CN103562180B - 新型六氢环戊二烯并吡咯酮,六氢吡咯并吡咯酮,八氢吡咯并吡啶酮和八氢吡啶酮化合物 - Google Patents
新型六氢环戊二烯并吡咯酮,六氢吡咯并吡咯酮,八氢吡咯并吡啶酮和八氢吡啶酮化合物 Download PDFInfo
- Publication number
- CN103562180B CN103562180B CN201280023662.XA CN201280023662A CN103562180B CN 103562180 B CN103562180 B CN 103562180B CN 201280023662 A CN201280023662 A CN 201280023662A CN 103562180 B CN103562180 B CN 103562180B
- Authority
- CN
- China
- Prior art keywords
- phenyl
- octahydro
- trifluoromethoxy
- pyrrolo
- pyridin
- 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
Links
- 229910052739 hydrogen Inorganic materials 0.000 title claims description 28
- 239000001257 hydrogen Substances 0.000 title claims description 28
- 125000004435 hydrogen atom Chemical class [H]* 0.000 title description 14
- DSILUGCORMLHPA-UHFFFAOYSA-N 2,3,3a,4,6,6a-hexahydro-1h-pyrrolo[3,2-b]pyrrol-5-one Chemical compound N1CCC2NC(=O)CC21 DSILUGCORMLHPA-UHFFFAOYSA-N 0.000 title 1
- BHSMGUQJBGQELF-UHFFFAOYSA-N 3,3a-dihydro-1H-cyclopenta[b]pyrrol-2-one Chemical compound N1C=2C(CC1=O)C=CC2 BHSMGUQJBGQELF-UHFFFAOYSA-N 0.000 title 1
- 150000005299 pyridinones Chemical class 0.000 title 1
- ORKUYZDMEWAUEZ-UHFFFAOYSA-N pyrrolo[3,2-b]pyridin-2-one Chemical compound N1=CC=CC2=NC(=O)C=C21 ORKUYZDMEWAUEZ-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 183
- 238000000034 method Methods 0.000 claims abstract description 41
- -1 Phenyl Chemical group 0.000 claims description 66
- 125000000217 alkyl group Chemical group 0.000 claims description 43
- 125000004863 4-trifluoromethoxyphenyl group Chemical group [H]C1=C([H])C(OC(F)(F)F)=C([H])C([H])=C1* 0.000 claims description 42
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 41
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 40
- 238000011282 treatment Methods 0.000 claims description 39
- 238000002360 preparation method Methods 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 24
- GCNTZFIIOFTKIY-UHFFFAOYSA-N 4-hydroxypyridine Chemical compound OC1=CC=NC=C1 GCNTZFIIOFTKIY-UHFFFAOYSA-N 0.000 claims description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 20
- 206010012601 diabetes mellitus Diseases 0.000 claims description 19
- 230000002265 prevention Effects 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 16
- 102000000019 Sterol Esterase Human genes 0.000 claims description 15
- 108010055297 Sterol Esterase Proteins 0.000 claims description 15
- 238000011321 prophylaxis Methods 0.000 claims description 15
- 201000001320 Atherosclerosis Diseases 0.000 claims description 14
- 208000008589 Obesity Diseases 0.000 claims description 14
- 230000004064 dysfunction Effects 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 230000002107 myocardial effect Effects 0.000 claims description 14
- 235000020824 obesity Nutrition 0.000 claims description 14
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 13
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 13
- 206010061218 Inflammation Diseases 0.000 claims description 13
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 13
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 13
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 13
- 230000004054 inflammatory process Effects 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 9
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- TZYWCWPNWKEQCG-ANEWXZNUSA-N (3ar,7as)-2-[2-(2,4-dichlorophenyl)-2-hydroxyethyl]-5-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical compound C([C@@H]1CN(C[C@@H]1C1=O)CC(O)C=2C(=CC(Cl)=CC=2)Cl)CN1C1=CC=C(OCC(F)(F)F)C=C1 TZYWCWPNWKEQCG-ANEWXZNUSA-N 0.000 claims description 4
- OOPXPUHSUWIQHN-PBHICJAKSA-N (3ar,7as)-5-[4-(2,2,2-trifluoroethoxy)phenyl]-2-[2-(trifluoromethoxy)phenyl]sulfonyl-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical compound C1=CC(OCC(F)(F)F)=CC=C1N1C(=O)[C@H]2CN(S(=O)(=O)C=3C(=CC=CC=3)OC(F)(F)F)C[C@H]2CC1 OOPXPUHSUWIQHN-PBHICJAKSA-N 0.000 claims description 4
- ICURKDZAOKAZKG-OWQGQXMQSA-N (3as,5s,6ar)-5-(butoxymethyl)-5-hydroxy-2-[4-(trifluoromethoxy)phenyl]-3a,4,6,6a-tetrahydro-1h-cyclopenta[c]pyrrol-3-one Chemical compound C([C@@H]1C[C@@](C[C@@H]1C1=O)(O)COCCCC)N1C1=CC=C(OC(F)(F)F)C=C1 ICURKDZAOKAZKG-OWQGQXMQSA-N 0.000 claims description 4
- RUZIVNMLRPKBGI-KUBVQFIISA-N (3as,7ar)-1-(2-phenylacetyl)-5-[4-(trifluoromethoxy)phenyl]-2,3,3a,6,7,7a-hexahydro-1h-pyrrolo[3,4-c]pyridin-4-one Chemical compound C1=CC(OC(F)(F)F)=CC=C1N1C(=O)[C@H](CNC2C(=O)CC=3C=CC=CC=3)[C@H]2CC1 RUZIVNMLRPKBGI-KUBVQFIISA-N 0.000 claims description 4
- IOHFWOZJENTFLA-XJKSGUPXSA-N (3as,7ar)-2-(2-chlorophenyl)sulfonyl-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical compound C1=CC(OC(F)(F)F)=CC=C1N1C(=O)[C@@H]2CN(S(=O)(=O)C=3C(=CC=CC=3)Cl)C[C@@H]2CC1 IOHFWOZJENTFLA-XJKSGUPXSA-N 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 3
- ZCLNJVVEHPLNDO-BSBHGOPBSA-N n-[(3as,6ar)-3-oxo-2-[4-(trifluoromethoxy)phenyl]-1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrol-5-yl]-2-chlorobenzenesulfonamide Chemical compound C1=CC(OC(F)(F)F)=CC=C1N1C(=O)[C@H]2CC(NS(=O)(=O)C=3C(=CC=CC=3)Cl)C[C@H]2C1 ZCLNJVVEHPLNDO-BSBHGOPBSA-N 0.000 claims description 3
- SDRXORFVMCHESD-CHEUHSMRSA-N (3ar,7as)-1-(2-phenylacetyl)-5-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3,3a,6,7,7a-hexahydro-1h-pyrrolo[3,4-c]pyridin-4-one Chemical compound C1=CC(OCC(F)(F)F)=CC=C1N1C(=O)[C@@H](CNC2C(=O)CC=3C=CC=CC=3)[C@@H]2CC1 SDRXORFVMCHESD-CHEUHSMRSA-N 0.000 claims description 2
- JWCAWYZVCBQCHU-PBHICJAKSA-N (3ar,7as)-2-(2-chlorophenyl)sulfonyl-5-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical compound C1=CC(OCC(F)(F)F)=CC=C1N1C(=O)[C@H]2CN(S(=O)(=O)C=3C(=CC=CC=3)Cl)C[C@H]2CC1 JWCAWYZVCBQCHU-PBHICJAKSA-N 0.000 claims description 2
- URZPTRWITOLAHH-CJNGLKHVSA-N (3ar,7as)-2-(2-chloropyridin-3-yl)sulfonyl-5-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical compound C1=CC(OCC(F)(F)F)=CC=C1N1C(=O)[C@H]2CN(S(=O)(=O)C=3C(=NC=CC=3)Cl)C[C@H]2CC1 URZPTRWITOLAHH-CJNGLKHVSA-N 0.000 claims description 2
- TUTZPAJFLXAIQH-PBHICJAKSA-N (3ar,7as)-2-(3,3-dimethylbutanoyl)-5-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical compound C([C@@H]1CN(C[C@@H]1C1=O)C(=O)CC(C)(C)C)CN1C1=CC=C(OCC(F)(F)F)C=C1 TUTZPAJFLXAIQH-PBHICJAKSA-N 0.000 claims description 2
- QLGSFDRAOBTLSJ-BEFAXECRSA-N (3ar,7as)-2-(benzenesulfonyl)-5-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical compound C1=CC(OCC(F)(F)F)=CC=C1N1C(=O)[C@H]2CN(S(=O)(=O)C=3C=CC=CC=3)C[C@H]2CC1 QLGSFDRAOBTLSJ-BEFAXECRSA-N 0.000 claims description 2
- VUKYNERAKZLTOZ-UZLBHIALSA-N (3ar,7as)-2-[2-(4-fluorophenyl)acetyl]-5-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical compound C1=CC(F)=CC=C1CC(=O)N1C[C@@H]2C(=O)N(C=3C=CC(OCC(F)(F)F)=CC=3)CC[C@@H]2C1 VUKYNERAKZLTOZ-UZLBHIALSA-N 0.000 claims description 2
- BMTUEDGSYHQHFI-NQIIRXRSSA-N (3ar,7as)-2-[2-(4-methylphenyl)acetyl]-5-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical compound C1=CC(C)=CC=C1CC(=O)N1C[C@@H]2C(=O)N(C=3C=CC(OCC(F)(F)F)=CC=3)CC[C@@H]2C1 BMTUEDGSYHQHFI-NQIIRXRSSA-N 0.000 claims description 2
- BWVIKPJQQKIUGB-PBHICJAKSA-N (3ar,7as)-5-[4-(2,2,2-trifluoroethoxy)phenyl]-2-[2-(trifluoromethyl)phenyl]sulfonyl-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical compound C1=CC(OCC(F)(F)F)=CC=C1N1C(=O)[C@H]2CN(S(=O)(=O)C=3C(=CC=CC=3)C(F)(F)F)C[C@H]2CC1 BWVIKPJQQKIUGB-PBHICJAKSA-N 0.000 claims description 2
- ZOSXIEYYQRCFQH-XEGUGMAKSA-N (3as,5s,6ar)-5-hydroxy-5-(2,2,2-trifluoroethoxymethyl)-2-[4-(trifluoromethoxy)phenyl]-3a,4,6,6a-tetrahydro-1h-cyclopenta[c]pyrrol-3-one Chemical compound C([C@@H]1C[C@](C[C@@H]1C1=O)(COCC(F)(F)F)O)N1C1=CC=C(OC(F)(F)F)C=C1 ZOSXIEYYQRCFQH-XEGUGMAKSA-N 0.000 claims description 2
- FWMIDUCEURWGLJ-DCPHZVHLSA-N (3as,5s,6ar)-5-hydroxy-5-(phenoxymethyl)-2-[4-(trifluoromethoxy)phenyl]-3a,4,6,6a-tetrahydro-1h-cyclopenta[c]pyrrol-3-one Chemical compound C([C@@]1(O)C[C@@H]2C(=O)N(C[C@@H]2C1)C=1C=CC(OC(F)(F)F)=CC=1)OC1=CC=CC=C1 FWMIDUCEURWGLJ-DCPHZVHLSA-N 0.000 claims description 2
- UQTFGVGNOYPZBT-NUTKFTJISA-N (3as,5s,6ar)-5-hydroxy-5-(propoxymethyl)-2-[4-(trifluoromethoxy)phenyl]-3a,4,6,6a-tetrahydro-1h-cyclopenta[c]pyrrol-3-one Chemical compound C([C@@H]1C[C@@](C[C@@H]1C1=O)(O)COCCC)N1C1=CC=C(OC(F)(F)F)C=C1 UQTFGVGNOYPZBT-NUTKFTJISA-N 0.000 claims description 2
- JQQBOTWLJXCTBZ-KEXXGOCASA-N (3as,6ar)-5-(anilinomethyl)-5-hydroxy-2-[4-(trifluoromethoxy)phenyl]-3a,4,6,6a-tetrahydro-1h-cyclopenta[c]pyrrol-3-one Chemical compound C([C@@H]1C(=O)N(C[C@@H]1C1)C=2C=CC(OC(F)(F)F)=CC=2)C1(O)CNC1=CC=CC=C1 JQQBOTWLJXCTBZ-KEXXGOCASA-N 0.000 claims description 2
- SNVFIFXXEAAXLK-XPFLZZBLSA-N (3as,6ar)-5-hydroxy-5-propyl-2-[4-(trifluoromethoxy)phenyl]-3a,4,6,6a-tetrahydro-1h-cyclopenta[c]pyrrol-3-one Chemical compound C([C@@H]1CC(C[C@@H]1C1=O)(O)CCC)N1C1=CC=C(OC(F)(F)F)C=C1 SNVFIFXXEAAXLK-XPFLZZBLSA-N 0.000 claims description 2
- NGLACRZGEXFSMJ-SJKOYZFVSA-N (3as,6as)-4-oxo-n,5-bis[4-(trifluoromethoxy)phenyl]-3,3a,6,6a-tetrahydro-1h-pyrrolo[3,4-c]pyrrole-2-carboxamide Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC(=O)N1C[C@H]2C(=O)N(C=3C=CC(OC(F)(F)F)=CC=3)C[C@H]2C1 NGLACRZGEXFSMJ-SJKOYZFVSA-N 0.000 claims description 2
- BVXPXCFIGDWPIB-DNVCBOLYSA-N (3as,6as)-5-(4-ethylphenyl)-4-oxo-n-[4-(trifluoromethoxy)phenyl]-3,3a,6,6a-tetrahydro-1h-pyrrolo[3,4-c]pyrrole-2-carboxamide Chemical compound C1=CC(CC)=CC=C1N1C(=O)[C@@H]2CN(C(=O)NC=3C=CC(OC(F)(F)F)=CC=3)C[C@@H]2C1 BVXPXCFIGDWPIB-DNVCBOLYSA-N 0.000 claims description 2
- UTWATDQGGKALAL-SUMWQHHRSA-N (3as,7ar)-2-(2-chlorobenzoyl)-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical compound C1=CC(OC(F)(F)F)=CC=C1N1C(=O)[C@@H]2CN(C(=O)C=3C(=CC=CC=3)Cl)C[C@@H]2CC1 UTWATDQGGKALAL-SUMWQHHRSA-N 0.000 claims description 2
- YXAQHOMOMXWBST-XJKSGUPXSA-N (3as,7ar)-2-(2-methylpropylsulfonyl)-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical compound C([C@H]1CN(C[C@H]1C1=O)S(=O)(=O)CC(C)C)CN1C1=CC=C(OC(F)(F)F)C=C1 YXAQHOMOMXWBST-XJKSGUPXSA-N 0.000 claims description 2
- FIADIBYFRWITEN-XJKSGUPXSA-N (3as,7ar)-2-(3-methylbutanoyl)-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical compound C([C@H]1CN(C[C@H]1C1=O)C(=O)CC(C)C)CN1C1=CC=C(OC(F)(F)F)C=C1 FIADIBYFRWITEN-XJKSGUPXSA-N 0.000 claims description 2
- TWMYWSDGOVHDKS-WMLDXEAASA-N (3as,7ar)-2-(3-methylbutylsulfonyl)-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical compound C([C@H]1CN(C[C@H]1C1=O)S(=O)(=O)CCC(C)C)CN1C1=CC=C(OC(F)(F)F)C=C1 TWMYWSDGOVHDKS-WMLDXEAASA-N 0.000 claims description 2
- MFAMMXPGEWSZTR-KBXCAEBGSA-N (3as,7ar)-2-(4-fluorobenzoyl)-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical compound C1=CC(F)=CC=C1C(=O)N1C[C@H]2C(=O)N(C=3C=CC(OC(F)(F)F)=CC=3)CC[C@H]2C1 MFAMMXPGEWSZTR-KBXCAEBGSA-N 0.000 claims description 2
- WPSQOKLLQVOTBZ-SCLBCKFNSA-N (3as,7ar)-2-(4-fluorophenyl)sulfonyl-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical compound C1=CC(F)=CC=C1S(=O)(=O)N1C[C@H]2C(=O)N(C=3C=CC(OC(F)(F)F)=CC=3)CC[C@H]2C1 WPSQOKLLQVOTBZ-SCLBCKFNSA-N 0.000 claims description 2
- UVQXTGZXMGDYMH-GHTZIAJQSA-N (3as,7ar)-2-(4-propan-2-ylbenzoyl)-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical compound C1=CC(C(C)C)=CC=C1C(=O)N1C[C@H]2C(=O)N(C=3C=CC(OC(F)(F)F)=CC=3)CC[C@H]2C1 UVQXTGZXMGDYMH-GHTZIAJQSA-N 0.000 claims description 2
- DXVHIIDHQSBIDF-HNAYVOBHSA-N (3as,7ar)-2-[(4-fluorophenyl)methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical compound C1=CC(F)=CC=C1CN1C[C@H]2C(=O)N(C=3C=CC(OC(F)(F)F)=CC=3)CC[C@H]2C1 DXVHIIDHQSBIDF-HNAYVOBHSA-N 0.000 claims description 2
- VTFOQHWGMPFGSF-SCLBCKFNSA-N (3as,7ar)-4-oxo-n,5-bis[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridine-2-carboxamide Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC(=O)N1C[C@H]2C(=O)N(C=3C=CC(OC(F)(F)F)=CC=3)CC[C@H]2C1 VTFOQHWGMPFGSF-SCLBCKFNSA-N 0.000 claims description 2
- RPGIAZHLHQUFBN-SCLBCKFNSA-N (3as,7ar)-n-(4-fluorophenyl)-4-oxo-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridine-2-carboxamide Chemical compound C1=CC(F)=CC=C1NC(=O)N1C[C@H]2C(=O)N(C=3C=CC(OC(F)(F)F)=CC=3)CC[C@H]2C1 RPGIAZHLHQUFBN-SCLBCKFNSA-N 0.000 claims description 2
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 claims description 2
- NYMDZLNOQPHCMN-CJNGLKHVSA-N tert-butyl (3ar,7as)-4-oxo-5-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridine-2-carboxylate Chemical compound C([C@@H]1CN(C[C@@H]1C1=O)C(=O)OC(C)(C)C)CN1C1=CC=C(OCC(F)(F)F)C=C1 NYMDZLNOQPHCMN-CJNGLKHVSA-N 0.000 claims description 2
- LMSUQMJAMATPBV-DOMZBBRYSA-N tert-butyl (3ar,7as)-4-oxo-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridine-2-carboxylate Chemical compound C([C@@H]1CN(C[C@@H]1C1=O)C(=O)OC(C)(C)C)CN1C1=CC=C(OC(F)(F)F)C=C1 LMSUQMJAMATPBV-DOMZBBRYSA-N 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 59
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 104
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 94
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 80
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 59
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 54
- 238000005160 1H NMR spectroscopy Methods 0.000 description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- RUZIVNMLRPKBGI-UHFFFAOYSA-N 1-(2-phenylacetyl)-5-[4-(trifluoromethoxy)phenyl]-2,3,3a,6,7,7a-hexahydro-1h-pyrrolo[3,4-c]pyridin-4-one Chemical compound C1=CC(OC(F)(F)F)=CC=C1N1C(=O)C(CNC2C(=O)CC=3C=CC=CC=3)C2CC1 RUZIVNMLRPKBGI-UHFFFAOYSA-N 0.000 description 33
- 235000019439 ethyl acetate Nutrition 0.000 description 28
- 239000000243 solution Substances 0.000 description 28
- 230000015572 biosynthetic process Effects 0.000 description 27
- 238000003786 synthesis reaction Methods 0.000 description 27
- 239000003208 petroleum Substances 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 15
- 125000003884 phenylalkyl group Chemical group 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- RNJLGPSFLHGBEX-UHFFFAOYSA-N 5-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3,3a,6,7,7a-hexahydro-1h-pyrrolo[3,4-c]pyridin-4-one Chemical compound C1=CC(OCC(F)(F)F)=CC=C1N1C(=O)C2CNCC2CC1 RNJLGPSFLHGBEX-UHFFFAOYSA-N 0.000 description 13
- 239000007832 Na2SO4 Substances 0.000 description 13
- 125000004438 haloalkoxy group Chemical group 0.000 description 13
- 229910052938 sodium sulfate Inorganic materials 0.000 description 13
- 239000012267 brine Substances 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
- 238000001035 drying Methods 0.000 description 11
- 235000021588 free fatty acids Nutrition 0.000 description 11
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 125000000753 cycloalkyl group Chemical group 0.000 description 10
- 125000001072 heteroaryl group Chemical group 0.000 description 10
- 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 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 125000001188 haloalkyl group Chemical group 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- 125000005359 phenoxyalkyl group Chemical group 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 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 6
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 210000000593 adipose tissue white Anatomy 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 125000004994 halo alkoxy alkyl group Chemical group 0.000 description 6
- 239000011347 resin Substances 0.000 description 6
- 229920005989 resin Polymers 0.000 description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
- 150000003626 triacylglycerols Chemical class 0.000 description 6
- 102000004877 Insulin Human genes 0.000 description 5
- 108090001061 Insulin Proteins 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 5
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 5
- 229940125396 insulin Drugs 0.000 description 5
- 230000004130 lipolysis Effects 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 125000006345 2,2,2-trifluoroethoxymethyl group Chemical group [H]C([H])(*)OC([H])([H])C(F)(F)F 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 239000001828 Gelatine Substances 0.000 description 4
- 210000001789 adipocyte Anatomy 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- RPZAAFUKDPKTKP-UHFFFAOYSA-N n-(methoxymethyl)-1-phenyl-n-(trimethylsilylmethyl)methanamine Chemical compound COCN(C[Si](C)(C)C)CC1=CC=CC=C1 RPZAAFUKDPKTKP-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 229920005862 polyol Polymers 0.000 description 4
- 150000003077 polyols Chemical class 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical compound OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 4
- 0 ****(CC1C(N2*)=N)CC1C2=O Chemical compound ****(CC1C(N2*)=N)CC1C2=O 0.000 description 3
- LGPKFIGMLPDYEA-UHFFFAOYSA-N 1-isocyanato-4-(trifluoromethoxy)benzene Chemical compound FC(F)(F)OC1=CC=C(N=C=O)C=C1 LGPKFIGMLPDYEA-UHFFFAOYSA-N 0.000 description 3
- PLGZTKPVHAEMEI-UHFFFAOYSA-N 2-benzyl-5-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical compound C1=CC(OCC(F)(F)F)=CC=C1N1C(=O)C2CN(CC=3C=CC=CC=3)CC2CC1 PLGZTKPVHAEMEI-UHFFFAOYSA-N 0.000 description 3
- KMVZDSQHLDGKGV-UHFFFAOYSA-N 2-chlorobenzenesulfonyl chloride Chemical compound ClC1=CC=CC=C1S(Cl)(=O)=O KMVZDSQHLDGKGV-UHFFFAOYSA-N 0.000 description 3
- XUJFOSLZQITUOI-UHFFFAOYSA-N 4-(trifluoromethoxy)aniline Chemical compound NC1=CC=C(OC(F)(F)F)C=C1 XUJFOSLZQITUOI-UHFFFAOYSA-N 0.000 description 3
- DMAYBPBPEUFIHJ-UHFFFAOYSA-N 4-bromobut-1-ene Chemical compound BrCCC=C DMAYBPBPEUFIHJ-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- 206010022489 Insulin Resistance Diseases 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- SWRXCONMBQZTAJ-UHFFFAOYSA-N n-but-3-enyl-n-[4-(trifluoromethoxy)phenyl]prop-2-enamide Chemical compound FC(F)(F)OC1=CC=C(N(CCC=C)C(=O)C=C)C=C1 SWRXCONMBQZTAJ-UHFFFAOYSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 238000012746 preparative thin layer chromatography Methods 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- BSTVMUJHSFCPDF-UHFFFAOYSA-N 1-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridin-6-one Chemical compound C1=CC(OC(F)(F)F)=CC=C1N1C(=O)C=CCC1 BSTVMUJHSFCPDF-UHFFFAOYSA-N 0.000 description 2
- QNYNUXQOTWCDOQ-UHFFFAOYSA-N 1-[4-(trifluoromethoxy)phenyl]pyrrole-2,5-dione Chemical compound C1=CC(OC(F)(F)F)=CC=C1N1C(=O)C=CC1=O QNYNUXQOTWCDOQ-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- QGQKWRYEFDBIMX-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]spiro[3a,4,6,6a-tetrahydro-1h-cyclopenta[c]pyrrole-5,2'-oxirane]-3-one Chemical compound C1=CC(OC(F)(F)F)=CC=C1N1C(=O)C2CC3(OC3)CC2C1 QGQKWRYEFDBIMX-UHFFFAOYSA-N 0.000 description 2
- UMXKKYACLSLTGK-UHFFFAOYSA-N 2-benzyl-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6a-tetrahydropyrrolo[3,4-c]pyrrole-4,6-dione Chemical compound C1=CC(OC(F)(F)F)=CC=C1N1C(=O)C2CN(CC=3C=CC=CC=3)CC2C1=O UMXKKYACLSLTGK-UHFFFAOYSA-N 0.000 description 2
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 2
- GFZXQBDELXEPTQ-UHFFFAOYSA-N 3-[(3-carboxy-2-nitrophenyl)disulfanyl]-2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC(SSC=2C(=C(C(O)=O)C=CC=2)[N+]([O-])=O)=C1[N+]([O-])=O GFZXQBDELXEPTQ-UHFFFAOYSA-N 0.000 description 2
- NGLACRZGEXFSMJ-UHFFFAOYSA-N 4-oxo-n,5-bis[4-(trifluoromethoxy)phenyl]-3,3a,6,6a-tetrahydro-1h-pyrrolo[3,4-c]pyrrole-2-carboxamide Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC(=O)N1CC2C(=O)N(C=3C=CC(OC(F)(F)F)=CC=3)CC2C1 NGLACRZGEXFSMJ-UHFFFAOYSA-N 0.000 description 2
- GIWADSRKPWKRSQ-UHFFFAOYSA-N 5-[4-(trifluoromethoxy)phenyl]-2,3,3a,6,7,7a-hexahydro-1h-pyrrolo[3,4-c]pyridin-4-one Chemical compound C1=CC(OC(F)(F)F)=CC=C1N1C(=O)C2CNCC2CC1 GIWADSRKPWKRSQ-UHFFFAOYSA-N 0.000 description 2
- CXYMCJJYMKWPKD-UHFFFAOYSA-N 5-amino-2-[4-(trifluoromethoxy)phenyl]-1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrol-3-one Chemical compound O=C1C2CC(N)CC2CN1C1=CC=C(OC(F)(F)F)C=C1 CXYMCJJYMKWPKD-UHFFFAOYSA-N 0.000 description 2
- ZOSXIEYYQRCFQH-UHFFFAOYSA-N 5-hydroxy-5-(2,2,2-trifluoroethoxymethyl)-2-[4-(trifluoromethoxy)phenyl]-3a,4,6,6a-tetrahydro-1h-cyclopenta[c]pyrrol-3-one Chemical class O=C1C2CC(O)(COCC(F)(F)F)CC2CN1C1=CC=C(OC(F)(F)F)C=C1 ZOSXIEYYQRCFQH-UHFFFAOYSA-N 0.000 description 2
- SNVFIFXXEAAXLK-UHFFFAOYSA-N 5-hydroxy-5-propyl-2-[4-(trifluoromethoxy)phenyl]-3a,4,6,6a-tetrahydro-1h-cyclopenta[c]pyrrol-3-one Chemical class O=C1C2CC(CCC)(O)CC2CN1C1=CC=C(OC(F)(F)F)C=C1 SNVFIFXXEAAXLK-UHFFFAOYSA-N 0.000 description 2
- ONFUGJXBVKZEEJ-UHFFFAOYSA-N 5-methylidene-2-[4-(trifluoromethoxy)phenyl]-3a,4,6,6a-tetrahydro-1h-cyclopenta[c]pyrrol-3-one Chemical class C1=CC(OC(F)(F)F)=CC=C1N1C(=O)C2CC(=C)CC2C1 ONFUGJXBVKZEEJ-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- 229910004664 Cerium(III) chloride Inorganic materials 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 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 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 101001005187 Homo sapiens Hormone-sensitive lipase Proteins 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 229910006124 SOCl2 Inorganic materials 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 108010062497 VLDL Lipoproteins Proteins 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 125000005594 diketone group Chemical group 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000003821 enantio-separation Methods 0.000 description 2
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 2
- AKFDBWIUWIWHRK-UHFFFAOYSA-N ethyl 2-amino-4-thiophen-2-ylthiophene-3-carboxylate Chemical compound CCOC(=O)C1=C(N)SC=C1C1=CC=CS1 AKFDBWIUWIWHRK-UHFFFAOYSA-N 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 208000015707 frontal fibrosing alopecia Diseases 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 150000003951 lactams Chemical class 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 230000002366 lipolytic effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- ZULCEIBVVTUFFN-UHFFFAOYSA-N n-but-3-enyl-4-(trifluoromethoxy)aniline Chemical compound FC(F)(F)OC1=CC=C(NCCC=C)C=C1 ZULCEIBVVTUFFN-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- DOYOPBSXEIZLRE-UHFFFAOYSA-N pyrrole-3-carboxylic acid Natural products OC(=O)C=1C=CNC=1 DOYOPBSXEIZLRE-UHFFFAOYSA-N 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- KNLKRAUJQBLECR-UHFFFAOYSA-N tert-butyl pyridine-2-carboxylate Chemical compound CC(C)(C)OC(=O)C1=CC=CC=N1 KNLKRAUJQBLECR-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Substances ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000003652 trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- UTIMXNSQVSYIOG-PBHICJAKSA-N (3ar,7as)-2-(2-hydroxyphenyl)-5-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical compound OC1=CC=CC=C1N1C[C@@H]2C(=O)N(C=3C=CC(OCC(F)(F)F)=CC=3)CC[C@@H]2C1 UTIMXNSQVSYIOG-PBHICJAKSA-N 0.000 description 1
- DRCWOKJLSQUJPZ-DZGCQCFKSA-N (4ar,9as)-n-ethyl-1,4,9,9a-tetrahydrofluoren-4a-amine Chemical compound C1C2=CC=CC=C2[C@]2(NCC)[C@H]1CC=CC2 DRCWOKJLSQUJPZ-DZGCQCFKSA-N 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- FIARMZDBEGVMLV-UHFFFAOYSA-N 1,1,2,2,2-pentafluoroethanolate Chemical group [O-]C(F)(F)C(F)(F)F FIARMZDBEGVMLV-UHFFFAOYSA-N 0.000 description 1
- SDRXORFVMCHESD-UHFFFAOYSA-N 1-(2-phenylacetyl)-5-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3,3a,6,7,7a-hexahydro-1h-pyrrolo[3,4-c]pyridin-4-one Chemical class C1=CC(OCC(F)(F)F)=CC=C1N1C(=O)C(CNC2C(=O)CC=3C=CC=CC=3)C2CC1 SDRXORFVMCHESD-UHFFFAOYSA-N 0.000 description 1
- NVNPLEPBDPJYRZ-UHFFFAOYSA-N 1-(bromomethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CBr)C=C1 NVNPLEPBDPJYRZ-UHFFFAOYSA-N 0.000 description 1
- BZSVGLXRSWLSNA-UHFFFAOYSA-N 1-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyridin-6-one Chemical compound C1=CC(OCC(F)(F)F)=CC=C1N1C(=O)C=CCC1 BZSVGLXRSWLSNA-UHFFFAOYSA-N 0.000 description 1
- DSVGFKBFFICWLZ-UHFFFAOYSA-N 1-fluoro-4-isocyanatobenzene Chemical compound FC1=CC=C(N=C=O)C=C1 DSVGFKBFFICWLZ-UHFFFAOYSA-N 0.000 description 1
- CGHHKOALSROLLD-UHFFFAOYSA-N 1-hydroxy-5-methylidene-2-[4-(trifluoromethoxy)phenyl]-3a,4,6,6a-tetrahydro-1h-cyclopenta[c]pyrrol-3-one Chemical compound OC1C2CC(=C)CC2C(=O)N1C1=CC=C(OC(F)(F)F)C=C1 CGHHKOALSROLLD-UHFFFAOYSA-N 0.000 description 1
- DVQWNQBEUKXONL-UHFFFAOYSA-N 1-iodo-2-methoxybenzene Chemical compound COC1=CC=CC=C1I DVQWNQBEUKXONL-UHFFFAOYSA-N 0.000 description 1
- UTWATDQGGKALAL-UHFFFAOYSA-N 2-(2-chlorobenzoyl)-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical class C1=CC(OC(F)(F)F)=CC=C1N1C(=O)C2CN(C(=O)C=3C(=CC=CC=3)Cl)CC2CC1 UTWATDQGGKALAL-UHFFFAOYSA-N 0.000 description 1
- JWCAWYZVCBQCHU-UHFFFAOYSA-N 2-(2-chlorophenyl)sulfonyl-5-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical class C1=CC(OCC(F)(F)F)=CC=C1N1C(=O)C2CN(S(=O)(=O)C=3C(=CC=CC=3)Cl)CC2CC1 JWCAWYZVCBQCHU-UHFFFAOYSA-N 0.000 description 1
- IOHFWOZJENTFLA-UHFFFAOYSA-N 2-(2-chlorophenyl)sulfonyl-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical class C1=CC(OC(F)(F)F)=CC=C1N1C(=O)C2CN(S(=O)(=O)C=3C(=CC=CC=3)Cl)CC2CC1 IOHFWOZJENTFLA-UHFFFAOYSA-N 0.000 description 1
- URZPTRWITOLAHH-UHFFFAOYSA-N 2-(2-chloropyridin-3-yl)sulfonyl-5-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical class C1=CC(OCC(F)(F)F)=CC=C1N1C(=O)C2CN(S(=O)(=O)C=3C(=NC=CC=3)Cl)CC2CC1 URZPTRWITOLAHH-UHFFFAOYSA-N 0.000 description 1
- UTIMXNSQVSYIOG-UHFFFAOYSA-N 2-(2-hydroxyphenyl)-5-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical class OC1=CC=CC=C1N1CC2C(=O)N(C=3C=CC(OCC(F)(F)F)=CC=3)CCC2C1 UTIMXNSQVSYIOG-UHFFFAOYSA-N 0.000 description 1
- YXAQHOMOMXWBST-UHFFFAOYSA-N 2-(2-methylpropylsulfonyl)-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical class O=C1C2CN(S(=O)(=O)CC(C)C)CC2CCN1C1=CC=C(OC(F)(F)F)C=C1 YXAQHOMOMXWBST-UHFFFAOYSA-N 0.000 description 1
- DWUJDNHHQKEOPR-UHFFFAOYSA-N 2-(2-piperidin-4-ylethyl)pyridine Chemical compound C1CNCCC1CCC1=CC=CC=N1 DWUJDNHHQKEOPR-UHFFFAOYSA-N 0.000 description 1
- TUTZPAJFLXAIQH-UHFFFAOYSA-N 2-(3,3-dimethylbutanoyl)-5-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical class O=C1C2CN(C(=O)CC(C)(C)C)CC2CCN1C1=CC=C(OCC(F)(F)F)C=C1 TUTZPAJFLXAIQH-UHFFFAOYSA-N 0.000 description 1
- FIADIBYFRWITEN-UHFFFAOYSA-N 2-(3-methylbutanoyl)-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical class O=C1C2CN(C(=O)CC(C)C)CC2CCN1C1=CC=C(OC(F)(F)F)C=C1 FIADIBYFRWITEN-UHFFFAOYSA-N 0.000 description 1
- TWMYWSDGOVHDKS-UHFFFAOYSA-N 2-(3-methylbutylsulfonyl)-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical class O=C1C2CN(S(=O)(=O)CCC(C)C)CC2CCN1C1=CC=C(OC(F)(F)F)C=C1 TWMYWSDGOVHDKS-UHFFFAOYSA-N 0.000 description 1
- MFAMMXPGEWSZTR-UHFFFAOYSA-N 2-(4-fluorobenzoyl)-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical class C1=CC(F)=CC=C1C(=O)N1CC2C(=O)N(C=3C=CC(OC(F)(F)F)=CC=3)CCC2C1 MFAMMXPGEWSZTR-UHFFFAOYSA-N 0.000 description 1
- HUPVBFQYJHFONM-UHFFFAOYSA-N 2-(4-fluorophenyl)acetamide Chemical compound NC(=O)CC1=CC=C(F)C=C1 HUPVBFQYJHFONM-UHFFFAOYSA-N 0.000 description 1
- WPSQOKLLQVOTBZ-UHFFFAOYSA-N 2-(4-fluorophenyl)sulfonyl-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical class C1=CC(F)=CC=C1S(=O)(=O)N1CC2C(=O)N(C=3C=CC(OC(F)(F)F)=CC=3)CCC2C1 WPSQOKLLQVOTBZ-UHFFFAOYSA-N 0.000 description 1
- UVQXTGZXMGDYMH-UHFFFAOYSA-N 2-(4-propan-2-ylbenzoyl)-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical class C1=CC(C(C)C)=CC=C1C(=O)N1CC2C(=O)N(C=3C=CC(OC(F)(F)F)=CC=3)CCC2C1 UVQXTGZXMGDYMH-UHFFFAOYSA-N 0.000 description 1
- QLGSFDRAOBTLSJ-UHFFFAOYSA-N 2-(benzenesulfonyl)-5-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical class C1=CC(OCC(F)(F)F)=CC=C1N1C(=O)C2CN(S(=O)(=O)C=3C=CC=CC=3)CC2CC1 QLGSFDRAOBTLSJ-UHFFFAOYSA-N 0.000 description 1
- CPHXLFKIUVVIOQ-UHFFFAOYSA-N 2-(trifluoromethoxy)benzaldehyde Chemical group FC(F)(F)OC1=CC=CC=C1C=O CPHXLFKIUVVIOQ-UHFFFAOYSA-N 0.000 description 1
- JLTBWYIUMFEOTN-UHFFFAOYSA-N 2-(trifluoromethoxy)benzenesulfonyl chloride Chemical compound FC(F)(F)OC1=CC=CC=C1S(Cl)(=O)=O JLTBWYIUMFEOTN-UHFFFAOYSA-N 0.000 description 1
- ZIZGWNOAHUCACM-UHFFFAOYSA-N 2-(trifluoromethyl)benzenesulfonyl chloride Chemical compound FC(F)(F)C1=CC=CC=C1S(Cl)(=O)=O ZIZGWNOAHUCACM-UHFFFAOYSA-N 0.000 description 1
- DXVHIIDHQSBIDF-UHFFFAOYSA-N 2-[(4-fluorophenyl)methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical class C1=CC(F)=CC=C1CN1CC2C(=O)N(C=3C=CC(OC(F)(F)F)=CC=3)CCC2C1 DXVHIIDHQSBIDF-UHFFFAOYSA-N 0.000 description 1
- TZYWCWPNWKEQCG-UHFFFAOYSA-N 2-[2-(2,4-dichlorophenyl)-2-hydroxyethyl]-5-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical class C=1C=C(Cl)C=C(Cl)C=1C(O)CN(CC1C2=O)CC1CCN2C1=CC=C(OCC(F)(F)F)C=C1 TZYWCWPNWKEQCG-UHFFFAOYSA-N 0.000 description 1
- VUKYNERAKZLTOZ-UHFFFAOYSA-N 2-[2-(4-fluorophenyl)acetyl]-5-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical class C1=CC(F)=CC=C1CC(=O)N1CC2C(=O)N(C=3C=CC(OCC(F)(F)F)=CC=3)CCC2C1 VUKYNERAKZLTOZ-UHFFFAOYSA-N 0.000 description 1
- BMTUEDGSYHQHFI-UHFFFAOYSA-N 2-[2-(4-methylphenyl)acetyl]-5-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical class C1=CC(C)=CC=C1CC(=O)N1CC2C(=O)N(C=3C=CC(OCC(F)(F)F)=CC=3)CCC2C1 BMTUEDGSYHQHFI-UHFFFAOYSA-N 0.000 description 1
- ZAVLPXGIJMECTG-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]-3a,4,6,6a-tetrahydro-1h-cyclopenta[c]pyrrole-3,5-dione Chemical compound C1=CC(OC(F)(F)F)=CC=C1N1C(=O)C2CC(=O)CC2C1 ZAVLPXGIJMECTG-UHFFFAOYSA-N 0.000 description 1
- DZNMJWXPFCSZLX-UHFFFAOYSA-N 2-benzyl-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical compound C1=CC(OC(F)(F)F)=CC=C1N1C(=O)C2CN(CC=3C=CC=CC=3)CC2CC1 DZNMJWXPFCSZLX-UHFFFAOYSA-N 0.000 description 1
- UJVOECHXMLWTHK-UHFFFAOYSA-N 2-benzyl-5-[4-(trifluoromethoxy)phenyl]-3,3a,6,6a-tetrahydro-1h-pyrrolo[3,4-c]pyrrol-4-one Chemical compound C1=CC(OC(F)(F)F)=CC=C1N1C(=O)C2CN(CC=3C=CC=CC=3)CC2C1 UJVOECHXMLWTHK-UHFFFAOYSA-N 0.000 description 1
- NZVPUVWQXQWSQS-UHFFFAOYSA-N 2-benzyl-6-hydroxy-5-[4-(trifluoromethoxy)phenyl]-3,3a,6,6a-tetrahydro-1h-pyrrolo[3,4-c]pyrrol-4-one Chemical compound C1C2C(=O)N(C=3C=CC(OC(F)(F)F)=CC=3)C(O)C2CN1CC1=CC=CC=C1 NZVPUVWQXQWSQS-UHFFFAOYSA-N 0.000 description 1
- ABDCELHRYJDOPX-UHFFFAOYSA-N 2-benzylsulfonyl-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical class C1=CC(OC(F)(F)F)=CC=C1N1C(=O)C2CN(S(=O)(=O)CC=3C=CC=CC=3)CC2CC1 ABDCELHRYJDOPX-UHFFFAOYSA-N 0.000 description 1
- DASJDMQCPIDJIF-UHFFFAOYSA-N 2-bromo-1-(2,4-dichlorophenyl)ethanone Chemical compound ClC1=CC=C(C(=O)CBr)C(Cl)=C1 DASJDMQCPIDJIF-UHFFFAOYSA-N 0.000 description 1
- UEBARDWJXBGYEJ-UHFFFAOYSA-N 2-bromo-3-methylbutanoic acid Chemical compound CC(C)C(Br)C(O)=O UEBARDWJXBGYEJ-UHFFFAOYSA-N 0.000 description 1
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 description 1
- MFJSIQDQIZEVJX-UHFFFAOYSA-N 2-chloropyridine-3-sulfonyl chloride Chemical compound ClC1=NC=CC=C1S(Cl)(=O)=O MFJSIQDQIZEVJX-UHFFFAOYSA-N 0.000 description 1
- NQLNHTOCFWUYQE-UHFFFAOYSA-N 2-methylpropane-1-sulfonyl chloride Chemical compound CC(C)CS(Cl)(=O)=O NQLNHTOCFWUYQE-UHFFFAOYSA-N 0.000 description 1
- APIXJSLKIYYUKG-UHFFFAOYSA-N 3 Isobutyl 1 methylxanthine Chemical compound O=C1N(C)C(=O)N(CC(C)C)C2=C1N=CN2 APIXJSLKIYYUKG-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- CAOXTJCSAJIUGW-UHFFFAOYSA-N 3-methylbutane-1-sulfonyl chloride Chemical compound CC(C)CCS(Cl)(=O)=O CAOXTJCSAJIUGW-UHFFFAOYSA-N 0.000 description 1
- ISULZYQDGYXDFW-UHFFFAOYSA-N 3-methylbutanoyl chloride Chemical compound CC(C)CC(Cl)=O ISULZYQDGYXDFW-UHFFFAOYSA-N 0.000 description 1
- OXFDNUZWKFKMSB-UHFFFAOYSA-N 4-(2,2,2-trifluoroethoxy)aniline Chemical compound NC1=CC=C(OCC(F)(F)F)C=C1 OXFDNUZWKFKMSB-UHFFFAOYSA-N 0.000 description 1
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 description 1
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 1
- BFXHJFKKRGVUMU-UHFFFAOYSA-N 4-fluorobenzenesulfonyl chloride Chemical compound FC1=CC=C(S(Cl)(=O)=O)C=C1 BFXHJFKKRGVUMU-UHFFFAOYSA-N 0.000 description 1
- CZKLEJHVLCMVQR-UHFFFAOYSA-N 4-fluorobenzoyl chloride Chemical compound FC1=CC=C(C(Cl)=O)C=C1 CZKLEJHVLCMVQR-UHFFFAOYSA-N 0.000 description 1
- VTFOQHWGMPFGSF-UHFFFAOYSA-N 4-oxo-n,5-bis[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridine-2-carboxamide Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC(=O)N1CC2C(=O)N(C=3C=CC(OC(F)(F)F)=CC=3)CCC2C1 VTFOQHWGMPFGSF-UHFFFAOYSA-N 0.000 description 1
- LBSYWDTVBUZMCM-UHFFFAOYSA-N 4-propan-2-ylbenzoyl chloride Chemical compound CC(C)C1=CC=C(C(Cl)=O)C=C1 LBSYWDTVBUZMCM-UHFFFAOYSA-N 0.000 description 1
- BVXPXCFIGDWPIB-UHFFFAOYSA-N 5-(4-ethylphenyl)-4-oxo-n-[4-(trifluoromethoxy)phenyl]-3,3a,6,6a-tetrahydro-1h-pyrrolo[3,4-c]pyrrole-2-carboxamide Chemical compound C1=CC(CC)=CC=C1N1C(=O)C2CN(C(=O)NC=3C=CC(OC(F)(F)F)=CC=3)CC2C1 BVXPXCFIGDWPIB-UHFFFAOYSA-N 0.000 description 1
- JQQBOTWLJXCTBZ-UHFFFAOYSA-N 5-(anilinomethyl)-5-hydroxy-2-[4-(trifluoromethoxy)phenyl]-3a,4,6,6a-tetrahydro-1h-cyclopenta[c]pyrrol-3-one Chemical class C1C2CN(C=3C=CC(OC(F)(F)F)=CC=3)C(=O)C2CC1(O)CNC1=CC=CC=C1 JQQBOTWLJXCTBZ-UHFFFAOYSA-N 0.000 description 1
- WSMXZJUTFKSJII-UHFFFAOYSA-N 5-(benzylamino)-2-[4-(trifluoromethoxy)phenyl]-1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrol-3-one Chemical compound C1=CC(OC(F)(F)F)=CC=C1N1C(=O)C2CC(NCC=3C=CC=CC=3)CC2C1 WSMXZJUTFKSJII-UHFFFAOYSA-N 0.000 description 1
- ICURKDZAOKAZKG-UHFFFAOYSA-N 5-(butoxymethyl)-5-hydroxy-2-[4-(trifluoromethoxy)phenyl]-3a,4,6,6a-tetrahydro-1h-cyclopenta[c]pyrrol-3-one Chemical class O=C1C2CC(COCCCC)(O)CC2CN1C1=CC=C(OC(F)(F)F)C=C1 ICURKDZAOKAZKG-UHFFFAOYSA-N 0.000 description 1
- IPEMCIBPDYCJLO-UHFFFAOYSA-N 5-[(3,5,5,8,8-pentamethyl-6,7-dihydronaphthalen-2-yl)methyl]-n-(2,4,6-trimethoxyphenyl)furan-2-carboxamide Chemical compound COC1=CC(OC)=CC(OC)=C1NC(=O)C(O1)=CC=C1CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C IPEMCIBPDYCJLO-UHFFFAOYSA-N 0.000 description 1
- OOPXPUHSUWIQHN-UHFFFAOYSA-N 5-[4-(2,2,2-trifluoroethoxy)phenyl]-2-[2-(trifluoromethoxy)phenyl]sulfonyl-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical class C1=CC(OCC(F)(F)F)=CC=C1N1C(=O)C2CN(S(=O)(=O)C=3C(=CC=CC=3)OC(F)(F)F)CC2CC1 OOPXPUHSUWIQHN-UHFFFAOYSA-N 0.000 description 1
- BWVIKPJQQKIUGB-UHFFFAOYSA-N 5-[4-(2,2,2-trifluoroethoxy)phenyl]-2-[2-(trifluoromethyl)phenyl]sulfonyl-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-4-one Chemical class C1=CC(OCC(F)(F)F)=CC=C1N1C(=O)C2CN(S(=O)(=O)C=3C(=CC=CC=3)C(F)(F)F)CC2CC1 BWVIKPJQQKIUGB-UHFFFAOYSA-N 0.000 description 1
- PNJQIGZDUWZJKH-UHFFFAOYSA-N 5-[4-(trifluoromethoxy)phenyl]-1,2,3,3a,6,6a-hexahydropyrrolo[3,4-c]pyrrol-4-one Chemical compound C1=CC(OC(F)(F)F)=CC=C1N1C(=O)C2CNCC2C1 PNJQIGZDUWZJKH-UHFFFAOYSA-N 0.000 description 1
- FWMIDUCEURWGLJ-UHFFFAOYSA-N 5-hydroxy-5-(phenoxymethyl)-2-[4-(trifluoromethoxy)phenyl]-3a,4,6,6a-tetrahydro-1h-cyclopenta[c]pyrrol-3-one Chemical class C1C2CN(C=3C=CC(OC(F)(F)F)=CC=3)C(=O)C2CC1(O)COC1=CC=CC=C1 FWMIDUCEURWGLJ-UHFFFAOYSA-N 0.000 description 1
- UQTFGVGNOYPZBT-UHFFFAOYSA-N 5-hydroxy-5-(propoxymethyl)-2-[4-(trifluoromethoxy)phenyl]-3a,4,6,6a-tetrahydro-1h-cyclopenta[c]pyrrol-3-one Chemical class O=C1C2CC(COCCC)(O)CC2CN1C1=CC=C(OC(F)(F)F)C=C1 UQTFGVGNOYPZBT-UHFFFAOYSA-N 0.000 description 1
- WBBNUKYIAWVFMJ-UHFFFAOYSA-N 5-methylidene-2-[4-(trifluoromethoxy)phenyl]-3a,4,6,6a-tetrahydrocyclopenta[c]pyrrole-1,3-dione Chemical compound C1=CC(OC(F)(F)F)=CC=C1N1C(=O)C2CC(=C)CC2C1=O WBBNUKYIAWVFMJ-UHFFFAOYSA-N 0.000 description 1
- VPCZJTZBDBBKCG-UHFFFAOYSA-N 5-methylidene-3a,4,6,6a-tetrahydrocyclopenta[c]furan-1,3-dione Chemical compound O=C1OC(=O)C2C1CC(=C)C2 VPCZJTZBDBBKCG-UHFFFAOYSA-N 0.000 description 1
- DHSSDEDRBUKTQY-UHFFFAOYSA-N 6-prop-2-enyl-4,5,7,8-tetrahydrothiazolo[4,5-d]azepin-2-amine Chemical compound C1CN(CC=C)CCC2=C1N=C(N)S2 DHSSDEDRBUKTQY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical group NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 1
- DBTSVVNRZUFBAX-AVVWSFFYSA-N CC(C)CC(N(CC1CCN2C(C=C3)=CCC3OC(F)(F)F)C[C@H]1C2=O)=O Chemical compound CC(C)CC(N(CC1CCN2C(C=C3)=CCC3OC(F)(F)F)C[C@H]1C2=O)=O DBTSVVNRZUFBAX-AVVWSFFYSA-N 0.000 description 1
- NPZUIIGVXNTSBU-GHTZIAJQSA-N CC(C)c(cc1)ccc1C(N(C[C@@H]1CCN2C(CC3)=CC=C3OC(F)(F)F)C[C@H]1C2=O)=O Chemical compound CC(C)c(cc1)ccc1C(N(C[C@@H]1CCN2C(CC3)=CC=C3OC(F)(F)F)C[C@H]1C2=O)=O NPZUIIGVXNTSBU-GHTZIAJQSA-N 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- SUZLHDUTVMZSEV-UHFFFAOYSA-N Deoxycoleonol Natural products C12C(=O)CC(C)(C=C)OC2(C)C(OC(=O)C)C(O)C2C1(C)C(O)CCC2(C)C SUZLHDUTVMZSEV-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000051325 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 101001008429 Homo sapiens Nucleobindin-2 Proteins 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 102100027441 Nucleobindin-2 Human genes 0.000 description 1
- ZAVLPXGIJMECTG-KBPLZSHQSA-N O=C(C[C@H]1CN2c(cc3)ccc3OC(F)(F)F)CC1C2=O Chemical compound O=C(C[C@H]1CN2c(cc3)ccc3OC(F)(F)F)CC1C2=O ZAVLPXGIJMECTG-KBPLZSHQSA-N 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 238000010958 [3+2] cycloaddition reaction Methods 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000005874 benzothiadiazolyl group Chemical group 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- PNPBGYBHLCEVMK-UHFFFAOYSA-L benzylidene(dichloro)ruthenium;tricyclohexylphosphane Chemical compound Cl[Ru](Cl)=CC1=CC=CC=C1.C1CCCCC1P(C1CCCCC1)C1CCCCC1.C1CCCCC1P(C1CCCCC1)C1CCCCC1 PNPBGYBHLCEVMK-UHFFFAOYSA-L 0.000 description 1
- PNPBGYBHLCEVMK-UHFFFAOYSA-N benzylidene(dichloro)ruthenium;tricyclohexylphosphanium Chemical compound Cl[Ru](Cl)=CC1=CC=CC=C1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1 PNPBGYBHLCEVMK-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- OHCQJHSOBUTRHG-UHFFFAOYSA-N colforsin Natural products OC12C(=O)CC(C)(C=C)OC1(C)C(OC(=O)C)C(O)C1C2(C)C(O)CCC1(C)C OHCQJHSOBUTRHG-UHFFFAOYSA-N 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007398 colorimetric assay Methods 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- CNXMDTWQWLGCPE-UHFFFAOYSA-N ditert-butyl-(2-phenylphenyl)phosphane Chemical group CC(C)(C)P(C(C)(C)C)C1=CC=CC=C1C1=CC=CC=C1 CNXMDTWQWLGCPE-UHFFFAOYSA-N 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000006232 ethoxy propyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 239000011984 grubbs catalyst Substances 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 210000001596 intra-abdominal fat Anatomy 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- UGVPKMAWLOMPRS-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].CC[CH2-] UGVPKMAWLOMPRS-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- SDRNBXQJIXBCGH-UHFFFAOYSA-N n-(4-fluorophenyl)-3-methyl-2-[4-oxo-5-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridin-2-yl]butanamide Chemical compound C=1C=C(F)C=CC=1NC(=O)C(C(C)C)N(CC1C2=O)CC1CCN2C1=CC=C(OCC(F)(F)F)C=C1 SDRNBXQJIXBCGH-UHFFFAOYSA-N 0.000 description 1
- RPGIAZHLHQUFBN-UHFFFAOYSA-N n-(4-fluorophenyl)-4-oxo-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridine-2-carboxamide Chemical compound C1=CC(F)=CC=C1NC(=O)N1CC2C(=O)N(C=3C=CC(OC(F)(F)F)=CC=3)CCC2C1 RPGIAZHLHQUFBN-UHFFFAOYSA-N 0.000 description 1
- USFWWLVSLZRYOV-UHFFFAOYSA-N n-but-3-enyl-4-(2,2,2-trifluoroethoxy)aniline Chemical compound FC(F)(F)COC1=CC=C(NCCC=C)C=C1 USFWWLVSLZRYOV-UHFFFAOYSA-N 0.000 description 1
- AEFMNUPCJTZMMW-UHFFFAOYSA-N n-but-3-enyl-n-[4-(2,2,2-trifluoroethoxy)phenyl]prop-2-enamide Chemical compound FC(F)(F)COC1=CC=C(N(CCC=C)C(=O)C=C)C=C1 AEFMNUPCJTZMMW-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000005949 ozonolysis reaction Methods 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 229950000964 pepstatin Drugs 0.000 description 1
- 108010091212 pepstatin Proteins 0.000 description 1
- FAXGPCHRFPCXOO-LXTPJMTPSA-N pepstatin A Chemical compound OC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC(=O)CC(C)C FAXGPCHRFPCXOO-LXTPJMTPSA-N 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- OAHKWDDSKCRNFE-UHFFFAOYSA-N phenylmethanesulfonyl chloride Chemical compound ClS(=O)(=O)CC1=CC=CC=C1 OAHKWDDSKCRNFE-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 210000000229 preadipocyte Anatomy 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000011012 sanitization Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- NYMDZLNOQPHCMN-UHFFFAOYSA-N tert-butyl 4-oxo-5-[4-(2,2,2-trifluoroethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridine-2-carboxylate Chemical compound O=C1C2CN(C(=O)OC(C)(C)C)CC2CCN1C1=CC=C(OCC(F)(F)F)C=C1 NYMDZLNOQPHCMN-UHFFFAOYSA-N 0.000 description 1
- LMSUQMJAMATPBV-UHFFFAOYSA-N tert-butyl 4-oxo-5-[4-(trifluoromethoxy)phenyl]-1,3,3a,6,7,7a-hexahydropyrrolo[3,4-c]pyridine-2-carboxylate Chemical compound O=C1C2CN(C(=O)OC(C)(C)C)CC2CCN1C1=CC=C(OC(F)(F)F)C=C1 LMSUQMJAMATPBV-UHFFFAOYSA-N 0.000 description 1
- QUBUSXXKRKBHSO-UHFFFAOYSA-N tert-butyl 4-oxo-5-[4-(trifluoromethoxy)phenyl]-3,3a,6,6a-tetrahydro-1h-pyrrolo[3,4-c]pyrrole-2-carboxylate Chemical compound O=C1C2CN(C(=O)OC(C)(C)C)CC2CN1C1=CC=C(OC(F)(F)F)C=C1 QUBUSXXKRKBHSO-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical group 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Endocrinology (AREA)
- Urology & Nephrology (AREA)
- Emergency Medicine (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Child & Adolescent Psychology (AREA)
- Gastroenterology & Hepatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
Abstract
本发明提供具有通式(I)的新型化合物,其中R1,R2,A,E,G和n如本文中所述,以及提供包含所述化合物的组合物和使用所述化合物的方法。
Description
本发明涉及可用于哺乳动物中的治疗或预防的有机化合物,并且尤其涉及用于治疗糖尿病、代谢综合征、异常脂肪血症、动脉粥样硬化、肥胖症、心血管病、心肌功能障碍、炎症、非酒精性脂肪肝病或非酒精性脂肪肝炎的激素敏感脂酶(HSL)的抑制剂。
本发明提供新型的式(I)的化合物
其中,
R1是烷基,卤代烷基,烷氧基烷基,卤代烷氧基烷基,羟基烷基,苯基,取代的苯基,苯基烷基,取代的苯基烷基,苯氧基烷基,取代的苯氧基烷基,杂芳基,取代的杂芳基,杂芳基烷基或取代的杂芳基烷基,其中取代的苯基,取代的苯基烷基,取代的苯氧基烷基,取代的杂芳基和取代的杂芳基烷基被独立地选自烷基,环烷基,环烷基烷基,卤素,卤代烷基,羟基,羟基烷基,烷氧基,烷氧基烷基,卤代烷氧基,羟基卤代烷基和烷氧基卤代烷基中的一至三个取代基取代;
R2是苯基,取代的苯基,杂芳基或取代的杂芳基,其中取代的苯基和取代的杂芳基被独立地选自烷基,环烷基,环烷基烷基,卤素,卤代烷基,羟基,羟基烷基,烷氧基,烷氧基烷基,卤代烷氧基,羟基卤代烷基和烷氧基卤代烷基中的一至三个取代基取代;
R3是氢,羟基或烷氧基,其中在R3是羟基或烷氧基的情况下,则E是-C(R5R6)-;
R4是氢,烷基或环烷基;
R5是氢,烷基或环烷基;
R6是氢,烷基或环烷基;
n是1或2;
A是-N或-CR3;
E是键或-C(R5R6)-;
G是-O-,-NR4-,-CH(OH)-,-C(O)-,-C(O)O-,-C(O)NR4-,-S(O)2-,-S(O)2NR4-或键;
其中在E和G均为键的情况下,则R1直接与A连接,
或其药用盐。
白脂肪组织(WAT)的主要生理作用是在其他组织需要时提供能量。在哺乳动物中,白脂肪组织是主要的能量储存库,在能量过剩时以三酰甘油(TAG)的形式积累能量储存。游离脂肪酸(FFA)从TAG的释放受儿茶酚胺刺激并受激素类如胰岛素、胰高血糖素和肾上腺素调节。据信在WAT中负责甘油三酯的激素调节水解的最重要的酶是激素敏感脂酶(HSL)。
导致升高的循环未酯化脂肪酸(NEFA)的脂肪细胞脂解的调节障碍与肥胖症和包括2型糖尿病发展的复合病变有关。肥胖或抗胰岛素的受试者具有增加的内脏脂肪组织贮存物。这些贮存物含有提高水平的HSL蛋白,并表现出提高的脂解活性,原因在于它们对于胰岛素介导的脂解抑制有耐性。这导致提高的游离脂肪酸(FFA)血浆水平,其进一步加剧了胰岛素抗性,这归因于甘油三酯在除了WAT以外的组织如肝、胰和肌肉中的累积。因此,由于提高的HSL活性所致的提高的FFA血浆水平促成并使肥胖和2型糖尿病个体的胰岛素抗性恶化。通过抑制HSL来恢复过高的血浆FFA和甘油三酯水平将减少甘油三酯在除了WAT以外的组织如肝、肌肉和胰中的累积,从而导致减少的肝葡萄糖输出、增加的肌肉脂肪酸氧化并改善β-细胞功能。
升高的FFA也与增加的心血管风险有关,包括动脉粥样硬化和心肌功能障碍。此外,高脂解活性和升高的FFA导致高血压大鼠中的增加的胰岛素抗性和高血压。FFA聚集在肝中并且导致增加的TAG产生,该TAG被包裹到分泌的极低密度脂蛋白(VLDL)中。因此,HSL活性的降低将减少FFA向血液中的释放,从而限制将FFA供应到肝中用于TAG合成。因此,HSL抑制剂可能具有治疗非酒精性脂肪肝疾病(NAFLD)和非酒精性脂肪肝炎(NASH)的有益效果。
本发明的目的是式(I)化合物和它们的上述盐和酯,以及它们作为治疗活性物质的用途,用于制备所述化合物的方法,中间体,药物组合物,含有所述化合物、它们的药用盐或酯的药物,所述化合物、盐或酯用于疾病的治疗或预防的用途,尤其是在糖尿病、代谢综合征、异常脂肪血症、动脉粥样硬化、肥胖症、心血管病、心肌功能障碍、炎症、非酒精性脂肪肝病或非酒精性脂肪肝炎的治疗或预防中的用途,以及所述化合物、盐或酯用于制备治疗或预防糖尿病、代谢综合征、异常脂肪血症、动脉粥样硬化、肥胖症、心血管病、心肌功能障碍、炎症、非酒精性脂肪肝疾病或非酒精性脂肪肝炎用药物的用途。
术语“烷氧基”表示式-O-R’的基团,其中R’是烷基。烷氧基的实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基和叔丁氧基。
术语“烷氧基烷基”表示这样的烷基,其中所述烷基中的至少一个氢原子已经被烷氧基代替。示例性的烷氧基烷基包括甲氧基甲基、乙氧基甲基、甲氧基甲基、乙氧基乙基、甲氧基丙基、乙氧基丙基、正丁氧基甲基和叔丁氧基甲基。特别的烷氧基烷基包括乙氧基甲基、正丁氧基甲基和叔丁氧基甲基。
术语″烷氧基卤代烷基″表示这样的烷基,其中所述烷基的至少一个氢原子已经被烷氧基代替并且其中所述烷基的至少一个氢原子已经被卤素代替。烷氧基卤代烷基的实例包括甲氧基三氟乙基或甲氧基三氟丙基。
术语“烷基”表示1至12个碳原子、特别是1至7个碳原子、更特别是1至4个碳原子的一价直链或支链的饱和烃基,例如,甲基、乙基、正丙基、异丙基、二甲基丙基、正丁基、异丁基、仲丁基、叔丁基、甲基丁基和二甲基丁基。
术语“环烷基”表示3至10个环碳原子的一价饱和的单环或双环烃基,特别是3至8个环碳原子的一价饱和单环烃基。双环是指由两个具有两个共用碳原子的饱和碳环构成。特别的环烷基是单环的。单环环烷基的实例是环丙基、环丁基、环戊基、环己基或环庚基。双环的环烷基是双环[2.2.1]庚基或双环[2.2.2]辛基。特别的单环环烷基是环丙基。
术语“环烷基烷基”表示这样的烷基,其中所述烷基的至少一个氢原子已经被环烷基代替。环烷基烷基的实例包括环丙基甲基、环丙基乙基、环丁基丙基和环戊基丁基。
术语“卤代烷氧基”表示这样的烷氧基,其中所述烷氧基的至少一个氢原子已经被相同或不同的卤素原子代替。卤代烷氧基的实例包括氟甲氧基、二氟甲氧基、三氟甲氧基、三氟乙氧基、三氟甲基乙氧基、三氟二甲基乙氧基和五氟乙氧基。特别的卤代烷氧基是三氟甲氧基和三氟乙氧基。更特别的卤代烷氧基是三氟甲氧基和三氟乙氧基。
术语“卤代烷氧基烷基”表示这样的烷基,其中所述烷基的至少一个氢原子已经被卤代烷氧基代替。卤代烷氧基烷基的实例包括氟甲氧基甲基、二氟甲氧基甲基、三氟甲氧基甲基、氟乙氧基甲基、二氟乙氧基甲基、三氟乙氧基甲基、氟甲氧基乙基、二氟甲氧基乙基、三氟甲氧基乙基、氟乙氧基乙基、二氟乙氧基乙基、三氟乙氧基乙基、氟甲氧基丙基、二氟甲氧基丙基、三氟甲氧基丙基、氟乙氧基丙基、二氟乙氧基丙基和三氟乙氧基丙基。特别的卤代烷氧基烷基是2,2,2-三氟乙氧基甲基。
术语“卤代烷基”表示这样的烷基,其中所述烷基的至少一个氢原子已经被相同或不同的卤素原子代替。卤代烷基的实例包括氟甲基、二氟甲基、三氟甲基、三氟乙基、三氟甲基乙基和五氟乙基。特别的卤代烷基是三氟甲基。
术语“卤素”和“卤代”在本文中可交换使用,并且表示氟、氯、溴或碘。特别的卤素是氯和氟。
术语“杂芳基”是指5至12个环原子的一价芳香性杂环单环或二双环体系,其包括选自N、O和S中的1、2、3或4个杂原子,剩余环原子是碳。杂芳基的实例包括吡咯基,呋喃基,噻吩基,咪唑基,唑基,噻唑基,***基,二唑基,噻二唑基,四唑基,吡啶基,吡嗪基,吡唑基,哒嗪基,嘧啶基,三嗪基,氮杂革基,二氮杂革基,异唑基,苯并呋喃基,异噻唑基,苯并噻吩基,吲哚基,异吲哚基,异苯并呋喃基,苯并咪唑基,苯并唑基,苯并异唑基,苯并噻唑基,苯并异噻唑基,苯并二唑基,苯并噻二唑基,苯并***基,嘌呤基,喹啉基,异喹啉基,喹唑啉基和喹喔啉基。特别的杂芳基是吡啶基。
术语“杂芳基烷基”表示这样的烷基,其中所述烷基的至少一个氢原子已经被杂芳基代替。杂芳基烷基的实例是吡啶基烷基。
术语“羟基”表示-OH基团。
术语″羟基卤代烷基″表示这样的烷基,其中所述烷基的至少一个氢原子已经被羟基代替并且其中所述烷基的至少一个氢原子已经被卤素代替。羟基卤代烷基的实例包括羟基三氟乙基、羟基三氟丙基和羟基六氟丙基。
术语“羟基烷基”表示这样的烷基,其中所述烷基的至少一个氢原子已经被羟基代替。羟基烷基的实例包括羟基甲基、羟基乙基、羟基丙基、羟基甲基丙基和二羟基丙基。
术语“苯氧基”表示式-O-R’的基团,其中R’是苯基。
术语“苯氧基烷基”表示这样的烷基,其中所述烷基的至少一个氢原子已经被苯氧基代替。示例性的苯氧基烷基包括苯氧基甲基、苯氧基乙基和苯氧基丙基。特别的烷氧基烷基是苯氧基甲基。
术语“苯基烷基”表示这样的烷基,其中所述烷基的至少一个氢原子已经被苯基代替。示例性的苯基烷基包括苯基甲基、苯基乙基、苯基丙基和苯基甲基丙基。特别的苯基烷基是苯基甲基。
术语“药用盐”是指保持游离碱或游离酸的生物学效用和性质的那些盐,它们不是在生物学或其他方面不适宜的。所述盐与以下酸形成:无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等,特别是盐酸,以及有机酸如乙酸、丙酸、乙醇酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸、N-乙酰半胱氨酸等。此外,可以通过向游离酸中添加无机碱或有机碱来制备这些盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐等。衍生自有机碱的盐包括但不限于以下各项的盐:伯、仲和叔胺,取代的胺,包括天然存在的取代的胺、环胺和碱性离子交换树脂,如异丙胺,三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、赖氨酸、精氨酸、N-乙基哌啶、哌啶、聚亚胺树脂等。特别的式(I)化合物的药用盐是盐酸盐、甲磺酸盐和柠檬酸盐。
“药用酯”是指通式(I)的化合物可以在官能团处衍生以提供能够在体内转化回母体化合物的衍生物。这样的化合物的实例包括生理学上可接受的且在代谢上不稳定的酯衍生物,如甲氧基甲酯,甲硫基甲酯和新戊酰氧基甲酯。另外,类似于在代谢上不稳定的酯,能够在体内生成通式(I)的母体化合物的通式(I)化合物的任何生理上可接受的等价物都在本发明的范围内。
术语“保护基团”(PG)表示这样的基团,在与其在合成化学中相关的传统含义中选择性地阻挡多官能化合物中的反应性位点以使得化学反应可以在另一个未保护的反应性位点选择性地进行。可以将保护基团在合适的点移除。示例性保护基团是氨基-保护基团、羧基-保护基团或羟基-保护基团。特别的保护基团是叔丁氧羰基(Boc),苄氧羰基(Cbz),芴基甲氧羰基(Fmoc)和苄基(Bn)。更特别的保护基团是叔丁氧羰基(Boc)和苄基(Bn)。
式(I)的化合物可以含有数个不对称中心,并且其存在形式可以是光学纯对映异构体,对映异构体的混合物,如例如外消旋物,光学纯非对映异构体,非对映异构体的混合物,非对映异构体外消旋物或非对映异构体外消旋物的混合物。
根据Cahn-Ingold-PrelogConvention,不对称碳原子可以为“R”或“S”构型。
本发明的还一个实施方案是如本文所述的根据式(I)的化合物及其药用盐或酯,特别是根据本文所述的式(I)的化合物及其药用盐,更特别是根据本文所述的式(I)的化合物。
本发明的再另一个实施方案是如本文所述的根据式(I)的化合物,其中R1是烷基,烷氧基烷基,卤代烷氧基烷基,羟基烷基,苯基,取代的苯基,苯基烷基,取代的苯基烷基,苯氧基烷基,取代的苯氧基烷基,吡啶基,取代的吡啶基,吡啶基烷基或取代的吡啶基烷基,其中取代的苯基,取代的苯基烷基,取代的苯氧基烷基,取代的吡啶基和取代的吡啶基烷基被独立地选自烷基,环烷基,环烷基烷基,卤素,卤代烷基,羟基,羟基烷基,烷氧基,烷氧基烷基,卤代烷氧基,羟基卤代烷基和烷氧基卤代烷基中的一至三个取代基取代。
本发明的更特别的实施方案是如本文所述的根据式(I)的化合物,其中R1是烷基,卤代烷氧基烷基,苯基,取代的苯基,苯基烷基,取代的苯基烷基或取代的吡啶基,其中取代的苯基,取代的苯基烷基和取代的吡啶基被独立地选自烷基,卤素,卤代烷基,羟基和卤代烷氧基中的一至三个取代基取代。
本发明的特别的实施方案是如本文所述的根据式(I)的化合物,其中R1是烷基,取代的苯基或苯基烷基,其中取代的苯基被独立地选自卤素和卤代烷氧基中的一至三个取代基取代。
在本发明的另一实施方案中是如本文所述的根据式(I)的化合物,其中R1是烷基。
本发明的又另一个实施方案是如本文所述的根据式(I)的化合物,其中R1是苯基烷基。
本发明的特别的实施方案是如本文所述的根据式(I)的化合物,其中R1是被独立地选自卤素和卤代烷氧基中的一至三个取代基取代苯基。
本发明的更特别的实施方案是如本文所述的根据式(I)的化合物,其中R1是被一或两个卤索取代的苯基。
本发明的实施方案还是如本文所述的根据式(I)的化合物,其中R1是2-氯苯基或2,4-二氯苯基。
本发明的另一实施方案是如本文所述的根据式(I)的化合物,其中R2是被选自烷基和卤代烷氧基中的一个取代基取代的苯基。
本发明还涉及如本文所述的根据式(I)的化合物,其中R2是被一个卤代烷氧基取代的苯基。
本发明的更特别的实施方案是如本文所述的根据式(I)的化合物,其中R2是4-三氟甲氧基苯基(14-trifluoromethoxyphenyl)。
本发明的更特别的实施方案是如本文所述的根据式(I)的化合物,其中A是-N。
本发明的实施方案还是如本文所述的根据式(I)的化合物,其中A是-CR3。
本发明还涉及如本文所述的根据式(I)的化合物,其中E是-C(R5R6)-。
本发明的另一个实施方案是如本文所述的根据式(I)的化合物,其中E是键。
本发明的更特别的实施方案是如本文所述的根据式(I)的化合物,其中G是-O-,-NR4-,-CH(OH)-,-C(O)-,-C(O)O-,-C(O)NR4-,-S(O)2-,-S(O)2NR4-或键。
本发明的特别的实施方案是如本文所述的根据式(I)的化合物,其中G是O,-C(O)-,-CH(OH)-或-S(O)2-。
本发明的实施方案还是如本文所述的根据式(I)的化合物,其中G是-C(O)-或-S(O)2-。
本发明的实施方案还是如本文所述的根据式(I)的化合物,其中G是-S(O)2-。
本发明的另一个实施方案是如本文所述的根据式(I)的化合物,其中R3是氢或羟基,其中在R3是羟基的情况下,则E是-C(R5R6)-。
本发明还涉及如本文所述的根据式(I)的化合物,其中R3是氢。
本发明的实施方案还是如本文所述的根据式(I)的化合物,其中R4是氢。
本发明的另一个实施方案是如本文所述的根据式(I)的化合物,其中R5是氢或烷基。
本发明的实施方案还是如本文所述的根据式(I)的化合物,其中R3是氢。
本发明的特别的实施方案是如本文所述的根据式(I)的化合物,其中R6是氢。
本发明的又一实施方案是如本文所述的根据式(I)的化合物,其中E和G均为键,并具有式I(a)。
本发明的实施方案还是如本文所述的根据式(I)的化合物,其中n是1。
本发明的特别的实施方案是如本文所述的根据式(I)的化合物,其中n是2。
如本文所述的式(I)的化合物的特别实例选自:
(3aR,7aS)-4-氧代-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-2-甲酸叔丁酯;
(3aS,7aR)-2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,7aR)-2-(4-氟-苯甲酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,7aR)-2-(3-甲基-丁酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,7aR)-4-氧代-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-2-甲酸(4-三氟甲氧基-苯基)-酰胺;
(3aS,7aR)-2-(4-氟-苄基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,7aR)-2-(2-氯-苯甲酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,7aR)-2-(4-异丙基-苯甲酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,7aR)-2-(3-甲基-丁-1-磺酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,7aR)-2-(2-甲基-丙-1-磺酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,7aR)-2-(2-氯-苯磺酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,7aR)-2-(4-氟-苯磺酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,7aR)-2-苯甲磺酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮:
(3aS,7aR)-4-氧代-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-2-甲酸(4-氟-苯基)-酰胺;
(3aR,7aS)-2-(2-氯-吡啶-3-磺酰基)-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aR,7aS)-2-苯磺酰基-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aR,7aS)-5-[4-(2,2,2-三氟-乙氧基)-苯基]-2-(2-三氟甲氧基-苯磺酰基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aR,7aS)-2-(2-对甲苯基-乙酰基)-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aR,7aS)-2-[2-(4-氟-苯基)-乙酰基]-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aR,7aS)-5-[4-(2,2,2-三氟-乙氧基)-苯基]-2-(2-三氟甲基-苯磺酰基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aR,7aS)-2-苯基乙酰基-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aR,7aS)-2-(3,3-二甲基-丁酰基)-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aR,7aS)-2-(2-氯-苯磺酰基)-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮;
N-(4-氟-苯基)-3-甲基-2-{(3aR,7aS)-4-氧代-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-2-基}-丁酰胺;
(3aR,7aS)-4-氧代-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-2-甲酸叔丁酯;
(3aR,7aS)-2-[2-(2,4-二氯-苯基)-2-羟基-乙基]-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aR,7aS)-2-(2-羟基-苯基)-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,6aS)-4-氧代-5-(4-三氟甲氧基-苯基)-六氢-吡咯并[3,4-c]吡咯-2-甲酸(4-三氟甲氧基-苯基)-酰胺;
(3aS,6aS)-5-(4-乙基-苯基)-4-氧代-六氢-吡咯并[3,4-c]吡咯-2-甲酸(4-三氟甲氧基-苯基)-酰胺;
(3aR,6aS)-5-羟基-5-丙基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮;
(3aR,5S,6aS)-5-羟基-5-(2,2,2-三氟-乙氧基甲基)-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮;
(3aR,6aS)-5-羟基-5-苯基氨基甲基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮;
2-氯-N-[(3aR,6aS)-1-氧代-2-(4-三氟甲氧基-苯基)-八氢-环戊二烯并[c]吡咯-5-基]-苯磺酰胺;
(3aR,5S,6aS)-5-羟基-5-苯氧基甲基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮;
(3aR,5S,6aS)-5-羟基-5-丙氧基甲基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮;
(3aR,5S,6aS)-5-丁氧基甲基-5-羟基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮;
及其药用盐。
如本文所述的式(I)的化合物的更特别的实例选自:
(3aS,7aR)-2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,7aR)-2-(2-氯-苯磺酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aR,7aS)-5-[4-(2,2,2-三氟-乙氧基)-苯基]-2-(2-三氟甲氧基-苯磺酰基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aR,7aS)-2-[2-(2,4-二氯-苯基)-2-羟基-乙基]-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aR,5S,6aS)-5-丁氧基甲基-5-羟基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮;
及其药用盐。
用于制备本文所述的式(I)化合物的方法是本发明的一个目的。
本发明的式(I)化合物的制备可以以顺序的或汇集的合成路线进行。本发明的合成显示在以下通用方案中。进行反应和所得产物的纯化所需的技能是本领域技术人员已知的。更详细地,式I的化合物可以通过下面给出的方法,通过实施例中给出的方法或通过类似的方法制备。对于本领域技术人员来说,各个反应步骤的合适反应条件是已知的。在反应过程中产生对映异构体或非对映异构体的混合物的情况下,可以通过本文描述的方法或者本领域技术人员已知的方法例如手性色谱法或结晶法分离这些对映异构体或非对映异构体。以下方法的描述中使用的取代基和标志具有本文给出的含义。
方案1
a)衍生物II是可商购的或可以从相应的式R2-NH2化合物和3-溴丙烯或4-溴丁-1-烯方便地合成,以提供衍生物II。这些可以与丙烯酰氯反应以获得化合物III。
b)III在过渡金属催化下的闭环复分解反应获得不饱和内酰胺IV。
c)内酰胺IV可以与N-苄基(甲氧基)-N-((三甲基甲硅烷基)甲基)甲胺(methanamine)在[3+2]环加成中反应以获得保护的双环V。
d)V中的保护基处理获得衍生物VI,其可以已经作为最终产物。然而,VI中的Boc-保护基可以在在酸性条件下断开,以获得游离胺XIII(步骤e),可以将其衍生化以提供最终的衍生物I(步骤n)。
方案2
f)5-亚甲基-四氢-环戊二烯并[c]呋喃-1,3-二酮VII是可商购的并且可以与式R2-NH2化合物在升高的温度下反应以提供二酮VIII。
g)方便地将二酮VIII在两步程序中用CeCl3·7H2O,NaBH4,NaCNBH3还原,以提供双环内酰胺IX。
h)方便地将IX的环氧化用mCPBA完成以提供X。
i)环氧化物X用各种亲核试剂的打开在碱的存在下完成以获得最终的化合物I,其中A是-CR3,R3是羟基,n是1,E是-C(R5R6)-,R5和R6是氢并且G是键。
j)提供酮XI的IX中双键的转化可以用臭氧分解方便地完成。
k)例如格氏试剂向酮XI的加成获得最终的叔醇I,其中A是-CR3,R3是羟基,n是1,E是-C(R5R6)-,R5和R6是氢,并且G是键。
l)酮XI可以通过用苄胺还原胺化而转化为胺衍生物,其在保护基处理下可以转变成相应的Boc-衍生物,由其可以在酸性条件下断开保护基以提供胺衍生物XII。
m)胺衍生物XII可以衍生化以获得最终的衍生物I,其中A是-CR3,R3是氢,n是1,E是键,并且G是-NR4,-C(O)NR4-或-S(O)2NR4-。
此外,本发明的一个实施方案还是一种制备如上定义的式(I)的化合物的方法,所述方法包括下列化合物的反应:
a)式(XIII)的化合物;
特别是在存在或不存在碱,特别是二异丙基乙胺和三乙胺的情况下,在溶剂,特别是CH2Cl2中,在介于RT和回流之间的温度进行,其中R1,R2,E,G和n如本文中所定义,并且A是-N。
此外,本发明的一个目的是如本文所述的根据式(I)的化合物,所述化合物用作治疗活性物质。
本发明的又一个目的是一种药物组合物,所述药物组合物包含如本文所述的根据式(I)的化合物和治疗惰性载体。
本发明的再一个目的是如本文所述的根据式(I)的化合物用于治疗或预防由与酶激素敏感脂酶(theenzymehormone-sensitivelipase)相关的紊乱引起的疾病的用途。
本发明涉及如上面所述的根据式(I)的化合物用于治疗或预防糖尿病、代谢综合征、异常脂肪血症、动脉粥样硬化、肥胖症、心血管病、心肌功能障碍、炎症、非酒精性脂肪肝病或非酒精性脂肪肝炎的用途。
本发明特别地涉及如上面所述的根据式(I)的化合物用于治疗或预防糖尿病、代谢综合征、异常脂肪血症、动脉粥样硬化或肥胖症的用途。
本发明的一个特别的实施方案是如上面所述的根据式(I)的化合物用于治疗或预防糖尿病的用途。
本发明的再一个特别的实施方案是如上面所述的根据式(I)的化合物用于治疗或预防II型糖尿病的用途。
本发明的另一个实施方案是如上面所述的根据式(I)的化合物用于治疗或预防心血管病、心肌功能障碍、炎症、非酒精性脂肪肝病或非酒精性脂肪肝炎的用途。
本发明的一个特别实施方案是如上面所述的根据式(I)的化合物用于治疗或预防非酒精性脂肪肝病或非酒精性脂肪肝炎的用途。
本发明涉及如上面所述的根据式(I)的化合物用于制备药物的用途,所述药物用于治疗或预防糖尿病、代谢综合征、异常脂肪血症、动脉粥样硬化、肥胖症、心血管病、心肌功能障碍、炎症、非酒精性脂肪肝病或非酒精性脂肪肝炎。
本发明特别涉及如上面所述的根据式(I)的化合物用于制备药物的用途,所述药物用于治疗或预防糖尿病、代谢综合征、异常脂肪血症、动脉粥样硬化或肥胖症。
本发明的一个特别实施方案是如上面所述的根据式(I)的化合物用于制备药物的用途,所述药物用于治疗或预防糖尿病。
本发明的再一个特别的实施方案是如上面所述的根据式(I)的化合物用于制备药物的用途,所述药物用于治疗或预防II型糖尿病。
本发明的另一个特别的实施方案是如上面所述的根据式(I)的化合物用于制备药物的用途,所述药物用于治疗或预防心血管病、心肌功能障碍、炎症、非酒精性脂肪肝病或非酒精性脂肪肝炎。
本发明的一个特别的实施方案是如上面所述的根据式(I)的化合物用于制备药物的用途,所述药物用于治疗或预防非酒精性脂肪肝病或非酒精性脂肪肝炎。
本发明特别地涉及如上面所述的根据式(I)的化合物,所述化合物用于治疗或预防糖尿病、代谢综合征、异常脂肪血症、动脉粥样硬化、肥胖症、心血管病、心肌功能障碍、炎症、非酒精性脂肪肝病或非酒精性脂肪肝炎。
本发明的一个特别的实施方案是如上面所述的根据式(I)的化合物,所述化合物用于治疗或预防糖尿病、代谢综合征、异常脂肪血症、动脉粥样硬化或肥胖症。
本发明的再一个特别的实施方案是如上面所述的根据式(I)的化合物,所述化合物用于治疗或预防糖尿病。
本发明的还一个特别的实施方案是如上面所述的根据式(I)的化合物,所述化合物用于治疗或预防II型糖尿病。
本发明的另一个特别的实施方案是如上面所述的根据式(I)的化合物,所述化合物用于治疗或预防心血管病、心肌功能障碍、炎症、非酒精性脂肪肝病或非酒精性脂肪肝炎。
本发明的再一个特别的实施方案是如上面所述的根据式(I)的化合物,所述化合物用于治疗或预防非酒精性脂肪肝病或非酒精性脂肪肝炎。
此外,本发明的一个目的是用于治疗或预防糖尿病、代谢综合征、异常脂肪血症、动脉粥样硬化、肥胖症、心血管病、心肌功能障碍、炎症、非酒精性脂肪肝病或非酒精性脂肪肝炎的方法,所述方法包括给药有效量的如上所述的根据式(I)的化合物。
此外,本发明的一个特别目的是用于治疗或预防糖尿病、代谢综合征、异常脂肪血症、动脉粥样硬化或肥胖症的方法,所述方法包括给药有效量的如上所述的根据式(I)的化合物。
本发明的一个特别实施方案是用于治疗或预防糖尿病的方法,所述方法包括给药有效量的如上所述的根据式(I)的化合物。
本发明的再一个特别实施方案是用于治疗或预防II型糖尿病的方法,所述方法包括给药有效量的如上所述的根据式(I)的化合物。
本发明的另一个特别实施方案是用于治疗或预防心血管病、心肌功能障碍、炎症、非酒精性脂肪肝病或非酒精性脂肪肝炎,所述方法包括给药有效量的如上所述的根据式(I)的化合物。
本发明的另一个特别实施方案是用于治疗或预防非酒精性脂肪肝病或非酒精性脂肪肝炎,所述方法包括给药有效量的如上所述的根据式(I)的化合物。
本发明的再一个目的包括如本文所述的根据式(I)的化合物,所述化合物根据任一项所述方法制备。
测定程序
人全长激素敏感脂酶-His6的制备:
1)克隆:cDNA由商品人脑polyA+RNA制备并且在重叠PCR中用作模板以产生具有3’-His6标记的全长人HSLORF。将此全长嵌入物克隆到pFast-BAC载体中并且检验若干单个克隆物的DNA序列。来自具有3'His6标记的正确全长克隆的DNA用于转化E.coli株DH10BAC。所得杆粒DNA用于产生用于蛋白质产生的效价的杆状病毒原种。编码HSL的序列符合Swissprot条目Q05469,具有额外C-末端His6-标记。
2)蛋白质纯化:培养:5.5L,表达人全长HSL-His6的High5细胞,48小时,含有25μME-64。细胞数:1.78x1010个细胞/ml,90%存活。
将细胞解冻。在冰上,将细胞悬浮在4℃的pH8.0的含有下列各项的碱缓冲液中:10%甘油,25mMTris-Cl,300mMNaCl,10mM咪唑,10mM2-巯基乙醇,2μg胃蛋白酶抑制剂/ml,2μg亮肽素/ml,2μg抗痛素/ml,最终体积为475ml,具有3.75x107个细胞/ml。以3x30秒完成卫生处理,添加LubrolPX至0.2%的最终浓度,接着在4℃搅拌15分钟并且在4℃以25kxg离心60分钟。将可溶性蛋白质与60ml预洗涤且平衡的Ni-NTA琼脂糖(Qiagen30210)混合,接着在4℃颠倒翻滚45分钟,1000rpm离心5分钟并且使树脂沉降5分钟。移除上清液,将树脂在离心容器中用5体积的含有0.2%LubrolPX的碱缓冲液洗涤。再次进行离心,然后废弃上清液。将树脂倾倒在一次性的过滤器单元(Nalge450-0080)中的0.8μm膜上,并且用5体积的含有0.2%LubrolPX的碱缓冲液洗涤。然后将其用30体积的4℃的pH7.5的含有60mM咪唑的碱缓冲液洗涤。用4℃、pH7.5的5体积的25mMTris-Cl、300mMNaCl、200mM咪唑、10mM2-巯基乙醇,通过在4℃用缓冲液将树脂颠倒翻滚30分钟将蛋白质洗脱。树脂被捕获在0.2μm膜一次性过滤器单元(MilliporeSCGPU02RE)上并且洗脱液被收集在储器中。使用30kMWCO离心过滤器装置(SartoriusVivascienceVivacell100,VC1022)将洗脱液浓缩至20ml。然后将其两次相对于4℃、pH7.5的2L的10%甘油、25mMTris-Cl、300mMNaCl、0.2mMEDTA、0.2mMDTT在4℃渗析过夜。使用0.22μm一次性过滤器单元(MilliporeSCGP00525)过滤蛋白质。利用280=0.67cm-1mg-1,从280nm处的吸光率计算蛋白质浓度。收率为总计235mg。将蛋白质在-80℃储存。
人激素敏感脂酶(HSL)酶抑制测定:
使用2,3-二巯基-1-丙醇三丁酸酯(Aldrich,St.Louis,MO)作为底物通过比色测定测量HSL酶活性。典型地,1.5mM的2,3-二巯基-1-丙醇三丁酸酯(DMPT),在100mMMOPS,pH7.2,0.2mg/ml无脂肪酸BSA中,通过在4℃超声至均匀的悬浮液来制备。将试验化合物(2mM原液,在DMSO中)连续地在DMSO中稀释3倍。将化合物溶液在含有1.5mMDMPT的溶液中稀释24倍,并且以每一个孔为18ul加入384-孔微量培养板(CorningCostar)中。每一个孔加入12微升的人HSL(15ug/ml),并且将反应混合物在37℃培育20分钟。加入6微升的在DMSO(加1.2%SDS和0.6%TritonX-100)中的12mM二硫代-双-(2-硝基苯甲酸)(DTNB),并且将混合物在室温培育15分钟。通过在EnvisionReader(PerkinElmerLifeandAnalyticalSciences,Shelton,CT)上读取405nm处的吸光率监控产物的产生。
细胞测定:
下列测定用于测量化合物在完整细胞(脂肪细胞)中抑制脂解的作用。
将3T3-L1前成脂肪细胞以在200ul生长培养基(DMEM/10%小牛血清/1x抗生素-抗真菌剂)中20,000个细胞/孔的密度加入96-孔板中直至汇合。在汇合后48小时,将培养基移除并且用分化培养基(DMEM/10%FBS/1x抗生素-抗真菌剂加上:1uM磷酸二酯酶的IBMX(3-异丁基-1-甲基黄嘌呤)抑制剂,1uM***,1uM罗西利宗,10ug/ml胰岛素)将细胞分化为脂肪细胞。将细胞在所述培养基中培育3天,然后将介质换成分化后培养基(DMEM/10%FBS加上:10ug/ml胰岛素)并且将细胞培育另外3天。然后将培养基换成维持培养基(DMEM/10%FBS)。每3天用维持培养基喂养细胞直至使用。可以在96孔板中分化开始后第9-14天进行脂解测定。
脂解测定如下进行。将脂肪细胞用200ulKrebsRingerBicarbonateHepes缓冲液(KRBH)/3%BSA洗涤2次。试验化合物以10mM在DMSO中,并且首先稀释至5mM在DMSO中。然后将它们连续地在DMSO中稀释5倍(5mM至320pM)。然后将每个化合物在KRBH/3%BSA中稀释200倍(最终0.5%DMSO)。最终所得溶液在25uM至1.6pM的范围内。将150ul稀释的化合物加入到每个孔中(一式三份),并且将细胞在37℃预培育30分钟。将Forskolin(最终50uM)加入孔中,并且将细胞在37℃培育120分钟。将100ul收集到新的96-孔板中用于甘油分析。所产生的甘油的量使用甘油测量试剂盒(Sigma)测定。
如上所述的式(I)化合物和它们的药用盐或酯具有0.0001uM至1000uM的IC50值,特别的化合物具有0.001uM至500uM的IC50值,更特别的化合物具有0.001uM至5uM的IC50值。这些结果已经通过使用上述HSL酶抑制测定获得(uM表示微摩尔浓度)。
式(I)化合物及其药用盐可以用作药物(例如以药物制剂的形式)。药物制剂可以以下列方式内部给药:如经口(例如以片剂,包衣片剂,糖衣丸,硬和软明胶胶囊,溶液剂,乳剂或混悬剂的形式),经鼻(例如以鼻喷雾的形式)或经直肠(例如以栓剂的形式)。然而,给药也可以在肠胃外实现,如肌肉内或静脉内(例如以注射液的形式)。
式(I)化合物及其药用盐可以用药物惰性的、无机或有机辅料处理,用于制备片剂、包衣片剂、糖衣丸和硬明胶胶囊。例如可以使用乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐等作为这样的用于片剂、糖衣丸和硬明胶胶囊的辅料。
合适的用于软明胶胶囊的辅料是例如植物油、蜡、脂肪、半固体物质和液体多元醇等。
合适的用于制备溶液剂和糖浆剂的辅料是例如水、多元醇、蔗糖、转化糖、葡萄糖等。
合适的用于注射液的辅料是例如水、醇、多元醇、甘油、植物油等。
合适的用于栓剂的辅料是例如天然或硬化油、蜡、脂肪、半固体或液体多元醇等。
此外,药物制剂可以含有防腐剂、增溶剂、增粘物质、稳定剂、润湿剂、乳化剂、增甜剂、着色剂、香料、用于调节渗透压的盐、缓冲剂、掩蔽剂或抗氧化剂。它们还可以含有其它有治疗价值的物质。
剂量可以在宽范围内变化,并且当然将适合每种特定情况下的个体需求。通常,在经口给药的情况下,每kg体重为约0.1mg至20mg、优选每kg体重为约0.5mg至4mg(例如每人约300mg)的每日剂量,优选分成1-3个可以例如由相同量组成的单个剂量,应当是适合的。然而,将清楚的是,当明确指示时,可以超过本文给出的上限。
以下通过非限制性的实施例示例本发明。
在制备实施例是作为对映异构体混合物的形式获得的情况下,可以通过本文中描述的方法或本领域技术人员已知的方法诸如例如手性色谱法或结晶来分离纯的对映异构体。
实施例
实施例1:4-氧代-5-(4-三氟甲氧基-苯基)-八氢-吡咯并13,4-c]吡啶-2-甲酸叔丁酯
a)丁-3-烯基-(4-三氟甲氧基-苯基)-胺
将4-三氟甲氧基-苯胺(2.5g,14mmol),4-溴丁-1-烯(2.0g,14mmol)和Cs2CO3(1.4g,4.2mmol)一起混合,并将混合物在环境温度搅拌7天。通过硅胶柱色谱(用石油醚/乙酸乙酯=10/1洗脱)获得标题化合物(0.2g,6.1%)。1HNMR(300MHz,CDCl3):δ7.12-7.02(m,2H),6.58-6.53(m,2H),5.80-5.46(m,1H),5.20-5.11(m,2H),3.17(t,2H,J=6.6Hz),2.43-2.35(m,2H)。LC-MS:[M+1]+232.2。
b)N-丁-3-烯基-N-(4-三氟甲氧基-苯基)-丙烯酰胺
将丙烯酰氯(0.7g,7.8mmol)滴加至丁-3-烯基-(4-三氟甲氧基-苯基)-胺(1.2g,5.2mmol)和Et3N(1.1g,10.4mmol)的溶液中。将混合物在环境温度搅拌过夜。将混合物用DCM萃取,用盐水洗涤,用无水Na2SO4干燥。将溶剂通过减压除去并将残余物通过硅胶柱色谱(用石油醚/乙酸乙酯=10/1洗脱)纯化,给出N-丁-3-烯基-N-(4-三氟甲氧基-苯基)-丙烯酰胺(0.8g,54%)。1HNMR(300MHz,CDCl3):δ7.35-7.18(m,4H),6.38-6.35(m,1H),5.96-5.93(m,1H),5.78-5.74(m,1H),5.68-5.64(m,1H),5.08-5.01(m,2H),3.84(t,2H,J=7.5Hz),2.31-2.27(m,2H)。LC-MS:[M+1]+286.1。
c)1-(4-三氟甲氧基-苯基)-5,6-二氢-1H-吡啶-2-酮
向在DCM(20mL)中的N-丁-3-烯基-N-(4-三氟甲氧基-苯基)-丙烯酰胺(0.8g,2.6mmol)加入Grubbs催化剂(0.12g,0.14mmol)并将混合物加热至45℃过夜。将溶剂通过减压除去并将残余物通过硅胶柱色谱(用石油醚/乙酸乙酯=10/1洗脱)纯化,提供标题化合物(0.6g,82%)。1HNMR(300MHz,CDCl3):δ7.35-7.21(m,4H),6.74-6.71(m,1H),6.07-6.05(m,1H),3.87-3.82(m,2H),2.57-2.51(m,2H);LC-MS:[M+1]+258.1。
d)2-苄基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮
在4℃,向在DCM(30mL)中的N-苄基(甲氧基)-N-((三甲基甲硅烷基)甲基)甲胺(1.7g,7.0mmol)和1-(4-三氟甲氧基-苯基)-5,6-二氢-1H-吡啶-2-酮(0.6g,2.3mmol)加入三氟乙酸(0.026g,0.23mmol)在DCM(10mL)中的溶液。将混合物在50℃搅拌3h后,将溶液用饱和碳酸氢钠和盐水洗涤,然后用无水Na2SO4干燥。在除去DCM后,将残余物通过在硅胶上采用石油醚/乙酸乙酯(10∶1至5∶1)的柱色谱纯化,获得标题化合物(0.19g,21%)。1HNMR(300MHz,CDCl3):δ7.34-7.20(m,9H),3.77-3.55(m,4H),3.18-3.01(m,2H),2.93-3.83(m,3H),2.43-2.41(m,1H),2.07-2.05(m,1H),1.80-1.75(m,1H);LC-MS:[M+1]+391.1。
e)4-氧代-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-2-甲酸叔丁酯
将2-苄基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮(1.0g,2.56mmol),10%Pd/C(0.5g,0.1(w/w))和二碳酸二叔丁酯(0.8g,3.8mmol)在甲醇(50mL)中的悬浮液在氢气氛下在室温搅拌3h。将催化剂滤出。将滤液浓缩并将残余物通过在硅胶上采用石油醚/乙酸乙酯(10∶1至5∶1)的柱色谱纯化,获得标题化合物(0.9g,90%)。1HNMR(300MHz,CDCl3):δ7.38-7.20(m,4H),3.89-3.59(m,5H),3.40-3.37(m,1H),3.20-3.15(m,1H),2.72-2.70(m,1H),2.07-1.89(m,2H),1.52(s,9H);LC-MS:[M+23]+422.9。
实施例2:2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮
a)5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮,盐酸盐
将4-氧代-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-2-甲酸叔丁酯(900mg,2.25mmol)加入在乙酸乙酯中的饱和盐酸溶液(4mL)。将反应混合物在环境温度搅拌过夜。在减压下除去溶剂,然后获得粗产物(800mg),其不经进一步纯化地使用。1HNMR(300MHz,d6-DMSO):δ7.51-7.38(m,4H),3.79-3.25(m,6H),3.04-3.01(m,1H),2.84-2.81(m,1H),2.06-2.03(m,1H),1.82-1.80(m,1H);LC-MS:[M+1]+302.7。
b)2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮
将5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮,盐酸盐(80mg,0.24mmol),2-苯基乙酰氯(74mg,0.48mmol)和Et3N(0.12g,1.2mmol)加入DCM(10mL)中,并将混合物在环境温度搅拌12h。通过制备型-TLC(用DCM/MeOH=25/1洗脱)获得产物(45mg,46%)。1HNMR(300MHz,CDCl3):δ7.34-7.23(m,9H),3.90-3.54(m,7H),3.23-3.20(m,2H),2.78-2.75(m,1H),2.07-2.02(m,1H),1.83(bs,1H);LC-MS:[M+1]+418.7。
实施例3:2-(4-氟-苯甲酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮
类似于对于合成2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮(实施例2)所述的程序,从5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮,盐酸盐和4-氟-苯甲酰氯制备标题化合物。1HNMR(300MHz,CDCl3):δ7.57-7.52(m,2H),7.29-7.21(m,4H),7.12-7.06(m,2H),3.91-3.68(m,6H),3.21-3.19(m,1H),2.85-2.83(m,1H),2.19-2.16(m,1H),1.91(bs,1H);LC-MS:[M+1]+423.1。
实施例4:2-(3-甲基-丁酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮
类似于对于合成2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮(实施例2)所述的程序,从5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮,盐酸盐和3-甲基-丁酰氯制备标题化合物。1HNMR(300MHz,CDCl3):δ7.29-7.21(m,4H),3.91-3.47(m,6H),3.26-3.23(m,1H),2.78-2.75(m,1H),2.18-1.90(m,5H),0.97(d,6H,J=6.3Hz);LC-MS:[M+1]+385.1。
实施例5:4-氧代-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-2-甲酸(4-三氟甲氧基-苯基)-酰胺
类似于对于合成2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮(实施例2)所述的程序,从5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮,盐酸盐和1-异氰酸基-4-(三氟甲氧基)苯制备标题化合物。1HNMR(300MHz,CDCl3):δ7.38-7.34(m,2H),7.28-7.18(m,4H),7.08-7.06(m,2H),6.74(s,1H),3.97-3.91(t,1H,J=9.6Hz),3.83-3.56(m,5H),3.33-3.31(m,1H),2.79-2.75(m,1H),2.12-1.95(m,2H);LC-MS:[M+1]+504.1。
实施例6:2-(4-氟-苄基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮
将5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮,盐酸盐(80mg,0.24mmol),1-(溴甲基)-4-氟苯(90mg,0.48mmol)和Et3N(0.12g,1.2mmol)加入二氯甲烷(2mL)中,并将混合物搅拌12h。通过制备型-TLC(用二氯甲烷:MeOH=25∶1洗脱)获得产物(30mg,31%)。1HNMR(300MHz,CDCl3):δ7.48-7.44(m,2H),7.29-7.09(m,6H),4.23-4.19(m,2H),3.85-3.25(m,7H),2.50-2.48(m,1H),2.28-2.24(m,1H),1.25-1.23(m,1H);LC-MS:[M+1]+409.1。
实施例7:2-(2-氯-苯甲酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮
类似于对于合成2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮(实施例2)所述的程序,从5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮,盐酸盐和2-氯-苯甲酰氯制备标题化合物。1HNMR(300MHz,CDCl3):δ7.42-7.21(m,8H),4.20-3.58(m,6H),3.29-3.26(m,1H),2.86-2.84(m,1H),2.13-3.12(m,1H),1.96-1.95(m,1H);LC-MS:[M+1]+439.1。
实施例8:2-(4-异丙基-苯甲酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮
类似于对于合成2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮(实施例2)所述的程序,从5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮,盐酸盐和4-异丙基-苯甲酰氯制备标题化合物。1HNMR(300MHz,CDCl3):δ7.47-7.44(m,2H),7.29-7.10(m,6H),3.98-3.67(m,6H),3.20-3.18(m,1H),2.87-2.82(m,2H),2.15-1.97(m,2H),1.24(d,6H,J=3.9Hz);LC-MS:[M+1]+447.2。
实施例9:2-(3-甲基-丁-1-磺酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮
类似于对于合成2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮(实施例2)所述的程序,从5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮,盐酸盐和3-甲基-丁-1-磺酰氯制备标题化合物。1HNMR(300MHz,CDCl3):δ7.31-7.22(m,4H),3.84-3.68(m,5H),3.39-3.25(m,2H),3.05-2.84(m,3H),2.28-1.97(m,2H),1.73-1.70(m,3H),0.94(d,6H,J=6.6Hz);LC-MS:[M+1]+435.1。
实施例10:2-(2-甲基-丙-1-磺酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮
类似于对于合成2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮(实施例2)所述的程序,从5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮,盐酸盐和2-甲基-丙-1-磺酰氯制备标题化合物。1HNMR(300MHz,CDCl3):δ7.30-7.22(m,4H),3.84-3.66(m,5H),3.46-3.31(m,2H),2.91-2.83(m,3H),2.32-2.30(m,1H),2.28-1.97(m,2H),1.13(d,6H,J=6.9Hz);LC-MS:[M+1]+421.1。
实施例11:2-(2-氯-苯磺酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮
类似于对于合成2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮(实施例2)所述的程序,从5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮,盐酸盐和2-氯-苯磺酰氯制备标题化合物。1HNMR(300MHz,CDCl3):δ8.12-8.09(m,1H),7.55-7.41(m,3H),7.39-7.21(m,4H),3.85-3.64(m,5H),3.52-3.50(m,1H),3.48-3.45(m,1H),2.83-2.85(m,1H),2.10-1.93(m,2H);LC-MS:[M+1]+476.1。
实施例12:2-(4-氟-苯磺酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮
类似于对于合成2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮(实施例2)所述的程序,从5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮,盐酸盐和4-氟-苯磺酰氯制备标题化合物。1HNMR(300MHz,CDCl3):δ7.90-7.85(m,2H),7.27-7.21(m,6H),3.73-3.44(m,5H),3.22-3.09(m,2H),2.78-2.75(m,1H),2.10-1.94(m,2H);LC-MS:[M+1]+459.1。
实施例13:2-苯甲磺酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮
类似于对于合成2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮(实施例2)所述的程序,从5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮,盐酸盐和苯基-甲磺酰氯制备标题化合物。1HNMR(300MHz,CDCl3):δ7.43-7.25(m,9H),4.31(s,2H),3.74-3.64(m,4H),3.36-3.34(m,2H),3.17-3.07(m,2H),2.00-1.84(m,2H);LC-MS:[M+1]+455.1。
实施例14:4-氧代-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-2-甲酸(4-氟-苯基)-酰胺
类似于对于合成2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮(实施例2)所述的程序,从5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮,盐酸盐和1-氟-4-异氰酸基-苯制备标题化合物。1HNMR(300MHz,CDCl3):δ7.34-7.21(m,6H),6.98-6.57(m,2H),6.36(s,1H),3.96-3.28(m,7H),2.82-2.79(m,1H),2.15-1.93(m,2H);LC-MS:[M+1]+438.1。
实施例15:2-(2-氯-吡啶-3-磺酰基)-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮
a)丁-3-烯基-[4-(2,2,2-三氟-乙氧基)-苯基]-胺
将4-(2,2,2-三氟-乙氧基)-苯胺(2.5g,13mmol),4-溴丁-1-烯(3.54g,26mmol)和Cs2CO3(6.41g,20mmol)的混合物在30mL的DMF中在环境温度搅拌72h。然后将混合物过滤并用水洗涤。将滤液用EtOAc(30mLx3)萃取。将合并的有机层用盐水洗涤并用无水硫酸钠干燥且蒸发至干。将残余物通过硅胶柱色谱(用石油醚/乙酸乙酯=30∶1洗脱)纯化。获得标题化合物(0.7g,22%),为褐色油状物。LC-MS:246.1[M+1]+。
b)N-丁-3-烯基-N-[4-(2,2,2-三氟-乙氧基)-苯基]-丙烯酰胺
在0℃向丁-3-烯基-[4-(2,2,2-三氟-乙氧基)-苯基]-胺(1.56g,6mmol)和NEt3(1.7g,17mmol)在30mL的DCM中的混合物中缓慢加入丙烯酰氯(0.65g,7mmol)。将混合物在环境温度搅拌过夜。然后将溶液用水(2x15mL)和盐水(2x20mL)洗涤,用无水硫酸钠干燥且蒸发至干。将残余物通过硅胶柱色谱(用石油醚/乙酸乙酯=20∶1洗脱)纯化,获得标题化合物(1.6g,89%),为无色油状物。LC-MS:300.1[M+1]+。
c)1-[4-(2,2,2-三氟-乙氧基)-苯基]-5,6-二氢-1H-吡啶-2-酮
将N-丁-3-烯基-N-[4-(2,2,2-三氟-乙氧基)-苯基]-丙烯酰胺(1.6g,5mmol)和Grubbs催化剂(0.24g)在30mL的DCM中的混合物加热至45℃过夜。将混合物蒸发至干。将残余物通过硅胶柱色谱(用石油醚/乙酸乙酯=5∶1洗脱)纯化,获得标题化合物,为灰色固体(0.9g,66%)。LC-MS:272.1[M+1]+。
d)2-苄基-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮
将1-[4-(2,2,2-三氟-乙氧基)-苯基]-5,6-二氢-1H-吡啶-2-酮(0.27g,0.1mmol),N-苄基(甲氧基)-N-((三甲基甲硅烷基)甲基)甲胺(0.71g,0.3mmol)和TFA(0.114g,0.1mmol)在20mL的DCM中的混合物在45℃搅拌30h。将混合物蒸发至干并将残余物通过硅胶柱色谱(用石油醚/乙酸乙酯=1∶1洗脱)纯化,获得标题化合物,为无色油状物(0.125g,31%)。LC-MS:405.2[M+1]+。
e)5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮
将2-苄基-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮(2g,5mmol),Pd/C(0.8g,20%),Boc2O(2.15g,10mmol)在30mL的MeOH中的混合物在环境温度在氢气氛下搅拌3h。将混合物过滤并蒸发至干。将残余物通过硅胶柱色谱(用DCM/MeOH=100∶1洗脱)纯化,获得Boc-中间体(0.7g,34%),为灰色固体。LC-MS:359.1[M-58]+。将HCl(气体)鼓泡至中间体(0.6g,1mmol)在20mL的EtOAc中的溶液中1.5h并将溶液蒸发至干。将残余物用10mL的EtOAc稀释,并且标题化合物沉淀,为白色固体(0.33g,92%)。
f)2-(2-氯-吡啶-3-磺酰基)-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮
类似于对于合成2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮(实施例2)所述的程序,从5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮和2-氯-吡啶-3-磺酰氯制备标题化合物。1HNMR(300MHz,CD3OD):δ8.57(dd,1H,J=1.8Hz),8.45(dd,1H,J=1.8Hz),7.57(dd,1H,J=6Hz),7.20(d,2H,J=12Hz),7.04(d,2H,J=12Hz),4.58-4.50(m,2H),3.84-3.62(m,5H),3.48-3.44(m,1H),3.36-3.21(m,1H),2.90-2.85(bs,1H),2.11-2.05(m,1H),1.95-1.31(m,1H)。LC-MS:490.1[M+1]+。
实施例16:2-苯磺酰基-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮
类似于对于合成2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮(实施例2)所述的程序,从5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮和苯磺酰氯制备标题化合物。1HNMR(300MHz,CD3OD):δ7.90(d,2H,J=6Hz),7.76-7.64(m,3H),7.15(t,2H,J=6Hz),4.59-4.51(m,2H),3.74-3.45(m,5H),3.26-3.21(m,1H),3.05(t,1H,J=6Hz),2.77-2.71(bs,1H),2.04-1.96(m,1H),1.75-1.66(m,1H)。LC-MS:455.1[M+1]+。
实施例17:5-[4-(2,2,2-三氟-乙氧基)-苯基]-2-(2-三氟甲氧基-苯磺酰基)-八氢-吡咯并[3,4-c]吡啶-4-酮
类似于对于合成2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮(实施例2)所述的程序,从5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮和2-三氟甲氧基-苯磺酰氯制备标题化合物。1HNMR(300MHz,CD3OD):δ8.02(t,1H,J=1.8Hz),7.79-7.73(m,1H),7.54(dd,2H,J=3Hz),7.20-7.14(m,2H),7.03(dd,2H,J=2.1Hz),4.57-4.49(m,2H),3.78-3.55(m,5H),3.38-3.31(m,1H),3.21-3.13(m,1H),2.76-2.82(bs,1H),2.06-2.00(m,1H),1.86-1.78(m,1H)。LC-MS:539.1[M+1]+。
实施例18:2-(2-对甲苯基-乙酰基)-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮
类似于对于合成2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮(实施例2)所述的程序,从5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮和对甲苯基-乙酰氯制备标题化合物。1HNMR(300MHz,CDCl3):δ7.31-7.23(m,5H),7.14(dd,2H,J=3.6Hz),6.93(dd,2H,J=4.2Hz),4.37-4.31(m,2H),4.29-3.53(m,6H),3.22-3.20(m,1H),2.65-2.80(bs,1H),2.04-2.02(m,1H),1.86-1.85(m,1H)。LC-MS:433.1[M+1]+。
实施例19:2-[2-(4-氟-苯基)-乙酰基]-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮
类似于对于合成2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮(实施例2)所述的程序,从5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮和2-(4-氟-苯基)-乙酰胺制备标题化合物。1HNMR(300MHz,CDCl3):δ7.25-7.12(m,4H),7.02-6.91(m,4H),4.33(q,2H,J=8.1Hz),3.87(d,2H,J=7.8Hz),3.94-3.50(m,6H),3.26-3.10(m,1H),2.80-2.68(m,1H),2.11-1.70(m,2H)。LC-MS:[M+1]+=451.1。
实施例20:5-[4-(2,2,2-三氟-乙氧基)-苯基]-2-(2-三氟甲基-苯磺酰基)-八氢-吡咯并[3,4-c]吡啶-4-酮
类似于对于合成2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮(实施例2)所述的程序,从5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮和2-三氟甲基-苯磺酰氯制备标题化合物。1HNMR(300MHz,CDCl3):δ8.16(t,1H,J=3.6Hz),7.88(dd,1H,J=6Hz),7.69(dd,2H,J=3Hz),7.14(d,2H,J=9Hz),6.93(d,2H,J=9Hz),4.36-4.28(m,2H),3.76-3.58(m,5H),3.42(dd,1H,J=1.8Hz),3.21-3.18(m,1H),2.78-2.82(bs,1H),2.03-2.01(m,1H),1.95-1.91(m,1H)。LC-MS:523.0[M+1]+。
实施例21:2-苯基乙酰基-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮
类似于对于合成2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮(实施例2)所述的程序,从5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮和苯基-乙酰氯制备标题化合物。1HNMR(300MHz,CDCl3):δ7.31-7.23(m,5H),7.14(dd,2H,J=3.6Hz),6.93(dd,2H,J=4.2Hz),4.37-4.31(m,2H),4.29-3.53(m,6H),3.22-3.20(m,1H),2.65-2.80(bs,1H),2.04-2.02(m,1H),1.86-1.85(m,1H)。LC-MS:433.1[M+1]+。
实施例22:2-(3,3-二甲基-丁酰基)-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮
类似于对于合成2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮(实施例2)所述的程序,从5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮和3,3-二甲基-丁酰氯制备标题化合物。1HNMR(300MHz,CDCl3):δ7.19(d,2H,J=9.0Hz),6.96(d,2H,J=9.0Hz),4.35(q,2H,J=7.8Hz),4.12-4.09(m,6H),3.28-3.13(m,1H),2.85-2.70(m,1H),2.22(s,2H),2.16-1.83(m,2H),1.08(s,9H)。LC-MS:[M+1]+=413.2。
实施例23:2-(2-氯-苯磺酰基)-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮
类似于对于合成2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮(实施例2)所述的程序,从5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮和2-氯-苯磺酰氯制备标题化合物。1HNMR(300MHz,CDCl3):δ8.25(d,1H,J=7.8Hz),7.70-7.53(m,3H),7.32(d,2H,J=9.0Hz),7.09(d,2H,J=9.0Hz),4.48(q,2H,J=8.1Hz),3.99-3.71(m,5H),3.65(dd,1H,J1=10.2Hz,J2=3.3Hz),3.37(q,1H,J=9.0Hz),3.02-2.86(m,1H),2.27-2.03(m,2H)。LC-MS:[M+1]+=489.1。
实施例24:N-(4-氟-苯基)-3-甲基-2-{4-氧代-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-2-基}-丁酰胺
将2-溴-3-甲基丁酸(2.5g,14mmol)加入20mL的SOCl2中。将混合物回流1h。将过剩的SOCl2除去。将残余物加入4-氟苯胺(1.33g,12mmol)在10mL的DCM中的溶液中。将混合物在环境温度搅拌0.5h且蒸发至干。将粗产物(3.0g,78%)不经进一步纯化地用于随后的步骤中。将5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮(90mg,26mmol),粗制α-溴酰胺(211mg,0.77mmol)和K2CO3(106mg,0.77mmol)在15mL的DMF中的混合物加热至85℃过夜。将混合物用水(15mL)稀释并用EtOAc(2x20mL)萃取,将合并的有机层用水(2x10mL),盐水(2x10mL)洗涤,用无水Na2SO4干燥且蒸发至干。将残余物用制备型-TLC(用DCM/MeOH=30∶1洗脱)纯化,获得标题化合物(33mg,25%),为无色油状物。1HNMR(300MHz,CDCl3):δ7.29-7.13(m,2H),7.01-6.84(m,4H),6.69-6.65(m,2H),6.61(bs,1H),4.43-4.35(m,2H),4.03-3.65(m,7H),3.29-3.27(m,1H),2.80(bs,1H),2.10-1.65(m,3H),1.11-1.07(t,6H,J=5.4Hz)。LC-MS:508.2[M+1]+。
实施例25:4-氧代-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-2-甲酸叔丁酯
将2-苄基-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮(2g,5mmol),Pd/C(0.8g,20%),Boc2O(2.15g,10mmol)在30mL的MeOH中的混合物在环境温度在氢气氛下搅拌3h。将混合物过滤并蒸发至干。将残余物通过硅胶柱色谱(用DCM/MeOH=100∶1洗脱)纯化,获得标题化合物(0.7g,34%),为灰色固体。LC-MS:359.1[M-58]+。
实施例26:2-[2-(2,4-二氯-苯基)-2-羟基-乙基]-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮
将5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮(60mg,0.17mmol),2-溴-1-(2,4-二氯苯基)乙酮(92mg,0.34mmol)和NEt3(80mg,0.8mmol)在20mL的THF中的混合物在环境温度搅拌4h且蒸发至干。将残余物用水洗涤并用DCM萃取。将有机层用盐水洗涤,用无水Na2SO4干燥,然后蒸发至干。将残余物用制备型-TLC(用DCM/MeOH=10∶1洗脱)纯化,获得相应的酮衍生物(30mg,35%)。将其放入5mL的MeOH中并加入NaBH4(15mg,0.4mmol)。将混合物在环境温度搅拌2h且蒸发至干。将残余物通过制备型-TLC(用DCM/MeOH=10∶1洗脱)纯化,获得标题化合物(12mg,40%),为无色油状物。1HNMR(300MHz,CDCl3):δ7.62(d,1H,J=8.4Hz),7.33-7.21(m,2H),7.18(d,2H,J=3Hz),6.95(d,2H,J=7.8Hz),5.18(bs,1H),4.34(dd,2H,J=7.2Hz),3.62(d,2H,J=12.9Hz),3.44-3.23(m,4H),2.86-2.61(m,4H),2.16-2.10(m,1H),1.86-1.82(m,1H)。LC-MS:503.1[M+1]+。
实施例27:2-(2-羟基-苯基)-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮
将5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮(200mg,0.6mmol),1-碘-2-甲氧基苯(300mg,1.3mmol),Pd2(dba)3(100mg,0.1mmol),tBuOK(200mg,1.8mmol)和2-(二叔丁基膦基)联苯(200mg,0.7mmol)在甲苯(20mL)中的混合物在氮气氛下回流过夜。将混合物冷却并过滤,将所得溶液在真空中浓缩。将残余物通过硅胶柱色谱(石油醚/乙酸乙酯=1/1)纯化,获得中间体醚(30mg,11%)。将其放入无水二氯甲烷(20mL)中。将混合物冷却至-78℃,将三氟硼烷(1mL)滴加至混合物中并将混合物在-78℃搅拌2h,在室温搅拌1h并在回流搅拌1h。将混合物倾倒入水(20mL)中,用二氯甲烷(3x20mL)萃取,将有机层合并,用无水硫酸钠干燥,过滤并浓缩。将残余物通过硅胶柱色谱(用乙酸乙酯/石油醚=1/2洗脱)纯化,获得标题化合物(20mg,69%)。1HNMR(300MHz,CDCl3):7.29-7.13(m,4H),7.10-6.86(m,5H),4.38(q,2H,J=8.1Hz),3.79-3.26(m,6H),3.08-2.92(m,2H),2.27-1.92(m,2H)。LC-MS:[M+1]+=407.2。
实施例28:4-氧代-5-(4-三氟甲氧基-苯基)-六氢-吡咯并[3,4-c]吡咯-2-甲酸(4-三氟甲氧基-苯基)-酰胺
a)5-苄基-2-(4-三氟甲氧基-苯基)-四氢-吡咯并[3,4-c]吡咯-1,3-二酮
在4℃将三氟乙酸(0.89g,0.78mmol)在二氯甲烷中的溶液加入到1-(4-(三氟甲氧基)苯基)-1H-吡咯-2,5-二酮(2.0g,7.8mmol)和N-(甲氧基甲基)(苯基)-N-((三甲基甲硅烷基)甲基)甲胺(2.2g,9.3mmol)在二氯甲烷(100mL)中的搅拌溶液中。在室温3h后,将溶液用饱和碳酸氢钠(80mL)和盐水(80mL)洗涤并用Na2SO4干燥。在除去二氯甲烷后,将残余物通过在硅胶上采用石油醚∶乙酸乙酯(10∶1至5∶1)的柱色谱纯化,获得标题化合物(2.8g,90%)。1HNMR(300MHz,CDCl3):δ7.46-7.41(m,5H),7.38-7.31(m,4H),4.19(s,2H),3.89-3.87(m,2H),3.67-3.65(m,2H),3.21(bs,2H),LC-MS:[M+1]+390.9。
b)5-苄基-3-羟基-2-(4-三氟甲氧基-苯基)-六氢-吡咯并[3,4-c]吡咯-1-酮
向5-苄基-2-(4-三氟甲氧基-苯基)-四氢-吡咯并[3,4-c]吡咯-1,3-二酮(0.6g,0.5mmol)和CeCl3·7H2O(0.56g,0.5mmol)在250mLEtOH/二氯甲烷(1.5∶1)中的冷却(-35~-40℃)溶液中依次加入NaBH4(0.057g,10mmol)。将温度在-35~-40℃保持2h,倾倒入冷水(100mL)中并用二氯甲烷(2x80mL)萃取。在将有机相用盐水(100mL)洗涤并用无水Na2SO4干燥后,将溶剂除去并将粗产物通过在硅胶上采用石油醚/乙酸乙酯(5∶1至2∶1)的柱色谱纯化,获得标题化合物(0.17g,29%)。1HNMR(300MHz,CDCl3):δ7.78(d,2H,J=9.0Hz),7.38-7.22(m,7H),5.52(d,1H,J=6.9Hz),3.69(q,2H,J=12.6Hz),3.20-3.18(m,3H),3.07(bs,1H),2.52(t,1H,J=10.1Hz),2.31-2.28(m,1H);LC-MS:[M+1]+393.0。
c)5-苄基-2-(4-三氟甲氧基-苯基)-六氢-吡咯并[3,4-c]吡咯-1-酮
向5-苄基-3-羟基-2-(4-三氟甲氧基-苯基)-六氢-吡咯并[3,4-c]吡咯-1-酮(6.0g,15.3mmol)在三氟乙酸(50mL)中的溶液中加入NaCNBH3(1.0g,15.3mmol)并将混合物在室温搅拌过夜。将三氟乙酸通过减压除去并将残余物加入二氯甲烷(50mL)中。加入Na2CO3的饱和溶液(70mL)。将混合物用二氯甲烷(2x60mL)萃取,用盐水(100mL)洗涤,用Na2SO4干燥。将溶剂除去并将粗产物通过在硅胶上采用石油醚∶乙酸乙酯(10∶1至5∶1)的柱色谱纯化,获得标题化合物(4.0g,70%)。1HNMR(300MHz,CDCl3):δ7.73-7.69(m,2H),7.31-7.22(m,7H),4.04(t,1H,J=9.5Hz),3.74-3.54(m,3H),3.28-3.17(m,2H),2.95(bs,1H),2.76-2.74(m,1H),2.63-2.53(m,2H);LC-MS:[M+1]+376.9。
d)4-氧代-5-(4-三氟甲氧基-苯基)-六氢-吡咯并[3,4-c]吡咯-2-甲酸叔丁酯
将5-苄基-2-(4-三氟甲氧基-苯基)-六氢-吡咯并[3,4-c]吡咯-1-酮(2.5g,6.6mmol),Pd/C(0.5g,0.1(w/w))和二碳酸二叔丁酯(9.8g,45.5mmol)在甲醇(50mL)中的悬浮液在氢气氛下在室温搅拌过夜。将催化剂滤出。将滤液浓缩并将残余物通过在硅胶上采用石油醚∶乙酸乙酯(10∶1至5∶1)的柱色谱纯化,获得标题化合物(2.4g,94%)。1HNMR(300MHz,CDCl3):δ7.67-7.64(m,2H),7.24-7.21(m,2H),4.07-4.05(m,1H),3.95-3.81(m,2H),3.66-3.62(m,2H),3.26-3.10(m,3H),1.46(s,9H);LC-MS:[M+23]+408.9。
e)2-(4-三氟甲氧基-苯基)-六氢-吡咯并[3,4-c]吡咯-1-酮,盐酸盐
在搅拌下向在乙酸乙酯中的饱和盐酸溶液(40mL)中加入4-氧代-5-(4-三氟甲氧基-苯基)-六氢-吡咯并[3,4-c]吡咯-2-甲酸叔丁酯(3.0g,7.8mmol)。将反应混合物搅拌过夜。在减压下除去溶剂,获得标题化合物(2.4g,96%)。1HNMR(300MHz,d6-DMSO):δ9.11(bs,1H),7.81-7.76(m,2H),7.40-7.38(m,2H),4.10-4.08(m,1H),3.73-3.70(m,1H),3.55-3.15(m,6H);LC-MS:[M+1]+287.8。
f)4-氧代-5-(4-三氟甲氧基-苯基)-六氢-吡咯并[3,4-c]吡咯-2-甲酸(4-三氟甲氧基-苯基)-酰胺
将2-(4-三氟甲氧基-苯基)-六氢-吡咯并[3,4-c]吡咯-1-酮,盐酸盐(0.11g,0.36mmol),1-异氰酸基-4-(三氟甲氧基)苯(0.15g,0.72mmol)和Et3N(0.15g,1.44mmol)加入二氯甲烷(2mL)中,将混合物在环境温度搅拌过夜。将混合物在减压下浓缩,通过制备型-HPLC纯化,获得标题化合物(50mg,28%),为白色固体。1HNMR(300MHz,CDCl3):δ7.68-7.65(m,2H),7.42-7.40(m,2H),7.39-7.13(m,4H),4.18-4.03(m,3H),3.79-3.69(m,2H),3.45-3.38(m,2H),3.22-3.20(m,1H);LC-MS:489.8[M+1]+。
实施例29:5-(4-乙基-苯基)-4-氧代-六氢-吡咯并[3,4-c]吡咯-2-甲酸(4-三氟甲氧基-苯基)-酰胺
a)2-(4-乙基-苯基)-六氢-吡咯并[3,4-c]吡咯-1-酮,盐酸盐
类似于对于合成2-(4-三氟甲氧基-苯基)-六氢-吡咯并[3,4-c]吡咯-1-酮,盐酸盐(实施例28步骤e)所述的程序,从N-(甲氧基甲基)(苯基)-N-((三甲基甲硅烷基)甲基)甲胺和1-(4-(三氟甲氧基)苯基)-1H-吡咯-2,5-二酮,并随后还原和保护基处理,制备标题化合物。1HNMR(300MHz,CDCl3):δ7.54-7.51(m,2H),7.20(d,J=8.4Hz,2H),4.11-4.07(m,1H),3.60-3.56(m,2H),3.25-3.19(m,3H),2.99-2.96(m,2H),2.64-2.61(q,2H,J=7.5Hz),2.39(bs,1H),1.23(t,3H,J=7.5Hz);LC-MS:[M+1]+231.1。b)5-(4-乙基-苯基)-4-氧代-六氢-吡咯并[3,4-c]吡咯-2-甲酸(4-三氟甲氧基-苯基)-酰胺
类似于对于合成4-氧代-5-(4-三氟甲氧基-苯基)-六氢-吡咯并[3,4-c]吡咯-2-甲酸(4-三氟甲氧基-苯基)-酰胺(实施例28,步骤f)所述的程序,从2-(4-乙基-苯基)-六氢-吡咯并[3,4-c]吡咯-1-酮,盐酸盐和1-异氰酸基-4-(三氟甲氧基)苯制备标题化合物。1HNMR(300MHz,CDCl3):δ7.49(d,2H,J=8.1Hz),7.42(d,2H,J=9.0Hz),7.22(d,2H,J=8.4Hz),7.12(d,2H,J=8.4Hz),6.39(s,1H),4.16-4.02(m,3H),3.77-3.66(m,2H),3.43-3.37(m,2H),3.21-3.14(m,1H),2.64(q,2H,J=7.5Hz),1.23(t,3H,J=7.5Hz)。LC-MS:432.0[M+1]+。
实施例30:5-羟基-5-丙基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮
a)5-亚甲基-2-(4-三氟甲氧基-苯基)-四氢-环戊二烯并[c]吡咯-1,3-二酮
将5-亚甲基-四氢-环戊二烯并[c]呋喃-1,3-二酮(2.8g,18.4mmol)和4-(三氟甲氧基)苯胺(2.6g,14.7mmol)的混合物在180℃搅拌0.5h。将混合物冷却至室温并通过硅胶柱(石油醚(petroleum)/乙酸乙酯=5/1)纯化,获得标题化合物(3.0g,66%)。1HNMR(300MHz,CDCl3):δ7.33-7.26(m,4H),4.99(s,2H),3.44-3.41(m,2H),2.84-2.78(m,4H);LC-MS:[M+1]+312.0。
b)3-羟基-5-亚甲基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮
向5-亚甲基-2-(4-三氟甲氧基-苯基)-四氢-环戊二烯并[c]吡咯-1,3-二酮(0.7g,2.25mmol)在EtOH/二氯甲烷(15/10mL)中的冷却(-20℃)溶液中依次加入CeCl3.7H2O(1.0g,2.7mmol)和NaBH4(0.84g,22.5mmol)。将混合物在-20℃搅拌0.5h,然后倾倒入冷水(20mL)中并用二氯甲烷(2x15mL)萃取。将溶剂通过减压除去并将残余物通过硅胶柱(石油醚/乙酸乙酯=5∶1)纯化,获得标题化合物(0.55g,78%)。HNMR(300MHz,CDCl3):δ7.64-7.60(m,2H),7.25-7.22(m,2H),5.67-5.61(m,1H),5.07(s,1H),4.98(s,1H),3.21-3.09(m,2H),2.81-2.56(m,5H);LC-MS:[M+1]+314.1。c)5-亚甲基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮
在-20℃向3-羟基-5-亚甲基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮(0.1g,0.32mmol)在三氟乙酸(20mL)中的溶液中加入NaCNBH3(0.04g,0.64mmol),并将混合物搅拌1h。加入水(30mL)。将混合物用二氯甲烷(3x20mL)萃取,用盐水(50mL)洗涤,并用无水Na2SO4干燥。将溶剂通过减压除去。将残余物通过在硅胶上采用石油醚/乙酸乙酯(10∶1至5∶1)的柱色谱纯化,获得标题化合物(40mg,40%)。1HNMR(300MHz,CDCl3):δ7.69-7.64(m,2H),7.25-7.19(m,2H),4.91(s,2H),4.07-4.01(m,1H),3.54-3.49(m,1H),3.19-3.12(m,1H),2.96-2.71(m,4H),2.25-2.18(m,1H);LC-MS:[M+1]+298.1。
d)2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1,5-二酮
将缓慢的臭氧流鼓泡至5-亚甲基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮(0.1g,0.34mmol)在30mL的二氯甲烷中在-78℃的溶液中。保持臭氧流直至持续微蓝色。在用氮气流除去过量臭氧后,在-78℃加入2mL的二甲基硫醚。然后使混合物升温至室温,并搅拌过夜。将溶剂除去,并将粗产物通过制备型-TLC(MeOH:二氯甲烷=1∶50)纯化,获得标题化合物(50mg,50%)。1HNMR(300MHz,CDCl3):δ7.69-7.65(m,2H),7.26-7.22(m,2H),4.20(t,1H,J=8.4Hz),3.69-3.66(m,1H),3.45-3.38(m,1H),3.22-3.16(m,1H),2.88-2.56(m,3H),2.25-2.18(m,1H);LC-MS:300.1[M+1]+。
e)5-羟基-5-丙基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮
将溴化丙基镁(0.2mL,0.6mmol,3M)加入2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1,5-二酮(0.1g,0.33mmol)在THF(10mL)中的溶液中,并将混合物在室温搅拌3h并在35℃搅拌过夜。将溶液冷却,然后倾倒入水(25mL)中并用***(3x20mL)萃取,用Na2SO4干燥。将溶剂除去并将残余物通过制备型-TLC(石油醚/乙酸乙酯=1∶1)纯化,获得标题化合物(25mg,21%)。1HNMR(300MHz,CDCl3):δ7.62-7.60(m,2H),7.32-7.23(m,2H),4.11(t,1H,J=9.5Hz),3.71-3.67(m,1H),3.18(t,1H,J=9.5Hz),2.95(d,1H,J=9.6Hz),2.25-2.21(m,1H),1.98-1.88(m,2H),1.81-1.76(m,1H),1.61-1.34(m,4H),0.95(t,3H,J=7.2Hz);LC-MS:344.2[M+1]+。
实施例31:5-羟基-5-(2,2,2-三氟-乙氧基甲基)-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮
a)外消旋-(3aR,5S,6aS)-2-[4-(三氟甲氧基)苯基]六氢-1H-螺[环戊二烯并[c]吡咯-5,2′-环氧乙烷]-1-酮
和
外消旋-(3aR,5R,6aS)-2-[4-(三氟甲氧基)苯基]六氢-1H-螺[环戊二烯并[c]吡咯-5,2′-环氧乙烷]-1-酮
在0℃向5-亚甲基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮(0.78g,2.6mmol)在二氯甲烷(20mL)中的溶液加入mCPBA(0.9g,5.2mmol),并将混合物在室温搅拌6h。加入NaHCO3的饱和溶液(30mL)并搅拌另外0.5h。将混合物用二氯甲烷(2x30mL)萃取,用盐水(60mL)洗涤并用Na2SO4干燥。将溶剂除去并将残余物通过采用石油醚/乙酸乙酯(1∶1)的制备型-TLC纯化,获得外消旋-(3aR,5S,6aS)-2-[4-(三氟甲氧基)苯基]六氢-1H-螺[环戊二烯并[c]吡咯-5,2′-环氧乙烷]-1-酮0.11g(13.5%)和外消旋-(3aR,5R,6aS)-2-[4-(三氟甲氧基)苯基]六氢-1H-螺[环戊二烯并[c]吡咯-5,2′-环氧乙烷]-1-酮0.27g(33.2%)。外消旋-(3aR,5S,6aS)-2-[4-(三氟甲氧基)苯基]六氢-1H-螺[环戊二烯并[c]吡咯-5,2′-环氧乙烷]-1-酮:1HNMR(300MHz,CDCl3):δ7.71-7.68(m,2H),7.27-7.22(m,2H),4.15-4.09(m,1H),3.62-3.58(m,1H),3.34-3.30(m,1H),3.16-3.11(m,1H),2.93-2.85(m,2H),2.55-2.49(m,1H),2.19-1.87(m,3H);LC-MS:314.0[M+1]+。外消旋-(3aR,5R,6aS)-2-[4-(三氟甲氧基)苯基]六氢-1H-螺[环戊二烯并[c]吡咯-5,2′-环氧乙烷]-1-酮:1HNMR(300MHz,CDCl3):δ7.69-7.65(m,2H),7.26-7.20(m,2H),4.16-4.10(m,1H),3.74-3.69(m,1H),3.24-3.22(m,1H),3.07-3.04(m,1H),2.95-2.84(m,2H),2.48-2.40(m,2H),2.12-2.06(m,1H),1.66-1.59(m,1H);LC-MS:314.0[M+1]+
b)5-羟基-5-(2,2,2-三氟-乙氧基甲基)-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮
将一小片的钠加入2,2,2-三氟-乙醇(20mL)中,并将混合物在80℃搅拌5分钟,然后加入外消旋-(3aR,5S,6aS)-2-[4-(三氟甲氧基)苯基]六氢-1H-螺[环戊二烯并[c]吡咯-5,2′-环氧乙烷]-1-酮。将混合物搅拌6h。然后将溶液倾倒入水(25mL)中并用***(3x20mL)萃取,用Na2SO4干燥。将溶剂除去并将残余物通过制备型-TLC(石油醚∶乙酸乙酯=1∶1)纯化,获得标题化合物。1HNMR(300MHz,CDCl3):δ7.66-7.63(m,2H),7.20-7.17(m,2H),4.13(t,1H,J=9.6Hz),3.86(q,2H,J=8.7Hz),3.71-3.61(m,3H),3.22-3.17(m,1H),3.05-2.99(m,1H),2.38-2.33(m,1H),2.09-1.76(m,4H);LC-MS:414.1[M+1]+。
实施例32:5-羟基-5-苯基氨基甲基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮
将外消旋-(3aR,5S,6aS)-2-[4-(三氟甲氧基)苯基]六氢-1H-螺[环戊二烯并[c]吡咯-5,2′-环氧乙烷]-1-酮(80mg,0.25mmol),苯胺(5mL)和PhOH(23mg,0.24mmol)一起混合,并将混合物在60℃搅拌24h。然后将溶液倾倒入水(25mL)中并用***萃取(3x20mL)。将合并的醚用氢氧化钠(10%,3x10mL)洗涤,用水(30mL)洗涤并用Na2SO4干燥。将溶剂除去并将残余物通过制备型-TLC(石油醚∶乙酸乙酯=1∶1)纯化,获得标题化合物(25mg,24%)。1HNMR(300MHz,CDCl3):δ7.57-7.55(m,2H),7.27-7.13(m,4H),7.00-6.93(m,3H),5.26(bs,1H),4.07(t,1H,J=9.3Hz),3.75-3.73(m,1H),3.34-2.22(m,3H),3.05-2.90(m,1H),2.46-2.42(m,1H),2.02-1.90(m,3H);LC-MS:407.1[M+1]+。
实施例33:2-氯-N-[(3aR,6aS)-1-氧代-2-(4-三氟甲氧基-苯基)-八氢-环戊二烯并[c]吡咯-5-基]-苯磺酰胺
a)5-苄基氨基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮
向2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1,5-二酮(0.5g,1.6mmol)和苄胺(0.34g,3.2mmol)在二氯甲烷(10mL)中的溶液中加入NaBH(AcO)3(1.0g,4.7mmol)。将混合物在环境温度搅拌6h。将混合物用二氯甲烷(2x15mL)萃取,用盐水(30mL)洗涤,用无水Na2SO4干燥。将溶剂除去,并将粗产物通过二氧化硅柱(MeOH/二氯甲烷=1/30)纯化,获得标题化合物(0.4g,63%)。1HNMR(300MHz,CDCl3):δ7.67-7.63(m,2H),7.32-7.07(m,7H),4.08(t,1H,J=9.3Hz),3.76-3.56(m,3H),3.34-3.31(m,1H),3.16-3.09(m,1H),2.88-2.83(m,1H),2.21-2.02(m,3H),1.65-1.58(m,1H)。
b)1-氧代-2-(4-三氟甲氧基-苯基)-八氢-环戊二烯并[c]吡咯-5-基]-氨基甲酸叔丁酯
将5-苄基氨基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮(0.4g,1mmol),Pd/C(0.2g,0.1(w/w))和二碳酸二叔丁酯(0.45g,2mmol)在甲醇(30mL)中的悬浮液在氢气氛下在室温搅拌过夜。将催化剂滤出。将滤液浓缩并将残余物通过在硅胶上采用石油醚∶乙酸乙酯(10∶1至5∶1)的柱色谱纯化,获得标题化合物(0.22g,55%)。1HNMR(300MHz,CDCl3):δ7.67-7.61(m,2H),7.25-7.19(m,2H),4.49-4.46(m,1H),4.10-3.96(m,1H),3.57-3.47(m,1H),3.14-3.06(m,1H),2.84-2.79(m,1H),2.43-2.32(m,2H),1.95-1.90(m,1H),1.59-1.50(m,1H),1.38(s,9H);LC-MS:423.1[M+23]+。
c)5-氨基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮,盐酸盐
在搅拌下向在甲醇中的盐酸饱和溶液(10mL)中加入1-氧代-2-(4-三氟甲氧基-苯基)-八氢-环戊二烯并[c]吡咯-5-基]-氨基甲酸叔丁酯(0.22g,0.55mmol)。将反应混合物搅拌6h。在减压下除去溶剂,然后将粗产物(0.2g)不经进一步纯化地用于后面的步骤。
d)2-氯-N-[(3aR,6aS)-1-氧代-2-(4-三氟甲氧基-苯基)-八氢-环戊二烯并[c]吡咯-5-基]-苯磺酰胺
将5-氨基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮,盐酸盐(60mg,0.18mmol),2-氯苯-1-磺酰氯(76mg,0.36mmol)和Et3N(82mg,0.81mmol)加入二氯甲烷(2mL)中,将混合物搅拌过夜。将溶剂除去,并将粗产物通过制备型-TLC(石油醚/乙酸乙酯=1∶1)纯化,获得标题化合物(30mg,33%)。1HNMR(300MHz,CDCl3):δ8.14-8.11(m,1H),7.68-7.49(m,5H),7.26-7.22(m,2H),5.04(d,1H,J=6.6Hz),4.05(t,1H,J=9.0Hz),3.68-3.62(m,2H),3.08-3.06(m,1H),2.79-2.76(m,1H),2.26-2.19(m,2H),1.95-1.93(m,1H),1.73-1.65(m,1H);LC-MS:475.0[M+1]+。
实施例34:5-羟基-5-苯氧基甲基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮
类似于对于合成5-羟基-5-(2,2,2-三氟-乙氧基甲基)-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮(实施例31)所述的程序,从外消旋-(3aR,5S,6aS)-2-[4-(三氟甲氧基)苯基]六氢-1H-螺[环戊二烯并[c]吡咯-5,2′-环氧乙烷]-1-酮和苯酚制备标题化合物。1HNMR(300MHz,CDCl3):δ7.69-7.65(m,2H),7.30-7.18(m,4H),6.98-6.86(m,3H),4.16(t,1H,J=9.3Hz),3.97-3.89(m,2H),3.76-3.73(m,1H),3.26-3.22(m,1H),3.11-2.98(m,1H),2.52-2.47(m,1H),2.21-1.87(m,4H);LC-MS:408.2[M+1]+。
实施例35:5-羟基-5-丙氧基甲基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮
类似于对于合成5-羟基-5-(2,2,2-三氟-乙氧基甲基)-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮(实施例31)所述的程序,从外消旋-(3aR,5S,6aS)-2-[4-(三氟甲氧基)苯基]六氢-1H-螺[环戊二烯并[c]吡咯-5,2′-环氧乙烷]-1-酮和苯酚制备标题化合物。1HNMR(300MHz,CDCl3):δ7.68-7.65(m,2H),7.21-7.18(m,2H),4.13(t,1H,J=9.3Hz),3.73-3.69(m,1H),3.46-3.39(m,4H),3.23-3.20(m,1H),3.17-2.98(m,1H),2.38-2.20(m,2H),2.06-1.56(m,5H),0.94(t,1H,J=7.8Hz);LC-MS:374.1[M+1]+。
实施例36:5-丁氧基甲基-5-羟基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮
类似于对于合成5-羟基-5-(2,2,2-三氟-乙氧基甲基)-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮(实施例31)所述的程序,从外消旋-(3aR,5S,6aS)-2-[4-(三氟甲氧基)苯基]六氢-1H-螺[环戊二烯并[c]吡咯-5,2′-环氧乙烷]-1-酮和丁醇制备标题化合物。1HNMR(300MHz,CDCl3):δ7.68-7.65(m,2H),7.21-7.18(m,2H),4.13(t,1H,J=9.3Hz),3.73-3.68(m,1H),3.51-3.47(m,4H),3.23-3.20(m,1H),3.10-2.94(m,1H),2.38-2.10(m,2H),2.06-1.80(m,3H),1.58-1.51(m,2H),1.50-1.33(m,2H),0.90(t,1H,J=6.9Hz);LC-MS:388.1[M+1]+。
实施例A
可以以本身已知的方式将式(I)化合物用作用于制备具有下列组成的片剂的活性成分:
实施例B
可以以本身已知的方式将式(I)化合物用作用于制备具有下列组成的胶囊的活性成分:
Claims (35)
1.式(I)的化合物
R1是C1-7烷基,卤代C1-7烷氧基C1-7烷基,苯基,取代的苯基,苯基C1-7烷基,取代的苯基C1-7烷基或取代的吡啶基,其中取代的苯基,取代的苯基C1-7烷基和取代的吡啶基被独立地选自C1-7烷基,卤素,卤代C1-7烷基,羟基和卤代C1-7烷氧基中的一至三个取代基取代;
R2是被选自C1-7烷基和卤代C1-7烷氧基中的一个取代基取代的苯基;
R3是氢,羟基或C1-7烷氧基,其中在R3是羟基或C1-7烷氧基的情况下,则E是-C(R5R6)-;
R4是氢或C1-7烷基;
R5是氢或C1-7烷基;
R6是氢或C1-7烷基;
n是1或2;
A是-N或-CR3;
E是键或-C(R5R6)-;
G是-O-,-NR4-,-CH(OH)-,-C(O)-,-C(O)O-,-C(O)NR4-,-S(O)2-,-S(O)2NR4-或键;
其中在E和G均为键的情况下,则R1直接与A连接,
或其药用盐。
2.根据权利要求1所述的化合物,其中R1是C1-7烷基,取代的苯基或苯基C1-7烷基,其中取代的苯基被独立地选自卤素和卤代C1-7烷氧基中的一至三个取代基取代。
3.根据权利要求1至2中任一项所述的化合物,其中R1是C1-7烷基。
4.根据权利要求1至2中任一项所述的化合物,其中R1是苯基C1-7烷基。
5.根据权利要求1至2中任一项所述的化合物,其中R1是被独立地选自卤素和卤代C1-7烷氧基中的一至三个取代基取代的苯基。
6.根据权利要求1至2中任一项所述的化合物,其中R1是被一或两个卤素取代的苯基。
7.根据权利要求1至2中任一项所述的化合物,其中R1是2-氯苯基或2,4-二氯苯基。
8.根据权利要求1至2中任一项所述的化合物,其中R2是被一个卤代C1-7烷氧基取代的苯基。
9.根据权利要求1至2中任一项所述的化合物,其中R2是4-三氟甲氧基苯基。
10.根据权利要求1至2中任一项所述的化合物,其中A是-N。
11.根据权利要求1至2中任一项所述的化合物,其中A是-CR3。
12.根据权利要求1至2中任一项所述的化合物,其中E是-C(R5R6)-。
13.根据权利要求1至2中任一项所述的化合物,其中E是键。
14.根据权利要求1至2中任一项所述的化合物,其中G是-O-,-NR4-,-CH(OH)-,-C(O)-,-C(O)O-,-C(O)NR4-,-S(O)2-,-S(O)2NR4-或键。
15.根据权利要求1至2中任一项所述的化合物,其中G是O,-C(O)-,-CH(OH)-或-S(O)2-。
16.根据权利要求1至2中任一项所述的化合物,其中G是-C(O)-或-S(O)2-。
17.根据权利要求1至2中任一项所述的化合物,其中G是-S(O)2-。
18.根据权利要求1至2中任一项所述的化合物,其中R3是氢或羟基,其中在R3是羟基的情况下,则E是-C(R5R6)-。
19.根据权利要求1至2中任一项所述的化合物,其中R3是氢。
20.根据权利要求1至2中任一项所述的化合物,其中R4是氢。
21.根据权利要求1至2中任一项所述的化合物,其中R5是氢。
22.根据权利要求1至2中任一项所述的化合物,其中R6是氢。
23.根据权利要求1至2中任一项所述的化合物,其中E和G均为键,并具有式I(a):
24.根据权利要求1至2中任一项所述的化合物,其中n是2。
25.根据权利要求1所述的化合物,所述化合物选自:
(3aR,7aS)-4-氧代-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-2-甲酸叔丁酯;
(3aS,7aR)-2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,7aR)-2-(4-氟-苯甲酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,7aR)-2-(3-甲基-丁酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,7aR)-4-氧代-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-2-甲酸(4-三氟甲氧基-苯基)-酰胺;
(3aS,7aR)-2-(4-氟-苄基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,7aR)-2-(2-氯-苯甲酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,7aR)-2-(4-异丙基-苯甲酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,7aR)-2-(3-甲基-丁-1-磺酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,7aR)-2-(2-甲基-丙-1-磺酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,7aR)-2-(2-氯-苯磺酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,7aR)-2-(4-氟-苯磺酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,7aR)-2-苯甲磺酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,7aR)-4-氧代-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-2-甲酸(4-氟-苯基)-酰胺;
(3aR,7aS)-2-(2-氯-吡啶-3-磺酰基)-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aR,7aS)-2-苯磺酰基-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aR,7aS)-5-[4-(2,2,2-三氟-乙氧基)-苯基]-2-(2-三氟甲氧基-苯磺酰基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aR,7aS)-2-(2-对甲苯基-乙酰基)-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aR,7aS)-2-[2-(4-氟-苯基)-乙酰基]-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aR,7aS)-5-[4-(2,2,2-三氟-乙氧基)-苯基]-2-(2-三氟甲基-苯磺酰基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aR,7aS)-2-苯基乙酰基-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aR,7aS)-2-(3,3-二甲基-丁酰基)-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aR,7aS)-2-(2-氯-苯磺酰基)-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮;
N-(4-氟-苯基)-3-甲基-2-{(3aR,7aS)-4-氧代-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-2-基-丁酰胺;
(3aR,7aS)-4-氧代-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-2-甲酸叔丁酯;
(3aR,7aS)-2-[2-(2,4-二氯-苯基)-2-羟基-乙基]-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aR,7aS)-2-(2-羟基-苯基)-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,6aS)-4-氧代-5-(4-三氟甲氧基-苯基)-六氢-吡咯并[3,4-c]吡咯-2-甲酸(4-三氟甲氧基-苯基)-酰胺;
(3aS,6aS)-5-(4-乙基-苯基)-4-氧代-六氢-吡咯并[3,4-c]吡咯-2-甲酸(4-三氟甲氧基-苯基)-酰胺;
(3aR,6aS)-5-羟基-5-丙基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮;
(3aR,5S,6aS)-5-羟基-5-(2,2,2-三氟-乙氧基甲基)-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮;
(3aR,6aS)-5-羟基-5-苯基氨基甲基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮;
2-氯-N-[(3aR,6aS)-1-氧代-2-(4-三氟甲氧基-苯基)-八氢-环戊二烯并[c]吡咯-5-基]-苯磺酰胺;
(3aR,5S,6aS)-5-羟基-5-苯氧基甲基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮;
(3aR,5S,6aS)-5-羟基-5-丙氧基甲基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮;
(3aR,5S,6aS)-5-丁氧基甲基-5-羟基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮;
及其药用盐。
26.根据权利要求1所述的化合物,所述化合物选自:
(3aS,7aR)-2-苯基乙酰基-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aS,7aR)-2-(2-氯-苯磺酰基)-5-(4-三氟甲氧基-苯基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aR,7aS)-5-[4-(2,2,2-三氟-乙氧基)-苯基]-2-(2-三氟甲氧基-苯磺酰基)-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aR,7aS)-2-[2-(2,4-二氯-苯基)-2-羟基-乙基]-5-[4-(2,2,2-三氟-乙氧基)-苯基]-八氢-吡咯并[3,4-c]吡啶-4-酮;
(3aR,5S,6aS)-5-丁氧基甲基-5-羟基-2-(4-三氟甲氧基-苯基)-六氢-环戊二烯并[c]吡咯-1-酮;
及其药用盐。
27.一种制备根据权利要求1至26中任一项所述的化合物的方法,所述方
法包括以下化合物的反应:
a)式(XIII)的化合物;
其中R1,R2,E,G和n如权利要求1中所定义,并且A是-N。
28.一种药物组合物,所述药物组合物包含根据权利要求1至26中任一项的化合物和治疗惰性载体。
29.根据权利要求1至26中任一项的化合物用于制备药物的用途,所述药物用于治疗或预防由与酶激素敏感脂酶相关的紊乱所引起的疾病。
30.根据权利要求1至26中任一项的化合物用于制备药物的用途,所述药物用于治疗或预防糖尿病、代谢综合征、异常脂肪血症、动脉粥样硬化、肥胖症、心血管病、心肌功能障碍、炎症、非酒精性脂肪肝病或非酒精性脂肪肝炎。
31.根据权利要求30所述的用于制备药物的用途,所述药物用于治疗或预防糖尿病、代谢综合征、异常脂肪血症、动脉粥样硬化或肥胖症。
32.根据权利要求30或31所述的用于制备药物的用途,所述药物用于治疗或预防糖尿病。
33.根据权利要求30至31中任一项所述的用于制备药物的用途,所述药物用于治疗或预防II型糖尿病。
34.根据权利要求30所述的用于制备药物的用途,所述药物用于治疗或预防心血管病、心肌功能障碍、炎症、非酒精性脂肪肝病或非酒精性脂肪肝炎。
35.根据权利要求30或34所述的用于制备药物的用途,所述药物用于治疗或预防非酒精性脂肪肝病或非酒精性脂肪肝炎。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11166437.1 | 2011-05-17 | ||
EP11166437 | 2011-05-17 | ||
PCT/EP2012/058852 WO2012156339A1 (en) | 2011-05-17 | 2012-05-14 | New hexahydrocyclopentapyrrolone, hexahydropyrrolopyrrolone, octahydropyrrolopyridinone and octahydropyridinone compounds |
Publications (2)
Publication Number | Publication Date |
---|---|
CN103562180A CN103562180A (zh) | 2014-02-05 |
CN103562180B true CN103562180B (zh) | 2016-04-20 |
Family
ID=46124329
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201280023662.XA Expired - Fee Related CN103562180B (zh) | 2011-05-17 | 2012-05-14 | 新型六氢环戊二烯并吡咯酮,六氢吡咯并吡咯酮,八氢吡咯并吡啶酮和八氢吡啶酮化合物 |
Country Status (12)
Country | Link |
---|---|
US (1) | US8501768B2 (zh) |
EP (1) | EP2709984B1 (zh) |
JP (1) | JP2014513703A (zh) |
KR (1) | KR20140042814A (zh) |
CN (1) | CN103562180B (zh) |
BR (1) | BR112013028368A2 (zh) |
CA (1) | CA2832334A1 (zh) |
ES (1) | ES2537591T3 (zh) |
HK (1) | HK1191942A1 (zh) |
MX (1) | MX346980B (zh) |
RU (1) | RU2013153898A (zh) |
WO (1) | WO2012156339A1 (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8497288B2 (en) * | 2011-05-09 | 2013-07-30 | Hoffmann-La Roche Inc. | Hexahydropyrroloimidazolone compounds |
ES2707739T3 (es) | 2013-09-26 | 2019-04-04 | Cadent Therapeutics Inc | Moduladores negativos de octahidro-ciclopenta[c]pirrol selectivo de NR2B |
JO3579B1 (ar) | 2014-09-26 | 2020-07-05 | Luc Therapeutics Inc | مُعدِلات تفاغرية سالبة لمستقبل nr2b من المركب n-ألكيل أريل-5-أوكسي أريل-ثامن هيدرو-خماسي الحلقة [c] بيرول |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1371369A (zh) * | 1999-09-04 | 2002-09-25 | 阿文蒂斯药物德国有限公司 | 取代的3-苯基-5-烷氧基-1,3,4-噁二唑-2-酮及其作为脂酶抑制剂的用途 |
CN1416424A (zh) * | 2000-03-07 | 2003-05-07 | 阿文蒂斯药物德国有限公司 | 取代的3-苯基-5-烷氧基-1,3,4-噁二唑-2-酮及其抑制激素敏感性脂酶的用途 |
CN101115741A (zh) * | 2005-02-15 | 2008-01-30 | 诺和诺德公司 | 3,4-二氢-1h-异喹啉-2-羧酸5-氨基吡啶-2-基酯 |
CN101336243A (zh) * | 2005-12-05 | 2008-12-31 | 因塞特公司 | 内酰胺化合物和其使用方法 |
CN101432265A (zh) * | 2006-04-25 | 2009-05-13 | 伊莱利利公司 | 11-β-羟类固醇脱氢酶1的抑制剂 |
WO2010108268A1 (en) * | 2009-03-23 | 2010-09-30 | Merck Frosst Canada Ltd. | Heterocyclic compounds as inhibitors of stearoyl-coenzyme a delta-9 desaturase |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004519435A (ja) * | 2000-12-01 | 2004-07-02 | ブリストル−マイヤーズ スクイブ カンパニー | 抗炎症性薬物として有用なヒダントイン化合物 |
KR20100015975A (ko) * | 2007-04-27 | 2010-02-12 | 사노피-아벤티스 | 2-헤테로아릴-피롤로[3,4-c]피롤 유도체 및 SCD 억제제로서의 이들의 용도 |
ME02437B (me) * | 2009-10-23 | 2016-09-20 | Janssen Pharmaceutica Nv | Disupstituirani oktahidropirolo[3,4-c]piroli kao modulatori oreksin receptora |
UY33227A (es) * | 2010-02-19 | 2011-09-30 | Novartis Ag | Compuestos de pirrolopirimidina como inhibidores de la cdk4/6 |
-
2012
- 2012-05-04 US US13/463,863 patent/US8501768B2/en not_active Expired - Fee Related
- 2012-05-14 CA CA2832334A patent/CA2832334A1/en not_active Abandoned
- 2012-05-14 JP JP2014510758A patent/JP2014513703A/ja active Pending
- 2012-05-14 RU RU2013153898/04A patent/RU2013153898A/ru not_active Application Discontinuation
- 2012-05-14 BR BR112013028368A patent/BR112013028368A2/pt not_active IP Right Cessation
- 2012-05-14 EP EP12721814.7A patent/EP2709984B1/en not_active Not-in-force
- 2012-05-14 MX MX2013011628A patent/MX346980B/es active IP Right Grant
- 2012-05-14 WO PCT/EP2012/058852 patent/WO2012156339A1/en active Application Filing
- 2012-05-14 ES ES12721814.7T patent/ES2537591T3/es active Active
- 2012-05-14 KR KR1020137033414A patent/KR20140042814A/ko not_active Application Discontinuation
- 2012-05-14 CN CN201280023662.XA patent/CN103562180B/zh not_active Expired - Fee Related
-
2014
- 2014-05-30 HK HK14105119.9A patent/HK1191942A1/zh not_active IP Right Cessation
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1371369A (zh) * | 1999-09-04 | 2002-09-25 | 阿文蒂斯药物德国有限公司 | 取代的3-苯基-5-烷氧基-1,3,4-噁二唑-2-酮及其作为脂酶抑制剂的用途 |
CN1416424A (zh) * | 2000-03-07 | 2003-05-07 | 阿文蒂斯药物德国有限公司 | 取代的3-苯基-5-烷氧基-1,3,4-噁二唑-2-酮及其抑制激素敏感性脂酶的用途 |
CN101115741A (zh) * | 2005-02-15 | 2008-01-30 | 诺和诺德公司 | 3,4-二氢-1h-异喹啉-2-羧酸5-氨基吡啶-2-基酯 |
CN101336243A (zh) * | 2005-12-05 | 2008-12-31 | 因塞特公司 | 内酰胺化合物和其使用方法 |
CN101432265A (zh) * | 2006-04-25 | 2009-05-13 | 伊莱利利公司 | 11-β-羟类固醇脱氢酶1的抑制剂 |
WO2010108268A1 (en) * | 2009-03-23 | 2010-09-30 | Merck Frosst Canada Ltd. | Heterocyclic compounds as inhibitors of stearoyl-coenzyme a delta-9 desaturase |
Non-Patent Citations (1)
Title |
---|
Pyrrolopyrazinedione-Based Inhibitors of Human Hormone-Sensitive Lipase;Deborah H. Slee,等;《Journal of Medicinal Chemistry》;20030228;第46卷(第7期);第1120-1122页 * |
Also Published As
Publication number | Publication date |
---|---|
ES2537591T3 (es) | 2015-06-09 |
KR20140042814A (ko) | 2014-04-07 |
EP2709984A1 (en) | 2014-03-26 |
US8501768B2 (en) | 2013-08-06 |
RU2013153898A (ru) | 2015-06-27 |
MX346980B (es) | 2017-04-07 |
EP2709984B1 (en) | 2015-03-18 |
US20120295934A1 (en) | 2012-11-22 |
MX2013011628A (es) | 2013-10-25 |
BR112013028368A2 (pt) | 2017-01-24 |
CA2832334A1 (en) | 2012-11-22 |
CN103562180A (zh) | 2014-02-05 |
HK1191942A1 (zh) | 2014-08-08 |
JP2014513703A (ja) | 2014-06-05 |
WO2012156339A1 (en) | 2012-11-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2476431C2 (ru) | Конденсированное производное аминодигидротиазина | |
EP1501803B1 (en) | Tetrahydropyranyl cyclopentyl tetrahydroisoquinoline modulators of chemokine receptor activity | |
US7935815B2 (en) | Imidazoyl pyridine compounds and salts thereof | |
US9453000B2 (en) | Polycyclic compound | |
CN110023291B (zh) | 三环rho激酶抑制剂 | |
DK3074400T3 (en) | Octahydro-cyclobuta [1,2-c; 3,4-c '] dipyrrole derivatives as autotaxin inhibitors | |
CA2701150C (fr) | Derives de quinazolinedione, leur preparation et leurs applications therapeutiques | |
EP2558464B1 (en) | Azacyclic spiroderivatives as hsl inhibitors | |
EP1819332B1 (en) | Pyrrolopyridine-2-carboxylic acid amides | |
JP2019504836A (ja) | アンドロゲン受容体アンタゴニストとしての置換チオヒダントイン誘導体 | |
CA2623154A1 (en) | Novel fused pyrrole derivative | |
CA2558923A1 (fr) | Derives pyrrolo (2,3-b) pyridine, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de kinases | |
CN103562180B (zh) | 新型六氢环戊二烯并吡咯酮,六氢吡咯并吡咯酮,八氢吡咯并吡啶酮和八氢吡啶酮化合物 | |
EP2688881B1 (en) | New azaspirodecanone compounds as hsl inhibitors | |
US8703807B2 (en) | Azaspirodecanone compounds | |
JP6126080B2 (ja) | 新規ヘキサヒドロピロロイミダゾロン化合物 | |
RU2603263C2 (ru) | Новые азациклические соединения | |
CA3180132A1 (en) | Pyrimidin-4(3h)-one derivatives as trpv4 antagonists |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1191942 Country of ref document: HK |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1191942 Country of ref document: HK |
|
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160420 Termination date: 20180514 |