CA2701053C - Oxadiazole- and oxazole-substituted benzimidazole- and indole-derivatives as dgat1 inhibitors - Google Patents
Oxadiazole- and oxazole-substituted benzimidazole- and indole-derivatives as dgat1 inhibitors Download PDFInfo
- Publication number
- CA2701053C CA2701053C CA2701053A CA2701053A CA2701053C CA 2701053 C CA2701053 C CA 2701053C CA 2701053 A CA2701053 A CA 2701053A CA 2701053 A CA2701053 A CA 2701053A CA 2701053 C CA2701053 C CA 2701053C
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- CA
- Canada
- Prior art keywords
- phenyl
- oxadiazol
- dichloro
- benzoimidazol
- benzoimidazole
- 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.)
- Expired - Fee Related
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- 229940127193 DGAT1 inhibitor Drugs 0.000 title description 2
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 title 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 262
- 102100036869 Diacylglycerol O-acyltransferase 1 Human genes 0.000 claims abstract description 43
- 150000003839 salts Chemical class 0.000 claims abstract description 38
- 101000927974 Homo sapiens Diacylglycerol O-acyltransferase 1 Proteins 0.000 claims abstract description 25
- 229940002612 prodrug Drugs 0.000 claims abstract description 25
- 239000000651 prodrug Substances 0.000 claims abstract description 25
- 208000008589 Obesity Diseases 0.000 claims description 22
- 235000020824 obesity Nutrition 0.000 claims description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims description 21
- 238000011282 treatment Methods 0.000 claims description 21
- 108050004099 Diacylglycerol O-acyltransferase 1 Proteins 0.000 claims description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 12
- 201000009104 prediabetes syndrome Diseases 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- UHVGYBNWKBRIIR-UHFFFAOYSA-N 2-(4-bromophenyl)-5-[2-(2,6-dichlorophenyl)-3h-benzimidazol-5-yl]-1,3,4-oxadiazole Chemical compound ClC1=CC=CC(Cl)=C1C1=NC2=CC=C(C=3OC(=NN=3)C=3C=CC(Br)=CC=3)C=C2N1 UHVGYBNWKBRIIR-UHFFFAOYSA-N 0.000 claims 1
- ICRPXSWLRUVPCF-UHFFFAOYSA-N 2-(4-chlorophenyl)-5-[2-(2,6-dichlorophenyl)-3h-benzimidazol-5-yl]-1,3,4-oxadiazole Chemical compound C1=CC(Cl)=CC=C1C1=NN=C(C=2C=C3NC(=NC3=CC=2)C=2C(=CC=CC=2Cl)Cl)O1 ICRPXSWLRUVPCF-UHFFFAOYSA-N 0.000 claims 1
- OXTKAAXEHMOYSB-UHFFFAOYSA-N 2-[2-(2,6-dichlorophenyl)-3h-benzimidazol-5-yl]-4,5-diphenyl-1,3-oxazole Chemical compound ClC1=CC=CC(Cl)=C1C1=NC2=CC=C(C=3OC(=C(N=3)C=3C=CC=CC=3)C=3C=CC=CC=3)C=C2N1 OXTKAAXEHMOYSB-UHFFFAOYSA-N 0.000 claims 1
- XVSWKRFZALESJD-UHFFFAOYSA-N 2-[2-(2,6-dichlorophenyl)-3h-benzimidazol-5-yl]-5-(2-methoxypyridin-3-yl)-1,3,4-oxadiazole Chemical compound COC1=NC=CC=C1C1=NN=C(C=2C=C3NC(=NC3=CC=2)C=2C(=CC=CC=2Cl)Cl)O1 XVSWKRFZALESJD-UHFFFAOYSA-N 0.000 claims 1
- DESKSOTVOPACDF-UHFFFAOYSA-N 2-[2-(2,6-dichlorophenyl)-3h-benzimidazol-5-yl]-5-(3-fluorophenyl)-1,3,4-oxadiazole Chemical compound FC1=CC=CC(C=2OC(=NN=2)C=2C=C3NC(=NC3=CC=2)C=2C(=CC=CC=2Cl)Cl)=C1 DESKSOTVOPACDF-UHFFFAOYSA-N 0.000 claims 1
- SUWWJNPNTQPDIE-UHFFFAOYSA-N 2-[2-(2,6-dichlorophenyl)-3h-benzimidazol-5-yl]-5-(3-methylphenyl)-1,3,4-oxadiazole Chemical compound CC1=CC=CC(C=2OC(=NN=2)C=2C=C3NC(=NC3=CC=2)C=2C(=CC=CC=2Cl)Cl)=C1 SUWWJNPNTQPDIE-UHFFFAOYSA-N 0.000 claims 1
- NWQFRYDNKKARGS-UHFFFAOYSA-N 2-[2-(2,6-dichlorophenyl)-3h-benzimidazol-5-yl]-5-(4-methoxyphenyl)-1,3,4-oxadiazole Chemical compound C1=CC(OC)=CC=C1C1=NN=C(C=2C=C3NC(=NC3=CC=2)C=2C(=CC=CC=2Cl)Cl)O1 NWQFRYDNKKARGS-UHFFFAOYSA-N 0.000 claims 1
- NOGWSCFVTMVTGU-UHFFFAOYSA-N 2-[2-(2,6-dichlorophenyl)-3h-benzimidazol-5-yl]-5-(4-methylphenyl)-1,3,4-oxadiazole Chemical compound C1=CC(C)=CC=C1C1=NN=C(C=2C=C3NC(=NC3=CC=2)C=2C(=CC=CC=2Cl)Cl)O1 NOGWSCFVTMVTGU-UHFFFAOYSA-N 0.000 claims 1
- HTYWVTNIQJLXRU-UHFFFAOYSA-N 2-[2-(2,6-dichlorophenyl)-3h-benzimidazol-5-yl]-5-pyrrolidin-1-yl-1,3,4-oxadiazole Chemical compound ClC1=CC=CC(Cl)=C1C1=NC2=CC=C(C=3OC(=NN=3)N3CCCC3)C=C2N1 HTYWVTNIQJLXRU-UHFFFAOYSA-N 0.000 claims 1
- KUXYJNMQOCSWIF-UHFFFAOYSA-N 2-[2-(2,6-dimethylphenyl)-3h-benzimidazol-5-yl]-5-(4-methoxyphenyl)-1,3,4-oxadiazole Chemical compound C1=CC(OC)=CC=C1C1=NN=C(C=2C=C3NC(=NC3=CC=2)C=2C(=CC=CC=2C)C)O1 KUXYJNMQOCSWIF-UHFFFAOYSA-N 0.000 claims 1
- UBGWQKWLRPICHU-UHFFFAOYSA-N 2-[3,5-dichloro-4-[6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1h-benzimidazol-2-yl]phenoxy]acetic acid Chemical compound ClC1=CC(OCC(=O)O)=CC(Cl)=C1C1=NC2=CC=C(C=3OC(=NN=3)C=3C=CC(Cl)=CC=3)C=C2N1 UBGWQKWLRPICHU-UHFFFAOYSA-N 0.000 claims 1
- FDLWFBGMODQLFQ-UHFFFAOYSA-N 2-benzyl-5-[2-(2,6-dichlorophenyl)-3h-benzimidazol-5-yl]-1,3,4-oxadiazole Chemical compound ClC1=CC=CC(Cl)=C1C1=NC2=CC=C(C=3OC(CC=4C=CC=CC=4)=NN=3)C=C2N1 FDLWFBGMODQLFQ-UHFFFAOYSA-N 0.000 claims 1
- LGTDFBSHHHDANY-UHFFFAOYSA-N 2-cyclohexyl-5-[2-(2,6-dichlorophenyl)-3h-benzimidazol-5-yl]-1,3,4-oxadiazole Chemical compound ClC1=CC=CC(Cl)=C1C1=NC2=CC=C(C=3OC(=NN=3)C3CCCCC3)C=C2N1 LGTDFBSHHHDANY-UHFFFAOYSA-N 0.000 claims 1
- MGVWTYUKSDBTQN-UHFFFAOYSA-N 2-cyclopentyl-5-[2-(2,6-dichlorophenyl)-3h-benzimidazol-5-yl]-1,3,4-oxadiazole Chemical compound ClC1=CC=CC(Cl)=C1C1=NC2=CC=C(C=3OC(=NN=3)C3CCCC3)C=C2N1 MGVWTYUKSDBTQN-UHFFFAOYSA-N 0.000 claims 1
- XVDXTYZDCQEZHB-UHFFFAOYSA-N 2-cyclopropyl-5-[2-(2,6-dichlorophenyl)-3h-benzimidazol-5-yl]-1,3,4-oxadiazole Chemical compound ClC1=CC=CC(Cl)=C1C1=NC2=CC=C(C=3OC(=NN=3)C3CC3)C=C2N1 XVDXTYZDCQEZHB-UHFFFAOYSA-N 0.000 claims 1
- HFCCYMGRZIVFNK-UHFFFAOYSA-N 2-tert-butyl-5-[2-(2,6-dichlorophenyl)-3h-benzimidazol-5-yl]-1,3,4-oxadiazole Chemical compound O1C(C(C)(C)C)=NN=C1C1=CC=C(N=C(N2)C=3C(=CC=CC=3Cl)Cl)C2=C1 HFCCYMGRZIVFNK-UHFFFAOYSA-N 0.000 claims 1
- SXYZIDPFWLLKCA-UHFFFAOYSA-N 3,5-dimethyl-4-[6-[5-[3-(trifluoromethyl)anilino]-1,3,4-oxadiazol-2-yl]-1H-benzimidazol-2-yl]phenol Chemical compound CC1=CC(O)=CC(C)=C1C1=NC2=CC=C(C=3OC(NC=4C=C(C=CC=4)C(F)(F)F)=NN=3)C=C2N1 SXYZIDPFWLLKCA-UHFFFAOYSA-N 0.000 claims 1
- DAHMVPDOQMZJTN-UHFFFAOYSA-N 3-[3,5-dichloro-4-[6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1h-benzimidazol-2-yl]phenyl]propanoic acid Chemical compound ClC1=CC(CCC(=O)O)=CC(Cl)=C1C1=NC2=CC=C(C=3OC(=NN=3)C=3C=CC(Cl)=CC=3)C=C2N1 DAHMVPDOQMZJTN-UHFFFAOYSA-N 0.000 claims 1
- QTPVKFXEJYLZKN-UHFFFAOYSA-N 3-[3,5-dimethyl-4-[6-[5-(2-methylphenyl)-1,3,4-oxadiazol-2-yl]-1h-benzimidazol-2-yl]phenyl]-2,2-dimethylpropanoic acid Chemical compound CC1=CC=CC=C1C1=NN=C(C=2C=C3NC(=NC3=CC=2)C=2C(=CC(CC(C)(C)C(O)=O)=CC=2C)C)O1 QTPVKFXEJYLZKN-UHFFFAOYSA-N 0.000 claims 1
- IUXLNGKBZRFMQT-UHFFFAOYSA-N 3-[4-[6-(5-cyclohexyl-1,3,4-oxadiazol-2-yl)-1h-benzimidazol-2-yl]-3,5-dimethylphenyl]-2,2-dimethylpropanoic acid Chemical compound CC1=CC(CC(C)(C)C(O)=O)=CC(C)=C1C1=NC2=CC=C(C=3OC(=NN=3)C3CCCCC3)C=C2N1 IUXLNGKBZRFMQT-UHFFFAOYSA-N 0.000 claims 1
- TUBPDBIOKLNJTG-UHFFFAOYSA-N 3-[4-[6-(5-methoxy-1,3,4-oxadiazol-2-yl)-1h-indol-2-yl]-3,5-dimethylphenyl]propanoic acid Chemical compound O1C(OC)=NN=C1C1=CC=C(C=C(N2)C=3C(=CC(CCC(O)=O)=CC=3C)C)C2=C1 TUBPDBIOKLNJTG-UHFFFAOYSA-N 0.000 claims 1
- LMSZAVQIIWOBAS-UHFFFAOYSA-N 3-[4-[6-[5-(3-chloroanilino)-1,3,4-oxadiazol-2-yl]-1h-benzimidazol-2-yl]-3,5-dimethylphenyl]propanoic acid Chemical compound CC1=CC(CCC(O)=O)=CC(C)=C1C1=NC2=CC=C(C=3OC(NC=4C=C(Cl)C=CC=4)=NN=3)C=C2N1 LMSZAVQIIWOBAS-UHFFFAOYSA-N 0.000 claims 1
- RZTAZOGZORFSEF-UHFFFAOYSA-N 3-[4-[6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1h-benzimidazol-2-yl]-3,5-dimethylphenyl]propanoic acid Chemical compound CC1=CC(CCC(O)=O)=CC(C)=C1C1=NC2=CC=C(C=3OC(=NN=3)C=3C=CC(Cl)=CC=3)C=C2N1 RZTAZOGZORFSEF-UHFFFAOYSA-N 0.000 claims 1
- GHLMRBVSXAZWDQ-UHFFFAOYSA-N 3-[4-[6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1h-benzimidazol-2-yl]-3,5-dimethylphenyl]propylphosphonic acid Chemical compound CC1=CC(CCCP(O)(O)=O)=CC(C)=C1C1=NC2=CC=C(C=3OC(=NN=3)C=3C=CC(Cl)=CC=3)C=C2N1 GHLMRBVSXAZWDQ-UHFFFAOYSA-N 0.000 claims 1
- ZMGNWJVVHPJXOV-UHFFFAOYSA-N 3-[4-[6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1h-indol-2-yl]-3,5-dimethylphenyl]-2,2-dimethylpropanoic acid Chemical compound CC1=CC(CC(C)(C)C(O)=O)=CC(C)=C1C1=CC2=CC=C(C=3OC(=NN=3)C=3C=CC(Cl)=CC=3)C=C2N1 ZMGNWJVVHPJXOV-UHFFFAOYSA-N 0.000 claims 1
- JOYPWBAZXFFWAK-UHFFFAOYSA-N 3-[4-[6-[5-(4-methoxy-2-methylphenyl)-1,3,4-oxadiazol-2-yl]-1h-benzimidazol-2-yl]-3,5-dimethylphenyl]-2,2-dimethylpropanoic acid Chemical compound CC1=CC(OC)=CC=C1C1=NN=C(C=2C=C3NC(=NC3=CC=2)C=2C(=CC(CC(C)(C)C(O)=O)=CC=2C)C)O1 JOYPWBAZXFFWAK-UHFFFAOYSA-N 0.000 claims 1
- DZTVXQZHWYUNLE-UHFFFAOYSA-N 3-[4-[6-[5-(4-methoxyanilino)-1,3,4-oxadiazol-2-yl]-1h-benzimidazol-2-yl]-3,5-dimethylphenyl]propanoic acid Chemical compound C1=CC(OC)=CC=C1NC1=NN=C(C=2C=C3NC(=NC3=CC=2)C=2C(=CC(CCC(O)=O)=CC=2C)C)O1 DZTVXQZHWYUNLE-UHFFFAOYSA-N 0.000 claims 1
- JMHFOGLVAUTEJQ-UHFFFAOYSA-N 3-[4-[6-[5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]-1h-benzimidazol-2-yl]-3,5-dimethylphenyl]-2,2-dimethylpropanoic acid Chemical compound C1=CC(OC)=CC=C1C1=NN=C(C=2C=C3N=C(NC3=CC=2)C=2C(=CC(CC(C)(C)C(O)=O)=CC=2C)C)O1 JMHFOGLVAUTEJQ-UHFFFAOYSA-N 0.000 claims 1
- MINLAUDEZKJETF-UHFFFAOYSA-N 3-[4-[6-[5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]-1h-benzimidazol-2-yl]-3,5-dimethylphenyl]propanoic acid Chemical compound C1=CC(OC)=CC=C1C1=NN=C(C=2C=C3NC(=NC3=CC=2)C=2C(=CC(CCC(O)=O)=CC=2C)C)O1 MINLAUDEZKJETF-UHFFFAOYSA-N 0.000 claims 1
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- WHPIFOJXIWHQAM-UHFFFAOYSA-N 5-[2-(2,6-dichlorophenyl)-3h-benzimidazol-5-yl]-n-[5-(trifluoromethyl)pyridin-2-yl]-1,3,4-oxadiazol-2-amine Chemical compound N1=CC(C(F)(F)F)=CC=C1NC1=NN=C(C=2C=C3NC(=NC3=CC=2)C=2C(=CC=CC=2Cl)Cl)O1 WHPIFOJXIWHQAM-UHFFFAOYSA-N 0.000 claims 1
- DYMJPLBOBJGENP-UHFFFAOYSA-N 5-tert-butyl-3-[2-(2,6-dichlorophenyl)-3h-benzimidazol-5-yl]-1,2,4-oxadiazole Chemical compound O1C(C(C)(C)C)=NC(C=2C=C3NC(=NC3=CC=2)C=2C(=CC=CC=2Cl)Cl)=N1 DYMJPLBOBJGENP-UHFFFAOYSA-N 0.000 claims 1
- HWEVIGFQWYGPTF-UHFFFAOYSA-N n-(1-adamantyl)-5-[2-(2,6-dichlorophenyl)-3h-benzimidazol-5-yl]-1,3,4-oxadiazol-2-amine Chemical compound ClC1=CC=CC(Cl)=C1C1=NC2=CC=C(C=3OC(NC45CC6CC(CC(C6)C4)C5)=NN=3)C=C2N1 HWEVIGFQWYGPTF-UHFFFAOYSA-N 0.000 claims 1
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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| AU2007266796B2 (en) | 2006-05-30 | 2011-02-10 | Astrazeneca Ab | Substituted 5-phenylamino-1,3,4-oxadiazol-2-ylcarbonylamino-4-phenoxy-cyclohexane carboxylic acid as inhibitors of acetyl coenzyme A diacylglycerol acyltransferase |
| AR066169A1 (es) * | 2007-09-28 | 2009-07-29 | Novartis Ag | Derivados de benzo-imidazoles, utiles para trastornos asociados con la actividad de dgat |
| WO2009112445A1 (en) * | 2008-03-10 | 2009-09-17 | Novartis Ag | Method of increasing cellular phosphatidyl choline by dgat1 inhibition |
| US8637507B2 (en) | 2009-03-18 | 2014-01-28 | Merck Sharp & Dohme Corp. | Bicyclic compounds as inhibitors of diacylglycerol acyltransferase |
| US8748426B2 (en) | 2009-12-31 | 2014-06-10 | Piramal Enterprises Limited | Inhibitors of diacylglycerol acyl transferase |
| EP2552441B1 (en) * | 2010-03-30 | 2016-05-04 | Novartis AG | Uses of dgat1 inhibitors |
| WO2012044567A2 (en) * | 2010-09-30 | 2012-04-05 | Merck Sharp & Dohme Corp. | Imidazole derivatives |
| WO2012064569A1 (en) * | 2010-11-08 | 2012-05-18 | Merck Sharp & Dohme Corp. | Imidazole derivatives |
| RU2609200C2 (ru) | 2011-07-08 | 2017-01-30 | Новартис Аг | Способ лечения атеросклероза у субъектов с высоким уровнем триглицеридов |
| WO2013074387A1 (en) * | 2011-11-14 | 2013-05-23 | Merck Sharp & Dohme Corp. | Imidazole derivatives |
| WO2013169648A1 (en) | 2012-05-07 | 2013-11-14 | Novartis Ag | Pharmaceutical combinations comprising a dgat1 inhibtor and a triglyceride lowering drug |
| EP2903985A1 (en) | 2012-10-03 | 2015-08-12 | Advinus Therapeutics Limited | Spirocyclic compounds, compositions and medicinal applications thereof |
| HRP20190099T1 (hr) * | 2012-11-23 | 2019-04-19 | Glaxosmithkline Llc | Novi spojevi kao inhibitori diacilglicerin aciltransferaze |
| WO2014081996A1 (en) * | 2012-11-23 | 2014-05-30 | Glaxosmithkline Llc | Novel compounds as diacylglycerol acyltransferase inhibitors |
| US9796729B2 (en) | 2012-11-23 | 2017-10-24 | Glaxosmithkline Llc | Compounds as diacylglycerol acyltransferase inhibitors |
| CN103087045B (zh) * | 2013-01-11 | 2015-08-12 | 上海交通大学 | 一种苯并咪唑类杂环化合物、药物组合物及其用途 |
| CN104672144A (zh) * | 2015-02-13 | 2015-06-03 | 佛山市赛维斯医药科技有限公司 | 一种环丙基酰肼和硝基苯类gpr119激动剂、制备方法及其用途 |
| CN104610152A (zh) * | 2015-02-13 | 2015-05-13 | 佛山市赛维斯医药科技有限公司 | 一类环丙基酰肼类gpr119激动剂、制备方法及其用途 |
| MY205335A (en) | 2018-03-16 | 2024-10-16 | Anji Pharmaceuticals Inc | Compositions and methods for treating severe constipation |
| WO2020110008A1 (en) | 2018-11-27 | 2020-06-04 | Novartis Ag | Cyclic pentamer compounds as proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for the treatment of metabolic disorder |
| UY38485A (es) | 2018-11-27 | 2020-06-30 | Novartis Ag | Compuestos tetrámeros cíclicos como inhibidores de proproteína convertasa subtilisina/kexina tipo 9 (pcsk9), método de tratamiento, uso y su preparación |
| JP7657151B2 (ja) | 2018-11-27 | 2025-04-04 | ノバルティス アーゲー | 代謝性障害の処置のためのプロタンパク質コンバターゼスブチリシン／ケキシン９型（ｐｃｓｋ９）阻害剤としての環状ペプチド |
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