CN1791405A - 苯并噻唑衍生物及其在治疗涉及腺苷a 2a受体的疾病中的应用 - Google Patents
苯并噻唑衍生物及其在治疗涉及腺苷a 2a受体的疾病中的应用 Download PDFInfo
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- CN1791405A CN1791405A CNA2004800139540A CN200480013954A CN1791405A CN 1791405 A CN1791405 A CN 1791405A CN A2004800139540 A CNA2004800139540 A CN A2004800139540A CN 200480013954 A CN200480013954 A CN 200480013954A CN 1791405 A CN1791405 A CN 1791405A
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- benzothiazole
- methoxyl group
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Abstract
本发明涉及通式(I)化合物及其可药用酸加成盐。该化合物可用于治疗涉及A2A受体的疾病。
Description
本发明涉及通式I化合物及其可药用酸加成盐:
其中
R是未取代的或者被羟基取代的C5,6-环烷基,或者是乙基、异丁基或甲氧基乙基,或者是四氢吡喃-4-基或-(CH2)n-四氢呋喃-2或3-基,或者是5-羟基-二环[2.2.1]庚-2-基;
X是CH或N;
n是0或1。
现出人意料地发现通式I化合物是腺苷受体的配体。具体来说,本发明化合物对A2A-受体具有良好亲和性,并且对A1-和A3受体具有高选择性。
腺苷通过与特定的细胞表面受体相互作用来调节多种生理学功能。在1982年首次提出了腺苷受体作为药物靶点的可能性。腺苷同时在结构学和代谢方面与生物活性的核苷酸三磷酸腺苷(ATP)、二磷酸腺苷(ADP)、一磷酸腺苷(AMP)和环腺苷一磷酸(cAMP)有关;并且同时在结构学和代谢方面与生物化学甲基化试剂S-腺苷-L-甲硫氨酸(SAM)有关;其在结构上与辅酶NAD、FAD和辅酶A有关;并且与RNA有关。腺苷和这些相关的化合物一起对于调节细胞代谢的许多方面以及调节不同的中枢神经系统活性具有重要意义。
腺苷受体被分类成A1、A2A、A2B和A3受体,属于G蛋白偶联的受体家族。腺苷激活腺苷受体引发信号传导机制。这些机制依赖于与G蛋白结合的受体。每一种腺苷受体亚型均通过腺苷酸环化酶效应器系统进行分类表征,该系统使用cAMP作为第二信使。与Gi蛋白偶联的A1和A3受体抑制腺苷酸环化酶,导致细胞cAMP水平降低;而A2A和A2B受体与Gs蛋白偶联并激活腺苷酸环化酶,导致细胞cAMP水平升高。已知A1受体系统包括磷脂酶C的激活以及钾和钙离子通道的调节。A3亚型除了与腺苷酸环化酶结合外,还可以刺激磷脂酶C,从而激活钙离子通道。
由各种物种(犬、人、大鼠、狗、鸡、牛、豚鼠)克隆了A1受体(326-328个氨基酸),在哺乳动物物种之间该受体具有90-95%的序列同一性。由犬、大鼠、人、豚鼠和小鼠克隆了A2A受体(409-412个氨基酸)。由人和小鼠克隆了A2B受体(332个氨基酸),人A2B与人A1和A2A受体具有45%的同源性。由人、大鼠、狗、兔子和绵羊克隆了A3受体(317-320个氨基酸)。
有人提出A1和A2A受体亚型在腺苷对能量供给的调节中起补充作用。腺苷是一种ATP的代谢产物,它从细胞扩散并局部地产生作用而激活腺苷受体,以降低氧的需求(A1)或增加氧供给(A2A),从而恢复组织内能量的供需平衡。两种亚型的作用都是增加组织可以利用的氧的量,并使细胞免受因短时间的氧失衡所引起的损伤。内源性腺苷的一个重要功能是防止创伤例如组织缺氧、局部缺血、低血压和癫痫发作过程中的损伤。
此外,已知腺苷受体激动剂与表达大鼠A3受体的肥大细胞的结合导致三磷酸肌醇和胞内钙浓度增高,这增强了抗原诱导的炎性介质的分泌。因此,A3受体在介导哮喘发作和其它过敏反应中起作用。
腺苷是一种神经调质,它能够调节脑生理功能的多个方面。内源性腺苷—能量代谢与神经元活性之间的中枢连接物—随着行为状态和(病)生理状况而改变。在能量需求增加和能量利用降低的条件下(例如组织缺氧、低血糖和/或过度神经元活性),腺苷提供有力的保护反馈机制。在很多神经和精神疾病例如癫痫、睡眠、运动障碍(帕金森病或亨廷顿舞蹈病)、阿尔茨海默氏病、抑郁症、精神分裂症或成瘾中,与腺苷受体的相互作用代表着治疗干预的有希望的靶点。在创伤例如组织缺氧、局部缺血和癫痫发作之后,神经递质释放增加。这些神经递质最终引起神经变性和神经死亡,这会引起脑损伤或个体死亡。因此,模拟腺苷的中枢抑制作用的腺苷A1激动剂可用作神经保护剂。有人提出腺苷是一种内源性抗惊厥剂,可以抑制兴奋性神经元释放谷氨酸并抑制神经元放电。因此,腺苷激动剂可用作抗癫痫剂。腺苷拮抗剂可以刺激CNS的活性,并且已证实其可用作认知促进剂。选择性A2a拮抗剂在治疗各种形式的痴呆,例如在阿尔茨海默氏病中的痴呆,和神经变性病症例如中风中具有潜在治疗作用。腺苷A2a受体拮抗剂调节纹状体GABA能神经元的活性,并调节平滑肌和良好协调的运动,从而给帕金森病症状提供了可能的治疗。腺苷还参与镇静、催眠状态、精神分裂症、焦虑、疼痛、呼吸、抑郁症和药物成瘾(安非他明、可卡因、阿片样物质、酒精、烟碱、大麻素)所涉及的多种生理学过程。因此,作用于腺苷受体的药物具有作为镇静剂、肌肉松弛剂、抗精神病药、抗焦虑药、镇痛药、呼吸兴奋药、抗抑郁药和治疗药物滥用的潜在治疗价值。它们还可用于治疗ADHD(注意力缺陷-多动症)。
腺苷在心血管系统中的一个重要作用是作为心脏保护剂。内源性腺苷水平会在局部缺血和组织缺氧时增加,并在创伤期间和之后(预适应)保护心脏组织。通过作用于A1受体,腺苷A1激动剂可保护心脏不受心肌缺血和再灌注引起的损伤。A2a受体对肾上腺素能功能的调节影响可涉及多种病症例如冠状动脉疾病和心力衰竭。对于希望提高抗肾上腺素能反应的情形,例如在急性心肌缺血期间,A2a拮抗剂可以有治疗价值。作用于A2a受体的选择性拮抗剂还可以提高腺苷在终止室上性心律失常方面的有效性。
腺苷调节肾功能的许多方面,包括肾素释放、肾小球滤过率和肾脏血流。拮抗腺苷的肾脏作用的化合物是潜在的肾脏保护剂。此外,腺苷A3和/或A2B拮抗剂可以用于治疗哮喘和其它过敏反应,或者可用于治疗糖尿病和肥胖。
许多文献描述了关于腺苷受体的现有知识,例如下列出版物:
Bioorganic & Medicinal Chemistry,6,(1998),619-641,
Bioorganic & Medicinal Chemistry,6,(1998),707-719,
J.Med.Chem.,(1998),41,2835-2845,
J.Med.Chem.,(1998),41,3186-3201,
J.Med.Chem.,(1998),41,2126-2133,
J.Med.Chem.,(1999),42,706-721,
J.Med.Chem.,(1996),39,1164-1171,
Arch.Pharm.Med.Chem.,332,39-41,(1999),
Am.J.Physiol.,276,H1113-1116,(1999)或
Naunyn Schmied,Arch.Pharmacol.362,375-381,(2000)。
本发明的目的是式I化合物本身,式I化合物及其可药用盐在制备用于治疗涉及腺苷A2受体的疾病的药物中的应用,其制备方法,基于本发明化合物的药物及它们的生产方法,以及式I化合物在控制或预防基于腺苷系统的调节作用的疾病中的应用,这些疾病是例如阿尔茨海默氏病、帕金森病、亨廷顿舞蹈病、神经保护、精神分裂症、焦虑、疼痛、呼吸不足、抑郁、药物成瘾例如安非他明、可卡因、阿片样物质、酒精、烟碱、大麻素成瘾,或哮喘、过敏反应、组织缺氧、局部缺血、癫痫发作和物质滥用。此外,本发明化合物还可用作镇静剂、肌肉松弛剂、抗精神病药、抗癫痫药、抗惊厥药和用于病症例如冠状动脉疾病和心力衰竭的心脏保护剂。本发明最优选的适应症是基于A2A受体拮抗活性的那些,包括中枢神经系统病症,例如阿尔茨海默氏病、某些抑郁症、药物成瘾、神经保护和帕金森病以及ADHD的治疗或预防。
术语“可药用酸加成盐”包括与无机酸和有机酸形成的盐,所述酸是例如盐酸、硝酸、硫酸、磷酸、柠檬酸、甲酸、富马酸、马来酸、乙酸、琥珀酸、酒石酸、甲磺酸、对甲苯磺酸等。
本申请的优选化合物是其中的R是任选地被羟基取代的C5,6-环烷基的式I化合物,例如下列化合物:
(反式)-[4-甲氧基-7-(四氢-吡喃-4-基)-苯并噻唑-2-基]-氨基甲酸4-羟基-环己基酯,
(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸环己基酯,
(反式)-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸4-羟基-环己基酯,
(顺式)-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸4-羟基-环己基酯,
或
(顺式/反式)-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸3-羟基-环戊基酯。
其它优选的化合物是其中的R是乙基、异丁基或甲氧基乙基的式I化合物,例如下列化合物:
[4-甲氧基-7-(四氢-吡喃-4-基)-苯并噻唑-2-基]-氨基甲酸乙酯,
(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸2-甲氧基-乙酯,或
(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸异丁基酯。
本申请的优选化合物是其中的R是四氢吡喃-4-基或-(CH2)n-四氢呋喃-2或3-基的式I化合物,例如下列化合物:
(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸四氢-吡喃-4-基酯,
(R)-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸四氢-呋喃-3-基酯,
[4-甲氧基-7-(四氢-吡喃-4-基)-苯并噻唑-2-基]-氨基甲酸四氢呋喃-2-基-甲基酯,或
[4-甲氧基-7-(四氢-吡喃-4-基)-苯并噻唑-2-基]-氨基甲酸(S)-(四氢-呋喃-3-基)酯。
其它优选的化合物是其中的R是5-羟基-二环[2.2.1]庚-2-基的式I化合物,例如下列化合物:
(外消旋)-(外型,外型)-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸5-羟基-二环[2.2.1]庚-2-基酯。
该式I化合物及其可药用盐可通过本领域已知的方法制得,例如通过下述方法制得,该方法包括
a)将式(II)化合物
与式(III)化合物反应
以生成式I化合物
其中R和X具有以上所给出的含义,或者
b)将式(IV)化合物
与式(V)化合物反应
HO-R V
以生成式I化合物
其中R和X如以上所定义,L是离去基例如卤素、-O-苯基或O-低级烷基;
并且
如果需要的话,将所得化合物转化成可药用酸加成盐。
在实施例1-13和下列反应方案1和2中更详细地描述了式I化合物的制备。
起始原料是已知化合物或者可按照本领域已知的方法制得。
式I化合物的制备
中间体7-(吗啉-4-基)-4-甲氧基-苯并噻唑-2-基胺和7-(四氢吡喃-4-基)-4-甲氧基-苯并噻唑-2-基胺可按照WO 01/97786中所公开的方法制得。WO 01/97786中还记载了利用式(II)中间体的式(I)化合物的制备。
反应方案1
式(VII)化合物的制备
将式(VI)的芳基溴化合物与稍微过量的二(频那醇)二硼在含有钯催化剂、优选二氯(1,1′-二(二苯基膦)二茂铁)钯(II)的二氯甲烷加合物和过量乙酸钾的有机溶剂、优选二甲亚砜中反应。反应在升高的温度、优选约80℃下反应约2-24小时,优选约2小时。将式(VII)的产物通过常规方法分离,优选通过色谱或重结晶进行纯化。
式(VIII)化合物的制备
制备式(VIII)化合物的一种方法是在钯催化剂、优选二氯(1,1′-二(二苯基膦)二茂铁)钯(II)二氯甲烷加合物和有机碱、优选碳酸钠的存在下用乙烯基溴、乙烯基碘或乙烯基三氟甲磺酸酯处理式(VII)化合物。反应在溶剂的混合物、优选乙醇、甲苯和水的混合物中进行。反应在升高的温度、优选约80℃下进行约0.1-2小时,优选约20分钟。将式(VIII)的产物通过常规方法分离,优选通过色谱或重结晶进行纯化。原料乙烯基溴、乙烯基碘或乙烯基三氟甲磺酸酯化合物可通过购买、例如从Fluka得到,或者可按照本领域已知的方法制得。
式(IX)化合物的制备
式(IX)化合物可通过将式(VIII)化合物在氢化催化剂、优选10%钯碳的存在下氢化来制得。这些反应可以在各种有机溶剂例如甲醇、乙醇或四氢呋喃、优选甲醇中,于室温下以及一个大气压或以上、优选在一个大气压下进行16-72小时,优选约72小时。将式(IX)的产物通过常规方法分离,优选通过色谱或重结晶进行纯化。
式(X)化合物的制备
向硫氰酸铵的丙酮溶液中加入苯甲酰氯和2-甲氧基-5-(四氢-吡喃-4-基)-苯基胺(IX)的溶液。反应在回流下进行约20分钟。将产物1-苯甲酰基-3-[2-甲氧基-5-(四氢-吡喃-4-基)-苯基]-硫脲(X)通过常规方法分离。
式(XI)化合物的制备
向1-苯甲酰基-3-[2-甲氧基-5-(四氢-吡喃-4-基)-苯基]-硫脲(X)的甲醇溶液中加入甲醇钠溶液并在室温下继续搅拌约1小时。将产物(XI)[2-甲氧基-5-(四氢-吡喃-4-基)-苯基]-硫脲通过常规方法分离。
式(XII)化合物的制备
向1-[2-甲氧基-5-(四氢-吡喃-4-基)-苯基]-硫脲(XI)的乙酸溶液中加入氢溴酸并在80℃下继续搅拌约30分钟。然后滴加DMSO并将反应混合物在80℃下继续搅拌30分钟。将产物(XII)4-甲氧基-7-(四氢-吡喃-4-基)-苯并噻唑-2-基胺通过常规方法分离。
式(Ib)化合物的制备
将4-甲氧基-7-(四氢-吡喃-4-基)-苯并噻唑-2-基胺(XII)首先与氯甲酸苯酯按照WO 01/97786中关于(4-甲氧基-7-苯基-苯并噻唑-2-基)-氨基甲酸苄酯所述的方法进行反应,然后与N-乙基-二异丙基胺和式HO-R的相应的醇在二甲亚砜中、在约50℃下反应2小时,如反应方案2所示。
方案2
R和X如上所述,L是离去基例如卤素、-O-苯基或O-低级烷基。
分离和纯化化合物
如果需要的话,可通过任意合适的分离或纯化方法进行本文所述化合物和中间体的分离和纯化,所述方法有例如过滤、萃取、结晶、柱色谱法、薄层色谱法、厚层色谱法、制备型低压或高压液相色谱法或这些方法的组合。关于合适的分离和纯化方法的具体举例说明可参见下文中的制备例和实施例。然而,当然也可以使用其它等同的分离或纯化方法。
式I化合物的盐
式I化合物可以是碱性的,例如当残基R含有碱性基团例如脂族或芳族胺基团时。在这样的情况下,可将式I化合物转化成相应的酸加成盐。
转化可通过用至少化学计算量的合适的酸处理来进行,所述酸有例如盐酸、氢溴酸、硫酸、硝酸、磷酸等,和有机酸例如乙酸、丙酸、乙醇酸、丙酮酸、草酸、苹果酸、丙二酸、琥珀酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等。通常是将游离碱形式的本发明化合物溶解在惰性有机溶剂例如乙醚、乙酸乙酯、氯仿、乙醇或甲醇等中,并将酸加到类似溶剂中。将温度保持在0℃-50℃。所形成的盐自发地沉淀出来,或者可用极性较弱的溶剂使其从溶液中沉淀出来。
可通过用至少化学计算量的合适的碱例如氢氧化钠、氢氧化钾、碳酸钾、碳酸氢钠、氨等处理来将式I化合物的酸加成盐转化成相应的游离碱。
式I化合物及其可药用加成盐具有有价值的药理学特性。具体而言,发现本发明化合物是腺苷受体配体,并且对腺苷A2A受体具有高亲和性。
按照下文中给出的试验对化合物进行研究。
人腺苷A2A受体
用塞姆利基森林病毒表达系统在中国仓鼠卵巢(CHO)细胞中重组表达人腺苷A2A受体。收获细胞,通过离心洗涤两次,匀化并再次通过离心进行洗涤。将最后洗涤的膜沉积物悬浮在Tris(50mM)缓冲液中,所述缓冲液中含有120mM NaCl、5mM KCl、2mM CaCl2和10mM MgCl2(pH 7.4)(缓冲液A)。在96孔培养板中进行[3H]-SCH-58261(Dionisotti等,1997,Br.J.Pharmacol.121,353;1nM)结合试验,试验在2.5μg膜蛋白、0.5mg Ysi-聚-l-赖氨酸SPA珠和0.1U腺苷脱氨酶的存在下、在最终体积为200μl的缓冲液A中进行。用黄嘌呤胺同类物(XAC;2μM)测定非特异性结合。在10μM至0.3nM的10种浓度下对化合物进行测定。所有试验均一式两份地进行并且重复至少两次。将测定培养板在室温下保温1小时,然后离心并用Packard Topcount闪烁计数器测定结合的配体。用非线性曲线拟合程序计算IC50值并用Cheng-Prussoff方程计算Ki值。
本申请的化合物的pKi值在7.6至8.7的范围内。最优选的化合物表现出pKi>8.0。
实施例号 | hA2(pKi) | 实施例号 | hA2(pKi) |
1 | 8.7 | 8 | 8.1 |
2 | 8.3 | 9 | 8.4 |
3 | 7.9 | 10 | 7.6 |
4 | 7.6 | 11 | 7.8 |
5 | 8.1 | 12 | 7.9 |
6 | 8.2 | 13 | 8.4 |
7 | 8.0 |
式I化合物及式I化合物的可药用盐可,例如以药物制剂的形式用作药物。药物制剂可例如以片剂、包衣片、糖衣丸、硬和软明胶胶囊、溶液、乳液或混悬液的形式经口服给药。但也可例如以栓剂的形式直肠给药,或者以注射液的形式胃肠外给药。
式I化合物可用药物惰性的、无机或有机载体加工以生产药物制剂。乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐等,可用作例如制备片剂、包衣片、糖衣丸和硬明胶胶囊的载体。用于软明胶胶囊的适宜载体是,例如植物油、蜡、脂肪、半固体和液体的多元醇等。根据活性物质的性质,在软明胶胶囊的情况下通常不需要载体。用于制备溶液和糖浆的适宜载体是,例如水、多元醇、甘油、植物油等。用于栓剂的适宜载体是,例如天然的或硬化的油、蜡、脂肪、半液体或者液体多元醇等。
此外,药物制剂还可包含防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、矫味剂、用于改变渗透压的盐、缓冲剂、掩蔽剂或抗氧剂。它们还可包含其它治疗学上有益的物质。
含有式I化合物或其可药用盐以及治疗惰性的载体的药物及其生产方法也是本发明的目的,所述生产方法包括,将一种或多种式I化合物和/或可药用酸加成盐以及,如果需要的话,一种或多种其它治疗学上有益的物质与一种或多种治疗学惰性的载体一起制成盖仑给药形式。
根据本发明,式I化合物及其可药用盐可用于控制或预防基于腺苷受体拮抗活性的疾病,例如阿尔茨海默氏病、帕金森病、神经保护、精神分裂症、焦虑、疼痛、呼吸不足、抑郁、哮喘、过敏反应、组织缺氧、局部缺血、癫痫发作和物质滥用。此外,本发明的化合物还可用作镇静剂、肌肉松弛剂、抗精神病药、抗癫痫药、抗惊厥药和心脏保护剂以及用于生产相应的药物。
根据本发明,最优选的适应症包括中枢神经系统疾病,例如某些抑郁症、神经保护和帕金森病的治疗或预防。
剂量可在较宽的限度内变化,但在每个具体病例中,当然应根据个体需求进行调整。在口服给药的情况下,对于成人的日剂量可以为约0.01mg-约1000mg通式I化合物或相应量的其可药用盐。该日剂量可以以单次剂量给药,或者以划分的剂量给药,此外,当需要时,剂量也可超过上限。
片剂(湿法制短)
项 | 成分 | mg/片 | |||
1.2.3.4.5. | 式I化合物无水乳糖DTGSta-Rx 1500微晶纤维素硬脂酸镁总计 | 5mg51256301167 | 25mg251056301167 | 100mg100306301167 | 500mg500150301501831 |
制备方法
1.混合1、2、3和4项并用纯水制粒。
2.在50℃下干燥该颗粒。
3.用适宜的研磨设备使该颗粒过筛。
4.加入第5项并混合3分钟;在适宜的压片机上压片。
胶囊制剂
项 | 成分 | mg/胶囊 | |||
1.2.3.4.5. | 式I化合物含水乳糖玉米淀粉滑石粉硬脂酸镁总计 | 5mg515925101200 | 25mg2512335152200 | 100mg10014840102300 | 500mg500---70255600 |
制备方法
1.将1、2和3项在适宜的混合器中混合30分钟。
2.加入第4和5项并混合3分钟。
3.填充到适合的胶囊中。
下列制备例和实施例用来举例说明本发明而不是限制本发明的范围。
实施例1
(反式)-[4-甲氧基-7-(四氢-吡喃-4-基)-苯并噻唑-2-基]-氨基甲酸4-羟基-环己基酯
将4-甲氧基-7-(四氢-吡喃-4-基)-苯并噻唑-2-基胺(69mg,0.26mmol)首先与氯甲酸苯酯按照WO 01/97786中关于(4-甲氧基-7-苯基-苯并噻唑-2-基)-氨基甲酸苄酯所述的方法进行反应,然后与N-乙基-二异丙基胺(0.090ml,0.52mmol)和(反式)-环己烷-1,4-二醇(60mg,0.52mmol)在二甲亚砜(10ml)中于50℃下反应2小时。然后加入100ml二氯甲烷,将混合物用饱和碳酸钠水溶液萃取,然后将有机相干燥并蒸发。进行快速色谱纯化(硅胶,用二氯甲烷/甲醇洗脱)得到白色固体状标题化合物(7%收率)。
MS:m/e=407(M+H+),mp 282-284℃。
按照实施例1的一般方法制得实施例2至11的化合物。
实施例2
[4-甲氧基-7-(四氢-吡喃-4-基)-苯并噻唑-2-基]-氨基甲酸乙酯
利用4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基胺和乙醇得到白色固体状标题化合物(35%收率)。MS:m/e=337(M+H+),mp 170-174℃。
实施例3
(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸2-甲氧基-乙酯
利用4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基胺和2-甲氧基-乙醇得到米白色固体状标题化合物(52%收率)。MS:m/e=368(M+H+),mp 149-152℃。
实施例4
(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸异丁酯
利用4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基胺和异丁醇得到黄色结晶状标题化合物(12%收率)。MS:m/e=366(M+H+),mp 164-168℃。
实施例5
(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸环己基酯
利用4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基胺和环己醇得到白色固体状标题化合物(60%收率)。MS:m/e=392(M+H+),mp 177-179℃。
实施例6
(反式)-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸4-羟基-环己基酯
利用4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基胺得到白色泡沫状标题化合物(14%收率)。MS:m/e=408(M+H+),mp 176-179℃。MS:m/e=407.49(M+H+)。
实施例7
(顺式)-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸4-羟基-环己基酯
利用4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基胺和(顺式)-环己烷-1,4-二醇得到无色结晶状标题化合物(40%收率)。MS:m/e=408(M+H+),mp204-206℃。
实施例8
(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸四氢-吡喃-4-基酯
利用4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基胺和四氢吡喃-4-醇得到白色固体状标题化合物(7%收率)。MS:m/e=394(M+H+),mp 187-188℃。
实施例9
(外消旋)-(外型,外型)-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸5-羟基-二环[2.2.1]庚-2-基酯
利用4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基胺和(外消旋)-(外型,外型)-二环[2.2.1]庚烷-2,5-二醇得到白色固体状标题化合物(10%收率)。MS:m/e=420(M+H+),mp 193-194℃。
实施例10
(R)-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸四氢-呋喃-3-基酯
利用4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基胺和(R)-四氢-呋喃-3-醇得到白色结晶状标题化合物(33%收率)。MS:m/e=380(M+H+),mp 198-200℃。
实施例11
(顺式/反式)-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸3-羟基-环戊酯
利用4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基胺和(顺式/反式)-环戊烷-1,3-二醇得到白色固体状标题化合物(42%收率)。MS:m/e=394(M+H+),mp188-189℃。
实施例12
[4-甲氧基-7-(四氢-吡喃-4-基)-苯并噻唑-2-基]-氨基甲酸四氢-呋喃-2-基甲基酯
利用7-(四氢吡喃-4-基)-4-甲氧基-苯并噻唑-2-基胺和(四氢-呋喃-2-基)-甲醇得到白色固体状标题化合物(8%收率)。MS:m/e=393(M+H+),mp175-180℃。
实施例13
[4-甲氧基-7-(四氢-吡喃-4-基)-苯并噻唑-2-基]-氨基甲酸(S)-(四氢-呋喃-3-基)酯
利用7-(四氢吡喃-4-基)-4-甲氧基-苯并噻唑-2-基胺和(S)-四氢-呋喃-3-醇得到白色固体状标题化合物(13%收率)。MS:m/e=379(M+H+),mp195-200℃。
中间体
实施例14
4-甲氧基-7-(四氢-吡喃-4-基)-苯并噻唑-2-基-胺(X)
a)2-(4-甲氧基-3-硝基-苯基)-4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷(VII)
向搅拌中的1.30g(5.60mmol)4-溴-2-硝基苯甲醚(VI)的25ml DMSO溶液中加入1.57g(6.16mmol)二(频那醇)二硼、123mg(0.17mmol)二氯(1,1′-二(二苯基膦)二茂铁)钯(II)的二氯甲烷加合物和1.65g(16.8mmol)乙酸钾。将混合物在80℃下加热2小时,然后冷却至室温,倒入水中并用乙酸乙酯萃取三次。将合并的有机相用硫酸钠干燥并真空浓缩。进行快速色谱(1/2乙酸乙酯/己烷,然后是乙酸乙酯)得到1.39g米白色固体状的2-(4-甲氧基-3-硝基-苯基)-4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷(VII)。ES-MS m/e(%):280(M+H+,100)。
b)4-(4-甲氧基-3-硝基-苯基)-3,6-二氢-2H-吡喃(VIII)
向搅拌中的4.36g(15.6mmol)2-(4-甲氧基-3-硝基-苯基)-4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷(VII)和3.30g(14.2mmol)三氟甲磺酸3,6-二氢-2H-吡喃-4-基酯的33ml乙醇和82ml甲苯溶液中加入580mg(0.71mmol)二氯(1,1′-二(二苯基膦)二茂铁)钯(II)的二氯甲烷加合物。将混合物在80℃下加热,然后滴加16.5ml(33.0mmol)2M碳酸钠水溶液。将反应混合物在80℃下搅拌20分钟,然后冷却至室温,倒入水中并用乙酸乙酯萃取三次。将合并的有机相用硫酸钠干燥并真空浓缩。进行快速色谱(1/4乙酸乙酯/己烷)得到2.00g(60%)浅黄色固体状的4-(4-甲氧基-3-硝基-苯基)-3,6-二氢-2H-吡喃(VIII)。ES-MS m/e(%):253(M+NH4 +,100),236(M+H+,24)。
c)2-甲氧基-5-(四氢-吡喃-4-基)-苯基胺(IX)
向搅拌中的3.30g(14.0mmol)4-(4-甲氧基-3-硝基-苯基)-3,6-二氢-2H-吡喃(VIII)在70ml甲醇和70ml二氯甲烷中的溶液中加入一刮铲尖10%钯碳,然后将混合物在室温及氢气氛下搅拌20分钟。然后将混合物过滤,用二氯甲烷洗涤,将滤液真空浓缩得到2.75g(95%)米白色结晶固体状的2-甲氧基-5-(四氢-吡喃-4-基)-苯基胺(IX)。ES-MS m/e(%):208(M+H+,100)。
d)1-苯甲酰基-3-[2-甲氧基-5-(四氢-吡喃-4-基)-苯基]-]-硫脲(X)
向搅拌中的1.11g(14.6mmol)硫氰酸铵的60ml丙酮溶液中滴加1.54ml(13.3mmol)苯甲酰氯并将混合物加热回流10分钟。然后滴加2.75g(13.3mmol)2-甲氧基-5-(四氢-吡喃-4-基)-苯基胺的30ml丙酮溶液并将反应混合物继续加热回流10分钟。然后将混合物冷却至室温,倒入碳酸氢钠溶液中并用二氯甲烷萃取三次。将合并的有机相用硫酸钠干燥并真空浓缩。进行快速色谱(1/1乙酸乙酯/己烷),然后用乙醚研制得到3.25g(66%)白色固体状的1-苯甲酰基-3-[2-甲氧基-5-(四氢-吡喃-4-基)-苯基]-硫脲。ES-MSm/e(%):371(M+H+,100)。
e)[2-甲氧基-5-(四氢-吡喃-4-基)-苯基]-硫脲(XI)
向搅拌中的3.25g(8.77mmol)1-苯甲酰基-3-[2-甲氧基-5-(四氢-吡喃-4-基)-苯基]-硫脲的45ml甲醇溶液中滴加0.25ml(1.32mmol)5.3M甲醇钠溶液并在室温下继续搅拌1小时。然后将混合物倒入水中并用乙酸乙酯萃取三次。将合并的有机相用硫酸钠干燥并真空浓缩。进行快速色谱(乙酸乙酯)得到1.90g(81%)白色泡沫状的[2-甲氧基-5-(四氢-吡喃-4-基)-苯基]-硫脲。ES-MS m/e(%):267(M+H+,100)。
f)4-甲氧基-7-(四氢-吡喃-4-基)-苯并噻唑-2-基-胺(XII)
向加热至80℃的搅拌中的1.90g(7.13mmol)[2-甲氧基-5-(四氢-吡喃-4-基)-苯基]-硫脲的20ml乙酸溶液中滴加1.45ml(8.27mmol)氢溴酸(5.7M的乙酸溶液)并在80℃下继续搅拌30分钟。然后滴加0.56ml(7.85mmol)DMSO并将反应混合物在80℃下继续搅拌30分钟。然后将混合物冷却至室温,缓慢倒入碳酸氢钠溶液中并加入乙酸乙酯。将混合物在室温下搅拌10分钟,将形成的结晶通过过滤收集,用乙酸乙酯洗涤。分离出母液相,将有机相真空浓缩至5ml。将形成的第二批结晶通过过滤收集并与第一批的结晶混合得到920mg(49%)白色固体状的4-甲氧基-7-(四氢-吡喃-4-基)-苯并噻唑-2-基胺。ES-MS m/e(%):265(M+H+,100)。
Claims (17)
1、通式I化合物及其可药用酸加成盐:
其中
R是未取代的或者被羟基取代的C5,6-环烷基,或者是乙基、异丁基或甲氧基乙基,或者是四氢吡喃-4-基或-(CH2)n-四氢呋喃-2或3-基,或者是5-羟基-二环[2.2.1]庚-2-基;
X是CH或N;
n是0或1。
2、通式I化合物及其可药用酸加成盐:
其中
R是未取代的或者被羟基取代的C5,6-环烷基,或者是乙基、异丁基或甲氧基乙基,或者是四氢吡喃-4-基或四氢呋喃-3-基,或者是5-羟基-二环[2.2.1]庚-2-基;
X是CH或N。
3、权利要求1的式I化合物,其中R是任选地被羟基取代的C5,6-环烷基。
4、权利要求3的式I化合物,所述化合物是:
(反式)-[4-甲氧基-7-(四氢-吡喃-4-基)-苯并噻唑-2-基]-氨基甲酸4-羟基-环己基酯,
(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸环己基酯,
(反式)-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸4-羟基-环己基酯,
(顺式)-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸4-羟基-环己基酯或(顺式/反式)-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸3-羟基-环戊基酯。
5、权利要求1的式I化合物,其中R是乙基、异丁基或甲氧基乙基。
6、权利要求4的式I化合物,所述化合物是:
[4-甲氧基-7-(四氢-吡喃-4-基)-苯并噻唑-2-基]-氨基甲酸乙酯,
(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸2-甲氧基-乙酯,或
(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸异丁基酯。
7、权利要求1的式I化合物,其中R是四氢吡喃-4-基或-(CH2)n-四氢呋喃-2或3-基。
8、权利要求7的式I化合物,所述化合物是:
(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸四氢-吡喃-4-基酯,
(R)-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸四氢-呋喃-3-基酯,
[4-甲氧基-7-(四氢-吡喃-4-基)-苯并噻唑-2-基]-氨基甲酸四氢呋喃-2-基-甲基酯,或
[4-甲氧基-7-(四氢-吡喃-4-基)-苯并噻唑-2-基]-氨基甲酸(S)-(四氢-呋喃-3-基)酯。
9、权利要求1的式I化合物,其中R是5-羟基-二环[2.2.1]庚-2-基。
10、权利要求9的式I化合物,所述化合物是:
(外消旋)-(外型,外型)-(4-甲氧基-7-吗啉-4-基-苯并噻唑-2-基)-氨基甲酸5-羟基-二环[2.2.1]庚-2-基酯。
12、通过权利要求11的方法或等同的方法制备的权利要求1至10任一项所述的化合物。
13、包含一种或多种权利要求1至10任一项所述的化合物和可药用赋形剂的药物。
14、用于治疗涉及腺苷受体的疾病的权利要求13的药物。
15、权利要求1至10任一项所述的化合物在治疗疾病中的应用。
16、权利要求1至10任一项所述的化合物在制备用于治疗涉及腺苷A2A受体的疾病的相应药物中的应用。
17、前述的本发明。
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WO2004103367A1 (en) | 2004-12-02 |
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US7304058B2 (en) | 2007-12-04 |
AU2004241720B2 (en) | 2008-11-06 |
ES2280964T3 (es) | 2007-09-16 |
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CA2525102A1 (en) | 2004-12-02 |
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EP1628662B1 (en) | 2007-02-14 |
KR20060014406A (ko) | 2006-02-15 |
ATE353648T1 (de) | 2007-03-15 |
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