CN101119980A - 新的苯并噻唑甲酰胺 - Google Patents
新的苯并噻唑甲酰胺 Download PDFInfo
- Publication number
- CN101119980A CN101119980A CNA2005800482643A CN200580048264A CN101119980A CN 101119980 A CN101119980 A CN 101119980A CN A2005800482643 A CNA2005800482643 A CN A2005800482643A CN 200580048264 A CN200580048264 A CN 200580048264A CN 101119980 A CN101119980 A CN 101119980A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- benzothiazole
- methane amide
- compound
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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Abstract
本发明涉及式I的新化合物或其盐、溶剂化物或溶剂化盐,式中R1~R4、m、n和p如说明书中所定义的,其制备方法及其制备中使用的新的中间体,包含所述化合物的药物组合物,及所述化合物在治疗中的用途。
Description
技术领域
本发明涉及新化合物,涉及含有所述化合物的药物组合物,以及涉及所述化合物在治疗中的用途。本发明进一步涉及用于制备所述化合物的方法,以及涉及在其制备中所用的新中间体。
背景技术
哺乳动物痛觉是由于激活特化感觉神经元(称为伤害性感受器)群体的末梢而引起的。辣椒辣素(Capsaicin)--尖辣椒中的活性成分--引起伤害性感受器的持久活化,并还在人类中引起剂量依赖性痛觉。克隆香草素受体1(VR1或TRPV1)表明,VR1是辣椒辣素及其类似物的分子靶标。(Caterina,M.J.等人Nature(1997)v.389 p 816-824)。使用VR1的功能研究表明,它还被有害的热、组织酸化作用和其它炎症介质激活(Tominaga,M.等人Neuron(1998)v.21,p.531-543)。VR1的表达还在导致神经性疼痛的类型的外周神经损伤后被调节。VR1的这些性质使它成为对于疼痛和对于包括炎症的疾病的高度相关的靶标。尽管VR1受体的激动剂可通过伤害性感受器破坏而充当镇痛药,但激动剂如辣椒辣素及其类似物的使用由于它们的刺激性、神经毒性和低温麻醉(induction of hypothermia)作用而受到限制。但是,证明阻断VR1活性的药物应当是更有用的。拮抗剂将保持止痛特性,但避免刺激性和神经毒性副作用。
具有VR1抑制剂活性的化合物被认为在治疗和/或预防下述病症具有潜在的应用,例如疼痛,特别是炎症性起源或创伤性起源(origin)的疼痛如关节炎、局部缺血(ischaemia)、纤维肌痛、腰(背)痛和术后痛(Walker等人JPharmacol Exp Ther.(2003)Jan;304(1):56-62)。除此之外,内脏痛如慢性骨盆痛,膀胱炎,过敏性肠综合征(irritable bowel syndrome,IBS),胰腺炎等,以及神经性疼痛如坐骨神经痛(sciatia),糖尿病性神经病,HIV神经病,多发性硬化症等(Walker等人,文献同上,J Pharmacol Exp Ther.(2003)Mar;304(3):940-8)是可利用VR1抑制作用来治疗可能疼痛状态。这些化合物也被认为可潜在性地用于炎症性疾病如哮喘、咳嗽、炎症性肠病(IBD)(Hwang等人Curr Opin Pharmacol(2002)Jun;2(3):235-42)。具有VR1阻断剂活性的化合物也可用于瘙痒和皮肤病如银屑病以及用于胃食管回流病(GERD)、呕吐、尿失禁和膀胱活动过度症(hyperactive bladder)(Yiangou等人BJU Int(2001)Jun;87(9):774-9,Szallasi Am J Clin Pathol(2002)118:110-21)。VR1抑制剂还可潜在地用于治疗和/或预防暴露于VR1活化剂如辣椒辣素或催泪气、酸或热的作用(Szallasi文献同上)。
VR1拮抗剂在炎症性肠病(inflammatory bowel disease,IBD)中的作用进一步被下列发现所支持:在DSS结肠炎模型中,与对照组相比,经皮下给药辣椒辣素至新生大鼠,以对初级感觉神经元去神经化,导致疾病活性指数(DAI)、MPO以及对肠道的组织损伤降低(N Kihara,et al.,Gut,2003.52:p.713-719)。TRPV1拮抗剂在小鼠DSS结肠炎模型中缓解宏观症状(E.S.KIMBALL,et al.,Neurogastroenterol Motil,2004.16:p.1-8)。
已经记载过VR1拮抗剂在过敏性肠综合征(IBS)中的潜在作用。发现排便急和直肠超敏反应的患者在肌肉、粘膜下层和粘膜层的神经纤维中TRPV1表达水平升高。这同样与对热和膨胀的敏感性升高有关(C L H Chan,et al.,THE LANCET,2003.361(Feb 1):p.385-91)。在TRPV1-/-大鼠中,空肠广动力范围(WDR)传入神经元对体外压力表现出较低的激发(firing)(Rong W,H.K.,et al.,J Physiol(Lond).2004.560:p.867-881)。利用急骤膨胀(rampdistension)和阶段性膨胀,TRPV1拮抗剂影响对空肠和结肠直肠膨胀的内脏运动反应(Winchester,EMG response to jejunal and colorectal distension in ratare affected by a TRPV1 antagonist in both ramp and phasic distensions.DDWabstract,2004)。在人实验模型中,施用于回肠的辣椒辣素引起疼痛和机械性痛觉过敏(Asbjrn Mohr Drewes,et al.,Pain,2003.104:p.333-341)。
文献中已经提及VR1拮抗剂在胃食管回流病(GERD)中的作用。发现患有食管炎的患者在削弱食管上皮外周神经中具有升高水平的TRPV1表达(P.J.Matthews,et al.,European J.of Gastroenterology & Hepatology,2004.16:p.897-902)。即使TRPV1拮抗剂JYL1421仅对酸引起的食管传入神经激发具有较小的作用,具有不同形态的拮抗剂仍然需要评价。由于TRPV1似乎在机械感觉中发挥作用,因此可能的情况是拮抗剂会抑制TLESR(胃食管反流的主要原因)。
进一步的潜在应用涉及对VR1活化剂耐受性的治疗。
VR1抑制剂还可用于治疗间质性膀胱炎及与间质性膀胱炎有关的疼痛。
发明内容
本发明的目的是提供对香草素受体1(VR1)具有抑制活性的化合物
本发明提供式I化合物或其盐、溶剂化物或溶剂化盐(solvated salt):
式中:
环P为C6-10芳基,C3-11环烷基或C5-10杂芳基;
R1为H,C1-4烷基,羟基C1-6烷基,C1-6烷基OC0-6烷基,COOC0-6烷基,NH2,NHC1-6烷基,N(C1-6烷基)2,NH(芳基)or N(芳基)2;
R2为H,C1-4烷基,卤素,羟基C0-6烷基或C1-6烷基OC0-6烷基;
m为0,1、2或3;
n为0,1,2,3,4或5;
R3为NO2,NH2C0-6烷基,卤素,N(C1-6烷基)2C0-6烷基,C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-6卤代烷基O,C5-6芳基C0-6烷基,C5-6杂芳基C0-6烷基,C3-7环烷基C0-6烷基,C3-7杂环烷基C0-6烷基,C1-6烷基OC0-6烷基,C1-6烷基SC0-6烷基,C1-6烷基NC0-6烷基,(C0-6烷基)2NC(O)C0-6烷基,(C0-6烷基)2OC(O)C0-6烷基或(C0-6烷基)2C(O)OC0-6烷基;
p为1,2,3,4或5;及
R4为H,C1-6烷基,芳基C0-6烷基,C1-6烷基OC0-6烷基或N(C1-6烷基)2C0-6烷基。
本发明的一个实施方案涉及式Ib的化合物,其中R1、R3、m和p如上面所定义的,及n为0且R2和R4为H。
本发明的一个实施方案涉及式Ic的化合物,其中R1、R3、m和p如上面所定义的,及n为1、2、3、4或5且R2和R4为H。
在本发明的进一步实施方案中,P为苯基。
在本发明的另一实施方案中,R1为甲基或羟基C1-3烷基。在一个实施方案中,R1为甲基、羟甲基、羟乙基或羟丙基。
在另一实施方案中,n为0、1或2。
在又一实施方案中,R3为卤素,C1-3烷基,C1-3卤代烷基,C5-6芳基,C1-2烷基O或(C0-6烷基)2NC(O)C0-6烷基。
在另一实施方案中,R3为叔丁基,苯基,氟甲基,二氟甲基或三氟甲基。
本发明的一个实施方案涉及选自下列的化合物:
N-4-叔丁基苯基-2-甲基-1,3-苯并噻唑-5-甲酰胺,
N-4-环己基苯基-2-甲基-1,3-苯并噻唑-5-甲酰胺,
2-甲基-N-[2-甲基-4-三氟甲基苯基]-1,3-苯并噻唑-5-甲酰胺,
2-甲基-N-[4-三氟甲基苯基]-1,3-苯并噻唑-5-甲酰胺,
2-甲基-N-[3-三氟甲基苯基]-1,3-苯并噻唑-5-甲酰胺,
2-甲基-N-[2-三氟甲基苄基]-1,3-苯并噻唑-5-甲酰胺,
2-甲基-N-[4-三氟甲基苄基]-1,3-苯并噻唑-5-甲酰胺,
2-甲基-N-[3-三氟甲基苄基]-1,3-苯并噻唑-5-甲酰胺,
N-4-甲氧基-2-萘基-2-甲基-1,3-苯并噻唑-5-甲酰胺,
N-4-叔丁基苯基-2-羟基甲基-1,3-苯并噻唑-5-甲酰胺,
N-(4-溴苯基)-2-甲基-1,3-苯并噻唑-5-甲酰胺,
2-甲基-N-[2-(4-甲基苯基)乙基]-1,3-苯并噻唑-5-甲酰胺,
N-[2-(3-氟苯基)乙基]-2-甲基-1,3-苯并噻唑-5-甲酰胺,
N-(5-异丙氧基-1-萘基)-2-甲基-1,3-苯并噻唑-5-甲酰胺,
2-甲基-N-{2-[4-(三氟甲基)苯基]乙基}-1,3-苯并噻唑-5-甲酰胺,
N-[2-(4-乙基苯基)乙基]-2-甲基-1,3-苯并噻唑-5-甲酰胺,
N-[2-(4-氟苯基)乙基]-2-甲基-1,3-苯并噻唑-5-甲酰胺,
N-[2-(4-叔丁基苯基)乙基]-2-甲基-1,3-苯并噻唑-5-甲酰胺,
N-[2-(4-甲氧基苯基)乙基]-2-甲基-1,3-苯并噻唑-5-甲酰胺,
N-(4-异丙基苯基)-2-甲基-1,3-苯并噻唑-5-甲酰胺,
N-[2-(4-氯苯基)乙基]-2-甲基-1,3-苯并噻唑-5-甲酰胺,
N-[2-(3,4-二氯苯基)乙基]-2-甲基-1,3-苯并噻唑-5-甲酰胺,
N-4-叔丁基苯基-2-羟基甲基-1,3-苯并噻唑-5-甲酰胺,
2-(羟基甲基)-N-[2-(4-甲基苯基)乙基]-1,3-苯并噻唑-5-甲酰胺,及
N-[2-(3-氟苯基)乙基]-2-(羟基甲基)-1,3-苯并噻唑-5-甲酰胺
或其盐、溶剂化物或溶剂化盐。
为了避免疑问,应当理解,在本说明书中,如果基团被修饰成“如本文中所定义的”、“如前文所定义的”或“如上面所定义的”,则该基团包括首次出现和最宽泛的定义以及有关该基团每个和所有其它定义。
为了避免疑问,应当理解,在说明书中‘C1-6’表示具有1、2、3、4、5或6个碳原子的碳基团。
在本说明书中,除非另有说明,术语“烷基”包括直链和支链烷基,并可为但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、叔戊基、新戊基、正己基、异己基或叔己基。术语具有1-3个碳原子的“C1-3烷基”可为甲基、乙基、正丙基或异丙基。
术语‘C0’代表化学键或不存在。例如当R3为C0烷基时,R3为化学键,并且“芳基C0烷基”等价于“芳基”,“C2烷基OC0烷基”等价于“C2烷基O”。
在本说明书中,除非另有说明,术语“烯基”包括直链和支链的烯基基团。术语具有2-6个碳原子和一个或两个双键的“C2-6烯基”,可为但不限于乙烯基、烯丙基、丙烯基、丁烯基、巴豆基(crotyl)、戊烯基或己烯基,并且丁烯基可为例如丁烯-2-基、丁烯-3-基或丁烯-4-基。
在本说明书中,除非另有说明,术语“炔基”包括直链和支链的炔基基团。术语具有2-6个碳原子和一个或两个叁键的“C2-6炔基”,可为但不限于乙炔基、炔丙基、戊炔基或己炔基,并且丁炔基可为例如丁炔-3-基或丁炔-4-基。
术语“环烷基”指的是任选取代的饱和环烃环系。术语“C3-7环烷基”可为环丙基、环丁基、环戊基、环己基或环庚基。
在本说明书中,除非另有说明,术语“杂环烷基”表示3-至7-元非芳族的、部分或全部饱和的烃基,其含有一个环和至少一个杂原子。所述杂环的实例包括但不限于吡咯烷基、吡咯烷酮基(pyrrolidonyl)、哌啶基、哌嗪基、吗啉基、唑基、2-唑烷酮基或四氢呋喃基。
在本说明书中,除非另有说明,术语“芳基”指的是任选取代的单环或二环烃不饱和芳族环系。“芳基”的实例可为但不限于苯基和萘基。
在本说明书中,除非另有说明,术语“杂芳基”指的是任选取代的单环或二环环系,其中至少一个环是芳族的,且其含有至少一个独立地选自N、O或S的杂原子。“杂芳基”的实例可为但不限于吡啶基、吡咯基、呋喃基、噻吩基、咪唑基、唑基、异唑基、噻唑基、吡唑基、苯并呋喃基、吲哚基、异吲哚基、苯并咪唑基、哒嗪基、嘧啶基、吡嗪基、四唑基、三唑基或唑基。
在本说明书中,除非另有说明,术语“杂芳基烷基”和“苯基烷基”指的是通过烷基与芳基或杂芳基基团相连的取代基。
在本说明书中,除非另有说明,术语“卤代(halo)”和“卤素(halogen)”可以是氟、碘、氯和溴。
在本说明书中,除非另有说明,术语“卤代烷基”指的是如上定义的烷基,其被如上定义的卤素所取代。术语“C1-6卤代烷基”可包括但不限于氟甲基、二氟甲基、三氟甲基、氟乙基、二氟乙基或溴代丙基。术语“C1-6卤代烷基O”可包括但不限于氟代甲氧基、二氟甲氧基、三氟甲氧基、氟代乙氧基或二氟乙氧基。
除非在本说明书中另有说明外,本说明书中使用的命名法通常遵循Nomenclature of Organic Chemistry,Sections A,B,C,D,E,F,and H,PergamonPress,Oxford,1979中规定的实例和规则,在此将示例性的化学结构和命名化学结构的规则引入本文作为参考。
本发明涉及如上所定义的式I化合物及其盐、溶剂化物或溶剂化盐。用于药物组合物的盐可为药用的盐,但其它盐也可用于制备式I化合物。
本发明化合物的合适药用的盐为例如酸加成盐,例如与无机或有机酸形成的酸加成盐。此外,本发明化合物的合适的药用的盐为碱金属盐、碱土金属盐或与有机碱形成的盐。
其它药用的盐和这些盐的制备方法可,参见例如Remington’sPharmaceutical Sciences(18th Edition,Mack Publishing Co.)。
一些式I化合物可具有手性中心和/或几何异构中心(E-和Z-异构体),并且应当理解本发明包括所有这样的旋光异构体、非对映异构体和几何异构体。
本发明还涉及式I化合物的任何以及所有互变异构形式。
医药用途
意料不到地,已发现本发明的化合物可用于治疗。式I化合物,或其盐、溶剂化物或溶剂化盐以及它们相应的活性代谢产物对单独的香草素受体1(VR1)组显示出高度的效能和选择性。因此,预期本发明的化合物可用于治疗与香草素受体1(VR1)的刺激性激活(excitatory activation)有关的病症。
该化合物可用于在哺乳动物包括人中产生VR1的抑制作用。
VR1在外周神经系统和其它组织中被高度表达。因此,预期本发明化合物很好地适于治疗VR1介导的病症。
预期式I化合物适于治疗急慢性疼痛(acute and chronic pain)、急慢性神经性疼痛(acute and chronic neuropathic pain)和急慢性炎性疼痛(acute andchronic inflammatory pain)。这类病症的实例可选自:关节炎,类风湿性关节炎,脊椎炎和痛风,纤维肌痛,腰背痛和坐骨神经痛,术后痛,癌痛(cancerpain),偏头痛和紧张性头痛,内脏痛如慢性骨盆痛,膀胱炎包括间质性膀胱炎,胰腺炎,肾绞痛和胆绞痛,月经有关的疼痛(menstruation associated pain),与局部缺血和心绞痛有关的疼痛,神经性疼痛病症如糖尿病性神经病、HIV神经病、化疗引起的神经病、疱疹后神经痛、创伤后神经痛(post traumaticneuralgia)和复杂的局部综合征(complex regional syndrome),以及瘙痒(itch)。
进一步有关的病症可以选自:胃食管回流病(GERD),机能性胃肠病症(functional gastrointestinal disorders,FGD),例如过敏性肠综合征(IBS),炎症性肠病(IBD),和机能性消化不良(functional dyspepsia,FD)。
进一步的病症实例为膀胱活动过度(“overactive bladder,OAB”),其是包括欲望性尿失禁,尿急和尿频的综合征的术语。本发明的化合物可以缓解尿失禁(“UI”),即无意识的尿遗失,其起因于膀胱无力保存尿,结果或者是强烈欲望(欲望性尿失禁)或者是身体或精神紧张(压迫性尿失禁)。
其它有关病症可以是银屑病和呕吐。
其它相关的疾病是与呼吸系统疾病相关的,可选自咳嗽、哮喘、慢性阻塞性肺部疾病和肺气肿、肺纤维化和间质性肺病。
用于呼吸用途的VR1抑制剂可口服或吸入给药。呼吸系统疾病可是急性和慢性的疾病,与感染和/或暴露在环境污染物中和/或刺激物有关。
式I化合物也可用作抗毒素以治疗在VR1活化剂如辣椒辣素、催泪气、酸或热中的(过度-)暴露。对于热,VR1拮抗剂对(阳光-)烧伤引起的疼痛,或由烧伤导致的炎性疼痛具有潜在作用。
该化合物还可进一步用于治疗对VR1活化剂的耐受。
本发明的一个实施方案涉及如上所定义的式I化合物在治疗中的用途。
本发明的另一个实施方案涉及如上所定义的式I化合物用于治疗VR1介导的病症的用途。
本发明的另一个实施方案涉及如上所定义的式I化合物用于治疗急慢性疼痛的用途。
本发明的另一个实施方案涉及如上所定义的式I化合物用于治疗急慢性神经性疼痛的用途。
本发明的另一个实施方案涉及如上所定义的式I化合物用于治疗急慢性炎性疼痛的用途。
本发明的一个实施方案涉及前文中所定义的式I化合物用于治疗下列疾病的用途:关节炎,类风湿性关节炎,脊椎炎和痛风,纤维肌痛,腰背痛和坐骨神经痛,术后痛,癌痛,偏头痛和紧张性头痛,内脏痛如慢性骨盆痛,膀胱炎包括间质性膀胱炎,胰腺炎,肾绞痛和胆绞痛,月经有关的疼痛,与局部缺血和心绞痛有关的疼痛,神经性疼痛病症如糖尿病性神经病、HIV神经病、化疗引起的神经病、疱疹后神经痛、创伤后神经痛和复杂的局部综合征,以及瘙痒。
本发明的另一实施方案涉及前文中所定义的式I化合物用于治疗下列的疾病的用途:胃食管回流病,功能性胃肠病症,过敏性肠综合征,炎症性肠病,及机能性消化不良。
本发明的其它实施方案涉及前文中所定义的式I化合物用于治疗膀胱活动过度的用途。
本发明的另一个实施方案涉及如上所定义的式I化合物用于治疗选自下列的呼吸系统疾病的用途:咳嗽,哮喘,慢性阻塞性肺部疾病和肺气肿,肺纤维化和间质性肺病。
本发明的一个实施方案涉及如上所定义的式I化合物在制备用于治疗VR1介导的病症和治疗急慢性疼痛、急慢性神经性疼痛、急慢性炎性疼痛和呼吸系统疾病,以及上述任何其它病症的药物中的用途。
本发明的另一个实施方案涉及治疗VR1介导的病症和急慢性疼痛、急慢性神经性疼痛、急慢性炎性疼痛和呼吸系统疾病,以及上述任何其它病症的方法,所述方法包括对需要所述治疗的哺乳动物(包括人)给药治疗有效量的如上所定义的式I化合物。
本发明另一个实施方案涉及一种药物组合物,其包括如上所定义的式I化合物,所述药物组合物用于治疗VR1介导的病症以及用于治疗急慢性疼痛、急慢性神经性疼痛、急慢性炎性疼痛和呼吸系统疾病,以及上述任何其它病症。
在本说明书的上下文中,除非另有说明与此相反,术语“疗法(therapy)”和“治疗(treatment)”包括防止(prevention)和预防(prophylaxis)。术语“治疗”、″治疗的″和″治疗地″也应相应地解释。
在本说明书中,除非另有说明,术语“抑制剂”和“拮抗剂”是指以任何方式,部分或完全地,阻断导致产生配体响应的传导路径的化合物。
术语“病症”或“疾病”,除非另有说明,是指与香草素受体活性相关的任何病症和疾病。
非医药用途
除用于治疗药物外,本发明的化合物、或其盐、溶剂化物或溶剂化盐还用作药理学工具,用于在实验动物,如猫、狗、家兔、猴、大鼠和小鼠中评价VR1相关活性的抑制剂作用的体外和体内测试系统的开发和标准化,作为寻找新治疗剂的组成部分。
药物组合物
根据本发明的一个实施方案,提供了一种药物组合物,其包括作为活性成分的治疗有效量的式I化合物,或其盐、溶剂化物或溶剂化盐,以及结合有一种或多种药用的稀释剂、赋形剂和/或惰性载体。
所述组合物可为适于口服给药的形式,例如为片剂、丸剂、糖浆剂、粉剂、颗粒剂或胶囊剂,适于肠胃外注射(包括静脉内、皮下、肌内、血管内或输注)给药的形式,为无菌溶液、混悬液或乳剂;适于局部给药的形式,例如作为软膏剂、贴片(patch)或霜膏剂;或适于直肠给药的形式,例如为栓剂。
通常,上述组合物可使用一种或多种常规的赋形剂、药用的稀释剂和/或惰性载体,按照常规的方法制备得到。
在治疗哺乳动物包括人时,式I化合物的合适日剂量,口服给药时为约0.01-250mg/kg体重,肠胃外给药时为约0.001-250mg/kg体重。
活性成分的典型日剂量在宽范围内变化,并取决于各种因素,如相关的适应症、所治疗的疾病的严重程度、给药途径、患者的年龄、体重和性别以及所用的具体化合物,以及可由医师确定。
药物组合物的实例
以下说明含有式I化合物,或其盐、溶剂化物或溶剂化盐(下文中化合物X)的代表性的药物剂型,其用于哺乳动物的预防或治疗用途:
(a):片剂 | mg/片剂 |
化合物X | 100 |
乳糖 | 182.75 |
交联羧甲基纤维素钠 | 12.0 |
玉米淀粉糊剂(5%w/v糊剂) | 2.25 |
硬脂酸镁 | 3.0 |
(b):胶囊 | mg/胶囊 |
化合物X | 10 |
乳糖 | 488.5 |
硬脂酸镁 | 1.5 |
(c):注射剂 | (50mg/ml) |
化合物X | 5.0%w/v |
1M氢氧化钠溶液 | 15.0%v/v |
0.1M盐酸 | (pH调至7.6) |
聚乙二醇400 | 4.5%w/v |
注射用水 | 至100% |
上述组合物可通过药学领域中熟知的常规操作制备得到。
制备方法
一般制备方法
本发明的一个实施方案涉及式I化合物的制备方法,式中R1~R4、m、n和p如上面所定义的,该方法包括:
a-i)通过金属卤素交换氰化式IIa的化合物。
该反应可以以本领域的技术人员已知的任何方式进行。氰化物的形成可通过钯催化反应由氰化锌来进行。
a-ii)式(IIc)的芳胺与亚硝酸钠在诸如HCl、H2SO4或TFA的酸存在下反应,得到重氮中间体(III),其就地与二氧化硫或者在氯化铜存在下反应,得到式(IV)的氰化物。
该反应可以以本领域的技术人员已知的任何方式进行。
适用于该反应的溶剂可以是水,丙酮,有机酸如乙酸和TFA,或者它们的混合物。温度可以为0~10℃,反应时间可以为0.5~30小时。
b)水解式(IV)的芳族氰化物,得到式(V)的羧酸。
该反应可以以本领域的技术人员已知的任何方式进行。在酸性条件下,合适的溶剂可以为水、盐酸、硫酸或者它们的混合物。作为选择,也可以在碱性条件下,通过与适宜的无机碱在水或有机溶剂(如甲醇、乙醇、异丙醇、叔丁醇或它们的混合物)反应来进行。温度可以为70~100℃。
其中halo为卤素
c)在金属卤素交换之后,用二氧化碳羰基化,得到式(V)的化合物。
该反应可以以本领域的技术人员已知的任何方式进行。金属卤素交换可通过烷基锂或二烷基镁实现。适用于该反应的溶剂可以为醚类如乙醚、四氢呋喃和二氧己环(dioxin)或者其任意混合物。温度可以为-60~-70℃,反应时间可以为1~3小时。锂或镁物质可与气体或固体的二氧化碳反应。
d)使式(VI)的芳族酰氯与适当取代的式(VII)的胺反应。
该反应可以以本领域的技术人员已知的任何方式进行。
适用于该反应的溶剂可以是叔胺如二甲基甲酰胺和二甲基乙酰胺,卤代烃如氯仿、二氯甲烷和二氯乙烷,芳族或杂芳族化合物如苯、甲苯、二甲苯、吡啶和二甲基吡啶,或者醚类如乙醚、四氢呋喃和二氧己环,或者它们的任意混合物。也可以使用催化剂,例如杂芳族碱如吡啶和二甲基吡啶或者叔胺如三乙胺、N-甲基吗啉和乙基二异丙基胺。温度可以为10~60℃,反应时间可以为3~30小时。
e)使式(V)的羧酸与式(VII)的芳胺反应。
适用于该反应的溶剂可以是叔胺如二甲基甲酰胺和二甲基乙酰胺,卤代烃如氯仿、二氯甲烷和二氯乙烷,或者芳族或杂芳族化合物如苯、甲苯、二甲苯、吡啶和二甲基吡啶,或者为醚类如乙醚、四氢呋喃和二氧己环,也可以是它们的任意混合物。同样可以使用催化剂,例如杂芳族碱如吡啶和二甲基吡啶或者叔胺如三乙胺、N-甲基吗啉和乙基二异丙基胺。温度可以为10~60℃,反应时间可以为3~30小时。
中间体
本发明的其它实施方案涉及化合物2-甲基-1,3-苯并噻唑-5-羧酸,该化合物可以用作制备适于治疗VR1介导的病症的化合物的中间体,特别是制备式I化合物的中间体。
实施例
现将通过下面的实施例阐述本发明,在这些实施例中,一般而言:
(i)操作在环境或室温即17~25℃以及惰性气体如氩气气氛下进行,除非另外声明;
(ii)蒸发通过旋转蒸发仪于真空中进行,而且后处理(work-up)程序是在通过过滤除去残余固体之后进行的;
(iii)柱色谱(通过快速操作)在Silicycle硅胶(等级230-400目,60,cat.Numb.R10030B,得自加拿大魁北克Silicycle)上进行,高压液相色谱(HPLC)在C18反相硅胶如Phenomenex(Luna C-18 100制备性反相色谱柱)上进行;
(iv)1H NMR光谱于400或600MHz下记录在Varian或Brucker;
(v)质谱利用电喷雾(LC-MS;LC:Waters 2790,column XTerra MS C8 2.5μm 2.1X30mm,缓冲梯度H2O+0.1%TFA:CH3CN+0.04%TFA,MS:微质量ZMD//乙酸铵缓冲液)电离技术;
(vi)收率,当其存在时,不必是可达到的最大值;
(vii)中间体不必充分纯化,但是其结构和纯度通过薄层色谱、HPLC和/或NMR分析进行评估;
(viii)使用下列缩写:
HPLC 高效液相色谱
LC 液相色谱
MS 质谱
ret.Time 保留时间
AcCl 乙酰氯
DCM 二氯甲烷
DMAP 二甲基氨基吡啶
DMF 二甲基甲酰胺
EtOH 乙醇
EtOAc 乙酸乙酯
EDC 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐
HCl 盐酸
MeOH 甲醇
THF 四氢呋喃
中间体1
2-甲基-1,3-苯并噻唑-5-羧酸。
将2-甲基-5-氨基苯并噻唑(10.0g,61.1mmol)于丙酮(250mL)中的溶液冷却至0℃,加入浓HCl(13.5mL)。向第一溶液中逐份地加入NaNO2(5.22g,75.7mmol)于水(75.0mL)中的溶液。将所得混合物搅拌3分钟,并加入KI(20.4g,123mmol)于水(75.0mL)中的溶液。将该混合物再搅拌10分钟,然后减压浓缩,得到残余物,将该残余物溶解于DCM和MeOH的9∶1混合物中,并用饱和的NaHCO3溶液洗涤。将有机级分用盐水洗涤,用Na2SO4干燥,过滤,减压浓缩,并于在高真空下干燥。将所得的碘化物,ZnCN2(7.17g,61.1mmol)和Pd(PPh3)4(2.00g,1.73mmol)混合于DMF(200mL)中,并在100℃和N2气氛下加热12小时。然后将该溶液冷却至室温,并减压蒸发溶剂。将残余物溶解于DCM并用饱和NaHCO3洗涤,接着用盐水洗涤。将有机相用Na2SO4干燥,过滤并减压浓缩,得到腈。1H NMR(400MHz,氯仿-D)δppm 2.89(s,3H)7.58(dd,J=8.40,1.56Hz,1H)7.93(d,J=8.20Hz,1H)8.22(d,J=0.98Hz,1H);MS[M+]计算值174.0,实测值174.8。将该腈于6.70N HCl(150mL)中的溶液回流12小时。将该溶液冷却至室温,然后减压浓缩。产物经快速色谱于反相硅胶上进行纯化,用EtOH和水的混合物(15/85至90/10)洗脱(4.45g,19.5mmol,三步为32%)。1H NMR(600MHz,DMSO-D6)δppm 2.81(s,3H)7.92(d,J=8.45Hz,1H)8.14(d,J=8.45Hz,1H)8.38(s,1H);MS[M+]计算值193.0,实测值193.8。
实施例1
N-4-叔丁基苯基-2-甲基-1,3-苯并噻唑-5-甲酰胺.
2-甲基-1,3-苯并噻唑-5-羧酸(90.0mg,0.400mml)溶解于DMF(3.00mL),并加入HATU(190mg,0.500mmol),4-叔丁基苯胺(75.0mg,0.500mmol)和Et3N(0.100mL)。将该混合物搅拌3小时,并蒸发溶剂。产物经快速色谱于硅胶上进行纯化,用己烷和EtOAc的混合物(9∶1至4∶1)洗脱,得到产物(42.0mg,0.129mmol,32.0%)。1H NMR(400MHz,DMSO-D6)δppm 1.27(s,9H)2.83(s,3H)4.90-5.18(br s,1H)7.36(d,J=8.98Hz,2H)7.71(dd,J=8.98,2.73Hz,2H)7.96(dd,J=8.40,1.76Hz,1H)8.16(d,J=8.40Hz,1H)8.51(d,J=1.37Hz,1H)10.31(s,1H);MS[M+H]计算值325.0,实测值325.0。
实施例2
N-4-环己基苯基-2-甲基-1,3-苯并噻唑-5-甲酰胺.
将2-甲基-1,3-苯并噻唑-5-羧酸(100mg,0.440mml)溶解于DMF(5.00mL),并加入HATU(190mg,0.500mmol),4-环己基苯胺(88.0mg,0.500mmol)和Et3N(0.100mL)。将该混合物搅拌3小时,并蒸发溶剂。产物经快速色谱于硅胶上进行纯化,用己烷和EtOAc的混合物(9∶1至4∶1)洗脱,得到几乎纯的产物,将该产物用庚烷和EtOAc重结晶,得到纯净的产物(15.1mg,0.043mmol,10.0%)。1H NMR(400MHz,DMSO-D6)δppm 1.15-1.50(m,5H)1.60-1.83(m,6H)2.82(s,3H)7.18(d,J=8.59Hz,2H)7.67(d,J=8.59,2H)7.94(dd,J=8.40,1.76Hz,1H)8.14(d,J=8.40Hz,1H)8.48(d,J=1.56Hz,1H)10.30(s,1H);MS[M+]计算值350.2,实测值351.0。
实施例3
2-甲基-N-[2-甲基-4-三氟甲基苯基]-1,3-苯并噻唑-5-甲酰胺.
将2-甲基-1,3-苯并噻唑-5-羧酸(90.0mg,0.470mmol)与2-甲基-4-三氟甲基苯胺(123mg,0.700mmol),EDC(134mg,0.700mmol)和DMAP(85.0mg,0.700mmol)在DCM(5.00mL)和DMF(3.00mL)中混合48小时。将该混合物浓缩,产物经快速色谱于硅胶上进行纯化,用庚烷和EtOAc的混合物(95/5至75/25)洗脱,得到产物(14.0mg,0.0400mmol,8.50%)。1H NMR(600MHz,氯仿-D)δppm 2.42(s,3H)2.89(s,3H)7.50(s,1H)7.54(d,J=8.45Hz,1H)7.85-8.05(m,3H)8.32(d,J=8.45Hz,1H)8.41(s,1H);MS[M+H]计算值351.0,实测值351.0。
实施例4
2-甲基-N-[4-三氟甲基苯基]-1,3-苯并噻唑-5-甲酰胺.
将2-甲基-1,3-苯并噻唑-5-羧酸(150mg,0.660mmol)与4-三氟甲基苯胺(209mg,1.30mmol),EDC(249mg,1.30mmol)和DMAP(158mg,1.30mmol)在DCM(5.00mL)和DMF(2.00mL)中混合18小时。将该混合物浓缩,产物经快速色谱于硅胶上进行纯化,用庚烷和EtOAc的混合物(95/5至0/100)洗脱,得到产物(111mg,0.329mmol,50.0%)。1H NMR(600MHz,氯仿-D)δ.ppm 2.85(s,3H)7.55(d,J=8.45Hz,2H)7.84(d,J=8.45Hz,2H)7.94(dd,J=8.45,1.79Hz,1H)8.04(d,J=8.45Hz,1H)8.38(d,J=1.02Hz,1H);MS[M+H]计算值337.0,实测值337.0。
实施例5
2-甲基-N-[3-三氟甲基苯基]-1,3-苯并噻唑-5-甲酰胺.
将2-甲基-1,3-苯并噻唑-5-羧酸(150mg,0.660mmol)与3-三氟甲基苯胺(209mg,1.30mmol),EDC(249mg,1.30mmo1)和DMAP(158mg,1.30mmol)在DCM(5.00mL)和DMF(2.00mL)中混合18小时。将该混合物浓缩,产物经快速色谱于硅胶上进行纯化,庚烷和EtOAc的混合物(95/5至50/25)洗脱,得到产物(58.1mg,0.173mmol,26.2%)。1H NMR(600MHz,氯仿-D)δppm2.83(s,3H)7.33(d,J=7.94Hz,1H)7.45(t,J=7.94Hz,1H)7.85(d,J=7.94Hz,1H)7.90-7.96(m,1H)8.03(t,J=8.19Hz,1H)8.08(s,1H)8.39(s,1H);MS[M+H]计算值337.0,实测值337.0。
实施例6
2-甲基-N-[2-三氟甲基苄基]-1,3-苯并噻唑-5-甲酰胺.
将2-甲基-1,3-苯并噻唑-5-羧酸(150mg,0.660mmol)与2-三氟甲基苄基胺(228mg,1.30mmol),EDC(249mg,1.30mmol)和DMAP(158mg,1.30mmol)在DCM(5.00mL)和DMF(2.00mL)中混合18小时。将该混合物浓缩,产物经快速色谱于硅胶上进行纯化,用庚烷和EtOAc的混合物(95/5至50/25)洗脱,得到(123mg,0.350mmol,53.3%)。1H NMR(600MHz,MeOD)δppm2.85(s,3H)4.70(s,2H)7.29-7.35(m,1H)7.43-7.50(m,2H)7.59(d,J=7.68Hz,1H)7.87-7.92(m,J=8.71Hz,1H)8.03(d,J=8.45Hz,1H)8.31(s,1H);MS[M+H]计算值351.0,实测值351.0。
实施例7
2-甲基-N-[4-三氟甲基苄基]-1,3-苯并噻唑-5-甲酰胺.
将2-甲基-1,3-苯并噻唑-5-羧酸(150mg,0.660mmol)与4-三氟甲基苄基胺(228mg,1.30mmol),EDC(249mg,1.30mmol)和DMAP(158mg,1.30mmol)在DCM(5.00mL)和DMF(2.00mL)中混合18小时。将该混合物浓缩,产物经快速色谱于硅胶上进行纯化,用庚烷和EtOAc的混合物(95/5至50/25)洗脱,得到产物(114mg,0.325mmol,49.2%)。1H NMR(600MHz,MeOD)δppm 2.84(s,3H)4.56(s,2H)7.43(d,J=7.94Hz,2H)7.51(d,J=8.19Hz,2H)7.88(d,J=8.45Hz,1H)8.02(dd,J=8.45,2.30Hz,1H)8.27-8.33(m,J=1.02Hz,1H);MS[M+H]计算值351.0,实测值351.0。
实施例8
2-甲基-N-[3-三氟甲基苄基]-1,3-苯并噻唑-5-甲酰胺.
将2-甲基-1,3-苯并噻唑-5-羧酸(150mg,0.660mmol)与3-三氟甲基苄基胺(228mg,1.30mmol),EDC(249mg,1.30mmol)和DMAP(158mg,1.30mmol)在DCM(5.00mL)和DMF(2.00mL)中混合18小时。将该混合物浓缩,产物经快速色谱于硅胶上进行纯化,用庚烷和EtOAc的混合物(95/5至50/50)洗脱,得到(131mg,0.370mmol,57.0%)。1H NMR(600MHz,MeOD)δppm2.84(s,3H)4.56(s,2H)7.43(s,2H)7.53(d,J=7.42Hz,1H)7.56(s,1H)7.87(dd,J=8.45,1.54Hz,1H)8.01(d,J=8.45Hz,1H)8.29(s,1H);MS[M+H]计算值351.0,实测值351.0。
实施例9
N-4-甲氧基-2-萘基-2-甲基-1,3-苯并噻唑-5-甲酰胺.
将2-甲基-1,3-苯并噻唑-5-羧酸(200mg,1.03mmol)与4-甲氧基萘-2-胺(358mg,1.03mmol),EDC(240mg,1.25mmol)和DMAP(153mg,1.25mmol)在DCM(10.0mL)中混合18小时。将该混合物浓缩,产物经快速色谱于硅胶上进行纯化,用庚烷和EtOAc的混合物(95/5至75/25)洗脱,得到产物(95.0mg,0.270mmol,27.0%)。1H NMR(600MHz,DMSO-D6)δppm 2.87(s,3H)3.99(s,3H)7.38-7.43(m,1H)7.46(d,J=2.05Hz,1H)7.48-7.53(m,1H)7.82(d,J=8.19Hz,1H)8.01-8.10(m,2H)8.16(d,J=4.86Hz,1H)8.22(d,J=8.45Hz,1H)8.62(d,J=1.28Hz,1H)10.53(s,1H);MS[M+H]计算值349.0,实测值349.0。
实施例10-21
下面的实施例通过实施例1~9的一般方法,利用2-甲基-1,3-苯并噻唑-5-羧酸(中间体1)和下表中所示的适宜胺制备。
实施例 | 化学名称 | 计算质量数 | 测量质量数 | 质子NMR | 胺 |
10 | N-(4-溴苯基)-2-甲基-1,3-苯并噻唑-5-甲酰胺 | 347.0 | 346.7 | (600MHz,DMSO-D6)δppm 2.84(s,3H)7.55(d,J=8.70Hz,2H)7.80(d,J=8.70Hz,2H)7.96(d,J=8.19Hz,1H)8.19(d,J=8.45Hz,1H)8.52(s,1H)10.49(s,1H) | (4-溴苯基)胺 |
11 | 2-甲基-N-[2-(4-甲基苯基)乙基]-1,3-苯并噻唑-5-甲酰胺 | 311.1 | 311.0 | (600MHz,DMSO-D6)δppm 2.26(s,3H)2.80-2.85(m,5H)3.49(q,J=6.66Hz,2H)7.09-7.15(m,4H)7.85(d,J=8.45Hz,1H)8.11(d,J=8.19Hz,1H)8.35(s,1H)8.71(s,1H) | [2-(4-甲基苯基)乙基]-胺 |
12 | N-[2-(3-氟苯基)乙基]-2-甲基-1,3-苯并噻唑-5-甲酰胺 | 315.1 | 315.0 | (600MHz,DM SO-D6)δppm 2.83(s,3H)2.90(t,J=7.17Hz,2H)3.54(q,J=6.91Hz,2H)7.01-7.06(m,1H)7.10(t,J=6.91Hz,2H)7.31-7.36(m,1H)7.84(dd,J=8.45,1.28Hz,1H)8.11(d,J=8.45Hz,1H)8.34(s,1H)8.72(t,J=5.12Hz,1H) | [2-(3-氟苯基)乙基]-胺 |
13 | N-(5-异丙氧基-1-萘基)-2-甲基-1,3-苯并噻唑-5-甲酰胺 | 377.1 | 377.0 | (400MHz,DMSO-D6)δppm 1.29(d,J=6.05Hz,6H)2.86(s,3H)4.62-4.73(m,1H)7.21(dd,J=8.89,2.44Hz,1H)7.28(d,J=2.15Hz,1H)7.38(t,J=7.71Hz,1H)7.55(d,J=7.23Hz,1H)7.78(d,J=8.01Hz,1H)7.90(d,J=8.98Hz,1H)8.06(dd,J=8.30,1.46Hz,1H)8.22(d,J=8.40Hz,1H)8.63(s,1H)10.46(s,1H) | 5-异丙氧基萘-1-胺 |
实施例 | 化学名称 | 计算质量数 | 测量质量数 | 质子NMR | 胺 |
14 | 2-甲基-N-{2-[4-(三氟甲基)苯基]乙基}-1,3-苯并噻唑-5-甲酰胺 | 365.1 | 365.0 | (400MHz,CD3OD)δppm 2.85(s,3H)3.03(t,J=7.23Hz,2H)3.67(t,J=7.23Hz,2H)7.47(d,J=8.01Hz,2H)7.60(d,J=8.01Hz,2H)7.79(dd,J=8.40,1.76Hz,1H)8.00(d,J=8.40Hz,1H)8.28(d,J=1.76Hz,1H)。 | {2-[4-(三氟甲基)-苯基]乙基}胺 |
15 | N-[2-(4-乙基苯基)乙基]-2-甲基-1,3-苯并噻唑-5-甲酰胺 | 325.1 | 325.0 | (400MHz,CD3OD).ppm 1.19(t,J=7.62Hz,3H)2.59(q,J=7.62Hz,2H)2.84(s,3H)2.90(t,J=7.42Hz,2H)3.60(t,J=7.42Hz,2H)7.12(d,J=8.20Hz,2H)7.17(d,J=8.20Hz,2H)7.79(dd,J=8.40,1.56Hz,1H)7.99(d,J=8.40Hz,1H)8.28(d,J=1.37Hz,1H)。 | [2-(4-乙基苯基)乙基]-胺 |
16 | N-[2-(4-氟苯基)乙基]-2-甲基-1,3-苯并噻唑-5-甲酰胺 | 315.1 | 315.0 | (400MHz,CD3OD)δppm 2.85(s,3H)2.93(t,J=7.32Hz,2H)3.61(t,J=7.32Hz,2H)7.01(ddd,J=8.89,6.64,2.05Hz,1H)7.23-7.32(m,2H)7.79(dd,J=8.40,1.76Hz,2H)7.99(d,J=8.40Hz,1H)8.27(d,J=1.76Hz,1H)。 | [2-(4-氟苯基)乙基]-胺 |
17 | N-[2-(4-叔丁基苯基)乙基]-2-甲基-1,3-苯并噻唑-5-甲酰胺 | 353.1 | 353.0 | (400MHz,CD3OD)δppm 1.29(s,9H)2.85(s,3H)2.90(t,J=7.42Hz,2H)3.60(t,J=7.42Hz,2H)7.19(d,J=8.20Hz,2H)7.33(d,J=8.40Hz,2H)7.80(d,J=8.40Hz,1H)7.99(d,J=8.40Hz,1H)8.29(s,1H)。 | [2-(4-叔丁基苯基)-乙基]胺 |
18 | N-[2-(4-甲氧基苯基)乙基]-2-甲基-1,3-苯并噻唑-5-甲酰胺 | 327.1 | 327.0 | (400MHz,CD3OD)δppm2.84(s,3H)2.87(t,J=7.44Hz,2H)3.58(t,J=7.32Hz,2H)3.74(s,3H)6.84(d,J=8.79Hz,2H)7.17(d,J=8.59Hz,2H)7.79(dd,J=8.40,1.76Hz,1H)7.98(d,J=8.40Hz,1H)8.27(d,J=1.37Hz,1H)。 | [2-(4-甲氧基苯基)-乙基]胺 |
实施例 | 化学名称 | 计算质量数 | 测量质量数 | 质子NMR | 胺 |
19 | N-(4-异丙基苯基)-2-甲基-1,3-苯并噻唑-5-甲酰胺 | 311.1 | 311.0 | (400MHz,CD3OD)δppm 1.24(d,J=7.0Hz,6H)2.83-2.93(m,1H)2.97(s,3H)7.19-7.26(m,2H)7.55-7.63(m,2H)8.04(dd,J=1.7,8.5Hz,1H)8.15(d,J=8.6Hz,1H)8.46(d,J=1.4Hz,1H) | 4-异丙基苯胺 |
20 | N-[2-(4-氯苯基)乙基]-2-甲基-1,3-苯并噻唑-5-甲酰胺 | 331.0 | 330.8 | (400MHz,CD3OD)δppm 2.86-2.95(m,5H)3.61(t,J=7.3Hz,2H)7.17-7.30(m,4H)7.84(dd,J=1.7,8.5Hz,1H)8.06(d,J=8.6Hz,1H)8.28(d,J=1.8Hz,1H) | [2-(4-氯苯基)-乙基]胺 |
21 | N-[2-(3,4-二氯苯基)乙基]-2-甲基-1,3-苯并噻唑-5-甲酰胺 | 365.0 | 364.8 | (400MHz,CD3OD)δppm 2.86-2.96(m,5H)3.61(t,J=7.1Hz,2H)7.18(dd,J=2.2,8.2Hz,1H)7.37-7.45(m,2H)7.84(dd,J=1.8,8.4Hz,1H)8.06(d,J=8.6Hz,1H)8.27(d,J=1.6Hz,1H) | [2-(3,4-二氟苯基)-乙基]胺 |
实施例22
N-4-叔丁基苯基-2-羟基甲基-1,3-苯并噻唑-5-甲酰胺.
将2-甲基-1,3-苯并噻唑-5-羧酸(430mg,1.89mmol)和SeO2(628mg,5.65mmol)混合于二氧己环(50.0mL)中,并于100℃加热18小时。将该混合物蒸发至干,然后溶解于MeOH(10.0mL)。加入NaBH4(214mg,5.65mmol),并将该混合物搅拌20分钟。将该混合物蒸发至干,并将残余物溶解于DCM(25.0mL)。加入AcCl(599mg,7.60mL),接着加入Et3N(769mg,7.60mmol)。将该混合物搅拌30分钟,然后蒸发至干。将残余物溶解于DCM(25.0mL)并加入苯胺(1.06g,11.3mmol)和Et3N(218mg,2.15mmol)。将该混合物搅拌30分钟,然后用饱和NaHCO3洗涤,接着用1N HCl洗涤。将有机相用Na2SO4干燥,过滤并浓缩,得到几乎纯的化合物(399mg,1.59mmol,84.0%)。将所得产物2-羟基甲基-1,3-苯并噻唑-5-羧酸(150mg,0.600mmol)与4-叔丁基苯胺(173mg,0.900mmol),EDC(110mg,0.900mmol)和DMAP(134mg,0.900mmol)在DCM(5.00mL)中混合12小时。将该混合物用饱和NaHCO3溶液洗涤,用Na2SO4干燥,过滤并浓缩。将残余物溶解于THF(3.00mL),并加入1N的NaOH溶液(3.00mL)。将该混合物搅拌1小时,然后蒸发至干。产物经快速色谱于硅胶上进行纯化,用庚烷和EtOAc的混合物(80/20至50/50)洗脱,得到产物(43.1mg,0.130mmol,两步为22.0%)。1H NMR(600MHz,MeOD)δppm 1.22(s,9H)4.90(s,2 H)7.30(d,J=8.70Hz,2H)7.50(d,J=8.70Hz,2H)7.89(d,J=8.45Hz,1H)8.04(dd,1H)8.37(d,J=1.28Hz,1H);MS计算值[M+H]341.0,实测值341.0。
实施例23
2-(羟基甲基)-N-[2-(4-甲基苯基)乙基]-1,3-苯并噻唑-5-甲酰胺.
将实施例11的2-甲基-N-[2-(4-甲基苯基)乙基]-1,3-苯并噻唑-5-甲酰胺(280mg,0.9mmol)溶解于10mL的二氧己环。加入研磨过的二氧化硒(485mg,4.37mmol,4.85当量),并将该混合物在密封管中于100℃加热过夜。待冷却至室温之后,将该混合物通过硅藻土过滤(用甲醇洗涤),并将滤液蒸发至干。将残余物溶解于15mL甲醇,小份地加入硼氢化钠(105mg,2.78mmol,3.1当量),并将该混合物搅拌20分钟。蒸发挥发物,将残余物溶解于乙酸乙酯,用水洗涤,用硫酸镁干燥,过滤并蒸发至干。粗产物经反相HPLC(水/乙腈80∶20至5∶95)进行纯化,得到产物(105mg,0.24mmol,27%),其为TFA盐。1H NMR(400MHz,MeOD)δppm 2.29(s,3H)2.89(t,J=7.42Hz,2H)3.60(t,J=7.42Hz,2H)4.97(s,2H)7.10(d,J=7.80Hz,2H)7.15(d,J=7.60Hz,2H)7.81(dd,J=8.40,1.56Hz,1H)8.06(dd,J=8.40,0.59Hz,1H)8.30(dd,J=1.76,0.39Hz,1H);MS[M+H]计算值327.1,实测值327.0。
实施例24
N-[2-(3-氟苯基)乙基]-2-(羟基甲基)-1,3-苯并噻唑-5-甲酰胺.
将实施例12的粗N-[2-(3-氟苯基)乙基]-2-甲基-1,3-苯并噻唑-5-甲酰胺(~1mmol)溶解于10mL的二氧己环。加入研磨过的二氧化硒(485mg,4.37mmol,4.85当量),并将该混合物在密封管中于95℃加热过夜。冷却至室温之后,蒸发挥发物,并将残余物溶解于10mL的甲醇。小份地加入硼氢化钠(105mg,2.78mmol,3.1当量),并将该混合物搅拌20分钟。蒸发挥发物,将残余物溶解于乙酸乙酯,用水洗涤,用硫酸镁干燥,过滤并蒸发至干。粗产物经反相HPLC(水/乙腈70∶30至50∶50)进行纯化,得到产物(87mg,0.2mmol,20%总收率,包括实施例12的制备),其为TFA盐。1H NMR(400MHz,MeOD)ppm 2.29(s,3H)2.89(t,J=7.42Hz,2H)3.60(t,J=7.42Hz,2H)4.97(s,2H)7.10(d,J=7.80Hz,2H)7.15(d,J=7.60Hz,2H)7.81(dd,J=8.40,1.56Hz,1H)8.06(dd,J=8.40,0.59Hz,1H)8.30(dd,J=1.76,0.39Hz,1H););MS[M+H]计算值331.1,实测值331.0。
药理学
1.hVR1 FLIPR(荧光成像板读数计)筛选测定
在实验前24-30小时,在黑色的透明底384板(Greiner)中,将稳定表达hVR1的转染CHO细胞(15,000细胞/孔)接种在50μL培养基中,并在加湿的培养箱(37℃,2%CO2)中生长。
随后,通过倒置将培养基从细胞板中除去,并使用多点加样器(multidrop)(Labsystems)加入2μM Fluo-4。于37℃和2%CO2下避光染色培养40分钟后,使用EMBLA(Scatron)洗掉存在的细胞外染料,细胞剩余在40μL试验缓冲液(1X HBSS,10mM D-葡萄糖,1mMCaCl2’10mM HEPES,10X 7.5%NaHCO3和2.5mM丙磺舒)中。
FLIPR测定-IC50测定方案
对于IC50测定,使用FLIPR filter 1(em 520-545nM)读取荧光。记录细胞基线30秒,随后通过加入20μL的10个滴定试验化合物的半对数稀释浓度,得到细胞浓度范围为3μM至0.1nM。再收集数据5分钟,每2秒收集一次,然后通过FLIPR移液器加入VR1激动剂溶液:50nM的辣椒辣素溶液或MES(2-[N-吗啉代]乙磺酸)缓冲液(pH5.2)。FLIPR继续再收集数据4分钟。对hVR1具有拮抗特性的化合物将抑制响应于辣椒辣素加入的细胞内钙的增加。因而,与没有化合物的缓冲液对照相比,这导致荧光信号的减少并提供了减少的荧光读数。数据由FLIPR程序导出,为通过加入辣椒辣素的曲线所计算的荧光的总和。对于每种化合物得到最大抑制作用、Hill斜率和IC50数据。
采用HEK T-REX hVR1的FLIPR(荧光成像板读数计)筛选试验
使HEK T-REX hVR1诱导性细胞在补充的DMEM培养基(10%FBS,2mM谷氨酰胺,5μg/ml Blasticidine & 350μg/ml Zeocin)中生长。将HEK细胞以10000细胞/孔/50μl或者5500细胞/孔铺板于384-黑色聚赖氨酸涂覆的板(Costar),并于加湿培养箱(5%CO2和37℃)和不含选择试剂的DMEM培养基中分别培养24小时或48小时。在实验前16小时,用0.1μg/ml四环素诱导HEK T-Rex hVR1细胞。
接下来,通过倒置从细胞板上除去培养基并利用多点加样器(Labsystems)加入2μM Fluo-4。在黑暗中于37℃和2%CO2下染色培养30~40分钟后,利用Microplate Washer Skatron Embla 384洗掉存在的细胞外染料,细胞剩余在25μl试验缓冲液中的细胞(不含Ca++/Mg++/钠碳酸氢盐的1X HBSS,1mMCaCl2,及5mM D-葡萄糖)中。
FLIPR试验-IC50测定方案
对于IC50测定,使用FLIPR filter 1(em 520-545nM)读取荧光。记录细胞基线30秒,随后通过加入12.5μL的试验化合物,10点稀释3倍浓度,得到细胞浓度范围为22.5μM至0.1nM。再收集数据5分钟,每2秒收集一次,然后通过FLIPR移液器加入VR1激动剂溶液:20nM(或50nM)的辣椒辣素溶液。FLIPR继续再收集数据4分钟。对hVR1具有拮抗特性的化合物将抑制响应于辣椒辣素加入的细胞内钙的增加。因而,与没有化合物的缓冲液对照相比,这导致荧光信号的减少并提供了减少的荧光读数。数据由FLIPR程序导出,为通过加入辣椒辣素的曲线所计算的荧光的总和。对于每种化合物得到最大抑制作用、Hill斜率和IC50数据。
缩写目录
VR1 香草素受体1
IBS 过敏性肠综合征
IBD 炎症性肠病
GERD 胃食管回流病
HEPES 4-(2-羟基乙基)哌嗪-1-乙磺酸
EGTA 乙二醇-双(2-氨基乙基醚)-N,N,N′,N′-四乙酸
EMBLA Skatron,得自Molecular Devices公司的板孔洗涤器
FLIPR 荧光成像板读数计
HBSS Hank的平衡盐溶液
MES (2-[N-吗啉代]乙磺酸)水合物,Sigma cat# M-5287
NUT 营养混合物F-12,培养细胞的培养基
MEM Minimal Eagle Medium
结果
如上述测定中所测量的,典型的IC50值为10μM或更低。在本发明的一个方面中,IC50低于500nM。
hVR1 FLIPR的测量结果
实施例 | IC50nM(激动剂) |
1 | 226(辣椒辣素) |
7 | 2782(辣椒辣素) |
8 | 1660(辣椒辣素) |
Claims (16)
1.式I化合物或其盐、溶剂化物或溶剂化盐:
式中:
环P为C6-10芳基,C3-11环烷基或C5-10杂芳基;
R1为H,C1-4烷基,羟基C1-6烷基,C1-6烷基OC0-6烷基,COOC0-6烷基,NH2,NHC1-6烷基,N(C1-6烷基)2,NH(芳基)或N(芳基)2;
R2为H,C1-4烷基,卤素,羟基C0-6烷基或C1-6烷基OC0-6烷基;
m为0,1、2或3;
n为0,1,2,3,4或5;
R3为NO2,NH2C0-6烷基,卤素,N(C1-6烷基)2C0-6烷基,C1-6烷基,C2-6烯基,C2-6炔基,C1-6卤代烷基,C1-6卤代烷基O,C5-6芳基C0-6烷基,C5-6杂芳基C0-6烷基,C3-7环烷基C0-6烷基,C3-7杂环烷基C0-6烷基,C1-6烷基OC0-6烷基,C1-6烷基SC0-6烷基,C1-6烷基NC0-6烷基,(C0-6烷基)2NC(O)C0-6烷基,(C0-6烷基)2OC(O)C0-6烷基或(C0-6烷基)2C(O)OC0-6烷基;
p为1,2,3,4或5;及
R4为H,C1-6烷基,芳基C0-6烷基,C1-6烷基OC0-6烷基或N(C1-6烷基)2C0-6烷基。
4.权利要求1或3中任一项的化合物,其中环P为苯基。
5.权利要求1或3中任一项的化合物,其中环R1为甲基或羟基C1-3烷基。
6.权利要求1~3中任一项的化合物,其中R3为叔丁基,苯基,氟甲基,二氟甲基或三氟甲基。
7.化合物或其盐、溶剂化物或溶剂化盐,其中所述化合物选自:
N-4-叔丁基苯基-2-甲基-1,3-苯并噻唑-5-甲酰胺,
N-4-环己基苯基-2-甲基-1,3-苯并噻唑-5-甲酰胺,
2-甲基-N-[2-甲基-4-三氟甲基苯基]-1,3-苯并噻唑-5-甲酰胺,
2-甲基-N-[4-三氟甲基苯基]-1,3-苯并噻唑-5-甲酰胺,
2-甲基-N-[3-三氟甲基苯基]-1,3-苯并噻唑-5-甲酰胺,
2-甲基-N-[2-三氟甲基苄基]-1,3-苯并噻唑-5-甲酰胺,
2-甲基-N-[4-三氟甲基苄基]-1,3-苯并噻唑-5-甲酰胺,
2-甲基-N-[3-三氟甲基苄基]-1,3-苯并噻唑-5-甲酰胺,
N-4-甲氧基-2-萘基-2-甲基-1,3-苯并噻唑-5-甲酰胺,
N-4-叔丁基苯基-2-羟基甲基-1,3-苯并噻唑-5-甲酰胺,
N-(4-溴苯基)-2-甲基-1,3-苯并噻唑-5-甲酰胺,
2-甲基-N-[2-(4-甲基苯基)乙基]-1,3-苯并噻唑-5-甲酰胺,
N-[2-(3-氟苯基)乙基]-2-甲基-1,3-苯并噻唑-5-甲酰胺,
N-(5-异丙氧基-1-萘基)-2-甲基-1,3-苯并噻唑-5-甲酰胺,
2-甲基-N-{2-[4-(三氟甲基)苯基]乙基}-1,3-苯并噻唑-5-甲酰胺,
N-[2-(4-乙基苯基)乙基]-2-甲基-1,3-苯并噻唑-5-甲酰胺,
N-[2-(4-氟苯基)乙基]-2-甲基-1,3-苯并噻唑-5-甲酰胺,
N-[2-(4-叔丁基苯基)乙基]-2-甲基-1,3-苯并噻唑-5-甲酰胺,
N-[2-(4-甲氧基苯基)乙基]-2-甲基-1,3-苯并噻唑-5-甲酰胺,
N-(4-异丙基苯基)-2-甲基-1,3-苯并噻唑-5-甲酰胺,
N-[2-(4-氯苯基)乙基]-2-甲基-1,3-苯并噻唑-5-甲酰胺,
N-[2-(3,4-二氯苯基)乙基]-2-甲基-1,3-苯并噻唑-5-甲酰胺,
N-4-叔丁基苯基-2-羟基甲基-1,3-苯并噻唑-5-甲酰胺,
2-(羟基甲基)-N-[2-(4-甲基苯基)乙基]-1,3-苯并噻唑-5-甲酰胺,及
N-[2-(3-氟苯基)乙基]-2-(羟基甲基)-1,3-苯并噻唑-5-甲酰胺。
8.权利要求1~7中任一项的化合物,其用于治疗。
9.权利要求1~7中任一项的化合物在治疗VR1介导的病症中的用途。
10.权利要求9的用途,其用于治疗急慢性疼痛,急慢性神经性疼痛,及急慢性炎性疼痛。
11.权利要求9的用途,其用于治疗呼吸系统疾病。
12.一种治疗VR1介导的病症以及用于治疗急慢性疼痛、急慢性神经性疼痛和急慢性炎性疼痛以及呼吸系统疾病的方法,该方法包括将治疗有效量的权利要求1~7中任一项的式I化合物给药于需要这种治疗的哺乳动物,所述哺乳动物包括人。
13.一种药物组合物,其包含治疗有效量的权利要求1~7中任一项的式I化合物作为活性成分,以及结合有一种或多种药用稀释剂、赋形剂和/或惰性载体。
14.权利要求13的药物组合物,其用于治疗VR1介导的病症并且用于治疗急慢性疼痛、急慢性神经性疼痛和急慢性炎性疼痛以及呼吸系统疾病。
16.化合物2-甲基-1,3-苯并噻唑-5-羧酸在式I化合物的制备中作为中间体的用途。
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