CN1547580A - 用於治疗爱滋病之ccr5拮抗剂 - Google Patents
用於治疗爱滋病之ccr5拮抗剂 Download PDFInfo
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- CN1547580A CN1547580A CNA028076540A CN02807654A CN1547580A CN 1547580 A CN1547580 A CN 1547580A CN A028076540 A CNA028076540 A CN A028076540A CN 02807654 A CN02807654 A CN 02807654A CN 1547580 A CN1547580 A CN 1547580A
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- alkyl
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- cycloalkyl
- heteroaryl
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
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Abstract
本发明公开了式I化合物或其医药上可接受之盐或异构物,其中Q,X与Z为CH或N;R,R4-R7与R13为H或烷基;R1为H、烷基、氟烷基、R9-芳烷基、R9-杂芳烷基、烷基-SO2-、环烷基-SO2-、氟烷基-SO2-、R9-芳基-SO2-、R9-杂芳基-SO2-、N(R22)(R23)-SO2-、烷基-C(O)-、环烷基-C(O)-、氟烷基-C(O)-、R9-芳基-C(O)-、NH-烷基-C(O)-或R9-芳基-NH-C(O)-;R2为H且R3为H、烷基、烷氧烷基、环烷基、环烷基烷基、R9-芳基、R9-芳烷基、R9-杂芳基或R9-杂芳基烷基,且当X与Z均为CH时,R3为烷氧基、R9-芳氧基、R9-杂芳氧基、烷基C(O)O-、烷氨基C(O)O-、烷基-C(O)NR13-、烷基OC(O)NR13-或烷氨基C(O)NR13-;或R2与R3合起来形成=O、=NOR10、=N-NR11R12或=CH-烷基;R8为经取代之苯基、经取代之杂芳基、萘基、芴基、二苯基甲基、α-取代苄基或α-取代的杂芳基甲基;R9至R12如本文中定义;该化合物可用於治疗HIV、固体器官移植物排斥、移植物抗宿主疾病、炎症、特应性皮炎、气喘、过敏或多发性硬化,还公开了医药组合物及与抗病毒剂或消炎剂之组合。
Description
发明背景
本发明涉及适合作为选择性CCR5拮抗剂使用的哌啶衍生物,含该化合物之医药组合物及使用该化合物之治疗方法。本发明亦涉及以本发明CCR5拮抗剂与一种或多种抗病毒剂或其他适用於治疗人类免疫缺损病毒(HIV)之药剂组合使用。本发明还涉及以本发明CCR5拮抗剂单独或与另一种药剂组合,用於治疗固体器官移植物排斥、移植物抗宿主疾病、关节炎、类风湿关节炎、发炎性肠部疾病、特应性皮炎、牛皮癣、气喘、过敏或多发性硬化。
造成获得性免疫缺损综合症(AIDS)之HIV无疑地已引起全球健康危机,虽然近年来之药物疗法已成功地减缓AIDS之进展,但仍需要寻求一种更安全、更有效、更便宜之方法来控制病毒。
已有文献指出,CCR5基因在抵抗HIV感染上扮演某种角色。HIV感染始於病毒通过与细胞受体CD4及继发趋化因子共同受体分子相互作用而附著在靶细胞膜上,并利用血液与其他组织,使已感染之细胞进行复制及播散。有各式各样的趋化因子受体,但是对于据信是感染初期体内复制的关键致病品系的亲巨噬细胞HIV,HIV进入细胞所需之主要趋化因子受体为CCR5。因此,干扰病毒受体CCR5与HIV之间的相互作用可以阻断HIV进入细胞。本发明涉及作为CCR5拮抗剂之小分子。
已有报告指出CCR5-受体在炎症中介导细胞转移,如:关节炎、类风湿关节炎、特应性皮炎、牛皮癣、气喘及过敏,并且此等受体之抑制剂,应适用於治疗这些疾病,及治疗其他炎症如:发炎性肠部疾病、多发性硬化、固体器官移植物排斥及移植物抗宿主疾病。
美国专利5,883,096、6,037,352、5,889,006、5,952,349和5,977,138公开了作为适用於治疗认知障碍如阿尔兹海默氏症之毒蕈硷拮抗剂的哌啶衍生物。
适用於治疗AIDS的哌啶与哌嗪衍生物已揭示於
WO 00/66559与WO 00/66558。
A-M.Vandamme et al.,
Antiviral Chemistry & Chemotherapy,9:187-203(1998)公开了目前用於治疗人类HIV-1感染之临床疗法,包括至少三种药物组合或所谓的高活性抗逆转录病毒疗法(″HAART″);HAART涉及多种核苷逆转录酶抑制剂(″NRTI″),非核苷逆转录酶抑制剂(″NNRTI″)与HIV蛋白酶抑制剂(″PI″)之不同组合。对于顺应的首次用药的患者,HAART可有效降低死亡率及HIV-1发展成AIDS之进度。然而,这些多重药物疗法仍无法消除HIV-1,且长期治疗经常造成多药耐药性。因此开发新药物疗法以提供更佳的HIV-1疗法仍是当务之急。
发明概要
本发明涉及适合作为CCR5拮抗剂之结构式I代表之化合物
或其医药上可接受之盐或异构物,其中:
Q、X与Z分别独立选自CH与N,但其限制条件为Q与Z中之一或二者为N;
R、R4、R5、R6与R7分别独立选自H与(C1-C6)烷基;
R1为H、(C1-C6)烷基、氟-(C1-C6)烷基-、R9-芳基(C1-C6)烷基-、R9-杂芳基-(C1-C6)烷基-、(C1-C6)烷基-SO2-、(C3-C6)环烷基-SO2-、氟-(C1-C6)烷基-SO2-、R9-芳基-SO2-、R9-杂芳基-SO2-、N(R22)(R23)-SO2-、(C1-C6)烷基-C(O)-、(C3-C6)环烷基-C(O)-、氟-(C1-C6)烷基-C(O)-、R9-芳基-C(O)-、NH-(C1-C6)烷基-C(O)-或R9-芳基NH-C(O)-;
R2为H或(C1-C6)烷基且R3为H、(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷基-、(C3-C10)-环烷基-、(C3-C10)环烷基(C1-C6)烷基-、R9-芳基、R9-芳基(C1-C6)烷基-、R9杂芳基或R9-杂芳基(C1-C6)烷基-,但其限制条件为X与Z不同时为N;
或R2与R3合起来为=O、=NOR10、=N-NR11R12或=CH(C1-C6)烷基,但其限制条件为当X与Z中之一或二者为N时,R2与R3合起来不是=CH(C1-C6)烷基;
且当X与Z分别为CH时,R3亦可为(C1-C6)烷氧基、R9-芳氧基、R9-杂芳氧基、(C1-C6)烷基-C(O)O-、(C1-C6)烷基-NH-C(O)O-、-N((C1-C6)烷基)2-C(O)O-、(C1-C6)烷基-C(O)-NR13-、(C1-C6)烷基-O-C(O)-NR13-、(C1-C6)烷基-NH-C(O)-NR13-或N((C1-C6)烷基)2-C(O)-NR13-;
R8为(R14,R15,R16)-取代之苯基、(R14,R15,R16)-取代之6元杂芳基、(R14,R15,R16)-取代之6元杂芳基N-氧化物、(R17,R18)-取代之5元杂芳基、萘基、芴基、二苯基甲基,
R9为1、2或3个独立选自下列之取代基:H、卤素、(C1-C6)烷基、(C1-C6)烷氧基、-CF3、-OCF3、CH3C(O)-、
-CN、CH3SO2-,CF3SO2-与-N(R22)(R23);
R10为H、(C1-C6)烷基、氟(C1-C6)烷基-、(C3-C10)环烷基(C1-C6)烷基-、羟基(C2-C6)烷基-、(C1-C6)烷基-O-(C2-C6)烷基-、(C1-C6)烷基-O-C(O)-(C1-C6)烷基-或N(R22)(R23)-C(O)-(C1-C6)烷基-;
R11与R12分别独立选自:H、(C1-C6)烷基与(C3-C10)环烷基,或R11与R12合起来为C2-C6亚烷基并与其连接之氮共同形成环;
R14与R15分别独立选自:(C1-C6)烷基、卤素、-NR22R23、-OH、-CF3、-OCH3、-O-醯基与-OCF3;
R16为R14、氢、苯基、-NO2、-CN、-CH2F、-CHF2、-CHO、-CH=NOR24、吡啶基、吡啶基N-氧化物、嘧啶基、吡嗪基、N(R24)CONR25R26、-NHCONH(氯-(C1-C6)烷基)、-NHCONH((C3-C10)环烷基(C1-C6)烷基)、-NHCO(C1-C6)烷基、-NHCOCF3、-NHSO2N(R22)(R23)、-NHSO2(C1-C6)烷基、-N(SO2CF3)2、-NHCO2-(C1-C6)烷基、C3-C10环烷基、-SR27、-SOR27、-SO2R27、-SO2NH(R22)、-OSO2(C1-C6)烷基、-OSO2CF3、羟基(C1-C6)烷基-、-CONR24R25、-CON(CH2CH2OCH3)2、-OCONH(C1-C6)烷基、-CO2R24、-Si(CH3)3或-B(OC(CH3)2)2;
R17为(C1-C6)烷基、-N(R22)(R23)或R19-苯基;
R13、R18、R22、R23、R24、R25与R26分别独立选自H与(C1-C6)烷基;
R19为1,2或3个分别独立选自下列之取代基:H、(C1-C6)烷基、-CF3、-CO2R25、-CN、(C1-C6)烷氧基与卤素;
R20与R21分别独立选自H与(C1-C6)烷基,或R20与R21及其所连接之碳合起来形成3-6个碳原子之螺环;且
R27为(C1-C6)烷基或苯基。
本发明另一方面为用於治疗HIV之医药组合物,其包含有效量之至少一种式I化合物与医药上可接受之载体组合。本发明另一方面为用於治疗固体器官移植物排斥、移植物抗宿主疾病、关节炎、类风湿关节炎、发炎性肠部疾病、特应性皮炎、牛皮癣、气喘、过敏或多发性硬化之医药组合物,其包含有效量的至少一种式I化合物与医药上可接受之载体组合。
本发明另一方面为治疗HIV之方法,其包括对需要此治疗之人类施用有效量之至少一种式I化合物。本发明另一方面为治疗固体器官移植物排斥、移植物抗宿主疾病、关节炎、类风湿关节炎、发炎性肠部疾病、特应性皮炎、牛皮癣、气喘、过敏或多发性硬化之方法,其包括对需要此治疗之人类施用有效量之至少一种式I化合物。亦包括使用至少一种式I化合物制备用于治疗HIV、固体器官移植物排斥、移植物抗宿主疾病、关节炎、类风湿关节炎、发炎性肠部疾病、特应性皮炎、牛皮癣、气喘、过敏或多发性硬化的药物。
本发明另一方面是以至少一种本发明式I化合物与一种或多种抗病毒剂或其他适用於治疗人类免疫缺损病毒之药剂组合,用於治疗AIDS。本发明另一方面是使用至少一种本发明式I化合物与一种或多种其他适用於治疗固体器官移植物排斥、移植物抗宿主疾病、发炎性肠部疾病、类风湿关节炎或多发性硬化之药剂组合。式I化合物与组合中之抗病毒剂或其他药剂成份可以在单一剂型中投药或可分开投药。因此,本发明涉及包含至少一种式I化合物与一种或多种抗病毒剂或其他适用於治疗HIV之药剂之医药组合物,及包含至少一种式I化合物与一种或多种抗病毒剂或其他适用於治疗固体器官移植物排斥、移植物抗宿主疾病、发炎性肠部疾病、类风湿关节炎或多发性硬化之药剂之医药组合物;亦包括一种试剂盒,其包含用於治疗HIV、固体器官移植物排斥、移植物抗宿主疾病、发炎性肠部疾病、类风湿关节炎或多发性硬化之活性成份的分开剂型。
本发明之详细说明
优选式I化合物中,Z为CH,且Q与X分别为N。还优选式I化合物中,R1为R9-芳基(C1-C6)烷基-、R9-杂芳基(C1-C6)烷基-、(C1-C6)烷基-SO2-、(C3-C6)环烷基-SO2-、氟-(C1-C6)烷基-SO2-、R9-芳基-SO2-、或R9-芳基-NH-C(O)-。更优选的是,R1为(C1-C6)烷基-SO2-、(C3-C6)环烷基-SO2-或R9-芳基-SO2-。优选R2为氢且R3为(C1-C6)烷基、R9-芳基、R9-芳基(C1-C6)-烷基、R9-杂芳基、或R9-杂芳基(C1-C6)烷基。当R2包括芳烷基或杂芳烷基时,芳烷基或杂芳烷基之烷基部份优选为甲基。R、R5与R7优选为氢。当X为N时,R4优选为(C1-C6)烷基,更优选为甲基;当X为CH时,R4优选为H。R6优选为-CH3。R9优选为H、卤素、(C1-C6)烷基或(C1-C6)烷氧基。当R1或R3包括芳基或杂芳基时,优选的芳基为苯基,优选的杂芳基为噻吩基、吡啶基与嘧啶基。
式I化合物中,R8优选为(R14,R15,R16)-苯基;(R14,R15,R16)-吡啶基或其N-氧化物;或(R14,R15,R16)-嘧啶基。当R8为吡啶基时,优选为3-或4-吡啶基,且当为嘧啶基时,优选为5-嘧啶基。R14与R15取代基最好是连接在与碳环中连接分子其余部分之碳相邻的碳环成员上,且R16取代基可连接在碳环中未被取代的其余任何成员上。因此,优选的R8取代基之结构式如下:
式I化合物之优选的R14与R15取代基为:(C1-C6)烷基,尤指甲基;卤素,尤指氯;及-NH2;优选的R16取代基为氢。
本文中,下列名词之定义如下,除非另有说明。
烷基(包括烷氧基、烷氨基与二烷氨基之烷基部份)代表直链与分支碳链且包含1-6个碳原子。
氟烷基代表如上述定义之烷基经一个或多个氟原子取代。其实例为-CH2F、-CHF2、-CF3、-CH2CF3、-CF2CF3,等等。
羟烷基代表如上述定义之烷基经1-3个羟基取代。
烯基代表具有一个或两个不饱和键之C2-C6碳链,但其限制条件为两个不饱和键不相邻。
经取代之苯基指苯环上任何可利用位置被取代之苯基。
醯基指如式烷基-C(O)-、芳基-C(O)-、芳烷基-C(O)-、(C3-C7)环烷基-C(O)-、(C3-C7)环烷基-(C1-C6)烷基-C(O)-、及杂芳基-C(O)-之羧酸基团,其中烷基与杂芳基如上述定义。
芳基为苯基或萘基。
杂芳基代表具有1或2个独立选自O、S或N中杂原子之5或6个原子之环状芳香基或11-12个原子之双环基,该(等)杂原子穿插在碳环结构中,且具有足够数目的离域π电子,形成芳香系特性,但其限制条件为该环不含相邻之氧与/或硫原子。氮原子可形成N-氧化物。R8上之6元杂芳基环中,可利用之碳原子可经R14、R15或R16基取代。其中包括所有的区域异构物,例如:2-吡啶基、3-吡啶基与4-吡啶基。典型之6元杂芳基为吡啶基、嘧啶基、吡嗪基、哒嗪基及其N-氧化物。R8上之5元杂芳基环中,可利用之碳原子可经R17或R18取代。R9取代之杂芳基环上可利用之碳原子可被1、2或3个独立选自R9之取代基取代。典型之5元杂芳基环为呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、咪唑基、吡唑基与异噁唑基。具有一个杂原子之5元环可利用2-或3-位连接,具有二个杂原子之5员环最好利用4-位连接。双环基通常为衍生自上述杂芳基之苯并稠合环系,例如:喹啉基、2,3-二氮杂萘基、喹唑啉基、苯并呋喃基、苯并噻吩基与吲哚基。
卤素代表氟、氯、溴与碘。
CCR5拮抗剂之医疗有效量为足以降低HIV-1-RNA血浆含量之量。
可使用一种或多种(以1-4种较佳)适用於抗-HIV-1疗法之抗病毒剂与至少一种(即1-4种,以一种较佳)本发明CCR5拮抗剂化合物组合。抗病毒剂可与CCR5拮抗剂组合成单一剂型,或CCR5拮抗剂与抗病毒剂可作为分开剂型同时或顺序投药。可与本发明化合物组合使用之抗病毒剂包括核苷与核苷酸逆转录酶抑制剂、非核苷逆转录酶抑制剂、蛋白酶抑制剂及下文中列出但不属于这些类别之其他抗病毒药物。特别是,已知为HAART之组合可与本发明之CCR5拮抗剂组合使用。
本文中所采用″核苷与核苷酸逆转录酶抑制剂″(″NRTI″)一词指可抑制HIV-1逆转录酶(系一种催化病毒基因组HIV-1 RNA转化成原病毒HIV-1 DNA的酶)活性之核苷与核苷酸及其类似物。
典型的合适NRTI包括齐多夫定(zidovudine(AZT)),可自葛来素-卫康研究中心(Glaxo-Wellcome Inc.,Research Triangle,NC27709)取得,商品名称为RETROVIR(立妥韦);去羟肌苷(didanosine(dd1)),可自百时美施贵宝公司(Bristol-Myers Squibb Co.,Princeton,NJ 08543)取得,商品名称为VIDEX(惠妥滋);扎西他滨(zalcitabine(ddC)),可自罗氏药厂(Roche Pharmaceuticals,Nutley,NJ 07110)取得,商品名称为HIVID;司他夫定(stavudine(d4T),可自百时美施贵宝公司(Bristol-Myers Squibb Co.,Princeton,NJ 08543)取得,商品名称为ZERIT(泽瑞特);拉米夫定(lamivudine(3TC),可自葛来素-卫康研究中心(Glaxo-WellcomeResearch Triangle,NC 27709取得,商品名称为EPIVIR;阿巴卡韦(abacavir(1 592U89),公开於WO96/30025中,且可得自葛来素-卫康研究中心(Glaxo-Wellcome Research Triangle,NC 27709),商品名称为 ZIAGEN;阿德福韦二匹伏酯(adefovir dipivoxil[bis(POM)-PMEA],可得自吉利德药厂(Gilead Sciences,FosterCity,CA 94404),商品名称为PREVON;洛布卡韦(lobucavir(BMS-180194),公开於EP-0358154与EP-0736533的一种核苷逆转录酶抑制剂,目前由百时美施贵宝公司(Bristol-Myers Squibb,Princeton,NJ 08543)研发中;BCH-1 0652,一种逆转录酶抑制剂(是BCH-10618与BCH-10619之消旋性混合物),目前由法马生化公司(BiochemPharma,Laval,Quebec H7V,4A7,Canada)研发中;恩曲他滨(emitricitabine[(-)-FTC]),已经由Emory大学依据Emory大学美国专利5,814,639授权,目前由三角药厂(TrianglePharmaceuticals,Durham,NC 27707)研发中;β-L-FD4(亦称为β-L-D4C,亦即β-L-2′,3′-二去氧-5氟-胞嘧啶核苷),已经由耶鲁大学授权给维恩药厂(Vion Pharmaceuticals,New Haven CT 511;DAPD,嘌呤核苷,(-)-β-D-2,6,-二氨基-嘌呤-二氧戊环,公开於EP0656778且已由三角药厂(Triangle Pharmaceuticals,Durham,NC27707)自Emory大学与Georgia大学取得授权;与洛德腺苷(lodenosine(FddA)),9-(2,3-二去氧-2-氟-b-D-苏型-呋喃戊糖基)腺嘌呤,系一种由NIH发现的对酸稳定的嘌呤基逆转录酶抑制剂,目前由美国生物科技公司(Bioscience Inc.,West Conshohoken,PA19428)研发中。
本文中所采用″非核苷逆转录酶抑制剂″(″NNRTI″s)一词指可抑制HIV-1逆转录酶活性之非核苷。
典型之合适NNRTI包括奈韦拉平(nevirapine(BI-RG-587)),可自洛参实验室(Roxane Laboratories,Columbus,OH 43216)之制造商百灵药厂(Boehringer Ingelheim)取得,商品名称为VIRAMUNE;地拉韦啶(delaviradine(BHAP,U-90152)),可自法马-普强药厂(Pharmacia & Upjohn Co.,Bridgewater NJ 08807)取得,商品名称为RESCRIPTOR;伊法韦仑(efavirenz(DMP-266)),WO94/03440公开的一种苯并噁嗪-2-酮,可自杜邦药厂(DuPont PharmaceuticalCo.,Wilmington,DE 19880-0723)取得,商品名称为SUSTIVA;PNU-142721,系一种呋喃并吡啶-硫代嘧啶,目前由法马-普强药厂(Pharmacia and Upjohn,Bridgewater NJ 08807)研发中;AG-1549(过去称为Shionogi # S1 153);碳酸5-(3,5-二氯苯基)-硫代-4-异丙基-1-(4-吡啶基)甲基-1H-咪唑-2-基甲酯,公开於WO 96/10019,目前由阿格伦药厂(Agouron Pharmaceuticals,Inc.,LaJolla CA 92037-1020)进行临床开发;MKC-442(1-(乙氧甲基)-5-(1-甲基乙基)-6-(苯基甲基)-(2,4(1H,3H)-嘧啶二酮),由三菱化学公司(Mitsubishi Chemical Co.)发现,目前由三角药厂(TrianglePharmaceuticals,Durham,NC 27707)开发中;与(+)-卡兰诺得(calanolide)A(NSC-675451)与B,系NIH的美国专利5,489,697公开的一种香豆素衍生物,已授权给医化研究所(Med ChemResearch),该公司正与Vita-Invest共同开发(+)卡兰诺得A的可口服产品。
本文中所采用″蛋白酶抑制剂″(PI)一词指HIV-1蛋白酶之抑制剂,HIV-1蛋白酶系病毒多蛋白前体(例如:病毒GAG与GAG Pol多蛋白)进行蛋白质水解裂解成在感染性HIV-1中发现的个别功能性蛋白质时所需之酶。HIV-1蛋白酶抑制剂包括具有拟肽结构、高分子量(7600道尔顿)且具基本肽特性之化合物,例如佳息患(CRIXIVAN,可得自默克药厂(Merck))及非肽蛋白酶抑制剂,例如:VIRACEPT(可得自阿格伦药厂(Agouron))。
典型之合适PI包括沙奎那韦(saquinavir(Ro 31-8959)),可自罗氏药厂(Roche Pharmaceuticals,Nutley,NJ 07110-1199)取得以商品名称INVIRASE供应之硬明胶囊形式,及以商品名称FORTOVASE供应之软明胶囊形式;利托那韦(ritonavir(ABT-538)),可自亚伯特实验室(Abbott Laboratories,Abbott Park,IL 60064)取得,商品名称为NORVIR(诺韦);茚地那韦(indinavir(MK-639)),可自默克公司(Merck & Co.,Inc.,West Point,PA 19486-0004)取得,商品名称为CRIXIVAN(佳息患);奈非那韦(nelfnavir(AG-1343)),可自阿格伦药厂(Agouron Pharmaceuticals,Inc.,LaJollaCA 92037-1020)取得,商品名称为VIRACEPT;氨普奈韦(amprenavir(141W94)),商品名称为AGENERASE,系一种非肽蛋白酶抑制剂,目前由菲特斯药厂(Vertex Pharmaceuticals,Inc.,Cambridge,MA02139-4211)研制,并可按葛来素-卫康研究中心(Glaxo-Wellcome,Research Triangle,NC)之扩大的索取程序取得;拉西那韦(lasinavir(BMS-234475)),可自百时美施贵宝公司(Bristol-MyersSquibb,Princeton,NJ 08543)取得(最早由瑞士Novartis,Basel发现(CGP-61755));DMP-450,系一种由杜邦药厂发现之环状脲,目前由三角药厂(Triangle Pharmaceuticals)研发;BMS-2322623,系一种氮杂肽,目前由百时美施贵宝公司(Bristol-Myers Squibb,Princeton,NJ 08543)研发,为第二代HIV-1 PI;ABT-378,目前由亚伯特公司(Abbott,Abbott Park,IL 60064)研发;与AG-1549,一种口服活性之氨基甲酸咪唑,由西诺奇药厂(Shionogi)发现(Shionogi # S-1153),目前由阿格伦药厂(Agouron Pharmaceuticals,Inc.,LaJolla CA 92037-1020)研发中。
其他抗病毒剂包括羟基脲、利巴韦林(ribavirin)、IL-2、IL-12、喷他夫西(pentafuside)与亿生计画(Yissum Project)No.11607。羟基脲(Droxia),系一种核糖核苷三磷酸还原酶(此酶与T-细胞之活化有关)之抑制剂,系由NCI发现,目前由百时美施贵宝公司(Bristol-Myers Squibb)研发中;其在临床前研究中显示对去羟肌苷之活性有增效作用;其对司他夫定(stavudine)之效果则正在研究中。IL-2公开於Ajinomoto EP-0142268,Takeda EP-0176299,及Chiron美国专利RE 33653、4530787、4569790、4604377、4748234、4752585与4949314,可自奇隆公司(Chiron Corp.,Emeryville,CA94608-2997)取得,商品名称为PROLEUKIN(阿地白介素),为一种冷冻乾燥粉末,可加水再组成及稀释,供IV输液或皮下投药;优选每日经皮下投与剂量约100万至约2000万IU;更优选每日经皮下投与剂量约1500万IU。IL-12公开於WO96/25171中,可自罗氏药厂(RochePharmaceuticals,Nutley,NJ 07110-1199)及美国家庭用品公司(American Home Prodocts,Madison,NJ 07940)取得;以每日经皮下投与剂量约0.5微克/千克至约10微克/千克较佳。喷他夫西(Pentafuside(DP-178,T-20))是一种36个氨基酸之合成肽,公开於美国专利5,464,933,已由奇莫公司(Trimeris)自杜克大学(DukeUniversity)取得授权,该公司目前与杜克大学合作研发喷他夫西;喷他夫西之作用为抑制HIV-1与靶细胞膜融合。喷他夫西(3-100毫克/天)系以连续皮下输液或注射方式,与依法韦仑(efavirenz)及二种PI共同施用于HIV-1阳性但对三重药物组合疗法没有反应之患者;每天使用100毫克较佳。亿生计画(Yissum Project)No.11607为一种以HIV-1 Vif蛋白质为基础的合成蛋白质,目前由亿生研发公司(Yissum Research Development Co.,Jerusalem 91042,Israel)进行临床前研发。利巴韦林(ribavirin)为1-β-D-呋喃核糖基-1H-1,2,4-三唑-3-甲醯胺,可自ICN药厂(ICN Pharmaceuticals,Inc.,Costa Mesa,CA)取得;其制造与调配法在美国专利4,211,771中有说明。
本文所采用的″抗HIV-1疗法″一词指任何适用於治疗人类HIV-1感染之单独疗法或作为多重药物组合疗法,尤指HAART三重与四重组合疗法中一部份之抗HIV-1药物。典型的已知抗HIV-1的合适疗法包括(但不限於)多重药物组合疗法,如:(i)选自两种NRTI,一种PI,第二种PI,与一种NNRTI的至少三种抗-HIV-1药物;与(ii)选自NNRTI与PI的至少两种抗-HIV-1药物。典型之合适HAART多重药物组合疗法包括:
(a)三重组合疗法,如:两种NRTI与一种PI;或(b)两种NRTI与一种NNRTI;及(c)四重组合疗法,如:两种NRTI,一种PI与第二种PI或一种NNRTI。治疗首次用药的患者时,最好先以三重药物组合疗法开始抗-HIV-1治疗;优选使用两种NRTI与一种PI,除非患者对PI无耐受性。药物适应性为基本条件。每3-6个月应监测一次CD4+与HIV-1-RNA血浆浓度。若病毒浓度达平顶期时,可添加第四种药物,例如:一种PI或一种NNRTI。参见下表有关典型疗法之进一步说明:
抗-HIV-1多重药物组合疗法
A.三重组合疗法
1.两种NRTI1+一种PI2
2.两种NRTI1+一种NNRTI3
B.四重组合疗法
两种NRTI1+一种PI2+第二种PI或一种NNRTI
C.其他:
5
两种NRTI1
一种NRTI5+一种PI2
两种PI6*一种NRTI7或NNRTI3
一种PI2+一种NRTI7+一种NNRTI3
注脚说明
1.下列一种:齐多夫定(zidovudine)+拉米夫定(lamivudine);齐多夫定(zidovudine))+去羟肌苷(didanosine);司他夫定(stavudine)+拉米夫定(lamivudine);司他夫定(stavudine)+去羟肌苷(didanosine);齐多夫定(zidovudine)+扎西他滨(zalcitabine)。
2.茚地那韦(indinavir),奈非那韦(nelfnavir),利托那韦(ritonavir)或沙奎那韦(saquinavir)软明胶囊。
3.奈韦拉平(nevirapine)或地拉韦啶(delaviradine)。
4.参见A-M.Vandamne et al Antiviral Chemistry &Chemotherapy 9:187,p.193-197及图1+2。
5.其他疗法用于因适应不良或毒性问题而无法采行建议疗法之患者,及接受建议疗法後失败或复发之患者。双重核苷组合可能使许多患者产生HIV-抗性和临床失败。
6.大多数数据得自沙奎那韦(saquinavir)或利托那韦(ritonavir)(各400毫克bid)。
7.齐多夫定(zidovudine),司他夫定(stavudine)或去羟肌苷(didanosine)。
可与本发明CCR5拮抗剂组合投药的已知治疗类风湿关节炎、移植物抗宿主疾病、发炎性肠部疾病与多发性硬化之药剂如下:
固体器官移植物排斥与移植物抗宿主疾病:免疫抑制剂,如:环胞菌素与白介素-10(IL-10)、他克莫司(tacrolimus)、抗淋巴细胞球蛋白、OKT-3抗体与类固醇;
发炎性肠部疾病:IL-10(参见:US 5,368,854)、类固醇与抑氮磺胺吡啶(azulfidine);
类风湿关节炎:甲氨蝶呤、硫唑嘌呤(azathioprine)、环磷醯胺、类固醇与麦考酚酸吗乙酯(mofetil);
多发性硬化:β-干扰素、α-干扰素、与类固醇。
某些本发明CCR5拮抗剂化合物可能出现不同异构物(例如:对映异构物、非对映异构物与阻转异构物)。本发明包括所有此等异构物之纯型与混合物,包括消旋性混合物。
某些化合物可能呈酸性,例如:具有羧基或酚系羟基之化合物。这些化合物可形成医药上可接受之盐类。此等盐类实例包括钠、钾、钙、铝、金与银盐。亦包括与医药上可接受之胺类形成之盐类,如:氨、烷基胺、羟烷基胺、N-甲基葡糖胺,等等。
某些硷性化合物亦可形成医药上可接受之盐类,例如酸加成盐。例如:吡啶基之氮原子可与强酸形成盐,而具有硷性取代基(如氨基)之化合物亦可与弱酸形成盐。适合形成盐之酸实例为盐酸、硫酸、磷酸、乙酸、柠檬酸、草酸、丙二酸、水杨酸、苹果酸、富马酸、琥珀酸、抗坏血酸、马来酸、甲磺酸与本领域熟知的其他矿物酸及羧酸。盐类之制法是使游离硷型与足量所需酸接触,依常规方式制成盐。此盐经合适稀硷水溶液(如:稀NaOH、碳酸钾、氨与碳酸氢钠水溶液)处理时,则再形成游离硷。游离硷型与其各盐型在某些物理性质方面稍有不同,例如在极性溶剂中之溶解度,但酸盐与硷盐对本发明之目的而言与其各游离硷型是等效的。
所有这些酸盐与硷盐均为本发明范围内之医药上可接受之盐类,且所有这些酸盐与硷盐对本发明之目的而言与其相应化合物之游离型是等效的。
本发明化合物可依本领域已知的方法制备,例如:依下列反应图所述之方法,及下文中实施例所述之方法。
一般反应图与具体实施例中采用的下列溶剂与试剂在本文中以下列缩写代表:四氢呋喃(THF);甲醇(MeOH);乙酸乙酯(EtOAc);三氟乙酸酐(TFAA);二甲基甲醯胺(DMF);苯并三唑(Bt);1-羟基-苯并三唑(HOBT);三乙胺(Et3N);乙醚(Et2O);叔丁氧羰基(BOC);N,N,N-二异丙基乙胺(iPr2Net);及1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDC)。室温为rt。其他缩写包括:苯基(Ph);甲基(Me);乙基(Et);与乙醯基(Ac)。
式Ia中Q为N,Z为CH,X为N,R2为H,R3不为H(但在其它方面与以上在R2为H时定义的相同),R6为甲基,且R1与R8如上述定义之化合物可依据下列反应图A制备(R4为甲基,且R、R5与R7为H,但可依类似方法制备式中R、R4、R5与R7为其他定义之化合物):
反应图A
合成式Ia化合物时,保护醇1,并氧化成醛2。取含醛2、苯并三唑、与哌啶基哌嗪3之溶液於甲苯或苯中加热并排除水。溶液冷却,真空排除溶剂。加成物4经格利雅试剂(R3MgX1,其中R3如上述定义且X1为例如:Br或Cl)处理,产生式5衍生物。脱除4中之BOC基(HCl),使哌啶NH与芳基酸偶合产生醯胺6。6中之4-甲氧苄基则接著经TFAA与1N NaOH水溶液处理而脱除。哌啶可经各种不同试剂官能化,例如:以R1SO2Cl处理,产生其R1为R1-SO2-之式Ia化合物。
式中R6为氢之类似化合物可以用用脱甲基哌啶基哌嗪替代化合物3来制备。
式Ib中,Q为N,Z为CH,X为N,R2与R3均为H,且R1与R8如上述定义之化合物系依下反应图B制备(R4与R6为甲基,且R5与R7为H,但亦可依类似方法制备R4-R7为其他定义之化合物):
反应图B
由醛2与哌啶基哌嗪3及三乙醯氧基硼氢化钠反应,得到衍生物7。此化合物以类似上述5之方式处理,得到式Ib化合物。
式Ic中,Q为N或CH,Z为N,X为CH,R2与R3均为H,且R、R1、R4、R5、R6、R7、与R8如上述定义之化合物之制法示於下列反应图C:
反应图C:
醛8可与Na(AcO)3BH及哌嗪(Q=N)或哌啶(Q=CH)9反应,得到化合物10。脱除10中之Boc基后,该仲胺进行标准的醯胺化(EDC/HOBT/R8CO2H或R8CO2H),制备Ic型醯胺。
式Id中,Q与Z为N,X为CH,R2为H,R3不为H(但在其它方面与R2为H的以上定义相同),且R、R1、R4、R5、R6、R7与R8如上述定义之化合物系依下列反应图D之方法制备:
反应图D:
由醛8与哌嗪14及苯并三唑反应,形成加成物15。15中之苯并三唑基被格利雅试剂(R3MgX1)或有机锌试剂(R3ZnX1)置换,得到16。脱除16中之BOC基後,依本领域技术人员已知之标准偶合条件反应,产生醯胺17。脱除17中之4-甲氧苄基,所得仲胺按照标准条件官能化,得到通式Id化合物。
与式Id的哌嗪基化合物相似的,式Ie哌啶基化合物按照反应图E之方法制备:
反应图E:
由醛8、哌啶18、与苯并三唑缩合形成加合物19。置换19中之苯并三唑(Bt)基,形成化合物20。脱除保护基及进行标准的醯胺化反应,产生化合物Ie。
式If中,Q为N,Z与X为CH,R2为H,R3为可任选取代之苯氧基或吡啶氧基,且R、R1、R4、R5、R6、R7与R8如上述定义之化合物按照下列反应图F制备:
反应图F:
由醛8与格利雅试剂反应,得到醇21。醇21氧化成酮22。22中之N-甲基经氯甲酸1-氯乙酯脱除,产生哌啶23。23还原後进行还原性烷基化反应,产生衍生物24。於硷之存在下,以苯基或吡啶基卤化物处理醇24,得到芳氧基(与杂芳氧基)化合物25。使25中Boc保护之胺脱除保护基,相应之哌啶进行标准的醯胺化处理(R8COOH、EDCI或DEC,与HOBT,或R8C(O)Cl)。脱除26中之4-甲氧苄基,自由的哌啶基NH经烷基卤化物、醯基氯化物、烷基氯甲酸酯、异氰化物、烷磺醯卤化物、芳基磺醯卤化物,及还原性烷基化法(Na(AcO)3BH/醛或酮)衍生转化,得到式If化合物。
式Ig中,Q为N,Z与X为CH,R2为H,R3为烷基-C(O)O-、烷基-NH-C(O)O-或-OC(O)-N(烷基)2,且R、R1、R4、R5、R6、R7与R8如上述定义之化合物按照下列反应图G制备:
反应图G:
24中之羟基经烷基卤化物、醯基氯化物、烷基氯甲酸酯及异氰化物衍化,得到化合物28。27脱除保护基/醯胺化,产生醯胺28。脱除28中苄基之保护,并使哌啶衍化产生式Ig化合物。
式Ih中,Q为N,Z与X为CH,R2为H,R3为烷基-C(O)-NH-、烷基-NH-C(O)NH-或-NH-C(O)-N(烷基)2,且R、R1、R4、R5、R6、R7与R8如上述定义之化合物按照下列反应图H制备:
反应图H:
由醇24氧化(DMSO/草醯氯,Swern反应条件形成酮29。由29脱除保护基/标准的醯胺化,产生醯胺30。酮30与CH3ONH2 HCI缩合,产生肟。该肟经BH3S(CH3)2还原成胺31。胺31与氯甲酸酯、醯基氯或异氰化物反应,分别形成式32的氨基甲酸酯、酯与脲,其中G如上述定义。脱除32中的苄基保护,使哌啶衍化成式Ih化合物。
式Ii中,Q为N,Z与X为CH,R2与R3共同为=NO10,且R10、R、R1、R4、R5、R6、R7与R8如上述定义之肟是按照下列反应图I制备:
反应图I:
由酮30与经取代之羟胺缩合,得到肟33。如上述脱除33中之4-甲氧基并官能化,得到式Ii化合物。
式Ij中,Q、Z与X分别为N,R2与R3合起来为=O,且R、R1、R4、R5、R6、R7与R8如上述定义之化合物按照下列反应图J制备:
反应图J:
哌啶基哌嗪34随後与N,N′-二琥珀醯亚胺基碳酸酯(DSC)及哌嗪14反应,得到脲35。Boc衍生物35采用反应图A所述条件加工成36与Ij。
式Ik中,Q为N或CH,Z与X分别为N,R2与R3合起来为=NH,且R、R1、R4、R5、R6、R7与R8如上述定义之化合物可按照几种方法制备,例如:下列反应图K:
反应图K:
哌啶基哌嗪34可依上述方法转化成胍39。胍39可依反应图A所述方法转化成式Ik醯胺。
用以下的制备实施例示例说明适用於本发明之化合物,它们不应被认为限制本发明的范围。对于本领域的技术人员,本发明范围内的其它机制的途径与类似的结构是显而易见的。
实施例1
步骤1:
由醇1(2.0g,17mmol)、4-甲氧基苯甲醛(2.5ml,21mmol)与Na(AcO)3BH(4.4g,21mmol)溶於CH2Cl2(50ml)中,於25℃下搅拌22小时。以CH2Cl2稀释溶液,以1N NaOH水溶液洗涤。以CH2Cl2萃取水层。合并之有机层脱水(Na2SO4)。过滤及浓缩。残质分布在Et2O与1M HCI之间。以Et2O萃取酸性水层。水层冷却至0℃。添加NaOH固体颗粒,至pH=11-12止。以CH2Cl2萃取硷性水层。取CH2Cl2层脱水(Na2SO4),过滤及浓缩,得到苄基保护之哌啶基醇(2.92g,73%)。
取DMSO(1.3ml,19mmol)溶於CH2Cl2(80ml)中,所得溶液冷却至-40℃(CO2/CH3CN)。缓缓添加草醯氯(1.6ml,19mmol)至-40℃之溶液中。此溶液於-40℃下搅拌0.5小时。添加含N-(4-甲氧苄基)-哌啶基醇(2.92g,12mmol)之CH2Cl2(15ml)溶液至-40℃之反应混合物中。所得溶液於-40℃下搅拌0.5小时。添加Et3N(5.2ml,37mmol)至-40℃之溶液中。所得白色浆物於此温度下搅拌20分钟。以CH2Cl2稀释混合物,以1N NaOH水溶液洗涤。以CH2Cl2萃取水层。合并之CH2Cl2层脱水(Na2SO4),过滤及浓缩,得到醛2之黄色油状物(2.8g,97%)。
步骤2:
由醛2(392mg,1.68mmol)、哌啶基-哌嗪3(500mg,1.68mmol)与苯并三唑(200mg,1.68mmol)溶於甲苯(20ml)中,於回流下加热排除水(狄恩-史塔克收集器。2小时後,溶液冷却及浓缩,得到1.0g(100%)苯并三唑加成物4之浅褐色胶状物。
步骤3:
取步骤2产物(300mg,0.48mmol)在N2气氛下溶於THF(4ml)中。添加PhMgBr(0.4ml,3.0M之Et2O溶液)至25℃之溶液中。溶液於此温度下搅拌2小时。使反应混合物分布在EtOAc与饱和NH4Cl之间。以EtOAc萃取水层。合并之EtOAc层以盐水洗涤及脱水(Na2SO4)。过滤及浓缩,产生黄色油状物。此物质经制备性薄层层析法纯化(2/1己烷/丙酮,SiO2),得到207mg(73%)化合物5a之黄色油状物。
步骤4:
取化合物5a(200mg,0.34mmol)与4.0M HCI之二噁烷(1ml)溶液溶於MeOH(5ml)中,於25℃下搅拌2小时。溶液浓缩,产生189mg(93%)脱除保护基之哌啶的三盐酸盐。
取此盐(189mg,0.32mmol)、EDC(92mg,0.48mmol)、HOBT(65mg,0.48mmol)、4,6-二甲基-3-嘧啶羧酸(73mg,0.48mmol)、iPr2NEt(0.4ml,2.24mmol)溶於DMF(5ml)中,於25℃下搅拌17小时。此溶液分布在EtOAc与1N NaOH之间。以EtOAc萃取水层。合并之EtOAc层以盐水洗涤,脱水(Na2SO4)。过滤及浓缩,产生粗产物。经制备性薄层层析法纯化(95/5 EtOAc/Et3N,SiO2),得到144mg(72%)化合物6a之无色油状物。HRMS(MH+)实测值:625.4222。
步骤5:
取化合物6a(129mg,0.21mmol)与iPr2NEt(0.11ml,0.63mmol)溶於CH2Cl2(6ml)中。添加TFAA(0.080ml,0.31mmol)至溶液中。此溶液於25℃下搅拌0.5小时後,浓缩。残质溶於MeOH中,添加1NNaOH至溶液中。此溶液於25℃下搅拌2.5小时後浓缩。残质分布在CH2Cl2与1N NaOH之间。以CH2Cl2萃取水层。合并之有机层脱水(Na2SO4),过滤及浓缩,得到实施例6b与4-甲氧基苯甲醇之混合物。取实施例6b经形成相应之HCl盐结晶纯化。HRMS(MH+)实测值:505.3661。
取实施例6b的游离碱(42mg,0.08mmol)与MeSO2Cl(0.020ml)分布在CH2Cl2与1N NaOH之间。溶液於25℃下搅拌4小时。分层,以CH2Cl2萃取水层。合并之有机层脱水(Na2SO4),过滤及浓缩。残质经制备性薄层层析法纯化(95/5 EtOAc/Et3N,SiO2),产生无色油状的标题化合物。取游离硷溶於EtOAc中後,与2M HCl之Et2O溶液研磨,形成双-HCl盐。HRMS(MH+)实测值:583.3425。
依类似方法及采用适当试剂,制备如下结构式化合物
其中R1、R3与R6如下表中之定义:
实施例 | R1 | R3 | R6 | HRMS(MH+)实测值 |
1A | 4-CH3OC3H4CH2 | 4-CF3C6H5 | CH3 | 693.4112 |
1B | H | 4-CF3C6H5 | CH3 | 573.3637 |
1C | CH3SO2 | 4-CF3C6H5 | CH3 | 651.3311 |
1D | 4-CH3OC6CH2 | CH2CH2CH3 | CH3 | 591.4386 |
1E | 4-CH3OC6H4CH2 | CH(CH2)2 | CH3 | 591.4392 |
1F | 4-CH3OC6H4CH2 | CH2C6H5 | CH3 | 639.4399 |
1G | 4-CH3OC6H4CH2 | CH3 | CH3 | 563.4079 |
1H | 4-CH3OC6H4CH2 | CH2CH3 | CH3 | 577.4226 |
1I | H | CH2CH2CH3 | CH3 | 471.3802 |
1J | CH2SO2 | CH2CH2CH3 | CH3 | 549.3580 |
1K | 4-CH3OC6H4CH2 | 环戊基 | CH3 | 617.4543 |
1L | H | CH(CH3)2 | CH3 | 471.3815 |
1M | CH2SO2 | CH(CH3)2 | CH3 | 549.3580 |
1N | 4-CH3C6H4SO2 | CH(CH3)2 | CH3 | 625.3917 |
1O | 4-CH3C6H4SO2 | CH2CH2CH3 | CH3 | 625.3895 |
1P | CH2SO2 | 环戊基 | CH3 | 575.3746 |
1Q | 4-CH3C6H4SO2 | 环戊基 | CH3 | 651.4055 |
1R | H | 环戊基 | CH3 | 497.3966 |
1S | 4-CH3C6H4SO2 | C6H5 | CH3 | 659.3752 |
1T | EtNHC(O) | C6H5 | CH3 | 576.4028 |
1U | C6H5NHC(O) | C6H5 | CH3 | 624.4027 |
1V | H | 环己基 | CH3 | 511.4120 |
1W | 4-CH3OC6H4CH2 | CH2CH2CH3 | H | 577.4230 |
1X | 4-CH3OC6H4CH2 | CH2C6H5 | H | 625.4221 |
1Y | 4-CH3OC6H4CH2 | C6H5 | H | 611.4089 |
1Z | 4-CH3OC6H4CH2 | C6H5 | CH3 | 675.3684 |
1AA | 3-Cl-C6H4SO2 | C6H5 | CH3 | 679.3188 |
1AB | CH3SO2 | CH2C6H5 | CH3 | 597.3583 |
1AC | CH3 | C6H5 | CH3 | 519.3815 |
1AD | 3-Cl-C6H4SO2 | CH2C6H5 | CH3 | 693.3345 |
1AE | CH3CH2SO2 | CH2C6H52 | CH3 | 611.3737 |
1AF | 4-CH3OC6H4SO2 | 4-F-C6H4 | CH3 | 693.3609 |
1AG | CH3SO2 | 4-F-C6H4 | CH3 | 601.3326 |
1AH | 3-Cl-C6H4SO2 | 4-F-C6H4 | CH3 | 697.3112 |
1AI | 4-CH3OC6H4CH2 | 3-F-C6H4 | CH3 | 643.4142 |
1AJ | CF3C(O) | 4-F-C6H4CH2 | CH3 | 633.3552 |
1AK | CH3SO2 | 3-F-C6H4 | CH3 | 601.3326 |
1AL | 3-Cl-C6H4SO2 | 3-F-C6H4 | CH3 | 697.3105 |
1AM | 4-CH3OC6H4SO2 | 3-F-C6H4 | CH3 | 693.3609 |
1AN | CH3SO2 | 4-F-C6H4CH2 | CH3 | 615.3482 |
1AO | 3-Cl-C6H4SO2 | 4-F-C6H4CH2 | CH3 | 711.3250 |
1AP | 4-CH3OC6H4SO2 | 4-F-C6H4CH2 | CH3 | 707.3751 |
1AQ | 4-CH3OC6H4CH2 | 2-噻吩基 | CH3 | 631.3805 |
1AR | CF3CH2SO2 | C6H5 | CH3 | 651.3201 |
1AS | CF3SO2 | C6H5 | CH3 | 637.3156 |
1AT | 4-CH3OC6H4CH2 | 3-噻吩基 | CH3 | 631.3784 |
1AU | 3-Cl-C6H4SO2 | 3-噻吩基 | CH3 | 685.2768 |
1AV | 4-CH3OC6H4SO2 | 3-噻吩基 | CH3 | 681.3266 |
1AW | CH3SO2 | 3-噻吩基 | CH3 | 589.3002 |
1AX | CH3SO2 | 3-噻吩基 | CH3 | 589.3002 |
1AY | 3-Cl-C6H4SO2 | 3-噻吩基 | CH3 | 685.2750 |
1AZ | 4-F-C6H4SO2 | CH2C6H5 | CH3 | 677.3633 |
1BA | 2-噻吩基-SO2 | CH2C6H5 | CH3 | 665.3317 |
1BB | C6H5SO2 | CH2C6H5 | CH3 | 653.3748 |
1BC | CF3SO2 | CH2C6H5 | CH3 | 651.3317 |
1BD | CF3CH2SO2 | CH2C6H5 | CH3 | 665.3449 |
1BE | (CH3)2NSO2 | CH2C6H5 | CH3 | 626.3859 |
1BF | 环丙基-SO2 | 3-F-C6H4 | CH3 | 627.3503 |
1BG | 4-F-C6H4SO2 | 3-F-C6H4 | CH3 | 681.3406 |
1BH | 4-CH3OC6H4CH2 | 正丁基 | CH3 | 605.4556 |
1BI | 3-Cl-C6H4SO2 | 正丁基 | CH3 | 659.3501 |
1BJ | 4-CH3OC6H4SO2 | 正丁基 | CH3 | 655.4009 |
1BK | 3-Cl-C6H4SO2 | 3-吡啶基 | CH3 | 680.3166 |
1BL | 4-CH3OC6H4SO2 | 3-吡啶基 | CH3 | 676.3637 |
1BM | 3-Cl-C6H4SO2 | 2-吡啶基 | CH3 | 680.3160 |
1BN | 环丙基-SO2 | C6H5 | CH3 | 609.3598 |
1BO | 4-CH3OC6H4CH2 | 2-嘧啶基 | CH3 | 627.4128 |
1BP | CH3CH2SO2 | C6H5 | CH3 | 597.3598 |
1BQ | CH3CH2CH2SO2 | C6H5 | CH3 | 611.3749 |
1BR | 异丙基-SO2 | C6H5 | CH3 | 611.3749 |
1BS | CH3C(O) | C6H5 | CH3 | 547.3768 |
1BT | CH3SO2 | 2-嘧啶基 | CH3 | 585.3343 |
1BU | 环丙基-C(O) | C6H5 | CH3 | 573.3923 |
1BV | CH3CH2C(O) | C6H5 | CH3 | 561.3928 |
1BW | 异丙基-C(O) | C6H5 | CH3 | 575.4075 |
1BX | 3-Cl-C6H4SO2 | 4-吡啶基 | CH3 | 680.3133 |
1BY | 4-CH3OC6H4CH2 | 3,5-二氟苯基 | CH3 | 661.4035 |
1BZ | 环丙基-SO2 | 3,5-二氟苯基 | CH3 | 645.3388 |
1CA | CH3SO2 | 环己基 | CH3 | 589.3904 |
1BF详细制法:
步骤A:
取实施例1中步骤2产物(1.0g,1.6mmol)在氮气氛下溶於THF(10ml)中,於25℃下添加3-氟苯基溴化镁溶液(13ml,0.5M之Et2O溶液)。溶液於25℃下搅拌6小时。反应混合物倒至含25%柠檬酸钠水溶液之分离漏斗中。以EtOAc萃取水层,合并之EtOAc层以盐水洗涤及脱水(Na2SO4)。过滤及浓缩,产生黄色油状物。残质经急骤层析法纯化(3/1己烷/丙酮,SiO2),产生640mg(66%)化合物5b之黄色油状物。
步骤B:
按照实施例1步骤4之方法脱除5b(640mg,1.05mmol)之保护基,得到脱除保护基之哌啶。取哌啶(533mg,0.32mmol)、EDC(400mg,0.48mmol)、HOBT(280mg,0.48mmol)、4,6-二甲基-3-嘧啶-5-羧酸(240mg,0.48mmol)与iPr2NEt(0.72ml,2.24mmol)溶於DMF(5ml)中并依照上述步骤4之条件处理,得到414mg(62%)6b之黄色油状物。
步骤C:
按照实施例1步骤5之方法处理6c(400mg,0.62mmol),得到6d。取6d游离硷(0.07g,0.13mmol)、环丙基磺醯氯(0.02g,0.14mmol)与Et3N(0.091ml)溶於CH2Cl2中,溶液於室温下搅拌4小时。溶液於旋转蒸发器上浓缩。残质经制备性薄层层析法纯化(10/1EtOAc/EtOH,SiO2),得到14mg(17%)of 1BF之无色油状物。依上述6a之方法形成双-HCl盐。M.p.=206-210℃。
实施例2
取醛2(0.93g,4.0mmol)、哌啶基哌嗪3(1.0g,3.4mmol)与Na(AcO)3BH(860mg,4.0mmol)溶於CH2Cl2(10ml)中,於25℃下搅拌18小时。以CH2Cl2稀释溶液,以1N NaOH洗涤。以CH2Cl2萃取水层。合并之有机层脱水(Na2SO4),过滤及浓缩。残质经急骤层析法纯化(丙酮/CH2Cl2梯度2/5-3/5,SiO2),产生1.24g(71%)7,为无色油状物。
按照实施例1步骤4与5之方法处理化合物7,得到标题化合物。
HRMS(MH+)实测值:507.3122。
依照类似方法及采用适当试剂,制备如下结构式化合物
其中R1与R6如下表中之定义:
实施例 | R1 | R6 | HRMS(MH+)实测值 |
2A | H | CH3 | 429.3340 |
2B | 4-CH3OC6H4CH2 | CH3 | 548.3838 |
2C | CF3SO2 | CH3 | 561.2840 |
2D | C6H5C(O) | CH3 | 533.3611 |
2E | 4-CH3C6H4SO2 | CH3 | 583.3442 |
实施例3
步骤1:
取醇1(2.0g,17.4mmol)、N-Boc-4-哌啶酮11(3.5g,17.4mmol)与Ti(OiPr)4(5.7ml,19mmol)溶於CH2Cl2(60ml)中,於25℃下搅拌64小时。添加二乙基氰化铝(42ml,1.0M甲苯溶液,42mmol)至25℃之反应混合物中。此溶液於25℃下再搅拌24小时。将溶液倒至0℃下含EtOAc与饱和NaHCO3水溶液之烧瓶中。混合物经硅藻土垫过滤。分层,以EtOAc萃取水层。合并之有机层以盐水洗涤,脱水(Na2SO4)。过滤及浓缩,产生氰化物粗产物(4.87g,87%)之黄色油状物。
此氰化物(4.87g,15mmol)溶於THF(75ml)中。添加CH3MgBr(25ml,3.0M之Et2O溶液)至0℃下之反应混合物中。使溶液回升至25℃,於此温度下搅拌18小时。使溶液分布在25重量%柠檬酸钠水溶液与EtOAc之间。以EtOAc萃取水层。合并之EtOAc层以盐水洗涤及脱水(Na2SO4)。过滤及浓缩,产生黄色油状物。经急骤层析法纯化(95/5至90/10 EtOAc/MeOH,SiO2),产生3.7g(79%)哌啶基哌啶12之黄色胶状物。
步骤2:
取DMSO(1.26ml,17.8mmol)溶於CH2Cl2(140ml)中。溶液冷却至-40℃(CH3CN/CO2)。滴加草醯氯(1.6ml,17.8mmol)至-40℃之此溶液中。溶液於此温度下搅拌0.75小时。添加醇12(3.7g,11.9mmol)之CH2Cl2溶液至-40℃之反应混合物中。所得溶液於此温度下搅拌0.75小时。添加Et3N(5.0ml,35.7mmol)至-40℃之反应混合物中。此白色浆状物於-40℃下搅拌0.5小时。混合物经CH2Cl2稀释,以1N NaOH洗涤。以CH2Cl2萃取水层。合并之有机层脱水(Na2SO4),过滤及浓缩,得到3.5g(95%)醛13之黄色油状物。
步骤3:
取哌嗪14a(133mg,0.65mmol)、醛13(200mg,0.65mmol)与Na(AcO)3BH(165mg,0.78mmol)溶於CH2Cl2中,於25℃下搅拌20小时。以CH2Cl2稀释溶液,以1N NaOH洗涤。以CH2Cl2萃取水层。合并之CH2Cl2层脱水(Na2SO4),过滤及浓缩。经制备性薄层层析法纯化(1/1己烷/丙酮,SiO2),产生160mg(46%)15a之油状物。
步骤4:
脱除15a之Boc保护基,所得哌啶按照反应图A步骤4中所述与嘧啶酸偶合,得到标题化合物之油状物:HRMS(MH+)实测值:535.3765。
其他R1衍生物可通过脱除4-甲氧苄基之保护,随後依上述反应图A进行衍化来制备。
实施例4
步骤1-2:
步骤1:取N-Boc-(S)-甲基哌嗪40(4.35g,21.8mmol)、苯甲醛(2.2ml,22mmol)与苯并三唑(2.59g,21.8mmol)溶於苯中,於回流下加热排除水(狄恩-史塔克收集器)。於110℃下加热4小时后,将溶液冷却及浓缩,得到8.9g(全收量)苯并三唑加成物41,为泡沫状物。
步骤2:取41(1.4g,3.4mmol)溶於THF(25ml)中。於25℃下添加哌啶基格利雅试剂(13.7ml之1.0M溶液)至41中。此溶液於此温度下搅拌5小时。将反应混合物倒至含EtOAc与25%柠檬酸钠之分液漏斗中。以EtOAc萃取水溶液层,合并之EtOAc层以盐水洗涤及脱水(Na2SO4)。过滤及浓缩,产生黄色油状物。经急骤层析法纯化(15/1 CH2Cl2/7N NH3之CH3OH溶液,SiO2),产生954mg(72%)哌嗪-哌啶42之异构物混合物。
步骤3-4:
步骤3:取42(954mg,2.46mmol)溶於CH3OH(15ml)中,添加3ml4.0M HCl之二噁烷溶液。此溶液於25℃下搅拌18小时后浓缩,产生脱除保护基的哌嗪HCl盐。将此盐粗产物(2.46mmol)分布在EtOAc与水之间。添加K2CO3(2.0g,14.8mmol)与氯甲酸烯丙酯(0.34ml,3.2mmol)至混合物中。混合物於25℃下激烈搅拌20小时。以EtOAc萃取水层,合并之EtOAc层以盐水洗涤及脱水(Na2SO4)。过滤及浓缩,产生以烯丙氧羰基(Alloc)保护之哌嗪43,为异构物混合物。
步骤4:取43溶於1,2-二氯乙烷中。取氯甲酸1-氯-乙酯
(0.5ml,4.9mmol)及结合在聚苯乙烯上的Hunig硷(Hunig′sbase)(PS-DIEA;DIEA为二异丙基乙醯胺)(2.7g)於90℃下加热1.5小时。将溶液冷却及浓缩,残质溶於CH3OH中,回流1小时。溶液浓缩,残质分布在CH2Cl2与1N NaOH水溶液之间。以CH2Cl2萃取水层。合并之有机层脱水(Na2SO4),过滤及浓缩,产生752mg(85%)44,为异构物混合物。
步骤5-6:
步骤5:取44(752mg,2.10mmol)、二碳酸二叔丁酯(550mg,2.5mmol)与K2CO3(870mg,6.3mmol)分布在EtOAc与H2O之间。以EtOAc萃取水层,合并之EtOAc层以盐水洗涤及脱水(Na2SO4)。过滤及浓缩,产生N-Boc哌啶45黄色油状粗产物。经急骤层析法纯化(4/1己烷/EtOAc,SiO2),产生606mg(63%)45之无色泡沫状物。
步骤6:取45(606mg,1.3mmol)、Et2NH(2.7ml,26.5mmol)与3,3′,3″-次膦基三(苯磺酸)三钠盐(30mg,0.052mmol)溶於CH3CN/H2O(1/1,40ml)中。添加Pd(OAc)2(6mg,0.026mmol),溶液於25℃下搅拌3小时。将溶液浓缩,残质分布在EtOAc与1N NaOH水溶液之间。以EtOAc萃取水层,合并之EtOAc层以盐水洗涤及脱水(Na2SO4)。过滤及浓缩,产生500mg(99%)46,为异构物之混合物。
步骤7-8:
步骤7:取46(500mg,1.3mmol)、对甲氧基苯甲醛(1.2ml,1.6mmol)与Na(AcO)3BH(340mg,1.6mmol)溶於CH2Cl2中,於25℃下搅拌18小时。以CH2Cl2稀释溶液,以1N NaOH水溶液洗涤。以CH2Cl2萃取水层。合并之有机层脱水(Na2SO4),过滤及浓缩,产生经对甲氧基苄基(PMB)保护之哌嗪粗产物47,为异构物混合物。经急骤层析法纯化(6/1己烷/EtOAc,SiO2),产生713mg之47半固体(为异构物混合物)。经再结晶纯化(己烷/CH2Cl2),产生220mg(34%)(S,S)异构物47之白色针状物。
步骤8:取47(220mg,0.45mmol)与4.0M HCl之二噁烷(2ml)溶液溶於CH3OH中,於25℃下搅拌4小时。溶液浓缩,残质分布在CH2Cl2与1N NaOH水溶液之间。以CH2Cl2萃取水层。合并之有机层脱水(Na2SO4),过滤及浓缩,产生182mg(100%)48之无色油状物。
步骤9-10:
步骤9:依照实施例3步骤1之方法将48衍生转化成49。
步骤10:脱除49之Boc保护基(HCl),所得哌啶按照反应图A之方法与嘧啶酸偶合,产生标题化合物,为黄色油状物:HRMS(MH+)实测值:625.4235。
按照类似方法及采用适当试剂,制备如下结构式化合物
其中R1如下表中之定义:
实施例 | R1 | HRMS(MH+)实测值 |
4A | CH3SO2 | 583.3419 |
4B | 3-Cl-C6H4SO2 | 679.3204 |
实施例5
步骤1:
取化合物3(2g,6.7mmol)、氯甲酸烯丙酯(0.93ml,8.7mmol)与K2CO3(5.6g,40mmol)分布在EtOAc与H2O之间。混合物於25℃下激烈搅拌24小时。分层,以EtOAc萃取水层,合并之EtOAc层以盐水洗涤及脱水(Na2SO4)。过滤及浓缩,产生2.6g(100%)受烯丙氧基羰基保护之哌嗪,为浓稠黄色油状物。
脱除Boc保护基,所得哌啶依反应图A,步骤4之方法与嘧啶酸偶合,产生2.3g(相对於3之85%)哌啶-醯胺50之黄色泡沫状物。
步骤2-3:
按照上述实施例4中对于45转化成46所述的方法脱除50之Alloc保护基,产生哌嗪51。
取51(450mg,1.36mmol)、亚氨酰氯52(360mg,1.36mmol)与iPr2NEt(1.2ml,6.8mmol)溶於CH2Cl2中,於25℃下搅拌18小时。以CH2Cl2稀释溶液,以水洗涤。以CH2Cl2萃取水层。合并之有机层脱水(Na2SO4),过滤及浓缩,产生醯胺-肟粗产物53。经制备性薄层层析法纯化(95/5 EtOAc/Et3N,SiO2),产生550mg(72%)醯胺-肟53,为异构物之混合物。
步骤4:
取53(550mg,0.99mmol)、EtI(0.16ml,1.98mmol)与Bu4NHSO4(3mg,0.01mmol)分布在甲苯与50%NaOH水溶液之间。混合物於25℃下激烈搅拌18小时。以EtOAc与水稀释混合物。以EtOAc萃取水层。合并之有机层以盐水洗涤及脱水(Na2SO4)。过滤及浓缩,产生黄色油状物。经制备性薄层层析法纯化(95/5 EtOAc/Et3N,SiO2),产生457mg(79%)54之黄色油状物,为异构物之混合物。
步骤5:
按照反应图A中步骤4之方法,使用HCl脱除54之Boc基。所得哌啶与3-氯苯磺醯氯依实施例1步骤5第二段所述之方法反应,得到实施例5之黄色油状物。HRMS(MH+):660.3089。
按照类似方法及采用适当试剂,制备如下结构式化合物
其中R1如下表中之定义:
实施例 | R1 | HRMS(MH+)实测值 |
5A | 4-CH3OC6H4SO2 | 656.3588 |
5B | CH3SO2 | 564.3328 |
下列分析法可用於测定本发明化合物的CCR5抑制与拮抗活性。
CCR5膜结合性分析法:
一种利用CCR5膜结合性分析的高通量筛选法可判别RANTES结合性抑制剂。此分析法采用之细胞膜系由表达能与RANTES(为受体的天然配位体)结合之人类CCR5趋化因子受体之NIH 3T3细胞制备。采用96-孔板模式,使膜制剂与125I-RANTES在含或不含化合物下培养1小时。化合物经一系列稀释至0.001ug/ml至1ug/ml之范围内,用三个重复样测试。经玻璃纤维滤器收集反应混合液,彻底洗涤。取得重覆测试之总数,计算平均值,数据以抑制125I-RANTES结合总量的50%时所需浓度表示。在膜结合性分析中具有强力活性之化合物则进一步於随后的基于细胞的HIV-1入侵与复制试验中鉴定。
HIV-1入侵分析法:
复制缺损型HIV-1报导基因病毒粒子之制法是按照Conner et al,Virology,206(1995),p.935-944所述,使用编码HIV-1之NL4-3菌株(经过被膜基因突变修饰并导入荧光素酶报道基因质粒)的质粒与编码数种HIV-1被膜基因之一的质粒进行共转染。这两种质粒经磷酸钙沉淀法进行转染后,於第三天收集病毒上清液,测定功能性病毒效价。这些保存液再用於感染稳定表达CD4与趋化因子受体CCR5且用或不用试验化合物预培养之U87细胞。於37℃下感染2小时,洗涤细胞,培养基换成含有化合物之新鲜培养基。将细胞培养3天,溶解细胞,测定荧光素酶活性。结果以相对於对照组培养物抑制50%荧光素酶活性时所需浓度表示。
HIV-1复制分析法:
此分析法使用原代外周血液单核细胞或稳定的U87-CCR5细胞系测定抗-CCR5化合物阻断原生HIV-1菌株感染的效果。自正常健康捐血者纯化原代淋巴细胞,感染前三天,先於活体外经PHA与IL-2刺激。采用96-孔板模式,使细胞於37℃下经药物预处理1小时後,用亲巨噬细胞之HIV-1分离物感染。感染後,洗除细胞上残余接种物,於化合物存在下培养4天。收集培养物上清液,通过确定病毒p24抗原浓度来测定病毒复制程度。
钙流动分析法:
向表达HIV共同受体CCR5之细胞中加入钙敏感性染料,然後添加化合物或天然CCR5配位体。具有激动剂性质之化合物会在细胞内诱发钙流动信号,本身不会诱发信号但可利用天然配位体RANTES阻断信号之化合物则判定为CCR5拮抗剂。
GTPγS结合性分析法(次级膜结合分析法):
GTPγS结合性分析法测定CCR5配位体对受体的活化作用。此分析法测定标记35S之GTP对与G-蛋白质偶合之受体的结合性,此结合作用系因受体被适当的配位体活化所致。此试验中,CCR5配位体(RANTES)与来自表达CCR5之细胞的膜培养,并与受体结合,分析已结合之35S标记物,决定活化(或结合)程度。此分析法可藉由诱发受体活化定量确定化合物是否具有激动剂特性,或以竞争或非竞争方式测定对RANTES结合的抑制作用,定量确定其拮抗剂性质。
趋化性分析法:
趋化性分析法为一种判别试验化合物为激动剂或拮抗剂性质之功能分析法。该分析法测定表达人类CCR5(BaF-550)之非粘附鼠细胞系受试验化合物或天然配位体(亦即RANTES,MIP-1β)的作用而迁移通过膜之能力。细胞会迁动通过可通透性膜,趋向具有激动剂活性之化合物。拮抗剂化合物不仅无法诱发趋化性,而且会响应已知的CCR5配位体的作用而抑制细胞迁移。
CC趋化因子受体如CCR-5受体在炎症中的作用已出示於例如下列文献中:
Immunology Letters,57,(1997),117-120(关节炎);Clinical & Experimental Rheumatology,17(4)(1999),p.419-425(类风湿关节类);
Clinical & Experimental Immunology, 117(2)(1999),p.237-243(特应性皮炎);
International Journal of Immunopharmacology,20(11)(1998),p.661-7(牛皮癣);Journal of Allergy & Clinical Immunology,100(6,Pt2)(1997),p.S52-5(气喘);与
Journal of Immunology,159(6)(1997),p.2962-72(过敏)。
测定HIV复制之分析法中,本发明化合物之活性范围为IC50约0.1至约1000nM,优选的化合物之活性范围为约0.1至约100nM,更优选为约0.1至约10nM。
由本发明化合物制备医药组合物时,医药上可接受之惰性载体可为固体或液体。固体剂型包括散剂、片剂、可分散性粒剂、胶囊、扁囊剂、与栓剂。散剂与片剂可包含约5至95%活性成份。合适之固体载体是本领域已知的,例如:碳酸镁、硬脂酸镁、滑石、糖或乳糖。片剂、散剂、扁囊剂与胶囊可用於适合口服之固体剂型。医药上可接受之载体实例与各种组合物之制造方法可参见A.Gennaaro(ed.),Remington′s Pharmaceutical Sciences,18th Edition,(1990),Mack Publishing Co.,Easton,Pennsylvania。
液体剂型包括溶液、悬浮液与乳液。其实例可述及供非肠道注射之水溶液或水-丙二醇溶液,或添加甜味剂与不透明剂供口服之溶液、悬浮液与乳液。液体剂型亦可包括供鼻内投药用之溶液。
适合吸入用之气雾剂可包括溶液与粉末形式之固体,其可与医药上可接受之载体组合,如:惰性压缩气体,例如:氮气。
还包括临用前转换成可供口服或非肠道投药之液体剂型的固体剂型。此等液体剂型包括溶液、悬浮液与乳液。
本发明化合物亦可透皮给药。透皮式组合物可呈霜剂、洗剂、气雾剂与/或乳液型式,且可包含在为此目的常用之基质型或储库型透皮式贴剂中。
优选化合物经口投药。
医药剂型优选是单位剂型。此等剂型中,制剂分成含有适量活性成份(例如:可达到所需目的之有效量)之合适大小的单位剂量。
制剂之单位剂量中之活性化合物含量可以在约10mg至约500mg中变化或调整,优选为约25mg至约300mg,更优选为约50mg至约250mg,最优选为约55mg至约200mg,依特定之用途而定。
所使用式I化合物之准确剂量可依患者需求与待治疗病症之严重性而变化。对特定情况下之适当剂量方案由本领域技术人员决定。为了方便起见,每日总剂量可再细分,依需要於一天内分几次投药。
本发明化合物与/或其医药上可接受之盐的投药量与投药频率将依据责任医师考虑患者之年龄、条件与体型,及待治疗之症状严重性等因素作判断而调整。建议的典型口服剂量方案可在约100mg/日至约300mg/日之范围内,以约150mg/日至约250mg/日之范围内较佳,约200mg/日更佳,分成2至4个分剂量。
NRTI、NNRTI、PI及可与CCR5拮抗剂化合物组合使用之其他药剂的剂量和剂量方案将由责任医师依据包装中插页说明或配制报告中说明之许可剂量及剂量方案,考量患者之年龄、性别与状况,及待治疗之症状严重性等因素决定。
本发明HIV-1疗法之目标在於将HIV-1-RNA病毒量降至检测限值以下。本发明说明中之″HIV-1-RNA检测限值″一词指依据多次循环逆转录酶PCR定量法测定,每毫升患者血浆中HIV-1-RNA复制数低於约200至低於约50。本发明最好采用Amplicor-1 Monitor 1.5(来自Roche Diagnostics)或Nuclisens HIV-1 QT-1之方法检测HIV-1-RNA。
虽然本发明已配合上述具体的实施方案作了说明,但许多替代法、修正法与变化对于本领域的普通技术人员是显而易见的。所有此等替代法、修正法与变化均在本发明的精神与范围内。
Claims (13)
1.一种结构式I化合物
或其医药上可接受之盐或异构物,其中:
Q、X与Z分别独立选自CH与N,但其限制条件为Q与Z中之一或二者为N;
R、R4、R5、R6与R7分别独立选自H与(C1-C6)烷基;
R1为H、(C1-C6)烷基、氟-(C1-C6)烷基-、R9-芳基(C1-C6)烷基-、R9-杂芳基-(C1-C6)烷基-、(C1-C6)烷基-SO2-、(C3-C6)环烷基-SO2-、氟-(C1-C6)烷基-SO2-、R9-芳基-SO2-、R9-杂芳基-SO2-、N(R22)(R23)-SO2-、(C1-C6)烷基-C(O)-、(C3-C6)环烷基-C(O)-、氟-(C1-C6)烷基-C(O)-、R9-芳基-C(O)-、NH-(C1-C6)烷基-C(O)-或R9-芳基NH-C(O)-;
R2为H或(C1-C6)烷基且R3为H、(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷基-、(C3-C10)-环烷基-、(C3-C10)环烷基(C1-C6)烷基-、R9-芳基、R9-芳基(C1-C6)烷基-、R9杂芳基或R9-杂芳基(C1-C6)烷基-,但其限制条件为X与Z不同时为N;
或R2与R3合起来为=O、=NOR10、=N-NR11R12或=CH(C1-C6)烷基,但其限制条件为当X与Z中之一或二者为N时,R2与R3合起来不是=CH(C1-C6)烷基;
且当X与Z分别为CH时,R3亦可为(C1-C6)烷氧基、R9-芳氧基、R9-杂芳氧基、(C1-C6)烷基-C(O)O-、(C1-C6)烷基-NH-C(O)O-、-N((C1-C6)烷基)2-C(O)O-、(C1-C6)烷基-C(O)-NR13、(C1-C6)烷基-O-C(O)-NR13-、(C1-C6)烷基-NH-C(O)-NR13-或N((C1-C6)烷基)2-C(O)-NR13;
R8为(R14,R15,R16)-取代之苯基、(R14,R15,R16)-取代之6元杂芳基、(R14,R15,R16)-取代之6元杂芳基N-氧化物、(R17,R18)-取代之5元杂芳基、萘基、芴基、二苯基甲基,
或
R9为1、2或3个独立选自下列之取代基:H、卤素、(C1-C6)烷基、(C1-C6)烷氧基、-CF3、-OCF3、CH3C(O)-、-CN、CH3SO2-、CF3SO2-与-N(R22)(R23);
R10为H、(C1-C6)烷基、氟(C1-C6)烷基-、(C3-C10)环烷基(C1-C6)烷基-、羟基(C2-C6)烷基-、(C1-C6)烷基-O-(C2-C6)烷基-、(C1-C6)烷基-O-C(O)-(C1-C6)烷基-或N(R22)(R23)-C(O)-(C1-C6)烷基-;
R11与R12分别独立选自:H、(C1-C6)烷基与(C3-C10)环烷基,或R11与R12合起来为C2-C6亚烷基并与其连接之氮共同形成环;
R14与R15分别独立选自:(C1-C6)烷基、卤素、-NR22R23、-OH、-CF3、-OCH3、-O-醯基与-OCF3;
R16为R14、氢、苯基、-NO2、-CN、-CH2F、-CHF2、-CHO、-CH=NOR14、吡啶基、吡啶基N-氧化物、嘧啶基、吡嗪基、N(R24)CONR25R26、-NHCONH(氯-(C1-C6)烷基)、-NHCONH((C3-C10)环烷基(C1-C6)烷基)、-NHCO(C1-C6)烷基、-NHCOCF3、-NHSO2N(R22)(R23)、-NHSO2(C1-C6)烷基、-N(SO2CF3)2、-NHCO2-(C1-C6)烷基、C3-C10环烷基、-SR27、-SOR27、-SO2R27、-SO2NH(R22)、
-OSO2(C1-C6)烷基、-OSO2CF3、羟基(C1-C6)烷基-、
-CONR24R25、-CON(CH2CH2OCH3)2、-OCONH(C1-C6)烷基、-CO2R24、-Si(CH3)3或-B(OC(CH3)2)2;
R17为(C1-C6)烷基、-N(R22)(R23)或R19-苯基;
R13、R18、R22、R23、R24、R25与R26分别独立选自H与(C1-C6)烷基;
R19为1,2或3个分别独立选自下列之取代基:H、(C1-C6)烷基、-CF3、-CO2R25、-CN、(C1-C6)烷氧基与卤素;
R20与R21分别独立选自H与(C1-C6)烷基,或R20与R21及其所连接之碳合起来形成3-6个碳原子之螺环;且
R27为(C1-C6)烷基或苯基。
2.根据权利要求1之化合物,其中Z为CH,且Q与X均为N。
3.根据权利要求1之化合物,其中R1为R9-芳基(C1-C6)烷基-、R9-杂芳基(C1-C6)烷基-、(C1-C6)烷基-SO2-、(C3-C6)环烷基-SO2-、氟-(C1-C6)烷基-SO2-、R9-芳基-SO2-、或R9-芳基-NH-C(O)-。
4.根据权利要求1之化合物,其中R2为氢且R3为(C1-C6)烷基、R9-芳基、R9-芳基(C1-C6)-烷基、R9-杂芳基、或R9-杂芳基(C1-C6)烷基。
5.根据权利要求1之化合物,其中R、R5与R7均为氢且R6为-CH3。
6.根据权利要求1之化合物,其中R8为(R14,R15,R16)-苯基;(R14,R15,R16)-吡啶基或其N-氧化物;或(R14,R15,R16)-嘧啶基。
7.根据权利要求1之化合物,其系选自下式化合物:
其中R1、R3与R6如下表中定义:
R1
R3
R6
4-CH3OC6H4CH2
C6H5
CH3
CH3SO2
C6H5
CH3
4-CH3OC6H4CH2
CH2C6H5
CH3
CH3SO2
CH2CH2CH3
CH3
4-CH3OC6H4SO2
CH2CH2CH3
CH3
4-CH3OC6H4SO2
C6H5
CH3
C6H5NHC(O)
C6H5
CH3
4-CH3OC6H4CH2
C6H5
H
4-CH3OC6H4SO2
C6H5
CH3
3-Cl-C6H4SO2
C6H5
CH3
CH3SO2
CH2C6H5
CH3
3-Cl-C6H4SO2
CH2C6H5
CH3
CH3CH2SO2
CH2C6H5
CH3
4-CH3OC6H4SO2
4-F-C6H4
CH3
CH3SO2
4-F-C6H4
CH3
3-Cl-C6H4SO2
4-F-C6H4
CH3
CF3C(O)
4-F-C6H4CH2
CH3
CH3SO2
3-F-C6H4
CH3
3-Cl-C6H4SO2
3-F-C6H4
CH3
4-CH3OC6H4SO2
3-F-C6H4
CH3
CH3SO2
4-F-C6H4CH2
CH3
3-Cl-C6H4SO2
4-F-C6H4CH2
CH3
4-CH3OC6H4SO2
4-F-C6H4CH2
CH3
4-CH3OC6H4CH2
2-噻吩基
CH3
CF3CH2SO2
C6H5
CH3
CF3SO2
C6H5
CH3
4-CH3OC6H4SO2
3-噻吩基
CH3
3-Cl-C6H4SO2
2-噻吩基
CH3
4-CH3OC6H4SO2
2-噻吩基
CH3
CH3SO2
2-噻吩基
CH3
CH3SO2
3-噻吩基
CH3
3-Cl-C6H4SO2
3-噻吩基
CH3
4-F-C6H4SO2
CH2C6H5
CH3
2-噻吩基-SO2
CH2C6H5
CH3
C6H5SO2
CH2C6H5
CH3
CF3SO2
CH2C6H5
CH3
CF3CH2SO2
CH2C6H5
CH3
(CH3)2NSO2
CH2C6H5
CH3
环丙基-SO2
3-F-C6H4
CH3
4-F-C6H4SO2
3-F-C6H4
CH3
4-CH3OC6H4CH2
正丁基
CH3
3-Cl-C6H4SO2
正丁基
CH3
4-CH3OC6H4SO2
正丁基
CH3
3-Cl-C6H4SO2
3-吡啶基
CH3
4-CH3OC6H4SO2
3-吡啶基
CH3
3-Cl-C6H4SO2
2-吡啶基
CH3
环丙基-SO2
C6H5
CH3
CH3CH2SO2
C6H5
CH3
CH3CH2CH2SO2
C6H5
CH3
异丙基-SO2
C6H5
CH3
CH3C(O)
C6H5
CH3
环丙基-C(O)
C6H5
CH3
CH3CH2C(O)
C6H5
CH3
异丙基-C(O)
C6H5
CH3
4-CH3OC6H4CH2
3,5-二氟苯基
CH3
环丙基-SO2
3,5-二氟苯基
CH3
CH3SO2
环己基
CH3
8.根据权利要求1之化合物,其系选自下式化合物:
和
9.一种医药组合物,其包含有效量的权利要求1之化合物与医药上可接受之载体组合。
10.一种医药组合物,其包含有效量权利要求1之化合物与一种或多种抗病毒剂或适用於治疗HIV之其他药剂组合,或与一种或多种适用於治疗固体器官移植物排斥、移植物抗宿主疾病、关节炎、类风湿关节炎、发炎性肠部疾病、特应性皮炎、牛皮癣、气喘、过敏或多发性硬化之药剂组合,并与医药上可接受之载体组合。
11.权利要求1的化合物单独或与一种或多种抗病毒剂或其他适用於治疗人类免疫缺损病毒之药剂组合,用於制备治疗人类免疫缺损病毒的药物。
12.权利要求1的化合物单独或与一种或多种适用於治疗固体器官移植物排斥、移植物抗宿主疾病、关节炎、类风湿关节炎、发炎性肠部疾病、特应性皮炎、牛皮癣、气喘、过敏或多发性硬化之药剂组合,用於制备治疗固体器官移植物排斥、移植物抗宿主疾病、关节炎、类风湿关节炎、发炎性肠部疾病、特应性皮炎、牛皮癣、气喘、过敏或多发性硬化的药物。
13.一种试剂盒,在其分开之容器内包含用於组合治疗人类免疫缺损病毒之单一包装的医药组合物,在一个容器内装有在医药上可接受之载体中包含有效量权利要求1化合物的医药组合物,在分开之另外容器中,装有在医药上可接受之载体中包含有效量抗病毒剂或其他适用於治疗人类免疫缺损病毒之药剂的一种或多种医药组合物。
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