CN102311396B - 一种吡嗪类衍生物和其制备方法及在制药中的应用 - Google Patents
一种吡嗪类衍生物和其制备方法及在制药中的应用 Download PDFInfo
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- CN102311396B CN102311396B CN201010217332.7A CN201010217332A CN102311396B CN 102311396 B CN102311396 B CN 102311396B CN 201010217332 A CN201010217332 A CN 201010217332A CN 102311396 B CN102311396 B CN 102311396B
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- pyrazine
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- butyl
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Abstract
本发明涉及一种吡嗪类衍生物，具有如下通式I的结构：
Description
技术领域
本发明涉及一种吡嗪类化合物，其制备方法和在制备用于治疗和预防由于自由基过量产生和/或血栓形成引起的神经系统疾病，心、脑血管系统疾病以及退行性老化疾病，代谢系统疾病等的药物中的应用。
背景技术
氧对人类和动物的生命都非常重要，作为正常代谢的一部分，人体产生出多种活性氧簇自由基(ROS)，同时人体有多种使ROS失去活性的机制。在正常状态下，ROS的产生速率不会超过组织代谢它们的能力，但是在某些情况下，ROS会升高到超出这些保护机制的水平(例如由于辐射、环境因素、铁离子负荷过多等)，或者当这些机制出现错误时(例如遗传缺陷)，ROS将造成细胞和组织损坏，导致多种疾病甚至死亡。蛋白质、脂肪和DNA都是ROS进攻的底物，每天进入细胞的1012个氧分子中，有1/100会破坏蛋白质，1/200会破坏DNA，特别是当人体自然抵抗力低下的时候，这种对DNA、蛋白质和脂质的破坏使得ROS变得非常有害。
正常情况下，人类机体本身存在的抗自由基的防御系统能很好的对抗这些自由基对机体的伤害。但是病理条件下，有些损伤性自由基逃脱清除，这些逃逸的自由基及其产物直接作用于细胞DNA、蛋白质及脂质引起DNA损伤和细胞膜脂质过氧化，这种ROS产生的结果，专业术语称为氧化应激，氧化应激可以影响正常的基因表达、细胞分化以及造成细胞死亡。现在氧化应激被认为是很多疾病的起因。
大脑动脉粥样硬化和血栓栓子的形成可以诱发脑中风，在发达国家，脑血管疾病已经成为继心脏病和肿瘤后的第三大死因，65岁老年人中有5％受到脑中风的困扰。在美国，每年有超过50万人饱受中风的折磨，70-85％的脑中风属于缺血性脑中风，其死亡率为15-33％。现有的治疗急性缺血性脑中风的方法包括细胞保护和溶栓，细胞保护力图保护在缺血再灌注期间的细胞死亡，溶栓主要是在疾病初期应用溶栓药保持血管畅通。尽管人们做了大量的努力，脑中风仍然是医学界最具破坏性的疾病之一，现有的脑中风治疗效果不理想的其中一个原因是还没有一个药物同时具有确切的溶栓和细胞保护作用。
帕金森氏病(PD)是一种临床表现为静止性震颤、肌强直、运动减少和姿势步态异常的疾病。目前已知本病的主要病变是黑质-纹状体变性，导致多巴胺的生成减少，引起上述临床表现。但是引起黑质变性的原因至今尚未清楚。目前多数研究认为氧化应急在帕金森氏病的发病过程中起重要作用。
研究发现有许多化学物质都具有清除自由基的能力。其中硝酮类化合物是具有强的抗氧化活性和体内生物活性的一类化合物。硝酮类化合物可以与自由基反应生成的最终产物包括羟胺衍生物、醛类、胺类及氮氧自由基化合物。
苯基叔丁基硝酮(PBN)可以与自由基反应生成氮氧自由基：氮氧自由基可以直接与自由基反应从而去除自由基，也可以氧化还原性金属从而抑制Fenton反应和金属催化的Haber-Weiss反应。给加速衰老的小鼠每天腹腔注射PBN，其寿命延长33％(Edamatsu et al.，Biochem.Biophys.Res.Commun.211：847，1995)。当24月大的大鼠每天腹腔注射32mg/kg PBN，连续给药9.5月，大鼠大脑中两个负责认知功能的重要区域(大脑皮层及苍白球)的脂质过氧化反应被减少，同时老年大鼠的认知能力被提高。更重要的是，实验进行32个月以后，11只注射PBN的大鼠中有7只仍然活着(Sack et al.，Neurosci.Lett.205：181，1996)。遗憾的是PBN至今仍然未能开发成一个药物，还只是作为科研工具。
川芎嗪(TMP)是从中药川芎当中提取的活性成分，川芎嗪具有清除自由基和抗凝溶栓的作用。其注射液临床上已经用来治疗心脑血管疾病。但是，川芎嗪的抗氧化作用微弱，生物利用度低，临床上需要多次给药才能达到有效浓度。
目前脑中风的治疗还没有特效药，已经上市的为数不多的药物都因为疗效不佳或毒副作用大而很难满足要求。治疗缺血性脑中风的药物必须具有两方面的功能：溶栓或/和保护神经细胞。
发明内容
本发明的目的在于提供一种吡嗪衍生物及其药学上可接受的盐，该类化合物具有较强的清除自由基能力和抗凝溶栓能力，具有很强的神经保护能力。
本发明的目的还在于提供所述吡嗪衍生物的制备方法。
本发明的目的还在于提供所述吡嗪衍生物及其药用组合物在治疗疾病和制备相应药物中的应用。
在一方面，本发明所提供的吡嗪衍生物具有下面的结构(通式I)或者为其药学上可接受的盐：
其中，R1和R2各自独立的为氢、羟基或选自下列取代或未取代的基团：氨基，羧基，烷基，烷氧基，芳基，芳杂基，酯类，胺类，氨基甲酸酯和硝酮基团；
R3和R4各自独立的为氢、羟基或选自下列取代或未取代的基团：氨基，羧基，烷基，烷氧基，芳基，芳杂基，酯类，胺类，氨基甲酸酯和硝酮基团，或者R3和R4与其所连接的碳一起形成取代或未取代的稠合的环；
R1，R2，R3和R4不能同时为氢，且不能同时为甲基；
当R1，R2，R3和R4仅其中之一为硝酮基团时，该硝酮基团不能为叔丁硝酮基团。
根据本发明的一些实施方式，通式I所述的化合物可通过其中R1和/或R4的取代形成具有二聚体或多聚体结构的吡嗪类衍生物。
另外，本发明所提供的吡嗪衍生物及其药学上可接受的盐能够形成一种药用组合物，包括有效治疗剂量的吡嗪类衍生物作为药用活性成分，以及药学上可接受的载体和赋形剂。
在另一方面，本发明所提供的制备所述吡嗪类衍生物的方法，包括例如将吡嗪类起始化合物通过活性二氧化硒氧化成醛，所述醛再与相应的羟胺回流而生成由硝酮基团单取代或多取代的吡嗪类衍生物。相应的制备方法还包括将吡嗪类起始化合物与NBS反应经溴代后与活性化合物反应生成吡嗪类组合物。
在又一方面，本发明所提供的吡嗪衍生物能用于治疗或预防由于ROS过量产生或血栓形成所导致的疾病并能用于制备用于治疗或预防相应疾病的药物。
本发明与现有技术相比，具有如下优点：本发明提供了一种全新结构的物质，同时具有双重作用机理(溶栓或/和细胞保护)，可以通过血脑屏障而且安全有效的化合物。这些化合物是值得开发的治疗和预防由于自由基过量产生和/或血栓形成引起的神经系统疾病，感染性疾病，代谢系统疾病，心、脑血管系统疾病以及退行性老化疾病等的新药。
附图说明
图1描述根据本发明的一种具体实施方式的化合物TN-2的合成方法。
图2描述根据本发明的另一具体实施方式的化合物TN-2的合成方法。
图3显示化合物TN-2对叔丁基过氧化氢(t-BHP)诱导的PC12细胞有明显的保护作用。
图4显示化合物TN-2对MCAo引起的脑缺血大鼠的保护作用。
图5显示化合物TN-2对MPP+诱导的多巴胺神经元损伤的保护作用。
具体实施方式
定义
以下阐明本文所用到的各种术语的含义以及范围。
本文所用的术语“烷基”是指未被取代的或被取代的直链、支链或环形的多至15个碳原子的烷基碳链。直链烷基包括如甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基和正辛基。支链烷基包括如异丙基、仲丁基、异丁基、叔丁基、新戊基。环状烷基(“环烷基”)包括如环丙基、环丁基、环戊基和环己基。烷基可被一个或多个取代基取代。上述取代基的非限定性例子包括NH2、NO2、N(CH3)2、ONO2、F、C1、Br、I、OH、OCH3、CO2H、CO2CH3、CN、芳基和杂芳基。术语“烷基”也指未取代或取代的直链、支链或环状的含有多至15个碳原子的在链上含有至少一个杂原子(例如氮、氧或硫)的烷基。上述直链烷基包括，例如，CH2CH2OCH3、CH2CH2N(CH3)2和CH2CH2SCH3。支链基团包括，例如，CH2CH(OCH3)CH3、CH2CH(N(CH3)2)CH3和CH2CH(OCH3)CH3。上述环状基团包括，例如六员环CH(CH2CH2)2O、CH(CH2CH2)2NCH3和CH(CH2CH2)2S及相应的五员环等。上述烷基可被一个或多个取代基取代。上述取代基的非限定性例子包括NH2、NO2、N(CH3)2、ONO2、F、Cl、Br、I、OH、OCH3、CO2H、CO2CH3、CN、芳基和杂芳基。
本文所用的术语“芳基”是指未被取代的或取代的芳香化合物、碳环基团和杂芳基。芳基或者是单环或者是多环稠合化合物。例如，苯基是单环芳基。萘基是具有多环稠合的芳基的例子。芳基可以被一个或多个取代基取代，取代基的非限制性的例子包括NH2、NO2、N(CH3)2、ONO2、F、Cl、Br、I、OH、OCH3、CO2H、CO2CH3、CN、芳基和杂芳基。
杂芳基涉及到取代的或非取代的单环或多环的基团，环内至少包括一个杂原子，譬如氮、氧以及硫。举例来说，典型的杂环基团包括一个或多个氮原子譬如四唑基、吡咯基、吡啶基(如4-吡啶基，3-吡啶基，2-吡啶基等)、哒嗪基、吲哚基、喹啉基(如2-喹啉基，3-喹啉基等)、咪唑基、异喹啉基，吡唑基、吡嗪基、嘧啶基、吡啶酮基或哒嗪基；典型的含一个氧原子的杂环基团包括2-呋喃基，3-呋喃基或苯并呋喃基；典型的硫杂原子基团包括噻吩基、苯并噻吩基；典型的混合杂原子基团包括呋吖基、噁唑基、异噁唑基、噻唑基和吩噻噁基。杂环基团能被一个或多个取代基取代。这些取代基包括NH2、NO2、O-烷基、NH-烷基、N(烷基)2、NHC(O)-烷基、ONO2、F、Cl、Br、I、OH、OCF3、OSO2CH3、CO2H、CO2-烷基、CN以及芳基和多芳基。这些情况同时包括环内杂原子被氧化，譬如形成N-氧化物、酮或砜。
本文使用的术语“药学上可接受的”指的是在化合物如盐或赋形剂中不具有不能接受的毒性。药学上可接受的盐包括无机阴离子，例如氯离子、溴离子、碘离子、硫酸根、亚硫酸根、硝酸根、亚硝酸根、磷酸根、磷酸氢根等。有机阴离子包括乙酸根、丙酸根、肉桂酸根、苯甲磺酸根、柠檬酸根、乳酸根、葡萄糖酸根等。药学上可接受的赋形剂在后文有描述，参见E.W.Martin，in Remington’s Pharmaceutical Sciences Mack PublishingCompany(1995)，Philadelphia，PA，19th ed。
化合物、制备、用途及剂量
在一方面，本发明所提供的吡嗪衍生物及其药学上可接受的盐，其中吡嗪衍生物具有通式I的结构：
其中，R1和R2各自独立的为氢、羟基或选自下列取代或未取代的基团：氨基，羧基，烷基，烷氧基，芳基，芳杂基，酯类，胺类，氨基甲酸酯和硝酮基团；
R3和R4各自独立的为氢、羟基或选自下列取代或未取代的基团：氨基，羧基，烷基，烷氧基，芳基，芳杂基，酯类，胺类，氨基甲酸酯和硝酮基团，或者R3和R4与其所连接的碳一起形成取代或未取代的稠合的环；
R1，R2，R3和R4不能同时为氢，且不能同时为甲基；
当R1，R2，R3和R4仅其中之一为硝酮基团时，该硝酮基团不能为叔丁硝酮基团。
根据一些具体实施方式，通式I中的R1和R3各自独立的为取代或未取代的硝酮基团，所述R2和R4为烷基，其具有如下通式II的结构：
其中，R5和R6各自独立的为取代或未取代的直链烷基、支链烷基或环烷基。
优选地，通式II中的R2和R4为甲基，R5和R6为叔丁基，从而其具有如下式TN-2的结构：
优选地，通式II中的R2和R4为甲基，所述R5和R6为环己基，其具有如下式TN-3的结构：
另外，根据不同的实施方式，通式I所示的化合物中，R3和R4与其所连接的碳一起形成取代的稠合的环，所述环上的取代可以为烷基、一个或多个硝酮基团。在具体的实施方式中，本发明的吡嗪类衍生物具有如下式TN-4或式TN-5的结构：
还有，根据不同的实施方式，通式I所示的化合物中，通过所述R4的取代形成具有二聚体结构的吡嗪类衍生物，其具有如下通式III的结构：
其中：R7、R8和R9各自独立的为氢或取代或未取代的羟基、烷基或硝酮基团；X为C、O、N或S，并与其相邻的碳形成烃链、醚、氨或巯基连接，或与其相邻的碳(可氧化成羰基)形成酮、酰氧基、酰胺基等连接。
根据一些具体的实施方式，上述具有二聚体结构的吡嗪类衍生物包括例如其中X为N-tBu，从而具有以下通式IV：
并选自下列TN-6至TN-14化合物之一的结构：
TN-6：R1，R2，R3，R7，R8，R9＝CH3；
TN-7：R1＝HC＝N+(O-)tBu，R2，R3，R7，R8，R9＝CH3；
TN-8：R1，R9＝HC＝N+(O-)tBu，R2，R3，R7，R8＝CH3；
TN-9：R1，R8＝HC＝N+(O-)tBu，R2，R3，R7，R9＝CH3；
TN-10：R1，R3，R8＝HC＝N+(O-)tBu，R2，R7，R9＝CH3；
TN-11：R1，R7，R8＝HC＝N+(O-)tBu，R2，R3，R9＝CH3；
TN-12：：R1，R2，R7，R8＝HC＝N+(O-)tBu，R3，R9＝CH3；
TN-13：R1，R2，R7，R8＝HC＝N+(O-)tBu，R3，R9＝CH3；
TN-14：R1，R2，R3，R7，R8，R9＝HC＝N+(O-)tBu。
根据另外的具体的实施方式，上述具有二聚体结构的吡嗪类衍生物具有如下式TN-15或TN-16的结构：
再有，根据不同的实施方案，通式I所述的吡嗪类衍生物具有如下通式V的结构：
其中，R10为取代或未取代的直链烷基、支链烷基或环烷基，也可以是具有生物活性的小分子化合物如硫辛酸或半胱氨酸等基团。
进一步，本发明所提供的吡嗪衍生物及其药学上可接受的盐能够形成一种药用组合物，包括有效治疗剂量的吡嗪类衍生物作为药用活性成分，以及药学上可接受的载体和赋形剂。
在另一方面，制备所述吡嗪类衍生物的方法，根据不同的实施方式例如包括将吡嗪类起始化合物通过活性二氧化硒氧化成醛，所述醛再与相应的羟胺回流3小时，而生成由硝酮基团单取代或多取代的吡嗪类衍生物。
根据其它的实施方式，制备所述吡嗪类衍生物的方法，还包括将吡嗪类起始化合物与NBS反应经溴代后与活性化合物反应生成吡嗪类组合物，其中所述活性化合物包括：
根据另外的实施方式，制备所述吡嗪类衍生物的方法，还包括所述吡嗪类衍生物由3，6-二甲基-2，5-吡嗪二甲醛与叔丁基羟胺反应得到，或者由3，6-二甲基-2，5-二溴甲基吡嗪与叔丁基羟胺反应后，经钨酸钠和过氧化氢氧化得到。
本发明中涉及的新化合物包括吡嗪的硝酮衍生物和吡嗪衍生物与生物活性化合物的组合物，它们都是具有抗血栓活性的抗氧化剂，一方面它们可以清除人血液和组织中的自由基包括超氧阴离子(O2 ·-)、过氧硝酸根(ONOO-)和羟自由基(·OH)，另一方面能够溶解血管中的血栓，因此，它们可用于预防和治疗自由基过量和或血栓形成引起的疾病，这些疾病包括但不限于神经系统疾病如缺血缺氧性脑损伤、中风、脑外伤、老年痴呆症、癫痫、帕金森氏病、亨廷顿氏病、肌萎缩侧索硬化症，艾滋病痴呆症、多发性硬化症、慢性疼痛、阴茎异常勃起、囊性纤维化、精神分裂症、抑郁症、经前期综合征、焦虑、成瘾和偏头痛等；还包括心血管疾病如心脏侧流、缺血-再灌注损伤、缺血-再灌注、中毒性休克症候群、成人呼吸窘迫症候群、恶病质、心肌炎、动脉粥样硬化、冠心病心脏疾病和心脏病发作等；还包括炎症感染性疾病如发炎性肠道疾病、糖尿病、类风湿关节炎、哮喘、肝硬化、异体排斥反应、脑脊髓炎、脑膜炎、胰腺炎、腹膜炎、血管炎、淋巴细胞性脉络丛脑膜炎、肾小球肾炎、系统性红斑狼疮、胃肠运动功能紊乱、肥胖、饮食过量、肝炎和肾功能衰竭；还包括眼科疾病，如糖尿病视网膜病变、葡萄膜炎、青光眼、眼睑炎、霰粒肿、过敏性眼病、角膜溃疡、角膜炎、白内障、老年黄斑变性和视神经炎；这些新的化合物也可用于预防、治疗癌症，如成神经细胞瘤。
本发明涉及吡嗪衍生物的硝酮衍生物和其与具有生物活性化合物的组合物，可以一种药学可接受的盐或药物复合物的形式对病人给药。某个复合物需与适当载体或赋形剂混合形成药物组合物从而保证达到有效治疗剂量。“有效治疗剂量”是指硝酮衍生物和耦合物达到治疗效果(抑制自由基过量，降低因为中风、心脏病突发或感染性疾病造成的细胞损伤等)所必须的剂量。
本发明涉及的化合物可以制成多种剂型，包括固体剂型，半固体剂型，液体制剂和气雾剂(Remington’s Pharmaceutical Sciences，Mack PublishingCompany(1995)，Philadelphia，PA，19th ed)。这几类剂型中的具体剂型包括片剂、丸剂、糖锭剂、颗粒剂、凝胶剂、膏剂、溶液剂、栓剂、注射剂、吸入剂以及喷雾剂。这些剂型既能用于局部或全身给药又能用于速释或缓续给药，此类药物的给药方式有很多种，除了上述方式，还有口腔给药、面颊给药、直肠给药、腹膜给药、腹膜内给药、皮表给药、皮下给药和气管内给药等。
当吡嗪衍生物的硝酮衍生物和其与具有生物活性化合物的组合物注射给药时，可以用水溶性或脂溶性的溶剂将此类化合物配制成溶液剂，悬浊剂和乳剂。脂溶性溶剂具体包括植物油及类似油类，合成脂肪酸甘油酯，高级脂肪酸酯以及乙二醇酯(proylene glycol)。这类化合物更易溶于Hank’s溶液，Ringer’s溶液或者生理盐水。
当吡嗪衍生物的硝酮衍生物和其与具有生物活性化合物的组合物口服给药时，可以采用常用技术将其与药学可接受的赋形剂制成复合物。这些赋形剂可以将这些化合物制成多种可以被病人剂型，如片剂、丸剂、混悬剂、凝胶剂等。口服制剂的配制有多种方法，如先把化合物和固体赋形剂混匀，充分研磨混合物，添加适当的辅料，加工处理成颗粒。可以用于制成口服剂型的辅料包括：糖类如乳糖、蔗糖、甘露醇或山梨醇；纤维素类如玉米淀粉、小麦淀粉、马铃薯淀粉、明胶、西黄薯胶、甲基纤维素、羟甲基纤维素(hydroxyproylmethyl-cellulose)、羧甲基纤维素纳、聚乙烯吡咯酮等。
本发明涉及的化合物也可以制成喷雾剂，此种剂型是通过一个加压器和一个喷雾器或者一个干粉吸入装置而实现的。可以用作喷射器里合适的喷射剂如二氯二氟甲烷、氟三氯甲烷、二氯四氟乙烷、二氧化碳和二甲醚等。气雾剂给药的剂量可以通过喷射器的阀门来调节。
本发明涉及的各种剂型都关系到所涉及化合物的有效治疗剂量。该类化合物的有效治疗剂量取决于接受治疗的病人。在决定适宜的剂量时，病人的体重、病情、服药方式以及处方医师的主观判断因素都要纳入考虑。治疗有效量应该由有能力和丰富经验的处方医师决定。
实施例
实施例1、TN-2的合成(图1)
向500mL三颈瓶中加入200mL甲醇，加入3，6-二甲基-2，5-吡嗪二甲醛2.0g(0.012mol)，然后加入4.3g(0.048mol)的叔丁基羟胺，加热回流3h。柱层析分离(乙酸乙酯100％)，得到淡黄色的固体化合物TN-21.0g。产率26.8％，mp：198-201℃.1H NMR(CDCl3)：1.61(s，18H)，2.48(s，3H)，2.50(s，3H)，7.83(s，2H)；ESI-MS：307[M+H]+，329[M+Na]+；Anal.(C12H19N3O)C.H.N；found C 62.52％，H 8.73％，N 18.19％；requires：C，65.13；H，8.65；N，18.99。
实施例2、TN-2的合成(图2)
将2，5-二叔丁胺甲基-3，6-二甲基吡嗪5.6g(0.02mol)加入到250mL圆底烧瓶中，加入适量的甲醇，加入1.64g(0.005mol)Na2WO4 ·2H2O，30％H2O2 10mL，室温搅拌2h。过滤，蒸除甲醇，加入饱和的Na2S2O3，乙酸乙酯萃取，蒸除大部分乙酸乙酯。经柱层析分离(乙酸乙酯100％)，得到白色的固体TN-21.97g，产率32％，检测数据同上。
实施例3、TN-4的合成
250mL的三颈瓶中加入2-甲基喹喔啉2.88g(0.02mol)，20mg过氧化苯甲酰，加入80mL CCl4，70℃回流10h。冷却过滤，得到2-溴甲基喹喔啉的粗品，化合物不经分离，加入过量的叔丁基胺，室温搅拌3h。得到5-叔丁胺甲基喹喔啉1.25mg，产率29.1％。
向上述得到的670mg(0.006mol)化合物中加入60mL甲醇，Na2WO4 ·2H2O 0.18g，30％H2O21.75mL，室温反应2.5h。柱层析分离(乙酸乙酯∶石油醚＝4∶1)得到淡黄色化合物TN-3，460mg，产率35.9％。1HNMR(CDCl3)：1.70(s，9H)，7.77(m，2H)，8.03(m，2H)，8.14(s，1H)，10.49(s，1H)；ESI-MS：230[M+H]+；Anal.(C13H15N3O)C.H.N；found C 67.80％，H 6.90％，N 17.86％；requires：C，68.10；H，6.59；N，18.33。
实施例4、TN-5的合成
在250mL的三颈瓶中加入5-甲基喹喔啉2.88g(0.02mol)，20mg过氧化苯甲酰，加入80mL CCl4，70℃回流10h。冷却过滤，得到5-溴甲基喹喔啉的粗品，化合物不经分离，加入过量的叔丁基胺，室温搅拌3h。得到5-叔丁胺甲基喹喔啉670mg，产率15.6％。
向上述得到的670mg(0.003mol)化合物中加入60mL甲醇，Na2WO4 ·2H2O 0.1g，30％H2O2 3.5mL，室温反应2.5h。柱层析分离(乙酸乙酯∶石油醚＝2∶1)得到淡黄色化合物TN-4，154mg，产率21.5％。1HNMR(CDCl3)：1.69(s，9H)，7.83(dd，1H)，8.10(dd，1H)，8.80(d，1H)，8.87(d，1H)，9.19(s，1H)，9.96(dd，1H)；ESI-MS：230[M+H]+；Anal.(C13H15N3O)C.H.N；found C 68.04％，H 6.95％，N 18.0％；requires：C，68.10；H，6.59；N，18.33。
实施例5、TN-6的合成
在250mL的圆底烧瓶中加入4.28g(0.02mol)的3，5，6-三甲基-2-溴甲基吡嗪，逐滴加入适量的叔丁基胺，室温搅拌12h，过滤，滤液蒸干，粗品经柱层析分离(石油醚∶乙酸乙酯＝5∶1)得白色的粉末固体1.57g，产率25％。1HNMR(CDCl3)：1.25(s，9H)，2.30(s，6H)，2.35(s，6H)，2.39(s，6H)，3.86(s，4H)；ESI-MS：342[M+H]+，364[M+Na]+；Anal.(C12H19N3O)C.H.N；found C62.52％，H 8.73％，N 18.19％；requires：C，65.13；H，8.65；N，18.99。
实施例6、TN-7的合成
向实施例5中的得到的化合物TN-6 0.682g(0.002mol)中加入100mL1，4-二氧六环，加入活性二氧化硒330mg(0.003mol)，加热107℃回流3h，用2，4-二硝基苯肼显色为淡黄色。冷却到室温，蒸除1，4-二氧六环，柱层析分离(石油醚∶乙酸乙酯＝2∶1)。得到固体237.8mg。产率33.5％。
向100mL乙醇中加入上述得到的237.8mg固体，叔丁基羟胺0.12g，84℃回流3h，冷却至室温。蒸除乙醇，逐层析分离(石油醚∶乙酸乙酯＝5∶1)，得到淡黄色固体183.5mg，产率64.3％。ESI-MS：427[M+H]+，449[M+Na]+。
实施例7、TN-15的合成
将3.04g(0.02mol)的2-羟甲基-3，5，6-三甲基吡嗪溶于适量的THF中，加入2g NaOH(0.05mol)，室温搅拌下加入3，5，6-三甲基-2-溴甲基吡嗪5.35g(0.025mol)。过滤，滤液蒸干，粗品经柱层析分离(石油醚∶乙酸乙酯＝3∶1)得白色的粉末固体4.8g，产率84％。ESI-MS：287[M+H]+，309[M+Na]+。
实施例8、TN-16的合成
将3.32g(0.02mol)的3，5，6-三甲基吡嗪-2-甲酸溶于适量的THF中，加入6.90g K2CO3(0.05mol)，室温搅拌下加入3，5，6-三甲基-2-溴甲基吡嗪5.35g(0.025mol)。过滤，滤液蒸干，粗品经柱层析分离(石油醚∶乙酸乙酯＝3∶1)得白色的粉末固体4.5g，产率75％。ESI-MS：301[M+H]+，323[M+Na]+。
实施例9、TN-17的合成
将4.88g(0.02mol)生物素溶解于100ml DMF中。搅拌下滴加2.9ml(0.02mol)三乙胺和3，5，6-三甲基-2-溴甲基吡嗪5.35g(0.025mol)。室温搅拌5h。TLC检测反应结束。加入80ml水稀释溶液，用(100ml×2)三氯甲烷萃取，合并有机相，用(100ml×2)水洗，无水Na2SO4干燥。经柱层析分离。得白色的粉末固体5.2g，产率68.8％。ESI-MS：379[M+H]+，401[M+Na]+。
实施例10、TBN对大鼠脑细胞保护作用实验(图3)
将PC12细胞接种于强吸附的96孔板上，每孔90μL，置37℃，5％CO2培养箱中培养36h。36h后加入四个浓度梯度的各药物。置37℃，5％CO2培养箱中孵育半个小时后，换为无血清培养基，在除去对照组(Control)的各孔中加入10μL的t-BHP(t-BHP终浓度是200μM)。然后放于培养箱中培养24小时。细胞培养24小时后，每孔中加入15μL MTT(5mg/mL)，放于培养箱中培养4h，然后每孔加入150μL的DMSO，继续孵育至少半小时以确保晶体完全溶解。酶标仪570nm测吸光度A值。结果表明TN-2对t-BHP诱导的细胞损伤有显著的保护作用，其作用强度显著高于TMP，(图3)。图3说明，与t-BHP组相比*P＜0.05，有显著性差异。
实施例11、TN-2对MCAO引起的脑缺血大鼠的保护作用实验(图4)
将体重为260-300g的大鼠(SD雌性大鼠)用10％的水合氯醛按400mg/kg的剂量腹腔注射麻醉抑或用3.5％氟烷吸入麻醉。在MCAO(大脑中动脉阻塞缺血模型)入口用尼龙线阻塞而致脑缺血。缺血1h后，分别静脉注射给予EDA(63mg/kg)，TBN(80mg/kg)，TN-2(65mg/kg)和生理盐水(对照组)。每组大鼠6只。缺血2h后，去除尼龙线阻塞，再灌注24h。取出脑组织，离去小脑。PBS溶液中冲洗干净，放入-20℃冰箱中冷冻片刻，将脑组织均匀的切成厚约2mm的薄片，立刻置于0.5％的红四氮唑染料(TTC)溶液中。37℃孵育30min。评价脑梗死的程度。结果表明TN-2对大鼠脑中风有显著的治疗作用(图4)。图中，数据经单尾t检验。*表示与对照相比。药物剂量：TBN(80mg/kg)；依达拉奉(Edaravone)(63mg/kg)。各药物为等摩尔浓度。
实施例12、TN-2对MPP+诱导的多巴胺神经元损伤的保护作用实验(图6)
多巴胺神经元培养5d后，加入L-Deprenyl，TMP，TN-2，浓度梯度为500μM，50μM，5μM。2小时后在除去对照组(Control)的各孔中加入MPP+(MPP+终浓度是10μM)。图5结果表明TN-2对MPP+诱导的细胞损伤有显著的保护作用。
等效性说明
上述对本发明的具体描述清晰说明了此新化合物对过量自由基引发的疾病如神经系统疾病，心血管疾病，炎症和癌症的治疗或预防提供了独特的方法。尽管具体的实施例已经在这里详细说明，这仅作为本发明目的实例说明，而不限制下述权利要求书对本发明权利要求的范围。特别指出，发明者经过审慎考虑，本发明不同的取代、改变和修饰都不偏离本发明权利要求所定义的内涵和外延。
Claims (10)
1.一种吡嗪类衍生物及其药学上可接受的盐，所述吡嗪类衍生物具有如下通式I的结构：
其中：R1和R3各自独立的为取代或未取代的硝酮基团，从而所述吡嗪类衍生物具有如下通式II的结构：
其中：R5和R6各自独立的为仲丁基、异丁基、叔丁基、环戊基或环己基；
R2和R4各自独立的为氢、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基或新戊基。
2.根据权利要求1所述的吡嗪类衍生物及其药学上可接受的盐，其中所述R2和R4为甲基，所述R5和R6为叔丁基，其具有如下式TN-2的结构：
3.根据权利要求1所述的吡嗪类衍生物及其药学上可接受的盐，其中所述R2和R4为甲基，所述R5和R6为环己基，其具有如下式TN-3的结构：
4.一种药用组合物，其包括有效治疗剂量根据权利要求1-3之一所述的吡嗪类衍生物作为药用活性成分，以及药学上可接受的载体和赋形剂。
5.制备权利要求1所述吡嗪类衍生物的方法，其包括将吡嗪类起始化合物通过活性二氧化硒氧化成醛，所述醛再与相应的羟胺回流3小时，而生成由硝酮基团取代的吡嗪类衍生物。
6.权利要求1-3之一所述的吡嗪类衍生物或其组合物在制备治疗中风、脑创伤、癫痫、帕金森症、亨廷顿氏病、肌萎缩性脊髓侧索硬化、阿耳茨海默氏病、缺氧缺血脑损伤、艾滋病、痴呆、多发性硬化症或慢性痛类脑疾病药物中的应用。
7.权利要求1-3之一所述的吡嗪类衍生物或其组合物在制备治疗心肺侧流、呼吸窘迫综合征、心脏缺血或再灌注、中毒性休克综合征、成人呼吸窘迫综合征、恶病质、心肌炎、动脉粥样硬化、冠心病或突发性心脏病类心脏和血管性疾病药物中的应用。
8.权利要求1-3之一所述的吡嗪类衍生物或其组合物在制备治疗炎性肠病、糖尿病、类风湿性关节炎、哮喘、肝硬变、异体排斥、脑脊髓炎、脑膜炎、胰腺炎、腹膜炎、血管炎病、肾小球肾炎、全身性红斑狼疮、胃肠蠕动紊乱、肥胖症、饥饿症、肝炎或肾衰竭类疾病药物中的应用。
9.权利要求1-3之一所述的吡嗪类衍生物或其组合物在制备治疗糖尿病性视网膜病、眼色素层炎、青光眼、睑炎、睑板腺囊肿、过敏性眼病、角膜溃疡、角膜炎、白内障、老年性黄斑退行性改变或视神经炎类眼科疾病药物中的应用。
10.权利要求1-3之一所述的吡嗪类衍生物或其组合物在制备治疗癌症药物中的应用，其中所述癌症为神经细胞瘤。
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| US9334244B2 (en) | 2010-05-12 | 2016-05-10 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of ATR kinase |
| EP2569289A1 (en) | 2010-05-12 | 2013-03-20 | Vertex Pharmaceuticals Incorporated | Pyrazines useful as inhibitors of atr kinase |
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| EP2569286B1 (en) | 2010-05-12 | 2014-08-20 | Vertex Pharmaceuticals Inc. | Compounds useful as inhibitors of atr kinase |
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| CN117986237B (zh) * | 2022-11-01 | 2025-06-17 | 南京知和医药科技有限公司 | 川芎嗪衍生物及其制备方法与用途 |
| CN116850188A (zh) * | 2023-05-29 | 2023-10-10 | 广州喜鹊医药有限公司 | 川芎嗪硝酮衍生物在制备预防或治疗2型糖尿病药物中的应用 |
| CN119679796A (zh) * | 2023-09-22 | 2025-03-25 | 广州喜鹊医药有限公司 | 川芎嗪硝酮衍生物在制备预防或治疗神经损伤引起的肌肉力量下降或功能损失药物中的应用 |
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| US20120115874A1 (en) | 2012-05-10 |
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