TW201002705A - Oxymethylene aryl compounds and uses thereof - Google Patents

Info

Publication number

TW201002705A

TW201002705A TW098110577A TW98110577A TW201002705A TW 201002705 A TW201002705 A TW 201002705A TW 098110577 A TW098110577 A TW 098110577A TW 98110577 A TW98110577 A TW 98110577A TW 201002705 A TW201002705 A TW 201002705A

Authority

TW

Taiwan

Prior art keywords

group

alkyl

substituted

aryl

compound

Prior art date

2008-03-31

Links

• Espacenet
• Global Dossier
• Discuss

• 239000003112 inhibitor Substances 0.000 claims abstract description 114
• 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 claims abstract description 74
• 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 claims abstract description 63
• 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 56
• 238000011282 treatment Methods 0.000 claims abstract description 47
• 150000001875 compounds Chemical class 0.000 claims description 241
• 125000000217 alkyl group Chemical group 0.000 claims description 180
• 125000000623 heterocyclic group Chemical group 0.000 claims description 171
• 125000001072 heteroaryl group Chemical group 0.000 claims description 169
• 125000003118 aryl group Chemical group 0.000 claims description 156
• -1 compound compound Chemical class 0.000 claims description 147
• 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 132
• 210000004369 blood Anatomy 0.000 claims description 118
• 239000008280 blood Substances 0.000 claims description 118
• 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 115
• 239000008103 glucose Substances 0.000 claims description 115
• 239000000203 mixture Substances 0.000 claims description 101
• 238000000034 method Methods 0.000 claims description 87
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 83
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 80
• 229910052739 hydrogen Inorganic materials 0.000 claims description 75
• 239000001257 hydrogen Substances 0.000 claims description 71
• 102000004877 Insulin Human genes 0.000 claims description 67
• 108090001061 Insulin Proteins 0.000 claims description 67
• 125000001424 substituent group Chemical group 0.000 claims description 67
• 229940125396 insulin Drugs 0.000 claims description 66
• 125000000304 alkynyl group Chemical group 0.000 claims description 61
• 125000003342 alkenyl group Chemical group 0.000 claims description 56
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 56
• 230000001965 increasing effect Effects 0.000 claims description 46
• 229910003827 NRaRb Inorganic materials 0.000 claims description 45
• 125000005843 halogen group Chemical group 0.000 claims description 43
• 239000003814 drug Substances 0.000 claims description 39
• 150000002431 hydrogen Chemical class 0.000 claims description 38
• 238000004519 manufacturing process Methods 0.000 claims description 35
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 34
• 229910052736 halogen Inorganic materials 0.000 claims description 34
• 150000002367 halogens Chemical class 0.000 claims description 34
• 150000003839 salts Chemical class 0.000 claims description 33
• 229910052705 radium Inorganic materials 0.000 claims description 32
• 229940079593 drug Drugs 0.000 claims description 30
• 239000000859 incretin Substances 0.000 claims description 30
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 29
• 230000001419 dependent effect Effects 0.000 claims description 29
• MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)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=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 claims description 29
• 229910052757 nitrogen Inorganic materials 0.000 claims description 27
• 125000004076 pyridyl group Chemical group 0.000 claims description 21
• 235000000346 sugar Nutrition 0.000 claims description 20
• 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 claims description 19
• 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 19
• 206010036790 Productive cough Diseases 0.000 claims description 19
• 210000003802 sputum Anatomy 0.000 claims description 19
• 208000024794 sputum Diseases 0.000 claims description 19
• 125000001931 aliphatic group Chemical group 0.000 claims description 18
• 239000003795 chemical substances by application Substances 0.000 claims description 18
• 125000001188 haloalkyl group Chemical group 0.000 claims description 18
• 125000000468 ketone group Chemical group 0.000 claims description 18
• 239000007788 liquid Substances 0.000 claims description 18
• 239000000052 vinegar Substances 0.000 claims description 17
• 235000021419 vinegar Nutrition 0.000 claims description 17
• 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 16
• UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 16
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 14
• 229960004034 sitagliptin Drugs 0.000 claims description 14
• MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 claims description 14
• 150000001345 alkine derivatives Chemical class 0.000 claims description 12
• 150000002148 esters Chemical class 0.000 claims description 12
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 11
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 11
• 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 10
• 229930194542 Keto Natural products 0.000 claims description 10
• 210000000936 intestine Anatomy 0.000 claims description 9
• QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 claims description 9
• 229960004937 saxagliptin Drugs 0.000 claims description 9
• 108010033693 saxagliptin Proteins 0.000 claims description 9
• SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 claims description 9
• 229960001254 vildagliptin Drugs 0.000 claims description 9
• 239000004215 Carbon black (E152) Substances 0.000 claims description 8
• ZSBOMTDTBDDKMP-OAHLLOKOSA-N alogliptin Chemical compound C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 ZSBOMTDTBDDKMP-OAHLLOKOSA-N 0.000 claims description 8
• 229930195733 hydrocarbon Natural products 0.000 claims description 8
• 125000003396 thiol group Chemical group [H]S* 0.000 claims description 8
• URRAHSMDPCMOTH-LNLFQRSKSA-N Denagliptin Chemical compound C=1C=C(F)C=CC=1C([C@H](N)C(=O)N1[C@@H](C[C@H](F)C1)C#N)C1=CC=C(F)C=C1 URRAHSMDPCMOTH-LNLFQRSKSA-N 0.000 claims description 7
• 150000001336 alkenes Chemical class 0.000 claims description 7
• 229960001667 alogliptin Drugs 0.000 claims description 7
• 229910052799 carbon Inorganic materials 0.000 claims description 7
• 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
• 229950010300 denagliptin Drugs 0.000 claims description 7
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
• 230000005764 inhibitory process Effects 0.000 claims description 5
• 229910052747 lanthanoid Inorganic materials 0.000 claims description 5
• 150000002602 lanthanoids Chemical class 0.000 claims description 5
• 150000002632 lipids Chemical class 0.000 claims description 5
• 125000005187 nonenyl group Chemical group C(=CCCCCCCC)* 0.000 claims description 5
• JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims description 5
• 239000002689 soil Substances 0.000 claims description 5
• 241000894007 species Species 0.000 claims description 5
• 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
• 235000011187 glycerol Nutrition 0.000 claims description 4
• 150000002430 hydrocarbons Chemical class 0.000 claims description 4
• 150000003626 triacylglycerols Chemical class 0.000 claims description 4
• 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
• 239000012530 fluid Substances 0.000 claims description 3
• 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 2
• 238000001647 drug administration Methods 0.000 claims description 2
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
• NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims description 2
• 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims 2
• 101000684208 Homo sapiens Prolyl endopeptidase FAP Proteins 0.000 claims 2
• 125000005070 decynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 claims 2
• 102200006760 rs730882194 Human genes 0.000 claims 2
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
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• 235000011399 aloe vera Nutrition 0.000 claims 1
• 125000003493 decenyl group Chemical group [H]C([*])=C([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
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• 125000001475 halogen functional group Chemical group 0.000 claims 1
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• 238000005481 NMR spectroscopy Methods 0.000 description 181
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