CN1728998A - 杂环胺类化合物作为神经保护剂的用途 - Google Patents
杂环胺类化合物作为神经保护剂的用途 Download PDFInfo
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- CN1728998A CN1728998A CNA2003801020445A CN200380102044A CN1728998A CN 1728998 A CN1728998 A CN 1728998A CN A2003801020445 A CNA2003801020445 A CN A2003801020445A CN 200380102044 A CN200380102044 A CN 200380102044A CN 1728998 A CN1728998 A CN 1728998A
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Abstract
本发明提供了杂环胺类化合物用于预防或减少患者神经元损伤的用途,这些患者患有或易患能够导致或引起神经元损伤的疾病或病症。
Description
发明领域
本发明涉及用于预防或减少受治疗者中枢神经系统中神经元损伤的治疗方法。
发明背景
已知,许多病理疾病或障碍是由中枢神经系统中神经细胞损失或神经元功能降低引起或者能够导致神经细胞损失或神经元功能降低,这些疾病或障碍包括急性或慢性神经元变性疾病。慢性神经元变性疾病的实例包括阿尔茨海默氏病、帕金森氏病、亨廷顿舞蹈病、AIDS痴呆、与韦-科氏病有关的痴呆(酒精引起的痴呆)、与年龄有关的痴呆、与年龄有关的记忆损伤、由脑创伤引起的脑细胞损伤、中风、低血糖、局部缺血、缺氧、低氧、脑水肿、动脉硬化、血肿或癫痫、由列入脑细胞损失的任何疾病引起的脊髓细胞损失以及外周神经病。其它已知的能够引起神经细胞损失或神经细胞功能降低的疾病一般被称为继发性神经元变性疾病,它们通常起因于代谢或中毒。
很多慢性和急性神经元变性疾病和急性神经细胞损伤以及相关的死亡率和发病率通过现有方法不能得到治疗。由这些疾病引起的患者病废会导致生活质量显著下降。此外,由于需要长期护理,这些疾病给患者和社会造成了高负担。因此,需要有效的治疗方法,用于预防或减少与神经元变性疾病和急性神经细胞损伤有关的神经细胞死亡或损伤。具体地讲,需要用于治疗由神经元损失引起的脑部疾病的有效方法,该方法较为无毒并且能轻易透过血-脑屏障进入脑中。
令人吃惊且出乎意料的是,现已发现,sumanirole及其类似物适合有益用作预防或减少神经细胞死亡或损伤的治疗方法。本发明化合物不仅具有神经保护作用,而且还表现出惊人的安全特性,且容易穿透血-脑屏障。
公开资料
US专利6,458,820公开了用作神经保护剂的多巴胺受体激动剂pramipexole。
US专利5,273,975和5,436,240以及国际专利申请WO 00/40226公开了可用于治疗帕金森氏病症状的化合物。
US专利6,426,342公开了使用β-内酰胺酶抑制剂来预防或减少患者神经细胞损失和神经细胞功能降低的方法。
US专利6,451,837公开了使用天然或合成生物黄酮类作为MAPK级联拮抗剂以保护神经细胞免于恶化和细胞死亡的方法。
据报道,与许多受体(包括多巴胺受体)结合的血管舒张药吡贝地尔会影响全脑局部缺血沙土鼠模型的功能和生化参数。参见,例如,Society forNeuroscience Abstracts,19:673(1993);同上,1645。
麦角乙脲(Lisuride)结合几种不同的受体,包括多巴胺D2和5-Htla受体。据报道,对于脑梗塞大鼠模型,如果在发病前给药,则麦角乙脲能减轻脑水肿并延长存活期。Miya Zawa,et al.Nippon-Yakurigaku-Zasshi 98(6):449-561,(1991)。
发明概述
本发明公开了一种预防或减轻人类神经元损伤或神经元损伤发展的方法,其中人类患有或易患能够导致所述神经元损伤的疾病,该方法包括对人类施用神经保护剂量的式(A)化合物或其可药用盐,
式(A)
其中:
R1、R2和R3各自独立地是氢、C1-6烷基、C3-5链烯基、C3-5炔基、C3-7环烷基、C4-10环烷基-或苯基-取代的C1-6烷基,或者R1和R2相连形成可含有其它杂原子和/或不饱和的C3-7环状胺;
X是氢、C1-6烷基、卤素、羟基、烷氧基、氰基、甲酰胺、羧基或烷氧羰基,
A是CH、CH2、CH-卤素、CHCH3、C=O、C=S、C-SCH3、C=NH、C-NH2、C-NHCH3、C-NHCOOCH3、C-NHCN、SO2或N;
B是CH2、CH、CH-卤素、C=O、N、NH或N-CH3或O;
n是0或1;和
D是CH、CH2、CH-卤素、C=O、O、N、NH或N-CH3。
本发明还公开了一种患者治疗方法,其中,患者患有或易患已知导致神经细胞损失或神经细胞功能降低的疾病或者患有或易患由神经细胞损失或神经细胞功能降低引起的疾病,该方法包括对需要这种治疗的患者施用神经保护剂量的式(A)化合物或其可药用盐。
本发明还公开了含有式(A)化合物或其可药用盐作为活性组分的神经保护药物组合物及其制备方法。这些药物组合物可以配制成适合于患者通过各种给药途径给药的单位剂型,给药途径包括,但不限于,口服、经颊、舌下、胃肠外、经皮和直肠给药。在一个实施方案中,配制剂型用以控释活性组分。
优选实施方案的描述
一方面,本发明提供了预防或减轻人类神经元损伤或神经元损伤发展的方法,其中人类患有或易患能够导致这种神经元损伤的疾病,该方法包括对需要这种治疗的患者施用神经保护剂量的式(A)化合物或其可药用盐。神经元损伤通常以神经细胞损失或神经细胞功能降低为特征。能够导致神经元损伤的疾病的实例包括中风,癫痫发作,神经外伤以及众多的源于各种不同病因的神经变性疾病,如亨廷顿舞蹈病、帕金森氏病、阿尔茨海默氏病以及其它的记忆障碍、血管性痴呆、多发性脑梗塞性痴呆、雷维小体性痴呆、或神经变性痴呆。本发明化合物的特别适应症是帕金森氏病。在此意义上,术语帕金森氏病也包括术语帕金森氏综合征。
另一方面,本发明提供了一种治疗人类的方法,其中人类患有或易患能够导致或产生神经细胞损失或神经细胞功能降低的疾病,该方法包括对人类施用神经保护剂量的式(A)化合物或其可药用盐。
再一方面,本发明提供了含有式(A)化合物或其可药用盐作为活性组分的神经保护药物组合物。
又一方面,本发明提供了制备含有式(A)化合物或其可药用盐作为活性组分的神经保护药物组合物的方法。
优选的式(A)化合物包括式(AI)和(AII)化合物及其可药用盐。
式(AI)化合物的化学名称为(R)-5,6-二氢-5-(甲基氨基)-4H-咪唑并[4,5,1-ij]-喹啉-2(1H)-酮(未转化的CAS命名)或(5R)-5-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-酮(由ACD/命名软件产生。对于本发明,优选(5R)-5-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-酮以可药用盐的形式存在。
式(AII)化合物的化学名称是(5R)-5-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-硫酮。优选(5R)-5-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-硫酮以可药用盐的形式存在。可药用盐包括无机酸和有机酸的盐。
合适的可药用盐包括无机酸和有机酸的盐;其实例包括但不限于下列酸的盐:甲磺酸、盐酸、氢溴酸、硫酸、磷酸、硝酸、苯甲酸、柠檬酸、酒石酸、富马酸、马来酸、CH3-(CH2)n-COOH(其中n是0-4)、HOOC-(CH2)N-COOH(其中n定义同上)。其它可药用盐参见Int.J.Pharm.,33,201-217(1986)。
特别优选的(5R)-5-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-酮和(5R)-5-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-硫酮的盐是马来酸盐,即,(2)-2-丁烯二酸盐(butenedioate),它们分别是(5R)-5-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-酮(Z)-2-丁烯二酸盐(1∶1)和(5R)-5-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-硫酮(Z)-2-丁烯二酸盐(1∶1)。(5R)-5-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-酮(Z)-2-丁烯二酸盐(1∶1)的属名为“sumanirole”。
可用于本发明方法的式(A)化合物及其可药用盐是已知的,参见,例如,US专利5,273,975和5,436,240以及国际专利申请WO 00/40226。上述US专利5,273,975和5,436,240以及国际专利申请WO 00/40226的全部公开内容在本发明中引作参考。制备优选式(A)化合物范围内的优选方法列于制备例1和用数字表示的实施例以及图表A中。另外,(5R)-5-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-硫酮可以由相应的非-硫类似物(5R)-(甲基氨基)-5,6-二氢-4H-咪唑并(4,5,1-ij)喹啉-(2H)-酮制得。一种将(5R)-(甲基氨基)-5,6-二氢-4H-咪唑并(4,5,1-ij)喹啉-(2H)-酮转化为(5R)-5-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-硫酮的方法列于实施例8中。
常规药物制剂,例如,基本上由惰性药用载体与有效剂量式(A)化合物或其可药用盐作为活性组分组成的药物制剂,可以用于本发明化合物。适当的剂型包括但不限于普通片剂或包衣片剂、胶囊、锭剂、粉剂、溶液、悬液、乳剂、糖浆、栓剂、透皮贴剂等,优选剂型为片剂。
可行的式(A)化合物神经保护剂量为大约0.2至大约8mg/人/剂。优选神经保护剂量为大约0.5至大约5mg/人/剂。更优选神经保护剂量为大约1至大约3mg/人/剂。如果使用的剂量低于该剂量,则不能获得所需的效果。如果使用的剂量高于该剂量,则可能发生不期望的副作用。根据本发明方法使用的本发明化合物的神经保护剂量取决于患者健康状况及给药方式,并且,根据患者情况和所观察的对初始剂量的临床反应,主治医师可以调高或调低本发明化合物的神经保护剂量。本发明的治疗通常包括1-4次本发明化合物日剂量。将本发明化合物配制成控释剂型(用于肠胃外给药或口服给药),那么,每天一或两次的给药方案是有效的。
本发明化合物可以口服、肠胃外给药、吸入喷雾、局部给药、经直肠、鼻、颊、阴道给药或者通过在含常规无毒可药用载体、辅剂和赋型剂的剂型中植入的存储器给药。优选口服给药,当然,如果患者病情是急性的,则胃肠外给药被认为是更适当/有效的。本发明化合物通常持续给药,直至患者情况正常或直至确定患者不再易患神经变性疾病或不再有神经变性疾病进一步发展或复发的倾向。为了预防患者的病情,可以采用相同或递减剂量制度持续剂量给药。
另一方面,本发明提供了含有神经保护剂量式(A)化合物或其可药用盐和可药用载体的神经保护药物组合物。在一个实施方案,以单位剂型制备药物组合物,例如,片剂、胶囊或口服剂型小胶囊(caplet)。
再一方面,本发明提供了制备可用于预防人类神经损伤或神经损伤进一步发展的药物组合物的方法,其中所述的人类患有或易患这种损伤。该方法包括制备含有式(A)化合物或其可药用盐和可药用载体的药物混合物的步骤。然后,将数份混合物用于制备含有神经保护剂量式(A)化合物或其可药用盐的单位剂型。
用于形成药物组合物的式(A)化合物或其可药用盐的量是:在通过预定给药途径递送时,能够在需要保护的神经元组织中有效提供神经保护浓度式(A)化合物或其可药用盐的量。
本发明使用的化合物可以与一种或多种可药用载体混合并可以使用诸如片剂、胶囊、小胶囊、可分散粉剂、粒剂、锭剂、粘膜贴剂、小药囊等剂型进行例如口服给药。在这些剂型中,本发明化合物单独或联合一种或多种配制赋型剂与可药用载体(例如,淀粉、乳糖或海藻糖)混合,并被压制成片剂或锭剂或被填充到胶囊中。任选,用于口服给药的剂型,如片剂、小胶囊或胶囊,可以包肠溶衣,以使胃中的水解/降解最小化。在另一个实施方案中,配制用于口服给药的剂型,并使用本领域公知的配制技术形成缓释剂型,以便释放本发明化合物经历预定时间。
本发明神经保护方法中也可以使用局部给药剂型,包括含有式(A)化合物或其可药用盐和常规无毒可药用载体、辅剂和赋型剂并适用于所述给药途径的透皮贴剂、鼻内和栓剂剂量单位制剂。
适合在本发明中注射使用的药物组合物包括无菌水溶液或分散液以及无菌粉剂或用于即时配制无菌注射溶液或分散液的lyopholysates。这种剂型必须无菌且在制备和存储条件下必须稳定。用于注射制剂的载体通常是水,但也可以包括乙醇、多元醇(例如,甘油、丙二醇和液体聚乙二醇)、其混合物和植物油。
也可以将可用于本发明的胃肠外剂型配制成可注射缓释制剂,其中,本发明化合物与一种或多种天然或合成的可生物降解或可生物分散聚合物混合,所述聚合物是例如碳水化合物,包括淀粉、树胶和酯化纤维素类衍生物、聚醚、聚酯、聚乙烯醇、凝胶或藻酸盐。这种剂型可以配制成,例如,微球悬液、凝胶或成形聚合基质植入体,本领域公知,这种植入体起到“贮藏-型”药物递送体系作用,提供延时释放生物活性组分。这种组合物可以采用本领域公知的配制技术制备,并设计成可用于各种药物释放特性的任何一种。
本发明化合物的任何一种的给药可以包括使用单一化合物或使用神经保护化合物的混合物。
如下列实施例1所详细描述的那样,通过试验已显示了由本发明方法获得的神经保护效应。
定义和规定
下列定义和解释用于本申请文件(包括说明书和权利要求书)中使用的术语。
I.
公式规定及变量定义
不同取代基的碳原子含量以两种方法之一来表示。第一个方法是给变量全名加前缀,如″C1-C4″,其中″1″和″4″是表示变量中碳原子数最小和最大值的整数。通过空格使前缀与变量分开。例如,″C1-C4烷基″表示具有1-4个碳原子的烷基(包括其异构体,除非另有说明)。当给出了单个前缀时,该前缀表明定义了变量的总碳原子含量。因此,C2-C4烷氧基羰基是指基团CH3-(CH2)n-O-CO-,其中n是0、1或2。第二种方法是,将″Ci-Cj″括入圆括号内并直接放在所定义部分的前方(不插入空格),从而仅单独指出各部分定义的碳原子含量。通过这种任选的规定,(C1-C3)烷氧基羰基与C2-C4烷氧基羰基的含义相同,因为,″C1-C3″仅指烷氧基的碳原子数。类似地,虽然C2-C6烷氧基烷基和(C1-C3)烷氧基(C1-C3)烷基都定义含2-6个碳原子的烷氧基烷基,但是,这两个定义不同,因为,前一个定义允许烷氧基或烷基部分独自含4或5个碳原子,而后一个定义则限制了这两个基团中的任一个最多含3个碳原子。
II.
定义
所有的温度均为摄氏度。
TLC是指薄层色谱法。
HPLC是指高压液相色谱法。
盐水是指饱和氯化钠水溶液。
色谱法(柱色谱法和闪式色谱法)是指化合物的提纯/分离(载体、洗脱液)。显然,合并适当的馏分并浓缩,得到所需的化合物。
NMR是指核(质子)磁共振波谱法,化学位移为与四甲基甲硅烷峰的低场距离,用ppm(δ)表示。
CMR是指C-13磁共振波谱法,化学位移为与TMS的低场距离,用ppm(δ)表示。
本发明可互换使用的术语“神经细胞”和“神经元”或“神经元细胞”是指中枢神经系统(包括脑)中的细胞。
本发明可互换使用的术语“神经细胞”和“神经元”或“神经元细胞”是指组成中枢神经系统的细胞,包括,例如,神经元、神经支持细胞、神经胶质、许旺细胞、中枢神经系统中含有的构成脉管系统的细胞,所述脉管系统向中枢神经系统(包括脑、脑干、脊髓和末梢神经系统)中的这些细胞供养。
本发明进行描述和定义时使用的″神经保护″是指对导致病人神经细胞功能死亡或损失的神经细胞损伤的预防、避免、改善或减轻作用,其中,病人患有影响神经细胞的疾病。该术语还用于指保护和/或复活细胞的能力或功能,其中所述细胞是损伤的细胞或者是暴露于或已暴露于细胞损伤环境之下的细胞。
“神经保护剂量”是指足以如上所述对受治疗患者起到神经保护作用的本发明化合物的量。
在说明书和权利要求书中,“神经变性疾病”被定义为在外周神经系统或中枢神经系统中神经元发生进行性损失的疾病。神经变性疾病的实例包括慢性神经变性疾病,如阿尔茨海默氏病、帕金森氏病、亨廷顿舞蹈病、糖尿病性外周神经病、多发性硬化、肌萎缩性脊髓侧索硬化、衰老,急性神经变性疾病,包括中风、外伤性脑损伤、精神分裂症、外周神经损伤、低血糖、脊髓损伤、癫痫症、缺氧和低氧。这些实例并不全面或不以任何方式限制本发明,而仅仅对术语“神经变性疾病”起说明作用。
“(Z)-2-丁烯二酸盐”是指马来酸盐。
实施例
无需更多的详细描述,相信本领域技术人员能够根据上文的描述在最大程度上实施本发明。下列详细的实施例描述了如何制备本发明各种化合物和/或进行本发明各种方法,这些实施例仅用于说明性解释,不以任何方式限制上文公开的任何内容。就反应物、反应条件和技术而言,本领域技术人员能够迅速认识到对操作步骤的适当改变。
制备例1.(R)-萘普生氯化物
R-萘普生(260g)、二氯甲烷(3.33kg)和DMF(8.2ml)加入反应器中。向混合物中缓慢加入草酰氯(191.8g)。加入草酰氯后,在5-10°搅拌浆料,然后慢慢升至20-25°。将得到的混合物浓缩,除去二氯甲烷,向浓缩物中加入支链辛烷,再次浓缩混合物。向混合物中加入更多支链的辛烷,冷却混合物至0°并搅拌使结晶。过滤结晶浆料,用辛烷洗涤结晶滤饼,在20-25°干燥,得到标题化合物。
将第一批收获的滤液浓缩,加入支链辛烷,冷却混合物并搅拌,得到第二批收获标题化合物。过滤浆料,用辛烷洗涤结晶滤饼并在20-25°干燥。
实施例1.1-苄基-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-酮(11)
将4H-咪唑并[4,5,1-ij]喹啉-2(1H)-酮(I,J.HeterocyclicChem.,19,837-49(1982),1.0g,5.8mmol)在DMF(10ml)中的混合物冷却至0°,保持反应温度为0°,用叔丁醇钾的THF溶液(1.98M,3.2ml,6.3mmol)处理。在0°搅拌得到的混合物10分钟。然后,保持反应温度为0°,加入苄基溴(0.73ml,6.1mmol)。1小时后,用甲基叔丁基醚(MTBE)从水中分配混合物,然后进行数次水洗。减压浓缩MTBE相。冷却浓缩物至0°,过滤并用0°MTBE洗涤2次。在氮气吹洗条件下,在50°减压干燥产物,得到标题化合物,CMR(CDCl3,100MHz)L 153.78,136.44,128.69,127.67,127.60,126.73,125.86,122.90,122.78,121.28,116.92,116.17,108.36,44.95和42.37。
实施例2.(5R*,6R*)-1-苄基-5-溴-6-羟基-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-酮(III)
混合1-苄基-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-酮(II,实施例1,240g)、乙腈(1.086kg)、水(227ml)和氟硼酸(48.5%,13.4g)并冷却至0-5°。使Dibromantin(163.5g)在乙腈中形成浆料并加入反应混合物中。在0-5°反应大约3小时。反应结束后,用大约45分钟加入甲基叔丁基醚,保持罐中反应温度低于10°。冷却浆料至-10--15°,搅拌1小时,然后过滤。用预先冷却的甲基叔丁基醚洗涤产物,用40°氮气干燥,得到标题化合物,CMR(CDC13)δ156.0,137.8,130.5,129.6,129.3,129.1,126.6,123.6,122.5,119.6,110.4,69.9,49.6,47.7,46.9和43.8。
实施例3.(5S,6S)-1-苄基-5-溴-2-氧代-1,2,5,6-四氢-4H-咪唑并[4,5,1-ij]喹啉-6-基(2R)-2-(6-甲氧基-2-萘基)丙酸盐(IVA)和(5R,6R)-1-苄基-5-溴-2-氧代-1,2,5,6-四氢-4H-咪唑并[4,5,1-ij]喹啉-6-基(2R)-2-(6-甲氧基-2-萘基)丙酸盐(IVB)
将(5R,6R)-1-苄基-5-溴-6-羟基-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-酮(III,实施例2,143g)、二氯甲烷(3,136g)、N-甲基吗啉(100.2g)和4-二甲基氨基吡啶(497mg)加入反应器中,并冷却混合物至0-5°。用大约1小时,将溶解在二氯甲烷(694ml)中的(R)-萘普生氯化物(制备例1,118.5g)加入反应器,在0-5°下搅拌混合物,使反应结束。如果需要,加入另外的萘普生氯化物使反应完成。向混合物中加入用水稀释的碳酸钾溶液。用二氯甲烷萃取水相并用水洗涤合并后的二氯甲烷相。通过真空蒸馏浓缩洗涤的混合物,用乙酸乙酯进行溶剂交换。冷却浓缩物至-10°并搅拌。过滤结晶的浆料,用预先冷却的甲基叔丁基醚洗涤结晶的滤饼,在50°干燥,得到固态标题化合物(5S,6S)-1-苄基-5-溴-2-氧代-1,2,5,6-四氢-4H-咪唑并[4,5,1-ij]喹啉-6-基(2R)-2-(6-甲氧基-2-萘基)丙酸盐(IVA),CMR(CDCl3)δ173.2,157.8,153.4,136.1,134.6,133.7,129.2,128.8,127.8,127.8,127.6,127.2,125.9,125.9,125.6,121.5,121.4,119.1,113.2,109.0,105.,105.6,69.2,55.3,45.4,45.2,42.5,41.7和18.3。
不需要的异构体(5R,6R)-1-苄基-5-溴-2-氧代-1,2,5,6-四氢-4H-咪唑并[4,5,1-ij]喹啉-6-基(2R)-2-(6-甲氧基-2-萘基)丙酸盐(IVB)在滤液中,可以通过本领域技术人员已知的方法加以回收,(5R,6R)-1-苄基-5-羟基-6-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-酮,CMR 173.2,157.9,153.4,136.1,135.0,133.8,129.2,128.9,128.8,127.8,127.6,127.4,125.8,125.8,125.7,121.6,121.5,119.3,113.1,109.1,105.7,68.7,55.3,45.3,45.2,42.2,41.3和18.18。
实施例4.(5R,6R)-1-苄基-5-羟基-6-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-酮(V)
使(5S,6S)-1-苄基-5-溴-2-氧代-1,2,5,6-四氢-4H-咪唑并[4,5,1-ij]喹啉-6-基(2R)-2-(6-甲氧基-2-萘基)丙酸盐(IVA,实施例3,110g)在乙腈(1,297g)中形成浆料。加入甲胺水溶液(40wt%,327g)后,在大约30°反应大约12小时。反应结束后,浓缩混合物并加入乙酸乙酯。加入稀盐酸,得到标题化合物的水溶性盐。副产物(R-萘普生乙酰胺杂质)不溶于水,保留在乙酸乙酯相中。进一步进行萃取和洗涤,以便更好地分离出杂质(萘普生乙酰胺),同时目标产物的损失最小。然后,向水相中加入氢氧化钠溶液,将标题化合物的盐酸盐转化为游离碱。该游离碱在水中溶解度较小,被萃取至乙酸乙酯中。浓缩产物混合物并用乙酸乙酯进行溶剂交换以除去水。通过加入支链辛烷并冷却进行结晶。将得到的浆料过滤,洗涤并在50°干燥,得到标题化合物,CMR(CDC13)δ153.7,136.3,128.7,127.8,127.7,125.7,121.3,119.9,118.6,107.5,66.2,60.1,45.1,42.6和34.0。
实施例5.(7aS,8aR)-4-苄基-8-甲基-7,7a,8,8a-四氢氮丙烯并(tetrahydroazireno)[2,3-c]咪唑并[4,5,1-ij]喹啉-5(4H)-酮(VI)
将(5R,6R)-1-苄基-5-羟基-6-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-酮(V,实施例4,70g)和THF(1,389g)浓缩,除去溜出物的任何水分以防备正丁基锂与水反应。冷却混合物至大约-10°,加入正丁基锂,在发热反应中得到起始物料的锂盐,同时获得正丁烷副产物。缓慢加入苯磺酰氯,在发热反应中形成苯磺酸盐。使反应混合物升至20-25°以完成反应。加入碳酸钾水溶液以除去苯磺酸,搅拌混合物形成结晶。加入水使结晶完全,搅拌浆料,冷却并过滤。用水洗涤结晶滤饼,然后用支链辛烷洗涤,在40-50°干燥,得到标题化合物,CMR(CDCl3)δ154.1,136.3,128.6,127.9,127.6,124.3,120.7,119.7,107.4,46.7,44.9,40.7,38.1和37.6。
实施例6.(5R)-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-酮(VII)
将(7aS,8aR)-4-苄基-8-甲基-7,7a,8,8a-四氢氮丙烯[2,3-c]咪唑并[4,5,1-ij]喹啉-5(4H)-酮(VI,实施例5,40g)、叔戊醇(42.4g)和无水氨(1,200g)用锂在-33°下处理,加入锂完毕后,反应混合物由黄色浆料变为深蓝色混合物。搅拌该深蓝色混合物30-60分钟,然后加入水淬灭反应。除去冷凝器的冷却,并蒸发氨。将残余物溶解在甲醇中。然后,浓缩混合物至干,多大标题化合物,无需分离直接用于下一步骤。
实施例7.(5R)-(甲基氨基)-5,6-二氢-4II-咪唑并[4,5,1-ij]喹啉-2(1H)-酮(Z)-2-丁烯二酸盐(1∶1)(VIII)
将(5R)-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-酮(VII,实施例6,28.0g)溶解在水中,添加盐酸调节pH至10。将混合物分批加到XAD-16树脂柱上,先用水然后用乙醇洗脱树脂柱。首先用乙醇从柱中洗脱出目标产物,然后从柱中洗脱出无机盐。用马来酸处理树脂柱的乙醇洗脱物,通过乙醇的共沸蒸馏降低水含量。过滤分离出沉淀产物,用乙酸乙酯漂洗并干燥得到标题化合物,CMR(DMSO-d6)δ167.6,153.9,136.4,127.1,121.5,119.6,114.1,107.5,51.9,31.3和26.5。
实施例8.(5R)-5-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-硫酮
在氮气气氛下,在125°油浴中加热(5R)-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-酮(VII,实施例6,15.0g,73.8mmol)和十硫化四磷(36.1g,81.2mmol)在吡啶(300mL)中的混合物。搅拌反应5小时。冷却混合物至20-25°并减压除去吡啶。加入氢氧化钠(2.2N,200mL)。然后加入氢氧化钠(1N)。用氯化钠饱和混合物并用二氯甲烷(2.5L,分为数份)萃取。将有机相吸收到硅胶(40g)上,并通过柱色谱法提纯(硅胶;225g;甲醇/二氯甲烷,3.5-5.0/96.5-95),得到固体。将该物料从甲醇/乙酸乙酯/己烷中重结晶,得到标题化合物,mp=210-213°;IR(漂移)2940,2907,2884,1483,1458,1391,1366,1354,1254,1239,1229,895,762,734,630cm-1;NMR(300MHz,CDCl3)7.12,7.03,7.00,4.30,3.96,3.30-3.50,3.15,2.88和2.578;MS(EI,m/z)219(M+),190,189,187,186,164,163,155,145;HRMS(快速原子轰击离子源)C11H13N3S理论值(MH+)=220.0908,测定值220.0904。
实施例9(5R)-5-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-硫酮苹果酸盐
将马来酸(0.317g,2.36mmol)在最小量甲醇(1mL)中的混合物加入到(5R)-5-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1ij]喹啉2(1II)硫酮(实施例8,0.493g,2.25mmol)在二氯甲烷中的混合物中。过滤收集所得到的固体,获得标题化合物,mp=195-196°;[α]25D=-60°(c0.93,甲醇);IR(漂移)3140,3112,3060,2969,1627,1619,1568,1481,1455,1398,1389,1361,1220,868和747cm-1;NMR(300MHz,CD3OD)7.20-7.30,7.10-7.20,6.26,4.49,4.31,4.05-4.20,3.47,3.28和2.83δ;CMR(100MHz,DMSO-d6+CD3OD)170.4,169.4,136.6,131.1,130.9,125.1,122.1,116.2,109.6,53.9,43.1,31.9和27.28;MS(ESI,m/z)220.1(MH+)。
实施例10.神经保护性能试验
为了证明本发明化合物的神经保护性能,在本领域已知的神经毒性动物模型中进行体内研究。
试验步骤:
给多组大鼠施用3-乙酰基吡啶(3-AP),一种烟酰胺拮抗剂和一种有效的大鼠神经毒素。
在3-AP处理前或处理后,给动物施用Sumanirole(1-20mg/kg,PO),96小时后处死动物。在下橄榄体和cGMP中进行神经细胞计数,使用ATP和转棒(rotorod)性能作为替代毒性标记。
结果:
3-AP处理显著降低了小脑中cGMP和ATP,减弱了转棒性能并明显减少了下橄榄体神经元。在3-AP之前或之后施用的Sumanirole通过与剂量相关的方式使得由3-AP诱导的cGMP、ATP和转棒性能的降低明显减弱。Sumanirole还大大减少了由3-AP导致的下橄榄体神经细胞损失。用雷氯必利预处理不会阻断summanirole的神经保护作用。
总结:
数据表明,sumanirole具有体内神经保护性能,并且该性能看来与化合物的D2激动性能无关。
图表
Claims (14)
1.一种人类治疗方法,其中人类患有或易患能够导致神经细胞损失或神经细胞功能损失的疾病或者患有或易患由神经细胞损失或神经细胞功能损失引起的疾病,该方法包括对所述人类施用神经保护剂量的式(A)化合物或其可药用盐,
式(A)
在式(A)中:
R1、R2和R3相同或不同,并且是
-H、
C1-C6烷基、
C3-C5链烯基、
C3-C5炔基、
C3-C5环烷基、
C4-C10环烷基、
苯基-取代的C1-C6烷基、
-NR1R2,其中R1和R2与相连的氮原子一种成环,形成吡咯烷基、哌啶基、吗啉基、4-甲基哌嗪基或咪唑基;
X是
-H、
C1-C6烷基、
-F、-Cl、-Br、-I、
-OH、
C1-C6烷氧基、
氰基、
甲酰胺、
羧基、
(C1-C6烷氧基)羰基;
A是
CH、
CH2、
CH-(卤素),其中卤素是-F、-Cl、-Br、-I、
CHCH3、
C=O、
C=S、
C-SCH3、
C=NH、
C-NH2、
C-NHCH3、
C-NHCOOCH3、
C-NHCN、
SO2、
N;
B是
CH2、
CH、
CH-(卤素),其中卤素定义同上、
C=O、
N、
NH、
N-CH3;
D是
CH、
CH2、
CH-(卤素),其中卤素定义同上、
C=O、
O、
N、
NH、
N-CH3;
并且n是0或1,其中—是单键或双键,前提条件是;
(1)当n是0,并且
A是CH2,CH-(卤素),其中卤素定义同上,CHCH3,C=O,C=S,C=NH,SO2时;
则D是CH2,CH-(卤素),其中卤素定义同上,C=O,O,NH,N-CH3;
(2)当n是0,并且
A是CH,C-SCH3,C-NH2,C-NHCH3,C-NHCOOCH3,C-NHCN,N时;
则D是CH,N;
(3)当n是1,并且
A是CH2,CH-(卤素),其中卤素定义同上,CHCH3,C=O,C=S,C=NH,SO2;和
B是CH2,CH-(卤素),其中卤素定义同上,C=O,NH,NCH3时;
则D是CH2,C=O,O,NH,N-CH3;
(4)当n是1,并且
A是CH,C-SCH3,C-NH2,C-NHCH3,C-NHCOOCH3,C-NHCN,N;和
B是CH,N时;
则D是CH2,C=O,O,NH,N-CHs;
(5)当n是1,并且
A是CH2,CHCH3,C=O,C=S,C=NH,SO2;和
B是CH,N时;
则D是CH,N。
2.一种预防患者神经元损伤或神经元损伤发展的方法,其中所述患者患有或易患这种神经元损伤,该方法包括对患者施用神经保护剂量的式(A)化合物或其可药用盐,
式(A)
在式(A)中:
R1、R2和R3相同或不同,并且是
-H、
C1-C6烷基、
C3-C5链烯基、
C3-C5炔基、
C3-C5环烷基、
C4-C10环烷基、
苯基-取代的C1-C6烷基、
-NR1R2,其中R1和R2与相连的氮原子一种成环,形成吡咯烷基、哌啶基、吗啉基、4-甲基哌嗪基或咪唑基;
X是
-H、
C1-C6烷基、
-F、-Cl、-Br、-I、
-OH、
C1-C6烷氧基、
氰基、
甲酰胺、
羧基、
(C1-C6烷氧基)羰基;
A是
CH、
CH2、
CH-(卤素),其中卤素是-F、-Cl、-Br、-I、
CHCH3、
C=O、
C=S、
C-SCH3、
C=NH、
C-NH2、
C-NHCH3、
C-NHCOOCH3、
C-NHCN、
SO2、
N;
B是
CH2、
CH、
CH-(卤素),其中卤素定义同上、
C=O、
N、
NH、
N-CH3;
D是
CH、
CH2、
CH-(卤素),其中卤素定义同上、
C=O、
O、
N、
NH、
N-CH3;
并且n是0或1,其中—是单键或双键,前提条件是;
(1)当n是0,并且
A是CH2,CH-(卤素),其中卤素定义同上,CHCH3,C=O,C=S,C=NH,SO2时;
则D是CH2,CH-(卤素),其中卤素定义同上,C=O,O,NH,N-CH3;
(2)当n是0,并且
A是CH,C-SCH3,C-NH2,C-NHCH3,C-NHCOOCH3,C-NHCN,N时;
则D是CH,N;
(3)当n是1,并且
A是CH2,CH-(卤素),其中卤素定义同上,CHCH3,C=O,C=S,C=NH,SO2;和
B是CH2,CH-(卤素),其中卤素定义同上,C=O,NH,NCH3时;
则D是CH2,C=O,O,NH,N-CH3;
(4)当n是1,并且
A是CH,C-SCH3,C-NH2,C-NHCH3,C-NHCOOCH3,C-NHCN,N;和
B是CH,N时;
则D是CH2,C=O,O,NH,N-CHs;
(5)当n是1,并且
A是CH2,CHCH3,C=O,C=S,C=NH,SO2;和
B是CH,N时;
D是CH,N。
3.根据权利要求1或2的方法,其中疾病选自帕金森氏病、原发性神经变性疾病、亨廷顿舞蹈病、中风和其它低氧性或缺血性病变、神经外伤、代谢诱导的神经病学损伤、脑癫痫后遗症、出血性中风、继发性神经变性疾病(代谢性或中毒性)、阿尔茨海默氏病、其它记忆障碍或血管性痴呆、多发性脑梗塞性痴呆、雷维小体性痴呆、神经变性痴呆。
4.根据权利要求3的方法,其中疾病是帕金森氏病。
5.根据权利要求1或2的方法,其中式(A)化合物经口、鼻、颊、肺、胃肠外和直肠给药。
6.根据权利要求5的方法,其中式(A)化合物口服给药。
7.根据权利要求1或2的方法,其中神经保护剂量为大约0.2-大约8mg/人/剂。
8.根据权利要求7的方法,其中神经保护剂量为大约0.5-大约5mg/人/剂。
9.根据权利要求8的方法,其中神经保护剂量为大约1-大约3mg/人/剂。
10.根据权利要求1或2的方法,其中可药用盐选自下列酸的盐:甲磺酸,盐酸,氢溴酸,硫酸,磷酸,硝酸,苯甲酸,柠檬酸,酒石酸,富马酸,马来酸,CH3-(CH2)n-COOH,其中n是0-4,HOOC-(CH2)N-COOH,其中n定义同前。
11.根据权利要求1或2的方法,其中式(A)化合物是(5R)-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-酮或其可药用盐。
12.根据权利要求11的方法,其中(5R)-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-酮的可药用盐是(5R)-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-酮(Z)-2-丁烯二酸盐(1∶1)。
13.根据权利要求1或2的方法,其中式(A)化合物是(5R)-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-硫酮或其可药用盐。
14.根据权利要求13的方法,其中(5R)-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-硫酮的可药用盐是(5R)-(甲基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-硫酮(Z)-2-丁烯二酸盐(1∶1)。
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KR102343165B1 (ko) * | 2020-01-08 | 2021-12-24 | 숙명여자대학교산학협력단 | 생물학적 시료를 이용한 대장암 발암물질 노출 여부 진단방법 |
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US6156777A (en) * | 1994-12-15 | 2000-12-05 | Pharmacia & Upjohn Company | Use of pramipexole as a neuroprotective agent |
US6197339B1 (en) * | 1997-09-30 | 2001-03-06 | Pharmacia & Upjohn Company | Sustained release tablet formulation to treat Parkinson's disease |
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AU2003267769A1 (en) | 2004-05-13 |
MXPA05004297A (es) | 2005-08-03 |
PL376452A1 (en) | 2005-12-27 |
WO2004037971A2 (en) | 2004-05-06 |
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