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CN1136193C - 酰胺衍生物或其盐类 - Google Patents

酰胺衍生物或其盐类 Download PDF

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CN1136193C
CN1136193C CNB981213758A CN98121375A CN1136193C CN 1136193 C CN1136193 C CN 1136193C CN B981213758 A CNB981213758 A CN B981213758A CN 98121375 A CN98121375 A CN 98121375A CN 1136193 C CN1136193 C CN 1136193C
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amino
ethyl
hydroxyl
phenylethyl
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CN1218045A (zh
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��ɽ��Ҳ
丸山龙也
֮
铃木贵之
����һ
恩田健一
早川昌彦
森友博幸
Ҳ
君塚哲也
松井哲夫
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Yamanouchi Pharmaceutical Co Ltd
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Abstract

本发明公开了一种用下式表示的酰胺衍生物或其盐类：其中环B是杂芳基；X是一个键或低级亚烷基；R是氢原子、卤原子、低级烷基、氨基、芳基低级烷基或卤代芳基低级烷基。还公开了一种有促进胰岛素分泌作用、增强胰岛素感受性作用和由于对β3受体的选择性刺激作用而具有抗肥胖病和抗高血糖作用的脂尿病治疗剂。

Description

酰胺衍生物或其盐类
技术领域
本发明涉及一类药物，更具体地涉及新的酰胺衍生物或其盐类和治疗糖尿病的治疗剂。
背景技术
糖尿病是一种伴随有持续高血糖症状的疾病，现在认为它是由于许多环境因素和遗传因素所造成的。血糖的主要控制因素是胰岛素，而且人们已经认识到高血糖是由于缺少胰岛素或抑制胰岛素反应的因素(如遗传上的原因、缺少运动、肥胖病和紧张)过多所造成的。
糖尿病主要分为两类。一类是由于自身免疫疾病使得胰腺分泌胰岛素的功能降低而引发的胰岛素依赖型糖尿病(IDDM)，另一类是由于胰腺连续高度分泌胰岛素产生疲劳使得胰腺分泌胰岛素的功能降低而引发的非胰岛素依赖型糖尿病(NIDDM)。在日本，95％或更多的糖尿病患者患有NIDDM，而且由于日常生活方式的改变，患者的数量还在增加，这已成为一个问题。
关于治疗糖尿病，在轻度病例中主要是采用饮食治疗、治疗性运动和治疗肥胖病，然而当病情发展时，要服用抗糖尿病口服药物(例如，胰岛素分泌促进剂如磺酰脲类和增强胰岛素感受性的胰岛素感受性增强剂)。在严重的病例中是服用胰岛素制剂。然而，希望能生产出更高效控制血糖的药物，并且希望能研制出有新的作用机理且非常有效的抗糖尿病药物。
美国专利4,396,627和4,478,849描述了苯乙醇胺衍生物，并指出这些化合物可用作治疗肥胖病和高血糖的药物。他们报道说，这些化合物的作用是由于它们有刺激β3-受体的作用。顺便提一下，已经知道β-肾上腺素受体分为β1、β2和β3亚类，刺激β1受体将引起心率加快，刺激β2受体将刺激肌肉内的糖原分解，从而抑制糖原合成，引起反应如肌肉震颤，而刺激β3受体有抗肥胖病和抗高血糖的作用(如降低甘油三酯，降低胆固醇和提高HDL-胆固醇)。
不幸的是，那些β3拮抗剂也有由于刺激β1和β2受体而产生的反应，如心率加快和肌肉震颤，因此它们存在副作用问题。
最近已经确认各种β受体间有差异，而且已经有报道说甚至是在啮齿类动物(如大鼠)中被确认有β3受体感受性的化合物在人体内也表现出对β1和β2受体有刺激作用。出于上述原因，目前已经用人细胞或表达人受体的细胞来对在人体内选择性刺激β3受体的化合物进行研究。例如，WO95/29159描述了一种有以下结构式的取代的磺胺衍生物：其中各符号参见该专利的说明书，该专利还指出，由于它们在人体内选择性地刺激β3受体，因此它们可用来抗肥胖病、高血糖等。然而，该专利没有指出这些化合物有促进胰岛素分泌和增强胰岛素感受性的作用。
因此，仍要求能生产一种新型的有高效临床用途的糖尿病治疗剂。
发明内容
本发明发明者对既有促进胰岛素分泌作用又有增强胰岛素感受性作用的化合物进行了深入细致的研究，发现新型的酰胺衍生物有非常好的促进胰岛素分泌的作用和增强胰岛素感受性的作用，而且它还表现出对β3受体有选择性刺激作用，从而实现了本发明。
因此，本发明涉及一种用以下结构式(I)表示的酰胺衍生物或其盐类：
Figure C9812137500042
其中环B是杂芳基；X是一个键或低级亚烷基；R是氢原子、卤原子、低级烷基、氨基、芳基低级烷基或卤代芳基低级烷基，该衍生物或其盐类既有促进胰岛素分泌的作用又有增强胰岛素感受性的作用，而且由于对β3受体的选择性刺激作用，其还有抗肥胖病和抗高血糖的作用。本发明也涉及一种含有该酰胺衍生物或其盐类作为有效组分的糖尿病治疗剂。
本发明另一方面涉及上述酰胺衍生物或其盐类在制备用于治疗糖尿病的药剂中的用途。
具体实施方式
下面将进一步描述结构式(I)的化合物。
在本说明书结构式中所用的定义中，术语“低级”，除非另有特指，是指有1-6个碳原子的直链或支链烃链。
“低级烷基”的实例是甲基、乙基和直链或支链丙基、丁基、戊基或己基，较佳地是有1-4个碳原子的烷基，特别佳的是甲基、乙基、丙基或异丙基。
“低级亚烷基”的实例是通过从上述“低级烷基”上移去一个氢原子而获得的二价基团，较佳地是有1-4个碳原子的亚烷基，特别佳的是亚甲基、亚乙基、亚丙基或亚丁基。
“杂芳基”的实例是单环杂芳基如呋喃基、噻嗯基、吡咯基、咪唑基、噻唑基、吡唑基、异噻唑基、异噁唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻二唑基、三唑基和四唑基；双环杂芳基如萘啶基(naphthylidinyl)和吡啶并嘧啶基。
“卤原子”的实例是氟原子、氯原子、溴原子或碘原子，  “卤代芳基低级烷基”的实例是上述芳基低级烷基中的芳基的一个或多个氢原子被一个或多个卤原子取代的基团。
当X是键时指-CO-的碳原子直接与环B连接。
本发明的化合物(I)有至少一个不对称碳原子，因此它有光学异构体如(R)-化合物和(S)-化合物、外消旋物、非对映物等。本发明包括所有这些单独的异构体及其混合物。本发明也包括化合物(I)的水合物、溶剂化物(如和乙醇的溶剂化物)和多晶型物质。
本发明的化合物(I)可与酸形成一种盐。盐的实例是与加入的无机酸如盐酸、氢溴酸、氢碘酸、硫酸、硝酸和磷酸形成的盐；与有机酸如甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、柠檬酸、酒石酸、碳酸、苦味酸、甲磺酸、乙磺酸和谷氨酸。
(生产方法)
本发明的化合物或其盐类可通过采用各种合成方法利用其基础骨架的特点或取代基的类型来生产。典型的生产方法如下所述。
第一种制备方法 (在结构式中，B、R和X如上定义；Ra是氨基的保护基团；Y1是离去基团，更具体的是羟基、低级烷氧基或卤原子。)
在该方法中，使化合物(II)和化合物(III)酰胺化，然后从上移去保护性基团，合成本发明的化合物(I)。
在该制备方法中，酰胺化可用常规方法来进行。
溶剂根据化合物(III)的Y1不同，大多数情况下可采用惰性溶剂或醇溶剂(如异丙醇)。
当Y1是羟基时，可采用在上述溶剂中在缩合剂的存在下进行反应的方法。缩合剂的例子是N，N′-二环己基碳化二亚胺(DCC)、1-乙基-3-(3-二甲基氨丙基)碳化二亚胺(EDCI)、1，1′-羰基-二咪唑(CDI)、二苯基磷酰叠氮(DPPA)和二乙基磷酰氰化物(DEPC)。
当Y1是低级烷氧基时，可采用在加热或回流下使其本身或在上述惰性溶剂中进行反应的方法。
当Y1是卤原子时，可采用在上述惰性溶剂中在碱存在下进行反应的方法。
惰性溶剂的例子是二甲基甲酰胺(DMF)、二甲基乙酰胺、四氯乙烷、二氯甲烷、二氯乙烷、氯仿、四氯化碳、四氢呋喃、二噁烷、二甲氧基乙烷、乙酸乙酯、苯、甲苯、二甲苯、乙腈、甲硫醚及其混合溶剂，它们可根据每一反应条件合适地选择。碱的例子是无机碱如氢氧化钠、氢氧化钾、碳酸钠和碳酸钾；以及有机碱如N-甲基吗啉、三乙胺、二异丙基乙胺和吡啶。
Ra表示的氨基保护基团是通常用来保护氨基的基团，其典型例子是酰基如甲酰基、乙酰基、丙酰基、甲氧基乙酰基、甲氧基丙酰基、苯甲酰基、噻嗯基乙酰基、噻唑基乙酰基、四唑基乙酰基、噻唑基乙醛酰基和噻嗯基乙醛酰基；低级烷氧基羰基如甲氧基羰基、乙氧基羰基和叔丁氧基羰基；芳烷氧基羰基，如苄氧基羰基和对硝基苄氧基羰基；低级链烷磺酰基如甲磺酰基和乙磺酰基；芳烷基如苄基、对硝基苄基、二苯甲基和三苯甲基；和三(低级烷基)甲硅烷基如三甲基甲硅烷基。
在该制备方法中，保护基团的除去可用常规方法来进行。例如，Ra表示的氨基保护基团很容易通过以下几种方法除去：i)当保护基团是二苯甲基、对甲氧基苄基、三苯甲基、叔丁氧基羰基、甲酰基等时，用酸(如甲酸、三氟乙酸、三氟乙酸和苯甲醚的混合物、氢溴酸和乙酸的混合物、盐酸和二噁烷的混合物等)进行处理的方法；ii)当保护基团是苄基、对硝基苄基、二苯甲基、三苯甲游基等时，用钯-碳或氢氧化钯-碳进行催化还原的方法；和iii)当保护基团是三(低级烷基)甲硅烷基等时，用水、氟化物阴离子(四正丁基氟化铵、氟化钠、氟化钾或氢氟酸)等进行处理的方法。
第二种制备方法 (在结构式中，B、R和X如上所确定。)
在该制备方法中，使化合物(IV)与化合物(V)反应，生成本发明的化合物(I)。
在加热或回流条件下，使胺类化合物(IV)和化合物(V)本身或在惰性溶剂中相互反应1-24小时，生成本发明的化合物(I)。
惰性溶剂的例子是乙腈、四氢呋喃、2-丁酮、甲硫醚和N-甲基吡咯烷酮。在反应中，可在反应混合物中加入碱如碳酸氢钠、碳酸钾或二异丙基乙胺。
顺便提一下，在上述制备方法中，可用重结晶、研磨、制备性薄层色谱法、硅胶快速色谱法(如W.C.Still等在J.Org.Chem.43，2923(1978)所述的)、中压液相色谱法和HPLC来除去不需要的副产物，对获得的物质进行纯化。用HPLC制得的混合物可以相应的盐形式分离得到。
上述制备方法中所用的起始材料很容易用本领域技术人员已知的方法来制得。下面显示了一种典型的方法。(起始化合物(II)的制备方法)
Figure C9812137500091
(在结构式中，Ra如上所确定；Rb是氢原子或氨基的芳烷基类保护基团；Rc是环氧、2-卤代乙酰基或1-羧基甲-1-醇。)
该制备方法由步骤(a)至步骤(c)组成，其中步骤(a)是使化合物(VI)与化合物(VII)反应，然后根据Rc的类型使其还原成化合物(VIIIa)；步骤(b)是当化合物(VIIIa)的Rb是氢原子时进行保护；步骤(c)是将硝基还原成氨基，从而生成化合物(II)。
上述制备方法中所用的氨基的芳烷基类保护基团例子是苄基、对硝基苄基、二苯甲基等。
步骤(a)：
下面描述三种情况。
1)当RC是环氧时，化合物(VI)可用上述第二种制备方法中的相同方法来与化合物(VII)反应。反应条件如反应温度、溶剂等与上相同。
2)当RC是2-卤代乙酰基时，使化合物(VI)在碱存在下与化合物(VII)反应，然后使其还原制成化合物(VIIIa)。碱与第一种制备方法中提及的碱相同。还原反应可在上述惰性溶剂或醇溶剂中在还原剂存在下搅拌进行。还原剂例子是氢硼化钠、氰基氢硼化钠、氢化锂铝和硼氢化物。
3)当RC是1-羧基甲-1-醇时，使化合物(VI)在缩合剂的存在下与化合物(VII)反应，然后使其受与2)中相同方式的还原，制成化合物(VIIIa)。施加与第一种制备方法中提及的相同缩合剂。
步骤(b)：
当化合物(VIIIa)中的Rb是氢原子时，采用常规方法用例如二碳酸二叔丁酯等来保护氨基，制得化合物(VIIIa)。
步骤(c)：
将硝基还原成氨基的方法可用常规方法来进行，如采用铁、锌等的金属还原方法和用催化剂(如钯-碳、氢氧化钯-碳、阮内镍等)的催化还原方法。根据还原条件，Ra变为氢原子，但是它可以再用常规方法保护。
对于其它化合物如化合物(III)、化合物(IV)、化合物(V)、化合物(VI)和化合物(VII)，可采用那些市售的或是可用已知的方法(如酰胺化、还原、N-烷基化、环化和水解)从市售化合物适当合成得到的化合物。
如此制得的本发明化合物(I)可以游离化合物、其盐类(通过常规的成盐方法获得)、水合物、与各种溶剂(如乙醇)一起的溶剂化物或多晶型晶体进行分离纯化。分离和纯化可以采用常见的化学操作如提取、浓缩、蒸发、结晶、过滤、重结晶和各种色谱法。
可用常规方法利用异构体间的物理-化学差异来分离各种异构体。例如，可用常见的外消旋离析(例如用常规的有光学活性的酸[例如酒石酸]将外消旋物变成非对映体盐，然后进行光学离析)将外消旋物转变成立体化学上纯的异构体。另外，非对映体的混合物可用常规方法(如分级结晶或色谱法)分离。对于光学活性化合物，可以从有适当光学活性的材料制得。
结构式(I)表示本发明的苯乙醇衍生物或其盐类既有促进胰岛素分泌作用，又有增强胰岛素感受性作用，而且可选择性地刺激β3受体，因此它可用作糖尿病治疗剂。
如后面所述的抗胰岛素模型动物中的葡萄糖耐量测试和低血糖测试所确定的，本发明的化合物既有良好的促进胰岛素分泌的作用，又有良好的增强胰岛素感受性的作用，因此预计它对糖尿病是非常有效的。尽管β3受体刺激作用可能参与了胰岛素分泌促进作用和胰岛素感受性增强作用的表达，但是其中也可能有其它机理参与，其详细情况目前还不知道。本发明的化合物的β3受体刺激作用对人体内的β3受体是有选择性的。已经得知β3受体的刺激作用刺激脂肪分解(将脂肪组织甘油三酯分解成甘油和游离脂肪酸)，从而加速了脂肪物质的消失。因此，本发明的化合物有抗肥胖病作用和抗高血糖作用(如降低甘油三酯的作用、降低胆固醇的作用和提高HDL胆固醇的作用)，并可用作防治肥胖病和高血脂(如血甘油三酯过多、血胆固醇过高和HD-脂蛋白过低)的药剂。这些疾病被称为糖尿病中的男性意象因素(animus factor)，这些疾病的改善可有助于防治糖尿病。
本发明的化合物也可用作其它疾病诸如缺血冠状动脉疾病(例如动脉硬化、心肌梗塞和心绞痛)、脑动脉硬化(例如脑梗塞)或动脉瘤的防治剂，它可通过减轻肥胖病和高血脂症状来改善这些疾病的症状。
另外，本发明化合物的选择性β3受体刺激作用有助于防治某些疾病，据报道可通过刺激β3受体来使疾病改善。这些疾病的例子如下所示。
已经提到，β3受体介导非括约肌平滑肌收缩的能动性，由于认为β3受体的选择性刺激作用有助于肠能动性的药理控制而不会伴随对心血管有作用，因此本发明化合物可用于治疗由于肠能动性异常引起的疾病(如各种肠胃疾病，包括过敏性结肠综合征)。它也可用来治疗消化性溃疡、食管炎、胃炎和十二指肠炎(包括由幽门螺旋菌Helicobacter pylori引起的十二指肠炎)、肠溃疡(如炎性肠疾病、溃疡性结肠炎、结肠疾病(clonal)和直肠炎。
进一步的显示表明，β3受体影响肺中感觉纤维的神经肽的释放抑制。感觉神经在呼吸道神经原性发炎(包括咳嗽)中起重要作用，因此，本发明的特异性β3拮抗剂可用于治疗神经原性发炎，另外对生龋性肺系统也稍有作用。
另外，由于β3受体在脑中的刺激，β3肾上腺素受体具有选择性抗忧郁作用，因此本发明化合物可用作抗忧郁剂。
经用人细胞试验，本发明化合物的作用被确认为对β3受体有选择性，而由其它β3受体刺激作用的引起的副作用很低或没有。
通过下列试验可测定本发明化合物的效果。
1.kk小鼠中的低血糖试验(抗胰岛素模型；肥胖病和高血糖)；
测定喂养下的雄性kk小鼠的血糖水平(血糖水平不低于200mg/dl)，并随机分成几组。用待测试药物进行强制性口服给药或皮下给药，每天一次共四天，然后比较最后一次给药15-18小时后的血糖水平与给药前的血糖水平(n＝6)。用玻璃毛细管(预先用肝素处理过)从小鼠尾静脉收集血液，从中除去蛋白质，用葡萄糖氧化酶法对上清液中的葡萄糖量(mg/dl)进行比色测定。
与相同药物给药前的血糖水平相比，在口服给药和皮下给药两种情况下，本发明的化合物均显著地降低了血糖水平。例如实施例6的化合物表现出，通过口服给药10mg/kg，平均血糖降低比例为48％。该结果表明，本发明的化合物对胰岛素感受性有良好的增强作用。
2.正常大鼠中的葡萄糖耐量试验：
将7周龄的SD株系雄性大鼠禁食一整昼夜，然后随机分组并进行口服葡萄糖耐量测试(OGTT)(n＝4)。在给药葡萄糖(2g/kg，口服给药)前30分钟用待测试化合物进行口服或皮下给药。用经肝素处理过的玻璃注射器从用戊巴比妥麻醉(65mg/kg)的大鼠的腹主动脉收集血液，从中除去蛋白质，然后用葡萄糖氧化酶法对上清液中的葡萄糖含量(mg/dl)进行比色测定。用放射免疫测定法(RIA)测定血浆中的胰岛素含量(ng/ml)，从而确定血液中的胰岛素数值。
在用本发明的化合物进行口服给药或皮下给药的一组中，经与未给药的一组比较，发现血液中的胰岛素值有显著增高。葡萄糖给药后的血糖水平增高被显著抑制。这些结果表明，本发明的化合物有良好的促进胰岛素分泌的作用和良好的抑制高血糖的作用。
3.对人β3、β2、和β1受体的刺激试验：
用SK-N-MC细胞体系(购得的细胞，细胞中持续表达人β3受体和人β1受体)来研究人β3刺激作用，而用CHO细胞体系(购得的细胞，在细胞中强制性表达人β2和β1受体)来研究β2和β1刺激作用。在24孔板上以105细胞/孔培育每种细胞，2天后用环腺苷酸(cAMP)生产活性作为指标在亚铺满状态下进行检查，对化合物的刺激作用进行研究。另外在β1受体阻断剂(CGP20712A，10-5M)存在下研究人β3刺激作用。用125I-cAMP进行放射免疫测定，测得每一细胞中的cAMP产生量(pmol/ml)。从获得的剂量-反应曲线计算得到pD2值和最大活性(I.A.(％)，10-8M异丙肾上腺素的最大反应定义为100％)，比较每种化合物的作用强度。
已经确定本发明的化合物对人β3受体有选择性的刺激作用。
用常见的药学上可接受的赋形剂制备含有一种或多种本发明化合物或其盐类作为有效组分的药物组合物。本发明的药物组合物的给药方式可以口服或是，用例如注射液、栓剂、皮下剂、吸入剂或囊内灌输来非肠胃给药。
剂量可根据每个具体情况通过考虑患者的症状、年龄、性别等来作适当的决定，但通常对于口服给药情况，对于成年人每天的剂量为0.01-100mg/kg，可一次给药或分成一天2-4次。当根据症状要进行静脉注射时，对于成年人每天的剂量通常约在0.001-10mg/kg，可一次给药或分成一天2次或多次。
关于制剂用赋形剂，可以采用无毒固体或液体药用物质。
本发明通过口服给药的固体组合物实例是片剂、丸剂、胶囊、稀释粉末或颗粒剂。在这些固体组合物中，一种或多种活性物质可与至少一种惰性赋形剂(如乳糖、甘露糖醇、葡萄糖、羟丙基纤维素、微晶纤维素、淀粉、聚乙烯吡咯烷酮、琼脂、果胶、偏硅酸铝酸镁和铝酸镁)混合。除惰性赋形剂外，组合物也可通过常规方式来含有添加剂，如润滑剂(如硬脂酸镁)、崩解剂(如纤维素甘醇酸钙)、稳定剂(如乳糖)和辅助增溶剂(如谷氨酸或天冬氨酸)，如果需要，片剂和丸剂可用糖衣(如蔗糖、明胶、羟丙基纤维素和羟丙基甲基纤维素邻苯二甲酸酯)或可用肠或胃包覆物质的薄膜包覆。
用于口服给药的液体组合物包括药学上可接受的乳剂、溶液、悬浮液、糖浆和酏剂，并含有常用的惰性赋形剂如纯水或乙醇。除了惰性赋形剂外，组合物还包含辅助剂如增湿剂或悬浮剂、甜味剂、调味剂(tasting agent)、芳香剂和防腐剂。用于非肠胃给药的注射液包括无菌的水性或非水性溶液、悬浮液和乳剂。非水性溶液和悬浮液包括，例如注射用蒸馏水和生理盐溶液。用于非水性溶液和悬浮液的溶剂的例子是丙二醇、聚乙二醇、植物油(如可可油、橄榄油和芝麻油)、醇(如乙醇)、阿拉伯树胶和吐温80(商品名)。这种组合物还可含有辅助剂如等渗剂、抗菌剂、增湿剂、乳化剂、分散剂、稳定剂(例如，乳糖)和辅助增溶剂(例如，谷氨酸和天冬氨酸)。它们可经过滤通过滤菌器或与杀菌剂混合或用杀菌剂辐照来灭菌。它们也可以生产无菌固体组合物然后在使用前溶解在注射用无菌水或无菌溶剂中的方式来使用。
本发明用下述实施例来进一步描述。本发明的化合物不限于下述实施例中所指的那些化合物，而是包括了所有用上式(I)表示的化合物及其盐、水合物、几何异构体、光学异构体和多晶型物。另外，采用本发明新颖的物质的例子通过下述对比实施例来描述。
                          对比实施例1
将2-吡啶羰酰氯(146mg)加入448mg(R)-N-[2-(4-氨基苯基)-N-(2-羟基-2-苯基乙基)乙基]氨基甲酸叔丁酯和330mg三乙胺在4ml氯仿的溶液中。反应溶液在室温下搅拌2小时，然后在真空下蒸发溶剂。用氯仿稀释残余物，用碳酸氢钠饱和水溶液洗涤有机层，然后用无水硫酸镁干燥。在真空下蒸发溶剂，残余物用硅胶柱层析(洗脱剂：己烷/乙酸乙酯＝1/3)纯化，制得321mg(R)-N-(2-羟基-2-苯基乙基)-N-[2-[4-[(2-吡啶羰基)氨基]苯基]乙基]氨基甲酸叔丁酯。
                           实施例1
将4N氯化氢-乙酸乙酯溶液(10ml)加入458mg(R)-N-(2-羟基-2-苯基乙基)-N-[2-[4-[(2-吡啶羰基)氨基]苯基]乙基]氨基甲酸叔丁酯的10ml乙醇溶液中。反应溶液在室温下搅拌3小时，然后在真空下蒸发溶剂。获得的粗制晶体用甲醇-乙醇-乙酸乙酯再结晶，获得289mg(R)-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]-2-吡啶羧酰苯胺二氯化氢。
实施例2-4的化合物用实施例1的方法制备。
                              实施例2
(R)-2-[1-(4-氯苄基)-1H-咪唑-2-基]-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰苯胺二氯化氢
                              实施例3
(R)-2-[1-(3，4-二氯苄基)-1H-四唑-5-基]-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰苯胺氯化氢
                              实施例4
(R)-2-(2-氨基吡啶-6-基)-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰苯胺二氯化氢
                              实施例5
将15ml 4N氯化氢-乙酸乙酯加入690mg(R)-N-[2-[4-[2-(2-氨基噻唑-4-基]乙酰氨基]苯基]乙基]-N-[(2-羟基-2-苯基)乙基]氨基甲酸叔丁酯在MeOH的溶液(30ml)中，在室温下搅拌混合物2小时。在真空下蒸发溶剂，然后用反相柱层析(洗脱剂：水/甲醇＝2/1)纯化残余物，然后获得310mg(R)-2-(2-氨基-噻唑-4-基)-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]-乙酰苯胺二氯化氢。
                             实施例6
将10％钯-碳(5.96g)加入20.1g 4′-[2-[N-苄基-N-(2-羟基-2-苯基乙基)氨基]乙基]-2-(2-吡啶基)乙酰苯胺的400ml甲醇溶液中。然后在大气压力下在氢气氛中搅拌反应液6小时。用硅藻土过滤除去不溶物，在真空下浓缩滤液。在残余物的甲醇溶液中加入10.8ml 4N氯化氢-乙酸乙酯溶液，然后在真空下蒸发溶剂。获得的粗晶体用甲醇-乙醇再结晶，获得(R)-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]2-(2-吡啶基)乙酰苯胺氯化氢。
实施例中的化合物的结构式列于表1中；对比实施例1中的化合物的物理和化学性质列于表2；实施例中的化合物的物理和化学性质列于表3中。
表中所用的符号有下列意义。Rex指对比实施例编号；Ex.指实施例号；数据指物理和化学性质；NMR指核磁共振谱(TMS内部标准；所用溶剂是DMSO-d，除非另有特指)；mp指熔点；dec指分解；MS(m/z)指质谱分析数据(m/z)。
                        表1
                                    表2
 Rex.                          数据
1  NMR(CDCl3)5：1.47(9H，s)，2.62-2.93(2H，m)，3.14-3.58(4H，m)，4.35(1H，brs)，4.90(1H，br)，7.06-7.40(7H，m)，7.45-7.50(1H，m)，7.67-7.72(2H，m)，7.90(1H，dt.J＝2.0，8.0Hz)，8.25-8.31(1H，m)，8.58-8.63(1H，m)，9.98(1H，brs)
                                     表3
实施例                          数据
1 mp：223-225℃NMRδ：2.95-3.28(6H，m)，4.98-5.07(1H，m)，7.23-7.44(6H，m)，7.65-7.75(1H，m)，7.88(2H，d，J＝8.4Hz)，8.05-8.22(2H，m)，8.75(1H，d，J＝4.4Hz)，8.97(1H，brs)，9.43(1H，brs)，10.65(1H，brs)
2 mp：203-209℃NMRδ：2.90-3.10(3H，m)，3.10-3.20(3H，m)，4.41-4.48(2H，m)，4.95-5.05(1H，m)，5.46(2H，s)，6.21(1H，brs)，7.20(2H，d，J＝8.6Hz)，7.30-7.42(6H，m)，7.50-7.54(2H，m)，7.70(2H，s)，8.92(1H，brs)，9.39(1H，brs)，10.88-10.95(1H，m)
3 mp：240-242℃NMR δ：2.90-3.10(3H，m)，3.10-3.25(3H，m)，4.32(2H，s)，4.98(1H，dt，J＝10.3，3，4Hz)，5.72(2H，s)，6.20(1H，d，J＝3.9Hz)，7.20(2H，d，J＝8.3Hz)，7.30-7.40(6H，m)，7.51(2H，d，J＝8.8Hz)，7.62(1H，d，J＝8.3Hz)，7.67(1H，d，J＝2.0Hz)，8.86(1H，brs)，9.17(1H，brs)，10.67(1H，s)
4 mp：151-159℃NMR δ：2.90-3.10(3H，m)，3.10-3.20(3H，m)，3.76(2H，s)，5.02(1H，dd，J＝10.2，2.7Hz)，6.70(1H，s)，7.20(2H，d，J＝8.8Hz)，7.25-7.40(5H，m)，7.59(2H，d，J＝8.8Hz)，8，96(1H，brs)，9.21(1H，brs)，9.43(1H，brs)，10.58(1H，s)
5 mp：150-152℃NMR δ：2.88-3.07(3H，m)，3.08(3H，m)，3.95(2H，s)，5.00(1H，dd，J＝2.8，10.0Hz)，6.21(1H，s)，6.82(1H，d，J＝7.6Hz)，6.91(1H，d，J＝8.0Hz)，7.17-7.23(2H，m)，7.28-7.43(5H，m)，7.55-7.62(2H，m)，7.82-8.04(3H，m)，8.90(1H，brs)，9.31(1H，brs)，10.67(1H，brs)，14.07(1H，brs)
6 mp：223-224℃NMR δ：2.86-3.22(6H，m)，3.49(2H，s)，4.93-5.03(1H，m)，6.20(1 H，d，J＝4.0Hz)，7.15-7.43(9H，m)，7.55-7.62(2H，m)，7.75(1H，dt，J＝1.6，8.0Hz)，8.45-8.53(1H，m)，8.06-9.50(2H，br)，10.35(1H，brs)

Claims (5)

1.一种用下式表示的酰胺衍生物或其盐类：其中环B是选自呋喃基、噻嗯基、吡咯基、咪唑基、噻唑基、吡唑基、异噻唑基、异噁唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻二唑基、三唑基和四唑基的杂芳基；X是一个键或C1-C6亚烷基；R是氢原子、卤原子、氨基或卤代苯基C1-C6烷基。
2.根据权利要求1所述的酰胺衍生物或其盐类化合物，所述化合物是下列化合物：(R)-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]-2-吡啶羧酰苯胺；(R)-2-[1-(4-氯苄基)-1H-咪唑-2-基]-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰苯胺；(R)-2-[1-(3，4-二氯苄基)-1H-四唑-5-基]-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰苯胺；(R)-2-(2-氨基-噻唑-4-基)-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰苯胺；(R)-2-(2-氨基吡啶-6-基)-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰苯胺；或(R)-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]-2-(2-吡啶基)乙酰苯胺或其盐类。
3.一种糖尿病治疗剂，其含有权利要求1所述的酰胺衍生物或其盐类。
4.根据权利要求3所述的糖尿病治疗剂，其中所述酰胺衍生物或其盐类化合物是下列化合物：(R)-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]-2-吡啶羧酰苯胺；(R)-2-[1-(4-氯苄基)-1H-咪唑-2-基]-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰苯胺；(R)-2-[1-(3，4-二氯苄基)-1H-四唑-5-基]-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰苯胺；(R)-2-(2-氨基-噻唑-4-基)-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰苯胺；(R)-2-(2-氨基吡啶-6-基)-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰苯胺；或(R)-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]-2-(2-吡啶基)乙酰苯胺或其盐类。
5.权利要求1所述的酰胺衍生物或其盐类在制备用于治疗糖尿病的药剂中的用途。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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CN109776373A (zh) * 2019-01-29 2019-05-21 广东东阳光药业有限公司 酰胺取代的吡咯烷酰胺衍生物及其用途

Families Citing this family (78)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2356197A (en) * 1999-10-12 2001-05-16 Merck & Co Inc Amide derivatives as beta 3 agonists
US6451814B1 (en) * 2000-07-17 2002-09-17 Wyeth Heterocyclic β-3 adrenergic receptor agonists
US6410734B1 (en) 2000-07-17 2002-06-25 Wyeth 2-substituted thiazolidinones as beta-3 adrenergic receptor agonists
US6525202B2 (en) * 2000-07-17 2003-02-25 Wyeth Cyclic amine phenyl beta-3 adrenergic receptor agonists
US6537994B2 (en) 2000-07-17 2003-03-25 Wyeth Heterocyclic β3 adrenergic receptor agonists
US6498170B2 (en) 2000-07-17 2002-12-24 Wyeth Cyclamine sulfonamides as β-3 adrenergic receptor agonists
US6465501B2 (en) 2000-07-17 2002-10-15 Wyeth Azolidines as β3 adrenergic receptor agonists
UA82048C2 (uk) * 2000-11-10 2008-03-11 Эли Лилли Энд Компани Агоністи альфа-рецепторів, активованих проліфератором пероксисом
US7342117B2 (en) * 2001-10-30 2008-03-11 Astellas Pharma Inc. α-form or β-form crystal of acetanilide derivative
WO2003042160A1 (en) 2001-11-13 2003-05-22 Theravance, Inc. Aryl aniline beta-2 adrenergic receptor agonists
TWI249515B (en) * 2001-11-13 2006-02-21 Theravance Inc Aryl aniline beta2 adrenergic receptor agonists
SI1458381T1 (sl) * 2001-12-20 2006-04-30 Applied Research Systems Triazoli kot oksitocinski antagonisti
KR100967070B1 (ko) 2002-11-07 2010-07-01 아스텔라스세이야쿠 가부시키가이샤 아세트산 아닐리드 유도체를 유효성분으로 하는 과활동방광 치료제
EP1424079A1 (en) * 2002-11-27 2004-06-02 Boehringer Ingelheim International GmbH Combination of a beta-3-receptor agonist and of a reuptake inhibitor of serotonin and/or norepinephrine
DE102004001413A1 (de) * 2004-01-09 2005-08-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg 3-Hydroxymethyl-4-Hydroxy-Phenyl-Derivate zur Behandlung von chronisch obstruktiver Lungenerkrankung
JP2008507532A (ja) * 2004-07-21 2008-03-13 セラヴァンス， インコーポレーテッド ジアリールエーテルβ２アドレナリン作用性レセプターアゴニスト
CN101595088B (zh) 2007-01-31 2013-06-19 东丽株式会社 苯甲胺衍生物或其药学上允许的酸加成盐及其医药用途
DK2216021T3 (da) 2007-11-02 2012-11-05 Astellas Pharma Inc Farmaceutisk sammensætning til behandling af overaktiv blære
WO2009081837A1 (ja) 2007-12-21 2009-07-02 Astellas Pharma Inc. 下部尿路症状の改善用医薬組成物
DE102008014523A1 (de) * 2008-03-15 2009-09-17 Robert Bosch Gmbh Heizgerät
EP2277858A4 (en) * 2008-05-14 2012-06-13 Astellas Pharma Inc AMIDE COMPOUND
TWI478712B (zh) 2008-09-30 2015-04-01 Astellas Pharma Inc 釋控性醫藥組成物
US8586760B2 (en) * 2009-06-15 2013-11-19 Auspex Pharmaceuticals, Inc. Aminothiazole modulators of beta-3-adrenoreceptor
PT2554168T (pt) 2010-03-29 2018-02-28 Astellas Pharma Inc Composição farmacêutica de libertação controlada
JP5849946B2 (ja) 2010-03-29 2016-02-03 アステラス製薬株式会社 放出制御医薬組成物
IN2013CN09704A (zh) * 2011-05-18 2015-07-03 Reddys Lab Ltd Dr
US9655885B2 (en) 2011-05-18 2017-05-23 Dr. Reddy's Laboratories Ltd. Amorphous mirabegron and processes for crystal forms of mirabegron
EP2832730A4 (en) 2012-03-30 2015-09-09 Astellas Pharma Inc MIRABEGRAPHIC PHARMACEUTICAL COMPOSITION
CN103387500A (zh) * 2012-05-11 2013-11-13 上海医药工业研究院 一种米拉贝隆及其中间体的制备方法
SG11201501415RA (en) 2012-08-31 2015-05-28 Astellas Pharma Inc Orally administered medical composition
WO2014108449A1 (en) 2013-01-08 2014-07-17 Atrogi Ab A screening method, a kit, a method of treatment and a compound for use in a method of treatment
CN103193730A (zh) * 2013-04-17 2013-07-10 苏州永健生物医药有限公司 一种米拉贝隆的合成方法
CN103232368B (zh) * 2013-04-18 2015-08-12 苏州永健生物医药有限公司 一种(r)-4-硝基苯乙基-(2-羟基-2-苯乙基)-氨基甲酸叔丁酯的合成方法
WO2015040573A1 (en) 2013-09-23 2015-03-26 Ranbaxy Laboratories Limited Mirabegron dimethyl sulphoxide solvate and its use for the treatment of overactive bladder
WO2015040605A1 (en) 2013-09-23 2015-03-26 Ranbaxy Laboratories Limited Crystalline form of mirabegron
WO2015044965A1 (en) 2013-09-30 2015-04-02 Megafine Pharma (P) Ltd. A process for preparation of mirabegron and alpha crystalline form thereof
ITMI20131653A1 (it) * 2013-10-07 2015-04-08 Dipharma Francis Srl Forme cristalline di un agonista adrenergico
CN104876889B (zh) * 2014-02-27 2017-02-22 人福医药集团股份公司 化合物的合成方法
WO2015162536A1 (en) * 2014-04-22 2015-10-29 Calyx Chemicals And Pharmaceuticals Ltd. Novel process for preparation of mirabegron and it's intermediate
CN103896872A (zh) * 2014-04-29 2014-07-02 黑龙江大学 米拉贝隆的合成方法
WO2016020440A1 (en) 2014-08-06 2016-02-11 Interquim, S.A. Method for the synthesis of mirabegron and its derivatives
WO2016024284A2 (en) 2014-08-07 2016-02-18 Wanbury Ltd. A process for the preparation of mirabegron and its intermediates
US20170291882A1 (en) * 2014-10-01 2017-10-12 Apotex Inc. Solid Forms of Mirabegron
CN104496841B (zh) * 2014-11-26 2017-01-25 南京工业大学 一种米拉贝隆中间体的合成方法
EP3253741A1 (en) 2015-02-02 2017-12-13 Lupin Limited Process for preparation of polymorphic form of mirabegron
JP2018090490A (ja) 2015-03-31 2018-06-14 アステラス製薬株式会社 ミラベグロン含有医薬組成物
CN105111165B (zh) * 2015-09-14 2017-10-31 保定博洋生物科技有限公司 一种米拉贝隆的制备方法
JP6887996B2 (ja) * 2015-09-23 2021-06-16 ザ ジェネラル ホスピタル コーポレイション Ｔｅａｄ転写因子自己パルミトイル化阻害剤
FR3043555B1 (fr) * 2015-11-17 2019-10-25 Centre National De La Recherche Scientifique (Cnrs) Mirabegron pour le traitement de maladies retiniennes
EP3184516A1 (en) 2015-12-23 2017-06-28 Enantia, S.L. Crystalline inclusion complexes of mirabegron with beta-cyclodextrin
HU231124B1 (hu) * 2016-02-10 2020-12-28 Egis Gyógyszergyár Zrt. Eljárás morfológiailag egységes mirabegron és mirabegron monohidroklorid előállítására
WO2017186593A1 (en) 2016-04-25 2017-11-02 Synthon B.V. Tablets comprising mirabegron and solifenacin
WO2017186598A1 (en) 2016-04-25 2017-11-02 Synthon B.V. Modified release tablet composition comprising mirabegron
GB201612165D0 (en) * 2016-07-13 2016-08-24 Atrogi Ab Combinations for the treatment of type 2 diabetes
US9988402B2 (en) 2016-08-19 2018-06-05 Purdue Research Foundation Amine-boranes bearing borane-intolerant functionalities
EP3335700A1 (de) 2016-12-13 2018-06-20 Stada Arzneimittel Ag Feste pharmazeutische orale darreichungsform mit verlängerter wirkstofffreisetzung umfassend mirabegron
PT3360866T (pt) 2017-02-14 2019-02-19 Tiefenbacher Alfred E Gmbh & Co Kg Pró-fármacos de mirabegrom
KR101868438B1 (ko) 2017-04-13 2018-06-20 (주) 성운파마코피아 아미드 유도체의 제조방법
CN117695286A (zh) 2017-06-06 2024-03-15 住友制药(苏州)有限公司 使用维贝隆以治疗膀胱过度活动症
KR102398639B1 (ko) 2017-06-20 2022-05-17 (주) 성운파마코피아 아미드 유도체의 염 및 그 제조방법
WO2019013583A2 (ko) 2017-07-14 2019-01-17 주식회사 대웅제약 약제학적 제제 및 그 제조방법
KR101937713B1 (ko) 2017-07-14 2019-01-14 주식회사 대웅제약 약제학적 제제 및 그 제조방법
GB201714740D0 (en) 2017-09-13 2017-10-25 Atrogi Ab New compounds and uses
GB201714734D0 (en) 2017-09-13 2017-10-25 Atrogi Ab New compounds and uses
GB201714745D0 (en) 2017-09-13 2017-10-25 Atrogi Ab New compounds and uses
GB201714736D0 (en) 2017-09-13 2017-10-25 Atrogi Ab New compounds and uses
US10478399B2 (en) 2017-10-12 2019-11-19 Synthon B.V. Modified release tablet composition comprising mirabegron
EP3292864A1 (en) 2017-10-12 2018-03-14 Synthon B.V. Modified release tablet composition comprising mirabegron
CA3078568A1 (en) 2017-10-12 2019-04-18 Synthon B.V. Modified release tablet composition comprising mirabegron
KR101928987B1 (ko) * 2018-08-28 2018-12-13 (주) 성운파마코피아 신규한 고순도 미라베그론의 결정질 일수화물, 이의 제조방법 또는 용도
CN109734712B (zh) * 2019-01-30 2020-10-20 广东东阳光药业有限公司 芳基或杂芳基取代的吡咯烷酰胺衍生物及其用途
KR20200117091A (ko) 2019-04-02 2020-10-14 제이투에이치바이오텍 (주) 미라베그론 전구체 약물 화합물 및 이의 과민성 방광 질환의 치료 또는 개선을 위한 의약 용도
KR20210012082A (ko) 2019-07-23 2021-02-03 콜마파마(주) 미라베그론 및 탐스로신을 포함하는 약학 조성물
CN110590699B (zh) * 2019-09-29 2022-11-15 广东先强药业有限公司 一种米拉贝隆的精制方法
EP3722285B1 (en) 2020-04-08 2022-03-30 Alfred E. Tiefenbacher (GmbH & Co. KG) Process for preparing mirabegron enacarbil
KR102333167B1 (ko) 2021-05-26 2021-12-01 유니셀랩 주식회사 효율적이고 대량생산이 가능한 미라베그론 무정형 제조방법
GB202205895D0 (en) 2022-04-22 2022-06-08 Atrogi Ab New medical uses
US12097189B1 (en) 2024-02-09 2024-09-24 Astellas Pharma Inc. Pharmaceutical composition for modified release

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2965655D1 (en) * 1978-06-28 1983-07-21 Beecham Group Plc Secondary amines, their preparation, pharmaceutical compositions containing them and their use
DE3743265A1 (de) * 1987-12-19 1989-06-29 Boehringer Ingelheim Kg Neue ammoniumverbindungen, ihre herstellung und verwendung
US5223614A (en) * 1987-12-19 1993-06-29 Boehringer Ingelheim Gmbh New quaternary ammonium compounds, their preparation and use
GB2280395B (en) 1992-03-27 1996-05-01 Kawasaki Steel Co Method for detecting setting errors of clearance between rollers in universal rolling mill, and method for rolling h-shaped steel having favourable flange dim
US5451677A (en) * 1993-02-09 1995-09-19 Merck & Co., Inc. Substituted phenyl sulfonamides as selective β 3 agonists for the treatment of diabetes and obesity
JP3722855B2 (ja) * 1993-09-14 2005-11-30 武田薬品工業株式会社 ２，４−オキサゾリジンジオン誘導体およびそれを含んでなる医薬
US5614544A (en) 1993-09-14 1997-03-25 Takeda Chemical Industries, Ltd. Oxazolidinedione derivatives and their use
US5541197A (en) * 1994-04-26 1996-07-30 Merck & Co., Inc. Substituted sulfonamides as selective β3 agonists for the treatment of diabetes and obesity
IL113410A (en) * 1994-04-26 1999-11-30 Merck & Co Inc Substituted sulfonamides having an asymmetric center and pharmaceutical compositions containing them
PL334655A1 (en) 1997-01-23 2000-03-13 Yamanouchi Pharma Co Ltd Novel amidic derivatives and therapeutic preparations containing them
JPH10218861A (ja) * 1997-02-04 1998-08-18 Yamanouchi Pharmaceut Co Ltd 新規なフェネタノール誘導体又はその塩

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105481705A (zh) * 2014-08-23 2016-04-13 南京海纳医药科技有限公司 (r)-2-[[2-(4-氨基苯基)乙基]氨基]-1-苯乙醇的制备及应用
CN109776373A (zh) * 2019-01-29 2019-05-21 广东东阳光药业有限公司 酰胺取代的吡咯烷酰胺衍生物及其用途

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