CN116854680A - 异噁唑-杂环类衍生物、药物组合物和用途 - Google Patents
异噁唑-杂环类衍生物、药物组合物和用途 Download PDFInfo
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- CN116854680A CN116854680A CN202210312824.7A CN202210312824A CN116854680A CN 116854680 A CN116854680 A CN 116854680A CN 202210312824 A CN202210312824 A CN 202210312824A CN 116854680 A CN116854680 A CN 116854680A
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Classifications
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/527—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim spiro-condensed
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Abstract
本发明涉及异噁唑‑杂环类衍生物、药物组合物和用途,具体提供一种式(I)所示化合物或其药学上可接受的盐、立体异构体、互变异构体、前体药物、无定形物、同位素体、多晶型物或者溶剂合物。含有该化合物的药物组合物以及所述化合物作为α5‑GABAA受体调节剂的用途。
Description
技术领域
本发明涉及对α5-GABAA受体具有调节功能的异噁唑-杂环类衍生物、含有它们的药物组合物和应用。
背景技术
γ-氨基丁酸(GABA)是哺乳动物中枢神经系统中重要的抑制性神经递质,有两类GABA受体存在于自然界中,一类是GABAA受体,该类受体为配体门控离子通道超家族的成员,另一类是GABAB受体,该类受体是为G蛋白偶联受体超家族的成员。哺乳动物中的GABAA受体亚基被发现的有α1-6、β1-4、γ1-3、δ、ε、θ和ρ1-3等亚基,其中α亚基、β亚基和γ亚基对形成一个完整的功能型GABAA受体是必不可少的,而α亚基对苯二氮与GABAA受体的结合是至关重要的。
含α5的GABAA受体(α5-GABAA受体)在哺乳动物大脑的GABAA受体中所占的比例小于5%,在大脑皮层中表达水平非常低,但在大脑海马组织中的GABAA受体中所占比例大于20%,其他大脑区域几乎不表达。考虑到α5-GABAA受体的在大脑海马组织中特异性分布和功能研究,包括罗氏、默沙东等在内的许多制药公司从事于α5-GABAA受体配体的研究,陆续有大量的化合物合成出来,特别是针对大脑海马组织的α5-GABAA受体的反向调节剂(或称负向调节剂、反向激动剂),其中α5IA和MRK-016在动物疾病模型中显示出良好的改善认知效果。普遍认为α5-GABAA受体反向调节剂可以用来治疗认知类疾病,特别是治疗阿尔茨海默氏病。专利申请US20110224278披露了α5-GABAA受体的反向调节剂可用于治疗多梗塞性痴呆和脑卒中相关疾病。
抑郁症是一个可能危及生命(如自杀)的严重的精神疾病。目前抗抑郁治疗的标准疗法为选择性5-羟色胺再摄取抑制剂(SSRI),但是该类药物一般在服药6-8周后才能达到最大药效,不仅如此,其有效率也很有限,仅在将近一半的病人上有治疗效果。其他已上市的和临床在研的抗抑郁药物也都有不同程度的副作用,限制了抗抑郁药物的使用。因此,临床上迫切需要一款有快速起效功能并且副作用更低的抗抑郁药物,来缓解抑郁病人和社会的负担。
Fishell等人报道了α5-GABAA受体反向调节剂的抗抑郁效果(J.Fischell等,Neuropsychopharmacology,2015,40(11),2499-2509;),认为选择性的α5-GABAA受体反向调节剂可以起到区别于传统抗抑郁药的快速起效的效果,并且其安全性优于现有的有同样快速起效能力的氯胺酮疗法。因此选择性的α5-GABAA受体反向调节剂有可能成为一款全新机制的有快速起效能力的抗抑郁疗法,满足现有临床抑郁症治疗上面的严重未满足的需求。
检测一个化合物是否是针对包含α5亚基的GABAA受体的反向调节剂或者拮抗剂,这方面的研究工作已经做了很多,例如在国际申请专利WO 1992022652和WO1994013799中,用GABAA受体的α5、β3和γ2组合来检测某一个化合物是否与该受体相结合;在进行药物筛选的过程中,通常用Goeders等(Goeders,N.E.and Kuhar,M.J.Life Sci.1985,37(4),345-355)所述的方法。检测一个能与GABAA受体α5亚基结合的配体是拮抗剂、激动剂还是反向调节剂,在这一方面的研究也很多,可以参照Wafford等(Wafford,K.A.Mol.Pharmacol.1993,43,240-244)所述的方法。
近期的研究结果表明,GABAA受体介导了至少2种抑制模式,时相型抑制(phasicinhibition)和紧张型抑制(tonic inhibition)。突触内的GABAA受体,由于动作电位引起突触内含有GABA的囊泡同步释放,使得突触间隙出现毫摩尔级的GABA浓度急剧增加,从而引起突触后GABAA受体的同步激活并迅速去敏化,形成时相型抑制。而位于突触外的GABAA受体,通常处在持续存在的几十纳摩尔至几毫摩尔的低浓度GABAA环境中,对GABA高亲和力的GABAA受体被持续非同步激活,形成紧张型抑制。时相型抑制和紧张型抑制共同调节神经兴奋性和信号传递。(Farrant,M.et al.,Nat Rev Neurosci,2005,6,215-229)。Yeung JY etal披露低浓度的GABA更易激活α5-GABAA受体(Yeung JY et al.Mol Pharmacol,2003,63,2-8)。K.Y.Lee报道在培养24小时的分离的DRG细胞上检测到了低浓度GABA激活的持续的高亲和力的GABAA电流。(Lee,K.Y.et al,Neuroscience 2012,208,133-142)。2013年I.Lecker等披露α5-GABAA受体反向调节剂L-655,708剂量依赖性的抑制低浓度GABA(5,50和500nM)引起的电流,当GABA浓度增至1μM时,最高浓度的L-655,708仅能抑制15%的电流,当GABA浓度继续增加时,L-655,708对GABA引起的电流没有抑制作用。(Lecker,I.et al,British Journal of Anaesthesia,2013,110(S1),i73-i81)。
开发α5-GABAA受体反向调节剂,靶点亚型选择性也很重要。因为苯二氮卓类药物作为非选择性的GABAA受体正向调节剂,已经在临床上用于抗焦虑和抗癫痫治疗,所以该靶点的反向调节剂可能会有促焦虑和促癫痫的效果(H.J.Little,et.al.,Br J Pharmacol1984,951-958),因此α5-GABAA受体反向调节剂的开发需要提高α5-GABAA受体的结合和功能选择性,避免潜在的促焦虑和促癫痫(主要由α2-GABAA受体活性导致的)副作用(TheresaM.Ballard et.al.,Psychopharmacology,2009,207-223)。以往披露的α5-GABAA受体反向调节剂在胃液中稳定性不足,在肠液中溶解度比较差,作为口服药物开发成药性不好,难以推广使用。
发明内容
根据本发明的一个方面,提供了一种式(I)所示化合物或其药学上可接受的盐、立体异构体、互变异构体、前体药物、无定形物、同位素体、多晶型物或者溶剂合物,该类化合物对α5-GABAA具有良好的胃液稳定性和溶解性:
其中,R1选自苯基或者吡啶基,其中苯基或者吡啶基任选地被1、2或3个卤素取代;
R2选自H、直链或支链的C1-C4的烷基、C1-C4的烷氧基或C3-C6的环烷基;
环A选自含有1、2或3个环杂原子的5-10元的杂环基,所述环杂原子选自N、P、O或者S;
R4选自杂环与杂环形成的稠合基,形成稠合基的杂环选自含有1、2或3个杂原子的5-10元的杂环基,所述杂原子选自N、P、O或者S;稠合基未被取代或被一个或多个选自如下的取代基取代:任选被取代的烷基、任选被取代的环烷基、任选被取代的甲酰基、任选被取代的磺酰基,或者任选被取代的含1、2或3个杂原子的杂环;其中杂原子选自N、P、O或者S;
R3选自卤素、直链或支链的C1-C4的烷基、C1-C4的烷氧基、C3-C6的环烷基;
m为0、1或2。
除特别指明外,下列定义用于说明和定义在本文中用于描述本发明时使用的各种术语的意义和范围。
无论是单独出现还是组合出现,一般术语的下列定义均适用。
本申请中使用的命名规则是基于AutoNomTM 2000,用于产生IUPAC系统命名的Beilstein Institute计算机化的系统。在本文中给出的化学结构是采用ChemDraw版本12得到的。在本文中给出的结构中的碳、氧、硫或氮原子上出现的任何开放价键表明存在氢原子。
除特别说明外,术语“取代的”是指特定的原子上的任意一个或多个氢原子被取代基取代,可以包括重氢和氢的变体,只要特定的原子的价态是正常的并且取代后的化合物是稳定的。术语“任选被取代的”是指可以被取代,也可以不被取代,除非另有规定,取代基的种类和数目再化学上可以实现的基础上可以是任意的。
术语“未取代”是指指定的基团上不具有取代基。
术语“任选取代的”是指指定的基团是未取代的或者是被一个或多个独立选自可能的取代基所取代的。
当指明取代基的数目时,术语“一个或多个”是指一个取代至取代的最多可能的数目,即取代一个氢至所有的氢均被取代基取代。除特别指明外,优选1、2、3、4或5个取代基。当基团上可以具有多个取代基并且给出了多种可能的取代基时,所述取代基独立选择,不必是相同的。
当任何变量取代基在化合物的组成或结构中出现一次以上时,其在每一种情况下的定义都是独立的。因此,例如,如果一个基团被0-2个取代基所取代,则所述基团可以任选地至多被两个取代基所取代,并且每种情况下的取代基都有独立的选项。此外,取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的,并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
当所列举的连接基团没有指明其连接方向时,其连接方向时任意的,例如,中连接基团L为/>此时/>既可以按与从左往右的读取顺序相同的方向连接苯环和环戊基构成/>也可以按照与从左往右的读取顺序相反的方向连接苯基和环戊基构成/>所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定,环上原子的数目通常被定义为环的元数,例如,“4-14元环”是指环绕排列4-14个原子的“环”。
除非另有规定,Cn-n+m或Cn-Cn+m包括n至n+m个碳的任何一种具体情况,例如C1-C6包括C1、C2、C3、C4、C5、C6,也包括n至n+m中的任何一个范围,例如C1-C6包括C1-C3、C1-C6、C3-C6等;同理,n元至n+m元表示环上原子数为n至n+m个,例如4-14元环包括4元、6元、8元、10元和14元环,也包括n至n+m中的任何一个范围,例如4-14元环包括4-6元环、4-7元环、5-10元环和5-7元环等。
术语“卤素”或“卤”是指氟、氯、溴、碘。“氧基”是指-O-基团。“酰氧基”是指-C(=O)O-基团。“羰基”或“酰基”是指-C(=O)-基团。“硝基”是指-NO2基团。“氰基”是指-CN。“氨基”是指-NH2;“磺酰基”是指-S(=O)2-基团。
术语“烷基”是指直链或者支链的,例如具有1-20个碳原子,优选1-12个碳原子的饱和烃基团。“任选被取代的烷基”分为未取代的烷基和取代的烷基,未取代的烷基是指未被取代基取代的烷基,“未取代的烷基”的实例包括但不局限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基等等。取代的烷基是指由1-4个取代基取代的烷基,所述取代基诸如:卤素、烷基、取代的烷基、环烷基、取代的环烷基、烯基、取代的烯基、炔基、取代的炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环、取代的杂环、烷基磺酰基、取代的烷基磺酰基等。
术语“环烷基”是指由碳原子和氢原子组成的非芳族的、饱和的或不饱和的环烃基团,其可包括稠合环体系、桥环体系或螺环体系。例如具有3-20个碳原子,优选3-12个碳原子。“任选被取代的环烷基”分为未取代的环烷基和取代的环烷基,未取代的环烷基是指未被取代基取代的环烷基,“未取代的环烷基”的实例包括但不局限于环丙基、环丁基、环戊基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、环己基、1-环己-1-烯基、环庚基、环辛基、二环[2.2.1]庚烷、二环[2.2.2]辛烷、二环[3.2.2]壬烷、金刚烷等等。取代的环烷基是指由1-4个取代基取代的环烷基,所述取代基诸如:卤素、硝基、氰基、羟基、烷基、芳基、取代的芳基、杂芳基、取代的杂芳基、烷氧基、芳氧基、烷酰氧基、芳酰氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺(其中所述的两个氨基取代基选自烷基、芳基或芳基烷基)。
术语“杂环基”或者“杂环”是指具有杂原子的饱和或部分不饱和的单环或多环基团,优选含有1个、2个、3个、4个、5个或6个选自N、P、O或S的环杂原子的饱和或部分不饱和的单环或多环基团。可以是非芳香环,也可以是芳香环,例如具有3至20个碳原子,例如它可以是3-8元单环、7-14元双环(也称“二环杂环”)或11-20元三环(也称“三环杂环”)等,还可以是3-8元环内酰胺,其在至少一个含碳原子的环中具有至少一个氮原子。实例包括但是不局限于吡啶环、嘧啶酮基、吡啶酮基、咪唑基、三唑基、吡咯烷基、四氢呋喃基、四氢吡喃基、吗啉代、硫吗啉代、哌嗪基、高哌嗪基、环氧丙烷基、咪唑烷基、3-氮杂二环[3.1.0]己烷基、3-氮杂二环[4.1.0]庚烷基、氮杂二环[2.2.2]己烷基、N-吡啶基脲、嘧啶酮基和1,1-二氧代-硫吗啉基等。
术语“环杂原子”是指杂环中组成环的杂原子。
术语“杂环与杂环形成的稠合基”中的杂环如前述定义,该稠合基可以是两个单杂环或者两个以上(例如三个或者四个)的单杂环稠合在一起。两个单杂环稠合形成双杂环。可以是未取代的稠合基,或者取代的稠合基,未取代的稠合基例如但不局限于噻吩[3,2-C]并吡啶、咪唑并吡啶基、吡唑并吡啶基、三唑并吡啶基或者嘧啶并咪唑并恶嗪。取代的稠合基是指由1个或者多个取代基取代的稠合基,所述取代基诸如:烷基、取代的烷基、环烷基、取代的环烷基、甲酰基、取代的甲酰基、磺酰基、取代的磺酰基、含1-3个杂原子的杂环、取代的含1-3个杂原子的杂环等,杂原子选自N、O、P或者S。
和*均表示连接位点。
术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其他问题或并发症,与合理的利益/风险比相称。
本发明的化合物可以含有不对称中心或手性中心,并且因此存在不同的立体异构体形式。本发明化合物的所有立体异构体形式,包括但不局限于,非对映体、对映体和位阻异构体,以及它们的混合物例如外消旋混合物,将形成本发明的一部分。在本文中,当任何特定手性原子的立体化学未确定时,所有立体异构体均被考虑。此外,本发明涉及所有的几何和位置异构体。本发明化合物可以以不同的互变异构体形式存在,并且所有这些形式均包括在本发明范围内。本发明化合物的所有立体异构体预期包括混合物形式或纯的或基本上纯的形式。可以通过物理方法例如分步结晶、非对映体衍生物的分离或结晶、或者通过手性柱层析分离来拆分。
术语“前体药物”是式(I)的化合物的功能性衍生物,该衍生物在体内容易转化成式(I)的化合物。可以通过本领域技术人员众所周知的常规技术选择和制备合适该衍生物,例如参见Design of Prodrugs,ed.H.Bundgaard,Elsevier,1985。
本文所用术语“药学上可接受的盐”,是指本发明化合物的药学上可接受有机或无机盐。示例性的盐包括但是不局限于硫酸盐、枸橼酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、酸式硫酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式枸橼酸盐、琥珀酸盐、马来酸盐、延胡索酸盐、葡萄糖酸盐、甲酸盐、甲磺酸盐和巴莫酸盐。“药学上可接受的盐”可涉及包括另一分子例如马来酸盐或其他平衡离子。平衡离子在母体化合物中稳定电荷。“药学上可接受的盐”可以有多于一个的荷电原子,多个荷电原子可具有多个平衡离子。
如果本发明化合物是碱,需要的“药学上可接受的盐”可通过适宜的方法制备,例如,用以下的无机酸处理该游离碱:盐酸、氢溴酸、硫酸、硝酸、磷酸;或者用如下的有机酸:乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、水杨酸、吡喃糖苷基酸如葡萄糖醛酸或半乳糖醛酸、α-羟基酸如枸橼酸或酒石酸、氨基酸如谷氨酸、芳香族酸如苯甲酸或肉桂酸、磺酸如甲磺酸或对甲苯磺酸。
如果本发明化合物是酸,需要的“药学上可接受的盐”可通过适宜的方法制备,例如,用如下的无机碱或者有机碱处理该游离酸:胺、碱金属氢氧化物或碱土金属氢氧化物等。适宜的盐的示例性的示例包括但是不限于由氨基酸得到的有机盐,伯、仲、叔胺盐,以及环状胺例如哌啶、吗啉和哌嗪的盐,以及由钠、钙、钾、镁、锰、铁、铜、锌、铝和锂得到的无机盐。
本发明的化合物可以以从完全无定形到完全结晶的连续固态存在。术语“无定形”是指材料在分子水平上缺少长程有序性的状态,并且取决于温度,可以表现出固体或液体的物理性质。典型地,这样的材料不给出明显的X射线衍射图案,并且在显示出固体性质的同时,更正式地描述为液体。在加热时,发生从固体性质到液体性质的变化,其特征在于状态的变化,通常是二级(“玻璃化转变”)。术语“晶体”指的是一种固相,其中材料在分子水平上具有规则有序的内部结构,并给出具有确定峰的独特的X射线衍射图。这样的材料在充分加热时也将表现出液体的性质,但是从固体到液体的变化的特征在于相变,通常是一级(“熔点”)。
本文所用术语“多晶型物”是指本发明的某些化合物在固体状态下由于存在两种或两种以上不同分子排列而产生的不同固体结晶相。本发明的某些化合物可以存在多于一种晶型,本发明旨在包括各种晶型及其混合物。
本文所用术语“溶剂合物”是指一个或多个溶剂分子与本发明化合物的结合物或络合物。形成溶剂合物的溶剂的示例包括但是不局限于水、异丙醇、乙醇、甲醇、二甲亚砜、乙酸乙酯、乙酸和乙醇胺。本发明化合物可以以非溶剂化形式存在,也可以与药学上可接受的溶剂如水、乙醇等以溶剂化形式存在,所以本发明将包括溶剂化和非溶剂化的形式。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素,术语“同位素体”具有相同的原子数,但是其原子质量或质量数不同于在自然界中占优势地存在的原子质量或质量数。例如,可用放射性同位素标记化合物,比如氘(2H)、氚(3H)、碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。同位素变体可能会提高某些治疗优点,比如氘富集可以增加体内半衰期或减少剂量需求,或者可以提供可用作生物样品的表征的标准品化合物。通过本领域技术人员众所周知的常规技术,或者通过与在本文的路线和实施例中所述的那些类似的方法,使用适当的同位素富集的试剂和/或中间体,无需过多实验,可以制备式(I)内的同位素富集的化合物。
除非另有说明,术语“立体异构体”可以是“非对映异构体”,也可以是“对映异构体”或者“顺反异构体”。
术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。术语“非对映异构体”是指分子具有两个或多个手性中心,并且分子间为非镜像关系的立体异构体。
除非另有说明,术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明,“(D)”或者“(+)”表示右旋,“(L)”或者“(-)”表示左旋,“(DL)”或者“(±)”表示外消旋。
除非另有说明,用楔形实线键和楔形虚线键/>表示一个立体中心的绝对构型,用直形实线键/>和直形虚线键/>表示立体中心的相对构型,用波浪线/>表示楔形实线键/>或楔形虚线键/>或用波浪线/>表示直形实线键/>和直形虚线键/>
星号*或者表示连接位点。
本发明的化合物可以存在特定的。除非另有说明,术语“互变异构体”或“互变异构体形式”是指在室温下,不同官能团异构体处于动态平衡,并能很快的相互转化。若互变异构体是可能的(如在溶液中),则可能达到互变异构体的化学平衡。例如,质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的相互转化,如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valencetautomer)包括一些成键单子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基-3-烯-2-酮两个互变异构体之间的互变。
进一步地,环A选自含1、2或3个氮原子作为环杂原子的5-6元杂环基。
作为优选的实施方式,环A选自吡啶、哒嗪、吡嗪、嘧啶、哌啶或者哌嗪。
作为更优选的实施方式,环A选自吡啶、哒嗪或者吡嗪。
进一步地,R3选自甲基或者甲氧基。
进一步地,m为0或者1,作为优选的实施方式,m为0。
进一步地,R4具有式(II)或(III)所示的结构:
其中,环B、环C或环D独立地选自含有1、2或3个杂原子的5-10元的杂环基,所述杂原子选自N、P、O或者S;
R5、R6或者R7独立地选自氧代、任选被取代的烷基、任选被取代的环烷基、任选被取代的甲酰基、任选被取代的磺酰基,或者任选被取代的含1、2或3个杂原子的杂环;其中杂原子选自N、O、S;
n、j或者q独立地选自1或2。
(R5)q是指环D上的氢原子被q个R5所取代,R5可以相同,也可以不相同;
(R6)n是指环B上的氢原子被n个R5所取代,R6可以相同,也可以不相同;
(R7)j是指环C上的氢原子被j个R5所取代,R7可以相同,也可以不相同。
作为优选的实施方式,R5、R6或者R7独立地选自氧代、C1-C6烷基、C3-C8环烷基、甲酰基、磺酰基或者含1、2或3个杂原子的C3-C8的杂环,其中杂原子选自N、O、S;其中,烷基、环烷基、甲酰基、磺酰基、杂环未取代或者被1、2或3个选自卤素或C1-C3烷基所取代。
进一步地,环B选自5至7元杂环,其含有1、2或3个氮原子作为组成环的杂原子。
在某些优选的实施方式中,环B选自三唑、吡唑、咪唑、6元环内酰胺或者二氮杂环戊烷,所述6元环内酰胺含有2个氮原子作为组成环的杂原子。
在某些更优选的实施方式中,环B为 或者/>
进一步地,环C选自5元至7元的杂环,其含有1-2个独立地选自氮原子、氧原子或者硫原子作为组成环的杂原子。
在某些优选的实施方式中,环C选自如下1)-2)中任一项所述的杂环;
1),吡咯、咪唑、三唑或者6元环内酰胺,所述6元环内酰胺含有2个氮原子作为组成环的杂原子;
2),5元至7元的杂环烷烃或者杂环烯烃,所述杂环烷烃或杂环烯烃含有1-2个独立地选自氮原子、氧原子或者硫原子作为组成环的杂原子。
在某些更优选的实施方式中,环C选自 或者
表示环C与环B的连接位点,*表述环C与环D的连接位点。
进一步地,环D选自5元至7元的杂环,其含有1-2个独立地选自氮原子、氧原子或者硫原子作为组成环的杂原子。
在某些优选的实施方式中,环D选自含有1个氮原子和1个氧原子的5-7元桥环或者含有1个氮原子的5-6元的桥环。
在某些更优选的实施方式中,环D选自或者/>
进一步地,R7选自C1-C6烷基、C3-C8环烷基、C1-C3烷基取代的甲酰基、C1-C3烷基取代的磺酰基、C3-C6的含1个O原子或者1个S原子的杂环基;其中,所述烷基、环烷基或者杂环基未被取代或者被1、2或3个卤素所取代。
在某些优选的实施方式中,R7选自甲基、乙基、-CF3、-COCH3、或者/>
在某些优选的实施方式中,当R4具有式(II)的结构时,n为0或1;当R4具有式(III)的结构时,n为0或1,且q为0。
作为优选的实施方式,R1选自1、2或3个卤素取代的苯基。
作为优选的实施方式,R2选自H、直链或支链C1-C4烷基。
作为更优选的实施方式,R1选自R2选自甲基。
进一步地,所述化合物具有如下(VI)、(V)、(IV)或者(IIV)所示的结构:
所述R3如前述所定义,R4如前述任一项所定义。
作为更优选的实施方式,所述化合物选自以下化合物中的任意一种:
/>
本发明还提供了一种药物组合物,其包含本发明任一项所述的化合物或其立体异构体、互变异构体、前体药物、药学上可接受的盐、无定形物、同位素体、多晶型物或溶剂合物中的至少一种,以及药学上可接受的载体和/或辅助剂。
本发明任一项所述的化合物或其立体异构体、互变异构体、前体药物、药学上可接受的盐、无定形物、多晶型物、溶剂合物、所述的药物混合物,或所述的药物组合物在制备治疗或预防与α5-GABAA受体有关的疾病的药物中的用途。
进一步地,所述与α5-GABAA受体有关的疾病选自如下至少一种:抑郁症、疼痛、阿尔茨海默症、多发梗塞性痴呆、脑卒中、焦虑症、泛化焦虑症、恐慌症、广场恐怖症、创伤后精神紧张性障碍、月经前期焦虑障碍、纤维肌痛、注意力不集中症、强迫观念和行为综合征、社交焦虑症、孤独症、自闭症、精神分裂症、肥胖、神经性食欲过盛或缺乏、图雷特综合症、血管舒缩性潮红、性功能障碍、边界人格障碍、慢性疲劳综合症、雷诺综合征、帕金森氏症、癫痫和头部损伤后的情绪障碍。
进一步地,所述的抑郁是双相抑郁、产后抑郁、严重的抑郁症、精神抑郁症、非典型抑郁症、精神忧郁症、难治性抑郁症、亨廷顿氏病有关的抑郁症、多发性硬化症有关的抑郁症或焦虑症有关的抑郁症。
本发明任一项所述的化合物或其立体异构体、互变异构体、前体药物、药学上可接受的盐、无定形物、多晶型物、溶剂合物、所述的药物混合物,或所述的药物组合物在制备治疗或预防下列疾病的药物中的用途:抑郁症、疼痛、阿尔茨海默症、多发梗塞性痴呆、脑卒中、焦虑症、泛化焦虑症、恐慌症、广场恐怖症、创伤后精神紧张性障碍、月经前期焦虑障碍、纤维肌痛、注意力不集中症、强迫观念和行为综合征、社交焦虑症、孤独症、自闭症、精神分裂症、肥胖、神经性食欲过盛或缺乏、图雷特综合症、血管舒缩性潮红、性功能障碍、边界人格障碍、慢性疲劳综合症、雷诺综合征、帕金森氏症、癫痫或者头部损伤后的情绪障碍。
本发明还提供了一种治疗或预防α5-GABAA受体有关的疾病的方法,向患者施用有效剂量的本发明任一项所述的化合物或其立体异构体、互变异构体、前体药物、药学上可接受的盐、无定形物、多晶型物、溶剂合物、所述的药物混合物,或所述的药物组合物。
本发明还提供了一种治疗或预防下列疾病中的方法:抑郁症、疼痛、阿尔茨海默症、多发梗塞性痴呆、脑卒中、焦虑症、泛化焦虑症、恐慌症、广场恐怖症、创伤后精神紧张性障碍、月经前期焦虑障碍、纤维肌痛、注意力不集中症、强迫观念和行为综合征、社交焦虑症、孤独症、自闭症、精神分裂症、肥胖、神经性食欲过盛或缺乏、图雷特综合症、血管舒缩性潮红、性功能障碍、边界人格障碍、慢性疲劳综合症、雷诺综合征、帕金森氏症、和、癫痫或者头部损伤后的情绪障碍,向患者施用有效剂量的本发明任一项所述的化合物或其立体异构体、互变异构体、前体药物、药学上可接受的盐、无定形物、多晶型物、溶剂合物、所述的药物混合物,或所述的药物组合物。
本发明所用的未具体定义的技术和科学术语具有本发明所属领域的技术人员通常理解的含义。
如本文所用,“治疗”指给患有疾病或者具有所述疾病的症状的个体施用一种或多种药物物质、特别是本发明所述的式(I)化合物和或其药学上可接受的盐,用以治愈、缓解、减轻、改变、医治、改善、改进或影响所述疾病或者所述疾病的症状。本发明所用的术语“预防”指给具有易患所述疾病的体质的个体施用一种或多种药物物质、特别是本发明所述的式(I)化合物和或其药学上可接受的盐,用以防止个体患该疾病。当涉及化学反应时,术语“处理”、“接触”和“反应”指在适当的条件下加入或混合两种或更多种试剂,以产生所示的和或所需的产物应当理解的是,产生所示的和/或所需的产物的反应可能不一定直接来自最初加入的两种试剂的组合,即,在混合物中可能存在生成的一个或多个中间体,这些中间体最终导致了所示的和或所需的产物的形成。
如本文所用,“患者”定义为任何温血动物,例如不限于小鼠、豚鼠、狗、马或人,所述患者最好是人。
本发明提供含治疗有效量的α5-GABAA受体反向调节剂的药物化合物的用途。尽管用于本发明治疗的α5-GABAA受体反向调节剂可以原料化合物的形式给药,但优选将活性成分,任选地以生理上可接受的盐的形式,与一种或多种添加剂、赋形剂、载体、缓冲剂、稀释剂和/或其它常规的药物辅料一起混合成药物组合物。
本发明所用的术语“有效量”指通常足以对个体产生有益效果的量。可以通过常规方法(例如建模、剂量递增研究或临床试验)结合常规影响因素(例如给药方式、化合物的药代动力学、疾病的严重程度和病程、个体的病史、个体的健康状况、个体对药物的响应程度等)来确定本发明的化合物的有效量。
在优选的实施方案中,本发明提供含α5-GABAA受体反向调节剂的药物组合物,其中α5-GABAA正受体反向调节剂与一种或多种药学上可接受的载体、和任选地与其它本领域已知的或使用的治疗性的和/或预防性的组份混合。该载体必须是“可接受的”,即与制剂中的其它成分相容且不会对其接受者有害。
因此可将用于本发明的化合物与常规的添加剂、或稀释剂一起制成药物组合物及其单位剂量的形式。诸如此类的形式包括固体(尤其是片剂、填充胶囊、粉末以及丸剂的形式)、和液体(尤其是水溶液或非水溶液、混悬液、乳剂、酏剂)、和填充上述形式的胶囊、所有口服给药的形式、直肠给药的栓剂、以及肠胃外给药的无菌可注射的溶液。诸如此类药物组合物及其单位剂量形式可包括常规比例的常规成分、含或不含另外的活性化合物或成分,这类单位剂量形式可含与所需的每日应用剂量范围相当的任何合适的有效量的活性成分。
用于本发明的化合物可以各种的口服的和胃肠外的剂型给药。对本说领域的技术人员来说下述的剂型可含作为活性成分的本发明的化合物或其药学上可接受的盐。
为将用于本发明的化合物制成药物组合物,药学上可接受的载体可以是固体或者液体。固体形式的制剂包括粉末、片剂、九剂、胶囊、扁囊剂、栓剂、以及可分散的颗粒剂。固体载体可以是一种或多种还起稀释剂、调味剂、增溶剂、润滑剂、悬浮剂、粘合剂、防腐剂、片剂崩解剂、或囊化材料作用的物质。
粉末中,载体为细分的固体,它与细分的活性成分混合。
片剂中,活性成分与具有必要的粘合性能的载体以适当的比例混合并压缩成所需的形状和大小。
粉末和片剂优选地含5%或10%到约70%的活性化合物。合适的载体为碳酸镁、硬脂酸镁、滑石粉、糖、乳糖、果胶、糊精、淀粉、明胶、西黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点的蜡、可可脂等等。术语“制剂”包括含与作为载体的囊化材料配制的活性化合物,囊化材料提供囊,其中含或不含载体的活性成分被载体包围,这样与其结合在一起。同样地,制剂包括扁囊剂和锭剂(lozenges)。片剂、散剂、胶囊、丸剂、扁囊剂和锭剂可以用作适合于口服给药的固体形式。
为制备栓剂,首先将低熔点的蜡,如脂肪酸甘油酯或可可脂的泥合物熔化,然后通过搅拌将活性成分均匀地分散于其中。然后将该熔化的均匀混合物倒入适当大小模具中,让其冷却并由此固化。
适合于阴道给药的组合物可以阴道栓剂、棉塞、乳膏剂、凝胶剂、糊剂、泡沫或喷雾剂的形式存在,组合物除含活性成分外还含本领域已知的合适的载体。
液体制剂包括溶液、混悬液和乳剂,例如,水溶液或水-丙二醇溶液。例如,肠胃外注射液体制剂可以配制成水-聚乙二醇的溶液。
因此用于本发明的化合物可配制成用于肠胃外给药(例如注射,如快速浓注或连续输注)的制剂,和可以与添加的防腐剂一起以单位剂量的形式存在于安瓿、预填充的注射器、小体积的输液袋中或多剂量容器中。该组合物可采取油性或水性载体的混悬液、溶液或乳剂的形式,并可含制剂成分,如悬浮剂、稳定剂和/或分散剂。另外,活性成分可以是粉末的形式,可由灭菌的固体无菌分离或由溶液冻干获得,用于临用前与合适的载体如无菌的、无热原的水重建。
适合于口服给药的水溶液可通过将活性成分溶解于水中和加入所需的着色剂、调味剂、稳定剂和增稠剂来制备。
适合于口服给药的水悬浮液可通过将细分的活性成分分散于含粘性物质,如天然的或合成的树胶、树脂、甲基纤维素、羧甲基纤维素钠、或其它公知的悬浮剂的水中而制备。
还包括为在临用前不久转化为用于口服给药的液态制剂而设计的固体制剂。这类液体制剂包括溶液、混悬液和乳剂。除活性成分之外,这类制剂可含着色剂、调味剂、稳定剂、缓冲剂、人造的和天然的甜味剂、分散剂增稠剂、增溶剂等。
为了局部施用到表皮,可将本发明的化合物配制成软膏剂、乳膏剂或洗剂或透皮贴剂。例如,软膏剂和乳膏剂可用水性或油性基质外加合适的增稠剂和/或胶凝剂配制而成。洗剂可用水性或油性基质配制而成,且通常还含一种或多种乳化剂、稳定剂、分散剂、悬浮剂、增稠剂或着色剂。
适合于口腔局部给药的组合物包括在调味基质通常为蔗糖和金合欢胶或西黄蓍胶中含有活性成分的锭剂(lozenges);在惰性的基质如明胶和甘油或蔗糖和金合欢胶中含活性成分的锭剂(pastiIles);以及在合适的液体载体中含活性成分的漱口药。
可将溶液或混悬液用常规方法例如用滴管、吸管或喷雾器直接应用到鼻腔。该组合物可以是单剂量或多剂量的形式。
呼吸道给药也可以通过气雾剂实现,其中活性成分与合适的推进剂一起装在加压的包装中,合适的推进剂包括氟氯化碳(CFC)例如二氯二氟甲烷、三氯氟甲烷或二氯四氟乙烷,二氧化碳或其它合适的气体。气雾剂还可适当地含表面活性剂,如卵磷脂。药物的剂量可通过量阀控制。
另外活性成分可以是干粉的形式,例如化合物与合适粉末基质如乳糖、淀粉、淀粉衍生物如羟丙基甲基纤维素和聚乙烯吡咯烷酮(PVP)的粉末混合物。粉末载体可方便地在鼻腔内形成凝胶。粉末组合物可以单位剂量的形式存在,例如存在于胶囊或药筒(如明胶的胶裘或药筒)中,或存在于粉末可经吸入器给药的泡罩包装中。
在用于呼吸道给药的组合物(包括鼻内用的组合物)中,通常化合物具有小的粒度,例如为5微米或更小数量级的粒度。这样的粒度可以用本领域已知的方法,例如通过微粉化获得。
需要时,可以应用适于活性成分缓释的组合物。
药物制剂优选为单位剂量形式。这类形式中,制剂被细分成合适量活性成分的单位剂量。单位剂量形式可以是封装的制剂,其中密封包装中含分离的大量制剂,如封装的片剂、胶囊和装入小瓶或安瓿中的粉末。此外,单位剂量形式可以是胶囊、片剂、扁裘剂或锭剂(lozenge)本身,或可以是任何封装形式的适量上述胶囊、片剂等。
用于口服给药的片剂或胶囊和用于静脉给药的液体以及连续的输液为优选的组合物。
关于制剂和给药技术的更详细的资料可以在Remington's PharmaceuticalSciences(雷明顿药物科学)(Maack Publishing Co.,Easton,PA)的最新的版本上见到。
单位剂量制剂中活性组份的量可根据具体的应用和活性组份的效力而变化,可调节自0.01mg至约0.1g。例如,在医药用途中,该药物可以0.01至约100mg的胶囊每天给药三次,必要时该组合物还可以含其他相容的治疗剂。
治疗方法
在治疗用途中,用于本发明的化合物以起始剂量每天0.001mg/kg至10mg/kg体重。但是,这些剂量可以根据患者的需要、被治疗病症的严重性以及使用的化合物而变化,一般来说,开始以小于该化合物最佳剂量的较小剂量治疗,此后,小量增加此剂量达到最佳效果,方便起见,如果需要可将总日剂量再细分为一天内分次给药。
本发明的药物组合物还可同时与其它治疗疼痛、癫痫、焦虑和抑郁的药物联合使用,包括但不限于吗啡、加巴喷丁等。因此,本发明提供了一种用于治疗疼痛、癫痫、焦虑和抑郁的药物的药物,该药物不仅有效,而且没有明显的副作用,本发明的另一个目的是提供一种对于特殊病人群体,如老人、患有肝或肾功能衰退、或心脏血管性疾病的病人,具有高度安全性的药物。
本发明还提供了一种治疗或预防疾病的方法,向患者施用有效剂量的如上所述的化合物或组合物。
本发明还提供了一种治疗或预防与α5-GABAA受体有关的疾病的方法,向患者施用有效剂量的如上所述的化合物或如上所述的组合物。
本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式。其与其他化学合成方法结合所形成的实施方式以及本领域技术人员所熟知的等同替换方式,优选的实施方式包括但不局限于本申请的实施例。
有益效果:
本发明的异噁唑-杂环类衍生物(即前述式(I)所示的化合物或其药学上可接受的盐、立体异构体、互变异构体、前体药物、无定形物、同位素体、多晶型物或者溶剂合物)具有重要的药理学性质,为α5-GABAA受体反向调节剂。本发明的化合物不仅对α5-GABAA受体具有优异的亲和活性、反向调控活性,更重要的是具有良好的胃液稳定性和溶解度,更适合于口服药物的开发以及口服吸收。因此,本发明化合物及其药学上可接受的盐或其前药可以单独使用或与其他药物组合使用,用于治疗或预防与α5-GABA A有关的疾病。
具体实施方式
下面对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。其中,下述实施例中纯化步骤(例如制备薄层色谱、柱层析等)采用的溶剂比例为体积比。
中间体1:3-(6-氟吡啶-3-基)-6,7-二氢-4H-[1,2,3]三唑并[5,1-c][1,4]恶嗪
第一步:3-(2-叠氮乙氧基)丙-1-炔
将60%钠氢(0.22g,5.5mmol)加入到无水四氢呋喃(30mL)中,反应混合物降温至0℃,缓慢滴加2-叠氮基乙醇(0.4g,4.6mmol)四氢呋喃(10mL)溶液。反应混合物0℃搅拌半小时,缓慢滴加3-溴丙-1-炔(0.82g,5.5mmol,80%纯度),滴加完后反应混合物室温搅拌16小时。用水(20mL)淬灭反应,乙酸乙酯(10mL)萃取三次,有机相浓缩得到浅黄色油状标题化合物(0.86g粗品)。LC-MS:m/z[M+H]+=126.
第二步:3-(6-氟吡啶-3-基)-6,7-二氢-4H-[1,2,3]三唑并[5,1-c][1,4]恶嗪
将2-氟-5-碘吡啶(268mg,1.2mmol),碘化亚铜(23mg,0.12mmol)和四(三苯基膦)钯(69mg,0.06mmol)加入到三乙胺(15mL)中,反应混合物氩气保护下室温搅拌1小时,3-(2-叠氮乙氧基)丙-1-炔(150mg粗品)加入。反应混合物氩气保护下60℃搅拌16小时。反应液降至室温,饱和氯化铵溶液(50mL)淬灭反应,乙酸乙酯(30mL)萃取三次,有机相浓缩,制备薄层色谱分离(二氯甲烷/甲醇=100/1)得到浅黄色固体标题化合物(40mg)。1H NMR(400MHz,CDCl3)δ8.32(s,1H),8.29-8.21(m,1H),7.07(dd,J=2.9,8.3Hz,1H),5.12(s,2H),4.54(t,J=5.1Hz,2H),4.18(t,J=5.1Hz,2H);LC-MS:m/z[M+H]+=221.
参考下表,除了采用“原料”一栏同摩尔量所述原料替代相应的原料(2-氟-5-碘吡啶)以外,参照中间体1的制备方法制备以下中间体2-3。
中间体4:4-(((5-溴吡啶-2-基)氧基)甲基)-3-(4-氟苯基)-5-甲基异恶唑
(3-(4-氟苯基)-5-甲基异恶唑-4-基)甲醇(0.2g,0.97mmol,按照US20130102778A1公开的方法合成)溶解在无水四氢呋喃(3mL)中,在0℃下加入60%钠氢(0.07g,2.91mmol)搅拌15分钟,然后缓慢滴加5-溴-2-氟吡啶(0.19g,1.07mmol)的四氢呋喃(3mL)溶液,滴加完后混合物室温反应2小时。加水(25mL)淬灭反应,乙酸乙酯(25mL)萃取两次,有机相合并,无水硫酸钠干燥,浓缩,制备薄层色谱(二氯甲烷/甲醇=100/1)分离得到油状标题化合物(150mg,收率43%)。LC-MS:m/z[M+H]+=363.
参考下表,除了采用“原料”一栏同摩尔量所述原料替代相应的原料(5-溴-2-氟吡啶)以外,参照中间体4的制备方法制备以下中间体5-6。
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中间体7:3-(4-氟苯基)-5-甲基-4-(((5-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)吡啶-2-基)氧基)甲基)异恶唑
将4-(((5-溴吡啶-2-基)氧基)甲基)-3-(4-氟苯基)-5-甲基异恶唑(0.270g,0.74mmol),联硼酸频那醇酯(0.2g,0.777mmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.061g,0.074mmol),醋酸钾(0.15g,1.48mmol)溶解在1,4二氧六环(6mL)中,氮气保护下100℃反应5小时。反应液硅藻土过滤,滤液浓缩,制备薄层色谱(二氯甲烷/甲醇=50/1)分离得到黄色固体标题化合物(140mg,收率52%)。LC-MS:m/z[M+H]+=329.
中间体8:3-溴-6,7-二氢-[1,2,4]三唑并[4,3-a]吡嗪-8(5H)-酮
第一步:3-溴-8-氧-5,6-二氢-[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-羧酸叔丁酯
将3-溴-5,6-二氢-[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-羧酸叔丁酯(250mg,0.82mmol,CAS:723286-80-4)溶于氯仿(3mL)和乙腈(3mL)中,加入高碘酸钠(807mg,3.77mmol)的水溶液(6ml),然后加入二氧化钌水合物(31mg,0.2mmol)。混合物在室温下搅拌1小时。加水(6mL)淬灭反应,氯仿(5mL)萃取三次,合并有机相,干燥,硅藻土过滤,滤液浓缩,柱层析(二氯甲烷/甲醇=50/1)分离纯化得到白色固体标题化合物(140mg,收率54%)。LC-MS:m/z[M+H]+=317.
第二步:3-溴-6,7-二氢-[1,2,4]三唑并[4,3-a]吡嗪-8(5H)-酮
3-溴-8-氧-5,6-二氢-[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-羧酸叔丁酯(140mg,0.44mmol)溶于二氯甲烷(3mL),加入三氟乙酸(150.51mg,1.32mmol),混合物在室温下搅拌过夜。反应液直接浓缩得到浅绿色固体标题化合物(100mg粗品),不再进一步纯化直接用于下一步。LC-MS:m/z[M+H]+=217.
中间体9:3-溴-7-甲基-6,7-二氢-[1,2,4]三唑并[4,3-a]吡嗪-8(5H)-酮
3-溴-6,7-二氢-[1,2,4]三唑并[4,3-a]吡嗪-8(5H)-酮(100mg,0.46mmol)溶于四氢呋喃(1ml)中,在冰浴条件下,加入60%氢化钠(22mg,0.92mmol),搅拌15分钟后加入碘甲烷(131mg,0.92mmol),混合物室温搅拌过夜。加水(20mL)淬灭反应,乙酸乙酯(15mL)萃取三次,合并有机相,浓缩,柱层析(二氯甲烷/甲醇=20/1)纯化得到白色固体标题化合物(42mg,两步收率29%)。LC-MS:m/z[M+H]+=231.
参考下表,除了采用“原料”一栏同摩尔量所述原料替代相应的原料(碘甲烷)以外,参照中间体9的制备方法制备以下中间体10。
中间体11:5-氯-3-甲基吡嗪-2-羧酸甲酯
第一步:3-(甲氧基羰基)-2-甲基吡嗪1-氧化物
3-甲基吡嗪-2-羧酸甲酯(2.0g,13.1mmol)溶解在氯仿(20mL)中,加入间氯过氧苯甲酸(2.49g,14.5mmol),混合物在70℃反应5小时。反应液用水(50mL)稀释,二氯甲烷(50mL)萃取两次,合并有机相,浓缩,柱层析纯化(二氯甲烷/甲醇=10/1)得到白色固体标题化合物产物(1.5g)。LC-MS:m/z[M+1]+=169.
第二步:5-氯-3-甲基吡嗪-2-羧酸甲酯
3-(甲氧基羰基)-2-甲基吡嗪1-氧化物(1.5g,9.28mmol)溶解在N,N-二甲基甲酰胺(15mL)中,三氯氧磷(2.54mL)缓慢滴加入,反应混合物100℃搅拌1小时。反应液缓慢滴加入饱和碳酸氢钠溶液中至弱碱性,二氯甲烷(50mL)萃取两次,合并有机相,浓缩,柱层析(石油醚/乙酸乙酯=5/1)纯化得到淡黄色液体标题化合物产物(1.0g)。LC-MS:m/z[M+1]+=187.
中间体12:6-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)-2-甲氧基烟酸甲酯
第一步:6-氟-2-甲氧基烟酸甲酯
2,6-二氟烟酸甲酯(2.0g,11.6mmol)溶解在四氢呋喃(35mL)中,加入甲醇钠(660mg,12.1mmol),反应混合物在5℃反应半小时。反应液用水(50mL)稀释,乙酸乙酯(50mL)萃取两次,合并有机相,浓缩,柱层析(石油醚/乙酸乙酯=10/1)纯化得到白色固体标题化合物产物(1.58g)。LC-MS:m/z[M+1]+=186.
第二步:6-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)-2-甲氧基烟酸甲酯
6-氟-2-甲氧基烟酸甲酯(1.5g,9.28mmol)溶解在N,N-二甲基甲酰胺(20mL)中,加入碳酸钾(2.24g,16.2mmol)和(3-(4-氟苯基)-5-甲基异恶唑-4-基)甲醇(1.68g,10.25mmol,按照US20130102778A1公开的方法合成),反应混合物在80℃反应12小时。反应液用水(100mL)稀释,乙酸乙酯(50mL)萃取两次,合并有机相,浓缩,柱层析(二氯甲烷/甲醇=50/1)纯化得到淡黄色液体标题化合物产物(1.5g)。LC-MS:m/z[M+1]+=373.
中间体13:4-(溴甲基)-3-(4-氟苯基)-5-甲基异恶唑
(3-(4-氟苯基)-5-甲基异恶唑-4-基)甲醇(2.4g,11.59mmol,按照US20130102778A1公开的方法合成)加到无水二氯甲烷(30mL)中,冷却到0℃,缓慢加入三溴化磷(1.5mL),室温搅拌1小时。将混合物缓慢滴入饱和的碳酸氢钠溶液中,混合物继续搅拌15分钟,分出有机层,用无水硫酸钠干燥,过滤,将滤液浓缩得到标题化合物(2g粗品)。LC-MS:m/z[M+H]+=270.
中间体14:6-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)-5-甲氧基烟酸甲酯
第一步:6-羟基-5-甲氧基烟酸
将6-氯-5-甲氧基烟酸甲酯(0.9g,4.46mmol)、氢氧化钾(0.3g,5.35mmol)、2-二-叔丁膦基-2',4',6'-三异丙基联苯(0.19g,0.45mmoL)和三(二亚苄基丙酮)二钯(0.41g,0.45mmoL)依次加入到混合溶剂1,4-二氧六环(10mL)和水(10mL)中,氩气保护下,反应混合物在90℃反应12小时。将反应液加入到水(50mL)中,乙酸乙酯(50mL)萃取两次,有机相丢弃。水相用1M盐酸调节pH至5~6,乙酸乙酯(50mL)萃取三次,合并后的有机相直接浓缩得到黄色固体标题化合物(0.9g粗品)。LC-MS:m/z[M+H]+=170.
第二步:6-羟基-5-甲氧基烟酸甲酯
将6-氯-5-甲氧基烟酸(0.8g粗品)溶解在甲醇(20mL)中,0℃条件下,二氯亚砜(0.84g,7.05mmoL)加入,随后反应混合物在68℃搅拌12小时。反应液直接浓缩,残渣加水(50mL)稀释,二氯甲烷(50mL)萃取三次,有机相合并浓缩,柱层析(二氯甲烷/甲醇=20/1)分离纯化得到白色固体标题化合物(0.8g)。LC-MS:m/z[M+H]+=184.
第三步:6-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)-5-甲氧基烟酸甲酯
将6-羟基-5-甲氧基烟酸甲酯(0.7g,2.59mmol)溶解在1,2-二氯乙烷(20mL)中,加入氧化银(0.9g,3.89mmoL)和4-(溴甲基)-3-(4-氟苯基)-5-甲基异恶唑(617mg,3.37mmoL),反应混合物在80℃搅拌12小时。反应液加水(50mL)稀释,乙酸乙酯(50mL)萃取三次,有机相合并浓缩,柱层析(二氯甲烷/甲醇=50/1)分离纯化得到黄色固体标题化合物(46mg,收率5%)。LC-MS:m/z[M+H]+=373.
中间体15:6-氯烟酰肼
6-氯烟酸甲酯(5g,3.4mmol)加到乙醇(30mL)中,加入水合肼(222mg,10.2mmol),室温搅拌过夜。有白色固体析出,过滤得到白色固体标题化合物(5g粗品)。LC-MS:m/z[M+H]+=172.
参考下表,除了采用“原料”一栏同摩尔量所述原料替代相应的原料(6-氯烟酸甲酯)以外,参照中间体15的制备方法来合成中间体16-21。
中间体22:5-甲氧基-3,6-二氢吡嗪-1(2H)-羧酸叔丁酯
3-氧代哌嗪-1-羧酸叔丁酯(10g,50mmol)和三甲基氧鎓四氟硼酸盐(10.34mg,70mmol)加入到二氯甲烷(100mL)中,反应混合物室温搅拌过夜。向反应液中加入饱和碳酸氢钠溶液继续搅拌1小时,二氯甲烷萃取多次,合并有机相,干燥浓缩得浅黄色胶状固体标题化合物(10g粗品),没有进一步纯化直接用于下一步反应。
中间体23:3-(4-氟苯基)-5-甲基-4-(((5-(5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪-3-基)吡嗪-2-基)氧基)甲基)异恶唑
第一步:3-(5-氯吡嗪-2-基)-5,6-二氢-[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-羧酸叔丁酯
5-甲氧基-3,6-二氢吡嗪-1(2H)-羧酸叔丁酯(1.24g,5.79mmol,中间体22)和5-氯吡嗪-2-碳酰肼(1g,5.79mmol,中间体17)溶于乙醇(20mL)中,混合物加热到120℃搅拌过夜。反应液直接浓缩,柱层析(二氯甲烷/甲醇=50/1)纯化得到浅黄色固体标题化合物(1g,收率51%)。LC-MS:m/z[M+H]+=337.
第二步:3-(5-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)吡嗪-2-基)-5,6-二氢-[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-羧酸叔丁酯
(3-(4-氟苯基)-5-甲基异恶唑-4-基)甲醇(500mg,2.4mmol,按照US20130102778A1公开的方法合成)溶于四氢呋喃(15mL)中,冰浴条件下加入60%氢化钠(193mg,4.8mmol),混合物搅拌30分钟后,加入3-(5-氯吡嗪-2-基)-5,6-二氢-[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-羧酸叔丁酯(812mg,2.4mmol),混合物室温搅拌过夜。反应液用饱和氯化铵溶液淬灭,乙酸乙酯萃取多次,合并有机相,干燥浓缩,柱层析(二氯甲烷/甲醇=50/1)纯化得到浅黄色油状标题化合物(600mg,收率49%)。LC-MS:m/z[M+H]+=508.
第三步:3-(4-氟苯基)-5-甲基-4-(((5-(5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪-3-基)吡嗪-2-基)氧基)甲基)异恶唑
3-(5-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)吡嗪-2-基)-5,6-二氢-[1,2,4]三唑基[4,3-a]吡嗪-7(8H)-羧酸叔丁酯(500mg,0.99mol)溶于甲醇(5mL)和水(5mL)中,混合物用微波反应器在150℃下微波反应1.5小时。混合物直接浓缩得到浅黄色油状物标题化合物(400mg,收率99%)。LC-MS:m/z[M+H]+=408.
参考下表,除了采用“原料”一栏同摩尔量所述原料替代相应的原料(5-氯吡嗪-2-碳酰肼)以外,参照中间体23的制备方法来合成中间体24。
中间体25:4-((5-(7-环丁基-5,6,7,8-四氢-[1,2,4]三唑基[4,3-a]吡嗪-3-基)吡嗪-2-基)氧基)甲基)-3-(4-氟苯基)-5-甲基异恶唑
将3-(4-氟苯基)-5-甲基-4-(((5-(5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪-3-基)吡嗪-2-基)氧基)甲基)异恶唑(200mg,0.49mmol,中间体23)溶于甲醇(12mL)中,加入环丁酮(84mg,0.98mmol),混合物在室温下搅拌30分钟后,加入氰基硼氢化钠(185mg,2.94mmol),混合物加热到60℃搅拌过夜。混合物经柱层析(二氯甲烷/甲醇=50/1)纯化得到白色固体标题化合物(100mg,收率44%)。LC-MS:m/z[M+H]+=462.
参考下表,除了采用“原料”一栏同摩尔量所述原料替代相应的原料(环丁酮)以外,参照中间体25的制备方法来合成中间体26。
中间体27:1,4-氧杂氮杂环庚烷-3-酮
第一步:2-(3-((叔丁氧基羰基)氨基)丙氧基)乙酸
(3-羟丙基)氨基甲酸叔丁酯(4g,23mmol)加到无水四氢呋喃(40mL)中,冷却到0℃,缓慢加入60%氢化钠(2.47g,68mmol),搅拌15分钟,随后再加入溴乙酸甲酯(5.24g,34mmol)室温搅拌过夜。加水淬灭反应,用乙酸乙酯萃取多次,有机相合并,用无水硫酸钠干燥,浓缩得到标题化合物(3g粗品)。LC-MS:m/z[M+1]+=234.
第二步:2-(3-氨基丙氧基)乙酸甲酯
2-(3-((叔丁氧基羰基)氨基)丙氧基)乙酸(3g粗品)溶解在甲醇(30mL)中,冷却到0℃,缓慢滴加氯化亚砜(4.6g,39mmol),反应混合物室温搅拌过夜。反应液浓缩得到标题化合物(1g粗品)。LC-MS:m/z[M+1]+=148.
第三步:1,4-氧杂氮杂环庚烷-3-酮
2-(3-氨基丙氧基)乙酸甲酯(1g粗品)溶解在甲醇(20mL)中,加入碳酸钾(1.9g,13.6mmol)加热到60℃,混合物搅拌1小时。反应液硅藻土过滤,滤液浓缩,柱层析(石油醚/乙酸乙酯=2/1)纯化得到标题化合物(0.16g,三步收率5%)。LC-MS:m/z[M+H]+=116.
中间体28:5-氯-3,6-二氢-2H-1,4-恶嗪
3-吗啉酮(4g)溶解在混合溶剂二氯甲烷(5mL)中,加入加入三氯氧磷,反应混合物40℃搅拌1小时。反应液浓缩得到标题化合物(4.5g粗品),没有进一步纯化直接用于下一步反应。
参考下表,除了采用“原料”一栏同摩尔量所述原料替代相应的原料(3-吗啉酮)以外,参照中间体28的制备方法来合成中间体29-33。
中间体34:3-(6-氯吡啶-3-基)-5,6-二氢-8H-[1,2,4]三唑并[3,4-c][1,4]恶嗪
5-氯-3,6-二氢-2H-1,4-恶嗪(5g,29mmol,中间体28)溶解在甲苯(250mL)中,6-氯烟酰肼(4.5g,37mmol,中间体15)和N,N-二异丙基乙胺(3.7g,28.9mmol)分别加入,130℃搅拌4小时,冷却到室温,饱和碳酸氢钠溶液调节pH至10-11,100℃搅拌16小时,乙酸乙酯萃取多次,合并有机相,浓缩得到标题化合物粗品(0.36g,三步收率38%)。LC-MS:m/z[M+H]+=237.
参考下表,除了采用“原料”一栏同摩尔量所述原料1和同摩尔量原料2分别替代相应的原料(6-氯烟酰肼和5-氯-3,6-二氢-2H-1,4-恶嗪)以外,参照中间体34的制备方法来合成中间体35-47。
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中间体48:4-(((5-(5,6-二氢-8H-[1,2,4]三唑并[3,4-c][1,4]噻嗪-3-基)吡啶-2-基)氧基)甲基)-3-(4-氟苯基)-5-甲基异恶唑
(3-(4-氟苯基)-5-甲基异恶唑-4-基)甲醇(141mg,0.68mmol,按照US20130102778A1公开的方法合成)加入到无水四氢呋喃(10mL)中,冷却到0℃,加入60%钠氢(82mg,2.04mmol),0℃搅拌30分钟。然后加入3-(6-氯吡啶-3-基)-5,6-二氢-8H-[1,2,4]三唑并[3,4-c][1,4]噻嗪(172mg,0.68mmol,中间体36),反应混合物室温搅拌过夜,反应液浓缩,制备薄层色谱分离(石油醚/乙酸乙酯=1/1)得到橙色固体标题化合物(160mg,收率56%)。LC-MS:m/z[M+H]+=424.
参考下表,除了采用“原料”一栏同摩尔量所述原料替代相应的原料(3-(6-氯吡啶-3-基)-5,6-二氢-8H-[1,2,4]三唑并[3,4-c][1,4]噻嗪)以外,参照中间体48的制备方法来合成中间体49。
中间体50:3-(6-氯吡啶-3-基)-6,7-二氢-5H-[1,2,4]三唑并[3,4-b][1,3]恶嗪
第一步:5-(6-氯吡啶-3-基)-1,3,4-恶二唑-2-硫醇
将6-氯烟酰肼(0.7g,4.06mmol,中间体15)溶解于乙醇(16mL)和水(8mL)中,再加入二硫化碳(3.09g,40.6mmol)和氢氧化钾(0.34g,6.09mmol),加热至90℃搅拌过夜。反应液浓缩得到标题化合物(0.84g粗品)。LC-MS:m/z[M+1]+=214.
第二步:2-(6-氯吡啶-3-基)-5-(甲硫基)-1,3,4-恶二唑
5-(6-氯吡啶-3-基)-1,3,4-恶二唑-2-硫醇(0.84g,3.9mmol)溶解于甲醇(20mL),再加入碘甲烷(1.12g,7.84mmol),室温搅拌过夜。反应液浓缩,柱层析(二氯甲烷/甲醇=100/1)纯化得到标题化合物(0.7g,收率78%)。LC-MS:m/z[M+H]+=228.
第三步:2-(6-氯吡啶-3-基)-5-(甲基磺酰基)-1,3,4-恶二唑
2-(6-氯吡啶-3-基)-5-(甲硫基)-1,3,4-恶二唑(0.7g,3.08mmol)溶解于二氯甲烷(10mL)中再加入间氯过氧苯甲酸(1.59g,9.24mmol)室温搅拌过夜。反应液浓缩,柱层析(二氯甲烷/甲醇=50/1)纯化得到标题化合物(280mg,收率35%)。LC-MS:m/z[M+H]+=260.
第四步:6-氯-N'-(5,6-二氢-4H-1,3-恶嗪-2-基)烟碱酰肼
2-(6-氯吡啶-3-基)-5-(甲基磺酰基)-1,3,4-恶二唑(280mg,1.05mmol)溶解在四氢呋喃(10mL)中,再加入3-氨基丙醇(94.64mg,1.26mmol),随后缓慢滴加三乙胺(319mg,3.15mmol),室温搅拌过夜。反应液浓缩,柱层析(二氯甲烷/甲醇=10/1)纯化得到标题化合物(120mg,收率37.5%)。LC-MS:m/z[M+H]+=255.
第五步:3-(6-氯吡啶-3-基)-6,7-二氢-5H-[1,2,4]三唑并[3,4-b][1,3]恶嗪
6-氯-N'-(5,6-二氢-4H-1,3-恶嗪-2-基)烟碱酰肼(120mg,0.47mmol)加入到二氯苯(8mL)中180℃微波反应4小时。反应液制备薄层色谱分离(二氯甲烷/甲醇=20/1)得到标题化合物(50mg,收率45%)。LC-MS:m/z[M+H]+=237.
中间体51:3-(4-氟苯基)-5-甲基-4-((5-(3-(三氟甲基)-5,6-二氢-[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基)吡嗪-2-基)氧基)甲基)异恶唑
4-((5-溴吡嗪-2-基)氧基)甲基)-3-(4-氟苯基)-5-甲基异恶唑(300mg,0.82mmol)加入到1,4-二氧六环(10mL)中,再加入3-(三氟甲基)-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪盐酸盐(158mg,0.82mmol),三(二亚苄基丙酮)二钯(75mg,0.082mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(51mg,0.088mmol)和碳酸铯(430mg,1.32mmol)反应混合物在氮气保护下100℃搅拌过夜。反应液浓缩,柱层析(二氯甲烷/甲醇=20/1)纯化得到标题化合物(80mg,收率20.5%)。LC-MS:m/z[M+1]+=476.
中间体52:3-(6-氟吡啶-3-基)-5,6-二氢-8H-咪唑并[5,1-c][1,4]恶嗪
第一步:(6-氟吡啶-3-基)(3-(羟甲基)吗啉代)甲酮
将6-氟烟酸(1.5g,10.6mmol),吗啉-3-基甲醇(1.25g,10.6mmol)和N,N-二异丙基乙胺(2.75g,21.3mmol)加入到二氯甲烷(20mL)中,在0℃下加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(4.85g,12.8mmol),室温搅拌过夜。柱层析(二氯甲烷/甲醇=50/1)纯化得到黄色液体标题化合物(2.1g,收率82%)。LC-MS:m/z[M+1]+=241.
第二步:4-(6-氟烟酰基)吗啉-3-甲醛
将(4-(6-氟吡啶-3-羰基)吗啉-3-基)甲醇(0.5g,2.08mmol)和戴斯-马丁试剂(0.88g,2.08mmol)溶解在二氯甲烷(20mL)中,室温搅拌2小时。硅藻土过滤,滤液浓缩,制备薄层色谱(二氯甲烷/甲醇=50/1)分离得到油状液体标题化合物(90mg,收率18%)。LC-MS:m/z[M+1]+=239.
第三步:3-(6-氟吡啶-3-基)-5,6-二氢-8H-咪唑并[5,1-c][1,4]恶嗪
将4-(6-氟吡啶-3-羰基)吗啉-3-甲醛(0.09g,0.38mmol)和乙酸铵(0.059g,0.76mmol)溶解在乙酸(4mL)中,在80℃条件下反应2小时。加饱和碳酸氢钠溶液淬灭反应,用乙酸乙酯萃取多次,合并有机相,无水硫酸钠干燥,浓缩,制备薄层色谱(二氯甲烷/甲醇=20/1)分离得到无色油状标题化合物(10mg,收率12%)。LC-MS:m/z[M+1]+=220.
中间体53:3-溴-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪
将3-溴-5,6-二氢-[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-羧酸叔丁酯(0.2g,0.66mmol)溶解在二氯甲烷(4mL)中,三氟乙酸(2mL)加入,室温搅拌过夜。向反应液中加入过量的碳酸氢钠固体。硅藻土过滤,滤液浓缩得到黄色油状标题化合物(0.1g,收率77%)。LC-MS:m/z[M+1]+=203.
中间体54:1-(3-溴-5,6-二氢-[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基)乙烷-1-酮
将3-溴-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪(0.13g,0.64mmol),乙酰氯(0.098g,0.96mmol)和碳酸氢钠(0.11g,1.28mmol)溶解在二氯甲烷(6mL)中,室温反应3小时。硅藻土过滤,滤液浓缩得到标题化合物(0.12g粗品)。LC-MS:m/z[M+1]+=245.
参考下表,除了采用“原料”一栏同摩尔量所述原料替代相应的原料(乙酰氯)以外,参照中间体54的制备方法来合成中间体55。
中间体56:(3S,11aR)-7-氯-3,4-二氢-1H,9H,11H-3,11a-甲桥嘧啶并[6',1':2,3]咪唑并[5,1-C][1,4]恶嗪-9-酮
中间体56参照专利WO2021089032A1的方法合成。
中间体57:3-氯-7,8-二氢-1H,6H,9H-7,8a-甲桥吡咯并[1',2':3,4]咪唑并[1,2-c]嘧啶-1-酮
中间体57参照专利WO2021089032A1的方法合成。
中间体58:7-氯-1-甲基-2,3-二氢咪唑并[1,2-c]嘧啶-5(1H)-酮
将7-氯-2,3-二氢咪唑并[1,2-c]嘧啶-5(1H)-酮(0.02g,0.12mmol),碘甲烷(0.026g,0.18mmol)和碳酸铯(0.078g,0.24mmol)溶解在N,N-二甲基甲酰胺(2mL)中,室温搅拌16小时。向反应液中加入水(20mL),乙酸乙酯(20mL)萃取两次,有机相合并,干燥,浓缩得到标题化合物(160mg)。LC-MS:m/z[M+1]+=186.
中间体59:3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-6,7-二氢-4H-吡唑并[5,1-c][1,4]恶嗪
第一步:4-溴-1-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-1H-吡唑
4-溴-1H-吡唑(2.0g,13.6mmol)溶解在N,N-二甲基甲酰胺(30mL)中,加入碳酸钾(5.64g,40.8mmol)和叔丁基(2-氯乙氧基)二甲基硅烷(4.88g,20.4mmol),反应混合物25℃反应12小时。反应液用水(50mL)稀释,乙酸乙酯(50mL)萃取两次,有机相合并,干燥,浓缩,柱层析(石油醚/乙酸乙酯=5/1)分离纯化得到白色固体标题化合物(3.2g)。LC-MS:m/z[M+1]+=305.
第二步:4-溴-1-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-1H-吡唑-5-甲醛
氮气保护条件下,4-溴-1-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-1H-吡唑(3.2g,11.7mmol)溶于四氢呋喃(50mL)中,在-78℃下滴加二异丙基氨基锂(11.76mL,23.52mmol,2M),搅拌半小时后,滴加N,N-二甲基甲酰胺(1.72g,23.5mmol),滴加完后反应混合物搅拌1小时。向反应液中滴加稀盐酸至弱酸性,然后加水(50mL)稀释,乙酸乙酯(50mL)萃取两次,有机相合并,干燥,浓缩,柱层析(石油醚/乙酸乙酯=2/1)分离纯化得到白色固体标题化合物(2.5g)。LC-MS:m/z[M+1]+=333.
第三步:3-溴-6,7-二氢-4H-吡唑并[5,1-c][1,4]恶嗪-4-醇
将4-溴-1-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-1H-吡唑-5-甲醛(2.5g,7.53mmol)加入到混合溶剂水(5mL)和2-甲基四氢呋喃(5mL)中,加入三氟乙酸(10mL),室温搅拌半小时后,向反应液加入饱和碳酸氢钠溶液至弱碱性。加水(50mL)稀释,乙酸乙酯(50mL)萃取两次,有机相合并,干燥,浓缩,柱层析(二氯甲烷/甲醇=20/1)分离纯化得到淡黄色固体标题化合物(1.35g)。LC-MS:m/z[M+H]+=219.
第四步:3-溴-6,7-二氢-4H-吡唑并[5,1-c][1,4]恶嗪
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3-溴-6,7-二氢-4H-吡唑并[5,1-c][1,4]恶嗪-4-醇(500mg,2.28mmol)加入到二氯甲烷(15mL)中,随后加入三氟乙酸(2.04mL,27.3mmol)和三乙基硅烷(1.59g,13.7mmol),反应液25℃搅拌16小时。向反应液加入饱和碳酸氢钠溶液至弱碱性。加水(50mL)稀释,乙酸乙酯(50mL)萃取两次,有机相合并,干燥,浓缩,柱层析(二氯甲烷/甲醇=20/1)分离纯化得到淡黄色液体标题化合物(440mg)。LC-MS:m/z[M+H]+=203.
第五步:3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-6,7-二氢-4H-吡唑并[5,1-c][1,4]恶嗪
3-溴-6,7-二氢-4H-吡唑并[5,1-c][1,4]恶嗪(200mg,0.99mmol)溶解在1,4-二氧六环(10mL)中,分别加入碳酸钾(290mg,2.97mmol),四丁基溴化铵(64mg,0.2mmol),双(频哪醇)二硼(50mg,1.98mmol)和双(三苯基膦)氯化钯(II)(140mg,0.2mmol),氩气饱和条件下,反应混合物105℃搅拌2小时。加水(50mL)稀释,乙酸乙酯(50mL)萃取两次,有机相合并,干燥,浓缩,柱层析(二氯甲烷/乙酸乙酯=20/1)纯化得到标题化合物(200mg)。LC-MS:m/z[M+H]+=251.
中间体60:2-甲基-5,6,7,8-四氢咪唑并[1,2-a]吡嗪
第一步:2-甲基咪唑并[1,2-a]吡嗪
吡嗪-2-胺(2.0g,21.0mmol)溶解在乙醇(25mL)中,加入1-溴丙烷-2-酮(3.46g,25.2mmol),混合物80℃反应2小时。反应液直接浓缩,柱层析(石油醚/乙酸乙酯=10/1)分离纯化得到白色固体标题化合物(1.3g)。LC-MS:m/z[M+1]+=134.
第二步:2-甲基-5,6,7,8-四氢咪唑并[1,2-a]吡嗪
2-甲基咪唑并[1,2-a]吡嗪(0.5g,3.76mmol)溶解在甲醇(10mL)中,加入钯碳催化剂(50mg),反应混合物在氢气环境下25℃搅拌2小时。反应液硅藻土过滤,滤液浓缩得到淡黄色液体标题化合物(0.8g)。LC-MS:m/z[M+1]+=138.
中间体61:3-(4-氟苯基)-5-甲基-4-(((5-(三丁基甲锡烷基)吡嗪-2-基)氧基)甲基)异恶唑
将4-(((5-溴吡嗪-2-基)氧基)甲基)-3-(4-氟苯基)-5-甲基异恶唑(1g,2.75mmol,中间体5),三环己基磷(77mg,0.28mmol),三(二亚苄基丙酮)二钯(151mg,16mmol)和氯化锂(525mg,12.4mmol)加入到1,4-二氧六环(40mL)中,向混合物中加入六丁基二锡(2.71g,4.67mmol),反应混合物在氩气氛围下加热到110℃搅拌过夜。向反应液中加入饱和氟化钾水溶液,搅拌2小时。有深色沉淀出现,硅藻土过滤,滤液干燥浓缩,经柱层析(二氯甲烷/甲醇=20/1)纯化得到浅黄色油状标题化合物(500mg,收率32%)。LC-MS:m/z[M+H]+=576.
中间体62:1-(2-氨基乙基)-4-(6-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)哒嗪-3-基)哌嗪-2-羧酸甲酯
第一步:1-叔丁基2-甲基4-[6-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)哒嗪-3-基]哌嗪-1,2-二羧酸酯
氮气保护条件下,将化合物4-(((6-氯哒嗪-3-基)氧基)甲基)-3-(4-氟苯基)-5-甲基异恶唑(300mg,0.94mmol,中间体6)、1-(叔丁基)2-甲基(S)-哌嗪-1,2-二羧酸酯(0.34g,1.41mmol,CAS:129799-15-1)、碳酸铯(0.55g,1.69mmol)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(0.079g,0.094mmol)和2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(0.044g,0.094mmol)加入到1,4-二氧六环(20mL)中,100℃搅拌16小时。反应液硅藻土过滤,滤液浓缩,经柱层析(二氯甲烷/甲醇=20/1)纯化得到白色固体标题化合物(450mg,产率91%)。LC-MS:m/z[M+H]+=528.
第二步:4-[6-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)哒嗪-3-基]哌嗪-2-羧酸甲酯
室温下,将1-叔丁基2-甲基4-[6-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)哒嗪-3-基]哌嗪-1,2-二羧酸酯(450mg,0.85mmol)溶于二氯甲烷(10mL)中,加入三氟乙酸(3mL),室温搅拌3小时。将反应液倒入饱和碳酸氢钠溶液(50mL)中淬灭,乙酸乙酯(100mL)萃取两次。合并有机相,无水硫酸钠干燥、浓缩得到标题化合物(360mg粗品)。LC-MS:m/z[M+H]+=428.
第三步:1-(2-((叔丁氧羰基)氨基)乙基)-4-(6-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)哒嗪-3-基)哌嗪-2-羧酸甲酯
氮气保护条件下,将化合物4-[6-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)哒嗪-3-基]哌嗪-2-羧酸甲酯(310mg,0.73mmol)、1,2,3-恶噻唑烷-3-羧酸叔丁酯2,2-二氧化物(0.20g,0.88mmol,CAS:459817-82-4)和碳酸铯(0.36g,1.09mmol)加入到乙腈(15mL)中,70℃搅拌3小时。反应液硅藻土过滤,滤液加水(50mL)稀释,乙酸乙酯(50mL)萃取三次。合并有机相,饱和食盐水(60mL)洗涤一次,无水硫酸钠干燥、过滤,滤液浓缩得到标题化合物(400mg粗品)。LC-MS:m/z[M+H]+=571.
第四步:1-(2-氨基乙基)-4-(6-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)哒嗪-3-基)哌嗪-2-羧酸甲酯
氮气保护条件下,1-(2-((叔丁氧羰基)氨基)乙基)-4-(6-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)哒嗪-3-基)哌嗪-2-羧酸甲酯(350mg,0.61mmol)溶于氯化氢乙酸乙酯溶液(5mL)中,25℃搅拌2小时。将反应液倒入饱和碳酸氢钠(150mL)中淬灭,乙酸乙酯(50mL)萃取三次。合并有机相,饱和食盐水(80mL)洗涤,无水硫酸钠干燥,过滤,滤液浓缩得到标题化合物(200mg粗品)。LC-MS:m/z[M+H]+=471.
中间体63:(S)-六氢-2H-吡嗪并[1,2-a]吡嗪-1(6H)-酮盐酸盐
第一步:(S)-1-叔丁基3-甲基4-(2-(((苄氧基)羰基)氨基)乙基)哌嗪-1,3-二羧酸酯
在室温下,将(S)-1-叔丁基3-甲基哌嗪-1,3-二羧酸酯(1.0g,4.09mmol)和(2-溴乙基)氨基甲酸苄酯(1.27g,4.91mmol)溶解在无水N,N-二甲基甲酰胺(15.0mL)中,加入碳酸钾(678mg,4.91mmol),100℃反应16小时。反应液加水(40mL)稀释,二氯甲烷萃取(30mL×3次),合并有机相,饱和食盐水洗涤(40mL×2次),无水硫酸钠干燥并过滤。滤液减压浓缩,残余物通过快速硅胶柱层析纯化(甲醇:二氯甲烷=0:1~1:10)得到黄色油状物标题化合物(370mg)。LC-MS:m/z[M+H]+=422.
第二步:(S)-9-氧代八氢-2H-吡嗪[1,2-a]吡嗪-2-羧酸叔丁酯
在室温下,将(S)-1-叔丁基3-甲基4-(2-(((苄氧基)羰基)氨基)乙基)哌嗪-1,3-二羧酸酯(370mg,0.87mmol)溶解在甲醇(6.0mL)中,加入钯/炭(30mg),氢气(15psi)氛围下反应16小时。反应液硅藻土过滤,滤液减压浓缩得到黄色油状标题化合物(210mg)。LC-MS:m/z[M+H]+=256.
第三步:(S)-六氢-2H-吡嗪并[1,2-a]吡嗪-1(6H)-酮盐酸盐
在室温下,将(S)-9-氧代八氢-2H-吡嗪[1,2-a]吡嗪-2-羧酸叔丁酯(60mg,0.24mmol)溶解在无水二氯甲烷(4mL)中,缓慢滴加4M氯化氢乙酸乙酯溶液(4mL),搅拌反应1小时。反应液减压浓缩得到黄色固体标题产物(50mg)。LC-MS:m/z[M+H]+=156.
中间体64:1-(6-氟吡啶-3-基)-1,4,6,7-四氢吡喃并[3,4-d][1,2,3]三唑
第一步:5-叠氮基-2-氟吡啶
将6-氟-3-吡啶胺(3g,26.7mmol)溶解于乙腈(60mL)中,并冷却至0℃。在0℃下依次加入亚硝酸叔丁酯(4.14g,40.1mmol)和叠氮基三甲基硅烷(3.7g,32.1mmol),反应混合物在室温下搅拌过夜。将反应液加入到水(200mL)中,二氯甲烷(200mL)萃取三次。有机相合并,饱和食盐水洗涤一次,干燥浓缩得到标题化合物(3g粗品),直接用于下一步反应。LC-MS:m/z[M+H]+=139.
第二步:1-(6-氟吡啶-3-基)-1,4,6,7-四氢吡喃并[3,4-d][1,2,3]三唑
将四氢-4H-吡喃-4-酮(1.23g,12.25mmol)加入甲苯(50mL)中,并将混合物加热至110℃,5-叠氮基-2-氟吡啶(2.2g,15.93mmol)的甲苯(10mL)溶液缓慢滴入,然后加入吡咯烷(0.96g,13.48mmol),反应液110℃搅拌3小时。冷却至0℃,依次加入二氯甲烷(100mL)、间氯过氧苯甲酸(4.97g,24.5mmol)和碳酸氢钠(2.06g,24.5mmol),反应混合物0℃搅拌过夜。加水(100mL)稀释,二氯甲烷(100mL)萃取两次。有机相合并,饱和食盐水洗涤一次,干燥浓缩,柱层析(二氯甲烷/甲醇=20/1)纯化得到淡黄色固体标题化合物(310mg)。LC-MS:m/z[M+H]+=221.
实施例1:3-(6-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)吡啶-3-基)-6,7-二氢-4H-[1,2,3]三唑并[5,1-c][1,4]恶嗪
方法A
将(3-(4-氟苯基)-5-甲基异恶唑-4-基)甲醇(33mg,0.16mmol,按照US20130102778A1公开的方法合成)溶解在无水四氢呋喃(2mL)中,冰浴条件下60%钠氢(7mg,0.19mmol)加入,反应混合物0℃搅拌半小时,3-(6-氟吡啶-3-基)-6,7-二氢-4H-[1,2,3]三唑并[5,1-c][1,4]恶嗪(35mg,0.16mmol,中间体1)加入,反应混合物室温搅拌16小时。水(20mL)淬灭反应,乙酸乙酯(20mL)萃取三次,有机相浓缩,制备薄层色谱分离(二氯甲烷/甲醇=50/1)得到白色固体标题化合物(33mg,收率51%),记为化合物1。1H NMR(400MHz,CDCl3)δ8.30(br.s.,1H),8.03(d,J=7.3Hz,1H),7.80(br.s.,2H),7.15(br.s.,2H),6.88(d,J=7.8Hz,1H),5.27(br.s.,2H),5.10(br.s.,2H),4.52(br.s.,2H),4.17(br.s.,2H),2.59(br.s.,3H);LC-MS:m/z[M+H]+=408.
实施例2
3-(6-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)吡啶-3-基)-7-甲基-6,7-二氢-[1,2,4]三唑基[4,3-a]吡嗪-8(5H)-酮
方法B
将3-(4-氟苯基)-5-甲基-4-(((5-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)吡啶-2-基)氧基)甲基)异恶唑(75mg,0.18mmol,中间体7),3-溴-7-甲基-6,7-二氢-[1,2,4]三唑并[4,3-a]吡嗪-8(5H)-酮(42mg,0.18mmol,中间体9),[1,1'-双(二苯基膦)二茂铁]二氯化钯(13mg,0.018mmol)和碳酸钠(38mg,0.36mmol)溶于1,4-二氧六环(3mL)中。混合物在氩气氛围下加热到110℃搅拌过夜。反应液硅藻土过滤,滤液浓缩,柱层析(二氯甲烷/甲醇=50/1)分离纯化得到白色固体标题化合物(23mg,收率29%),记为化合物2。1H NMR(400MHz,CDCl3)δ8.49(br.s.,1H),8.04(d,J=8.3Hz,1H),7.86-7.69(m,2H),7.16(t,J=8.3Hz,2H),6.95(d,J=8.3Hz,1H),5.32(s,2H),4.38(br.s.,2H),3.81(br.s.,2H),3.23(s,3H),2.60(s,3H);LC-MS:m/z[M+H]+=435.
实施例3
4-((5-(5,6-二氢-4H-吡咯[1,2-b]吡唑-3-基)吡嗪-2-基)氧基)甲基)-3-(4-氟苯基)-5-甲基异恶唑
方法C
4-(((5-溴吡嗪-2-基)氧基)甲基)-3-(4-氟苯基)-5-甲基异恶唑(200mg,0.55mmol,中间体5),3-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-5,6-二氢-4H-吡咯并(1,2-b)吡唑(129mg,0.55mmol,CAS:1314138-13-0)溶于1,4-二氧六环(6mL)中,加入1,1'-双二苯基膦二茂铁二氯化钯(40mg,0.055mmol)和碳酸钠(117mg,1.1mmol),混合物在氩气氛围下加热到100℃搅拌过夜,混合物直接柱层析(二氯甲烷/甲醇=50/1)纯化得到浅黄色固体标题化合物(15mg,收率7%),记为化合物3。1H NMR(400MHz,CDCl3)δ8.21(s,2H),7.97(br.s.,1H),7.78(t,J=6.6Hz,2H),7.16(t,J=8.3Hz,2H),5.24(s,2H),4.22(d,J=6.8Hz,2H),3.16(br.s.,2H),2.80-2.65(m,2H),2.59(s,3H);LC-MS:m/z[M+H]+=392.
实施例4
7-环丁基-3-(5-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)吡嗪-2-基)-6,7-二氢-[1,2,4]三唑并[4,3-a]吡嗪-8(5H)-酮
方法D
4-((5-(7-环丁基-5,6,7,8-四氢-[1,2,4]三唑基[4,3-a]吡嗪-3-基)吡嗪-2-基)氧基)甲基)-3-(4-氟苯基)-5-甲基异恶唑(100mg,0.22mmol,中间体25)溶于氯仿(1mL),乙腈(1mL)和水(2mL)的混合溶剂中,加入高碘酸钠(141mg,0.66mmol)和二氧化钌水合物(7mg,0.044mmol),混合物室温搅拌10分钟。向反应液中加入水(4mL),用二氯甲烷(3mL)萃取3次,合并有机相,硅藻土过滤,滤液干燥浓缩,柱层析(二氯甲烷/甲醇=20/1)纯化得白色固体标题化合物(19mg,收率18%),记为化合物4。1H NMR(400MHz,CDCl3)δ9.22(br.s.,1H),8.25(br.s.,1H),7.78(br.s.,2H),7.18(br.s.,2H),5.38(br.s.,2H),5.22(br.s.,1H),4.82(br.s.,2H),3.82(br.s.,2H),2.62(br.s.,3H),2.30(br.s.,2H),2.18(br.s.,2H),1.80(br.s.,2H);LC-MS:m/z[M+H]+=476.
实施例5
3-(4-氟苯基)-5-甲基-4-((5-(7-(四氢呋喃-3-基)-5,6,7,8-四氢呋喃-[1,2,4]三唑基[4,3-a]吡嗪-3-基)吡嗪-2-基)氧基)甲基)异恶唑
方法E
将3-(4-氟苯基)-5-甲基-4-(((5-(5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪-3-基)吡嗪-2-基)氧基)甲基)异恶唑(100mg,0.245mmol,中间体23)溶于甲醇(10mL)中,加入二氢-3(2H)-呋喃酮(63mg,0.73mmol),混合物在室温下搅拌30分钟后,加入氰基硼氢化钠(46mg,0.73mmol),混合物加热到60℃搅拌过夜。混合物经柱层析(二氯甲烷/甲醇=20/1)纯化得到白色固体标题化合物(41mg,收率35%),记为化合物5。1H NMR(400MHz,CDCl3)δ9.09(s,1H),8.22(s,1H),7.78(t,J=6.1Hz,2H),7.18(t,J=8.1Hz,2H),5.35(s,2H),4.49(br.s.,2H),4.14-4.01(m,2H),4.01-3.89(m,2H),3.89-3.69(m,2H),3.33(br.s.,1H),2.99(br.s.,1H),2.92(br.s.,1H),2.61(s,3H),2.19(d,J=6.8Hz,1H),1.99(d,J=6.8Hz,1H);LC-MS:m/z[M+H]+=478.
实施例6
(S)-8-(5-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)吡嗪-2-基)六氢-2H-吡嗪并[1,2-a]吡嗪-1(6H)-酮
方法F
4-(((5-溴吡嗪-2-基)氧基)甲基)-3-(4-氟苯基)-5-甲基异恶唑(50mg,0.135mmol,中间体5),碳酸铯(110mg,0.34mmol),(S)-六氢-2H-吡嗪并[1,2-a]吡嗪-1(6H)-酮盐酸盐(46mg,0.24mmol,中间体63),2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(13mg,0.027mmol),甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(23mg,0.027mmol)溶于1,4-二氧六环(5mL),混合物在氩气氛围下加热110℃搅拌过夜。混合物用硅藻土过滤,向滤液中加入饱和氯化铵溶液,乙酸乙酯萃取三次,合并有机相,干燥浓缩,柱层析(二氯甲烷/甲醇=20/1)纯化得到浅黄色固体标题化合物(8mg,收率7%),记为化合物6。1H NMR(400MHz,CDCl3)δ7.88(s,1H),7.84-7.76(m,2H),7.74(s,1H),7.16(t,J=8.3Hz,2H),5.84(br.s.,1H),5.16(s,2H),4.44(d,J=11.2Hz,1H),4.16(d,J=13.2Hz,1H),3.66(br.s.,1H),3.30(d,J=11.7Hz,1H),3.11-2.84(m,4H),2.65(br.s.,1H),2.57(s,3H),2.49(br.s.,1H);LC-MS:m/z[M+H]+=439.
实施例7
3-(6-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)吡啶-3-基)-5,6-二氢-8H-[1,2,4]三唑并[3,4-c][1,4]噻嗪7,7-二氧化物
方法G
4-(((5-(5,6-二氢-8H-[1,2,4]三唑并[3,4-c][1,4]噻嗪-3-基)吡啶-2-基)氧基)甲基)-3-(4-氟苯基)-5-甲基异恶唑(280mg,0.9mmol,中间体48)和钨酸钠(650mg,4.5mmol),过氧化氢(620mg,4.8mmol)加入到甲醇(8mL)中,搅拌2小时。反应液过滤,滤液浓缩,制备薄层色谱分离(石油醚/乙酸乙酯=1/2)得到标题化合物(30mg,收率17%),记为化合物7。1H NMR(400MHz,CDCl3)δ8.45(s,1H),7.91(d,J=8.8Hz,1H),7.86-7.74(m,2H),7.17(t,J=8.6Hz,2H),6.95(d,J=8.3Hz,1H),5.32(s,2H),4.73(s,2H),4.57(t,J=5.4Hz,2H),3.51(br.s.,2H),2.60(s,3H);LC-MS:m/z[M+H]+=456.
实施例8
方法H
3-(6-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)-2-甲氧基吡啶-3-基)-5,6-二氢-8H-[1,2,4]三唑并[3,4-c][1,4]恶嗪
将6-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)-2-甲氧基烟酰肼(500mg,1.34mmol,中间体20)加入到甲苯(50mL)中,分别加入三乙胺(2mL,10.1mmol)和5-氯-3,6-二氢-2H-1,4-恶嗪(240mg,2.01mmol,中间体28),130℃搅拌4小时后,加入饱和碳酸氢钠溶液至pH=10-11,反应液100℃搅拌16小时,加水(100mL)稀释,乙酸乙酯(100mL)萃取两次,有机相合并,干燥浓缩,柱层析(二氯甲烷/乙酸乙酯=20/1)纯化得到标题化合物(5.2mg),记为化合物8。1H NMR(400MHz,CD3OD)δ2.57(s,3H),3.96(s,3H),3.99(d,J=4.88Hz,2H),4.05(d,J=4.88Hz,2H),4.99(s,2H),5.40(s,2H),6.55(d,J=8.32Hz,1H),7.23(t,J=8.32Hz,2H),7.70-7.78(m,2H),7.80(d,J=8.32Hz,1H);LC-MS:m/z[M+H]+=438.
实施例9
3-(5-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)吡嗪-2-基)-7,8-二氢-1H,6H,9H-7,8a-甲桥吡咯并[1',2':3.4]咪唑并[1,2-c]嘧啶-1-酮
方法I
将3-(4-氟苯基)-5-甲基-4-(((5-(三丁基甲锡烷基)吡嗪-2-基)氧基)甲基)异恶唑(200mg,0.35mmol,中间体61),3-氯-7,8-二氢-1H,6H,9H-7,8a-甲桥吡咯并[1',2':3,4]咪唑并[1,2-c]嘧啶-1-酮(78mg,0.35mmol,中间体57)加入到1,4-二氧六环(4mL)中,向混合物中加入四三苯基膦钯(40mg,0.035mmol)和碘化亚铜(10mg,0.053mmol),反应混合物在氩气氛围下回流搅拌过夜。反应液硅藻土过滤,滤液浓缩,经柱层析(二氯甲烷/甲醇=20/1)纯化得到浅黄色固体标题化合物(12mg,收率7%),记为化合物9。1H NMR(400MHz,CDCl3)δ9.33-9.24(m,1H),8.27-8.19(m,1H),7.87-7.74(m,2H),7.22-7.12(m,2H),6.64(s,1H),5.35(br.s.,2H),4.22-4.05(m,2H),3.60-3.43(m,2H),3.14-3.04(m,1H),2.60(s,3H),2.14(br.s.,2H),1.76(br.s.,2H);LC-MS:m/z[M+H]+=473.
实施例10
8-(6-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)哒嗪-3-基)六氢-2H-吡嗪并[1,2-a]吡嗪-1(6H)-酮
方法J
氮气保护条件下,1-(2-氨基乙基)-4-(6-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)哒嗪-3-基)哌嗪-2-羧酸甲酯(200mg,0.43mmol,中间体62)溶于甲醇(50mL)中,加入三乙胺(0.44g,4.3mmol),反应混合物60℃搅拌1小时。向反应液中加水(60mL)淬灭,乙酸乙酯(50mL)萃取三次。合并有机相,饱和食盐水(80mL)洗涤,无水硫酸钠干燥、过滤,滤液减压浓缩。残余物经柱层析(二氯甲烷/甲醇=20/1)纯化得到标题化合物(25mg),记为化合物10。1H NMR(400MHz,DMSO-d6)δ7.78-7.75(m,3H),7.39-7.34(m,3H),7.03(d,J=9.6Hz,1H),5.28(s,2H),4.47–4.45(m,1H),4.04–4.01(m,1H),3.35–3.32(m,1H),3.10–3.07(m,1H),2.96–2.89(m,3H),2.65–2.63(m,2H),2.55(s,3H),2.44-2.38(m,1H),2.31-2.24(m,1H);LC-MS:m/z[M+H]+=439.
参照实施例1的方法(方法A)制备得到,区别仅在于采用同摩尔量的下表原料替换实施例1中的3-(6-氟吡啶-3-基)-6,7-二氢-4H-[1,2,3]三唑并[5,1-c][1,4]恶嗪具体见下表所示:
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化合物11:1H NMR(400MHz)CDCl3:δ8.35(d,J=8.8Hz,1H),7.81-7.68(m,2H),7.22-7.06(m,3H),5.47(s,2H),5.33(s,2H),4.54(t,J=4.9Hz,2H),4.18(t,J=4.9Hz,2H),2.59(s,3H).LC-MS:m/z[M+H]+=409.
化合物12:1H NMR(400MHz)CDCl3:δ8.97(s,1H),8.19(s,1H),7.87-7.68(m,2H),7.17(t,J=8.6Hz,2H),5.31(s,2H),5.21(s,2H),4.51(t,J=4.6Hz,2H),4.15(t,J=4.9Hz,2H),2.61(s,3H).LC-MS:m/z[M+H]+=409.
化合物17:1H NMR(400MHz)CDCl3:δ8.51(s,1H),8.01(d,J=8.8Hz,1H),7.88-7.71(m,2H),7.17(t,J=8.3Hz,2H),6.93(d,J=8.8Hz,1H),5.32(s,2H),5.09(s,2H),4.14(d,J=4.9Hz,2H),4.09(d,J=4.9Hz,2H),2.61(s,3H).LC-MS:m/z[M+H]+=408.
化合物18:1H NMR(400MHz)CDCl3:δ8.46(d,J=9.3Hz,1H),7.81-7.65(m,2H),7.21-7.09(m,3H),5.50(s,2H),5.11(s,2H),4.69(t,J=4.9Hz,2H),4.11(t,J=4.9Hz,2H),2.61(s,3H).LC-MS:m/z[M+H]+=409.
化合物19:1H NMR(400MHz)CDCl3:δ9.11(s,1H),8.23(s,1H),7.85-7.71(m,2H),7.18(t,J=8.6Hz,2H),5.35(s,2H),5.08(s,2H),4.53(br.s.,2H),4.08(br.s.,2H),2.61(s,3H).LC-MS:m/z[M+H]+=409.
化合物20:1H NMR(400MHz)CDCl3:δ8.37(s,1H),7.93-7.72(m,3H),7.16(t,J=8.3Hz,2H),6.92(d,J=8.8Hz,1H),5.31(s,2H),4.92(s,2H),4.27-4.15(m,2H),4.15-4.06(m,2H),2.60(s,3H),2.04(br.s.,2H).LC-MS:m/z[M+H]+=422.
化合物21:1H NMR(400MHz)CDCl3:δ8.44(d,J=8.8Hz,1H),7.80-7.66(m,2H),7.22-7.08(m,3H),5.50(s,2H),5.14-4.98(m,2H),4.94(s,2H),4.22-4.02(m,2H),2.60(s,3H),2.10(br.s.,2H).LC-MS:m/z[M+H]+=423.
化合物22:1H NMR(400MHz)CDCl3:δ8.40(d,J=9.3Hz,1H),7.73(dd,J=5.1,8.6Hz,2H),7.20-7.05(m,3H),5.49(s,2H),4.50(t,J=7.3Hz,2H),3.09(t,J=7.6Hz,2H),2.86(t,J=7.3Hz,2H),2.60(s,3H).LC-MS:m/z[M+H]+=393.
化合物23:1H NMR(400MHz)CDCl3:δ9.07(s,1H),8.21(s,1H),7.85-7.67(m,2H),7.17(t,J=8.6Hz,2H),5.34(s,2H),4.36(t,J=7.1Hz,2H),3.05(t,J=7.1Hz,2H),2.92-2.73(m,2H),2.60(s,3H).LC-MS:m/z[M+H]+=393.
化合物24:1H NMR(400MHz)DMSO-d6:δ8.83(s,1H),8.45(s,1H),7.78(d,J=5.4Hz,2H),7.37(t,J=8.1Hz,2H),5.39(s,2H),4.82(s,2H),4.64(m,2H),3.99(s,2H),2.60(m,3H),1.89(m,2H).LC-MS:m/z[M+H]+=423.
化合物25:1H NMR(400MHz)CDCl3:δ8.45(s,1H),7.98(d,J=8.6Hz,1H),7.78(t,J=12Hz,2H),7.15(t,J=8.3Hz,2H),6.89(d,J=8.7Hz,1H),5.28(s,2H),4.52–4.49(m,2H),4.12(t,J=5.9Hz,2H),2.59(s,3H),2.27–2.24(m,2H).LC-MS:m/z[M+H]+=408.
化合物28:1H NMR(400MHz)CDCl3:δ8.43(br.s.,1H),7.93(d,J=8.3Hz,1H),7.84-7.76(m,2H),7.16(t,J=8.3Hz,2H),6.94(br.s.,1H),6.86(d,J=8.3Hz,1H),5.28(s,2H),4.95(s,2H),4.22-3.91(m,4H),2.69-2.52(m,3H);LC-MS:m/z[M+1]+=407.
化合物32:1H NMR(400MHz)DMSO-d6:δ8.84(s,1H),8.40(s,1H),7.84-7.71(m,2H),7.35(t,J=8.6Hz,2H),5.43-5.29(m,2H),4.26(t,J=5.4Hz,2H),2.91(t,J=6.1Hz,2H),2.57(s,3H),1.98-1.76(m,4H).LC-MS:m/z[M+H]+=407.
化合物33:1H NMR(400MHz)DMSO-d6:δ8.80(s,1H),8.41(s,1H),7.81-7.71(m,2H),7.35(t,J=8.6Hz,2H),5.36(s,2H),4.60(br.s.,2H),3.79(br.s.,4H),3.19(br.s.,2H),2.57(s,3H).LC-MS:m/z[M+H]+=423.
化合物42:1H NMR(400MHz)CD3OD:δ2.53(s,3H),2.74(s,3H),4.02(t,J=4.88Hz,2H),4.25(t,J=5.12Hz,2H),5.03(s,2H),5.36(s,2H),7.19(t,J=8.56Hz,2H),7.61-7.76(m,2H),8.27(s,1H).LC-MS:m/z[M+H]+=423.
化合物43:1H NMR(400MHz)CD3OD:δ2.39(s,3H),2.57-2.69(m,3H),3.91(d,J=4.40Hz,2H),4.05(d,J=4.40Hz,2H),5.00(s,2H),5.33-5.43(m,2H),6.79(d,J=8.32Hz,1H),7.25(t,J=8.32Hz,2H),7.72(d,J=8.32Hz,1H),7.83(t,J=6.12Hz,2H).LC-MS:m/z[M+H]+=422.
化合物50:1H NMR(400MHz)DMSO-d6:δ8.52(d,J=2.5Hz,1H),8.08(dd,J=8.9,2.7Hz,1H),7.86–7.73(m,2H),7.37(t,J=8.9Hz,2H),7.08(d,J=8.8Hz,1H),5.34(s,2H),4.78(s,2H),3.89(t,J=5.5Hz,2H),2.92(t,J=5.4Hz,2H),2.59(s,3H).LC-MS:m/z[M+H]+=408.
参照实施例2的方法(方法B)制备得到,区别仅在于采用同摩尔量的下表原料替换实施例2中的3-溴-7-甲基-6,7-二氢-[1,2,4]三唑并[4,3-a]吡嗪-8(5H)-酮,具体见下表所示:
化合物13:1H NMR(400MHz)CDCl3:δ8.49(br.s.,1H),8.04(d,J=8.3Hz,1H),7.79(br.s.,2H),7.17(t,J=8.1Hz,2H),6.95(d,J=8.3Hz,1H),5.32(s,2H),4.37(br.s.,2H),3.80(br.s.,2H),3.72(d,J=6.8Hz,2H),2.60(s,3H),1.34(br.s.,3H).LC-MS:m/z[M+H]+=449.
化合物30:1H NMR(400MHz)DMSO-d6:δ8.53(br.s.,1H),8.07(br.s.,1H),7.79(br.s.,2H),7.37(d,J=5.9Hz,2H),7.01(br.s.,1H),5.33(br.s.,2H),4.95(br.s.,1H),4.83(br.s.,1H),4.20(br.s.,1H),4.10(br.s.,1H),3.86(br.s.,2H),2.58(d,J=4.4Hz,3H),2.15(br.s.,3H).LC-MS:m/z[M+H]+=449.
化合物31:1H NMR(400MHz)DMSO-d6:δ8.56(br.s.,1H),8.11(d,J=6.8Hz,1H),7.80(br.s.,2H),7.42-7.30(m,2H),7.02(d,J=8.3Hz,1H),5.33(br.s.,2H),4.64(br.s.,2H),4.26(br.s.,2H),3.64(br.s.,2H),3.11(br.s.,3H),2.59(br.s.,3H).LC-MS:m/z[M+H]+=485.
化合物38:1H NMR(400MHz)DMSO-d6:δ8.85(s,1H),8.32(d,J=8.3Hz,1H),7.79(t,J=6.6Hz,2H),7.35(t,J=8.6Hz,2H),6.91(d,J=8.8Hz,1H),6.42(s,1H),5.32(s,2H),4.71(s,1H),4.35(d,J=12.2Hz,1H),4.01(d,J=12.7Hz,1H),3.93-3.86(m,2H),3.43(s,2H),2.58(s,3H),1.89(q,J=9.9Hz,2H).LC-MS:m/z[M+H]+=488.
化合物39:1H NMR(400MHz)CDCl3:δ8.81(s,1H),8.33(d,J=8.3Hz,1H),7.87-7.76(m,2H),7.15(t,J=8.6Hz,2H),6.82(d,J=8.8Hz,1H),5.98(s,1H),5.29(s,2H),4.11(s,2H),3.48(s,2H),3.09(br.s.,1H),2.60(s,3H),2.15(br.s.,2H),1.76(d,J=3.9Hz,2H).LC-MS:m/z[M+H]+=472.
化合物41:1H NMR(400MHz)DMSO-d6:δ8.81(s,1H),8.28(d,J=8.8Hz,1H),7.82-7.74(m,2H),7.35(t,J=8.8Hz,2H),6.88(d,J=8.3Hz,1H),6.22(s,1H),5.29(s,2H),3.97(t,J=8.6Hz,2H),3.68-3.61(m,2H),2.97(s,3H),2.56(s,3H).LC-MS:m/z[M+H]+=434.
参照实施例3的方法(方法C)制备得到,区别仅在于采用同摩尔量的下表原料替换实施例3中的3-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-5,6-二氢-4H-吡咯并(1,2-b)吡唑,具体见下表所示:
化合物44:1H NMR(400MHz)CD3OD:δ2.51-2.65(m,3H),4.13(br.s,2H),4.19(br.s,2H),5.12(br.s,2H),5.33(br.s.,2H),7.24(t,J=8.08Hz,2H),7.80(br.s,2H),8.00(br.s,1H),8.19(br.s,1H),8.43(br.s,1H).LC-MS:m/z[M+H]+=408.
参照实施例4的方法(方法D)制备得到,区别仅在于采用同摩尔量的下表原料替换实施例4中的4-((5-(7-环丁基-5,6,7,8-四氢-[1,2,4]三唑基[4,3-a]吡嗪-3-基)吡嗪-2-基)氧基)甲基)-3-(4-氟苯基)-5-甲基异恶唑,具体见下表所示:
化合物14:1H NMR(400MHz)CDCl3:δ8.60-8.48(m,1H),7.73(br.s.,2H),7.22-7.11(m,3H),5.53-5.47(m,2H),5.05-4.95(m,2H),3.90-3.80(m,2H),3.29-3.23(m,3H),2.63-2.58(m,3H).LC-MS:m/z[M+H]+=436.
化合物26:1H NMR(400MHz)CDCl3:δ8.95(s,1H),8.08(s,1H),7.81–7.73(m,2H),7.17(t,J=8.4Hz,2H),5.31(s,2H),4.59(d,J=7.8Hz,4H),2.60(s,3H).LC-MS:m/z[M+H]+=490.
化合物36:1H NMR(400MHz)DMSO-d6:δ8.00(d,J=9.3Hz,1H),7.82-7.73(m,2H),7.40-7.30(m,3H),5.43(s,2H),4.46(d,J=5.4Hz,2H),4.33(d,J=5.9Hz,2H),2.58(s,3H),2.45(s,3H).LC-MS:m/z[M+H]+=436.
化合物37:1H NMR(400MHz)DMSO-d6:δ7.99(d,J=9.8Hz,1H),7.78(t,J=6.6Hz,2H),7.51(s,1H),7.39-7.26(m,3H),7.22(s,1H),5.42(s,2H),4.43(br.s.,4H),2.58(s,3H).LC-MS:m/z[M+H]+=421.
参照实施例5的方法(方法E)制备得到,区别仅在于采用同摩尔量的下表原料替换实施例5中的二氢-3(2H)-呋喃酮,具体见下表所示:
化合物15:1H NMR(400MHz)CDCl3:δ9.08(br.s.,1H),8.21(br.s.,1H),7.77(br.s.,2H),7.22-7.09(m,2H),5.34(br.s.,2H),4.78(br.s.,2H),4.67(br.s.,2H),4.51(br.s.,2H),3.84(br.s.,3H),2.83(br.s.,2H),2.60(br.s.,3H).LC-MS:m/z[M+H]+=464.
化合物16:1H NMR(400MHz)CDCl3:δ9.08(s,1H),8.22(s,1H),7.78(d,J=6.4Hz,2H),7.17(t,J=8.3Hz,2H),5.34(s,2H),4.49(br.s.,2H),3.89(br.s.,2H),2.89(br.s.,2H),2.56(s,3H),2.60(s,3H).LC-MS:m/z[M+H]+=422.
参照实施例6的方法(方法F)制备得到,区别仅在于采用同摩尔量的下表原料1和原料2分别替换实施例6中的4-(((5-溴吡嗪-2-基)氧基)甲基)-3-(4-氟苯基)-5-甲基异恶唑和(S)-六氢-2H-吡嗪并[1,2-a]吡嗪-1(6H)-酮盐酸盐,具体见下表所示:
化合物27:1H NMR(400MHz)CDCl3:δ7.90(s,1H),7.77(dd,J=8.5,5.4Hz,2H),7.73(s,1H),7.15(t,J=8.5Hz,2H),5.17(s,2H),4.76(s,2H),4.07–4.04(m,2H),4.00(d,J=5.3Hz,2H),2.56(s,3H),2.44(s,3H).LC-MS:m/z[M+H]+=422.
化合物34:1H NMR(400MHz)DMSO-d6:δ7.80-7.72(m,2H),7.62(d,J=9.8Hz,1H),7.34(t,J=8.6Hz,2H),7.13(d,J=9.8Hz,1H),5.28(s,2H),4.82(s,2H),3.98(s,4H),2.54(s,3H),2.29(s,3H).LC-MS:m/z[M+H]+=422.
化合物35:1H NMR(400MHz)DMSO-d6:δ7.81-7.69(m,2H),7.58-7.52(m,1H),7.34(t,J=8.6Hz,2H),7.20-7.09(m,2H),6.94(s,1H),5.28(s,2H),4.74(s,2H),4.10(d,J=4.4Hz,2H),4.00(d,J=4.9Hz,2H),2.54(s,3H).LC-MS:m/z[M+H]+=407.
化合物40:1H NMR(400MHz)CD3OD:δ7.89-7.70(m,4H),7.33-7.12(m,2H),5.33-5.13(m,2H),4.05(d,J=12.2Hz,1H),3.93(d,J=11.7Hz,1H),3.89-3.75(m,2H),3.70(t,J=10.8Hz,1H),3.23-3.12(m,1H),3.04-2.85(m,2H),2.85-2.72(m,1H),2.63-2.52(m,3H),2.50-2.32(m,4H).LC-MS:m/z[M+H]+=426.
化合物45:1H NMR(400MHz)CD3OD:δ2.60(s,3H),4.33(br.s,2H),4.58(br.s,2H),5.36(s,2H),6.28(br.s,1H),6.93-7.06(m,2H),7.25(t,J=8.56Hz,2H),7.74-7.85(m,2H),8.10(s,1H),8.65(s,1H).LC-MS:m/z[M+H]+=420.
化合物46:1H NMR(400MHz)CD3OD:δ2.17(s,3H),2.58(s,3H),3.96-4.02(m,2H),4.05-4.12(m,2H),4.60(s,2H),5.24(s,2H),6.76(s,1H),7.24(t,J=8.56Hz,2H),7.77-7.84(m,2H),7.89(d,J=3.42Hz,2H).LC-MS:m/z[M+H]+=421.
化合物48:1H NMR(400MHz)CDCl3:δ7.91(s,1H),7.83-7.73(m,2H),7.71(s,1H),7.16(t,J=8.3Hz,2H),7.09(s,1H),6.91(s,1H),5.17(s,2H),4.68(s,2H),4.14(d,J=4.9Hz,2H),4.06(d,J=4.9Hz,2H),2.57(s,3H).LC-MS:m/z[M+H]+=407.
化合物49:1H NMR(400MHz)DMSO-d6:δ7.80–7.72(m,2H),7.42–7.30(m,3H),7.04(d,J=9.6Hz,1H),5.27(s,2H),4.08–4.05(m,1H),3.98–3.95(m,1H),3.76–3.70(m,2H),3.55–3.50(m,1H),3.17–3.13(m,1H),2.92–2.86(m,1H),2.81-2.78(m,1H),2.67–2.65(m,1H),2.54(s,3H),2.44–2.38(m,1H),2.26–2.11(m,3H).LC-MS:m/z[M+H]+=426.
参照实施例7的方法(方法G)制备得到,区别仅在于采用同摩尔量的下表原料替换实施例7中的4-(((5-(5,6-二氢-8H-[1,2,4]三唑并[3,4-c][1,4]噻嗪-3-基)吡啶-2-基)氧基)甲基)-3-(4-氟苯基)-5-甲基异恶唑,具体见下表所示:
化合物29:1H NMR(400MHz)DMSO-d6:δ8.30(d,J=9.3Hz,1H),7.81-7.73(m,2H),7.45(d,J=9.3Hz,1H),7.36(t,J=8.8Hz,2H),5.52(s,2H),5.04(s,2H),4.94(t,J=5.9Hz,2H),3.94-3.84(m,2H),2.60(s,3H).LC-MS:m/z[M+H]+=457.
参照实施例8的方法(方法H)制备得到,区别仅在于采用同摩尔量的下表原料替换实施例8中的6-((3-(4-氟苯基)-5-甲基异恶唑-4-基)甲氧基)-2-甲氧基烟酰肼,具体见下表所示:
化合物51:1H NMR(400MHz)CD3OD:δ7.56(dd,J=5.4,8.8Hz,2H),7.19(t,J=8.8Hz,2H),7.12(d,J=5.9Hz,2H),5.23(s,2H),4.98(s,2H),4.07-4.02(m,2H),3.88(t,J=4.9Hz,2H),3.85(s,3H),2.59(s,3H).LC-MS:m/z[M+H]+=438.
参照实施例9的方法(方法I)制备得到,区别仅在于采用同摩尔量的下表原料替换实施例9中的3-氯-7,8-二氢-1H,6H,9H-7,8a-甲桥吡咯并[1',2':3,4]咪唑并[1,2-c]嘧啶-1-酮,具体见下表所示:
实施例47:1H NMR(400MHz)CDCl3:δ9.05-8.94(m,1H),8.35-8.22(m,1H),7.87-7.70(m,2H),7.23-7.12(m,2H),6.85-6.72(m,1H),5.32(br.s.,2H),4.18(br.s.,2H),3.73(br.s.,2H),3.12(br.s.,3H),2.61(br.s.,3H).LC-MS:m/z[M+H]+=435.
一、生物学实验方法:
1.细胞系构建和传代培养
α亚基、β亚基和γ亚基对形成一个完整的功能型GABAA受体是必不可少的。在该实施例中,本发明通过脂质体转染法(Felgner,P.L.,et al.Proceedings of the NationalAcademy of Sciences,1987,84:7413-7417)构建并分别筛选出稳定表达人源α5-GABAA受体(包含α5β3γ2亚基)和α2-GABAA受体(包含α2β3γ2亚基)的HEK293细胞株。具体亚基蛋白序列如下:α5亚基(蛋白序列见GenBank登录号:NM_000810.3);α2亚基(蛋白序列见GenBank登录号:NM_000807.4);β3亚基(蛋白序列见GenBank登录号:NM_000814.5);γ2亚基(蛋白序列见GenBank登录号:NM_000816.3)。
将以上细胞系进行传代培养。扩增α5β3γ2-HEK293和α2β3γ2-HEK293细胞用于化合物对GABAA受体的苯二氮卓位点(BZD)亲和力测试。α5β3γ2-HEK293细胞在传代过程中部分悬浮细胞铺在用Poly-D-Lysine(多聚赖氨酸)预处理的玻片上用于电生理测试。
2.本发明化合物对α5-GABAA受体和α2-GABAA受体的亲和活性
Flunitrazepam(氟硝西泮)是一种非特异高效结合BZD位点的试剂。通过化合物与3H-flunitrazepam(同位素3H标记的氟硝西泮)竞争结合人源α5β3γ2和α2β3γ2受体可测定化合物对这两种受体BZD位点的亲和力。
膜制备:收集稳定表达人源α5β3γ2受体或α2β3γ2受体的HEK293细胞,细胞悬浮于50mM Tris-HCl缓冲液(pH=7.4)中,在冰上经匀浆机匀浆20秒10次,4℃,1000g离心10min。取上清,重复以上步骤。将上清在4℃(33800g;离心机购自Thermo(赛默飞),转子型号:A27-8x50)离心60min,取沉淀重悬于Tris缓冲液(50mM Tris-HCl,10mM MgCl2,0.5mMEDTA,10%glycerol)中,此沉淀即为细胞膜。使用BCA(Bicinchoninic Acid,二辛可宁酸)法测定蛋白质含量(BCA试剂盒购自Pierce(安诺伦生物))。将细胞膜制备1ml等分物,-80℃保存。
放射性配体竞争结合试验:本试验在在200μL体系中(96孔板,购自Agilent(安捷伦科技))进行,其中有装有100μL细胞膜。3H-flunitrazepam(购自PerkinElmer(珀金埃尔默仪器),货号:NET567250UC)的浓度为1nM,待测化合物的浓度在1x10-5-10-6M范围内。以flumazenil(氟马西尼,购自T℃ris,货号:1318)为对照。低信号对照孔(Low control,LC)加入1μL 2mM flumazenil(终浓度10μM),高信号对照孔(High control,HC)加入1μL DMSO(购自Sigma aldrich(西格玛奥德里奇),货号:472301)。最终靶点膜蛋白的浓度为5μg/孔。所有待测化合物样品储存液均为10mM DMSO溶液。样品工作浓度为将所有样品用DMSO稀释至0.2mM,然后进行4倍连续梯度稀释,共8个浓度梯度。用封板膜将96孔板密封,然后置于室温摇床孵育1小时。同时用浸板缓冲液(0.3%PEI,聚乙烯亚胺,购自:Sigma aldrich,型号:P314,4℃保存)浸泡GF/C过滤板,至少0.5小时。结合孵育完毕用细胞收集器收集到GF/C过滤板上,用洗板缓冲液(50mM Tris-HCl,pH 7.4,4℃保存)洗4次。50℃烘箱干燥1小时后把干燥好的GF/C过滤板底部封膜,用液体闪烁计数法检测滤膜残留放射性,每孔加入50μL闪烁液,并密封,使用Microbeta2(微孔板计数器,购自:PerkinElmer,型号:CNLL0153)读数。计算待测样品对3H-flunitrazepam与GABAA受体膜蛋白结合的抑制活性,通过量效曲线拟合(GraphPad Prism 5软件)计算各待测样品的IC50,并通过IC50计算样品的Ki(抑制常数),从而评估化合物与α5-GABAA受体和α2-GABAA受体BZD位点的结合能力。
3.本发明化合物对α5-GABAA受体的功能活性
通过电生理的方法检测待测药物对α5-GABAA受体的反向调控活性。具体方法如下所示:
化合物浓度设定:化合物筛选使用的化合物终浓度均为100nM。GABA浓度为0.05~0.06μM(约EC7~8)。电生理试验采用全细胞膜片钳技术,该方法可参照文献(Nickolls,S.A.,et al.British Journal of Pharmacology,2018,175:708–725)报道的方法。电生理用细胞外液(ECS)成分如下:150mM NaCl,5mM KCl,2.5mM CaCl2,1mM MgCl2,10mM HEPES和10mMglucose(pH 7.4);电生理用电极内液(ICS)配方如下:140mM CsCl,11mM EGTA,10mMHEPES,2mM CaCl2,1mM MgCl2,4mM MgATP,2mM TEA(pH 7.3)。以上试剂均购自Sigmaaldrich。将GABA(γ-氨基丁酸,购自sigma aldrich,货号:A5385)粉末用纯水配制成母液,在稀释于ECS中;化合物先用DMSO配制成为4mM的母液,再逐步稀释相应浓度的GABA-ECS中。溶液均在电生理测试前新鲜配制。
电生理信号采集使用EPC 10放大器及PatchMaster软件(HEKA)或Axon700B放大器及Clampex软件(AXON)。记录电极使用硼硅酸盐(购自sutter)玻璃拉制,电极电阻为4~6MΩ。胞外给药采用ALA-VC-8PG(购自ALA,美国)系统。选取单个独立生长的细胞,玻璃电极与细胞形成良好封接后破膜,形成全细胞模式。将细胞膜电位被钳制在-60mV,Gap-free模式下记录。试验时,先在胞外施加约20秒的细胞外液。待基线(Iprebaseline)稳定后,将胞外液切换至GABA-ECS。此时,可以检测到GABA引起的电流(Igaba)。大约20~40秒,待电流稳定后,将胞外液切换至化合物和GABA-ECS的混合溶液,直到此时可以检测到化合物和GABA共同引起的电流(Itreatment)。最后,将溶液切换至细胞外液,记录20~40秒终止试验。只有基线平稳、对照电流大小(Igaba-Iprebaseline)绝对值大于40pA且10~20秒内电流相对平稳的细胞才会用于化合物测试。
实验结果的分析采用PatchMaster v2x90.1或PatchMaster v2x90.3软件(EPC 10放大器)和Clampex10.6软件(Axon700B放大器)。各阶段的电流值按相应条件下稳定后电流的平均值计算。我们将对照电流定义为Igaba-Iprebaseline,化合物处理后电流定义为Itreatment-Iprebaseline。化合物的反向调节活性以百分比表示,按以下公式计算:反向调节效率=[(Itreatment-Igaba)/(Igaba-Iprebaseline)]×100%。
表1化合物对α5-GABAA受体的亲和力活性和反向调节活性
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结果表明,本发明化合物对α5-GABAA受体具有良好的亲和力活性和反向调节活性。
表2化合物的受体结合选择性
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与对比化合物相比,本发明化合物具有更好的α5-GABAA受体亚基选择性,由反向调节α2-GABAA受体导致的潜在副作用更小,安全性更好。
二、本发明化合物溶解度和在人工模拟胃液(SGF)中的稳定性
1.化合物在人工模拟肠液中的热力学溶解度
(1)实验材料与设备:
50mM磷酸盐缓冲液pH=7.4:称取0.39g NaH2PO4·2H2O,1.4025g Na2HPO4,置于锥形瓶中,加水240ml,溶解并混匀,用10M NaOH溶液调整pH到7.4,转移到250ml的容量瓶中,用水稀释到刻度。
模拟肠液FaSSIF:称取54.76mg FaSSIF-V2(Biorelevant,batch.V2FAS-0619-A,lot.V2FAS01)加至15ml缓冲液中,溶解后补足溶液至30ml,室温下放置1小时后使用。
Waters e2695 HPLC高效液相色谱,Mettler XSE105分析天平。
(2)实验方法:
先用DMSO配置含10mM各待测化合物的储备液,用稀释剂(ACN:PB缓冲液,体积比50:50)稀释成1M~200M标曲溶液,用HPLC测定,得到各待测化合物浓度与峰面积的标准曲线。
模拟肠液中的热力学溶解度(TS in FaSSIF)。各称取样品(待测化合物)约0.3mg加入FaSSIF溶液1.5mL,平行两份,1000rpm在37℃振摇4小时,过滤,弃掉初滤液1mL,取续滤液400μL,滤液用高效液相色谱仪(UV)检测。本发明化合物测试结果如下表所示。
表3溶解度测试结果
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与对比化合物相比,本发明化合物具有更好的溶解度,更适合于口服药物的开发以及口服吸收。
2.化合物在人工模拟胃液(SGF)中的稳定性
(1)试剂
人工模拟胃液(SGF),厂家:东菀市创峰自动化科技有限公司;产品型号:CF-006。
(2)仪器设备
振荡恒温金属浴,型号:Thermo;厂家:Digital Skaking Drybath。
(3)测试条件。
温度:37℃;转速:1000rpm;取样时间:0,4小时。
(4)液相条件
色谱柱:Welch Xtimate C18 3.0×100mm,5μm。流动相:A:0.04%三氟乙酸(TFA)/H2O(v/v),B:乙腈(ACN)。按照下表进行梯度洗脱,流速:1.0mL/min;进样量:5μL;柱温:35℃;波长:254nm。
时间(分钟) | 流动相A(%) | 流动相B(%) |
0-10 | 90-25 | 10-75 |
10-12 | 25-0 | 75-100 |
12-12.1 | 0-90 | 100-10 |
15 | Stop |
(5)实验过程
(a)0.04%TFA/H2O制备:量取400μLTFA于1LH2O中,混匀;
(b)样品储备液:称取待测样品约3mg,用DMSO配制成10mmol/L的储备液;
(c)取样品储备液50μL至5mL量瓶,加SGF定容,混匀。取溶液400μL,平行4份,在1000rpm,37℃下振摇;
(d)每两份分别于0和4小时取样加乙腈400μL,混匀,液相进样,计算溶液中主峰面积4小时相对于0小时变化情况%,每个时间点,取两份均值报告。
本发明化合物测试结果如下表所示。
表4化合物模拟胃液4小时稳定性
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与对比化合物相比,本发明化合物具有更好的模拟胃液稳定性,更适合于口服药物的开发以及口服吸收。
显然,上述实施例仅仅是为清楚地说明所作的举例,而并非对实施方式的限定。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (18)
1.一种式(I)所示化合物或其药学上可接受的盐、立体异构体、互变异构体、前体药物、无定形物、同位素体、多晶型物或者溶剂合物:
其中,R1选自苯基或者吡啶基,其中苯基或者吡啶基任选地被1、2或3个卤素取代;
R2选自H、直链或支链的C1-C4的烷基、C1-C4的烷氧基或C3-C6的环烷基;
环A选自含有1、2或3个环杂原子的5-10元的杂环基,所述环杂原子选自N、P、O或者S;
R4选自杂环与杂环形成的稠合基,形成稠合基的杂环选自含有1、2或3个杂原子的5-10元的杂环基,所述杂原子选自N、P、O或者S;稠合基未被取代或被一个或多个选自如下的取代基取代:任选被取代的烷基、任选被取代的环烷基、任选被取代的甲酰基、任选被取代的磺酰基,或者任选被取代的含1、2或3个杂原子的杂环;其中杂原子选自N、P、O或者S;
R3选自氢、卤素、直链或支链的C1-C4的烷基、C1-C4的烷氧基、C3-C6的环烷基;m选自0、1或2。
2.根据权利要求1所述的化合物,其特征在于,环A选自含1、2或3个氮原子作为环杂原子的5-6元杂环基,优选地,环A选自吡啶、哒嗪、吡嗪、嘧啶、哌啶或者哌嗪,更优选地,环A选自吡啶、哒嗪或者吡嗪。
3.根据权利要求1所述的化合物,其特征在于,R3选自氢、甲基或者甲氧基。
4.根据权利要求1所述的化合物,其特征在于,m为0或者1,优选为0。
5.根据权利要求1所述的化合物,其特征在于,R4具有式(II)或(III)所示的结构:
环B、环C或环D独立地选自含有1、2或3个杂原子的5-10元的杂环基,所述杂原子选自N、P、O或者S;
R5、R6或者R7独立地选自氧代、任选被取代的烷基、任选被取代的环烷基、任选被取代的甲酰基、任选被取代的磺酰基,或者任选被取代的含1、2或3个杂原子的杂环;其中杂原子选自N、O、S;优选地,R5、R6或者R7独立地选自氧代、C1-C6烷基、C3-C8环烷基、甲酰基、磺酰基或者含1、2或3个杂原子的C3-C8的杂环,其中杂原子选自N、O、S;其中,烷基、环烷基、甲酰基、磺酰基、杂环未取代或者被1、2或3个选自卤素或C1-C3烷基所取代;
n、j或者q独立地选自0、1或2。
6.根据权利要求5所述的化合物,其特征在于,环B选自5至7元杂环,其含有1、2或3个氮原子作为组成环的杂原子;优选地,环B选自三唑、吡唑、咪唑、6元环内酰胺或者二氮杂环戊烷,所述6元环内酰胺含有2个氮原子作为组成环的杂原子,更优选地,环B选自 或者/>
7.根据权利要求5所述的化合物,其特征在于,环C选自5元至7元的杂环,其含有1-2个独立地选自氮原子、氧原子或者硫原子作为组成环的杂原子;优选地,环C选自如下1)-2)中任一项所述的杂环;
1),吡咯、咪唑、三唑或者6元环内酰胺,所述6元环内酰胺含有2个氮原子作为组成环的杂原子;
2),5元至7元的杂环烷烃或者杂环烯烃,所述杂环烷烃或杂环烯烃含有1-2个独立地选自氮原子、氧原子或者硫原子作为组成环的杂原子;
更优选地,环C选自 或者/>
8.根据权利要求5所述的化合物,其特征在于,环D选自5元至7元的杂环,其含有1-2个独立地选自氮原子、氧原子或者硫原子作为组成环的杂原子;优选地,环D选自含有1个氮原子和1个氧原子的5-7元桥环或者含有1个氮原子的5-6元的桥环;更优选地,环D选自或者/>
9.根据权利要求5或7所述的化合物,其特征在在于,R7选自C1-C6烷基、C3-C8环烷基、C1-C3烷基取代的甲酰基、C1-C3烷基取代的磺酰基、C3-C6的含1个O原子或者1个S原子的杂环基;其中,所述烷基、环烷基或者杂环基未被取代或者被1、2或3个卤素所取代;优选地,R7选自甲基、乙基、-CF3、-COCH3、或者/>
10.根据权利要求1-9中任一所述的化合物,其特征在于,当R4具有式(II)的结构时,n为0或1;当R4具有式(III)的结构时,n为0或1,且q为0。
11.根据权利要求1-10中任一所述的化合物,其特征在于,R1选自1、2或3个卤素取代的苯基。
12.根据权利要求1-11中任一所述的化合物,其特征在于,R2选自H、直链或支链C1-C4烷基。
13.根据权利要求1-10中任一所述的化合物,其特征在于,R1为R2选自甲基。
14.根据权利要求1所述的化合物,其特征在于,所述化合物具有如下(VI)、(V)、(IV)或者(IIV)所示的结构:
所述R3如权利要求1或3所定义,R4如权利要求1、5、6、7、8、9或中任一项所定义。
15.如权利要求1所述的化合物,其特征在于,所述化合物选自以下化合物中的任意一种:
16.一种药物组合物,其包含如权利要求1-15中任一项所述的化合物或其立体异构体、互变异构体、前体药物、药学上可接受的盐、无定形物、同位素体、多晶型物或溶剂合物中的至少一种,以及药学上可接受的载体和/或辅助剂。
17.如权利要求1-15中任一项所述的化合物或其立体异构体、互变异构体、前体药物、药学上可接受的盐、无定形物、同位素体、多晶型物、溶剂合物,或权利要求16所述的药物组合物在制备治疗或预防与α5-GABAA受体有关的疾病的药物中的用途。
18.如权利要求1-15中任一项所述的化合物或其立体异构体、互变异构体、前体药物、药学上可接受的盐、无定形物、同位素体、多晶型物、溶剂合物,或权利要求16所述的药物组合物在制备治疗或预防下列疾病的药物中的用途:抑郁症、疼痛、阿尔茨海默症、多发梗塞性痴呆、脑卒中、焦虑症、泛化焦虑症、恐慌症、广场恐怖症、创伤后精神紧张性障碍、月经前期焦虑障碍、纤维肌痛、注意力不集中症、强迫观念和行为综合征、社交焦虑症、孤独症、自闭症、精神分裂症、肥胖、神经性食欲过盛或缺乏、图雷特综合症、血管舒缩性潮红、性功能障碍、边界人格障碍、慢性疲劳综合症、雷诺综合征、帕金森氏症、癫痫或者头部损伤后的情绪障碍。
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PCT/CN2023/083976 WO2023185704A1 (zh) | 2022-03-28 | 2023-03-27 | 异噁唑-杂环类衍生物、药物组合物和用途 |
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AU2008333326B2 (en) * | 2007-12-04 | 2013-05-30 | F. Hoffmann-La Roche Ag | Isoxazolo-pyridine derivatives |
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JP5301556B2 (ja) * | 2007-12-04 | 2013-09-25 | エフ.ホフマン−ラ ロシュ アーゲー | イソオキサゾロ−ピラジン誘導体 |
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