NZ579645A - Pyrazolo (3, 4-b) pyridine derivatives as phosphodiesterase inhibitors - Google Patents

Info

Publication number

NZ579645A

NZ579645A NZ579645A NZ57964508A NZ579645A NZ 579645 A NZ579645 A NZ 579645A NZ 579645 A NZ579645 A NZ 579645A NZ 57964508 A NZ57964508 A NZ 57964508A NZ 579645 A NZ579645 A NZ 579645A

Authority

NZ

New Zealand

Prior art keywords

compound

pyrazolo

pyridin

ethyl

oxa

Prior art date

2007-03-14

Links

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• 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 title description 3
• 239000002571 phosphodiesterase inhibitor Substances 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 1562
• 238000002360 preparation method Methods 0.000 claims abstract description 85
• 238000000034 method Methods 0.000 claims abstract description 49
• 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 claims abstract description 35
• 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 claims abstract description 35
• 239000003112 inhibitor Substances 0.000 claims abstract description 24
• 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims abstract description 18
• 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims abstract description 18
• 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims abstract description 18
• 201000000028 adult respiratory distress syndrome Diseases 0.000 claims abstract description 18
• 230000009977 dual effect Effects 0.000 claims abstract description 12
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract description 10
• 206010010744 Conjunctivitis allergic Diseases 0.000 claims abstract description 9
• 208000011231 Crohn disease Diseases 0.000 claims abstract description 9
• 206010012438 Dermatitis atopic Diseases 0.000 claims abstract description 9
• 241000124008 Mammalia Species 0.000 claims abstract description 9
• 201000004681 Psoriasis Diseases 0.000 claims abstract description 9
• 206010039085 Rhinitis allergic Diseases 0.000 claims abstract description 9
• 208000002205 allergic conjunctivitis Diseases 0.000 claims abstract description 9
• 201000010105 allergic rhinitis Diseases 0.000 claims abstract description 9
• 208000006673 asthma Diseases 0.000 claims abstract description 9
• 208000024998 atopic conjunctivitis Diseases 0.000 claims abstract description 9
• 201000008937 atopic dermatitis Diseases 0.000 claims abstract description 9
• 206010009887 colitis Diseases 0.000 claims abstract description 9
• 201000008482 osteoarthritis Diseases 0.000 claims abstract description 9
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
• 230000035939 shock Effects 0.000 claims abstract description 9
• 208000030507 AIDS Diseases 0.000 claims abstract description 8
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 8
• 206010033645 Pancreatitis Diseases 0.000 claims abstract description 8
• 206010006451 bronchitis Diseases 0.000 claims abstract description 8
• 201000006417 multiple sclerosis Diseases 0.000 claims abstract description 8
• 230000002265 prevention Effects 0.000 claims abstract description 8
• 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 8
• 238000004519 manufacturing process Methods 0.000 claims abstract description 6
• 239000003814 drug Substances 0.000 claims abstract description 5
• 201000011510 cancer Diseases 0.000 claims abstract description 4
• -1 hydroxy, carboxy Chemical group 0.000 claims description 316
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 294
• 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 claims description 254
• NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 claims description 200
• 229960004979 fampridine Drugs 0.000 claims description 200
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 186
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 146
• 125000000217 alkyl group Chemical group 0.000 claims description 106
• 238000006243 chemical reaction Methods 0.000 claims description 78
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 69
• NZNMSOFKMUBTKW-UHFFFAOYSA-N Cyclohexanecarboxylic acid Natural products OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 claims description 61
• 239000002253 acid Substances 0.000 claims description 60
• 125000003118 aryl group Chemical group 0.000 claims description 60
• 125000001072 heteroaryl group Chemical group 0.000 claims description 57
• 125000000623 heterocyclic group Chemical group 0.000 claims description 56
• 239000001257 hydrogen Substances 0.000 claims description 55
• 229910052739 hydrogen Inorganic materials 0.000 claims description 55
• VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 claims description 48
• 125000003342 alkenyl group Chemical group 0.000 claims description 44
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 43
• 229910052736 halogen Inorganic materials 0.000 claims description 43
• 125000000304 alkynyl group Chemical group 0.000 claims description 41
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 39
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 36
• WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 34
• 150000002367 halogens Chemical group 0.000 claims description 33
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 28
• 150000003839 salts Chemical class 0.000 claims description 28
• 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 27
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 26
• 125000004432 carbon atom Chemical group C* 0.000 claims description 22
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
• 239000012453 solvate Substances 0.000 claims description 18
• 125000002252 acyl group Chemical group 0.000 claims description 16
• 229920006395 saturated elastomer Polymers 0.000 claims description 16
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
• 125000005842 heteroatom Chemical group 0.000 claims description 14
• 230000005764 inhibitory process Effects 0.000 claims description 14
• DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 14
• 229910052760 oxygen Inorganic materials 0.000 claims description 13
• 125000006239 protecting group Chemical group 0.000 claims description 12
• 229910052717 sulfur Inorganic materials 0.000 claims description 12
• 201000010099 disease Diseases 0.000 claims description 11
• 230000003301 hydrolyzing effect Effects 0.000 claims description 11
• 208000027866 inflammatory disease Diseases 0.000 claims description 11
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
• 238000010438 heat treatment Methods 0.000 claims description 10
• 150000001204 N-oxides Chemical class 0.000 claims description 9
• 229910052799 carbon Inorganic materials 0.000 claims description 9
• 206010069698 Langerhans' cell histiocytosis Diseases 0.000 claims description 8
• PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 8
• 208000003401 eosinophilic granuloma Diseases 0.000 claims description 8
• 229940043355 kinase inhibitor Drugs 0.000 claims description 8
• 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 8
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 8
• QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 8
• 208000023275 Autoimmune disease Diseases 0.000 claims description 7
• 208000015114 central nervous system disease Diseases 0.000 claims description 7
• 239000003246 corticosteroid Substances 0.000 claims description 7
• 229960001334 corticosteroids Drugs 0.000 claims description 7
• 230000001629 suppression Effects 0.000 claims description 7
• 102000001301 EGF receptor Human genes 0.000 claims description 6
• 108060006698 EGF receptor Proteins 0.000 claims description 6
• 239000000556 agonist Substances 0.000 claims description 6
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 6
• TXWOGHSRPAYOML-UHFFFAOYSA-N cyclobutanecarboxylic acid Chemical compound OC(=O)C1CCC1 TXWOGHSRPAYOML-UHFFFAOYSA-N 0.000 claims description 6
• JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexyloxide Natural products O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 6
• 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 5
• ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 5
• RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 claims description 5
• 239000000043 antiallergic agent Substances 0.000 claims description 5
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
• 239000003085 diluting agent Substances 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 5
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 5
• AYDXLWXCBIPIKU-UHFFFAOYSA-N 6-azaspiro[3.4]oct-6-en-2-ol Chemical compound C1C(O)CC21CN=CC2 AYDXLWXCBIPIKU-UHFFFAOYSA-N 0.000 claims description 4
• 229940121948 Muscarinic receptor antagonist Drugs 0.000 claims description 4
• 239000001099 ammonium carbonate Substances 0.000 claims description 4
• 235000012501 ammonium carbonate Nutrition 0.000 claims description 4
• 239000005557 antagonist Substances 0.000 claims description 4
• 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 claims description 4
• 239000000812 cholinergic antagonist Substances 0.000 claims description 4
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
• 230000002401 inhibitory effect Effects 0.000 claims description 4
• 239000003199 leukotriene receptor blocking agent Substances 0.000 claims description 4
• 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 claims description 4
• 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 claims description 3
• 108010012236 Chemokines Proteins 0.000 claims description 3
• 102000019034 Chemokines Human genes 0.000 claims description 3
• 239000000867 Lipoxygenase Inhibitor Substances 0.000 claims description 3
• 230000003266 anti-allergic effect Effects 0.000 claims description 3
• KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims description 3
• HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 claims description 3
• 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 3
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
• DRZBCIAUXVHGHE-UHFFFAOYSA-N n-cyclopentyl-1-ethyl-5-(1-oxa-2-azaspiro[4.4]non-2-en-3-yl)pyrazolo[3,4-b]pyridin-4-amine Chemical compound N=1OC2(CCCC2)CC=1C1=CN=C2N(CC)N=CC2=C1NC1CCCC1 DRZBCIAUXVHGHE-UHFFFAOYSA-N 0.000 claims description 3
• ZCSBTWLRBOLTEV-UHFFFAOYSA-N n-cyclopropyl-1,3-dimethyl-5-(1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)pyrazolo[3,4-b]pyridin-4-amine Chemical compound C1CC1NC1=C2C(C)=NN(C)C2=NC=C1C(C1)=NOC21CCCCC2 ZCSBTWLRBOLTEV-UHFFFAOYSA-N 0.000 claims description 3
• VIPCTCKPMPYPIE-UHFFFAOYSA-N n-cyclopropyl-1,3-dimethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)pyrazolo[3,4-b]pyridin-4-amine Chemical compound C1CC1NC1=C2C(C)=NN(C)C2=NC=C1C(C1)=NOC21CCC2 VIPCTCKPMPYPIE-UHFFFAOYSA-N 0.000 claims description 3
• HTBLBHHGZZBQSS-UHFFFAOYSA-N n-cyclopropyl-1-ethyl-5-(1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)pyrazolo[3,4-b]pyridin-4-amine Chemical compound N=1OC2(CCCCC2)CC=1C1=CN=C2N(CC)N=CC2=C1NC1CC1 HTBLBHHGZZBQSS-UHFFFAOYSA-N 0.000 claims description 3
• DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 claims description 3
• WBIARPRQECTNGD-UHFFFAOYSA-N 2-azaspiro[4.5]dec-2-en-8-amine Chemical compound C1CC(N)CCC11CN=CC1 WBIARPRQECTNGD-UHFFFAOYSA-N 0.000 claims description 2
• ZGUWPCGNBLCWKV-UHFFFAOYSA-N 2-azaspiro[4.5]dec-2-en-8-ol Chemical compound C1CC(O)CCC11CN=CC1 ZGUWPCGNBLCWKV-UHFFFAOYSA-N 0.000 claims description 2
• RCQYCQISHIZAGY-UHFFFAOYSA-N 2-azaspiro[4.5]dec-2-ene-8-carbonitrile Chemical compound C1CC(C#N)CCC11CN=CC1 RCQYCQISHIZAGY-UHFFFAOYSA-N 0.000 claims description 2
• ZDZROFWSHJXQOA-UHFFFAOYSA-N 6-azaspiro[3.4]oct-6-ene-2-carbonitrile Chemical compound C1C(C#N)CC21CN=CC2 ZDZROFWSHJXQOA-UHFFFAOYSA-N 0.000 claims description 2
• RSGOKCNCUOQNKF-UHFFFAOYSA-N 6-azaspiro[3.4]oct-6-ene-2-carboxylic acid Chemical compound C1C(C(=O)O)CC21CN=CC2 RSGOKCNCUOQNKF-UHFFFAOYSA-N 0.000 claims description 2
• VEZUQRBDRNJBJY-UHFFFAOYSA-N cyclohexanone-oximeFRProcd Natural products ON=C1CCCCC1 VEZUQRBDRNJBJY-UHFFFAOYSA-N 0.000 claims description 2
• 229940079593 drug Drugs 0.000 claims description 2
• AWMHNKYDWKCDSU-UHFFFAOYSA-N n-cyclopentyl-1-ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)pyrazolo[3,4-b]pyridin-4-amine Chemical compound N=1OC2(CCC2)CC=1C1=CN=C2N(CC)N=CC2=C1NC1CCCC1 AWMHNKYDWKCDSU-UHFFFAOYSA-N 0.000 claims description 2
• CBFZWGRQXZYRRR-UHFFFAOYSA-N pyridin-4-amine;hydrochloride Chemical class Cl.NC1=CC=NC=C1 CBFZWGRQXZYRRR-UHFFFAOYSA-N 0.000 claims description 2
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 21
• 125000005843 halogen group Chemical group 0.000 claims 10
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• DZJPJBDPVMXSOM-UHFFFAOYSA-N 1-oxa-7-azaspiro[3.4]oct-6-ene-2-carbonitrile Chemical compound O1C(CC12CN=CC2)C#N DZJPJBDPVMXSOM-UHFFFAOYSA-N 0.000 claims 1
• PZFASKFTDVVUES-UHFFFAOYSA-N 1-oxa-7-azaspiro[3.4]oct-6-ene-2-carboxamide Chemical compound O1C(C(=O)N)CC11CN=CC1 PZFASKFTDVVUES-UHFFFAOYSA-N 0.000 claims 1
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• 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
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• 150000002170 ethers Chemical class 0.000 description 31
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 31
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