CN1910185B - 吡咯并嘧啶和吡咯并三嗪衍生物作为crf受体拮抗剂 - Google Patents
吡咯并嘧啶和吡咯并三嗪衍生物作为crf受体拮抗剂 Download PDFInfo
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- CN1910185B CN1910185B CN2005800020220A CN200580002022A CN1910185B CN 1910185 B CN1910185 B CN 1910185B CN 2005800020220 A CN2005800020220 A CN 2005800020220A CN 200580002022 A CN200580002022 A CN 200580002022A CN 1910185 B CN1910185 B CN 1910185B
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- 108010056643 Corticotropin-Releasing Hormone Receptors Proteins 0.000 title abstract description 6
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Classifications
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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Abstract
本发明的目的是提供一种CRF受体拮抗剂,其有效地作为被认为是与CRF相关疾病的治疗或预防剂,被认为与CRF相关的疾病是例如抑郁症、焦虑症、阿尔海默氏病、帕金森氏病、亨庭顿氏舞蹈病、饮食性疾病、高血压、消化道疾病、药物依赖、癫痫症、脑梗死、脑缺血、脑水肿、脑外伤、炎症、免疫相关性疾病、脱发、肠易激综合征、睡眠障碍、皮炎、精神分裂症、疼痛等。用下式[I]表示的氨基甲酰基取代的吡咯并嘧啶或吡咯并三嗪的衍生物,其具有CRF受体的高度亲和力,并且有效地对抗被认为是与CRF相关的疾病。
Description
技术领域
本发明涉及一种被认为是与促肾上腺皮质激素释放因子(CRF)相关的疾病的治疗剂,例如抑郁症、焦虑症、阿尔海默氏病、帕金森氏病、亨庭顿氏舞蹈病、饮食性疾病、高血压、消化道疾病、药物依赖、脑梗死、脑缺血、脑水肿、脑外伤、炎症、免疫相关性疾病、脱发(alpecia)、肠易激综合征、睡眠障碍、癫痫症、皮炎、精神分裂症、疼痛等。
背景技术
CRF为含有41个氨基酸的激素(Science,213,1394-1397,1981;和J.Neurosci.,7,88-100,1987),并且认为CRF在对抗应激时的生物反应中发挥核心作用(Cell.Mol.Neurobiol.,14,579-588,1994;Endocrinol.,132,723-728,1994;和Neuroendocrinol.61,445-452,1995)。对于CRF而言,有下列两种路径:CRF通过下丘脑-垂体-肾上腺系统对外周免疫系统或交感神经系统起作用的路径,以及CRF在中枢神经系统起神经递质作用的路径(Corticotropin Releasing Factor:Basic and ClinicalStudies of a Neuropeptide,29-52页,1990)。切除垂体的大鼠和正常大鼠心室内的CRF给药在这两类大鼠中均导致焦虑样症状(Pharmacol.Rev.,43,425-473,1991;和Brain Res.Rev.,15,71-100,1990)。即,提出了CRF对下丘脑-垂体-肾上腺系统的参与以及CRF在中枢神经系统中起神经递质作用的路径。
Owens和Nemeroff在1991年的综述中总结了CRF所相关的疾病(Pharmacol.Rev.,43,425-474,1991)。即,CRF与抑郁症、焦虑症、阿尔海默氏病、帕金森氏病、亨庭顿氏舞蹈病、饮食性疾病、高血压、消化道疾病、药物依赖、炎症、免疫相关性疾病等相关。近来有报道称CRF还与癫痫症、脑梗死、脑缺血、脑水肿、和脑外伤相关(BrainRes.545,339-342,1991;Ann.Neurol.31,48-498,1992;Dev.Brain Res.91,245-251,1996;和Brain Res.744,166-170,1997)。相应地,CRF受体的拮抗剂被用作上述疾病的治疗剂。
WO98/35967公开了分别作为CRF受体拮抗剂的吡咯并嘧啶或吡咯并三嗪衍生物。但是,没有公开本发明所提供的化合物。
发明内容
本发明的一个目的是提供CRF受体拮抗剂,其有效地作为被认为是与CRF相关疾病的治疗或预防剂,被认为与CRF相关的疾病是例如抑郁症、焦虑症、阿尔海默氏病、帕金森氏病、亨庭顿氏舞蹈病、饮食性疾病、高血压、消化道疾病、药物依赖、癫痫症、脑梗死、脑缺血、脑水肿、脑外伤、炎症、免疫相关性疾病、脱发、肠易激综合征、睡眠障碍、皮炎、精神分裂症、疼痛等。
本发明者认真研究了具有CRF受体高度亲和力的、氨基甲酰基取代的吡咯并嘧啶或吡咯并三嗪,从而实现本发明。
本发明是下面描述的氨基甲酰基取代的吡咯并嘧啶或吡咯并三嗪衍生物。
氨基甲酰基取代的吡咯并嘧啶或吡咯并三嗪衍生物用下式[I]表示:
(其中E为N或CR10;
R1为-OR4、-S(O)1R4或-NR4R5;
R2为氢、C1-6烷基、C3-7环烷基、C3-7环烷基-C1-6烷基、卤素、C1-6烷氧基、C3-7环烷氧基、C1-6烷基硫代或-N(R6)R7;
R3为氢、C1-6烷基、C3-7环烷基、C3-7环烷基-C1-6烷基或芳基;
R4和R5相同或不同,并且独立地为氢、C1-9烷基、C3-7环烷基、C3-7环烷基-C1-6烷基、二(C3-7环烷基)-C1-6烷基、C1-6烷氧基-C1-6烷基、二(C1-6烷氧基)-C1-6烷基、羟基-C1-6烷基、氰基-C1-6烷基、氨基甲酰基-C1-6烷基或二(C1-6烷基)氨基-C2-6烷基;或者R4和R5一起形成(CH2)m-A-(CH2)n-,其中A为亚甲基、氧、硫、NR8或CHR9;
R6和R7相同或不同,并且独立地为氢或C1-6烷基;
R8为氢、C1-6烷基、C3-7环烷基、芳基或芳基-C1-6烷基;
R9为氢、羟基、羟基-C1-6烷基、氰基或氰基-C1-6烷基;
R10为氢、卤素或C1-6烷基;
l为选自0、1和2的整数;
m为选自1、2、3和4的整数;
n选自0、1、2和3的整数;
条件是,当A为氧、硫或NR8时,n为1、2或3;
Ar为芳基或杂芳基,其中芳基或杂芳基为非取代的或用1个或多个相同或不同的取代基取代,该取代基选自卤素、C1-6烷基、C3-7环烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷基硫代、C1-6烷基亚硫酰基、C1-6烷基磺酰基、氰基、硝基、羟基、-CO2R11、-C(=O)R12、-CONR13R14、-OC(=O)R15、-NR16CO2R17、-S(=O)rNR18R19、三氟甲基、三氟甲氧基、二氟甲氧基、氟甲氧基和-N(R20)R21;
R11和R17相同或不同,并且独立地为氢、C1-5烷基、C3-8环烷基、C3-8环烷基-C1-5烷基、芳基或芳基-C1-5烷基;
R12、R13、R14、R15、R16、R18、R19、R20和R21相同或不同,并且独立地为氢、C1-5烷基和C3-8环烷基;
r为1或2)、其单独的异构体或其异构体的外消旋或非-外消旋混合物、或其药学上可接受的盐和水合物。
在本说明书中使用的术语具有下列含义。
术语“C1-9烷基”指1到9个碳原子的直链或支链烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、异戊基、1-甲基丁基、己基、异己基、1-乙基丙基、1-乙基丁基、1,3-二甲基丁基、1-丙基丁基、1-丙基戊基、1-丁基戊基或类似基团。
术语“C3-7环烷基”指3到7个碳原子的环烷基,例如环丙基、环丁基、环戊基、环己基、环庚基或类似基团。
术语“C3-7环烷基-C1-6烷基”指具有上述C3-7环烷基作为取代基的取代的C1-6烷基,例如环丙基甲基、1-环丙基乙基、1-环丁基乙基、1-环戊基乙基、2-环丙基乙基、2-环丁基乙基、2-环戊基乙基、1-环丙基丙基、1-环丁基丙基、1-环戊基丙基、1-环丙基甲基丙基、1-环丙基甲基丁基或类似基团。
术语“C3-8环烷氧基”指3到8个碳原子的环烷氧基,例如环丙氧基、环丁氧基、环戊氧基或类似基团。
术语“二(C3-7环烷基)-C1-6烷基”指具有两个上述C3-7环烷基作为取代基的取代C1-6烷基,例如二(环丙基)甲基、二(环丁基)甲基、二(环戊基)甲基或类似基团。
术语“C1-6烷氧基”指1到6个碳原子的直链或支链烷氧基,例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、戊氧基、异戊氧基或类似基团。
术语“C1-6烷氧基-C1-6烷基”指具有上述C1-6烷氧基作为取代基的取代C1-6烷基,例如甲氧基甲基、2-甲氧基乙基、2-乙氧基乙基、1-甲氧基甲基丙基、1-甲氧基甲基丁基或类似基团。
术语“二(C1-6烷氧基)-C1-6烷基”指具有两个上述C1-6烷氧基作为取代基的取代C1-6烷基,例如2,3-二(甲氧基)-丙基、2-甲氧基-1-甲氧基甲基-乙基、2,4-二(乙氧基)戊基或类似基团。
术语“羟基-C1-6烷基”指具有羟基的取代C1-6烷基,例如羟基甲基、1-羟基乙基、2-羟基乙基、1-羟基丙基、2-羟基丙基、3-羟基丙基、4-羟基丁基、5-羟基戊基、1-羟基甲基丙基、1-羟基甲基丁基、1-羟基甲基-3-甲基丁基或类似基团。
术语“氰基-C1-6烷基”指具有氰基的取代C1-6烷基,例如氰基甲基、1-氰基乙基、2-氰基乙基、1-氰基丙基、1-氰基丁基、5-氰基戊基、2-氰基-1-乙基乙基、1-氰基甲基丁基、1-氰基-3-甲基丁基、1-氰基甲基-3-甲基-丁基或类似基团。
术语“氨基甲酰基-C1-6烷基”指具有氨基甲酰基的取代C1-6烷基,例如氨基甲酰基甲基、1-氨基甲酰基乙基、2-氨基甲酰基乙基、1-氨基甲酰基丙基、1-氨基甲酰基丁基、5-氨基甲酰基戊基、1-氨基甲酰基-3-甲基丁基、1-氨基甲酰基甲基丁基、1-氨基甲酰基甲基丙基、1-氨基甲酰基甲基-3-甲基丁基或类似基团。
术语“二(C1-6烷基)氨基”指具有两个上述C1-6烷基的氨基,例如二甲基氨基、二乙基氨基、二丙基氨基或类似基团。
术语“二(C1-6烷基)氨基-C2-6烷基”指具有上述二(C1-6烷基)氨基的取代C2-6烷基,例如2-二甲基氨基乙基、3-二甲基氨基丙基或类似基团。
术语“芳基”指具有至少一个芳香环的、6到12个环碳原子的单环或双环基团,例如苯基、萘基或类似基团。
术语“杂芳基”指具有至少一个芳香环的、5到12个环原子的单环或双环基团,且其环中1到4个原子可以相同或不同并且选自氮、氧和硫,例如吡啶基、嘧啶基、咪唑基、喹啉基、吲哚基、苯并呋喃基、喹喔啉基、苯并[1,2,5]硫二唑基、苯并[1,2,5]噁二唑基或类似基团。
术语“芳基-C1-5烷基”指具有上述芳基作为取代基的取代C1-5烷基,例如苯甲基、苯乙基或类似基团。
术语“卤素”指氟、氯、溴或碘原子。
术语“C2-6烯基”指具有2到6个碳原子的直链或支链烯基,例如乙烯基、异丙烯基、烯丙基或类似基团。
术语“C2-6炔基”指具有2到6个碳原子的直链或支链炔基,例如乙炔基、丙-1-炔基、丙-2-炔基或类似基团。
术语“C1-6烷基硫代”指具有1到6个碳原子的直链或支链烷基硫代,例如甲基硫代、乙基硫代、丙基硫代或类似基团。
措词“芳基或杂芳基,其中芳基或杂芳基为非取代的或用1个或多个相同或不同的取代基取代,该取代基选自卤素、C1-6烷基、C3-7环烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷基硫代、C1-6烷基亚硫酰基、C1-6烷基磺酰基、氰基、硝基、羟基、-CO2R9、-C(=O)R10、-CONR11R12、-OC(=O)R13、-NR14CO2R15、-S(=O)rNR16R17、三氟甲基、三氟甲氧基、二氟甲氧基、氟甲氧基和-N(R18)R19”包括,例如,2,4-二甲基苯基、2,6-二甲基苯基、2,4-二溴苯基、2-溴-4-异丙基苯基、2,4-二氯苯基、2,6-二氯苯基、2-氯-4-三氟甲基苯基、4-甲氧基-2-甲基苯基、2-氯-4-三氟甲氧基苯基、4-异丙基-2-甲基硫苯基、2,4,6-三甲基苯基、4-溴-2,6-二甲基苯基、4-溴-2,6-二乙基苯基、4-氯-2,6-二甲基苯基、2,4,6-三溴苯基、2,4,5-三溴苯基、2,4,6-三氯苯基、2,4,5-三氯苯基、4-溴-2,6-二氯苯基、6-氯-2,4-二溴苯基、2,4-二溴-6-氟苯基、2,4-二溴-6-甲基苯基、2,4-二溴-6-甲氧基苯基、2,4-二溴-6-甲基硫苯基、2,6-二溴-4-异丙基苯基、2,6-二溴-4-三氟甲基苯基、2-溴-4-三氟甲基苯基、4-溴-2-氯苯基、2-溴-4-氯苯基、4-溴-2-甲基苯基、4-氯-2-甲基苯基、2,4-二甲氧基苯基、2,6-二甲基-4-甲氧基苯基、4-氯-2,6-二溴苯基、4-溴-2,6-二氟苯基、2,6-二氯-4-三氟甲基苯基、2,6-二氯-4-三氟甲氧基苯基、2,6-二溴-4-三氟甲氧基苯基、2-氯-4,6-二甲基苯基、2-溴-4,6-二甲氧基苯基、2-溴-4-异丙基-6-甲氧基苯基、2,4-二甲氧基-6-甲基苯基、6-二甲基氨基-4-甲基吡啶-3-基、2-氯-6-三氟甲基吡啶-3-基、2-氯-6-三氟甲氧基吡啶-3-基、2-氯-6-甲氧基吡啶-3-基、6-甲氧基-2-三氟甲基吡啶-3-基、2-氯-6-二氟甲基吡啶-3-基、6-甲氧基-2-甲基吡啶-3-基、2,6-二甲氧基吡啶-3-基、4,6-二甲基-2-三氟甲基嘧啶-5-基和2-二甲氨基-6-甲基吡啶-3-基。
在本发明中“药学上可接受的盐”包括,例如,无机酸的盐,例如硫酸、盐酸、氢溴酸、磷酸、硝酸或类似物的盐;有机酸的盐,例如乙酸、草酸、乳酸、酒石酸、富马酸、马来酸、柠檬酸、苯磺酸、甲磺酸、对甲苯磺酸、苯甲酸、樟脑磺酸、乙磺酸、葡庚糖酸、葡糖酸、谷氨酸、乙醇酸、苹果酸、丙二酸、扁桃酸、半乳糖二酸、萘-2-磺酸或类似物的盐;一种或多种金属离子的盐,例如锂离子、钠离子、钾离子、钙离子、镁离子、锌离子、铝离子或类似离子的盐;胺盐,例如氨、精氨酸、赖氨酸、哌嗪、胆碱、二乙胺、4-苯基环己基胺、2-氨基乙醇、苄星青霉素或类似物的盐。
在本发明的化合物中,可以存在例如非对映异构体、对映异构体、几何异构体和互变异构体形式的异构体。本发明的化合物包括单独的异构体以及异构体的外消旋和非-外消旋混合物。
本发明的化合物的优选例子如下。
优选的为式[II]的化合物,其中R1、R2、R3和Ar如式[I]所定义。更优选的为式[II]的化合物,其中R1为-OR4或-NR4R5;R2为C1-6烷基;R3为氢或C1-6烷基;R4和R5相同或不同,并且独立地为氢、C1-9烷基、C3-7环烷基、C3-7环烷基-C1-6烷基、二(C3-7环烷基)-C1-6烷基、C1-6烷氧基-C1-6烷基、二(C1-6烷氧基)-C1-6烷基、羟基-C1-6烷基或氰基-C1-6烷基;Ar为苯基,其中苯基用两个或三个相同或不同的取代基取代,该取代基选自卤素、C1-3烷基、C1-3烷氧基、C1-3烷基硫代、三氟甲基、三氟甲氧基和-N(R20)R21(其中R20和R21相同或不同,并且独立地为氢或C1-3烷基);更优选的为式[II]的化合物,其中R1为-OR4或-NR4R5;R2为C1-6烷基;R3为氢或C1-6烷基;R4为C1-9烷基、C3-7环烷基、C3-7环烷基-C1-6烷基、二(C3-7环烷基)-C1-6烷基、C1-6烷氧基-C1-6烷基、二(C1-6烷氧基)-C1-6烷基、羟基-C1-6烷基或氰基-C1-6烷基;R5为氢;Ar为苯基,其中苯基用两个或三个相同或不同的取代基取代,该取代基选自卤素和C1-3烷基。
其它优选的为式[III]的化合物,其中R1、R2、R3和Ar如式[I]所定义。更优选的为式[III]的化合物,其中R1为-OR4或-NR4R5;R2为C1-6烷基;R3为氢或C1-6烷基;R4和R5相同或不同,并且独立地为氢、C1-9烷基、C3-7环烷基、C3-7环烷基-C1-6烷基、二(C3-7环烷基)-C1-6烷基、C1-6烷氧基-C1-6烷基、二(C1-6烷氧基)-C1-6烷基、羟基-C1-6烷基或氰基-C1-6烷基;Ar为苯基,其中苯基用两个或三个相同或不同的取代基取代,该取代基选自卤素、C1-3烷基、C1-3烷氧基、C1-3烷基硫代、三氟甲基、三氟甲氧基和-N(R20)R21(其中R20和R21相同或不同,并且独立地为氢或C1-3烷基);更优选的为式[III]的化合物,其中R1为-OR4或-NR4R5;R2为C1-6烷基;R3为氢或C1-6烷基;R4为C1-9烷基、C3-7环烷基、C3-7环烷基-C1-6烷基、二(C3-7环烷基)-C1-6烷基、C1-6烷氧基-C1-6烷基、二(C1-6烷氧基)-C1-6烷基、羟基-C1-6烷基或氰基-C1-6烷基;R5为氢;Ar为苯基,其中苯基用两个或三个相同或不同的取代基取代,该取代基选自卤素和C1-3烷基。
结构式[I]的化合物可以通过例如下列反应方案1制造(在下列反应方案中,R1、R2、R3和Ar如上定义,LG为氯、溴、碘、甲基磺酰氧基、苯磺酰氧基、甲苯磺酰氧基或三氟甲基磺酰氧基,Ra为C1-6烷基或苯甲基,p为1或2)。
反应方案1
步骤1:
化合物(2)可以通过在碱存在或不存在的条件下,化合物(1)和相应的胺在惰性溶剂中反应而获得。在这里,碱包括,例如,胺,例如三乙胺、N,N-二异丙基乙胺、吡啶等;无机碱,例如碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、氢氧化钾、氢氧化钠、氢氧化锂、氢氧化钡、氢化钠等;金属醇化物,例如甲醇钠、乙醇钠、叔丁醇钾等;金属氨化物,例如氨基钠、二异丙基氨基锂等;和格氏试剂,例如溴化甲基镁等。惰性溶剂包括,例如,醇,例如甲醇、乙醇、异丙醇、乙二醇等;醚,例如乙醚、四氢呋喃、1,4-二恶烷、1,2-二甲氧基乙烷等;烃,例如苯、甲苯、二甲苯等;酯,例如乙酸乙酯、甲酸乙酯;酰胺,例如N,N-二甲基甲酰胺、N-甲基吡咯烷酮、N,N-二甲基乙酰胺等;乙腈;二氯甲烷;氯仿;二甲亚砜;吡啶;水;以及选自上述惰性溶剂的溶剂混合物。
步骤2:
化合物(2)中的氰基转化为氨基甲酰基可以在惰性溶剂存在或不存在的条件下,在酸或碱的存在下而实现。当R1具有氰基时,该氰基可以同时转变为氨基甲酰基。在这里,酸包括无机酸,例如硫酸、盐酸、氢溴酸、磷酸、多磷酸、硝酸等;有机酸,例如苯磺酸、甲苯磺酸等。碱包括无机碱,例如氢氧化锂、氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁、氢氧化锌、氢氧化铝等。惰性溶剂包括,例如,醇,例如甲醇、乙醇、异丙醇、叔丁醇、乙二醇等;醚,例如乙醚、四氢呋喃、1,4-二恶烷、1,2-二甲氧基乙烷等;烃,例如苯、甲苯等;酰胺,例如N,N-二甲基甲酰胺、N-甲基吡咯烷酮、N,N-二甲基乙酰胺等;乙腈;二氯甲烷;氯仿;二甲亚砜;吡啶;水;以及选自上述惰性溶剂的溶剂混合物。
本发明的化合物可以在惰性溶剂中用酸转变为盐。该酸包括无机酸,例如硫酸、盐酸、氢溴酸、磷酸、硝酸等;有机酸,例如乙酸、草酸、乳酸、酒石酸、富马酸、马来酸、柠檬酸、苯磺酸、甲磺酸、对甲苯磺酸、苯甲酸、樟脑磺酸、乙磺酸、葡庚糖酸、葡糖酸、谷氨酸、乙醇酸、苹果酸、丙二酸、扁桃酸、半乳糖二酸、萘-2-磺酸等。
惰性溶剂包括,例如,醇,例如甲醇、乙醇、异丙醇、乙二醇等;醚,例如乙醚、四氢呋喃、1,4-二恶烷、1,2-二甲氧基乙烷等;烃,例如苯、甲苯等;酰胺,例如N,N-二甲基甲酰胺、N-甲基吡咯烷酮、N,N-二甲基乙酰胺等;酯,例如乙酸乙酯、甲酸乙酯等;酮,例如丙酮、甲乙酮等;乙腈;二氯甲烷;氯仿;二甲亚砜;吡啶;水;以及选自上述惰性溶剂的溶剂混合物。
反应方案2
步骤3:
化合物(4)转化为化合物(5)可以通过在惰性溶剂中用硫脲处理(4),并且随后在碱存在或不存在的条件下,在惰性溶剂中与烷基化剂反应而进行。在这里,烷基化剂包括常规的烷基化剂,例如碘甲烷、溴甲烷、硫酸二甲酯、碘乙烷、溴乙烷、硫酸二乙酯、苄基氯、苄基溴等。碱包括胺,例如三乙胺、N,N-二异丙基乙胺、吡啶等;无机碱,例如碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、氢氧化钾、氢氧化钠、氢氧化锂、氢氧化钡、氢化钠等;金属醇化物,例如甲醇钠、乙醇钠、叔丁醇钾等;金属氨化物,例如氨基钠、二异丙基氨基锂等;和格氏试剂,例如溴化甲基镁等。惰性溶剂包括,例如,醇,例如甲醇、乙醇、异丙醇、乙二醇等;醚,例如乙醚、四氢呋喃、1,4-二恶烷、1,2-二甲氧基乙烷等;烃,例如苯、甲苯、二甲苯等;酰胺,例如N,N-二甲基甲酰胺、N-甲基吡咯烷酮、N,N-二甲基乙酰胺等;乙腈;二氯甲烷;氯仿;二甲亚砜;吡啶;水;以及选自上述惰性溶剂的溶剂混合物。
步骤4:
化合物(5)转化为化合物(6)可以按照步骤2的相同方式实现。
步骤5:
化合物(6)转化为化合物(7)可以在惰性溶剂中,通过化合物(6)与氧化剂反应而进行。在这里,氧化剂包括常规的氧化硫化物基团的氧化剂,例如过氧乙酸、过氧化氢、3-氯过苯甲酸、过硫酸氢钾制剂、高碘酸钠、过硼酸钠等。惰性溶剂包括,例如,醇,例如甲醇、乙醇、异丙醇、乙二醇等;醚,例如乙醚、四氢呋喃、1,4-二恶烷、1,2-二甲氧基乙烷等;烃,例如苯、甲苯、二甲苯等;酰胺,例如N,N-二甲基甲酰胺、N-甲基吡咯烷酮、N,N-二甲基乙酰胺等;乙腈;二氯甲烷;氯仿;二甲亚砜;吡啶;水;以及选自上述惰性溶剂的溶剂混合物。
步骤6:
化合物(7)转化为化合物(8)可以按照步骤1的相同方式进行。
本发明的化合物作为与CRF相关的疾病的治疗剂或预防剂有效。为了该目的,通过常规的制备工艺,通过加入常规的填充剂、粘合剂、崩解剂、pH调节剂、溶剂等,本发明的化合物可以制成片剂、丸剂、胶囊剂、颗粒剂、粉末剂、溶液、乳剂、悬浮液、注射剂等。
本发明的化合物可以按照每天0.1到500mg的剂量,分一次或数次口服或非胃肠道对成年患者给药。剂量可以根据疾病的种类以及患者的年龄、体重和症状而适当增或减。
具体实施方式
本发明通过参考下列实施例和检测实施例进行具体解释,但是不局限于此。
实施例1
合成8-(4-溴-2,6-二甲基-苯基)-2-甲基-4-(1-丙基-丁基氨基)-吡咯[1,2-α]嘧啶-6-羧酸酰胺盐酸盐(化合物1-001)
(1)将8-(4-溴-2,6-二甲基-苯基)-4-氯-2-甲基-吡咯[1,2-α]嘧啶-6-腈(30.0g)、1-丙基-丁胺(18.5g)、N,N-二异丙基乙胺(15.5g)在乙醇(90mL)中的混合物加热回流2小时。反应混合物冷却至室温后,注入到饱和碳酸氢钠水溶液中,并随后用乙酸乙酯萃取。有机层用盐水洗涤,用无水硫酸钠干燥并过滤。减压浓缩滤出液得到固体。将该固体用二异丙基醚洗涤,从而得到8-(4-溴-2,6-二甲基-苯基)-2-甲基-4-(1-丙基-丁基氨基)-吡咯[1,2-α]嘧啶-6-腈(27.0g)。
(2)将8-(4-溴-2,6-二甲基-苯基)-2-甲基-4-(1-丙基-丁基氨基)-吡咯[1,2-α]嘧啶-6-腈(10.0g)加入浓H2SO4(50mL)中,并在55℃加热5小时。反应混合物冷却到室温后,注入到冰水中,并随后加入饱和碳酸氢钠水溶液以使得混合物水溶液呈碱性(pH=8),并用乙酸乙酯萃取。有机层用盐水洗涤,用无水硫酸钠干燥并过滤。滤出液在减压下浓缩并且残余物通过硅胶柱色谱法纯化(硅胶:Wako Gel(C200),洗脱液:己烷/乙酸乙酯/氯仿=10∶3∶1)以得到固体。固体从乙酸乙酯中重结晶,从而得到8-(4-溴-2,6-二甲基-苯基)-2-甲基-4-(1-丙基-丁基氨基)-吡咯[1,2-α]嘧啶-6-羧酸酰胺(5.8g)。
(3)在冰冷却浴中,8-(4-溴-2,6-二甲基-苯基)-2-甲基-4-(1-丙基-丁基氨基)-吡咯[1,2-α]嘧啶-6-羧酸酰胺(5.8g)的乙醇(30mL)悬浮液中加入4M HCl/乙酸乙酯(3.7mL)。所得溶液在减压下浓缩。残余物从乙酸乙酯中结晶,从而得到题述化合物。
表1和表2列出实施例1所获得的化合物以及按照实施例1所描述的类似步骤获得的化合物。
实施例2
合成8-(4-溴-2,6-二甲基-苯基)-2-甲基-4-(N,N-二丙基氨基)-吡咯[1,2-α]嘧啶-6-羧酸酰胺(化合物1-022)
(1)将8-(4-溴-2,6-二甲基-苯基)-4-氯-2-甲基-吡咯[1,2-α]嘧啶-6-腈(7.50g)、硫脲(7.11g)在乙醇(50mL)中的混合物加热回流2小时。反应混合物冷却到室温后,注入到0.5M NaOH水溶液中,搅拌1小时,并用乙酸乙酯萃取。有机层用盐水洗涤,用无水硫酸钠干燥并过滤。滤出液在减压下浓缩,并且残余物通过硅胶柱色谱法纯化(硅胶:Wako Gel(C200),洗脱液:氯仿/甲醇=10∶1),从而得到8-(4-溴-2,6-二甲基-苯基)-4-巯基-2-甲基-吡咯[1,2-α]嘧啶-6-腈(7.52g)。
(2)将8-(4-溴-2,6-二甲基-苯基)-4-巯基-2-甲基-吡咯[1,2-α]嘧啶-6-腈(7.50g)、MeI(12.5mL)在1M NaOH水溶液(100mL)中的混合物在室温下搅拌1小时。反应混合物用乙酸乙酯萃取。有机层用盐水洗涤后,用无水硫酸钠干燥并过滤。滤出液在减压下浓缩以得到粗8-(4-溴-2,6-二甲基-苯基)-2-甲基-4-甲基硫烷基-吡咯[1,2-α]嘧啶-6-腈(5.75g)。该产物在下一步中使用而不需要进一步纯化。
(3)将8-(4-溴-2,6-二甲基-苯基)-2-甲基-4-甲基硫烷基-吡咯[1,2-α]嘧啶-6-腈(5.70g)加入浓H2SO4(100mL)中,并在60℃加热5小时。反应混合物冷却到室温后,注入到冰水中,并随后加入10%NaOH水溶液以使得混合物水溶液呈碱性(pH=8),并用乙酸乙酯萃取。有机层用盐水洗涤,用无水硫酸钠干燥并过滤。滤出液在减压下浓缩并且残余物通过硅胶柱色谱法纯化(硅胶:Wako Gel(C200),洗脱液:乙酸乙酯)以得到8-(4-溴-2,6-二甲基-苯基)-2-甲基-4-甲基硫烷基-吡咯[1,2-α]嘧啶-6-羧酸酰胺(3.12g)
(4)在冰冷却浴中,在过硫酸氢钾制剂(9.12g)的水溶液(50mL)中加入8-(4-溴-2,6-二甲基-苯基)-2-甲基-4-甲基硫烷基-吡咯[1,2-α]嘧啶-6-腈羧酸酰胺(3.00g)的乙醇(50mL)溶液。反应混合物在冰冷却下搅拌30分钟后,注入水中,并用乙酸乙酯萃取。有机层用饱和碳酸氢钠水溶液和盐水洗涤,用无水硫酸钠干燥并过滤。滤出液在减压下浓缩,并且残余物通过硅胶柱色谱法纯化(硅胶:Wako Gel(C200),洗脱液:乙酸乙酯)以得到8-(4-溴-2,6-二甲基-苯基)-4-甲基亚磺酰-2-甲基-吡咯[1,2-α]嘧啶-6-羧酸酰胺(1.68g)。
(5)将8-(4-溴-2,6-二甲基-苯基)-4-甲基亚磺酰-2-甲基-吡咯[1,2-α]嘧啶-6-羧酸酰胺(100mg)、N,N-二丙胺(48mg)在乙醇(1mL)中的混合物加热回流1小时。反应混合物冷却到室温,注入到饱和碳酸氢钠水溶液中,并随后用乙酸乙酯萃取。有机层用盐水洗涤,用无水硫酸钠干燥并过滤。滤出液在减压下浓缩,并且残余物通过硅胶柱色谱法纯化(硅胶:Wako Gel(C200),洗脱液:己烷/乙酸乙酯=1∶1)以得到固体。该固体用二异丙基醚和乙酸乙酯的混合物洗涤,从而得到题述化合物(50mg)。
表1列出实施例2所获得的化合物以及按照实施例2所描述的类似步骤获得的化合物。
表1*1
*1:Com.No.=化合物编号,Ex.No.=实施例编号,
结晶用溶剂;EtOAc=乙酸乙酯,EtOH=乙醇
下面描述非晶体化合物的分析数据。
1-024:
MS(Pos,ES):442(M+Na)+,444(M+Na+2)+;NMR(300MHz,CDCl3)δ2.04(3H,s),2.09(3H,s),2.58(3H,s),3.17(3H,s),5.54-5.66(2H,m),7.26(1H,s),7.31(2H,s),7.59(1H,s)
1-028:
MS(Pos,ES):486(M+1)+,488(M+3)+,508(M+Na)+,510(M+Na+2)+;NMR(300MHz,CDCl3)δ0.98(3H,t,J=7.3Hz),1.40-1.64(2H,m),1.68-1.79(2H,m),2.09(3H,s),2.10(3H,s),2.37(3H,s),2.51(1H,dd,J=5.9,14.4Hz),2.65(1H,dd,J=7.4,14.4Hz),4.07-4.18(1H,m),5.28-5.39(1H,br s),5.48-5.58(2H,br s),5.72-5.87(1H,br s),5.89(1H,s),7.22(1H,s),7.26(3H,s),10.75-10.92(1H,br s)
*2:HCl盐(化合物1-015为2HCl盐)
*3:从纯化的(硅胶柱色谱法)化合物静置结晶并干燥。
表2*1
*1:Com.No.=化合物编号,Ex.No.=实施例编号,
结晶用溶剂;EtOAc=乙酸乙酯,IPE=二异丙基醚
*2:HCl盐
检测实施例[CRF受体结合试验]
猴扁桃体膜用作受体标本(preparation)。
125I-CRF用作125I标记的配体。
使用125I标记的配体,按照The Journal of Neuroscience,7,88(1987)所描述的下列方法进行结合反应。
制备受体膜:
猴扁桃体在含有10mM MgCl2、2mM EDTA的50mM Tris-HCl缓冲液(pH 7.0)中匀化,并以48,000×g离心20min,随后将沉淀物用Tris-HCl缓冲液洗涤一次。洗过的沉淀物在含有10mM MgCl2、2mMEDTA、0.1%牛血清白蛋白和100激肽释放酶单位/ml抑肽酶的50mMTris-HCl缓冲液中悬浮,从而获得膜标本。
CRF受体结合试验:
膜标本(0.3mg蛋白质/ml)、125I-CRF(0.2nM)和试验药物在25℃下反应2小时。当反应结束后,反应混合物通过抽吸,经过0.3%聚乙烯亚胺处理过的玻璃滤器(GF/C)过滤,并且将玻璃滤器用含有0.01%Triton X-100的磷酸缓冲的盐水洗涤三次。洗后,用γ计数器测量滤纸的放射性。
当反应在1μM CRF存在的条件下进行时,将125I-CRF结合的量作为125I-CRF非特异性结合的程度,并且将125I-CRF结合的总程度与非特异性125I-CRF结合的程度的差值作为125I-CRF特异性结合的程度。在上述条件下,通过将一定浓度(0.2nM)的125I-CRF和各浓度的各种试验药物进行反应以获得抑制曲线。从抑制曲线可确定当125I-CRF的结合被抑制50%(IC50)时的试验药物的浓度。
结果发现化合物1-001、1-002、1-003、1-004、1-005、1-006、1-007、1-008、1-009、1-010、1-011、1-012、1-013、1-016、1-017、1-018、1-019、1-022、1-027、2-001、2-002、2-003、2-004、2-005和2-006为IC50值小于或等于100nM的典型化合物的例子。
本发明的效果
根据本发明,提供具有高度CRF受体亲和力的化合物。该化合物有效地对抗被认为是与CRF相关的疾病,例如抑郁症、焦虑症、阿尔海默氏病、帕金森氏病、亨庭顿氏舞蹈病、饮食性疾病、高血压、消化道疾病、药物依赖、癫痫症、脑梗死、脑缺血、脑水肿、脑外伤、炎症、免疫相关性疾病、脱发、肠易激综合征、睡眠障碍、皮炎、精神分裂症、疼痛等。
Claims (5)
1.一种用下式[II]表示的氨基甲酰基取代的吡咯并嘧啶衍生物、或其药学上可接受的盐:
其中
R1为-OR4、-S(O)1R4或-NR4R5;
R2为C1-6烷基;
R3为氢;
R4和R5相同或不同,并且独立地为氢、C1-9烷基、C3-7环烷基、C3-7环烷基-C1-6烷基、二(C3-7环烷基)-C1-6烷基、C1-6烷氧基-C1-6烷基、二(C1-6烷氧基)-C1-6烷基、羟基-C1-6烷基、氰基-C1-6烷基、氨基甲酰基-C1-6烷基或二(C1-6烷基)氨基-C2-6烷基;或者R4和R5一起形成(CH2)m-A-(CH2)n-,其中A为亚甲基、氧、硫、NR8或CHR9;
R8为氢、C1-6烷基、C3-7环烷基、芳基或芳基-C1-6烷基;
R9为氢、羟基、羟基-C1-6烷基、氰基或氰基-C1-6烷基;
l为选自0、1和2的整数;
m为选自1、2、3和4的整数;
n选自0、1、2和3的整数;
条件是,当A为氧、硫或NR8时,n为1、2或3;
Ar为苯基,其中苯基为用1个或多个相同或不同的取代基取代,该取代基选自卤素、C1-6烷基和三氟甲基。
2.根据权利要求1所述的由式[II]表示的氨基甲酰基取代的吡咯并嘧啶衍生物、或其药学上可接受的盐,其中R1为-OR4或-NR4R5;R2为C1-6烷基;R3为氢;R4和R5相同或不同,并且独立地为氢、C1-9烷基、C3-7环烷基、C3-7环烷基-C1-6烷基、二(C3-7环烷基)-C1-6烷基、C1-6烷氧基-C1-6烷基、二(C1-6烷氧基)-C1-6烷基、羟基-C1-6烷基或氰基-C1-6烷基;Ar为苯基,其中苯基用两个或三个相同或不同的取代基取代,所述取代基选自卤素、C1-3烷基和三氟甲基。
3.根据权利要求2所述的由式[II]表示的氨基甲酰基取代的吡咯并嘧啶衍生物、或其药学上可接受的盐,其中R1为-OR4或-NR4R5;R2为C1-6烷基;R3为氢;R4为C1-9烷基、C3-7环烷基、C3-7环烷基-C1-6烷基、二(C3-7环烷基)-C1-6烷基、C1-6烷氧基-C1-6烷基、二(C1-6烷氧基)-C1-6烷基、羟基-C1-6烷基或氰基-C1-6烷基;R5为氢;Ar为苯基,其中苯基用两个或三个相同或不同的取代基取代,所述取代基选自卤素和C1-3烷基。
4.一种CRF受体拮抗剂,其含有根据权利要求1到3中任意一项所述的氨基甲酰基取代的吡咯并嘧啶衍生物、或其药学上可接受的盐作为活性成分。
5.根据权利要求1到3中任意一项所述的氨基甲酰基取代的吡咯并嘧啶衍生物、或其药学上可接受的盐在制造作为CRF受体拮抗剂的治疗剂中的应用。
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JP4766393B2 (ja) | 2004-01-06 | 2011-09-07 | 大正製薬株式会社 | トリアザ−シクロペンタ[cd]インデン誘導体 |
RU2006128580A (ru) | 2004-01-06 | 2008-02-20 | Тайсо Фармасьютикал Ко., Лтд. (Jp) | Производные тиенопиримидина и тиенопиридина, замещенные циклической аминогруппой |
JP2007161585A (ja) | 2004-06-25 | 2007-06-28 | Taisho Pharmaceut Co Ltd | 環状アミノ基で置換されているピロロピリミジン及びピロロピリジン誘導体 |
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EP3317282B1 (en) * | 2015-07-01 | 2020-12-09 | Northwestern University | Substituted 4-methyl-pyrrolo[1.2-a]pyrimidine-8-carboxamide compounds and uses thereof for modulating glucocerebrosidase activity |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0729758A2 (en) * | 1995-03-02 | 1996-09-04 | Pfizer Inc. | Pyrazolopyrimidines and pyrrolopyrimidines for treatment of neuronal and other disorders |
WO1998035967A2 (en) * | 1997-02-18 | 1998-08-20 | Neurocrine Biosciences, Inc. | Biazacyclic crf antagonists |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR19990067704A (ko) | 1992-12-17 | 1999-08-25 | 디. 제이. 우드, 스피겔 알렌 제이 | 부신피질자극호르몬 유리인자 길항제로서의 피롤로피리미딘을함유하는 약학 조성물 |
CA2233307A1 (en) | 1996-02-07 | 1997-08-14 | Terence J. Moran | Thiophenopyrimidines |
ATE340176T1 (de) | 1996-08-28 | 2006-10-15 | Pfizer | Substituierte 6,5-heterobicyclische-derivate |
EP0976745B1 (en) | 1997-03-26 | 2003-08-13 | Taisho Pharmaceutical Co., Ltd | 4-tetrahydropyridylpyrimidine derivatives |
AU751710B2 (en) | 1997-04-22 | 2002-08-22 | Neurocrine Biosciences Inc. | CRF antagonistic thiophenopyridines |
JP2002510687A (ja) | 1998-04-02 | 2002-04-09 | ニューロゲン コーポレイション | アミノアルキル置換ピロロ[2,3−b]ピリジンおよびピロロ[2,3−d]ピリミジン誘導体:crf1レセプタのモジュレータ |
EP1068205A1 (en) | 1998-04-02 | 2001-01-17 | Neurogen Corporation | Aminoalkyl substituted 5,6,7,8-tetrahydro-9h pyrimidino 2,3-b]indole and 5,6,7,8-tetrahydro-9h-pyrimidino 4,5-b]indole derivatives: crf1 specific ligands |
AU3464599A (en) | 1998-04-02 | 1999-10-25 | Neurogen Corporation | Aminoalkyl substituted 9h-pyridino(2,3-b)indole and 9h-pyrimidino(4,5-b)indole derivatives |
ES2239592T3 (es) | 1999-03-11 | 2005-10-01 | Taisho Pharmaceutical Co., Ltd | Derivados de carbamoil tetrahidropirina. |
AR028782A1 (es) | 2000-07-05 | 2003-05-21 | Taisho Pharmaceutical Co Ltd | Derivados heterociclicos tetrahidropiridino o piperidino |
AR042667A1 (es) | 2002-12-26 | 2005-06-29 | Taisho Pharmaceutical Co Ltd | Derivados de pirrolopirimidina y pirrolopiridina sustituidos con un grupo amino ciclico |
JP4766393B2 (ja) | 2004-01-06 | 2011-09-07 | 大正製薬株式会社 | トリアザ−シクロペンタ[cd]インデン誘導体 |
WO2005066142A2 (en) | 2004-01-06 | 2005-07-21 | Taisho Pharmaceutical Co., Ltd. | Pyrrolopyrimidine and pyrrolotriazine derivatives as crf receptor antagonists |
RU2006128580A (ru) | 2004-01-06 | 2008-02-20 | Тайсо Фармасьютикал Ко., Лтд. (Jp) | Производные тиенопиримидина и тиенопиридина, замещенные циклической аминогруппой |
JP2007526906A (ja) | 2004-03-05 | 2007-09-20 | 大正製薬株式会社 | ピロロピリミジン誘導体 |
JP2007161585A (ja) | 2004-06-25 | 2007-06-28 | Taisho Pharmaceut Co Ltd | 環状アミノ基で置換されているピロロピリミジン及びピロロピリジン誘導体 |
JP2008503443A (ja) | 2004-06-25 | 2008-02-07 | 大正製薬株式会社 | テトラヒドロピリジンで置換されたピロロピリミジン及びピロロピリジンの誘導体 |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0729758A2 (en) * | 1995-03-02 | 1996-09-04 | Pfizer Inc. | Pyrazolopyrimidines and pyrrolopyrimidines for treatment of neuronal and other disorders |
WO1998035967A2 (en) * | 1997-02-18 | 1998-08-20 | Neurocrine Biosciences, Inc. | Biazacyclic crf antagonists |
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EP1706410A2 (en) | 2006-10-04 |
RU2006128581A (ru) | 2008-02-20 |
CA2552503C (en) | 2011-09-13 |
HK1097539A1 (en) | 2007-06-29 |
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