CN102036664A - 选择性亚型α2肾上腺素能药物及其使用方法 - Google Patents
选择性亚型α2肾上腺素能药物及其使用方法 Download PDFInfo
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- CN102036664A CN102036664A CN2009801187258A CN200980118725A CN102036664A CN 102036664 A CN102036664 A CN 102036664A CN 2009801187258 A CN2009801187258 A CN 2009801187258A CN 200980118725 A CN200980118725 A CN 200980118725A CN 102036664 A CN102036664 A CN 102036664A
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Abstract
本发明提供了用于治疗哺乳动物疼痛的方法。具体地,本发明提供了明确定义的氨基咪唑啉、氨基噻唑啉、氨基噁唑啉及其药物组合物来治疗疼痛。
Description
相关专利申请
本申请要求享有2008年3月24日提交的序列号为61/038,928的美国临时申请和2009年3月23日提交的序列号为12/408,823的美国非临时申请的优先权,所述两项专利申请的全部公开内容在此通过引证的方式纳入本说明书。
技术领域
本发明总体上涉及用于治疗哺乳动物中各种类型疼痛的方法。本发明具体而言涉及使用某些氨基咪唑啉、氨基噻唑啉、氨基噁唑啉化合物及其药物组合物来治疗疼痛。
背景技术
人的肾上腺素能受体是分为两大类的膜内在蛋白,即α和β肾上腺素能受体。这两种受体与儿茶酚胺、去甲肾上腺素和肾上腺素结合后介导外周交感神经系统的作用。
去甲肾上腺素是由肾上腺素能神经末梢产生的,而肾上腺素是由肾上腺髓质产生的。肾上腺素能受体对这些化合物的结合亲和力形成一个分类基础:α受体对去甲肾上腺素的结合力最强,其次是肾上腺素,对于合成的化合物异丙肾上腺素的结合力最弱。而β受体对这些激素的优先结合亲和力则与之相反。在许多组织中,由α受体活化所诱导的功能性应答(如平滑肌收缩)与β受体结合所诱导的应答相反。
随后,通过对不同动物和组织来源的这些受体的药理学表征,α受体和β受体的功能性差异得到更进一步突出和完善。结果,α和β肾上腺素能受体进一步细分为α1、α2、β1和β2亚型。α1和α2受体的功能性差异已经得到认知,并且对这两种亚型表现出选择性结合的化合物已经得到开发。因此,在公开的国际专利申请WO 92/0073中,报道了特拉唑嗪(terazosin)的R(+)对映异构体选择性结合α1亚型肾上腺素能受体的选择能力。该化合物的α1/α2选择性的公开很有意义,因为据称对α2受体的激动刺激作用可以抑制肾上腺素和去甲肾上腺素的分泌,而据称对α2受体的拮抗作用可以增加这些激素的分泌。因此,据称非选择性α肾上腺素能阻滞剂(如酚苄明(phenoxybenzamine)和酚妥拉明(phentolamine))的使用因其α2肾上腺素能受体介导的如下作用而受到限制:诱导血浆儿茶酚胺浓度增加以及伴随的生理后遗症(心率的增加和平滑肌的收缩)。
如读者要更深一步的了解α肾上腺素能受体,则可参阅Robert R.Ruffolo,Jr.,alpha-Adrenoreceptors:Molecular Biology,Biochemistry and Pharmacology,(Progress in Basic and Clinical Pharmacology series,Karger,1991),其中研究了α1/α2亚型分类的原则、分子生物学、信号转导、激动剂的构效关系、受体功能和具有α肾上腺素受体亲合力的化合物的治疗应用。
通过对于来自动物组织的α受体亚型的克隆、测序和表达已经将α1肾上腺素受体进一步细分为α1A、α1B和α1D。类似地,α2肾上腺素受体已分为α2A、α2B和α2C受体。每一个α2受体亚型看来都具有自己的药理学和组织特异性。相对于α2受体泛激动剂(如药物可乐宁(clonidine))或泛拮抗剂,对这些亚型的一种或多种具有一定程度特异性的化合物可能是对一种既定的适应症具有更高特异性的治疗剂。
在其他的适应症如青光眼、高血压、性功能障碍和抑郁症的治疗中,某些具有α2肾上腺素能受体激动剂活性的化合物是已知的镇痛剂。可是,很多具有这样活性的化合物在治疗由α2肾上腺素受体调控的障碍中,并没有表现出理想的活性和特异性。例如,很多在疼痛治疗中被发现是有效药剂的化合物经常被发现具有不良副作用,如在全身有效剂量下产生低血压和镇静作用。这就需要缓解疼痛而不产生那些不良副作用的新药物。而且,需要一种表现出抗疼痛活性的药剂,尤其是抗慢性疼痛如慢性神经性疼痛和内脏疼痛。
发明内容
本发明提供了用于治疗哺乳动物疼痛的方法。特别是,本发明提供了明确定义的氨基咪唑啉、氨基噻唑啉、氨基噁唑啉及其药物组合物来治疗疼痛。
在本发明的一个实施方案中,提供了用于治疗疼痛的方法。可以通过以下方式实施该方法,例如通过给予需要治疗的哺乳动物一种药物组合物,该药物组合物包含治疗有效量的至少一种具有下述结构的化合物或其任意结合物,或者其可药用盐、水合物、溶剂化物、晶形、异构体、互变异构体、对映异构体和非对映异构体:
结构1
其中,X为O、S或NH;
n和m各自独立地为1到5;
R1和R2各自独立地为氢原子、烷基、环烷基、芳基、烯基、炔基、卤化物、羟基、烷氧基、三氟甲基、-N(R6)2、-CN、-CO2R6,或-CH2OH;并且
R3、R4、R5和R6各自独立地为氢原子或是低级烷基。
具体实施方式
应理解,上文概括说明和下下详细说明只是举例说明和进行解释,并非对要求保护的本发明做出限制。除非另外有具体说明,本文使用的单数包含复数在内。除非另有说明,本文使用的“或”表示“和/或”。此外,词语“包含”以及其他形式如“包括”和“含有”的使用不具有限制性。本文中使用的各部分标题只是出于组织目的,并不能解释为限制所述主题。
除非有具体的定义,否则本文中所述的与分析化学、合成有机化学和无机化学相关的术语和实验室操作及技术在本领域中是已知的。标准的化学符号与由这类符号所代表的全称可以互换使用。因此,例如,词语“氢”和“H”被认为具有相同的含义。标准技术可以用于化学合成、化学分析和制剂。
本文使用的“烷基”是指具有1至最高约100个碳原子的直链或支链烃基。每当一个数字范围在本文中出现时,它(如“1到100”或“C1-C100”)是指在所给定范围内的每个整数;例如“C1-C100烷基”是指一个可只包含1个碳原子、2个碳原子、3个碳原子等等,最高达并且包括100个碳原子的烷基,但词语“烷基”也包含其中没有指定碳原子数字范围的实例。“取代的烷基”是指具有包括下述基团在内的取代基的烷基部分,即烷基、烯基、炔基、羟基、氧代、烷氧基、巯基、环烷基、取代的环烷基、杂环基、取代的杂环基、芳基、取代的芳基、杂芳基、取代的杂芳基、芳氧基、取代的芳氧基、卤素、卤代烷基、氰基、硝基、硝酮(nitrone)、氨基、低级烷氨基、低级烷二氨基、酰氨基(amido)、叠氮基、-C(O)H、-C(O)R7、-CH2OR7、-C(O)-、-C(O)-、-S-、-S(O)2、-OC(O)-O-,其中R7为氢或低级烷基、酰基、氧酰基(oxyacyl)、羧基、氨基甲酸酯、磺酰基、磺酰胺、硫酰基(sulfuryl)等等。本文使用的“低级烷基”指具有1到大约6个碳原子的烷基部分。
本文使用的“烯基”是指至少有1个碳-碳双键且具有约2至最高达约100个碳原子的直链或支链烃基;“取代的烯基”是指进一步具有上文所列的一个或多个取代基的烯基。本文使用的“低级烯基”是指具有2至约6个碳原子的烯基部分。
本文使用的“炔基”是指至少有1个碳-碳三键且具有约2至最高达约100个碳原子的直链或支链烃基;“取代的炔基”是指进一步具有上文所列的一个或多个取代基的炔基。本文使用的“低级炔基”是指具有2至约6个碳原子的炔基部分。
本文使用的“环烷基”是指通常含有约3至最高达约8个碳原子的环状(即含环)烷基部分;“取代的环烷基”是指进一步具有上文所列的一个或多个取代基的环烷基基团。
本文使用的“芳基”是指具有6至最高达14个碳原子的芳族基团,“取代的芳基”是指进一步具有上文所列的一个或多个取代基的芳基基团。
本文使用的“杂芳基”是指含有一个或多个杂原子(如:N、O、S等)作为环状结构一部分并且环状结构中具有总计5至最高达14个原子(即碳原子和杂原子)的芳族部分。“取代的杂环基”是指进一步具有上文所列的一个或多个取代基的杂环基基团。
本文使用的“杂环基”是指含有一个或多个杂原子(如:N、O、S等)作为环状结构一部分并且具有3至最高达14个碳原子的非芳族环状(即含环)基团;“取代的杂环基”是指进一步具有上文所列的一个或多个取代基的杂环基基团。
本文使用的“卤素”或“卤化物”是指氟、氯、溴或碘。
对本领域技术人员来说,容易明了本发明的一些化合物可能包含一个或多个不对称中心,使得所述化合物可能以对映异构体和非对映异构体形式存在。除非另外特别说明,本发明的范围包括所有对映异构体、非对映异构体和外消旋混合物。本发明的一些化合物可与可药用酸或碱形成盐,本文中所描述化合物的这类可药用盐也属于本发明的范围。
此外,结构1所表示的化合物可以经过互变异构转化,并且可以通过下文所示的互变异构结构表示。参照结构1,当X是N时,可能存在以下的互变异构体:
当X是S时,可能存在以下的互变异构体:
当X是O时,可能存在以下的互变异构体:
结构1的所有互变异构体都在本发明范围内。
“可药用盐”是任何保留母体化合物活性的盐,并且与母体化合物相比,在将其进行给药的情况下,以及对于其所给药的受试者,不会产生任何附加的有害或不良的作用。可药用盐也指任何由于给予酸、另一种盐或可转化为一种酸或盐的前药而可在体内形成的盐。
酸性官能团的可药用盐可来源于有机碱或无机碱。该盐可包含单价或多价离子。特别值得关注的是无机离子锂、钠、钾、钙和镁。有机盐可用胺制备,特别是铵盐如单烷基胺、二烷基胺和三烷基胺或乙醇胺。也可用咖啡因、氨基丁三醇和类似的分子制备盐。可用盐酸或一些其他可药用酸与包含碱性基团(如胺或吡啶环)的化合物形成盐。
“前药”是一种在给药后转变为治疗活性化合物的化合物,该术语应如其在本领域中通常所理解的那样在本文作广义的解释。并非想要限制本发明的范围,转化可通过水解酯基或是某种其他生物学上不稳定的基团而发生。一般地,但不是必须地,前药是没有活性的,或者与它所转变的治疗活性化合物相比,活性很低。
本发明提供了用于治疗疼痛的方法。可以通过以下方式实施这类方法,例如,通过给予一个需要治疗的哺乳动物一种药物组合物,该药物组合物包含治疗有效量的至少一种具有下述结构的化合物或其任意结合物,或者其可药用盐、水合物、溶剂化物、晶形、异构体、互变异构体、对映异构体和非对映异构体:
其中,
X是O、S或NH;
n和m各自独立地为1到5;
R1和R2各自独立地选为氢、烷基、环烷基、芳基、烯基、炔基、卤化物、羟基、烷氧基、三氟甲基、-N(R6)2、-CN、-CO2R6或-CH2OH;并且
R3、R4、R5和R6各自独立地为氢或是低级烷基。
在一些实施方案中,本发明的方法中所使用的化合物包括如下这样的化合物:其中R1和R2各自独立地为氢、低级烷基、氟、氯、溴、三氟甲基、羟基或甲氧基。在某些实施方案中,本发明的方法使用如下这样的化合物:其中R1和R2各自独立地为氢、低级烷基或氯。
在一些实施方案中,本发明的方法使用其中X是S的化合物。本发明的这个实施方案的化合物包括但是不限于具有下述结构的化合物:
在一些实施方案中,本发明的方法采用其中X是NH的化合物。本发明的这个实施方案的化合物包括但不局限于具有下述结构的化合物:
在一些实施方案中,本发明的方法使用其中X是O的化合物。本发明的这个实施方案的化合物包括但不局限于具有下述结构的化合物:
本文所列的化合物通常通过使适当取代的胺与异氰酸酯、异硫氰酸酯或咪唑啉磺酸反应来制备。下述方案A描述了用于制备本发明化合物的前体胺的示例性合成。实验的详细内容在实施例中描述,参阅下文。
方案A:
胺与异氰酸酯、异硫氰酸酯或咪唑啉磺酸中任一种的偶联都可按照下述方案1-3中所述完成。
方案1
方案2
方案3
本发明方法中所使用的化合物的α2肾上腺素能活性通过一种名为受体选择和扩增技术(RSAT)检测的检测法证明,该检测法在Messier等人的出版物《药理学与毒理学》1995年,76卷,308-311页(Messier et.al.,1995,Pharmacol.Toxicol.76,pp.308-311,通过引证的方式纳入本文)中有记载,而且在下文中也有描述。
RSAT检测法测量受体介导的接触抑制损失,该损失可导致汇合细胞的混合群中含有受体的细胞选择性增殖。细胞数的增加通过适当的转染标记物基因如β-半乳糖苷酶进行测定,该基因的活性可以容易地通过96孔板来测定。激活G蛋白的受体——Gq引发这一反应。正常情况下与Gi偶联的α2受体在与具有Gi受体识别结构域一个杂合Gq蛋白——名为Gq/i5——共同表达时会激活RSAT反应。
将NIH-3T3细胞以2×106个细胞的密度铺于15厘米的皿中,并且在补充有10%小牛血清的达尔伯克氏改良伊格尔氏(DMEM)培养基中进行培养。一天后,将细胞与编码p-SV-β-半乳糖苷酶(5-10μg)、受体(1-2μg)和G蛋白(1-2μg)的哺乳动物表达质粒通过磷酸钙沉淀法进行共转染。40μg的鲑鱼精DNA也可包括在转染混合物中。第二天加新鲜培养基,1-2天后,收获细胞并以50个检测等份试样进行冷冻。细胞解冻后,取100μL加入到96孔板中不同浓度的三重复试样的药物的100μL等分试样中。在37℃下继续孵育72-96小时。用磷酸盐缓冲盐水洗涤之后,通过以下方式测定β-半乳糖苷酶活性:加入200μL显色底物(由溶于磷酸盐缓冲盐水的3.5mM邻硝基苯基-β-D-吡喃半乳糖苷和0.5% nonidet P-40组成),在30℃下孵育过夜并在420nm下测量光密度。吸光度是酶活性的量度,它依赖于细胞数目并且反映受体介导的细胞增殖。效能或内在活性按照以下方式计算:药物的最大作用与每一种受体亚型的标准全激动剂的最大作用之比。溴莫尼定(Brimonidine),化学结构如下所示,它用作α2B和α2C受体的标准激动剂。
溴莫尼定
使用几种本发明方法所使用的示例性化合物进行的RSAT测定的结果如以下表1中所示,这些示例性化合物的化学结构也一并列出。
本发明的方法可用于治疗疼痛,包括急性疼痛和慢性疼痛。“急性疼痛”是由以下原因造成通常具有高阈值的即刻疼痛:损伤(如切伤、压伤、烧伤)或者化学品的刺激(如暴露于辣椒的活性成分辣椒素时所经历的刺激)。而“慢性疼痛”是急性疼痛以外的疼痛,例如但不限于神经性疼痛、内脏疼痛(包括克隆氏病(Crohn’s disease)、肠易激综合症(irritable bowel syndrome(IBS))、功能性消化不良(functional dyspepsia)等等导致的疼痛)和牵涉痛。
众所周知,慢性疼痛(如来自癌症、关节炎和很多神经损害的疼痛)和急性疼痛(如直接机械性刺激如组织切开、捏、刺或压所产生的疼痛)是截然不同的神经学现象,很大程度上是由不同的神经纤维和神经受体所介导的或是由慢性刺激时这些神经功能的重排或改变所介导的。急性疼痛的感觉传导非常迅速,主要通过称作C型纤维的传入神经纤维传导,这种纤维对于机械刺激、热刺激和化学刺激有高阈值。然而慢性疼痛的机制并不是完全清楚,急性组织损伤在最初刺激之后的几分钟或几小时内可以引发继发症状,包括引起疼痛反应所必需的刺激量的区域性减小。这种现象——其通常发生在发源自(但是大于)原始刺激位点的区域中——称作痛觉过敏。再次应答可以产生明显增强的对机械刺激或热刺激的敏感性。
A型传入纤维(Aβ和Aδ纤维)可以在一个比C型纤维低的阈值被刺激,并且它似乎与慢性疼痛的感觉有关。例如,在正常情况下,对这些神经的低阈刺激(如轻擦或瘙痒)是不痛的。然而,在某些情况下如那些神经损伤后的情况或是称为带状疱疹的疱疹病毒介导的病症中,即使施加这样的轻微接触或衣物摩擦都可能是非常疼痛的。这种情况被称作痛觉异常(allodynia),似乎至少部分是由Aβ传入神经介导的。C型纤维也可能与慢性疼痛的感觉有关,但是如果是这样,则似乎有一点是清楚的,即神经元的持久激动随着时间的推移会引起某种变化,这会导致对慢性疼痛的感觉。
本发明的方法采用以药学有效剂量下给予的化合物和/或可药用组合物。这些剂量通常是达到所需治疗效果所需的最小剂量;例如,在慢性疼痛的治疗中,这个量大体上是将慢性疼痛所引起的不适降低到可以忍耐的水平所需的量。一般来讲,这些剂量是在1-1000mg/天的范围;更优选地是在10-500mg/天的范围。然而,在任何给定情况下,待给予的化合物和/或组合物的实际量是由医师在考虑相关的情况后决定的,所述相关情况如疼痛的严重程度、患者的年龄和体重、患者的一般身体状况、疼痛的原因和用药途径。
本发明的方法可用于治疗哺乳动物特别是人的疼痛。在某些情况下,通过口服途径给予患者任何可接受形式的化合物和/或药物组合物,所述可接受形式如片剂、液体剂、胶囊剂、粉剂等等。然而其他途径可能是符合需要的或是必需的,特别是如果患者感到恶心。这些其他途径可能包括且毫无例外地有经皮、肠胃外、皮下、鼻内、鞘内、肌内、静脉和直肠内给药方式。此外,可设计所述药物组合物以在给定时间内延迟释放活性化合物,或在治疗过程中仔细控制在给定时间释放的活性化合物的量。
在另一个实施方案中,本发明方法所使用的药物组合物包含在一种可药用载体中的至少一种具有结构1的化合物。短语“可药用”是指载体、稀释剂或赋形剂必须可与组合物中的其他成分相容并且对其接受者无害。
本文使用的词语“治疗有效量”是指引发有需要的哺乳动物的生物或医学反应的药物组合物的量,所述量是研究人员、兽医、医生或其他临床医生正在寻找的。在一些实施方案中,所述哺乳动物指人。
本发明的药物组合物可以以如下形式使用:固体、溶液、乳剂、分散系、微团、脂质体等,其中最终的组合物中包含至少一种本发明的化合物,其作为活性成分并与适合用于肠道或肠胃外应用的有机或无机载体或赋形剂混合。所述化合物可例如与通常无毒的可药用载体结合,所述载体用于片剂、丸剂、胶囊剂、栓剂、溶液剂、乳剂、悬浮液和任何其他适合使用的形式。可以使用的载体包括葡萄糖、乳糖、阿拉伯胶、明胶、甘露醇、淀粉糊、三硅酸镁、滑石、玉米淀粉、角蛋白、胶体硅、马铃薯淀粉、尿素、中等链长的甘油三酯、葡聚糖和其他适合以固体、半固体或液体形式用于制备制剂的载体。此外,还可使用助剂、稳定剂、增稠剂、着色剂和芳香剂。本文所述的化合物被包含在其量足以对过程或疾病状况产生所需作用的药物组合物中。
本发明的药物组合物可以是适合口服的形式,例如片剂、糖锭(troche)、锭剂、水性或油性悬浮液、可分散粉末或颗粒、乳剂、硬胶囊或软胶囊、糖浆或酏剂。用于口服的组合物可依照本领域已知的任何用于制造药物组合物的方法制备,这样的组合物可含一种或多种选自以下的试剂以提供药物学上讲究(elegant)和适口的制剂:甜味剂如蔗糖、乳糖或糖精,调味剂如薄荷、冬青油或樱桃油,着色剂和防腐剂。包含混有无毒的可药用赋形剂的本文所述的化合物的片剂也可通过已知的方法制造。使用的赋形剂可以是,例如(1)惰性稀释剂如碳酸钙、乳糖、磷酸钙或磷酸钠;(2)粒化剂和崩解剂如玉米淀粉、马铃薯淀粉或海藻酸;(3)粘合剂如黄蓍胶、玉米淀粉、明胶或阿拉伯胶;以及(4)润滑剂如硬脂酸镁、硬脂酸或滑石。片剂可以是不包衣的或者它们可以通过已知的技术包衣以延迟在胃肠道的崩解和吸收,从而在更长的时间内发挥持续的作用。例如,使用一种延迟时间的物质如单硬脂酸甘油酯或二硬脂酸甘油酯。
在某些情况下,口服使用的剂型可为硬明胶胶囊的形式,其中本发明化合物与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土相混合。它们也可以是软明胶胶囊的形式,其中本发明化合物与水或油性介质如花生油、液体石蜡或橄榄油相混合。
药物组合物可为无菌的可注射悬浮液的形式。这种悬浮液可根据已知的方法使用合适的分散剂或润湿剂和助悬剂来配制。无菌的可注射制剂也可以是溶于无毒的可肠胃外使用的稀释剂或溶剂中的无菌的可注射溶液或悬液,例如为溶于1,3-丁二醇的溶液形式。无菌的不挥发性油通常用作溶剂或悬浮介质。为了这个目的,任何温和的不挥发性油都可以使用,包括合成的甘油单酯或甘油二酯、脂肪酸(包括油酸)、天然存在的植物油(如芝麻油、椰子油、花生油、棉花籽油等),或是合成的脂肪载物(vehicle)如油酸乙酯等。缓冲剂、防腐剂、抗氧化剂等也可按需要纳入其中。
本文所描述的药物组合物也可以用于药物的直肠给药的栓剂形式给予。这些组合物可以是通过将本文所描述的化合物与合适的无刺激性赋形剂混合来制备,所述赋形剂例如可可脂和合成的聚乙二醇甘油酯在常温下是固态,但是在直肠腔内会液化和/或溶解从而释放药物。
由于个体受试者的症状严重性可能具有很大的差异并且每一种药物均有其独特的治疗特征,因此用于每个哺乳动物的准确给药方式和剂量由医师斟酌决定。
以下的实施例只是对本发明的举例说明,绝不应该解释为对本发明的限制。
实施例
胺前体的通用合成
A.3-氯-2-甲基苯甲醛
在-78℃下向3-氯-2-甲基苯甲腈(5g,33mmol)的二氯甲烷(150mL)溶液中加入DiBAL(在二氯甲烷中浓度为1M,41mL)。反应混合物在-78℃下搅拌2小时,然后用甲醇停止反应。将混合物升温至0℃,然后加入HCl(10%)。将冰水浴移去,并且将混合物在室温下搅拌10分钟。将两相分离,水相以二氯甲烷萃取。将合并的二氯甲烷用盐水洗涤,硫酸钠干燥并浓缩。用柱色谱法(5%乙酸乙酯/正己烷)得到3-氯-2-甲基苯甲醛(3.5g,69%)。
1H NMR(300MHz,CDCl3)δ2.64(s,3H),7.21-7.26(m,1H),7.50-7.53(m,1H),7.63-7.66(m,1H),10.20(s,1H)
B.1-(3-氯-2-甲基苯基)-2-苯乙胺
在0℃下向3-氯-2-甲基苯甲醛(2.85g,18.5mmol)的四氢呋喃(THF)(5mL)溶液中加入双(三甲基硅烷基)氨基锂(在THF中浓度为1M,22.2mL)。将冰水浴移去,将反应混合物从0℃升至室温并搅拌2小时。随后将反应混合物再冷却至0℃,加入苄基氯化镁(在THF中浓度为1M,22.2mL)。反应混合物从0℃升至室温并搅拌1小时,然后用NH4Cl(饱和)停止反应,以乙酸乙酯萃取。将合并的乙酸乙酯用盐水洗涤,硫酸钠干燥并浓缩。加入HCl(在甲醇中的浓度为1.25M)至pH为2。移除甲醇后得到黄色固体,向所述固体中加入二氯甲烷。过滤悬液,并用二氯甲烷洗涤以得到白色固体。将所述白色固体溶于甲醇中,以NaOH(1N)碱化,并且用乙酸乙酯萃取。合并的乙酸乙酯用盐水洗涤,硫酸钠干燥并浓缩得到淡黄色油状物1-(3-氯-2-甲基苯基)-2-苯乙胺(22.73g,60%)。
1H NMR(300MHz,CDCl3)δ2.37(s,3H),2.67-2.75(m,1H),2.95-3.01(m,1H),4.46-4.50(m,1H),7.17-7.19(m,3H),7.24-7.33(m,4H),7.46-7.49(m,1H).
氨基咪唑啉、氨基噁唑啉和氨基噻唑啉的通用合成
N-(1,2-二苯基乙基)-4,5-二氢-1H-咪唑-2-胺的合成,化合物1
将1,2-二苯基乙胺(7.0g,35.5mmol)和2-甲硫基-2-咪唑啉氢碘化物(5.0g,39.1mmol)的异丙醇(50mL)溶液加热回流16小时。将反应混合物浓缩后,用乙醚重结晶得到N-(1,2-二苯基乙基)-4,5-二氢-1H-咪唑-2-胺,即化合物1。
1H NMR(300MHz,DMSO)δ2.90-3.14(m,2H),3.36(s,4H),4.78(dd,J=8.21,6.45Hz,1H),6.87-7.55(m,10H).
N-(1,2-二苯基乙基)-4,5-二氢噁唑-2-胺的合成,化合物2
A.1-(2-氯乙基)-3-(1,2-二苯基乙基)脲
向1,2-二苯基-乙胺(818mg,4.14mmol)的二氯甲烷(5mL)溶液中加入2-氯乙基异氰酸酯(0.53mL,6.21mmol)和三乙胺(0.86mL)。将混合物在室温下搅拌1.5小时。移除二氯甲烷后,用柱色谱法(2-3% MeOH/CH2Cl2)得到白色固体1-(2-氯乙基)-3-(1,2-二苯基乙基)脲(905mg,72%)。
1H NMR(300MHz,CDCl3)δ2.98-3.00(m,2H),3.30-3.41(m,4H),4.89-4.96(m,1H),7.00-7.03(m,2H),7.17-7.30(m,8H).
B.N-(1,2-二苯基乙基)-4,5-二氢噁唑-2-胺,化合物2
将1-(2-氯乙基)-3-(1,2-二苯基乙基)脲(543mg,1.8mmol)的水(5mL)溶液在100℃下加热1.5小时。将反应混合物冷却至室温,加入碳酸钠(饱和)至pH>8。混合物用乙酸乙酯萃取。合并的乙酸乙酯用盐水洗涤,硫酸钠干燥并浓缩。用柱色谱法(5%的溶于MeOH/CH2Cl2中的7N NH3)得到白色固体N-(1,2-二苯基乙基)-4,5-二氢噁唑-2-胺(381mg,80%),即化合物2。
1H NMR(300MHz,CDCl3)δ3.03-3.06(m,2H),3.60-3.66(m,2H),4.07-4.13(m,2H),4.86-4.90(m,1H),7.03-7.06(m,2H),7.15-7.25(m,8H).
N-(1,2-二苯基乙基)-4,5-二氢噻唑-2-胺的合成,化合物3
向1,2-二苯基乙胺(818mg,4.14mmol)的二氯甲烷(5mL)溶液中加入2-氯乙基异硫氰酸酯(0.097mL,0.99mmol)。将混合物在室温下搅拌1小时。移除二氯甲烷后,用柱色谱法(6%MeOH/CH2Cl2)得到白色固体N-(1,2-二苯基乙基)-4,5-二氢噻唑-2-胺(330mg,29%),即化合物3。
1H NMR(300MHz,CDCl3)δ3.10-3.16(m,1H),3.24-3.87(m,3H),3.81-3.87(m,2H),4.51-4.56(m,1H),7.18-7.34(m,10H).
N-(1-(3-氯苯基)-2-m-甲苯基乙基)-4,5-二氢噁唑-2-胺,化合物4
1H NMR(300MHz,CDCl3)δ2.29(s,3H),2.94-3.06(m,2H),3.65-3.71(m,2H),4.16-4.22(m,2H),4.83-4.88(m,1H),6.83-6.87(m,2H),7.01-7.04(m,1H),7.09-7.16(m,2H),7.20-7.26(m,3H).
N-(1-(3-氯苯基)-2-m-甲苯基乙基)-4,5-二氢噻唑-2-胺,化合物5
1H NMR(300MHz,CDCl3)δ2.28(s,3H),2.98-3.12(m,2H),3.21-3.26(m,2H),3.81-3.86(m,2H),4.70-4.74(m,1H),6.87-6.90(m,2H),7.00-7.03(m,1H),7.11-7.18(m,3H),7.20-7.26(m,2H).
N-(1-(3-氯苯基)-2-苯基乙基)-4,5-二氢噁唑-2-胺,化合物6
1H NMR(300MHz,CDCl3)δ3.03-3.06(m,2H),3.66-3.72(m,2H),4.17-4.23(m,2H),4.86-4.90(m,1H),7.05-7.12(m,3H),7.1227.28(m,6H).
N-(1-(3-氯苯基)-2-苯基乙基)-4,5-二氢噻唑-2-胺,化合物7
1H NMR(300MHz,CDCl3)δ3.06-3.08(m,2H),3.23-3.28(m,2H),3.85-3.90(m,2H),4.87-4.92(m,1H),7.03-7.10(m,3H),7.21-7.28(m,6H).
N-(1-(3-氯苯基)-2-苯基乙基)-4,5-二氢-1H-咪唑-2-胺的合成,化合物8
向1-(3-氯苯基)-2-苯基乙胺(400mg,1.73mmol)的乙腈(5mL)溶液中加入4,5-二氢-1H-咪唑-2-磺酸(260mg,1.73mmol)和三乙胺(0.24mL)。将混合物在70℃下加热45分钟。将反应混合物冷却至室温。将白色固体过滤并用乙腈洗涤得到N-(1-(3-氯苯基)-2-苯基乙基)-4,5-二氢-1H-咪唑-2-胺,即化合物8(272mg,53%)。
1H NMR(300MHz,CD3OD)δ3.00-3.07(m,1H),3.13-3.21(m,1H),3.52(s,4H),4.62-4.67(m,1H),7.18-7.36(m,9H).
下列化合物通过上述通用方法中的一种合成。
N-(1-(3-氯苯基)-2-m-甲苯基乙基)-4,5-二氢-1H-咪唑-2-胺,化合物9
1H NMR(300MHz,CD3OD)δ2.26(s,3H),2.94-2.98(m,2H),3.39(s,4H),4.69-4.74(m,1H),6.92-6.99(m,3H),7.07-7.12(m,1H),7.18-7.25(m,3H),7.30(s,1H).
N-(1-(3-氯苯基)-2-p-甲苯基乙基)-4,5-二氢噻唑-2-胺,化合物10
1H NMR(300MHz,CDCl3)δ2.30(s,3H),3.00-3.03(m,2H),3.22-3.26(m,2H),3.85-3.90(m,2H),4.86-4.90(m,1H),6.91-6.93(m,2H),7.04-7.09(m,3H),7.20-7.26(m,3H).
N-(1-(3-氯苯基)-2-p-甲苯基乙基)-4,5-二氢-1H-咪唑-2-胺,化合物11
1H NMR(300MHz,CD3OD)δ2.26(s,3H),2.95-3.01(m,1H),3.08-3.16(m,1H),3.52(s,4H),4.57-4.62(m,1H),7.03-7.10(m,4H),7.24-7.34(m,4H).
N-(1-(3-氯苯基)-2-o-甲苯基乙基)-4,5-二氢-1h-咪唑-2-胺,化合物12
1H NMR(300MHz,CD3OD)δ2.26(s,3H),3.10-3.13(m,2H),3.58(s,4H),4.70-4.75(m,1H),7.07-7.15(m,4H),7.21-7.24(m,1H),7.29-7.34(m,3H).
N-(1-(2,3-二甲基苯基)-2-苯基乙基)-4,5-二氢-1H-咪唑-2-胺,化合物13
1H NMR(300MHz,CD3OD)δ2.20(s,3H),2.27(s,3H),2.99-3.03(m,2H),3.49(s,4H),4.86-4.92(m,1H),7.09-7.11(m,2H),7.20-7.33(m,6H).
N-(1-(3-氯苯基)-2-p-甲苯基乙基)-4,5-二氢噁唑-2-胺,化合物14
1H NMR(300MHz,CDCl3)δ2.30(s,3H),2.91-3.04(m,2H),3.65-3.71(m,2H),4.11-4.20(m,2H),4.84-4.89(m,1H),6.91-6.93(m,2H),7.04-7.10(m,3H),7.20-7.26(m,3H).
N-(1-(3-氯苯基)-2-o-甲苯基乙基)-4,5-二氢噻唑-2-胺,化合物15
1H NMR(300MHz,CDCl3)δ2.20(s,3H),3.02-3.06(m,2H),3.20-3.25(m,2H),3.81-3.86(m,2H),4.78-4.83(m,1H),6.97-6.99(m,1H),7.04-7.12(m,4H),7.19-7.21(m,3H).
N-(1-(2,3-二甲基苯基)-2-苯基乙基)-4,5-二氢噻唑-2-胺,化合物16
1H NMR(300MHz,CDCl3)δ2.15(s,3H),2.26(s,3H),3.05-3.08(m,2H),3.19-3.24(m,2H),3.84-3.89(m,2H),5.06-5.11(m,1H),7.06-7.13(m,4H),7.18-7.27(m,4H).
N-(1-(3-氯苯基)-2-o-甲苯基乙基)-4,5-二氢噁唑-2-胺,化合物17
1H NMR(300MHz,CDCl3)δ2.21(s,3H),2.99-3.03(m,2H),3.64-3.70(m,2H),4.14-4.20(m,2H),4.83-4.88(m,1H),6.98-7.01(m,1H),7.07-7.14(m,4H),7.20-7.26(m,3H).
N-(1-(3-氯-2-氟苯基)-2-苯基乙基)-4,5-二氢-1H-咪唑-2-胺,化合物18
1H NMR(300MHz,CD3OD)δ3.04-3.08(m,2H),3.44(s,4H),5.02-5.06(m,1H),7.09-7.40(m,8H).
N-(1-(3-氯-2-甲基苯基)-2-苯基乙基)-4,5-二氢-1H-咪唑-2-胺,化合物19
1H NMR(300MHz,CD3OD)δ2.32(s,3H),3.02-3.05(m,2H),3.50(s,4H),4.85-4.89(m,1H),7.17-7.32(m,7H),7.52-7.55(m,1H).
N-(1-(2,3-二甲基苯基)-2-苯基乙基)-4,5-二氢噁唑-2-胺,化合物20
1H NMR(300MHz,CDCl3)δ2.18(s,3H),2.25(s,3H),2.97-3.01(m,2H),3.63-3.68(m,2H),4.07-4.13(m,2H),5.16-5.21(m,1H),7.03-7.09(m,5H),7.12-7.23(m,3H).
N-(1-(3-氯-2-氟苯基)-2-苯基乙基)-4,5-二氢噁唑-2-胺,化合物21
1H NMR(300MHz,CDCl3)δ3.04-3.13(m,2H),3.64-3.70(m,2H),4.13-4.19(m,2H),5.12-5.17(m,1H),6.94-7.08(m,4H),7.19-7.30(m,4H).
N-(1-(3-氯-2-氟苯基)-2-苯基乙基)-4,5-二氢噻唑-2-胺,化合物22
1H NMR(300MHz,CDCl3)δ3.10-3.12(m,2H),3.21-3.26(m,2H),3.82-3.87(m,2H),5.07-5.12(m,1H),6.99-7.04(m,1H),7.09-7.16(m,3H),7.20-7.31(m,4H).
N-(1-(2,3-二氯苯基)-2-苯基乙基)-4,5-二氢-1H-咪唑-2-胺,化合物23
1H NMR(300MHz,CD3OD)δ2.94-3.02(m,1H),3.15-3.21(m,1H),3.49(s,4H),5.02-5.06(m,1H),7.19-7.41(m,6H),7.47-7.51(m,1H),7.64-7.68(m,1H).
N-(1-(2,3-二氯苯基)-2-(4-氟苯基)乙基)-4,5-二氢-1H-咪唑-2-胺,化合物24
1H NMR(300MHz,CD3OD)δ2.91-2.96(m,1H),3.21-3.24(m,1H),3.53(s,4H),5.06-5.09(m,1H),7.02-7.06(m,2H),7.31-7.38(m,3H),7.43-7.44(m,1H),7.52-7.54(m,1H).
N-(2-(2-溴苯基)-1-(2,3-二氯苯基)乙基)-4,5-二氢-1H-咪唑-2-胺,化合物25
1H NMR(300MHz,CD3OD)δ3.21-3.25(m,2H),3.43(s,4H),5.28-5.32(m,1H),7.12-7.14(m,1H),7.19-7.23(m,2H),7.29-7.32(m,1H),7.42-7.47(m,2H),7.53-7.56(m,1H).
N-(1-(2,3-二氯苯基)-2-(3-甲氧基苯基)乙基)-4,5-二氢-1H-咪唑-2-胺,化合物26
1H NMR(300MHz,CD3OD)δ2.91-2.96(m,1H),3.25-3.28(m,1H),3.57(s,4H),3.78(s,3H),5.10-5.13(m,1H),6.83-6.86(m,2H),6.89-6.91(m,1H),7.23-7.26(m,1H),7.37-7.43(m,2H),7.55-7.57(m,1H).
N-(1-(2,3-二氯苯基)-2-(3-氟-2-甲基苯基)乙基)-4,5-二氢-1H-咪唑-2-胺,化合物27
1H NMR(300MHz,CD3OD)δ2.28(s,3H),3.11-3.16(m,1H),3.29-3.33(m,1H),3.57(s,4H),5.14-5.17(m,1H),6.95-7.01(m,2H),7.12-7.16(m,1H),7.38-7.41(m,1H),7.46-7.47(m,1H),7.56-7.58(m,1H).
N-(1-(2,3-二氯苯基)-2-(2,5-二氯苯基)乙基)-4,5-二氢-1H-咪唑-2-胺,化合物28
1H NMR(300MHz,CD3OD)δ3.09-3.17(m,1H),3.24-3.34(m,1H),3.45(s,4H),5.25-5.30(m,1H),7.21-7.25(m,1H),7.29-7.36(m,3H),7.44-7.49(m,2H).
N-(2-(2-氯-6-氟苯基)-1-(2,3-二氯苯基)乙基)-4,5-二氢-1H-咪唑-2-胺,化合物29
1H NMR(300MHz,CD3OD)δ3.25-3.29(m,2H),3.38(s,4H),5.29-5.34(m,1H),6.94-7.00(m,1H),7.17-7.28(m,3H),7.40-7.47(m,2H).
N-(1-(2,3-二氯苯基)-2-(3,5-二氯苯基)乙基)-4,5-二氢-1H-咪唑-2-胺,化合物30
1H NMR(300MHz,CD3OD)δ2.85-2.93(m,1H),3.13-3.20(m,1H),3.46(s,4H),5.11-5.14(m,1H),7.26-7.27(m,2H),7.31-7.36(m,2H),7.48-7.51(m,2H).
N-(1-(2,3-二氯苯基)-2-(2,4-二氯苯基)乙基)-4,5-二氢-1H-咪唑-2-胺,化合物31
1H NMR(300MHz,CD3OD)δ3.09-3.16(m,1H),3.21-3.28(m,1H),3.42(s,4H),5.24-5.29(m,1H),7.22-7.23(m,2H),7.27-7.33(m,1H),7.41-7.48(m,3H).
N-(1-(2,3-二氯苯基)-2-(3,4-二氯苯基)乙基)-4,5-二氢-1H-咪唑-2-胺,化合物32
1H NMR(300MHz,CD3OD)δ2.80-2.87(m,1H),3.10-3.16(m,1H),3.40(s,4H),5.10-5.14(m,1H),7.18-7.21(m,1H),7.28-7.33(m,2H),7.41-7.48(m,3H).
3-(2-(2,3-二氯苯基)-2-(4,5-二氢-1H-咪唑-2-基氨基)乙基)苯酚,化合物33
1H NMR(300MHz,CD3OD)δ2.75-2.83(m,1H),3.12-3.18(m,1H),3.51(s,4H),5.05-5.09(m,1H),6.62-6.74(m,3H),7.05-7.11(m,1H),7.31-7.44(m,2H),7.50-7.53(m,1H).
N-(1-(3-氯苯基)-2-(2-甲氧基苯基)乙基)-4,5-二氢-1H-咪唑-2-胺,化合物34
1H NMR(300MHz,CD3OD)δ2.98-3.14(m,2H),3.53(s,4H),3.84(s,3H),4.77-4.82(m,1H),6.80-6.85(m,1H),6.93-6.96(m,1H),7.03-7.06(m,1H),7.19-7.34(m,5H).
N-(1-(3-氯苯基)-2-(2-甲氧基苯基)乙基)-4,5-二氢噁唑-2-胺,化合物35
1H NMR(300MHz,CD3COCD3)δ3.02-3.04(m,2H),3.45-3.51(m,2H),3.85(s,3H),4.03-4.08(m,2H),4.87-4.92(m,1H),6.80-6.85(m,1H),6.94-6.96(m,1H),7.12-7.23(m,3H),7.28-7.30(m,2H),7.39-7.40(m,1H).
N-(2-(2-溴苯基)-1-(3-氯苯基)乙基)-4,5-二氢-1H-咪唑-2-胺,化合物36
1H NMR(300MHz,CD3OD)δ3.14-3.16(m,2H),3.40(s,4H),4.80-4.85(m,1H),7.06-7.11(m,1H),7.19-7.27(m,4H),7.36(m,1H),7.51-7.54(m,1H).
N-(2-(2-溴苯基)-1-(3-氯苯基)乙基)-4,5-二氢噁唑-2-胺,化合物37
1H NMR(300MHz,CD3OD)δ3.03-3.15(m,2H),3.50-3.56(m,2H),4.15-4.21(m,2H),4.85-4.90(m,1H),7.08-7.27(m,6H),7.33-735(m,1H),7.53-7.56(m,1H).
在参照这些具体实施例描述本发明的同时,应该理解其他的修饰和变化在不脱离本发明精神的前提下都是可能的。
Claims (13)
2.权利要求1的方法,其中R1和R2各自独立地为氢、低级烷基、氟、氯、溴、三氟甲基、羟基或甲氧基。
3.权利要求1的方法,其中X为S。
4.权利要求3的方法,其中R1和R2各自独立地为氢、低级烷基、氟、氯、溴、三氟甲基、羟基或甲氧基。
6.权利要求1的方法,其中X为NH。
7.权利要求6的方法,其中R1和R2各自独立地为氢、低级烷基、氟、氯、溴、三氟甲基、羟基或甲氧基。
9.权利要求1的方法,其中X为O。
10.权利要求9的方法,其中R1和R2各自独立地为氢、低级烷基、氟、氯、溴、三氟甲基、羟基或甲氧基。
12.权利要求1方法,其中将所述药物组合物给予哺乳动物以治疗神经性疼痛、慢性疼痛或内脏疼痛。
13.权利要求1方法,其中将所述药物组合物给予哺乳动物以治疗痛觉异常。
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US3892808P | 2008-03-24 | 2008-03-24 | |
US61/038,928 | 2008-03-24 | ||
US12/408,823 US20090239918A1 (en) | 2008-03-24 | 2009-03-23 | Selective subtype alpha 2 adrenergic agents and methods for use thereof |
US12/408,823 | 2009-03-23 | ||
PCT/US2009/038004 WO2009120648A1 (en) | 2008-03-24 | 2009-03-24 | Selective subtype alpha 2 adrenergic agents and methods for use thereof |
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CN102036664A true CN102036664A (zh) | 2011-04-27 |
CN102036664B CN102036664B (zh) | 2012-11-28 |
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CN2009801187258A Expired - Fee Related CN102036664B (zh) | 2008-03-24 | 2009-03-24 | 选择性亚型α2肾上腺素能药物及其使用方法 |
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US (1) | US20090239918A1 (zh) |
EP (1) | EP2265269A1 (zh) |
JP (1) | JP2011515479A (zh) |
KR (1) | KR20100126821A (zh) |
CN (1) | CN102036664B (zh) |
AU (1) | AU2009228449A1 (zh) |
BR (1) | BRPI0910058A2 (zh) |
CA (1) | CA2719226A1 (zh) |
RU (1) | RU2010141940A (zh) |
WO (1) | WO2009120648A1 (zh) |
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US5212176A (en) * | 1990-06-29 | 1993-05-18 | Abbott Laboratories | R(+)-terazosin |
AR047342A1 (es) * | 2003-12-23 | 2006-01-18 | Basf Ag | Compuestos de 1-(azolin-2-il)amino-1,2difeniletano para combatir insectos, aracnidos y nematodos |
WO2008123821A1 (en) * | 2007-03-01 | 2008-10-16 | Albireo Ab | 4, 5-dihydro-lh-imidazol-2-amine derivatives for use in the treatment of respiratory, cardiovascular, neurological or gastrointestinal disorders |
WO2008115141A1 (en) * | 2007-03-19 | 2008-09-25 | Albireo Ab | 4, 5-dihydro-1,3-thiazol-2-amine derivatives and their use in the treatment of respiratory, cardiovascular, neurological or gastrointestinal disorders |
-
2009
- 2009-03-23 US US12/408,823 patent/US20090239918A1/en not_active Abandoned
- 2009-03-24 WO PCT/US2009/038004 patent/WO2009120648A1/en active Application Filing
- 2009-03-24 CN CN2009801187258A patent/CN102036664B/zh not_active Expired - Fee Related
- 2009-03-24 JP JP2011501961A patent/JP2011515479A/ja active Pending
- 2009-03-24 KR KR1020107023527A patent/KR20100126821A/ko not_active Application Discontinuation
- 2009-03-24 AU AU2009228449A patent/AU2009228449A1/en not_active Abandoned
- 2009-03-24 EP EP09723978A patent/EP2265269A1/en not_active Withdrawn
- 2009-03-24 BR BRPI0910058-0A patent/BRPI0910058A2/pt not_active IP Right Cessation
- 2009-03-24 CA CA2719226A patent/CA2719226A1/en not_active Abandoned
- 2009-03-24 RU RU2010141940/15A patent/RU2010141940A/ru unknown
Also Published As
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AU2009228449A1 (en) | 2009-10-01 |
RU2010141940A (ru) | 2012-04-27 |
BRPI0910058A2 (pt) | 2019-03-06 |
KR20100126821A (ko) | 2010-12-02 |
CA2719226A1 (en) | 2009-10-01 |
US20090239918A1 (en) | 2009-09-24 |
JP2011515479A (ja) | 2011-05-19 |
CN102036664B (zh) | 2012-11-28 |
EP2265269A1 (en) | 2010-12-29 |
WO2009120648A1 (en) | 2009-10-01 |
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