EA020773B1 - Производные тиенопиридона в качестве активаторов амр-активированной протеинкиназы (амрк) - Google Patents

Info

Publication number

EA020773B1

EA020773B1 EA201001733A EA201001733A EA020773B1 EA 020773 B1 EA020773 B1 EA 020773B1 EA 201001733 A EA201001733 A EA 201001733A EA 201001733 A EA201001733 A EA 201001733A EA 020773 B1 EA020773 B1 EA 020773B1

Authority

EA

Eurasian Patent Office

Prior art keywords

pyridin

hydroxy

phenyl

dihydrothieno

hydroxybiphenyl

Prior art date

2008-05-05

Links

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• 239000012190 activator Substances 0.000 title description 12
• 102000014156 AMP-Activated Protein Kinases Human genes 0.000 title 1
• 108010011376 AMP-Activated Protein Kinases Proteins 0.000 title 1
• 101100321932 Rattus norvegicus Prkaa2 gene Proteins 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 120
• 238000011282 treatment Methods 0.000 claims abstract description 19
• 238000002360 preparation method Methods 0.000 claims abstract description 10
• -1 1,3-benzodioxan-5-yl Chemical group 0.000 claims description 248
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 74
• 150000003839 salts Chemical class 0.000 claims description 57
• 239000000203 mixture Substances 0.000 claims description 39
• 239000003814 drug Substances 0.000 claims description 33
• UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 32
• 229940079593 drug Drugs 0.000 claims description 27
• 230000004190 glucose uptake Effects 0.000 claims description 22
• 239000002253 acid Substances 0.000 claims description 18
• 239000012453 solvate Substances 0.000 claims description 17
• 239000000126 substance Substances 0.000 claims description 12
• 206010028980 Neoplasm Diseases 0.000 claims description 11
• 201000011510 cancer Diseases 0.000 claims description 10
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 9
• 208000001145 Metabolic Syndrome Diseases 0.000 claims description 8
• 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 8
• 206010012601 diabetes mellitus Diseases 0.000 claims description 8
• 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims description 7
• 208000008589 Obesity Diseases 0.000 claims description 7
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
• 235000020824 obesity Nutrition 0.000 claims description 7
• 238000004519 manufacturing process Methods 0.000 claims description 6
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
• YHTGTTPAZVKQBC-UHFFFAOYSA-N 4-hydroxy-5-phenyl-3-(4-phenylphenyl)-7h-thieno[2,3-b]pyridin-6-one Chemical compound O=C1NC=2SC=C(C=3C=CC(=CC=3)C=3C=CC=CC=3)C=2C(O)=C1C1=CC=CC=C1 YHTGTTPAZVKQBC-UHFFFAOYSA-N 0.000 claims description 5
• 125000002541 furyl group Chemical group 0.000 claims description 5
• 125000001989 1,3-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([H])C([*:2])=C1[H] 0.000 claims description 4
• 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
• XBRXAVIHKNUPSS-UHFFFAOYSA-N 4-[4-(4-hydroxy-6-oxo-5-phenyl-7h-thieno[2,3-b]pyridin-3-yl)phenyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=C(C=2C=3C(O)=C(C=4C=CC=CC=4)C(=O)NC=3SC=2)C=C1 XBRXAVIHKNUPSS-UHFFFAOYSA-N 0.000 claims description 4
• NNJMFJSKMRYHSR-UHFFFAOYSA-N 4-phenylbenzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=CC=C1 NNJMFJSKMRYHSR-UHFFFAOYSA-N 0.000 claims description 4
• 206010061218 Inflammation Diseases 0.000 claims description 4
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
• 230000004054 inflammatory process Effects 0.000 claims description 4
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
• 210000000663 muscle cell Anatomy 0.000 claims description 4
• 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 3
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
• 238000006069 Suzuki reaction reaction Methods 0.000 claims description 3
• 150000001642 boronic acid derivatives Chemical class 0.000 claims description 3
• 125000005843 halogen group Chemical group 0.000 claims description 3
• HTLCUUIJMHNWKW-UHFFFAOYSA-N 2-[4-(4-hydroxy-6-oxo-5-phenyl-7h-thieno[2,3-b]pyridin-3-yl)phenyl]benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C1=CC=C(C=2C=3C(O)=C(C=4C=CC=CC=4)C(=O)NC=3SC=2)C=C1 HTLCUUIJMHNWKW-UHFFFAOYSA-N 0.000 claims description 2
• HPTTXYJXYLWZMP-UHFFFAOYSA-N 2-chloro-4-hydroxy-3-[4-(2-methoxyphenyl)phenyl]-5-phenyl-7h-thieno[2,3-b]pyridin-6-one Chemical compound COC1=CC=CC=C1C1=CC=C(C=2C=3C(O)=C(C=4C=CC=CC=4)C(=O)NC=3SC=2Cl)C=C1 HPTTXYJXYLWZMP-UHFFFAOYSA-N 0.000 claims description 2
• OLEPAMDDNFQSNH-UHFFFAOYSA-N 4-[4-(4-hydroxy-6-oxo-5-phenyl-7h-thieno[2,3-b]pyridin-3-yl)-3-methoxyphenyl]benzoic acid Chemical compound COC1=CC(C=2C=CC(=CC=2)C(O)=O)=CC=C1C(C=1C=2O)=CSC=1NC(=O)C=2C1=CC=CC=C1 OLEPAMDDNFQSNH-UHFFFAOYSA-N 0.000 claims description 2
• KQFDGZOTTHQOMD-UHFFFAOYSA-N 4-hydroxy-3-[4-(2-hydroxyphenyl)phenyl]-5-pyridin-3-yl-7h-thieno[2,3-b]pyridin-6-one Chemical compound OC1=CC=CC=C1C1=CC=C(C=2C=3C(O)=C(C=4C=NC=CC=4)C(=O)NC=3SC=2)C=C1 KQFDGZOTTHQOMD-UHFFFAOYSA-N 0.000 claims description 2
• UJLDWASVYPAWCU-UHFFFAOYSA-N 4-hydroxy-3-[4-[3-(hydroxymethyl)phenyl]-3-methoxyphenyl]-5-phenyl-7h-thieno[2,3-b]pyridin-6-one Chemical compound COC1=CC(C=2C=3C(O)=C(C(=O)NC=3SC=2)C=2C=CC=CC=2)=CC=C1C1=CC=CC(CO)=C1 UJLDWASVYPAWCU-UHFFFAOYSA-N 0.000 claims description 2
• JCRPTFPMOYQHRY-UHFFFAOYSA-N 4-hydroxy-3-[4-[3-(hydroxymethyl)phenyl]phenyl]-5-pyridin-3-yl-7h-thieno[2,3-b]pyridin-6-one Chemical compound OCC1=CC=CC(C=2C=CC(=CC=2)C=2C=3C(O)=C(C=4C=NC=CC=4)C(=O)NC=3SC=2)=C1 JCRPTFPMOYQHRY-UHFFFAOYSA-N 0.000 claims description 2
• RFDKYLBVQFNJEF-UHFFFAOYSA-N 4-hydroxy-3-[6-(2-hydroxyphenyl)pyridin-3-yl]-5-phenyl-7H-thieno[2,3-b]pyridin-6-one Chemical compound Oc1ccccc1-c1ccc(cn1)-c1csc2[nH]c(=O)c(-c3ccccc3)c(O)c12 RFDKYLBVQFNJEF-UHFFFAOYSA-N 0.000 claims description 2
• ARAPWNFBCAHDTI-UHFFFAOYSA-N 4-hydroxy-5-phenyl-3-(3-phenylphenyl)-7h-thieno[2,3-b]pyridin-6-one Chemical compound O=C1NC=2SC=C(C=3C=C(C=CC=3)C=3C=CC=CC=3)C=2C(O)=C1C1=CC=CC=C1 ARAPWNFBCAHDTI-UHFFFAOYSA-N 0.000 claims description 2
• JANQQPWTLXUSCD-UHFFFAOYSA-N 9-(5,5-difluoro-5-phosphonopentyl)guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2CCCCC(F)(F)P(O)(O)=O JANQQPWTLXUSCD-UHFFFAOYSA-N 0.000 claims description 2
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
• HKWQMQBRXWPSSR-UHFFFAOYSA-N 2-chloro-4-hydroxy-3-[4-(2-hydroxyphenyl)phenyl]-5-phenyl-7h-thieno[2,3-b]pyridin-6-one Chemical compound OC1=CC=CC=C1C1=CC=C(C=2C=3C(O)=C(C=4C=CC=CC=4)C(=O)NC=3SC=2Cl)C=C1 HKWQMQBRXWPSSR-UHFFFAOYSA-N 0.000 claims 2
• IXUWSTYUHBAYBN-UHFFFAOYSA-N 4-hydroxy-5-phenyl-3-[4-[3-(trifluoromethyl)phenyl]phenyl]-7h-thieno[2,3-b]pyridin-6-one Chemical compound O=C1NC=2SC=C(C=3C=CC(=CC=3)C=3C=C(C=CC=3)C(F)(F)F)C=2C(O)=C1C1=CC=CC=C1 IXUWSTYUHBAYBN-UHFFFAOYSA-N 0.000 claims 2
• 125000000896 monocarboxylic acid group Chemical group 0.000 claims 2
• APOWVDDKGUFNPB-UHFFFAOYSA-N 3-[4-(4-fluoro-2-methoxyphenyl)phenyl]-4-hydroxy-5-phenyl-7h-thieno[2,3-b]pyridin-6-one Chemical compound COC1=CC(F)=CC=C1C1=CC=C(C=2C=3C(O)=C(C(=O)NC=3SC=2)C=2C=CC=CC=2)C=C1 APOWVDDKGUFNPB-UHFFFAOYSA-N 0.000 claims 1
• YLVCSWFJCLXOGO-UHFFFAOYSA-N 3-[4-(4-fluorophenyl)-3-methoxyphenyl]-4-hydroxy-5-phenyl-7h-thieno[2,3-b]pyridin-6-one Chemical compound COC1=CC(C=2C=3C(O)=C(C(=O)NC=3SC=2)C=2C=CC=CC=2)=CC=C1C1=CC=C(F)C=C1 YLVCSWFJCLXOGO-UHFFFAOYSA-N 0.000 claims 1
• FDLAYOULWSBJHH-UHFFFAOYSA-N 3-[4-(4-hydroxy-6-oxo-5-phenyl-7h-thieno[2,3-b]pyridin-3-yl)phenyl]benzoic acid Chemical compound OC(=O)C1=CC=CC(C=2C=CC(=CC=2)C=2C=3C(O)=C(C=4C=CC=CC=4)C(=O)NC=3SC=2)=C1 FDLAYOULWSBJHH-UHFFFAOYSA-N 0.000 claims 1
• LQMSUXUHIPMIIL-UHFFFAOYSA-N 4-hydroxy-3-[3-hydroxy-4-(4-methylphenyl)phenyl]-5-phenyl-7h-thieno[2,3-b]pyridin-6-one Chemical compound C1=CC(C)=CC=C1C1=CC=C(C=2C=3C(O)=C(C=4C=CC=CC=4)C(=O)NC=3SC=2)C=C1O LQMSUXUHIPMIIL-UHFFFAOYSA-N 0.000 claims 1
• FYCALVCMMOVGQW-UHFFFAOYSA-N 4-hydroxy-3-[3-methoxy-4-(2-methylphenyl)phenyl]-5-phenyl-7h-thieno[2,3-b]pyridin-6-one Chemical compound COC1=CC(C=2C=3C(O)=C(C=4C=CC=CC=4)C(=O)NC=3SC=2)=CC=C1C1=CC=CC=C1C FYCALVCMMOVGQW-UHFFFAOYSA-N 0.000 claims 1
• GXRDHQVJWKNVBT-UHFFFAOYSA-N 4-hydroxy-3-[3-methoxy-4-(4-methylphenyl)phenyl]-5-phenyl-7h-thieno[2,3-b]pyridin-6-one Chemical compound COC1=CC(C=2C=3C(O)=C(C=4C=CC=CC=4)C(=O)NC=3SC=2)=CC=C1C1=CC=C(C)C=C1 GXRDHQVJWKNVBT-UHFFFAOYSA-N 0.000 claims 1
• ZDMGVZOJYKQXRY-UHFFFAOYSA-N 4-hydroxy-3-[4-(2-hydroxyphenyl)-3-methoxyphenyl]-5-phenyl-7h-thieno[2,3-b]pyridin-6-one Chemical compound COC1=CC(C=2C=3C(O)=C(C=4C=CC=CC=4)C(=O)NC=3SC=2)=CC=C1C1=CC=CC=C1O ZDMGVZOJYKQXRY-UHFFFAOYSA-N 0.000 claims 1
• ZCZUMSNNMVMMAS-UHFFFAOYSA-N 4-hydroxy-3-[4-(2-hydroxyphenyl)phenyl]-5-pyridin-4-yl-7H-thieno[2,3-b]pyridin-6-one Chemical compound OC1=CC=CC=C1C1=CC=C(C=2C=3C(O)=C(C=4C=CN=CC=4)C(=O)NC=3SC=2)C=C1 ZCZUMSNNMVMMAS-UHFFFAOYSA-N 0.000 claims 1
• BDOHZQBXOOSVHB-UHFFFAOYSA-N 4-hydroxy-3-[4-(4-hydroxyphenyl)phenyl]-5-pyridin-4-yl-7H-thieno[2,3-b]pyridin-6-one Chemical compound C1=CC(O)=CC=C1C1=CC=C(C=2C=3C(O)=C(C=4C=CN=CC=4)C(=O)NC=3SC=2)C=C1 BDOHZQBXOOSVHB-UHFFFAOYSA-N 0.000 claims 1
• WZMCUNQPVYPJAZ-UHFFFAOYSA-N 4-hydroxy-3-[4-(4-methylsulfonylphenyl)phenyl]-5-phenyl-7h-thieno[2,3-b]pyridin-6-one Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=CC=C(C=2C=3C(O)=C(C=4C=CC=CC=4)C(=O)NC=3SC=2)C=C1 WZMCUNQPVYPJAZ-UHFFFAOYSA-N 0.000 claims 1
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• MGJOTBAPEZWQAT-UHFFFAOYSA-N 4-hydroxy-3-[6-(2-methoxyphenyl)pyridin-3-yl]-5-phenyl-7h-thieno[2,3-b]pyridin-6-one Chemical compound COC1=CC=CC=C1C1=CC=C(C=2C=3C(O)=C(C=4C=CC=CC=4)C(=O)NC=3SC=2)C=N1 MGJOTBAPEZWQAT-UHFFFAOYSA-N 0.000 claims 1
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