CN116888115A - 二氟甲基-吡啶-2-基三唑 - Google Patents
二氟甲基-吡啶-2-基三唑 Download PDFInfo
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- CN116888115A CN116888115A CN202180066477.8A CN202180066477A CN116888115A CN 116888115 A CN116888115 A CN 116888115A CN 202180066477 A CN202180066477 A CN 202180066477A CN 116888115 A CN116888115 A CN 116888115A
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- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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Abstract
本发明涉及通式(I)的二氟甲基‑吡啶‑2‑基三唑,其为含有α5亚基的GABAA受体的调节剂,可用于治疗中枢神经系统疾病和其他疾病。另外,本发明涉及用于制备药物组合物的方法以及制造根据本发明的化合物的方法。
Description
技术领域
本发明涉及通式(I)的二氟甲基-吡啶-2-基三唑,其为含有α5亚基的GABAA受体的调节剂。所述化合物可用于治疗中枢神经系统和其他疾病。另外,本发明涉及用于制备药物组合物的方法以及制造根据本发明的化合物的方法。
背景技术
已经表明GABAAα5亚基代表用于治疗中枢神经系统的各种疾病和障碍的治疗靶点。已经建立了作为治疗靶点的GABAAα5亚基与各种神经障碍、昼夜节律障碍、疼痛病症之间的联系。特别期望能够调节含有α5亚基的GABAA受体的化合物是尤其治疗认知障碍、阿尔茨海默病、精神分裂症、与精神分裂症相关的阳性、阴性和/或认知症状、与精神分裂症相关的认知损害、以及与唐氏综合征、自闭症、I型神经纤维瘤病、或中风后相关的认知缺陷的有用候选物。
WO 2012/062687 A1(对应于EP-2638029-A1)披露了用于治疗神经障碍的三唑衍生物。
WO 2020/016443 A1披露了二氟甲基-苯基三唑,作为GABA受体调节剂用于治疗神经系统疾病。所述化合物含有与连接三唑环的苯基附接的二氟甲基。
本发明描述了二氟甲基-吡啶-2-基三唑。所述化合物含有与连接三唑环的2-吡啶附接的二氟甲基。与WO 2020/016443中描述的类似化合物相比,2-吡啶基与附接的二氟甲基的组合令人惊讶地导致化合物成为含有α5亚基的GABAA受体的显著更有效调节剂。化合物的调节效力可以在以下描述的测定A中以化合物的Ki值来测量。在本发明的情况下,吡啶基(代替WO 2020/016443的苯基三唑中使用的苯基)与4位的二氟甲基的组合出乎意料地使所要求保护的化合物的效力增加为总体上至少约10倍或更多。
效力与GABAA5R结合常数Ki相关,其中增加的效力转化为用于疾病治疗的相应化合物的较低有效剂量。
发明目的
令人惊讶地发现通式(I)的吡啶-2-基-三唑,
其中:
·Xa和Xb彼此不相同并且表示C或N,并且
·R1是经取代的苯基或含有1或2或3个杂原子的5或6元杂环基环
是GABAA5R的优异负性调节剂(即,GABAAα5亚基的负性调节剂),其具有与GABAA5R结合特性有关的改善特性,这意味着用于疾病治疗的较低化合物剂量和最小化副作用。此外,本发明的化合物具有优异的CNS渗透性,具有从脑室中低的外排比率,这是在CNS中具有预期作用的药物所必需的,并且具有高代谢稳定性。
因此,本发明的一个方面涉及根据式(I)的化合物或其盐,它们是GABAA5R的负性调节剂。
本发明的另一方面涉及根据式(I)的化合物或其药学上可接受的盐,它们是GABAA5R的负性调节剂,其具有高的GABAA5R结合特性。
本发明的另一方面涉及根据式(I)的化合物或其药学上可接受的盐,它们是GABAA5R的负性调节剂,其具有高的GABAA5R结合特性和优异的CNS渗透性以及从脑室中低的外排比率和高的代谢稳定性。
再又一方面,本发明涉及药物组合物,所述药物组合物含有至少一种根据式(I)的化合物或其药学上可接受的盐,任选地以及一种或多种惰性载体和/或稀释剂。
本发明的另一方面涉及制造本发明化合物的方法。
特别地,本发明涉及根据式(I)的化合物或其药学上可接受的盐或者包含根据式(I)的化合物或其药学上可接受的盐的药物组合物,用于预防和/或治疗可能受GABAA5R的负性调节影响的疾病或病症,诸如急性神经障碍、慢性神经障碍、认知障碍、阿尔茨海默病、记忆缺陷、精神分裂症、与精神分裂症相关的阳性、阴性和/或认知症状、与精神分裂症相关的认知损害、双相障碍、自闭症、唐氏综合征、I型神经纤维瘤病、术后认知衰退、睡眠障碍、昼夜节律障碍、肌萎缩侧索硬化症、AIDS引起的痴呆、精神病性障碍、物质诱发的精神病性障碍、焦虑障碍、广泛性焦虑障碍、惊恐性障碍、妄想性障碍、强迫性障碍、急性应激障碍、药物成瘾、运动障碍、帕金森病、不宁腿综合征、认知缺陷障碍、多发梗塞性痴呆、心境障碍、抑郁症、重度抑郁障碍、神经精神病性病症、精神病、注意缺陷多动障碍、神经性疼痛、中风、注意力障碍、进食障碍、厌食症、神经性厌食症、恶病质、体重减轻、肌肉萎缩、疼痛病症、慢性疼痛、伤害性疼痛、术后疼痛、骨关节炎疼痛、类风湿性关节炎疼痛、肌肉骨骼疼痛、烧伤疼痛、眼部疼痛、由于炎症引起的疼痛、由于骨折引起的疼痛、痛觉过敏、神经性疼痛、疱疹相关疼痛、HIV相关神经性疼痛、创伤性神经损伤、创伤性脑损伤后的恢复、中风后疼痛、缺血后疼痛、纤维肌痛、慢性头痛、偏头痛、紧张型头痛、糖尿病性神经性疼痛、幻肢疼痛、内脏疼痛和皮肤疼痛。
本发明的其他结果或结论对于技术人员而言直接从前述和以下评论中变得显而易见。
具体实施方式
本发明涉及通式(I)的化合物,
或其盐,其中
Xa和Xb彼此不相同并且表示C或N,并且
R1是经取代的苯基或含有1或2或3个杂原子的5或6元经取代的杂环基环。
特别地,Xa或Xb是C。
R1优选选自
·被氨基甲酰基取代的苯基;
·未经取代的2-吡啶酮或者被卤素诸如氟取代的或在氮上被甲基或乙基取代的2-吡啶酮;
·被氰基-(NC-)或甲硫基化物-、氨基-、甲基-氨基-、甲基磺酰基-或卤素取代的2、3或4-吡啶基;
·未经取代的嘧啶基-或被C1-6-烷基-、氨基-、-羟甲基-取代的嘧啶基-;或吡嗪基-或哒嗪基;
·被C1-6-烷基-或NC-CH2-CH2-取代的吡咯基-和被C1-6-烷基-、C3-5-环烷基-、NC-CH2-CH2-、氨基-、甲基-氨基-或卤素取代的吡唑基-;
·被C1-6-烷基-、氨基甲酰基-、NC-CH2-CH2-、氨基-或-甲基氨基-取代的咪唑基-;
·未经取代的三唑基-或被C1-3-烷基-诸如甲基取代的三唑基-;
·被甲基取代的噁唑基-和被NC-CH2-CH2-取代的噻吩基-。
除非另外说明,否则基团、残基和取代基(特别是R1)是如上文和下文中所定义的。如果残基、取代基或基团在化合物中出现多次,则它们可以具有相同或不同的含义。根据本发明化合物的基团和取代基的一些优选含义将在下文中给出。
在本发明的又一个实施方案中,R1选自
·被氨基甲酰基取代的苯基,诸如
以及
·未经取代的2-吡啶酮或者被卤素诸如氟取代的或在氮上被甲基或乙基取代的2-吡啶酮,诸如
在本发明的又一个实施方案中,R1是
·被NC-或-甲硫基化物-、氨基-、甲基-氨基-或-甲基磺酰基或卤素取代的2、3或4-吡啶基,诸如
在本发明的又一个实施方案中,R1选自
根据权利要求1所述的化合物或其盐,其中R1是
·未经取代的嘧啶基-或被C1-6-烷基-、氨基-、-羟甲基-取代的嘧啶基-;或吡嗪基-或哒嗪基,诸如
在本发明的又一个实施方案中,R1是
·被C1-6-烷基-或NC-CH2-CH2-取代的吡咯基-和被C1-6-烷基-、C3-5-环烷基-、NC-CH2-CH2-、-氨基、-甲基-氨基或-卤素取代的吡唑基-,诸如
在本发明的又一个实施方案中,R1是
·被C1-6-烷基-、氨基甲酰基、NC-CH2-CH2-、氨基-或-甲基氨基-取代的咪唑基-,诸如
在本发明的又一个实施方案中,R1是
·未经取代的三唑基-或被C1-3-烷基-取代的三唑基-,诸如
在本发明的再又一个实施方案中,R1是
·被甲基取代的噁唑基-或被NC-CH2-CH2-取代的噻吩基-,诸如
进一步优选的是表1中列出的以下化合物:
表1:化合物(C#)1至56
现在将更严密地定义上文和下文中用于描述根据本发明的化合物的一些术语。
在本文中没有明确定义的术语应当被给出本领域技术人员根据本公开文本和上下文而给出的含义。然而,如本说明书所用,除非规定相反,否则以下术语具有所指示的含义并且遵守以下约定。
在以下定义的基团(group、radical)或部分中,碳原子数量通常在基团之前指定,例如,C1-6-烷基是指具有1至6个碳原子的烷基基团(group)或基团(radical)。通常,在像HO-、H2N-、(O)S-、(O)2S-、NC-(氰基)、HOOC-、F3C-等基团中,技术人员可以从基团本身的自由化合价中看出与分子的一个或多个基团附接点。对于包含两个或更多个子基团的组合基团,最后命名的子基团是基团附接点,例如,取代基“芳基-C1-3-烷基-”意指与C1-3-烷基结合的芳基,所述C1-3-烷基结合至核心或结合至取代基所附接的基团。
一般而言,给定残基与另一个基团的附接位点应该是可变的,即,此残基中任何带有待替代氢的有能力的原子都可以是与所附接基团的连接点连接,除非另有说明。
在本发明化合物以化学名称的形式或作为结构式进行描述时,在任何不一致的情况下,应以所述结构式为准。
除非明确指示,否则贯穿整个说明书和所附权利要求书,给定的化学式或名称应当包括互变异构体和所有立体异构体、光学异构体和几何异构体(例如对映异构体、非对映异构体、E/Z异构体等…)及其外消旋体以及处于不同比例的单独的对映异构体的混合物、非对映异构体的混合物、或任何前述形式的混合物,其中存在此类异构体和对映异构体,以及盐,包括其药学上可接受的盐及其溶剂化物,例如像水合物,包括游离化合物的溶剂化物或化合物的盐的溶剂化物。
短语“药学上可接受的”或“生理上可接受的”在本文中用于指代这样的化合物、材料、组合物和/或剂型,它们在合理的医学判断的范围内适用于与人类和动物的组织接触而没有过多毒性、刺激、过敏反应或者其他问题或并发症,并且与合理的受益/风险比相称。
如本文所用,“药学上可接受的盐”是指所公开化合物的衍生物,其中母体化合物通过制备其酸式盐或碱式盐而修饰。药学上可接受的盐的例子包括但不限于诸如胺等碱性残基的矿物酸盐或有机酸盐;诸如羧酸等酸性残基的碱盐或有机盐等。例如,此类盐包括来自苯磺酸、苯甲酸、柠檬酸、乙磺酸、富马酸、龙胆酸、氢溴酸、盐酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、4-甲基-苯磺酸、磷酸、水杨酸、琥珀酸、硫酸和酒石酸的盐。
可以用来自氨、L-精氨酸、钙、2,2’-亚氨基双乙醇、L-赖氨酸、镁、N-甲基-D-葡糖胺、钾、钠和三(羟甲基)-氨基甲烷的阳离子形成其他药学上可接受的盐。
本发明的药学上可接受的盐可以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。通常,此类盐可以通过使这些化合物的游离酸或碱形式与足量的适当的碱或酸在水中或在有机稀释剂(诸如醚、乙酸乙酯、乙醇、异丙醇或乙腈或其混合物)中反应来制备。除上文所提及那些之外的其他酸的盐(其例如可用于纯化或分离本发明的化合物,例如三氟乙酸盐)也构成本发明的一部分。
如本文所用的术语“经取代的”意指,指定原子上的任何一个或多个氢被来自所指示组的选择替代,条件是不超过所述指定原子的可行价数,并且所述取代产生稳定化合物。
如本文所用的术语“部分不饱和的”意指在指定的基团或部分中存在1、2或更多个,优选1或2个双键。优选地,如本文所用,术语“部分不饱和的”不包括完全不饱和的基团或部分。
术语“卤素”通常表示氟(F)、氯(Cl)、溴(Br)和碘(I)。
单独的或与另一个自由基组合的术语“C1-n-烷基”(其中n是从2至n的整数)表示具有1个至n个C原子的无环的、饱和的、支链的或直链的烃自由基。例如,术语C1-5-烷基包括基团H3C-、H3C-CH2-、H3C-CH2-CH2-、H3C-CH(CH3)-、H3C-CH2-CH2-CH2-、H3C-CH2-CH(CH3)-、H3C-CH(CH3)-CH2-、H3C-C(CH3)2-、H3C-CH2-CH2-CH2-CH2-、H3C-CH2-CH2-CH(CH3)-、H3C-CH2-CH(CH3)-CH2-、H3C-CH(CH3)-CH2-CH2-、H3C-CH2-C(CH3)2-、H3C-C(CH3)2-CH2-、H3C-CH(CH3)-CH(CH3)-和H3C-CH2-CH(CH2CH3)-。
单独的或与另一个自由基组合的术语“C3-n-环烷基”(其中n是从4至n的整数)表示具有3至n个C原子的环状、饱和的、非支链的烃自由基。例如,术语C3-7-环烷基包括环丙基、环丁基、环戊基、环己基和环庚基。
上文给出的许多术语可以在式或基团的定义中重复使用,并且在每种情况下彼此独立地具有上文给出的含义之一。
根据本发明的化合物可以使用原则上已知的合成方法获得。优选地,所述化合物通过以下根据本发明的方法获得,所述方法将在下文中更详细地描述。
用于本文公开的化合物的一般化学合成路线是
路线1:
路线2:
缩写:
分析型HPLC方法
方法A
分析柱:Sunfire C18(Waters)2.5μm;3.0x 30mm;柱温:60℃
方法B
分析柱:Xbridge BEH C18,2.1x 30mm,1.7μm;柱温:60℃
方法C
分析柱:Sunfire(Waters)2.5μm;3.0x 30mm;柱温:60℃
方法D
分析柱:XBridge C18(Waters)2.5μm;3.0x 30mm;柱温:60℃
方法E
分析柱:Sunfire C18(Waters)2.5μm;3.0x 30mm;柱温:60℃
方法F
分析柱:Sunfire C18(Waters)2.5μm;3.0x 30mm;柱温:60℃
方法G
分析柱:XBridge C18(Waters)2.5μm;3.0x 30mm;柱温:60℃
方法H
分析柱:XBridge C18(Waters)2.5μm;3.0x 30mm;柱温:60℃方法I
分析柱:XBridge BEH C18_2.1x 30mm_1.7μm;柱温:60℃
方法J
分析柱:Sunfire C18(Waters)2.5μm;3.0x 30mm;柱温:60℃
方法K
分析柱:Sunfire C18(Waters)2.5μm;3.0x 30mm;柱温:60℃
方法L
分析柱:Hypercarb_3.0x 30mm_3μm;柱温:60℃
方法M
分析柱:Acquity UPLC 1.8μm C18(2.1x50mm),柱温:25℃
方法N
分析柱:Kinetex XB-C18 2.6μm(4.6x50mm),柱温:25℃
起始化合物I至XVIII的制备
实施例I:[3-(5-二氟甲基-吡啶-2-基)-5-甲基-3H-[1,2,3]三唑-4-基]-甲醇
将在50mL丁-2-烷-1-醇中的2-叠氮基-5-二氟甲基-吡啶(25.7g,151mmol)在120℃下搅拌5天。尽可能多地在真空中蒸发过量的醇。通过在硅胶上的柱色谱法使用DCM/丙酮(10:1)作为洗脱剂获得9.00g呈白色固体的3-(5-二氟甲基-吡啶-2-基)-5-甲基-3H-[1,2,3]三唑-4-基]-甲醇。
1H NMR(400MHz,DMSO-d6)δppm 2.32-2.43(m,3H)4.86(s,2H)7.26(t,J=56Hz 1H)8.11(d,J=8.59Hz,1H)8.31(s,1H)8.84(d,J=0.76Hz,1H)。
实施例II:2-溴-5-(二氟甲基)吡啶
向在0℃下的6-溴-吡啶-3-甲醛(186g,1.00mol)在1.86L二氯甲烷中的溶液中逐滴添加二乙基氨基三氟化硫(185ml;1.40mol)。将混合物在室温下搅拌18h。将反应混合物倒入冰和饱和NaHCO3中。将水相用DCM萃取3次。将合并的有机层经Na2SO4干燥,过滤并且浓缩。将残余物通过柱色谱法纯化(硅胶,己烷/EE(4/1))以得到170g产物。
C6H4 BrF2N (M=208.0g/mol)
ESI-MS: 208[M+H]+
1H NMR(DMSO-d6,400MHz):δ=8.65(d,J=1.3Hz,1H),7.91-8.08(m,1H),7.76-7.92ppm(m,1H),7.17(t,J=56Hz,1H)。
实施例III:5-(二氟甲基)-2-[2-(三甲基甲硅烷基)乙炔基]吡啶
向在0℃下的实施例II(120g,0.58mol)、双(三苯基膦)氯化钯(II)(20.2g,0.03mol)、碘化铜(I)(5.49g,0.03mol)和三乙胺(250mL,1.73mol)在600mL四氢呋喃中的混合物中逐滴添加乙炔基-三甲基-硅烷(160mL,1.15mol)。将所得混合物在室温下搅拌18h。将混合物通过硅藻土过滤。将滤饼用EtOAc洗涤。将滤液用水洗涤,经Na2SO4干燥,过滤并且浓缩。通过柱色谱法纯化(硅胶,己烷/EE(19/1))得到117g产物。
C11H13F2Nsi (M=225.3g/mol)
ESI-MS: 226[M+H]+
1H NMR(DMSO-d6,400MHz):δ=8.76(d,J=0.8Hz,1H),8.01(dt,J=8.1,0.9Hz,1H),7.69(d,J=8.1Hz,1H),7.16(t,J=56Hz,1H)0.23-0.30ppm(m,9H)。
实施例IV:5-二氟甲基-2-乙炔基-吡啶
向实施例III(100.0g,0.42mol)在800mL四氢呋喃)中的溶液中添加水(15.0mL,834mmol)。将所得溶液冷却至0℃,然后逐滴添加在THF中的1.0M四丁基氟化铵(143mL;0.50mol)。1h后,TLC指示反应完成。添加水,并且将水层用乙醚萃取3次。将合并的有机层干燥,过滤并且谨慎浓缩。将残余物通过柱色谱法纯化(硅胶,己烷/DCM(1/1至0/1))以得到产物。
C8H5F2N (M=153.1g/mol)
ESI-MS: 154[M+H]+
1H NMR(DMSO-d6,400MHz):δ=8.77(d,J=0.8Hz,1H),8.03(br d,J=8.1Hz,1H),7.72(d,J=8.1Hz,1H),7.17(t,J=56Hz,1H)4.50ppm(s,1H)。
实施例V:5-二氟甲基-2-(1-三甲基硅烷基甲基-1H-[1,2,3]三唑-4-基)-吡啶
向实施例IV(50.0g,0.30mol)在1,5L DMF中的溶液中添加碘化铜(I)(10.9g,0.06mol)和N,N-二异丙基乙胺(50.360mL,0.29mol),然后逐滴添加三甲基甲硅烷基甲基叠氮化物(50.6mL,0.34mol)。将所得混合物在室温下搅拌24h。通过添加水/盐水淬灭反应,然后添加EtOAc,并且将混合物通过硅藻土过滤。将滤液用EtOAc萃取3次,经Na2SO4干燥,过滤并且浓缩。通过柱色谱法纯化(硅胶,己烷/EE(3/1)),然后用戊烷研磨固体并且干燥得到68.0g产物。
C12H16F2N4Si (M=282.4g/mol)
ESI-MS: 283[M+H]+
Rt(HPLC): 3.52min(方法M)
1H NMR(DMSO-d6,400MHz):δ=8.78(s,1H),8.52(s,1H),8.13-8.20(m,1H),8.05-8.12(m,1H),7.17(t,J=56Hz,1H)4.10(s,2H),0.11ppm(s,9H)。
实施例VI:5-二氟甲基-2-(1-甲基-1H-[1,2,3]三唑-4-基)-吡啶
向实施例V(93.0g,0.33mol)在1.86L四氢呋喃中的溶液中添加水(11.9ml,0.66mol)。将所得溶液冷却至0℃,并且逐滴添加四丁基氟化铵(395.2ml,0.40mol)。将反应混合物在0℃下搅拌1.5h。添加水并且蒸发THF。将形成的沉淀物过滤,用水洗涤并且干燥以得到51.0g产物。
C9H8F2N4 (M=210.1g/mol)
ESI-MS: 211[M+H]+
1H NMR(DMSO-d6,400MHz):δ=8.80(d,J=1.0Hz,1H),8.65(s,1H),8.14-8.19(m,1H),8.03-8.13(m,1H),7.17(t,J=56Hz,1H),4.13ppm(s,3H)。
实施例VII:5-(5-二氟甲基-吡啶-2-基)-3-甲基-3H-[1,2,3]三唑-4-甲醛
向在-65℃下的实施例VI(40.0g,0.19mol)在1.2L四氢呋喃中的溶液中逐滴添加正丁基锂(114.2mL,0.29mol)在己烷中的2.5M溶液。将所得混合物在此温度下搅拌1.5h。然后,逐滴添加N,N-二甲基甲酰胺(147.4mL,1.90mol)并且然后将反应混合物在0℃下搅拌30min。通过缓慢添加NH4Cl水溶液将反应淬灭。将水层用EtOAc萃取3次。将合并的有机层经Na2SO4干燥,过滤并且浓缩。通过柱色谱法纯化(硅胶,DCM/EE(7/3至5/5)),然后用戊烷研磨得到19.9g产物。
C9H8F2N4 (M=238.2g/mol)
ESI-MS: 239[M+H]+
Rt(HPLC): 2.68min(方法M)
1H NMR(DMSO-d6,400MHz):δ=10.68(s,1H),8.92(d,J=0.8Hz,1H),8.34(d,J=8.3Hz,1H),8.22(dd,J=8.1,1.0Hz,1H),7.23(t,J=56Hz,1H),4.29ppm(s,3H)。
实施例VIII:5-(5-二氟甲基-吡啶-2-基)-3-甲基-3H-[1,2,3]三唑-4-甲醛
将实施例VII(19.9g,0.08mol)溶解在199mL甲醇和99.5mL四氢呋喃中。将所得溶液冷却至0℃。然后分批添加硼氢化钠(6.32g,0.17mol),并且将反应混合物在此温度下搅拌2h。通过添加水将反应淬灭。蒸发MeOH,并且通过过滤收集所得沉淀物,用水洗涤并且干燥。将固体用戊烷研磨以得到19.4g产物。
C9H8F2N4 (M=240.2g/mol)
ESI-MS: 241[M+H]+
Rt(HPLC): 3.52min(方法N)
1H NMR(DMSO-d6,400MHz):δ=8.83(s,1H),8.22(d,J=8.1Hz,1H),8.11(br d,J=8.1Hz,1H),7.18(t,J=56Hz,1H),5.53(s,1H),5.09(d,J=3.8Hz,2H),4.11ppm(s,3H)。
实施例IX.1:3-[3-(5-二氟甲基-吡啶-2-基)-5-甲基-3H-[1,2,3]三唑-4-基甲氧基]-6-碘-哒嗪
向在50mL THF中的实施例I(4.00g,16.6mmol)中添加氢化钠(1.10g,25.0mmol)和3,6-二碘-哒嗪(5.50g,17.0mmol),将反应混合物在80℃下搅拌过夜。将反应混合物蒸发。将残余物用水淬灭,并且将产物用DCM萃取。将有机相合并,并且将有机相用MgSO4干燥并且蒸发。将粗产物通过柱色谱法纯化(硅胶,CH/EE(6/4))以得到6.30g产物。
C14H11F2IN6O (M=444.2g/mol)
ESI-MS: 445[M+H]+
Rt(HPLC): 0.57min(方法A)
1H NMR(DMSO-d6,400MHz):δ=8.53-8.80(m,1H),8.33(dt,J=8.5,1.1Hz,1H),7.96(d,J=9.1Hz,1H),7.22(t,J=52Hz,1H),6.95(d,J=9.1Hz,1H),5.95(s,2H),2.36-2.45ppm(m,3H)。
根据上述实施例IX.1的一般程序制备以下实施例IX.2至IX.4化合物的表中提到的实施例IX.2至IX.4。
实施例IX.2至IX.4化合物的表:
下表中提到的反应条件用于实施例IX.2至IX.4
表:用于上述实施例IX.2至IX.4的反应条件
实施例X.1:1-(6-氯哒嗪-3-基)-1H-吡唑-4-甲腈
向在5mL DMF中的4-氰基吡唑(312mg,3.40mmol)中添加3,6-二氯哒嗪(500mg,3.40mmol)和碳酸钾(1.40g,10.1mmol),并且将反应混合物在室温下搅拌过夜。将混合物用冰水淬灭,并且过滤沉淀。将残余物用水洗涤,并且将分离的固体在真空干燥柜中干燥以得到524mg产物。
C8H4ClN5 (M=205.6g/mol)
ESI-MS: 206[M+H]+
Rt(HPLC): 0.80min(方法C)
根据上述实施例X.1的通用程序制备以下化合物:
实施例XI:3-氯-6-(5-甲基-1H-1,2,4-三唑-1-基)哒嗪
将6-氯-哒嗪-3-基)-肼(16.4g,113mmol)和N-[1-二甲基氨基-甲-(E)-亚基]-乙酰胺(15.5g,136mmol)溶解在164mL乙酸中。将混合物置于80℃预热油浴中。将反应在此温度下搅拌30min(TLC监测),并且在真空下蒸发乙酸。将残余物溶解在EtOAc中,并且将有机层用NaHCO3(浓水溶液)缓慢中和。将有机层经Na2SO4干燥并且蒸发溶剂。使用EtOAc/己烷(3:1)作为洗脱剂在硅胶上纯化产物。获得10.2g呈奶油状固体的3-氯-6-(5-甲基-[1,2,4]三唑-1-基)-哒嗪。
实施例XII:1-(6-氯哒嗪-3-基)-1H-咪唑-4-甲酸甲酯
在0℃下向在50mL DMF中的氢化钠(1.74g,43.6mmol)添加1H-咪唑-4-甲酸甲酯(5.00g,39.6mmol)。将反应混合物搅拌30min。在0℃下向反应混合物中添加3,6-二氯哒嗪(5.90g,39.6mmol)在30mL DMF中的溶液,并且将混合物搅拌20h以达到室温。将反应混合物在冰冷却下用水淬灭,并且过滤沉淀,洗涤并且干燥以得到3.90g产物。
C9H7ClN4O2 (M=238.6g/mol)
ESI-MS: 239[M+H]+
1H NMR(400MHz,DMSO-d6)δ=8.74(d,J=1.3Hz,1H),8.72(d,J=1.0Hz,1H),8.43(d,J=9.3Hz,1H),8.25(d,J=9.3Hz,1H),3.82(s,3H)。
实施例XIII:1-(6-氯哒嗪-3-基)-1H-咪唑-4-甲酸
向在100mL 1,4-二噁烷中的实施例XII(3.80g,15.8mmol)中添加1M NaOH(16.0mL,16.0mmol)并且在室温下搅拌18h。将反应混合物用冰和1M HCl(16.0mL,16.0mmol)淬灭。将沉淀过滤,洗涤并且干燥以产生3.30g产物。
C8H5ClN4O2 (M=224.6g/mol)
ESI-MS: 225[M+H]+
Rt(HPLC): 0.58min(方法C)
实施例XIV:1-(6-氯哒嗪-3-基)-1H-咪唑-4-甲酰胺
向在10mL DMF中的实施例VI(1.00g,4.50mmol)中添加DIPEA(2.30mL,13.4mmol)和TBTU(1.40g,4.50mmol),并且在室温下搅拌10min。添加碳酸氢铵(1.10g,13.4mmol),并且将反应混合物在室温下搅拌1h。将混合物用冰淬灭,并且将沉淀过滤,洗涤并且干燥以得到0.80g产物。
C8H6ClN5O (M=223,6g/mol)
ESI-MS: 224[M+H]+
Rt(HPLC): 0,54min(方法C)
实施例XV:1-[6-(4-氰基-1H-咪唑-1-基)哒嗪-3-基]-1H-咪唑-4-甲腈
向在100mL DMF中的1H-咪唑-4-甲腈(9.30g,99.9mmol)添加实施例III(20.5g,99.9mmol)和碳酸钾(41.4g,299mmol),并且将反应混合物在50℃下搅拌18h。添加1H-咪唑-4-甲腈(5.00g,53.7mmol),并且将混合物在50℃下搅拌3天。
将混合物用水淬灭,并且将沉淀过滤以在干燥后得到25.8g产物。
C12H6N8 (M=262.2g/mol)
ESI-MS: 263[M+H]+
Rt(HPLC): 0.74min(方法C)
实施例XVI.1:3-氯-6-(4-氯-1H-吡唑-1-基)哒嗪
向在5mL DMF中的4-氯-1H-吡唑(688mg,7.00mmol)添加3,6-二氯-哒嗪(500mg,3.36mmol)和碳酸铯(2.40g,7.38mmol),并且将反应混合物在室温下搅拌过夜。将混合物用水淬灭,并且将沉淀过滤以得到686mg产物。
C8H6N8 (M=215.0g/mol)
ESI-MS: 216[M+H]+
Rt(HPLC): 0,51min(方法A)
根据上述通用程序(实施例XVI.1)制备以下化合物:
实施例XVII:6-(吡嗪-2-基)-2,3-二氢哒嗪-3-酮
向在K2CO3水溶液(6.79g,在30mL水中49.0mmol)中的2-氧代乙酸水合物(2.26g,25.0mmol)中添加乙酰基吡嗪(3.00g,24.6mmol)。将混合物在室温下搅拌6h。然后添加乙酸(12.9mL,221mmol)和水合肼(1.42mL,29.0mmol),并且将反应混合物回流2h。将溶液冷却至室温并且用K2CO3碱化至pH 7。将沉淀物过滤,在40℃烘箱中干燥以获得1.29g产物。
C8H6N4O (M=174.1g/mol)
ESI-MS: 175[M+H]+
Rt(HPLC): 0.23min(方法A)
实施例XVIII:3-氯-6-(吡嗪-2-基)哒嗪
将在POCl3(5.00mL,53.6mmol)中的实施例XVII(1.50g,6.03mmol)在100℃下搅拌1h。将反应混合物蒸发,并且将残余物在冷却下用DCM稀释。添加10mL饱和NaHCO3溶液,并且在搅拌下将此溶液逐滴添加到冰冷的饱和NaHCO3溶液中,直到溶液为中性。30min后,将溶液经硅藻土过滤并且将其用DCM萃取。收集有机层,干燥并且蒸发溶剂。将产物通过柱色谱法纯化(硅胶,CH/EE(1/1))以得到570mg产物。
C8H6ClN4 (M=192.6g/mol)
ESI-MS: 193[M+H]+
Rt(HPLC): 0.33min(方法A)
最终化合物的制备
实施例1:5-[6-({1-[5-(二氟甲基)吡啶-2-基]-4-甲基-1H-1,2,3-三唑-5-基}甲氧基)哒嗪-3-基]-1-甲基-1,2-二氢吡啶-2-酮
在氩气下,向1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,2-二氢吡啶-2-酮(159mg,0.70mmol)中添加在1.5mL甲醇中的实施例IX.1(250mg,0.60mmol)、3mL 1,4-二噁烷、2M碳酸钠水溶液(0.60mL,1.10mmol)和Pd-PEPPSI(9.50mg 0.01mmol),并且将反应混合物在100℃下搅拌3h。将混合物通过制备型HPLC纯化以获得96.1mg产物。
C20H17F2N7O2 (M=425.4g/mol)
ESI-MS: 426[M+H]+
Rt(HPLC): 0.58min(方法D)
1H NMR(400MHz,DMSO-d6)δppm 2.41-2.46(m,3H)3.48-3.57(m,3H)5.96-6.08(m,2H)6.47-6.58(m,1H)7.21(t,J=56Hz 1H)7.23(s,1H)7.95-8.06(m,1H)8.13-8.22(m,2H)8.29-8.38(m,1H)8.51(d,J=2.66Hz,1H)8.65-8.71(m,1H)。
根据上述实施例1的通用程序制备以下化合物:
对于实施例化合物,使用表2中的反应条件。
表2:实施例1-35的反应条件
实施例36
在0℃下,向在2mL DMSO中的实施例I(50.0mg,0.20mmol)和实施例XIV(46.5mg,0.20mmol)中逐滴添加2mol/L叔戊醇钠在Me-THF(83.9μL,0.20mmol)中的溶液。将反应混合物在室温下搅拌过夜,然后在50℃下搅拌过夜,并且然后在75℃下搅拌3天。将混合物通过制备型HPLC纯化以获得3.20mg产物。
C18H15F2N9O2 (M=427.4g/mol)
ESI-MS: 428[M+H]+
Rt(HPLC): 0.77min(方法C)
根据上述实施例36的通用程序制备以下化合物:
对于实施例化合物37-41,使用下表中的反应条件。实施例化合物37-41的反应条件的表
实施例42:1-[6-({1-[5-(二氟甲基)吡啶-2-基]-4-甲基-1H-1,2,3-三唑-5-基}甲氧基)哒嗪-3-基]-1H-咪唑-4-甲腈
向在5mL ACN中的实施例I(200mg,1.00mmol)中添加碳酸铯(814mg,2.00mmol)和实施例XV(273mg,1.00mol),并且将混合物在90℃下搅拌过夜。将反应混合物用水淬灭,并且过滤沉淀以获得粗产物。将粗产物通过硅胶柱(CH/EE)纯化,最后在MeOH/EE/醚中重结晶得到151mg产物。
C18H13F2N9O (M=409.3g/mol)
ESI-MS: 410[M+H]+
Rt(HPLC): 0.50min(方法A)
1H NMR(400MHz,DMSO-d6)δppm 2.34-2.48(m,3H)5.97-6.14(m,2H)7.22(t,J=56Hz,1H)7.50-7.64(m,1H)8.16-8.19(m,1H)8.19-8.21(m,1H)8.31-8.43(m,1H)8.67(d,J=1.14Hz,1H)8.73(d,J=1.27Hz,1H)8.90-8.95(m,1H)。
根据上述实施例42的通用程序制备下表的以下化合物43-47:
化合物43-47的表
对于实施例化合物43-47,使用下表中的反应条件。实施例化合物43-47的反应条件的表
实施例48:3-({4-[5-(二氟甲基)吡啶-2-基]-1-甲基-1H-1,2,3-三唑-5-基}甲氧基)-6-(5-甲基-1H-1,2,4-三唑-1-基)哒嗪
向在10mL二噁烷中的实施例VIII(200mg,0.83mmol)和实施例XI(163mg,0.83mmol)中添加叔戊醇钠(101mg,0.92mmol)。将反应混合物在90℃下搅拌过夜,然后在室温下搅拌周末。将反应混合物用水稀释并且将过滤物沉淀。将粗固体在MeOH中重结晶以获得212mg产物。
C17H15F2N9O (M=399.4g/mol)
ESI-MS: 400[M+H]+
Rt(HPLC): 0.46min(方法A)
根据上述实施例48的通用程序制备以下化合物49和50:
对于实施例化合物49-50,使用下表中的反应条件。
实施例化合物49-50的反应条件的表
实施例51:3-(4-氯-1H-吡唑-1-基)-6-({4-[5-(二氟甲基)吡啶-2-基]-1-甲基-1H-1,2,3-三唑-5-基}甲氧基)哒嗪
向2 mL DCM中的实施例VIII(100 mg,0.42 mmol)和实施例XVI.1(89.5 mg,0.42mmol)中添加氢化钠(21.8 mg,0.50 mmol)。将反应混合物在室温下搅拌过夜。将反应混合物直接通过制备型HPLC纯化以获得41.6 mg产物。
C17H13ClF2N8O(M=418.8 g/mol)
ESI-MS:397[M+H]+
Rt(HPLC):0.86 min(方法F)
根据上述通用程序(实施例51)制备以下化合物:
对于实施例化合物52-53,使用下表中的反应条件。
实施例化合物52-53的反应条件的表
实施例54:3-({1-[5-(二氟甲基)吡啶-2-基]-4-甲基-1H-1,2,3-三唑-5-基}甲氧基)-6-(4-氟-1H-吡唑-1-基)哒嗪
在氩气下向在1mL二噁烷中的4-氟-1H-吡唑(6.00mg,0.10mmol)中添加实施例IX.1(30.0mg,0.10mmol)、碘化铜(I)(5.10mg,0.03mmol)、磷酸钾(57.3mg,0.30mmol)和(1R,2R)-N,N'-二甲基-1,2-环己二胺(8.50μL,0.05mmol)。然后添加100μL 25%氨,并且将混合物再搅拌15min。将反应混合物经alox柱筒和SPE-硫醇柱筒过滤,并且然后将其通过制备型HPLC纯化以获得20.2mg产物。
C17H13F3N8O(M=402.3g/mol)
ESI-MS: 403[M+H]+
Rt(HPLC): 0,84min(方法F)
根据上述实施例54的通用程序制备以下化合物55:
对于实施例化合物55,使用以下反应条件。
实施例56:3-({1-[5-(二氟甲基)吡啶-2-基]-4-甲基-1H-1,2,3-三唑-5-基}甲氧基)-6-(吡嗪-2-基)哒嗪
在氩气下向在2mL二噁烷中的2-三丁基甲锡烷基吡嗪(83.0mg,0.23mmol)中添加实施例IX.2(53.0mg,0.15mmol)、氟化铯(46.0mg,0.30mmol)和xphos(26.0mg,0.03mmol)。将反应混合物通过制备型HPLC纯化以获得17.0mg产物。
C18H14F2N8O (M=396.3g/mol)
ESI-MS: 397[M+H]+
Rt(HPLC): 0,92min(方法G)
1H NMR(400MHz,DMSO-d6)δppm 2.47(s,3H)6.11(s,2H)7.22(t,J=56Hz,1H)7.35(d,J=9.25Hz,1H)8.20(d,J=8.49Hz,1H)8.32-8.37(m,1H)8.39(d,J=9.25Hz,1H)8.67(d,J=1.14Hz,1H)8.74-8.84(m,2H)9.55-9.66(m,1H)。
生物学实施例
测定A:体外抑制3H-氟马西尼(3H-Ro15-1788)结合表达人GABAAα5β3γ2s受体的HEK
细胞
可以选择性地将苯并二氮杂卓调节剂单元用拮抗剂3H-氟马西尼标记。
据报道,3H-氟马西尼对不同亚基组合的亲和力对于α1β2γ2;α2β2γ2;α3β2γ2和α5β2γ2s受体分别为1.0nM、1.1nM、1.5nM和0.4nM,并且对于α4β2γ2和α6β2γ2受体为107nM和90nM(参见Sieghart;Pharmacol.Rev.1995 47 181-234)。
就3H-氟马西尼结合而言,突变α5β3γ2s GABAA受体的药理学与野生型受体的药理学类似。
细胞培养和膜制备
将稳定表达重组人GABAAα5β3γ2s受体(质粒H46/E9/B10)的HEK-293细胞系接种在T175聚苯乙烯烧瓶或滚瓶(1700cm2,Fisher Scientific CCI-431191)中并且在杜尔贝科改良型伊格尔培养基(Dulbecco's Modified Eagle Medium,DMEM)(含GlutaMAXTM,补充有10%胎牛血清和以下抗生素:潮霉素B(50pg/ml;γ2亚基)或G418(0.5mg/ml;Ω5亚基)中的一种或两种)中培养(37℃,5% CO2)。
当培养物达到融合时,去除DMEM,并且将细胞在杜尔贝科磷酸盐缓冲盐水(DPBS)中洗涤(对于T175烧瓶为10ml;对于滚瓶为50ml)一次。在大约5min内向培养物中添加DPBS(对于T175烧瓶为10ml;对于滚瓶为100ml)后,通过轻轻摇动或轻敲烧瓶,使细胞容易地从表面脱离。将细胞悬浮液转移到Falcon管中,并且在2℃下以23,500x g离心10min。使用Ultra-Turrax匀浆器将沉淀物在15ml Tris-柠檬酸盐缓冲液(50mM,pH 7.1)中洗涤一次并且在2℃下以27,000x g离心10min。将经洗涤的沉淀物重新悬浮在15ml Tris-柠檬酸盐缓冲液中并且在-80℃下冷冻,直到结合实验当天。
测定
在实验当天,将细胞膜制剂解冻,并且在2℃下以27,000x g离心10min。使用UltraTurrax匀浆器将沉淀物重新悬浮在Tris-柠檬酸盐缓冲液中至15-50pg蛋白质/测定,并且然后用于结合测定。
将500μl细胞悬浮液等分试样添加到25μl测试化合物溶液和25μl 3H-氟马西尼(1nM,最终浓度)中,混合并且在2℃下孵育40min。使用氯硝西泮(1μM,最终浓度)确定非特异性结合。
在玻璃小瓶/96小瓶板中进行测试化合物的所有稀释和测定的孵育。将测试化合物和3H-氟马西尼的溶液制备为所希望最终浓度的22x。将化合物溶解在100% DMSO(10mM储备液)中,在48%乙醇-水中稀释,并且以连续的1:3或1:10稀释度一式三份地测试。当筛选大量化合物时,在单孔中测试每种化合物的仅一种浓度。常规地不包括参考化合物,但对于每一个进行的实验,将总结合和非特异性结合与在测定验证期间获得的数据进行比较。
通过以下方式终止结合:
1)使用Brandel细胞收获器快速过滤到Whatman GF/C玻璃纤维过滤器上,然后用1ml冰冷缓冲液洗涤5次,或者2)使用Tomtec细胞收获器快速过滤到UniFilter GF/C玻璃纤维过滤器板上,然后用大约5ml冰冷缓冲液洗涤。
通过常规液体闪烁计数使用以下来确定在过滤器上的放射量:
1)Tri-GarbTM计数器(PerkinElmer Life and Analytical Sciences),用于单独的大型过滤器,或
2)TopcountTM计数器(PerkinElmer Life and Analytical Sciences),用于96孔过滤器板。特异性结合是总结合减去非特异性结合。
计算
在计算IC50(使3H-氟马西尼的特异性结合抑制50%的测试化合物浓度(μM))之前,必须获得25%-75%的特异性结合抑制。
测试化合物的IC50值基于以下等式确定:
B=100-(100*Cn/(IC50 n+Cn))
其中B是占总特异性结合的百分比结合;c是测试化合物的浓度;并且n是希尔系数。出于筛选目的,n被设置为1。使用曲线拟合程序GraphPad Prism通过非线性回归方法由浓度响应曲线计算IC50值。
可以使用Cheng和Prusoff的等式从IC50值计算测试化合物的Ki值:
K=IC50/(1+L/Kd)
其中3H-氟马西尼的Kd是0.36nM,并且L是抑制测定中3H-氟马西尼的测量浓度。
结果
对于WO 2020/016433的实施例化合物1、13、10和28以及本发明的实施例化合物42、56、5和55在测定A中观察到的效力在下表中示出。
测定B:α5β2γ2GABAA受体调节的体外评价。
式(I)的化合物的调节功效是使用双电极电压钳(TEVC)技术在卵母细胞中确定的电生理记录。以3:1:3的比率向卵母细胞注射人GABAA受体亚基α5、β2和γ2的cRNA,并且通过与次最大EC5-20 GABA浓度(0.5μM)(称为GABA对照)共同应用来评价调节功效。作为标准,从最低浓度开始,在每个卵母细胞上以五种浓度(3.16、0.316、0.0316、0.00316和0.000316μM)测试化合物。将减去背景的峰值电流振幅归一化为相应的GABA对照电流,转化为变化%,并且描绘+/-S.E.M.随递增的化合物浓度的变化。使用非线性回归将绘制的数据点拟合到经验希尔方程。从此拟合程序得出针对最大功效(底部)和效力(Log EC50)的95%置信区间。
这些数据显示,本发明的化合物显示出靶接合和GABA受体功能的强负性调节。数据还显示,所述化合物,特别是与从WO 2020/016433中已知的化合物相比,在GABAA5R结合方面具有改善的特性,这意味着用于疾病治疗的化合物的有效剂量较低(还参见:Ballard,T.M.等人(2009).RO4938581,a novel cognitive enhancer acting at GABAAα5subunit-containing receptors.Psychopharmacology(2009)202:207-223;J.Pharmacol.Exp.Ther.(2006)316:1335-1345)。
评估用30人MDR1基因转染的Madin-Darby犬肾(MDCK)细胞中的外排以评估脑渗透(Drug Metabolism and Disposition February 2008,36(2)268-275;DOI:https://doi.org/10.1124/dmd.107.017434)
在顶端到基底(AB)和基底到顶端(BA)转运方向上测量(pH 7.4,37℃)化合物跨越MDCK-MDR1细胞单层的表观渗透系数(PE)。AB渗透性(PEAB)代表将从血液到35脑中的药物吸收,并且BA渗透性(PEBA)代表经由被动渗透性以及由外排和摄取转运蛋白介导的主动转运机制二者从脑外回到血液中的药物外排,所述外排和摄取转运蛋白在MDCK-MDR1细胞上表达,主要由过表达的人MDR1 P-gp表达。通过将AB渗透性与具有在人体中已知的体外渗透性和口服吸收的参考化合物的AB渗透性进行比较,将化合物划分至渗透性/吸收类别。渗透性在两个转运方向上相同或类似表明被动渗透,而矢量渗透性指向另外的主动转运机制。PEBA高于PEAB表明由MDR1 P-gp介导的主动外排的参与。主动转运是浓度依赖性饱和的。
将MDCK-MDR1细胞(1-2x 10e5个细胞/1cm2面积)接种在过滤器插入物(Costartranswell聚碳酸酯或PET过滤器,0.4μm孔径)上,并且培养(DMEM)7天。随后,通过在完全培养基中用5mM丁酸钠培养细胞2天来增强MDR1表达。将化合物溶解于适当的溶剂(如DMSO,1-20mM储备溶液)中。将储备溶液用HTP-4缓冲液(128.13mM NaCl、5.36mM KCl、1mM MgSO4、1.8mM CaCl2、4.17mM NaHCO3、1.19mM Na2HPO4 x 7H2O、0.41mM NaH2PO4xH2O、15mM HEPES、20mM葡萄糖、0.25% BSA,pH 7.4)稀释以制备运输溶液(0.1-300μM化合物,最终DMSO<=0.5%)。将运输溶液(TL)分别应用于顶端或基底侧供体侧以测量A-B或B-A渗透性(3个过滤器重复)。受体(receiver)侧含有与供体侧相同的缓冲液。在实验开始和结束时从供体(donor)收集样品,并且以不同的时间间隔在长达2小时内还从受体侧收集样品用于通过HPLC-MS/MS或闪烁计数进行浓度测量。用新鲜的受体溶液更换采样的受体体积
这些数据显示,本发明的化合物具有优异的脑渗透特性以及从脑室中低的外排比率。评估在人肝微粒体(人MST)中的代谢稳定性
根据本发明的化合物的代谢稳定性可以如下研究:
在37℃下用合并的人肝微粒体测定测试化合物的代谢降解。100μL的最终孵育体积/时间点含有TRIS缓冲液pH 7.6(在室温下)(0.1M)、MgCl2(5mM)、微粒体蛋白(1mg/mL)和最终浓度为1μM的测试化合物。在37℃下短的预孵育期后,通过添加还原形式的β-烟酰胺腺嘌呤二核苷酸磷酸(NADPH,1mM)使反应开始,并且通过在不同时间点后将等分试样转移到溶剂中使反应终止。在离心(10000g,5min)后,通过LCMS/MS测定上清液的等分样品中母体化合物的量。通过浓度-时间曲线的半对数图的斜率来确定半衰期(t1/2)。
实施例 | 人MST t1/2[min] | 实施例 | 人MST t1/2>[min] |
1 | >130 | 28 | >130 |
3 | >130 | 29 | 97 |
4 | 40 | 30 | >130 |
5 | 83 | 31 | 127 |
6 | 116 | 32 | 78 |
7 | >130 | 33 | 98 |
8 | >130 | 35 | >130 |
9 | 101 | 37 | 129 |
17 | >130 | 39 | >130 |
18 | >130 | 48 | >130 |
20 | >130 | 49 | >130 |
22 | >130 | 50 | 130 |
23 | >130 | 52 | >130 |
24 | 62 | 53 | >130 |
25 | >130 | 56 | >130 |
鉴于其调节含有α5亚基的GABAA受体的活性的能力以及其有利的药代动力学特性,根据本发明的通式(I)的化合物或其生理上可接受的盐适用于治疗和/或预防性治疗所有可能受含有α5亚基的GABAA受体的调节影响的那些疾病或病症。因此,根据本发明的化合物,包括其生理上可接受的盐,特别适用于预防或治疗疾病,特别是急性神经障碍、慢性神经障碍、认知障碍、阿尔茨海默病、记忆缺陷、精神分裂症、与精神分裂症相关的阳性、阴性和/或认知症状、与精神分裂症相关的认知损害、双相障碍、自闭症、唐氏综合征、I型神经纤维瘤病、术后认知衰退、睡眠障碍、昼夜节律障碍、肌萎缩侧索硬化症、AIDS引起的痴呆、精神病性障碍、物质诱发的精神病性障碍、焦虑障碍、广泛性焦虑障碍、惊恐性障碍、妄想性障碍、强迫性障碍、急性应激障碍、药物成瘾、运动障碍、帕金森病、不宁腿综合征、认知缺陷障碍、多发梗塞性痴呆、心境障碍、抑郁症、重度抑郁障碍、神经精神病性病症、精神病、注意缺陷多动障碍、神经性疼痛、中风、注意力障碍、进食障碍、厌食症、神经性厌食症、恶病质、体重减轻、肌肉萎缩、疼痛病症、慢性疼痛、伤害性疼痛、术后疼痛、骨关节炎疼痛、类风湿性关节炎疼痛、肌肉骨骼疼痛、烧伤疼痛、眼部疼痛、由于炎症引起的疼痛、由于骨折引起的疼痛、痛觉过敏、神经性疼痛、疱疹相关疼痛、HIV相关神经性疼痛、创伤性神经损伤、创伤性脑损伤后的恢复、中风后疼痛、缺血后疼痛、纤维肌痛、慢性头痛、偏头痛、紧张型头痛、糖尿病性神经性疼痛、幻肢疼痛、内脏疼痛和皮肤疼痛。
根据本发明的化合物,包括其生理上可接受的盐,甚至更适用于尤其是治疗认知障碍、术后认知衰退、阿尔茨海默病、精神分裂症、与精神分裂症相关的阳性、阴性和/或认知症状、与精神分裂症相关的认知损害、与唐氏综合征相关的认知缺陷、与自闭症相关的认知缺陷、与I型神经纤维瘤病相关的认知缺陷、或中风后认知缺陷。
在本发明的又一方面,本发明涉及用于治疗或预防上述疾病和病症的方法,所述方法包括向人类施用有效量的通式(I)的化合物或其药学上可接受的盐。
每天可应用的通式(I)的化合物的剂量范围通常为通过口服途径从0.1至1000mg,优选从1至500mg,在每种情况下每天施用1至4次。
各剂量单位可以方便地含有从0.1至500mg,优选1至100mg。
实际药学有效量或治疗剂量当然将取决于本领域技术人员已知的因素,诸如患者的年龄和体重、施用途径和疾病的严重性。在任何情况下,施用所述组合的剂量和方式将允许基于患者的独特状况递送药学有效量。
用于施用式(I)的化合物(包括其药学上可接受的盐)的合适制剂对于本领域普通技术人员来说将是显而易见的,并且包括例如片剂、丸剂、胶囊、栓剂、锭剂、糖锭、溶液、糖浆、酏剂、小药囊、注射剂、吸入剂、散剂等。一种或多种药物活性化合物的含量应在作为整体的组合物的从0.1至95wt.-%、优选5.0至90wt.-%的范围内变化。
合适的片剂可以例如通过将一种或多种根据式I的化合物与已知的赋形剂混合获得,所述赋形剂例如惰性稀释剂、载体、崩解剂、佐剂、表面活性剂、粘合剂和/或润滑剂。片剂也可以由若干层组成。
为此目的,可以配制根据本发明制备的式I的化合物,任选地与其他活性物质一起,与一种或多种惰性常规载体和/或稀释剂一起,例如与玉米淀粉、乳糖、葡萄糖、微晶纤维素、硬脂酸镁、柠檬酸、酒石酸、水、聚乙烯吡咯烷酮、水/乙醇、水/甘油、水/山梨醇、水/聚乙二醇、丙二醇、鲸蜡硬脂醇、羧甲基纤维素或脂肪物质诸如硬脂肪或其合适的混合物一起。
根据本发明的化合物还可以与其他活性物质联合使用,特别是用于治疗和/或预防上述疾病和病症。实施例列表为:多奈哌齐、美金刚、乙酰唑胺、卡马西平、醋酸艾司利卡西平、乙琥胺、加巴喷丁、拉科酰胺、拉莫三嗪、左乙拉西坦、布瓦西坦、硝基安定、奥卡西平、哌仑帕奈、吡拉西坦、苯巴比妥、苯妥英、普瑞巴林、普里米酮、卢非酰胺、丙戊酸钠、司替戊醇、噻加宾、托吡酯、氨己烯酸、唑尼沙胺、左旋多巴、卡比多巴、氟哌啶醇、洛沙平、硫利达嗪、吗啉酮、甲哌硫丙硫蒽、羟哌氟丙嗪、美索达嗪、三氟啦嗪、奋乃静、氯丙嗪、阿立哌唑、马来酸阿塞那平、氯氮平、伊潘立酮、鲁拉西酮、奥氮平、帕利哌酮、喹硫平、利培酮、齐拉西酮和唑吡坦。
上述组合配偶体的剂量通常是正常推荐的最低剂量的1/5至多正常推荐剂量的1/1。
因此,在另一个方面,本发明涉及与至少一种作为组合配偶体的上述活性物质组合的根据本发明的化合物或其药学上可接受的盐用于制备适用于治疗或预防上述疾病或病症的药物组合物的用途。
与另一种活性物质组合的根据本发明的化合物的使用可以同时或在交错的时间进行,但特别是在短时间间隔内。如果同时施用它们,则两种活性物质一起给予患者;而如果在交错的时间使用它们,则两种活性物质在少于或等于12小时,特别是少于或等于6小时的时间段内给予患者。
因此,在另一个方面,本发明涉及一种药物组合物,所述药物组合物包含根据本发明的化合物或其药学上可接受的盐和至少一种作为组合配偶体的上述活性物质,任选地与一种或多种惰性载体和/或稀释剂一起。
根据本发明的化合物可以一起存在于一种配制品中,例如片剂或胶囊,或分开地存在于两种相同或不同的配制品中,例如呈所谓的成套试剂盒的形式。
Claims (20)
1.一种具有式(I)的化合物或其盐
其中:
Xa和Xb彼此不相同并且表示C或N,并且
R1是经取代的苯基或含有1或2或3个杂原子的5或6元经取代的杂环基环。
2.根据权利要求1所述的化合物或其盐,其中Xa或Xb是C。
3.根据权利要求1所述的化合物或其盐,其中R1选自
·被氨基甲酰基取代的苯基
以及
·未经取代的2-吡啶酮或者被卤素诸如氟取代的或在氮上被甲基或乙基取代的2-吡啶酮
4.根据权利要求1所述的化合物或其盐,其中R1是
被NC-或-甲硫基化物-、氨基-、甲基-氨基-或-甲基磺酰基或卤素取代的3-吡啶基,
5.根据权利要求1所述的化合物或其盐,其中R1是
经取代或未经取代的嘧啶基-(被C1-6-烷基-、-氨基、-羟甲基取代)或吡嗪基-,
6.根据权利要求1所述的化合物或其盐,其中R1是
被C1-6-烷基-或NC-CH2-CH2-取代的吡咯基-和被C1-6-烷基-、C3-5-环烷基-、NC-CH2-CH2-、-氨基、-甲基-氨基或-卤素取代的吡唑基-
7.根据权利要求1所述的化合物或其盐,其中R1是
被C1-6-烷基-、氨基甲酰基、NC-CH2-CH2-、氨基-或-甲基氨基-取代的咪唑基-
8.根据权利要求1所述的化合物或其盐,其中R1是
未经取代的三唑基-或被C1-3-烷基-诸如甲基取代的三唑基-
9.根据权利要求1所述的化合物或其盐,其中R1是
被甲基取代的噁唑基-或被NC-CH2-CH2-取代的噻吩基-
10.根据权利要求1所述的化合物或其盐,其中R1选自
·被氨基甲酰基取代的苯基;
·未经取代的2-吡啶酮或者被卤素诸如氟取代的或在氮上被甲基或乙基取代的2-吡啶酮;
·被NC-或-甲硫基化物-、氨基-、甲基-氨基-、-甲基磺酰基或卤素取代的3-吡啶基;
·未经取代的嘧啶基-或被C1-6-烷基-、氨基-、-羟甲基-取代的嘧啶基-;或吡嗪基-;
·被C1-6-烷基-或NC-CH2-CH2-取代的吡咯基-和被C1-6-烷基-、C3-5-环烷基-、NC-CH2-CH2-、氨基-、甲基-氨基-或卤素取代的吡唑基-;
·被C1-6-烷基-、氨基甲酰基-、NC-CH2-CH2-、氨基-或-甲基氨基-取代的咪唑基-;
·未经取代的三唑基-或被C1-3-烷基-诸如甲基取代的三唑基-;
·被甲基取代的噁唑基-和被NC-CH2-CH2-取代的噻吩基-。
11.根据权利要求1所述的化合物或其盐,选自:
12.根据权利要求1-11中任一项所述的化合物的盐,其用作药剂。
13.一种用根据权利要求1至11中任一项所述的化合物或其盐制备的药剂。
14.根据权利要求1所述的化合物或其盐,其中式(I)是化合物22至56和39中任一个的式。
15.一种用于制备根据权利要求1所述的化合物的方法,所述方法包括以下化学反应路线
(a)
16.一种用于制备根据权利要求1所述的化合物的方法,所述方法包括以下化学反应路线
17.一种药物组合物,所述药物组合物含有至少一种根据权利要求1至11中一项或多项所述的化合物或其药学上可接受的盐以及一种或多种药学上可接受的载体。
18.根据权利要求17所述的药物组合物,所述药物组合物用于治疗或预防急性神经障碍、慢性神经障碍、认知障碍、阿尔茨海默病、记忆缺陷、精神分裂症、与精神分裂症相关的阳性、阴性和/或认知症状、与精神分裂症相关的认知损害、双相障碍、自闭症、唐氏综合征、I型神经纤维瘤病、术后认知衰退、睡眠障碍、昼夜节律障碍、肌萎缩侧索硬化症、AIDS引起的痴呆、精神病性障碍、物质诱发的精神病性障碍、焦虑障碍、广泛性焦虑障碍、惊恐性障碍、妄想性障碍、强迫性障碍、急性应激障碍、药物成瘾、运动障碍、帕金森病、不宁腿综合征、认知缺陷障碍、多发梗塞性痴呆、心境障碍、抑郁症、重度抑郁障碍、神经精神病性病症、精神病、注意缺陷多动障碍、神经性疼痛、中风、注意力障碍、进食障碍、厌食症、神经性厌食症、恶病质、体重减轻、肌肉萎缩、疼痛病症、慢性疼痛、伤害性疼痛、术后疼痛、骨关节炎疼痛、类风湿性关节炎疼痛、肌肉骨骼疼痛、烧伤疼痛、眼部疼痛、由于炎症引起的疼痛、由于骨折引起的疼痛、痛觉过敏、神经性疼痛、疱疹相关疼痛、HIV相关神经性疼痛、创伤性神经损伤、创伤性脑损伤后的恢复、中风后疼痛、缺血后疼痛、纤维肌痛、慢性头痛、偏头痛、紧张型头痛、糖尿病性神经性疼痛、幻肢疼痛、内脏疼痛和皮肤疼痛
19.根据权利要求18所述的药物组合物,所述药物组合物包含治疗有效量的0.1至1000mg、优选1至500mg的根据权利要求1至11中任一项所述的化合物或其药学上可接受的盐。
20.根据权利要求1到11中一项或多项所述的化合物或其药学上可接受的盐或根据权利要求17所述的药物组合物,用于预防或治疗认知障碍、术后认知衰退、阿尔茨海默病、精神分裂症、与精神分裂症相关的阳性、阴性和/或认知症状、与精神分裂症相关的认知损害、与唐氏综合征相关的认知缺陷、与自闭症相关的认知缺陷、与I型神经纤维瘤病相关的认知缺陷、或中风后认知缺陷。
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EP20189671.9 | 2020-08-05 | ||
EP20197363.3 | 2020-09-22 | ||
EP20204664.5A EP3992188A1 (en) | 2020-10-29 | 2020-10-29 | Difluoromethyl-pyridin-2-yl triazoles |
EP20204664.5 | 2020-10-29 | ||
PCT/EP2021/071755 WO2022029170A1 (en) | 2020-08-05 | 2021-08-04 | Difluoromethyl-pyridin-2-yl triazoles |
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US8742097B2 (en) * | 2010-11-09 | 2014-06-03 | Hoffmann-La Roche Inc. | Triazole compounds I |
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