CA2557730A1

CA2557730A1 - Novel heterocyclyl-substituted hydroxy-6-phenylphenanthridines and their use as pde4 inhibitors

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

Info

Publication number: CA2557730A1
Authority: CA; Canada
Prior art keywords: alkyl; hydrogen; alkoxy; compounds; methoxy
Prior art date: 2004-03-03
Legal status : Abandoned

Application number

CA002557730A

Other languages

English (en)

French (fr)

Inventor

Ulrich Kautz

Current Assignee

Takeda GmbH

Original Assignee

Individual

Priority date

2004-03-03

Filing date

2005-03-03

Publication date

2005-09-29

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

2005-09-29 Publication of CA2557730A1 publication Critical patent/CA2557730A1/en

Status Abandoned legal-status Critical Current

Links

229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 title description 7
239000002587 phosphodiesterase IV inhibitor Substances 0.000 title description 7
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 373
-1 2,2-difluoroethoxy Chemical group 0.000 claims abstract description 249
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 169
239000001257 hydrogen Substances 0.000 claims abstract description 168
150000002431 hydrogen Chemical class 0.000 claims abstract description 121
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 43
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 34
125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 25
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 18
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 83
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 76
229910052757 nitrogen Inorganic materials 0.000 claims description 69
150000001204 N-oxides Chemical class 0.000 claims description 61
238000000034 method Methods 0.000 claims description 52
101100177165 Caenorhabditis elegans har-1 gene Proteins 0.000 claims description 46
125000004433 nitrogen atom Chemical group N* 0.000 claims description 40
229910052760 oxygen Inorganic materials 0.000 claims description 36
125000005842 heteroatom Chemical group 0.000 claims description 35
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 34
239000001301 oxygen Substances 0.000 claims description 34
229910052717 sulfur Inorganic materials 0.000 claims description 34
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 32
239000011593 sulfur Substances 0.000 claims description 32
125000002950 monocyclic group Chemical group 0.000 claims description 28
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 26
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 25
239000008194 pharmaceutical composition Substances 0.000 claims description 17
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 14
125000000714 pyrimidinyl group Chemical group 0.000 claims description 14
238000011282 treatment Methods 0.000 claims description 14
125000004076 pyridyl group Chemical group 0.000 claims description 13
125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 claims description 12
125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 claims description 12
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
125000004512 1,2,3-thiadiazol-4-yl group Chemical group S1N=NC(=C1)* 0.000 claims description 9
238000004519 manufacturing process Methods 0.000 claims description 8
229920006395 saturated elastomer Polymers 0.000 claims description 8
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 7
125000002883 imidazolyl group Chemical group 0.000 claims description 7
125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 7
125000003831 tetrazolyl group Chemical group 0.000 claims description 7
125000002971 oxazolyl group Chemical group 0.000 claims description 6
239000000546 pharmaceutical excipient Substances 0.000 claims description 6
125000000335 thiazolyl group Chemical group 0.000 claims description 6
125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 claims description 5
125000001766 1,2,4-oxadiazol-3-yl group Chemical group [H]C1=NC(*)=NO1 0.000 claims description 5
125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims description 5
125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 5
125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 5
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 5
125000003226 pyrazolyl group Chemical group 0.000 claims description 5
125000000168 pyrrolyl group Chemical group 0.000 claims description 5
125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 claims description 5
125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 claims description 4
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
RDOWQLZANAYVLL-UHFFFAOYSA-N phenanthridine Chemical group C1=CC=C2C3=CC=CC=C3C=NC2=C1 RDOWQLZANAYVLL-UHFFFAOYSA-N 0.000 claims description 4
125000004571 thiomorpholin-4-yl group Chemical group N1(CCSCC1)* 0.000 claims description 4
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
ZPORNJQEXSZMBO-YVWKXTFCSA-N (2r,4ar,10br)-9-(2,2-difluoroethoxy)-6-[4-(2-ethyltetrazol-5-yl)phenyl]-8-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol Chemical compound CCN1N=NC(C=2C=CC(=CC=2)C=2C3=CC(OC)=C(OCC(F)F)C=C3[C@H]3C[C@H](O)CC[C@H]3N=2)=N1 ZPORNJQEXSZMBO-YVWKXTFCSA-N 0.000 claims description 2
LNLWSHCOTARULO-VCOUNFBDSA-N (2s,4as,10bs)-9-ethoxy-6-(4-imidazol-1-ylphenyl)-8-methoxy-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)=C1C(C=C1)=CC=C1N1C=CN=C1 LNLWSHCOTARULO-VCOUNFBDSA-N 0.000 claims description 2
AGUUKKXWABRVBZ-UHFFFAOYSA-N 8-[[4-(furan-2-carbonyl)piperazin-1-yl]methyl]-1,3-dimethyl-7-(3-methylbutyl)purine-2,6-dione Chemical compound N=1C=2N(C)C(=O)N(C)C(=O)C=2N(CCC(C)C)C=1CN(CC1)CCN1C(=O)C1=CC=CO1 AGUUKKXWABRVBZ-UHFFFAOYSA-N 0.000 claims description 2
GTVACIGITVIEJP-UHFFFAOYSA-N 9-(2,2-difluoroethoxy)-6-(4-imidazol-1-ylphenyl)-8-methoxy-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=C1N1C=CN=C1 GTVACIGITVIEJP-UHFFFAOYSA-N 0.000 claims description 2
HGVHHZNEXADATD-UHFFFAOYSA-N 9-(2,2-difluoroethoxy)-8-methoxy-6-[4-(1,2,4-triazol-1-yl)phenyl]-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=C1N1C=NC=N1 HGVHHZNEXADATD-UHFFFAOYSA-N 0.000 claims description 2
LNLWSHCOTARULO-UHFFFAOYSA-N 9-ethoxy-6-(4-imidazol-1-ylphenyl)-8-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol Chemical compound C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C(C=C1)=CC=C1N1C=CN=C1 LNLWSHCOTARULO-UHFFFAOYSA-N 0.000 claims description 2
QOIQNNLUKOMSCE-UHFFFAOYSA-N 9-ethoxy-8-methoxy-6-(4-morpholin-4-ylphenyl)-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol Chemical compound C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C(C=C1)=CC=C1N1CCOCC1 QOIQNNLUKOMSCE-UHFFFAOYSA-N 0.000 claims description 2
201000010099 disease Diseases 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims description 2
LNLWSHCOTARULO-SYYKKAFVSA-N (2r,4ar,10br)-9-ethoxy-6-(4-imidazol-1-ylphenyl)-8-methoxy-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)=C1C(C=C1)=CC=C1N1C=CN=C1 LNLWSHCOTARULO-SYYKKAFVSA-N 0.000 claims 1
NGYWRRIFHRYUMJ-UHFFFAOYSA-N 8,9-dimethoxy-6-[4-(2-propyltetrazol-5-yl)phenyl]-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol Chemical compound CCCN1N=NC(C=2C=CC(=CC=2)C=2C3=CC(OC)=C(OC)C=C3C3CC(O)CCC3N=2)=N1 NGYWRRIFHRYUMJ-UHFFFAOYSA-N 0.000 claims 1
HMXMFSLGLXNCHE-UHFFFAOYSA-N 8-(difluoromethoxy)-6-[4-(2-ethyltetrazol-5-yl)phenyl]-9-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol Chemical compound CCN1N=NC(C=2C=CC(=CC=2)C=2C3=CC(OC(F)F)=C(OC)C=C3C3CC(O)CCC3N=2)=N1 HMXMFSLGLXNCHE-UHFFFAOYSA-N 0.000 claims 1
ZPORNJQEXSZMBO-UHFFFAOYSA-N 9-(2,2-difluoroethoxy)-6-[4-(2-ethyltetrazol-5-yl)phenyl]-8-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol Chemical compound CCN1N=NC(C=2C=CC(=CC=2)C=2C3=CC(OC)=C(OCC(F)F)C=C3C3CC(O)CCC3N=2)=N1 ZPORNJQEXSZMBO-UHFFFAOYSA-N 0.000 claims 1
DJIBHIIEAHNVCQ-UHFFFAOYSA-N 9-(2,2-difluoroethoxy)-8-methoxy-6-[3-(2-methyl-1,3-thiazol-4-yl)phenyl]-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=1C1=CSC(C)=N1 DJIBHIIEAHNVCQ-UHFFFAOYSA-N 0.000 claims 1
WZJCFWGFAXCQMA-UHFFFAOYSA-N 9-(2,2-difluoroethoxy)-8-methoxy-6-[4-(1,3-oxazol-5-yl)phenyl]-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=C1C1=CN=CO1 WZJCFWGFAXCQMA-UHFFFAOYSA-N 0.000 claims 1
VHWLGWAAJQZHEG-UHFFFAOYSA-N 9-(difluoromethoxy)-6-[4-(2-ethyltetrazol-5-yl)phenyl]-8-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol Chemical compound CCN1N=NC(C=2C=CC(=CC=2)C=2C3=CC(OC)=C(OC(F)F)C=C3C3CC(O)CCC3N=2)=N1 VHWLGWAAJQZHEG-UHFFFAOYSA-N 0.000 claims 1
YTJZJQKYNQPQME-UHFFFAOYSA-N 9-ethoxy-6-[3-(2-ethyltetrazol-5-yl)phenyl]-8-methoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol Chemical compound C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C(C=1)=CC=CC=1C=1N=NN(CC)N=1 YTJZJQKYNQPQME-UHFFFAOYSA-N 0.000 claims 1
ZNQUPDVKAKYDGF-UHFFFAOYSA-N 9-ethoxy-8-methoxy-6-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol Chemical compound C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C(C=1)=CC=CC=1C1=NOC(C)=N1 ZNQUPDVKAKYDGF-UHFFFAOYSA-N 0.000 claims 1
ULOQXALFJYYVSY-UHFFFAOYSA-N 9-ethoxy-8-methoxy-6-[4-(4-methylpiperazin-1-yl)phenyl]-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol Chemical compound C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C(C=C1)=CC=C1N1CCN(C)CC1 ULOQXALFJYYVSY-UHFFFAOYSA-N 0.000 claims 1
BAUCQVJTUPZQPK-UHFFFAOYSA-N 9-ethoxy-8-methoxy-6-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-1,2,3,4,4a,10b-hexahydrophenanthridin-2-ol Chemical compound C1=2C=C(OC)C(OCC)=CC=2C2CC(O)CCC2N=C1C(C=C1)=CC=C1C1=NOC(C)=N1 BAUCQVJTUPZQPK-UHFFFAOYSA-N 0.000 claims 1
125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
229940124531 pharmaceutical excipient Drugs 0.000 claims 1
208000023504 respiratory system disease Diseases 0.000 claims 1
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LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
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125000004432 carbon atom Chemical group C* 0.000 description 17
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IUHSKHLYJAVALM-UHFFFAOYSA-N 3-(3,4-dimethoxyphenyl)-4-nitrocyclohexan-1-one Chemical compound C1=C(OC)C(OC)=CC=C1C1C([N+]([O-])=O)CCC(=O)C1 IUHSKHLYJAVALM-UHFFFAOYSA-N 0.000 description 10
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