TW200922578A - Bicyclic heterocycle derivatives and methods of use thereof - Google Patents

Info

Publication number

TW200922578A

TW200922578A TW097140281A TW97140281A TW200922578A TW 200922578 A TW200922578 A TW 200922578A TW 097140281 A TW097140281 A TW 097140281A TW 97140281 A TW97140281 A TW 97140281A TW 200922578 A TW200922578 A TW 200922578A

Authority

TW

Taiwan

Prior art keywords

group

compound

alkyl

aryl

cycloalkyl

Prior art date

2007-10-22

Links

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• 238000000034 method Methods 0.000 title claims abstract description 272
• 125000002618 bicyclic heterocycle group Chemical group 0.000 title abstract description 38
• 239000000203 mixture Substances 0.000 claims abstract description 89
• 208000008589 Obesity Diseases 0.000 claims abstract description 10
• 235000020824 obesity Nutrition 0.000 claims abstract description 10
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
• 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 7
• 150000001875 compounds Chemical class 0.000 claims description 1193
• 125000000217 alkyl group Chemical group 0.000 claims description 375
• 125000003118 aryl group Chemical group 0.000 claims description 168
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 161
• OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine group Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 160
• -1 dentyl Chemical group 0.000 claims description 125
• 125000001072 heteroaryl group Chemical group 0.000 claims description 120
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 116
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 90
• 125000001424 substituent group Chemical group 0.000 claims description 81
• 125000005843 halogen group Chemical group 0.000 claims description 79
• 150000003839 salts Chemical class 0.000 claims description 70
• 239000012453 solvate Substances 0.000 claims description 63
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 59
• 229940002612 prodrug Drugs 0.000 claims description 54
• 239000000651 prodrug Substances 0.000 claims description 54
• 125000004076 pyridyl group Chemical group 0.000 claims description 46
• 150000002148 esters Chemical class 0.000 claims description 44
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 42
• 125000004432 carbon atom Chemical group C* 0.000 claims description 40
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 36
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 35
• 125000003342 alkenyl group Chemical group 0.000 claims description 30
• 125000000623 heterocyclic group Chemical group 0.000 claims description 28
• 125000002947 alkylene group Chemical group 0.000 claims description 27
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 26
• 125000000304 alkynyl group Chemical group 0.000 claims description 25
• 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 25
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 22
• 229910052757 nitrogen Inorganic materials 0.000 claims description 22
• 125000001188 haloalkyl group Chemical group 0.000 claims description 20
• 229910052799 carbon Inorganic materials 0.000 claims description 19
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 19
• 229910052739 hydrogen Inorganic materials 0.000 claims description 17
• 239000003814 drug Substances 0.000 claims description 16
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 14
• 150000002923 oximes Chemical class 0.000 claims description 14
• 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 13
• 239000000126 substance Substances 0.000 claims description 12
• 239000002689 soil Substances 0.000 claims description 11
• 125000004429 atom Chemical group 0.000 claims description 10
• 229940079593 drug Drugs 0.000 claims description 10
• 150000002576 ketones Chemical class 0.000 claims description 10
• 229910052698 phosphorus Inorganic materials 0.000 claims description 10
• 238000011282 treatment Methods 0.000 claims description 10
• 150000001335 aliphatic alkanes Chemical class 0.000 claims description 8
• 229910052736 halogen Inorganic materials 0.000 claims description 8
• 229910052707 ruthenium Inorganic materials 0.000 claims description 8
• KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical group [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 7
• MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Natural products C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 7
• 125000002619 bicyclic group Chemical group 0.000 claims description 7
• 150000002367 halogens Chemical class 0.000 claims description 7
• 125000003003 spiro group Chemical group 0.000 claims description 7
• 239000000052 vinegar Substances 0.000 claims description 7
• 235000021419 vinegar Nutrition 0.000 claims description 7
• 125000006164 6-membered heteroaryl group Chemical group 0.000 claims description 6
• DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 claims description 6
• 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
• 108090000623 proteins and genes Proteins 0.000 claims description 6
• 229940124597 therapeutic agent Drugs 0.000 claims description 6
• 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 5
• 125000001118 alkylidene group Chemical group 0.000 claims description 5
• 239000003795 chemical substances by application Substances 0.000 claims description 5
• 239000008103 glucose Substances 0.000 claims description 5
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• 201000010099 disease Diseases 0.000 claims description 4
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
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• 208000024891 symptom Diseases 0.000 claims description 4
• 208000001145 Metabolic Syndrome Diseases 0.000 claims description 3
• 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 3
• 238000010521 absorption reaction Methods 0.000 claims description 3
• 125000006612 decyloxy group Chemical group 0.000 claims description 3
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
• OOKAZRDERJMRCJ-KOUAFAAESA-N (3r)-7-[(1s,2s,4ar,6s,8s)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-3-hydroxy-5-oxoheptanoic acid Chemical compound C1=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(O)=O)C2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C[C@@H]21 OOKAZRDERJMRCJ-KOUAFAAESA-N 0.000 claims description 2
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 2
• 239000000556 agonist Substances 0.000 claims description 2
• 125000005275 alkylenearyl group Chemical group 0.000 claims description 2
• 229910052797 bismuth Inorganic materials 0.000 claims description 2
• JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 claims description 2
• 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 description 2
• 239000002243 precursor Substances 0.000 claims description 2
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• 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 claims 5
• 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 5
• 102400000322 Glucagon-like peptide 1 Human genes 0.000 claims 5
• 239000003112 inhibitor Substances 0.000 claims 5
• 229940122199 Insulin secretagogue Drugs 0.000 claims 3
• 229940122355 Insulin sensitizer Drugs 0.000 claims 3
• 239000012190 activator Substances 0.000 claims 3
• 239000000883 anti-obesity agent Substances 0.000 claims 3
• 229940125710 antiobesity agent Drugs 0.000 claims 3
• 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 claims 2
• 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 claims 2
• 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 claims 2
• 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 claims 2
• 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 claims 2
• 229960001667 alogliptin Drugs 0.000 claims 2
• 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 2
• 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 2
• MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 claims 1
• 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 1
• SUDBRAWXUGTELR-HPFNVAMJSA-N 5-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]-1h-pyrimidine-2,4-dione Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OCC1=CNC(=O)NC1=O SUDBRAWXUGTELR-HPFNVAMJSA-N 0.000 claims 1
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims 1
• 102000002281 Adenylate kinase Human genes 0.000 claims 1
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• 235000016425 Arthrospira platensis Nutrition 0.000 claims 1
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• JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical group C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 claims 1
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