NO328129B1 - Farmasoytisk sammensetning samt anvendelse - Google Patents
Farmasoytisk sammensetning samt anvendelse Download PDFInfo
- Publication number
- NO328129B1 NO328129B1 NO20005770A NO20005770A NO328129B1 NO 328129 B1 NO328129 B1 NO 328129B1 NO 20005770 A NO20005770 A NO 20005770A NO 20005770 A NO20005770 A NO 20005770A NO 328129 B1 NO328129 B1 NO 328129B1
- Authority
- NO
- Norway
- Prior art keywords
- methyl
- pharmaceutically acceptable
- benzyl
- nmr
- dmso
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 28
- 150000001875 compounds Chemical class 0.000 claims description 123
- 239000000262 estrogen Substances 0.000 claims description 68
- 229940011871 estrogen Drugs 0.000 claims description 65
- 150000003839 salts Chemical class 0.000 claims description 40
- 238000011282 treatment Methods 0.000 claims description 38
- 229960005309 estradiol Drugs 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 150000002367 halogens Chemical class 0.000 claims description 21
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 20
- 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 claims description 19
- 210000001519 tissue Anatomy 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 14
- 206010065687 Bone loss Diseases 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 9
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 claims description 6
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 229940035811 conjugated estrogen Drugs 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 229960002568 ethinylestradiol Drugs 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 201000009273 Endometriosis Diseases 0.000 claims description 5
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 229960003399 estrone Drugs 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 4
- 125000005907 alkyl ester group Chemical group 0.000 claims description 4
- 229930182833 estradiol Natural products 0.000 claims description 4
- HVDGDHBAMCBBLR-UHFFFAOYSA-N Enterolactone Natural products OC1=CC=CC(CC2C(C(=O)OC2)CC=2C=C(O)C=CC=2)=C1 HVDGDHBAMCBBLR-UHFFFAOYSA-N 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- PDRGHUMCVRDZLQ-UHFFFAOYSA-N d-equilenin Natural products OC1=CC=C2C(CCC3(C4CCC3=O)C)=C4C=CC2=C1 PDRGHUMCVRDZLQ-UHFFFAOYSA-N 0.000 claims description 3
- 230000006806 disease prevention Effects 0.000 claims description 3
- HVDGDHBAMCBBLR-WMLDXEAASA-N enterolactone Chemical compound OC1=CC=CC(C[C@@H]2[C@H](C(=O)OC2)CC=2C=C(O)C=CC=2)=C1 HVDGDHBAMCBBLR-WMLDXEAASA-N 0.000 claims description 3
- PDRGHUMCVRDZLQ-WMZOPIPTSA-N equilenin Chemical compound OC1=CC=C2C(CC[C@]3([C@H]4CCC3=O)C)=C4C=CC2=C1 PDRGHUMCVRDZLQ-WMZOPIPTSA-N 0.000 claims description 3
- ADFCQWZHKCXPAJ-GFCCVEGCSA-N equol Chemical compound C1=CC(O)=CC=C1[C@@H]1CC2=CC=C(O)C=C2OC1 ADFCQWZHKCXPAJ-GFCCVEGCSA-N 0.000 claims description 3
- 235000019126 equol Nutrition 0.000 claims description 3
- 230000012010 growth Effects 0.000 claims description 3
- ADFCQWZHKCXPAJ-UHFFFAOYSA-N indofine Natural products C1=CC(O)=CC=C1C1CC2=CC=C(O)C=C2OC1 ADFCQWZHKCXPAJ-UHFFFAOYSA-N 0.000 claims description 3
- 230000035755 proliferation Effects 0.000 claims description 3
- 159000000000 sodium salts Chemical class 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- DNWWBBQJWGPFNQ-UHFFFAOYSA-N 1-[[4-[2-(azepan-1-yl)ethoxy]-3-methoxyphenyl]methyl]-2-(4-hydroxyphenyl)-3-methylindol-5-ol Chemical compound C=1C=C(OCCN2CCCCCC2)C(OC)=CC=1CN(C1=CC=C(O)C=C1C=1C)C=1C1=CC=C(O)C=C1 DNWWBBQJWGPFNQ-UHFFFAOYSA-N 0.000 claims description 2
- 229930182834 17alpha-Estradiol Natural products 0.000 claims description 2
- VOXZDWNPVJITMN-SFFUCWETSA-N 17α-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-SFFUCWETSA-N 0.000 claims description 2
- BTDOAVCSLJTYJU-UHFFFAOYSA-N 2-(4-cyclopentyloxyphenyl)-3-methyl-1-[[4-(2-piperidin-1-ylethoxy)phenyl]methyl]indol-5-ol Chemical compound C=1C=C(OCCN2CCCCC2)C=CC=1CN1C2=CC=C(O)C=C2C(C)=C1C(C=C1)=CC=C1OC1CCCC1 BTDOAVCSLJTYJU-UHFFFAOYSA-N 0.000 claims description 2
- LKLLLUUCQTWHTR-UHFFFAOYSA-N 2-(4-ethoxyphenyl)-3-methyl-5-phenylmethoxy-1-[[4-(2-piperidin-1-ylethoxy)phenyl]methyl]indole Chemical compound C1=CC(OCC)=CC=C1C1=C(C)C2=CC(OCC=3C=CC=CC=3)=CC=C2N1CC(C=C1)=CC=C1OCCN1CCCCC1 LKLLLUUCQTWHTR-UHFFFAOYSA-N 0.000 claims description 2
- BJBPHCBRZFMJDW-UHFFFAOYSA-N 2-(4-hydroxyphenyl)-1-[[3-methoxy-4-(2-piperidin-1-ylethoxy)phenyl]methyl]-3-methylindol-5-ol Chemical compound C=1C=C(OCCN2CCCCC2)C(OC)=CC=1CN(C1=CC=C(O)C=C1C=1C)C=1C1=CC=C(O)C=C1 BJBPHCBRZFMJDW-UHFFFAOYSA-N 0.000 claims description 2
- WTRRIQCGCGCMQA-CBZIJGRNSA-N 3-Hydroxyestra-1,3,5(10),6-tetraen-17-one Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3C=CC2=C1 WTRRIQCGCGCMQA-CBZIJGRNSA-N 0.000 claims description 2
- VGEMBQMSELNKPV-UHFFFAOYSA-N 3-methyl-1-[[4-(2-piperidin-1-ylethoxy)phenyl]methyl]-2-[4-(trifluoromethyl)phenyl]indol-5-ol Chemical compound C=1C=C(OCCN2CCCCC2)C=CC=1CN1C2=CC=C(O)C=C2C(C)=C1C1=CC=C(C(F)(F)F)C=C1 VGEMBQMSELNKPV-UHFFFAOYSA-N 0.000 claims description 2
- MUISBZFKLKRXON-UHFFFAOYSA-N 3-methyl-2-phenyl-1-[[4-(2-piperidin-1-ylethoxy)phenyl]methyl]indole Chemical compound C=1C=C(OCCN2CCCCC2)C=CC=1CN1C2=CC=CC=C2C(C)=C1C1=CC=CC=C1 MUISBZFKLKRXON-UHFFFAOYSA-N 0.000 claims description 2
- IPCBICMFFHDIIG-UHFFFAOYSA-N 4-[5-fluoro-3-methyl-1-[[4-(2-piperidin-1-ylethoxy)phenyl]methyl]indol-2-yl]phenol Chemical compound C=1C=C(OCCN2CCCCC2)C=CC=1CN1C2=CC=C(F)C=C2C(C)=C1C1=CC=C(O)C=C1 IPCBICMFFHDIIG-UHFFFAOYSA-N 0.000 claims description 2
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
- 230000002159 abnormal effect Effects 0.000 claims description 2
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 2
- QXNDZONIWRINJR-UHFFFAOYSA-N azocane Chemical compound C1CCCNCCC1 QXNDZONIWRINJR-UHFFFAOYSA-N 0.000 claims description 2
- UCJGJABZCDBEDK-UHFFFAOYSA-N bazedoxifene Chemical compound C=1C=C(OCCN2CCCCCC2)C=CC=1CN1C2=CC=C(O)C=C2C(C)=C1C1=CC=C(O)C=C1 UCJGJABZCDBEDK-UHFFFAOYSA-N 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 238000011161 development Methods 0.000 claims description 2
- 230000018109 developmental process Effects 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 210000004696 endometrium Anatomy 0.000 claims 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 483
- 238000005481 NMR spectroscopy Methods 0.000 description 155
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 85
- 238000000034 method Methods 0.000 description 75
- 229910001868 water Inorganic materials 0.000 description 64
- 238000006243 chemical reaction Methods 0.000 description 58
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 55
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 45
- 239000000243 solution Substances 0.000 description 43
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 41
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 36
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 36
- 239000000203 mixture Substances 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
- 235000019439 ethyl acetate Nutrition 0.000 description 33
- 239000007787 solid Substances 0.000 description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 32
- 230000015572 biosynthetic process Effects 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 31
- 239000000047 product Substances 0.000 description 29
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 28
- 239000003921 oil Substances 0.000 description 26
- 235000019198 oils Nutrition 0.000 description 25
- 238000003786 synthesis reaction Methods 0.000 description 25
- 238000009472 formulation Methods 0.000 description 24
- 235000002639 sodium chloride Nutrition 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 230000000694 effects Effects 0.000 description 22
- 210000004027 cell Anatomy 0.000 description 21
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- 239000000460 chlorine Substances 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 14
- 241000700159 Rattus Species 0.000 description 14
- 239000006260 foam Substances 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 210000000988 bone and bone Anatomy 0.000 description 13
- 235000019441 ethanol Nutrition 0.000 description 13
- ZFRKQXVRDFCRJG-UHFFFAOYSA-N skatole Chemical class C1=CC=C2C(C)=CNC2=C1 ZFRKQXVRDFCRJG-UHFFFAOYSA-N 0.000 description 13
- 239000007858 starting material Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000000328 estrogen antagonist Substances 0.000 description 12
- -1 phenol Chemical class 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 150000002475 indoles Chemical class 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- 210000004291 uterus Anatomy 0.000 description 11
- 230000001833 anti-estrogenic effect Effects 0.000 description 10
- 239000012267 brine Substances 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 229940046836 anti-estrogen Drugs 0.000 description 8
- 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 description 8
- 239000002609 medium Substances 0.000 description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 210000000481 breast Anatomy 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 239000000583 progesterone congener Substances 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 206010027304 Menopausal symptoms Diseases 0.000 description 6
- 229910019142 PO4 Inorganic materials 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 239000003610 charcoal Substances 0.000 description 6
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 235000021317 phosphate Nutrition 0.000 description 6
- 239000002953 phosphate buffered saline Substances 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- UFZKWTITXBRSPK-UHFFFAOYSA-N (4-phenylmethoxyphenyl)hydrazine Chemical compound C1=CC(NN)=CC=C1OCC1=CC=CC=C1 UFZKWTITXBRSPK-UHFFFAOYSA-N 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 5
- 229920002307 Dextran Polymers 0.000 description 5
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 5
- 206010014733 Endometrial cancer Diseases 0.000 description 5
- 206010014759 Endometrial neoplasm Diseases 0.000 description 5
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- MOIPGXQKZSZOQX-UHFFFAOYSA-N carbonyl bromide Chemical class BrC(Br)=O MOIPGXQKZSZOQX-UHFFFAOYSA-N 0.000 description 5
- 210000003169 central nervous system Anatomy 0.000 description 5
- 210000000172 cytosol Anatomy 0.000 description 5
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 5
- 239000012091 fetal bovine serum Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 5
- 239000002243 precursor Substances 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- CHIFTAQVXHNVRW-UHFFFAOYSA-N 1h-indole-3-carbonitrile Chemical compound C1=CC=C2C(C#N)=CNC2=C1 CHIFTAQVXHNVRW-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 4
- 150000001649 bromium compounds Chemical class 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 4
- QTTMOCOWZLSYSV-QWAPEVOJSA-M equilin sodium sulfate Chemical compound [Na+].[O-]S(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4C3=CCC2=C1 QTTMOCOWZLSYSV-QWAPEVOJSA-M 0.000 description 4
- 230000001076 estrogenic effect Effects 0.000 description 4
- VUCAHVBMSFIGAI-ZFINNJDLSA-M estrone sodium sulfate Chemical compound [Na+].[O-]S(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 VUCAHVBMSFIGAI-ZFINNJDLSA-M 0.000 description 4
- 150000007857 hydrazones Chemical class 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000012423 maintenance Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
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- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Physical Education & Sports Medicine (AREA)
- Diabetes (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Gynecology & Obstetrics (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Pregnancy & Childbirth (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US7956198A | 1998-05-15 | 1998-05-15 | |
| PCT/US1999/010217 WO1999059581A1 (en) | 1998-05-15 | 1999-05-11 | 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole in combination with estrogens |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO20005770D0 NO20005770D0 (no) | 2000-11-14 |
| NO20005770L NO20005770L (no) | 2001-01-12 |
| NO328129B1 true NO328129B1 (no) | 2009-12-14 |
Family
ID=22151320
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO20005770A NO328129B1 (no) | 1998-05-15 | 2000-11-14 | Farmasoytisk sammensetning samt anvendelse |
| NO2015015C NO2015015I2 (no) | 1998-05-15 | 2015-06-02 | Bazedoksifen, eventuelt på form av et farmasøytisk akseptabelt salt slik som acetatsaltet, og konjugerte østrogener. |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO2015015C NO2015015I2 (no) | 1998-05-15 | 2015-06-02 | Bazedoksifen, eventuelt på form av et farmasøytisk akseptabelt salt slik som acetatsaltet, og konjugerte østrogener. |
Country Status (42)
| Country | Link |
|---|---|
| EP (1) | EP1076558B1 (zh) |
| JP (3) | JP2002515431A (zh) |
| KR (1) | KR100620772B1 (zh) |
| CN (1) | CN1230163C (zh) |
| AP (1) | AP1424A (zh) |
| AR (1) | AR020074A1 (zh) |
| AT (1) | ATE245026T1 (zh) |
| AU (1) | AU760378B2 (zh) |
| BE (1) | BE2015C026I2 (zh) |
| BG (1) | BG64783B1 (zh) |
| BR (1) | BR9911040A (zh) |
| CA (1) | CA2329530A1 (zh) |
| CU (1) | CU23241B7 (zh) |
| CY (1) | CY2015020I1 (zh) |
| CZ (1) | CZ299334B6 (zh) |
| DE (1) | DE69909616T2 (zh) |
| DK (1) | DK1076558T3 (zh) |
| EA (1) | EA005932B1 (zh) |
| EE (1) | EE04262B1 (zh) |
| ES (1) | ES2203131T3 (zh) |
| FR (1) | FR15C0035I2 (zh) |
| GE (1) | GEP20033079B (zh) |
| HK (1) | HK1031691A1 (zh) |
| HR (1) | HRP20000778B1 (zh) |
| HU (2) | HU226587B1 (zh) |
| ID (1) | ID26890A (zh) |
| IL (1) | IL139130A (zh) |
| IN (1) | IN192220B (zh) |
| LT (1) | LTC1076558I2 (zh) |
| LU (1) | LU92699I2 (zh) |
| NO (2) | NO328129B1 (zh) |
| NZ (1) | NZ508200A (zh) |
| OA (1) | OA11552A (zh) |
| PL (1) | PL194750B1 (zh) |
| PT (1) | PT1076558E (zh) |
| SI (1) | SI1076558T1 (zh) |
| SK (1) | SK284666B6 (zh) |
| TR (1) | TR200003377T2 (zh) |
| TW (1) | TW565554B (zh) |
| UA (1) | UA66861C2 (zh) |
| WO (1) | WO1999059581A1 (zh) |
| ZA (1) | ZA200006959B (zh) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT1076558E (pt) * | 1998-05-15 | 2003-11-28 | Wyeth Corp | 2-fenil-1-¬4-(2-aminoetoxi)-benzil|-indole em combinacao com estrogenios |
| US6465445B1 (en) | 1998-06-11 | 2002-10-15 | Endorecherche, Inc. | Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors |
| US7005428B1 (en) | 1998-06-11 | 2006-02-28 | Endorecherche, Inc. | Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors |
| CN1390126B (zh) | 1999-07-06 | 2012-06-13 | 恩多研究公司 | 选择性雌激素受体调节剂在制备用于治疗或降低肥胖症发展危险性的药物中的用途 |
| US20020013327A1 (en) * | 2000-04-18 | 2002-01-31 | Lee Andrew G. | Compositions and methods for treating female sexual dysfunction |
| US6455568B2 (en) | 2000-07-06 | 2002-09-24 | Wyeth | Combination therapy for inhibiting sphincter incontinence |
| CN1450913A (zh) * | 2000-07-06 | 2003-10-22 | 惠氏公司 | 二膦酸酯、雌激素药物以及任选雌激素的联合应用 |
| AU2001271785A1 (en) * | 2000-07-06 | 2002-01-21 | American Home Products Corporation | Combinations of statins, estrogenic agents and optionally estrogens |
| WO2002003992A2 (en) * | 2000-07-06 | 2002-01-17 | Wyeth | Use of substituted indole compounds for treating prosthesis-related bone degeneration |
| WO2002003989A2 (en) * | 2000-07-06 | 2002-01-17 | Wyeth | Use of substituted indole compounds for treating sphincter incontinence |
| US6376486B1 (en) | 2000-07-06 | 2002-04-23 | American Home Products Corporation | Methods of inhibiting sphincter incontinence |
| DE10117441A1 (de) * | 2001-04-03 | 2002-10-10 | Schering Ag | 1-Indolylderivate, deren Verwendung zur Herstellung von Arzneimitteln, ein Verfahren zur Herstellung der 1-Indolylderivate sowie 1-Indolylderivate enthaltende pharmzeutische Präparate |
| PL367094A1 (en) | 2001-07-31 | 2005-02-21 | Pfizer Products Inc. | Pharmaceutical compositions, kits and methods comprising combinations of estrogen agonists/antagonists, estrogens and progestins |
| KR100470274B1 (ko) | 2002-11-08 | 2005-02-05 | 진 장 | 덮개층을 이용한 비정질 물질의 상 변화 방법 |
| US7781478B2 (en) | 2004-07-14 | 2010-08-24 | Ptc Therapeutics, Inc. | Methods for treating hepatitis C |
| FR2880625B1 (fr) * | 2005-01-07 | 2007-03-09 | Sanofi Aventis Sa | Derives de n-(heteroaryl)-1h-indole-2-carboxamides, leur preparation et leur application en therapeutique |
| MX2010011408A (es) | 2008-04-16 | 2010-12-20 | Karobio Ab | Ligandos de receptor de estrogeno novedosos. |
| AR072297A1 (es) * | 2008-06-27 | 2010-08-18 | Novartis Ag | Derivados de indol-2-il-piridin-3-ilo, composicion farmaceutica que los comprende y su uso en medicamentos para el tratamiento de enfermedades mediadas por la sintasa aldosterona. |
| GB201113538D0 (en) | 2011-08-04 | 2011-09-21 | Karobio Ab | Novel estrogen receptor ligands |
| CN102690225B (zh) * | 2012-04-11 | 2014-12-24 | 南京友杰医药科技有限公司 | 巴多昔芬的合成方法 |
| CN103709090A (zh) * | 2014-01-16 | 2014-04-09 | 江苏万特制药有限公司 | 醋酸巴多昔芬的制备方法及其关键中间体 |
| CN103739540B (zh) * | 2014-01-20 | 2016-05-04 | 华润赛科药业有限责任公司 | 一种醋酸巴多昔芬中间体的制备方法 |
| CN105669518B (zh) * | 2014-12-04 | 2019-06-04 | 上海医药集团股份有限公司 | 醋酸巴多昔芬及其a晶型的制备方法 |
| BR112020011668A2 (pt) * | 2017-12-15 | 2020-11-17 | Bristol-Myers Squibb Company | compostos de éter de indol substituído |
| IT201800006562A1 (it) * | 2018-06-21 | 2019-12-21 | Procedimento e intermedi utili per la preparazione di indoli | |
| WO2021185291A1 (zh) * | 2020-03-17 | 2021-09-23 | 南京明德新药研发有限公司 | 蛋白降解调节剂与其使用方法 |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4729999A (en) * | 1984-10-12 | 1988-03-08 | Bcm Technologies | Antiestrogen therapy for symptoms of estrogen deficiency |
| US5496844A (en) * | 1992-05-08 | 1996-03-05 | Otsuka Pharmaceutical Factory, Inc. | Indole derivatives |
| TW366342B (en) * | 1992-07-28 | 1999-08-11 | Lilly Co Eli | The use of 2-phenyl-3-aroylbenzothiophenes in inhibiting bone loss |
| GB9326332D0 (en) * | 1993-12-23 | 1994-02-23 | Karo Bio | Indole derivatives |
| DE4426625A1 (de) * | 1994-07-27 | 1996-03-14 | Schering Ag | 2-Phenylindole, Verfahren zu deren Herstellung, diese enthaltende pharmazeutische Präparate sowie deren Verwendung zur Herstellung von Arzneimitteln |
| TW397821B (en) * | 1996-04-19 | 2000-07-11 | American Home Produits Corp | 3-[4-(2-phenyl-indole-1-ylmethyl)-phenyl]-acrylamides and 2-phenyl-1-[4-(amino-1-yl-alk-1-ynyl)-benzyl]-1H-indol-5-ol as well as pharmaceutical compositions of estrogenic agents thereof |
| ATE206701T1 (de) * | 1996-04-19 | 2001-10-15 | American Home Prod | Östrogene verbindungen |
| JP2000514074A (ja) * | 1996-07-09 | 2000-10-24 | スミスクライン・ビーチャム・ソシエタ・ペル・アチオニ | 骨粗鬆症の治療のためのインドール誘導体 |
| US5672609A (en) * | 1996-07-18 | 1997-09-30 | Eli Lilly And Company | Pyridine compounds, intermediates compositions and methods of use |
| EP1777214A3 (en) * | 1997-10-15 | 2007-05-09 | Wyeth | Novel aryloxy-alkyl-dialkylamines |
| CA2308069A1 (en) * | 1997-10-28 | 1999-05-06 | Merck & Co., Inc. | Antagonists of gonadotropin releasing hormone |
| UA68365C2 (en) * | 1997-11-06 | 2004-08-16 | Wyeth Corp | Peroral contraception by combination of anti-estrogen and progestin |
| PT1076558E (pt) * | 1998-05-15 | 2003-11-28 | Wyeth Corp | 2-fenil-1-¬4-(2-aminoetoxi)-benzil|-indole em combinacao com estrogenios |
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1999
- 1999-05-11 PT PT99921834T patent/PT1076558E/pt unknown
- 1999-05-11 CZ CZ20004254A patent/CZ299334B6/cs not_active IP Right Cessation
- 1999-05-11 OA OA1200000311A patent/OA11552A/en unknown
- 1999-05-11 DE DE69909616T patent/DE69909616T2/de not_active Expired - Lifetime
- 1999-05-11 KR KR1020007012821A patent/KR100620772B1/ko not_active IP Right Cessation
- 1999-05-11 EA EA200001193A patent/EA005932B1/ru not_active IP Right Cessation
- 1999-05-11 IL IL13913099A patent/IL139130A/xx not_active IP Right Cessation
- 1999-05-11 ID IDW20002312A patent/ID26890A/id unknown
- 1999-05-11 EE EEP200000652A patent/EE04262B1/xx active Protection Beyond IP Right Term
- 1999-05-11 BR BR9911040-7A patent/BR9911040A/pt not_active Application Discontinuation
- 1999-05-11 AU AU38944/99A patent/AU760378B2/en not_active Expired
- 1999-05-11 JP JP2000549246A patent/JP2002515431A/ja not_active Withdrawn
- 1999-05-11 CN CNB99808655XA patent/CN1230163C/zh not_active Expired - Lifetime
- 1999-05-11 CA CA002329530A patent/CA2329530A1/en not_active Abandoned
- 1999-05-11 UA UA2000127184A patent/UA66861C2/uk unknown
- 1999-05-11 ES ES99921834T patent/ES2203131T3/es not_active Expired - Lifetime
- 1999-05-11 AP APAP/P/2000/001970A patent/AP1424A/en active
- 1999-05-11 NZ NZ508200A patent/NZ508200A/en not_active IP Right Cessation
- 1999-05-11 SK SK1720-2000A patent/SK284666B6/sk not_active IP Right Cessation
- 1999-05-11 HU HU0103096A patent/HU226587B1/hu active Protection Beyond IP Right Term
- 1999-05-11 AT AT99921834T patent/ATE245026T1/de active
- 1999-05-11 WO PCT/US1999/010217 patent/WO1999059581A1/en active IP Right Grant
- 1999-05-11 GE GEAP19995675A patent/GEP20033079B/en unknown
- 1999-05-11 DK DK99921834T patent/DK1076558T3/da active
- 1999-05-11 EP EP99921834A patent/EP1076558B1/en not_active Expired - Lifetime
- 1999-05-11 TR TR2000/03377T patent/TR200003377T2/xx unknown
- 1999-05-11 SI SI9930339T patent/SI1076558T1/xx unknown
- 1999-05-11 PL PL99345268A patent/PL194750B1/pl unknown
- 1999-05-13 TW TW088107747A patent/TW565554B/zh not_active IP Right Cessation
- 1999-05-14 AR ARP990102310A patent/AR020074A1/es not_active Application Discontinuation
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2000
- 2000-11-08 BG BG104930A patent/BG64783B1/bg unknown
- 2000-11-14 NO NO20005770A patent/NO328129B1/no not_active IP Right Cessation
- 2000-11-15 CU CU20000255A patent/CU23241B7/es not_active IP Right Cessation
- 2000-11-15 HR HR20000778A patent/HRP20000778B1/xx not_active IP Right Cessation
- 2000-11-27 ZA ZA200006959A patent/ZA200006959B/en unknown
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2001
- 2001-03-26 HK HK01102189A patent/HK1031691A1/xx not_active IP Right Cessation
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2008
- 2008-07-29 JP JP2008195115A patent/JP5607871B2/ja not_active Expired - Lifetime
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2014
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2015
- 2015-04-15 LT LTPA2015018C patent/LTC1076558I2/lt unknown
- 2015-04-17 HU HUS1500023C patent/HUS1500023I1/hu unknown
- 2015-04-24 LU LU92699C patent/LU92699I2/xx unknown
- 2015-04-28 BE BE2015C026C patent/BE2015C026I2/fr unknown
- 2015-05-06 FR FR15C0035C patent/FR15C0035I2/fr active Active
- 2015-05-29 CY CY2015020C patent/CY2015020I1/el unknown
- 2015-06-02 NO NO2015015C patent/NO2015015I2/no not_active IP Right Cessation
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Free format text: PRODUCT NAME: BAZEDOKSIFEN, EVENTUELT PA FORM AV ET FARMASOEYTISK AKSEPTABELT SALT SLIK SOM ACETATSALTET, OG KONJUGERTE OESTROGENER.; REG. NO/DATE: EU/1/14/960 20150112 Spc suppl protection certif: 2015015 Filing date: 20150602 Extension date: 20240511 |
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