JP5675359B2 - Ｄｇａｔ１阻害剤としてのオキサジアゾールおよびオキサゾール置換ベンゾイミダゾールおよびインドール誘導体 - Google Patents
Ｄｇａｔ１阻害剤としてのオキサジアゾールおよびオキサゾール置換ベンゾイミダゾールおよびインドール誘導体 Download PDFInfo
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- JP5675359B2 JP5675359B2 JP2010526300A JP2010526300A JP5675359B2 JP 5675359 B2 JP5675359 B2 JP 5675359B2 JP 2010526300 A JP2010526300 A JP 2010526300A JP 2010526300 A JP2010526300 A JP 2010526300A JP 5675359 B2 JP5675359 B2 JP 5675359B2
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- Prior art keywords
- phenyl
- substituted
- oxadiazol
- unsubstituted
- dichloro
- 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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- -1 oxazole-substituted benzimidazole Chemical class 0.000 title claims description 309
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 title description 4
- 229940127193 DGAT1 inhibitor Drugs 0.000 title description 2
- 229940054051 antipsychotic indole derivative Drugs 0.000 title 1
- 150000002475 indoles Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 277
- 125000000217 alkyl group Chemical group 0.000 claims description 150
- 229910052739 hydrogen Inorganic materials 0.000 claims description 91
- 239000001257 hydrogen Substances 0.000 claims description 91
- 125000000623 heterocyclic group Chemical group 0.000 claims description 85
- 229910052736 halogen Inorganic materials 0.000 claims description 67
- 150000002367 halogens Chemical class 0.000 claims description 67
- 229940002612 prodrug Drugs 0.000 claims description 65
- 239000000651 prodrug Substances 0.000 claims description 65
- 125000003545 alkoxy group Chemical group 0.000 claims description 62
- 125000003118 aryl group Chemical group 0.000 claims description 61
- 125000001072 heteroaryl group Chemical group 0.000 claims description 61
- 150000002431 hydrogen Chemical class 0.000 claims description 61
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 60
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 53
- 150000003839 salts Chemical class 0.000 claims description 53
- 102100036869 Diacylglycerol O-acyltransferase 1 Human genes 0.000 claims description 44
- 125000002252 acyl group Chemical group 0.000 claims description 42
- 125000001424 substituent group Chemical group 0.000 claims description 41
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 35
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 35
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 33
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 31
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 30
- 125000003282 alkyl amino group Chemical group 0.000 claims description 29
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical group [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 29
- 101000927974 Homo sapiens Diacylglycerol O-acyltransferase 1 Proteins 0.000 claims description 27
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 27
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 27
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 23
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 23
- 229940124530 sulfonamide Drugs 0.000 claims description 22
- 150000003456 sulfonamides Chemical class 0.000 claims description 22
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 22
- 125000004104 aryloxy group Chemical group 0.000 claims description 20
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 20
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 18
- 125000001589 carboacyl group Chemical group 0.000 claims description 17
- 208000008589 Obesity Diseases 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- 235000020824 obesity Nutrition 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 125000004423 acyloxy group Chemical group 0.000 claims description 15
- 125000004414 alkyl thio group Chemical group 0.000 claims description 14
- 125000002950 monocyclic group Chemical group 0.000 claims description 14
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 14
- 125000005110 aryl thio group Chemical group 0.000 claims description 13
- 125000002619 bicyclic group Chemical group 0.000 claims description 13
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 12
- 125000005907 alkyl ester group Chemical group 0.000 claims description 12
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 12
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 10
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 9
- 230000001404 mediated effect Effects 0.000 claims description 9
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 7
- 150000001735 carboxylic acids Chemical class 0.000 claims description 7
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 7
- 201000009104 prediabetes syndrome Diseases 0.000 claims description 7
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 6
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 6
- 239000004305 biphenyl Substances 0.000 claims description 6
- 235000010290 biphenyl Nutrition 0.000 claims description 6
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 6
- 125000003003 spiro group Chemical group 0.000 claims description 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
- 125000005333 aroyloxy group Chemical group 0.000 claims description 5
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 5
- 125000004470 heterocyclooxy group Chemical group 0.000 claims description 5
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 4
- SSCBDEUAEZBUIJ-UHFFFAOYSA-N 2-[4-[6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1h-benzimidazol-2-yl]-3,5-dimethylphenoxy]acetic acid Chemical compound CC1=CC(OCC(O)=O)=CC(C)=C1C1=NC2=CC=C(C=3OC(=NN=3)C=3C=CC(Cl)=CC=3)C=C2N1 SSCBDEUAEZBUIJ-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000003435 aroyl group Chemical group 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 4
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims description 3
- 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 description 3
- 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 description 3
- 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 description 3
- LNVAFTZCCRGKBM-UHFFFAOYSA-N 3,5-dimethyl-4-[6-[5-[4-(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=CC(=CC=4)C(F)(F)F)=NN=3)C=C2N1 LNVAFTZCCRGKBM-UHFFFAOYSA-N 0.000 claims description 3
- 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 description 3
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 claims description 3
- VCAFQDZGTWSJAS-UHFFFAOYSA-N 5-(4-chlorophenyl)-2-[2-(2,6-dichlorophenyl)-3h-benzimidazol-5-yl]-1,3-oxazole Chemical compound C1=CC(Cl)=CC=C1C1=CN=C(C=2C=C3NC(=NC3=CC=2)C=2C(=CC=CC=2Cl)Cl)O1 VCAFQDZGTWSJAS-UHFFFAOYSA-N 0.000 claims description 3
- FPYKBORVKFNMHS-UHFFFAOYSA-N 5-(4-chlorophenyl)-2-[2-(2,6-dichlorophenyl)-3h-benzimidazol-5-yl]-4-methyl-1,3-oxazole Chemical compound CC=1N=C(C=2C=C3NC(=NC3=CC=2)C=2C(=CC=CC=2Cl)Cl)OC=1C1=CC=C(Cl)C=C1 FPYKBORVKFNMHS-UHFFFAOYSA-N 0.000 claims description 3
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 3
- BFPLMTPHDFFMTG-UHFFFAOYSA-N [1,3]oxazolo[5,4-b]pyridine Chemical compound C1=CN=C2OC=NC2=C1 BFPLMTPHDFFMTG-UHFFFAOYSA-N 0.000 claims description 3
- WFIHKLWVLPBMIQ-UHFFFAOYSA-N [1,3]thiazolo[5,4-b]pyridine Chemical compound C1=CN=C2SC=NC2=C1 WFIHKLWVLPBMIQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 230000004962 physiological condition Effects 0.000 claims description 3
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 3
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 claims description 3
- 238000003797 solvolysis reaction Methods 0.000 claims description 3
- 150000003852 triazoles Chemical class 0.000 claims description 3
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 2
- HNGVSOBRRWEVHO-UHFFFAOYSA-N 2-[2-(2,6-dichlorophenyl)-3h-benzimidazol-5-yl]-5-[6-(trifluoromethyl)pyridin-3-yl]-1,3,4-oxadiazole Chemical compound C1=NC(C(F)(F)F)=CC=C1C1=NN=C(C=2C=C3NC(=NC3=CC=2)C=2C(=CC=CC=2Cl)Cl)O1 HNGVSOBRRWEVHO-UHFFFAOYSA-N 0.000 claims description 2
- GOLORTLGFDVFDW-UHFFFAOYSA-N 3-(1h-benzimidazol-2-yl)-7-(diethylamino)chromen-2-one Chemical compound C1=CC=C2NC(C3=CC4=CC=C(C=C4OC3=O)N(CC)CC)=NC2=C1 GOLORTLGFDVFDW-UHFFFAOYSA-N 0.000 claims description 2
- 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 description 2
- 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 description 2
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 2
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 claims description 2
- 150000002460 imidazoles Chemical class 0.000 claims description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 2
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical group C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 claims description 2
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 2
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 3
- 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
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims 1
- 150000001556 benzimidazoles Chemical class 0.000 claims 1
- RTCQRWIAYHAAMH-UHFFFAOYSA-N n-(2-chloropyridin-4-yl)-5-[2-(2,6-dichlorophenyl)-3h-benzimidazol-5-yl]-1,3,4-oxadiazol-2-amine Chemical compound C1=NC(Cl)=CC(NC=2OC(=NN=2)C=2C=C3NC(=NC3=CC=2)C=2C(=CC=CC=2Cl)Cl)=C1 RTCQRWIAYHAAMH-UHFFFAOYSA-N 0.000 claims 1
- HGPIAKILLFPJJN-UHFFFAOYSA-N n-(2-tert-butylpyridin-4-yl)-5-[2-(2,6-dichlorophenyl)-3h-benzimidazol-5-yl]-1,3,4-oxadiazol-2-amine Chemical compound C1=NC(C(C)(C)C)=CC(NC=2OC(=NN=2)C=2C=C3NC(=NC3=CC=2)C=2C(=CC=CC=2Cl)Cl)=C1 HGPIAKILLFPJJN-UHFFFAOYSA-N 0.000 claims 1
- RYTPRXOADAOEEW-UHFFFAOYSA-N n-(3-bicyclo[2.2.1]heptanyl)-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(NC4C5CCC(C5)C4)=NN=3)C=C2N1 RYTPRXOADAOEEW-UHFFFAOYSA-N 0.000 claims 1
- NWZRLVDNPHRTNT-UHFFFAOYSA-N n-(5-chloropyridin-2-yl)-5-[2-(2,6-dichlorophenyl)-3h-benzimidazol-5-yl]-1,3,4-oxadiazol-2-amine Chemical compound N1=CC(Cl)=CC=C1NC1=NN=C(C=2C=C3NC(=NC3=CC=2)C=2C(=CC=CC=2Cl)Cl)O1 NWZRLVDNPHRTNT-UHFFFAOYSA-N 0.000 claims 1
- RQIPEQYAIHAQAG-UHFFFAOYSA-N n-(6-chloropyridin-3-yl)-5-[2-(2,6-dichlorophenyl)-3h-benzimidazol-5-yl]-1,3,4-oxadiazol-2-amine Chemical compound C1=NC(Cl)=CC=C1NC1=NN=C(C=2C=C3NC(=NC3=CC=2)C=2C(=CC=CC=2Cl)Cl)O1 RQIPEQYAIHAQAG-UHFFFAOYSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 252
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 159
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- 238000000034 method Methods 0.000 description 92
- 238000005160 1H NMR spectroscopy Methods 0.000 description 87
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 81
- 239000000203 mixture Substances 0.000 description 81
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
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- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 58
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 57
- 239000002904 solvent Substances 0.000 description 54
- 230000002829 reductive effect Effects 0.000 description 48
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
- 239000012074 organic phase Substances 0.000 description 39
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 34
- 239000011541 reaction mixture Substances 0.000 description 33
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 32
- YSHOWEKUVWPFNR-UHFFFAOYSA-N burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 description 32
- 239000011734 sodium Substances 0.000 description 30
- 239000000725 suspension Substances 0.000 description 29
- 238000010898 silica gel chromatography Methods 0.000 description 28
- 238000003756 stirring Methods 0.000 description 28
- MUASQIQKPHHGEG-UHFFFAOYSA-N 2-(2,6-dichlorophenyl)-3h-benzimidazole-5-carbohydrazide Chemical compound N1C2=CC(C(=O)NN)=CC=C2N=C1C1=C(Cl)C=CC=C1Cl MUASQIQKPHHGEG-UHFFFAOYSA-N 0.000 description 27
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Classifications
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Landscapes
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| PCT/EP2008/062900 WO2009040410A1 (en) | 2007-09-28 | 2008-09-26 | Oxadiazole- and oxazole-substituted benzimidazole- and indole-derivatives as dgat1 inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| AU2005315430B2 (en) | 2004-12-14 | 2010-05-27 | Astrazeneca Ab | Oxadiazole derivatives as DGAT inhibitors |
| AR058562A1 (es) | 2005-12-22 | 2008-02-13 | Astrazeneca Ab | Derivados de pirimido [4,5 b] (1,4) oxazinas , procedimientos de obtencion y su uso como inhibidores de acetil coa y dgat 1 |
| MX2008015228A (es) | 2006-05-30 | 2008-12-12 | Astrazeneca Ab | Acido 5-fenilamino-1,3,4-oxadiazol-2-ilcarbonilamino-4-fenoxi-cicl ohexanocarboxilico sustituido como inhibidor de diacilglicerol aciltransferasa de acetil coenzima a. |
| 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 |
| AU2010226829A1 (en) * | 2009-03-18 | 2011-09-15 | Schering Corporation | Bicyclic compounds as inhibitors of diacylglycerol acyltransferase |
| RU2012132682A (ru) | 2009-12-31 | 2014-02-10 | Пирамал Энтерпрайзис Лимитед | Ингибиторы диацилглицерин ацилтрансферазы |
| MA34097B1 (fr) * | 2010-03-30 | 2013-03-05 | Novartis Ag | Utilisations d'inhibiteurs de dgat1 |
| 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 |
| US9867811B2 (en) | 2011-07-08 | 2018-01-16 | Novartis Ag | Method of treating atherosclerosis in high triglyceride subjects |
| 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 |
| US9796729B2 (en) | 2012-11-23 | 2017-10-24 | Glaxosmithkline Llc | Compounds as diacylglycerol acyltransferase inhibitors |
| WO2014081996A1 (en) * | 2012-11-23 | 2014-05-30 | Glaxosmithkline Llc | Novel compounds as diacylglycerol acyltransferase inhibitors |
| EP3492474B1 (en) * | 2012-11-23 | 2021-08-11 | GlaxoSmithKline LLC | Intermediates used in the production of 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 |
| CA3093970A1 (en) | 2018-03-16 | 2019-09-19 | Anji Pharmaceuticals Inc. | Compositions and methods for treating severe constipation |
| EP3887363A1 (en) | 2018-11-27 | 2021-10-06 | Novartis AG | Cyclic pentamer compounds as proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for the treatment of metabolic disorder |
| CN113166204B (zh) * | 2018-11-27 | 2025-01-28 | 诺华股份有限公司 | 作为治疗代谢障碍的蛋白质原转换酶枯草杆菌蛋白酶/kexin 9型（PCSK9）抑制剂的环状肽 |
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