RU2287522C2 - Замещенные кислотными группами дифенилазетидиноны, способ их получения, содержащие эти соединения лекарственные средства и их применение - Google Patents
Замещенные кислотными группами дифенилазетидиноны, способ их получения, содержащие эти соединения лекарственные средства и их применение Download PDFInfo
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- RU2287522C2 RU2287522C2 RU2005101093/04A RU2005101093A RU2287522C2 RU 2287522 C2 RU2287522 C2 RU 2287522C2 RU 2005101093/04 A RU2005101093/04 A RU 2005101093/04A RU 2005101093 A RU2005101093 A RU 2005101093A RU 2287522 C2 RU2287522 C2 RU 2287522C2
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- Prior art keywords
- cooh
- compounds
- fluorophenyl
- alkylene
- formula
- Prior art date
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- 238000000034 method Methods 0.000 title abstract description 6
- 230000002378 acidificating effect Effects 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 97
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 31
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 30
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 19
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 19
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 12
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 6
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims abstract 4
- -1 4- {1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl] -4-oxoazetidin-2-yl} phenoxy Chemical group 0.000 claims description 28
- 229910052740 iodine Inorganic materials 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 8
- VDOXIAUNJCHYRC-UHFFFAOYSA-N 1,3-diphenylazetidin-2-one Chemical class O=C1C(C=2C=CC=CC=2)CN1C1=CC=CC=C1 VDOXIAUNJCHYRC-UHFFFAOYSA-N 0.000 claims description 4
- 235000012000 cholesterol Nutrition 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 3
- 230000000694 effects Effects 0.000 abstract description 10
- 239000000126 substance Substances 0.000 abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 2
- 125000004429 atom Chemical group 0.000 abstract 3
- 229910006069 SO3H Inorganic materials 0.000 abstract 2
- 239000003795 chemical substances by application Substances 0.000 abstract 2
- 230000003247 decreasing effect Effects 0.000 abstract 1
- 230000007721 medicinal effect Effects 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 239000000203 mixture Substances 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000000556 agonist Substances 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 15
- 239000013543 active substance Substances 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 229940088623 biologically active substance Drugs 0.000 description 10
- ZIFWYCYPTCFKCS-UHFFFAOYSA-N 1-[4-(aminomethyl)phenyl]-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)azetidin-2-one Chemical compound C1=CC(OC)=CC=C1C1N(C=2C=CC(CN)=CC=2)C(=O)C1CCC(O)C1=CC=C(F)C=C1 ZIFWYCYPTCFKCS-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- ITKUJUGSTGCXAR-UHFFFAOYSA-N 4-[[5-[tert-butyl(dimethyl)silyl]oxy-5-(4-fluorophenyl)-1-(4-methoxyphenyl)-2-(2-oxo-4-phenyl-1,3-oxazolidine-3-carbonyl)pentyl]amino]benzonitrile Chemical compound C1=CC(OC)=CC=C1C(C(CCC(O[Si](C)(C)C(C)(C)C)C=1C=CC(F)=CC=1)C(=O)N1C(OCC1C=1C=CC=CC=1)=O)NC1=CC=C(C#N)C=C1 ITKUJUGSTGCXAR-UHFFFAOYSA-N 0.000 description 7
- 102000004877 Insulin Human genes 0.000 description 7
- 108090001061 Insulin Proteins 0.000 description 7
- 229940125396 insulin Drugs 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 6
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 6
- GDKKHSCEPWPPSA-UHFFFAOYSA-N 4-[[4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]phenyl]methylamino]butane-1-sulfonic acid Chemical compound C1=CC(OC)=CC=C1C1N(C=2C=CC(CNCCCCS(O)(=O)=O)=CC=2)C(=O)C1CCC(O)C1=CC=C(F)C=C1 GDKKHSCEPWPPSA-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
- 210000004185 liver Anatomy 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- BWZRBAKIQCNTGD-UHFFFAOYSA-N 2-[[4-[1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl]phenyl]methylamino]-2-oxoethanesulfonic acid Chemical compound C=1C=C(F)C=CC=1C(O)CCC(C1=O)C(C=2C=CC(CNC(=O)CS(O)(=O)=O)=CC=2)N1C1=CC=C(F)C=C1 BWZRBAKIQCNTGD-UHFFFAOYSA-N 0.000 description 5
- CQXYQHZDPOQVGG-UHFFFAOYSA-N 3-[5-[tert-butyl(dimethyl)silyl]oxy-5-(4-fluorophenyl)pentanoyl]-4-phenyl-1,3-oxazolidin-2-one Chemical compound C=1C=C(F)C=CC=1C(O[Si](C)(C)C(C)(C)C)CCCC(=O)N(C(OC1)=O)C1C1=CC=CC=C1 CQXYQHZDPOQVGG-UHFFFAOYSA-N 0.000 description 5
- RUWHEHABHPGZNK-UHFFFAOYSA-N 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzonitrile Chemical compound C1=CC(OC)=CC=C1C1N(C=2C=CC(=CC=2)C#N)C(=O)C1CCC(O)C1=CC=C(F)C=C1 RUWHEHABHPGZNK-UHFFFAOYSA-N 0.000 description 5
- RFQNMZOCNZXPSA-UHFFFAOYSA-N 4-[3-[3-[tert-butyl(dimethyl)silyl]oxy-3-(4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzonitrile Chemical compound C1=CC(OC)=CC=C1C1N(C=2C=CC(=CC=2)C#N)C(=O)C1CCC(O[Si](C)(C)C(C)(C)C)C1=CC=C(F)C=C1 RFQNMZOCNZXPSA-UHFFFAOYSA-N 0.000 description 5
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 229910004298 SiO 2 Inorganic materials 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 229940100389 Sulfonylurea Drugs 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- VQWVQHLXLOLUMW-UHFFFAOYSA-N 2-[1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl]benzonitrile Chemical compound C=1C=C(F)C=CC=1C(O)CCC(C1=O)C(C=2C(=CC=CC=2)C#N)N1C1=CC=C(F)C=C1 VQWVQHLXLOLUMW-UHFFFAOYSA-N 0.000 description 4
- HIALIZQROKUEJE-UHFFFAOYSA-N 4-[1-(4-fluoroanilino)-5-(4-fluorophenyl)-5-hydroxy-2-(2-oxo-4-phenyl-1,3-oxazolidine-3-carbonyl)pentyl]benzonitrile Chemical compound C=1C=C(F)C=CC=1C(O)CCC(C(=O)N1C(OCC1C=1C=CC=CC=1)=O)C(C=1C=CC(=CC=1)C#N)NC1=CC=C(F)C=C1 HIALIZQROKUEJE-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 4
- 229960003105 metformin Drugs 0.000 description 4
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 4
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 4
- BPULZCDBMRXTDP-UHFFFAOYSA-N 4-[4-[1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl]phenoxy]butane-1-sulfonic acid Chemical compound C=1C=C(F)C=CC=1C(O)CCC(C1=O)C(C=2C=CC(OCCCCS(O)(=O)=O)=CC=2)N1C1=CC=C(F)C=C1 BPULZCDBMRXTDP-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
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- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
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- 229910052739 hydrogen Inorganic materials 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
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- 150000002500 ions Chemical class 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- MHYFEEDKONKGEB-UHFFFAOYSA-N oxathiane 2,2-dioxide Chemical compound O=S1(=O)CCCCO1 MHYFEEDKONKGEB-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
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- 239000000651 prodrug Substances 0.000 description 3
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- 150000003254 radicals Chemical class 0.000 description 3
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 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 description 2
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- OLNTVTPDXPETLC-UHFFFAOYSA-N 1-(4-Fluorophenyl)-3-(3-(4-fluorophenyl)-3-hydroxypropyl)-4-(4-hydroxyphenyl)azetidin-2-one Chemical compound C=1C=C(F)C=CC=1C(O)CCC(C1=O)C(C=2C=CC(O)=CC=2)N1C1=CC=C(F)C=C1 OLNTVTPDXPETLC-UHFFFAOYSA-N 0.000 description 2
- VQJRCIBPEHETCL-UHFFFAOYSA-N 1-[4-(4-fluorobutoxy)phenyl]-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)azetidin-2-one Chemical compound C1=CC(OC)=CC=C1C1N(C=2C=CC(OCCCCF)=CC=2)C(=O)C1CCC(O)C1=CC=C(F)C=C1 VQJRCIBPEHETCL-UHFFFAOYSA-N 0.000 description 2
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- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- SLZIZIJTGAYEKK-CIJSCKBQSA-N molport-023-220-247 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CN)[C@@H](C)O)C1=CNC=N1 SLZIZIJTGAYEKK-CIJSCKBQSA-N 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- LYAUICDWKQJAGX-UHFFFAOYSA-N n-(7-hydroxy-2,2,4,6-tetramethyl-1,3-dihydroinden-1-yl)-2-[4-(3-methoxyphenyl)piperazin-1-yl]acetamide Chemical compound COC1=CC=CC(N2CCN(CC(=O)NC3C(CC4=C3C(=C(C)C=C4C)O)(C)C)CC2)=C1 LYAUICDWKQJAGX-UHFFFAOYSA-N 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000002474 noradrenergic effect Effects 0.000 description 1
- 238000013421 nuclear magnetic resonance imaging Methods 0.000 description 1
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- 108060005714 orexin Proteins 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- YDCVQGAUCOROHB-UHFFFAOYSA-N oxadiazolidine-4,5-dione Chemical class O=C1NNOC1=O YDCVQGAUCOROHB-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 229960003562 phentermine Drugs 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 1
- 230000018656 positive regulation of gluconeogenesis Effects 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- ZLMJMSJWJFRBEC-AKLPVKDBSA-N potassium-42 Chemical compound [42K] ZLMJMSJWJFRBEC-AKLPVKDBSA-N 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000003488 releasing hormone Substances 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 229960000672 rosuvastatin Drugs 0.000 description 1
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000000952 serotonin receptor agonist Substances 0.000 description 1
- 239000003772 serotonin uptake inhibitor Substances 0.000 description 1
- 230000002295 serotoninergic effect Effects 0.000 description 1
- 229960004425 sibutramine Drugs 0.000 description 1
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000004544 sputter deposition Methods 0.000 description 1
- 239000004059 squalene synthase inhibitor Substances 0.000 description 1
- 235000000891 standard diet Nutrition 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
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- 238000013268 sustained release Methods 0.000 description 1
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- 230000002195 synergetic effect Effects 0.000 description 1
- WBWWGRHZICKQGZ-GIHLXUJPSA-N taurocholic acid Chemical compound C([C@@H]1C[C@H]2O)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@H](O)C1 WBWWGRHZICKQGZ-GIHLXUJPSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- SIOVKLKJSOKLIF-HJWRWDBZSA-N trimethylsilyl (1z)-n-trimethylsilylethanimidate Chemical compound C[Si](C)(C)OC(/C)=N\[Si](C)(C)C SIOVKLKJSOKLIF-HJWRWDBZSA-N 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 1
- 229960001641 troglitazone Drugs 0.000 description 1
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- 239000000777 urocortin Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/568—Four-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Biochemistry (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10227508.4 | 2002-06-19 | ||
| DE10227508A DE10227508A1 (de) | 2002-06-19 | 2002-06-19 | Säuregruppen-substituierte Diphenylazetidinone, Verfahren zu deren Herstellung, diese Verbindungen enthaltende Arzneimittel und deren Verwendung |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| RU2005101093A RU2005101093A (ru) | 2005-07-20 |
| RU2287522C2 true RU2287522C2 (ru) | 2006-11-20 |
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| RU2005101093/04A RU2287522C2 (ru) | 2002-06-19 | 2003-06-04 | Замещенные кислотными группами дифенилазетидиноны, способ их получения, содержащие эти соединения лекарственные средства и их применение |
Country Status (28)
| Country | Link |
|---|---|
| EP (1) | EP1517891B1 (enExample) |
| JP (1) | JP2005533073A (enExample) |
| KR (1) | KR20050008835A (enExample) |
| CN (1) | CN100467448C (enExample) |
| AR (1) | AR039690A1 (enExample) |
| AU (1) | AU2003238210B2 (enExample) |
| BR (1) | BR0311896A (enExample) |
| CA (1) | CA2490112A1 (enExample) |
| DE (1) | DE10227508A1 (enExample) |
| EC (1) | ECSP045497A (enExample) |
| HN (1) | HN2003000185A (enExample) |
| HR (1) | HRPK20041201B3 (enExample) |
| IL (1) | IL165789A0 (enExample) |
| MA (1) | MA27206A1 (enExample) |
| MX (1) | MXPA04012093A (enExample) |
| NO (1) | NO20050134L (enExample) |
| OA (1) | OA12869A (enExample) |
| PA (1) | PA8576101A1 (enExample) |
| PE (1) | PE20040564A1 (enExample) |
| PL (1) | PL372700A1 (enExample) |
| RS (1) | RS108404A (enExample) |
| RU (1) | RU2287522C2 (enExample) |
| SV (1) | SV2004001548A (enExample) |
| TN (1) | TNSN04250A1 (enExample) |
| TW (1) | TW200413311A (enExample) |
| UA (1) | UA78577C2 (enExample) |
| UY (1) | UY27853A1 (enExample) |
| WO (1) | WO2004000805A1 (enExample) |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
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| GB0215579D0 (en) | 2002-07-05 | 2002-08-14 | Astrazeneca Ab | Chemical compounds |
| DE602004029715D1 (de) | 2003-12-23 | 2010-12-02 | Astrazeneca Ab | Diphenylazetidinonderivate mit die cholesterinabsorption hemmender wirkung |
| JP5254620B2 (ja) | 2004-12-03 | 2013-08-07 | メルク・シャープ・アンド・ドーム・コーポレーション | Ｃｂ１アンタゴニストとしての置換ピペラジン |
| US8361999B2 (en) | 2005-04-04 | 2013-01-29 | Pontificia Universidad Catolica De Chile | Methods of treating cholesterol gallstone disease with ezetimibe |
| CN101243072A (zh) | 2005-06-20 | 2008-08-13 | 先灵公司 | 用作组胺h3拮抗剂的哌啶衍生物 |
| SA06270191B1 (ar) | 2005-06-22 | 2010-03-29 | استرازينيكا ايه بي | مشتقات من 2- أزيتيدينون جديدة باعتبارها مثبطات لامتصاص الكوليسترول لعلاج حالات فرط نسبة الدهون في الدم |
| AR060623A1 (es) | 2006-04-27 | 2008-07-02 | Astrazeneca Ab | Compuestos derivados de 2-azetidinona y un metodo de preparacion |
| KR20090024811A (ko) * | 2006-06-23 | 2009-03-09 | 아보트 러보러터리즈 | 히스타민 ｈ3 수용체 조절제로서의 사이클로프로필 아민 유도체 |
| BRPI0715160A2 (pt) | 2006-08-08 | 2013-06-11 | Sanofi Aventis | imidazolidina-2,4-dionas substituÍdas por arilamimoaril-alquil-, processo para preparÁ-las, medicamentos compeendendo estes compostos, e seu uso |
| DE102007002260A1 (de) | 2007-01-16 | 2008-07-31 | Sanofi-Aventis | Verwendung von substituierten Pyranonsäurederivaten zur Herstellung von Medikamenten zur Behandlung des Metabolischen Syndroms |
| EP2025674A1 (de) | 2007-08-15 | 2009-02-18 | sanofi-aventis | Substituierte Tetrahydronaphthaline, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
| CN101200443B (zh) * | 2007-10-17 | 2011-06-29 | 中国药科大学 | 氮杂环丁酮衍生物、其制备方法及含有它们的药物组合 |
| DE102007054497B3 (de) | 2007-11-13 | 2009-07-23 | Sanofi-Aventis Deutschland Gmbh | Neue kristalline Diphenylazetidinonhydrate und Verfahren zu deren Herstellung |
| WO2010003624A2 (en) | 2008-07-09 | 2010-01-14 | Sanofi-Aventis | Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof |
| WO2010068601A1 (en) | 2008-12-08 | 2010-06-17 | Sanofi-Aventis | A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof |
| US9212175B2 (en) | 2009-03-06 | 2015-12-15 | Lipideon Biotechnology Ag | Pharmaceutical hypocholesterolemic compositions |
| CN101993403B (zh) | 2009-08-11 | 2012-07-11 | 浙江海正药业股份有限公司 | 氮杂环丁酮类化合物及医药应用 |
| ES2443016T3 (es) | 2009-08-26 | 2014-02-17 | Sanofi | Nuevos hidratos cristalinos de fluoroglicósidos heteroaromáticos, productos farmacéuticos que comprenden estos compuestos, y su empleo |
| US8933024B2 (en) | 2010-06-18 | 2015-01-13 | Sanofi | Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases |
| WO2012120053A1 (de) | 2011-03-08 | 2012-09-13 | Sanofi | Verzweigte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung |
| US8871758B2 (en) | 2011-03-08 | 2014-10-28 | Sanofi | Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof |
| EP2766349B1 (de) | 2011-03-08 | 2016-06-01 | Sanofi | Mit carbozyklen oder heterozyklen substituierte oxathiazinderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung |
| WO2012120055A1 (de) | 2011-03-08 | 2012-09-13 | Sanofi | Di- und trisubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung |
| US8828994B2 (en) | 2011-03-08 | 2014-09-09 | Sanofi | Di- and tri-substituted oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
| EP2567959B1 (en) | 2011-09-12 | 2014-04-16 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994014433A1 (en) * | 1992-12-23 | 1994-07-07 | Schering Corporation | COMBINATION OF A CHOLESTEROL BIOSYNTHESIS INHIBITOR AND A β-LACTAM CHOLESTEROL ABSORPTION INHIBITOR |
| RU2181297C2 (ru) * | 2000-06-20 | 2002-04-20 | Эпштейн Олег Ильич | Способ лечения патологического синдрома и лекарственное средство |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5631365A (en) * | 1993-09-21 | 1997-05-20 | Schering Corporation | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
| US5756470A (en) * | 1996-10-29 | 1998-05-26 | Schering Corporation | Sugar-substituted 2-azetidinones useful as hypocholesterolemic agents |
| DE10042447A1 (de) * | 2000-08-29 | 2002-03-28 | Aventis Pharma Gmbh | Protein aus dem Darm von Wirbeltieren, welches Cholesterin absorbiert, sowie Verwendung dieses Proteins zur Identifizierung von Inhibitoren des intestinalen Cholesterintransports |
| EP1345924B1 (de) * | 2000-12-21 | 2006-08-30 | Sanofi-Aventis Deutschland GmbH | Diphenylazetidinonderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung |
| CA2431983C (en) * | 2000-12-21 | 2010-06-08 | Aventis Pharma Deutschland Gmbh | Novel 1,2-diphenylazetidinones, processes for their preparation, medicaments comprising these compounds and their use for treating impaired lipid metabolism |
| IL156552A0 (en) * | 2000-12-21 | 2004-01-04 | Aventis Pharma Gmbh | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
-
2002
- 2002-06-19 DE DE10227508A patent/DE10227508A1/de not_active Withdrawn
-
2003
- 2003-04-06 UA UAA200500488A patent/UA78577C2/uk unknown
- 2003-06-02 SV SV2003001548A patent/SV2004001548A/es not_active Application Discontinuation
- 2003-06-04 MX MXPA04012093A patent/MXPA04012093A/es active IP Right Grant
- 2003-06-04 WO PCT/EP2003/005816 patent/WO2004000805A1/de not_active Ceased
- 2003-06-04 CA CA002490112A patent/CA2490112A1/en not_active Abandoned
- 2003-06-04 RU RU2005101093/04A patent/RU2287522C2/ru not_active IP Right Cessation
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994014433A1 (en) * | 1992-12-23 | 1994-07-07 | Schering Corporation | COMBINATION OF A CHOLESTEROL BIOSYNTHESIS INHIBITOR AND A β-LACTAM CHOLESTEROL ABSORPTION INHIBITOR |
| RU2181297C2 (ru) * | 2000-06-20 | 2002-04-20 | Эпштейн Олег Ильич | Способ лечения патологического синдрома и лекарственное средство |
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Effective date: 20100605 |