[3,4]环戊二烯并[1,2-d][1,3]间二氧杂环戊烯-3b(3aH)-甲酰胺(57f)
按照与对于化合物57a相同的方法,从化合物56f制备化合物57f(80%)。1H NMR(CD3OD,400MHz)δ8.17(s,1H),7.70-7.68(m,2H),7.53-7.47(m,4H),7.18-7.13(m,2H),5.81(d,J=7.2Hz,1H),5.05(s,1H),3.10(br s,1H),2.79(s,3H),2.21-2.16(m,2H),1.59-1.53(m,4H),1.45-1.36(m,3H),1.31(s,3H)。对于HRMSC33H31N6O3F2(M+H)+理论值:597.2420;实测值597.2420。
(1S,2R,3S,4R,5S)-2,3-二羟基-N-甲基-4-(6-((2-苯基环丙基)氨基)-2-(苯基乙炔基)-9H-嘌呤-9-基)双环[3.1.0]己烷-1-甲酰胺(21)
将化合物57a(10mg,0.017mmol)在甲醇(2mL)和10%三氟甲磺酸(2mL)中的溶液在70℃加热5h。将溶剂在真空下蒸发,并且将残留物在急骤硅胶柱色谱(CH2Cl2∶MeOH=25∶1)上纯化,得到化合物21(8mg,87%),为浆液。1H NMR(CD3OD,400MHz)δ8.13(s,1H),7.65-7.63(m,2H),7.46(d,J=1.6Hz,3H),7.36(d,J=7.6Hz,2H),7.30-7.19(m,3H),5.07(d,J=6.0Hz,1H),4.9(s,1H),4.03(d,J=6.8Hz,1H),3.19(br s,1H),2.85(s,3H),2.25-2.20(m,1H),2.13-2.10(m,1H),1.88(t,J=4.8Hz,1H),1.45-1.39(m,2H),1.37-1.28(m,1H)。对于C30H29N6O3(M+H)+的HRMS:计算值521.2301;实测值521.2303。
(1S,2R,3S,4R,5S)-2,3-二羟基-N-甲基-4-(2-(苯基乙炔基)-6-((2-(间甲苯基)环丙基)氨基)-9H-嘌呤-9-基)双环[3.1.0]己烷-1-甲酰胺(22)
将PdCl2(PPh3)2(5.9mg,0.008mmol)、CuI(1.0mg,0.005mmol)、2-(间甲苯基)环丙烷-1-胺(27μL,0.25mmol)和三乙胺(60μL,0.43mmol)加入至化合物56b(25.2mg,0.041mmol)在无水DMF(1mL)中的溶液,并且将混合物在室温搅拌过夜。将溶剂在真空下蒸发,并且将残留物在急骤硅胶柱色谱上粗略地纯化。将得到的化合物溶解在MeOH(2mL)和10%三氟乙酸(2mL)中并且在70℃加热5h。将溶剂在真空下蒸发,并且将残留物在急骤硅胶柱色谱(CH2Cl2∶MeOH=25∶1)上纯化,得到化合物6(6.82mg,31%),为浆液。1H NMR(CD3OD,400MHz)δ8.12(s,1H),7.64-7.62(m,2H),7.47-7.44(m,3H),7.17-7.14(m,3H),7.01(d,J=6.8Hz,1H),5.07(d,J=6.8Hz,1H),4.90(s,1H),4.03(d,J=6.8Hz,1H),3.20(br s,1H),2.84(s,3H),2.30(s,3H),2.21-2.16(m,1H),2.13-2.10(m,1H),1.88(t,J=4.8Hz,1H),1.43-1.38(m,2H),1.32-1.28(m,1H)。对于C31H31N6O3(M+H)+的HRMS:计算值535.2458;实测值535.2462。
(1S,2R,3S,4R,5S)-4-(6-((2-(3-氟苯基)环丙基)氨基)-2-(苯基乙炔基)-9H-嘌呤-9-基)-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-甲酰胺(23)
按照与对于化合物22相同的方法,从化合物56c制备化合物23(62%)。1H NMR(CD3OD,400MHz)δ8.13(s,1H),7.68-7.62(m,2H),7.46-7.44(m,3H),7.31-7.26(m,1H),7.18-7.16(m,2H),6.95-6.90(m,1H),5.06(d,J=5.2Hz,1H),4.90(s,1H),4.03(d,J=6.0Hz,1H),3.15(br s,1H),2.26-2.21(m,1H),2.14-2.10(m,1H),1.88(t,J=4.8Hz,1H),1.47-1.39(m,3H)。对于C30H28N6O3F(M+H)+的HRMS:计算值539.2207;实测值539.2214。
(1S,2R,3S,4R,5S)-4-(6-((2-(3-氯苯基)环丙基)氨基)-2-(苯基乙炔基)-9H-嘌呤-9-基)-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-甲酰胺(24)
将化合物57d(34mg,0.057mmol)在甲醇(2mL)和10%三氟甲磺酸(2mL)中的溶液在70℃加热5h。将溶剂在真空下蒸发,并且将残留物在急骤硅胶柱色谱(CH2Cl2∶MeOH=30∶1)上纯化,得到化合物24(11mg,31%),为浆液,其在进一步用(CH2Cl2∶MeOH=15∶1)洗脱后,得到化合物28(6mg,25%),为浆液。对于化合物24的数据:1H NMR(CD3OD,400MHz)δ8.12(s,1H),7.78(d,J=4.0Hz,1H),7.64-7.62(m 2H),7.46-7.41(m,3H),7.31-7.19(m,3H),5.06(d,J=6.4Hz,1H),4.90(s,1H),4.03(d,J=6.8Hz,1H),3.15(br s,1H),2.84(d,J=4.4Hz,3H),2.21-2.19(m,1H),2.13-2.10(m,1H),1.88(t,J=4.8Hz,1H),1.44-1.39。对于C30H28N6O3Cl(M+H)+的HRMS:计算值555.1911;实测值555.1921。对于化合物28的数据:1HNMR(CD3OD,400MHz)δ8.19(s,1H),7.65-7.63(m,2H),7.46-7.44(m,3H),5.08(d,J=5.6Hz,1H),4.90(s,1H),4.04(d,J=6.4Hz,1H),2.84(s,3H),2.14-2.10(m,1H),1.88(t,J=4.8Hz,1H),1.42-1.40(m,1H)。对于C21H21N6O3(M+H)+的HRMS:计算值405.1675;实测值405.1668。
(1S,2R,3S,4R,5S)-4-(6-((2-(3-溴苯基)环丙基)氨基)-2-(苯基乙炔基)-9H-嘌呤-9-基)-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-甲酰胺(25)
按照与对于化合物21相同的方法,从化合物57e制备化合物25(66%)。1H NMR(CD3OD,400MHz)δ8.12(s,1H),7.64-7.62(m,2H),7.55(s,1H),7.45-7.43(m,3H),7.34(d,J=7.6Hz,2H),7.19(t,J=8.0Hz,1H),5.05(d,J=6.4Hz,1H),4.89(s,1H),4.02(d,J=6.8Hz,1H),3.18(br s,1H),2.84(s,3H),2.20-2.21(m,1H),2.13-2.10(m,1H),1.88(t,J=4.8Hz,1H),1.45-1.38(m,3H)。对于C30H28N6O3Br(M+H)+的HRMS:计算值599.1401;实测值599.1403。
(1S,2R,3S,4R,5S)-4-(6-((2-(3,4-二氟苯基)环丙基)氨基)-2-(苯基乙炔基)-9H-嘌呤-9-基)-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-甲酰胺(26)
按照与对于化合物21相同的方法,从化合物57f制备化合物26(59%)。1H NMR(CD3OD,400MHz)δ8.16(s,1H),7.66-7.64(m,2H),7.47-7.45(m,4H),7.18-7.13(m,2H),5.07(d,J=5.2Hz,1H),4.91(s,1H),4.04(d,J=6.8Hz,1H),3.14(br s,1H),2.22-2.18(m,1H),2.13-2.10(m,1H),1.89(t,J=4.8Hz,1H),1.43-1.37(m,3H)。对于C30H27N6O3F2(M+H)+的HRMS:计算值557.2107;实测值557.2109。
(1S,2R,3S,4R,5S)-4-(6-((2-(3,4-二氟苯基)环丙基)氨基)-2-(吡啶-2-基乙炔基)-9H-嘌呤-9-基)-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-甲酰胺(27)
按照与对于化合物22相同的方法,从化合物56f制备化合物27(64%)。1H NMR(CD3OD,400MHz)δ8.64(s,1H),8.17(s,1H),7.95(t,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),7.53-7.41(m,2H),7.19-7.14(m,2H),5.16(d,J=6.4Hz,1H),4.91(s,1H),4.06(d,J=6.8Hz,1H),3.18(s,1H),2.83(s,3H),2.18-2.15(m,1H),2.10-2.07(m,1H),1.85(t,J=4.8Hz,1H),1.42-1.36(m,2H),1.19-1.04(m,1H)。对于C29H26N7O3F2(M+H)+的HRMS:计算值558.2065;实测值558.2046。
(3aS,3bS,4aS,5R,5aR)-5-(2,6-双(苯基乙炔基)-9H-嘌呤-9-基)-2,2-二甲基四氢环丙基[3,4]环戊二烯并[1,2-d][1,3]间二氧杂环戊烯-3b(3aH)-甲酸乙酯(58a)
将PdCl2(PPh3)2(14mg,0.02mmol)、CuI(1.9mg,0.01mmol)、苯基乙炔(66μL,0.16mmol)和三乙胺(0.14mL,1.0mmol)加入至化合物52a(50.6mg,0.10mmol)在无水DMF(2.0mL)中的溶液中,并且将混合物在室温搅拌过夜。将溶剂在真空下蒸发,并且将残留物在急骤硅胶柱色谱(己烷∶乙酸乙酯=1∶1)上纯化,得到化合物58a(46mg,84%),为浆液。
1H NMR(CDCl3,400MHz)δ8.14(s,1H),7.77-7.75(m,4H),7.44-7.28(m,6H),5.96(d,J=7.2Hz,1H),5.08(s,1H),4.81(d,J=6.4Hz,1H),4.25-4.22(m,2H),2.32-2.29(m,1H),1.82-1.78(m,1H),1.60(s,3H),1.33(s,3H),1.29-1.26(m,1H),1.22(t,J=7.2Hz,3H)。对于C33H29N4O4(M+H)+的HRMS:计算值545.2189;实测值545.2197。
(3aS,3bS,4aS,5R,5aR)-5-(2,6-双((4-(叔丁基)苯基)乙炔基)-9H-嘌呤-9-基)-2,2-二甲基四氢环丙基[3,4]环戊二烯并[1,2-d][1,3]间二氧杂环戊烯-3b(3aH)-甲酸乙酯(58b)
按照与对于化合物58a相同的方法,从化合物52a制备化合物58b(86%)。1H NMR(CD3OD,400MHz)δ8.61(s,1H),7.72(d,J1=2.8,J2=8.4Hz,4H),7.54(t,J=8.4Hz,4H),5.97(d,J=6.8Hz,1H),5.16(s,1H),4.97(d,J=6.0Hz,1H),4.27-4.17(m,2H),2.43-2.39(m,1H),1.75-1.71(m,1H),1.60-1.56(m,4H),1.38(s,18H),1.32(s,3H),1.18(t,J=6.8Hz,3H)。对于C41H45N4O4(M+H)+的HRMS:计算值657.3441;实测值657.3446。
(3aR,3bS,4aS,5R,5aS)-5-(2,6-双((2-氯苯基)乙炔基)-9H-嘌呤-9-基)-2,2-二甲基四氢环丙基[3,4]环戊二烯并[1,2-d][1,3]间二氧杂环戊烯-3b(3aH)-甲酸乙酯(58c)
按照与对于化合物58a相同的方法,从化合物52a制备化合物58c(82%)。1H NMR(CD3OD,400MHz)δ8.65(s,1H),7.91-7.88(m,2H),7.60-7.51(m,2H),7.50-7.40(m,4H),5.99(d,J=7.2Hz,1H),5.18(s,1H),5.01(d,J=6.0Hz,1H),4.21-4.10(m,2H),2.43-2.39(m,1H),1.74-1.70(m,1H),1.60-1.56(m,4H),1.31(s,3H),1.15(t,J=7.2Hz,3H)。对于C33H27N4O4Cl2(M+H)+的HRMS:计算值613.1409;实测值613.1400。
(3aR,3bS,4aS,5R,5aS)-5-(2-氯-6-(苯基乙炔基)-9H-嘌呤-9-基)-2,2-二甲基四氢环丙基[3,4]环戊二烯并[1,2-d][1,3]间二氧杂环戊烯-3b(3aH)-甲酸乙酯(60)
按照与对于化合物58a相同的方法,从化合物52b制备化合物60(85%)。1H NMR(CD3OD,400MHz)δ8.59(s,1H),7.80(d,J=6.8Hz,1H),7.53-7.50(m,4H),5.88(d,J=7.2Hz,1H),5.13(s,1H),4.92-4.88(m 1H),4.28-4.25(m,2H),2.40-2.36(m,1H),1.73-1.70(m,1H),1.59-1.55(m,4H),1.34(t,J=7.2Hz,3H),1.30(s,3H)。对于C25H24N4O4Cl(M+H)+的HRMS:计算值479.1481;实测值479.1482。
(3aS,3bS,4aS,5R,5aR)-N,2,2-三甲基-5-(6-((Z)-2-(甲基氨基)-2-苯基乙烯基)-2-(苯基乙炔基)-9H-嘌呤-9-基)四氢环丙基[3,4]环戊二烯并[1,2-d][1,3]间二氧杂环戊烯-3b(3aH)-甲酰胺(59a)
将40%甲基胺溶液(2.5mL)加入至化合物58a(46mg,0.084mmol)在甲醇(3.0mL)中的溶液中并且将混合物在室温搅拌过夜。将溶剂在真空下蒸发,并且将残留物在急骤硅胶柱色谱(CH2Cl2∶MeOH=40∶1)上纯化,得到化合物59a(32mg,68%),为荧光黄色浆液。1H NMR(CDCl3,400MHz)δ10.27(d,J=5.2Hz,1H),7.85(s,1H),7.71-7.68(m,2H),7.50-7.45(m,8H),5.83(s,1H),5.81(s,1H),4.90(d,J=6.8Hz,1H),4.87(s,1H),3.02(d,J=5.2Hz,3H),2.85(d,J=4.8Hz,3H),2.03-1.99(m,1H),1.73-1.69(m,1H),1.68-1.55(m,4H),1.32(s,3H)。对于C33H33N6O3(M+H)+的HRMS:计算值561.2614;实测值561.2612。
(3aS,3bS,4aS,5R,5aR)-5-(6-((Z)-2-(4-(叔丁基)苯基)-2-(甲基氨基)乙烯基)-2-((4-(叔丁基)苯基)乙炔基)-9H-嘌呤-9-基)-N,2,2-三甲基四氢环丙基[3,4]环戊二烯并[1,2-d][1,3]间二氧杂环戊烯-3b(3aH)-甲酰胺(59b)
按照与对于化合物59a相同的方法,从化合物58b制备化合物59b(71%)。1H NMR(CDCl3,400MHz)δ10.28(d,J=5.2Hz,1H),7.84(s,1H),7.62(d,J=8.4Hz,2H),7.47-7.44(m,8H),8.32(d,J=7.2Hz,1H),5.80(s,1H),4.88(d,J=6.0Hz,1H),4.85(s,1H),3.04(d,J=5.2Hz,3H),2.87(d,J=4.8Hz,3H),2.01-1.97(m,1H),1.72-1.68(m,1H),1.58(s,3H),1.37(s,18H),1.35-1.30(m,4H)。对于C41H49N6O3(M+H)+的HRMS:计算值673.3866;实测值673.3876。
(3aS,3bS,4aS,5R,5aR)-5-(6-((Z)-2-(2-氯苯基)-2-(甲基氨基)乙烯基)-2-((2-氯苯基)乙炔基)-9H-嘌呤-9-基)-N,2,2-三甲基四氢环丙基[3,4]环戊二烯并[1,2-d][1,3]间二氧杂环戊烯-3b(3aH)-甲酰胺(59c)
按照与对于化合物59a相同的方法,从化合物58c制备化合物59c(72%)。1H NMR(CDCl3,400MHz)δ10.41(s,1H),7.86(s,1H),7.72(d,J=6.0Hz,1H),7.54-7.47(m,2H),7.42-7.38(m,5H),5.83(d,J=6.8Hz,1H),5.69(s,1H),4.91(t,J=7.2Hz,1H),4.86(s,1H),2.91(d,J=5.2Hz,3H),2.83(d,J=4.8Hz,3H),2.04-1.97(m,1H),1.72-1.69(m,1H),1.58(s,3H),1.30-1.32(m,4H)。对于C33H31N6O3Cl2(M+H)+的HRMS:计算值629.1829;实测值629.1835。
(3aS,3bS,4aS,5R,5aR)-5-(2-氯-6-((Z)-2-(甲基氨基)-2-苯基乙烯基)-9H-嘌呤-9-基)-N,2,2-三甲基四氢环丙基[3,4]环戊二烯并[1,2-d][1,3]间二氧杂环戊烯-3b(3aH)-甲酰胺(61)
按照与化合物59a对于相同的方法,从化合物60制备化合物61(70%)。1H NMR(CDCl3,400MHz)δ9.98(s,1H),7.78(s,1H),7.49-7.46(m,5H),6.95(d,J=4.4Hz,1H),5.76(s,1H),5.70(d,J=6.8Hz,1H),4.83-4.80(m,2H),3.01(d,J=5.2Hz,3H),2.95(d,J=4.8Hz,1H),2.08-2.04(m,1H),1.72-1.68(m,1H),1.57(s,3H),1.34-1.30(m,4H)。对于C25H28N6O3Cl(M+H)+的HRMS:计算值495.1906;实测值495.1907。
(1S,2S,3R,4R,5S)-2,3-二羟基-4-(6-((Z)-2-羟基-2-苯基乙烯基)-2-(苯基乙炔基)-9H-嘌呤-9-基)-N-甲基双环[3.1.0]己烷-1-甲酰胺(38)
将化合物59a(32mg,0.057mmol)在甲醇(3.0mL)和10%三氟甲磺酸(2.5mL)中的溶液在70℃加热过夜。将溶剂在真空下蒸发,并且将残留物在急骤硅胶柱色谱(CH2Cl2∶MeOH=25∶1)上纯化,得到化合物38(9mg,31%),为黄色浆液,其在进一步用(CH2Cl2∶MeOH=12∶1)洗脱后,得到化合物39(6mg,26%),为无色浆液。对于化合物38的数据:1H NMR(CD3OD,400MHz)δ8.43(s,1H),8.01-7.99(m,2H),7.73(dd,J1=1.6,J2=5.6Hz,2H),7.52-7.49(m,6H),6.84(s,1H),5.13(d,J=5.6Hz,1H),4.99(s,1H),4.12(d,J=6.8Hz,1H),2.85(s,3H),2.18-2.15(m,1H),1.89(t,J=4.8Hz,1H),1.44-1.40(m,1H)。对于C29H26N5O4(M+H)+的HRMS:计算值508.1985;实测值508.1991。
对于化合物(1S,2S,3R,4R,5S)-2,3-二羟基-N-甲基-4-(6-甲基-2-(苯基乙炔基)-9H-嘌呤-9-基)双环[3.1.0]己烷-1-甲酰胺(39)的数据:1H NMR(CD3OD,400MHz)δ8.52(s,1H),7.70-7.67(m,2H),7.48-7.46(m,3H),5.15(d,J=5.2Hz,1H),5.00(s,1H),4.11(d,J=6.4Hz,1H),2.85(s,3H),2.83(s,3H),2.16-2.13(m,1H),1.88(t,J=4.8Hz,1H),1.43-1.39(m,1H)。对于C22H22N5O3(M+H)+的HRMS:计算值404.1723;实测值404.1719。
(1S,2S,3R,4R,5S)-4-(6-((Z)-2-(4-(叔丁基)苯基)-2-羟基乙烯基)-2-((4-(叔丁基)苯基)乙炔基)-9H-嘌呤-9-基)-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-甲酰胺(40)
按照与对于化合物38和39相同的方法,从化合物59b制备化合物40(32%)和41(21%)。对于化合物40的数据:1H NMR(CD3OD,400MHz)δ8.36(s,1H),7.91(d,J=4.8Hz,2H),7.64-7.62(m,2H),4.55-7.52(m,4H),6.75(s,1H),5.09(d,J=5.6Hz,1H),4.95(s,1H),4.10(d,J=6.4Hz,1H),2.85(s,3H),2.17-2.13(m,1H),1.88(t,J=5.2Hz,1H),1.38-1.37(m,19H)。对于C37H42N5O4(M+H)+的HRMS:计算值620.3237;实测值620.3232。对于化合物(1S,2S,3R,4R,5S)-4-(2-((4-(叔丁基)苯基)乙炔基)-6-甲基-9H-嘌呤-9-基)-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-甲酰胺(41)的数据:1H NMR(CD3OD,400MHz)δ8.51(s,1H),7.62(d,J=8.4Hz,2H),7.52(d,J=8.4Hz,2H),5.15(d,J=5.2Hz,1H),5.00(s,1H),4.11(d,J=5.2Hz,1H),2.86(s,3H),2.83(s,3H),2.16-2.13(m,1H),1.88(t,J=4.8Hz,1H),1.44-1.40(m,1H),1.37(s,18H)。对于C26H30N5O3(M+H)+的HRMS:计算值460.2349;实测值460.2341。
(1S,2S,3R,4R,5S)-4-(6-((Z)-2-(2-氯苯基)-2-羟基乙烯基)-2-((2-氯苯基)乙炔基)-9H-嘌呤-9-基)-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-甲酰胺(42)
按照与对于化合物38相同的方法,从化合物59c制备化合物42(72%),并且未检测到C6-甲基产物。1H NMR(CD3OD,400MHz)δ8.43(s,1H),7.78(d,J=6.0Hz,1H),7.68-7.60(m,1H),7.58(d,J=7.2Hz,1H),7.53-7.42(m,5H),6.47(s,1H),5.14(d,J=5.6Hz,1H),5.00(s,1H),4.13(d,J=6.4Hz,1H),2.84(s,3H),2.18-2.14(m,1H),1.88(d,J=4.8Hz,1H),1.44-1.40(m,1H)。对于C29H24N5O4Cl2(M+H)+的HRMS:计算值576.1205;实测值576.1208。
(1S,2S,3R,4R,5S)-4-(2-氯-6-((Z)-2-羟基-2-苯基乙烯基)-9H-嘌呤-9-基)-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-甲酰胺(43)
按照与对于化合物38相同的方法,从化合物61制备化合物43(75%),并且未检测到C6-甲基产物。1H NMR(CD3OD,400MHz)δ8.43(s,1H),7.99-7.97(m,2H),7.52-7.50(m,3H),6.87(s,1H),5.13(d,J=6.4Hz,1H),4.93(s,1H),4.08(d,J=6.8Hz,1H),2.90(s,3H),2.14-2.11(m,1H),1.85(d,J=4.8Hz,1H),1.43-1.39(m,1H)。对于C21H21N5O4Cl(M+H)+的HRMS:计算值442.1277;实测值442.1279。
实施例3
本实施例举例说明根据本发明的实施方案的化合物在神经性疼痛的体内模型中的性能
实验动物。在可随意获得食物和水的受控环境(12h亮/暗循环)中将来自Harlan(Indianapolis,IN)的雄性CD-1小鼠(25-30g)圈养,每笼中4-5只(对于小鼠)。根据国际疼痛研究协会(International Association for the Study of Pain)、实验室动物福利的NIH指南(NIH guidelines on laboratory animal welfare)和圣路易斯大学机构动物护理与使用委员会(Saint Louis University Institutional Animal Care and UseCommittee)建议进行实验。在所有实验中实验者对处理条件为盲法研究(blinded)。
神经性疼痛的CCI模型。对小鼠左后腿的坐骨神经的CCI在全身麻醉下使用良好表征的Bennett模型(Bennett,G.J.等人,Pain 1988,33,87-107)进行。简言之,用3%异氟醚/100%O2吸入麻醉小鼠(在手术时称重为25-30g)并在手术期间维持2%异氟醚/100%O2。将左大腿剃毛,用Nolvasan(Zoetis,Madison,NJ)刷洗,并且在左大腿的侧面中间形成小切口(长度1-1.5cm)以暴露坐骨神经。使用丝缝合线(6.0)在三个不同部位(间隔开1mm)处围绕神经的整个直径松散结扎神经。将手术部位利用单个肌肉缝合线和皮肤夹闭合。中试表明,在实验条件下,在CCI后5-7天产生峰机械性痛觉超敏。在峰机械性痛觉超敏时(第7天),测试物质或它们的媒介物以通过强饲法(0.2ml口服)给予的3μmol/kg剂量施用。使用的媒介物由在0.5%甲基纤维素中的10%DMSO组成(从在DMSO中的5mM储液稀释的)。甲基纤维素(批号021M0067V)获自Sigma粘度400cP并且在无菌蒸馏水(UPS)中制备。
用于体内实验的统计学分析。数据表示为对于n只动物的平均值±SEM。行为数据通过具有Bonferroni比较的双向ANOVA分析。在P<0.05定义为显著差异。所有统计分析使用GraphPad Prism(v5.03,GraphPad软件,Inc.,San Diego,CA)进行。
如Chen,Z.等人,FASEB J.2012,26,1855-1865和Paoletta,S.等人,J.Med.Chem.2013,56,5949-5963中描述的进行测定。
结果列在表6和7中。由化合物7(MRS5914)、8(MRS5917)和17(MRS5969)表现出的机械性痛觉超敏随时间的逆转分别在图1A-1C中示出。由化合物13(MRS5967)、16(MRS5968)、17(MRS5969)、14(MRS5970)和11(MRS5971)表现出的机械性痛觉超敏随时间的逆转在图2中描述。由化合物6(MRS5913)、7(MRS5914)、8(MRS5917)、9(MRS5921)和10(MRS5929)表现出的机械性痛觉超敏随时间的逆转在图3中描述。MRS5698(参照)的结构在图6中描述。由0.3mmol/kg、1mmol/kg和3mmol/kg剂量的化合物7、17和32表现出的机械性痛觉超敏随时间的逆转在图8A-8C中描述。在神经性疼痛的慢性缩窄性损伤模型中由化合物40(MRS5918)、41(MRS5919)、37(MRS5979)和32(MRS5980)表现出的机械性痛觉超敏随时间的逆转在图5中描述。在神经性疼痛的慢性缩窄性损伤模型中由化合物8、16和100表现出的机械性痛觉超敏随时间的逆转在图10中示出。在神经性疼痛的慢性缩窄性损伤模型中分别由化合物100(MRS7110),105(MRS7113)、103(MRS7114)、101(MRS7115)和104(MRS7116)表现出的机械性痛觉超敏随时间的逆转在图11中描述。在神经性疼痛的慢性缩窄性损伤模型中分别由化合物112(MRS7121)、102(MRS7117)、108(MRS7118)、111(MRS7119)、106(MRS7120)和110(MRS7126)表现出的机械性痛觉超敏随时间的逆转在图12中示出。由以0.3、1、2、10和30μmol/kg配药口服用药的化合物126(MRS7135)表现出的机械性痛觉超敏随时间的逆转在图16中示出。在神经性疼痛的慢性缩窄性损伤模型中,分别由化合物125(MRS7137)、120(MRS7138)、121(MRS7139)和127(MRS7140)表现出的机械性痛觉超敏随时间的逆转在图17中示出。
表6.口服施用的AR激动剂(3μmol/kg)在小鼠的神经性疼痛的CCI模型中的活性
a对于同侧后爪显示的效果;对对侧没有效果。
b使用ChemDraw计算的。
表7.口服施用的AR激动剂(3μmol/kg)在小鼠神经性疼痛的CCI模型中的活性和理化参数。
a对于侧后爪显示的效果;对对侧没有效果。
b使用ChemBioDraw第13.0版计算的。
将各种N6-甲基衍生物的体内活性进行比较并与结构相关联。在慢性神经性疼痛(NP)的CCI模型中,未取代的C2-苯基乙炔基类似物400(现有技术)显示低的效力(在峰值效果处为完全逆转的~30%)。用甲氧基替代苯环提高最大效果(~70),但仅在13的邻位。在吡啶基类似物401(现有技术)、300和15中氮的所有位置导致与苯基类似物400相同的低效力。然而,在吡嗪7中的二氮取代增大效力至~100%,但含有在不同位置6和10处的氮的异构体的效力导致小于完全效力。2-呋喃基17和2-噻吩基8类似物在作用的~3h持续期间内完全有效。向化合物32中的噻吩类似物添加氯延长作用的持续时间同时维持完全效力。当硫存在于16中的噻吩环的不同位置时,效力减弱。二茂铁衍生物37是完全有效的。环烷基类似物19和20显示在体内小于完全效力(60-70%)。综上,在体内逆转NP方面达到完全(~100%效力)的类似物为:7、18、17、8、32和37。
实施例4
该实施例表明由根据本发明的实施方案的化合物表现出的对CHO细胞中的细胞内cAMP水平的效果。
在表达重组hA3AR的CHO细胞中的细胞内cAMP水平使用ELISA测定(Nordstedt等人,Anal.Biochem.1990,189,231-234)测量。首先通过胰蛋白酶消化来收获细胞。在离心并在培养基中重悬后,将细胞在0.1mL培养基中接种在96-孔板中。24h后,移除培养基并且将细胞用含有50mM HEPES,pH 7.4的0.2mL DMEM洗涤三次。然后在咯利普兰(rolipram)(10μM)和腺苷脱氨酶(3单位/mL)存在下将细胞用激动剂(对于hA3AR,10μM43)或测试化合物处理。在30min之后,将毛喉素(10μM)加入培养基中,并且继续温育另外的15min。通过移除上清终止反应,并且在加入100μL的0.1M冰冷HCl后,裂解细胞。将细胞裂解物重悬并储存在-20℃。为了确定cAMP产生,在Amersham cAMP酶免疫测定中,按照试剂盒提供的说明,使用50μL的HCl溶液。使用SpectroMax M5微孔板读数器(Molecular Devices,Sunnyvale,CA)在450nm阐明结果。对于四个代表性的实施方案,即化合物7(MRS5914)、8(MRS5917)、40(MRS5918)和41(MRS5919)的结果分别在图7A-7D中示出。
利用表达mA1AR或mA3AR的HEK293细胞进行类似的cAMP测定。将HEK293细胞从细胞培养板脱离,重悬浮在含有25mM HEPES(pH 7.4)、1单位/ml腺苷脱氨酶、4-(3-丁氧基-4-甲氧基苯基)甲基-2-咪唑烷酮(Tocris,Ro 20,1724,20μM)和300nM 8-[4-[4-(4-氯苄基)哌啶(piperazide)-1-磺酰基)苯基]]-1-丙基黄嘌呤(Tocris,PSB603,300nM)的无血清DMEM,抑制HEK293细胞中内源性地表达的A2BAR,然后转移至聚丙烯管(2x105细胞/管)。在振荡下,在37℃将细胞与毛喉素(10μM)和AR配体共温育15min,之后通过加入500μL 1N HCl终止测定。将裂解物在4000xg离心10min。如之前描述的59,使用竞争性结合测定确定上清中的cAMP浓度。通过将数据拟合至:E=Emin+(Emax-Emin)/(1+10X-logEC50),计算EC50和Emax值。
实施例5
该实施例表明缺乏MRS5698表现出的毒性。
MRS5698的结构在图6中示出。将MRS5698配制包含在水中的40%PEG 300和在10%HP-β-CD中的10%solutol的媒介物中。通过强饲给Sprague Dawley大鼠将制剂以多至150mg/kg用药。在150mg/kg的高剂量下未观察到异常结果。这些结果表明在其体内作用中MRS5698是高度A3特异的。
实施例6
该实施例表明从根据本发明的实施方案的化合物的结合实验的脱靶(非靶标,off-target)相互作用。
测定的受体在表5中显示。
表5
测试的化合物是MRS5698(现有技术)、MRS5676(现有技术)、7、18、17、8和32。结果在以下提供。检索表:Ki<1.0μM+++;1-10μM++;>10μM+(当已知时,Ki值在括号中)。
MRS5698
在其他受体处无相互作用。
MRS5676
在多巴胺转运蛋白处的放射性配体结合由以10μM的化合物增强~7X。
在其他受体处无相互作用。
7
在其他受体处无相互作用。
18
在所有α受体、β受体、组胺、5HT受体、毒蕈碱性受体、多巴胺受体、BZP大鼠脑、SERT、NET、GABA-A、KOR、DOR、MOR、BZP处无相互作用(10μM)。然而,PBR、σ-1、σ-2显示弱的相互作用。
17
在所有α受体、β受体、组胺、5HT受体、毒蕈碱性受体、多巴胺受体、BZP大鼠脑、SERT、NET、GABA-A、KOR、DOR、MOR、BZP处无相互作用(10μM)。然而,PBR、σ-1、σ-2显示弱的相互作用。
8
α2B ++(5.5μM)
DAT +++(0.76μM)
D2 +(>10μM)
在其他受体处无相互作用。
32
在所有α受体、β受体、组胺、5HT受体、毒蕈碱性受体、多巴胺受体、BZP大鼠脑、SERT、NET、GABA-A、KOR、DOR、MOR、BZP处无相互作用(10μM)。然而,PBR、σ-1(Ki 1.4μM)、σ-2(Ki 0.63μM)显示在10μM 60-70%抑制。在多巴胺转运蛋白处的放射性配体结合由以10μM的化合物增强~5X。
101
无显著相互作用(>50%,以10μM)。
37
在5HT2A、5HT2B、5HT2C、5HT3、5HT6、5HT7、α2B、α2C、M1、M3、M4和H1受体处有显著相互作用(<10μM)。在5HT2C和5HT3受体处的Ki值分别确定为0.277和2.62μM。在其他处无显著相互作用(>50%,在10μM)。
如从上述结果显而易见的,化合物7、18、17、8、32、101和37显示比MRS5698和MRS5676显著更少的脱靶作用。
实施例7
根据本发明的实施方案,对于所选择的化合物的体外稳定性参数在表6中显示。
表6
a-对于n=3的平均值(±SD,在给出的情况下)。
b-在10μM的%抑制:1A2,15.0;2C9,24.2;2C19,34.0;2D6,57.5(IC507.4μM);3A4,3.1(平均n=2)。
c-在10μM的%抑制:1A2,30.5;2C9,17.2;2C19,18.1;2D6,20.5;3A4,51.6(IC509.4μM),(n=2的平均值)。
d-人肝微粒体中的CLint值(μL/min/mg蛋白):7,2.99;17,3.09;32,3.69;100,3.38。
实施例8
该实施例表明,根据本发明的实施方案,化合物32在Sprague Dawley大鼠中以单个剂量在升高的剂量水平(100和150mg/kg,其大致为100倍于药理学活性剂量)中的最大耐受剂量。
总共十八只大鼠(3只大鼠/性别/剂量水平)用于研究中。测试的剂量水平是经口服途径的100和150mg/kg单个剂量,然后是剂量后两天的观察期。在三组(3只大鼠/性别/剂量水平)中以交错的方式进行研究。用于确定化合物32的最大耐受剂量的考察的参数包括:临床观察、死亡率、体重、肉眼尸检和器官重量。
在整个研究持续期间,没有观察到不良的临床迹象。在整个研究持续期间,与媒介物对照组的动物相比,未观察到体重方面的显著变化。
没有由于用化合物32处理导致的器官重量的显著改变。没有器官重量与体重比方面显著变化。
实施例9
该实施例表明。化合物7和8是A3AR的有效、完全的激动剂。
对于化合物7和8,评价在人A1AR和A3AR处抑制环状AMP形成的活性。结果在图9A(化合物7)和9B(化合物8)中用图示地描述。
实施例10
该实施例表明,根据本发明的实施方案,高剂量的化合物32不显示急性肝毒性。
将十只雄性C57BL/6J(6至8周龄)小鼠分为对照组(n=5)和化合物32-治疗组(n=5)。将溶解在玉米油中的化合物32以50mg/kg体重的剂量通过口服强饲来给予,并且将对照小鼠仅用玉米油处理。在体内暴露于化合物32的24h期间,肝组织学保持正常,并且未观察到肝中的GSH和GSSG水平的改变。这表明,没有由于由GSH和化合物32的反应导致的可能的GSH波动造成的显著急性毒性作用。
实施例11
该实施例表明,在用药时期内,化合物32(MRS5980)和MRS5698可以恢复吗啡的效力。
使用如实施例3中描述的慢性缩窄性损伤(CCI)模型。每日皮下注射(0.2ml体积)或硫酸吗啡(10.5μmol/kg/天)±MRS5698或化合物32(0.18μmol/kg/天)的组合,或在第7天开始其媒介物(1%DMSO,在盐水中)给予吗啡,然后继续直到第25天。
在手术前第0天、在手术后第7天(峰值疼痛时间)然后在隔日进行行为测量。在药物注射后1小时进行测试,因为这代表峰值吗啡镇痛的时间。如之前描述的使用von Frey上下法(升降法,up and down method)来评估机械性痛觉超敏。将校准的von Frey丝[Stoelting(小动物立体定位仪),范围为2.83(0.07g)至4.31(2g)弯曲力]应用于后爪的中足底表面(2)。数据表示为在峰值(用药后1h)时机械性痛觉超敏的%逆转。让所有动物都在围栏中在升高的网格平台适应~15分钟。
如图14中看到的,在第7天(小鼠中在压缩坐骨神经后的机械性痛觉超敏的峰值发展的时间)皮下(s.c)注射吗啡引起机械性痛觉超敏的接近于最大的逆转。然而,当在典型为公知发展出止痛剂耐受性的神经损伤大鼠中经25天的每日给予时,吗啡丧失逆转机械性痛觉超敏的能力。然而,当与本身不具有止痛剂作用的A3AR激动剂(MRS5698;化合物32(MRS5980))的剂量一起注射时,在该用药时期内,吗啡保留其逆转神经性疼痛的能力。这些结果表明,A3AR激动剂在延长的使用期间可以通过阻断止痛剂耐受性而恢复阿片样物质的效力;阿片样物质/A3AR方法的组合可以允许阿片类的长期使用,而不需要预期促成已知的不希望副作用的剂量增大。这样的在痛觉缺失方面的药代动力学差异不是通过与A3AR共同施用改变的吗啡药代动力学解释,因为在存在或不存在A3AR激动剂的情况下吗啡浓度的血浆水平类似。
实施例12
该实施例表明化合物32(MRS5980)在雄性SD大鼠中的生物利用度。
以1mg/kg静脉内和以1、3和10mg/kg口服用药的雄性SD大鼠。作为时间的函数的血浆浓度在图15中描述。生物利用度数据在表7中提供。
表7
实施例13
该实施例表明根据本发明的实施方案在结合测定中与多巴胺转运蛋白的变构相互作用。
在结合测定中,一些化合物与多巴胺转运蛋白(DAT)变构地相互作用。例如,10μMMRS5980的作用是增强放射性配体([3H]WIN35428)在人DAT处的结合,以556%增大结合水平。10μM MRS7135的作用是增强在人DAT处放射性配体([3H]WIN35428)的结合,以329%增大结合水平。
已经发现,1-脱氮修饰不表现出这种非靶标相互作用。MRS5980的1-脱氮等价物是MRS7140,并且MRS7135的1-脱氮等价物是MRS7144。MRS7140对放射性配体([3H]WIN35428)在人DAT处的结合没有影响(1%抑制)。MRS7144在慢性疼痛抑制中具有比MRS7140长的作用时期,这可能与在这一系列中的N6-乙基相对于N6-甲基相关。
因此,在这一化学系列中的1-脱氮修饰可以被认为是避免与DAT相互作用的通用手段。
去除与DAT相互作用的另一方式是放大N6取代基。因为N6-甲基和N6-乙基衍生物(上述MRS5980和MRS7135)与DAT相互作用,类似的N6-(3-氯苄基)衍生物MRS5698不与DAT相互作用。
因此,包括较大的N6-烷基、烷基-芳基和烷基-环烷基减弱这种脱靶相互作用。这样的较大基团的实例包括N6-环丙基、N6-环丁基、N6-环丙基甲基、N6-环丁基甲基,以及其他直链或支链烷基如异丁基。
本文引用的所有参考文献,包括出版物、专利申请和专利在此通过引用结合于此,其程度如同各个参考文献个别和具体地指明通过引用结合一样并且在本文中以其整体提供。
在描述本发明的情况下中(特别是在所附权利要求的情况下),术语“一个(a)”和“一种(an)”和“该(the)”和“至少一个”以及类似的指代的使用要理解为覆盖单数和复数,除非在本文中另有说明或与上下文明显矛盾。在一个或多个项目的列表后的术语“至少一个”(例如,“A和B的至少一个”)的使用要解释为是指选自所列项目(A或B)中的一项或所列项目(A和B)的两个或更多个的任意组合,除非在本文中另有说明或与上下文明显矛盾。除非另有说明,术语“包含(comprising)”、“具有(having)”、“包括(including)”和“含有(containing)”要理解为开放的术语(即,意为“包括,但不限于”)。除非本文中另有说明,本文中数值范围的陈述仅意在用作各自涉及落在该范围内的各个分离的值的速记法,并且各个单独的值如其在本文中各自被陈述那样结合入说明书。本文中描述的所有方法可以以任何合适的顺序进行,除非本文中另有说明或与上下文明显矛盾。本文中提供的任何和所有实例,或示例性表述(例如,“如”),仅意在更好地举例说明本发明并且不对本发明的范围具有限制作用,除非另外要求。说明书中的术语不应该被解释为表明任何非要求保护的要素是对于本发明的实施是必要的。
本发明的优选的实施方案在本文中描述,包括发明人已知的对于实现本发明的最佳方式。在阅读上述描述后,那些优选的实施方案的变形对于本领域普通技术人员会变得明显。本发明的发明人预期在适当时技术人员要采用所述变形,并且本发明的发明人意在将本发明以除本文具体描述的之外的另外方式实施。因此,本发明包括如由所适用的法律允许的所附权利要求中陈述的主题的所有更改和等同替换。此外,在其所有变形中的上述要素的任意组合包括在本发明中,除非在本文中另有说明或与上下文明显矛盾。
Claims (24)
1.一种式(I)的化合物:
其中X选自NHR1、CH3和CH=C(Ra)(Rb),其中Ra和Rb独立地选自氢、羟基、C1-C6烷基和C6-C14芳基,
Y是N或CH,
R1选自C1-C6烷基、C3-C8环烷基、C6-C14芳基C3-C8环烷基和C3-C8环烷基C1-C6烷基,其中R1的所述芳基部分任选地被一个或多个选自以下各项的取代基取代:卤代和C1-C6烷基及其任意组合;
R2选自C6-C12芳基、C3-C8环烷基、杂芳基和茂金属基,其中所述芳基基团被一个或多个选自以下各项的取代基取代:三氟甲基、羟基C1-C6烷基和C1-C6烷氧基及其任意组合,其中所述杂芳基基团任选地被一个或多个选自卤代、羟基、和C1-C6烷基的取代基取代,其中所述杂芳基是指含有一个或多个选自由O、N、S及其组合组成的组中的杂原子的单环或二环5-或6-元环体系,并且是不饱和的且满足休克尔规则;
R3和R4是羟基;
R5是C1-C3烷基氨基羰基;并且
R6是氢;
或其药用盐,
条件是,当R1是甲基,R3和R4都是羟基,R6是氢,并且R5是甲基氨基羰基时,R2不是2-吡啶基或苯基。
2.权利要求1所述的化合物或盐,其中Y是N。
3.权利要求2所述的化合物或盐,其中X是NHR1。
4.权利要求2所述的化合物或盐,其中R1是C1-C6烷基。
5.权利要求2所述的化合物或盐,其中R2是C6-C10芳基。
6.权利要求1所述的化合物或盐,其中所述化合物选自:
7.权利要求6所述的化合物或盐,其中所述化合物选自:
8.权利要求1所述的化合物或盐,其中所述化合物是:
9.权利要求1所述的化合物或盐,其中所述化合物选自:
10.权利要求1所述的化合物或盐,其中R1是C6-C14芳基C3-C8环烷基,其中所述芳基任选地被甲基、F、Cl和Br取代。
11.权利要求10所述的化合物或盐,其中所述化合物选自:
12.权利要求1所述的化合物或盐,其中X是CH3。
13.权利要求1所述的化合物或盐,其中X是CH=C(Ra)(Rb)。
14.权利要求1所述的化合物或盐,其中Y是CH。
15.权利要求14所述的化合物或盐,其中X是NHR1。
16.权利要求14所述的化合物或盐,其中R1是C1-C6烷基。
17.权利要求14所述的化合物或盐,其中R2是C6-C10芳基。
18.权利要求14所述的化合物或盐,其中R2是杂芳基。
19.权利要求1所述的化合物或盐,其中所述化合物选自:
20.一种化合物,所述化合物是
21.一种药物组合物,所述药物组合物包含权利要求1的化合物或盐以及药用载体。
22.权利要求1的化合物或其药用盐在制备用于选择性地激活哺乳动物中的A3腺苷受体的药物中的用途。
23.权利要求1的化合物或其药用盐在制备用于在有需要的哺乳动物中治疗或预防神经性疼痛的药物中的用途。
24.权利要求23所述的用途,其中所述神经性疼痛由于癌症化疗而发生。
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KR20220132042A (ko) | 2016-04-21 | 2022-09-29 | 아스트로사이트 파마슈티컬스, 인코포레이티드 | 신경계 및 심혈관계 병태 치료를 위한 화합물 및 방법 |
CA3022385A1 (en) * | 2016-04-26 | 2017-11-02 | Saint Louis University | Highly selective adenosine a3 receptor subtype agonsists for the prevention and treatment of neurodegenerative disorders |
US11839615B2 (en) | 2018-02-09 | 2023-12-12 | Astrocyte Pharmaceuticals, Inc. | Compounds and methods for treating addiction and related disorders |
CA3113250A1 (en) | 2018-09-26 | 2020-04-02 | Astrocyte Pharmaceuticals, Inc. | Polymorphic compounds and uses thereof |
WO2020106773A1 (en) * | 2018-11-19 | 2020-05-28 | Saint Louis University | Treatment of irritable bowel syndrome |
US20220117985A1 (en) * | 2019-02-15 | 2022-04-21 | Saint Louis University | Treatment of chronic headaches |
WO2020176544A1 (en) * | 2019-02-25 | 2020-09-03 | Saint Louis University | Treatment of alzheimer's disease |
WO2020247540A1 (en) * | 2019-06-03 | 2020-12-10 | Biointervene, Inc. | Adenosine analogs for the treatment of disease |
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Extended N6 substitution of rigid C2-arylethynyl nucleosides for exploring the role of extracellular loops in ligand recognition at the A3 adenosine receptor;Dilip K. Tosh et al.;《Bioorganic & Medicinal Chemistry Letters》;20140611;第24卷(第15期);第3302-3306页 |
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EP3074398B1 (en) | 2021-03-17 |
CN105934433A (zh) | 2016-09-07 |
CN110003212A (zh) | 2019-07-12 |
US9963450B2 (en) | 2018-05-08 |
US20170002007A1 (en) | 2017-01-05 |
WO2015080940A1 (en) | 2015-06-04 |
CN110003212B (zh) | 2022-12-06 |
EP3074398A1 (en) | 2016-10-05 |
US10577368B2 (en) | 2020-03-03 |
US20180230150A1 (en) | 2018-08-16 |
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