CN1253502A - 利用环氧化酶-2的抑制物预防心血管疾病的方法 - Google Patents
利用环氧化酶-2的抑制物预防心血管疾病的方法 Download PDFInfo
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- CN1253502A CN1253502A CN98804252A CN98804252A CN1253502A CN 1253502 A CN1253502 A CN 1253502A CN 98804252 A CN98804252 A CN 98804252A CN 98804252 A CN98804252 A CN 98804252A CN 1253502 A CN1253502 A CN 1253502A
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- phenyl
- alkyl
- oligomeric
- benzsulfamide
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- 208000024172 Cardiovascular disease Diseases 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims description 33
- 230000002265 prevention Effects 0.000 title claims description 18
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 title abstract 2
- -1 heterocyclic radical Chemical class 0.000 claims description 212
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 64
- 125000000217 alkyl group Chemical group 0.000 claims description 62
- 150000001875 compounds Chemical class 0.000 claims description 50
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 40
- 230000004054 inflammatory process Effects 0.000 claims description 38
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 38
- 206010061218 Inflammation Diseases 0.000 claims description 36
- 125000003545 alkoxy group Chemical group 0.000 claims description 30
- 125000000623 heterocyclic group Chemical group 0.000 claims description 28
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 26
- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 25
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 24
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 24
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 24
- 238000011282 treatment Methods 0.000 claims description 24
- 150000002367 halogens Chemical class 0.000 claims description 23
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 22
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 22
- 125000001188 haloalkyl group Chemical group 0.000 claims description 22
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 18
- 125000003282 alkyl amino group Chemical group 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000004414 alkyl thio group Chemical group 0.000 claims description 15
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 15
- 238000006467 substitution reaction Methods 0.000 claims description 15
- 239000011737 fluorine Substances 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 239000001301 oxygen Substances 0.000 claims description 14
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- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 13
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 13
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 12
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 11
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 10
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 10
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
- 235000021395 porridge Nutrition 0.000 claims description 9
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 238000002054 transplantation Methods 0.000 claims description 8
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- 125000005097 aminocarbonylalkyl group Chemical group 0.000 claims description 7
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 7
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 7
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 7
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 229960001929 meloxicam Drugs 0.000 claims description 7
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 7
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- HYWYRSMBCFDLJT-UHFFFAOYSA-N nimesulide Chemical compound CS(=O)(=O)NC1=CC=C([N+]([O-])=O)C=C1OC1=CC=CC=C1 HYWYRSMBCFDLJT-UHFFFAOYSA-N 0.000 claims description 7
- 229960000965 nimesulide Drugs 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 125000002971 oxazolyl group Chemical group 0.000 claims description 7
- 150000003254 radicals Chemical class 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000000335 thiazolyl group Chemical group 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
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- 125000003368 amide group Chemical group 0.000 claims description 6
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 208000007536 Thrombosis Diseases 0.000 claims description 5
- 241000700605 Viruses Species 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 239000008280 blood Substances 0.000 claims description 5
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- 125000005816 fluoropropyl group Chemical group [H]C([H])(F)C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 5
- 210000003462 vein Anatomy 0.000 claims description 5
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 claims description 4
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 claims description 4
- 206010002329 Aneurysm Diseases 0.000 claims description 4
- 206010002383 Angina Pectoris Diseases 0.000 claims description 4
- 206010002388 Angina unstable Diseases 0.000 claims description 4
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 4
- 241000606161 Chlamydia Species 0.000 claims description 4
- 208000005189 Embolism Diseases 0.000 claims description 4
- 208000006011 Stroke Diseases 0.000 claims description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 4
- 208000001435 Thromboembolism Diseases 0.000 claims description 4
- 208000007814 Unstable Angina Diseases 0.000 claims description 4
- 206010047249 Venous thrombosis Diseases 0.000 claims description 4
- 238000002399 angioplasty Methods 0.000 claims description 4
- 230000001580 bacterial effect Effects 0.000 claims description 4
- 210000004204 blood vessel Anatomy 0.000 claims description 4
- 208000029078 coronary artery disease Diseases 0.000 claims description 4
- 210000004351 coronary vessel Anatomy 0.000 claims description 4
- 125000005167 cycloalkylaminocarbonyl group Chemical group 0.000 claims description 4
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 4
- 210000001951 dura mater Anatomy 0.000 claims description 4
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 4
- 201000004332 intermediate coronary syndrome Diseases 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 claims description 4
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims description 4
- 208000010125 myocardial infarction Diseases 0.000 claims description 4
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 4
- 230000000250 revascularization Effects 0.000 claims description 4
- 238000001356 surgical procedure Methods 0.000 claims description 4
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 4
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 3
- ZZBKFGAUXXMYNA-UHFFFAOYSA-N 2-(4-chlorophenyl)-1-(4-methylsulfonylphenyl)-4-phenylimidazole Chemical class C1=CC(S(=O)(=O)C)=CC=C1N1C(C=2C=CC(Cl)=CC=2)=NC(C=2C=CC=CC=2)=C1 ZZBKFGAUXXMYNA-UHFFFAOYSA-N 0.000 claims description 3
- NECDCTAHUMBLQG-UHFFFAOYSA-N 2-bromo-6-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)pyridine-3-carbonitrile Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=CC(C#N)=C(Br)N=C1C1=CC=C(F)C=C1 NECDCTAHUMBLQG-UHFFFAOYSA-N 0.000 claims description 3
- ILPBINAXDRFYPL-UHFFFAOYSA-N 2-octene Chemical compound CCCCCC=CC ILPBINAXDRFYPL-UHFFFAOYSA-N 0.000 claims description 3
- JSEDBZHLLXWYHV-UHFFFAOYSA-N 6-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-phenylpyridine-3-carbonitrile Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=CC(C#N)=C(C=2C=CC=CC=2)N=C1C1=CC=C(F)C=C1 JSEDBZHLLXWYHV-UHFFFAOYSA-N 0.000 claims description 3
- FOXNVXAFLYGETJ-UHFFFAOYSA-N ClC1=CC=C(C=C1)C1C(C(=O)O)(C=CC(=C1C(=O)O)C)C1=CC=C(C=C1)S(=O)(=O)C Chemical compound ClC1=CC=C(C=C1)C1C(C(=O)O)(C=CC(=C1C(=O)O)C)C1=CC=C(C=C1)S(=O)(=O)C FOXNVXAFLYGETJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
- 125000002837 carbocyclic group Chemical group 0.000 claims description 3
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 claims description 3
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 3
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- BWRYNNCGEDOTRW-GXDHUFHOSA-N (4e)-4-[(3,5-ditert-butyl-4-hydroxyphenyl)methylidene]-2-methyloxazinan-3-one Chemical compound O=C1N(C)OCC\C1=C/C1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 BWRYNNCGEDOTRW-GXDHUFHOSA-N 0.000 claims description 2
- GWMFOHRUWPDLIP-UHFFFAOYSA-N 1-(4-methylsulfonylphenyl)-2-phenyl-4-(trifluoromethyl)imidazole Chemical class C1=CC(S(=O)(=O)C)=CC=C1N1C(C=2C=CC=CC=2)=NC(C(F)(F)F)=C1 GWMFOHRUWPDLIP-UHFFFAOYSA-N 0.000 claims description 2
- VCLNQQUCGTWUKD-UHFFFAOYSA-N 2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-1,3-thiazole Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC(F)=CC=2)N=C(C=2C(=CC=CC=2)Cl)S1 VCLNQQUCGTWUKD-UHFFFAOYSA-N 0.000 claims description 2
- SOOKCKQNOCMHPV-UHFFFAOYSA-N 2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-1,3-thiazole Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC(F)=CC=2)N=C(C=2C=C(Cl)C(F)=CC=2)S1 SOOKCKQNOCMHPV-UHFFFAOYSA-N 0.000 claims description 2
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- SAVMISCIBLZUAE-UHFFFAOYSA-N 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(trifluoromethyl)-1,3-thiazole Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC(F)=CC=2)N=C(C(F)(F)F)S1 SAVMISCIBLZUAE-UHFFFAOYSA-N 0.000 claims description 2
- ISMZMNIRFHOTII-UHFFFAOYSA-N 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-thiophen-2-yl-1,3-thiazole Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC(F)=CC=2)N=C(C=2SC=CC=2)S1 ISMZMNIRFHOTII-UHFFFAOYSA-N 0.000 claims description 2
- ZPMVBXDFUCFRLF-UHFFFAOYSA-N 5-(4-fluorophenyl)-2-methyl-4-(4-methylsulfonylphenyl)-1,3-thiazole Chemical compound S1C(C)=NC(C=2C=CC(=CC=2)S(C)(=O)=O)=C1C1=CC=C(F)C=C1 ZPMVBXDFUCFRLF-UHFFFAOYSA-N 0.000 claims description 2
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- WTDOUHRTSZVJMQ-UHFFFAOYSA-N CS(C(C=C1)=CC=C1N1C(C2=CC(F)=CC(CN)=C2)=NC(C(F)(F)F)=C1)(=O)=O Chemical class CS(C(C=C1)=CC=C1N1C(C2=CC(F)=CC(CN)=C2)=NC(C(F)(F)F)=C1)(=O)=O WTDOUHRTSZVJMQ-UHFFFAOYSA-N 0.000 claims description 2
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- KDHWCFCNNGUJCP-UHFFFAOYSA-N 2-phenylimidazo[1,2-a]pyridine Chemical compound N1=C2C=CC=CN2C=C1C1=CC=CC=C1 KDHWCFCNNGUJCP-UHFFFAOYSA-N 0.000 claims 2
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- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
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Abstract
本发明涉及利用环氧化酶-2的抑制物或其衍生物预防心血管疾病。
Description
发明领域
本发明属于预防心血管疾病领域。更具体地说,本发明利用环氧化酶-2的抑制物或其衍生物预防心血管疾病,包括动脉粥样硬化。
发明背景
前列腺素在发炎过程中起作重要的作用,抑制前列腺素的产生,尤其是PGG2、PGH2和PGE2的产生,已经成为开发消炎药的共同目标。但是,通常用于缓解因前列腺素引起的疼痛及与发炎相伴随的肿胀的非类固醇类消炎药(NSAID’s)也会同时影响与发炎过程无关的其它前列腺素调节过程。因此,使用高剂量的最通常的NSAID’s可导致严重的副作用,包括危及生命的溃疡,这限制了它们的治疗潜能。NSAID’s的替代物是使用皮质类固醇,这也会产生严重的不利影响,尤其是当长期治疗时。
已经发现NSAIDs通过抑制人体内二十碳四烯酸/前列腺素途径中的酶来防止前列腺素的产生,这些酶包括环氧化酶(COX)。最近发现的与发炎有关的可诱导的酶(称为“环氧化酶-2(COX-2)”或“前列腺素G/H合成酶II”)提供了一种可行的抑制目标,它能更有效地缓解炎症和更少地导致激烈的副作用。
最近,发炎在心血管疾病中的作用得到了进一步的认识。Ridker etal.(New Eng.J.Med.,336,973-9(1997))描述了发炎在心血管疾病中的一种可能作用。J.Boyle(J.Path.,181,93-9(1997))描述了血小板破裂与动脉粥样硬化发炎的关联。
美国专利5,380,738,5,344,991,5,393,790,5,434,178,5,474,995,5,510,368和WO文献WO96/06840,WO96/03388,WO96/03387,WO96/19469,WO96/25405,WO95/15316,WO94/15932,WO94/27980,WO95/00501,WO94/13635,WO94/20480,和WO94/26731中记载了选择性地抑制环氧化酶-2的化合物。
吡唑基-1-苯磺酰胺已被记述为环氧化酶-2的抑制物,有希望用于治疗发炎,关节炎和疼痛,且在临床前及临床试验上表现出有很小的副作用。它们在血管疾病中治疗炎症的应用已经在美国专利5,466,823中记载,但是它们用于预防心血管相关疾病的应用在此前还未有记载。
本发明目的在于利用环氧化酶-2的抑制物预防与心血管疾病相关的炎症。更具体地说,本发明涉及利用环氧化酶-2的抑制物或其衍生物预防心血管疾病。
发明的详细描述
本发明为需要预防心血管疾病的受治疗者提供了一种预防方法,该方法包括用治疗上有效剂量的环氧化酶-2的抑制物或其衍生物或其药用盐来治疗受治疗者。
上述方法可用于预防受治疗者的与炎症相关的心血管疾病,但又不局限于此。该方法可用于预防冠状动脉疾病、动脉瘤、动脉硬化、粥样动脉硬化,包括心脏移植粥样动脉硬化、心肌梗塞、栓塞、中风、血栓,包括静脉血栓、心绞痛,包括不稳定心绞痛、冠状血小板发炎、细菌引起的发炎,包括衣原体引起的发炎、病毒引起的发炎、和与外科手术相关的发炎,如血管移植,包括冠状动脉搭桥手术、换血管术,包括血管成形术、斯滕特固定模定位、动脉硬膜切除术、或其它对动脉、静脉和毛细血管的侵害性过程。
术语“预防”在这里包括对于临床上明显的心血管疾病征兆的预防和对个体出现临床前心血管疾病明显阶段性征兆的预防。这包括对有发展成心血管疾病危险的人的预防性治疗。
短语“治疗上有效”是用于衡量在避免一般与替代的治疗方法相关的不利副反应的同时,获得改善疾病严重性和每种药剂单独治疗期间发病率的目标的药剂剂量。
对治疗来说,“受治疗者”包括易患任意一种已知的心血管疾病的任何人或动物受治疗者,一般指人。受治疗者可能因饮食、受细菌或病毒的感染,具有通常的特征,在遗传上易患心血管疾病等等而处于危险中。
在上述方法中,心血管疾病包括(但不限于)已知包含发炎症状的那些疾病和可受环氧化酶-2调节的那些疾病。
心血管疾病的预防中使用的二十碳四烯酸的新陈代谢途径中环氧化酶的抑制物可通过多种机理抑制酶的活性。举例而言,这里描述的方法中使用的抑制物可通过作为酶的被作用物来直接抑制酶的活性。使用环氧化酶-2的选择性抑制物非常有利在于使使用非选择性的NSAID’s会产生的胃的副作用减至最小,尤其是期望用于长期的预防性治疗。
术语“环氧化酶-2抑制物”表示能够抑制环氧化酶-2,而不会明显抑制环氧化酶-1的化合物。它最好包含具有小于0.2uM的环氧化酶-2 IC50的化合物,并且环氧化酶-2抑制比环氧化酶-1抑制的选择性比率至少为50,最好至少为100。更好的是,化合物具有大于1uM的环氧化酶-1 IC50,最好大于10uM。
这里提供的方法涉及利用环氧化酶-2的抑制物或其衍生物预防与发炎相关的心血管疾病。在最佳实施例中,环氧化酶-2的抑制物选自meloxicam(Boehringer Ingelheim),nimesulide(Helsinn),MK-966(Merck & Co),L-783003(Merck & Co),T-614(Toyama),D-1367(Chiroscience),L-748731(Merck & Co),CT3(AtlanticPharmaceutical),CGP-28238(Novartis),BF-389(Biofor/Scherer),GR-253035(Glaxo Wellcome),(E)-4-(1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl)cinamic acid(Glaxo Wellcome),L-745337(Merck & Co),及分子式I的化合物:
其中A取代基选自部分不饱和或不饱和杂环及部分不饱和或不饱和碳环;
其中R1是至少一个选自杂环基、环烷基、环烯基和芳香基的取代基,其中R1在可取代位置上被一个或多个选自烷基、卤代烷基、氰基、羧基、烷氧羰基、羟基、羟烷基、卤代烷氧基、氨基、烷基氨基、芳香氨基、硝基、烷氧基烷基、烷基亚磺酰基、卤基、烷氧基和烷硫基的自由基选择性取代;
其中R2是甲基或氨基;
其中R3是选自氢基、卤基、烷基、链烯基、炔基、氧代基、氰基、羧基、氰烷基、杂环氧基、烷基氧、烷硫基、烷基羰基、环烷基、芳香基、卤代烷基、杂环基、环烯基、芳烷基、杂环烷基、酰基、烷基硫代烷基、羟基烷基、烷氧羰基、芳羰基、芳烷基羰基、芳烯基、烷氧烷基、芳基硫代烷基、芳氧烷基、芳烷基硫代烷基、芳烷氧烷基、烷氧芳烷氧烷基、烷氧羰基烷基、氨基羰基、氨基羰基烷基、烷基氨基羰基、N-芳氨基羰基、N-烷基-N-芳氨基羰基、烷基氨基羰基烷基、羧基烷基、烷基氨基、N-芳氨基、N-芳烷基氨基、N-烷基-N-芳烷基氨基、N-烷基-N-芳氨基、氨基烷基、烷基氨基烷基、N-芳基氨基烷基、N-芳烷基氨基烷基、N-烷基-N-芳烷基氨基烷基、N-烷基-N-芳氨基烷基、芳氧基、芳烷氧基、芳硫基、芳烷硫基、烷基亚磺酰基、烷基磺酰基、氨基磺酰基、烷基氨基磺酰基、N-芳基氨基磺酰基、芳基磺酰基、N-烷基-N-芳基氨基磺酰基的自由基;或者是它们的药用盐。
抑制环氧化酶-2的一类最好化合物由meloxicam(BoehringerIngelheim),nimesulide(Helsinn),MK-966(Merck & Co),L-783003(Merck & Co),T-614(Toyama),D-1367(Chiroscience),L-748731(Merck & Co),L-745337(Merck & Co),和分子式I的化合物组成,其中A选自5-或6-节的部分不饱和杂环,5-或6-节不饱和杂环,9-或10-节不饱和稠合杂环,低聚环链烯基和苯基;其中R1选自5-和6-节杂环,低聚环烷基,低聚环链烯基和选自苯基、联苯基和萘基的芳香基,其中R1在取代位置上被选自低聚烷基、低聚卤代烷基、氰基、羧基、低聚烷氧羰基、羟基、低聚羟烷基、低聚卤代烷氧基、氨基、低聚烷基氨基、苯氨基、低聚烷氧基烷基、低聚烷基亚磺酰基、卤基、低聚烷氧基和低聚烷硫基的一个或多个自由基选择性取代;其中R2是甲基或氨基;其中R3是选自氢基、氧基、氰基、羧基、低聚烷氧羰基、低聚羧基烷基、低聚氰基烷基、卤基、低聚烷基、低聚烷氧基、低聚环烷基、苯基、低聚卤代烷基、5-或6-节杂环基、低聚羟基烷基、低聚芳烷基、芳香基、苯基羰基、低聚烷氧烷基、5-或6-节杂烷氧基、氨基羰基、低聚烷基氨基羰基、低聚烷基氨基、低聚氨基烷基、低聚烷基氨基烷基、苯氧基和低聚芳烷氧基的自由基;或者是它们的药用盐。
抑制环氧化酶-2的更好的一类化合物由meloxicam(Boehringer Ingelheim),nimesulide(Helsinn),MK-966(Merck &Co),L-783003(Merck & Co),T-614(Toyama),D-1367(Chiroscienee),L-748731(Merck & Co),L-745337(Merck & Co),和分子式I的化合物组成,其中A选自恶唑基、异恶唑基、呋喃基、噻吩基、二氢呋喃基、吡咯基、吡唑基、噻唑基、咪唑基、异噻唑基、苯并呋喃基、环戊烯基、环戊二烯基、苯基和吡啶基;其中R1选自在取代位置被一个或多个甲基基团选择性取代的吡啶基,在取代位置被下述一个或多个自由基团选择性取代的苯基:甲基、乙基、异丙基、丁基、叔丁基、异丁基、戊基、己基、氟甲基、二氟甲基、三氟甲基、氰基、羧基、甲氧羰基、乙氧羰基、羟基、羟基甲基、三氟甲氧基、氨基、N-甲氨基、N、N-二甲氨基、N-乙氨基、N、N-二丙氨基、N-丁氨基、N-甲基-N-乙氨基、苯氨基、甲氧甲基、甲基亚磺酰基、氟基、氯基、溴基、甲氧基、乙氧基、丙氧基、n-丁氧基、戊氧基和甲硫基;其中R2是甲基或氨基;其中R3是选自氢基、氧基、氰基、羧基、甲氧羰基、乙氧羰基、羧基丙基、羧基甲基、羧基乙基、氰基甲基、氟基、氯基、溴基、甲基、乙基、异丙基、丁基、叔丁基、异丁基、戊基、己基、二氟甲基、三氟甲基、五氟乙基、六氟丙基、二氟乙基、二氟丙基、甲氧基、乙氧基、丙氧基、n-丁氧基、戊氧基、环己基、苯基、吡啶基、噻吩基、噻唑基、恶唑基、呋喃基、吡唑基、羟基甲基、羟基丙基、苯甲基、甲酰基、苯基羰基、甲氧基甲基、呋喃甲氧基、氨基羰基、N-甲基氨基羰基、N、N-二甲基氨基羰基、N、N-二甲基氨基、N-乙基氨基、N、N-二丙基氨基、N-丁基氨基、N-甲基-N-乙基氨基、氨基甲基、N、N-二甲基氨基甲基、N-甲基-N-乙基氨基甲基、苄氧基、和苯氧基的自由基;或者是它们的药用盐。
具有特别兴趣的一族特殊化合物由下列化合物及其药用盐组成:
meloxicam(Boehringer Ingelheim),nimesulide(Helsinn),MK-966(Merck & Co),L-783003(Merck & Co),T-614(Toyama),D-1367(Chiroscience),L-748731(Merck & Co),L-745337(Merck & Co);
8-乙酰基-3-(4-氟苯基)-2-(4-甲磺酰基)苯基-咪唑基(1,2-a)吡啶;
5,5二甲基-4-(4-甲磺酰基)苯基-3-苯基-2-(5H)-呋喃;
5-(4-氟苯基)-1-[4-(甲磺酰基)苯基]-3-(三氟甲基)吡唑;
4-(4-氟苯基)-5-[4-(甲磺酰基)苯基]-1-苯基-3-(三氟甲基)吡唑;
4-(5-(4-氯苯基)-3-(4-甲氧苯基)-1H-吡唑-1-基)苯磺酰胺;
4-(3,5-二(4-甲基苯基)-1H-吡唑-1-基)苯磺酰胺;
4-(5-(4-氯苯基)-3-苯基-1H-吡唑-1-基)苯磺酰胺;
4-(3,5-二(4-甲氧苯基)-1H-吡唑-1-基)苯磺酰胺;
4-(5-(4-氯苯基)-3-(4-甲基苯基)-1H-吡唑-1-基)苯磺酰胺;
4-(5-(4-氯苯基)-3-(4-硝基苯基)-1H-吡唑-1-基)苯磺酰胺;
4-(5-(4-氯苯基)-3-(5-氯-2-噻吩基)-1H-吡唑-1-基)苯磺酰胺;
4-(4-氯-3,5-二苯基-1H-吡唑-1-基)苯磺酰胺;
4-[5-(4-氯苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-苯基-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-(4-氟苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-(4-甲氧苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-(4-氯苯基)-3-(二氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-(4-甲基苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[4-氯-5-(4-氯苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[3-(二氟甲基)-5-(4-甲基苯基)-1H-吡唑-1-基]苯磺酰胺;
4-[3-(二氟甲基)-5-基苯-1H-吡唑-1-基]苯磺酰胺;
4-[3-(二氟甲基)-5-(4-甲氧苯基)-1H-吡唑-1-基]苯磺酰胺;
4-[3-氰基-5-(4-氟基苯基)-1H-吡唑-1-基]苯磺酰胺;
4-[3-(二氟甲基)-5-(3-氟-4-甲氧苯基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-(3-氟-4-甲氧苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[4-氯-5-苯基-1H-吡唑-1-基]苯磺酰胺;
4-[5-(4-氯苯基)-3-(羟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-(4-(N,N-二甲基氨基)苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
5-(4-氟苯基)-6-[4-(甲磺酰基)苯基]螺[2.4]庚-5-烯;
4-[6-(4-氟苯基)螺[2.4]庚-5-烯-5-基]苯磺酰胺;
6-(4-氟苯基)-7-[4-(甲磺酰基)苯基]螺[3.4]辛-6-烯;
5-(3-氯-4-甲氧苯基)-6-[4-(甲磺酰基)苯基]螺[2.4]庚-5-烯;
4-[6-(3-氯-4-甲氧苯基)螺[2.4]庚-5-烯-5-基]苯磺酰胺;
5-(3,5-二氯-4-甲氧苯基)-6-[4-(甲磺酰基)苯基]螺[2.4]庚-5-烯;
5-(3-氯-4-氟苯基)-6-[4-(甲磺酰基)苯基]螺[2.4]庚-5-烯;
4-[6-(3,4-二氯苯基)螺[2.4]庚-5-烯-5-基]苯磺酰胺;
2-(3-氯-4-氟苯基)-4-(4-氟苯基)-5-(4-甲磺酰苯基)噻唑;
2-(2-氯苯基)-4-(4-氟苯基)-5-(4-甲磺酰苯基)噻唑;
5-(4-氟苯基)-4-(4-甲磺酰苯基)-2-甲基噻唑;
4-(4-氟苯基)-5-(4-甲磺酰苯基)-2-三氟甲基噻唑;
4-(4-氟苯基)-5-(4-甲磺酰苯基)-2-(2-噻吩基)噻唑;
4-(4-氟苯基)-5-(4-甲磺酰苯基)-2-苄氨基噻唑;
4-(4-氟苯基)-5-(4-甲磺酰苯基)-2-(1-丙氨基)噻唑;
2-[(3,5-二氯苯氧基)甲基]-4-(4-氟苯基)-5-[4-(甲磺酰基)苯基]噻唑;
5-(4-氟苯基)-4-(4-甲磺酰苯基)-2-三氟甲基噻唑;
1-甲磺酰基-4-[1,1-二甲基-4-(4-氟苯基)环戊-4,6-二烯-3-基]苯;
4-[4-(4-氟苯基)-1,1-二甲基环戊-2,4-二烯-3-基]苯磺酰胺;
5-(4-氟苯基)-6-[4-(甲磺酰基)苯基]螺[2.4]庚-4,6-二烯;
4-[6-(4-氟苯基)螺[2.4]庚-4,6-二烯-5-基]苯磺酰胺;
6-(4-氟苯基)-2-甲氧基-5-[4-(甲磺酰基)苯基]-吡啶-3-腈;
2-溴-6-(4-氟苯基)-5-[4-(甲磺酰基)苯基]-吡啶-3-腈;
6-(4-氟苯基)-5-[4-(甲磺酰基)苯基]-2-苯基-吡啶-3-腈;
4-[2-(4-甲基吡啶-2-基)-4-(三氟甲基)-1H-咪唑-1-基]苯磺酰胺;
4-[2-(5-甲基吡啶-3-基)-4-(三氟甲基)-1H-咪唑-1-基]苯磺酰胺;
4-[2-(2-甲基吡啶-3-基)-4-(三氟甲基)-1H-咪唑-1-基]苯磺酰胺;
3-[1-[4-(甲磺酰基)苯基]-4-(三氟甲基)-1H-咪唑-2-基]吡啶;
2-[1-[4-(甲磺酰基)苯基]-4-(三氟甲基)-1H-咪唑-2-基]吡啶;
2-甲基-4-[1-[4-(甲磺酰基)苯基]-4-(三氟甲基)-1H-咪唑-2-基]吡啶;
2-甲基-6-[1-[4-(甲磺酰基)苯基]-4-(三氟甲基)-1H-咪唑-2-基]吡啶;
4-[2-(6-甲基吡啶-3-基)-4-(三氟甲基)-1H-咪唑-2-基]苯磺酰胺;
2-(3,4-二氟苯基)-1-[4-(甲磺酰基)苯基]-4-(三氟甲基)-1H-咪唑;
4-[2-(4-甲基苯基)-4-(三氟甲基)-1H-咪唑-1-基]苯磺酰胺;
2-(4-氯苯基)-1-[4-(甲磺酰基)苯基]-4-甲基-1H-咪唑;
2-(4-氯苯基)-1-[4-(甲磺酰基)苯基]-4-苯基-1H-咪唑;
2-(4-氯苯基)-4-(4-氟苯基)-1-[4-(甲磺酰基)苯基]-1H-咪唑;
2-(3-氟-4-甲氧苯基)-1-[4-(甲磺酰基)苯基]-4-(三氟甲基)-1H-咪唑;
1-[4-(甲磺酰基)苯基]-2-苯基-4-(三氟甲基)-1H-咪唑;
2-(4-甲基苯基)-1-[4-(甲磺酰基)苯基]-4-三氟甲基-1H-咪唑;
4-[2-(3-氯-4-甲基苯基)-4-(三氟甲基)-1H-咪唑-1-基]苯磺酰胺;
2-(3-氟-5-甲基苯基)-1-[4-(甲磺酰基)苯基]-4-(三氟甲基)-1H-咪唑;
4-[2-(3-氟-5-甲基苯基)-4-(三氟甲基)-1H-咪唑-1-基]苯磺酰胺;
2-(3-甲基苯基)-1-[4-(甲磺酰基)苯基]-4-三氟甲基-1H-咪唑;
4-[2-(3-甲基苯基)-4-三氟甲基-1H-咪唑-1-基]苯磺酰胺;
1-[4-(甲磺酰基)苯基]-2-(3-氯苯基)-4-三氟甲基-1H-咪唑;
4-[2-(3-氯苯基)-4-三氟甲基-1H-咪唑-1-基]苯磺酰胺;
4-[2-苯基-4-三氟甲基-1H-咪唑-1-基]苯磺酰胺;
4-[2-(4-甲氧基-3-氯苯基)-4-三氟甲基-1H-咪唑-1-基]苯磺酰胺;
1-烯丙基-4-(4-氟苯基)-3-[4-(甲磺酰基)苯基]-5-(三氟甲基)-1H-吡唑;
4-[1-乙基-4-(4-氟苯基)-5-(三氟甲基)-1H-吡唑-3-基]苯磺酰胺;
N-苯基-[4-(4-氟苯基)-3-[4-(甲磺酰基)苯基]-5-(三氟甲基)-1H-吡唑-1-基]乙酰胺;
乙基[4-(4-氟苯基)-3-[4-(甲磺酰基)苯基]-5-(三氟甲基)-1H-吡唑-1-基]乙酸酯;
4-(4-氟苯基)-3-[4-(甲磺酰基)苯基]-1-(2-苯乙基)-1H-吡唑;
4-(4-氟苯基)-3-[4-(甲磺酰基)苯基]-1-(2-苯乙基)-5-(三氟甲基)吡唑;
1-乙基-4-(4-氟苯基)-3-[4-(甲磺酰基)苯基]-5-(三氟甲基)-1H-吡唑;
5-(4-氟苯基)-4-(4-甲磺酰苯基)-2-三氟甲基-1H-咪唑;
4-[4-(甲磺酰基)苯基]-5-(2-苯硫基)-2-(三氟甲基)-1H-咪唑;
5-(4-氟苯基)-2-甲氧基-4-[4-(甲磺酰基)苯基]-6-(三氟甲基)吡啶;
2-乙氧基-5-(4-氟苯基)-4-[4-(甲磺酰基)苯基]-6-(三氟甲基)吡啶;
5-(4-氟苯基)-4-[4-(甲磺酰基)苯基]-2-(2-丙炔氧基)-6-(三氟甲基)吡啶;
2-溴-5-(4-氟苯基)-4-[4-(甲磺酰基)苯基]-6-(三氟甲基)吡啶;
4-[2-(3-氯-4-甲氧苯基)-4,5-二氟苯基]苯磺酰胺;
1-(4-氟苯基)-2-[4-(甲磺酰基)苯基]苯;
5-二氟甲基-4-(4-甲磺酰苯基)-3-苯基异恶唑;
4-[3-乙基-5-苯基异恶唑-4-基]苯磺酰胺;
4-[5-二氟甲基-5-苯基异恶唑-4-基]苯磺酰胺;
4-[5-羟甲基-5-苯基异恶唑-4-基]苯磺酰胺;
4-[5-甲基-3-苯基-异恶唑-4-基]苯磺酰胺;
1-[2-(4-氟苯基)环戊烯-1-基]-4-(甲磺酰基)苯;
1-[2-(4-氟-2-甲基苯基)环戊烯-1-基]-4-(甲磺酰基)苯;
1-[2-(4-氯苯基)环戊烯-1-基]-4-(甲磺酰基)苯;
1-[2-(2,4-二氯苯基)环戊烯-1-基]-4-(甲磺酰基)苯;
1-[2-(4-三氟甲基苯基)环戊烯-1-基]-4-(甲磺酰基)苯;
1-[2-(4-甲基硫代苯基)环戊烯-1-基]-4-(甲磺酰基)苯;
1-[2-(4-氟苯基)-4,4-二甲基环戊烯-1-基]-4-(甲磺酰基)苯;
4-[2-(4-氟苯基)-4,4-二甲基环戊烯-1-基]苯磺酰胺;
1-[2-(4-氯苯基)-4,4-二甲基环戊烯-1-基]-4-(甲磺酰基)苯;
4-[2-(4-氯苯基)-4,4-二甲基环戊烯-1-基]苯磺酰胺;
4-[2-(4-氟苯基)环戊烯-1-基]苯磺酰胺;
4-[2-(4-氯苯基)环戊烯-1-基]苯磺酰胺;
1-[2-(4-甲氧苯基)环戊烯-1-基]-4-(甲磺酰基)苯;
1-[2-(2,3-二氟苯基)环戊烯-1-基]-4-(甲磺酰基)苯;
4-[2-(3-氟-4-甲氧苯基)环戊烯-1-基]苯磺酰胺;
1-[2-(3-氯-4-甲氧苯基)环戊烯-1-基]-4-(甲磺酰基)苯;
4-[2-(3-氯-4-氟苯基)环戊烯-1-基]苯磺酰胺;
4-[2-(2-甲基吡啶-5-基)环戊烯-1-基]苯磺酰胺;
乙基2-[4-(4-氟苯基)-5-[4-(甲磺酰基)苯基]恶唑-2-基]-2-苯甲基-乙酸酯;
2-[4-(4-氟苯基)-5-[4(甲磺酰基)苯基]恶唑-2-基]乙酸;
2-(叔-丁基)-4-(4-氟苯基)-5-[4-(甲磺酰基)苯基]恶唑;
4-(4-氟苯基)-5-[4-(甲磺酰基)苯基]-2-苯基恶唑;
4-(4-氟苯基)-2-甲基-5-[4-(甲磺酰基)苯基]恶唑;和
4-[5-(3-氟-4-甲氧苯基)-2-三氟甲基-4-恶唑]苯磺酰胺。
更特别关心的一族特殊化合物由下列化合物及其药用盐组成:
MK-966(Merck & Co),L-752,860(Merck & Co);L-783003(Merck& Co),T-614(Toyama),D-1367(Chiroscience),L-748731(Merck& Co),L-745337(Merck & Co);和分子式I的化合物
4-[5-(4-氯苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-(4-甲基苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-(3-氟-4-甲氧苯基)-3-(二氟甲基)-1H-吡唑-1-基]苯磺酰胺;
3-[1-[4-(甲磺酰基)苯基]-4-三氟甲基-1H-咪唑-2-基]吡啶;
2-甲基-5-[1-[4-(甲磺酰基)苯基]-4-三氟甲基-1H-咪唑-2-基]吡啶;
4-[2-(5-甲基吡啶-3-基)-4-(三氟甲基)-1H-咪唑-1-基]苯磺酰胺;
4-[5-甲基-3-苯基异恶唑-4-基]苯磺酰胺;
4-[5-羟甲基-3-苯基异恶唑-4-基]苯磺酰胺;
[2-三氟甲基-5-(3,4-二氟苯基)-4-恶唑基]苯磺酰胺;
4-[2-甲基-4-苯基-5-恶唑基]苯磺酰胺;和
4-[5-(3-氟-4-甲氧苯基-2-三氟甲基)-4-恶唑基]苯磺酰胺。
其中R4选自氢基、烷基、卤代烷基、烷氧羰基、氰基、氰基烷基、羧基、氨基羰基、烷基氨基羰基、环烷基氨基羰基、芳氨基羰基、羧基烷基氨基羰基、羧基烷基、芳烷氧基羰基烷基氨基羧基、氨基羰基烷基、烷氧基羰基氰基链烯基、和羟基烷基;
其中R5选自氢基、烷基、氰基、羟基烷基、环烷基、烷基磺酰基和卤基;
其中R6选自芳烯基、芳香基、环烷基、环链烯基和杂环;其中R4在取代位置被下述一个或多个自由基团选择性取代,卤基、烷硫基、烷基磺酰基、氰基、硝基、卤代烷基、烷基、羟基、链烯基、羟基烷基、羧基、环烷基、烷基氨基、二烷基氨基、烷氧羰基、氨基羰基、烷氧基、卤代烷氧基、氨磺酰基、杂环和氨基;
或它们的药用盐或衍生物。
特别关心的一类化合物由分子式I的化合物组成,其中R4选自氢基、低聚烷基、低聚卤代烷基、低聚烷氧基羰基、氰基、低聚氰基烷基、羧基、氨基羰基、低聚烷基氨基羰基、低聚环烷基氨基羰基、芳氨基羰基、低聚羧基烷基氨基羰基、低聚氨基羰基烷基、低聚芳烷氧基羰基烷基氨基羰基、低聚羧基烷基、低聚烷氧基羰基氰基链烯基和低聚羟基烷基;其中R5选自氢基、低聚烷基、氰基、低聚羟基烷基、低聚环烷基、低聚烷基磺酰基和卤基;其中R6选自芳烯基、芳香基、环烷基、环链烯基和杂环化合物;其中R4在取代位置被下述一个或多个自由基团选择性取代,卤基、低聚烷硫基、低聚烷基磺酰基、氰基、硝基、低聚卤代烷基、低聚烷基、羟基、低聚链烯基、低聚羟基烷基、羧基、低聚环烷基、低聚烷基氨基、低聚二烷基氨基、低聚烷氧羰基、氨基羰基、低聚烷氧基、低聚卤代烷氧基、氨磺酰基、五或六节的杂环化合物和氨基;或其药用盐或衍生物。
分子式I的化合物内特别关心的一族特殊化合物由下列化合物、其衍生物和药用盐组成;
4-[5-(4-氯苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-苯基-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-(4-氟苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-(4-甲氧苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-(氯苯基)-3-(二氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-(4-甲基苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[4-氯-5-(4-氯苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[3-(二氟甲基)-5-(4-甲基苯基)-1H-吡唑-1-基]苯磺酰胺;
4-[3-(二氟甲基)-5-苯基-1H-吡唑-1-基]苯磺酰胺;
4-[3-(二氟甲基)-5-(4-甲氧苯基)-1H-吡唑-1-基]苯磺酰胺;
4-[3-氰基-5-(4-氟苯基)-1H-吡唑-1-基]苯磺酰胺;
4-[3-(二氟甲基)-5-(3-氯-4-甲氧苯基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-(3-氟-4-甲氧苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[4-氯-5-苯基-1H-吡唑-1-基]苯磺酰胺;
4-[5-(4-氯苯基)-3-(羟基甲基)-1H-吡唑-1-基]苯磺酰胺;和
4-[5-(4-(N,N-二甲基氨基)苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺。
分子式I的化合物内更特别关心的一族特殊化合物由下列化合物、其衍生物和药用盐组成;
4-[5-(4-甲基苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-(4-氯苯基)-3-(二氟甲基)-1H-吡唑-1-基]苯磺酰胺;和
4-[5-(3-氟-4-甲氧苯基)-3-(二氟甲基)-1H-吡唑-1-基]苯磺酰胺;
衍生物包括结构上与环氧化酶-2抑制物相关的或具有大体相同的生物活性的所有化合物。举例而言,这些抑制物包括(但不局限于)药物前体。
术语“氢基”指单个氢原子(H)。该氢自由基可和例如一个氧原子结合形成羟基基团,或两个氢自由基与一个碳原子结合形成一个亚甲基(-CH2-)。当单独使用或与其它词,如“卤代烷基”、“烷基硫酰基”、“烷氧基烷基”和“羟基烷基”合用时,术语“烷基”指包含具有1~20个碳原子,或较好是1~12个碳原子的直链或支链基团。更好的烷基基团是具有1~10个碳原子的“低聚烷基”。最好的烷基基团是具有1~6个碳原子的“低聚烷基”。这些基团的例子包括甲基、乙基、n-丙基、异丙基、n-丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、己基和类似物。术语“链烯基”指包括具有至少一个碳-碳双键的2~20个碳原子的直链或支链基团,或较好是2~12个碳原子的直链或支链基团。更好的烷基基团是具有2~6个碳原子的“低聚链烯基”基团。链烯基基团的例子包括乙烯基、丙烯基、2-丙烯基、丙烯基、丁烯基和4-甲基丁烯基。术语“炔基”指具有2~20个碳原子的直链或支链基团,或较好是2~12个碳原子的直链或支链基团。更好的炔基基团是具有2~10个碳原子的“低聚炔基”基团。最好的炔基基团是具有2~6个碳原子的低聚炔基基团。这些基团的例子包括丙炔基、丁炔基和类似物。术语“链烯基”、“低聚链烯基”包括具有“顺式”和“反式”方向,或另称为“E”和“Z”方向的基团。术语“环烷基”包括具有3~12个碳原子的饱和碳环基团。更好的环烷基基团是具有3~8个碳原子的“低聚环烷基”基团。这些基团的例子包括环丙烷、、环丁烷、环戊烷和环己烷。术语“环链烯基”包括具有3~12个碳原子的部分不饱和碳环基团。更好的环链烯基基团是具有4~8个碳原子的“低聚环链烯基”基团。这些基团的例子包括环丁烯、环戊烯、环戊二烯和环己烯。术语“卤基”指卤原子如氟、氯、溴或碘。术语“卤代烷基”包括选择性一个或多个烷基碳原子被上述卤原子取代的基团。具体地包括单卤代烷基、双卤代烷基和多卤代烷基基团。一个单卤代烷基基团在基团内可能有一个碘、溴、氯或氟原子。双卤代或多卤代烷基基团可能具有两个或多个相同的卤原子或由不同的卤代基团的组合物。“低聚卤代烷基”包括具有1~6个碳原子的基团。卤代烷基的例子包括氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、三氯甲基、五氟乙基、七氟丙基、二氟氯甲基。二氯氟甲基、二氟乙基、二氟丙基、二氯乙基和二氯丙基。术语“羟基烷基”包括具有1~10个碳原子的直链或支链烷基基团,其中选择性一个碳原子可被一个或多个羟基基团取代。更好的羟基烷基基团是具有1~6个碳原子和一个或多个羟基基团的低聚羟基烷基。这些基团的例子包括羟基甲基、羟基乙基、羟基丙基、羟基丁基和羟基己基。术语“烷氧基”和“烷基化氧”包括均具有1~10个碳原子的烷基部分的直链或支链含氧基团。更好的烷氧基基团是具有1~6个碳原子的“低聚烷氧基”基团。这些基团的例子包括甲氧基、乙氧基、丙氧基、丁氧基、和叔丁氧基。术语“烷氧基烷基”包括具有连接在烷基基团上的一个或多个烷氧基的烷基基团,即形成单烷氧基烷基和双烷氧基烷基基团。“烷氧基”基团可进一步被一个或多个卤原子,例如氟、氯或溴取代,形成卤代烷氧基基团。更好的卤代烷氧基基团是具有1~6个碳原子和一个或多个卤基的“低聚卤代烷氧基”。这些基团的例子包括氟甲氧基、氯甲氧基、三氟甲氧基、三氟乙氧基、氟乙氧基和氟丙氧基。术语“芳香基”单独或组合使用时表示含有一个、两个或三个环的碳环芳香系统,这些环可以悬挂方式连接在一起,或者可稠合在一起。术语“芳香基”包括芳香基团,例如苯基、萘基、四羟基萘基、1,2-二氢化茚和联二苯。芳香基部分在取代位置可以被一个或多个取代基取代,取代基独立地选自烷基、烷氧基烷基、烷基氨基烷基、羧基烷基、烷氧基羰基烷基、氨基羰基烷基、烷氧基、芳烷氧基、羟基、氨基、卤基、硝基、烷基氨基、酰基、氰基、羧基、氨基羰基、烷氧基羰基和芳烷氧羰基。术语“杂环基”包括饱和、部分不饱和和不饱和的含杂原子环状基团,其中杂原子可以选自氮、硫和氧。饱和杂环基基团的例子包括含1到4个氮原子的饱和的3~6节杂单环基团(例如:吡咯烷基、咪唑烷基、哌啶子基、哌嗪基等等);含1~2个氧原子和1~3个氮原子的饱和的3~6节杂单环基团(例如:吗啉基等等);含1~2个硫原子和1~3个氮原子的饱和的3~6节杂单环基团(例如:噻唑烷基等等)。部分不饱和杂环基团的例子包括二氢噻吩、二氢吡喃、二氢呋喃和二氢噻唑。术语“杂芳香基”包含不饱和杂环基团。不饱和杂环基团也称为“杂芳香基”,其例子包括含1~4个氮原子的不饱和的3~6节杂单环基团,例如,吡咯基、吡咯烷基、咪唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、三唑基(例如,4H-1,2,4-三唑基、1H-1,2,3-三唑基、2H-1,2,3-三唑基等等)、四唑基(例如,1H-四唑基、2H-四唑基等等)等等;含1~5个氮原子的不饱和稠合杂环基团,例如,吲哚基、异吲哚基、中氮茚基、苯咪唑基、喹啉基、异喹啉基、吲唑基、苯三唑基、四唑哒嗪基(例如,四唑[1,5-b]哒嗪基等)等等;含一个氧原子的不饱和3~6节杂单环基团,例如,吡喃基、呋喃基等等;含一个硫原子的不饱和的3~6节杂单环基团,例如,噻吩基等等;含1~2个氧原子和1~3个氮原子的不饱和的3~6节杂单环基团,例如,恶唑基、异恶唑基、恶二唑基(例如,1,2,4-恶二唑基、1,3,4-恶二唑基、1,2,5-恶二唑基等)等等;含1~2个氧原子和1~3个氮原子的不饱和稠合杂环基团(例如,苯恶唑基、苯恶二唑基等等);含1~2个硫原子和1~3个氮原子的不饱和3~6节杂单环基团,例如,噻唑基、噻二唑基(例如,1,2,4-噻二唑基、1,3,4-噻二唑基、1,2,5-噻二唑基等)等等;含1~2个硫原子和1~3个氮原子的不饱和稠合杂环基团(例如,苯噻唑基、苯噻二唑基等等)和类似物。该术语还包含杂环基团与芳香基团稠合而成的基团。这些稠合的双环基团的例子包括苯呋喃、苯噻吩和类似物。所述的“杂环基团”可以有1到3个取代基,例如烷基、羟基、卤基、烷氧基、氧基、氨基和烷基氨基。术语“烷硫基”包含含有与一个二价硫原子相连的1~10个碳原子的直链或支链烷基的基团。更好的烷硫基是具有1~6个碳原子的烷基基团“低聚烷硫基”基团。这些低聚烷硫基基团的例子是甲硫基、乙硫基、丙硫基、丁硫基和己硫基。术语“烷硫基烷基”包括含有通过二价硫原子与1~10个碳原子的烷基相连的烷硫基的基团。更好的烷硫基烷基基团是具有1~6个碳原子的烷基的“低聚烷硫基烷基”基团。这些低聚烷硫基烷基基团的例子包括甲硫基甲基。术语“烷基亚磺酰基”包含含有连接在一个二价-S(=O)基团上的1~10个碳原子的直链或支链烷基的基团。更好的烷基亚磺酰基基团是具有1~6个碳原子的烷基的“低聚烷基亚磺酰基”基团。这些低聚烷基亚磺酰基的例子包括甲基亚磺酰基、乙基亚磺酰基、丁基亚磺酰基及己基亚磺酰基。不论是单独使用或与其它术语联合使用,例如烷基碘酰基,术语“磺酰基”分别表示二价基团-SO2-。“烷基磺酰基”包括连接在磺酰基基团上的烷基基团,其中烷基如上所述。更好的烷基磺酰基基团是具有1~6个碳原子的“低聚烷基磺酰基”。这些低聚烷基磺酰基基团的例子包括甲基磺酰基、乙基磺酰基及丙基磺酰基。“烷基磺酰基”还可进一步由一个或多个卤原子,例如氟、氯或溴取代,以提供卤代烷基磺酰基基团。术语“氨磺酰基(sulfamyl)”、“氨基磺酰基”及“氨磺酰基(sulfonamidyl)”表示NH2O2S-。术语“酰基”表示有机酸除去羟基之后形成的基团。这种酰基基团的例子包括烷酰基及芳酰基基团。这种低聚烷酰基的例子包括甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、新戊酰基、己酰基、三氟乙酰基。术语“羰基”无论是单独或与其它词合用,如“烷氧基羰基”,均指-(C=O)-。术语“芳酰基”包括带有上述羰基基团的芳香基基团。芳酰基的例子包括苯酰基,萘酰基及类似物,所述芳酰基中的芳香基可被另外取代。术语“羧基(carboxy)”或“羧基(carboxyl)”无论单独或与其它词合用,如羧基烷基,均指-CO2H。术语“羧基烷基”包含以羧基基团取代的烷基基团。更好的是包含上述低聚烷基的“低聚羧基烷基”,并且可在烷基基团上被卤基进一步取代。这些低聚羧基烷基基团的例子包括羧基甲基,羧基乙基和羧基丙基。术语“烷氧基羰基”指包含有通过氧原子和羰基基团相连的上述烷氧基的基团。更好的烷氧基羰基基团是其烷基部分具有1~6个碳原子的“低聚烷氧基羰基”基团。这些低聚烷氧基羰基(酯)基团的例子包括取代或未被取代的甲氧基羰基、乙氧基羰基、丙氧基羰基、丁氧基羰基和己氧基羰基。术语“烷基羰基”、“芳香基羰基”和“芳烷基羰基”包括具有连接到羰基基团上的上述烷基、芳香基和芳烷基的基团,这些基团的例子包括取代或未取代的甲基羰基,乙基羰基,苯基羰基和苄基羰基。术语“芳烷基”包含芳香基取代的烷基基团,如苄基、二苯甲基、三苯甲基、苯乙基和二苯乙基。所述芳烷基中的芳香基可进一步被卤基、烷基、烷氧基、卤氧烷基和卤烷氧基取代。苄基和苯甲基术语可以互换。术语“杂环烷基”包含饱和及部分不饱和的杂环取代烷基,例如吡咯烷基甲基,和杂芳香基取代的烷基基团,如吡啶甲基、喹啉甲基、噻吩甲基、呋喃甲基、和喹啉乙基。所述杂芳烷基中的杂芳香基可另外被卤基、烷基、烷氧基、卤氧烷基和卤烷氧基取代。术语“芳烷氧基”包含通过氧原子与其它基团相连的芳烷基。术语“芳烷氧烷基”包含通过氧原子与烷基相连的芳烷氧基。术语“芳烷硫基”包含连有一个硫原子的芳烷基。术语“芳烷硫基烷基”包含通过一个硫原子与一个烷基相连的芳烷硫基。术语“氨基烷基”包含以一个或多个氨基取代的烷基基团。更好的是“低聚氨基烷基”基团。这些基团的例子包括氨基甲基、氨基乙基和类似物。术语“烷基氨基”指被一个或两个烷基基团取代的氨基基团。较好的是烷基部分有1~6个碳原子的“低聚N-烷基氨基”基团。合适的低聚烷基氨基可以是单或双烷基氨基,例如N-甲基氨基、N-乙基氨基、N,N-二甲基氨基,N,N-二乙基氨基或类似物。“芳氨基”指被一个或两个芳香基取代的氨基基团,如N-苯基氨基。“芳香基氨基”基团可在基团的芳香环部分上被进一步取代。术语“芳烷基氨基”包含通过一个氨基氮原子与其它基团相连的芳烷基基团。术语“N-芳香基氨基烷基”和“N-芳香基-N-烷基-氨基烷基”指分别被一个芳香基,或一个芳香基和一个烷基取代,并且具有与烷基基团相连的氨基的氨基基团。这些基团的例子包括N-苯基氨基甲基和N-苯基-N-甲基氨基甲基。术语“氨基羰基”指分子式为-C(=O)NH2的酰胺基。术语“烷基氨基羰基”指在氨基氮原子上被一个或两个烷基取代的氨基羰基基团。较好的是“N-烷基氨基羰基”,“N,N-二烷基氨基羰基”基团。更好的是具有如上所述的低聚烷基部分的“低聚N-烷基氨基羰基”,“低聚N,N-二烷基氨基羰基”。术语“烷基氨基烷基”包含具有与氨基烷基相连的一个或多个烷基的基团。术语“芳烷氧基”包括具有通过二价氧原子与一个烷基相连的芳香基的基团。“芳硫基烷基”包括具有通过二价硫原子与一个烷基相连的芳香基的基团。
本发明的方法中所用的化合物可以其游离碱或药用酸加合盐的方式存在。术语“药用盐”包含通常用于形成碱金属盐和形成游离酸或游离碱的加合盐的盐。盐若是药用的,其性质并不重要。分子式I的化合物的合适的药用酸加合盐可以由无机酸或有机酸制备。无机酸的例子有盐酸、溴化氢、碘化氢、硝酸、碳酸、硫酸和磷酸。合适的有机酸可以选自脂族酸、环脂族酸、芳香酸、芳脂族酸、杂环酸、羧酸和带磺基的有机酸,例子有甲酸、乙酸、丙酸、琥珀酸、乙二酸、葡糖酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、葡糖醛酸、马来酸、富马酸、丙酮酸、天冬酸、谷氨酸、苯甲酸、邻氨基苯甲酸、甲酰酸、4-羟基苯甲酸、苯乙酸、扁桃酸、双羟萘酸(pamoic)、甲基磺酰酸、乙基磺酰酸、苯基磺酰酸、泛酸、2-羟基乙基磺酰酸、甲苯磺酰酸、磺胺酸、环己胺磺酰酸、硬脂酸、algenic,β-羟基丁酸、水杨酸、半乳糖酸和半乳糖醛酸。分子式I的化合物的合适的药用碱加合盐包括由铝、钙、锂、镁、钾、钠及锌制成的金属盐,或由N,N-二苯基乙二胺,氯代普鲁卡因碱,胆碱,二羟基乙二胺,麦格鲁明碱(N-甲基葡糖胺)和普鲁卡因碱制成的有机盐。所有这些盐都可以由分子式I的相应化合物通过常规方式制得,例如,通过使合适的酸或碱与分子式I的化合物反应制得。
生物学评估
几种动物模型可以用来评估对心血管疾病的预防作用,包括对动脉粥样硬化的预防。见Stehbens,Prog.Card.Dis.,XXIX,1007-28(1986)和Zhang et al.,Science,258,468-71(1992)。
一种用于动脉粥样硬化的APOe小鼠模型已经被Roselear等人描述(Arterioscle.Thromb.Vasc.Biol.,16,1013-18(1996))。环氧化酶-2的抑制剂在剂量为20毫克/千克时对预防动脉粥样硬化损伤应有活性。
本发明包括预防心血管疾病的药用成分,包含治疗上有效剂量的分子式I的化合物,同时有至少一种药用载体,辅助剂或稀释剂(在此合称为“载体”材料),如果需要,还包括其它活性成分。本发明中的活性化合物可以由本领域的技术人员众所周知的适当路线,最好以适于该路线的药用成份的形式,并以对计划的治疗有效的剂量给药。活性化合物和成分可以通过,例如,口服、静脉注射、腹腔、鼻腔、支气管、皮下、肌肉或局部给药的方式(包括喷雾器)给药。
这里所用的方法和成分可以单独使用或与本领域技术人员熟知的辅助疗法一起使用预防心血管疾病。这里描述的方法和成分可以用作辅助治疗。举例而言,环氧化酶-2的抑制剂可以单独或与其它药剂、药品或营养品联合使用。
具有大量已经商业化、临床评估和处于临床前研发阶段的治疗心血管疾病的药剂,这些药剂可供选择与环氧化酶-2选择性抑制剂一起使用,通过联合药物疗法预防心血管疾病。这些药剂可以是选自(但不限于)几大类药剂中的一或多种药剂,所述几大类药剂为,低脂药,包括IBAT抑制剂、祛脂乙酯、烟酸、statin、CETP抑制剂、胆汁酸多价螯合剂,抗氧化剂,包括维生素E和丙丁酚,IIbIIIa拮抗剂(包括xemilofiban和orbofiban),醛固酮抑制剂(包括螺甾内酯和epoxymexrenone),AII拮抗剂(包括losartan),β-阻滞剂,阿斯匹林、强效利尿药和ace抑制剂。
定义利用环氧化酶-2抑制剂和一种或多种其它药剂的“联合治疗”术语(或“辅助治疗”)意图包括以使联合用药产生有利效果的方式,将每种药剂按一定的顺序给药,及包括大体上同时将这些药剂给药,如将这些活性药剂按固定比例以单一配方给药,或将每种药剂以各自独立的配方一起给药。
对于口服给药,药用成分可以是,例如,片剂、胶囊、悬浮液或液体的形式。药用成份最好以含有特定量的活性成分的剂量单位的形式制成。这些剂量单位的例子包括胶囊、片剂、粉末、丸剂或悬浮液,带有传统的添加剂例如乳糖、甘露醇、玉米淀粉或土豆淀粉;带有粘合剂例如结晶纤维素、纤维素衍生物、阿拉伯胶、玉米淀粉或明胶;带有分解剂例如玉米淀粉、土豆淀粉或钠羧甲基纤维素;及带有润滑剂例如滑石粉或硬脂酸镁。活性成分也可以化合物的方式通过注射给药,其中例如,生理盐水、葡萄糖或水用作合适的载体。
对于静脉、肌肉、皮下、或腹腔给药,化合物可与无菌溶液混合,无菌溶液最好与受体的血液等渗压。这种配方可通过将固体活性成份溶于水中而制得,该水含有生理相容物质,例如氯化纳、甘氨酸和类似物,具有和生理条件相适的缓冲pH值以产生水溶液,并使所述溶液无菌。该配方可存在于单一或多剂量容器中,例如密封的安瓿瓶或小瓶。
适合非肠胃给药的配方包括活性化合物的无菌溶液制剂,它最好等渗制成。注射制剂也可通过把化合物悬浮或乳化在非水溶剂,例如植物油、合成硬脂酸甘油、高硬脂酸酯或丙二醇,乙二醇中配制而成。
局部使用的配方包括已知的凝胶、乳霜、油、和类似物。对于通过气雾输送,化合物可以由已知的气雾exipient,例如生理盐水配制而成,并利用可商业获得的喷雾器给药。以脂肪酸方式的配方可用于提高生物相容性。对于需输送到肺的预防应用,气雾输送是优选的方法。
对于直肠给药,可利用碱把活性成分配制成栓剂,碱在室温是固体,而在体温下融化或溶解。常用的碱包括古柯油、甘油制的胶、氢化植物油、不同分子量的聚乙二醇、和聚乙烯硬脂酸盐的脂肪酸酯。
可以参考已知的治疗或预防制度确定剂量形式和数量。给药的治疗上有效的化合物的数量及利用本发明的化合物和/或合成物治疗疾病的制剂制度取决于多种因素,包括年龄、体重、性别和受治疗者的身体条件,疾病的严重程度,实施的路线和频率,采用的特定化合物,部位,及接受治疗的个体的药物动力学特性,所有可以产生很大的变化。如果局部给药,而不是全身给药,预防给药,而不是治疗给药,则所用化合物的剂量可以较低。既可以根据必要施以经常性的治疗也可以根据主治医生的判断施以阶段性治疗。本领域的技术人员将领会要用药的抑制物的剂量制度或者治疗上有效的数量需要根据不同的个体情况被优化。药用合成物中可包含约0.1~2000毫克的活性成分,较好的是约0.5~500毫克的活性成分,最好是1~200毫克的活性成分。每天的剂量为约0.01~100毫克/千克体重,较好的是约0.5~50毫克/千克体重,最好的是约0.1~20毫克/千克体重较合适。每日的剂量可以每天一到四剂的形式给药。
所有这里引用的专利文献均作为参考文献包含于此。
虽然已经通过特殊实施例描述了本发明,但本发明并不限于这些实施例的细节。
Claims (12)
1.一种需要预防心血管疾病的受治疗者中与发炎相关的心血管疾病的预防方法,该方法包括用治疗上有效数量的环氧化酶-2的抑制物或其衍生物或其药用盐治疗受治疗者。
2.按照权利要求1所述的方法,其中心血管疾病选自冠状动脉疾病的预防、动脉瘤、动脉硬化、粥样动脉硬化,包括心脏移植粥样动脉硬化、心肌梗塞、栓塞、中风、血栓,包括静脉血栓、心绞痛,包括不稳定心绞痛、冠状血小板发炎、细菌引起的发炎,包括衣原体引起的发炎、病毒引起的发炎、和与外科手术相关的发炎,所述外科手术是例如血管移植,包括冠状动脉搭桥手术、换血管术,包括血管成形术、斯滕特固定模定位、动脉硬膜切除术、或其它对动脉、静脉和毛细血管的侵害性过程。
3.按照权利要求2所述的方法,其中心血管疾病是粥样动脉硬化。
4.按照权利要求2所述的方法,其中心血管疾病是血栓。
5.一种在受治疗者中预防与发炎相关的心血管疾病的方法,所述方法包括利用治疗上有效数量的化合物治疗该受治疗者,该化合物选自美洛昔康(Boehringer Ingelheim),尼美舒利(Helsinn),MK-966(Merck & Co),L-783003(Merck & Co),T-614(Toyama),D-1367(Chiroscience),L-748731(Merck & Co),CT3(AtlanticPharmaceutical),CGP-28238(Novartis),BF-389(Biofor/Scherer),6R-253035(Glaxo Wellcome),(E)-4-(1,3-二(环己基甲基)-1,2,3,6-四氢-2,6-二氧代-9H-嘌呤-8-基)肉桂酸(Glaxo Wellcome),L-745337(Merck & Co),及分子式I的化合物或者是它们的药用盐:
其中A是选自部分不饱和或不饱和杂环及部分不饱和或不饱和碳环的取代基;
其中R1是至少一个选自杂环基、环烷基、环烯基和芳香基的取代基,其中R1在可取代位置上被一个或多个选自烷基、卤代烷基、氰基、羧基、烷氧羰基、羟基、羟烷基、卤代烷氧基、氨基、烷基氨基、芳香氨基、硝基、烷氧基烷基、烷基亚磺酰基、卤基、烷氧基和烷硫基的基团随意取代;
其中R2是甲基或氨基;
其中R3是选自氢基、卤基、烷基、链烯基、炔基、氧代基、氰基、羧基、氰烷基、杂环氧基、烷基氧、烷硫基、烷基羰基、环烷基、芳香基、卤代烷基、杂环基、环烯基、芳烷基、杂环烷基、酰基、烷基硫代烷基、羟基烷基、烷氧羰基、芳羰基、芳烷基羰基、芳烯基、烷氧烷基、芳基硫代烷基、芳氧烷基、芳烷基硫代烷基、芳烷氧烷基、烷氧芳烷氧烷基、烷氧羰基烷基、氨基羰基、氨基羰基烷基、烷基氨基羰基、N-芳氨基羰基、N-烷基-N-芳氨基羰基、烷基氨基羰基烷基、羧基烷基、烷基氨基、N-芳氨基、N-芳烷基氨基、N-烷基-N-芳烷基氨基、N-烷基-N-芳氨基、氨基烷基、烷基氨基烷基、N-芳基氨基烷基、N-芳烷基氨基烷基、N-烷基-N-芳烷基氨基烷基、N-烷基-N-芳氨基烷基、芳氧基、芳烷氧基、芳硫基、芳烷硫基、烷基亚磺酰基、烷基磺酰基、氨基磺酰基、烷基氨基磺酰基、N-芳基氨基磺酰基、芳基磺酰基、N-烷基-N-芳基氨基磺酰基的基团。
6.按照权利要求5所述的方法,其中A选自5-或6-节的部分不饱和杂环,5-或6-节不饱和杂环,9-或10-节不饱和稠合杂环,低聚环链烯基和苯基;其中R1选自5-和6-节杂环,低聚环烷基,低聚环链烯基和选自苯基、联苯基和萘基的芳香基,其中R1在取代位置上被选自低聚烷基、低聚卤代烷基、氰基、羧基、低聚烷氧羰基、羟基、低聚羟烷基、低聚卤代烷氧基、氨基、低聚烷基氨基、苯氨基、低聚烷氧基烷基、低聚烷基亚磺酰基、卤基、低聚烷氧基和低聚烷硫基的一个或多个基团任意取代;其中R2是甲基或氨基;其中R3是选自氢基、氧基、氰基、羧基、低聚烷氧羰基、低聚羧基烷基、低聚氰基烷基、卤基、低聚烷基、低聚烷氧基、低聚环烷基、苯基、低聚卤代烷基、5-或6-节杂环基、低聚羟基烷基、低聚芳烷基、酰基、苯基羰基、低聚烷氧烷基、5-或6-节杂芳氧基、氨基羰基、低聚烷基氨基羰基、低聚烷基氨基、低聚氨基烷基、低聚烷基氨基烷基、苯氧基和低聚芳烷氧基的基团;或者是它们的药用盐。
7.按照权利要求6所述的方法,其中A选自恶唑基、异恶唑基、呋喃基、噻吩基、二氢呋喃基、吡咯基、吡唑基、噻唑基、咪唑基、异噻唑基、苯并呋喃基、环戊烯基、环戊二烯基、苯基和吡啶基;其中R1选自在取代位置被一个或多个甲基基团任意取代的吡啶基,在取代位置被下述一个或多个基团任意取代的苯基:甲基、乙基、异丙基、丁基、叔丁基、异丁基、戊基、己基、氟甲基、二氟甲基、三氟甲基、氰基、羧基、甲氧羰基、乙氧羰基、羟基、羟基甲基、三氟甲氧基、氨基、N-甲氨基、N、N-二甲氨基、N-乙氨基、N、N-二丙氨基、N-丁氨基、N-甲基-N-乙氨基、苯氨基、甲氧甲基、甲基亚磺酰基、氟基、氯基、溴基、甲氧基、乙氧基、丙氧基、正丁氧基、戊氧基和甲硫基;其中R2是甲基或氨基;其中R3是选自氢基、氧基、氰基、羧基、甲氧羰基、乙氧羰基、羧基丙基、羧基甲基、羧基乙基、氰基甲基、氟基、氯基、溴基、甲基、乙基、异丙基、丁基、叔丁基、异丁基、戊基、己基、二氟甲基、三氟甲基、五氟乙基、六氟丙基、二氟乙基、二氟丙基、甲氧基、乙氧基、丙氧基、正丁氧基、戊氧基、环己基、苯基、吡啶基、噻吩基、噻唑基、恶唑基、呋喃基、吡嗪基、羟基甲基、羟基丙基、苯甲基、甲酰基、苯基羰基、甲氧基甲基、呋喃甲氧基、氨基羰基、N-甲基氨基羰基、N、N-二甲基氨基羰基、N、N-二甲基氨基、N-乙基氨基、N、N-二丙基氨基、N-丁基氨基、N-甲基-N-乙基氨基、氨基甲基、N、N-二甲基氨基甲基、N-甲基-N-乙基氨基甲基、苄氧基、和苯氧基的基团;或者是它们的药用盐。
8.按照权利要求5所述的方法,其中的化合物选自下列化合物及它们的药用盐:
美洛昔康(Boehringer Ingelheim),尼美舒利(Helsinn),MK-966(Merck & Co),L-783003(Merck & Co),T-614(Toyama),D-1367(Chiroscience),L-748731(Merck & Co),L-745337(Merck & Co);
8-乙酰基-3-(4-氟苯基)-2-(4-甲磺酰基)苯基-咪唑并(1,2-a)吡啶;
5,5二甲基-4-(4-甲磺酰基)苯基-3-苯基-2-(5H)-呋喃酮;
5-(4-氟苯基)-1-[4-(甲磺酰基)苯基]-3-(三氟甲基)吡唑;
4-(4-氟苯基)-5-[4-(甲磺酰基)苯基]-1-苯基-3-(三氟甲基)吡唑;
4-(5-(4-氯苯基)-3-(4-甲氧苯基)-1H-吡唑-1-基)苯磺酰胺;
4-(3,5-二(4-甲基苯基)-1H-吡唑-1-基)苯磺酰胺;
4-(5-(4-氯苯基)-3-苯基-1H-吡唑-1-基)苯磺酰胺;
4-(3,5-二(4-甲氧苯基)-1H-吡唑-1-基)苯磺酰胺;
4-(5-(4-氯苯基)-3-(4-甲基苯基)-1H-吡唑-1-基)苯磺酰胺;
4-(5-(4-氯苯基)-3-(4-硝基苯基)-1H-吡唑-1-基)苯磺酰胺;
4-(5-(4-氯苯基)-3-(5-氯-2-噻吩基)-1H-吡唑-1-基)苯磺酰胺;
4-(4-氯-3,5-二苯基-1H-吡唑-1-基)苯磺酰胺;
4-[5-(4-氯苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-苯基-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-(4-氟苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-(4-甲氧苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-(4-氯苯基)-3-(二氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-(4-甲基苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[4-氯-5-(4-氯苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[3-(二氟甲基)-5-(4-甲基苯基)-1H-吡唑-1-基]苯磺酰胺;
4-[3-(二氟甲基)-5-基苯-1H-吡唑-1-基]苯磺酰胺;
4-[3-(二氟甲基)-5-(4-甲氧苯基)-1H-吡唑-1-基]苯磺酰胺;
4-[3-氰基-5-(4-氟基苯基)-1H-吡唑-1-基]苯磺酰胺;
4-[3-(二氟甲基)-5-(3-氟-4-甲氧苯基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-(3-氟-4-甲氧苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[4-氯-5-苯基-1H-吡唑-1-基]苯磺酰胺;
4-[5-(4-氯苯基)-3-(羟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-(4-(N,N-二甲基氨基)苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
5-(4-氟苯基)-6-[4-(甲磺酰基)苯基]螺[2.4]庚-5-烯;
4-[6-(4-氟苯基)螺[2.4]庚-5-烯-5-基]苯磺酰胺;
6-(4-氟苯基)-7-[4-(甲磺酰基)苯基]螺[3.4]辛-6-烯;和分子式I的化合物组成,其中A选自恶唑基、异恶唑基、呋喃基、噻吩基、二氢呋喃基、吡咯基、吡唑基、噻唑基、咪唑基、异噻唑基、苯并呋喃基、环戊烯基、环戊二烯基、苯基和吡啶基;其中R1选自在取代位置被一个或多个甲基基团选择性取代的吡啶基,在取代位置被下述一个或多个自由基团选择性取代的苯基:甲基、乙基、异丙基、丁基、叔丁基、异丁基、戊基、己基、氟甲基、二氟甲基、三氟甲基、氰基、羧基、甲氧羰基、乙氧羰基、羟基、羟基甲基、三氟甲氧基、氨基、N-甲氨基、N、N-二甲氨基、N-乙氨基、N、N-二丙氨基、N-丁氨基、N-甲基-N-乙氨基、苯氨基、甲氧甲基、甲基亚磺酰基、氟基、氯基、溴基、甲氧基、乙氧基、丙氧基、n-丁氧基、戊氧基和甲硫基;其中R2是甲基或氨基;其中R3是选自氢基、氧基、氰基、羧基、甲氧羰基、乙氧羰基、羧基丙基、羧基甲基、羧基乙基、氰基甲基、氟基、氯基、溴基、甲基、乙基、异丙基、丁基、叔丁基、异丁基、戊基、己基、二氟甲基、三氟甲基、五氟乙基、六氟丙基、二氟乙基、二氟丙基、甲氧基、乙氧基、丙氧基、n-丁氧基、戊氧基、环己基、苯基、吡啶基、噻吩基、噻唑基、恶唑基、呋喃基、吡唑基、羟基甲基、羟基丙基、苯甲基、甲酰基、苯基羰基、甲氧基甲基、呋喃甲氧基、氨基羰基、N-甲基氨基羰基、N、N-二甲基氨基羰基、N、N-二甲基氨基、N-乙基氨基、N、N-二丙基氨基、N-丁基氨基、N-甲基-N-乙基氨基、氨基甲基、N、N-二甲基氨基甲基、N-甲基-N-乙基氨基甲基、苄氧基、和苯氧基的自由基;或者是它们的药用盐。
具有特别兴趣的一族特殊化合物由下列化合物及其药用盐组成:
meloxicam(Boehringer Ingelheim),nimesulide(Helsinn),MK-966(Merck & Co),L-783003(Merck & Co),T-614(Toyama),D-1367(Chiroscience),L-748731(Merck & Co),L-745337(Merck & Co);
8-乙酰基-3-(4-氟苯基)-2-(4-甲磺酰基)苯基-咪唑并(1,2-a)吡啶;
5,5二甲基-4-(4-甲磺酰基)苯基-3-苯基-2-(5H)-呋喃酮;
6-(4-氟苯基)-2-甲氧基-5-[4-(甲磺酰基)苯基]-吡啶-3-腈;
2-溴-6-(4-氟苯基)-5-[4-(甲磺酰基)苯基]-吡啶-3-腈;
6-(4-氟苯基)-5-[4-(甲磺酰基)苯基]-2-苯基-吡啶-3-腈;
4-[2-(4-甲基吡啶-2-基)-4-(三氟甲基)-1H-咪唑-1-基]苯磺酰胺;
4-[2-(5-甲基吡啶-3-基)-4-(三氟甲基)-1H-咪唑-1-基]苯磺酰胺;
4-[2-(2-甲基吡啶-3-基)-4-(三氟甲基)-1H-咪唑-1-基]苯磺酰胺;
3-[1-[4-(甲磺酰基)苯基]-4-(三氟甲基)-1H-咪唑-2-基]吡啶;
2-[1-[4-(甲磺酰基)苯基]-4-(三氟甲基)-1H-咪唑-2-基]吡啶;
2-甲基-4-[1-[4-(甲磺酰基)苯基]-4-(三氟甲基)-1H-咪唑-2-基]吡啶;
2-甲基-6-[1-[4-(甲磺酰基)苯基]-4-(三氟甲基)-1H-咪唑-2-基]吡啶;
4-[2-(6-甲基吡啶-3-基)-4-(三氟甲基)-1H-咪唑-1-基]苯磺酰胺;
2-(3,4-二氟苯基)-1-[4-(甲磺酰基)苯基]-4-(三氟甲基)-1H-咪唑;
4-[2-(4-甲基苯基)-4-(三氟甲基)-1H-咪唑-1-基]苯磺酰胺;
2-(4-氯苯基)-1-[4-(甲磺酰基)苯基]-4-甲基-1H-咪唑;
2-(4-氯苯基)-1-[4-(甲磺酰基)苯基]-4-苯基-1H-咪唑;
2-(4-氯苯基)-4-(4-氟苯基)-1-[4-(甲磺酰基)苯
4-[3-(二氟甲基)-5-苯基-1H-吡唑-1-基]苯磺酰胺;
4-[3-(二氟甲基)-5-(4-甲氧苯基)-1H-吡唑-1-基]苯磺酰胺;
4-[3-氰基-5-(4-氟基苯基)-1H-吡唑-1-基]苯磺酰胺;
4-[3-(二氟甲基)-5-(3-氟-4-甲氧苯基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-(3-氟-4-甲氧苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[4-氯-5-苯基-1H-吡唑-1-基]苯磺酰胺;
4-[5-(4-氯苯基)-3-(羟甲基)-1H-吡唑-1-基]苯磺酰胺;
4-[5-(4-(N,N-二甲基氨基)苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺;
5-(4-氟苯基)-6-[4-(甲磺酰基)苯基]螺[2.4]庚-5-烯;
4-[6-(4-氟苯基)螺[2.4]庚-5-烯-5-基]苯磺酰胺;
6-(4-氟苯基)-7-[4-(甲磺酰基)苯基]螺[3.4]辛-6-烯;
5-(3-氯-4-甲氧苯基)-6-[4-(甲磺酰基)苯基]螺[2.4]庚-5-烯;
4-[6-(3-氯-4-甲氧苯基)螺[2.4]庚-5-烯-5-基]苯磺酰胺;
5-(3,5-二氯-4-甲氧苯基)-6-[4-(甲磺酰基)苯基]螺[2.4]庚-5-烯;
5-(3-氯-4-氟苯基)-6-[4-(甲磺酰基)苯基]螺[2.4]庚-5-烯;
4-[6-(3,4-二氯苯基)螺[2.4]庚-5-烯-5-基]苯磺酰胺;
2-(3-氯-4-氟苯基)-4-(4-氟苯基)-5-(4-甲磺酰苯基)噻唑;
2-(2-氯苯基)-4-(4-氟苯基)-5-(4-甲磺酰苯基)噻唑;
5-(4-氟苯基)-4-(4-甲磺酰苯基)-2-甲基噻唑;
4-(4-氟苯基)-5-(4-甲磺酰苯基)-2-三氟甲基噻唑;
4-(4-氟苯基)-5-(4-甲磺酰苯基)-2-(2-噻吩基)噻唑;
4-(4-氟苯基)-5-(4-甲磺酰苯基)-2-苄氨基噻唑;
4-(4-氟苯基)-5-(4-甲磺酰苯基)-2-(1-丙氨基)噻唑;
2-[(3,5-二氯苯氧基)甲基]-4-(4-氟苯基)-5-[4-(甲磺酰基)苯基]噻唑;
5-(4-氟苯基)-4-(4-甲磺酰苯基)-2-三氟甲基噻唑;
1-甲磺酰基-4-[1,1-二甲基-4-(4-氟苯基)环戊-2,4-二烯-3-基]苯;
4-[4-(4-氟苯基)-1,1-二甲基环戊-2,4-二烯-3-基]苯磺酰胺;
5-(4-氟苯基)-6-[4-(甲磺酰基)苯基]螺[2.4]庚-4,6-二烯;
4-[6-(4-氟苯基)螺[2.4]庚-4,6-二烯-5-基]苯磺酰胺;
6-(4-氟苯基)-2-甲氧基-5-[4-(甲磺酰基)苯基]-吡啶-3-腈;
2-溴-6-(4-氟苯基)-5-[4-(甲磺酰基)苯基]-吡啶-3-腈;
6-(4-氟苯基)-5-[4-(甲磺酰基)苯基]-2-苯基-吡啶-3-腈;
4-[2-(4-甲基吡啶-2-基)-4-(三氟甲基)-1H-咪唑-1-基]苯磺酰胺;
4-[2-(5-甲基吡啶-3-基)-4-(三氟甲基)-1H-咪唑-1-基]苯磺酰胺;
4-[2-(2-甲基吡啶-3-基)-4-(三氟甲基)-1H-咪唑-1-基]苯磺酰胺;
3-[1-[4-(甲磺酰基)苯基]-4-(三氟甲基)-1H-咪唑-2-基]吡啶;
2-[1-[4-(甲磺酰基)苯基]-4-(三氟甲基)-1H-咪唑-2-基]吡啶;
2-甲基-4-[1-[4-(甲磺酰基)苯基]-4-(三氟甲基)-1H-咪唑-2-基]吡啶;
2-甲基-6-[1-[4-(甲磺酰基)苯基]-4-(三氟甲基)-1H-咪唑-2-基]吡啶;
4-[2-(6-甲基吡啶-3-基)-4-(三氟甲基)-1H-咪唑-1-基]苯磺酰胺;
2-(3,4-二氟苯基)-1-[4-(甲磺酰基)苯基]-4-(三氟甲基)-1H-咪唑;
4-[2-(4-甲基苯基)-4-(三氟甲基)-1H-咪唑-1-基]苯磺酰胺;
2-(4-氯苯基)-1-[4-(甲磺酰基)苯基]-4-甲基-1H-咪唑;
2-(4-氯苯基)-1-[4-(甲磺酰基)苯基]-4-苯基-1H-咪唑;
2-(4-氯苯基)-4-(4-氟苯基)-1-[4-(甲磺酰基)苯基]-1H-咪唑;
2-(3-氟-4-甲氧苯基)-1-[4-(甲磺酰基)苯基]-4-(三氟甲基)-1H-咪唑;
1-[4-(甲磺酰基)苯基]-2-苯基-4-(三氟甲基)-1H-咪唑;
2-(4-甲基苯基)-1-[4-(甲磺酰基)苯基]-4-三氟甲基-1H-咪唑;
4-[2-(3-氯-4-甲基苯基)-4-(三氟甲基)-1H-咪唑-1-基]苯磺酰胺;
2-(3-氟-5-甲基苯基)-1-[4-(甲磺酰基)苯基]-4-(三氟甲基)-1H-咪唑;
4-[2-(3-氟-5-甲基苯基)-4-(三氟甲基)-1H-咪唑-1-基]苯磺酰胺;酰胺。
9.按照权利要求5所述的方法,其中心血管疾病选自冠状动脉疾病的预防、动脉瘤、动脉硬化、粥样动脉硬化,包括心脏移植粥样动脉硬化、心肌梗塞、栓塞、中风、血栓,包括静脉血栓、心绞痛,包括不稳定心绞痛、冠状血小板发炎、细菌引起的发炎,包括衣原体引起的发炎、病毒引起的发炎、和与外科手术相关的发炎,所述外科手术是例如血管移植,包括冠状动脉搭桥手术、换血管术,包括血管成形术、斯滕特固定模定位、动脉硬膜切除术、或其它对动脉、静脉和毛细血管的侵害性过程。
其中R4选自氢基、烷基、卤代烷基、烷氧羰基、氰基、氰基烷基、羧基、氨基羰基、烷基氨基羰基、环烷基氨基羰基、芳氨基羰基、羧基烷基氨基羰基、羧基烷基、芳烷氧基羰基烷基氨基羰基、氨基羰基烷基、烷氧基羰基氰基链烯基、和羟基烷基;
其中R5选自氢基、烷基、氰基、羟基烷基、环烷基、烷基磺酰基和卤基;
其中R6选自芳烯基、芳香基、环烷基、环烯基和杂环;其中R4在取代位置被下述一个或多个基团任意取代:卤基、烷硫基、烷基磺酰基、氰基、硝基、卤代烷基、烷基、羟基、链烯基、羟基烷基、羧基、环烷基、烷基氨基、二烷基氨基、烷氧羰基、氨基羰基、烷氧基、卤代烷氧基、氨磺酰基、杂环和氨基。
11.按照权利要求10所述的方法,其中R4选自氢基、低聚烷基、低聚卤代烷基、低聚烷氧基羰基、氰基、低聚氰基烷基、羧基、氨基羰基、低聚烷基氨基羰基、低聚环烷基氨基羰基、芳氨基羰基、低聚羧基烷基氨基羰基、低聚氨基羰基烷基、低聚芳烷氧基羰基烷基氨基羰基、低聚羧基烷基、低聚烷氧基羰基氰基链烯基和低聚羟基烷基;其中R5选自氢基、低聚烷基、氰基、低聚羟基烷基、低聚环烷基、低聚烷基磺酰基和卤基;其中R6选自芳烯基、芳香基、环烷基、环烯基和杂环;其中R4在取代位置被下述一个或多个基团任意取代,卤基、低聚烷硫基、低聚烷基磺酰基、氰基、硝基、低聚卤代烷基、低聚烷基、羟基、低聚链烯基、低聚羟基烷基、羧基、低聚环烷基、低聚烷基氨基、低聚二烷基氨基、低聚烷氧羰基、氨基羰基、低聚烷氧基、低聚卤代烷氧基、氨磺酰基、五或六节的杂环和氨基;或其药用盐或衍生物。
12.按照权利要求10所述的方法,其中与发炎相关的心血管疾病选自冠状动脉疾病的预防、动脉瘤、动脉硬化、粥样动脉硬化,包括心脏移植粥样动脉硬化、心肌梗塞、栓塞、中风、血栓,包括静脉血栓、心绞痛,包括不稳定心绞痛、冠状血小板发炎、细菌引起的发炎,包括衣原体引起的发炎、病毒引起的发炎、和与外科手术相关的发炎,所述外科手术是例如血管移植,包括冠状动脉搭桥手术、换血管术,包括血管成形术、斯滕特固定模定位、动脉硬膜切除术、或其它对动脉、静脉和毛细血管的侵害性过程。
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Families Citing this family (38)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6514949B1 (en) | 1994-07-11 | 2003-02-04 | University Of Virginia Patent Foundation | Method compositions for treating the inflammatory response |
US6448235B1 (en) | 1994-07-11 | 2002-09-10 | University Of Virginia Patent Foundation | Method for treating restenosis with A2A adenosine receptor agonists |
US6710033B1 (en) | 1996-08-14 | 2004-03-23 | Vanderbilt University | Methods and treatment of multiple sclerosis |
US7030152B1 (en) | 1997-04-02 | 2006-04-18 | The Brigham And Women's Hospital, Inc. | Systematic inflammatory markers as diagnostic tools in the prevention of atherosclerotic diseases and as tools to aid in the selection of agents to be used for the prevention and treatment of atherosclerotic disease |
US6890526B2 (en) | 1997-05-06 | 2005-05-10 | Vanderbilt University | Methods and reagents for the treatment of multiple sclerosis |
US6117878A (en) * | 1998-02-24 | 2000-09-12 | University Of Virginia | 8-phenyl- or 8-cycloalkyl xanthine antagonists of A2B human adenosine receptors |
US7427606B2 (en) | 1999-02-01 | 2008-09-23 | University Of Virginia Patent Foundation | Method to reduce inflammatory response in transplanted tissue |
US7378400B2 (en) | 1999-02-01 | 2008-05-27 | University Of Virginia Patent Foundation | Method to reduce an inflammatory response from arthritis |
US6232297B1 (en) | 1999-02-01 | 2001-05-15 | University Of Virginia Patent Foundation | Methods and compositions for treating inflammatory response |
US6322771B1 (en) | 1999-06-18 | 2001-11-27 | University Of Virginia Patent Foundation | Induction of pharmacological stress with adenosine receptor agonists |
EP1520590A1 (en) * | 1999-08-31 | 2005-04-06 | The Brigham and Women's Hospital, Inc. | Systemic inflammatory markers as diagnostic tools in the prevention of atherosclerotic diseases |
JP2003508453A (ja) * | 1999-08-31 | 2003-03-04 | ザ・ブリガーム・アンド・ウーメンズ・ホスピタル・インコーポレーテッド | アテローム性動脈硬化疾患の予防における診断的ツールとしての全身性炎症マーカー |
EP1767223A1 (en) * | 1999-08-31 | 2007-03-28 | The Brigham And Women's Hospital, Inc. | Systemic inflammatory markers as diagnostic tools in the prevention of atherosclerotic diseases |
OA12983A (en) * | 2001-07-19 | 2006-10-13 | Pharmacia Corp | Combination of an aldosterone receptor antagonist and an HMG COA reductase inhibitor. |
EP1434782A2 (en) | 2001-10-01 | 2004-07-07 | University of Virginia Patent Foundation | 2-propynyl adenosine analogs having a2a agonist activity and compositions thereof |
MY151199A (en) | 2001-11-02 | 2014-04-30 | Rigel Pharmaceuticals Inc | Substituted diphenyl heterocycles useful for treating hcv infection |
KR100686537B1 (ko) * | 2001-12-28 | 2007-02-27 | 씨제이 주식회사 | 사이클로옥시게나제-2 의 저해제로서 선택성이 뛰어난디아릴 1,2,4-트리아졸 유도체 |
EP1480689A1 (en) * | 2002-02-28 | 2004-12-01 | Eli Lilly And Company | Method of treating atherosclerosis and hypercholesterolemia |
BR0313755A (pt) | 2002-08-23 | 2005-06-21 | Rigel Pharmaceuticals Inc | Composto, métodos para inibir a replicação ou proliferação de um vìrion da hepatite c e para tratar ou prevenir uma infecção por hcv, e, composição |
EP1400243A1 (en) * | 2002-09-19 | 2004-03-24 | Tanabe Seiyaku Co., Ltd. | Calcium-activated K channel activator |
JP2004189711A (ja) * | 2002-12-11 | 2004-07-08 | Raul Altman | 急性冠動脈症候群および関連病態の治療のための抗血小板薬と組合せたメロキシカムの使用 |
WO2004069158A2 (en) | 2003-01-27 | 2004-08-19 | Merck & Co., Inc. | Substituted pyrazoles, compositions containing such compounds and methods of use |
US7115642B2 (en) | 2003-05-02 | 2006-10-03 | Rigel Pharmaceuticals, Inc. | Substituted diphenyl isoxazoles, pyrazoles and oxadiazoles useful for treating HCV infection |
US7326790B2 (en) | 2003-05-02 | 2008-02-05 | Rigel Pharmaceuticals, Inc. | Diphenylisoxazole compounds and hydro isomers thereof |
JP4354984B2 (ja) | 2003-05-07 | 2009-10-28 | オステオロジックス エイ/エス | 水溶性ストロンチウム塩を用いる軟骨/骨症状の治療 |
US7220745B2 (en) | 2003-05-15 | 2007-05-22 | Rigel Pharmaceuticals | Heterocyclic compounds useful to treat HCV |
WO2005049065A2 (en) | 2003-11-19 | 2005-06-02 | Rigel Pharmaceuticals, Inc. | Synergistic combinations of dihaloacetamide with interferon or ribavirin for treatment hcv infections |
US7514434B2 (en) | 2004-02-23 | 2009-04-07 | Rigel Pharmaceuticals, Inc. | Heterocyclic compounds having an oxadiazole moiety and hydro isomers thereof |
MY143599A (en) | 2004-06-04 | 2011-06-15 | Merck Sharp & Dohme | Pyrazole derivatives, compositions containing such compounds and methods of use |
WO2006015357A2 (en) | 2004-08-02 | 2006-02-09 | University Of Virginia Patent Foundation | 2-propynyl adenosine analogs with modified 5'-ribose groups having a2a agonist activity |
US7442687B2 (en) | 2004-08-02 | 2008-10-28 | The University Of Virginia Patent Foundation | 2-polycyclic propynyl adenosine analogs having A2A agonist activity |
WO2006028618A1 (en) | 2004-08-02 | 2006-03-16 | University Of Virginia Patent Foundation | 2-polycyclic propynyl adenosine analogs with modified 5'-ribose groups having a2a agonist activity |
EP1883633A2 (en) | 2005-05-02 | 2008-02-06 | Rigel Pharmaceuticals, Inc. | Heterocyclic anti-viral compounds comprising metabolizable moieties and their uses |
US20070037797A1 (en) * | 2005-08-15 | 2007-02-15 | Hellstrom Harold R | Method of reducing the risk of adverse cardiovascular (CV) events associated with the administration of pharmaceutical agents which favor CV events |
US8404275B2 (en) | 2007-07-01 | 2013-03-26 | Vitalis Llc | Combination tablet with chewable outer layer |
AU2010232729A1 (en) | 2009-03-31 | 2011-10-20 | Arqule, Inc. | Substituted indolo-pyridinone compounds |
CN104105478A (zh) | 2011-10-28 | 2014-10-15 | 维塔利斯公司 | 抗发红组合物 |
CN115671097B (zh) * | 2022-08-23 | 2024-02-13 | 上海交通大学医学院附属第九人民医院 | 用于防治动脉粥样硬化及斑块不稳定性的化合物及其应用 |
Family Cites Families (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3103372A1 (de) * | 1981-01-27 | 1982-09-02 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | Neue indanyl-derivate, ihre herstellung und verwendung |
JP2893903B2 (ja) * | 1990-09-12 | 1999-05-24 | 藤沢薬品工業株式会社 | 虚血―再灌流障害予防、治療剤 |
JP3086312B2 (ja) * | 1991-10-28 | 2000-09-11 | 富山化学工業株式会社 | インターロイキン6の産生抑制剤並びにその産生抑制作用が有効な疾患の治療・予防剤 |
US5380738A (en) * | 1993-05-21 | 1995-01-10 | Monsanto Company | 2-substituted oxazoles further substituted by 4-fluorophenyl and 4-methylsulfonylphenyl as antiinflammatory agents |
US5344991A (en) * | 1993-10-29 | 1994-09-06 | G.D. Searle & Co. | 1,2 diarylcyclopentenyl compounds for the treatment of inflammation |
US5434178A (en) * | 1993-11-30 | 1995-07-18 | G.D. Searle & Co. | 1,3,5 trisubstituted pyrazole compounds for treatment of inflammation |
RU2139281C1 (ru) * | 1993-11-30 | 1999-10-10 | Джи Ди Сирл энд Компани | Пиразолилзамещенный бензолсульфонамид или его фармацевтически приемлемая соль, фармацевтическая композиция, способ лечения от воспаления или связанного с воспалением заболевания |
US5393790A (en) * | 1994-02-10 | 1995-02-28 | G.D. Searle & Co. | Substituted spiro compounds for the treatment of inflammation |
EP1125932A3 (en) * | 1994-07-27 | 2001-08-29 | G.D. Searle & Co. | Substituted thiazoles for the treatment of inflammation |
US5620999A (en) * | 1994-07-28 | 1997-04-15 | Weier; Richard M. | Benzenesulfonamide subtituted imidazolyl compounds for the treatment of inflammation |
US5616601A (en) * | 1994-07-28 | 1997-04-01 | Gd Searle & Co | 1,2-aryl and heteroaryl substituted imidazolyl compounds for the treatment of inflammation |
RO119946B1 (ro) * | 1995-02-13 | 2005-06-30 | G.D. Searle & Co. | Derivaţi de izoxazol, utilizaţi pentru tratamentul inflamaţiilor |
WO1996036617A1 (en) * | 1995-05-19 | 1996-11-21 | G.D. Searle & Co. | Substituted oxazoles for the treatment of inflammation |
US5643933A (en) * | 1995-06-02 | 1997-07-01 | G. D. Searle & Co. | Substituted sulfonylphenylheterocycles as cyclooxygenase-2 and 5-lipoxygenase inhibitors |
AU5886296A (en) * | 1995-06-02 | 1996-12-18 | G.D. Searle & Co. | Heterocyclo substituted hydroxamic acid derivatives as cyclo oxygenase-2 and 5-lipoxygenase inhibitors |
EP0833622B8 (en) * | 1995-06-12 | 2005-10-12 | G.D. Searle & Co. | Compositions comprising a cyclooxygenase-2 inhibitor and a 5-lipoxygenase inhibitor |
US5700816A (en) * | 1995-06-12 | 1997-12-23 | Isakson; Peter C. | Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitor and a leukotriene A4 hydrolase inhibitor |
EP0833664A1 (en) * | 1995-06-12 | 1998-04-08 | G.D. SEARLE & CO. | Combination of a cyclooxygenase-2 inhibitor and a leukotriene b 4? receptor antagonist for the treatment of inflammations |
GB9520584D0 (en) * | 1995-10-09 | 1995-12-13 | Fujisawa Pharmaceutical Co | Pyrazole derivatives,processes for preparation thereof and pharmaceutical composition comprising the same |
-
1998
- 1998-04-16 NZ NZ500141A patent/NZ500141A/en unknown
- 1998-04-16 CN CN98804252A patent/CN1253502A/zh active Pending
- 1998-04-16 AU AU74662/98A patent/AU745797B2/en not_active Ceased
- 1998-04-16 EE EEP199900517A patent/EE9900517A/xx unknown
- 1998-04-16 TR TR1999/02545T patent/TR199902545T2/xx unknown
- 1998-04-16 EA EA199900837A patent/EA199900837A1/ru unknown
- 1998-04-16 SK SK1387-99A patent/SK138799A3/sk unknown
- 1998-04-16 UA UA99105689A patent/UA68348C2/uk unknown
- 1998-04-16 HU HU0001777A patent/HUP0001777A3/hu unknown
- 1998-04-16 CA CA002286673A patent/CA2286673A1/en not_active Abandoned
- 1998-04-16 JP JP54611398A patent/JP2001527542A/ja not_active Withdrawn
- 1998-04-16 YU YU53899A patent/YU53899A/sh unknown
- 1998-04-16 EP EP04023890A patent/EP1498140A2/en not_active Withdrawn
- 1998-04-16 KR KR1019997009533A patent/KR20010006443A/ko active Search and Examination
- 1998-04-16 ID IDW991219A patent/ID23687A/id unknown
- 1998-04-16 GE GEAP19985037A patent/GEP20022812B/en unknown
- 1998-04-16 EE EEP200300169A patent/EE200300169A/xx unknown
- 1998-04-16 IL IL13216398A patent/IL132163A0/xx not_active IP Right Cessation
- 1998-04-16 WO PCT/US1998/007318 patent/WO1998047509A1/en not_active Application Discontinuation
- 1998-04-16 EP EP98922028A patent/EP0979077A1/en not_active Withdrawn
- 1998-04-16 AP APAP/P/1999/001674A patent/AP9901674A0/en unknown
- 1998-04-16 BR BR9808932-3A patent/BR9808932A/pt not_active Application Discontinuation
- 1998-04-16 PL PL98337098A patent/PL337098A1/xx unknown
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1999
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- 1999-10-18 OA OA9900228A patent/OA11261A/en unknown
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WO1998047509A1 (en) | 1998-10-29 |
IS5203A (is) | 1999-09-30 |
EE200300169A (et) | 2003-06-16 |
AU7466298A (en) | 1998-11-13 |
JP2001527542A (ja) | 2001-12-25 |
ZA983249B (en) | 1999-04-19 |
OA11261A (en) | 2003-07-24 |
UA68348C2 (en) | 2004-08-16 |
HUP0001777A2 (hu) | 2001-05-28 |
NO995077L (no) | 1999-12-17 |
EA199900837A1 (ru) | 2000-10-30 |
EP1498140A2 (en) | 2005-01-19 |
PL337098A1 (en) | 2000-07-31 |
GEP20022812B (en) | 2002-10-25 |
IL132163A0 (en) | 2001-03-19 |
KR20010006443A (ko) | 2001-01-26 |
EE9900517A (et) | 2000-06-15 |
SK138799A3 (en) | 2001-01-18 |
NZ500141A (en) | 2002-05-31 |
CA2286673A1 (en) | 1998-10-29 |
HUP0001777A3 (en) | 2001-07-30 |
TR199902545T2 (xx) | 2000-01-21 |
NO995077D0 (no) | 1999-10-18 |
AP9901674A0 (en) | 1999-12-31 |
YU53899A (sh) | 2002-10-18 |
EP0979077A1 (en) | 2000-02-16 |
ID23687A (id) | 2000-05-11 |
AU745797B2 (en) | 2002-03-28 |
BR9808932A (pt) | 2000-08-01 |
BG103803A (bg) | 2000-05-31 |
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