HRP20040309A2 - 1,6-nafthyridine derivatives as antidiabetics - Google Patents

Info

Publication number

HRP20040309A2

HRP20040309A2 HR20040309A HRP20040309A HRP20040309A2 HR P20040309 A2 HRP20040309 A2 HR P20040309A2 HR 20040309 A HR20040309 A HR 20040309A HR P20040309 A HRP20040309 A HR P20040309A HR P20040309 A2 HRP20040309 A2 HR P20040309A2

Authority

HR

Croatia

Prior art keywords

carbon atoms

group

heterocycloalkyl

substituted

groups

Prior art date

2001-09-26

Links

• Espacenet
• Global Dossier
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• 230000003178 anti-diabetic effect Effects 0.000 title 1
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 477
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 94
• 239000001257 hydrogen Substances 0.000 claims abstract description 93
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 93
• 238000000034 method Methods 0.000 claims abstract description 55
• 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 53
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 20
• 125000004432 carbon atom Chemical group C* 0.000 claims description 1349
• 125000005842 heteroatom Chemical group 0.000 claims description 478
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 447
• 229910052717 sulfur Inorganic materials 0.000 claims description 408
• 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 243
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 184
• 125000000217 alkyl group Chemical group 0.000 claims description 175
• 125000001188 haloalkyl group Chemical group 0.000 claims description 135
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 129
• 229910052760 oxygen Inorganic materials 0.000 claims description 119
• 229910052799 carbon Inorganic materials 0.000 claims description 117
• 150000001875 compounds Chemical class 0.000 claims description 111
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 97
• 125000003342 alkenyl group Chemical group 0.000 claims description 90
• 125000000304 alkynyl group Chemical group 0.000 claims description 89
• -1 alkoxy carbon Chemical compound 0.000 claims description 56
• 125000001072 heteroaryl group Chemical group 0.000 claims description 56
• 125000003118 aryl group Chemical group 0.000 claims description 51
• 150000001721 carbon Chemical group 0.000 claims description 46
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 38
• 229910052736 halogen Inorganic materials 0.000 claims description 38
• 150000002367 halogens Chemical group 0.000 claims description 37
• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 36
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 34
• 239000003814 drug Substances 0.000 claims description 29
• 229940079593 drug Drugs 0.000 claims description 28
• 125000003545 alkoxy group Chemical group 0.000 claims description 26
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 21
• WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 19
• 239000008103 glucose Substances 0.000 claims description 19
• 150000002825 nitriles Chemical group 0.000 claims description 19
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• PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 18
• 125000004429 atom Chemical group 0.000 claims description 18
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• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 17
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 16
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 16
• 150000003839 salts Chemical class 0.000 claims description 15
• DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 claims description 14
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
• 229920006395 saturated elastomer Polymers 0.000 claims description 14
• 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 claims description 13
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• RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 claims description 8
• 229960001761 chlorpropamide Drugs 0.000 claims description 8
• ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 8
• 229960004580 glibenclamide Drugs 0.000 claims description 8
• 229960004346 glimepiride Drugs 0.000 claims description 8
• WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 claims description 8
• ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 claims description 8
• 229960001381 glipizide Drugs 0.000 claims description 8
• ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 claims description 8
• 239000003112 inhibitor Substances 0.000 claims description 8
• 239000000825 pharmaceutical preparation Substances 0.000 claims description 8
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 7
• 229940077274 Alpha glucosidase inhibitor Drugs 0.000 claims description 7
• 101100240522 Caenorhabditis elegans nhr-18 gene Proteins 0.000 claims description 7
• 208000002705 Glucose Intolerance Diseases 0.000 claims description 7
• 229940122355 Insulin sensitizer Drugs 0.000 claims description 7
• 239000003888 alpha glucosidase inhibitor Substances 0.000 claims description 7
• 201000009104 prediabetes syndrome Diseases 0.000 claims description 7
• 210000002237 B-cell of pancreatic islet Anatomy 0.000 claims description 6
• YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 claims description 6
• 102100037505 Secretin Human genes 0.000 claims description 6
• 108010086019 Secretin Proteins 0.000 claims description 6
• 125000002252 acyl group Chemical group 0.000 claims description 6
• 201000010099 disease Diseases 0.000 claims description 6
• 230000002440 hepatic effect Effects 0.000 claims description 6
• 208000001921 latent autoimmune diabetes in adults Diseases 0.000 claims description 6
• XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical group CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims description 6
• HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 claims description 6
• 229960002101 secretin Drugs 0.000 claims description 6
• OWMZNFCDEHGFEP-NFBCVYDUSA-N secretin human Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(N)=O)[C@@H](C)O)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)C1=CC=CC=C1 OWMZNFCDEHGFEP-NFBCVYDUSA-N 0.000 claims description 6
• SWLAMJPTOQZTAE-UHFFFAOYSA-N 4-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]benzoic acid Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(C(O)=O)C=C1 SWLAMJPTOQZTAE-UHFFFAOYSA-N 0.000 claims description 5
• FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 claims description 5
• 229940126033 PPAR agonist Drugs 0.000 claims description 5
• 230000003579 anti-obesity Effects 0.000 claims description 5
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 5
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• OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 claims description 5
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• 239000002307 peroxisome proliferator activated receptor agonist Substances 0.000 claims description 5
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• ILPUOPPYSQEBNJ-UHFFFAOYSA-N 2-methyl-2-phenoxypropanoic acid Chemical class OC(=O)C(C)(C)OC1=CC=CC=C1 ILPUOPPYSQEBNJ-UHFFFAOYSA-N 0.000 claims description 4
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• YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 claims description 4
• XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical group O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 claims description 3
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