CN101448816B - 作为11-β-羟类固醇脱氢酶1的抑制剂的哌啶基取代的吡咯烷酮类 - Google Patents
作为11-β-羟类固醇脱氢酶1的抑制剂的哌啶基取代的吡咯烷酮类 Download PDFInfo
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- CN101448816B CN101448816B CN2007800154205A CN200780015420A CN101448816B CN 101448816 B CN101448816 B CN 101448816B CN 2007800154205 A CN2007800154205 A CN 2007800154205A CN 200780015420 A CN200780015420 A CN 200780015420A CN 101448816 B CN101448816 B CN 101448816B
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- alkyl
- halogen
- chloro
- compound
- ylmethyl
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- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- WPGGHFDDFPHPOB-BBWFWOEESA-N mitiglinide Chemical compound C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)O)C1=CC=CC=C1 WPGGHFDDFPHPOB-BBWFWOEESA-N 0.000 description 1
- 229960003365 mitiglinide Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- BFYLULHOYZNWPC-UHFFFAOYSA-N n-[[4,5-dimethyl-1-[(2-methylphenyl)methyl]imidazol-2-yl]methyl]-2,4-dimethoxy-n-(3-methylbutyl)benzamide Chemical compound COC1=CC(OC)=CC=C1C(=O)N(CCC(C)C)CC1=NC(C)=C(C)N1CC1=CC=CC=C1C BFYLULHOYZNWPC-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 108091008725 peroxisome proliferator-activated receptors alpha Proteins 0.000 description 1
- 108091008765 peroxisome proliferator-activated receptors β/δ Proteins 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 229960002797 pitavastatin Drugs 0.000 description 1
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 208000024896 potassium deficiency disease Diseases 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 238000003822 preparative gas chromatography Methods 0.000 description 1
- 229960003912 probucol Drugs 0.000 description 1
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000022558 protein metabolic process Effects 0.000 description 1
- 108020000494 protein-tyrosine phosphatase Proteins 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229950008257 ragaglitazar Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229940047431 recombinate Drugs 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- XMSXOLDPMGMWTH-UHFFFAOYSA-N rivoglitazone Chemical compound CN1C2=CC(OC)=CC=C2N=C1COC(C=C1)=CC=C1CC1SC(=O)NC1=O XMSXOLDPMGMWTH-UHFFFAOYSA-N 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 231100000489 sensitizer Toxicity 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 229960002277 tolazamide Drugs 0.000 description 1
- OUDSBRTVNLOZBN-UHFFFAOYSA-N tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 229960001729 voglibose Drugs 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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Abstract
本发明公开了新颖的式I化合物,(I)具有1型11β-HSD拮抗剂活性,以及制备此类化合物的方法。在另一实施方案中,本发明公开了包含式I化合物的药物组合物,以及使用所述化合物和组合物治疗糖尿病、高血糖症、肥胖症、高血压、高脂血症、代谢综合征、以及与1型11β-HSD活性相关的其它病症的方法。
Description
本申请要求2006年4月28日提交的美国临时申请No.60/796,112的权益。
本发明涉及的是1型11-β-羟类固醇脱氢酶(“11-β-HSD1”)的抑制剂的化合物及其药物组合物,以及这些化合物和组合物在治疗人或动物机体中的用途,并涉及用于制备所述抑制剂的新型中间体。本发明化合物显示了有效和选择性的11-β-HSD1抑制作用,因此这类化合物可用于治疗对11-β-HSD1调节有响应的病症,如糖尿病、代谢综合征、认知障碍等。
作用于肝脏、脂肪组织和肌肉中的糖皮质激素类是葡萄糖、脂质和蛋白质代谢的重要调节剂。长期糖皮质激素过量与胰岛素抗性、内脏肥大、高血压和血脂异常相关,上述病症也代表了代谢综合征的经典标志。11-β-HSD1催化无活性的可的松向活性的氢化可的松的转化,并且与代谢综合征的发展有关连。在啮齿类和人类中的证据使11-β-HSD1与代谢综合征关联。证据表明在2型糖尿病患者中特异性抑制11-β-HSD1的药物将通过减少肝脏糖异生而降低血葡萄糖、减轻向心性肥胖、增加致动脉粥样硬化性脂蛋白表型(atherogenic lipoprotein phenotypes)、降低血压、以及减轻胰岛素抗性。肌肉中的胰岛素作用将增强,并且来自胰岛β细胞的胰岛素分泌也可增加。动物和人研究的证据也表明过量糖皮质激素损伤认知功能。近来的结果表明11-β-HSD1的失活在人和小鼠中都增强记忆功能。11-β-HSD抑制剂甘珀酸显示出在健康老年男性和2型糖尿病中改善认知功能,并且11-β-HSD1基因的失活在小鼠中阻止衰老诱发的损伤。最近已显示,用药物选择性抑制11-β-HSD1在小鼠中改善记忆保持。
近年来出现了大量报告抑制11-β-HSD1的药物的出版物。参见国际申请WO2004/056744,其公开了作为11-β-HSD抑制剂的金刚烷基乙酰胺类;国际申请WO2005/108360,其公开了作为11-β-HSD抑制剂的吡咯烷-2-酮和哌啶-2-酮衍生物,以及国际申请WO2005/108361,其公开了作为11-β-HSD抑制剂的金刚烷基吡咯烷-2-酮衍生物。虽然治疗了一定数量的与11-β-HSD1相关的疾病,当前的治疗具有一种或多种缺点,包括疗效差或不完全、不能接受的副作用和对于某些患者人群的禁忌症。因此,仍需要一种改良的治疗法,该治疗法使用可选择的或改良的抑制11-β-HSD1并治疗受益于11-β-HSD1抑制的疾病的药物。基于发现一类新化合物具有有效和选择性的抑制11-β-HSD1活性,本发明给本领域提供了贡献。在具体结构及其活性方面本发明是不同的。仍然需要治疗糖尿病、代谢综合征和认知障碍的新方法,本发明的目的是满足这些和其它需要。
本发明提供了结构上由式I代表的化合物:
或其药学可接受的盐,其中
Ra是-H、-(C1-C6)烷基、-(C3-C6)环烷基或苯基;
Rb是-(C1-C6)烷基、-(C3-C6)环烷基或苯基;
Rc是-(C1-C6)烷基、-(C3-C6)环烷基或苯基;
R1是-H、-卤素、-O-CH3(任选被1至3个卤素取代)或-CH3(任选被1至3个卤素取代);
R2是-H、-卤素、-O-CH3(任选被1至3个卤素取代)或-CH3(任选被1至3个卤素取代);
R3是-H或-卤素;
R4是-OH、-卤素、-氰基、-(C1-C4)烷基(任选被1至3个卤素取代)、-(C1-C6)烷氧基(任选被1至3个卤素取代)、-SCF3、-C(O)O(C1-C4)烷基、-O-CH2-C(O)NH2、-(C3-C8)环烷基、-O-苯基-C(O)O-(C1-C4)烷基、-CH2-苯基、-NHSO2-(C1-C4)烷基、-NHSO2-苯基(R21)(R21)、-(C1-C4)烷基-C(O)N(R10)(R11)、-C(O)N(R10)(R11)、
R5是
-H、-卤素、-OH、-CN、-(C1-C4)烷基(任选被1至3个卤素取代)、-C(O)OH、-C(O)O-(C1-C4)烷基、-C(O)-(C1-C4)烷基、-O-(C1-C4)烷基(任选被1至3个卤素取代)、-SO2-(C1-C4)烷基、-N(R8)(R8)、-苯基(R21)(R21)、-C(O)-NH-(C3-C6)环烷基,
其中m是1、2或3;
其中n是0、1或2,其中当n是0时,则“(CH2)n”是键;
R7是-H、-卤素或-(C1-C4)烷基(任选被1至3个卤素取代);
R8在每次出现时独立地是-H、-(C1-C6)烷基(任选被1至3个卤素取代)、-C(O)(C1-C6)烷基(任选被1至3个卤素取代)、-C(O)-(C3-C8)环烷基、-S(O2)-(C3-C8)环烷基或-S(O2)-(C1-C3)烷基(任选被1至3个卤素取代);
R9是-H或-卤素;
R10和R11各自独立地是-H或-(C1-C4)烷基,或R10和R11与它们相连接的氮一起形成哌啶基、哌嗪基或吡咯烷基;
R20在每次出现时独立地是-H或-(C1-C3)烷基(任选被1至3个卤素取代);
R21在每次出现时独立地是-H、-卤素或-(C1-C3)烷基(任选被1至3个卤素取代);
R22在每次出现时独立地是-H或-(C1-C6)烷基(任选被1至3个卤素取代);
和
R23在每次出现时独立地是-H、-(C1-C4)烷基或-C(O)O-(C1-C4)烷基。
本发明提供了式I的化合物,其可有效和选择性地抑制11-β-HSD1。本发明进一步提供了药物组合物,其包含式I的化合物或其药学盐和药学可接受的载体、稀释剂或赋形剂。此外,本发明提供了治疗代谢性综合症和相关病症的方法,该方法包括:给予需要的患者有效量的式I化合物或其药学可接受的盐。
在一个实施方案中,本发明提供了上面详细描述的式I化合物或其药学可接受的盐。同时,所有本发明化合物是有用的,某些化合物是特别令人感兴趣和优选的。下面的列表列出了几组优选的化合物。
在另一个实施方案中,本发明提供了结构上由下式代表的化合物:
或其药学可接受的盐,其中
Ra是-(C1-C6)烷基、-(C3-C6)环烷基或苯基;
Rb是-(C1-C6)烷基、-(C3-C6)环烷基或苯基;
Rc是-(C1-C6)烷基、-(C3-C6)环烷基或苯基;
R1是-H、-卤素、-O-CH3(任选被1至3个卤素取代)或-CH3(任选被1至3个卤素取代);
R2是-H、-卤素、-O-CH3(任选被1至3个卤素取代)或-CH3(任选被1至3个卤素取代);
R3是-H或-卤素;
R4是-OH、-卤素、-氰基、-(C1-C4)烷基(任选被1至3个卤素取代)、-(C1-C6)烷氧基(任选被1至3个卤素取代)、-SCF3、-C(O)O(C1-C4)烷基、-O-CH2-C(O)NH2、-(C3-C8)环烷基、-O-苯基-C(O)O-(C1-C4)烷基、-CH2-苯基、-NHSO2-(C1-C4)烷基、-NHSO2-苯基(R21)(R21)、-(C1-C4)烷基-C(O)N(R10)(R11)、-C(O)N(R10)(R11),
R5是-H、-卤素、-OH、-CN、-(C1-C4)烷基(任选被1至3个卤素取代)、-C(O)OH、-C(O)O-(C1-C4)烷基、-C(O)-(C1-C4)烷基、-O-(C1-C4)烷基(任选被1至3个卤素取代)、-SO2-(C1-C4)烷基、-N(R8)(R8)、-苯基(R21)(R21)、-C(O)-NH-(C3-C6)环烷基,
其中m是1、2或3;
其中n是0、1或2,且其中当n是0时,则“(CH2)n”是键;
R7是-H、-卤素或-(C1-C4)烷基(任选被1至3个卤素取代);
R8在每次出现时独立地是-H、-(C1-C6)烷基(任选被1至3个卤素取代)、-C(O)(C1-C6)烷基(任选被1至3个卤素取代)、-C(O)-(C3-C8)环烷基、-S(O2)-(C3-C8)环烷基或-S(O2)-(C1-C3)烷基(任选被1至3个卤素取代);
R9是-H或-卤素;
R10和R11各自独立地是-H或-(C1-C4)烷基,或R10和R11与它们相连接的氮一起形成哌啶基、哌嗪基或吡咯烷基;
R20在每次出现时独立地是-H或-(C1-C3)烷基(任选被1至3个卤素取代);
R21在每次出现时独立地是-H、-卤素或-(C1-C3)烷基(任选被1至3个卤素取代);
R22在每次出现时独立地是-H或-(C1-C6)烷基(任选被1至3个卤素取代);
和
R23在每次出现时独立地是-H、-(C1-C4)烷基或-C(O)O-(C1-C4)烷基。
在另一个实施方案中,本发明提供了结构上由式Ia代表的化合物:
或其药学可接受的盐,其中
Ra是-(C1-C3)烷基;Rb是-(C1-C3)烷基;Rc是-(C1-C3)烷基;
R1是-卤素;R2是-卤素;R3是-H或-卤素;
R4是-OH、-卤素、-氰基、-(C1-C4)烷基(任选被一至三个卤素取代)、-(C1-C6)烷氧基(任选被一至三个卤素取代)、-SCF3、-C(O)O(C1-C4)烷基、-O-CH2-C(O)NH2、-(C3-C8)环烷基、-O-苯基-C(O)O-(C1-C4)烷基、-CH2-苯基、-NHSO2-(C1-C4)烷基、-NHSO2-苯基(R21)(R21)、-(C1-C4)烷基-C(O)N(R10)(R11),
或,其中虚线表示与式Ia的R4位置的连接点;
R5是-H、-卤素、-OH、-CN、-(C1-C4)烷基(任选被1至3个卤素取代)、-C(O)OH、-C(O)O-(C1-C4)烷基、-C(O)-(C1-C4)烷基、-O-(C1-C4)烷基(任选被1至3个卤素取代)、-SO2-(C1-C4)烷基、-N(R8)(R8)、-苯基(R21)(R21)、-C(O)-NH-(C3-C6)环烷基,
其中m是1、2或3;
其中n是0、1或2,其中当n是0时,则“(CH2)n”是键;
R6是-H、-卤素、-CN或-(C1-C4)烷基(任选被1至3个卤素取代);
R7是-H、-卤素或-(C1-C4)烷基(任选被1至3个卤素取代);
R8在每次出现时独立地是-H、-(C1-C6)烷基(任选被1至3个卤素取代)、-C(O)(C1-C6)烷基(任选被1至3个卤素取代)、-C(O)-(C3-C8)环烷基或-S(O2)-(C1-C3)烷基(任选被1至3个卤素取代);
R9是-H或-卤素;
R20在每次出现时独立地是-H或-(C1-C3)烷基(任选被1至3个卤素取代);
R21在每次出现时独立地是-H、-卤素或-(C1-C3)烷基(任选被1至3个卤素取代);
R22在每次出现时独立地是-H或-(C1-C3)烷基(任选被1至3个卤素取代);
和
R23在每次出现时独立地是-H、-(C1-C3)烷基或-C(O)O-(C1-C4)烷基。
在另一个实施方案中,本发明提供了结构上由式Ia代表的化合物:
或其药学可接受的盐,其中
Ra是-(C1-C3)烷基;Rb是-(C1-C3)烷基;Rc是-(C1-C3)烷基;
R1是-氯、-氟或-溴;R2是-氯、-氟或-溴;R3是-H或-卤素;
R4是
R5是-H、-卤素、-OH、-CN、-(C1-C4)烷基(任选被1至3个卤素取代)、-C(O)OH、-C(O)O-(C1-C4)烷基、-C(O)-(C1-C4)烷基、-O-(C1-C4)烷基(任选被1至3个卤素取代)、-SO2-(C1-C4)烷基、-N(R8)(R8)、-苯基(R21)(R21)、-C(O)-NH-(C3-C6)环烷基,
其中m是1、2或3;
R6是-H、-卤素、-CN或-(C1-C4)烷基(任选被1至3个卤素取代);
R7是-H、-卤素或-(C1-C4)烷基(任选被1至3个卤素取代);
R8在每次出现时独立地是-H、-(C1-C6)烷基(任选被1至3个卤素取代)、-C(O)(C1-C6)烷基(任选被1至3个卤素取代)、-C(O)-(C3-C8)环烷基或-S(O2)-(C1-C3)烷基(任选被1至3个卤素取代);
R9是-H或-卤素;
R20在每次出现时独立地是-H或-(C1-C3)烷基(任选被1至3个卤素取代);
R21在每次出现时独立地是-H、-卤素或-(C1-C3)烷基(任选被1至3个卤素取代);
R22在每次出现时独立地是-H或-(C1-C3)烷基(任选被1至3个卤素取代);
和
R23在每次出现时独立地是-H、-(C1-C3)烷基或.C(O)O-(C1-C4)烷基。
在另一个实施方案中,本发明提供了结构上由式Ia代表的化合物:
或其药学可接受的盐,其中
Ra是-(C1-C3)烷基;Rb是-(C1-C3)烷基;Rc是-(C1-C3)烷基;
R1是-氯、-氟或-溴;R2是-氯、-氟或-溴;R3是-H或-卤素;
R4是
R5是-H、-卤素、-OH、-CN、-(C1-C4)烷基(任选被1至3个卤素取代)、一C(O)OH、-C(0)O-(C1-C4)烷基、-C(O)-(C1-C4)烷基、-O-(C1-C4)烷基(任选被1至3个卤素取代)、-SO2-(C1-C4)烷基、-N(R8)(R8)、-苯基(R21)(R21)、-C(O)-NH-(C3-C6)环烷基,
其中m是1、2或3;
R6是-H、-卤素、-CN或-(C1-C4)烷基(任选被1至3个卤素取代);
R7是-H、-卤素或-(C1-C4)烷基(任选被1至3个卤素取代);
R8在每次出现时独立地是-H、-(C1-C6)烷基(任选被1至3个卤素取代)、-C(O)(C1-C6)烷基(任选被1至3个卤素取代)、-C(O)-(C3-C8)环烷基或-S(O2)-(C1-C3)烷基(任选被1至3个卤素取代);
R9是-H或-卤素;
R20在每次出现时独立地是-H或-(C1-C3)烷基(任选被1至3个卤素取代);
R21在每次出现时独立地是-H、-卤素或-(C1-C3)烷基(任选被1至3个卤素取代);
R22在每次出现时独立地是-H或-(C1-C3)烷基(任选被1至3个卤素取代);
和
R23在每次出现时独立地是-H、-(C1-C3)烷基或-C(O)O-(C1-C4)烷基。
在另一个实施方案中,本发明提供了结构上由式Ia代表的化合物:
或其药学可接受的盐,其中
Ra是-(C1-C3)烷基;Rb是-(C1-C3)烷基;Rc是-(C1-C3)烷基;
R1是-氯、-氟或-溴;R2是-氯、-氟或-溴;R3是-H或-卤素;
R4是
R5是-H、-卤素、-(C1-C4)烷基(任选被1至3个卤素取代)、-C(O)OH、-C(O)O-(C1-C4)烷基、-C(O)-(C1-C4)烷基、-O-(C1-C4)烷基(任选被1至3个卤素取代)、-SO2-(C1-C4)烷基、-N(R8)(R8),
其中m是1、2或3;
R6是-H、-卤素、-CN或-(C1-C4)烷基(任选被1至3个卤素取代);
R7是-H、-卤素或-(C1-C4)烷基(任选被1至3个卤素取代);
R8在每次出现时独立地是-H、-(C1-C6)烷基(任选被1至3个卤素取代)、-C(O)(C1-C6)烷基(任选被1至3个卤素取代)、-C(O)-(C3-C8)环烷基或-S(O2)-(C1-C3)烷基(任选被1至3个卤素取代);
R9是-H或-卤素;
R20在每次出现时独立地是-H或-(C1-C3)烷基(任选被1至3个卤素取代);
R21在每次出现时独立地是-H、-卤素或-(C1-C3)烷基(任选被1至3个卤素取代);
R22在每次出现时独立地是-H或-(C1-C3)烷基(任选被1至3个卤素取代);
和
R23在每次出现时独立地是-H、-(C1-C3)烷基或-C(O)O-(C1-C4)烷基。
在另一个实施方案中,本发明提供了结构上由式Ia代表的化合物:
或其药学可接受的盐,其中
Ra是-(C1-C3)烷基;Rb是-(C1-C3)烷基;Rc是-(C1-C3)烷基;
R1是-氯、-氟或-溴;R2是-氯、-氟或-溴;R3是-H或-卤素;
R4是
R5是
R6是-H、-卤素、-CN或-(C1-C4)烷基(任选被1至3个卤素取代);
R7是-H、-卤素或-(C1-C4)烷基(任选被1至3个卤素取代);
R8在每次出现时独立地是-H、-(C1-C6)烷基(任选被1至3个卤素取代)、-C(O)(C1-C6)烷基(任选被1至3个卤素取代)、-C(O)-(C3-C8)环烷基或-S(O2)-(C1-C3)烷基(任选被1至3个卤素取代);
R9是-H或-卤素;
R20在每次出现时独立地是-H或-(C1-C3)烷基(任选被1至3个卤素取代);
R21在每次出现时独立地是-H、-卤素或-(C1-C3)烷基(任选被1至3个卤素取代);
R22在每次出现时独立地是-H或-(C1-C3)烷基(任选被1至3个卤素取代);
和
R23在每次出现时独立地是-H、-(C1-C3)烷基或-C(O)O-(C1-C4)烷基。
在另一个实施方案中,本发明提供了结构上由式Ia代表的化合物:
或其药学可接受的盐,其中
Ra是-(C1-C3)烷基;Rb是-(C1-C3)烷基;Rc是-(C1-C3)烷基;
R1是-氯、-氟或-溴;R2是-氯、-氟或-溴;R3是-H或-卤素;
R4是
R5是
R6是-H、-卤素、-CN或-(C1-C4)烷基(任选被1至3个卤素取代);
R7是-H、-卤素或-(C1-C4)烷基(任选被1至3个卤素取代);
R8在每次出现时独立地是-H、-(C1-C6)烷基(任选被1至3个卤素取代)、-C(O)(C1-C6)烷基(任选被1至3个卤素取代)、-C(O)-(C3-C8)环烷基或-S(O2)-(C1-C3)烷基(任选被1至3个卤素取代);
R9是-H或-卤素;
R20在每次出现时独立地是-H或-(C1-C3)烷基(任选被1至3个卤素取代);
R21在每次出现时独立地是-H、-卤素或-(C1-C3)烷基(任选被1至3个卤素取代);
R22在每次出现时独立地是-H或-(C1-C3)烷基(任选被1至3个卤素取代);
和
R23在每次出现时独立地是-H、-(C1-C3)烷基或-C(O)O-(C1-C4)烷基。
在另一个实施方案中,本发明提供了结构上由式Ia代表的化合物:
或其药学可接受的盐,其中
Ra是-(C1-C3)烷基;Rb是-(C1-C3)烷基;Rc是-(C1-C3)烷基;
R1是-氯、-氟或-溴;R2是-氯、-氟或-溴;R3是-H或-卤素;
R4是
R5是
其中m是1、2或3;
R6是-H、-卤素、-CN或-(C1-C4)烷基(任选被1至3个卤素取代);
R7是-H、-卤素或-(C1-C4)烷基(任选被1至3个卤素取代);和
R8在每次出现时独立地是-H、-(C1-C6)烷基(任选被1至3个卤素取代)、-C(O)(C1-C6)烷基(任选被1至3个卤素取代)、-C(O)-(C3-C8)环烷基或-S(O2)-(C1-C3)烷基(任选被1至3个卤素取代)。
本发明其它实施方案提供的是这样的,其中上文所述各个实施方案如以下选项所述进一步限定。特别地,以下各选项独立地与上文各实施方案组合,并且具体组合提供了另一实施方案,在其中选项中所示变量根据所述选项限定。
优选R1是-卤素。优选R1是-CH3。优选R1是-氯、氟或-溴。优选R1是-氯。优选R1是氟。优选R1是-溴。优选R2是-卤素。优选R2是-CH3。优选R2是氯、-氟或-溴。优选R2是-氯。优选R2是-氟。优选R2是-溴。优选R1是-氯,R2是-氯。优选R3是-H。优选R3是-卤素。优选R1和R2是氯,R3是氢。
优选R5是卤素、
优选R5是优选R5是卤素。优选R5是氯或氟。优选R6是-H。优选R6是-卤素。优选R6是-(C1-C4)烷基(任选被1至3个卤素取代)。优选R7是-H。优选R7是-卤素或-(C1-C4)烷基(任选被1至3个卤素取代)。优选R7是-卤素。优选R7是-(C1-C4)烷基(任选被1至3个卤素取代)。优选R8在每次出现时独立地是-H。优选R8在每次出现时独立地是-(C1-C3)烷基。优选R8在每次出现时独立地是-CH3。优选R9是-H。优选R9是-卤素。优选R7是-氟,R9是氟。
本发明的优选实施方案是式4-{(R)-3-[3,5-二氯-4′-(4-三氟甲基-哌啶-1-羰基)-联苯-4-基甲基]-2-氧代-吡咯烷-1-基}-哌啶-1-羧酸甲基酯和4-[(R)-3-(3,5-二氯-4′-氟-联苯-4-基甲基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸甲基酰胺的化合物。本发明的进一步实施方案是本文所描述的新型中间体制品,其可用于制备按照式I和本文实施方案所描述的11-β-HSD1抑制剂。本发明的进一步实施方案是本文所描述的新型中间体制品,其可用于制备4-{(R)-3-[3,5-二氯-4′-(4-三氟甲基-哌啶-1-羰基)-联苯-4-基甲基]-2-氧代-吡咯烷-1-基}-哌啶-1-羧酸甲基酯和4-[(R)-3-(3,5-二氯-4′-氟-联苯-4-基甲基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸甲基酰胺或其药学可接受的盐。
2型糖尿病患者通常发展“胰岛素抗性”,这导致异常的葡萄糖稳态和高血糖,从而导致发病率和过早死亡率增加。异常的葡萄糖稳态与肥胖,高血压以及脂质、脂蛋白和载脂蛋白代谢变化相关。2型糖尿病发展心血管并发症的风险增加,所述心血管并发症例如动脉粥样硬化、冠状动脉性心脏病、中风、周围血管疾病、高血压、肾病、神经病变和视网膜病变。因此,治疗性控制葡萄糖稳态、脂质代谢、肥胖和高血压在处理和治疗糖尿病中是重要的。许多患有胰岛素抗性但是未发展为2型糖尿病的患者也存在发展为“综合征X”或“代谢综合征”的风险。代谢综合征的特征为胰岛素抗性,伴有异常肥胖、高胰岛素血症、高血压、低HDL、高VLDL、高血压、动脉粥样硬化、冠状动脉心脏病和慢性肾功能衰竭。这些患者存在发生上文所列的心血管并发症的风险,不论他们是否发展为显性糖尿病。
由于其抑制11-β-HSD1,本发明化合物可用于治疗其中11-β-HSD1的抑制是有益的各种病症和疾病。这些疾病和病症在本文被定义为“糖尿病病症”和“代谢综合征病症”。本领域的技术人员通过疾病的病理生理学中或疾病的内环境稳定性反应中涉及的11-β-HSD1活性能辨别“糖尿病病症”和“代谢综合征病症”。 因此,这些化合物可用于例如预防、治疗或缓解疾病或病症,或“糖尿病病症”和“代谢综合征病症”相关的症状或后遗症。
“糖尿病病症”和“代谢综合征病症”包括,但不限于,糖尿病、1型糖尿病、2型糖尿病、高血糖症、高胰岛素血症、β-细胞休眠(beta-cell rest)、通过修复1相反应改善的β-细胞功能、餐后高血糖症、阻止细胞凋亡、空腹血糖受损(IFG)、代谢综合征、低血糖症、高-/低钾血症、正常化胰高血糖素水平、提高的LDL/HDL比率、减少吃零食、进食障碍疾患、体重降低、多囊性卵巢综合征(PCOS)、糖尿病引发的肥胖、成人隐匿性自身免疫糖尿病(LADA)、胰岛炎、胰岛移植、儿科糖尿病、妊娠糖尿病、糖尿病晚期并发症、微-/巨白蛋白尿、肾病、视网膜病变、神经病变、糖尿病足溃疡、由于给予胰高血糖素减少肠能动性、短肠综合征、止泻、增加胃液分泌、减少血流量、勃起机能障碍、青光眼、手术后应激、改善由缺血后血流再灌注引起的器官组织损伤、缺血性心脏损伤、心脏机能不全、充血性心力衰竭、中风、心肌梗塞、心律失常、早产儿死亡、抗-凋亡、创伤愈合、受损的葡萄糖耐量(IGT)、胰岛素抗性综合征、代谢综合征、综合征X、高脂血症、血脂异常、高甘油三酯血症、高脂蛋白血症、高胆固醇血症、动脉硬化包括动脉粥样硬化、胰高血糖素瘤、急性胰腺炎、心血管疾病、高血压、心脏肥大、胃肠道病症、肥胖、肥胖引起的糖尿病、糖尿病性血脂异常等。因而,本发明还提供了一种治疗“糖尿病病症”和“代谢综合征病症”的方法,同时减少和或消除一种或多种与当前治疗相关的不需要的副作用。
另外,本发明提供了一种式I化合物,或其药学可接受的盐,或包含式I化合物或其药学可接受的盐和药学可接受的载体、稀释剂或赋形剂的药物组合物:用于抑制11-β-HSD1活性,用于抑制在哺乳动物中调节细胞响应的11-β-HSD1的活性;用于降低哺乳动物中血糖水平;用于治疗由过度11-β-HSD1活性引起的疾病;用于治疗哺乳动物中的糖尿病或其它代谢综合征病症;以及用于治疗糖尿病、代谢综合征、肥胖症、高血糖症、动脉粥样硬化、缺血性心脏病、中风、神经病变和创伤愈合。因此,本发明的方法包含预防和治疗性给予式I化合物。
本发明进一步提供了式I化合物或其药学可接受的盐的下列用途:用于制备抑制11-β-HSD1活性的医药;用于制备抑制在哺乳动物中调节细胞响应的11-β-HSD1的活性的医药;用于制备降低哺乳动物中血糖水平的医药;用于制备治疗由过度11-β-HSD1活性引起的疾病的医药;用于制备治疗哺乳动物中的糖尿病及其它代谢综合征病症的医药;以及用于制备预防或治疗以下疾病的医药:糖尿病、代谢综合征、肥胖症、高血糖症、动脉粥样硬化、缺血性心脏病、中风、神经病变和不合适的创伤愈合。
本发明进一步提供了一种治疗哺乳动物中由过度11-β-HSD1活性引起的病症的方法;一种抑制哺乳动物中11-β-HSD1活性的方法;一种抑制在哺乳动物中调节细胞响应的11-β-HSD1的活性的方法;一种降低哺乳动物中血糖水平的方法;一种治疗哺乳动物中的糖尿病及其它代谢综合征病症的方法;一种预防或治疗以下疾病的方法:糖尿病、代谢综合征、肥胖症、高血糖症、动脉粥样硬化、缺血性心脏病、中风、神经病变和不合适的创伤愈合;所述方法包括给予需要此治疗的哺乳动物抑制11-β-HSD1活性量的式I化合物或其药学可接受的盐、或者药物组合物,该药物组合物包含式I化合物或其药学可接受的盐和药学可接受的载体、稀释剂或赋形剂。
另外,本发明提供了包含式I化合物或其药学可接受的盐和药学可接受的载体、稀释剂或辅料的药物组合物:适合用于抑制11-β-HSD1活性;适合用于抑制由11-β-HSD1活性介导的细胞响应;适合用于降低哺乳动物中血糖水平;适合用于治疗哺乳动物中的糖尿病和其它代谢综合征病症;以及适合用于预防或治疗糖尿病、代谢综合征、肥胖症、高血糖症、动脉粥样硬化、缺血性心脏病、中风、神经病变和创伤愈合。
在本发明进一步的方面,本发明化合物与一种或多种另外的活性物质以任何适宜的比率联用。这类另外的活性物质可选自,例如,抗糖尿病剂、减肥药、抗高血压剂、用于治疗由糖尿病引起或与糖尿病相关的并发症的药物和用于治疗由肥胖引起或与肥胖相关的并发症和疾病的药物。以下列表显示了几组联合。应当理解,每一个命名的药物都可以和其它的命名药物组合,以创建另外的联用。
因此,在本发明进一步的实施方案中,本发明化合物可与一种或多种抗糖尿病药联合给予。
适宜的抗糖尿病药物包括胰岛素、胰岛素类似物和衍生物,例如在以下文献中所公开的:EP792290(Novo Nordisk A/S)例如NεB29-十四烷酰基脱(B30)人胰岛素;EP214826和EP705275(Novo Nordisk A/S)例如AspB28人胰岛素;US5,504,188(Eli Lilly)例如LysB28ProB29人胰岛素;EP368187(Aventis)例如GLP-1和GLP-1衍生物,如在WO98/08871(Novo Nordisk A/S)中所公开的,以及口服活性降血糖药。
口服活性降血糖药优选包括咪唑啉类,磺酰脲类,双胍类,氯茴苯酸类(meglitinides),噁二唑烷二酮类,噻唑烷二酮类,胰岛素致敏剂,促胰岛素分泌剂如格列美脲,α-葡萄糖苷酶抑制剂,作用于β-细胞的ATP-依赖性钾通道例如钾通道开放剂,如WO97/26265、WO99/03861和WO00/37474(Novo Nordisk A/S)中所公开的,或米格列奈,或者钾通道阻滞剂如BTS-67582,那格列奈,高血糖素拮抗剂如WO99/01423和WO00/39088(Novo Nordisk A/S and Agouron Pharmaceuticals,Inc.)中所公开的,GLP-1拮抗剂,DPP-IV(二肽基肽酶-IV)抑制剂,PTP酶(蛋白质酪氨酸磷酸酶)抑制剂,涉及刺激葡萄糖异生和/或糖原分解的肝脏酶抑制剂,葡萄糖摄取调节剂,葡萄糖激酶(GK)激活剂如在WO00/58293、WO01/44216、WO01/83465、WO01/83478、WO01/85706、WO01/85707和WO02/08209(Hoffman-La Roche)中所公开的或在WO03/00262、WO03/00267和WO03/15774(AstraZeneca)中所公开的,GSK-3(糖原合成酶激酶-3)抑制剂,修饰脂类代谢的化合物如降血脂药如HMG CoA抑制剂(他汀类),减少食物摄取的化合物,PPAR(过氧化物酶体增生物激活受体)配体其包括PPAR-α、PPAR-γ和PPAR-δ亚型,以及RXR(视黄醇类X受体)激动剂,如ALRT-268、LG-1268或LG-1069。
在另一个实施方案中,本发明化合物与胰岛素或胰岛素类似物或衍生物例如NεB29-十四烷酰基脱(B30)人胰岛素、AspB28人胰岛素、LysB28ProB29人胰岛素、联合给予,或包含上述一个或多个化合物的混合制品。
本发明的另一个实施方案中,本发明化合物与磺酰脲例如格列本脲、格列吡嗪、甲苯磺丁脲(tolbautamide)、chloropamidem、妥拉磺脲、格列美脲(glimepride)、格列齐特(glicazide)和格列本脲联合给予。
本发明的另一个实施方案中,本发明化合物与双胍例如二甲双胍联合给予。
本发明的再另一个实施方案中,本发明化合物与氯茴苯酸例如瑞格列奈或那格列奈联合给予。
本发明的再另一个实施方案中,本发明化合物与噻唑烷二酮胰岛素致敏剂例如曲格列酮、环格列酮、吡格列酮、罗格列酮、isaglitazone、达格列酮、恩格列酮、CS-011/CI-1037或T 174联合给予,或者与WO97/41097、WO97/41119、WO97/41120、WO00/41121和WO98/45292(Dr.Reddy’s Research Foundation)中所公开的化合物联合给予。
本发明的再另一个实施方案中,本发明化合物可与胰岛素致敏剂联合给予,该致敏剂例如GI 262570、YM-440、MCC-555、JTT-501、AR-H039242、KRP-297、GW-409544、CRE-16336、AR-H049020、LY510929、MBX-102、CLX-0940、GW-501516或WO99/19313、WO00/50414、WO00/63191、WO00/63192、WO00/63193中公开的化合物,如ragaglitazar(NN 622或(-)DRF 2725)(Dr.Reddy’s ResearchFoundation),以及WO00/23425、WO00/23415、WO00/23451、WO00/23445、WO00/23417、WO00/23416、WO00/63153、WO63196、WO00/63209、WO00/63190和WO00/63189(Novo Nordisk A/S)公开的化合物。
本发明的另一个实施方案中,本发明化合物与α-葡萄糖苷酶抑制剂例如伏格列波糖、乙格列酯、米格列醇或阿卡波糖联合给予。
本发明的另一个实施方案中,本发明化合物与作用于β-细胞的ATP-依赖性钾通道的药物例如甲苯磺丁脲、格列本脲、格列吡嗪、格列齐特、BTS-67582或瑞格列奈联合给予。
本发明的再另一个实施方案中,本发明化合物可与那格列奈联合给予。
本发明的再另一个实施方案中,本发明化合物与降血脂药或抗高血脂药联合给予,所述降血脂药或抗高血脂药例如考来烯胺、考来替泊、氯贝丁酯、吉非贝齐、洛伐他汀、普伐他汀、辛伐他汀、匹伐他汀、罗苏伐他汀、普罗布考、右甲状腺素、非诺贝特和阿托伐他汀。
本发明的再另一个实施方案中,本发明化合物与减少食物摄取的化合物联合给予。
本发明的另一个实施方案中,本发明化合物与一个以上的上述化合联合给予,例如与二甲双胍和磺酰脲如格列本脲;磺酰脲和阿卡波糖;那格列奈和二甲双胍;瑞格列奈和二甲双胍;阿卡波糖和二甲双胍;磺酰脲、二甲双胍和曲格列酮;胰岛素和磺酰脲;胰岛素和二甲双胍;胰岛素、二甲双胍和磺酰脲;胰岛素和曲格列酮;胰岛素和洛伐他汀等联合。
本文所述化合物的描述中所使用的一般术语具有其通常的含义。
如本文所使用的,术语“(C1-C3)烷基”、“(C1-C4)烷基”或“(C1-C6)烷基”是指标示碳原子数目的直链或支链的饱和脂肪族基团,如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基等。术语“(C1-C6)烷氧基”代表通过氧连接的C1-C6烷基基团,并且包括例如以下的基团:甲氧基、乙氧基、正丙氧基、异丙氧基等。术语″卤素″是指氟、氯、溴和碘。术语″(C3-C8)环烷基″是指饱和的或部分饱和的3-8个碳原子的碳环,一般是3-7个碳原子的碳环。(C3-C8)环烷基的实例包括但不限于,环丙基、环丁基、环戊基、环己基、环庚基等。
如本文所使用的,术语“任选取代的”或“任选的取代基”表示所讨论的基团是未取代的或被一个或多个特定的取代基取代。当所讨论的基团被超过一个的取代基取代时,该取代基可以是相同的或不同的。此外,当使用术语“独立地”、“独立地是”和“独立地选自”时,其表示所讨论的基团可以是相同的或不同的。本文所定义的某些术语在结构式中可出现多次,一旦出现这种情况,各术语将独立于其它术语而被定义。
应当理解,豚鼠、犬、猫、大鼠、小鼠、仓鼠和灵长类,包括人类,是术语“患者”的含义范围之内的患者实例。优选的患者包括人类。术语“患者”包括家畜动物。家畜动物是饲养以用于食品制造的动物。反刍动物或“反刍-咀嚼”动物如奶牛、公牛、小母牛、去势牛、绵羊、水牛、野牛、山羊和羚羊是家畜的实例。家畜的其它实例包括猪和禽类(家禽)如小鸡、鸭子、火鸡和鹅。待治疗的患者优选哺乳动物,特别是人类。
如本文所使用的,术语“治疗(treatment)”、″治疗(treating)″和″治疗(treat)″包括其通常可接受的含义,即为了以下目的而管理和护理患者:预防给定病症或疾病、降低给定病症或疾病发生或发展的风险;抑制、阻止、缓解、改善、减慢、停止、延缓或逆转进程或严重度;以及保持检查和/或治疗本文所述疾病、病症或病理状态存在的特性,包括减轻或缓解症状或并发症,或者治愈或消除疾病、障碍或病症。如果需要,本发明的方法包括药物治疗性和/或预防性治疗。
如本文所使用的,术语″治疗有效量″表示能缓解本文所述的各种病理学状态的症状的本发明化合物的量。当然,根据本发明给予的化合物的具体的量应由围绕该案例的特殊情况确定,包括,例如给予的化合物、给药途径、患者的状态和待治疗的病理状态。
″组合物″表示药物组合物,并意欲包括医药产品,该医药产品包含了包括式I化合物的活性成分和制作载体的惰性成分。相应地,本发明的药物组合物包含通过混合本发明的化合物和药学可接受的载体制成的任何组合物。
术语“适当的溶剂”是指任何溶剂或溶剂的混合物,对于正在进行的充分溶解反应物的反应是惰性的,得到在其中进行希望的反应的介质。
术语″单位剂型″表示适于作为人受试者和其它非-人类动物的单元剂量的物理分离的单元,含有计算的预定量活性物质联合适宜的药学载体的各单元产生希望的治疗效应。
本发明的化合物可具有一个或多个手性中心,并且可以以多种立体异构构型存在。由于这些手性中心,本发明化合物可以以外消旋物、以单一对映体或对映体混合物、以及以非对映体和非对映体混合物存在。所有这些外消旋物、对映体、非对映体和混合物,不论是纯化、部分纯化的混合物还是未纯化的混合物,都在本发明的范围之内。对于本文提供的实施例,当包含已知构型的一个手性中心或多个中心的分子存在时,其立体化学在分子的名称和结构描述中被指明。如果立体化学是未知的或未定义,其立体化学未在分子的名称和结构描述中指明。本发明的实施方案包括本文提供的实施例,并且尽管提供的实施例可能是一个手性的或构象的形式或其盐,但是本发明另外的实施方案包括实施例描述的所有其它立体异构的和/或构象的形式,以及其药学可接受的盐。这些实施方案包括这些结构的任何分离出来的对映体、非对映体和或构象异构体,以及包含超过一个形式的任何混合物。
此外,当双键、完全或部分饱和的环系统、或超过一个的不对称中心或旋转受限的键存在于分子中时,可形成非对映体。人们期望任何非对映体,分离的、纯化或部分纯化的非对映体或其混合物,包括在本发明的范围之内。此外,本发明的一些化合物可以不同的互变异构形式存在,并且人们期望化合物可形成的任何互变异构形式均包括在本发明的范围之内。
如本文所使用的,术语″对映体的富集″是指与另一个对映体相比,一个对映的量增加。表达对映体达到富集的便利方法是对映体过量或″ee″的概念,对映体过量使用以下方程计算:
其中E1是第一个对映体的量,并且E2是第二个对映体的量。因此,如果两个对映体的初始比值是50:50,如在外消旋混合物中存在的,且达到足以产生终比值70:30的对映体富集,对于第一个对映体的ee为40%。然而,如果终比值是90:10,则对于第一个对映体的ee是为80%。高于90%的ee是优选的,高于95%的ee是最优选的,并且高于99%的ee是最特别优选的。对映体富集通过本领域的普通技术之一很容易确定,使用标准技术和操作,如气相或手性柱的高效液相色谱法。对需要实现对映体对的分离适宜的手性柱、洗脱液和条件进行选择在本领域普通技术人员的知识范围之内。另外,式I化合物的具体立体异构体和对映体可由本领域的普通技术之一制备,利用公知的技术和过程,如那些由J.Jacques,et al.,″Enantiomers,Racemates,and Resolutions″,John Wiley andSons,Inc.,1981,和E.L. Eliel and S.H.Wilen,”Stereochemistry of Organic Compounds”,(Wiley-Interscience 1994),以及1998年4月29日公开的欧洲专利申请EP-A-838448公开的技术。拆分的实例包括重结晶技术或手性色谱法。
式I化合物可通过本领域普通技术人员根据各种操作制备,其中一些操作在下文阐述的操作和图解进行了说明。为制备式I化合物需要的步骤的具体顺序取决于待合成的具体化合物、起始化合物和取代部分的相对不稳定性。试剂或起始原料对于本领域的技术人员很容易得到,并且对于不是市售可得的那些,通过本领域普通技术人员根据本领域通常应用的标准操作以及下文所述各种操作和图解可以很容易合成。
提供了以下图解、制品、实施例和操作,以更好地解释本发明的实践,并且不应以任何方式理解为限制它们的范围。本领域的技术人员应理解,可进行各种修饰而不会脱离本发明的精神和范围。本说明书中提及的所有出版物预示属于本发明领域的技术人员的水平。
执行图解、制品、实施例和操作的反应的最佳时间可以经常规的色谱技术通过监测反应进程确定。此外,优选在惰性气氛下进行本发明的反应,该惰性气氛例如氩气、氮气。溶剂的选择通常不是关键性的,只要所使用的溶剂对于正在进行的反应是惰性的,并且充分溶解反应物以进行需要的反应。化合物在其用于后面的反应之前优选是分离出来的和纯化的。一些化合物在其形成期间可从反应溶液中结晶出来,然后经过滤收集,或者反应溶剂可经萃取、蒸发或滗析被除去。如果需要,通过普通技术如重结晶或经固体载体如硅胶或氧化铝的色谱法,可进一步纯化式I的中间体和终产物。
技术人员应理解,不是所有取代基都和所有反应条件相容。这些化合物在合成中的方便点可通过本领域公知的方法被保护或修饰。
除另有说明外,此处的图解、制品、实施例和操作中所使用的术语和缩写具有其常规的含义。例如,如本文所使用的,以下术语具有标示的含义:″psi″是指磅/平方英寸;″TLC″是指薄层色谱法;″HPLC″是指高效液相色谱法;″Rf″是指保留因子,″Rt″是指保留时间;″δ″是指四甲基硅烷低场的百万分之一;“MS”是指质谱法,除另有说明外,实测质量表示[M+H]。“MS(APCi)是指大气压化学电离质谱法,“UV”是指紫外分光法,“1H NMR”是指质子核磁共振波谱法。“LCMS”是指液相色谱法-质谱法,“GC/MS”是指气相色谱法/质谱法。“IR”是指红外光谱测定法,列出的IR光谱的最大吸收仅是那些有意义的光谱,并不是所有观察到的最大吸收。“RT”是指室温。
″THF″是指四氢呋喃,“LAH”是指氢化铝锂,“LDA”是指二异丙基酰胺锂,“DMSO”是指二甲基亚砜,“DMF”是指二甲基甲酰胺,“EtOAc”是指乙酸乙酯,“Pd-C”是指钯/碳,“DCM”是指二氯甲烷,“DMAP”是指二甲基氨基吡啶,“LiHMDS”是指六甲基二甲硅烷锂(LithiumHexamethyldisilisane),“TFA”是指三氟乙酸,“EDAC”是指N-乙基-N′-(3-二甲基氨基丙基)碳二亚胺盐酸盐,“HOBT”是指1-羟基苯并三唑,“Bn-9-BBN”是指苄基-9-硼二环[3.3.1]壬烷,“Pd(dpPf)Cl2”是指[1,1’-二(二苯膦)-二茂铁)二氯化钯(II),“EDCI”是指N-乙基-N′-(3-二甲基氨基丙基)碳二亚胺盐酸盐,“DBU”是指1,8-二氮杂双环[5.4.0]十一碳烯-7,“TBSCl”是指叔丁基-二甲基-硅烷基氧基甲基氯化物,“NBS”是指N-溴代琥珀酰亚胺,“TsOH”是指对甲苯磺酸,“DCE”是指二氯乙烷,“DAST”是指(二乙氨基)硫三氟化物,“EA/H”是指乙酸乙酯/己烷混合物,“Pd2(dba)3”是指二(二亚苄基丙酮)钯,“BINAP”是指2,2’-二(二苯膦-1,1’-二萘,“NMP”是指N-甲基吡咯烷,“TMSCN”是指三甲基甲硅烷基氰化物,“TBAF”是指四丁基氟化铵,“Tf2O”是指三氟甲磺酸酐,“TBSO”是指叔丁基-二甲基-硅烷氧基,“OTf”是指三氟甲磺酸盐,MeTi(Oi-Pr)3是指三异丙氧基甲基钛(methyltitanium triisopropoxide),“BBr3”是指三溴化硼,“PBr3”是指三溴化磷,“Pd(PPh3)4”是指四(三苯膦)钯(0),“OAc”是指醋酸盐,“DME”是指二甲基乙烷,“Et2O″是指乙醚,″(Ph3P)4Pd″是指四(三苯膦)钯(0),″DMFDMA”是指N,N-二甲基甲酰胺二甲基缩醛,″Et3N″是指三乙胺,″tBu″是指叔丁基,″DIPEA″是指二异丙基乙胺,“EDC″是指-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐,″HOAc″是指醋酸,“boc″是指叔定氧基羰基。在结构中,“Ph”是指苯基,“Me”是指甲基,“Et”是指乙基,“Bn”是指苄基,“MeOH”是指甲醇,“OTf”是指三氟甲磺酸盐,“TIPSO”是指三异丙基硅烷基氧基,“TBSO”是指叔丁基-二甲基硅烷基氧基。
本文提供的实施例解释说明了本文所要求的本发明,并且不打算以任何方式限制本发明所要求的范围。制品和实例使用来自 MDLInformation Systems,Inc.的AutoNom 2.2 in ChemDraw Ultra或AutoNom2000 in MDL ISIS/Draw version 2.5 SP1命名,或者由Chemical AbstractsServices提供。
使用Varian INOVA 400MHz分光计,获得在标明的溶剂中的1HNMR谱。使用装配有质谱仪(Agilent MSD SL)的Agilent HP1100仪器,获得LCMS。Waters Xterra C18(2.1X50mm,3.5微米)用作固定相,并且标准方法是含有0.2%甲酸铵的5-100%乙腈/甲醇(50:50)的梯度历经3.5分钟,然后在柱温50℃和流速1.0mL/min下,在100%B时保持0.5分钟。另一种标准方法是含有0.2%甲酸铵的5-100%乙腈/甲醇(50:50)的梯度历经7.0分钟,然后在柱温50℃和流速1.0mL/min下,在100%B时保持1.0分钟。另外的经Agilent MSD(loop machine)的MS分析是标准的流动注射分析(FIA),不存在柱子,且流速为0.5ml/min,80%MeOH和6.5mM醋酸铵运行30秒。
图解A
在图解A中,将任选取代的酚(1)保护(例如用TBSCl),形成化合物2,而后将化合物2转变为醛(3)。使化合物3与含有保护基团(Pg)和离去基团(Lg)的化合物反应,得到醚化合物4。Pg可以是-CH3或-CH2-苯基,Lg可以是甲磺酸酯或卤素。优选,Lg-Pg化合物是I-CH3或Br-CH2-苯基。将醛还原,形成醇(5),而后转变为化合物6。优选,将化合物5用PBr3卤化,得到2-溴-甲基化合物。
为了形成式I等等化合物而进行的化合物的保护和脱保护对于技术人员是熟知的,并且描述在文献中。(例如,参见:Greene and Wuts,Protective Groups in Organic Synthesis,Third Edition,John Wiley andSons Inc.,1999)。
图解B
图解B显示了形成中间体化合物9的立体特异性合成。化合物7是用4-戊烯酰基氯化物将商业购买的(R)-4-苄基-噁唑烷-2-酮进行酰化而形成的。然后用任选取代的化合物6将其烷基化(参见图解A),得到8的化合物。使用臭氧和三苯基膦或四氧化锇和氧化剂例如高碘酸钠,将化合物8氧化,形成醛中间体化合物9。
图解C
图解D
图解E
图解F
制品1
2,6-二氯-4-羟基-苯甲醛
将3,5二氯苯酚(1kg,6.13mol)溶解于3L二甲基甲酰胺(DMF),再冷却至0℃。添加咪唑(918.74g,6.75mol),接着添加叔丁基二甲基甲硅烷基氯化物(1017.13g,6.75mol)。将该混合物温热至室温,再搅拌15分钟。倾入到水(6L)中,再用醚(4L)萃取。将有机层用水(2次)、10%氯化锂水溶液、盐水洗涤,然后用硫酸钠干燥。过滤,再在真空下浓缩,获得叔丁基-(3,5-二氯-苯氧基)-二甲基-甲硅烷(1700g)为油。
将叔丁基-(3,5-二氯-苯氧基)-二甲基-甲硅烷(425g,1.5mol)溶解于4L干燥四氢呋喃,再冷却至-68℃。在-68℃下缓缓添加1.1当量的仲丁基锂(103.1g,1.61mol)(~1.75hr)。添加完毕之后,将该反应在-70℃下搅拌30min。添加二甲基甲酰胺(168.5g,2.3mol),再将该反应在-70℃下搅拌1hr。添加1M盐酸/水(3.5L),再使反应温热至室温。
将反应混合物倾入到醚(5L)中,用水、盐水洗涤。用硫酸钠干燥,再在真空下浓缩成橙色固体。用冷的二氯甲烷研磨,过滤,回收250g(80%)浅黄色固体。
制品2
2,6-二氯-4-甲氧基-苯甲醛
将2,6-二氯-4-羟基-苯甲醛(120g,628.24mmol)和碳酸钾(173.65g,1256.5mmol)在900mL二甲基甲酰胺中合并,再用碘甲烷(107g,753.9mmol)处理。将反应在室温下搅拌3小时。滤出固体,再倾入到6L水中。过滤固体,用水洗涤数次,风干,再溶解在乙酸乙酯中。用水洗涤,接着用盐水洗涤,然后用硫酸钠干燥。过滤,再在真空下浓缩至~100mL体积,此时,固体开始沉落。过滤,再浓缩滤液,得到第二批量。用己烷洗涤,合并全部固体,真空干燥,得到112.3g的灰白色固体:1HNMR(400MHz,CDCl3)δ10.41(s,1H),6.90(s,2H),3.87(s,3H)。
制品3
2,6-二氯-4-苄氧基-苯甲醛
将2,6-二氯-4-羟基-苯甲醛(250g,1.3mol)和碳酸钾(361.8g,2.62mol)在2L二甲基甲酰胺中的混合物用苄基溴(268.64g,1.57mol)处理。将该反应在室温下搅拌1小时。滤出固体,再倾入到12L水中。过滤固体,用水洗涤数次,风干,再溶解在乙酸乙酯中。用硫酸镁干燥,过滤,再在真空下浓缩至~1.5L。放置过夜,然后过滤。用最小量的己烷洗涤固体,再真空干燥。在真空下浓缩滤液,再用己烷研磨,得到第二批量的产物,其与第一批量合并时等于245g白色结晶。重复,获得第三批量80g为淡褐色粉末(88%总产率):1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),7.43(m,5H),7.28(s,2H),5.25(s,2H)。
制品4
(2,6-二氯-4-甲氧基-苯基)-甲醇
将2,6-二氯-4-甲氧基-苯甲醛(112g,546mmol)混悬于1500mL乙醇中,再在冰浴中冷却至7℃。分批添加硼氢化钠(20.67,546mmol),获得溶液。移去冰浴,再搅拌2小时。小心将反应混合物添加至饱和氯化铵溶液(~4L)中,搅拌直到完全猝灭。用二氯甲烷(3x1L)萃取,再用硫酸钠将合并的有机萃取物干燥。过滤,再在真空下浓缩,得到113g的淡褐色固体:1H NMR(400MHz,CDCl3)δ6.86(s,2H),4.86(s,2H),3.78(s,3H),2.07(s,1H)。
制品5
(2,6-二氯-4-苄氧基-苯基)-甲醇
基本上如通过制品4的方法制备该标题化合物。NMR(DMSO-d6)δ7.38(m,4H),7.33(m,1H),7.12(s,2H),5.14(s,2H),5.05(t,1H),4.59(d,2H)。
制品6
2-溴甲基-1,3-二氯-5-甲氧基-苯
将(2,6-二氯-4-甲氧基-苯基)-甲醇(113g,545.76mmol)溶解于1200mL干燥的THF中,再在氮气下冷却至0℃。在氮气下添加PBr3(59.1g,218.3mmol),再在0℃下搅拌30分钟。倾入到饱和NaHCO3水溶液中,再用EtOAc萃取.干燥,再在真空下浓缩,获得129.4g产物为灰白色固体。NMR(CDCl3)δ6.88(s,2H),4.73(s,2H),3.79(s,3H)。
制品7
2-溴甲基-1,3-二氯-5-苄氧基-苯
基本上如通过制品6的方法制备该标题化合物,89%产率。ES MS(m/z):347(M+1)。
制品8
(R)-4-苄基-3-戊-4-烯酰基-噁唑烷-2-酮
用氮气吹扫12L三颈圆底烧瓶达20min,该烧瓶装配有机械搅拌器、内部温度探针/N2入口和1L加料漏斗,然后添加(R)-4-苄基-2-噁唑烷酮(250g,1.41mol)。用四氢呋喃(THF)(1.8L)稀释,再在干冰/丙酮浴中冷却,直到内部温度为-74℃。将1.6M正丁基锂的己烷溶液(970mL,1.552mol)通过插管转移到加料漏斗中,再以使内部温度不会达到-65℃以上的速度添加到所述噁唑烷酮溶液中。添加完毕之后,使反应在冷却浴中搅拌30min。将4-戊烯酰基氯化物(175mL,1.585mol)转移到加料漏斗中,再经25min时间滴加至该阴离子溶液中。在冷却浴中将反应搅拌45min。移去冷却浴,再将反应搅拌18hr,同时其缓缓达到室温。将该混合物用1N盐酸水溶液(1.5L)和二乙醚(1L)稀释。层分离,有机相用水(2X1L)、然后用盐水(1L)洗涤。将该合并的水层用醚(1L)洗涤。将合并的有机相用无水硫酸镁干燥,过滤,浓缩成390g的浅褐色油。通过硅胶色谱法使用己烷:乙酸乙酯将此物质纯化,获得345g(94.5%)的澄清黄色油。
制品9
(R)-4-苄基-3-[(S)-2-(4-苄氧基-2,6-二氯-苄基)-戊-4-烯酰基]-噁唑烷-2-酮
将(R)-4-苄基-3-戊-4-烯酰基-噁唑烷-2-酮(345g,1.33mol)和THF(1.8L)的混合物在12L三颈圆底烧瓶中的混合物在氮气氛下搅拌,该烧瓶装配有内部温度探针/氮气入口和加料漏斗,再冷却至-75℃。将1MLiHMDS(1.6L)转移到加料漏斗中,再以使内部温度不会达到-60℃以上的速度添加。添加完毕之后,使反应在-25℃下搅拌30min,然后冷却至约-60℃。此时经5分钟分批添加固体2-溴甲基-1,3-二氯-5-苄氧基-苯。添加完毕之后,将反应容器转移到-10℃丙酮浴中,并维持内部温度低于10℃达1hr。将该混合物冷却至0℃,然后用2L的1N盐酸水溶液猝灭。将该混合物转移至22L分液漏斗中,再用2.5L水和2L醚稀释。层分离,水层用醚萃取。将合并的有机相用无水硫酸镁干燥,过滤,浓缩成800g的粘稠油。通过硅胶色谱法使用己烷:乙酸乙酯纯化,获得597g,(86%)的无色油。
制品10
(R)-4-((R)-4-苄基-2-氧代-噁唑烷-3-基)-3-(4-苄氧基-2,6-二氯-苄基)-4-氧代-丁醛
将(R)-4-苄基-3-[(S)-2-(4-苄氧基-2,6-二氯-苄基)-戊-4-烯酰基]-噁唑烷-2-酮(100g,190.68mmol)和二氯甲烷(800mL)的混合物冷却至-74℃。将以75%的比率通过A-113臭氧发生器产生的臭氧经由载气以5CFM的速率鼓泡通过该反应,直到溶液产生蓝色(约3hr)。添加三苯膦(60g,228.8mmol)在200mL二氯甲烷中的溶液,达到室温同时搅拌反应过夜。在真空下浓缩该溶液,再通过硅胶色谱法使用20-50%乙酸乙酯/己烷的梯度纯化,获得82.1g(82%)的产物为白色泡沫:MS(m/z):526(M+)。
备选的制备(R)-4-((R)-4-苄基-2-氧代-噁唑烷-3-基)-3-(4-苄氧基-2,6-二氯-苄基)-4-氧代-丁醛的方法:
将(R)-4-苄基-3-[(S)-2-(4-苄氧基-2,6-二氯-苄基)-戊-4-烯酰基]-噁唑烷-2-酮(0.96g,1.8mmol)、THF(21mL)和水(7mL)的混合物用2.5%四氧化锇/叔丁醇(46mg,0.18mmol)处理。添加高碘酸钠(1.17g,5.5mmol),再在室温下将反应搅拌4hr。用水猝灭反应,再用乙酸乙酯萃取。将该有机相用1N硫代硫酸钠水溶液洗涤,然后用盐水洗涤。将有机层用硫酸镁干燥,过滤,再在真空下浓缩。通过硅胶色谱法纯化该粗物质,使用己烷:乙酸乙酯洗脱该纯产物。在真空下浓缩含有产物的级分,得到0.46g(48%)的需要的产物。MS(m/z):526(M+)。
制品11
(R)-4-苄基-3-[(S)-2-(4-甲氧基-2,6-二氯-苄基)-戊-4-烯酰基]-噁唑烷-2-酮
在250mL圆底烧瓶中,在-75℃,搅拌(R)-4-苄基-3-戊-4-烯酰基噁唑烷-2-酮(5.0g,19.3mmol)和四氢呋喃(75mL)的混合物。将2M LDA(14.5mL)通过针筒转移到烧瓶中,并以使内部温度不达到-60℃以上的速度加入。加入结束之后,在-25℃搅拌反应30分钟,然后冷却至大约-60℃。此时,加入2-溴甲基-1,3-二氯-5-甲氧基-苯(7.76g,28.96mmol)的THF(25mL)溶液。加入结束之后,使反应容器慢慢地温热至0℃,使内反应温度保持在0℃4小时。用30mL 1N盐酸水溶液猝灭反应。将混合物转移到500mL分液漏斗中,用100mL水和100mL醚稀释。分离各层,用醚提取水层。用无水硫酸钠干燥合并的有机相,过滤,浓缩,得到稠油。用硅胶色谱纯化,使用己烷∶乙酸乙酯,获得6.65g(76%)浅黄色油。
制品12
(R)-4-((R)-苄基-2-氧代-噁唑烷-3-基)-3-(4-甲氧基-2,6-二氯-苄基)-4-氧代-丁醛
将(R)-4-苄基-3-[(S)-2-(4-甲氧基-2,6-二氯-苄基)-戊-4-烯酰基]-噁唑烷-2-酮(6.65g,14.87mmol)、四氢呋喃(140mL)和水(45mL)的混合物用2.5%四氧化锇/叔丁醇(378mL,1.487mmol)处理。加入高碘酸钠(9.55g,44.63mmol),并在室温下搅拌反应4小时。用水猝灭反应,用乙酸乙酯提取。用1N硫代硫酸钠水溶液、然后盐水洗涤有机相。用硫酸镁干燥有机层,过滤,真空浓缩。用硅胶色谱纯化粗品,使用己烷∶乙酸乙酯洗脱纯产物。真空浓缩含有产物的馏份,得到3.35g(49%)目标产物。MS(m/z):451(M+)。
制品13
4-[(R)-3-(4-苄氧基-2,6-二氯-苄基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸叔丁基酯
将(R)-4-((R)-苄基-2-氧代-噁唑烷-3-基)-3-(4-苄氧基-2,6-二氯-苄基)-4-氧代-丁醛(制品10)(4.0g,7.6mmol)和4-氨基-1N-Boc-哌啶(1.5g,7.6mmol)的CH2Cl2(100mL)溶液用乙酸(0.4mL,7.6mmol)处理,并在室温下搅拌反应1小时。用三乙酰氧基硼氢化钠(3.2g,15mmol)处理反应,在室温下搅拌过夜。用水猝灭反应,分离有机层。用盐水洗涤有机层,用MgSO4干燥,过滤,除去溶剂。用硅胶柱色谱纯化粗品,使用己烷∶EtOAc洗脱纯产物。除去溶剂,得到2.35g(58%)目标产物。MS(m/e):555(M+Na+)。
制品14
4-[(R)-3-(2,6-二氯-4-羟基-苄基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸叔丁基酯
将4-[(R)-3-(4-苄氧基-2,6-二氯-苄基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸叔丁基酯(制品13)(2.2g,4.1mmol)的EtOAc(50mL)溶液用氢氧化钯/碳(0.1g)处理。用氢气吹扫溶液,并在1atm氢气下搅拌反应过夜。通过硅藻土过滤反应,除去催化剂。除去溶剂,得到1.6g(87%)目标产物。MS(m/e):441(M-1)。
制品15
4-[(R)-3-(2,6-二氯-4-三氟甲磺酰基氧基-苄基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸叔丁基酯
将4-[(R)-3-(2,6-二氯-4-羟基-苄基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸叔丁基酯(制品14)(1.5g,3.3mmol)的吡啶(15mL)溶液冷却到0℃,并用三氟甲磺酸酸酐(0.8mL,4.9mmol)处理。使反应升温到室温。在室温下搅拌2小时之后,用1N HCl猝灭反应,并用EtOAc提取。用盐水洗涤有机层,用MgSO4干燥,过滤。除去溶剂,得到1.6g(86%)目标产物。MS(m/e):597(M+Na+)。
制品16
4-[(R)-3-(3,5-二氯-4′-甲氧羰基-联苯-4-基甲基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸叔丁基酯
将4-[3-(2,6-二氯-4-三氟甲磺酰基氧基-苄基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸叔丁基酯(制品15)(0.5g,0.9mmol)、4-甲氧羰基苯基硼酸(0.31g,1.7mmol)和四(三苯基膦)钯(0)(0.1g,0.1mmol)的DME(5mL)溶液用2M K2CO3水溶液(1.3mL)处理,加热反应至80℃,搅拌过夜。冷却反应,用1N HCl淬灭。用EtOAc提取水溶液。用盐水洗涤有机层,用MgSO4干燥,过滤。用硅胶柱色谱纯化粗品,使用己烷∶EtOAc洗脱纯产物。除去溶剂,得到0.43g(88%)目标产物。MS(m/e):583(M+Na+)。
表1:基本上按照制品16中描述的方法,制备表1中的制品,只不过用3栏中标明的试剂来替代4-甲氧羰基苯基硼酸。
制品25
4-[(R)-3-(4′-羧基-3,5-二氯-联苯-4-基甲基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸叔丁基酯
将4-[(R)-3-(3,5-二氯-4′-甲氧羰基-联苯-4-基甲基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸叔丁基酯(制品16)(0.4g,0.7mmol)的THF(5mL)溶液用1N LiOH水溶液(3.6mL)处理。在室温下搅拌反应过夜。用1N HCl猝灭反应,用EtOAc提取。用盐水洗涤有机层,用MgSO4干燥,过滤。除去溶剂,得到0.37g(96%)目标产物。MS(m/e):569(M+Na+)。
制品26
4-{(R)-3-[3,5-二氯-4′-(4-三氟甲基-哌啶-1-羰基)-联苯-4-基甲基]-2-氧代-吡咯烷-1-基}-哌啶-1-羧酸叔丁基酯
将4-[(R)-3-(4′-羧基-3,5-二氯-联苯-4-基甲基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸叔丁基酯(制品25)(0.1g,0.18mmol)、4-(三氟甲基)哌啶盐酸盐(42mg,0.22mmol)、N-(3-二甲基氨基丙基)-N-乙基碳二亚胺盐酸盐(42mg,0.22mmol)、1-羟基苯并三唑(73mg,0.22mmol)和4-甲基吗啉(0.08mL,0.73mmol)的CH2Cl2(3mL)溶液在室温下搅拌6小时。用1N HCl猝灭反应,用EtOAc提取。用盐水洗涤有机层,用MgSO4干燥,过滤。用硅胶柱色谱纯化粗品,使用己烷∶EtOAc洗脱纯产物。除去溶剂,得到0.10g(80%)目标产物。MS(m/e):582(M-BOC+)。
表2:基本上按照制品26中描述的方法,制备表2中的制品,只不过用3栏中标明的试剂来替代4-(三氟甲基)哌啶盐酸盐。
*Journal of Organic Chemistry,vol 31,no 11,pg 3867(1966)。
制品29
(R)-3-(3,5-二氯-4′-氟-联苯-4-基甲基)-1-哌啶-4-基-吡咯烷-2-酮三氟乙酸
将4-[(R)-3-(3,5-二氯-4′-氟-联苯-4-基甲基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸叔丁基酯(制品17)(0.85g,0.18mmol)的CH2Cl2(10mL)溶液用三氟乙酸(2mL)处理。在室温下搅拌反应1小时。真空浓缩反应。在SCX柱上纯化粗品,使用2M NH4/MeOH洗脱纯产物。除去溶剂,得到0.59g(85%)目标产物。MS(m/e):421(M+1)。
表3:基本上按照制品29中描述的方法,制备表3中的制品,只不过用3栏所列制品来替代4-[(R)-3-(3,5-二氯-4′-氟-联苯-4-基甲基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸叔丁基酯。
制品 | 结构和命名 | 试剂制品 | 质谱 |
30 | (R)-3-[3,5-二氯-4′-(4-三氟甲基-哌啶-1-羰基)-联苯-4-基甲基]-1-哌啶-4-基-吡咯烷-2-酮三氟乙酸 | 26 | MS(m/z):582(M+1) |
31 | (R)-3-[3,5-二氯-4′-(吗啉-4-羰基)-联苯-4-基甲基]-1-哌啶-4-基-吡咯烷-2-酮三氟乙酸 | 27 | MS(m/z):516(M+1) |
32 | (R)-3-{3,5-二氯-4′-[4-(2,2,2-三氟-乙基)-哌嗪-1-羰基]-联苯-4-基甲基}-1-哌啶-4-基-吡咯烷-2-酮 | 28 | MS(m/z):597(M+1) |
33 | (R)-3-(3,5-二氯-4′-三氟甲氧基-联苯-4-基甲基)-1-哌啶-4-基-吡咯烷-2-酮三氟乙酸 | 19 | MS(m/z):487(M+1) |
34 | (R)-3-(3,5-二氯-4′-氰基-联苯-4-基甲基)-1-哌啶-4-基-吡咯烷-2-酮三氟乙酸 | 20 | MS(m/z):428(M+1) |
35 | (R)-3-(3,5-二氯-4′-异丙氧基-联苯-4-基甲基)-1-哌啶-4-基-吡咯烷-2-酮三氟乙酸 | 21 | MS(m/z):461(M+1) |
36 | (R)-3-(3,5-二氯-4′-三氟甲基-联苯-4-基甲基)-1-哌啶-4-基-吡咯烷-2-酮三氟乙酸 | 18 | MS(m/z):471(M+1) |
37 | 3-(3,5-二氯-4′-甲基-联苯-4-基甲基)-1-哌啶-4-基-吡咯烷-2-酮三氟乙酸 | 22 | MS(m/z):418(M+1) |
38 | 3-(3,5-二氯-2′-三氟甲基-联苯-4-基甲基)-1-哌啶-4-基-吡咯烷-2-酮三氟乙酸 | 23 | MS(m/z):428(M+1) |
39 | 3-(3,5-二氯-3′-三氟甲基-联苯-4-基甲基)-1-哌啶-4-基-吡咯烷-2-酮三氟乙酸 | 24 | MS(m/z):428(M+1) |
实施例1
(R)-3-(3,5-二氯-4′-氟-联苯-4-基甲基)-1-(1-甲磺酰基-哌啶-4-基)-吡咯烷-2-酮
将(R)-3-(3,5-二氯-4′-氟-联苯-4-基甲基)-1-哌啶-4-基-吡咯烷-2-酮三氟乙酸(制品29)(0.10g,0.19mmol)的CH2Cl2(3mL)溶液用甲磺酰氯(0.02mL,0.28mmol)和三乙胺(0.07mL,0.48mmol)处理,并在室温下搅拌反应1小时。用1N HCl猝灭反应,用Et2O提取。用盐水洗涤有机层,用MgSO4干燥,过滤。除去溶剂,得到0.07g(73%)产物。MS(m/e):500(M+1)。
实施例2
3-{3,5-二氯-4′-[4-(2,2,2-三氟-乙基)-哌嗪-1-羰基]-联苯-4-基甲基}-1-(1-甲磺酰基-哌啶-4-基)-吡咯烷-2-酮
基本上按照实施例1中描述的方法制备实施例2,只不过使用(R)-3-{3,5-二氯-4′-[4-(2,2,2-三氟-乙基)-哌嗪-1-羰基]-联苯-4-基甲基}-1-哌啶-4-基-吡咯烷-2-酮(制品28)。MS(m/z):675(M+1)。
实施例3
4-[(R)-3-(3,5-二氯-4′-氟-联苯-4-基甲基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸甲基酯
将(R)-3-(3,5-二氯-4′-氟-联苯-4-基甲基)-1-哌啶-4-基-吡咯烷-2-酮三氟乙酸(制品29)(0.10g,0.19mmol)的CH2Cl2(3mL)溶液用氯甲酸甲酯(0.03mL,0.36mmol)和三乙胺(0.07mL,0.48mmol)处理。在室温下搅拌反应1小时。用1N HCl猝灭反应,用Et2O提取。用盐水洗涤有机层,用MgSO4干燥,过滤。除去溶剂,得到0.085g(74%)产物。MS(m/e):479(M+1)。
表4:基本上按照实施例3中描述的方法制备表4中的实施例,只不过用列于3栏中的制品替代(R)-3-(3,5-二氯-4′-氟-联苯-4-基甲基)-1-哌啶-4-基-吡咯烷-2-酮三氟乙酸。
实施例6
4-[(R)-3-(3,5-二氯-4′-氟-联苯-4-基甲基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸甲基酰胺
将(R)-3-(3,5-二氯-4′-氟-联苯-4-基甲基)-1-哌啶-4-基-吡咯烷-2-酮三氟乙酸(制品29)(0.10g,0.19mmol)的CH2Cl2(3mL)溶液用异氰酸甲酯(21mg,0.36mmol)和三乙胺(0.07mL,0.48mmol)处理。在室温下搅拌反应过夜。用1N HCl猝灭反应,用Et2O提取。用盐水洗涤有机层,用MgSO4干燥,过滤。用硅胶柱色谱纯化粗品,使用己烷∶EtOAc洗脱纯产物。除去溶剂,得到0.097g(84%)产物。MS(m/e):478(M+1)。
表5:基本上按照实施例6中描述的方法制备表5中的实施例,只不过用3栏中标明的试剂来替代异氰酸甲酯。
实施例11
4-[(R)-3-(3,5-二氯-4′-三氟甲氧基-联苯-4-基甲基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸甲基酰胺
将(R)-3-(3,5-二氯-4′-三氟甲氧基-联苯-4-基甲基)-1-哌啶-4-基-吡咯烷-2-酮三氟乙酸(制品33)(85mg,0.17mmol)的CH2Cl2(4mL)溶液用异氰酸甲酯(11mg,0.19mmol)处理。在室温下搅拌反应过夜。用1N HCl猝灭反应,用Et2O提取。用盐水洗涤有机层,用MgSO4干燥,过滤。用硅胶柱色谱纯化粗品,使用己烷∶EtOAc洗脱纯产物。除去溶剂,得到0.035g(37%)产物。MS(m/e):544(M+1)。
表6:基本上按照实施例11中描述的方法制备表6中的实施例,只不过用列于3栏中的制品替代(R)-3-(3,5-二氯-4′-三氟甲氧基-联苯-4-基甲基)-1-哌啶-4-基-吡咯烷-2-酮三氟乙酸。
实施例18
(R)-4-{3-[3,5-二氯-4′-(4-三氟甲基-哌啶-1-羰基)-联苯-4-基甲基]-2-氧代-吡咯烷-1-基}-哌啶-1-羧酸甲基酰胺
将(R)-3-[3,5-二氯-4′-(4-三氟甲基-哌啶-1-羰基)-联苯-4-基甲基]-1-哌啶-4-基-吡咯烷-2-酮三氟乙酸(制品30)(112mg,0.16mmol)和碳酸钾(40mg,0.32mmol)的丙酮(5mL)溶液用三甲基甲硅烷基-异氰酸酯(30mg,0.24mmol)处理。将反应在室温下搅拌过夜。用1N HCl猝灭反应,用Et2O提取。用盐水洗涤有机层,用MgSO4干燥,过滤。用硅胶柱色谱纯化粗品,使用己烷∶EtOAc洗脱纯产物。除去溶剂,得到0.038g(38%)产物。MS(m/e):626(M+1)。
表7:基本上按照实施例18中描述的方法制备表7中的实施例,只不过用3栏中标明的制品来替代(R)-3-[3,5-二氯-4′-(4-三氟甲基-哌啶-1-羰基)-联苯-4-基甲基]-1-哌啶-4-基-吡咯烷-2-酮三氟乙酸。
在下面部分中,描述了酶和功能试验,其可用于评价本发明的化合物。
11β-HSD1型酶测定法
人1型11β-HSD活性通过荧光测定法测定NADPH的产生来测定。固体化合物溶解于DMSO中,浓度为10mM。然后,将各溶液20微升转移至96-孔聚丙烯Nunc平板的一栏中,在此处溶液被进一步稀释50-倍,随后双重滴定,使用Tecan Genesis 200自动系统用另外的DMSO10倍交叉通过此板。然后将板转移至Tecan Freedom 200系统,其连接TecanTemo 96-孔前端和Ultra 384板读数器。将试剂加入96-孔聚丙烯Nunc平板中,并各自以下列方式加入到黑色96-孔分子装置高效测定板(40μL/孔容量)中:9μL/孔的底物(2.22mM NADP、55.5μM氢化可的松、10mM Tris、0.25%Prionex、0.1%Triton X100)、化合物孔中3μL/孔的水或者对照和标准孔中3μL水、6μL/孔重组11β-HSD1型酶、2μL/孔的化合物稀释液。对于抑制百分比的最终的计算,加入了代表测定最小值和最大值的一系列孔:一组包含667μM甘珀酸底物(背景),以及另一组包含底物和酶,而没有化合物(最大信号)。对于所有化合物、对照和标准品,DMSO的终浓度均为0.5%。然后,通过Tecan的机器臂将平板置于振荡器中15秒钟后,加盖并堆叠,在室温孵育3小时。孵育一旦完成,Tecan机器臂各自从存储器中移出各平板,并将其置于合适的位置中,添加5μL/孔的250μM甘珀酸溶液以终止酶促反应。将板再次振摇15秒钟,然后,置于Ultra 384全自动定量绘图酶标仪(355EX/460EM)中,以检测NADPH荧光。
以与所述的11-βHSD1相似的测定法,也可检测本发明化合物对11-βHSD2的选择性,只是要使用11-βHSD2酶。使用11-βHSD2酶的测定法可通过本文所述的方法进行,并且可通过本领域已知的方法补充。
人主动脉平滑肌细胞测定法
初级人主动脉平滑肌细胞(AoSMC)在5%FBS生长介质中培养,至传代数为6,然后通过离心沉积成片,并以密度9x104细胞/mL再混悬于含有12ng/mL hTNFα的0.5%FBS测定介质中,以诱发11β-HSD1的表达。将细胞以100μL/孔(9x103细胞/孔)接种于96-孔组织培养测定平板中,并在37℃、5%CO2中孵育48小时。孵育后,细胞在含有待测化合物的测定介质中于37℃、5%CO2孵育4小时,然后用10μL/孔的溶解于测定介质中的10μM可的松处理,并在37℃、5%CO2中孵育16小时。将各孔中的介质转移至板中,随后使用竞争性荧光响应时间分辨免疫测定法分析氢化可的松。溶液中,别藻蓝蛋白(APC)-氢化可的松缀合物和游离氢化可的松分析物竞争结合小鼠抗氢化可的松抗体/铕(Eu)-抗小鼠IgG复合物。较高水平的游离氢化可的松导致从铕-IgG到APC-氢化可的松复合物的能量传递减少,从而导致APC荧光减少。铕和APC的荧光强度使用LJL Analyst AD测定。铕和APC激发分别使用360nm激发和615nm及650nm发射过滤器测定。铕的时间分辨参数为1000μs积分时间和200μs延缓。APC参数设为150μs积分之间和50μs延缓。测定的APC荧光强度通过被Eu荧光除(APC/Eu)而被修正。然后,通过内插法,使用由4-参数对数方程拟合的氢化可的松标准曲线,这个比率用于确定未知的氢化可的松浓度。然后,通过标绘浓度对%抑制作用,拟合4-参数曲线并报告IC50,将这些浓度用于确定化合物活性。
本文公开的所有实施例证实了人主动脉平滑肌细胞测定中的活性,IC50低于300nM。实施例化合物在人主动脉平滑肌细胞测定法中的数据显示如下:
急性体内可的松转化测定法
通常,化合物经口给予小鼠,小鼠通过注射化合物后在设定时间点皮下注射可的松被激发,并且一段时间后采集每一只动物的血。然后,将分层的血清分离,并用于经LC-MS/MS分析可的松和氢化可的松的水平,随后计算各剂量组的平均氢化可的松百分抑制作用。具体地,雄性C57BL/6小鼠得自Harlan Sprague Dawley,平均体重25克。到达时记录确切体重,并且小鼠随机分为相似体重的组。在1%w-w HEC、0.25%w-w聚山梨酯80、0.05%w-w Dow Corning消泡剂#1510-US中,根据假设的平均体重25克,以不同的剂量制备化合物。化合物经口给予,每只动物200μl,随后在化合物给予后1-24小时皮下给予,每只动物200μl的30mg/kg可的松。可的松激发10分钟时,在CO2室中1分钟,将每只动物处死,随后通过心脏穿刺采集血液至血清分离试管中。一旦完全凝结,将试管在2500xg、4℃旋转15分钟,血清转移至96-孔板(CorningInc,Costar#4410,cluster tubes,1.2ml,聚丙烯)的孔中,并将板于20℃冷冻直至经LC-MS/MS分析时。为了分析,溶化血清样品,并通过加入含有d4-氢化可的松内标物的乙腈沉淀蛋白质。将样品涡旋混合并离心。移出上清液并在暖氮气流下干燥。提出物在乙腈/水(1:1)中重新配制,并注入LC-MS/MS系统。可的松和氢化可的松的水平通过选择性反应监测模式,随后在三联四极质谱分光光度计上正ACPI电离测定。
在急性体内可的松转化试验中的实施例化合物的数据如下所示:
药学可接受的盐及其制备的通常方法在本领域中是众所周知的。见,例如,P.Stahl,et al.,HANDBOOK OF PHARMACEUTICAL SALTS:PROPERTIES,SELECTION AND USE,(VCHA/Wiley-VCH,2002);S.MBerge,et al.,″Pharmaceutical Salts,″Journal of Pharmaceutical Sciences,Vol.66,No.1,January 1977。本发明的化合物优选配制成通过各种途径给药的药物组合物,最优选地,这类组合物用于口服给药。这类药物组合物及其制备方法在本领域内是众所周知的。见,例如,REMINGTON:THE SCIENCE AND PRACTICE OF PHARMACY(A.Gennaro,et al.,eds.,19thed.,Mack Publishing Co.,1995)。
根据本发明需要构成有效量的式(I)化合物或其药学可接受盐的具体剂量将取决于待治疗的病症的具体状况。考虑因素例如剂量、给药途径和给药频率最好由主治医生决定。通常,口服或肠胃外给药的可接受的有效剂量范围是约0.1mg/kg/天~约10mg/kg/天,对于人类患者其转变为约6mg~600mg,且更通常为30mg~200mg。这些剂量将每天分1~3次给予需要此治疗的患者,或者常常需要有效治疗选自本文所述的疾病中的疾病。
在制备制剂领域中的技术人员根据所选化合物的特殊性质、待治疗的疾病或病症、疾病或病症的阶段以及其它相关状况容易选择适宜的剂型和给药方式。(Remington′s Pharmaceutical Sciences,18th Edition,MackPublishing Co.(1990))。本文所要求的化合物可通过各种途径给予。在患有本文所述的疾病或发展成为本文所述的疾病风险的患者治疗中,式(I)化合物或其药物学上可接受的盐可以使化合物在有效量下是生物有效的任何剂型或模式给予,包括口服和肠胃外途径。例如,有效化合物可经直肠、经口、经吸入或通过皮下、肌内、静脉内、经皮肤、鼻内、直肠、眼、局部、舌下、口腔或其它途径给予。用于治疗本文所述的疾病,口服给药是优选的。当口服给药不可能或不优选时,组合物可以制成适于肠胃外给药的形式,例如静脉内、腹膜内或肌内。
Claims (14)
1.结构由下式代表的化合物或其药学可接受的盐:
其中
Ra是-(C1-C6)烷基、-(C3-C6)环烷基或苯基;
Rb是-(C1-C6)烷基、-(C3-C6)环烷基或苯基;
Rc是-(C1-C6)烷基、-(C3-C6)环烷基或苯基;
R1是-H、-卤素、任选被1至3个卤素取代的-O-CH3或任选被1至3个卤素取代的-CH3;
R2是-H、-卤素、任选被1至3个卤素取代的-O-CH3或任选被1至3个卤素取代的-CH3;
R3是-H或-卤素;
R6是-H。
4.权利要求1的化合物或其药学可接受的盐,其中R0是其中Ra是-(C1-C3)烷基。
6.权利要求1至5的任一项所要求的化合物或其药学可接受的盐,其中R1和R2是氯,R3是氢。
7.权利要求1所要求的化合物或其药学可接受的盐,其中R5是
9.一种化合物,其是4-{(R)-3-[3,5-二氯-4′-(4-三氟甲基-哌啶-1-羰基)-联苯-4-基甲基]-2-氧代-吡咯烷-1-基}-哌啶-1-羧酸甲基酯或其药学可接受的盐。
10.一种化合物,其是4-[(R)-3-(3,5-二氯-4′-氟-联苯-4-基甲基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸甲基酰胺或其药学可接受的盐。
11.药物组合物,其包含权利要求1至10的任一项所要求的化合物或其药学可接受的盐与药学可接受的载体。
12.权利要求1-10的任一项所要求的化合物或其药学可接受的盐用于制备用于治疗2型糖尿病或动脉粥样硬化的医药的用途。
13.选自下列的化合物:
(R)-3-(3,5-二氯-4′-氟-联苯-4-基甲基)-1-(1-甲磺酰基-哌啶-4-基)-吡咯烷-2-酮;
3-{3,5-二氯-4′-[4-(2,2,2-三氟-乙基)-哌嗪-1-羰基]-联苯-4-基甲基}-1-(1-甲磺酰基-哌啶-4-基)-吡咯烷-2-酮;
4-[(R)-3-(3,5-二氯-4′-氟-联苯-4-基甲基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸甲基酯;
4-{(R)-3-[3,5-二氯-4′-(4-三氟甲基-哌啶-1-羰基)-联苯-4-基甲基]-2-氧代-吡咯烷-1-基}-哌啶-1-羧酸甲基酯;
4-[(R)-3-(3,5-二氯-4′-氟-联苯-4-基甲基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸甲基酰胺;
4-[(R)-3-(3,5-二氯-4′-氟-联苯-4-基甲基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸环己基酰胺;
4-[(R)-3-(3,5-二氯-4′-氟-联苯-4-基甲基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸苯基酰胺;
4-[(R)-3-(3,5-二氯-4′-三氟甲氧基-联苯-4-基甲基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸甲基酰胺;
4-[(R)-3-(3,5-二氯-4′-氰基-联苯-4-基甲基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸甲基酰胺;
4-[(R)-3-(3,5-二氯-4′-三氟甲基-联苯-4-基甲基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸甲基酰胺;
4-[(R)-3-(3,5-二氯-4′-异丙氧基-联苯-4-基甲基)-2-氧代-吡咯烷-1-基]-哌啶-1-羧酸甲基酰胺;和
(R)-4-{3-[3,5-二氯-4′-(4-三氟甲基-哌啶-1-羰基)-联苯-4-基甲基]-2-氧代-吡咯烷-1-基}-哌啶-1-羧酸甲基酰胺;
或其药学可接受的盐。
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BR0315166A (pt) * | 2002-10-11 | 2005-08-16 | Astrazeneca Ab | Uso de um composto ou de um sal farmaceuticamente aceitável do mesmo, composto ou um sal farmaceuticamente aceitável do mesmo, composição farmacêutica, e, método para produzir um efeito inibidor de 11betahsd1 em um animal de sangue quente, tal como o homem, que necessita de tratamento |
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AU2007240450B2 (en) | 2006-04-21 | 2011-12-22 | Eli Lilly And Company | Cyclohexylimidazole lactam derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1 |
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ES2533263T3 (es) | 2006-04-21 | 2015-04-08 | Eli Lilly And Company | Derivados de ciclohexilpirazol-lactama como inhibidores de 11-beta-hidroxiesteroide deshidrogenasa 1 |
UA94741C2 (en) | 2006-04-24 | 2011-06-10 | Эли Лилли Энд Компани | Inhibitors of 11-beta-hydroxysteroid dehydrogenase 1 |
AU2007244971B2 (en) | 2006-04-24 | 2012-01-19 | Eli Lilly And Company | Cyclohexyl substituted pyrrolidinones as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1 |
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CL2008001839A1 (es) | 2007-06-21 | 2009-01-16 | Incyte Holdings Corp | Compuestos derivados de 2,7-diazaespirociclos, inhibidores de 11-beta hidroxil esteroide deshidrogenasa tipo 1; composicion farmaceutica que comprende a dichos compuestos; utiles para tratar la obesidad, diabetes, intolerancia a la glucosa, diabetes tipo ii, entre otras enfermedades. |
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WO2005108361A1 (en) * | 2004-05-07 | 2005-11-17 | Janssen Pharmaceutica N.V. | Adamantyl pyrrolidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors |
WO2005108360A1 (en) * | 2004-05-07 | 2005-11-17 | Janssen Pharmaceutica N.V. | Pyrrolidin-2-one and piperidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors |
WO2006049952A1 (en) * | 2004-10-29 | 2006-05-11 | Eli Lilly And Company | Cycloalkyl lactam derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1 |
WO2006104280A1 (ja) * | 2005-03-31 | 2006-10-05 | Takeda Pharmaceutical Company Limited | 糖尿病の予防・治療剤 |
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US20090088430A1 (en) | 2009-04-02 |
TNSN08432A1 (en) | 2010-04-14 |
NO20084874L (no) | 2008-11-19 |
CN101448816A (zh) | 2009-06-03 |
EA200870489A1 (ru) | 2009-04-28 |
KR20090007371A (ko) | 2009-01-16 |
US7829582B2 (en) | 2010-11-09 |
CA2650627A1 (en) | 2007-11-08 |
JP5225980B2 (ja) | 2013-07-03 |
ZA200808816B (en) | 2009-12-30 |
PL2049513T3 (pl) | 2012-06-29 |
AU2007244742B2 (en) | 2012-03-08 |
PT2049513E (pt) | 2012-03-20 |
MA30421B1 (fr) | 2009-05-04 |
CA2650627C (en) | 2013-07-16 |
ATE542811T1 (de) | 2012-02-15 |
EP2049513A1 (en) | 2009-04-22 |
DK2049513T3 (da) | 2012-02-27 |
ECSP088849A (es) | 2008-11-27 |
BRPI0710469A2 (pt) | 2011-08-16 |
EA014719B1 (ru) | 2011-02-28 |
WO2007127901A1 (en) | 2007-11-08 |
MX2008013844A (es) | 2008-11-10 |
SI2049513T1 (sl) | 2012-04-30 |
CY1112466T1 (el) | 2015-12-09 |
JP2009535362A (ja) | 2009-10-01 |
IL194879A0 (en) | 2009-08-03 |
EP2049513B1 (en) | 2012-01-25 |
AU2007244742A1 (en) | 2007-11-08 |
KR101060016B1 (ko) | 2011-08-29 |
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