WO1992014714A1 - Substituted pyridinones and pyrimidinones as angiotensin ii antagonists - Google Patents
Substituted pyridinones and pyrimidinones as angiotensin ii antagonists Download PDFInfo
- Publication number
- WO1992014714A1 WO1992014714A1 PCT/GB1992/000280 GB9200280W WO9214714A1 WO 1992014714 A1 WO1992014714 A1 WO 1992014714A1 GB 9200280 W GB9200280 W GB 9200280W WO 9214714 A1 WO9214714 A1 WO 9214714A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- biphenyl
- dihydro
- butyl
- hydroxy
- Prior art date
Links
- 229940123413 Angiotensin II antagonist Drugs 0.000 title abstract description 7
- 239000002333 angiotensin II receptor antagonist Substances 0.000 title abstract description 7
- 150000005299 pyridinones Chemical class 0.000 title description 2
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical class OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 189
- 238000000034 method Methods 0.000 claims abstract description 80
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 87
- 125000000217 alkyl group Chemical group 0.000 claims description 64
- 229910052739 hydrogen Inorganic materials 0.000 claims description 57
- 239000001257 hydrogen Substances 0.000 claims description 57
- -1 6-Butyl-1,2-dihydro-3-((phenylmethoxy) carbonylmethyl)aminocarbonyl-2-oxo-pyridin-1-yl Chemical group 0.000 claims description 45
- 150000002431 hydrogen Chemical group 0.000 claims description 41
- 150000003839 salts Chemical class 0.000 claims description 41
- 150000002148 esters Chemical class 0.000 claims description 40
- 238000002360 preparation method Methods 0.000 claims description 25
- 150000001408 amides Chemical class 0.000 claims description 24
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000006239 protecting group Chemical group 0.000 claims description 12
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- ILYSAKHOYBPSPC-UHFFFAOYSA-N 2-phenylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1C1=CC=CC=C1 ILYSAKHOYBPSPC-UHFFFAOYSA-N 0.000 claims description 9
- 235000010290 biphenyl Nutrition 0.000 claims description 9
- 150000002825 nitriles Chemical class 0.000 claims description 9
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 230000003301 hydrolyzing effect Effects 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 239000011734 sodium Chemical class 0.000 claims description 6
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims description 4
- 230000002152 alkylating effect Effects 0.000 claims description 4
- 150000001540 azides Chemical class 0.000 claims description 4
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 4
- 230000002140 halogenating effect Effects 0.000 claims description 4
- WXHJCMCYHAUERG-UHFFFAOYSA-N 1-[[3-bromo-2-[2-(2h-tetrazol-5-yl)phenyl]-1-benzofuran-5-yl]methyl]-6-butyl-4-hydroxypyridin-2-one Chemical compound CCCCC1=CC(O)=CC(=O)N1CC1=CC=C(OC(=C2Br)C=3C(=CC=CC=3)C3=NNN=N3)C2=C1 WXHJCMCYHAUERG-UHFFFAOYSA-N 0.000 claims description 3
- CCKXYWFTVIOSKT-UHFFFAOYSA-N 2-[4-[(3-butyl-4-hydroxy-7-methoxy-2-oxoquinolin-1-yl)methyl]phenyl]benzoic acid Chemical compound O=C1C(CCCC)=C(O)C2=CC=C(OC)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O CCKXYWFTVIOSKT-UHFFFAOYSA-N 0.000 claims description 3
- HACOSYGZFWKHGF-UHFFFAOYSA-N 4-hydroxy-6-propyl-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]pyridin-2-one Chemical compound CCCC1=CC(O)=CC(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)C=C1 HACOSYGZFWKHGF-UHFFFAOYSA-N 0.000 claims description 3
- XSJDHHQBUVYHBD-UHFFFAOYSA-N 4-hydroxy-7-methylsulfanyl-3-phenyl-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]quinolin-2-one Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C2=NNN=N2)C2=CC(SC)=CC=C2C(O)=C1C1=CC=CC=C1 XSJDHHQBUVYHBD-UHFFFAOYSA-N 0.000 claims description 3
- KCFUGYPJZJORQH-UHFFFAOYSA-N 7-ethoxy-4-hydroxy-3-phenyl-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]quinolin-2-one Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C2=NNN=N2)C2=CC(OCC)=CC=C2C(O)=C1C1=CC=CC=C1 KCFUGYPJZJORQH-UHFFFAOYSA-N 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- TWVLZIJIZRQBQZ-UHFFFAOYSA-N ethyl 2-butyl-6-oxo-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]pyridine-4-carboxylate Chemical compound CCCCC1=CC(C(=O)OCC)=CC(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)C=C1 TWVLZIJIZRQBQZ-UHFFFAOYSA-N 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 150000003536 tetrazoles Chemical class 0.000 claims description 3
- YFHCJUMNDCPERH-UHFFFAOYSA-N 1-[[3-bromo-2-[2-(2h-tetrazol-5-yl)phenyl]-1-benzofuran-5-yl]methyl]-7-ethoxy-4-hydroxy-3-phenylquinolin-2-one Chemical compound O=C1N(CC=2C=C3C(Br)=C(OC3=CC=2)C=2C(=CC=CC=2)C2=NNN=N2)C2=CC(OCC)=CC=C2C(O)=C1C1=CC=CC=C1 YFHCJUMNDCPERH-UHFFFAOYSA-N 0.000 claims description 2
- QYZQEGHYCSWHCJ-UHFFFAOYSA-N 2-[3-bromo-5-[(7-ethoxy-4-hydroxy-2-oxo-3-phenylquinolin-1-yl)methyl]-1-benzofuran-2-yl]benzoic acid Chemical compound O=C1N(CC=2C=C3C(Br)=C(OC3=CC=2)C=2C(=CC=CC=2)C(O)=O)C2=CC(OCC)=CC=C2C(O)=C1C1=CC=CC=C1 QYZQEGHYCSWHCJ-UHFFFAOYSA-N 0.000 claims description 2
- PEGYUYWEHBCNSR-UHFFFAOYSA-N 2-[4-(4-butyl-2-oxopyrimidin-1-yl)phenyl]-6-methylbenzoic acid Chemical compound O=C1N=C(CCCC)C=CN1C1=CC=C(C=2C(=C(C)C=CC=2)C(O)=O)C=C1 PEGYUYWEHBCNSR-UHFFFAOYSA-N 0.000 claims description 2
- YOZLTAKLFDSWLJ-UHFFFAOYSA-N 2-[4-[(2-butyl-4-hydroxy-6-oxopyridin-1-yl)methyl]phenyl]benzoic acid Chemical compound CCCCC1=CC(O)=CC(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 YOZLTAKLFDSWLJ-UHFFFAOYSA-N 0.000 claims description 2
- MJOYIHQPFMMPPX-UHFFFAOYSA-N 2-[4-[(2-butyl-6-oxopyridin-1-yl)methyl]phenyl]benzoic acid Chemical class CCCCC1=CC=CC(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 MJOYIHQPFMMPPX-UHFFFAOYSA-N 0.000 claims description 2
- MOPSYRWCTPUCPE-UHFFFAOYSA-N 2-[4-[(3-acetamido-6-butyl-4-hydroxy-2-oxopyridin-1-yl)methyl]phenyl]benzoic acid Chemical compound CCCCC1=CC(O)=C(NC(C)=O)C(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 MOPSYRWCTPUCPE-UHFFFAOYSA-N 0.000 claims description 2
- JPPZNXLLQPINKN-UHFFFAOYSA-N 2-[4-[(3-acetyl-4-hydroxy-7-methoxy-2-oxoquinolin-1-yl)methyl]phenyl]benzoic acid Chemical compound C12=CC(OC)=CC=C2C(O)=C(C(C)=O)C(=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O JPPZNXLLQPINKN-UHFFFAOYSA-N 0.000 claims description 2
- YXNCUEJUDMKKAV-UHFFFAOYSA-N 2-[4-[(4-hydroxy-2-oxo-6-propylpyridin-1-yl)methyl]phenoxy]-2-phenylacetic acid Chemical compound CCCC1=CC(O)=CC(=O)N1CC(C=C1)=CC=C1OC(C(O)=O)C1=CC=CC=C1 YXNCUEJUDMKKAV-UHFFFAOYSA-N 0.000 claims description 2
- VFFRTNQFWFGOSH-UHFFFAOYSA-N 2-[4-[(4-hydroxy-7-methoxy-2-oxo-3-phenylquinolin-1-yl)methyl]phenyl]benzoic acid Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C(O)=O)C2=CC(OC)=CC=C2C(O)=C1C1=CC=CC=C1 VFFRTNQFWFGOSH-UHFFFAOYSA-N 0.000 claims description 2
- ZRWBPRSATATQHI-UHFFFAOYSA-N 2-[4-[(4-hydroxy-7-methoxy-2-oxoquinolin-1-yl)methyl]phenyl]benzoic acid Chemical compound C12=CC(OC)=CC=C2C(O)=CC(=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O ZRWBPRSATATQHI-UHFFFAOYSA-N 0.000 claims description 2
- ASBMGJGVOKGGTC-UHFFFAOYSA-N 2-[4-[(6-butyl-3-cyano-2-oxopyridin-1-yl)methyl]phenyl]benzoic acid;n-cyclohexylcyclohexanamine Chemical compound C1CCCCC1NC1CCCCC1.CCCCC1=CC=C(C#N)C(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 ASBMGJGVOKGGTC-UHFFFAOYSA-N 0.000 claims description 2
- MAHXGCWBDKKVGG-UHFFFAOYSA-N 2-[4-[(6-butyl-4-hydroxy-3-nitro-2-oxopyridin-1-yl)methyl]phenyl]benzoic acid Chemical compound CCCCC1=CC(O)=C([N+]([O-])=O)C(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 MAHXGCWBDKKVGG-UHFFFAOYSA-N 0.000 claims description 2
- PNHHGWZILUYRFK-UHFFFAOYSA-N 2-[4-[(7-ethoxy-4-hydroxy-2-oxo-3-phenylquinolin-1-yl)methyl]phenyl]benzoic acid Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C(O)=O)C2=CC(OCC)=CC=C2C(O)=C1C1=CC=CC=C1 PNHHGWZILUYRFK-UHFFFAOYSA-N 0.000 claims description 2
- JERHLDWHRCNTQX-UHFFFAOYSA-N 2-[4-[(7-ethyl-4-hydroxy-2-oxo-3-phenylquinolin-1-yl)methyl]phenyl]benzoic acid Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C(O)=O)C2=CC(CC)=CC=C2C(O)=C1C1=CC=CC=C1 JERHLDWHRCNTQX-UHFFFAOYSA-N 0.000 claims description 2
- KYUOSLGZJUXLCI-UHFFFAOYSA-N 2-[4-[[6-butyl-3-(morpholine-4-carbonyl)-2-oxopyridin-1-yl]methyl]phenyl]benzoic acid Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C(O)=O)C(CCCC)=CC=C1C(=O)N1CCOCC1 KYUOSLGZJUXLCI-UHFFFAOYSA-N 0.000 claims description 2
- NKKPPXALRJNREZ-UHFFFAOYSA-N 2-butyl-1-[[4-(2-carboxyphenyl)phenyl]methyl]-6-oxopyridine-4-carboxylic acid Chemical compound CCCCC1=CC(C(O)=O)=CC(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 NKKPPXALRJNREZ-UHFFFAOYSA-N 0.000 claims description 2
- QIIWZOPXFFSSQH-UHFFFAOYSA-N 4-hydroxy-7-methoxy-3-phenyl-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]quinolin-2-one Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C2=NNN=N2)C2=CC(OC)=CC=C2C(O)=C1C1=CC=CC=C1 QIIWZOPXFFSSQH-UHFFFAOYSA-N 0.000 claims description 2
- JUASJFGIKDGDSN-UHFFFAOYSA-N 4-hydroxy-7-methyl-3-phenyl-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]-1,8-naphthyridin-2-one Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C2=NNN=N2)C2=NC(C)=CC=C2C(O)=C1C1=CC=CC=C1 JUASJFGIKDGDSN-UHFFFAOYSA-N 0.000 claims description 2
- KGDHXMCWBKOSBL-UHFFFAOYSA-N 4-hydroxy-7-methylsulfonyl-3-phenyl-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]quinolin-2-one Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C2=NNN=N2)C2=CC(S(=O)(=O)C)=CC=C2C(O)=C1C1=CC=CC=C1 KGDHXMCWBKOSBL-UHFFFAOYSA-N 0.000 claims description 2
- PMFOEBYVDYZGRZ-UHFFFAOYSA-N 6-butyl-4-hydroxy-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]pyridin-2-one Chemical compound CCCCC1=CC(O)=CC(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)C=C1 PMFOEBYVDYZGRZ-UHFFFAOYSA-N 0.000 claims description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- JTXJZBMXQMTSQN-UHFFFAOYSA-N amino hydrogen carbonate Chemical compound NOC(O)=O JTXJZBMXQMTSQN-UHFFFAOYSA-N 0.000 claims description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N benzyl-alpha-carboxylic acid Natural products OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims description 2
- 235000005152 nicotinamide Nutrition 0.000 claims description 2
- 239000011570 nicotinamide Substances 0.000 claims description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N nicotinic acid amide Natural products NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 2
- 230000000802 nitrating effect Effects 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 6
- 125000002252 acyl group Chemical group 0.000 claims 2
- XYOMDCKWPXSBLG-UHFFFAOYSA-N 2-[4-[(2-butyl-4-ethoxycarbonyl-6-oxopyridin-1-yl)methyl]phenyl]benzoic acid Chemical compound CCCCC1=CC(C(=O)OCC)=CC(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 XYOMDCKWPXSBLG-UHFFFAOYSA-N 0.000 claims 1
- HBUXBKPOUQFSLX-UHFFFAOYSA-N 2-[4-[(2-butyl-4-methoxy-6-oxopyridin-1-yl)methyl]phenyl]benzoic acid Chemical compound CCCCC1=CC(OC)=CC(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 HBUXBKPOUQFSLX-UHFFFAOYSA-N 0.000 claims 1
- KHMTYJPTHGTVMC-UHFFFAOYSA-N 2-[4-[(2-butyl-6-oxopyridin-1-yl)methyl]naphthalen-1-yl]benzoic acid Chemical class CCCCC1=CC=CC(=O)N1CC(C1=CC=CC=C11)=CC=C1C1=CC=CC=C1C(O)=O KHMTYJPTHGTVMC-UHFFFAOYSA-N 0.000 claims 1
- KTDCSWVKOZVHOE-UHFFFAOYSA-N 2-[4-[(3-cyano-6-methyl-2-oxopyridin-1-yl)methyl]phenyl]benzoic acid Chemical class CC1=CC=C(C#N)C(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 KTDCSWVKOZVHOE-UHFFFAOYSA-N 0.000 claims 1
- GTFAXMSRVURHRI-UHFFFAOYSA-N 2-[4-[(5-cyano-2-methyl-6-oxo-3-propylpyridin-1-yl)methyl]phenyl]benzoic acid Chemical class CC1=C(CCC)C=C(C#N)C(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 GTFAXMSRVURHRI-UHFFFAOYSA-N 0.000 claims 1
- YEKQWCAZNWPBRL-UHFFFAOYSA-N 2-[4-[[6-butyl-3-(2-carboxyethylcarbamoyl)-2-oxopyridin-1-yl]methyl]phenyl]benzoic acid Chemical compound CCCCC1=CC=C(C(=O)NCCC(O)=O)C(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 YEKQWCAZNWPBRL-UHFFFAOYSA-N 0.000 claims 1
- PVPLXKNKBAHKBN-UHFFFAOYSA-N 2-[4-[[6-butyl-3-(4-methylpiperazine-1-carbonyl)-2-oxopyridin-1-yl]methyl]phenyl]benzoic acid Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C(O)=O)C(CCCC)=CC=C1C(=O)N1CCN(C)CC1 PVPLXKNKBAHKBN-UHFFFAOYSA-N 0.000 claims 1
- FXXYBMSBOZFDKV-UHFFFAOYSA-N 2-[4-[[6-butyl-3-(carboxymethylcarbamoyl)-2-oxopyridin-1-yl]methyl]phenyl]benzoic acid Chemical compound CCCCC1=CC=C(C(=O)NCC(O)=O)C(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 FXXYBMSBOZFDKV-UHFFFAOYSA-N 0.000 claims 1
- WTFYGYHPBCDHOV-UHFFFAOYSA-N 2-[4-[[6-butyl-3-(hydroxymethyl)-2-oxopyridin-1-yl]methyl]phenyl]benzoic acid Chemical compound CCCCC1=CC=C(CO)C(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 WTFYGYHPBCDHOV-UHFFFAOYSA-N 0.000 claims 1
- LRCXTYFVMRQERT-UHFFFAOYSA-N 2-[4-[[6-butyl-3-[(2-methoxy-2-oxoethyl)-methylcarbamoyl]-2-oxopyridin-1-yl]methyl]phenyl]benzoic acid Chemical compound CCCCC1=CC=C(C(=O)N(C)CC(=O)OC)C(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 LRCXTYFVMRQERT-UHFFFAOYSA-N 0.000 claims 1
- DTSYLBRFSKKSGW-UHFFFAOYSA-N 3,5-dibromo-6-butyl-4-hydroxy-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]pyridin-2-one Chemical compound CCCCC1=C(Br)C(O)=C(Br)C(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)C=C1 DTSYLBRFSKKSGW-UHFFFAOYSA-N 0.000 claims 1
- UKZDORWCIXSWBU-UHFFFAOYSA-N 3-bromo-6-butyl-4-hydroxy-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]pyridin-2-one Chemical compound CCCCC1=CC(O)=C(Br)C(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)C=C1 UKZDORWCIXSWBU-UHFFFAOYSA-N 0.000 claims 1
- HJHFCEZNBVVGDA-UHFFFAOYSA-N 4-hydroxy-1-[[4-[phenyl(2h-tetrazol-5-yl)methoxy]phenyl]methyl]-6-propylpyridin-2-one Chemical compound CCCC1=CC(O)=CC(=O)N1CC(C=C1)=CC=C1OC(C=1C=CC=CC=1)C1=NNN=N1 HJHFCEZNBVVGDA-UHFFFAOYSA-N 0.000 claims 1
- NVEKGJOISJDKBU-UHFFFAOYSA-N 6-butyl-1-[[4-(2-carboxyphenyl)phenyl]methyl]-2-oxopyridine-3-carboxylic acid Chemical class CCCCC1=CC=C(C(O)=O)C(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 NVEKGJOISJDKBU-UHFFFAOYSA-N 0.000 claims 1
- SSAZAOYIWZMMOT-UHFFFAOYSA-N 6-butyl-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]pyridin-2-one;potassium Chemical compound [K].[K].CCCCC1=CC=CC(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)C=C1 SSAZAOYIWZMMOT-UHFFFAOYSA-N 0.000 claims 1
- UKFHPDQFCIECTB-UHFFFAOYSA-N 6-butyl-4-hydroxy-1-[[4-[phenyl(2h-tetrazol-5-yl)methoxy]phenyl]methyl]pyridin-2-one Chemical compound CCCCC1=CC(O)=CC(=O)N1CC(C=C1)=CC=C1OC(C=1C=CC=CC=1)C1=NNN=N1 UKFHPDQFCIECTB-UHFFFAOYSA-N 0.000 claims 1
- DUHOKLQDRPENGN-UHFFFAOYSA-N 6-butyl-4-hydroxy-3-nitro-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]pyridin-2-one Chemical compound CCCCC1=CC(O)=C([N+]([O-])=O)C(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)C=C1 DUHOKLQDRPENGN-UHFFFAOYSA-N 0.000 claims 1
- QHYDTDZELLWLRF-UHFFFAOYSA-N benzyl 6-butyl-2-oxo-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]pyridine-3-carboxylate Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C2=NNN=N2)C(CCCC)=CC=C1C(=O)OCC1=CC=CC=C1 QHYDTDZELLWLRF-UHFFFAOYSA-N 0.000 claims 1
- LLYSJSKOLFALPJ-UHFFFAOYSA-N ethyl 4-hydroxy-5-methyl-6-oxo-2-propyl-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]pyridine-3-carboxylate Chemical compound CCCC1=C(C(=O)OCC)C(O)=C(C)C(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)C=C1 LLYSJSKOLFALPJ-UHFFFAOYSA-N 0.000 claims 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Natural products OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 claims 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 1
- 229960003424 phenylacetic acid Drugs 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- GSWBFCGAODIZMK-UHFFFAOYSA-M sodium;2-[4-[(6-butyl-2-oxo-3-phenylmethoxycarbonylpyridin-1-yl)methyl]phenyl]benzoate Chemical compound [Na+].O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C([O-])=O)C(CCCC)=CC=C1C(=O)OCC1=CC=CC=C1 GSWBFCGAODIZMK-UHFFFAOYSA-M 0.000 claims 1
- 206010020772 Hypertension Diseases 0.000 abstract description 7
- 238000011282 treatment Methods 0.000 abstract description 5
- 125000000623 heterocyclic group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 123
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 87
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 58
- 239000000047 product Substances 0.000 description 58
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 50
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 49
- 239000000243 solution Substances 0.000 description 49
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 43
- 229940093499 ethyl acetate Drugs 0.000 description 41
- 235000019439 ethyl acetate Nutrition 0.000 description 41
- 239000000203 mixture Substances 0.000 description 34
- 239000003921 oil Substances 0.000 description 34
- 235000019198 oils Nutrition 0.000 description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 25
- 239000002904 solvent Substances 0.000 description 25
- 239000012267 brine Substances 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 24
- 239000007787 solid Substances 0.000 description 22
- 239000002253 acid Substances 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
- 239000000377 silicon dioxide Substances 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 229960004132 diethyl ether Drugs 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- 238000001704 evaporation Methods 0.000 description 13
- 230000008020 evaporation Effects 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 102000005862 Angiotensin II Human genes 0.000 description 11
- 101800000733 Angiotensin-2 Proteins 0.000 description 11
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 11
- 229950006323 angiotensin ii Drugs 0.000 description 11
- 238000004587 chromatography analysis Methods 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 9
- 239000000546 pharmaceutical excipient Substances 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 238000001665 trituration Methods 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- OSJRGDBEYARHLX-UHFFFAOYSA-N azido(trimethyl)stannane Chemical compound [N-]=[N+]=[N-].C[Sn+](C)C OSJRGDBEYARHLX-UHFFFAOYSA-N 0.000 description 7
- 238000009835 boiling Methods 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- JKMIKOXRUFLHPB-UHFFFAOYSA-N 6-butyl-2-oxo-1h-pyridine-3-carboxylic acid Chemical compound CCCCC1=CC=C(C(O)=O)C(=O)N1 JKMIKOXRUFLHPB-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 5
- 239000003586 protic polar solvent Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 239000001117 sulphuric acid Substances 0.000 description 5
- 235000011149 sulphuric acid Nutrition 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 239000001828 Gelatine Substances 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 229940030600 antihypertensive agent Drugs 0.000 description 4
- 239000002220 antihypertensive agent Substances 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- QSLPNSWXUQHVLP-UHFFFAOYSA-N $l^{1}-sulfanylmethane Chemical compound [S]C QSLPNSWXUQHVLP-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- LFFIEVAMVPCZNA-UHFFFAOYSA-N 2-[4-(bromomethyl)phenyl]benzonitrile Chemical compound C1=CC(CBr)=CC=C1C1=CC=CC=C1C#N LFFIEVAMVPCZNA-UHFFFAOYSA-N 0.000 description 3
- RCFKQVYRBFDUJN-UHFFFAOYSA-N 2-[4-[(2-butyl-4-hydroxy-6-oxopyridin-1-yl)methyl]phenyl]benzonitrile Chemical compound CCCCC1=CC(O)=CC(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C#N)C=C1 RCFKQVYRBFDUJN-UHFFFAOYSA-N 0.000 description 3
- WLPATYNQCGVFFH-UHFFFAOYSA-N 2-phenylbenzonitrile Chemical compound N#CC1=CC=CC=C1C1=CC=CC=C1 WLPATYNQCGVFFH-UHFFFAOYSA-N 0.000 description 3
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 3
- 230000008485 antagonism Effects 0.000 description 3
- 230000000949 anxiolytic effect Effects 0.000 description 3
- 239000004305 biphenyl Substances 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000001589 carboacyl group Chemical group 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000002934 diuretic Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- GXJWTIDOERUZTH-UHFFFAOYSA-N methyl 2-[4-[(2-butyl-4-hydroxy-6-oxopyridin-1-yl)methyl]phenyl]benzoate Chemical compound CCCCC1=CC(O)=CC(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C(=O)OC)C=C1 GXJWTIDOERUZTH-UHFFFAOYSA-N 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000002798 polar solvent Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- TZCQPHOSHKXEQV-UHFFFAOYSA-N 2,2,2-trifluoro-n-(3-methoxyphenyl)acetamide Chemical compound COC1=CC=CC(NC(=O)C(F)(F)F)=C1 TZCQPHOSHKXEQV-UHFFFAOYSA-N 0.000 description 2
- QQHZAARABFGGBY-UHFFFAOYSA-N 2-[4-(bromomethyl)phenyl]benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C1=CC=C(CBr)C=C1 QQHZAARABFGGBY-UHFFFAOYSA-N 0.000 description 2
- ZLXPTAIWTWWWOV-UHFFFAOYSA-N 2-[4-[(6-butyl-2-oxo-3-phenylmethoxycarbonylpyridin-1-yl)methyl]phenyl]benzoic acid Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C(O)=O)C(CCCC)=CC=C1C(=O)OCC1=CC=CC=C1 ZLXPTAIWTWWWOV-UHFFFAOYSA-N 0.000 description 2
- YTIGAWOBZRUABE-UHFFFAOYSA-N 2-butyl-6-oxo-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]pyridine-4-carboxylic acid Chemical compound CCCCC1=CC(C(O)=O)=CC(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)C=C1 YTIGAWOBZRUABE-UHFFFAOYSA-N 0.000 description 2
- IPOVOSHRRIJKBR-UHFFFAOYSA-N 2-ethylpropanedioyl dichloride Chemical compound CCC(C(Cl)=O)C(Cl)=O IPOVOSHRRIJKBR-UHFFFAOYSA-N 0.000 description 2
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical compound O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- RXYDTBOPZHIQFH-UHFFFAOYSA-N 6-butyl-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]pyridin-2-one Chemical compound CCCCC1=CC=CC(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 RXYDTBOPZHIQFH-UHFFFAOYSA-N 0.000 description 2
- GKHPDWUKQJHOBM-UHFFFAOYSA-N 6-butyl-2-oxo-1h-pyridine-3-carbonitrile Chemical compound CCCCC1=CC=C(C#N)C(=O)N1 GKHPDWUKQJHOBM-UHFFFAOYSA-N 0.000 description 2
- FRRSHSFSXPLQBU-UHFFFAOYSA-N 6-butyl-4-hydroxypyran-2-one Chemical compound CCCCC1=CC(O)=CC(=O)O1 FRRSHSFSXPLQBU-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 102000008873 Angiotensin II receptor Human genes 0.000 description 2
- 108050000824 Angiotensin II receptor Proteins 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 0 CC(*)C(C)C(C)NC Chemical compound CC(*)C(C)C(C)NC 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- 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 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 239000002249 anxiolytic agent Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- AWCNBBLQWVRKEF-UHFFFAOYSA-N benzyl 6-butyl-2-oxo-1h-pyridine-3-carboxylate Chemical compound O=C1NC(CCCC)=CC=C1C(=O)OCC1=CC=CC=C1 AWCNBBLQWVRKEF-UHFFFAOYSA-N 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- FGYDHYCFHBSNPE-UHFFFAOYSA-N diethyl phenylmalonate Chemical compound CCOC(=O)C(C(=O)OCC)C1=CC=CC=C1 FGYDHYCFHBSNPE-UHFFFAOYSA-N 0.000 description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 2
- 238000007907 direct compression Methods 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 229940030606 diuretics Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229960002003 hydrochlorothiazide Drugs 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-M isonicotinate Chemical compound [O-]C(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-M 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229910000000 metal hydroxide Inorganic materials 0.000 description 2
- 150000004692 metal hydroxides Chemical class 0.000 description 2
- RMXGTMRDXKUUDJ-UHFFFAOYSA-N methyl 2-[4-(bromomethyl)phenyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1C1=CC=C(CBr)C=C1 RMXGTMRDXKUUDJ-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 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 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- SBXWFLISHPUINY-UHFFFAOYSA-N triphenyltin Chemical compound C1=CC=CC=C1[Sn](C=1C=CC=CC=1)C1=CC=CC=C1 SBXWFLISHPUINY-UHFFFAOYSA-N 0.000 description 2
- 239000005526 vasoconstrictor agent Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- NVXFXLSOGLFXKQ-JMSVASOKSA-N (2s)-1-[(2r,4r)-5-ethoxy-2,4-dimethyl-5-oxopentanoyl]-2,3-dihydroindole-2-carboxylic acid Chemical compound C1=CC=C2N(C(=O)[C@H](C)C[C@@H](C)C(=O)OCC)[C@H](C(O)=O)CC2=C1 NVXFXLSOGLFXKQ-JMSVASOKSA-N 0.000 description 1
- YKFCISHFRZHKHY-NGQGLHOPSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid;trihydrate Chemical compound O.O.O.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 YKFCISHFRZHKHY-NGQGLHOPSA-N 0.000 description 1
- FTYVYAGWBXTWTN-ZVZYQTTQSA-N (2s)-5-tert-butyl-3-[(2s)-2-[[(2s)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]propanoyl]-2h-1,3,4-thiadiazole-2-carboxylic acid Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](SC(=N1)C(C)(C)C)C(O)=O)CC1=CC=CC=C1 FTYVYAGWBXTWTN-ZVZYQTTQSA-N 0.000 description 1
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- MDXMLENFSQCSCS-UHFFFAOYSA-N 1-[[3-bromo-2-[2-(2h-tetrazol-5-yl)phenyl]-1-benzofuran-5-yl]methyl]-4-hydroxy-6-propylpyridin-2-one Chemical compound CCCC1=CC(O)=CC(=O)N1CC1=CC=C(OC(=C2Br)C=3C(=CC=CC=3)C3=NNN=N3)C2=C1 MDXMLENFSQCSCS-UHFFFAOYSA-N 0.000 description 1
- HULKPKBPQBOUIE-UHFFFAOYSA-N 1-benzofuran;1h-imidazole Chemical class C1=CNC=N1.C1=CC=C2OC=CC2=C1 HULKPKBPQBOUIE-UHFFFAOYSA-N 0.000 description 1
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical class C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 1
- XTRGUXUTYJTZGH-UHFFFAOYSA-N 1-benzothiophene;1h-imidazole Chemical class C1=CNC=N1.C1=CC=C2SC=CC2=C1 XTRGUXUTYJTZGH-UHFFFAOYSA-N 0.000 description 1
- GLJPFZKCYYDBIQ-UHFFFAOYSA-N 1-ethenyl-3,5-difluorobenzene Chemical compound FC1=CC(F)=CC(C=C)=C1 GLJPFZKCYYDBIQ-UHFFFAOYSA-N 0.000 description 1
- ZLTWIJREHQCJJL-UHFFFAOYSA-N 1-trimethylsilylethanol Chemical compound CC(O)[Si](C)(C)C ZLTWIJREHQCJJL-UHFFFAOYSA-N 0.000 description 1
- MMQFYDQGJNKDBV-UHFFFAOYSA-N 1h-imidazole;1h-indole Chemical class C1=CNC=N1.C1=CC=C2NC=CC2=C1 MMQFYDQGJNKDBV-UHFFFAOYSA-N 0.000 description 1
- RUASFXZJFLIHKK-UHFFFAOYSA-N 2,2,2-trifluoro-n-(3-methylsulfanylphenyl)acetamide Chemical compound CSC1=CC=CC(NC(=O)C(F)(F)F)=C1 RUASFXZJFLIHKK-UHFFFAOYSA-N 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- IKAWYCDFPYMOQO-UHFFFAOYSA-N 2-(4-aminophenyl)benzonitrile Chemical compound C1=CC(N)=CC=C1C1=CC=CC=C1C#N IKAWYCDFPYMOQO-UHFFFAOYSA-N 0.000 description 1
- ZSTUEICKYWFYIC-UHFFFAOYSA-N 2-(4-methylphenyl)benzoic acid Chemical compound C1=CC(C)=CC=C1C1=CC=CC=C1C(O)=O ZSTUEICKYWFYIC-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- BUNIQRODCAAAQY-UHFFFAOYSA-N 2-[4-(aminomethyl)phenyl]benzoic acid Chemical compound C1=CC(CN)=CC=C1C1=CC=CC=C1C(O)=O BUNIQRODCAAAQY-UHFFFAOYSA-N 0.000 description 1
- JYCATFNLBBRJDM-UHFFFAOYSA-N 2-[4-[(2-butyl-4-hydroxy-6-oxopyridin-1-yl)methyl]phenoxy]-2-phenylacetic acid Chemical compound CCCCC1=CC(O)=CC(=O)N1CC(C=C1)=CC=C1OC(C(O)=O)C1=CC=CC=C1 JYCATFNLBBRJDM-UHFFFAOYSA-N 0.000 description 1
- OPVYTOPNQDMZBI-UHFFFAOYSA-N 2-[4-[(2-butyl-4-methoxy-6-oxopyridin-1-yl)methyl]phenyl]benzonitrile Chemical compound CCCCC1=CC(OC)=CC(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C#N)C=C1 OPVYTOPNQDMZBI-UHFFFAOYSA-N 0.000 description 1
- IXFCXVFJXPOVGH-UHFFFAOYSA-N 2-[4-[(2-butyl-6-oxopyridin-1-yl)methyl]phenyl]benzonitrile Chemical compound CCCCC1=CC=CC(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C#N)C=C1 IXFCXVFJXPOVGH-UHFFFAOYSA-N 0.000 description 1
- XJVVREGPMNJFFU-UHFFFAOYSA-N 2-[4-[(3,5-dibromo-2-butyl-4-hydroxy-6-oxopyridin-1-yl)methyl]phenyl]benzonitrile Chemical compound CCCCC1=C(Br)C(O)=C(Br)C(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C#N)C=C1 XJVVREGPMNJFFU-UHFFFAOYSA-N 0.000 description 1
- BGJJQLUDXOTBPA-UHFFFAOYSA-N 2-[4-[(4-butyl-2-oxopyrimidin-1-yl)methyl]phenyl]benzoic acid Chemical compound O=C1N=C(CCCC)C=CN1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 BGJJQLUDXOTBPA-UHFFFAOYSA-N 0.000 description 1
- MULZICCKRVEATL-UHFFFAOYSA-N 2-[4-[(4-hydroxy-2-oxo-6-propylpyridin-1-yl)methyl]phenyl]benzonitrile Chemical compound CCCC1=CC(O)=CC(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C#N)C=C1 MULZICCKRVEATL-UHFFFAOYSA-N 0.000 description 1
- ZBIYDDOIBSWTKQ-UHFFFAOYSA-N 2-[4-[(4-hydroxy-7-methyl-2-oxo-3-phenyl-1,8-naphthyridin-1-yl)methyl]phenyl]benzonitrile Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C#N)C2=NC(C)=CC=C2C(O)=C1C1=CC=CC=C1 ZBIYDDOIBSWTKQ-UHFFFAOYSA-N 0.000 description 1
- KFDYMQSNXXGPOD-UHFFFAOYSA-N 2-[4-[(6-butylpyridin-2-yl)oxymethyl]phenyl]benzonitrile Chemical compound CCCCC1=CC=CC(OCC=2C=CC(=CC=2)C=2C(=CC=CC=2)C#N)=N1 KFDYMQSNXXGPOD-UHFFFAOYSA-N 0.000 description 1
- CBPFOZSFBPQLIZ-UHFFFAOYSA-N 2-carbonochloridoylhexanoic acid Chemical compound CCCCC(C(O)=O)C(Cl)=O CBPFOZSFBPQLIZ-UHFFFAOYSA-N 0.000 description 1
- ZORGKHKVEAHWEJ-UHFFFAOYSA-N 2-methyl-6-phenylbenzoic acid Chemical compound CC1=CC=CC(C=2C=CC=CC=2)=C1C(O)=O ZORGKHKVEAHWEJ-UHFFFAOYSA-N 0.000 description 1
- IEEHKTFVUIVORU-UHFFFAOYSA-N 2-methylpropanedioyl dichloride Chemical compound ClC(=O)C(C)C(Cl)=O IEEHKTFVUIVORU-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 1
- MXWSQXWVYZRXNB-UHFFFAOYSA-N 2-trimethylsilylethyl 5-methyl-2-phenylbenzoate Chemical compound C[Si](C)(C)CCOC(=O)C1=CC(C)=CC=C1C1=CC=CC=C1 MXWSQXWVYZRXNB-UHFFFAOYSA-N 0.000 description 1
- OXTNCQMOKLOUAM-UHFFFAOYSA-N 3-Oxoglutaric acid Chemical compound OC(=O)CC(=O)CC(O)=O OXTNCQMOKLOUAM-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
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- BDCLDNALSPBWPQ-UHFFFAOYSA-N 3-oxohexanoic acid Chemical compound CCCC(=O)CC(O)=O BDCLDNALSPBWPQ-UHFFFAOYSA-N 0.000 description 1
- DBVFYWQXVNAKCZ-UHFFFAOYSA-N 4-(4-ethoxyphenyl)-1,3-thiazol-2-amine Chemical compound C1=CC(OCC)=CC=C1C1=CSC(N)=N1 DBVFYWQXVNAKCZ-UHFFFAOYSA-N 0.000 description 1
- GDZPJRWUSJZKIB-UHFFFAOYSA-N 4-hydroxy-5-methyl-6-oxo-2-propyl-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]pyridine-3-carboxylic acid Chemical compound CCCC1=C(C(O)=O)C(O)=C(C)C(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)C=C1 GDZPJRWUSJZKIB-UHFFFAOYSA-N 0.000 description 1
- ARLWUMFTZMAEDP-UHFFFAOYSA-N 4-hydroxy-6-propylpyran-2-one Chemical compound CCCC1=CC(O)=CC(=O)O1 ARLWUMFTZMAEDP-UHFFFAOYSA-N 0.000 description 1
- XMSQPJQMGRILNM-UHFFFAOYSA-N 5-(3-phenyl-2-tritylphenyl)-2H-tetrazole Chemical compound C1(=CC=CC=C1)C(C1=C(C=CC=C1C1=NN=NN1)C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 XMSQPJQMGRILNM-UHFFFAOYSA-N 0.000 description 1
- WZCKHOUKPWOUTB-UHFFFAOYSA-N 5-[2-[3-bromo-5-(bromomethyl)-1-benzofuran-2-yl]phenyl]-2-trityltetrazole Chemical compound BrC=1C2=CC(CBr)=CC=C2OC=1C1=CC=CC=C1C(=N1)N=NN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 WZCKHOUKPWOUTB-UHFFFAOYSA-N 0.000 description 1
- LDNRHZVUCSYMAI-UHFFFAOYSA-N 5-[2-[5-(azidomethyl)-3-bromo-1-benzofuran-2-yl]phenyl]-2-trityltetrazole Chemical compound O1C2=CC=C(CN=[N+]=[N-])C=C2C(Br)=C1C1=CC=CC=C1C(=N1)N=NN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 LDNRHZVUCSYMAI-UHFFFAOYSA-N 0.000 description 1
- KPOKLVPNESGKHT-UHFFFAOYSA-N 6-butyl-1h-pyridin-2-one Chemical compound CCCCC1=CC=CC(=O)N1 KPOKLVPNESGKHT-UHFFFAOYSA-N 0.000 description 1
- HTPSITOWTHBKRP-UHFFFAOYSA-N 6-butyl-1h-pyrimidin-2-one Chemical compound CCCCC1=CC=NC(=O)N1 HTPSITOWTHBKRP-UHFFFAOYSA-N 0.000 description 1
- CNHLYAUCWBKXJV-UHFFFAOYSA-N 6-butyl-2-oxo-1-[[4-[2-(2-trimethylsilylethoxycarbonyl)phenyl]phenyl]methyl]pyridine-3-carboxylic acid Chemical compound CCCCC1=CC=C(C(O)=O)C(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C(=O)OCC[Si](C)(C)C)C=C1 CNHLYAUCWBKXJV-UHFFFAOYSA-N 0.000 description 1
- HXIDBRXQKGULGI-UHFFFAOYSA-N 6-butyl-4-methoxy-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]pyridin-2-one Chemical compound CCCCC1=CC(OC)=CC(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)C=C1 HXIDBRXQKGULGI-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 1
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 241000220438 Arachis Species 0.000 description 1
- 235000003911 Arachis Nutrition 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- YGZMOFAICCSFQJ-UHFFFAOYSA-N COC1=CC=CC(NCC=2C=CC(=CC=2)C=2C(=CC=CC=2)C#N)=C1 Chemical compound COC1=CC=CC(NCC=2C=CC(=CC=2)C=2C(=CC=CC=2)C#N)=C1 YGZMOFAICCSFQJ-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- 108010066671 Enalaprilat Proteins 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010020571 Hyperaldosteronism Diseases 0.000 description 1
- 208000029422 Hypernatremia Diseases 0.000 description 1
- 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 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 108010007859 Lisinopril Proteins 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
- 241001465754 Metazoa Species 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 229920003072 Plasdone™ povidone Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 201000003099 Renovascular Hypertension Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 229910007161 Si(CH3)3 Inorganic materials 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- ITLHXEGAYQFOHJ-UHFFFAOYSA-N [diazo(phenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(=[N+]=[N-])C1=CC=CC=C1 ITLHXEGAYQFOHJ-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229960002478 aldosterone Drugs 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 1
- 229960002576 amiloride Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 229940005530 anxiolytics Drugs 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent 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
- 238000003556 assay Methods 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- AOJDZKCUAATBGE-UHFFFAOYSA-N bromomethane Chemical compound Br[CH2] AOJDZKCUAATBGE-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical class C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229940083181 centrally acting adntiadrenergic agent methyldopa Drugs 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 229960002155 chlorothiazide Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 150000001907 coumarones Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229960005227 delapril Drugs 0.000 description 1
- WOUOLAUOZXOLJQ-MBSDFSHPSA-N delapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N(CC(O)=O)C1CC2=CC=CC=C2C1)CC1=CC=CC=C1 WOUOLAUOZXOLJQ-MBSDFSHPSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000006251 dihalogenation reaction Methods 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical class [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 1
- JZBWUTVDIDNCMW-UHFFFAOYSA-L dipotassium;oxido sulfate Chemical compound [K+].[K+].[O-]OS([O-])(=O)=O JZBWUTVDIDNCMW-UHFFFAOYSA-L 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- 229960002680 enalaprilat Drugs 0.000 description 1
- LZFZMUMEGBBDTC-QEJZJMRPSA-N enalaprilat (anhydrous) Chemical compound C([C@H](N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 LZFZMUMEGBBDTC-QEJZJMRPSA-N 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- AVOLMBLBETYQHX-UHFFFAOYSA-N etacrynic acid Chemical compound CCC(=C)C(=O)C1=CC=C(OCC(O)=O)C(Cl)=C1Cl AVOLMBLBETYQHX-UHFFFAOYSA-N 0.000 description 1
- 229960003199 etacrynic acid Drugs 0.000 description 1
- CJGUXACFAJZALH-UHFFFAOYSA-N ethyl 1-[[4-(2-cyanophenyl)phenyl]methyl]-4-hydroxy-5-methyl-6-oxo-2-propylpyridine-3-carboxylate Chemical compound C(#N)C1=C(C=CC=C1)C1=CC=C(C=C1)CN1C(C(=C(C(=C1CCC)C(=O)OCC)O)C)=O CJGUXACFAJZALH-UHFFFAOYSA-N 0.000 description 1
- QTEWLCIJCJQMLI-UHFFFAOYSA-N ethyl 2-butyl-6-oxo-1h-pyridine-4-carboxylate Chemical compound CCCCC1=CC(C(=O)OCC)=CC(=O)N1 QTEWLCIJCJQMLI-UHFFFAOYSA-N 0.000 description 1
- GTONTGWYZSWUNC-UHFFFAOYSA-N ethyl 4-hydroxy-5-methyl-6-oxo-2-propylpyran-3-carboxylate Chemical compound CCCC=1OC(=O)C(C)=C(O)C=1C(=O)OCC GTONTGWYZSWUNC-UHFFFAOYSA-N 0.000 description 1
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229960001880 fosinopril sodium Drugs 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229910052742 iron Inorganic materials 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
- LRDFRRGEGBBSRN-UHFFFAOYSA-N isobutyronitrile Chemical compound CC(C)C#N LRDFRRGEGBBSRN-UHFFFAOYSA-N 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 229960002394 lisinopril Drugs 0.000 description 1
- RLAWWYSOJDYHDC-BZSNNMDCSA-N lisinopril Chemical compound C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 RLAWWYSOJDYHDC-BZSNNMDCSA-N 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 201000005857 malignant hypertension Diseases 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910001507 metal halide Inorganic materials 0.000 description 1
- 150000005309 metal halides Chemical class 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- HUAXADAVUXKYIH-UHFFFAOYSA-N methyl 2-[4-[[n-(2-ethoxycarbonylhexanoyl)-3-methoxyanilino]methyl]phenyl]benzoate Chemical compound C=1C=CC(OC)=CC=1N(C(=O)C(C(=O)OCC)CCCC)CC(C=C1)=CC=C1C1=CC=CC=C1C(=O)OC HUAXADAVUXKYIH-UHFFFAOYSA-N 0.000 description 1
- QAOAQECDFSZYLY-UHFFFAOYSA-N methyl 2-[[4-(2-cyanophenyl)phenyl]methylamino]-6-methylpyridine-3-carboxylate Chemical compound COC(=O)C1=CC=C(C)N=C1NCC1=CC=C(C=2C(=CC=CC=2)C#N)C=C1 QAOAQECDFSZYLY-UHFFFAOYSA-N 0.000 description 1
- SHKDOGHJQHIIRD-UHFFFAOYSA-N methyl 2-chloro-6-methylpyridine-3-carboxylate Chemical compound COC(=O)C1=CC=C(C)N=C1Cl SHKDOGHJQHIIRD-UHFFFAOYSA-N 0.000 description 1
- ZFWPTXCVPCTANI-UHFFFAOYSA-N methyl 6-butyl-1-[[4-(2-methoxycarbonylphenyl)phenyl]methyl]-2-oxopyridine-3-carboxylate Chemical compound CCCCC1=CC=C(C(=O)OC)C(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C(=O)OC)C=C1 ZFWPTXCVPCTANI-UHFFFAOYSA-N 0.000 description 1
- XSTJDEBYEYOGGY-UHFFFAOYSA-N methyl 6-butyl-2-oxo-1h-pyridine-3-carboxylate Chemical compound CCCCC1=CC=C(C(=O)OC)C(=O)N1 XSTJDEBYEYOGGY-UHFFFAOYSA-N 0.000 description 1
- 210000001589 microsome Anatomy 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 230000000956 myotropic effect Effects 0.000 description 1
- ANJBAKJHPNPSQD-UHFFFAOYSA-N n-(2-ethoxyphenyl)-2,2,2-trifluoroacetamide Chemical compound CCOC1=CC=CC=C1NC(=O)C(F)(F)F ANJBAKJHPNPSQD-UHFFFAOYSA-N 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000000269 nucleophilic effect Effects 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
- 239000002674 ointment Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229950008492 pentopril Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 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
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229920003133 pregelled starch Polymers 0.000 description 1
- 230000002315 pressor effect Effects 0.000 description 1
- 230000036584 pressor response Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 1
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- STWNGMSGPBZFMX-UHFFFAOYSA-N pyridine-3-carboxamide Chemical compound NC(=O)C1=CC=CN=C1.NC(=O)C1=CC=CN=C1 STWNGMSGPBZFMX-UHFFFAOYSA-N 0.000 description 1
- IBBLRJGOOANPTQ-JKVLGAQCSA-N quinapril hydrochloride Chemical compound Cl.C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 IBBLRJGOOANPTQ-JKVLGAQCSA-N 0.000 description 1
- 229960003042 quinapril hydrochloride Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- TVTJZMHAIQQZTL-WATAJHSMSA-M sodium;(2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylate Chemical compound [Na+].C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C([O-])=O)CCCC1=CC=CC=C1 TVTJZMHAIQQZTL-WATAJHSMSA-M 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 125000001174 sulfone group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 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
- 229960004605 timolol Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- PIILXFBHQILWPS-UHFFFAOYSA-N tributyltin Chemical compound CCCC[Sn](CCCC)CCCC PIILXFBHQILWPS-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LYRCQNDYYRPFMF-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C LYRCQNDYYRPFMF-UHFFFAOYSA-N 0.000 description 1
- 229950005696 utibapril Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- 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
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
-
- 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
- A61P9/08—Vasodilators for multiple indications
-
- 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
-
- 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
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
- C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Definitions
- This invention relates to new compounds, methods for their preparation and compositions containing them.
- Patent Application No: 0419048 Such compounds are useful as angiotensin II antagonists.
- Angiotensin II is an arterial vasoconstrictor which interacts with cell membrane receptors.
- Angiotensin II receptor antagonism is thought therefore to be useful in the prevention or alleviation of, inter alia, hypertension.
- R 2 is hydrogen, alkyl C1 to 6, halogen or -COOR 21 , or together R 1 and R 2 form a chain
- B is -N- or -CR 6 -
- R 6 , R 7 , R 8 and R 9 which may be the same or
- R 3 is hydrogen, hydroxy, alkyl C1 to 6, alkoxy C1 to 6, -(CH 2 ) r COOR 10 -(CH 2 ) t OR 31 or
- R 5 is hydrogen, alkyl C1 to 6, alkanoyl C2 to 7, phenyl, halogen, nitrile, nitro, -NR 24 R 25 ,
- Z is a group of formulae II or III
- X is -O-, -S- or -NR 18 -,
- R 17 is hydrogen, halogen, alkyl C1 to 6 or nitrile, Y is -(CH 2 ) S -, -OCHR 20 -, -SCHR 20 -, or
- R 4 and R 20 is -COOH or tetrazolyl and the remainder is hydrogen.
- R 12 , R 24 and R 27 which may be the same or
- R 10 , R 14 and R 30 which may be the same or
- R 32 which may be the same or different, are each hydrogen or alkyl C1 to 6, or R 11 and R 12 may together form a group -CH 2 CH 2 MCH 2 CH 2 -
- R 26 is hydrogen, alkyl C1 to 6 or -COR 29
- R 1 , R 22 and R 29 which may be the same or
- M is -O- or -NR 32 -
- n, m and p which may be the same or different, are each an integer from 1 to 6, provided that when R 27 is -(CH 2 ) p COOR 30 , p may be o,
- l, r, s and t which may be the same or different, are each an integer from 0 to 6, and,
- q 0, 1 or 2
- R 1 is alkyl C1 to 6
- R 2 is hydrogen, alkyl C1 to 6 or -COOR 21 ,
- R 3 is hydroxy
- R 5 is hydrogen, alkyl C1 to 6, phenyl or
- R 1 c is alkyl C1 to 6
- R 2 C is hydrogen, alkyl C1 to 6 or -COOR 21
- R 3 C is hydroxy
- R 5 C is hydrogen, alkyl C1 to 6, phenyl or
- R 3 is hydroxy
- R 5 is hydrogen, alkyl C1 to 6, phenyl, -NR 24 R 25 or -(CH 2 ) m OR 13 ,
- R 9 are as defined above,
- R 5 d is hydrogen, alkyl C1 to 6, phenyl
- R d is alkyl C1 to 6
- R e is alkyl C1 to 6
- X i is -O- or -S-
- the protecting group can be any organic compound.
- alkyl C1 to 6 which may be a straight chain or branched alkyl, eg
- phenylalkyl C7 to 12, eg benzyl can be removed by hydrolysis, for example basic hydrolysis, eg using aqueous methanolic sodium hydroxide; or cleavage using, for example, trifluoracetic acid; or by
- acid protecting groups include trialkylsilylalkyl groups, eg trimethylsilyl ethyl, which may be removed by fluoride ion decomposition.
- Amino-protecting groups which may be mentioned include alkyloxycarbonyl C2 to 7, eg t-butyloxycarbonyl or
- protecting group such as trityl, benzhydryl, trialkyltin (for example trimethyltin or tributyltin) or triphenyltin, affixed to a nitrogen of the tetrazolyl may be used.
- Deprotection of the tetrazolyl may be carried out by decomposition, for example, when the protecting group is trityl, benzhydryl, trialkyltin or triphenyltin, the decompostion conditions may include, for example, acid catalysed hydrolysis in a protic acid such as aqueous hydrochloric acid conventionally in an aqueous solvent such as aqueous dioxan or 2-propanol. Alternatively, a trityl or benzhydryl group may be removed by hydrogenolysis.
- a protic acid such as aqueous hydrochloric acid conventionally in an aqueous solvent such as aqueous dioxan or 2-propanol.
- a trityl or benzhydryl group may be removed by hydrogenolysis.
- Hydroxy protecting groups include, for example, alkyl C1 to 6, especially methyl; phenylalkyl C7 to 12,
- alkanoyl C2 to 6 such as acetyl and haloalkanoyl C2 to 6, especially trifluoroacetyl.
- Removal of the hydroxy protecting group depends on the nature of the protecting group; conventional techniques may generally be employed, including acidic or basic cleavage or hydrogenolysis.
- protecting alkyl or phenylalkyl groups may be removed by cleavage using a protic acid, eg hydrochloric acid or a hydrobromic acid at a temperature of from about 0 to 150oC, or a Lewis acid, eg by reacting with boron trihalide in a halocarbon solvent.
- a protic acid eg hydrochloric acid or a hydrobromic acid at a temperature of from about 0 to 150oC
- a Lewis acid eg by reacting with boron trihalide in a halocarbon solvent.
- 1-Phenylalkyl groups eg, benzyl, may be removed by
- a suitable catalyst eg palladium
- a suitable solvent eg methanol or acetic acid
- the reaction of process b) is preferably carried out in a polar solvent eg, N,N-dimethyl formamide at between 0* and the boiling point of the solvent.
- the reaction is preferably carried out in the presence of a base eg a hydride, such as sodium hydride.
- the reaction of process c) may be carried out in a polar solvent eg an alcohol such as ethanol, dimethyl formamide, or water or a mixture of polar solvents.
- a polar solvent eg an alcohol such as ethanol, dimethyl formamide, or water or a mixture of polar solvents.
- the reaction may be carried out at an elevated temperature, eg the boiling point of the solvent.
- the reaction of process d) may be carried out at elevated temperature eg in excess of 150° and preferably in excess of 200° eg up to 250°. Although a solvent may be used in the reaction depending upon the temperature required, it is preferred that the reaction is carried out in the absence of a solvent.
- the reductions of process e) may be carried out using general reducing procedures known per se.
- the reducing agent may be, for example when reducing a carbonyl group, electrophilic eg diborane, or nucleophilic, eg a complex metal hydride such as sodium borohydride.
- Aprotic solvents are preferred, eg tetrahydrofuran, diethyl ether or 1,2- dimethoxyethane.
- the reaction is preferably carried out low temperature eg 0° to -30° eg -15°.
- the reducing agent may be a metal in an acidic solvent, eg iron in glacial acetic acid, although other known reducing agents may also be used.
- Such reductions are preferably carried out at elevated temperature eg at the boiling point of the solvent.
- the oxidation of process f) may be carried out using conventional oxidising agents, eg potassium
- the reaction is preferably carried out in a protic solvent, eg water, and at elevated temperature, eg the boiling point of the solvent.
- a protic solvent eg water
- halogenation of process g) may be carried out using conventional halogenating agents.
- dihalogenation may be achieved by reaction with the
- halogenation can be achieved by reaction with a selective halogenating agent eg an N-haloamide or N-haloimide eg a succinimide.
- a selective halogenating agent eg an N-haloamide or N-haloimide eg a succinimide.
- the preferred halogen in this case is bromine.
- the reaction of process h) is preferably carried out under basic conditions eg using a metal hydroxide such as sodium hydroxide.
- the reaction may be carried out in a protic solvent or a mixture of protic solvents eg methanol and water.
- the reaction may be carried out at elevated temperature eg at the boiling point of the solvent.
- reaction of process i) may be carried out in an inert solvent eg toluene at elevated temperature.
- an inert solvent eg toluene at elevated temperature.
- Any conventional azide may be used eg an azido alkyl tin such as azido trimethyl tin.
- the rection of process j) may be carried out under basic conditions eg using a metal hydroxide such as sodium hydroxide.
- the reaction is preferably carried out in a protic solvent eg water, or a mixture of solvents, and preferably at elevated temperature, eg the boiling point of the solvent.
- the nitration of process k) is preferably carried out under acidic conditions using nitric acid and an acidic solvent eg an alkanoic acid such as acetic acid or a protic acid such as sulphuric acid.
- the reaction is preferably carried out at elevated temperature, eg the boiling point of the solvent.
- conventional alkylating or acylating groups may be used eg such as those described under process a) .
- Conventional alkylating conditions may be used eg alkylation may be under basic or acidic conditions and acylation may be in the presence of a catalyst eg a metal halide such as aluminium chloride.
- the salts may be formed by reacting the free acid, or a salt, ester, amide or derivative thereof, or the free base, or a salt, ester, amide, enantiomer, tautomer or protected derivative thereof, with one or more equivalents of the appropriate base or acid.
- the reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, eg water, dioxan, ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents, which may be removed in vacuo or by freeze drying.
- the reaction may also be a metathetical process or it may be carried out on an ion exchange resin.
- Compounds of formulae IV, V and VII are either known or may be prepared from known compounds using conventional processes known per se.
- compounds of formula IV may be prepared from the methods disclosed in US Patent No: 4451469 and/or J. Med. Chem, (1985) 28, page 1790.
- Compounds of formulae V and VII wherein Z is a group of formula III may be prepared by the methods described in European Patent Application Nos: 434249 (benzofurans), 429257 (indoles) and 430709 (benzothiophenes).
- the compounds of formulae VIII and IX may be prepared b analogous methods to those described for the preparation of compounds of formula I.
- R 4 e and Y e have the same significance as R 4
- L y is a leaving group, eg halogen
- L x is a protecting group eg -COCF 3 , or hydrogen.
- R d is as defined above.
- compounds of formula XV may be prepared by reacting a compound of formula XXI with a compound of formula XXII
- R 5 d and R d are as defined above, and
- hal is halogen
- salts of the compounds of formula I include ammonium salts, alkali metal salts, eg sodium and potassium salts; alkaline earth metal salts, eg the calcium and magnesium salts; salts with organic bases, eg salts with dicyclohexylamine or N-methyl-D-glucamine;
- salts with amino acids eg with arginine, lysine etc.
- salts with organic or inorganic acids eg with HCl, HBr, H 2 SO 4 ,
- physiologically acceptable salts are preferred, although other salts are also useful, eg in isolating or purifying the product.
- esters include esters with C1 to 10 alcohols, eg alkyl C1 to 6 esters and esters with benzyl alcohol.
- the amides may be, for example,
- unsubstituted or mono-or di-C 1 to 6 alkyl amides may be made by conventional techniques, eg reaction of an ester of the corresponding acid with ammonia or an appropriate amin
- R 1 c , R 2 c and R 5 c are as defined
- L c is a leaving group
- a preferred group of compounds is compounds of formula
- B is -CR 6 -.
- a preferred group of compounds is compounds of formula I, or a salt, ester, amide, enantiomer or tautomer thereof,
- n 1,
- Z is a group of formula II
- R 1 , R 2 , R 3 , R 4 , R 5 , R 15 and R 16 are as
- A is -CR 5 -
- R 1 is alkyl C1 to 6
- R 2 is hydrogen, alkyl C 1 to 6, halogen or
- Z, Y, R 3 , R 4 , R 5 and n are as defined above.
- A is -CR 5 -
- R 7 is hydrogen, alkyl C1 to 6, alkoxy C1 to 6,
- R 6 , R 8 and R 9 are each hydrogen, and Z, Y, R 3 , R 4 and R 5 are as defined above.
- A is -CR 5 -
- R 1 is alkyl C1 to 6
- R 2 and R 5 are each hydrogen
- R 3 is hydroxy, alkoxy C1 to 6 or -(CH 2 ) r COOR 10 ,
- n 1,
- Z is a group of formula II
- R 4 , R 15 and R 16 are as defined above.
- a further sub-group of compounds is compounds of
- A represents -CR 5 - n is 1,
- R 1 , R 2 , R 3 and R 4 are as defined above.
- a further sub-group of compounds is compounds of
- A represents -CR 5 -
- n 1
- Y is -OCHR 20 -, -SCHR 10 - or and R 1 , R 2 and R 3 are as defined above, and
- R 4 is hydrogen
- a further preferred group of compounds is compounds of formula I, or a salt, ester, amide, enantiomer or tautomer thereof wherein,
- R 1 is propyl or ethyl
- R 7 is methoxy or ethoxy
- R 6 , R 8 and R 9 are each hydrogen
- R 3 is hydrogen, hydroxy or -(CH 2 ) r COOR 10 ,
- n 1,
- Z is a group of formula II
- R 4 and R 5 are as defined above.
- R 1 is alkyl C1 to 6, when R 1 is alkyl C1 to 6 it is preferably C1 to 4, preferably butyl and especially propyl.
- R 2 is preferably -COOR 21 , halogen or alkyl C1 to
- R 5 is preferably hydrogen
- n is preferably 1 to 2 and especially 1.
- R 15 and R 16 are preferably both hydrogen.
- R 4 is preferably tetrazolyl and especially tetrazol 5-yl .
- R 3 is preferably hydrogen, alkyl C1 to 6,
- R 7 is preferably alkyl C1 to 6, eg ethyl, and especially alkoxy C1 to 6, eg methoxy or ethoxy,
- R 6 , R 8 and R 9 are preferably hydrogen.
- R 21 is preferably alkyl C1 to 6, eg methyl or ethyl q, r, s and 1 are each preferably O.
- R 22 is preferably alkyl C1 to 6, eg methyl.
- R 16 , R 18 and R 28 are each preferably hydrogen.
- R 27 is preferably phenylalkyl C7 to 12, eg
- R 17 is preferably halogen and especially bromine X is preferably -O-.
- R 29 is preferably ethyl and especially methyl.
- R 30 is preferably phenylalkyl C7 to 12 eg
- alkyl we mean straight, branched or cycloalkyl, eg containing up to and including 6 carbon atoms, but we especially prefer alkyl to mean straight chain alkyl.
- Specific compounds which may be mentioned include, 4-hydroxy-6-propyl-1-( ⁇ 2'-[1H-tetrazol-5-yl][1,1'- biphenyl]-4-yl ⁇ methyl)-2(1H)-pyridinone,
- the compounds of the invention are advantageous in that they are more therapeutically, produce less side effects, are longer acting, more readily absorbed, less toxic, distributed in the body tissues in a different manner or have other advantageous properties when compared to compounds of similar structure.
- the compounds of the invention are useful because they possess pharmacological properties. In particular they antagonise the actions of angiotensin II (see Example A).
- Angiotensin II is a potent vasoconstrictor in mammals. It also stimulates aldosterone release which results in salt and fluid retention. Increased blood pressure is the physiological result of these changes.
- Antagonists of angiotensin II are thus effective antihypertensive agents in a variety of animal models (see Example D) and are indicated for use clinically in all conditions where antagonism of angiotensin II may be beneficial, for
- angiotensin II antagonists have been found to be useful in treating disorders of the central nervous system.
- the compounds of this invention are useful as antihypertensives in treating hypertensive mammals, including humans and they can be utilised to achieve reduction of blood pressure, eg in formulations containing appropriate pharmaceutically acceptable excipients, diluents or carriers.
- the compounds of the invention may be used in the treatment or prophylaxis of hypertension.
- the compounds of the invention may also be used as cognition enhancers, as anxiolytics and in the treatment or prophylaxis of cognitive disorders such as dementia (eg Alzheimer's disease), schizophrenia and other diseases such as renal failure, hyperaldosteronism, cardiac insufficiency, congestive heart failure, post-myocardial infarction, cerebrovascular disorders, perioperative organ protection, glaucoma, diabetic retinopathy and disorders of intracellular hemeostasis.
- dementia eg Alzheimer's disease
- schizophrenia and other diseases such as renal failure, hyperaldosteronism, cardiac insufficiency, congestive heart failure, post-myocardial infarction, cerebrovascular disorders, perioperative organ protection, glaucoma, diabetic retinopathy and disorders of intracellular hemeostasis.
- the compounds of the invention can be administered (to animals or humans) in unit dosages of 1 to 500mg generally given several times, eg 1 to 4 times, per day thus giving a total daily dose of from 1 to 2000 mg per day.
- the dose will vary depending on the type and severity of disease, weight of patient and other factors which a person skilled in the art will recognise.
- the compounds of this invention may be given in combination with other pharmaceutically active compounds, eg diuretics or antihypertensives.
- the dosage of the other pharmaceutically active compound can be that conventionally used when the compound is administered on its own, but is preferably somewhat lower.
- one of the compounds of this invention effective clinically in the range, eg 1-200 milligrams per day, can be combined at levels ranging, eg from 1-200 milligrams per day with the following antihypertensives and diuretics in dose ranges per day as indicated:
- methyldopa 120-480mg and methyldopa (65-2000mg).
- the above dose ranges may be adjusted on a unit basis as necessary to permit divided daily dosage. Also, the dose may vary depending on the severity of the disease, weight of patient and other factors which a person skilled in the art will recognise.
- the compounds of the invention may also be combined with ACE inhibitors such as captopril, delapril
- the formulation preferably comprises less than 80%, more preferably less than 50%, eg 1 to 20%, by weight of a compound of formula I.
- the compound may be put up as a tablet, capsule, dragee, suppository, suspension, solution, injection, implant, a topical, eg transdermal, preparation such as a gel, cream, ointment, aerosol or a polymer system, or an inhalation form, eg an aerosol or a powder
- compositions which are designed to be taken oesophageally and to release their contents in the
- tablets which may, for example, be made by direct compression.
- the active ingredient is mixed with one or more of modified forms of starch, calcium phosphate, a sugar eg lactose, microcrystalline cellulose and/or other directly compressible excipients, together with lubricant(s), eg stearic acid or magnesium stearate, flow aid(s), eg talc or colloidal silicon dioxide, and disintegrant(s), eg starch or the materials sold under the Trade Marks, Nymcel,
- the active ingredient may be granulated before tabletting.
- the active ingredient is mixed with one or more of starch, calcium phosphate, a sugar eg lactose, microcrystalline cellulose or other suitable excipients and granulated with a binder such as starch, pregelled starch, polyvinylpyrrolidone, gelatine, a modified gelatine, or a cellulose derivative, eg
- hydroxypropylmethylcellulose The mass is then dried, sieved and mixed with lubricant(s), flow aid(s) and
- granules and may be sugar or film coated, eg with
- a powder, blend or granules such as are described above as intermediates in tabletting, may be filled into a suitable, eg gelatine, capsule.
- the compound may be:- a) dissolved in a suitable solvent, eg polyethylene glycol, Gelucaire, arachis oil, a (hydrogenated) vegetable oil or beeswax and the solution is then filled into a gelatine capsule,
- a suitable solvent eg polyethylene glycol, Gelucaire, arachis oil, a (hydrogenated) vegetable oil or beeswax
- the compounds may be formulated in a controlled release form.
- the compound may be dispersed, or contained in, a polymer matrix formed from, for example, ethylcellulose, hydroxypropylmethylcellulos or the product sold under the Trade Mark Eudragit.
- the compound may be formulated as a tablet or beads which are surrounded by a semi-permeable membrane, eg shellac, ethylcellulose or an acrylate/methacrylate polymer.
- compounds of formula IV may exist as the unsaturated 2-hydroxy derivative, eg
- Compounds of formulae I, V, VII, XV, XII, VIII and IX may exist as different stereoisomers, in particular, compounds in which Y is -OCHR 20 or -SCHR 20 - may exist as different stereoisomers.
- Example 1 (l.lg; 0.0003M) was refluxed in 4/1 tetrahydrofuran/water (20ml) with lithium hydroxide monohydrate (0.12g; 0.003M) overnight.
- the mixture was poured into water and extracted with ethyl acetate.
- the aqueous phase was acidified with 2N hydrochloric acid solution and extracted with ethyl acetate.
- the organic phase was then washed with brine.
- 6-Butyl-3-cyano-2(1H)-pyridinone (9.0g) was refluxed in concentrated hydrochloric acid solution (100ml) for 6 hours. The solution was poured into water and extracted with ethyl acetate, which was then extracted with saturated sodium hydrogen carbonate solution. The aqueous phase was acidified with 2N hydrochloric acid solution and extracted with ethyl acetate, which was then washed with brine, dried and evaporated. Trituration of the residue with diethyl ether gave 6-butyl-1,2-dihydro-2-oxopyridine-3-carboxylic acid (7.03g) as a cream solid.
- step (a) The product from step (a) was reacted with methyl 4'- bromomethyl [1,1'-biphenyl]-2-carboxylate using the method of Example 1 (a) to give the subtitle compound (0.51g) as a colourless solid, mp 126-127°.
- step (b) The product from step (b) was hydrolysed using the method of Example 1 (b) to yield the title compound, recrystallized from ethyl acetate, (0.36g).
- step (a) The product from step (a) was reacted with methyl
- Example 6 was made by the methods of Examples 5 and 8e) Example 6
- step (a) was hydrolysed by the method of Example 1(b) to yield the title acid, mp 259-260°.
- the acid-ester product from step d) (0.49g) was dissolved together with sodium hydrogen carbonate (0.083g) in water (50ml) and dioxan (10ml) . The resulting solution was freeze-dried to afford the title sodium salt as a solid.
- Example 9 was prepared by the methods of Example 8 and Example 1b).
- Example 8 a By the method of Example 8 a) the product from step a) was reacted with the benzyl ester of glycine to afford the 5 sub-title product as an oil.
- Examples 18 and 19 were prepared by the methods of Examples 10 and 17.
- dichloromethane The chromatogram was developed using dichloromethane/methanol mixtures as eluant and the
- Examples 21 to 23 were prepared using the methods analogous to those of Example 20.
- step (a) was condensed with methyl 4'-bromomethyl[1,1'-biphenyl]-2-carboxylate using the method of Example 1 (a) to furnish the methyl ester of the title product, mp 92-94°.
- the position of alkylation was
- the ester was hydrolysed by the method of Example 1 (b) to give the title acid as a gum.
- step c) To the product from step c) (0.8g) in methanol/water (5:1) was added 10% sodium hydroxide solution (20ml).
- step b) The sub-title compound for step b) (120mg) was heated at reflux with sodium hydroxide (100mg) in water (5ml) and methanol (5ml) for 8 hours. The solution was poured into water, acidified with 2M hydrochloric acid and the
- the sub-title compound was prepared by the method of Example 24 a) from 4-hydroxy-6-propyl-2-pyrone.
- the compound was obtained as an oil.
- Example 29 was prepared by the methods of Example lb) and 15.
- step a) The product from step a) (6.4g) was heated at 220-240° for 14 hours. The residue was extracted with hot
- step b) The product from step b) was hydrolysed by the method of Example 26 d) to afford the product,
- Example 35 was prepared by the method of Example 30.
- Example 35 was prepared by the method of Example 30.
- step a) The product of step a) was reacted with trimethyltin azide by the method of Example 20 b) to give the title compound,
- step a) The product of step a) was converted by the method of
- Examples 41 to 42 were prepared by the methods of
- step a) By the method of Example 20 b), the product of step a) was converted to the title compound.
- step a The product from step a) was stirred in ethanol (80ml) containing concentrated hydrochloric acid (0.8ml) for 16
- step a) The product from step a) (4.7g) and diethylphenylmalona (3.4g) were heated as a melt at 220° with stirring for 5 hours as in the method of Example 26 c) to give the
- Example 31 c By the method of Example 31 c), the product from step b) was refluxed in toluene with trimethyltin azide to give the title compound.
- step a) The product from step a) was reacted with phenylacetyl chloride in dichloromethane containing triethylamine to give methyl 2- ⁇ N-[(2'-cyano[1,1'-biphenyl]-4-yl)methyl]-N-(phenylacetyl)amino-6-methylpyridine-3-carboxylate, which was treated with one equivalent of sodium methoxide in methanol to afford 4'-((1,2-dihydro-4-hydroxy-7-methyl-2-oxo-3-phenyl naphthyridin-1-yl ⁇ methyl)[1,1'-biphenyl]-2-carbonitrile.
- test compounds were determined by the degree of inhibition of contractions of isolated rabbit aorta, maintained in a physiological salt solution at 37°, induced by accumulative doses of
- test compounds dosed parentally or orally to conscious normotensive rats were evaluated in procedures similar to those described by Wong et al,
- Angiotensin II were determined.
- Angiotensin II was determined.
- test compounds compared, to diazepam as a standard were demonstrated using rats in an elevated plus-maze, in the shape of a cross, with two open arms and two enclosed arms. Decreased preference for the closed arms was assessed, using different doses of the compounds.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Neurology (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Psychiatry (AREA)
- Endocrinology (AREA)
- Vascular Medicine (AREA)
- Diabetes (AREA)
- Hospice & Palliative Care (AREA)
- Anesthesiology (AREA)
- Ophthalmology & Optometry (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP4504196A JPH06505715A (en) | 1991-02-16 | 1992-02-17 | Compound |
Applications Claiming Priority (20)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB919103326A GB9103326D0 (en) | 1991-02-16 | 1991-02-16 | Compounds |
GB9103326.6 | 1991-02-16 | ||
GB919112975A GB9112975D0 (en) | 1991-06-15 | 1991-06-15 | Compounds |
GB9112975.9 | 1991-06-15 | ||
GB919113492A GB9113492D0 (en) | 1991-06-21 | 1991-06-21 | Compounds |
GB9113492.4 | 1991-06-21 | ||
GB919114829A GB9114829D0 (en) | 1991-07-10 | 1991-07-10 | Compounds |
GB9114829.6 | 1991-07-10 | ||
GB9120677.1 | 1991-09-28 | ||
GB919120677A GB9120677D0 (en) | 1991-09-28 | 1991-09-28 | Compounds |
GB9124168.7 | 1991-11-14 | ||
GB919124168A GB9124168D0 (en) | 1991-11-14 | 1991-11-14 | Compounds |
GB9125059.7 | 1991-11-26 | ||
GB919125059A GB9125059D0 (en) | 1991-11-26 | 1991-11-26 | Compounds |
GB9126575.1 | 1991-12-12 | ||
GB919126573A GB9126573D0 (en) | 1991-12-12 | 1991-12-12 | Compounds |
GB919126575A GB9126575D0 (en) | 1991-12-12 | 1991-12-12 | Compounds |
GB9126573.6 | 1991-12-12 | ||
GB929200101A GB9200101D0 (en) | 1992-01-04 | 1992-01-04 | Compounds |
GB9200101.5 | 1992-01-04 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1992014714A1 true WO1992014714A1 (en) | 1992-09-03 |
Family
ID=27579392
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1992/000280 WO1992014714A1 (en) | 1991-02-16 | 1992-02-17 | Substituted pyridinones and pyrimidinones as angiotensin ii antagonists |
Country Status (6)
Country | Link |
---|---|
EP (2) | EP0572455A1 (en) |
JP (1) | JPH06505715A (en) |
AU (1) | AU1228792A (en) |
IE (1) | IE920490A1 (en) |
IL (1) | IL100917A0 (en) |
WO (1) | WO1992014714A1 (en) |
Cited By (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5356911A (en) * | 1991-11-12 | 1994-10-18 | Bayer Aktiengesellschaft | Substituted biphenylpyridones |
US5684022A (en) * | 1994-04-08 | 1997-11-04 | Sumitomo Chemical Company, Limited | Ether compounds, their use, and intermediates for use in their production |
US5972949A (en) * | 1994-04-22 | 1999-10-26 | Sumito Chemical Co., Ltd. | Ether compounds and their use |
US6706699B2 (en) | 2001-06-21 | 2004-03-16 | Ariad Pharmaceuticals, Inc. | Quinolines and uses thereof |
WO2007006591A2 (en) * | 2005-07-13 | 2007-01-18 | Bayer Cropscience Sa | Dihalogenation of n,o-disubstituted hydroxipyridones and uses thereof |
EP1925303A2 (en) | 1999-08-27 | 2008-05-28 | Sanofi-Aventis Deutschland GmbH | Use of Angiotensin II type 1 receptor antagonists for the prevention of stroke, diabetes and/or congestive heart failure |
WO2010137336A1 (en) * | 2009-05-29 | 2010-12-02 | 興和株式会社 | NOVEL α-PHENOXYBENZENEACETIC ACID DERIVATIVE AND PHARMACEUTICAL PREPARATION COMPRISING SAME |
US7989462B2 (en) | 2003-07-03 | 2011-08-02 | Myrexis, Inc. | 4-arylamin-or-4-heteroarylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof |
US8101767B2 (en) | 2004-06-24 | 2012-01-24 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
US8258145B2 (en) | 2005-01-03 | 2012-09-04 | Myrexis, Inc. | Method of treating brain cancer |
US8309562B2 (en) | 2003-07-03 | 2012-11-13 | Myrexis, Inc. | Compounds and therapeutical use thereof |
US8354427B2 (en) | 2004-06-24 | 2013-01-15 | Vertex Pharmaceutical Incorporated | Modulators of ATP-binding cassette transporters |
US8410274B2 (en) | 2005-12-28 | 2013-04-02 | Vertex Pharmaceuticals | Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
WO2013138352A1 (en) | 2012-03-15 | 2013-09-19 | Synergy Pharmaceuticals Inc. | Formulations of guanylate cyclase c agonists and methods of use |
US8802700B2 (en) | 2010-12-10 | 2014-08-12 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-Binding Cassette transporters |
WO2014151200A2 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
WO2014151206A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
EP2810951A2 (en) | 2008-06-04 | 2014-12-10 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
WO2014197720A2 (en) | 2013-06-05 | 2014-12-11 | Synergy Pharmaceuticals, Inc. | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
EP2923706A1 (en) | 2009-12-03 | 2015-09-30 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia |
EP2998314A1 (en) | 2007-06-04 | 2016-03-23 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
US9701639B2 (en) | 2014-10-07 | 2017-07-11 | Vertex Pharmaceuticals Incorporated | Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator |
US9751839B2 (en) | 2009-03-20 | 2017-09-05 | Vertex Pharmaceuticals Incorporated | Process for making modulators of cystic fibrosis transmembrane conductance regulator |
EP3241839A1 (en) | 2008-07-16 | 2017-11-08 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
US10272046B2 (en) | 2012-02-27 | 2019-04-30 | Vertex Pharmaceuticals Incorporated | Pharmaceutical composition and administrations thereof |
US10646481B2 (en) | 2008-08-13 | 2020-05-12 | Vertex Pharmaceuticals Incorporated | Pharmaceutical composition and administrations thereof |
Families Citing this family (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU1625192A (en) * | 1991-05-31 | 1992-12-03 | Zeneca Limited | Heterocyclic derivatives |
US5332750A (en) * | 1991-09-04 | 1994-07-26 | Merck Patent Gesellschaft Mit Beschrankter Haftung | 1,2-dihydro-2-oxopyridines |
DE4129340A1 (en) * | 1991-09-04 | 1993-03-11 | Merck Patent Gmbh | 1,2-dihydro-2-OXOPYRIDINE |
GB9201694D0 (en) * | 1992-01-27 | 1992-03-11 | Smithkline Beecham Intercredit | Compounds |
DE4208304A1 (en) * | 1992-03-16 | 1993-09-23 | Merck Patent Gmbh | 2-OXOCHINOLINDERIVATE |
DE4215588A1 (en) * | 1992-05-12 | 1993-11-18 | Bayer Ag | Biphenylmethyl-substituted pyridones |
DE4319041A1 (en) * | 1992-10-23 | 1994-04-28 | Bayer Ag | Trisubstituted biphenyls |
DE4319040A1 (en) * | 1992-10-23 | 1994-04-28 | Bayer Ag | Alkoxymethyl-substituted pyridone biphenyls |
ES2064229B1 (en) * | 1992-11-06 | 1996-03-01 | Merck Patent Gmbh | NEW 1,2-DIHYDRO-2-OXOPYRIDINES FROM FORMULA I. |
DE4301900A1 (en) * | 1993-01-25 | 1994-07-28 | Bayer Ag | 2-oxoquinoline-1-yl-methylphenylessigsäurederivate |
US5466692A (en) * | 1993-03-24 | 1995-11-14 | American Home Products Corporation | Substituted pyridopyrimidines and antihypertensives |
DE69415706T2 (en) * | 1993-03-24 | 1999-05-20 | American Home Prod | Substituted pyridopyrimidines as antihypertensives |
US5814645A (en) * | 1993-03-24 | 1998-09-29 | Bayer Aktiengesellschaft | Arylor hetaryl substituted nitrogen heterocycles and their use as pesticides |
DE4309552A1 (en) * | 1993-03-24 | 1994-09-29 | Bayer Ag | Substituted nitrogen heterocycles |
DE4314963A1 (en) * | 1993-05-06 | 1994-11-10 | Bayer Ag | Substituted pyridines and 2-oxo-1,2-dihydropyridines |
DE4316077A1 (en) * | 1993-05-13 | 1994-11-17 | Bayer Ag | Substituted mono- and bihydridylmethylpyridones |
DE4336051A1 (en) * | 1993-10-22 | 1995-04-27 | Merck Patent Gmbh | 1,2-Dihydro-2-oxopyridines |
BR0102252B1 (en) * | 2001-04-10 | 2013-10-22 | Angiotensin II AT1 Receptor Antagonist Controlled Release System, Pharmaceutical Composition and Use | |
US7482366B2 (en) | 2001-12-21 | 2009-01-27 | X-Ceptor Therapeutics, Inc. | Modulators of LXR |
AU2002351412B2 (en) * | 2001-12-21 | 2010-05-20 | Exelixis Patent Company Llc | Modulators of LXR |
KR100705519B1 (en) | 2002-02-14 | 2007-04-10 | 파마시아 코포레이션 | Substituted Pyridinones as Modulators of P38 MAP Kinase |
EP1960363B1 (en) | 2005-12-09 | 2014-01-22 | Amgen, Inc. | Quinolone based compounds exhibiting prolyl hydroxylase inhibitory activity, compositions and uses thereof |
WO2008005457A2 (en) | 2006-06-30 | 2008-01-10 | Sunesis Pharmaceuticals | Pyridinonyl pdk1 inhibitors |
EP2111399A2 (en) | 2006-12-18 | 2009-10-28 | Amgen Inc. | Naphthalenone compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof |
EP2097416B1 (en) | 2006-12-18 | 2012-09-12 | Amgen, Inc | Azaquinolone based compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof |
EP2155680B1 (en) | 2007-04-18 | 2013-12-04 | Amgen, Inc | Indanone derivatives that inhibit prolyl hydroxylase |
ES2442847T3 (en) | 2007-04-18 | 2014-02-13 | Amgen, Inc | Quinolones and azaquinolones that inhibit prolyl hydroxylase |
ES2389063T3 (en) | 2007-05-04 | 2012-10-22 | Amgen, Inc | Thienopyridine and thiazolopyridine derivatives that inhibit prolyl hydroxylase activity |
WO2008137084A2 (en) | 2007-05-04 | 2008-11-13 | Amgen Inc. | Diazaquinolones that inhibit prolyl hydroxylase activity |
GB0800855D0 (en) | 2008-01-17 | 2008-02-27 | Syngenta Ltd | Herbicidal compounds |
WO2021182898A1 (en) * | 2020-03-11 | 2021-09-16 | 애니젠 주식회사 | Composition for anti-diabetes and anti-obesity comprising novel compound |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0407342A2 (en) * | 1989-07-06 | 1991-01-09 | Ciba-Geigy Ag | Pyrimidine derivatives |
EP0411766A1 (en) * | 1989-07-03 | 1991-02-06 | Merck & Co. Inc. | Substituted quinazolinones as angiotensin II antagonists |
EP0434249A2 (en) * | 1989-12-01 | 1991-06-26 | Glaxo Group Limited | Benzofuran derivatives |
-
1992
- 1992-02-11 IL IL100917A patent/IL100917A0/en unknown
- 1992-02-14 IE IE049092A patent/IE920490A1/en unknown
- 1992-02-17 EP EP92904509A patent/EP0572455A1/en not_active Withdrawn
- 1992-02-17 WO PCT/GB1992/000280 patent/WO1992014714A1/en not_active Application Discontinuation
- 1992-02-17 JP JP4504196A patent/JPH06505715A/en active Pending
- 1992-02-17 AU AU12287/92A patent/AU1228792A/en not_active Abandoned
- 1992-02-17 EP EP92301283A patent/EP0500297A1/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0411766A1 (en) * | 1989-07-03 | 1991-02-06 | Merck & Co. Inc. | Substituted quinazolinones as angiotensin II antagonists |
EP0407342A2 (en) * | 1989-07-06 | 1991-01-09 | Ciba-Geigy Ag | Pyrimidine derivatives |
EP0434249A2 (en) * | 1989-12-01 | 1991-06-26 | Glaxo Group Limited | Benzofuran derivatives |
Non-Patent Citations (1)
Title |
---|
CHEMICAL ABSTRACTS, vol. 116, no. 17, 27 April 1992, Columbus, Ohio, US; abstract no. 174009P, K. KATANO ET AL.: 'Preparation of pyridine derivatives as angiotensin II antagonists.' page 848 ; * |
Cited By (47)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0542059B1 (en) * | 1991-11-12 | 1996-03-20 | Bayer Ag | Substituted biphenylpyridinones as angiotensin II antagonists |
US5599823A (en) * | 1991-11-12 | 1997-02-04 | Bayer Aktiengesellschaft | Substituted biphenylpyridones |
US5356911A (en) * | 1991-11-12 | 1994-10-18 | Bayer Aktiengesellschaft | Substituted biphenylpyridones |
US5684022A (en) * | 1994-04-08 | 1997-11-04 | Sumitomo Chemical Company, Limited | Ether compounds, their use, and intermediates for use in their production |
US5972949A (en) * | 1994-04-22 | 1999-10-26 | Sumito Chemical Co., Ltd. | Ether compounds and their use |
EP1925303A2 (en) | 1999-08-27 | 2008-05-28 | Sanofi-Aventis Deutschland GmbH | Use of Angiotensin II type 1 receptor antagonists for the prevention of stroke, diabetes and/or congestive heart failure |
EP2277519A2 (en) | 1999-08-27 | 2011-01-26 | Sanofi-Aventis Deutschland GmbH | Use of Angiotensin II type 1 receptor antagonists for the prevention of stroke, diabetes and/or congestive heart failure |
US6706699B2 (en) | 2001-06-21 | 2004-03-16 | Ariad Pharmaceuticals, Inc. | Quinolines and uses thereof |
US8309562B2 (en) | 2003-07-03 | 2012-11-13 | Myrexis, Inc. | Compounds and therapeutical use thereof |
US7989462B2 (en) | 2003-07-03 | 2011-08-02 | Myrexis, Inc. | 4-arylamin-or-4-heteroarylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof |
US10662192B2 (en) | 2004-06-24 | 2020-05-26 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
US8101767B2 (en) | 2004-06-24 | 2012-01-24 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
US8324242B2 (en) | 2004-06-24 | 2012-12-04 | Vertex Pharmaceutical Incorporated | Modulators of ATP-binding cassette transporters |
US8354427B2 (en) | 2004-06-24 | 2013-01-15 | Vertex Pharmaceutical Incorporated | Modulators of ATP-binding cassette transporters |
US9090619B2 (en) | 2004-06-24 | 2015-07-28 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
US8741925B2 (en) | 2004-06-24 | 2014-06-03 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
US8614327B2 (en) | 2004-06-24 | 2013-12-24 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
US8629162B2 (en) | 2004-06-24 | 2014-01-14 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
US8258145B2 (en) | 2005-01-03 | 2012-09-04 | Myrexis, Inc. | Method of treating brain cancer |
WO2007006591A2 (en) * | 2005-07-13 | 2007-01-18 | Bayer Cropscience Sa | Dihalogenation of n,o-disubstituted hydroxipyridones and uses thereof |
WO2007006591A3 (en) * | 2005-07-13 | 2007-05-10 | Bayer Cropscience Sa | Dihalogenation of n,o-disubstituted hydroxipyridones and uses thereof |
US8754224B2 (en) | 2005-12-28 | 2014-06-17 | Vertex Pharmaceuticals Incorporated | Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
US11291662B2 (en) | 2005-12-28 | 2022-04-05 | Vertex Pharmaceuticals Incorporated | Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
US10537565B2 (en) | 2005-12-28 | 2020-01-21 | Vertex Pharmaceuticals Incorporated | Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
US8410274B2 (en) | 2005-12-28 | 2013-04-02 | Vertex Pharmaceuticals | Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
US9139530B2 (en) | 2005-12-28 | 2015-09-22 | Vertex Pharmaceuticals Incorporated | Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
US9931334B2 (en) | 2005-12-28 | 2018-04-03 | Vertex Pharmaceuticals Incorporated | Solid forms of N[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
US9670163B2 (en) | 2005-12-28 | 2017-06-06 | Vertex Pharmaceuticals Incorporated | Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
EP2998314A1 (en) | 2007-06-04 | 2016-03-23 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
EP2810951A2 (en) | 2008-06-04 | 2014-12-10 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
EP3241839A1 (en) | 2008-07-16 | 2017-11-08 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
US11564916B2 (en) | 2008-08-13 | 2023-01-31 | Vertex Pharmaceuticals Incorporated | Pharmaceutical composition and administrations thereof |
US10646481B2 (en) | 2008-08-13 | 2020-05-12 | Vertex Pharmaceuticals Incorporated | Pharmaceutical composition and administrations thereof |
US9751839B2 (en) | 2009-03-20 | 2017-09-05 | Vertex Pharmaceuticals Incorporated | Process for making modulators of cystic fibrosis transmembrane conductance regulator |
WO2010137336A1 (en) * | 2009-05-29 | 2010-12-02 | 興和株式会社 | NOVEL α-PHENOXYBENZENEACETIC ACID DERIVATIVE AND PHARMACEUTICAL PREPARATION COMPRISING SAME |
EP2923706A1 (en) | 2009-12-03 | 2015-09-30 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia |
US8802700B2 (en) | 2010-12-10 | 2014-08-12 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-Binding Cassette transporters |
US10272046B2 (en) | 2012-02-27 | 2019-04-30 | Vertex Pharmaceuticals Incorporated | Pharmaceutical composition and administrations thereof |
US11147770B2 (en) | 2012-02-27 | 2021-10-19 | Vertex Pharmaceuticals Incorporated | Pharmaceutical composition and administrations thereof |
US11752106B2 (en) | 2012-02-27 | 2023-09-12 | Vertex Pharmaceuticals Incorporated | Pharmaceutical composition and administrations thereof |
WO2013138352A1 (en) | 2012-03-15 | 2013-09-19 | Synergy Pharmaceuticals Inc. | Formulations of guanylate cyclase c agonists and methods of use |
EP3708179A1 (en) | 2012-03-15 | 2020-09-16 | Bausch Health Ireland Limited | Formulations of guanylate cyclase c agonists and methods of use |
EP4309673A2 (en) | 2012-03-15 | 2024-01-24 | Bausch Health Ireland Limited | Formulations of guanylate cyclase c agonists and methods of use |
WO2014151206A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
WO2014151200A2 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
WO2014197720A2 (en) | 2013-06-05 | 2014-12-11 | Synergy Pharmaceuticals, Inc. | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
US9701639B2 (en) | 2014-10-07 | 2017-07-11 | Vertex Pharmaceuticals Incorporated | Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator |
Also Published As
Publication number | Publication date |
---|---|
IL100917A0 (en) | 1992-11-15 |
AU1228792A (en) | 1992-09-15 |
JPH06505715A (en) | 1994-06-30 |
EP0572455A1 (en) | 1993-12-08 |
IE920490A1 (en) | 1992-08-26 |
EP0500297A1 (en) | 1992-08-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO1992014714A1 (en) | Substituted pyridinones and pyrimidinones as angiotensin ii antagonists | |
AU623546B2 (en) | Nitrogen compounds | |
JP3120873B2 (en) | Pyridine derivatives | |
US5128356A (en) | Benzimidazole derivatives and their use | |
US5126344A (en) | Diazine derivatives and pharmaceutical use | |
US5171748A (en) | Benz[4,5]imidazole-containing angiotensin antagonists | |
KR100200541B1 (en) | Benzimidazole derivatives, their production and use | |
CA2036304C (en) | Pyrimidinedione derivatives, their production and use | |
US5217976A (en) | 1,6-naphthyridone derivatives having angiotensin ii antagonist activity | |
CA2032831A1 (en) | Fused imidazole derivatives, their production and use | |
US5236937A (en) | Pyridinyl compounds which are useful as angiotensin ii antagonists | |
IL94282A (en) | Substituted imidazopyridines and imidazodiazines their preparation and pharmaceutical compositions containing them | |
AU651740B2 (en) | Quinoline derivatives, process for their preparation, and their therapeutic applications | |
SK285153B6 (en) | Heterocyclic-substituted tricyclic compound, pharmaceutical composition containing it and its use | |
JPH04225959A (en) | Heterocyclic compound | |
JPH05255327A (en) | Heterocyclic derivative | |
JP2529798B2 (en) | 4-Pyrimidinone derivative, its production method and therapeutic application | |
JPH05186462A (en) | Heterocyclic compound, its production and medicinal preparation containing said compound for hypertension and congestive heart failure | |
US5219863A (en) | Angiotensin ii antagonizing compounds containing a 1,5-naphthyridine or a quinoline moiety | |
US5371227A (en) | Quinoline derivatives, process for their preparation, and their therapeutic applications | |
CA2104108A1 (en) | Substituted pyridinones and pyrimidinones as angiotensin ii antagonists | |
JP3099096B2 (en) | Thienoimidazole derivatives | |
US5457112A (en) | 3-(6-quinolylmethyl)-4H-imidazol-4-one derivatives, their preparation and their application in therapy | |
WO1994011379A1 (en) | Heterocyclic compounds as angiotensin ii antagonists | |
GB2234748A (en) | 4-(substituted-phenyl)methoxy-quinoline derivitives having pharmacological activity |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU BR CA CS DK FI HU JP KR NO PL RU US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IT LU MC NL SE |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) |
Free format text: DK,PL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1992904509 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2104108 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 1993 107715 Country of ref document: US Date of ref document: 19930816 Kind code of ref document: A |
|
WWP | Wipo information: published in national office |
Ref document number: 1992904509 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1992904509 Country of ref document: EP |