KR20100075643A - 비사이클릭 헤테로사이클 유도체 및 ｇｐｒ119의 활성의 조절인자로서의 이의 용도 - Google Patents

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Publication number

KR20100075643A

KR20100075643A KR1020107010766A KR20107010766A KR20100075643A KR 20100075643 A KR20100075643 A KR 20100075643A KR 1020107010766 A KR1020107010766 A KR 1020107010766A KR 20107010766 A KR20107010766 A KR 20107010766A KR 20100075643 A KR20100075643 A KR 20100075643A

Authority

KR

South Korea

Prior art keywords

alkyl

alkylene

aryl

cycloalkyl

group

Prior art date

2007-10-22

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.)

Withdrawn

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• 125000002618 bicyclic heterocycle group Chemical group 0.000 title abstract description 38
• 230000000694 effects Effects 0.000 title abstract description 4
• 239000000203 mixture Substances 0.000 claims abstract description 91
• 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 14
• 208000008589 Obesity Diseases 0.000 claims abstract description 12
• 235000020824 obesity Nutrition 0.000 claims abstract description 12
• 150000001875 compounds Chemical class 0.000 claims description 1239
• 125000000217 alkyl group Chemical group 0.000 claims description 374
• 238000000034 method Methods 0.000 claims description 367
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 210
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 187
• 125000005843 halogen group Chemical group 0.000 claims description 137
• 125000003118 aryl group Chemical group 0.000 claims description 132
• -1 -alkylene-aryl Chemical group 0.000 claims description 106
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 104
• 125000001072 heteroaryl group Chemical group 0.000 claims description 89
• 150000003839 salts Chemical class 0.000 claims description 84
• 125000004076 pyridyl group Chemical group 0.000 claims description 81
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 81
• 239000012453 solvate Substances 0.000 claims description 74
• 239000000651 prodrug Substances 0.000 claims description 69
• 229940002612 prodrug Drugs 0.000 claims description 69
• 150000002148 esters Chemical class 0.000 claims description 62
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 57
• 125000002947 alkylene group Chemical group 0.000 claims description 53
• 125000004432 carbon atom Chemical group C* 0.000 claims description 49
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 49
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 48
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 48
• 125000003342 alkenyl group Chemical group 0.000 claims description 43
• 125000001188 haloalkyl group Chemical group 0.000 claims description 43
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 38
• 229910052757 nitrogen Inorganic materials 0.000 claims description 38
• 239000011734 sodium Substances 0.000 claims description 36
• 125000001424 substituent group Chemical group 0.000 claims description 35
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 34
• 125000000304 alkynyl group Chemical group 0.000 claims description 29
• 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 28
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 23
• 229910052799 carbon Inorganic materials 0.000 claims description 23
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 20
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 19
• 125000006164 6-membered heteroaryl group Chemical group 0.000 claims description 10
• 239000003795 chemical substances by application Substances 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
• 125000002015 acyclic group Chemical group 0.000 claims description 7
• 239000003814 drug Substances 0.000 claims description 7
• 239000003937 drug carrier Substances 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
• 239000008103 glucose Substances 0.000 claims description 5
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
• 229940124597 therapeutic agent Drugs 0.000 claims description 4
• 238000011282 treatment Methods 0.000 claims description 4
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 4
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
• 108090000623 proteins and genes Proteins 0.000 claims description 3
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
• 230000036772 blood pressure Effects 0.000 claims description 2
• 229910052708 sodium Inorganic materials 0.000 claims description 2
• 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
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• 239000000883 anti-obesity agent Substances 0.000 claims 4
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• 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 4
• 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 claims 3
• 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 claims 3
• 239000012190 activator Substances 0.000 claims 3
• 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 claims 2
• 102400000322 Glucagon-like peptide 1 Human genes 0.000 claims 2
• 102000004877 Insulin Human genes 0.000 claims 2
• 108090001061 Insulin Proteins 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
• 239000000556 agonist Substances 0.000 claims 2
• 239000005557 antagonist Substances 0.000 claims 2
• 230000003178 anti-diabetic effect Effects 0.000 claims 2
• 229940125396 insulin Drugs 0.000 claims 2
• ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical group O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-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
• 102000002281 Adenylate kinase Human genes 0.000 claims 1
• 108020000543 Adenylate kinase Proteins 0.000 claims 1
• 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
• 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 1
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• 102400000064 Neuropeptide Y Human genes 0.000 claims 1
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• 229940123464 Thiazolidinedione Drugs 0.000 claims 1
• 229940125708 antidiabetic agent Drugs 0.000 claims 1
• 239000003472 antidiabetic agent Substances 0.000 claims 1
• 102000006995 beta-Glucosidase Human genes 0.000 claims 1
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• 229950010300 denagliptin Drugs 0.000 claims 1
• 230000029142 excretion Effects 0.000 claims 1
• 230000004190 glucose uptake Effects 0.000 claims 1
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• XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical group CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims 1
• 229960003105 metformin Drugs 0.000 claims 1
• URPYMXQQVHTUDU-OFGSCBOVSA-N nucleopeptide y Chemical group C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 URPYMXQQVHTUDU-OFGSCBOVSA-N 0.000 claims 1
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• HFLCZNNDZKKXCS-OUUBHVDSSA-N sergliflozin Chemical compound C1=CC(OC)=CC=C1CC1=CC=CC=C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HFLCZNNDZKKXCS-OUUBHVDSSA-N 0.000 claims 1
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