CN1491112A - 4型磷酸二酯酶抑制剂在治疗心肌疾病中的应用 - Google Patents
4型磷酸二酯酶抑制剂在治疗心肌疾病中的应用 Download PDFInfo
- Publication number
- CN1491112A CN1491112A CNA028048776A CN02804877A CN1491112A CN 1491112 A CN1491112 A CN 1491112A CN A028048776 A CNA028048776 A CN A028048776A CN 02804877 A CN02804877 A CN 02804877A CN 1491112 A CN1491112 A CN 1491112A
- Authority
- CN
- China
- Prior art keywords
- ketone
- tetrahydro pyridazine
- methoxyphenyl
- ethyl
- aminobenzyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 208000031229 Cardiomyopathies Diseases 0.000 title claims abstract description 15
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 title abstract description 4
- 239000002571 phosphodiesterase inhibitor Substances 0.000 title abstract description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 88
- 150000001721 carbon Chemical group 0.000 claims description 74
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 50
- 150000001875 compounds Chemical class 0.000 claims description 48
- 229910052736 halogen Inorganic materials 0.000 claims description 44
- 150000002367 halogens Chemical class 0.000 claims description 44
- 150000003839 salts Chemical class 0.000 claims description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
- 239000012453 solvate Substances 0.000 claims description 32
- -1 methylene dioxy Chemical group 0.000 claims description 31
- 229910052731 fluorine Inorganic materials 0.000 claims description 30
- 125000001153 fluoro group Chemical group F* 0.000 claims description 20
- 229910052801 chlorine Inorganic materials 0.000 claims description 18
- 125000001118 alkylidene group Chemical group 0.000 claims description 16
- 229910052794 bromium Inorganic materials 0.000 claims description 16
- 229910052740 iodine Inorganic materials 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 13
- 239000011737 fluorine Substances 0.000 claims description 12
- 208000037803 restenosis Diseases 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- DHALQLNIDMSKHU-REOHCLBHSA-N (2s)-2-(fluoroamino)propanoic acid Chemical compound FN[C@@H](C)C(O)=O DHALQLNIDMSKHU-REOHCLBHSA-N 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 230000002427 irreversible effect Effects 0.000 claims description 5
- 208000031225 myocardial ischemia Diseases 0.000 claims description 5
- 125000004434 sulfur atom Chemical group 0.000 claims description 5
- 206010007556 Cardiac failure acute Diseases 0.000 claims description 4
- 206010007558 Cardiac failure chronic Diseases 0.000 claims description 4
- 230000001154 acute effect Effects 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 208000029078 coronary artery disease Diseases 0.000 claims description 4
- 230000002441 reversible effect Effects 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 208000007201 Myocardial reperfusion injury Diseases 0.000 claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 230000002757 inflammatory effect Effects 0.000 claims 1
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 15
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 102000004127 Cytokines Human genes 0.000 description 9
- 108090000695 Cytokines Proteins 0.000 description 9
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 9
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 8
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 8
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 7
- 210000002540 macrophage Anatomy 0.000 description 7
- 210000001744 T-lymphocyte Anatomy 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 4
- 108010036949 Cyclosporine Proteins 0.000 description 4
- 108090000174 Interleukin-10 Proteins 0.000 description 4
- 102000003814 Interleukin-10 Human genes 0.000 description 4
- 108010002350 Interleukin-2 Proteins 0.000 description 4
- 102000000588 Interleukin-2 Human genes 0.000 description 4
- 229960001265 ciclosporin Drugs 0.000 description 4
- 208000028867 ischemia Diseases 0.000 description 4
- 230000002107 myocardial effect Effects 0.000 description 4
- 208000005189 Embolism Diseases 0.000 description 3
- 102100037850 Interferon gamma Human genes 0.000 description 3
- 108010074328 Interferon-gamma Proteins 0.000 description 3
- 108010065805 Interleukin-12 Proteins 0.000 description 3
- 102000013462 Interleukin-12 Human genes 0.000 description 3
- 208000001435 Thromboembolism Diseases 0.000 description 3
- 210000004351 coronary vessel Anatomy 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 210000004165 myocardium Anatomy 0.000 description 3
- 229930105110 Cyclosporin A Natural products 0.000 description 2
- 101100296720 Dictyostelium discoideum Pde4 gene Proteins 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 206010028851 Necrosis Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 2
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 2
- 101100082610 Plasmodium falciparum (isolate 3D7) PDEdelta gene Proteins 0.000 description 2
- 206010063837 Reperfusion injury Diseases 0.000 description 2
- 230000006052 T cell proliferation Effects 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 230000005961 cardioprotection Effects 0.000 description 2
- GYNNRVJJLAVVTQ-UHFFFAOYSA-N cloricromen Chemical compound CC1=C(CCN(CC)CC)C(=O)OC2=C(Cl)C(OCC(=O)OCC)=CC=C21 GYNNRVJJLAVVTQ-UHFFFAOYSA-N 0.000 description 2
- 229960002571 cloricromen Drugs 0.000 description 2
- 229930182912 cyclosporin Natural products 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000000004 hemodynamic effect Effects 0.000 description 2
- 206010020718 hyperplasia Diseases 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 210000002751 lymph Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 230000017074 necrotic cell death Effects 0.000 description 2
- 210000000440 neutrophil Anatomy 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- UGSLDMJXBQKDCT-WOPDTQHZSA-N (2s)-5-oxo-n-[(1s,2r)-2-phenylcyclopropyl]pyrrolidine-2-carboxamide Chemical group C1([C@H]2C[C@@H]2NC(=O)[C@H]2NC(=O)CC2)=CC=CC=C1 UGSLDMJXBQKDCT-WOPDTQHZSA-N 0.000 description 1
- KKJUPNGICOCCDW-UHFFFAOYSA-N 7-N,N-Dimethylamino-1,2,3,4,5-pentathiocyclooctane Chemical compound CN(C)C1CSSSSSC1 KKJUPNGICOCCDW-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 208000031104 Arterial Occlusive disease Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000001778 Coronary Occlusion Diseases 0.000 description 1
- 206010011086 Coronary artery occlusion Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102000003777 Interleukin-1 beta Human genes 0.000 description 1
- 108090000193 Interleukin-1 beta Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 102000004889 Interleukin-6 Human genes 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 229940123263 Phosphodiesterase 3 inhibitor Drugs 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000021328 arterial occlusion Diseases 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 210000004413 cardiac myocyte Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 230000008828 contractile function Effects 0.000 description 1
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 description 1
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical class C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 230000001057 ionotropic effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000002570 phosphodiesterase III inhibitor Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 1
- 229950005741 rolipram Drugs 0.000 description 1
- YEENEYXBHNNNGV-XEHWZWQGSA-M sodium;3-acetamido-5-[acetyl(methyl)amino]-2,4,6-triiodobenzoate;(2r,3r,4s,5s,6r)-2-[(2r,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound [Na+].CC(=O)N(C)C1=C(I)C(NC(C)=O)=C(I)C(C([O-])=O)=C1I.O[C@H]1[C@H](O)[C@@H](CO)O[C@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 YEENEYXBHNNNGV-XEHWZWQGSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000006433 tumor necrosis factor production Effects 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines having two or more nitrogen atoms in the same ring, e.g. oxadiazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明涉及4型磷酸二酯酶抑制剂在治疗心肌疾病中的用途。
Description
本发明涉及4型磷酸二酯酶抑制剂在治疗心肌疾病中的应用。
冠状动脉疾病是在西方世界引起死亡的最普遍的原因。在存在严重的冠状动脉狭窄时,降低的血流量可以导致心肌局部缺血。根据前局部缺血期的严重程度,再灌注的开始导致心肌的可逆或不可逆损伤,其特征为长期持续抑制或不可逆的收缩功能丧失。根据受影响心肌区域的大小,可发展为急性或慢性心力衰竭。
上面所提情况的具体临床问题是,由于PTCA的干预在起初的成功的再灌注后再狭窄的发展,甚至在移植膜移植,血栓溶解或冠状动脉旁路搭桥后。
从动物实验和临床研究的证据表明,在上述不同的心脏疾病中,即冠状动脉疾病自身、可逆或不可逆心肌局部缺血/再灌注损伤、急性或慢性心力衰竭和再狭窄,包括支架再狭窄(instent-restenosis)和支架内支架再狭窄(stent-in-stent-restenosis),炎症过程都扮演了偶然的角色。这些炎症过程包括固有的和入侵的巨噬细胞及嗜中性细胞和TH1和TH2辅助细胞。此白血球反应产生特征性的细胞素型,包括TNF-α、IL-1β、IL-2、和IL-6、及IL-10和IL-13(Pulkki KJ:Cytokinesand cardiomyocyte death.Ann.Med.1997 29:339-343。Birks EJ,YacoubMH:The role of nitric oxide and cytokines in heart failure。Coron.Artery.Dis.1997 8:389-402)。
在心肌局部缺血的患者中显示有这些物质的形成。动物模型显示细胞素的产生与外周的巨噬细胞和嗜中性细胞的侵入有关,其可将损伤扩散到完整无伤的心肌层。然而在细胞素反应中的主要角色是TNF-α,其整合炎症和pro-apoptotic反应并另外具有对心肌细胞的直接阴离子的离子移变作用。(Ceconi C,Curello S,Bachetti T,Corti A,Ferrari R:Tumor necrosis factor in congestive heart hilure:amechanism of disease for the new millennium?Prog.Cardiovasc.Dis.1998 41:25-30.Mann DL:The eeffect of tumor necrosis factor-alpha oncardiac structure and function:a tale of two cytokines.J.Card.Fail.1996 2:S165-S172.Squadrito F,Altavilla D,Zingareli B,et al:Tumornecrosis factor involvement in myocardial ischaemia-reperfusion injury.Eur.J.Pharmacol.1993 237:223-230)。
心肌炎的动物模型显示,在再灌注相过程中TNF-α被迅速释放(Herskowitz A,Choi S,Ansari AA,Wesselingh S:Cytokine mRNAexpression in postischemic/reperfused myocardium.Am.J.Pathol.1995146:419-428)和药物如地塞米松的保护作用(Arras M,Strasser R,Mohri M,et al:Tumor necrosis factor-alpha is expressed bymonocytes/macrophages following cardiac microembolization and isantagonized by cyclosporine.Basic.es.Cardiol.1998 93:97-107),环孢菌素A(Arras M,Strasser R,Mohri M,et al:Tumor necrosis factor-alpha is expressed by monocytes/macrophages following cardiacmicroembolization and is antagonized by cyclosporine.Basic.Res.Cardiol.1998 93:97-107.Squadrito F,Altavilla D,Squadrito G,et al:Cyclosporin-A reduces leukocyte accumulation and protects againstmyocardial ischaemia reperfusion injury in rats.Eur.J.Pharmacol.1999 364:159-168)或氯克罗孟(Squadrito F,Altavilla D,Zingarelli B,et al:The effect of cloricromene,a coumarine derivative,on leukocyteaccumulation,myocardial necrosis and TNF-alpha production inmyocardial ischaemia-reperfusion injury.Life Sci.1993 53:341-355)可相应的减少TNF-α循环。
下述优选的PDE4抑制剂是巨噬细胞和T-细胞细胞素产生的潜在的激动剂。它们也抑制T细胞增殖。结果,PDE4抑制可能在那些心肌疾病中具有有益作用,其对于细胞素产生和炎症过程也具有因果关系。
与PDE3抑制剂比较,早期的PDE4抑制剂是罗利普令,优选的PDE4抑制剂避免具有血液动力副作用,其可用于多数心血管疾病的治疗。
本发明基于此目的发现了有价值特性的化合物的用途,特别是那些可以用于制备药物的化合物。
已发现,优选的PDE IV抑制剂和它们的盐联合,对于心肌疾病的治疗具有好的耐受性而非常有药物价值。
本发明特别提供以下化合物在制备治疗心肌疾病的药物中的用途
a)在EP0763534中公开的通式I化合物和它们的立体异构体和生理上可接受的盐和溶剂化物
其中
B是1-4个N、O和/或S原子的芳香杂环,通过N或C键合,其可以是未取代的或被卤素、A和/或OA单、二或三取代,并也可与苯环或吡啶环稠合,
Q不存在或是1-6个碳原子的亚烷基,
X是CH2、S或O,
R1和R2各自独立地是H或A,
R3和R4各自独立地是-OH、OR5、-S-R5、-SO-R5、-SO2-R5、卤素、亚甲基二氧基、-NO2、-NH2、-NHR5或NR5R6,
R5和R6各自独立地是A、具有3-7个碳原子的环烷基、具有4-8个碳原子的亚甲基环烷基或具有2-8个碳原子的链烯基,
A是可以被1-5个F和/或Cl原子取代的1-10个碳原子的烷基,和
卤素是F、Cl、Br或I;
b)在WO 99/65880中公开的通式I化合物和它们的生理可接受的盐和溶剂化物
B是未取代的或被R3单-或多取代的苯环,
Q不存在或是1-4个碳原子的亚烷基,
R1,R2各自独立地是-OR4、-S-R4、-SO-R4、-SO2-R4或卤素,
R1和R2一起也可是-O-CH2-O,
R3是R4、卤素、OR4、OPh、-NO2、-NHR4、-N(R4)2、NHCOR4、NHSO2R4或NHCOOR4,
R4是A、具有3-7个碳原子的环烷基、具有5-10个碳原子的亚烷基环烷基或具有2-8个碳原子的链烯基,
A是可以被1-5个F和/或Cl原子取代的有1-10个碳原子的烷基,和
卤素是F、Cl、Br或I;
c)在WO 00/26201中公开的通式I化合物和它们的生理可接受的盐和溶剂化物
R1,R2各自独立地是-OH、-OR5、-S-R5、-SO-R5、-SO2-R5或卤素,
R1和R2一起也可是-O-CH2-O,
R5是NH2、NHA、NAA′或具有1-4个N、O和/或S原子的饱和杂环,其可以是未取代的或被卤素、A和/或OA单-、二-或三-取代,
Q不存在或是具有1-10个碳原子的枝化或未枝化的亚烷基,
R5是A、具有3-7个碳原子的环烷基、具有4-8个碳原子的亚烷基环烷基或具有2-8个碳原子的链烯基,
A,A′各自独立地是可以被1-5个F和/或Cl原子取代的有1-10个碳原子的烷基,和
卤素是F、Cl、Br或I;
d)在WO 98/06704中公开的通式I化合物和它们的立体异构体和生理可接受的盐和溶剂化物
其中
B是A、OA、NH2、NHA、NAA′或有1-4个N、O和/或S原子的不饱和杂环,其可以是未取代的或被卤素、A和/或OA单、二或三取代,
Q不存在或是1-6个碳原子的亚烷基,
R1,R2各自独立地是-OH、-OR5、-S-R5、-SO-R5、-SO2-R5、卤素、-NO2、-NHR5或-NHR5R6,
R1和R2一起也可是-O-CH2-O,
R3,R4各自独立地是H或A,
R5,R6各自独立地是A、具有3-7个碳原子的环烷基、具有4-8个碳原子的亚甲基环烷基或具有2-8个碳原子的链烯基,
A,A′各自独立地是可以被1-5个F和/或Cl原子取代的有1-10个碳原子的烷基,和
卤素是F、Cl、Br或I;
e)在WO 00/59890中公开的化合物和它们的生理可接受的盐和溶剂化物
1-(4-脲基苯甲酰基)-3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-烟酰基氨基苯甲酰基)-3-(3-丙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-三氟乙酰氨基苯甲酰基)-3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-乙氧基羰基氨基苯甲酰基)-3-(3-丙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-异丙氧基羰基氨基苯甲酰基)-3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-丙氧基羰基氨基苯甲酰基)-3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-烟酰基氨基苯甲酰基)-3-(3,4-二甲氧苯基)-4-乙基-1,4,5,6-四氢哒嗪,
1-(4-乙氧基羰基氨基苯甲酰基)-3-(3,4-二甲氧苯基)-4-乙基-1,4,5,6-四氢哒嗪和
1-(4-乙酰氨基苯甲酰基)-3-(3,4-二甲氧苯基)-4-乙基-1,4,5,6-四氢哒嗪;
f)在DE19604388中公开的通式I化合物和它们的立体异构体和生理可接受的盐和溶剂化物
其中
R1,R2各自独立地是H或A,
R3,R4各自独立地是-OH、OA、-S-A、-SO-A、-SO2-A、卤素、亚甲二氧基、-NO2、-NH2、-NHA或-NAA′,
A,A′各自独立地是可以被1-5个F和/或Cl原子取代的有1-10个碳原子的烷基、3-7个碳原子的环烷基或4-8个碳原子的亚甲基环烷基,
B是-Y-R5或-O-Y-R5,
Q不存在或是1-4个碳原子的亚烷基,
Y不存在或是1-10个碳原子的亚烷基,
X是CH2或S,
R5是NH2、NHA、NAA′或是具有至少一个N原子的3-8元饱和杂环,其中其他CH2基团可以任意被NH、NA、S或O取代,其可以是未取代的或被A或OH单取代,
卤素是F、Cl、Br或I;
g)在DE19932315中公开的通式I化合物和它们的生理可接受的盐和溶剂化物
R1,R2各自独立地是H、OH、OA、SA、SOA、SO2A、F、Cl或A′2N-(CH2)n-O-,
R1和R2一起也可是-O-CH2-O,
R3,R4各自独立地是H、A、卤素、OH、OA、NO2、NHA、NA2、CN、COOH、COOA、NHCOA、-NHSO2A或NHCOOA,
R5,R6各自独立地是H或1-6个碳原子的烷基,
A是可以被1-5个F和/或Cl原子取代的1-10个碳原子的烷基、是3-7个碳原子的环烷基、5-10个碳原子的亚烷基环烷基或2-8个碳原子的链烯基,
A′是1、2、3、4、5或6个碳原子的烷基,
n是1、2、3或4,
卤素是F、Cl、Br或I;
h)在EP0723962中公开的通式I化合物和它们的生理可接受的盐和溶剂化物
R1和R2各自独立地是H或A,
R3和R4各自独立地是-OH、-OR10、-S-R10、-SO-R10、-SO2-R10、卤素、亚甲基二氧基、-NO2、-NH2、-NHR10或-NR10R11,
R5是未取代的或被R6和/或R7单-或二取代的苯基,
Q不存在或是1-6个碳原子的亚烷基,
R6和R7各自独立地是NH2、NR8R9、NHR10、-NR10R11、-NO2、卤素、-CN、-OA、-COOH或-COOA,
R8和R9各自独立地是H、被1-5个F和/或Cl原子取代的1-8个碳原子的酰基、-COOA、-S-A、-SO-A、SO2-A、-CONH2、-CONHA、-CONA2、-CO-COOH、-CO-COOA、-CO-CONH2、-CO-CONHA或-CO-CONA2,
A是被1-5个F和/或Cl原子取代的1-6个碳原子的烷基,
R10和R11各自独立地是A、3-7个碳原子的环烷基、4-8个碳原子的亚甲基环烷基或2-8个碳原子的链烯基,和
卤素是F、Cl、Br或I;
i)在EP0738715中公开的通式I化合物和它们的生理可接受的盐和溶剂化物
其中
R1,R2各自独立地是H或A,
R3,R4各自独立地是-OH、-OR10、-S-R10、-SO-R10、-SO2-R10、卤素、亚甲基二氧基、-NO2、-NH2、-NHR10或-NR10R11,
R5是未取代的或被R6和/或R7单-或二取代的苯基,
Q不存在或是1-6个碳原子的亚烷基,
R6和R7各自独立地是-NH2、-NR8R9、-NHR10、-NR10R11、-NO2、卤素、-CN、-OA、-COOH或-COOA,
R8和R9各自独立地是H、可被1-5个F和/或Cl原子取代的1-8个碳原子的酰基、-COOA、-SO-A、SO2-A、-CONH2、-CONHA、-CONA2、-CO-COOH、-CO-COOA、-CO-CONH2、-CO-CONHA或-CO-CONA2,
A是被1-5个F和/或Cl原子取代的1-6个碳原子的烷基,
R10和R11各自独立地是A、3-7个碳原子的环烷基、4-8个碳原子的亚甲基环烷基或2-8个碳原子的链烯基,和
卤素是F、Cl、Br或I。
本发明优选提供以下化合物在制备治疗心肌疾病的药物中的用途
a)在EP0763534中公开的化合物和它们的立体异构体和生理可接受的盐和溶剂化物:
2-(3-烟酰基氨基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(2-烟酰基氨基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(3-烟酰基氨基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(2-烟酰基氨基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3-甲氧基-4-三氟甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3-甲氧基-4-二氟甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3-甲氧基-4-氟甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3-二氟甲氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3-三氟甲氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3-氟甲氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3-甲氧基-4-乙氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3-羟基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(4-甲磺酰基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(4-亚甲基氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(3-烟酰基氨基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苯乙基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苯乙基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
3-(4-烟酰基氨基苄基)-5-(3,4-二甲氧基苯基)-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(3-烟酰基氨基苄基)-5-(3,4-二甲氧基苯基)-3,6-二氢-1,3,4-噻二嗪哒嗪-2-酮,
3-(2-烟酰基氨基苄基)-5-(3,4-二甲氧基苯基)-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3,4-二甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(3-烟酰基氨基苄基)-5-(3,4-二甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(2-烟酰基氨基苄基)-5-(3,4-二甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-甲氧基-4-三氟甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-甲氧基-4-二氟甲氧基苯基)-6-乙基-3,6-
二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-甲氧基-4-氟甲氧基苯基)-6-乙基-3,6-
二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-二氟甲氧基-4-甲氧基苯基)-6-乙基-3,6-
二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-三氟甲氧基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-氟甲氧基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-甲氧基-4-乙氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-乙氧基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-乙氧基-4-甲氧基苯基)-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-羟基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(4-甲磺酰苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(4-亚甲基氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-环戊基氧基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(3-烟酰基氨基苄基)-5-(3-环戊基氧基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苯乙基)-5-(3,4-二甲氧基苯基)-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苯乙基)-5-(3,4-二甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3,4-二甲氧基苯基)-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(3-烟酰基氨基苄基)-5-(3,4-二甲氧基苯基)-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(2-烟酰基氨基苄基)-5-(3,4-二甲氧基苯基)-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3,4-二甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(3-烟酰基氨基苄基)-5-(3,4-二甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(2-烟酰基氨基苄基)-5-(3,4-二甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-甲氧基-4-三氟甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-甲氧基-4-二氟甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-甲氧基-4-氟甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-二氟甲氧基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-三氟甲氧基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-氟甲氧基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮;
3-(4-烟酰基氨基苄基)-5-(3-甲氧基-4-乙氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-乙氧基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-羟基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(4-甲磺酰基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(4-亚甲基氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-环戊基氧基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(3-烟酰基氨基苄基)-5-(3-环戊基氧基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苯乙基)-5-(3,4-二甲氧基苯基)-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苯乙基)-5-(3,4-二甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
2-(3-烟酰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-异烟酰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-吡嗪羰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-(异噁唑-5-羰基氨基)苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,盐酸盐;
b)在WO99/65880中公开的化合物和其生理可接受的盐和溶剂化物:
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-4-甲氧基苯甲酰基-3-甲酰胺,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-4-甲基苯甲酰基-3-甲酰胺,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)苯甲酰基-3-甲酰胺,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-3,4-二氯苯甲酰基-3-甲酰胺,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-4-三氟甲基苯甲酰基-3-甲酰胺,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-3-氯苯甲酰基-3-甲酰胺,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-4-氟苯甲酰基-3-甲酰胺,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-4-丁氧基苯甲酰基-3-甲酰胺,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-4-戊氧基苯甲酰基-3-甲酰胺,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-4-乙氧基苯甲酰基-3-甲酰胺,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-3,4-二甲氧基苯甲酰基-3-甲酰胺,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-3-甲基苯甲酰基-3-甲酰胺,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-3-甲氧基苯甲酰基-3-甲酰胺;
c)在WO 00/26201中公开的化合物和其生理可接受的盐和溶剂化物:
3-二甲基氨基丙基{4-[3-(3-乙氧基-4-甲氧基苯基)-1,2,3,4-四氢哒嗪-1-基羰基]苯基}氨基甲酸酯,
N-甲基哌啶-4-基{4-[3-(3-乙氧基-4-甲氧基苯基)-1,2,3,4-四氢哒嗪-1-基羰基]苯基}氨基甲酸酯,
3-二甲基氨基丙基{4-[3-(3-异丙氧基-4-甲氧基苯基)-1,2,3,4-四氢哒嗪-1-基羰基]苯基}氨基甲酸酯,
3-二甲基氨基丙基{3-[3-(3-乙氧基-4-甲氧基苯基)-1,2,3,4-四氢哒嗪-1-基羰基]苯基}氨基甲酸酯,
3-二甲基氨基丙基{3-[3-(3-环戊基氧基-4-甲氧基苯基)-1,2,3,4-四氢哒嗪-1-基羰基]苯基}氨基甲酸酯,
N-甲基哌啶-4-基{3-[3-(3-环戊基氧基-4-甲氧基苯基)-1,2,3,4-四氢哒嗪-1-基羰基]苯基}氨基甲酸酯,
3-二甲基氨基丙基{3-[3-(3-丙氧基-4-甲氧基苯基)-1,2,3,4-四氢哒嗪-1-基羰基]苯基}氨基甲酸酯,
3-二甲基氨基丙基{4-[3-(3,4-二乙氧基苯基)-1,2,3,4-四氢哒嗪-1-基羰基]苯基}氨基甲酸酯,
N-甲基哌啶-4-基{4-[3-(3,4-二乙氧基苯基)-1,2,3,4-四氢哒嗪-1-基羰基]苯基}氨基甲酸酯,
3-二甲基氨基丙基{3-[3-(3,4-二甲氧基苯基)-1,2,3,4-四氢哒嗪-1-基羰基]苯基}氨基甲酸酯,
3-二甲基氨基丙基{4-[3-(3,4-二甲氧基苯基)-1,2,3,4-四氢哒嗪-1-基羰基]苯基}氨基甲酸酯;
d)在WO 98/06704中公开的化合物和其立体异构体及生理可接受的盐和溶剂化物:
1-(4-烟酰基氨基苯甲酰基)-3-(3,4-二甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(3-烟酰基氨基苯甲酰基)-3-(3,4-二甲氧基苯基)-1,4,5,6-四氢哒嗪盐酸盐,
1-(2-烟酰基氨基苯甲酰基)-3-(3,4-二甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-烟酰基氨基苯甲酰基)-3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(3-烟酰基氨基苯甲酰基)-3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-烟酰基氨基苯甲酰基)-3-(3-环戊基氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(3-烟酰基氨基苯甲酰基)-3-(3-环戊基氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-烟酰基氨基苯甲酰基)-3-(3,4-亚甲基-二氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-烟酰基氨基苯甲酰基)-3-(3-甲氧基-4-甲基磺酰苯基)-1,4,5,6-四氢哒嗪,
1-(4-烟酰基氨基苯甲酰基)-3-(3-三氟-甲氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-乙氧基-羰基氨基苯甲酰基)-3-(3,4-二甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(3-乙氧基羰基氨基苯甲酰基)-3-(3,4-二甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(2-乙氧基羰基氨基苯甲酰基)-3-(3,4-二甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-乙氧基羰基氨基苯甲酰基)-3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(3-乙氧基羰基氨基苯甲酰基)-3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-乙氧基羰基氨基苯甲酰基)-3-(3-环戊基氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(3-乙氧基羰基氨基苯甲酰基)-3-(3-环戊基氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-乙氧基羰基氨基苯甲酰基)-3-(3,4-亚甲基-二氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-乙氧基羰基氨基苯甲酰基)-3-(3-甲氧基-4-甲磺酰基苯基)-1,4,5,6-四氢哒嗪,
1-(4-乙氧基羰基氨基苯甲酰基)-3-(3-三氟甲氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪;
e)在EP0723962中公开的化合物和其生理可接受的盐和溶剂化物:
3-(4-乙氧基羰基氨基苄基)-5-(3-乙氧基-4-甲氧基苯基)-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-乙氧基羰基氨基苄基)-5-(3-环戊基氧基-4-甲氧基苯基)-3,6-二氢-1,3,4-噻二嗪-2-酮;
f)在EP0738715中公开的化合物和其生理可接受的盐和溶剂化物:
2-(4-丁酰胺基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-乙酰胺基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-三氟乙酰胺基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲磺酰胺基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-丙酰基氨基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-叔丁基羰基氨基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-异丁酰基氨基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲氧基羰基氨基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-新戊酰基氨基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-环戊基氨基甲酰基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-乙氧基羰基氨基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲草酰氨基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-脲基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-戊酰基氨基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-己酰氨基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-五氟丙酰胺基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-乙酰胺基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-三氟乙酰胺基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲磺酰胺基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-丙酰胺基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-叔丁基羰基氨基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-丁酰氨基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-异丁酰基氨基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲氧基羰基氨基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-新戊酰基氨基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-环戊基氨基甲酰基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-乙氧基羰基氨基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲草酰氨基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-脲基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-戊酰基氨基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-己酰氨基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-五氟丙酰胺基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-乙酰胺基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-三氟乙酰胺基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲磺酰胺基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-丙酰胺基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-叔丁基羰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-丁酰氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-异丁酰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲氧基羰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-新戊酰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-环戊基氨基甲酰基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-乙氧基羰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲草酰氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-脲基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-戊酰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-己酰氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-五氟丙酰胺基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-乙酰胺基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-三氟乙酰胺基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲磺酰胺基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-丙酰胺基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-叔丁基羰基氨基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-丁酰氨基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-异丁酰基氨基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲氧基羰基氨基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-新戊酰基氨基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-环戊基氨基甲酰基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-乙氧基羰基氨基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲草酰氨基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-脲基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-戊酰基氨基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-己酰氨基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-五氟丙酰胺基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-乙酰胺基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-三氟乙酰胺基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲磺酰胺基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-丙酰胺基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-叔丁基羰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-丁酰氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-异丁酰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲氧基羰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-新戊酰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-环戊基氨基甲酰基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-乙氧基羰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲草酰氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-脲基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-戊酰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-己酰氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-五氟丙酰胺基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮。
本发明提供以下最优选化合物和它们的生理可接受的盐和溶剂化物在制备治疗心肌疾病的药物中的用途
3-(4-烟酰基氨基苄基)-5-(3-乙氧基-4-甲氧基苯基)--3,6-二氢-1,3,4-噻二嗪-2-酮,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-4-甲氧基苯甲酰基-3-甲酰胺,
1-(4-烟酰基氨基苯甲酰基)-3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-乙氧基羰基氨基苯甲酰基)-3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
2-(4-乙氧基羰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢-哒嗪-3-酮。
优选的化合物对磷酸二酯酶IV显示选择性抑制,其与细胞内的cAMP增加有关(N.Sommer等,天然药物,1,244-248(1995))。
PDE IV的抑制可以用实验证明,例如类似于C.W.Davis在Biochim.Biophys.Acta797,354-362(1984)中描述的。
本发明化合物对于磷酸二酯酶IV的亲和力通过确定他们的IC50值(获得酶活性50%抑制所需的抑制剂的浓度)测定。
优选地,本发明提供使用上述化合物制备治疗心肌疾病的药物的用途,其中所说的心肌疾病显示炎症和免疫特征。
最优选地,本发明提供使用上述化合物制备治疗冠状动脉疾病、可逆或不可逆心肌局部缺血/再灌注损伤、急性或慢性心力衰竭和restenosis,包括instent-restenosis和instent-in-instent-restenosis的药物的用途。
治疗上述疾病的制剂可以用作人用或兽用药物。可能的赋形剂是适于胃肠内(如口服)或胃肠外给药或局部给药并不与新化合物反应的有机或无机物,例如水、植物油、苯甲醇、亚烷基二醇、聚乙二醇、硝酸甘油、明胶、碳水化合物如乳糖或淀粉、硬脂酸镁、滑石和凡士林。具体地说,片剂、丸剂、包衣片、胶囊剂、粉剂、颗粒剂、糖浆、汤剂或滴剂用于口服给药,栓剂用于肠内给药,溶液,优选油或水溶液,还有混悬剂、乳剂或植入剂用于胃肠外给药,软膏、乳膏或粉末用于局部给药。新化合物也可以冷冻干燥并使用获得的冻干品,例如用于注射剂的生产。所述制剂可以是灭菌的和/或可含助剂如润滑剂、防腐剂、稳定剂和/或湿润剂,影响渗透压的乳化剂、盐,缓冲物、着色剂、矫味剂和/或另外更多的活性化合物,如一种或多种维生素。
上述提到的物质一般优选在约1-500mg的剂量范围内给药,特别是5-100mg每剂量单位。日剂量优选约0.02-10mg/kg体重。特定的剂量根据每个患者的多方面因素确定,例如所使用具体的化合物的作用效果、患者年龄、体重、健康状况、性别、饮食、给药时间次数和途径、排泄次数、联合用药和所治疗疾病的严重程度。优选口服给药。
实施例1:PDE4抑制剂对T-细胞增生的作用
外周血液单核细胞(PBMC)是从健康供体的血液中通过淋巴(Lymphoprep)梯度法分离得到的。在含5%热失活的人血清(Abpool)的RPMI 1640培养介质中以200000 PBMC/孔的浓度在37℃培养5天并以10%CO2吹洗96孔微量板的底部。PBMC制剂中的T细胞用单克隆抗体选择性刺激CD3。包括未经处理的对照组培养物重复三份。将PDE4抑制剂溶解在DMSO(10-2M)中并用培养介质稀释。对照组培养物用与抑制剂相当浓度的DMSO处理。在测定结束前18小时,向培养物中加入3H-胸苷。然后在β-计数器中测定细胞的放射活性的结合率。
至少独立地进行三次实验并计算数据作为相对于无抑制剂的对照组的百分抑制率(平均±SEM)。从此数据确定IC-50值。
结果:
PDE4抑制剂显著地减少T-细胞增殖(见表1)。
表1 PDE4抑制剂对T-细胞增生的作用
IL2 IFN-γ TNF-α IL10 IL12 T-细胞增殖
T-细胞 T-细胞 巨噬细胞 巨噬细胞 巨噬细胞 IC50[μM]
IC50[μM] IC50[μM] IC50[μM] EC50[μM] IC50[μM]
Rolipram 0.7 1 0.6 0.05 >0.1 0.3
EMD 94360 0.3 0.05 0.03 0.001 0.006 0.02
EMD 95832 0.2 0.01 0.009 0.02 0.0005 0.05
EMD 125025 0.002 0.007 0.003 no effect <1E-13M 0.006
EMD 125059 0.06 0.008 0.03 0.008 <1E-13M 0.04
EMD 219901 0.003 0.005 0.002 0.001 <1E-13M 0.007
EMD 94360(EP 0738715;17页,41行):
EMD 84721(EP 0763534):
EMD 125025(WO 98/06704;13页,16-17行):
EMD 125059(WO 98/06704;27页,2-3行):
EMD 219901(WO 99/65880;14页,20-21行):
实施例2:在人外周血液单核血球细胞中PDE4抑制剂对细胞素产生的作用
外周血液单核细胞(PBMC)是从健康供体的血液中通过淋巴梯度法分离得到的。在含5%热失活的人血清(Ab pool)的RPMI 1640培养介质中以200000 PBMC/孔的浓度在37℃培养5天并以10%CO2吹洗96孔微量板的底部。包括未经处理的对照组培养物重复三份。将PDE4抑制剂溶解在DMSO(10-2M)中并用培养介质稀释。对照组培养物用与抑制剂相当浓度的DMSO处理。感兴趣的细胞素如表2所示被刺激,将三次独立实验的培养物上清液合并并用可商购的ELISA试剂盒测定上清液中的细胞素活性。
表2 PBMC活化形成T-细胞和巨噬细胞的特定细胞素
细胞素 活化剂 培养物培养
IL2 mab anti-CD3 24h
IL10 LPS 48h
TNF-α LPS 48h
IFN-γ mab anti-CD3 48h
IL-12 SAC+IFNγ 48h
数据以相对于无化合物的对照组百分抑制/刺激计算,并计算其刺激情况下的IC50值或EC50值。
结果
PDE4抑制剂显著地减少IL-2、IFN-γ、TNF-α和IL-12的释放。但是,免疫抑制细胞素IL-10被多数PDE4抑制剂刺激(见表1)。
实施例3:PDE4抑制剂对于小鼠试验性心肌梗塞的作用
将化合物5以1、3和10mg/kg腹膜内给药,小鼠左冠状动脉的可逆性闭塞前1小时显著地随剂量栓塞大小减少至38%。通过ELISA测定,相对与此保护,发现血浆TNF-□水平减少。
实施例4:PDE4抑制剂对于兔试验性心肌梗塞的作用
通过将麻醉的家兔进行30分钟的冠状动脉闭塞(左冠状动脉旋支的侧枝),随后进行120分钟再灌注进行PDE4抑制的心脏保护作用测定。在动脉闭塞前使用PDE4抑制剂与空白对照比较减小的栓塞大小。比较verum和空白对照组的危险面积。心脏保护作用对有利的血液动力无贡献,因为心率和平均的主动脉压在整个实验记录中固定不变。
Claims (5)
1.以下化合物在制备治疗心肌疾病的药物中的用途
a)EP0763534中公开的通式I化合物和它们的立体异构体和生理可接受的盐和溶剂化物
其中
B是1-4个N、O和/或S原子的芳香杂环,通过N或C键合,其可以是未取代的或被卤素、A和/或OA单、二或三取代,并也可与苯环或吡啶环稠合,
Q不存在或是1-6个碳原子的亚烷基,
X是CH2、S或O,
R1和R2各自独立地是H或A,
R3和R4各自独立地是-OH、OR5、-S-R5、-SO-R5、-SO2-R5、卤素、亚甲基二氧基、-NO2、-NH2、-NHR5或NR5R6,
R5和R6各自独立地是A、具有3-7个碳原子的环烷基、具有4-8个碳原子的亚甲基环烷基或具有2-8个碳原子的链烯基,
A是可以被1-5个F和/或Cl原子取代的1-10个碳原子的烷基,和
卤素是F、Cl、Br或I;
b)WO 99/65880中公开的通式I化合物和它们的生理可接受的盐和溶剂化物
其中
B是未取代的或被R3单-或多取代的苯环,
Q不存在或是1-4个碳原子的亚烷基,
R1,R2各自独立地是-OR4、-S-R4、-SO-R4、-SO2-R4或卤素,
R1和R2一起也可是-O-CH2-O,
R3是R4、卤素、OR4、OPh、-NO2、-NHR4、-N(R4)2、NHCOR4、NHSO2R4或NHCOOR4,
R4是A、具有3-7个碳原子的环烷基、具有5-10个碳原子的亚烷基环烷基或具有2-8个碳原子的链烯基,
A是可以被1-5个F和/或Cl原子取代的1-10个碳原子的烷基,和
卤素是F、Cl、Br或I;
c)在WO 00/26201中公开的通式I化合物和它们的生理可接受的盐和溶剂化物
其中
R1,R2各自独立地是-OH、-OR5、-S-R5、-SO-R5、-SO2-R5或卤素,
R1和R2一起也可是-O-CH2-O,
R3是NH2、NHA、NAA′或具有1-4个N、O和/或S原子的饱和杂环,其可以是未取代的或被卤素、A和/或OA单-、二-或三-取代,
Q不存在或具有1-10个碳原子的枝化或未枝化的亚烷基,
R5是A、具有3-7个碳原子的环烷基、具有4-8个碳原子的亚烷基环烷基或具有2-8个碳原子的链烯基,
A,A′各自独立地是可以被1-5个F和/或Cl原子取代的1-10个碳原子的烷基,和
卤素是F、Cl、Br或I;
d)在WO 98/06704中公开的通式I化合物和它们的立体异构体和生理可接受的盐和溶剂化物
其中
B是A、OA、NH2、NHA、NAA′或1-4个N、O和/或S原子的不饱和杂环,其可以是未取代的或被卤素、A和/或OA单、二或三取代,
Q不存在或是1-6个碳原子的亚烷基,
R1,R2各自独立地是-OH、-OR5、-S-R5、-SO-R5、-SO2-R5、卤素、-NO2、-NHR5或-NHR5R6,
R1和R2一起也可是-O-CH2-O,
R3,R4各自独立地是H或A,
R5,R6各自独立地是A、具有3-7个碳原子的环烷基、具有4-8个碳原子的亚甲基环烷基或具有2-8个碳原子的链烯基,
A,A′各自独立地是可以被1-5个F和/或Cl原子取代的1-10个碳原子的烷基,和
卤素是F、Cl、Br或I;
e)在WO 00/59890中公开的化合物和它们的生理可接受的盐和溶剂化物
1-(4-脲基苯甲酰基)-3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-烟酰基氨基苯甲酰基)-3-(3-丙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-三氟乙酰氨基苯甲酰基)-3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-乙氧基羰基氨基苯甲酰基)-3-(3-丙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-异丙氧基羰基氨基苯甲酰基)-3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-丙氧基羰基氨基苯甲酰基)-3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-烟酰基氨基苯甲酰基)-3-(3,4-二甲氧苯基)-4-乙基-1,4,5,6-四氢哒嗪,
1-(4-乙氧基羰基氨基苯甲酰基)-3-(3,4-二甲氧苯基)-4-乙基-1,4,5,6-四氢哒嗪和
1-(4-乙酰氨基苯甲酰基)-3-(3,4-二甲氧苯基)-4-乙基-1,4,5,6-四氢哒嗪;
f)在DE19604388中公开的通式I化合物和它们的立体异构体和生理可接受的盐和溶剂化物
其中
R1,R2各自独立地是H或A,
R3,R4各自独立地是-OH、OA、-S-A、-SO-A、-SO2-A、卤素、亚甲二氧基、-NO2、-NH2、-NHA或-NAA′,
A,A′各自独立地是可以被1-5个F和/或Cl原子取代的1-10个碳原子的烷基、3-7个碳原子的环烷基或4-8个碳原子的亚甲基环烷基,
B是-Y-R5或-O-Y-R5,
Q不存在或是1-4个碳原子的亚烷基,
Y不存在或是1-10个碳原子的亚烷基,
X是CH2或S,
R5是NH2、NHA、NAA′或是具有至少一个N原子的3-8元饱和杂环,其中其他CH2基团可以任意被NH、NA、S或O取代,其可以是未取代的或被A或OH单取代,
卤素 是F、Cl、Br或I;
g)在DE19932315中公开的通式I化合物和它们的生理可接受的盐和溶剂化物
其中
R1,R2各自独立地是H、OH、OA、SA、SOA、SO2A、F、Cl或A′2N-(CH2)n-O-,
R1和R2一起也可是-O-CH2-O,
R3,R4各自独立地是H、A、卤素、OH、OA、NO2、NHA、NA2、CN、COOH、COOA、NHCOA、-NHSO2A或NHCOOA,
R5,R6各自独立地是H或1-6个碳原子的烷基,
A是可以被1-5个F和/或Cl原子取代的1-10个碳原子的烷基、是3-7个碳原子的环烷基、5-10个碳原子的亚烷基环烷或2-8个碳原子的链烯基,
A′是1、2、3、4、5或6个碳原子的烷基,
n是1、2、3或4,
卤素 是F、Cl、Br或I;
h)在EP0723962中公开的通式I化合物和它们的生理可接受的盐和溶剂化物
其中
R1和R2各自独立地是H或A,
R3和R4各自独立地是-OH、-OR10、-S-R10、-SO-R10、-SO2-R10、卤素、亚甲基二氧基、-NO2、-NH2、-NHR10或-NR10R11,
R5是未取代的或被R6和/或R7单-或二取代的苯基,
Q不存在或是1-6个碳原子的亚烷基,
R6和R7各自独立地是NH2、NR8R9、NHR10、-NR10R11、-NO2、卤素、-CN、-OA、-COOH或-COOA,
R8和R9各自独立地是H、被1-5个F和/或Cl原子取代的1-8个碳原子的酰基、-COOA、-S-A、-SO-A、SO2-A、-CONH2、-CONHA、-CONA2、-CO-COOH、-CO-COOA、-CO-CONH2、-CO-CONHA或-CO-CONA2,
A是被1-5个F和/或Cl原子取代的1-6个碳原子的烷基,
R10和R11各自独立地是A、3-7个碳原子的环烷基、4-8个碳原子的亚甲基环烷基或2-8个碳原子的链烯基,和
卤素是F、Cl、Br或I;
i)在EP0738715中公开的通式I化合物和它们的生理可接受的盐和溶剂化物
R1,R2各自独立地是H或A,
R3,R4各自独立地是-OH、-OR10、-S-R10、-SO-R10、-SO2-R10、卤素、亚甲基二氧基、-NO2、-NH2、-NHR10或-NR10R11,
R5是未取代的或被R6和/或R7单-或二取代的苯基,
Q不存在或是1-6个碳原子的亚烷基,
R6和R7各自独立地是-NH2、-NR8R9、-NHR10、-NR10R11、-NO2、卤素、-CN、-OA、-COOH或-COOA,
R8和R9各自独立地是H、可被1-5个F和/或Cl原子取代的1-8个碳原子的酰基、-COOA、-SO-A、SO2-A、-CONH2、-CONHA、-CONA2、-CO-COOH、-CO-COOA、-CO-CONH2、-CO-CONHA或-CO-CONA2,
A是被1-5个F和/或Cl原子取代的1-6个碳原子的烷基,
R10和R11各自独立地是A、3-7个碳原子的环烷基、4-8个碳原子的亚甲基环烷基或2-8个碳原子的链烯基,和
卤素是F、Cl、Br或I。
2.权利要求1的化合物在制备治疗心肌疾病的药物中的用途,其中的化合物是:
a)EP0763534中公开的化合物和它们的立体异构体和生理可接受的盐和溶剂化物:
2-(3-烟酰基氨基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(2-烟酰基氨基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(3-烟酰基氨基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(2-烟酰基氨基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3-甲氧基-4-三氟甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3-甲氧基-4-二氟甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3-甲氧基-4-氟甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3-二氟甲氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3-三氟甲氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3-氟甲氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3-甲氧基-4-乙氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3-羟基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(4-甲磺酰基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(4-亚甲基氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(3-烟酰基氨基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苯乙基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苯乙基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
3-(4-烟酰基氨基苄基)-5-(3,4-二甲氧基苯基)-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(3-烟酰基氨基苄基)-5-(3,4-二甲氧基苯基)-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(2-烟酰基氨基苄基)-5-(3,4-二甲氧基苯基)-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3,4-二甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(3-烟酰基氨基苄基)-5-(3,4-二甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(2-烟酰基氨基苄基)-5-(3,4-二甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-甲氧基-4-三氟甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-甲氧基-4-二氟甲氧基苯基)-6-乙基-3,6-
二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-甲氧基-4-氟甲氧基苯基)-6-乙基-3,6-
二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-二氟甲氧基-4-甲氧基苯基)-6-乙基-3,6-
二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-三氟甲氧基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-氟甲氧基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-甲氧基-4-乙氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-乙氧基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-乙氧基-4-甲氧基苯基)-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-羟基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(4-甲磺酰苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(4-亚甲基氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-环戊基氧基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(3-烟酰基氨基苄基)-5-(3-环戊基氧基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苯乙基)-5-(3,4-二甲氧基苯基)-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苯乙基)-5-(3,4-二甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3,4-二甲氧基苯基)-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(3-烟酰基氨基苄基)-5-(3,4-二甲氧基苯基)-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(2-烟酰基氨基苄基)-5-(3,4-二甲氧基苯基)-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3,4-二甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(3-烟酰基氨基苄基)-5-(3,4-二甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(2-烟酰基氨基苄基)-5-(3,4-二甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-甲氧基-4-三氟甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-甲氧基-4-二氟甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-甲氧基-4-氟甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-二氟甲氧基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-三氟甲氧基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-氟甲氧基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-甲氧基-4-乙氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-乙氧基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-羟基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(4-甲磺酰基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(4-亚甲基氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苄基)-5-(3-环戊基氧基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(3-烟酰基氨基苄基)-5-(3-环戊基氧基-4-甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苯乙基)-5-(3,4-二甲氧基苯基)-3,6-二氢-1,3,4-噁二嗪-2-酮,
3-(4-烟酰基氨基苯乙基)-5-(3,4-二甲氧基苯基)-6-乙基-3,6-二氢-1,3,4-噁二嗪-2-酮,
2-(3-烟酰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-异烟酰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-吡嗪羰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-(异噁唑-5-羰基氨基)苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-烟酰基氨基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,盐酸盐;
b)WO99/65880中公开的化合物和其生理可接受的盐和溶剂化物:
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-4-甲氧基苯甲酰基-3-甲酰胺,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-4-甲基苯甲酰基-3-甲酰胺,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)苯甲酰基-3-甲酰胺,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-3,4-二氯苯甲酰基-3-甲酰胺,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-4-三氟甲基苯甲酰基-3-甲酰胺,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-3-氯苯甲酰基-3-甲酰胺,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-4-氟苯甲酰基-3-甲酰胺,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-4-丁氧基苯甲酰基-3-甲酰胺,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-4-戊氧基苯甲酰基-3-甲酰胺,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-4-乙氧基苯甲酰基-3-甲酰胺,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-3,4-二甲氧基苯甲酰基-3-甲酰胺,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-3-甲基苯甲酰基-3-甲酰胺,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-3-甲氧基苯甲酰基-3-甲酰胺;
c)在WO 00/26201中公开的化合物和其生理可接受的盐和溶剂化物:
3-二甲基氨基丙基{4-[3-(3-乙氧基-4-甲氧基苯基)-1,2,3,4-四氢哒嗪-1-基羰基]苯基}氨基甲酸酯,
N-甲基哌啶-4-基{4-[3-(3-乙氧基-4-甲氧基苯基)-1,2,3,4-四氢哒嗪-1-基羰基]苯基}氨基甲酸酯,
3-二甲基氨基丙基{4-[3-(3-异丙氧基-4-甲氧基苯基)-1,2,3,4-四氢哒嗪-1-基羰基]苯基}氨基甲酸酯,
3-二甲基氨基丙基{3-[3-(3-乙氧基-4-甲氧基苯基)-1,2,3,4-四氢哒嗪-1-基羰基]苯基}氨基甲酸酯,
3-二甲基氨基丙基{3-[3-(3-环戊基氧基-4-甲氧基苯基)-1,2,3,4-四氢哒嗪-1-基羰基]苯基}氨基甲酸酯,
N-甲基哌啶-4-基{3-[3-(3-环戊基氧基-4-甲氧基苯基)-1,2,3,4-四氢哒嗪-1-基羰基]苯基}氨基甲酸酯,
3-二甲基氨基丙基{3-[3-(3-丙氧基-4-甲氧基苯基)-1,2,3,4-四氢哒嗪-1-基羰基]苯基}氨基甲酸酯,
3-二甲基氨基丙基{4-[3-(3,4-二乙氧基苯基)-1,2,3,4-四氢哒嗪-1-基羰基]苯基}氨基甲酸酯,
N-甲基哌啶-4-基{4-[3-(3,4-二乙氧基苯基)-1,2,3,4-四氢哒嗪-1-基羰基]苯基}氨基甲酸酯,
3-二甲基氨基丙基{3-[3-(3,4-二甲氧基苯基)-1,2,3,4-四氢哒嗪-1-基羰基]苯基}氨基甲酸酯,
3-二甲基氨基丙基{4-[3-(3,4-二甲氧基苯基)-1,2,3,4-四氢哒嗪-1-基羰基]苯基}氨基甲酸酯;
d)在WO 98/06704中公开的化合物和其立体异构体及生理可接受的盐和溶剂化物:
1-(4-烟酰基氨基苯甲酰基)-3-(3,4-二甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(3-烟酰基氨基苯甲酰基)-3-(3,4-二甲氧基苯基)-1,4,5,6-四氢哒嗪盐酸盐,
1-(2-烟酰基氨基苯甲酰基)-3-(3,4-二甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-烟酰基氨基苯甲酰基)-3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(3-烟酰基氨基苯甲酰基)-3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-烟酰基氨基苯甲酰基)-3-(3-环戊基氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(3-烟酰基氨基苯甲酰基)-3-(3-环戊基氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-烟酰基氨基苯甲酰基)-3-(3,4-亚甲基-二氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-烟酰基氨基苯甲酰基)-3-(3-甲氧基-4-甲磺酰基苯基)-1,4,5,6-四氢哒嗪,
1-(4-烟酰基氨基苯甲酰基)-3-(3-三氟-甲氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-乙氧基-羰基氨基苯甲酰基)-3-(3,4-二甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(3-乙氧基羰基氨基苯甲酰基)-3-(3,4-二甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(2-乙氧基羰基氨基苯甲酰基)-3-(3,4-二甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-乙氧基羰基氨基苯甲酰基)-3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(3-乙氧基羰基氨基苯甲酰基)-3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-乙氧基羰基氨基苯甲酰基)-3-(3-环戊基氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(3-乙氧基羰基氨基苯甲酰基)-3-(3-环戊基氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-乙氧基羰基氨基苯甲酰基)-3-(3,4-亚甲基-二氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-乙氧基羰基氨基苯甲酰基)-3-(3-甲氧基-4-甲磺酰基苯基)-1,4,5,6-四氢哒嗪,
1-(4-乙氧基羰基氨基苯甲酰基)-3-(3-三氟甲氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪;
e)在EP0723962中公开的化合物和其生理可接受的盐和溶剂化物:
3-(4-乙氧基羰基氨基苄基)-5-(3-乙氧基-4-甲氧基苯基)-3,6-二氢-1,3,4-噻二嗪-2-酮,
3-(4-乙氧基羰基氨基苄基)-5-(3-环戊基氧基-4-甲氧基苯基)-3,6-二氢-1,3,4-噻二嗪-2-酮;
f)在EP0738715中公开的化合物和其生理可接受的盐和溶剂化物:
2-(4-丁酰胺基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-乙酰胺基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-三氟乙酰胺基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲磺酰胺基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-丙酰基氨基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-叔丁基羰基氨基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-异丁酰基氨基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲氧基羰基氨基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-新戊酰基氨基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-环戊基氨基甲酰基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-乙氧基羰基氨基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲草酰氨基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-脲基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-戊酰基氨基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-己酰氨基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-五氟丙酰胺基苄基)-6-(3,4-二甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-乙酰胺基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-三氟乙酰胺基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲磺酰胺基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-丙酰胺基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-叔丁基羰基氨基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-丁酰氨基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-异丁酰基氨基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲氧基羰基氨基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-新戊酰基氨基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-环戊基氨基甲酰基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-乙氧基羰基氨基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲草酰氨基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-脲基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-戊酰基氨基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-己酰氨基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-五氟丙酰胺基苄基)-6-(3,4-二甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-乙酰胺基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-三氟乙酰胺基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲磺酰胺基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-丙酰胺基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-丁酰氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-异丁酰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲氧基羰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-新戊酰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-环戊基氨基甲酰基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-乙氧基羰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲草酰氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-脲基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-戊酰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-己酰氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-五氟丙酰胺基苄基)-6-(3-乙氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-乙酰胺基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-三氟乙酰胺基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲磺酰胺基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-丙酰胺基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-叔丁基羰基氨基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-丁酰氨基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-异丁酰基氨基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲氧基羰基氨基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-新戊酰基氨基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-环戊基氨基甲酰基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-乙氧基羰基氨基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲草酰氨基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-脲基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-戊酰基氨基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-己酰氨基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-五氟丙酰胺基苄基)-6-(3-环戊基氧基-4-甲氧基苯基)-5-乙基-2,3,4,5-四氢哒嗪-3-酮,
2-(4-乙酰胺基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-三氟乙酰胺基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲磺酰胺基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-丙酰胺基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-丁酰氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-异丁酰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲氧基羰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-新戊酰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-环戊基氨基甲酰基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-乙氧基羰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-甲草酰氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-脲基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-戊酰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-己酰氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮,
2-(4-五氟丙酰胺基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢哒嗪-3-酮。
3.按权利要求1或2的用途,其中的化合物选自以下化合物和其生理可接受的盐和溶剂化物
3-(4-烟酰基氨基苄基)-5-(3-乙氧基-4-甲氧基苯基)--3,6-二氢-1,3,4-噻二嗪-2-酮,
N-(3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪-1-基羰基)苯基)-4-甲氧基苯甲酰基-3-甲酰胺,
1-(4-烟酰基氨基苯甲酰基)-3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
1-(4-乙氧基羰基氨基苯甲酰基)-3-(3-乙氧基-4-甲氧基苯基)-1,4,5,6-四氢哒嗪,
2-(4-乙氧基羰基氨基苄基)-6-(3-乙氧基-4-甲氧基苯基)-2,3,4,5-四氢-哒嗪-3-酮。
4.按权利要求1、2或3的用途,其中所说的心肌疾病显示炎性和免疫特征。
5.按权利要求1、2或3的用途其中所说的心肌疾病是冠状动脉疾病、可逆或不可逆心肌局部缺血/再灌注损伤、急性或慢性心力衰竭和再狭窄,包括支架再狭窄和支架内支架再狭窄。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP01102811 | 2001-02-12 | ||
EP01102811.5 | 2001-02-12 | ||
EP01119875.1 | 2001-08-17 | ||
EP01119875 | 2001-08-17 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1491112A true CN1491112A (zh) | 2004-04-21 |
CN1235589C CN1235589C (zh) | 2006-01-11 |
Family
ID=26076468
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB028048776A Expired - Fee Related CN1235589C (zh) | 2001-02-12 | 2002-01-15 | 4型磷酸二酯酶抑制剂在制备治疗心肌疾病药物中的应用 |
Country Status (9)
Country | Link |
---|---|
US (1) | US20050070529A1 (zh) |
EP (1) | EP1368035A1 (zh) |
JP (1) | JP2004521928A (zh) |
KR (1) | KR20040012720A (zh) |
CN (1) | CN1235589C (zh) |
CA (1) | CA2437932A1 (zh) |
HU (1) | HUP0303181A2 (zh) |
NO (1) | NO20033541D0 (zh) |
WO (1) | WO2002072103A1 (zh) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW200848036A (en) | 2006-12-14 | 2008-12-16 | Astellas Pharma Inc | Novel oxycarbonyl compound |
AU2012382373A1 (en) | 2012-06-12 | 2014-12-11 | Abbvie Inc. | Pyridinone and pyridazinone derivatives |
WO2019025554A1 (en) | 2017-08-04 | 2019-02-07 | Bayer Aktiengesellschaft | 6-PHENYL-4,5-DIHYDROPYRIDAZIN-3 (2H) -ONE DERIVATIVES AS INHIBITORS OF PDE3A AND PDE3B FOR THE TREATMENT OF CANCER |
JOP20200024A1 (ar) * | 2017-08-04 | 2020-02-02 | Bayer Ag | مركبات ثنائي هيدروكساديازينون |
WO2020097442A2 (en) * | 2018-11-08 | 2020-05-14 | Board Of Regents Of The University Of Nebraska | Compositions and methods for the treatment of peripheral artery disease and cardiopulmonary diseases |
CN111840557A (zh) * | 2019-04-28 | 2020-10-30 | 中国医学科学院阜外医院 | 磷酸二酯酶4抑制剂的用途 |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4310699A1 (de) * | 1993-04-01 | 1994-10-06 | Merck Patent Gmbh | Thiadiazinone |
DE19502699A1 (de) * | 1995-01-28 | 1996-08-01 | Merck Patent Gmbh | Arylalkyl-thiadiazinone |
DE19514568A1 (de) * | 1995-04-20 | 1996-10-24 | Merck Patent Gmbh | Arylalkyl-pyridazinone |
DE19533975A1 (de) * | 1995-09-14 | 1997-03-20 | Merck Patent Gmbh | Arylalkyl-diazinone |
DE19604388A1 (de) * | 1996-02-07 | 1997-08-14 | Merck Patent Gmbh | Arylalkyl-diazinone |
GB9604926D0 (en) * | 1996-03-08 | 1996-05-08 | Sandoz Ltd | Organic compounds |
DE19632549A1 (de) * | 1996-08-13 | 1998-02-19 | Merck Patent Gmbh | Arylalkanoylpyridazine |
DE19737436A1 (de) * | 1997-08-21 | 1999-02-25 | Schering Ag | Inhibition der Monozyten-Extravasation |
DE19826841A1 (de) * | 1998-06-16 | 1999-12-23 | Merck Patent Gmbh | Arylalkanoylpyridazine |
DE19850701A1 (de) * | 1998-11-04 | 2000-05-11 | Merck Patent Gmbh | Benzoylpyridazine |
DE19915365A1 (de) * | 1999-04-06 | 2000-10-12 | Merck Patent Gmbh | Tetrahydropyridazin-Derivate |
US6180650B1 (en) * | 1999-04-23 | 2001-01-30 | Merck Frosst Canada & Co. | Heterosubstituted pyridine derivatives as PDE 4 inhibitors |
DE19932315A1 (de) * | 1999-07-10 | 2001-01-11 | Merck Patent Gmbh | Benzoylpyridazine |
-
2002
- 2002-01-15 CA CA002437932A patent/CA2437932A1/en not_active Abandoned
- 2002-01-15 EP EP02710008A patent/EP1368035A1/en not_active Withdrawn
- 2002-01-15 JP JP2002571062A patent/JP2004521928A/ja not_active Withdrawn
- 2002-01-15 WO PCT/EP2002/000320 patent/WO2002072103A1/en not_active Application Discontinuation
- 2002-01-15 US US10/467,793 patent/US20050070529A1/en not_active Abandoned
- 2002-01-15 KR KR10-2003-7010432A patent/KR20040012720A/ko not_active Application Discontinuation
- 2002-01-15 HU HU0303181A patent/HUP0303181A2/hu unknown
- 2002-01-15 CN CNB028048776A patent/CN1235589C/zh not_active Expired - Fee Related
-
2003
- 2003-08-11 NO NO20033541A patent/NO20033541D0/no not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
JP2004521928A (ja) | 2004-07-22 |
CA2437932A1 (en) | 2002-09-19 |
CN1235589C (zh) | 2006-01-11 |
NO20033541L (no) | 2003-08-11 |
KR20040012720A (ko) | 2004-02-11 |
EP1368035A1 (en) | 2003-12-10 |
HUP0303181A2 (hu) | 2004-01-28 |
WO2002072103A1 (en) | 2002-09-19 |
NO20033541D0 (no) | 2003-08-11 |
US20050070529A1 (en) | 2005-03-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1184208C (zh) | 取代的苯并咪唑及其制备和用途 | |
CN1198613C (zh) | 氨基苯氧基乙酸衍生物和含有它们的药用组合物 | |
CN1732006A (zh) | 作为p2x7抑制剂、用于治疗炎性疾病的3-(3,5-二氧代-4,5-二氢-3h-(1,2,4)三嗪-2-基)-苯甲酰胺衍生物 | |
CN1310621A (zh) | 取代的n-酰苯胺化合物和方法 | |
CN1906190A (zh) | 选择性激酶抑制剂 | |
CN1515248A (zh) | 用作肌苷-5'-一磷酸脱氢酶抑制剂的脲衍生物 | |
CN1376156A (zh) | 苯并二氮杂䓬衍生物、其制备和用途 | |
CN1646531A (zh) | 作为髓过氧化物酶抑制剂的硫代黄嘌呤衍生物 | |
CN1015054B (zh) | N-吲哚基乙基-磺酰胺类的制备方法 | |
CN1071427A (zh) | 6-苯并嗪基和6-苯并噻嗪基-2,3,4,5-四氢哒嗪-3-酮 | |
CN1585636A (zh) | 内皮素受体拮抗剂用于治疗肿瘤性疾病的用途 | |
CN1235589C (zh) | 4型磷酸二酯酶抑制剂在制备治疗心肌疾病药物中的应用 | |
CN1169797C (zh) | 抗病毒的嘧啶二酮衍生物及其制备方法 | |
CN1277820C (zh) | 作为单胺氧化酶b的抑制剂的邻苯二甲酰亚氨基衍生物 | |
CN1510034A (zh) | 新型吲唑化合物,其制备方法及含有它们的药物组合物 | |
CN1147477C (zh) | 新的烯丙硫基哒嗪衍生物及其制备方法 | |
CN1254334A (zh) | 新颖的对苯二甲酰胺衍生物 | |
CN1191241C (zh) | 用于抗充血性心力衰竭的哒嗪基苯基腙 | |
CN1564687A (zh) | 磷酸二酯酶iv抑制剂的用途 | |
CN1060769C (zh) | 1,4-苯并嗪衍生物,含该化合物的药物组合物及其用途 | |
CN1148351C (zh) | 用于治疗脉管并发症的化合物,其制备方法及治疗应用 | |
CN1531529A (zh) | 用于治疗心脏病和过敏症、具有抑制pde iv作用和 t n f拮抗作用的4-(亚苄基氨基)-3-(甲基硫基)-4h-1,2,4-三嗪-5-酮衍生物 | |
CN1747930A (zh) | 具有脯氨酰基寡肽酶抑制活性的化合物 | |
CN1732160A (zh) | 1,2,4-三唑衍生物、其制备方法和含有所述化合物的药物组合物 | |
CN1622945A (zh) | 噻唑烷二酮衍生物以及包含该衍生物的药物组合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C19 | Lapse of patent right due to non-payment of the annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |