LV11177B - Novel pharmaceutical product - Google Patents
Novel pharmaceutical product Download PDFInfo
- Publication number
- LV11177B LV11177B LVP-95-284A LV950284A LV11177B LV 11177 B LV11177 B LV 11177B LV 950284 A LV950284 A LV 950284A LV 11177 B LV11177 B LV 11177B
- Authority
- LV
- Latvia
- Prior art keywords
- benzo
- benzoyl
- piperidinoethoxy
- hydroxy
- reaction
- Prior art date
Links
- 239000000825 pharmaceutical preparation Substances 0.000 title description 3
- 229940127557 pharmaceutical product Drugs 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 63
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 28
- BKXVVCILCIUCLG-UHFFFAOYSA-N raloxifene hydrochloride Chemical compound [H+].[Cl-].C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 BKXVVCILCIUCLG-UHFFFAOYSA-N 0.000 claims description 22
- 239000013078 crystal Substances 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 239000012535 impurity Substances 0.000 claims description 14
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims description 8
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 claims description 8
- 238000002441 X-ray diffraction Methods 0.000 claims description 7
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 4
- 229910052802 copper Inorganic materials 0.000 claims description 4
- 239000010949 copper Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 230000005855 radiation Effects 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- OFHAGSNEHHNRSV-UHFFFAOYSA-N 1-benzothiophene;hydrochloride Chemical compound Cl.C1=CC=C2SC=CC2=C1 OFHAGSNEHHNRSV-UHFFFAOYSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims 1
- 230000009965 odorless effect Effects 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 93
- 238000006243 chemical reaction Methods 0.000 description 40
- 239000000203 mixture Substances 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 32
- 239000002904 solvent Substances 0.000 description 32
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- 238000005917 acylation reaction Methods 0.000 description 28
- 238000000034 method Methods 0.000 description 25
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 24
- 230000010933 acylation Effects 0.000 description 24
- 238000006900 dealkylation reaction Methods 0.000 description 24
- 239000012453 solvate Substances 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 230000020335 dealkylation Effects 0.000 description 17
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 16
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 15
- 229910052796 boron Inorganic materials 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- 229910052782 aluminium Inorganic materials 0.000 description 10
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 9
- -1 aluminum alkoxides Chemical class 0.000 description 9
- 239000002178 crystalline material Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 8
- 125000001309 chloro group Chemical group Cl* 0.000 description 8
- 239000002002 slurry Substances 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 229960000443 hydrochloric acid Drugs 0.000 description 7
- 235000011167 hydrochloric acid Nutrition 0.000 description 7
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 6
- CFXQEHVMCRXUSD-UHFFFAOYSA-N 1,2,3-Trichloropropane Chemical compound ClCC(Cl)CCl CFXQEHVMCRXUSD-UHFFFAOYSA-N 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- 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 compound 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 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- 235000019645 odor Nutrition 0.000 description 5
- 238000005580 one pot reaction Methods 0.000 description 5
- 238000000634 powder X-ray diffraction Methods 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- APMJBTGDXWLDED-UHFFFAOYSA-N 1,2-dichloroethane;[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone;hydrochloride Chemical compound Cl.ClCCCl.C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 APMJBTGDXWLDED-UHFFFAOYSA-N 0.000 description 4
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 229960004622 raloxifene Drugs 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 3
- VFLQQZCRHPIGJU-UHFFFAOYSA-N 1-(2-chloroethyl)piperidine;hydron;chloride Chemical compound Cl.ClCCN1CCCCC1 VFLQQZCRHPIGJU-UHFFFAOYSA-N 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 150000003568 thioethers Chemical class 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 2
- HRWAGCVMOGWQJF-UHFFFAOYSA-N 6-methoxy-2-(4-methoxyphenyl)-1-benzothiophene Chemical compound C1=CC(OC)=CC=C1C1=CC2=CC=C(OC)C=C2S1 HRWAGCVMOGWQJF-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- MPPNHHUKVJDWQV-UHFFFAOYSA-N [6-methoxy-2-(4-methoxyphenyl)-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone;hydrochloride Chemical compound Cl.C1=CC(OC)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(OC)C=C2S1 MPPNHHUKVJDWQV-UHFFFAOYSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 239000003849 aromatic solvent Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 239000000356 contaminant Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 229920000137 polyphosphoric acid Polymers 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 229960002119 raloxifene hydrochloride Drugs 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- AVGQTJUPLKNPQP-UHFFFAOYSA-N 1,1,1-trichloropropane Chemical compound CCC(Cl)(Cl)Cl AVGQTJUPLKNPQP-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- KNKRKFALVUDBJE-UHFFFAOYSA-N 1,2-dichloropropane Chemical compound CC(Cl)CCl KNKRKFALVUDBJE-UHFFFAOYSA-N 0.000 description 1
- WNRWEBKEQARBKV-UHFFFAOYSA-N 1-(2-chloroethyl)piperidine Chemical compound ClCCN1CCCCC1 WNRWEBKEQARBKV-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- XQJAHBHCLXUGEP-UHFFFAOYSA-N 2-bromo-1-(4-methoxyphenyl)ethanone Chemical compound COC1=CC=C(C(=O)CBr)C=C1 XQJAHBHCLXUGEP-UHFFFAOYSA-N 0.000 description 1
- QMVAZEHZOPDGHA-UHFFFAOYSA-N 3-methoxybenzenethiol Chemical compound COC1=CC=CC(S)=C1 QMVAZEHZOPDGHA-UHFFFAOYSA-N 0.000 description 1
- WHKJLXLFQNXNNR-UHFFFAOYSA-N 4-(2-piperidin-1-ylethoxy)benzoyl chloride;hydrochloride Chemical compound Cl.C1=CC(C(=O)Cl)=CC=C1OCCN1CCCCC1 WHKJLXLFQNXNNR-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical class [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- KOFDGHCTXVZHIH-UHFFFAOYSA-N [2-(4-hydroxyphenyl)-6-methoxy-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone Chemical compound C=1C=C(O)C=CC=1C=1SC2=CC(OC)=CC=C2C=1C(=O)C(C=C1)=CC=C1OCCN1CCCCC1 KOFDGHCTXVZHIH-UHFFFAOYSA-N 0.000 description 1
- CTMKIRXPVZYQJP-UHFFFAOYSA-N [6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]-(4-hydroxyphenyl)methanone Chemical compound C1=CC(O)=CC=C1C(=O)C1=C(C=2C=CC(O)=CC=2)SC2=CC(O)=CC=C12 CTMKIRXPVZYQJP-UHFFFAOYSA-N 0.000 description 1
- JBIHVYAFZJAHFD-UHFFFAOYSA-N [6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidin-1-ylethoxy)benzoyl]-1-benzothiophen-5-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC(C(=O)C=3C=CC(OCCN4CCCCC4)=CC=3)=C(O)C=C2S1 JBIHVYAFZJAHFD-UHFFFAOYSA-N 0.000 description 1
- ZIQUILNLPRCFRB-UHFFFAOYSA-N [6-hydroxy-2-(4-hydroxyphenyl)-7-[4-(2-piperidin-1-ylethoxy)benzoyl]-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C(C(=O)C=3C=CC(OCCN4CCCCC4)=CC=3)=C2S1 ZIQUILNLPRCFRB-UHFFFAOYSA-N 0.000 description 1
- RPDULJACWWWFGZ-UHFFFAOYSA-N [6-hydroxy-2-(4-methoxyphenyl)-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone Chemical compound C1=CC(OC)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 RPDULJACWWWFGZ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001346 alkyl aryl ethers Chemical class 0.000 description 1
- 150000001356 alkyl thiols Chemical class 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- REDXJYDRNCIFBQ-UHFFFAOYSA-N aluminium(3+) Chemical compound [Al+3] REDXJYDRNCIFBQ-UHFFFAOYSA-N 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007805 chemical reaction reactant Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 229940075894 denatured ethanol Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- GEBZGEGHFMUFJA-UHFFFAOYSA-N ethyl 4-(2-piperidin-1-ylethoxy)benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1OCCN1CCCCC1 GEBZGEGHFMUFJA-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- CMVTYSMYHSVDIU-UHFFFAOYSA-N hydron;4-(2-piperidin-1-ylethoxy)benzoic acid;chloride Chemical compound Cl.C1=CC(C(=O)O)=CC=C1OCCN1CCCCC1 CMVTYSMYHSVDIU-UHFFFAOYSA-N 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- UKTBQGVEVDLQQH-UHFFFAOYSA-N methyl 4-(2-piperidin-1-ylethoxy)benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1OCCN1CCCCC1 UKTBQGVEVDLQQH-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- JBJTXURYSFPIAH-UHFFFAOYSA-N o-propyl 4-(2-piperidin-1-ylethoxy)benzenecarbothioate Chemical compound C1=CC(C(=S)OCCC)=CC=C1OCCN1CCCCC1 JBJTXURYSFPIAH-UHFFFAOYSA-N 0.000 description 1
- WLGDAKIJYPIYLR-UHFFFAOYSA-M octane-1-sulfonate Chemical compound CCCCCCCCS([O-])(=O)=O WLGDAKIJYPIYLR-UHFFFAOYSA-M 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 150000003577 thiophenes Chemical class 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- 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
- C07D409/10—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 linked by a carbon chain containing aromatic rings
-
- 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
-
- 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
- A61P15/18—Feminine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Gynecology & Obstetrics (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Claims (7)
- LV 11177 Izgudrojuma formula 1. 6-Hidroksi-2-(4-hidroksifenil)-3-[4-(2-piperidinoetoksi)-benzoil]benzo[b]tiofēna hidrogenhlorīds nesolvatētu kristālu formā, kas dod pamatā šādu rentgenstaru difrakcijas ainu ar vara katoda starojumu: 13,3864 71,31 9,3598 .33,16 8,4625 2,08 7,3888 7,57 6,9907 5,80 6,6346 51,04 6,1717 29,57 5,9975 5,67 5,9135 9,87 5,6467 38,47 5,4773 10,54 5,2994 4,74 4,8680 4,03 4,7910 5,98 4,6614 57,50 4,5052 5,75 4,3701 9,03 4,2516 69,99 4,2059 57,64 4,1740 65,07 4,0819 12,44 3,9673 22,53 3,9318 100,00 3,8775 9,07 3,7096 33,38 3,6561 21,65 1 l/lo(x100) 3,5576 3,36 3,5037 7,97 3,4522 18,02 3,4138 4,65 3,2738 10,23 3,1857 8,90 3,1333 6,24 3,0831 9,43 3,0025 12,13 2,9437 4,96 2,8642 7,70 2,7904 11,95 2,7246 3,05 2,6652 3,32 2,5882 7,30 d-liniju attālumi (angstrēmos)
- 2. benzoil]benzo[b]tiofēna hidrogenhlorīds nesolvatētu kristālu formā pēc 1. punkta, kurā 6-hidroksi-2-(4-hidroksifenil)-3-[4-(2-piperidinoetoksi)-benzoil]-benzo[b]tiofēna hidrogenhlorīda saturs ir vismaz 95 masas %.
- 3. 6-Hidroksi-2-(4-hidroksifenil)-3-[4-(2-piperidinoetQksL)r benzoil]benzo[b]tiofēna hidrogenhlorīds kristālu formā pēc 1. vai 2. punkta, kas praktiski nesatur hlorbenzolu.
- 4. 6-Hidroksi-2-(4-hidroksifenil)-3-[4-(2-piperidinoetoksi)-benzoil]benzo[b]tiofēna hidrogenhlorīds kristālu formā pēc 1., 2. vai 3. punkta, kas praktiski nesatur alumīnija sālis vai alumīnijorganisko savienojumu piemaisījumus.
- 5. 6-Hidroksi-2-(4-hidroksifenil)-3-[4-(2-piperidinoetQksi)-benzoil]benzo[b]tiofēna hidrogenhlorīds kristālu formā pēc jebkura no iepriekšējiem punktiem, kas praktiski ir bez smaržas.
- 6. Farmaceitiskā kompozīcija, kas satur kristālisko vielu pēc jebkura no iepriekšējiem punktiem un vienu vai vairākus farmaceitiski pieņemamus nesējus, atšķaidītājus vai pildvielas.
- 7. Savienojuma kristāliskā veidā pēc jebkura no 1.-5. punktiem pielietojums par medikamentu. 2
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/308,325 US5629425A (en) | 1994-09-19 | 1994-09-19 | Haloalkyl hemisolvates of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-piperidinoethoxy)-benzoyl]benzo[b]thiophene |
| US42791495A | 1995-04-26 | 1995-04-26 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| LV11177A LV11177A (lv) | 1996-04-20 |
| LV11177B true LV11177B (en) | 1996-08-20 |
Family
ID=26976194
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| LVP-95-284A LV11177B (en) | 1994-09-19 | 1995-09-18 | Novel pharmaceutical product |
| LVP-95-285A LV11178B (en) | 1994-09-19 | 1995-09-18 | Synthesis of 3-£4-(2-aminoethoxy) benzoyl|-2-aryl-6-hydroxybenzo £b| thiophenes |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| LVP-95-285A LV11178B (en) | 1994-09-19 | 1995-09-18 | Synthesis of 3-£4-(2-aminoethoxy) benzoyl|-2-aryl-6-hydroxybenzo £b| thiophenes |
Country Status (50)
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| USRE38968E1 (en) | 1992-07-28 | 2006-02-07 | Eli Lilly And Company | Methods for inhibiting bone loss using 6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thien-3-yl-4-[2-(piperidin-1-yl) ethoxyphenylimethanone hydrochloride |
| US5478847A (en) | 1994-03-02 | 1995-12-26 | Eli Lilly And Company | Methods of use for inhibiting bone loss and lowering serum cholesterol |
| CO4410191A1 (es) * | 1994-09-19 | 1997-01-09 | Lilly Co Eli | SINTESIS DE 3-[4-(2-AMINOETOXI)BENZOIL]-2-ARIL-6- HIDROXIBENZO [b] TIOFENOS |
| DE69739855D1 (de) * | 1996-03-26 | 2010-06-02 | Lilly Co Eli | Benzothiophene und denen enthaltende zusammensetzungen |
| US6458811B1 (en) * | 1996-03-26 | 2002-10-01 | Eli Lilly And Company | Benzothiophenes formulations containing same and methods |
| ZA979723B (en) | 1996-10-30 | 1999-07-29 | Lilly Co Eli | Methods of preventing breast cancer. |
| CA2236254A1 (en) * | 1997-04-30 | 1998-10-30 | David Warren Hoard | Process for preparing benzo¬b|thiophenes |
| CA2372720C (en) | 1999-05-04 | 2007-09-11 | John Antony Kanis | Androgen glycosides and androgenic activity thereof |
| US6921827B2 (en) * | 2000-11-27 | 2005-07-26 | Eli Lilly And Company | Process for preparing 3-aryl-benzo{b} thiophenes |
| EP1490090A4 (en) | 2002-02-22 | 2006-09-20 | New River Pharmaceuticals Inc | SYSTEMS FOR DELIVERING ACTIVE AGENTS AND METHODS FOR PROTECTING AND DELIVERING ACTIVE AGENTS |
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| CN104496963A (zh) * | 2014-12-02 | 2015-04-08 | 千辉药业（安徽）有限责任公司 | 一种盐酸雷洛昔芬的制备方法 |
| WO2017211979A1 (en) | 2016-06-10 | 2017-12-14 | Boehringer Ingelheim International Gmbh | Combinations of linagliptin and metformin |
| KR102815172B1 (ko) * | 2020-02-25 | 2025-05-29 | 엘지전자 주식회사 | 히트펌프 및 그 동작방법 |
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| GB1456323A (en) * | 1974-06-06 | 1976-11-24 | Labaz | Benzothiophenes process for preparing them and pharmaceutical compositions containing the same |
| US4133814A (en) | 1975-10-28 | 1979-01-09 | Eli Lilly And Company | 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents |
| US4358593A (en) | 1981-04-03 | 1982-11-09 | Eli Lilly And Company | Process for preparing 3-(4-aminoethoxybenzoyl)benzo[b]thiophenes |
| IL65378A (en) * | 1981-04-03 | 1986-02-28 | Lilly Co Eli | Process for preparing 3-(4-aminoethoxybenzoyl)benzo-(b)thiophenes |
| IL65379A0 (en) * | 1981-04-03 | 1982-05-31 | Lilly Co Eli | Process for preparing acylated benzothiophenes |
| US4380635A (en) * | 1981-04-03 | 1983-04-19 | Eli Lilly And Company | Synthesis of acylated benzothiophenes |
| ZA822247B (en) | 1981-04-03 | 1983-11-30 | Lilly Co Eli | Benzothiophene compounds and process for preparing them |
| EP0062503A1 (en) * | 1981-04-03 | 1982-10-13 | Eli Lilly And Company | Benzothiophene compounds and process for preparing them |
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| DE4117512A1 (de) | 1991-05-25 | 1992-11-26 | Schering Ag | 2-phenylbenzo(b)furane und -thiophene, verfahren zu deren herstellung und diese enthaltende pharmazeutische praeparate |
| JP3157882B2 (ja) * | 1991-11-15 | 2001-04-16 | 帝国臓器製薬株式会社 | 新規なベンゾチオフエン誘導体 |
| US5169860A (en) | 1992-03-13 | 1992-12-08 | Eli Lilly And Company | Antitumor compositions and methods of treatment |
| TW383306B (en) * | 1992-12-22 | 2000-03-01 | Lilly Co Eli | New use of 2-phenyl-3-aroylbenzothiophenes in lowering serum cholesterol |
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| US6756388B1 (en) * | 1993-10-12 | 2004-06-29 | Pfizer Inc. | Benzothiophenes and related compounds as estrogen agonists |
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1995
- 1995-06-02 CO CO95023870A patent/CO4410191A1/es unknown
- 1995-06-02 CO CO95023869A patent/CO4410190A1/es unknown
- 1995-06-05 TW TW084105613A patent/TW412534B/zh not_active IP Right Cessation
- 1995-06-06 US US08/467,485 patent/US5731327A/en not_active Expired - Lifetime
- 1995-06-06 US US08/469,961 patent/US6472531B1/en not_active Expired - Lifetime
- 1995-06-06 US US08/469,093 patent/US6399778B1/en not_active Expired - Fee Related
- 1995-06-07 PE PE1995270673A patent/PE32796A1/es not_active IP Right Cessation
- 1995-06-07 PE PE1995270674A patent/PE14796A1/es not_active Application Discontinuation
- 1995-09-13 ES ES009501775A patent/ES2129293B1/es not_active Expired - Fee Related
- 1995-09-13 ES ES09501774A patent/ES2109882B1/es not_active Revoked
- 1995-09-14 NL NL1001196A patent/NL1001196C2/nl active Search and Examination
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- 1995-09-14 NL NL1001194A patent/NL1001194C2/nl active Search and Examination
- 1995-09-14 UA UA95094168A patent/UA44240C2/uk unknown
- 1995-09-15 RO RO95-01619A patent/RO115259B1/ro unknown
- 1995-09-15 KR KR1019950030210A patent/KR100381346B1/ko not_active Expired - Lifetime
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- 1995-09-15 IT IT95MI001935A patent/IT1277601B1/it active IP Right Grant
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- 1995-09-18 BE BE9500760A patent/BE1009625A3/fr active
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- 1995-09-18 BE BE9500761A patent/BE1009626A3/fr active
- 1995-09-18 AU AU31731/95A patent/AU692907B2/en not_active Ceased
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- 1995-09-18 LU LU88661A patent/LU88661A1/fr unknown
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- 1995-09-19 AU AU37186/95A patent/AU3718695A/en not_active Abandoned
- 1995-09-19 RS YU61495A patent/RS49513B/sr unknown
- 1995-09-19 RS YUP-613/95A patent/RS49578B/sr unknown
- 1995-09-19 AP APAP/P/1997/000938A patent/AP754A/en active
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1997
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- 1997-01-09 DK DK199700028A patent/DK175886B1/da not_active IP Right Cessation
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- 1997-03-19 OA OA60977A patent/OA10406A/en unknown
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2002
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