CN101938906A - 作为a2ar激动剂的取代的4-{3-[6-氨基-9-(3,4-二羟基-四氢呋喃-2-基)-9h-嘌呤-2-基]-丙-2-炔基}-哌啶-1-羧酸酯 - Google Patents
作为a2ar激动剂的取代的4-{3-[6-氨基-9-(3,4-二羟基-四氢呋喃-2-基)-9h-嘌呤-2-基]-丙-2-炔基}-哌啶-1-羧酸酯 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
本发明提供了作为A2A腺苷受体(AR)的选择性激动剂的取代的4-{3-[6-氨基-9-(3,4-二羟基-四氢呋喃-2-基)-9H-嘌呤-2-基]-丙-2-炔基}-哌啶-1-羧酸酯和包含所述化合物的药物组合物。这些化合物和组合物用作药剂。
Description
政府权利的声明
本发明是在美国国立卫生研究院的联邦基金1 R41 AR052960的帮助下完成的。政府可能具有本发明的某些权利。
技术领域
本发明涉及作为A2A腺苷受体(AR)的选择性激动剂的取代的4-{3-[6-氨基-9-(3,4-二羟基-四氢呋喃-2-基)-9H-嘌呤-2-基]-丙-2-炔基}-哌啶-1-羧酸酯和药物组合物。这些化合物和组合物用作药剂。
发明背景
基于放射配体结合测定和生理反应,作为A2A腺苷受体(AR)的激动剂的越来越有效和/或选择性的化合物有了很大进展。例如,Linden等人的美国专利6,232,297描述了具有以下通式的化合物:
其中,各个R可以是H,各个X可以是乙氨基羰基,以及R1可以是4-甲氧羰基环己基甲基(DWH-146e)。据报道这些化合物为A2A激动剂。
Linden等人的美国专利7,214,665描述了具有以下通式的化合物:
其中,R7可以是H,X可以是醚或酰胺,CR1R2可以是CH2,以及Z可以是杂环。据报道这些化合物为A2A激动剂。
Rieger等人的美国专利申请2006/004088描述了具有以下通式的化合物:
其中,R7可以是H,X可以是环烷基取代的醚或酰胺,CR1R2可以是CH2,以及Z可以是杂环。据报道这些化合物为A2A激动剂。
Rieger等人的美国专利申请2007/0270373描述了具有以下通式的化合物:
其中,NR1R2可以是NH2,R4可以是醚或酰胺,R5可以是乙炔基,Y可以是O或NR1,以及Z可以是芳基或杂芳基。据报道这些化合物为A2A激动剂。
即便鉴于如上所述,仍然存在对于用于治疗应用的A2腺苷受体激动剂的需要。
发明内容
本发明提供了可以作为A2A腺苷受体激动剂的取代的4-{3-[6-氨基-9-(3,4-二羟基-四氢呋喃-2-基)-9H-嘌呤-2-基]-丙-2-炔基}-哌啶-1-羧酸酯或立体异构体或药学上可以接受的盐。
本发明也提供了包括本发明的化合物或其立体异构体或药学上可以接受的盐结合药学上可接受的赋形剂的药物组合物。
本发明提供了使用本发明的化合物和组合物的治疗和诊断的新方法。
本发明提供了本发明的用于医学治疗的新化合物。
本发明也提供了本发明的新化合物用于生产治疗哺乳动物的病理状况或症状的药物的用途,所述病理状况或症状涉及A2A受体,并且受体的激动提供治疗益处。
鉴于本文所述的取代的4-{3-[6-氨基-9-(3,4-二羟基-四氢呋喃-2-基)-9H-嘌呤-2-基]-丙-2-炔基}-哌啶-1-羧酸酯的发现,已经实现了本发明的这些和其他方面。
具体实施方式
本发明提供了作为腺苷A2A受体激动剂的新的取代的4-{3-[6-氨基-9-(3,4-二羟基-四氢呋喃-2-基)-9H-嘌呤-2-基]-丙-2-炔基}-哌啶-1-羧酸酯,以及在治疗疾病和状况的方法中使用所述化合物的方法,所述疾病和状况涉及A2A受体,并且受体的激动提供治疗益处。例如,化合物可以用于治疗哺乳动物组织的炎症活动,或用于治疗镰状细胞病。炎症组织活动可以归因于病理因素或可以归因于物理、化学或热损伤,或医疗方法(例如器官、组织或细胞移植、血管成形术(PCTA))的损伤,缺血/再灌注后的炎症、或移植)。本发明的化合物也可以结合其他抗炎治疗或结合抗病原体药物而使用。
在一个实施方式中,本发明提供了式I、II、或III的新化合物,或其立体异构体或药学上可以接受的盐:
其中:
R1和R2独立地选自H和C1-3烷基;
Z选自环丙基、环丁基、环戊基、四氢呋喃基、氮杂环丁烷-2-酮基(azetidin-2-onyl)、吡咯烷基和吡咯烷-2-酮基;
Z被0-2个Z2取代;
Z1选自四氢呋喃基、氮杂环丁烷-2-酮基、吡咯烷基和吡咯烷-2-酮基;
Z1被0-2个Z2取代;
Z2独立地选自F、C1-4烷基、CF3、OCF3、(CH2)aOR3、(CH2)aNR3R3、NO2、(CH2)aCN、(CH2)aCO2R3和(CH2)aCONR3R3;
R3独立地选自H和C1-6烷基;
R4选自CH2OR或C(O)NRR;
各个R独立地选自H、C1-4烷基、环丁基和(CH2)a环丙基;
a选自0、1和2,以及,
q选自1、2和3。
在另一个实施方式中,本发明提供了新化合物,其中,该化合物为式I:
R1和R2为H;
Z2独立地选自F、C1-2烷基、CF3、OCF3和OR3;
R3独立地选自H和C1-2烷基;
R4是C(O)NRR;
各个R独立地选自H、C1-4烷基、环丙基、环丁基和-CH2-环丙基;以及,
q为1。
在另一个实施方式中,本发明提供新化合物,其中,化合物选自:
在另一个实施方式中,本发明提供了新化合物,其中,化合物为式II:
R1和R2为H;
Z被0-1个Z2取代;
Z2独立地选自F、C1-2烷基、CF3、OCF3和OR3;
R3独立地选自H和C1-2烷基;
R4为C(O)NRR;以及,
各个R独立地选自H、C1-4烷基、环丙基、环丁基和-CH2-环丙基。
在另一个实施方式中,本发明提供了新化合物,其中,化合物选自:
在另一个实施方式中,本发明提供了新化合物,其中,化合物选自:
在另一个实施方式中,本发明提供了新化合物,其中,化合物为式III:
R1和R2为H;
Z1被0-1个Z2取代;
Z2独立地选自F、C1-2烷基、CF3、OCF3和OR3;
R3独立地选自H和C1-2烷基;
R4为C(O)NRR;
各个R独立地选自H、C1-4烷基、环丙基、环丁基和-CH2-环丙基;
q为0。
在另一个实施方式中,本发明提供了新化合物,其中,化合物选自:
在另一个实施方式中,本发明提供了新化合物,其中,化合物选自:
在另一个实施方式中,本发明提供了新化合物,其中,化合物选自:
在另一个实施方式中,本发明提供了新化合物,其中,化合物为式III:
R1和R2为H;
Z1被0-1个Z2取代;
Z2独立地选自F、C1-2烷基、CF3、OCF3和OR3;
R3独立地选自H和C1-2烷基;
R4为C(O)NRR;
各个R独立地选自H、C1-4烷基、环丙基、环丁基和-CH2-环丙基;
q为1。
在另一个实施方式中,本发明提供了新化合物,其中,化合物选自:
在另一个实施方式中,本发明提供了新化合物,其中,化合物选自:
在另一个实施方式中,本发明提供了新化合物,其中,化合物选自:
本发明提供了用于医学治疗的新化合物,优选用于治疗炎症或保护哺乳动物组织免受如炎症反应(例如源自过敏、外伤或缺血/再灌注损伤)的炎症的新化合物,以及本发明的化合物用于生产治疗哺乳动物的由于与炎症有关的病理状况或症状引起的炎症反应的药物的用途。
本发明旨在包括存在于本发明化合物中的原子的所有同位素。同位素包括那些具有相同的原子序数但不同质量数的原子。以下作为一般的例子但不限于,氢的同位素包括氘和氚。碳的同位素包括C-13和C-14。
本发明也包括这些化合物和至少一种抗炎化合物的组合的使用。这种化合物的例子是IV型磷酸二酯酶抑制剂,且这种组合可用于导致由白细胞介导的炎症反应的协同减少。
本发明也提供了包括有效量的本发明化合物或其药学上可以接受的盐结合药学上可以接受的稀释剂或载体和任选地结合抗炎化合物的药物组合物。组合物可以以单位剂型的形式出现。载体可以是液体载体。可以调整组合物用于口服、静脉内、眼睛、肠胃外、气溶胶或经皮施用。
本发明的组合物可以进一步包括IV型磷酸二酯酶抑制剂或另一种抗炎化合物(例如,除PDE抑制剂之外)。IV型磷酸二酯酶抑制剂可以是,例如,咯利普兰(rolipram)、西洛司特(cilomilast)、罗氟司特(roflumilast)。
此外,本发明提供了用于治疗哺乳动物的病理状况或症状的治疗方法(其中,涉及A2A腺苷受体的活性,并且需要所述受体的激动),包括向需要这种治疗的哺乳动物施用有效量的本发明的化合物或其药学上可以接受盐。据认为A2A腺苷受体的活化通过作用于中性粒细胞、肥大细胞、单核细胞/巨噬细胞、血小板T-细胞和/或嗜酸性粒细胞来抑制炎症。对这些炎症细胞的抑制导致组织损伤之后的组织保护。
此外,本发明提供了用于治疗生物学疾病的治疗方法,包括施用有效量的合适的抗生素、抗真菌剂或抗病毒剂结合A2A腺苷受体激动剂。如果没有抗病原体药物是已知的,A2A激动剂可以单独用于减少炎症,这可能出现于具有耐抗生素的细菌或如引起SARS或埃博拉病毒病(Ebola)的某些病毒的感染过程。任选地,本方法包括施用IV型PDE抑制剂。A2A腺苷受体激动剂可以在例如处理生物恐怖武器(如炭疽、兔热病、大肠杆菌、鼠疫等)施用抗生素时,为治疗条件(由例如人的尿毒综合症的脓毒症引起的炎症)提供辅助治疗。本发明也提供了治疗致命细菌、真菌和病毒感染(如炭疽、兔热病、埃希氏菌属和鼠疫)的辅助治疗,包括施用抗菌剂、抗真菌剂或抗病毒剂结合选择性的A2A腺苷受体激动剂。
本发明提供了单独或结合疾病治疗药物(disease killing medicine)治疗引起炎症的生物学疾病的方法。这些包括与抗生素相结合的细菌,包括但不限于引起炭疽、兔热病、鼠疫、莱姆病和炭疽的细菌。也包括病毒,包括但不限于引起RSV、严重急性呼吸综合症(SARS)、流感和埃博拉病毒病的病毒,使用或不用抗病毒疗法。也包括使用或不用抗酵母剂或抗真菌剂的酵母和真菌感染。
抗细菌剂、抗真菌剂或抗病毒剂可以与A2A腺苷受体激动剂共施用(如同时施用),或它们同时施用或作为混合物施用,或顺序施用。可以在药剂施用前,在药剂施用数分钟到高达大约48小时后,顺序施用A2A腺苷受体激动剂。优选在大约24小时内和更优选大约12小时内施用A2A腺苷受体激动剂。
本发明的方法也用于治疗患有脓毒症、严重脓毒症、以及除了脓毒性休克还有潜在的全身炎症反应综合症的病人。A2A腺苷受体激动剂在炎症级联的早期发挥多重抗炎效应,因此这种激动剂的短期应用对于人类的严重的、威胁生命的感染和炎症性疾病(包括吸入性炭疽、兔热病、埃希氏菌属和鼠疫)具有深远的益处。
已有文献证明A2A受体激动剂在脑膜炎、腹膜炎和关节炎的实验模型中的体内抗炎作用。细菌性脓毒症的潜在的致命性综合症是急性监护病房中的越来越普遍的问题。脓毒症和脓毒性休克,在美国是排名第十一位的致死原因,呈现了增长的频率。目前的估计表明每年在美国出现大约900,000个脓毒症新病例(大约60%的革兰氏阴性),具有估计35%的粗死亡率。而且,目前的临床试验评估的死亡率大约为25%,而大约10%的病人死于其潜在疾病。每年休克病例大约为200,000,具有可归因于此的46%的死亡率(92,000人死亡)。脓毒症在每年的卫生保健支出中占估计50-100亿美元。人们普遍认为在非冠心病重症监护病房中的住院病人中,脓毒症是最常见的死亡原因。脓毒症综合症是一个非常重要的公共健康问题。A2AAR激动剂预计用作新的独特的辅助医疗方法以减少发病率和死亡率。据认为这种治疗会提升全身性炭疽、兔热病、埃希氏菌属和鼠疫的治疗效果。
本发明的A2A腺苷受体激动剂可以抑制中性粒细胞、巨噬细胞和T细胞活化,因此可以减少由细菌和病毒感染引起的炎症。这些化合物,结合抗生素和抗病毒剂可以阻止或减少由脓毒症或溶血性尿毒症综合症或其他炎症条件导致的死亡率。腺苷A2A受体激动剂的效果可以被IV型磷酸酯酶抑制剂(如咯利普兰)增强。
本发明也提供了用于医学治疗(例如,用作治疗潜在的致命性细菌感染(如炭疽、兔热病、埃希氏菌属、鼠疫)或其他细菌或病毒感染,和治疗由细菌和/或病毒感染导致的全身性中毒的辅剂)的本发明的化合物,以及本发明的化合物在用于生产减少由细菌或病毒引起的炎症或治疗哺乳动物(如人)的所述炎症的药物中的用途。本发明的化合物也用于治疗其中由细菌或病毒制剂直接引起炎症或由于治疗(如应用抗生素或抗病毒剂)引起的全身性中毒。
脓毒症是由血流被产生毒素的细菌或病毒的暴发性感染导致的严重疾病。这种感染(可以表现为炎症)可以被细菌或病毒病原体直接引起或源于其治疗(即,由于用抗细菌剂或抗病毒剂的治疗导致病原菌的死亡)。脓毒症也可以理解为身体对感染的反应。感染可能由微生物或“病菌”(通常为细菌)侵入身体引起,可以被限制在特定的身体部位(如牙脓肿),或可以在血液中传播(常常称为“败血症”或“血中毒”)。
全身性中毒或炎症性休克常常称为脓毒性休克、菌血症休克、内毒素休克、败血症休克或温性休克。
脓毒性休克是当暴发性感染导致低血压和低血流时出现的严重、异常的状况。重要器官(如脑、心脏、肾脏和肝脏)不能正常发挥作用或可能衰竭。脓毒性休克最经常出现在老人和幼儿。也会出现在患有基础疾病的人。任何细菌生物都可以引起脓毒性休克。真菌和病毒也会引起这种状况。细菌、真菌或病毒释放的毒素可以引起直接的组织损伤,并可以引起低血压和/或不良的器官功能。这些毒素也可以产生来自身体的强力的炎症反应,这加重脓毒性休克。
另一方面,本发明也提供了治疗严重急性呼吸系统综合症(SARS)的方法,包括向需要所述治疗的哺乳动物施用有效抗炎剂量的A2A腺苷受体激动剂、任选地结合PDE-IV抑制剂(如咯利普兰)。
本发明也提供了通过向患有镰状细胞疾病的患者施用本文所述的A2A激动剂来治疗镰状细胞疾病的方法。
本发明提供了用于检测哺乳动物(如人或家畜)中冠状动脉狭窄的存在并评估其严重性的化合物和方法。优选地,本发明的化合物用作用于检测和评估冠状动脉疾病的药理应激(pharmacological stress)成像中的药理应激诱导剂或应激源(stressor)。本发明的用作应激诱导剂的特定化合物对于A2A腺苷受体是强效和选择性,但也是短效的,因而它们在成像过程后被身体快速清除。
因此,本发明提供了用于检测哺乳动物(如人受试者)中冠状动脉狭窄的存在和严重性的方法,包括:(1)施用一定量的本发明的一种或多种化合物,和(2)在所述哺乳动物上使用技术来检测和/或确定所述冠状动脉狭窄的严重性。
本发明提供了本发明的化合物用于医学诊断方法,优选用于检测人受试者中冠状动脉狭窄的存在并评估其严重性。本发明提供了本发明的化合物的用于生产药理血管舒张剂的用途,所述药理血管舒张剂与临床灌注成像技术一起用于诊断和评估冠状动脉疾病的程度。优选的灌注成像技术是平面或单光子发射计算机断层显像(SPECT)伽玛相机闪烁扫描法、正电子发射断层显像(PET)、核磁共振(NMR)成像、磁共振成像(MRI)成像、灌注对比超声心电图、数字减影血管造影(DSA)和超快X-射线计算断层扫描(CINE CT)。
本发明也提供了包括有效量的本发明化合物或其药学上可以接受的盐结合药学上可以接受的稀释剂或载体的药物组合物。优选地,组合物作为单位剂型出现,可以适用于肠胃外(如静脉输注)。
除非另有说明,使用下面的定义。
哺乳动物或受试者包括人、马、猪、犬和猫。
术语“取代的”指指定的原子上的任何一个或多个氢原子被选择的指示的基团取代,只要不超过指定原子的正常化合价,而且取代产生稳定的化合物。当取代基是酮(即=O)时,该原子上的2个氢原子被取代。酮基取代基不能出现在芳香部分上。
卤素是氟、氯、溴或碘。
烷基指直链或支链的烷基基团;但当提到单个的基团(如“丙基”)时,只包括直链基团,支链的异构体(如“异丙基”)会特别提到。特别地,C1-6烷基可以是甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、3-戊基、新戊基、己基等,可以存在任何支链形式。
下面列出的对于基团、取代基和范围的特定的和优选的值,仅用于说明目的;它们不排除其他定义值或对于基团和取代基定义范围内的其他值。
“治疗”(“Treating”或“treatment”)包括哺乳动物的疾病状态的治疗,包括:(a)预防哺乳动物出现疾病状态,尤其是在哺乳动物倾向于这种疾病状态但还没有诊断为患有疾病时;(b)抑制疾病状态,如,阻止它的发展;和/或(c)减轻疾病状态,例如,使疾病状态恢复,直到达到希望的终点。治疗也包括疾病的症状的改善(如,减轻疼痛或不适),其中,这种改善可以或不可以直接影响这种疾病(例如,原因、传输、表达等)。
本文使用的术语“结合”指抗排斥药和A2A腺苷受体激动剂的共施用。药物和A2A腺苷受体激动剂的共施用包括同时施用或作为混合物施用或顺序施用药物和A2A腺苷受体激动剂。A2A腺苷受体激动剂的顺序施用可先于药物的施用,在施用药物前数分钟或最高达大约48小时之内。A2A腺苷受体激动剂也可以在药物后施用。优选A2A腺苷受体激动剂的施用在大约24小时之内,更优选大约12小时之内。
本发明的化合物一般根据IUPAC或CAS命名系统来命名。可以使用本领域的技术人员所熟知的缩写(例如,″Ph″代表苯基,″Me″代表甲基,″Et″代表乙基,″h″代表1小时或数小时,和″rt″代表室温)。
本领域的那些技术人员可以理解:本发明的化合物具有多于1个的手性中心,可以以光学活性或外消旋形式分离得到。优选地,本发明的核苷部分源自D-核糖。某些化合物会呈现出多晶型现象。要理解的是,本发明包括本发明化合物的外消旋、光学活性、多晶型或立体异构形式或其混合物,其具有本文描述的有用的性质,本领域的人员熟知如何制备光学活性形式(例如,通过重结晶技术或酶技术、通过从光学活性起始原料合成、通过手性合成、或通过使用手性固定相色谱分离来拆分外消旋形式),和使用本文描述的测试或使用本领域熟知的其他相似测试如何测定腺苷受体激动剂活性。
可以用本发明的化合物和任选地结合IV型PDE抑制剂治疗(包括预防性治疗)的炎症反应,包括由以下原因引起的炎症:(a)自身免疫刺激(自身免疫疾病),如红斑狼疮、多发性硬化症、子宫内膜异位症不孕、I型糖尿病(包括破坏胰岛产生的糖尿病)和糖尿病的炎症后果(包括腿部溃疡)、克罗恩病、溃疡性结肠炎、炎性肠病、骨质疏松和类风湿关节炎;(b)过敏性疾病,如哮喘、花粉症、鼻炎、毒常春藤、春季结膜炎和其他嗜酸性粒细胞介导的状况;(c)皮肤病,如牛皮癣、接触性皮炎、湿疹、感染性皮肤溃疡、开放性伤口的愈合、蜂窝组织炎;(d)感染疾病,包括脓毒症、脓毒性休克、脑炎、感染性关节炎、内毒素性休克、革兰氏阴性休克、雅里施-赫克斯海默反应、炭疽、鼠疫、兔热病、埃博拉病毒病、带状疱疹、中毒性休克、脑型疟疾、细菌性脑膜炎、急性呼吸窘迫综合征(ARDS)、慢性阻塞性肺病(COPD)、莱姆病、HIV感染、(TNFα-增强的HIV复制、逆转录酶抑制剂活性的TNFα抑制);(e)消耗性疾病:继发于癌和HIV的恶病质;(f)器官、组织或细胞移植(例如骨髓、角膜、肾脏、肺、肝脏、心脏、皮肤、胰岛),包括移植排斥反应和移植物抗宿主病;(g)药物治疗的副作用,包括两性霉素B治疗的副作用、免疫抑制治疗(如白细胞介素-2治疗)的副作用、OKT3治疗、造影剂、抗生素的副作用、GM-CSF治疗的副作用、环孢霉素治疗的副作用、氨基糖苷类治疗的副作用、由于免疫抑制产生的口腔炎和粘膜炎;(h)心血管疾病,包括炎症反应诱导的或激发的循环系统疾病,如缺血、动脉粥样硬化、外周血管疾病、血管成形术后再狭窄、炎性主动脉瘤、血管炎、中风、脊髓损伤、充血性心力衰竭、失血性休克、缺血/再灌注损伤、蛛网膜下腔出血后的血管痉挛、脑血管意外后的血管痉挛、胸膜炎、心包炎和糖尿病的心血管并发症;(i)透析,包括由于腹膜透析引起的心包炎;(j)痛风;和(k)由于烧伤、酸、碱等引起的化学或热损伤。
其他疾病包括马的病症,如蹄叶炎和马跛病(founder’s disease)。
本发明的化合物用于限制炎症反应是特别令人感兴趣和有效的,其中,血管成形术或溶栓(throbolysis)导致缺血/再灌注损伤。本发明的化合物用于限制由于器官、组织或细胞移植的炎症反应也是特别令人感兴趣和有效的,即同种异体或异种组织移植进入哺乳动物接受体内,由于循环系统病理和其治疗(包括血管成形术、支架植入、支路放置或移植)导致的自身免疫性疾病和炎症反应。出人意料的,发现在炎症反应开始后施用本发明的一种或多种化合物是有效的,例如,在受试者患有引发炎症反应的病状或创伤之后。
包括结合配体的受体位点的组织或细胞可以用于测试试验化合物对于特定受体亚型的选择性、在血液或其他生理性液体中的生物活性化合物的量,或用作鉴定潜在的用于治疗与受体位点活化有关的疾病或状态的药物的工具,通过将所述药物和所述配体受体复合物接触,并测试配体的取代和/或药物的结合或细胞对所述药物的应答(如cAMP的积累)的程度。
下面的缩写用于本文:
2-Aas 2-炔基腺苷
125I-ABA N6-(4-氨基-3-125碘-苯甲基)腺苷
APCI 大气压化学电离
CCPA 2-氯-N6-环戊基腺苷
Cl-IB-MECA N6-3-碘-2-氯苯甲基腺苷-5’-N-甲基uronamide
CPA N6-环戊基腺苷
DMF 二甲基甲酰胺
DMSO 二甲基亚砜
DMSO-d6 氘代二甲基亚砜
EtOAc 乙酸乙酯
eq 当量
GPCR G蛋白偶联受体;hA2AAR,重组人A2A腺苷受体;
IADO 2-碘腺苷
125I-APE 2-[2-(4-氨基-3-[125I]碘苯基)乙氨基]腺苷
NECA 5’-N-乙基酰胺基腺苷
IB-MECA N6-3-碘苯甲基腺苷-5’-N-甲基uronamide
2-Iodoadenosine 5-(6-氨基-2-碘-嘌呤-9-基)-3,4-二羟基四氢呋喃-2
羧酸乙酰胺
HPLC 高效液相色谱
HRMS 高分辨质谱
125I-ZM241385 125I-4-(2-[7-氨基-2-[2-呋喃基][1,2,4]三唑并[2,3-a]-
[1,3,5]三嗪-5-基-氨基]乙基)苯酚
INECA 2-碘-N-乙基酰胺基腺苷
LC/MS 液相色谱/质谱
m.p. 熔点
MHz 兆赫
MRS 1220 N-(9-氯-2-呋喃-2-基-[1,2,4]三唑并[1,5-c]喹唑
啉-5-基)-2-苯基乙酰胺
MS 质谱
NECA N-乙基酰胺基腺苷
NMR 核磁共振
RP-HPLC 反相高效液相色谱
TBAF 四丁基氟化铵
TBS 叔丁基二甲基甲硅烷基
TBDMSCl 氯化叔丁基二甲基甲硅烷
TEA 三乙胺
TFA 三氟乙酸
THF 四氢呋喃
TLC 薄层色谱
p-TSOH 对甲苯磺酸
XAC 8-(4-((2-氨基乙基)氨基羰基-甲氧基)苯基)-1-3-二
丙基黄嘌呤。
用于实施本发明的特定的IV型磷酸二酯酶(PDE)抑制剂包括美国专利4,193,926中公开和描述的外消旋和光学活性的4-(聚烷氧苯基)-2-吡咯烷酮。咯利普兰是合适的IV型磷酸二酯酶抑制剂的例子。
本发明进一步提供了包括本发明的化合物结合选自下面的一种或多种成员的药物组合物:(a)白三烯生物合成抑制剂、5-脂肪加氧酶(5-LO)抑制剂和选自齐留通、ABT-761、芬留顿、替泊沙林、Abbott-79175、Abbott-85761、式(5.2.8)的N-(5-取代的)-噻吩-2-烷基磺酰胺、式(5.2.10)的2,6-二叔丁基苯酚腙、式(5.2.11)的Zeneca ZD-2138、式(5.2.12)的SB-210661、吡啶基取代的2-氰基萘化合物L-739,010、2-氰基喹啉化合物L-746,530、吲哚和喹啉化合物MK-591、MK-886和BAY x 1005的5-脂肪加氧酶活化蛋白(FLAP)拮抗剂;(b)白三烯LTB4、LTC4、LTD4和LTE4的受体拮抗剂,选自下面:吩噻嗪-3-酮化合物L-651,392、脒基化合物CGS-25019c、苯并噁唑胺化合物昂唑司特、苯甲脒(benzenecarboximidamide)化合物BIIL 284/260、化合物扎鲁司特、阿鲁司特、孟鲁司特、普仑司特、维鲁司特(MK-679)、RG-12525、Ro-245913、伊拉司特(CGP 45715A)和BAY x 7195;(d)5-脂肪加氧酶(5-LO)抑制剂和5-脂肪加氧酶活化蛋白(FLAP)拮抗剂;(e)双重5-脂肪加氧酶(5-LO)抑制剂和血小板活化因子(PAF)拮抗剂;(f)茶碱和氨茶碱;(g)COX-1抑制剂(NSAID)和一氧化氮NSAID;(h)COX-2选择性抑制剂罗非昔布;(i)具有较少全身副作用的吸入糖皮质激素,选自泼尼松、泼尼松龙、氟尼缩松、曲安奈德、倍氯美松双丙酸酯、布地奈德、丙酸氟替卡松和糠酸莫米松;(j)血小板活化因子(PAF)拮抗剂;(k)有效对抗内源性炎症实体的单克隆抗体;(l)抗肿瘤坏死因子(TNFα)剂,选自依纳西普、英夫利昔单抗和D2E7;(m)粘附分子抑制剂,包括VLA-4拮抗剂;(n)免疫抑制剂,选自环孢霉素、硫唑嘌呤和甲氨蝶呤;或(o)秋水仙碱抗痛风剂。
药学上可以接受的盐的例子是由形成药学上可以接受的阴离子(如甲苯磺酸根、甲磺酸根、苹果酸根、醋酸根、柠檬酸根、丙二酸根、酒石酸根、琥珀酸根、苯甲酸根、抗坏血酸根、α-酮戊二酸根和α-甘油磷酸根)的有机酸形成的有机酸加合盐。也可形成合适的无机盐,包括盐酸盐、硫酸盐、硝酸盐、碳酸氢盐和碳酸盐。
药学上可以接受的盐可使用本领域熟知的标准程序获得,例如,通过将足量的碱性化合物(如胺)和提供药学上可以接受的阴离子的合适的酸反应。也可以制成碱金属(如钠、钾、锂)或碱土金属(如钙)的羧酸盐。
本发明的化合物可以制成药物组合物,并向哺乳动物宿主(如人类患者)以适于选定的施用方式的各种途径施用,即,口服或肠胃外(通过静脉内、肌内、局部或皮下途径)。
因此,本发明的化合物结合药学上可以接受的载体(如惰性稀释剂或可同化的可食用的载体)可以全身施用,例如,口服。它们可以封闭在硬或软壳的明胶胶囊中,可以压为片剂,或可以直接掺入病人饮食的食物中。对于口服治疗施用,活性化合物可以结合一种或多种赋形剂,并以可吞咽的片剂、颊含片剂、含片、胶囊剂、酏剂、悬浮剂、糖浆、圆片等的形式使用。这种组合物和制剂应该包含至少0.1%的活性化合物。这种组合物和制剂的比例当然可以变化,可以占给定的单位剂型重量的大约2%至大约60%。在这种治疗有用的组合物中,活性化合物的量使得能够获得有效剂量水平。
片剂、含片、丸剂、胶囊剂等也可以包含:粘合剂,如黄蓍胶、阿拉伯胶、玉米淀粉或明胶;赋形剂,如磷酸氢二钙;崩解剂,如玉米淀粉、马铃薯淀粉、藻酸等;润滑剂,如硬脂酸镁;和甜味剂,如蔗糖、果糖、乳糖或阿司帕坦;或调味剂,如薄荷、冬青油或樱桃香味。当单位剂型是胶囊时,除了上面类型的材料,它还可以包含液体载体,如植物油或聚乙二醇。各种其他材料可以存在,作为包衣,或以其他方式改变固体单位剂型的物理形式。例如,片剂、丸剂或胶囊剂可以用明胶、蜡、虫胶或糖等包衣。糖浆或酏剂可以包含活性化合物,蔗糖或果糖作为甜味剂,对羟苯甲酸甲酯或对羟苯甲酸丙酯作为防腐剂,染料和调味剂(如樱桃香料或桔子香料)。当然,用于制备任何单位剂型的任何材料应该是药学上可以接受的且以应用的量基本上无毒。此外,活性化合物可以掺入缓释制剂和缓释装置中。
活性化合物也可以通过输注或注射来静脉内或腹膜内施用。可以制备活性化合物或其盐的水溶液,任选地混和无毒的表面活性剂。也可以制备在甘油、液体聚乙二醇、甘油三乙酸酯及其混合物以及油中的分散剂。在普通的储存和使用条件下,这些制剂包含防腐剂以防止微生物生长。
适于注射或输注的药物剂型可以包括包含适于无菌的可注射或可输注的溶液或分散剂的即时制剂的活性成分(任选封装在脂质体中)的无菌水溶液或分散剂或无菌粉末。在所有情况下,最终的剂型在生产和储存条件下必须是无菌的、液体的和稳定的。液体载体可以是溶剂或液体分散介质,包括,例如水、乙醇、多元醇(例如,甘油、丙二醇、液体聚乙二醇等)、植物油、无毒的甘油酯及其合适的混合物。可以维持合适的流动性,例如,通过脂质体的形成,通过在分散剂的情况下维持所需的粒子大小,或通过表面活性剂的使用。可以通过各种抗细菌剂和抗真菌剂(如对羟苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等)产生预防微生物的作用。在许多情况下,优选包括等渗剂,如糖、缓冲剂或氯化钠。通过使用延缓吸收剂的组合物(例如,单硬脂酸铝和明胶)可以产生可注射的组合物的延长吸收。
通过将合适的溶剂中的需要量的活性化合物与需要的上面列举的各种其他成分结合,然后进行过滤灭菌,制备无菌可注射溶液。在用于制备无菌注射溶液的无菌粉末的情况下,优选的制备方法是真空干燥和冷冻干燥技术,这会产生活性成分加上任何另外需要的以前无菌过滤溶液中存在的成分的粉末。
对于局部施用,本发明的化合物可以以纯的形式应用,即,当它们是液体时。然而,在向皮肤施用时,一般需要作为组合物或配方,结合皮肤学可以接受的载体,所述载体可以是固体、液体或皮肤贴剂。
有用的固体载体包括细分的固体(如滑石、粘土、微晶纤维素、二氧化硅、氧化铝等)。有用的液体载体包括水、乙醇或乙二醇或水-乙醇/乙二醇混合物,本发明的化合物可以任选在无毒的表面活性剂的帮助下以有效含量溶解或分散在其中。可以加入佐剂(如香味)和另外的抗微生物剂来优化对于给定用途的性质。产生的液体组合物可以从用于加固绷带和其他敷料的吸收垫应用,或使用泵型或气雾喷雾器喷射到病患区域。
增稠剂(如合成的聚合物、脂肪酸、脂肪酸盐和酯、脂肪醇、改性纤维素或改性无机材料)也可和液体载体用于形成可涂覆的糊剂、凝胶、软膏、肥皂等,直接用于使用者的皮肤上。
在Jacquet等人(美国专利4,608,392)、Geria(美国专利4,992,478)、Smith等人(美国专利4,559,157)和Wortzman(美国专利4,820,508)中公开了可以向皮肤递送本发明化合物的有用的皮肤学的组合物的例子。
通过比较体外活性与在动物模型中的体内活性可以确定本发明化合物的有用剂量。鼠、其他动物中的有效剂量向人类外推的方法是本领域已知的;例如,美国专利4,938,949。IV型磷酸二酯酶抑制剂的有用剂量是本领域已知的。例如,参见,美国专利5,877,180,Col.12。
一般地,本发明化合物在液体组合物(如洗剂)中的浓度为大约0.1重量%-25重量%,优选0.5重量%-10重量%。在半固体或固体组合物(如凝胶或粉末)中的浓度为大约0.1重量%-5重量%,优选0.5重量%-2.5重量%。
化合物或其活性盐或衍生物的治疗需要量,不仅取决于选择的特定的盐,而且取决于施药方式、待治疗的疾病的本质和患者的年龄和状态,最终取决于在场医师或临床医生的决定。
然而,一般地,合适的剂量为大约0.5到大约100μg/kg,例如,每天大约10到大约75μg/kg体重,如每天3到大约50μg/kg接受者体重,优选6到90μg/kg/天,最优选15到60μg/kg/天。
化合物方便地以单位剂型施用;例如,每单位剂型含有5到1000μg,方便地10到750μg,最方便地50到500μg的活性成分。
理想地,应该施用活性成分,以达到大约0.1到大约10nM、优选大约0.2到10nM、最优选大约0.5到大约5nM的活性化合物的峰值血浆浓度。这可以达到,例如,通过静脉注射0.05%到5%的活性成分溶液(任选生理盐水),或作为包含大约1-100μg的活性成分的大丸剂口服。通过连续输注来提供大约0.01-5.0μg/kg/小时或通过间歇输注包含大约0.4-15μg/kg的活性成分来维持所需的血液水平。
需要的剂量可以方便地以单一剂量,或以合适的间隔施用的亚剂量(例如,每天2、3、4或更多个亚量)出现。亚剂量本身也可以进一步细分,例如,成为许多分开的松散间隔的施用;如从吹入器多次吸入或应用多次滴入眼中。例如,需要在引起炎症的损伤后的延长的时间内静脉内施用本发明的组合物。
可以使用本领域熟知的药理模型,或使用下文描述的试验,确定本发明的给定化合物作为A2A腺苷受体激动剂的能力。
本发明的化合物或包含它们的组合物作为药理应激源施用,或结合几种无创诊断方法中的一种来测量心脏灌注的方面。例如,静脉注射腺苷结合铊-201心脏灌注成像用来评估心肌缺血的严重性。在这种情况下,几种不同的放射性药物中的任何一种可以被铊-201取代(例如,锝-99m-标记的放射性药物(即,Tc-99m-司他比、Tc-99m-替肟)、碘-123-标记的放射性药物(如I-123-IPPA或BMIPP)、铷-82、氮-13等)。类似地,本发明化合物中的一种可以作为药理应激源施用结合放射性核素心室造影法来评估心肌收缩功能障碍的严重性。在这种情况下,放射性核素心室造影研究可以是右和/或左心室的首次通过(first pass)或门控心室平衡研究。类似地,本发明的化合物可以作为药理应激源施用结合超声心电图来评估室壁运动异常的存在。类似地,本发明的活性化合物可以作为药理应激源施用结合冠脉血流量的侵入测定(如通过心内导管),来评估狭窄冠状血管的功能显著性。
本发明也提供了诊断哺乳动物心脏灌注异常的方法,包括:(a)向所述哺乳动物肠胃外施用一定量的上述化合物或组合物,和(b)在哺乳动物上使用技术来检测冠状动脉狭窄的存在,评估冠状动脉狭窄的严重性,或进行这两项。心肌功能障碍可以是,例如,冠状动脉疾病、心室功能障碍和通过无病冠状动脉血管和/或狭窄冠状动脉血管的血流差异。检测冠状动脉疾病的存在和评估其严重性的技术可以是,例如,放射性药物的心肌灌注成像、心室功能成像或测量冠状血流速度的技术。放射性药物的心肌灌注成像可以是,例如:平面闪烁扫描法、单光子发射计算机断层显像(SPECT)、正电子发射断层显像(PET)、核磁共振(NMR)成像、灌注对比超声心电图、数字减影血管造影(DSA)和超快X-射线计算断层扫描(CINE CT)。放射性药物制剂可以结合放射性药物心肌灌注成像使用,并且放射性药物可以包括例如选自铊-201、锝-99m、氮-13、铷-82、碘-123和氧-15的放射性核素。当放射性药物心肌灌注成像是闪烁扫描法时,放射性药物可以是铊-201。心室功能成像技术可以是,例如,超声心电图、对比心室造影或放射性核素心室造影。用于测量冠状血流速度的技术可以是,例如,多普勒血流导管、数字减影血管造影和放射性药物成像技术。这些诊断方法也可以包括以下步骤:(a)通过静脉输注或快速输注向人施用一定量的上面所述的化合物或组合物来提供冠状动脉扩张;(b)向人施用包含铊-201或锝-99m的放射性药物;和(c)为了检测冠状动脉疾病的存在并评估其严重性,在人上实施闪烁扫描法。放射性药物可以是Tc-99m司他比。
本方法通常包括通过静脉输注(大约0.25-500、优选1-250mcg/kg/分钟)施用有效提供冠状动脉扩张的剂量的本发明的一种或多种化合物。然而,其在侵入设置内的使用可以包括冠状动脉内施用5-50mcg的推注剂量的药物。
优选的方法包括使用本发明的化合物作为运动的替代物,结合心肌灌注成像来检测人的冠状动脉疾病的存在和/或评估其严重性,其中,通过以下几种技术中的任一种进行心肌灌注显像:包括使用平面闪烁扫描法或单光子发射计算机断层显像(SPECT)、正电子发射断层显像(PET)、核磁共振(NMR)成像、灌注对比超声心电图、数字减影血管造影(DSA)或超快X-射线计算断层扫描(CINE CT)的放射性药物的心肌灌注成像。
也提供了以下方法:包括使用本发明的化合物作为运动的替代物,结合成像来检测人的缺血性心室功能障碍的存在和/或评估其严重性,其中,通过以下几种成像技术中的任一种测量缺血性心室功能障碍:包括超声心电图、对比心室造影或放射性核素心室造影。心肌功能障碍可以是冠状动脉疾病、心室功能障碍和通过无病冠状动脉血管和/或狭窄冠状动脉血管的血流差异等。
也提供了包括使用本发明的化合物作为冠状动脉充血剂,结合测定冠状动脉血流速度的方法来评估人的冠状动脉舒张能力(存储能力),其中,冠状动脉血流速度通过以下几种技术中的任何测定:包括多普勒血流导管或数字减影血管造影。
参考下面详细的实施例进一步描述本发明,给出的这些例子是为了说明本发明,而不是限制。
实施例
用300兆赫的Varian Gemini 2000分光光度计(或类似仪器)记录质子的核磁共振谱(1H NMR)。化学位移值相对于四甲基硅烷用ppm(百万分之一)表示。对于数据报道,s=单峰、d=双峰、t=三重峰、q=四重峰和m=多重锋。用Finnigan LCQ Advantage测定质谱。用如下所述的Shimazdu LC10或LC20 Systemtimes(150mm)进行分析HPLC。用室温下运行的具有Shim-pack VP-ODS C18(20x100mm)柱的Shimazdu Discovery HPLC进行制备HPLC。用15分钟内的水(含0.1%TFA)-甲醇20%-80%的梯度以30mL/分钟的速度洗脱化合物,用SPD10A VP可调节检测器在254nm处紫外检测。出现的所有的最终化合物通过HPLC测定纯度超过98%。用Silicyle 60A凝胶(230-400目)或用可重复使用的色谱柱和来自RT Scientific,Manchester N.H.的系统进行快速色谱。除非另有说明,所有反应在火焰干燥的玻璃器皿中在氮气氛下进行。
实施例1
4-{3-[6-氨基-9-(5-环丙基氨基甲酰基-3,4-二羟基-四氢呋喃-2-基)-9H-嘌呤-2-基]-丙-2-炔基}-哌啶-1-羧酸环丁酯
在惰性气氛中,在0℃下,向HTF中的搅拌的三光气(0.34当量),缓慢加入作为在干燥THF中的溶液的醇(1.0当量)和二甲基苯胺(1.1当量),。10分钟后,加热该反应到室温,同时再搅拌3小时。接着加入干燥DCM,然后在0℃下将混合物缓慢倒入N-羟基琥珀酰亚胺(1.3当量)的干燥DCM溶液中。缓慢加热该反应到室温,并搅拌过夜。向混合物中加入水,再搅拌3小时后,用EtOAc稀释溶液。用水洗有机层3次,用盐水洗1次,然后干燥(MgSO4)并浓缩。产生的油(油可以是碳酸酯和对称酐的混合物)直接进入下一步反应。
哌啶衍生物(0.75当量)溶于干燥THF中,在惰性气氛下室温下缓慢加入TEA(过量)。用THF稀释碳酸酯化合物(1.0当量),然后滴加到哌啶溶液中。将混合物搅拌24小时,接着浓缩应用于硅胶色谱(梯度从100%正己烷开始,直到正己烷中的80% DCM)。产生的油(~60%产率)在4℃储存直到进一步使用。
碘代衍生物(1.0当量)溶于DMF∶ACN∶TEA 5∶5∶1(所有的溶剂剧烈脱气)的溶液中,并在惰性气体中室温下搅拌。加入钯催化剂(~5摩尔%)和碘化铜[I](1.05当量),接着加入炔烃衍生物(4.0当量)。产生的深色溶液搅拌过夜,然后浓缩,应用于硅胶色谱(梯度从100%的DCM开始,直到DCM中的10%MeOH)。产生的油进一步通过制备HPLC纯化,得到灰白色固体(~30%产率)。
1H NMR(DDMSO)δ8.56(s,1H),8.30(s,1H),7.52(s,2H),5.97(d,1H,J=6.6),5.67(dd,2H,J=21.3,4.8),4.84(p,1H,J=5.9),4,64(q,1H,J=4.8),4.30(d,1H,J=2.1),4.21(m,1H),4.00(d,2H,J=12.9),3.12(m,1H),2.719(m,4H),2.430(d,2H,J=6.3),2.272(m,2H),2.00(m,2H),1.77(m,2H),1.56(m,2H),1.207(m,2H),0.68(m,1H),0.50(m,1H)。
LRMS ESI(M+H+)540.35。
HPLC:在40℃下,4分钟内20%-95%的MeOH水溶液的梯度,共6分钟。保留时间为3.04分钟(6分钟方法)。
实施例2
N-环丙基2-{3-[1-((四氢呋喃-3-基氧)羰基)哌啶-4-基]丙炔-1-基}腺苷-5′-uronamide
按照实施例1提供的C-2偶合的一般方法,将4-(丙-2-炔基)哌啶-1-羧酸四氢呋喃-3-酯(1.620g,6.83mmol)加入到N-环丙基2-碘酰胺基腺苷(N-cyclopropyl 2-iodocarboxamidoadenosine)(0.101g,0.226mmol)的溶液中:54mg,产率为43%。LRMS ESI(M+H+)556.3。HPLC保留时间=6.0分钟。
实施例3
N-环丙基2-{3-[1-((四氢-2H-吡喃-4-基氧)羰基)哌啶-4-基]丙炔-1-基}腺苷-5′-uronamide。
按照实施例1提供的C-2偶合的一般方法,将4-(丙-2-炔基)哌啶-1-羧酸四氢-2H-吡喃-4-酯(3.290g,13.09mmol)加入到N-环丙基2-碘酰胺基腺苷(0.100g,0.224mmol)的溶液中:41mg,产率为32%。LRMS ESI(M+H+)570.3。HPLC保留时间=6.5分钟。
细胞培养和膜的制备。Sf9细胞在50% N2/50% O2气氛下,在补充有10%的胎牛血清、2.5μg/ml两性霉素B、50μg/ml庆大霉素的Grace介质中培养。用对于每种使用的病毒的2次多重感染,以2.5x106细胞/毫升的密度对细胞进行病毒感染。在感染3天后收获受感染的细胞,并在昆虫PBS(PBS pH 6.3)中洗涤两次。接着将细胞再悬浮在溶胞缓冲液中(20mM HEPES pH 7.5、150mM NaCl、3mM MgCl2、1mM β-巯基乙醇(BME)、5μg/mL亮抑蛋白酶肽、5μg/mL的酶抑胃素A、1μg/mL抑肽酶和0.1mM PMSF),并快速冷冻在-80℃下储存。将细胞在冰上解冻,使溶胞缓冲液成为30mL的总体积,并通过N2空化作用(600psi进行20分钟)爆裂。进行低速离心(1000xg进行10分钟)以去除任何未溶解的细胞,接着进行高速离心(17,000xg进行30分钟)。使用小的玻璃均化器使最终离心得到的片状沉淀物在含有20mM HEPES pH 8、100mM NaCl、1%甘油、2μg/mL亮抑蛋白酶肽、2μg/mL胃酶抑素A、2μg/mL抑肽酶、0.1mM PMSF和10μM GDP的缓冲液中均质化,然后通过26计量注射针。将膜等分,在液氮中快速冷冻,并在-80℃下储存。如(Robeva等人,1996)所述,制备来自稳定表达人的A1 AR(CHO K1细胞)或A3 AR(HEK 293细胞)的细胞的膜。
放射配体结合测定。使用放射标记的激动剂125I-APE(Luthin等人,1995)或放射标记的拮抗剂125I-ZM241385(125I-ZM),将放射配体结合到Sf9细胞膜的重组人A2A受体。为了检测高亲和力、A1和A3 AR的GTPγS-敏感态,我们使用激动剂125I-ABA(Linden等人,1985;Linden等人,1993)。用0.1mL HE缓冲液(20mM HEPES和1mM EDTA)总体积中的5μg(A2A)或25μg(A1和A3)膜蛋白,用1U/mL腺苷脱氨酶和5mM MgCl2,用或不用50μM GTPγS,一式三份地进行结合实验。在Millipore96-孔GF/C过滤板中,在室温下用放射性配体温孵膜3小时(对激动剂而言)或2小时(对拮抗剂而言),并通过在细胞收集器(Brandel,Gaithersburg,MD)上快速过滤接着用4×150μl的冰冷的10mM Tris-HCl、pH 7.4、10mM MgCl2洗液洗30秒来终止测定。在50μMNECA的存在下,测定非特异结合。如(Robeva等人,1996)描述,使用0.5-1nM 125I-APE、125I-ZM241385或125I-ABA进行竞争性结合测定。我们发现每次系列稀释后改变移液管尖端来防止尖端上的强效的疏水化合物的转移有时是重要的。如以前(Linden,1982)所述,借助放射配体和竞争化合物消耗的校正,从IC50值推导竞争性化合物对单一位点的结合的Ki值。
Linden J(1982)Calculating the Dissociation Constant of an Unlabeled Compound From the Concentration Required to Displace Radiolabel Binding by 50%.J Cycl Nucl Res 8:163-172.
Linden J,Patel A和Sadek S(1985)[125I]Aminobenzyladenosine,a New Radioligand With Improved Specific Binding to Adenosine Receptors in Heart.Circ Res 56:279-284.
Linden J,Taylor HE,Robeva AS,Tucker AL,Stehle JH,Rivkees SA,Fink JS和Reppert SM(1993)Molecular Cloning and Functional Expression of a Sheep A3 Adenosine Receptor With Widespread Tissue Distribution.Mol Pharmacol 44:524-532.
Luthin DR,Olsson RA,Thompson RD,Sawmiller DR和Linden J(1995)Characterization of Two Affinity States of Adenosine A2A Receptors With a New Radioligand,
2-[2-(4-Amino-3-[125I]Iodophenyl)Ethylamino]Adenosine.Mol Pharmacol47:307-313.
Robeva AS,Woodard R,Luthin DR,Taylor HE和Linden J(1996)Double Tagging Recombinant A1-and A2A-Adenosine Receptors With Hexahistidine and the FLAG Epitope.Development of an Efficient Generic Protein Purification Procedure.Biochem Pharmacol 51:545-555.
化学发光方法:鲁米诺增强化学发光(中性粒细胞氧化活性的测定)取决于过氧化物的产生和颗粒酶髓过氧化酶的动员。光从不稳定的高能氧物质(如次氯酸和活化的中性粒细胞产生的单线态氧)发射。
在有或没有rhTNF(10U/ml)的存在下,在水浴(37C)中温孵悬浮在含有0.1%人血清白蛋白(HA)、腺苷脱氨酶(1U/mL)和咯利普兰(100nM)的Hanks平衡盐溶液中的纯化的人中性粒细胞(2X106/ml)15分钟。温孵后,将PMN的100L等分试样转移到含有50lHA和鲁米诺(终浓度为100M)、具有或不具有腺苷激动剂(最终激动剂的浓度为0.01-1000nM)的孔(白壁澄清底的96孔组织培养板,Costar #3670;2孔/条件)。温孵板5分钟(37C),接着向所有的孔中加入fMLP(在HA中50l;终浓度为1M)。
使用Wallac工作站软件,用化学发光模式下的Victor 1420多重标记计数器测定峰值化学发光。作为峰值化学发光的数据表示为在缺乏腺苷激动剂的情况下活性的百分比。使用PRISM软件测定EC50值。所有化合物用来自三个独立的供体的PMN测试。
A2A激动剂对于中性粒细胞氧化活性的作用:f-met-leu-phe(fMLP)、鲁米诺、过氧化物歧化酶、细胞色素C、纤维蛋白原、腺苷脱氨酶和台盼蓝购自Sigma Chemical。聚蔗糖-泛影葡胺(Ficoll-hypaque)购自ICN(Aurora,OH)和Cardinal Scientific(Santa Fe,NM)和Accurate Chemicals和Scientific(Westerbury,NY)。内毒素(脂多糖;E.coli K235)购自List Biologicals(Campbell,CA)。Hanks平衡盐溶液(HBSS)和鲎阿米巴样细胞溶解物测定试剂盒(limulus amebocyte lysate assay kit)购自BioWittaker(Walkersville,MD)。人血清白蛋白(HSA)购自Cutter Biological(Elkhart,IN)。重组人肿瘤坏死因子-α购自Dianippon Pharmaceutical Co.Ltd.(Osaka,Japan)。ZM241385(4-(2-[7-氨基-2-(2-呋喃基)[1,2,4]三唑并[2,3-a][1,3,5]三嗪-5-基氨基]乙基)苯酚)由Simon Poucher,Zeneca Pharmaceuticals,Cheshire,UK赠予。制备储备溶液(在DMSO中为1mM和10mM),并在-20℃储存。
人中性粒细胞的制备:通过一步聚蔗糖-泛影葡胺分离方法(A.Ferrante等人,J.Immunol.Meth.,36,109(1980)),从正常肝素化(10U/ml)的静脉血获得包含<1个血小板/5个中性粒细胞和<50pg/ml内毒素(鲎阿米巴样细胞溶解物测定)的纯化的中性粒细胞(98%中性粒细胞和通过台盼蓝排除>95%的可存活)。
从接触过抗原的(primed)和刺激的人中性粒细胞化学发光释放炎症活性氧物质:鲁米诺增强化学发光(中性粒细胞氧化活性的测定)取决于过氧化物的产生和颗粒酶髓过氧化酶的动员。光从由活化的中性粒细胞产生的不稳定的高能氧物质发射。在摇动的水浴中,在37℃下,在具有测试的A2A激动剂、具有或不具有咯利普兰和具有或不具有肿瘤坏死因子α(1U/mL)、含有0.1%人血清白蛋白(1ml)的Hanks平衡盐溶液中,温孵纯化的中性粒细胞(5-10X106/ml)30分钟。然后在37℃下,用Photometer(Crono-log Corp.,Havertown,PA)读取鲁米诺增强的f-met-leu-phe(1 mcM)刺激的化学发光2-4分钟。化学发光被报道为相对于具有肿瘤坏死因子-α和不具有激动剂或咯利普兰的样品的发射的相对峰值光(=曲线的高度)。
所有的出版物、专利和专利文件通过引用被结合入本文,就好像单独地通过引用被结合入本文。参考各个特定的和优选的实施方式和技术描述了本发明。然而,应该理解:在保持在本发明的精神和范围的同时,可以做出各种变化和修改。
Claims (17)
1.式I、II、或III的化合物或其立体异构体或药学上可以接受的盐:
其中:
R1和R2独立地选自H和C1-3烷基;
Z选自环丙基、环丁基、环戊基、四氢呋喃基、氮杂环丁烷-2-酮基、吡咯烷基和吡咯烷-2-酮基;
Z被0-2个Z2取代;
Z1选自四氢呋喃基、氮杂环丁烷-2-酮基、吡咯烷基和吡咯烷-2-酮基;
Z1被0-2个Z2取代;
Z2独立地选自F、C1-4烷基、CF3、OCF3、(CH2)aOR3、(CH2)aNR3R3、NO2、(CH2)aCN、(CH2)aCO2R3和(CH2)aCONR3R3;
R3独立地选自H和C1-6烷基;
R4选自CH2OR或C(O)NRR;
各个R独立地选自H、C1-4烷基、环丁基和(CH2)a环丙基;
a选自0、1和2;以及,
q选自1、2和3。
2.根据权利要求1所述的化合物,其中,所述化合物为式I:
R1和R2为H;
Z2独立地选自F、C1-2烷基、CF3、OCF3和OR3;
R3独立地选自H和C1-2烷基;
R4是C(O)NRR;
各个R独立地选自H、C1-4烷基、环丙基、环丁基和-CH2-环丙基;以及,
q为1。
4.根据权利要求1所述的化合物,其中,所述化合物为式II,其中:
R1和R2为H;
Z被0-1个Z2取代;
Z2独立地选自F、C1-2烷基、CF3、OCF3和OR3;
R3独立地选自H和C1-2烷基;
R4为C(O)NRR;以及,
各个R独立地选自H、C1-4烷基、环丙基、环丁基和-CH2-环丙基。
7.根据权利要求1所述的化合物,其中,所述化合物为式III:
R1和R2为H;
Z1被0-1个Z2取代;
Z2独立地选自F、C1-2烷基、CF3、OCF3和OR3;
R3独立地选自H和C1-2烷基;
R4为C(O)NRR;
各个R独立地选自H、C1-4烷基、环丙基、环丁基和-CH2-环丙基;
q为0。
11.根据权利要求1所述的化合物,其中,所述化合物为式III:
R1和R2为H;
Z1被0-1个Z2取代;
Z2独立地选自F、C1-2烷基、CF3、OCF3和OR3;
R3独立地选自H和C1-2烷基;
R4为C(O)NRR;
各个R独立地选自H、C1-4烷基、环丙基、环丁基和-CH2-环丙基;
q为1。
15.药物组合物,包含权利要求1所述的化合物和药学上可接受的载体。
16.权利要求1至14中的任一项所述的化合物,用于医学治疗。
17.权利要求1至14中的任一项所述的化合物用于生产治疗哺乳动物的疾病的药物的用途。
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JP5046930B2 (ja) * | 2004-08-02 | 2012-10-10 | ユニバーシティ オブ バージニア パテント ファウンデーション | A2aアゴニスト活性を有する修飾5’−リボース基を備えた2−プロピニルアデノシン類似体 |
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US8188063B2 (en) * | 2006-06-19 | 2012-05-29 | University Of Virginia Patent Foundation | Use of adenosine A2A modulators to treat spinal cord injury |
US8058259B2 (en) * | 2007-12-20 | 2011-11-15 | University Of Virginia Patent Foundation | Substituted 4-{3-[6-amino-9-(3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-piperidine-1-carboxylic acid esters as A2AR agonists |
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US9822141B2 (en) | 2012-08-01 | 2017-11-21 | Lewis And Clark Pharmaceuticals, Inc. | N-alkyl 2-(disubstituted)alkynyladenosine-5-uronamides as A2A agonists |
EP2879683B1 (en) | 2012-08-01 | 2020-01-22 | Lewis and Clark Pharmaceuticals, Inc. | N-alkyl-alkynyladenosine-5-uronamide compounds as agonists of a2a receptor |
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