NL1001196C2 - Nieuw farmaceutisch produkt. - Google Patents

Nieuw farmaceutisch produkt. Download PDF

Info

Publication number: NL1001196C2
Authority: NL; Netherlands
Prior art keywords: benzo; benzoyl; hydroxy; piperidinoethoxy; crystalline
Prior art date: 1994-09-19

Application number

NL1001196A

Other languages

English (en)

Dutch (nl)

Other versions

NL1001196A1 (nl

Inventor

Elizabeth Smith Labell

Wayne Douglas Luke

Randal Scot Miller

John Mcneill Mcgill Iii

Original Assignee

Lilly Co Eli

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1994-09-19

Filing date

1995-09-14

Publication date

1997-04-04

Family has litigation

First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26976194&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=NL1001196(C2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

1994-09-19 Priority claimed from US08/308,325 external-priority patent/US5629425A/en

1995-09-14 Application filed by Lilly Co Eli filed Critical Lilly Co Eli

1996-03-19 Publication of NL1001196A1 publication Critical patent/NL1001196A1/xx

1997-04-04 Application granted granted Critical

1997-04-04 Publication of NL1001196C2 publication Critical patent/NL1001196C2/nl

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 62
MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 30
FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 22
-1 piperidinoethoxy Chemical group 0.000 claims description 20
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 17
239000012535 impurity Substances 0.000 claims description 16
125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 13
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 9
238000002441 X-ray diffraction Methods 0.000 claims description 7
AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims description 7
230000005855 radiation Effects 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
239000003085 diluting agent Substances 0.000 claims 1
239000003937 drug carrier Substances 0.000 claims 1
239000000546 pharmaceutical excipient Substances 0.000 claims 1
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 110
239000000203 mixture Substances 0.000 description 40
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
238000006243 chemical reaction Methods 0.000 description 38
239000000243 solution Substances 0.000 description 38
239000002904 solvent Substances 0.000 description 35
WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 31
238000000034 method Methods 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
238000006900 dealkylation reaction Methods 0.000 description 25
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
230000010933 acylation Effects 0.000 description 23
239000013078 crystal Substances 0.000 description 22
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
FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 19
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
230000020335 dealkylation Effects 0.000 description 18
238000002360 preparation method Methods 0.000 description 15
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 12
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
229910052796 boron Inorganic materials 0.000 description 12
ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 12
238000004128 high performance liquid chromatography Methods 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
VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 11
239000002178 crystalline material Substances 0.000 description 11
238000002844 melting Methods 0.000 description 11
230000008018 melting Effects 0.000 description 11
239000011541 reaction mixture Substances 0.000 description 11
229910052782 aluminium Inorganic materials 0.000 description 10
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 9
239000002002 slurry Substances 0.000 description 9
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
239000000460 chlorine Substances 0.000 description 8
229910052801 chlorine Inorganic materials 0.000 description 8
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 7
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 7
238000001953 recrystallisation Methods 0.000 description 7
238000010992 reflux Methods 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
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
125000005605 benzo group Chemical group 0.000 description 6
BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 6
125000001309 chloro group Chemical group Cl* 0.000 description 6
239000000706 filtrate Substances 0.000 description 6
239000000463 material Substances 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
239000002245 particle Substances 0.000 description 6
239000007787 solid Substances 0.000 description 6
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
239000002585 base Substances 0.000 description 5
239000006227 byproduct Substances 0.000 description 5
239000003153 chemical reaction reagent Substances 0.000 description 5
125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
238000000634 powder X-ray diffraction Methods 0.000 description 5
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 description 5
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-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
150000001338 aliphatic hydrocarbons Chemical class 0.000 description 4
230000015572 biosynthetic process Effects 0.000 description 4
239000003795 chemical substances by application Substances 0.000 description 4
238000002425 crystallisation Methods 0.000 description 4
230000008025 crystallization Effects 0.000 description 4
238000001914 filtration Methods 0.000 description 4
125000002496 methyl group Chemical group [H]C([H])([H])* 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
229960002119 raloxifene hydrochloride Drugs 0.000 description 4
239000007858 starting material Substances 0.000 description 4
238000003786 synthesis reaction Methods 0.000 description 4
OFHAGSNEHHNRSV-UHFFFAOYSA-N 1-benzothiophene;hydrochloride Chemical compound Cl.C1=CC=C2SC=CC2=C1 OFHAGSNEHHNRSV-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
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
229910052794 bromium Inorganic materials 0.000 description 3
239000003054 catalyst Substances 0.000 description 3
238000004821 distillation Methods 0.000 description 3
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 3
238000004817 gas chromatography Methods 0.000 description 3
238000010438 heat treatment Methods 0.000 description 3
238000004519 manufacturing process Methods 0.000 description 3
229910052757 nitrogen Inorganic materials 0.000 description 3
238000005580 one pot reaction Methods 0.000 description 3
ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
239000000843 powder Substances 0.000 description 3
238000010791 quenching Methods 0.000 description 3
230000000171 quenching effect Effects 0.000 description 3
229960004622 raloxifene Drugs 0.000 description 3
238000007363 ring formation reaction Methods 0.000 description 3
238000003756 stirring Methods 0.000 description 3
238000004809 thin layer chromatography Methods 0.000 description 3
150000003568 thioethers Chemical class 0.000 description 3
VFLQQZCRHPIGJU-UHFFFAOYSA-N 1-(2-chloroethyl)piperidine;hydron;chloride Chemical compound Cl.ClCCN1CCCCC1 VFLQQZCRHPIGJU-UHFFFAOYSA-N 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
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
KHKWHMPEDILGEQ-UHFFFAOYSA-N ClCCCl.Cl.S1C2=C(C=C1)C=CC=C2 Chemical compound ClCCCl.Cl.S1C2=C(C=C1)C=CC=C2 KHKWHMPEDILGEQ-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
238000005863 Friedel-Crafts acylation reaction Methods 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
238000005481 NMR spectroscopy Methods 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
150000001298 alcohols Chemical class 0.000 description 2
125000000217 alkyl group Chemical group 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
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
230000000711 cancerogenic effect Effects 0.000 description 2
239000006229 carbon black Substances 0.000 description 2
231100000357 carcinogen Toxicity 0.000 description 2
239000003183 carcinogenic agent Substances 0.000 description 2
238000006555 catalytic reaction Methods 0.000 description 2
238000005660 chlorination reaction Methods 0.000 description 2
238000003776 cleavage reaction Methods 0.000 description 2
239000012043 crude product Substances 0.000 description 2
238000004090 dissolution Methods 0.000 description 2
238000001035 drying Methods 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
238000002955 isolation Methods 0.000 description 2
239000011159 matrix 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
235000019645 odor Nutrition 0.000 description 2
239000012074 organic phase Substances 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
239000002244 precipitate Substances 0.000 description 2
238000012545 processing Methods 0.000 description 2
230000007017 scission Effects 0.000 description 2
238000001228 spectrum Methods 0.000 description 2
239000000126 substance Substances 0.000 description 2
238000010189 synthetic method Methods 0.000 description 2
238000012360 testing method 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
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 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
YPSXFMHXRZAGTG-UHFFFAOYSA-N 4-methoxy-2-[2-(5-methoxy-2-nitrosophenyl)ethyl]-1-nitrosobenzene Chemical compound COC1=CC=C(N=O)C(CCC=2C(=CC=C(OC)C=2)N=O)=C1 YPSXFMHXRZAGTG-UHFFFAOYSA-N 0.000 description 1
125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 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
102100021569 Apoptosis regulator Bcl-2 Human genes 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
OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
239000007836 KH2PO4 Substances 0.000 description 1
239000005909 Kieselgur Substances 0.000 description 1
PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
229910019142 PO4 Inorganic materials 0.000 description 1
UAUVDTRIPPZZCC-UHFFFAOYSA-N [2-(4-hydroxyphenyl)-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=CC=C2S1 UAUVDTRIPPZZCC-UHFFFAOYSA-N 0.000 description 1
OFJKVKPVCPNSMW-UHFFFAOYSA-N [2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone;hydrochloride Chemical compound Cl.C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=CC=C2S1 OFJKVKPVCPNSMW-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
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
MSRYQTKAUSVEDP-UHFFFAOYSA-N [6-methoxy-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(OC)C=C2S1 MSRYQTKAUSVEDP-UHFFFAOYSA-N 0.000 description 1
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 1
238000010521 absorption reaction Methods 0.000 description 1
239000002253 acid Substances 0.000 description 1
230000002378 acidificating effect Effects 0.000 description 1
239000013543 active substance Substances 0.000 description 1
230000002411 adverse Effects 0.000 description 1
125000003545 alkoxy group Chemical group 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
150000001412 amines Chemical class 0.000 description 1
239000011260 aqueous acid Substances 0.000 description 1
125000004429 atom Chemical group 0.000 description 1
UIJGNTRUPZPVNG-UHFFFAOYSA-N benzenecarbothioic s-acid Chemical compound SC(=O)C1=CC=CC=C1 UIJGNTRUPZPVNG-UHFFFAOYSA-N 0.000 description 1
235000010233 benzoic acid Nutrition 0.000 description 1
238000009835 boiling Methods 0.000 description 1
239000000872 buffer Substances 0.000 description 1
238000011088 calibration curve Methods 0.000 description 1
150000001732 carboxylic acid derivatives Chemical class 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
238000009826 distribution 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
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 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
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
VEIWYFRREFUNRC-UHFFFAOYSA-N hydron;piperidine;chloride Chemical compound [Cl-].C1CC[NH2+]CC1 VEIWYFRREFUNRC-UHFFFAOYSA-N 0.000 description 1
KQDJZZWCYTXUDE-UHFFFAOYSA-N hydron;thiophene;chloride Chemical compound Cl.C=1C=CSC=1 KQDJZZWCYTXUDE-UHFFFAOYSA-N 0.000 description 1
238000011065 in-situ storage 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
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
SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 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
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
WLGDAKIJYPIYLR-UHFFFAOYSA-M octane-1-sulfonate Chemical compound CCCCCCCCS([O-])(=O)=O WLGDAKIJYPIYLR-UHFFFAOYSA-M 0.000 description 1
230000009965 odorless effect Effects 0.000 description 1
239000012044 organic layer Substances 0.000 description 1
230000020477 pH reduction Effects 0.000 description 1
239000012071 phase Substances 0.000 description 1
150000008379 phenol ethers Chemical class 0.000 description 1
150000002989 phenols Chemical class 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
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
238000010926 purge 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
229920006395 saturated elastomer Polymers 0.000 description 1
239000012047 saturated solution Substances 0.000 description 1
238000000926 separation method Methods 0.000 description 1
239000000741 silica gel Substances 0.000 description 1
229910002027 silica gel Inorganic materials 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
238000010561 standard procedure Methods 0.000 description 1
125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
230000002194 synthesizing effect Effects 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
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
238000001291 vacuum drying 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)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Preparation Of Compounds By Using Micro-Organisms (AREA)

NL1001196A 1994-09-19 1995-09-14 Nieuw farmaceutisch produkt. NL1001196C2 (nl)

Applications Claiming Priority (4)

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
US30832594		1994-09-19
US42791495A	1995-04-26	1995-04-26
US42791495		1995-04-26

Publications (2)

Publication Number	Publication Date
NL1001196A1 NL1001196A1 (nl)	1996-03-19
NL1001196C2 true NL1001196C2 (nl)	1997-04-04

Family

ID=26976194

Family Applications (2)

Application Number	Title	Priority Date	Filing Date
NL1001196A NL1001196C2 (nl)	1994-09-19	1995-09-14	Nieuw farmaceutisch produkt.
NL1001194A NL1001194C2 (nl)	1994-09-19	1995-09-14	Synthese van 3-£4-(2-aminoethoxy)-benzoyl\|-2-aryl-6-hydroxybenzo£b\|thio- fenen.

Family Applications After (1)

Application Number	Title	Priority Date	Filing Date
NL1001194A NL1001194C2 (nl)	1994-09-19	1995-09-14	Synthese van 3-£4-(2-aminoethoxy)-benzoyl\|-2-aryl-6-hydroxybenzo£b\|thio- fenen.

Country Status (50)

Country	Link
US (4)	US6399778B1 (fr)
JP (2)	JP2860071B2 (fr)
KR (2)	KR100381346B1 (fr)
CN (2)	CN1068324C (fr)
AP (1)	AP754A (fr)
AT (2)	AT407988B (fr)
AU (3)	AU691955B2 (fr)
BE (2)	BE1009626A3 (fr)
BG (1)	BG62793B1 (fr)
BR (2)	BR9504060A (fr)
CA (2)	CA2158399C (fr)
CH (3)	CH691125A5 (fr)
CO (2)	CO4410190A1 (fr)
CZ (2)	CZ292007B6 (fr)
DE (3)	DE19534744A1 (fr)
DK (4)	DK175903B1 (fr)
EE (1)	EE03386B1 (fr)
EG (1)	EG23763A (fr)
ES (2)	ES2129293B1 (fr)
FI (2)	FI112226B (fr)
FR (2)	FR2724655B1 (fr)
GB (2)	GB2293382B (fr)
GE (1)	GEP19991821B (fr)
GR (2)	GR1002697B (fr)
HR (2)	HRP950483B1 (fr)
HU (2)	HU225417B1 (fr)
IE (2)	IE950722A1 (fr)
IL (3)	IL115314A (fr)
IS (1)	IS1788B (fr)
IT (2)	IT1277602B1 (fr)
LU (2)	LU88660A1 (fr)
LV (2)	LV11178B (fr)
MY (1)	MY116371A (fr)
NL (2)	NL1001196C2 (fr)
NO (2)	NO313996B1 (fr)
NZ (2)	NZ280028A (fr)
OA (1)	OA10406A (fr)
PE (2)	PE14796A1 (fr)
PL (2)	PL182450B1 (fr)
PT (2)	PT101770B (fr)
RO (2)	RO115260B1 (fr)
RS (2)	RS49513B (fr)
SE (2)	SE509265C2 (fr)
SI (2)	SI9500293A (fr)
SK (1)	SK283502B6 (fr)
TR (1)	TR199501136A2 (fr)
TW (1)	TW412534B (fr)
UA (2)	UA42716C2 (fr)
UY (1)	UY24040A1 (fr)
WO (1)	WO1996009045A1 (fr)

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IT1403083B1 (it) *	2010-10-25	2013-10-04	Fidia Farmaceutici	Nuova forma polimorfa di raloxifene cloridrato
AR083878A1 (es)	2010-11-15	2013-03-27	Boehringer Ingelheim Int	Terapia antidiabetica vasoprotectora y cardioprotectora, linagliptina, metodo de tratamiento
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CA2841552C (fr)	2011-07-15	2020-06-23	Boehringer Ingelheim International Gmbh	Quinazolines substituees, la preparation de celles-ci et l'utilisation de celles-ci dans des compositions pharmaceutiques
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WO2013174767A1 (fr)	2012-05-24	2013-11-28	Boehringer Ingelheim International Gmbh	Dérivé de xanthine en tant qu'inhibiteur de la dpp-4 à utiliser dans la modification de l'apport alimentaire et dans la régulation des préférences alimentaires
WO2014135834A1 (fr)	2013-03-05	2014-09-12	Cipla House	Sels d'addition d'acide oxalique et/ou solvates d'un modulateur sélectif du récepteur d'œstrogènes
WO2015011236A1 (fr)	2013-07-26	2015-01-29	Boehringer Ingelheim International Gmbh	Traitement du syndrome myélodysplasique
ES2950384T3 (es)	2014-02-28	2023-10-09	Boehringer Ingelheim Int	Uso médico de un inhibidor de DPP-4
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WO2017211979A1 (fr)	2016-06-10	2017-12-14	Boehringer Ingelheim International Gmbh	Combinaisons de linagliptine et de metformine
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1995
- 1995-06-02 CO CO95023869A patent/CO4410190A1/es unknown
- 1995-06-02 CO CO95023870A patent/CO4410191A1/es unknown
- 1995-06-05 TW TW084105613A patent/TW412534B/zh not_active IP Right Cessation
- 1995-06-06 US US08/469,093 patent/US6399778B1/en not_active Expired - Fee Related
- 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
- 1995-06-07 PE PE1995270674A patent/PE14796A1/es not_active Application Discontinuation
- 1995-06-07 PE PE1995270673A patent/PE32796A1/es not_active IP Right Cessation
- 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 UA UA95094169A patent/UA42716C2/uk unknown
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- 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
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- 1995-09-14 UA UA95094168A patent/UA44240C2/uk unknown
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- 1995-09-17 EG EG76395A patent/EG23763A/xx active
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- 1995-09-18 AU AU31731/95A patent/AU692907B2/en not_active Ceased
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- 1995-09-18 BE BE9500761A patent/BE1009626A3/fr active
- 1995-09-18 FI FI954402A patent/FI112226B/fi not_active IP Right Cessation
- 1995-09-18 AT AT0154295A patent/AT407988B/de not_active IP Right Cessation
- 1995-09-18 HU HU9502723A patent/HU227683B1/hu not_active IP Right Cessation
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- 1995-09-18 JP JP7238209A patent/JPH08193081A/ja active Pending
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- 1995-09-19 WO PCT/US1995/011872 patent/WO1996009045A1/fr not_active Ceased
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- 1995-09-19 PL PL95310517A patent/PL187686B1/pl not_active IP Right Cessation
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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
2002
- 2002-02-26 US US10/083,179 patent/US20020173645A1/en not_active Abandoned

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Also Published As

Publication number	Publication date
ITMI951936A1 (it)	1997-03-15
TR199501136A2 (tr)	1996-06-21
CN1068324C (zh)	2001-07-11
BE1009625A3 (fr)	1997-06-03
IL115314A (en)	2000-02-29
BG62793B1 (bg)	2000-08-31
CH691125A5 (de)	2001-04-30
HRP950482A2 (en)	1998-02-28
FI112226B (fi)	2003-11-14
CZ290343B6 (cs)	2002-07-17
SE9503213D0 (sv)	1995-09-15
HU227683B1 (en)	2011-11-28
FI954402L (fi)	1996-03-20
IL115314A0 (en)	1996-05-14
DK2797A (da)	1997-01-09
NO308107B1 (no)	2000-07-24
HUT74178A (en)	1996-11-28
HRP950482B1 (en)	2007-04-30
SE9503213L (sv)	1996-03-20
CZ240395A3 (en)	1996-04-17
OA10406A (en)	2001-12-05
RO115260B1 (ro)	1999-12-30
HRP950483B1 (en)	2003-02-28
DK2897A (da)	1997-01-09
CH691594A5 (de)	2001-08-31
CZ240295A3 (en)	1996-04-17
PL187686B1 (pl)	2004-09-30
HU9502721D0 (en)	1995-11-28
ITMI951936A0 (it)	1995-09-15
GB2293602B (en)	1998-05-06
ITMI951935A1 (it)	1997-03-15
RS49578B (sr)	2007-04-10
SI9500293A (en)	1996-06-30
DK102795A (da)	1996-03-20
IL115315A (en)	1999-09-22
KR960010634A (ko)	1996-04-20
AT407988B (de)	2001-07-25
NO953657D0 (no)	1995-09-15
IS4446A (is)	1997-03-18
PT101770B (pt)	1997-04-30
NZ280028A (en)	1997-05-26
LV11177B (en)	1996-08-20
JPH08193081A (ja)	1996-07-30
ES2129293B1 (es)	2000-01-16
GB2293602A (en)	1996-04-03
EE03386B1 (et)	2001-04-16
PT101771B (pt)	1997-04-30
ITMI951935A0 (it)	1995-09-15
RO115259B1 (ro)	1999-12-30
UA42716C2 (uk)	2001-11-15
FR2724655B1 (fr)	1997-11-14
AU691955B2 (en)	1998-05-28
IE80883B1 (en)	1999-05-19
CN1132205A (zh)	1996-10-02
LV11178A (lv)	1996-04-20
WO1996009045A1 (fr)	1996-03-28
AU3173095A (en)	1996-04-04
PE32796A1 (es)	1996-08-07
PT101770A (pt)	1996-04-30
IL115315A0 (en)	1995-12-31
GR1002697B (el)	1997-05-22
DK175887B1 (da)	2005-05-23
BE1009626A3 (fr)	1997-06-03
GEP19991821B (en)	1999-11-05
IL125283A (en)	2001-06-14
CN1075069C (zh)	2001-11-21
ATA154295A (de)	2000-12-15
AP754A (en)	1999-07-22
DE19534744A1 (de)	1996-03-21
MY116371A (en)	2004-01-31
GB2293382B (en)	1998-08-19
UA44240C2 (uk)	2002-02-15
KR100381346B1 (ko)	2004-04-13
AU3718695A (en)	1996-04-09
CA2158399C (fr)	2001-03-20
NO953658D0 (no)	1995-09-15
CA2158400A1 (fr)	1996-03-20
AT502957A1 (de)	2007-06-15
US6472531B1 (en)	2002-10-29
NO953657L (no)	1996-03-20
FI954403A0 (fi)	1995-09-18
YU61495A (sh)	1998-05-15
DE19534745A1 (de)	1996-04-04
PE14796A1 (es)	1996-05-19
AP9700938A0 (en)	1997-04-30
NL1001194A1 (nl)	1996-03-19
SE9503214D0 (sv)	1995-09-15
IE950722A1 (en)	1996-03-20
JP2860071B2 (ja)	1999-02-24
IT1277601B1 (it)	1997-11-11
LV11178B (en)	1996-08-20
GR1002709B (el)	1997-06-04
SK23397A3 (en)	1997-08-06
NO953658L (no)	1996-03-20
AU692907B2 (en)	1998-06-18
AU3173195A (en)	1996-04-04
CZ292007B6 (cs)	2003-07-16
PL310517A1 (en)	1996-04-01
YU61395A (sh)	1998-09-18
FI954403A7 (fi)	1996-03-20
BR9504059A (pt)	1996-09-24
GB9519028D0 (en)	1995-11-15
LU88661A1 (fr)	1996-07-15
SE520721C2 (sv)	2003-08-12
CA2158400C (fr)	2006-10-24
BR9504060A (pt)	1996-09-24
GB9519032D0 (en)	1995-11-15
US5731327A (en)	1998-03-24
TW412534B (en)	2000-11-21
LU88660A1 (fr)	1996-07-15
KR100367376B1 (ko)	2003-03-06
HU225417B1 (en)	2006-11-28
CO4410191A1 (es)	1997-01-09
NO313996B1 (no)	2003-01-13
EE9700055A (et)	1997-08-15
BG101242A (en)	1998-03-31
US20020173645A1 (en)	2002-11-21
RS49513B (sr)	2006-10-27
ES2129293A1 (es)	1999-06-01
LV11177A (lv)	1996-04-20
ES2109882B1 (es)	1998-08-16
US6399778B1 (en)	2002-06-04
CH691478A5 (de)	2001-07-31
EG23763A (en)	2007-08-08
IS1788B (is)	2001-11-28
PL310518A1 (en)	1996-04-01
GB2293382A (en)	1996-03-27
CO4410190A1 (es)	1997-01-09
CA2158399A1 (fr)	1996-03-20
DE19534745B4 (de)	2004-06-09
DK175886B1 (da)	2005-05-23
PT101771A (pt)	1996-04-30
SI9500292A (en)	1996-06-30
PL182450B1 (pl)	2002-01-31
HU9502723D0 (en)	1995-11-28
NZ280027A (en)	1997-05-26
FI954402A0 (fi)	1995-09-18
FI121424B (fi)	2010-11-15
UY24040A1 (es)	1996-03-07
SE509265C2 (sv)	1998-12-21
DK102895A (da)	1996-03-20
IE950721A1 (en)	1996-03-20
ES2109882A1 (es)	1998-01-16
HK1019009A1 (en)	2000-01-14
DK175903B1 (da)	2005-06-06
NL1001196A1 (nl)	1996-03-19
JPH08176147A (ja)	1996-07-09
FR2732020B1 (fr)	1997-11-14
FR2724655A1 (fr)	1996-03-22
IT1277602B1 (it)	1997-11-11
SE9503214L (sv)	1996-03-20
NL1001194C2 (nl)	1997-04-04
DK175897B1 (da)	2005-05-30
KR960010637A (ko)	1996-04-20
FR2732020A1 (fr)	1996-09-27
DE19549755B4 (de)	2005-05-04
HRP950483A2 (en)	1997-10-31
SK283502B6 (sk)	2003-08-05
HUT75033A (en)	1997-03-28
CN1127253A (zh)	1996-07-24

Legal Events

Date	Code	Title	Description
1996-06-03	AD1A	A request for search or an international type search has been filed
1997-02-03	RD2N	Patents in respect of which a decision has been taken or a report has been made (novelty report)	Effective date: 19961202
1997-06-02	PD2B	A search report has been drawn up

Publication	Publication Date	Title
CA2158399C (fr)	2001-03-20	Produit pharmaceutique
RU2108331C1 (ru)	1998-04-10	Способ получения кристаллического сольвата, кристаллический сольват 6-гидрокси-2-(4-гидроксифенил)-3-[4-(2-пиперидиноэтокси)бензоил]бензо(b)тиофенгидрохлорида и способ получения несольватированного кристаллического 6-гидрокси-2-(4-гидроксифенил)-3-[4-(2-пиперидиноэтокси)бензоил]бензо(b)тиофенгидрохлорида