CN102264733B - 新型多巴胺d3受体配体,其制备方法及其医药用途 - Google Patents
新型多巴胺d3受体配体,其制备方法及其医药用途 Download PDFInfo
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- CN102264733B CN102264733B CN200980139777.3A CN200980139777A CN102264733B CN 102264733 B CN102264733 B CN 102264733B CN 200980139777 A CN200980139777 A CN 200980139777A CN 102264733 B CN102264733 B CN 102264733B
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- carboxamide
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Abstract
本发明涉及具有多巴胺D3受体调节活性的通式I所示新型哌嗪衍生物、其立体异构体,其药用盐、其溶剂化物及含有这些化合物的药物组合物,其制备方法,及其在预防或治疗中枢神经系统紊乱相关的疾病如帕金森氏症、精神分裂症、药物成瘾与复吸等,及在肾脏保护和免疫调节中的用途,或作为工具药用于研究D3R功能及其D3R功能紊乱相关的疾病的用途。
Description
技术领域
本发明涉及如通式I所示的具有多巴胺D3受体(D3R)调节活性的新型哌嗪衍生物、其立体异构体、其药用盐和其溶剂化物的制备,及其在预防或治疗中枢神经系统紊乱相关的疾病如帕金森氏症、精神分裂症、药物成瘾与复吸等,及在肾脏保护和免疫调节中的应用,或作为工具药用于研究D3R功能及其D3R功能紊乱相关的疾病的用途,以及含有这些化合物的药物组合物。
背景技术
多巴胺(DA)是中枢神经系统的重要神经介质。脑内DA神经的失衡可导致精神分裂症、帕金森氏症、药物成瘾与复吸、注意力缺陷或性功能障碍等病症。
1990年,Sokoloff等发现了多巴胺D3受体(D3R),并发现与D2R具有50%氨基酸序列同源性,进一步明确了多巴胺受体的具体分型,D3R选择性分布在边缘脑区,如伏核、Callejia岛、嗅结节,现有研究资料表明,D3R与多种神经功能病变密切相关,例如,精神分裂症、帕金森氏症、药物依赖(或药物成瘾)、各种形式的精神紧张、焦虑、睡眠障碍等,此外,D3R在肾脏功能保护、免疫调节等生理功能调节相关。
在探寻D3R的生理功能及其与中枢疾病、肾功能和免疫功能紊乱之间病理联系的同时,D3R配体的研究也成为药物研究的热点。D3R配体根据其选择性的高低可分为D3R偏爱性配体和D3R选择性配体;按其药理学功能又可分为D3R激动剂、D3R部分激动剂和D3R拮抗剂。
目前,具有较高亲和力和选择性的D3R配体已有许多相关的技术描述,按化学结构分类,现有的D3R配体主要有2-氨基茚满类(WO95/04713)、2-氨基四氢化萘类(EP-A286516)、四氢异喹啉类(WO97/43262、WO98/06699、US 6465485B1)、苯并氮杂类(CN01821985.3)、二氢吲哚类(US 6521638B1)、芳基哌嗪衍生物(FR2878524)、杂环酰胺类(EP 1749529)、磺酰胺类(US2007054918)、苯并噻吩类(WO95/10513)、异唑衍生物(US 6673800B2)、取代咪唑类(US6358955B1)、三氮唑类(US6602867B1、WO2007022936)、嘧啶基哌嗪衍生物(CA2574827)等。总体上分为芳甲酰胺类、芳甲酰氨基的生物电子等排体类和1,2,3,4-四氢萘-2-胺及其类似物。其中芳甲酰胺类最大,其芳基有多种多样,而氨基部分又主要分为哌嗪类和四氢异喹啉,氨基则通过四个亚甲基或相当的连接链与芳甲酰氨基相连(杨日芳,恽榴红.多巴胺D3受体选择性配研究进展.在彭司勋主编:药物化学进展5,化学工业出版社,北京,2007,pp90-108)。
一些D3R选择性配体在相应的动物模型和临床研究中已显示出以D3R为靶点创制新药的潜在价值,例如,Pramipexole(ALieberman.Acta Neurol Scand,2006,113:1)、FAUC329(FBoeckler,et al.Biochem Phamacol,2003,66(6):1025),及BP897(US5872119)在MPTP致损的猕猴帕金森氏症模型中表现出极好的神经保护作用;D3R偏爱性配体S33138、A437203(T Dubuffer,et al.Bioorg Med Chem Lett,1999,9(14):2059;JF Joyce,MJ Millan.DrugDisc Today,2005,10:917)已进入治疗精神分裂症的II期临床试验;BP897(CA Heidbreder.Curr Psychiatry Rev,2005,1:45)、SB277011A(CA Heidbreder,et al.Brain Res Rev,2005,49(1):77)和NGB2904(P Grundt,et al.J Med Chem,2005,48(13):917)等在药物成瘾机制的研究和对应的药物滥用与复吸治疗药物的开发中受到广泛关注,其中BP897作为戒烟药目前处于II期临床研究;另有报道,D3R激动剂可用于防治男性性功能障碍(WO2003/051370,J Bragg,et al.Bioorg Med Chem Lett,2007,17:6691)。
最近的研究发现,偏爱性D3R配体对于防治药物滥用与复吸可能更有效,且不至于表现D2R配体的毒副作用(Z-X Xi,et al.Neuropharmacology,2007,53:771)。
目前仍然需要寻找新型多巴胺D3受体配体的化合物以供临床应用。
发明内容
本发明人经研究发现具有调节D3R功能作用的式I所示的化合物,该类化合物可用于预防或治疗精神分裂症、帕金森氏症、药物依赖(或药物成瘾)与复吸、各种形式的精神紧张、焦虑、睡眠障碍和男性性功能障碍等,及肾脏保护和免疫调节。研究表明,式I所示的化合物具有调节D3R功能的作用。进一步的合成与研究表明,本发明所包括的衍生物与适当的无机酸或有机酸或与无机碱或有机碱形成的药用盐也同样具有调节D3R功能的作用。本发明基于上述发现得以完成。
发明概述
本发明第一方面涉及具有调节D3R功能的通式I所示的化合物,或其互变异构体、消旋体、光学异构体、药用盐或溶剂化物,
其中:
L为CH2CH2CH2CH2、顺式-或反式-CH2CH=CHCH2或反式-环己基-4-乙基;
R1、R2和R3各自独立地为H、卤素(F、Cl、Br或I)、烷基、取代的烷基、链烯基、取代的链烯基、苯基、取代的苯基、杂芳基、取代的杂芳基、C1-C6烷氧基、C5-C10芳氧基、取代芳氧基、C1-C6烷氨基、C5-C10芳氨基、取代芳氨基、二-(C1-C6烷基)氨基、二-(C5-C10芳基)氨基、二-(取代芳基)氨基、C1-10烃酰氧基、C6-10芳酰氧基、C1-10烃酰氨基、C6-10芳酰氨基、羧基、C1-10烃氧甲酰基、C6-10芳氧甲酰基、氨甲酰基、C1-10烃胺甲酰基或C6-10芳胺甲酰基;其中所述的杂芳环为含有1-3个选自N、O或S的杂原子的单环或稠环芳香烃基,每个带有取代基的基团之取代基独立地选自卤素、羟基、氰基、硝基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、一-、二-或三-卤代的C1-6烷基、氨基、C1-6烷氨基、C1-10烃酰氧基、C1-10烃酰氨基、C6-10芳酰氧基或C6-10芳酰氨基;或R1与R3闭合成五、六或七元环;
X为O或S;Y和Z各自独立地为CH或N,二者可相同,也可不同;
甲酰基可位于唑啉-2-酮或噻唑啉-2-酮环的4-、5-、6-或7-位。
具体地,本发明第一方面提供了式I化合物,或其互变异构体、消旋体、光学异构体、药用盐或溶剂化物,
其中:
L为-CH2CH2CH2CH2-、顺式或反式的-CH2CH=CHCH2-或反式-环己基-4-乙基;
R1、R2和R3各自独立地为H、卤素(F、Cl、Br或I)、C1-C6烷基、取代的C1-C6烷基、C1-C6烯基、取代的C1-C6烯基、苯基、取代的苯基、杂芳基、取代的杂芳基、C1-C6烷氧基、C5-C10芳氧基、取代的C5-C10芳氧基、C1-C6烷氨基、C5-C10芳氨基、取代的芳氨基、二-(C1-C6烷基)氨基、二-(C5-C10芳基)氨基、二-(取代的C5-C10芳基)氨基、C1-10烃酰氧基、C6-10芳酰氧基、C1-10烃酰氨基、C6-10芳酰氨基、羧基、C1-10烃氧甲酰基、C6-10芳氧甲酰基、氨甲酰基、C1-10烃胺甲酰基或C6-10芳胺甲酰基;其中所述的杂芳环为含有1-3个选自N、O或S的杂原子的单环或稠环芳香烃基,每个带有取代基的基团的取代基选自卤素、羟基、氰基、硝基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、一-、二-或三-卤代的C1-6烷基、氨基、C1-6烷氨基、C1-10烃酰氧基、C1-10烃酰氨基、C6-10芳酰氧基或C6-10芳酰氨基;
或者R1与R3一起闭合形成五、六或七元环;
X为O或S;
Y和Z各自独立地为C或N,二者可相同,也可不同;甲酰基可位于苯并-唑啉(或噻唑啉)-2-酮环的4-、5-、6-或7-位。
根据本发明第一方面任一项所述的式I化合物,或其互变异构体、消旋体、光学异构体、药用盐或溶剂化物,其中L为-CH2CH2CH2CH2-、顺式或反式的-CH2CH=CHCH2-或反式-环己基-4-乙基。在本发明第一方面的一个实施方案中,L为-CH2CH2CH2CH2-或者顺式或反式的-CH2CH=CHCH2-。在本发明第一方面的一个实施方案中,L为-CH2CH2CH2CH2-。在本发明第一方面的一个实施方案中,L为顺式或反式的-CH2CH=CHCH2-。
根据本发明第一方面任一项所述的式I化合物,或其互变异构体、消旋体、光学异构体、药用盐或溶剂化物,其中R1、R2、R3各自独立地为H、卤素(F、Cl、Br或I)、C1-C6烷基、取代的C1-C6烷基、C1-C6烯基、取代的C1-C6烯基、苯基、取代的苯基、杂芳基、取代的杂芳基、C1-C6烷氧基、C5-C10芳氧基、取代的C5-C10芳氧基、C1-C6烷氨基、C5-C10芳氨基、取代的芳氨基、二-(C1-C6烷基)氨基、二-(C5-C10芳基)氨基、二-(取代的C5-C10芳基)氨基、C1-10烃酰氧基、C6-10芳酰氧基、C1-10烃酰氨基、C6-10芳酰氨基、羧基、C1-10烃氧甲酰基、C6-10芳氧甲酰基、氨甲酰基、C1-10烃胺甲酰基或C6-10芳胺甲酰基;其中所述的杂芳环为含有1-3个选自N、O或S的杂原子的单环或稠环芳香烃基,每个带有取代基的基团的取代基选自卤素、羟基、氰基、硝基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、一-、二-或三-卤代的C1-6烷基、氨基、C1-6烷氨基、C1-10烃酰氧基、C1-10烃酰氨基、C6-10芳酰氧基或C6-10芳酰氨基。在本发明第一方面的一个实施方案中,R1、R2、R3各自独立地为H、卤素(F、Cl、Br或I)、C1-C6烷基、取代的C1-C6烷基或C1-C6烷氧基;其中所述的杂芳环为含有1-3个选自N、O或S的杂原子的单环或稠环芳香烃基,每个带有取代基的基团的取代基选自卤素、羟基、氰基、硝基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、一-、二-或三-卤代的C1-6烷基、氨基、C1-6烷氨基、C1-10烃酰氧基、C1-10烃酰氨基、C6-10芳酰氧基或C6-10芳酰氨基。在本发明第一方面的一个实施方案中,R1、R2、R3各自独立地为H、F、Cl、Br、I、C1-C6烷基或C1-C6烷氧基。在本发明第一方面的一个实施方案中,R1、R2、R3各自独立地为H、F、Cl、Br、C1-C4烷基或C1-C4烷氧基。在本发明第一方面的一个实施方案中,R1、R2、R3各自独立地为H、F、Cl、甲基、乙基、甲氧基或乙氧基。
根据本发明第一方面任一项所述的式I化合物,或其互变异构体、消旋体、光学异构体、药用盐或溶剂化物,其中X为O或S。在本发明第一方面的一个实施方案中,X为O。在本发明第一方面的一个实施方案中,X为S。
根据本发明第一方面任一项所述的式I化合物,或其互变异构体、消旋体、光学异构体、药用盐或溶剂化物,其中Y和Z各自独立地为C或N。在本发明第一方面的一个实施方案中,Y为C。在本发明第一方面的一个实施方案中,Z为C。在本发明第一方面的一个实施方案中,Y和Z均为C。
根据本发明第一方面任一项所述的式I化合物,其选自:
N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]丁基}-苯并唑啉-2-酮-5-甲酰胺;
N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]丁基}-苯并唑啉-2-酮-6-甲酰胺;
N-{4-[4-(2-甲氧基苯基)哌嗪基]丁基}-苯并唑啉-2-酮-5-甲酰胺;
N-{4-[4-(2-甲氧基苯基)哌嗪基]丁基}-苯并唑啉-2-酮-6-甲酰胺;
N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]-反式-2-丁烯-1-基}-苯并唑啉-2-酮-6-甲酰胺;
N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]-顺式-2-丁烯-1-基}-苯并唑啉-2-酮-5-甲酰胺;
N-{4-[4-(2-甲氧基苯基)哌嗪基]-反式-2-丁烯-1-基}-苯并唑啉-2-酮-5-甲酰胺;
N-{4-[4-(2-甲氧基苯基)哌嗪基]-反式-2-丁烯-1-基}-苯并唑啉-2-酮-6-甲酰胺;
N-{4-[4-(2-甲氧基苯基)哌嗪基]丁基}-苯并噻唑啉-2-酮-6-甲酰胺;
N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]丁基}-苯并噻唑啉-2-酮-6-甲酰胺;
N-{4-[4-(2-甲氧基苯基)哌嗪基]-反式-2-丁烯-1-基}-苯并噻唑啉-2-酮-6-甲酰胺;
N-{4-[4-(2-甲氧基苯基)哌嗪基]丁基}-苯并噻唑啉-2-酮-5-甲酰胺;或
N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]丁基}-苯并噻唑啉-2-酮-5-甲酰胺,
或其互变异构体、消旋体、光学异构体、药用盐或溶剂化物。
本发明第二方面涉及本发明第一方面任一项所述的式I化合物或其互变异构体、消旋体、光学异构体、药用盐或溶剂化物在制备可用于预防或治疗D3R功能紊乱相关的疾病如精神分裂症、帕金森氏症、药物依赖(或药物成瘾)、各种形式的精神紧张、焦虑、睡眠障碍和男性性功能障碍等,及肾脏保护和免疫调节的药物中的用途,或作为用于研究D3R功能或D3R功能紊乱相关的疾病的工具药的用途。
本发明第三方面提供了本发明第一方面任一项所述式I化合物,或其互变异构体、消旋体、光学异构体、药用盐或溶剂化物在制备具有多巴胺D3受体调节活性的药物中的用途。
本发明第四方面提供了一种药物组合物,其中含有至少一种本发明第一方面任一项所述的式I化合物,或其互变异构体、其消旋体或光学异构体、其药用盐,及药用载体或赋形剂。根据此方面,本发明还涉及所述药物组合物在制备可用于预防或治疗D3R功能紊乱相关的疾病如精神分裂症、帕金森氏症、药物依赖(或药物成瘾)与复吸、各种形式的精神紧张、焦虑、睡眠障碍和男性性功能障碍等,及肾脏保护和免疫调节的药物中的用途,或作为用于研究D3R功能或D3R功能紊乱相关的疾病的工具药的用途。
本发明第五方面提供了预防和/或治疗与D3R功能紊乱相关的疾病如精神分裂症、帕金森氏症、药物依赖(或药物成瘾)与复吸、各种形式的精神紧张、焦虑、睡眠障碍、男性性功能障碍、肾脏功能紊乱、和免疫功能紊乱的方法,该方法包括向有此需要的受试者给予预防和/或治疗有效量的本发明第一方面任一项所述的式I化合物,或其互变异构体、外消旋体、立体异构体或药用盐。
本发明第六方面提供了制备本发明第一方面任一项所述的式I化合物,或其互变异构体、其消旋体或光学异构体、其药用盐的方法,其包括以下步骤:
a)使以下式II羧酸化合物:
转化成以下式IIa酰氯化合物:
b)在适宜的碱存在下,使步骤a)所得的式IIa酰氯化合物与以下式III胺化合物反应:
得到式I化合物:
其中各符号的定义如本发明第一方面任一项式I化合物所述。
根据本发明第六方面的方法,其中所述的式II羧酸化合物是由以下式IV羧酸化合物:
与ClCO2R代表的化合物反应得到的,
其中各符号的定义如本发明第一方面任一项式I化合物所述。
根据本发明第六方面的方法,其中所述的式III胺化合物是由以下式V化合物:
在适宜的试剂(例如水合肼)存在下反应得到的,
其中各符号的定义如本发明第一方面任一项式I化合物所述。
发明详述
本发明所引述的所有文献,它们的全部内容通过引用并入本文,并且如果这些文献所表达的含义与本发明不一致时,以本发明的表述为准。此外,本发明使用的各种术语和短语具有本领域技术人员公知的一般含义,即便如此,本发明仍然希望在此对这些术语和短语作更详尽的说明和解释,提及的术语和短语如有与公知含义不一致的,以本发明所表述的含义为准。
本发明中所采用的术语“卤”、“卤素”、“Hal”或“卤代”是指氟、氯、溴、和碘。
本发明中所采用的术语“烷基”、“链烯基”和“炔基”具有本领域公知的一般含义,它们是直链或支链的烃基基团,例如但不限于甲基、乙基、丙基、异丙基、正丁基、仲丁基、叔丁基、烯丙基、丙烯基、丙炔基等,并且所述的“烷基”、“链烯基”和“炔基”可以统称为“烃基”或“链烃基”。
如本文使用的,短语“取代或未取代的C1-C6烷基”是指具有指定数目碳原子的取代或未取代的烷基基团,其实例包括但不限于:甲基、乙基、丙基、异丙基、丁基、叔丁基、戊基、新戊基、己基。
对于式I化合物中的Y和Z,它们可以相互独立地是C或N。本领域技术人员理解,此处的Y和Z应当满足它们所在的六元环的化合价要求。例如,当R1、R2、和R3均为氢时,如果Y或Z均为碳,则该六元环形成苯环,从而Y或Z均为-CH-原子团;如果Y为氮,Z为碳,则该六元环形成吡啶环,从而Y为-N-原子团,Z为-CH-原子团。又例如,在Y为氮,Z为碳的情况下,如果R1为卤素,并且R2和R3均为氢,则该卤素可以与Z连接,形成-CCl-原子团。
根据本发明的第一方面,通式I所示的化合物,R1、R2、R3优选为H、氟、氯、溴、甲基、乙基、甲氧基、乙氧基、二甲氨基、二乙氨基、氨甲酰基或苯氧基;
L优选为-CH2CH2CH2CH2-,反式-CH2CH=CHCH2-;
X优选为O或S;Y、Z优选为CH或N。
根据本发明的第一方面,通式I所示的化合物,R1、R2、R3优选为5-氯-2-甲基、2,3-二氯,或2-甲氧基;
L优选为-CH2CH2CH2CH2-,反式-CH2CH=CHCH2-;
X优选为O;Y、Z优选为N。
根据本发明的式I化合物,其优选下文实施例的化合物。
在本发明的优选实施方案中,所述的化合物为N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]丁基}-苯并唑啉-2-酮-5-甲酰胺和N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]丁基}-苯并唑啉-2-酮-6-甲酰胺。
根据本发明的教导,本领域技术根据已有知识可以合成本发明式I化合物。
在制备本发明式I化合物的方法的一个实施方案中,系将相应的羧酸II制成酰氯,然后与相应的胺III在去酸剂的作用下反应制备;或直接将相应的羧酸II与相应的胺III的混合物在1-羟基苯并三氮唑存在下经碳二亚胺(如N,N’-二环己基碳二亚胺等)等缩合剂脱水合成。其中,羧酸II由相邻取代的相应的氨基与羟基或巯基羧酸IV在去酸剂存在下和氯甲酸酯加热反应环合而得;而胺III则由相应的邻苯二甲酰亚胺V与水合肼反应制备。其中,
羧酸IV由相应的羟基苯甲酸经硝化、分离硝基与羟基成邻位取代的苯甲酸,再还原制得邻氨基的羟基苯甲酸IV,或由相应的氯代苯甲酸经硝化、分离硝基与氯成邻位取代的苯甲酸,再以过量的硫化钠取代还原合成氨基和巯基为邻位取代的苯甲酸IV(铃木忠之,等.药学杂志1974,94:891-897),或由氨基苯甲腈或氨基苯甲酸经硫氰化、关环成2-氨基苯并噻唑,再碱水解生成氨基和巯基为邻位取代的苯甲酸IV;而邻苯二甲酰亚胺V则由相应的卤代物或活泼酯VI与相应的芳基哌嗪反应制备,其中卤代物或活泼酯VI可由邻苯二甲酰亚胺钾盐与相应的二卤代物或活泼酯反应合成。
在本发明合成式I化合物的方法中,反应所用的各种原材料是本领域技术人员根据已有知识可以制备得到的,或者是可以通过文献公知的方法制得的,或者是可以通过商业购得的。以上反应方案中所用的中间体、原材料、试剂、反应条件等均可以根据本领域技术人员已有知识可以作适当改变的。或者,本领域技术人员也可以根据本发明第二方面方法合成本发明未具体列举的其它式I化合物。
根据本发明,本发明中所用术语“D3R功能紊乱相关的疾病”是指因多巴胺D3受体功能紊乱直接或间接引起的疾病如精神分裂症、帕金森氏症、药物滥用(或药物成瘾)与复吸、各种形式的精神紧张、焦虑、睡眠障碍和男性性功能障碍等,及由此诱导的肾脏功能或免疫功能紊乱所引起疾病。
根据本发明,式I化合物的药用盐可以是酸加成盐或与碱形成的盐。酸加成盐举例讲可以是无机酸盐例如但不限于盐酸盐、硫酸盐、磷酸盐、氢溴酸盐;或有机酸盐例如但不限于乙酸盐、草酸盐、柠檬盐、葡萄糖酸盐、琥珀酸盐、酒石酸盐、对甲苯磺酸盐、甲磺酸盐、苯甲酸盐、乳酸盐和马来酸盐;式I化合物与碱形成盐举例讲可以是碱金属盐例如但不限于锂、钠和钾盐;碱土金属盐例如但不限于钙和镁盐;有机碱盐例如但不限于二乙醇胺盐和胆碱盐等;或手性碱盐例如但不限于烷基苯基胺盐。
本发明的化合物的溶剂化物可以是水合物或包含其它的结晶溶剂如醇类例如乙醇。
根据本发明,式I化合物可以存在顺/反异构体,本发明涉及顺式形式和反式形式以及这些形式的混合物。如果需要,单一立体异构体的制备可根据常规方法拆分混合物,或通过例如立体选择合成制备。如果存在机动的氢原子,本发明也涉及式I化合物的互变异构形式。
根据本发明,式I化合物及其立体异构体在预防或治疗与D3R功能紊乱相关的疾病如精神分裂症、帕金森氏症、药物依赖(或药物成瘾)与复吸、各种形式的精神紧张、焦虑、睡眠障碍和男性性功能障碍,及肾脏功能和免疫功能紊乱等疾病的药物中的用途,所述药物用于动物,优选用于哺乳动物,特别是人。
本发明因此还涉及含有作为活性成份的有效剂量的至少一种式I化合物,或其药用盐和/或其立体异构体以及常规药物赋形剂或辅剂的药物组合物。通常本发明药物组合物含有0.1-90重量%的式I化合物和/或其生理上可接受的盐。药物组合物可根据本领域已知的方法制备。用于此目的时,如果需要,可将式I化合物和/或立体异构体与一种或多种固体或液体药物赋形剂和/或辅剂结合,制成可作为人用的适当的施用形式或剂量形式。
本发明的式I化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、肌肉、皮下、鼻腔、口腔粘膜、皮肤、腹膜或直肠等。给药剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、脂质体、透皮剂、口含片、栓剂、冻干粉针剂等。可以是普通制剂、缓释制剂、控释制剂及各种微粒给药系统。为了将单位给药剂型制成片剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如稀释剂与吸收剂,如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等;湿润剂与粘合剂,如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等;崩解剂,例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等;崩解抑制剂,例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等;吸收促进剂,例如季铵盐、十二烷基硫酸钠等;润滑剂,例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。为了将给药单元制成丸剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如稀释剂与吸收剂,如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、高岭土、滑石粉等;粘合剂如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等;崩解剂,如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。为了将给药单元制成栓剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如聚乙二醇、卵磷脂、可可脂、高级醇、高级醇的酯、明胶、半合成甘油酯等。为了将给药单元制成胶囊,将有效成分式I化合物或其立体异构体与上述的各种载体混合,并将由此得到的混合物置于硬的明明胶囊或软胶囊中。也可将有效成分式I化合物或其立体异构体制成微囊剂,混悬于水性介质中形成混悬剂,亦可装入硬胶囊中或制成注射剂应用。为了将给药单元制成注射用制剂,如溶液剂、乳剂、冻干粉针剂和混悬剂,可以使用本领域常用的所有稀释剂,例如,水、乙醇、聚乙二醇、1,3-丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酯等。另外,为了制备等渗注射液,可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油,此外,还可以添加常规的助溶剂、缓冲剂、pH调节剂等。
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。
本发明式I化合物,或其异构体的给药剂量取决于许多因素,例如所要预防或治疗疾病的性质和严重程度,患者或动物的性别、年龄、体重及个体反应,所用的具体化合物,给药途径及给药次数等。上述剂量可以单一剂量形式或分成几个,例如二、三或四个剂量形式给药。
本文所用的术语“组合物”意指包括包含指定量的各指定成分的产品,以及直接或间接从指定量的各指定成分的组合产生的任何产品。
可改变本发明药物组合物中各活性成分的实际剂量水平,以便所得的活性化合物量能有效针对具体患者、组合物和给药方式得到所需的治疗反应。剂量水平须根据具体化合物的活性、给药途径、所治疗病况的严重程度以及待治疗患者的病况和既往病史来选定。但是,本领域的做法是,化合物的剂量从低于为得到所需治疗效果而要求的水平开始,逐渐增加剂量,直到得到所需的效果。
当用于上述治疗和/或预防或其他治疗和/或预防时,治疗和/或预防有效量的一种本发明化合物可以以纯形式应用,或者以药学可接受的酯或前药形式(在存在这些形式的情况下)应用。或者,所述化合物可以以含有该目的化合物与一种或多种药物可接受赋形剂的药物组合物给药。词语“预防和/或治疗有效量”的本发明化合物指以适用于任何医学预防和/或治疗的合理效果/风险比治疗障碍的足够量的化合物。但应认识到,本发明化合物和组合物的总日用量须由主诊医师在可靠的医学判断范围内作出决定。对于任何具体的患者,具体的治疗有效剂量水平须根据多种因素而定,所述因素包括所治疗的障碍和该障碍的严重程度;所采用的具体化合物的活性;所采用的具体组合物;患者的年龄、体重、一般健康状况、性别和饮食;所采用的具体化合物的给药时间、给药途径和排泄率;治疗持续时间;与所采用的具体化合物组合使用或同时使用的药物;及医疗领域公知的类似因素。例如,本领域的做法是,化合物的剂量从低于为得到所需治疗效果而要求的水平开始,逐渐增加剂量,直到得到所需的效果。一般说来,本发明式I化合物用于哺乳动物特别是人的剂量可以介于0.001~1000mg/kg体重/天,例如介于0.01~100mg/kg体重/天,例如介于0.01~10mg/kg体重/天。
根据本发明的化合物可以有效地预防和/或治疗本发明所述的各种疾病或病症。
附图说明
图1表示实施例化合物1对D3R放射性配体的竞争结合曲线。
图2代表实施例化合物1对D2R放射性配体的竞争结合曲线。
图3表示实施例化合物1对35S-GTPγS结合D3R活性的影响。图中“basal”表示基础。
图4代表实施例化合物1对喹吡罗激动的35S-GTPγS结合D3R活性的影响。图中“basal”表示基础。
图5表示化合物1(Y-QA14)对吗啡引起的大鼠条件性位置偏爱的影响。图中,**P<0.005与盐水组相比;#P<0.02与吗啡组相比mean±SD;n=10。图中纵座标“Time spent in the testcompartment(sec)”表示在所述试验间隔区中渡过的时间(秒)。
具体实施方式
实施例
本发明可通过下列实施例得到进一步说明,但这些实施例子不意味着对本发明的任何限制。
实施例1:N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]丁基}-苯并唑啉-2-酮-5-甲酰胺(化合物1,亦称为Y-QA14)的制备
(7)苯并唑啉-2-酮-5-羧酸:称取7.8g(0.05mol)3-氨基-4-羟基苯甲酸,搅拌下加入到溶有8.5g(0.08mol)无水碳酸钠的45mL水溶液中,于45℃油浴中加热,滴加7.1g的氯甲酸甲酯,加毕,继续搅拌反应半小时,然后升温到80℃反应过夜。次日,在冰水冷却下酸化到pH2~3,滤集固体,少量冷水洗涤,干燥得浅棕色粉末状固体7.5g(83.3%),mp:329-331℃。1H-NMR(ppm,d6-DMSO)δ:7.385(d,1H,J=8.40Hz,7-H),7.566(d,1H,J=1.68Hz,4-H),7.74(dd,1H,J1=8.40Hz,J2=1.68Hz,6-H),11.868(br-s,1H,NH),13.006(br-s,1H,CO2H)。
(8)苯并唑啉-2-酮-5-甲酰氯:称取0.5g(2.80mmol)苯并唑啉-2-酮-5-羧酸,混溶于30ml 1,2-二氯乙烷,室温滴加0.67g(5.6mmol)氯化亚砜,加毕,加入10滴N,N-二甲基甲酰胺催化,升温至100℃左右回流搅拌反应3h,回收溶剂,转溶于15ml无水丙酮,即用。
(9)N-(4-溴丁烷)邻苯二甲酰亚胺:称取93.6g(0.43mol)1,4-二溴丁烷,加到380mL丙酮中,在搅拌下加72.5g(0.39mol)邻苯二甲酰亚胺钾盐和2.1g四丁基碘化铵,回流反应18小时,冷却,滤去固体,丙酮洗涤,合并丙酮溶液,减压回收溶剂,趁热加入石油醚结晶,滤集固体,石油醚洗涤,干燥得48.0g(43.6%),mp 75~78℃。母液浓缩,析晶,冰冷,又得固体5.5g(5.0%),mp 73~76℃。
(10)N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]丁基}邻苯二甲酰亚胺:称取N-(4-溴丁烷)邻苯二甲酰亚胺7.0g(0.025mol),溶于30ml乙腈,搅拌下溶加4.2g(0.02mol)5-氯-2-甲基苯基-哌嗪,加毕,滴加5.05g(0.05mol)三乙胺,升温回流反应16小时,待反应完成,减压回收溶剂,水洗,乙酸乙酯萃取3次,合并有机层,无水硫酸钠干燥过夜,回收溶剂,得白色稠状产物,经盐酸乙醚成盐得白色固体产物7.55g(78.0%),mp:280-282℃。1H-NMR(ppm,CDCl3)δ:1.60(br-s,2H),1.76(m,2H),2.23(s,3H),2.45-2.60(m,4H),2.88-2.96(m,6H),3.75(t,J=6.72Hz,2H),6.95(d,J=8.12Hz,2H),7.08(d,J=7.85Hz,1H),7.72(q,J=3.08Hz,2H),7.84(q,J=3.37Hz,2H).
(11)4-[4-(5-氯-2-甲基苯基)哌嗪基]丁胺:称取N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]丁基}邻苯二甲酰亚胺盐酸盐7.50g(0.015mol)混溶于60ml无水乙醇,滴加1.82g(0.030mol)水合肼溶液(含量85%),加热至70℃左右回流搅拌反应4h,待反应完全,减压回收乙醇,剩余固体产物,加入15ml 40%氢氧化钾溶液,搅拌溶解,加水30ml稀释,乙酸乙酯萃取萃取3次,合并有机层,无水硫酸钠干燥过夜,回收溶剂得淡黄色油状产物3.83g(88.2%).1H-NMR(ppm,CDCl3)δ:1.56(br-m,4H),2.24(s,3H),2.42(t,J=7.01Hz,2H),2.60(br-s,4H),2.76(t,J=6.72Hz,2H),2.92(t,J=4.48Hz,4H),6.94(m,2H),7.06(d,J=8.12Hz,1H).
(12)N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]丁基}-苯并唑啉-2-酮-5-甲酰胺:称取0.73g(2.60mmol)4-[4-(5-氯-2-甲基苯基)哌嗪基]丁胺,搅拌下加入到溶加有1.1g(7.8mmol)无水碳酸钾的30mL丙酮溶液中,滴加(2)新制备的苯并唑啉-2-酮-5-甲酰氯丙酮溶液(按2.80mmol计),室温搅拌过夜,次日,抽滤,丙酮充分洗涤,收集滤液,减压回收丙酮,水洗,二氯甲烷萃取3次,合并有机层,无水硫酸钠干燥,回收二氯甲烷,经柱层析纯化,盐酸乙醚成盐得白色固体产物0.89g(78.1%)mp:329-331℃.1H-NMRδ(ppm,d6-DMSO):1.59(br-s,2H),1.77(br-s,2H),2.23(s,3H),3.15(br-m,4H),3.24(br-m,4H),3.39(q,J=7.00Hz,2H),3.53(d,J=12.05Hz,2H),7.06(m,2),7.23(d,J=8.12Hz,1H),7.37(d,J=8.40Hz,1H),7.58(d,J=1.68Hz,1H),7.67(dd,J1=8.40Hz,J2=1.68Hz,1H),8.62(br-s,1H,NH),10.57(br-s,1H,CO2H).MS(ESI+,m/z):443.2/445.3(M+H+,3∶1).
实施例2:N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]丁基}-苯并唑啉-2-酮-6-甲酰胺(化合物2)的制备
(3)苯并唑啉-2-酮-6-羧酸:按实施例1的方法,取4-氨基-3-羟基苯甲酸与氯甲酸甲酯,在去酸剂碳酸钠存在下,加热反应环合制备。产率84.6%,mp:312-316℃。1H-NMR(ppm,d6-DMSO)δ:7.19(d,1H,J=8.12Hz,4-H),7.74(s,1H,7-H),7.81(dd,1H,J1=8.12Hz,J2=0.84Hz,5-H),12.07(br-s,1H,NH),12.85(br-s,1H,CO2H)。
(4)N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]丁基}-苯并唑啉-2-酮-6-甲酰胺:按实施例1的方法,取苯并唑啉-2-酮-6-羧酸制备苯并唑啉-2-酮-6-甲酰氯,然后与4-[4-(5-氯-2-甲基苯基)哌嗪基]丁胺反应,在去酸剂碳酸钠存在下,酰化制备。产率81.2%,mp:205-209℃。1H-NMR(ppm,CDCl3)δ:1.57-1.59(s,br.,2H),1.74(s,br.,2H),2.23(s,3H),3.01(m,2H),3.18(br,4H),3.38(br,4H),3.54(d,J=10.92Hz,2H),7.06(m,2H),7.15(d,J=8.2Hz,1H),7.72-7.77(m,2H),8.55(s,1H).
实施例3:N-{4-[4-(2-甲氧基苯基)哌嗪基]丁基}-苯并唑啉-2-酮-5-甲酰胺(化合物3)的制备
(3)4-[4-(2-甲氧基苯基)哌嗪基]丁胺:按实施例1的方法,取N-(4-溴丁烷)邻苯二甲酰亚胺与2-甲氧基苯基-哌嗪反应制备N-{4-[4-(2-甲氧基苯基)哌嗪基]丁基}邻苯二甲酰亚胺,然后与水合肼反应制备。产率:84.3%.盐酸盐mp:173-175℃。
(4)N-{4-[4-(2-甲氧基苯基)哌嗪基]丁基}-苯并唑啉-2-酮-5-甲酰胺:按实施例1的方法,取苯并唑啉-2-酮-5-甲酰氯与4-[4-(2-甲氧基苯基)哌嗪基]丁胺,在去酸剂碳酸钠存在下,酰化制备。产率79.2%,mp:208-212℃。1HNMR(ppm,CDCl3)δ:1.53(m,4H),2.36(m,2H),2.94(s,br.,4H),3.27(m.,2H),3.35(m,4H),3.76(s,3H),6.85(m,2H),6.94(m,2H),7.34(d,J=8.4Hz,1H),7.55(d,J=1.4Hz,1H),7.55(dd,J1=1.4Hz,J2=8.4Hz,2H),8.51(t,J=5.6Hz,1H).
实施例4:N-{4-[4-(2-甲氧基苯基)哌嗪基]丁基}-苯并唑啉-2-酮-6-甲酰胺(化合物4)的制备
按实施例3的方法,取4-[4-(2-甲氧基苯基)哌嗪基]丁胺与苯并唑啉-2-酮-6-甲酰氯,在去酸剂碳酸钠存在下,酰化制备。产率:71.2%.mp:175-177℃。1HNMR(ppm,DMSO-d6)δ:1.53(m,4H),2.36(m,2H),2.50(s,br.,4H),2.94(s,br.,4H),3.28(m,2H),3.76(s,3H),6.86(m,2H),6.93(m,2H),7.15(d,J=8.1Hz,1H),7.70-7.74(m,2H),8.42(t,J=5.6Hz,1H).
实施例5:N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]-反式-2-丁烯基}-苯并唑啉-2-酮-6-甲酰胺(化合物5)的制备
(3)反式-4-[4-(5-氯-2-甲基苯基)哌嗪基]-2-丁烯-1-胺:按实施例1的方法,取邻苯二甲酰亚胺钾盐与反式-1,4-二氯-2-丁烯反应制备N-(反式-4-氯-2-丁烯-1-基)邻苯二甲酰亚胺,mp 108-110℃;再与5-氯-2-甲基苯基哌嗪反应制备N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]-反式-2-丁烯-1-基}邻苯二甲酰亚胺,然后与水合肼反应制备。产率:89.3%.盐酸盐mp:140-142℃。1HNMR(ppm,CDCl3)δ:1.46(br-s,4H),2.25(s,3H),2.61(br-s,2H,NH2),2.93(m,4H),3.10(d,J=7.0Hz),3.39(d,J=6.72Hz,2H),5.58(m,1H),5.71(m,1H),6.96(m,2H),7.06(d,J=7.84,1H).
(4)N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]-反式-2-丁烯-1-基}-苯并唑啉-2-酮-6-甲酰胺:按实施例2的方法,取苯并唑啉-2-酮-6-甲酰氯与反式-4-[4-(5-氯-2-甲基苯基)哌嗪基]-2-丁烯-1-胺,在去酸剂碳酸钠存在下,酰化制备。产率88.6%,mp:250-252℃。1HNMR δ(ppm,DMSO-d6):2.19(s,3H),2.83(br-s,4H),3.31(s,br.,2H),3.88(s,br.,4H),3.91(d,J=1.15Hz,2H),5.67(m,2H),6.97(t,J=1.96Hz,2H),7.16(q,J=4.48Hz,2H),7.75(m,2H),8.63(br-s,1H).
实施例6:N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]-顺式-2-丁烯-1-基}-苯并唑啉-2-酮-5-甲酰胺(化合物6)的制备
(3)顺式-4-[4-(5-氯-2-甲基苯基)哌嗪基]-2-丁烯-1-胺:按实施例5的方法,取邻苯二甲酰亚胺钾盐与顺式-1,4-二氯-2-丁烯反应制备N-(顺式-4-氯-2-丁烯-1-基)邻苯二甲酰亚胺;再与5-氯-2-甲基苯基哌嗪反应制备N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]-顺式-2-丁烯-1-基}邻苯二甲酰亚胺,然后与水合肼反应制备。产率:85.7%.盐酸盐mp:127-129℃。1HNMR(ppm,CDCl3)δ:1.56(br-s,4H),2.23(s,3H),2.71(br-s,2H,NH2),2.96(m,4H),3.12(d,J=7.0Hz),3.41(d,J=6.72Hz,2H),5.60(m,1H),5.73(m,1H),6.96(m,2H),7.08(d,J=7.84,1H).
(4)N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]-顺式-2-丁烯基}-苯并唑啉-2-酮-5-甲酰胺:按实施例5的方法,取苯并唑啉-2-酮-5-甲酰氯与顺式-4-[4-(5-氯-2-甲基苯基)哌嗪基]-2-丁烯-1-胺,在去酸剂碳酸钠存在下,酰化制备。产率86.3%,mp:251-253℃。1H-NMR(ppm,CDCl3)δ:2.20(s,3H),2.49(m,4H),2.84(br-s,4H),3.12(d,J=6.44Hz,2H),3.97(t,J=5.60,2H),5.62(m,2H),6.99(m,2H),7.17(d,J=9.1Hz,1H),7.36(d,J=8.4Hz 1H),7.66(m,2H).
实施例7:N-{4-[4-(2-甲氧基苯基)哌嗪基]-反式-2-丁烯-1-基}-苯并唑啉-2-酮-5-甲酰胺(化合物7)的制备
(3)反式-4-[4-(2-甲氧基苯基)哌嗪基]-2-丁烯-1-胺:按实施例5的方法,取N-(反式-4-氯-2-丁烯-1-基)邻苯二甲酰亚胺与1-(2-甲氧基苯基)哌嗪反应制备N-{4-[4-(2-甲氧基苯基)哌嗪基]-反式-2-丁烯-1-基}邻苯二甲酰亚胺,然后与水合肼反应制备。产率:85.6%,盐酸盐mp:178-180℃。
(4)N-{4-[4-(2-甲氧基苯基)哌嗪基]-反式-2-丁烯-1-基}-苯并唑啉-2-酮-5-甲酰胺:按实施例1的方法,取苯并唑啉-2-酮-5-甲酰氯与反式-4-[4-(2-甲氧基苯基)哌嗪基]-2-丁烯-1-胺,在去酸剂碳酸钠存在下,酰化制备。产率:85.6%,mp:208-212℃。1H-NMR(ppm,DMSO-d6)δ:2.99(m,4H),3.09(m,2H),3.78(s,br.,4H),3.79(s,3H),3.96(t,J=5.6Hz,2H),5.73(m,1H),6.02(m,1H),6.92(m,2H),6.98(m,2H),7.36(d,J=8.4Hz,1H),7.58(d,J=1.4Hz,1H),7.66(dd,J1=1.4Hz,J2=8.4Hz,2H),8.81(t,J=5.5Hz,1H).
实施例8:N-{4-[4-(2-甲氧基苯基)哌嗪基]-反式-2-丁烯-1-基}-苯并唑啉-2-酮-6-甲酰胺(化合物8)的制备
按实施例7的方法,取反式-4-[4-(2-甲氧基苯基)哌嗪基]-2-丁烯-1-胺与苯并唑啉-2-酮-6-甲酰氯,在去酸剂碳酸钠存在下,酰化制备。产率:87.5%.mp:200-202℃。1HNMR(ppm,DMSO-d6)δ:2.50(m,4H),2.96(s,br.,4H),3.31(m,2H),3.75(s,3H),3.89(t,2H),5.62-5.67(m,2H),6.86(m,2H),6.91(m,2H),7.14(d,J=8.2Hz,1H),7.73-7.77(m,2H),8.63(t,J=5.6Hz,1H).
实施例9:N-{4-[4-(2-甲氧基苯基)哌嗪基]丁基}-苯并噻唑啉-2-酮-6-甲酰胺(化合物9)的制备
(6)4-氨基-3-硫氰基-苯甲腈:称取10.0g(0.08mol)对氨基苯甲腈,13.0g(0.17mol)硫氰酸铵,混溶于100ml冰醋酸,冰水浴冷却下,滴加溶有4ml溴的冰醋酸溶液,加毕,搅拌反应3h,室温继续反应30min,反应完全,加水促析,静置过夜,过滤,收集析出沉淀,少量水洗,晾干,得橙黄色固体产物13.2g(89.7%).mp 168-170℃.1H-NMR δ(ppm,d6-DMSO):6.68(d,J=8.68Hz,1H),6.96(br-s,2H,NH2),7.58(dd,J1=8.70Hz,J2=1.68Hz,1H),7.96(d,J=1.60Hz,1H).
(7)2-氨基-苯并[d]噻唑-6-羧酸:称取13.0g(0.07mol)4-氨基-3-硫氰基-苯甲腈,溶于120ml水,均匀搅拌,加入60ml浓盐酸,于100℃左右回流搅拌反应6h,反应完全后,静置,滤集析出固体,晾干,得淡黄色固体产物8.5g(59.0%)。mp 280-282℃。1H-NMR(ppm,d6-DMSO)δ:7.45(d,J=8.40Hz,1H),7.67(dd,J1=8.40Hz,J2=1.68Hz,1H),8.22(d,J=1.68Hz,1H),8.51(br-s,2H,NH2).
(8)4-氨基-3-巯基-苯甲酸:称取25.0g氢氧化钾,溶于50ml水,稍冷,氮气保护下,加入8.3g(0.04mol)2-胺-苯并[d]噻唑-6-甲酸,回流搅拌反应24h,待反应完成,冰浴冷却下,加入盐酸酸化,静置,滤集析出固体,得白色固体产物5.2g(67.9%).mp 280-284℃。1H-NMR δ(ppm,d6-DMSO):6.75(d,J=8.69Hz,1H),7.46(d,J=1.96Hz,1H),7.63(dd,J1=1.96Hz,J2=8.40Hz,1H),12.13(br-s,1H,CO2H).
(9)苯并噻唑啉-2-酮-6-羧酸:称取5.0g(0.03mol)4-氨基-3-巯基-苯甲酸,搅拌下加入到溶有5.3g(0.05mol)无水碳酸钠的40mL水溶液中,氮气保护下,于45℃油浴中加热,滴加4.3g(0.04mol)的氯甲酸甲酯,加毕,继续搅拌反应半小时,然后升温到80℃反应过夜。次日,在冰水冷却下酸化到pH2~3,滤集固体,少量冷水洗涤,干燥得白色粉末状固体4.8g(82.2%),mp 322-328℃。1H-NMRδ(ppm,d6-DMSO):7.1(d,J=8.40Hz,1H),7.8(dd,J1=8.40Hz,J2=1.68Hz,1H),8.18(d,J=1.68Hz,1H),12.25(br-s,1H,NH),12.89(br-s,1H,CO2H).MS(ESI-,m/z):194.2(M-1).
(10)N-{4-[4-(2-甲氧基苯基)哌嗪基]丁基}-苯并噻唑啉-2-酮-6-甲酰胺:按实施例3的方法,取苯并噻唑啉-2-酮-6-羧酸制备苯并噻唑啉-2-酮-6-甲酰氯,然后与4-[4-(2-甲氧基苯基)哌嗪基]丁胺反应,在去酸剂碳酸钠存在下,酰化制备。产率:81.0%。mp:154-159℃。1H-NMR(ppm,CDCl3)δ:1.58(m,4H),1.72(m,2H),2.79(br.,4H),3.11(br.,4H),3.49(m,2H),3.85(s,3H),6.86(m,2H),6.98(m,2H),7.08(d,J=8.4Hz,1H),7.62(dd,J1=1.7Hz,J2=8.4Hz,1H),7.83(d,J=1.7Hz,1H).
实施例10:N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]丁基}-苯并噻唑啉-2-酮-6-甲酰胺(化合物10)的制备
按实施例1的方法,取4-[4-(5-氯-2-甲基苯基)哌嗪基]丁胺与苯并噻唑啉-2-酮-6-甲酰氯,在去酸剂碳酸钠存在下,酰化制备。产率:79.6%。mp:216-220℃。1H-NMR(ppm,DMSO-d6)δ:1.51(m,2H),1.73(m,2H),2.04(s,3H),2.19(s,br.,4H),3.13(br,4H),3.35(m,2H),7.13(m,2H),7.15(m,2H),7.17(d,J=8.2Hz,1H),7.76(dd,J1=1.7Hz,J2=8.2Hz,1H),8.05(d,J=1.7Hz,1H).
实施例11:N-{4-[4-(2-甲氧基苯基)哌嗪基]-反式-2-丁烯-1-基}-苯并噻唑啉-2-酮-6-甲酰胺(化合物11)的制备
按实施例7的方法,取反式-4-[4-(2-甲氧基苯基)哌嗪基]-2-丁烯胺与苯并噻唑啉-2-酮-6-甲酰氯,在去酸剂碳酸钠存在下,酰化制备。产率:80.7%。mp:160-164℃。1H-NMR(CDCl3)δ:2.76(s,br.,4H),3.13(s,br.,6H),3.85(s,3H),4.08(t,J=5.3Hz,2H),5.79(m,2H),6.84(m,2H),6.90(m,2H),7.05(d,J=8.2Hz,1H),7.63(dd,J1=1.7Hz,J2=8.2Hz,1H),7.78(d,J=1.7Hz,1H).
实施例12:N-{4-[4-(2-甲氧基苯基)哌嗪基]丁基}-苯并噻唑啉-2-酮-5-甲酰胺(化合物12)的制备
(1)3-氨基-4-巯基苯甲酸:将100g(0.53mol)4-氯-3-硝基苯甲酸悬浮于400mL水中,一次加入溶有300g(1.25mol)硫化钠的300mL水溶液,反应液搅拌回流反应7小时,冷却,以乙酸中和到pH7.5,活性炭脱色,过滤,再以乙酸酸化到pH4.5,滤集固体,水洗涤,固体再以甲醇-水重结晶,得黄色固体62.5g(62.5%),mp:185℃(dec.).
(2)苯并噻唑啉-2-酮-5-羧酸:参照苯并噻唑啉-2-酮-6-羧酸的方法合成,产率78.5%,mp:>320℃.
(3)N-{4-[4-(2-甲氧基苯基)哌嗪基]丁基}-苯并噻唑啉-2-酮-5-甲酰胺:称取4-[4-(2-甲氧基苯基)哌嗪基]丁胺2.70g(0.010mol)溶于60mL二氯甲烷,搅拌下加入2.00g(0.010mol)苯并噻唑啉-2-酮-6-羧酸,补加15mL丙酮,再加入1.38g(0.010mol)1-羟基苯并三氮唑和2.25g(0.011mol)N,N’-二环己基碳二亚胺,补加3mL无水甲醇,搅拌反应过夜。次日,滤去固体,二氯甲烷洗涤,合并,补加4mL乙醇,加水分液,干燥,硅胶柱层析,取大极性主点,浓缩,得稠状物,以盐酸-乙醚成盐,得目标产物3.50g(73.4%),mp:135-138℃。1H-NMR(CDCl3)δ:1.81(m→br,2H),2.05(m→br,2H),3.25(m→br,2H),3.49-3.74(m,6H),4.031(s,3H),4.20(m→br,2H),4.77(m→br,2H),7.044(d,J=8.12Hz,2H),7.172(s,1H),7.41(m,2H),7.50(m→br,1H),7.604(d,J=7.00Hz),7.977(br-s,1H),8.511(s,1H),12.914(br-s,1H).
实施例13:N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]丁基}-苯并噻唑啉-2-酮-5-甲酰胺(化合物13)的制备
按实施例12的方法,以4-[4-(5-氯-2-甲基苯基)哌嗪基]丁胺代替4-[4-(2-甲氧基苯基)哌嗪基]丁胺合成,产率78.5%,mp:130-133℃。1H-NMR(ppm,DMSO-d6)δ:1.59(m,2H),1.78(m,2H),2.231(s,3H),3.10-3.25(m,8H),3.12(m,2H),3.53(m,2H),4.819(br,2H),7.04(d,J=1.96Hz,1H),7.07(dd,J1=1.96Hz,J2=8.12Hz,1H),7.22(d,J=8.12Hz,1H),7.606(s,1H),7.665(s,2H),8.675(t,J=5.32Hz,1H),10.838(br-s,1H),12.187(s,1H).
下面的生物活性实验用来进一步说明本发明。
生物效应实验1:目标化合物对多巴胺D3和D2受体(D2R)的放射性配体结合试验
实验材料:稳定转染的CHO-D3R细胞株和CHO-D2R细胞株,3H-螺环哌啶酮(Spiperone)购自GE公司,氟哌啶醇(Haloperidol)、喹吡罗(Quinpirole)购自Sigma公司,35S-GTPγS购自PE公司,GTP-γS、GDP、Tris、EDTA-Na2、EGTA、HEPES、PMSF、PPO和POPOP购自Sigma公司,NaCl、KCl、KH 2PO4、CaCl2、Glucose、MgSO4、MgCl2和CaCl2分析纯购自北京化学试剂公司,二氧六环、萘和乙二醇乙醚购自北京化学试剂公司,GF/C滤纸购自Whatman公司,化合物由上述方法合成。
实验步骤:各自称取合成化合物待细胞融合度达到90%时,消化细胞,4℃、2000rpm离心5min。弃上清,将沉淀于5mM Tris、5mM EDTA.2Na和5mM EGTA裂解液(pH 7.4)中,冰上放置30min。冰浴下过针头(4号针头,0.45×13mm一次性注射器)5-10次,4℃、40000g离心20min。弃上清,沉淀重悬于冰冷50mMTris-HCl(pH 7.4)缓冲液中,过针头5-10次,4℃、40000g离心20min。考马斯亮蓝G-250法测蛋白浓度。冰水浴中加入反应体系。反应缓冲液为50mM Tris-HCl(pH 7.4)缓冲液,含1.5mM CaCl2、4mMMgCl2、1mM EDTA、5mM KCl和120mM NaCl.放射配基3H-Spiperone浓度为0.15-4.8nM,膜蛋白25-30μg/管;非特异结合管还含氟哌啶醇10μM,其他各种化合物终浓度为1μM或50nM,反应总体积0.2mL,25℃水浴反应60min,抽滤,装闪烁液1mL,隔夜测定cpm。结果见表1和表2。
表1:浓度为10-6M时,目标化合物对D3R和D2R选择性筛选比较结果
表2:浓度为50nM时,目标化合物对D3R和D2R亲和力和选择性筛选比较结果
本发明其它实施例的化合物也具有与以上表1和表2中本发明实施例化合物基本上相似的试验结果。
生物效应实验2:化合物1(Y-QA14)对D3R和D2R的竞争抑制常数Ki试验
实验方法与步骤同生物效应实验1,受试化合物Y-QA14的浓度分别为10-16-10-5M,从10-16M开始,按10倍递增,共12个浓度进行试验,数据用OriginPro 7.0软件中竞争曲线分析处理,计算Ki值。
结果见图1和图2。由结果可知,化合物1(Y-QA14)在D3R上具有两个结合位点,Ki分别为KiH=0.052±0.003pM,KiL=2.03±0.4nM;而化合物1在D2R上只有一个结合位点,Ki为134.5±10.2nM。通过比较可得化合物1对于D3R和D2R具有较高的选择性分别为106和66倍左右,其高亲和力位点比现有的高选择性的D3R的化合物高出1000倍左右。
生物效应实验3:化合物1(Y-QA14)内在活性的研究
实验方法:膜蛋白的制冰水浴中加入反应体系。反应缓冲液为50mM Tris-HCl(pH 7.4)缓冲液,含3mM MgCl2、100mM NaCl和10μMGDP.放射配基35S-GTPγS 0.17nM,膜蛋白40-45μg/管;刺激药物预先与蛋白30℃孵育30min(不加35S-GTPγS),之后加入35S-GTPγS于30℃继续孵育30min。非特异结合管还含GTPγS 40μM。反应总体积0.5mL,冰水浴终止。反应液Whatman-GF/C滤纸负压抽滤,并用冰冷的50mM Tris-HCl(pH 7.4)含5mM MgCl2和50mM NaCl缓冲液冲洗5次。滤纸烤干后置于1.5mL Ep管中,加入1mL闪烁液,置于闪烁杯中,用β液闪仪记录放射强度(cpm)。特异结合量=总结合量-非特异结合量,每一结合点均由复管决定。数据用OriginPro 7.0软件中Logistic公式分析处理。结果见图3和图4。由结果可知,在35S-GTPγS结合实验中,单药Y-QA14不能激活D3R偶联的G蛋白,但其可以浓度依赖地抑制D3R激动剂喹吡咯的激动活性。
生物效应实验4:化合物1(Y-QA14)对吗啡诱导大鼠条件性位置偏爱的影响
实验原理:条件性位置偏爱实验(Conditioned Place Preference,CPP)实验是目前评价药物精神依赖性的经典实验模型,该实验将实验动物(大鼠、小鼠)置于条件性位置偏爱箱的白色观察区,并给予精神依赖性药物吗啡,然后观察实验动物在条件性位置偏爱箱的黑色区和白色区的活动情况,白色区、黑色区以及其中的灰色区之间有小门可供动物自由穿梭。动物每次处于给药区就会在药物奖赏效应的作用下对黑色和白色区域产生位置上的偏好,其程度与药物的精神依赖性相关。
实验材料:动物:wistar大鼠,雄性,体重180-220g;试剂:盐酸吗啡(青海制药厂);化合物Y-QA14由发明人合成。
仪器:大鼠条件性位置偏爱仪器
药品配制:
吗啡:10mg/kg称1mg吗啡溶于1mL双蒸水;
Y-QA14:1.0mg/kg,称0.1mg Y-QA14先溶于DMSO,再加双蒸水至1mL;5.0mg/kg,称0.5mg Y-QA14先溶于DMSO,再加双蒸水至1mL;10.0mg/kg,称1mg Y-QA14先溶于DMSO,再加双蒸水至1mL。
实验步骤:实验包括三阶段:预测期、训练期和测试期,共需要13天的连续操作才能完成。
1)预测期
第1-3天,抽出两个箱之间的隔板,将小鼠放在中间箱,让小鼠在三个箱内自由跑动15min,并测定动物在两个箱内的停留时间,以判断其对黑、白箱的自然偏爱。动物停留时间较短的一测为伴药箱,一般白箱为伴药箱;停留时间较长的一侧为偏爱侧,为非伴药箱。
2)训练期
第4-12天,插入两箱间的隔板,使动物不能在箱间自由穿梭。实验在每天上午8:30和下午14:30进行。每天用盐水和药物各训练1次,连续训练7天。Y-QA14的3个剂量组,腹腔给Y-QA14各个剂量20分钟后,皮下注射吗啡10mg/kg,后立即放入白箱(伴药箱)45min,皮下注射盐水后立即放入黑箱(非伴药箱)45min,每1天循环一次。吗啡组腹腔给予溶剂30分钟后,皮下注射吗啡(10mg/kg)后立即放于白箱(伴药箱)45min,注射盐水后立即放入黑箱(非伴药箱)45min,每天循环一次。溶剂组腹腔给予盐水30分钟后,皮下注射溶剂后立即放入白箱45min,注射盐水后放入黑箱中45min,每天循环一次。
3)测试期
第13天,抽出两箱间的隔板,把小鼠放在中间箱,让小鼠在三个箱子内自由跑动15min,用计算机记录小鼠在白箱(伴药箱)内的停留时间。
实验分为五组:(1)溶剂+生理盐水;(2)吗啡+溶剂;(3)吗啡+Y-QA14 1.0mg/kg;(4)吗啡+Y-QA145.0mg/kg;(5)吗啡+Y-QA1410.0mg/kg。
实验结果:比较各组小鼠在伴药箱中的停留时间;以单因素多水平方差分析数据统计分析。结果见图5。由实验结果可知,在吗啡诱导的大鼠条件性位置偏爱实验中,Y-QA14在5mg/kg和10mg/kg两个剂量时可显著对抗吗啡诱发的条件位置偏爱的发生。
生物效应实验5:化合物1(Y-QA14)对抗精神病作用的观察
实验目的:选用2种代表中枢多巴胺功能行为药理学试验方法,用典型抗精神病药氟哌啶醇作参比,初步探讨Y-QA14作为潜在抗精神病药的可能。
实验材料:动物:昆明种小鼠,雄性,体重20-30g;试剂:硫酸苯丙胺(SIGMA);阿朴吗啡(SIGMA);氟哌啶醇(军事医学科学院毒物药物研究所);化合物Y-QA14由发明人合成。
药品配制:硫酸苯丙胺以蒸馏水配制;阿朴吗啡和氟哌啶醇以0.5N盐酸溶解后加5%DMSO水溶液配制;Y-QA14以DMSO溶解后以水稀释配制。
实验方法:
1)小鼠阿朴吗啡攀爬试验
小鼠皮下注射多巴胺激动剂阿朴吗啡2mg/kg后,置于金属丝网笼中,5分钟时动物出现明显攀爬行为,动物爬上笼壁,悬挂,四肢离地,以持续20秒以上者为阳性动物,注射后15-30分钟模型动物达到作用高峰。抗精神病药氟哌啶醇和Y-QA14在给阿朴吗啡前30分钟腹腔注射。试验记录和比较每组动物在阿朴吗啡注射后15分钟和30分钟两次测得的阳性动物的攀爬率,计算较高者。[见:Moore NA et al.J Clin Psychiatry 1997,58(Suppl 10):37-44.]
2)小鼠苯丙胺高活动性试验
小鼠皮下注射苯丙胺6mg/kg后15分钟,自发活动性升高,置于红外自发活动仪中(中国医学科学院药物研究所研制),每1只放一箱中,计10分钟活动数。抗精神病药和Y-QA14在给苯丙胺前15分钟腹腔注射。试验记录和比较各组动物平均自发活动计数。[见:Moore NA et al.J Clin Psychiatry 1997,58(Suppl 10):37-44.]
实验结果:
1)小鼠阿朴吗啡攀爬试验
阿朴吗啡2mg/kg,sc引起87%动物出现攀爬行为,氟哌啶醇0.1mg/kg拮抗后只有25%动物出现攀爬行为,氟哌啶醇0.2mg/kg拮抗后进一步减少至12.5%动物出现攀爬行为。Y-QA14腹腔注射20mg/kg拮抗作用不显著,30mg/kg有部分拮抗作用,而40mg/kg拮抗作用显著,无一动物出现攀爬行为,见表3。
表3腹腔注射Y-QA14对小鼠阿朴吗啡攀爬行为的拮抗作用
注:与对照组比较,*P<0.05,**P<0.01。
2)小鼠苯丙胺高活动性试验
苯丙胺6mg/kg,sc较正常对照动物自发活动计数增加2倍余,氟哌啶醇0.1mg/kg拮抗作用明显,动物自发活动计数降至模型动物的12%,氟哌啶醇0.2mg/kg拮抗作用更明显,动物自发活动计数仅相当模型动物的6%,均低于正常动物。Y-QA14 20和30mg/kg动物自发活动计数大约相当模型动物的75%,40mg/kg相当于模型动物的60%,均表现为明显拮抗,见表4。
表4腹腔注射YQA对小鼠苯丙胺高活动性的影响
注:与对照比活动增加,#P<0.05;与苯丙胺比活动减少,*P<0.05,**P<0.01.
实验结果表明,Y-QA14可明显拮抗阿朴吗啡引起的小鼠攀爬和苯丙胺诱发的小鼠高活动性,显示Y-QA14具有潜在的治疗精神病的作用。
在以上生物效应试验2至5中,本发明其它实施例的化合物也具有与化合物Y-QA14基本上相似的试验结果。
Claims (11)
1.式I的化合物,
或其药用盐,
其中:
L为-CH2CH2CH2CH2-、顺式或反式的-CH2CH=CHCH2-或反式-环己基-4-乙基;
R1、R2和R3各自独立地为H、F、Cl、Br、I、C1-C6烷基、C1-C6烷氧基;
X为O或S;
Y和Z各自独立地为C、CH或N,二者可相同,也可不同;
甲酰基位于苯并唑啉-2-酮或噻唑啉-2-酮环的4-、5-、6-或7-位。
2.根据权利要求1的式I化合物,或药用盐,其中L为-CH2CH2CH2CH2-或者顺式或反式的-CH2CH=CHCH2-。
3.根据权利要求1的式I化合物,或其药用盐,其中R1、R2、R3各自独立地为H、F、Cl、Br、I、C1-C6烷基或C1-C6烷氧基。
4.根据权利要求1的式I化合物,或其药用盐,其中R1、R2、R3各自独立地为H、F、Cl、甲基、乙基、甲氧基或乙氧基。
5.根据权利要求1的式I化合物,或其药用盐,其中X为O。
6.根据权利要求1的式I化合物,或其药用盐,其中Y和Z均为C。
7.根据权利要求1所述的式I化合物,其选自:
N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]丁基}-苯并唑啉-2-酮-5-甲酰胺;
N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]丁基}-苯并唑啉-2-酮-6-甲酰胺;
N-{4-[4-(2-甲氧基苯基)哌嗪基]丁基}-苯并唑啉-2-酮-5-甲酰胺;
N-{4-[4-(2-甲氧基苯基)哌嗪基]丁基}-苯并唑啉-2-酮-6-甲酰胺;
N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]-反式-2-丁烯-1-基}-苯并唑啉-2-酮-6-甲酰胺;
N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]-顺式-2-丁烯-1-基}-苯并唑啉-2-酮-5-甲酰胺;
N-{4-[4-(2-甲氧基苯基)哌嗪基]-反式-2-丁烯-1-基}-苯并唑啉-2-酮-5-甲酰胺;
N-{4-[4-(2-甲氧基苯基)哌嗪基]-反式-2-丁烯-1-基}-苯并唑啉-2-酮-6-甲酰胺;
N-{4-[4-(2-甲氧基苯基)哌嗪基]丁基}-苯并噻唑啉-2-酮-6-甲酰胺;
N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]丁基}-苯并噻唑啉-2-酮-6-甲酰胺;
N-{4-[4-(2-甲氧基苯基)哌嗪基]-反式-2-丁烯-1-基}-苯并噻唑啉-2-酮-6-甲酰胺;
N-{4-[4-(2-甲氧基苯基)哌嗪基]丁基}-苯并噻唑啉-2-酮-5-甲酰胺;或
N-{4-[4-(5-氯-2-甲基苯基)哌嗪基]丁基}-苯并噻唑啉-2-酮-5-甲酰胺,
或其药用盐。
8.权利要求1至7任一项所述的式I化合物或其药用盐在制备药物中的用途,或在制备用于研究D3R功能或D3R功能紊乱相关的疾病的工具药中的用途,其中所制备的药物用于预防或治疗与D3R功能紊乱相关的疾病,或用于肾脏保护和免疫调节,所述与D3R功能紊乱相关的疾病选自精神分裂症、帕金森氏症、药物依赖或药物成瘾、各种形式的精神紧张、焦虑、睡眠障碍和男性性功能障碍。
9.权利要求1至7任一项所述的式I化合物或其药用盐在制备用于调节多巴胺D3受体活性的药物中的用途。
10.一种药物组合物,其含有至少一种权利要求1至7任一项所述的式I化合物,或其药用盐,以及药用载体或赋形剂。
11.制备权利要求1所述的式I化合物,或其药用盐的方法,其包括以下步骤:
a)使以下式II羧酸化合物:
转化成以下式IIa酰氯化合物:
b)在适宜的碱存在下,使步骤a)所得的式IIa酰氯化合物与以下式III胺化合物反应:
得到式I化合物:
式中的各符号具有权利要求1中所定义的含义。
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EP2354136A1 (en) | 2011-08-10 |
US8829001B2 (en) | 2014-09-09 |
EP2354136B1 (en) | 2016-02-24 |
US20110319423A1 (en) | 2011-12-29 |
EP2354136A4 (en) | 2012-04-18 |
JP5701213B2 (ja) | 2015-04-15 |
CN102264733A (zh) | 2011-11-30 |
WO2010040274A1 (zh) | 2010-04-15 |
JP2012505165A (ja) | 2012-03-01 |
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