CN101384257A - 药物组合 - Google Patents
药物组合 Download PDFInfo
- Publication number
- CN101384257A CN101384257A CNA2007800053030A CN200780005303A CN101384257A CN 101384257 A CN101384257 A CN 101384257A CN A2007800053030 A CNA2007800053030 A CN A2007800053030A CN 200780005303 A CN200780005303 A CN 200780005303A CN 101384257 A CN101384257 A CN 101384257A
- Authority
- CN
- China
- Prior art keywords
- glyoxalidine
- thioketone
- ethyl
- amino
- benzodihydropyran
- 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.)
- Pending
Links
- 239000000890 drug combination Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- 239000002934 diuretic Substances 0.000 claims abstract description 12
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- 150000002367 halogens Chemical class 0.000 claims abstract description 12
- 239000003112 inhibitor Substances 0.000 claims abstract description 12
- -1 hydroxy, nitro, amino Chemical group 0.000 claims abstract description 11
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 230000009977 dual effect Effects 0.000 claims abstract description 8
- 239000000674 adrenergic antagonist Substances 0.000 claims abstract description 7
- 230000003288 anthiarrhythmic effect Effects 0.000 claims abstract description 7
- 239000003416 antiarrhythmic agent Substances 0.000 claims abstract description 7
- 239000002876 beta blocker Substances 0.000 claims abstract description 7
- 239000005541 ACE inhibitor Substances 0.000 claims abstract description 6
- 229940127291 Calcium channel antagonist Drugs 0.000 claims abstract description 6
- 239000000048 adrenergic agonist Substances 0.000 claims abstract description 6
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims abstract description 6
- 239000003420 antiserotonin agent Substances 0.000 claims abstract description 6
- 125000003118 aryl group Chemical group 0.000 claims abstract description 6
- 239000000480 calcium channel blocker Substances 0.000 claims abstract description 6
- 229940097217 cardiac glycoside Drugs 0.000 claims abstract description 6
- 239000002368 cardiac glycoside Substances 0.000 claims abstract description 6
- 150000002632 lipids Chemical class 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims abstract description 6
- 239000002571 phosphodiesterase inhibitor Substances 0.000 claims abstract description 6
- 239000002461 renin inhibitor Substances 0.000 claims abstract description 6
- 229940086526 renin-inhibitors Drugs 0.000 claims abstract description 6
- 229930002534 steroid glycoside Natural products 0.000 claims abstract description 6
- 229940124549 vasodilator Drugs 0.000 claims abstract description 6
- 239000003071 vasodilator agent Substances 0.000 claims abstract description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000002877 alkyl aryl group Chemical group 0.000 claims abstract description 5
- 239000000460 chlorine Substances 0.000 claims abstract description 5
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 5
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 5
- 239000004036 potassium channel stimulating agent Substances 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 3
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims abstract description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 3
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 3
- 239000011737 fluorine Substances 0.000 claims abstract description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract description 3
- 239000011630 iodine Substances 0.000 claims abstract description 3
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 3
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 3
- 150000002823 nitrates Chemical class 0.000 claims abstract description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 229960005486 vaccine Drugs 0.000 claims abstract description 3
- 239000002792 enkephalinase inhibitor Substances 0.000 claims abstract 2
- 239000003814 drug Substances 0.000 claims description 25
- 238000011282 treatment Methods 0.000 claims description 21
- 229940079593 drug Drugs 0.000 claims description 14
- VYFYYTLLBUKUHU-UHFFFAOYSA-N Dopamine Natural products NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims description 12
- 229940097420 Diuretic Drugs 0.000 claims description 11
- 230000001882 diuretic effect Effects 0.000 claims description 11
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 9
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 claims description 8
- 206010020772 Hypertension Diseases 0.000 claims description 7
- 210000003169 central nervous system Anatomy 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 229960003638 dopamine Drugs 0.000 claims description 7
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 claims description 6
- 239000003451 thiazide diuretic agent Substances 0.000 claims description 6
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 claims description 5
- 229940121792 Thiazide diuretic Drugs 0.000 claims description 5
- 239000000951 adrenergic alpha-1 receptor antagonist Substances 0.000 claims description 5
- 239000002333 angiotensin II receptor antagonist Substances 0.000 claims description 5
- 239000000400 angiotensin II type 1 receptor blocker Substances 0.000 claims description 5
- 229960000648 digitoxin Drugs 0.000 claims description 5
- WDJUZGPOPHTGOT-XUDUSOBPSA-N digitoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)CC5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O WDJUZGPOPHTGOT-XUDUSOBPSA-N 0.000 claims description 5
- 239000002308 endothelin receptor antagonist Substances 0.000 claims description 5
- LPMXVESGRSUGHW-HBYQJFLCSA-N ouabain Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C[C@@]2(O)CC[C@H]3[C@@]4(O)CC[C@H](C=5COC(=O)C=5)[C@@]4(C)C[C@@H](O)[C@@H]3[C@@]2(CO)[C@H](O)C1 LPMXVESGRSUGHW-HBYQJFLCSA-N 0.000 claims description 5
- 206010007558 Cardiac failure chronic Diseases 0.000 claims description 4
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 claims description 4
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 claims description 4
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 229940063699 lanoxin Drugs 0.000 claims description 4
- 229960002237 metoprolol Drugs 0.000 claims description 4
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 claims description 4
- 229960002748 norepinephrine Drugs 0.000 claims description 4
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 claims description 4
- 229960003712 propranolol Drugs 0.000 claims description 4
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 claims description 4
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 claims description 4
- CESYKOGBSMNBPD-UHFFFAOYSA-N Methyclothiazide Chemical compound ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)N(C)C(CCl)NC2=C1 CESYKOGBSMNBPD-UHFFFAOYSA-N 0.000 claims description 3
- 229910002651 NO3 Inorganic materials 0.000 claims description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 3
- 229940122767 Potassium sparing diuretic Drugs 0.000 claims description 3
- 239000002170 aldosterone antagonist Substances 0.000 claims description 3
- 229940083712 aldosterone antagonist Drugs 0.000 claims description 3
- 230000006793 arrhythmia Effects 0.000 claims description 3
- 229940060038 chlorine Drugs 0.000 claims description 3
- 229940125753 fibrate Drugs 0.000 claims description 3
- 239000002171 loop diuretic Substances 0.000 claims description 3
- 229960003739 methyclothiazide Drugs 0.000 claims description 3
- 229960002817 metolazone Drugs 0.000 claims description 3
- AQCHWTWZEMGIFD-UHFFFAOYSA-N metolazone Chemical compound CC1NC2=CC(Cl)=C(S(N)(=O)=O)C=C2C(=O)N1C1=CC=CC=C1C AQCHWTWZEMGIFD-UHFFFAOYSA-N 0.000 claims description 3
- 239000003286 potassium sparing diuretic agent Substances 0.000 claims description 3
- 229940097241 potassium-sparing diuretic Drugs 0.000 claims description 3
- 229960002578 sitaxentan Drugs 0.000 claims description 3
- PHWXUGHIIBDVKD-UHFFFAOYSA-N sitaxentan Chemical compound CC1=NOC(NS(=O)(=O)C2=C(SC=C2)C(=O)CC=2C(=CC=3OCOC=3C=2)C)=C1Cl PHWXUGHIIBDVKD-UHFFFAOYSA-N 0.000 claims description 3
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 claims description 2
- HMJIYCCIJYRONP-UHFFFAOYSA-N (+-)-Isradipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC2=NON=C12 HMJIYCCIJYRONP-UHFFFAOYSA-N 0.000 claims description 2
- VLPIATFUUWWMKC-SNVBAGLBSA-N (2r)-1-(2,6-dimethylphenoxy)propan-2-amine Chemical compound C[C@@H](N)COC1=C(C)C=CC=C1C VLPIATFUUWWMKC-SNVBAGLBSA-N 0.000 claims description 2
- BUJAGSGYPOAWEI-SECBINFHSA-N (2r)-2-amino-n-(2,6-dimethylphenyl)propanamide Chemical compound C[C@@H](N)C(=O)NC1=C(C)C=CC=C1C BUJAGSGYPOAWEI-SECBINFHSA-N 0.000 claims description 2
- LPUDGHQMOAHMMF-JBACZVJFSA-N (2s)-2-[[[(2s)-6-amino-2-(methanesulfonamido)hexanoyl]amino]methyl]-3-[1-[[(1s)-1-carboxy-2-(4-hydroxyphenyl)ethyl]carbamoyl]cyclopentyl]propanoic acid Chemical compound N([C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C(=O)C1(C[C@@H](CNC(=O)[C@H](CCCCN)NS(=O)(=O)C)C(O)=O)CCCC1 LPUDGHQMOAHMMF-JBACZVJFSA-N 0.000 claims description 2
- YKFCISHFRZHKHY-NGQGLHOPSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid;trihydrate Chemical compound O.O.O.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 YKFCISHFRZHKHY-NGQGLHOPSA-N 0.000 claims description 2
- YFDSDRDMDDGDFC-HOQQKOLYSA-N (2s)-2-benzyl-n-[(2s)-1-[[(2s,3r,4s)-1-cyclohexyl-3,4-dihydroxy-6-methylheptan-2-yl]amino]-1-oxo-3-(1,3-thiazol-4-yl)propan-2-yl]-3-(4-methylpiperazin-1-yl)sulfonylpropanamide Chemical compound C([C@@H]([C@@H](O)[C@@H](O)CC(C)C)NC(=O)[C@H](CC=1N=CSC=1)NC(=O)[C@H](CC=1C=CC=CC=1)CS(=O)(=O)N1CCN(C)CC1)C1CCCCC1 YFDSDRDMDDGDFC-HOQQKOLYSA-N 0.000 claims description 2
- PODHJNNUGIBMOP-HOQQKOLYSA-N (2s)-2-benzyl-n-[(2s)-1-[[(2s,3r,4s)-1-cyclohexyl-4-cyclopropyl-3,4-dihydroxybutan-2-yl]amino]-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]-3-(2-methyl-1-morpholin-4-yl-1-oxopropan-2-yl)sulfonylpropanamide Chemical compound C([C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1)S(=O)(=O)C(C)(C)C(=O)N1CCOCC1 PODHJNNUGIBMOP-HOQQKOLYSA-N 0.000 claims description 2
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 claims description 2
- BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C(O)=O)CCCC1=CC=CC=C1 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 claims description 2
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 claims description 2
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 claims description 2
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 claims description 2
- KOHIRBRYDXPAMZ-YHBROIRLSA-N (S,R,R,R)-nebivolol Chemical compound C1CC2=CC(F)=CC=C2O[C@H]1[C@H](O)CNC[C@@H](O)[C@H]1OC2=CC=C(F)C=C2CC1 KOHIRBRYDXPAMZ-YHBROIRLSA-N 0.000 claims description 2
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 claims description 2
- SGUAFYQXFOLMHL-UHFFFAOYSA-N 2-hydroxy-5-{1-hydroxy-2-[(4-phenylbutan-2-yl)amino]ethyl}benzamide Chemical compound C=1C=C(O)C(C(N)=O)=CC=1C(O)CNC(C)CCC1=CC=CC=C1 SGUAFYQXFOLMHL-UHFFFAOYSA-N 0.000 claims description 2
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 claims description 2
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 claims description 2
- UXOWGYHJODZGMF-QORCZRPOSA-N Aliskiren Chemical compound COCCCOC1=CC(C[C@@H](C[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)C(C)C)=CC=C1OC UXOWGYHJODZGMF-QORCZRPOSA-N 0.000 claims description 2
- ITPDYQOUSLNIHG-UHFFFAOYSA-N Amiodarone hydrochloride Chemical compound [Cl-].CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCC[NH+](CC)CC)C(I)=C1 ITPDYQOUSLNIHG-UHFFFAOYSA-N 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- 206010002383 Angina Pectoris Diseases 0.000 claims description 2
- 208000019901 Anxiety disease Diseases 0.000 claims description 2
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims description 2
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims description 2
- MREBEPTUUMTTIA-PCLIKHOPSA-N Azimilide Chemical compound C1CN(C)CCN1CCCCN1C(=O)N(\N=C\C=2OC(=CC=2)C=2C=CC(Cl)=CC=2)CC1=O MREBEPTUUMTTIA-PCLIKHOPSA-N 0.000 claims description 2
- XPCFTKFZXHTYIP-PMACEKPBSA-N Benazepril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 XPCFTKFZXHTYIP-PMACEKPBSA-N 0.000 claims description 2
- 239000002083 C09CA01 - Losartan Substances 0.000 claims description 2
- 239000002080 C09CA02 - Eprosartan Substances 0.000 claims description 2
- 239000004072 C09CA03 - Valsartan Substances 0.000 claims description 2
- 239000002947 C09CA04 - Irbesartan Substances 0.000 claims description 2
- 239000002053 C09CA06 - Candesartan Substances 0.000 claims description 2
- 239000005537 C09CA07 - Telmisartan Substances 0.000 claims description 2
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 claims description 2
- 229920001268 Cholestyramine Polymers 0.000 claims description 2
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 claims description 2
- 229920002911 Colestipol Polymers 0.000 claims description 2
- WDJUZGPOPHTGOT-OAXVISGBSA-N Digitoxin Natural products O([C@H]1[C@@H](C)O[C@@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@@](C)([C@H](C6=CC(=O)OC6)CC5)CC4)CC3)CC2)C[C@H]1O)[C@H]1O[C@@H](C)[C@H](O[C@H]2O[C@@H](C)[C@@H](O)[C@@H](O)C2)[C@@H](O)C1 WDJUZGPOPHTGOT-OAXVISGBSA-N 0.000 claims description 2
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Abstract
本发明涉及包含至少两种成分的组合，所述成分选自：(i)式I的化合物及其单独的(R－)和(S－)对映异构体或对映异构体的混合物和药学可接受的盐：R其中R1、R2和R3相同或不同并且表示氢、卤素、烷基、烷氧基、羟基、硝基、氨基、烷基羰基氨基、烷基氨基或二烷基氨基；R4表示氢、烷基或烷基芳基；X表示CH2、氧原子或硫原子；n是1、2或3，条件是当n为1时，X不是CH2；其中术语烷基意指任选地被芳基、烷氧基、卤素、烷氧羰基或羟基羰基取代的含有1－ 6个碳原子的直链或支链烃链；术语芳基意指任选地被烷氧基、卤素或硝基取代的苯基或萘基；术语卤素意指氟、氯、溴或碘；和(ii)至少一种选自以下几类化合物的化合物：利尿剂、β－肾上腺素能拮抗剂、α2－肾上腺素能激动剂、α1－肾上腺素能拮抗剂、双重β－和α－肾上腺素能拮抗剂、钙通道阻滞剂、钾通道激活剂、抗心律失常药、ACE抑制剂、ATI受体拮抗剂、肾素抑制剂、降脂药、血管肽酶抑制剂、硝酸盐、内皮缩血管肽拮抗剂、中性内肽酶抑制剂、抗血管紧张素疫苗、血管扩张药、磷酸二酯酶抑制剂、强心苷、5－羟色胺拮抗剂和中枢神经系统作用药。
Description
本发明涉及药物组合，更具体而言心血管药物组合。
化合物1((R)-5-(2-氨基乙基)-1-(6，8-二氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐)是新的化学实体，它融合了一系列多巴胺β-羟化酶(DBH)的有效抑制剂，所述抑制剂被设计并合成引入了对奈匹司他(nepicastat)核心结构的修饰。目的是提供对脑中多巴胺(DA)和去甲肾上腺素(NA)水平影响最小的新的DBH抑制剂。化合物1事实上是有效的外周选择性DBH抑制剂。在小鼠和大鼠中的试验中，在Tmax(给药后9小时)时，化合物1以剂量依赖性方式降低左心房和左心室中的NA水平，且最大抑制效应在100mg/kg的剂量下获得。与在心脏中发现的相反，化合物1不能影响脑中的NA和DA组织水平。因此化合物1作为临床评价治疗慢性心力衰竭和高血压的候选药物而被提出。化合物1与一系列相关化合物一起在WO 2004/033447中得到了描述。
使用DBH抑制剂的基本原理是基于它们抑制经多巴胺(DA)的酶促羟基化实现的去甲肾上腺素(NA)的生物合成的能力。神经体液系统，主要是交感神经系统的活化，是高血压和充血性心力衰竭的主要临床表现。高血压个体和充血性心力衰竭患者血浆NA浓度升高，中枢交感神经流出增加并且心肾NA溢出增加。心肌长时间过量暴露于NA可能导致心脏α1-肾上腺素受体下调、左心室重塑、心律失常和坏死，所有这些均可削弱心脏的功能完整性。血浆NA浓度高的充血性心力衰竭患者还具有最不利的长期预后。更重要的发现是，血浆NA浓度在没有明显心力衰竭的无症状患者中已经升高，这可被用于预测随后的死亡率和发病率。这意味着活化的交感神经传动不仅仅是高血压和充血性心力衰竭的临床标志，而且可能是两种疾病逐渐恶化的原因。
考虑到高血压和充血性心力衰竭病理生理学机制的复杂性，即交感神经系统活性增加和肾素-血管紧张素-醛固酮系统活性增加，治疗上有意义的是考虑化合物1和以不同水平作用于前述系统的药物的联合给药。由于其独特的作用机制(DBH的选择性外周抑制)，化合物1会加强以不同水平作用于交感神经系统和肾素-血管紧张素-醛固酮系统的药物所发挥的效应。
广泛地说，本发明涉及包含下类式I的化合物及其单独的(R-)和(S-)对映异构体或对映异构体的混合物和药学可接受的盐的药物组合：
其中R1、R2和R3相同或不同并且表示氢、卤素、烷基、烷基芳基、烷氧基、羟基、硝基、氨基、烷基羰基氨基、烷基氨基或二烷基氨基；R4表示氢、烷基或烷基芳基；X表示CH2、氧原子或硫原子；n是1、2或3，条件是当n为1时，X不是CH2；其中术语烷基意指任选地被芳基、烷氧基、卤素、烷氧羰基或羟基羰基取代的含有1-6个碳原子的直链或支链烃链；术语芳基意指任选地被烷氧基、卤素或硝基取代的苯基或萘基；术语卤素意指氟、氯、溴或碘。盐酸盐是优选的。
更具体而言，本发明涉及包含以下具体的式I化合物的药物组合：(S)-5-(2-氨基乙基)-1-(1，2，3，4-四氢萘-2-基)-1，3-二氢咪唑-2-硫酮；(S)-5-(2-氨基乙基)-1-(5，7-二氟-1，2，3，4-四氢萘-2-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(6-羟基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(8-羟基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(6-甲氧基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(8-甲氧基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(6-氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(8-氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(6，7-二氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(6，8-二氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(S)-5-(2-氨基乙基)-1-(6，8-二氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(6，7，8-三氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(6-氯-8-甲氧基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(6-甲氧基-8-氯苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(6-硝基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(8-硝基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-[6-(乙酰氨基)苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-氨基甲基-1-苯并二氢吡喃-3-基-1，3-二氢咪唑-2-硫酮；(R)-5-氨基甲基-1-(6-羟基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(6-羟基-7-苄基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-氨基甲基-1-(6，8-二氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(3-氨基丙基)-1-(6，8-二氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(S)-5-(3-氨基丙基)-1-(5，7-二氟-1，2，3，4-四氢萘-2-基)-1，3-二氢咪唑-2-硫酮；(R，S)-5-(2-氨基乙基)-1-(6-羟基硫代苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R，S)-5-(2-氨基乙基)-1-(6-甲氧基硫代苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-苄氨基乙基)-1-(6-甲氧基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-苄氨基乙基)-1-(6-羟基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-1-(6-羟基苯并二氢吡喃-3-基)-5-(2-甲氨基乙基)-1，3-二氢咪唑-2-硫酮；(R)-1-(6，8-二氟苯并二氢吡喃-3-基)-5-(2-甲氨基乙基)-1，3-二氢咪唑-2-硫酮或(R)-1-苯并二氢吡喃-3-基-5-(2-甲氨基乙基)-1，3-二氢咪唑-2-硫酮；以及所述化合物的药学可接受的盐。
更具体而言，本发明涉及包含以下具体的式I化合物的药物组合：(S)-5-(2-氨基乙基)-1-(1，2，3，4-四氢萘-2-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(S)-5-(2-氨基乙基)-1-(5，7-二氟-1，2，3，4-四氢萘-2-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(6-羟基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(8-羟基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(6-甲氧基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(8-甲氧基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(6-氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(8-氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(6，7-二氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(6，8-二氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(S)-5-(2-氨基乙基)-1-(6，8-二氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(6，7，8-三氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(6-氯-8-甲氧基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(6-甲氧基-8-氯苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(6-硝基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(8-硝基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-[6-(乙酰氨基)苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-氨基甲基-1-苯并二氢吡喃-3-基-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-氨基甲基-1-(6-羟基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(6-羟基-7-苄基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-氨基甲基-1-(6，8-二氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(3-氨基丙基)-1-(6，8-二氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(S)-5-(3-氨基丙基)-1-(5，7-二氟-1，2，3，4-四氢萘-2-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R，S)-5-(2-氨基乙基)-1-(6-羟基硫代苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R，S)-5-(2-氨基乙基)-1-(6-甲氧基硫代苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-苄氨基乙基)-1-(6-甲氧基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-苄氨基乙基)-1-(6-羟基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-1-(6-羟基苯并二氢吡喃-3-基)-5-(2-甲氨基乙基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-1-(6，8-二氟苯并二氢吡喃-3-基)-5-(2-甲氨基乙基)-1，3-二氢咪唑-2-硫酮盐酸盐或(R)-1-苯并二氢吡喃-3-基-5-(2-甲氨基乙基)-1，3-二氢咪唑-2-硫酮盐酸盐。
更具体而言，本发明涉及包含以下具体的式I化合物的药物组合：化合物1((R)-5-(2-氨基乙基)-1-(6，8-二氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐)。化合物1可与选自下述几类的一种或多种化合物一起配制。
具体而言，式I的化合物可与以下几类化合物中的一种或多种组合：利尿剂、β-肾上腺素能拮抗剂、α2-肾上腺素能激动剂、α1-肾上腺素能拮抗剂、双重(dual)β-和α-肾上腺素能拮抗剂、钙通道阻滞剂、钾通道激活剂、抗心律失常药、ACE抑制剂、AT1受体拮抗剂、肾素抑制剂、降脂药(lipidlowerer)、血管肽酶抑制剂、硝酸酯(nitrates)、内皮缩血管肽拮抗剂、中枢肽链内切酶抑制剂、抗血管紧张素疫苗、血管舒张药、磷酸二酯酶抑制剂、强心苷、5-羟色胺拮抗剂和中枢神经系统作用药(CNS acting agent)。
最有用的利尿剂包括：
(1)袢利尿剂，具体而言，呋塞米、布美他尼、依他尼酸、托拉塞米、阿佐塞米、莫唑胺、吡咯他尼、曲帕胺。
(2)噻嗪类利尿剂，具体而言，苄氟噻唑(bendroflumethiazole)、氯噻嗪、氢氯噻嗪、氢氟噻嗪、甲氯噻嗪(methylclothiazide)、泊利噻嗪、三氯噻嗪。
(3)类似噻嗪类(thiazide-like)利尿剂，具体而言，氯噻酮、吲达帕胺、美托拉宗(metozalone)、喹乙宗。
(4)保钾利尿剂，具体而言，阿米洛利、氨苯蝶啶。
(5)醛固酮拮抗剂，具体而言，螺内酯、坎利酮、依普利酮。
(6)上述利尿剂的组合。
可以使用多于一种的上述利尿剂。
最有用的β-肾上腺素能拮抗剂包括：噻吗咯尔、美托洛尔、阿替洛尔、普萘洛尔、比索洛尔、奈必洛尔。可以使用多于一种的上述β-肾上腺素能拮抗剂。
最有用的α2-肾上腺素能激动剂包括：可乐定、胍那苄、胍法辛。可以使用多于一种的上述α2-肾上腺素能激动剂。
最有用的α1-肾上腺素能拮抗剂包括：哌唑嗪、多沙唑嗪、酚妥拉明。可以使用多于一种的上述α1-肾上腺素能拮抗剂。
最有用的双重β-和α-肾上腺素能拮抗剂包括：卡维地洛、拉贝洛尔。可以使用多于一种的上述双重β-和α-肾上腺素能拮抗剂。替代上面刚刚列出的化合物或者除上面刚刚列出的化合物之外，本申请中其它地方提到的化合物中的一些也可用作双重β-和α-肾上腺素能拮抗剂。
钾通道激活剂包括尼可地尔。
最有用的钙通道阻滞剂包括：氨氯地平、苄普地尔、地尔硫卓、非洛地平、伊拉地平、尼卡地平、硝苯地平、尼莫地平、尼索地平、维拉帕米。可以使用多于一种的上述钙通道阻滞剂。
抗心律失常药包括：钠通道阻滞剂如奎尼丁、普鲁卡因胺、丙吡胺、利多卡因、美西律、妥卡尼、苯妥英、恩卡尼、氟卡尼、莫雷西嗪和普罗帕酮；钾通道阻滞剂如：胺碘酮、溴苄胺、伊布利特、多非利特、阿齐利特、氯非铵、替地沙米、司美利特、索他洛尔；和艾司洛尔、普萘洛尔、美托洛尔。可以使用多于一种的本说明书中提到的抗心律失常药。替代上面刚刚列出的化合物或者除上面刚刚列出的化合物之外，本申请中其它地方提到的化合物中的一些也可用作抗心律失常药。
最有用的ACE抑制剂包括：贝那普利(benzepril)、卡托普利、依那普利、福辛普利、赖诺普利、咪达普利、莫昔普利、培哚普利、喹那普利、雷米普利、群多普利。可以使用多于一种的上述ACE抑制剂。
最有用的AT1受体拮抗剂包括：坎地沙坦、厄贝沙坦、氯沙坦、替米沙坦、缬沙坦、依普罗沙坦。可以使用多于一种的上述AT1受体拮抗剂。
降脂药包括：抑制素如阿托伐他汀、西立伐他汀、氟伐他汀、洛伐他汀、美伐他汀、匹伐他汀、普伐他汀、瑞舒伐他汀、辛伐他汀；胆汁酸螯合剂如考来烯胺、考来替泊和烤来维仑；胆固醇吸收抑制剂如依泽替米贝；贝特类药物(fibrates)如非诺贝特、吉非贝齐；烟酸。可以使用多于一种的上述降脂药。
最有用的硝酸酯包括，有机硝酸酯如亚硝酸异戊酯、硝酸甘油、硝酸异山梨酯、5-单硝酸异山梨醇酯、丁四硝酯。可以使用多于一种的上述有机硝酸酯。
内皮缩血管肽拮抗剂包括：波生坦、西他生坦(sitaxsentan)。可以使用多于一种的上述内皮缩血管肽拮抗剂。
最有用的血管扩张药包括：肼苯哒嗪、米诺地尔、硝普钠、二氮嗪。可以使用多于一种的上述血管扩张药。替代上面刚刚列出的化合物或者除上面刚刚列出的化合物之外，本申请中其它地方提到的化合物中的一些也可用作血管扩张药。
最有用的磷酸二酯酶抑制剂包括：米力农、氨力农。可以使用多于一种的上述磷酸二酯酶抑制剂。
强心苷包括：毛花苷丙(allocar)、克拉米丹(corramedan)、洋地黄毒苷、地高辛、拉诺辛、强心素(purgoxin)、西地兰-D、洋地黄毒甙制剂(crystodigin)、地高辛胶囊剂(lanoxicaps)。可以使用多于一种的上述强心苷。
5-羟色胺拮抗剂包括：氯氮平、洛沙平、奥氮平、利培酮、齐拉西酮、利坦色林、酮色林、阿莫沙平。可以使用多于一种的上述5-羟色胺拮抗剂。
中枢神经系统作用药包括咪唑啉激动剂如莫索尼定。最有用的中枢神经系统作用药是甲基多巴。替代上面刚刚列出的化合物或者除上面刚刚列出的化合物之外，本申请中其它地方提到的化合物中的一些也可用作中枢神经系统作用药。
最有用的肾素抑制剂包括：阿利吉仑、依那吉仑、地替吉仑、特拉吉仑、瑞米吉仑、占吉仑、环丙吉仑。可以使用多于一种的上述肾素抑制剂。
最有用的血管肽酶抑制剂包括：奥马曲拉、山帕曲拉、吉莫曲拉(gemopatrilat)。可以使用多于一种的上述血管肽酶抑制剂。
用于治疗心力衰竭的其它药物也可与化合物1组合。它们包括钙增敏剂；HMG CoA还原酶抑制剂；加压素拮抗剂；腺苷A1受体拮抗剂；心房钠尿肽(ANP)激动剂；螯合剂；促肾上腺皮质激素释放因子受体；胰高血糖素样肽-1激动剂；钠、钾ATP酶抑制剂；高级糖基化终产物(AGE)交联裂解剂；混合的肾胰岛素残基溶酶/内皮缩血管肽转化酶(NEP/ECE)抑制剂；孤菲肽受体(ORL-1)激动剂(如阿普唑仑)；黄嘌呤氧化酶抑制剂；苯二氮杂卓激动剂；心肌球蛋白激活剂；糜蛋白酶抑制剂；内皮细胞氮氧化物合酶(ENOS)转录增强子；中枢肽链内切酶抑制剂如硫甲基氧代苯丙甘氨酸。
本发明还设想奈匹司他与上述几类化合物一起使用。
因此，本发明包括式I的化合物与上述附加化合物的组合。所述组合可任选地与至少一种药学可接受的载体配制成药物组合物。药物制剂可采用任何合适的形式，包括口服组合物，如片剂、胶囊剂、散剂和混悬剂。
本发明还涉及治疗疾病的方法，其包括向有此需要的个体给药治疗有效量的上述组合之一的步骤。
可通过使用本发明的组合有效治疗的疾病和病症包括但不限于以下：高血压；心力衰竭如慢性或充血性心力衰竭；咽峡炎；心律失常；循环障碍如雷诺现象；偏头痛和焦虑性障碍。
如本文所用，术语治疗(treatment)及变体如“治疗(treat)”或“治疗(treating)”指的是任何有益于人或非人动物的方案。因此，治疗可以是关于已存在的病症或者可以是预防性的(预防性治疗)。治疗可包括治愈、减轻或预防效应。
根据本发明的另一方面，提供了如上所述的组合在制备用于治疗其中多巴胺羟基化成去甲肾上腺素的减少具有治疗益处的病症的药物中的用途。
根据本发明的另一方面，提供了如上所述的组合在制备用于治疗患有心血管病症的患者的药物中的用途。
根据本发明的另一方面，提供了如上所述的组合在制备用于治疗高血压或慢性心力衰竭的药物中的用途。
根据本发明的另一方面，提供了如上所述的组合在制备用于抑制多巴胺-β-羟化酶的药物中的用途。
本发明还涉及药物包装，其包含如上所述的组合与关于其同时、单独或依次使用的说明书。所述说明书可描述在任何上述治疗中的使用。
会理解，本发明可在权利要求的范围内进行修改。
Claims (39)
1.包含至少两种成分的组合，所述成分选自：
(i)式I的化合物及其单独的(R-)和(S-)对映异构体或对映异构体的混合物和药学可接受的盐：
其中R1、R2和R3相同或不同并且表示氢、卤素、烷基、烷基芳基、烷氧基、羟基、硝基、氨基、烷基羰基氨基、烷基氨基或二烷基氨基；R4表示氢、烷基或烷基芳基；X表示CH2、氧原子或硫原子；n是1、2或3，条件是当n为1时，X不是CH2；其中术语烷基意指任选地被芳基、烷氧基、卤素、烷氧羰基或羟基羰基取代的含有1-6个碳原子的直链或支链烃链；术语芳基意指任选地被烷氧基、卤素或硝基取代的苯基或萘基；术语卤素意指氟、氯、溴或碘；和
(ii)至少一种选自以下几类化合物的化合物：利尿剂、β-肾上腺素能拮抗剂、α2-肾上腺素能激动剂、α1-肾上腺素能拮抗剂、双重β-和α-肾上腺素能拮抗剂、钙通道阻滞剂、钾通道激活剂、抗心律失常药、ACE抑制剂、AT1受体拮抗剂、肾素抑制剂、降脂药、血管肽酶抑制剂、硝酸酯类、内皮缩血管肽拮抗剂、中性内肽酶抑制剂、抗血管紧张素疫苗、血管扩张药、磷酸二酯酶抑制剂、强心苷、5-羟色胺拮抗剂和中枢神经系统作用药；
(iii)任选地，至少一种药学可接受的载体，
其中所述(i)和(ii)的组合被配制以同时、单独或依次使用。
2.根据权利要求1的组合，其中所述式I的化合物是(S)-5-(2-氨基乙基)-1-(1，2，3，4-四氢萘-2-基)-1，3-二氢咪唑-2-硫酮；(S)-5-(2-氨基乙基)-1-(5，7-二氟-1，2，3，4-四氢萘-2-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(6-羟基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(8-羟基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(6-甲氧基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(8-甲氧基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(6-氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(8-氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(6，7-二氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(6，8-二氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(S)-5-(2-氨基乙基)-1-(6，8-二氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(6，7，8-三氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(6-氯-8-甲氧基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(6-甲氧基-8-氯苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(6-硝基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(8-硝基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-[6-(乙酰氨基)苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-氨基甲基-1-苯并二氢吡喃-3-基-1，3-二氢咪唑-2-硫酮；(R)-5-氨基甲基-1-(6-羟基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-氨基乙基)-1-(6-羟基-7-苄基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-氨基甲基-1-(6，8-二氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(3-氨基丙基)-1-(6，8-二氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(S)-5-(3-氨基丙基)-1-(5，7-二氟-1，2，3，4-四氢萘-2-基)-1，3-二氢咪唑-2-硫酮；(R，S)-5-(2-氨基乙基)-1-(6-羟基硫代苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R，S)-5-(2-氨基乙基)-1-(6-甲氧基硫代苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-苄氨基乙基)-1-(6-甲氧基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-5-(2-苄氨基乙基)-1-(6-羟基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮；(R)-1-(6-羟基苯并二氢吡喃-3-基)-5-(2-甲氨基乙基)-1，3-二氢咪唑-2-硫酮；(R)-1-(6，8-二氟苯并二氢吡喃-3-基)-5-(2-甲氨基乙基)-1，3-二氢咪唑-2-硫酮或(R)-1-苯并二氢吡喃-3-基-5-(2-甲氨基乙基)-1，3-二氢咪唑-2-硫酮；或它们的药学可接受的盐。
3.根据权利要求1的组合，其中所述式I的化合物是(S)-5-(2-氨基乙基)-1-(1，2，3，4-四氢萘-2-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(S)-5-(2-氨基乙基)-1-(5，7-二氟-1，2，3，4-四氢萘-2-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(6-羟基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(8-羟基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(6-甲氧基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(8-甲氧基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(6-氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(8-氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(6，7-二氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(6，8-二氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(S)-5-(2-氨基乙基)-1-(6，8-二氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(6，7，8-三氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(6-氯-8-甲氧基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(6-甲氧基-8-氯苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(6-硝基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(8-硝基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-[6-(乙酰氨基)苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-氨基甲基-1-苯并二氢吡喃-3-基-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-氨基甲基-1-(6-羟基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-氨基乙基)-1-(6-羟基-7-苄基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-氨基甲基-1-(6，8-二氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(3-氨基丙基)-1-(6，8-二氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(S)-5-(3-氨基丙基)-1-(5，7-二氟-1，2，3，4-四氢萘-2-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R，S)-5-(2-氨基乙基)-1-(6-羟基硫代苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R，S)-5-(2-氨基乙基)-1-(6-甲氧基硫代苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-苄氨基乙基)-1-(6-甲氧基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-5-(2-苄氨基乙基)-1-(6-羟基苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-1-(6-羟基苯并二氢吡喃-3-基)-5-(2-甲氨基乙基)-1，3-二氢咪唑-2-硫酮盐酸盐；(R)-1-(6，8-二氟苯并二氢吡喃-3-基)-5-(2-甲氨基乙基)-1，3-二氢咪唑-2-硫酮盐酸盐或(R)-1-苯并二氢吡喃-3-基-5-(2-甲氨基乙基)-1，3-二氢咪唑-2-硫酮盐酸盐。
4.根据权利要求1的组合，其中所述式I的化合物是((R)-5-(2-氨基乙基)-1-(6，8-二氟苯并二氢吡喃-3-基)-1，3-二氢咪唑-2-硫酮盐酸盐)。
5.根据权利要求1、2、3或4的组合，其中所述利尿剂是袢利尿剂。
6.根据权利要求1、2、3或4的组合，其中所述袢利尿剂是呋塞米、布美他尼、依他尼酸、托拉塞米、阿佐塞米、莫唑胺、吡咯他尼和/或曲帕胺。
7.根据权利要求1、2、3或4的组合，其中所述利尿剂是噻嗪类利尿剂。
8.根据权利要求7的组合，其中所述噻嗪类利尿剂是苄氟噻唑、氯噻嗪、氢氯噻嗪、氢氟噻嗪、甲氯噻嗪、泊利噻嗪、三氯噻嗪。
9.根据权利要求1、2、3或4的组合，其中所述利尿剂是类似噻嗪类利尿剂。
10.根据权利要求9的组合，其中所述类似噻嗪类利尿剂是氯噻酮、吲达帕胺、美托拉宗和/或喹乙宗。
11.根据权利要求1、2、3或4的组合，其中所述利尿剂是保钾利尿剂。
12.根据权利要求11的组合，其中所述保钾利尿剂是阿米洛利和/或氨苯蝶啶。
13.根据权利要求1、2、3或4的组合，其中所述利尿剂是醛固酮拮抗剂。
14.根据权利要求13的组合，其中所述醛固酮拮抗剂是螺内酯、坎利酮和/或依普利酮。
15.根据任何前述权利要求的组合，其中所述β-肾上腺素能拮抗剂是：噻吗咯尔、美托洛尔、阿替洛尔、普萘洛尔、比索洛尔和/或奈必洛尔。
16.根据任何前述权利要求的组合，其中所述α2-肾上腺素能激动剂是：可乐定、胍那苄和/或胍法辛。
17.根据任何前述权利要求的组合，其中所述α1-肾上腺素能拮抗剂是：哌唑嗪、多沙唑嗪和/或酚妥拉明。
18.根据任何前述权利要求的组合，其中所述双重β-和α-肾上腺素能拮抗剂是卡维地洛和/或拉贝洛尔。
19.根据任何前述权利要求的组合，其中所述钾通道激活剂是尼可地尔。
20.根据任何前述权利要求的组合，其中所述钙通道阻滞剂是：氨氯地平、苄普地尔、地尔硫卓、非洛地平、伊拉地平、尼卡地平、硝苯地平、尼莫地平、尼索地平和/或维拉帕米。
21.根据任何前述权利要求的组合，其中所述抗心律失常药是：钾通道阻滞剂如：胺碘酮、溴苄胺、伊布利特、多非利特、阿齐利特、氯非铵、替地沙米、司美利特和索他洛尔；奎尼丁、普鲁卡因胺、丙吡胺、利多卡因、美西律、妥卡尼、苯妥英、恩卡尼、氟卡尼、莫雷西嗪、普罗帕酮、艾司洛尔、普萘洛尔和/或美托洛尔。
22.根据任何前述权利要求的组合，其中所述ACE抑制剂是：贝那普利、卡托普利、依那普利、福辛普利、赖诺普利、咪达普利、莫昔普利、培哚普利、喹那普利、雷米普利和/或群多普利。
23.根据任何前述权利要求的组合，其中所述AT1受体拮抗剂是：坎地沙坦、厄贝沙坦、氯沙坦、替米沙坦、缬沙坦和/或依普罗沙坦。
24.根据任何前述权利要求的组合，其中所述降脂药是：抑制素如阿托伐他汀、西立伐他汀、氟伐他汀、洛伐他汀、美伐他汀、匹伐他汀、普伐他汀、瑞舒伐他汀和辛伐他汀；胆汁酸螯合剂如考来烯胺、考来替泊和烤来维仑；胆固醇吸收抑制剂如依泽替米贝；贝特类药物如非诺贝特和吉非贝齐；和/或烟酸。
25.根据任何前述权利要求的组合，其中所述硝酸酯是：亚硝酸异戊酯、硝酸甘油、硝酸异山梨酯、5-单硝酸异山梨醇酯和/或丁四硝酯。
26.根据任何前述权利要求的组合，其中所述内皮缩血管肽拮抗剂是：波生坦和/或西他生坦。
27.根据任何前述权利要求的组合，其中所述血管扩张药是：肼苯哒嗪、米诺地尔、硝普钠和/或二氮嗪。
28.根据任何前述权利要求的组合，其中所述磷酸二酯酶抑制剂是：米力农和/或氨力农。
29.根据任何前述权利要求的组合，其中所述强心苷是：毛花苷丙、克拉米丹、洋地黄毒苷、地高辛、拉诺辛、强心素、西地兰-D、洋地黄毒甙制剂和/或地高辛胶囊剂。
30.根据任何前述权利要求的组合，其中所述5-羟色胺拮抗剂是：氯氮平、洛沙平、奥氮平、利培酮、齐拉西酮、利坦色林、酮色林和/或阿莫沙平。
31.根据任何前述权利要求的组合，其中所述中枢神经系统作用药是莫索尼定和/或甲基多巴。
32.根据任何前述权利要求的组合，其中所述肾素抑制剂是：阿利吉仑、依那吉仑、地替吉仑、特拉吉仑、瑞米吉仑、占吉仑和/或环丙吉仑。
33.根据任何前述权利要求的组合，其中所述血管肽酶抑制剂是：奥马曲拉、山帕曲拉和/或吉莫曲拉。
34.根据任何前述权利要求的组合在制备用于治疗其中多巴胺羟基化成去甲肾上腺素的减少具有治疗益处的病症的药物中的用途。
35.权利要求1-33中任一项的组合在制备用于治疗患有心血管病症的个体的药物中的用途。
36.权利要求1-33中任一项的组合在制备用于治疗高血压或慢性心力衰竭的药物中的用途。
37.权利要求1-33中任一项的组合在制备用于治疗一种或多种以下适应症的药物中的用途：咽峡炎、心律失常、循环障碍、偏头痛和焦虑性障碍。
38.权利要求1-33中任一项的组合在制备用于抑制多巴胺-β-羟化酶的药物中的用途。
39.商品包装，其包含权利要求1-33中任一项的组合与关于其同时、单独或依次使用的说明书。
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| GBGB0600709.0A GB0600709D0 (en) | 2006-01-13 | 2006-01-13 | Drug combinations |
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| CN101384257A true CN101384257A (zh) | 2009-03-11 |
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| US (1) | US20090221656A1 (zh) |
| EP (1) | EP1983982A1 (zh) |
| JP (1) | JP2009523720A (zh) |
| KR (1) | KR20080092436A (zh) |
| CN (1) | CN101384257A (zh) |
| AU (1) | AU2007205298A1 (zh) |
| BR (1) | BRPI0706863A2 (zh) |
| CA (1) | CA2636941A1 (zh) |
| GB (1) | GB0600709D0 (zh) |
| MX (1) | MX2008009044A (zh) |
| RU (1) | RU2008133215A (zh) |
| WO (1) | WO2007081232A1 (zh) |
| ZA (1) | ZA200806318B (zh) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102247345A (zh) * | 2011-05-30 | 2011-11-23 | 北京阜康仁生物制药科技有限公司 | 一种新型降血脂组合物 |
| CN107569495A (zh) * | 2017-08-10 | 2018-01-12 | 新疆医科大学 | 依普利酮对慢性心力衰竭患者辅助性t细胞活化/增殖的抑制作用 |
| CN113599387A (zh) * | 2021-09-15 | 2021-11-05 | 山东中医药大学附属医院 | 一种复方制剂及其在制备治疗心绞痛药物中的用途 |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2231648A1 (en) * | 2007-12-05 | 2010-09-29 | BIAL - Portela & Ca., S.A. | New salts and crystal forms |
| WO2010065489A1 (en) * | 2008-12-02 | 2010-06-10 | Sciele Pharma, Inc. | Alpha2-adrenergic agonist and angiotensin ii receptor antagonist composition |
| US9023788B2 (en) * | 2010-04-20 | 2015-05-05 | New York University | Methods compounds and pharmaceutical compositions for treating anxiety and mood disorders |
| CA2890920C (en) | 2012-11-14 | 2020-12-15 | Bial - Portela & Ca, S.A. | 1,3-dihydroimidazole-2-thione derivatives for use in the treatment of pulmonary arterial hypertension and lung injury |
| KR101771766B1 (ko) * | 2013-12-30 | 2017-08-28 | 알보젠코리아 주식회사 | 안지오텐신-Ⅱ 수용체 차단제 및 HMG-CoA 환원효소 저해제를 포함하는 약제학적 복합제제 |
| KR20150120008A (ko) * | 2014-04-16 | 2015-10-27 | 씨제이헬스케어 주식회사 | 비소프롤롤 및 로수바스타틴을 포함하는 경구용 약제학적 복합제제 |
| WO2016191294A1 (en) * | 2015-05-22 | 2016-12-01 | The Trustees Of Columbia University In The City Of New York | Sk and ik channel agonists for treatment of heart failure |
| KR101710441B1 (ko) | 2015-12-28 | 2017-02-28 | 신풍제약주식회사 | 안정성 및 용출성이 향상된 정제 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4217347A (en) * | 1977-12-27 | 1980-08-12 | E. R. Squibb & Sons, Inc. | Method of treating hypertension and medicaments therefor |
| JPS625964A (ja) * | 1985-07-01 | 1987-01-12 | Shionogi & Co Ltd | ５，６，７，８−テトラヒドロ−５，８−メタノイソキノリン誘導体および抗潰瘍剤 |
| EP0295401A3 (de) * | 1987-04-30 | 1990-03-21 | Wacker-Chemie Gmbh | Verfahren zur Polymerisation von polaren Verbindungen |
| US5438150A (en) * | 1994-04-26 | 1995-08-01 | Syntex (U.S.A.) Inc. | Process for making 1-benzocycloalkyl-1,3-dihydroimidazole-2-thione derivatives |
| WO1995029165A2 (en) * | 1994-04-26 | 1995-11-02 | Syntex (U.S.A.) Inc. | Benzocycloalkylaz0lethione derivatives as dopamin beta-hydroxylase inhibitors |
| US5538988A (en) * | 1994-04-26 | 1996-07-23 | Martinez; Gregory R. | Benzocycloalkylazolethione derivatives |
| US7125904B2 (en) * | 2002-10-11 | 2006-10-24 | Portela & C.A., S.A. | Peripherally-selective inhibitors of dopamine-β-hydroxylase and method of their preparation |
-
2006
- 2006-01-13 GB GBGB0600709.0A patent/GB0600709D0/en not_active Ceased
-
2007
- 2007-01-15 MX MX2008009044A patent/MX2008009044A/es not_active Application Discontinuation
- 2007-01-15 US US12/160,762 patent/US20090221656A1/en not_active Abandoned
- 2007-01-15 EP EP07709265A patent/EP1983982A1/en not_active Withdrawn
- 2007-01-15 JP JP2008550258A patent/JP2009523720A/ja active Pending
- 2007-01-15 CN CNA2007800053030A patent/CN101384257A/zh active Pending
- 2007-01-15 RU RU2008133215/15A patent/RU2008133215A/ru not_active Application Discontinuation
- 2007-01-15 AU AU2007205298A patent/AU2007205298A1/en not_active Abandoned
- 2007-01-15 WO PCT/PT2007/000002 patent/WO2007081232A1/en active Application Filing
- 2007-01-15 KR KR1020087019668A patent/KR20080092436A/ko not_active Application Discontinuation
- 2007-01-15 CA CA002636941A patent/CA2636941A1/en not_active Abandoned
- 2007-01-15 ZA ZA200806318A patent/ZA200806318B/xx unknown
- 2007-01-15 BR BRPI0706863-8A patent/BRPI0706863A2/pt not_active IP Right Cessation
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102247345A (zh) * | 2011-05-30 | 2011-11-23 | 北京阜康仁生物制药科技有限公司 | 一种新型降血脂组合物 |
| CN107569495A (zh) * | 2017-08-10 | 2018-01-12 | 新疆医科大学 | 依普利酮对慢性心力衰竭患者辅助性t细胞活化/增殖的抑制作用 |
| CN113599387A (zh) * | 2021-09-15 | 2021-11-05 | 山东中医药大学附属医院 | 一种复方制剂及其在制备治疗心绞痛药物中的用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| GB0600709D0 (en) | 2006-02-22 |
| KR20080092436A (ko) | 2008-10-15 |
| MX2008009044A (es) | 2008-11-14 |
| AU2007205298A1 (en) | 2007-07-19 |
| WO2007081232A1 (en) | 2007-07-19 |
| EP1983982A1 (en) | 2008-10-29 |
| US20090221656A1 (en) | 2009-09-03 |
| JP2009523720A (ja) | 2009-06-25 |
| RU2008133215A (ru) | 2010-02-20 |
| BRPI0706863A2 (pt) | 2011-04-12 |
| AU2007205298A8 (en) | 2008-08-28 |
| CA2636941A1 (en) | 2007-07-19 |
| ZA200806318B (en) | 2009-10-28 |
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