CN107787322B - 三环化合物以及它们作为磷酸二酯酶抑制剂的用途 - Google Patents
三环化合物以及它们作为磷酸二酯酶抑制剂的用途 Download PDFInfo
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- CN107787322B CN107787322B CN201680034997.XA CN201680034997A CN107787322B CN 107787322 B CN107787322 B CN 107787322B CN 201680034997 A CN201680034997 A CN 201680034997A CN 107787322 B CN107787322 B CN 107787322B
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Abstract
Description
技术领域
本发明涉及式I的三环化合物,其为PDE4同功酶的抑制剂,尤其对PDE4A、PDE4B和PDE4C同工型具有结合亲和力,及涉及所述化合物在治疗中枢神经系统(CNS)、代谢、自体免疫及炎症性疾病或病症的方法中的用途。
背景技术
磷酸二酯酶(PDEs)为一类裂解在第二信使分子3',5'-环腺苷单磷酸(cAMP)和3',5'-环鸟苷单磷酸(cGMP)上的磷酸二酯键的细胞内酶。环核苷酸cAMP和cGMP在各种细胞途径中充当第二信使。
cAMP用作调节体内许多细胞内过程的第二信使。一实例为在中枢神经系统的神经元中,其中cAMP-依赖性激酶的活化和蛋白质之后续磷酸化参与突触传递的急性调控以及神经元分化和存活。环核苷酸信号传导的复杂性由参与cAMP的合成及降解的酶的分子多样性指示。有至少10个腺苷酸环化酶家族及11个磷酸二酯酶家族。此外,已知不同类型的神经元表达这些类别中的每一者的多种同功酶,且在给定神经元内的不同同功酶的功能的划分及特异性存在良好证据。
调节环核苷酸信号传导的主要机制为经由磷酸二酯酶催化的环核苷酸代谢。十一个已知PDE家族由21种不同基因编码;各基因通常产生多种剪接变异体,其进一步有助于同功酶多样性。PDE家族根据环核苷酸受质特异性、调节机制及对抑制剂的敏感性而在功能上进行区别。此外,PDE在整个生物体中(包括中枢神经系统中)差异表达。由于这些不同酶活性及位置,不同PDE的同功酶可提供不同生理功能。此外,可选择性抑制不同PDE同功酶的化合物可提供特定治疗效果、较少副作用或两者(Deninno,M.,Future Directions inPhosphodiesterase Drug Discovery.Bioorganic and Medicinal Chemistry Letters2012,22,6794-6800)。
本发明系关于对PDE的第四家族(亦即,PDE4A、PDE4B、PDE4C及PDE4D)具有结合亲和力且特别是对PDE4A、PDE4B和PDE4C同工型具有结合亲和力的化合物。
PDE4同功酶进行第二信使3',5'-环腺苷单磷酸(cAMP)的选择性高亲和力水解降解。由该抑制引起的有利药理作用已显示于各种疾病模型中。近年来已发现许多其他PDE4抑制剂。例如,罗氟司特(Roflumilast)(由Forest Pharmaceuticals,Inc.销售)获准用于严重慢性阻塞性肺病(COPD)以减少突然发作的次数或防止COPD症状恶化。阿普司特(Apremilast)已获美国食品药物管理局(U.S.Food and DrugAdministration)批准用于治疗患有活动性牛皮癣性关节炎的成人。
虽然已显示PDE4抑制剂的有利药理活性,但这些疗法的常见副作用为诱发胃肠症状,诸如心、呕吐及腹泻,其被假设为与抑制PDE4D同工型有关。已尝试开发具有对PDE4B同工型的亲和力超过对PDE4D同工型的化合物(参见:Donnell,A.F.等人,Identificationof pyridazino[4,5-b]indolizines as selective PDE4B inhibitors.Bioorganic andMedicinal Chemistry Letters 2010;20:2163-7;及Naganuma,K.等人,Discovery ofselective PDE4B inhibitors.Bioorganic and Medicinal Chemistry Letters 2009;19:3174-6)。然而,仍需要开发选择性PDE4抑制剂,尤其对PDE4A、PDE4B和PDE4C同工型具有亲和力的选择性PDE4抑制剂。特别是,具有对PDE4A和PDE4B同工型的增强亲和力超过对PDE4D同工型的化合物预期可用于治疗中枢神经系统(CNS)的各种疾病及病症。发现本发明的所选化合物解决此持续需要,且提供治疗中枢神经系统(CNS)的各种疾病及病症以及代谢、自体免疫性及炎症性疾病或病症的其他疗法。
发明概述
本发明系关于式I化合物:
或其药学上可接受的盐,其中:
环A为稠合(4至8元)含氧杂环烷基环、稠合苯基环或稠合(5至8元)含氮杂芳基环,且在化学上允许的情况下,该稠合(4至8元)含氧杂环烷基环、稠合苯基环及稠合(5至8元)含氮杂芳基环任选地被一至六个R8取代;
R1选自由下列所组成的群组:(C3-C8)环烷基、(4至10元)-杂环烷基、(C6-C10)芳基及(5至14元)杂芳基,且在化学上允许的情况下,该(C3-C8)环烷基、(4至10元)杂环烷基、(C6-C10)芳基及(5至14元)杂芳基部分任选地被一至六个R9取代;
R2选自由下列所组成的群组:氢、(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C15)烷基-OR5、-C(=O)-R5、-C(=O)-OR5、-C(=O)-N(R5)(R6)、-(SO2)R5、(C3-C8)环烷基、(4至10元)杂环烷基、(C6-C10)芳基及(5至14元)杂芳基,且在化学上允许的情况下,该(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C8)环烷基、(4至10元)杂环烷基、(C6-C10)芳基及(5至14元)杂芳基任选地被一至六个R8取代;
R3a,在化学上允许的情况下,选自由下列所组成的群组:氢、卤素、氧代、氰基、羟基、-SF5、硝基、N(R5)(R6)、任选被取代的(C1-C6)烷硫基、任选被取代的(C1-C6)烷基、任选被取代的(C1-C6)烷氧基及任选被取代的(C3-C8)环烷基;或
R2和R3a与它们所连接的氮和碳原子一起形成(4至6元)杂环烷基环,且在化学上允许的情况下,该(4至6元)杂环烷基环任选地被一至六个R8取代;
当存在时,R3b选自由下列所组成的群组:氢、卤素、氧代、氰基、羟基、-SF5、硝基、N(R5)(R6)、任选被取代的(C1-C6)烷硫基、任选被取代的(C1-C6)烷基、任选被取代的(C1-C6)烷氧基及任选被取代的(C3-C8)环烷基;或
R3a和R3b与它们所连接的碳原子一起形成(C3-C6)环烷基或(4至6元)杂环烷基,且在化学上允许的情况下,该(C3-C6)环烷基或(4至6元)杂环烷基、在化学上允许的情况下,任选地被一至六个R8取代。
R4a,在化学上允许的情况下,选自由下列所组成的群组:氢、卤素、氧代、氰基、羟基、-SF5、硝基、N(R5)(R6)、任选被取代的(C1-C6)烷硫基、任选被取代的(C1-C6)烷基及任选被取代的(C1-C6)烷氧基;
当存在时,R4b选自由下列所组成的群组:氢、卤素、氧代、氰基、羟基、-SF5、硝基、N(R5)(R6)、任选被取代的(C1-C6)烷硫基、任选被取代的(C1-C6)烷基及任选被取代的(C1-C6)烷氧基;或
R4a和R4b与它们所连接的碳原子一起形成(C3-C6)环烷基或(4至6元)杂环烷基,且在化学上允许的情况下,该(C3-C6)环烷基或(4至6元)杂环烷基任选地被一至六个R8取代;
R5和R6在每次出现时各自独立地选自由下列所组成的群组:氢及(C1-C6)烷基;
R7为(C1-C6)烷基;
当存在时,R8在每次出现时各自独立地选自由下列所组成的群组:卤素、氧代、氰基、羟基、-SF5、硝基、N(R5)(R6)、任选被取代的(C1-C6)烷硫基、任选被取代的(C1-C6)烷基、及任选被取代的(C1-C6)烷氧基;
当存在时,R9在每次出现时各自独立地选自由下列所组成的群组:卤素、氧代、氰基、羟基、-SF5、硝基、任选被取代的(C1-C6)烷基、任选被取代的(C2-C6)烯基、任选被取代的(C2-C6)炔基、任选被取代的(C1-C6)烷硫基、任选被取代的(C1-C6)烷氧基、-N(R5)(R6)、-N(R5)(C(O)R6)、-C(=O)、-C(=O)-R5、-C(=O)-OR5、-(SO2)R7、及-S(=O2)N(R5)(R6);
-------系不存在(形成单键)或为一键(形成双键);以及
n为选自0或1的整数,假若当------系存在以形成双键时,则n为0,而当------系不存在以形成单键时,n为1。
本发明化合物包括如本文所述的实例1-97或其药学上可接受的盐。
式I化合物为PDE4A、PDE4B及/或PDE4C同工型的抑制剂。
式I化合物可用于治疗或预防中枢神经系统(CNS)的疾病及/或病症、疼痛、创伤、心脏病性、血栓性、代谢、自体免疫性及炎症性疾病或病症以及与增强的内皮活性/受损的内皮障壁功能有关的病症。
本发明亦涉及本文所述的化合物或其药学上可接受的盐的用途,其用于制备供治疗或预防易受调节PDE4A、PDE4B和PDE4C基因家族(亦即,PDE4B酶)影响的病况的药物。
本发明亦涉及配制成药物剂型的药学上可接受的制剂,其含有本发明化合物及至少一种赋形剂的掺合物。所述剂型的实例包括锭剂、胶囊、栓剂、凝胶、乳膏、软膏、洗剂、注射用溶液/悬浮液(例如储库(depot))、用于吸入的气溶胶及用于口服摄取的溶液/悬浮液。
发明的详细说明
本文件内的标题仅用于由读者加速理解其综述。其不应理解为以任何方式限制本发明或申请专利范围。
定义及例证
如本申请案整篇(包括权利要求书)中所用,除非另外明确指明,否则以下术语具有下文所定义的意义。复数及单数应视为可互换,而非数字的指示:
如本文所用,其中n为整数的术语“n员”通常描述部分中形成环的原子的数目,其中形成环的原子的数目为n。例如,吡啶为6元杂芳环的实例及噻吩为5元杂芳基的实例。
在本说明书的各个位置处,本发明化合物的取代基以群组或范围的形式揭示。特别希望本发明包括所述群组及范围的成员的各个及每个个别子组合。例如,术语“(C1-C6)烷基”特别意欲包括C1烷基(甲基)、C2烷基(乙基)、C3烷基、C4烷基、C5烷基、及C6烷基。对于另一实例,术语“5至14元杂芳基”尤其意欲包括任何5、6、7、8、9、10、11、12、13和14员杂芳基。
术语“(C1-C6)烷基”如本文所用,系指含有1至6个碳原子的饱和的支链或直链烷基,诸如(但不限于)甲基、乙基、正丙基、异丙基、正丁基、第二丁基、异丁基、叔丁基、正戊基、异戊基、新戊基及正己基。
术语“任选被取代的(C1-C6)烷基”,如本文所用,系指如上述所定义的(C1-C6)烷基,其中一或多个氢原子被选自由下列所组成的群组的取代基取代:卤素、氧代、氰基、羟基、-SF5、(C1-C6)烷硫基、硝基、-C(=O)-R5及-N(R5)(R6),其中R5和R6各自独立地为氢或(C1-C6)烷基。例如,(C1-C6)烷基部分可被一或多个卤素原子取代以形成“卤代(C1-C6)烷基”。卤代(C1-C6)烷基的代表性实例包括(但不限于)氟甲基、二氟甲基、2-氟乙基、三氟甲基、五氟乙基、及2-氯-3-氟戊基。
术语"(C2-C6)烯基"系指具有2至6个碳原子且具有至少一个碳-碳双键的脂族烃,包括具有至少一个碳-碳双键的直链或支链基团。代表性实例包括(但不限于)乙烯基、1-丙烯基、2-丙烯基(烯丙基)、异丙烯基、2-甲基-1-丙烯基、1-丁烯基、2-丁烯基等等。当本发明化合物含有(C2-C6)烯基时,该化合物可以纯E(异侧(entgegen))型、纯Z(同侧(zusammen))型或其任何混合物形式存在。
术语"任选被取代的(C2-C6)烯基"系指如上文所定义的(C2-C6)烯基,其中一或多个氢原子被选自由下列所组成的群组的取代基取代:卤素、氧代、氰基、羟基、-SF5、-(C1-C6)烷硫基、硝基、-C(=O)-R5、及-N(R5)(R6),其中R5和R6各自独立地为氢或(C1-C6)烷基。
术语"(C2-C6)炔基"系指具有2至6个碳原子和至少一个碳-碳参键的脂族烃,包括具有至少一个碳-碳参键的直链或支链基团。代表性实例包括(但不限于)乙炔基、丙炔基、丁炔基、戊炔基及丁炔基。
术语"任选被取代的(C2-C6)炔基"系指如上文所定义的(C2-C6)烯基,其中一或多个氢原子被选自由下列所组成的群组的取代基取代:卤素、氧代、氰基、羟基、-SF5、-(C1-C6)烷硫基、硝基、-C(=O)-R5、及-N(R5)(R6),其中R5和R6各自独立地为氢或(C1-C6)烷基。
术语“(C1-C6)烷氧基”如本文所用,系指如上述所定义的(C1-C6)烷基,其经由氧原子连接于母分子部分。(C1-C6)烷氧基的代表性实例包括(但不限于)甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基、叔丁氧基、戊氧基及己氧基。
术语“任选被取代的(C1-C6)烷氧基”如本文所用,系指如上述所定义的(C1-C6)烷氧基,其中一或多个氢原子被选自由下列所组成的群组的取代基取代:卤素、氧代、氰基、羟基、-SF5、(C1-C6)烷硫基、硝基、-C(=O)-R5、及-N(R5)(R6),其中R5和R6各自独立地为氢或(C1-C6)烷基。例如,“(C1-C6)烷氧基可被一或多个卤素原子取代以形成“卤代(C1-C6)烷氧基”。卤代(C1-C6)烷氧基的代表性实例包括(但不限于)氟甲氧基、二氟甲氧基、2-氟乙氧基、三氟甲氧基、及五氟乙氧基。
术语“(C1-C6)烷硫基”如本文所用,系指如上述所定义的(C1-C6)烷基,其经由硫原子连接于母分子部分。(C1-C6)烷硫基的代表性实例包括(但不限于)甲硫基、乙硫基、丙硫基等等。
术语“任选被取代的(C1-C6)烷硫基”如本文所用,系指如上述所定义的(C1-C6)烷硫基,其中一或多个氢原子被选自由下列所组成的群组的取代基取代:卤素、氧代、氰基、羟基、-SF5、(C1-C6)烷硫基、硝基、-C(=O)-R5、及-N(R5)(R6),其中R5和R6各自独立地为氢或(C1-C6)烷基。
如本文所用,术语“(C3-C8)环烷基”系指藉由自其中环状构架具有3至8个碳的饱和碳环分子移除氢而获得的碳环取代基。“(C3-C6)环烷基”系指藉由自具有3至6个碳原子的饱和碳环分子移除氢而获得的碳环取代基。“环烷基”可为单环的环,其实例包括环丙基、环丁基、环戊基、环己基、环庚基及环辛基。环烷基的定义中亦包括不饱和非芳族环烷基,诸如(但不限于)环己烯基、环己二烯基、环戊烯基、环庚烯基及环辛烯基。或者,环烷基可含有超过一个环,诸如“(C4-C8)双环烷基”。术语诸如“(C4-C8)双环烷基”系指含有4至8个碳原子的双环系统。双环烷基可稠合,诸如双环[1.1.0]丁基、双环[2.1.0]戊基、双环[2.2.0]己基、双环[3.1.0]己基、双环[3.2.0]庚基及双环[3.3.0]辛基。术语“双环烷基”亦包括桥接的双环烷基系统,诸如(但不限于)双环[2.2.1]庚基及双环[1.1.1]戊基。
术语“任选被取代的“(C3-C8)环烷基”系指如上述所定义的(C3-C8)环烷基,其中一或多个氢原子被选自由下列所组成的群组的取代基取代:卤素、氧代、氰基、羟基、-SF5、硝基、-C(=O)-R5、及-N(R5)(R6),其中R5和R6各自独立地为氢或(C1-C6)烷基。
“杂环烷基”,如本文所用,系指如上述所定义的环烷基,其中至少一个环碳原子经选自氮、氧或硫的杂原子置换。术语“(4至6元)杂环烷基”意指杂环烷基取代基含有总共4至6个环原子,其中至少一者为杂原子。术语“(4至8元)杂环烷基”意指杂环烷基取代基含有总共4至8个环原子,其中至少一者为杂原子。术语“(4至10元)杂环烷基”意指杂环烷基取代基含有总共4至10个环原子。“(6元)杂环烷基”意指杂环烷基取代基含有总共6个环原子,其中至少一者为杂原子。“(4至8元)含氧杂环烷基”意指杂环烷基取代基含有总共4至8个环原子,其中至少一者为氧原子。“(4至6元)含氧杂环烷基”意指杂环烷基取代基含有总共4至6个环原子,其中至少一者为氧原子。“(5元)杂环烷基”意指杂环烷基取代基含有总共5个环原子,其中所述环原子中的至少一者为杂原子。杂环烷基可为具有最多总共10个成员的单个环。或者,如上文所定义的杂环烷基可包含2或3个稠合在一起的环,其中至少一个该环含有杂原子(亦即,氮、氧或硫)作为环原子。杂环烷基取代基可经由具有适当价态的氮原子或经由任何环碳原子连接至本发明化合物的核心。杂环烷基部分可在具有适当价态的氮原子处或在任何可用碳原子处任选地被一或多个取代基取代。
“杂环烷基”定义中亦包括与苯基或萘基环或杂芳基环(诸如(但不限于),吡啶基环或嘧啶基环)稠合的杂环烷基。
杂环烷基环的实例包括(但不限於)氮杂环丁烷基、二氢呋喃基、二氢噻吩基、四氢噻吩基、四氢呋喃基、四氢三嗪基、四氢吡唑基、四氢嗪基、四氢嘧啶基、八氢苯并呋喃基、八氢苯并咪唑基、八氢苯并噻唑基、咪唑烷基、吡咯烷基、哌啶基、哌嗪基、唑烷基、噻唑烷基、吡唑烷基、硫代吗啉基、四氢吡喃基、四氢噻嗪基、四氢噻二嗪基、四氢唑基、吗啉基、氧杂环丁烷基、二氧杂环丁烷基、二氧五环烷基(dioxolanyl)、二烷基、氧杂环庚烷基(oxapanyl)、二氧杂环庚烷基(dioxapanyl)、氧杂环辛烷基(oxacanyl)、二氧杂环辛烷基(dioxacanyl)、四氢二嗪基、嗪基、噻嗪基、奎宁环基、色满基、异色原烷基(isochromanyl)、二氢苯并二氧杂环己烯基(dihydrobenzodioxinyl)、苯并二氧杂环戊烯基(benzodioxolyl)、苯并嗪基、二氢吲哚基、二氢苯并呋喃基、四氢喹啉基、异色满基(isochromyl)、二氢-1H-异吲哚基、2-氮杂双环[2.2.1]庚酮基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基等等。杂环烷基环的其他实例包括四氢呋喃-2-基、四氢呋喃-3-基、咪唑烷-1-基、咪唑烷-2-基、咪唑烷-4-基、吡咯烷-1-基、吡咯烷-2-基、吡咯烷-3-基、哌啶-1-基、哌啶-2-基、哌啶-3-基、哌啶-4-基、哌嗪-1-基、哌嗪-2-基、1,3-唑啶-3-基、1,4-氧杂氮杂环庚烷-1-基、异噻唑烷基、1,3-噻唑烷-3-基、1,2-吡唑烷基-2-基、1,2-四氢噻嗪-2-基、1,3-噻嗪烷-3-基(1,3-thiazinan-3-yl)、1,2-四氢二嗪-2-基、1,3-四氢二嗪-1-基、1,4-嗪-4-基、唑烷酮基、2-氧代-哌啶基(例如,2-氧代-哌啶-1-基)等等。
术语“任选被取代的杂环烷基”[例如,任选被取代的(4至10元)杂环烷基]系指如上述所定义的杂环烷基,其中一或多个氢原子被选自由下列所组成的群组的取代基取代:卤素、氧代、氰基、羟基、-SF5、(C1-C6)烷硫基、硝基、-C(=O)-R5、及N(R5)(R6),其中R5和R6各自独立地为氢或(C1-C6)烷基。
“(C6-C10)芳基”系指具有含有6至10个碳原子的共轭π电子系统的所有碳单环或稠合环多环芳族基,诸如苯基或萘基。
术语“任选被取代的(C6-C10)芳基”系指如上述所定义的(C6-C10)芳基,其中一或多个氢原子被选自由下列所组成的群组的取代基取代:卤素、氧代、氰基、羟基、-SF5、(C1-C6)烷硫基、硝基、-C(=O)-R5、及-N(R5)(R6),其中R5和R6各自独立地为氢或(C1-C6)烷基。
如本文所用,术语“杂芳基”系指单环或稠合环多环芳族杂环基团,其具有至少一个环中的一或多个杂原子环成员(形成环的原子)系各自独立地选自氧(O)、硫(S)和氮(N)。“(5至14元)杂芳基”环系指具有5至14个环原子的杂芳基环,其中至少一个环原子为杂原子(亦即,氧、氮或硫),且其余环原子独立地选自由碳、氧、氮和硫所组成的群组。“(5至10元)杂芳基”环系指具有5至10个环原子的杂芳基环,其中至少一个环原子为杂原子(亦即,氧、氮或硫),且其余环原子独立地选自由碳、氧、氮和硫所组成的群组。“(5至8元)杂芳基”环系指具有5至8个环原子的杂芳基环,其中至少一个环原子为杂原子(亦即,氧、氮或硫),且其余环原子独立地选自由碳、氧、氮和硫所组成的群组。“(5至8元)含氮杂芳基”环系指具有5至8个环原子的杂芳基环,其中至少一个环原子为氮,且其余环原子独立地选自由碳、氧、硫和氮所组成的群组。“(5至6元)杂芳基”系指具有5至6个环原子的杂芳基环,其中至少一个环原子为杂原子(亦即,氧、氮或硫),且其余环原子独立地选自由碳、氧、氮和硫所组成的群组。“(5至6元)含氮杂芳基”系指具有5至6个环原子的杂芳基环,其中至少一个环原子为氮,且其余环原子独立地选自由碳、氧、硫和氮所组成的群组。“(6元)含氮杂芳基”系指具有6个环原子的杂芳基环,其中至少一个环原子为氮,且其余环原子独立地选自由碳、氧、硫和氮所组成的群组。“(5元)含氮杂芳基”系指具有5个环原子的杂芳基环,其中至少一个环原子为氮,且其余环原子独立地选自由碳、氧、硫和氮所组成的群组。杂芳基可为单环或2或3个稠合环。杂芳基的实例包括(但不限于)6元环取代基诸如吡啶基、吡嗪基、嘧啶基及哒嗪基;5元杂芳基诸如三唑基、咪唑基、呋喃基、异唑基、异噻唑基、1,2,3-、1,2,4-、1,2,5-、或1,3,4-二唑基、唑基、噻吩基、噻唑基、异噻唑基、及吡唑基;6/5元稠合环取代基诸如吲哚基、吲唑基、苯并呋喃基、苯并咪唑基、苯并噻吩基、苯并二唑基、苯并噻唑基、异苯并硫代呋喃基、苯并硫代呋喃基、苯并异唑基、苯并唑基、苯并二氧杂环戊烯基、呋喃并吡啶基、嘌呤基、咪唑并吡啶基、咪唑并嘧啶基、吡咯并吡啶基、吡唑并吡啶基、吡唑并嘧啶基、噻吩并吡啶基、三唑并嘧啶基、三唑并吡啶基(例如,5,6,7,8-四氢[1,2,4]三唑并[1,5-a]吡啶-2-基)、及蒽基(anthranilyl);及6/6元稠合环取代基诸如喹啉基、异喹啉基、噌啉基、喹唑啉基、氧代色满基、及1,4-苯并嗪基。
含氮杂芳基包括(但不限于)三唑基、咪唑基、异唑基、异噻唑基、1,2,3-、1,2,4-、1,2,5-、或1,3,4-二唑基、唑基、噻唑基、异噻唑基、吡唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、吲哚基、吲唑基、苯并咪唑基、苯并二唑基、苯并噻唑基、苯并异唑基、苯并唑基、呋喃并吡啶基、嘌呤基、咪唑并吡啶基、咪唑并嘧啶基、吡咯并吡啶基、吡唑并吡啶基、吡唑并嘧啶基、噻吩并吡啶基、三唑并嘧啶基、三唑并吡啶基、喹啉基、异喹啉基、噌啉基、及喹唑啉基。5元含氮杂芳基包括(但不限于)三唑基、咪唑基、异唑基、异噻唑基、1,2,3-、1,2,4-、1,2,5-、或1,3,4-二唑基、唑基、噻唑基、异噻唑基、及吡唑基。6元含氮杂芳基包括(但不限于)吡啶基、吡嗪基、嘧啶基及哒嗪基。
应理解杂芳基可任选地与如本文所定义的环烷基或杂环烷基稠合。
杂芳基取代基可任选地被由具有适当价态的氮原子或经由任何环碳原子连接至本发明化合物的核心或连接至核心上的酰胺部分的氮。杂芳基部分可在具有适当价态的氮原子处或在任何可用碳原子处任选地被一或多个取代基取代。
术语“任选被取代的(5至14元)杂芳基”、“任选被取代的(5至8元)杂芳基”、“任选被取代的(5至6元)杂芳基”和“任选被取代的(5至6元)含氮杂芳基”系指如上述所定义的(5至14元)杂芳基、(5至8元)杂芳基、(5至6元)杂芳基、及(5至6元)含氮杂芳基,其中一或多个氢原子,在化学上允许的情况下,被选自由下列所组成的群组的取代基取代:卤素、氧代、氰基、羟基、-SF5、(C1-C6)烷硫基、硝基、-C(=O)-R5、及-N(R5)(R6),其中R5和R6各自独立地为氢或任选被取代的(C1-C6)烷基。取代基可在任何可用碳原子处连接至杂芳基部分或在杂原子为具有适当价态的氮时连接至杂原子。
“卤代”或“卤素”如本文所用,系指氯、氟、溴或碘原子。
“羟基”或“羟基”如本文所用,意指-OH基。
“硝基”如本文所用,意指-NO2基。
“氧代”如本文所用,意指=O部分。当氧代取代在碳原子上时,它们一起形成羰基部分[-C(=O)-]。当一个氧代取代在硫原子上时,它们一起形成亚磺酰基部分[-S(=O)-];当两个氧代取代在硫原子上时,它们一起形成磺酰基部分[-S(=O)2-]。
术语“任选地被取代”如本文所使用,意指取代为任选的且因此包括未被取代与被取代的原子及部分。“被取代”的原子或部分表示在指定原子或部分上的任何氢可被从所指示的取代基的选择来取代(多至且包括在指定原子或部分上的每个氢原子经从所指示的取代基的选择取代),其限制条件为不超出指定原子或部分的正常价态且取代产生稳定化合物。例如,若甲基(亦即,-CH3)任选地被取代,则碳原子上的3个氢原子可被取代基取代。
如本文所用,除非规定,否则取代基的连接点可为从取代基的任何适合位置。例如,吡啶基(或吡啶基)可为2-吡啶基(或吡啶-2-基)、3-吡啶基(或吡啶-3-基)、或4-吡啶基(或吡啶-4-基)。
“治疗有效量”系指在某种程度上减轻所治疗病症的一或多种症状的所给药的化合物的量。
“患者”系指温血动物诸如举例而言,猪、牛、鸡、马、天竺鼠、小鼠、大鼠、沙鼠、猫、兔、狗、猴、黑猩猩及人。
除非另外指明,否则如本文中所用,术语“治疗(treating或treat)”意指逆转、缓解、抑制该术语所应用的病症或病况或该病症或病况的一或多种症状的进展或预防该病症或病况。除非另外指明,否则如本文所用的术语“治疗(treatment)”系指如上文定义的“治疗”般的治疗作用。术语“治疗(treating)”亦包括对个体的辅佐及新辅佐治疗。
“药学上可接受”表示物质或组合物必须在化学上及/或毒理学上与构成制剂的其他成分及/或与用其治疗的哺乳动物相容。
“同工型(isoform)”意指相同蛋白质的数种不同形式中的任一者。
“同功酶”或“同功异构酶”意指氨基酸序列不同但催化相同化学反应的酶的密切相关变异体。
“异构体”意指如下文所定义的“立体异构体”和“几何异构体”。
“立体异构体”系指具有一或多个手性中心的化合物,其可各以R或S构型存在。立体异构体包括所有非对映异构体、对映异构体及差向异构体的形式以及其外消旋物和混合物。
“几何异构体”系指可以顺、反、对侧、异侧(E)及同侧(Z)形式以及其混合物存在的化合物。
本说明书可互换地使用术语“取代基”、“基团(radical)”和“基团(group)”。
若取代基描述为“独立地选”自一群组,则取代基的各实例系彼此独立地选择。各取代基因此可与其他取代基相同或不同。
如本文所用,术语“式I”在下文可称为“本发明化合物”。所述术语亦定义以包括本发明化合物的所有形式,包括其水合物、溶剂合物、异构体、晶形及非晶形、同晶形体、多晶体及代谢物。例如,本发明化合物或其药学上可接受的盐可以非溶剂合物及溶剂合物形式存在。当溶剂或水紧密结合时,复合物将具有与湿度无关的确定化学计量。然而,当溶剂或水弱结合时(如在通道溶剂合物及吸湿化合物中),水/溶剂含量将取决于湿度及干燥条件。在所述情况下,以非化学计量为常态。
本发明化合物可以包合物或其他复合物存在。在本发明的范围内所包括者为复合物,诸如包合物、药物-基质包含复合物,其中药物及基质以化学计量或非化学计量存在。亦包括的是含有二或多种有机及/或无机组分的本发明化合物的复合物,其可于学计量或非化学计量。所得复合物可离子化、部分离子化或未经离子化。关于所述复合物的评论,参见J.Pharm.Sci.,64(8),1269-1288,Haleblian(1975年8月)。
本发明化合物具有不对称碳原子。本发明化合物的碳-碳键在本文中可使用实线实线楔形或虚线楔形描绘。使用实线描绘连接至不对称碳原子的键以意欲指示包括于碳原子的所有可能的立体异构体(例如特定对映异构体、外消旋混合物等等)。使用实线或虚线楔形来描绘连接于不对称碳原子的键意欲指示所示立体异构体存在。当以外消旋化合物存在时,实线及虚线楔形系用于定义相对立体化学,而非绝对立体化学。具有该指示的相对立体化学之外消旋化合物用(+/-)标记。例如,除非另外说明,否则,预期本发明化合物可以立体异构体存在,其包括顺及反异构体、光学异构体(诸如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构形异构体、阻转异构体及其混合物(诸如外消旋物及非对映异构体对)。本发明化合物可呈现超过一种类型的异构现象。亦包括的是酸加成盐类或碱加成盐类,其中相对离子具有光学活性,例如D-乳酸盐或L-离胺酸,或为外消旋,例如DL-酒石酸盐或DL-精胺酸。
当任何外消旋物结晶时,可能有两种不同类型的晶体。第一种类型为上文所提及之外消旋化合物(真实消旋物),其中产生一种均质形式晶体,其含有等摩尔量的两种对映异构体。第二种类型为外消旋混合物或聚结物(conglomerate),其中产生等摩尔量的两种形式的晶体,各包含单一对映异构体。
本发明化合物可以由从无机酸类或有机酸类衍生的盐类形式使用。取决于特定化合物,由于盐类的一或多种物理特性(诸如在不同温度及湿度下的提高的药物稳定性或于水或油中的理想溶解度),故化合物的盐类可为有利的。在一些情况下,化合物的盐类亦可有助于化合物的分离、纯化及/或拆分。
在欲将盐类给药至患者的情况(与例如用于活体外的情况下相反),该盐类优选为药学上可接受的。术语"药学上可接受的盐"系指藉由组合本发明化合物与酸(其阴离子)或碱(其阳离子)而制备的盐一般认为适合于人消耗。药学上可接受的盐因为其相对于母化合物较大的水溶性而特别可用作为本发明方法的产物。
本发明化合物的适当药学上可接受的酸加成盐当可能时包括它们衍生自下列者:无机酸类,诸如(但不限于)盐酸、氢溴酸、氢氟酸、硼酸、氟硼酸、磷酸、偏磷酸、硝酸、碳酸、磺酸和硫酸;及有机酸类,诸如乙酸、苯磺酸、苯甲酸、柠檬酸、乙磺酸、反丁烯二酸、葡萄糖酸、乙醇酸、羟乙磺酸、乳酸、乳糖酸、顺丁烯二酸、苹果酸、甲磺酸、三氟甲磺酸、丁二酸、甲苯磺酸、酒石酸和三氟乙酸。适当有机酸一般包括(但不限于)有机酸的脂族、环脂族、芳族、芳脂族、杂环、羧酸及磺酸类别。
适当有机酸的特定实例包括乙酸盐、三氟乙酸盐、甲酸盐、丙酸盐、丁二酸盐、甘醇酸盐、葡萄糖酸盐、二葡萄糖酸盐、乳酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、抗坏血酸盐、葡糖醛酸盐、马来酸盐、反丁烯二酸盐、丙酮酸盐、天门冬胺酸盐、谷氨酸盐、苯甲酸盐、邻胺酸苯甲酸盐、硬脂酸盐、水杨酸盐、对-羟基苯甲酸盐、苯基乙酸盐、杏仁酸盐、恩波酸盐(embonate)(双羟萘酸盐)、甲磺酸盐、乙磺酸盐、苯磺酸盐、泛酸盐、甲苯磺酸盐、2-羟基乙磺酸盐、磺胺酸盐、环己氨基磺酸盐、海藻酸、β-羟基丁酸、半乳糖二酸盐、半乳糖醛酸盐、己二酸盐、海藻酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、十二烷基硫酸盐、葡糖庚酸盐、甘油磷酸盐、庚酸盐、己酸盐、烟碱酸盐、2-萘磺酸盐、草酸盐、棕榈酸盐、果胶酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、硫代氰酸盐及十一烷酸盐。
此外,在本发明化合物带有酸性部份的情况,其适当药学上可接受的盐可包括碱金属盐类,亦即钠或钾盐类;碱土金属盐类,例如钙或镁盐类;及与适当有机配位基所形成的盐类,例如四级铵盐类。在另一实施方案中,碱盐类系从形成无毒性盐类的碱类所形成,包括铝、精胺酸、苄星(benzathine)、胆碱、二乙胺、二醇胺、甘胺酸、离胺酸、甲基葡胺(meglumine)、乙醇胺(olamine)、胺丁三醇(tromethamine)及锌盐类。
有机盐类可从二级、三级或四级胺盐类制得,诸如胺丁三醇、二乙胺、N,N’-二苯甲基乙二胺、氯普鲁卡因(chloroprocaine)、胆碱、二乙醇胺、乙二胺、甲基葡胺(N-甲基葡糖胺)、及普鲁卡因(procaine)。碱性含氮基团可用诸如下列试剂四级化:低碳烷基(C1-C6)卤化物(例如,甲基、乙基、丙基及丁基氯化物、溴化物及碘化物)、硫酸二烷酯(亦即硫酸二甲酯、二乙酯、二丁酯及二戊酯)、长链卤化物(亦即癸基、月桂基、肉豆蔻基及硬脂基氯化物、溴化物及碘化物)、芳烷基卤化物(亦即苯甲基及苯乙基溴化物)、及其他。
在一实施方案中,亦可形成酸类及碱类的半盐类,例如半硫酸盐及半钙盐类。
某些本发明化合物可以几何异构体的形式存在。本发明化合物可具有一或多个不对称中心,因此以二或更多种立体异构体形式存在。本发明包括本发明化合物的所有个别立体异构体及几何异构体及其混合物。个别对映异构体可藉由手性分离或在合成中使用相关对映异构体而获得。
此外,本发明化合物可以非溶剂合物以及以与药学上可接受的溶剂(诸如水、乙醇等等)的溶剂合物形式存在。一般而言,为了本发明的目的,认为溶剂化形式与非溶剂化形式等效。所述化合物亦可以一或多种晶态(亦即,多晶形)存在,或它们可以非晶形固体存在。申请专利范围涵盖所有所述形式。
亦在本发明的范围内者为所谓的本发明化合物的“前药”。因此,本身具有很少或没有药物活性的本发明化合物的某些衍生物当给药至身体内或身体上时,可例如藉由水解裂解而转化成具有所要活性的本发明化合物。所述衍生物系称为“前药”。有关前药的使用的进一步信息可发现于“Pro-drugs as Novel Delivery Systems,第14册,ACS SymposiumSeries(T.Higuchi和W.Stella)和“Bioreversible Carriers in Drug Design,”PergamonPress,1987(ed.E.B.Roche,American Pharmaceutical Association)中。根据本发明的前药可例如藉由以本领域技术人员已知为“前-部分(pro-moieties)”的某些部分置换本发明化合物中所存在的适当官能团(functionalities)来制备,如例如H.Bundgaard的“Designof Prodrugs”(Elsevier,1985)中所述。
本发明亦涵盖含有保护基的本发明化合物。本领域技术人员亦了解本发明化合物也可用具有可用于纯化或储存且可在给药患者前移除的某些保护基制备。官能基的保护及去除保护系描述于“Protective Groups in Organic Chemistry”,由J.W.F.McOmie编辑,Plenum Press(1973)及“Protective Groups in Organic Synthesis”,第3版,T.W.Greene及P.G.M.Wuts,Wiley-Interscience(1999)中。
本发明亦包括所有药学上可接受的经同位素标记的化合物,其等同于本文所述的化合物,其中一或多个原子经具有相同原子数但原子质量或质量数不同于自然界中占优势的原子质量或质量数的原子置换。适合于包括于本发明化合物中的同位素的实例包括(但不限于)以下的同位素:氢,诸如2H、3H;碳,诸如11C、13C、及14C;氯,诸如36Cl;氟,诸如18F;碘,诸如123I和125I;氮,诸如13N和15N;氧,诸如15O、17O、及18O;磷,诸如32P;及硫,诸如35S。某些经同位素标记的本发明化合物(例如并入放射性同位素者)可用于药物及/或受质组织分布研究(例如检定)。放射性同位素氚(亦即3H)及碳-14(亦即14C)由于其易于并入性及现成检测装置而特别可用于此目的。以较重的同位素(诸如氘,亦即,2H)取代可供给由较大的代谢安定性所产生的某些治疗优势(例如,活体内半衰期增加或剂量需求减少),且因此在一些状况中可为优选。以正电子放射同位素(诸如11C、15F、18F、15O和13N)取代可用于检查受质受体占有率的正电子发射断层扫描(PET)研究。经同位素标记的本发明化合物一般可藉由熟习此项技术者已知的常规技术或藉由类似于随附流程及/或实施例及制备中所述的方法使用适当经同位素标记的试剂替代先前所用的未经标记的试剂制备。根据本发明的药学上可接受的溶剂合物包括其中结晶的溶剂可经同位素取代的溶剂合物,例如D2O、丙酮-d6或DMSO-d6。包括下述实施例1至97中所例示的化合物的本发明化合物包括这些化合物的经同位素(诸如(但不限于)氘化及氚化同位素及如上文所述的所有其他同位素)标记的型式(version)。
在某些实施方案中,本发明系关于新颖的选择性放射性标记的PDE4配位基,其可使用正电子发射断层摄影术(PET)而用于成像和定量组织(例如,脑)中的PDE4B受体。
在某些实施方案中,本发明系关于4-(8-环丙基-9-氧代-6,7,8,9-四氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-10-基)-2-[18F]氟苯甲腈,或其药学上可接受的盐和其于体外或体内将组织、细胞或宿主成像的用途。
化合物
式I化合物,如上所述,具有稠合至以A表示的环部分的吡咯并[1,2-a]吡嗪酮核心。如上所述,A与其所连接的碳原子一起可形成稠合(4至8元)含氧杂环烷基环、稠合苯基环、或稠合(5至8元)含氮杂芳基环(即,环A的(4至8元)含氧杂环烷基、苯基或杂芳基系稠合至吡咯并[1,2-a]吡嗪酮核心的吡咯环且因此称为稠合(4至8元)含氧杂环烷基、稠合苯基及稠合杂芳基)。
在某些实施方案中,在式I中,A选自由下列所组成的群组:任选被取代的稠合(4至8元)含氧杂环烷基环、任选被取代的稠合苯基环、或任选被取代的稠合(5至6元)含氮杂芳基环。
在某些实施方案中,当A为稠合(4至8元)含氧杂环烷基环时,该杂环烷基环选自由下列所组成的群组:氧杂环丁烷基、二氢呋喃基、四氢呋喃基、四氢吡喃基、氧杂环庚烷基、及氧杂环辛烷基(oxocanyl)。
在某些实施方案中,A选自由下列所组成的群组的稠合(4至6元)含氧杂环烷基环:氧杂环丁烷基、二氢呋喃基、四氢呋喃基、及四氢吡喃基。在某些实施方案中,稠合(4至6元)含氧杂环烷基环为四氢吡喃基。
在某些其他实施方案中,A为稠合苯基环。
在某些其他实施方案中,当A为稠合(5至6元)含氮杂芳基环时,该杂芳基环选自由下列所组成的群组:吡啶基、吡嗪基、嘧啶基、哒嗪基、三唑基、咪唑基、异唑基、异噻唑基、1,2,3-、1,2,4-、1,2,5-、或1,3,4-二唑基、唑基、噻唑基、异噻唑基、及吡唑基。
在某些实施方案中,A为选自由下列所组成的群组的稠合(5元)含氮杂芳基环:三唑基、咪唑基、异唑基、异噻唑基、1,2,3-、1,2,4-、1,2,5-、或1,3,4-二唑基、唑基、噻唑基、异噻唑基、及吡唑基。在某些实施方案中,稠合(5元)含氮杂芳基环为噻唑基。
在某些实施方案中,A为选自由下列所组成的群组的稠合(6元)含氮杂芳基环:吡啶基、吡嗪基、嘧啶基及哒嗪基。在某些实施方案中,A为稠合吡啶基环。在某些实施方案中,A为稠合嘧啶基环。在某些实施方案中,A为稠合吡嗪基环。在某些实施方案中,A为稠合哒嗪基环。
在前述实施方案的任一者中,在化学上允许的情况下,A任选地被一至三个R8取代,其中各个R8独立地选自由下列所组成的群组:卤素、氧代、氰基、羟基、-SF5、硝基、N(R5)(R6)、任选被取代的(C1-C6)烷硫基、任选被取代的(C1-C6)烷基、及任选被取代的(C1-C6)烷氧基。
在某些实施方案中,当R8为卤素时,该卤素选自氟及氯。
在某些其他实施方案中,当R8为任选被取代的(C1-C6)烷基时,该烷基选自甲基、乙基或丙基,且该甲基、乙基及丙基任选地被一至三个氟原子取代。例如,任选被取代的烷基包括(但不限于)氟甲基、二氟甲基、三氟甲基、氟乙基、二氟乙基、三氟乙基等等。
在又另一实施方案中,当R8为任选被取代的(C1-C6)烷氧基时,该烷氧基选自甲氧基、乙氧基或丙氧基且该甲氧基、乙氧基及丙氧基任选地被一至三个氟原子取代。例如,任选被取代的烷氧基包括(但不限于)氟甲氧基、二氟甲氧基、三氟甲氧基、氟乙氧基、二氟乙氧基、三氟乙氧基等等。
在某些实施方案中A系未经取代。
应理解A的上述亚类中任一者可与如上下文所述的R1、R2、R3a、R3b、R4a、R4b和n的实施方案中任一者组合。
在另一实施方案中,在如上所述的式I中,R1选自由下列所组成的群组:任选被取代的(C3-C6)环烷基、任选被取代的(4至10元)杂环烷基、任选被取代的(C6-C10)芳基、及任选被取代的(5至14元)杂芳基。
在某些实施方案中,当R1为任选被取代的(C3-C6)环烷基时,该环烷基选自由下列所组成的群组:环丙基、环丁基、环戊基、环己基、环己烯基、环己二烯基、及环戊烯基。在某些实施方案中,(C3-C6)环烷基为环戊基。
在另一实施方案中,当R1为任选被取代的(4至10元)杂环烷基时,该杂环烷基选自由下列所组成的群组:氮杂环丁烷基、二氢呋喃基、二氢噻吩基、四氢噻吩基、四氢呋喃基、四氢三嗪基、四氢吡唑基、四氢嗪基、四氢嘧啶基、八氢苯并呋喃基、八氢苯并咪唑基、八氢苯并噻唑基、咪唑烷基、吡咯烷基、哌啶基、哌嗪基、唑烷基、噻唑烷基、吡唑烷基、硫代吗啉基、四氢吡喃基、四氢噻嗪基、四氢噻二嗪基、四氢唑基、吗啉基、氧杂环丁烷基、四氢二嗪基、嗪基、噻嗪基、奎宁环基、色满基、异色原烷基(isochromanyl)、二氢苯并二氧杂环己烯基(dihydrobenzodioxinyl)、苯并二氧杂环戊烯基(benzodioxolyl)、苯并嗪基、二氢吲哚基、二氢苯并呋喃基、四氢喹啉基、异色满基(isochromyl)、二氢-1H-异吲哚基、2-氮杂双环[2.2.1]庚酮基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基等等。杂环烷基环的其他实例包括四氢呋喃-2-基、四氢呋喃-3-基、咪唑烷-1-基、咪唑烷-2-基、咪唑烷-4-基、吡咯烷-1-基、吡咯烷-2-基、吡咯烷-3-基、哌啶-1-基、哌啶-2-基、哌啶-3-基、哌啶-4-基、哌嗪-1-基、哌嗪-2-基、1,3-唑啶-3-基、1,4-氧杂氮杂环庚烷-1-基、异噻唑烷基、1,3-噻唑烷-3-基、1,2-吡唑烷基-2-基、1,2-四氢噻嗪-2-基、1,3-噻嗪烷-3-基、1,2-四氢二嗪-2-基、1,3-四氢二嗪-1-基、1,4-嗪-4-基、唑烷酮基、2-氧代-哌啶基。在某些实施方案中,(4至10元)杂环烷基为二氢苯并呋喃基。
在某些其他实施方案中,R1为选自由下列所组成的群组的任选被取代的(4至6元)杂环烷基:氮杂环丁烷基、二氢呋喃基、二氢噻吩基、四氢噻吩基、四氢呋喃基、四氢三嗪基、四氢吡唑基、四氢嗪基、四氢嘧啶基、咪唑烷基、吡咯烷基、哌啶基、哌嗪基、唑烷基、噻唑烷基、吡唑烷基、硫代吗啉基、四氢吡喃基、四氢噻嗪基、四氢噻二嗪基、四氢唑基、吗啉基、氧杂环丁烷基、嗪基、及噻嗪基。
在某些其他实施方案中,当R1为任选被取代的(C6-C10)芳基时,该芳基选自苯基或萘基。在某些实施方案中,(C6-C10)芳基为苯基。
在某些实施方案中,当R1为任选被取代的(5至10元)杂芳基时,该杂芳基选自由下列所组成的群组:吡啶基、吡嗪基、嘧啶基、哒嗪基、三唑基、咪唑基、呋喃基、异唑基、异噻唑基、1,2,3-、1,2,4-、1,2,5-、1,3,4-二唑基、唑基、噻吩基、噻唑基、异噻唑基、吡唑基、吲哚基、吲唑基、苯并呋喃基、苯并咪唑基、苯并噻吩基、苯并二唑基、苯并噻唑基、异苯并硫代呋喃基、苯并硫代呋喃基、苯并异唑基、苯并唑基、苯并二氧杂环戊烯基、呋喃并吡啶基、嘌呤基、咪唑并吡啶基、咪唑并嘧啶基、吡咯并吡啶基、吡唑并吡啶基、吡唑并嘧啶基、噻吩并吡啶基、三唑并嘧啶基、三唑并吡啶基、蒽基(anthranilyl)、喹啉基、异喹啉基、噌啉基、喹唑啉基、氧代色满基、及1,4-苯并嗪基。在某些实施方案中,(5至10元)杂芳基为三唑并吡啶基或呋喃并吡啶基。
在某些实施方案中,R1为选自吡唑基或三唑基的任选被取代的(5元)含氮杂芳基。
在某些其他实施方案中,R1为选自吡啶基或嘧啶基的任选被取代的(6元)含氮杂芳基。
在前述实施方案的任一者中,在化学上允许的情况下,R1任选地被一至三个R9取代,其中各个R9独立地选自由下列所组成的群组:卤素、氧代、氰基、羟基、-SF5、硝基、任选被取代的(C1-C6)烷硫基、任选被取代的(C1-C6)烷基、任选被取代的(C1-C6)烷氧基、-N(R5)(R6)、-(SO2)R7、及-S(=O2)N(R5)(R6),其中R5和R6在每次出现时各自独立地选自由下列所组成的群组:氢及(C1-C6)烷基、及R7为(C1-C6)烷基。
在某些实施方案中,当R9为卤素时,该卤素选自氟及氯。
在某些其他实施方案中,当R9为任选被取代的(C1-C6)烷基时,该烷基选自甲基、乙基或丙基,且该甲基、乙基及丙基任选地被一至三个氟原子取代。例如,任选被取代的烷基包括(但不限于)氟甲基、二氟甲基、三氟甲基、氟乙基、二氟乙基、三氟乙基等等。
在又另一实施方案中,当R9为任选被取代的(C1-C6)烷氧基时,该烷氧基选自甲氧基、乙氧基或丙氧基且该甲氧基、乙氧基及丙氧基任选地被一至三个氟原子取代。例如,任选被取代的烷氧基包括(但不限于)氟甲氧基、二氟甲氧基、三氟甲氧基、氟乙氧基、二氟乙氧基、三氟乙氧基等等。
应理解R1的上述亚类中任一者可与如上下文所述的A、R2、R3a、R3b、R4a、R4b及n中任一者的实施方案组合。
在另一实施方案中,在如上所述的式I中,R2选自由下列所组成的群组:氢、任选被取代的(C1-C6)烷基、任选被取代的(C3-C8)环烷基、任选被取代的(4至6元)杂环烷基及任选被取代的(5至6元)杂芳基。
在某些实施方案中,R2为氢。
在某些其他实施方案中,当R2为任选被取代的(C1-C6)烷基时,该烷基选自甲基、乙基、丙基、丁基、戊基或己基。在某些实施方案中,该烷基为甲基。在其他实施方案中,该烷基为乙基。在其他实施方案中,该烷基为丙基。
在某些其他实施方案中,当R2为任选被取代的(C3-C8)环烷基时,该环烷基选自环丙基、环丁基、环戊基、环己基、环戊基或环辛基。在某些实施方案中,该环烷基为环丙基。
在某些其他实施方案中,当R2为任选被取代的(4至6元)杂环烷基时,该杂环烷基选自由下列所组成的群组:氮杂环丁烷基、二氢呋喃基、二氢噻吩基、四氢噻吩基、四氢呋喃基、四氢三嗪基、四氢吡唑基、四氢嗪基、四氢嘧啶基、咪唑烷基、吡咯烷基、哌啶基、哌嗪基、唑烷基、噻唑烷基、吡唑烷基、硫代吗啉基、四氢吡喃基、四氢噻嗪基、四氢噻二嗪基、四氢唑基、吗啉基、氧杂环丁烷基、嗪基、及噻嗪基。
在某些其他实施方案中,当R2为任选被取代的(5至6元)杂芳基时,该杂芳基选自由下列所组成的群组:唑基、吡唑基、噻吩基、噻唑基、三唑基、吡啶基、及嘧啶基。在某些实施方案中,R2为唑基。在某些其他实施方案中,R2为三唑基。在某些其他实施方案中,R2为嘧啶基。
在前述实施方案的任一者中,在化学上允许的情况下,R2任选地被一至三个R8取代,其中各个R8独立地选自由下列所组成的群组:卤素、氧代、氰基、羟基、-SF5、任选被取代的(C1-C6)烷硫基、任选被取代的、硝基、任选被取代的(C1-C6)烷基、及任选被取代的(C1-C6)烷氧基。
在某些实施方案中,当R8为卤素时,该卤素选自氟及氯。
在某些其他实施方案中,当R8为任选被取代的(C1-C6)烷基时,该烷基选自甲基、乙基或丙基,且该甲基、乙基及丙基任选地被一至三个氟原子取代。例如,任选被取代的烷基包括(但不限于)氟甲基、二氟甲基、三氟甲基、氟乙基、二氟乙基、三氟乙基等等。
在又另一实施方案中,当R8为任选被取代的(C1-C6)烷氧基时,该烷氧基选自甲氧基、乙氧基或丙氧基且该甲氧基、乙氧基及丙氧基任选地被一至三个氟原子取代。例如,任选被取代的烷氧基包括(但不限于)氟甲氧基、二氟甲氧基、三氟甲氧基、氟乙氧基、二氟乙氧基、三氟乙氧基等等。
应理解R2的上述亚类中任一者可与如上下文所述的A、R1、R3a、R3b、R4a、R4b和n的实施方案中任一者组合。
在某些实施方案中,在式I中,R3a,在化学上允许的情况下,选自由下列所组成的群组:氢、卤素、氧代、氰基、羟基、-SF5、硝基、N(R5)(R6)、任选被取代的(C1-C6)烷硫基、任选被取代的(C1-C6)烷基、任选被取代的(C1-C6)烷氧基、及任选被取代的(C3-C8)环烷基。
在某些实施方案中,R3a为氢。
在某些实施方案中,当R3a为卤素时,该卤素选自氟及氯。
在某些其他实施方案中,当R3a为任选被取代的(C1-C6)烷基时,该烷基选自甲基、乙基或丙基,且该甲基、乙基及丙基任选地被一至三个氟原子取代。例如,任选被取代的烷基包括(但不限于)氟甲基、二氟甲基、三氟甲基、氟乙基、二氟乙基、三氟乙基等等。在某些实施方案中,R3a为甲基。
在又另一实施方案中,当R3a为任选被取代的(C1-C6)烷氧基时,该烷氧基选自甲氧基、乙氧基或丙氧基且该甲氧基、乙氧基及丙氧基任选地被一至三个氟原子取代。例如,任选被取代的烷氧基包括(但不限于)氟甲氧基、二氟甲氧基、三氟甲氧基、氟乙氧基、二氟乙氧基、三氟乙氧基等等。
应理解R3a的上述亚类中任一者可与如上下文所述的A、R1、R2、R3b、R4a、R4b和n的实施方案中任一者组合。
在某些实施方案中,在式I中,R2和R3a与它们所连接的氮和碳原子一起形成选自由下列所组成的群组的任选被取代的(4至6元)杂环烷基环:氮杂环丁烷基、吡咯烷基、及吗啉基。
在前述实施方案的任一者中,当R2和R3a与它们所连接的氮和碳原子一起形成(4至6元)杂环烷基时,在化学上允许的情况下,杂环烷基可经一至三个R8取代,其中各个R8独立地选自由下列所组成的群组:卤素、氧代、氰基、羟基、-SF5、硝基、任选被取代的(C1-C6)烷基、及任选被取代的(C1-C6)烷氧基。
应理解R2和R3a的上述亚类中任一者与它们所连接的氮一起可与如上下文所述的A、R1、R3b、R4a、R4b和n的实施方案中任一者组合。
在某些实施方案中,在式I中,当R3b存在时,在化学上允许的情况下,选自由下列所组成的群组:氢、卤素、氧代、氰基、羟基、-SF5、硝基、N(R5)(R6)、任选被取代的(C1-C6)烷硫基、任选被取代的(C1-C6)烷基、任选被取代的(C1-C6)烷氧基、及任选被取代的(C3-C8)环烷基。
在某些实施方案中,R3b为氢。
在某些实施方案中,当R3b为卤素时,该卤素选自氟及氯。
在某些其他实施方案中,当R3b为任选被取代的(C1-C6)烷基时,该烷基选自甲基、乙基或丙基,且该甲基、乙基及丙基任选地被一至三个氟原子取代。例如,任选被取代的烷基包括(但不限于)氟甲基、二氟甲基、三氟甲基、氟乙基、二氟乙基、三氟乙基等等。在某些实施方案中,R3b为甲基。
在又另一实施方案中,当R3b为任选被取代的(C1-C6)烷氧基时,该烷氧基选自甲氧基、乙氧基或丙氧基且该甲氧基、乙氧基及丙氧基任选地被一至三个氟原子取代。例如,任选被取代的烷氧基包括(但不限于)氟甲氧基、二氟甲氧基、三氟甲氧基、氟乙氧基、二氟乙氧基、三氟乙氧基等等。
应理解R3b的上述亚类中任一者可与如上下文所述的A、R1、R2、R3a、R4a、R4b和n的实施方案中任一者组合。
在某些实施方案中,在式I中,在化学上允许的情况下。R3a和R3b与它们所连接的碳原子一起形成选自环丙基、环丁基、环戊基或环己基的任选被取代的(C3-C6)环烷基。在某些实施方案中,该环烷基为环丙基。
应理解R3a和R3b的上述亚类中任一者与它们所连接的碳原子一起可与如上下文所述的A、R1、R2、R4a、及R4b的实施方案中任一者组合。
在某些实施方案中,在式I中,在化学上允许的情况下,R4a选自由下列所组成的群组:氢、卤素、氧代、氰基、羟基、-SF5、硝基、-N(R5)(R6)、任选被取代的(C1-C6)烷硫基、任选被取代的(C1-C6)烷基、任选被取代的(C1-C6)烷氧基、及任选被取代的(C3-C8)环烷基。
在某些实施方案中,R4a为氢。
在某些实施方案中,当R4a为卤素时,该卤素选自氟及氯。
在某些其他实施方案中,当R4a为任选被取代的(C1-C6)烷基时,该烷基选自甲基、乙基或丙基,且该甲基、乙基及丙基任选地被一至三个氟原子取代。例如,任选被取代的烷基包括(但不限于)氟甲基、二氟甲基、三氟甲基、氟乙基、二氟乙基、三氟乙基等等。在某些实施方案中,R4a为甲基。
在又另一实施方案中,当R4a为任选被取代的(C1-C6)烷氧基时,该烷氧基选自甲氧基、乙氧基或丙氧基且该甲氧基、乙氧基及丙氧基任选地被一至三个氟原子取代。例如,任选被取代的烷氧基包括(但不限于)氟甲氧基、二氟甲氧基、三氟甲氧基、氟乙氧基、二氟乙氧基、三氟乙氧基等等。
应理解R4a的上述亚类中任一者可与如上下文所述的A、R1、R2、R3a、R3b、R4b和n的实施方案中任一者组合。
在某些实施方案中,在式I中,当R4b存在时,在化学上允许的情况下,选自由下列所组成的群组:氢、卤素、氧代、氰基、羟基、-SF5、硝基、-N(R5)(R6)、任选被取代的(C1-C6)烷硫基、任选被取代的(C1-C6)烷基、任选被取代的(C1-C6)烷氧基、及任选被取代的(C3-C8)环烷基。
在某些实施方案中,R4b为氢。
在某些实施方案中,当R4b为卤素时,该卤素选自氟及氯。
在某些其他实施方案中,当R4b为任选被取代的(C1-C6)烷基时,该烷基选自甲基、乙基或丙基,且该甲基、乙基及丙基任选地被一至三个氟原子取代。例如,任选被取代的烷基包括(但不限于)氟甲基、二氟甲基、三氟甲基、氟乙基、二氟乙基、三氟乙基等等。在某些实施方案中,R4b为甲基。
在又另一实施方案中,当R4b为任选被取代的(C1-C6)烷氧基时,该烷氧基选自甲氧基、乙氧基或丙氧基且该甲氧基、乙氧基及丙氧基任选地被一至三个氟原子取代。例如,任选被取代的烷氧基包括(但不限于)氟甲氧基、二氟甲氧基、三氟甲氧基、氟乙氧基、二氟乙氧基、三氟乙氧基等等。
在又另一实施方案中,R4a和R4b与它们所连接的碳原子一起形成(C3-C6)环烷基或(4至6元)杂环烷基,且在化学上允许的情况下,该(C3-C6)环烷基或(4至6元)杂环烷基任选地被一至三个R8取代;
应理解R4a和R4b的上述亚类中任一者可与如上下文所述的A、R1、R2、R3a、R3b和n的实施方案中任一者组合。
在某些实施方案中,在式I中,-------系不存在或一键。在某些实施方案中--------为一键且n为0。在某些实施方案中--------系不存在且n为1。
应理解-------的上述亚类中任一者可与如上所述的A、R1、R2、R3a、R3b、R4a和R4b的实施方案中任一者组合。
在另一实施方案中,所选本发明化合物可用于治疗PDE4A、PDE4B、及/或PDE4C介导的病症,包含将治疗有效量的有效抑制PDE4A、PDE4B及/或PDE4C活性的本发明化合物给药至有需要的哺乳动物(优选为人);更优选地,给药一定量的具有对PDE4A、PDE4B及/或PDE4C的改良结合亲和力同时对PDE4D具有较少抑制活性的本发明化合物。
在某些其他实施方案中,所选本发明化合物可呈现对PDE4B同工型的结合亲和力。在某些其他实施方案中,所选本发明化合物可呈现对PDE4A同工型的结合亲和力。在某些其他实施方案中,所选本发明化合物可呈现对PDE4C同工型的结合亲和力。
在某些实施方案中,本发明化合物具有对PDE4B同工型超过对PDE4D同工型的增强结合亲和力而使得化合物表现对PDE4B同工型超过对PDE4D同工型约2倍至约325倍的结合亲和力。在某些其他实施方案中,本发明化合物表现对PDE4B同工型超过对PDE4D同工型约10倍至约50倍的结合亲和力。在某些其他实施方案中,本发明化合物表现对PDE4B同工型超过对PDE4D同工型约51倍至约100倍的结合亲和力。在某些其他实施方案中,本发明化合物表现对PDE4B同工型超过对PDE4D同工型约101倍至约200倍的结合亲和力。在某些实施方案中,本发明化合物表现对PDE4B同工型超过对PDE4D同工型至少约2倍的结合亲和力。在某些实施方案中,本发明化合物表现对PDE4B同工型超过对PDE4D同工型至少约5倍的结合亲和力。在某些实施方案中,本发明化合物表现对PDE4B同工型超过对PDE4D同工型至少约10倍的结合亲和力。在某些实施方案中,本发明化合物表现对PDE4B同工型超过对PDE4D同工型至少约20倍的结合亲和力。在某些其他实施方案中,本发明化合物表现对PDE4B同工型超过对PDE4D同工型至少约40倍的结合亲和力。在某些其他实施方案中,本发明化合物表现对PDE4B同工型超过对PDE4D同工型至少约50倍的结合亲和力。在某些其他实施方案中,本发明化合物表现对PDE4B同工型超过对PDE4D同工型至少约75倍的结合亲和力。在某些其他实施方案中,本发明化合物表现对PDE4B同工型超过对PDE4D同工型至少约100倍的结合亲和力。在某些其他实施方案中,本发明化合物表现对PDE4B同工型超过对PDE4D同工型至少约200倍的结合亲和力。在某些其他实施方案中,本发明化合物表现对PDE4B同工型超过对PDE4D同工型至少约325倍的结合亲和力。本发明化合物对PDE4B和PDE4D同工型的结合亲和力显示于下述实验部分的表9和10中。
在另一实施方案中,本发明提供一种药物组合物,其包含本发明化合物、或其药学上可接受的盐,与至少一种药学上可接受的赋形剂掺合。
在又另一实施方案中,本发明化合物给药至有需要的患者亦可导致目前被认为与给药具有对其他PDE4同工型(尤其PDE4D同工型)的结合亲和力的化合物有关的胃肠不适(诸如呕吐、腹泻及心)减少,从而使患者顺应性以及整个治疗结果提高。
在另一实施方案中,本发明提供一种治疗中枢神经系统(CNS)、神经炎症性、代谢、自体免疫性及炎症性疾病或病症的方法,其包含将治疗有效量的本发明化合物或其药学上可接受的盐给药至需要该治疗的哺乳动物(特别为人)。
在另一实施方案中,本发明提供本发明化合物或其药学上可接受的盐的用途,其用于制造供治疗中枢神经系统(CNS)、神经炎症性、自体免疫性及炎症性疾病或病症的药物。
药理
PDE4家族的磷酸二酯酶(PDE)的特征为第二信使环核苷酸(3',5'-环腺苷单磷酸(cAMP))的选择性高亲和力水解降解。PDE4A、PDE4B及PDE4D同工型已知广泛表现于整个脑中,其中PDE4A、PDE4B及PDE4D同工型的局部及胞内分布不同,而PDE4C同工型以较低含量表现于整个中枢神经系统中(参见:Siuciak,J.A.等人,Antipsychotic profile ofrolipram:efficacy in rats and reduced sensitivity in mice deficient in thephosphodiesterase-4B(PDE4B)enzyme,Psychopharmacology(2007)192:415-424)。PDE4同工型的位置使其成为探究中枢神经系统疾病及病症的新疗法的受关注标靶。例如,PDE4B已鉴别为精神分裂症的遗传易感因素(参见:Millar,J.K.等人,Disrupted inschizophrenia 1 and phosphodiesterase 4B:towards an understanding ofpsychiatric illness,J.Physiol.584(2007)第401-405页)。
PDE4抑制剂洛利普兰(rolipram)已显示可用于经由衰减神经元炎症及细胞凋亡介导的cAMP/CREB信号传导来治疗或逆转Aβ诱发性记忆缺失,及为治疗与AD有关的认知缺陷的潜在标靶。(参见:Wang,C.等人,The phosphodiesterase-4 inhibitor rolipramreverses Aβ-induced cognitive impairment and neuroinflammatory and apoptoticresponses in rats,International Journal of Neuropsychopharmacology(2012),15,749-766)。
PDE4抑制剂亦已显示藉由减少患有重度忧郁症(MDD)的个体中PDE4的脑含量而具有抗抑郁作用(参见:Fujita,M.等人,C-(R-)-Rolipram Positron Emission Tomographyin Major Depressive Disorder,Biological Psychiatry,71,2012,548-554)。
此外,PDE4抑制剂已显示具有涉及治疗多发性硬化的治疗活性(参见:Sun,X.等人,Roliprampromotes remyelination possibly via MEK-ERK signal pathway incuprizone-induced demyelination mouse,Experimental Neurology 2012;237:304-311)。
鉴于上述,在某些实施方案中,本发明化合物具有用于治疗中枢神经系统的病况或疾病(其包括神经、神经退化性及/或精神病症)的范围广泛的治疗应用。神经、神经退化性及/或精神病症包括(但不限于)(1)情绪[情感]病症;(2)神经性、压力相关及躯体形障碍,包括焦虑症;(3)哺乳动物(包括人)的包含认知缺陷症状的病症;(4)包含注意力缺失、执行功能缺失(工作记忆缺失)、冲动控制功能障碍、锥体外症状的病症,以基底神经节功能障碍为主的病症;(5)发作通常发生在儿童期及青年期的行为及情感病症;(6)心理发展障碍;(7)主要影响中枢神经系统的全身性萎缩症;(8)锥体外及运动障碍;(9)与生理紊乱及身体因素有关的行为综合征;(10)成人人格及行为障碍;(11)精神分裂症及其他精神病症;(12)由于精神活性物质使用的精神和行为障碍;(13)包括性欲过度的性功能障碍;(14)智力迟钝;(15)人为障碍,例如急性幻觉性躁症;(16)阵发性及发作性病症,癫痫;(17)嗜睡病;及(18)痴呆。
可根据本发明治疗的情绪[情感]病症的实例包括(但不限于)双相情感障碍I、轻躁狂(躁狂及混合形式)、双相情感障碍II;抑郁症诸如单次抑郁发作或复发性重度抑郁症、慢性抑郁、精神病性抑郁、轻微抑郁症、产后发作的抑郁症、具有精神病性症状的抑郁症;持久性情绪[情感]障碍,诸如循环精神病、轻郁症、情感愉快(euthymia);经前综合征(PMS)及经前情绪低落症。
可根据本发明治疗的神经性、压力相关及似体形障碍的实例包括(但不限于)焦虑症、社交焦虑症、一般焦虑症、有或无广场恐怖的恐慌症、特定恐惧症、社交恐惧症、慢性焦虑症;强迫症;对严重压力的反应及适应障碍症,诸如创伤后压力症(PTSD)、急性压力症;其他神经性病症诸如人格解体-现实解体综合征。
词组"认知缺陷"如本文用于"包含认知缺陷症状的病症"中系指相较于相同一般年龄人群的其他个体,特定个体在一或多个认知方面(诸如记忆、智力、学习及逻辑能力)或注意力及执行功能(工作记忆)中的次正常功能或次优功能。
可根据本发明治疗的包含认知缺陷症状的病症的实例包括(但不限于)主要但不完全与健忘症、精神病(精神分裂症)、帕金森症、阿尔茨海默病、多发梗塞性痴呆、刘易斯体痴呆、中风、额颞叶痴呆、进行性核上性麻痹、亨丁顿氏症、HIV疾病(HIV相关的痴呆)、脑创伤和药物滥用;轻度认知病症ADHD、亚斯伯格症和年龄相关的记忆损伤相关的认知缺陷。
可根据本发明治疗的通常最先在婴儿、儿童和青春期诊断出来的病症的实例包括(但不限于)多动症,包括活动和注意的干扰、注意力缺失/多动症(ADHD)、多动行为规范障碍症;注意力缺失障碍(ADD);行为规范障碍症,包括(但不限于)抑郁性行为规范障碍症;抽动障碍,包括短暂性抽动障碍、慢性运动或发声抽动障碍、发声和多种运动联合型抽动障碍(妥瑞氏症(Gilles de la Tourette's syndrome))、物质诱发的抽动障碍;自闭症;巴登氏病(Batten disease)、过度自慰咬指甲、挖鼻孔和吮拇癖。
可根据本发明治疗的心理发展障碍的实例包括(但不限于)广泛性发展障碍,包括(但不限于)亚斯伯格症和雷特氏综合征、自闭症、儿童自闭症和与智能迟缓和刻板动作有关的过动症、运动功能的特定发展障碍症、学习技能的特定发展障碍症。
可根据本发明治疗的主要影响中枢神经系统的全身性萎缩症的实例包括(但不限于)主要影响基底神经节的多发性硬化性全身性萎缩症,包括亨丁顿氏症,及肌肉萎缩性侧索硬化。
可根据本发明治疗的具有基底神经节功能障碍及/或退化的锥体外及运动障碍的实例包括(但不限于)帕金森氏病;第二帕金森氏症诸如脑炎后帕金森氏症;其他病症中包含的帕金森氏症;尼曼匹克病(Niemann-Pick disease)、路易体病;基底神经节的退化性疾病;其他锥体外及运动障碍,包括震颤、自发性震颤及药物诱发性震颤、肌阵挛、舞蹈症及药物诱发性舞蹈症、药物诱发性抽动及器质性抽动、药物诱发性急性紧张不足、药物诱发性迟发性运动不能、肌肉痉挛及与肌肉痉挛或无力有关的病症(包括震颤);智力不足(包括痉挛、唐氏综合征(Down syndrome)及脆弱X染色体综合征)、左旋多巴诱发性运动困难;腿不宁综合征及僵人综合征。
可根据本发明治疗的具有基底神经节功能障碍及/或退化的运动障碍的其他实例包括(但不限于)紧张不足,包括(但不限于)局部肌肉紧张不足、多发性局部或区段性紧张不足、扭转紧张不足、半球性、全身性及迟发性紧张不足(由精神药理药物诱发)。局部肌肉紧张不足包括颈紧张不足(斜颈)、眼睑痉挛(眼睑的痉挛)、附肢紧张不足(肢端中痉挛,如书写痉挛)或下颌紧张不足及痉挛性发声障碍(声带痉挛);抗精神病药诱发性运动障碍,包括(但不限于)抗精神病药性综合征(NMS)、抗精神病药诱发性帕金森氏症、抗精神病药诱发性早期发作或急性运动困难、抗精神病药诱发性急性紧张不足、抗精神病药诱发性急性静坐不能、抗精神病药诱发性迟发性运动不能、抗精神病药诱发性震颤。
根据本发明的与生理紊乱和身体因素相关的行为综合征的实例包括但不限制于非器质性睡眠障碍(包括但不限制于非器质性嗜睡症、睡眠觉醒周期的非器质性障碍(昼夜节律性睡眠障碍)、失眠、类睡症及睡眠剥夺;与产褥期有关的精神及行为障碍,包括产后及分娩后抑郁;饮食障碍,包括(但不限于)神经性厌食、神经性贪食、暴食症、过食症、肥胖、强迫性饮食障碍及食冰癖。
可根据本发明治疗的成人人格及行为障碍的实例包括(但不限于)人格异常,包括但不限制于情绪不稳定、边缘型、强迫性、强迫型(anankastic)、依赖和被动攻击型人格异常;习惯与冲动控制障碍(冲动控制障碍),包括间歇性狂暴症、病态性赌博、病态性纵火(纵火症)、病态性偷窃(偷窃癖)、拔毛癖;孟乔森氏综合征(Munchausen syndrome)。
可根据本发明治疗的精神分裂症及其他精神病症的实例包括(但不限于)不同类型的持续或间歇性精神分裂症(例如妄想型、青春型、僵直型、未分化型、后遗症型及类精神分裂病性病症);分裂型病症(诸如边缘型、潜伏型、前精神病型、前驱型、假神经病性假精神变态性精神分裂症及分裂型人格障碍);持久性妄想症;急性、短暂及持久性精神病症;诱发性妄想症;不同类型的精神分裂感情型障碍(例如躁狂抑郁或混合型);产后精神病及其他和未指定的非器质性精神病。
可根据本发明治疗的由于精神活性物质使用的精神和行为障碍的实例包括(但不限于)由于使用酒精、类鸦片、大麻素、镇静剂或安眠药、古柯碱的精神和行为障碍,由于使用其他兴奋剂(包括咖啡因)的精神和行为障碍、由于药物依赖及滥用(例如,麻醉剂依赖、酒精中毒、安非他明(amphetamine)及甲基安非他明(methamphetamine)依赖、类鸦片依赖、古柯碱成瘾、尼古丁依赖及药物戒断综合征、及复发预防、使用迷幻药、烟草(烟碱)、挥发性溶剂所致的精神及行为障碍;及由于使用多种药物及使用其他神经活性物质的精神及行为障碍,包括以下同工型症状:有害使用、依赖综合征、戒断状态及有谵妄的戒断状态。
可根据本发明治疗的痴呆的实例包括(但不限于)血管性痴呆;由于库贾氏病(Creutzfeld-Jacob disease)、HIV、头部创伤、帕金森氏病、亨丁顿氏症、皮克氏病所致的痴呆;阿兹海默氏型痴呆。
在某些实施方案中,本本发明系关于藉由将治疗有效量的本发明三环化合物给药至有需要的患者来治疗精神分裂症的方法。
在某些其他实施方案中,本发明进一步系关于一种藉由将治疗有效量的本发明三环化合物给药至有需要的患者来治疗与精神分裂症有关的认知损伤的方法。
除上述中枢神经系统病症以外,该项技术中有大量文献描述PDE抑制剂对各种自体免疫性及炎症性细胞反应的作用,其除cAMP增加以外,亦包括抑制嗜酸细胞、嗜中性粒细胞及单核细胞中的过氧化物产生、去颗粒、趋化及肿瘤坏死因子(TNF)释放。因此,本发明化合物可用于治疗自体免疫性及炎症性疾病。(参见:Schett,G.等人,Apremilast:A novelPDE4Inhibitor in the Treatment of Autoimmune and Inflammatory Diseases,Ther.Adv.Musculoskeletal Dis.2010;2(5):271-278)。例如,本发明化合物可用于治疗与白塞氏病( disease)(Id.)有关的口腔溃疡。本发明化合物亦可用于治疗与关节炎有关的疼痛(参见:Hess,A.等人,Blockade of TNF-αrapidly inhibits painresponses in the central nervous system,PNAS,第108卷,第9期,3731-3736(2011)或治疗牛皮癣或牛皮癣性关节炎(参见:Schafer,P.,Apremilast mechanism of action andapplication to psoriasis and psoriatic arthritis,Biochem.Pharmacol.(2012),15;83(12):1583-90)。因此,本发明的三环化合物亦可用于治疗僵直性脊椎炎[参见:Patan,E.等人,Efficacy and safety of apremilast,an oral phosphodiesterase 4inhibitor,in ankylosing spondylitis,Ann.Rheum.Dis.(2102年9月14日)]。可藉由给药本发明化合物治疗的其他病况包括(但不限于)急性及慢性呼吸道疾病,诸如(但不限于)哮喘、慢性或急性支气管收缩、慢性支气管炎、支气管扩张、小呼吸道阻塞、肺气肿、阻塞性或炎症性呼吸道疾病、急性呼吸窘迫综合征(ARDS)、COPD、尘肺症、季节性过敏性鼻炎或常年性过敏性鼻炎或鼻窦炎、及急性肺损伤(ALI)。
在又另一实施方案中,本发明化合物可用于治疗勃起功能障碍、类风湿性关节炎、骨关节炎、骨质疏松症、痛风及发热、与炎症有关的水肿及疼痛、嗜酸细胞相关病症、皮肤和结缔组织病症诸如皮肤炎或湿疹、荨麻疹、结膜炎、葡萄膜炎、牛皮癣、炎症性肠病、溃疡性结肠炎、败血症、败血性休克、肝损伤、肺高血压、肺水肿、骨质流失病、足溃疡及感染。
在又另一实施方案中,本发明化合物可用于治疗癌症。例如,本发明化合物可用于治疗脑癌(例如,神经管胚细胞瘤)(参见:Schmidt,A.L.,BDNF and PDE4,but not GRPR,Regulate Viability of Human Medulloblastoma Cells,J.Mol.Neuroscience(2010)40:303-310)。本发明化合物亦可用于治疗黑色素瘤(参见:Marquette,A.等人,ERK and PDE4cooperate to induce RAF isoform switching in melanoma,Nature Structural&Molecular Biology,第18卷,第5期,584-91,2011)。在某些实施方案中,本发明化合物可用于治疗白血病,例如,慢性淋巴细胞性白血病,(参见:Kim,D.H.等人,Type 4CyclicAdenosine Monophosphate Phosphodiesterase as a Therapeutic Target in ChronicLymphocytic Leulemia,Blood Journal of The American Society of Hematology,1998年10月1日,第92卷,第7期2484-2494)。
在某些其他实施方案中,本发明化合物可用于治疗糖尿病或与糖尿病有关的疾病(参见:Vollert,S.等人,The glucose-lowering effects of the PDE4 inhibitorsroflumilast and roflumilast-N-oxide in db/db mice,Diabetologia(2012)55:2779-2788。Wouters,E.F.M.等人,Effect of the Phosphodiesterase 4 InhibitorRoflumilast on Glucose Metabolism in Patients with Treatment-NewlyDiagnosed Type 2 Diabetes Mellitus,Journal of Clinical Endocrinology andMetabolism 2012,97,1720-1725)。其他实例包括(但不限于)糖尿病性黄斑变性、糖尿病性神经病、肥胖、I型糖尿病、II型糖尿病、自发性I型糖尿病(第Ib型)、成人迟发性自体免疫糖尿病(LADA)、早发性II型糖尿病(EOD)、年轻发作性非典型糖尿病(YOAD)、年轻人成年型糖尿病(maturity onset diabetes of the young)(MODY)、营养不良相关性糖尿病、妊娠性糖尿病、代谢综合征、X综合征、葡萄糖代谢受损、葡萄糖失耐、葡萄糖失耐受损(IGT)的病况、空腹血糖受损的病况、高糖血症、高胰岛素血症、胰岛素抗性、代谢性酸中毒、酮症、尿失禁(例如,膀胱过度活动)、糖尿病性黄斑水肿、肾病及相关健康风险(例如,糖尿病肾病变)、症状或病症。因此,化合物亦可用于降低超重或肥胖个体的体脂肪或体重。
在某些其他实施方案中,本发明化合物可用于预防及治疗与增强的内皮活性、受损的内皮障壁功能及/或增强的血管新生有关的病症,诸如败血性休克;血管性水肿、末梢水肿、沟通性或非沟通性水脑、血管水肿、大脑水肿;减少的钠尿病变;炎症性疾病,包括哮喘、鼻炎、关节炎及类风湿性疾病及自体免疫疾病;急性及/或慢性肾或肝衰竭、肾小球硬化、肝功能障碍;非酒精性脂肪肝炎(NASH)、非酒精性脂肪肝疾病(NAFLD)、牛皮癣、肠易激综合征(IBD)、克罗恩氏病(Crohn's disease)及良性/恶性瘤形成。
在某些其他实施方案中,本发明化合物可用于治疗脊髓及/或末梢神经系统的疾病,包括脊髓损伤、脊髓水肿、脊髓肿瘤、血管畸形或脊髓异常、脊髓空洞症、脊髓积水。
在某些其他实施方案中,本文所述化合物进一步可用于预防及治疗与心血管疾病、血栓、栓塞或局部缺血性病症有关的病症,包括(但不限于)冠状动脉疾病、脑血管疾病(包括大脑动脉硬化、大脑淀粉样血管病、遗传性大脑出血及脑缺氧性缺血)及/或末梢血管疾病中的血栓诱发性组织梗塞;左心室肥大、末梢动脉疾病、超低apo B脂蛋白血症、高脂血症,高甘油三酯血症、血脂异常、餐后脂血症、稳定及不稳定绞痛、心绞痛、短暂性缺血发作、中风、间歇性跛行、动脉粥样硬化、充血性心力衰竭、高血压、心肌梗塞(例如坏死和凋亡)、大脑梗塞、再灌注损伤(脑/心肌)、创伤性脑损伤、硬膜下、硬膜外或蛛膜下出血、偏头痛、丛集性及紧张性头痛、胎盘不全、手术程序(诸如分流、血管成形术)后的血栓、血管成形术、支架更换及心脏瓣膜更换后的再狭窄、术后或与重症监护治疗、脑或眼科肿瘤相关的认知衰退或谵妄。
在某些其他实施方案中,本文所述化合物进一步可用于治疗疼痛病况及病症。所述疼痛病况及病症的实例包括(但不限于)炎症性疼痛、痛觉过敏、炎症性痛觉过敏、偏头痛、癌症痛、骨关节炎痛、手术后疼痛、非炎症性疼痛、神经痛、神经痛的亚类(包括末梢神经痛综合征)、化学疗法诱发性神经病、复杂区域疼痛综合征、HIV感觉神经病、继发于肿瘤浸润的神经病、疼痛性糖尿病性神经病、幻肢痛、带状疱疹后神经痛、乳房切除术后疼痛、三叉神经痛、中枢神经痛综合征、中枢中风后疼痛、多发性硬化痛、帕金森病痛及脊髓损伤痛。
在某些其他实施方案中,本文所述化合物进一步可用于治疗创伤或促进创伤愈合、烧伤、疤痕及相关病况。
在某些其他实施方案中,本文所述化合物进一步可用于治疗神经元破坏病症(包括眼损伤、白内障、视网膜病(包括糖尿病性黄斑水肿或眼部黄斑变性)、耳鸣、听觉损伤及丧失、及脑水肿)。
在某些其他实施方案中,本文所述的化合物进一步可用于治疗移植排斥、同种异体移植排斥、肾和肝衰竭、及不宁腿综合征。
本发明化合物亦可用于治疗及/或预防由IRAK酶介导或以其他方式与IRAK酶有关的疾病或病况;该方法包含将有效量的本发明化合物给药至有需要其的个体。
疾病可为(但不限于)以下类别的一:自体免疫疾病、炎症性疾病、过敏性疾病、代谢疾病、以感染为主的疾病、以创伤或组织损伤为主的疾病、纤维化疾病、遗传疾病、由IL1路径的过度活性驱动的疾病、心血管疾病、血管疾病、心脏疾病、神经疾病、神经退化性疾病、呼吸性疾病、肺病、呼吸道疾病、肾病、皮肤及/或皮肤学疾病、肝病、胃肠疾病、口腔疾病、疼痛及感官疾病、造血疾病、关节疾病、肌肉疾病、骨骼疾病及眼科及/或眼疾病。
特定自体免疫疾病包括(但不限于):类风湿性关节炎、骨关节炎、牛皮癣、过敏性皮炎、全身性红斑狼疮(及所得并发症)、休格连氏综合征( syndrome)、多发性硬化、哮喘、肾小球肾炎、肠易激综合征、炎症性肠病、克罗恩氏病(Crohn's disease)、僵直性脊椎炎、白塞氏疾病( disease)、狼疮肾炎、硬皮病、全身性硬皮病、第1型或幼年发作型糖尿病、全身性秃发(alopecia universalis)、急性弥漫性脑脊髓炎、艾迪森氏病(Addison's disease)、抗磷脂抗体综合征、性贫血的萎缩性胃炎、自体免疫秃发症、自体免疫性溶血性贫血、自体免疫肝炎、自体免疫脑脊髓炎、自体免疫血小板减少症、大疱性类天疱疮、却格司氏病(Chagas disease)、乳糜泻、慢性肝炎、科干氏综合征(Cogan'ssyndrome)、皮肌炎、子宫内膜异位、巴士德氏综合征(Goodpasture's syndrome)、格雷夫斯氏病(Graves'disease)、古德格-巴二氏综合征(Guillain-Barré syndrome)、桥本氏疾病(Hashimoto's disease)(或桥本氏甲状腺炎)、溶血性贫血、化脓性汗腺炎、自发性血小板减少性紫癜、间质性膀胱炎、膜性肾小球病变、硬斑病、重症肌无力、嗜睡病、天疱疮、性贫血、结节性多动脉炎、多发性肌炎、原发性胆汁性肝硬化、莱特氏综合征(Reiter'ssyndrome)、精神分裂症、交感性眼炎、全身性硬化症、颞动脉炎、甲状腺炎、血管炎、白斑病、外阴疼痛、韦格纳氏肉芽肿病、掌跖角化病、幼年发作型全身性自发性关节炎(SJIA)、或本文其他类别中所列的适应症。
特定炎症性疾病包括(但不限于):慢性阻塞性肺病、呼吸道超反应性、囊肿性纤维化、急性呼吸窘迫综合征、窦炎、鼻炎、齿龈炎、动脉粥样硬化、慢性前列腺炎、肾小球肾炎、溃疡性结肠炎、葡萄膜炎、牙周病、或本文中其他类别中所列的适应症。
特定疼痛病况包括(但不限于):炎症性疼痛、手术疼痛、内脏疼痛、牙疼、月经前期疼痛、中枢疼痛、由于烧伤的疼痛、偏头痛或丛集性头痛、神经损伤、间质性膀胱炎、癌痛、病毒、寄生虫或细菌感染、创伤后损伤、与肠易激综合征有关的疼痛、痛风、与本说明书内所列的其他适应症中的任一者有关的疼痛、或本文中其他类别中所列的适应症。
特定呼吸性、呼吸道及肺病况包括(但不限于):哮喘(其可涵盖慢性、晚期、支气管、过敏性、内因性、外因性或灰尘)、慢性阻塞性肺病、自发性肺部纤维化、肺动脉高血压、囊肿性纤维化、间质性肺病、急性肺损伤、类肉瘤病、过敏性鼻炎、慢性咳嗽、支气管炎、复发性呼吸道阻塞、肺气肿或支气管痉挛、或本文中其他疾病类别中所列的适应症。
特定胃肠(GI)病症包括(但不限于):肠易激综合征(IBS)、炎症性肠病(IBD)、胆绞痛及其他胆病症、肾绞痛、腹泻型IBS、与GI膨胀有关的疼痛、溃疡性结肠炎、克罗恩氏病、肠易激综合征、乳糜泻、直肠炎、嗜酸细胞性胃肠炎、肥大细胞增多症、或本文中其他疾病类别中所列的适应症。
特定过敏性疾病包括(但不限于):过敏反应、过敏性鼻炎、过敏性皮肤炎、过敏性风疹、血管性水肿、过敏性哮喘、对下列的过敏性反应:食物、药物、昆虫叮咬、花粉;或本文中其他疾病类别中所列的适应症。
特定以感染为主的疾病包括(但不限于):败血症、败血性休克、病毒性疾病、疟疾、莱姆病(Lyme disease)、眼感染、结膜炎、惠普尔病(Whipple Disease)、或本文中其他疾病类别中所列的适应症。
特定以创伤及组织损伤为主的病况包括(但不限于):肾小球损害、再灌注损伤(例如对心脏、肾脏、肺脏)、脊髓损伤、组织疤痕、组织黏着、组织修复、移植排斥(例如对心脏、肺脏、骨髓、软骨、角膜、肾脏、肢体、肝脏、肌肉、肌母细胞、胰脏、胰岛、皮肤、神经、小肠、气管)、过敏症、或本文中其他疾病类别中所列的适应症。
特定纤维化疾病包括(但不限于):自发性肺纤维化、肝纤维化、肾纤维化、或本文中其他疾病类别中所列的适应症。
被认为由IL1路径的过度活性驱动的特定疾病包括(但不限于):隐热蛋白(Cryopyrin)相关性周期综合征、肌炎,及以下评论文章中所包括的适应症:C.A.Dinarello,A.Simon及J.W.M.van der Meer,Treating inflammation by blockinginterleukin-1 in a broad spectrum of diseases,Nat Rev Drug Discov,2012,11(8),633-652,http://dx.doi.org/10.1038/nrd3800,及其中所含的补充数据、或本文中其他疾病类别中所列的适应症。
特定眼科/眼疾病包括(但不限于):葡萄膜炎、年龄相关性黄斑变性、糖尿病性黄斑水肿、角膜结膜炎、与氏疾病有关的葡萄膜炎、春季结膜炎、角膜炎、晶状体诱发的葡萄膜炎、疱疹性角膜炎、圆锥角膜炎、角膜上皮营养不良、眼天疱疮、穆伦氏溃疡(Mooren's ulcer)、巩膜炎、格雷夫氏眼病(Graves'ophthalmopathy)、沃格特-小柳-原田综合征(Vogt-Koyanagi-Harada syndrome)、干燥性角膜结膜炎、小水泡、虹膜睫状体炎、交感性眼炎、过敏性结膜炎、眼新血管生成、干眼综合征、或本文中其他疾病类别中所列的适应症。
特定的关节、肌肉及骨骼病症包括(但不限于):骨关节炎、骨质疏松、类风湿性关节炎、幼年型关节炎、牛皮癣性关节炎、手侵蚀性骨关节炎、关节纤维化/创伤性膝损伤、前十字形膝韧带撕裂、复发性多软骨炎、复发性多灶性骨髓炎、玛基德综合征(MajeedSyndrome)、僵直性脊椎炎、腰椎痛风、抗合成酶综合征、自发性炎症性肌病、关节软骨钙质沉着病、幼年发作型全身性自发性关节炎(SJIA)、痛风及焦磷酸盐晶体关节炎、或本文中其他疾病类别中所列的适应症。
特定的皮肤/皮肤学疾病包括(但不限于):牛皮癣、异位性皮肤炎、皮肤狼疮、痤疮、皮肌炎、湿疹、瘙痒症、硬皮病、斯维特综合征(Sweet Syndrome)/嗜中性皮肤病、嗜中性脂层炎、肢端皮炎(脓疱型牛皮癣的形式)、本文中其他疾病类别中所列的适应症。
特定肾病包括(但不限于):急性肾脏损伤(AKI)(败血症-AKI、冠状动脉绕通移植-AKI、心脏手术-AKI、非心脏手术-AKI、移植手术-AKI、顺铂-AKI、造影剂/显影剂诱发性AKI)、肾小球肾炎、IgA肾病变、新月形GN、狼疮肾炎、HIV相关肾病变、膜性肾病变、C3肾小球病、致密物沈积病、ANCA血管炎、糖尿病性肾病变、溶血性-尿毒症性综合征、非典型性溶血性-尿毒症性综合征、肾病综合征(nephrotic syndrome)、肾炎综合征(nephriticsyndrome)、高血压肾硬化、ApoL1肾病变、病灶性区段性肾小球硬化、奥尔波特综合征(Alport syndrome)、范康尼氏综合征(Fanconi syndrome)、结晶性肾病变、肾结石、肾病综合征、肾移植排斥、淀粉样变性、SJIA中的肾小球肾炎、或本文中其他疾病类别中所列的适应症。
特定遗传疾病包括(但不限于):家族性地中海热(FMF)、CAPS(FCAS、穆克尔-韦尔斯综合征(Muckle-Wells Syndrome)、NOMID/CINCA)、CAPS中的雄性不孕症、NLRP12自炎症综合征、或本文中其他疾病类别中所列的适应症。
特定造血系病包括(但不限于):溶血性贫血、或本文中其他疾病类别中所列的适应症。
特定肝病包括(但不限于):肝纤维化、肝硬化、非酒精性脂肪肝炎(NASH)、或本文中其他疾病类别中所列的适应症。
特定口腔疾病包括(但不限于):齿龈炎、牙周病,或本文中其他疾病类别中所列的适应症。
特定代谢疾病包括(但不限于):2型糖尿病(及所致并发症)、痛风及高尿酸血症、代谢综合征、胰岛素抗性、肥胖、或本文中其他疾病类别中所列的适应症。
本发明化合物亦可用于治疗选自下列的增生性疾病:良性或性肿瘤、实体肿瘤、脑、肾、肝、肾上腺、膀胱、乳、胃、胃肿瘤、卵巢、结肠、直肠、前列腺、胰脏、肺、阴道、宫颈、睪九、泌尿生殖道、食道、喉、皮肤、骨或甲状腺的癌、肉瘤、神经胶母细胞瘤、神经母细胞瘤、多发性骨髓瘤、胃肠癌(尤其为结肠癌或结肠直肠腺瘤)、颈部及头部的肿瘤、表皮过度增生、牛皮癣、前列腺增生、赘瘤、上皮特征的赘瘤、腺瘤、腺癌、角化棘皮瘤、表皮样癌、大细胞癌、非小细胞肺癌、淋巴瘤、霍奇金氏(Hodgkins)及非霍奇金氏、乳腺癌、滤泡癌、未分化性癌、乳头状癌、精原细胞瘤、黑色素瘤、闷烧型无痛多发性骨髓瘤、或血液性疾病(包括白血病、弥漫性大B细胞淋巴瘤(DLBCL)、ABC DLBCL、慢性淋巴球性白血病(CLL)、慢性淋巴细胞性淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤(Burkitt lymphoma)/白血病、急性淋巴细胞性白血病、B细胞前淋巴细胞白血病、淋巴浆细胞淋巴瘤、瓦尔登斯特伦氏巨球蛋白血症(Waldenstrom's macroglobulinemia,WM)、脾边缘区淋巴瘤、多发性骨髓瘤、浆细胞瘤、血管内大B细胞淋巴瘤)、或本文中其他疾病类别中所列的适应症。
心血管病况包括(但不限于)冠心病、急性冠状综合征、缺血性心脏病、初发性或复发性心肌梗塞、继发性心肌梗塞、非ST段升高型心肌梗塞或ST段升高型心肌梗塞、缺血性猝死、暂时性缺血性发作、周边闭塞性动脉疾病、绞痛、动脉粥样硬化、高血压、心脏衰竭(诸如充血性心脏衰竭)、舒张性功能障碍(诸如左心室舒张性功能障碍、舒张性心脏衰竭及舒张性填充能力受损)、收缩性功能障碍(诸如收缩期低收缩分率心衰竭)、血管炎、ANCA血管炎、心肌梗塞后心脏重塑心房震颤、心律不整(心室)、局部缺血、肥厚性心肌病、心因性猝死、心肌及血管纤维化、动脉顺应性受损、心肌坏死性病变、血管损害、左心室肥大、低收缩分率、心脏病变、血管壁肥大、内皮增厚、冠状动脉的类纤维蛋白坏死、不良重塑、中风等、或本文中其他疾病类别中所列的适应症。且,包括的是静脉血栓、深静脉血栓、血栓性静脉炎、动脉栓塞、冠状动脉血栓、脑动脉血栓、脑栓塞、肾脏栓塞、肺栓塞,及由下列所产生的血栓:(a)人工瓣膜或其他植入物;(b)留置导管;(c)支架;(d)心肺分流;(e)血液透析或(f)使血液暴露于促进血栓的人工表面的其他程序。应该注意的是:血栓包括血管闭塞(例如,在分流之后)、及再闭塞(例如,在经皮腔内冠状动脉成形术(percutaneous transluminal coronaryangioplasty)期间或之后)。
2型糖尿病的心血管并发症系与炎症有关,因此,本发明化合物可用于治疗糖尿病及糖尿病性并发症,诸如大血管疾病、高血糖症、代谢综合征、葡萄糖耐受性受损、高尿酸血症、葡萄糖尿、白内障、糖尿病性神经病变、糖尿病性肾病变、糖尿病性视网膜病变、肥胖、血脂异常、高血压、高胰岛素血症及胰岛素抗性综合征、或本文中其他疾病类别中所列的适应症。
先天性免疫力及炎症与疾病的关系已在神经炎症性及神经退化性病况中得到证明。因此,本发明化合物特别指出用于治疗哺乳动物(包括人)的神经炎症性及神经退化性病况(亦即病症或疾病),诸如多发性硬化、偏头痛;癫痫;阿尔茨海默病;帕金森氏症;脑损伤;中风;脑血管病(包括脑动脉硬化、脑淀粉样血管病、遗传性脑出血和脑缺氧缺血);认知障碍(包括健忘症、老年痴呆、HIV相关性痴呆、阿尔茨海默病相关性痴呆、亨汀顿氏相关性痴呆、路易氏体痴呆、血管性痴呆、药物相关性痴呆、谵妄和轻度认知损伤);智力缺陷(包括唐氏症及脆弱X染色体综合征);睡眠障碍(包括嗜睡、昼夜节律性睡眠障碍、失眠症、异睡症及睡眠剥夺)和精神障碍(诸如焦虑(包括急性压力障碍、广泛性焦虑症、社交焦虑症、恐慌症、创伤后压力症及强迫症);人为障碍(包括急性幻觉躁狂);冲动控制障碍(包括强迫性赌博和阵发性暴怒障碍);情绪障碍(包括I型双相情感障碍、II型双相情感障碍、躁狂症、混合情感状态、重度抑郁症、慢性抑郁症、季节性抑郁症、精神性抑郁、及产后抑郁症);精神运动障碍;精神障碍(包括精神分裂症、精神分裂感情型障碍、精神分裂症样和妄想症);药物依赖(包括麻醉药依赖、酒精中毒、安非他命依赖、古柯碱成瘾、尼古丁依赖和药物戒断征候群);饮食障碍(包括厌食症、贪食症、暴食症、过食症、及食冰癖);及小儿精神科病症(包括注意力缺失症、注意力缺失/过动症、行为规范障碍症、及自闭症)、肌萎缩性侧索硬化、慢性疲劳综合征、或本文中其他疾病类别中所列的适应症。
制剂
本发明化合物可口服给药。口服给药可包括吞服,以使化合物进入胃肠道中,或可使用经颊或舌下给药,从而化合物从口腔直接进入血流中。
在另一实施方案中,本发明化合物亦可直接给药进入血流中、进入肌肉中或进入内部器官中。适合于肠胃外给药的方式包括静脉内给药、动脉内给药、腹膜内给药、鞘内给药、心室内给药、尿道内给药、胸骨内给药、颅内给药、肌肉内给药及皮下给药。适合于肠胃外给药的装置包括针(包括微针)注射器、无针注射器及输注技术。
在另一实施方案中,本发明化合物亦可经调配以使局部给药至皮肤或黏膜(即,皮肤或经皮))导致化合物的全身性吸收。在另一实施方案中,本发明化合物亦可经调配以使鼻内或藉由吸入给药导致化合物的全身性吸收。在另一实施方案中,本发明化合物可经调配以使经直肠或经阴道给药导致化合物的全身性吸收。
所述化合物及/或含有所述化合物的组合物的给药方案系根据多种因素,包括患者的类型、年龄、体重、性别及医学病况;病况的严重程度;给药途径;及所用特定化合物的活性。因此,给药方案可广泛地变化。每天每公斤体重约0.01mg至约100mg的等级的剂量水平可用于治疗上文所示的病况。在一实施方案中,本发明化合物的总日剂量(以单次剂量或分次剂量给药)通常为约0.01至约100mg/kg。在另一实施方案中,本发明化合物的总日剂量为约0.1至约50mg/kg,且在另一实施方案中,为约0.5至约30mg/kg(亦即,每公斤体重的mg本发明化合物)。在一实施方案中,剂量为0.01至10mg/kg/日。在另一实施方案中,剂量为0.1至1.0mg/kg/日。剂量单元组合物可含有所述量或其次分量以构成日剂量。在许多情况下,一天内重复多次给药化合物(通常不超过4次)。必要时,每日多次剂量通常可用以增加总日剂量。
对于口服给药,组合物以含有0.01、0.05、0.1、0.5、1.0、2.5、5.0、10.0、15.0、25.0、50.0、75.0、100、125、150、175、200、250及500毫克活性成分的锭剂形式提供,根据症状来调节给与患者的剂量。药剂通常含有约0.01mg至约500mg活性成分,或在另一实施方案中,约1mg至约100mg活性成分。对于静脉内给药,在恒定速率输注期间,剂量可在约0.1至约10mg/kg/分钟范围内。
根据本发明的适合个体包括哺乳动物个体。根据本发明的哺乳动物包括(但不限于)犬、猫、牛、山羊、马、绵羊、猪、啮齿动物、兔类动物、灵长类动物等等,且涵盖子宫内的哺乳动物。在一实施方案中,人为适合个体。人个体可为任一性别且处于任一发育阶段。
在另一实施方案中,本发明包含一或多种本发明化合物的用途,其用于制备供治疗本文所述病况的药剂。
为了治疗上文所提及的病况,本发明化合物可以化合物本身给药。或者,药学上可接受的盐由于其相对于母化合物的水溶性较大故适用于医学应用。
在另一实施方案中,本发明包含药物组合物。所述药物组合物包含与药学上可接受的载剂一起提供的本发明化合物。该载剂可为固体、液体或二者,且可与化合物一起调配为单位剂量组合物,例如,锭剂,其可含有0.05重量%至95重量%的活性化合物。本发明化合物可与作为靶向药物载剂的适合聚合物偶合。其他药理活性物质亦可存在。
本发明化合物可藉由任何适合途径给药,优选以适于该途径的药物组合物的形式且以对于所欲治疗有效的剂量给药。活性化合物及组合物例如可口服、经直肠、肠胃外或局部(例如鼻内或经眼)给药。
固体剂型的口服给药可例如以个别单元呈现,诸如硬或软胶囊、丸剂、扁囊剂、菱形锭或锭剂,各含有预定量的至少一种本发明化合物。在另一实施方案中,该口服给药可于粉末或颗粒形式。在另一实施方案中,该口服剂量形式为舌下形式,诸如菱形锭。在所述固体剂型中,本发明化合物通常与一或多种佐剂组合。所述胶囊或锭剂可含有控制释放的制剂。在胶囊、锭剂及丸剂情况下,所述剂型亦可包含缓冲剂或可经制备而具有肠溶衣。
在另一实施方案中,口服给药可呈液体剂型。用于口服给药的液体剂型包括例如含有此项技术中常用的惰性稀释剂(例如水)的药学上可接受的乳液、溶液、悬浮液、糖浆及酏剂。所述组合物亦可包含佐剂,诸如润湿剂、乳化剂、悬浮剂、调味剂(例如甜味剂)及/或芳香剂。
在另一实施方案中,本发明包含肠胃外剂型。"肠胃外给药"包括例如皮下注射、静脉内注射、腹膜内注射、肌肉内注射、胸骨内注射及输注。可根据已知技术使用适合的分散剂、湿润剂及/或悬浮剂来调配可注射制剂(亦即无菌可注射水性或油性悬浮液),且包括储槽式制剂。
在另一实施方案中,本发明包含局部剂型。"局部给药"包括例如经皮给药,诸如经由经皮贴片或电离子透入装置、眼内给药、或鼻内或吸入给药。用于局部给药的组合物亦包括例如局部凝胶、喷雾、软膏及乳膏。局部制剂可包括增强活性成分经由皮肤或其他受感染区域吸附或穿透的化合物。当本发明化合物藉由经皮装置给药时,给药将使用储集器及多孔膜类型或固体基质种类的贴片来实现。用于此目的的典型制剂包括凝胶、水凝胶、洗剂、溶液、乳膏、软膏、撒布剂、敷料、发泡体、薄膜、皮肤贴片、薄片、植入物、海绵、纤维、绷带及微乳液。亦可使用脂质体。典型载剂包括醇、水、矿物油、液态石蜡、白石蜡、甘油、聚乙二醇及丙二醇。可并入渗透增强剂,参见例如Finnin及Morgan,J.Pharm.Sci.,88(10),955-958(1999)。
适合于局部给药至眼的制剂包括例如滴眼剂,其中本发明化合物溶解或悬浮于适合载剂中。适合于经眼或耳给药的典型制剂可呈于等张pH值经调节的无菌生理食盐水中的微粉化悬浮液或溶液的滴剂形式。适合于经眼及耳给药的其他制剂包括软膏、生物可降解型(例如可吸收凝胶海绵、胶原蛋白)及非生物可降解型(例如聚硅氧)植入物、薄片、镜片及微粒或囊泡系统,诸如泡囊体(niosome)或脂质体。聚合物(诸如交联聚丙烯酸、聚乙烯醇、玻尿酸、纤维素聚合物(例如羟丙基甲基纤维素、羟乙基纤维素或甲基纤维素)或杂多醣聚合物(例如结冷胶)可与防腐剂(诸如苯扎氯氨(benzalkonium chloride))一起并入。所述制剂亦可藉由电离子透入法递送。
对于鼻内给药或藉由吸入给药,本发明的活性化合物系以溶液或悬浮液形式自泵喷雾容器(其由患者挤压或泵吸)方便地递送,或以气溶胶喷雾呈现形式使用适当推进剂自压缩容器或雾化器递送。适合于鼻内给药的制剂通常以干粉形式(单独;呈例如与乳糖干燥掺合的混合物形式,或呈例如与磷脂(诸如卵磷脂)混合的混合组分粒子)自干粉吸入器给药,或在使用或不使用适合推进剂(诸如1,1,1,2-四氟乙烷或1,1,1,2,3,3,3-七氟丙烷)下自加压容器、泵、喷雾器、雾化器(优选为用电流体动力产生细雾的雾化器)、或雾化器以气溶胶喷雾形式给药。对于鼻内使用而言,粉末可包含生物黏着剂,例如聚葡萄胺糖或环糊精。
在另一实施方案中,本发明包含直肠剂型。该直肠剂型可呈例如栓剂形式。可可脂为传统栓剂基质,但适当时可使用各种替代物。
亦可使用在医药技艺中已知的其他载剂材料及给药模式。本发明的药物组合物可以任何熟知的医药技术(诸如有效的调配及给药步骤)制备。上述关于有效的调配及给药步骤的考虑为该技艺中所熟知,且说明于标准教科书中。药物的调配系讨论于例如Hoover,John E.,Remington’s Pharmaceutical Sciences,宾夕法尼亚州伊斯顿Mack出版公司,1975;Liberman等人编辑的Pharmaceutical Dosage Forms,Marcel Decker,纽约,N.Y.,1980;及Kibbe等人编辑的Handbook of Pharmaceutical Excipients(第3版),AmericanPharmaceutical Association,华盛顿,1999中。
本发明化合物可单独或与其他的治疗剂组合用于治疗各种病况或疾病状态。本发明化合物及其他治疗剂可同时地(以相同剂型或分开剂型)给药或顺序地给药。例示性治疗剂可为例如代谢性谷氨酸盐受体激动剂。
二或多种化合物“组合”给药意指二种化合物在时间上足够靠近地给药以使一者的存在改变另一者的生物效应。二或多种化合物可同时地、并行地、顺序地给药。另外,同时给药可藉由在给药前混合化合物或藉由在相同的时间点但是不同的解剖位置上给药化合物或使用不同的给药途径给药来进行。
词组“并行给药”、“共同给药”、“同时给药”及“同时地给药”意谓化合物系组合给药。
本发明包括本发明的PDE4抑制剂化合物及一或多种额外医药活性剂的组合使用。若给药活性剂的组合,则它们可以单独剂型或以组合成单一剂型依序或同时给药。因此,本发明亦包括药物组合物,其包含一数量的:(a)第一种药剂,其包含本发明化合物或该化合物的药学上可接受的盐类;(b)第二种医药活性剂;及(c)药学上可接受的载剂、媒液或稀释剂。
可取决于欲治疗的疾病、病症或病况而选择各种医药活性剂连同本发明化合物一起使用。可与本发明组合物组合使用的医药活性剂包括(非限制):
(i)乙酰胆碱酯酶抑制剂,诸如多奈哌齐(donepezil)盐酸盐(ARICEPT、MEMAC)、水杨酸毒扁豆碱(ANTILIRIUM)、硫酸毒扁豆碱(ESERINE)、美曲磷酯(metrifonate)、新斯替明(neostigmine)、葛斯替明(ganstigmine)、吡斯替明(pyridostigmine)(MESTINON)、安贝氯铵(ambenonium)(MYTELASE)、戴马克利(demarcarium)、Debio 9902(亦称为ZT-1;Debiopharm)、利斯的明(rivastigmine)(EXELON)、拉多替吉(ladostigil)、NP-0361、氢溴酸加兰他敏(galantamine)(RAZADYNE、RIMINYL、NIVALIN)、塔克林(tacrine)(COGNEX)、托丝胺酸(tolserine)、顺丁烯二酸维吖啶(velnacrine)、美莫昆(memoquin)、石杉碱(huperzine)A(HUP-A;NeuroHitech)、吩丝胺酸(phenserine)、腾喜忧(edrophonium)(ENLON、TENSILON)和INM-176;
(ii)类淀粉蛋白-β(或其片段),诸如共轭至泛HLA DR-结合表位的Aβ1-15(PADRE)、ACC-001(Elan/Wyeth)、ACI-01、ACI-24、AN-1792、Affitope AD-01、CAD106和V-950;
(iii)类淀粉蛋白-β(或其片段)的抗体,诸如泊尼珠单抗(ponezumab)、索兰珠单抗(solanezumab)、巴平珠单抗(bapineuzumab)(也称为AAB-001)、AAB-002(Wyeth/Elan)、ACI-01-Ab7、BAN-2401、静脉内Ig(GAMMAGARD)、LY2062430(人化m266;Lilly)、R1450(Roche)、ACU-5A5、huC091及它们揭示于国际专利公开案号WO04/032868、WO05/025616、WO06/036291、WO06/069081、WO06/118959,于美国专利公开案号US2003/0073655、US2004/0192898、US2005/0048049、US2005/0019328,于欧洲专利公开案号EP0994728和1257584以及于US专利案号5,750,349中者;
(iv)类淀粉蛋白-降低或-抑制剂(包括它们减少类淀粉制造、累积及纤维化者)诸如廸美朋(dimebon)、达内替德(davunetide)、伊罗地塞(eprodisate)、亮丙瑞林(leuprolide)、SK-PC-B70M、塞来昔布(celecoxib)、洛伐他汀(lovastatin)、安纳普斯(anapsos)、奥拉西坦(oxiracetam)、普拉西坦(pramiracetam)、伐尼克兰(varenicline)、麦角溴烟碱酯(nicergoline)、初乳素(colostrinin)、双诺斯立(bisnorcymserine)(也称为BNC)、NIC5-15(Humanetics)、E-2012(Eisai)、匹格列酮(pioglitazone)、氯碘羟喹(clioquinol)(也称为PBT1)、PBT2(Prana Biotechnology)、氟比洛芬(flurbiprofen)(ANSAID、FROBEN)和其R-对映异构体泰利福比(tarenflurbil)(FLURIZAN)、硝基氟比洛芬(nitroflurbiprofen)、非诺洛芬(fenoprofen)(FENOPRON、NALFON)、布洛芬(ibuprofen)(ADVIL、MOTRIN、NUROFEN)、布洛芬离胺酸盐、甲氯芬那酸(meclofenamic acid)、甲氯芬那酸钠(MECLOMEN)、吲哚美辛(indomethacin)(INDOCIN)、双氯芬酸钠(diclofenac sodium)(VOLTAREN)、双氯芬酸钾(diclofenac potassium)、舒林酸(sulindac)(CLINORIL)、硫化舒林酸(sulindac sulfide)、二氟尼柳(diflunisal)(DOLOBID)、奈普生(naproxen)(NAPROSYN)、奈普生钠(naproxen sodium)(ANAPROX、ALEVE)、ARC031(ArcherPharmaceuticals)、CAD-106(Cytos)、LY450139(Lilly)、胰岛素-分解酵素(也称为胰岛素溶酶(insulysin))、银杏萃取物EGb-761(ROKAN、TEBONIN)、叉米沙特(tramiprosate)(CEREBRIL、ALZHEMED)、依罗沙特(eprodisate)(FIBRILLEX、KIACTA)、化合物W(3,5-双(4-硝基苯氧基)苯甲酸)、NGX-96992、脑啡肽酶(neprilysin)(也称为中性肽链内切酶(NEP))、鲨肌醇(scyllo-inositol)(也称为青蟹肌醇(scyllitol))、阿伐他汀(atorvastatin)(LIPITOR)、辛伐他汀(simvastatin)(ZOCOR)、KLVFF-(EEX)3、SKF-74652、伊布莫仑甲磺酸盐(ibutamoren mesylate)、BACE抑制剂诸如ASP-1702、SCH-745966、JNJ-715754、AMG-0683、AZ-12304146、BMS-782450、GSK-188909、NB-533、E2609和TTP-854;γ-分泌调节剂诸如ELND-007;及RAGE(晚期糖基化终产物的受体)抑制剂,诸如TTP488(Transtech)和TTP4000(Transtech)、及它们美国专利号7,285,293中所揭示者,包括PTI-777;
(v)α-肾上腺素性受体激动剂,诸如胍法辛(guanfacine)(INTUNIV、TENEX)、可尼丁(clonidine)(CATAPRES)、间羟胺(metaraminol)(ARAMINE)、甲基多巴(methyldopa)(ALDOMET、DOPAMET、NOVOMEDOPA)、替扎尼定(tizanidine)(ZANAFLEX)、脱羟肾上腺素(也称为脱氧肾上腺素(neosynephrine))、甲氧胺(methoxamine)、西拉唑啉(cirazoline)、胍法辛(INTUNIV)、洛非西定(lofexidine)、赛拉嗪(xylazine)、莫达非尼(modafinil)(PROVIGIL)、阿屈非尼(adrafinil)、及阿莫达非尼(armodafinil)(NUVIGIL);
(vi)β-肾上腺素性受体阻断剂(β阻断剂),诸如卡替洛尔(carteolol)、艾司洛尔(esmolol)(BREVIBLOC)、拉贝洛尔(labetalol)(NORMODYNE、TRANDATE)、氧烯洛尔(oxprenolol)(LARACOR、TRASACOR)、吲哚洛尔(pindolol)(VISKEN)、普萘洛尔(propanolol)(INDERAL)、索他洛尔(sotalol)(BETAPACE、SOTALEX、SOTACOR)、噻吗洛尔(timolol)(BLOCADREN、TIMOPTIC)、醋丁洛尔(acebutolol)(SECTRAL、PRENT)、纳多洛尔(nadolol)(CORGARD)、酒石酸美托洛尔(metoprolol tartrate)(LOPRESSOR)、丁二酸美托洛尔(metoprolol succinate)(TOPROL-XL)、阿替洛尔(atenolol)(TENORMIN)、丁氧胺(butoxamine)以及SR 59230A(Sanofi);
(vii)抗胆碱剂,诸如阿米替林(amitriptyline)(ELAVIL、ENDEP)、丁替林(butriptyline)、甲磺酸苯扎托品(benztropine mesylate)(COGENTIN)、苯海索(trihexyphenidyl)(ARTANE)、苯海拉明(diphenhydramine)(BENADRYL)、奥芬那君(orphenadrine)(NORFLEX)、莨菪碱(hyoscyamine)、阿托品(atropine)(ATROPEN)、东莨菪碱(scopolamine)(TRANSDERM-SCOP)、甲溴东莨菪碱(scopolamine methylbromide)(PARMINE)、双环维林(dicycloverine)(BENTYL、BYCLOMINE、DIBENT、DILOMINE)、托特罗定(tolterodine)(DETROL)、奥昔布宁(oxybutynin)(DITROPAN、LYRINEL XL、OXYTROL)、喷噻溴铵(penthienate bromide)、丙胺太林(propantheline)(PRO-BANTHINE)、赛克利辛(cyclizine)、盐酸丙米嗪(imipramine hydrochloride)(TOFRANIL)、顺丁烯二酸丙米嗪(imipramine maleate)(SURMONTIL)、洛非帕明(lofepramine)、地昔帕明(desipramine)(NORPRAMIN)、多塞平(doxepin)(SINEQUAN、ZONALON)、曲米帕明(trimipramine)(SURMONTIL)、及格隆溴胺(glycopyrrolate)(ROBINUL);
(viii)抗惊厥剂,诸如卡马西平(carbamazepine)(TEGRETOL、CARBATROL)、奥卡西平(oxcarbazepine)(TRILEPTAL)、苯妥英钠(phenytoin sodium)(PHENYTEK)、磷苯妥英(fosphenytoin)(CEREBYX、PRODILANTIN)、双丙戊酸钠(divalproex sodium)(DEPAKOTE)、加巴喷丁(gabapentin)(NEURONTIN)、普瑞巴林(pregabalin)(LYRICA)、托派瑞美(topirimate)(TOPAMAX)、丙戊酸(valproic acid)(DEPAKENE)、丙戊酸钠(valproatesodium)(DEPACON)、1-苯甲基-5-嗅尿嘧啶、普罗加比(progabide)、贝克拉胺(beclamide)、唑尼沙胺(zonisamide)(TRERIEF、EXCEGRAN)、CP-465022、瑞提加宾(retigabine)、他仑帕奈(talampanel)、及扑米酮(primidone)(MYSOLINE);
(ix)抗精神病剂(antipsychotics),诸如鲁拉西酮(lurasidone)(LATUDA,也称为SM-13496;大日本住友)、阿立哌唑(aripiprazole)(ABILIFY)、氯丙嗪(chlorpromazine)(THORAZINE)、氟哌啶醇(haloperidol)(HALDOL)、伊潘立酮(iloperidone)(FANAPTA)、癸酸氟哌噻吨(flupentixol decanoate)(DEPIXOL、FLUANXOL)、利血平(reserpine)(SERPLAN)、匹莫齐特(pimozide)(ORAP)、癸酸氟奋乃静(fluphenazine decanoate)、盐酸氟奋乃静(fluphenazine hydrochloride)、丙氯拉嗪(prochlorperazine)(COMPRO)、阿森那平(asenapine)(SAPHRIS)、洛沙平(loxapine)(LOXITANE)、吗茚酮(molindone)(MOBAN)、奋乃静(perphenazine)、硫利达嗪(thioridazine)、替沃噻吨(thiothixine)、三氟拉嗪(trifluoperazine)(STELAZINE)、雷美替胺(ramelteon)、氯氮平(clozapine)(CLOZARIL)、正氯氮平(norclozapine)(ACP-104)、利培酮(risperidone)(RISPERDAL)、帕潘立酮(paliperidone)(INVEGA)、美哌隆(melperone)、奥氮平(olanzapine)(ZYPREXA)、喹硫平(quetiapine)(SEROQUEL)、他内坦特(talnetant)、阿米舒必利(amisulpride)、齐拉西酮(ziprasidone)(GEODON)、布南色林(blonanserin)(LONASEN)、及ACP-103(AcadiaPharmaceuticals);
(x)钙通道阻断剂诸如洛美利嗪(lomerizine)、齐考诺肽(ziconotide)、尼伐地平(nilvadipine)(ESCOR、NIVADIL)、地佩地平(diperdipine)、氨氯地平(amlodipine)(NORVASC、ISTIN、AMLODIN)、非洛地平(felodipine)(PLENDIL)、尼卡地平(nicardipine)(CARDENE)、硝苯地平(nifedipine)(ADALAT、PROCARDIA)、MEM 1003及其母化合物尼莫地平(nimodipine)(NIMOTOP)、尼索地平(nisoldipine)(SULAR)、尼群地平(nitrendipine)、拉西地平(lacidipine)(LACIPIL、MOTENS)、乐卡地平(lercanidipine)(ZANIDIP)、利法利嗪(lifarizine)、地尔硫卓(diltiazem)(CARDIZEM)、维拉帕米(verapamil)(CALAN、VERELAN)、AR-R 18565(AstraZeneca)、及依奈卡定(enecadin);
(xi)儿茶酚O-甲基转移酶(COMT)抑制剂,诸如硝替卡朋(nitecapone)、托卡朋(tolcapone)(TASMAR)、恩他卡朋(entacapone)(COMTAN)、及卓酚酮(tropolone);
(xii)中枢神经系统兴奋剂,诸如阿托莫西汀(atomoxetine)、瑞波西汀(reboxetine)、育亨宾(yohimbine)、咖啡因、苯甲吗啉(phenmetrazine)、苯甲曲秦(phendimetrazine)、匹莫林(pemoline)、芬坎法明(fencamfamine)(GLUCOENERGAN、REACTIVAN)、芬乙茶碱(fenethylline)(CAPTAGON)、哌苯甲醇(pipradol)(MERETRAN)、地阿诺(deanol)(也称为二甲氨基乙醇)、派醋甲酯(methylphenidate)(DAYTRANA)、盐酸派醋甲酯(methylphenidate hydrochloride)(RITALIN)、右旋哌醋甲酯(dexmethylphenidate)(FOCALIN)、安非他命(amphetamine)(单独或与其它CNS兴奋剂组合使用,例如ADDERALL(天门冬胺酸安非他命、硫酸安非他命、蔗糖酸右旋安非他命以及硫酸右旋安非他命))、硫酸右旋安非他命(DEXEDRINE、DEXTROSTAT)、甲基安非他命(DESOXYN)、赖氨酸安非他命(VYVANSE)、及甲苯异丙胺(DIDREX);
(xiii)皮质类固醇,诸如普赖松(prednisone)(STERAPRED、DELTASONE)、泼尼松龙(prednisolone)(PRELONE)、乙酸泼尼松龙(predisolone acetate)(OMNIPRED、PRED MILD、PRED FORTE)、泼尼松龙磷酸钠(prednisolone sodum phosphate)(ORAPRED ODT)、甲基泼尼松龙(methylprednisolone)(MEDROL);乙酸甲基泼尼松龙(methylprednisoloneacetate)(DEPO-MEDROL)、及甲基泼尼松龙丁二酸钠(methylprednisolone sodiumsuccinate)(A-METHAPRED、SOLU-MEDROL);
(xiv)多巴胺受体激动剂,诸如阿朴吗啡(apomorphine)(APOKYN)、溴隐亭(bromocriptine)(PARLODEL)、卡麦角林(cabergoline)(DOSTINEX)、二氢瑞西定(dihydrexidine)、二氢麦角隐亭(dihydroergocryptine)、非诺多泮(fenoldopam)(CORLOPAM)、麦角乙脲(lisuride)(DOPERGIN)、特麦角脲(terguride)斯培高利特(spergolide)(PERMAX)、吡贝地尔(piribedil)(TRIVASTAL、TRASTAL)、普拉克索(pramipexole)(MIRAPEX)、喹吡罗(quinpirole)、罗匹尼罗(ropinirole)(REQUIP)、罗替高汀(rotigotine)(NEUPRO)、SKF-82958(GlaxoSmithKline)、卡利拉嗪(cariprazine)、帕多芦诺(pardoprunox)和沙利左坦(sarizotan);
(xv)多巴胺受体拮抗剂,诸如氯丙嗪(chlorpromazine)、氟奋乃静(fluphenazine)、氟哌啶醇(haloperidol)、洛沙平(loxzpine)、利培酮(resperidone)、硫利达嗪(thioridazine)、替沃噻吨(thiothixine)、三氟拉嗪(trifluoperazine)、四苯嗪(tetrabenazine)(NITOMAN、XENAZINE)、7-羟基阿莫沙平(7-hydroxyamoxapine)、氟哌利多(droperidol)(INAPSINE、DRIDOL、DROPLETAN)、多潘立酮(domperidone)(MOTILIUM)、L-741742、L-745870、雷氯必利(raclopride)、SB-277011A、SCH-23390、艾寇皮潘(ecopipam)、SKF-83566、及甲氧氯普胺(metoclopramide)(REGLAN);
(xvi)多巴胺再吸收抑制剂,诸如安非他酮(bupropion)、沙非酰胺(safinamide)、顺丁烯二酸诺米芬辛(nomifensine maleate)(MERITAL)、伐诺司林(vanoxerine)(也称为GBR-12909)、及其癸酸酯DBL-583以及安咪奈丁(amineptine);
(xvii)γ-氨基-丁酸(GABA)受体激动剂,诸如巴氯芬(baclofen)(LIORESAL、KEMSTRO)、西克芬(siclofen)、戊巴比妥(pentobarbital)(NEMBUTAL)、普罗加比(progabide)(GABRENE)、及氯美噻唑(clomethiazole);
(xviii)组织胺3(H3)拮抗剂诸如塞普西芬(ciproxifan)、替洛利生(tiprolisant)、S-38093、伊达必生(irdabisant)、匹托利生(pitolisant)、GSK-239512、GSK-207040、JNJ-5207852、JNJ-17216498、HPP-404、SAR-110894、反-3-氟-3-(3-氟-4-吡咯烷-1-基甲基-苯基)-环丁烷羧酸乙基酰胺(PF-3654746)和它们美国专利公开号US2005-0043354、US2005-0267095、US2005-0256135、US2008-0096955、US2007-1079175和US2008-0176925;国际专利公开号WO2006/136924、WO2007/063385、WO2007/069053、WO2007/088450、WO2007/099423、WO2007/105053、WO2007/138431和WO2007/088462;及美国专利号7,115,600)中所揭示者;
(xix)免疫调节剂诸如乙酸格拉替雷(glatiramer acetate)(也称为共聚物-1;COPAXONE)、MBP-8298(合成的髓鞘白质(myelin)基础蛋白质肽)、反丁烯二酸二甲酯、芬戈莫德(fingolimod)(也称为FTY720)、罗喹美克(roquinimex)(LINOMIDE)、拉喹莫德(laquinimod)(也称为ABR-215062和SAIK-MS)、ABT-874(人抗-IL-12抗体;Abbott)、利妥昔单抗(rituximab)(RITUXAN)、来氟米特(leflunomide)、环索奈德(ciclesonide)、阿仑珠单抗(alemtuzumab)(CAMPATH)、达克珠单抗(daclizumab)(ZENAPAX)、及那他珠单抗(natalizumab)(TYSABRI);
(xx)免疫抑制剂诸如甲胺喋呤(methotrexate)(TREXALL、RHEUMATREX)、米托蒽醌(mitoxantrone)(NOVANTRONE)、特立氟胺(teriflunomide)、甲磺司特(suplatasttosilate)、麦考酚酸酯(mycophenolate mofetil)(CELLCEPT)、麦考酚钠(mycophenolatesodium)(MYFORTIC)、硫唑嘌呤(azathioprine)(AZASAN、IMURAN)、巯嘌呤(mercaptopurine)(PURI-NETHOL)、环磷酰胺(cyclophosphamide)(NEOSAR、CYTOXAN)、伏环孢素(voclosporin)、PUR-118、AMG 357、AMG 811、BCT197、苯丁酸氮芥(chlorambucil)(LEUKERAN)、克拉曲滨(cladribine)(LEUSTATIN、MYLINAX)、α-胎儿蛋白(fetoprotein)、依那西普(etanercept)(ENBREL)、来氟米特(leflunomide)、环索奈德氯喹(ciclesonidechloroquine)、羟氯喹(hydroxychloroquine)、d-青霉胺(d-penicillamine)、金诺芬(auranofin)、柳氮磺胺吡啶(sulfasalazine)、金硫基丁二酸钠(sodiumaurothiomalate)、环孢灵(cyclosporine)、色甘酸(cromolyn)、英利昔单抗(infliximab)、阿达木单抗(adalimumab)、聚乙二醇化赛妥珠单抗(certolizumab pegol)、戈利木单抗(golimumab)、利妥昔单抗、奥克珠单抗(ocrelizumab)、奥伐木单抗(ofatumumab)、及4-苯甲氧基-5-((5-十一-2H-吡咯-2-亚基)甲基)-2,2'-联-1H-吡咯(也称为PNU-156804);
(xxi)干扰素,包括干扰素β-1a(AVONEX、REBIF)和干扰素β-1b(BETASERON、BETAFERON);
(xxii)左旋多巴(levodopa)(或其甲酯或乙酯),单独或与DOPA去羧酶抑制剂组合(例如,卡比多巴(carbidopa)(SINEMET、CARBILEV、PARCOPA)、芐丝肼(benserazide)(MADOPAR)、α-甲基多巴、单氟甲基多巴、二氟甲基多巴、溴克立新(brocresine)或间-羟苯甲基肼);
(xxiii)N-甲基-D-天冬胺酸盐(NMDA)受体拮抗剂,诸如美金胺(memantine)(NAMENDA、AXURA、EBIXA)、金刚烷胺(amantadine)(SYMMETREL)、阿坎酸(acamprosate)(CAMPRAL)、贝所玻第(besonprodil)、克他明(ketamine)(KETALAR)、德芦西明(delucemine)、地塞米诺(dexanabinol)、右依法克生(dexefaroxan)、右美沙芬(dextromethorphan)、右啡烷(dextrorphan)、曲索罗地(traxoprodil)、CP-283097、西玛坦(himantane)、爱大塔多(idantadol)、伊培沙宗(ipenoxazone)、L-701252(Merck)、拉西赛明(lancicemine)、左啡诺(levorphanol)(DROMORAN)、LY-233536和LY-235959(二者皆为Lilly)、美沙酮(methadone)(DOLOPHINE)、奈拉美生(neramexane)、培净福太(perzinfotel)、五氯酚(phencyclidine)、噻萘普汀(tianeptine)(STABLON)、地佐环平(dizocilpine)(也称为MK-801)、EAB-318(Wyeth)、伊玻盖因(ibogaine)、佛卡基(voacangine)、替来他明(tiletamine)、力鲁唑(riluzole)(RILUTEK)、阿替加奈(aptiganel)(CERES0TAT)、加维斯替奈(gavestinel)、及瑞马希麦德(remacimide);
(xxiv)单胺氧化酶(MAO)抑制剂,诸如司来吉兰(selegiline)(EMSAM)、盐酸司来吉兰(1-丙炔苯丙胺(l-deprenyl)、ELDEPRYL、ZELAPAR)、二甲基司来吉兰、溴法罗明(brofaromine)、苯乙肼(phenelzine)(NARDIL)、反苯环丙胺(tranylcypromine)(PARNATE)、吗氯贝胺(moclobemide)(AURORIX、MANERIX)、贝氟沙通(befloxatone)、沙非酰胺(safinamide)、异卡波肼(isocarboxazid)(MARPLAN)、烟肼酰胺(nialamide)(NIAMID)、雷沙吉兰(rasagiline)(AZILECT)、异丙异烟肼(iproniazide)(MARSILID、IPROZID、IPRONID)、CHF-3381(Chiesi Farmaceutici)、异丙氯肼(iproclozide)、托洛沙酮(toloxatone)(HUMORYL、PERENUM)、二苯美仑(bifemelane)、脱氧鸭嘴花碱(desoxypeganine)、肉叶芸碱(harmine)(也称为太利帕赛(telepathine)或巴那斯特菱(banasterine))、骆驼蓬碱(harmaline)、利奈唑胺(linezolid)(ZYVOX、ZYVOXID)、及帕吉林(pargyline)(EUDATIN、SUPIRDYL);
(xxv)蕈毒碱受体(特别是M1同工型)激动剂,诸如西维美林(cevimeline)、左乙拉西坦(levetiracetam)、氯贝胆碱(bethanechol chloride)(DUVOID、URECHOLINE)、伊他美林(itameline)、毛果芸香碱(pilocarpine)(SALAGEN)、NGX267、槟榔碱(arecoline)、L-687306(Merck)、L-689660(Merck)、呋索碘铵(furtrethonium iodide)(FURAMON、FURANOL)、呋索苯磺酸铵(furtrethonium benzensulfonate)、呋索对甲苯磺酸铵(furtrethonium p-toluenesulfonate)、McN-A-343、氧化震颤素(oxotremorine)、沙可美林(sabcomeline)、AC-90222(Acadia Pharmaceuticals)、及碳酰胆碱(carbachol)(CARBASTAT、MIOSTAT、CARBOPTIC);
(xxvi)神经保护性药物诸如博舒替尼(bosutinib)、肯多立斯(condoliase)、阿莫氯醇(airmoclomol)、拉莫三嗪(lamotrigine)、吡仑帕奈(perampanel)、阿尼西坦(aniracetam)、米那帕立(minaprime)、威鲁唑(viluzole)2,3,4,9-四氢-1H-咔唑-3-酮肟、去氨普酶(desmoteplase)、安那提邦(anatibant)、虾青素、神经肽NAP(例如,AL-108与AL-208;两者均为Allon Therapeutics)、纽柔措(neurostrol)、佩兰配臬(perampenel)、依斯普尼可林(ispronicline)、双(4-β-D-葡萄哌喃糖氧基苯甲基)-2-β-D-葡萄哌喃糖基(glucopyranosyl)-2-异丁基酒石酸酯(也称为达替洛新(dactylorhin)B或DHB)、弗莫巴汀(formobactin)、扎利罗登(xaliproden)(XAPRILA)、乳胞素(lactacystin)、盐酸代美玻林(dimeboline)(DIMEBON)、地舒芬通(disufenton)(CEROVIVE)、阿伦酸(arundic acid)(ONO-2506、PROGLIA、CEREACT)、胞二磷胆碱(citicoline)(亦称为胞嘧啶核苷5'-二磷酰胆碱)、依达拉奉(edaravone)(RADICUT)、AEOL-10113与AEOL-10150(两者均为AeolusPharmaceuticals)、AGY-94806(亦称为SA-450与Msc-1)、粒性细胞-菌落刺激因子(亦称为AX-200)、BAY-38-7271(亦称为KN-387271;Bayer AG)、安克洛酶(ancrod)(VIPRINEX、ARWIN)、DP-b99(D-Pharm Ltd)、HF-0220(17-β-羟基表雄甾酮;Newron Pharmaceuticals)、HF-0420(亦称为寡特罗平(oligotropin))、吡哆醛5'-磷酸盐(亦称为MC-1)、微纤维蛋白溶酶(microplasmin)、S-18986、吡氯佐坦(piclozotan)、NP031112、他克莫司(tacrolimus)、L-丝胺酰基-L-甲硫丁胺酰基-L-丙胺酰基-L-离胺酰基-L-麸胺酰基-甘胺酰基-L-缬胺酸、AC-184897(Acadia Pharmaceuticals)、ADNF-14(国家卫生研究所)、二苯乙烯薁基硝酮(stilbazulenyl nitrone)、SUN-N8075(Daiichi Suntory生物医学研究)、及唑那巴臬(zonampanel);
(xxvii)烟碱受体激动剂,诸如地棘蛙素(epibatidine)、安非他酮(bupropion)、CP-601927、伐尼克兰(varenicline)、ABT-089(Abbott)、ABT-594、AZD-0328(AstraZeneca);EVP-6124、R3487(也称为MEM3454;Roche/Memory Pharmaceuticals)、R4996(也称为MEM63908;Roche/Memory Pharmaceuticals)、TC-4959和TC-5619(二者皆为Targacept),及RJR-2403;
(xxviii)正肾上腺素(去甲肾上腺素)再吸收抑制剂,诸如阿托莫西汀(atomoxetine)(STRATTERA)、多塞平(doxepin)(APONAL、ADAPIN、SINEQUAN)、去甲替林(nortriptyline)(AVENTYL、PAMELOR、NORTRILEN)、阿莫沙平(amoxapine)(ASENDIN、DEMOLOX、MOXIDIL)、瑞波西汀(reboxetine)(EDRONAX、VESTRA)、维洛沙秦(viloxazine)(VIVALAN)、马普替林(maprotiline)(DEPRILEPT、LUDIOMIL、PSYMION)、安非他酮(bupropion)(WELLBUTRIN)和拉达新芬(radaxafine);
(xxix)磷酸二酯酶(PDE)抑制剂,包括但不限于(a)PDE1抑制剂(例如,长春西汀(vinpocetine)(CAVINTON、CERACTIN、INTELECTOL)和所述美国专利号6,235,742中所揭示者,(b)PDE2抑制剂(例如,赤藓型(erythro)-9-(2-羟基-3-壬基)腺嘌呤(EHNA)、BAY 60-7550和所述美国专利号6,174,884)中所述者,(c)PDE3抑制剂(例如,阿那格雷(anagrelide)、西洛他唑(cilostazol)、米力农(milrinone)、奥普力农(olprinone)、帕罗格列(parogrelil)和匹莫苯(pimobendan)),(d)PDE4抑制剂(例如,阿普司特(apremilast)、异丁司特罗氟司特(ibudilastroflumilast)、洛利普兰(rolipram)、Ro20-1724、异丁司特(ibudilast)(KETAS)、吡拉米司特(piclamilast)(也称为RP73401)、CDP840、西洛司特(cilomilast)(ARIFLO)、罗氟司特(roflumilast)、托菲司特(tofimilast)、欧格司特(oglemilast)(也称为GRC 3886)、替托司特(tetomilast)(也称为OPC-6535)、利林司特(lirimifast)、茶碱(theophylline)(UNIPHYL、THEOLAIR)、阿罗茶碱(arofylline)(也称为LAS-31025)、多索茶碱(doxofylline)、RPR-122818或松叶菊碱(mesembrine),和(e)PDE5抑制剂(例如西地那非(sildenafil)(VIAGRA、REVATIO)、他达拉非(tadalafil)(CIALIS)、伐地那非(vardenafil)(LEVITRA、VIVANZA)、乌地那非(udenafil)、阿伐那非(avanafil)、双嘧达莫(dipyridamole)(PERSANTINE)、E-4010、E-4021、E-8010、扎普司特(zaprinast)、洛地那非(iodenafil)、米罗那非(mirodenafil)、DA-8159及它们国际专利申请案WO2002/020521、WO2005/049616、WO2006/120552、WO2006/126081、WO2006/126082、WO2006/126083及WO2007/122466中所揭示者),(f)PDE7抑制剂;(g)PDE8抑制剂;(h)PDE9抑制剂(例如,BAY 73-6691(Bayer AG)和它们美国专利公开号US2003/0195205、US2004/0220186、US2006/0111372、US2006/0106035和USSN 12/118,062(申请于2008年5月9日))中所揭示者,(i)PDE10抑制剂诸如2-[4-(1-甲基-4-吡啶-4-基-1H-吡唑-3-基)苯氧基甲基]喹啉(PF-2545920)、及SCH-1518291;及(j)PDE11抑制剂;
(xxx)喹啉,诸如奎宁(quinine)(包括其盐酸盐、二盐酸盐、硫酸盐、硫酸氢盐及葡糖酸盐)、氯奎(chloroquine)、甲氯喹啉(sontoquine)、羟基氯奎(hydroxychloroquine)(PLAQUENIL)、甲氟喹(mefloquine)(LARIAM)、及阿莫地喹(amodiaquine)(CAMOQUIN、FLAVOQUINE);
(xxxi)β-分泌酶抑制剂,诸如ASP-1702、SCH-745966、JNJ-715754、AMG-0683、AZ-12304146、BMS-782450、GSK-188909、NB-533、LY-2886721、E-2609、HPP-854、(+)-酒石酸芬色林(phenserine tartrate)(POSIPHEN)、LSN-2434074(也称为LY-2434074)、KMI-574、SCH-745966、Ac-rER(N2-乙酰基-D-精胺酰基-L-精胺酸)、罗斯他汀(loxistatin)(也称为E64d)、及CA074Me;
(xxxii)γ-分泌酶抑制剂和调节剂,诸如BMS-708163(Avagacest)、WO20060430064(Merck)、DSP8658(Dainippon)、ITI-009、L-685458(Merck)、ELAN-G、ELAN-Z、4-氯-N-[2-乙基-1(S)-(羟甲基)丁基]苯磺酰胺;
(xxxiii)血清素(5-羟色胺)1A(5-HT1A)受体拮抗剂,诸如螺哌隆(spiperone)、左旋吲哚洛尔(levo-pindolol)、BMY 7378、NAD-299、S(-)-UH-301、NAN 190、列可左坦(lecozotan);
(xxxiv)血清素(5-羟基色胺)2C(5-HT2c)受体激动剂,诸如戊卡色林(vabicaserin)和齐洛那平(zicronapine);
(xxxv)血清素(5-羟色胺)4(5-HT4)受体激动剂,诸如PRX-03140(Epix);
(xxxvi)血清素(5-羟色胺)6(5-HT6)受体拮抗剂,诸如A-964324、AVI-101、AVN-211、米安色林(mianserin)(TORVOL、BOLVIDON、NORVAL)、梅塞平(methiothepin)(亦已知为甲替平(metitepine))、利坦色林(ritanserin)、ALX-1161、ALX-1175、MS-245、LY-483518(也称为SGS518;Lilly)、MS-245、Ro 04-6790、Ro 43-68544、Ro 63-0563、Ro 65-7199、Ro65-7674、SB-399885、SB-214111、SB-258510、SB-271046、SB-357134、SB-699929、SB-271046、SB-742457(GlaxoSmithKline)、Lu AE58054(Lundbeck A/S)、及PRX-07034(Epix);
(xxxvii)血清素(5-HT)再吸收抑制剂,诸如阿拉丙酯(alaproclate)、西酞普兰(citalopram)(CELEXA,CIPRAMIL)、依地普伦(escitalopram)(LEXAPRO,CIPRALEX)、氯米帕明(clomipramine)(ANAFRANIL)、度洛西汀(duloxetine)(CYMBALTA)、非莫西汀(femoxetine)(MALEXIL)、芬氟拉明(fenfluramine)(PONDIMIN)、去乙芬氟拉明(norfenfluramine)、氟西汀(fluoxetine)(PROZAC)、氟伏沙明(fluvoxamine)(LUVOX)、吲达品(indalpine)、米那普仑(milnacipran)(IXEL)、帕罗西汀(paroxetine)(PAXIL、SEROXAT)、舍曲林(sertraline)(ZOLOFT、LUSTRAL)、曲唑酮(trazodone)(DESYREL、MOLIPAXIN)、文拉法辛(venlafaxine)(EFFEXOR)、齐美利定(zimelidine)(NORMUD、ZELMID)、比西发定(bicifadine)、去甲文拉法辛(desvenlafaxine)(PRISTIQ)、巴索芳新(brasofensine)、维拉佐酮(vilazodone)、卡利拉嗪(cariprazine)、纽若斯坦(neuralstem)、及泰索芳新(tesofensine);
(xxxviii)营养因子(trophic factors),诸如神经生长因子(NGF)、碱性成纤维细胞生长因子(bFGF;ERSOFERMIN)、神经营养素-3(NT-3)、心肌营养素-1、脑衍生神经营养因子(BDNF)、神经胚素(neublastin)、美替瑞(meteorin)、及神经胶质-衍生的神经营养因子(GDNF),及刺激营养因子生成的药剂,诸如丙戊非林(propentofylline)、艾地苯醌(idebenone)、PYM50028(COGANE;Phytopharm)、及AIT-082(NEOTROFIN);
(xxxix)甘胺酸转运蛋白-1抑制剂诸如帕利伐替(paliflutine)、ORG-25935、JNJ-17305600和ORG-26041;
(xl)AMPA-型谷氨酸盐受体调节剂诸如吡仑帕奈(perampanel)、米贝帕托(mibampator)、舍路帕内(selurampanel)、GSK-729327、及N-{(3S,4S)-4-[4-(5-氰基噻吩-2-基)苯氧基]四氢-呋喃-3-基}丙烷-2-磺酰胺等等;
(xli)杰纳斯激酶(Janus kinase)抑制剂(JAK),诸如(但不限于)托法替尼(tofacitinib)、芦可替尼(ruxolitinib)、巴瑞替尼(baricitinib)、CYT387、GLPG0634、来他替尼(lestaurtinib)、帕瑞替尼(pacritinib)和TG101348。
在本发明的另一优选实施方案中,式I化合物可与抗肥胖剂共同给药,其中该抗肥胖剂选自由下列所组成的群组:肠选择性MTP抑制剂(例如地洛他派(dirlotapide)、米瑞他匹(mitratapide)和英普他派(implitapide)、R56918(CAS号403987)和CAS号913541-47-6)、CCKa激动剂(例如,PCT公开第WO 2005/116034号或US公开第2005-0267100 A1号中所述的N-苯甲基-2-[4-(1H-吲哚-3-基甲基)-5-氧代-1-苯基-4,5-二氢-2,3,6,10b-四氮杂-苯并[e]薁-6-基]-N-异丙基-乙酰胺)、5HT2c激动剂(例如,氯卡色林(lorcaserin))、MCR4激动剂(例如,US 6,818,658中所述的化合物)、脂肪酶抑制剂(例如,西替利司他(Cetilistat))、PYY3-36(如使用在本文中“PYY3-36”包括类似物(诸如聚乙二醇化(peglated)PYY3-36,例如所述US公开第2006/0178501号中所述者)、类鸦片拮抗剂(例如那屈酮(naltrexone))、那屈酮与安非他酮(buproprion)的组合、油酰雌酮(oleoy1-estrone)(CAS号180003-17-2)、奥尼匹肽(obinepitide)(TM30338)、普兰林肽(pramlintide)特索芬辛(tesofensine)(NS2330)、瘦素、利拉鲁肽(liraglutide)、溴隐亭(bromocriptine)、奥利司他(orlistat)、艾塞那肽(exenatide)AOD-9604(CAS号221231-10-3)和西布曲明(sibutramine)。
其他抗肥胖剂类包括11β-羟基类固醇去氢酶-1(11β-HSD型1)抑制剂、硬脂酰基-CoA去饱和酶-1(SCD-1)抑制剂、胆囊收缩素-A(CCK-A)激动剂、单胺再吸收抑制剂(诸如西布曲明)、交感神经剂、β3肾上腺素激动剂、多巴胺激动剂(诸如溴隐亭)、促黑激素类似物、黑色素聚集激素拮抗剂、瘦素(OB蛋白质)、瘦素类似物、瘦素激动剂、甘丙胺素拮抗剂、脂肪酶抑制剂(诸如四氢利泼斯汀(tetrahydrolipstatin),亦即奥利司他)、减食欲剂(诸如铃蟾素(bombesin)激动剂)、神经肽-Y拮抗剂(例如NPY Y5拮抗剂)、拟甲状腺素剂、脱氢表雄甾酮或其类似物、醣皮质素激动剂或拮抗剂、食欲素拮抗剂、类升糖素肽-1激动剂、睫状神经营养因子(诸如AxokineTM,可得自Regeneron Pharmaceuticals,Inc.,Tarrytown,NY和Procter&Gamble Company,Cincinnati,OH)、人刺鼠相关蛋白质(AGRP)抑制剂、饥饿肽(ghrelin)拮抗剂、组织胺3拮抗剂或逆激动剂、神经激素U激动剂、MTP/ApoB抑制剂(例如肠-选择性MTP抑制剂,诸如地洛他派)、类阿片拮抗剂、食欲素拮抗剂、那屈酮与安非他酮的组合等等。
在本发明的另一实施方案中,式I化合物可与抗糖尿病剂共同给药,其该抗糖尿病剂选自由下列所组成的群组:乙酰基CoA羧酶-(ACC)抑制剂诸如它们WO2009144554、WO2003072197、WO2009144555及WO2008065508中所述者;二酰基甘油O-酰基转移酶1(DGAT-1)抑制剂,诸如它们WO09016462或WO2010086820中所述者、AZD7687或LCQ908、单酰基甘油O-酰基转移酶抑制剂、磷酸二酯酶(PDE)-10抑制剂、AMPK活化剂、磺酰脲(例如,乙酰苯磺酰环己脲、氯磺丙脲、特泌胰(diabinese)、格列本脲(glibenclamide)、格列吡嗪(glipizide)、格列本脲(glyburide)、格列美脲(glimepiride)、格列齐特(gliclazide)、格列戊脲(glipentide)、格列喹酮(gliquidone)、格列索脲(glisolamide)、妥拉磺脲(tolazamide)、及甲苯磺丁脲(tolbutamide))、美格替耐(meglitinide)、α-淀粉酶抑制剂(例如,淀粉酶抑肽(tendamistat)、萃他丁(trestatin)和AL-3688)、α-葡萄糖苷水解酶抑制剂(例如,阿卡波糖(acarbose))、α-葡萄糖苷酶抑制剂(例如,脂解素(adiposine)、卡格列波糖(camiglibose)、乙格列酯(emiglitate)、米格列醇(miglitol)、伏格列波糖(voglibose)、帕地霉素-Q(pradimicin-Q)、及沙司他丁(salbostatin))、PPARγ激动剂(例如,巴拉格列酮(balaglitazone)、环格列酮(ciglitazone)、达格列酮(darglitazone)、恩格列酮(englitazone)、伊格列酮(isaglitazone)、吡格列酮(pioglitazone)和罗格列酮(rosiglitazone))、PPARα/γ激动剂(例如CLX-0940、GW-1536、GW-1929、GW-2433、KRP-297、L-796449、LR-90、MK-0767及SB-219994)、双胍(例如二甲双胍(metformin))、类升糖素肽1(GLP-1)调节剂诸如激动剂(例如,艾生丁(exendin)-3、艾生丁-4、ZYOG-1和TTP273)、利拉鲁肽(liraglutide)阿必鲁肽(albiglutide)、艾塞那肽阿必鲁肽、利司那肽(lixisenatide)、度拉糖肽(dulaglutide)、司美鲁肽(semaglutide)(NN-9924)、TTP-054;蛋白质酪胺酸磷酸酶-1B(PTP-1B)抑制剂(例如特罗杜明(trodusquemine)、西替欧醛萃取物(hyrtiosal extract)、及Zhang,S.等人所揭示的化合物(Drug Discovery Today,12(9/10),373-381(2007))、SIRT-1活化剂(例如白藜芦醇、GSK2245840或GSK184072);二肽基肽酶IV(DPP-IV)抑制剂(例如它们WO2005116014中者、西他列汀(sitagliptin)、维格列汀(vildagliptin)、阿格列汀(alogliptin)、多格列汀(dutogliptin)、利拉利汀(linagliptin)、及沙格列汀(saxagliptin))、胰岛素促泌素、脂肪酸氧化抑制剂、A2拮抗剂、c-jun氨基末端激酶(JNK)抑制剂、葡糖激酶活化剂(GKa)诸如它们WO2010103437、WO2010103438、WO2010013161、WO2007122482中所述者、TTP-399、TTP-355、TTP-547、AZD1656、ARRY403、MK-0599、TAK-329、AZD5658或GKM-001、胰岛素;胰岛素模拟物、肝糖磷酸化酶抑制剂(例如GSK1362885);VPAC2受体激动剂、SGLT2抑制剂,诸如它们E.C.Chao等人Nature Reviews Drug Discovery,9,551-559(2010年7月)中所述者,包括达格列净(dapagliflozin)、卡格列净(canagliflozin)、依帕列净(empagliflozin)、托格列净(tofogliflozin)(CSG452)、ASP-1941、THR1474、TS-071、ISIS388626及LX4211以及它们者WO2010023594;升糖素受体调节剂,诸如它们Demong,D.E.等人Annual Reports in Medicinal Chemistry 2008,43,119-137中所述者、GPR119调节剂,特别是激动剂,诸如它们WO2010140092、WO2010128425、WO2010128414、WO2010106457、Jones,R.M.等人的Medicinal Chemistry 2009,44,149-170中所述者(例如MBX-2982、GSK1292263、APD597及PSN821)、FGF21衍生物或类似物诸如它们Kharitonenkov,A.等人,Current Opinion in Investigational Drugs 2009,10(4)359-364中所述者;TGR5(亦称为GPBAR1)受体调节剂,特别是激动剂诸如它们Zhong,M.,CurrentTopics in Medicinal Chemistry,2010,10(4),386-396中所述者及INT777、GPR40激动剂,诸如它们Medina,J.C.,Annual Reports in Medicinal Chemistry,2008,43,75-85中所述者,包括(但不限于)TAK-875、GPR120调节剂,特别是激动剂,高亲和力烟碱酸受体(HM74A)活化剂;及SGLT1抑制剂,诸如GSK1614235,抗糖尿病剂的清单可见于例如WO2011005611的第28页第35行至第30页第19行,肉碱软脂酰基转移酶的抑制剂或调节剂;果糖1,6-二磷酸酶的抑制剂;醛醣还原酶的抑制剂;盐皮质激素受体抑制剂;TORC2的抑制剂;CCR2及/或CCR5的抑制剂;PKC同工型(例如PKCα、PKCβ1、PKCβ2等等…)的抑制剂;脂肪酸合成酶的抑制剂;丝胺酸软脂酰基转移酶的抑制剂;GPR81、GPR39、GPR43、GPR41、GPR105、Kv1.3、视黄醇结合蛋白4、糖皮质激素受体、生长抑素受体(例如SSTR1、SSTR2、SSTR3及SSTR5)的调节剂;PDHK2或PDHK4的抑制剂或调节剂;MAP4K4的抑制剂;IL1家族(包括IL1β)的调节剂;及RXRα的调节剂,适合的抗糖尿病剂包括Carpino,P.A.,Goodwin,B.Expert Opin.Ther.Pat,2010,20(12),1627-51所列的机制。
优选抗糖尿病剂为二甲双胍及DPP-IV抑制剂(例如西他列汀、维格列汀、阿格列汀、多格列汀、利拉利汀及沙格列汀)。其他抗糖尿病剂将包括肉碱软脂酰基转移酶的抑制剂或调节剂;果糖1,6-二磷酸酶的抑制剂;醛醣还原酶的抑制剂;盐皮质激素受体抑制剂;TORC2的抑制剂;CCR2及/或CCR5的抑制剂;PKC同工型(例如PKCα、PKCβ、PKCγ)的抑制剂;脂肪酸合成酶的抑制剂;丝胺酸软脂酰基转移酶的抑制剂;GPR81、GPR39、GPR43、GPR41、GPR105、Kv1.3、视黄醇结合蛋白4、糖皮质激素受体、生长抑素受体(例如SSTR1、SSTR2、SSTR3及SSTR5)的调节剂;PDHK2或PDHK4的抑制剂或调节剂;MAP4K4的抑制剂;IL1家族(包括IL1β)的调节剂;及RXRα的调节剂。
在本发明的另一实施方案中,式I化合物可与胆固醇/脂质调节剂共同给药,其中该胆固醇/脂质调节剂选自由下列所组成的群组:HMG-CoA还原酶抑制剂(例如普伐他汀(pravastatin)、洛伐他汀(lovastatin)、阿伐他汀(atorvastatin)、辛伐他汀(simvastatin)、氟伐他汀(fluvastatin)、NK-104(a.k.a.依伐他汀(itavastatin)、或尼伐他汀(nisvastatin)或尼贝他汀(nisbastatin))与ZD-4522(a.k.a.罗苏伐他汀(rosuvastatin)、或阿托伐他汀(atavastatin)或维沙他汀(visastatin));HMG-CoA还原酶基因表现抑制剂;鲨烯合成酶抑制剂;鲨烯环氧酶抑制剂;鲨烯环化酶抑制剂;混合型鲨烯环氧酶/鲨烯环化酶抑制剂;CETP抑制剂;纤维酸(fibrates);烟碱酸、离子交换树脂、抗氧化剂;胆酸螯合剂(例如降胆敏(questran));ACAT抑制剂;MTP/APOβ分泌抑制剂;脂氧合酶抑制剂;胆固醇吸收抑制剂;胆固醇酯转移蛋白抑制剂;诸如密波默生(mipomersen)的药剂;及或动脉粥样硬化剂(包括PCSK9调节剂)。
在另一实施方案中,式I的化合物可与用于治疗非酒精性脂肪肝炎(NASH)及/或非酒精性脂肪肝疾病(NAFLD)的药剂共同给药,诸如奥利司他(Orlistat)、TZDs与其他胰岛素敏化剂、FGF21类似物、二甲双胍(Metformin)、ω-3-脂肪酸乙酯(例如Lovaza)、贝特类(Fibrates)、HMG-CoA还原酶抑制剂、依泽替米贝(Ezitimbe)、普罗布考(Probucol)、熊脱氧胆酸、TGR5激动剂、FXR激动剂、维生素E、甜菜碱、己酮可可碱(Pentoxifylline)、CB1拮抗剂、肉毒碱、N-乙酰半胱胺酸、还原型谷胱甘肽、氯卡色林、那屈酮与苯丙胺的组合、SGLT2抑制剂、苯丁胺(phentermine)、托吡酯(topiramate)、肠促胰岛素(GLP与GIP)类似物及血管收缩素受体阻断剂。
另外的治疗剂包括抗凝血药或凝血抑制剂、抗血小板药或血小板抑制剂、凝血酶抑制剂、血栓溶解剂或纤维蛋白溶解剂、抗心律不整药、抗高血压药、钙通道阻断剂(L型和T型)、强心苷、利尿剂、矿物性皮质激素受体拮抗剂、NO提供剂(诸如有机硝酸盐)、NO促进剂(例如磷酸二酯酶抑制剂)、胆固醇/脂质降低剂与脂质剖面疗法(lipid profiletherapy)、降血糖剂、抗忧郁药、消炎药(类固醇型与非类固醇型)、抗骨质疏松药、激素取代治疗、口服避孕药、抗肥胖剂、抗焦虑药、抗增生剂、抗肿瘤剂、抗溃疡与胃食道回流疾病药、生长激素与/或生长激素促分泌剂、拟甲状腺素剂(包括甲状腺素受体拮抗剂)、抗感染药、抗病毒剂、抗细菌剂、及抗真菌剂。适当矿物性皮质激素受体拮抗剂的实例包括螺内酯(sprionolactone)和依普利酮(eplerenone)。
本领域技术人员将认知本发明化合物也可与下列结合使用:其他心血管或脑血管治疗(包括PCI、支架置入术、药物洗脱支架、干细胞疗法)及医疗装置(诸如植入式心律调节器、除颤器)、或心脏再同步化疗法。
ICU设置中所用的药剂,例如多巴酚丁胺(dobutamine)、多巴胺(dopamine)、肾上腺素(dpinephrine)、硝化甘油(nitroglycerin)、硝普盐(nitroprusside)等等。
可用于治疗血管炎的组合药剂包括,例如,硫唑嘌呤、环磷酰胺、霉酚酸吗啉乙酯(mycophenolate mofetil)、利妥昔单抗等等。
在另一实施方案中,本发明提供一种组合,其中该第二药剂为至少一种选自下列的药剂:因子Xa抑制剂、抗凝血剂、抗血小板剂、凝血酶抑制剂、血栓溶解剂、及纤维蛋白溶解剂。示例性因子Xa抑制剂包括阿派沙班(apixaban)和利伐沙班(rivaroxaban)。与本发明化合物组合使用的适当抗凝血药的实例包括肝素(例如,普通(unfractioned)肝素和低分子量肝素,诸如依诺肝素(enoxaparin)和达肝素(dalteparin)。
在另一优选实施方案中,该第二药剂为至少一种选自下列的药剂:华法林(warfarin)、达比加群(dabigatran)、普通肝素、低分子量肝素、合成五糖(syntheticpentasaccharide)、水蛭素(hirudin)、阿加曲班(argatrobanas)、阿斯匹林(aspirin)、布洛芬、萘普生、舒林酸、吲哚美辛、甲芬那酸(mefenamate)、屈昔康(droxicam)、双氯芬酸、苯磺唑酮(sulfinpyrazone)、吡罗昔康(piroxicam)、噻氯匹定(ticlopidine)、氯吡格雷(clopidogrel)、替罗非班(tirofiban)、埃替非巴肽(eptifibatide)、阿昔单抗(abciximab)、美拉加群(melagatran)、二硫酸水蛭素、组织性血浆蛋白原活化剂、经修饰的组织性血浆蛋白原活化剂、阿尼普酶(anistreplase)、尿激酶及链激酶。
优选第二药剂为至少一种抗血小板药。尤佳抗血小板药为阿斯匹林与氯吡格雷。
如本文所用,术语抗血小板剂(或血小板抑制剂)表示抑制血小板功能(例如藉由抑制血小板的聚集、黏附或颗粒分泌)的药剂。该药剂包括(但不限于)各种已知的非类固醇消炎药(NSAIDS)诸如阿斯匹林、布洛芬、萘普生、舒林酸、吲哚美辛、甲芬那酸、屈昔康、双氯芬酸、苯磺唑酮、吡罗昔康、及其药学上可接受的盐或前药。在NSAIDS中,阿斯匹林(乙酰水杨酸或ASA)与COX-2抑制剂诸如CELEBREX或匹吡罗昔康为优选。其他适当血小板抑制剂包括IIb/IIIa拮抗剂(例如替罗非班(tirofiban)、埃替非巴肽、及阿昔单抗)、凝血脂素A2受体拮抗剂(例如伊非曲班(ifetroban))、凝血脂素A2-合成酶抑制剂、PDE-III抑制剂(例如普达(Pletal)、双嘧达莫)、及其药学上可接受的盐或前药。
如本文所用,术语抗血小板剂(或血小板抑制剂)也意欲包括ADP(二磷酸腺苷)受体拮抗剂(优选为嘌呤受体P2Y1和P2Y12,且P2Y12甚至为更优选)。优选的P2Y12受体拮抗剂包括替卡格雷(ticagrelor)、普拉格雷(prasugrel)、噻氯匹定(ticlopidine)和氯吡格雷、包括其药学上可接受的盐或前药。氯吡格雷为甚至更优选的药剂。噻氯匹定和氯吡格雷也是优选的化合物,因它们在使用时对消化道温和。
如本文所用,术语凝血酶抑制剂(或抗凝血酶剂)表示丝胺酸蛋白酶凝血酶的抑制剂。藉由抑制凝血酶,中断各种凝血酶介导过程,诸如凝血酶介导的血小板活化(亦即,例如血小板凝集及/或血浆蛋白原活化因子抑制剂-1及/或血清素的颗粒分泌)及/或纤维蛋白形成。许多凝血酶抑制剂为熟习此项技术者已知,且预期这些抑制剂与本发明化合物组合使用。所述抑制剂包括(但不限于)硼精胺酸(boroarginine)衍生物、硼肽(boropeptides)、达比加群、肝素、水蛭素、阿加曲班及美拉加群,包括其药学上可接受的盐及前药。硼精胺酸衍生物及硼肽包括硼酸的N-乙酰基及肽衍生物,诸如离胺酸、鸟胺酸、精胺酸、高精胺酸及其对应异硫脲类似物的C端α-氨基硼酸衍生物。如本文所用,术语水蛭素包括水蛭素的适当衍生物或类似物,在本文中称为水蛭肽(hirulog),诸如二硫酸水蛭素(disulfatohirudin)。如本文所用,术语溶栓剂或纤维蛋白溶解剂(或溶栓剂或血纤蛋白分解药)表示溶解血块(血栓)的药剂。所述药剂包括组织性血浆蛋白原活化剂(天然或重组)及其修饰形式、阿尼普酶、尿激酶、链激酶、替奈普酶(tenecteplase;TNK)、兰替普酶(lanoteplase;nPA)、VIIa因子抑制剂、PAI-1抑制剂(亦即,组织性血浆蛋白原活化剂抑制剂的不活化剂)、α2-抗纤维蛋白溶酶抑制剂,及大茴香酰化(anisoylated)血浆蛋白及链球菌激酶活化聚合体,包括其药学上可接受的盐或前药。如本文所用,术语阿尼普酶系指大茴香酰化血浆蛋白及链球菌激酶活化聚合体,如例如EP 028,489中所描述,其揭示内容以引用的方式并入本文中。如本文所用,术语尿激酶意欲表示双链尿激酶和单链尿激酶二者,后者在本文中亦称作前尿激酶。
适当抗心律不整剂的实例包括:I级药剂(诸如普罗帕酮(propafenone));II级药剂(诸如美托洛尔(metoprolol)、阿替洛尔、卡伐地洛(carvadiol)和普萘洛尔(propranolol));III级药剂(诸如索他洛尔、多非利特(dofetilide)、胺碘酮(amiodarone)、阿齐利特(azimilide)及伊布利特(ibutilide));IV级药剂(诸如地尔硫卓及维拉帕米);K+通道开放剂,诸如IAch抑制剂、及IKur抑制剂(例如WO01/40231中揭示的化合物)。
本发明化合物可和抗高血压剂组合使用且该降血压活性由本领域技术人员根据标准检定(例如,血压测量)容易地测定。适当抗高血压剂的实例包括:α肾上腺素阻断剂;β肾上腺素阻断剂;钙离子通道阻断剂(例如地尔硫卓、维拉帕米、硝苯地平和氨氯地平(amlodipine));血管扩张剂(例如肼屈嗪(hydralazine));利尿剂(例如氯苯噻(chlorothiazide)、氢氯苯噻哒嗪(hydrochlorothiazide)、三氟甲噻(flumethiazide)、氢氟噻嗪(hydroflumethiazide)、苄氟噻嗪(bendroflumethiazide)、甲氯噻嗪(methylchlorothiazide)、三氯噻嗪(trichloromethiazide)、多噻嗪(polythiazide)、苄噻嗪(benzthiazide)、依他尼酸三克那汾(ethacrynic acid tricrynafen)、氯噻酮(chlorthalidone)、托拉塞米(torsemide)、呋塞米(furosemide)、musolimine、布美他尼(bumetanide)、triamtrenene、阿米洛利(amiloride)、螺内酯);肾素抑制剂;ACE抑制剂(例如卡托普利(captopril)、佐芬普利(zofenopril)、福辛普利(fosinopril)、依那普利(enalapril)、瑟蓝普利(ceranopril)、西拉普利(cilazopril)、地拉普利(delapril)、喷托普利(pentopril)、奎纳普利(quinapril)、雷米普利(ramipril)、赖诺普利(lisinopril));AT-1受体拮抗剂(例如洛沙东(losartan)、艾比沙坦(irbesartan)、缬沙坦(valsartan);ET受体拮抗剂(例如司他生坦(sitaxsentan)、阿曲生坦(atrsentan)与在美国专利第5,612,359和6,043,265号中所揭示的化合物);双重ET/AII拮抗剂(例如在WO00/01389中所揭示的化合物);中性肽链内切酶(NEP)抑制剂;血管肽酶抑制剂(双重NEP-ACE抑制剂)(例如(gemopatrilat)和硝酸盐)。示例性抗心绞痛药是伊伐布雷定(ivabradine)。
适当钙离子通道阻断剂(L-型或T-型)的实例包括(例如地尔硫卓、维拉帕米、硝苯地平和氨氯地平及米贝地尔(mybefradil));
适当强心苷实例包括毛地黄(digitalis)与乌巴苷(ouabain)。
在一实施方案中,式I的化合物可与一或多种利尿剂共同给药。适当利尿剂的实例包括(a)环利尿剂诸如呋塞米(furosemide)(诸如LASIXTM)、托拉塞米(torsemide)(诸如DEMADEXTM)、贝美他尼(bemetanide)(诸如BUMEXTM)、及利尿酸(ethacrynic acid)(诸如EDECRINTM);(b)噻嗪型利尿剂,诸如氯苯噻(诸如DIURILTM、ESIDRIXTM或HYDRODIURILTM)、氢氯苯噻哒嗪(诸如MICROZIDETM或ORETICTM)、苄噻嗪、氢氟噻嗪(诸如SALURONTM)、苄氟噻嗪、甲氯噻嗪、多噻嗪、三氯噻嗪、与吲达帕胺(indapamide)(诸如LOZOLTM);(c)苄甲内酰胺型利尿剂,例如氯噻酮(诸如HYGROTONTM)与美托拉腙(metolazone)(诸如ZAROXOLYNTM);(d)喹唑啉型利尿剂诸如喹乙唑酮(quinethazone);及(e)保钾利尿剂,例如氨苯喋啶(triamterene)(诸如DYRENIUMTM)、及阿米洛利(诸如MIDAMORTM或MODURETICTM)。
在另一实施方案中,式I的化合物可与一或多种环利尿剂共同给药。在又另一实施方案中,环利尿剂选自呋塞米和托拉塞米。在又另一实施方案中,一或多种式I化合物可与呋塞米共同给药。在又另一实施方案中,一或多种式I化合物可与托拉塞米共同给药,其可随意地为托拉塞米的控制释放型或调控释放型。
在另一实施方案中,式I可与噻嗪型利尿剂共同给药。在又另一实施方案中,该噻嗪型利尿剂选自由下列所组成的群组:氯苯噻和氢氯苯噻哒嗪。在又另一实施方案中,一或多种式I化合物可与氯苯噻共同给药。在又另一实施方案中,一或多种式I化合物可与氢氯苯噻哒嗪共同给药。
在另一实施方案中,一或多种式I的化合物可与苄甲内酰胺型利尿剂共同给药。在又另一实施方案中,该苄甲内酰胺型利尿剂为氯噻酮。
在另一实施方案中,本发明化合物也可与下列共同给药:
止泻药,诸如苯乙哌啶(diphenoxylate,Lomotil)及洛哌丁胺(loperamide,Imodium);
胆酸结合剂,诸如消胆胺(cholestyramine)、阿洛司琼(alosetron,Lotronex)及鲁比前列酮(ubiprostone,Amitiza);
轻泻剂,诸如镁乳(Milk of Magnesia)、聚乙二醇(MiraLax)、双醋苯啶(Dulcolax)、考莱托尔(Correctol)和散肚秘(Senokot),及抗胆碱剂或镇痉剂,诸如双环胺(dicyclomine,Bentyl);
淋巴细胞活化抑制剂,包括(但不限于)阿巴西普(abatacept);
抗IL1治疗,包括(但不限于)阿那白滞素(anakinra)、利纳西普(rilonacept)、康纳单抗(canakinumab)、介维单抗(gevokizumab)、MABp1及MEDI-8968;
可口服、藉由吸入、藉由注射、局部、直肠、经眼递送剂量的糖皮质激素受体调节剂,包括(但不限于)倍他米松(betamethasone)、泼尼松(prednisone)、氢皮质酮(hydrocortisone)、泼尼龙(prednisolone)、氟尼缩松(flunisolide)、曲安奈德(triamcinoline acetonide)、倍氯米松(beclomethasone)、二丙酸酯(dipropionate)、布地奈德(budesonide)、丙酸氟替卡松(fluticasone propionate)、环索奈德(ciclesonide)、糠酸莫米松(mometasone furoate)、氟西奈德(fluocinonide)、去羟米松(desoximetasone)、甲基泼尼松龙或PF-04171327;
氨基水杨酸衍生物,包括(但不限于)柳氮磺胺吡啶(sulfasalazine)和美色拉嗪(mesalazine);
抗α4整合素剂,包括(但不限于)那他珠单抗;
α1-或α2-肾上腺素激动剂,包括(但不限于)环己丙甲胺(propylhexidrine)、苯肾上腺素(phenylephrine)、苯丙醇胺(phenylpropanolamine)、假麻黄素(pseudoephedrine)或盐酸萘唑啉(naphazoline hydrochloride)、盐酸羟间唑啉(oxymetazolinehydrochloride)、盐酸四氢唑啉(tetrahydrozoline hydrochloride)、盐酸赛洛唑啉(xylometazoline hydrochloride)或盐酸乙基正肾上腺素(ethylnorepinephrinehydrochloride);
α-肾上腺素激动剂,包括(但不限于)间羟异丙肾上腺素(metaproterenol)、异丙去甲肾上腺素(isoprotenerol)、异丙肾上腺素(isoprenaline)、沙丁胺醇(albuterol)、羟甲异丁肾上腺素(salbutamol)、福莫特罗(formoterol)、沙美特罗(salmeterol)、特布他林(terbutaline)、奥西那林(orciprenaline)、双甲苯喘定甲磺酸盐(botolterolmesylate)、吡布特罗(pirbuterol);
抗胆碱剂,包括(但不限于)异丙托溴铵(ipratropium bromide)、噻托溴铵(tiotropium bromide)、氧托溴铵(oxitropium bromide)、阿地溴铵(aclindiniumbromide)、格隆溴铵(glycopyrrolate)、哌仑西平(pirenzipine)或替仑西平(telenzepine);
本发明另外包含适合使用于进行上述治疗方法的试剂盒。在一实施方案中,该试剂盒含有包含一或多种本发明化合物的第一剂型及用于剂量的容器,其量足以进行本发明的方法。
在另一实施方案中,该本发明的试剂盒包含一或多种本发明化合物。
本发明化合物或其药学上可接受的盐可藉由该项技术中类似已知的多种方法制备。下述反应流程与有机化学技术中已知的合成方法或一般技术者熟悉的修改及衍生方法说明用于制备化合物的方法。本领域技术人员将容易地显而易知其他方法(包括其修改)。
本文所用的起始材料为市售或可藉由该项技术中已知的例行方法(诸如它们标准参考书(诸如COMPENDIUM OF ORGANIC SYNTHETIC METHODS,第I-XII卷(Wiley-Interscience出版))中所公开的方法)制备。优选方法包括(但不限于)它们下述方法。
在下列的合成顺序任一者期间,可能需要及/或希望保护相关分子任一者上的敏感性或反应性基团。这可利用常规保护基实现,诸如它们在T.W.Greene,ProtectiveGroups in Organic Chemistry,John Wiley&Sons,1981;T.W.Greene和P.G.M.Wuts,Protective Groups in Organic Chemistry,John Wiley&Sons,1991;及T.W.Greene和P.G.M.Wuts,Protective Groups in Organic Chemistry,John Wiley&Sons,1999:及T.W.Greene和P.G.M.Wuts,Protective Groups in Organic Chemistry,John Wiley&Sons,2007中所述者,它们特此以引用方式并入。
本发明化合物或所述化合物或互变异构体及放射性同位素的药学上可接受的盐类可根据下文所讨论的反应流程制备。除非另有其他指明,否则流程中的取代基系如上述所定义。产物的分离及纯化系藉由一般技术的化学技术人员已知的标准步骤达成。
本领域技术人员应认知在许多情况下,流程1至11中的化合物将以非对映异构体及/或对映异构体的混合物产生;这些在合成流程的各种阶段可使用常规技术或所述技术的组合(诸如但不限制于结晶、正相层析、反相层析和手性层析)分离以提供本发明的单一对映异构体。
本领域技术人员应了解在流程、方法以及实例中所使用的各种符号、上标和下标是为了方便呈现及/或反映所述在流程中引入的顺序而使用,并不意欲必须对应于所附权利要求书中的符号、上标或下标。流程为可用于合成本发明化合物的方法的代表。它们不以任何方式限制本发明的范围。
以下流程图1说明一种制备如上所述的式I化合物的一合成顺序,其中A为稠合含氧杂环烷基、稠合苯基或稠合杂芳基环;及哌嗪基环为饱和(C6和C7之间的键为单键)。
在合成的初始步骤中,如所述,利用式1的杂环作为起始材料。式1的杂环经由烷基卤化物在碱作为质子清除剂的存在下或经由烷基醇在Mitsunobu条件下进行烷基化。在烷基化步骤期间,Z表示适当离去基团,式2的R3a、R3b、R4a、R4b取代基及n应表示终产物中所要的相同部分或其经保护的变形。例如,实施例2的终产物可利用反应流程图1制备,其中式2的R3a、R3b、R4a、及R4b取代基系各自以氢表示及n为1。
该顺序的下一个步骤为式II的卤化物与式3的胺在碱作为质子清除剂的存在下、于从室温至60℃的温度下的SN2置换,以提供式III的胺。在SN2反应步骤期间,在式3的胺亲核剂上的R2取代基应以与终产物中所要相同的部分表示。例如,实施例2的终产物可利用反应流程图1制备,其中式3的胺亲核剂的R2系以环丙基胺表示。
在下一步骤中,式IV的三环系统可在各种条件(诸如在乙腈中(ACN)的K2CO3、在MeOH中的Mg(OMe)2、或在MeOH中的CaCl2,于从室温至80℃的温度下)经由分子间胺加成至式III的乙酯而形成。
在流程图1的最后步骤中,式IV化合物转化成式I化合物可经由亲电子溴化接着Suzuki偶合而完成。所得溴化物与式4的硼酸在碱、金属催化剂(Pd、Ni、Cu)、膦配位基的存在下、于从室温至100℃的温度下进行Suzuki偶合,以提供所要环系统式I(参见de Vries,J.G.Topics in Organometallic Chemistry 2012,42,pg 12-20参考文献和其中所含的参考文献)。在Suzuki偶合期间,式4的硼酸的R1取代基应以与终产物中所要相同的部分或其经保护的变形表示。例如,上述实施例2的终产物可利用反应流程图1制备,其中式4的硼酸的R1系以4-氯苯基表示。
流程图1
以下流程图2描述制备式I化合物的替代合成顺序,其中A为稠合含氧杂环烷基、稠合苯基或稠合杂芳基环;及哌嗪基环为饱和(C6和C7之间的键为单键)。
合成中的初始步骤,如所述,利用式1的杂环作为起始材料。式1的杂环进行亲电溴化,接着与式4的硼酸在碱、金属催化剂(Pd、Ni、Cu)、膦配位基的存在下、于从室温至100℃的温度下的Suzuki偶合以提供式V化合物。在偶合期间,式4的硼酸的R1取代基应表示以与终产物中所要相同的部分或其经保护的变形。
Suzuki偶合步骤之后,式VI化合物可经由与式5的硅醚官能化的烷基卤化物在标准条件下的烷基化制备。在烷基化步骤期间,式5的R3a、R3b、R4a、及R4b取代基及n应以与终产物中所要相同的部分或其经保护的变形表示。
在下一步骤中,式VII的内酯可藉由甲硅烷基去保护和接着式VI化合物在酸性条件下、于从室温至100℃的温度下的内酯形成而产生。
烷基化步骤之后,式VIII化合物可藉由在胺与式3的存在下将内酯还原至半缩醛而产生。在加成期间,式3的胺的R2取代基应以与终产物中所要相同的部分或其经保护的变形表示。
在流程图2的最后步骤中,式VIII化合物转化成式I化合物可在标准Mitsunobu条件下完成(参见Mitsunobu,O.Synthesis 1981 1,pg1-28参考文献和其中所含的参考文献)。
流程图2
以下流程图3描述制备式I化合物的替代合成顺序,其中A为稠合含氧杂环烷基、稠合苯基或稠合杂芳基环;及哌嗪基环为饱和(C6和C7之间的键为单键)。
在合成的初始步骤中,如所述,利用式V化合物作为起始材料。式V化合物可通过各种条件进行直接转化成所要的酰胺;其一些描述于流程图1中的式IV的合成。或者,以式V描述的化合物可在酸性或碱性条件下、于从室温至80℃的温度下进行皂化以产生羧酸,其然后可在酰胺偶合或脱水剂(诸如2,4,6-三丙基-1,3,5,2,4,6-三氧杂三磷烷2,4,6-三氧化物(T3P)、六氟磷酸O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲(HATU)、二环己基碳化二亚胺(DCC)等等)存在下、于-20℃至100℃范围内的温度下与式3的胺偶合。在偶合期间,式3的胺的R2取代基应以与终产物中所要相同的部分或其经保护的变形表示。
在流程图3的最后步骤中,式IX化合物可藉由式6的经取代的双卤化物在碱的存在下、在100℃的温度下烷基化,以产生式I化合物。在烷基化步骤期间,式6的R3a、R3b、R4a、及R4b取代基及n应以与终产物中所要相同的部分或其经保护的变形表示。
流程图3
以下流程图4描述制备式Ia1化合物(其为式I的子集)的可能合成顺序,其中A为稠合吡啶基环;及哌嗪基环为饱和(C6和C7之间的键为单键)。
合成中的初始步骤,如所述,利用式7的2,3-二溴吡啶作为起始材料。式7的2,3-二溴吡啶在锂源诸如TMSCH2Li和LiDMEA的存在下于2位置进行金属-卤素交换,接着将所得阴离子加成至亲电子剂诸如式8的醛,以提供式X的醇。在阴离子加成至亲电子剂的步骤期间,式8的醛的R1取代基应以与终产物中所要相同的部分或其经保护的变形表示。
在下一步骤中,式XI化合物可藉由式X的醇以标准氧化条件诸如MnO2、Swern氧化、或戴斯-马丁高碘烷(Dess-Martin periodinane)而氧化产生。
在流程图4的最后步骤中,式XI化合物转化成式Ia1化合物系藉由金属催化的偶合进行。式XI与式9的经取代的哌嗪-2-酮在碱、金属催化剂(Pd、Ni、Cu)、膦配位基的存在下,于从室温至100℃的温度下进行金属-介导的Buchwald-Hartwig型偶合以提供式Ia1(参见Buchwald,S.L.等人,Current Organic Synthesis 2011,8(1),pg53-78参考文献和其中所含的参考文献)。在金属介导的偶合期间,式9的哌嗪-2-酮的R2、R3a、R3b、R4a、及R4b取代基及n应以与终产物中所要相同的部分或其经保护的变形表示。
流程图4
以下流程图5描述制备式Ia1化合物(其为式I的子集)的替代合成顺序,其中A为稠合吡啶基环;及哌嗪基环为饱和(C6和C7之间的键为单键)。
合成中的初始步骤,如所述,利用式10的2-溴-3-卤吡啶作为起始材料。式10的2-溴-3-卤吡啶与式9的经取代的哌嗪-2-酮在碱、金属催化剂(Pd、Ni、Cu)、膦配位基的存在下、于从室温至100℃的温度下进行金属催化的偶合以提供式XII化合物。在此转变期间,X以适当离去基团表示,式9的哌嗪-2-酮的R2、R3a、R3b、R4a、及R4b取代基及n应以与终产物中所要相同的部分或其经保护的变形表示。
在下一个步骤中,式XIII化合物可藉由添加氯磷酸二乙酯在碱的存在下、于在从0至-78℃的温度下而从式XII化合物制备。
在下一个步骤中,式XIV化合物可利用Horner-Wadsworth-Emmons反应(参见Maryanoff,B.E.等人Chemical Review 1989,89,pg863-927参考文献和其中所含的参考文献)藉由式XIII化合物和式8的醛的缩合而产生。在Horner-Wadsworth-Emmons反应期间,式8的醛的R1取代基应以与终产物中所要相同的部分或其经保护的变形表示。
在流程图5的最后步骤中,式Ia1化合物可经由式XIV化合物在碱、金属催化剂、膦配位基的存在下、于从50至100℃的温度下的分子内Heck反应制备(参见Vries,J.G.Topicsin Organometallic Chemistry 2012,42,pg3-11参考文献和其中所含的参考文献)。
流程图5
流程圖5
以下流程图6描述式Ia2(其为式I的子集)化合物的合成顺序,其中A为“逆”稠合吡啶环;及哌嗪基环为饱和(C6和C7之间的键为单键)。
合成中的初始步骤,如所述,利用式7的2,3-二溴嘧啶作为起始材料。式7的2,3-二溴嘧啶进行金属交换,接着对应阴离子加至式8的醛,以提供式XV的醇(参见Trécourt,FTetrahedron 2000,56(10),1349-1360)。在阴离子加成期间,式8的醛的R1取代基应以与终产物中所要相同的部分或其经保护的变形表示。
在下一步骤中,式XVI化合物可藉由式XV的醇在室温下的氧化产生。
在流程图6的最后步骤中,式XVI化合物转化成式Ia2化合物藉由金属催化的偶合反应发生。式XVI与式9的哌嗪-2-酮在碱、金属催化剂(Pd、Ni、Cu)、膦配位基的存在下、于从室温至100℃的温度下进行金属偶合以提供式Ia2。在金属偶合期间,式9的哌嗪-2-酮的R2、R3a、R3b、R4a、及R4b取代基及n应以与终产物中所要相同的部分或其经保护的变形表示。
流程图6
流程圖6
流程图7描述制备式I化合物的合成顺序,其中A为稠合含氧杂环烷基、苯基或杂芳基环;哌嗪基环为饱和或不饱和(C6和C7之间的键为单键或双键);当C6和C7之间的键为单键时,R3a、R3b、R4a、及R4b为氢和n为;当C6和C7之间的键为双键时,或R3a和R4a为氢、R3b和R4b不存在和n为0。
合成中的初始步骤,如所述,利用式V化合物作为起始材料。式V化合物与烯丙基醇经由Mitsunobu条件(参见:Current Organic Chemistry(2009),13(16),1610-1632)或与烯丙基卤化物经由SN2条件进行烷基化以提供式XVII的烯丙基吡咯并吡啶。在烷基化步骤期间式V的R1取代基应以与终产物中所要相同的部分或其经保护的变形表示。
在下一步骤中,式XVIII化合物可在氧化条件诸如OsO4下,从式XVII产生。
在烯的氧化之后,式XIX化合物可藉由利用试剂诸如NaIO4等等的二醇的氧化裂解来制备,以提供式XVIII化合物。
在下一步骤中,式XX化合物可藉由在还原胺化条件下、于从室温至80℃的温度下组合式XIX的化合物和式3的胺而产生。在还原胺化期间,式3的胺的R2取代基应以与终产物中所要相同的部分或其经保护的变形表示。
在流程图7的最后步骤中,式XX化合物转化成式I化合物的混合物可藉由在极性质子溶剂用刘易斯酸处理来完成。式I化合物(饱和及不饱和)然后可藉由层析方法分离。
流程图7
以下流程图8描述制备式I化合物的替代合成顺序(其中A为稠合含氧杂环烷基、稠合苯基或稠合杂芳基环;哌嗪基环为不饱和;R3b和R4b不存在;及n为0。
合成中的初始步骤,如所述,利用式XVII的化合物(流程图7)作为起始材料。式XVII化合物藉由在刘易斯酸的存在下以适当胺处理酯的直接转化或在酸性或碱性条件的皂化的二-步骤方法进行酰胺形成以提供羧酸,其可在酰胺偶合或脱水剂(诸如2,4,6-三丙基-1,3,5,2,4,6-三氧杂三磷烷2,4,6-三氧化物(T3P)、六氟磷酸O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲(HATU)、二环己基碳化二亚胺(DCC)等等)存在下、于-20℃至100℃范围内的温度下与式3的胺混合以产生式XXI化合物。在偶合期间,式XVII的R1、R3a、及R4a取代基及式3的胺的R2取代基应以与终产物中所要相同的部分或其经保护的变形表示。
酰胺偶合步骤之后,式XXII化合物可藉由式XXI化合物的烯部分的氧化裂解制备。
在流程图8的最后步骤中,式I化合物可藉由在酸性条件下对式XXII化合物的脱水以产生式I化合物来完成。
流程图8
以下流程图9描述式Ib(其为式I的另一子集)的稠合酰胺的合成,其中A为稠合含氧杂环烷基、稠合苯基或稠合杂芳基环;R2和R3a与它们所连接的氮一起形成(4至6元)杂环烷环;R4a为氢;哌嗪基环为饱和;及Y可为-CH2-、-CH2-CH2-、-CH2-CH2-CH2-或-CH2-CH2-O-)。合成中的初始步骤,如所述,利用式1化合物作为起始材料。式1化合物与式11的醇在标准Mitsunobu条件下进行烷基化以提供式XXIII化合物。在Mitsunobu步骤期间,式11的醇上的Y取代基应以与终产物或其产物中所要相同的部分表示。
接下来,将式XXIII化合物在酸性条件下去保护,接着Mg(OMe)2摧化的分子内胺成加至乙酯以提供式XXIV的稠合酰胺。
在流程图9的最后步骤中,式XXIV化合物转化成式Ib化合物可经由亲电子溴化接着Suzuki偶合来完成。式XXIV化合物进行亲电子溴化以提供芳基/杂芳基溴化物,其与式4的硼酸在碱、金属催化剂(Pd、Ni、Cu)、膦配位基的存在下、于从室温至100℃的温度下进行Suzuki偶合以提供所要环系统式Ib。在Suzuki偶合期间,式4的硼酸的R1取代基应以与终产物中所要相同的部分或其经保护的变形表示。
流程图9
以下流程图10描述用于制备式Ic化合物(其为式I的另一子集)的合成顺序,其中A为稠合含氧杂环烷基、稠合苯基或稠合杂芳基环;及哌嗪基环为饱和(C6和C7之间的键为单键)。从式XXV化合物开始,其可经由流程图1-3制备,式XXV化合物的硝基在碱(诸如,K2CO3或KOAc)的存在下经[18F]氟阴离子的置换提供式Ic化合物。
流程图10
以下流程图11描述制备式Ia5化合物(其为式I的另一子集)的可能合成顺序,其中A为稠合四氢哌喃环;及哌嗪基环为饱和。合成中的初始步骤,如所述,利用式12的1H-吡咯-2-甲酸甲酯作为起始材料。式12的1H-吡咯-2-甲酸甲酯经由式2的烷基卤化物在碱作为质子清除剂的存在下或经由烷基醇在Mitsunobu条件下进行烷基化以形成式XXVI化合物。在烷基化步骤期间,Z系以适当离去基团表示,式2的R3a、R3b、R4a、及R4b取代基及n应以与终产物中所要相同的部分或其经保护的变形表示。该顺序的下一个步骤为卤化物与胺在碱作为质子清除剂的存在下、于从室温至60℃的温度下的SN2置换,以提供式XXVII的胺。在SN2反应步骤期间,式3的胺亲核剂上的R2取代基应以与终产物中所要相同的部分表示。
在下一步骤中,式XXVIII的内酰胺可在各种条件(诸如在乙腈(ACN)中的K2CO3、在MeOH中的Mg(OMe)2、或在MeOH中的CaCl2、于从室温至80℃的温度下)经由分子间胺加成至所述甲基酯而形成。
在流程图11的下一个步骤中,式XXIX化合物可经由式XXVIII化合物在POCl3和N,N-二甲基甲酰胺的存在下的甲酰化而制备。
甲酰化步骤之后,式XXX化合物可利用对式XXIX化合物的Horner-Wadsworth-Emmons或Wittig反应,接着所得烯在金属催化剂(Pd、Pt等等)和氢的存在下的还原而制备。
在下一步骤中,式XXXI化合物可经由亲电子溴化(诸如NBS或Br2),接着酯与金属氢化物(LiBH4、LiAlH4等等)的还原而完成。
接下来,利用在碱、金属催化剂(Cu、Pt)的存在下、于从100至120℃的温度下的式XXXI化合物的分子内死循环制备式XXXII化合物。
在中流程图11的最后步骤,式XXXII化合物转化成式Ia5化合物可经由亲电子溴化(NBS或Br2)接着Suzuki偶合而完成。式XXXII化合物进行亲电子溴化以提供杂芳基溴化物,其与式4的硼酸在碱、金属催化剂(Pd、Ni、Cu)、膦配位基的存在下,于从室温至100℃的温度下进行Suzuki偶合以提供所要环系统式Ia5(参见de Vries,J.G.Topics inOrganometallic Chemistry 2012,42,pg 12-20参考文献和其中所含的参考文献)。在Suzuki偶合期间,式4的硼酸的R1取代基应以与终产物中所要相同的部分或其经保护的变形表示。
流程图11
以下流程图P1描述制备式P1化合物的合成顺序,其中U可为碳或氮。式P1化合物的合成为用于制备如上述流程图1、2和9中所述的式1化合物的合成顺序。合成中的初始步骤,如所述,利用式13的杂环作为起始材料。式13的杂环与2-氧代丙酸酯式14在催化量的酸的存在下进行缩合以提供式XXXIII化合物(参见Trécourt,F Tetrahedron 2000,56(10),1349-1360)。
在下一步骤中,式P1化合物可经由式XXXIII化合物在碱、金属催化剂的存在下、于从100℃至140℃的温度下的分子内Heck反应产生。
流程图P1
以下流程图P2描述制备式P2化合物的合成顺序。式P2化合物的合成为用于制备如上述流程图1、2和9中所述的式1化合物的另一合成顺序。合成中的初始步骤,如所述,利用式15的杂环作为起始材料。式15的杂环与式16的2-叠氮基乙酸乙酯在碱的存在下进行缩合以提供式XXXIV化合物。
在下一步骤中,式P2化合物可经由式XXXIV化合物于从100℃至140℃的温度下的环化反应产生。
流程图P2
实验步骤和实施例
下列说明本发明各种化合物的合成。在本发明范围内的其他化合物可使用这些实例中所说明的方法单独或与该项技术中一般已知的技术组合使用来制备。
通常在惰性氛围(氮气或氩气)下进行实验,特别是在使用氧气或水分敏感性试剂或中间体时。市售溶剂及试剂通常不经进一步纯化即使用。在适当时使用无水溶剂,通常为来自Acros Organics的产品或来自EMD Chemicals的产品。在其他情况下,使市售溶剂系通过用分子筛填充的柱直至达到下列水的QC标准为止:a)就二氯甲烷、甲苯、N,N-二甲基甲酰胺及四氢呋喃而言<100ppm;b)就甲醇、乙醇、1,4-二烷及二异丙胺而言<180ppm。对于极敏感性反应,用金属钠、氢化钙或分子筛进一步处理溶剂且在使用前夕蒸馏。产物在进行其他反应或提交以供生物测试的前通常在真空下干燥。由液相层析-质谱分析(LCMS)、大气压化学电离(APCI)或气相层析-质谱分析(GCMS)仪器报导质谱数据。核磁共振(NMR)数据的化学位移系参考来自所用的氘化溶剂的残余峰而以百万分率(ppm,δ)表示。在一些实施例中,进行手性分离以分离某些本发明化合物的对映异构体或阻转异构体(或阻转对映异构体(atropenantiomer))(在一些实施例中,所分离的阻转异构体根据其洗脱次序指定为ENT-1及ENT-2)。在一些实施例中,使用偏光计量测对映异构体或阻转异构体的旋光度。根据其所观察的旋转数据(或其特定旋转数据),具有顺时针旋转的对映异构体或阻转异构体(或阻转对映异构体)指定为(+)-对映异构体或(+)-阻转异构体[或(+)阻转对映异构体]和具有逆时针旋转的对映异构体或阻转异构体(或阻转对映异构体)指定为(-)-对映异构体或(-)-阻转异构体[或(-)阻转对映异构体]。
在经由可检测中间体进行的反应通常接着进行LCMS,且使进行至完全转化,随后添加后续试剂。对于参考其他实例或方法中的合成程序,反应条件(反应时间及温度)可改变。一般而言,反应接着薄层层析或质谱,且适当时进行后处理。实验之间的纯化可改变:通常,选择用于洗脱液/梯度的溶剂及溶剂比率以提供适当Rf或保留时间。
实施例1
10-(4-氯苯基)-8-(嘧啶-2-基)-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮(1)
步骤1. 3-溴-1H-吡咯并[3,2-b]吡啶-2-甲酸乙酯(C1)的合成。
将N-溴丁二酰亚胺(15.4g,86.5mmol)加至1H-吡咯并[3,2-b]吡啶-2-甲酸乙酯(15.0g,78.9mmol)在二氯甲烷(150mL)中的0℃溶液,并将反应混合物在室温下搅拌16小时。添加二氯甲烷(150mL)和水(200mL)之后,以二氯甲烷(3×150mL)萃取水层。将合并的有机层用饱和氯化钠水溶液(5×50mL)洗涤,经硫酸钠干燥,过滤,和在真空中浓缩。硅胶层析(梯度:在石油醚中的0%至50%乙酸乙酯)提供呈黄色固体的产物。产量:13g,48mmol,61%。1H NMR(400MHz,CDCl3)δ9.94(br s,1H),8.65(dd,J=4.5,1.1Hz,1H),7.78(dd,J=8.4,1.0Hz,1H),7.31(dd,J=8.4,4.5Hz,1H),4.49(q,J=7.1Hz,2H),1.45(t,J=7.1Hz,3H)。
步骤2. 3-(4-氯苯基)-1H-吡咯并[3,2-b]吡啶-2-甲酸乙酯(C2)的合成。
此实验进行5次。将[1,1’-双(二苯膦基)二茂铁]二氯钯(II)(146mg,200μmol)加至C1(1.08g,4.01mmol)、(4-氯苯基)硼酸(936mg,5.99mmol)和碳酸钠(1.27g,12.0mmol)在1,4-二烷(20mL)和水(2mL)中的混合物。将反应混合物在100℃下搅拌18小时,及然后在真空中浓缩。加水(30mL),并将混合物用乙酸乙酯(3×30mL)萃取。将合并的有机层用饱和氯化钠水溶液洗涤(3×20mL),经硫酸钠干燥,过滤,在减压下浓缩,及藉由硅胶层析纯化(梯度:在石油醚中的0%至30%乙酸乙酯)以提供呈黄色固体的产物。总产量:5.2g,17mmol,85%。1H NMR(400MHz,CDCl3)δ9.25(br s,1H),8.62(dd,J=4.5,1.4Hz,1H),7.78(dd,J=8.3,1.3Hz,1H),7.66(br d,J=8.7Hz,2H),7.43(br d,J=8.5Hz,2H),7.30(dd,J=8.3,4.5Hz,1H),4.36(q,J=7.2Hz,2H),1.29(t,J=7.2Hz,3H)。
步骤3. 1-(2-{[叔丁基(二甲基)甲硅烷基]氧基}乙基)-3-(4-氯苯基)-1H-吡咯并[3,2-b]吡啶-2-甲酸乙酯的合成(C3)。
将氢化钠(在矿物油中的60%,1.4g,35mmol)和N,N-二甲基甲酰胺(30mL)的混合物冷却至0℃并以滴加方式用C2(7.00g,23.3mmol)在N,N-二甲基甲酰胺(40mL)中的溶液处理。将此在室温下搅拌1小时,然后冷却至0℃。添加(2-溴乙氧基)(叔丁基)二甲基硅烷(11.2g,46.8mmol)之后,使反应混合物在室温下搅拌16小时,且然后用水(150mL)淬灭。将混合物用乙酸乙酯(3×150mL)萃取,及将合并的有机层用饱和氯化钠水溶液(5×50mL)洗涤,经硫酸钠干燥,过滤,和在真空中浓缩。硅胶层析(梯度:在石油醚中的0%至10%乙酸乙酯)提供呈黄色油状物的产物。产量:6.8g,15mmol,64%。1H NMR(400MHz,CDCl3)δ8.57(dd,J=4.4,1.4Hz,1H),7.86(dd,J=8.5,1.4Hz,1H),7.45(br AB四重峰,JAB=8.6Hz,ΔνAB=22.3Hz,4H),7.26(dd,J=8.4,4.5,1H,假设;部分被溶剂峰遮蔽),4.65-4.71(m,2H),4.23(q,J=7.2Hz,2H),3.98-4.03(m,2H),1.12(t,J=7.1Hz,3H),0.73(s,9H),-0.20(s,6H)。
将C3(6.5g,14mmol)在6M盐酸水溶液(78mL)和四氢呋喃(156mL)中的溶液在70℃下加热3小时。在真空中移除四氢呋喃之后,将含水残余物缓慢倒入饱和碳酸氢钠水溶液及用二氯甲烷(3×100mL)萃取。将合并的有机层用饱和氯化钠水溶液(2×50mL)洗涤,经硫酸钠干燥,过滤,在减压下浓缩,及藉由硅胶层析(梯度:在石油醚中的0%至70%乙酸乙酯)纯化,提供呈白色固体的产物。产量:3.23g,10.8mmol,77%。1H NMR(400MHz,CDCl3)δ8.69(dd,J=4.5,1.3Hz,1H),7.81(br d,J=8.7Hz,2H),7.75(dd,J=8.5,1.3Hz,1H),7.47(br d,J=8.7Hz,2H),7.39(dd,J=8.5,4.5Hz,1H),4.79-4.84(m,2H),4.40-4.45(m,2H)。
步骤5. 3-(4-氯苯基)-1-(2-羟乙基)-N-(嘧啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-甲酰胺(C5)的合成。
在室温下以三部分经2分钟将双(三甲基铝)-1,4-二氮杂双环[2.2.2]辛烷加合物(97%,202mg,0.764mmol)加至嘧啶-2-胺(72.7mg,0.764mmol)在四氢呋喃(9mL)中的溶液。将此混合物搅拌5分钟,及然后以一次全部用C4(114mg,0.382mmol)处理。将反应混合物在70℃下加热20小时且然后冷却到室温;此时,添加另外嘧啶-2-胺(35mg,0.37mmol)和双(三甲基铝)-1,4-二氮杂双环[2.2.2]辛烷加合物(97%,100mg,0.38mmol)混合物,其已在四氢呋喃(2mL)中搅拌5分钟,及将反应混合物在70℃下加热另外3.5小时。其已冷却至周围温度之后,将反应混合物用1M氢氧化钠水溶液处理直到其为强碱性;将此混合物用萃取二氯甲烷三次。用1M盐酸水溶液将水相酸化至大约5-6的pH,和随后用二氯甲烷萃取三次。将来自酸性萃取的合并有机层经硫酸镁干燥,过滤,和在真空中浓缩以提供呈灰白色固体的产物。产量:119mg,0.302mmol,79%。LCMS m/z 394.1,396.2[M+H]+。1H NMR(400MHz,CDCl3)δ8.62(dd,J=4.5,1.4Hz,1H),8.51(br d,J=4.8Hz,2H),8.32(br s,1H),7.86(dd,J=8.5,1.4Hz,1H),7.57(br d,J=8.5Hz,2H),7.42(br d,J=8.6Hz,2H),7.32(dd,J=8.5,4.5Hz,1H),7.02(t,J=4.9Hz,1H),4.68-4.73(m,2H),4.08-4.14(m,2H)。
步骤6. 10-(4-氯苯基)-8-(嘧啶-2-基)-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮(1)的合成。
将偶氮二羧酸二异丙酯(0.147mL,0.742mmol)和受载于聚合物的三苯膦(1.6mmol/g,464mg,0.742mmol)加至C5(117mg,0.297mmol)在四氢呋喃(2mL)中的溶液。反应混合物在室温下已搅拌1.5小时之后,将其用乙酸乙酯稀释,及使上清液通过装有过滤器的抛弃式注射器。将滤液用水洗涤,经硫酸镁干燥,和在真空中浓缩。硅胶层析(梯度:在二氯甲烷中的0%至4%甲醇)提供呈白色泡沫的产物。产量:99mg,0.26mmol,88%。LCMS m/z 376.1,378.1[M+H]+。1H NMR(400MHz,CDCl3)δ8.76(d,J=4.8Hz,2H),8.66(dd,J=4.4,1.4Hz,1H),7.74-7.79(m,3H),7.41(br d,J=8.8Hz,2H),7.36(dd,J=8.4,4.5Hz,1H),7.15(t,J=4.8Hz,1H),4.57-4.62(m,2H),4.49-4.54(m,2H)。
实施例2
10-(4-氯苯基)-8-环丙基-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮(2)
步骤1. 1-(2-溴乙基)-1H-吡咯并[3,2-b]吡啶-2-甲酸乙酯(C6)的合成。
将1H-吡咯并[3,2-b]吡啶-2-甲酸乙酯(23g,0.12mol)、2-溴乙醇(37.9g,0.303mol)和三苯膦(79.4g,0.303mol)在四氢呋喃中的溶液冷却至0℃。经20分钟滴加偶氮二羧酸二异丙酯(61.2g,0.303mol)并将所得混合物加温至25℃及搅拌18小时。已在减压下除去溶剂之后,将残余物用乙酸乙酯(300mL)稀释并用盐酸水溶液(1M,3×100mL)萃取。使用饱和碳酸钠水溶液将合并的含水萃取液碱化至pH 8-9,并将所得混合物用乙酸乙酯(3×100mL)萃取。将合并的有机层在真空中浓缩;硅胶层析(洗脱液:5:1石油醚/乙酸乙酯)提供呈白色固体的产物。产量:25g,84mmol,70%。1H NMR(400MHz,CDCl3)δ8.59(dd,J=4.5,1.3Hz,1H),7.81(br d,J=8.5Hz,1H),7.50(br s,1H),7.28(dd,J=8.5,4.5Hz,1H),4.92(t,J=6.7Hz,2H),4.42(q,J=7.2Hz,2H),3.73(t,J=6.7Hz,2H),1.44(t,J=7.2Hz,3H)。
步骤2. 1-[2-(环丙氨基)乙基]-1H-吡咯并[3,2-b]吡啶-2-甲酸乙酯(C7)的合成。
将碳酸钾(17.4g,0.126mol),接着环丙胺(192g,3.36mol)加至C6(25g,84mmol)在乙腈(400mL)中的溶液。将反应混合物在60℃下搅拌16小时,随的将其过滤及然后在减压下浓缩,以提供呈黄色半固体的产物(23g)。藉由LCMS分析,存在二种所欲的产物C7(m/z273.9[M+H]+)和C8,得自分子内环化的三环化合物(m/z 227.8[M+H]+)。此材料不经进一步纯化而用于下列步骤。
步骤3. 8-环丙基-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮(C8)的合成。
将甲氧化镁(7.26g,84.1mmol)加至C7(来自前步骤,23g,≤84mmol)在甲醇(350mL)中的溶液。反应混合物已在80℃下搅拌1小时之后,经由过滤除去固体及将滤液在减压下浓缩。经由硅胶层析(洗脱液:1:1石油醚/乙酸乙酯)的纯化提供呈白色固体的产物。产量:18.5g,81.4mmol,97%经过2步骤。1H NMR(400MHz,CDCl3)δ8.51(dd,J=4.5,1.3Hz,1H),7.59(br d,J=8.5Hz,1H),7.40(br s,1H),7.19(dd,J=8.5,4.5Hz,1H),4.18-4.23(m,2H),3.80-3.85(m,2H),2.81-2.88(m,1H),0.93-0.99(m,2H),0.74-0.80(m,2H)。
步骤4. 10-溴-8-环丙基-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮(C9)的合成。
将N-溴丁二酰亚胺(17.4g,97.8mmol)加至C8(18.5g,81.4mmol)在二氯甲烷(400mL)中的溶液,及将反应混合物在25℃下搅拌1小时。然后将其在减压下浓缩,冷却,并用饱和硫代硫酸钠水溶液(100mL)处理。将混合物用二氯甲烷(3×100mL)萃取,并将合并的有机层干燥,过滤,和在真空中浓缩。硅胶层析(洗脱液:20:1二氯甲烷/甲醇)提供呈淡黄色固体的产物。产量:17.9g,58.5mmol,72%。LCMS m/z 307.9[M+H]+。1H NMR(400MHz,CDCl3)δ8.61(br d,J=4.5Hz,1H),7.63(br d,J=8.4Hz,1H),7.29(dd,J=8.4,4.5Hz,1H,假设;部分被溶剂峰遮蔽),4.23-4.28(m,2H),3.82-3.87(m,2H),2.82-2.89(m,1H),0.95-1.02(m,2H),0.77-0.83(m,2H)。
步骤5. 10-(4-氯苯基)-8-环丙基-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮(2)的合成。
将此反应进行四次。将双(三-叔丁膦)钯(0)(83mg,0.16mmol)加至C9(500mg,1.63mmol)、(4-氯苯基)硼酸(509mg,3.26mmol)、1,4-二烷(15mL)、及碳酸钠(864g,8.15mmol,呈在水中的3M溶液)的混合物。将反应混合物在90℃下搅拌16小时,然后用水(50mL)和乙酸乙酯(50mL)稀释。用乙酸乙酯(3×30mL)萃取水层之后,将合并的有机层用饱和氯化钠水溶液洗涤,经硫酸钠干燥,过滤,和在真空中浓缩。合并的粗制产物经由硅胶层析(梯度:在石油醚中的0%至100%乙酸乙酯)的纯化提供呈黄色固体的产物。产量:870mg,2.58mmol,39%。LCMS m/z 337.8[M+H]+。1H NMR(400MHz,CDCl3)δ8.60(dd,J=4.5,1.4Hz,1H),7.76(br d,J=8.5Hz,2H),7.67(dd,J=8.4,1.4Hz,1H),7.43(br d,J=8.4Hz,2H),7.29(dd,J=8.4,4.5Hz,1H),4.27-4.32(m,2H),3.86-3.92(m,2H),2.81-2.87(m,1H),0.92-0.99(m,2H),0.73-0.80(m,2H)。
实施例2的替代合成
10-(4-氯苯基)-8-环丙基-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮(2)
步骤1. 3-(4-氯苯基)-1H-吡咯并[3,2-b]吡啶-2-甲酸(C10)的合成。
将C2(300mg,1.0mmol)和氢氧化锂单水合物(126mg,3.00mmol)在乙醇(10mL)和水(1mL)中的混合物在室温下搅拌3小时。将反应混合物用水稀释并用盐酸水溶液酸化至小于5的pH。在真空中移除乙醇,接着冷冻干燥,提供呈黄色固体的产物。产量:300mg,假设定量。
步骤2. 3-(4-氯苯基)-N-环丙基-1H-吡咯并[3,2-b]吡啶-2-甲酰胺(C11)的合成。
将N,N-二异丙基乙胺(0.40mL,2.3mmol)加至C10(200mg,0.73mmol)和O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸盐(HATU,555mg,1.46mmol)在N,N-二甲基甲酰胺(6mL)中的溶液,并将所得混合物在室温下搅拌10分钟。添加环丙胺(63mg,1.1mmol),及将反应混合物在室温下搅拌3小时,然后用水稀释并用乙酸乙酯(4×25mL)萃取。将合并的有机层在真空中浓缩及藉由高效液相层析(HPLC)(柱:DIKMA Diamonsil(2)C18,5μm;流动相A:在水中的0.225%甲酸;流动相B:乙腈;梯度:10%至30%B)纯化以提供呈白色固体的产物。产量:20mg,64μmol,9%。LCMS m/z 311.9[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.26(br s,1H),8.48(d,J=4.3Hz,1H),8.32(br d,J=3.8Hz,1H),7.95-8.02(m,1H),7.75(d,J=8.3Hz,2H),7.50(d,J=8.5Hz,2H),7.32-7.39(m,1H),2.78-2.87(m,1H),0.66-0.73(m,2H),0.44-0.50(m,2H)。
步骤3. 10-(4-氯苯基)-8-环丙基-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮(2)的合成。
将C11(25mg,80μmol)、碳酸钾(98mg,0.71mmol)和1,2-二溴乙烷(0.5mL)在乙腈(2.5mL)中的溶液在100℃下搅拌4小时。过滤混合物之后,将滤液在减压下浓缩并藉由反相HPLC(柱:Kromasil Eternity-5-C18,5μm;流动相A:在水中的0.225%甲酸;流动相B:乙腈;梯度:15%至35%B)纯化以提供呈黄色固体的产物。产量:9.9mg,29μmol,36%。LCMS m/z338.0[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.48(br d,J=4.3Hz,1H),8.06(br d,J=8.3Hz,1H),7.77(br d,J=8.5Hz,2H),7.44(br d,J=8.8Hz,2H),7.36(dd,J=8.4,4.6Hz,1H),4.35-4.41(m,2H),3.78-3.83(m,2H),2.82-2.90(m,1H),0.71-0.83(m,4H)。
实施例3
(6aR)-12-(4-氯苯基)-6a,7,8,9-四氢-6H,11H-吡啶并[2',3':4,5]吡咯并[1,2-a]吡咯并[1,2-d]吡嗪-11-酮,三氟乙酸盐(3)
步骤1. 1-{[(2R)-1-(叔丁氧羰基)吡咯烷-2-基]甲基}-1H-吡咯并[3,2-b]吡啶-2-甲酸乙酯(C12)的合成。
将1H-吡咯并[3,2-b]吡啶-2-甲酸乙酯(200mg,1.05mmol)、(2R)-2-(羟甲基)吡咯烷-1-甲酸叔丁酯(529mg,2.63mmol)、及三苯膦(690mg,2.63mmol)溶解在四氢呋喃(200mL)中并冷却至0℃。经20分钟滴加偶氮二羧酸二异丙酯(0.521mL,2.63mmol),和使反应混合物加温至室温并搅拌18小时。在真空中移除溶剂,及经由硅胶层析(梯度:在庚烷中的0%至100%乙酸乙酯)的纯化提供仍含有污染物的产物(500mg)。将此材料直接用于下一步骤。LCMS m/z 374.3[M+H]+。
步骤2. 1-[(2R)-吡咯烷-2-基甲基]-1H-吡咯并[3,2-b]吡啶-2-甲酸乙酯(C13)的合成。
将C12(来自前面步骤,≤1.05mmol)在乙醚中的溶液用氯化氢在乙醚中的溶液(4M,5mL)处理,和使反应混合物搅拌3天。以LCMS分析反应混合物并发现主要由化合物C13组成:m/z 274.2[M+H]+。在真空中移除溶剂,及将残余物与水混合并用乙酸乙酯萃取。经由添加饱和碳酸钠水溶液将水层碱化且然后用乙酸乙酯(2×100mL)萃取。合并这两个有机层并经硫酸镁干燥,过滤,和在减压下浓缩以提供产物(90mg),其以NMR分析,基本上完全环化至C14,步骤3的产物。此物质仍然进行下列步骤。
步骤3. (6aR)-6a,7,8,9-四氢-6H,11H-吡啶并[2',3':4,5]吡咯并[1,2-a]吡咯并[1,2-d]吡嗪-11-酮(C14)的合成。
将来自前步骤的材料(90mg)与甲氧化镁在甲醇中的溶液(6-10%溶液,4mL)混合并将反应混合物加热至回流经18小时。在减压下蒸发溶剂之后添加水并用乙酸乙酯(2×100mL)萃取。将合并的有机层经硫酸镁干燥,过滤,和在真空中浓缩;硅胶层析(梯度:在二氯甲烷中的0%至10%甲醇)提供产物。产量:70mg,0.31mmol,30%经3个步骤。LCMS m/z228.1[M+H]+。1H NMR(400MHz,CD3OD)δ8.43(dd,J=4.6,1.3Hz,1H),8.00(ddd,J=8.5,1.2,1.1Hz,1H),7.36(dd,J=8.4,4.7Hz,1H),7.25(br s,1H),4.85(dd,J=12.1,4.5Hz,1H,假设;部分被水峰遮蔽),4.19-4.29(m,1H),3.87(dd,J=12.1,12.1Hz,1H),3.77-3.84(m,1H),3.60-3.69(m,1H),2.36-2.44(m,1H),2.17-2.25(m,1H),1.98-2.11(m,1H),1.87-1.98(m,1H)。
步骤4. (6aR)-12-溴-6a,7,8,9-四氢-6H,11H-吡啶并[2',3':4,5]吡咯并[1,2-a]吡咯并[1,2-d]吡嗪-11-酮(C15)的合成。
根据实施例1中C1的合成所述的方法将化合物C14转化成产物。在此情况下,用在二氯甲烷中的5%甲醇作为洗脱液进行层析纯化。产量:70mg,0.23mmol,58%。LCMS m/z306.0,308.0[M+H]+。1H NMR(400MHz,CD3OD)δ8.49(dd,J=4.6,1.3Hz,1H),8.02(dd,J=8.5,1.3Hz,1H),7.43(dd,J=8.5,4.6Hz,1H),4.87(dd,J=12.1,4.3Hz,1H),4.16-4.25(m,1H),3.88(dd,J=12.0,12.0Hz,1H),3.75-3.82(m,1H),3.59-3.68(m,1H),2.35-2.42(m,1H),2.16-2.25(m,1H),1.97-2.10(m,1H),1.86-1.97(m,1H)。
步骤5. (6aR)-12-(4-氯苯基)-6a,7,8,9-四氢-6H,11H-吡啶并[2',3':4,5]吡咯并[1,2-a]吡咯并[1,2-d]吡嗪-11-酮,三氟乙酸盐(3)的合成。
根据实施例1中C2的合成所述的一般方法将化合物C15转化成产物。在此情况下纯化系藉由反相HPLC(柱:Waters Sunfire C18,5μm;流动相A:在水中的0.05%三氟乙酸(v/v);流动相B:在乙腈中的0.05%三氟乙酸乙酸(v/v);梯度:10%至30%B)进行以提供产物。产量:33mg,73μmol,74%。LCMS m/z 338.0,340.0[M+H]+。1H NMR(600MHz,DMSO-d6)δ8.48(dd,J=4.4,1.4Hz,1H),8.04(br d,J=8.4Hz,1H),7.84(br d,J=8.6Hz,2H),7.44(br d,J=8.7Hz,2H),7.37(dd,J=8.4,4.4Hz,1H),4.89(dd,J=12.1,3.9Hz,1H),4.16-4.22(m,1H),3.87(dd,J=12.1,12.0Hz,1H),3.60-3.65(m,1H),3.46-3.52(m,1H),2.25-2.31(m,1H),2.03-2.10(m,1H),1.87-1.95(m,1H),1.78-1.87(m,1H)。
实施例4
4-(8-环丙基-9-氧代-6,7,8,9-四氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-10-基)-2-氟苯甲腈(4)
将[1,1’-双(二苯膦基)二茂铁]二氯钯(II)(242mg,0.331mmol)加至碳酸钠(1.04g,9.81mmol,呈在水中的3M溶液)、C9(1.0g,3.3mmol)、及(4-氰基-3-氟苯基)硼酸(592mg,3.59mmol)在1,4-二烷(30mL)中的混合物。将反应混合物在90℃下搅拌16小时,随的将其用水(30mL)和乙酸乙酯(30mL)稀释。以乙酸乙酯(3×30mL)萃取水层,并将合并的有机层用饱和氯化钠水溶液洗涤,经硫酸钠干燥,过滤,和在真空中浓缩。在硅胶上的层析纯化(梯度:在石油醚中的0%至75%乙酸乙酯,接着使用在庚烷中的80%乙酸乙酯作为洗脱液的第二柱)提供固体,将其在二乙基醚中浆化,搅拌30分钟,并经由过滤收集以提供呈白色固体的产物。产量:590mg,1.70mmol,52%。LCMS m/z 347.2[M+H]+。1H NMR(400MHz,CDCl3)δ8.62(br d,J=4.4Hz,1H),7.76-7.81(m,2H),7.73(br d,J=8.4Hz,1H),7.67(dd,J=7.9,7.0Hz,1H),7.34(dd,J=8.4,4.5Hz,1H),4.30-4.36(m,2H),3.90-3.95(m,2H),2.83-2.90(m,1H),0.96-1.02(m,2H),0.75-0.81(m,2H)。
实施例4a
4-(8-环丙基-9-氧代-6,7,8,9-四氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-10-基)-2-(18F)氟苯甲腈(4a)
步骤1. 2-硝基-4-(4,4,5,5-四甲基-1,3,2-氧杂环戊硼烷(dioxaborolan)-2-基)苯甲腈(C16)的合成。
将4-溴-2-硝基苯甲腈(800mg,3.52mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-联-1,3,2-氧杂环戊硼烷(940mg,3.70mmol)、及乙酸钾(1.0g,10mmol)合并在1,4-二烷(35mL)中,及将混合物脱气15分钟。添加[1,1’-双(二苯膦基)二茂铁]二氯钯(II)(120mg,0.16mmol),及将反应混合物在100℃下加热2小时。其己冷却至室温之后,在真空中移除溶剂,并将残余物经由层析在硅胶上(洗脱液:二氯甲烷)纯化,提供呈棕黄色固体的产物。产量:940mg,3.43mmol,97%。1H NMR(400MHz,CDCl3)δ8.69(br s,1H),8.18(dd,J=7.6,1.0Hz,1H),7.90(d,J=7.6Hz,1H),1.38(s,12H)。
步骤2. 4-(8-环丙基-9-氧代-6,7,8,9-四氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-10-基)-2-硝基苯甲腈(C17)的合成。
使用实施例13中C49的合成所述的方法进行C9与C16的反应。获得呈黄色固体的产物。产量:315mg,0.844mmol,98%。LCMS m/z374.2[M+H]+。1H NMR(500MHz,CDCl3)δ8.90(d,J=1.5Hz,1H),8.56(dd,J=4.4,1.2Hz,1H),8.36(dd,J=7.9,1.6Hz,1H),7.85(d,J=8.0Hz,1H),7.78(dd,J=8.5,1.2Hz,1H),7.33(dd,J=8.3,4.4Hz,1H),4.33-4.40(m,2H),3.90-3.97(m,2H),2.82-2.89(m,1H),0.91-0.99(m,2H),0.73-0.81(m,2H)。HRMS(m/z):[M+H]+C20H15N5O3的计算值,374.1248;发现值,374.1246。
步骤3. 4-(8-环丙基-9-氧代-6,7,8,9-四氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-10-基)-2-(18F)氟苯甲腈(4a)的合成。
在水中的[18F]氟化物系在CTI RDS-111回旋加速器上的18O(p,n)18F核反应中制造产生。p/n反应的起始材料为来自Huayi/Isoflex的富水的97%O-18;在束线(beamline)2F-18HP靶(体积=2.4mL)上进行照射,在60μamp下经30分钟。在实验开始的前,将半制备型HPLC柱用流动相以3mL/分钟平衡15分钟。
将活性从目标卸除并递送至通用电气FX-FN合成模块上的玻璃V-小瓶。将[18F]氟化物通过Chromafix PS-HCO3筒(Macherey-Nagel),其已用乙醇(1mL)接着水(1mL)预处理,然后使用注射器排出水。将氟化物用碳酸钾(3mg,20μmol)在水(0.5mL)中的溶液,接着4,7,13,16,21,24-六氧杂-1,10-二氮杂双环[8.8.8]二十六烷(222,20mg,53μmol)在乙腈(1mL)中的溶液洗脱。干燥F-18/Kryptofix混合物之后,将残余物溶解在C17(2mg,6μmol)在无水N,N-二甲基甲酰胺(0.5mL)中的溶液并在130℃下加热10分钟。将反应混合物冷却至35℃,然后用在0.05M乙酸铵(4.5mL)中的30%乙腈稀释。将所得浅黄色溶液通过Waters Alumina N Sep-Pak Light筒[用水(10mL)预调节]进入中间体小瓶。然后将粗制反应混合物藉由半制备型HPLC(柱:Phenomenex Luna Phenyl-Hexyl,10×250mm,5μm;洗脱液:在0.05M乙酸铵水溶液中的30%乙腈;流速:6.0mL/分钟),藉由自动化填充5.0mLRheodyne环,接着注入柱中来纯化。与4a有关的活性从33分钟至36分钟洗脱(14000cps),及4a收集开始于2000cps且结束于6000cps。4a的滞留时间为34分钟。与此收集有关的HPLC洗脱液用含有抗坏血酸(12mg)的水(50mL)稀释,接着捕集在经调节的PhenomenexC18-E 50mg筒上。将该筒用水(3mL)洗涤,然后用乙醇(0.5mL)和盐水溶液(4.5mL)洗脱。合成结束时4a的比活性:14305Ci/mmol;产物活性:289mCi;4a的放射化学纯度:>99%;化学纯度:>99%。
实施例5和6
10-(4-氯苯基)-8-(4H-1,2,4-三唑-3-基)-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮(5)和10-(4-氯苯基)-8-(4H-1,2,4-三唑-3-基)吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(8H)-酮(6)
步骤1. 3-(4-氯苯基)-1-(丙-2-烯-1-基)-1H-吡咯并[3,2-b]吡啶-2-甲酸乙酯(C18)的合成。
将氢化钠(在矿物油中的60%,150mg,3.75mmol)缓慢加至C2(750mg,2.49mmol)在N,N-二甲基甲酰胺(10mL)中的0℃溶液。10分钟之后,滴加3-溴丙-1-烯(99%,0.432mL,4.98mmol),和移去冷却浴。4.5小时之后,将反应混合物倒入水(25mL)中并用乙酸乙酯(100mL)稀释。将有机层用半饱和氯化钠水溶液(4×50mL)洗涤,然后用饱和氯化钠水溶液(50mL)洗涤,经硫酸钠干燥,过滤,和在真空中浓缩。将残余物进行硅胶层析(梯度:在庚烷中的5%至50%乙酸乙酯),提供呈黄色油状物的产物(900mg)。将此材料直接用于下一步骤。1H NMR(400MHz,CDCl3)δ8.61(dd,J=4.5,1.3Hz,1H),7.76(dd,J=8.5,1.3Hz,1H),7.48(br AB四重峰,JAB=8.7Hz,ΔνAB=33.5Hz,4H),7.30(dd,J=8.5,4.5Hz,1H),5.98-6.09(m,1H),5.17-5.22(m,3H),4.99-5.06(m,1H),4.25(q,J=7.1Hz,2H),1.14(t,J=7.1Hz,3H)。
步骤2. 3-(4-氯苯基)-1-(2,3-二羟丙基)-1H-吡咯并[3,2-b]吡啶-2-甲酸乙酯(C19)的合成。
将4-甲基吗啉N-氧化物单水合物(674mg,4.99mmol)加至C18(来自前步骤,900mg,≤2.49mmol)在四氢呋喃(35mL)中的溶液。20分钟之后,将四氧化锇(在叔丁醇中的2.5重量百分比溶液,0.94mL,75μmol)加至混合物。4.5小时之后,经由添加10%硫代硫酸钠水溶液(20mL)淬灭反应,及使混合物搅拌20分钟,随的将其用乙酸乙酯(4×45mL)萃取。将合并的有机层用硫代硫酸钠水溶液和用饱和氯化钠水溶液洗涤,经硫酸钠干燥,过滤,和在真空中浓缩,提供呈白色固体的产物。产量:850mg,2.27mmol,91%经过2步骤。1H NMR(400MHz,CD3OD)δ8.41(dd,J=4.6,1.4Hz,1H),8.06(dd,J=8.5,1.3Hz,1H),7.38-7.44(m,4H),7.32(dd,J=8.6,4.6Hz,1H),4.73(dd,J=14.5,4.1Hz,1H),4.55(dd,J=14.5,7.9Hz,1H),4.20(q,J=7.1Hz,2H),3.99-4.05(m,1H),3.61(dd,ABX图案的一半,J=11.3,4.7Hz,1H),3.55(dd,ABX图案的一半,J=11.3,5.2Hz,1H),1.08(t,J=7.1Hz,3H)。
步骤3. 3-(4-氯苯基)-1-(2-氧代乙基)-1H-吡咯并[3,2-b]吡啶-2-甲酸乙酯(C20)的合成。
将化合物C19(来自类似于上述步骤1和2的反应顺序,≤2.49mmol)溶解在乙酸乙酯和四氢呋喃(50mL)的1:1混合物中,并用过碘酸钠(815mg,4.27mmol)在水(30mL)中的溶液逐滴处理。在室温下搅拌18小时之后,将反应混合物用另外过碘酸钠(815mg,4.27mmol)处理并使反应,直到以LCMS分析,起始材料已被消耗。添加亚硫酸氢钠的水溶液(10%,30mL),和以乙酸乙酯(2×250mL)萃取水层。将合并的有机层经硫酸镁干燥,过滤,和在真空中浓缩;经由硅胶层析(梯度:在庚烷中的0%至70%乙酸乙酯)的纯化提供呈固体的产物。产量:290mg,0.846mmol,≥34%。LCMS m/z 341.1,343.1[M-1]。1H NMR(400MHz,CDCl3)δ9.79(s,1H),8.60(dd,J=4.5,1.4Hz,1H),7.63(dd,J=8.5,1.3Hz,1H),7.45(br AB四重峰,JAB=8.4Hz,ΔνAB=33Hz,4H),7.30(dd,J=8.5,4.5Hz,1H),4.87-5.04(m,2H),4.20(q,J=7.1Hz,2H),1.10(t,J=7.1Hz,3H)。
步骤4. 3-(4-氯苯基)-1-[2-(4H-1,2,4-三唑-3-基氨基)乙基]-1H-吡咯并[3,2-b]吡啶-2-甲酸乙酯(C21)的合成。
将化合物C20(200mg,0.58mmol)、4H-1,2,4-三唑-3-胺(65.0mg,0.773mmol)与乙醇和甲苯(15mL)的5:1混合物合并于小瓶中并在80℃下加热4小时。此时,除去盖子,并将反应混合物在100℃下加热直到80%的溶剂蒸发。冷却至室温之后,将混合物用硼氢化钠(73.1mg,1.93mmol)和甲醇(10mL)处理并使在室温下搅拌18小时。添加饱和碳酸氢钠水溶液(10mL),且继续搅拌30分钟。然后将混合物分溶在乙酸乙酯(100mL)和水(30mL)之间,并将有机层用饱和氯化钠水溶液(30mL)洗涤,经硫酸镁干燥,过滤,和在真空中浓缩以提供粗制产物(265mg),其不经纯化而用于下列步骤。
步骤5. 10-(4-氯苯基)-8-(4H-1,2,4-三唑-3-基)-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮(5)和10-(4-氯苯基)-8-(4H-1,2,4-三唑-3-基)吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(8H)-酮(6)的合成。
将化合物C21(来自前步骤,≤0.58mmol)溶解在甲醇(15mL)中并用氢氧化钠水溶液(2M,2mL)处理。在室温下6小时之后,LCMS分析指示存在预期的产物5和不饱和类似物6。将反应混合物分溶在乙酸乙酯(130mL)和水(10mL)之间,并将有机层经硫酸镁干燥,过滤,和在真空中浓缩。将粗制产物与得自在C21(78mg,≤0.19mmol)上进行的类似反应的产物合并,以提供250mg的材料。其的三分之一进行反相HPLC(柱:Waters XBridge C18,5μm;流动相A:在水中的0.03%氢氧化铵(v/v);流动相B:在乙腈中的0.03%氢氧化铵(v/v);梯度:20%至30%B)以提供5。产量:4.0mg,11μmol,4%经过二个步骤。5:LCMS m/z 365.1,367.1[M+H]+。1H NMR(600MHz,DMSO-d6),特征峰:δ8.54(d,J=4Hz,1H),8.14(d,J=8Hz,1H),7.84(br s,1H),7.78(br d,J=8.4Hz,2H),7.49(br d,J=8Hz,2H),7.44(dd,J=8.4,4.4Hz,1H),4.62(br s,2H)。
将另外三分之一的粗制产物使用反相HPLC(柱:Waters XBridge C18,5μm;流动相A:在水中的0.03%氢氧化铵(v/v);流动相B:在乙腈中的0.03%氢氧化铵(v/v);梯度:20%至30%B)纯化以提供6。产量:2.6mg,7.2μmol,3%经过二个步骤。6:LCMS m/z 363.1,365.1[M+H]+。1H NMR(600MHz,DMSO-d6)δ8.72(dd,J=4.4,1Hz,1H),8.64(br d,J=8.4Hz,1H),8.46(br s,1H),8.12(d,J=5.7Hz,1H),7.80(br d,J=8.4Hz,2H),7.56(dd,J=8.4,4.4Hz,1H),7.49(br d,J=8.4Hz,2H),7.28(br d,J=5.7Hz,1H)。
实施例7
10-(4-氯-3-氟苯基)-8-环丙基-7,8-二氢吡嗪并[1',2':1,5]吡咯并[3,2-d]嘧啶-9(6H)-酮(7)
步骤1. 2-[(4-氯嘧啶-5-基)氨基]丙-2-烯酸乙酯(C22)的合成。
将4-氯嘧啶-5-胺(8.0g,62mmol)、2-氧代丙酸乙酯(14.4g,124mmol)和对-甲苯磺酸单水合物(0.90g,4.7mmol)在甲苯(100mL)中的混合物在回流下搅拌3小时,同时用Dean-Stark分水器共沸除去水。随后将混合物浓缩至小体积及藉由硅胶层析(梯度:在石油醚中的0%至30%乙酸乙酯)纯化以提供呈黄色固体的产物。产量:2.1g,9.2mmol,15%。
步骤2. 5H-吡咯并[3,2-d]嘧啶-6-甲酸乙酯的合成(C23)
将C22(2.1g,9.2mmol)、N,N-二异丙基乙胺(3mL)、及肆(三苯膦)钯(0)(0.2g,0.2mmol)在吡啶(25mL)中的混合物用氮脱气几次并在140℃下搅拌4小时。在真空中移除去溶剂之后,将残余物藉由硅胶层析(梯度:在石油醚中的0%至100%乙酸乙酯)纯化,以提供呈棕色固体的产物。产量:500mg,2.6mmol,28%。1H NMR(400MHz,CDCl3)δ9.33(br s,1H),9.12(s,1H),9.05(d,J=0.5Hz,1H),7.34-7.36(m,1H),4.50(q,J=7.2Hz,2H),1.47(t,J=7.2Hz,3H)。
步骤3. 5-(2-溴乙基)-5H-吡咯并[3,2-d]嘧啶-6-甲酸乙酯(C24)的合成。
将C23(400mg,2.1mmol)、1,2-二溴乙烷(1.57g,8.36mmol)和碳酸钾(1.1g,8.0mmol)在乙腈(20mL)中的混合物在50℃下加热18小时。将反应混合物已冷却至室温和倒入水(20mL)中之后,将其在减压下浓缩以移除乙腈。用乙酸乙酯(3×20mL)萃取含水残余物、及将合并的有机层用饱和氯化钠水溶液洗涤,经硫酸钠干燥,过滤,和在真空中浓缩以提供呈棕色固体的产物。产量:350mg,1.2mmol,57%。1H NMR(400MHz,CDCl3)δ9.12(s,2H),7.45(s,1H),5.01(t,J=6.2Hz,2H),4.46(q,J=7.1Hz,2H),3.80(t,J=6.3Hz,2H),1.46(t,J=7.1Hz,3H)。
步骤4. 8-环丙基-7,8-二氢吡嗪并[1',2':1,5]吡咯并[3,2-d]嘧啶-9(6H)-酮(C25)的合成。
将碳酸钾(284mg,2.05mmol)加至C24(300mg,1.0mmol)和环丙胺(3.0g,52mmol)在乙腈(10mL)中的溶液,及将反应混合物在80℃下搅拌18小时。在真空中移除挥发物及将残余物与乙腈(15mL)和N,N-二异丙基乙胺(5mL)混合,并在80℃下搅拌3小时。将反应混合物过滤并将滤液在减压下浓缩以提供呈褐色固体的产物。产量:180mg,0.79mmol,79%。1HNMR(400MHz,CDCl3)δ9.07(s,1H),8.91(d,J=0.6Hz,1H),7.38(d,J=0.7Hz,1H),4.33-4.38(m,2H),3.87-3.92(m,2H),2.86-2.93(m,1H),0.98-1.04(m,2H),0.78-0.84(m,2H)。
步骤5. 10-溴-8-环丙基-7,8-二氢吡嗪并[1',2':1,5]吡咯并[3,2-d]嘧啶-9(6H)-酮(C26)的合成。
使用实施例1中C1的合成所述的方法将化合物C25转化成产物,除了在此情况下没有进行层析纯化之外。获得呈褐色固体的产物。产量:500mg,1.6mmol,91%。1H NMR(400MHz,CDCl3)δ9.15(s,1H),9.00(s,1H),4.39-4.44(m,2H),3.88-3.93(m,2H),2.86-2.92(m,1H),0.99-1.05(m,2H),0.80-0.85(m,2H)。
步骤6. 10-(4-氯-3-氟苯基)-8-环丙基-7,8-二氢吡嗪并[1',2':1,5]吡咯并[3,2-d]嘧啶-9(6H)-酮(7)的合成。
将化合物C26(400mg,1.3mmol)、(4-氯-3-氟苯基)硼酸(341mg,1.96mmol)和碳酸铯(1.0g,3.1mmol)合并于1,4-二烷(20mL)和水(2mL)的混合物中,并用氮脱气2分钟。添加二氯双(三环己基膦)-钯(II)(20mg,27μmol),及将反应混合物加热至100℃经18小时,然后在真空中浓缩,用水(50mL)稀释、并用乙酸乙酯(3×30mL)萃取。将合并的有机层在减压下浓缩且经由反相高效液相层析(柱:Phenomenex Gemini C18,8μm;流动相A:氨水,pH 10;流动相B:乙腈;梯度:36%至56%B)纯化以提供呈黄色固体的产物。产量:30mg,84μmol,6%。LCMS m/z 357.1[M+H]+。1H NMR(400MHz,CDCl3)δ9.12(s,1H),8.98(s,1H),7.65(dd,J=10.2,1.7Hz,1H),7.56(br dd,J=8.4,1.5Hz,1H),7.48(dd,J=8.2,7.8,1H),4.39-4.45(m,2H),3.92-3.98(m,2H),2.85-2.92(m,1H),0.97-1.04(m,2H),0.77-0.83(m,2H)。
实施例8
10-(4-氯-3-氟苯基)-8-环丙基-7,8-二氢吡咯并[1,2-a:4,5-b']二吡嗪-9(6H)-酮(8)
步骤1. 2-[(3-氯吡嗪-2-基)氨基]丙-2-烯酸乙酯(C27)的合成。
使用实施例7中C22的合成所述的方法将3-氯吡嗪-2-胺转化成产物。将产物分离呈白色固体。产量:14.0g,61.5mmol,77%。1H NMR(400MHz,CDCl3)δ8.11(br s,1H),8.09(d,J=2.8Hz,1H),7.78(d,J=2.6Hz,1H),6.70(s,1H),5.87(d,J=1.4Hz,1H),4.36(q,J=7.2Hz,2H),1.39(t,J=7.2Hz,3H)。
步骤2. 5H-吡咯并[2,3-b]吡嗪-6-甲酸乙酯(C28)的合成。
根据实施例7中C23的合成所述的方法将化合物C27转化成产物。获得呈黄色固体的产物。产量:7.6g,40mmol,83%。LCMS m/z 191.9[M+H]+。1H NMR(400MHz,CDCl3)δ11.43(br s,1H),8.63(d,J=2.5Hz,1H),8.55(d,J=2.5Hz,1H),7.39(d,J=2.1Hz,1H),4.51(q,J=7.2Hz,2H),1.48(t,J=7.2Hz,3H)。
步骤3. 5-(2-溴乙基)-5H-吡咯并[2,3-b]吡嗪-6-甲酸乙酯(C29)的合成。
使用实施例3中C12的合成所述的方法使化合物C28与2-溴乙醇反应。在此情况下,使用在石油醚中的10%至40%乙酸乙酯的梯度进行层析,并获得呈白色固体的产物。产量:2.0g,6.7mmol,64%。1H NMR(400MHz,CDCl3)δ8.58(d,J=2.4Hz,1H),8.42(d,J=2.4Hz,1H),7.46(s,1H),5.13(t,J=7.1Hz,2H),4.46(q,J=7.2Hz,2H),3.74(t,J=7.0Hz,2H),1.46(t,J=7.2Hz,3H)。
步骤4. 8-环丙基-7,8-二氢吡咯并[1,2-a:4,5-b']二吡嗪-9(6H)-酮(C30)的合成。
将碳酸钾(2.8g,20mmol)加至C29(2.0g,6.7mmol)和环丙胺(33mL)在乙腈(100mL)中的溶液、及将反应混合物在80℃下搅拌18小时。在减压下除去挥发物之后,将残余物分溶在二氯甲烷和水之间。分离有机相,将水相用二氯甲烷(2×80mL)萃取,及将合并的有机层用饱和氯化钠水溶液(50mL)洗涤,经硫酸钠干燥,和在真空中浓缩。硅胶层析(梯度:在石油醚中的70%至100%乙酸乙酯)提供呈黄色固体的产物。产量:665mg,2.91mmol,43%。LCMSm/z 228.9[M+H]+。1H NMR(400MHz,CDCl3)δ8.53(d,J=2.5Hz,1H),8.35(d,J=2.5Hz,1H),7.40(s,1H),4.40-4.45(m,2H),3.84-3.89(m,2H),2.87-2.94(m,1H),0.97-1.04(m,2H),0.78-0.84(m,2H)。
步骤5. 10-溴-8-环丙基-7,8-二氢吡咯并[1,2-a:4,5-b']二吡嗪-9(6H)-酮(C31)的合成。
经由实施例1中C1的合成所述的方法进行C30至产物的转化。在此情况下,所使用的层析梯度为在二氯甲烷中的0%至9%甲醇,提供呈黄色固体的产物,经1H NMR其保留一定数量的杂质。产量:3.0g,9.8mmol,<75%。1H NMR(400MHz,CDCl3)δ8.55(d,J=2.4Hz,1H),8.39(d,J=2.4Hz,1H),4.44-4.48(m,2H),3.84-3.89(m,2H),2.86-2.93(m,1H),0.97-1.04(m,2H),0.79-0.86(m,2H)。
步骤6. 10-(4-氯-3-氟苯基)-8-环丙基-7,8-二氢吡咯并[1,2-a:4,5-b']二吡嗪-9(6H)-酮(8)的合成。
将C31(190mg,0.62mmol)、(4-氯-3-氟苯基)硼酸(220mg,1.26mmol)和氟化铯(380mg,2.50mmol)在1,4-二烷(8mL)中的混合物用氮脱气2分钟。添加双[二-叔丁基(4-二甲氨基苯基)膦]二氯钯(II)(22mg,31μmol)之后,将反应混合物在100℃下搅拌18小时。在真空中移除挥发物及将残余物进行硅胶层析(梯度:在石油醚中的乙酸乙酯)接着在硅胶上的制备型薄层层析(洗脱液:1:1石油醚/乙酸乙酯)以提供呈黄色固体的产物。产量:32.2mg,90.2μmol,15%。LCMS m/z 356.8[M+H]+。1H NMR(400MHz,CDCl3)δ8.57(d,J=2.4Hz,1H),8.42(d,J=2.4Hz,1H),7.69(dd,J=10.4,1.9Hz,1H),7.60(br dd,J=8.3,1.5Hz,1H),7.47(dd,J=8.0,7.9Hz,1H),4.46-4.52(m,2H),3.87-3.93(m,2H),2.85-2.92(m,1H),0.96-1.02(m,2H),0.76-0.83(m,2H)。
实施例9
5-(4-氯苯基)-7-环丙基-8,9-二氢吡啶并[3',2':4,5]吡咯并[1,2-a]吡嗪-6(7H)-酮(9)
步骤1.(2-溴吡啶-3-基)(4-氯苯基)甲醇(C32)的合成。
将正丁基锂(在己烷中的2.5M,0.56mL,1.4mmol)滴加至氯化正丁基镁(在二乙醚中的2.0M,0.35mL,0.70mmol)在四氢呋喃(2mL)中的0℃溶液。其已搅拌10分钟之后,将混合物冷却至-78℃并用2,3-二溴吡啶(474mg,2.00mmol)在四氢呋喃(2mL)中的溶液逐滴处理。使反应混合物在-78℃下搅拌30分钟,随的添加4-氯苯甲醛(422mg,3.00mmol);在-78℃下继续搅拌10分钟,然后在0℃下经10分钟。添加饱和碳酸氢钠水溶液,及将混合物用乙酸乙酯萃取。将合并的有机层经硫酸镁干燥,过滤,和在真空中浓缩。硅胶层析(梯度:在庚烷中的5%至45%乙酸乙酯)提供呈无色胶状物的产物。产量:0.28g,0.94mmol,47%。LCMS m/z297.9,299.9,301.9[M+H]+。1H NMR(400MHz,CDCl3)δ8.31(ddd,J=4.7,2.0,0.3Hz,1H),7.90(ddd,J=7.7,2.0,0.6Hz,1H),7.34-7.35(m,4H),7.33(ddd,J=7.7,4.7,0.5Hz,1H),6.13(br s,1H)。
步骤2.(2-溴吡啶-3-基)(4-氯苯基)甲酮(C33)的合成。
将C32(0.28g,0.94mmol)和氧化锰(IV)(815mg,9.37mmol)在二氯甲烷(5mL)中的混合物在室温下搅拌16小时。然后使用另外二氯甲烷将反应混合物通过硅藻土过滤,及将滤液在真空中浓缩。硅胶层析(梯度:在庚烷中的0%至40%乙酸乙酯)提供呈白色固体的产物。产量:203mg,0.684mmol,73%。LCMS m/z 295.9,297.9,299.9[M+H]+。1H NMR(400MHz,CDCl3)δ8.55(dd,J=4.8,2.0Hz,1H),7.76(br d,J=8.5Hz,2H),7.67(dd,J=7.5,2.0Hz,1H),7.48(br d,J=8.5Hz,2H),7.44(dd,J=7.5,4.8Hz,1H)。
步骤3. 5-(4-氯苯基)-7-环丙基-8,9二氢吡啶并[3',2':4,5]-吡咯并[1,2-a]吡嗪-6(7H)-酮(9)的合成。
将C33(137mg,0.462mmol)、1-环丙基哌嗪-2-酮(97.9mg,0.554mmol)和碳酸铯(903mg,2.77mmol)在甲苯(1mL)中的混合物用乙酸钯(II)(5.2mg,23μmol)和1,1'-联二萘-2,2'-二基双(二苯膦)(BINAP,14.3mg,23.0μmol)在甲苯(0.5mL)中的混合物(其已在室温下搅拌10分钟)处理。将反应混合物在120℃下加热16小时,然后过滤。经由硅胶层析(梯度:在庚烷中的10%至100%乙酸乙酯)将滤液纯化;随后从乙酸乙酯/庚烷结晶提供呈白色固体的产物。产量:83mg,0.25mmol,54%。LCMS m/z 338.1,340.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.48(dd,J=4.6,1.5Hz,1H),8.00(dd,J=8.0,1.5Hz,1H),7.54(br AB四重峰,JAB=8.7Hz,ΔνAB=44.1Hz,4H),7.22(dd,J=8.0,4.6Hz,1H),4.38-4.44(m,2H),3.76-3.82(m,2H),2.80-2.87(m,1H),0.69-0.82(m,4H)。
实施例10
(7R)-10-(4-氯苯基)-8-环丙基-7-甲基-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮(10)
步骤1. 2,2'-{[(苯甲氧基)羰基]亚氨基}二乙酸(C34)的合成
将2,2'-亚氨基二乙酸(150g,1.13mol)和氢氧化钠水溶液(2N,1.5L,3mol)的混合物在0℃下搅拌30分钟。在0℃下滴加氯甲酸苯甲酯(211g,1.24mol)之后,将反应混合物在10℃下搅拌18小时。然后将反应混合物用乙酸乙酯(1L)洗涤,并将水层酸化至大约2的pH及用乙酸乙酯(2×1L)萃取。合并此二有机层,经硫酸钠干燥,过滤,和在真空中浓缩以提供呈黄色胶状物的产物。产量:180g,0.674mol,60%。1H NMR(400MHz,CDCl3)δ8.07(br s,2H),7.27-7.37(m,5H),5.16(s,2H),4.19(br s,2H),4.13(br s,2H)。
步骤2.([(苯甲氧基)羰基]{2-[甲氧基(甲基)氨基]-2-氧代乙基}氨基)乙酸(C35)的合成。
将1-[3-(二甲氨基)丙基]-3-乙基碳二亚胺盐酸盐(EDCI,97g,0.51mol)、N,N-二异丙基乙胺(65g,0.50mol)和N,O-二甲基羟胺盐酸盐(46g,0.47mol)加至C34(180g,0.674mol)在N,N-二甲基甲酰胺(900mL)中的溶液,及将反应混合物在10℃下搅拌18小时。在真空中移除去溶剂之后,将残余物溶解在乙酸乙酯(2L)中,用1N盐酸水溶液洗涤,并用碳酸氢钠水溶液萃取。用盐酸水溶液将碳酸氢钠水溶液相调整至大约2的pH及然后用乙酸乙酯(2L)萃取。将合并的有机层用饱和氯化钠水溶液洗涤,经硫酸钠干燥,过滤,和在减压下浓缩以提供呈黄色胶状物的产物(155g),从其1H NMR光谱的检查推测其由旋转异构体的混合物组成。将此材料直接用于下一步骤。1H NMR(400MHz,CDCl3),特征峰:δ7.29-7.40(m,5H),5.14-5.21(m,2H),3.51和3.81(2s,总3H),3.30和3.21(2s,总3H)。
步骤3. N-[(苯甲氧基)羰基]-N-(2-氧代丙基)甘胺酸(C36)的合成。
将溴化甲镁(在二乙基醚中的3.0M溶液,670mL,2.0mol)滴加至C35(来自前反应,155g,≤0.47mol)在四氢呋喃(2L)中的0℃溶液,及使所得混合物缓慢升温至12℃并在该温度下搅拌18小时。藉由添加饱和氯化铵水溶液将反应混合物淬灭,用盐酸水溶液调整至大约2的pH,及用乙酸乙酯萃取。将有机层经由添加1N氢氧化钠水溶液碱化;将碱性水相用乙酸乙酯洗涤,然后用盐酸水溶液酸化至大约2的pH并用乙酸乙酯(2L)萃取。将有机萃取物用饱和氯化钠水溶液洗涤,经硫酸钠干燥,过滤,和在真空中浓缩以提供呈红色油状物的粗制产物(60g),其直接用于下列步骤。
步骤4. N-[(苯甲氧基)羰基]-N-[2-(环丙氨基)丙基]甘胺酸(C37)的合成。
将环丙胺(39g,0.68mol)、三乙酰氧基硼氢化钠(145g,0.684mol)和乙酸(20mL)加至C36(60g,≤230mmol)在二氯甲烷(2L)中的溶液,及将反应混合物在13℃下搅拌3天。在真空中移除溶剂提供呈橙色油状物的粗制产物,其直接用于下一步骤。
步骤5. 4-环丙基-3-甲基-5-氧代哌嗪-1-甲酸苯甲酯(C38)的合成。
将1-[3-(二甲氨基)丙基]-3-乙基碳二亚胺盐酸盐(EDCI,200g,1.04mol)和N,N-二异丙基乙胺(215g,1.66mol)加至C37(来自前步骤)在N,N-二甲基甲酰胺(2L)中的溶液,并将反应混合物在14℃下搅拌18小时。将反应混合物在减压下浓缩,并将残余物溶解在乙酸乙酯(1.5L)中,依次用1N盐酸水溶液、饱和碳酸氢钠水溶液、及饱和氯化钠水溶液洗涤,经硫酸钠干燥,过滤,和在真空中浓缩。经由硅胶层析(梯度:在石油醚中的30%至100%乙酸乙酯)的纯化提供呈黄色油状物的产物。产量:18g,62.4mmol,13%经四步骤。LCMS m/z288.9[M+H]+。1H NMR(400MHz,CDCl3)δ7.30-7.41(m,5H),5.16(AB四重峰,JAB=12.4Hz,ΔνAB=7.6Hz,2H),4.23-4.36(br m,1H),3.97(d,J=18.2Hz,1H),3.69-3.84(br m,1H),3.36-3.60(br m,2H),2.60-2.69(m,1H),1.21-1.33(br m,3H),1.00-1.10(m,1H),0.69-0.80(m,2H),0.48-0.61(br m,1H)。
步骤6.(3R)-4-环丙基-3-甲基-5-氧代哌嗪-1-甲酸苯甲酯(C39)和(3S)-4-环丙基-3-甲基-5-氧代哌嗪-1-甲酸苯甲酯(C40)的分离。
经由超临界流体层析(柱:Phenomenex Lux Cellulose-4;洗脱液:3:1二氧化碳/甲醇)将化合物C38(2.60g,9.02mmol)分离成其组分对映异构体。获得为固体的呈现负(-)旋转的第一洗脱对映异构体指定为C39。产量:1.0g,3.5mmol,39%。获得为胶状物的具有正(+)旋转的第二洗脱对映异构体指定为C40。产量:1.0g,3.5mmol,39%。此二化合物的绝对构型指定如根据对得自C39的产物的X射线晶体结构测定所表示;参见下述实施例10的X-射线数据。C39:LCMS m/z 289.2[M+H]+。1H NMR(400MHz,CDCl3)δ7.30-7.41(m,5H),5.16(AB四重峰,JAB=12.5Hz,ΔνAB=7.0Hz,2H),4.29(br d,J=18.0Hz,1H),3.96(d,J=18.0Hz,1H),3.70-3.84(br m,1H),3.37-3.59(br m,2H),2.60-2.69(m,1H),1.21-1.33(br m,3H),1.00-1.10(m,1H),0.69-0.80(m,2H),0.48-0.61(br m,1H)。C40:LCMS m/z 289.2[M+H]+。1HNMR(400MHz,CDCl3)δ7.30-7.41(m,5H),5.16(AB四重峰,JAB=12.4Hz,ΔνAB=7.0Hz,2H),4.29(br d,J=18Hz,1H),3.96(d,J=18.2Hz,1H),3.70-3.84(br m,1H),3.47-3.59(br m,1H),3.42(br d,J=13.5Hz,1H),2.60-2.68(m,1H),1.22-1.32(br m,3H),1.00-1.10(m,1H),0.69-0.79(m,2H),0.49-0.60(br m,1H)。
步骤7.(6R)-1-环丙基-6-甲基哌嗪-2-酮(C41)的合成
将钯/碳(10%,湿,40mg)加至C39(200mg,0.694mmol)在乙醇(12mL)中的溶液,及将反应混合物在50psi氢气下在Parr振荡器上氢化18小时,然后通过硅藻土过滤。将滤液在真空中浓缩以提供呈油状物的产物。产量:103mg,0.668mmol,96%。LCMS m/z 155.1[M+H]+。1HNMR(400MHz,CDCl3)δ3.47(AB四重峰,JAB=17.3Hz,ΔνAB=11.6Hz,2H),3.41-3.49(m,1H),3.13(dd,J=13.2,4.6Hz,1H),2.77(dd,J=13.0,5.5Hz,1H),2.56-2.63(m,1H),1.31(d,J=6.3Hz,3H),1.02-1.11(m,1H),0.66-0.76(m,2H),0.53-0.62(m,1H)。
步骤8.(3-溴吡啶-2-基)(4-氯苯基)甲醇(C42)的合成。
使用P.C.Gros和F.Elaachbouni,Chem.Commun.2008,4813-4815的方法合成化合物。将[(三甲基甲硅烷基)甲基]锂(在戊烷中的1.0M溶液,12.7mL,12.7mmol)滴加至2-(二甲氨基)乙醇(423μL,4.22mmol)在甲苯(14mL)中的0℃溶液,并将混合物搅拌20分钟。然后将其冷却至-30℃并用2,3-二溴吡啶(1.0g,4.2mmol)在甲苯(6mL)中的溶液处理。反应混合物已在-30℃下搅拌40分钟之后,以逐滴的方式添加4-氯苯甲醛(99%,899mg,6.33mmol)在甲苯(5mL)中的溶液,和继续在-30℃下搅拌30分钟。此时,经由添加饱和碳酸氢钠水溶液(25mL)猝灭反应,及使混合物加温至室温。将其用乙酸乙酯萃取三次,及将合并的有机层用饱和氯化钠水溶液洗涤,经硫酸钠干燥,过滤,和在真空中浓缩。硅胶层析(梯度:在庚烷中的0%至40%乙酸乙酯)提供呈白色固体的产物。产量:949mg,3.18mmol,76%。LCMS m/z298.0,300.0,302.0[M+H]+。1H NMR(400MHz,CDCl3)δ8.60(dd,J=4.7,1.3Hz,1H),7.88(dd,J=8.0,1.5Hz,1H),7.26-7.32(m,4H),7.20(dd,J=8.0,4.7Hz,1H),5.95(s,1H),5.27(brs,1H)。
步骤9.(3-溴吡啶-2-基)(4-氯苯基)甲酮(C43)的合成。
根据实施例9中C33的合成的一般程序将化合物C42转化成产物,除了没有进行层析纯化。获得呈白色固体的产物。产量:257mg,0.867mmol,98%。LCMS m/z 295.9,297.9,300.0[M+H]+。1H NMR(400MHz,CDCl3)δ8.63(dd,J=4.7,1.3Hz,1H),8.04(dd,J=8.2,1.3Hz,1H),7.80(br d,J=8.5Hz,2H),7.46(br d,J=8.6Hz,2H),7.35(dd,J=8.2,4.7Hz,1H)。
步骤10.(7R)-10-(4-氯苯基)-8-环丙基-7-甲基-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮(10)的合成。
根据实施例9中9的合成的一般程序使化合物C43与C41反应。在此情况下,硅胶层析之后,将所得黄色玻璃状固体(155mg)用乙醚(1mL)处理并在真空中浓缩;将残余物与乙醚(1mL)和戊烷(1mL)混合,并用另外戊烷分批处理直到固体停止从溶液沉淀。在真空中移除去溶剂,并用乙酸乙酯将残留材料冲入产物。在减压下的浓缩提供浅黄色固体(135mg)。此与戊烷(1.5mL)混合,进行超音波处理3分钟,然后使静置30分钟。用移液管去除戊烷之后,将残余物在真空下干燥以提供呈近白色固体的产物。产量:115mg,0.327mmol,57%。LCMS m/z 352.2,354.0[M+H]+。1H NMR(400MHz,CDCl3)δ8.62(dd,J=4.5,1.4Hz,1H),7.78(br d,J=8.5Hz,2H),7.67(dd,J=8.4,1.4Hz,1H),7.44(br d,J=8.5Hz,2H),7.30(dd,J=8.4,4.5Hz,1H),4.28(dd,ABX图案的一半,J=12.1,4.1Hz,1H),4.22(dd,ABX图案的一半,J=12.1,1.7Hz,1H),4.02-4.10(m,1H),2.80-2.86(m,1H),1.39(d,J=6.6Hz,3H),1.09-1.17(m,1H),0.87-0.94(m,1H),0.78-0.86(m,1H),0.57-0.64(m,1H)。
将一部分化合物10从叔丁基甲基醚和己烷中再结晶。将所得晶体的一者进行X射线结构分析,其确立如所示的绝对立体化学。结晶学数据提供如下。
实施例10的单晶X-射线分析
数据收集系在室温下在Bruker APEX衍射仪上进行。数据收集系由ω及φ扫描所组成。数据收集相当长,且晶体小且弱衍射。发现晶体为非缺面双晶(twinned non-merohedrally),并且直接精制,在积分期间分离所述域。
结构系使用SHELX软件的直接方法以空间群P1解析。该结构随后以全矩阵最小平方法精修。发现所有的非氢原子且使用各向异性位移参数精修。覆盖不对称单元中的四个分子显示它们几乎相同。Cell_now,platon和框架文件表明不对称单元被正确鉴定,具有四个独立分子。
将所有的氢原子置于经计算的位置上且使依在它们的载体原子上。最终精修包括用于所有氢原子的各向同性位移参数。
绝对构型系藉由检查Flack参数来决定。在此情况下,Flack参数=0.0729具有esd0.0197,在绝对构型测定范围内。
最终R-指数为4.8%。最终差异傅里叶(Fourier)显示无缺失或错位的电子密度。
有关的晶体、数据收集和精修总结于表1中。原子坐标、键长、键角、扭转角和位移列在表2-5中。
软件和参考
SHELXTL,版本5.1,Bruker AXS,1997。
PLATON,A.L.Spek,J.Appl.Cryst.2003,36,7-13。
MERCURY,C.F.Macrae,P.R.Edington,P.McCabe,E.Pidcock,G.P.Shields,R.Taylor,M.Towler及J.van de Streek,J.Appl.Cryst.2006,39,453-457。
R.W.Hooft等人,J.Appl.Cryst.2008,41,96-103。
H.D.Flack,Acta Cryst.1983,A39,867-881。
表1
10的晶体数据和结构精算。
表2
用于产生等效原子的对称性变换。
表4
各向异性位移因子指数采用形式:
-2π2[h2 a*2U11+…+2 h k a* b* U12]
表5
实施例11
(7S)-10-(4-氯苯基)-8-环丙基-7-甲基-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮(11)
步骤1.(6S)-1-环丙基-6-甲基哌嗪-2-酮(C44)的合成。
将1-甲基环己-1,4-二烯(1mL)加至C40(255mg,0.884mmol)在乙醇(4mL)中的溶液,及将混合物加热至50℃。将氢氧化钯/碳(25mg,0.18mmol)一次全部添加,并在70℃下继续加热3小时。将反应混合物通过硅藻土过滤,及将滤饼用乙醇洗涤三次;将合并的滤液在真空中浓缩以提供呈油状物的产物。产量:150mg,呈现定量。1H NMR(400MHz,CDCl3)δ3.46-3.57(m,3H),3.19(dd,J=13.0,4.5Hz,1H),2.81(dd,J=13.1,5.9Hz,1H),2.56-2.64(m,1H),1.33(d,J=6.5Hz,3H),1.03-1.12(m,1H),0.67-0.79(m,2H),0.55-0.64(m,1H)。
步骤2.(7S)-10-(4-氯苯基)-8-环丙基-7-甲基-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮(11)的合成。
根据实施例9中9的合成的一般程序使化合物C44与C43反应;获得呈白色固体的产物。产量:123mg,0.350mmol,39%。LCMS m/z 352.2.354.1[M+H]+。1H NMR(400MHz,CDCl3)δ8.63(dd,J=4.6,1.4Hz,1H),7.78(br d,J=8.6Hz,2H),7.70(dd,J=8.4,1.4Hz,1H),7.44(br d,J=8.7Hz,2H),7.32(dd,J=8.4,4.6Hz,1H),4.29(dd,ABX图案的一半,J=12.1,4.0Hz,1H),4.23(dd,ABX图案的一半,J=12.1,1.6Hz,1H),4.02-4.10(m,1H),2.80-2.86(m,1H),1.39(d,J=6.7Hz,3H),1.09-1.18(m,1H),0.78-0.94(m,2H),0.57-0.65(m,1H)。
实施例12
10-(4-氯苯基)-2-环丙基-3,4-二氢吡嗪并[1,2-a]吲哚-1(2H)-酮(12)
步骤1. 1-(2-溴乙基)-1H-吲哚-2-甲酸乙酯(C45)的合成。
将1H-吲哚-2-甲酸乙酯(4.12g,21.8mmol)、1,2-二溴乙烷(4.51g,24.0mmol)和碳酸钾(4.51g,32.6mmol)与N,N-二甲基甲酰胺(100mL)合并且在100℃下加热18小时。将反应混合物在减压下浓缩以移除N,N-二甲基甲酰胺,及将残余物用水(100mL)稀释并用乙酸乙酯(3×200mL)萃取。将合并的有机层用饱和氯化钠水溶液(100mL)洗涤,经硫酸钠干燥,过滤,和在真空中浓缩;硅胶层析(梯度:在石油醚中的5%至9%乙酸乙酯)提供呈白色固体的产物。产量:544mg,1.84mmol,8%。1H NMR(400MHz,CDCl3)δ7.69(br d,J=8Hz,1H),7.46(brd,half of AB四重峰,J=8.3Hz,1H),7.34-7.42(m,2H),7.15-7.22(m,1H),4.93(t,J=7.3Hz,2H),4.40(q,J=7Hz,2H),3.70(t,J=7.3Hz,2H),1.43(t,J=7.0Hz,3H)。
步骤2. 1-[2-(环丙氨基)乙基]-1H-吲哚-2-甲酸乙酯(C46)的合成
将环丙胺(4.2g,73.6mmol)加至C45(544mg,1.84mmol)和碳酸钾(381mg,2.76mmol)在乙腈(15mL)中的悬浮液,及将反应容器密封并在60℃下加热18小时,然后在80℃下加热4小时。在真空中移除溶剂之后,将残余物用水(5mL)稀释并用乙酸乙酯(3×10mL)萃取。将合并的有机层用饱和氯化钠水溶液(15mL)洗涤,经硫酸钠干燥,过滤,和在减压下浓缩以提供呈白色固体的产物。产量:250mg,0.92mmol,50%。1H NMR(400MHz,CDCl3)δ7.68(d,J=7.8Hz,1H),7.47(d,J=8Hz,1H),7.31-7.38(m,2H),7.16(dd,J=7.5,7.5Hz,1H),4.70(t,J=6.8Hz,2H),4.38(q,J=7.0Hz,2H),3.11(t,J=6.8Hz,2H),2.13-2.20(m,1H),1.42(t,J=7.2Hz,3H),0.40-0.47(m,2H),0.29-0.35(m,2H)。
步骤3. 2-环丙基-3,4-二氢吡嗪并[1,2-a]吲哚-1(2H)-酮(C47)的合成。
将氯化钙(41mg,0.37mmol)加至C46(100mg,0.37mmol)在甲醇(5mL)中的溶液,并将反应混合物在80℃下搅拌2天。将该混合物与得生自100mg的C46的相同反应混合物合并和在真空中浓缩,提供残余物,其然后用水稀释并用二氯甲烷(3×10mL)萃取。将合并的有机层用饱和氯化钠水溶液(10mL)洗涤,经硫酸钠干燥,过滤,和在减压下浓缩以提供呈灰白色固体的产物。产量:160mg,0.707mmol,96%。1H NMR(400MHz,DMSO-d6)δ7.66(d,J=7.8Hz,1H),7.52(d,J=8.4Hz,1H),7.26-7.31(m,1H),7.10(dd,J=7.4,7.4Hz,1H),7.03(s,1H),4.26-4.30(m,2H),3.73-3.77(m,2H),2.81-2.88(m,1H),0.78-0.84(m,2H),0.70-0.76(m,2H)。
步骤4. 10-溴-2-环丙基-3,4-二氢吡嗪并[1,2-a]吲哚-1(2H)-酮(C48)的合成。
将N-溴丁二酰亚胺(180mg,1.01mmol)加至C47(200mg,0.88mmol)在二氯甲烷(20mL)中的-50℃溶液。5分钟之后,将混合物用水(10mL)洗涤并用二氯甲烷(3×10mL)萃取。将合并的有机层用饱和氯化钠水溶液(10mL)洗涤,经硫酸钠干燥,过滤,和在真空中浓缩以提供呈白色固体的产物。产量:200mg,0.655mmol,74%。1H NMR(400MHz,CDCl3)δ7.70(d,J=8.0Hz,1H),7.37-7.42(m,1H),7.28-7.31(m,1H),7.22-7.27(m,1H,假设;部分被溶剂峰遮蔽),4.22-4.27(m,2H),3.79-3.84(m,2H),2.81-2.87(m,1H),0.94-1.01(m,2H),0.76-0.82(m,2H)。
步骤5. 10-(4-氯苯基)-2-环丙基-3,4-二氢吡嗪并[1,2-a]吲哚-1(2H)-酮(12)的合成。
将C48(100mg,0.33mmol)、(4-氯苯基)硼酸(52mg,0.33mmol)、及碳酸铯(210mg,0.644mmol)在1,4-二烷(4mL)和水(0.5mL)中的混合物用氮脱气2分钟。以一次全部添加二氯双(三环己基膦)钯(II)(36mg,49μmol),及将反应容器密封并在90℃下加热18小时。将反应混合物浓缩至干并藉由制备型薄层层析纯化残余物;使用反相HPLC进行进一步纯化(柱:Phenomenex Gemini C18,5μm;流动相A:氨水,pH 10;流动相B:乙腈;梯度:50%至70%B)以提供呈白色固体的产物。产量:13.5mg,40.1μmol,12%。LCMS m/z 336.9[M+H]+。1H NMR(400MHz,CDCl3)δ7.65(d,J=8.0Hz,1H),7.59(br d,J=8.5Hz,2H),7.42(br d,J=8.3Hz,2H),7.33-7.40(m,2H),7.18(dd,J=7.3,7.3Hz,1H),4.26-4.32(m,2H),3.83-3.89(m,2H),2.77-2.84(m,1H),0.90-0.97(m,2H),0.71-0.78(m,2H)。
实施例13
8-环丙基-10-(4-甲基苯基)吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(8H)-酮(13)
步骤1. 3-(4-甲基苯基)-1H-吡咯并[3,2-b]吡啶-2-甲酸乙酯(C49)的合成。
经由真空抽空将甲苯(10mL)脱气接着氮填充。C1(138mg,0.513mmol)和(4-甲基苯基)硼酸(140mg,1.03mmol)之后续添加各自接着相同的脱气程序。引入氟化铯的水溶液(1.0M,2.56mL,2.56mmol),接着添加双[二-叔丁基(4-二甲氨基苯基)膦]二氯钯(II)(45.3mg,64μmol)在1,2-二氯乙烷中的溶液,并将反应混合物加热至100℃经3小时。在真空中移除去溶剂之后,经由硅胶层析(洗脱液:在庚烷中的30%乙酸乙酯)的纯化提供呈黄色固体的产物。产量:137mg,0.489mmol,95%。LCMS m/z 281.2[M+H]+。1H NMR(400MHz,CDCl3)δ9.81(br s,1H),8.60(br d,J=4.4Hz,1H),7.68(br d,J=8.4Hz,1H),7.59(br d,J=7.9Hz,2H),7.23(dd,J=8.5,4.5Hz,1H),7.21(br d,J=7.6Hz,2H),4.33(q,J=7.1Hz,2H),2.36(s,3H),1.25(t,J=7.1Hz,3H)。
步骤2. 3-(4-甲基苯基)-1-(丙-2-烯-1-基)-1H-吡咯并[3,2-b]吡啶-2-甲酸乙酯(C50)的合成。
将粉状无水氢氧化钾(109mg,1.94mmol)用二甲亚砜(1.0mL)处理并在室温下搅拌5分钟。将此加至C49(136mg,0.485mmol)在二甲亚砜(1.0mL)中的溶液,和额外二甲亚砜(0.5mL)用于进行完全转移。然后添加3-溴丙-1-烯(82μL,0.97mmol),并将反应混合物在室温下搅拌10分钟,随的藉由添加1N盐酸水溶液将其小心地中和。将所得混合物分溶在水和乙酸乙酯之间;将有机层经硫酸镁干燥,过滤,和在真空中浓缩以提供呈黄色油状物的产物。产量:155mg,0.484mmol,100%。LCMS m/z 321.2[M+H]+。1H NMR(400MHz,CDCl3)δ8.58(br d,J=4.5Hz,1H),7.71(br d,J=8.4Hz,1H),7.44(br d,J=7.9Hz,2H),7.22-7.27(m,3H),5.96-6.07(m,1H),5.14-5.19(m,3H),5.01(d,J=16.6Hz,1H),4.22(q,J=7.1Hz,2H),2.39(s,3H),1.11(t,J=7.1Hz,3H)。
步骤3. 3-(4-甲基苯基)-1-(丙-2-烯-1-基)-1H-吡咯并[3,2-b]吡啶-2-甲酸(C51)的合成。
将C50(155mg,0.484mmol)、环丙胺(98%,0.346mL,4.83mmol)和氯化钙(53.7mg,0.484mmol)在甲醇(5mL)中的混合物在压力瓶中在50℃下加热18小时,然后在65℃下加热5小时。藉由LCMS,主要成分不是预期的酰胺,而是起始材料的甲酯。将反应混合物冷却至室温并在真空中浓缩。将残余物溶解在乙醇(5mL)和水(6mL)中,用氢氧化钠水溶液(12N,80μL,0.96mmol)处理,并加热至70℃经7小时。将反应混合物浓缩至干,然后在乙醇、四氢呋喃和水(1:1:1,6mL)的混合物中成浆。添加氢氧化锂(58mg,2.4mmol),及使反应混合物在室温下搅拌18小时。在减压下除去挥发物之后,将含水残余物用6N盐酸水溶液中和;将此用氯仿和2-丙醇的3:1混合物萃取两次,并将合并的有机层经硫酸镁干燥,过滤,和在真空中浓缩以提供呈固体的产物。产量:105mg,0.359mmol,74%。LCMS m/z 293.1[M+H]+。1H NMR(400MHz,CD3OD),特征峰:δ8.32(dd,J=4.9,1.2Hz,1H),8.06(dd,J=8.3,1.1Hz,1H),7.52(br d,J=8.1Hz,2H),7.32(dd,J=8.3,5.0Hz,1H),7.16(br d,J=7.9Hz,2H),5.97-6.08(m,1H),2.32(br s,3H)。
步骤4. N-环丙基-3-(4-甲基苯基)-1-(丙-2-烯-1-基)-1H-吡咯并[3,2-b]吡啶-2-甲酰胺(C52)的合成。
将三乙胺(0.249mL,1.80mmol)和环丙胺(0.124mL,1.80mmol)加入到C51(105mg,0.359mmol)在乙酸乙酯(4mL)中的浆料,然后将其用2,4,6-三丙基-1,3,5,2,4,6-三氧杂三磷烷2,4,6-三氧化物(T3P,在乙酸乙酯中的~50%溶液,0.7mL,1mmol)处理。使反应混合物在室温下搅拌20分钟,随的藉由添加饱和碳酸氢钠水溶液猝灭并用乙酸乙酯萃取两次。将合并的有机层经硫酸镁干燥,通过1/2英寸硅胶层过滤,和在真空中浓缩。硅胶层析(洗脱液:在庚烷中的40%乙酸乙酯)提供呈白色固体的产物。产量:53mg,0.16mmol,45%。LCMSm/z 332.2[M+H]+。1H NMR(400MHz,CDCl3)δ8.55(br d,J=4.3Hz,1H),7.71(br d,J=8.2Hz,1H),7.48(br d,J=7.9Hz,2H),7.30(br d,J=7.8Hz,2H),7.22(dd,J=8.4,4.5Hz,1H),5.99-6.10(m,1H),5.86(br s,1H),5.14-5.19(m,3H),5.04(d,J=16.4Hz,1H),2.69-2.77(m,1H),2.42(s,3H),0.69-0.76(m,2H),0.26-0.32(m,2H)。
步骤5. 8-环丙基-7-羟基-10-(4-甲基苯基)-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮(C53)的合成。
将四氧化锇(在叔丁醇中的2.5重量百分比溶液,0.8mL,60μmol)加至C52(53mg,0.16mmol)在丙酮(5mL)和水(5mL)中的溶液,并将反应混合物搅拌5分钟。添加过碘酸钠(110mg,0.51mmol),且继续搅拌2小时,随的添加硫代硫酸钠水溶液。将混合物分溶在二氯甲烷和水之间;以二氯甲烷萃取水层,并将合并的有机层经硫酸镁干燥,过滤,和在真空中浓缩。使残余物通过硅胶塞,用二氯甲烷和乙酸乙酯洗脱,并将洗脱液在减压下浓缩以提供呈淡桃红色固体的产物,将其直接使用,无需另外纯化。产量:22mg,66μmol,41%。LCMS m/z334.1[M+H]+。1H NMR(400MHz,CD3OD),特征峰:δ8.42(br d,J=4.4Hz,1H),8.03(br d,J=8.4Hz,1H),7.54(br d,J=8.0Hz,2H),7.41(dd,J=8.5,4.5Hz,1H),7.25(br d,J=8Hz,2H),5.48-5.50(m,1H),4.63(dd,J=13.1,1.7Hz,1H),4.26(dd,J=13,3Hz,1H),2.85-2.91(m,1H),2.41(s,3H)。
步骤6. 8-环丙基-10-(4-甲基苯基)吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(8H)-酮(13)的合成。
将粉末分子筛接着对-甲苯磺酸单水合物(13.1mg,69.0μmol)加至C53(22mg,66μmol)在二氯甲烷(2mL)中的溶液,和使反应混合物搅拌1小时。然后将其通过硅藻土过滤,用另外二氯甲烷冲洗,并将合并的滤液在真空中浓缩。经由硅胶层析(洗脱液:乙酸乙酯,接着1:1乙酸乙酯/甲醇)进行纯化。将此材料分溶在二氯甲烷和饱和碳酸氢钠水溶液之间;在减压下浓缩有机层提供呈荧光黄色固体的产物。产量:16mg,51μmol,77%。LCMS m/z 316.3[M+H]+。1H NMR(400MHz,CDCl3)δ8.74(dd,J=4.5,1.2Hz,1H),7.97(dd,J=8.5,1.1Hz,1H),7.72(br d,J=8.0Hz,2H),7.33(dd,J=8.5,4.5Hz,1H),7.30(br d,J=7.9Hz,2H),7.22(d,J=6.0Hz,1H),6.56(d,J=6.0Hz,1H),3.17-3.24(m,1H),2.40(s,3H),1.05-1.11(m,2H),0.85-0.91(m,2H)。
实施例14
4-(7-环丙基-8-氧代-5,6,7,8-四氢[1,3]噻唑并[4',5':4,5]吡咯并[1,2-a]吡嗪-9-基)-3-甲基苯甲腈(14)
步骤1. 2-叠氮基-3-(1,3-噻唑-4-基)丙-2-烯酸乙酯(C54)的合成。
经1.5小时将1,3-噻唑-4-甲醛(9.13g,80.7mmol)和叠氮基乙酸乙酯(20.64g,159.8mmol)在乙醇(120mL)中的溶液慢慢加至乙氧化钠[从钠金属(7.36g,320mmol)和乙醇(120mL)制备]的0℃溶液。将反应混合物在10℃下搅拌另外1小时,冷却至-40℃,并用氯化铵(8.4g,160mmol)在水(100mL)中的溶液处理。将所得混合物倒入冰冷却的水,并经由过滤收集沉淀物以提供呈灰白色固体的产物。产量:3.94g,17.6mmol,22%。1H NMR(400MHz,CDCl3)δ8.81(d,J=2.0Hz,1H),8.24(br d,J=2.0Hz,1H),7.27(br s,1H),4.38(q,J=7.1Hz,2H),1.40(t,J=7.2Hz,3H)。
步骤2. 4H-吡咯并[3,2-d][1,3]噻唑-5-甲酸乙酯(C55)的合成。
将C54(2.0g,8.9mmol)在二甲苯(200mL)中的溶液在回流下加热20分钟,然后在真空中浓缩。硅胶层析(梯度:在石油醚中的10%至30%乙酸乙酯)提供呈白色固体的产物。产量:0.83g,4.2mmol,47%。1H NMR(400MHz,CDCl3)δ9.40(br s,1H),8.56(s,1H),7.34(s,1H),4.40(q,J=7.1Hz,2H),1.41(t,J=7.2Hz,3H)。
步骤3. 4-(2-溴乙基)-4H-吡咯并[3,2-d][1,3]噻唑-5-甲酸乙酯(C56)的合成。
使用实施例3中C12的合成所述的方法将化合物C55转化成产物,除了使用2-溴乙醇代替(2R)-2-(羟甲基)吡咯烷-1-甲酸叔丁酯之外。在此情况下使用在石油醚中的5%至16%乙酸乙酯的梯度进行层析。分离产物,呈白色固体。产量:7.0g,23mmol,92%。1H NMR(400MHz,CDCl3)δ8.56(s,1H),7.43(s,1H),4.84(t,J=6.3Hz,2H),4.35(q,J=7.1Hz,2H),3.80(t,J=6.3Hz,2H),1.41(t,J=7.1Hz,3H)。
步骤4. 4-[2-(环丙氨基)乙基]-4H-吡咯并[3,2-d][1,3]噻唑-5-甲酸乙酯(C57)的合成。
根据实施例12中C46的合成所述的方法将化合物C56转化成产物。经由硅胶层析(梯度:在石油醚中的10%至50%乙酸乙酯)进行纯化,提供呈无色油状物的产物。产量:6.34g,22.7mmol,99%。1H NMR(400MHz,CDCl3)δ8.52(s,1H),7.38(s,1H),4.59(t,J=6.3Hz,2H),4.34(q,J=7.1Hz,2H),3.16(t,J=6.3Hz,2H),2.12-2.18(m,1H),1.39(t,J=7.1Hz,3H),0.39-0.45(m,2H),0.25-0.30(m,2H)。
步骤5. 7-环丙基-6,7-二氢[1,3]噻唑并[4',5':4,5]吡咯并[1,2-a]吡嗪-8(5H)-酮(C58)的合成。
将碳酸钾(3.13g,22.6mmol)加至C57(6.34g,22.7mmol)在甲醇(200mL)中的溶液,并将反应混合物在35℃下搅拌18小时。已在真空中浓缩混合物之后,将残余物用二氯甲烷(3×300mL)萃取。将合并的有机层用饱和氯化钠水溶液(300mL)洗涤,经硫酸钠干燥,过滤,和在减压下浓缩。硅胶层析(梯度:在石油醚中的50%至80%乙酸乙酯)提供呈黄色固体的产物。产量:3.5g,15mmol,66%。LCMS m/z 233.8[M+H]+。1H NMR(400MHz,CDCl3)δ8.52(s,1H),7.38(s,1H),4.16-4.22(m,2H),3.79-3.84(m,2H),2.78-2.84(m,1H),0.92-0.99(m,2H),0.72-0.78(m,2H)。
步骤6. 9-溴-7-环丙基-6,7-二氢[1,3]噻唑并[4',5':4,5]-吡咯并[1,2-a]吡嗪-8(5H)-酮(C59)的合成。
将N-溴丁二酰亚胺(420mg,2.36mmol)加至C58(500mg,2.14mmol)在二氯甲烷(21mL)中的0℃溶液。在0℃下20分钟之后,将反应混合物用水处理,并将所述层分离。将有机层经硫酸镁干燥,过滤,和在真空中浓缩以提供呈浅褐色固体的产物。产量:670mg,2.1mmol,98%。LCMS m/z 312.0,314.0[M+H]+。1H NMR(400MHz,CDCl3)δ8.57(s,1H),4.17-4.21(m,2H),3.78-3.83(m,2H),2.76-2.83(m,1H),0.93-0.99(m,2H),0.73-0.79(m,2H)。
步骤7. 4-(7-环丙基-8-氧代-5,6,7,8-四氢[1,3]噻唑并[4',5':4,5]吡咯并[1,2-a]吡嗪-9-基)-3-甲基苯甲腈(14)的合成。
使用实施例13中C49的合成所述的方法使化合物C59与(4-氰基-2-甲基苯基)硼酸反应,除了使反应进行48小时之外。在此情况下,用乙酸乙酯作为洗脱液进行硅胶层析;将从层析分离的材料在乙醚中浆化30分钟,然后藉过滤收集以提供呈固体的产物。产量:3.0mg,8.6μmol,11%。LCMS m/z 349.1[M+H]+。1H NMR(400MHz,CDCl3)δ8.54(s,1H),7.57-7.59(m,1H),7.49-7.54(m,2H),4.25-4.29(m,2H),3.84-3.90(m,2H),2.72-2.78(m,1H),2.31(br s,3H),0.88-0.95(m,2H),0.68-0.74(m,2H)。
实施例15
10-(4-氯-2-氟-5-甲氧基苯基)-8-环丙基-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮(15)
步骤1. 4-(2-氯吡啶-3-基)-1-环丙基哌嗪-2-酮(C60)的合成
将1,1'-联二萘-2,2'-二基双(二苯膦)(BINAP,2.5g,4.0mmol)和乙酸钯(II)(1.0g,4.5mmol)加至1-环丙基哌嗪-2-酮盐酸盐(12.6g,71.3mmol)、2-氯-3-碘吡啶(20.5g,85.6mmol)和碳酸铯(139g,427mmol)在甲苯(500mL)中的混合物。用氮气脱气几次之后,将反应混合物在室温下搅拌20分钟及然后在120℃下经18小时。将混合物过滤并将滤饼用乙酸乙酯(2×200mL)洗涤;将合并的滤液在真空中浓缩并藉由层析(梯度:在石油醚中的50%至100%乙酸乙酯)在硅胶上纯化以提供呈棕色固体的产物。产量:7.3g,29.0mmol,41%。LCMS m/z 251.9[M+H]+。1H NMR(400MHz,CD3OD)δ8.07(d,J=4.6Hz,1H),7.58(d,J=7.9Hz,1H),7.38(dd,J=8.0,4.6Hz,1H),3.76(s,2H),3.46-3.52(m,2H),3.37-3.42(m,2H),2.76-2.83(m,1H),0.82-0.89(m,2H),0.73-0.80(m,2H)。
步骤2. [1-(2-氯吡啶-3-基)-4-环丙基-3-氧代哌嗪-2-基]膦酸二乙酯(C61)的合成。
将正丁基锂(在己烷中的2.5M,8.4mL,21mmol)加至二异丙基胺(2.94mL,21.0mmol)在四氢呋喃(40mL)中的-78℃溶液。此混合物已搅拌10分钟之后,滴加C60(2.52g,10.0mmol)在四氢呋喃(10mL)中的溶液,及在-78℃下继续搅拌另外10分钟。然后添加氯亚磷酸二乙酯(3.16mL,22.0mmol),及将反应混合物在-78℃下维持30分钟,随的将其加温至室温,用柠檬酸水溶液(10%溶液,20mL)处理并冷却至0℃。添加过氧化氢(在水中的30%,3.4mL,30mmol),并将反应混合物在0℃下搅拌10分钟。然后将亚硫酸钠(3.78g,30mmol)加至冷反应混合物,并继续搅拌30分钟。将混合物用乙酸乙酯萃取两次,并将合并的有机层经硫酸镁干燥,过滤,和在真空中浓缩。硅胶层析(洗脱液:乙酸乙酯,接着在乙酸乙酯中的5%甲醇)提供浅黄色油状物(3.68g),其以LCMS和1H NMR分析指定为预期产物和其烯醇磷酸酯的混合物。LCMS m/z 388.2和524.2[M+H]+。1H NMR(400MHz,CDCl3),特征峰:δ[8.13(br dd,J=4.6,1.6Hz)和8.06(dd,J=4.6,1.7Hz),总计1H],[7.49(dd,J=7.9,1.8Hz)和7.39(br dd,J=7.9,1.6Hz),总计1H],[7.21(br dd,J=7.9,4.6Hz)和7.15(dd,J=7.9,4.6Hz),总计1H]。将此物质与几种类似反应的产物合并,使用C60(总计C60:7.81g,31.0mmol)水解烯醇磷酸酯:合并的产物在乙醇中回流下加热16小时,然后在真空中浓缩并经由层析在硅胶上(梯度:在乙酸乙酯中的0%至10%甲醇)纯化。分离的材料(11g)仍含有烯醇磷酸酯,因此将其溶解在乙醇(30mL)中并在回流下加热另外4小时。在减压下移除溶剂之后,将残余物从庚烷/乙酸乙酯中结晶以提供呈白色固体的产物。产量:7.0g,18mmol,58%。LCMS m/z 388.2,390.2[M+H]+。1H NMR(400MHz,CDCl3)δ8.13(dd,J=4.6,1.7Hz,1H),7.39(dd,J=8.0,1.7Hz,1H),7.22(dd,J=7.9,4.6Hz,1H),4.62(dd,J=22.8,1.5Hz,1H),4.13-4.27(m,3H),3.98-4.08(m,2H),3.26-3.45(m,3H),2.79-2.86(m,1H),1.33(br t,J=7.1Hz,3H),1.13(br t,J=7.1Hz,3H),0.82-0.95(m,2H),0.71-0.78(m,1H),0.63-0.71(m,1H)。
步骤3. 3-(4-氯-2-氟-5-甲氧基亚苄基)-4-(2-氯吡啶-3-基)-1-环丙基哌嗪-2-酮(C62)的合成。
将氢氧化锂单水合物(16.8mg,0.400mmol)加至4-氯-2-氟-5-甲氧基苯甲醛(20.7mg,0.110mmol)和C61(38.8mg,0.100mmol)在四氢呋喃(0.5mL)和乙醇(50μL)中的混合物。反应混合物在室温下已搅拌5小时之后,将其用饱和氯化钠水溶液稀释并用乙酸乙酯萃取。将合并的有机层在真空中浓缩以提供产物。产量:34mg,80μmol,80%。LCMS m/z422.1,424.1,426.0[M+H]+。
步骤4. 10-(4-氯-2-氟-5-甲氧基苯基)-8-环丙基-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮(15)的合成。
将C62(42.2mg,99.9μmol)、二氯双(三苯膦)钯(II)(7.0mg,10μmol)和N,N-二异丙基乙胺(87μL,0.50mmol)在N,N-二甲基甲酰胺(0.5mL)中的混合物在120℃下搅拌16小时,然后在真空中浓缩。经由反相HPLC(柱:Waters XBridge C18,5μm;流动相A:在水中的0.03%氢氧化铵(v/v);流动相B:在乙腈中的0.03%氢氧化铵(v/v);梯度:30%至100%B)的纯化提供产物。产量:9.5mg,25μmol,25%。LCMS m/z 386.2,388.1[M+H]+。1H NMR(600MHz,DMSO-d6)δ8.46(dd,J=4.3,1.2Hz,1H),8.07(dd,J=8.5,1.0Hz,1H),7.43(d,J=8.9Hz,1H),7.36(dd,J=8.4,4.4Hz,1H),7.23(d,J=6.4Hz,1H),4.40(br s,2H),3.82(s,3H),3.81(br s,2H),2.81-2.87(m,1H),0.70-0.82(m,4H)。
实施例16
4-(8-环丙基-9-氧代-3,4,6,7,8,9-六氢-2H-哌喃并[2',3':4,5]吡咯并[1,2-a]吡嗪-10-基)-2-氟-5-甲基苯甲腈(16)
步骤1. 2-氟-5-甲基-4-(4,4,5,5-四甲基-1,3,2-氧杂环戊硼烷(dioxaborolan)-2-基)苯甲腈(C63)的合成。
根据实施例4a中C16的合成所述的方法将4-溴-2-氟-5-甲基苯甲腈转化成产物。获得呈白色固体的产物。产量:281mg,1.08mmol,45%。GCMS m/z 261[M+]。1H NMR(400MHz,CDCl3)δ7.56(d,J=9.3Hz,1H),7.38(br d,J=5.9Hz,1H),2.51(br s,3H),1.36(s,12H)。
步骤2. 1-(2-溴乙基)-1H-吡咯-2-甲酸甲酯(C64)的合成。
将氢氧化钾(11.2g,200mmol)一次全部加到1H-吡咯-2-甲酸甲酯(5.0g,40mmol)在二甲亚砜(40mL)中的溶液,并将混合物搅拌1.25小时,在此时大约一半氢氧化钾已溶解。将反应混合物冷却至0℃及经过3-5分钟经由注射器添加1,2-二溴乙烷(37.5g,200mmol)。移除冷却浴,及使反应混合物加温至室温并搅拌18小时。然后将其分溶在乙醚(150mL)和水(100mL)之间;将有机层半饱和氯化钠水溶液洗涤两次,用饱和氯化钠水溶液洗涤一次,经硫酸镁干燥,过滤,和在真空中浓缩。硅胶层析(梯度:在庚烷中的0%至60%乙酸乙酯)提供呈无色油状物的产物。产量:7.05g,30.4mmol,76%。1H NMR(400MHz,CDCl3)δ7.00(dd,J=4.0,1.8Hz,1H),6.93(br dd,J=2.6,1.8Hz,1H),6.16(dd,J=4.0,2.6Hz,1H),4.67(t,J=6.4Hz,2H),3.83(s,3H),3.69(t,J=6.4Hz,2H)。
步骤3. 1-[2-(环丙氨基)乙基]-1H-吡咯-2-甲酸甲酯(C65)的合成。
使用实施例2中C7的合成所述的方法将化合物C64转化成产物。获得呈浅黄色油状的产物。产量:6.30g,30.2mmol,99%。LCMS m/z 209.2[M+H]+。1H NMR(400MHz,CDCl3)δ6.97(dd,J=4.0,1.8Hz,1H),6.89-6.91(m,1H),6.14(dd,J=4.0,2.5Hz,1H),4.45(t,J=6.3Hz,2H),3.82(s,3H),3.07(t,J=6.3Hz,2H),2.10-2.16(m,1H),0.42-0.47(m,2H),0.31-0.36(m,2H)。
步骤4. 2-环丙基-3,4-二氢吡咯并[1,2-a]吡嗪-1(2H)-酮(C66)的合成。
使用实施例2中C8的合成所述的方法将化合物C65转化成产物。获得呈白色固体的产物。产量:3.23g,18.3mmol,61%。LCMS m/z 177.1[M+H]+。1H NMR(400MHz,CDCl3)δ6.93(dd,J=3.9,1.6Hz,1H),6.70(dd,J=2.5,1.6Hz,1H),6.21(dd,J=3.8,2.5Hz,1H),4.06-4.11(m,2H),3.66-3.70(m,2H),2.72-2.78(m,1H),0.87-0.93(m,2H),0.68-0.73(m,2H)。
步骤5. 2-环丙基-1-氧代-1,2,3,4-四氢吡咯并[1,2-a]吡嗪-6-甲醛(C67)的合成。
将磷酰氯(1.43mL,15.6mmol)逐滴加至N,N-二甲基甲酰胺(98%,1.23mL,15.5mmol)和1,2-二氯乙烷(15mL)的0℃混合物。20分钟之后,经由注射器添加C66(2.49g,14.1mmol)在1,2-二氯乙烷(10mL)中的溶液,并将反应混合物在回流下加热3.5小时。将水加至反应混合物,然后用1M氢氧化钠水溶液和少量饱和碳酸氢钠水溶液将其调整至9的pH。将水层用二氯甲烷萃取两次,并将合并的有机层经硫酸镁干燥,过滤,和在真空中浓缩。硅胶层析(梯度:在庚烷中的0%至100%乙酸乙酯)提供呈白色固体的产物。产量:1.18g,5.78mmol,41%。LCMS m/z 205.1[M+H]+。1H NMR(400MHz,CDCl3)δ9.67(s,1H),6.95(AB四重峰,高场半变宽,JAB=4.2Hz,ΔνAB=6.4Hz,2H),4.57-4.61(m,2H),3.69-3.73(m,2H),2.77-2.83(m,1H),0.91-0.97(m,2H),0.72-0.77(m,2H)。
步骤6.(2E)-3-(2-环丙基-1-氧代-1,2,3,4-四氢吡咯并-[1,2-a]吡嗪-6-基)丙-2-烯酸甲酯(C68)的合成。
经3-4分钟将(二甲氧基磷酰基)乙酸甲酯(98%,1.05mL,7.14mmol)滴加至氢化钠(在矿油中的60%,285mg,7.13mmol)在四氢呋喃(15mL)中的0℃悬浮液。添加另外四氢呋喃(10mL)以促进搅拌,并将反应混合物搅拌30分钟,随的添加C67(1.12g,5.47mmol)在四氢呋喃(5mL)中的溶液。使反应混合物加温至室温并搅拌18小时。在真空中移除去溶剂之后,将残余物分溶在水和二氯甲烷之间。将水层用二氯甲烷萃取两次,及将合并的有机层经硫酸镁干燥,过滤,和在减压下浓缩。在硅胶上的层析(梯度:在二氯甲烷中的0%至4%甲醇)提供呈白色固体的产物。产量:1.21g,4.65mmol,85%。LCMS m/z 261.2[M+H]+。1H NMR(400MHz,CDCl3)δ7.51(br d,J=15.7Hz,1H),6.97(dd,J=4.2,0.6Hz,1H),6.67(d,J=4.2Hz,1H),6.29(d,J=15.7Hz,1H),4.12-4.16(m,2H),3.80(s,3H),3.71-3.75(m,2H),2.74-2.80(m,1H),0.90-0.96(m,2H),0.70-0.75(m,2H)。
步骤7. 3-(2-环丙基-1-氧代-1,2,3,4-四氢吡咯并[1,2-a]吡嗪-6-基)丙酸甲酯(C69)的合成。
根据实施例11中C44的合成所述的方法将化合物C68转化成产物。获得呈灰色固体状的产物,其一部分不经进一步纯化而用于下列步骤。
步骤8. 3-(7-溴-2-环丙基-1-氧代-1,2,3,4-四氢吡咯并[1,2-a]吡嗪-6-基)丙酸甲酯(C70)的合成。
使用实施例1中C1的合成所述的方法将化合物C69转化成产物。获得呈白色固体的产物。产量:618mg,1.81mmol,79%。LCMS m/z 341.0,343.0[M+H]+。1H NMR(400MHz,CDCl3)δ6.91(s,1H),4.06-4.11(m,2H),3.67(s,3H),3.63-3.67(m,2H),2.90(dd,J=7.2,7.1Hz,2H),2.17-2.77(m,1H),2.64(dd,J=7.3,7.0Hz,2H),0.87-0.93(m,2H),0.67-0.72(m,2H)。
步骤9. 7-溴-2-环丙基-6-(3-羟基丙基)-3,4-二氢吡咯并-[1,2-a]吡嗪-1(2H)-酮(C71)的合成。
将硼氢化锂在四氢呋喃中的溶液(2M,1.12mL,2.24mmol)加至C70(586mg,1.72mmol)在四氢呋喃(6mL)中的溶液。将反应混合物加热至回流经2小时,在室温下搅拌18小时,及然后用饱和碳酸氢钠水溶液淬灭。将混合物用乙酸乙酯萃取三次,并将合并的有机层经硫酸镁干燥,过滤,和在真空中浓缩。硅胶层析(梯度:在二氯甲烷中的0%至4%甲醇)提供呈白色固体的产物。产量:429mg,1.37mmol,80%。LCMS m/z 313.1,315.0[M+H]+。1HNMR(400MHz,CDCl3)δ6.92(s,1H),3.99-4.04(m,2H),3.61-3.68(m,4H),2.70-2.78(m,3H),1.76-1.84(m,2H),1.51(br t,J=5Hz,1H),0.87-0.93(m,2H),0.67-0.72(m,2H)。
步骤10. 8-环丙基-3,4,7,8-四氢-2H-哌喃并[2',3':4,5]吡咯并-[1,2-a]吡嗪-9(6H)-酮(C72)的合成。
经由注射器将2-甲基丁-2-醇钾(在甲苯中的~1.7M,0.44mL,0.75mmol)的溶液加至C71(79mg,0.25mmol)和二氯(1,10-啡啉)铜(II)(9mg,0.03mmol)在四氢呋喃(2mL)中的混合物。将氩气吹过溶液经2分钟,随的将反应混合物在微波反应器中在100℃下加热18小时。然后将其用水和乙酸乙酯稀释,并将水层用乙酸乙酯萃取两次。将合并的有机层经硫酸镁干燥,过滤,和在减压下浓缩。硅胶层析(梯度:在庚烷中的0%至100%乙酸乙酯)提供产物。产量:17mg,73μmol,29%。LCMS m/z 233.2[M+H]+。1H NMR(400MHz,CDCl3)δ6.46(s,1H),4.06-4.10(m,2H),3.82-3.87(m,2H),3.63-3.67(m,2H),2.69-2.75(m,1H),2.60(dd,J=6.5,6.5Hz,2H),1.99-2.06(m,2H),0.85-0.91(m,2H),0.65-0.70(m,2H)。
步骤11. 10-溴-8-环丙基-3,4,7,8-四氢-2H-哌喃并-[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮(C73)的合成。
将N-溴丁二酰亚胺(13mg,73μmol)加至C72(17mg,73μmol)在二氯甲烷(1mL)中的0℃溶液,并将反应混合物在0℃下搅拌15分钟。然后将其用0.5M氢氧化钠水溶液洗涤并在真空中浓缩以提供呈黄色油状物的产物。产量:22mg,71μmol,97%。LCMS m/z 311.1,313.0[M+H]+。1H NMR(400MHz,CDCl3)δ4.13-4.17(m,2H),3.83-3.87(m,2H),3.62-3.67(m,2H),2.68-2.74(m,1H),2.61(dd,J=6.5,6.4Hz,2H),2.02-2.08(m,2H),0.85-0.91(m,2H),0.66-0.71(m,2H)。
步骤12. 4-(8-环丙基-9-氧代-3,4,6,7,8,9-六氢-2H-哌喃并[2',3':4,5]吡咯并[1,2-a]吡嗪-10-基)-2-氟-5-甲基苯甲腈(16)的合成。
将氟化铯(53mg,0.35mmol)在水(0.40mL)中的溶液加至C63(42.3mg,0.162mmol)和C73(36mg,0.12mmol)在甲苯(2mL)中的混合物;然后添加双[二-叔丁基(4二甲氨基苯基)膦]二氯钯(II)(8.5mg,12μmol)。将反应烧瓶抽空并填充氮气三次,随的将反应混合物在80℃下加热18小时。在真空中移除溶剂,并将残余物分溶在水和二氯甲烷之间。将水层用二氯甲烷萃取两次,并将合并的有机层在减压下浓缩。经由反相HPLC(柱:Waters Sunfire C18,5μm;流动相A:在水中的0.05%三氟乙酸(v/v);流动相B:在乙腈中的0.05%三氟乙酸乙酸(v/v);梯度:30%至100%B)的纯化提供产物。产量:17mg,46μmol,38%。LCMS m/z 366.2[M+H]+。1H NMR(600MHz,DMSO-d6)δ7.70(d,J=6.8Hz,1H),7.19(d,J=10.5Hz,1H),3.98-4.01(m,2H),3.94(dd,J=5.8,5.8Hz,2H),3.56-3.64(m,2H),2.62-2.67(m,3H),2.15(s,3H),1.92-1.97(m,2H),0.67-0.71(m,2H),0.56-0.60(m,2H)。
制备
制备P1
10-溴-8-环丙基吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(8H)-酮(P1)
步骤1. 3-溴-1-(丙-2-烯-1-基)-1H-吡咯并[3,2-b]吡啶-2-甲酸乙酯(C74)的合成。
使用实施例13中C50的合成所述的方法将化合物C1转化成产物。当经由LCMS分析判定反应为完全时,加水,并用乙酸乙酯将反应混合物萃取三次。将合并的有机层用饱和氯化钠水溶液洗涤,经硫酸钠干燥,过滤,及在真空中浓缩。硅胶层析(梯度:在石油醚中的3%至15%乙酸乙酯)提供呈白色固体的产物。产量:2.7g,8.7mmol,79%。LCMS m/z 308.9[M+H]+。
步骤2. 3-溴-1-(丙-2-烯-1-基)-1H-吡咯并[3,2-b]吡啶-2-甲酸(C75)的合成。
将氢氧化锂(0.42g,17.5mmol)加至C74(2.7g,8.7mmol)在四氢呋喃、乙醇、及水的混合物(1:1:1比,45mL)的溶液,及将反应混合物在室温下搅拌2小时。在真空中移除溶剂提供呈黄色固体的产物,其不经另外的纯化而使用。产量:1.7g,6.0mmol,69%。
步骤3. 3-溴-N-环丙基-1-(丙-2-烯-1-基)-1H-吡咯并[3,2-b]吡啶-2-甲酰胺(C76)的合成。
使用实施例13中C52的合成所述的方法将化合物C75转化成产物,除了使反应进行24小时之外。获得呈灰色固体的产物。产量:2.81g,8.78mmol,80%。1H NMR(400MHz,CDCl3)δ8.63(dd,J=4.5,1.2Hz,1H),7.71(dd,J=8.4,1.1Hz,1H),7.28(dd,J=8.4,4.4Hz,1H,假设;部分被溶剂峰遮蔽),6.95(br s,1H),5.94-6.05(m,1H),5.21(br d,J=5.1Hz,2H),5.15(br d,J=10.4Hz,1H),4.97(br d,J=17.1Hz,1H),2.92-3.00(m,1H),0.91-0.98(m,2H),0.70-0.76(m,2H)。
步骤4. 10-溴-8-环丙基-7-羟基-7,8-二氢吡啶并-[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮(C77)的合成。
使用实施例13中C53的合成所述的方法将化合物C76转化成产物。获得呈白色固体的产物。产量:3.4g,11mmol,69%。1H NMR(400MHz,DMSO-d6)δ8.52(dd,J=4.4,1.2Hz,1H),8.10(dd,J=8.5,1.2Hz,1H),7.40(dd,J=8.5,4.5Hz,1H),6.69(d,J=5.5Hz,1H),5.32-5.37(m,1H),4.58(dd,J=13.0,1.4Hz,1H),4.19(dd,J=12.9,2.5Hz,1H),2.80-2.87(m,1H),0.90-0.98(m,1H),0.70-0.80(m,3H)。
步骤5. 10-溴-8-环丙基吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(8H)-酮(P1)的合成。
将对-甲苯磺酸单水合物(619mg,3.25mmol)和分子筛(7.9g)加至C77(1.0g,3.1mmol)在二氯甲烷(30mL)中的溶液,并将反应混合物在室温下搅拌。18小时之后,将其通过硅藻土过滤并用二氯甲烷洗涤过滤垫;随后将合并的滤液用饱和碳酸氢钠水溶液及饱和氯化钠水溶液洗涤,经硫酸钠干燥,过滤,和在真空中浓缩。硅胶层析(梯度:在石油醚中的10%至50%乙酸乙酯)提供呈黄色固体的产物。产量:0.56g,1.8mmol,58%。LCMS m/z304.1[M+H]+。1H NMR(400MHz,CDCl3)δ8.79(br d,J=4.4Hz,1H),7.95(br d,J=8.5Hz,1H),7.37(dd,J=8.5,4.5Hz,1H),7.19(d,J=6.2Hz,1H),6.57(d,J=6.2Hz,1H),3.18-3.26(m,1H),1.10-1.17(m,2H),0.90-0.96(m,2H)。
方法A
经由Suzuki反应的8-环丙基-10-(取代的苯基)-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮的合成
在小瓶中将C9(61mg,0.20mmol)在脱气1,4-二烷(0.8mL)中的悬浮液加至适当取代的苯基硼酸(0.3mmol)。碳酸钾水溶液(3M,0.2mL,0.6mmol)和[1,1’-双(二苯膦基)二茂铁]二氯钯(II)、二氯甲烷络合物(8mg,0.01mmol),和经两个循环的真空抽空将反应混合物脱气接着氮填充。将反应混合物在70℃下加热与摇晃20小时,然后分溶在水(1.5mL)和乙酸乙酯(2.5mL)之间。将有机层装载到SCX-2固相萃取筒(Silicycle,6mL,1g)上。水层的萃取进行两次以上,将有机层装载到同一筒上。用甲醇(5mL),及然后用三乙胺在甲醇中的溶液(1M,7.2mL)洗脱该筒;收集碱性洗脱液并在真空中浓缩。经由反相HPLC(柱:WatersXBridge C18,5μm;流动相A:在水中的0.03%氢氧化铵(v/v);流动相B:在乙腈中的0.03%氢氧化铵(v/v);梯度:10%至100%B)纯化产物。
使用上述关于实施例1-16的方法,合成实施例17-77。所采用的具体方法以及这些实施例的特征数据参见表6和表7。
表6
实施例17-29的合成方法和理化数据。
1.将化合物C2与(2-羟乙基)胺甲酸叔丁酯进行Mitsunobu反应以提供1-{2-[(叔丁氧羰基)氨基]乙基}-3-(4-氯苯基)-1H-吡咯并[3,2-b]吡啶-2-甲酸乙酯。叔丁氧羰基的酸介导的移除提供1-(2-氨基乙基)-3-(4-氯苯基)-1H-吡咯并[3,2-b]吡啶-2-甲酸乙酯,使用在甲醇中的三乙胺和氯化钙于50℃下将其环化成实施例19。
2.在此情况下,使用4,4,5,5-四甲基-1,3,2-氧杂环戊硼烷-2-基衍生物,而不是硼酸。
表7
实施例30-77的合成方法和理化数据。
1. 3-(4-氯苯基)-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲酰胺系经由C2与甲基胺在高温下的反应制备。
2. 1H-吡咯并[3,2-b]吡啶-2-甲酸乙酯与2-(乙氨基)乙醇的氯化钙介导的反应(参见M.W.Bundesmann等人,Tetrahedron Lett.2010,51,3879-3882)提供N-乙基-N-(2-羟乙基)-1H-吡咯并[3,2-b]吡啶-2-甲酰胺,将其与三苯膦和偶氮二羧酸二异丙酯进行分子内Mitsunobu反应以提供8-乙基-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮。使该化合物与1-溴-4-氯苯在乙酸银、乙酸钯(II)、乙酸铜(II)、三苯膦和碳酸钾的存在下于高温下反应以产生
实施例31。
3.在此情况下,使用4,4,5,5-四甲基-1,3,2-氧杂环戊硼烷-2-基衍生物,而不是硼酸。
4.在此情况下,中间体3-(4-氯苯基)-1-{2-[(5-甲基-1,2-唑-3-基)氨基]乙基}-1H-吡咯并[3,2-b]吡啶-2-甲酸乙酯系经由C2与2-[(5-甲基-1,2-唑-3-基)氨基]乙醇的Mitsunobu反应制备。
5.必要6-(4,4,5,5-四甲基-1,3,2-氧杂环戊硼烷-2-基)[1,2,4]三唑并[1,5-a]吡啶系经由与4,4,4',4',5,5,5',5'-八甲基-2,2'-联-1,3,2-氧杂环戊硼烷的[1,1’-双(二苯膦基)二茂铁]二氯钯(II)介导的反应而从6-溴[1,2,4]三唑并[1,5-a]吡啶制备。
6.必要2-(3,5-二氟-4-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-氧杂环戊硼烷系经由与4,4,4',4',5,5,5',5'-八甲基-2,2'-联-1,3,2-氧杂环戊硼烷的[1,1’-双(二苯膦基)二茂铁]二氯钯(II)-介导的反应而从5-溴-1,3-二氟-2-甲氧基苯制备。
7. 6a,7,9,10-四氢-6H,12H-吡啶并[2”,3”:4',5']吡咯并[1',2':4,5]吡嗪并[2,1-c][1,4]嗪-12-酮经由在1H-吡咯并[3,2-b]吡啶-2-甲酸和吗啉-3-基甲醇之间的O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸盐介导的反应合成以提供[3-(羟甲基)吗啉-4-基](1H-吡咯并[3,2-b]吡啶-2-基)甲酮,借着分子内Mitsunobu反应。
8.经由超临界流体层析(柱:Chiral Technologies,Chiralpak AS-H,5μm;洗脱液:3:1二氧化碳/2-丙醇)将外消旋实施例67分离成其组分阻转对映异构体。第一洗脱阻转对映异构体(ENT-1)指定为实施例68,和第二洗脱阻转对映异构体(ENT-2)指定为实施例69。
9.使用在实施例1中所述的化学将化合物C1转化成10-溴-6,7-二氢-9H-吡啶并[2',3':4,5]吡咯并[2,1-c][1,4]嗪-9-酮。随后如实施例1中所述用嘧啶-2-胺将内酯开环提供3-溴-1-(2-羟乙基)-N-(嘧啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-甲酰胺,使用Mitsunobu反应将其环化以提供所要的10-溴-8-(嘧啶-2-基)-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮。
10.如脚注9中所述制备10-溴-8-(嘧啶-2-基)-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮。
使用类似于化合物1-77所述的方法,或可通过本领域技术人员已知的方法制备表8中的化合物。
表8
实施例78-97的理化数据
利用以下生物学分析测定本发明化合物的PDE4A、PDE4B、PDE4C及PDE4D结合亲和力:
生物学分析
将人PDE4A3编码序列(来自寄存编号NP_001104779的序列的氨基酸2至825)选殖于杆状病毒表现载体pFastBac(Invitrogen)中,该表现载体经工程改造以包括N端His6亲和标签及c端FLAG亲和标签以辅助纯化。分离重组杆粒(Bacmid)且用于转染昆虫细胞以产生病毒储备液。为了产生用于纯化的细胞浆料,用病毒储备液感染昆虫细胞且感染72小时后收集细胞。将昆虫细胞浆料溶解且在离心后,使上清液分批结合于Ni-NTA琼脂糖(GEHealthcare)且用250mM咪唑洗脱。用FLAG缓冲液(50mM Tris HCL pH 7.5,100mM NaCl,5%甘油,1mM含蛋白酶抑制剂的TCEP)稀释此洗脱液,且在4℃下分批结合于ant-FLAG M2琼脂糖(Sigma)过夜。将琼脂糖填充于柱中,用缓冲液洗涤且用含有使用250μg/ml Flag-肽的洗涤液的缓冲液洗脱。使用SDS-PAGE考马斯蓝(Coomassie blue)染色分析部分且根据纯度汇集。于S200 120ml柱(GE Healthcare)上于50mM Tris HCL pH 7.5、150mM NaCl、10%甘油、2mM含蛋白酶抑制剂的TCEP中层析所汇集的部分。藉由SDS-PAGE考马斯蓝染色分析PDE4A3部分,根据纯度汇集,对50mM Tris HCL pH 7.5、100mM NaCl、20%甘油、2mM TCEP透析,冷冻且储存在-80℃下。
将具有导致氨基酸取代S134E、S654A、S659A及S661A的突变的人PDE4B1编码序列(来自寄存编号Q07343的序列的氨基酸122至736)选殖于杆状病毒表现载体pFastBac(Invitrogen)中,该表现载体经工程改造以包括辅助纯化的N端His6亲和标签接着凝血酶裂解位点。分离重组杆粒(Bacmid)且用于转染昆虫细胞以产生病毒储备液。为了产生用于纯化的细胞浆料,如Seeger,T.F.等人,Brain Research 985(2003)113-126中所述,用病毒储备液感染昆虫细胞且感染72小时后收集细胞。溶解昆虫细胞浆料且在离心后,如Seeger,T.F.等人,Brain Research 985(2003)113-126中所述,于Ni-NTA琼脂糖(Qiagen)上层析上清液。汇集含有PDE4的Ni-NTA琼脂糖洗脱部分,用Q缓冲液A(20mM Tris HCl pH 8,5%甘油,1mM TCEP)稀释,以使NaCl降至~100mM且装载于Source 15Q(GE Healthcare)柱上。用Q缓冲液A/10%缓冲液B洗涤至基线后,用10%至60%缓冲液B(20mM Tris HCl pH 8,1MNaCl,5%甘油,1mM TCEP)的梯度洗脱PDE4D。藉由SDS-PAGE考马斯蓝染色分析PDE4D部分,根据纯度汇集,冷冻且储存在-80℃下。
将人PDE4C1编码序列(来自寄存编号NP_000914.2的序列的氨基酸2至712)选殖于杆状病毒表现载体pFastBac(Invitrogen)中,该表现载体经工程改造以包括N端His6亲和标签及c端FLAG亲和标签以辅助纯化。分离重组杆粒(Bacmid)且用于转染昆虫细胞以产生病毒储备液。为了产生用于纯化的细胞浆料,用病毒储备液感染昆虫细胞且感染72小时后收集细胞。将昆虫细胞浆料溶解且在离心后,使上清液分批结合于Ni-NTA琼脂糖(GEHealthcare)且用250mM咪唑洗脱。用FLAG缓冲液(50mM Tris HCL pH 7.5,100mM NaCl,5%甘油,1mM含蛋白酶抑制剂的TCEP)稀释此洗脱液,且在4℃下分批结合于ant-FLAG M2琼脂糖(Sigma)过夜。将琼脂糖填充于柱中,用缓冲液洗涤且用含有使用250μg/ml Flag-肽的洗脱液的缓冲液洗脱。使用SDS-PAGE考马斯蓝染色分析部分且根据纯度汇集。于S200 120ml柱(GE Healthcare)上于50mM Tris HCl pH 7.5、150mM NaCl、10%甘油、2mM含蛋白酶抑制剂的TCEP中层析所汇集的部分。藉由SDS-PAGE考马斯蓝染色分析PDE4C1部分,根据纯度汇集,对50mM Tris HCL pH 7.5、100mM NaCl、20%甘油、2mM TCEP透析,冷冻且储存在-80℃下。
如Seeger,T.F.等人,Brain Research 985(2003)113-126中所述,将人PDE4D3编码序列(来自寄存编号Q08499-2的序列的氨基酸50至672)的一部分选殖于杆状病毒表现载体pFastBac(Invitrogen)中,该表现载体经工程改造以包括C端His6亲和标签而辅助纯化。分离重组杆粒(Bacmid)且用于转染昆虫细胞以产生病毒储备液。为了产生用于纯化的细胞浆料,使昆虫细胞感染且感染72小时后收集细胞。溶解昆虫细胞浆料且在离心后,如Seeger,T.F.等人,Brain Research985(2003)113-126中所述,于Ni-NTA琼脂糖(Qiagen)上层析上清液。汇集含有PDE4的Ni-NTA琼脂糖洗脱部分,用Q缓冲液A(50mM Tris HCl pH 8,4%甘油,100mM NaCl,1mM TCEP,无蛋白酶抑制剂EDTA(Roche))稀释以使NaCl降至~200mM且装载于Q琼脂糖(GE Healthcare)柱上。用Q缓冲液A洗涤至基线后,用10%至60%缓冲液B(50mM Tris HCl pH 8,1M NaCl,4%甘油,1mM TCEP)的梯度洗脱PDE4D。藉由SDS-PAGE考马斯蓝染色分析PDE4D部分,根据纯度汇集,冷冻且储存在-80℃下。
PDE4A3、PDE4B1、PDE4C1及PDE4D3分析使用闪烁近接分析(SPA)技术来量测化合物在活体外对人重组PDE4A1、PDE4B3、PDE4C1及PDE4D3酶活性的抑制。除酶浓度以外(80pMPDE4A3、40pM PDE4B3、40pM PDE4C1及10pM PDE4D),使用相同参数平行进行PDE4A1、PDE4B3、PDE4C1及PDE4D3分析。于384孔形式中用50μL含有足够的PDE4A3、PDE4B1、PDE4C1、及PDE4D以转化约20%受质(由20nM 3H-cAMP+980μM冷cAMP组成的1μM cAMP)及一范围的抑制剂的分析缓冲液(50mM TRIS pH7.5;1.3mM MgCl2;.01%Brij)进行分析。将反应在25℃下培养30分钟。添加20μL 8mg/ml硅酸钇SPA珠粒(Perkin Elmer)终止反应。将培养盘密封(TopSeal,Perkin Elmer)且使珠粒静置8小时,之后于Trilux Microbeta上读取过夜。
表9
实施例1-77的生物数据。
a.除非另外指明,否则值表示2-9个测定值的几何平均值。
b.值表示≥10个测定值的几何平均值。
c.值表示单一测定值。
ND.未测定值
实施例78-97的化合物的生物数据可发现于下表10中:
表10
a.除非另外指明,否则值表示2-9个测定值的几何平均值。
b.值表示1个测定值。
ND.未测定值。
Claims (31)
1.一种式I的PDE4抑制剂:
或其药学上可接受的盐,其中:
环A为稠合(4至8元)含氧杂环烷基环或稠合(5至8元)含氮杂芳基环,且在化学上允许的情况下,该稠合(4至8元)含氧杂环烷基环及稠合(5至8元)含氮杂芳基环任选地被一至六个R8取代;
R1选自由下列所组成的群组:(C3-C8)环烷基、(4至10元)-杂环烷基、(C6-C10)芳基及(5至14元)杂芳基,且在化学上允许的情况下,该(C3-C8)环烷基、(4至10元)杂环烷基、(C6-C10)芳基及(5至14元)杂芳基部分任选地被一至六个R9取代;
R2选自由下列所组成的群组:氢、(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C15)烷基-OR5、-C(=O)-R5、-C(=O)-OR5、-C(=O)-N(R5)(R6)、-(SO2)R5、(C3-C8)环烷基、(4至10元)杂环烷基、(C6-C10)芳基及(5至14元)杂芳基,且在化学上允许的情况下,该(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C8)环烷基、(4至10元)杂环烷基、(C6-C10)芳基及(5至14元)杂芳基任选地被一至六个R8取代;
R3a,在化学上允许的情况下,选自由下列所组成的群组:氢、卤素、氧代、氰基、羟基、-SF5、硝基、N(R5)(R6)、(C1-C6)烷硫基、(C1-C6)烷基、(C1-C6)烷氧基及(C3-C8)环烷基,其中所述烷基、烷氧基和环烷基各自任选地被一至三个选自由下列所组成的群组的取代基取代:卤素、氧代、氰基、羟基、-SF5、硝基、-C(=O)-R5、及-N(R5)(R6);或
R2和R3a与它们所连接的氮和碳原子一起形成(4至6元)杂环烷基环,且在化学上允许的情况下,该(4至6元)杂环烷基环任选地被一至六个R8取代;
当存在时,R3b选自由下列所组成的群组:氢、卤素、氧代、氰基、羟基、-SF5、硝基、N(R5)(R6)、(C1-C6)烷硫基、(C1-C6)烷基、(C1-C6)烷氧基及(C3-C8)环烷基,其中所述烷基、烷氧基和环烷基任选地被一至三个R8取代;或
R3a和R3b与它们所连接的碳原子一起形成(C3-C6)环烷基或(4至6元)杂环烷基,且在化学上允许的情况下,该(C3-C6)环烷基或(4至6元)杂环烷基、在化学上允许的情况下,任选被一至六个R8取代;
R4a,在化学上允许的情况下,选自由下列所组成的群组:氢、卤素、氧代、氰基、羟基、-SF5、硝基、N(R5)(R6)、(C1-C6)烷硫基、(C1-C6)烷基及(C1-C6)烷氧基,其中所述烷基和烷氧基各自任选地被一至三个选自由下列所组成的群组的取代基取代:卤素、氧代、氰基、羟基、-SF5、硝基、-C(=O)-R5、及-N(R5)(R6);
当存在时,R4b选自由下列所组成的群组:氢、卤素、氧代、氰基、羟基、-SF5、硝基、N(R5)(R6)、(C1-C6)烷硫基、(C1-C6)烷基及(C1-C6)烷氧基,其中所述烷基和烷氧基任选地被一至三个R8取代;或
R4a和R4b与它们所连接的碳原子一起形成(C3-C6)环烷基或(4至6元)杂环烷基,且在化学上允许的情况下,该(C3-C6)环烷基或(4至6元)杂环烷基任选地被一至六个R8取代;
R5和R6在每次出现时各自独立地选自由下列所组成的群组:氢及(C1-C6)烷基;
R7为(C1-C6)烷基;
当存在时,R8在每次出现时各自独立地选自由下列所组成的群组:卤素、氧代、氰基、羟基、-SF5、硝基、N(R5)(R6)、(C1-C6)烷硫基、(C1-C6)烷基、及(C1-C6)烷氧基,其中所述烷基和烷氧基各自任选地被一至三个选自由下列所组成的群组的取代基取代:卤素、氧代、氰基、羟基、-SF5、硝基、-C(=O)-R5、及-N(R5)(R6);
当存在时,R9在每次出现时各自独立地选自由下列所组成的群组:卤素、氧代、氰基、羟基、-SF5、硝基、(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)烷硫基、(C1-C6)烷氧基、-N(R5)(R6)、-N(R5)(C(O)R6)、-C(=O)、-C(=O)-R5、-C(=O)-OR5、-(SO2)R7、及
-S(=O2)N(R5)(R6),其中所述烷基和烷氧基各自任选地被一至三个选自由下列所组成的群组的取代基取代:卤素、氧代、氰基、羟基、-SF5、硝基、-C(=O)-R5、及-N(R5)(R6);
-------系不存在(形成单键)或为一键(形成双键);以及
n为选自0或1的整数,条件是当------存在从而形成双键时,则n为0,以及当------不存在从而形成单键时,n为1。
3.根据权利要求2的PDE4抑制剂,或其药学上可接受的盐,其中环A为稠合(4至6元)含氧杂环烷基环及该杂环烷基环为任选地被一至三个R8取代的四氢吡喃基。
4.根据权利要求2的PDE4抑制剂,或其药学上可接受的盐,其中环A为选自由下列所组成的群组的稠合(5至6元)含氮杂芳基环:吡啶基环、嘧啶基环、吡嗪基及噻唑基环,其各自任选地被一至三个R8取代。
5.根据权利要求1-4任一项的PDE4抑制剂,或其药学上可接受的盐,其中各R8独立地选自由下列所组成的群组:卤素、(C1-C6)烷基、及(C1-C6)烷氧基,其中该烷基及烷氧基各自任选地被一至三个选自由下列所组成的群组的取代基取代:卤素、氧代、氰基、羟基、-SF5、硝基、-C(=O)-R5及-N(R5)(R6)。
6.根据权利要求5的PDE4抑制剂,或其药学上可接受的盐,其中R1选自由下列所组成的群组:
i)选自由下列所组成的群组的(C3-C6)环烷基:环丙基、环丁基、环戊基、环己基、环己烯基、环己二烯基、及环戊烯基,其各自任选地被一至三个R9取代;
ii)选自由下列所组成的群组的(4至10元)杂环烷基:氮杂环丁烷基、二氢呋喃基、二氢噻吩基、四氢噻吩基、四氢呋喃基、四氢三嗪基、四氢吡唑基、四氢嗪基、四氢嘧啶基、八氢苯并呋喃基、八氢苯并咪唑基、八氢苯并噻唑基、咪唑烷基、吡咯烷基、哌啶基、哌嗪基、唑烷基、噻唑烷基、吡唑烷基、硫代吗啉基、四氢吡喃基、四氢噻嗪基、四氢噻二嗪基、四氢唑基、吗啉基、氧杂环丁烷基、四氢二嗪基、嗪基、噻嗪基、奎宁环基、色满基、异色原烷基、二氢苯并二氧杂环己烯基、苯并二氧杂环戊烯基、苯并嗪基、二氢吲哚基、二氢苯并呋喃基、四氢喹啉基、异色满基、二氢-1H-异吲哚基、2-氮杂双环[2.2.1]庚酮基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、异噻唑烷基、1,3-噻嗪烷-3-基、唑烷酮基、2-氧代-哌啶基,其各自任选地被一至三个R9取代;
iii)选自苯基或萘基的(C6-C10)芳基,其各自任选地被一至三个R9取代;以及
iv)选自由下列所组成的群组的(5至14元)杂芳基:吡啶基、吡嗪基、嘧啶基、哒嗪基、三唑基、咪唑基、呋喃基、异唑基、异噻唑基、1,2,3-、1,2,4-、1,2,5-、1,3,4-二唑基、唑基、噻吩基、噻唑基、异噻唑基、吡唑基、吲哚基、吲唑基、苯并呋喃基、苯并咪唑基、苯并噻吩基、苯并二唑基、苯并噻唑基、异苯并硫代呋喃基、苯并硫代呋喃基、苯并异唑基、苯并唑基、苯并二氧杂环戊烯基、呋喃并吡啶基、嘌呤基、咪唑并吡啶基、咪唑并嘧啶基、吡咯并吡啶基、吡唑并吡啶基、吡唑并嘧啶基、噻吩并吡啶基、三唑并嘧啶基、三唑并吡啶基、蒽基、喹啉基、异喹啉基、噌啉基、喹唑啉基、氧代色满基、及1,4-苯并嗪基,其各自任选地被一至三个R9取代。
8.根据权利要求6的PDE4抑制剂,或其药学上可接受的盐,其中R1为(C6-C10)芳基且该芳基为任选地被一至三个独立地选自由下列所组成的群组的R9取代的苯基:卤素、氧代、氰基、羟基、-SF5、硝基、(C1-C6)烷基、(C1-C6)烷氧基、-N(R5)(R6)、-(SO2)R7、及-S(=O2)N(R5)(R6),其中所述烷基和烷氧基各自任选地被一至三个选自由下列所组成的群组的取代基取代:卤素、氧代、氰基、羟基、-SF5、硝基、-C(=O)-R5、及-N(R5)(R6),以及其中R5和R6在每次出现时各自独立地选自由下列所组成的群组:氢及(C1-C6)烷基,以及R7为(C1-C6)烷基。
9.根据权利要求6的PDE4抑制剂,或其药学上可接受的盐,其中R1为(5至14元)杂芳基且该杂芳基选自由下列所组成的群组:唑基、吡唑基、噻吩基、噻唑基、三唑基、吡啶基、嘧啶基、三唑并吡啶基及呋喃并吡啶基,其各自任选地被一至三个独立地选自由下列所组成的群组的R9取代:卤素、氧代、氰基、羟基、-SF5、硝基、(C1-C6)烷基、(C1-C6)烷氧基、-N(R5)(R6)、-(SO2)R7、及-S(=O2)N(R5)(R6),其中所述烷基和烷氧基各自任选地被一至三个选自由下列所组成的群组的取代基取代:卤素、氧代、氰基、羟基、-SF5、硝基、-C(=O)-R5、及-N(R5)(R6),以及其中R5和R6在每次出现时各自独立地选自由下列所组成的群组:氢及(C1-C6)烷基,以及R7为(C1-C6)烷基。
10.根据权利要求6-9任一项的PDE4抑制剂,或其药学上可接受的盐,其中各R9独立地选自氟、氯、氰基、(C1-C6)烷基或(C1-C6)烷氧基,其中该烷基及烷氧基各自任选地被一至三个选自由下列所组成的群组的取代基取代:卤素、氧代、氰基、羟基、-SF5、硝基、-C(=O)-R5及-N(R5)(R6)。
11.根据权利要求10的PDE4抑制剂,或其药学上可接受的盐,其中R9选自:
i)(C1-C6)烷基,其选自甲基、乙基或丙基,且该甲基、乙基及丙基任选地被一至三个氟原子取代;及
ii)(C1-C6)烷氧基,其选自甲氧基、乙氧基或丙氧基且该甲氧基、乙氧基及丙氧基任选地被一至三个氟原子取代。
12.根据权利要求1的PDE4抑制剂,或其药学上可接受的盐,其中R2选自由下列所组成的群组:氢、(C1-C6)烷基、(C3-C8)环烷基、(4至6元)杂环烷基及(5至6元)杂芳基,其中该(C1-C6)烷基、(C3-C8)环烷基、(4至6元)杂环烷基及(5至6元)杂芳基任选地被一至三个独立地选自由下列所组成的群组的R8取代:卤素、氰基、(C1-C6)烷基、及(C1-C6)烷氧基,其中该烷基及烷氧基各自任选地被一至三个选自由下列所组成的群组的取代基取代:卤素、氧代、氰基、羟基、-SF5、硝基、-C(=O)-R5及-N(R5)(R6)。
13.根据权利要求12的PDE4抑制剂,或其药学上可接受的盐,其中R2为氢。
14.根据权利要求12的PDE4抑制剂,或其药学上可接受的盐,其中R2为选自甲基、乙基、或丙基的(C1-C6)烷基,其各自任选地被一至三个独立地选自由下列所组成的群组的R8取代:卤素、氰基、(C1-C6)烷基、及(C1-C6)烷氧基,其中该烷基及烷氧基各自任选地被一至三个选自由下列所组成的群组的取代基取代:卤素、氧代、氰基、羟基、-SF5、硝基、-C(=O)-R5及-N(R5)(R6)。
15.根据权利要求12的PDE4抑制剂,或其药学上可接受的盐,其中R2为选自环丙基、环丁基、环戊基、环己基、环戊基或环辛基的(C3-C8)环烷基,其各自任选地被一至三个独立地选自由下列所组成的群组的R8取代:卤素、氰基、(C1-C6)烷基、及(C1-C6)烷氧基,其中该烷基及烷氧基各自任选地被一至三个选自由下列所组成的群组的取代基取代:卤素、氧代、氰基、羟基、-SF5、硝基、-C(=O)-R5及-N(R5)(R6)。
16.根据权利要求15的PDE4抑制剂,或其药学上可接受的盐,其中R2为环丙基。
18.根据权利要求1的PDE4抑制剂,或其药学上可接受的盐,其中R3a,在化学上允许的情况下,选自由下列所组成的群组:氢、卤素、(C1-C6)烷基、(C1-C6)烷氧基、及(C3-C8)环烷基,其中该烷基、烷氧基及环烷基各自任选地被一至三个选自由下列所组成的群组的取代基取代:卤素、氧代、氰基、羟基、-SF5、硝基、-C(=O)-R5及-N(R5)(R6)。
19.根据权利要求1的PDE4抑制剂,或其药学上可接受的盐,其中R4a,在化学上允许的情况下,选自由下列所组成的群组:氢、卤素、(C1-C6)烷基、及(C1-C6)烷氧基,其中所述烷基和烷氧基各自任选地被一至三个选自由下列所组成的群组的取代基取代:卤素、氧代、氰基、羟基、-SF5、硝基、-C(=O)-R5及-N(R5)(R6)。
20.根据权利要求1的PDE4抑制剂,或其药学上可接受的盐,其中R2和R3a与它们所连接的氮和碳原子一起形成选自由下列所组成的群组的(4至6元)杂环烷基环:氮杂环丁烷基、吡咯烷基、及吗啉基,其各自任选地被一至三个R8取代。
21.根据权利要求1的PDE4抑制剂,或其药学上可接受的盐,其中R3b,在化学上允许的情况下,选自由下列所组成的群组:氢、卤素、氧代、氰基、羟基、-SF5、硝基、(C1-C6)烷基、(C1-C6)烷氧基、及(C3-C8)环烷基,其中所述烷基、烷氧基、及环烷基任选地被一至三个R8取代。
22.根据权利要求1的PDE4抑制剂,或其药学上可接受的盐,其中R4b,在化学上允许的情况下,选自由下列所组成的群组:氢、卤素、氧代、氰基、羟基、-SF5、硝基、(C1-C6)烷基及(C1-C6)烷氧基,其中所述烷基和烷氧基任选地被一至三个R8取代。
23.根据权利要求1的PDE4抑制剂,其选自由下列所组成的群组:
10-(4-氯苯基)-8-环丙基-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮;
10-(4-氯-2-氟苯基)-8-环丙基-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮;
4-(7-环丙基-8-氧代-5,6,7,8-四氢[1,3]噻唑并[4',5':4,5]吡咯并[1,2-a]吡嗪-9-基)-3-甲基苯甲腈;
(6aS)-12-(4-氯苯基)-6a,7,8,9-四氢-6H,11H-吡啶并[2',3':4,5]吡咯并[1,2-a]吡咯并[1,2-d]吡嗪-11-酮;
10-(4-氯苯基)-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮;
4-(8-环丙基-9-氧代-6,7,8,9-四氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-10-基)-3-氟苯甲腈;
8-环丙基-10-(4-氟-2-甲基苯基)-7,8二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮;
8-环丙基-10-(6-甲氧基吡啶-3-基)-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮;
(7S)-10-(4-氯苯基)-8-环丙基-7-甲基-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮;
4-(8-环丙基-9-氧代-6,7,8,9-四氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-10-基)-3-甲基苯甲腈;
5-(8-环丙基-9-氧代-6,7,8,9-四氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-10-基)吡啶-2-甲腈;及
10-(4-氯-2-甲基苯基)-8-环丙基-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮;
4-(7-环丙基-8-氧代-5,6,7,8-四氢[1,3]噻唑并[4',5':4,5]吡咯并[1,2-a]吡嗪-9-基)-2-氟-5-甲基苯甲腈;及
8-环丙基-10-(3-氟-4-甲氧基苯基)-7,8二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮;
或其药学上可接受的盐。
24.根据权利要求1的PDE4抑制剂,其中所述PDE4抑制剂是4-(7-环丙基-8-氧代-5,6,7,8-四氢[1,3]噻唑并[4',5':4,5]吡咯并[1,2-a]吡嗪-9-基)-2-氟-5-甲基苯甲腈,或其药学上可接受的盐。
25.根据权利要求1的PDE4抑制剂,其中所述PDE4抑制剂是8-环丙基-10-(3-氟-4-甲氧基苯基)-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮,或其药学上可接受的盐。
26.根据权利要求1的PDE4抑制剂,其中所述PDE4抑制剂是10-(4-氯-2-氟苯基)-8-环丙基-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮,或其药学上可接受的盐。
27.根据权利要求1的PDE4抑制剂,其中所述PDE4抑制剂是10-(4-氯-2-甲基苯基)-8-环丙基-7,8-二氢吡啶并[2',3':4,5]吡咯并[1,2-a]吡嗪-9(6H)-酮,或其药学上可接受的盐。
28.一种药物组合物,其包含根据权利要求1至27任一项的PDE4抑制剂,或其药学上可接受的盐,及药学上可接受的赋形剂。
29.根据权利要求1至27任一项中所定义的PDE4抑制剂或其药学上可接受的盐或根据权利要求28的药物组合物在制备用于治疗罹患由PDE4B同工型介导的疾病或病况的患者的药物中的用途,其中该疾病或病况选自由下列所组成的群组:精神分裂症、抑郁、焦虑、阿尔茨海默病、帕金森氏病、脑血管疾病、精神病、创伤性脑损伤、癫痫、自体免疫性及炎症性疾病和由药物依赖及滥用所致的行为障碍。
30.根据权利要求29的用途,其中所述自体免疫性及炎症性疾病选自多发性硬化、慢性阻塞性肺病、炎症、哮喘、过敏性结膜炎和牛皮癣性关节炎。
31.根据权利要求29的用途,其中所述脑血管疾病是中风。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US201562180815P | 2015-06-17 | 2015-06-17 | |
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CN109438448B (zh) * | 2018-11-07 | 2021-08-27 | 成都大学 | 一种吲哚并七元环化合物及其制备方法和用途 |
EP3914701A4 (en) * | 2019-01-23 | 2022-10-19 | Path Therapeutics Inc. | METHODS OF TREATMENT OF EPILEPSY VIA PHOSPHODIESTERASE 4-(PDE4) INHIBITION |
JP2023502441A (ja) * | 2019-11-25 | 2023-01-24 | アルカームス インコーポレーテッド | 置換大環状化合物および関連する治療方法 |
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