CA2716352C - Conformationally constrained carboxylic acid derivatives useful for treating metabolic disorders - Google Patents
Conformationally constrained carboxylic acid derivatives useful for treating metabolic disorders Download PDFInfo
- Publication number
- CA2716352C CA2716352C CA2716352A CA2716352A CA2716352C CA 2716352 C CA2716352 C CA 2716352C CA 2716352 A CA2716352 A CA 2716352A CA 2716352 A CA2716352 A CA 2716352A CA 2716352 C CA2716352 C CA 2716352C
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- CA
- Canada
- Prior art keywords
- compound
- ester
- alkyl
- pharmaceutically acceptable
- acceptable salt
- Prior art date
- 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.)
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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 712
- 239000000203 mixture Substances 0.000 claims abstract description 230
- 239000003814 drug Substances 0.000 claims abstract description 64
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 62
- 150000003839 salts Chemical class 0.000 claims description 210
- 229910052739 hydrogen Inorganic materials 0.000 claims description 177
- 150000002148 esters Chemical class 0.000 claims description 145
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 143
- -1 -N((C1-C4)alkyl)2 Chemical group 0.000 claims description 130
- 125000000217 alkyl group Chemical group 0.000 claims description 129
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 123
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 96
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 74
- 102100026148 Free fatty acid receptor 1 Human genes 0.000 claims description 70
- 101000912510 Homo sapiens Free fatty acid receptor 1 Proteins 0.000 claims description 70
- 201000010099 disease Diseases 0.000 claims description 59
- 125000000623 heterocyclic group Chemical group 0.000 claims description 59
- 125000003342 alkenyl group Chemical group 0.000 claims description 56
- 239000012453 solvate Substances 0.000 claims description 56
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 53
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 47
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 46
- 208000017169 kidney disease Diseases 0.000 claims description 46
- 229910052731 fluorine Inorganic materials 0.000 claims description 44
- 229940124597 therapeutic agent Drugs 0.000 claims description 36
- 125000003118 aryl group Chemical group 0.000 claims description 34
- 125000005842 heteroatom Chemical group 0.000 claims description 34
- 125000001424 substituent group Chemical group 0.000 claims description 33
- 208000008589 Obesity Diseases 0.000 claims description 27
- 235000020824 obesity Nutrition 0.000 claims description 27
- 206010020772 Hypertension Diseases 0.000 claims description 26
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 25
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 25
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 25
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 25
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 24
- 206010018429 Glucose tolerance impaired Diseases 0.000 claims description 24
- 206010023379 Ketoacidosis Diseases 0.000 claims description 24
- 208000007976 Ketosis Diseases 0.000 claims description 24
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 24
- 201000006549 dyspepsia Diseases 0.000 claims description 24
- 201000001320 Atherosclerosis Diseases 0.000 claims description 23
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 23
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 23
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 23
- 206010060378 Hyperinsulinaemia Diseases 0.000 claims description 23
- 208000013016 Hypoglycemia Diseases 0.000 claims description 23
- 206010022489 Insulin Resistance Diseases 0.000 claims description 23
- 206010028980 Neoplasm Diseases 0.000 claims description 23
- 206010030113 Oedema Diseases 0.000 claims description 23
- 201000001880 Sexual dysfunction Diseases 0.000 claims description 23
- 208000007536 Thrombosis Diseases 0.000 claims description 23
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 23
- 201000011510 cancer Diseases 0.000 claims description 23
- 201000001421 hyperglycemia Diseases 0.000 claims description 23
- 230000003451 hyperinsulinaemic effect Effects 0.000 claims description 23
- 201000008980 hyperinsulinism Diseases 0.000 claims description 23
- 208000020346 hyperlipoproteinemia Diseases 0.000 claims description 23
- 230000002218 hypoglycaemic effect Effects 0.000 claims description 23
- 231100000872 sexual dysfunction Toxicity 0.000 claims description 23
- 125000006709 (C5-C7) cycloalkenyl group Chemical group 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 22
- 208000011580 syndromic disease Diseases 0.000 claims description 22
- 125000001072 heteroaryl group Chemical group 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 229920006395 saturated elastomer Polymers 0.000 claims description 20
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 18
- 230000001225 therapeutic effect Effects 0.000 claims description 18
- 239000003112 inhibitor Substances 0.000 claims description 17
- 230000003213 activating effect Effects 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 15
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims description 14
- 125000002619 bicyclic group Chemical group 0.000 claims description 14
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 13
- 125000002950 monocyclic group Chemical group 0.000 claims description 12
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 claims description 11
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 claims description 11
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 claims description 11
- 206010012601 diabetes mellitus Diseases 0.000 claims description 11
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 9
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 9
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical group CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims description 9
- 229960003105 metformin Drugs 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 claims description 8
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 8
- 229940123464 Thiazolidinedione Drugs 0.000 claims description 8
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000004494 ethyl ester group Chemical group 0.000 claims description 4
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 3
- 102000005962 receptors Human genes 0.000 claims description 2
- 108020003175 receptors Proteins 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N methyl acetate Chemical compound COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims 10
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 2
- XSBVZFNDDKWSBI-FKSKYRLFSA-N (2R)-2-[5-[[3-tert-butyl-4-(2-fluoro-5-methoxyphenyl)phenyl]methoxy]-2,3-dihydro-1H-inden-1-yl]propanoic acid Chemical compound C[C@@H](C(=O)O)C1CCC2=CC(=CC=C12)OCC1=CC(=C(C=C1)C1=C(C=CC(=C1)OC)F)C(C)(C)C XSBVZFNDDKWSBI-FKSKYRLFSA-N 0.000 claims 1
- SCNZBIVUHMIHHJ-FKSKYRLFSA-N (2r)-2-[6-[[3-tert-butyl-4-(2-fluoro-5-methoxyphenyl)phenyl]methoxy]-2,3-dihydro-1h-inden-1-yl]propanoic acid Chemical compound COC1=CC=C(F)C(C=2C(=CC(COC=3C=C4C([C@@H](C)C(O)=O)CCC4=CC=3)=CC=2)C(C)(C)C)=C1 SCNZBIVUHMIHHJ-FKSKYRLFSA-N 0.000 claims 1
- XSBVZFNDDKWSBI-XNUZUHMRSA-N (2s)-2-[5-[[3-tert-butyl-4-(2-fluoro-5-methoxyphenyl)phenyl]methoxy]-2,3-dihydro-1h-inden-1-yl]propanoic acid Chemical compound COC1=CC=C(F)C(C=2C(=CC(COC=3C=C4CCC(C4=CC=3)[C@H](C)C(O)=O)=CC=2)C(C)(C)C)=C1 XSBVZFNDDKWSBI-XNUZUHMRSA-N 0.000 claims 1
- SCNZBIVUHMIHHJ-XNUZUHMRSA-N (2s)-2-[6-[[3-tert-butyl-4-(2-fluoro-5-methoxyphenyl)phenyl]methoxy]-2,3-dihydro-1h-inden-1-yl]propanoic acid Chemical compound COC1=CC=C(F)C(C=2C(=CC(COC=3C=C4C([C@H](C)C(O)=O)CCC4=CC=3)=CC=2)C(C)(C)C)=C1 SCNZBIVUHMIHHJ-XNUZUHMRSA-N 0.000 claims 1
- PHXIAMKEMZWYLC-CQTOTRCISA-N 2-[(1r)-1-ethyl-6-[[4-(2-fluoro-5-methoxyphenyl)-3-[(1r)-1-methoxy-2,2-dimethylpropyl]phenyl]methoxy]-2,3-dihydroinden-1-yl]acetic acid Chemical compound C([C@@](C1=C2)(CC(O)=O)CC)CC1=CC=C2OCC(C=C1[C@H](OC)C(C)(C)C)=CC=C1C1=CC(OC)=CC=C1F PHXIAMKEMZWYLC-CQTOTRCISA-N 0.000 claims 1
- PHXIAMKEMZWYLC-ZQWAWDFXSA-N 2-[(1r)-1-ethyl-6-[[4-(2-fluoro-5-methoxyphenyl)-3-[(1s)-1-methoxy-2,2-dimethylpropyl]phenyl]methoxy]-2,3-dihydroinden-1-yl]acetic acid Chemical compound C([C@@](C1=C2)(CC(O)=O)CC)CC1=CC=C2OCC(C=C1[C@@H](OC)C(C)(C)C)=CC=C1C1=CC(OC)=CC=C1F PHXIAMKEMZWYLC-ZQWAWDFXSA-N 0.000 claims 1
- OGJAOOACDMAIAT-SSEXGKCCSA-N 2-[(1r)-6-[[3-(5,5-dimethylcyclopenten-1-yl)-4-(2-fluoro-5-methoxyphenyl)phenyl]methoxy]-2,3-dihydro-1h-inden-1-yl]-2-methylpropanoic acid Chemical compound COC1=CC=C(F)C(C=2C(=CC(COC=3C=C4[C@@H](CCC4=CC=3)C(C)(C)C(O)=O)=CC=2)C=2C(CCC=2)(C)C)=C1 OGJAOOACDMAIAT-SSEXGKCCSA-N 0.000 claims 1
- ZCUQNULMPKGYIV-ZBWWXOROSA-N 2-[(1r)-6-[[3-[(1r)-2,2-dimethylcyclopentyl]-4-(2-fluoro-5-methoxyphenyl)phenyl]methoxy]-1-ethyl-2,3-dihydroinden-1-yl]acetic acid Chemical compound C([C@@](C1=C2)(CC(O)=O)CC)CC1=CC=C2OCC(C=1)=CC=C(C=2C(=CC=C(OC)C=2)F)C=1[C@@H]1CCCC1(C)C ZCUQNULMPKGYIV-ZBWWXOROSA-N 0.000 claims 1
- KACRNYACSLHGIN-VCTRWQRLSA-N 2-[(1r)-6-[[3-[(1r)-2,2-dimethylcyclopentyl]-4-(5-fluoro-2-methoxypyridin-4-yl)phenyl]methoxy]-1-ethyl-2,3-dihydroinden-1-yl]acetic acid Chemical compound C([C@@](C1=C2)(CC(O)=O)CC)CC1=CC=C2OCC(C=1)=CC=C(C=2C(=CN=C(OC)C=2)F)C=1[C@@H]1CCCC1(C)C KACRNYACSLHGIN-VCTRWQRLSA-N 0.000 claims 1
- ZCUQNULMPKGYIV-ANHUGMMASA-N 2-[(1r)-6-[[3-[(1s)-2,2-dimethylcyclopentyl]-4-(2-fluoro-5-methoxyphenyl)phenyl]methoxy]-1-ethyl-2,3-dihydroinden-1-yl]acetic acid Chemical compound C([C@@](C1=C2)(CC(O)=O)CC)CC1=CC=C2OCC(C=1)=CC=C(C=2C(=CC=C(OC)C=2)F)C=1[C@H]1CCCC1(C)C ZCUQNULMPKGYIV-ANHUGMMASA-N 0.000 claims 1
- KACRNYACSLHGIN-ZORMNXRFSA-N 2-[(1r)-6-[[3-[(1s)-2,2-dimethylcyclopentyl]-4-(5-fluoro-2-methoxypyridin-4-yl)phenyl]methoxy]-1-ethyl-2,3-dihydroinden-1-yl]acetic acid Chemical compound C([C@@](C1=C2)(CC(O)=O)CC)CC1=CC=C2OCC(C=1)=CC=C(C=2C(=CN=C(OC)C=2)F)C=1[C@H]1CCCC1(C)C KACRNYACSLHGIN-ZORMNXRFSA-N 0.000 claims 1
- OQYNVRFRUSEMOT-AREMUKBSSA-N 2-[(1r)-6-[[3-tert-butyl-4-(2-fluoro-5-methoxyphenyl)phenyl]methoxy]-2,3-dihydro-1h-inden-1-yl]-2-methylpropanoic acid Chemical compound COC1=CC=C(F)C(C=2C(=CC(COC=3C=C4[C@@H](CCC4=CC=3)C(C)(C)C(O)=O)=CC=2)C(C)(C)C)=C1 OQYNVRFRUSEMOT-AREMUKBSSA-N 0.000 claims 1
- GQSWMVKSEBWUCW-IGYGKHONSA-N 2-[(1r)-6-[[4-(5-fluoro-2-methoxypyridin-4-yl)-3-[(1r)-1-methoxy-2,2-dimethylpropyl]phenyl]methoxy]-1-methyl-2,3-dihydroinden-1-yl]acetic acid Chemical compound CO[C@H](C(C)(C)C)C1=CC(COC=2C=C3[C@@](C)(CC(O)=O)CCC3=CC=2)=CC=C1C1=CC(OC)=NC=C1F GQSWMVKSEBWUCW-IGYGKHONSA-N 0.000 claims 1
- GQSWMVKSEBWUCW-BVRKHOPBSA-N 2-[(1r)-6-[[4-(5-fluoro-2-methoxypyridin-4-yl)-3-[(1s)-1-methoxy-2,2-dimethylpropyl]phenyl]methoxy]-1-methyl-2,3-dihydroinden-1-yl]acetic acid Chemical compound CO[C@@H](C(C)(C)C)C1=CC(COC=2C=C3[C@@](C)(CC(O)=O)CCC3=CC=2)=CC=C1C1=CC(OC)=NC=C1F GQSWMVKSEBWUCW-BVRKHOPBSA-N 0.000 claims 1
- AHSGOLFYAFOENF-OAQYLSRUSA-N 2-[(1r)-7-[[3-tert-butyl-4-(2-fluoro-5-methoxyphenyl)phenyl]methoxy]-1,2,3,4-tetrahydronaphthalen-1-yl]acetic acid Chemical compound COC1=CC=C(F)C(C=2C(=CC(COC=3C=C4[C@@H](CC(O)=O)CCCC4=CC=3)=CC=2)C(C)(C)C)=C1 AHSGOLFYAFOENF-OAQYLSRUSA-N 0.000 claims 1
- PHXIAMKEMZWYLC-WEZIJMHWSA-N 2-[(1s)-1-ethyl-6-[[4-(2-fluoro-5-methoxyphenyl)-3-[(1r)-1-methoxy-2,2-dimethylpropyl]phenyl]methoxy]-2,3-dihydroinden-1-yl]acetic acid Chemical compound C([C@](C1=C2)(CC(O)=O)CC)CC1=CC=C2OCC(C=C1[C@H](OC)C(C)(C)C)=CC=C1C1=CC(OC)=CC=C1F PHXIAMKEMZWYLC-WEZIJMHWSA-N 0.000 claims 1
- PHXIAMKEMZWYLC-VTIYRKAUSA-N 2-[(1s)-1-ethyl-6-[[4-(2-fluoro-5-methoxyphenyl)-3-[(1s)-1-methoxy-2,2-dimethylpropyl]phenyl]methoxy]-2,3-dihydroinden-1-yl]acetic acid Chemical compound C([C@](C1=C2)(CC(O)=O)CC)CC1=CC=C2OCC(C=C1[C@@H](OC)C(C)(C)C)=CC=C1C1=CC(OC)=CC=C1F PHXIAMKEMZWYLC-VTIYRKAUSA-N 0.000 claims 1
- OGJAOOACDMAIAT-PMERELPUSA-N 2-[(1s)-6-[[3-(5,5-dimethylcyclopenten-1-yl)-4-(2-fluoro-5-methoxyphenyl)phenyl]methoxy]-2,3-dihydro-1h-inden-1-yl]-2-methylpropanoic acid Chemical compound COC1=CC=C(F)C(C=2C(=CC(COC=3C=C4[C@H](CCC4=CC=3)C(C)(C)C(O)=O)=CC=2)C=2C(CCC=2)(C)C)=C1 OGJAOOACDMAIAT-PMERELPUSA-N 0.000 claims 1
- KACRNYACSLHGIN-CMVGPNDKSA-N 2-[(1s)-6-[[3-[(1r)-2,2-dimethylcyclopentyl]-4-(5-fluoro-2-methoxypyridin-4-yl)phenyl]methoxy]-1-ethyl-2,3-dihydroinden-1-yl]acetic acid Chemical compound C([C@](C1=C2)(CC(O)=O)CC)CC1=CC=C2OCC(C=1)=CC=C(C=2C(=CN=C(OC)C=2)F)C=1[C@@H]1CCCC1(C)C KACRNYACSLHGIN-CMVGPNDKSA-N 0.000 claims 1
- ZCUQNULMPKGYIV-SJHOIFEDSA-N 2-[(1s)-6-[[3-[(1s)-2,2-dimethylcyclopentyl]-4-(2-fluoro-5-methoxyphenyl)phenyl]methoxy]-1-ethyl-2,3-dihydroinden-1-yl]acetic acid Chemical compound C([C@](C1=C2)(CC(O)=O)CC)CC1=CC=C2OCC(C=1)=CC=C(C=2C(=CC=C(OC)C=2)F)C=1[C@H]1CCCC1(C)C ZCUQNULMPKGYIV-SJHOIFEDSA-N 0.000 claims 1
- KACRNYACSLHGIN-SYBRLPANSA-N 2-[(1s)-6-[[3-[(1s)-2,2-dimethylcyclopentyl]-4-(5-fluoro-2-methoxypyridin-4-yl)phenyl]methoxy]-1-ethyl-2,3-dihydroinden-1-yl]acetic acid Chemical compound C([C@](C1=C2)(CC(O)=O)CC)CC1=CC=C2OCC(C=1)=CC=C(C=2C(=CN=C(OC)C=2)F)C=1[C@H]1CCCC1(C)C KACRNYACSLHGIN-SYBRLPANSA-N 0.000 claims 1
- OQYNVRFRUSEMOT-SANMLTNESA-N 2-[(1s)-6-[[3-tert-butyl-4-(2-fluoro-5-methoxyphenyl)phenyl]methoxy]-2,3-dihydro-1h-inden-1-yl]-2-methylpropanoic acid Chemical compound COC1=CC=C(F)C(C=2C(=CC(COC=3C=C4[C@H](CCC4=CC=3)C(C)(C)C(O)=O)=CC=2)C(C)(C)C)=C1 OQYNVRFRUSEMOT-SANMLTNESA-N 0.000 claims 1
- AHSGOLFYAFOENF-NRFANRHFSA-N 2-[(1s)-7-[[3-tert-butyl-4-(2-fluoro-5-methoxyphenyl)phenyl]methoxy]-1,2,3,4-tetrahydronaphthalen-1-yl]acetic acid Chemical compound COC1=CC=C(F)C(C=2C(=CC(COC=3C=C4[C@H](CC(O)=O)CCCC4=CC=3)=CC=2)C(C)(C)C)=C1 AHSGOLFYAFOENF-NRFANRHFSA-N 0.000 claims 1
- QTMAZYGAVHCKKX-UHFFFAOYSA-N 2-[(4-amino-5-bromopyrrolo[2,3-d]pyrimidin-7-yl)methoxy]propane-1,3-diol Chemical compound NC1=NC=NC2=C1C(Br)=CN2COC(CO)CO QTMAZYGAVHCKKX-UHFFFAOYSA-N 0.000 claims 1
- UJHOHEFFZVNOMC-LJQANCHMSA-N 2-[(7r)-4-[[3-tert-butyl-4-(2-fluoro-5-methoxyphenyl)phenyl]methoxy]-7-bicyclo[4.2.0]octa-1(6),2,4-trienyl]acetic acid Chemical compound COC1=CC=C(F)C(C=2C(=CC(COC=3C=C4[C@@H](CC(O)=O)CC4=CC=3)=CC=2)C(C)(C)C)=C1 UJHOHEFFZVNOMC-LJQANCHMSA-N 0.000 claims 1
- UJHOHEFFZVNOMC-IBGZPJMESA-N 2-[(7s)-4-[[3-tert-butyl-4-(2-fluoro-5-methoxyphenyl)phenyl]methoxy]-7-bicyclo[4.2.0]octa-1(6),2,4-trienyl]acetic acid Chemical compound COC1=CC=C(F)C(C=2C(=CC(COC=3C=C4[C@H](CC(O)=O)CC4=CC=3)=CC=2)C(C)(C)C)=C1 UJHOHEFFZVNOMC-IBGZPJMESA-N 0.000 claims 1
- BGGALFIXXQOTPY-NRFANRHFSA-N C1(=C(C2=C(C=C1)N(C(C#N)=C2)C[C@@H](N1CCN(CC1)S(=O)(=O)C)C)C)CN1CCC(CC1)NC1=NC(=NC2=C1C=C(S2)CC(F)(F)F)NC Chemical compound C1(=C(C2=C(C=C1)N(C(C#N)=C2)C[C@@H](N1CCN(CC1)S(=O)(=O)C)C)C)CN1CCC(CC1)NC1=NC(=NC2=C1C=C(S2)CC(F)(F)F)NC BGGALFIXXQOTPY-NRFANRHFSA-N 0.000 claims 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 claims 1
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- LPOIGVZLNWEGJG-UHFFFAOYSA-N n-benzyl-5-(4-methylpiperazin-1-yl)-2-nitroaniline Chemical compound C1CN(C)CCN1C1=CC=C([N+]([O-])=O)C(NCC=2C=CC=CC=2)=C1 LPOIGVZLNWEGJG-UHFFFAOYSA-N 0.000 claims 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 63
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 336
- 239000000243 solution Substances 0.000 description 165
- 238000006243 chemical reaction Methods 0.000 description 134
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 128
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 119
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 99
- 239000000741 silica gel Substances 0.000 description 95
- 229910002027 silica gel Inorganic materials 0.000 description 95
- 239000000047 product Substances 0.000 description 86
- 239000012230 colorless oil Substances 0.000 description 81
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 68
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 60
- 230000002829 reductive effect Effects 0.000 description 58
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 57
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 57
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 55
- 239000011541 reaction mixture Substances 0.000 description 50
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 47
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Landscapes
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Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
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| US6873308P | 2008-03-06 | 2008-03-06 | |
| US61/068,733 | 2008-03-06 | ||
| US19624908P | 2008-10-15 | 2008-10-15 | |
| US61/196,249 | 2008-10-15 | ||
| PCT/US2009/001435 WO2009111056A1 (en) | 2008-03-06 | 2009-03-04 | Conformationally constrained carboxylic acid derivatives useful for treating metabolic disorders |
Publications (2)
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| CA2716352A1 CA2716352A1 (en) | 2009-09-11 |
| CA2716352C true CA2716352C (en) | 2013-05-28 |
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| Application Number | Title | Priority Date | Filing Date |
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| CA2716352A Expired - Fee Related CA2716352C (en) | 2008-03-06 | 2009-03-04 | Conformationally constrained carboxylic acid derivatives useful for treating metabolic disorders |
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| US (1) | US8450522B2 (https=) |
| EP (1) | EP2260017A1 (https=) |
| JP (1) | JP2011515341A (https=) |
| AU (1) | AU2009220163B2 (https=) |
| CA (1) | CA2716352C (https=) |
| MX (1) | MX2010009654A (https=) |
| WO (1) | WO2009111056A1 (https=) |
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- 2009-03-04 AU AU2009220163A patent/AU2009220163B2/en not_active Ceased
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- 2009-03-04 US US12/863,578 patent/US8450522B2/en active Active
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- 2009-03-04 MX MX2010009654A patent/MX2010009654A/es active IP Right Grant
- 2009-03-04 JP JP2010549669A patent/JP2011515341A/ja not_active Ceased
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| EP2260017A1 (en) | 2010-12-15 |
| US20100298367A1 (en) | 2010-11-25 |
| MX2010009654A (es) | 2010-09-28 |
| AU2009220163A1 (en) | 2009-09-11 |
| CA2716352A1 (en) | 2009-09-11 |
| JP2011515341A (ja) | 2011-05-19 |
| AU2009220163B2 (en) | 2011-10-06 |
| WO2009111056A1 (en) | 2009-09-11 |
| US8450522B2 (en) | 2013-05-28 |
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|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20170306 |