CN115803085A - 新型细胞代谢调节化合物及用途 - Google Patents
新型细胞代谢调节化合物及用途 Download PDFInfo
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- CN115803085A CN115803085A CN202180045833.8A CN202180045833A CN115803085A CN 115803085 A CN115803085 A CN 115803085A CN 202180045833 A CN202180045833 A CN 202180045833A CN 115803085 A CN115803085 A CN 115803085A
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- methyl
- carboxylic acid
- indole
- cyclohepta
- hexyl
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 162
- 230000019522 cellular metabolic process Effects 0.000 title description 2
- 230000001105 regulatory effect Effects 0.000 title description 2
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- 101001062864 Homo sapiens Fatty acid-binding protein, adipocyte Proteins 0.000 claims abstract description 26
- 239000003814 drug Substances 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- 101100226596 Gallus gallus FABP gene Proteins 0.000 claims abstract description 5
- 239000013543 active substance Substances 0.000 claims abstract description 4
- 239000003085 diluting agent Substances 0.000 claims abstract description 4
- -1 6- ({ 4-carboxy-7-hexyl-5H, 6H,7H,8H, 1H-cyclohepta [ b ] indol-5-yl } methyl) pyridine-2-carboxylic acid Chemical compound 0.000 claims description 77
- 125000000217 alkyl group Chemical group 0.000 claims description 52
- 150000003839 salts Chemical class 0.000 claims description 50
- 238000000034 method Methods 0.000 claims description 49
- 125000004432 carbon atom Chemical group C* 0.000 claims description 39
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 37
- 239000000203 mixture Substances 0.000 claims description 34
- 229910052736 halogen Chemical class 0.000 claims description 33
- 150000002367 halogens Chemical class 0.000 claims description 33
- 239000002253 acid Substances 0.000 claims description 32
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 24
- 201000010099 disease Diseases 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- 125000003118 aryl group Chemical group 0.000 claims description 18
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- 208000035475 disorder Diseases 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 10
- 230000001684 chronic effect Effects 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
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- ROGHUJUFCRFUSO-UHFFFAOYSA-N 1h-indole-4-carboxylic acid Chemical compound OC(=O)C1=CC=CC2=C1C=CN2 ROGHUJUFCRFUSO-UHFFFAOYSA-N 0.000 claims description 5
- 208000024827 Alzheimer disease Diseases 0.000 claims description 5
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- YYZSBFGKQDRWNC-UHFFFAOYSA-N 7-butyl-5-[(3-carbamoylphenyl)methyl]-7,8,9,10-tetrahydro-6H-cyclohepta[b]indole-4-carboxylic acid Chemical compound CCCCC(CCC1)CC2=C1C1=CC=CC(C(O)=O)=C1N2CC1=CC(C(N)=O)=CC=C1 YYZSBFGKQDRWNC-UHFFFAOYSA-N 0.000 claims description 4
- MXVYQVKIYQRWLJ-UHFFFAOYSA-N 9-[(3-carboxyphenyl)methyl]-7-hexyl-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid Chemical compound CCCCCCC(CC1)CC2=C1C1=CC=CC(C(O)=O)=C1N2CC1=CC(C(O)=O)=CC=C1 MXVYQVKIYQRWLJ-UHFFFAOYSA-N 0.000 claims description 4
- 150000002431 hydrogen Chemical group 0.000 claims description 4
- KPPVNWGJXFMGAM-UUILKARUSA-N (e)-2-methyl-1-(6-methyl-3,4-dihydro-2h-quinolin-1-yl)but-2-en-1-one Chemical compound CC1=CC=C2N(C(=O)C(/C)=C/C)CCCC2=C1 KPPVNWGJXFMGAM-UUILKARUSA-N 0.000 claims description 3
- PZFBQDQAOBEYCD-UHFFFAOYSA-N 7-butyl-5-[(3-cyanophenyl)methyl]-7,8,9,10-tetrahydro-6H-cyclohepta[b]indole-4-carboxylic acid Chemical compound CCCCC(CCC1)CC2=C1C1=CC=CC(C(O)=O)=C1N2CC1=CC(C#N)=CC=C1 PZFBQDQAOBEYCD-UHFFFAOYSA-N 0.000 claims description 3
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- 239000004480 active ingredient Substances 0.000 claims description 3
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 3
- LOTBYPQQWICYBB-UHFFFAOYSA-N methyl n-hexyl-n-[2-(hexylamino)ethyl]carbamate Chemical compound CCCCCCNCCN(C(=O)OC)CCCCCC LOTBYPQQWICYBB-UHFFFAOYSA-N 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- GZUUXAYZUIYLMR-UHFFFAOYSA-N 10-butyl-5-[(3-carbamoylphenyl)methyl]-7,8,9,10-tetrahydro-6H-cyclohepta[b]indole-4-carboxylic acid Chemical compound CCCCC(CCCC1)C(C2=CC=C3)=C1N(CC1=CC(C(N)=O)=CC=C1)C2=C3C(O)=O GZUUXAYZUIYLMR-UHFFFAOYSA-N 0.000 claims description 2
- OOUKMRXMEYGLOA-UHFFFAOYSA-N 3-butyl-4-[(3-carbamoylphenyl)methyl]-2,3-dihydro-1H-cyclopenta[b]indole-5-carboxylic acid Chemical compound CCCCC(CC1)C2=C1C1=CC=CC(C(O)=O)=C1N2CC1=CC(C(N)=O)=CC=C1 OOUKMRXMEYGLOA-UHFFFAOYSA-N 0.000 claims description 2
- BDPWWGDKRXWQRP-UHFFFAOYSA-N 3-butyl-4-[(3-cyanophenyl)methyl]-2,3-dihydro-1H-cyclopenta[b]indole-5-carboxylic acid Chemical compound CCCCC(CC1)C2=C1C1=CC=CC(C(O)=O)=C1N2CC1=CC(C#N)=CC=C1 BDPWWGDKRXWQRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
- SUFIOZISEOHGQW-UHFFFAOYSA-N 4-[(3-carbamoylphenyl)methyl]-2-pentyl-2,3-dihydro-1H-cyclopenta[b]indole-5-carboxylic acid Chemical compound CCCCCC(C1)CC2=C1C1=CC=CC(C(O)=O)=C1N2CC1=CC(C(N)=O)=CC=C1 SUFIOZISEOHGQW-UHFFFAOYSA-N 0.000 claims description 2
- NZWIGFGVIMJOLP-UHFFFAOYSA-N 4-[(3-cyanophenyl)methyl]-2-pentyl-2,3-dihydro-1H-cyclopenta[b]indole-5-carboxylic acid Chemical compound CCCCCC(C1)CC2=C1C1=CC=CC(C(O)=O)=C1N2CC1=CC(C#N)=CC=C1 NZWIGFGVIMJOLP-UHFFFAOYSA-N 0.000 claims description 2
- RBBXJFNTXRIQOB-UHFFFAOYSA-N 4-[(3-cyanophenyl)methyl]-3-ethyl-2,3-dihydro-1H-cyclopenta[b]indole-5-carboxylic acid Chemical compound CCC(CC1)C2=C1C1=CC=CC(C(O)=O)=C1N2CC1=CC(C#N)=CC=C1 RBBXJFNTXRIQOB-UHFFFAOYSA-N 0.000 claims description 2
- AFUCITXWOAEVQM-UHFFFAOYSA-N 4-[(3-cyanophenyl)methyl]-3-propyl-2,3-dihydro-1H-cyclopenta[b]indole-5-carboxylic acid Chemical compound CCCC(CC1)C2=C1C1=CC=CC(C(O)=O)=C1N2CC1=CC(C#N)=CC=C1 AFUCITXWOAEVQM-UHFFFAOYSA-N 0.000 claims description 2
- JOULTSNVGQIWGS-UHFFFAOYSA-N 5-(1,3-benzoxazol-5-ylmethyl)-7-hexyl-7,8,9,10-tetrahydro-6H-cyclohepta[b]indole-4-carboxylic acid Chemical compound CCCCCCC(CCC1)CC2=C1C1=CC=CC(C(O)=O)=C1N2CC(C=C1)=CC2=C1OC=N2 JOULTSNVGQIWGS-UHFFFAOYSA-N 0.000 claims description 2
- XPIWUEOIDSKMAZ-UHFFFAOYSA-N 5-(1,3-benzoxazol-6-ylmethyl)-7-hexyl-7,8,9,10-tetrahydro-6H-cyclohepta[b]indole-4-carboxylic acid Chemical compound CCCCCCC(CCC1)CC2=C1C1=CC=CC(C(O)=O)=C1N2CC(C=C1)=CC2=C1N=CO2 XPIWUEOIDSKMAZ-UHFFFAOYSA-N 0.000 claims description 2
- KVYUQZYDKHPFTF-UHFFFAOYSA-N 5-(1,3-benzoxazol-7-ylmethyl)-7-hexyl-7,8,9,10-tetrahydro-6H-cyclohepta[b]indole-4-carboxylic acid Chemical compound CCCCCCC(CCC1)CC2=C1C1=CC=CC(C(O)=O)=C1N2CC1=CC=CC2=C1OC=N2 KVYUQZYDKHPFTF-UHFFFAOYSA-N 0.000 claims description 2
- VVIXAIRCSKMOAZ-UHFFFAOYSA-N 5-(3-cyanobenzoyl)-7-hexyl-7,8,9,10-tetrahydro-6H-cyclohepta[b]indole-4-carboxylic acid Chemical compound CCCCCCC(CCC1)CC2=C1C1=CC=CC(C(O)=O)=C1N2C(C1=CC(C#N)=CC=C1)=O VVIXAIRCSKMOAZ-UHFFFAOYSA-N 0.000 claims description 2
- XDNHERUANGTDQI-UHFFFAOYSA-N 5-[(2-carbamoylphenyl)methyl]-7-hexyl-7,8,9,10-tetrahydro-6H-cyclohepta[b]indole-4-carboxylic acid Chemical compound CCCCCCC(CCC1)CC2=C1C1=CC=CC(C(O)=O)=C1N2CC(C=CC=C1)=C1C(N)=O XDNHERUANGTDQI-UHFFFAOYSA-N 0.000 claims description 2
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- APINOAIRKDOEEX-UHFFFAOYSA-N 5-[(2-fluoropyridin-4-yl)methyl]-7-hexyl-7,8,9,10-tetrahydro-6H-cyclohepta[b]indole-4-carboxylic acid Chemical compound CCCCCCC(CCC1)CC2=C1C1=CC=CC(C(O)=O)=C1N2CC1=CC(F)=NC=C1 APINOAIRKDOEEX-UHFFFAOYSA-N 0.000 claims description 2
- HJZSIJREGABIAJ-UHFFFAOYSA-N 5-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-7-hexyl-7,8,9,10-tetrahydro-6H-cyclohepta[b]indole-4-carboxylic acid Chemical compound CCCCCCC(CCC1)CC2=C1C1=CC=CC(C(O)=O)=C1N2CC1=C(C)ON=C1C HJZSIJREGABIAJ-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/94—[b, c]- or [b, d]-condensed containing carbocyclic rings other than six-membered
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
一类新型的根据式I、II、或III的化合物,其中W1‑W4、Z1‑Z4、Z1‑Z5、X、Y、n、和R1‑R8如权利要求和具体实施方式中定义,这些化合物结合脂肪酸结合蛋白FABP4并调节脂肪细胞代谢以驱动增强的葡萄糖利用,以及药物组合物,其包含该类别的化合物以及药学上可接受的稀释剂或载体和任选地还有治疗活性剂,以及这些化合物在药物中以及用于制备治疗作用于该FABP4的病症的药物的用途。在实例中,环Z含有Z1‑Z4。在其他实例中,该环Z含有Z1‑Z5。
Description
相关申请章节的交叉引用
本申请要求2020年6月27日提交的美国临时专利申请S/N 63/045,079的优先权,其全部内容特此通过引用以其整体并入。
技术领域
本发明涉及用于治疗或预防与代谢和炎症相关的疾病的新型化合物,这些疾病包括但不限于2型糖尿病、肥胖症、心血管疾病、哮喘、癌症和其他疾病。本发明中的化合物特别地与脂肪酸结合蛋白(FABP)4相互作用,并且改善脂肪细胞中的葡萄糖消耗。
背景技术
FABP是可逆地结合游离脂肪酸及其他脂质分子并促进其在细胞中的转运的蛋白质家族。迄今为止,已经在哺乳动物中鉴定出九种不同的FABP亚型。FABP亚型在不同组织中表现出不同的表达模式。脂肪酸结合蛋白4(FABP4)(在文献中也常被称为aP2)主要在脂肪细胞和巨噬细胞中表达,并介导这些细胞中的关键代谢和炎症途径,如脂质储存和降解、信号传导和类花生酸产生。此外,FABP4也分泌到血浆中,并被认为是调节全身葡萄糖稳态的脂肪衍生因子。
小鼠的基因敲除研究为FABP4的组织特异性和系统性功能提供了一些见解。重要的是,当携带FABP4基因纯合缺失的小鼠接受长期高脂肪饮食时,它们的体重增加与野生型相当,但不受高血糖症和胰岛素抵抗的影响(Hotamisligil等人,Science[科学].1996年11月22日;274(5291):1377-9)。此外,FABP4缺陷显著保护载脂蛋白E(ApoE)敲除小鼠免于动脉粥样硬化,这是一种归因于FABP4调节巨噬细胞中的炎症途径的表型(Makowski等人,NatMed[自然科学].2001年6月;7(6):699-705)。在气道上皮细胞中也检测到了FABP4表达,并且在过敏性肺部炎症的小鼠模型中证明了FABP4缺陷是有保护作用的(Shum等人,J ClinInvest[临床研究杂志].2006年8月;116(8):2183-2192)。
文献中已经公开了几份报告,将FABP4表达水平和功能与人类的许多病状联系起来。例如,在携带导致此基因表达降低的FABP4(rs77878271)的启动子区中的遗传变异的个体中观察到2型糖尿病和冠心病的风险降低(Tuncman等人,Proc Natl Acad Sci U S A[美国科学院院刊].2006年5月2日;103(18):6970-5)。在一项独立研究中,相同的多态性也与动脉粥样硬化疾病表现的减少相关(Saksi等人,Circ Cardiovasc Genet[循环心血管遗传学].2014年10月;7(5):588-98)。此外,在FABP4(rs1054135-GG基因型)的3'非翻译区(UTR)具有还导致FAB4表达降低的单核苷酸多态性的三阴性乳腺癌患者与疾病进展的风险降低和无病生存期延长相关(Wang等人,Oncotarget[癌症靶标].2016年4月5日;7(14):18984-98)。此外,已在先兆子痫胎盘中观察到FABP4表达增加,并提出FABP4表达增加在先兆子痫的发病机制中发挥作用(Yan等人,Placenta[胎盘].2016年3月;39:94-100)。类似地,多囊卵巢综合征患者的颗粒细胞也显示出FABP4表达增加,并且这与疾病的临床特征相关(Hu和Qiao,Endocrine[内分泌].2011年10月;40(2):196-202)。总之,这些研究证明了FAPB4在调节全身代谢和炎症中的积极作用,并且表明FABP4的药理学靶向可以用作治疗与FABP4功能相关的各种疾病的策略。
脂肪细胞在全身葡萄糖稳态中起着重要作用。它们的主要作用之一是吸收血浆中过量的葡萄糖,并以脂质的形式储存。由于代谢应激和炎症,脂肪细胞功能障碍通常导致并发症,如高血糖症和胰岛素抵抗。值得注意的是,FABP4缺陷小鼠显示出脂肪组织葡萄糖沉积增加。与它们的野生型对应物相比,从这些动物中分离的脂肪细胞显示出显著提高的葡萄糖转化为脂肪酸的速率。(Shaughnessy等人,Diabetes[糖尿病]2000年6月;49(6):904-911)。因此,可以通过靶向FABP4来实现脂肪细胞中的葡萄糖消耗增加。
虽然文献和某些现有技术专利申请(例如,WO 00/47734、WO 00/15229、WO 00/15230、WO 02/40448、WO 01/54694、WO 00/59506和WO 2004/063156)总体上已经提供了FABP抑制概念的各种介绍,并且特别是FABP4抑制概念的介绍,但是这些现有技术文献中的讨论都没有像本发明那样提供对所有未满足需求的一种或多种解决方案。具体地,本发明描述了一类新型的化合物,其结合FABP4并调节脂肪细胞代谢以驱动增强的葡萄糖利用。
发明内容
本发明在其实施例中的一个中涉及一种具有式(I)的化合物:
其中:
W1-4和Z1-Z5各自独立地是-C、-CH、CH2、O、S、或N;
X独立地是CH2、N或CHR4;
Y独立地是CH2、或CHR5;
n是在0与3之间的数;
环Z上的一个或多个R1独立地选自由以下组成的组:CN、OH、COOH、OCH3、CF3、CONH2、B(OH)2、B(OR)2、酸等排体、取代的胺、醚、和卤素、取代的或未取代的烷基、取代的或未取代的环或杂环、取代的或未取代的环芳基或环杂芳基,其中该取代的环芳基或环杂芳基可以被氢、CN、OH、COOH、OCH3、CF3、CONH2、B(OH)2、B(OR)2、酸等排体、取代的胺、醚、和卤素、取代的或未取代的烷基、取代的或未取代的环或杂环、取代的或未取代的环芳基或环杂芳基、SO2NH2取代;
环W上的一个或多个R2独立地选自由以下组成的组:CN、OH、CHF2、CH2F、CF3、COOH、CONH2、B(OH)2、B(OR)2、酸等排体、卤素、和双环杂芳基;
R7是氢或CN、COOH、CONH2、B(OH)2、B(OR)2或酸等排体;
R是烷基;
R3、R4、R5或R8、或R6(当n不是零时)各自独立地选自:
(1)氢;
(2)具有1至12个碳原子的烷基或醚;
(3)取代的胺;或
(4)--(CH2)mG,其中m是1至12,并且G独立地选自:
(a)含有3至6个碳原子的环烷基,
(b)芳基或杂芳基,
(c)CF3、CF2H或CFH2,或
(d)杂环,
其前提是R3、R4、R5、R8、或R6不都是氢;
或其药学上可接受的盐或立体异构体。
本发明的目的是根据式(I)、(II)或(III)的化合物,其用于在治疗作用于脂肪酸结合蛋白(FABP4)的病症中使用。
本发明的又另一个目的是一种用于在治疗作用于FABP4的病症中使用的药物组合物,该药物组合物包含作为活性成分的根据式(I)、(II)或(III)的化合物以及药学上可接受的稀释剂或载体。在此,该药物组合物可以进一步包含另外的治疗活性剂。
本发明的又另一个目的是一种用于治疗作用于FABP4的病症的方法,该方法包括向需要此类治疗的受试者(优选地,人类)施用有效量的根据式(I)、(II)或(III)的化合物,包括任选地与其他治疗剂以单(或多)剂量且同时或顺序地共同施用。
本发明的又另一个目的是一种用于抑制FABP4的方法,该方法包括向需要此类治疗的受试者(优选地,人类)施用有效量的根据式(I)、(II)或(III)的化合物。
本发明的又另一个目的是根据式(I)、(II)或(III)的化合物用于制造用于治疗作用于脂肪酸结合蛋白FABP4的病症的药物的用途。此类病症的实例包括2型糖尿病、高血糖症、代谢综合征、肥胖症、动脉粥样硬化、颅内动脉粥样硬化疾病、非酒精性脂肪性肝炎、哮喘、血管性痴呆、多发性硬化、阿尔茨海默病、其他慢性炎症和自身免疫性/炎症性疾病、慢性心脏病、多囊卵巢综合征、先兆子痫、和癌症。
本发明的其他特征和优点将从具体实施方式和权利要求中显而易见。
具体实施方式
现在将参考附图来描述本发明的优选实施例。在各个附图中相同的元件用相同的附图标记标识。
现在将详细参考本发明的每个实施例。此类实施例是通过解释本发明的方式提供的,而不是旨在限制于此。事实上,本领域的普通技术人员在阅读本说明书和查看附图时可以理解可以做出各种修改和变化。
在一个实施例中,本发明是一种具有式(I)的化合物,其包含:
其中:
W1-4和Z1-Z5各自独立地是-C、-CH、CH2、O、S、或N;
X独立地是CH2、N或CHR4;
Y独立地是CH2、或CHR5;
n是在0与3之间的数;
环Z上的一个或多个R1独立地选自由以下组成的组:CN、OH、COOH、OCH3、CF3、CONH2、B(OH)2、B(OR)2、酸等排体、取代的胺、醚、和卤素、取代的或未取代的烷基、取代的或未取代的环或杂环、取代的或未取代的环芳基或环杂芳基,其中该取代的环芳基或环杂芳基可以被氢、CN、OH、COOH、OCH3、CF3、CONH2、B(OH)2、B(OR)2、酸等排体、取代的胺、醚、和卤素、取代的或未取代的烷基、取代的或未取代的环或杂环、取代的或未取代的环芳基或环杂芳基、SO2NH2取代;
环W上的一个或多个R2独立地选自由以下组成的组:CN、OH、CHF2、CH2F、CF3、COOH、CONH2、B(OH)2、B(OR)2、酸等排体、卤素、和双环杂芳基;
R7是氢或CN、COOH、CONH2、B(OH)2、B(OR)2或酸等排体;
R是烷基;
R3、R4、R5或R8、或R6(当n不是零时)各自独立地选自:
(1)氢;
(2)具有1至12个碳原子的取代的或未取代的烷基或醚;
(3)取代的胺;或
(4)--(CH2)mG,其中m是1至12,并且G独立地选自:
(a)含有3至6个碳原子的环烷基,
(b)芳基或杂芳基,
(c)CF3、CF2H或CFH2,或
(d)杂环,
其前提是R3、R4、R5、R8、或R6不都是氢;
或其药学上可接受的盐或立体异构体。
此外,具有式I的化合物,其中,当R1和R2两者都存在时,各自独立地是CN、COOH、或CONH2。
此外,具有式I的化合物,其中该式I包含多个R1和R2。
此外,具有式I的化合物,其中R3、R4、R5、R8、或R6(当n不是零时)各自独立地是具有4个碳原子的烷基。
此外,具有式I的化合物,其中R3、R4、R5、R8、或R6(当n不是零时)各自独立地是具有5个碳原子的烷基。
此外,具有式I的化合物,其中R3、R4、R5、R8、或R6(当n不是零时)各自独立地是具有6个碳原子的烷基。
此外,具有式I的化合物的环Z可以具有不同的大小(例如,可以是五元环、六元环等)。
在一些实例中,具有式I的化合物的环Z含有Z1-Z4。
在其他实例中,具有式I的化合物的环Z含有Z1-Z5。
在实例中,环Z上的一个或多个R1是卤素。
在实例中,环Z上的一个或多个R1是CN。
在实例中,环Z上的一个或多个R1是CF3。
在实例中,环W上的一个或多个R2是卤素。
在实例中,环Z上的一个或多个R1包含CN和/或卤素。
在实例中,环Z上的一个或多个R1包含CN和/或卤素,并且环W上的一个或多个R2包含另一个卤素。在一些实例中,该卤素与该另一个卤素相同。在其他实例中,该卤素与该另一个卤素不同。
在另一个实施例中,本发明是一种具有式(II)的化合物,其包含:
其中:
n=0、1、或2;
R1选自由以下组成的组:CN、COOH、CONH2、B(OH)2、B(OR)2、酸等排体、和卤素;
R2选自由以下组成的组:CN、COOH、CONH2、B(OH)2、B(OR)2、酸等排体、卤素、和双环化合物;
R7是氢或CN、COOH、CONH2、B(OH)2、B(OR)2或酸等排体;
R是烷基;
R3、R4、R5或R8、或R6(当n不是零时)各自独立地选自:
(1)氢;
(2)具有1至12个碳原子的烷基;或
(3)--(CH2)mG,其中m是1至12,并且G独立地选自:
(a)含有3至6个碳原子的环烷基
(b)芳基或杂芳基,或
(c)CF3、CF2H或CFH2
其前提是G不是含氮或氧的基团;并且
其前提是R3、R4、R5、R8、或R6不都是氢;
或其药学上可接受的盐。
此外,具有式II的化合物,其中,当R1和R2两者都存在时,各自独立地是CN、COOH、或CONH2。
此外,具有式II的化合物包含多个R1和R2。
此外,具有式II的化合物,其中R3、R4、R5、R8、或R6(当n不是零时)各自独立地是具有4个碳原子的烷基。
此外,具有式I的化合物,其中R3、R4、R5、R8、或R6(当n不是零时)各自独立地是具有5个碳原子的烷基。
此外,具有式I的化合物,其中R3、R4、R5、R8、或R6(当n不是零时)各自独立地是具有6个碳原子的烷基。
在又另一个实施例中,本发明是一种具有式(III)的化合物,其包含:
其中:
n=0、1或2;
R1和R2各自独立地是CN、COOH、CONH2、B(OH)2、B(OR)2或酸等排体;
R是烷基;
R3独立地选自:
(1)具有1至12个碳原子的烷基;
(2)--(CH2)mG,其中m是1至12,并且G独立地选自:
(a)含有3至6个碳原子的环烷基;和
(b)苯基;并且
其前提是G不是含氮或氧的基团;
或其药学上可接受的盐。
根据式III的化合物,其中n=0并且R3附接至h-、i-、或j-位。
根据式III的化合物,其中n=1并且R3附接至h-、i-、或j-位。
根据式III的化合物,其中n=2并且R3附接至h-、i-、或j-位。
根据式III的化合物,其为纯光学异构体。
根据式III的化合物,其是(+)-异构体。
定义
如本文所用,术语“酸等排体”包括但不限于以下官能团,其中R是烷基基团:
术语“烷基”是指具有从1至10个碳原子的饱和直链或支链烃基。代表性烷基基团包括但不限于甲基、乙基、正丙基、异丙基、2-甲基-1-丙基、2-甲基-2-丙基、2-甲基-1-丁基、3-甲基-1-丁基、2-甲基-3-丁基、2,2-二甲基-1-丙基、2-甲基-1-戊基、3-甲基-1-戊基、4-甲基-1-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2,2-二甲基-1-丁基、3,3-二甲基-1-丁基、2-乙基-1-丁基、丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基等,以及高级烷基基团,如庚基、辛基等。如本文所用,“低级烷基”意指具有从1至6个碳原子的烷基。
术语“亚烷基”是指二价烷基基团。
如本文所用,术语“烷氧基”包括-O-(烷基),其中烷基如上定义。
如本文所用,术语“氨基”是指-NH2基团。
“芳基”意指单环、双环或三环芳香族基团,其中该基团的所有环都是芳香族的,并且所有环原子都是碳原子。对于双环或三环体系,各个芳香族环彼此稠合。芳基基团的实例为6元和10元芳基。芳基基团的另外实例包括但不限于苯基、萘、和蒽。
如本文所用,术语“氰基”意指具有通过三键与氮原子相连的碳原子的取代基。
如本文所用,术语“氘”意指具有一个质子和一个中子的氢的稳定同位素。
术语“卤基”表示氯、氟、溴、或碘。在一些实施例中,卤基是氯、氟、或溴。如本文所用,术语“卤素”是指氟、氯、溴、或碘。
术语“羟基”意指-OH基团。
术语“氧代(oxo)”意指=O基团,并且可以附接至碳原子或硫原子。
术语“N-氧化物”是指氮原子的氧化形式。
如本文所用,术语“环烷基”是指具有从3至15个碳环原子的饱和或部分饱和的单环、稠合多环、桥接多环、或螺多环碳环。非限制性类别的环烷基基团是具有从3至6个碳原子的饱和或部分饱和的单环碳环。环烷基基团的说明性实例包括但不限于以下部分:
如本文所用,“杂环烷基”是指单环的、或稠合的、桥接的、或螺多环的环结构,其是饱和的或部分饱和的,并且具有从3至12个选自碳原子的环原子和至多3个选自氮、氧、和硫的杂原子。该环结构可以任选地在碳或硫环成员上含有至多两个氧代基团,或N-氧化物。说明性杂环烷基实体包括但不限于:
如本文所用,术语“杂芳基”是指具有从3至15个选自碳、氧、氮、和硫的环原子的单环、或稠合多环、芳香族杂环。合适的杂芳基基团不包括必须带电荷才是芳香族的环体系,如吡喃鎓。合适的5元杂芳基环(作为单环杂芳基或作为多环杂芳基的一部分)具有一个氧、硫、或氮环原子,或一个氮加一个氧或硫,或2、3、或4个氮环原子。合适的6元杂芳基环(作为单环杂芳基或作为多环杂芳基的一部分)具有1、2、或3个氮环原子。杂芳基基团的实例包括但不限于吡啶基、咪唑基、咪唑并吡啶基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、噌啉基、吲唑基、吲嗪基、酞嗪基、哒嗪基、三嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、三唑基、噻二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、喹噁啉基、萘啶基、和呋喃并吡啶基。
术语“双环杂芳基”是指如上定义的杂芳基,其具有两个芳香族环组成部分,其中这两个环彼此稠合并且至少一个环是如上定义的杂芳基。双环杂芳基包括包含1、2、3、或4个选自O、N或S的杂原子环原子的双环杂芳基基团。在某些实施例中,其中该杂原子是N,其可以是N-氧化物。双环杂芳基还包括8元、9元、或10元双环杂芳基基团。双环杂芳基还包括8元、9元、或10元双环杂芳基基团,其具有1、2、3、或4个选自O、N或S的杂原子环原子。双环杂芳基的说明性实例包括但不限于:
本领域的技术人员将认识到,上文列出或说明的杂芳基、环烷基、和杂环烷基基团的种类不是穷举的,并且也可以选择在这些定义的术语范围内的另外的种类。
如本文所用,术语“取代的”意指指定的基团或部分带有一个或多个合适的取代基。如本文所用,术语“未取代的”意指指定的基团不带有取代基。如本文所用,术语“任选取代的”意指指定的基团未被取代或未被指定数目的取代基取代。当术语“取代的”用于描述结构体系时,取代意味着发生在体系上任何化合价允许的位置。
如本文所用,表述“一个或多个取代基”指示在体系上任何化合价允许的位置上可以发生的一个至最大可能数目的取代。在某些实施例中,一个或多个取代基意指1、2、3、4、或5个取代基。在另一个实施例中,一个或多个取代基意指1、2、或3个取代基。
本文中任何以未满足的化合价表示的原子都被假设具有足够数目的氢原子以满足该原子的化合价。
当任何变量(例如,烷基或Ra)出现在本文提供的任何式或描述中的多于一个位置时,该变量在每次出现时的定义独立于其在每两次出现时的定义。
如本文所用,数值范围旨在包括连续的整数。例如,表示为“从0到4”或“0-4”的范围包括0、1、2、3和4。
当显示多官能部分时,与式的其余部分的附接点可以在多官能部分上的任何点处。在一些实施例中,附接点由线或连字符指示。例如,芳氧基-是指其中氧原子是与核心分子的附接点而芳基与氧原子附接的部分。
另外的定义
如本文所用,“质子核磁共振”或1H NMR是核磁共振在NMR光谱中的应用,涉及物质分子内的氢-1核,以便确定其分子的结构。
如本文所用,术语“受试者”涵盖哺乳动物和非哺乳动物。哺乳动物的实例包括但不限于哺乳动物类的任何成员:人类;非人类灵长类动物,如黑猩猩、和其他猿和猴类;农场动物,如牛、马、绵羊、山羊、猪;家畜,如兔、狗、和猫;以及实验室动物,包括啮齿动物,如大鼠、小鼠和豚鼠,等。非哺乳动物的实例包括但不限于鸟类、鱼类等。在本发明的一个实施例中,该哺乳动物是人类。
“患者”包括人类和动物两者。
术语“抑制剂”是指阻断或以其他方式干扰特定生物活性的分子,如化合物、药物、酶激活剂、或激素。
术语“调节剂”是指增加或减少或以其他方式影响给定酶或蛋白质的活性的分子,如本发明的化合物。
术语“有效量”或“治疗有效量”是指足以提供所希望的生物学结果的药剂的量。该结果可以是疾病或医学病况的体征、症状、或病因的减少和/或减轻,或生物系统的任何其他所希望的改变。例如,用于治疗用途的“有效量”是提供疾病状态、症状、或医学病况的临床相关变化所需的化合物或包含该化合物的组合物的量。在任何个别情况下,适当的“有效”量可以由本领域的一名普通技术人员确定。因此,表述“有效量”通常是指活性物质具有治疗上所希望的效果的量。
如本文所用,术语“治疗(treat)”或“治疗(treatment)”涵盖“预防性”治疗和“治愈性”治疗两者。“预防性”治疗意指延缓疾病、疾病症状、或医学病况的发展,抑制可能出现的症状,或降低疾病或症状发展或复发的风险。“治愈性”治疗包括降低现有疾病、症状、或病况的严重程度或抑制其恶化。因此,治疗包括改善或预防现有疾病症状的恶化、预防另外症状的发生、改善或预防症状的潜在代谢原因、抑制病症或疾病,例如阻止病症或疾病的发展、缓解病症或疾病、引起病症或疾病的消退、缓解由疾病或病症引起的病况、或停止疾病或病症的症状。
另外的化学描述
本文给出的任何式旨在表示具有由结构式描绘的结构以及某些变体或形式的化合物。例如,本文给出的任何式的化合物可以具有不对称或手性中心,并且因此以不同的立体异构形式存在。具有通式的化合物的所有立体异构体(包括光学异构体、对映异构体、和非对映异构体)及其混合物都被认为落入该式的范围内。此外,某些结构可能以几何异构体(即,顺式和反式异构体)、互变异构体、或阻转异构体的形式存在。所有此类异构形式、及其混合物在本文中被考虑作为本发明的一部分。因此,本文给出的任何式旨在表示外消旋体、一种或多种对映异构形式、一种或多种非对映异构形式、一种或多种互变异构或阻转异构形式、及其混合物。
非对映异构体混合物可以通过本领域普通技术人员熟知的方法(例如像通过色谱法和/或分级结晶),基于其物理化学差异而被分离成它们各自的非对映异构体。对映异构体可以通过以下方式来分离:通过与适当的光学活性化合物(例如,手性助剂,如手性醇或莫舍酰氯(Mosher's acid chloride)反应、或形成非对映异构体盐的混合物)将对映异构体混合物转化为非对映异构体混合物,分离非对映异构体并且将单独的非对映异构体转化(例如,水解或脱盐)为相应的纯对映异构体。对映异构体也可以通过使用手性HPLC柱来分离。本发明化合物的手性中心可以指示为如由IUPAC 1974建议(IUPAC1974Recommendations)所定义的“R”或“S”。
本发明的化合物可以形成药学上可接受的盐,它们也在本发明的范围内。“药学上可接受的盐”是指具有式I、II、或III的化合物的游离酸或碱的盐,其是无毒的、生理上可耐受的、与其配制的药物组合物相容的、并且另外适合配制和/或施用于受试者。除非另有说明,否则本文提及的化合物应理解为包括提及所述化合物的药学上可接受的盐。
化合物盐包括与无机酸和/或有机酸形成的酸式盐,以及与无机碱和/或有机碱形成的碱式盐。此外,当给定化合物含有碱性部分(诸如但不限于吡啶或咪唑)和酸性部分(诸如但不限于羧酸)两者时,本领域技术人员将认识到该化合物可能以两性离子(“内盐”)的形式存在;此类盐包括在如本文所用的术语“盐”内。本发明化合物的盐可以例如通过使化合物与一定量的合适酸或碱(如当量量)在介质(如盐在其中沉淀的介质)中或在水性介质中反应,随后冻干而制备。
示例性盐包括但不限于硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、亚硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、丹宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡萄糖酸盐、葡萄糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲基磺酸盐(“甲磺酸盐”)、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、和双羟萘酸盐(即,1,1'-亚甲基-双(2-羟基-3-萘甲酸盐))盐。药学上可接受的盐可以涉及包含另一种分子,如乙酸根离子、琥珀酸根离子或其他抗衡离子。抗衡离子可以是使母体化合物上的电荷稳定化的任何有机或无机部分。此外,药学上可接受的盐可以在其结构中具有多于一个的带电荷的原子。多个带电荷的原子是药学上可接受的盐的一部分的情况可以具有多个抗衡离子。因此,药学上可接受的盐可以具有一个或多个带电荷的原子和/或一个或多个抗衡离子。
示例性的酸加成盐包括乙酸盐、抗坏血酸盐、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、富马酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐、硝酸盐、草酸盐、磷酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐(toluenesulfonate)(也称为甲苯磺酸盐(tosylate))等。
示例性的碱式盐包括铵盐、碱金属盐(如钠盐、锂盐、和钾盐)、碱土金属盐(如钙盐和镁盐)、与有机碱(例如,有机胺)(如二环己基胺、叔丁基胺)的盐、以及与氨基酸(如精氨酸、赖氨酸)的盐等。碱性含氮基团可以用试剂如低级烷基卤化物(例如,甲基、乙基、和丁基的氯化物、溴化物和碘化物)、二烷基硫酸酯(二甲基、二乙基和二丁基的硫酸酯)、长链卤化物(例如,癸基、月桂基、和硬脂酰基的氯化物、溴化物和碘化物)、芳烷基卤化物(例如,苄基和苯乙基的溴化物)等季铵化。
此外,通常认为适合于由药物化合物形成药学上有用的盐的酸和碱例如由以下文献描述:P.Stahl等人,Camille G.(编辑)Handbook ofPharmaceutical Salts:Properties,Selection and Use[药用盐手册:特性、选择与使用].(2002)苏黎世:Wiley-VCH出版社;S.Berge等人,J.Pharm.Sci.[药学科学杂志](1977)66(1)1-19;P.Gould,Int.J.Pharm.[国际药剂学杂志](1986)33201-217;Anderson等人,The PracticeofMedicinal Chemistry[药物化学实践](1996),学术出版社,纽约;以及The Orange Book[橘皮书](食品药品管理局,马里兰州,从FDA获得)。这些披露通过引用并入本文。
此外,本文所述的任何化合物还旨在指代任何非溶剂化形式,或这种化合物的水合物、溶剂化物、或多晶型物,以及其混合物,即使此类形式未明确列出。“溶剂化物”意指本发明的化合物与一个或多个溶剂分子的物理缔合。这种物理缔合涉及不同程度的离子键合和共价键合,包括氢键合。在某些情况下,例如当一个或多个溶剂分子被并入结晶固体的晶格中时,溶剂化物将能够分离。“溶剂化物”涵盖溶液相以及可分离的溶剂化物两者。合适的溶剂化物包括与药学上可接受的溶剂如水、乙醇等形成的那些。在一些实施例中,溶剂是水,并且溶剂化物是水合物。
本发明的一种或多种化合物可以任选地转化为溶剂化物。制备溶剂化物的方法通常是已知的。因此,例如M.Caira等人,J.Pharm.Sci.[药学科学杂志],93(3),601-611(2004)描述了在乙酸乙酯以及水中制备抗真菌药氟康唑的溶剂化物。溶剂化物、半溶剂化物、水合物等的类似制备由E.C.van Tonder等人,AAPS PharmSciTech.[AAPS药学科技],5(1),文章12(2004);以及A.L.Bingham等人,Chem.Commun.[化学通讯],603-604(2001)描述。典型的非限制性方法包括在高于环境温度下将本发明化合物溶解在适量的溶剂(有机溶剂或水或其混合物)中,并以足以形成晶体的速率冷却溶液,然后将其通过标准方法分离。分析技术(例如像红外光谱)显示晶体中溶剂(或水)以溶剂化物(或水合物)的形式存在。
本发明还涉及具有式I、II、或III的化合物的药学上可接受的前药,以及采用此类药学上可接受的前药的治疗方法。术语“前药”意指指定化合物的前体,在施用于受试者后,其经由化学或生理过程(如溶剂分解或酶促裂解)、或在生理条件下在体内产生化合物(例如,前药在达到生理pH时转化为具有式I、II、或III的化合物)。“药学上可接受的前药”是无毒的、生物学上可耐受的、以及另外适合配制和/或施用于受试者的前药。用于选择和制备合适前药衍生物的说明性程序例如描述于“Design ofProdrugs[前药的设计]”,H.Bundgaard编辑,爱思唯尔(Elsevier),1985中。
前药的实例包括本发明化合物的药学上可接受的酯,它们也被认为是本发明的一部分。本发明化合物的药学上可接受的酯包括以下组:(1)通过羟基基团的酯化获得的羧酸酯,其中酯基的羧酸部分的非羰基部分选自直链或支链烷基(例如,乙酰基、正丙基、叔丁基、或正丁基)、烷氧基烷基(例如,甲氧基甲基)、芳烷基(例如,苄基)、芳氧基烷基(例如,苯氧基甲基)、芳基(例如,任选地被例如卤素、C1-4烷基、C1-4烷氧基、或氨基取代的苯基);(2)磺酸酯,如烷基-或芳烷基磺酰基(例如,甲磺酰基);(3)氨基酸酯(例如,L-缬氨酰基或L-异亮氨酰基);(4)膦酸酯;和(5)单、二或三磷酸酯。这些磷酸酯可以进一步通过例如C1-20醇或其反应性衍生物、或通过2,3-二(C6-24)酰基甘油酯化。前药的另外讨论提供在T.Higuchi和V.Stella,A.C.S.研讨会系列中的Pro-drugs as Novel Delivery Systems[作为新型递送系统的前药](1987)14以及Bioreversible Carriers in Drug Design[药物设计中的生物可逆载体],(1987)Edward B.Roche编辑,美国制药协会和佩加蒙出版社(AmericanPharmaceutical Association andPergamon Press)。
例如,如果具有式I、II、或III的化合物含有羧酸官能团,则前药可以包含通过将酸基团的氢原子替代为例如像以下的基团而形成的酯:(C1-C8)烷基、(C2-C12)烷酰氧基甲基、具有从4至9个碳原子的1-(烷酰氧基)乙基、具有从5至10个碳原子的1-甲基-1-(烷酰氧基)-乙基、具有从3至6个碳原子的烷氧基羰氧基甲基、具有从4至7个碳原子的1-(烷氧基羰氧基)乙基、具有从5至8个碳原子的1-甲基-1-(烷氧基羰氧基)乙基、具有从3至9个碳原子的N-(烷氧基羰基)氨基甲基、具有从4至10个碳原子的1-(N-(烷氧基羰基)氨基)乙基、3-酞基、4-巴豆酸内酯基、γ-丁内酯-4-基、二-N,N-(C1-C2)烷基氨基(C2-C3)烷基(如β-二甲基氨基乙基)、氨基甲酰基-(C1-C2)烷基、N,N-二(C1-C2)烷基氨基甲酰基-(C1-C2)烷基以及哌啶子基-、吡咯烷子基-或吗啉(C2-C3)烷基等。
类似地,如果具有式I、II、或III的化合物含有醇官能团,则前药可以通过将醇基团的氢原子替代为例如像以下的基团而形成:(C1-C6)烷酰氧基甲基、1-((C1-C6)烷酰氧基)乙基、1-甲基-1-((C1-C6)烷酰氧基)乙基、(C1-C6)烷氧基羰氧基甲基、N-(C1-C6)烷氧基羰基氨基甲基、琥珀酰基、(C1-C6)烷酰基、α-氨基(C1-C4)烷酰基、芳基酰基和α-氨基酰基、或α-氨基酰基-α-氨基酰基,其中每个α-氨基酰基基团独立地选自天然存在的L-氨基酸、P(O)(OH)2、-P(O)(O(C1-C6)烷基)2或糖基(所述基团由去除半缩醛形式的碳水化合物的羟基基团而得到)等。
如果具有式I、II、或III的化合物并入了胺官能团,则前药可以通过将胺基团中的氢原子替代为例如像以下的基团而形成:R”-羰基、R”O-羰基、NR”R'-羰基,其中R”和R'各自独立地是(C1-C10)烷基、(C3-C7)环烷基、苄基,或R”-羰基是天然的α-氨基酰基或天然的α-氨基酰基;-C(OH)C(O)OY1,其中Y1为H、(C1-C6)烷基或苄基;-C(OY2)Y3,其中Y2是(C1-C4)烷基并且Y3是(C1-C6)烷基、羧基(C1-C6)烷基、氨基(C1-C4)烷基或单-N-或二-N,N-(C1-C6)烷基氨基烷基;-C(Y4)Y5,其中Y4是H或甲基并且Y5是单-N-或二-N,N-(C1-C6)烷基氨基吗啉代、哌啶-1-基或吡咯烷-1-基等。
本发明还涉及具有式I、II、或III的化合物的药学活性代谢物,以及此类代谢物在本发明方法中的用途。“药学活性代谢物”意指具有式I、II或III的化合物或其盐在体内代谢的药学活性产物。化合物的前药和活性代谢物可以使用本领域已知或可获得的常规技术来确定。参见,例如Bertolini等人,J.Med.Chem.[药物化学杂志]1997,40,2011-2016;Shan等人,J.Pharm.Sci.[药学科学杂志]1997,86(7),765-767;Bagshawe,DrugDev.Res.[药物开发研究]1995,34,220-230;Bodor,Adv.DrugRes.[先进药物研究]1984,13,255-331;Bundgaard,Design ofProdrugs[前药的设计](爱思唯尔出版社(ElsevierPress),1985);以及Larsen,Design andApplication ofProdrugs[前药的设计和应用],Drug DesignandDevelopment[药物设计和开发](Krogsgaard-Larsen等人编辑,哈伍德学术出版社(HarwoodAcademic Publishers),1991)。
本文给出的任何式也旨在表示化合物的未标记形式以及同位素标记形式。同位素标记的化合物具有由本文给出的式描绘的结构,不同之处在于一个或多个原子被具有选定的原子质量或质量数的原子替代。可以并入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟、氯、和碘的同位素,如对应地是2H、3H、11C、13C、14C、15N、18O、17O、31P、32P、35S、18F、36Cl、和125I。此类同位素标记的化合物可用于代谢研究(例如用14C)、反应动力学研究(例如,用2H或3H)、检测或成像技术[如正电子发射断层扫描(PET)或单光子发射计算机断层扫描(SPECT)](包括药物或底物组织分布测定)、或用于患者的放射治疗。特别地,18F或11C标记的化合物可能特别适合PET或SPECT研究。此外,用较重的同位素(如氘(即,2H))取代可以提供某些治疗优势,这些优势源于更高的代谢稳定性,例如增加体内半衰期或减少剂量需求。本发明的同位素标记的化合物及其前药通常可以通过方案中或实例中披露的程序以及下文所述的制备通过用容易获得的同位素标记的试剂代替非同位素标记的试剂来制备。
关于本文所述的化合物,术语“盐”、“溶剂化物”、“多晶型物”、“前药”等的使用旨在同样适用于本发明化合物的对映异构体、立体异构体、旋转异构体、互变异构体、阻转异构体、和外消旋体的盐、溶剂化物、多晶型物、和前药形式。
本发明还可以是选自由以下组成的组的化合物:5-[(3-氰基苯基)甲基]-2-氟-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(6-氰基吡啶-2-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(6-氨基甲酰基吡啶-2-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、6-({4-羧基-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-5-基}甲基)吡啶-2-甲酸、5-[(3-氰基-2-氟苯基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(1,3-苯并噁唑-6-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(1,3-苯并噁唑-5-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(6-氟吡啶-2-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(2-氟吡啶-4-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-己基-5-{[6-(三氟甲基)吡啶-2-基]甲基}-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-己基-5-{[2-(三氟甲基)吡啶-4-基]甲基}-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(5-氰基吡啶-3-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(5-氰基噻吩-2-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(4-氰基噻吩-2-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(5-氰基呋喃-2-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3,5-二甲基-1,2-噁唑-4-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-(3-氰基苯甲酰基)-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(1,3-苯并噁唑-7-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(5-氰基噻吩-3-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-己基-5-[(1H-吲哚-4-基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氨基甲酰基苯基)甲基]-7-丙基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(3-氨基甲酰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(3-氰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(吡啶-3-基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(3-甲基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(3-甲氧基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(3-氯苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(3-羟基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(2-甲氧基吡啶-4-基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(4-氨基甲酰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(2-氨基甲酰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(4-甲基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(2-氰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(2-甲基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(2-氟苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氨基甲酰基苯基)甲基]-7-戊基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氰基苯基)甲基]-7-戊基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氨基甲酰基苯基)甲基]-7-(2-苯基乙基)-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氰基苯基)甲基]-7-(2-苯基乙基)-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氨基甲酰基苯基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氰基苯基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氨基甲酰基苯基)甲基]-7-辛基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氰基苯基)甲基]-7-辛基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氟苯基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-己基-5-[(吡啶-3-基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-己基-5-[(3-甲基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-己基-5-[(3-甲氧基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氯苯基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-己基-5-[(2-甲氧基吡啶-4-基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-羧基苯基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(4-氨基甲酰基苯基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(2-氨基甲酰基苯基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-己基-5-[(4-甲基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(4-氰基苯基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(2-氰基苯基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-己基-5-[(2-甲基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(2-氟苯基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(4-氟苯基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、9-[(3-氨基甲酰基苯基)甲基]-2-己基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氰基苯基)甲基]-2-己基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-羧基苯基)甲基]-2-己基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氟苯基)甲基]-2-己基-2,3,4,9-四氢-1H-咔唑-8-甲酸、2-己基-9-[(吡啶-3-基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、2-己基-9-[(3-甲基苯基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、2-己基-9-[(3-甲氧基苯基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氯苯基)甲基]-2-己基-2,3,4,9-四氢-1H-咔唑-8-甲酸、2-己基-9-[(3-羟基苯基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、2-己基-9-[(2-甲氧基吡啶-4-基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-羧基苯基)甲基]-2-己基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(4-氨基甲酰基苯基)甲基]-2-己基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(2-氨基甲酰基苯基)甲基]-2-己基-2,3,4,9-四氢-1H-咔唑-8-甲酸、2-己基-9-[(4-甲基苯基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(4-氰基苯基)甲基]-2-己基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(2-氰基苯基)甲基]-2-己基-2,3,4,9-四氢-1H-咔唑-8-甲酸、2-己基-9-[(2-甲基苯基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(2-氟苯基)甲基]-2-己基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氨基甲酰基苯基)甲基]-2-(2-苯基乙基)-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氰基苯基)甲基]-2-(2-苯基乙基)-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氨基甲酰基苯基)甲基]-4-(2-苯基乙基)-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氰基苯基)甲基]-4-(2-苯基乙基)-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氨基甲酰基苯基)甲基]-2-丙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氰基苯基)甲基]-2-丙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、2-丁基-9-[(3-氨基甲酰基苯基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氨基甲酰基苯基)甲基]-2-戊基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氰基苯基)甲基]-2-戊基-2,3,4,9-四氢-1H-咔唑-8-甲酸、1-丁基-9-[(3-氨基甲酰基苯基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氨基甲酰基苯基)甲基]-1-(戊氧基)-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氰基苯基)甲基]-1-(戊氧基)-2,3,4,9-四氢-1H-咔唑-8-甲酸、1-丁基-9-[(3-氰基苯基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、6-丁基-5-[(3-氨基甲酰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、6-丁基-5-[(3-氰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、9-[(3-氨基甲酰基苯基)甲基]-1-乙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氰基苯基)甲基]-1-乙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-羧基苯基)甲基]-1-乙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氨基甲酰基苯基)甲基]-1-丙氧基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氨基甲酰基苯基)甲基]-4-乙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、4-[(3-氨基甲酰基苯基)甲基]-3-乙基-1H,2H,3H,4H-环戊烷并[b]吲哚-5-甲酸、4-[(3-氰基苯基)甲基]-3-乙基-1H,2H,3H,4H-环戊烷并[b]吲哚-5-甲酸、3-丁基-4-[(3-氨基甲酰基苯基)甲基]-1H,2H,3H,4H-环戊烷并[b]吲哚-5-甲酸、3-丁基-4-[(3-氰基苯基)甲基]-1H,2H,3H,4H-环戊烷并[b]吲哚-5-甲酸、2-丁基-4-[(3-氨基甲酰基苯基)甲基]-1H,2H,3H,4H-环戊烷并[b]吲哚-5-甲酸、2-丁基-4-[(3-氰基苯基)甲基]-1H,2H,3H,4H-环戊烷并[b]吲哚-5-甲酸、5-[(3-氨基甲酰基苯基)甲基]-10-乙基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氰基苯基)甲基]-10-乙基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氨基甲酰基苯基)甲基]-10-丙基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氰基苯基)甲基]-10-丙基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、9-[(3-羧基苯基)甲基]-4-乙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氨基甲酰基苯基)甲基]-3-乙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、10-丁基-5-[(3-氨基甲酰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、10-丁基-5-[(3-氰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氨基甲酰基苯基)甲基]-10-戊基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氰基苯基)甲基]-10-戊基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、4-[(3-氨基甲酰基苯基)甲基]-2-戊基-1H,2H,3H,4H-环戊烷并[b]吲哚-5-甲酸、4-[(3-氰基苯基)甲基]-2-戊基-1H,2H,3H,4H-环戊烷并[b]吲哚-5-甲酸、9-[(3-氨基甲酰基苯基)甲基]-2-乙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-羧基苯基)甲基]-2-乙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、5-[(3-氨基甲酰基苯基)甲基]-7-乙基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氰基苯基)甲基]-7-乙基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、9-[(3-氰基苯基)甲基]-3-乙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氨基甲酰基苯基)甲基]-4-丙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氨基甲酰基苯基)甲基]-3-丙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氰基苯基)甲基]-3-丙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、4-丁基-9-[(3-氨基甲酰基苯基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、4-丁基-9-[(3-氰基苯基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、3-丁基-9-[(3-氨基甲酰基苯基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、3-丁基-9-[(3-氰基苯基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氨基甲酰基苯基)甲基]-4-戊基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氰基苯基)甲基]-4-戊基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氨基甲酰基苯基)甲基]-3-戊基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氰基苯基)甲基]-3-戊基-2,3,4,9-四氢-1H-咔唑-8-甲酸、4-[(3-氨基甲酰基苯基)甲基]-3-丙基-1H,2H,3H,4H-环戊烷并[b]吲哚-5-甲酸、4-[(3-氰基苯基)甲基]-3-丙基-1H,2H,3H,4H-环戊烷并[b]吲哚-5-甲酸、2-({7-丁基-5-[(3-氨基甲酰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-基}甲酰胺基)乙酸、2-({7-丁基-5-[(3-氰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-基}甲酰胺基)乙酸、7-丁基-5-[(3-氨基甲酰基苯基)甲基]-N-(2-羟基乙基)-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酰胺、7-丁基-5-[(3-氰基苯基)甲基]-N-(2-羟基乙基)-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酰胺、7-丁基-5-[(3-氟苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、和7-丁基-5-[(3-羧基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、或其药学上可接受的盐或立体异构体。
又另一个实施例是一种用于通过向有需要的受试者(例如,人类)施用本发明的药物配制品而向所述受试者施用本发明的化合物的方法。
又另一个实施例是一种通过混合至少一种本发明的药学上可接受的化合物和任选地一种或多种药学上可接受的添加剂或赋形剂来制备本发明的药物配制品的方法。
对于由通过本发明描述的化合物制备药物组合物,惰性的药学上可接受的载体可以是固体或液体。固体形式制剂包括粉剂、片剂、可分散颗粒剂、胶囊剂、扁囊剂和栓剂。粉剂和片剂可以包含从约5%至约95%的活性成分。合适的固体载体是本领域已知的,例如碳酸镁、硬脂酸镁、滑石、糖或乳糖。片剂、粉剂、扁囊剂和胶囊剂可以用作适合口服施用的固体剂型。各种组合物的药学上可接受的载体和制造方法的实例可见于A.Gennaro(编辑),Remington's Pharmaceutical Sciences[雷明顿制药科学],第18版,(1990),麦克出版公司(Mack Publishing Co.),宾夕法尼亚州伊斯顿。
本发明的组合物和配制品可以作为无菌组合物和无菌配制品施用。无菌药物配制品根据本领域技术人员已知的药物级灭菌标准(例如,美国药典第797、1072、和1211章;加利福尼亚州商业和职业条例4127.7;16加利福尼亚州法规1751、21联邦法规21、或美国以外的此类法规的对应物)配混或制造。
液体形式制剂包括溶液、悬浮液和乳液。作为实例,可以提及用于肠胃外注射的水或水-丙二醇溶液或用于口服溶液、悬浮液和乳液的甜味剂和遮光剂的添加。液体形式制剂还可以包括用于鼻内施用的溶液。
适合吸入的气雾剂制剂可以包括溶液和粉末形式的固体,其可以与药学上可接受的载体(如惰性压缩气体,例如氮气)组合。
还包括的是固体形式制剂,这些固体形式制剂旨在使用前不久被转化为液体形式制剂用于口服或肠胃外施用。此类液体形式包括溶液、悬浮液和乳液。
本发明的化合物还可以透皮递送。透皮组合物可以采取乳膏剂、洗剂、气雾剂和/或乳液的形式,并且可以包含在基质或储库型的透皮贴剂中,如本领域为此目的常规剂型。
本发明的化合物也可以皮下递送。
该化合物可以口服或静脉内施用。
该药物制剂可以以单位剂型。在这种形式中,制剂被细分成含有适当量的活性组分的合适大小的单位剂量,例如,实现所希望的目的的有效量。
根据具体应用,单位剂量的制剂中活性化合物的量可以从约1mg至约1000mg、例如从约1mg至约500mg、特别地从约1mg至约250mg、或从约1mg至约25mg变化或调节。
所采用的实际剂量可以根据患者的需要和正治疗的病况的严重程度而变化。针对特定情况的适当剂量方案的确定是在本领域的技能内。为了方便起见,根据需要,可以在一天内分次并且分部分施用总日剂量。
本发明化合物和/或其药学上可接受的盐的施用量和施用频率将根据主治临床医生的判断来调节,该临床医生考虑了诸如患者的年龄、状况和大小以及所治疗症状的严重程度等因素。口服施用的典型推荐日剂量方案可以范围为约1mg/天至约500mg/天、优选1mg/天至200mg/天,分二至四个分剂量。
方案和实例
现在将通过参考以下用于其通用制备的说明性合成方案和以下具体实例来描述可用于制备本发明化合物的示例性、非限制性化学实体和方法。本领域技术人员将理解,其他合成途径可以用于合成根据本发明的化合物。尽管本文描绘并讨论了具体的起始材料和试剂,但其他起始材料和试剂可以容易地被取代以提供多种衍生物和/或反应条件。此外,根据本披露,使用本领域技术人员熟知的常规化学,可以进一步修饰通过所述方法制备的许多示例性化合物。
技术人员将认识到,为了获得本文的各种化合物,可以适当地选择起始材料,使得最终所希望的取代基将在有或没有保护的情况下通过反应方案而携带,以适当地产生所希望的产物。可替代地,可能需要或希望采用合适的基团代替最终所希望的取代基,该基团可以在反应方案中携带并视情况用所希望的取代基替代。反应方案中描绘的各个反应优选在从约0℃至所用溶剂的回流温度的温度下进行。除非另有说明,否则以下方案中所示的变量如以上参考式(I)所定义。
根据本发明的化合物可以通过合成途径合成,这些合成途径包括与化学领域中熟知的那些方法类似的方法,特别是根据本文所含的描述,以及在以下文献中描述的用于其他杂环的那些方法:Comprehensive Heterocyclic Chemistry II[综合杂环化学II],Katritzky和Rees编辑,爱思唯尔,1997,例如第3卷;LiebigsAnnalen der Chemie[李比希化学年鉴],(9):1910-16,(1985);Helvetica Chimica Acta[瑞士化学学报],41:1052-60,(1958);Arzneimittel-Forschung[药物研究],40(12):1328-31,(1990),其各自通过引用明确地并入。起始材料通常可从商业来源(如西格玛-奥德里奇化学公司(Sigma-AldrichChemicals)(威斯康辛州密尔沃基)获得,或者使用本领域技术人员熟知的方法容易地制备(例如,通过Louis F.Fieser和Mary Fieser,Reagents for Organic Synthesis[用于有机合成的试剂],第1-23卷,纽约威利(1967-2006辑)或Beilsteins Handbuch derorganischen Chemie[贝尔斯坦有机化学手册],4,Aufl.编辑,施普林格出版社(Springer-Verlag),柏林(包括增刊)(还经由贝尔斯坦在线数据库获得)中通常描述的方法制备)。
可用于合成根据本发明的化合物的合成化学转化和保护基方法(保护和去保护)以及必要的试剂和中间体是本领域已知的,并且包括例如R.Larock,ComprehensiveOrganic Transformations[有机转化大全],VCH出版社(1989);T.W.Greene和P.G.M.Wuts,Protective Groups in Organic Synthesis[有机合成中的保护基团],第3版,约翰威利父子出版公司(John Wiley and Sons)(1999);以及L.Paquette编辑,Encyclopedia ofReagents for Organic Synthesis[有机合成试剂百科全书],约翰威利父子出版公司(1995)及其后续版本。对这种保护的需要将根据远程官能团的性质和制备方法的条件而变化。合适的氨基保护基包括乙酰基、三氟乙酰基、叔丁氧基羰基(BOC)、苄氧基羰基(CBz)和9-芴基亚甲氧基羰基(Fmoc)。对这种保护的需要由本领域的技术人员容易地确定。
制备本发明化合物的另外特别有用的反应包括烷基化、还原胺化、氧化、还原、和水解反应。这类转化对于本领域普通技术人员来说是熟知的。
根据本发明的化合物可以单独地或作为化合物库制备,这些化合物库包含例如至少两种、或5至1,000种化合物、或10至100种化合物。具有式I、II、或III的化合物的库可以通过组合的“分开和混合”方法或通过使用溶液相或固相化学的多重平行合成,通过本领域技术人员已知的程序制备。因此,根据本发明的另一方面,提供了一种包含至少两种具有式I、II、或III的化合物或其药学上可接受的盐的化合物库。
在制备根据本发明的化合物的方法中,将反应产物彼此分离和/或与起始材料分离可能是有利的。通过本领域常用的技术将每个步骤或系列步骤的所希望的产物分离和/或纯化到所希望的均匀度。典型地,此类分离包括多相萃取、从溶剂或溶剂混合物中结晶、蒸馏、升华、或色谱法。色谱法可以涉及任何数量的方法,包括例如:反相和正相;尺寸排阻;离子交换;高压、中压和低压液相色谱方法和装置;小规模分析;模拟移动床(SMB)和制备型薄层或厚层色谱法,以及小规模薄层和快速色谱法的技术。
另一类分离方法包括用选择的试剂处理混合物,以结合所希望的产物、未反应的起始材料、反应副产物等或使得所希望的产物、未反应的起始材料、反应副产物等可以其他方式分离。此类试剂包括吸附剂或吸收剂,如活性炭、分子筛、离子交换介质等。可替代地,这些试剂可以是酸(在碱性材料的情况下)、碱(在酸性材料的情况下)、结合试剂(如抗体)、结合蛋白、选择性螯合剂(如冠醚)、液/液离子萃取试剂(LIX)等。适当分离方法的选择取决于所涉及的材料的性质,如蒸馏和升华中的沸点和分子量、色谱法中极性官能团的存在或不存在、多相萃取中酸性介质和碱性介质中材料的稳定性等。
基本上不含其立体异构体的单一立体异构体(例如,对映异构体)可以通过使用方法(如使用光学活性拆分剂形成非对映异构体)拆分外消旋混合物而获得(Eliel,E.和Wilen,S.“Stereochemistry ofOrganic Compounds[有机化合物的立体化学],”约翰威利父子出版公司,纽约,1994;Lochmuller,C.H.,(1975)J.Chromatogr.[色谱杂志],113(3):283-302)。本发明的手性化合物的外消旋混合物可以通过任何合适的方法分离和离析,这些方法包括:(1)用手性化合物形成离子的非对映异构体盐,并通过分级结晶或其他方法分离,(2)用手性衍生试剂形成非对映异构化合物,分离非对映异构体,并转化为纯的立体异构体,和(3)直接在手性条件下分离基本上纯的或富集的立体异构体。参见:“DrugStereochemistry,Analytical Methods and Pharmacology[药物立体化学、分析方法和药理学],”Irving W.Wainer编辑,马塞尔德克尔公司(Marcel Dekker,Inc.),纽约(1993)。
在方法(1)中,可以通过使对映异构纯的手性碱(如番木鳖碱、奎宁、麻黄碱、士的宁(strychnine))、a-甲基-b-苯基乙胺(安非他明)等与携带酸性官能团的不对称化合物(如羧酸和磺酸)反应形成非对映异构体盐。可以通过分级结晶或离子色谱法诱导分离非对映异构体盐。为了分离氨基化合物的光学异构体,添加手性羧酸或磺酸(如樟脑磺酸、酒石酸、扁桃酸、或乳酸)可以导致形成非对映异构体盐。
可替代地,通过方法(2),使待拆分的底物与手性化合物的一种对映异构体反应,形成非对映异构体对(E.和Wilen,S.“Stereochemistry ofOrganic Compounds[有机化合物的立体化学]”,约翰威利父子出版公司,1994,第322页)。非对映异构化合物可以通过使不对称化合物与对映异构纯的手性衍生试剂(如薄荷基衍生物)反应,随后分离非对映异构体并水解以产生纯的或富集的对映异构体来形成。测定光学纯度的方法包括制备外消旋混合物的手性酯(如薄荷酯,例如,在碱存在下(-)氯甲酸薄荷酯)或莫舍酯,乙酸a-甲氧基-a-(三氟甲基)苯酯,并分析1H NMR谱中两种阻转异构体对映异构体或非对映异构体的存在(Jacob III.J.Org.Chem.[有机化学杂志](1982)47:4165)。阻转异构体化合物的稳定的非对映异构体可以通过正相和反相色谱法按照用于分离阻转异构体萘基-异喹啉的方法(WO96/15111)分离和离析。通过方法(3),两种对映异构体的外消旋混合物可以通过使用手性固定相的色谱法(“Chiral Liquid Chromatography[手性液相色谱法]”(1989)W.J.Lough编辑,查普曼和霍尔出版社(Chapman and Hall),纽约;Okamoto,J.Chromatogr.[色谱杂志],(1990)513:375-378)分离。富集的或纯化的对映异构体可以通过用于区分具有不对称碳原子的其他手性分子的方法(如旋光度和圆二色光谱)来区分。
具体实施方式
合成方法A:使用β取代的环状酮和2-羧酸酯-苯肼进行费舍尔吲哚合成,随后酯化得到吲哚中间体。吲哚氮与所需的烷基溴进行烷基化,随后水解,纯化后得到所希望的产物。
代表性实例:7-丁基-5-[(3-氨基甲酰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸
步骤1.1:将肼(1.12g)和酮(3g)在AcOH中混合,并且在130℃下搅拌,3小时后,蒸馏出AcOH。然后将反应物用饱和碳酸氢钠中和,并且用EtOAc(300mL×3)萃取,将其干燥并通过旋转蒸发浓缩。通过柱色谱法(30%EtOAc:石油醚)纯化,得到1g所希望的吲哚产物。
步骤1.2:将1g吲哚溶解于15mL MeOH中。添加1mL H2SO4并在80℃下加热。16小时后,从反应混合物中蒸馏出MeOH,用饱和碳酸氢钠中和,并且用EtOAc(300mL×3)萃取,将其干燥并通过旋转蒸发浓缩。通过柱色谱法(20%EtOAc:石油醚)纯化,得到900mg所希望的吲哚酯产物
步骤2.1:将吲哚酯(900mg)和3-氰基苄基溴(1.18g)溶解于DMSO(10mL)中,并且然后在室温下添加KOH(842mg)并搅拌。2小时后,将反应物用水稀释,并且用EtOAc(300mL×3)萃取,将其干燥并通过旋转蒸发浓缩。通过柱色谱法(15%EtOAc:石油醚)纯化,得到700mg所希望的吲哚酯产物
步骤2.2:将苄基吲哚溶解于EtOH:H2O(30:6mL)中,并且然后在室温下添加KOH(473mg),并且加热至70℃。15分钟后,将反应物冷却至室温,用1N HCl溶液中和,并且用EtOAc(300mL×3)萃取。然后将收集的有机萃取物干燥并通过旋转蒸发浓缩。通过MS定向纯化进行纯化,得到110mg 7-丁基-5-[(3-氰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸和105mg 7-丁基-5-[(3-氨基甲酰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸。
合成方法B:使用未取代的环状酮和2-羧酸酯-苯肼进行费舍尔吲哚合成,随后酯化得到吲哚中间体。用所需的亲核试剂进行TFAA-DMSO烷基化方案(Masanori Tayu等人,Org.Biomol.Chem.[有机生物分子化学](2013)11496),随后酯水解,纯化后得到所希望的产物。
代表性实例:9-[(3-氨基甲酰基苯基)甲基]-2-戊基-2,3,4,9-四氢-1H-咔唑-8-甲酸
步骤1.1:将肼(6.0g)和酮(6.2g)在AcOH(100mL)中混合,并且在130℃下搅拌,3小时后,蒸馏出AcOH。然后将反应物用饱和碳酸氢钠中和,并且用EtOAc(300mL×3)萃取,将其干燥并通过旋转蒸发浓缩。通过柱色谱法(30%EtOAc:石油醚)纯化,得到5g所希望的吲哚产物。
步骤1.2:将5g吲哚溶解于100mL MeOH中。添加7mL浓H2SO4并在80℃下加热。16小时后,从反应混合物中蒸馏出MeOH,用饱和碳酸氢钠中和,并且用EtOAc(300mL×3)萃取,将其干燥并通过旋转蒸发浓缩。通过柱色谱法(20%EtOAc:石油醚)纯化,得到4.2g所希望的吲哚酯产物。
步骤2:将吲哚酯(3g)溶解于DMSO(50mL)中,并且然后在室温下添加KOH(3.675g)。然后分批添加3-氰基-苄基溴(5.13g)并搅拌。2小时后,将反应物缓慢倒入具有冰浴的烧瓶中的1N HCl中,并且然后用EtOAc(300mL×3)萃取有机物,将其干燥并通过旋转蒸发浓缩。通过柱色谱法(20%EtOAc:石油醚)纯化,得到3.5g所希望的吲哚酯产物
步骤3:在-40℃下,向吲哚酯(500mg)在二氯甲烷(7mL)中的溶液中添加DMSO(0.315mL)。向此混合物中滴加三氟乙酸酐(0.617mL),并在-40℃下搅拌。1小时后,向此混合物中滴加乙基溴化镁(17.647mL,1M)。2小时后,将反应物缓慢倒入10mL饱和NaHCO3+20mLH2O+30mL EtOAc的溶液中。将有机层分离并干燥,并且真空浓缩。通过柱色谱法(20%EtOAc:石油醚)纯化,得到300mg所希望的产物
步骤4:将苄基吲哚(150mg)溶解于EtOH:H2O(5:2mL)中,并且然后在室温下添加KOH(156mg),并搅拌。16小时后,将反应物用1N HCl中和并且过滤出为9-[(3-氨基甲酰基苯基)甲基]-2-戊基-2,3,4,9-四氢-1H-咔唑-8-甲酸的固体(30mg)。
上述技术结果反映在下表1中:
表1.
可以使用的代表性HPLC方法包括以下:
方法A
柱:Kinetex EVO C18(50mm x 4.6mm,5um)
流动相:B1:在水中的0.1%FAA1:在ACN中的0.1%FA
梯度:时间(min)/%A1:0/2、0.4/2、2.7/98、3.40/98、3.41/2、3.5/2
柱流速:2.0ml/min
柱温:45℃
方法B
柱:ACQUITYUPLC BEH C18(50mm x 2.1mm,1.7um)
流动相:B1:在水中的0.1%FAA1:在ACN中的0.1%FA
梯度:时间(min)/%A1:0/2、0.4/2、2.8/98、3.4/98、3.41/2、3.5/2
柱流速:0.6ml/min
柱温:60℃
方法C
柱:ACQUITYUPLC BEH C18(50mm x 2.1mm,1.7um)
流动相:B1:在水中的0.1%FAA1:在ACN中的0.1%FA
梯度:时间(min)/%A1:0/2、0.3/2、2.3/98、2.8/98、2.81/2、3.0/2
柱流速:0.8ml/min
柱温:60℃
方法D
柱:X-BRIDGE C18(4.6x 150mm)5μm
流动相:A:10mM乙酸铵(水性),B:乙腈
梯度时间%B:稀释剂0/10、1/10、12/95、15/98、20/98、20.01/10
柱温流速:环境:1ml/min
:(ACN:水)
方法E
柱:ACQUITYUPLC BEH C18(50mm x 2.1mm,1.7um)
流动相:B1:在水中的0.1%FAA1:在ACN中的0.1%FA
梯度:时间(min)/%A1:0/2、0.2/2、5.0/98、5.8/98、5.81/2.0、6.00/2.0
柱流速:0.8ml/min
柱温:60℃
方法F
流动相A:在水中的0.1%FA
流动相B:在ACN中的0.1%FA
B的梯度%:
0/5、0.3/5、1.5/60、2/98、4/98、5/5
流速:0.6ml/min
柱:BEH C18,2.1*50mm,1.7um,
下表2将所用的HPLC方法与IUPAC名称相关联:
表2.
化合物对脂肪细胞葡萄糖消耗的活性在分化的3T3-L1小鼠脂肪细胞中测试。在由DMEM高葡萄糖(西格玛公司(Sigma))、10%FBS(吉布科公司(Gibco))、10U/ml青霉素和10μg/ml链霉素(P/S;吉布科公司)组成的生长培养基中常规培养3T3-L1前脂肪细胞(ATCC)。为了诱导成脂分化,将汇合层的3T3-L1细胞与含有2μM罗格列酮、1μM地塞米松、500μM IBMX、和1μg/ml胰岛素(西格玛公司)的生长培养基一起孵育。四十八(48)小时后(在第2天)以及在第4天和第6天,用含有1μg/ml胰岛素的新鲜培养基替换细胞培养基。在第8天和第10天,用常规生长培养基更新培养基,并且省略胰岛素的添加。在第11天或第12天,用含有所示化合物(10μM)或其中溶解有化合物的媒介物(DMSO)的新鲜培养基替换细胞培养基。DMSO的终浓度为0.1%(v/v)。将含有0.1%DMSO的生长培养基在不含细胞的培养孔中孵育,并用作对照。二十二至24小时后,收获培养基,并以10,000g进行离心5分钟。上清液中的葡萄糖浓度使用比色测定(葡萄糖测定试剂盒I,伊顿生物科学公司(Eton Biosciences))测定。化合物和媒介物处理的细胞中的葡萄糖消耗被测量为培养基中葡萄糖的损失,并且表示为平均倍数变化(化合物/DMSO)±标准偏差(SD)。
使用基于铽(Tb)的时间分辨荧光能量转移(TR-FRET)测定分析化合物对FABP4的活性。经由记录从抗His6-标签抗体上的TB供体分子到受体BODIPY部分的能量转移,该测定测量化合物介导的荧光脂肪酸BODIPY FL C12(赛默飞世尔公司(Thermo Fisher);目录号D3822)从His6标记的人重组FABP4(His6-FABP4;开曼化学公司(Cayman Chemicals),目录号10009549)的替换。简短地讲,制备浓度为0.362mM和0.0362mM的化合物,并在DMSO中制备浓度为4.2μM的BODIPYFL C12。将1.2μL每种化合物或DMSO(媒介物对照)和1.2μL BODIPYFL C12添加到384孔黑色聚丙烯板的孔中。在测定缓冲液(25mM Tris/HCl,pH 7.4,0.4mg/mlγ-球蛋白,0.010%NP-40,1mM DTT)中制备浓度分别为83nM和49.6nM的His6-FABP4和Tb抗His6抗体。然后将蛋白质和抗体溶液以34:7(v/v)的比率混合,并在冰上孵育30分钟。通过将41μL所得蛋白质/抗体溶液添加到含有化合物和BODIPYFL C12的孔中来开始测定。将板离心并在室温下孵育10分钟。使用EnVision多标记读板仪(珀金埃尔默公司(PerkinElmer);TB激发320nm,BODIPY FL C12发射520nm;TB发射615nm)记录TR-FRET信号。使用相对荧光比率(520nm*10,000/615nm)计算化合物介导的对BODIPY C12 FL脂肪酸与FABP4的结合的抑制。一式三份测试化合物,并且将结果显示为平均抑制百分比(化合物*100/DMSO)±标准偏差(SD)。葡萄糖消耗和FABP4抑制显示在下表3中。
表3.
尽管本发明已经以一定程度的特殊性进行了描述,但是应当理解,本披露仅通过说明的方式进行,并且在不脱离本发明的精神和范围的情况下,可以采取在部件的构造和布置的细节上的许多改变。
Claims (46)
1.一种具有式I的化合物,该化合物包含:
其中:
W1-4和Z1-Z5各自独立地是-C、-CH、CH2、O、S、或N;
X独立地是CH2、N或CHR4;
Y独立地是CH2、或CHR5;
n是在0与3之间的数;
环Z上的一个或多个R1独立地选自由以下组成的组:CN、OH、COOH、OCH3、CF3、CONH2、B(OH)2、B(OR)2、酸等排体、取代的胺、醚、和卤素、取代的或未取代的烷基、取代的或未取代的环或杂环、取代的或未取代的环芳基或环杂芳基,其中该取代的环芳基或环杂芳基可以被氢、CN、OH、COOH、OCH3、CF3、CONH2、B(OH)2、B(OR)2、酸等排体、取代的胺、醚、和卤素、取代的或未取代的烷基、取代的或未取代的环或杂环、取代的或未取代的环芳基或环杂芳基、和SO2NH2取代;
环W上的一个或多个R2独立地选自由以下组成的组:CN、OH、CHF2、CH2F、CF3、COOH、CONH2、B(OH)2、B(OR)2、酸等排体、卤素、和双环杂芳基;
R7是氢或CN、COOH、CONH2、B(OH)2、B(OR)2或酸等排体;
R是烷基;
R3、R4、R5或R8、或R6—当n不是零时—各自独立地选自:
(1)氢;
(2)具有1至12个碳原子的取代的或未取代的烷基或醚;
(3)取代的胺;或
(4)--(CH2)m G,其中m是1至12,并且G独立地选自:
(a)含有3至6个碳原子的环烷基,
(b)芳基或杂芳基,
(c)CF3、CF2H或CFH2,或
(d)杂环,
其前提是R3、R4、R5、R8、或R6不都是氢;
或其药学上可接受的盐或立体异构体。
2.根据权利要求1所述的化合物,其中,R1和R2两者都存在,并且各自独立地是CN、COOH、或CONH2。
3.根据权利要求1所述的化合物,其中,该式I包含多个R1和R2。
4.根据权利要求1所述的化合物,其中,R3、R4、R5、R8、或R6—当n不是零时—各自独立地是具有4个碳原子的烷基。
5.根据权利要求1所述的化合物,其中,R3、R4、R5、R8、或R6—当n不是零时—各自独立地是具有5个碳原子的烷基。
6.根据权利要求1所述的化合物,其中,R3、R4、R5、R8、或R6—当n不是零时—各自独立地是具有6个碳原子的烷基。
7.根据权利要求1所述的化合物,其中,该环Z含有Z1-Z4。
8.根据权利要求1所述的化合物,其中,该环Z含有Z1-Z5。
9.根据权利要求1所述的化合物,其中,该环Z上的一个或多个R1是卤素。
10.根据权利要求1所述的化合物,其中,该环Z上的一个或多个R1是CN。
11.根据权利要求1所述的化合物,其中,该环Z上的一个或多个R1是CF3。
12.根据权利要求1所述的化合物,其中,该环W上的一个或多个R2是卤素。
13.根据权利要求1所述的化合物,其中,该环Z上的一个或多个R1包含CN和/或卤素。
14.根据权利要求1所述的化合物,其中,该环Z上的一个或多个R1包含CN和/或卤素,并且其中该环W上的一个或多个R2包含另一个卤素。
15.根据权利要求14所述的化合物,其中,该卤素与该另一个卤素相同。
16.根据权利要求14所述的化合物,其中,该卤素与该另一个卤素不同。
17.一种具有式II的化合物,该化合物包含:
其中:
n=0、1、或2;
R1选自由以下组成的组:CN、COOH、CONH2、B(OH)2、B(OR)2、酸等排体、和卤素;
R2选自由以下组成的组:CN、COOH、CONH2、B(OH)2、B(OR)2、酸等排体、卤素、和双环化合物;
R7是氢或CN、COOH、CONH2、B(OH)2、B(OR)2或酸等排体;
R是烷基;
R3、R4、R5或R8、或R6—当n不是零时—各自独立地选自:
(1)氢;
(2)具有1至12个碳原子的烷基;或
(3)--(CH2)m G,其中m是1至12,并且G独立地选自:
(a)含有3至6个碳原子的环烷基,
(b)芳基或杂芳基,或
(c)CF3、CF2H或CFH2;
其前提是G不是含氮或氧的基团;并且
其前提是R3、R4、R5、R8、或R6不都是氢;
或其药学上可接受的盐。
18.根据权利要求17所述的化合物,其中,R1和R2两者都存在,并且各自独立地是CN、COOH、或CONH2。
19.根据权利要求17所述的化合物,其中,该式II包含多个R1和R2。
20.根据权利要求17所述的化合物,其中,R3、R4、R5、R8、或R6—当n不是零时—各自独立地是具有4个碳原子的烷基。
21.根据权利要求17所述的化合物,其中,R3、R4、R5、R8、或R6—当n不是零时—各自独立地是具有5个碳原子的烷基。
22.根据权利要求17所述的化合物,其中,R3、R4、R5、R8、或R6—当n不是零时—各自独立地是具有6个碳原子的烷基。
24.根据权利要求23所述的化合物,其中,n=0并且R3附接至h-、i-或j-位。
25.根据权利要求23所述的化合物,其中:n=1并且R3附接至h-、i-或j-位。
26.根据权利要求23所述的化合物,其中:n=2并且R3附接至h-、i-或j-位。
27.根据权利要求1、17、或23所述的化合物,该化合物是纯光学异构体。
28.根据权利要求23所述的化合物,该化合物是(+)-异构体。
29.根据权利要求23所述的化合物,该化合物是(-)-异构体。
30.一种化合物,该化合物选自由以下组成的组:5-[(3-氰基苯基)甲基]-2-氟-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(6-氰基吡啶-2-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(6-氨基甲酰基吡啶-2-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、6-({4-羧基-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-5-基}甲基)吡啶-2-甲酸、5-[(3-氰基-2-氟苯基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(1,3-苯并噁唑-6-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(1,3-苯并噁唑-5-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(6-氟吡啶-2-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(2-氟吡啶-4-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-己基-5-{[6-(三氟甲基)吡啶-2-基]甲基}-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-己基-5-{[2-(三氟甲基)吡啶-4-基]甲基}-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(5-氰基吡啶-3-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(5-氰基噻吩-2-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(4-氰基噻吩-2-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(5-氰基呋喃-2-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3,5-二甲基-1,2-噁唑-4-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-(3-氰基苯甲酰基)-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(1,3-苯并噁唑-7-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(5-氰基噻吩-3-基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-己基-5-[(1H-吲哚-4-基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氨基甲酰基苯基)甲基]-7-丙基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(3-氨基甲酰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(3-氰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(吡啶-3-基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(3-甲基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(3-甲氧基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(3-氯苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(3-羟基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(2-甲氧基吡啶-4-基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(4-氨基甲酰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(2-氨基甲酰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(4-甲基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(2-氰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(2-甲基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-丁基-5-[(2-氟苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氨基甲酰基苯基)甲基]-7-戊基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氰基苯基)甲基]-7-戊基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氨基甲酰基苯基)甲基]-7-(2-苯基乙基)-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氰基苯基)甲基]-7-(2-苯基乙基)-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氨基甲酰基苯基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氰基苯基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氨基甲酰基苯基)甲基]-7-辛基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氰基苯基)甲基]-7-辛基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氟苯基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-己基-5-[(吡啶-3-基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-己基-5-[(3-甲基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-己基-5-[(3-甲氧基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氯苯基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-己基-5-[(2-甲氧基吡啶-4-基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-羧基苯基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(4-氨基甲酰基苯基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(2-氨基甲酰基苯基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-己基-5-[(4-甲基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(4-氰基苯基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(2-氰基苯基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、7-己基-5-[(2-甲基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(2-氟苯基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(4-氟苯基)甲基]-7-己基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、9-[(3-氨基甲酰基苯基)甲基]-2-己基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氰基苯基)甲基]-2-己基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-羧基苯基)甲基]-2-己基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氟苯基)甲基]-2-己基-2,3,4,9-四氢-1H-咔唑-8-甲酸、2-己基-9-[(吡啶-3-基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、2-己基-9-[(3-甲基苯基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、2-己基-9-[(3-甲氧基苯基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氯苯基)甲基]-2-己基-2,3,4,9-四氢-1H-咔唑-8-甲酸、2-己基-9-[(3-羟基苯基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、2-己基-9-[(2-甲氧基吡啶-4-基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-羧基苯基)甲基]-2-己基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(4-氨基甲酰基苯基)甲基]-2-己基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(2-氨基甲酰基苯基)甲基]-2-己基-2,3,4,9-四氢-1H-咔唑-8-甲酸、2-己基-9-[(4-甲基苯基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(4-氰基苯基)甲基]-2-己基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(2-氰基苯基)甲基]-2-己基-2,3,4,9-四氢-1H-咔唑-8-甲酸、2-己基-9-[(2-甲基苯基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(2-氟苯基)甲基]-2-己基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氨基甲酰基苯基)甲基]-2-(2-苯基乙基)-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氰基苯基)甲基]-2-(2-苯基乙基)-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氨基甲酰基苯基)甲基]-4-(2-苯基乙基)-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氰基苯基)甲基]-4-(2-苯基乙基)-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氨基甲酰基苯基)甲基]-2-丙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氰基苯基)甲基]-2-丙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、2-丁基-9-[(3-氨基甲酰基苯基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氨基甲酰基苯基)甲基]-2-戊基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氰基苯基)甲基]-2-戊基-2,3,4,9-四氢-1H-咔唑-8-甲酸、1-丁基-9-[(3-氨基甲酰基苯基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氨基甲酰基苯基)甲基]-1-(戊氧基)-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氰基苯基)甲基]-1-(戊氧基)-2,3,4,9-四氢-1H-咔唑-8-甲酸、1-丁基-9-[(3-氰基苯基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、6-丁基-5-[(3-氨基甲酰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、6-丁基-5-[(3-氰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、9-[(3-氨基甲酰基苯基)甲基]-1-乙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氰基苯基)甲基]-1-乙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-羧基苯基)甲基]-1-乙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氨基甲酰基苯基)甲基]-1-丙氧基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氨基甲酰基苯基)甲基]-4-乙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、4-[(3-氨基甲酰基苯基)甲基]-3-乙基-1H,2H,3H,4H-环戊烷并[b]吲哚-5-甲酸、4-[(3-氰基苯基)甲基]-3-乙基-1H,2H,3H,4H-环戊烷并[b]吲哚-5-甲酸、3-丁基-4-[(3-氨基甲酰基苯基)甲基]-1H,2H,3H,4H-环戊烷并[b]吲哚-5-甲酸、3-丁基-4-[(3-氰基苯基)甲基]-1H,2H,3H,4H-环戊烷并[b]吲哚-5-甲酸、2-丁基-4-[(3-氨基甲酰基苯基)甲基]-1H,2H,3H,4H-环戊烷并[b]吲哚-5-甲酸、2-丁基-4-[(3-氰基苯基)甲基]-1H,2H,3H,4H-环戊烷并[b]吲哚-5-甲酸、5-[(3-氨基甲酰基苯基)甲基]-10-乙基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氰基苯基)甲基]-10-乙基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氨基甲酰基苯基)甲基]-10-丙基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氰基苯基)甲基]-10-丙基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、9-[(3-羧基苯基)甲基]-4-乙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氨基甲酰基苯基)甲基]-3-乙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、10-丁基-5-[(3-氨基甲酰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、10-丁基-5-[(3-氰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氨基甲酰基苯基)甲基]-10-戊基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氰基苯基)甲基]-10-戊基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、4-[(3-氨基甲酰基苯基)甲基]-2-戊基-1H,2H,3H,4H-环戊烷并[b]吲哚-5-甲酸、4-[(3-氰基苯基)甲基]-2-戊基-1H,2H,3H,4H-环戊烷并[b]吲哚-5-甲酸、9-[(3-氨基甲酰基苯基)甲基]-2-乙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-羧基苯基)甲基]-2-乙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、5-[(3-氨基甲酰基苯基)甲基]-7-乙基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、5-[(3-氰基苯基)甲基]-7-乙基-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、9-[(3-氰基苯基)甲基]-3-乙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氨基甲酰基苯基)甲基]-4-丙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氨基甲酰基苯基)甲基]-3-丙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氰基苯基)甲基]-3-丙基-2,3,4,9-四氢-1H-咔唑-8-甲酸、4-丁基-9-[(3-氨基甲酰基苯基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、4-丁基-9-[(3-氰基苯基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、3-丁基-9-[(3-氨基甲酰基苯基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、3-丁基-9-[(3-氰基苯基)甲基]-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氨基甲酰基苯基)甲基]-4-戊基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氰基苯基)甲基]-4-戊基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氨基甲酰基苯基)甲基]-3-戊基-2,3,4,9-四氢-1H-咔唑-8-甲酸、9-[(3-氰基苯基)甲基]-3-戊基-2,3,4,9-四氢-1H-咔唑-8-甲酸、4-[(3-氨基甲酰基苯基)甲基]-3-丙基-1H,2H,3H,4H-环戊烷并[b]吲哚-5-甲酸、4-[(3-氰基苯基)甲基]-3-丙基-1H,2H,3H,4H-环戊烷并[b]吲哚-5-甲酸、2-({7-丁基-5-[(3-氨基甲酰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-基}甲酰胺基)乙酸、2-({7-丁基-5-[(3-氰基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-基}甲酰胺基)乙酸、7-丁基-5-[(3-氨基甲酰基苯基)甲基]-N-(2-羟基乙基)-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酰胺、7-丁基-5-[(3-氰基苯基)甲基]-N-(2-羟基乙基)-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酰胺、7-丁基-5-[(3-氟苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、和7-丁基-5-[(3-羧基苯基)甲基]-5H,6H,7H,8H,9H,10H-环庚烷并[b]吲哚-4-甲酸、或其药学上可接受的盐或立体异构体。
31.根据权利要求30所述的化合物,该化合物是纯光学异构体。
32.一种抑制哺乳动物中的脂肪酸结合蛋白FABP4的方法,该方法包括向哺乳动物施用有效量的根据权利要求1、17或23所述的化合物。
33.根据权利要求32所述的方法,其中,受试者是人类。
34.根据权利要求1、17或23所述的化合物,其用于在预防或治疗作用于该脂肪酸结合蛋白FABP4的病症中使用。
35.根据权利要求34所述的化合物,其中,这些病症选自2型糖尿病、高血糖症、代谢综合征、肥胖症、动脉粥样硬化、颅内动脉粥样硬化疾病、非酒精性脂肪性肝炎、哮喘、血管性痴呆、多发性硬化、阿尔茨海默病、其他慢性炎症和自身免疫性/炎症性疾病、慢性心脏病、多囊卵巢综合征、先兆子痫、和癌症。
36.一种药物组合物,该药物组合物包含根据权利要求1、17或23所述的化合物作为活性成分以及药学上可接受的稀释剂或载体。
37.一种药物组合物,该药物组合物用于在预防或治疗作用于脂肪酸结合蛋白FABP4的病症中使用。
38.根据权利要求37所述的药物组合物,其中,这些病症选自2型糖尿病、高血糖症、代谢综合征、肥胖症、动脉粥样硬化、颅内动脉粥样硬化疾病、非酒精性脂肪性肝炎、哮喘、血管性痴呆、多发性硬化、阿尔茨海默病、其他慢性炎症和自身免疫性/炎症性疾病、慢性心脏病、多囊卵巢综合征、先兆子痫、和癌症。
39.根据权利要求36至38中任一项所述的药物组合物,该药物组合物进一步包含另外的治疗活性剂。
40.一种用于预防或治疗作用于脂肪酸结合蛋白FABP4的病症的方法,该方法包括向需要此类治疗的受试者施用有效量的根据权利要求1、17、或23所述的化合物。
41.根据权利要求40所述的方法,其中,该受试者是人类。
42.根据权利要求40和41中任一项所述的方法,其中,这些病症选自2型糖尿病、高血糖症、代谢综合征、肥胖症、动脉粥样硬化、颅内动脉粥样硬化疾病、非酒精性脂肪性肝炎、哮喘、血管性痴呆、多发性硬化、阿尔茨海默病、其他慢性炎症和自身免疫性/炎症性疾病、慢性心脏病、多囊卵巢综合征、先兆子痫、和癌症。
43.一种用于抑制FABP4的方法,该方法包括向需要此类治疗的受试者施用有效量的根据权利要求1、17、或23所述的化合物。
44.根据权利要求43所述的方法,其中,该受试者是人类。
45.根据权利要求1、17、或23所述的化合物用于制造用于在预防或治疗作用于脂肪酸结合蛋白FABP4的病症中使用的药物的用途。
46.根据权利要求45所述的用途,其中,这些病症选自2型糖尿病、高血糖症、代谢综合征、肥胖症、动脉粥样硬化、颅内动脉粥样硬化疾病、非酒精性脂肪性肝炎、哮喘、血管性痴呆、多发性硬化、阿尔茨海默病、其他慢性炎症和自身免疫性/炎症性疾病、慢性心脏病、多囊卵巢综合征、先兆子痫、和癌症。
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