CN101573356A - 糖皮质激素受体、AP-1和/或NF-kB活性的调节剂及其用途 - Google Patents
糖皮质激素受体、AP-1和/或NF-kB活性的调节剂及其用途 Download PDFInfo
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- CN101573356A CN101573356A CNA200780049023XA CN200780049023A CN101573356A CN 101573356 A CN101573356 A CN 101573356A CN A200780049023X A CNA200780049023X A CN A200780049023XA CN 200780049023 A CN200780049023 A CN 200780049023A CN 101573356 A CN101573356 A CN 101573356A
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- Psychiatry (AREA)
Abstract
本发明提供了用于治疗与调节糖皮质激素受体AP-1和/或NF-κB活性相关的疾病,包括代谢性疾病或病症和炎症性或免疫相关的疾病或病症的新颖的非甾类化合物或其对映异构体、非对映异构体、互变异构体或药用盐,所述化合物具有式I的结构,其中:A为5、6或7元杂环基或5、6或7元杂芳基,各自含有选自N、O和S的1、2或3个杂原子并且每个所述杂环基或杂芳基被一至四个基团R1、R2、R3和/或R4取代;M选自烷基、环烷基、芳基、杂环基和杂芳基;Z选自烷基、CF3、OH、环烷基、杂环基、芳基、杂芳基、-C(=O)NR8R9、-C(=O)R8、-C(NCN)NR8R9、-C(=O)OR8、-SO2R8和-SO2NR8R9。本发明还提供了药物组合物、组合和使用所述化合物治疗代谢性疾病或病症和炎症性或免疫相关的疾病或病症的方法。
Description
本申请要求提交于2006年11月1日的美国临时申请系列号60/855,952的优先权,将其引入本申请作为参考。
技术领域
本发明涉及新的非甾类化合物(non-steroidal compound),所述化合物是糖皮质激素受体、AP-1和/或NF-κB活性的有效调节剂,由此用于治疗包括代谢性疾病或病症和炎症性或免疫相关的疾病或病症在内的疾病或病症。本发明还提供了所述化合物的组合物和组合(combination),以及使用所述化合物和组合物治疗这些疾病和相关疾病或病症的方法。
背景技术
转录因子(transcription factor)NF-κB和AP-1涉及调节介导炎症和免疫应答所牵涉的多种基因的表达。其中,NF-κB对以下基因的转录进行调节,所述基因包括TNF-α、IL-1、IL-2、IL-6、粘附分子(如内皮细胞选择素(E-selectin))和趋化因子(如Rantes)。AP-1调节细胞因子TNF-α、IL-1、IL-2以及基质金属蛋白酶(matrix metalloprotease)的生成。已经显示,靶向于TNF-α(一种表达同时受NF-κB和AP-1调节的基因)的药物治疗对于几种炎症性人类疾病(包括类风湿性关节炎和克罗恩病(Crohn’s disease))是高度有效的。因此,NF-κB和AP-1在炎症性疾病和免疫性疾病的引发和延续(perpetuation)中起着关键作用。参见Baldwin,A.S.,Journal of Clin.Investigation,107,3(2001);Firestein,G.S.,and Manning,A.M.,Arthritis andRheumatism,42,609(1999);和Peltz,G.,Curr.Opin.in Biotech.8,467(1997)。
在AP-1和NF-κB的上游存在许多信号分子(激酶和磷酸酶),它们是潜在的治疗药物靶标。激酶JNK在调节c-jun(构成AP-1复合物(fos/c-jun)的亚单位之一)的磷酸化和随后的激活中起着关键作用。抑制JNK的化合物已经显示在炎症性疾病的动物模型中是有效的。参见Manning,A.M.and Davis,R.J.,Nature Rev.Drug Disc.,V.2,554(2003)。对于激活NF-κB至关重要的激酶是IκB激酶(IKK)。这种激酶在IκB中的磷酸化中起着关键作用。一旦IκB被磷酸化,其便进行降解,导致NF-κB的释放,所述NF-κB可易位进入细胞核中并且激活上述基因的转录。已经显示IKK的抑制剂在炎症性疾病的动物模型中是有效的。参见Burke,J.R.,Curr.Opin.Drug Discov.Devel.,Sep;6(5),720-8,(2003)。
除了抑制在NF-κB和AP-1激活中牵涉的信号级联放大(signalingcascade)之外,已经显示糖皮质激素受体通过直接物理相互作用抑制NF-κB和AP-1的活性。糖皮质激素受体(GR)是转录因子的细胞核激素受体家族(nuclear hormone receptor family)的一员,并且是转录因子的甾类激素家族的一员。对糖皮质激素受体蛋白进行亲和标记(Affinity labeling)使得对抗所述受体的抗体产生,这利于克隆糖皮质激素受体。对于人类中的结果,参见Weinberger等人.,Science,228,740-742(1985);Weinberger等人.,Nature,318,670-672(1986),以及对于大鼠中的结果,参见Miesfeld,R.,Nature,312,779-781(1985)。
与GR相互作用的糖皮质激素已经用于治疗炎症性疾病超过50年。已经清楚地显示糖皮质激素通过由GR抑制转录因子NF-κB和AP-1从而发挥其抗炎活性。这种抑制称为反式阻抑(transrepression)。已经显示,由GR抑制这些转录因子的主要机理是通过直接的物理相互作用。这种相互作用改变了转录因子复合物,并且抑制NF-κB和AP-1刺激转录的能力。参见Jonat,C.等人.,Cell,62,1189(1990);Yang-Yen,H.F.等人.,Cell,62,1205(1990);Diamond,M.I.等人.,Science 249,1266(1990)和Caldenhoven,E.等人.,Mol.Endocrinol.,9,401(1995)。也提出了其它机理,例如通过GR隔离(sequestrate)辅激活因子(co-activator)。参见Kamei,Y.等人.,Cell,85,403(1996);和Chakravarti,D.等人.,Nature,383,99(1996)。
除了引起反式阻抑外,糖皮质激素与GR的相互作用可引起GR诱导某些基因的转录。这种对转录的诱导称为反式激活(transactivation)。反式激活需要GR二聚化并与糖皮质激素应答元件(glucocorticoid response element,GRE)结合。
最近研究使用不能结合DNA的转基因GR二聚化缺陷的小鼠(transgenic GR dimerization defective mouse),这些研究已经显示,GR的反式激活(DNA结合)活性可与GR的反式阻抑(非DNA结合)作用分开。这些研究还指明糖皮质激素治疗的许多副作用是由于GR诱导在代谢中牵涉的各种基因的转录的能力所造成的,然而,不需要DNA结合的反式阻抑导致了对炎症的抑制。参见Reichardt,H.M.等人.,Cell,93,531(1998)和Reichardt,H.M.,EMBO J.,20,7168(2001)。
调节AP-1和NF-κB活性的化合物可用于治疗炎症性和免疫性疾病和病症,如骨关节炎(osteoarthritis)、类风湿性关节炎、多发性硬化(multiplesclerosis)、哮喘、炎症性肠病(inflammatory bowel disease)、移植排斥(transplantrejection)和移植物抗宿主病(graft vs.host disease)。
此外,关于糖皮质激素受体途径,已知的是糖皮质激素是强效的抗炎药,然而它们的全身使用受副作用的限制。在保持糖皮质激素的抗炎功效的同时使副作用(如糖尿病、骨质疏松症(osteoporosis)和青光眼(glaucoma))最小化的化合物对于众多患有炎症性疾病的患者而言是非常有益的。
此外,关于GR,本领域需要对抗反式激活的化合物。所述化合物可用于治疗与糖皮质激素水平增加相关的代谢性疾病,如糖尿病、骨质疏松症和青光眼。
此外,关于GR,本领域需要引起反式激活的化合物。所述化合物可用于治疗与糖皮质激素缺乏相关的代谢性疾病。所述疾病包括艾迪生病(Addison’s disease)。
发明内容
本发明涉及新的非甾类化合物,所述化合物是糖皮质激素受体、AP-1和/或NF-κB活性的有效调节剂,由此用于治疗包括代谢性疾病或病症和炎症性或免疫相关的疾病或病症在内的疾病或病症。本发明还提供了所述化合物的组合物,以及使用所述化合物和组合物治疗这些疾病和相关疾病或病症的方法。
根据本发明的一个方面,其提供了具有式(I)结构的化合物或其对映异构体、非对映异构体、互变异构体或药用盐,
(I)
其中:
A为5、6或7元杂环基或5、6或7元杂芳基,所述杂环基或杂芳基各自含有选自N、O和S的1、2或3个杂原子并且每个所述杂环基或杂芳基被一至四个基团R1、R2、R3和/或R4取代,条件是(i)A不是四唑基,或(ii)若A为噻吩基或呋喃基,则Z选自不是琥珀酰亚胺基或邻苯二甲酰亚胺基(thalimido)的基团;
M选自烷基、环烷基、芳基、杂环基和杂芳基;
Ma为碳原子和M之间的连接基并且选自化学键和C1-C3亚烷基;
Q选自
(i)氢、卤素、硝基、氰基、羟基、C1-4烷基和取代的C1-4烷基;或
(ii)Q与R6和它们所连接的碳原子结合形成3至6元环烷基;或
(iii)Q和M与它们所连接的碳原子结合形成含有1-2个杂原子的3至7元环,所述杂原子独立选自O、S、SO2和N,所述环可任选被0-2个R5基团或羰基取代;
Z选自烷基、CF3、OH、环烷基、杂环基、芳基、杂芳基、-C(=O)NR8R9、-C(=O)R8、-C(NCN)NR8R9、-C(=O)OR8、-SO2R8和-SO2NR8R9;
Za为氮原子和Z之间的连接基并且选自化学键和C1-C6亚烷基;
R1、R2、R3和R4在每次出现时独立选自氢、卤素、烷基、取代的烷基、烯基、取代的烯基、炔基、取代的炔基、硝基、氰基、-OR10、-SR10、-NR10R11、-C(=O)R10、-CO2R10、-C(=O)NR10R11、-O-C(=O)R10、-NR10C(=O)R11、-NR10C(=O)OR11、-NR10C(S)OR11、-S(=O)pR12、-NR10SO2R12、-SOpNR10R11、环烷基、杂环基、芳基和杂芳基;
R5在每次出现时独立选自氢、卤素、烷基、取代的烷基、烯基、取代的烯基、炔基、取代的炔基、硝基、氰基、-OR13、-NR13R14、-C(=O)R13、-CO2R13、-C(=O)NR13R14、-O-C(=O)R13、-NR13C(=O)R14、-NR13C(=O)OR14、-NR13C(S)OR14、-S(=O)pR15、-NR13SO2R15、-SO2NR13R14、环烷基、杂环基、芳基或杂芳基;
R6选自烷基、取代的烷基、烯基、取代的烯基、炔基、取代的炔基、氰基、-C(=O)R17、-CO2R17、-C(=O)NR16R17、环烷基、杂环基、芳基和杂芳基,条件是杂环基或杂芳基通过碳原子相连;
R7选自氢、卤素、烷基、取代的烷基、烯基、取代的烯基、炔基、取代的炔基、硝基、氰基、-OR19、-NR19R20、-C(=O)R19、-CO2R19、-C(=O)NR19R20、-O-C(=O)R19、-NR19C(=O)R20、-NR19C(=O)OR20、-NR19C(=S)OR20、-S(=O)pR21、-NR19SO2R21、-SO2NR19R20、环烷基、杂环基、芳基和杂芳基;
或R6和R7与它们所连接的碳连在一起形成环烷基或杂环基;
R8、R9、R10、R11、R13、R14、R16、R17、R19和R20在每次出现时独立选自:
(i)氢、烷基、取代的烷基、烯基、取代的烯基、炔基、取代的炔基、烷基SOp-、环烷基、芳基、杂芳基和杂环基;或
(ii)R8与R9连在一起;和/或R10与R11连在一起;和/或R16与R17连在一起;和/或R19与R20连在一起形成4至7元杂芳基环或4至7元杂环基环;
R12、R15、R18和R21独立选自烷基、取代的烷基、烯基、取代的烯基、炔基、取代的炔基、环烷基、芳基、杂芳基或杂环基;
R22选自氢、烷基、取代的烷基、烷基C(=O)-、烷基OC(=O)-、烷基SO2-、烷氧基、氨基、取代的氨基、芳基、杂芳基、杂环基和环烷基;以及
p为1或2。
优选的是,在式(I)的化合物中A选自吡咯基、吡唑基、吡唑啉基、咪唑基、噁唑基、异噁唑基、噁二唑基、三唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、噻吩基、噁二唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基和三唑基,其中的每个任选被一至四个基团R1、R2、R3和/或R4取代。甚至更优选地,A为噻吩基、噻唑基、噻二唑基、呋喃基、吡咯基、吡唑基、吡啶基或嘧啶基,每个基团任选被一至四个基团R1、R2、R3和/或R4取代。
还优选的是,在式(I)的化合物中
Q为氢或烷基;
M为烷基、芳基、环烷基、杂芳基、芳基烷基、杂环基、烷基芳基烷基、烷基芳基或卤代芳基;
R6选自C1-4烷基、取代的C1-4烷基、氰基和C3-7环烷基;以及
R7选自氢、C1-4烷基、取代的C1-4烷基、硝基、-NR19R20、氰基、羟基、C1-4烷氧基和C3-7环烷基;
或R6和R7与它们所连接的碳连在一起形成C3-7环烷基;
或Q和R6与它们所连接的碳原子结合在一起形成
或Q和Ma-M与它们共同连接的碳原子结合在一起形成
更优选的是,在式(I)的化合物中
Ma为化学键;
M选自C1-6烷基和芳基(更优选地,M为未取代的苯基或被1-3个选自卤素的基团取代的苯基和/或具有至少一个选自N、S和O的杂原子的6元杂环基);以及
Q为氢或C1-6烷基(更优选地,Q为氢)。
还优选的是,在式(I)的化合物中
Za为化学键;
Z为杂芳基,所述杂芳基含有1、2或3个选自N、S和O的杂原子,并且所述杂芳基被一、二或三个基团Rm、Rn和/或Ro取代;
Rm、Rn和/或Ro独立选自(i)氢、卤素、烷基、取代的烷基、烯基、取代的烯基、炔基、取代的炔基、硝基、氰基、-OR23、-NR23R24、-C(=O)R23、-CO2R23、-C(=O)NR23R24、-O-C(=O)R23、-NR23C(=O)R24、-NR23C(=O)OR24、-NR23C(=S)OR24、-S(=O)pR25、-NR23SO2R25、-SO2NR23R24、环烷基、杂环基、芳基和杂芳基;或(ii)位于相邻的原子上的Rm、Rn和/或Ro中的两个与它们所连接的原子可结合形成环烷基环、芳基环、杂芳基环或杂环基环;
R23和R24在每次出现时独立选自氢、烷基、取代的烷基、烷基C(=O)-、烷基OC(=O)-、烷基SO2-、烯基、取代的烯基、炔基、取代的炔基、氨基、芳基、杂芳基、杂环基和环烷基;
R25选自烷基、取代的烷基、烯基、取代的烯基、炔基、取代的炔基、氨基、取代的氨基、杂芳基、杂环基、环烷基和芳基。
在式(I)的化合物的更优选的实施方案中,
Za为化学键;
Rm和Rn在每次出现时独立选自氢、卤素、环烷基、氰基、卤代烷基、烷硫基、-CO2R23、-NR23R24、-C(=O)R23、-C(O)N(R23)(R24)、-OR23、C1-4烷基、取代的C1-4烷基、芳基、杂芳基和杂环基;
或Rm和Rn与它们所连接的原子结合在一起形成任选取代的稠合的5至7元环烷基环、5至7元芳基环、5至7元杂芳基环或5至7元杂环基环;以及
R23和R24在每次出现时独立选自氢、烷基、取代的烷基、烷基C(=O)-、烷基OC(=O)-、烷基SO2-、烯基、取代的烯基、炔基、取代的炔基、氨基、芳基、杂芳基、杂环基和环烷基。
在式(I)的化合物的更优选的实施方案中,
A为噻吩基、噻唑基、异噻唑基、噻二唑基、呋喃基、吡咯基、吡唑基、吡啶基或嘧啶基,每个基团任选被1至4个基团R1、R2、R3和/或R4取代;
R1、R2、R3和/或R4独立选自(i)氢、卤素、C1-4烷基、CN、C2-4烯基、C2-4炔基、-CO2R10、-SR10、-SO2R12、-OR10、-SOpNR10R11和-NR10R11;和/或(ii)被任选取代的基团取代的C0-3亚烷基,所述任选取代的基团选自苯基和5至7元杂芳基;
R10和R11在每次出现时独立选自(i)氢、C1-6烷基、取代的C1-6烷基和SO2(C1-4烷基);和/或(ii)C3-7环烷基、杂环基、芳基和杂芳基,每个基团任选被取代;和/或(iii)R10与R11和它们同时连接的氮原子连在一起形成4至6元杂芳基环或4至6元杂环基环,每个基团任选被取代;以及
R12在每次出现时选自任选取代的基团,所述取代的基团选自C1-6烷基、C3-7环烷基、杂环基、芳基和杂芳基。
更优选地,R1、R2、R3和R4独立选自氢、卤素、烷氧基、任选被OH取代的吗啉基、哌啶基、-NH(CH2)n(任选被C1-4烷基取代的苯基)、吡咯烷基、呋喃基或任选被一至二个取代基取代的苯基,所述一至二个取代基选自卤素、烷氧基、C1-6烷基、-CO2R10(例如-COOH、-C(O)OC1-4烷基)和-C(O)NR10R11(例如-C(O)N(C1-4烷基)2或C(O)N(C3-6环烷基)2、-C(O)NH(C1-4烷基)或-C(O)NH(C3-6环烷基),或-C(O)(N-吗啉基、N-哌啶基、N-吡咯烷基或N-氮丙啶基,每个基团任选被卤素取代));以及n为0、1或2。
在式(I)的化合物的其它优选的实施方案中,A选自:
Q为H或CH3;
本发明的式(I)的化合物的更优选的实施方案具有式(Ia)或其对映异构体、非对映异构体或药用盐,
其中:
A为噻吩基、噻唑基、异噻唑基、噻二唑基、呋喃基、吡咯基、吡唑基、吡啶基或嘧啶基,每个基团任选被1至4个基团R1、R2、R3和/或R4取代;
Rm和Rn在每次出现时独立选自(i)氢、卤素、环烷基、氰基、卤代烷基、烷硫基、-CO2R23、-NR23R24、-C(=O)R23、-C(O)N(R23)(R24)、-OR23、C1-4烷基、取代的C1-4烷基、芳基、杂芳基和杂环基;或(ii)Rm和Rn与它们所连接的原子结合在一起形成5至7元环烷基环、5至7元芳基环、5至7元杂芳基环或5至7元杂环基环;
R1、R2、R3、R4、R1a、R2a、R3a和R4a独立选自(i)氢、卤素、C1-4烷基CNC2-4烯基、C2-4炔基、SR10、SO2R12、OR10、SOpNR10R11和NR10R11;和/或(ii)被任选取代的基团取代的C0-3亚烷基,所述任选取代的基团选自苯基和5至7元杂环基或5至7元杂芳基;
R6选自C1-4烷基、C1-4取代的烷基、氰基和C3-7环烷基;
R7选自氢、C1-4烷基、C1-4取代的烷基、硝基、氰基、羟基、C1-4烷氧基和C3-7环烷基;
或R6和R7与它们所连接的碳连在一起形成C3-7环烷基;
R10和R11在每次出现时独立选自(i)氢、C1-6烷基、取代的C1-6烷基和-SO2(C1-4烷基);和/或(ii)C3-7环烷基、杂环基、芳基和杂芳基,每个为任选被取代的基团;和/或(iii)R10与R11和它们同时连接的氮原子连在一起形成4至6元杂芳基环或4至6元杂环基环,每个基团任选被取代;
R12在每次出现时独立选自任选取代的基团,所述取代的基团选自C1-6烷基、C3-7环烷基、杂环基、芳基和杂芳基;以及
R23和R24在每次出现时独立选自氢、烷基、取代的烷基、烷基C(=O)-、烷基OC(=O)-、烷基SO2-、烯基、取代的烯基、炔基、取代的炔基、氨基、芳基、杂芳基、杂环基和环烷基。
包括在式(Ia)范围内的优选的化合物是下述的化合物:其中A为任选被一个或两个基团取代的噻吩基或吡啶基,所述基团选自卤素、烷氧基、吗啉基、哌啶基、-NH(CH2)n(任选被C1-4烷基取代的苯基)、吡咯烷基、呋喃基和任选被选自卤素、烷氧基、C1-6烷基、-CO2R10或-C(O)NR10R11的一个或两个取代基取代的苯基;以及n为0、1或2。
包括在式(Ia)范围内的其它优选的化合物是下述的化合物:其中A选自:
包括在式(Ia)范围内的更优选的化合物是下述的化合物,其中:
R2为氢或卤素;以及
R23和R24独立选自C1-4烷基;或
R23和R24与它们所连接的氮原子结合在一起形成任选取代的(优选的取代基为卤素)4至7元杂环(更优选地为吗啉基)。
包括在式(Ia)范围内的其它优选的化合物是下述的化合物:其中R1a、R2a、R3a和R4a选自氢、C1-4烷基、卤素、硝基、氰基、羟基、C1-4烷氧基、吗啉基、哌啶基、哌嗪基和吡咯烷基(更优选地R3a和R4a都是氢;以及R1a和R2a独立为氢、甲基、氟或吗啉基)。
包括在式(Ia)范围内的其它优选的化合物是下述的化合物:其中
R23和R24在每次出现时独立选自氢和C1-4烷基;或R23和R24与它们所连接的氮原子一起形成5至7元杂环基;
R26和R27独立为氢、卤素或羟基;或R26和R27一起形成=O;以及
R28为卤素;C1-4烷氧基、嘧啶基、异噁唑基、吡唑基或吡啶基,每个基团任选被氢、吗啉基、C1-4烷氧基或C1-4烷基取代。
包括在式(I)和(Ia)范围内的其它优选的化合物是下述的化合物:其中R6选自C1-4烷基;以及R7选自氢和C1-4烷基(尤其是甲基)。
本发明可通过其它特定形式体现而不背离其精神或本质属性。本发明还包括本申请记载的本发明供选方面的所有组合。应该理解的是,本发明的任何和所有实施方案可与任何其它实施方案结合在一起以描述本发明的另外实施方案。此外,一个实施方案的任何元素(包括单独的变量定义)意在与任何实施方案的所有其它元素结合以描述另外实施方案。本发明还提供了药物组合物,所述药物组合物包含式(I)的化合物或其对映异构体、非对映异构体或药用盐,以及药用载体。
本发明的其它实施方案是治疗疾病或病症的方法,所述方法包括给予需要治疗的患者治疗有效量的式(I)的化合物,用于治疗疾病或病症的式(I)的化合物,以及式(I)的化合物在制备用于治疗疾病或病症的药物中的用途,其中所述疾病或病症选自内分泌病症(endocrine disorder)、风湿病(rheumaticdisorder)、胶原性疾病(collagen disease)、皮肤病(dermatologic disease)、变应性疾病(allergic disease)、眼病(ophthalmic disease)、呼吸系统疾病(respiratorydisease)、血液病(hematologic disease)、胃肠道疾病(gastrointestinal disease)、炎症性疾病(inflammatory disease)、免疫性疾病(immune disease)、肿瘤性疾病(neoplastic disease)和代谢性疾病。
在另一个实施方案中,本发明提供了治疗以下疾病的方法:内分泌病症、风湿病、胶原性疾病、皮肤病、变应性疾病、眼病、呼吸系统疾病、血液病、胃肠道疾病、炎症性疾病、免疫性疾病、肿瘤性疾病和代谢性疾病、与转录受糖皮质激素受体刺激或阻抑的基因的表达产物相关的疾病,或与AP-1和/或NF-κB诱导的转录相关的疾病,或与AP-1和/或NF-κB依赖的基因表达相关的疾病,其中所述疾病与在AP-1和/或NF-κB(特别是AP-1)的调控下基因的表达相关,包括如下文所述的炎症性和免疫性疾病和病症,所述方法包括给予患者治疗有效量的本发明的式(I)的化合物的步骤。
本发明的其它实施方案提供了治疗疾病或病症的方法,所述方法包括给予需要治疗的患者治疗有效量的式(I)的化合物,用于治疗疾病或病症的式(I)的化合物,以及式(I)的化合物在制备用于治疗疾病或病症的药物中的用途,其中所述疾病或病症选自代谢性疾病或炎症性或免疫性疾病,所述方法包括给予需要治疗的患者治疗有效量的式(I)的化合物。
本发明的更优选的实施方案提供了治疗疾病或病症的方法,所述方法包括给予需要治疗的患者治疗有效量的式(I)的化合物,用于治疗疾病或病症的式(I)的化合物,以及式(I)的化合物在制备用于治疗疾病或病症的药物中的用途,其中所述疾病或病症选自代谢性疾病,其中所述疾病为选自I型糖尿病、II型糖尿病、青少年糖尿病(juvenile diabetes)和肥胖症(obesity)的代谢性疾病。
本发明的其它优选的实施方案是治疗疾病或病症的方法,所述方法包括给予需要治疗的患者治疗有效量的式(I)的化合物,用于治疗疾病或病症的式(I)的化合物,以及式(I)的化合物在制备用于治疗疾病或病症的药物中的用途,其中所述疾病或病症为炎症性或免疫性疾病,所述疾病选自肾、肝、心、肺、胰、骨髓、角膜、小肠、皮肤同种异体移植物(skin allograft)、皮肤同种移植物(skin homograft)、心瓣膜异种移植物(heart valve xenograft)移植排斥、血清病(serum sickness)和移植物抗宿主病、类风湿性关节炎、牛皮癣性关节炎(psoriatic arthritis)、多发性硬化、哮喘、炎症性肠病、克罗恩病、溃疡性结肠炎(ulcerative colitis)、坏疽性脓皮病(pyoderma gangrenum)、系统性红斑狼疮(systemic lupus erythematosis)、重症肌无力(myastheniagravis)、牛皮癣(psoriasis)、皮炎(dermatitis)、皮肌炎(dermatomyositis)、湿疹(eczema)、皮脂溢(seborrhoea)、肺部炎症(pulmonary inflammation)、眼葡萄膜炎(eye uveitis)、肝炎(hepatitis)、格雷夫斯病(Graves’disease)、桥本氏甲状腺炎(Hashimoto’s thyroiditis)、自身免疫性甲状腺炎(autoimmune thyroiditis)、白塞综合征或舍格伦综合征(Behcet’s or Sjogren’s syndrome)、恶性贫血或免疫性溶血性贫血(pernicious or immunohaemolytic anaemia)、动脉粥样硬化(atherosclerosis)、艾迪生病、特发性肾上腺皮质功能不全(idiopathic adrenalinsufficiency)、自身免疫性多腺体疾病(autoimmune polyglandular disease)、肾小球肾炎(glomerulonephritis)、硬皮病(scleroderma)、硬斑病(morphea)、扁平苔藓(lichen planus)、白癜风(vitiligo)、斑秃(alopecia areata)、自身免疫性脱发(autoimmune alopecia)、自身免疫性垂体功能减退症(autoimmunehypopituitarism)、吉-巴综合征(Guillain-Barre syndrome)、肺泡炎(alveolitis)、接触过敏(contact hypersensitivity)、迟发型超敏反应(delayed-typehypersensitivity)、接触性皮炎(contact dermatitis)、荨麻疹(urticaria)、皮肤变应性(skin allergies)、呼吸系统变态反应(respiratory allergy)、枯草热(hayfever)、麸胶敏感性肠病(gluten-sensitive enteropathy)、骨关节炎、急性胰腺炎(acute pancreatis)、慢性胰腺炎(chronic pancreatitis)、急性呼吸窘迫综合征(acute respiratory distress syndrome)、塞泽里综合征(Sezary’s syndrome)、再狭窄(restenosis)、狭窄(stenosis)、先天性肾上腺增生(congenital adrenalhyperplasia)、非化脓性甲状腺炎(nonsuppurative thyroiditis)、癌症相关的高钙血症(hypercalcemia associated with cancer)、青少年类风湿性关节炎(juvenile rheumatoid arthritis)、强直性脊柱炎(Ankylosing spondylitis)、急性和亚急性滑囊炎(acute and subacute bursitis)、急性非特异性腱鞘炎(acutenonspecific tenosynovitis)、急性痛风性关节炎(acute gouty arthritis)、创伤后骨关节炎(post-traumatic osteoarthritis)、骨关节炎滑膜炎(synovitis ofosteoarthritis)、上髁炎(epicondylitis)、急性风湿性心脏炎(acute rheumaticcarditis)、天疱疮(pemphigus)、疱疹样大疱性皮炎(bullous dermatitisherpetiformis)、重症多型性红斑(severe erythema multiforme)、剥脱性皮炎(exfoliative dermatitis)、脂溢性皮炎(seborrheic dermatitis)、季节性或常年性变应性鼻炎(seasonal or perennial allergic rhinitis)、支气管哮喘(bronchialasthma)、特应性皮炎(atopic dermatitis)、药物超敏反应(drug hypersensitivityreactions)、变应性结膜炎(allergic conjunctivitis)、角膜炎(keratitis)、眼带状疱疹(herpes zoster ophthalmicus)、虹膜炎(iritis)和虹膜睫状体炎(iridocyclitis)、脉络膜视网膜炎(chorioretinitis)、视神经炎(optic neuritis)、症状性结节病(symptomatic sarcoidosis)、暴发性或散布性肺结核化学治疗(fulminating ordisseminated pulmonary tuberculosis chemotherapy)、成人特发性血小板减小性紫癜(idiopathic thrombocytopenic purpura in adults)、成人继发性血小板减少症(secondary thrombocytopenia in adults)、获得性(自身免疫性)溶血性贫血(acquired(autoimmune)hemolytic anemia)、成人白血病和淋巴瘤(leukemia andlymphoma in adults)、儿童急性白血病(acute leukemia of childhood)、局限性回肠炎(regional enteritis)、自身免疫性血管炎(autoimmune vasculitis)、败血病(sepsis)和慢性阻塞性肺病(chronic obstructive pulmonary disease)。
特别优选的实施方案是治疗疾病或病症的方法,所述方法包括给予需要治疗的患者治疗有效量的式(I)的化合物,用于治疗疾病或病症的式(I)的化合物,以及式(I)的化合物在制备用于治疗疾病或病症的药物中的用途,其中所述疾病或病症选自移植排斥、类风湿性关节炎、牛皮癣性关节炎、多发性硬化、哮喘、炎症性肠病、系统性红斑狼疮和牛皮癣。
本发明的另一个实施方案涉及治疗与转录受糖皮质激素受体刺激或阻抑的基因的表达产物相关的疾病或病症的方法,或治疗与AP-1和/或NFκB(特别是AP-1)诱导的转录相关的疾病或病症的方法,或治疗与AP-1和/或NFκB(特别是AP-1)依赖的基因表达相关的疾病或病症的方法,其中所述疾病与在AP-1和/或NF-κB(特别是AP-1)的调控下基因的表达相关,如炎症性和免疫性病症、癌症和肿瘤病症如实体瘤、淋巴瘤和白血病,以及真菌感染如蕈样肉芽肿病(mycosis fungoides)。
在另一个实施方案中,本发明提供了药物组合(pharmaceuticalcombination),所述药物组合包含一种或多种式(I)的化合物和免疫抑制剂、抗癌剂、抗病毒剂、抗炎剂、抗真菌剂、抗生素、抗血管过度增殖药(anti-vascular hyperproliferation agent)、抗抑郁药、降脂药(lipid-loweringagent)、调脂药(lipid modulating agent)、抗糖尿病药、抗肥胖症药、抗高血压药、血小板聚集抑制剂(platelet aggregation inhibitor)和/或抗骨质疏松药,其中所述抗糖尿病药为双胍(biguanide)、磺酰脲(sulfonyl urea)、葡糖苷酶抑制剂(glucosidase inhibitor)、PPAR γ激动剂(PPAR γagonist)、PPAR α/γ双重激动剂(PPAR α/γdual agonist)、SGLT2抑制剂、DP4抑制剂、aP2抑制剂、胰岛素敏化剂(insulin sensitizer)、胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)、胰岛素和/或氯茴苯酸(meglitinide)中的1、2、3或更多种,其中所述抗肥胖症药为β-3肾上素能激动剂(beta 3adrenergic agonist)、脂酶抑制剂(lipase inhibitor)、5-羟色胺(和多巴胺)再摄取抑制剂、甲状腺受体激动剂、aP2抑制剂和/或厌食药(anorectic agent),其中所述降脂药为MTP抑制剂、HMG CoA还原酶抑制剂、角鲨烯合成酶抑制剂、苯乙酸(fibric acid)衍生物、LDL受体活性上调剂、脂氧化酶(lipoxygenase)抑制剂或ACAT抑制剂,其中所述抗高血压药为ACE抑制剂、血管紧张素II受体拮抗剂、NEP/ACE抑制剂、钙通道阻滞剂和/或β-肾上腺素能阻滞剂。
甚至更优选的组合如下:其中所述抗糖尿病药为以下药物中的1、2、3或更多种:二甲双胍、格列本脲、格列美脲、格列吡脲(glipyride)、格列吡嗪、氯磺丙脲、格列齐特、阿卡波糖、米格列醇、吡格列酮、曲格列酮、罗格列酮、胰岛素、Gl-262570、伊格列酮(isaglitazone)、JTT-501、NN-2344、L895645、YM-440、R-119702、AJ9677、瑞格列奈、那格列奈、KAD1129、AR-HO39242、GW-409544、KRP297、AC2993、LY315902、P32/98和/或NVP-DPP-728A,其中所述抗肥胖症药为奥利司他(orlistat)、ATL-962、AJ9677、L750355、CP331648、西布曲明(sibutramine)、托吡酯(topiramate)、睫状体神经营养因子(axokine)、右旋苯丙胺(dexamphetamine)、芬特明(phentermine)、苯丙醇胺(phenylpropanolamine)和/或马吲哚,其中所述降脂药为普伐他汀、洛伐他汀、辛伐他汀、阿托伐他汀、西立伐他汀、氟伐他汀、伊伐他汀(itavastatin)、维沙他汀(visastatin)、非诺贝特、吉非贝齐、氯贝丁酯、阿伐麦布、TS-962,MD-700、考来胶(cholestagel)、烟酸(niacin)和/或LY295427,其中所述抗高血压药为ACE抑制剂,其为卡托普利、福辛普利、赖诺普利、喹那普利、贝那普利、芬替普利(fentiapril)、雷米普利或莫昔普利;NEP/ACE抑制剂,其为奥马曲拉(omapatrilat)、[S[(R*,R*)]-六氢-6-[(2-巯基-1-氧代-3-苯基丙基)氨基]-2,2-二甲基-7-氧代-1H-氮杂-1-乙酸(gemopatrilat)或CGS 30440;
血管紧张素II受体拮抗剂,其为厄贝沙坦、氯沙坦或缬沙坦;
苯磺酸氨氯地平(amlodipine besylate)、哌唑嗪HCl、维拉帕米、硝苯地平、纳多洛尔、普萘洛尔、卡维地洛或可乐定HCl,其中所述血小板聚集抑制剂为阿司匹林、氯吡格雷、噻氯匹定、双嘧达莫或伊非曲班;
所述免疫抑制剂为环孢菌素、霉酚酸酯(mycophenolate)、干扰素-β、脱氧精胍菌素(deoxyspergolin)、FK-506或Ant.-IL-2;
所述抗癌剂为硫唑嘌呤(azathiprine)、5-氟尿嘧啶、环磷酰胺、顺铂、甲氨喋呤、塞替派或卡铂;
所述抗病毒剂为阿巴卡韦、阿昔洛韦、更昔洛韦、zidanocin或阿糖腺苷;以及
所述抗炎药为布洛芬、塞来考昔、罗非考昔、阿司匹林、萘普生、酮洛芬(ketoprofen)、双氯芬酸钠、吲哚美辛、吡罗昔康、泼尼松、地塞米松、氢化可的松或双醋曲安西龙(triamcinolone diacetate)。
本申请使用的术语“与GR反式激活相关的疾病”是指与转录由GR反式激活的基因的转录产物相关的疾病。所述疾病包括但不限于骨质疏松症、糖尿病、青光眼、肌肉损耗(muscle loss)、面部肿胀(facial swelling)、人格改变(personality change)、高血压、肥胖症、抑郁和AIDS、伤口愈合的病症(condition of wound healing)、原发性或继发性肾上腺皮质缺乏(primary orsecondary andrenocortical insufficiency)和艾迪生病。
本申请使用的所有语法形式的术语“治疗(treat)”、“治疗(treating)”或“治疗(treatment)”是指对疾病、障碍或病症的预防、减少或改善、部分或完全减轻,或治愈,其中预防表示对面临感染所述疾病、障碍或病症危险的人进行治疗。
本申请使用的术语“糖皮质激素受体”和“GR”是指与糖皮质激素结合并刺激或阻抑转录的转录因子的细胞核激素受体(“NHR”)家族的一员,或指GR-β。
本申请使用的这些术语,是指任何来源的糖皮质激素受体,包括但不限于:如Weinberger,等人.,Science,228:740-742(1985)和Weinberger,等人.,Nature,318:670-672(1986)中披露的人糖皮质激素受体;如Miesfeld,R.,Nature,312:779-781(1985)中披露的大鼠糖皮质激素受体;如Danielson,M.等人.,EMBO J.,5:2513中披露的小鼠糖皮质激素受体;如Yang,K.等人.,J.Mol.Endocrinol.,8:173-180(1992)中披露的羊糖皮质激素受体;如Brandon,D.D.等人.,J.Mol.Endocrinol.7:89-96(1991)中披露的绒猴糖皮质激素受体,以及如Hollenberg,S.M.等人.,Nature,318:635(1985);Bamberger,C.M.等人.,J.Clin Invest.,95:2435(1995)中披露的人GR-β。
本申请使用的“与AP-1和/或NF-κB相关的疾病和病症”是指与在AP-1和/或NF-κB的调控下基因的表达产物相关的疾病。所述疾病包括但不限于:炎症性和免疫性疾病和病症;癌症和肿瘤病症如实体瘤、淋巴瘤和白血病;以及真菌感染如蕈样肉芽肿病。
本申请中使用术语“炎症性或免疫性相关的疾病或病症”,包括具有炎症性或免疫性组成的任何病症、疾病或障碍,包括但不限于每一种以下的病症:移植排斥(例如肾、肝、心、肺、胰(例如胰岛细胞)、骨髓、角膜、小肠、皮肤同种异体移植物、皮肤同种移植物(如烧伤治疗中采用的皮肤同种移植物)、心瓣膜异种移植物)、血清病和移植物抗宿主病、自身免疫性疾病(如类风湿性关节炎、牛皮癣性关节炎)、多发性硬化、I型和II型糖尿病、青少年糖尿病、肥胖症、哮喘、炎症性肠病(如克罗恩病和溃疡性结肠炎)、坏疽性脓皮病、狼疮(系统性红斑狼疮)、重症肌无力、牛皮癣、皮炎、皮肌炎、湿疹(、皮脂溢、肺部炎症、眼葡萄膜炎、肝炎、格雷夫斯病、桥本氏甲状腺炎、自身免疫性甲状腺炎、白塞综合征或舍格伦综合征(干眼/口)、恶性贫血或免疫性溶血性贫血、动脉粥样硬化、艾迪生病(肾上腺的自身免疫性疾病)、特发性肾上腺皮质功能不全、自身免疫性多腺体疾病(也称为自身免疫性多腺综合征)、肾小球肾炎、硬皮病、硬斑病、扁平苔藓、白癜风(皮肤色素脱失(depigmentation of the skin))、斑秃、自身免疫性脱发、自身免疫性垂体功能减退症、吉-巴综合征和肺泡炎;T细胞介导的过敏性疾病,包括接触过敏、迟发型超敏反应、接触性皮炎(包括由野葛(poison ivy)引起的接触性皮炎)、荨麻疹、皮肤变应性、呼吸系统变态反应(枯草热、变应性鼻炎)和麸胶敏感性肠病(乳糜泻(Celiac disease));炎症性疾病如骨关节炎、急性胰腺炎、慢性胰腺炎、急性呼吸窘迫综合征、塞泽里综合征和具有炎症性或增殖性组成的血管疾病,如再狭窄、狭窄和动脉粥样硬化。炎症性或免疫性相关的疾病或病症还包括但不限于:内分泌病症、风湿病、胶原性疾病、皮肤病、变应性疾病、眼病、呼吸系统疾病、血液病、胃肠道疾病、炎症性疾病、自身免疫性疾病、先天性肾上腺增生、非化脓性甲状腺炎、癌症相关的高钙血症、青少年类风湿性关节炎、强直性脊柱炎、急性和亚急性滑囊炎、急性非特异性腱鞘炎、急性痛风性关节炎、创伤后骨关节炎、骨关节炎滑膜炎、上髁炎、急性风湿性心脏炎、天疱疮、大疱性皮炎、重症多型性红斑、剥脱性皮炎、脂溢性皮炎、季节性或常年性变应性鼻炎、支气管哮喘、接触性皮炎、特应性皮炎、药物超敏反应、变应性结膜炎、角膜炎、眼带状疱疹、虹膜炎和虹膜睫状体炎、脉络膜视网膜炎、视神经炎、症状性结节病、暴发性或散布性肺结核。
具体实施方式
合成
本发明化合物可根据有机合成领域公知的操作制备。本领域技术人员应该理解的是,可将使用下文描述的方法与有机化学领域已知的合成方法或其变化形式一起使用来合成本发明化合物。
下文方法中表示的反应在适于采用的试剂和材料并适于进行转化的溶剂中进行。此外,在下文描述的合成方法的描述中,应该理解所有提出的反应条件,包括溶剂的选择、反应大气压、反应温度、实验的持续时间和后处理操作都在标准反应条件下进行,这些条件是本领域技术人员容易理解的。本领域技术人员还应理解,所选择的试剂和反应必须与分子的各部分上存在的官能团相容。
在一些情况中,在合成中的各步可以交替的连续次序进行以便得到期望的一种或多种化合物。由一般方案描述的方法制备的本发明化合物的实例在下文列出的制备和实施例部分给出。实施例化合物通常制备为外消旋混合物。纯手性实例的制备可根据本领域技术人员已知的技术进行。例如,纯手性化合物可通过由手性相制备性HPLC分离外消旋产物来制备。可供选择地,实施例化合物可通过已知方法制备以得到富含对映异构体的产物(enantiomerically enriched product)。这些方法包括但不限于,将手性助剂官能团引入外消旋中间体,所述手性助剂官能团用于控制转化的非对映立体选择性,在手性助剂断裂时提供富含对映异构体的产物。
在以下的方案中,各基团A、M、Ma、Z、Za和R22对应于上文就式(I)所述的基团:
方案A
式2化合物如下构建:通过本领域技术人员公知的一种方法将有机金属化合物M-Ma-“金属(metal)”与式1化合物加成。术语“金属”是MgBr、MgCl或Li,其中每种金属从相应的溴化物或氯化物制备。可供选择地,式2化合物可如下构建,以类似于上文描述的方式将有机金属化合物A-“金属”与化合物MMaCOQ加成。
方案B
式2化合物可与式3化合物在路易斯酸如TiCl4或SnCl4的存在下,在适当的溶剂如二氯甲烷、1,2-二氯乙烷或THF中,在-78℃至室温的温度反应,形成式(Iaa)的化合物。(Ia)中的A基团还可进一步通过本领域技术人员公知的方法来加工。
方案C
通过碱性水解从式(Iaa)的化合物制备的式(Ib)的化合物,式(Ib)的化合物可与式4的胺通过本领域技术人员公知的许多酰胺化方法反应,得到本发明的式(Ic)的化合物。例如,可将式(Ib)的化合物于适当的溶剂如乙腈中的溶液用1-[3-(二甲基氨基)丙基]-3-乙基碳二亚胺盐酸盐(EDC)、1-羟基-7-氮杂苯并三唑、三乙胺和胺4反应形成式(Ic)的化合物。式(Ic)中的A基团还可进一步通过本领域技术人员公知的方法来加工。
方案D
A’=A-芳基或A-烷基
含有至少一个卤素原子(I、Br和/或Cl)或位于A基团上的OTf(三氟甲磺酸酯(triflate))基团的式(Ic)的化合物使用本领域技术人员公知的一种方法与有机金属性的化合物(如有机硼化合物或有机锡化合物)进行金属(如钯)催化的偶联反应,得到式(Id)的化合物,其中所述A基团被芳基或烷基取代。
方案E
A’=A-NR’R”或A-O-芳基
含有至少一个卤素原子(I、Br和Cl)或位于A基团上的OTf(三氟甲磺酸酯)基团的式(Iaa)的化合物可与胺(NHR’R”)或芳基-OH进行金属(如钯)催化的偶联反应,得到式(Id)的化合物,其中A基团与NR’R”或O-芳基相连。参见,例如S.Buchwald,等人.,Acc.Chem.Res.31,pp.805(1998)和J.Org.Chem.65,pp,1158(2000)。
应该理解的是,在上文描述的合成方案至始至终可适当利用保护基。对于含胺杂环的常见保护基为脲、磺酰胺、氨基甲酸酯和烷基(如苄基)。保护基的审慎使用是本领域技术人员已知的,并且描述在Greene and Wuts“Protecting Groups in Organic Synthesis 3rd Ed.1999。
定义
以下是在本说明书和所附的权利要求中使用的术语的定义。除非另有说明,本申请就基团或术语而言提供的初始的定义适用于说明书和权利要求通篇使用的基团或术语,不论是单独使用还是作为另一基团的部分使用。
术语“烷基”是指含有1至12个碳原子,优选1至6个碳原子的直链或支链烃基。低级烷基,即含有1至4个碳原子的烷基,是最优选的。当数字在符号“C”之后以下标形式出现时,所述下标更具体地定义了具体基团可含有的碳原子的数目。例如,“C1-6烷基”是指含有1至6个碳原子的直链和支链烷基,如甲基、乙基、正丙基、异丙基、正丁基、叔丁基、正戊基等等。下标“0”是指化学键。由此,术语羟基(C0-2)烷基或(C0-2)羟基烷基包括羟基、羟甲基和羟乙基。
术语“取代的烷基”是指如上文定义的具有一个、两个或三个取代基的烷基,所述取代基选自卤素(例如,三氟甲基)、烯基、取代的烯基、炔基、硝基、氰基、氧代(=O)、ORa、SRa,(=S)、-NRaRb、-N(烷基)3 +、-NRaSO2、-NRaSO2Rc、-SO2Rc-SO2NRaRb、-SO2NRaC(=O)Rb、SO3H、-PO(OH)2、-OC(O)Ra、-C(=O)Ra、-CO2Ra、-C(=O)NRaRb、-C(=O)(C1-4亚烷基)NRaRb、-C(=O)NRa(SO2)Rb、-CO2(C1-4亚烷基)NRaRb、-NRaC(=O)Rb、-NRaCO2Rb、-NRa(C1-4亚烷基)CO2Rb、=N-OH、=N-O-烷基、芳基、环烷基、杂环基和/或杂芳基,其中Ra和Rb选自氢、烷基、烯基、CO2H、烷基OC(=O)-、C3-7环烷基、苯基、苄基、苯乙基、萘基、四至七元杂环基或五至六元杂芳基,或当Ra和Rb与相同的氮原子相连时可一起形成杂环基或杂芳基,以及Rc选自与Ra和Rb相同的基团,但不是氢。每个基团Ra和Rb当不是氢时,每个Rc基团任选具有连接在Ra、Rb和/或Rc的任何可用的碳原子或氮原子上的三个其它取代基,所述取代基选自(C1-6)烷基、(C2-6)烯基、羟基、卤素、氰基、硝基、=O(当化合价允许时)、CF3、O(C1-6烷基)、OCF3、C(=O)H、C(=O)(C1-6烷基)、CO2H、CO2(C1-6烷基)、NHCO2(C1-6烷基)、-S(C1-6烷基)、-NH2、NH(C1-6烷基)、N(C1-6烷基)2、N(CH3)3 +、SO2(C1-6烷基)、C(=O)(C1-4亚烷基)NH2、C(=O)(C1-4亚烷基)NH(烷基)、C(=O)(C1-4亚烷基)N(C1-4烷基)2、C3-7环烷基、苯基、苄基、苯乙基、苯基氧基、苄基氧基、萘基、四至七元杂环或四至七元环烷基或五至六元杂芳基。当取代的烷基被芳基(包括例如苯基和萘基)、杂环基、环烷基、或杂芳基取代时,所述环系统如下文所定义,由此可具有也如下文所定义的0、1、2或3个取代基。
当术语“烷基”与另一基团一起使用时,如在“芳基烷基”中使用时,这种结合更具体地定义了所述取代的烷基含有的至少一个取代基。例如,“芳基烷基”是指至少一个取代基为芳基的如上文定义的取代的烷基,如苄基。由此,术语芳基(C0-4)烷基包括具有至少一个芳基取代基的的取代的低级烷基,还包括直接与另一个基团结合的芳基,即芳基(C0)烷基。
术语“烯基”是指具有2至12个碳原子和至少一个双键的直链或支链烃基。具有2至6个碳原子并具有一个双键的烯基是最优选的。
术语“炔基”是指具有2至12个碳原子和至少一个三键的直链或支链烃基。具有2至6个碳原子并具有一个三键的炔基是最优选的。
术语“亚烷基”是指含有1至12个碳原子,优选1至8个碳原子的二价直链或支链烃基,例如{-CH2-}n,其中n为1至12,优选1-8。低级亚烷基,即含有1至4个碳原子的亚烷基是最优选的。术语“亚烯基”和“亚炔基”分别是指如上文定义的烯基和炔基的二价基团。
当提及取代的烯基、炔基、亚烷基、亚烯基或亚炔基时,这些基团被如上文就取代的烷基所定义的一至三个取代基取代。
本申请中使用“亚杂烃基(heteroalkylene)”,是指具有2至12个碳原子,优选2至8个碳原子的饱和或不饱和二价直链或支链烃基,其中在直链中的至少一个或两个碳原子被杂原子替代,所述杂原子选自-O-、-S-、-S(=O)-、-SO2-、-NH-和-NHSO2-。由此,术语“亚杂烃基”包括如下文定义的二价烷氧基、烷硫基和氨基烷基,以及在烷基链中具有杂原子的组合的亚烷基和亚烯基。作为示例,本申请的“亚杂烃基”可包含基团如-S-(CH2)1-5NH-CH2-、-O-(CH2)1-5S(=O)-CH2-、-NHSO2-CH2-、-CH2-NH-等等。优选地,亚杂烃基不具有同时选自-O-和-S-的两个相邻原子。当下标与术语亚杂烃基一起使用时,例如在C2-3亚杂烃基中的情况中,所述下标是指除了杂原子之外基团中碳原子的数目。由此,例如,C1-2亚杂烃基可包括基团如-NH-CH2-、-CH2-NH-CH2-、-CH2-CH2-NH-、-S-CH2-、-CH2-S-CH2-、-O-CH2-NH-CH2-、CH2-O-CH2等等。
术语“取代的亚杂烃基”是指如上文定义的亚杂烃基,其中在亚杂烃基链中的至少一个氮原子或碳原子与不是氢的基团结合(或被不是氢的基团取代)。在亚杂烃基链中的碳原子可被基团取代(所述基团选自上文就取代的烷基所述的那些取代基),或还被烷基或取代的烷基取代。亚杂烃基链的氮原子可被基团取代,所述基团选自烷基、烯基、炔基、氰基或A1-Q-A2-Rh,其中A1为化学键、C1-2亚烷基或C2-3亚烯基;Q为化学键、-C(=O)-、-C(=O)NRd-、-C(=S)NRd-、-SO2-、-SO2NRd-、-CO2-或-NRdCO2-;A2为化学键、C1-3亚烷基、C2-3亚烯基、-C1-4亚烷基-NRd-、-C1-4亚烷基-NRdC(=O)-、-C1-4亚烷基-S-、-C1-4亚烷基-SO2-或-C1-4亚烷基-O-,其中所述A2亚烷基为支链或直链,并且任选如本申请就取代的亚烷基所定义的情况被取代;Rh为氢、烷基、取代的烷基、烯基、取代的烯基、芳基、杂芳基、杂环或环烷基;以及Rd选自氢、烷基和如本申请定义的取代的烷基,然而条件是,对于取代的亚杂烃基而言,当A1、Q和A2各自为化学键时,Rh不是氢。当Rh为芳基、杂芳基、环烷基或杂环时,这些环本身任选被如下文这些术语的定义中所定义的一至三个基团取代。
术语“烷氧基”是指被烷基或如本申请定义的取代的烷基所取代的氧原子。例如,术语“烷氧基”或者包括基团-O-C1-6烷基。
术语“烷基硫基”是指被烷基或如本申请定义的取代的烷基所取代的硫原子。例如,术语“烷硫基”包括基团-S-C1-6烷基等等。
术语“烷基氨基”是指是指被烷基或如上文定义的取代的烷基所取代的氨基。例如,术语“烷基氨基”包括基团-NR-C1-12烷基(其中R优选为氢,但可包括烷基或如上文定义的取代的烷基)。
当下标关于烷氧基、烷硫基或氨基烷基使用时,所述下标是指除杂原子之外所述基团可含有的碳原子的数目。由此,例如,单价C1-2氨基烷基包括基团-CH2-N(CH3)2和-(CH2)2-NH2。低级氨基烷基包含具有一至四个碳原子的氨基烷基。术语(C1-4烷基)0-2氨基包括基团NH2、-NH(C1-4烷基)和-N(C1-4烷基)2。“氨基”是指基团NH2。“取代的氨基”是指如上文就亚杂烃基链的氮原子所述被取代的氨基,并且包括,例如术语烷基氨基和酰基氨基(-NRdC(O)Re)。
烷氧基、烷硫基或氨基烷基可以是单价的或二价的。提及“单价”时,这表示所述基团具有一个化合价(即与另一个基团结合的能力),而提及“二价”时,这表示所述基团具有两个化合价。由此,例如,单价烷氧基包括基团如-O-C1-12烷基,而二价烷氧基包括基团如-O-C1-12亚烷基-。
应该理解的是,对于所有基团,包括例如烷氧基、烷硫基和氨基烷基的选择,将由本领域技术人员进行,以提供稳定的化合物。由此,例如,在式(I)的化合物中,当G与环A的氮原子(N*)相连并选自烷氧基或烷基硫基时,所述烷氧基和烷基硫基应具有至少一个与环A(在N*上)直接结合的碳原子,同时氧原子或硫原子距离所述氮原子至少一个原子。
术语“羰基”是指二价羰基-C(=O)-。当术语“羰基”与另一个基团一起使用时,如在“杂环羰基”的情况中,这种结合更具体地定义了所述取代的羰基含有的至少一个取代基。例如,“杂环羰基”是指如上文定义的羰基,其中至少一个取代基为杂环如吗啉基。
术语“酰基”是指与有机基团相连的羰基,更具体地为基团C(=O)Re。基团Re可选自如本申请定义的烷基、烯基、炔基、氨基烷基、取代的烷基(即取代的亚烷基)、取代的烯基、取代的炔基、环烷基、杂环基、芳基或杂芳基。当RE为芳基、杂芳基、环烷基或杂环时,这些环本身任选被如下文这些术语的定义中所定义的一至三个基团取代。
术语“烷氧基羰基”是指与有机基团(CO2Re)相连的羧基(或),以及与式(I)的化合物中的有机基团相连的二价基团-CO2-、-CO2Re-,其中Re如上文就酰基而言所定义。与羧基相连的有机基团可以是单价的(例如-CO2-烷基或-OC(=O)烷基)或二价的(例如,-CO2-亚烷基、-OC(=O)亚烷基等)。因此,在式(I)的化合物中,当描述了G可以是“烷氧基羰基”时,这旨在包括对于-CO2-的G的选择,以及基团-CO2Re-或-ReCO2-,其中在这种情况下,基团Re可选自二价基团,如亚烷基、亚烯基、亚炔基、二价氨基烷基、取代的亚烷基、取代的亚烯基或取代的亚炔基。
术语“甲酰氨基(carboxamide)”、“氨基酰基(carboxamidyl)”或“氨基酰基(carboxamido)”是指基团-NRdC(=O)Re,其中基团Rd和Re如上文在杂烷基、烷氧基羰基和酰基的定义中所述而定义。例如,基团
术语“酰胺(amide)”、“酰胺基(amidyl)”或“酰氨基(amido)”是指基团-C(=O)NRaRb,其中基团Ra和Rb如上文在取代的烷基的定义中所述而定义。
术语“脲基”是指基团-NRdC(=O)NRaRb,其中基团Ra、Rb和Rd如上文在取代的烷基的定义中所述而定义。此外,所述脲基可以是二价的,在这种情况中,Ra和Rb中的一个基团将为化学键。由此,在式(I)的化合物中,当指出G可以是脲基时,其可表示适当时G为基团-NRd(C(=O)NRa-。
术语“磺酰基”是指与式(I)的化合物中的有机基团相连的亚砜基,更具体地为单价基团-S(O)2-Re。此外,磺酰基可以是二价的,在这种情况中Re为化学键。因此,在式(I)的化合物中,当描述G可以是“磺酰基”时,其可以表示适当时G为基团-S(O)。基团Re选自上文就酰基和烷氧基羰基所述的基团,不同的是Re不是氢。
术语“氨磺酰(sulfonamide)”、“氨磺酰基(sulfonamidyl)”或“亚磺酰氨基(sulfonamido)”是指基团-S(O)2NRaRb,其中Ra和Rb如上文就取代的烷基所定义。
术语“环烷基(cycloalkyl)”是指具有3至9,优选3至7个碳原子的完全饱和和部分饱和的烃环(以及由此包括亦称为“环烯基环”的烃环)。术语“环烷基”包括具有0、1、2或3个取代基的所述环,所述取代基选自卤素、三氟甲基、三氟甲氧基、烷基、取代的烷基、烯基、取代的烯基、炔基、硝基、氰基、氧代(=O)、ORa、SRa,(=S)、-NRaRb、-N(烷基)3 +、-NRaSO2、-NRaSO2Rc、-SO2Rc-SO2NRaRb、-SO2NRaC(=O)Rb、SO3H、-PO(OH)2、-C(=O)Ra、-CO2Ra、-C(=O)NRaRb、-C(=O)(C1-4亚烷基)NRaRb、-C(=O)NRa(SO2)Rb、-CO2(C1-4亚烷基)NRaRb、-NRaC(=O)Rb、-NRaCO2Rb、-NRa(C1-4亚烷基)CO2Rb、=N-OH、=N-O-烷基、芳基、环烷基、杂环基和/或杂芳基,其中Ra、Rb和Rc如上文就取代的烷基所定义,并且本身还任选被上文在取代的烷基的定义中所述的取代基取代。术语“环烷基”还包括具有与之稠合的另一个环(例如,包括苯并环、杂环基环或杂芳基环)或具有3至4个碳原子的碳-碳桥的环。当环烷基被另一个环取代(或具有与之稠合的另一个环)时,所述环本身任选被一至两个以下基团取代:(C1-4)烷基、(C2-4)烯基、(C2-4)炔基、卤素、羟基、氰基、硝基、CF3、O(C1-4烷基)、OCF3、C(=O)H、C(=O)(C1-4烷基)、CO2H、CO2(C1-4烷基)、NHCO2(C1-4烷基)、-S(C1-4烷基)、-NH2,NH(C1-4烷基)、N(C1-4烷基)2、N(C1-4烷基)3 +、SO2(C1-4烷基)、C(=O)(C1-4亚烷基)NH2、C(=O)(C1-4亚烷基)NH(烷基)、C(=O)(C1-4亚烷基)N(C1-4烷基)2和/或任选被任何前述基团取代的苯基。当化合价允许时,若所述另一个环为环烷基或杂环,其还任选被=O(氧代)取代。
因此,在式(I)的化合物中,术语“环烷基”包括环丙基、环丁基、环戊基、环己基、环庚基、二环辛基等,以及以下环系统: 等等,上述环系统可任选在环的任何可用原子上被取代。优选的环烷基包括环丙基、环戊基、环己基和
术语“卤代”或“卤素”是指氯、溴、氟和碘。
术语“卤代烷基”表示具有一个或多个卤素取代基的取代的烷基。例如,“卤代烷基”包括氟甲基、二氟甲基和三氟甲基。
术语“卤代烷氧基”表示具有一个或多个卤素取代基的烷氧基。例如,“卤代烷氧基”包括OCF3。
术语“芳基”是指苯基、联苯基、芴基、1-萘基和2-萘基。术语“芳基”包括具有0、1、2或3个取代基的所述环,所述取代基选自卤素、三氟甲基、三氟甲氧基、烷基、取代的烷基、烯基、取代的烯基、炔基、硝基、氰基、ORa、SRa,(=S)、SO3H、-NRaRb、-N(烷基)3 +、-NRaSO2、-NRaSO2Rc、-SO2Rc、-SO2NRaRb、-SO2NRaC(=O)Rb、SO3H、-PO(OH)2、-C(=O)Ra、-CO2Ra、-C(=O)NRaRb、-C(=O)(C1-4亚烷基)NRaRb、-C(=O)NRa(SO2)Rb、-CO2(C1-4亚烷基)NRaRb、-NRaC(=O)Rb、-NRaCO2Rb、-NRa(C1-4亚烷基)CO2Rb、芳基、环烷基、杂环基和/或杂芳基,其中Ra、Rb和Rc如上文就取代的烷基所定义,并且本身还任选如上所述被取代。此外,与芳基特别是苯基相连的两个取代基可连在一起形成另一个环,如稠环或螺环,如环戊基或环己基,或稠合的杂环基或杂芳基。当芳基被另一个环取代(或具有与之稠合的另一个环)时,所述环本身任选被一至两个以下基团取代:(C1-4)烷基、(C2-4)烯基、(C2-4)炔基、卤素、羟基、氰基、硝基、CF3,O(C1-4烷基)、OCF3、C(=O)H、C(=O)(C1-4烷基)、CO2H、CO2(C1-4烷基)、NHCO2(C1-4烷基)、-S(C1-4烷基)、-NH2,NH(C1-4烷基)、N(C1-4烷基)2、N(C1-4烷基)3 +、SO2(C1-4烷基)、C(=O)(C1-4亚烷基)NH2、C(=O)(C1-4亚烷基)NH(烷基)、C(=O)(C1-4亚烷基)N(C1-4烷基)2和/或任选被任何前述基团取代的苯基。当化合价允许时,若所述另一个环为环烷基或杂环,其还任选被=O(氧代)取代。
由此,芳基的实例包括:
术语“杂环基”、“杂环的”或“杂环烷基(heterocycloalkyl)”可交替使用,并且指取代的和未取代的非芳族3至7元单环基团、7至11元二环基团和10至15元三环基团,其中至少一个环具有至少一个杂原子(O、S或N),所述含有杂原子的环优选含有1、2或3个选自O、S和N的杂原子。所述含有杂原子的基团的每个环可含有一或两个氧原子或硫原子和/或一至四个氮原子,条件是每个环中的杂原子总数为四个或更少,以及此外条件是所述环含有至少一个碳原子。氮原子和硫原子可任选被氧化,以及氮原子可任选被季铵化。构成二环和三环基团的稠环可仅含有碳原子,以及可以是饱和的、部分饱和的或不饱和的。杂环基可连接在任何可用的氮原子或碳原子上。所述杂环可含有0、1、2或3个取代基,所述取代基选自卤素、三氟甲基、三氟甲氧基、烷基、取代的烷基、烯基、取代的烯基、炔基、硝基、氰基、氧代(=O)、ORa、SRa,(=S)、-NRaRb、-N(烷基)3 +、-NRaSO2、-NRaSO2Rc、-SO2Rc-SO2NRaRb、-SO2NRaC(=O)Rb、SO3H、-PO(OH)2、-C(=O)Ra、-CO2Ra、-C(=O)NRaRb、-C(=O)(C1-4亚烷基)NRaRb、-C(=O)NRa(SO2)Rb、-CO2(C1-4亚烷基)NRaRb、-NRaC(=O)Rb、-NRaCO2Rb、-NRa(C1-4亚烷基)CO2Rb、=N-OH、=N-O-烷基、芳基、环烷基、杂环基和/或杂芳基,其中Ra、Rb和Rc如上文就取代的烷基所定义,并且本身还任选如上所述被取代。当杂环被另一个环取代时,所述环本身任选被一至两个以下基团取代:(C1-4)烷基、(C2-4)烯基、(C2-4)炔基、卤素、羟基、氰基、硝基、CF3,O(C1-4烷基)、OCF3、C(=O)H、C(=O)(C1-4烷基)、CO2H、CO2(C1-4烷基)、NHCO2(C1-4烷基)、-S(C1-4烷基)、-NH2,NH(C1-4烷基)、N(C1-4烷基)2、N(C1-4烷基)3 +、SO2(C1-4烷基)、C(=O)(C1-4亚烷基)NH2、C(=O)(C1-4亚烷基)NH(烷基)、C(=O)(C1-4亚烷基)N(C1-4烷基)2和/或任选被任何前述基团取代的苯基。当化合价允许时,若所述另一个环为环烷基或杂环,其还任选被=O(氧代)取代。
单环基团包括氮杂环丁烷基、吡咯烷基、氧杂环丁烷基(oxetanyl)、咪唑啉基、噁唑烷基、异噁唑啉基、噻唑烷基、异噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代氮杂基、氮杂基(azepinyl)、4-哌啶酮基、四氢吡喃基、吗啉基、硫吗啉基、1-氧化硫吗啉基(thiomorpholinyl sulfoxide)、1,1-二氧化硫吗啉基(thiomorpholinyl sulfone)、1,3-二氧戊环基和四氢-1,1-二氧代噻吩基等等。示例性的二环杂环基团包括奎宁环基(quinuclidinyl)。
式(I)的化合物中的杂环基团包括
术语“杂芳基”是指取代的和未取代的芳族5或6元单环基团、9或10元二环基团和11至14元三环基团,其在至少一个环上具有至少一个杂原子(O、S或N),所述含有杂原子的环优选含有1、2或3个选自O、S和N的杂原子。含有杂原子的杂芳基的每个环可含有一或两个氧原子或硫原子和/或一至四个氮原子,条件是每个环中的杂原子总数为四个或更少,以及每个环含有至少一个碳原子。构成二环和三环基团的稠环可仅含有碳原子,以及可以是饱和的、部分饱和的或不饱和的。氮原子和硫原子可任选被氧化,以及氮原子可任选被季铵化。二环的或三环的杂芳基必须包括至少一个全芳族的环,但其它稠环或环可为芳族的或非芳族的。所述杂芳基可连接在任何环的任何可用的氮原子或碳原子上。杂芳基环系统可含有0、1、2或3个取代基,所述取代基选自卤素、三氟甲基、三氟甲氧基、烷基、取代的烷基、烯基、取代的烯基、炔基、硝基、氰基、ORa、SRa、(=S)、-NRaRb、-N(烷基)3 +、-NRaSO2、-NRaSO2Rc、-SO2Rc-SO2NRaRb、-SO2NRaC(=O)Rb、SO3H、-PO(OH)2、-C(=O)Ra,-CO2Ra、-C(=O)NRaRb、-C(=O)(C1-4亚烷基)NRaRb、-C(=O)NRa(SO2)Rb、-CO2(C1-4亚烷基)NRaRb、-NRaC(=O)Rb、-NRaCO2Rb、-NRa(C1-4亚烷基)CO2Rb、芳基、环烷基、杂环基和/或杂芳基,其中Ra、Rb和Rc如上文就取代的烷基所定义,以及本身还任选如上所述被取代。当杂芳基被另一个环取代时,所述环本身任选被一至两个以下基团取代:(C1-4)烷基、(C2-4)烯基、(C2-4)炔基、卤素、羟基、氰基、硝基、CF3,O(C1-4烷基)、OCF3、C(=O)H、C(=O)(C1-4烷基)、CO2H、CO2(C1-4烷基)、NHCO2(C1-4烷基)、-S(C1-4烷基)、-NH2,NH(C1-4烷基)、N(C1-4烷基)2、N(C1-4烷基)3 +、SO2(C1-4烷基)、C(=O)(C1-4亚烷基)NH2、C(=O)(C1-4亚烷基)NH(烷基)、C(=O)(C1-4亚烷基)N(C1-4烷基)2和/或任选被任何前述基团取代的苯基。当化合价允许时,若所述另一个环为环烷基或杂环,其还任选被=O(氧代)取代。
单环杂芳基包括吡咯基、吡唑基、吡唑啉基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、噻吩基、噁二唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三嗪基等等。
二环杂芳基包括吲哚基、苯并噻唑基、苯并二氧杂环戊烯基、苯并噁唑基、苯并噻吩基、喹啉基、四氢异喹啉基、异喹啉基、苯并咪唑基、苯并吡喃基、吲嗪基、苯并呋喃基、色酮基、香豆素基、苯并吡喃基、噌啉基、喹喔啉基、吲唑基、吡咯并吡啶基、呋喃并吡啶基、二氢异吲哚基、四氢喹啉基等等。
示例性的三环杂芳基包括咔唑基、苯并吲哚基、菲咯啉基、吖啶基、菲啶基、呫吨基等等。
在式(I)的化合物中,优选的杂芳基包括
除非另有说明,当提及具体命名的芳基(例如,苯基)、环烷基(例如,环己基)、杂环(例如,吡咯烷基、哌啶基和吗啉基)或杂芳基(例如,四唑基、咪唑基、吡唑基、三唑基、噻唑基和呋喃基)时,除非另有具体说明,适当时其旨在包括具有0至3个,优选0-2个取代基的环,所述取代基选自上文就芳基、环烷基、杂环基和/或杂芳基所述的那些基团。
术语“杂原子”包括氧、硫和氮。
术语“碳环”表示饱和或不饱和的单环或二环,其中所有环的所有原子都为碳。由此,术语包括环烷基环及芳基环。碳环可被取代,在这种情况下,取代基选自上文就环烷基及芳基所述的那些取代基。
当术语“不饱和”在本申请中用来指示环或基团时,所述环或基团可为完全不饱和的或部分不饱和的。
当术语“任选取代的”在本申请中用来指示环或基团时,所述环或基团可为取代的或未取代的。
在整个说明书中,本领域技术人员可对基团及其取代基进行选择,以提供稳定的部分及化合物,以及用作药用化合物和/或在制备药用化合物中所使用的中间体化合物。
式(I)的化合物可形成亦在本发明的范畴内的盐。除非另有说明,提及的本发明化合物时,应理解为包括其盐。术语“盐”表示与无机酸及碱和/或有机酸及碱形成的酸性盐和/或碱性盐。此外,术语“盐”可包括两性离子(内盐),例如,当式(I)的化合物同时含有碱性部分如胺或吡啶或咪唑环以及酸性部分如羧酸时。药学上可接受的(即无毒的生理学上可接受的)盐是优选的,例如,可接受的金属盐和胺盐(其中阳离子不显著促成所述盐的毒性或生物活性)。然而,其它盐可用于例如制备期间可使用的分离或纯化步骤中,以及由此包括在本发明范围内。式(I)的化合物的盐可例如通过以下方法形成:将式(I)的化合物与一定量(诸如当量)的酸或碱在介质(诸如其中盐发生沉淀的介质)中或在水性介质中反应且接着冻干。
示例性的酸加成盐包括乙酸盐(诸如与乙酸或三卤乙酸(例如三氟乙酸)形成的盐)、己二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡糖酸盐(digluconate)、十二烷基硫酸盐、乙烷磺酸盐、富马酸盐、葡糖庚酸盐(glucoheptanoate)、甘油磷酸盐(glycerophosphate)、半硫酸盐、庚酸盐、己酸盐、盐酸盐(与盐酸形成)、氢溴酸盐(与氢溴酸形成)、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐(与马来酸形成)、甲磺酸盐与甲磺酸形成)、2-萘磺酸盐、烟酸盐(nicotinate)、硝酸盐、草酸盐、果胶酸盐(pectinate)、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐(picrate)、特戊酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐(诸如与硫酸形成的盐)、磺酸盐(诸如本申请中提及的盐)、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十一碳酸盐等。
示例性的碱性盐包括铵盐;碱金属盐,诸如钠盐、锂盐及钾盐;碱土金属盐,诸如钙盐及镁盐;钡盐、锌盐和铝盐;与有机碱(例如有机胺)(诸如三烷基胺,如三乙胺、普鲁卡因(procaine)、二苄胺、N-苄基-β-苯乙胺、1-二苯羟甲胺(1-ephenamine)、N,N′-二苄基乙二胺、脱氢枞胺(dehydroabietylamine)、N-乙基哌啶、苄胺、二环己胺或类似的药用胺)、N-甲基-D-葡糖胺、N-甲基-D-咪唑双酰胺、叔丁胺)形成的盐;及与氨基酸诸如精氨酸、赖氨酸等形成的盐。碱性含氮基团可用以下试剂来季铵化:诸如低级烷基卤化物(例如甲基、乙基、丙基及丁基的氯化物、溴化物及碘化物)、硫酸二烷基酯(例如硫酸的二甲酯、二乙酯、二丁酯及二戊酯)、长链卤化物(例如癸基、十二烷基、肉豆蔻基及硬脂酰基的氯化物、溴化物及碘化物)、芳烷基卤化物(例如苄基及苯乙基的溴化物)及其它试剂。优选的盐包括一盐酸盐、硫酸氢盐、甲磺酸盐、磷酸盐或硝酸盐。
也预期了本发明化合物的前药和溶剂化物(例如水合物)。术语“前药”表示如下的化合物,一旦将所述化合物给予受试者,其通过代谢或化学过程进行化学转化,得到式(I)的化合物和/或其盐和/或溶剂化物。在体内转化以提供生物活性药物(即式I化合物)的任何化合物是包括在本发明的范围和精神中的前药。例如,含有羧基的化合物可形成生理学可水解的酯,其可通过在体内水解得到式(I)化合物本身,从而充当前药。所述前药优选口服给药,因为在许多情况中水解主要在消化酶的影响下进行。当酯本身是有活性的,或当水解发生在血液中时,可使用肠胃外给药。式(I)的化合物的生理学可水解的酯包括C1-6烷基苄基、4-甲氧基苄基、茚满基、邻苯二甲酰基、甲氧基甲基、C1-6烷酰基氧基-C1-6烷基(例如乙酰氧基甲基、特戊酰基氧基甲基或丙酰基氧基甲基)、C1-6烷氧基羰基氧基-C1-6烷基(例如甲氧基羰基-氧基甲基或乙氧基羰基氧基甲基)、甘氨酰氧基甲基、苯基甘氨酰氧基甲基、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)-甲基和在青霉素和头孢菌素领域使用的其它公知的生理学可水解的酯。所述酯可通过本领域已知的常规技术制备。
各种形式的前药是本领域公知的。对于所述前药衍生物的实例而言,参见:
a)Design of Prodrugs,由H.Bundgaard编辑,(Elsevier,1985)和Methodsin Enzymology,Vol.112,pp.309-396,由K.Widder等人编辑(Academic Press,1985);
b)ATextbook of Drug Design and Development,由Krosgaard-Larsen和H.Bundgaard编辑,第5章,“Design and Application of Prodrugs,”by H.Bundgaard,pp.113-191(1991);以及
c)H.Bundgaard,Advanced Drug Delivery Reviews,Vol.8,pp.1-38(1992),将上述每篇文献引入本申请作为参考。
式(I)的化合物及其盐可以其互变异构形式存在,其中氢原子转移到分子的其它部分,因此分子的原子之间的化学键发生重排。应该理解的是,所有互变异构形式,只要它们可以存在,就包括在本发明的范围中。此外,本发明化合物可具有反式和顺式异构体,并且可含有一个或多个手性中心,因此以对映异构和非对映异构形式存在。本发明包括所有这些异构体,以及顺式和反式异构体的化合物、非对映异构体的混合物和对映异构体的外消旋混合物(光学异构体)。当没有具体提及化合物(或不对称碳)的构象(顺式、反式或R或S)时,则意指任何一种异构体或多于一种异构体的混合物。制备的方法可使用外消旋体、对映异构体或非对映异构体作为起始原料。当制备对映异构或非对映异构产物时,它们可通过常规方法(例如色谱法或分级结晶)分离。
联用
期望时,结构I的化合物可与一种或多种其它类型的治疗药物联用,所述其它类型的治疗药物如免疫抑制剂、抗癌剂、抗病毒剂、抗炎剂、抗真菌剂、抗生素、抗血管过度增殖药、抗抑郁药、降血脂药或降脂药或调脂药、抗糖尿病药、抗肥胖症药、抗高血压药、血小板聚集抑制剂,和/或抗骨质疏松药,所述药物可以相同的剂型,以单独的口服剂型口服给药,或经注射给药。
可任选与本发明的式I化合物联用的免疫抑制剂包括环孢菌素,例如环孢菌素A、霉酚酸酯、干扰素-β、脱氧精胍菌素、FK-506或Ant.-IL-2。
可任选与本发明的式I化合物联用的抗癌剂包括硫唑嘌呤、5-氟尿嘧啶、环磷酰胺、顺铂、甲氨喋呤、塞替派或卡铂等等。
可任选与本发明的式I化合物联用的抗病毒剂包括阿巴卡韦、阿昔洛韦、更昔洛韦、zidanocin或阿糖腺苷等等。
可任选与本发明的式I化合物联用的抗炎剂包括非甾类抗炎药(NSAIDs)如布洛芬,cox-2抑制剂如塞来考昔、罗非考昔、阿司匹林、萘普生、酮洛芬、双氯芬酸钠、吲哚美辛、吡罗昔康,甾类如泼尼松、地塞米松、氢化可的松、双醋曲安西龙,金化合物如硫代苹果酸金钠(gold sodiumthiomalate),TNF-α抑制剂如替尼达普(tenidap)、抗-TNF抗体或可溶性TNF受体和雷帕霉素(西罗莫司(sirolimus)或Rapamune)或其衍生物,英夫利昔单抗(Centocor,Inc.)、CTLA-4Ig、LEA29Y,抗体如抗-ICAM-3、抗-IL-2受体(Anti-Tac)、抗-CD45RB、抗-CD2、抗-CD3(OKT-3)、抗-CD4、抗-CD80、抗-CD86,单克隆抗体OKT3,阻断CD40和CD154(也称为“gp39”)之间的相互作用的药物如CD40和/或CD154的特异性抗体,融合蛋白如依那西普、从CD40和/或CD154gp39(例如CD40Ig和CD8gp39)构建的融合蛋白,抑制剂如核转位抑制剂(nuclear translocation inhibitor)、NF-κB功能的抑制剂如脱氧精胍菌素(DSG)。
可任选与本发明的式I化合物联用的抗真菌剂包括氟康唑(fluconazole)、咪康唑(miconazole)、两性霉素B(amphotericin B)等等。
可任选与本发明的式I化合物联用的抗生素包括青霉素、四环素、阿莫西林、氨苄西林、红霉素、多西环素、万古霉素、米诺环素、克林霉素或头孢氨苄。
可任选与本发明的式I化合物联用的抗血管过度增殖药包括甲氨喋呤、来氟米特、FK506(他克莫司(tacrolimus),Prograf)。
可任选与本发明的式I化合物联用的降血脂药或降脂药或调脂药包括1、2、3或更多种MTP抑制剂、HMG CoA还原酶抑制剂、角鲨烯合成酶抑制剂、苯乙酸衍生物、ACAT抑制剂、脂氧化酶抑制剂、胆固醇吸收抑制剂、回肠Na+/胆汁酸协同转运蛋白抑制剂(ileal Na+/bile acid cotransporterinhibitor)、LDL受体活性上调剂、胆汁酸多价螯合剂和/或烟酸及其衍生物。
本申请中采用的MTP抑制剂包括以下文献中披露的MTP抑制剂:美国专利5,595,872、美国专利5,739,135、美国专利5,712,279、美国专利5,760,246、美国专利5,827,875、美国专利5,885,983和提交于1998年10月20日的美国申请09/175,180,目前为美国专利5,962,440。优选的是每篇上述专利和申请中披露的每一种优选的MTP抑制剂。
将所有上述美国专利和申请都引入本申请作为参考。
根据本发明采用的更优选的MTP抑制剂包括美国专利5,739,135和5,712,279和美国专利5,760,246中列出的MTP抑制剂。
更优选的MTP抑制剂为9-[4-[4-[[2-(2,2,2-三氟乙氧基)苯甲酰基]氨基]-哌啶-1-基]丁基]-N-(2,2,2-三氟乙基)-9H-芴-9-甲酰胺
降血脂药可以是HMG CoA还原酶抑制剂,其包括但不限于在美国专利3,983,140中披露的美伐他汀及相关化合物、在美国专利4,231,938中披露的洛伐他汀(美维诺林(mevinolin))及相关化合物、在美国专利4,346,227中披露的普伐他汀及相关化合物、在美国专利4,448,784和4,450,171中披露的辛伐他汀及相关化合物。本申请可采用的其它HMG CoA还原酶抑制剂包括但不限于在美国专利5,354,772中披露的氟伐他汀、在美国专利5,006,530和5,177,080中披露的西立伐他汀(cerivastatin)、在美国专利4,681,893、5,273,995、5,385,929和5,686,104中披露的阿托伐他汀、在美国专利5,011,930中披露的伊伐他汀(Nissan/Sankyo的尼伐他汀(nisvastatin)(NK-104))、在美国专利5,260,440中披露的Shionogi-Astra/Zeneca维沙他汀(visastatin)(ZD-4522)以及在美国专利5,753,675中披露的相关抑制素化合物、在美国专利4,613,610中披露的甲羟戊酸内酯衍生物的吡唑类似物、在PCT申请WO 86/03488中披露的甲羟戊酸内酯衍生物的茚类似物、在美国专利4,647,576中披露的6-[2-(取代的吡咯-1-基)-烷基)吡喃-2-酮及其衍生物、Searle的SC-45355(3-取代的戊二酸衍生物)二氯乙酸乙酯、在PCT申请WO 86/07054中披露的甲羟戊酸内酯的咪唑类似物、在法国专利2,596,393中披露的3-羧基-2-羟基-丙烷-膦酸衍生物、在欧洲专利申请0221025中披露的2,3-二取代的吡咯、呋喃和噻吩衍生物、在美国专利4,686,237中披露的甲羟戊酸内酯的萘基类似物、在美国专利4,499,289中披露的八氢萘、在欧洲专利申请0142146A2中披露的美维诺林(洛伐他汀)的酮类似物以及在美国专利5,506,219和5,691,322中披露的喹啉和吡啶衍生物。
此外,适于在本申请中使用的用于抑制HMG CoA还原酶的膦酸化合物披露在GB 2205837中。
适于在本申请中使用的角鲨烯合成酶抑制剂包括但不限于在美国专利5,712,396中披露的α-膦酰基-磺酸酯、Biller等人,J.Med.Chem.,1988,Vol.31,No.10,pp 1869-1871(1988)所披露的物质(包括类异戊二烯(膦基-甲基)膦酸酯)以及其它已知的角鲨烯合成酶抑制剂,例如在美国专利4,871,721和4,924,024以及Biller,S.A.,Neuenschwander,K.,Ponpipom,M.M.,and Poulter,C.D.,Current Pharmaceutical Design,Vol.2,pp.1-40(1996)中披露的物质。
此外,适于在本申请中使用的其它角鲨烯合成酶抑制剂包括P.Ortiz deMontellano等人,J.Med.Chem.,1977,20,243-249所披露的萜类焦磷酸酯(terpenoid pyrophosphate)、Corey and Volante,J.Am.Chem.Soc.,98,1291-1293(1976)所披露的法尼基二磷酸酯类似物A和前角鲨烯焦磷酸酯(presqualenepyrophosphate,PSQ-PP)类似物、McClard,R.W.等人,J.Am.Chem.Soc.,1987,109,5544(1987)所报道的膦基磷酸酯和Capson,T.L,PhD dissertation,Dept.Med.Chem.U.of Utah,Abstract,Table of Contents,pp.16,17,40-43,48-51,Summary (June,1987)所报道的环丙烷类。
适于在本申请中使用的其它降血脂药包括但不限于苯乙酸衍生物,如非诺贝特、吉非贝齐、氯贝丁酯、苯扎贝特、环丙贝特、克利贝特等、在美国专利3,674,836中披露的普罗布考及相关化合物(优选为普罗布考和吉非贝齐)、胆汁酸多价螯合剂(例如考来烯胺、考来替泊和DEAE-葡聚糖凝胶和考来胶(Sankyo/Geltex)),以及保脂妥(Rhone-Poulenc)、Eisai E-5050(N-取代的乙醇胺衍生物)、伊马昔尔(imanixil,HOE-402)、四氢抑脂素(tetrahydrolipstatin,THL)、istigmastanylphos-phorylcholine(SPC,Roche)、氨基环糊精(Tanabe Seiyoku)、AjinomotoAJ-814(薁衍生物,azulene derivative)、甲亚油酰胺(Sumitomo)、Sandoz58-035、American Cyanamid CL-277,082和CL-283,546(二取代的脲衍生物)、烟酸(niacin)、阿昔莫司、阿昔呋喃、新霉素、对氨基水杨酸、阿司匹林、在美国专利4,759,923中披露的聚(二烯丙基甲胺)衍生物、在美国专利4,027,009中披露的季胺聚(二烯丙基二甲基氯化铵)和紫罗烯类(ionenes)以及其它已知的降血清胆固醇药物。
降血脂药可以是ACAT抑制剂,例如如以下文献中披露的物质:Drugsof the Future,24,9-15(1999),(Avasimibe(阿伐麦布));“The ACAT inhibitor,Cl-1011is effective in the prevention and regression of aortic fatty streak area inhamsters”,Nicolosi等人.,Atherosclerosis(Shannon,Irel).137(1),77-85(1998);“The pharmacological profile of FCE 27677:a novel ACAT inhibitorwith potent hypolipidemic activity mediated by selective suppression of thehepatic secretion of ApoB100-containing lipoprotein”,Ghiselli,Giancarlo,Cardiovasc.Drug Rev.(1998),16(1),16-30;“RP 73163:a bioavailablealkylsulfinyl-diphenylimidazole ACAT inhibitor”,Smith,C.,等人,Bioorg.Med.Chem.Lett.6(1),47-50(1996);“ACAT inhibitors:physiologic mechanisms forhypolipidemic and anti-atherosclerotic activities in experimental animals”,Krause等人,Editor(s):Ruffolo,Robert R.,Jr.;Hollinger,Mannfred A.,Inflammation:Mediators Pathways 173-98(1995),Publisher:CRC,Boca Raton,Fla.;“ACAT inhibitors:potential anti-atherosclerotic agents”,Sliskovic等人,Curr.Med.Chem.1(3),204-251994);“Inhibitors of acyl-CoA:cholesterolO-acyl transferase(ACAT)as hypocholesterolemic agents.6.The firstwater-soluble ACAT inhibitor with lipid-regulating activity.Inhibitors ofacyl-CoA:cholesterol acyltransferase(ACAT).7.Development of a series ofsubstituted N-phenyl-N’-[(1-phenylcyclopentyl)methyl]ureas with enhancedhypocholesterolemic activity”,Stout等人,Chemtracts:Org.Chem.8(6),359-62(1995),或TS-962(N-[2,6-二(1-甲基乙基)苯基]-2-(十四烷基硫基)-乙酰胺)(Taisho Pharmaceutical Co.Ltd)。
降血脂药可以是LD2受体活性的上调剂例如MD-700(3-(13-羟基-10-氧代十四烷基)-5,7-二甲氧基1(3H)-异苯并呋喃酮)(Taisho Pharmaceutical Co.Ltd)和LY295427(4-(2-丙烯基)-(3a,4a,5a)-胆甾烷-3-醇)(Eli Lilly)。
降血脂药可以是胆固醇吸收抑制剂,优选为Schering-Plough的依泽替米贝(ezetimibe,SCH58235)和SCH48461以及在Atherosclerosis 115,45-63(1995)和J.Med.Chem.41,973(1998)中披露的物质。
降血脂药可以是回肠Na+/胆汁酸协同转运蛋白抑制剂,如在Drugs ofthe Future,24,425-430(1999)中披露的化合物。
调脂药可以是胆固醇脂转移蛋白(CETP)抑制剂如Pfizer的CP 529,414(torcetrapib)(WO/0038722和EP 818448)和Pharmacia的SC-744和SC-795。
可与本发明的化合物联用的ATP枸橼酸裂解酶抑制剂(ATP citrate lyaseinhibitor)可包括例如在美国专利5,447,954中披露的化合物。
优选的降血脂药是普伐他汀、洛伐他汀、辛伐他汀、阿托伐他汀、氟伐他汀、西立伐他汀、伊伐他汀、维沙他汀和ZD-4522。
将上述美国专利引入本申请作为参考。采用的量和剂量如Physicians’Desk Reference中所指示和/或在上文列出的专利中所指示。
本发明的式I化合物与降血脂药(存在时)一起使用时的重量比例在约500∶1至约1∶500,优选约100∶1至约1∶100的范围中。
所给药的剂量必须根据患者的年龄、体重和健康状况,以及给药途径、剂型和给药方案和期望的结果而谨慎调整。
降血脂药的剂量和制剂披露在上文讨论的各种专利和申请中。
所采用的其它降血脂药的剂量和制剂,在适用时,在Physicians’DeskReference(PDR)最近的版本中列出。
对于口服给药而言,当采用的MTP抑制剂的量在约0.01mg至约500mg,以及优选约0.1mg至约100mg的范围中,每日一至四次时,可获得满意的结果。
优选的口服剂型(如片剂或胶囊剂)中含有的MTP抑制剂的量为约1至约500mg,优选约2至约400mg,更优选约5至约250mg,每日一至四次。
对于口服给药而言,当在给药时采用的HMG CoA还原酶抑制剂(例如,普伐他汀、洛伐他汀、辛伐他汀、阿托伐他汀、氟伐他汀或西立伐他汀)的剂量与Physicians’Desk Reference中所指示的相同(如用量在约1至2000mg,优选约4至约200mg的范围中)时,可获得满意的结果。
在给药时可采用的角鲨烯合成酶抑制剂的量在约10mg至约2000mg以及优选约25mg至约200mg的范围中。
优选的口服剂型(如片剂或胶囊剂)中含有的HMG CoA还原酶抑制剂的量为约0.1至约100mg,优选约0.5至约80mg,以及更优选约1至约40mg。
优选的口服剂型(如片剂或胶囊剂)中含有的角鲨烯合成酶抑制剂的量为约10至约500mg,优选约25至约200mg。
降血脂药也可以是脂氧化酶抑制剂,包括15-脂氧化酶(15-LO)抑制剂,例如在WO 97/12615中披露的苯并咪唑衍生物、在WO 97/12613中披露的15-LO抑制剂、在WO 96/38144中披露的异噻唑酮类以及Sendobry等人“Attenuation of diet-induced atherosclerosis in rabbits with a highly selective15-lipoxygenase inhibitor lacking significant antioxidant properties”,Brit.J.Pharmacology 120,1199-1206(1997)和Cornicelli等人,“15-Lipoxygenase andits Inhibition:A Novel Therapeutic Target for Vascular Disease”,CurrentPharmaceutical Design,5,11-20(1999)披露的15-LO抑制剂。
式I化合物和降血脂药可以以相同的口服剂型或同时服用的单独的口服剂型一起使用。
上文描述的组合物可以上述剂型,以每日一至四次的单一或分份剂量给药。可以是适当的是,以低剂量组合开始给予患者,逐步发展为高剂量组合。
优选的降血脂药为普伐他汀、辛伐他汀、洛伐他汀、阿托伐他汀、氟伐他汀或西立伐他汀以及烟酸和/或考来胶。
可任选与式I化合物联用的其它抗糖尿病药可以是1、2、3或更多种抗糖尿病药或抗高血糖药(antihyperglycemic agent),包括促胰岛素分泌剂(insulin secretagogue)或胰岛素敏化剂,或优选具有不同于本发明的式I化合物的作用机理的其它抗糖尿病药,所述其它抗糖尿病药可包括双胍、磺酰脲、葡糖苷酶抑制剂、PPARγ激动剂如噻唑烷二酮类、aP2抑制剂、二肽基肽酶IV(DP4)抑制剂、SGLT2抑制剂和/或氯茴苯酸,以及胰岛素和/或胰高血糖素样肽-1(GLP-1)。
其它抗糖尿病药可以是口服抗高血糖药,优选为双胍如二甲双胍或苯乙双胍或其盐,优选为苯乙双胍HCl。
当所述抗糖尿病药为双胍时,采用的结构I的化合物与双胍的重量比例在约0.001∶1至约10∶1,优选约0.01∶1至约5∶1的范围中。
其它抗糖尿病药也可优选为磺酰脲,如格列本脲(也已知为glibenclamide)、格列美脲(披露于美国专利4,379,785中)、格列吡嗪、格列齐特或氯磺丙脲,其它已知的磺酰脲或作用于β-细胞的ATP-依赖的通道的其它抗高血糖药,优选格列本脲和格列吡嗪,其可以相同或单独的口服剂型给药。
采用的结构I的化合物与磺酰脲的重量比例在约0.01∶1至约100∶1,优选约0.02∶1至约5∶1的范围中。
所述口服抗糖尿病药也可为葡糖苷酶抑制剂如阿卡波糖(披露于美国专利4,904,769中)或米格列醇(披露于美国专利4,639,436中),其可以相同或单独的口服剂型给药。
采用的结构I的化合物与葡糖苷酶抑制剂的重量比例在约0.01∶1至约100∶1,优选约0.05∶1至约10∶1的范围中。
结构I的化合物可与PPARγ激动剂联用,所述PPARγ激动剂如噻唑烷二酮类口服抗糖尿病药或其它胰岛素敏化剂(其在NIDDM患者中具有胰岛素敏化效应)如曲格列酮(Warner-Lambert’s披露于美国专利4,572,912中)、罗格列酮(SKB)、吡格列酮(Takeda)、Mitsubishi的MCC-555(披露于美国专利5,594,016中)、Glaxo-Wellcome的GL-262570(法格立他扎(farglitazar))、恩格列酮(CP-68722,Pfizer)或达格列酮(CP-86325,Pfizer)、伊格列酮(isaglitazone)(MIT/J&J)、JTT-501(reglitazar)(JPNT/P&U)、L-895645(Merck)、R-119702(利格列酮(rivoglitazone))(Sankyo/WL)、NN-2344(巴格列酮(balaglitazone))(Dr.Reddy/NN)或YM-440((Z)-1,4-二-4-[(3,5-二氧代-1,2,4-噁二唑啉-2-基-甲基)]-苯氧基丁-2-烯)(Yamanouchi),优选罗格列酮和吡格列酮。
采用的结构I的化合物与噻唑烷二酮类的重量比例在约0.01∶1至约100∶1,优选约0.05至约10∶1的范围中。
在含有结构I的化合物的单片剂中可引入的磺酰脲和噻唑烷二酮类的量少于约150mg口服抗糖尿病药。
结构I的化合物也可与抗高血糖药(如胰岛素)或胰高血糖素样肽-1(GLP-1)联用,所述胰高血糖素样肽-1如GLP-1(1-36)酰胺、GLP-1(7-36)酰胺、GLP-1(7-37)(披露于授予Habener的美国专利5,614,492中,将其中的公开引入本申请作为参考),以及AC2993(艾塞那肽(exenatide))(Amylin)和LY-315902(8-37-胰高血糖素样肽-1(人),N-[3-(1H-咪唑-4-基)-1-氧代丙基]-26-L-精氨酸-34-[N6-(1-氧代辛基)-L-赖氨酸]-)(Lilly),上述药物可经注射、鼻内、吸入给药或经透皮或含服装置给药。
当二甲双胍、磺酰脲如格列本脲、格列美脲、格列吡脲(glipyride)、格列吡嗪、氯磺丙脲、格列齐特和葡糖苷酶抑制剂阿卡波糖或米格列醇或胰岛素(可注射的、肺部使用、含服或口服胰岛素)存在时,可以上文描述的制剂和Physicians’Desk Reference(PDR)指示的量和给药法使用上述药物。
当二甲双胍或其盐存在时,可采用的所述药物的量在约每日500至约2000mg的范围中,其可以单剂量或分份剂量给药,每日一至四次。
当噻唑烷二酮类抗糖尿病药存在时,可采用的所述药物的量在约0.01至约2000mg/日的范围中,其可以单剂量或分份剂量给药,每日一至四次。
当胰岛素存在时,可以Physicians’Desk Reference指示的制剂、量和给药法使用胰岛素。
当GLP-1肽存在时,如美国专利5,346,701(TheraTech)、5,614,492和5,631,224(将所述专利引入本申请作为参考)中所述,其可以口服含服制剂给药、经鼻给药或肠胃外给药。
其它抗糖尿病药也可以是PPAR α/γ双重激动剂如AR-HO39242(tesaglitazar)(Astra/Zeneca)、GW-409544(Glaxo-Wellcome)、KRP297(5-[(2,4-二氧代-5-噻唑烷基)甲基]-2-甲氧基-N-[[4-(三氟甲基)苯基]甲基]-苯甲酰胺)(Kyorin Merck)以及Murakami等人,“A Novel Insulin Sensitizer Acts As aColigandfor Peroxisome Proliferation-Activated Receptor Alpha(PPAR alpha)and PPAR gamma.Effect on PPAR alpha Activation on Abnormal LipidMetabolism in Liver of Zucker Fatty Rats”,Diabetes 47,1841-1847(1998)披露的物质。
所述抗糖尿病药可以是SGLT2抑制剂,如2000年10月4日提交的美国申请09/679,027中披露的物质,采用其中列出的剂量。在上述申请中指定为优选的化合物是优选的。
所述抗糖尿病药可以是aP2抑制剂,如1999年9月7日提交的美国申请09/391,053和2000年3月6日提交的美国申请09/519,079中披露的物质,采用其中所列出的剂量。在上述申请中指定为优选的化合物是优选的。
所述抗糖尿病药可以是DP4抑制剂,如2001年2月16日提交的美国申请09/788,173、WO99/38501、WO99/46272、WO99/67279(PROBIODRUG)、WO99/67278(PROBIODRUG)、WO99/61431(PROBIODRUG)中披露的物质,saxagliptin(优选的),Hughes等人,Biochemistry,38(36),11597-11603,(1999)披露的NVP-DPP728A(1-[[[2-[(5-氰基吡啶-2-基)氨基]乙基]氨基]乙酰基]-2-氰基-(S)-吡咯烷)(Novartis)(优选的),Yamada等人,Bioorg.&Med.Chem.Lett.81537-1540(1998)披露的TSL-225(色氨酰-1,2,3,4-四氢-异喹啉-3-羧酸),Ashworth等人,Bioorg.&Med.Chem.Lett.,Vol.6,No.22,pp1163-1166和2745-2748(1996)披露的2-氰基吡咯烷和4-氰基吡咯烷,采用上述文献中列出的剂量。
可任选与本发明的式I化合物联用的氯茴苯酸可以是瑞格列奈、那格列奈(Novartis)或KAD 1229(米格列奈)(PF/Kissei),瑞格列奈是优选的。
可采用的式I化合物与氯茴苯酸、PPARγ激动剂、PPARα/γ双重激动剂、aP2抑制剂、DP4抑制剂或SGLT2抑制剂的重量比例在约0.01∶1至约100∶1,优选约0.05至约10∶1的范围中。
可任选与式I化合物联用的其它类型的治疗药物可以是抗肥胖症药,包括β3肾上腺素能激动剂、脂酶抑制剂、5-羟色胺(和多巴胺)再摄取抑制剂和Ap2抑制剂、甲状腺受体激动剂和/或厌食药中的1、2、3或更多种。
可任选与式I化合物联用的β3肾上腺素能激动剂可以是AJ9677(rafabegron)(Takeda/Dainippon)、L750355(N-[4-[2-[[(2S)-3-[(6-氨基-吡啶-3-基)氧基]-2-羟基丙基]氨基]乙基]苯基]-4-(1-甲基乙基)-苯磺酰胺)(Merck)或CP331684(4-[2-[[2-(6-氨基吡啶-3-基)-2(R)-羟基乙基]-氨基]乙氧基]苯基]乙酸)(Pfizer)或美国专利5,541,204、5,770,615、5,491,134、5,776,983和5,488,064中披露的其它已知的β3激动剂,AJ9677、L750,355(N-[4-[2-[[(2S)-3-[(6-氨基-吡啶-3-基)氧基]-2-羟基丙基]氨基]乙基]苯基]-4-(1-甲基乙基)-苯磺酰胺)和CP331684是优选的。
可任选与式I化合物联用的脂酶抑制剂可以是奥利司他(orlistat)或ATL-962(Alizyme),奥利司他是优选的。
可任选与式I化合物联用的5-羟色胺(和多巴胺)再摄取抑制剂可以是西布曲明、托吡酯(Johnson&Johnson)或睫状体神经营养因子(Regeneron),西布曲明和托吡酯是优选的。
可任选与式I化合物联用的甲状腺受体激动剂可以是甲状腺受体的配体,例如在WO97/21993(U.Cal SF)、WO99/00353(KaroBio)、WO00/039077(KaroBio)和于2000年2月17日提交的美国临时申请60/183,223中披露的物质,KaroBio申请和上文美国临时申请中披露的化合物是优选的。
可任选与式I化合物联用的厌食药可以是右旋苯丙胺、芬特明、苯丙醇胺或马吲哚,右旋苯丙胺是优选的。
上述的各种抗肥胖症药可以以与式I化合物相同的剂型,或以不同的剂型,以本领域或PDR中通常已知的剂量和方案使用。
可与本发明的式I化合物联用的抗高血压药包括ACE抑制剂、血管紧张素II受体拮抗剂、NEP/ACE抑制剂以及钙通道阻滞剂、β-肾上腺素能阻滞剂和其它类型的抗高血压药,包括利尿剂。
本申请可采用的血管紧张素转化酶抑制剂包括含有巯基(-S-)部分的化合物,如取代的脯氨酸衍生物(如上述的授予Ondetti等人的美国专利4,046,889中披露的任何化合物,卡托普利即1-[(2S)-3-巯基-2-甲基丙酰基]-L-脯氨酸是优选的),以及取代的脯氨酸的巯基酰基衍生物,如美国专利4,316,906中披露的任何化合物,佐芬普利是优选的。
本申请可采用的含有巯基的ACE抑制剂的其它实例包括Clin.Exp.Pharmacol.Physiol.10∶131(1983)中披露的伦唑普利(芬替普利,Santen)以及匹伏普利(pivopril)和YS980。
本申请可采用的血管紧张素转化酶抑制剂的其它实例包括上述美国专利4,374,829中披露的任何化合物,N-(1-乙氧基羰基-3-苯基丙基)-L-丙氨酰-L-脯氨酸即依那普利是优选的;美国专利4,452,790中披露的任何膦酸酯取代的氨基酸或亚氨基酸或盐,(S)-1-[6-氨基-2-[[羟基-(4-苯基丁基)膦酯基]氧基]-1-氧代己基]-L-脯氨酸或(西罗普利)是优选的;上述美国专利4,168,267中披露的膦酯基烷酰基脯氨酸,福辛普利是优选的;美国专利4,337,201中披露的任何膦酯基烷酰基取代的脯氨酸,以及上文讨论的美国专利4,432,971中披露的膦酰胺酯(phosphonamidate)。
本申请可采用的ACE抑制剂的其它实例包括欧洲专利申请80822和60668中披露的Beecham的BRL 36,378;C.A.102:72588v和Jap.J.Pharmacol.40:373(1986)中披露的Chugai的MC-838;英国专利2103614中披露的Ciba-Geigy的CGS 14824(3-([1-乙氧基羰基-3-苯基-(1S)-丙基]氨基)-2,3,4,5-四氢-2-氧代-1-(3S)-苯并氮杂-1-乙酸HCl)和美国专利4,473,575中披露的CGS16,617(3(S)-[[(1S)-5-氨基-1-羧基戊基]氨基]-2,3,4,5-四氢-2-氧代-1H-1-苯并氮杂-1-乙醇酸);Eur.Therap.Res.39:671(1986)中披露的阿拉普利(alacepril,Dainippon);欧洲专利79-022和Curr.Ther.Res.40:74(1986)中披露的雷米普利(Hoechsst);Arzneimittelforschung 34:1254(1985)中披露的Ru 44570(Hoechst)、J.Cardiovasc.Pharmacol.9:39(1987)中披露的西拉普利(Hoffman-LaRoche);FEBS Lett.165:201(1984)中披露的R 31-2201(Hoffman-LaRoche);美国专利4,385,051中披露的赖诺普利(Merck)、地拉普利(delapril);J.Cardiovasc.Pharmacol.5:643,655(1983)中披露的吲哚普利(Schering);Acta.Pharmacol.Toxicol.59(Supp.5):173(1986)中披露的螺普利(Schering);Eur.J.Clin.Pharmacol.31:519(1987)中披露的培哚普利(Servier);美国专利4,344,949中披露的喹那普利(Warner-Lambert)和Pharmacologist26:243,266(1984)中披露的CI925(Warner-Lambert)([3S-[2[R(*)R(*)]]3R(*)]-2-[2-[[1-(乙氧基-羰基)-3-苯基丙基]氨基]-1-氧代丙基]-1,2,3,4-四氢-6,7-二甲氧基-3-异喹啉羧酸HCl)、J.Med.Chem.26:394(1983)中披露的WY-44221(Wyeth)。
优选的ACE抑制剂是卡托普利、福辛普利、依那普利、赖诺普利、喹那普利、贝那普利、芬替普利、雷米普利和莫昔普利。
本申请中也可采用NEP/ACE抑制剂,因为它们具有中性肽链内切酶(neutral endopeptidase,NEP))抑制活性和血管紧张素转化酶(ACE)抑制活性。适用于本申请的NEP/ACE抑制剂的实例包括以下文献中披露的化合物:美国专利5,362,727、5,366,973、5,225,401、4,722,810、5,223,516、4,749,688、美国专利5,552,397、美国专利5,504,080、美国专利5,612,359、美国专利5,525,723、欧洲专利申请0599444、0481522、0599444、0595610、欧洲专利申请0534363A2、534396和534492,以及欧洲专利申请0629627A2。
优选的是上述专利/申请中指定为优选的NEP/ACE抑制剂及其剂量,将美国专利引入本申请作为参考;最优选的是奥马曲拉([S-(R*,R*)]-六氢-6-[(2-巯基-1-氧代-3-苯基丙基)氨基]-2,2-二甲基-7-氧代-1H-氮杂-1-乙酸(gemopatrilat))和CGS 30440。
适用于本申请的血管紧张素II受体拮抗剂(本申请中也称为血管紧张素II拮抗剂或AII拮抗剂)包括但不限于厄贝沙坦、氯沙坦、缬沙坦、坎地沙坦(candesartan)、替米沙坦、他索沙坦(tasosartan)或依普罗沙坦(eprosartan),厄贝沙坦、氯沙坦或缬沙坦是优选的。
优选的口服剂型如片剂或胶囊剂,其中含有的ACE抑制剂或AII拮抗剂的量在约0.1至约500mg,优选约5至约200mg以及更优选地约10至约150mg的范围中。
对于肠胃外给药而言,所采用的ACE抑制剂、血管紧张素II拮抗剂或NEP/ACE抑制剂的量在约0.005mg/kg至约10mg/kg以及优选约0.01mg/kg至约1mg/kg的范围中。
当将药物经静脉内给药时,可将其在常规媒介物如蒸馏水、盐水、林格溶液(Ringer’s solution)或其它常规载体中配制。
应该理解的是,ACE抑制剂和AII拮抗剂以及本申请披露的其它抗高血压药的优选的剂量在Physicians’Desk Reference最近的版本中列出。
适用于本申请的优选的抗高血压药的其它实例包括奥马曲拉苯磺酸氨氯地平哌唑嗪HCl维拉帕米、硝苯地平、纳多洛尔、地尔硫、非洛地平、尼索地平、伊拉地平(isradipine)、尼卡地平、阿替洛尔、卡维地洛、索他洛尔、特拉唑嗪(terazosin)、多沙唑嗪(doxazosin)、普萘洛尔和可乐定HCl
可与式I化合物联用的利尿剂包括氢氯噻嗪(hydrochlorothiazide)、托拉塞米(torasemide)、呋赛米(furosemide)、螺内酯(spironolactone)和吲达帕胺(indapamide)。
可与本发明的式I化合物联用的抗血小板药(Antiplatelet agent)包括阿司匹林、氯吡格雷、噻氯匹定、双嘧达莫、阿昔单抗、替罗非班、依替巴肽(eptifibatide)、阿那格雷(anagrelide)和伊非曲班,氯吡格雷和阿司匹林是优选的。
可以采用的抗血小板药的量如PDR中所指示。可以采用的伊非曲班的量在美国专利5,100,889中列出。
适于在本申请中与本发明的式I化合物联用的抗骨质疏松药包括甲状旁腺激素(parathyroid hormone)或二膦酸盐(bisphosphonate),如MK-217(阿伦膦酸盐)
上述药物的使用剂量在Physicians’Desk Reference中列出。
药物制剂
本发明的药物组合物包括药用载体、辅料或媒介物,所述药用载体、辅料或媒介物可与本发明化合物一起给药于受试者,并且不破坏本发明化合物的药理学活性。可在本发明的药物组合物中使用的药用载体、辅料和媒介物包括但不限于以下物质:离子交换剂、氧化铝(alumina)、硬脂酸铝、卵磷脂、自乳化药物递送系统(self-emulsifying drug delivery systems,“SEDDS”)如d(-生育酚聚乙二醇1000琥珀酸酯)、用于药物剂型中的表面活性剂如吐温或其它类似的聚合物递送基质(polymeric delivery matrices)、血清蛋白如人血清白蛋白、缓冲物质如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的部分甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白(protamine sulfate)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐)、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段共聚物、聚乙二醇和羊毛脂。环糊精如α-、β-和γ-环糊精或化学修饰的衍生物如羟基烷基环糊精(包括2-和3-羟基丙基-β-环糊精)或其它增溶衍生物也可用来增强本发明的调节剂的递送。
本发明的组合物可含有如下文所述的其它治疗药物,并且可通过以下方式配制:例如,根据例如药物制剂领域熟知的技术,采用常规固态或液态媒介物或稀释剂以及适于期望的给药模式的药物添加剂类型(例如,赋形剂、粘合剂、防腐剂、稳定剂、调味剂等等)。
本发明的化合物可通过任何合适的方式给药,所述方式例如以片剂、胶囊剂、颗粒剂或粉末剂的形式口服给药;舌下给药;含服给药;如经皮下、静脉内、肌内或胸骨内注射或输注技术(例如作为无菌可注射水性溶液或非水性溶液或混悬液)肠胃外给药;通过吸入喷雾经鼻给药;以乳膏或软膏形式局部给药;或以栓剂形式经直肠给药;以含有非毒性药用媒介物或稀释剂的剂量单位制剂给药。本发明的化合物可例如以适于立即释放或延迟释放的形式来给药。立即释放或延迟释放可通过以下方法来实现:使用包括本发明化合物的合适药物组合物,或尤其在延迟释放的情况下,使用诸如皮下植入物或渗透泵那样的装置。本发明的化合物也可经脂质体(liposomally)给药。
用于口服给药的示例性组合物包括以下制剂形式:混悬剂,其可含有例如用于赋予松密度(bulk)的微晶纤维素、作为助悬剂的海藻酸或海藻酸钠,作为粘度增强剂的甲基纤维素,以及如本领域已知的那些增甜剂和调味剂;以及立即释放片剂,其可含有例如微晶纤维素、磷酸二钙、淀粉、硬脂酸镁和/或乳糖和/或其它如本领域已知的那些赋形剂、粘合剂、膨胀剂(extender)、崩解剂、稀释剂和润滑剂。本发明化合物还可经舌下和/或含服给药通过口腔递送。模制片剂、压制片剂或冷冻干燥的片剂是可用的示例性形式。示例性组合物包括用快速溶出稀释剂(如甘露醇、乳糖、蔗糖和/或环糊精)配制本发明化合物的那些组合物。还包括在所述制剂中的可以是高分子量赋形剂如纤维素(Avicel)或聚乙二醇(PEG)。所述制剂还可包括辅助粘膜吸附的赋形剂如羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、羧甲基纤维素钠(SCMC)和/或马来酸酐共聚物(例如,Gantrez);以及控制释放的试剂如聚丙烯酸共聚物(例如,Carbopol 934)。还可添加润滑剂、助流剂、香料、着色剂和稳定剂以便于加工和使用。
用于鼻气雾剂或吸入给药的示例性组合物包括于盐水中的溶液剂,其可含有例如,苄醇或其它合适的防腐剂、增强生物利用度的吸收促进剂,和/或如本领域已知的那些其它增溶剂或分散剂。
用于肠胃外给药的示例性组合物包括可注射的溶液或混悬液,其可含有例如合适的无毒的肠胃外可接受的稀释剂或溶剂,诸如甘露醇、1,3-丁二醇、水、林格溶液(Ringer’s solution)和等张氯化钠溶液,或其它合适的分散剂或湿润剂及助悬剂,包括合成的甘油一酯或甘油二酯及脂肪酸,包括油酸。
本申请使用的术语“肠胃外”包括皮下、皮内、静脉内、肌内、关节内、动脉内、滑膜腔内、胸骨内、鞘膜内(intrathecal)、病灶内(intralesional)和颅内注射或输注技术。
用于直肠给药的示例性组合物包括栓剂,其可含有例如合适的非刺激性赋形剂,如可可酯、合成的甘油酯或聚乙二醇,所述栓剂在常温是固态的,但在直肠腔道中液化和/或溶解以释放药物。
用于局部给药的示例性组合物包括局部载体如Plastibase(与聚乙烯胶化的矿物油)。
本发明的化合物的有效量可由本领域技术人员来确定,且包括约0.1至500mg/kg体重的活性化合物的示例性成人日剂量,或0.5至2000mg的日剂量,其可按单剂量的形式给药或按分份剂量的形式(诸如每日1至5次)给药。应该理解的是,用于任何具体受试者的具体剂量水平及给药频率可发生变化且取决于多种因素,这些因素包括所使用的具体化合物的活性、所述化合物的代谢稳定性及作用持续时间、受试者的物种、年龄、体重、一般健康情况、性别及饮食、给药模式及时间、排泄速率、药物组合及具体病症的严重程度。接受治疗的优选受试者包括动物,最优选为哺乳动物物种,诸如人类及家畜(诸如狗、猫等)。
用于口服给药的典型胶囊剂含有结构I的化合物(250mg)、乳糖(75mg)和硬脂酸镁(15mg)。使混合物经过60目筛过筛,然后填充入1号明胶胶囊中。
典型的注射剂如下生产:将250mg结构I的化合物采用无菌操作置于小瓶中,采用无菌操作冷冻干燥并密封。使用时,将小瓶中的内含物与2mL生理盐水混合,以产生注射剂。
本发明的式I化合物是糖皮质激素受体调节剂,这是通过在GR结合测定中所述化合物与糖皮质激素受体结合的能力,或通过在细胞反式阻抑测定中指示的其抑制AP-1活性的能力,以及在细胞反式激活测定中指示的不引起任何反式激活的能力表明的。
本发明的化合物,包括其实施例中描述的化合物,已经在以下的至少一种测定中进行了测试,并且具有糖皮质激素受体(GR)/地塞米松(Dex)抑制活性(在10μM时>25%)和/或AP-1抑制活性(EC50小于15μM)。
相同和/或类似的测定描述在2003年7月17日提交的美国申请10/621,807中,将其全文引入本申请作为参考。
GR结合测定
糖皮质激素受体结合测定(I)a
为了评价测试化合物对人糖皮质激素受体的亲和力,使用市售试剂盒(糖皮质激素受体竞争测定试剂盒,Invitrogen Part#2893)。简而言之,将纯化的人重组体全长糖皮质激素受体(2nM)与荧光标记的糖皮质激素(1nMFluormone GS Red)在存在或不存在测试化合物的情况下混合。在室温避光孵育两个小时后,测量样品的荧光偏振(fluorescence polarization,FP)。受体、荧光探针(即Fluormone GS Red)和5μM地塞米松的混合物的FP表示背景荧光或100%抑制,相反,认为不含地塞米松(但是存在媒介物)的混合物的FP表示100%结合。然后将测试化合物的抑制百分数与含有5μM地塞米松的样品比较,并且表达为%相对结合活性形式,其中地塞米松为100%,而没有抑制为0%。对测试化合物在8.5E-05μM至5μM的浓度范围分析。
糖皮质激素受体结合测定(II)b
为了评价化合物与人糖皮质激素受体的结合,使用市售试剂盒(糖皮质激素受体竞争测定试剂盒,PanVera Co.,Madison,WI,P2816)。简而言之,将含有重组表达的人全长糖皮质激素受体的细胞溶解物(cell lysate)与荧光标记的糖皮质激素(1nM Fluormone GS1)在存在或不存在测试化合物的情况下混合。在室温避光孵育一个小时后,测量样品的荧光偏振(FP)。受体、荧光探针(即Fluormone GS1)和1μM地塞米松的混合物的FP表示背景荧光或100%抑制,相反,认为不含地塞米松的混合物的FP表示100%结合。然后将测试分子的抑制百分数与含有1μM地塞米松的样品比较,并且表达为%相对结合活性形式,其中地塞米松为100%,而没有抑制为0%。对测试分子在2.4nM至40微摩尔的浓度范围分析。
对任何NHR(细胞核激素受体)的位点I结合测定以类似于上文的方式进行。适当的细胞溶胞产物或纯化的NHR用作NHR的来源。荧光探针和未标记的竞争物对于特异性NHR是适当的,即是特异性NHR的配体。
细胞反式阻抑测定
为了测量测试分子抑制AP-1诱导的转录活性的能力,本发明利用了A549细胞,将其先后用含有7x AP-1DNA结合位点(pAP-1-Luc质粒,Stratagene Co.La Jolla,CA)的质粒和萤光素酶(luciferase)的基因稳定转染。将细胞用10ng/ml佛波醇肉豆蔻酸(phorbol myristic acid,PMA)(在存在或不存在测试分子的情况下)激活7小时。7小时后,加入萤光素酶以测量萤光素酶在细胞中的酶活性。将萤光素酶试剂与细胞一起孵育10分钟后,在TopCount发光计数器中测量发光。对AP-1活性的阻抑计算为由PMA单独诱导的信号的降低百分数。对测试分子以0.1nM至40μM的浓度范围进行分析。EC50通过使用标准曲线拟合法如Excel拟合(Microsoft Co.)来确定。EC50为存在最大转录抑制的50%阻抑(即AP-1活性降低50%)时测试分子的浓度。
其它报道分子(reporter)和细胞系也可用于细胞反式阻抑测定。进行了类似的测定,在其中测量了NF-κB活性。使用了含有NF-κB DNA结合位点的质粒,如pNF-kB-Luc(Stratagene,LaJolla CA),而PMA或其它刺激物如TNF-α或脂多糖用于激活NF-κB途径。可使用类似于Yamamoto K.,等人.,J.Biol.Chem.,Dec 29;270(52):31315-20(1995)中描述的NF-κB测定。
上述细胞反式阻抑测定可用于测量任何NHR的反式阻抑。本领域技术人员应该理解,所述测定可能需要加入将诱导由AP-1或NF-κB介导的转录的组分,如刺激物(如PMA、脂多糖、TNF-α等)。
此外,AR介导的反式阻抑可通过Palvimo JJ,等人.J.Biol.Chem.,Sep27;271(39):24151-6(1996)中描述的测定进行测量,以及PR介导的反式阻抑可通过Kalkhoven E.,等人.J.Biol.Chem.,Mar 15;271(11):6217-24(1996)中描述的测定进行测量。
由一般方案描述的方法制备的本发明化合物的实例在下文列出的制备和实施例部分给出。实施例化合物通常制备为外消旋混合物。纯手性实例的制备可根据本领域技术人员已知的技术进行。例如,纯手性化合物可通过由手性相制备性HPLC分离外消旋产物来制备。可供选择地,实施例化合物可通过已知方法制备以得到富含对映异构体的产物。这些方法包括但不限于,将手性助剂官能团引入外消旋中间体,所述手性助剂官能团用于控制转化的非对映立体选择性,在手性助剂断裂时提供富含对映异构体的产物。
缩写
在以下的制备和实施例中使用以下缩写:
Ph=苯基
Bn=苄基
t-Bu=叔丁基
Me=甲基
Et=乙基
ACN=乙腈
TMS=三甲基硅烷基
TMSN3=叠氮化三甲基硅烷(trimethylsilyl azide)
TBS=叔丁基二甲基硅烷基
FMOC=芴基甲氧基羰基
Boc=叔丁氧基羰基
Cbz=苄酯基或苄氧羰基或苄基氧基羰基
THF=四氢呋喃
Et2O=乙醚
hex=己烷
EtOAc=乙酸乙酯
DMF=二甲基甲酰胺
MeOH=甲醇
EtOH=乙醇
i-PrOH=异丙醇
DMSO=二甲基亚砜
DME=1,2-二甲氧基乙烷
DCE=1,2-二氯乙烷
HMPA=六甲基磷酸三酰胺(hexamethyl phosphoric triamide)
HOAc或AcOH=乙酸
TFA=三氟乙酸
TFAA=三氟乙酸酐
i-Pr2NEt=二异丙基乙胺
Et3N=三乙胺
NMM=N-甲基吗啉
DMAP=4-二甲基氨基吡啶
NaBH4=硼氢化钠
NaBH(OAc)3=三乙酰氧基硼氢化钠
DIBALH=二异丁基氢化铝
LAH或LiAlH4=氢化铝锂
n-BuLi=正丁基锂
LDA=二异丙基氨基锂
Pd/C=钯/碳
PtO2=氧化铂
KOH=氢氧化钾
NaOH=氢氧化钠
LiOH=氢氧化锂
K2CO3=碳酸钾
NaHCO3=碳酸氢钠
DBU=1,8-二氮杂二环[5.4.0]十一碳-7-烯
EDC(或EDC.HCl)或EDCI(或EDCI.HCl)或EDAC=3-乙基-3’-(二甲基氨基)丙基-碳二亚胺盐酸盐(或1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐)
HOBT或HOBT.H2O=1-羟基苯并三唑水合物
HOAT=1-羟基-7-氮杂苯并三唑
BOP试剂=苯并三唑-1-基氧基-三(二甲基氨基)鏻六氟磷酸盐
NaN(TMS)2=六甲基二硅氨基锂钠(sodium hexamethyl disilazide)或二(三甲基硅烷基)氨基钠
Ph3P=三苯基膦
Pd(OAc)2=醋酸钯
(Ph3P)4Pdo=四(三苯基膦)钯
DEAD=偶氮二羧酸二乙酯
DIAD=偶氮二羧酸二异丙酯
Cbz-Cl=氯甲酸苄基酯
CAN=硝酸铈铵
SAX=强阴离子交换器
SCX=强阳离子交换器
Ar=氩
N2=氮气
min=分钟
h或hr=小时
L=升
mL=毫升
μL=微升
g=克
mg=毫克
mol=摩尔
mmol=毫摩尔
meq=毫当量
rt或RT=室温
sat或sat’d=饱和的
aq.=水溶液
TLC=薄层色谱
HPLC=高效液相色谱
反相HPLC=反相高效液相色谱,使用YMC ODS S5柱和二元溶剂A/溶剂B洗脱剂
溶剂A=10%MeOH-90%H2O-0.1%TFA
溶剂B=90%MeOH-10%H2O-0.1%TFA;或
溶剂A=含有0.1%TFA的H2O
溶剂B=含有0.1%TFA的ACN
LC/MS=高效液相色谱/质谱
MS或Mass Spec=质谱
NMR=核磁共振
NMR光谱数据:s=单峰;d=双峰;m=多重峰;br=宽峰;t=三重峰
mp=熔点
实施例
以下实施例阐明了本发明化合物和起始原料的实施方案,并不是旨在限制权利要求的范围。
制备
下文列出的制备方法用于合成不能从商业来源获得的试剂,以及用于制备本发明的式I化合物。除非另有说明,表和方案中的所有手性化合物都是外消旋体。
反相制备性高效液相色谱(“HPLC”)用Shimadzu 8A液相色谱仪进行,使用YMC S5ODS柱(20×100,20×250或30×250毫米(“mm”))。梯度系统用甲醇(“MeOH”)/水的混合物,在0.1%三氟乙酸(“TFA”)的存在下进行。
分析性HPLC方法
分析性HPLC在Shimadzu SCL10A液相色谱仪上进行,使用以下方法:除非另有说明,方法D的条件用于产生通篇制备和实施例中出现的化合物的数据。
方法A:柱:YMC Combiscreen ODS-A,4.6×50mm,流动相:10-90%CH3OH水溶液/0.2%H3PO4,4.0分钟梯度,保持1.0分钟,流速:4ml/min,220nm检测波长。
方法B:柱:XETRRA C-184.6×50mm,流动相:10-90%CH3OH水溶液/0.2%H3PO4,4.0分钟梯度,保持1分钟,流速:4.0mL/min.220nm检测波长。
方法C:柱:Phenomenex Synergi C-184.6×50mm,流动相:10-90%CH3OH水溶液/0.2%H3PO4,4.0分钟梯度,保持1分钟,流速:4.0mL/min,220nm检测波长。
方法D:柱:Shimadzu VP-0DS;C-18Ballistic 4.6×50mm,.流动相:10-90%CH3OH水溶液/0.2%H3PO4,4.0分钟梯度,保持1分钟,流速:4.0mL/min,220nm检测波长。
制备
下文列出的制备方法用于合成不能从商业来源获得的试剂,以及用于制备本发明的式I化合物。除非另有说明,表和方案中的所有化学结构都是外消旋体。
制备1
步骤1
在0℃向(3-氟苯基)溴化镁溶液(1M的THF溶液,6.8ml.6.8mmol)中滴加5-溴-噻吩-2-甲醛(650mg,3.4mmol)于THF(10ml)中的溶液。在0℃搅拌10分钟并在室温搅拌3小时后,将反应混合物倒在冰的NH4Cl水溶液上。将溶液用乙酸乙酯萃取。有机层用盐水洗涤,经MgSO4干燥,然后浓缩得到(5-溴-噻吩-2-基)-(3-氟-苯基)-甲醇,其为粘稠液体(1.19g,定量收率)。LC/MS(m/z)271,273[(M-OH)+];HPLC(柱:方法D-除非另有说明,方法DHPLC条件用于对示例性化合物进行分析)Rt:3.176分钟。
步骤2
在0℃向(5-溴-噻吩-2-基)-(3-氟-苯基)-甲醇(3.40mmol)和(1-甲氧基-2-甲基-丙烯基氧基)-三甲基-硅烷(3.45ml,17mmol)于二氯甲烷(10ml)中的溶液中缓慢加入四氯化钛于二氯甲烷(1M溶液,7.4ml,7.4mmol)中的溶液。在0℃搅拌10分钟并在室温搅拌3小时后,将反应混合物倒在冰的K2CO3水溶液上。溶液用二氯甲烷萃取。将有机层洗涤,干燥(MgSO4),然后浓缩得到3-(5-溴-噻吩-2-基)-3-(3-氟-苯基)-2,2-二甲基-丙酸甲酯,,其为粘稠的黄色油状物(1.104g,87.5%收率)。LC/MS(m/z)393.13[(M+23)+];HPLC Rt:3.883分钟。
步骤3
向3-(5-溴-噻吩-2-基)-3-(3-氟-苯基)-2,2-二甲基-丙酸甲酯(419mg,1.128mmol)于MeOH(4ml)和DMSO(2ml)中的溶液中加入40%氢氧化钾水溶液(4ml)。将反应混合物在75℃加热6小时。除去甲醇后,将溶液调节至pH为2,然后用乙醚萃取。将醚层洗涤,干燥并蒸发,得到3-(5-溴-噻吩-2-基)-3-(3-氟-苯基)-2,2-二甲基-丙酸(1a),其为白色玻璃状物(346.2mg,86%收率)。1HNMR(400MHz,CDCl3):1.06(s,3H),1.15(s,3H),3.21(s,1H),6.75(d,1H,J=3.8Hz),6.82(d,1H,J=3.8Hz),6.87(td,1H,J=8.1,2.6Hz),7.02(m,1H),7.10(br d,J=8.1Hz),7.20(m,1H)。HPLC Rt:3.695分钟。
根据上述操作,式(1b)的酸从5-溴-噻吩-2-甲醛和苯基溴化镁制备。
制备2
步骤1
以与制备1,步骤2类似的方式,使由4-吗啉代苯甲醛和噻吩-2-基溴化镁制备的(4-吗啉代苯基)-(噻吩-2-基)甲醇(675mg,2.45mmol),与(1-甲氧基-2-甲基丙-1-烯基氧基)三甲基硅烷(2.48ml,12.3mmol)在四氯化钛(1M inDCM,5.40ml.5.40mmol)的存在下反应,得到2,2-二甲基-3-(4-吗啉代苯基)-3-(噻吩-2-基)丙酸甲酯(725mg,82.5%收率)。1H NMR(400MHz,CDCl3):1.15(s,3H),1.20(s,3H),3.06(m,4H),3.51(s,3H),3.78(m,4H),4.59(s,1H),6.76(d,1H,J=8.5Hz),6.83(m,1H),6.87(m,1H),7.06(m,1H),7.20(d,1H,J=8.5Hz)。HPLC Rt:3.181分钟。
步骤2
以与制备1,步骤3类似的方式,使2,2-二甲基-3-(4-吗啉代苯基)-3-(噻吩-2-基)丙酸甲酯(530mg,1.47mmol)进行碱性水解,得到2,2-二甲基-3-(4-吗啉代苯基)-3-(噻吩-2-基)丙酸(2a)(469mg,92.5%收率)。1H NMR(400MHz,CDCl3):δ1.17(s,3H),1.24(s,3H),3.06(m,4H),3.77(m,4H),4.62(s,1H),6.77(d,1H,J=8.7Hz),6.91(m,1H),6.87(d,1H,J=3.16Hz),7.07(m,1H),7.22(d,1H,J=8.7Hz)./MS(m/z)346.35[(M+H)+];HPLC Rt:2.863分钟。
根据上述操作,式(2b)的酸从苯基-吡啶-4-基-甲酮制备。
制备3
步骤1
将3-(5-溴噻吩-2-基)-3-(3-氟苯基)-2,2-二甲基-丙酸甲酯(制备1,步骤2的产物)(367mg,0.988mmol)、吗啉(0.572mL)、醋酸钯(44mg,0.20mmol)、2-(二叔丁基膦基)-联苯(118mg,0.40mmol)和叔丁醇钠(228mg,2.37mmol)于甲苯(5ml)中的混合物在80℃加热2h。将反应混合物冷却至室温,经过滤除去固体,然后将滤液真空浓缩。粗产物经硅胶快速色谱(使用20%乙酸乙酯/己烷)纯化,得到3-(3-氟苯基)-2,2-二甲基-3-(5-吗啉代噻吩-2-基)丙酸甲酯,其为油状物(120mg,32.2%)。LC/MS(m/z)378.33[(M+H)+];HPLC Rt:3.548分钟。
步骤2
以与制备1,步骤3类似的方式,使3-(3-氟苯基)-2,2-二甲基-3-(5-吗啉代噻吩-2-基)丙酸甲酯(120mg,0.318mmol)进行碱性水解,得到3-(3-氟苯基)-2,2-二甲基-3-(5-吗啉代噻吩-2-基)丙酸(4)(110mg,95.3%收率)。LC/MS(m/z)364.31[(M+H)+];HPLC Rt:3.323分钟。
制备4
步骤1
向(6-氯-吡啶-3-基)-苯基-甲醇(2g,9.10mmol)于二氯甲烷(25ml)中的溶液中加入乙酸酐(3.5ml,36.4mmol)和DMAP(1.10g,9.10mmol)。将反应混合物搅拌16小时,然后用水洗涤,干燥并浓缩得到乙酸(6-氯-吡啶-3-基)-苯基-甲酯,其为粘稠液体。LC/MS(m/z)262.12[(M+H)+];HPLC Rt:3.011分钟。
步骤2
以与制备1,步骤2类似的方式,使步骤1的产物(1g,3.82mmol)和(1-甲氧基-2-甲基丙-1-烯基氧基)三甲基硅烷(5.5ml,26.7mmol)在四氯化钛(1Min DCM,8.40ml.8.40mmol)存在下反应,得到3-(6-氯-吡啶-3-基)-2,2-二甲基-3-苯基-丙酸甲酯,其为浅黄色油状物(1.1g,81%收率)。LC/MS(m/z)304.16[(M+H)+];HPLC Rt:3.401分钟。
步骤3
以与制备1,步骤3类似的方式,使步骤2的产物(1g,3.29mmol)进行碱性水解,得到3-(6-氯-吡啶-3-基)-2,2-二甲基-3-苯基-丙酸(4)(947mg,99%收率)。LC/MS(m/z)290.16[(M+H)+];HPLC Rt:3.018分钟。
制备5
步骤1
以与制备3,步骤1类似的方式,使3-(6-氯-吡啶-3-基)-2,2-二甲基-3-苯基-丙酸甲酯(制备4,步骤2的产物,255mg,0.85mmol)与吗啉(3ml)进行Buchwald偶联反应(Buchwald coupling reaction),得到2,2-二甲基-3-(6-(吗啉-4-基)-吡啶-3-基)-3-苯基-丙酸甲酯,其为灰白色无定形固体。(208mg,69%收率)。LC/MS(m/z)355.17[(M+H)+];HPLC Rt:2.13分钟。
步骤2
以与制备1,步骤3类似的方式,使步骤1的产物(80mg,0.226mmol)进行碱性水解,得到2,2-二甲基-3-(6-(吗啉-4-基)-吡啶-3-基)-3-苯基-丙酸(5a)(76mg,99%收率)。LC/MS(m/z)341.17[(M+H)+];HPLC Rt:1.898分钟。
可供选择地,酸(5a)可如下制备:将3-(6-氯-吡啶-3-基)-2,2-二甲基-3-苯基-丙酸(制备4a的酸,110mg)于吗啉(1ml)中的溶液在200℃加热3小时(71%收率)。
根据步骤1和2中描述的操作,式(5b)至(5e)的酸如下制备:使3-(6-氯-吡啶-3-基)-2,2-二甲基-3-苯基-丙酸甲酯与相应的仲胺反应,接着进行碱性水解。
制备6
使用手性超临界流体色谱(SFC)将制备(1b)的酸拆分为其相应的对映异构体,式(6a)和(6b)的酸,条件如下。
Chiral-SFS制备条件:Chiralpak AD(0.46x25cm,10μm);BPR压力100巴;温度:35℃;流动相:CO2/MeOH(73/27);流速:70mL/min;UV检测:220nm。
分析性HPLC(柱:-AD,4.6×250mm 10μm,流动相:CO2/MeOH(85/85),流速:2mL/min,检测UV 220nM)保留时间:对映异构体A(6a):6.66分钟(ee>99.9%);对映异构体B(6b):12.13分钟(ee>99.9%)。
一般而言,若两种对映异构体的绝对立体化学尚未确定,则异构体A表示第一次洗脱的对映异构体,异构体B表示第二次洗脱的对映异构体。
制备7
以与制备6类似的方式,使用手性超临界流体色谱(SFC)将制备(1a)的酸拆分为其对映异构体,式(7a)和(7b)的酸。
分析性HPLC(柱:-AD,4.6×250mm 10μm,流动相:CO2/MeOH(80/20),BPR压力100巴,流速:2.4mL/min,检测:220nm);保留时间:(S)-对映异构体(7a):2.59分钟(ee>99.9%);(R)-对映异构体(7b):4.58分钟(ee>99.5%)。
制备8
步骤1
在0℃向(5-溴-噻吩-2-基)-(3-氟-苯基)-甲醇(2g,6.96mmol)和(1-甲氧基-2-甲基-丙烯基氧基)-三甲基-硅烷(2.23g,13.92mmol)于二氯甲烷(20ml)中的溶液中缓慢加入四氯化钛于二氯甲烷(1M溶液,7.7ml,7.66mmol)中的溶液。在0℃搅拌10分钟并在室温搅拌过夜后,将反应混合物倒入冰的K2CO3的水溶液中。将溶液用二氯甲烷萃取。有机层洗涤,干燥(MgSO4)并浓缩得到粗产物。粗产物经硅胶快速色谱(使用10%乙酸乙酯/己烷)纯化,得到3-(5-溴噻吩-2-基)-3-(3-氟苯基)-2-甲基-丙酸甲酯,其为粘稠的黄色油状物(1.74g,70%收率)。HPLC Rt:3.97分钟。
步骤2
向步骤步骤1的产物即3-(5-溴噻吩-2-基)-3-(3-氟苯基)-2-甲基-丙酸甲酯(600mg,1.68mmol)于MeOH(10ml)和DMSO(4ml)中的溶液中加入40%氢氧化钾水溶液(10ml)。将反应混合物在75℃加热1.5小时。除去甲醇后,将溶液调节至pH为2,然后用乙醚萃取。将醚层洗涤,干燥并蒸发,得到粗产物。粗产物经硅胶快速色谱(使用20-30%乙酸乙酯/己烷)纯化,得到3-(5-溴噻吩-2-基)-3-(3-氟苯基)-2-甲基丙酸(8a),其为1∶1的非对映异构体混合物,浅黄色固体(570mg,99%收率)。1H NMR(400MHz,MeOD)δppm7.24-7.39(1H,m)7.10-7.19(1H,m)7.03-7.10(1H,m)6.86-7.01(2H,m)6.79-6.85(1H,m)4.29(0.5H,d,J=2.77Hz),4.29(0.5H,d,J=2.77Hz),4.31(0.5H,d,J=2.77Hz),3.12-3.24(1H,m)1.20-1.22(3H,2单峰),1.03-1.05(3H,2单峰)。MS ESI(m/z)341,343[M-1];HPLC Rt:3.765分钟。
根据上述操作,式(8b)的酸从(5-溴噻吩-2-基)(苯基)甲醇制备。
制备9
使用手性超临界流体色谱(SFC)将制备(8a)的酸拆分为其相应的四种式(9a)、(9b)、(9c)和(9d)的对立体异构体,条件如下。分离以两步进行。
步骤1:第三次洗脱的异构体和第四次洗脱的异构体
Chiral-SFS制备条件:柱:Chiralpak AD-H(0.46x25cm,5μm);BPR压力100巴;温度:35℃;流动相:CO2/(IPA/MEOH=50/50)=90/10;流速:120mL/min;UV检测:252nm。在这些条件下,第一次洗脱的异构体和第二次洗脱的异构体不可分离,它们使用第二种SFC条件分离。
分析性HPLC条件:柱:Chiralpak AD-H(0.46x25cm,5μm),流动相:CO2/(IPA/MEOH=50/50)=90/10,温度:35℃,流速:3mL/min,检测:UV(252nm)。保留时间:第三次洗脱的异构体(9c),7.41分钟(ee>99.9%);第四次洗脱的异构体(9d),7.50分钟(ee>99.5%)。
上文描述的制备性(SFC)条件下要洗脱出的第一个峰在上述分析性手性LC条件下也首先洗脱出。相应的第二个、第三个和第四个峰亦是如此。
步骤2:第一次洗脱的异构体和第二次洗脱的异构体的分离
Chiral-SFS制备条件:柱:Chiralcel OJ-H(0.46x25cm,5μm),流动相:CO2/MeOH=88∶12,BPR压力:100巴;温度:35℃;流速:70mL/min,检测:UV(252nm)。
分析性HPLC条件:柱:Chiralcel OJ-H(0.46x25cm,5μm),流动相:CO2/MeOH=95∶5,温度:35℃,流速:3mL/min,检测:UV(252nm)。保留时间(min):第一次洗脱的异构体(9a),6.79(>99%ee);第二次洗脱的异构体(9b),8.21(>99%ee)。
第三次洗脱的异构体(9c)样品与(+)-β-甲基苯乙基胺在乙腈中共结晶。由此获得的晶体物质的X射线晶体结构测定证明(9c)为(2R,3S)构型。第四次洗脱的异构体(9c)与(+)-β-甲基苯乙胺在乙腈中共结晶。由此获得的晶体物质的X射线晶体结构测定证明(9d)为(2R,3R)构型。(9a)即(9d)的对映体的构型由此指定为(2S,3S),(9b)即(9c)的对映体的构型指定为(2R,3S)。
制备10
以与制备9类似的方式,使用手性超临界流体色谱(SFC)分两步将制备(8b)的酸拆分为其相应的4中立体异构体,式(10a,10b,10c)和(10d)的酸。
分析性HPLC(Chiralcel OJ-H(0.46x25cm,5μm),流动相:CO2/(IPA∶MeOH/1∶1)=85∶15,流速:2mL/min,检测:UV 252nm)保留时间:第三次洗脱的异构体(10c)6.60分钟(ee>99.9%);第四次洗脱的异构体(10d):8.62分钟(ee>99.9%)。
分析性HPLC(柱:-AD,流动相:CO2/(IPA∶CH3CN/1∶1)=88∶12,流速:3mL/min,检测:UV 249nm)保留时间:第一次洗脱的异构体(10a)5.79分钟(ee>99.9%);第二次洗脱的异构体(10b):8.29分钟(ee>99.9%)。第一次和第四次洗脱的异构体的绝对立体化学分别确定为(2S,3S)和(2R,3R)。第二次和第三次洗脱的异构体的绝对立体化学尚未确定。
实施例
实施例1
3-(5-溴-噻吩-2-基)-3-(3-氟苯基)-2,2-二甲基-N-1,3,4-噻二唑-2-基丙酰胺
向制备1a的酸(150mg,0.42mmol)于CH3CN(5mL)中的溶液中加入1-[3-(二甲基氨基)丙基]-3-乙基碳二亚胺盐酸盐(EDC)(120mg,0.63mmol)和1-羟基-7-苯并三唑(HOBt)(84mg,0.63mmol)。搅拌5分钟后,向该溶液中加入4-(4-甲基-萘-1-基)-噻唑-2-基胺(126mg,1.26mmol)和二异丙基乙胺(0.22ml,1.26mmol)。将反应混合物在75℃加热12小时。将反应混合物过滤,浓缩,然后经硅胶快速色谱(使用25%乙酸乙酯/己烷)纯化,得到实施例1的标题化合物,其为白色固体(129mg,69.6%收率)。1H NMR(400MHz,CDCl3):1.24(s,3H),1.31(s,3H),4.79(s,1H),6.75(d,1H,J=4.1Hz),6.81(d,1H,J=4.1Hz),6.89(m,1H),7.11(m,1H),7.22(m,1H),8.91(s,1H).LC/MS(m/z)440.16,442.16[(M+H)+];HPLC Rt:3.58分钟。
实施例2至19
以与实施例1类似的方式,实施例2至19通过制备(1)和(3)以及(5)与适当的胺进行的酰胺化反应(5)制备(除非另有说明,化合物为外消旋体)。
实施例20至21
2,2-二甲基-3-(6-(吗啉-4-基)-吡啶-3-基)-3-苯基-N-1,3-噻唑-2-基丙酰胺
实施例13的标题化合物(42mg)通过手性制备性HPLC拆分为其相应的对映异构体,条件如下:柱:-AD,30×250mm,流动相:60%(1∶1MeOH/EtOH)/40%己烷,温度:环境温度,流速:20mL/min,检测:UV(254nm)。保留时间:较快洗脱的对映异构体实施例19(17mg),22min,较慢洗脱的对映异构体实施例20(15mg),30分钟。分析性HPLC条件,柱:-AD,4.6×250mm,流动相:60%(1∶1MeOH/EtOH)/40%己烷,温度:环境温度,流速:1mL/min,检测:UV(250&220nm)。保留时间:对映异构体A,9.14(ee>99.9%)min;对映异构体B,12.48分钟(ee>99.9%)。
实施例编号 | 结构 | MS[m/z(M+H)] | HPLC Rt:分钟 |
20 | 对映异构体A | 2.210 | 423.3 |
21 | 对映异构体B | 2.222 | 423.3 |
实施例22至23
2,2-二甲基-3-(6-(吗啉-4-基)-吡啶-3-基)-3-苯基-N-1,3,4-噻二唑-2-基丙酰胺
以与实施例13类似的方式,通过手性制备性HPLC将实施例14的标题化合物14(53mg)拆分为其相应的对映异构体,对映异构体A,(18mg)和对映异构体B(14mg)。分析性HPLC(柱:-AD,4.6×250mm,流动相:60%(1∶1MeOH/EtOH)/40%己烷,流速:1mL/min)。保留时间:对映异构体A:5.64分钟(ee>99.9%);对映异构体B:7.71分钟(ee>99.9%)。
实施例编号 | 结构 | MS[m/z(M+H)] | HPLC Rt:分钟 |
22 | 对映异构体A | 1.972 | 424.16 |
23 | 对映异构体B | 1.970 | 424.16 |
实施例24
3-(6-(4-甲氧基苯基)-吡啶-3-基)-2,2-二甲基-3-苯基-N-1,3,4-噻二唑-2-基丙酰胺
步骤1
将3-(6-氯-吡啶-3-基)-2,2-二甲基-3-苯基-丙酸(制备4,100mg,0.345mmol)、1-[3-(二甲基氨基)丙基]-3-乙基碳二亚胺盐酸盐(EDC)(132mg,0.69mmol)和1-羟基-7-苯并三唑(HOBt)(93mg,0.69mmol)、1,3,4-噻二唑-2-胺(103mg,1.04mmol)和二异丙基乙胺(0.21ml,1.21mmol)于CH3CN(1mL)中的溶液在75℃加热12小时。将反应混合物过滤,浓缩,然后经硅胶快速色谱(使用50%乙酸乙酯/己烷)纯化,得到3-(6-氯-吡啶-3-基)-2,2-二甲基-3-苯基-N-[1,3,4]噻二唑-2-基-丙酰胺,其为白色固体(102mg,79.3%收率)。1HNMR(400MHz,CDCl3):1.31(s,3H),1.32(s,3H),4.57(s,1H),7.15(m,1H),7.20(m,2H),7.28(m,3H),7.85(m,1H),8.26(br s,1H),8.90(s,1H).LC/MS(m/z)373.19[(M+H)+];HPLC Rt:2.913分钟。
步骤2
向EmryTM加工瓶(process vial)中装入3-(6-氯-吡啶-3-基)-2,2-二甲基-3-苯基-N-[1,3,4]噻二唑-2-基-丙酰胺(30mg,0.080mmol)和4-甲氧基-苯基硼酸(37mg,0.241mmol)、四(三苯基膦)钯(0)(10mg,0.008mmol)、0.080mL 2MK2CO3和1mL DMF。通过通入氮气15分钟对反应混合物进行脱气,然后密封,并在150℃暴露于微波辐射30分钟。将反应混合物冷却、过滤,然后用乙酸乙酯乙酸。将有机溶液洗涤,干燥并浓缩。粗产物经硅胶快速色谱(使用50%乙酸乙酯/己烷)纯化,得到实施例24的标题化合物,其为白色固体(18mg,51%)。1H NMR(400MHz,CDCl3):1.46(s,3H),1.47(s,3H),3.85(s,3H),4.72(s,1H),7.02(d,2H,J=8.8Hz),7.25(m,1H),7.32(t,2H,J=7.2Hz),7.45(d,2H,J=7.2),7.73(d,1H,J=8.6Hz),7.86(d,2H,J=8.8Hz),7.97(m,1H),8.56(m,1H),9.00(s,1H).LC/MS(m/z)445.24[(M+H)+];HPLCRt:2.700分钟。
实施例25至26
以与实施例24类似的方式,实施例25至26通过相应的芳基硼酸与3-(6-氯-吡啶-3-基)-2,2-二甲基-3-苯基-N-噻唑-2-基-丙酰胺(从制备(4)的酸和噻唑-2-基胺以与实施例24-步骤1类似的方式制备)进行Suzuki偶联反应(Suzuki coupling reaction)来制备(除非另有说明,化合物为外消旋体)。
实施例27至28
实施例27
3-(5-氯-6-甲氧基-吡啶-3-基)-2,2-二甲基-3-苯基-N-1,3,4-噻二唑-2-基丙酰胺
实施例28
3-(5-氯-6-(吗啉-4-基)-吡啶-3-基)-2,2-二甲基-3-苯基-N-1,3,4-噻二唑-2-基丙酰胺
使3-(5,6-二氯-吡啶-3-基)-2,2-二甲基-3-苯基-丙酸甲酯(1.07g,3.17mmol)(根据制备4,步骤2中描述的操作从乙酸(5,6-二氯-吡啶-3-基)-苯基-甲酯制备)以与制备1,步骤3类似的方式进行水解,产生两种酸的混合物(978mg):3-(5,6-二氯-吡啶-3-基)-2,2-二甲基-3-苯基-丙酸和3-(5-氯-6-甲氧基-吡啶-3-基)-2,2-二甲基-3-苯基-丙酸,比例为1∶2。
将一批混合酸(200mg)溶于吗啉(1ml)中,然后在140℃加热4小时。冷却后,将反应混合物用乙醚和水吸收。用1N HCl将溶液调节至pH为2。将有机层洗涤,干燥,然后浓缩,得到白色无定形固体(196mg),其为3-(5-氯-6-甲氧基-吡啶-3-基)-2,2-二甲基-3-苯基-丙酸和3-(5-氯-6-(吗啉-4-基)-吡啶-3-基)-2,2-二甲基-3-苯基-丙酸的混合物。LC/MS(m/z)320[(M+H)+]和375[(M+H)+];HPLC Rt:3.701分钟。
根据就实施例1而言所述的操作,使上述两种酸的混合物与[1,3,4]噻二唑-2-基胺反应。粗产物混合物经制备性HPLC纯化,得到实施例27和28的标题化合物。
实施例27(19.4mg),LC/MS(m/z)403.07[(M+H)+];HPLC Rt:3.610分钟。
实施例28(20.4mg),LC/MS(m/z)458.12[(M+H)+];HPLC Rt:3.54分钟。
实施例29至33
以与实施例24-步骤2类似的方式,实施例29至33通过相应的芳基硼酸和实施例24-步骤1的标题化合物3-(6-氯-吡啶-3-基)-2,2-二甲基-3-苯基-N-[1,3,4]噻二唑-2-基-丙酰胺进行Suzuki偶联反应来制备(除非另有说明,化合物为外消旋体)。
实施例34
4-(5-(3-(1,3,4-噻二唑-2-基氨基)-2,2-二甲基-3-氧代-1-苯基丙基)吡啶-2-基)-2-氯-N,N-二甲基苯甲酰胺
向闪烁瓶中装入3-(6-氯-吡啶-3-基)-2,2-二甲基-3-苯基-N-[1,3,4]噻二唑-2-基-丙酰胺(30mg,0.068mmol)、3-氯-4-(二甲基-氨基甲酰基)苯基硼酸(31mg,0.136mmol)、0.136mL(0.272mmol)2M K2CO3和1mL DMF。将溶液用氮气脱气15分钟。向该溶液中加入四(三苯基膦)钯(0)(10mg,0.008mmol)。将反应混合物再脱气5分钟,然后密封,并在加热块(OptiChem DigitalHotplate Stirrer)中在100℃加热70分钟。将反应混合物冷却,过滤然后用乙酸乙酯稀释。有机溶液洗涤,干燥并浓缩。粗产物经制备性HPLC纯化,得到实施例34的标题化合物,其为白色固体(17mg,48%收率)。1H NMR(400MHz,MeOD):δ8.97(1H,s),8.64(1H,d,J=2.03Hz),8.09(1H,s),8.02(1H,dd,J=8.39,2.29Hz),7.96(1H,br d,J=8.14Hz),7.85(1H,br d,J=8.14Hz),7.37-7.50(3H,m),7.30(2H,t,J=7.63Hz),7.22(1H,m),4.73(1H,s),3.12(3H,s),2.90(3H,s),1.46(3H,s),1.43(3H,s)。LC/MS(m/z)520.6,522.6[(M+H)+];HPLC Rt:3.365分钟。
实施例35至41
以与实施例24-步骤2类似的方式,实施例35-41通过实施例1的标题化合物和相应的芳基硼酸进行Suzuki偶联反应制备(除非另有说明,化合物为外消旋体)。
实施例42
4-(5-(1-(3-氟苯基)-2,2-二甲基-3-氧代-3-(1,3-噻唑-2-基氨基)丙基)-噻吩-2-基)-N,N-二甲基苯甲酰胺
以与实施例24-步骤2类似的方式,使实施例2的标题化合物和4-(二甲基氨基甲酰基)苯基硼酸进行Suzuki偶联反应,得到实施例42的标题化合物。LC/MS(m/z)508.4[(M+H)+];HPLC Rt:3.633分钟。
实施例43
2-氯-4-(5-(2,2-二甲基-3-氧代-1-苯基-3-(1,3,4-噻二唑-2-基氨基)丙基)-噻吩-2-基)-N,N-二甲基苯甲酰胺
向闪烁瓶中装入实施例3的标题化合物(30mg,0.071mmol)、3-氯-4-(二甲基-氨基甲酰基)苯基硼酸(33mg,0.143mmol)、0.140mL(0.85mmol)2M K2CO3和1mL DMF。将溶液用氮气脱气15分钟。向该溶液中加入四(三苯基膦)钯(0)(8.1mg,0.007mmol)。将反应混合物再脱气5分钟,然后密封并在加热块(OptiChem Digital Hotplate Stirrer)中在100℃加热30分钟。将反应混合物冷却,过滤然后用乙酸乙酯稀释。有机溶液洗涤,干燥并浓缩。粗产物经制备性HPLC纯化,得到实施例43的标题化合物,其为白色固体(20.2mg,54%收率)。1H NMR(400MHz,MeOD)δ9.00(1H,s),7.65(1H,d,J=2.03Hz),7.56(1H,d,J=9.66Hz),7.46(2H,d,J=7.12Hz),7.22-7.35(5H,m),7.06(1H,d,J=4.07Hz),4.95(1H,s),3.10(3H,s),2.89(3H,s),1.46(3H,s),1.37(3H,s).LC/MS(m/z)525.11[(M+H)+];HPLC Rt:3.73分钟。
实施例44至53
以与实施例41类似的方式,实施例44至53通过实施例3的标题化合物和相应的芳基硼酸进行Suzuki偶联反应制备(除非另有说明,化合物为外消旋体)。
实施例54
4-(5-(2,2-二甲基-3-氧代-1-苯基-3-(1,3-噻唑-2-基氨基)丙基)-噻吩-2-基)-N,N-二甲基苯甲酰胺
以与实施例24-步骤2类似的方式,使实施例4的标题化合物和4-(二甲基氨基甲酰基)苯基硼酸进行Suzuki偶联反应,得到实施例54的标题化合物。LC/MS(m/z)490.4[(M+H)+];HPLC Rt:3.605分钟。
实施例55
3-(5-(4-((4,4-二氟-哌啶-1-基)羰基)苯基)-噻吩-2-基)-2,2-二甲基-3-苯基-N-1,3,4-噻二唑-2-基丙酰胺
步骤1
向闪烁瓶中装入实施例3的标题化合物(30mg,0.071mmol)、4-(甲氧基羰基)苯基硼酸(38mg,0.215mmol)、0.140mL(0.85mmol)2M K2CO3和1.4mL DMF。将溶液用氮气脱气15分钟。向该溶液中加入四(三苯基膦)钯(0)(8.1mg,0.007mmol)。将反应混合物再脱气5分钟,然后密封在加热块(OptiChem Digital Hotplate Stirrer)中在100℃加热60分钟。将反应混合物冷却,过滤然后用乙酸乙酯稀释。有机溶液洗涤,干燥并浓缩。经硅胶柱(0-35%EtOAc/己烷)纯化,得到4-(5-(3-(1,3,4-噻二唑-2-基氨基)-2,2-二甲基-3-氧代-1-苯基丙基)噻吩-2-基)苯甲酸甲酯,其为白色固体(18mg,53%收率)。LC/MS(m/z)478.29[(M+H)+];HPLC Rt:3.96分钟。
步骤2
以与制备1,步骤3类似的方式,使步骤1的产物进行碱性水解,得到粗制的酸。LC/MS(m/z)462[(M+H)+];HPLC Rt:3.641分钟。
步骤3
以与实施例1类似的方式,使步骤2的酸与3,3-二氟吡咯烷进行酰胺化反应,得到实施例55的标题化合物(4mg,2步收率19%)。LC/MS(m/z)567.28[(M+H)+];HPLC Rt:3.716分钟。
实施例56和57
以与手性分离实施例13(得到实施例20和21)类似的方式,使用手性超临界流体色谱(-OJ,CO2/IPA:80%/20%,100巴)将实施例1的标题化合物拆分为其相应的对映异构体。分析性HPLC(柱:-OJ,CO2/IPA:80%/20%)保留时间:(S)-对映异构体(实施例56),8.92分钟(ee>99.9%);(R)-对映异构体(实施例57),10.44分钟(ee>99.9%)。
将实施例57以纯的形式和溶剂化形式结晶。用反常散射测量(anomalous scattering measurement)进行的单晶分析确定了实施例57的绝对立体化学(R)。
可供选择地,实施例56和57的标题化合物如下制备:以与实施例1类似的方式,使制备(7a)和(7b)的酸分别与1,3,4-噻二唑-2-胺进行酰胺化反应。
实施例58至63
以与实施例43类似的方式,实施例58至63通过实施例的标题化合物56和相应的芳基硼酸进行Suzuki偶联反应来制备(所有化合物都具有S-构型)。
实施例64
(3R)-3-(3-氟苯基)-2,2-二甲基-3-(5-(4-(吗啉-4-基羰基)苯基)-噻吩-2-基)-N-1,3,4-噻二唑-2-基丙酰胺
以与实施例43类似的方式,实施例64通过Suzuki偶联反应制备。实施例57的标题化合物(200mg,0.454mmol)和4-(二甲基氨基甲酰基)苯基硼酸(213mg,0.908mmol)在四(三苯基膦)钯(0)(52mg,0.045mmol)的存在下,在2M K2CO3溶液(0.91ml)和DMF(6ml)中进行Suzuki偶联反应,得到实施例64的标题化合物,经制备性HPLC纯化后其为白色固体(124mg,50%收率)。1H NMR(400MHz,MeOD)δppm 8.99(1H,s)7.64(2H,d,J=8.14Hz)7.41(2H,d,J=8.14Hz)7.23-7.36(3H,m)7.17-7.22(1H,m)7.06(1H,d,J=4.07Hz)6.96-7.03(1H,m)4.97(1H,s)3.40-3.82(8H,m)1.46(3H,s)1.39(3H,s).MS ESI(m/z)551.3[(M+H)+];HPLC Rt:3.571分钟。
实施例65至82
以与实施例43类似的方式,实施例65-82通过实施例57的标题化合物和相应的芳基硼酸进行Suzuki偶联反应来制备(所有化合物都具有R-构型)。
实施例83
(3R)-3-(5-(3-氟-4-(吗啉-4-基羰基)苯基)-噻吩-2-基)-3-(3-氟苯基)-2,2-二甲基-N-1,3,4-噻二唑-2-基丙酰胺
向实施例78的标题化合物(25mg,0.05mmol)于CH3CN(1mL)中的溶液中加入1-[3-(二甲基氨基)丙基]-3-乙基碳二亚胺盐酸盐(EDC)(19mg,0.10mmol)和1-羟基-7-苯并三唑(HOBt)(14mg,0.10mmol)。搅拌5分钟后,向该溶液中加入吗啉(0.013ml,0.15mmol)和二异丙基乙胺(0.031ml,0.18mmol)。将反应混合物在60℃加热18小时。将反应混合物过滤,浓缩,然后经制备性HPLC纯化,得到实施例83的标题化合物,其为白色固体(14mg,49%收率)。1H NMR(400MHz,MeOD)δppm 9.00(1H,s)7.47(1H,dd,J=8.06,1.76Hz)7.39-7.44(1H,m)7.36(1H,d,J=8.06Hz)7.29-7.34(2H,m)7.25-7.29(1H,m)7.20(1H,dd,J=12.34,2.01Hz)7.08(1H,d,J=3.78Hz)7.00(1H,t,J=7.81Hz)4.98(1H,s)3.75(4H,d,J=4.03Hz)3.59-3.65(2H,m)3.34-3.40(2H,m)1.46(3H,s)1.39(3H,s).MS ESI(m/z)569.3[(M+H)+];HPLC Rt:3.606分钟。
实施例84和85
以与实施例1类似的方式,实施例84和85通过使制备(6a)和(6b)的酸分别与1,3,4-噻二唑-2-胺进行酰胺化反应制备(所有化合物都是对映异构纯的。绝对立体化学尚未确定)。
实施例86至88
以与实施例43类似的方式,实施例86至88通过实施例84的标题化合物和相应的芳基硼酸进行Suzuki偶联反应来制备(所有化合物都是对映异构纯的)。
实施例89至92
以与实施例43类似的方式,实施例89至92通过实施例19的标题化合物与相应的芳基硼酸进行Suzuki偶联反应来制备(所有化合物都是外消旋体)。
实施例93至97
以与实施例1类似的方式,实施例93至97通过3-(5-溴噻吩-2-基)-3-(3-氟苯基)-2-甲基丙酸,制备(8a)、(9a)、(9b)、(9c)和(9d)的酸分别与1,3,4-噻二唑-2-胺进行酰胺化反应来制备。实施例94-97为光学纯的,并且已经确定了它们的立体化学,表示于下表中。实施例93为1∶1的非对映异构体混合物。
实施例98和99
N-乙基-4-(5-(1-(3-氟苯基)-2-甲基-3-氧代-3-(1,3,4-噻二唑-2-基氨基)丙基)-噻吩-2-基)-N-甲基苯甲酰胺(非对映异构体A和B)
以与实施例43类似的方式,实施例98和99通过Suzuki偶联反应制备。使实施例93的标题化合物即3-(5-溴噻吩-2-基)-3-(3-氟苯基)-2-甲基-N-(1,3,4-噻二唑-2-基)丙酰胺(50mg,0.117mmol)和4-(二甲基氨基甲酰基)苯基硼酸(49mg,0.234mmol)在四(三苯基膦)钯(0)(14mg,0.012mmol)的存在下,在2M K2CO3水溶液(1ml)和DMF(1ml)中进行Suzuki偶联反应,得到粗产物,其为1∶1的非对映异构体混合物。非对映异构体对通过制备性HPLC分离,得到较快洗脱的异构体A,其为实施例98的标题化合物和较慢洗脱的异构体B,其为实施例99的标题化合物。实施例98(白色固体,18mg):1H NMR(400MHz,MeOD)δppm 8.96(1H,s)7.67(2H,d,J=8.31Hz)7.40(2H,t,J=7.30Hz)7.34(1H,d,J=3.78Hz)7.19-7.28(2H,m)7.15(1H,d,J=10.07Hz)7.10(1H,d,J=3.78Hz)6.82-6.90(1H,m)4.49(1H,d,J=11.33Hz)3.48-3.61(2H,m)3.32-3.38(1H,m)3.03(3H,d,J=25.68Hz)1.32(3H,d,J=6.80Hz)1.12-1.27(3H,m).MS ESI(m/z)509.3[(M+H)+];HPLC Rt:3.521分钟。实施例99(白色固体,16mg):1H NMR(400MHz,MeOD)δppm8.99(1H,s)7.56(2H,d,J=8.31Hz)7.29-7.45(3H,m)7.26(1H,d,J=7.55Hz)7.15-7.22(2H,m)6.98-7.07(1H,m)6.96(1H,d,J=3.53Hz)4.53(1H,d,J=11.58Hz)3.45-3.61(2H,m)3.30(m,1H)2.99(3H,d,J=30.97Hz)1.06-1.25(6H,m).MS ESI(m/z)509.3[(M+H)+];HPLC Rt:3.566分钟。
实施例100至105
以与实施例43类似的方式,使实施例93的化合物与相应的芳基硼酸进行Suzuki偶联反应,得到偶联产物,其为非对映异构体对。每种非对映异构体对通过制备性HPLC分离,得到实施例100至105的标题化合物(所有化合物都是外消旋体)。
实施例106和107
使用手性超临界流体色谱(SFC),将实施例98的标题化合物拆分为其相应的对映异构体,条件如下。
Chiral-SFS制备条件:柱:Chiralpak AS-H(3x25cm,5μm);BPR压力100巴;温度:35℃;流动相:CO2/MeOH(70/30);流速:70mL/min;UV检测:308nm。
分析性HPLC条件:(柱:Chiralpak AS(0.46x25cm,10μm)流动相:CO2/MeOH(70/30),温度:35℃,流速:2mL/min,检测:308nm)。保留时间:(2S,3S)-异构体(实施例106),13.55分钟(ee>99.9%);(2R,3R)-异构体(实施例107),16.65分钟(ee>99.9%)。
可供选择地,实施例107的标题化合物可通过与实施例43类似的方式使实施例97和4-(乙基(甲基)氨基甲酰基)苯基硼酸进行Suzuki偶联反应来制备。
实施例108至109
以与手性分离实施例98从而得到实施例106和107的类似的方式,使用手性超临界流体色谱(SFC)将实施例100的标题化合物拆分为相应的对映异构体。
分析性HPLC(柱:Chiralpak AS,CO2/MeOH 70∶30,流速:2mL/min,检测:220&254nm);保留时间:(2S,3S)-对映异构体(实施例108),23.87分钟(ee>99.9%);(2R,3R)-对映异构体(实施例109),29.31分钟(ee>99.9%)。
实施例110
2-氯-4-(5-((1R,2R)-1-(3-氟苯基)-2-甲基-3-氧代-3-(1,3,4-噻二唑-2-基氨基)丙基)-噻吩-2-基)-N,N-二甲基苯甲酰胺
以与实施例43类似的方式,使实施例97的标题化合物即(2R,3R)-3-(5-溴噻吩-2-基)-3-(3-氟苯基)-2-甲基-N-(1,3,4-噻二唑-2-基)丙酰胺(240mg,0.563mmol)和3-氯-4-(二甲基-氨基甲酰基)苯基硼酸(256mg,1.126mmol)进行Suzuki偶联反应,得到实施例110的标题化合物(147mg,0.278mmol,49.4%收率)。1H NMR(400MHz,MeOD)δppm 8.96(1H,s)7.71(1H,d,J=1.51Hz)7.61(1H,dd,J=7.93,1.64Hz)7.39(1H,d,J=3.78Hz)7.33(1H,d,J=8.06Hz)7.19-7.28(2H,m)7.15(1H,dd,J=10.07,2.01Hz)7.11(1H,d,J=3.78Hz)6.83-6.89(1H,m)4.51(1H,d,J=11.33Hz)3.48-3.57(1H,m)3.11(3H,s)2.91(3H,s)1.32(3H,d,J=6.55Hz).LC/MS(m/z)529.11(M+H)+];HPLC Rt:3.448分钟。
实施例111至122
以与实施例43类似的方式,实施例111至122通过实施例97的标题化合物和相应的芳基硼酸进行Suzuki偶联反应来制备(所有化合物都具有(2R,3R)-构型)。
实施例123至125
以与实施例43类似的方式,实施例123-125通过实施例94的标题化合物即(2S,3S)-3-(5-溴噻吩-2-基)-3-(3-氟苯基)-2-甲基-N-(1,3,4-噻二唑-2-基)丙酰胺与相应的芳基硼酸进行Suzuki偶联反应来制备(所有化合物都具有(2S,3S)-构型)。
实施例126至128
以与实施例43类似的方式,实施例126至128通过实施例95的标题化合物即(2S,3R)-3-(5-溴噻吩-2-基)-3-(3-氟苯基)-2-甲基-N-(1,3,4-噻二唑-2-基)丙酰胺和相应的芳基硼酸进行Suzuki偶联反应来制备(所有化合物都具有(2S,3R)-构型)。
实施例129至131
以与实施例43类似的方式,实施例129至131通过实施例96的标题化合物96即(2R,3S)-3-(5-溴噻吩-2-基)-3-(3-氟苯基)-2-甲基-N-(1,3,4-噻二唑-2-基)丙酰胺与相应的芳基硼酸进行Suzuki偶联反应来制备(所有化合物都具有(2R,3S)-构型)。
实施例132至136
以与实施例1类似的方式,实施例132至136通过制备(8b)、(10a)、(10b)、(10c)和(10d)的酸与1,3,4-噻二唑-2-胺分别进行酰胺化反应来制备。实施例133-136是光学纯的。确定了实施例133和138的绝对立体化学,表示于下表中。实施例132为1∶1的非对映异构体混合物。
实施例137至140
以与实施例43类似的方式,实施例137至140通过实施例133、134、135和136与4-(二甲基氨基甲酰基)苯基硼酸进行Suzuki偶联反应来制备。所有化合物都是光学纯的。确定了实施例137和140的绝对立体化学,表示于下表中。
实施例141
N-乙基-4-(5-((1R,2R)-1-(3-氟苯基)-2-甲基-3-((5-甲基-1,3,4-噻二唑-2-基)氨基)-3-氧代丙基)-噻吩-2-基)-N-甲基苯甲酰胺
步骤1
向闪烁瓶中装入酸(9d)即(2R,3R)-3-(5-溴噻吩-2-基)-3-(3-氟苯基)-2-甲基丙酸(200mg,0.583mmol)、4-(乙基(甲基)氨基甲酰基)苯基硼酸(241mg,1.165mmol)和2M K2CO3水溶液(1.165mL,2.331mmol)与DMF(4ml)中的溶液。将溶液用氮气脱气15分钟。向该溶液中加入四(三苯基膦)钯(0)(67.3mg,0.058mmol)。将反应混合物再脱气5分钟,然后密封,在加热块(OptiChem Digital Hotplate Stirrer)中在100℃加热20分钟。将反应混合物用1N NaOH溶液和DCM吸收。用浓HCl将水层调节至pH为3-4。酸性水溶液用乙酸乙酯萃取三次。将合并的有机相洗涤,经MgSO4干燥,过滤并浓缩,得到(2R,3R)-3-(5-(4-(乙基(甲基)氨基甲酰基)苯基)噻吩-2-基)-3-(3-氟苯基)-2-甲基丙酸,其为胶状物(120mg)。LC/MS(m/z)426.16[(M+H)+];HPLCRt:3.475分钟。
步骤2
向步骤1的化合物即(2R,3R)-3-(5-(4-(乙基(甲基)氨基甲酰基)苯基)噻吩-2-基)-3-(3-氟苯基)-2-甲基丙酸(30mg,0.071mmol)与乙腈(1mL)中的溶液中加入HOBT(21.59mg,0.141mmol)和EDC(27.0mg,0.141mmol)。将反应混合物在室温搅拌5分钟。先后向该溶液中加入5-甲基-1,3,4-噻二唑-2-胺(24.36mg,0.212mmol)和许尼希碱(Hunig’s base)(0.043mL,0.247mmol)。将反应混合物在75℃搅拌18小时。对反应混合物进行过滤然后真空浓缩。粗产物使用制备性HPLC[C18;Luna 5微米;21×100mm;20mL/min;220波长;梯度:在12分钟内,60至100%溶剂B(水/MeOH/TFA 10∶90∶0.1),保持3分钟。在Rt=10.379分钟时洗脱出产物]纯化,得到实施例141的标题化合物,其为白色固体(14mg,37.6%收率)。1H NMR(400MHz,MeOD)δppm 7.67(2H,d,J=8.56Hz)7.41(2H,t,J=8.06Hz)7.34(1H,d,J=3.53Hz)7.17-7.29(2H,m)7.11-7.17(1H,m)7.09(1H,d,J=3.78Hz)6.82-6.92(1H,m)4.47(1H,d,J=11.33Hz)3.52-3.63(1H,m)3.44-3.52(1H,m)3.34(1H,d,J=9.06Hz)3.03(3H,d,J=24.93Hz)2.60(3H,s)1.30(3H,d,J=6.80Hz)1.11-1.26(3H,m)。MS ESI(m/z)523.2[(M+H)+];HPLC Rt:3.625分钟。
实施例142和143
以与实施例1类似的方式,实施例142-143通过实施例141-步骤1的酸与5-甲基噻唑-2-胺和噻唑-2-胺分别进行酰胺化反应来制备。
实施例144至151
以与实施例43类似的方式,使实施例132的标题化合物与相应的芳基硼酸进行Suzuki偶联反应,得到偶联产物,其为非对映异构体对。每种非对映异构体对通过制备性HPLC分离,得到实施例144-151的标题化合物(所有化合物都是外消旋体)。
实施例152至155
以与手性分离实施例98从而得到实施例106和107的类似的方式,使用手性超临界流体色谱(SFC)将以下实施例的标题化合物拆分为相应的对映异构体。
将实施例144拆分为实施例152和153。分析性HPLC(柱:ChiralpakAD,CO2/EtOH 65∶35,流速:2mL/min,检测:305nm)保留时间:(2S,3S)-对映异构体(实施例152),14.19分钟(ee>99.9%);(2R,3R)-对映异构体(实施例153),16.17分钟(ee>98%)。
将实施例150拆分为实施例154和155。分析性HPLC(柱:ChiralpakAS,CO2/MeOH 70∶30,流速:2mL/min,检测:300nm)保留时间:(2S,3S)-对映异构体(实施例154),14.32分钟(ee>99.9%);(2R,3R)-对映异构体(实施例155),22.07分钟(ee>99.9%)。
生物学活性数据
给出了实施例1至155的AP-1活性,其中AP-1EC50小于1uM。还给出了附随的AP-1最大抑制值。当AP-1EC50超过1uM和/或最大抑制小于20%时,给出了糖皮质激素受体(GR)结合亲和力(Ki)。
下文表示的数据使用下表中提及的测定和本申请在上述测定部分描述的测定获得。
实施例编号 | GR(Ki,nM)(GR结合测定(I)a) | GR(%RBA*@10μM)(GR结合测定(II)b) | AP-1EC50,nM(细胞反式阻抑测定) | AP-1Max%inh(细胞反式阻抑测定) |
1 | 6.40 | |||
2 | 10.10 | |||
3 | 3.66 | |||
4 | 6.97 | |||
5 | 18.70 | 89.86 | ||
6 | 501.50 | |||
7 | 160.70 | |||
8 | ||||
9 | 24.55 | 49.70 | ||
10 | 699.60 | 39.98 | ||
11 | 7.40 | |||
12 | 6.10 | |||
13 | 245.20 | 42.20 | ||
14 | 62.91 | 46.02 | ||
15 | 14.70 | |||
16 | 90.40 | |||
17 | 112.20 | |||
18 | 37.20 | |||
19 | 2.93 | |||
20 | 152.00 | |||
21 | 40.45 | 23.95 |
实施例编号 | GR(Ki,nM)(GR结合测定(I)a) | GR(%RBA*@10μM)(GR结合测定(II)b) | AP-1EC50,nM(细胞反式阻抑测定) | AP-1Max%inh(细胞反式阻抑测定) |
22 | 477.30 | |||
23 | 142.20 | 29.42 | ||
24 | 16.30 | |||
25 | 73.40 | |||
26 | 316.10 | 41.43 | ||
27 | 52.80 | |||
28 | 186.70 | |||
29 | 7.69 | |||
30 | 48.99 | 39.36 | ||
31 | 21.53 | 46.75 | ||
32 | 73.92 | 43.12 | ||
33 | 24.02 | 37.67 | ||
34 | ||||
35 | 5.75 | |||
36 | 1.46 | |||
37 | 53.49 | |||
38 | 8.43 | 23.10 | ||
39 | 18.81 | 44.23 | ||
40 | 5.36 | 37.26 | ||
41 | 6.50 | 65.52 | ||
42 | 11.63 | 42.89 | ||
43 | 10.69 | 38.40 | ||
44 | 0.89 | |||
45 | 5.88 | 51.02 | ||
46 | 11.71 | |||
47 | 3.71 | 39.94 | ||
48 | 17.35 | |||
49 | 3.58 | |||
50 | 13.20 | 39.62 | ||
51 | 79.65 | |||
52 | 12.07 | 38.47 | ||
53 | 151.80 | |||
54 | 9.45 | 62.42 | ||
55 | 36.76 | |||
56 | 1.21 | |||
57 | 2.39 | |||
58 | 29.24 | |||
59 | 66.95 | |||
60 | 160.50 | |||
61 | 100.60 | |||
62 | 87.59 | |||
63 | 565.20 | |||
64 | 3.04 | 53.84 | ||
65 | 7.00 | 49.65 | ||
66 | 5.16 | 50.37 | ||
67 | 12.84 | 51.23 | ||
68 | 7.31 | 49.38 | ||
69 | 1.03 | |||
70 | 833.30 | 22.97 | ||
71 | 1.51 | |||
72 | 29.84 | |||
73 | 6.13 |
实施例编号 | GR(Ki,nM)(GR结合测定(I)a) | GR(%RBA*@10μM)(GR结合测定(II)b) | AP-1EC50,nM(细胞反式阻抑测定) | AP-1Max%inh(细胞反式阻抑测定) |
74 | 2.24 | |||
75 | 1.52 | |||
76 | 27.03 | |||
77 | 4.19 | |||
78 | 24.47 | |||
79 | 30.34 | 42.56 | ||
80 | 34.73 | 33.59 | ||
81 | 4.32 | |||
82 | 2.66 | |||
83 | 16.65 | 32.70 | ||
84 | 5.06 | |||
85 | 2.74 | |||
86 | 53.94 | 36.20 | ||
87 | 8.49 | 41.07 | ||
88 | 15.70 | 43.56 | ||
89 | 2.41 | 36.74 | ||
90 | 20.57 | 32.70 | ||
91 | 4.59 | |||
92 | 1.14 | |||
93 | 2.79 | |||
94 | 4.11 | |||
95 | 0.76 | |||
96 | 71.09 | 27.36 | ||
97 | 1.96 | |||
98 | 15.76 | 55.31 | ||
99 | 279.00 | 49.36 | ||
100 | 8.80 | 50.60 | ||
101 | 575.90 | 51.00 | ||
102 | 10.64 | 52.60 | ||
103 | 879.30 | 49.86 | ||
104 | 38.68 | 49.53 | ||
105 | 446.40 | 48.50 | ||
106 | 2.44 | |||
107 | 15.88 | 52.51 | ||
108 | 5.39 | |||
109 | 8.39 | 57.47 | ||
110 | 24.61 | 47.00 | ||
111 | 21.21 | 53.26 | ||
112 | 18.46 | 53.98 | ||
113 | 17.88 | 37.84 | ||
114 | 45.45 | 36.56 | ||
115 | 31.00 | 39.12 | ||
116 | 67.66 | 40.77 | ||
117 | 14.37 | 56.55 | ||
118 | 61.60 | 55.28 | ||
119 | 22.71 | 47.56 | ||
120 | 22.92 | 42.90 | ||
121 | 66.84 | 28.67 | ||
122 | 1.91 | |||
123 | 7.16 | |||
124 | 7.27 | |||
125 | 5.71 |
实施例编号 | GR(Ki,nM)(GR结合测定(i)a) | GR(%RBA*@10μM)(GR结合测定(II)b) | AP-1EC50,nM(细胞反式阻抑测定) | AP-1Max%inh(细胞反式阻抑测定) |
126 | 220.00 | |||
127 | 148.30 | |||
128 | 277.30 | |||
129 | 157.70 | |||
130 | 160.30 | |||
131 | 235.80 | |||
132 | 3.20 | |||
133 | 4.85 | |||
134 | 1.06 | |||
135 | 1.25 | |||
136 | 1.98 | |||
137 | 4.73 | |||
138 | 360.40 | |||
139 | 258.60 | |||
140 | 15.19 | 54.06 | ||
141 | 62.20 | 45.96 | ||
142 | 3.20 | |||
143 | 16.86 | 63.62 | ||
144 | 5.98 | 49.49 | ||
145 | 64.61 | 25.24 | ||
146 | 14.58 | 59.12 | ||
147 | 167.70 | 48.44 | ||
148 | 24.62 | 51.50 | ||
149 | 216.50 | 54.20 | ||
150 | 17.51 | 57.18 | ||
151 | 203.30 | 48.08 | ||
152 | 4.85 | |||
153 | 11.96 | 63.60 | ||
154 | 2.15 | |||
155 | 8.27 | 61.47 |
*%RBA=与地塞米松的%相对结合亲和力
Claims (14)
1.式(I)的化合物或其对映异构体、非对映异构体、互变异构体或药用盐,
其中:
A为5、6或7元杂环基或5、6或7元杂芳基,每个所述杂环基或杂芳基含有选自N、O和S的1、2或3个杂原子并且每个所述杂环基或杂芳基被一至四个基团R1、R2、R3和/或R4取代,条件是(i)A不是四唑基,或(ii)若A为噻吩基或呋喃基,则Z选自不是琥珀酰亚胺基或邻苯二甲酰亚胺基的基团;
M选自烷基、环烷基、芳基、杂环基和杂芳基;
Ma为碳原子和M之间的连接基并且选自化学键和C1-C3亚烷基;
Q选自
(i)氢、卤素、硝基、氰基、羟基、C1-4烷基和取代的C1-4烷基;或
(ii)Q与R6和它们所连接的碳原子结合形成3至6元环烷基;或
(iii)Q和M与它们所连接的碳原子结合形成含有1-2个独立选自O、S、SO2和N的杂原子的3至7元环,并且所述环任选被0-2个R5基团或羰基取代;
Z选自烷基、CF3、OH、环烷基、杂环基、芳基、杂芳基、-C(=O)NR8R9、-C(=O)R8、-C(NCN)NR8R9、-C(=O)OR8、-SO2R8和-SO2NR8R9;
Za为氮原子和Z之间的连接基并且选自化学键和C1-C6亚烷基;
R1、R2、R3和R4在每次出现时独立选自氢、卤素、烷基、取代的烷基、烯基、取代的烯基、炔基、取代的炔基、硝基、氰基、-OR10、-SR10、-NR10R11、-C(=O)R10、-CO2R10、-C(=O)NR10R11、-O-C(=O)R10、-NR10C(=O)R11、-NR10C(=O)OR11、-NR10C(S)OR11、-S(=O)pR12、-NR10SO2R12、-SOpNR10R11、环烷基、杂环基、芳基和杂芳基;
R5在每次出现时独立选自氢、卤素、烷基、取代的烷基、烯基、取代的烯基、炔基、取代的炔基、硝基、氰基、-OR13、-NR13R14、-C(=O)R13、-CO2R13、-C(=O)NR13R14、-O-C(=O)R13、-NR13C(=O)R14、-NR13C(=O)OR14、-NR13C(S)OR14、-S(=O)pR15、-NR13SO2R15、-SO2NR13R14、环烷基、杂环基、芳基或杂芳基;
R6选自烷基、取代的烷基、烯基、取代的烯基、炔基、取代的炔基、氰基、-C(=O)R17、-CO2R17、-C(=O)NR16R17、环烷基、杂环基、芳基和杂芳基、条件是杂环基或杂芳基通过碳原子相连;
R7选自氢、卤素、烷基、取代的烷基、烯基、取代的烯基、炔基、取代的炔基、硝基、氰基、-OR19、-NR19R20、-C(=O)R19、-CO2R19、-C(=O)NR19R20、-O-C(=O)R19、-NR19C(=O)R20、-NR19C(=O)OR20、-NR19C(=S)OR20、-S(=O)pR21、-NR19SO2R21、-SO2NR19R20、环烷基、杂环基、芳基和杂芳基;
或R6和R7与它们所连接的碳连在一起形成环烷基或杂环基;
R8、R9、R10、R11、R13、R14、R16、R17、R19和R20在每次出现时独立选自:
(i)氢、烷基、取代的烷基、烯基、取代的烯基、炔基、取代的炔基、烷基SOp-、环烷基、芳基、杂芳基和杂环基;或
(ii)R8与R9连在一起;和/或R10与R11连在一起;和/或R16与R17连在一起;和/或R19与R20连在一起,从而形成4至7元杂芳基环或4至7元杂环基环;
R12、R15、R18和R21独立选自烷基、取代的烷基、烯基、取代的烯基、炔基、取代的炔基、环烷基、芳基、杂芳基或杂环基;
R22选自氢、烷基、取代的烷基、烷基C(=O)-、烷基OC(=O)-、烷基SO2-、烷氧基、氨基、取代的氨基、芳基、杂芳基、杂环基和环烷基;以及
p为1或2。
2.权利要求1的化合物或其对映异构体、非对映异构体或药用盐,其中A选自吡咯基、吡唑基、吡唑啉基、咪唑基、噁唑基、异噁唑基、噁二唑基、三唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、噻吩基、噁二唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基和三唑基,其中的每个任选被一至四个基团R1、R2、R3和/或R4取代。
4.权利要求3的化合物或其对映异构体、非对映异构体或药用盐,其中:
Ma为化学键;
M选自C1-6烷基和芳基;以及
Q为氢或C1-6烷基。
5.权利要求1的化合物或其对映异构体、非对映异构体或药用盐,其中:
Za为化学键;
Z为杂芳基,所述杂芳基含有1、2或3个选自N、S和O的杂原子,并且所述杂芳基被一、二或三个基团Rm、Rn和/或Ro取代;
Rm、Rn和/或Ro独立选自(i)氢、卤素、烷基、取代的烷基、烯基、取代的烯基、炔基、取代的炔基、硝基、氰基、-OR23、-NR23R24、-C(=O)R23、-CO2R23、-C(=O)NR23R24、-O-C(=O)R23、-NR23C(=O)R24、-NR23C(=O)OR24、-NR23C(=S)OR24、-S(=O)pR25、-NR23SO2R25、-SO2NR23R24、环烷基、杂环基、芳基和杂芳基;或(ii)位于相邻的原子上的Rm、Rn和/或Ro中的两个与它们所连接的原子任选一起形成环烷基环、芳基环、杂芳基环或杂环基环;
R23和R24在每次出现时独立选自氢、烷基、取代的烷基、烷基C(=O)-、烷基OC(=O)-、烷基SO2-、烯基、取代的烯基、炔基、取代的炔基、氨基、芳基、杂芳基、杂环基和环烷基;以及
R25选自烷基、取代的烷基、烯基、取代的烯基、炔基、取代的炔基、氨基、取代的氨基、杂芳基、杂环基、环烷基和芳基。
6.权利要求1的化合物或其对映异构体、非对映异构体或药用盐,其具有式(Ia)的结构
其中:
A为噻吩基、噻唑基、异噻唑基、噻二唑基、呋喃基、吡咯基、吡唑基、吡啶基或嘧啶基,每个基团任选被1至4个基团R1、R2、R3和/或R4取代;
Rm和Rn在每次出现时独立选自(i)氢、卤素、环烷基、氰基、卤代烷基、烷硫基、-CO2R23、-NR23R24、-C(=O)R23、-C(O)N(R23)(R24)、-OR23、C1-4烷基、取代的C1-4烷基、芳基、杂芳基和杂环基;或(ii)Rm和Rn与它们所连接的原子结合在一起形成稠合的5至7元环烷基环、5至7元芳基环、5至7元杂芳基环或5至7元杂环基环;
R1、R2、R3、R4、R1a、R2a、R3a和R4a独立选自(i)氢、卤素、C1-4烷基、CN、C2-4烯基、C2-4炔基、-SR10、-SO2R12、-OR10、-SOpNR10R11和-NR10R11;和/或(ii)被任选取代的基团取代的C0-3亚烷基,所述任选取代的基团选自苯基和5至7元杂环基或5至7元杂芳基;
R6选自C1-4烷基、C1-4取代的烷基、氰基和C3-7环烷基;
R7选自氢、C1-4烷基、C1-4取代的烷基、硝基、氰基、羟基、C1-4烷氧基和C3-7环烷基;
或R6和R7与它们所连接的碳连在一起形成C3-7环烷基;
R10和R11在每次出现时独立选自(i)氢、C1-6烷基、取代的C1-6烷基和-SO2(C1-4烷基);和/或(ii)C3-7环烷基、杂环基、芳基和杂芳基,每个所述基团任选被取代;和/或(iii)R10与R11和它们同时连接的氮原子连在一起形成4至6元杂芳基环或4至6元杂环基环,所述每个基团任选被取代;
R12在每次出现时独立选自取代的基团,所述取代的基团选自C1-6烷基、C3-7环烷基、杂环基、芳基和杂芳基;以及
R23和R24在每次出现时独立选自氢、烷基、取代的烷基、烷基C(=O)-、烷基OC(=O)-、烷基SO2-、烯基、取代的烯基、炔基、取代的炔基、氨基、芳基、杂芳基、杂环基和环烷基。
7.权利要求6的化合物或其对映异构体、非对映异构体或药用盐,其中A为任选被一个或两个基团取代的噻吩基或吡啶基,所述基团选自卤素、烷氧基、吗啉基、任选被OH取代的哌啶基、-NH(CH2)n(任选被C1-4烷基取代的苯基)、吡咯烷基、呋喃基和任选被一个或两个取代基取代的苯基,所述取代基选自卤素、烷氧基、C1-6烷基、-CO2R10或-C(O)NR10R11;以及n为0、1或2。
9.权利要求6的化合物或其对映异构体、非对映异构体或药用盐,其中R1a、R2a、R3a和R4a选自氢、C1-4烷基、卤素、硝基、氰基、羟基、C1-4烷氧基、吗啉基、哌啶基、哌嗪基和吡咯烷基。
11.权利要求1的化合物或其对映异构体、非对映异构体或药用盐,其中:
R6选自C1-4烷基;以及
R7选自氢和C1-4烷基。
12.治疗选自代谢性疾病和炎症性或免疫性疾病的疾病或病症的方法,所述方法包括给予需要治疗的患者治疗有效量的权利要求1的化合物。
13.一种药物组合物,其包含权利要求1的化合物和药用载体。
14.药物组合,其包含如权利要求1定义的化合物和免疫抑制剂、抗癌剂、抗病毒剂、抗炎剂、抗真菌剂、抗生素、抗血管过度增殖药、抗抑郁药、降脂药、调脂药、抗糖尿病药、抗肥胖症药、抗高血压药、血小板聚集抑制剂和/或抗骨质疏松药,其中所述抗糖尿病药为双胍、磺酰脲、葡糖苷酶抑制剂、PPAR γ激动剂、PPAR α/γ双重激动剂、SGLT2抑制剂、DP4抑制剂、aP2抑制剂、胰岛素敏化剂、胰高血糖素样肽-1(GLP-1)、胰岛素和/或氯茴苯酸中的1、2、3或更多种,其中所述抗肥胖症药为β-3肾上素能激动剂、脂酶抑制剂、5-羟色胺(和多巴胺)再摄取抑制剂、甲状腺受体激动剂、aP2抑制剂和/或厌食药,其中所述降脂药为MTP抑制剂、HMG CoA还原酶抑制剂、角鲨烯合成酶抑制剂、苯乙酸衍生物、LDL受体活性上调剂、脂氧化酶抑制剂或ACAT抑制剂,其中所述抗高血压药为ACE抑制剂、血管紧张素II受体拮抗剂、NEP/ACE抑制剂、钙通道阻滞剂和/或β-肾上腺素能阻滞剂。
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