JP2008518999A - １１β−ＨＳＤ１阻害剤 - Google Patents

Info

Publication number

JP2008518999A

JP2008518999A JP2007539549A JP2007539549A JP2008518999A JP 2008518999 A JP2008518999 A JP 2008518999A JP 2007539549 A JP2007539549 A JP 2007539549A JP 2007539549 A JP2007539549 A JP 2007539549A JP 2008518999 A JP2008518999 A JP 2008518999A

Authority

JP

Japan

Prior art keywords

alkyl

cycloalkyl

phenyl

optionally substituted

heterocyclyl

Prior art date

2004-11-08

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Abandoned

Links

• Espacenet
• Global Dossier
• Discuss

• 229940126558 11β-HSD1 inhibitor Drugs 0.000 title claims description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 463
• -1 4′-fluorobiphen-4-yl Chemical group 0.000 claims abstract description 93
• 108010088011 11-beta-Hydroxysteroid Dehydrogenase Type 1 Proteins 0.000 claims abstract description 42
• 102000008645 11-beta-Hydroxysteroid Dehydrogenase Type 1 Human genes 0.000 claims abstract description 42
• 239000003112 inhibitor Substances 0.000 claims abstract description 15
• 239000003814 drug Substances 0.000 claims abstract description 8
• 238000004519 manufacturing process Methods 0.000 claims abstract description 7
• 125000000217 alkyl group Chemical group 0.000 claims description 176
• 125000000623 heterocyclic group Chemical group 0.000 claims description 111
• 239000000203 mixture Substances 0.000 claims description 102
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 99
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 93
• 229910052736 halogen Inorganic materials 0.000 claims description 77
• 150000002367 halogens Chemical class 0.000 claims description 77
• 229910052739 hydrogen Inorganic materials 0.000 claims description 57
• 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 44
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 44
• 229910052799 carbon Inorganic materials 0.000 claims description 36
• 150000003839 salts Chemical class 0.000 claims description 29
• 229910052757 nitrogen Inorganic materials 0.000 claims description 26
• 102000004877 Insulin Human genes 0.000 claims description 22
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• 206010022489 Insulin Resistance Diseases 0.000 claims description 22
• 229940125396 insulin Drugs 0.000 claims description 22
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 21
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
• 150000001412 amines Chemical class 0.000 claims description 16
• 201000010099 disease Diseases 0.000 claims description 16
• 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 14
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
• 125000001624 naphthyl group Chemical group 0.000 claims description 14
• 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 13
• 239000008103 glucose Substances 0.000 claims description 13
• 229920006395 saturated elastomer Polymers 0.000 claims description 13
• YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical group C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 12
• 125000004855 decalinyl group Chemical group C1(CCCC2CCCCC12)* 0.000 claims description 12
• 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 12
• 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 12
• 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 12
• 238000011282 treatment Methods 0.000 claims description 12
• 229910052717 sulfur Inorganic materials 0.000 claims description 11
• LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical group C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 claims description 10
• 208000004611 Abdominal Obesity Diseases 0.000 claims description 10
• 239000000556 agonist Substances 0.000 claims description 10
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 10
• 239000008194 pharmaceutical composition Substances 0.000 claims description 10
• 208000008589 Obesity Diseases 0.000 claims description 9
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 9
• 201000001421 hyperglycemia Diseases 0.000 claims description 9
• 235000020824 obesity Nutrition 0.000 claims description 9
• 201000001320 Atherosclerosis Diseases 0.000 claims description 8
• 208000032928 Dyslipidaemia Diseases 0.000 claims description 8
• 208000017170 Lipid metabolism disease Diseases 0.000 claims description 8
• 125000004429 atom Chemical group 0.000 claims description 8
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
• 229910052801 chlorine Inorganic materials 0.000 claims description 8
• 229910052731 fluorine Inorganic materials 0.000 claims description 8
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• 208000024827 Alzheimer disease Diseases 0.000 claims description 7
• 206010049287 Lipodystrophy acquired Diseases 0.000 claims description 7
• 108010015847 Non-Receptor Type 1 Protein Tyrosine Phosphatase Proteins 0.000 claims description 7
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
• 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 7
• 230000005764 inhibitory process Effects 0.000 claims description 7
• 208000006132 lipodystrophy Diseases 0.000 claims description 7
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
• 239000000651 prodrug Substances 0.000 claims description 7
• 229940002612 prodrug Drugs 0.000 claims description 7
• 239000011593 sulfur Substances 0.000 claims description 7
• UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 6
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
• 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 claims description 6
• 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 claims description 6
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 6
• 208000006575 hypertriglyceridemia Diseases 0.000 claims description 6
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
• 150000002632 lipids Chemical class 0.000 claims description 6
• 229910052760 oxygen Inorganic materials 0.000 claims description 6
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 5
• 206010065941 Central obesity Diseases 0.000 claims description 5
• 206010028980 Neoplasm Diseases 0.000 claims description 5
• 208000001132 Osteoporosis Diseases 0.000 claims description 5
• 208000017442 Retinal disease Diseases 0.000 claims description 5
• 206010038923 Retinopathy Diseases 0.000 claims description 5
• 229940100389 Sulfonylurea Drugs 0.000 claims description 5
• 201000011510 cancer Diseases 0.000 claims description 5
• 208000035475 disorder Diseases 0.000 claims description 5
• 206010015037 epilepsy Diseases 0.000 claims description 5
• 208000017169 kidney disease Diseases 0.000 claims description 5
• 239000002207 metabolite Substances 0.000 claims description 5
• 201000001119 neuropathy Diseases 0.000 claims description 5
• 230000007823 neuropathy Effects 0.000 claims description 5
• 208000033808 peripheral neuropathy Diseases 0.000 claims description 5
• 125000004076 pyridyl group Chemical group 0.000 claims description 5
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
• 229940123208 Biguanide Drugs 0.000 claims description 4
• 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 claims description 4
• 102100039994 Gastric inhibitory polypeptide Human genes 0.000 claims description 4
• 208000031226 Hyperlipidaemia Diseases 0.000 claims description 4
• PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 4
• 206010033645 Pancreatitis Diseases 0.000 claims description 4
• 102000002808 Pituitary adenylate cyclase-activating polypeptide Human genes 0.000 claims description 4
• 108010004684 Pituitary adenylate cyclase-activating polypeptide Proteins 0.000 claims description 4
• 150000004283 biguanides Chemical class 0.000 claims description 4
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
• GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
• 208000037765 diseases and disorders Diseases 0.000 claims description 4
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
• 230000004770 neurodegeneration Effects 0.000 claims description 4
• 208000015122 neurodegenerative disease Diseases 0.000 claims description 4
• 208000037803 restenosis Diseases 0.000 claims description 4
• 150000003852 triazoles Chemical class 0.000 claims description 4
• 230000002792 vascular Effects 0.000 claims description 4
• 229940077274 Alpha glucosidase inhibitor Drugs 0.000 claims description 3
• 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 claims description 3
• 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 3
• 208000035150 Hypercholesterolemia Diseases 0.000 claims description 3
• 229940122199 Insulin secretagogue Drugs 0.000 claims description 3
• 102000023984 PPAR alpha Human genes 0.000 claims description 3
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• WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 3
• 239000003888 alpha glucosidase inhibitor Substances 0.000 claims description 3
• 108091008725 peroxisome proliferator-activated receptors alpha Proteins 0.000 claims description 3
• POTIYWUALSJREP-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroquinoline Chemical compound N1CCCC2CCCCC21 POTIYWUALSJREP-UHFFFAOYSA-N 0.000 claims description 2
• FKNNFFNBSFNFSP-UHFFFAOYSA-N 2-hydroxy-5-[2,2,2-trichloro-1-[(4-chlorophenyl)sulfonylamino]ethyl]benzamide Chemical compound C1=C(O)C(C(=O)N)=CC(C(NS(=O)(=O)C=2C=CC(Cl)=CC=2)C(Cl)(Cl)Cl)=C1 FKNNFFNBSFNFSP-UHFFFAOYSA-N 0.000 claims description 2
• MVQVNTPHUGQQHK-UHFFFAOYSA-N 3-pyridinemethanol Chemical compound OCC1=CC=CN=C1 MVQVNTPHUGQQHK-UHFFFAOYSA-N 0.000 claims description 2
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