CA2558375A1

CA2558375A1 - Novel isoamido-substituted hydroxy-6-phenylphenanthridines and their use as pde4 inhibitors

Novel isoamido-substituted hydroxy-6-phenylphenanthridines and their use as pde4 inhibitors Download PDF

Info

Publication number: CA2558375A1
Authority: CA; Canada
Prior art keywords: hydrogen; alkyl; alkoxy; compounds; methoxy
Prior art date: 2004-03-09
Legal status : Abandoned

Application number

CA002558375A

Other languages

English (en)

French (fr)

Inventor

Ulrich Kautz

Current Assignee

Takeda GmbH

Original Assignee

Individual

Priority date

2004-03-09

Filing date

2005-03-08

Publication date

2005-09-15

2005-03-08 Application filed by Individual filed Critical Individual

2005-09-15 Publication of CA2558375A1 publication Critical patent/CA2558375A1/en

Status Abandoned legal-status Critical Current

Links

229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 title abstract description 6
239000002587 phosphodiesterase IV inhibitor Substances 0.000 title abstract description 6
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 3
150000001875 compounds Chemical class 0.000 claims abstract description 341
-1 2,2-difluoroethoxy Chemical group 0.000 claims abstract description 180
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 174
239000001257 hydrogen Substances 0.000 claims abstract description 173
150000002431 hydrogen Chemical class 0.000 claims abstract description 103
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 58
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 44
125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 25
101100177165 Caenorhabditis elegans har-1 gene Proteins 0.000 claims abstract description 22
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 17
229910052736 halogen Inorganic materials 0.000 claims abstract description 16
150000002367 halogens Chemical group 0.000 claims abstract description 16
229910052757 nitrogen Inorganic materials 0.000 claims description 71
150000003839 salts Chemical class 0.000 claims description 65
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 54
125000004433 nitrogen atom Chemical group N* 0.000 claims description 50
238000000034 method Methods 0.000 claims description 47
150000001204 N-oxides Chemical class 0.000 claims description 43
125000005842 heteroatom Chemical group 0.000 claims description 26
229910052760 oxygen Inorganic materials 0.000 claims description 26
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 25
239000001301 oxygen Chemical group 0.000 claims description 25
229910052717 sulfur Chemical group 0.000 claims description 25
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 24
239000011593 sulfur Chemical group 0.000 claims description 24
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 22
125000000623 heterocyclic group Chemical group 0.000 claims description 21
239000008194 pharmaceutical composition Substances 0.000 claims description 18
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
229910052799 carbon Inorganic materials 0.000 claims description 15
125000004076 pyridyl group Chemical group 0.000 claims description 15
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 14
150000001721 carbon Chemical group 0.000 claims description 13
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 13
238000011282 treatment Methods 0.000 claims description 13
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
238000004519 manufacturing process Methods 0.000 claims description 9
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
229920006395 saturated elastomer Polymers 0.000 claims description 9
125000004043 oxo group Chemical group O=* 0.000 claims description 8
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 claims description 7
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 6
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
239000000546 pharmaceutical excipient Substances 0.000 claims description 6
230000001404 mediated effect Effects 0.000 claims description 5
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 4
125000004093 cyano group Chemical group *C#N 0.000 claims description 4
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
CEABVLPXHAQPPU-UHFFFAOYSA-N C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C1=CC=CC(N)=C1 Chemical compound C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C1=CC=CC(N)=C1 CEABVLPXHAQPPU-UHFFFAOYSA-N 0.000 claims description 3
125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
RDOWQLZANAYVLL-UHFFFAOYSA-N phenanthridine Chemical group C1=CC=C2C3=CC=CC=C3C=NC2=C1 RDOWQLZANAYVLL-UHFFFAOYSA-N 0.000 claims description 3
125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
201000010099 disease Diseases 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims description 2
WCESRWVTCVMYMU-GFCCVEGCSA-N n-[2,4-dimethoxy-5-[[(2r)-2-methyl-2,3-dihydroindol-1-yl]sulfonyl]phenyl]acetamide Chemical compound C1=C(NC(C)=O)C(OC)=CC(OC)=C1S(=O)(=O)N1C2=CC=CC=C2C[C@H]1C WCESRWVTCVMYMU-GFCCVEGCSA-N 0.000 claims description 2
FWXYMUQQKREYMH-UHFFFAOYSA-N n-[3-(9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl)phenyl]-2-methoxyacetamide Chemical compound C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C1=CC=CC(NC(=O)COC)=C1 FWXYMUQQKREYMH-UHFFFAOYSA-N 0.000 claims description 2
IZKVULTYCSJCOE-UHFFFAOYSA-N n-[3-(9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl)phenyl]-3-methoxypropanamide Chemical compound C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C1=CC=CC(NC(=O)CCOC)=C1 IZKVULTYCSJCOE-UHFFFAOYSA-N 0.000 claims description 2
ROMNXRPWLQQSNH-UHFFFAOYSA-N n-[3-(9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl)phenyl]cyclopropanecarboxamide Chemical compound C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C(C=1)=CC=CC=1NC(=O)C1CC1 ROMNXRPWLQQSNH-UHFFFAOYSA-N 0.000 claims description 2
QVDMPGWNJCLHPZ-UHFFFAOYSA-N n-[3-(9-ethoxy-3-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl)phenyl]cyclopropanecarboxamide Chemical compound C1=2C=C(OC)C(OCC)=CC=2C2CCC(O)CC2N=C1C(C=1)=CC=CC=1NC(=O)C1CC1 QVDMPGWNJCLHPZ-UHFFFAOYSA-N 0.000 claims description 2
HYVWIZBUHDYWGY-UHFFFAOYSA-N 2-(dimethylamino)-n-[3-(9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl)phenyl]butanamide Chemical compound C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C1=CC=CC(NC(=O)C(CC)N(C)C)=C1 HYVWIZBUHDYWGY-UHFFFAOYSA-N 0.000 claims 1
IVCVCRUEDNZWRO-UHFFFAOYSA-N 2-(dimethylamino)-n-[4-(9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl)phenyl]butanamide Chemical compound C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C1=CC=C(NC(=O)C(CC)N(C)C)C=C1 IVCVCRUEDNZWRO-UHFFFAOYSA-N 0.000 claims 1
YICUAMQTWNFMMF-UHFFFAOYSA-N 3-(carbamoylamino)-n-[3-(9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl)phenyl]propanamide Chemical compound C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C1=CC=CC(NC(=O)CCNC(N)=O)=C1 YICUAMQTWNFMMF-UHFFFAOYSA-N 0.000 claims 1
GYLNEKSNRPYZNU-UHFFFAOYSA-N C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C1=CC=C(N)C=C1 Chemical compound C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C1=CC=C(N)C=C1 GYLNEKSNRPYZNU-UHFFFAOYSA-N 0.000 claims 1
BTXGYNTYEYOGMV-UHFFFAOYSA-N CCOC(C(OC)=C1)=CC2=C1C(C(C=C1)=CC=C1N)=NC(CC1)C2CC1O.OC(C1CC1)=O Chemical compound CCOC(C(OC)=C1)=CC2=C1C(C(C=C1)=CC=C1N)=NC(CC1)C2CC1O.OC(C1CC1)=O BTXGYNTYEYOGMV-UHFFFAOYSA-N 0.000 claims 1
CMZGSSOQYWWEBL-UHFFFAOYSA-N CN1CCC(C(O)=O)CC1.C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C(C=1)=CC=CC=1NC(=O)CCN1CCCCC1 Chemical compound CN1CCC(C(O)=O)CC1.C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C(C=1)=CC=CC=1NC(=O)CCN1CCCCC1 CMZGSSOQYWWEBL-UHFFFAOYSA-N 0.000 claims 1
OTWFNFMGAQJGRV-UHFFFAOYSA-N N-[4-(9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl)phenyl]-N',N'-dimethylbutanediamide 1-methylpiperidine-4-carboxylic acid Chemical compound CN1CCC(C(O)=O)CC1.C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C1=CC=C(NC(=O)CCC(=O)N(C)C)C=C1 OTWFNFMGAQJGRV-UHFFFAOYSA-N 0.000 claims 1
FSBRGVFWZQMBFX-UHFFFAOYSA-N n'-[3-(9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl)phenyl]butanediamide Chemical compound C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C1=CC=CC(NC(=O)CCC(N)=O)=C1 FSBRGVFWZQMBFX-UHFFFAOYSA-N 0.000 claims 1
KCSCHSMBXFCGBU-UHFFFAOYSA-N n-[3-(9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl)phenyl]-2,6-dimethoxypyridine-3-carboxamide Chemical compound C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C(C=1)=CC=CC=1NC(=O)C1=CC=C(OC)N=C1OC KCSCHSMBXFCGBU-UHFFFAOYSA-N 0.000 claims 1
GTBKUYBWFLTYIB-UHFFFAOYSA-N n-[3-(9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl)phenyl]-n',n'-dimethylbutanediamide Chemical compound C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C1=CC=CC(NC(=O)CCC(=O)N(C)C)=C1 GTBKUYBWFLTYIB-UHFFFAOYSA-N 0.000 claims 1
CVKMJAWIHLMWJC-UHFFFAOYSA-N n-[4-(9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl)phenyl]-2-methoxyacetamide Chemical compound C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C1=CC=C(NC(=O)COC)C=C1 CVKMJAWIHLMWJC-UHFFFAOYSA-N 0.000 claims 1
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229940124531 pharmaceutical excipient Drugs 0.000 claims 1
208000023504 respiratory system disease Diseases 0.000 claims 1
125000004571 thiomorpholin-4-yl group Chemical group N1(CCSCC1)* 0.000 claims 1
235000013350 formula milk Nutrition 0.000 description 138
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