CN108349908B - 一种取代的苯并咪唑酮化合物及包含该化合物的组合物 - Google Patents
一种取代的苯并咪唑酮化合物及包含该化合物的组合物 Download PDFInfo
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Abstract
本发明提供了一种取代的苯并咪唑酮化合物及包含该化合物的组合物,本发明公开了如式(I)所示的取代的苯并咪唑酮化合物以及含有该化合物、或其晶型、药学上可接受的盐、水合物或溶剂合物、立体异构体、前药或同位素变体的药物组合物。本发明公开的取代的苯并咪唑酮化合物及包含该化合物的组合物对5HT2受体具有优异的抑制性,同时具有更好的药代动力学参数特性,能够提高化合物在动物体内的药物浓度,以提高药物疗效和安全性。
Description
技术领域
本发明属于医药技术领域,尤其涉及一种取代的苯并咪唑酮化合物及包含该化合物的组合物。
背景技术
血清紧张素(5-羟色胺,5-HT)受体是一种重要的G蛋白-偶联受体。一般认为血清紧张素在与学习和记忆、睡眠、温度调节、情绪、自发活动、疼痛、性和攻击性行为、食欲、神经变性的调节和生物节律有关的过程中发挥作用。正如所料,血清紧张素与疾病生理状况比如焦虑、抑郁症、强迫-强制症、精神分裂症、自杀、孤独症、偏头痛、呕吐、酒精中毒和神经变性病症是相联系的。
目前血清紧张素受体被归类为七个亚族(5-HT1至5-HT7)。参见,Hoyer,D.等人,Pharmacol.Rev.,1994,56,157-203。亚族已经被进一步分成亚型。例如,5-HT2受体目前被分成三个亚型:5-HT2a、5-HT2b和5-HT2c。其中,5-HT2受体的三个亚型是与产生两个第二信使:甘油二酯(其活化蛋白激酶C)和肌醇三磷酸酯(其释放胞内存储的Ca2+)的磷脂酶C相连接的。
发明内容
针对以上技术问题,本发明公开了一种取代的苯并咪唑酮化合物及包含该化合物的组合物,其具有更好的血清紧张素受体抑制活性和/或具有更好药效学/药代动力学性能。
对此,本发明采用的技术方案为:
本发明的目的是提供一类新型的具有血清紧张素受体抑制活性的和/或具有更好药效学/药代动力学性能的化合物。
本发明的第一方面中,提供了一种式(I)所示的取代的苯并咪唑酮化合物,或其晶型、药学上可接受的盐、水合物或溶剂化合物。
其中,R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20和R21各自独立地为氢、氘、卤素或三氟甲基;
X为C、N;
附加条件是R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20和R21中至少一个是氘。
氘在药物分子中的形状和体积与氢基本上相同,如果药物分子中氢被选择性替换为氘,氘代药物一般还会保留原来的生物活性和选择性。同时发明人经过实验证实,碳氘键的结合比碳氢键的结合更稳定,可直接影响一些药物的吸收、分布、代谢和排泄等属性,从而提高药物的疗效、安全性和耐受性。
在另一优选例中,氘在各氘代位置的氘同位素含量至少是大于天然氘同位素含量(0.015%),较佳地大于30%,更佳地大于50%,更佳地大于75%,更佳地大于95%,更佳地大于99%。
具体地说,在本发明中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20和R21各氘代位置中氘同位素含量至少是5%,较佳地大于10%,更佳地大于15%,更佳地大于20%,更佳地大于25%,更佳地大于30%,更佳地大于35%,更佳地大于40%,更佳地大于45%,更佳地大于50%,更佳地大于55%,更佳地大于60%,更佳地大于65%,更佳地大于70%,更佳地大于75%,更佳地大于80%,更佳地大于85%,更佳地大于90%,更佳地大于95%,更佳地大于99%。
在另一优选例中,式(I)中化合物的R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20和R21,至少其中一个R含氘,更佳地两个R含氘,更佳地三个R含氘,更佳地四个R含氘,更佳地五个R含氘,更佳地六个R含氘,更佳地七个R含氘,更佳地八个R含氘,更佳地九个R含氘,更佳地十个R含氘,更佳地十一个R含氘,更佳地十二个R含氘,更佳地十三个R含氘,更佳地十四个R含氘,更佳地十五个R含氘,更佳地十六个R含氘,更佳地十七个R含氘,更佳地十八个R含氘,更佳地十九个R含氘,更佳地二十个R含氘,更佳地二十一个R含氘。
在另一优选例中,R18是三氟甲基。
在另一优选例中,R1、R2、R3和R4各自独立地为氘或氢。
在另一优选例中,R5、R6、R7和R8各自独立地为氘或氢。
在另一优选例中,R9、R10、R11、R12、R13、R14、R15和R16各自独立地为氘或氢。
在另一优选例中,R17、R19、R20和R21各自独立地为氘或氢。
在另一优选例中,其特征在于,R1、R2、R3、R4是氘。
在另一优选例中,其特征在于,R5、R6、R7、R8是氘。
在另一优选例中,其特征在于,R9、R10、R11、R12、R13、R14、R15、R16是氘。
在另一优选例中,R17、R19、R20、R21是氘。
在另一优选例中,所述化合物选自下组化合物或其药学上可接受的盐:
在另一优选例中,所述化合物不包括非氘代化合物。
在另一优选例中,所述的非氘代化合物为3-[2-[4-[4-(三氟甲基)苯基]哌嗪-1-基]乙基]-1H-苯并咪唑-2-酮。
在本发明的第二方面中,提供了一种制备药物组合物的方法,包括步骤:将药学上可接受的载体与本发明第一方面中所述的化合物,或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合,从而形成药物组合物。
在本发明的第三方面中,提供了一种药物组合物,它含有药学上可接受的载体和本发明第一方面中所述的化合物,或其晶型、药学上可接受的盐、水合物或溶剂合物。
在另一优选例中,所述的药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。
本发明的化合物可以与其它药物联合给药,比如载脂蛋白-B/MTP抑制剂、MCR-4激动剂、CCK-A激动剂、单胺再摄取抑制剂、拟交感神经药、β3肾上腺素能受体激动剂、多巴胺激动剂、促黑素细胞激素受体类似物、大麻素1受体拮抗剂、黑色素浓缩激素拮抗药、瘦激素、瘦激素类似物、瘦激素受体激动剂、甘丙肽拮抗剂、脂肪酶抑制剂、铃蟾肽激动剂、神经肽-Y拮抗剂、拟甲状腺素药、脱氢异雄甾酮或其类似物、糖皮质激素受体激动剂或拮抗剂、阿立新(orexin)受体拮抗剂、尿皮质素结合蛋白拮抗剂、胰高血糖素样肽-1受体激动剂、睫状神经营养因子、AGRPs(人野灰相关蛋白质)、生长素释放肽受体拮抗剂、组胺3受体拮抗剂或反向激动剂、神经调节肽U受体激动剂等。
联合治疗可以以下方式给药:(1)单一的药物组合物,包含本发明的化合物,至少一种如上所述的其它药剂以及药学可接受的赋形剂、稀释剂或载体;或(2)两种分开的药物组合物,包含式(I)的化合物和药学可接受的赋形剂、稀释剂或载体。药物组合物可同时或依次和以任何顺序给药。
在本发明的另一方面,提供了一种消费者使用的药物试剂盒,用于治疗动物中5-HT2受体-介导的疾病、状况或障碍。该试剂盒包含a)包含本发明化合物的适宜剂型;和b)描述使用该剂型治疗或预防5-HT2受体-介导的疾病、状况或障碍的方法的说明书。
本发明的另一实施方案是一种药物试剂盒,包含:a)第一种剂型,包含(i)本发明的化合物和(ii)药学可接受的载体、赋形剂或稀释剂;b)第二种剂型,包含(i)一种如上所述的其它药剂,和(ii)药学可接受的载体、赋形剂或稀释剂;和c)一种容器。
本发明的另一个方面是一种治疗雌性动物性功能障碍(FSD)的方法,包含给予需要该治疗的雌性动物治疗有效量的本发明化合物的步骤。该方法可更进一步包括给予一或多种另外的用于治疗FSD的活性药物。另外的活性剂可以选自:(1)雌激素受体蛋白调节剂、雌激素激动剂、雌激素拮抗剂或其组合;(2)睾酮替代剂、睾酮、二氢睾酮、脱氢异雄甾酮、睾酮植入物或其组合;(3)雌激素、雌激素和甲羟孕酮或醋酸甲羟孕酮的组合,或雌激素和甲基睾酮激素代替治疗剂;(4)一或多种多巴胺能药;(5)一或多种NPY(神经肽Y)抑制剂;(6)一或多种黑皮质素受体激动剂或调节剂或黑皮质素增强剂;(7)一或多种中性内肽酶(NEP)抑制剂;(8)一或多种磷酸二酯酶(PDE)抑制剂;和(9)一或多种铃蟾肽受体拮抗剂或调节剂。FSD治疗包括雌性动物性唤起障碍(FSAD)、雌性动物性高潮障碍(FOD)、机能减退的性欲障碍(HSDD)或性交疼痛障碍。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
本发明还包括同位素标记的化合物,等同于原始化合物在此公开。可以列为本发明的化合物同位素的例子包括氢,碳,氮,氧,磷,硫,氟和氯同位素,分别如2H,3H,13C,14C,15N,17O,18O,31P,32P,35S,18F以及36Cl。本发明中的化合物,或对映体,非对映体,异构体,或药学上可接受的盐或溶剂化物,其中含有上述化合物的同位素或其他其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物,例如3H和14C的放射性同位素也在其中,在药物和底物的组织分布实验中是有用的。氚,即3H和碳-14,即14C,它们的制备和检测比较容易,是同位素中的首选。此外,较重同位素取代如氘,即2H,由于其很好的代谢稳定性在某些疗法中有优势,例如在体内增加半衰期或减少用量,因此,在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法,通过用易得的同位素标记试剂替换为非同位素的试剂,用示例中的方案可以制备。
本发明化合物可有效用作5HT2部分激动剂或拮抗剂;因此,本发明的另一个实施方案是一种药物组合物,包括治疗有效量的本发明化合物和药物可接受的赋形剂、稀释剂或载体。
典型的制剂是通过本发明化合物与载体、稀释剂或赋形剂进行混合制备的。适宜的载体、稀释剂和赋形剂是本领域技术人员所熟知的,包括物质比如碳水化合物、石蜡、水溶性的和/或可膨胀的聚合物、亲水的或疏水性的物质、明胶、油剂、溶剂、水等。所使用的具体载体、稀释剂或赋形剂将取决于应用本发明化合物的方式和目的。溶剂通常选自以本领域技术人员认为对所给药的哺乳动物安全的的溶剂。通常,安全的溶剂是无毒的含水溶剂比如水及其它在水中可溶的或可混溶的无毒溶剂。适宜的含水溶剂包括水、乙醇、丙二醇、聚乙二醇(例如,PEG400、PEG300)等及其混合物。制剂还可以包括一或多种缓冲液、稳定剂、表面活性剂、润湿剂、润滑剂、乳化剂、助悬剂、防腐剂、抗氧化剂、避光剂、助流剂、过程助剂、着色剂、甜味剂、香料、调味剂及其它已知的添加剂,以提供药物(即,本发明化合物或它们的药物组合物)精美的外观,或有助于药剂(即,药物)的制造。
可使用常规的溶解和混合过程制备制剂。例如,可在如上所述的一或多种赋形剂的存在下,将批量药物物质(即,本发明化合物或该化合物的稳定化形式(例如,与环糊精衍生物或其它已知的复合试剂的复合物))溶于适宜的溶剂中。可将本发明化合物典型地配制成药物剂型,以提供容易控制的药物剂量并为患者提供精致的和容易使用的产物。
用于给药的药物组合物(或制剂)可以被以各种方法包装,取决于所使用的给药方法。通常,分配的物品包括可将药物制剂以适当的形式放置于其中的容器。适宜的容器是本领域技术人员所熟知的,包括材料比如瓶(塑料的和玻璃的)、小袋、安瓿、塑料袋、金属圆筒等。容器还可以包括防干扰的装配件以防止轻率地使用包装的内容物。此外,在容器上加标签以记载容器中的内容物。标签还可以包括适当的警告。
本发明更进一步为需要这样的治疗的动物中提供了治疗5HT2受体-介导的疾病、状况或障碍的方法,包括给予动物治疗有效量的本发明化合物或包含有效量的本发明化合物和药学可接受的赋形剂、稀释剂或载体的药物组合物。该方法可特别有用于治疗5HT2受体-介导的疾病、状况或障碍。优选地,本发明的化合物作为5HT2受体地部分激动剂。更优选地,本发明的化合物作为5HT2受体地部分激动剂并且作用5HT2受体地拮抗剂。
优选地,5HT2受体-介导的疾病、状况或障碍选自:体重减轻(例如、在热量摄入下降)、肥胖、贪食症、经前期综合征或迟黄体期综合症、抑郁症、非典型性抑郁症、躁狂抑郁性精神病、精神病、精神分裂症、偏头痛、酒精中毒、烟草滥用、恐慌症、焦虑、创伤后综合征、记忆丧失、老年痴呆、社会恐怖症、注意缺陷障碍伴多动症、破坏性行为障碍、冲动控制障碍、临界人格障碍、强迫性强制障碍、慢性疲乏综合征、雄性性功能障碍(例如,早泄和勃起困难)、雌性性功能障碍、神经性厌食症、睡眠障碍(例如,睡眠呼吸暂停)、孤独症、癫痫发作、癫痫、缄默症、脊髓损伤、中枢神经系统损伤(例如,外伤、中风、神经退行性疾病或有毒或传染性CNS疾病(例如,脑炎或脑膜炎))、心血管疾病(例如,血栓形成)、胃肠道病症(例如,胃肠运动性功能障碍)、尿崩症和II型糖尿病。相应地,这里描述的本发明化合物可有效用于治疗或预防5-HT2受体-介导的疾病、状况或障碍。因此,本发明化合物(包括组合物和其中所使用的方法)可用于制造用于这里所描述的治疗应用的药物。
本发明化合物可以以每天约0.7毫克到约7,000毫克的剂量水平对患者给药。对于正常体重约70千克的成年人,典型地每公斤体重约0.01毫克到约100毫克的剂量是足够的。然而,通常的剂量范围可根据所要治疗患者的年龄和重量、给药的途径、给予的特定的化合物等等进行一些改变。对于特定患者的剂量范围和最佳剂量的确定,是在得益于本公开的本领域普通技术人员的能力范围之内的。还应注意本发明的化合物可以缓释释放、控制释放和迟延释放制剂的形式使用,其形式是普通技术人员所熟知的。
本发明的化合物还可以与其它用于治疗本文中所描述的疾病/状况的药物结合使用。因此,还提供了包括给予与其它药物组合的本发明化合物的治疗方法。可与本发明的化合物联用的适宜的药物包括抗肥胖剂比如载脂蛋白-B分泌/微粒体甘油三酸酯转移蛋白(apo-B/MTP)抑制剂,MCR-4激动剂、缩胆囊肽-A(CKK-A)激动剂、单胺再摄取抑制剂(比如西布曲明)、拟交感神经药剂、β3肾上腺素能受体激动剂、多巴胺激动剂(比如溴麦角环肽)、促黑素细胞激素受体类似物、大麻素1受体拮抗剂、黑色素浓缩激素拮抗药、瘦激素(OB蛋白)、瘦激素类似物、瘦激素受体激动剂、甘丙肽拮抗剂、脂肪酶抑制剂(比如tetrahydrolipstatin,即奥利司他)、减食欲剂(比如A铃蟾肽激动剂)、神经肽-Y拮抗剂、拟甲状腺素药、脱氢异雄甾酮或它们的类似物、糖皮质激素受体激动剂或拮抗剂、阿立新受体拮抗剂、尿皮质素结合蛋白拮抗剂、胰高血糖素样肽-1受体激动剂、睫状神经营养因子(比如AxokineTM,Regeneron Pharmaceuticals,Inc.,Tarrytown,NY和Procter &GambleCompany,Cincinnati,OH)、人野灰相关蛋白质(AGRP)、生长素释放肽受体拮抗剂、组胺3受体拮抗剂或反向激动剂、神经调节肽铀受体激动剂。其它抗肥胖药剂,包括在下文所列出的优选药剂是为大家所熟知的,或按照本公开的教导对普通技术人员是很明显的。
尤其优选的抗肥胖药剂选自:奥利司他、西布曲明、溴麦角环肽、麻黄素、瘦激素和假麻黄碱。优选地,本发明化合物以及联合治疗应结合锻炼和合理的饮食。
在联合用药、药物组合物和本发明的方法中所使用的代表性的抗肥胖药剂可以使用普通技术人员所熟知的方法制备,例如,西布曲明可以按照美国专利US 4,929,629中所述制备;溴麦角环肽可以按照美国专利U.S.3,752,814和3,752,888中所述方法制备;而奥利司他可按照美国专利U.S.5,274,143;5,420,305;5,540,917;和5,643,874中所述方法制备。上述所有引用的美国专利在此引入作为参考。
其它药物(例如,抗肥胖药剂)的剂量通常还将还取决于许多因素,包括要被治疗的患者的健康状况,所需要治疗的程度,并存治疗的性质和种类(如果有的话),以及治疗的次数和目标效果的性质。通常,抗肥胖药剂的剂量范围为每人每公斤体重每天约0.001毫克到约100毫克,优选每人每公斤体重每天约0.1毫克到约10毫克。然而,通常的剂量范围还可根据要进行治疗的患者的年龄和重量、给药的途径、给予的特定的抗肥胖药剂等等进行一些改变。对于特定患者的剂量范围和最佳剂量的确定,也是在得益于本公开的本领域普通技术人员的能力范围之内的。
在本发明的另一个实施方案中,发现本发明的化合物可用于治疗性功能障碍。性功能障碍(SD)是一种值得注意的临床问题,雄性和雌性动物都可能被波及。导致SD的原因既可能是器质性的也可能是心理上的。器质方面的SD典型地由潜在的血管疾病比如与高血压或糖尿病有关的血管疾病,由处方药物和/或由精神性疾病比如抑郁症所引起。生理的因素包括恐惧、行为焦虑和人际冲突。SD损害性行为、消弱自尊和破坏人际关系,由此引起个人的痛苦。在临床中,SD障碍被分成雌性性机能(FSD)障碍和雄性性功能障碍(MSD)。FSD可明确定义为妇女对性表现感到满意的困难或无能。MSD通常与勃起机能障碍有关,亦称雄性勃起机能障碍(MED)(Benet等人,Comp.Ther.,1994,20,669-673)。
本发明的化合物可特别有益于预防和/或治疗雄性动物中的性功能障碍(例如雄性勃起功能障碍-MED)和雌性动物中的-雌性性功能障碍(FSD),例如雌性动物性唤起障碍(FSAD)。
本文中,如无特别说明,“卤素”指F、Cl、Br、和I。更佳地,卤原子选自F、Cl和Br。
本文中,如无特别说明,“C1-C6烷基”是指包括1-6个碳原子的直链或支链的烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、或类似基团。
本文中,如无特别说明,“氘代”指化合物或基团中的一个或多个氢被氘所取代;氘代可以是一取代、二取代、多取代或全取代。术语“一个或多个氘代的”与“一次或多次氘代”可互换使用。
本文中,如无特别说明,“非氘代的化合物”是指含氘原子比例不高于天然氘同位素含量(0.015%)的化合物。
本发明中,药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸;甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸;以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。另一类优选的盐是本发明化合物与碱形成的盐,例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐),例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐,以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”是指本发明化合物与水进行配位形成的配合物。
与现有技术相比,本发明的有益效果为:(1)本发明化合物对血清紧张素受体具有优异的抑制性;(2)通过氘化这一技术改变化合物在生物体中的代谢,使化合物具有更好的药代动力学参数特性。在这种情况下,可以改变剂量并形成长效制剂,改善适用性;用氘取代化合物中的氢原子,由于其氘同位素效应,能够提高化合物在动物体内的药物浓度,以提高药物疗效;用氘取代化合物中的氢原子,由于某些代谢产物被抑制,可能提高化合物的安全性。
具体实施方式
下面更具体地描述本发明式(I)结构化合物的制备方法,但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得,这样的组合可由本发明所属领域的技术人员容易地进行。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则份数和百分比为重量份和重量百分比。
实施例1. 4,5,6,7-d4-3-[2-[4-[4-(三氟甲基)苯基]哌嗪-1-基]乙基]-1H-苯并
咪唑-2-酮(化合物9)的合成
步骤1:化合物2的合成。将Pt/C(40mg)加入至1,2-苯二胺的氘水溶液(4mL)中,用氢气鼓泡5分钟,在100℃下加热14小时,待反应液恢复至室温后,用水稀释,二氯甲烷萃取,旋干得到黄色固体产物150mg,收率为72.5%。1H NMR(300MHz,DMSO-d6)(δ/ppm)4.39(s,4H);LC-MS(APCI):m/z=113.2(M+1)+。
步骤2:化合物4的合成。将乙酰乙酸乙酯加入至化合物2(150mg,1.34mmol)与KOH(3mg,53μmol)的甲苯溶液(4mL)中,回流14小时,旋干过柱得无色油状产物95mg,收率为39.9%。1H NMR(300MHz,DMSO-d6)(δ/ppm)10.97(s,1H),5.34(d,J=1.5Hz,1H),5.13(d,J=0.6Hz,1H),2.14(s,3H);LC-MS(APCI):m/z=179.2(M+1)+。
步骤3:化合物6的合成。将化合物4(95mg,545μmol)与NaOH(44mg,1.09mmol)的混合物在室温下搅拌1小时,加入1,2-二溴乙烷(205mg,1.09mmol),继续在室温下搅拌1.5小时。将15mL水倒入反应体系中,用二氯甲烷萃取,旋干过柱得黄色油状产物100mg,收率为65.4%。1H NMR(300MHz,DMSO-d6)(δ/ppm)5.38(d,J=1.5Hz,1H),5.23(d,J=0.9Hz,1H),5.35(s,1H),5.20(s,1H),4.30(t,J=7.2Hz,2H),3.68(t,J=6.9Hz,4H),2.25(s,3H);LC-MS(APCI):m/z=285.2(M+1)+。
步骤4:化合物8的合成。将氢氧化钠(17mg,423μmol)的水溶液(3mL)加入至化合物6(100mg,356μmol)、化合物7(90mg,391μmol)的丙酮溶液(3mL)中,在室温下搅拌过夜,旋干丙酮,溶于二氯甲烷,萃取后旋干过柱得黄色固体产物100mg,收率为65.4%。1H NMR(300MHz,CDCl3)(δ/ppm)7.35(t,J=7.8Hz,1H),7.10-7.05(m,3H),5.35(s,1H),5.20(s,1H),4.07(t,J=6.6Hz,2H),3.23(t,J=5.1Hz,4H),2.81-2.72(m,6H);LC-MS(APCI):m/z=435..3(M+1)+。
步骤5:化合物9的合成。将盐酸(5mL,2M/L)加入至化合物8(100mg,230μmol)的1,4-二氧六环溶液(5mL)中,在63℃下搅拌2小时后,恢复至室温,用乙酸乙酯稀释,萃取后旋干纯化得白色固体产物47mg,收率为51.8%。1H NMR(300MHz,DMSO-d6)(δ/ppm)10.82(s,1H),7.40(t,J=7.8Hz,1H),7.20(d,J=7.8Hz,1H),7.18(s,1H),7.05(d,J=7.5Hz,1H),3.94(t,J=6.6Hz,2H),3.18-3.15(m,4H),2.65-2.59(m,6H);LC-MS(APCI):m/z=395.3(M+1)+。
实施例2. 3-[2-[4-[4-(三氟甲基)苯基]2,2,3,3,5,5,6,6-d8-哌嗪-1-基]乙
基]-1H-苯并咪唑-2-酮(化合物17)的合成
步骤1:化合物13的合成。将碳酸钾加入至化合物11(1.03g,6.17mmol)、化合物12(300mg,1.23mmol)的DMF溶液(5mL)中,在120℃下搅拌过夜,倒入50mL水,用乙酸乙酯萃取,旋干后得白色固体产物380mg,收率为96.9%。1H NMR(300MHz,DMSO-d6)(δ/ppm)7.32(t,J=1.8Hz,1H),7.16-7.14(m,2H),2.35(br s,1H);LC-MS(APCI):m/z=317.2(M+1)+。
步骤2:化合物14的合成。将Pd/C(35mg)加入至化合物13(350mg,1.1mmol)的甲醇溶液(10mL)中,在氢气氛围下室温搅拌2小时,过滤,旋干滤液得白色固体产物250mg,收率为71%。1H NMR(300MHz,DMSO-d6)(δ/ppm)8.77(s,2H),7.45(t,J=8.1Hz,,1H),7.30-7.25(m,2H),7.15(d,J=7.5Hz,1H);LC-MS(APCI):m/z=238.3(M+1)+。
步骤3:化合物16的合成。反应步骤与实施例1步骤4相同,得到无色油状产物154mg,收率为54.2%。1H NMR(300MHz,CDCl3)(δ/ppm)7.35(t,J=7.5Hz,1H),7.28-7.04(m,7H),5.34(s,2H),4.08(t,J=6.6Hz,2H),3.62(t,J=7.8Hz,2H),0.93(t,J=8.4Hz,2H),0.05(s,9H);LC-MS(APCI):m/z=529.4(M+1)+。
步骤4:化合物17的合成。0℃下,将三氟乙酸(1mL)逐滴加入至化合物16(154mg,291μmol)的二氯甲烷溶液中,滴加完毕后,室温下搅拌1小时,旋干,在室温下加入NH3/MeOH(15mL,7N)搅拌1小时,旋干溶于二氯甲烷,过滤,旋干滤液,过柱得白色固体产物90mg,收率为77.6%。1H NMR(300MHz,DMSO-d6)(δ/ppm)9.34(s,1H),7.35(t,J=7.5Hz,1H),7.13-7.02(m,7H),4.08(t,J=6.6Hz,2H),2.80(t,J=6.6Hz,2H);LC-MS(APCI):m/z=399.3(M+1)+。
实施例3. 3-[2-[4-[4-(三氟甲基)-6-d-苯基哌嗪-1-基]乙基]-1H-苯并咪唑-2-
酮(化合物22)的合成
步骤1:化合物19的合成。反应步骤与实施例1步骤4相同,得到白色固体产物960mg,收率为75.6%。1H NMR(300MHz,DMSO-d6)(δ/ppm)7.32(s,1H),7.16-7.15(m,2H),3.16(t,J=4.5,4H),2.80(t,J=4.5Hz,4H);LC-MS(APCI):m/z=309.1(M+1)+。
步骤2:化合物20的合成。反应步骤与实施例2步骤2相同,得到白色固体产物200mg,收率为99%。LC-MS(APCI):m/z=232.3(M+1)+。
步骤3:化合物21的合成。反应步骤与实施例2步骤3相同,得到无色油状产物90mg,收率为32%。1H NMR(300MHz,DMSO-d6)(δ/ppm)7.26-7.18(m,3H)7.11-7.04(m,4H),5.24(s,2H),4.01(t,J=6.3Hz,2H),3.50(t,J=7.8Hz,2H),3.12(t,J=4.5Hz,2H),2.68-2.57(m,6H),0.15(s,9H);LC-MS(APCI):m/z=522.4(M+1)+。
步骤4:化合物22的合成。反应步骤与实施例2步骤4相同,得到白色固体产物42mg,收率为62.2%。1H NMR(300MHz,DMSO-d6)(δ/ppm)9.71(s,1H),7.12-7.03(m,7H),4.08(t,J=6.9Hz,2H),3.22(t,J=4.8Hz,4H),2.82-2.72(m,6H);LC-MS(APCI):m/z=392.3(M+1)+。
实施例4. 3-[2-[4-[4-(三氟甲基苯基哌嗪-1-基]-1,1,2,2-d4-乙基]-1H-苯并
咪唑-2-酮(化合物31)的合成
步骤1:化合物24的合成。将LiAlD4(1.12g,22.69mmol)的四氢呋喃(THF)溶液(20mL)在0℃下加入至草酸二乙酯(2.6g,17.79mmol)的THF溶液(10mL)中,滴加完后,在80℃下搅拌3小时,加入2mL水,过滤旋干滤液得到无色油状产物700mg,收率为59.3%。
步骤2:化合物26的合成。将吡啶加入至化合物24(700mg,1059mmol)、化合物25(TsCl,4.64g,24.36mmol)的50mL二氯甲烷溶液中,室温下搅拌过夜,水洗后过柱得到黄色固体产物400mg,收率为10.1%。1H NMR(300MHz,DMSO-d6)(δ/ppm)7.74(d,J=8.4Hz,4H),7.35(d,J=8.4Hz,4H),2.46(s,6H);LC-MS(APCI):m/z=375.2(M+1)+。
步骤3:化合物28的合成。反应步骤与实施例2步骤3相同,得到黄色油状产物22mg,收率为89.8%。LC-MS(APCI):m/z=467.4(M+1)+。
步骤4:化合物30的合成。将碳酸钾(272mg,1.97mmol)、碘化钠(197mg,1.31mmol)加入至化合物28(220mg,656μmol)、化合物29(302mg,1.31mmol)的乙腈溶液(15mL)中,80℃下搅拌16小时,旋干过柱纯化得到无色油状产物110mg,收率为32.0%。1H NMR(300MHz,DMSO-d6)(δ/ppm)7.34(t,J=4.8Hz,1H),7.20-7.18(m,1H),7.14-7.01(m,7H),5.33(s,2H),3.61(t,J=5.1Hz,2H),3.21(t,J=3.0Hz,4H),2.72(t,J=3Hz,4H),0.93-0.90(m,2H),-0.05(s,9H);LC-MS(APCI):m/z=525.4(M+1)+。
步骤5:化合物31的合成。反应步骤与实施例2步骤4相同,得到白色固体产物51mg,收率为61.4%。1H NMR(300MHz,DMSO-d6)(δ/ppm)9.71(s,1H),7.12-7.03(m,7H),4.08(t,J=6.9Hz,2H),3.22(t,J=4.8Hz,4H),2.82-2.72(m,6H);LC-MS(APCI):m/z=395.3(M+1)+。
实施例5. 3-[2-[4-[4-(三氟甲基苯基哌嗪-1-基]-1,1-d2-乙基]-1H-苯并咪唑-
2-酮(化合物38)的合成
步骤1:化合物33的合成。将三乙胺(440mg,4.34mmol)加入至2-溴乙酸甲酯(399mg,2.61mmol)、化合物29(500mg,2.17mmol)的二氯甲烷溶液(15mL)中,室温下搅拌2小时,旋干过柱得无色油状产物600mg,收率为91.4%。1H NMR(300MHz,CDCl3)(δ/ppm)7.35(t,J=4.8Hz,1H),7.11-7.05(m,3H),3.75(s,3H),3.31-3.29(m,6H),2.76(t,J=3.6Hz,4H);LC-MS(APCI):m/z=303.4(M+1)+。
步骤2:化合物34的合成。反应步骤与实施例4步骤1相同,得到无色油状产物210mg,收率为76.1%。1H NMR(300MHz,CDCl3)(δ/ppm)7.37(t,J=6Hz,1H),7.13-7.07(m,3H),3.27(t,J=3.6Hz,4H),2.70(t,J=3.9Hz,4H),2.63(s,2H);LC-MS(APCI):m/z=277.3(M+1)+。
步骤3:化合物36的合成。反应步骤与实施例4步骤2相同,得到黄色油状产物250mg,收率为98.0%。LC-MS(APCI):m/z=355.4(M+1)+。
步骤4:化合物37的合成。反应步骤与实施例4步骤4相同,得到黄色固体产物158mg,收率为42.8%。1H NMR(300MHz,CDCl3)(δ/ppm)7.34(t,J=7.8Hz,1H),7.21-7.03(m,7H),5.33(s,2H),4.06(s,1H),3.61(t,J=8.1Hz,2H),3.23-3.18(m,4H)),2.76-2.70(m,5H),0.91(t,J=8.1Hz,2H),0.05(s,9H);LC-MS(APCI):m/z=523.4(M+1)+。
步骤5:化合物38的合成。反应步骤与实施例2步骤4相同,得到白色固体产物1HNMR(300MHz,CDCl3)(δ/ppm)9.31(brs,1H),7.30(t,J=8.1Hz,1H),7.27-7.06(m,7H),4.06(s,1H),3.24-3.22(m,4H),2.78(s,1H),2.77-2.73(m,4H)。LC-MS(APCI):m/z=393.3(M+1)+。
实施例6. 3-[2-[4-[4-(三氟甲基苯基哌嗪-1-基]-2,2-d2-乙基]-1H-苯并咪唑-
2-酮(化合物43)的合成
步骤1:化合物39的合成。将碳酸钾(261mg,1.89mmol)加入至2-溴乙酸甲酯(217mg,1.42mmol)、化合物27(250mg,945μmol)的乙腈溶液(10mL)中,室温下搅拌12小时,加入二氯甲烷,萃取得无色油状固体190mg,收率为59.7%。LC-MS(APCI):m/z=337.4(M+1)+。
步骤2:化合物40的合成。反应步骤与实施例4步骤1相同,得到无色油状产物150mg,收率为90.1%。LC-MS(APCI):m/z=311.3(M+1)+。
步骤3:化合物41的合成。反应步骤与实施例4步骤2相同,得到黄色油状产物130mg,收率为69.1%。LC-MS(APCI):m/z=389.4(M+1)+。
步骤4:化合物42的合成。反应步骤与实施例4步骤4相同,得到黄色固体产物120mg,收率为68.6%。1H NMR(300MHz,CDCl3)(δ/ppm)7.36-7.06(m,8H),5.33(s,2H),4.06(s,2H),3.64-3.58(m,2H),3.21(s,4H)),2.72(s,4H),0.94-0.86(m 2H),-0.05(s,9H)。LC-MS(APCI):m/z=523.4(M+1)+。
步骤5:化合物43的合成。反应步骤与实施例2步骤4相同,得到白色固体产物50mg,收率为55.6%。1H NMR(300MHz,CDCl3)(δ/ppm)9.18(s,1H),7.33(t,J=7.5Hz,1H),7.11-7.02(m,7H),4.12(t,J=7.2Hz,2H),3.22(t,J=4.8Hz,4H)),2.73(t,J=4.8Hz,,4H)。LC-MS(APCI):m/z=393.3(M+1)+。
实施例7. 3-[2-[4-[4-(三氟甲基-2,4,6-d3-苯基哌嗪-1-基]乙基]-1H-苯并咪
唑-2-酮(化合物47)的合成
步骤1:化合物44的合成。在0℃下,将二碳酸二叔丁酯(711mg,3.26mmol)加入至化合物29(500mg,2.17mmol)、三乙胺(439mg,4.34mmol)的二氯甲烷溶液(15mL)中,滴加完成后,室温下搅拌1小时,旋干过柱得黄色固体产物680mg,收率为93.4%。LC-MS(APCI):m/z=331.4(M+1)+。
步骤2:化合物45的合成。在0℃下,将盐酸(217mg,2.03mmol)加入至化合物44(670mg,2.03mmol)的氘水溶液(5mL)中,在180℃下搅拌30分钟后,用碳酸氢钠溶液调节至中性,二氯甲烷萃取,旋干得黄色固体产物400mg,收率为84.6%。LC-MS(APCI):m/z=234.3(M+1)+。
步骤3:化合物46的合成。反应步骤与实施例4步骤4相同,得到黄色固体产物230mg,收率为58.2%。1H NMR(300MHz,DMSO-d6)(δ/ppm)7.38(s,1H),7.26-7.18(m,1H),7.09-7.04(m,3H),5.24(s,2H),4.01(t,J=6.9Hz,2H),3.50(t,J=7.8Hz,2H),3.12(t,J=4.8Hz,4H)),2.67-2.57(m,6H),0.77(t,J=7.8Hz,2H);LC-MS(APCI):m/z=524.5(M+1)+。
化合物的生物评价
对本发明的化合物在多个测试中进行评价以确定它们的生物学活性。一些测试的化合物对血清紧张素受体显示出强效的抑制活性。
(1)5HT2受体抑制作用评价
实施例1-7均用DMSO溶解至0.01mol/L,然后用去离子水稀释至100μmol/L。将待测化合物与放射性配基各10μL及80μL受体蛋白加入反应试管中,使受试化合物及阳性药物终浓度均为10μmol/L,37℃水浴孵育15分钟后,即刻移至冰浴终止其反应;在Millipore细胞样品收集器上,经过GF/B玻璃纤维滤纸快速抽滤,并用洗脱液(50mM Tris-HCl,PH 7.7)3ml洗涤3次,用微波炉8~9分钟烘干,将滤纸移入0.5mL离心管中,加入500μL脂溶性闪烁液。避光静置30分钟以上,计数测定放射性强度。计算各化合物对同位素配基结合的抑制百分率,抑制率高90%的化合物进行一系列浓度的受体结合试验,确定半数抑制量(IC50,抑制50%阳性对照药物与受体结合所需化合物浓度)。每浓度测定两副管,每个化合物进行两次独立试验。结果如表1所示,实施例1-7对5HT2具有高选择性活性。
表1实施例化合物对5HT2受体抑制作用评价
实施例编号 | 5HT<sub>2</sub>IC<sub>50</sub>(nM) |
实施例1 | <20 |
实施例2 | <20 |
实施例3 | <20 |
实施例4 | <20 |
实施例5 | <20 |
实施例6 | <20 |
实施例7 | <20 |
(2)大鼠中的药代动力学评价
8只雄性Sprague-Dawley大鼠,7-8周龄,体重约210g,分成2组,每组4只,单次口服给予5mg/kg剂量的(a)对照组:3-[2-[4-[4-(三氟甲基)苯基]哌嗪-1-基]乙基]-1H-苯并咪唑-2-酮;(b)试验组:实施例1-13,比较其药代动力学差异。
大鼠采用标准饲料饲养,给予水。试验前16小时开始禁食。药物用PEG400和二甲亚砜溶解。眼眶采血,采血的时间点为给药后0.083小时,0.25小时、0.5小时、1小时、2小时、4小时、6小时、8小时、12小时和24小时。
大鼠吸入乙醚后短暂麻醉,眼眶采集300μL血样于试管。试管内有30μL1%肝素盐溶液。使用前,试管于60℃烘干过夜。在随后一个时间点血样采集完成之后,大鼠乙醚麻 醉后处死。
血样采集后,立即温和地颠倒试管至少5次,保证混合充分后放置于冰上。血样在4℃5000rpm离心5分钟,将血浆与红细胞分离。用移液器吸出100μL血浆到干净的塑料离心管中,表明化合物的名称和时间点。血浆在进行分析前保存在-80℃。用LC-MS/MS测定血浆中本发明化合物的浓度。药代动力学参数基于每只动物在不同时间点的血药浓度进计算。
实验结果表明,相对于对照化合物flibanserin,本发明化合物在动物体内具有更好的药物动力学,因而具有更好的药效学和治疗效果。
应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围,实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则份数和百分比为重量份和重量百分比。
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明,不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干简单推演或替换,都应当视为属于本发明的保护范围。
Claims (6)
2.根据权利要求1所述的化合物,其中,R5、R6、R7和R8为氘。
3.根据权利要求1所述的化合物,其中,R9、R10、R11、R12、R13、R14、R15和R16为氘。
5.一种药物组合物,其含有药学上可接受的载体和权利要求1~4任意一项所述的化合物,或其药学上可接受的盐。
6.权利要求1~4任意一项所述的化合物或其药学上可接受的盐或者权利要求5所述的药物组合物在制备用于治疗和/或预防与5-HT2受体相关疾病的药物中的用途。
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