DK175897B1 - Fremgangsmåde til fremstilling af ikke-solvatiseret krystallinsk 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(piperidinoethoxy)benzoyl]benzo[b]thiophenhydrochlorid og krystallinske solvater heraf til brug ved fremgangsmåden - Google Patents

Fremgangsmåde til fremstilling af ikke-solvatiseret krystallinsk 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(piperidinoethoxy)benzoyl]benzo[b]thiophenhydrochlorid og krystallinske solvater heraf til brug ved fremgangsmåden Download PDF

Info

Publication number: DK175897B1
Authority: DK; Denmark
Prior art keywords: crystalline; hydroxy; benzo; benzoyl; hydroxyphenyl
Prior art date: 1994-09-19

Application number

DK199501028A

Other languages

Danish (da)

English (en)

Other versions

DK102895A (da

Inventor

Elizabeth Smith Labell

Wayne Douglas Luke

Randal Scot Miller

Mcneill Mcgill John 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

1995-09-15

Publication date

2005-05-30

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=DK175897(B1) "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

1995-09-15 Application filed by Lilly Co Eli filed Critical Lilly Co Eli

1996-03-20 Publication of DK102895A publication Critical patent/DK102895A/da

1997-01-09 Priority to DK199700028A priority Critical patent/DK175886B1/da

1997-01-09 Priority to DK199700027A priority patent/DK175887B1/da

2005-05-30 Application granted granted Critical

2005-05-30 Publication of DK175897B1 publication Critical patent/DK175897B1/da

Links

238000000034 method Methods 0.000 title claims description 39
239000012453 solvate Substances 0.000 title claims description 31
238000002360 preparation method Methods 0.000 title claims description 27
230000008569 process Effects 0.000 title claims description 19
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 title description 8
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 132
150000001875 compounds Chemical class 0.000 claims description 70
239000000203 mixture Substances 0.000 claims description 50
239000002904 solvent Substances 0.000 claims description 42
238000006243 chemical reaction Methods 0.000 claims description 41
238000005917 acylation reaction Methods 0.000 claims description 33
FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 32
230000010933 acylation Effects 0.000 claims description 32
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
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238000006900 dealkylation reaction Methods 0.000 claims description 24
-1 methoxy, methyl Chemical group 0.000 claims description 24
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238000002441 X-ray diffraction Methods 0.000 claims description 18
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VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 15
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229910052801 chlorine Inorganic materials 0.000 claims description 9
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
125000000217 alkyl group Chemical group 0.000 claims description 7
125000004356 hydroxy functional group Chemical group O* 0.000 claims description 7
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 5
150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 5
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
229910052794 bromium Inorganic materials 0.000 claims description 5
239000003795 chemical substances by application Substances 0.000 claims description 5
229910052802 copper Inorganic materials 0.000 claims description 5
239000010949 copper Substances 0.000 claims description 5
230000001747 exhibiting effect Effects 0.000 claims description 5
239000003960 organic solvent Substances 0.000 claims description 5
ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 5
230000005855 radiation Effects 0.000 claims description 5
OFHAGSNEHHNRSV-UHFFFAOYSA-N 1-benzothiophene;hydrochloride Chemical compound Cl.C1=CC=C2SC=CC2=C1 OFHAGSNEHHNRSV-UHFFFAOYSA-N 0.000 claims description 4
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IQZINSWCHGPKQP-UHFFFAOYSA-N Cl.N1(CCCCC1)CCOC1=CC=C(C(=O)C2=CC3=C(S2)C=CC=C3)C=C1 Chemical compound Cl.N1(CCCCC1)CCOC1=CC=C(C(=O)C2=CC3=C(S2)C=CC=C3)C=C1 IQZINSWCHGPKQP-UHFFFAOYSA-N 0.000 claims 1
125000003545 alkoxy group Chemical group 0.000 claims 1
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239000011541 reaction mixture Substances 0.000 description 20
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229910052796 boron Inorganic materials 0.000 description 17
ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 15
VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 14
239000002178 crystalline material Substances 0.000 description 14
CFXQEHVMCRXUSD-UHFFFAOYSA-N 1,2,3-Trichloropropane Chemical compound ClCC(Cl)CCl CFXQEHVMCRXUSD-UHFFFAOYSA-N 0.000 description 12
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238000005481 NMR spectroscopy Methods 0.000 description 7
230000015572 biosynthetic process Effects 0.000 description 7
239000000463 material Substances 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
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
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
239000012535 impurity Substances 0.000 description 6
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
238000001953 recrystallisation Methods 0.000 description 6
238000010992 reflux Methods 0.000 description 6
238000003786 synthesis reaction Methods 0.000 description 6
SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 5
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
229910052782 aluminium Inorganic materials 0.000 description 5
XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 5
125000005605 benzo group Chemical group 0.000 description 5
239000000706 filtrate Substances 0.000 description 5
239000012467 final product Substances 0.000 description 5
239000000543 intermediate Substances 0.000 description 5
PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 5
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
238000005727 Friedel-Crafts reaction Methods 0.000 description 4
YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 4
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WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
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WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 4
239000006227 byproduct Substances 0.000 description 4
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125000001309 chloro group Chemical group Cl* 0.000 description 4
238000001914 filtration Methods 0.000 description 4
238000004817 gas chromatography Methods 0.000 description 4
KQDJZZWCYTXUDE-UHFFFAOYSA-N hydron;thiophene;chloride Chemical compound Cl.C=1C=CSC=1 KQDJZZWCYTXUDE-UHFFFAOYSA-N 0.000 description 4
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238000005580 one pot reaction Methods 0.000 description 4
239000002245 particle Substances 0.000 description 4
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239000007858 starting material Substances 0.000 description 4
238000003756 stirring Methods 0.000 description 4
125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 3
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239000002253 acid Substances 0.000 description 3
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238000005804 alkylation reaction Methods 0.000 description 3
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
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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 3
125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 2
VFLQQZCRHPIGJU-UHFFFAOYSA-N 1-(2-chloroethyl)piperidine;hydron;chloride Chemical compound Cl.ClCCN1CCCCC1 VFLQQZCRHPIGJU-UHFFFAOYSA-N 0.000 description 2
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 2
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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
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239000002244 precipitate Substances 0.000 description 2
238000000746 purification Methods 0.000 description 2
AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
238000012958 reprocessing Methods 0.000 description 2
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150000003839 salts Chemical class 0.000 description 2
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230000007017 scission Effects 0.000 description 2
PUGUQINMNYINPK-UHFFFAOYSA-N tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1 PUGUQINMNYINPK-UHFFFAOYSA-N 0.000 description 2
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150000003568 thioethers Chemical class 0.000 description 2
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ZSUXOVNWDZTCFN-UHFFFAOYSA-L tin(ii) bromide Chemical compound Br[Sn]Br ZSUXOVNWDZTCFN-UHFFFAOYSA-L 0.000 description 2
230000007306 turnover Effects 0.000 description 2
JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
WNRWEBKEQARBKV-UHFFFAOYSA-N 1-(2-chloroethyl)piperidine Chemical compound ClCCN1CCCCC1 WNRWEBKEQARBKV-UHFFFAOYSA-N 0.000 description 1
RMGFLMXDCGQKPS-UHFFFAOYSA-N 1-(2-chloroethyl)pyrrolidine Chemical compound ClCCN1CCCC1 RMGFLMXDCGQKPS-UHFFFAOYSA-N 0.000 description 1
RSUFKEGMFFPMIB-UHFFFAOYSA-N 1-(2-phenoxyethyl)piperidine Chemical compound C=1C=CC=CC=1OCCN1CCCCC1 RSUFKEGMFFPMIB-UHFFFAOYSA-N 0.000 description 1
ZEXIVBYDDCIOKA-UHFFFAOYSA-N 1-benzothiophen-2-ol Chemical compound C1=CC=C2SC(O)=CC2=C1 ZEXIVBYDDCIOKA-UHFFFAOYSA-N 0.000 description 1
LDVWIJSHXKXJLT-UHFFFAOYSA-N 1-benzothiophen-2-yl-[4-(2-piperidin-1-ylethoxy)phenyl]methanone Chemical compound N1(CCCCC1)CCOC1=CC=C(C(=O)C2=CC3=C(S2)C=CC=C3)C=C1 LDVWIJSHXKXJLT-UHFFFAOYSA-N 0.000 description 1
238000005160 1H NMR spectroscopy Methods 0.000 description 1
AKLKIGMEFVPQFJ-UHFFFAOYSA-N 2-bromo-2-methoxy-1-phenylethanone Chemical compound COC(Br)C(=O)C1=CC=CC=C1 AKLKIGMEFVPQFJ-UHFFFAOYSA-N 0.000 description 1
125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
YRNDGUSDBCARGC-UHFFFAOYSA-N 2-methoxyacetophenone Chemical compound COCC(=O)C1=CC=CC=C1 YRNDGUSDBCARGC-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
101150110188 30 gene Proteins 0.000 description 1
ZAPMTSHEXFEPSD-UHFFFAOYSA-N 4-(2-chloroethyl)morpholine Chemical compound ClCCN1CCOCC1 ZAPMTSHEXFEPSD-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
239000005711 Benzoic acid Substances 0.000 description 1
239000004215 Carbon black (E152) Substances 0.000 description 1
CDLMCCHHYJVARA-UHFFFAOYSA-N Cl.O=C(c1csc2ccccc12)c1ccc(OCCN2CCCCC2)cc1 Chemical compound Cl.O=C(c1csc2ccccc12)c1ccc(OCCN2CCCCC2)cc1 CDLMCCHHYJVARA-UHFFFAOYSA-N 0.000 description 1
239000005909 Kieselgur Substances 0.000 description 1
FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
229910019142 PO4 Inorganic materials 0.000 description 1
241000577218 Phenes Species 0.000 description 1
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-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
YLFHUDANHUPRPK-UHFFFAOYSA-N [4-(2-aminoethoxy)phenyl]-(1-benzothiophen-3-yl)methanone Chemical class C1=CC(OCCN)=CC=C1C(=O)C1=CSC2=CC=CC=C12 YLFHUDANHUPRPK-UHFFFAOYSA-N 0.000 description 1
PJFBFZVLRDRRRH-UHFFFAOYSA-N [4-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone hydrochloride Chemical compound Cl.Oc1ccc(cc1)-c1sc2cccc(O)c2c1C(=O)c1ccc(OCCN2CCCCC2)cc1 PJFBFZVLRDRRRH-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
238000010521 absorption reaction Methods 0.000 description 1
230000009471 action Effects 0.000 description 1
150000001262 acyl bromides Chemical class 0.000 description 1
125000001931 aliphatic group Chemical group 0.000 description 1
150000001346 alkyl aryl ethers Chemical class 0.000 description 1
AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
239000011260 aqueous acid Substances 0.000 description 1
239000003849 aromatic solvent Substances 0.000 description 1
125000003118 aryl group Chemical group 0.000 description 1
125000005002 aryl methyl group Chemical group 0.000 description 1
125000004391 aryl sulfonyl group Chemical group 0.000 description 1
239000012298 atmosphere Substances 0.000 description 1
235000010233 benzoic acid Nutrition 0.000 description 1
CSCFNOKJIMTZSC-UHFFFAOYSA-N benzoyl chloride;hydrochloride Chemical compound Cl.ClC(=O)C1=CC=CC=C1 CSCFNOKJIMTZSC-UHFFFAOYSA-N 0.000 description 1
JHXKRIRFYBPWGE-UHFFFAOYSA-K bismuth chloride Chemical compound Cl[Bi](Cl)Cl JHXKRIRFYBPWGE-UHFFFAOYSA-K 0.000 description 1
238000009835 boiling Methods 0.000 description 1
239000000872 buffer Substances 0.000 description 1
239000013590 bulk material Substances 0.000 description 1
238000011088 calibration curve Methods 0.000 description 1
229910052799 carbon Inorganic materials 0.000 description 1
125000004432 carbon atom Chemical group C* 0.000 description 1
150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
230000003197 catalytic effect Effects 0.000 description 1
239000007810 chemical reaction solvent Substances 0.000 description 1
230000009089 cytolysis Effects 0.000 description 1
238000000354 decomposition reaction Methods 0.000 description 1
238000010520 demethylation reaction Methods 0.000 description 1
230000001419 dependent effect Effects 0.000 description 1
238000001514 detection method Methods 0.000 description 1
229940117389 dichlorobenzene Drugs 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
239000002019 doping agent Substances 0.000 description 1
239000003480 eluent Substances 0.000 description 1
230000002124 endocrine Effects 0.000 description 1
125000004185 ester group Chemical group 0.000 description 1
150000002148 esters Chemical class 0.000 description 1
229940011871 estrogen Drugs 0.000 description 1
239000000262 estrogen Substances 0.000 description 1
RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
150000002170 ethers Chemical class 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
238000002474 experimental method Methods 0.000 description 1
238000000605 extraction Methods 0.000 description 1
BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
230000026030 halogenation Effects 0.000 description 1
238000005658 halogenation reaction Methods 0.000 description 1
229910000856 hastalloy Inorganic materials 0.000 description 1
229930195733 hydrocarbon Natural products 0.000 description 1
150000002430 hydrocarbons Chemical class 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
QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
238000011065 in-situ storage Methods 0.000 description 1
QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical class COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
238000002955 isolation Methods 0.000 description 1
239000010410 layer Substances 0.000 description 1
238000002386 leaching Methods 0.000 description 1
239000007788 liquid Substances 0.000 description 1
229910052943 magnesium sulfate Inorganic materials 0.000 description 1
235000019341 magnesium sulphate Nutrition 0.000 description 1
239000011159 matrix material Substances 0.000 description 1
238000002844 melting Methods 0.000 description 1
230000008018 melting Effects 0.000 description 1
229930182817 methionine Natural products 0.000 description 1
150000004702 methyl esters Chemical class 0.000 description 1
239000012452 mother liquor Substances 0.000 description 1
125000006606 n-butoxy group Chemical group 0.000 description 1
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 description 1
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 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
230000001575 pathological effect Effects 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
229920000137 polyphosphoric acid Polymers 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
230000001681 protective effect Effects 0.000 description 1
238000007363 ring formation reaction Methods 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
235000017557 sodium bicarbonate Nutrition 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
229910000029 sodium carbonate Inorganic materials 0.000 description 1
239000011780 sodium chloride Substances 0.000 description 1
238000010561 standard procedure Methods 0.000 description 1
239000001119 stannous chloride Substances 0.000 description 1
235000011150 stannous chloride Nutrition 0.000 description 1
230000003637 steroidlike Effects 0.000 description 1
150000003431 steroids Chemical class 0.000 description 1
239000000758 substrate Substances 0.000 description 1
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
239000011593 sulfur Substances 0.000 description 1
229910052717 sulfur Inorganic materials 0.000 description 1
150000003464 sulfur compounds Chemical class 0.000 description 1
230000008961 swelling Effects 0.000 description 1
238000001308 synthesis method Methods 0.000 description 1
238000010189 synthetic method Methods 0.000 description 1
229940124597 therapeutic agent Drugs 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
239000010936 titanium Substances 0.000 description 1
229910052719 titanium Inorganic materials 0.000 description 1
XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
230000009466 transformation Effects 0.000 description 1
FEONEKOZSGPOFN-UHFFFAOYSA-K tribromoiron Chemical compound Br[Fe](Br)Br FEONEKOZSGPOFN-UHFFFAOYSA-K 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
238000010626 work up procedure Methods 0.000 description 1
239000011592 zinc chloride Substances 0.000 description 1
235000005074 zinc chloride Nutrition 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)
General Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Bioinformatics & Cheminformatics (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
Engineering & Computer Science (AREA)
Public Health (AREA)
Chemical Kinetics & Catalysis (AREA)
Endocrinology (AREA)
Diabetes (AREA)
Gynecology & Obstetrics (AREA)
Reproductive Health (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Preparation Of Compounds By Using Micro-Organisms (AREA)

DK199501028A 1994-09-19 1995-09-15 Fremgangsmåde til fremstilling af ikke-solvatiseret krystallinsk 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(piperidinoethoxy)benzoyl]benzo[b]thiophenhydrochlorid og krystallinske solvater heraf til brug ved fremgangsmåden DK175897B1 (da)

Priority Applications (2)

Application Number	Priority Date	Filing Date	Title
DK199700028A DK175886B1 (da)	1994-09-19	1997-01-09	Fremgangsmåde til fremstilling af ikke-solvatiseret krystallinsk 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophenhydrochlorid
DK199700027A DK175887B1 (da)	1994-09-19	1997-01-09	Fremgangsmåde til fremstilling af krystallinske solvater af 3-[4-(2-aminoethoxy)-benzoyl]-2-aryl-6-hydroxybenzo(b)thiophener

Applications Claiming Priority (4)

Application Number	Priority Date	Filing Date	Title
US30832594		1994-09-19
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
US42791495		1995-04-26

Publications (2)

Publication Number	Publication Date
DK102895A DK102895A (da)	1996-03-20
DK175897B1 true DK175897B1 (da)	2005-05-30

Family

ID=26976194

Family Applications (4)

Application Number	Title	Priority Date	Filing Date
DK199501028A DK175897B1 (da)	1994-09-19	1995-09-15	Fremgangsmåde til fremstilling af ikke-solvatiseret krystallinsk 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(piperidinoethoxy)benzoyl]benzo[b]thiophenhydrochlorid og krystallinske solvater heraf til brug ved fremgangsmåden
DK199501027A DK175903B1 (da)	1994-09-19	1995-09-15	Ikke-solvatiseret krystallinsk form af 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(piperidinoethoxy)benzoyl]benzo[b]thiophenhydrochlorid
DK199700027A DK175887B1 (da)	1994-09-19	1997-01-09	Fremgangsmåde til fremstilling af krystallinske solvater af 3-[4-(2-aminoethoxy)-benzoyl]-2-aryl-6-hydroxybenzo(b)thiophener
DK199700028A DK175886B1 (da)	1994-09-19	1997-01-09	Fremgangsmåde til fremstilling af ikke-solvatiseret krystallinsk 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophenhydrochlorid

Family Applications After (3)

Application Number	Title	Priority Date	Filing Date
DK199501027A DK175903B1 (da)	1994-09-19	1995-09-15	Ikke-solvatiseret krystallinsk form af 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(piperidinoethoxy)benzoyl]benzo[b]thiophenhydrochlorid
DK199700027A DK175887B1 (da)	1994-09-19	1997-01-09	Fremgangsmåde til fremstilling af krystallinske solvater af 3-[4-(2-aminoethoxy)-benzoyl]-2-aryl-6-hydroxybenzo(b)thiophener
DK199700028A DK175886B1 (da)	1994-09-19	1997-01-09	Fremgangsmåde til fremstilling af ikke-solvatiseret krystallinsk 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophenhydrochlorid

Country Status (50)

Country	Link
US (4)	US6399778B1 (is)
JP (2)	JP2860071B2 (is)
KR (2)	KR100367376B1 (is)
CN (2)	CN1068324C (is)
AP (1)	AP754A (is)
AT (2)	AT407988B (is)
AU (3)	AU692907B2 (is)
BE (2)	BE1009626A3 (is)
BG (1)	BG62793B1 (is)
BR (2)	BR9504060A (is)
CA (2)	CA2158399C (is)
CH (3)	CH691594A5 (is)
CO (2)	CO4410190A1 (is)
CZ (2)	CZ292007B6 (is)
DE (3)	DE19534744A1 (is)
DK (4)	DK175897B1 (is)
EE (1)	EE03386B1 (is)
EG (1)	EG23763A (is)
ES (2)	ES2129293B1 (is)
FI (2)	FI121424B (is)
FR (2)	FR2732020B1 (is)
GB (2)	GB2293602B (is)
GE (1)	GEP19991821B (is)
GR (2)	GR1002709B (is)
HR (2)	HRP950482B1 (is)
HU (2)	HU227683B1 (is)
IE (2)	IE80883B1 (is)
IL (3)	IL125283A (is)
IS (1)	IS1788B (is)
IT (2)	IT1277601B1 (is)
LU (2)	LU88660A1 (is)
LV (2)	LV11178B (is)
MY (1)	MY116371A (is)
NL (2)	NL1001194C2 (is)
NO (2)	NO308107B1 (is)
NZ (2)	NZ280027A (is)
OA (1)	OA10406A (is)
PE (2)	PE14796A1 (is)
PL (2)	PL187686B1 (is)
PT (2)	PT101770B (is)
RO (2)	RO115259B1 (is)
RS (2)	RS49578B (is)
SE (2)	SE520721C2 (is)
SI (2)	SI9500293A (is)
SK (1)	SK283502B6 (is)
TR (1)	TR199501136A2 (is)
TW (1)	TW412534B (is)
UA (2)	UA44240C2 (is)
UY (1)	UY24040A1 (is)
WO (1)	WO1996009045A1 (is)

Families Citing this family (74)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
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
USRE39049E1 (en)	1992-07-28	2006-03-28	Eli Lilly And Company	Methods for inhibiting bone loss
TW366342B (en) *	1992-07-28	1999-08-11	Lilly Co Eli	The use of 2-phenyl-3-aroylbenzothiophenes in inhibiting bone loss
US5478847A (en)	1994-03-02	1995-12-26	Eli Lilly And Company	Methods of use for inhibiting bone loss and lowering serum cholesterol
CO4410190A1 (es) *	1994-09-19	1997-01-09	Lilly Co Eli	3-[4-(2-AMINOETOXI)-BENZOIL]-2-ARIL-6-HIDROXIBENZO [b] TIOFENO CRISTALINO
US6458811B1 (en) *	1996-03-26	2002-10-01	Eli Lilly And Company	Benzothiophenes formulations containing same and methods
PT910369E (pt) *	1996-03-26	2010-06-04	Lilly Co Eli	Benzotiofenos, formulações que os contêm, e métodos
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
IL146284A0 (en)	1999-05-04	2002-07-25	Strakan Ltd	Androgen glycosides and pharmaceutical compositions containing the same
AU2002230409A1 (en) *	2000-11-27	2002-06-03	Eli Lilly And Company	Process for preparing 3-aryl-benzo(b)thiophenes
AU2003217676B2 (en)	2002-02-22	2009-06-11	Takeda Pharmaceutical Company Limited	Active agent delivery systems and methods for protecting and administering active agents
US7407955B2 (en)	2002-08-21	2008-08-05	Boehringer Ingelheim Pharma Gmbh & Co., Kg	8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
CA2499819A1 (en) *	2002-09-30	2004-04-08	A/S Gea Farmaceutisk Fabrik	Novel raloxifene acid addition salts and/or solvates thereof, improved method for purification of said raloxifene acid addition salts and/or solvates thereof and pharmaceutical compositions comprising these
US6861422B2 (en)	2003-02-26	2005-03-01	Boehringer Ingelheim Pharma Gmbh & Co. Kg	Dihydropteridinones, processes for preparing them and their use as pharmaceutical compositions
US20060106010A1 (en) *	2003-05-27	2006-05-18	Black Larry J	Methods for inhibiting bone loss
US7501426B2 (en)	2004-02-18	2009-03-10	Boehringer Ingelheim International Gmbh	8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
DE102004029784A1 (de)	2004-06-21	2006-01-05	Boehringer Ingelheim Pharma Gmbh & Co. Kg	Neue 2-Benzylaminodihydropteridinone, Verfahren zur deren Herstellung und deren Verwendung als Arzneimittel
DE102004030502A1 (de)	2004-06-24	2006-01-12	Boehringer Ingelheim Pharma Gmbh & Co. Kg	Neue Imidazole und Triazole, deren Herstellung und Verwendung als Arzneimittel
DE102004033670A1 (de)	2004-07-09	2006-02-02	Boehringer Ingelheim Pharma Gmbh & Co. Kg	Neue Pyridodihydropyrazinone, Verfahren zu Ihrer Herstellung und Ihre Verwendung als Arzneimittel
US20060058311A1 (en)	2004-08-14	2006-03-16	Boehringer Ingelheim International Gmbh	Combinations for the treatment of diseases involving cell proliferation
US20060035903A1 (en)	2004-08-14	2006-02-16	Boehringer Ingelheim International Gmbh	Storage stable perfusion solution for dihydropteridinones
US7759485B2 (en)	2004-08-14	2010-07-20	Boehringer Ingelheim International Gmbh	Process for the manufacture of dihydropteridinones
US7728134B2 (en)	2004-08-14	2010-06-01	Boehringer Ingelheim International Gmbh	Hydrates and polymorphs of 4[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)-benzamide, process for their manufacture and their use as medicament
US20060074088A1 (en)	2004-08-14	2006-04-06	Boehringer Ingelheim International Gmbh	Dihydropteridinones for the treatment of cancer diseases
EP1630163A1 (de)	2004-08-25	2006-03-01	Boehringer Ingelheim Pharma GmbH & Co.KG	Dihydropteridinonderivative, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel
EP1797038B1 (en)	2004-09-29	2012-06-13	Bayer Pharma Aktiengesellschaft	Thermodynamically stable form of bay 43-9006 tosylate
US20060068010A1 (en) *	2004-09-30	2006-03-30	Stephen Turner	Method for improving the bioavailability of orally delivered therapeutics
DE102004054054A1 (de)	2004-11-05	2006-05-11	Boehringer Ingelheim Pharma Gmbh & Co. Kg	Verfahren zur Herstellung chiraler 8-(3-Amino-piperidin-1-yl)-xanthine
DE102004058337A1 (de)	2004-12-02	2006-06-14	Boehringer Ingelheim Pharma Gmbh & Co. Kg	Verfahren zur Herstellung von annelierten Piperazin-2-on Derivaten
DE102005035891A1 (de)	2005-07-30	2007-02-08	Boehringer Ingelheim Pharma Gmbh & Co. Kg	8-(3-Amino-piperidin-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
US7439358B2 (en)	2006-02-08	2008-10-21	Boehringer Ingelheim International Gmbh	Specific salt, anhydrous and crystalline form of a dihydropteridione derivative
EP1852108A1 (en)	2006-05-04	2007-11-07	Boehringer Ingelheim Pharma GmbH & Co.KG	DPP IV inhibitor formulations
PE20080251A1 (es)	2006-05-04	2008-04-25	Boehringer Ingelheim Int	Usos de inhibidores de dpp iv
MX2008014024A (es)	2006-05-04	2008-11-14	Boehringer Ingelheim Int	Formas poliformas.
AR062927A1 (es)	2006-10-11	2008-12-17	Bayer Healthcare Ag	4- [4-( [ [ 4- cloro-3-( trifluorometil) fenil) carbamoil] amino] -3- fluorofenoxi) -n- metilpiridin-2- carboxamida monohidratada
GB2456096B (en) *	2006-10-17	2011-08-17	Cipla Ltd	Crystalline form of benzothiophene compound and process for preparation thereof
US20080103295A1 (en) *	2006-10-25	2008-05-01	David Losan Ho	Process for the preparation of sucrose-6-ester by esterification in the presence of solid superacid catalyst
US8258291B2 (en) *	2006-10-25	2012-09-04	Mamtek International Limited	Process for the preparation of sucralose by the chlorination of sugar with triphosgene (BTC)
DE102007032451B4 (de)	2007-07-12	2010-09-30	Icfs Gmbh	Verfahren zur Herstellung von aromatischen Ketonen
WO2009015004A1 (en) *	2007-07-20	2009-01-29	King Pharmaceuticals Research And Development, Inc.	Crystals of (2-amino-4,5,6,7-tetrahydrobenzo[b]thien-3-yl)(4-chlorophenyl)methanone
EP3098223A1 (en)	2007-08-03	2016-11-30	Boehringer Ingelheim International GmbH	Crystalline form of a dihydropteridione derivative
WO2009080364A1 (en) *	2007-12-21	2009-07-02	Synthon B.V.	Raloxifene composition
PE20091730A1 (es)	2008-04-03	2009-12-10	Boehringer Ingelheim Int	Formulaciones que comprenden un inhibidor de dpp4
EP2307399B1 (en) *	2008-06-09	2016-05-18	ERREGIERRE S.p.A.	Process for controlling the growth of a raloxifene hydrochloride crystal
KR20200118243A (ko)	2008-08-06	2020-10-14	베링거 인겔하임 인터내셔날 게엠베하	메트포르민 요법이 부적합한 환자에서의 당뇨병 치료
UY32030A (es)	2008-08-06	2010-03-26	Boehringer Ingelheim Int	"tratamiento para diabetes en pacientes inapropiados para terapia con metformina"
JP2012502081A (ja)	2008-09-10	2012-01-26	ベーリンガーインゲルハイムインターナショナルゲゼルシャフトミットベシュレンクテルハフツング	糖尿病及び関連症状の治療のための組み合わせ治療
US20200155558A1 (en)	2018-11-20	2020-05-21	Boehringer Ingelheim International Gmbh	Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug
CN102256976A (zh)	2008-12-23	2011-11-23	贝林格尔.英格海姆国际有限公司	有机化合物的盐形式
TW201036975A (en)	2009-01-07	2010-10-16	Boehringer Ingelheim Int	Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy
ES2437916T3 (es)	2009-07-02	2014-01-15	Synthon B.V.	Composición de raloxifeno
EP2314581B1 (en)	2009-10-23	2012-07-25	Hexal AG	A process for preparing benzo[b]thiophene derivatives
CN107115530A (zh)	2009-11-27	2017-09-01	勃林格殷格翰国际有限公司	基因型糖尿病患者利用dpp‑iv抑制剂例如利拉利汀的治疗
WO2011099942A1 (en)	2010-02-09	2011-08-18	Silverstone Pharma	New addition salts of raloxifene, process for the preparation thereof and use thereof in therapy
CA2797310C (en)	2010-05-05	2020-03-31	Boehringer Ingelheim International Gmbh	Glp-1 receptor agonist and dpp-4 inhibitor combination therapy
EP3124041A1 (en)	2010-06-24	2017-02-01	Boehringer Ingelheim International GmbH	Diabetes therapy
US8546566B2 (en)	2010-10-12	2013-10-01	Boehringer Ingelheim International Gmbh	Process for manufacturing dihydropteridinones and intermediates thereof
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
US9358233B2 (en)	2010-11-29	2016-06-07	Boehringer Ingelheim International Gmbh	Method for treating acute myeloid leukemia
US9370535B2 (en)	2011-05-17	2016-06-21	Boehringer Ingelheim International Gmbh	Method for treatment of advanced solid tumors
HUE061596T2 (hu)	2011-07-15	2023-07-28	Boehringer Ingelheim Int	Szubsztituált dimer kinazolin származék, annak elõállítása és alkalmazása az I. és II. típusú cukorbetegség kezelésére szolgáló gyógyszerkészítményekben
US9555001B2 (en)	2012-03-07	2017-01-31	Boehringer Ingelheim International Gmbh	Pharmaceutical composition and uses thereof
EP3685839A1 (en)	2012-05-14	2020-07-29	Boehringer Ingelheim International GmbH	Linagliptin for use in the treatment of albuminuria and kidney related diseases
EP4151218A1 (en)	2012-05-14	2023-03-22	Boehringer Ingelheim International GmbH	Linagliptin, a xanthine derivative as dpp-4 inhibitor, for use in the treatment of sirs and/or sepsis
WO2013174767A1 (en)	2012-05-24	2013-11-28	Boehringer Ingelheim International Gmbh	A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference
IN2013MU00665A (is)	2013-03-05	2015-07-03	Cipla Ltd
JP2016525532A (ja)	2013-07-26	2016-08-25	ベーリンガーインゲルハイムインターナショナルゲゼルシャフトミットベシュレンクテルハフツング	骨髄異形成症候群の処置
WO2015128453A1 (en)	2014-02-28	2015-09-03	Boehringer Ingelheim International Gmbh	Medical use of a dpp-4 inhibitor
US9867831B2 (en)	2014-10-01	2018-01-16	Boehringer Ingelheim International Gmbh	Combination treatment of acute myeloid leukemia and myelodysplastic syndrome
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
US10155000B2 (en)	2016-06-10	2018-12-18	Boehringer Ingelheim International Gmbh	Medical use of pharmaceutical combination or composition
KR102815172B1 (ko) *	2020-02-25	2025-05-29	엘지전자 주식회사	히트펌프 및 그 동작방법

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US3869485A (en) *	1969-09-25	1975-03-04	Allied Chem	Preparation of acid chlorides with phosgene in the presence of a catalyst
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
US4380635A (en) *	1981-04-03	1983-04-19	Eli Lilly And Company	Synthesis of acylated benzothiophenes
US4418068A (en) *	1981-04-03	1983-11-29	Eli Lilly And Company	Antiestrogenic and antiandrugenic benzothiophenes
NZ200204A (en)	1981-04-03	1985-05-31	Lilly Co Eli	Benzothiophene derivatives and process for preparation
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
ZA822247B (en)	1981-04-03	1983-11-30	Lilly Co Eli	Benzothiophene compounds and process for preparing them
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
NZ260790A (en)	1993-06-24	1997-06-24	Lilly Co Eli	Antiestrogen compositions for treatment of diabetes mellitus
US6756388B1 (en)	1993-10-12	2004-06-29	Pfizer Inc.	Benzothiophenes and related compounds as estrogen agonists
US5523416A (en)	1994-07-22	1996-06-04	Eli Lilly And Company	Process for preparing 3-(4-aminoethoxy-benzoyl) benzo (B)-thiophenes
CO4410190A1 (es) *	1994-09-19	1997-01-09	Lilly Co Eli	3-[4-(2-AMINOETOXI)-BENZOIL]-2-ARIL-6-HIDROXIBENZO [b] TIOFENO CRISTALINO

1995
- 1995-06-02 CO CO95023869A patent/CO4410190A1/es unknown
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- 1995-06-05 TW TW084105613A patent/TW412534B/zh not_active IP Right Cessation
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- 1995-06-06 US US08/469,961 patent/US6472531B1/en not_active Expired - Lifetime
- 1995-06-06 US US08/467,485 patent/US5731327A/en not_active Expired - Lifetime
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Also Published As

Publication number	Publication date
DK102795A (da)	1996-03-20
LV11178A (lv)	1996-04-20
IL115315A (en)	1999-09-22
HUT75033A (en)	1997-03-28
RS49578B (sr)	2007-04-10
US6472531B1 (en)	2002-10-29
RO115260B1 (ro)	1999-12-30
SE9503214L (sv)	1996-03-20
AT502957A1 (de)	2007-06-15
IL115314A0 (en)	1996-05-14
GEP19991821B (en)	1999-11-05
SE509265C2 (sv)	1998-12-21
CH691478A5 (de)	2001-07-31
PE14796A1 (es)	1996-05-19
YU61395A (sh)	1998-09-18
PL187686B1 (pl)	2004-09-30
HK1019009A1 (en)	2000-01-14
LV11178B (en)	1996-08-20
NL1001194A1 (nl)	1996-03-19
ATA154295A (de)	2000-12-15
IT1277601B1 (it)	1997-11-11
CO4410191A1 (es)	1997-01-09
FI954402L (fi)	1996-03-20
LU88661A1 (fr)	1996-07-15
DK175903B1 (da)	2005-06-06
IE950721A1 (en)	1996-03-20
FI954403A7 (fi)	1996-03-20
PE32796A1 (es)	1996-08-07
ES2109882B1 (es)	1998-08-16
HU225417B1 (en)	2006-11-28
IS4446A (is)	1997-03-18
HU9502721D0 (en)	1995-11-28
ITMI951936A0 (it)	1995-09-15
LV11177B (en)	1996-08-20
JP2860071B2 (ja)	1999-02-24
KR960010637A (ko)	1996-04-20
AP754A (en)	1999-07-22
NO953658L (no)	1996-03-20
SE9503213L (sv)	1996-03-20
CA2158400A1 (en)	1996-03-20
CH691594A5 (de)	2001-08-31
KR100367376B1 (ko)	2003-03-06
BG101242A (en)	1998-03-31
CA2158399A1 (en)	1996-03-20
CZ290343B6 (cs)	2002-07-17
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OA10406A (en)	2001-12-05
FI121424B (fi)	2010-11-15
CO4410190A1 (es)	1997-01-09
ES2109882A1 (es)	1998-01-16
CH691125A5 (de)	2001-04-30
UA44240C2 (uk)	2002-02-15

Publication	Publication Date	Title
DK175897B1 (da)	2005-05-30	Fremgangsmåde til fremstilling af ikke-solvatiseret krystallinsk 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(piperidinoethoxy)benzoyl]benzo[b]thiophenhydrochlorid og krystallinske solvater heraf til brug ved fremgangsmåden
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

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