CN1867336A - 1-芳基-4-取代的哌嗪衍生物用作ccr1拮抗剂以治疗炎症和免疫疾病 - Google Patents
1-芳基-4-取代的哌嗪衍生物用作ccr1拮抗剂以治疗炎症和免疫疾病 Download PDFInfo
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- CN1867336A CN1867336A CNA038193027A CN03819302A CN1867336A CN 1867336 A CN1867336 A CN 1867336A CN A038193027 A CNA038193027 A CN A038193027A CN 03819302 A CN03819302 A CN 03819302A CN 1867336 A CN1867336 A CN 1867336A
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- alkyl
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- haloalkyl
- phenyl
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- C07D401/02—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 two hetero rings
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
提供了作为CCR1受体强有力拮抗剂的化合物,还在动物试验中确定了其对抗炎症,一种CCR1所致的标志性疾病状态,的功能。该化合物通常是芳基哌嗪衍生物并可用于药物组合物,用于治疗CCR1-介导的疾病的方法,以及在鉴定竞争性CCR1拮抗剂的试验中作为对照。
Description
相关申请的交叉引用
本申请要求2002年6月12日提交的临时申请序列号No.60/453,711(USSN10/171,398,2002年6月12日提交)的权利,在此将其内容并入以供参考。
关于在联邦资助研究或开发下作出本发明的权利声明
本申请部分是由DARPA许可号N65236-99-1-5420的支持下进行的。美国政府对本申请可享有一定的权利。
以高密度磁盘作为附件提交的“序列表”、表格或计算机程序无。
发明背景
本发明提供了化合物,药物组合物,该药物组合物含有一种或多种所述化合物或其药学上可接受的盐,它们可有效抑制各种趋化因子,如MIP-1α、leukotactin、MPIF-1和RANTES与CCR1受体结合。作为CCR1受体的拮抗剂或调节剂,所述化合物和组合物可用于治疗炎性或免疫紊乱症状和疾病。
人类健康取决于机体察觉和摧毁可能会从个体摄入有价值资源和/或导致疾病的外部病原体的能力。免疫系统是机体的防御系统,它包括白细胞(白血细胞(WBC):T和B淋巴细胞,单核细胞,巨噬细胞粒细胞,NK细胞,肥大细胞,树突细胞和免疫衍生细胞(例如破骨细胞),淋巴组织和淋巴管。为抵御感染,白血细胞在身体里循环以探测病原体。一旦病原体被发现,天生的免疫细胞,尤其是细胞毒T细胞就在感染部位聚集以破坏病原体。趋化因子作为免疫细胞(如淋巴细胞,单核细胞和粒细胞)聚集和活化的分子标志,它可鉴别存在病原体的部位。
除了免疫系统对病原体的调节,某些不适当的趋化因子也会产生信号,且会触发类风湿性关节炎、多发性硬化等炎性疾病或使之持续。例如,在类风湿性关节炎中,不受调节的趋化因子在骨关节中的聚集会吸引和活化浸润巨噬细胞和T细胞。这些细胞的活化会诱导滑液细胞增殖,这会导致,至少部分导致炎症,最终造成骨和软骨流失(参见DeVries,M.E.等,Semin Immunol 11(2):95-104(1999))。一些脱髓鞘疾病如多发性硬化的一个标志是趋化因子介导的单核细胞/巨噬细胞和T细胞向中枢神经系统聚集(参见Kennedy等,J.Clin.Immunol.19(5):273-279(1999))。趋化因子介导的破坏性WBC向植入物聚集与随后的排斥有关。参见DeVries,M.E.等,ibid。由于趋化因子在炎症和淋巴细胞的发育中扮演关键角色,特定操纵其活性的能力对于减轻和治愈疾病非常重要,而这些疾病目前还不能满意治疗。此外,移植物排斥可被降低至最低程度,且不会产生费用昂贵的免疫抑制药物的全身性效果和并发症。
趋化因子是40多个小肽(7-10kD)的集合,它连接主要在WBC或免疫衍生细胞上表达的受体,并通过G-蛋白偶合的信号级联产生信号以介导其化学引诱和化学刺激物的功能。受体可结合一个以上的配体;例如,受体CCR1结合RANTES(活化后可调节的正常T细胞表达的因子),MIP-1α(巨噬细胞炎性蛋白),MPIF-L/CKβ8和Leukotactin趋化因子(这些中亲和力较小的趋化因子)。迄今已知24种趋化因子受体。趋化因子,多配体结合受体的准确数目和在免疫细胞上的不同受体特征使得能够被紧密控制并负责特定的免疫应答。参见Rossi等,Ann.Rev.Immunol.18(1):217-242(2000)。趋化因子的活性可通过调节其相应的受体、治疗相关炎性疾病和免疫疾病来控制并使器官和组织移植成为可能。
受体CCR1及其趋化因子配体,包括例如MIP-1α,MPIF-1/CKβ8,Leukotactin和RANTES,是明显的治疗靶点(参见Saeki等,Current Pharmaceutical Design9:1201-1208(2003)),这是由于它们与类风湿性关节炎、移植物排斥(参见DeVries,M.E.等,ibid.)和多发性硬化(参见Fischer等,J.Neuroimmunol.110(1-2):195-208(2000);Izikson等,J.Exp.Med.192(7):1075-1080(2000);Rottman等,Eur.J.Immunol.30(8):2372-2377(2000)有关。实际上,封闭功能的抗体、经过修饰的趋化因子受体配体和小的有机化合物已经被发现,其中有些已经已经被成功证实可预防或治疗一些趋化因子-介导的疾病(参见Rossi等,ibid.)。需要注意的是,在类风湿性关节炎的试验模型中,当给予封闭的信号、经修饰的RANTES配体时,疾病的发展被减缓到(参见Plater-Zyberk等,Immunol Lett.57(1-3):117-120(1997))。尽管封闭的功能抗体和小肽治疗是有前景的,但一旦施用,它们就有降解的危险,半衰期极短,开发和生成它们的无法忍受的成本,这是大多数蛋白质药物的特征。小的有机化合物则比较好,因为它们通常有较长的体内半衰期,较小剂量就有效,通常可通过口服给药,且费用较低廉。CCR1的一些有机拮抗剂已经被描述过(参见Hesselgesser等,J.Biol.Chem.273(25):15687-15692(1998);Ng等,J.Med.Chem.42(22):4680-4694(1999);Liang等,J.Biol.Chem.275(25):19000-19008(2000)和Liang等,Eur.J.Pharmacol.389(1):41-49(2000))。考虑到在动物模型中已被证实的疾病的治疗效果(参见Liang等,J.Biol.Chem.275(25):19000-19008(2000)),继续寻找、鉴定其它可用于治疗由CCR1信号发生介导的疾病的化合物。
发明简述
本发明提供具有下式的化合物:
或其药学上可接受的盐。在上式中,下标n是1-2的整数,优选是1。下标m是0-10的整数,受其所连接的哌嗪或高哌嗪环上可用的取代基位置个数的限制。例如,哌嗪衍生物(n是1)可以有0-8个R1基,优选有0-4个R1基,更优选有0、1或2个R1基。每个R1是独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、-CORa、-CO2Ra、-CONRaRb、-NRaCORb、-SO2Ra、-X1CORa、-X1CO2Ra、-X1CONRaRb、-X1NRaCORb、-X1SO2Ra、-X1SO2NRaRb、-X1NRaRb、-X1ORa的取代基,其中,X1选自C1-4亚烷基、C2-4亚烯基、C2-4亚炔基,每个Ra和Rb独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基,其中,每个所述R1取代基的脂肪族部分任选被OH、O(C1-8烷基)、SH、S(C1-8烷基)、CN、NO2、NH2、NH(C1-8烷基)、N(C1-8烷基)2中1-3个成员取代。
符号Ar1代表任选取代的芳基或杂芳基。优选的芳基是苯基、萘基。优选的杂芳基是那些有5-10个环原子,且其中至少一个是氮原子的基团(例如吡啶基、吡嗪基、哒嗪基、嘧啶基、三嗪基、喹啉基、喹喔啉基、嘌呤基等)。各个Ar1环都任选被1-5个R2取代基取代,R2取代基独立选自卤素、-ORc、-OC(O)Rc、-NRcRd、-SRc、-Re、-CN、-NO2、-CO2Rc、-CONRcRd、-C(O)Rc、-OC(O)NRcRd、-NRdC(O)Rc、-NRdC(O)2Re、-NRc-C(O)NRcRd、-NH-C(NH2)=NH、-NReC(NH2)=NH、-NH-C(NH2)=NRe、-NH-C(NHRe)=NH、-S(O)Re、-S(O)2Re、-NRcS(O)2Re、-S(O)2NRcRd、-N3、-X2ORc、-X2OC(O)Rc、-X2NRcRd、-X2SRc、-X2CN、-X2NO2、-X2CO2Rc、-X2CONRcRd、-X2C(O)Rc、-X2OC(O)NRcRd、-X2NRdC(O)Rc、-X2NRdC(O)2Re、-X2NRcC(O)NRcRd、-X2NH-C(NH2)=NH、-X2NReC(NH2)=NH、-X2NH-C(NH2)=NRe、-X2NH-C(NHRe)=NH、-X2S(O)Re、-X2S(O)2Rd、-X2NRcS(O)2Re、-X2S(O)2NRcRd、-X2N3,其中,X2选自C1-4亚烷基、C2-4亚烯基、C2-4亚炔基,每个Rc和Rd独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、芳基-C1-4烷基、芳氧基-C1-4烷基,每个Re独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、芳基-C1-4烷基、芳氧基-C1-4烷基,每个Rc、Rd和Re还可任选被1-3个选自OH、O(C1-8烷基)、SH、S(C1-8烷基)、CN、NO2、NH2、NH(C1-8烷基)、N(C1-8烷基)2的成员取代。
符号HAr代表任选取代的杂芳基。HAr的杂芳基可以和Ar1的杂芳基相同或不同。通常,HAr是单环的,但也可以是含有5-10个环原子且其中至少一个是氮原子的稠合双环系统。某些优选的杂芳基是至少有一个氮原子作为环原子的5或6元环,以及具有与苯环稠合的5元环的稠合环系统,例如吡唑基、咪唑基、三唑基、四唑基、唑基、异唑基、二唑基、噻二唑基、吡咯基、噻唑基、异噻唑基、苯并咪唑基、苯并吡唑基、苯并三唑基的杂芳基,其中每个都被1-5个独立选自卤素、苯基、噻吩基、呋喃基、吡啶基、嘧啶基、吡嗪基、吡地嗪基(pyridizinyl)、吡唑基、咪唑基、噻唑基、唑基、异唑基、异噻唑基、三唑基、四唑基、二唑基、-ORf、-OC(O)Rf、-NRfRg、-SRf、-Rh、-CN、-NO2、-CO2Rf、-CONRfRg、-C(O)Rf、-OC(O)NRfRg、-NRgC(O)Rf、-NRgC(O)2Rh、-NRf-C(O)NRfRg、-NH-C(NH2)=NH、-NRhC(NH2)=NH、-NH-C(NH2)=NRh、-NH-C(NHRh)=NH、-S(O)Rh、-S(O)2Rh、-NRfS(O)2Rh、-S(O)2NRfRg、-NRfS(O)2Rh、-NRfS(O)2NRfRg、-N3、-X3ORf、-X3OC(O)Rf、-X3NRfRg、-X3SRf、-X3CN、-X3NO2、-X3CO2Rf、-X3CONRfRg、-X3C(O)Rf、-X3OC(O)NRfRg、-X3NRgC(O)Rf、-X3NRgC(O)2Rh、-X3NRf-C(O)NRfRg、-X3NH-C(NH2)=NH、-X3NRhC(NH2)-NH、-X3NH-C(NH2)-NRh、-X3NH-C(NHRh=NH、-X3S(O)Rh、-X3S(O)2Rh、-X3NRfS(O)2Rh、-X3S(O)2NRfRb、-X3N3的R3取代基取代,其中,X3选自C1-4亚烷基、C2-4亚烯基、C2-4亚炔基,每个Rf和Rg独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、芳基-C1-4烷基、芳氧基-C1-4烷基,每个Rh独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、芳基-C1-4烷基、芳氧基-C1-4烷基,其中,Rf、Rg和Rh的脂肪族部分还任选被1-3个选自OH、O(C1-8烷基)、SH、S(C1-8烷基)、CN、NO2、NH2、NH(C1-8烷基)、N(C1-8烷基)2的成员取代,其中,任何苯基、噻吩基、呋喃基、吡啶基、嘧啶基、吡嗪基、吡地嗪基(pyridizinyl)、吡唑基、咪唑基、噻唑基、唑基、异唑基、异噻唑基、三唑基、四唑基或二唑基任选被1-3个选自卤素、-ORf、-NRfRg、-Rh、-CN、-NO2、-CO2Rf、-CONRfRg、-C(O)Rf、-X3ORf、-X3NRfRg、-X3NRfS(O)2Rh和-X3S(O)ZNRfRg的取代基取代。最优选的HAr基是取代或未取代的吡唑和取代或未取代的苯并吡唑。优选的,取代或未取代的吡唑通过吡唑环的氮原子连接到分子的其余部分。在那些HAr是苯并吡唑环的实施方案中,优选通过稠合环系统吡唑部分上的氮连接到分子的其余部分。
符号L1是含有1-3个选自C,N,O和S的主链原子的连接基、并任选被1-3个选自卤素、苯基、-ORi、-OC(O)Ri、-NRiRj、-SRi、-Rk、-CN、-NO2、-CO2Ri、-CONRiRj、-C(O)Ri、-OC(O)NRiRj、-NRjC(O)Ri、-NRjOC(O)2Rk、-X4ORi、-X4OC(O)Ri,-X4NRiRj、-X4SRi、-X4CN、-X4NO2、-X4CO2Ri、-X4CONRiRj、-X4C(O)Ri、-X4OC(O)NRiRj、-X4NRjC(O)Ri、-X4NRjC(O)2Rk的取代基取代,其中,X4选自C1-4亚烷基、C2-4亚烯基、C2-4亚炔基,每个Ri和Rj独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、芳基-C1-4烷基、芳氧基-C1-4烷基,每个Rk独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、芳基-C1-4烷基、芳氧基-C1-4烷基。在一些优选的实施方案中,连接基是未取代的,而在其它优选的实施方案中,取代基是存在的,这可增加分配进入所选溶剂或进入所选组织。例如,在丙烯链连接羟基通常可提供在水中有更好溶解性的化合物。优选地,L1选自-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2O-、-CH2NH-、-CH2OCH2-、-CH2NHCH2-。
除了这里提供的化合物,本发明还提供了含有一种或多种这些化合物的药物组合物,以及将这些化合物用于治疗方法的方法,主要是治疗与CCR1信号发生活性有关的疾病。
附图简述
图1为式I、II和III的化合物提供了经过选择和优选的Ar1基。
图2和3为式I、II、III和IV的化合物提供了经过选择和优选的HAr基。
图4A-4C提供了经过选择的市售起始物质的结构。
图5A-5N为式I的化合物提供了经过选择和优选的结构。
发明详述
I.缩写和定义
除非另有说明,术语″烷基″,其自身或作为其它取代基的一部分,代表含有所指定碳原子数(即C1-8表示1-8个碳原子)的直链或支链烃基团。烷基的例子包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、叔丁基、正戊基、正己基、正庚基、正辛基等。术语″烯基″代表含有一个或多个双键的不饱和的烷基。类似地,术语″炔基″代表含有一个或多个三键的不饱和的烷基。这种不饱和烷基的例子包括乙烯基、2-丙烯基、丁烯基、2-异戊烯基、2-(丁间二烯基)、2,4-戊二烯基、3-(1,4-戊二烯基)、乙炔基、1-和3-丙炔基、3-丁炔基、高级同系物和同分异构体。术语“环烷基”代表含有指定环原子数(例如,C3-6环烷基)的烃环,它可被完全饱和或在环原子之间有不超过一个的双键,例如,“环烷基”还指二环或多环烃环,如二环[2.2.1]庚烷,二环[2.2.2]辛烷等。
术语″亚烷基″其自身或作为其它取代基的一部分是指衍生自烷烃的二价基团,例如-CH2CH2CH2CH2-。通常,烷基(或亚烷基)含有1-24个碳原子,其中,含有10个或更少碳原子的在本发明中是优选的。″低级烷基″或″低级亚烷基″是较短的链烷基或亚烷基、通常含有四个或更少的碳原子。
术语″烷氧基″、″烷基氨基″和″烷硫基″(硫代烷氧基)以其常规含义使用,是指那些分别通过氧原子、氨基或硫原子连接到分子其余部分的烷基。此外,对于二烷基氨基、所述烷基部分可以相同或不同,并可与和它们连接的N原子合起来形成3-7元环。因此,基团-NRaRb可包括哌啶基、吡咯烷基、吗啉基、吖丁啶基等。
除非另有说明,术语″卤代″或″卤素″,其自身或作为其它取代基的一部分是指氟、氯、溴、碘原子。此外,术语″卤代烷基″包括单卤代烷基、多卤代烷基。例如,术语″C1-4卤代烷基″将包括三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基等。
除非另有说明,术语″芳基″是指多不饱和的,通常是芳香性的烃基,它可以是单环或多环(最多三环),环相互稠合或共价连接。术语″杂芳基″代表含有1-5个选自N、O和S的杂原子的芳基(或环),其中,氮和硫原子是任选氧化的,且氮原子是任选季铵化的。杂芳基可通过杂原子连接到分子的其余部分。芳基的非限制性的例子包括苯基、萘基、联苯基、杂芳基的非限制性的例子包括1-吡咯基、2-吡咯基、3-吡咯基、1-吡唑基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-唑基、4-唑基、5-唑基、3-异唑基、4-异唑基、5-异唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、苯并吡唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基、6-喹啉基。上述芳基、杂芳环系统的取代基选自下面描述的可接受的取代基。
简言之,术语″芳基″当与其它术语联合使用时(例如,芳氧基、芳基硫氧基、芳基烷基)包括上述芳基、杂芳环。因此,术语″芳基烷基″包括那些芳基与烷基相结合的基团(例如,苄基、苯乙基、吡啶基甲基等)。
在一些实施方案中,上面的术语(例如,″烷基″、″芳基″和″杂芳基″)将包括所述基团的取代和未取代的形式。各种类型的基团的优选取代基在下面提供。简言之,除非另有说明,术语芳基、杂芳基将包括下面提供的取代或未取代的形式,而术语″烷基″和相关的脂肪族基团是指未取代的形式(除非指明是取代的)。
烷基(包括那些通常称为亚烷基、烯基、炔基、环烷基的基团)的取代基可以是选自以下的各种基团:-卤素、-OR’、-NR’R”、-SR’、-SiR’R”R、-OC(O)R’、-C(O)R’、-CO2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、-NR’-C(O)NR”R、-NR”C(O)2R’、-NH-C(NH2)=NH、-NR’C(NH2)=NH、-NH-C(NH2)=NR’、-S(O)R’、-S(O)2R’、-S(O)2NR’R”、-NR’S(O)2R”、-CN和-NO2。取代基的个数为0到(2m’+1),其中m’是所述基团中碳原子的总数。R’、R”和R代表氢,未取代的C1-8烷基、未取代的杂烷基、未取代的芳基、被1-3个卤素取代的芳基、未取代的C1-8烷基、C1-8烷氧基或C1-8硫代烷氧基、或未取代的芳基-C1-4烷基。当R’和R”结合到相同的氮原子上时,它们可与氮原子结合形成3-,4-,5-,6-或7-元环。例如、-NR’R”可包括1-吡咯烷基、4-吗啉基。
类似地,芳基、杂芳基的取代基可以有多种,且通常选自:-卤素、-OR’、-OC(O)R’、-NR’R”、-SR’、-R’、-CN、-NO2、-CO2R’、-CONR’R”、-C(O)R’、-OC(O)NR’R”、-NR”C(O)R’、-NR”C(O)2R’、-NR’-C(O)NR”R、-NH-C(NH2)=NH、-NR’C(NH2)=NH、-NH-C(NH2)=NR’、-S(O)R’、-S(O)2R’、-S(O)2NR’R”、-NR’S(O)2R”、-N3,全氟(C1-C4)烷氧基、全氟(C1-C4)烷基、取代基的个数从0到所述芳香环系统的开放的化学价的总数;且R’、R”和R独立选自氢、C1-8烷基、C3-6环烷基、C2-8烯基、C2-8炔基、未取代的芳基、杂芳基、(未取代的芳基)-C1-4烷基、未取代的芳氧基--C1-4烷基。其它合适的取代基包括上述芳基的各个取代基,它通过1-4个碳原子的亚烷基链结合到环原子。
芳基或杂芳环邻近原子上的两个取代基可任选被式-T-C(O)-(CH2)q-U-的取代基代替,其中,T和U各自为-NH-、-O-、-CH2-或单键,q是0-2的整数。或者,芳基或杂芳环邻近原子上的两个取代基可任选被式-A-(CH2)r-B-的取代基代替,其中,A和B各自为-CH2-、-O-、-NH-、-S-、-S(O)-、-S(O)2-、-S(O)2NR’-或单键,r是1-3的整数。如此形成的新环的一个单键可任选被双键代替。或者,芳基或杂芳环邻近原子上的两个取代基可任选被式-(CH2)s-X-(CH2)t-的取代基代替,其中,s和t各自为0-3的整数,X是-O-、-NR’-、-S-、-S(O)-、-S(O)2-、-S(O)2NR’-。-NR’-和-S(O)2NR’-中的R’取代基选自氢或未取代的C1-8烷基。
当用作这里时,术语″杂原子″包括氧(O)、氮(N)、硫(S)和硅(Si)。
术语″药学上可接受的盐″是指可用相对无毒的酸或碱制备的活性化合物的盐,取决于在这里所述的化合物中发现的特定取代基。当本发明的化合物相对具有酸官能度时,将该化合物的中性形式与足量的所需碱接触可获得碱加成盐,无论是直接进行或在合适的惰性溶剂中进行。衍生自药学上可接受的无机碱的盐包括铝盐,铵盐,钙盐,铜盐,铁盐,亚铁盐,锂盐,镁盐,锰盐,二价锰盐,钾盐,钠盐,锌盐等。衍生自药学上可接受的有机碱的盐包括伯、仲和叔胺的盐,包括取代的胺、环胺、天然产生的胺等,如精氨酸、甜菜碱、咖啡因、胆碱、N,N’-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、正乙基吗啉、正乙基哌啶、葡糖胺、氨基葡萄糖、组氨酸、哈胺(hydrabamine)、异丙胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、piperadine、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲铵、三丙胺、氨丁三醇等。当本发明的化合物相对含有碱性官能度时,可将这种化合物的中性形式与足量的所需酸接触以得到酸加成盐,无论是直接进行或在合适的惰性溶剂中进行。药学上可接受的酸加成盐的例子包括那些衍生自无机酸,如盐酸,氢溴酸,硝酸,碳酸,一氢碳酸,磷酸,一氢磷酸,二氢磷酸,硫酸,一氢硫酸,氢碘酸或亚磷酸等的盐,以及衍生自相对无毒的有机酸如乙酸,丙酸,异丁酸,丙二酸,苯甲酸,琥珀酸,辛二酸,延胡索酸,扁桃酸,酞酸,丙磺酸,对甲苯磺酸,柠檬酸,酒石酸,甲烷磺酸等的盐。还包括氨基酸的盐,如精氨酸盐等,以及有机酸如葡糖醛酸或半乳糖醛酸等的盐(参见例如,Berge,S.M.等,″药物盐(Pharmaceutical Salts)″,Journal of Pharmaceutical Science,1977,66,1-19)。一些特殊的本发明的化合物同时含有碱和酸官能度,这就可将该化合物转化成碱或酸加成盐。
所述化合物的中性形式可通过使盐与碱或酸接触并用一般方法分离本发明的化合物来制备。本发明的化合物在某些物理特性上有别于许多盐形式,如在极性溶剂中的溶解度,但出于本发明的目的,其它的盐也可等价与本发明的化合物。
除了盐形式,本发明提供了前药形式的化合物。这里所述化合物的前药是那些在生理条件下容易进行化学变化以提供本发明化合物的化合物。此外,在体外环境下通过化学或生化方法可使前药转化成本发明的化合物。例如,当将前药置于含有合适的酶或化学试剂的透皮贴时它可缓慢转化成本发明的化合物。
本发明的一些化合物可以非溶剂化的形式以及溶剂化的形式存在,包括水合物形式。通常,溶剂化形式等同于非溶剂化形式,并同样包含在本发明的范围之内。本发明的一些化合物可与多晶型或无定形形式存在。通常,所有的物理形式对于本发明的用途都是等价的且包含在本发明的范围之内。
本发明的一些化合物含有不对称碳原子(光学中心)或双键;消旋物,非对映异构体,几何异构体异构体,区域异构体(regioisomer)和单独的异构体(例如,分离的对映异构体)都包含在本发明的范围之内。本发明的化合物可在一个或多个构成该化合物的原子上含有非天然发生的原子同位素。例如,可用放射性同位素标记该化合物,例如用氚(3H)、碘-125(125I)或碳-14(14C)。本发明化合物所有的同位素变异,无论是否是反射性同位素,都包含在本发明的范围之内。
II.概述
本发明来自作为CCR1受体有效拮抗剂的式I的化合物(以及亚属化合物II、III和IV)的发现。在动物试验中进一步确认了其对炎症的拮抗活性,炎症是一种CCR1造成的标志性疾病状态。因此,这里提供的化合物可用于药物组合物,治疗CCR1-介导的疾病的方法,以及在鉴定竞争性CCR1拮抗剂的试验中作为对照。
III.化合物
一方面,本发明提供具有下式的化合物:
或其药学上可接受的盐。
在上式中,下标n是1-2的整数,优选是1。下标m是0-10的整数,受其所连接的哌嗪或高哌嗪环上可有的取代基位置个数的限制。例如,哌嗪衍生物(n是1)可以有0-8个R1基,优选有0-4个R1基,更优选有0、1或2个R1基。
符号Ar1代表任选取代的芳基或杂芳基。优选的芳基是苯基、萘基。优选的杂芳基是那些含有5-10个环原子且其中至少一个是氮原子的基团(如吡啶基、吡嗪基、哒嗪基、嘧啶基、三嗪基、喹啉基、喹喔啉基、嘌呤基等)。每个Ar1环都任选被1-5个R2取代基取代,R2取代基独立选自卤素、-ORc、-OC(O)Rc、-NRcRd、-SRc、-Re、-CN、-NO2、-CO2Rc、-CONRcRd、-C(O)Rc、-OC(O)NRcRd、-NRdC(O)Rc、-NRdC(O)2Re、-NRc-C(O)NRcRd、-NH-C(NH2)=NH、-NReC(NH2)=NH、-NH-C(NH2)=NRe、-NH-C(NHRe)=NH、-S(O)Re、-S(O)2Re、-NRcS(O)2Re、-S(O)2NRcRd、-N3、-X2ORc、-X2OC(O)Rc、-X2NRcRd、-X2SRc、-X2CN、-X2NO2、-X2CO2Rc、-X2CONRcRd、-X2C(O)Rc、-X2OC(O)NRcRd、-X2NRdC(O)Rc、-X2NRdC(O)2Re、-X2NRcC(O)NRcRd、-X2NH-C(NH2)=NH、-X2NReC(NH2)=NH、-X2NH-C(NH2)=NRe、-X2NH-C(NHRe)=NH、-X2S(O)Re、-X2S(O)2Re、-X2NRcS(O)2Re、-X2S(O)2NRcRd、-X2N3,其中,X2选自C1-4亚烷基、C2-4亚烯基、C2-4亚炔基,每个Rc和Rd独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、芳基-C1-4烷基、芳氧基-C1-4烷基,每个Re独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、芳基-C1-4烷基、芳氧基-C1-4烷基,每个Rc、Rd和Re还可任选被1-3个选自OH、O(C1-8烷基)、SH、S(C1-8烷基)、CN、NO2、NH2、NH(C1-8烷基)、N(C1-8烷基)2的成员取代。
符号HAr是任选取代的杂芳基。HAr杂芳基与Ar1杂芳基可以相同或不同。通常,HAr基是单环的,但可以是含有5-10个环原子且至少一个是氮原子的稠合的二环系统。一些优选的杂芳基是含有至少一个氮原子作为环原子的的5-6元环,以及含有稠合到苯环的5元环的稠合环系统,例如吡唑基、咪唑基、三唑基、四唑基、唑基、异唑基、二唑基、噻二唑基、吡咯基、噻唑基、异噻唑基、苯并咪唑基、苯并吡唑基、苯并三唑基的杂芳基、优选的是,稠合的HAr部分(当存在时)通过5元环与分子的其余部分连接。此外,每个HAr基团都被1-5个独立选自卤素、苯基、噻吩基、呋喃基、吡啶基、嘧啶基、吡嗪基、吡地嗪基(pyridizinyl)、吡唑基、咪唑基、噻唑基、唑基、异唑基、异噻唑基、三唑基、四唑基、二唑基、-ORf、-OC(O)Rf、-NRfRg、-SRf、-Rh、-CN、-NO2、-CO2Rf、-CONRfRg、-C(O)Rf、-OC(O)NRfRg、-NRgC(O)Rf、-NRgC(O)2Rh、-NRf-C(O)NRfRg、-NH-C(NH2)=NH、-NRhC(NH2)=NH、-NH-C(NH2)=NRh、-NH-C(NHRh)=NH、-S(O)Rh、-S(O)2Rh、-NRfS(O)2Rh、-S(O)2NRfRg、-NRfS(O)2Rh、-NRfS(O)2NRfRg、-N3、-X3ORf、-X3OC(O)Rf、-X3NRfRg、-X3SRf、-X3CN、-X3NO2、-X3CO2Rf、-X3CONRfRg、-X3C(O)Rf、-X3OC(O)NRfRg、-X3NRgC(O)Rf、-X3NRgC(O)2Rh、-X3NRf-C(O)NRfRg、-X3NH-C(NH2)=NH、-X3NRhC(NH2)-NH、-X3NH-C(NH2)-NRh、-X3NH-C(NHRh=NH、-X3S(O)Rh、-X3S(O)2Rh、-X3NRfS(O)2Rh、-X3S(O)2NRfRb、-X3N3的R3取代基取代,其中,X3选自C1-4亚烷基、C2-4亚烯基、C2-4亚炔基,每个Rf和Rg独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、芳基-C1-4烷基、芳氧基-C1-4烷基,每个Rh独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、芳基-C1-4烷基、芳氧基-C1-4烷基,其中,Rf、Rg和Rh的脂肪族部分还任选被1-3个选自OH、O(C1-8烷基)、SH、S(C1-8烷基)、CN、NO2、NH2、NH(C1-8烷基)、N(C1-8烷基)2的成员取代,其中,任何苯基、噻吩基、呋喃基、吡啶基、嘧啶基、吡嗪基、吡地嗪基(pyridizinyl)、吡唑基、咪唑基、噻唑基、唑基、异唑基、异噻唑基、三唑基、四唑基或二唑基任选被1-3个选自卤素、-ORf、-NRfRg、-Rh、-CN、-NO2、-CO2Rf、-CONRfRg、-C(O)Rf、-X3ORf、-X3NRfRg、-X3NRfS(O)2Rh和-X3S(O)ZNRfRg的取代基取代。最优选的HAr基是取代或未取代的吡唑和取代或未取代的苯并吡唑。优选的,取代或未取代的吡唑通过吡唑环的氮原子连接到分子的其余部分。在那些实施方案中,其中HAr是苯并吡唑环,优选通过稠合环系统吡唑部分上的氮连接到分子的其余部分。
符号L1代表含有1-3个选自C,N,O和S的主链原子的连接基、并任选被1-3个选自卤素、苯基、-ORi、-OC(O)Ri、-NRiRj、-SRi、-Rk、-CN、-NO2、-CO2Ri、-CONRiRj、-C(O)Ri、-OC(O)NRiRj、-NRjC(O)Ri、-NjOC(O)2Rk、-X4ORi、-X4OC(O)Ri,-X4NRiRj、-X4SRi、-X4CN、-X4NO2、-X4CO2Ri、-X4CONRiRj、-X4C(O)Ri、-X4OC(O)NRiRj、-X4NRjC(O)Ri、-X4NRjC(O)2Rk的取代基取代,其中,X4选自C1-4亚烷基、C2-4亚烯基、C2-4亚炔基,每个Ri和Rj独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、芳基-C1-4烷基、芳氧基-C1-4烷基,每个Rk独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、芳基-C1-4烷基、芳氧基-C1-4烷基。在一些优选的实施方案中,连接基是未取代的,而在其它优选的实施方案中,取代基是存在的,这可加快分配进入所选溶剂或进入所选组织。例如,在丙烯链上连接羟基通常可提供在水中有更好溶解性的化合物。优选地,L1选自-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2O-、-CH2NH-、-CH2OCH2-、-CH2NHCH2-。
回到该化合物的哌嗪或高哌嗪部分,每个R1是独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、-CORa、-CO2Ra、-CONRaRb、-NRaCORb、-SO2Ra、-X1CORa、-X1CO2Ra、-X1CONRaRb、-X1NRaCORb、-X1SO2Ra、-X1SO2NRaRb、-X1NRaRb、-X1ORa的取代基,其中,X1选自C1-4亚烷基、C2-4亚烯基、C2-4亚炔基,每个Ra和Rb独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基,其中,每个所述R1取代基的脂肪族部分任选被OH、O(C1-8烷基)、SH、S(C1-8烷基)、CN、NO2、NH2、NH(C1-8烷基)、N(C1-8烷基)2中1-3个成员取代。
除了上述化合物,以及下式的各个化合物,还有可通过商业获得的或文献中已知的,包括:CAS Reg.No.492422-98-7,1-[[4-溴-5-甲基-3-(三氟甲基)-1H-吡唑-1-基]乙酰基]-4-(5-氯-2-甲基苯基)-哌嗪;CAS Reg.No.351986-92-0,1-[[4-氯-5-甲基-3-(三氟甲基)-1H-吡唑-1-基]乙酰基]-4-(4-氟苯基)-哌嗪;CASReg.No.356039-23-1,1-[(3,5-二甲基-4-硝基-1H-吡唑-1-基)乙酰基]-4-(4-氟苯基)-哌嗪;1-(2-{4-硝基-3,5-二甲基-1H-吡唑-1-基}丙酰基)-4-苯基哌嗪;2-(2,4-二硝基-咪唑-1-基)-1-[4-(4-氟苯基)-哌嗪-1-基]-乙酮;2-(2,4-二硝基-咪唑-1-基)-1-(4-苯基-哌嗪-1-基)-乙酮;2-(4-硝基-咪唑-1-基)-1-(4-苯基-哌嗪-1-基)-乙酮;和CAS Reg.No.492992-15-1,3-[3-氟-4-[4-[(1-吡唑基)乙酰基]哌嗪-1-基]苯基]-5-[[(异唑-3-基)氨基]甲基]异唑。
许多优选的实施方案组可在下面列出。
在第一组优选的实施方案中,该化合物可用式I表示,其中,Ar1选自
(i)苯基,被1-5个R2基取代;
(ii)吡啶基,被1-4个R2基取代;和
(iii)嘧啶基,被1-3个R2基取代;
(iv)吡嗪基,被1-3个R2基取代;和
(v)哒嗪基,被1-3个R2基取代;
其中,每个R2独立选自卤素、-ORc、-OC(O)Rc、-NRcRd、-SRc、-Re、-CN、-NO2、-CO2Rc、-CONRcRd、-C(O)Rc、-OC(O)NRcRd、-NRdC(O)Rc、-NRdC(O)2Re、-NRc-C(O)NRcRd、-S(O)Re、-S(O)2Re、-NRcS(O)2Re、-S(O)2NRcRd、-N3,其中,每个Rc和Rd独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Re独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,其中,Rc、Rd和Re的脂肪族部分任选被1-3个选自OH、O(C1-8烷基)、SH、S(C1-8烷基)、CN、NO2、NH2、NH(C1-8烷基)、N(C1-8烷基)2的成员取代。更优选的,Ar1是被1-3个R2基取代的苯基。最优选的Ar1基表示如下:
其中,Hal是F、Cl或Br,各个R独立为C1-6烷基或C3-6环烷基。
进一步优选的是那些实施方案,其中,L1是-CH2-,并任选被苯基、-Rk、-X4ORi、-X4OC(O)Ri、-X4NRiRj、-X4SRi、-X4CN或-X4NO2取代。在进一步优选的实施方案中,HAr选自吡唑基、三唑基、四唑基,其中每个任选被1-3个独立选自卤素、苯基、噻吩基、-ORf、-OC(O)Rf、-NRfRg、-SRf、-Rh、-CN、-NO2、-CO2Rf、-CONRfRg、-C(O)Rf、-OC(O)NRfRg、-NRgC(O)Rf、-NRgC(O)2Rh、-NRf-C(O)NRfRg、-S(O)Rh、-S(O)2Rh、-S(O)2NRfRg、-NRfS(O)2Rh、-NRfS(O)2NRfRg、-N3、-X3ORf、-X3OC(O)Rf、-X3NRfRg、-X3SRf、-X3CN、-X3NO2、-X3CO2Rf、-X3CONRfRg、-X3C(O)Rf、-X3OC(O)NRfRg、-X3NRgC(O)Rf、-X3NRgC(O)2Rh、-X3NRf-C(O)NRfRg、-X3S(O)Rh、-X3S(O)2Rh、-X3NRfS(O)2Rh、-X3S(O)2NRfRg、-X3N3的R3基取代,其中,Rf和Rg各自独立选自H、C1-8烷基、C1-8卤代烷基,每个Rh独立选自C1-8烷基、C1-8卤代烷基。
在进一步优选的实施方案中,下标n是1,m是0-2,Ar1是被1-3个R2基取代的苯基,HAr是被3个R3基取代的吡唑基,L1是-CH2-。在最优选的实施方案中,Ar1选自图1中提供的那些取代的苯基部分。
在第二组优选的实施方案中,所述化合物可用式I表示,其中,Ar1选自:
(i)苯基,被1-5个R2基取代;
(ii)吡啶基,被1-4个R2基取代;和
(iii)嘧啶基,被1-3个R2基取代;
(iv)吡嗪基,被1-3个R2基取代;和
(v)哒嗪基,被1-3个R2基取代;
其中,每个R2独立选自卤素、-X2(O)Rc、-X2OC(O)Rc、-X2NRcRd、-X2SRc、-X2CN、-X2NO2、-X2CO2Rc、-X2CONRcRd、-X2C(O)Rc、-X2OC(O)NRcRd、-X2NRdC(O)Rc、-X2NRdC(O)2Re、-X2NRcC(O)NRcRd、-X2S(O)Re、-X2S(O)2Re、-X2NRcS(O)2Re、-X2S(O)2NReRd、-X2N3,其中,每个Re和Rd独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Re独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基。
在第三组优选的实施方案中,该化合物可用式I表示,其中,HAr选自吡唑基、三唑基、四唑基、苯并咪唑基、苯并吡唑基、苯并三唑基,其中每个任选被1-5个立选自卤素、苯基、噻吩基、-ORf、-CORf、-CO2Rf-CONRfRg、-NO2、-Rh、-CN、-SRf、-S(O)Rh、-S(O)2Rh、-NRfRg的R3基取代,其中,Rf和Rg各自独立选自H、C1-8烷基、C3-6环烷基、C1-8卤代烷基,每个Rh独立选自C1-8烷基、C3-6环烷基、C1-8卤代烷基。
在另一个优选的实施方案组中,该化合物可用式II表示:
或其药学上可接受的盐,其中,R1a、R1b、R1c、R1d、R1e、R1f、R1g和R1h各自独立选自H、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基。其余的基团与上文式I中所述有相同的含义,用其最完整的解释。优选地,Ar1选自苯基、萘基,其各自任选被1-5个取代独立选自卤素、-ORc、-OC(O)Rc、-NRcRd、-SRc、-Re、-CN、-NO2、-CO2Rc、-CONRcRd、-C(O)Rc、-OC(O)NRcRd、-NRdC(O)Rc、-NRdC(O)2Re、-NRc-C(O)NRcRd、-S(O)Re、-S(O)2Re、-NRcS(O)2Re、-S(O)2NRcRd、-N3的R2取代基取代,其中,每个Rc和Rd独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Re独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基。在有关的优选的实施方案中,Ar1选自苯基、萘基,其各自任选被1-5个独立选自卤素、-X2ORc、-X2OC(O)Rc、-X2NRcRd、-X2SRc、-X2CN、-X2NO2、-X2CO2Rc、-X2CONRcRd、-X2C(O)Rc、-X2OC(O)NRcRd、-X2NRdC(O)Rc、-X2NRdC(O)2Re、-X2NRcC(O)NRcRd、-X1S(O)Re、-X2S(O)2Re、-X2NRcS(O)2Re、-X2S(O)2NRcRd、-X2N3的R2取代基取代,其中,每个Rc和Rd独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Re独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基。更优选地,L1选自-CH2-、-CH2CH2-、-CH2O-、-CH2NH-,其各自任选被一个或多个独立选自C1-4烷基、C1-4卤代烷基、苯基的取代基取代。在更优选的实施方案中,HAr选自吡唑基、三唑基、四唑基、苯并吡唑基,其各自任选被1-5个独立选自卤素、苯基、噻吩基、-ORf、-OC(O)Rf、-NRfRg、-SRf、-Rh、-CN、-NO2、-CO2Rf、-CONRfRg、-C(O)Rf、-OC(O)NRfRg、-NRgC(O)Rf、-NRgC(O)2Rh、-NRf-C(O)NRfRg、-S(O)Rh、-S(O)2Rh、-S(O)2NRfRg、-NRfS(O)2Rh、-NRfS(O)2NRfRg、-X3OR、-X3OC(O)Rf、-X3NRfRg、-X3SRf、-X3CN、-X3NO2、-X3CO2Rf、-X3CONRfRg、-X3C(O)Rf、-X3OC(O)NRfRg、-X3NRgC(O)Rf、-X3NRgC(O)2Rh、-X3NRf-C(O)NRfRg、-X3S(O)Rh、-X3S(O)2Rh、-X3NRfS(O)2Rh、-X3S(O)2NRfRg的R3基取代,其中,X3选自C1-4亚烷基、C2-4亚烯基、C2-4亚炔基,每个Rf和Rg独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Rh独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,其中,任何存在的苯基或噻吩基都任选被1-3个选自卤素、-ORf、-NRfRg、-Rh、-CN、-NO2、-CO2Rf、-CONRfRg、-C(O)Rf、-X3ORf、-X3NRfRg、-X3NRfS(O)2Rh、-X3S(O)2NRfRg的取代基取代。再优选地,HAr是吡唑基或苯并吡唑基,其各自任选被1-3个独立选自卤素、苯基、噻吩基、-ORf、-CO2Rf、-CORf、-CONRfRg、-NO2、-Rh、-CN、-SRf、-S(O)Rh、-S(O)2Rh、-NRfRg的R3基取代,其中,每个Rf和Rg独立选自H、C1-8烷基、C1-8卤代烷基,每个Rh独立选自C1-8烷基、C1-8卤代烷基。最优选的,HAr选自图2和3中提供的取代的吡唑部分。
在有关的优选的实施方案中,该化合物可用上述式II表示,其中,Ar1是苯基,任选被1-5个独立选自卤素、-ORc、-OC(O)Rc、-NRcRd、-SRc、-Re、-CN、-NO2、-CO2Rc、-CONRcRd、-C(O)Rc、-OC(O)NRcRd、-NRdC(O)Rc、-NRdC(O)2Re、-NRc-C(O)NRcRd、-S(O)Re、-S(O)Re、-S(O)2NRcRd、-N3的R2取代基取代,其中,每个Rc和Rd独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Re独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,其中,所述取代基的烷基部分任选被一个或两个羟基或氨基取代;L1是-CH2-;HAr是吡唑基或苯并吡唑基,其各自任选被1-3个独立选自卤素、苯基、噻吩基、ORf、CO2Rf、CONRfRg、NO2、Rh、CN、SRf、S(O)Rh、S(O)2Rh、NRfRg的R3基取代,其中,每个Rf和Rg独立选自H、C1-8烷基、C1-8卤代烷基,每个Rh独立选自C1-8烷基、C1-8卤代烷基;每个R1a、R1b、R1c、R1d、R1e、R1f、R1g和R1h独立选自H、C1-4烷基、C1-4卤代烷基,其中,R1a-R1h中至少六个是H。
在另一组优选的实施方案中,所提供的化合物具有式III
或其药学上可接受的盐,其中,下标m是0-2的整数;每个R1选自C1-4烷基、C1-4卤代烷基;R2a、R2h、R2c、R2d和R2e独立选自氢、卤素、-ORc、-OC(O)Rc、-NRcRd、-SRc、-Re、-CN、-NO2、-CO2Rc、-CONRcRd、-C(O)Rc、-OC(O)NRcRd、-NRdC(O)Rc、-NRdC(O)2Re、-NRc-C(O)NRcRd、-S(O)Re、-S(O)2Re、-NRcS(O)2Re、-S(O)2NRcRd、-N3、-X2ORc、-X2OC(O)Rc、-X2NRcRd、-X2SRc、-X2CN、-X2NO2、-X2CO2Rc、-X2CONRcRd、-X2C(O)Rc、-X2OC(O)NRcRd、-X2NRdC(O)Rc、-X2NRdC(O)2Re、-X2NRcC(O)NRcRd、-X2S(O)Re、-X2S(O)2Re、-X2NRcS(O)2Re、-X2S(O)2NRcRd、-X2N3,其中,X2是C1-4亚烷基,每个Rc和Rd独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Re独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Rc、Rd和Re还任选被1-3个选自OH、O(C1-8烷基)、SH、S(C1-8烷基)、CN、NO2、NH2、NH(C1-8烷基)、N(C1-8烷基)2的成员取代;R3a、R3b和R3c各独立选自氢、卤素、苯基、噻吩基、呋喃基、吡啶基、嘧啶基、吡嗪基、吡地嗪基(pyridizinyl)、吡唑基、咪唑基、噻唑基、唑基、异唑基、异噻唑基、三唑基、四唑基、二唑基、-ORf、-OC(O)Rf、-NRfRg、-SRf、-Rh、-CN、-NO2、-CO2Rf、-CONRfRg、-C(O)Rf、-OC(O)NRfRg、-NRgC(O)Rf、-NRgC(O)2Rh、-NRf-C(O)NRfRg、-S(O)Rh、-S(O)2Rh、-NRfS(O)2Rh、-S(O)2NRfRg、-NRfS(O)2Rb、-NRfS(O)2NRfRg、-X3ORf、-X3OC(O)Rf、-X3NRfRg、-X3SRf、-X3CN、-X3NO2、-X3CO2Rf、-X3CONRfRg、-X3C(O)Rf、-X3OC(O)NRfRg、-X3NRgC(O)Rf、-X3NRgC(O)2Rh、-X3NRf-C(O)NRfRg、-X3S(O)Rh、-X3S(O)2Rh、-X3NRfS(O)2Rh、-X3S(O)2NRfRg,其中,X3是C1-4亚烷基,每个Rf和Rg独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Rh独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,其中,任何存在的苯基、噻吩基、呋喃基、吡啶基、嘧啶基、吡嗪基、吡地嗪基(pyridizinyl)、吡唑基、咪唑基、噻唑基、唑基、异唑基、异噻唑基、三唑基、四唑基或二唑基任选被1-3个选自卤素、-ORf、NRfRg、-Rh、-CN、-NO2、-CO2Rf、-CONRfRg、-C(O)Rf、-X3OR、-X3NRfRg、-X3NRfS(O)2Rh、-X3S(O)2NRfRg的取代基取代。
在上述式III的优选的组中,该实施方案的一些基团是特别优选的。在一组特别优选的实施方案中,下标m是0或1;至少R2a和R2e之一是氢。更加优选的,R3a、R3b和R3c之一选自卤素或C1-4卤代烷基。再优选的,R2d是氢,且至少R3a、R3b和R3c之二选自卤素或C1-4卤代烷基,且其余都不是氢。在相关的优选的实施方案中,m是0或1且至少R2a或R2e之一是氢,R2d是氢,R2c选自F、Cl、Br、CN、NO2、CO2CH3、C(O)CH3、S(O)2CH3S(O)2CH3,且至少R3a、R3b和R3c之二选自氢和C1-4卤代烷基,其余不是氢。在另一个特别优选的实施方案的组中,下标m是0或1;R2b和R2e都是氢。更加优选的,至少R3a、R3b和R3c之一选自卤素或C1-4卤代烷基。再优选的,至少R3a、R3b和R3c之一选自卤素或C1-4卤代烷基、R3a、R3b和R3c的其余部分不是氢。在另一组特别优选的实施方案中,下标m是0或1;R2b和R2a都是氢。更加优选的,至少R3a、R3b和R3c之一选自卤素或C1-4卤代烷基。再优选的,至少R3a、R3b和R3c之一选自卤素或C1-4卤代烷基、R3a、R3b和R3c的其余部分不是氢。
其它优选的式III的组是:
首先看式IIIa的化合物,R3b优选是卤素、硝基或氰基、更加优选是卤素或最优选是氯或溴;R3c优选C1-6烷基、C1-6卤代烷基、C3-6环烷基;R2c是卤素、R2b是-ORc或Re,其中,Rc选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、Re选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Rc和Re还可任选被1-3个选自OH、O(C1-8烷基)、SH、S(C1-8烷基)、CN、NO2、NH2、NH(C1-8烷基)、N(C1-8烷基)2的成员取代。
再看式IIIb的化合物,R3b优选为卤素,硝基或氰基、更优选是卤素,最优选是氯或溴;R3a优选为C1-6烷基、C1-6卤代烷基或C3-6环烷基;R2c优选为卤素,R2b优选为-ORc或Re,其中,Rc选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、Re选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Re和Re还任选被1-3个选自OH、O(C1-8烷基)、SH、S(C1-8烷基)、CN、NO2、NH2、NH(C1-8烷基)、N(C1-8烷基)2的成员取代。
对于式IIIc的化合物,R3a选自NH2、CF3、SCH3、Ph、噻吩基;R3b是氯或溴;R3c优选为C1-6烷基、C1-6卤代烷基或C3-6环烷基;R2c是氢,卤素,氰基或硝基;R2b选自氢、卤素、-ORc、-OC(O)Rc、-NRcRd、-SRc、-Re、-CO2Rc、-CONRcRd、-C(O)Rc、-S(O)Rc、-S(O)2Re、-X2ORc、-X2OC(O)Rc、-X2NRcRd、-X2SRc、-X2CO2Rc、-X2CONRcRd、-X2C(O)Rc、-X2OC(O)NRcRd、-C(O)Rc、-X2NRdC(O)2Re、-X2NRcC(O)NRcRd、-X2S(O)Re、-X2S(O)2Re、-X2NRcS(O)2Re、-X2S(OO2NRcRd、-X2N3,其中,X2是C1-4亚烷基,每个Rc和Rd独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Re独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Rc、Rd和Re还任选被1-3个选自OH、O(C1-8烷基)、SH、S(C1-8烷基)、CN、NO2、NH2、NH(C1-8烷基)、N(C1-8烷基)2的成员取代。在最优选的实施方案中,R2c是卤素、氰基或硝基;R2b是R3或-ORc;R3a选自NH2、CF3、SCH3、Ph、噻吩基;R3b是氯或溴;R3c选自C1-6烷基、C3-6环烷基。
在相关的优选的实施方案中,提供了式IIIc的化合物,其中,R3c选自NH2、CF3、SCH3、Ph、噻吩基;R3b是氯或溴;R3a优选为C1-6烷基、C1-6卤代烷基或C3-6环烷基;R2c是氢,卤素,氰基或硝基、优选卤素;R2b选自氢、卤素、-ORc、-OC(O)ROC、-NRcRd、-SRc、-Re、-CO2Rc、-CONRcRd、-C(O)Rc、-S(O)Re、-S(O)2Re、-X2ORc、-X2OC(O)Rc、-X2NRcRd、-X2SRc、-X2CO2Rc、-X2CONRcRd、-X2C(O)Rc、-X2OC(O)NRcRd、-X2NRdC(O)Rc、-X2NRdC(O)2Re、-X2NRcC(O)NRcRd、-X2S(O)Re、-X2S(O)2Re、-X2NRcS(O)2Re、-X2S(O)2NRcRd、-X2N3,其中,X2是C1-4亚烷基,每个Rc和Rd独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Re独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Rc、Rd和Re还任选被1-3个选自OH、O(C1-8烷基)、SH、S(C1-8烷基)、CN、NO2、NH2、NH(C1-8烷基)、N(C1-8烷基)2的成员取代。在最优选的实施方案中,R2c是卤素、氰基或硝基;R2b是Re或-ORc;R3a选自C1-6烷基、C3-6环烷基;R3c选自NH2、CF3、SCH3、Ph、噻吩基;R3b是氯或溴。
对于式IIId的化合物,R3a选自NH2、CF3、SCH3、Ph、噻吩基;R3b是氯或溴;R3优选为C1-6烷基、C1-6卤代烷基或C3-6环烷基;R2a优选不是氢,并选自卤素、-ORc、-OC(O)ROC、-NRcRd、-SRc、-Re、-CO2Rc、-CONRcRd、-C(O)Rc、-S(O)Re、-S(O)2Re、-X2ORc、-X2OC(O)Rc、-X2NRcRd、-X2SRc、-X2CO2Rc、-X2CONRcRd、-X2C(O)Rc、-X2OC(O)NRcRd、-X2NRdC(O)Rc、-X2NRdC(O)2Re、-X2NRcC(O)NRcRd、-X2S(O)Re、-X2S(O)2Re、-X2NRcS(O)2Re、-X2S(O)2NRcRd、-X2N3;R2c是氢,卤素,氰基或硝基、优选卤素;R2d选自氢、卤素、-ORc、-OC(O)Rc、-NRcRd、-SRc、-Re、-CO2Rc、-CONRcRd、-C(O)Rc、-S(O)Re、-S(O)Re、-X2ORc、-X2OC(O)Rc、-X2NRcRd、-X2SRc、-X2CO2Rc、-X2CONRcRd、-X2C(O)Rc、-X2OC(O)NRcRd、-X2NRdC(O)Rc、-X2NRdC(O)2Re、-X2NRcC(O)NRcRd、-X2S(O)Re、-X2S(O)2Re、-X2NRcS(O)2Re、-X2S(O)2NRcRd、-X2N3,其中,各个X2是C1-4亚烷基,每个Rc和Rd独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Re独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Rc、Rd和Re还任选被1-3个选自OH、O(C1-8烷基)、SH、S(C1-8烷基)、CN、NO2、NH2、NH(C1-8烷基)、N(C1-8烷基)2的成员取代;R2a和R2d中最多一个是氢。优选地,R2a和R2d皆不是氢。在最优选的实施方案中,R2a不是氢;R2c是卤素、氰基或硝基;R2d是Re或-ORc;R3a选自C1-6烷基、C3-6环烷基;R3b是氯或溴;R3c选自NH2、CF3、SCH3、Ph、噻吩基。
在相关的优选的实施方案中,提供了式IIId的化合物,其中,R3c选自NH2、CF3、SCH3、Ph、噻吩基;R3b是氯或溴;R3a优选为C1-6烷基、C1-6卤代烷基或C3-6环烷基;R2a是氢,卤素、-ORc、-OC(O)Rc、-NRcRd、-SRc、-Re、-CO2Rc、-CONRcRd、-C(O)Rc、-S(O)Re、-S(O)2Re、-X2ORc、-X2OC(O)Rc、-X2NRcRd、-X2SRc、-X2CO2Rc、-X2CONRcRd、-X2C(O)Rc、-X2OC(O)NRcRd、-X2NRdC(O)Rc、-X2NRdC(O)2Re、-X2NRcC(O)NRcRd、-X2S(O)Re、-X2S(O)2Re、-X2NRcS(O)2Re、-X2S(O)2NRcRd、-X2N3;R2c是氢,卤素,氰基或硝基;R2d选自氢、卤素、-ORc、-OC(O)Re、-NRcRd、-SRc、-Re、-CO2Re、-CONRcRd、-C(O)Rc、-S(O)Re、-S(O)2Re、-X2ORc、-X2OC(O)Rc、-X2NRcRd、-X2SRc、-X2CO2Rc、-X2CONRcRd、-X2C(O)Rc、-X2OC(O)NRcRd-X2NRdC(O)Rc、-X2NRdC(O)2Re、-XNRcC(O)NRcRd、-X2S(O)Re、-X2S(O)2Re、-X2NRcS(O)2Re、-X2S(O)2NRcRd、-X2N3,其中,各个X2是C1-4亚烷基,每个Rc和Rd独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Re独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Re、Rd和Re还任选被1-3个选自OH、O(C1-8烷基)、SH、S(C1-8烷基)、CN、NO2、NH2、NH(C1-8烷基)、N(C1-8烷基)2的成员取代;R2a和R2d中最多一个是氢。优选R2a和R2d都不是氢。在最优选的实施方案中,R2a不是氢;R2c是卤素、氰基或硝基;R2d是Re或-ORc;R3a选自NH2、CF3、SCH3、Ph、噻吩基;R3b是氯或溴;R3c选自C1-6烷基、C3-6环烷基。
在其它优选的实施方案的组中,所述化合物选自式IVa-IVe:
其中,R1和下标m有以上式III中提供的含义,每个R2a、R2b、R2c和R2d是独立选自氢、卤素、-ORc、-OC(O)Rc、-NRcRd、-SRc、-Re、-CN、-NO2、-CO2Rc、-CONRcRd、-C(O)Rc、-OC(O)NRcRd、-NRdC(O)Rc、-NRdC(O)2Re、-NRc-C(O)NRcRd、-NH-C(NH2)=NH、-NReC(NH2)=NH、-NH-C(NH2)=NRe、-NH-C(NHRe)=NH、-S(O)Re、-S(O)2Re、-S(O)2NRcRd、-NRcS(O)2Re、-NRcS(O)2NRcRd、-N3、-X2ORc、-X2OC(O)Rc、-X2NRcRd、-X2SRc、-X2CN、-X2NO2、-X2CO2Rc、-X2CONRcRd、-X2C(O)Rc、-X2OC(O)NRcRd、-X2NRdC(O)Rc、-X2NRdC(O)2Re、-X2NRcC(O)NRcRd、-X2NH-C(NH2)=NH、-X2NRdC(NH2)=NH、-X2NH-C(NH2)=NRe、-X2NH-C(NHRe)=NH、-X2S(O)Re、-X2S(O)2Re、-X2S(O)2NRcRd、-X2NRcS(O)2Re、-X1N3、芳基、杂芳基的取代基,其中,X2、Rc、Rd和Re具有上述式I的化合物所提供的含义。类似地,各个R3a、R3b和R3c代表独立选自氢、卤素、苯基、噻吩基、呋喃基、吡啶基、嘧啶基、吡嗪基、吡地嗪基(pyridizinyl)、吡唑基、咪唑基、噻唑基、唑基、异唑基、异噻唑基、三唑基、四唑基、二唑基、-ORf、-OC(O)Rf、-NRfRg、-SRf、-Rh、-CN、-NO2、-CO2Rf、-CONRfRg、-C(O)Rf、-OC(O)NRfRg、-NRgC(O)Rf、-NRgC(O)2Rh、-NRf-C(O)NRfRg、-NH-C(NH2)=NH、-NRhC(NH2)=NH、-NH-C(NH2)=NRh、-NH-C(NHRh)=NH、-S(O)Rh、-S(O)2Rh、-S(O)2NRfR8、-NRfS(O)2Rh、-NRfS(O)2NRfRg、-N3、-X3ORf、-X3OC(L)Rf、-X3NRfRg、-X3SRf、-X3CN、-X3NO2、-X3CO2Rf、-X3CONRfRg、-X3C(O)Rf、-X3OC(O)NRfRg、-X3NRgC(O)Rf、-X3NRgC(O)2Rh、-X3NRf-(O)NRfRg、-X3NH-C(NH2)=NH、-X3NRhC(NH2)=NH、-X3NH-C(NH2)=NRh、-X3NH-C(NHRh)=NH、-X3S(O)Rh、-X3S(O)2Rh、-X3S(O)2NRfRg、-X3NRfS(O)2Rh、-X3N3的取代基,其中,X3、Rf、Rg和Rh具有对式I的化合物提供的含义,且其中R3e、R3b和R3c中最多有两个是氢,优选R3a、R3b和R3c中最多有一个是氢,再优选R3a、R3b和R3c都不是氢。
对于式IVa的化合物,在一组特别优选的实施方案中,至少R3a、R3b和R3c之一选自卤素或C1-4卤代烷基。更加优选的,至少R2b和R2d之一是氢,且至少R3a、R3b和R3c之二选自卤素或C1-4卤代烷基。在相关的优选的实施方案中,R2c选自F、Cl、Br、CN、NO2、CO2CH3、C(O)CH3、S(O)2CH3S(O)2CH3,且至少R3a、R3b和R3c之二选自卤素或C1-4卤代烷基,且其余部分不是氢。
类似地,一些式IVb的化合物是优选的。特别优选的式IVb的化合物中,至少R3a、R3b和R3c之一选自卤素或C1-4卤代烷基。再优选的,至少R2b和R2d之一是氢且至少R2a、R3b和R3c之二选自卤素或C1-4卤代烷基。在相关的优选的实施方案中,R2c选自F、Cl、Br、CN、NO2、CO2CH3、C(O)CH3、S(O)2CH3S(O)2CH3且至少R3a、R3b和R3c之二选自卤素或C1-4卤代烷基,且其余部分不是氢。
然后讨论式IVc的化合物,优选是实施方案中,至少R2a、R2c和R2d之一,优选是R2c选自F、Cl、Br、CN、NO2、CO2CH3、C(O)CH3、S(O)2CH3S(O)2CH3;至少R3a、R3b和R3c之二选自卤素或C1-4卤代烷基,且其余部分不是氢。在其它优选的实施方案中,R2c和R2d之一选自F、Cl、Br、CN、NO2、CO2CH3、C(O)CH3、S(O)2CH3S(O)2CH3,其它是芳基或杂芳基,例如,苯基、噻吩基、呋喃基、唑基、异唑基、噻唑基、异噻唑基,且至少R3a、R3b和R3c之二选自卤素或C1-4卤代烷基,其余部分不是氢。
对于式IVd的化合物,优选的实施方案中,至少R2a、R2b和R2d之一选自F、Cl、Br、CN、NO2、CO2CH3、C(O)CH3、S(O)2CH3S(O)2CH3,且至少R3a、R3b和R3c之二选自卤素或C1-4卤代烷基,其余部分不是氢。在其它优选的实施方案中,R2b和R2d之一选自F、Cl、Br、CN、NO2、CO2CH3、C(O)CH3、S(O)2CH3S(O)2CH3且其它为芳基或杂芳基,例如,苯基、噻吩基、呋喃基、唑基、异唑基、噻唑基、异噻唑基,且至少R3a、R3b和R3c之一选自卤素或C1-4卤代烷基,其余部分不是氢。
对于式IVe的化合物,优选的实施方案中,至少R2a、R2b和R2c之一选自F、Cl、Br、CN、NO2、CO2CH3、C(O)CH3、S(O)2CH3S(O)2CH3,且至少R3a、R3b和R3c之二选自卤素或C1-4卤代烷基,其余部分不是氢。在其它优选的实施方案中,R2b和R2c之一选自F、Cl、Br、CN、NO2、CO2CH3、C(O)CH3、S(O)2CH3S(O)2CH3,且其它是芳基或杂芳基,例如,苯基、噻吩基、呋喃基、唑基、异唑基、噻唑基、异噻唑基,且至少R3a、R3b和R3c之二选自卤素或C1-4卤代烷基,其余部分不是氢。
在另一个优选的实施方案的组中,所述化合物选自式IVf-IVi:
其中,R1和下标m具有上面式III所提供的含义,每个R2a、R2b、R2c、R2d、R3a、R3b和R3c具有上面式IVa-IVe所提供的含义。此外,R2e代表的取代基选自为以上式IVa-IVe中R2a所提供的基团。
再在其它实施方案中,提供了具有式Va和Vb的化合物:
其中,各个R1,下标m、R2a、R2b、R2c、R2d、R3a、R3b和R3具有上面式IVa-IVe所提供的含义。
IV.药物组合物
除了上面提供的化合物,在人类和动物中调节CCR1活性的组合物通常将含有一种药物载体或稀释剂。
术语″组合物″在这里包含一种含有特定量的特定组分的产品,以及任何直接或间接来自特定量的特定组分的组合的产品。″药学上可接受的″是指载体,稀释剂或赋形剂必需与制剂的其它组成成分相配伍,且对其接受者无害。
用来给予本发明化合物的药物组合物通常为单位剂型,并可用药物和药物输递熟知的任何方法制备。所有方法都包括使活性成分与由一种或多种附加成分构成的载体相结合的步骤。简言之,药物组合物是将活性成分与液体载体或细分的固体载体或这两者均匀紧密地混合,然后,如果需要,将产品压制成所需形状制成的。在药物组合物中,活性化合物的量足以对疾病进程或疾病症状产生所需效果。
含有活性成分的药物组合物可以是适合口服使用的形式,例如可以是片剂,含片,锭剂,水性或油性悬液,可分散的粉末或颗粒,乳剂或自乳化剂(如美国专利申请20020012680所述),硬或软胶囊,糖浆剂,酏剂,溶液剂,含片,口服凝胶,咀嚼凝胶,可咀嚼片剂,泡腾粉末和泡腾片。供口服使用的组合物可用药物组合物制造领域的已知的方法制造,这种组合物可含有一种或多种选自甜味剂,芳香剂,染色剂,抗氧化剂和防腐剂的试剂以得到外观良好且可口的药物制剂。片剂中含有与适合制造片剂的无毒的药学上可接受的赋形剂混合的活性成分。这些赋形剂可以是,例如,惰性稀释剂,如纤维素,二氧化硅,氧化铝,碳酸钙,碳酸钠,葡萄糖,甘露醇,山梨糖醇,乳糖,磷酸钙或硫酸钠;造粒和分散剂,例如玉米淀粉或褐藻酸;粘合剂,例如PVP,纤维素,PEG,淀粉,明胶或阿拉伯胶,以及润滑剂,例如硬脂酸镁,硬脂酸或滑石。片剂可以是未包衣的,或可用此领域已知的技术完全或部分包衣,以延迟其在胃肠道的降解和吸收从而在一段较长的时期提供持续的活性。例如,可使用甘油单硬脂酸酯或甘油二硬脂酸酯等延时物质。也可用美国专利申请Nos.4,256,108;4,166,452和4,265,874中描述的方法进行包衣,以形成供控制释放的渗透性治疗片剂。
供口服使用的片剂可以硬明胶胶囊的形式存在,其中,所述活性成分与惰性固体稀释剂如碳酸钙,磷酸钙或高岭土混合物,或者可以是软明胶胶囊的形式,其中活性成分与水性或油性介质如花生油,液体石蜡或橄榄油混合。此外,可用不与水混溶的成分如油制造乳剂,并用表面活性剂如单-二甘油酯,PEG酯等使其稳定。
含水悬液含有与适合制造含水悬液的赋形剂混合的活性物质。这种赋形剂是悬浮剂,例如羧甲基纤维素钠,甲基纤维素,羟丙基甲基纤维素,藻酸钠,聚乙烯-吡咯烷酮,黄蓍胶和阿拉伯胶;分散剂或润湿剂可以是天然产生的磷脂,例如卵磷脂,或烯化氧与脂肪酸的缩合产物,例如聚氧乙烯硬脂酸酯,或环氧乙烷与长链脂肪醇的缩合产物,如十七烷基乙烯氧基十六醇,或环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物,例如聚乙烯山梨聚糖单油酸酯。含水悬液还可含有一种或多种防腐剂,例如乙基-,或正丙基-,对羟基苯甲酸酯,一种或多种芳香剂,以及一种或多种甜味剂,如蔗糖或糖精。
油性悬液可将活性成分悬浮于植物油如花生油,橄榄油,芝麻油或椰子油,或矿物油如液体石蜡中制成。所述油性悬液可含有增稠剂,如蜂蜡,固体石蜡或鲸腊醇。甜味剂,如上述那些,以及芳香剂,以制造具有良好外观和味道的制剂。还可加入抗氧化剂如抗坏血酸来使这些组合物反防腐。
可分散的粉末和颗粒可通过加水形成含水悬液,其中的活性成分与分散剂或润湿剂,悬浮剂以及一种或多种防腐剂混合。合适的分散剂或润湿剂以及悬浮剂的例子已在上面列出。还可含有其它的赋形剂,如甜味剂,芳香剂和染色剂。
本发明的药物组合物还可以是水包油乳剂的形式。所述油相可以是植物油,例如橄榄油或花生油,或矿物油,例如液体石蜡,或它们的混合物。合适的乳化剂可以是天然产生的树胶,例如阿拉伯胶或黄蓍胶,天然产生的磷脂,如大豆磷脂,卵磷脂,以及衍生自脂肪酸和己糖醇苷的酯或偏酯,例如山梨聚糖单油酸酯,以及所述偏酯和环氧乙烷的缩合产物,例如聚氧乙烯山梨聚糖单油酸酯。所述乳剂中也可含有甜味剂和芳香剂。
可用甜味剂,例如甘油,丙二醇,山梨糖醇或蔗糖来制备糖浆剂和酏剂。这种制剂可含有润滑剂,防腐剂和芳香剂以及染色剂。可与例如环糊精,PEG和表面活性剂混合来制备口服溶液。
所述药物组合物还可以是无菌可注射的含水或含油悬液的形式。可按照此领域已知的方法,用合适的分散剂或润湿剂以及悬浮剂(如上所述)来制备这种悬液。所述无菌可注射制品还可以是无菌可注射的溶液或悬液,其含在无毒的肠道外注射物可接受的稀释剂或溶剂中,例如1,3-丁二醇。可以使用的可接受的载体和溶剂有水,林格溶液和等渗的氯化钠溶液。此外,无菌的不挥发的油通常也可用作溶剂或悬浮介质。出于此目的,任何品牌的不挥发的油都可使用,其中包括合成的单-或二甘油酯。此外,脂肪酸如油酸也可用于可注射的制品。
本发明的化合物还可以直肠施用的栓剂的形式给予。可将药物与合适的非刺激性赋形剂混合来制备这些组合物,所述赋形剂在常温下是固体但在直肠温度下是液体,从而将在制成中熔化以释放药物。这样的物质包括可可脂和聚乙烯醇。此外,可以溶液或软膏剂的方式通过眼的途径施用这些混合物。此外,可通过离子渗透透皮贴等的方式透皮输递所述化合物。当具体使用使,可使用含有本发明化合物的霜剂,软膏剂,凝胶剂,溶液剂或悬液剂等。局部施用在这里包括使用口洗剂和含漱剂。
V.治疗CCR1介导的疾病的方法
在另一方面,本发明提供了通过给患有这种疾病或病症的受试者施用治疗有效量的上述式I的化合物来治疗CCR1-介导的病症或疾病的方法。″受试者″在这里包括动物如哺乳动物,其中包括但不限于灵长类(如人类),牛,绵羊,山羊,马,狗,猫,兔,大鼠,小鼠等。
在哺乳动物如人的许多细胞类型中,CCR1为干扰或促进特定的免疫细胞功能提供了靶点,一般的说,是与CCR1的表达有关的方面。出于治疗目的,抑制CCR1的化合物对于调节单核细胞,巨噬细胞,淋巴细胞,粒细胞,NK细胞,肥大细胞,树突细胞和某些免疫衍生细胞(如破骨细胞)的功能特别有效。因此,本发明涉及可用于预防和/或治疗各种炎性和免疫调节紊乱和疾病的化合物(参见Szeki等,CurrentPharmaceutical Design 9:1201-1208(2003))。
例如,可施用本发明的抑制CCR1一种或多种功能的化合物来抑制(即减轻或预防)与免疫失调有关的炎症或细胞浸润。其结果是,一种或多种炎症过程,如白细胞渗出或浸润,趋化性,胞吐作用(例如,酶,组胺)或炎性介质的释放,可被抑制。例如,单核细胞向炎性部位的浸润(例如关节炎中受累的关节,或进入MS的CNS)可用本发明的方法抑制。
类似地,可促进CCR1一种或多种功能的本发明的化合物被施用以刺激(诱导或增强)炎性应答,如白细胞渗出,趋化性,胞吐作用(例如,酶,组胺)或炎性介质的释放,从而可有益刺激炎性进程。例如,单核细胞可被聚集以抵抗细菌感染。
可用本发明的方法治疗和炎症,免疫紊乱和感染有关的疾病和病症。在一个优选的实施方案中,在这些疾病或病症中,单核细胞,巨噬细胞,淋巴细胞,粒细胞,NK细胞,肥大细胞,树突细胞或某些免疫衍生细胞(例如破骨细胞)等免疫细胞的活动将被抑制或促进,以调节炎性或自身免疫应答。
在一组实施方案中,可用CCR1功能调节剂来治疗疾病或病症,其中包括人类或其它物种的慢性疾病。这些疾病或病症包括:(1)过敏疾病,如全身性过敏反应或超敏反应,药物过敏,虫蜇过敏和食物过敏,(2)炎性肠病,如Crohn病,溃疡性结肠炎,回肠炎和小肠炎,(3)阴道炎,(4)银屑病和炎性皮肤病,如皮炎,湿疹,特应性皮炎,应变性接触性皮炎,荨麻疹和骚痒症,(5)血管炎,(6)脊椎关节病,(7)硬皮病,(8)哮喘和呼吸应变性疾病,如应变性哮喘,应变性鼻炎,超敏性肺病等,(9)自身免疫疾病,如纤维肌痛,硬皮病,强直性脊柱炎,幼年型类类风湿性关节炎,Still病,多关节幼年型类类风湿性关节炎,少关节幼年型类类风湿性关节炎,风湿性多肌痛,类风湿性关节炎,银屑病关节炎,骨关节炎,多发性关节炎,多发性硬化,系统性红斑狼疮,I型糖尿病,II型糖尿病,肾小球肾炎等,(10)移植物排斥(包括同种异体移植物排斥和移植物-宿主疾病),和(11)其它疾病,其中不需要的炎性应答或免疫紊乱将被抑制,如神经变性疾病(例如,阿耳茨海默病),脑炎,脑膜炎,肝炎,肾炎,败血病,结节病,应变性结膜炎,耳炎,慢性阻塞性肺疾患,窦炎,Behcet综合征和痛风,以及(12)免疫介导的食物过敏,如Celiac病。
在另一组实施方案中,疾病和病症可用CCR1功能的调节剂治疗。可用CCR1功能的调节剂治疗的疾病的例子包括癌症,心血管疾病,血管发生或新血管形成起作用的疾病(肿瘤病,视网膜病和黄斑变性),感染疾病(病毒感染,例如HIV感染和细菌感染)以及免疫抑制疾病,如器官移植和皮肤移植。术语″器官移植″包括骨髓移植和实体器官(例如肾脏,肝脏,肺脏,心脏,胰脏或其组合)移植。
因此,本发明的化合物可有效预防和治疗各种炎性和免疫调节紊乱和疾病。
更加要被治疗的疾病和受试者的状况,本发明的化合物可通过以下途径施用:口服,肠道外(例如肌肉内,腹膜内,静脉内,ICV,池内注射或输注,皮下注射,或植入),通过吸入喷雾,经鼻,阴道,直肠,舌下或局部途径,并且可被单独或混合制成合适的单位剂型制剂,其中含有常规的无毒的药学上可接受的载体,佐剂以及适合各种用药途径的运载体。
在治疗或预防需要对趋化因子受体进行调节的病症时,合适的剂量水平通常为每天每千克体重约0.001-100mg,可以单剂量或多剂量施用。优选地,剂量水平为每天约0.01-25mg/kg;更优选每天约0.05-10mg/kg。合适的剂量水平可以是每天约0.01-25mg/kg,每天约0.05-10mg/kg,或每天约0.1-5mg/kg。在此范围内,剂量可以是每天0.005-0.05,0.05-0.5或0.5-5.0mg/kg。对于口服给药,该组合物优选以片剂的形式提供,其中含有1.0-1000毫克活性成分,优选含有1.0,5.0,10.0,15.0.20.0,25.0,50.0,75.0,100.0,150.0,200.0,250.0,300.0,400.0,500.0,600.0,750.0,800.0,900.0和1000.0毫克活性成分,作为可调节被治疗患者症状的剂量。该化合物可每天施用1-4次,优选每天一次或两次。
然而,应该理解的是,对任何特殊患者的特定剂量水平和用药频率是可变的,这将取决于各种因素,其中包括所用特定化合物的活性,该化合物的代谢稳定性和作用时间,受试者的年龄,体重,遗传特征,健康状况,性别以及饮食情况,以及用药模式和时间,排泄率,药物组成,以及接受治疗的受试者的病症的严重程度。
可用本发明的化合物,组合物和方法来治疗或预防与炎症,免疫紊乱,感染和癌症有关的疾病和病症。
本发明的化合物和组合物可与其它具有预防和治疗相关症状或疾病功效的化合物或组合物配伍,所述相关症状或疾病如炎性或自身免疫紊乱,症状和疾病,其中包括炎性肠病,类风湿性关节炎,骨关节炎,银屑病关节炎,多关节性关节炎,多发性硬化,应变性疾病,银屑病,特应性皮炎和哮喘以及上述病变。
例如,在炎症或自身免疫性疾病或例如骨丢失相关关节炎的治疗或预防中,本发明的化合物和组合物可与一种消炎药或镇痛药结合使用,这些药物如5-脂氧合酶抑制剂,环加氧酶抑制剂如环加氧酶-2抑制剂,白介素抑制剂如白介素-1抑制剂,NMDA拮抗剂,氮氧化物抑制剂或氮氧化物合成抑制剂,非甾族消炎药,或细胞因子抑制性消炎药,例如可以和醋氨酚,阿斯匹林,可待因,芬太尼,布洛芬,消炎痛,酮咯酸,吗啡,萘普生,非那西丁,吡罗昔康,甾族镇痛药,舒芬太尼,sunlindac,替尼达帕等化合物配伍。类似地,本发明的化合物和组合物可与以下药物一起施用:上述镇痛药;增强剂如咖啡因,H2拮抗剂(例如雷尼替丁),二甲硅油,铝或镁的氢氧化物;解充血药如苯福林,苯丙醇胺,伪麻黄碱,羟甲喹啉,氢可酮,萘唑啉,丁苄唑啉,环己丙甲胺或左旋脱氧麻黄碱;镇咳药如可待因,氢可酮,卡拉美芬,咳必清或右美沙芬;利尿药;以及有或没有镇定作用的抗组胺药。
类似地,本发明的化合物和组合物可与其它药物联合使用,这些药物被用于治疗,预防,移植或减轻本发明的的化合物和组合物对其有效的疾病或病症。所述其它药物可以其通常使用的量和途径与本发明的化合物或组合物同时或相继施用。当本发明的化合物或组合物与一种或多种其它药物同时使用时,含有除本发明的化合物和组合物外的其它药物的药物组合物是优选的。因此,本发明的药物组合物包括那些除本发明的化合物或组合物外还含有一种或多种其它活性成分或治疗剂的药物组合物。可与本发明的化合物或组合物配伍使用的其它治疗剂的例子包括但不限于:(a)VLA-4拮抗剂,(b)皮质甾类,如倍氯米松,甲泼尼松,倍他米松,强的松,prenisolone,地塞米松,氟替卡松,氢化可的松,布地缩松,去炎松,沙美特罗,沙美特罗,沙丁胺醇,;(c)免疫抑制剂,如环孢菌素(环孢菌素A,Sandimmune,Neoral),他克罗司(FK-506,Prograf),雷帕霉素(西罗莫司,Rapamune)和其它FK-506型的免疫抑制剂,以及麦考酚酯,例如霉酚酸酯(CellCept);(d)抗组胺药(H1-组胺拮抗剂),如溴屈米(bromophenir胺),氯屈米,右氯屈米(dexchloiphenir胺),曲普利啶,氯马斯汀,苯海拉明,二苯拉林,曲吡那敏,羟嗪,甲地拉嗪,异丙嗪,阿利马嗪,阿扎他定,塞庚啶,安它唑啉,非尼拉敏,美吡拉敏,阿司咪唑,特非那定,氯雷他定,西替利嗪,非索非那定,脱碳乙氧基氯雷他定等;(e)非甾类抗哮喘药(例如特布他林,奥西那林,非诺特罗,乙基异丙肾上腺素,沙丁胺醇,比托特罗和吡布特罗),茶碱,色甘酸钠,阿托品,异丙托溴铵,白三烯拮抗剂(例如扎鲁司特,孟鲁司特,普仑司特,伊拉司特,泊比司特和SKB-106,203),白三烯生物合成抑制剂(齐留通,BAY-1005);(f)非甾类消炎药(NSAID),如丙酸衍生物(例如阿明洛芬,苯洛芬,布氯酸,卡洛芬,芬布芬,非诺洛芬,氟洛芬,氟比洛芬,布洛芬,吲哚洛芬,酮洛芬,咪洛芬,萘普生,奥沙普秦,吡洛芬,普拉洛芬,舒洛芬,噻洛芬酸和硫洛芬),乙酸衍生物(例如消炎痛,阿西美辛,阿氯芬酸,环氯茚酸,双氯芬酸,芬氯酸,芬克洛酸,芬替酸,呋罗芬酸,异丁芬酸,伊索克酸,oxpinac,舒林酸,硫平酸,托美丁,齐多美辛和佐美酸),灭酸衍生物(例如氟芬那酸,甲氯芬那酸,甲芬那酸,尼氟酸和托芬那酸),联苯羧酸衍生物(例如二氟尼柳和氟苯柳),昔康类(例如伊索昔康,吡罗昔康,舒多昔康和替诺昔康),水杨酸盐类(例如,乙酰水杨酸和柳氮磺吡啶)和吡唑啉酮类(例如阿扎丙宗,bezpiperylon,非普拉宗,莫非布宗,羟布宗和保泰松);(g)环加氧酶-2(COX-2)抑制剂,如塞来昔布(Celebrex和罗非昔布(Vioxx);(h)IV型磷酸二酯酶抑制剂(PDE IV);(i)金化合物,如金诺芬和硫代葡萄糖金,(j)依那西普(Enbrel),(k)抗体治疗,如orthoclone(OKT3),达(克)珠单抗(Zenapax),巴利昔单抗(Simulect)和英夫利昔单抗(Remicade),(l)其它趋化因子受体的拮抗剂,尤其是CCR5,CXCR2,CXCR3,CCR2,CCR3,CCR4,CCR7,CX3CR1和CXCR6;(m)润滑剂或软化剂,如凡士林和羊毛脂,(n)角质软化剂(例如他佐罗汀),(o)维生素D3衍生物,例如卡泊三烯或卡泊三醇(Dovonex),(p)PUVA,(q)地蒽酚(Dri throcreme),(r)阿维A酯(Tegi son)和异维A酸和(s)多发性硬化治疗剂,如干扰素β-1β(Betaseron),干扰素(β-1α(Avonex),硫唑嘌呤(Imurek,Imuran),盐酸格拉默(Capoxone),糖皮质激素(例如泼尼松龙)和环磷酰胺,(t)DMARDS,如甲氨蝶呤,(u)其它化合物,日5-氨基水杨酸及其前药;羟氯喹;D-青霉胺;抗代谢物,如硫唑嘌呤,6-巯基嘌呤和甲氨蝶呤;DNA合成抑制剂,如羟基脲;以及破坏微管的试剂,如秋水仙碱。本发明化合物与第二组活性成分的重量比是可变的,并取决于各种成分的有效剂量。通常可采用各自的有效剂量。因此,例如,当本发明的化合物与NSAID配伍时,本发明化合物和NSAID的重量比通常约为1000∶1-1∶1000,优选约为200∶1-1∶200。本发明的化合物和其它活性成分的组合通常也含在上述范围内,但在各种情况下,应使用各种活性成分的有效剂量。
VI.实施例
以下实施例用于说明,但决不是用于限制所述的发明。
以下所述试剂和溶剂可以通过商业途径获得,如Aldrich ChemicalCo.(Milwaukee,Wisconsin,USA)。在Varian MeRcury400MHz NMR分光光度计上记录1H-NMR。按以下顺序将显著的峰列表:多样性(s,单峰;d,双峰;t,三峰;q,四峰;m,多峰)和质子数。
质谱测定结果记录为质量和电荷的比率,之后测定各离子的相对丰度(在括号中)。在表中,单个m/e值记录为M+H(或如所示的,M-H)离子,包含最常见的原子同位素。所有情况下,同位素样品对应于预定的公式。对于样品递送,在Hewlett-PackaRd MSD electrospray质谱仪上,使用HP1100 HPLC进行电喷离子化(ESI)质谱仪分析。通常,所述分析物溶解在甲醇中,为0.1mg/ml;将1微升传递溶剂注射质谱仪中,从100道尔顿扫描到1500道尔顿。所有化合物可以使用具有1%甲酸的乙腈/水作为传递溶剂,以正的ESI模式进行分析。以下化合物也可以使用乙腈/水中的2mM NH4OAc作为传递系统,以负的ESI模式进行分析。
本发明范围内的化合物可以使用技术人员已知的各种反应,如下所述进行合成。以下提供了芳基哌嗪亚单元和杂芳族亚单元的有用途径。在合成说明中,由商业来源获得一些芳基哌嗪和吡咯前提。这些商业来源包括Aldrich Chemical Co.,AcrosOrganics,Ryan Scientific IncorpoRated,Oakwood Products IncorpoRated,Lancaster Chemicais,Sigma Chemical Co.,Lancaster Chemical Co.,TCI-America,Alfa Aesar,Davos Chemicals和GFS Chemicals。这些商业获得的化合物的一些例子如图4A-4C所示。而且,使用合适的最佳连接剂如本发明正文中所述的乙酰基单元,已经使用标准的化学试剂来连结芳基哌嗪和杂芳族亚单元(不论是否通过以下方法购得或制备)。
本领域的技术人员也意识到可以使用任选的方法合成本发明的目标化合物,并本文献所述的途径不是排他性的,而是广泛提供所述化合物的可行途径。
本专利中所主张的某些分子存在不同的对映体和非对映体形式,这些化合物的所有变量均被主张。
区域异构现象是有机化学中常见的性质,对本文提供的某些结构类型尤其常见。对于本文所述的化合物,本领域那些技术人员将意识到具有杂芳环系统的偶合反应会形成一种可检测的区域异构体或者其混合物。
本文中,用于合成关键化合物的试验步骤的详细说明会形成由鉴别它们的物理数据及其相关结构描述所述的分子。
两种区域异构体有时在本发明的某些化合物中存在。例如,可以制备化合物如通式III所示的化合物,其中,所述吡唑分子通过吡唑环上的任一氮原子连接到分子的剩余部分。在这些情况下,两种区域异构体类型都已经证实了生物性质,并且都已在所有附带权利要求的范围内,不论是否明显画出。
本领域那些技术人员也意识到,在有机化学的标准后处理步骤中,常常使用酸和碱。若在本专利所述实验步骤中母体化合物本身具有酸性或碱性,则有时会制得所述化合物的盐。
实施例1
可用数种方法在末端芳基单元上连接哌嗪环:通过芳香性亲核取代反应,金属催化的偶合反应(仲胺的芳基化反应),环的扩展,重排和环化反应等。同时,也可采用不同的保护/去保护方法。因此,在关键的芳基偶合步骤中可以存在所有或仅仅部分最终的分子结构。各种芳基偶合法的例子在下面列出。
方案A:金属催化的仲胺的芳基化作用
(5-氯-2-哌嗪-1-基-苯基)-苯基-甲酮的合成
将哌嗪(3.6g,42.5mmol),乙酸钯(II)(0.007g,0.043mmol),叔丁醇钠(0.22g,2.4mmol)和BINAP(0.042g,0.068mmol)在10mL无水甲苯中在室温下搅拌15分钟。然后在反应混合物中加入在10mL无水甲苯中的(2-溴-5-氯-苯基)-苯基-甲酮(0.5g,1.7mmol)。反应混合物在110℃回流20小时,通过硅藻土床过滤,用甲苯洗涤,浓缩,加入乙酸乙酯并用1.5(N)HCl溶液萃取三次。合并的水性层用二乙醚洗涤。水性层用10%的氢氧化钠水溶液中和,然后用乙酸乙酯萃取三次。合并的乙酸乙酯层用水和饱和盐水洗涤,用无水硫酸钠干燥并浓缩。通过快速色谱法纯化(用CHCl3-MeOH洗脱)以得到标题化合物作为产物。
1-(4-三氟甲氧基-苯基)-哌嗪的合成
将哌嗪(0.588g,6.84mmol),乙酸钯(II)(0.027g,0.123mmol),叔丁醇钠(0.837g,10.06mmol)和BINAP(0.154g,0.286mmol)在10mL无水甲苯中在室温下搅拌15分钟。在反应混合物中加入在10mL无水甲苯中的4-三氟甲氧基溴苯(1.5g,6.22mmol)。然后将反应混合物在110℃回流20小时,通过硅藻土床过滤,用甲苯洗涤,浓缩,加入乙酸乙酯并用1.5(N)HCl溶液萃取三次。合并的水性层用二乙醚洗涤。水性层用10%的氢氧化钠水溶液中和,然后用乙酸乙酯萃取三次。合并的乙酸乙酯层用水和饱和盐水洗涤,用无水硫酸钠干燥并浓缩以得到产物。
1-(4-甲基磺酰-苯基)-哌嗪的合成
将哌嗪(0.98g,11.5mmol),乙酸钯(II)(0.017g),叔丁醇钠(0.37g,4.2mmol)和BINAP(0.049g)在10mL无水甲苯中在室温下搅拌15分钟。在反应混合物中加入在10mL无水甲苯中的1-溴-4-甲基磺酰-苯(0.9g,3.8mmol)。然后将反应混合物在110℃回流20小时,通过硅藻土床过滤,用甲苯洗涤,浓缩,加入乙酸乙酯并用1.5(N)HCl溶液萃取三次。合并的水性层用二乙醚洗涤。水性层用10%的氢氧化钠水溶液中和,然后用乙酸乙酯萃取三次。合并的乙酸乙酯层用水和饱和盐水洗涤,用无水硫酸钠干燥,浓缩并层析(9/1-CHCl3/MeOH)以得到产物。
1-(4-氯-3-甲氧基-苯基)-哌嗪的合成
在用烤箱干燥过的玻璃容器中加入5-溴-2-氯苯甲醚(1.0mmol),N-BOC哌嗪(1.2mmol),NaOtBu(1.4mmol),三(二亚苄基丙酮)-二钯(O){Pd2dba3}(0.0025mmol,0.5mol%)和BINAP(0.0075mmol),然后用氮气吹扫此容器并盖紧。混合物在80℃加热过夜,然后冷却至室温,取出放入乙醚,过滤并浓缩。在硅胶上用乙酸乙酯通过快速柱层析纯化粗制产物以得到4-(4-氯-3-甲氧基-苯基)-哌嗪-1-羧酸叔丁酯。
将此产物(ca.1mmol)溶于二氯甲烷(10mL)并将反应混合物冷却至0℃。在反应混合物中缓慢加入TFA∶CH2Cl2(2∶1)(占总量的50%)并使反应物回复室温。当TLC(1∶1乙酸乙酯∶己烷)显示起始物质完全反应时除去溶剂,将油性残余物加入乙酸乙酯(2×25mL)并用饱和的碳酸氢钠水溶液洗涤。有机层用MgSO4干燥并除去溶剂以得到黄色油状的标题化合物,将其静置固化。1H NMR(400MHz,CDCl3):7.18-7.22(d,1H),6.44-6.48(d,1H),6.36-6.42(dd,1H),4.8(s,2H),6.62-3.8(m,4H),3.46-3.6(m,4H)。13C NMR(400MHz,CDCl3):164,158.2,156.4,148,119.2,117,52.8,52.2,48.5,46.2,42,40.4。
采用关键的Buckwald偶合,进行类似的反应以制备相关的苯基哌嗪,一些实施例如下。
1-(4-氯-3-异丙氧基-苯基)-哌嗪的合成
将1-溴-3-异丙氧基-4-氯苯(用上述方法制备)与1.11g(6mmol)1-Boc哌嗪,672mg(7.0mmol)叔丁醇钠,93mg(0.15mmol)rac-2,2’-二(二苯基膦)-1,1’-联萘和45mg(0.05mmol)三(二亚苄基丙酮)二钯(O)在烧瓶中在氮气下混合,并将混合物在85℃加热3.5小时。残余物在乙醚和乙酸乙酯与水的1/1的混合物中分配并将各相分离。乙醚/乙酸乙酯相用1体积己烷稀释,用0.5M pH=7磷酸盐缓冲液洗涤两次,并用1M NaOH和盐水洗涤一次。最终的有机相用硫酸钠干燥,过滤并在真空下浓缩至油状。将此油状物溶于溶于乙酸乙酯,加入在乙醚和甲醇中的2M HCl各10mL,并在结晶后通过过滤分离产物。1H NMR(D2O,400MHz):7.23(d,1H),6.69(s,1H),6.59(d,1H),4.53(m,1H),3.28(m,8H),1.20(d,6H)ppm。
1-(4-氯-3-乙氧基-苯基)-哌嗪的合成
用上述同样的方法获得标题化合物以得到1-(4-氯-3-异丙氧基-苯基)-哌嗪盐酸,不同之处在于,在形成醚的反应中用加入乙醇来代替异丙醇。1H NMR(D2O,400MHz)7.22(d,1H),6.64(s,1H),6.54(d,1H),4.03(q,2H),3.29(m,8H),1.25(t,3H)ppm。
4-哌嗪-1-4基-苯甲酸甲酯的合成
将BINAP(230mg,0.37mmol),乙酸钯(II)(417mg,0.186mmol),tBuONa(1.25g,13mmol),N-boc哌嗪(1.9g,10.2mmol)和THF(40mL)一起混合并在室温下在氮气下搅拌30分钟。在混合物中逐滴加入在THF(10mL)中的4-溴甲基苯甲酸盐(2g,9.3mmol)并在70℃加热14h。然后蒸发去过量的THF并用乙酸乙酯萃取。用盐水洗涤并干燥后在乙酸乙酯层浓缩物上得到粗制产物。在硅胶上进行快速层析,用在石油醚中的8%的乙酸乙酯洗涤以得到纯的N-BOC保护的产物。将此中间体(650mg,2.01mmol)溶于甲醇(20mL)然后加入HCl饱和的乙醚(7mL)。混合物在室温下搅拌14小时并浓缩。用石油醚洗涤此浓缩产物以得到白色固体4-哌嗪-1-基-苯甲酸甲酯。
1-(2,4-二氯-苯基)-哌嗪的合成
将BINAP(219mg),乙酸钯(II)(397mg,0.176mmol),tBuONa(1.19g,12.3mmol),哌嗪(837mg,9.73mmol)和THF(40mL)混合在一起并在室温下在氮气下搅拌30分钟。在混合物在逐滴加入在THF(10mL)中的2,4-二氯溴苯(2g,8.84mmol)并在70℃加热14h。然后蒸发去过量的THF并用乙酸乙酯萃取。用盐水洗涤并干燥后在乙酸乙酯层浓缩物上得到粗制产物。在硅胶上进行快速层析用含在CHCl3中的2%MeOH洗脱以得到1-(2,4-二氯-苯基)-哌嗪。
1-(4-氯-苯基)-3-(R)-甲基-哌嗪的合成
在单颈圆底烧瓶中加入1-氯-4-碘苯(1.0g,0.0041mol)和R(-)-2-甲基哌嗪(0.5g,0.005mol),叔丁醇钾(0.705g,0.0062mol),三(亚苄基丙酮)二钯(O)(0.095g,0.0002mol)和1,3二(2,6-二异丙基苯基)咪唑-2-亚基)(0.073g,0.0001mol)。将烧瓶排空并用氮气充满。加入无水二烷(20mL)并在70℃搅拌过夜。反应混合物用二氯甲烷稀释并过滤。粗制化合物通过柱层析纯化。将化合物溶于乙醚并用HCl气体纯化以得到1-(4-氯-苯基)-3-甲基-哌嗪。
1-(4-氯-2-氟苯基)-哌嗪的合成
将哌嗪(1.5g,17.8mmol),乙酸钯(II)(0.032g,0.143mmol),叔丁醇钠(0.688g,10.06mmol)和BINAP(0.18g,0.286mmol)在10mL无水甲苯中在室温下搅拌15分钟。在反应混合物中加入在10mL无水甲苯中的1-溴-4-氯-2-氟苯(1.5g,7.15mmol)。然后将反应混合物在110℃回流20小时。将反应混合物通过硅藻土床过滤并用甲苯洗涤,然后浓缩,将反应混合物加入乙酸乙酯并用1.5(N)HCl溶液萃取三次。合并的水性层用二乙醚洗涤。水性层用10%的氢氧化钠水溶液中和和然后用乙酸乙酯萃取三次。合并的乙酸乙酯层用水和饱和盐水洗涤,用无水硫酸钠干燥并浓缩以得到白色固体状的产物。
用金属催化的芳基化方法合成芳基哌嗪的其它实施例(方案A)。
除了上面列出的特定的实施方案,还用类似的钯介导的偶合法制备了许多其它的芳基哌嗪衍生物。具体例子如下。
方案B:通过环化反应形成哌啶环
1-(3,4-二氟-苯基)-哌嗪的合成
将3,4-二氟-苯胺(1g,7.7mmol)溶于无水正丁醇(10mL)并在其中加入无水碳酸钠(3.2g,30mmol),将反应混合物在氮气下搅拌1小时。然后用注射器在混合物中加入在nBuOH(10mL)中的二(2-氯乙基)胺盐酸盐(1.38g,7.7mmol)。然后将反应物在120℃加热48h。在真空下蒸发去nBuOH并用乙酸乙酯萃取残余物。用硫酸钠干燥有机层,然后浓缩以得到粗制产物。用快速柱层析(氯仿/甲醇)纯化以得到米色固体状的1-(3,4-二氟-苯基)-哌嗪。
1-(4-溴-苯基)-哌嗪的合成
将4-溴-苯胺(2g,1.162mmol)放入无水nBuOH(25mL),在其中加入无水碳酸钾(4.8g,34.8mmol)并在室温下在氮气下搅拌1小时。然后通过注射器在混合物中加入在nBuOH(10mL)中的二-(2-氯乙基)胺盐酸盐2(2.49g,13.9mmol)。然后将反应物在100℃加热12小时。在真空下蒸发去nBuOH并用乙酸乙酯萃取残余物。用硫酸钠干燥有机层,然后浓缩以得到粗制产物,用硅胶柱(氯仿/甲醇)纯化粗制产物以得到标题化合物。
方案C:通过开环/环化方法形成哌啶环
3-[2-(5-甲氧基-2-甲基-苯基氨基)-乙基]-唑烷-2-酮的合成:
在烧瓶中加入2.95g(10.3mmol)甲苯-4-磺酸,2-(2-氧代-唑烷-3-基)-乙酯,1.56g(11.4mmol)2-甲基-5-甲氧基苯胺,2.58g(18.7mmol)碳酸钾和22mL无水二甲基甲酰胺,并将化合物在100℃加入7小时。使反应物回复室温并在乙酸乙酯和水之间分配。将相分离,用盐水洗涤乙酸乙酯相,用Na2SO4干燥,过滤并浓缩成油状。该油相通过层析(120mL硅,60乙酸乙酯/40己烷)纯化以得到相应的透明油状产物,将油状产物干燥固化:1H NMR(DMSO-d6,400MHz)6.81(d,1H),6.11(s,1H),6.04(d,1H),4.92(t,1H),4.21(t,2H),3.65(s,3H),3.59(m,2H),3.31(m,2H),3.23(m,2H),1.95(s,3H)ppm。
1-(5-甲氧基-2-甲基-苯基)-哌嗪的合成
在装于烧瓶中的505mg(2.0mmol)3-[2-(5-甲氧基-2-甲基-苯基氨基)-乙基]-唑烷-2-酮中加入2mL 48%的溶于乙酸的HBr,1mL乙酸和1mL苯甲醚,并将化合物在90℃加热6小时。使溶液冷却至室温并加入5mL CH2Cl2。将产物结晶并通过过滤分离。将固体溶于55mL乙醇,加入201mg(2mmol)三乙胺并将溶液加热回流3小时。然后将溶液在真空下浓缩以得到残余物,用1M NaOH将其碱化。水相用乙酸乙酯萃取两次。合并的乙酸乙酯相用盐水洗涤一次,用Na2SO4干燥,过滤并在乙醚中用2M HCl将其酸化。产物通过过滤分离。
通过芳基-卤素置换法将各种哌嗪加到芳基卤化物和杂芳基卤化物
直接卤素置换法,如果需要可加热,可作为上述金属参与的方法的补充,被用于构建这里所述的环系统。
4-哌嗪-1-基-苯甲酸乙酯的合成
在4-溴苯甲酸(25g)和乙醇(1000mL)中逐滴加入浓硫酸(20g)。将反应混合物在85℃加热过夜。将反应物冷却并通过蒸馏除去乙醇,用水反应混合物停止反应并用乙酸乙酯萃取。萃取物用10%溴化钠、水和盐水萃取,然后浓缩以得到粗制的酯。然后将4-溴乙基苯甲酸酯(10.0g,0.0437mol)加入250mL无水DMF,加入哌嗪(37g,0.437mol),然后加入30g(0.2185mol)无水碳酸钾,1.0g TBAI和1.5g碘化钾。反应混合物在135℃加热过夜。反应混合物用水停止反应并用乙酸乙酯萃取。萃取物用水和盐水洗涤,然后浓缩以得到乳白色固体状的4-哌嗪-1-基-苯甲酸乙酯。
1-(4-甲氧基-吡啶-2-基)-哌嗪的合成:
在置于耐压烧瓶中的756mg(5.29mmol)2-氯-4-甲氧基吡啶和2.27g(26mmol)哌嗪中加入2.7mL二甲基甲酰胺并将混合物在115℃加热5小时。将溶液冷却,然后打开烧瓶并将所得浆状物在乙酸乙酯和水之间分配。将各相分离并用乙酸乙酯将水相反萃取一次。合并的乙酸乙酯相用盐水洗涤一次,用Na2SO4干燥,过滤,滤液在乙醚中用2M HCl酸化。将产物结晶过夜并通过过滤分离固体以得到白色固体状的产物:1H NMR(D2O,400MHz)7.72(d,1H),6.61(d,1H),6.48(s,1H),3.88(s,3H),3.79(m,4H),3.36(m,4H)ppm。
1-(3-甲氧基-吡啶-2-基)-哌嗪的合成:
在置于耐压烧瓶中的966mg(6.7mmol)2-氯-6-甲氧基吡啶和2.90g(34mmol)哌嗪中加入3.3mL二甲基甲酰胺并将混合物在115℃搅拌5小时。将溶液冷却然后打开烧瓶,并将所得浆状物在乙酸乙酯和水之间分配。将各相分离并用乙酸乙酯将水相反萃取一次。合并的乙酸乙酯相用盐水洗涤一次,用Na2SO4干燥,过滤,滤液在乙醚中用2M HCl酸化。将产物结晶过夜并通过过滤分离固体以得到白色固体状的产物:1H NMR(D2O,400MHz)7.73(t,1H),6.52(d,1H),6.31(d,1H),3.81(s,3H),3.68(m,4H),3.26(m,4H)ppm。
方案D:合成哌嗪并通过芳基-卤素置换法将所得哌嗪加到芳基、杂芳基卤化物
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-哌嗪-1-基-乙酮的合成
0℃下,在20mL二甲基甲酰胺中的1.69g(9.1mmol)Boc--哌嗪,2.0g(8.3mmol)(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸和1.12g(8.3mmol)1-羟基苯并三唑溶液中加入1.73g(9.1mmol)1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐。将反应物搅拌并加热至室温过夜,然后在乙醚和水之间分配。将各相分离,乙醚相用1M HCl,水,1M NaOH和盐水洗涤一次。乙醚相然后用Na2SO4干燥,过滤并浓缩成残余物。
将这种粗制的残余物溶于20mL乙醚和8mL乙酸乙酯并加入20mL在异丙醇中的5MHCl。1小时后,将混合物放入冰箱过夜。产物通过过滤分离以得到白色固体。1HNMR(DMSO-d6,400MHz)9.21(br s,2H),5.38(s,2H),3.69(m,4H),3.32(m,4H),2.20(s,3H)ppm。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-哌嗪-1-基-乙酮的另一种合成方法
将(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸(1.5g,6.18mmol)置于无水DCM(20mL)并冷却至0℃。在此冷的混合物中加入N-boc哌嗪(1.15g,6.18mmol)然后加入T3P(8g,12.4mmol,50%溶液,在EtOAc中)。使反应物在室温下过夜。混合物用CH2Cl2稀释,用NaHCO3溶液,盐水洗涤,干燥(Na2SO4)并浓缩以得到粗制产物,粗制产物用乙醚-石油醚洗涤以得到4-[2-(4-氯-5甲基-3-三氟甲基-吡唑-1-基)-乙酰基]-哌嗪-1-羧酸叔丁酯(1.2g,2.9mmol)。将其溶于冷却至0℃的甲醇(25mL)并在其中加入HCl饱和的乙醚(3mL)。将混合物在室温下搅拌4h并浓缩。从MeOH/石油醚中结晶得到产物。
1-[4-(5-溴-嘧啶-2-基)-哌嗪-1-基]-2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酮(方案D)的合成
在置于玻璃瓶的86mg(0.25mmol)2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-哌嗪-1-基-乙酮盐酸,76mg(0.6mmol)碳酸钾和48mg(0.3mmol)5-溴-2-氯嘧啶中加入0.7mL无水二甲基甲酰胺并将化合物在120℃加热12小时。将反应物冷却至室温并在乙酸乙酯和水之间分配。将各相分离,水相用乙酸乙酯反萃取一次。合并的乙酸乙酯相用水,0.5M pH=7磷酸盐缓冲液,水,1M NaOH和盐水洗涤一次。乙酸乙酯相用硫酸钠干燥,过滤并在乙醚中用2M HCl酸化以得到粉末状的产物:1HNMR(DMSO-d6,400MHz)8.48(s,2H),5.37(s,2H),3.81(m,2H),3.72(m,2H),3.57(m,4H),2.18(s,3H)ppm;MS(ES)M+H预测值=467.0,实测值:466.9。
用芳基-卤素置换法制得的本发明的其它化合物
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(7H-嘌呤-6-基)哌嗪-基]-乙酮的合成:
标题化合物是按方案D制备的,其中,将6-氯嘌呤被用作杂芳基卤化物组分:1HNMR(DMSO-d6,400MHz)8.23(s,1H),8.14(s,1H),5.39(s,2H),4.32(br,2H),4.22(br,2H),3.60(m,4H),2.19(s,3H)ppm;MS(ES)预测值:M+H=429.1,实测值:429.0。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-(4-喹啉-2-基-哌嗪-1-基)乙酮的合成:
标题化合物是按方案D制备的,其中,2-氯喹啉被用作杂芳基卤化物组分:1HNMR(DMSO-d6,400MHz)8.44(d,1H),8.29(br,1H),7.91(d,1H),7.77(t,1H),7.57(d,1H),7.48(t,1H),5.44(s,2H),4.14(br,2H),4.01(br,2H),3.78(br,2H),3.70(br,2H),2.20(s,3H)ppm;MS(ES)预测值:M+H=438.1,实测值:438.0。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(5-氯-嘧啶-2-基)-哌嗪-1-基]-乙酮的合成:
标题化合物是按方案D制备的,其中,2,5-二氯吡啶被用作杂芳基卤化物组分:MS(ES)预测值:M+H=422.1,实测值=422.0;HPLC保留时间=4.75分钟(AgilentZorbax SB-C18,2.0×50MM,5g,35℃),20%-95%B梯度4.5分钟,95%B洗涤1.1分钟(A=0.1%甲酸/5%乙腈/94.9%水,B=0.08%甲酸/99.9%乙腈)。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-(2,3,5,6-四氢-[1,2’]联吡嗪基-4-基)-乙酮的合成:
标题化合物是按方案D制备的,其中,2-氯吡嗪被用作杂芳基卤化物组分:1HNMR(DMSO-d6,400MHz)8.34(s,1H),8.09(d,1H),7.85(d,1H),5.38(s,2H),3.68(m,2H),3.58(m,4H),3.44(m,2H),2.19(s,3H)ppm;MS(ES)预测值:M+H=389.1,实测值:389.0。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(6-甲基-哒嗪-3-基)-哌嗪-1-基]-乙酮的合成:
标题化合物是按方案D制备的,其中,3-氯-6-甲基哒嗪被用作杂芳基卤化物组分:MS(ES)预测值:M+H=403.1,实测值=403.0;HPLC保留时间=1.68分钟(AgilentZorbax SB-C18,2.1×50mm,5g,35℃),20%-95%B梯度4.5分钟,95%B洗涤1.1分钟(A=0.1%甲酸/5%乙腈/94.9%水,B=0.08%甲酸/99.9%乙腈)。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(4,6-二甲氧基-[1,3,5]三嗪-2-基)-哌嗪-1-基]-乙酮的合成:
标题化合物是按方案D制备的,其中,2-氯-4,6-二甲氧基三嗪e被用作杂芳基卤化物组分:MS(ES)预测值:M+H=450.1,实测值=450.0;HPLC保留时间=4.24分钟(Agilent Zorbax SB-C18,2.1×50mm,5,U,35℃),20%-95%B梯度4.5分钟,95%B洗涤1.1分钟(A=0.1%甲酸/5%乙腈/94.9%水,B=0.08%甲酸/99.9%乙腈)。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(2-甲基硫烷基-嘧啶-4-基)-哌嗪-1-基]-乙酮的合成:
标题化合物是按方案D制备的,其中,4-氯-2-甲基硫代嘧啶被用作杂芳基卤化物组分:1H NMR(DMSO-d6,400MHz)8.16(d,1H),6.87(d,1H),5.41(s,2H),3.90(brm,4H),3.62(m,4H),2.57(s,3H),2.19(s,3H)ppm;MS(ES)预测值:M+Na=435.1,实测值:435.0。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(4,6-二甲氧基-嘧啶-2-基)-哌嗪-1-基]-乙酮的合成:
标题化合物是按方案D制备的,其中,2-氯-4,6-二甲氧基嘧啶被用作杂芳基卤化物组分:MS(ES)预测值:M+H=449.1,实测值=449.0;HPLC保留时间=4.92分钟(Agilent Zorbax SB-C 18,2.1×50mm,5F,35℃),20%-95%B梯度4.5分钟,95%B洗涤1.1分钟(A=0.1%甲酸/5%乙腈/94.9%水,B=0.08%甲酸/99.9%乙腈)。
1-[4-(6-氯-5-甲基-哒嗪-3-基)-哌嗪-1-基]-2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酮的合成:
标题化合物是按方案D制备的,其中,3,6-二氯-4-甲基哒嗪被用作杂芳基卤化物组分:MS(ES)预测值:M+H=437.1,实测值=437.0;HPLC保留时间=4.17分钟(Agilent Zorbax SB-C18,2.1×50mm,5μ,35℃),20%-95%B梯度4.5分钟,95%B洗涤1.1分钟(A=0.1%甲酸/5%乙腈/94.9%水,B=0.08%甲酸/99.9%乙腈)。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(5-甲氧基-1-H-苯并咪唑-2-基)-哌嗪-1-基]-乙酮的合成:
标题化合物是按方案D制备的,其中,2-氯-5-甲氧基苯并咪唑被用作杂芳基卤化物组分:MS(ES)预测值:M+H=457.1,实测值=457.0;HPLC保留时间=2.85分钟(Agilent Zorbax SB-C18,2.L×SOMM,SP,35℃),20%-95%B梯度4.5分钟,95%B洗涤1.1分钟(A=0.1%甲酸/5%乙腈/94.9%水,B=0.08%甲酸/99.9%乙腈)。
芳基哌嗪环系统正式形成后的进一步官能化
除了其它经过选择的取代基、本发明的关键化合物还在2-或4-位有卤素原子。下面描述了对其进行的研究。
通常,芳基哌嗪环系统内芳环的官能化可在哌嗪环被引入之前或之后发生,如下面的实施例所述。
方案E:联结哌嗪环系统后芳香系统卤化的经过选择的实施例
1-(4-溴-3-甲氧基-苯基)-哌嗪盐酸盐的合成:
0℃下,在70mL乙酸和15mL水中的2.33g(8.8mmol)1-(3-甲氧基苯基)哌嗪二盐酸盐和756mg(9.7mmol)乙酸钠溶液中加入1.55g(9.7mmol)溴。1小时后,在真空下将反应物浓缩成油状物并将此油状物在乙酸乙酯和1M NaOH之间分配。将各相分离,乙酸乙酯相用水和盐水洗涤一次,用Na2SO4干燥,过滤滤液在真空下浓缩成油状。将此油状物溶于中等体积的甲醇,并在乙醚中用2M HCl将此溶液酸化。产物通过过滤分离。1H NMR(D2O,400MHz)7.36(d,1H),6.73(s,1H),6.50(d,1H),3.75(s,3H),3.32(m,8H)ppm。
1-(4-溴-3-甲基-苯基)-哌嗪盐酸盐的合成:
0℃下,在9mL乙酸和1mL水中的966mg(4.0mmol)1-(3-甲基苯基)哌嗪二盐酸盐溶液中加入640mg(4.0mmol)溴。1小时后,将反应物在真空下浓缩成油状并将此油状物在乙酸乙酯和1M NaOH之间分配。将各相分离,乙酸乙酯相用水和盐水洗涤一次,用Na2SO4干燥,过滤,滤液在真空下浓缩成油状。将此油状物溶于中等体积的甲醇,在乙醚中用2M HCl将此溶液酸化。产物通过过滤分离。1H NMR(D2O,400MHz)7.37(d,1H),6.85(s,1H),6.76(d,1H),3.37(m,8H),2.17(s,3H)ppm。
1-(2-氯-5-甲氧基-苯基)-哌嗪盐酸盐的合成:
0℃下,在120mL乙酸和30mL水中的5.3g(20mmol)1-(3-甲氧基苯基)哌嗪二盐酸盐溶液中加入3.3g(20mmol)N-氯琥珀酰亚胺。5小时后,将反应物在真空下浓缩成油状并将此油状物在乙酸乙酯和1M NaOH之间分配。将各相分离,乙酸乙酯相用水和盐水洗涤一次,用Na2SO4干燥,过滤滤液在真空下浓缩成油状。将此油状物溶于中等体积的甲醇在乙醚中用2M HCl将此溶液酸化。产物通过过滤分离。1H NMR(D20,400MHz)7.28(d,1H),6.66(m,3H),3.70(s,3H),3.32(m,4H),3.20(m,4H)ppm。
1-(2,4-二氯-5-甲氧基-苯基)-哌嗪盐酸盐的合成:
0℃下,在7mL乙酸和4mL水中的530mg(2.0mmol)1-(3-甲氧基苯基)哌嗪二盐酸盐溶液中加入700mg(4.4mmol)N-氯琥珀酰亚胺。2小时后将反应物从冰/水浴中取出并搅拌过夜。12小时后,将反应物在真空下浓缩成油状并将此油状物在乙醚和水之间分配。将各相分离,水相用1M NaOH碱化并用乙酸乙酯萃取。乙酸乙酯相用水和盐水各洗涤一次,用Na2SO4干燥,过滤滤液在真空下浓缩成油状。将此油状物溶于中等体积的甲醇,溶液在异丙醇中用5M HCl酸化并用乙酸乙酯稀释以有效结晶。产物通过过滤分离。1H NMR(D2O,400MHz)7.38(s,1H),6.72(s,1H),3.78(s,3H),3.32(m,4H),3.19(m,4H)ppm。
方案F:将芳香前体去甲基化/醚化用于将哌嗪环系统的连接以得到关键芳基哌嗪部分的经过选择的实施例
3-溴-6-氯苯酚的合成:
0℃下,在50mL 1M三溴化硼的CH2Cl2溶液中加入5.71g(25.8mmol)5-溴-2-氯苯甲醚。2小时后,使反应物回复室温。5小时后,将溶液冷却至0℃并用甲醇终止反应。所得溶液在水和乙酸乙酯之间分配并将各相分离。水相用乙酸乙酯反萃取一次。合并的乙酸乙酯相用1体积乙醚稀释并用1M NaOH萃取两次。合并的碱性水相用12M HCl酸化并用乙酸乙酯萃取两次。最终的乙酸乙酯相用盐水洗涤一次,用MgSO4干燥,过滤并浓缩以得到棕褐色固体状的酚。1H NMR(DMSO-d6,400MHz)10.66(s,1H),7.27(d,1H),7.08(s,1H),6.95(d,1H)ppm。
1-溴-3-异丙氧基-4-氯苯的合成:
0℃下,在25mL CH2Cl2中的1.70g(6.5mmol)三苯基膦加入1.14g(6.5mmol)偶氮二羧酸二乙酯。10分钟后,加入390mg(6.5mmol)异丙醇,然后迅速加入1.03g(5.0mmol)3-溴-6-氯酚。使反应在3小时内完成并在乙醚和水之间分配。将各相分离,乙醚相用己烷稀释并用10%甲醇水溶液洗涤两次并用盐水洗涤一次。乙醚/己烷相用Na2SO4干燥,过滤并在真空下浓缩以得到透明油状产物。
方案F:用类似的去甲基化/醚化法构建类似环系统的其它实施例
方案G:从苯胺合成经过加工的芳基溴化物的一般方法
4-氯-2-氟-1-溴苯的合成
在-10℃浴温度下,将亚硝酸钠(2.35g,34.13mmol)溶液(40mL)逐滴加入在170mL HBr中的4-氯-2-氟苯胺(4.5g,31mmol),然后将混合物在-10℃浴温度下搅拌30分钟。同时,将硫酸铜(10.22g,24.29mmol)和溴化钠(3.79g,36.8mmol)混合并将反应混合物在60℃加热30分钟。然后在此硫酸铜反应混合物中加入亚硫酸钠(2.66g,21.2mmol)并在95℃加热30分钟。使反应混合物冷却至室温并用水洗涤所形成的固体以得到白色固体状的溴化亚铜。在将重氮盐一次性加入在-10℃浴温度下的在40mLHBr中的新鲜制备的溴化亚铜,然后使反应混合物回复室温。将反应混合物在55℃加热20分钟,冷却,然后用乙酸乙酯萃取三次。合并的有机层用水和饱和盐水洗涤,用硫酸钠干燥并浓缩。粗物质通过柱层析纯化(5∶95乙酸乙酯∶石油醚)以得到固体产物。
(2-溴-5-氯-苯基)-苯基-甲酮的合成
在-10℃浴温度下,将亚硝酸钠(2.5g,36.28mmol)溶液(40mL)逐滴加入100mLHBr中的苯胺(7g,30.2mmol),然后将混合物在-10℃浴温度下搅拌30分钟以制造重氮盐。
硫酸铜(10.22g,24.29mmol)和溴化钠(3.79g,36.8mmol)在60℃加热30分钟。然后将亚硫酸钠(2.66g,21.2mmol)加入硫酸铜反应混合物并在95℃加热30分钟。然后将反应混合物冷却至室温并用水洗涤所形成的固体以得到白色固体状的溴化亚铜。
在将重氮盐一次性加入在-10℃浴温度下的在40mL HBr中的新鲜制备的溴化亚铜,然后使反应混合物回复室温。将反应混合物在55℃加热20分钟,冷却,然后用乙酸乙酯萃取三次。合并的有机层用水和饱和盐水洗涤,用硫酸钠干燥并浓缩。物质从DCM/PET醚中结晶纯化。
方案G:用类似的Sandmeyer法构建类似环系统的其它实施例
已经描述过将上述芳基溴和类似物质用于各种化学物质以得到下列芳基哌嗪。
杂芳环系统的合成:核心环结构的形成
可用于合成关键杂芳环结构的化学反应的类型在下面列出。在环形成和官能化反应中将分别讲述。
方案H:通过将肼加到α,β-炔酮来合成吡唑
5-丁基-3-三氟甲基-1H-吡唑的合成
在溶于THF(30mL)的1-己炔(3.37mL,29.4mmol)溶液中加入n-BuLi(2.78M,10.2mL,29.4mmol)。将溶液在-78℃搅拌30分钟,然后依次加入CF3CO2ET(3.5mL,29.35mL)和BF3-OEt2。将反应物在-78℃再搅拌2h并用饱和NH4Cl停止反应。然后使其回复室温。除去THF,将残余物加入乙醚,用饱和盐水洗涤,用Na2SO4干燥并还原。然后将粗制产物溶于苯(25mL)并加入肼(29.4mmol)。反应混合物回流过夜,然后冷却,蒸发去溶剂并将残余物加入CH2Cl2(30mL),用盐水洗涤,用Na2SO4干并浓缩以得到无色油状的标题化合物。
5-异丙基-3-三氟甲基-1H-吡唑的合成
按照方案H,在THF中用n-BuLi,CF3CO2Et和BF3-OET2处理3-甲基丁炔。在类似的反应条件下在苯中与肼反应反应制得标题化合物。
5-丙基-3-三氟甲基-1H-吡唑的合成
按照方案H,在THF中用n-BuLi,CF3CO2ET和BF3-OET2处理1-戊炔。在类似的反应条件下在苯中与肼反应反应制得标题化合物。
5-(3-氟苯基)-3-三氟甲基-1H-吡唑的合成
按照方案H,在THF中用n-BuLi,CF3CO2ET和BF3-OET2处理1-乙炔基-3-氟-苯。在类似的反应条件下在苯中与肼反应反应制得标题化合物。
方案I:通过缩合肼和β-二酮来合成吡唑的一般方法:
5-乙基-3-三氟甲基-1H-吡唑的合成
0℃下,在溶于无水乙醇(10mL)的1,1,1-三氟-己烷-2,4-二酮(1g,5.95mmol)溶液中逐滴加入NH2NH2.xH2O。使反应混合物在1小时内回复室温并回流过夜。然后蒸发去乙醇,将残余物溶于乙酸乙酯(20mL),依次用饱和盐水和水洗涤,用Na2SO4干燥并浓缩以得到无色油状的标题化合物。
方案J:通过缩合肼和β-氰基酮合成吡唑
5-苯基-1-吡唑-3-胺的合成
在溶于40mL无水乙醇的2.0g(0.0138mol,leg)苯甲酰乙腈中加入2.0g(0.0399mol,3eq)无水肼,将反应混合物在85℃搅拌2小时。于50℃在真空下除去乙醇。得到黄色固体状的5-苯基-1-吡唑-3-胺,用石油醚(100mL)洗涤并在真空下干燥。
官能化杂芳环系统的合成
吡唑的氯化或溴化
方案K:在冰醋酸中用NaOCl将吡唑氯化
4-氯-1H-吡唑的合成
在冰醋酸(4mL)中的吡唑(0.5g,7.34mmol)溶液中加入NaOCl(0.55g,7.34mmol)。反应混合物在室温下放置18h,然后用饱和Na2CO3溶液中和,用CH2Cl2(2×25mL)萃取,浓缩合并的有机层,然后用NaOH稀释并进一步用CH2Cl2(3×20mL)萃取。合并有机萃取物,用Na2SO4干燥并浓缩以得到白色固体状的标题化合物。
4-氯-3-三氟甲基-lH-吡唑的合成
按照方案K,用冰醋酸和NaOCl处理3-三氟甲基吡唑,得到标题化合物。
4-氯-3-甲基-1H-吡唑的合成
按照方案K,用冰醋酸和NaOCl处理3-甲基吡唑,得到标题化合物。
4-氯-5-丙基-1H-吡唑-3-羧酸乙酯的合成
按照方案K,在类似的反应条件下用冰醋酸和NaOCl处理5-丙基-1H-吡唑-3-羧酸乙酯,得到标题化合物。
方案L:用N-氯琥珀酰亚胺(NCS)或N-溴琥珀酰亚胺(NBS)将吡唑氯化或溴化:
4-氯-3-甲基-5-三氟甲基-1H-吡唑的合成
将3-甲基-5-三氟甲基吡唑加入无水DMF(20mL)并一次性加入N-氯琥珀酰亚胺(1.78g)。然后将混合物在70℃加热22h,冷却至室温,然后加入水(100mL)并用乙酸乙酯萃取混合物(4×25mL)。有机层用水和盐水洗涤并用硫酸钠干燥。将溶剂蒸发得到标题化合物。
4-氯-5-噻吩-2-基-2H-吡唑-3-羧酸乙酯的合成
用NCS(1.5eq.)一次性处理DMF(0.14M溶液)中的吡唑(1eq),当所有的NCS溶于反应混合物后在70℃加热过夜。然后将反应混合物冷却至室温并用水终止反应,用乙酸乙酯萃取并在硫酸镁中干燥。将两种产物分离,其中包括标题化合物
4-氯-3,5-二异丙基-吡唑的合成
按照方案L,边剧烈搅拌边在DMF(10mL)中的3,5-二异丙基-吡唑(0.5g,3.57mmol)溶液中一次性加入NCS(0.72g,5.3mmol)。然后将反应混合物在80℃加热14H,然后用水终止反应。然后用乙酸乙酯对其进行萃取(2×30mL)。合并的有机层用盐水洗涤。合并有机萃取物并用硫酸钠干燥,最终蒸发以得到无色油状的标题化合物。
4-氯-3-噻吩-2-基-1H-吡唑的合成
按照方案L,在DMF中用NCS处理3-噻吩-2-基-1H-吡唑,以得到标题化合物。
5-叔丁基-4-氯-3-三氟甲基-1H-吡唑的合成
按照方案L,在DMF中用NCS处理5-叔丁基-3-三氟甲基-1H-吡唑,以得到标题化合物。
4-氯-3-甲基-1H-吡唑-5-羧酸乙酯的合成
按照方案L,在DMF中用NCS处理3-甲基-2H-吡唑-5-羧酸乙酯,以得到标题化合物。
4-氯-3-噻吩-2-基-1H-吡唑-5-羧酸乙酯的合成
按照方案L,在DMF中用NCS处理3-噻吩-2-基-1H-吡唑-5-羧酸乙酯,以得到标题化合物。
4-氯-5-(5-氯-噻吩-2-基)-2H-吡唑-3-羧酸乙酯的合成
按照方案L,在DMF中用NCS处理3-噻吩-2-基-1H-吡唑-5-羧酸乙酯,以得到标题化合物。
4-氯-3-(4-氟-苯基)-5-甲基硫烷基-1H-吡唑的合成
按照方案L,在DMF中用NCS处理3-(4-氟-苯基)-5-甲基硫烷基-1H-吡唑,以得到标题化合物。
5-丁基-4-氯-3-三氟甲基-1H-吡唑的合成
按照方案L,在DMF中用NCS处理5-丁基-3-三氟甲基-1H-吡唑,以得到标题化合物。
4-氯-5-苯基-1-吡唑-3-胺的合成
按照方案L,在25mL无水乙腈中的0.5g(0.0031mol,1eq)5-苯基-1-吡唑-3-胺中一次性加入0.4g(0.0031mol,1eq)N-氯琥珀酰亚胺,然后将反应混合物在室温下搅拌30分钟。反应混合物用水停止反应并用乙酸乙酯萃取。有机层用水和盐水洗涤并浓缩。产物用60-120硅胶柱(1%甲醇,在氯仿中)纯化。
4-溴-5-苯基-1-吡唑-3-胺的合成
按照方案L,在25mL无水乙腈中的0.5g(0.0031mol,1eq)5-苯基-1-吡唑-3-胺中一次性加入0.55g(0.0031mol,1eq)N-溴琥珀酰亚胺,然后将反应混合物在室温下搅拌30分钟。反应混合物用水停止反应并用乙酸乙酯萃取。有机层用水和盐水洗涤并浓缩。产物用60-120硅胶柱(1%甲醇,在氯仿中)纯化。
4-氯-5-异丙基-3-三氟甲基吡唑的合成
按照方案L,边剧烈搅拌边在CH3CN(10mL)中的3-三氟甲基-5-异丙基-吡唑(0.22g,1.23mmol)溶液中一次性加入NCS(0.19g,1.43mmol)。反应混合物然后加热回流14h,冷却并用饱和碳酸氢钠终止反应,用二氯甲烷(2×30mL)萃取,合并的有机萃取物用盐水洗涤,用硫酸钠干燥并蒸发以得到白色固体状的标题化合物。
4-氯-5-乙基-3-三氟甲基-1H-吡唑的合成
按照方案L,在CH3CN中用NCS处理5-乙基-3-三氟甲基-1H-吡唑以得到标题化合物。
4-氯-5-丙基-3-三氟甲基-1H-吡唑的合成
按照方案L,在CH3CN中用NCS处理5-丙基-3-三氟甲基-1H-吡唑以得到标题化合物
4-氯-5-(3-氟苯基)-3-三氟甲基-1H-吡唑的合成
按照方案L,在CH3CN中用NCS处理5-(3-氟苯基)-3-三氟甲基-1H-吡唑以得到标题化合物。
4-氯-3,5-二(三氟甲基)-1H-吡唑的合成
按照方案L,在CH3CN中用NCS处理3,5-二(三氟甲基)-1H-吡唑以得到标题化合物。
N-(4-氯-5-甲基-1H-吡唑-3-基)-2,2,2-三氟-乙酰胺的合成
按照方案L,在CH3CN中用NCS处理2,2,2-三氟-N-(5-甲基-1H-吡唑-3-基)-乙酰胺以得到标题化合物。
方案M:还原硝基吡唑的一般方法
3-七氟丙基-5-甲基-1H-吡唑-4-基胺的合成
将冰醋酸(5mL)中的3-七氟丙基-5-甲基-4-硝基-1H-吡唑(0.295g,1.0mmol)溶液逐滴加入冰醋酸(10mL)中的锌粉(1.5g)悬液。然后将反应混合物在室温下搅拌14h。通过过滤除去锌盐,并用乙酸乙酯洗涤残余物。合并的有机萃取物在真空下浓缩,重溶于CHCl3,用NaHCO3,水和盐水洗涤。最终的有机层用硫酸钠干燥并蒸发去溶剂以得到白色固体状的标题化合物。
合成溴-吡唑用于芳基-芳基交叉偶合反应和金属参与的胺化
氨基吡唑三氟乙酰化的一般过程:
2,2,2-三氟-N-(5-甲基-1H-吡唑-3-基)-乙酰胺的合成
10℃下,在二烷(25mL)中的3-氨基-5-甲基吡唑(0.97g,10mmol)和Et3N(1.39mL,10mmol)溶液中逐滴加入三氟乙酸酐(TFAA)(1.39mL,10mmol)。反应混合物在此温度下搅拌1h,然后用1小时使其缓慢回复室温。一旦反应结束将过量的二烷蒸发,残余物溶于溶于水(20mL),用二氯甲烷(30mL)洗涤。有机层然后用硫酸钠干燥并浓缩以得到白色固体状的标题化合物。
方案N:烷基取代的杂芳环系统的官能化:氨甲基化
(5-溴甲基-4-氯-3-甲基-吡唑-1-基)-乙酸乙酯的合成
将4-氯-3-甲基-5-三氟甲基-1H-吡唑(10g,54mmol)溶于乙腈(100mL)并加入碳酸钾(30g,0.215mol)。在室温下搅拌1小时后,加入溴乙酸乙酯(11g,65mmol)。在70℃加热14小时后将混合物过滤并将滤液浓缩以得到粗制产物,粗制产物再从石油醚中重结晶。
将此中间体酯(5g,0.019mol)放入CCl4(100mL)并在氮气下在其中加入AIBN(0.053g,0.33mmol)。用常规的灯泡照射此混合物。将此混合物回流然后在混合物中分四次加入NBS(3.42g,0.019mol),每次间隔15分钟。完全加入后将混合物在光照下回流3h。然后过滤反应混合物并用水和盐水洗涤滤液。干燥有机层(Na2SO4)然后蒸发去溶剂以得到(5-溴甲基-4-氯-3-三氟甲基-吡唑-1-基)-乙酸乙酯。
方案O:(5-叠氮甲基-4-氯-3-三氟甲基-吡唑-1-基)-乙酸的合成:
在溶于40mL无水二甲基甲酰胺的4.6g(13.2mmol)(5-溴甲基-4-氯-3-三氟甲基-吡唑-1-基)-乙酸乙酯中加入1.03g(15.8mmol)叠氮化钠。搅拌12小时后,将溶液在乙酸乙酯和水之间分配。将各相分离,水相用乙酸乙酯反萃取,合并的乙酸乙酯相用水和盐水洗涤,用Na2SO4干燥,过滤并在真空下浓缩以得到橙色油状物。将此油状物溶于25mL四氢呋喃,加入25mL 1M NaOH并将混合物剧烈搅拌3小时。然后在真空下除去四氢呋喃并用乙醚洗涤水溶液一次。水相然后用1M HCl酸化并用乙酸乙酯提取两次。合并的乙酸乙酯相用盐水洗涤,用Na2SO4干燥,过滤并浓缩以得到橙色固体状的标题化合物。
方案P(见下页):2-(5-叠氮甲基-4-氯-3-三氟甲基-吡唑-1-基)-1-[4-(4-氯苯基)-哌嗪-1-基]-乙酮的合成:
在溶于40mL无水二甲基甲酰胺的2.71g(13.7mmol)1-(4-氯苯基)哌嗪和3.58g(12.5mmol)(5-叠氮甲基-4-氯-3-三氟甲基-吡唑-1-基)-乙酸中加入4.36mL(31.2mmol)三乙胺。将溶液冷却至0℃并加入5.21g(13.7mmol)O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸盐(HATU)。2小时后用2体积水稀释反应物并从所得油状物中倒出溶剂。将此油状物溶于甲醇并加入少量水以使其结晶出。通过过滤分离出白色固体状的产物:1H NMR(DMSO-d6,400MHz)7.23(d,2H),6.97(d,2H),5.48(s,2H),4.62(s,2H),3.60(m,4H),3.24(m,2H),3.12(m,2H)ppm;MS(ES)M+H预测值=462.1,实测值=462.0。
方案O:2-(5-氨甲基-4-氯-3-三氟甲基-吡唑-1-基)-1-[4-(4-氯苯基)-哌嗪-1-基]-乙酮的合成
将2.85g(6.2mmol)2-(5-叠氮甲基-4-氯-3-三氟甲基-吡唑-1-基)-1-[4-(4-氯苯基)-哌嗪-1-基]-乙酮溶于80mL甲醇并加入3.61g(16.0mmol)SnCl2水合物。2小时后,在真空下浓缩反应物以除去甲醇。残余物在0.5M NaOH和乙酸乙酯之间分配并将各相分离。水相用乙酸乙酯反萃取一次。合并的乙酸乙酯相用1M HCl萃取两次。用1M NaOH将酸性的水相碱化并用乙酸乙酯萃取一次。最终的乙酸乙酯相用盐水洗涤一次,用Na2SO4干燥,过滤并浓缩成油状。将此油状物溶于甲醇,在乙醚中用2M HCl酸化并在沉淀后通过过滤分离产物:1H NMR(DMSO-d6,400MHz)8.58(s,3H),7.27(d,2H),7.03(d,2H),5.71(s,2H),4.10(d,2H),3.64(m,4H),3.32(m,2H),3.19(m,2H)ppm;MS(ES)M+H预测值=436.1,实测值=436.0.
2-(5-N,N-二甲基氨甲基-4-氯-3-三氟甲基-吡唑-1-基)-1-[4-(4-氯苯基)-哌嗪-1-基]-乙酮的合成:
在溶于0.7mL甲醇的50mg(0.1mmol)2-(5-氨甲基-4-氯-3-三氟甲基-吡唑-1-基)-1-[4-(4-氯苯基)-哌嗪-1-基]-乙酮盐酸盐和13mg(0.20mmol)氰基氢硼化钠在0.7mL甲醇中的溶液中加入0.025mL(0.3mmol)37%的甲醛水溶液。搅拌4小时后,用0.1mL 12M HCl终止反应。1小时后,在真空下浓缩溶液。残余物在水和乙醚之间分配并将各相分离。乙醚相用水反萃取一次。合并的水相用1M NaOH碱化并用乙酸乙酯萃取一次。乙酸乙酯相用盐水洗涤一次,用Na2SO4干燥,过滤并浓缩成油状。将此油状物溶于甲醇,在乙醚中用2M HCl酸化,通过过滤分离白色固体状的产物:1HNMR(DMSO-d6,400MHz)11.07(br,1H),7.26(d,2H),7.02(d,2H),5.76(s,2H),4.43(s,2H),3.62(m,4H),3.31(m,2H),3.18(m,2H),2.81(s,6H)ppm;MS(ES)M+H预测值=464.1,实测值=464.0。
方案R:吡唑环系统上氨甲基官能度的脲衍生化作用
1-(4-氯-2-{2-[4-(4-氯-苯基)-哌嗪-1-基]-2-氧代-乙基}-5-三氟甲基-2H-吡唑-3-基甲基)-脲的合成:
0℃下,在1.0mL CH2Cl2中的12mg(0.07mmol)羰基二咪唑和25mg(0.05mmol)2-(5-氨甲基-4-氯-3-三氟甲基-吡唑-1-基)-1-[4-(4-氯苯基)-哌嗪-1-基]-乙酮盐酸盐浆状物中加入23mg(0.22mmol)溶于0.2mL CH2Cl2的三乙胺,用时5分钟。使混合物在1小时后回复室温,并继续搅拌1小时。
加入1.0mL(0.5mmol)0.5M氨的二烷溶液,并将所得溶液搅拌12小时。将溶液在真空下浓缩并将所得残余物在乙酸乙酯和水之间分配。将各相分离,水相用乙酸乙酯反萃取一次。合并的乙酸乙酯相用水,1M NaOH,盐水各洗涤一次,用Na2SO4干燥,过滤并浓缩成残余物。所得残余物和乙酸乙酯一起研磨并通过过滤分离白色固体状的产物:1H NMR(DMSO-d6,400MHz)7.23(d,2H),6.96(d,2H),6.48(t,1H),5.62(s,2H),5.48(s,2H),4.16(d,2H),3.57(m,4H),3.25(m,2H),3.14(m,2H)ppm;MS(ES)M+H预测值=479.1,实测值=479.0。
3-(4-氯-2-{2-[4-(4-氯-苯基)-哌嗪-1-基]-2-氧代-乙基}-5-三氟甲基-2H-吡唑-3-基甲基)-1,1-二甲基-脲的合成:
标题化合物是按照方案R制备的,在第二步中用2M溶于四氢呋喃的二甲胺作为胺组分,以得到固态的所需产物:1H NMR(DMSO-d6,400MHz):7.23(d,2H),6.96(d,2H),6.81(t,1H),5.43(s,2H),4.21(d,2H),3.56(m,4H),3.22(m,2H),3.13(m,2H),2.73(s,3H)ppm;MS(ES)M+H预测值=507.1,实测值=507.1。
1-(4-氯-2-{2-[4-(4-氯-苯基)-哌嗪-1-基]-2-氧代-乙基}-5-三氟甲基-2H-吡唑-3-基甲基)-3-甲基-脲的合成:
标题化合物是按照方案R制造的,在第二步中用2M溶于四氢呋喃的甲胺作为胺组分,以得到固态的所需产物标题化合物:1H NMR(DMSO-d6,400MHz)7.23(d,2H),6.96(d,2H),6.45(t,1H),5.86(m,1H),5.48(s,2H),4.18(d,2H),3.58(m,4H),3.31(s,3H),3.25(m,2H),3.13(m,2H)ppm;MS(ES)M+H预测值=493.1,实测值=493.0。
3-(4-氯-2-{2-[4-(4-氯-苯基)-哌嗪-1-基]-2-氧代-乙基}-5-三氟甲基-2H-吡唑-3-基甲基)-1-甲氧基-1-甲基-脲的合成:
标题化合物是按照方案R制造的,在第二步中用2M溶于四氢呋喃的N,O-二甲基羟基胺作为胺组分,以得到固态的所需产物标题化合物:1H NMR(DMSO-d6,400MHz)7.63(t,1H),7.23(d,2H),6.96(d,2H),5.42(s,2H),4.25(d,2H),3.57(m,4H),3.52(s,3H),3.25(m,2H),3.13(m,2H),2.89(s,3H)ppm;MS(ES)M+H预测值=523.1,实测值:523.0。
1-(4-氯-2-{2-[4-(4-氯-苯基)-哌嗪-1-基]-2-氧代-乙基}-5-三氟甲基-2H-吡唑-3-基甲基)-3-乙基-脲的合成:
标题化合物是按照方案R制造的,在第二步中用2M溶于四氢呋喃的乙胺作为胺组分,以得到固态的所需产物标题化合物:1H NMR(DMSO-d6,400MHz)7.26(d,2H),7.03(d,2H),6.95(br,1H),6.47(br,1H),5.49(s,2H),4.17(s,IH),3.61(m,4H),3.28(m,2H),3.17(m,2H),2.95(q,2H),0.93(t,3H)ppm;MS(ES)M+H预测值=507.1,实测值=507.0
吡唑基系统与羧酸等价物的偶合
以下合成是这种化学类型的例子:在本发明其它地方描述了其它的实施例(方案N)。
4-氯-3-甲基-5-三氟甲基吡唑-1-基)-乙酸的合成
将4-氯-3-甲基-5-三氟甲基吡唑(10g,0.0539mol)加入乙腈(100mL)并在其中加入K2CO3(30g,0.213mol)。将混合物在室温下搅拌1小时并在其中缓慢加入溴乙酸乙酯(11g,0.065mol)。混合物然后在70℃搅拌12h。将混合物过滤并浓缩以得到粗制混合物。将此粗制产物从石油醚中重结晶以获得相应的酯。
将该酯(14.8g,0.0565mol)溶于THF(100mL)并在其中加入LiOH(6.9g)水溶液(50mL)。将混合物在室温下搅拌10小时。减压蒸发去过量的THF并用乙酸乙酯洗涤水性层以除去所有不水解的物质。水性层然后用1.5N HCl酸化并用乙酸乙酯萃取。将乙酸乙酯层干燥并浓缩以得到粗制的酸。从乙醚/pet中重结晶,所得产物为白色晶体。
将芳基哌嗪与吡唑基-乙酸衍生物偶合
方案P:通过HATU参与的偶合制备化合物:
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(2,5-二甲基-苯基)-哌嗪-1-基]-乙酮的合成
在溶于1.6mL无水二甲基甲酰胺的38mg(0.20mmol)1-(2,5-二甲基苯基)哌嗪和53mg(0.22mmol)(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸中加入62mg(0.6mmol)三乙胺,然后加入84mg(0.22mmol)O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸盐(HATU)。6小时后,将反应物在乙酸乙酯和水之间分配并将各相分离。水相用乙酸乙酯反萃取一次,合并的乙酸乙酯相用0.5M pH=7磷酸盐缓冲液,水,1M NaOH,水,盐水各洗涤一次。乙酸乙酯相然后用Na2SO4干燥,过滤并在真空下浓缩成残余物。将残余物溶于中等体积的在异丙醇中的5M HCl并用乙酸乙酯稀释溶液以进行沉淀。产物通过过滤分离以得到白色固体:1H NMR(DMSO-d6,400MHz)7.07(d 1H),6.90(s,1H),6.82(d,1H),5.39(s,2H),3.66(M,4H),2.98(m,2H),2.89(m,2H),2.26(s,3H),2.24(s,3H),2.20(s,3H)ppm;MS(ES)M+H预测值=415.1,实测值:415.1。
用HATU参与的偶合法制备的其它化合物的例子:
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(3-甲氧基-苯基)-哌嗪-1-基]-乙酮的合成:
标题化合物是按照方案P制备的,其中,1-(3-甲氧基苯基)哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到白色固体状的产物:1HNMR(DMSO-d6,400MHz)7.15(t,1H),6.65(d,1H),6.60(s,1H),6.47(d,1H),5.38(s,2H),3.72(s,3H),3.65(m,4H),3.28(m,2H),3.19(m,2H),2.18(s,3H)ppm;MS(ES)M+H预测值=417.1,实测值=417.1。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(4-氯-苯基)-2-(R)-甲基-哌嗪-1-基]-乙酮的合成:
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(4-氯苯基)-3-(R)-甲基哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到白色固体状的产物:1H NMR(CDCl3,300MHz)7.25(d 2H),6.83(d,2H),4.91(m,3H),4.28(m,1H),3.80-3.10(m,4H),2.86(m,IH),2.71(m,1H),2.29(s,3H),1.40(m,3H)ppm;MS(ES)预测值:M+H=435.1,实测值:435.0.
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-(4-O-甲苯基-哌嗪-1-基)-乙酮的合成:
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(2-甲基苯基)哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1HNMR(DMSO-d6,400MHz)7.14(m,2H),6.98(m,2H),5.37(s,2H),3.60(m,4H),2.89(m,2H),2.81(m,2H),2.27(s,3H),2.20(s,3H)ppm;MS(ES)M+H预测值=401.1,实测值=401.1。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(4-氯-苯基)-2-(S)-甲基-哌嗪-1-基]-乙酮的合成:
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(4-氯苯基)-3-(S)-甲基哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-I-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(CDCl3,300MHz)7.25(d 2H),6.83(d,2H),4.91(m,3H),4.28(m,1H),3.80-3.10(m,4H),2.86(m,1H),2.71(m,1H),2.29(s,3H),1.40(m,3H)ppm;MS(ES)M+H预测值=435.1,实测值=435.0.
2-(4-氯-3-三氟甲基-5-甲基-吡唑-1-基)-1-[4-(5-氟-2-甲氧基-苯基)-哌嗪-1-基]-乙酮的合成
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(2-甲氧基-5-氟苯基)哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz)6.93(m,1H),6.77(m,3H),5.36(s,2H),3.77(s,3H),3.59(m,4H),3.07(m,2H),2.98(m,2H),2.19(s,3H)ppm;MS(ES)M+H预测值:435.1,实测值:435.0。
2-{4-氯-3-甲基-5-三氟甲基-吡唑-1-基}-1-[4-(3-甲基硫烷基-苯基)-哌嗪-1-基]-乙酮的合成
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(3-甲基硫代苯基)哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-I-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz)7.21(t,IH),6.98(s,1H),6.91(d,IH),6.81(d,1H),5.39(s,2H),3.68(m,4H),3.34(m,2H),3.24(m,2H),2.44(s,3H),2.19(s,3H)ppm;MS(ES)M+H预测值:433.1,实测值:433.0.
1-[4-(4-溴-苯基)-哌嗪-1-基]-2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酮的合成:
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(4-溴苯基)哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1HNMR(DMSO-d6,400MHz)7.36(d,2H),6.92(d,2H),5.37(s,2H),3.60(m,4H),3.24(m,2H),3.14(m,2H),2.18(s,3H)ppm;MS(ES)M+H预测值=465.0,实测值=465.0。
2-(4-氯-3-三氟甲基-5-甲基-吡唑-1-基)-1-[4-(2,3-二甲基-苯基)哌嗪-1-基]-乙酮的合成
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(2,3-二甲基苯基)哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz)7.04(t,1H),6.99(m,2H),5.38(s,2H),3.64(m,4H),2.89(m,2H),2.81(m,2H),2.21(m,9H)ppm;MS(ES)M+H预测值:415.1,实测值:415.1.
2-(4-氯-3-三氟甲基-5-甲基-吡唑-1-基)-1-[4-(2-氯-5-甲氧基-苯基)-哌嗪-1-基]-乙酮的合成
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(2-氯-5-甲氧基苯基)哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz)7.31(d,1H),6.65(m,2H),5.37(s,2H),3.73(s,3H),3.62(m,4H),3.02(m,2H),2.96(m,2H),2.19(s,3H)ppm;MS(ES)M+H预测值=451.1,实测值=451.0。
1-[4-(4-溴-3-甲氧基-苯基)-哌嗪-1-基]-2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酮的合成:
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(4-溴-3-甲氧基苯基)哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz)7.34(d,1H),6.71(s,LH),6.52(d,1H),5.39(s,2H),3.82(s,3H),3.62(m,4H),3.30(m,2H),3.20(m,2H),2.19(s,3H)ppm;MS(ES)M+H预测值=495.0,实测值=495.0.
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(2,4-二氯-苯基)-哌嗪-1-基]-乙酮的合成:
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(2,4-二氯苯基)哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz)7.56(s,1H),7.36(d,1H),7.15(d,1H),5.37(s,2H),3.61(m,4H),3.01(m,2H),2.94(m,2H),2.19(s,3H)ppm;MS(ES)M+H预测值:455.0,实测值=454.9.
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(4-甲氧基-吡啶-2-基)-哌嗪-1-基]-乙酮的合成:
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(4-甲氧基-吡啶-2-基)-哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz)7.92(d,1H),6.67(s 1H),6.63(d,1H),5.42(s,2H),3.96(s,3H),3.88(m,2H),3.73(m,4H),3.62(m,2H),2.19(s,3H)ppm;MS(ES)M+H预测值=418.1,实测值=418.0.
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(3,4-二甲基-苯基)-哌嗪-基]-乙酮的合成:
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(3,4-二甲基苯基)-哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz)7.03(d,1H),6.94(br s,1H),6.84(br s,1H),5.38(s,2H),3.68(m,4H),3.25(m,2H),3.15(m,2H),2.18(s,6H),2.14(s,3H)ppm;MS(ES)M+H预测值=415.1,实测值=415.1。
2-(4-氯-3-三氟甲基-5-甲基-吡唑-1-基)-1-[4-(4-三氟甲氧基-苯基)-哌嗪-1-基]-乙酮的合成
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(4-三氟甲氧基苯基)-哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz)7.20(d,2H),7.04(d,2H),5.38(s,2H),3.60(m,4H),3.27(m,2H),3.17(m,2H),2.18(s,3H)ppm;MS(ES)M+H预测值=471.1,实测值=471.0.
2-(4-氯-3-三氟甲基-5-甲基-吡唑-1-基)-1-[4-(2,4-二氯-5-甲氧基-苯基)-哌嗪-1-基]-乙酮的合成
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(2,4-二氯-5-甲氧基苯基)-哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz)7.50(s,1H),6.84(s,1H),5.37(s,2H),3.85(s,3H),3.62(m,4H),3.07(m,2H),3.00(m,2H),2.19(s,3H)ppm;MS(ES)M+H预测值=485.1,实测值=485.0。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(4-硝基-苯基)-哌嗪-1-基]乙酮的合成:
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(4-硝基苯基)-哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,to give theproduct as a yellow solid:1H NMR(DMSO-d6,400MHz)8.05(d,2H),7.01(d,2H),5.38(s,2H),3.62(m,6H),3.52(m,2H),2.19(s,3H)ppm;MS(ES)预测值:M+H=432.1,实测值=432.0.
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(4-氯-2-甲氧基-苯基)-哌嗪-1-基]-乙酮的合成
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(4-氯-2-甲氧基苯基)-哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-I-基)-乙酸被用作偶合组分,以得到固体产物:LH NMR(DMS0-d6,400MHz)7.02(s,1H),6.93(m,2H),5.36(s,2H),3.82(s,3H),3.60(m,4H),3.03(m,2H),2.95(m,2H),2.19(s,3H)ppm;MS(ES)M+H预测值=451.1,实测值=451.0。
1-[4-(4-溴-3-甲基-苯基)-哌嗪-1-基]-2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酮的合成:
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(4-溴-3-甲基苯基)-哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz)7.38(d,1H),7.01(s,LH),6.78(d,1H),5.38(s,2H),3.60(m,4H),3.26(m,2H),3.16(m,2H),2.28(s,3H),2.19(s,3H)ppm;MS(ES)M+H预测值=479.0,实测值=478.9.
1-[4-(4-乙酰基-苯基)-哌嗪-1-基]-2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酮的合成:
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(4-乙酰基-苯基)哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz)7.80(d,1H),6.98(d,2H),5.38(s,2H),3.61(m,4H),3.48(m,2H),3.39(m,2H),2.46(s,3H),2.19(s,3H)ppm;MS(ES)M+H预测值=429.1,实测值=429.0。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(3,4-二氯-苯基)-哌嗪-1-基]-乙酮的合成:
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(3,4-二氯苯基)哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz)7.40(d,IH),7.16(s,IH),6.95(d,1H),5.37(s,2H),3.59(m,4H),3.31(m,2H),3.21(m,2H),2.18(s,3H)ppm;MS(ES)M+H预测值=455.0,实测值=455.0.
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(3-氯-苯基)-哌嗪-1-基]-乙酮:
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(3-氯苯基)哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1HNMR(DMSO-d6,400MHz)7.23(t,1H),7.19(s,1H),6.90(d,1H),6.79(d,1H),5.37(s,2H),3.58(m,4H),3.29(m,2H),3.19(m,2H),2.18(s,3H)ppm;MS(ES)M+H预测值=421.1,实测值=421.0。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-(4-间甲苯基-哌嗪-1-基)-乙酮的合成
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(3-甲基苯基)哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:HNMR(DMSO-d6,400MHz)7.17(t,IH),6.97(br,2H),6.77(d,1H),5.39(s,2H),3.68(m,4H),3.31(m,2H),3.22(m,2H),2.27(s,3H),2.19(s,3H)ppm;MS(ES)M+H预测值=401.1,实测值=401.1.
1-[4-(4-氯-3-甲氧基-苯基)-哌嗪-1-基]-2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酮的合成:
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(4-氯-3-甲氧基苯基)哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-I-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz)7.21(d,1H),6.74(s,1H),6.56(d,1H),5.39(s,2H),3.82(s,3H),3.63(m,4H),3.30(m,2H),3.19(m,2H),2.19(s,3H)ppm;MS(ES)M+H预测值=451.1,实测值:451.0。
4-{4-[2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酰基]-哌嗪-1-基}-苯甲酸甲酯:
标题化合物是按照HATU参与的偶合方案P制备的,其中,4-哌嗪-I-基-苯甲酸甲酯和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz)7.78(d,2H),6.98(d,2H),5.38(s,2H),3.71(s,3H),3.60(m,4H),3.46(m,2H),3.37(m,2H),2.19(s,3H)ppm;MS(ES)预测值:M+H=445.1,实测值:445.0.
2-(4-氯-3,5-二甲基-吡唑-1-基)-1-(4-吡啶-4-基-哌嗪-1-基)-乙酮的合成
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(4-吡啶基)哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:LHNMR(DMSO-d6,400MHz)8.28(d,2H),7.18(d,2H),5.41(s,2H),3.83(m,2H),3.72(m,4H),3.63(m,2H),2.18(s,3H)ppm;MS(ES)M+H预测值=388.1,实测值=388.0。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(5-甲氧基-2-甲基-苯基)-哌嗪-1-基]-乙酮的合成
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(3-甲氧基-5-甲基苯基)哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz)7.06(d,1H),6.56(m,2H),5.38(s,2H),3.69(s,3H),3.62(m,4H),2.92(m,2H),2.84(m,2H),2.20(s,3H)ppm;MS(ES)M+H预测值=431.1,实测值=431.1.
2-(4-氯-3-三氟甲基-5-甲基-吡唑-1-基)-1-(4-苯基-哌嗪-1-基)-乙酮的合成:
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-苯基哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1HNMR(DMSO-d6,400MHz)7.32(m 4H),7.02(m,1H),5.40(s,2H),3.74(m,4H),3.39(m,2H),3.29(m,2H),2.19(s,3H)ppm;MS(ES)预测值:M+H=387.1,实测值:387.1。
1-[4-(4-氯-3-乙氧基-苯基)-哌嗪-1-基]-2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酮的合成:
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(4-氯-3-乙氧基苯基)哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz)7.20(d,1H),6.66(s,1H),6.48(d,1H),5.38(s,2H),4.08(q,2H),3.61(m,4H),3.25(m,2H),3.16(m,2H),2.18(s,3H),1.33(t,3H)ppm;MS(ES)M+H预测值=465.1,实测值:465.0.
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-(4-吡啶-2-基-哌嗪-1-基)-乙酮的合成:
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(2-吡啶基)哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1HNMR(DMSO-d6,400MHz)8.11(d,IH),7.53(t,1H),6.85(d,1H),6.65(t,1H),5.37(s,2H),3.59-3.50(m,8H),2.18(s,3H)ppm;MS(ES)M+H预测值=388.1,实测值=388.0。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-(4-P-甲苯基-哌嗪-1-基)-乙酮的合成:
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(4-甲基苯基)哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1HNMR(DMSO-d6,400MHz)7.20(m,4H),5.40(s,2H),3.79(m,4H),3.37(m,2H),3.28(m,2H),2.49(s,3H),2.19(s,3H)ppm;MS(ES)M+H预测值=401.1,实测值:401.0.
1-[(4-甲烷磺酰基-苯基)-哌嗪-1-基]-2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酮的合成
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(4-甲基磺酰-苯基)-哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz)7.69(d,2H),7.08(d,2H),5.38(s,2H),3.59(m,4H),3.49(m,2H),3.38(m,2H),3.09(s,3H),2.19(s,3H)ppm;MS(ES)M+H预测值=465.1,实测值=465.0。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(4-氯-苯基)-哌嗪-1-基]-乙酮的合成。
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(4-氯苯基)-哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1HNMR(CDCl3,400MHz)7.22(d,2H),6.83(d,2H),4.99(s,2H),3.77(m,2H),3.72(m,2H),3.19(m,2H),3.16(m,2H),2.28(s,3H)ppm;MS(ES)M+Na预测值=443.0,实测值:443.0。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(4-甲氧基-苯基)-哌嗪-1-基]-乙酮的合成。
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(4-甲氧基苯基)-哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(CDCl3,400MHz)6.88(m,4H),5.00(s,2H),3.78(m,3H),3.76(m,2H),3.70(m,2H),3.08(m,4H),2.30(s,3H)ppm;MS(ES)M+Na预测值=439.0,实测值:439.0。
4-{4-[2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酰基]-哌嗪-1-基}-苯腈的合成
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(4-氰基苯基)-哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1HNMR(CDCl3,400MHz)7.44(d,2H),6.77(d,2H),4.90(s,2H),3.67(m,4H),3.29(m,4H),2.22(s,3H)ppm;MS(ES)M+Na预测值=434.0,实测值:434.0。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(2-氟-苯基)-哌嗪-1-基]-乙酮的合成
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(2-氟苯基)-哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1HNMR(CDCl3,400MHz)7.02(m,4H),5.00(s,2H),3.80(m,2H),3.70(m,2H),3.53(m,2H),3.25(m,2H),2.30(s,3H)ppm;MS(ES)M+Na预测值=427.0,实测值:427.0.
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(2-甲氧基-苯基)-哌嗪-1-基]-乙酮的合成
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(2-甲氧基苯基)-哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:LH NMR(CDCl3,400MHz)6.62(m,1H),6.48(m,3H),5.01(s,2H),3.73(s,3H),3.61(m,4H),3.43(m,2H),2.31(s,3H)ppm;MS(ES)M+H预测值=439.0,实测值:439.1。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(3-三氟甲基-苯基)-哌嗪-1-基]-乙酮的合成
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(3-三氟甲基苯基)-哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(CDCl3,400MHz)7.38(m,1H),7.11(m,3H),5.00(s,2H),3.79(m,2H),3.73(m,2H),3.27(m,2H),3.23(m,2H),2.30(s,3H)ppm;MS(ES)M+H预测值=455.0,实测值:455.0。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-(4-嘧啶-2-基-哌嗪-1-基)-乙酮的合成:
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(2-嘧啶基)-哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:MS(ES)M+H预测值=389.1,实测值=389.0;HPLC保留时间=3.99分钟(AgilentZorbax SB-C18,2.1×50mm,5U,35℃),20%-95%B梯度4.5分钟(A=0.1%甲酸/5%乙腈/94.9%水,B=0.08%甲酸/99.9%乙腈)。
1-[4-(4-氯-3-异丙氧基-苯基)-哌嗪-1-基]-2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酮的合成
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(4-氯-3-异丙氧基-苯基)-哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz)7.21(d,1H),6.71(s,1H),6.53(d,1H),5.38(s,2H),4.66(m,1H),3.58(m,4H),3.25(m,2H),3.15(m,2H),2.18(s,3H),1.26(d,6H)ppm;MS(ES)M+H预测值=479.1,实测值=479.0。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(3,4-二氟-苯基)哌嗪-1-基]-乙酮的合成
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(3,4-二氟苯基)-哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz,非F-去偶合的)7.25(q,1H),7.04(m,LH),6.74(d,IH),5.37(s,2H),3.57(m,4H),3.24(m,2H),3.12(m,2H),2.18(s,3H)ppm;MS(ES)M+H预测值=423.1,实测值:423.0。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(6-甲氧基-吡啶-2-基)-哌嗪-1-基]-乙酮的合成
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(6-甲氧基-吡啶-2-基)-哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz)7.45(t,1H),6.34(d,LH),6.05(d,1H),5.37(s,2H),3.77(s,3H),3.50(m,6H),3.34(m,2H),2.18(s,3H)ppm;MS(ES)M+H预测值=418.1,实测值=418.0。
4-{4-[2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酰基]-哌嗪-1-基}-N,N-二甲基-苯磺酰胺的合成:
标题化合物是按照HATU参与的偶合方案P制备的,其中,N,N-二甲基-4-哌嗪-1-基-苯磺酰胺和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz)7.54(d,2H),7.08(d,2H),5.38(s,2H),3.62(m,4H),3.48(m,2H),3.37(m,2H),2.19(s,3H)ppm;MS(ES)M+H预测值=494.1,实测值=494.0.
1-[4-(4-氯-3-甲基-苯基)-哌嗪-1-基]-2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酮的合成
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(4-氯-3-甲基苯基)-哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz)7.25(d,1H),7.05(s,1H),6.90(d,1H),5.38(s,2H),3.64(m,4H),3.27(m,2H),3.17(m,2H),2.26(s,3H),2.19(s,3H)ppm;MS(ES)M+H预测值=435.1,实测值=435.0。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(3-羟基-苯基)-哌嗪-1-基]-乙酮的合成
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(3-羟基苯基)-哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:IH NMR(DMSO-d6,400MHz)7.10(t,1H),6.66(m,2H),6.45(d,1H),5.39(s,2H),3.74(m,4H),3.33(br,2H),3.24(br,2H),2.19(s,3H)ppm;MS(ES)M+H预测值=403.1,实测值:403.0.
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(4-三氟甲基-苯基)-哌嗪-1-基]-乙酮的合成
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(4-三氟甲基苯基)-哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz)7.50(d,2H),7.07(d,2H),5.38(s,2H),3.60(m,4H),3.41(m,2H),3.31(m,2H),2.19(s,3H)ppm;MS(ES)M+H预测值=455.1,实测值=455.0。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-(3-甲基-4-间甲苯基-哌嗪-1-基)-乙酮的合成:
标题化合物是按照HATU参与的偶合方案P制备的,其中,1-(3-甲基苯基)-2-甲基-哌嗪和(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-乙酸被用作偶合组分,以得到固体产物:1H NMR(DMSO-d6,400MHz)7.68(br,1H),7.17(br,1H),6.71(br,2H),5.41(m,2H),4.08(m,4H),3.70(m,2H),3.50(br m,2H),2.30(s,3H),2.18(s,3H),1.01(m,3H)ppm;MS(ES)M+H预测值=415.1,实测值=415.1。
方案S:氯乙酰基芳基哌嗪的制备
2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮的合成
将1-(4-氟苯基)哌嗪(2.8mmol)溶于10mL CH2Cl2。在其中加入三乙胺(5.5mmol)并使反应物冷却至0℃。在其中缓慢加入氯乙酰氯(4.2mmol)并使反应物在室温下过夜。反应完成后用盐水终止反应并用二氯甲烷萃取反应混合物。合并的有机相用盐水和水洗涤并用硫酸镁干燥。蒸发去溶剂并通过柱层析(己烷/乙酸乙酯=1.5/1)纯化化合物以得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):86.9-7.2(m,2H),6.82-6.92(m,2H),4.1(s,2H),6.62-3.8(m,4H),3.46-3.6(m,4H)。13C NMR(400MHz,CDCl3):164,158,156.2,148.5,118.2,116.8,52.6,52.2,48,46,42.1,40.6。
2-氯-1-[4-(4-氯-苯基)-哌嗪-1-基]-乙酮的合成
用1-(4-氯-苯基)哌嗪,Et3N,氯乙酰氯和二氯甲烷按照方案S进行制备。用溶剂混合物(己烷/乙酸乙酯=1.5/1)进行柱层析得到白色固体状的标题化合物。
2-氯-1-[4-(4-氯-3-甲氧基-苯基)-哌嗪-1-基]-乙酮的合成
用1-(4-氯-3-甲氧基苯基)哌嗪,Et3N,氯乙酰氯和二氯甲烷按照方案S进行制备。用溶剂混合物(己烷/乙酸乙酯=1.5/1)进行柱层析以得到白色固体状的标题化合物。
2-氯-1-[4-(4-溴-3-甲氧基-苯基)-哌嗪-1-基]-乙酮的合成
用1-(4-溴-3-甲氧基苯基)哌嗪,Et3N,氯乙酰氯和二氯甲烷按照方案S进行制备。用溶剂混合物(己烷/乙酸乙酯=1.5/1)进行柱层析以得到白色固体状的标题化合物。
2-氯-1-[4-(4-氯-苯基)-2-甲基-(R)-哌嗪-1-基]-乙酮的合成
用1-(4-氯-苯基)-3-(R)-甲基-哌嗪,ET3N,氯乙酰氯和二氯甲烷按照方案S进行制备。进行柱层析以得到标题化合物。
2-氯-1-[4-(4-氯-苯基)-2-甲基-(S)-哌嗪-1-基]-乙酮的合成
用1-(4-氯-苯基)-3-(S)-甲基-哌嗪,Et3N,氯乙酰氯和二氯甲烷按照方案S进行制备。进行柱层析以得到标题化合物。
方案T:K2CO3参与的氯乙酰基芳基哌嗪和吡唑的偶合反应
1-[4-(4-氟-苯基)-哌嗪-1-基]-2-吡唑-1-基-乙酮的合成
将吡唑(112.33mg,1.65mmol)溶于DMF(10mL)。在其中加入K2CO3(228.05mg,1.65mmol)和2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮(300mg,1.67mmol)。将反应物在80℃加热14h。反应完成后,将反应物冷却至室温,用盐水终止反应然后用乙酸乙酯萃取。有机层再用水(2×25mL)和盐水(2×25mL)洗涤并用硫酸镁干燥。然后通过旋转蒸发除去溶剂以得到粗制产物,粗制产物在硅胶上用溶剂混合物(己烷/乙酸乙酯=1/1)通过柱层析纯化,以得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):7.2-7.58(d,2H),6.94-7.2(t,2H),6.84-6.9(dd,2H),6.32-6.36(t,1H),5.6(s,2H),3.76-3.82(m,2H),3.68-3.74(m,2H),3.04-3.1(m,2H),3.0-3.04(m,2H)。13C NMR(400MHz,CDCl3):165,158,146.5,140,130,118.4,118.2,116,115.8,107,54,51,50.845.8,42.8。
2-(4-氯-5-苯基-3-三氟甲基-吡唑-1-基)-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和2-(4-氯-3-苯基-5-三氟甲基-吡唑-1-基)-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮的合成
用4-氯-5-苯基-3-三氟甲基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF,按照方案T进行制备。用溶剂混合物(己烷/乙酸乙酯=1.5/1)进行柱层析以得到标题化合物的混合物,它们都是白色固体。
1H NMR(400MHz,CDCl3):7.44-7.54(m,5H),6.94-7.2(t,2H),6.84-6.9(dd,2H),4.94(s,1H),3.72-3.8(m,2H),3.5-3.6(m,2H),3.0-3.1(m,4H)。13C NMR(400MHz,CDCl3)0163.8,158,146.5,130,128.6,128.2,118.2,114.5,52,50,44.5,42.
1H NMRR(400MHz,CDCl3):7.82-7.88(m,2H),7.38-7.48(m,3H),6.96-7.04(m,2H),6.86-6.94(m,2H),5.2(s,1H),3.76-3.86(m,2H),3.62-3.68(m,2H),3.06-3.22(m,4H)。3C NMR(400MHz,CDCl3):164,130,128.4,126,118,116.4,52,50,43.8,41.6。
2-{2-[4-(4-氟-苯基)-哌嗪-1-基]-2-氧代-乙基}-5-噻吩-2-基-2H-吡唑-3-羧酸乙酯的合成
用5-噻吩-2-基-2H-吡唑-3-羧酸乙酯,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物(己烷/乙酸乙酯=1.5/1)进行柱层析以得到标题化合物。1H NMR(400MHz,CDCl3):7.32-7.36(m,1H),7.22-7.26(m,1H),7.08(s,1H),7.02-7.08(dd,1H),6.96-7.2(m,2H),6.86-6.92(m,2H),4.3-4.4(q,2H),3.52-3.58(m,4H),3.05-3.25(m,4H),1.3-1.42(m,3H)。13CNMR(400MHz,CDCl3):164,130,126.8,126.4,120,118.2,115.4,62.3,54,50.5,42,44.5,14.6。
2-(3-氨基-4-溴-5-苯基-吡唑-1-基)-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮的合成
用4-溴-5-苯基-1H-吡唑-3-基胺,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=3/7)以得到黄色固体状的标题化合物。1H NMR(400MHz,CDCl3):7.74-7.78(m,2H),7.24-7.36(m,3H),6.86-6.92(m,2H),6.74-6.78(m,2H),4.9(s,2H),4.22(s,2H),3.64-3.74(m,4H),2.86-3.04(m,4H)。’3C NMR(400MHz,CDCl3):164,146.2,144.8,128,126.8,118,114.8,60,50.2,50,48.8,46,42,20。
2-(3-氨基-4-溴-5-苯基-吡唑-1-基)-1-[4-(4-氯-苯基)-哌嗪-1-基]-乙酮的合成
用4-溴-5-苯基-1H-吡唑-3-基胺,K2CO3,2-氯-1-[4-(4-氯-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/4)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3);7.7-7.8(m,2H),7.24-7.3(m,3H),6.8-6.92(m,2H),6.74-6.78(m,2H),4.9(s,2H),4.2(s,2H),3.6-3.7(m,4H),2.86-3.04(m,4H)。13C NMR(400MHz,CDCl3):164,146,145,128,127,118,114.8,60.2,50.4,50,48.8,46,42,22。
1-[4-(4-氟-苯基)-哌嗪-1-基]-2-(3-七氟丙基-5-甲基-4-硝基-吡唑-1-基)-乙酮的合成
用3-七氟丙基-5-甲基-4-硝基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=3/7)以得到标题化合物as OIL.1H NMR(400MHz,CDCl3):6.9-7.0(m,2H),6.8-6.9(m,2H),5.06-5.14(d,2H),3.6-3.8(m,4H),3.06-3.18(m,4H),2.56-2.66(d,3H)。13C NMR(400MHz,CDCl3):160,146.2,144,119.2,118,52.2,50.8,50.4,46,42.2,12。
1-[4-(4-氯-苯基)-哌嗪-1-基]-2-(4-氯-5-苯基-3-三氟甲基-吡唑-1-基)-乙酮的合成
用4-氯-5-苯基-3-三氟甲基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氯-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=2/3)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3);7.82-7.84(m,2H),7.4-7.48(m,3H),6.9-7.04(m,2H),6.88-6.94(m,2H),5.22(s,1H),3.76-3.88(m,2H),3.6-3.68(m,2H),3.1-3.22(m,4H)。13C NMR(400MHz,CDCl3):164.2,130.4,128,126,118.2,116.4,52.2,50,44,41.8。
1-[4-(4-氟-苯基)-哌嗪-1-基]-2-(4-溴-5-甲基-3-三氟甲基-吡唑-1-基)-乙酮的合成
用4-溴-5-甲基-3-三氟甲基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=2/3)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):6.96-7(m,2H),6.84-6.9(m,2H),5(s,2H),3.6-3.8(m,4H),3.02-3.16(m,4H),2.3(s,3H)。13C NMR(400MHz,CDCl3):162.6,146.5,142,118.5,116,52.2,50.4,46,42.2,15。
1-[4-(4-氯-苯基)-哌嗪-1-基]-2-(4-溴-5-甲基-3-三氟甲基-吡唑-1-基)-乙酮的合成
用4-溴-5-甲基-3-三氟甲基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氯-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=2/3)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):6.96-7.1(m,2H),6.84-6.89(m,2H),5.2(s,2H),3.6.2-3.8(m,4H),3.0-3.16(m,4H),2.32(s,3H)。13C NMR(400MHz,CDCl3):162,146.4,142.2,118.5,116.2,52,50.4,46.2,42.2,15.2。
1-[4-(4-氯-苯基)-哌嗪-1-基]-2-(3-七氟丙基-5-甲基-4-硝基-吡唑-1-基)-乙酮的合成
用3-七氟丙基-5-甲基-4-硝基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氯-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/4,Rf=0.81)以得到无色油状的标题化合物。1H NMR(400MHz,CDCl3):66.92-7.02(m,2H),6.82-6.9(m,2H),5.04-5.14(m,2H),3.64-3.82(m,4H),3.06-3.18(m,4H),2.6-2.66(d,3H)。13C NMR(400MHz,CDCl3):160.4,146,144.2,119.2,118.2,52,50.8,50.6,46,42,12.2。
1-[4-(4-氯-3-甲氧基苯基)-哌嗪-1-基]-2-(4-氯-5-苯基-3-三氟甲基-吡唑-1-基)-乙酮的合成
用4-氯-5-苯基-3-三氟甲基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氯-3-甲氧基-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=2/3)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):7.4-7.52(m,5H),7.18-7.22(d,1H),6.44-6.48(d,1H),6.36-6.42(dd,1H),4.72(s,2H),3.86(s,3H),3.5-3.78(m,4H),3.1(s,4H)。3C NMR(400MHz,CDCl3)164,156.2,150.4,130.5,130,128.5,110,102.2,56,52,50,44.8,42。
1-[4-(4-溴-3-甲氧基苯基)-哌嗪-1-基]-2-(4-氯-3-苯基-5-三氟甲基-吡唑-1-基)-乙酮的合成
用4-氯-5-苯基-3-三氟甲基-1H-吡唑,K2CO3,2-氯-1-[4-(4-溴-3-甲氧基-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=2/3)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):7.42-7.52(m,4H),7.36-7.38(d,1H),6.42-6.46(d,1H),6.34-6.38(dd,1H),4.72(s,2H),3.88(s,3H),3.74-3.78(m,2H),3.54-3.58(m,2H),3.12-3.18(m,4H)。13C NMR(400MHz,CDCl3):164,156.2,152,132.6,130.2,130,128.8,110,102.2,56,52,50,44.8,42。
1-[4-(4-氯-3-甲氧基-哌嗪-1-基)-2-(4-溴-5-甲基-3-三氟甲基-吡唑-1-基)-乙酮的合成
用4-溴-5-甲基-3-三氟甲基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氯-3-甲氧基-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/4)得到白色固体状的标题化合物。IH NMR(400MHz,CDCl3):7.18-7.22(d,1H),6.44-6.48(d,1H),6.36-6.42(dd,1H),5.0(s,2H),3.6.2-3.8(m,4H),3.1-3.2(m,4H),2.3(s,3H)。3C NMR(400MHz,CDCl3):162,146.6,142.2,118.8,116,52.2,50.4,46.2,42.2,15.2。
2-(3-氨基-4-溴-5-苯基-吡唑-1-基)-1-[4-(4-氯-3-甲氧基苯基)-哌嗪-1-基]-乙酮的合成
用4-溴-5-苯基-1H-吡唑-3-基胺,K2CO3,2-氯-1-[4-(4-氯-3-甲氧基-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/4)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):7.78-7.84(d,2H),7.32-7.42(m,3H),7.18-7.22(d,1H),6.44-6.48(d,1H),6.36-6.42(dd,1H),4.94(s,2H),4.28(s,2H),3.88(s,3H),3.76-3.86(m,4H),3.12-3.18(m,4H)。3C NMR(400MHz,CDCl3):164.6,154.8,150.2,144.6,130,128.2,128,126.4,109.2,102,56,51,50,49.6,45.6,42。
2-(3-氨基-4-氯-5-甲基-吡唑-1-基)-1-[4-(4-氯-3-甲氧基苯基)-哌嗪-1-基]-乙酮的合成
用4-氯-5-甲基-1H-吡唑-3-基胺,K2CO3,2-氯-1-[4-(4-氯-3-甲氧基-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/4)以得到无色油状的标题化合物。1H NMR(400MHz,CDCl3):7.18-7.22(d,1H),6.44-6.48(d,1H),6.36-6.42(dd,1H),5.0(s,2H),4.24(s,2H),2.4(s,3H),3.76-3.86(m,4H),3.12-3.18(m,4H)。13C NMR(400MHz,CDCl3):164.6,154.8,144.6,130.2,130,128.8,109.2,102,56,51,49.6,45.6,42。
1-[4-(4-溴-3-甲氧基-哌嗪-1-基)-2-(4-溴-5-甲基-3-三氟甲基-吡唑-1-基)-乙酮的合成
用4-溴-5-甲基-3-三氟甲基-1H-吡唑,K2CO3,2-氯-1-[4-(4-溴-3-甲氧基-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/4)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):7.38-7.4(d,1H),6.44-6.46(d,1H),6.26-6.4(dd,2H),5.0(s,2H),3.88(s,3H),3.68-3.8(m,4H),3.14-3.22(m,4H),2.3(s,3H)。13C NMR(400MHz,CDCl3):164.4,158,152.2,144,134,110,102.2,56.6,54.2,50,48.8,46,42.2,12.
1-[4-(4-氟-苯基)-哌嗪-1-基]-2-(3-噻吩-2-基-吡唑-1-基)-乙酮的合成
用3-(2-噻吩基)吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/1)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3);7.48-7.52(d,1H),7.24-7.28(dd,1H),7.14-7.2(dd,1H),6.98-7.2(m,1H),6.88-6.96(m,2H),6.78-6.84(m,2H),6.46-6.52(d,1H),5.0(s,2H),3.64-3.8(m,4H),2.94-3.1(m,4H)。13C NMR(400MHz,CDCl3):164.4,158,152.2,144,134,132,126,124,123.8,118,116,115.8,102.2,54,51.2,50.8,45.8,42.2。
2-(4-氯-3-三氟甲基-吡唑-1-基)-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮的合成
用4-氯-3-三氟甲基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/1)以得到无色油状的标题化合物。1H NMR(400MHz,CDCl3):7.64-7.68(d,1H),6.98-7.4(m,2H),6.86-6.92(m,2H),6.98-7.2(m,1H),5.4(s,2H),3.78-3.84(m,2H),3.68-3.92(m,2H),3-3.1(m,4H)。L3C NMR(400MHz,CDCl3):164.4,158,152.2,144,132,118.2,116,54,50.2,50.0,46.0,42.2.
1-[4-(4-氟-苯基)-哌嗪-1-基]-2-(3,4,5-三溴-吡唑-1-基)-乙酮的合成
用3,4,5-三溴-1H-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/4)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):6.96-7.2(m,2H),6.84-6.9(m,2H),5.4(s,2H),3.74-3.8(m,2H),3.6-3.68(m,2H),3.04-3.14(m,4H)。13C NMR(400MHz,CDCl3):164.4,158,156,144.2,128,118.4,118.2,116,100,52.8,50.2,50.0,46.0,42.2。
2-(3-叔丁基-4-氯-5-三氟甲基-吡唑-1-基)-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮的合成
用5-叔丁基-4-氯-3-三氟甲基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/1)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):6.94-7.22(m,2H),6.84-6.92(m,2H),5.3(s,2H),3.68-3.8(m,2H),3.6-3.68(m,2H),3.04-3.2(m,4H),1.4(s,9H)。13C NMR(400MHz,CDCl3):164.8,119,118.4,118.2,116.2,116,54,51,50.8,45.4,42.2,30,29,27.
2-[3-(4-氟-苯基)-5-甲基硫烷基-吡唑-1-基]-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮的合成
用3-(4-氟-苯基)-5-甲基硫烷基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=2/3)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):7.7-7.76(m,2H),6.96-7.1(m,4H),6.88-6.92(m,2H),6.64(s,1H),5.3(s,2H),3.7-3.84(m,4H),3.04-3.2(m,4H),2.5(s,3H)。13C NMR(400MHz,CDCl3):164.8,152,140,127.4,119,118.4,118.2,116.2,116,108,52.8,52,51.8,45.4,42.2,20。
2-[4-氯-5-(4-氟-苯基)-3-甲基硫烷基-吡唑-1-基]-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮的合成
用4-氯-3-(4-氟-苯基)-5-甲基硫烷基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=2/3)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):7.82-7.88(m,2H),7.06-7.12(m,2H),6.96-7.1(m,2H),6.88-6.92(m,2H),5.2(s,2H),3.68-3.84(m,4H),3.06-3.18(m,4H),2.4(s,3H)。�;3C NMR(400MHz,CDCl3):164.8,158,147,135,127.4,127,119,112.4,112.2,110,108.8,52.8,52,51.8,45.4,42.2,18.6。
2-[4-氯-3-(4-氟-苯基)-5-甲基硫烷基-吡唑-1-基]-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮的合成
用4-氯-3-(4-氟-苯基)-5-甲基硫烷基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=2/3)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):7.46-7.5(m,2H),7.12-7.18(m,2H),6.96-7.1(m,2H),6.88-6.92(m,2H),4.86(s,2H),3.72-3.78(m,2H),3.56-3.62(m,2H),3.06-3.18(m,4H),2.54(s,3H)。
2-{2-[4-(4-氟-苯基)-哌嗪-1-基]-2-氧代-乙基}-4-氯-3-噻吩-2-基-2H-吡唑-5-羧酸乙酯的合成
用4-氯-3-噻吩-2-基-2H-吡唑-5-羧酸乙酯,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1.5/1,Rf=0.62)以得到标题化合物。1H NMR(400MHz,CDCl3):7.06-7.36(m,1H),6.96-7.2(m,3H),6.84-6.92(m,3H),54.46(s,2H),4.3-4.4(q,2H),3.6-3.82(m,4H),3.05-3.25(m,4H),1.3-1.42(m,3H)。
2-(4-氨基-3-七氟丙基-5-甲基-吡唑-1-基)-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮的合成
用4-氨基-3-七氟丙基-5-甲基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/4)以得到无色油状的标题化合物。1H NMR(400MHz,CDCl3);6.92-7.02(m,4H),5.14(s,2H),3.64-3.82(m,4H),3.6(s,2H),3.1-3.22(m,4H),2.16(s,3H)。13C NMR(400MHz,CD6CO):160.4,158,146,144.2,119.8,118.2,52,50.8,50.6,46,42,12.2。
2-(5-丁基-3-三氟甲基-吡唑-1-基)-1-[4-(4-氯-苯基)-哌嗪-1-基]-乙酮的合成
用5-正丁基-3-三氟甲基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/4)以得到无色油状的标题化合物。1H NMR(400MHz,CDCl3):7.18-7.24(m,2H),6.78-6.84(m,2H),6.32(s,1H),5.0(s,2H),3.66-3.78(m,4H),3.08-3.18(m,4H),2.58-2.64(t,2H),1.6-1.7(m,2H),1.38-1.48(m,2H),0.6-1.0(t,3H)。13C NMR(400MHz,CDCl3):160.4,150,148,142,130,126,119.8,103.2,52,50.8,50.6,46,42,30,26,22,14。
2-(4-氯-5-丁基-3-三氟甲基-吡唑-1-基)-1-[4-(4-氯-苯基)-哌嗪-1-基]-乙酮的合成
用4-氯-5-正丁基-3-三氟甲基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/4)以得到无色油状的标题化合物。1H NMR(400MHz,CDCl3):7.18-7.24(m,2H),6.78-6.84(m,2H),5.0(s,2H),3.66-3.78(m,4H),3.08-3.2(m,4H),2.58-2.64(t,2H),1.5-1.54(m,2H),1.38-1.48(m,2H),0.6-1.0(t,3H)。3C NMR(400MHz,CDCl3):160.4,148,142,130,128,119.8,52,50.8,50.6,46,42,30.4,26,23,14。
2-(3-氨基-4-溴-5-苯基-吡唑-1-基)-1-[4-(4-溴-3-甲氧基苯基)-哌嗪-1-基]-乙酮的合成
用4-溴-5-苯基-1H-吡唑-3-基胺,K2CO3,2-氯-1-[4-(4-溴-3-甲氧基-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/1.5)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):7.78-7.84(d,2H),7.32-7.42(m,3H),7.18-7.22(d,1H),6.44-6.52(d,1H),6.36-6.42(dd,1H),4.94(s,2H),4.28(s,2H),3.84(s,3H),3.76-3.82(m,4H),3.12-3.18(m,4H)。13C NMR(400MHz,CDCl3):164.6,154.8,150.2,144.6,130,128.8,128.6,126.4,109.2,102,56,51,50,49.6,45.6,42。
2-(4-溴吡唑)-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮的合成
用4-溴-1H-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/1)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):7.52-7.58(d,1H),7.48-7.52(d,1H),6.95-7.0(m,2H),6.82-6.92(dd,2H),5.00(s,2H),3.72-3.80(t,2H),3.64-3.72(t,2H),3.02-3.12(m,4H)。″C NMR(400MHz,CDCl3):164.6,158.2,156.2,146.6,141.6,140.2,130.5,129.6,118.2,118.0,115.2,116.4,94.2,53.8,50.8,50.2,45.4,42。
2-(4-碘吡唑)-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮的合成
用4-碘-1H-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/1)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3);7.58-7.62(d,1H),7.52(s,1H),6.95-7.1(m,2H),6.84-6.92(dd,2H),5.00(s,2H),3.72-3.80(t,2H),3.64-3.72(t,2H),3.02-3.12(m,4H)。13C NMR(400MHz,CDCl3):164.6,158.2,156.2,146.8,140.8,140.2,130.5,129.6,118.2,118.0,115.4,116.8,96.0,53.4,51.2,50.2,45.2,42。
2-(3,5-二异丙基-吡唑-1-基)-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮的合成
用3,5-二异丙基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/1)以得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):6.92-7.0(m,2H),6.80-6.88(dd,2H),5.88(s,1H),4.92(s,2H),3.70-3.80(t,4H),2.90-3.10(m,4H),1.40-1.60(m,12H)。13C NMR(400MHz,CDCl3):160.6,158.2,150.2,119.2,118.0,100.0,50.8,50.5,50.2,45.2,42,28.2,26.0,22.4。
1-{2-[4-(4-氟-苯基)-哌嗪-1-基]-2-氧代-乙基}-3-三氟甲基-1H-吡唑-4-羧酸乙酯的合成
用3-三氟甲基-1H-吡唑-4-羧酸乙酯,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/1)以得到无色油状的标题化合物。1H NMR(400MHz,CDCl3);8.15(s,1H),6.98-7.04(m,2H),6.86-6.92(m,2H),5.1(s,2H),4.28-4.38(q,2H),3.78-3.84(m,2H),3.62-3.74(m,2H),3.04-3.2(m,4H),1.3-1.4(t,3H)。13C NMR(400MHz,CDCl3):163.4,160.5,159.2,156.2,147,137.2,119,118.8,116,115.8,61,54,50.8,50.0,45.0,42.2,14.2。
1-[4-(4-氟-苯基)-哌嗪-1-基]-2-(4-碘-3,5-二甲基-吡唑-1-基)-乙酮的合成
用4-碘-3,5-二甲基-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/1)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3);6.95-7.1(m,2H),6.84-6.92(dd,2H),5.00(s,2H),3.62-3.82(m,4H),3.02-3.12(m,4H),2.22-2.32(d,6H)。13CNMR(400MHz,CDCl3):165,158.2,156.2,150.2,146.8,141.8,118.8,115.4,115.2,52.8,51.6,50.2,45.2,42,14.8,12.6。
2-(3-氯-吲唑-1-基)-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮的合成
用3-氯-1H-吲唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/4)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3);7.64-7.70(m,1H),7.38-7.48(m,2H),7.18-7.26(m,2H),6.94-7.0(m,2H),6.82-6.88(dd,2H),5.2(s,2H),3.72-3.82(m,4H),3.02-3.08(m,4H)。13C NMR(400MHz,CDCl3):165,158.2,142.8,134.8,128.8,128.4,122,121.6,118.8,118.6,115.4,115.2,110.6,110.0,51.8,50.6,50.2,45.2,42。
2-{2-[4-(4-氟-苯基)-哌嗪-1-基]-2-氧代-乙基}-5-丙基-2H-吡唑-3-羧酸乙酯的合成
用5-丙基-2H-吡唑-3-羧酸乙酯,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/1)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):6.94-7.0(m,2H),6.82-6.90(dd,2H),6.7(s,1H),5.5(s,2H),4.26-4.32(q,2H),3.62-3.82(m,4H),3.04-3.18(m,4H),2.58-2.64(t,2H),1.64-1.74(m,2H),1.34-1.38(t,3H),0.96-1.0(t,3H)。’3C NMR(400MHz,CDCl3):165,160,156.2,152.4,146.8,132.8,118.2,118.1,115.8,115.4,110.2,61,53,50.6,50.2,45,42,30,22.8,14.2,14.
2-{2-[4-(4-氟-苯基)-哌嗪-1-基]-2-氧代-乙基}-3-丙基-2H-吡唑-5-羧酸乙酯的合成
用5-丙基-2H-吡唑-3-羧酸乙酯,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/1)得到白色固体状的标题化合物。1H NMR(400MHz,CDCIS):6.94-7.0(m,2H),6.82-6.90(dd,2H),6.2(s,1H),5.06(s,2H),4.34-4.40(q,2H),3.62-3.8(m,4H),3.02-3.12(m,4H),2.54-2.60(t,2H),1.64-1.78(m,2H),1.34-1.38(t,3H),0.98-1.4(t,3H)。’3C NMR(400MHz,CDCl3):165,160,156.4,152.2,146.6,132.8,118.4,118.2,115.8,115.4,113.2,61,53,50.6,50.2,45.2,42,28,21.8,14.2,14。
2-(3,5-二-三氟甲基-吡唑-1-基)-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮的合成
用3,5-二-三氟甲基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/1)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):6.94-7.0(m,2H),6.92(s,1H),6.82-7.90(dd,2H),5.2(s,2H),3.72-3.8(t,2H),3.58-3.66(t,2H),3.12-3.18(t,2H),3.02-3.12(t,2H)。�;3C NMR(400MHz,CDCl3):162.2,158.2,156.4,146.5,118.4,116.2,115.8,113.2,60.4,53.2,50.6,50.2,45.2,42.2,21.2,14.2。
1-{2-[4-(4-氟-苯基)-哌嗪-1-基]-2-氧代-乙基}-1H-吡唑-3,5-二羧酸二乙酯的合成
用1H-吡唑-3,5-二羧酸二乙酯,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/1)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):7.38(s,1H),6.94-7.0(m,2H),6.82-7.90(dd,2H),5.54(s,2H),4.36-4.42(q,2H),4.26-4.32(q,2H),3.60-3.80(m,4H),3.02-3.20(m,4H),1.22-1.42(m,6H)。13C NMR(400MHz,CDCl3):164.2,162.2,158.2,157.4,156.2,148.5,144.4,134.2,118.4,116.2,115.8,114.2,62,61.8,54.2,50.6,50.2,45.2,42.2,14.6,14.2。
2-(3-氨基-4-T-丁基-吡唑-1-基)-1-[4-(4-氟苯基)-哌嗪-1-基]-乙酮的合成
用5-叔丁基-1H-吡唑-3-基胺,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=3/7:Rf=0.49)以得到无色油状的标题化合物。1H NMR(400MHz,CDCl3):6.92-7.98(t,2H),6.82-6.88(dd,2H),4.84(s,2H),3.95(s,2H),3.70-3.90(m,4H),2.95-3.10(m,4H),1.25(s,9H)。
2-{2-[4-(4-氟-苯基)-哌嗪-1-基]-2-氧代-乙基}-4-氯-5-丙基-2H-吡唑-3-羧酸乙酯的合成
用4-氯-5-丙基-2H-吡唑-3-羧酸乙酯,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=3/7)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):6.94-7.0(m,2H),6.82-6.90(dd,2H),5.0(s,2H),4.36-4.40(q,2H),3.62-3.82(m,4H),3.04-3.18(m,4H),2.58-2.66(t,2H),1.64-1.76(m,2H),1.34-1.38(t,3H),0.94-1.0(t,3H)。13C NMR(400MHz,CDCl3):165,160.2,156.2,152.4,147,133,118.4,118.2,115.8,115.4,112.2,61,53,50.6,50.2,45,42,30,22.8,14.4,14.2。
2-(3-叔丁基-5-三氟甲基-吡唑-1-基)-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮的合成
用5-叔丁基-3-三氟甲基-1H-吡唑,K2CO3,2-氯-f1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/1)以得到无色油状的标题化合物。H NMR(400MHz,CDCl3);6.92-7.08(t,2H),6.82-6.88(dd,2H),6.52(s,1H),5.08(s,2H),3.70-3.80(m,2H),3.58-3.68(m,2H),3.05-3.15(m,4H),1.3(s,9H)。3C NMR(400MHz,CDCl3):164,161.2,158.2,156.4,147.2,118.4,118.2,115.8,115.4,108.2,54,50.6,50.2,45,44,30.
2-(5-氨基-3-呋喃-2-基-吡唑-1-基)-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮的合成
用3-呋喃-2-基-2H-吡唑-5-基胺,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用100%乙酸乙酯进行柱层析以得到白色固体状的标题化合物。1H NMR(400MHz,CD6CO);7.48-7.52(m,1H),6.98-7.06(m,2H),6.52-6.56(m,2H),6.44-6.48(m,2H),5.74(s,1H),4.98(s,2H),3.68-3.88(m,4H),3.12-3.24(m,4H)。MS(ES)M+H)预测值=369.4,实测值:370.1.
1-[4-(4-氟-苯基)-哌嗪-1-基]-2-(4-溴-3,5-二甲基-吡唑-1-基)-乙酮的合成
用4-溴-3,5-二甲基-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/1)得到白色固体状的标题化合物NMR(400MHz,CDl3):6.95-7.1(m,2H),6.84-6.92(dd,2H),4.90(s,2H),3.62-3.82(m,4H),3.02-3.12(m,4H),2.24-2.34(d,6H)。13C NMR(400MHz,CDCl3):165,158.4,156.6,150.6,146.8,141.4,119,115.6,115.2,52.6,51.6,50.4,45.2,42.2,14.8,12.6。
2-[4-氯-3-(5-氯-噻吩-2-基)-吡唑-1-基]-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮的合成
用4-氯-3-(5-氯-噻吩-2-基)-1H-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=2/3)以得到黄色固体状的标题化合物。1H NMR(400MHz,CDCl3):7.58(s,1H),7.38-7.42(d,1H),6.94-7.1(m,2H),6.84-6.88(dd,2H),4.96(s,2H),3.62-3.81(m,4H),3.02-3.14(m,4H)。13C NMR(400MHz,CDCl3):165,158.8,156.8,142.4,131,126.8,124.8,119,116,115.6,54,52,51.6,46,42.6.
4-氯-2-{2-[4-(4-氟-苯基)-哌嗪-1-基]-2-氧代-乙基}-5-甲基-2H-吡唑-3-羧酸乙酯的合成
用4-氯-5-甲基-2H-吡唑-3-羧酸乙酯,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=2/3)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):6.94-7.1(m,2H),6.84-6.88(dd,2H),5.04(s,2H),4.38-4.44(q,2H),3.62-3.80(m,4H),3.02-3.14(m,4H),2.3(s,3H),1.36-1.42(t,3H)。13C NMR(400MHz,CDCl3):182,165,119,116.2,116,61.4,52.3,51,50.8,45.8,42.6,14.4,10。
4-氯-5-(5-氯-噻吩-2-基)-2-{2-[4-(4-氟-苯基)-哌嗪-1-基]-2-氧代-乙基}-2H-吡唑-3-羧酸乙酯的合成
用4-氯-5-(5-氯-噻吩-2-基)-2H-吡唑-3-羧酸乙酯,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=2/3)以得到黄色固体状的标题化合物。1H NMR(400MHz,CDCl3):7.46-7.48(m,1H),6.94-7.1(m,2H),6.84-6.92(m,3H),5.4(s,2H),4.34-4.4(q,2H),3.62-3.81(m,4H),3.04-3.24(m,4H),1.36-1.44(m,3H)。MS(ES)M+H)预测值=511.41,实测值:511。
2-(3-氨基-4-氯-5-甲基-吡唑-1-基)-1-[4-(4-氯苯基)-哌嗪-1-基]-乙酮的合成
用按照方案T进行制备4-氯-5-甲基-1H-吡唑-3-基胺,K2CO3,2-氯-1-[4-(4-氯-苯基)-哌嗪-1-基]-乙酮和DMF。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/4)以得到无色油状的标题化合物。1H NMR(400MHz,CDCl3):7.18-7.22(d,1H),6.78-6.84(d,2H),4.8(s,2H),4.4(s,2H),3.72-3.82(m,4H),3.08-3.18(m,4H),2.14(s,3H)。
1-[4-(4-溴-3-甲氧基苯基)-哌嗪-1-基]-2-(4-氯-5-苯基-3-三氟甲基-吡唑-1-基)-乙酮的合成
用4-氯-5-苯基-3-三氟甲基-1H-吡唑,K2CO3,2-氯-1-[4-(4-溴-3-甲氧基-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=2/3:Rf=0.58)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):7.81-7.86(m,1H),7.36-7.44(m,4H),6.42-6.48(d,1H),6.34-6.38(dd,2H),5.2(s,2H),3.88(s,3H),3.62-3.82(m,4H),3.12-3.22(m,4H)。
1-[4-(4-氟苯基)-哌嗪-1-基]-2-(3-三氟甲基-吡唑)-乙酮的合成
用3-三氟甲基-1H-吡唑,K2CO3,2-氯-1-[4-(4-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/1)得到白色固体状的标题化合物。IH NMR(400MHz,CDCl3):7.54-7.60(m,1H),6.94-7.0(m,2H),6.80-6.88(m,2H),6.52-6.58(d,1H),5.2(s,2H),3.72-3.80(t,2H),3.62-3.72(t,2H),3.02-3.12(m,4H)。MS(ES)M+H理论值:356.33,实测值:357.1。
1-[4-(4-氟苯基)-哌嗪-1-基]-2-(3-甲基-吡唑)-乙酮的合成
用3-甲基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/1)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):7.38-7.41(m,1H),6.94-7.0(m,2H),6.80-6.88(m,2H),6.08-6.10(d,1H),4.95(s,2H),3.74-3.82(t,2H),3.62-3.72(t,2H),3.0-3.1(m,4H),2.28(s,3H)。MS(ES)M+H理论值:302.05,实测值:303.1.
1-{2-[4-(4-氟-苯基)-哌嗪-1-基]-2-氧代-乙基}-1H-吡唑-4-羧酸乙酯的合成
用1H-吡唑-4-羧酸乙酯,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/1)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):8.2(s,1H),7.92(s,1H),6.94-7.0(m,2H),6.82-6.88(m,2H),5.0(s,2H),4.1-4.2(q,2H),3.74-3.82(t,2H),3.62-3.72(t,2H),3.0-3.12(m,4H),1.28-1.42(t,3H)。MS(ES)M+H理论值:360.39,实测值:361.1。
1-[4-(4-氟苯基)-哌嗪-1-基]-2-(4-甲基-吡唑)-乙酮的合成
用4-甲基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/1)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):7.26-7.32(m,1H),6.94-7.0(m,2H),6.80-6.88(m,2H),5.0(s,2H),3.62-3.82(m,4H),3.0-3.1(m,4H),2.1(s,3H)。MS(ES)M+H理论值:302.35,实测值:303.1。
1-[4-(4-氟苯基)-哌嗪-1-基]-2-(3-氨基-4-溴吡唑)-乙酮的合成
用4-溴-3-氨基吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=3/7)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):7.23(s,1H),6.94-7.0(m,2H),6.80-6.88(m,2H),4.9(s,2H),4.2(s,2H),3.72-3.82(m,4H),3.0-3.14(m,4H)。MS(ES)M+H理论值:382.24,实测值:382。
1-[4-(4-氟苯基)-哌嗪-1-基]-2-(3-氨基-4-氰基吡唑)-乙酮的合成
用3-氨基-4-氰基-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=3/7)以得到标题化合物as a SOLID.1H NMR(400MHz,CDCl3):7.48(s,1H),6.96-7.2(m,2H),6.86-6.92(m,2H),4.96(s,2H),4.88(s,2H),3.78-3.86(m,4H),3.08-3.16(m,4H)。MS(ES)M+H理论值:328.25,实测值:329.1
3-氨基-5-氰基甲基-1-{2-[4-(4-氟-苯基)-哌嗪-1-基]-2-氧代-乙基}-1H-吡唑-4-甲腈的合成
用5-氨基-3-氰基甲基-1H-吡唑-4-甲腈,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=3/2)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):6.96-7.2(m,2H),6.86-6.92(m,2H),5.2(s,2H),4.86(s,2H),3.78-3.86(m,4H),3.7(s,2H),3.08-3.16(m,4H)。MS(ES)M+H理论值:367.39,实测值:368.1。
1-[4-(4-氟苯基)-哌嗪-1-基]-2-(4-氯-吡唑)-乙酮的合成
用4-氯-1H-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=3/2)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):7.54-7.56(d,2H),7.46(s,1H),6.94-7.2(m,2H),6.84-6.88(m,2H),4.98(s,2H),3.62-3.82(m,4H),3.0-3.1(m,4H)。MS(ES)M+H理论值:322.77,实测值:323.1
2-(3-氨基-5-甲基-吡唑-1-基)-1-[4-(4-氟苯基)-哌嗪-1-基]-乙酮的合成
用5-甲基-1H-吡唑-3-基胺,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/4)以得到无色油状的标题化合物。1H NMR(400MHz,CDCl3):7.12-7.18(m,3H),7.0-7.08(t,2H),4.8(s,2H),5.1(s,2H),3.78-3.88(m,4H),3.18-3.38(m,4H),2.28(s,3H)。MS(ES)M+H理论值:317.37,实测值:318.1
3-氨基-1-{2-[4-(4-氟-苯基)-哌嗪-1-基]-2-氧代-乙基}-5-甲基-1H-吡唑-4-羧酸乙酯的合成
3-氨基-5-甲基-1H-吡唑-4-羧酸乙酯,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF用按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/4)以得到无色油状的标题化合物。1H NMR(400MHz,CDCl3):6.94-7.1(m,2H),6.84-6.88(m,2H),5.52(s,2H),4.78(s,2H),4.24-4.32(q,2H),3.74-3.82(m,4H),3.0-3.1(m,4H),2.3(s,3H),1.31-1.38(t,3H)。MS(ES)M+H理论值:389.43,实测值:390.1.
2-(3-氨基-4-氯-5-甲基-吡唑-1-基)-1-[4-(4-氟苯基)-哌嗪-1-基]-乙酮的合成
用4-氯-5-甲基-1H-吡唑-3-基胺,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/4)以得到无色油状的标题化合物。1H NMR(400MHz,CDCl3):7.02-7.08(m,2H),6.94-7.0(t,2H),4.85(s,2H),4.2(s,2H),3.80-3.88(m,4H),3.14-3.34(m,4H),2.34(s,3H)。MS(ES)M+H理论值:317.37,实测值:318.1.MS(ES)M+H理论值:351.81,实测值:352.1。
2-(3-氨基-4-溴-5-甲基-吡唑-1-基)-1-[4-(4-氟苯基)-哌嗪-1-基]-乙酮的合成
用4-溴-5-甲基-1H-吡唑-3-基胺,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用乙酸乙酯进行柱层析以得到无色油状的标题化合物。1H NMR(400MHz,CDCl3):6.94-7.02(m,2H),6.82-6.88(t,2H),4.84(s,2H),4.1(s,2H),3.72-3.78(m,4H),3.04-3.08(m,4H),2.16(s,3H)。MS(ES)M+H理论值:317.37,实测值:318.1.MS(ES)M+H理论值:396.27,实测值:396.
2-(5-叔丁基-3-三氟甲基-吡唑-1-基)-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮的合成
用5-叔丁基-3-三氟甲基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/1)以得到无色油状的标题化合物。1H NMR(400MHz,CDCl3);6.94-7.08(t,2H),6.82-6.88(dd,2H),6.32(s,1H),5.14(s,2H),3.62-3.80(m,4H),3.05-3.18(m,4H),1.35(s,9H)。MS(ES)M+H理论值:412.43,实测值:413.1
2-{2-[4-(4-氟-苯基)-哌嗪-1-基]-2-氧代-乙基}-5-甲基-2H-吡唑-3-羧酸乙酯的合成
用5-甲基-2H-吡唑-3-羧酸乙酯,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/1)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):6.94-7.0(m,2H),6.84-6.88(dd,2H),6.58(s,1H),5.04(s,2H),4.3-4.38(q,2H),3.62-3.80(m,4H),3.02-3.14(m,4H),2.3(s,3H),1.32-1.38(t,3H)。13C NMR(400MHz,CDCl3):180,165,119,116.2,116,109,61.8,52,51.5,50.8,45.8,42.6,14.4,10.2。
2-(3,5-二异丙基-4-氯-吡唑-1-基)-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮的合成
用3,5-二异丙基-4-氯-1H-吡唑,K2CO3,2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/1,Rf=0.76)以得到白色固体状的标题化合物。MS(ES)M+H)预测值=406.9,实测值:407.1。
2-{2-[4-(4-氯-苯基)-哌嗪-1-基]-2-氧代-乙基}-5-噻吩-2-基-2H-吡唑-3-羧酸乙酯的合成
用5-噻吩-2-基-2H-吡唑-3-羧酸乙酯,K2CO3,2-氯-1-[4-(4-氯-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物(己烷/乙酸乙酯=1.5/1)进行柱层析以得到标题化合物。1H NMR(400MHz,CDCl3):7.34-7.38(m,1H),7.24-7.26(m,1H),7.12(s,1H),7.04-7.08(dd,1H),6.96-7.2(m,2H),6.88-6.94(m,2H),4.32-4.42(q,2H),3.52-3.58(m,4H),3.05-3.35(m,4H),1.32-1.42(m,3H)。13CNMR(400MHz,CDCl3):164.2,128,126.8,126.6,120.2,118.4,115.2,62.5,54.2,50.5,42.6,44,14.6。
2-(4-氨基-3-七氟丙基-5-甲基-吡唑-1-基)-1-[4-(4-氯-苯基)-哌嗪-1-基]-乙酮的合成
用4-氨基-3-七氟丙基-5-甲基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氯-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/4,Rf=0.42)以得到无色油状的标题化合物。1H NMR(400MHz,CDCl3);6.88-6.94(d,2H),7.22-7.26(d,2H),4.98(s,2H),3.64-3.82(m,4H),3.1-3.22(m,4H),2.98(s,2H),2.18(s,3H)。MS(ES)M+H)预测值=501.82,实测值:502.1。
1-[4-(4-氯-3-甲氧基-苯基)-哌嗪-1-基]-2-(4-氯-5-乙基-3-三氟甲基-吡唑-1-基)-乙酮的合成:
用4-氯-5-乙基-3-三氟甲基-1-H-吡唑,K2CO3,1-[4-(4-氯-3-甲氧基苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=2/3,Rf=0.53)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3);7.18-7.22(d,2H),6.38-6.48(m,2H),4.98(s,2H),3.86(s,3H),3.66-3.76(m,4H),3.1-3.2(m,4H),2.66-2.74(q,2H),1.18-1.28(m,3H)。MS(ES)M+H)预测值=464.82,实测值:465。
2-(4-氯-5-异丙基-3-三氟甲基-吡唑-1-基)-1-[4-(4-氯-3-甲氧基-苯基)-哌嗪-1-基]-乙酮的合成:
用4-氯-5-异丙基-3-三氟甲基-1-H-吡唑,K2CO3,1-[4-(4-氯-3-甲氧基苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=5.5/4.5,Rf=0.52)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3);7.19-7.22(d,2H),6.42-6.48(m,2H),5.18(s,2H),3.88(s,3H),3.56-3.78(m,4H),3.22-3.44(m,4H),3.04-3.14(m,1H),1.44-1.48(d,6H)。13C NMR(400MHz,CDCl3):164.2,154.8,151,130,109.8,102,56.2,54,50.5,50,45.2,42.6,26.2,22.1.
2-(4-氯-3-异丙基-5-三氟甲基-吡唑-1-基)-1-[4-(4-氯-3-甲氧基-苯基)-哌嗪-1-基]-乙酮的合成:
用4-氯-3-异丙基-5-三氟甲基-1-H-吡唑,K2CO3,1-[4-(4-氯-3-甲氧基苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=2/3,Rf=0.45)得到白色固体状的标题化合物。1HNMR(400MHz,CDCl3);7.19-7.22(d,2H),6.38-6.48(m,2H),5(s,2H),3.86(s,3H),3.62-3.78(m,4H),3.08-3.18(m,4H),2.98-3.04(m,1H),1.35-1.41(d,6H)。13C NMR(400MHz,CDCl3):163.8,154.8,150.5,130,109.8,102,56.4,52.8,50,49.8,45.2,42.6,26.8,20。
2-(4-氯-3-正丙基-5-三氟甲基-吡唑-1-基)-1-[4-(4-氯-3-甲氧基-苯基)-哌嗪-1-基]-乙酮的合成:
用4-氯-3-正丙基-5-三氟甲基-1-H-吡唑,K2CO3,1-[4-(4-氯-3-甲氧基苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=3/7,Rf=0.78)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3);7.22-7.24(d,2H),6.42-6.48(m,2H),5.7(s,2H),3.8(s,3H),3.72-3.78(m,4H),3.22-3.42(m,4H),2.66-2.72(t,2H),1.58-1.68(m,2H),0.98-1.02(t,3H)。13C NMR(400MHz,CDCl3):164,154.8,150.5,130,109.8,102.2,56.4,52.8,50,49.8,45.2,42.6,26,21.8,14.
1-[4-(4-氯-3-甲氧基苯基)-哌嗪-1-基]-2-(4-溴-3-苯基-5-三氟甲基-吡唑-1-基)-乙酮的合成
用4-溴-3-苯基-5-三氟甲基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氯-3-甲氧基-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=1/1,Rf=0.51)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):7.42-7.52(m,SH),7.18-7.22(d,1H),6.38-6.42(dd,1H),6.46-6.48(d,1H),4.94(s,2H),3.88(s,3H),3.5-3.78(m,4H),3.18(s,4H)。
1-[4-(4-氯-3-甲氧基苯基)-哌嗪-1-基]-2-(4-氯-5-苯基-3-三氟甲基-吡唑-1-基)-乙酮的合成
用4-氯-5-苯基-3-三氟甲基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氯-3-甲氧基-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=2/3,Rf=0.92)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):7.78-7.84(m,2H),7.36-7.52(m,4H),6.38-6.48(m,2H),5.2(s,2H),3.88(s,3H),3.62-3.78(m,4H),3.18-3.26(s,4H)。13C NMR(400MHz,CDCl3)164.4,156,150.4,130.4,130,128.6,110.2,102.4,56.4,52,50.4,44.6,42。
1-[4-(4-氯-3-甲氧基苯基)-哌嗪-1-基]-2-(4-氯-3-[3-氟-苯基]-5-三氟甲基-吡唑-1-基)-乙酮的合成
用4-氯-3-[3-氟苯基]-5-三氟甲基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氯-3-甲氧基-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=2/3,Rf=0.51)得到白色固体状的标题化合物。1H NMR(400MHz,CDC):7.44-7.52(m,1H),7.18-7.28(m,4H),6.38-6.48(m,2H),4.94(s,2H),3.84(s,3H),3.52-3.78(m,4H),3.12(s,4H)。
1-[4-(4-氯-3-甲氧基苯基)-哌嗪-1-基]-2-(4-氯-5-[3-氟-苯基]-3-三氟甲基-吡唑-1-基)-乙酮的合成
用4-氯-5-[3-氟苯基]-3-三氟甲基-1H-吡唑,K2CO3,2-氯-1-[4-(4-氯-3-甲氧基-苯基)-哌嗪-1-基]-乙酮和DMF按照方案T进行制备。用溶剂混合物进行柱层析(己烷/乙酸乙酯=2/3,Rf=0.59)得到白色固体状的标题化合物。1H NMR(400MHz,CDCl3):7.64-7.68(d,1H),7.56-7.62(d,1H),7.36-7.42(m,1H),7.22-7.24(m,2H),7.08-7.12(m,1H),6.42-6.52(m,2H),5.2(s,2H),3.9(s,3H),3.62-3.82(m,4H),3.12-3.22(m,4H)。
方案U:K2CO3参与的氯乙酰基取代的芳基哌嗪与新杂芳环系统的偶合反应
1-[4-(4-氟-苯基)-哌嗪-1-基]-2-[5-硝基-吲唑-1-基]-乙酮的合成
将2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮(0.834g,3.3mmol)加入无水DMF(15mL)并在其中加入无水碳酸钾(1.6g,11.6mmol),将反应混合物在氮气下在室温下搅拌1小时。然后通过注射器在混合物中加入溶于DMF(2mL)的5-硝基-1H-吲唑(0.5g,2.9mmol)。将反应物在70℃加热14h,冷却,用水停止反应,并用乙酸乙酯萃取。用硫酸钠干燥有机层,然后浓缩以得到一种物质,将该物质在中性铝柱(石油醚/乙酸乙酯)上纯化以得到淡黄色固体状的标题化合物。
1-[4-(4-氟-苯基)-哌嗪-1-基]-2-[7-硝基-吲唑-1-基]-乙酮的合成
将2-氯-1-[4-(4-氟-苯基)-哌嗪-1-基]-乙酮(0.834g,3.3mmol)加入无水DMF(15mL)并在其中加入无水碳酸钾(1.6g,11.6mmol),反应混合物在氮气下在室温下搅拌1小时。然后通过注射器在混合物中加入溶于DMF(2mL)的5-硝基-1H-吲唑(0.5g,2.9mmol)。将反应物在70℃加热14h,冷却,用水停止反应,并用乙酸乙酯萃取。用硫酸钠干燥有机层,然后浓缩以得到一种物质,将该物质在中性铝柱(石油醚/乙酸乙酯)上纯化。所得固体从DCM/石油醚中重结晶以得到纯的淡黄色固体状的产物。
2-苯并咪唑-1-基-1-[4-(4-氯-苯基)-哌嗪-1-基]-乙酮的合成
将苯并咪唑(0.785g,0.7mmol)加入无水DMF(15ml)并在其中加入无水碳酸钾(340mg)和KI(20mg),反应混合物在氮气下在室温下搅拌1小时。然后通过注射器在混合物中加入溶于DMF(5mL)的2-氯-1-[4-(4-氯-苯基)-哌嗪-1-基]-乙酮(200mg,1.1mmol)。将反应物在140℃加热14h,冷却,用水停止反应,并用乙酸乙酯萃取。用硫酸钠干燥有机层,然后浓缩以得到一种物质,该物质通过快速色谱法纯化(CHCl3/MeOH)以得到纯的产物:1H NMR(300MHz,CDCl3):68.10-7.65(m,4H),7.26(d,2H),6.83(d,2H),4.99(s,2H),3.79-3.66(m,4H),3.14(br,4H)。
1-[4-(4-氯-苯基)-哌嗪-1-基]-2-(2,4-二甲基-咪唑-1-基)-乙酮的合成
将2,4-二甲基咪唑(0.633g,0.7mmol)加入无水DMF(15ml)并在其中加入无水碳酸钾(340mg)和KI(20mg),反应混合物在氮气下在室温下搅拌1小时。然后通过注射器在混合物中加入溶于DMF(5mL)的2-氯-1-[4-(4-氯-苯基)-哌嗪-1-基]-乙酮(200mg,1.1mmol)。将反应物在140℃加热14h,冷却,用水停止反应,并用乙酸乙酯萃取。用硫酸钠干燥有机层,然后浓缩以得到一种物质,该物质在硅胶柱(CHCl3/MeOH)上纯化:1H NMR(300MHz,CDCl3):67.25(d,2H),6.80(d,2H),6.53(s,1H),4.62(s,2H),3.78(br,2H),3.59(br,2H),3.21(br,4H),2.31(s,3H),2.17(s,1H)。
2-(5-氨基-3-甲基硫烷基-[1,2,4]三唑-1-基)-1-[4-(4-氯-苯基)-哌嗪-1-基]-乙酮的合成
将5-甲基硫烷基-2H-[1,2,4]三唑-3-基胺(0.216g,1.7mmol)加入无水DMF(15mL)和无水碳酸钾(800MG)并在其中加入KI(20mg),反应混合物在氮气下在室温下搅拌1小时。然后通过注射器在混合物中加入溶于DMF(5mL)的2-氯-1-[4-(4-氯-苯基)-哌嗪-1-基]-乙酮(500mg,1.8mmol)。将反应物在140℃加热14h,冷却,用水停止反应,并用乙酸乙酯萃取。用硫酸钠干燥有机层,然后浓缩以得到粗制产物,粗制产物通过柱层析(CHCl3/MeOH)纯化:1H NMR(300MHz,DMSO-d6):67.24(d,2H),6.98(d,2H),6.24(s,2H),4.84(s,2H),3.57(m,4H),3.21(m,2H),3.13(m,2H),2.37(s,3H)。
2-[5-(2-溴-苯基)-四唑-1-基]-1-[4-(4-氯-苯基)-哌嗪-1-基]-乙酮的合成
将5-苯基-1H-四唑(0.1216g,0.832mmol)加入无水DMF(15ml)并在其中加入无水碳酸钾(400mg)和KI(20mg),反应混合物在氮气下在室温下搅拌1小时。然后通过注射器在混合物中加入溶于DMF(5mL)的2-氯-1-[4-(4-氯-苯基)-哌嗪-1-基]-乙酮(250mg,0.92mmol)。将反应物在140℃加热14h,冷却,用水停止反应,并用乙酸乙酯萃取。用硫酸钠干燥有机层,然后浓缩以得到一种物质,该物质通过快速柱层析(乙酸乙酯/石油醚)进一步纯化:1H NMR(300MHz,CDCl3):68.17(br,2H),7.49(br,3H),7.24(br,2H),6.85(br,2H),5.60(s,2H),3.82(m,2H),3.71(m,2H),3.19(m,4H)。
2-[5-(2-溴-苯基)-四唑-1-基]-1-[4-(4-氯-苯基)-哌嗪-1-基]-乙酮的合成
将5-(2-溴-苯基)-1H-四唑(0.374g,1.66mmol)加入无水DMF(15mL)和无水碳酸钾(800mg)并在其中加入KI(20mg),反应混合物在氮气下在室温下搅拌1小时。然后通过注射器在混合物中加入溶于DMF(5mL)的2-氯-1-[4-(4-氯-苯基)-哌嗪-1-基]-乙酮(500mg,1.8mmol)。将反应物在140℃加热14h,冷却,用水停止反应,并用乙酸乙酯萃取。用硫酸钠干燥有机层,然后浓缩以得到一种物质,该物质通过快速柱层析(乙酸乙酯/石油醚)进一步纯化:1H NMR(300MHz,CDCl3):67.90(d,1H),7.74(d,1H),7.45(t,1H),7.35(t,1H),7.25(d,2H),6.87(d,2H),5.65(s,2H),3.84(m,2H),3.73(m,2H),3.20(m,4H)。
用修饰的连接基区域制备化合物
α-取代的乙酰基连接基
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(4-氟-苯基)-哌嗪-1-基]-丙-1-酮的合成
将溶于无水CH2Cl2(20ml)的1-(4-氟苯基)-哌嗪(Lg,5.5mmol)冷却至0℃并在其中加入三乙胺(1.66g,16.5mmol)。缓慢加入2-溴丙酰氯(1.14g,6.6mol)并将反应混合物在同样温度下再搅拌1小时。混合物用碳酸氢钠和盐水洗涤,干燥(Na2SO4)。蒸发去溶剂以得到作为中间体的烷基溴化物(0.68g,3.7mmol),将中间体加入无水DMF(20ml)。加入碳酸钾(2.1g)。在氮气下在室温搅拌1小时后,通过注射器在混合物中加入溶于DMF(5mL)的3-甲基-4-氯-5-三氟甲基-(1H)-吡唑(1.3g,4.1mmol)。将反应物在70℃加热14h,冷却,用水停止反应,并用乙酸乙酯萃取。用硫酸钠干燥有机层,然后浓缩以得到一种物质,该物质用中性铝柱(氯仿/甲醇)纯化。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(4-氯-苯基)-哌嗪-1-基]-2-苯基-乙酮的合成
在20ml无水CH2Cl2中的4-氯-5-甲基-3-(三氟甲基)-1H-吡唑-1-基]苯基乙酸(0.1g,0.00036mol)和1-(4-氯苯基)哌嗪(0.060g,0.00031mol)中加入0.2ml三乙胺,将反应混合物在室温下搅拌30分钟。然后加入TBTU(0.1g,0.00031mol)并将反应混合物在室温下搅拌17小时。反应混合物用60ml CH2Cl2稀释并用饱和NaHCO3溶液(2×50ml),盐水洗涤,然后用硫酸钠干燥。所得粗产物在浓缩后通过柱层析纯化以得到乳白色固体状产物:1H NMR(CDCl3,300MHz)7.40-6.61(m,10H),3.99(m,1H),3.80(m,1H),3.50-2.81(m,6H),1.90(s,3H)ppm;MS(ES)M+H预测值=497.1,实测值:497.2。
2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(4-氯-苯基)-哌嗪-1-基]-2-(3-甲氧基-苯基)-乙酮的合成
将AIBN(10mg)加入溶于CCl4(30ml)的(3-甲氧基-苯基)-乙酸甲酯(2g,11mmol)溶于。然后加热回流溶液并一次性加入NBS(2.3g,13mmol)。添加完成后将反应混合物回流4h。冷却后,将残余固体滤出并将滤液浓缩以得到溴-(3-甲氧基-苯基)-乙酸甲酯,用石油醚反复洗涤该产品。
将4-氯-3-甲基-5-三氟甲基-1H-吡唑(610mg,3.3mmol)加入无水CH3CN(15mL),在其中加入无水碳酸钾(1.15g)并将所得混合物在氮气下在室温下搅拌1小时。然后通过注射器在混合物中加入溶于CH3CN(5mL)的溴-(3-甲氧基-苯基)-乙酸甲酯(900mg,2.8mmol)。反应物然后被加热回流10h,冷却,然后通过硅藻土滤床过滤。将滤液浓缩以得到(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-(3-甲氧基-苯基)-乙酸乙酯,将其通过硅柱层析纯化(石油醚/乙酸乙酯)
然后将(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-(3-甲氧基-苯基)-乙酸甲酯溶于THF(20ml)并加入溶于水(5ml)的LiOH(0.39g)。混合物在室温下搅拌4h。然后减压从反应混合物中完全蒸发去THF。所得水性层用乙酸乙酯萃取(3×5ml)并丢弃有机层。水性层在冰中冷却并用浓HCl中和。水性层用乙酸乙酯萃取(3×10mL),有机层用Na2SO4干燥,浓缩,并通过快速层析纯化(CHCl3/MeOH)以得到(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-(3-甲氧基-苯基)-乙酸
将该化合物(90mg,0.275mmol)加入无水CH2Cl2(10mL)并冷却至0℃。在冷的混合物中先加入4-氯苯基-哌嗪(0.059g,0.31mmol),然后加入T3P(0.35g,0.55mmol,50%的EtOAc溶液)。使反应物在室温下过夜。混合物用CH2Cl2稀释然后依次用饱和NaHCO3溶液,盐水洗涤,用Na2SO4干燥并浓缩以得到粗制产物。在中性氧化铝上通过柱层析纯化以得到2-(4-氯-5-甲基-3-三氟甲基-吡唑-1-基)-1-[4-(4-氯-苯基)-哌嗪-1-基]-2-(3-甲氧基-苯基)-乙酮:1H NMR(300MHz,CDCl3):67.37-7.21(m,3H),6.96-6.79(m,4H),6.60(s,1H),5.31(s,1H),3.99(m,1H),3.80(s,3H),3.79(m,1H),3.46(m,2H),3.24(m,1H),3.13(m,2H),2.91(m,1H),1.95(s,3H)。
实施例2
本实施例说明了本发明代表性化合物有关的活性。
材料和方法
A.细胞
CCRI表达细胞
a.THP-1细胞
THP-1细胞由ATCC制得,并在加入2mML-谷氨酸盐、1.5g/l碳酸氢钠、4.5g/l葡萄糖、10mM HEPES、1mM丙酮酸钠、0.05%2-巯基乙醇和10%FBS的RPMI-1640介质中作为悬浮液进行培养。细胞在37℃下的5%CO2/95%空气,100%湿度条件下生长,并以1∶5每周进行两次次培养,并以1×106细胞/ml进行收集。THP-1细胞表达CCR1,并且可以用在CCR1结合和功能试验中。
b.分离的人单核细胞
使用Miltenyi小珠分离系统(Miltenyi,Auburn,CA)从人的淡黄色表皮上分离出单核细胞。简而言之,按Ficoll梯度分离法分离出周边血单核细胞,用PBS洗涤所述细胞,并使用标准步骤细胞溶解所述血红细胞。剩余的细胞用偶合到磁性小珠(Miltenyi Biotech,Auburn,CA)上的抗-CD14抗体标记。所述标记的细胞经过AutoMACS(Miltenyi,Auburn,CA),并收集阳性组分。单核细胞表达CCR1,可以用在CCR1结合和功能试验中。
B.试验
抑制CCR1配体结合
表达CCR1的细胞在试验缓冲液(20mM HEPES pH7.1,140mM NaCl,1mM CaCl2,5mM MgCl2,并具有0.2%牛血清白蛋白)中进行离心分离和再次悬浮,至THP-1细胞的浓度为2.2×105细胞/ml,单核细胞的浓度为1.1×106。如下所述进行结合试验。首先,将0.09ml细胞(1×105THP-1细胞/孔或5×105单核细胞)加入包含所述化合物的试验板中,得到进行筛选的各化合物的最终浓度为2-10微摩(或者响应化合物IC50测定的剂量的部分)。然后,加入在试验缓冲液中稀释至最终浓度为~50pM的0.09ml125I标记的MIP-α(由Amersham;Piscataway,NJ制得),形成~30000cpm/孔,在振荡器平台上,在4℃下孵化约3小时。在真空细胞收集器(PackaRd Instruments;Meriden,CT)中,将所述反应物吸到预先浸泡在0.3%聚乙烯亚胺(PEI)溶液中的GF/B玻璃过滤器中。将闪烁流体(50微升;Microscint20,PackaRd Instruments)加入各孔中,将板密封,所述板密封,并在Top Count闪烁计数器(PackaRd Instrument s)中测定放射性。仅包含稀释剂(对于总计数)或过量的MIP-1α或MIP-1β(1微克/ml,对非特异性结合)的对照孔用于计算化合物的总抑制百分数。用来自GraphPad,Inc.(San Diego,Ca)的计算机程序Prism计算IC50值。IC50值是使标记MIP-1α和受体的结合降低50%所需的浓度。
钙迁移
为了测定细胞内钙储存的释放,在室温下,用3微摩INDO-1AM染料(分子探针,Eugene,OR)在细胞介质中孵化细胞(THP-1或单核细胞)45分钟,并用磷酸盐缓冲的盐水(PBS)洗涤。当加入INDO-1AM之后,所述细胞在通量缓冲液(Hank平衡盐水(HBSS)和1%FBS)中再次悬浮。使用Photon Technology International分光光度计(PhotonTechnology International;New Jersey)测量钙迁移,在350nm下激发,并在400nm和490nm下同时记录荧光发射。相对的细胞内钙水平表示为400nm/490nm发射比。在2ml通量缓冲液中,在各包含106细胞的小试管中,在匀速混合条件下,在37℃下进行实验。所述趋化因子配体可以在1-100nM的范围内使用。将所述发射比对时间(通常为2-3分钟)进行绘图。在10秒时加入候选的配体阻塞化合物(最高10微摩),之后在60秒时加入趋化因子(即MIP-1α;R&D Systems;Minneapolis,MN),在150秒时加入对照趋化因子(即,SDF-la;R&D Systems;Minneapolis,MN)。
趋化性试验
在96孔趋化室(Neuroprobe;GaithersbuRg,MD)中,使用5μm多孔聚碳酸酯、涂布聚乙烯基吡咯烷酮的过滤器,使用趋化缓冲液(Hank平衡盐水(HBSS)和1%FBS)进行趋化性试验。使用CCR1趋化因子配体(即,MIP-1α,Leukotactin;R&D Systems;Minneapolis,MN)来评价CCR1介导的迁移的化合物介质抑制性。其它趋化因子(即,SDF-LON R&D Systems;Minneapolis,MN)用作特性性对照物。将29微升的趋化因子(即,0.1nM MIP-1α)加入下室中,并改变化合物的量,上室包含20微升的100000THP-1或单核细胞。所示室在37℃下孵化1-2小时,在下室中的细胞数通过在5个高能场/孔的直接细胞计数来定量,或者通过CyQuant试验(分子探针)(即测量核酸含量的荧光染色方法和显微观察)进行定量。
CCR1抑制剂的鉴别
A.试验
为了评价阻止受体CCR1与配体结合的有机小分子,可以使用能检测与在细胞(例如,THP-1细胞或分离的人单核细胞)表面表达CCR1的细胞的放射性配体(即,MIP-1α或Leukotactin)结合的试验。对于抑制结合的化合物,不论是否相竞争的结合,当和非抑制性对照物进行比较时观察到较少的放射性计数。
THP-1细胞和单核细胞缺乏,结合相同一套趋化因子配体,如CCR1(即,MIP-1α,MPIF-1、Leukotactin)的其它趋化因子受体。将等量的细胞加入板中的各孔中。然后,用放射性标记的MIP-1α孵化所述细胞。通过洗涤所述细胞除去未结合的配体,并通过定量放射性计数来测定所述结合的配体。不用任何有机化合物孵化的细胞给出总计数;通过用非标记配体和标记的配体孵化的细胞来测定非特异性结合。通过如下方程式确定抑制%:
%抑制=(1-[(样品cpm)-(非特异性cpm)]/[(总cpm)-(非特异性cpm)])×100
B.使用CCR1表达细胞鉴定来自化合物库的抑制体
在一套化合物的筛选中,归一化的标准偏差是17%,表明34%或以上的抑制活性是显著的,而且使用40%的阀值。这些集合的化合物板形成呈现大于40%MIP-1α结合抑制的39个孔。当作为集合的化合物板进行第二次筛选时,这些孔中有14个孔降低配体大于40%。为了确定各孔中哪一种化合物抑制了MIP-1α的CCR1连接,通过试验各化合物的抑制活性来解析所述集合。由于一些化合物可能一起作用来抑制结合,而解析试验仅个别地试验化合物,因此在本实验中不能发现组合在一起有效但单独无效的化合物。单个地试验所述化合物来鉴别抑制剂候选化合物:
C.使用CCR1表达细胞鉴别来自化合物库的抑制剂
由化合物筛选工作来鉴定了CCX-105。
剂量响应曲线
为了确定候选化合物对CCR1的亲合性,并确定其抑制配体结合的能力,在1×10-10-1×10-4M的化合物浓度范围内滴定抑制活性。在所述试验中,化合物的量各不相同,而细胞数和配体浓度保持恒定。滴定化合物CCX-105,发现是CCR1特异性趋化因子结合的强效抑制剂(见表,对于化合物1.001)。
CCR1功能试验
CCR1是7个跨膜的G-蛋白质连接的受体。一些这种受体的连接诱发的信号级联反应的特点是脉冲状释放细胞内储量的钙离子。进行钙迁移试验,确定候选CCR1抑制化合物是否也能阻塞CCR1信号的特征。能抑制配体结合并且以比其它趋化因子和非趋化因子受体更高的特异性发出信号的候选化合物是需要的。
使用钙指示INDO-1测量响应CCR1趋化因子配体(即,MIP-1α,MPIF-1,Leukotactin等)的钙离子释放。THP-1细胞或单核细胞加入INDO-1/AM,并测定响应CCR1趋化因子配体(即,MIP-1α)加入的钙释放。为了控制特异性,加入非CCR1配体,具体为缓激肽,它也通过7个跨膜的受体来发生信号。在没有化合物时,当加入MIP-1α时可以看见荧光信号脉冲。若化合物特异性抑制CCR1-MIP-1α的信号发生,那么当加入MIP-1α时只看见很小的信号脉冲或看不见信号脉冲,但是在加入缓激肽时可以观察到脉冲。但是,若化合物非特异性地抑制信号发生时,那么在加入MIP-1α和缓激肽时均看不见脉冲。
如下所示,CCX-105能显著地或特异性地抑制来自CCr1的信号发生。
表2钙信号发生的抑制
化合物 | MIP-1α1 | 缓激肽1 | 评价 |
CCX-105 | - | + | 特异性抑制 |
+,观察到脉冲;-没有观察到脉冲,n.s.,非特异性信号(见正文) |
趋化因子的一个主要功能是调节趋化因子受体表达细胞,如白血细胞的迁移能力。为了证实CCX-105不仅抑制CCR1特异性结合和信号发生(至少如钙迁移试验所述确定的),还抑制CCR1介导的迁移,使用了趋化性试验。THP-1髓单核细胞(myelomonocytic)白血病细胞(像单核细胞)以及新鲜分离的单核细胞可以用作通过CCR1趋化因子配体(即,MIP-1α,CCL15/Leukotactin)的趋化吸引(chemoattraction)的靶标。细胞置于微孔迁移室的上隔室中,而MIP-1α(或其它强效的CCr1趋化因子配体)和CCX-105或其它候选化合物的递增的浓度位于下室中。当没有抑制剂时,细胞将响应趋化因子激动剂而迁移到下室中;若化合物抑制了CCR1功能,那么细胞的主体仍保持在上室中。为了确定候选化合物的CCR1亲合性,并确定其抑制CCR1介导的细胞迁移的能力,在这种趋化性试验中,抑制活性在1×10-10-1×10-4M的范围内进行滴定。在这种试验中,化合物的量各不相同,而细胞数和趋化因子激动剂浓度保持恒定。当趋化室在37℃下孵化1-2小时之后,下室中的响应细胞通过用CyQuant试验(分子探针)来标记来定量,上述CyQuant试验是测量核酸含量的荧光染色法。并用Spectrafluor PluS(Tecan)测量来进行测定,使用来自GraphPad,Inc.(SanDiego,Ca)的计算机程序Prism用于计算IC60值。IC50值是将响应CCR1激动剂的细胞数抑制50%所需的化合物浓度。
体内效用
兔模型的破坏性关节炎症
进行研究,评价CCX-105抑制兔子对内关节注射细菌膜组分脂多糖(LPS)的炎症响应的效果。这一研究设计模仿关节炎中所见的破坏性关节炎症。内关节注射LPS导致极性炎症响应,其特征在于释放细胞因子和趋化因子,它们中许多已经在类风湿症关节炎的关节中被鉴别。在滑膜流体和滑膜中由于响应这些趋化介体的升高而使白细胞明显增多。趋化因子受体的选择性拮抗剂已经显示在这种模型中的效用(见Podolin等,J.Immunol.169(11):6435-6444(2002))。
在基本如Podolin等人(ibid)所进行的兔LPS研究中,用仅具有赋形剂(含1%DMSO的磷酸盐缓冲的盐水)或还加入CCX-105(剂量1=50微摩或者剂量2=100微摩)的总体积为1.0ml的LPS(10ng)内关节处理New Zealand兔子(约2千克)的一个膝盖。当注射LPS之后16小时,灌洗所述膝盖,并进行细胞计数。通过组织病理学评价滑液炎症来确定治疗的有利效果。使用以下炎症分数来进行组织病理学评价:1-最小,2-温和,3-中等,4-中等-显著。如下所示,CCX-105能显著并特异性地抑制剂内试验中的炎症响应。
表3
CCX-105在破坏性关节炎症的兔模型中的效用
滑液炎症分数 | |
赋形剂 | 3 |
CCX-105(剂量1) | 2 |
CCX-105(剂量2) | 1 |
化合物1.028在大鼠胶原质诱发的关节炎模型中的评价
进行发展17天的II型胶原质关节炎研究,评价化合物1.028对关节炎诱发的临床踝关节肿胀的效果。大鼠胶原质关节炎是多发性关节炎的实验模型,它已经广泛用于许多抗关节炎剂的临床前实验(见Trentham等人的J.Exp.Med.146(3):857-868(1977),Bendele等,Toxicologic Pathol.27:134-142(1999),Bendele等,ArthritisRheum 42:498-506(1999))。这种模型的特点是强烈的可方便测量的多发性关节炎、与关节翳形成有关的明显软骨破坏、轻微到中等的骨再吸收和骨膜增生的可靠的发作和进行。
用异氟烷麻痹雌性Lewis大鼠(约0.2千克),并在该17天研究的第0天和第6天,在尾巴的根部以及背部的两个位点注射包含2mg/ml牛II型胶原质的Freund不完全辅剂。从第0天到第17天,以下皮方式每天注射化合物1.028,剂量为25mg/kg,在以下赋形剂中体积为1ml/kg:20%N,N-二甲基乙酰氨,75%玉米油,5%Tween-80。用测径器测量踝关节的直径,并测量关节肿胀减轻的程度,作为效用的量度。如下所示,在体内实验中,化合物1.028能显著和特异性地抑制关节炎导致的踝关节肿胀。
表4
化合物1.028在大鼠胶原质诱发关节炎实验中的药效
第9天到第17天的关节直径变化 | |
赋形剂 | 15.7% |
正常 | 0% |
化合物1.028 | 9.1%+/-1.8% |
在下表中,提供了本文代表性的化合物的结构和活性。如上所述,如下提供了趋化性实验和/或结合实验的活性的一个或二者:IC50>12.5μM++,2500nM<IC50<12.5μM;+++,500nM<IC50<2500nM;和++++,IC50<500nM。
应理解,本文所述实施例和实施方式仅用于说明的目的,本领域那些技术人员可以提出各种修改或变化,它可以包含于本申请的精神和范围以及附带权利要求书的范围内。本文引用的所有公开、专利和专利申请均参考引用于此。
Claims (44)
1.一种具有下式的化合物:
或其药学上可接受的盐,其中,
下标n是1-2的整数;
下标m是0-10的整数;
每个R1是独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、-CORa、-CO2Ra、-CONRaRb、-NRaCORb、-SO2Ra、-X1CORa、-X1CO2Ra、-X1CONRaRb、-X1NRaCORb、-X1SO2Ra、-X1SO2NRaRb、-X1NRaRb、-X1ORa的取代基,其中,X1选自C1-4亚烷基、C2-4亚烯基、C2-4亚炔基,每个Ra和Rb独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基,其中,每个所述R1取代基的脂肪族部分任选被选自OH、O(C1-8烷基)、SH、S(C1-8烷基)、CN、NO2、NH2、NH(C1-8烷基)、N(C1-8烷基)2中的1-3个成员取代;
Ar1选自苯基、萘基、吡啶基、吡嗪基、哒嗪基、嘧啶基、三嗪基、喹啉基、喹喔啉基、嘌呤基,它们各自都任选被1-5个R2取代基取代,R2取代基独立选自卤素、-ORc、-OC(O)Rc、-NRcRd、-SRc、-Re、-CN、-NO2、-CO2Rc、-CONRcRd、-C(O)Rc、-OC(O)NRcRd、-NRdC(O)Rc、-NRdC(O)2Re、-NRc-C(O)NRcRd、-NH-C(NH2)=NH、-NReC(NH2)=NH、-NH-C(NH2)=NRe、-NH-C(NHRe)=NH、-S(O)Re、-S(O)2Re、-NRcS(O)2Re、-S(O)2NRcRd、-N3、-X2ORc、-X2OC(O)Rc、-X2NRcRd、-X2SRc、-X2CN、-X2NO2、-X2CO2Rc、-X2CONRcRd、-X2C(O)Rc、-X2OC(O)NRcRd、-X2NRdC(O)Rc、-X2NRdC(O)2Re、-X2NRcC(O)NRcRd、-X2NH-C(NH2)=NH、-X2NReC(NH2)=NH、-X2NH-C(NH2)=NRe、-X2NH-C(NHRe)=NH、-X2S(O)Re、-X2S(O)2Re、-X2NRcS(O)2Re、-X2S(O)2NRcRd、-X2N3,其中,X2选自C1-4亚烷基、C2-4亚烯基、C2-4亚炔基,每个Rc和Rd独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、芳基-C1-4烷基、芳氧基-C1-4烷基,每个Re独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、芳基-C1-4烷基、芳氧基-C1-4烷基,每个Rc、Rd和Re还可任选被1-3个选自OH、O(C1-8烷基)、SH、S(C1-8烷基)、CN、NO2、NH2、NH(C1-8烷基)、N(C1-8烷基)2的成员取代;
HAr是选自吡唑基、咪唑基、三唑基、四唑基、唑基、异唑基、二唑基、噻二唑基、吡咯基、噻唑基、异噻唑基、苯并咪唑基、苯并吡唑基、苯并三唑基的杂芳基,其中每个都被1-5个独立选自卤素、苯基、噻吩基、呋喃基、吡啶基、嘧啶基、吡嗪基、吡地嗪基(pyridizinyl)、吡唑基、咪唑基、噻唑基、唑基、异唑基、异噻唑基、三唑基、四唑基、二唑基、-ORf、-OC(O)Rf、-NRfRg、-SRf、-Rh、-CN、-NO2、-CO2Rf、-CONRfRg、-C(O)Rf、-OC(O)NRfRg、-NRgC(O)Rf、-NRgC(O)2Rh、-NRf-C(O)NRfRg、-NH-C(NH2)=NH、-NRhC(NH2)=NH、-NH-C(NH2)=NRh、-NH-C(NHRh)=NH、-S(O)Rh、-S(O)2Rh、-NRfS(O)2Rh、-S(O)2NRfRg、-NRfS(O)2Rh、-NRfS(O)2NRfRg、-N3、-X3ORf、-X3OC(O)Rf、-X3NRfRg、-X3SRf、-X3CN、-X3NO2、-X3CO2Rf、-X3CONRfRg、-X3C(O)Rf、-X3OC(O)NRfRg、-X3NRgC(O)Rf、-X3NRgC(O)2Rh、-X3NRf-C(O)NRfRg、-X3NH-C(NH2)=NH、-X3NRhC(NH2)-NH、-X3NH-C(NH2)-NRh、-X3NH-C(NHRh=NH、-X3S(O)Rh、-X3S(O)2Rh、-X3NRfS(O)2Rh、-X3S(O)2NRfRb、-X3N3的R3取代基取代,其中,X3选自C1-4亚烷基、C2-4亚烯基、C2-4亚炔基,每个Rf和Rg独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、芳基-C1-4烷基、芳氧基-C1-4烷基,每个Rh独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、芳基-C1-4烷基、芳氧基-C1-4烷基,其中,Rf、Rg和Rh的脂肪族部分还任选被1-3个选自OH、O(C1-8烷基)、SH、S(C1-8烷基)、CN、NO2、NH2、NH(C1-8烷基)、N(C1-8烷基)2的成员取代,其中,任何存在的苯基、噻吩基、呋喃基、吡啶基、嘧啶基、吡嗪基、吡地嗪基(pyridizinyl)、吡唑基、咪唑基、噻唑基、唑基、异唑基、异噻唑基、三唑基、四唑基、二唑基任选被1-3个选自卤素、-ORf、-NRfRg、-Rh、-CN、-NO2、-CO2Rf、-CONRfRg、-C(O)Rf、-X3ORf、-X3NRfRg、-X3NRfS(O)2Rh或-X3S(O)ZNRfRg的取代基取代;
L1是含有1-3个选自C,N,O和S的主链原子的连接基、并任选被1-3个选自卤素、苯基、-ORi、-OC(O)Ri、-NRiRj、-SRi、-Rk、-CN、-NO2、-CO2Ri、-CONRiRj、-C(O)Ri、-OC(O)NRiRj、-NRjC(O)Ri、-NRjOC(O)2Rk、-X4ORi、-X4OC(O)Ri,-X4NRiRj、-X4SRi、-X4CN、-X4NO2、-X4CO2Ri、-X4CONRiRj、-X4C(O)Ri、-X4OC(O)NRiRj、-X4NRjC(O)Ri、-X4NRjC(O)2Rk的取代基取代,其中,X4选自C1-4亚烷基、C2-4亚烯基、C2-4亚炔基,每个Ri和Rj独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、芳基-C1-4烷基、芳氧基-C1-4烷基,每个Rk独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、芳基-C1-4烷基、芳氧基-C1-4烷基;以及
条件是,所述化合物不是CAS Reg.No.492422-98-7,1-[[4-溴-5-甲基-3-(三氟甲基)-1H-吡唑-1-基]乙酰基]-4-(5-氯-2-甲基苯基)-哌嗪;CAS Reg.No.351986-92-0,1-[[4-氯-5-甲基-3-(三氟甲基)-1H-吡唑-1-基]乙酰基]-4-(4-氟苯基)-哌嗪;CASReg.No.356039-23-1,1-[(3,5-二甲基-4-硝基-1H-吡唑-1-基)乙酰基]-4-(4-氟苯基)-哌嗪;1-(2-{4-硝基-3,5-二甲基-1H-吡唑-1-基}丙酰基)-4-苯基哌嗪;2-(2,4-二硝基-咪唑-1-基)-1-[4-(4-氟苯基)-哌嗪-1-基]-乙酮;2-(2,4-二硝基-咪唑-1-基)-1-(4-苯基-哌嗪-1-基)-乙酮;2-(4-硝基-咪唑-1-基)-1-(4-苯基-哌嗪-1-基)-乙酮和CAS Reg.No.492992-15-1,3-[3-氟-4-[4-[(1-吡唑基)乙酰基]哌嗪-1-基]苯基]-5-[[(异唑-3-基)氨基]甲基]异唑。
2.如权利要求1所述的化合物,其中,Ar1选自:
(i)苯基,被1-5个R2基取代;
(ii)吡啶基,被1-4个R2基取代;和
(iii)嘧啶基,被1-3个R2基取代;
(iv)吡嗪基,被1-3个R2基取代;和
(v)哒嗪基,被1-3个R2基取代;
其中,每个R2独立选自卤素、-ORc、-OC(O)Rc、-NRcRd、-SRc、-Re、-CN、-NO2、-CO2Rc、-CONRcRd、-C(O)Rc、-OC(O)NRcRd、-NRdC(O)Rc、-NRdC(O)2Re、-NRc-C(O)NRcRd、-S(O)Re、-S(O)2Re、-NRcS(O)2Re、-S(O)2NRcRd、-N3,其中,每个Rc和Rd独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Re独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,其中,Rc、Rd和Re的脂肪族部分任选被1-3个选自OH、O(C1-8烷基)、SH、S(C1-8烷基)、CN、NO2、NH2、NH(C1-8烷基)、N(C1-8烷基)2的成员取代。
3.如权利要求1所述的化合物,其中,Ar1选自:
(i)苯基,被1-5个R2基取代;
(ii)吡啶基,被1-4个R2基取代;和
(iii)嘧啶基,被1-3个R2基取代;
(iv)吡嗪基,被1-3个R2基取代;和
(v)哒嗪基,被1-3个R2基取代;
其中,每个R2独立选自卤素、-X2(O)Rc、-X2OC(O)Rc、-X2NRcRd、-X2SRc、-X2CN、-X2NO2、-X2CO2Rc、-X2CONRcRd、-X2C(O)Rc、-X2OC(O)NRcRd、-X2NRdC(O)Rc、-X2NRdC(O)2Re、-X2NRcC(O)NRcRd、-X2S(O)Re、-X2S(O)2Re、-X2NRcS(O)2Re、-X2S(O)2NRcRd、-X2N3,其中,每个Rc和Rd独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Re独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基。
4.如权利要求2所述的化合物,其中,Ar1是被1-3个R2基取代的苯基。
5.如权利要求4所述的化合物,其中,L1是-CH2-,并任选被苯基、-Rk、-X4ORi、-X4OC(O)Ri、-X4NRiRj、-X4SRi、-X4CN或-X4NO2取代。
6.如权利要求5所述的化合物,其中,HAr选自吡唑基、三唑基、四唑基,其中每个任选被1-3个独立选自卤素、苯基、噻吩基、-ORf、-OC(O)Rf、-NRfRg、-SRf、-Rh、-CN、-NO2、-CO2Rf、-CONRfRg、-C(O)Rf、-OC(O)NRfRg、-NRgC(O)Rf、-NRgC(O)2Rh、-NRf-C(O)NRfRg、-S(O)Rh、-S(O)2Rh、-S(O)2NRfRg、-NRfS(O)2Rh、-NRfS(O)2NRfRg、-N3、-X3ORf、-X3OC(O)Rf、-X3NRfRg、-X3SRf、-X3CN、-X3NO2、-X3CO2Rf、-X3CONRfRg、-X3C(O)Rf、-X3OC(O)NRfRg、-X3NRgC(O)Rf、-X3NRgC(O)2Rh、-X3NRf-C(O)NRfRg、-X3S(O)Rh、-X3S(O)2Rh、-X3NRfS(O)2Rh、-X3S(O)2NRfRg、-X3N3的R3基取代,其中,Rf和Rg各自独立选自H、C1-8烷基、C1-8卤代烷基,每个Rh独立选自C1-8烷基、C1-8卤代烷基。
7.如权利要求6所述的化合物,其中,n是1,m是0-2,Ar1是被1-3个R2基取代的苯基,HAr是被3个R3基取代的吡唑基,L1是-CH2-。
9.如权利要求1所述的化合物,其中,HAr选自吡唑基、三唑基、四唑基、苯并咪唑基、苯并吡唑基、苯并三唑基,其中每个任选被1-5个立选自卤素、苯基、噻吩基、-ORf、-CORf、-CO2Rf-CONRfRg、-NO2、-Rh、-CN、-SRf、-S(O)Rh、-S(O)2Rh、-NRfRg的R3基取代,其中,Rf和Rg各自独立选自H、C1-8烷基、C3-6环烷基、C1-8卤代烷基,每个Rh独立选自C1-8烷基、C3-6环烷基、C1-8卤代烷基。
10.如权利要求1所述的化合物,其中,L1选自-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2O-、-CH2NH-、-CH2OCH2-、-CH2NHCH2-。
12.如权利要求11所述的化合物,其中,Ar1选自苯基、萘基,其各自任选被1-5个取代独立选自卤素、-ORc、-OC(O)Rc、-NRcRd、-SRc、-Re、-CN、-NO2、-CO2Rc、-CONRcRd、-C(O)Rc、-OC(O)NRcRd、-NRdC(O)Rc、-NRdC(O)2Re、-NRc-C(O)NRcRd、-S(O)Re、-S(O)2Re、-NRcS(O)2Re、-S(O)2NRcRd、-N3的R2取代基取代,其中,每个Rc和Rd独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Re独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基。
13.如权利要求11所述的化合物,其中,Ar1选自苯基、萘基,其各自任选被1-5个独立选自卤素、-X2ORc、-X2OC(O)Rc、-X2NRcRd、-X2SRc、-X2CN、-X2NO2、-X2CO2Rc、-X2CONRcRd、-X2C(O)Rc、-X2OC(O)NRcRd、-X2NRdC(O)Rc、-X2NRdC(O)2Re、-X2NRcC(O)NRcRd、-X1S(O)Re、-X2S(O)2Re、-X2NRcS(O)2Re、-X2S(O)2NRcRd、-X2N3的R2取代基取代,其中,每个Rc和Rd独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Re独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基。
14.如权利要求12所述的化合物,其中,L1选自-CH2-、-CH2CH2-、-CH2O-、-CH2NH-,其各自任选被一个或多个独立选自C1-4烷基、C1-4卤代烷基、苯基的取代基取代。
15.如权利要求14所述的化合物,其中,HAr选自吡唑基、三唑基、四唑基、苯并吡唑基,其各自任选被1-5个独立选自卤素、苯基、噻吩基、-ORf、-OC(O)Rf、-NRfRg、-SRf、-Rh、-CN、-NO2、-CO2Rf、-CONRfRg、-C(O)Rf、-OC(O)NRfRg、-NRgC(O)Rf、-NRgC(O)2Rh、-NRf-C(O)NRfRg、-S(O)Rh、-S(O)2Rh、-S(O)2NRfRg、-NRfS(O)2Rh、-NRfS(O)2NRfRg、-X3OR、-X3OC(O)Rf、-X3NRfRg、-X3SRf、-X3CN、-X3NO2、-X3CO2Rf、-X3CONRfRg、-X3C(O)Rf、-X3OC(O)NRfRg、-X3NRgC(O)Rf、-X3NRgC(O)2Rh、-X3NRf-C(O)NRfRg、-X3S(O)Rh、-X3S(O)2Rh、-X3NRfS(O)2Rh、-X3S(O)2NRfRg的R3基取代,其中,X3选自C1-4亚烷基、C2-4亚烯基、C2-4亚炔基,每个Rf和Rg独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Rh独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,其中,任何苯基或噻吩基都任选被1-3个选自卤素、-ORf、-NRfRg、-Rh、-CN、-NO2、-CO2Rf、-CONRfRg、-C(O)Rf、-X3ORf、-X3NRfRg、-X3NRfS(O)2Rh、-X3S(O)2NRfRg的取代基取代。
16.如权利要求15所述的化合物,其中,HAr是吡唑基或苯并吡唑基,其各自任选被1-3个独立选自卤素、苯基、噻吩基、-ORf、-CO2Rf、-CORf、-CONRfRg、-NO2、-Rh、-CN、-SRf、-S(O)Rh、-S(O)2Rh、-NRfRg的R3基取代,其中,每个Rf和Rg独立选自H、C1-8烷基、C1-8卤代烷基,每个Rh独立选自C1-8烷基、C1-8卤代烷基。
19.如权利要求16所述的化合物,其中,L1是-CH2-。
20.如权利要求11所述的化合物,其中,Ar1是苯基,任选被1-5个独立选自卤素、-ORc、-OC(O)Rc、-NRcRd、-SRc、-Re、-CN、-NO2、-CO2Rc、-CONRcRd、-C(O)Rc、-OC(O)NRcRd、-NRdC(O)Rc、-NRdC(O)2Re、-NRc-C(O)NRcRd、-S(O)Re、-S(O)Re、-S(O)2NRcRd、-N3的R2取代基取代,其中,每个Rc和Rd独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Re独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,其中,所述取代基的烷基部分任选被一个或两个羟基或氨基取代;L1是-CH2-;HAr是吡唑基或苯并吡唑基,其各自任选被1-3个独立选自卤素、苯基、噻吩基、ORf、CO2Rf、CONRfRg、NO2、Rh、CN、SRf、S(O)Rh、S(O)2Rh、NRfRg的R3基取代,其中,每个Rf和Rg独立选自H、C1-8烷基、C1-8卤代烷基,每个Rh独立选自C1-8烷基、C1-8卤代烷基;每个R1a、R1b、R1c、R1d、R1e、R1f、R1g和R1h独立选自H、C1-4烷基、C1-4卤代烷基,其中,R1a-R1h中至少六个是H。
21.如权利要求1所述的化合物,所述化合物具有下式:
其中,下标m是0-2的整数;每个R1选自C1-4烷基、C1-4卤代烷基;R2a、R2b、R2c、R2d和R2e独立选自氢、卤素、-ORc、-OC(O)Rc、-NRcRd、-SRc、-Re、-CN、-NO2、-CO2Rc、-CONRcRd、-C(O)Rc、-OC(O)NRcRd、-NRdC(O)Rc、-NRdC(O)2Re、-NRc-C(O)NRcRd、-S(O)Re、-S(O)2Re、-NRcS(O)2Re、-S(O)2NRcRd、-N3、-X2ORc、-X2OC(O)Rc、-X2NRcRd、-X2SRc、-X2CN、-X2NO2、-X2CO2Rc、-X2CONRcRd、-X2C(O)Rc、-X2OC(O)NRcRd、-X2NRdC(O)Rc、-X2NRdC(O)2Re、-X2NRcC(O)NRcRd、-X2S(O)Re、-X2S(O)2Re、-X2NRcS(O)2Re、-X2S(O)2NRcRd、-X2N3,其中,X2是C1-4亚烷基,每个Rc和Rd独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Re独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Rc、Rd和Re还任选被1-3个选自OH、O(C1-8烷基)、SH、S(C1-8烷基)、CN、NO2、NH2、NH(C1-8烷基)、N(C1-8烷基)2的成员取代;R3a、R3b和R3c独立选自氢、卤素、苯基、噻吩基、-ORf、-OC(O)Rf、-NRfRg、-SRf、-Rh、-CN、-NO2、-CO2Rf、-CONRfRg、-C(O)Rf、-OC(O)NRfRg、-NRgC(O)Rf、-NRgC(O)2Rh、-NRf-C(O)NRfRg、-S(O)Rh、-S(O)2Rh、-NRfS(O)2Rh、-S(O)2NRfRg、-NRfS(O)2Rh、-NRfS(O)2NRfRg、-X3ORf、-X3OC(O)Rf、-X3NRfRg、-X3SRf、-X3CN、-X3NO2、-X3CO2Rf、-X3CONRfRg、-X3C(O)Rf、-X3OC(O)NRfRg、-X3NRgC(O)Rf、-X3NRgC(O)2Rh、-X3NRf-C(O)NRfRg、-X3S(O)Rh、-X3S(O)2Rh、-X3NRfS(O)2Rh、-X3S(O)2NRfRg,其中,X3是C1-4亚烷基,每个Rf和Rg独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,每个Rh独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基,其中,任何存在的苯基或噻吩基任选被1-3个选自卤素、-ORf、NRfRg、-Rh、-CN、-NO2、-CO2Rf、-CONRfRg、-C(O)Rf、-X3OR、-X3NRfRg、-X3NRfS(O)2Rh、-X3S(O)2NRfRg的取代基取代。
22.如权利要求21所述的化合物,其中,m是0或1;至少R2a和R2e之一是氢。
23.如权利要求22所述的化合物,其中,至少R3a、R3b和R3c之一选自卤素或C1-4卤代烷基。
24.如权利要求23所述的化合物,其中,R2d是氢,且至少R3a、R3b和R3c之二选自卤素或C1-4卤代烷基。
25.如权利要求24所述的化合物,其中,R2c选自F、Cl、Br、CN、NO2、CO2CH3、C(O)CH3、S(O)2CH3,每个R3a、R3b和R3a不是氢。
26.如权利要求21所述的化合物,其中,m是0或1;R2a和R2e各为氢。
27.如权利要求26所述的化合物,其中,至少R3a、R3b和R3c之一选自卤素或C1-4卤代烷基。
28.如权利要求27所述的化合物,其中,R3a、R3b和R3c各不为氢。
29.如权利要求21所述的化合物,其中,m是0或1;R2b和R2e各为氢。
31.如权利要求30所述的化合物,其中,R3c和R3a各自独立选自C1-6烷基、C1-6卤代烷基、C3-6环烷基。
33.如权利要求21所述的化合物,所述化合物具有下式:
其中,R2c是卤素、氰基或硝基;R2b是Re或-ORc;R3a选自C1-6烷基、C1-6卤代烷基、C3-6环烷基;R3c选自NH2、CF3、SCH3、Ph、噻吩基;R3b是氯或溴。
34.如权利要求21述的化合物,所述化合物具有下式:
其中,R2a不是氢;R2c是卤素、氰基或硝基;R2d是Re或-ORc;R3a选自C1-6烷基、C1-6卤代烷基、C3-6环烷基;R3b是氯或溴;R3c选自NH2、CF3、SCH3、Ph、噻吩基。
36.如权利要求29所述的化合物,其中,至少R3a、R3b和R3c之一选自卤素或C1-4卤代烷基。
37.如权利要求36所述的化合物,其中,R3a、R3b和R3c各不为氢。
38.一种药物组合物,所述组合物含有药学上可接受的赋形剂和权利要求1所述的化合物。
39.一种治疗CCR1-介导的疾病或症状的方法,所述方法包括给予有此需要的受试者治疗有效量的具有下式的化合物:
或其药学上可接受的盐,其中,
下标n是1-2的整数;
下标m是0-10的整数;
每个R1是独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、-CORa、-CO2Ra、-CONRaRb、-NRaCORb、-SO2Ra、-X1CORa、-X1CO2Ra、-X1CONRaRb、-X1NRaCORb、-X1SO2Ra、-X1SO2NRaRb、-X1NRaRb、-X1ORa的取代基,其中,X1选自C1-4亚烷基、C2-4亚烯基、C2-4亚炔基,每个Ra和Rb独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基,其中,每个所述R1取代基的脂肪族部分任选被OH、O(C1-8烷基)、SH、S(C1-8烷基)、CN、NO2、NH2、NH(C1-8烷基)、N(C1-8烷基)2中1-3个成员取代;
Ar1选自苯基、萘基、吡啶基、吡嗪基、哒嗪基、嘧啶基、三嗪基、喹啉基、喹喔啉基、嘌呤基,它们各自都任选被1-5个R2取代基取代,R2取代基独立选自卤素、-ORc、-OC(O)Rc、-NRcRd、-SRc、-Re、-CN、-NO2、-CO2Rc、-CONRcRd、-C(O)Rc、-OC(O)NRcRd、-NRdC(O)Rc、-NRdC(O)2Re、-NRc-C(O)NRcRd、-NH-C(NH2)=NH、-NReC(NH2)=NH、-NH-C(NH2)=NRe、-NH-C(NHRe)=NH、-S(O)Re、-S(O)2Re、-NRcS(O)2Re、-S(O)2NRcRd、-N3、-X2ORc、-X2OC(O)Rc、-X2NRcRd、-X2SRc、-X2CN、-X2NO2、-X2CO2Rc、-X2CONRcRd、-X2C(O)Rc、-X2OC(O)NRcRd、-X2NRdC(O)Rc、-X2NRdC(O)2Re、-X2NRcC(O)NRcRd、-X2NH-C(NH2)=NH、-X2NReC(NH2)=NH、-X2NH-C(NH2)=NRe、-X2NH-C(NHRe)=NH、-X2S(O)Re、-X2S(O)2Re、-X2NRcS(O)2Re、-X2S(O)2NRcRd、-X2N3,其中,X2选自C1-4亚烷基、C2-4亚烯基、C2-4亚炔基,每个Rc和Rd独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、芳基-C1-4烷基、芳氧基-C1-4烷基,每个Re独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、芳基-C1-4烷基、芳氧基-C1-4烷基,每个Rc、Rd和Re还可任选被1-3个选自OH、O(C1-8烷基)、SH、S(C1-8烷基)、CN、NO2、NH2、NH(C1-8烷基)、N(C1-8烷基)2的成员取代;
HAr是选自吡唑基、咪唑基、三唑基、四唑基、唑基、异唑基、二唑基、噻二唑基、吡咯基、噻唑基、异噻唑基、苯并咪唑基、苯并吡唑基、苯并三唑基的杂芳基,其中每个都被1-5个独立选自卤素、苯基、噻吩基、呋喃基、吡啶基、嘧啶基、吡嗪基、吡地嗪基(pyridizinyl)、吡唑基、咪唑基、噻唑基、唑基、异唑基、异噻唑基、三唑基、四唑基、二唑基、-ORf、-OC(O)Rf、-NRfRg、-SRf、-Rh、-CN、-NO2、-CO2Rf、-CONRfRg、-C(O)Rf、-OC(O)NRfRg、-NRgC(O)Rf、-NRgC(O)2Rh、-NRf-C(O)NRfRg、-NH-C(NH2)=NH、-NRhC(NH2)=NH、-NH-C(NH2)=NRh、-NH-C(NHRh)=NH、-S(O)Rh、-S(O)2Rh、-NRfS(O)2Rh、-S(O)2NRfRg、-NRfS(O)2Rh、-NRfS(O)2NRfRg、-N3、-X3ORf、-X3OC(O)Rf、-X3NRfRg、-X3SRf、-X3CN、-X3NO2、-X3CO2Rf、-X3CONRfRg、-X3C(O)Rf、-X3OC(O)NRfRg、-X3NRgC(O)Rf、-X3NRgC(O)2Rh、-X3NRf-C(O)NRfRg、-X3NH-C(NH2)=NH、-X3NRhC(NH2)-NH、-X3NH-C(NH2)-NRh、-X3NH-C(NHRh=NH、-X3S(O)Rh、-X3S(O)2Rh、-X3NRfS(O)2Rh、-X3S(O)2NRfRb、-X3N3的R3取代基取代,其中,X3选自C1-4亚烷基、C2-4亚烯基、C2-4亚炔基,每个Rf和Rg独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、芳基-C1-4烷基、芳氧基-C1-4烷基,每个Rh独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、芳基-C1-4烷基、芳氧基-C1-4烷基,其中,Rf、Rg和Rh的脂肪族部分还任选被1-3个选自OH、O(C1-8烷基)、SH、S(C1-8烷基)、CN、NO2、NH2、NH(C1-8烷基)、N(C1-8烷基)2的成员取代,其中,任何苯基、噻吩基、呋喃基、吡啶基、嘧啶基、吡嗪基、吡地嗪基(pyridizinyl)、吡唑基、咪唑基、噻唑基、唑基、异唑基、异噻唑基、三唑基、四唑基或二唑基任选被1-3个选自卤素、-ORf、-NRfRg、-Rh、-CN、-NO2、-CO2Rf、-CONRfRg、-C(O)Rf、-X3ORf、-X3NRfRg、-X3NRfS(O)2Rh和-X3S(O)ZNRfRg的取代基取代;
L1是含有1-3个选自C,N,O和S的主链原子的连接基、并任选被1-3个选自卤素、苯基、-ORi、-OC(O)Ri、-NRiRj、-SRi、-Rk、-CN、-NO2、-CO2Ri、-CONRiRj、-C(O)Ri、-OC(O)NRiRj、-NRjC(O)Ri、-NRjOC(O)2Rk、-X4ORi、-X4OC(O)Ri,-X4NRiRj、-X4SRi、-X4CN、-X4NO2、-X4CO2Ri、-X4CONRiRj、-X4C(O)Ri、-X4OC(O)NRiRj、-X4NRjC(O)Ri、-X4NRjC(O)2Rk的取代基取代,其中,X4选自C1-4亚烷基、C2-4亚烯基、C2-4亚炔基,每个Ri和Rj独立选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、芳基-C1-4烷基、芳氧基-C1-4烷基,每个Rk独立选自C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、芳基-C1-4烷基、芳氧基-C1-4烷基。
40.如权利要求39所述的方法,其中,所述CCR1-介导的疾病或病症是一种炎性症状。
41.如权利要求39所述的方法,其中,所述CCR1-介导的疾病或病症是一种免疫调节疾病。
42.如权利要求39所述的方法,其中,所述CCR1-介导的疾病或病症选自类风湿性关节炎,多发性硬化,移植物排斥,皮炎,湿疹,荨麻疹,血管炎,炎性肠病,食物过敏和脑脊髓炎。
43.如权利要求39所述的方法,其中,所述给药是口服,肠道外,直肠,经皮,舌下,经鼻或局部给药。
44.如权利要求39所述的方法,其中,所述化合物是与一种消炎剂或止痛剂结合施用的。
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Cited By (1)
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CN101808990B (zh) * | 2007-07-24 | 2012-09-05 | 百时美施贵宝公司 | 作为趋化因子受体活性调节剂的哌啶衍生物 |
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EP1531822B1 (en) | 2009-08-05 |
JP2006508036A (ja) | 2006-03-09 |
WO2003105853A1 (en) | 2003-12-24 |
DE60328690D1 (de) | 2009-09-17 |
US7157464B2 (en) | 2007-01-02 |
DK1531822T3 (da) | 2009-12-07 |
HK1099206A1 (zh) | 2007-08-10 |
US7449576B1 (en) | 2008-11-11 |
CA2488202C (en) | 2011-03-08 |
MXPA04012393A (es) | 2005-06-17 |
US20040082571A1 (en) | 2004-04-29 |
KR20050042754A (ko) | 2005-05-10 |
EP1531822A1 (en) | 2005-05-25 |
AU2003236500B9 (en) | 2009-07-02 |
ES2329356T3 (es) | 2009-11-25 |
KR101255356B1 (ko) | 2013-04-17 |
ATE438401T1 (de) | 2009-08-15 |
JP4723242B2 (ja) | 2011-07-13 |
AU2003236500A1 (en) | 2003-12-31 |
CN1867336B (zh) | 2010-05-12 |
CA2488202A1 (en) | 2003-12-24 |
US20080261987A1 (en) | 2008-10-23 |
AU2003236500B2 (en) | 2009-01-08 |
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