HRP20041233A2 - Selective estrogen receptor modulators containing a phenylsulfonyl group - Google Patents
Selective estrogen receptor modulators containing a phenylsulfonyl group Download PDFInfo
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- HRP20041233A2 HRP20041233A2 HR20041233A HRP20041233A HRP20041233A2 HR P20041233 A2 HRP20041233 A2 HR P20041233A2 HR 20041233 A HR20041233 A HR 20041233A HR P20041233 A HRP20041233 A HR P20041233A HR P20041233 A2 HRP20041233 A2 HR P20041233A2
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- Prior art keywords
- mmol
- compound
- phenyl
- solution
- added
- Prior art date
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- 229940095743 selective estrogen receptor modulator Drugs 0.000 title abstract description 10
- 239000000333 selective estrogen receptor modulator Substances 0.000 title abstract description 10
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 44
- 201000010260 leiomyoma Diseases 0.000 claims abstract description 14
- 201000009273 Endometriosis Diseases 0.000 claims abstract description 12
- 206010046798 Uterine leiomyoma Diseases 0.000 claims abstract description 7
- 201000007954 uterine fibroid Diseases 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 348
- -1 NR3R3a Chemical group 0.000 claims description 48
- 239000000460 chlorine Substances 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 23
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 16
- 210000004291 uterus Anatomy 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical group N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 4
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- 239000002253 acid Substances 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 737
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 411
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 355
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 352
- 239000000243 solution Substances 0.000 description 218
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 208
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 174
- 239000000203 mixture Substances 0.000 description 142
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 135
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 134
- 235000019439 ethyl acetate Nutrition 0.000 description 128
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 126
- 239000012044 organic layer Substances 0.000 description 123
- 238000006243 chemical reaction Methods 0.000 description 112
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 110
- 229940093499 ethyl acetate Drugs 0.000 description 99
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 94
- 229920006395 saturated elastomer Polymers 0.000 description 93
- 150000002500 ions Chemical class 0.000 description 83
- 238000001819 mass spectrum Methods 0.000 description 82
- 239000007921 spray Substances 0.000 description 82
- 239000010410 layer Substances 0.000 description 79
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 77
- 229910052938 sodium sulfate Inorganic materials 0.000 description 77
- 235000011152 sodium sulphate Nutrition 0.000 description 77
- 239000011541 reaction mixture Substances 0.000 description 70
- 239000007787 solid Substances 0.000 description 70
- 238000002360 preparation method Methods 0.000 description 69
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 68
- 239000000741 silica gel Substances 0.000 description 65
- 229910002027 silica gel Inorganic materials 0.000 description 65
- 235000017557 sodium bicarbonate Nutrition 0.000 description 65
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 65
- 229910052681 coesite Inorganic materials 0.000 description 62
- 229910052906 cristobalite Inorganic materials 0.000 description 62
- 239000000377 silicon dioxide Substances 0.000 description 62
- 235000012239 silicon dioxide Nutrition 0.000 description 62
- 229910052682 stishovite Inorganic materials 0.000 description 62
- 229910052905 tridymite Inorganic materials 0.000 description 62
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 60
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 55
- 235000019341 magnesium sulphate Nutrition 0.000 description 55
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 54
- 239000000725 suspension Substances 0.000 description 54
- 239000012266 salt solution Substances 0.000 description 52
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 50
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- 238000003756 stirring Methods 0.000 description 45
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- 239000000047 product Substances 0.000 description 41
- 239000007864 aqueous solution Substances 0.000 description 35
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 35
- 230000002829 reductive effect Effects 0.000 description 35
- 239000007832 Na2SO4 Substances 0.000 description 33
- 239000002904 solvent Substances 0.000 description 33
- 239000012267 brine Substances 0.000 description 32
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 32
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 31
- 229910052757 nitrogen Inorganic materials 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 239000012458 free base Substances 0.000 description 27
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 27
- 239000000706 filtrate Substances 0.000 description 26
- 238000003818 flash chromatography Methods 0.000 description 26
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 25
- 238000010992 reflux Methods 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- 239000000463 material Substances 0.000 description 24
- 241000700159 Rattus Species 0.000 description 22
- 239000002244 precipitate Substances 0.000 description 22
- 239000000843 powder Substances 0.000 description 20
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 19
- 229910015845 BBr3 Inorganic materials 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 239000012065 filter cake Substances 0.000 description 18
- 239000003921 oil Substances 0.000 description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 17
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 16
- 235000019270 ammonium chloride Nutrition 0.000 description 15
- 229940011871 estrogen Drugs 0.000 description 15
- 239000000262 estrogen Substances 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 239000000284 extract Substances 0.000 description 14
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 13
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- 229960005309 estradiol Drugs 0.000 description 13
- 239000012299 nitrogen atmosphere Substances 0.000 description 13
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 239000013058 crude material Substances 0.000 description 12
- 239000002609 medium Substances 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000012312 sodium hydride Substances 0.000 description 10
- 229910000104 sodium hydride Inorganic materials 0.000 description 10
- MDNDJMCSXOXBFZ-UHFFFAOYSA-N 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane Chemical compound O1CC(C)(C)COB1B1OCC(C)(C)CO1 MDNDJMCSXOXBFZ-UHFFFAOYSA-N 0.000 description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 9
- 229960000583 acetic acid Drugs 0.000 description 9
- 235000011114 ammonium hydroxide Nutrition 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 9
- 229930182833 estradiol Natural products 0.000 description 9
- 239000012091 fetal bovine serum Substances 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 description 9
- 235000017550 sodium carbonate Nutrition 0.000 description 9
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 9
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 206010067269 Uterine fibrosis Diseases 0.000 description 8
- 239000000556 agonist Substances 0.000 description 8
- GHQPBDDZGPAVJP-UHFFFAOYSA-N azanium;methanol;hydroxide Chemical compound N.O.OC GHQPBDDZGPAVJP-UHFFFAOYSA-N 0.000 description 8
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 8
- 235000008504 concentrate Nutrition 0.000 description 8
- 239000012141 concentrate Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
- 238000002953 preparative HPLC Methods 0.000 description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 8
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 7
- 239000013543 active substance Substances 0.000 description 7
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- 238000005192 partition Methods 0.000 description 7
- 235000011056 potassium acetate Nutrition 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- 230000000638 stimulation Effects 0.000 description 7
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- 239000000908 ammonium hydroxide Substances 0.000 description 6
- 230000003042 antagnostic effect Effects 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 6
- 239000012911 assay medium Substances 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 229910002092 carbon dioxide Inorganic materials 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 238000011534 incubation Methods 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 5
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 206010062662 Uterine mass Diseases 0.000 description 5
- 230000001270 agonistic effect Effects 0.000 description 5
- 238000009739 binding Methods 0.000 description 5
- 210000000988 bone and bone Anatomy 0.000 description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000006260 foam Substances 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 239000007758 minimum essential medium Substances 0.000 description 5
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 5
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 5
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 5
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
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- 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
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/32—Antioestrogens
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/56—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D333/64—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/72—Benzo[c]thiophenes; Hydrogenated benzo[c]thiophenes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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- Diabetes (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US39786902P | 2002-07-22 | 2002-07-22 | |
US45023303P | 2003-02-25 | 2003-02-25 | |
PCT/IB2003/003349 WO2004009086A1 (en) | 2002-07-22 | 2003-07-16 | Selective estrogen receptor modulators containing a phenylsulfonyl group |
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Publication Number | Publication Date |
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HRP20041233A2 true HRP20041233A2 (en) | 2005-02-28 |
Family
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HR20041233A HRP20041233A2 (en) | 2002-07-22 | 2004-12-30 | Selective estrogen receptor modulators containing a phenylsulfonyl group |
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US (2) | US7399867B2 (ja) |
EP (1) | EP1530470B9 (ja) |
JP (2) | JP4656939B2 (ja) |
CN (1) | CN1668303B (ja) |
AT (1) | ATE433322T1 (ja) |
AU (1) | AU2003253129B2 (ja) |
BR (1) | BR0312675A (ja) |
CA (1) | CA2490580C (ja) |
CO (1) | CO5680445A2 (ja) |
CR (1) | CR7657A (ja) |
DE (1) | DE60327931D1 (ja) |
EA (1) | EA008024B1 (ja) |
EC (1) | ECSP055549A (ja) |
ES (1) | ES2326593T3 (ja) |
HK (1) | HK1078003A1 (ja) |
HR (1) | HRP20041233A2 (ja) |
IL (1) | IL165745A0 (ja) |
MX (1) | MXPA05000898A (ja) |
MY (1) | MY141879A (ja) |
NO (1) | NO20050832L (ja) |
NZ (1) | NZ537138A (ja) |
PE (1) | PE20040678A1 (ja) |
PL (1) | PL374845A1 (ja) |
TW (1) | TWI314860B (ja) |
WO (1) | WO2004009086A1 (ja) |
Families Citing this family (27)
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EP1530470B9 (en) * | 2002-07-22 | 2010-04-07 | Eli Lilly And Company | Selective estrogen receptor modulators containing a phenylsulfonyl group |
MXPA05009098A (es) * | 2003-02-25 | 2005-11-17 | Lilly Co Eli | Clorhidrato de 1- (4-(2 -piperidiniletoxifenoxi) -2-(4-metansulfonilfenil) -6-hidroxinaftaleno cristalino no solvatado. |
KR100693242B1 (ko) * | 2003-02-25 | 2007-03-12 | 일라이 릴리 앤드 캄파니 | 결정성 비-용매화1-(4-(2-피페리디닐에톡시)페녹시)-2-(4-메탄술포닐페닐)-6-하이드록시나프탈렌 하이드로클로라이드 |
EP1709023B1 (en) * | 2004-01-22 | 2009-11-11 | Eli Lilly And Company | Selective estrogen receptor modulators |
CN1910167B (zh) * | 2004-01-22 | 2011-08-10 | 伊莱利利公司 | 用于治疗血管舒缩症状的选择性雌激素受体调节剂 |
KR101008804B1 (ko) | 2004-01-22 | 2011-01-14 | 일라이 릴리 앤드 캄파니 | 혈관운동 증상의 치료를 위한 선택적 에스트로겐 수용체조절제 |
EP1713770A1 (en) * | 2004-01-29 | 2006-10-25 | Eli Lilly And Company | Selective estrogen receptor modulators |
BRPI0512395A (pt) | 2004-06-22 | 2008-03-11 | Smithkline Beecham Corp | composto, composição farmacêutica, uso de um composto, e, métodos para o tratamento ou a profilaxia de condições ou distúrbios associadas(os) com a modulação de receptor de estrogênio seletiva, e para o tratamento ou a profilaxia relacionado(a) com condições ou distúrbios |
CA2617146A1 (en) * | 2005-07-29 | 2007-02-08 | Eli Lilly And Company | Crystalline non-solvated methanesulfonic acid salt of 1-(4-(2-piperidinylethoxy)phenoxy)-2-(3-hydroxyphenyl)-6-hydroxynaphthalene |
CA2738878C (en) | 2008-09-29 | 2013-08-13 | Eli Lilly And Company | Selective estrogen receptor modulator for the treatment of osteoarthritis |
DE102008057230A1 (de) * | 2008-11-11 | 2010-05-12 | Bayer Schering Pharma Aktiengesellschaft | Synergistische pharmazeutische Kombination mit einem Estrogenrezeptorantagonisten und einem Progestin |
US20110319379A1 (en) | 2009-03-11 | 2011-12-29 | Corbett Jeffrey W | Substituted Indazole Amides And Their Use As Glucokinase Activators |
KR20170127044A (ko) | 2010-06-16 | 2017-11-20 | 앙도르쉐르슈 인코포레이티드 | 에스트로겐-관련 질병의 치료 또는 예방 방법 |
JP6292744B2 (ja) * | 2012-09-19 | 2018-03-14 | 富士カプセル株式会社 | 医薬品組成物 |
RS57106B1 (sr) | 2013-02-19 | 2018-06-29 | Novartis Ag | Derivati benzotiofena i njihove kompozicije kao selektivni degraderi estrogenskog receptora |
US20220167618A1 (en) | 2019-03-08 | 2022-06-02 | Syngenta Crop Protection Ag | Pesticidally active azole-amide compounds |
EP3941915A1 (en) | 2019-03-20 | 2022-01-26 | Syngenta Crop Protection AG | Pesticidally active azole amide compounds |
BR112021018822A2 (pt) | 2019-03-22 | 2021-11-23 | Syngenta Crop Protection Ag | Derivados de n-[1-(5-bromo-2-pirimidin-2-il-1,2,4-triazol-3-il)etil]-2-ciclopropil-6-(trifluorometil)piridina-4-carboxamida e compostos relacionados como inseticidas |
UY38623A (es) | 2019-03-29 | 2020-10-30 | Syngenta Crop Protection Ag | Compuestos de diazina-amida activos como pesticidas |
KR20210149113A (ko) | 2019-04-05 | 2021-12-08 | 신젠타 크롭 프로텍션 아게 | 살충 활성 디아진-아미드 화합물 |
WO2021037614A1 (en) | 2019-08-23 | 2021-03-04 | Syngenta Crop Protection Ag | Pesticidally active pyrazine-amide compounds |
CN110526881B (zh) * | 2019-08-27 | 2020-09-22 | 河南省锐达医药科技有限公司 | 一种萘胺类化合物及其生物学可接受的盐,其制备方法和应用 |
US20230143596A1 (en) | 2020-02-27 | 2023-05-11 | Syngenta Crop Protection Ag | Pesticidally active diazine-bisamide compounds |
WO2022237904A1 (zh) * | 2021-05-14 | 2022-11-17 | 江苏亚虹医药科技股份有限公司 | 一种含萘环的化合物、含其的药物组合物及其应用 |
EP4352050A1 (en) | 2021-06-09 | 2024-04-17 | Syngenta Crop Protection AG | Pesticidally active diazine-amide compounds |
WO2023283315A1 (en) * | 2021-07-07 | 2023-01-12 | South Dakota Board Of Regents | Compositions and methods for treatment of cervical and ovarian cancer |
WO2024042187A1 (en) | 2022-08-25 | 2024-02-29 | Sanofi | Novel substituted benzothiophene-6-carboxylic acid derivatives, processes for their preparation and therapeutic uses thereof |
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US4418068A (en) | 1981-04-03 | 1983-11-29 | Eli Lilly And Company | Antiestrogenic and antiandrugenic benzothiophenes |
CA2135160A1 (en) | 1992-05-08 | 1993-11-25 | Masatoshi Inai | Indole derivative |
US6756388B1 (en) | 1993-10-12 | 2004-06-29 | Pfizer Inc. | Benzothiophenes and related compounds as estrogen agonists |
US5484798A (en) | 1994-09-20 | 1996-01-16 | Eli Lilly And Company | Benzothiopene compounds, compositions, and method of inhibiting restenosis |
US7501441B1 (en) | 1994-09-20 | 2009-03-10 | Eli Lilly And Company | Naphthyl compounds, intermediates, processes, compositions, and methods |
US5552412A (en) | 1995-01-09 | 1996-09-03 | Pfizer Inc | 5-substitued-6-cyclic-5,6,7,8-tetrahydronaphthalen2-ol compounds which are useful for treating osteoporosis |
US5998401A (en) | 1995-02-28 | 1999-12-07 | Eli Lilly And Company | Naphthyl compounds, intermediates, compositions, and methods |
IL117276A (en) | 1995-02-28 | 2001-10-31 | Lilly Co Eli | Benziophene compounds, their preparation and their related compositions |
US5599822A (en) | 1995-06-06 | 1997-02-04 | Eli Lilly And Company | Methods for minimizing bone loss |
DE69634045T2 (de) * | 1995-10-31 | 2005-05-19 | Eli Lilly And Co., Indianapolis | Antithrombotische diamine |
EA000767B1 (ru) * | 1996-02-22 | 2000-04-24 | Эли Лилли Энд Компани | Бензотиофены, составы, их содержащие, и способы с их использованием |
NZ314601A (en) | 1996-04-19 | 1999-09-29 | American Home Prod | 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole derivatives as estrogenic agents and pharmaceutical compositions |
CA2214070C (en) | 1996-08-29 | 2006-03-14 | Eli Lilly And Company | Dihydronaphthalene and naphthalene compounds, intermediates, formulations, and methods |
CA2213814A1 (en) | 1996-08-29 | 1998-02-28 | Henry Uhlman Bryant | Naphthalene compounds, intermediates, formulations, and methods |
CA2213810C (en) | 1996-08-29 | 2006-06-06 | Lewis Dale Pennington | Benzo¬b|thiophene compounds, intermediates, processes, compositions and methods |
ID19392A (id) | 1996-08-29 | 1998-07-09 | Lilly Co Eli | Senyawa naftil dan bahan pertengahan serta komposisi dan metode penggunaan |
CA2217810A1 (en) * | 1996-10-10 | 1998-04-10 | Eli Lilly And Company | 2-aryl-3-aminoaryloxynaphthyl compounds, intermediates, compositions and methods |
CA2218756A1 (en) | 1996-10-25 | 1998-04-25 | Kristin Sue Marron | Substituted benzo¢b!thiophene compounds having activity as selective estrogen receptor modulators |
EP1530470B9 (en) * | 2002-07-22 | 2010-04-07 | Eli Lilly And Company | Selective estrogen receptor modulators containing a phenylsulfonyl group |
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2003
- 2003-07-16 EP EP03765254A patent/EP1530470B9/en not_active Expired - Lifetime
- 2003-07-16 BR BR0312675-7A patent/BR0312675A/pt not_active IP Right Cessation
- 2003-07-16 WO PCT/IB2003/003349 patent/WO2004009086A1/en active Application Filing
- 2003-07-16 JP JP2004522648A patent/JP4656939B2/ja not_active Expired - Fee Related
- 2003-07-16 NZ NZ537138A patent/NZ537138A/en not_active IP Right Cessation
- 2003-07-16 DE DE60327931T patent/DE60327931D1/de not_active Expired - Lifetime
- 2003-07-16 PL PL03374845A patent/PL374845A1/xx unknown
- 2003-07-16 CN CN038172011A patent/CN1668303B/zh not_active Expired - Fee Related
- 2003-07-16 CA CA2490580A patent/CA2490580C/en not_active Expired - Fee Related
- 2003-07-16 AT AT03765254T patent/ATE433322T1/de not_active IP Right Cessation
- 2003-07-16 US US10/521,896 patent/US7399867B2/en not_active Expired - Fee Related
- 2003-07-16 ES ES03765254T patent/ES2326593T3/es not_active Expired - Lifetime
- 2003-07-16 MX MXPA05000898A patent/MXPA05000898A/es active IP Right Grant
- 2003-07-16 AU AU2003253129A patent/AU2003253129B2/en not_active Ceased
- 2003-07-16 EA EA200500248A patent/EA008024B1/ru not_active IP Right Cessation
- 2003-07-18 TW TW092119725A patent/TWI314860B/zh not_active IP Right Cessation
- 2003-07-18 PE PE2003000717A patent/PE20040678A1/es not_active Application Discontinuation
- 2003-07-18 MY MYPI20032711A patent/MY141879A/en unknown
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2004
- 2004-12-13 IL IL16574504A patent/IL165745A0/xx unknown
- 2004-12-30 HR HR20041233A patent/HRP20041233A2/hr not_active Application Discontinuation
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- 2005-01-18 CR CR7657A patent/CR7657A/es unknown
- 2005-01-19 EC EC2005005549A patent/ECSP055549A/es unknown
- 2005-01-20 CO CO05004232A patent/CO5680445A2/es not_active Application Discontinuation
- 2005-02-16 NO NO20050832A patent/NO20050832L/no not_active Application Discontinuation
- 2005-10-28 HK HK05109638.4A patent/HK1078003A1/xx not_active IP Right Cessation
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- 2008-04-09 US US12/100,093 patent/US7585977B2/en not_active Expired - Fee Related
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