CA2066094C - Fused heterocyclic compounds, their production and use - Google Patents
Fused heterocyclic compounds, their production and use Download PDFInfo
- Publication number
- CA2066094C CA2066094C CA002066094A CA2066094A CA2066094C CA 2066094 C CA2066094 C CA 2066094C CA 002066094 A CA002066094 A CA 002066094A CA 2066094 A CA2066094 A CA 2066094A CA 2066094 C CA2066094 C CA 2066094C
- Authority
- CA
- Canada
- Prior art keywords
- methyl
- tetrazol
- group
- optionally substituted
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- 150000002391 heterocyclic compounds Chemical class 0.000 title abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 38
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 36
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 27
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 25
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 18
- 150000001450 anions Chemical class 0.000 claims abstract description 14
- 150000004945 aromatic hydrocarbons Chemical group 0.000 claims abstract description 14
- 201000010099 disease Diseases 0.000 claims abstract description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
- 206010020772 Hypertension Diseases 0.000 claims abstract description 13
- 230000003042 antagnostic effect Effects 0.000 claims abstract description 11
- 102000005862 Angiotensin II Human genes 0.000 claims abstract description 6
- 101800000733 Angiotensin-2 Proteins 0.000 claims abstract description 6
- 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 claims abstract description 6
- 229950006323 angiotensin ii Drugs 0.000 claims abstract description 6
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 6
- 125000006850 spacer group Chemical group 0.000 claims abstract description 6
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims abstract description 4
- JCZAVVUIFWZMQI-UHFFFAOYSA-N 1h-thieno[2,3-d]imidazole Chemical group N1C=NC2=C1C=CS2 JCZAVVUIFWZMQI-UHFFFAOYSA-N 0.000 claims abstract description 4
- PZLNWHURFHXSTA-UHFFFAOYSA-N 1h-thieno[3,4-d]imidazole Chemical compound S1C=C2NC=NC2=C1 PZLNWHURFHXSTA-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 215
- -1 nitro, amino Chemical group 0.000 claims description 137
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 102
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 54
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 44
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 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 37
- 125000003282 alkyl amino group Chemical group 0.000 claims description 23
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 23
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 23
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 21
- VVQNAFBGAWCMLU-UHFFFAOYSA-N 1h-benzimidazole-4-carboxylic acid Chemical compound OC(=O)C1=CC=CC2=C1N=CN2 VVQNAFBGAWCMLU-UHFFFAOYSA-N 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 125000003342 alkenyl group Chemical group 0.000 claims description 14
- 239000002168 alkylating agent Substances 0.000 claims description 13
- 229940100198 alkylating agent Drugs 0.000 claims description 13
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- 125000001589 carboacyl group Chemical group 0.000 claims description 11
- 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 claims description 11
- 125000004414 alkyl thio group Chemical group 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- QRDZFPUVLYEQTA-UHFFFAOYSA-M quinoline-8-carboxylate Chemical compound C1=CN=C2C(C(=O)[O-])=CC=CC2=C1 QRDZFPUVLYEQTA-UHFFFAOYSA-M 0.000 claims description 8
- 239000011593 sulfur Substances 0.000 claims description 8
- IPDOBVFESNNYEE-UHFFFAOYSA-N 1h-indole-7-carboxylic acid Chemical compound OC(=O)C1=CC=CC2=C1NC=C2 IPDOBVFESNNYEE-UHFFFAOYSA-N 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 7
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- 150000001540 azides Chemical class 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 6
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 claims description 5
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 5
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- KAKQVSNHTBLJCH-UHFFFAOYSA-N trifluoromethanesulfonimidic acid Chemical compound NS(=O)(=O)C(F)(F)F KAKQVSNHTBLJCH-UHFFFAOYSA-N 0.000 claims description 5
- 125000005955 1H-indazolyl group Chemical group 0.000 claims description 4
- PRGTYQHOBXABTG-UHFFFAOYSA-N 2-butyl-3-[[2-[2-(2h-tetrazol-5-yl)phenyl]quinazolin-6-yl]methyl]benzimidazole-4-carboxylic acid Chemical compound CCCCC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1C=N2)=CC=C1N=C2C1=CC=CC=C1C=1N=NNN=1 PRGTYQHOBXABTG-UHFFFAOYSA-N 0.000 claims description 4
- CSYMZATWIMBUIH-UHFFFAOYSA-N 2-ethyl-4-oxo-9-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]thieno[2,3-b]quinoline-8-carboxylic acid Chemical compound S1C(CC)=CC(C(C2=CC=CC(=C22)C(O)=O)=O)=C1N2CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 CSYMZATWIMBUIH-UHFFFAOYSA-N 0.000 claims description 4
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 claims description 4
- 125000001041 indolyl group Chemical group 0.000 claims description 4
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 claims description 4
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 4
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 4
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 4
- 125000002971 oxazolyl group Chemical group 0.000 claims description 4
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- 125000005936 piperidyl group Chemical group 0.000 claims description 4
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 claims description 4
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 4
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000005493 quinolyl group Chemical group 0.000 claims description 4
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 4
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 4
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000004306 triazinyl group Chemical group 0.000 claims description 4
- 125000001425 triazolyl group Chemical group 0.000 claims description 4
- XRAJUVRMUWDTGW-UHFFFAOYSA-N 2,2-dimethylpropanoyloxymethyl 2-propyl-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]pyrazolo[1,5-b][1,2,4]triazole-7-carboxylate Chemical compound CCCC1=NN2N=CC(C(=O)OCOC(=O)C(C)(C)C)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 XRAJUVRMUWDTGW-UHFFFAOYSA-N 0.000 claims description 3
- GEQRETIVMLCFHM-UHFFFAOYSA-N 2,8-diethoxy-7-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]purine-6-carboxylic acid Chemical compound CCOC1=NC2=NC(OCC)=NC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 GEQRETIVMLCFHM-UHFFFAOYSA-N 0.000 claims description 3
- UVPJWTFAFQDNBB-UHFFFAOYSA-N 2-butyl-3-[[4-[4-(2h-tetrazol-5-yl)pyrimidin-5-yl]phenyl]methyl]benzimidazole-4-carboxylic acid Chemical compound CCCCC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CN=CN=C1C=1N=NNN=1 UVPJWTFAFQDNBB-UHFFFAOYSA-N 0.000 claims description 3
- RZWGTFIFBQSSSL-UHFFFAOYSA-N 2-butyl-3-[[4-[5-(2h-tetrazol-5-yl)pyrimidin-4-yl]phenyl]methyl]benzimidazole-4-carboxylic acid Chemical compound CCCCC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=NC=NC=C1C1=NN=NN1 RZWGTFIFBQSSSL-UHFFFAOYSA-N 0.000 claims description 3
- NUWHWGFPSZEYQJ-UHFFFAOYSA-N 7-methyl-2-propyl-3-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]imidazo[4,5-c]pyridine-4-carboxylic acid Chemical compound CCCC1=NC2=C(C)C=NC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 NUWHWGFPSZEYQJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 3
- 230000004962 physiological condition Effects 0.000 claims description 3
- 125000004549 quinolin-4-yl group Chemical group N1=CC=C(C2=CC=CC=C12)* 0.000 claims description 3
- QRDZFPUVLYEQTA-UHFFFAOYSA-N quinoline-8-carboxylic acid Chemical compound C1=CN=C2C(C(=O)O)=CC=CC2=C1 QRDZFPUVLYEQTA-UHFFFAOYSA-N 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- 229910052721 tungsten Inorganic materials 0.000 claims description 3
- PPWZUVVOKPCYHX-UHFFFAOYSA-N 1-cyclohexyloxycarbonyloxyethyl 2-ethyl-4-oxo-9-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]thieno[2,3-b]quinoline-8-carboxylate Chemical compound S1C(CC)=CC(C(C2=CC=CC(=C22)C(=O)OC(C)OC(=O)OC3CCCCC3)=O)=C1N2CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 PPWZUVVOKPCYHX-UHFFFAOYSA-N 0.000 claims description 2
- BZJCWJNRYFDDQX-UHFFFAOYSA-N 2,2-dimethylpropanoyloxymethyl 2-butyl-3-[[2-[2-(2h-tetrazol-5-yl)phenyl]quinazolin-6-yl]methyl]benzimidazole-4-carboxylate Chemical compound CCCCC1=NC2=CC=CC(C(=O)OCOC(=O)C(C)(C)C)=C2N1CC(C=C1C=N2)=CC=C1N=C2C1=CC=CC=C1C=1N=NNN=1 BZJCWJNRYFDDQX-UHFFFAOYSA-N 0.000 claims description 2
- NVKIIQCJDZEXMY-UHFFFAOYSA-N 2-butyl-3-[[3-methyl-4-oxo-2-[2-(2h-tetrazol-5-yl)phenyl]quinazolin-6-yl]methyl]benzimidazole-4-carboxylic acid Chemical compound CCCCC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1C(=O)N2C)=CC=C1N=C2C1=CC=CC=C1C1=NN=NN1 NVKIIQCJDZEXMY-UHFFFAOYSA-N 0.000 claims description 2
- FIQVQFQOVCGBHU-UHFFFAOYSA-N 2-butyl-3-[[4-[2-(2h-tetrazol-5-yl)-1-benzofuran-3-yl]phenyl]methyl]benzimidazole-4-carboxylic acid Chemical compound CCCCC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C(C1=CC=CC=C1O1)=C1C=1N=NNN=1 FIQVQFQOVCGBHU-UHFFFAOYSA-N 0.000 claims description 2
- BGTLQOZYHXZDPK-UHFFFAOYSA-N 2-butyl-3-[[4-oxo-3-[2-(2h-tetrazol-5-yl)phenyl]quinazolin-7-yl]methyl]benzimidazole-4-carboxylic acid Chemical compound CCCCC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=1)=CC=C(C2=O)C=1N=CN2C1=CC=CC=C1C1=NN=NN1 BGTLQOZYHXZDPK-UHFFFAOYSA-N 0.000 claims description 2
- BLQIVQZCDOGCPE-UHFFFAOYSA-N 2-butyl-3-[[6-[2-(2h-tetrazol-5-yl)phenyl]pyridin-3-yl]methyl]benzimidazole-4-carboxylic acid Chemical compound CCCCC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=N1)=CC=C1C1=CC=CC=C1C1=NN=NN1 BLQIVQZCDOGCPE-UHFFFAOYSA-N 0.000 claims description 2
- GCEPCIJDUCGARX-UHFFFAOYSA-N 2-butyl-7-methyl-3-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]imidazo[4,5-c]pyridine-4-carboxylic acid Chemical compound CCCCC1=NC2=C(C)C=NC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 GCEPCIJDUCGARX-UHFFFAOYSA-N 0.000 claims description 2
- WVHRBRLBDOITMY-UHFFFAOYSA-N 2-propyl-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]indole-7-carboxylic acid Chemical compound CCCC1=CC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 WVHRBRLBDOITMY-UHFFFAOYSA-N 0.000 claims description 2
- BACARPCBZOUACP-UHFFFAOYSA-N 2-propyl-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]pyrazolo[1,5-b][1,2,4]triazole-7-carboxylic acid Chemical compound CCCC1=NN2N=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 BACARPCBZOUACP-UHFFFAOYSA-N 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 15
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 13
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 6
- 125000002471 4H-quinolizinyl group Chemical group C=1(C=CCN2C=CC=CC12)* 0.000 claims 2
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 1
- OQPOXAUDYAZMMX-UHFFFAOYSA-N 2,2-dimethylpropanoyloxymethyl 2-ethyl-4-oxo-9-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]thieno[2,3-b]quinoline-8-carboxylate Chemical compound S1C(CC)=CC(C(C2=CC=CC(=C22)C(=O)OCOC(=O)C(C)(C)C)=O)=C1N2CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 OQPOXAUDYAZMMX-UHFFFAOYSA-N 0.000 claims 1
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims 1
- AYYOZKHMSABVRP-UHFFFAOYSA-N methyl 1h-indole-6-carboxylate Chemical compound COC(=O)C1=CC=C2C=CNC2=C1 AYYOZKHMSABVRP-UHFFFAOYSA-N 0.000 claims 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 1
- CIEQXUBLKKQRIS-UHFFFAOYSA-N purine-6-carboxylic acid Chemical compound OC(=O)C1=NC=NC2=C1N=CN2 CIEQXUBLKKQRIS-UHFFFAOYSA-N 0.000 claims 1
- 208000006011 Stroke Diseases 0.000 abstract description 13
- 239000003814 drug Substances 0.000 abstract description 12
- 230000003389 potentiating effect Effects 0.000 abstract description 9
- 208000019622 heart disease Diseases 0.000 abstract description 8
- 201000008383 nephritis Diseases 0.000 abstract description 7
- 150000002430 hydrocarbons Chemical group 0.000 abstract description 6
- 206010019280 Heart failures Diseases 0.000 abstract description 5
- 230000003276 anti-hypertensive effect Effects 0.000 abstract description 5
- 206010008190 Cerebrovascular accident Diseases 0.000 abstract description 4
- 206010061216 Infarction Diseases 0.000 abstract description 4
- 230000000747 cardiac effect Effects 0.000 abstract description 4
- 230000002490 cerebral effect Effects 0.000 abstract description 4
- 230000007574 infarction Effects 0.000 abstract description 4
- 229940124597 therapeutic agent Drugs 0.000 abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 232
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 214
- 239000000203 mixture Substances 0.000 description 172
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 165
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 160
- 239000000243 solution Substances 0.000 description 155
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 150
- 239000011541 reaction mixture Substances 0.000 description 114
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 107
- 238000004440 column chromatography Methods 0.000 description 107
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 105
- 239000000741 silica gel Substances 0.000 description 105
- 229910002027 silica gel Inorganic materials 0.000 description 105
- 239000013078 crystal Substances 0.000 description 85
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 81
- 239000000843 powder Substances 0.000 description 74
- 235000019439 ethyl acetate Nutrition 0.000 description 72
- 239000000284 extract Substances 0.000 description 70
- 238000010992 reflux Methods 0.000 description 66
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 63
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 61
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 60
- 238000001953 recrystallisation Methods 0.000 description 59
- 239000006188 syrup Substances 0.000 description 58
- 235000020357 syrup Nutrition 0.000 description 58
- 238000000921 elemental analysis Methods 0.000 description 56
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 42
- 238000001914 filtration Methods 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 35
- 239000002904 solvent Substances 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 239000000706 filtrate Substances 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 26
- 239000002198 insoluble material Substances 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
- 238000001704 evaporation Methods 0.000 description 24
- 230000008020 evaporation Effects 0.000 description 24
- 238000001816 cooling Methods 0.000 description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 238000000034 method Methods 0.000 description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 20
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 18
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 18
- 239000012312 sodium hydride Substances 0.000 description 18
- 229910000104 sodium hydride Inorganic materials 0.000 description 18
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- 239000006185 dispersion Substances 0.000 description 15
- 239000002480 mineral oil Substances 0.000 description 15
- 235000010446 mineral oil Nutrition 0.000 description 15
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 14
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 14
- 108010064733 Angiotensins Proteins 0.000 description 13
- 239000005557 antagonist Substances 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- 229910000027 potassium carbonate Inorganic materials 0.000 description 13
- 102000015427 Angiotensins Human genes 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- 101150041968 CDC13 gene Proteins 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 235000011054 acetic acid Nutrition 0.000 description 9
- OSJRGDBEYARHLX-UHFFFAOYSA-N azido(trimethyl)stannane Chemical compound [N-]=[N+]=[N-].C[Sn+](C)C OSJRGDBEYARHLX-UHFFFAOYSA-N 0.000 description 9
- 239000005457 ice water Substances 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 230000009471 action Effects 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 229910052742 iron Inorganic materials 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- VPRPZAPGAGSCAL-UHFFFAOYSA-N methyl 3-nitro-2-(pentanoylamino)benzoate Chemical compound CCCCC(=O)NC1=C(C(=O)OC)C=CC=C1[N+]([O-])=O VPRPZAPGAGSCAL-UHFFFAOYSA-N 0.000 description 7
- 230000005855 radiation Effects 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 239000004342 Benzoyl peroxide Substances 0.000 description 6
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 235000019400 benzoyl peroxide Nutrition 0.000 description 6
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- HEGXUBFMGZWSNA-UHFFFAOYSA-N amino 3-nitrobenzoate Chemical compound NOC(=O)C1=CC=CC([N+]([O-])=O)=C1 HEGXUBFMGZWSNA-UHFFFAOYSA-N 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 5
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- WVDDGKGOMKODPV-UHFFFAOYSA-N hydroxymethyl benzene Natural products OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 5
- PELJISAVHGXLAL-UHFFFAOYSA-N iodomethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCI PELJISAVHGXLAL-UHFFFAOYSA-N 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 5
- 125000003107 substituted aryl group Chemical group 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 150000003536 tetrazoles Chemical class 0.000 description 5
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- 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 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 229940064734 aminobenzoate Drugs 0.000 description 4
- 230000036772 blood pressure Effects 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 235000008504 concentrate Nutrition 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 4
- DJLUGWFUVRDHLO-UHFFFAOYSA-N ethyl 4,5-dimethyl-6-oxo-7-propyl-7,8-dihydrocyclopenta[e][1]benzofuran-2-carboxylate Chemical compound O=C1C(CCC)CC2=C1C(C)=C(C)C1=C2C=C(C(=O)OCC)O1 DJLUGWFUVRDHLO-UHFFFAOYSA-N 0.000 description 4
- WDCDAAMJNUHOIY-UHFFFAOYSA-N ethyl acetate;2-propan-2-yloxypropane Chemical compound CCOC(C)=O.CC(C)OC(C)C WDCDAAMJNUHOIY-UHFFFAOYSA-N 0.000 description 4
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- GFISDBXSWQMOND-UHFFFAOYSA-N 2,5-dimethoxyoxolane Chemical compound COC1CCC(OC)O1 GFISDBXSWQMOND-UHFFFAOYSA-N 0.000 description 3
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 3
- 239000005541 ACE inhibitor Substances 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 125000005336 allyloxy group Chemical group 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 108010083984 angiotensin A Proteins 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 3
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 3
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 3
- WHQLQYRFIHPMNA-UHFFFAOYSA-N ethyl acetate;oxolane Chemical compound C1CCOC1.CCOC(C)=O WHQLQYRFIHPMNA-UHFFFAOYSA-N 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 229940102396 methyl bromide Drugs 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 230000033116 oxidation-reduction process Effects 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 3
- 230000036454 renin-angiotensin system Effects 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- BLCNYQRVZUFCJU-UHFFFAOYSA-N (2-cyanophenyl) trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OC1=CC=CC=C1C#N BLCNYQRVZUFCJU-UHFFFAOYSA-N 0.000 description 2
- CHCOFDZSJYMQMX-NOQNJSOHSA-N (2s)-2-[[(2s)-1-[(2s)-2-[[(2s,3s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-aminopropanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-methylpentanoyl]amino]-3-(1h-imidazol-5-yl)propanoyl]py 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](CCCN=C(N)N)NC(=O)[C@H](C)N)C(C)C)C1=CC=C(O)C=C1 CHCOFDZSJYMQMX-NOQNJSOHSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- VKDATGWAEJIAHE-UHFFFAOYSA-N 1-(2-chloro-4-methylphenyl)pyrrole Chemical compound ClC1=CC(C)=CC=C1N1C=CC=C1 VKDATGWAEJIAHE-UHFFFAOYSA-N 0.000 description 2
- ASFPSMFKRRQDIX-UHFFFAOYSA-N 1-(4-methylphenyl)pyrrole-2-carbonitrile Chemical compound C1=CC(C)=CC=C1N1C(C#N)=CC=C1 ASFPSMFKRRQDIX-UHFFFAOYSA-N 0.000 description 2
- ODYLNZJNYHOMGL-UHFFFAOYSA-N 1-(4-methylphenyl)pyrrole-3-carbonitrile Chemical compound C1=CC(C)=CC=C1N1C=C(C#N)C=C1 ODYLNZJNYHOMGL-UHFFFAOYSA-N 0.000 description 2
- MNDDCROBALRCRO-UHFFFAOYSA-N 1-[4-(bromomethyl)phenyl]pyrrole-2-carbonitrile Chemical compound C1=CC(CBr)=CC=C1N1C(C#N)=CC=C1 MNDDCROBALRCRO-UHFFFAOYSA-N 0.000 description 2
- NEXDAVKFVSYLPV-UHFFFAOYSA-N 1-[4-(bromomethyl)phenyl]pyrrole-3-carbonitrile Chemical compound C1=CC(CBr)=CC=C1N1C=C(C#N)C=C1 NEXDAVKFVSYLPV-UHFFFAOYSA-N 0.000 description 2
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 2
- AWNXKZVIZARMME-UHFFFAOYSA-N 1-[[5-[2-[(2-chloropyridin-4-yl)amino]pyrimidin-4-yl]-4-(cyclopropylmethyl)pyrimidin-2-yl]amino]-2-methylpropan-2-ol Chemical compound N=1C(NCC(C)(O)C)=NC=C(C=2N=C(NC=3C=C(Cl)N=CC=3)N=CC=2)C=1CC1CC1 AWNXKZVIZARMME-UHFFFAOYSA-N 0.000 description 2
- YXCRRSXSLYIVKO-UHFFFAOYSA-N 2,2-dimethylpropanoyloxymethyl 2-propyl-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]indole-7-carboxylate Chemical compound CCCC1=CC2=CC=CC(C(=O)OCOC(=O)C(C)(C)C)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 YXCRRSXSLYIVKO-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- YZUGCURPDMXZPU-UHFFFAOYSA-N 2-[2-(4-methylbenzoyl)phenoxy]acetonitrile Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=CC=C1OCC#N YZUGCURPDMXZPU-UHFFFAOYSA-N 0.000 description 2
- ZBMJLTTZKPNPAR-UHFFFAOYSA-N 2-[5-(bromomethyl)pyridin-2-yl]benzonitrile Chemical compound N1=CC(CBr)=CC=C1C1=CC=CC=C1C#N ZBMJLTTZKPNPAR-UHFFFAOYSA-N 0.000 description 2
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 2
- FRVPTPUZCYIPJT-UHFFFAOYSA-N 2-butyl-3-[[3-chloro-4-[2-(2h-tetrazol-5-yl)pyrrol-1-yl]phenyl]methyl]benzimidazole-4-carboxylic acid Chemical compound CCCCC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1Cl)=CC=C1N1C=CC=C1C1=NN=NN1 FRVPTPUZCYIPJT-UHFFFAOYSA-N 0.000 description 2
- ONERFKYCJMGEQW-UHFFFAOYSA-N 2-butyl-3-[[6-(2-carboxyphenyl)pyridin-3-yl]methyl]benzimidazole-4-carboxylic acid Chemical compound CCCCC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=N1)=CC=C1C1=CC=CC=C1C(O)=O ONERFKYCJMGEQW-UHFFFAOYSA-N 0.000 description 2
- 125000000094 2-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
- FSEXLNMNADBYJU-UHFFFAOYSA-N 2-phenylquinoline Chemical compound C1=CC=CC=C1C1=CC=C(C=CC=C2)C2=N1 FSEXLNMNADBYJU-UHFFFAOYSA-N 0.000 description 2
- QXBUNNASEFMKQH-UHFFFAOYSA-N 3-(4-methylphenyl)-1-benzofuran-2-carbonitrile Chemical compound C1=CC(C)=CC=C1C1=C(C#N)OC2=CC=CC=C12 QXBUNNASEFMKQH-UHFFFAOYSA-N 0.000 description 2
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 2
- NRMWPZRDOFTKPO-UHFFFAOYSA-N 4-(4-methylphenyl)pyrimidine-5-carbonitrile Chemical compound C1=CC(C)=CC=C1C1=NC=NC=C1C#N NRMWPZRDOFTKPO-UHFFFAOYSA-N 0.000 description 2
- UQZHQNOFMRIALT-UHFFFAOYSA-N 4-[4-(bromomethyl)phenyl]pyrimidine-5-carbonitrile Chemical compound C1=CC(CBr)=CC=C1C1=NC=NC=C1C#N UQZHQNOFMRIALT-UHFFFAOYSA-N 0.000 description 2
- CDTIOSNDFAJVNQ-UHFFFAOYSA-N 4-chloro-5-(4-methylphenyl)pyrimidine Chemical compound C1=CC(C)=CC=C1C1=CN=CN=C1Cl CDTIOSNDFAJVNQ-UHFFFAOYSA-N 0.000 description 2
- KZLLSSGOPIGKDO-UHFFFAOYSA-N 4-methyl-2-nitrobenzoic acid Chemical compound CC1=CC=C(C(O)=O)C([N+]([O-])=O)=C1 KZLLSSGOPIGKDO-UHFFFAOYSA-N 0.000 description 2
- SEIHGWIQBIUBGU-UHFFFAOYSA-N 5-(4-methylphenyl)-1h-pyrimidin-6-one Chemical compound C1=CC(C)=CC=C1C1=CN=CN=C1O SEIHGWIQBIUBGU-UHFFFAOYSA-N 0.000 description 2
- FPHQEBZFACGIAJ-UHFFFAOYSA-N 5-(4-methylphenyl)pyrimidine-4-carbonitrile Chemical compound C1=CC(C)=CC=C1C1=CN=CN=C1C#N FPHQEBZFACGIAJ-UHFFFAOYSA-N 0.000 description 2
- ZTFVTXDWDFIQEU-UHFFFAOYSA-N 5-[2-[4-(bromomethyl)phenyl]phenyl]-1-trityltetrazole Chemical compound C1=CC(CBr)=CC=C1C1=CC=CC=C1C1=NN=NN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 ZTFVTXDWDFIQEU-UHFFFAOYSA-N 0.000 description 2
- MTWUJKNUYJDBJW-UHFFFAOYSA-N 5-[4-(bromomethyl)phenyl]pyrimidine-4-carbonitrile Chemical compound C1=CC(CBr)=CC=C1C1=CN=CN=C1C#N MTWUJKNUYJDBJW-UHFFFAOYSA-N 0.000 description 2
- ZVXXEMMIVLDQAH-UHFFFAOYSA-N 5-bromo-4-(4-methylphenyl)pyrimidine Chemical compound C1=CC(C)=CC=C1C1=NC=NC=C1Br ZVXXEMMIVLDQAH-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 208000001647 Renal Insufficiency Diseases 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- OCBFFGCSTGGPSQ-UHFFFAOYSA-N [CH2]CC Chemical compound [CH2]CC OCBFFGCSTGGPSQ-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 description 2
- QSKWJTXWJJOJFP-UHFFFAOYSA-N chloroform;ethoxyethane Chemical compound ClC(Cl)Cl.CCOCC QSKWJTXWJJOJFP-UHFFFAOYSA-N 0.000 description 2
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- WRBLBPRJIBIRBP-UHFFFAOYSA-N cyclohexyl 1-iodoethyl carbonate Chemical compound CC(I)OC(=O)OC1CCCCC1 WRBLBPRJIBIRBP-UHFFFAOYSA-N 0.000 description 2
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- GORJIFRUPPQKPQ-UHFFFAOYSA-N ethyl 3-methyl-2-nitrobenzoate Chemical compound CCOC(=O)C1=CC=CC(C)=C1[N+]([O-])=O GORJIFRUPPQKPQ-UHFFFAOYSA-N 0.000 description 2
- YPXGHKWOJXQLQU-UHFFFAOYSA-N ethyl 5-amino-1h-pyrazole-4-carboxylate Chemical compound CCOC(=O)C=1C=NNC=1N YPXGHKWOJXQLQU-UHFFFAOYSA-N 0.000 description 2
- YHQANNYVKZBLHQ-UHFFFAOYSA-N ethyl 5-propylimidazo[1,2-b]pyrazole-3-carboxylate Chemical compound C1=C(C(=O)OCC)N2N(CCC)C=CC2=N1 YHQANNYVKZBLHQ-UHFFFAOYSA-N 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- MOTRZVVGCFFABN-UHFFFAOYSA-N hexane;2-propan-2-yloxypropane Chemical compound CCCCCC.CC(C)OC(C)C MOTRZVVGCFFABN-UHFFFAOYSA-N 0.000 description 2
- JUINSXZKUKVTMD-UHFFFAOYSA-N hydrogen azide Chemical compound N=[N+]=[N-] JUINSXZKUKVTMD-UHFFFAOYSA-N 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 208000017169 kidney disease Diseases 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 2
- ACWFSUIFELFZJV-UHFFFAOYSA-N methyl 2-butyl-3-[[4-(2-cyano-1-benzofuran-3-yl)phenyl]methyl]benzimidazole-4-carboxylate Chemical compound C1=CC=C2C(C3=CC=C(C=C3)CN3C4=C(C(=O)OC)C=CC=C4N=C3CCCC)=C(C#N)OC2=C1 ACWFSUIFELFZJV-UHFFFAOYSA-N 0.000 description 2
- CWVQLKAQWGQCAF-UHFFFAOYSA-N methyl 2-butyl-3-[[4-(2-cyanopyrrol-1-yl)phenyl]methyl]benzimidazole-4-carboxylate Chemical compound CCCCC1=NC2=CC=CC(C(=O)OC)=C2N1CC(C=C1)=CC=C1N1C=CC=C1C#N CWVQLKAQWGQCAF-UHFFFAOYSA-N 0.000 description 2
- FQHCCMKIPRAMII-UHFFFAOYSA-N methyl 2-butyl-3-[[4-(3-cyanopyrrol-1-yl)phenyl]methyl]benzimidazole-4-carboxylate Chemical compound CCCCC1=NC2=CC=CC(C(=O)OC)=C2N1CC(C=C1)=CC=C1N1C=CC(C#N)=C1 FQHCCMKIPRAMII-UHFFFAOYSA-N 0.000 description 2
- AJAFNFOOESLTPF-UHFFFAOYSA-N methyl 2-butyl-3-[[4-(4-cyanopyrimidin-5-yl)phenyl]methyl]benzimidazole-4-carboxylate Chemical compound CCCCC1=NC2=CC=CC(C(=O)OC)=C2N1CC(C=C1)=CC=C1C1=CN=CN=C1C#N AJAFNFOOESLTPF-UHFFFAOYSA-N 0.000 description 2
- CIBRIMDGLCZGGN-UHFFFAOYSA-N methyl 2-butyl-3-[[4-[2-(2h-tetrazol-5-yl)-1-benzofuran-3-yl]phenyl]methyl]benzimidazole-4-carboxylate Chemical compound CCCCC1=NC2=CC=CC(C(=O)OC)=C2N1CC(C=C1)=CC=C1C(C1=CC=CC=C1O1)=C1C=1N=NNN=1 CIBRIMDGLCZGGN-UHFFFAOYSA-N 0.000 description 2
- QURQPBWFWDKVCC-UHFFFAOYSA-N methyl 2-butyl-3-[[4-[2-(2h-tetrazol-5-yl)pyrrol-1-yl]phenyl]methyl]benzimidazole-4-carboxylate Chemical compound CCCCC1=NC2=CC=CC(C(=O)OC)=C2N1CC(C=C1)=CC=C1N1C=CC=C1C1=NN=NN1 QURQPBWFWDKVCC-UHFFFAOYSA-N 0.000 description 2
- LTFFMYVYAGIRLS-UHFFFAOYSA-N methyl 2-butyl-3-[[4-[3-(2h-tetrazol-5-yl)pyrrol-1-yl]phenyl]methyl]benzimidazole-4-carboxylate Chemical compound CCCCC1=NC2=CC=CC(C(=O)OC)=C2N1CC(C=C1)=CC=C1N(C=1)C=CC=1C1=NN=NN1 LTFFMYVYAGIRLS-UHFFFAOYSA-N 0.000 description 2
- FMENYNBQRPXORM-UHFFFAOYSA-N methyl 2-butyl-3-[[4-[4-(2h-tetrazol-5-yl)pyrimidin-5-yl]phenyl]methyl]benzimidazole-4-carboxylate Chemical compound CCCCC1=NC2=CC=CC(C(=O)OC)=C2N1CC(C=C1)=CC=C1C1=CN=CN=C1C=1N=NNN=1 FMENYNBQRPXORM-UHFFFAOYSA-N 0.000 description 2
- STICULMOCORXLL-UHFFFAOYSA-N methyl 2-butyl-7-methyl-3-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]imidazo[4,5-c]pyridine-4-carboxylate Chemical compound CCCCC1=NC2=C(C)C=NC(C(=O)OC)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 STICULMOCORXLL-UHFFFAOYSA-N 0.000 description 2
- YSHHLMPJLDQUNH-UHFFFAOYSA-N methyl 2-nitro-3-(2-oxopropyl)benzoate Chemical compound COC(=O)C1=CC=CC(CC(C)=O)=C1[N+]([O-])=O YSHHLMPJLDQUNH-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 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
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 230000003639 vasoconstrictive effect Effects 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 229910052727 yttrium Inorganic materials 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- RMMJUQSANCPTMV-UHFFFAOYSA-N (2-aminophenyl)-(4-methylphenyl)methanone Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=CC=C1N RMMJUQSANCPTMV-UHFFFAOYSA-N 0.000 description 1
- CEVCYBWRNWZIAA-UHFFFAOYSA-N (2-hydroxyphenyl)-(4-methylphenyl)methanone Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=CC=C1O CEVCYBWRNWZIAA-UHFFFAOYSA-N 0.000 description 1
- MXCUYSMIELHIQL-UHFFFAOYSA-N (4-carbamoyl-1h-imidazol-5-yl)azanium;chloride Chemical compound Cl.NC(=O)C=1NC=NC=1N MXCUYSMIELHIQL-UHFFFAOYSA-N 0.000 description 1
- KOPMZTKUZCNGFY-UHFFFAOYSA-N 1,1,1-triethoxybutane Chemical compound CCCC(OCC)(OCC)OCC KOPMZTKUZCNGFY-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- RNFIRCUQAQFVAN-UHFFFAOYSA-N 1,1-diethoxy-n,n-dimethylpropan-1-amine Chemical compound CCOC(CC)(N(C)C)OCC RNFIRCUQAQFVAN-UHFFFAOYSA-N 0.000 description 1
- FBZVZUSVGKOWHG-UHFFFAOYSA-N 1,1-dimethoxy-n,n-dimethylethanamine Chemical compound COC(C)(OC)N(C)C FBZVZUSVGKOWHG-UHFFFAOYSA-N 0.000 description 1
- AZVRIFBXUXFRLJ-UHFFFAOYSA-N 1-(2-chloro-4-methylphenyl)pyrrole-2-carbaldehyde Chemical compound ClC1=CC(C)=CC=C1N1C(C=O)=CC=C1 AZVRIFBXUXFRLJ-UHFFFAOYSA-N 0.000 description 1
- GNQPINYQVQYOHG-UHFFFAOYSA-N 1-(2-chloro-4-methylphenyl)pyrrole-2-carbonitrile Chemical compound ClC1=CC(C)=CC=C1N1C(C#N)=CC=C1 GNQPINYQVQYOHG-UHFFFAOYSA-N 0.000 description 1
- VYUNLDVEMSMJNP-UHFFFAOYSA-N 1-(4-methylphenyl)pyrrole Chemical compound C1=CC(C)=CC=C1N1C=CC=C1 VYUNLDVEMSMJNP-UHFFFAOYSA-N 0.000 description 1
- LASYAEOJPVQNFO-UHFFFAOYSA-N 1-(4-methylphenyl)pyrrole-2-carbaldehyde Chemical compound C1=CC(C)=CC=C1N1C(C=O)=CC=C1 LASYAEOJPVQNFO-UHFFFAOYSA-N 0.000 description 1
- WUOVFHPNARHASP-UHFFFAOYSA-N 1-(4-methylphenyl)pyrrole-3-carbaldehyde Chemical compound C1=CC(C)=CC=C1N1C=C(C=O)C=C1 WUOVFHPNARHASP-UHFFFAOYSA-N 0.000 description 1
- DVLNUPJKBBBTII-UHFFFAOYSA-N 1-[4-(bromomethyl)-2-chlorophenyl]pyrrole-2-carbonitrile Chemical compound ClC1=CC(CBr)=CC=C1N1C(C#N)=CC=C1 DVLNUPJKBBBTII-UHFFFAOYSA-N 0.000 description 1
- ZBTMRBYMKUEVEU-UHFFFAOYSA-N 1-bromo-4-methylbenzene Chemical compound CC1=CC=C(Br)C=C1 ZBTMRBYMKUEVEU-UHFFFAOYSA-N 0.000 description 1
- XNHTZBFSFZSWOO-UHFFFAOYSA-N 1-bromopentan-2-one Chemical compound CCCC(=O)CBr XNHTZBFSFZSWOO-UHFFFAOYSA-N 0.000 description 1
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 1
- NKTKVEJZIJWVQB-UHFFFAOYSA-N 2,2-dimethylpropanoyloxymethyl 2-butyl-3-[[2-[2-(1-trityltetrazol-5-yl)phenyl]quinazolin-6-yl]methyl]benzimidazole-4-carboxylate Chemical compound CCCCC1=NC2=CC=CC(C(=O)OCOC(=O)C(C)(C)C)=C2N1CC(C=C1C=N2)=CC=C1N=C2C1=CC=CC=C1C1=NN=NN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 NKTKVEJZIJWVQB-UHFFFAOYSA-N 0.000 description 1
- ZWQLQAXIEGGWOG-UHFFFAOYSA-N 2,2-dimethylpropanoyloxymethyl 2-propyl-1-[[4-[2-(1-trityltetrazol-5-yl)phenyl]phenyl]methyl]indole-7-carboxylate Chemical compound CCCC1=CC2=CC=CC(C(=O)OCOC(=O)C(C)(C)C)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 ZWQLQAXIEGGWOG-UHFFFAOYSA-N 0.000 description 1
- YZMSWEUVXZEGNT-UHFFFAOYSA-N 2,2-dimethylpropanoyloxymethyl 2-propyl-1-[[4-[2-(1-trityltetrazol-5-yl)phenyl]phenyl]methyl]pyrazolo[1,5-b][1,2,4]triazole-7-carboxylate Chemical compound CCCC1=NN2N=CC(C(=O)OCOC(=O)C(C)(C)C)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 YZMSWEUVXZEGNT-UHFFFAOYSA-N 0.000 description 1
- FYYFMFVOADLRES-UHFFFAOYSA-N 2-(2-bromophenyl)-3,6-dimethylquinazolin-4-one Chemical compound CN1C(=O)C2=CC(C)=CC=C2N=C1C1=CC=CC=C1Br FYYFMFVOADLRES-UHFFFAOYSA-N 0.000 description 1
- NQFMFNPKWGICBJ-UHFFFAOYSA-N 2-(2-bromophenyl)-4-chloro-6-methylquinazoline Chemical compound N1=C(Cl)C2=CC(C)=CC=C2N=C1C1=CC=CC=C1Br NQFMFNPKWGICBJ-UHFFFAOYSA-N 0.000 description 1
- RBXZFBGDVPROFL-UHFFFAOYSA-N 2-(2-bromophenyl)-6-methyl-1h-quinazolin-4-one Chemical compound N1C(=O)C2=CC(C)=CC=C2N=C1C1=CC=CC=C1Br RBXZFBGDVPROFL-UHFFFAOYSA-N 0.000 description 1
- WACMXPXMOVHSCE-UHFFFAOYSA-N 2-(2-bromophenyl)-6-methylquinazoline Chemical compound N1=CC2=CC(C)=CC=C2N=C1C1=CC=CC=C1Br WACMXPXMOVHSCE-UHFFFAOYSA-N 0.000 description 1
- MGDPIYUTVTXBQI-UHFFFAOYSA-N 2-(3,6-dimethyl-4-oxoquinazolin-2-yl)benzonitrile Chemical compound CN1C(=O)C2=CC(C)=CC=C2N=C1C1=CC=CC=C1C#N MGDPIYUTVTXBQI-UHFFFAOYSA-N 0.000 description 1
- RNHKXHKUKJXLAU-UHFFFAOYSA-N 2-(4-methylphenyl)acetonitrile Chemical compound CC1=CC=C(CC#N)C=C1 RNHKXHKUKJXLAU-UHFFFAOYSA-N 0.000 description 1
- FXRJRJPWWNQURG-UHFFFAOYSA-N 2-(5-methylpyridin-2-yl)benzonitrile Chemical compound N1=CC(C)=CC=C1C1=CC=CC=C1C#N FXRJRJPWWNQURG-UHFFFAOYSA-N 0.000 description 1
- FPUCIQQWEVLZBK-UHFFFAOYSA-N 2-(6-methylquinazolin-2-yl)benzonitrile Chemical compound N1=CC2=CC(C)=CC=C2N=C1C1=CC=CC=C1C#N FPUCIQQWEVLZBK-UHFFFAOYSA-N 0.000 description 1
- VEQAXUPMHWAXLT-UHFFFAOYSA-N 2-(7-methyl-4-oxoquinazolin-3-yl)benzonitrile Chemical compound C=1C(C)=CC=C(C2=O)C=1N=CN2C1=CC=CC=C1C#N VEQAXUPMHWAXLT-UHFFFAOYSA-N 0.000 description 1
- 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 1
- IJLPPOTUWWDRRL-UHFFFAOYSA-N 2-[6-(bromomethyl)-3-methyl-4-oxoquinazolin-2-yl]benzonitrile Chemical compound N=1C2=CC=C(CBr)C=C2C(=O)N(C)C=1C1=CC=CC=C1C#N IJLPPOTUWWDRRL-UHFFFAOYSA-N 0.000 description 1
- LLSGVPKOCZZLTF-UHFFFAOYSA-N 2-amino-5-methylbenzamide Chemical compound CC1=CC=C(N)C(C(N)=O)=C1 LLSGVPKOCZZLTF-UHFFFAOYSA-N 0.000 description 1
- HLCPWBZNUKCSBN-UHFFFAOYSA-N 2-aminobenzonitrile Chemical compound NC1=CC=CC=C1C#N HLCPWBZNUKCSBN-UHFFFAOYSA-N 0.000 description 1
- YWNJQQNBJQUKME-UHFFFAOYSA-N 2-bromo-5-methylpyridine Chemical compound CC1=CC=C(Br)N=C1 YWNJQQNBJQUKME-UHFFFAOYSA-N 0.000 description 1
- XRXMNWGCKISMOH-UHFFFAOYSA-N 2-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Br XRXMNWGCKISMOH-UHFFFAOYSA-N 0.000 description 1
- PDEOEYYCSWKULJ-UHFFFAOYSA-N 2-butyl-3-[[4-[3-(2h-tetrazol-5-yl)pyrrol-1-yl]phenyl]methyl]benzimidazole-4-carboxylic acid Chemical compound CCCCC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1N(C=1)C=CC=1C1=NN=NN1 PDEOEYYCSWKULJ-UHFFFAOYSA-N 0.000 description 1
- KYRMSJGJAJLCQL-UHFFFAOYSA-N 2-butyl-3-[[4-[3-(2h-tetrazol-5-yl)quinolin-4-yl]phenyl]methyl]benzimidazole-4-carboxylic acid Chemical compound CCCCC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C(C1=CC=CC=C1N=C1)=C1C1=NN=NN1 KYRMSJGJAJLCQL-UHFFFAOYSA-N 0.000 description 1
- UXTOJBHDQIOJEI-UHFFFAOYSA-N 2-butyl-7-methyl-3-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]imidazo[4,5-c]pyridine Chemical compound CCCCC1=NC2=C(C)C=NC=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 UXTOJBHDQIOJEI-UHFFFAOYSA-N 0.000 description 1
- DEIOHSMJLTZPKE-UHFFFAOYSA-N 2-butyl-7-methyl-3h-imidazo[4,5-c]pyridine Chemical compound N1=CC(C)=C2NC(CCCC)=NC2=C1 DEIOHSMJLTZPKE-UHFFFAOYSA-N 0.000 description 1
- MTCGZZLDBYSKBR-UHFFFAOYSA-N 2-butyl-7-methyl-5-oxido-4h-imidazo[4,5-c]pyridin-5-ium Chemical compound C1=[N+]([O-])CC2=NC(CCCC)=NC2=C1C MTCGZZLDBYSKBR-UHFFFAOYSA-N 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- XGYLSRFSXKAYCR-UHFFFAOYSA-N 2-chloro-4-methylaniline Chemical compound CC1=CC=C(N)C(Cl)=C1 XGYLSRFSXKAYCR-UHFFFAOYSA-N 0.000 description 1
- OWRJCRMJEQJUNN-UHFFFAOYSA-N 2-ethyl-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]indole-7-carboxylic acid Chemical compound CCC1=CC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 OWRJCRMJEQJUNN-UHFFFAOYSA-N 0.000 description 1
- DNTWUQLOFFIJHM-UHFFFAOYSA-N 2-ethyl-4-oxo-9-[[4-[2-(1-trityltetrazol-5-yl)phenyl]phenyl]methyl]thieno[2,3-b]quinoline-8-carboxylic acid Chemical compound S1C(CC)=CC(C(C2=CC=CC(=C22)C(O)=O)=O)=C1N2CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 DNTWUQLOFFIJHM-UHFFFAOYSA-N 0.000 description 1
- CHZCERSEMVWNHL-UHFFFAOYSA-N 2-hydroxybenzonitrile Chemical compound OC1=CC=CC=C1C#N CHZCERSEMVWNHL-UHFFFAOYSA-N 0.000 description 1
- HNUKTDKISXPDPA-UHFFFAOYSA-N 2-oxopropyl Chemical group [CH2]C(C)=O HNUKTDKISXPDPA-UHFFFAOYSA-N 0.000 description 1
- WLPATYNQCGVFFH-UHFFFAOYSA-N 2-phenylbenzonitrile Chemical group N#CC1=CC=CC=C1C1=CC=CC=C1 WLPATYNQCGVFFH-UHFFFAOYSA-N 0.000 description 1
- 125000006325 2-propenyl amino group Chemical group [H]C([H])=C([H])C([H])([H])N([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- GJXMJUGBZJBKRS-UHFFFAOYSA-N 2-propyl-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]imidazo[1,2-c]imidazole-7-carbonitrile Chemical compound CCCC1=CN2C=NC(C#N)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 GJXMJUGBZJBKRS-UHFFFAOYSA-N 0.000 description 1
- ZZKGYTZVFHTYHN-UHFFFAOYSA-N 2-propyl-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]imidazo[1,2-c]imidazole-7-carboxamide Chemical compound CCCC1=CN2C=NC(C(N)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 ZZKGYTZVFHTYHN-UHFFFAOYSA-N 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- JYHSJQNYYLGMEI-UHFFFAOYSA-N 3,3-dimethoxypropanenitrile Chemical compound COC(OC)CC#N JYHSJQNYYLGMEI-UHFFFAOYSA-N 0.000 description 1
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-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
- HIOGZAIIUIIPCM-UHFFFAOYSA-N 3-ethoxycarbonyl-7-ethyl-5-propyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylic acid Chemical compound N1C(CCC)=C(C(O)=O)C(CC)N2N=CC(C(=O)OCC)=C21 HIOGZAIIUIIPCM-UHFFFAOYSA-N 0.000 description 1
- GUXYMXAQOPCVLS-UHFFFAOYSA-N 4-(2-formylpyrrol-1-yl)benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1N1C(C=O)=CC=C1 GUXYMXAQOPCVLS-UHFFFAOYSA-N 0.000 description 1
- 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 1
- MCSMDPRCMRGINW-UHFFFAOYSA-N 4-(4-methylphenyl)quinoline-3-carbonitrile Chemical compound C1=CC(C)=CC=C1C1=C(C#N)C=NC2=CC=CC=C12 MCSMDPRCMRGINW-UHFFFAOYSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- HXXOPVULXOEHTK-UHFFFAOYSA-N 4-methyl-1,3-dioxol-2-one Chemical compound CC1=COC(=O)O1 HXXOPVULXOEHTK-UHFFFAOYSA-N 0.000 description 1
- QGBSLPHQCUIZKK-UHFFFAOYSA-N 4-methyl-2-nitrobenzonitrile Chemical compound CC1=CC=C(C#N)C([N+]([O-])=O)=C1 QGBSLPHQCUIZKK-UHFFFAOYSA-N 0.000 description 1
- ICGLPKIVTVWCFT-UHFFFAOYSA-N 4-methylbenzenesulfonohydrazide Chemical compound CC1=CC=C(S(=O)(=O)NN)C=C1 ICGLPKIVTVWCFT-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- YQEZHVXMMAAHSU-UHFFFAOYSA-N 5-(4-methylphenyl)pyrimidin-4-amine Chemical compound C1=CC(C)=CC=C1C1=CN=CN=C1N YQEZHVXMMAAHSU-UHFFFAOYSA-N 0.000 description 1
- IJIBRSFAXRFPPN-UHFFFAOYSA-N 5-bromo-2-methoxybenzaldehyde Chemical compound COC1=CC=C(Br)C=C1C=O IJIBRSFAXRFPPN-UHFFFAOYSA-N 0.000 description 1
- GYCPLYCTMDTEPU-UHFFFAOYSA-N 5-bromopyrimidine Chemical compound BrC1=CN=CN=C1 GYCPLYCTMDTEPU-UHFFFAOYSA-N 0.000 description 1
- QRRSIFNWHCKMSW-UHFFFAOYSA-N 5-methyl-2-nitrobenzoic acid Chemical compound CC1=CC=C([N+]([O-])=O)C(C(O)=O)=C1 QRRSIFNWHCKMSW-UHFFFAOYSA-N 0.000 description 1
- HMPMGEOXIHKAQR-UHFFFAOYSA-N 5-methylpyridine-3,4-diamine Chemical compound CC1=CN=CC(N)=C1N.CC1=CN=CC(N)=C1N HMPMGEOXIHKAQR-UHFFFAOYSA-N 0.000 description 1
- OPGJGRWULGFTOS-UHFFFAOYSA-N 5-nitro-2,4-dioxo-1h-pyrimidine-6-carboxylic acid Chemical compound OC(=O)C=1NC(=O)NC(=O)C=1[N+]([O-])=O OPGJGRWULGFTOS-UHFFFAOYSA-N 0.000 description 1
- QRIKTTFYHIKAKM-UHFFFAOYSA-N 6-O-tert-butyl 3-O-ethyl 7-ethyl-5-propyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarboxylate Chemical compound C(C)OC(=O)C=1C=NN2C=1NC(=C(C2CC)C(=O)OC(C)(C)C)CCC QRIKTTFYHIKAKM-UHFFFAOYSA-N 0.000 description 1
- GAAPWASQZLIBLJ-UHFFFAOYSA-N 6-methyl-2-[2-(1-trityltetrazol-5-yl)phenyl]quinazoline Chemical compound N1=CC2=CC(C)=CC=C2N=C1C1=CC=CC=C1C1=NN=NN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 GAAPWASQZLIBLJ-UHFFFAOYSA-N 0.000 description 1
- LIVYMRJSNFHYEN-UHFFFAOYSA-N 6-methyl-5-nitro-1h-pyrimidine-2,4-dione Chemical compound CC=1NC(=O)NC(=O)C=1[N+]([O-])=O LIVYMRJSNFHYEN-UHFFFAOYSA-N 0.000 description 1
- AIAODQOERQONPI-UHFFFAOYSA-N 7-ethyl-5-propyl-4-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]-7h-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid Chemical compound CCCC1=CC(CC)N2N=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 AIAODQOERQONPI-UHFFFAOYSA-N 0.000 description 1
- AJAGZFBUFQHNJL-UHFFFAOYSA-N 7-methyl-2-propyl-3h-imidazo[4,5-c]pyridine Chemical compound N1=CC(C)=C2NC(CCC)=NC2=C1 AJAGZFBUFQHNJL-UHFFFAOYSA-N 0.000 description 1
- LJFKOJCBPKGKCX-UHFFFAOYSA-N 7-methyl-2-propyl-3h-imidazo[4,5-c]pyridine-4-carbonitrile Chemical compound N1=CC(C)=C2NC(CCC)=NC2=C1C#N LJFKOJCBPKGKCX-UHFFFAOYSA-N 0.000 description 1
- PZASAAIJIFDWSB-CKPDSHCKSA-N 8-[(1S)-1-[8-(trifluoromethyl)-7-[4-(trifluoromethyl)cyclohexyl]oxynaphthalen-2-yl]ethyl]-8-azabicyclo[3.2.1]octane-3-carboxylic acid Chemical compound FC(F)(F)C=1C2=CC([C@@H](N3C4CCC3CC(C4)C(O)=O)C)=CC=C2C=CC=1OC1CCC(C(F)(F)F)CC1 PZASAAIJIFDWSB-CKPDSHCKSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 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
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 102000011632 Caseins Human genes 0.000 description 1
- 108010076119 Caseins Proteins 0.000 description 1
- 208000018152 Cerebral disease Diseases 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 1
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 1
- 206010009192 Circulatory collapse Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 206010020880 Hypertrophy 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
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 108010083387 Saralasin Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- MOQOOKGPCBQMCY-UHFFFAOYSA-N acetic acid;hexane Chemical compound CC(O)=O.CCCCCC MOQOOKGPCBQMCY-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 210000004404 adrenal cortex Anatomy 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229960002478 aldosterone Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- BJUSKQNPSWYMEI-UHFFFAOYSA-N azido(triphenyl)stannane Chemical compound C=1C=CC=CC=1[Sn](C=1C=CC=CC=1)(N=[N+]=[N-])C1=CC=CC=C1 BJUSKQNPSWYMEI-UHFFFAOYSA-N 0.000 description 1
- 150000001556 benzimidazoles Chemical class 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- CSTBBLHIGMTEAZ-UHFFFAOYSA-N chloroform;ethyl acetate;hexane Chemical compound ClC(Cl)Cl.CCCCCC.CCOC(C)=O CSTBBLHIGMTEAZ-UHFFFAOYSA-N 0.000 description 1
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 1
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000000748 compression moulding Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 1
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- LNDXFGLDIOCTIJ-UHFFFAOYSA-N diethyl 7-propan-2-yl-5-propyl-4-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]-7h-pyrazolo[1,5-a]pyrimidine-3,6-dicarboxylate Chemical compound CCCC1=C(C(=O)OCC)C(C(C)C)N2N=CC(C(=O)OCC)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 LNDXFGLDIOCTIJ-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- OYJXTOVLKZDGFK-UHFFFAOYSA-N ethanol;2-propan-2-yloxypropane Chemical compound CCO.CC(C)OC(C)C OYJXTOVLKZDGFK-UHFFFAOYSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- HBFXVTVOSLPOEY-UHFFFAOYSA-N ethoxyethane;2-propan-2-yloxypropane Chemical compound CCOCC.CC(C)OC(C)C HBFXVTVOSLPOEY-UHFFFAOYSA-N 0.000 description 1
- BDHXJIRTSWHBPR-UHFFFAOYSA-N ethyl 1-iodoethyl carbonate Chemical compound CCOC(=O)OC(C)I BDHXJIRTSWHBPR-UHFFFAOYSA-N 0.000 description 1
- XLMKCFKNYBYDLD-UHFFFAOYSA-N ethyl 2-(2-methylpropylidene)-3-oxohexanoate Chemical compound CCCC(=O)C(=CC(C)C)C(=O)OCC XLMKCFKNYBYDLD-UHFFFAOYSA-N 0.000 description 1
- UINVGXPKTSRWHH-UHFFFAOYSA-N ethyl 2-ethyl-1-[[4-[2-(1-trityltetrazol-5-yl)phenyl]phenyl]methyl]indole-7-carboxylate Chemical compound C1=2C(C(=O)OCC)=CC=CC=2C=C(CC)N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 UINVGXPKTSRWHH-UHFFFAOYSA-N 0.000 description 1
- ATRSGXKDEFXKRF-UHFFFAOYSA-N ethyl 2-ethyl-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]indole-7-carboxylate Chemical compound C1=2C(C(=O)OCC)=CC=CC=2C=C(CC)N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 ATRSGXKDEFXKRF-UHFFFAOYSA-N 0.000 description 1
- QFNRDWWMUBSCTI-UHFFFAOYSA-N ethyl 2-nitro-3-(2-oxobutyl)benzoate Chemical compound CCOC(=O)C1=CC=CC(CC(=O)CC)=C1[N+]([O-])=O QFNRDWWMUBSCTI-UHFFFAOYSA-N 0.000 description 1
- FOPSYGDCFSJLLZ-UHFFFAOYSA-N ethyl 2-nitro-3-(2-oxopentyl)benzoate Chemical compound CCCC(=O)CC1=CC=CC(C(=O)OCC)=C1[N+]([O-])=O FOPSYGDCFSJLLZ-UHFFFAOYSA-N 0.000 description 1
- LJTMEUQEFRDJJI-UHFFFAOYSA-N ethyl 2-propyl-1-[[4-[2-(1-trityltetrazol-5-yl)phenyl]phenyl]methyl]indole-7-carboxylate Chemical compound CCCC1=CC2=CC=CC(C(=O)OCC)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 LJTMEUQEFRDJJI-UHFFFAOYSA-N 0.000 description 1
- PUDZRLBFIUDLEW-UHFFFAOYSA-N ethyl 2-propyl-1-[[4-[2-(1-trityltetrazol-5-yl)phenyl]phenyl]methyl]pyrazolo[1,5-b][1,2,4]triazole-7-carboxylate Chemical compound CCCC1=NN2N=CC(C(=O)OCC)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 PUDZRLBFIUDLEW-UHFFFAOYSA-N 0.000 description 1
- JLWFZTPHNKTNLK-UHFFFAOYSA-N ethyl 2-propyl-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]indole-7-carboxylate Chemical compound CCCC1=CC2=CC=CC(C(=O)OCC)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 JLWFZTPHNKTNLK-UHFFFAOYSA-N 0.000 description 1
- YIAXEFJFLDDBDM-UHFFFAOYSA-N ethyl 2-propyl-1h-indole-7-carboxylate Chemical compound C1=CC(C(=O)OCC)=C2NC(CCC)=CC2=C1 YIAXEFJFLDDBDM-UHFFFAOYSA-N 0.000 description 1
- XOHSCUJFFBTHJL-UHFFFAOYSA-N ethyl 2-propyl-3h-pyrazolo[1,5-b][1,2,4]triazole-7-carboxylate Chemical compound N1=CC(C(=O)OCC)=C2NC(CCC)=NN21 XOHSCUJFFBTHJL-UHFFFAOYSA-N 0.000 description 1
- WTNOWOBAMZQUCU-UHFFFAOYSA-N ethyl 3-aminopyrazole-3-carboxylate Chemical compound CCOC(=O)C1(N)C=CN=N1 WTNOWOBAMZQUCU-UHFFFAOYSA-N 0.000 description 1
- RVGRLNXKWPFKBL-UHFFFAOYSA-N ethyl 5-amino-1-(2-oxopentyl)pyrazole-4-carboxylate Chemical compound CCCC(=O)CN1N=CC(C(=O)OCC)=C1N RVGRLNXKWPFKBL-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 210000003191 femoral vein Anatomy 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000003284 homeostatic effect Effects 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 229940064880 inositol 100 mg Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- RHMQNXNXUZLEIY-UHFFFAOYSA-N methanol;2-propan-2-yloxypropane Chemical compound OC.CC(C)OC(C)C RHMQNXNXUZLEIY-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- QOZVZJLPNJOHFA-UHFFFAOYSA-N methyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate Chemical compound COC(=O)C1=NC(Cl)=NC(Cl)=C1[N+]([O-])=O QOZVZJLPNJOHFA-UHFFFAOYSA-N 0.000 description 1
- MMIHKVQCDPUOAQ-UHFFFAOYSA-N methyl 2,8-diethoxy-7-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]purine-6-carboxylate Chemical compound CCOC1=NC2=NC(OCC)=NC(C(=O)OC)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 MMIHKVQCDPUOAQ-UHFFFAOYSA-N 0.000 description 1
- DLBZSNMTKZFXCF-UHFFFAOYSA-N methyl 2,8-diethoxy-7h-purine-6-carboxylate Chemical compound CCOC1=NC(C(=O)OC)=C2NC(OCC)=NC2=N1 DLBZSNMTKZFXCF-UHFFFAOYSA-N 0.000 description 1
- VCBPILCXNPSFDA-UHFFFAOYSA-N methyl 2-butyl-3-[[3-(2-cyanophenyl)-4-oxoquinazolin-7-yl]methyl]benzimidazole-4-carboxylate Chemical compound CCCCC1=NC2=CC=CC(C(=O)OC)=C2N1CC(C=1)=CC=C(C2=O)C=1N=CN2C1=CC=CC=C1C#N VCBPILCXNPSFDA-UHFFFAOYSA-N 0.000 description 1
- ZIKXPQYZEAOHRK-UHFFFAOYSA-N methyl 2-butyl-3-[[4-(2-cyano-5-methylpyrrol-1-yl)phenyl]methyl]benzimidazole-4-carboxylate Chemical compound CCCCC1=NC2=CC=CC(C(=O)OC)=C2N1CC(C=C1)=CC=C1N1C(C)=CC=C1C#N ZIKXPQYZEAOHRK-UHFFFAOYSA-N 0.000 description 1
- LZEUNRZTVLLBIC-UHFFFAOYSA-N methyl 2-butyl-3-[[4-[5-(2h-tetrazol-5-yl)pyrimidin-4-yl]phenyl]methyl]benzimidazole-4-carboxylate Chemical compound CCCCC1=NC2=CC=CC(C(=O)OC)=C2N1CC(C=C1)=CC=C1C1=NC=NC=C1C1=NN=NN1 LZEUNRZTVLLBIC-UHFFFAOYSA-N 0.000 description 1
- NDWBNUFYPPGFPY-UHFFFAOYSA-N methyl 2-butyl-3-[[6-(2-cyanophenyl)pyridin-3-yl]methyl]benzimidazole-4-carboxylate Chemical compound CCCCC1=NC2=CC=CC(C(=O)OC)=C2N1CC(C=N1)=CC=C1C1=CC=CC=C1C#N NDWBNUFYPPGFPY-UHFFFAOYSA-N 0.000 description 1
- CFXMLKGBGNWOFF-UHFFFAOYSA-N methyl 2-butyl-3-[[6-(2-methoxycarbonylphenyl)pyridin-3-yl]methyl]benzimidazole-4-carboxylate Chemical compound CCCCC1=NC2=CC=CC(C(=O)OC)=C2N1CC(C=N1)=CC=C1C1=CC=CC=C1C(=O)OC CFXMLKGBGNWOFF-UHFFFAOYSA-N 0.000 description 1
- CRFGJWUGGSWFED-UHFFFAOYSA-N methyl 2-butyl-7-methyl-3-[[4-[2-(1-trityltetrazol-5-yl)phenyl]phenyl]methyl]imidazo[4,5-c]pyridine-4-carboxylate Chemical compound CCCCC1=NC2=C(C)C=NC(C(=O)OC)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 CRFGJWUGGSWFED-UHFFFAOYSA-N 0.000 description 1
- QUUFCTCZXVWLFN-UHFFFAOYSA-N methyl 2-methyl-1-[[4-[2-(1-trityltetrazol-5-yl)phenyl]phenyl]methyl]indole-7-carboxylate Chemical compound C1=2C(C(=O)OC)=CC=CC=2C=C(C)N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 QUUFCTCZXVWLFN-UHFFFAOYSA-N 0.000 description 1
- KVQWPLOXYBCNMG-UHFFFAOYSA-N methyl 2-methyl-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]indole-7-carboxylate Chemical compound C1=2C(C(=O)OC)=CC=CC=2C=C(C)N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 KVQWPLOXYBCNMG-UHFFFAOYSA-N 0.000 description 1
- WXTXCGBDIOPWCB-UHFFFAOYSA-N methyl 2-methyl-1h-indole-7-carboxylate Chemical compound COC(=O)C1=CC=CC2=C1NC(C)=C2 WXTXCGBDIOPWCB-UHFFFAOYSA-N 0.000 description 1
- AIYQKKAJTIQEIC-UHFFFAOYSA-N methyl 3-(2-amino-5-ethylthiophene-3-carbonyl)-2-fluorobenzoate Chemical compound S1C(CC)=CC(C(=O)C=2C(=C(C(=O)OC)C=CC=2)F)=C1N AIYQKKAJTIQEIC-UHFFFAOYSA-N 0.000 description 1
- KVJRENQVAZJNNT-UHFFFAOYSA-N methyl 3-(2-cyanoacetyl)-2-fluorobenzoate Chemical compound COC(=O)C1=CC=CC(C(=O)CC#N)=C1F KVJRENQVAZJNNT-UHFFFAOYSA-N 0.000 description 1
- NJHDBIXFFZVJGZ-UHFFFAOYSA-N methyl 3-methyl-2-nitrobenzoate Chemical compound COC(=O)C1=CC=CC(C)=C1[N+]([O-])=O NJHDBIXFFZVJGZ-UHFFFAOYSA-N 0.000 description 1
- KEYRSXBMIRMGBI-UHFFFAOYSA-N methyl 4-(2-cyano-5-methylpyrrol-1-yl)benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1N1C(C#N)=CC=C1C KEYRSXBMIRMGBI-UHFFFAOYSA-N 0.000 description 1
- MWSJEIOZZYEZOY-UHFFFAOYSA-N methyl 4-(2-methylpyrrol-1-yl)benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1N1C(C)=CC=C1 MWSJEIOZZYEZOY-UHFFFAOYSA-N 0.000 description 1
- LZXXNPOYQCLXRS-UHFFFAOYSA-N methyl 4-aminobenzoate Chemical compound COC(=O)C1=CC=C(N)C=C1 LZXXNPOYQCLXRS-UHFFFAOYSA-N 0.000 description 1
- XCBRROUJSCMUGF-UHFFFAOYSA-N methyl 4-pyrrol-1-ylbenzoate Chemical compound C1=CC(C(=O)OC)=CC=C1N1C=CC=C1 XCBRROUJSCMUGF-UHFFFAOYSA-N 0.000 description 1
- OWCOUHFPJTXDKF-UHFFFAOYSA-N methyl 5,6-diamino-2-ethoxypyrimidine-4-carboxylate Chemical compound CCOC1=NC(N)=C(N)C(C(=O)OC)=N1 OWCOUHFPJTXDKF-UHFFFAOYSA-N 0.000 description 1
- KPNLMRWITBJHTK-UHFFFAOYSA-N methyl 5-nitro-2,4-dioxo-1h-pyrimidine-6-carboxylate Chemical compound COC(=O)C=1NC(=O)NC(=O)C=1[N+]([O-])=O KPNLMRWITBJHTK-UHFFFAOYSA-N 0.000 description 1
- BSDJCASOEYPFGQ-UHFFFAOYSA-N methyl 6-amino-2-chloro-5-nitropyrimidine-4-carboxylate Chemical compound COC(=O)C1=NC(Cl)=NC(N)=C1[N+]([O-])=O BSDJCASOEYPFGQ-UHFFFAOYSA-N 0.000 description 1
- COAWPKCQURMFRI-UHFFFAOYSA-N methyl 6-amino-2-ethoxy-5-nitropyrimidine-4-carboxylate Chemical compound CCOC1=NC(N)=C([N+]([O-])=O)C(C(=O)OC)=N1 COAWPKCQURMFRI-UHFFFAOYSA-N 0.000 description 1
- FFULRDZOAGICQY-UHFFFAOYSA-N methyl 7-methyl-2-propyl-3-[[4-[2-(1-trityltetrazol-5-yl)phenyl]phenyl]methyl]imidazo[4,5-c]pyridine-4-carboxylate Chemical compound CCCC1=NC2=C(C)C=NC(C(=O)OC)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 FFULRDZOAGICQY-UHFFFAOYSA-N 0.000 description 1
- BZJCPEKOANALDS-UHFFFAOYSA-N methyl 7-methyl-2-propyl-3-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]imidazo[4,5-c]pyridine-4-carboxylate Chemical compound CCCC1=NC2=C(C)C=NC(C(=O)OC)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 BZJCPEKOANALDS-UHFFFAOYSA-N 0.000 description 1
- ZBYRIAXPLZWIKZ-UHFFFAOYSA-N methyl 7-methyl-2-propyl-3h-imidazo[4,5-c]pyridine-4-carboxylate Chemical compound N1=CC(C)=C2NC(CCC)=NC2=C1C(=O)OC ZBYRIAXPLZWIKZ-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 230000010807 negative regulation of binding Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 150000002829 nitrogen Chemical group 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- QIXHCRFULVPKSL-UHFFFAOYSA-N propan-2-yl 3-(2-cyanoacetyl)-2-fluorobenzoate Chemical compound CC(C)OC(=O)C1=CC=CC(C(=O)CC#N)=C1F QIXHCRFULVPKSL-UHFFFAOYSA-N 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- MCSKRVKAXABJLX-UHFFFAOYSA-N pyrazolo[3,4-d]triazole Chemical compound N1=NN=C2N=NC=C21 MCSKRVKAXABJLX-UHFFFAOYSA-N 0.000 description 1
- 150000008318 pyrimidones Chemical class 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 150000003246 quinazolines Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052702 rhenium Inorganic materials 0.000 description 1
- PFGWGEPQIUAZME-NXSMLHPHSA-N saralasin Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)CNC)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(O)=O)C1=CC=C(O)C=C1 PFGWGEPQIUAZME-NXSMLHPHSA-N 0.000 description 1
- 229960004785 saralasin Drugs 0.000 description 1
- 206010040560 shock Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- CSMWJXBSXGUPGY-UHFFFAOYSA-L sodium dithionate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)S([O-])(=O)=O CSMWJXBSXGUPGY-UHFFFAOYSA-L 0.000 description 1
- 229940075931 sodium dithionate Drugs 0.000 description 1
- GOOXAUGUEUPBTD-UHFFFAOYSA-M sodium;7-methyl-2-propyl-3-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]imidazo[4,5-c]pyridine-4-carboxylate Chemical compound [Na+].CCCC1=NC2=C(C)C=NC(C([O-])=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 GOOXAUGUEUPBTD-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 229940042055 systemic antimycotics triazole derivative Drugs 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- DHHKPEUQJIEKOA-UHFFFAOYSA-N tert-butyl 2-[6-(nitromethyl)-6-bicyclo[3.2.0]hept-3-enyl]acetate Chemical compound C1C=CC2C(CC(=O)OC(C)(C)C)(C[N+]([O-])=O)CC21 DHHKPEUQJIEKOA-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- CWLNAJYDRSIKJS-UHFFFAOYSA-N triethoxymethoxyethane Chemical compound CCOC(OCC)(OCC)OCC CWLNAJYDRSIKJS-UHFFFAOYSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N valeric aldehyde Natural products CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 150000003752 zinc compounds Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- 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
- C07D401/06—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 only aliphatic carbon atoms
-
- 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
- C07D401/14—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 three or more hetero rings
-
- 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
- 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
- C07D403/14—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 three or more hetero 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
- C07D405/14—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/28—Oxygen atom
- C07D473/30—Oxygen atom attached in position 6, e.g. hypoxanthine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP173473/1991 | 1991-04-16 | ||
| JP17347391 | 1991-04-16 | ||
| JP263341/1991 | 1991-07-05 | ||
| JP26334191 | 1991-07-05 | ||
| JP31562991 | 1991-09-25 | ||
| JP315629/1991 | 1991-09-25 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2066094A1 CA2066094A1 (en) | 1992-10-17 |
| CA2066094C true CA2066094C (en) | 2003-06-24 |
Family
ID=27323786
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002066094A Expired - Fee Related CA2066094C (en) | 1991-04-16 | 1992-04-15 | Fused heterocyclic compounds, their production and use |
Country Status (8)
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10588900B2 (en) | 2016-02-09 | 2020-03-17 | Pharmakea, Inc. | Quinolinone lysyl oxidase-like 2 inhibitors and uses thereof |
| US11407733B2 (en) | 2016-06-29 | 2022-08-09 | Bristol-Myers Squibb Company | Biarylmethyl heterocycles |
Families Citing this family (48)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04235974A (ja) * | 1990-06-08 | 1992-08-25 | Roussel Uclaf | 新規なイミダゾール誘導体、それらの製造法、得られる新規な中間体、それらの薬剤としての使用及びそれらを含有する製薬組成物 |
| AU1625192A (en) * | 1991-05-31 | 1992-12-03 | Zeneca Limited | Heterocyclic derivatives |
| CA2115996A1 (en) * | 1991-09-03 | 1993-03-18 | Toshio Okazaki | Pyrazolotriazole derivative |
| GB9201789D0 (en) * | 1992-01-28 | 1992-03-11 | Fujisawa Pharmaceutical Co | Heterocyclic derivatives |
| US5354759A (en) * | 1991-09-12 | 1994-10-11 | Fujisawa Pharmaceutical Co., Ltd. | Angiotenin II antagonizing heterocyclic compounds |
| WO1993018030A1 (en) * | 1992-03-03 | 1993-09-16 | Fujisawa Pharmaceutical Co., Ltd. | Benzimidazole derivatives as angiotensin ii antagonists |
| CA2106135A1 (en) * | 1992-09-14 | 1994-03-15 | Keiji Kubo | Cyclic compounds and their use |
| CA2115985A1 (en) * | 1993-02-25 | 1994-08-26 | Kohei Nishikawa | Vascular hypertrophy suppressor |
| JP3810020B2 (ja) | 1993-04-22 | 2006-08-16 | 武田薬品工業株式会社 | 腎疾患の予防または治療剤 |
| US5721263A (en) * | 1993-06-07 | 1998-02-24 | Takeda Chemical Industries, Ltd. | Pharmaceutical composition for angiotensin II-mediated diseases |
| DE4320432A1 (de) * | 1993-06-21 | 1994-12-22 | Bayer Ag | Substituierte Mono- und Bipyridylmethylderivate |
| CZ154994A3 (en) * | 1993-07-02 | 1995-09-13 | Senju Pharma Co | Visual hypotensive agent |
| US5998402A (en) * | 1996-04-19 | 1999-12-07 | American Home Products Corporation | 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents |
| BR9810508A (pt) | 1997-07-03 | 2000-09-05 | Du Pont Pharm Co | Composto, composição farmacêutica e método de tratamento de uma desordem |
| SK11902000A3 (sk) | 1998-03-04 | 2001-02-12 | Takeda Chemical Industries, Ltd. | Prostriedok s predĺženým uvoľňovaním pre antagonistu angiotenzínu ii, jeho príprava a použitie |
| US6069153A (en) * | 1998-05-12 | 2000-05-30 | American Home Products Corporation | Indenoindoles and benzocarbazoles as estrogenic agents |
| US6479535B1 (en) * | 1998-05-15 | 2002-11-12 | Wyeth | 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole and estrogen formulations |
| US6365589B1 (en) | 1998-07-02 | 2002-04-02 | Bristol-Myers Squibb Pharma Company | Imidazo-pyridines, -pyridazines, and -triazines as corticotropin releasing factor antagonists |
| US6124463A (en) * | 1998-07-02 | 2000-09-26 | Dupont Pharmaceuticals | Benzimidazoles as corticotropin release factor antagonists |
| NZ508118A (en) | 1998-07-06 | 2003-07-25 | Bristol Myers Squibb Co | Heteroaryl substituted biphenyl sulfonamides useful as dual angiotensin endothelin receptor antogonists |
| US6159959A (en) * | 1999-05-06 | 2000-12-12 | American Home Products Corporation | Combined estrogen and antiestrogen therapy |
| SE9903028D0 (sv) | 1999-08-27 | 1999-08-27 | Astra Ab | New use |
| RU2002110282A (ru) * | 1999-10-08 | 2003-12-20 | Грюненталь ГмбХ (DE) | Замещенные в 6-членном кольце бициклические производные имидазо-3-иламина |
| DE19948436B4 (de) * | 1999-10-08 | 2006-11-16 | Grünenthal GmbH | Bicyclische Imidazo-5-aminderivate |
| BR0014818A (pt) | 1999-10-08 | 2002-06-18 | Gruenenthal Gmbh | Imidazo-3-il-aminas bicìclicas procedimento de preparação e medicamentos que contém como substância ativa pelo menos uma imidazo-3-il-amina bicìclica |
| CA2388476C (en) | 1999-10-08 | 2008-08-05 | Gruenenthal Gmbh | Bicyclic imidazo-5-yl-amine derivatives |
| JP2002205986A (ja) * | 2000-11-08 | 2002-07-23 | Takeda Chem Ind Ltd | ピリミジン誘導体およびそれを含有する除草剤 |
| EP1444988A4 (en) | 2001-11-13 | 2007-04-25 | Takeda Pharmaceutical | CANCER AGENT |
| US7232828B2 (en) | 2002-08-10 | 2007-06-19 | Bethesda Pharmaceuticals, Inc. | PPAR Ligands that do not cause fluid retention, edema or congestive heart failure |
| JPWO2008143262A1 (ja) * | 2007-05-21 | 2010-08-12 | 武田薬品工業株式会社 | 複素環化合物およびその用途 |
| US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
| CN103601792B (zh) | 2007-06-04 | 2016-06-29 | 协同医药品公司 | 有效用于胃肠功能紊乱、炎症、癌症和其他疾病治疗的鸟苷酸环化酶激动剂 |
| CN101531638B (zh) * | 2008-03-13 | 2011-12-28 | 中国科学院广州生物医药与健康研究院 | 用作雌激素相关受体调节剂的化合物及其应用 |
| CA2726917C (en) | 2008-06-04 | 2018-06-26 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| EP2321341B1 (en) | 2008-07-16 | 2017-02-22 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
| CN101628913B (zh) | 2008-07-18 | 2013-01-23 | 中国科学院广州生物医药与健康研究院 | 用作雌激素相关受体调节剂的化合物及其应用 |
| US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
| US8809372B2 (en) | 2011-09-30 | 2014-08-19 | Asana Biosciences, Llc | Pyridine derivatives |
| US9199975B2 (en) | 2011-09-30 | 2015-12-01 | Asana Biosciences, Llc | Biaryl imidazole derivatives for regulating CYP17 |
| CN102702114B (zh) * | 2012-05-28 | 2014-12-17 | 浙江海正化工股份有限公司 | 一种硝基乳清酸的制备方法 |
| CA2905438A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
| US9486494B2 (en) | 2013-03-15 | 2016-11-08 | Synergy Pharmaceuticals, Inc. | Compositions useful for the treatment of gastrointestinal disorders |
| SI3004138T1 (sl) | 2013-06-05 | 2024-07-31 | Bausch Health Ireland Limited | Ultra čisti agonisti gvanilat ciklaze C, postopek za njihovo pripravo in uporabo |
| CN104402892B (zh) * | 2014-12-03 | 2017-01-25 | 南京华威医药科技开发有限公司 | 血管紧张素ii拮抗化合物 |
| CA3002144C (en) | 2015-10-16 | 2024-01-23 | Eisai R&D Management Co., Ltd. | Ep4 antagonists |
| CN108290884A (zh) * | 2015-11-16 | 2018-07-17 | 先正达参股股份有限公司 | 具有含硫取代基的杀有害生物活性杂环衍生物 |
| CN105732648B (zh) * | 2016-02-02 | 2017-10-20 | 华南理工大学 | 一种吡咯并呋喃的含氮杂环化合物及合成方法 |
| WO2023078252A1 (en) | 2021-11-02 | 2023-05-11 | Flare Therapeutics Inc. | Pparg inverse agonists and uses thereof |
Family Cites Families (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5671073A (en) * | 1979-11-12 | 1981-06-13 | Takeda Chem Ind Ltd | Imidazole derivative |
| JPS5671074A (en) * | 1979-11-12 | 1981-06-13 | Takeda Chem Ind Ltd | 1,2-disubstituted-4-halogenoimidazole-5-acetic acid derivative |
| US4812462A (en) * | 1986-04-01 | 1989-03-14 | Warner-Lambert Company | 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid analogs having antihypertensive activity |
| CA1334092C (en) * | 1986-07-11 | 1995-01-24 | David John Carini | Angiotensin ii receptor blocking imidazoles |
| US4820843A (en) * | 1987-05-22 | 1989-04-11 | E. I. Du Pont De Nemours And Company | Tetrazole intermediates to antihypertensive compounds |
| US5015651A (en) * | 1988-01-07 | 1991-05-14 | E. I. Du Pont De Nemours And Company | Treatment of hypertension with 1,2,4-angiotensin II antagonists |
| US4880804A (en) * | 1988-01-07 | 1989-11-14 | E. I. Du Pont De Nemours And Company | Angiotensin II receptor blocking benzimidazoles |
| DE3928177A1 (de) * | 1989-04-08 | 1991-02-28 | Thomae Gmbh Dr K | Benzimidazole, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
| EP0400835A1 (en) * | 1989-05-15 | 1990-12-05 | Merck & Co. Inc. | Substituted benzimidazoles as angiotensin II antagonists |
| GB8911854D0 (en) * | 1989-05-23 | 1989-07-12 | Ici Plc | Heterocyclic compounds |
| IE64514B1 (en) * | 1989-05-23 | 1995-08-09 | Zeneca Ltd | Azaindenes |
| IL94390A (en) * | 1989-05-30 | 1996-03-31 | Merck & Co Inc | The 6-membered trans-nitrogen-containing heterocycles are compressed with imidazo and pharmaceutical preparations containing them |
| US5164407A (en) * | 1989-07-03 | 1992-11-17 | Merck & Co., Inc. | Substituted imidazo-fused 5-membered ring heterocycles and their use as angiotensin ii antagonsists |
| EP0411507B1 (en) * | 1989-08-02 | 1994-10-26 | Takeda Chemical Industries, Ltd. | Pyrazole derivatives, their production and use |
| IE70593B1 (en) * | 1989-09-29 | 1996-12-11 | Eisai Co Ltd | Biphenylmethane derivative the use of it and pharmacological compositions containing same |
| IL95975A (en) * | 1989-10-24 | 1997-06-10 | Takeda Chemical Industries Ltd | N-benzyl- 2-alkylbenzimidazole derivatives, their production and pharmaceutical compositions containing them |
| IL96019A0 (en) * | 1989-10-31 | 1991-07-18 | Fujisawa Pharmaceutical Co | Imidazole derivatives,processes for the preparation thereof and pharmaceutical compositions containing the same |
| EP0434038A1 (en) * | 1989-12-22 | 1991-06-26 | Takeda Chemical Industries, Ltd. | Fused imidazole derivatives, their production and use |
| CA2079344A1 (en) * | 1990-03-30 | 1991-10-01 | Eric E. Allen | Substituted pyrimidines, pyrimidinones and pyridopyrimidines |
| US5196444A (en) * | 1990-04-27 | 1993-03-23 | Takeda Chemical Industries, Ltd. | 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof |
| CA2041763A1 (en) * | 1990-05-11 | 1991-11-12 | Sheih-Shung T. Chen | Microbial transformation process for antihypertensive products |
| DK0461039T3 (da) * | 1990-06-08 | 1999-06-14 | Hoechst Marion Roussel Inc | Nye benzimidazolafledte forbindelser, fremgangsmåde til deres fremstilling, de opnåede mellemprodukter, deres anvendelse so |
| JPH04235974A (ja) * | 1990-06-08 | 1992-08-25 | Roussel Uclaf | 新規なイミダゾール誘導体、それらの製造法、得られる新規な中間体、それらの薬剤としての使用及びそれらを含有する製薬組成物 |
| CA2044806A1 (en) * | 1990-07-18 | 1992-01-19 | Roland Jaunin | Purine derivatives |
| EP0470543A1 (de) * | 1990-08-10 | 1992-02-12 | Dr. Karl Thomae GmbH | Heterocyclische Imidazole, diese Verbindungen enthaltende Arzneimittel und Verfahren zur ihrer Herstellung |
| US5210092A (en) * | 1990-09-25 | 1993-05-11 | Fujisawa Pharmaceutical Co., Ltd. | Angiotensin ii antagonizing heterocyclic derivatives |
| AU636066B2 (en) * | 1990-10-30 | 1993-04-08 | Takeda Chemical Industries Ltd. | Thienoimidazole derivatives, their production and use |
| US5124335A (en) * | 1991-01-30 | 1992-06-23 | Merck & Co., Inc. | Substituted pyrollo-fused 6 membered heterocycles as angiotensin ii antagonists |
| SI9210098B (sl) * | 1991-02-06 | 2000-06-30 | Dr. Karl Thomae | Benzimidazoli, zdravila, ki te spojine vsebujejo, in postopek za njihovo pripravo |
| EP0503838A3 (en) * | 1991-03-08 | 1992-10-07 | Merck & Co. Inc. | Heterocyclic compounds bearing acidic functional groups as angiotensin ii antagonists |
| US5187179A (en) * | 1991-03-22 | 1993-02-16 | Merck & Co., Inc. | Angiotensin II antagonists incorporating a substituted imidazo [1,2-b][1,2,4]triazole |
| US5128327A (en) * | 1991-03-25 | 1992-07-07 | Merck & Co., Inc. | Angiotensin II antagonists incorporating a nitrogen containing six membered ring heterocycle |
| US5177074A (en) * | 1991-03-26 | 1993-01-05 | Merck & Co., Inc. | Angiotensin ii antagonists incorporating a substituted thiophene or furan |
-
1992
- 1992-04-08 TW TW081102668A patent/TW274551B/zh active
- 1992-04-15 CA CA002066094A patent/CA2066094C/en not_active Expired - Fee Related
- 1992-04-15 JP JP13748592A patent/JP3260415B2/ja not_active Expired - Fee Related
- 1992-04-16 DE DE69233113T patent/DE69233113T2/de not_active Expired - Fee Related
- 1992-04-16 AT AT92106621T patent/ATE244240T1/de not_active IP Right Cessation
- 1992-04-16 EP EP92106621A patent/EP0518033B1/en not_active Expired - Lifetime
- 1992-04-16 EP EP03006453A patent/EP1327631A3/en not_active Withdrawn
- 1992-04-16 KR KR1019920006383A patent/KR100217164B1/ko not_active Expired - Fee Related
-
1993
- 1993-09-28 US US08/127,356 patent/US5389641A/en not_active Expired - Fee Related
-
2001
- 2001-05-28 JP JP2001159745A patent/JP2001328988A/ja not_active Ceased
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10588900B2 (en) | 2016-02-09 | 2020-03-17 | Pharmakea, Inc. | Quinolinone lysyl oxidase-like 2 inhibitors and uses thereof |
| US11407733B2 (en) | 2016-06-29 | 2022-08-09 | Bristol-Myers Squibb Company | Biarylmethyl heterocycles |
| US12037324B2 (en) | 2016-06-29 | 2024-07-16 | Bristol-Myers Squibb Company | Biarylmethyl heterocycles |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2001328988A (ja) | 2001-11-27 |
| TW274551B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) | 1996-04-21 |
| CA2066094A1 (en) | 1992-10-17 |
| EP0518033A1 (en) | 1992-12-16 |
| KR100217164B1 (ko) | 1999-09-01 |
| EP0518033B1 (en) | 2003-07-02 |
| EP1327631A2 (en) | 2003-07-16 |
| DE69233113D1 (de) | 2003-08-07 |
| DE69233113T2 (de) | 2004-06-03 |
| KR920019794A (ko) | 1992-11-20 |
| JPH05163267A (ja) | 1993-06-29 |
| JP3260415B2 (ja) | 2002-02-25 |
| EP1327631A3 (en) | 2004-02-11 |
| ATE244240T1 (de) | 2003-07-15 |
| US5389641A (en) | 1995-02-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2066094C (en) | Fused heterocyclic compounds, their production and use | |
| US5705517A (en) | Benzimidazole derivatives and use thereof | |
| US5962491A (en) | Benzimidazole derivatives and use thereof | |
| US5354766A (en) | Compound and salts thereof which antagonize angiotensin II | |
| US7538133B2 (en) | Benzimidazole derivatives, their production and use | |
| EP0483683B1 (en) | Thienoimidazole derivatives, their production and use | |
| CA2032831A1 (en) | Fused imidazole derivatives, their production and use | |
| SK322192A3 (en) | Substituted pyrimidines, process for their preparation, pharmaceutical composition containing the same and their use | |
| EP0499415A1 (en) | Pyridine and quinoline derivatives, processes for their manufacture and their use as angiotensin II antagonists | |
| SK73293A3 (en) | Benzimidazoles, process for their preparation and medicaments contained this compounds | |
| EP0829479A1 (en) | Heterocyclic compounds and their use as angiotensin II antagonists | |
| JP3099096B2 (ja) | チエノイミダゾール誘導体 | |
| WO1993019060A1 (en) | Isoindazole compound | |
| IL97882A (en) | N-aralkylbenzimidazole derivatives their production and pharmaceutical compositions containing them | |
| SK282473B6 (sk) | Benzimidazolová zlúčenina a spôsob jej prípravy, stabilný kryštál, farmaceutický prípravok a medziprodukt |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |