CA2558390A1

CA2558390A1 - Novel thio-containing hydroxy-6-phenylphenanthridines and their use as pde4 inhibitors

Novel thio-containing hydroxy-6-phenylphenanthridines and their use as pde4 inhibitors Download PDF

Info

Publication number: CA2558390A1
Authority: CA; Canada
Prior art keywords: methoxy; hydrogen; alkyl; compounds; phenanthridin
Prior art date: 2004-03-10
Legal status : Abandoned

Application number

CA002558390A

Other languages

English (en)

French (fr)

Inventor

Ulrich Kautz

Current Assignee

Takeda GmbH

Original Assignee

Individual

Priority date

2004-03-10

Filing date

2005-03-09

Publication date

2005-09-22

2005-03-09 Application filed by Individual filed Critical Individual

2005-09-22 Publication of CA2558390A1 publication Critical patent/CA2558390A1/en

Status Abandoned legal-status Critical Current

Links

229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 title abstract description 5
239000002587 phosphodiesterase IV inhibitor Substances 0.000 title abstract description 5
125000000446 sulfanediyl group Chemical group *S* 0.000 title description 3
ZCOWHHNEZZCOJZ-UHFFFAOYSA-N 6-phenylphenanthridin-1-ol Chemical class C=12C=CC=CC2=C2C(O)=CC=CC2=NC=1C1=CC=CC=C1 ZCOWHHNEZZCOJZ-UHFFFAOYSA-N 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims abstract description 365
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 203
239000001257 hydrogen Substances 0.000 claims abstract description 203
150000002431 hydrogen Chemical class 0.000 claims abstract description 135
-1 2,2-difluoroethoxy Chemical group 0.000 claims abstract description 133
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 38
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 34
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 17
125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 15
229910052736 halogen Inorganic materials 0.000 claims abstract description 12
150000002367 halogens Chemical group 0.000 claims abstract description 12
150000003839 salts Chemical class 0.000 claims description 81
150000001204 N-oxides Chemical class 0.000 claims description 59
238000000034 method Methods 0.000 claims description 45
125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 38
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
229910052757 nitrogen Inorganic materials 0.000 claims description 31
125000004433 nitrogen atom Chemical group N* 0.000 claims description 24
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 21
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
239000008194 pharmaceutical composition Substances 0.000 claims description 18
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
125000000623 heterocyclic group Chemical group 0.000 claims description 15
238000011282 treatment Methods 0.000 claims description 14
125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 11
229910052760 oxygen Inorganic materials 0.000 claims description 11
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 10
125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 10
125000002757 morpholinyl group Chemical group 0.000 claims description 10
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 10
238000004519 manufacturing process Methods 0.000 claims description 9
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
229910052801 chlorine Inorganic materials 0.000 claims description 8
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 8
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
239000001301 oxygen Substances 0.000 claims description 8
125000003386 piperidinyl group Chemical group 0.000 claims description 8
229910052717 sulfur Chemical group 0.000 claims description 8
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
229910052731 fluorine Inorganic materials 0.000 claims description 7
239000011737 fluorine Substances 0.000 claims description 7
RDOWQLZANAYVLL-UHFFFAOYSA-N phenanthridine Chemical group C1=CC=C2C3=CC=CC=C3C=NC2=C1 RDOWQLZANAYVLL-UHFFFAOYSA-N 0.000 claims description 7
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
239000000460 chlorine Substances 0.000 claims description 6
125000005842 heteroatom Chemical group 0.000 claims description 6
239000000546 pharmaceutical excipient Substances 0.000 claims description 6
239000011593 sulfur Chemical group 0.000 claims description 6
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
230000001404 mediated effect Effects 0.000 claims description 4
125000004568 thiomorpholinyl group Chemical group 0.000 claims description 4
201000010099 disease Diseases 0.000 claims description 3
FPZPVAPRNYQXEV-UHFFFAOYSA-N 4-fluoro-n-[4-(2-hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl)phenyl]benzenesulfonamide Chemical compound C1=2C=C(OC)C(OC)=CC=2C2CC(O)CCC2N=C1C(C=C1)=CC=C1NS(=O)(=O)C1=CC=C(F)C=C1 FPZPVAPRNYQXEV-UHFFFAOYSA-N 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims description 2
QZZRXLYUGXDACT-UHFFFAOYSA-N n-[[4-[8-(difluoromethoxy)-2-hydroxy-9-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl]phenyl]methyl]-4-methylbenzenesulfonamide Chemical compound C1=2C=C(OC(F)F)C(OC)=CC=2C2CC(O)CCC2N=C1C(C=C1)=CC=C1CNS(=O)(=O)C1=CC=C(C)C=C1 QZZRXLYUGXDACT-UHFFFAOYSA-N 0.000 claims description 2
LGHMEPPEZLGICK-XFQXTVEOSA-N (2r,4ar,10br)-9-ethoxy-8-methoxy-6-(4-methylsulfanylphenyl)-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol Chemical compound N([C@@H]1CC[C@@H](O)C[C@@H]1C=1C=C(C(=CC=11)OC)OCC)=C1C1=CC=C(SC)C=C1 LGHMEPPEZLGICK-XFQXTVEOSA-N 0.000 claims 1
VWUCGPZLORIGTL-LCROSDBPSA-N (2r,4ar,10br)-9-ethoxy-8-methoxy-6-(4-methylsulfinylphenyl)-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol Chemical compound N([C@@H]1CC[C@@H](O)C[C@@H]1C=1C=C(C(=CC=11)OC)OCC)=C1C1=CC=C(S(C)=O)C=C1 VWUCGPZLORIGTL-LCROSDBPSA-N 0.000 claims 1
WLFJXIHVWWQMSM-UHFFFAOYSA-N 3-[8-(difluoromethoxy)-2-hydroxy-9-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl]-n,n-bis(2-methoxyethyl)benzenesulfonamide Chemical compound COCCN(CCOC)S(=O)(=O)C1=CC=CC(C=2C3=CC(OC(F)F)=C(OC)C=C3C3CC(O)CCC3N=2)=C1 WLFJXIHVWWQMSM-UHFFFAOYSA-N 0.000 claims 1
DJSGJMKNMQOXMV-UHFFFAOYSA-N 3-[8-(difluoromethoxy)-2-hydroxy-9-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl]-n,n-dimethylbenzenesulfonamide Chemical compound C1=2C=C(OC(F)F)C(OC)=CC=2C2CC(O)CCC2N=C1C1=CC=CC(S(=O)(=O)N(C)C)=C1 DJSGJMKNMQOXMV-UHFFFAOYSA-N 0.000 claims 1
TVBOYUWMRQNCKY-UHFFFAOYSA-N 4-(2-hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl)-n,n-dipropylbenzenesulfonamide Chemical compound C1=CC(S(=O)(=O)N(CCC)CCC)=CC=C1C(C1=CC(OC)=C(OC)C=C11)=NC2C1CC(O)CC2 TVBOYUWMRQNCKY-UHFFFAOYSA-N 0.000 claims 1
DWJIBOLMRJNRCQ-UHFFFAOYSA-N 4-(9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl)-n,n-dipropylbenzenesulfonamide Chemical compound C1=CC(S(=O)(=O)N(CCC)CCC)=CC=C1C(C1=CC(OC)=C(OCC)C=C11)=NC2C1CC(O)CC2 DWJIBOLMRJNRCQ-UHFFFAOYSA-N 0.000 claims 1
ZLNKCILVUPCDMK-UHFFFAOYSA-N 4-(9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl)-n-(2-methoxyethyl)-n-methylbenzenesulfonamide Chemical compound C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C1=CC=C(S(=O)(=O)N(C)CCOC)C=C1 ZLNKCILVUPCDMK-UHFFFAOYSA-N 0.000 claims 1
YKYBWJPJPYUMMX-UHFFFAOYSA-N 4-[8-(difluoromethoxy)-2-hydroxy-9-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl]-n,n-dipropylbenzenesulfonamide Chemical compound C1=CC(S(=O)(=O)N(CCC)CCC)=CC=C1C(C1=CC(OC(F)F)=C(OC)C=C11)=NC2C1CC(O)CC2 YKYBWJPJPYUMMX-UHFFFAOYSA-N 0.000 claims 1
AIXUMCSAWMORJJ-UHFFFAOYSA-N 8,9-dimethoxy-6-(3-methylsulfonylphenyl)-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol Chemical compound C1=2C=C(OC)C(OC)=CC=2C2CC(O)CCC2N=C1C1=CC=CC(S(C)(=O)=O)=C1 AIXUMCSAWMORJJ-UHFFFAOYSA-N 0.000 claims 1
VEYGYIUBIIUIOO-UHFFFAOYSA-N 8-(difluoromethoxy)-9-methoxy-6-(3-morpholin-4-ylsulfonylphenyl)-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol Chemical compound C1=2C=C(OC(F)F)C(OC)=CC=2C2CC(O)CCC2N=C1C(C=1)=CC=CC=1S(=O)(=O)N1CCOCC1 VEYGYIUBIIUIOO-UHFFFAOYSA-N 0.000 claims 1
PUWZSYQMTRFIOS-UHFFFAOYSA-N 8-(difluoromethoxy)-9-methoxy-6-(3-pyrrolidin-1-ylsulfonylphenyl)-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol Chemical compound C1=2C=C(OC(F)F)C(OC)=CC=2C2CC(O)CCC2N=C1C(C=1)=CC=CC=1S(=O)(=O)N1CCCC1 PUWZSYQMTRFIOS-UHFFFAOYSA-N 0.000 claims 1
LMPQGEDLHYNERP-UHFFFAOYSA-N 8-(difluoromethoxy)-9-methoxy-6-(4-morpholin-4-ylsulfonylphenyl)-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol Chemical compound C1=2C=C(OC(F)F)C(OC)=CC=2C2CC(O)CCC2N=C1C(C=C1)=CC=C1S(=O)(=O)N1CCOCC1 LMPQGEDLHYNERP-UHFFFAOYSA-N 0.000 claims 1
MLEZSJPLYAPOQA-UHFFFAOYSA-N 8-(difluoromethoxy)-9-methoxy-6-[3-(4-methylpiperazin-1-yl)sulfonylphenyl]-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol Chemical compound C1=2C=C(OC(F)F)C(OC)=CC=2C2CC(O)CCC2N=C1C(C=1)=CC=CC=1S(=O)(=O)N1CCN(C)CC1 MLEZSJPLYAPOQA-UHFFFAOYSA-N 0.000 claims 1
DSWVGEVUEAYSLJ-UHFFFAOYSA-N 9-(2,2-difluoroethoxy)-8-methoxy-6-(3-methylsulfanylphenyl)-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol Chemical compound N=1C2CCC(O)CC2C=2C=C(OCC(F)F)C(OC)=CC=2C=1C1=CC=CC(SC)=C1 DSWVGEVUEAYSLJ-UHFFFAOYSA-N 0.000 claims 1
AAHXSKMTZNLLDS-UHFFFAOYSA-N 9-(2,2-difluoroethoxy)-8-methoxy-6-(3-methylsulfinylphenyl)-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol Chemical compound N=1C2CCC(O)CC2C=2C=C(OCC(F)F)C(OC)=CC=2C=1C1=CC=CC(S(C)=O)=C1 AAHXSKMTZNLLDS-UHFFFAOYSA-N 0.000 claims 1
CTMIWKUQCCVGMQ-UHFFFAOYSA-N 9-(2,2-difluoroethoxy)-8-methoxy-6-(4-methylsulfanylphenyl)-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol Chemical compound N=1C2CCC(O)CC2C=2C=C(OCC(F)F)C(OC)=CC=2C=1C1=CC=C(SC)C=C1 CTMIWKUQCCVGMQ-UHFFFAOYSA-N 0.000 claims 1
XUSMXKSNAAONBI-UHFFFAOYSA-N 9-(2,2-difluoroethoxy)-8-methoxy-6-(4-pyrrolidin-1-ylsulfonylphenyl)-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol Chemical compound N=1C2CCC(O)CC2C=2C=C(OCC(F)F)C(OC)=CC=2C=1C(C=C1)=CC=C1S(=O)(=O)N1CCCC1 XUSMXKSNAAONBI-UHFFFAOYSA-N 0.000 claims 1
VNEOUOJNAPMDRD-UHFFFAOYSA-N 9-(2,2-difluoroethoxy)-8-methoxy-6-[3-(4-methylpiperazin-1-yl)sulfonylphenyl]-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol Chemical compound N=1C2CCC(O)CC2C=2C=C(OCC(F)F)C(OC)=CC=2C=1C(C=1)=CC=CC=1S(=O)(=O)N1CCN(C)CC1 VNEOUOJNAPMDRD-UHFFFAOYSA-N 0.000 claims 1
LGHMEPPEZLGICK-UHFFFAOYSA-N 9-ethoxy-8-methoxy-6-(4-methylsulfanylphenyl)-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol Chemical compound C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C1=CC=C(SC)C=C1 LGHMEPPEZLGICK-UHFFFAOYSA-N 0.000 claims 1
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
NGYRGWAKJULXKZ-UHFFFAOYSA-N n-[4-(2-hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl)-2-methylphenyl]-4-methylbenzenesulfonamide Chemical compound C1=2C=C(OC)C(OC)=CC=2C2CC(O)CCC2N=C1C(C=C1C)=CC=C1NS(=O)(=O)C1=CC=C(C)C=C1 NGYRGWAKJULXKZ-UHFFFAOYSA-N 0.000 claims 1
WJALITREPKNFHM-UHFFFAOYSA-N n-[4-(2-hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl)phenyl]-4-methylbenzenesulfonamide Chemical compound C1=2C=C(OC)C(OC)=CC=2C2CC(O)CCC2N=C1C(C=C1)=CC=C1NS(=O)(=O)C1=CC=C(C)C=C1 WJALITREPKNFHM-UHFFFAOYSA-N 0.000 claims 1
TZWQEFCHDOOVRJ-UHFFFAOYSA-N n-[4-(2-hydroxy-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl)phenyl]-n,4-dimethylbenzenesulfonamide Chemical compound C1=2C=C(OC)C(OC)=CC=2C2CC(O)CCC2N=C1C(C=C1)=CC=C1N(C)S(=O)(=O)C1=CC=C(C)C=C1 TZWQEFCHDOOVRJ-UHFFFAOYSA-N 0.000 claims 1
OKXOJOAZUOLEOE-UHFFFAOYSA-N n-[4-[8-(difluoromethoxy)-2-hydroxy-9-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl]phenyl]-4-fluorobenzenesulfonamide Chemical compound C1=2C=C(OC(F)F)C(OC)=CC=2C2CC(O)CCC2N=C1C(C=C1)=CC=C1NS(=O)(=O)C1=CC=C(F)C=C1 OKXOJOAZUOLEOE-UHFFFAOYSA-N 0.000 claims 1
OUBMTAUZCZAKCX-UHFFFAOYSA-N n-[4-[8-(difluoromethoxy)-2-hydroxy-9-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl]phenyl]-4-methylbenzenesulfonamide Chemical compound C1=2C=C(OC(F)F)C(OC)=CC=2C2CC(O)CCC2N=C1C(C=C1)=CC=C1NS(=O)(=O)C1=CC=C(C)C=C1 OUBMTAUZCZAKCX-UHFFFAOYSA-N 0.000 claims 1
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