AU2009220163B2 - Conformationally constrained carboxylic acid derivatives useful for treating metabolic disorders - Google Patents
Conformationally constrained carboxylic acid derivatives useful for treating metabolic disorders Download PDFInfo
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- AU2009220163B2 AU2009220163B2 AU2009220163A AU2009220163A AU2009220163B2 AU 2009220163 B2 AU2009220163 B2 AU 2009220163B2 AU 2009220163 A AU2009220163 A AU 2009220163A AU 2009220163 A AU2009220163 A AU 2009220163A AU 2009220163 B2 AU2009220163 B2 AU 2009220163B2
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- alkyl
- compound
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- mmol
- alkenyl
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- 208000030159 metabolic disease Diseases 0.000 title abstract description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 452
- 239000000203 mixture Substances 0.000 claims abstract description 238
- 238000000034 method Methods 0.000 claims abstract description 81
- 239000003814 drug Substances 0.000 claims abstract description 50
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 50
- 125000000217 alkyl group Chemical group 0.000 claims description 342
- 229910052739 hydrogen Inorganic materials 0.000 claims description 181
- 125000003342 alkenyl group Chemical group 0.000 claims description 113
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 75
- 102100026148 Free fatty acid receptor 1 Human genes 0.000 claims description 68
- 101000912510 Homo sapiens Free fatty acid receptor 1 Proteins 0.000 claims description 68
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 67
- 150000003839 salts Chemical class 0.000 claims description 65
- 201000010099 disease Diseases 0.000 claims description 59
- 125000000623 heterocyclic group Chemical group 0.000 claims description 58
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 51
- 239000012453 solvate Substances 0.000 claims description 46
- 229910052731 fluorine Inorganic materials 0.000 claims description 41
- 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 38
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- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 35
- 125000003118 aryl group Chemical group 0.000 claims description 33
- 125000005842 heteroatom Chemical group 0.000 claims description 33
- 125000001424 substituent group Chemical group 0.000 claims description 33
- 125000003545 alkoxy group Chemical group 0.000 claims description 32
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 32
- 229940124597 therapeutic agent Drugs 0.000 claims description 29
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- 235000020824 obesity Nutrition 0.000 claims description 23
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- 208000024172 Cardiovascular disease Diseases 0.000 claims description 21
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 21
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 21
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 20
- 206010018429 Glucose tolerance impaired Diseases 0.000 claims description 20
- 206010023379 Ketoacidosis Diseases 0.000 claims description 20
- 208000007976 Ketosis Diseases 0.000 claims description 20
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 20
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
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- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 19
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- 102000004877 Insulin Human genes 0.000 claims description 19
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- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 19
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- 201000001421 hyperglycemia Diseases 0.000 claims description 19
- 230000002218 hypoglycaemic effect Effects 0.000 claims description 19
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- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 18
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- 238000002360 preparation method Methods 0.000 claims description 18
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- 125000002877 alkyl aryl group Chemical group 0.000 claims description 16
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- 238000011282 treatment Methods 0.000 claims description 14
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- 125000002950 monocyclic group Chemical group 0.000 claims description 11
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 claims description 10
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 claims description 10
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- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical group CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims description 9
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- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 claims description 7
- 229940123464 Thiazolidinedione Drugs 0.000 claims description 7
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 7
- 230000000052 comparative effect Effects 0.000 claims description 7
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- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 230000003247 decreasing effect Effects 0.000 claims description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 470
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 373
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- 239000000243 solution Substances 0.000 description 180
- 238000006243 chemical reaction Methods 0.000 description 155
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 111
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 109
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 94
- 239000012230 colorless oil Substances 0.000 description 94
- -1 hexyl ester Chemical class 0.000 description 87
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 76
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 75
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 71
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 68
- 230000002829 reductive effect Effects 0.000 description 67
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 66
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- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 47
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- 239000012267 brine Substances 0.000 description 43
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 43
- 238000005481 NMR spectroscopy Methods 0.000 description 41
- 239000012044 organic layer Substances 0.000 description 38
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 35
- 229910052757 nitrogen Inorganic materials 0.000 description 35
- 238000003818 flash chromatography Methods 0.000 description 32
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 30
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- 125000001072 heteroaryl group Chemical group 0.000 description 20
- 125000004432 carbon atom Chemical group C* 0.000 description 19
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- DIOHEXPTUTVCNX-UHFFFAOYSA-N 1,1,1-trifluoro-n-phenyl-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=CC=C1 DIOHEXPTUTVCNX-UHFFFAOYSA-N 0.000 description 17
- 125000005907 alkyl ester group Chemical group 0.000 description 17
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- IPTZOWYBCLEBOE-UHFFFAOYSA-N (2-fluoro-5-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(F)C(B(O)O)=C1 IPTZOWYBCLEBOE-UHFFFAOYSA-N 0.000 description 16
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- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 16
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- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 12
- 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 11
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- RKTUVUTWPYUGDI-UHFFFAOYSA-N 2-(5,5-dimethylcyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)CCC=C1B1OC(C)(C)C(C)(C)O1 RKTUVUTWPYUGDI-UHFFFAOYSA-N 0.000 description 8
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- OPQVJAZQITXPLP-UHFFFAOYSA-N methyl 3-(3,3-dimethylbut-1-en-2-yl)-4-(trifluoromethylsulfonyloxy)benzoate Chemical compound COC(=O)C1=CC=C(OS(=O)(=O)C(F)(F)F)C(C(=C)C(C)(C)C)=C1 OPQVJAZQITXPLP-UHFFFAOYSA-N 0.000 description 1
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- MSFLKIALVBVGHI-UHFFFAOYSA-N methyl 3-(5,5-dimethylcyclopenten-1-yl)-4-(5-ethoxy-2-fluorophenyl)benzoate Chemical compound CCOC1=CC=C(F)C(C=2C(=CC(=CC=2)C(=O)OC)C=2C(CCC=2)(C)C)=C1 MSFLKIALVBVGHI-UHFFFAOYSA-N 0.000 description 1
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- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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- A61P7/10—Antioedematous agents; Diuretics
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- A61P9/00—Drugs for disorders of the cardiovascular system
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| PCT/US2009/001435 WO2009111056A1 (en) | 2008-03-06 | 2009-03-04 | Conformationally constrained carboxylic acid derivatives useful for treating metabolic disorders |
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- 2009-03-04 MX MX2010009654A patent/MX2010009654A/es active IP Right Grant
- 2009-03-04 EP EP09717135A patent/EP2260017A1/en not_active Withdrawn
- 2009-03-04 CA CA2716352A patent/CA2716352C/en not_active Expired - Fee Related
- 2009-03-04 JP JP2010549669A patent/JP2011515341A/ja not_active Ceased
- 2009-03-04 WO PCT/US2009/001435 patent/WO2009111056A1/en not_active Ceased
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1630152A1 (en) * | 2003-05-30 | 2006-03-01 | Takeda Pharmaceutical Company Limited | Condensed ring compound |
| WO2005086661A2 (en) * | 2004-02-27 | 2005-09-22 | Amgen Inc. | Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders |
Also Published As
| Publication number | Publication date |
|---|---|
| MX2010009654A (es) | 2010-09-28 |
| CA2716352A1 (en) | 2009-09-11 |
| US20100298367A1 (en) | 2010-11-25 |
| CA2716352C (en) | 2013-05-28 |
| US8450522B2 (en) | 2013-05-28 |
| WO2009111056A1 (en) | 2009-09-11 |
| EP2260017A1 (en) | 2010-12-15 |
| JP2011515341A (ja) | 2011-05-19 |
| AU2009220163A1 (en) | 2009-09-11 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FGA | Letters patent sealed or granted (standard patent) | ||
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |