CN101084211A - 杂环衍生物及其作为治疗剂的用途 - Google Patents
杂环衍生物及其作为治疗剂的用途 Download PDFInfo
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- CN101084211A CN101084211A CNA2005800397867A CN200580039786A CN101084211A CN 101084211 A CN101084211 A CN 101084211A CN A2005800397867 A CNA2005800397867 A CN A2005800397867A CN 200580039786 A CN200580039786 A CN 200580039786A CN 101084211 A CN101084211 A CN 101084211A
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- cyclic hydrocarbon
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- hydrocarbon radical
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Abstract
公开了治疗哺乳动物的,优选人的SCD-介导的疾病或疾病状态的方法,其中该方法包括将通式(I)化合物对需要该治疗的哺乳动物给药:其中y、G、K、L、M、W、V、R2、R3、R4a、R6、R6a、R7、R7a、R8和R8a均如本文所定义的。还公开了包含通式(I)化合物的药物组合物。
Description
发明领域
本发明通常涉及硬脂酰CoA去饱和酶抑制剂领域,以及这类化合物在治疗和/或预防多种人类疾病中的用途,所述硬脂酰CoA去饱和酶抑制剂例如是杂环衍生物,所述人类疾病包括由硬脂酰CoA去饱和酶(SCD)介导的疾病,优选由SCD1介导的疾病,尤其是与升高的脂质水平相关的疾病、心血管疾病、糖尿病、肥胖症、代谢综合征等疾病。
发明背景
酰基去饱和酶催化来自饮食来源或肝脏中从头合成的脂肪酸中双键的形成。哺乳动物合成至少三种不同链长特异性的脂肪酸去饱和酶,该脂肪酸去饱和酶可催化在δ-9、δ-6及δ-5位置上双键的引入。硬脂酰CoA去饱和酶(SCDs)在饱和脂肪酸的C9-C10位置上引入双键。优选的底物为棕榈酰基CoA(16∶0)及硬脂酰基CoA(18∶0),其可分别转化成棕榈油酰基CoA(16∶1)及油酰基CoA(18∶1)。所得单不饱和脂肪酸为用于并入磷脂质、甘油三酯及胆固醇酯的底物。
已克隆出许多哺乳动物的SCD基因。例如,已经从大鼠中克隆出二种基因(SCD1、SCD2),且已经从小鼠分离出四种SCD基因(SCD1、2、3和4)。虽然自1970年代就已知了SCD在大鼠及小鼠中的基本生物化学作用(Jeffcoat,R.等人,Elsevier Science(1984),Vol.4,pp.85-112;de Antueno,RJ,Lipids(1993),Vol.28,No.4,pp.285-290),但仅在最近才发现与人类疾病过程有直接关联。
已经在人类中表征出了单一的SCD基因,即SCD1。Brownlie等人的PCT公开专利申请WO01/62954中描述了SCD1,本文将其公开的全部内容引入作为参考。最近已鉴别出了第二种人SCD同工酶,且因为其与其它的小鼠或大鼠同工酶具有很少的序列同源性,因此将其命名为人SCD5或hSCD5(PCT公开专利申请WO 02/26944,本文将其全文引入作为参考)。
迄今为止,特异性抑制或调节SCD活性的为小分子的类似药物的化合物是未知的。某些长链烃在过去已被用来研究SCD活性。已知的实例包括硫代脂肪酸、环丙烯类脂肪酸及某些共轭亚油酸异构体。特别地,认为顺-12,反-10共轭亚油酸抑制SCD酶活性并降低SCD1 mRNA的丰度,而顺-9,反-11共轭亚油酸则不能。还已知环丙烯类脂肪酸,诸如在苹婆籽及棉花籽中发现的环丙烯类脂肪酸抑制SCD活性。例如,苹婆酸(8-(2-辛基环丙烯基)辛酸)及锦葵酸(7-(2-辛基环丙烯基)庚酸)分别为在其C9-C10位置上具有环丙烯环的苹婆酰基脂肪酸和锦葵酰基脂肪酸的C8和C16衍生物。认为这些试剂可通过与酶的直接相互作用来抑制SCD酶活性,从而抑制δ-9去饱和作用。可抑制SCD活性的其它试剂包括硫代脂肪酸,如9-硫代硬脂酸(也被称为8-壬基硫代辛酸)及其它具有sulfxoy部分的脂肪酸。
这些已知的δ-9去饱和酶活性调节剂不能用于治疗与SCD1生物活性相关的疾病和病症。已知的SCD抑制剂化合物对SCD或δ-9去饱和酶均不具有选择性,因为其还抑制其它去饱和酶和酶。硫代脂肪酸、共轭亚油酸及环丙烯脂肪酸(锦葵酸及苹婆酸)既不能在合理的生理剂量下使用,也不是SCD1生物活性的特异性抑制剂,反而它们却显示出对其它去饱和酶的交叉抑制作用,尤其是环丙烯脂肪酸对δ-5及δ-6去饱和酶的交叉抑制作用。
缺乏SCD酶活性的小分子抑制剂是主要的科学及医学挫折,因为目前引入注目的证据表明SCD活性直接涉及普遍的人类疾病过程:例如参见Attie,A.D.等人的“Relationship between stearoyl-CoAdesaturate activity and plasma triglycerides in human and mousehypertriglyceridemia(人类和小鼠高甘油三酯血症中硬脂酰CoA去饱和酶活性和血浆甘油三酯间的关系)”,J.Lipid Res.(2002),Vol.43,No.11,pp.1899-907;Cohen,P.等人的“Role for stearoyl-CoA desaturate-1 inleptin-mediated weight loss(硬脂酰CoA去饱和酶-1在瘦素介导的体重减轻中的作用)”,Science(2002),Vol.297,No.5579,pp.240-3;Ntambi,J.M.等人的“Loss of stearoyl-CoA desaturate-1 function protectsmice against adiposity(硬脂酰CoA去饱和酶-1功能的丧失保护小鼠免于肥胖)”,Proc.Natl.Acad.Sci.U SA.(2002),Vol.99,No.7,pp.11482-6。
本发明通过提供可用于调节SCD活性并调节脂质水平,尤其是血浆脂质水平的一类新化合物解决了上述问题,所述化合物可用于治疗SCD介导的疾病,如与血脂异常相关的疾病以及脂质代谢紊乱,尤其治疗是与升高的脂质水平相关的疾病、心血管疾病、糖尿病、肥胖症、代谢综合征等疾病。
发明概述
本发明提供了调节硬脂酰CoA去饱和酶活性的杂环衍生物。本发明还涵盖了使用这类衍生物调节硬脂酰CoA去饱和酶活性的方法及包含这类衍生物的药物组合物。
因此,一方面,本发明提供了通式(I)所示的化合物,其立体异构体、其对映异构体或其互变异构体,其立体异构体的混合物,其药物可接受的盐或其前药:
其中:
y为0、1、2或3;
G为-N(R4)-、-O-、-S(O)t-(其中t为0、1或2)、-C(R4)=或-C(R4)=C(R4)-;
K为N或C(R10);
L和M均独立为-N=或-C(R4)=,其前提是当G为-C(R4)=或-C(R4)=C(R4)-时,L和M不同时为-C(R4)=;
V为-N(R1)-、-O-、-C(R10)2-、-C(O)-、-C(O)O-、-C(S)-、-C(O)N(R1)-、-S(O)t-(其中t为0、1或2)、或-S(O)pN(R1)-(其中p为1或2),其前提是当K为N时,V不为-S-;
W为化学键、-N(R1)C(O)-、-C(O)N(R1)-、-OC(O)N(R1)-、-N(R1)C(O)N(R1)-、-O-、-N(R1)-、-S(O)t-(其中t为0、1或2)、-N(R1)S(O)p-(其中p为1或2)、-S(O)pN(R1)-(其中p为1或2)、-C(O)-、-OS(O)2N(R1)-、-OC(O)-、-C(O)O-或-N(R1)C(O)O-;
每一R1独立地选自氢、C1-C12烷基、C2-C12羟烷基、C4-C12环烃基烷基和C7-C19芳烷基;
R2选自C1-C12烷基、C2-C12烯基、C2-C12羟烷基、C2-C12羟烯基、C2-C12烷氧基烷基、C3-C12环烃基、C4-C12环烃基烷基、芳基、C7-C19芳烷基、C3-C12杂环基、C3-C12杂环基烷基、C1-C12杂芳基和C3-C12杂芳基烷基;
或R2为具有2至4个环的多环结构,其中所述环独立地选自环烃基、杂环基、芳基及杂芳基,且其中部分或所有环可彼此稠合;
R3选自C1-C12烷基、C2-C12烯基、C2-C12羟烷基、C2-C12羟烯基、C2-C12烷氧基烷基、C3-C12环烃基、C4-C12环烃基烷基、芳基、C7-C19芳烷基、C3-C12杂环基、C3-C12杂环基烷基、C1-C12杂芳基和C3-C12杂芳基烷基;
或R3为具有2至4个环的多环结构,其中所述环独立地选自环烃基、杂环基、芳基及杂芳基,且其中部分或所有环可彼此稠合;
每一R4独立地选自氢、氟、氯、C1-C12烷基、C1-C12烷氧基、卤代烷基、氰基、硝基或-N(R9)2;
或者两个相邻的R4基团与其所连接的碳一起可以形成芳基、杂芳基或杂环基环体系;
R4a为氢、氟、氯、C1-C12烷基、C1-C12烷氧基、卤代烷基、氰基、硝基或-N(R9)2;
或R4a为与相邻碳之间的化学键;
R6、R6a、R7、R7a、R8和R8a均独立地选自氢或C1-C3烷基;
或者R6与R6a一起、或R7与R7a一起、或R8与R8a一起为氧代基团,其前提是当V为-C(O)-时,R6与R6a一起或R8与R8a一起不形成氧代基团,而其余的R6、R6a、R7、R7a、R8和R8a均独立地选自氢或C1-C3烷基;
或者R6和R6a之一与R7、R7a、R8和R8a之一一起形成化学键或亚烷基桥,而其余的R6、R6a、R7、R7a、R8和R8a均独立地选自氢或C1-C3烷基;
每一R9独立地选自氢或C1-C6烷基;以及
R10独立地选自氢、氟、氯、C1-C12烷基或C1-C12烷氧基。
另一方面,本发明提供了治疗哺乳动物的,优选为人的SCD介导的疾病或疾病状态的方法,其中该方法包括将治疗有效剂量的上述本发明化合物对需要该治疗的哺乳动物给药。
另一方面,本发明提供了用于治疗、预防和/或诊断与SCD生物活性相关的疾病或疾病状态的化合物或药物组合物,所述疾病或疾病状态例如为包括心血管病症和/或代谢综合征(包括血脂异常、胰岛素抵抗及肥胖症)在内的疾病。
另一方面,本发明为具有升高的脂质水平的患者提供预防或治疗与升高的脂质水平相关的疾病或疾病状态的方法,该脂质水平例如为血浆脂质水平,尤其为升高的甘油三酯或胆固醇水平,所述方法包括将治疗或预防有效剂量的本文公开的组合物对所述患者给药。本发明还涉及具有降低动物脂质水平,尤其是甘油三酯及胆固醇水平的治疗能力的新化合物。
另一方面,本发明提供包含前述的本发明化合物和药物可接受的赋形剂的药物组合物。在一实施方案中,本发明涉及在药物可接受的载体中含有一定量的本发明化合物的药物组合物,该量为当对动物,优选对哺乳动物,最优选对人类患者给药时,有效调节甘油三酯水平或治疗与血脂异常相关的疾病和脂质代谢紊乱。在这种组合物的实施方案中,所述患者在所述化合物给药前以及所述化合物以有效降低所述脂质水平的量存在之前,该患者已经具有升高的脂质水平,如升高的血浆甘油三酯或胆固醇。
另一方面,本发明提供了治疗患有硬脂酰CoA去饱和酶(SCD)介导的疾病或疾病状态的患者或预防患者发展为硬脂酰CoA去饱和酶(SCD)介导的疾病或疾病状态的方法,该方法包括将治疗有效剂量的化合物对患有该疾病或疾病状态的患者或处于患有该疾病或疾病状态危险之中的患者给药,该化合物在对所述患者给药时,抑制SCD活性。
另一方面,本发明提供了使用由本文公开的方法鉴别的化合物来治疗涉及脂质代谢的一系列疾病的方法。因此,本文公开了基于筛选分析的具有所述活性的一系列化合物,该筛选分析用于从测试化合物库中鉴定出调节所述SCD的生物活性且可用于治疗与脂质的血清水平相关的人类疾病或疾病状态的治疗剂,所述脂质例如甘油三酯、VLDL、HDL、LDL和/或总胆固醇。
应了解与上述通式(I)化合物或包含通式(I)化合物的组合物相关的本发明范围并不旨在涵盖先前公开中特别公开和/或要求保护的化合物,其包括但不限于PCT公开的专利申请WO 2005/016910中特定公开的化合物。
发明的详细说明
定义
由表明在指定化学基团中发现的碳原子总数的简化符号在前面标示本文中命名的某些化学基团。例如,C7-C12烷基描述具有总数为7至12个碳原子的如下定义的烷基,以及C4-C12环烃基烷基描述具有总数为4至12个碳原子的如下定义的环烃基烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
因此,除非另有相反的说明,否则说明书和所附权利要求中所用的如下术语具有如下的含意:
“甲氧基”指-OCH3基。
“氰基”指-CN基。
“硝基”指-NO2基。
“三氟甲基”指-CF3基。
“氧代”指=O取代基。
“硫代”指=S取代基。
“烷基”指直链或支链的烃链基团,所述烃链基团仅由碳和氢原子组成、不含不饱和,具有1至12个碳原子,优选1至8个碳原子或1至6个碳原子,且通过单键与分子的其余部分连接,例如甲基、乙基、正丙基、1-甲基乙基(异丙基)、正丁基、正戊基、1,1-二甲基乙基(叔丁基)等等。除非说明书中另有明确说明,烷基可被如下基团之一任意取代:烷基、烯基、卤素、卤代烯基、氰基、硝基、芳基、环烃基、杂环基、杂芳基、-OR14、-OC(O)-R14、-N(R14)2、-C(O)R14、-C(O)OR14、-C(O)N(R14)2、-N(R14)C(O)OR16、-N(R14)C(O)R16、-N(R14)(S(O)tR16)(其中t为1至2)、-S(O)tOR16(其中t为1至2)、-S(O)tR16(其中t为0至2)和-S(O)tN(R14)2(其中t为1至2),其中每一R14独立地为氢、烷基、卤代烷基、环烃基、环烃基烷基、芳基(被一或多个选自卤素或卤代烷基的基团任意取代)、芳烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基;以及每一R16为烷基、卤代烷基、环烃基、环烃基烷基、芳基、芳烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基,且其中除非另有说明,每一上述取代基是未取代的。
“C1-C3烷基”指含有1至3个碳原子的上述定义的烷基。C1-C3烷基可以如对烷基基团所定义的那样被任意取代。
“C1-C6烷基”指含有1至6个碳原子的上述定义的烷基。C1-C6烷基可以如对烷基基团所定义的那样被任意取代。
“C1-C12烷基”指含有1至12个碳原子的上述定义的烷基。C1-C12烷基可以如对烷基基团所定义的那样被任意取代。
“C2-C6烷基”指含有2至6个碳原子的上述定义的烷基。C2-C6烷基可以如对烷基基团所定义的那样被任意取代。
“C3-C6烷基”指含有3至6个碳原子的上述定义的烷基。C3-C6烷基可以如对烷基基团所定义的那样被任意取代。
“C3-C12烷基”指含有3至12个碳原子的上述定义的烷基。C3-C12烷基可以如对烷基基团所定义的那样被任意取代。
“C6-C12烷基”指含有6至12个碳原子的上述定义的烷基。C6-C12烷基可以如对烷基基团所定义的那样被任意取代。
“C7-C12烷基”指含有7至12个碳原子的上述定义的烷基。C7-C12烷基可以如对烷基基团所定义的那样被任意取代。
“烯基”指仅由碳和氢原子组成、含有至少一个双键、具有2至12个碳原子、优选2至8个碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团,例如乙烯基、丙-1-烯基、丁-1-烯基、戊-1-烯基、戊-1,4-二烯基等等。除非说明书中另有明确说明,烯基可已被如下基团之一任意取代:烷基、烯基、卤素、卤代烷基、卤代烯基、氰基、硝基、芳基、芳烷基、环烃基、环烃基烷基、杂环基、杂环基烷基、杂芳基、杂芳基烷基、-OR14、-OC(O)-R14、-N(R14)2、-C(O)R14、-C(O)OR14、-C(O)N(R14)2、-N(R14)C(O)OR16、-N(R14)C(O)R16、-N(R14)(S(O)tR16)(其中t为1至2)、-S(O)tOR16(其中t为1至2)、-S(O)tR16(其中t为0至2)和-S(O)tN(R14)2(其中t为1至2),其中每一R14独立地为氢、烷基、卤代烷基、环烃基、环烃基烷基、芳基、芳烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基;以及每一R16为烷基、卤代烷基、环烃基、环烃基烷基、芳基、芳烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基,且其中每一上述取代基是未取代的。
“C3-C12烯基”指含有3至12个碳原子的上述定义的烯基。C3-C12烯基可以如对烯基基团所定义的那样被任意取代。
“C2-C12烯基”指含有2至12个碳原子的上述定义的烯基。C2-C12烯基可以如对烯基基团的上述定义那样被任意取代。
“亚烷基”及“亚烷基链”指仅由碳和氢组成、不含不饱和且具有1至12个碳原子、优选1至8个碳原子、将分子的其余部分与基团相连接的直链或支链的二价烃链,例如亚甲基、亚乙基、亚丙基、正亚丁基等等。亚烷基链可以通过该链中的一个碳或通过该链中的任意二个碳与分子的其余部分和基团连接。亚烷基链可以被如下基团之一任意取代:烷基、烯基、卤素、卤代烯基、氰基、硝基、芳基、环烃基、杂环基、杂芳基、-OR14、-OC(O)-R14、-N(R14)2、-C(O)R14、-C(O)OR14、-C(O)N(R14)2、-N(R14)C(O)OR16、-N(R14)C(O)R16、-N(R14)(S(O)tR16)(其中t为1至2)、-S(O)tOR16(其中t为1至2)、-S(O)tR16(其中t为0至2)和-S(O)tN(R14)2(其中t为1至2),其中每一R14独立地为氢、烷基、卤代烷基、环烃基、环烃基烷基、芳基(被一或多个选自卤素或卤代烷基的基团任意取代)、芳烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基;以及每一R16为烷基、卤代烷基、环烃基、环烃基烷基、芳基、芳烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基,且其中除非另有说明,每一上述取代基是未取代的。
“亚烯基”及“亚烯基链”指仅由碳及氢组成、含有至少一个双键、且具有2至12个碳原子、将分子的其余部分与基团相连接的直链或支链二价烃链,例如亚乙烯基、亚丙烯基、正亚丁烯基等等。亚烯基链可通过单键与分子的其余部分连接以及可通过双键或单键与所述基团连接。亚烷基链与分子的其余部分的连接点以及其与基团残基的连接点可以是通过链中的一个碳或任二个碳。亚烯基链可已被如下基团之一任意取代:烷基、烯基、卤素、卤代烯基、氰基、硝基、芳基、环烃基、杂环基、杂芳基、-OR14、-OC(O)-R14、-N(R14)2、-C(O)R14、-C(O)OR14、-C(O)N(R14)2、-N(R14)C(O)OR16、-N(R14)C(O)R16、-N(R14)(S(O)tR16)(其中t为1至2)、-S(O)tOR16(其中t为1至2)、-S(O)tR16(其中t为0至2)和-S(O)tN(R14)2(其中t为1至2),其中每一R14独立地为氢、烷基、卤代烷基、环烃基、环烃基烷基、芳基(被一或多个选自卤基或卤代烷基的基团任意取代)、芳烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基;以及每一R16为烷基、卤代烷基、环烃基、环烃基烷基、芳基、芳烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基,且其中除非另有说明,每一上述取代基是未取代的。
“亚烷基桥”指仅由碳和氢组成、不含不饱和且具有1至12个碳原子、优选具有1至8个碳原子、连接相同环结构的两个不同碳的直链或支链的二价烃桥,例如亚甲基、亚乙基、亚丙基、正亚丁基等等。亚烷基桥可连接所述环结构中的任意两个碳。
“烷氧基”指通式-ORa的基团,其中Ra为上述定义的烷基。烷氧基基团的烷基部分可以如对烷基基团的上述定义那样被任意取代。
“C1-C6烷氧基”指含有1至6个碳原子的上述定义的烷氧基。C1-C6烷氧基基团的烷基部分可以如对烷基基团的上述定义那样被任意取代。
“C1-C12烷氧基”指含有1至12个碳原子的上述定义的烷氧基。C1-C12烷氧基基团的烷基部分可以如对烷基基团的上述定义那样被任意取代。
“C3-C12烷氧基”指含有3至12个碳原子的上述定义的烷氧基。C3-C12烷氧基的烷基部分可以如对烷基基团的上述定义那样被任意取代。
“烷氧基烷基”指通式-Ra-O-Ra的基团,其中每一Ra独立地为上述定义的烷基。氧原子可与任一烷基基团中的任意碳成键。烷氧基烷基基团的每一烷基部分可以如对烷基基团的上述定义那样被任意取代。
“C2-C12烷氧基烷基”指含2至12个碳原子的上述定义的烷氧基烷基基团。C2-C12烷氧基烷基基团的每一烷基部分可以如对烷基基团的上述定义那样被任意取代。
“C3烷氧基烷基”指含3个碳原子的上述定义的烷氧基烷基基团。C3烷氧基烷基基团的每一烷基部分可以如对上述烷基基团所定义的那样被任意取代。
“C3-C12烷氧基烷基”指含有3至12个碳原子的上述定义的烷氧基烷基基团。C3-C12烷氧基烷基基团的每一烷基部分可以如对烷基基团的上述定义那样被任意取代。
“烷基磺酰基”指通式-S(O)2Ra基团,其中Ra为上述定义的烷基。烷基磺酰基基团的烷基部分可以如对烷基基团的上述定义那样被任意取代。
“C1-C6烷基磺酰基”指具有1至6个碳原子的上述定义的烷基磺酰基基团。C1-C6烷基磺酰基基团可以如对烷基磺酰基基团的上述定义那样被任意取代。
“芳基”指仅由氢和碳组成、且含6至19个碳原子、优选6至10个碳原子的芳香族单环或多环烃环体系,其中所述环体系可以是部分饱和或完全饱和。芳基包括但不限于诸如芴基、苯基及萘基的基团。除非说明书中另有明确说明,术语“芳基”或前缀“芳-(ar-)”(如“芳烷基”)指包括被一个或多个取代基任意取代的芳基基团,所述取代基选自烷基、烯基、卤素、卤代烷基、卤代烯基、氰基、硝基、芳基、芳烷基、环烃基、环烃基烷基、杂环基、杂环基烷基、杂芳基、杂芳基烷基、-R15-OR14、-R15-OC(O)-R14、-R15-N(R14)2、-R15-C(O)R14、-R15-C(O)OR14、-R15-C(O)N(R14)2、-R15-N(R14)C(O)OR16、-R15-N(R14)C(O)R16、-R15-N(R14)(S(O)tR16)(其中t为1至2)、-R15-S(O)tOR16(其中t为1至2)、-R15-S(O)tR16(其中t为0至2)和-R15-S(O)tN(R14)2(其中t为1至2),其中每一R14独立地为氢、烷基、卤代烷基、环烃基、环烃基烷基、芳基、芳烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基;每一R15独立地为化学键或直链或支链的亚烷基链或亚烯基链;以及每一R16为烷基、卤代烷基、环烃基、环烃基烷基、芳基、芳烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基,且其中每一上述取代基是未取代的。
“芳烷基”指通式-RaRb的基团,其中Ra为上述定义的烷基且Rb为上述定义的一个或多个芳基基团,例如苄基、二苯基甲基等等。芳烷基基团的芳基部分可以如对芳基基团的上述定义那样被任意取代。芳烷基基团的烷基部分可以如对烷基基团的上述定义那样被任意取代。
“C7-C12芳烷基”指含有7至12个碳原子的上述定义的芳烷基基团。C7-C12芳烷基基团的芳基部分可以如对芳基基团的上述定义那样被任意取代。C7-C12芳烷基基团的烷基部分可以如对烷基基团的上述定义那样被任意取代。
“C7-C19芳烷基”指含有7至19个碳原子的上述定义的芳烷基基团。C7-C19芳烷基基团的芳基部分可以如对芳基基团的上述定义那样被任意取代。C7-C19芳烷基基团的烷基部分可以如对烷基基团的上述定义那样被任意取代。
“C13-C19芳烷基”指含有13至19个碳原子的上述定义的芳烷基基团。C13-C19芳烷基基团的芳基部分可以如对芳基基团的上述定义那样被任意取代。C13-C19芳烷基基团的烷基部分可以如对烷基基团的上述定义那样被任意取代。
“芳烯基”指通式-RcRb的基团,其中Rc为上述定义的烯基且Rb为上述定义的一个或多个芳基,其可如上所述被任意取代。芳烯基基团的芳基部分可以如对芳基基团的上述定义那样被任意取代。芳烯基基团的烯基部分可以如对烯基基团的上述定义那样被任意取代。
“芳氧基”指通式-ORb的基团,其中Rb为上述定义的芳基。芳氧基基团的芳基部分可以如上述定义那样被任意取代。
“芳基-C1-C6烷基”指通式-Rh-Ri的基团,其中Rh为具有1至6个碳的无支链的烷基基团,以及Ri为与该烷基基团的末端碳原子连接的芳基基团。
“环烃基”指仅由碳和氢原子组成、具有3至15个碳原子、优选具有3至12个碳原子、且为饱和或不饱和、通过单键与分子的其余部分连接的稳定非芳香族单环或双环烃基团,例如环丙基、环丁基、环戊基、环己基、环癸基(decalinyl)等等。除非说明书中明确说明,否则术语“环烃基”指包括被一个或多个取代基任意取代的环烃基,该取代基选自烷基、烯基、卤素、卤代烷基、卤代烯基、氰基、硝基、芳基、芳烷基、环烃基、环烃基烷基、杂环基、杂环基烷基、杂芳基、杂芳基烷基、-R15-OR14、-R15-OC(O)-R14、-R15-N(R14)2、-R15-C(O)R14、-R15-C(O)OR14、-R15-C(O)N(R14)2、-R15-N(R14)C(O)OR16、-R15-N(R14)C(O)R16、-R15-N(R14)(S(O)tR16)(其中t为1至2)、-R15-S(O)tOR16(其中t为1至2)、-R15-S(O)tR16(其中t为0至2)和-R15-S(O)tN(R14)2(其中t为1至2),其中每一R14独立地为氢、烷基、卤代烷基、环烃基、环烃基烷基、芳基、芳烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基;每一R15独立地为化学键或直链或支链的亚烷基链或亚烯基链;以及每一R16为烷基、卤代烷基、环烃基、环烃基烷基、芳基、芳烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基,且其中每一上述取代基是未取代的。
“C3-C6环烃基”指具有3至6个碳原子的上述定义的环烃基。C3-C6环烃基基团可以如对环烃基基团的上述定义那样被任意取代。
“C3-C12环烃基”指具有3至12个碳原子的上述定义的环烃基。C3-C12环烃基基团可以如对环烃基基团的上述定义那样被任意取代。
“环烃基烷基”指通式-RaRd基团,其中Ra为上述定义的烷基基团,且Rd为上述定义的环烃基基团。环烃基烷基基团的环烃基部分可以如对环烃基基团的上述定义那样被任意取代。环烃基烷基基团的烷基部分可以如对烷基基团的上述定义那样被任意取代。
“C4-C12环烃基烷基”指具有4至12个碳原子的上述定义的环烃基烷基基团。C4-C12环烃基烷基基团可以如对环烃基烷基基团的上述定义那样被任意取代。
“卤素”指溴、氯、氟或碘。
“卤代烷基”指被一个或多个上述定义的卤素基团取代的上述定义的烷基基团,例如三氟甲基、二氟甲基、三氯甲基、2,2,2-三氟乙基、1-氟甲基-2-氟乙基、3-溴-2-氟丙基、1-溴甲基-2-溴乙基等等。卤代烷基基团的烷基部分可以如对烷基基团的上述定义那样被任意取代。
“卤代烯基”指被一个或多个上述定义的卤素基团取代的上述定义的烯基基团,例如2-溴乙烯基、3-溴丙-1-烯基等等。卤代烯基基团的烯基部分可以如对烯基基团的上述定义那样被任意取代。
“杂环基”指由碳原子和1至5个选自氮、氧和硫的杂原子组成的稳定的3至18元非芳香族环基团。为了本发明的目的,所述杂环基可为单环、双环、三环或四环环体系,其可包括稠合环体系或桥环体系,且所述杂环基中的氮、碳或硫原子可任选地被氧化;氮原子可以任选地被季铵化;且杂环基基团可以部分饱和或全部饱和。这类杂环基的实例包括但不限于二氧环戊基、十氢异喹啉基、咪唑啉基、咪唑烷基、异噻唑烷基、异噁唑烷基、吗啉基、八氢吲哚基、八氢异吲哚基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、噁唑烷基、哌啶基、哌嗪基、4-哌啶酮基、吡咯烷基、吡唑烷基、噻唑烷基、四氢呋喃基、三噻烷基、四氢吡喃基、硫代吗啉基、噻吗啉基、1-氧代-硫代吗啉基和1,1-二氧代-硫代吗啉基。除非说明书中另有明确说明,否则术语“杂环基”指包括被一或多个取代基任意取代的上述定义的杂环基,该取代基选自烷基、烯基、卤素、卤代烷基、卤代烯基、氰基、氧代、硫代、硝基、芳基、芳烷基、环烃基、环烃基烷基、杂环基、杂环基烷基、杂芳基、杂芳基烷基、-R15-OR14、-R15-OC(O)-R14、-R15-N(R14)2、-R15-C(O)R14、-R15-C(O)OR14、-R15-C(O)N(R14)2、-R15-N(R14)C(O)OR16、-R15-N(R14)C(O)R16、-R15-N(R14)(S(O)tR16)(其中t为1至2)、-R15-S(O)tOR16(其中t为1至2)、-R15-S(O)tR16(其中t为0至2)和-R15-S(O)tN(R14)2(其中t为1至2),其中每一R14独立地为氢、烷基、烯基、卤代烷基、环烃基、环烃基烷基、芳基、芳烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基;每一R15独立地为化学键或直链或支链的亚烷基链或亚烯基链;以及每一R16为烷基、烯基、卤代烷基、环烃基、环烃基烷基、芳基、芳烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基,且其中每一上述取代基是未取代的。
“C3-C12杂环基”指具有3至12个碳的上述定义的杂环基。C3-C12杂环基可以如对杂环基基团的上述定义那样被任意取代。
“杂环基烷基”指通式-RaRe基团,其中Ra为上述定义的烷基基团且Re为上述定义的杂环基基团,且如果杂环基为含氮的杂环基,则该杂环基可在该氮原子处与烷基基团连接。杂环基烷基基团的烷基部分可以如对烷基基团的上述定义那样被任意取代。杂环基烷基基团的杂环基部分可以如对杂环基基团的上述定义那样被任意取代。
“C3-C12杂环基烷基”指具有3至12个碳的上述定义的杂环基烷基。C3-C12杂环基烷基基团可以如对杂环基烷基基团的上述定义那样被任意取代。
“杂芳基”指由碳原子和1至5个选自氮、氧和硫的杂原子组成的5至18元芳环基团。为了本发明的目的,所述杂芳基可为单环、双环、三环或四环环体系,其可包括稠合环体系或桥环体系;且杂芳基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化。实例包括但不限于氮杂基、吖啶基、苯并咪唑基、苯并噻唑基、苯并吲哚基、苯并噻二唑基、苯并萘并呋喃基、苯并噁唑基、苯并间二氧杂环戊烯基(benzodioxolyl)、苯并噁英基(benzodioxinyl)、苯并吡喃基、苯并吡喃酮基、苯并呋喃基、苯并呋喃酮基、苯并噻吩基(苯并苯硫基)、苯并三唑基、苯并[4,6]咪唑并[1,2-a]吡啶基、咔唑基、噌啉基、二苯并呋喃基、呋喃基、呋喃酮基、异噻唑基、咪唑基、吲哚基、吲唑基、异吲哚基、二氢吲哚基、异二氢吲哚基、中氮茚基、异噁唑基、萘啶基、噁二唑基、2-氧代氮杂基、噁唑基、环氧乙烷基、吩嗪基、吩噻嗪基、吩噁嗪基、2,3-二氮杂萘基、喋啶基、嘌呤基、吡咯基、吡唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、喹唑啉基、喹喔啉基、喹啉基、奎宁环基、异喹啉基、噻唑基、噻二唑基、三唑基、四唑基、三嗪基及苯硫基。除非说明书中另有明确说明,否则术语“杂芳基”旨在包括被一或多个取代基任意取代的上述定义的杂芳基基团,该取代基选自烷基、烯基、卤素、卤代烷基、卤代烯基、氰基、氧代、硫代、硝基、芳基、芳烷基、环烃基、环烃基烷基、杂环基、杂环基烷基、杂芳基、杂芳基烷基、-R15-OR14、-R15-OC(O)-R14、-R15-N(R14)2、-R15-C(O)R14、-R15-C(O)OR14、-R15-C(O)N(R14)2、-R15-N(R14)C(O)OR16、-R15-N(R14)C(O)R16、-R15-N(R14)(S(O)tR16)(其中t为1至2)、-R15-S(O)tOR16(其中t为1至2)、-R15-S(O)tR16(其中t为0至2)和-R15-S(O)tN(R14)2(其中t为1至2),其中每一R14独立地为氢、烷基、烯基、卤代烷基、环烃基、环烃基烷基、芳基、芳烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基;每一R15独立地为化学键或直链或支链的亚烷基链或亚烯基链;且每一R16为烷基、烯基、卤代烷基、环烃基、环烃基烷基、芳基、芳烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基,且其中每一上述取代基是未取代的。
“C1-C12杂芳基”指具有1至12个碳原子的上述定义的杂芳基。C1-C12杂芳基基团可以如对杂芳基基团的上述定义那样被任意取代。
“C5-C12杂芳基”指具有5至12个碳原子的上述定义的杂芳基。C5-C12杂芳基可以如对杂芳基基团的上述定义那样被任意取代。
“杂芳基烷基”指通式-RaRf基团,其中Ra为上述定义的烷基,且Rf为上述定义的杂芳基。杂芳基烷基基团的杂芳基部分可以如对杂芳基基团的上述定义那样被任意取代。杂芳基烷基基团的烷基部分可以如对烷基基团的上述定义那样被任意取代。
“C3-C12杂芳基烷基”指具有3至12个碳原子的上述定义的杂芳基烷基。C3-C12杂芳基烷基基团可以如对杂芳基烷基基团的上述定义那样被任意取代。
“杂芳基环烃基”指通式-RdRf基团,其中Rd为上述定义的环烃基基团,且Rf为上述定义的杂芳基基团。杂芳基环烃基基团的环烃基部分可以如对环烃基基团的上述定义那样被任意取代。杂芳基环烃基基团的杂芳基部分可以如对杂芳基基团的上述定义那样被任意取代。
“杂芳基烯基”指通式-RbRf基碳,其中Rb为上述定义的烯基基团,且Rf为上述定义的杂芳基基团。杂芳基烯基基团的杂芳基部分可以如对杂芳基基团的上述定义那样被任意取代。杂芳基烯基基团的烯基部分可以如对烯基基团的上述定义那样被任意取代。
“羟烷基”指通式-Ra-OH基团,其中Ra为上述定义的烷基。羟基可在该烷基基团内的任一碳上与该烷基连接。羟烷基基团的烷基部分可以如对烷基基团的上述定义那样被任意取代。
“C2-C12羟烷基”指含有2至12个碳原子的上述定义的羟烷基基团。C2-C12羟烷基基团的烷基部分可以如对烷基基团的上述定义那样被任意取代。
“C3-C12羟烷基”指含有3至12个碳原子的上述定义的羟烷基基团。C3-C12羟烷基基团的烷基部分可以如对烷基基团的上述定义那样被任意取代。
“C7-C12羟烷基”指含有7至12个碳原子的上述定义的羟烷基基团。C7-C12羟烷基基团的烷基部分可以如对烷基基团的上述定义那样被任意取代。
“羟烯基”指通式-Rc-OH基团,其中Rc为上述定义的烯基。羟基可以在该烯基基团内的任一碳上与该烯基连接。羟烯基基团的烯基部分可以如对烯基基团的上述定义那样被任意取代。
“C2-C12羟烯基”指含有2至12个碳原子的上述定义的羟烯基。C2-C12羟烯基基团的烯基部分可以如对烯基基团的上述定义那样被任意取代。
“C3-C12羟烯基”指含有3至12个碳原子的上述定义的羟烯基。C3-C12羟烯基基团的烯基部分可以如对烯基基团的上述定义那样被任意取代。
“羟基-C1-C6-烷基”指通式-Rh-OH基团,其中Rh为具有1至6个碳原子的直链烷基,且羟基与末端碳原子连接。
“三卤代烷基”指被三个上述定义的卤素基团取代的上述定义的烷基基团,例如三氟甲基。三卤代烷基基团的烷基部分可以如对烷基基团的上述定义那样被任意取代。
“C1-C6三卤代烷基”指具有1至6个碳原子的上述定义的三卤代烷基。C1-C6三卤代烷基可以如对三卤代烷基基团的上述定义那样被任意取代。
“三卤代烷氧基”指通式-ORg基团,其中Rg为上述定义的三卤代烷基。三卤代烷氧基基团的三卤代烷基部分可以如对三卤代烷基基团的上述定义那样被任意取代。
“C1-C6三卤代烷氧基”指具有1至6个碳原子的上述定义的三卤代烷氧基基团。C1-C6三卤代烷氧基基团可以如对三卤代烷氧基基团的上述定义那样被任意取代。
“多环结构”指包含2至4个环的多环环体系,其中所述环独立地选自上述定义的环烃基、芳基、杂环基或杂芳基。每一环烃基可以如对环烃基基团的上述定义那样被任意取代。每一芳基可以如对芳基基团的上述定义那样被任意取代。每一杂环基可以如对杂环基基团的上述定义那样被任意取代。每一杂芳基可以如对杂芳基基团的上述定义那样被任意取代。所述环可通过化学键与其它环连接,或者部分或所有环可彼此稠合。实例包括但不限于被芳基基团取代的环烃基基团;被芳基基团取代的环烃基基团,该芳基基团依次被另一芳基基团取代;等等。
“前药”指可在生理条件下或通过溶剂分解作用转化为本发明的生物活性化合物的化合物。因此,术语“前药”指药物可接受的本发明化合物的代谢前体。在对需要该前药的个体给药时,前药可以是无活性的,但在体内转化为本发明的活性化合物。前药通常在体内快速转化,产生本发明的母体化合物,例如通过在血液中的水解作用被快速转化。前药化合物通常在哺乳动物生物体中提供关于溶解度、组织相容性或延释的优点(参见Bundgard,H.,Design ofProdrugs(前药的设计)(1985),pp.7-9,21-24(Elsevier,Amsterdam))。
在Higuchi,T.,等人,“Pro-drugs as Novel Delivery Systems(前药作为新颖的输送系统),”A.C.S.Symposium Series,Vol.14和Edward B.Roche编辑的Bioreversible Carriers in Drug Design(医药设计中的生物可逆载体),American Pharmaceutical Association and Pergamon Press,1987年中提供了有关前药的讨论,本文将二者的全文引入作为参考。
术语“前药”还旨在包括当将该前药对哺乳动物个体给药时,在体内释放出本发明的活性化合物的任何共价键结合的载体。通过以这样一种方式修饰本发明化合物中存在的官能团来制备本发明化合物的前药,该方式为这种修饰或者以常规操作或者在体内被裂解为本发明的母体化合物。前药包含本发明的化合物,其中羟基、氨基或巯基基团与任意基团成键,在将本发明化合物的前药对哺乳动物给体给药时,所述成键的基团裂解以分别形成游离的羟基、游离的氨基或游离的巯基。前药的实例包括但不限于本发明化合物中醇或胺官能团的乙酸盐、甲酸盐及苯甲酸盐衍生物等。
“稳定的化合物”和“稳定的结构”旨在表示化合物足够稳定以便能够从反应混合物中分离出有用程度的纯度,并组方为有效治疗剂。
“哺乳动物”包含人类和家畜,如猫、狗、猪、牛、绵羊、山羊、马、兔等。
“任意的”或“任意地”指随后叙述的状况可能出现或可能不出现,且该叙述包括所述事件或情形出现的情况及不会出现的情况。例如,“任意取代的芳基”指所述芳基可能被取代或可能不被取代,且该叙述包括取代的芳基基团和未取代的芳基基团。
“药物可接受的载体、稀释剂或赋形剂”包括但不限于已经被美国食品药物管理局认可在人类或家畜中使用的可接受的任何佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、味道增强剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
“药物可接受的盐”包括酸加合盐及碱加合盐。
“药物可接受的酸加合盐”指保持游离碱的生物学有效性和性质的那些盐,所述酸加合盐在生物学或其它方面是合适的并且是使用无机酸或有机酸来形成的,无机酸例如但不限于盐酸、氢溴酸、硫酸、硝酸、磷酸等,有机酸例如但不限于乙酸、2,2-二氯乙酸、己二酸、海藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯甲酸、4-乙酰胺基苯甲酸、樟脑酸、樟脑-10-磺酸、癸酸、己酸、辛酸、碳酸、肉桂酸、柠檬酸、环己烷基氨基磺酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟基乙烷磺酸、甲酸、富马酸、粘酸、龙胆酸、葡庚糖酸、葡萄糖酸、葡萄糖醛酸、谷氨酸、戊二酸、2-氧代-戊二酸、甘油磷酸、羟乙酸、马尿酸、异丁酸、乳酸、乳糖醛酸、月桂酸、马来酸、苹果酸、丙二酸、扁桃酸、甲烷磺酸、黏酸、萘-1,5-二磺酸、萘-2-磺酸、1-羟基-2-萘甲酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、焦谷氨酸、丙酮酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、琥珀酸、酒石酸、硫氰酸、对甲苯磺酸、三氟乙酸、十一烯酸等。
“药物可接受的碱加合盐”指保持游离酸的生物学有效性和性质的那些盐,所述碱加合盐在生物学或其它方面是合适的。向游离酸中加入无机碱或有机碱来制备这些盐。由无机碱衍生的盐包括但不限于钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝盐等。优选的无机盐为铵、钠、钾、钙合镁盐。由有机碱衍生的盐包括但不限于伯胺、仲胺和叔胺的盐、包括天然存在的取代的胺在内的取代的胺的盐、环胺和碱性离子交换树脂的盐,例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、二乙醇胺、乙醇胺、二甲氨基乙醇、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、海巴明(hydrabamine)、胆碱、甜菜碱、苄胺(benethamine)、苯乙二胺(benzathine)、乙二胺、葡萄糖胺、甲基葡糖胺、可可碱、三乙醇胺、氨基丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等等的盐。特别优选的有机碱为异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因。
结晶化通常会产生本发明化合物的溶剂化物。本文所用的术语“溶剂化物”指包含带有一个或多个溶剂分子的一个或多个本发明化合物分子的聚集体。所述溶剂可为水,在这种情况下所述溶剂化物为水合物。或者,所述溶剂可能为有机溶剂。因此,本发明化合物可以以水合物的形式存在,包括一水合物、二水合物、半水合物、一倍半水合物、三水合物、四水合物等等,以及相应的溶剂化形式存在。本发明的化合物可为真正的溶剂化物,但在其它情况下,本发明的化合物可以仅保留不定的水或为水和某些不定溶剂的混合物。
“药物组合物”指本发明的化合物与本领域中通常接受的用于将所述生物活性化合物输送至诸如人等哺乳动物体内的介质所形成的制剂。这类介质包括所有药物可接受的载剂、稀释剂或赋形剂。
“治疗有效剂量”指当对哺乳动物给药时,优选对人给药时,本发明所述化合物足以有效治疗(如下所定义)哺乳动物的,优选人的SCD介导的疾病或疾病状态的量。根据所述化合物、疾病状态及其严重性以及待治疗的哺乳动物的年龄,组成“治疗有效之量”的本发明化合物的量将会不同,但本领域普通技术人员根据其自身知识和本公开可以常规地确定本发明化合物的量。
本文所用的“进行治疗”或“治疗”涵盖了在患有所关注的疾病或病症的哺乳动物,优选人类中治疗所关注的疾病或疾病状态,以及包括:
(i)预防疾病或疾病状态在哺乳动物中发生,尤其是当该哺乳动物易感于所述疾病状态,但尚未被诊断出患有该疾病状态;
(ii)抑制所述疾病或疾病状态,即阻止其发展;或
(iii)缓解所述疾病或疾病状态,即使所述疾病或疾病状态消退。
本文所用的术语“疾病”及“疾病状态”可相互交换使用,或可以是不同的,因为特殊的疾病或疾病状态可能没有已知的致病因子(因此不能用病因学解决),因此其不被公认为疾病而是为不合适的疾病状态或症状,其中临床医生已经鉴定出或多或少的特异系列症状。
本发明所述化合物或其药物可接受的盐可含一个或多个不对称中心,且因此产生对映异构体、非对映异构体和其它立体异构体形式,可根据绝对立体化学将其定义成(R)-或(S)-,或为氨基酸的(D)-或(L)-。本发明旨在包括所有的这类可能的异构体,以及其外消旋形式和光学纯形式。可使用手性合成子或手性试剂制备旋光的(+)和(-)、(R)-和(S)-、或(D)-和(L)-异构体,或使用诸如采用手性柱的HPLC等常规技术进行拆分。当本文所述的化合物含有烯双键或其它几何不对称中心时,除非另有明确说明,否则所述化合物旨在包括E和Z几何异构体。同样的,还旨在包括所有的互变异构形式。
“立体异构体”指由相同的键键合的相同原子构成的,但具有不可互换的不同三维结构的化合物。本发明包括多种立体异构体及其混合物,且包括“对映异构体”,对映异构体指分子彼此为不可叠加的镜像的两个立体异构体。
“互变异构体”指质子从分子的一个原子向同一分子的另一个原子上移动。本发明包括任何所述化合物的互变异构体。
本文所用的化学命名原则及结构图使用且依据Chemdraw 7.0.1版(可以从Cambridgesoft Corp.,Cambridge,MA获得)所用的化学命名特征。对于本文所用的复杂的化学名,在取代基相连接的基团前命名该取代基。例如,环丙基乙基包括具有环丙基取代基的乙基主链。化学结构图中,除了某些碳原子被假定键合足够的氢原子以完成配价以外,所有的键都是确定的。
例如,通式(I)化合物,其中y为1;G为-C(H)=C(H)-;K为N;L为-C(H)=且M为-N=,W为-N(H)C(O)-,V为-C(O)-;R4a、R6、R6a、R7、R7a、R8和R8a均为氢,R2为2-环丙基乙基且R3为2-三氟甲基,即如下式化合物:
在本文中命名为1′-(2-三氟甲基苯甲酰基)-1’,2’,3’,4’,5’,6’-六氢-[2,4’]联吡啶基-5-羧酸(2-环丙基乙基)酰胺。
本发明化合物的某些基团在本文中被描述为本发明化合物的两个部分间的连接。例如,在如下通式(I)中:
W被描述为例如-N(R1)C(O)-、-C(O)N(R1)-或-N(R1)C(O)N(R1)-;且V被描述为例如-C(O)-或-C(S)-。该叙述旨在将与R2基团相连接的W基团描述如下:R2-N(R1)C(O)-、R2-C(O)N(R1)-、或R2-N(R1)C(O)N(R1)-;且旨在将与R3基团相连接的V基团描述如下:-C(O)-R3或-C(S)-R3。换言之,鉴于上述通式(I),对W和V连接基团的叙述意味着由左边读到右边。
发明的实施方案
在上述的发明概述中描述的通式(I)化合物中,通式(I)化合物的一实施方案是其中K为N,即具有如下式(Ia)的化合物:
在该组化合物中,亚组化合物包括如下化合物,其中x和y均为1;
G为-C(R4)=C(R4)-;L为-C(R4)=且M为-N=或者L为-N=且M为-C(R4)=;V为-C(O)-;W为化学键、-N(R1)C(O)-、-C(O)N(R1)-、-OC(O)N(R1)-、-N(R1)C(O)N(R1)-、-O-、-N(R1)-、-S(O)t-(其中t为0、1或2)、-N(R1)S(O)p-(其中p为1或2)、-S(O)pN(R1)-(其中p为1或2)、-C(O)-、-OS(O)2N(R1)-、-OC(O)-、-C(O)O-或-N(R1)C(O)O-;每一R1独立地选自氢、C1-C12烷基、C2-C12羟烷基、C4-C12环烃基烷基和C7-C19芳烷基;R2选自C1-C12烷基、C2-C12烯基、C2-C12羟烷基、C2-C12羟烯基、C2-C12烷氧基烷基、C3-C12环烃基、C4-C12环烃基烷基、芳基、C7-C19芳烷基、C3-C12杂环基、C3-C12杂环基烷基、C1-C12杂芳基和C3-C12杂芳基烷基;R3选自C1-C12烷基、C2-C12烯基、C2-C12羟烷基、C2-C12羟烯基、C2-C12烷氧基烷基、C3-C12环烃基、C4-C12环烃基烷基、芳基、C7-C19芳烷基、C3-C12杂环基、C3-C12杂环基烷基、C1-C12杂芳基和C3-C12杂芳基烷基;每一R4独立地选自氢、氟、氯、C1-C12烷基、C1-C12烷氧基、卤代烷基、氰基、硝基或-N(R9)2;R4a为氢或与相邻碳之间的化学键;以及R6、R6a、R7、R7a、R8和R8a均独立地选自氢或C1-C3烷基。
在该亚组化合物中,一套化合物包括如下化合物,其中L为-C(R4)=且M为-N=。
在该套化合物中,亚套化合物包括如下化合物,其中V为-C(O)-。
该亚套化合物的具体实施方案包括但不限于以下化合物:
1’-(2-三氟甲基苯甲酰基)-1’,2’,3’,6’-四氢-[2,4’]联吡啶基-5-羧酸(2-环丙基乙基)酰胺;以及
1’-(2-三氟甲基苯甲酰基)-1’,2’,3’,4’,5’,6’-六氢[2,4’]联吡啶基-5-羧酸(2-环丙基乙基)酰胺。
本发明概述中上述的该组通式(Ia)化合物中,另一亚组化合物包括如下化合物,其中x和y均为1;G为-C(R4)=C(R4)-;L和N均为-N=且M为-C(R4)=;V为-C(O)-;W为化学键、-N(R1)C(O)-、-C(O)N(R1)-、-OC(O)N(R1)-、-N(R1)C(O)N(R1)-、-O-、-N(R1)-、-S(O)t-(其中t为0、1或2)、-N(R1)S(O)p-(其中p为1或2)、-S(O)pN(R1)-(其中p为1或2)、-C(O)-、-OS(O)2N(R1)-、-OC(O)-、-C(O)O-或-N(R1)C(O)O-;每一R1独立地选自氢、C1-C12烷基、C2-C12羟烷基、C4-C12环烃基烷基和C7-C19芳烷基;R2选自C1-C12烷基、C2-C12烯基、C2-C12羟烷基、C2-C12羟烯基、C2-C12烷氧基烷基、C3-C12环烃基、C4-C12环烃基烷基、芳基、C7-C19芳烷基、C3-C12杂环基、C3-C12杂环基烷基、C1-C12杂芳基和C3-C12杂芳基烷基;R3选自C1-C12烷基、C2-C12烯基、C2-C12羟烷基、C2-C12羟烯基、C2-C12烷氧基烷基、C3-C12环烃基、C4-C12环烃基烷基、芳基、C7-C19芳烷基、C3-C12杂环基、C3-C12杂环基烷基、C1-C12杂芳基和C3-C12杂芳基烷基;每一R4独立地选自氢、氟、氯、C1-C12烷基、C1-C12烷氧基、卤代烷基、氰基、硝基或-N(R9)2;R4a为氢或与相邻碳之间的化学键;以及R6、R6a、R7、R7a、R8和R8a均独立地选自氢或C1-C3烷基。
在该亚组化合物中,特定的实施方案包括但不限于以下化合物:6-[1-(2-三氟甲基苯甲酰基)哌啶-4-基]哒嗪-3-羧酸(2-环丙基乙基)酰胺。
在本文下述的制备和实施例中公开了包括上述那些特定实施方案在内的本发明特定实施方案的制备和用途。
在一实施方案,本发明所述方法涉及通过将有效剂量的本发明化合物给药,治疗和/或预防由硬脂酰CoA去饱和酶(SCD),尤其是人SCD(hSCD)介导的疾病,优选与血脂异常相关的疾病和脂质代谢紊乱,且尤其为与升高的脂质水平相关的疾病、心血管疾病、糖尿病、肥胖症、代谢综合征等等。
本发明还涉及含有本发明化合物的药物组合物。在一实施方案中,本发明涉及含有在药物可接受载体中的一定量的本发明化合物的药物组合物,该化合物的量为当对动物,优选哺乳动物,最优选人类患者给药时有效调节甘油三酯水平或治疗与血脂异常相关的疾病和脂质代谢紊乱。在该组合物的一实施方案中,在本发明所述化合物给药前以及本发明所述化合物以可有效降低脂质水平的量存在之前,患者具有升高的脂质水平,如升高的甘油三酯或胆固醇。
本发明化合物的效用和测试
本发明涉及化合物、药物组合物和使用该化合物及药物组合物来治疗和/或预防由硬脂酰CoA去饱和酶(SCD),尤其是人SCD(hSCD)介导的疾病的方法,优选为与血脂异常相关的疾病和脂质代谢紊乱,且尤其是与升高的血浆脂质水平相关的疾病、尤其是心血管疾病、糖尿病、肥胖症、代谢综合征等等,通过将有效剂量的SDC调节剂,尤其是抑制剂对需要这种治疗的患者给药来实施该方法。
通常,本发明提供了治疗患有与血脂异常相关的疾病和/或脂质代谢紊乱的患者或预防患者发展为与血脂异常相关的疾病和/或脂质代谢紊乱的方法,其中动物,尤其是人的脂质水平超出正常范围(即不正常的脂质水平,如升高的血浆脂质水平),尤其是高于正常水平的水平,优选其中所述脂质为脂肪酸,如游离的或复合的脂肪酸、甘油三酯、磷脂或胆固醇,例如其中LDL-胆固醇水平是升高的或HDL-胆固醇水平是降低的,或它们的任意组合,其中所述与脂质相关的疾病状态或疾病为SCD介导的疾病或疾病状态,所述方法包括将治疗有效剂量的本发明化合物或包含本发明化合物的药物组合物对动物给药,例如对哺乳动物,尤其是人类患者给药,其中该化合物调节SCD活性,优选调节人SCD1的活性。
本发明化合物调节,优选抑制人SCD酶的活性、尤其是人SCD1的活性。
采用下文实施例3中描述的分析,可确定本发明化合物在调节,尤其抑制SCD活性中的通常值。或者,可以在工业标准动物模型中建立化合物在治疗病症和疾病的通常值,所述工业标准动物模型用于证明化合物在治疗肥胖症、糖尿病或升高的甘油三酯或胆固醇水平或用于改善葡萄糖耐量的有效性。该模型包括Zucker肥胖fa/fa大鼠(可以从Harlan Sprague Dawley,Inc.(Indianapolis,Indiana)得到),或Zucker糖尿病肥胖大鼠(ZDF/GmiCrl-fa/fa)(可以从Charles River Laboratories(Montréal,Quebec)得到)。
本发明的化合物为δ-9去饱和酶的抑制剂且可用于治疗人类及其它生物体的疾病及病症,包括所有那些由异常的δ-9去饱和酶生物活性造成的、或可通过调节δ-9去饱和酶生物活性进行改善的人类疾病和病症。
如本文所定义的,SCD介导的疾病或疾病状态包括但不限于心血管疾病、血脂异常(包括但不限于血清甘油三酯水平紊乱、高甘油三酯血症、VLDL、HDL、LDL、脂肪酸脱饱和指数(例如18∶1/18∶0脂肪酸,或者本文其它处所定义的其它脂肪酸的比例)、胆固醇及总胆固醇、高胆固醇血症以及胆固醇病症(包括特征为有缺陷的胆固醇逆转运的病症)、家族性混合型高脂血症、冠状动脉疾病、动脉粥样硬化、心脏病、脑血管疾病(包括但不限于中风、缺血性中风及短暂性脑缺血发作(TIA))、外周血管性疾病以及缺血性视网膜病,或与之相关的疾病或疾病状态。在优选实施方案中,本发明化合物将提高患者的HDL水平和/或降低甘油三酯水平和及/或降低LDL或非HDL胆固醇水平。
SCD介导疾病或疾病状态还包括代谢综合征(包括但不限于血脂异常、肥胖症和胰岛素抵抗、高血压、微白蛋白血症、高尿酸血症和血液高凝状态)、X综合征、糖尿病、胰岛素抵抗、葡萄糖耐量减低、非胰岛素依赖性糖尿病、II型糖尿病、I型糖尿病、糖尿病并发症、体重异常(包括但不限于肥胖症、超重、恶病质和厌食症)、体重减轻、体重指数以及与瘦素相关的疾病。在优选实施方案中,本发明化合物用于治疗糖尿病和肥胖症。
本文所用的术语“代谢综合征”是用于描述疾病状态的公认的临床术语,该疾病状态包括II型糖尿病、葡萄糖耐量减低、胰岛素抵抗、高血压、肥胖症、增加的腹围、高甘油三酯血症、低HDL、高尿酸血症、血液高凝状态和/或微白蛋白血症的组合。
SCD介导的疾病或疾病状态还包括脂肪肝、肝脏脂肪变性、肝炎、非酒精性肝炎、非酒精性脂肪性肝炎(NASH)、酒精性肝炎、急性脂肪肝、妊娠脂肪肝、药物诱导的肝炎、红细胞生成性原卟啉症(erythrohepatic protoporphyria)、铁超负荷病症、遗传性血色病、肝纤维化、肝硬化、肝癌以及与其相关的疾病状态。
SCD介导的疾病或疾病状态还包括但不限于原发性高甘油三酯血症、续发于另一病症或疾病的高甘油三酯血症,未知或未指明病因学的高甘油三酯血症,或与之相关的疾病或疾病状态,所述另一病症或疾病例如高脂蛋白血症、家族性组织细胞性网状细胞增多症、脂蛋白脂酶缺乏症、载脂蛋白缺乏(如ApoCII缺乏或ApoE缺乏)等。
SCD介导的疾病或疾病状态还包括多不饱和脂肪酸(PUFA)异常的病症或皮肤病症,所述皮肤病症包括但不限于湿疹、痤疮、牛皮癣、瘢痕瘤瘢痕形成或预防、与黏膜的产生或诸如单不饱和脂肪酸、蜡酯等黏膜分泌物相关的疾病。
SCD介导的疾病或疾病状态还包括炎症、鼻窦炎、哮喘、胰腺炎、骨关节炎、类风湿性关节炎、囊性纤维化及月经前期综合征。
SCD介导的疾病或症状还包括但不限于癌、瘤形成、恶性肿瘤、转移、肿瘤(良性或恶性)、致癌作用、肝癌等,或与之相关的疾病或疾病状态。
SCD介导的疾病或疾病状态还包括需要增加瘦体重或精益肌肉量的疾病状态,例如需要通过强健肌肉来增强性能。本文还包括肌病和脂质肌病,如肉毒碱棕榈酰基转移酶缺乏症(CPTI或CPTII)。该治疗可用于人类及畜牧业,包括对牛、猪或禽类家畜或任何其它动物给药,以降低甘油三酯的产生和/或提供更加瘦的肉产品和/或更健康的动物。
SCD介导的疾病或疾病状态还包括神经学疾病、精神病学疾病、多发性硬化症、眼疾病以及免疫病症,或与之相关的疾病或疾病状态。
SCD介导的疾病或疾病状态还包括病毒疾病或病毒感染,或与之相关的疾病或疾病状态,所述病毒包括但不限于所有的正链RNA病毒、冠状病毒、SARS病毒、与SARS相关的冠状病毒、披膜病毒(Togaviruses)、微小核糖核酸病毒(Picornaviruses)、柯萨奇病毒、黄热病病毒、黄病毒科、α病毒(披盖病毒科),其包括风疹病毒、东方马脑炎病毒、西方马脑炎病毒、委内瑞拉马脑炎病毒、辛德比斯病毒、塞姆利基森林病毒、基孔肯亚病毒、欧利翁尼翁-尼翁病毒(O′nyong′nyongvirus)、罗斯河病毒、马亚罗病毒、α病毒;星状病毒科,其包括星状病毒、人类星状病毒;嵌杯样病毒科,其包括猪水疱疹病毒、诺沃克病毒、嵌杯样病毒、牛嵌杯样病毒、猪嵌杯样病毒、戊型肝炎;冠状病毒科,其包括冠状病毒、SARS病毒、鸟传染性支气管炎病毒、牛冠状病毒、犬冠状病毒、猫传染性腹膜炎病毒、人冠状病毒299E、人冠状病毒OC43、鼠肝炎病毒、猪流行性腹泻病毒、猪血凝性脑脊髓炎病毒、猪传染性肠胃炎病毒、大鼠冠状病毒、火鸡冠状病毒、兔冠状病毒、伯尔尼病毒、布里达病毒;黄病毒科,其包括丙型肝炎病毒、西尼罗病毒、黄热病病毒、圣路易斯脑炎病毒、登革热属、庚型肝炎病毒、流行性乙型脑炎病毒、墨莱溪谷脑炎病毒、中欧蜱传脑炎病毒、远东蜱传脑炎病毒、科萨努尔森林病毒、跳跃病病毒、波瓦桑病毒、鄂木斯克出血热病毒、Kumilinge病毒、Absetarov anzalova hypr病毒、伊列乌斯病毒、罗西奥脑炎病毒、Langat病毒、瘟病毒、牛病毒性腹泻、猪瘟病毒、Rio Bravo属、Tyuleniy属、Ntaya属、乌干达S属、Modoc属;小核糖核酸病毒科,其包括柯萨奇A病毒、鼻病毒、甲型肝炎病毒、脑心肌炎病毒、门戈病毒、ME病毒、人脊髓灰质炎病毒1、柯萨奇B病毒;马铃薯Y病毒科,其包括马铃薯Y病毒、黑麦草花叶病毒、大麦黄化花叶病毒。此外,还可以是由肝炎病毒、乙型肝炎病毒、丙型肝炎病毒、人类免疫缺陷病毒(HIV)引起的或与之相关的疾病或感染。可治疗的病毒感染包括病毒使用RNA中间体作为复制周期一部分的病毒感染(肝炎或HIV);另外,还可以是由诸如流感冒和副流感病毒等RNA负链病毒引起的或与之相关的疾病或感染。
本说明书中鉴定出的化合物通过诸如硬脂酰CoA去饱和酶1(SCD1)等δ-9去饱和酶来实现抑制多种脂肪酸的去饱和作用(例如硬脂酰CoA的C9-C10去饱和作用)。同样地,这些化合物抑制多种脂肪酸及其下游代谢产物的生成。这可能造成硬脂酰CoA或棕榈酰CoA及多种脂肪酸的其它上游前体的蓄积,这可能会造成负反馈圈,引起脂肪酸代谢全部改变。这些结果中的任何一种结果可能最终带来由化合物所提供的整体治疗益处。
通常,成功的SCD抑制治疗剂将满足部分或全部的以下标准。口服利用度应该等于或大于20%。动物模型效能小于约2mg/Kg、1mg/Kg或0.5mg/Kg,并且目标人类剂量为50至250mg/70Kg,但超出该范围的剂量也是可接受(“mg/Kg”指每千克进行给药个体体重的毫克化合物)。治疗指数(或毒性剂量与治疗剂量之比)应大于100。效价(以IC50值表示)应低于10μM,优选低于1μM,并且最优选低于50nM。IC50(“抑制浓度-50%”)是在SCD生物活性分析中,在特定时段内达到50%SCD活性抑制所需的化合物量的测量值。测定SCD酶活性,优选小鼠或人SCD酶活性的任何方法均可用于分析本发明方法中使用的化合物在抑制所述SCD活性中的活性。在15分钟微粒体分析中,本发明化合物表现出IC50优选低于10μM、低于5μM、低于2.5μM、低于1μM、低于750nM、低于500nM、低于250nM、低于100nM、低于50nM,并且最优选低于20nM。本发明化合物可以显示可逆抑制作用(即竞争性抑制),且优选不抑制其它铁结合蛋白。所需给药优选不应超过每天约一次或两次或不超过用餐次数。
使用Brownlie等人在supra.文献中描述的SCD酶和微粒体分析步骤可以容易地完成本发明化合物作为SCD抑制剂的鉴定。当在该分析中测试时,在测试化合物的浓度为10μM下,本发明化合物具有低于50%的剩余SCD活性,优选在测试化合物的浓度为10μM下,具有低于40%的剩余SCD活性,并且更优选在测试化合物的浓度为10μM下具有低于30%的剩余SCD活性,并且甚至更优选在测试化合物的浓度为10μM下具有低于20%的剩余SCD活性,因此表明本发明化合物为SCD活性的有效抑制剂。
这些结果为分析测试化合物和SCD之间的构效关系(SAR)提供了基础。某些R基团倾向于提供更有效的抑制性化合物。SAR分析是本领域技术人员的工具之一,如今可用于鉴别本发明化合物用做治疗剂使用的优选实施方案。
测试本文公开的化合物的其它方法对于本领域技术人员也是容易得到的。因而,此外,可以在体内完成所述接触。在一这样的实施方案中,通过将所述化学剂对患有与甘油三酯(TG)或极低密度脂蛋白(VLDL)相关病症的动物给药,并且随后检测所述动物的血浆甘油三酯水平的变化,从而鉴定可用于治疗与甘油三酯(TG)或极低密度脂蛋白(VLDL)相关病症的治疗剂,以完成步骤(a)中所述的接触。在该实施方案中,所述动物可以是人类,例如患有该病症并且需要治疗所述病症的人类患者。
在该体内方法的特定实施方案中,所述动物的SCD1活性的所述变化是活性降低,优选其中所述SCD1调节剂基本上不抑制δ-5去饱和酶、δ-6去饱和酶或脂肪酸合成酶的生物活性。
用于化合物评价的模型系统可以包括但不限于肝微粒体的使用,例如来自以高碳水化合物膳食维持的小鼠的肝微粒体,或来自包括患有肥胖症的人在内的人类供者的肝微粒体。还可以使用无限增殖细胞系,例如HepG2(来自人类肝脏)、MCF-7(来自人类乳腺癌)以及3T3-L1(来自小鼠脂细胞)。还可使用诸如小鼠原代肝细胞等原代细胞系以测试本发明化合物。当使用整个动物时,也可以使用用作原代肝细胞源的小鼠,其中所述小鼠以高碳水化合物膳食维持以增加微粒体中的SCD活性和/或提高血浆甘油三酯水平(即18∶1/18∶0之比);或者可以使用喂食正常膳食的小鼠或具有正常甘油三酯水平的小鼠。使用针对高甘油三酯血症设计的转基因小鼠的小鼠模型还可用作小鼠表型组数据库。兔子和仓鼠也可以用作动物模型,尤其是表达CEPT(胆固醇酯转运蛋白)的动物模型。
确定本发明化合物的体内有效性的另一合适方法是在所述化合物给药后通过测量个体的去饱和作用指数来间接测量其对SCD酶抑制作用的影响。本说明书中使用的“去饱和作用指数”指产物与来自给定组织样品的被测量的SCD酶底物的比。可以使用三种不同的方程18∶1n-9/18∶0(油酸比硬脂酸);16∶1n-7/16∶0(棕榈油酸比棕榈酸);和/或16∶1n-7+18∶1n-7/16∶0(测量16∶0去饱作用的全部反应产物与16∶0底物的比)来计算该指数。主要在肝脏或血浆甘油三酯中测量去饱和作用指数,但也可以在来自多种组织的其它选定的脂质部分中测量。一般说来,去饱和作用指数是用于血浆脂质谱的工具。
许多人类疾病和病症是异常的SCD1生物活性的结果,并且可以通过使用本发明的治疗剂调节SCD1生物活性而获得改善。
SCD表达的抑制还可以影响膜磷脂的脂肪酸组成以及甘油三酯和胆固醇酯的产生或水平。磷脂的脂肪酸组成最终决定膜的流动性,而对甘油三酯和胆固醇酯组成的作用会影响脂蛋白的代谢及肥胖。
在进行本发明的操作中,当然可以理解所指的特殊缓冲液、介质、试剂、细胞、培养条件等并不受限制,而应将其理解为包括本领域普通技术人员认为在此处讨论的特定背景下所关注的或有价值的所有相关的材料。例如,通常可以使用一种缓冲系统或培养基来代替另一种缓冲系统或培养基,并且仍可达到类似的但不相同的结果。本领域技术人员具有关于该体系的足够的知识和方法论,因而无需过度实验就能够进行这样的替代以最佳地实现使用本文公开的方法和操作所达到的目的。
本发明的药物组合物和给药
本发明还涉及含有本文公开的本发明化合物的药物组合物。在一实施方案中,本发明涉及在药物可接受载体中含有一定量的本发明化合物的组合物,所述量为当对动物,优选对哺乳动物,最优选对人类患者给药时,该化合物有效调节甘油三酯水平或治疗与血脂异常相关的疾病和脂质代谢紊乱。在该组合物的一实施方案中,在本发明所述化合物给药以及本发明化合物以有效降低所述脂质水平的量存在之前,所述患者具有升高的脂质水平,例如升高的甘油三酯或胆固醇。
本文使用的药物组合物还含有包括任何合适的稀释剂或赋形剂在内的药物可接受的载体,所述药物可接受的载体包括本身并不诱导产生对接受所述组合物的个体有害的抗体的药剂,并且可以给药而不会有不适当的毒性。药物可接受的载体包括但不限于液体,例如水、盐水、甘油和乙醇等。REMINGTON′S PHARMACEUTICAL SCIENCES(Mack Pub.Co.,N.J.current edition)中有药物可接受的载体、稀释剂以及其它赋形剂的详细讨论。
本领域技术人员知道如何确定用于治疗本文所关注的疾病和病症的化合物的适合剂量。通常基于动物研究的初步证据,通过关于人类的剂量范围的研究来确定治疗剂量。剂量必须足以达到期望的治疗效果而又不对患者造成不期望的副作用。对于动物,优选剂量范围为0.001mg/Kg至10,000mg/Kg,包括0.5mg/Kg、1.0mg/Kg和2.0mg/Kg,但超出该范围的剂量仍然是可以接受的。给药方案可以是每天一次或两次,但更多或更少的给药次数也是令人满意的。
本领域技术人员对确定给药方法(口服、静脉、吸入、皮下等)、剂型、合适的药物赋形剂以及与将化合物输送至需要治疗的个体的相关的其它物质也是熟悉的。
在本发明的另一用途中,出于对比目的,可以将本发明的化合物作为示例性试剂用于体外或体内研究,以寻找也可用于治疗或预防本文公开的多种疾病的其它化合物。
本发明化合物的制备
应当理解,在以下说明中,只有当取代基的组合和/或所述通式的变体可以得到稳定的化合物时,这类取代基的组合和/或所述通式的变体才是允许的。
本领域技术人员可以理解,在下所述的方法中,中间体化合物的官能团可能需要被适当的保护基保护。这样的官能团包括羟基、氨基、巯基和羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等等。合适的氨基、咪基和胍基保护基包括叔丁氧基羰基、苄氧基羰基等等。合适的巯基保护基包括-C(O)-R”(其中R”是烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧酸保护基包括烷基、芳基或芳烷基酯类。
根据本领域技术人员公知的和本文描述的标准技术可以引入或除去保护基。
Green,T.W.和P.G.M.Wutz,Protective Groups in Organic Synthesis(有机合成中的保护基)(1999),3rd Ed.,Wiley中详细地描述了保护基的用途。所述保护基还可以是聚合物树脂,例如Wang树脂或2-氯三苯甲基氯树脂。
本领域技术人员还可以理解,虽然本发明化合物的这些被保护的衍生物本身可能不具有药物活性,但是将其对哺乳动物给药并且随后在体内代谢以形成具有药物活性的本发明化合物。因此,这样的衍生物可被称之为“前药”。本发明化合物的所有前药均被包括在本发明的范围内。
以下反应方案说明了制备本发明所述化合物的方法。应该理解,本领域技术人员可以通过类似的方法或通过本领域技术人员已知的方法制备这些化合物。通常,可由诸如Sigma Aldrich、Lancaster Synthesis,Inc.,、Maybridge、Matrix Scientific、TCI和Fluorochem USA等来源获得起始组分,或者根据本领域技术人员已知的来源合成起始组分(例如参见Advanced Organic Chemistry:Reactions,Mechanisms,and Structure(高等有机化学:反应、机理及结构),5th edition(Wiley,December2000)),或者如本发明所述制备起始组分。除非另有明确定义,R1、R2、R3、R4、R6、R7、R7a、R8、R8a和V均如说明书中所定义的。PG代表保护基,如BOC、苄基等。
通常,可根据反应方案1中所述的一般操作合成本发明的通式(I)化合物,其中G为-C(R4)=C(R4)-;W为-N(R1)C(O)-;K为N且V为-C(O)-)。
反应方案1
可在诸如但不限于二异丙基乙胺、1-羟基-1H-苯并三唑和1-乙基-3-(3-二甲氨基丙基)碳二亚胺的碱存在下,在诸如但不限于二氯甲烷的溶剂中通过与适宜的胺反应,由羧酸101合成酰胺102。或者,可通过101的酰氯衍生物与适宜的胺反应来制备酰胺102。该反应可在诸如但不限于二异丙基乙胺的碱存在下,在诸如但不限于二氯甲烷的溶剂中进行。在诸如但不限于四氢呋喃的溶剂中,用诸如但不限于二异丙基酰胺锂的强碱和三氟甲磺酸酐或N-苯基三氟甲磺酰胺处理酮103,获得三氟甲磺酸酯化合物104。在钯催化下,在钯催化剂(例如四(三苯基膦)钯(O)和诸如但不限于乙酸钾的碱存在下,在诸如但不限于二甲基亚砜的溶剂中,可使三氟甲磺酸酯104与双(频哪醇基)二硼反应,获得硼酸酯105。可在钯催化(例如四(三苯基膦)钯(O))下,在诸如但不限于碳酸钠或碳酸钾的碱存在下,在诸如但不限于四氢呋喃或N,N’-二甲基甲酰胺的溶剂中进行氯化合物102与硼酸酯105的Suzuki偶联反应,获得所需的产物106。可通过使用如Green,T.W.和P.G.M.Wutz,有机合成中的保护基(Protective Groups in Organic Synthesis)(1999),3rd Ed.,Wiley中所述的酸性条件去除化合物1 06中的保护基,通常为叔丁氧基羰基,获得环化的胺107。可在诸如但不限于三乙胺的碱存在下,在诸如但不限于二氯甲烷的溶剂中,通过化合物107与酰氯的反应得到酰胺108。在钯炭的存在下,在诸如但不限于甲醇的溶剂中使108氢化,获得饱和的产物109。
虽然本领域技术人员能够根据上文公开的一般技术制备本发明化合物,但为方便起见,本说明书中另行提供了关于本发明化合物的合成技术的更具体细节。另外,合成中所用阿所有试剂和反应条件均为本领域技术人员已知的或可由平常的市售来源获得。
制备1
1’,2’,3’,6’-四氢[2,4’]联吡啶基-5-羧酸(2-环丙基乙基)酰胺的合成
A.在-78℃下向正丁基锂(18.8mL,30.113mmol)的THF(40.0mL)搅拌溶液中加入二异丙胺(4.2mL,30.113mmol)。将所得混合物在-78℃下搅拌10分钟。将溶于THF(40mL)中的4-氧代-哌啶-1-羧酸叔丁酯(4.000g,20.075mmol)加入该混合物中,并使整个体系在-78℃下再搅拌30分钟。在-78℃下将N-苯基三氟甲磺酰胺加入混合物中,并使溶液在3小时内升温至室温。将乙酸乙酯(200mL)加入混合物中,用水(100mL)、盐水(100mL)洗涤有机相,用MgSO4干燥,然后真空浓缩。通过柱层析,用20%乙酸乙酯和80%己烷的溶剂梯度进行洗脱来纯化粗产物,获得所需产物4-三氟甲磺酰基氧基-3,6-二氢-2H-吡啶-1-羧酸叔丁酯(4.000g,60%)。
B.向瓶中加入双(频哪醇基)二硼(1.550g,6.142mmol)、乙酸钾(1.650g,18.426mmol)、四(三苯基膦)钯(0.700g,0.558mmol),且用氮气冲洗内容物。将溶于DMSO(40mL)中的4-三氟甲磺酰基氧基-3,6-二氢-2H-吡啶-1-羧酸叔丁酯(1.850g,5.583mmol)溶液加入此混合物中。在80℃下使所得溶液搅拌过夜。向混合物中加入乙酸乙酯(100mL)并分离有机相,用水(50mL)、盐水(50mL)洗涤有机相,用MgSO4干燥,然后真空浓缩。通过柱层析,用20%乙酸乙酯和80%己烷的溶剂梯度进行洗脱来纯化粗产物,获得所需产物,4-(4,4,5,5-四甲基-[1,3,2]二氧杂戊硼烷-2-基)-3,6-二氢-2H-吡啶-1-羧酸叔丁酯(0.940g,54%)。
C.向6-氯烟酸(2-环丙基乙基)酰胺(0.650g,2.893mmol)的DMF(15mL)搅拌溶液中加入4-(4,4,5,5-四甲基-[1,3,2]二氧杂戊硼烷-2-基)-3,6-二氢-2H-吡啶-1-羧酸叔丁酯(1.075g,3.479mmol)、碳酸钾(1.202g,8.697mmol)和四(三苯基膦)钯(0.347g,0.300mmol)。使所得混合物加热至80℃,持续24小时,然后过滤。将乙酸乙酯(40.0mL)加入此混合物中,用水(20mL)、饱和NaCl(20mL)洗涤有机溶液,用MgSO4干燥,然后真空浓缩。通过柱层析纯化粗产物,获得所需产物,5-(2-环丙基乙基氨基甲酰基)-3’,6’-二氢-2’H[2,4’]联吡啶基-1’-羧酸叔丁酯(0.453g,42%)。
D.向5-(2-环丙基乙基氨基甲酰基)-3’,6’-二氢-2’H[2,4’]联吡啶基-1’-羧酸叔丁酯(0.338g,0.910mmol)的二氯甲烷(10mL)搅拌溶液中加入三氟乙酸(0.7mL)。使所得混合物在室温下搅拌6小时,然后用饱和Na2CO3水溶液(5mL)猝灭反应。用水(10mL)、饱和NaCl(10mL)洗涤有机相,用MgSO4干燥,接着真空浓缩。获得粗制的标题化合物,且未经进一步纯化就使用。
由以下(但不限于)实施例示例性说明本发明化合物的合成。
实施例1
1’-(2-三氟甲基苯甲酰基)-1’,2’,3’,6’-四氢[2,4’]联吡啶基-5-羧酸(2-环丙基乙基)酰胺的合成
向1’,2’,3’,6’-四氢[2,4’]联吡啶基-5-羧酸(2-环丙基乙基)酰胺(0.050g,0.184mmol)的二氯甲烷(5.0mL)搅拌溶液中加入2-(三氟甲基)苯甲酰氯(32μL,0.203mmol)和三乙胺(31μL,0.203mmol)。使所得混合物在室温下搅拌30分钟。用水(5mL)、饱和NaCl(5mL)洗涤有机层,用gSO4干燥,然后真空浓缩。通过柱层析纯化粗产物,获得纯的标题化合物,收率42%(0.453g)。1H NMR(300MHz,CDCl3)δ8.88(s,1H),8.09(d,J=8.3Hz,1H),7.73-7.67(m,1H),7.63-7.51(m,3H),7.46-7.41(m,1H),7.38-7.32(m,1H),6.77(s,1H),6.49-6.43(m,1H),4.70-4.43(m,1H),4.33-4.26(m,1H),4.15-4.06(m,1H),3.96-3.88(m,1H),3.56-3.49(dd,J=6.7和6.3Hz,2H),3.47-3.30(m,2H),2.76-2.60(m,2H),1.54-1.47(dd,J=6.8和7.0Hz,2H),0.74-0.66(m,1H),0.49-0.44(m,2H),0.10-0.045(m,2H).13C NMR(75MHz,CDCl3)δ167.7,165.3,158.8,147.2,135.6,134.7,132.3,129.3,128.6,127.2,127.1,125.4,124.3,118.6,60.4,47.1,43.9,42.3,40.4,34.3,25.9,8.6,4.2.MS(ES+)m/z444.0(M+1)。
实施例2
1’-(2-三氟甲基苯甲酰基)-1’,2’,3’,4’,5’,6’-六氢[2,4’]联吡啶基-5-羧酸(2-环丙基乙基)酰胺的合成
向1’-(2-三氟甲基苯甲酰基)-1’,2’,3’,6’-四氢[2,4’]联吡啶基-5-羧酸(2-环丙基乙基)酰胺(0.030g,0.068mmol)的甲醇(5mL)搅拌溶液中加入Pd/C(0.010g,12mmol%)。将混合物在氢气氛中放置24小时,再用硅藻土过滤。真空浓缩滤液。通过柱层析纯化粗产物,获得标题化合物,收率50%(0.015g)。1H NMR(300MHz,CDCl3)δ8.91(s,1H),8.12-8.08(m,1H),7.71-7.67(m,1H),7.60-7.47(m,2H),7.38(d,J=7.5Hz,1H),7.31-7.22(m,1H),6.62(s,1H),4.95-4.85(m,1H),3.55-3.41(m,3H),3.18-2.84(m,3H),2.07-2.02(m,1H),1.92-1.65(m,2H),1.52-1.45(dd,J=6.9和7.0Hz,2H),0.71-0.66(m,1H),0.46-0.44(m,2H),0.07-0.04(m,2H).13C NMR(CDCl3,75MHz)δ167.4,166.0,165.2,147.1,146.9,136.6,136.5,132.3,132.2,129.1,127.2,121.1,120.8,47.4,44.0,41.8,40.4,34.3,31.5,30.7,8.6,4.2。MS(ES+)m/z446.1(M+1)。
实施例3
使用小鼠肝微粒体测定测试化合物的硬脂酰CoA去饱和酶抑制活性
使用SCD酶和Brownlie等人的PCT公开专利申请WO 01/62954中所述的微粒体分析方法可以容易地实施本发明化合物作为SCD抑制剂的鉴定。
小鼠肝微粒体的制备
经轻度氟烷(矿物油中含15%氟烷)麻醉的以高碳水化合物低脂膳食喂饲的雄性ICP小鼠在高酶活性期间通过放血使其死亡。立即用冷的0.9%NaCl溶液洗涤肝脏,称重并用剪刀切碎。除非另有说明,所有操作均在4℃下进行。将肝脏在含0.25M蔗糖、62mM磷酸钾缓冲液(pH7.0)、0.15M KCl、1.5mM N-乙酰基半胱氨酸、5mM MgCl2和0.1mMEDTA的溶液(1∶3w/v)中,采用4冲程的Potter-Elvehjem组织匀浆器将肝脏匀浆化。将均浆在10,400×g下离心20分钟以除去粒线体和细胞碎片。上清液经3-层纱布过滤并在105,000×g下离心60分钟。用小的玻璃/特氟纶均浆器使微粒体片状沉淀物缓慢地再悬浮于相同的匀浆化溶液中,且储存在-70℃下。经过酶评价不存在粒线体污染。使用胎牛血清蛋白作为标准测量蛋白质浓度。
用测试化合物孵育小鼠肝脏微粒体
通过将2mg微粒体蛋白加入到含0.20μCi底物脂肪酸(1-14C棕榈酸)的预孵育管中使开始反应,微粒体蛋白在1.5ml匀浆化溶液中的最终浓度为33.3μM,该匀浆化溶液含42mM NaF、0.33mM烟酰胺、1.6mMATP、1.0mM NADH、0.1mM辅酶A和10μM浓度的测试化合物。将该试管剧烈地呈涡旋形振荡,并且在振荡水浴(37℃)中孵育15分钟后,终止反应并分析脂肪酸。
如下分析脂肪酸:用10%KOH使反应混合物皂化,获得游离的脂肪酸,并在甲醇中用BF3使其进一步甲基化。使用Hewlett Packard 1090,Series II色谱仪,通过高效液相色谱(HPLC)分析脂肪酸甲酯,该色谱仪配备有设定在205nm的二极管阵列检测器、带有固体闪烁盒(对于14C-检测,效率为97%)的放射性同位素检测器(Model 171,Beckman,CA),以及与带有μBondapak C-18(Beckman)插入物的前置柱相连接的反相ODS(C-18)Beckman柱(250mm×4.6mm id.;粒度μm)。以1ml/min的流速,用乙腈/水(95∶5v/v)等度分离脂肪酸甲酯,且通过与可靠标准比较进行鉴定。或者,可通过毛细管柱气相色谱(GC)或薄层色谱(TLC)分析脂肪酸甲酯。
本领域技术人员应了解对该分析可进行多种修改,这些修改可用于测定测试化合物对微粒体中的硬脂酰CoA去饱和酶活性的抑制。
当在该分析中进行测试时,本发明的代表性化合物显示了作为SCD抑制剂的活性。活性定义为在测试化合物的期望浓度下剩余的SCD酶活性的百分比。
本文将本说明书中提及的和/或申请数据表中所列的所有美国专利、美国专利申请公开、美国专利申请、外国专利、外国专利申请以及非专利出版物的全部内容引入作为参考。
由前述中可以了解,虽然为了示例性说明目的描述了本发明的具体实施方案,但在不偏离本发明的精神和范围的条件下可进行各种修改。因此,本发明只受所附权利要求的限制。
Claims (18)
1.抑制人硬脂酰-CoA去饱和酶(hSCD)活性的方法,所述方法包括将hSCD源与通式(I)化合物、其立体异构体、其对映异构体或其互变异构体、其立体异构体的混合物、其药物可接受的盐或其前药相接触,
其中:
y为0、1、2或3;
G为-N(R4)-、-O-、-S(O)t-(其中t为0、1或2)、-C(R4)=或-C(R4)=C(R4)-;
K为N或C(R10);
L和M均独立地为-N=或-C(R4)=,其前提是当G为-C(R4)=或-C(R4)=C(R4)-时,L和M不同时为-C(R4)=;
V为-N(R1)-、-O-、-C(R10)2-、-C(O)-、-C(O)O-、-C(S)-、-C(O)N(R1)-、-S(O)t-(其中t为0、1或2)或-S(O)pN(R1)-(其中p为1或2),其前提是当K为N时,V不为-S-;
W为化学键、-N(R1)C(O)-、-C(O)N(R1)-、-OC(O)N(R1)-、-N(R1)C(O)N(R1)-、-O-、-N(R1)-、-S(O)t-(其中t为0、1或2)、-N(R1)S(O)p-(其中p为1或2)、-S(O)pN(R1)-(其中p为1或2)、-C(O)-、-OS(O)2N(R1)-、-OC(O)-、-C(O)O-或-N(R1)C(O)O-;
每-R1独立地选自氢、C1-C12烷基、C2-C12羟烷基、C4-C12环烃基烷基和C7-C19芳烷基;
R2选自C1-C12烷基、C2-C12烯基、C2-C12羟烷基、C2-C12羟烯基、C2-C12烷氧基烷基、C3-C12环烃基、C4-C12环烃基烷基、芳基、C7-C19芳烷基、C3-C12杂环基、C3-C12杂环基烷基、C1-C12杂芳基和C3-C12杂芳基烷基;
或R2为具有2至4个环的多环结构,其中所述环独立地选自环烃基、杂环基、芳基和杂芳基,且其中部分或所有的所述环可以彼此稠合;
R3选自C1-C12烷基、C2-C12烯基、C2-C12羟烷基、C2-C12羟烯基、C2-C12烷氧基烷基、C3-C12环烃基、C4-C12环烃基烷基、芳基、C7-C19芳烷基、C3-C12杂环基、C3-C12杂环基烷基、C1-C12杂芳基和C3-C12杂芳基烷基;
或R3为具有2至4个环的多环结构,其中所述环独立地选自环烃基、杂环基、芳基和杂芳基,且其中部分或所有的所述环可以彼此稠合;
每一R4独立的选自氢、氟、氯、C1-C12烷基、C1-C12烷氧基、卤代烷基、氰基、硝基或-N(R9)2;
或者两个相邻的R4基团与其所连接的碳一起可以形成芳基、杂芳基或杂环基环体系;
R4a为氢、氟、氯、C1-C12烷基、C1-C12烷氧基、卤代烷基、氰基、硝基或-N(R9)2;
或R4a为与相邻碳之间的化学键;
R6、R6a、R7、R7a、R8和R8a均独立地选自氢或C1-C3烷基;
或者R6与R6a一起、或R7与R7a一起、或R8与R8a一起为氧代基团,但前提是当V为-C(O)-时,R6与R6a一起或R8与R8a一起不形成氧代基团,而其余的R6、R6a、R7、R7a、R8和R8a均独立地选自氢或C1-C3烷基;
或者R6和R6a之一与R7、R7a、R8和R8a之一一起形成化学键或亚烷基桥,而其余的R6、R6a、R7、R7a、R8和R8a均独立地选自氢或C1-C3烷基;
每一R9独立地选自氢或C1-C6烷基;以及
R10独立地选自氢、氟、氯、C1-C12烷基或C1-C12烷氧基。
2.治疗哺乳动物的由硬脂酰-CoA去饱和酶(SCD)介导的疾病或疾病状态的方法,其中所述方法包括将治疗有效剂量的通式(I)化合物、其立体异构体、其对映异构体或其互变异构体、或其立体异构体的混合物、其药物可接受的盐或其前药对需要所述治疗的所述哺乳动物给药,
其中:
y为0、1、2或3;
G为-N(R4)-、-O-、-S(O)t-(其中t为0、1或2)、-C(R4)=或-C(R4)=C(R4)-;
K为N或C(R10);
L和M均独立地为-N=或-C(R4)=,其前提是当G为-C(R4)=或-C(R4)=C(R4)-时,L和M不同时为-C(R4)=;
V为-N(R1)-、-O-、-C(R10)2-、-C(O)-、-C(O)O-、-C(S)-、-C(O)N(R1)-、-S(O)t-(其中t为0、1或2)或-S(O)pN(R1)-(其中p为1或2),其前提是当K为N时,V不为-S-;
W为化学键、-N(R1)C(O)-、-C(O)N(R1)-、-OC(O)N(R1)-、-N(R1)C(O)N(R1)-、-O-、-N(R1)-、-S(O)t-(其中t为0、1或2)、-N(R1)S(O)p-(其中p为1或2)、-S(O)pN(R1)-(其中p为1或2)、-C(O)-、-OS(O)2N(R1)-、-OC(O)-、-C(O)O-或-N(R1)C(O)O-;
每一R1独立地选自氢、C1-C12烷基、C2-C12羟烷基、C4-C12环烃基烷基和C7-C19芳烷基;
R2选自C1-C12烷基、C2-C12烯基、C2-C12羟烷基、C2-C12羟烯基、C2-C12烷氧基烷基、C3-C12环烃基、C4-C12环烃基烷基、芳基、C7-C19芳烷基、C3-C12杂环基、C3-C12杂环基烷基、C1-C12杂芳基和C3-C12杂芳基烷基;
或R2为具有2至4个环的多环结构,其中所述环独立地选自环烃基、杂环基、芳基和杂芳基,且其中部分或所有的所述环可以彼此稠合;
R3选自C1-C12烷基、C2-C12烯基、C2-C12羟烷基、C2-C12羟烯基、C2-C12烷氧基烷基、C3-C12环烃基、C4-C12环烃基烷基、芳基、C7-C19芳烷基、C3-C12杂环基、C3-C12杂环基烷基、C1-C12杂芳基和C3-C12杂芳基烷基;
或R3为具有2至4个环的多环结构,其中所述环独立地选自环烃基、杂环基、芳基和杂芳基,且其中部分或所有的所述环可以彼此稠合;
每一R4独立地选自氢、氟、氯、C1-C12烷基、C1-C12烷氧基、卤代烷基、氰基、硝基或-N(R9)2;
或者两个相邻的R4基团与其所连接的碳一起可以形成芳基、杂芳基或杂环基环体系;
R4a为氢、氟、氯、C1-C12烷基、C1-C12烷氧基、卤代烷基、氰基、硝基或-N(R9)2;
或R4a为与相邻碳之间的化学键;
R6、R6a、R7、R7a、R8和R8a均独立地选自氢或C1-C3烷基;
或者R6与R6a一起、或R7与R7a一起、或R8与R8a一起为氧代基团,但前提是当V为-C(O)-时,R6与R6a一起或R8与R8a一起不形成氧代基团,而其余的R6、R6a、R7、R7a、R8和R8a均独立地选自氢或C1-C3烷基;
或者R6和R6a之一与R7、R7a、R8和R8a之一一起形成化学键或亚烷基桥,而其余的R6、R6a、R7、R7a、R8和R8a均独立地选自氢或C1-C3烷基;
每一R9独立地选自氢或C1-C6烷基;以及
R10独立地选自氢、氟、氯、C1-C12烷基或C1-C12烷氧基。
3.如权利要求2所述的方法,其中所述哺乳动物为人类。
4.如权利要求3所述的方法,其中所述疾病或疾病状态选自II型糖尿病、葡萄糖耐量减低、胰岛素抵抗、肥胖症、脂肪肝、非酒精性脂肪性肝炎、血脂异常和代谢综合征及上述的任意组合。
5.如权利要求4所述的方法,其中所述疾病或疾病状态为II型糖尿病。
6.如权利要求4所述的方法,其中所述疾病或疾病状态为肥胖症。
7.如权利要求4所述的方法,其中所述疾病或疾病状态为代谢综合征。
8.如权利要求4所述的方法,其中所述疾病或疾病状态为脂肪肝。
9.如权利要求4所述的方法,其中所述疾病或疾病状态为非酒精性脂肪性肝炎。
10.通式(I)化合物、其立体异构体、其对映异构体或其互变异构体、或其立体异构体的混合物、其药物可接受的盐或其前药,
其中:
y为0、1、2或3;
G为-N(R4)-、-O-、-S(O)t-(其中t为0、1或2)、-C(R4)=或-C(R4)=C(R4)-;
K为N或C(R10);
L和M均独立地为-N=或-C(R4)=,其前提是当G为-C(R4)=或-C(R4)=C(R4)-时,L和M不同时为-C(R4)=;
V为-N(R1)-、-O-、-C(R10)2-、-C(O)-、-C(O)O-、-C(S)-、-C(O)N(R1)-、-S(O)t-(其中t为0、1或2)、或-S(O)pN(R1)-(其中p为1或2),其前提是当K为N时,V不为-S-;
W为化学键、-N(R1)C(O)-、-C(O)N(R1)-、-OC(O)N(R1)-、-N(R1)C(O)N(R1)-、-O-、-N(R1)-、-S(O)t-(其中t为0、1或2)、-N(R1)S(O)p-(其中p为1或2)、-S(O)pN(R1)-(其中p为1或2)、-C(O)-、-OS(O)2N(R1)-、-OC(O)-、-C(O)O-或-N(R1)C(O)O-;
每一R1独立地选自氢、C1-C12烷基、C2-C12羟烷基、C4-C12环烃基烷基和C7-C19芳烷基;
R2选自C1-C12烷基、C2-C12烯基、C2-C12羟烷基、C2-C12羟烯基、C2-C12烷氧基烷基、C3-C12环烃基、C4-C12环烃基烷基、芳基、C7-C19芳烷基、C3-C12杂环基、C3-C12杂环基烷基、C1-C12杂芳基和C3-C12杂芳基烷基;
或R2为具有2至4个环的多环结构,其中所述环独立地选自环烃基、杂环基、芳基和杂芳基,且其中部分或所有的所述环可以彼此稠合;
R3选自C1-C12烷基、C2-C12烯基、C2-C12羟烷基、C2-C12羟烯基、C2-C12烷氧基烷基、C3-C12环烃基、C4-C12环烃基烷基、芳基、C7-C19芳烷基、C3-C12杂环基、C3-C12杂环基烷基、C1-C12杂芳基和C3-C12杂芳基烷基;
或R3为具有2至4个环的多环结构,其中所述环独立地选自环烃基、杂环基、芳基和杂芳基,且其中部分或所有的所述环可以彼此稠合;
每一R4独立地选自氢、氟、氯、C1-C12烷基、C1-C12烷氧基、卤代烷基、氰基、硝基或-N(R9)2;
或者两个相邻的R4基团与其所连接的碳一起可以形成芳基、杂芳基或杂环基环体系;
R4a为氢、氟、氯、C1-C12烷基、C1-C12烷氧基、卤代烷基、氰基、硝基或-N(R9)2;
或R4a为与相邻碳之间的化学键;
R6、R6a、R7、R7a、R8和R8a均独立地选自氢或C1-C3烷基;
或者R6与R6a一起、或R7与R7a一起、或R8与R8a一起为氧代基团,其前提是当V为-C(O)-时,R6与R6a一起或R8与R8a一起不形成氧代基团,而其余的R6、R6a、R7、R7a、R8和R8a均独立地选自氢或C1-C3烷基;
或者R6和R6a之一与R7、R7a、R8和R8a之一一起形成化学键或亚烷基桥,而其余的R6、R6a、R7、R7a、R8和R8a均独立地选自氢或C1-C3烷基;
每一R9独立地选自氢或C1-C6烷基;以及
R10独立地选自氢、氟、氯、C1-C12烷基或C1-C12烷氧基。
11.如权利要求10所述的化合物,其中K为N,即具有如下通式(Ia)的化合物:
12.如权利要求11所述的化合物,其中:
y为1;
G为-C(R4)=C(R4)-;
L为-C(R4)=且M为-N=或者L为-N=且M为-C(R4)=;
V为-C(O)-;
W为化学键、-N(R1)C(O)-、-C(O)N(R1)-、-OC(O)N(R1)-、-N(R1)C(O)N(R1)-、-O-、-N(R1)-、-S(O)t-(其中t为0、1或2)、-N(R1)S(O)p-(其中p为1或2)、-S(O)pN(R1)-(其中p为1或2)、-C(O)-、-OS(O)2N(R1)-、-OC(O)-、-C(O)O-或-N(R1)C(O)O-;
每一R1独立地选自氢、C1-C12烷基、C2-C12羟烷基、C4-C12环烃基烷基和C7-C19芳烷基;
R2选自C1-C12烷基、C2-C12烯基、C2-C12羟烷基、C2-C12羟烯基、C2-C12烷氧基烷基、C3-C12环烃基、C4-C12环烃基烷基、芳基、C7-C19芳烷基、C3-C12杂环基、C3-C12杂环基烷基、C1-C12杂芳基和C3-C12杂芳基烷基;
R3选自C1-C12烷基、C2-C12烯基、C2-C12羟烷基、C2-C12羟烯基、C2-C12烷氧基烷基、C3-C12环烃基、C4-C12环烃基烷基、芳基、C7-C19芳烷基、C3-C12杂环基、C3-C12杂环基烷基、C1-C12杂芳基和C3-C12杂芳基烷基;
每一R4独立地选自氢、氟、氯、C1-C12烷基、C1-C12烷氧基、卤代烷基、氰基、硝基或-N(R9)2;
R4a为氢或与相邻碳之间的化学键;以及
R6、R6a、R7、R7a、R8和R8a均独立地选自氢或C1-C3烷基。
13.如权利要求12所述的化合物,其中L为-C(R4)=且M为-N=。
14.如权利要求13所述的化合物,其中V为-C(O)-。
15.如权利要求14所述的化合物,其选自如下:
1’-(2-三氟甲基苯甲酰基)-1’,2’,3’,6’-四氢-[2,4’]联吡啶基-5-羧酸(2-环丙基乙基)酰胺;以及
1’-(2-三氟甲基苯甲酰基)-1’,2’,3’,4’,5’,6’-六氢[2,4’]联吡啶基-5-羧酸(2-环丙基乙基)酰胺。
16.如权利要求11所述的化合物,其中:
y为1;
G为-C(R4)=C(R4)-;
L和N均为-N=且M为-C(R4)=;
V为-C(O)-;
W为化学键、-N(R1)C(O)-、-C(O)N(R1)-、-OC(O)N(R1)-、-N(R1)C(O)N(R1)-、-O-、-N(R1)-、-S(O)t-(其中t为0、1或2)、-N(R1)S(O)p-(其中p为1或2)、-S(O)pN(R1)-(其中p为1或2)、-C(O)-、-OS(O)2N(R1)-、-OC(O)-、-C(O)O-或-N(R1)C(O)O-;
每一R1独立地选自氢、C1-C12烷基、C2-C12羟烷基、C4-C12环烃基烷基和C7-C19芳烷基;
R2选自C1-C12烷基、C2-C12烯基、C2-C12羟烷基、C2-C12羟烯基、C2-C12烷氧基烷基、C3-C12环烃基、C4-C12环烃基烷基、芳基、C7-C19芳烷基、C3-C12杂环基、C3-C12杂环基烷基、C1-C12杂芳基和C3-C12杂芳基烷基;
R3选自C1-C12烷基、C2-C12烯基、C2-C12羟烷基、C2-C12羟烯基、C2-C12烷氧基烷基、C3-C12环烃基、C4-C12环烃基烷基、芳基、C7-C19芳烷基、C3-C12杂环基、C3-C12杂环基烷基、C1-C12杂芳基和C3-C12杂芳基烷基;
每一R4独立地选自氢、氟、氯、C1-C12烷基、C1-C12烷氧基、卤代烷基、氰基、硝基或-N(R9)2;
每一R4a为氢或与相邻碳之间的化学键;
以及R6、R6a、R7、R7a、R8和R8a均独立地选自氢或C1-C3烷基。
17.如权利要求16所述的化合物,即为6-[1-(2-三氟甲基苯甲酰基)哌啶-4-基]哒嗪-3-羧酸(2-环丙基乙基)酰胺。
18.药物组合物,包括药物可接受的赋形剂或载体和治疗有效剂量的通式(I)化合物、其立体异构体、对映异构体或互变异构体、或其立体异构体的混合物、其药物可接受的盐或其前药:
其中:
y为0、1、2或3;
G为-N(R4)-、-O-、-S(O)t-(其中t为0、1或2)、-C(R4)=或-C(R4)=C(R4)-;
K为N或C(R10);
L和M均独立地为-N=或-C(R4)=,其前提是当G为-C(R4)=或-C(R4)=C(R4)-时,L和M不同时为-C(R4)=;
V为-N(R1)-、-O-、-C(R10)2-、-C(O)-、-C(O)O-、-C(S)-、-C(O)N(R1)-、-S(O)t-(其中t为0、1或2)、或-S(O)pN(R1)-(其中p为1或2),其前提是当K为N时,V不为-S-;
W为化学键、-N(R1)C(O)-、-C(O)N(R1)-、-OC(O)N(R1)-、-N(R1)C(O)N(R1)-、-O-、-N(R1)-、-S(O)t-(其中t为0、1或2)、-N(R1)S(O)p-(其中p为1或2)、-S(O)pN(R1)-(其中p为1或2)、-C(O)-、-OS(O)2N(R1)-、-OC(O)-、-C(O)O-或-N(R1)C(O)O-;
每一R1独立地选自氢、C1-C12烷基、C2-C12羟烷基、C4-C12环烃基烷基和C7-C19芳烷基;
R2选自C1-C12烷基、C2-C12烯基、C2-C12羟烷基、C2-C12羟烯基、C2-C12烷氧基烷基、C3-C12环烃基、C4-C12环烃基烷基、芳基、C7-C19芳烷基、C3-C12杂环基、C3-C12杂环基烷基、C1-C12杂芳基和C3-C12杂芳基烷基;
或R2为具有2至4个环的多环结构,其中所述环独立地选自环烃基、杂环基、芳基和杂芳基,且其中部分或所有的所述环可以彼此稠合;
R3选自C1-C12烷基、C2-C12烯基、C2-C12羟烷基、C2-C12羟烯基、C2-C12烷氧基烷基、C3-C12环烃基、C4-C12环烃基烷基、芳基、C7-C19芳烷基、C3-C12杂环基、C3-C12杂环基烷基、C1-C12杂芳基和C3-C12杂芳基烷基;
或R3为具有2至4个环的多环结构,其中所述环独立地选自环烃基、杂环基、芳基和杂芳基,且其中部分或所有的所述环可以彼此稠合;
每一R4独立地选自氢、氟、氯、C1-C12烷基、C1-C12烷氧基、卤代烷基、氰基、硝基或-N(R9)2;
或者两个相邻的R4基团与其所连接的碳一起可以形成芳基、杂芳基或杂环基环体系;
R4a为氢、氟、氯、C1-C12烷基、C1-C12烷氧基、卤代烷基、氰基、硝基或-N(R9)2;
或R4a为与相邻碳之间的化学键;
R6、R6a、R7、R7a、R8和R8a均独立地选自氢或C1-C3烷基;
或者R6与R6a一起、或R7与R7a一起、或R8与R8a一起为氧代基团,其前提是当V为-C(O)-时,R6与R6a一起或R8与R8a一起不形成氧代基团,而其余的R6、R6a、R7、R7a、R8和R8a均独立地选自氢或C1-C3烷基;
或者R6和R6a之一与R7、R7a、R8和R8a之一一起形成化学键或亚烷基桥,而其余的R6、R6a、R7、R7a、R8和R8a均独立地选自氢或C1-C3烷基;
每一R9独立地选自氢或C1-C6烷基;以及
R10独立地选自氢、氟、氯、C1-C12烷基或C1-C12烷氧基。
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-
2005
- 2005-09-20 JP JP2007532616A patent/JP5043668B2/ja not_active Expired - Fee Related
- 2005-09-20 TW TW094132542A patent/TW200626138A/zh unknown
- 2005-09-20 EP EP05812357A patent/EP1799667B1/en not_active Not-in-force
- 2005-09-20 AU AU2005286846A patent/AU2005286846A1/en not_active Abandoned
- 2005-09-20 WO PCT/US2005/033680 patent/WO2006034279A1/en active Application Filing
- 2005-09-20 CA CA002580762A patent/CA2580762A1/en not_active Abandoned
- 2005-09-20 US US11/575,638 patent/US7777036B2/en not_active Expired - Fee Related
- 2005-09-20 BR BRPI0515488-0A patent/BRPI0515488A/pt not_active IP Right Cessation
- 2005-09-20 MX MX2007003321A patent/MX2007003321A/es unknown
- 2005-09-20 AR ARP050103904A patent/AR051090A1/es unknown
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EP1799667A1 (en) | 2007-06-27 |
BRPI0515488A (pt) | 2008-07-29 |
EP1799667B1 (en) | 2013-03-20 |
MX2007003321A (es) | 2007-06-05 |
JP2008513496A (ja) | 2008-05-01 |
TW200626138A (en) | 2006-08-01 |
US7777036B2 (en) | 2010-08-17 |
AU2005286846A1 (en) | 2006-03-30 |
JP5043668B2 (ja) | 2012-10-10 |
AR051090A1 (es) | 2006-12-20 |
US20080015230A1 (en) | 2008-01-17 |
WO2006034279A1 (en) | 2006-03-30 |
CA2580762A1 (en) | 2006-03-30 |
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