NZ570085A - Pyrazolo[3,4-b]pyridine compounds, and their use as phosphodiesterase inhibitors - Google Patents

Info

Publication number

NZ570085A

NZ570085A NZ570085A NZ57008503A NZ570085A NZ 570085 A NZ570085 A NZ 570085A NZ 570085 A NZ570085 A NZ 570085A NZ 57008503 A NZ57008503 A NZ 57008503A NZ 570085 A NZ570085 A NZ 570085A

Authority

NZ

New Zealand

Prior art keywords

ethyl

pyrazolo

pyridin

pyran

tetrahydro

Prior art date

2002-12-23

Links

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• Global Dossier
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• 239000002571 phosphodiesterase inhibitor Substances 0.000 title description 4
• 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 title description 3
• 150000005230 pyrazolo[3,4-b]pyridines Chemical class 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 359
• 150000003839 salts Chemical class 0.000 claims abstract description 184
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 83
• 241000282414 Homo sapiens Species 0.000 claims abstract description 34
• 239000002245 particle Substances 0.000 claims abstract description 25
• 241000124008 Mammalia Species 0.000 claims abstract description 20
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract description 16
• 208000006673 asthma Diseases 0.000 claims abstract description 15
• 230000002829 reductive effect Effects 0.000 claims abstract description 15
• 230000002757 inflammatory effect Effects 0.000 claims abstract description 14
• 208000027866 inflammatory disease Diseases 0.000 claims abstract description 11
• 208000026935 allergic disease Diseases 0.000 claims abstract description 10
• 206010039085 Rhinitis allergic Diseases 0.000 claims abstract description 8
• 201000010105 allergic rhinitis Diseases 0.000 claims abstract description 8
• 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 6
• 208000028698 Cognitive impairment Diseases 0.000 claims abstract description 5
• 208000010877 cognitive disease Diseases 0.000 claims abstract description 5
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 203
• -1 hydroxyimino Chemical group 0.000 claims description 193
• NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 claims description 187
• 229960004979 fampridine Drugs 0.000 claims description 187
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 184
• 125000001424 substituent group Chemical group 0.000 claims description 136
• 229910052799 carbon Inorganic materials 0.000 claims description 129
• 239000000203 mixture Substances 0.000 claims description 119
• 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 claims description 112
• 238000000034 method Methods 0.000 claims description 104
• 239000002904 solvent Substances 0.000 claims description 89
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 84
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 83
• 125000001153 fluoro group Chemical group F* 0.000 claims description 74
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 63
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 59
• 150000001721 carbon Chemical group 0.000 claims description 58
• 125000000217 alkyl group Chemical group 0.000 claims description 54
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 50
• 239000007787 solid Substances 0.000 claims description 50
• 125000003118 aryl group Chemical group 0.000 claims description 49
• 229910052760 oxygen Inorganic materials 0.000 claims description 49
• 229910052717 sulfur Inorganic materials 0.000 claims description 48
• 229910052757 nitrogen Inorganic materials 0.000 claims description 46
• 230000008569 process Effects 0.000 claims description 41
• 239000008194 pharmaceutical composition Substances 0.000 claims description 39
• 239000000126 substance Substances 0.000 claims description 36
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 35
• 238000011282 treatment Methods 0.000 claims description 35
• 229910052739 hydrogen Inorganic materials 0.000 claims description 32
• 239000003814 drug Substances 0.000 claims description 28
• 125000006413 ring segment Chemical group 0.000 claims description 28
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 25
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 24
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 24
• 125000005842 heteroatom Chemical group 0.000 claims description 24
• 238000011321 prophylaxis Methods 0.000 claims description 24
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 23
• 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 21
• 101100294106 Caenorhabditis elegans nhr-3 gene Proteins 0.000 claims description 21
• 239000003153 chemical reaction reagent Substances 0.000 claims description 21
• 150000001412 amines Chemical class 0.000 claims description 20
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 20
• 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 17
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 16
• RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 15
• 125000003545 alkoxy group Chemical group 0.000 claims description 14
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
• 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 13
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 13
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
• 125000003709 fluoroalkyl group Chemical group 0.000 claims description 13
• 125000001841 imino group Chemical group [H]N=* 0.000 claims description 13
• 125000002541 furyl group Chemical group 0.000 claims description 11
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 10
• 125000004428 fluoroalkoxy group Chemical group 0.000 claims description 10
• 230000002685 pulmonary effect Effects 0.000 claims description 10
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
• 239000003937 drug carrier Substances 0.000 claims description 9
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 8
• 201000010099 disease Diseases 0.000 claims description 8
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
• 238000004128 high performance liquid chromatography Methods 0.000 claims description 8
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 8
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
• 101100006941 Caenorhabditis elegans sex-1 gene Proteins 0.000 claims description 7
• 102100022087 Granzyme M Human genes 0.000 claims description 7
• 101000900697 Homo sapiens Granzyme M Proteins 0.000 claims description 7
• 125000000468 ketone group Chemical group 0.000 claims description 7
• 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 7
• 125000001544 thienyl group Chemical group 0.000 claims description 7
• ROGKJJGNQJKPFJ-UHFFFAOYSA-N 1h-pyrazolo[3,4-b]pyridin-4-amine Chemical compound NC1=CC=NC2=C1C=NN2 ROGKJJGNQJKPFJ-UHFFFAOYSA-N 0.000 claims description 6
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 6
• 101100294102 Caenorhabditis elegans nhr-2 gene Proteins 0.000 claims description 6
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
• 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
• 229930194542 Keto Natural products 0.000 claims description 5
• FZZMTSNZRBFGGU-UHFFFAOYSA-N 2-chloro-7-fluoroquinazolin-4-amine Chemical compound FC1=CC=C2C(N)=NC(Cl)=NC2=C1 FZZMTSNZRBFGGU-UHFFFAOYSA-N 0.000 claims description 4
• 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
• 125000001246 bromo group Chemical group Br* 0.000 claims description 4
• JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexyloxide Natural products O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 4
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
• 125000004509 1,3,4-oxadiazol-2-yl group Chemical group O1C(=NN=C1)* 0.000 claims description 3
• XRRDFIPYLFCYLU-UHFFFAOYSA-N 1,3,5-trimethylbenzene Chemical group [CH2]C1=CC(C)=CC(C)=C1 XRRDFIPYLFCYLU-UHFFFAOYSA-N 0.000 claims description 3
• 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 3
• BGTOWKSIORTVQH-UHFFFAOYSA-N cyclo-pentanone Natural products O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 claims description 3
• 125000002883 imidazolyl group Chemical group 0.000 claims description 3
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 3
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
• 125000004076 pyridyl group Chemical group 0.000 claims description 3
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
• 230000001225 therapeutic effect Effects 0.000 claims description 3
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
• 238000004519 manufacturing process Methods 0.000 claims description 2
• 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 2
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 claims 3
• NRPFNQUDKRYCNX-UHFFFAOYSA-N 4-methoxyphenylacetic acid Chemical compound COC1=CC=C(CC(O)=O)C=C1 NRPFNQUDKRYCNX-UHFFFAOYSA-N 0.000 claims 2
• GISRWBROCYNDME-PELMWDNLSA-N F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C Chemical compound F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C GISRWBROCYNDME-PELMWDNLSA-N 0.000 claims 2
• RAROYFBUEHDELU-UHFFFAOYSA-N 1-ethyl-5-[5-(methylsulfonylmethyl)-1,3,4-oxadiazol-2-yl]-n-(oxan-4-yl)pyrazolo[3,4-b]pyridin-4-amine Chemical compound N=1N=C(CS(C)(=O)=O)OC=1C1=CN=C2N(CC)N=CC2=C1NC1CCOCC1 RAROYFBUEHDELU-UHFFFAOYSA-N 0.000 claims 1
• ONWXJMCAIRWEKW-UHFFFAOYSA-N 1-ethyl-6-methyl-n-(oxan-4-yl)-5-[5-(oxan-4-yl)-1,3,4-oxadiazol-2-yl]pyrazolo[3,4-b]pyridin-4-amine Chemical compound N=1N=C(C2CCOCC2)OC=1C1=C(C)N=C2N(CC)N=CC2=C1NC1CCOCC1 ONWXJMCAIRWEKW-UHFFFAOYSA-N 0.000 claims 1
• WVSSDMGQAQMULY-UHFFFAOYSA-N 2-[5-[1-ethyl-4-(oxan-4-ylamino)pyrazolo[3,4-b]pyridin-5-yl]-1,2,4-oxadiazol-3-yl]-1-pyrrolidin-1-ylethanone Chemical compound N=1C(CC(=O)N2CCCC2)=NOC=1C1=CN=C2N(CC)N=CC2=C1NC1CCOCC1 WVSSDMGQAQMULY-UHFFFAOYSA-N 0.000 claims 1
• MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 claims 1
• 125000001963 4 membered heterocyclic group Chemical group 0.000 claims 1
• 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 1
• HQESRZJRDCZAJW-UHFFFAOYSA-N 5-(4,4-dimethyl-5h-1,3-oxazol-2-yl)-1-ethyl-n-(oxan-4-yl)pyrazolo[3,4-b]pyridin-4-amine Chemical compound N=1C(C)(C)COC=1C1=CN=C2N(CC)N=CC2=C1NC1CCOCC1 HQESRZJRDCZAJW-UHFFFAOYSA-N 0.000 claims 1
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• 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims 1
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