HRP20050181A2 - Indoles having anti-diabetic activity - Google Patents
Indoles having anti-diabetic activityInfo
- Publication number
- HRP20050181A2 HRP20050181A2 HR20050181A HRP20050181A HRP20050181A2 HR P20050181 A2 HRP20050181 A2 HR P20050181A2 HR 20050181 A HR20050181 A HR 20050181A HR P20050181 A HRP20050181 A HR P20050181A HR P20050181 A2 HRP20050181 A2 HR P20050181A2
- Authority
- HR
- Croatia
- Prior art keywords
- alkyl
- group
- optionally substituted
- image
- compound according
- Prior art date
Links
- 230000003178 anti-diabetic effect Effects 0.000 title claims 2
- 150000002475 indoles Chemical class 0.000 title abstract description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 43
- 238000011282 treatment Methods 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims description 194
- 229910052736 halogen Inorganic materials 0.000 claims description 79
- 150000002367 halogens Chemical class 0.000 claims description 79
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 60
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 57
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 51
- 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 49
- 125000000217 alkyl group Chemical group 0.000 claims description 44
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 41
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 31
- -1 3-benzisoxazolyl Chemical group 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 26
- 229940125396 insulin Drugs 0.000 claims description 25
- 102000004877 Insulin Human genes 0.000 claims description 24
- 108090001061 Insulin Proteins 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 241000124008 Mammalia Species 0.000 claims description 9
- 229940079593 drug Drugs 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 8
- 125000002950 monocyclic group Chemical group 0.000 claims description 7
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000002619 bicyclic group Chemical group 0.000 claims description 5
- 150000001721 carbon Chemical group 0.000 claims description 5
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims description 5
- 229960003105 metformin Drugs 0.000 claims description 5
- 125000005493 quinolyl group Chemical group 0.000 claims description 5
- 150000003536 tetrazoles Chemical class 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims description 4
- 229940100389 Sulfonylurea Drugs 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 claims description 4
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 3
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 claims description 3
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
- 229960002855 simvastatin Drugs 0.000 claims description 3
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims description 3
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 claims description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims description 2
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims description 2
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 claims description 2
- 229960005370 atorvastatin Drugs 0.000 claims description 2
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000004599 benzpyrazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- GPUADMRJQVPIAS-QCVDVZFFSA-M cerivastatin sodium Chemical compound [Na+].COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 GPUADMRJQVPIAS-QCVDVZFFSA-M 0.000 claims description 2
- 229960003765 fluvastatin Drugs 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 229960004844 lovastatin Drugs 0.000 claims description 2
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 claims description 2
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 claims description 2
- 229960002797 pitavastatin Drugs 0.000 claims description 2
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 claims description 2
- 229960000672 rosuvastatin Drugs 0.000 claims description 2
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 claims description 2
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical compound [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 claims description 2
- 102000000536 PPAR gamma Human genes 0.000 abstract description 21
- 108010016731 PPAR gamma Proteins 0.000 abstract description 19
- 239000000556 agonist Substances 0.000 abstract description 17
- 239000002253 acid Substances 0.000 abstract description 11
- 201000001421 hyperglycemia Diseases 0.000 abstract description 11
- 239000004031 partial agonist Substances 0.000 abstract description 8
- 206010020772 Hypertension Diseases 0.000 abstract description 5
- 208000032928 Dyslipidaemia Diseases 0.000 abstract description 4
- 208000035150 Hypercholesterolemia Diseases 0.000 abstract description 4
- 208000017170 Lipid metabolism disease Diseases 0.000 abstract description 4
- 208000031226 Hyperlipidaemia Diseases 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 136
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 94
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 79
- 238000005160 1H NMR spectroscopy Methods 0.000 description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 58
- 239000000243 solution Substances 0.000 description 52
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 235000019439 ethyl acetate Nutrition 0.000 description 38
- 239000000047 product Substances 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 239000000203 mixture Substances 0.000 description 28
- 239000012044 organic layer Substances 0.000 description 27
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 26
- 229910052938 sodium sulfate Inorganic materials 0.000 description 26
- 235000011152 sodium sulphate Nutrition 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 25
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 25
- 239000012267 brine Substances 0.000 description 23
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 22
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 20
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- 230000000694 effects Effects 0.000 description 20
- 238000003786 synthesis reaction Methods 0.000 description 19
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 16
- 239000008103 glucose Substances 0.000 description 16
- 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 description 15
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 102000023984 PPAR alpha Human genes 0.000 description 13
- 238000003818 flash chromatography Methods 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- 239000007832 Na2SO4 Substances 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 11
- 206010012601 diabetes mellitus Diseases 0.000 description 11
- 201000010099 disease Diseases 0.000 description 11
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 11
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 235000019198 oils Nutrition 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 11
- 206010022489 Insulin Resistance Diseases 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- 108091008725 peroxisome proliferator-activated receptors alpha Proteins 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 239000003446 ligand Substances 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- NAFITOVUIPDYLZ-UHFFFAOYSA-N 4-methoxy-2-prop-2-enoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C(OCC=C)=C1 NAFITOVUIPDYLZ-UHFFFAOYSA-N 0.000 description 7
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 7
- 102100039556 Galectin-4 Human genes 0.000 description 7
- 208000008589 Obesity Diseases 0.000 description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 235000020824 obesity Nutrition 0.000 description 7
- 239000000651 prodrug Substances 0.000 description 7
- 229940002612 prodrug Drugs 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 101000608765 Homo sapiens Galectin-4 Proteins 0.000 description 6
- 108010015181 PPAR delta Proteins 0.000 description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 125000000623 heterocyclic group Chemical group 0.000 description 6
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 6
- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- DTDBZXHUNNTHIA-UHFFFAOYSA-N (4-methoxy-2-prop-2-enoxyphenyl)-[2-methyl-6-(trifluoromethoxy)-1h-indol-3-yl]methanone Chemical compound C=CCOC1=CC(OC)=CC=C1C(=O)C1=C(C)NC2=CC(OC(F)(F)F)=CC=C12 DTDBZXHUNNTHIA-UHFFFAOYSA-N 0.000 description 5
- MIGXZZLNKNTXBE-UHFFFAOYSA-N 6-methoxy-3-[2-methyl-1-(4-methylphenyl)sulfonyl-6-(trifluoromethoxy)indol-3-yl]-1,2-benzoxazole Chemical compound N=1OC2=CC(OC)=CC=C2C=1C(C1=CC=C(OC(F)(F)F)C=C11)=C(C)N1S(=O)(=O)C1=CC=C(C)C=C1 MIGXZZLNKNTXBE-UHFFFAOYSA-N 0.000 description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- 238000005119 centrifugation Methods 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 150000002632 lipids Chemical class 0.000 description 5
- 230000001404 mediated effect Effects 0.000 description 5
- JVUCJPMQFNYUDX-UHFFFAOYSA-N methyl 4-methoxy-2-prop-2-enoxybenzoate Chemical compound COC(=O)C1=CC=C(OC)C=C1OCC=C JVUCJPMQFNYUDX-UHFFFAOYSA-N 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 235000019260 propionic acid Nutrition 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US40674102P | 2002-08-29 | 2002-08-29 | |
US44067203P | 2003-01-17 | 2003-01-17 | |
PCT/US2003/026677 WO2004020408A1 (en) | 2002-08-29 | 2003-08-27 | Indoles having anti-diabetic activity |
Publications (1)
Publication Number | Publication Date |
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HRP20050181A2 true HRP20050181A2 (en) | 2006-03-31 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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HR20050181A HRP20050181A2 (en) | 2002-08-29 | 2005-02-23 | Indoles having anti-diabetic activity |
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US (2) | US7186746B2 (zh) |
JP (1) | JP4377815B2 (zh) |
KR (1) | KR20050057074A (zh) |
CN (1) | CN100457730C (zh) |
AU (1) | AU2003265681A1 (zh) |
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CA (1) | CA2495943C (zh) |
DE (1) | DE60332125D1 (zh) |
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EC (1) | ECSP055632A (zh) |
ES (1) | ES2342596T3 (zh) |
HK (1) | HK1083836A1 (zh) |
HR (1) | HRP20050181A2 (zh) |
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PT (1) | PT1537078E (zh) |
RU (1) | RU2328483C2 (zh) |
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JP4340232B2 (ja) * | 2002-08-29 | 2009-10-07 | メルク エンド カムパニー インコーポレーテッド | 抗糖尿病活性を有するインドール類 |
PT1537078E (pt) * | 2002-08-29 | 2010-06-18 | Merck Sharp & Dohme | Indoles que possuem actividade antidiabética |
US8293751B2 (en) | 2003-01-14 | 2012-10-23 | Arena Pharmaceuticals, Inc. | 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia |
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- 2003-08-27 BR BR0313825-9A patent/BR0313825A/pt not_active IP Right Cessation
- 2003-08-27 CN CNB038206919A patent/CN100457730C/zh not_active Expired - Fee Related
- 2003-08-27 PL PL03375302A patent/PL375302A1/xx not_active Application Discontinuation
- 2003-08-27 WO PCT/US2003/026677 patent/WO2004020408A1/en not_active Application Discontinuation
- 2003-08-27 DK DK03791952.9T patent/DK1537078T3/da active
- 2003-08-27 DE DE60332125T patent/DE60332125D1/de not_active Expired - Lifetime
- 2003-08-27 MX MXPA05002303A patent/MXPA05002303A/es active IP Right Grant
- 2003-08-27 KR KR1020057003552A patent/KR20050057074A/ko active IP Right Grant
- 2003-08-27 CA CA002495943A patent/CA2495943C/en not_active Expired - Fee Related
- 2003-08-27 ES ES03791952T patent/ES2342596T3/es not_active Expired - Lifetime
- 2003-08-27 US US10/524,697 patent/US7186746B2/en not_active Expired - Lifetime
- 2003-08-27 NZ NZ538031A patent/NZ538031A/en unknown
- 2003-08-27 AU AU2003265681A patent/AU2003265681A1/en not_active Abandoned
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- 2003-08-27 WO PCT/US2003/027156 patent/WO2004020409A1/en active Application Filing
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2005
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- 2005-02-08 IL IL16676405A patent/IL166764A0/xx not_active IP Right Cessation
- 2005-02-23 HR HR20050181A patent/HRP20050181A2/hr not_active Application Discontinuation
- 2005-02-25 EC EC2005005632A patent/ECSP055632A/es unknown
- 2005-03-16 MA MA28147A patent/MA27396A1/fr unknown
- 2005-03-23 NO NO20051546A patent/NO20051546L/no not_active Application Discontinuation
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2006
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Also Published As
Publication number | Publication date |
---|---|
KR20050057074A (ko) | 2005-06-16 |
IL166764A0 (en) | 2006-01-15 |
RU2328483C2 (ru) | 2008-07-10 |
US20050277685A1 (en) | 2005-12-15 |
NZ538031A (en) | 2007-10-26 |
US7186746B2 (en) | 2007-03-06 |
HK1083836A1 (en) | 2006-07-14 |
CA2495943A1 (en) | 2004-03-11 |
ES2342596T3 (es) | 2010-07-09 |
JP2006500384A (ja) | 2006-01-05 |
ECSP055632A (es) | 2005-04-18 |
AU2003265681A1 (en) | 2004-03-19 |
BR0313825A (pt) | 2005-07-12 |
US7345085B2 (en) | 2008-03-18 |
MA27396A1 (fr) | 2005-06-01 |
JP4377815B2 (ja) | 2009-12-02 |
DE60332125D1 (de) | 2010-05-27 |
MXPA05002303A (es) | 2005-06-08 |
DK1537078T3 (da) | 2010-08-02 |
CN1678578A (zh) | 2005-10-05 |
IS7680A (is) | 2005-01-31 |
RU2005108668A (ru) | 2005-08-27 |
WO2004020409A1 (en) | 2004-03-11 |
US20070161689A1 (en) | 2007-07-12 |
CA2495943C (en) | 2009-07-21 |
WO2004020408A1 (en) | 2004-03-11 |
PL375302A1 (en) | 2005-11-28 |
NO20051546L (no) | 2005-05-24 |
CN100457730C (zh) | 2009-02-04 |
PT1537078E (pt) | 2010-06-18 |
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