CN1121859C - 用于治疗或预防高血压症的药物组合物的制备方法 - Google Patents
用于治疗或预防高血压症的药物组合物的制备方法 Download PDFInfo
- Publication number
- CN1121859C CN1121859C CN97126347A CN97126347A CN1121859C CN 1121859 C CN1121859 C CN 1121859C CN 97126347 A CN97126347 A CN 97126347A CN 97126347 A CN97126347 A CN 97126347A CN 1121859 C CN1121859 C CN 1121859C
- Authority
- CN
- China
- Prior art keywords
- methyl
- group
- reaction
- cooh
- ethyl
- 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 - Lifetime
Links
- 238000011282 treatment Methods 0.000 title claims abstract description 16
- 206010020772 Hypertension Diseases 0.000 title claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 3
- 230000002265 prevention Effects 0.000 title description 4
- 238000004519 manufacturing process Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 404
- 238000000034 method Methods 0.000 claims abstract description 101
- 150000002148 esters Chemical class 0.000 claims abstract description 44
- 150000003839 salts Chemical class 0.000 claims abstract description 39
- 238000011321 prophylaxis Methods 0.000 claims abstract description 4
- -1 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl Chemical group 0.000 claims description 412
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 222
- 229910052799 carbon Inorganic materials 0.000 claims description 146
- 150000001721 carbon Chemical group 0.000 claims description 141
- 125000000217 alkyl group Chemical group 0.000 claims description 82
- 125000004432 carbon atom Chemical group C* 0.000 claims description 59
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 55
- 125000003545 alkoxy group Chemical group 0.000 claims description 46
- 125000001589 carboacyl group Chemical group 0.000 claims description 26
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 18
- 125000005633 phthalidyl group Chemical group 0.000 claims description 14
- 125000001118 alkylidene group Chemical group 0.000 claims description 10
- 239000002220 antihypertensive agent Substances 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 162
- 230000008569 process Effects 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 349
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 221
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 214
- 239000002585 base Substances 0.000 description 211
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 199
- 239000002904 solvent Substances 0.000 description 172
- 239000000203 mixture Substances 0.000 description 154
- 239000000243 solution Substances 0.000 description 135
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 112
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 99
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 96
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 95
- 239000003153 chemical reaction reagent Substances 0.000 description 92
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 89
- 229910052760 oxygen Inorganic materials 0.000 description 88
- 239000001301 oxygen Substances 0.000 description 88
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 80
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 77
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 77
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N methylimidazole Natural products CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 76
- 230000004044 response Effects 0.000 description 73
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 71
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 70
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 70
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 66
- 125000001424 substituent group Chemical group 0.000 description 61
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 60
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 60
- 239000000376 reactant Substances 0.000 description 53
- 239000002253 acid Substances 0.000 description 49
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 49
- 238000010586 diagram Methods 0.000 description 49
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
- 239000000047 product Substances 0.000 description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 46
- 125000003118 aryl group Chemical group 0.000 description 43
- 125000004494 ethyl ester group Chemical group 0.000 description 42
- 239000003513 alkali Substances 0.000 description 41
- 235000002639 sodium chloride Nutrition 0.000 description 41
- 238000001035 drying Methods 0.000 description 40
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 40
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 39
- 239000007787 solid Substances 0.000 description 39
- 150000004702 methyl esters Chemical class 0.000 description 36
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 36
- 230000002829 reductive effect Effects 0.000 description 34
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 33
- 239000000460 chlorine Substances 0.000 description 31
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 31
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 29
- 230000000694 effects Effects 0.000 description 29
- 239000000843 powder Substances 0.000 description 29
- 238000003756 stirring Methods 0.000 description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- 238000010898 silica gel chromatography Methods 0.000 description 27
- 239000007864 aqueous solution Substances 0.000 description 26
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 25
- 230000009467 reduction Effects 0.000 description 25
- 238000006722 reduction reaction Methods 0.000 description 25
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 24
- 125000003710 aryl alkyl group Chemical group 0.000 description 24
- 239000012141 concentrate Substances 0.000 description 24
- 235000008504 concentrate Nutrition 0.000 description 24
- 125000005843 halogen group Chemical group 0.000 description 24
- 239000013078 crystal Substances 0.000 description 23
- 125000004093 cyano group Chemical group *C#N 0.000 description 23
- 230000002349 favourable effect Effects 0.000 description 23
- 235000011054 acetic acid Nutrition 0.000 description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 22
- 229910052783 alkali metal Inorganic materials 0.000 description 21
- 229910052801 chlorine Inorganic materials 0.000 description 21
- 150000008282 halocarbons Chemical class 0.000 description 21
- 238000009834 vaporization Methods 0.000 description 21
- 230000008016 vaporization Effects 0.000 description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- 239000003795 chemical substances by application Substances 0.000 description 20
- 239000003960 organic solvent Substances 0.000 description 20
- 229910000027 potassium carbonate Inorganic materials 0.000 description 20
- 235000011181 potassium carbonates Nutrition 0.000 description 20
- 125000006239 protecting group Chemical group 0.000 description 20
- 235000011121 sodium hydroxide Nutrition 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 19
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 19
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 19
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 19
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 18
- 150000002170 ethers Chemical class 0.000 description 18
- 238000001953 recrystallisation Methods 0.000 description 18
- NKWCGTOZTHZDHB-UHFFFAOYSA-N 1h-imidazol-1-ium-4-carboxylate Chemical compound OC(=O)C1=CNC=N1 NKWCGTOZTHZDHB-UHFFFAOYSA-N 0.000 description 17
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 17
- 230000002411 adverse Effects 0.000 description 17
- 239000010410 layer Substances 0.000 description 17
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 16
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 16
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 16
- 239000003921 oil Substances 0.000 description 16
- 239000012312 sodium hydride Substances 0.000 description 16
- 229910000104 sodium hydride Inorganic materials 0.000 description 16
- PSEJBIODJNSJNT-UHFFFAOYSA-N CCCCC([O])=O Chemical compound CCCCC([O])=O PSEJBIODJNSJNT-UHFFFAOYSA-N 0.000 description 15
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 15
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 15
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 15
- 125000001309 chloro group Chemical group Cl* 0.000 description 15
- 238000004587 chromatography analysis Methods 0.000 description 15
- 238000003810 ethyl acetate extraction Methods 0.000 description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 14
- 150000001540 azides Chemical class 0.000 description 14
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 13
- 239000003638 chemical reducing agent Substances 0.000 description 13
- 238000007796 conventional method Methods 0.000 description 13
- 230000032050 esterification Effects 0.000 description 13
- 238000005886 esterification reaction Methods 0.000 description 13
- 229910052731 fluorine Inorganic materials 0.000 description 13
- 229910052744 lithium Inorganic materials 0.000 description 13
- 239000002480 mineral oil Substances 0.000 description 13
- 235000010446 mineral oil Nutrition 0.000 description 13
- 238000007254 oxidation reaction Methods 0.000 description 13
- 238000001556 precipitation Methods 0.000 description 13
- 238000000039 preparative column chromatography Methods 0.000 description 13
- 238000012746 preparative thin layer chromatography Methods 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 12
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 12
- 125000000753 cycloalkyl group Chemical group 0.000 description 12
- 230000026030 halogenation Effects 0.000 description 12
- 238000005658 halogenation reaction Methods 0.000 description 12
- 150000002460 imidazoles Chemical class 0.000 description 12
- 229910052500 inorganic mineral Inorganic materials 0.000 description 12
- 150000002500 ions Chemical class 0.000 description 12
- 235000010755 mineral Nutrition 0.000 description 12
- 239000011707 mineral Substances 0.000 description 12
- 230000003647 oxidation Effects 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-O oxonium Chemical compound [OH3+] XLYOFNOQVPJJNP-UHFFFAOYSA-O 0.000 description 12
- 238000005406 washing Methods 0.000 description 12
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 11
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 11
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 230000001476 alcoholic effect Effects 0.000 description 10
- 238000013459 approach Methods 0.000 description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 10
- 239000002274 desiccant Substances 0.000 description 10
- 229930195733 hydrocarbon Natural products 0.000 description 10
- 150000002430 hydrocarbons Chemical class 0.000 description 10
- 125000002883 imidazolyl group Chemical group 0.000 description 10
- 150000002576 ketones Chemical class 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 10
- 239000001117 sulphuric acid Substances 0.000 description 10
- 235000011149 sulphuric acid Nutrition 0.000 description 10
- CUKWUWBLQQDQAC-VEQWQPCFSA-N (3s)-3-amino-4-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s,3s)-1-[[(2s)-1-[(2s)-2-[[(1s)-1-carboxyethyl]carbamoyl]pyrrolidin-1-yl]-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-methyl-1-ox 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](C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 CUKWUWBLQQDQAC-VEQWQPCFSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 102000005862 Angiotensin II Human genes 0.000 description 9
- 101800000733 Angiotensin-2 Proteins 0.000 description 9
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 9
- 239000007818 Grignard reagent Substances 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 9
- 125000004423 acyloxy group Chemical group 0.000 description 9
- 150000001340 alkali metals Chemical class 0.000 description 9
- 229950006323 angiotensin ii Drugs 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 9
- 238000000354 decomposition reaction Methods 0.000 description 9
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 9
- 239000000284 extract Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 150000004795 grignard reagents Chemical class 0.000 description 9
- 150000007524 organic acids Chemical class 0.000 description 9
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 9
- 239000002994 raw material Substances 0.000 description 9
- 239000012279 sodium borohydride Substances 0.000 description 9
- 229910000033 sodium borohydride Inorganic materials 0.000 description 9
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 9
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 8
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 8
- 125000002252 acyl group Chemical group 0.000 description 8
- 150000001298 alcohols Chemical class 0.000 description 8
- 239000011737 fluorine Substances 0.000 description 8
- 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 8
- 238000006386 neutralization reaction Methods 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- HZQLUIZFUXNFHK-UHFFFAOYSA-N 1-(bromomethyl)-4-phenylbenzene Chemical group C1=CC(CBr)=CC=C1C1=CC=CC=C1 HZQLUIZFUXNFHK-UHFFFAOYSA-N 0.000 description 7
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 description 7
- FREDNUVVPQMYKQ-UHFFFAOYSA-N 5-(2-hydroxypropan-2-yl)-2-propyl-1h-imidazole-4-carboxylic acid Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1 FREDNUVVPQMYKQ-UHFFFAOYSA-N 0.000 description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 7
- 229910001515 alkali metal fluoride Inorganic materials 0.000 description 7
- 125000003342 alkenyl group Chemical group 0.000 description 7
- 230000029936 alkylation Effects 0.000 description 7
- 238000005804 alkylation reaction Methods 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 235000019270 ammonium chloride Nutrition 0.000 description 7
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 7
- 229960003328 benzoyl peroxide Drugs 0.000 description 7
- 229910052794 bromium Inorganic materials 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 230000007062 hydrolysis Effects 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- 235000017550 sodium carbonate Nutrition 0.000 description 7
- VMJNTFXCTXAXTC-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbonitrile Chemical group C1=C(C#N)C=C2OC(F)(F)OC2=C1 VMJNTFXCTXAXTC-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 125000005041 acyloxyalkyl group Chemical group 0.000 description 6
- 125000005530 alkylenedioxy group Chemical group 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 6
- 238000003379 elimination reaction Methods 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 229940098779 methanesulfonic acid Drugs 0.000 description 6
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 6
- 125000001624 naphthyl group Chemical group 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 238000011084 recovery Methods 0.000 description 6
- 150000003462 sulfoxides Chemical class 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 125000003831 tetrazolyl group Chemical group 0.000 description 6
- 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 5
- HCXJFMDOHDNDCC-UHFFFAOYSA-N 5-$l^{1}-oxidanyl-3,4-dihydropyrrol-2-one Chemical group O=C1CCC(=O)[N]1 HCXJFMDOHDNDCC-UHFFFAOYSA-N 0.000 description 5
- OYWXYOFIVDAAFS-UHFFFAOYSA-N 5-(2-hydroxypropan-2-yl)-3-[[4-[2-[(2-methylpropan-2-yl)oxycarbonyl]phenyl]phenyl]methyl]-2-propylimidazole-4-carboxylic acid Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C(=O)OC(C)(C)C)C=C1 OYWXYOFIVDAAFS-UHFFFAOYSA-N 0.000 description 5
- 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 5
- QRWSUXGRFSTIRN-UHFFFAOYSA-N S1CCCC1.[O] Chemical compound S1CCCC1.[O] QRWSUXGRFSTIRN-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 5
- MJYGPNBYCMSMFL-UHFFFAOYSA-N [O].C1CCOC1 Chemical compound [O].C1CCOC1 MJYGPNBYCMSMFL-UHFFFAOYSA-N 0.000 description 5
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- 230000036772 blood pressure Effects 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 125000000000 cycloalkoxy group Chemical group 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 230000008030 elimination Effects 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- 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 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 150000002825 nitriles Chemical class 0.000 description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 150000003254 radicals Chemical class 0.000 description 5
- 238000006884 silylation reaction Methods 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 238000010025 steaming Methods 0.000 description 5
- 229910052720 vanadium Inorganic materials 0.000 description 5
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 4
- SPEVUDLSWSJVSS-UHFFFAOYSA-N C(C)(C)OC(=O)[O].N1C=NC=C1C(=O)O Chemical compound C(C)(C)OC(=O)[O].N1C=NC=C1C(=O)O SPEVUDLSWSJVSS-UHFFFAOYSA-N 0.000 description 4
- RVALHFUETCPXNI-UHFFFAOYSA-N C(CCCC)(=O)[O].N1C=NC=C1C(=O)O Chemical compound C(CCCC)(=O)[O].N1C=NC=C1C(=O)O RVALHFUETCPXNI-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 4
- 150000008046 alkali metal hydrides Chemical class 0.000 description 4
- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 210000004204 blood vessel Anatomy 0.000 description 4
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 4
- 238000010531 catalytic reduction reaction Methods 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 125000004185 ester group Chemical group 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- 125000002541 furyl group Chemical group 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 230000002140 halogenating effect Effects 0.000 description 4
- 208000019622 heart disease Diseases 0.000 description 4
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 4
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 4
- DVLGIQNHKLWSRU-UHFFFAOYSA-N methyl 1h-imidazole-5-carboxylate Chemical compound COC(=O)C1=CN=CN1 DVLGIQNHKLWSRU-UHFFFAOYSA-N 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 125000001544 thienyl group Chemical group 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 3
- KTERHTDIRJEXHA-UHFFFAOYSA-N 2-butyl-5-(hydroxymethyl)-1H-imidazole-4-carboxylic acid Chemical compound C(CCC)C=1NC(=C(N1)CO)C(=O)O KTERHTDIRJEXHA-UHFFFAOYSA-N 0.000 description 3
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 3
- PHMIILSQQVFWKC-UHFFFAOYSA-N 2-methyl-5-phenyl-1h-imidazole Chemical compound N1C(C)=NC=C1C1=CC=CC=C1 PHMIILSQQVFWKC-UHFFFAOYSA-N 0.000 description 3
- YPAWMJLSBPSGII-UHFFFAOYSA-N 3-[[4-(2-carboxyphenyl)phenyl]methyl]-5-(2-hydroxypropan-2-yl)-2-propylimidazole-4-carboxylic acid Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 YPAWMJLSBPSGII-UHFFFAOYSA-N 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- 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 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 3
- DYXDWXAHDIDPJP-UHFFFAOYSA-N C(C)(C)(C)OC(=O)C1=C(C=CC=C1)C1=CC=C(C=C1)CN1C(=NC(=C1C(=O)OC)O)CCCC Chemical compound C(C)(C)(C)OC(=O)C1=C(C=CC=C1)C1=CC=C(C=C1)CN1C(=NC(=C1C(=O)OC)O)CCCC DYXDWXAHDIDPJP-UHFFFAOYSA-N 0.000 description 3
- BNXMIEVTOMCNSJ-UHFFFAOYSA-N C1(CCC(N1C(C=1N=C(N(C1C(=O)O)CC1=CC=C(C=C1)C1=C(C=CC=C1)C(=O)OC(C)(C)C)CCCC)O)=O)=O Chemical compound C1(CCC(N1C(C=1N=C(N(C1C(=O)O)CC1=CC=C(C=C1)C1=C(C=CC=C1)C(=O)OC(C)(C)C)CCCC)O)=O)=O BNXMIEVTOMCNSJ-UHFFFAOYSA-N 0.000 description 3
- GVIKYKLHRZAVLJ-UHFFFAOYSA-N CCCCC1=NC(C(C)(C)O)=C(C)N1C(C=C1)=CC=C1C(C=CC=C1)=C1C1=NNN=N1 Chemical compound CCCCC1=NC(C(C)(C)O)=C(C)N1C(C=C1)=CC=C1C(C=CC=C1)=C1C1=NNN=N1 GVIKYKLHRZAVLJ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 241001597008 Nomeidae Species 0.000 description 3
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 150000001447 alkali salts Chemical class 0.000 description 3
- 125000005234 alkyl aluminium group Chemical group 0.000 description 3
- 229910000091 aluminium hydride Inorganic materials 0.000 description 3
- 229910000147 aluminium phosphate Chemical class 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 125000005129 aryl carbonyl group Chemical group 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 150000001718 carbodiimides Chemical class 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
- 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
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 125000001924 fatty-acyl group Chemical group 0.000 description 3
- 125000004438 haloalkoxy group Chemical group 0.000 description 3
- 230000009931 harmful effect Effects 0.000 description 3
- 125000005935 hexyloxycarbonyl group Chemical group 0.000 description 3
- 230000003301 hydrolyzing effect Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 3
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 3
- 229910000103 lithium hydride Inorganic materials 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 238000012423 maintenance Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 3
- 239000011736 potassium bicarbonate Substances 0.000 description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 229960002668 sodium chloride Drugs 0.000 description 3
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 3
- 229910001134 stannide Inorganic materials 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 3
- 125000002769 thiazolinyl group Chemical group 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 description 2
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 2
- OTEKOJQFKOIXMU-UHFFFAOYSA-N 1,4-bis(trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=C(C(Cl)(Cl)Cl)C=C1 OTEKOJQFKOIXMU-UHFFFAOYSA-N 0.000 description 2
- OXBLVCZKDOZZOJ-UHFFFAOYSA-N 2,3-Dihydrothiophene Chemical compound C1CC=CS1 OXBLVCZKDOZZOJ-UHFFFAOYSA-N 0.000 description 2
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 2
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- ATVJJNGVPSKBGO-UHFFFAOYSA-N 3,4-dihydro-2h-thiopyran Chemical compound C1CSC=CC1 ATVJJNGVPSKBGO-UHFFFAOYSA-N 0.000 description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 description 2
- SXIFAEWFOJETOA-UHFFFAOYSA-N 4-hydroxy-butyl Chemical group [CH2]CCCO SXIFAEWFOJETOA-UHFFFAOYSA-N 0.000 description 2
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 description 2
- 239000005541 ACE inhibitor Substances 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 239000007848 Bronsted acid Substances 0.000 description 2
- AVJVLNDOWXOALE-UHFFFAOYSA-N C(=O)=Cl.[O] Chemical compound C(=O)=Cl.[O] AVJVLNDOWXOALE-UHFFFAOYSA-N 0.000 description 2
- OORQUBFRPHIGQI-UHFFFAOYSA-N C(CCCC)(=O)[O].C(C)(C)(C)OC(=O)C1=C(C=CC=C1)C1=CC=C(C=C1)CN1C(=NC(=C1C(=O)O)C(C)(C)O)CCC Chemical compound C(CCCC)(=O)[O].C(C)(C)(C)OC(=O)C1=C(C=CC=C1)C1=CC=C(C=C1)CN1C(=NC(=C1C(=O)O)C(C)(C)O)CCC OORQUBFRPHIGQI-UHFFFAOYSA-N 0.000 description 2
- MUZDMBMWUICMFR-UHFFFAOYSA-N CCCCC1=NC(C(CC)(CC)O)=C(C)N1C(C=C1)=CC=C1C(C=CC=C1)=C1C1=NNN=N1 Chemical compound CCCCC1=NC(C(CC)(CC)O)=C(C)N1C(C=C1)=CC=C1C(C=CC=C1)=C1C1=NNN=N1 MUZDMBMWUICMFR-UHFFFAOYSA-N 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 102100028255 Renin Human genes 0.000 description 2
- 108090000783 Renin Proteins 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 125000004442 acylamino group Chemical group 0.000 description 2
- 125000004849 alkoxymethyl group Chemical group 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 229910052788 barium Inorganic materials 0.000 description 2
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229940073608 benzyl chloride Drugs 0.000 description 2
- 230000002902 bimodal effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 2
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 description 2
- 150000001991 dicarboxylic acids Chemical class 0.000 description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- AYOYKQGWHGDCTQ-UHFFFAOYSA-N ethyl 2-butyl-5-(2-hydroxypropan-2-yl)-1h-imidazole-4-carboxylate Chemical compound CCCCC1=NC(C(C)(C)O)=C(C(=O)OCC)N1 AYOYKQGWHGDCTQ-UHFFFAOYSA-N 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 235000011087 fumaric acid Nutrition 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 2
- 150000002366 halogen compounds Chemical class 0.000 description 2
- 150000002440 hydroxy compounds Chemical class 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- GUWHRJQTTVADPB-UHFFFAOYSA-N lithium azide Chemical compound [Li+].[N-]=[N+]=[N-] GUWHRJQTTVADPB-UHFFFAOYSA-N 0.000 description 2
- PQXKHYXIUOZZFA-UHFFFAOYSA-M lithium fluoride Chemical compound [Li+].[F-] PQXKHYXIUOZZFA-UHFFFAOYSA-M 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- OKHRRIGNGQFVEE-UHFFFAOYSA-N methyl(diphenyl)silicon Chemical compound C=1C=CC=CC=1[Si](C)C1=CC=CC=C1 OKHRRIGNGQFVEE-UHFFFAOYSA-N 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 2
- CPGRMGOILBSUQC-UHFFFAOYSA-N phosphoryl azide Chemical compound [N-]=[N+]=NP(=O)(N=[N+]=[N-])N=[N+]=[N-] CPGRMGOILBSUQC-UHFFFAOYSA-N 0.000 description 2
- 229910003446 platinum oxide Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- TZLVRPLSVNESQC-UHFFFAOYSA-N potassium azide Chemical compound [K+].[N-]=[N+]=[N-] TZLVRPLSVNESQC-UHFFFAOYSA-N 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 2
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- IDELNEDBPWKHGK-UHFFFAOYSA-N thiobutabarbital Chemical compound CCC(C)C1(CC)C(=O)NC(=S)NC1=O IDELNEDBPWKHGK-UHFFFAOYSA-N 0.000 description 2
- PCTNAMGLSYHIPL-UHFFFAOYSA-N tin(4+) tetraazide Chemical compound [Sn+4].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-] PCTNAMGLSYHIPL-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- MEFKFJOEVLUFAY-UHFFFAOYSA-N (2,2,2-trichloroacetyl) 2,2,2-trichloroacetate Chemical class ClC(Cl)(Cl)C(=O)OC(=O)C(Cl)(Cl)Cl MEFKFJOEVLUFAY-UHFFFAOYSA-N 0.000 description 1
- DXYQLGFRXWUTCF-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 2-butyl-5-(1-hydroxy-2,2-dimethylpropyl)-3-[[4-[2-[(2-methylpropan-2-yl)oxycarbonyl]phenyl]phenyl]methyl]imidazole-4-carboxylate Chemical compound C=1C=C(C=2C(=CC=CC=2)C(=O)OC(C)(C)C)C=CC=1CN1C(CCCC)=NC(C(O)C(C)(C)C)=C1C(=O)ON1C(=O)CCC1=O DXYQLGFRXWUTCF-UHFFFAOYSA-N 0.000 description 1
- RPAJSBKBKSSMLJ-DFWYDOINSA-N (2s)-2-aminopentanedioic acid;hydrochloride Chemical class Cl.OC(=O)[C@@H](N)CCC(O)=O RPAJSBKBKSSMLJ-DFWYDOINSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- DPZSNGJNFHWQDC-ARJAWSKDSA-N (z)-2,3-diaminobut-2-enedinitrile Chemical compound N#CC(/N)=C(/N)C#N DPZSNGJNFHWQDC-ARJAWSKDSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- 125000005846 1-(alkanoyloxy)ethyl group Chemical group 0.000 description 1
- 125000005848 1-(alkoxycarbonyloxy)ethyl group Chemical group 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 1
- KKKDZZRICRFGSD-UHFFFAOYSA-N 1-benzylimidazole Chemical compound C1=CN=CN1CC1=CC=CC=C1 KKKDZZRICRFGSD-UHFFFAOYSA-N 0.000 description 1
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- 125000006055 1-methyl-4-pentenyl group Chemical group 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- JDIIGWSSTNUWGK-UHFFFAOYSA-N 1h-imidazol-3-ium;chloride Chemical compound [Cl-].[NH2+]1C=CN=C1 JDIIGWSSTNUWGK-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- WZXXZHONLFRKGG-UHFFFAOYSA-N 2,3,4,5-tetrachlorothiophene Chemical compound ClC=1SC(Cl)=C(Cl)C=1Cl WZXXZHONLFRKGG-UHFFFAOYSA-N 0.000 description 1
- WCRSSAALOJQEJP-UHFFFAOYSA-N 2-[4-[[2-butyl-5-ethoxycarbonyl-4-(2-hydroxypropan-2-yl)imidazol-1-yl]methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC(C(C)(C)O)=C(C(=O)OCC)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 WCRSSAALOJQEJP-UHFFFAOYSA-N 0.000 description 1
- HAOUFXGQLSBLCY-UHFFFAOYSA-N 2-butyl-1H-imidazole-5-carbonitrile Chemical compound C(CCC)C=1NC(=CN=1)C#N HAOUFXGQLSBLCY-UHFFFAOYSA-N 0.000 description 1
- LGUALZXKGLXSGO-UHFFFAOYSA-N 2-butyl-3-[[4-(2-carboxyphenyl)phenyl]methyl]-5-(1-hydroxyethyl)imidazole-4-carboxylic acid Chemical compound CCCCC1=NC(C(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 LGUALZXKGLXSGO-UHFFFAOYSA-N 0.000 description 1
- OHURTDKJRNRRPD-UHFFFAOYSA-N 2-butyl-5-(1-hydroxy-2,2-dimethylpropyl)-3-[[4-[2-[(2-methylpropan-2-yl)oxycarbonyl]phenyl]phenyl]methyl]imidazole-4-carboxylic acid Chemical compound CCCCC1=NC(C(O)C(C)(C)C)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C(=O)OC(C)(C)C)C=C1 OHURTDKJRNRRPD-UHFFFAOYSA-N 0.000 description 1
- SZLHWZBMYBTZIJ-UHFFFAOYSA-N 2-butyl-5-(hydroxymethyl)-3-[[4-[2-[(2-methylpropan-2-yl)oxycarbonyl]phenyl]phenyl]methyl]imidazole-4-carboxylic acid Chemical compound CCCCC1=NC(CO)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C(=O)OC(C)(C)C)C=C1 SZLHWZBMYBTZIJ-UHFFFAOYSA-N 0.000 description 1
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- JJKWHOSQTYYFAE-UHFFFAOYSA-N 2-methoxyacetyl chloride Chemical class COCC(Cl)=O JJKWHOSQTYYFAE-UHFFFAOYSA-N 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000006053 2-methyl-3-pentenyl group Chemical group 0.000 description 1
- 125000006056 2-methyl-4-pentenyl group Chemical group 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- ILYSAKHOYBPSPC-UHFFFAOYSA-N 2-phenylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1C1=CC=CC=C1 ILYSAKHOYBPSPC-UHFFFAOYSA-N 0.000 description 1
- 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 1
- BSHYBKDYLYQPNC-UHFFFAOYSA-N 2-propyl-1h-imidazole-5-carboxylic acid Chemical compound CCCC1=NC=C(C(O)=O)N1 BSHYBKDYLYQPNC-UHFFFAOYSA-N 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- OXRMQBIEGBLFPJ-UHFFFAOYSA-N 3-[(4-phenylphenyl)methyl]imidazole-4-carboxylic acid Chemical compound C1(=CC=C(C=C1)CN1C=NC=C1C(=O)O)C1=CC=CC=C1 OXRMQBIEGBLFPJ-UHFFFAOYSA-N 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- GWFALVUXAGYMHR-UHFFFAOYSA-N 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one Chemical compound CC=1OC(=O)OC=1CBr GWFALVUXAGYMHR-UHFFFAOYSA-N 0.000 description 1
- 125000001999 4-Methoxybenzoyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C(*)=O 0.000 description 1
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006042 4-hexenyl group Chemical group 0.000 description 1
- GVXGRCLEDUXFPC-UHFFFAOYSA-N 5-(1-hydroxybutyl)-2-propyl-1H-imidazole-4-carbonitrile Chemical compound OC(CCC)C=1N=C(NC=1C#N)CCC GVXGRCLEDUXFPC-UHFFFAOYSA-N 0.000 description 1
- QPZPFALOVSVHBX-UHFFFAOYSA-N 5-(1-hydroxyethyl)-2-propyl-1H-imidazole-4-carboxylic acid Chemical compound OC(C)C=1N=C(NC1C(=O)O)CCC QPZPFALOVSVHBX-UHFFFAOYSA-N 0.000 description 1
- DDFHBQSCUXNBSA-UHFFFAOYSA-N 5-(5-carboxythiophen-2-yl)thiophene-2-carboxylic acid Chemical compound S1C(C(=O)O)=CC=C1C1=CC=C(C(O)=O)S1 DDFHBQSCUXNBSA-UHFFFAOYSA-N 0.000 description 1
- YGRKKKIDGHTEHL-UHFFFAOYSA-N 5-(hydroxymethyl)-1h-imidazole-4-carboxylic acid Chemical compound OCC=1NC=NC=1C(O)=O YGRKKKIDGHTEHL-UHFFFAOYSA-N 0.000 description 1
- GMQWMLVZRXUUJT-UHFFFAOYSA-N 5-(hydroxymethyl)-3-[[4-[2-[(2-methylpropan-2-yl)oxycarbonyl]phenyl]phenyl]methyl]-2-propylimidazole-4-carboxylic acid Chemical compound CCCC1=NC(CO)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C(=O)OC(C)(C)C)C=C1 GMQWMLVZRXUUJT-UHFFFAOYSA-N 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 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
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 101800000734 Angiotensin-1 Proteins 0.000 description 1
- 102400000344 Angiotensin-1 Human genes 0.000 description 1
- 108090001067 Angiotensinogen Proteins 0.000 description 1
- 102000004881 Angiotensinogen Human genes 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- RTESCXBOUIGCED-UHFFFAOYSA-N C(=O)(OCC)Cl.NCCC(=O)O Chemical compound C(=O)(OCC)Cl.NCCC(=O)O RTESCXBOUIGCED-UHFFFAOYSA-N 0.000 description 1
- VLWKHQGNKNKARR-UHFFFAOYSA-N C(C)(C)OC(C(C(OOCCCCC)(OC(C)(C)C)OC(C)CC)(C)C)(OCC(C)C)OCCCC Chemical compound C(C)(C)OC(C(C(OOCCCCC)(OC(C)(C)C)OC(C)CC)(C)C)(OCC(C)C)OCCCC VLWKHQGNKNKARR-UHFFFAOYSA-N 0.000 description 1
- WFMKVVCIZPHGSV-UHFFFAOYSA-N C(C)OC(=O)C1=C(N=C(N1)CCCC)OCC Chemical compound C(C)OC(=O)C1=C(N=C(N1)CCCC)OCC WFMKVVCIZPHGSV-UHFFFAOYSA-N 0.000 description 1
- YTICHALBPMKCDJ-UHFFFAOYSA-N C(C)OC(=O)[O].C(=O)(O)C1=C(C=CC=C1)C1=CC=C(C=C1)CN1C(=NC(=C1C(=O)O)C(C)(C)O)CCC Chemical compound C(C)OC(=O)[O].C(=O)(O)C1=C(C=CC=C1)C1=CC=C(C=C1)CN1C(=NC(=C1C(=O)O)C(C)(C)O)CCC YTICHALBPMKCDJ-UHFFFAOYSA-N 0.000 description 1
- VHAVNYIUOLAQOL-UHFFFAOYSA-N C(C)OC(=O)[O].C(C)(C)(C)OC(=O)C1=C(C=CC=C1)C1=CC=C(C=C1)CN1C(=NC(=C1C(=O)O)C(C)(C)O)CCC Chemical compound C(C)OC(=O)[O].C(C)(C)(C)OC(=O)C1=C(C=CC=C1)C1=CC=C(C=C1)CN1C(=NC(=C1C(=O)O)C(C)(C)O)CCC VHAVNYIUOLAQOL-UHFFFAOYSA-N 0.000 description 1
- GYHOYPGGUXZDLG-UHFFFAOYSA-N C(CCC)C=1N(C(=C(N1)C(C)(C)O)C)C1=CC=C(C=C1)C1=C(C=CC=C1)C1=NN=NN1C(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound C(CCC)C=1N(C(=C(N1)C(C)(C)O)C)C1=CC=C(C=C1)C1=C(C=CC=C1)C1=NN=NN1C(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 GYHOYPGGUXZDLG-UHFFFAOYSA-N 0.000 description 1
- CGVACVQROQBMKM-UHFFFAOYSA-N C(CCC)C=1N(C(=C(N1)C(CC)(O)CC)C)C1=CC=C(C=C1)C1=C(C=CC=C1)C1=NN=NN1C(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound C(CCC)C=1N(C(=C(N1)C(CC)(O)CC)C)C1=CC=C(C=C1)C1=C(C=CC=C1)C1=NN=NN1C(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 CGVACVQROQBMKM-UHFFFAOYSA-N 0.000 description 1
- PABVKFFVFMTYAK-UHFFFAOYSA-N C(CCC)C=1N(C(=C(N1)CC1=C(C=CC=C1)O)C(=O)O)CC1=CC=C(C=C1)C1=C(C=CC=C1)C(=O)O Chemical compound C(CCC)C=1N(C(=C(N1)CC1=C(C=CC=C1)O)C(=O)O)CC1=CC=C(C=C1)C1=C(C=CC=C1)C(=O)O PABVKFFVFMTYAK-UHFFFAOYSA-N 0.000 description 1
- AFFSIXWYDRNWIO-UHFFFAOYSA-N C(CCC)C=1N(C(=C(N1)CO)C)C1=CC=C(C=C1)C1=C(C=CC=C1)C1=NN=NN1C(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound C(CCC)C=1N(C(=C(N1)CO)C)C1=CC=C(C=C1)C1=C(C=CC=C1)C1=NN=NN1C(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 AFFSIXWYDRNWIO-UHFFFAOYSA-N 0.000 description 1
- CQFSCGBFRMBKDS-UHFFFAOYSA-N C(CCC)C=1N(C(=C(N1)O)C(=O)OC)CC1=CC=C(C=C1)C1=C(C=CC=C1)C(=O)O Chemical compound C(CCC)C=1N(C(=C(N1)O)C(=O)OC)CC1=CC=C(C=C1)C1=C(C=CC=C1)C(=O)O CQFSCGBFRMBKDS-UHFFFAOYSA-N 0.000 description 1
- DEZOIWJQNVDWSL-UHFFFAOYSA-N C(CCC)C=1N(C(=C(N1)OCC)C(=O)O)CC1=CC=C(C=C1)C1=C(C=CC=C1)C(=O)O Chemical compound C(CCC)C=1N(C(=C(N1)OCC)C(=O)O)CC1=CC=C(C=C1)C1=C(C=CC=C1)C(=O)O DEZOIWJQNVDWSL-UHFFFAOYSA-N 0.000 description 1
- QVUMNXXQQVMIPF-UHFFFAOYSA-N C(CCCC)(=O)[O].C(=O)(O)C1=C(C=CC=C1)C1=CC=C(C=C1)CN1C(=NC(=C1C(=O)O)C(C)(C)O)CCC Chemical compound C(CCCC)(=O)[O].C(=O)(O)C1=C(C=CC=C1)C1=CC=C(C=C1)CN1C(=NC(=C1C(=O)O)C(C)(C)O)CCC QVUMNXXQQVMIPF-UHFFFAOYSA-N 0.000 description 1
- LGGUSBWBRNMRBM-UHFFFAOYSA-N C(CCCC)(=O)[O].C(C)(C)(C)OC(=O)C1=C(C=CC=C1)C1=CC=C(C=C1)CN1C(=NC(=C1C(=O)O)CO)CCCC Chemical compound C(CCCC)(=O)[O].C(C)(C)(C)OC(=O)C1=C(C=CC=C1)C1=CC=C(C=C1)CN1C(=NC(=C1C(=O)O)CO)CCCC LGGUSBWBRNMRBM-UHFFFAOYSA-N 0.000 description 1
- DLFLXANGJBOXRS-UHFFFAOYSA-N C(CCCC)(=O)[O].C(CCC)C=1N(C(=C(N1)CO)C(=O)O)CC1=CC=C(C=C1)C1=C(C=CC=C1)C(=O)O Chemical compound C(CCCC)(=O)[O].C(CCC)C=1N(C(=C(N1)CO)C(=O)O)CC1=CC=C(C=C1)C1=C(C=CC=C1)C(=O)O DLFLXANGJBOXRS-UHFFFAOYSA-N 0.000 description 1
- CYZUDSAJHXOGRA-UHFFFAOYSA-N C(CCCC)(=O)[O].C(CCC)C=1NC(=C(N1)CO)C(=O)O Chemical compound C(CCCC)(=O)[O].C(CCC)C=1NC(=C(N1)CO)C(=O)O CYZUDSAJHXOGRA-UHFFFAOYSA-N 0.000 description 1
- VJZYTXKYDQLLDY-UHFFFAOYSA-N C(CCCC)(=O)[O].OC(C)(C)C=1N=C(NC1C(=O)O)CCC Chemical compound C(CCCC)(=O)[O].OC(C)(C)C=1N=C(NC1C(=O)O)CCC VJZYTXKYDQLLDY-UHFFFAOYSA-N 0.000 description 1
- DGFQXXDHYHWWSP-UHFFFAOYSA-N CC(C)OC([O])=O Chemical compound CC(C)OC([O])=O DGFQXXDHYHWWSP-UHFFFAOYSA-N 0.000 description 1
- SLYXSYQZMGEULF-UHFFFAOYSA-N CC1=C(OC(O1)=O)COC(=O)C1=CN=CN1 Chemical compound CC1=C(OC(O1)=O)COC(=O)C1=CN=CN1 SLYXSYQZMGEULF-UHFFFAOYSA-N 0.000 description 1
- LFLSQXQKYRGADT-UHFFFAOYSA-N CCCCC1=NC(C(C)(CC)O)=C(C)N1C(C=C1)=CC=C1C(C=CC=C1)=C1C1=NNN=N1 Chemical compound CCCCC1=NC(C(C)(CC)O)=C(C)N1C(C=C1)=CC=C1C(C=CC=C1)=C1C1=NNN=N1 LFLSQXQKYRGADT-UHFFFAOYSA-N 0.000 description 1
- XQCKXOKBWVXUJH-UHFFFAOYSA-N CCOC([O])=O Chemical compound CCOC([O])=O XQCKXOKBWVXUJH-UHFFFAOYSA-N 0.000 description 1
- PHZDLMOVTNOUBV-UHFFFAOYSA-N CCl.[O] Chemical compound CCl.[O] PHZDLMOVTNOUBV-UHFFFAOYSA-N 0.000 description 1
- FUCOFSWTIIBXQJ-UHFFFAOYSA-N COC(=O)C1=C(N=C(N1)CCCC)OC Chemical compound COC(=O)C1=C(N=C(N1)CCCC)OC FUCOFSWTIIBXQJ-UHFFFAOYSA-N 0.000 description 1
- WBZXXNULCKONIA-UHFFFAOYSA-N COC(=O)C1=C(N=C(N1CC1=CC=C(C=C1)C1=C(C=CC=C1)C(=O)O)CCCC)OC Chemical compound COC(=O)C1=C(N=C(N1CC1=CC=C(C=C1)C1=C(C=CC=C1)C(=O)O)CCCC)OC WBZXXNULCKONIA-UHFFFAOYSA-N 0.000 description 1
- ZDEYWLMYCBAZLK-UHFFFAOYSA-N COC(=O)C1=C(N=C(N1CC1=CC=C(C=C1)C1=C(C=CC=C1)C(=O)OC(C)(C)C)CCCC)OC Chemical compound COC(=O)C1=C(N=C(N1CC1=CC=C(C=C1)C1=C(C=CC=C1)C(=O)OC(C)(C)C)CCCC)OC ZDEYWLMYCBAZLK-UHFFFAOYSA-N 0.000 description 1
- 101100004280 Caenorhabditis elegans best-2 gene Proteins 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
- WWVHZMSGYSMTDX-UHFFFAOYSA-N Cl.C(CCC)C=1N(C=C(N1)C(C1=CC=CC=C1)O)CC1=CC=C(C=C1)C1=C(C=CC=C1)C(=O)O Chemical compound Cl.C(CCC)C=1N(C=C(N1)C(C1=CC=CC=C1)O)CC1=CC=C(C=C1)C1=C(C=CC=C1)C(=O)O WWVHZMSGYSMTDX-UHFFFAOYSA-N 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- WBOHXLDSPBIPTP-UHFFFAOYSA-N N,N-dimethyl-1,8-naphthyridin-4-amine Chemical compound CN(C1=CC=NC2=NC=CC=C12)C WBOHXLDSPBIPTP-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 108010083387 Saralasin Proteins 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- GCTFWCDSFPMHHS-UHFFFAOYSA-M Tributyltin chloride Chemical compound CCCC[Sn](Cl)(CCCC)CCCC GCTFWCDSFPMHHS-UHFFFAOYSA-M 0.000 description 1
- 241001300078 Vitrea Species 0.000 description 1
- DOSUCUXINJKXIU-UHFFFAOYSA-N [Cl].C(C(=O)O)(=O)O Chemical compound [Cl].C(C(=O)O)(=O)O DOSUCUXINJKXIU-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 1
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000005042 acyloxymethyl group Chemical group 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 238000004026 adhesive bonding Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229960002478 aldosterone Drugs 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000005081 alkoxyalkoxyalkyl group Chemical group 0.000 description 1
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000006350 alkyl thio alkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I 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)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Natural products C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000005164 aryl thioalkyl group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 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
- 150000003851 azoles Chemical class 0.000 description 1
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- AQIHMSVIAGNIDM-UHFFFAOYSA-N benzoyl bromide Chemical compound BrC(=O)C1=CC=CC=C1 AQIHMSVIAGNIDM-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 229910010277 boron hydride Inorganic materials 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- RHDGNLCLDBVESU-UHFFFAOYSA-N but-3-en-4-olide Chemical compound O=C1CC=CO1 RHDGNLCLDBVESU-UHFFFAOYSA-N 0.000 description 1
- QAWBXZYPFCFQLA-UHFFFAOYSA-N butanoyl bromide Chemical compound CCCC(Br)=O QAWBXZYPFCFQLA-UHFFFAOYSA-N 0.000 description 1
- ILJDFBVQZFJJJS-UHFFFAOYSA-N butyl $l^{1}-oxidanylformate Chemical compound CCCCOC([O])=O ILJDFBVQZFJJJS-UHFFFAOYSA-N 0.000 description 1
- NRDQFWXVTPZZAZ-UHFFFAOYSA-N butyl carbonochloridate Chemical compound CCCCOC(Cl)=O NRDQFWXVTPZZAZ-UHFFFAOYSA-N 0.000 description 1
- KMGBZBJJOKUPIA-UHFFFAOYSA-N butyl iodide Chemical compound CCCCI KMGBZBJJOKUPIA-UHFFFAOYSA-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
- 239000002775 capsule Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- PIMYDFDXAUVLON-UHFFFAOYSA-M chloro(triethyl)stannane Chemical compound CC[Sn](Cl)(CC)CC PIMYDFDXAUVLON-UHFFFAOYSA-M 0.000 description 1
- KWTSZCJMWHGPOS-UHFFFAOYSA-M chloro(trimethyl)stannane Chemical compound C[Sn](C)(C)Cl KWTSZCJMWHGPOS-UHFFFAOYSA-M 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000005170 cycloalkyloxycarbonyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- FBCCMZVIWNDFMO-UHFFFAOYSA-N dichloroacetyl chloride Chemical compound ClC(Cl)C(Cl)=O FBCCMZVIWNDFMO-UHFFFAOYSA-N 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- VLNZUSMTOFYNPS-UHFFFAOYSA-N diethylphosphorylformonitrile Chemical compound CCP(=O)(CC)C#N VLNZUSMTOFYNPS-UHFFFAOYSA-N 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- ROBXZHNBBCHEIQ-BYPYZUCNSA-N ethyl (2s)-2-aminopropanoate Chemical compound CCOC(=O)[C@H](C)N ROBXZHNBBCHEIQ-BYPYZUCNSA-N 0.000 description 1
- KLWYPRNPRNPORS-UHFFFAOYSA-N ethyl 1h-imidazole-5-carboxylate Chemical compound CCOC(=O)C1=CN=CN1 KLWYPRNPRNPORS-UHFFFAOYSA-N 0.000 description 1
- ZSANATMGGJSHMX-UHFFFAOYSA-N ethyl 2-butyl-5-(2-hydroxypropan-2-yl)-3-[[4-[2-[(2-methylpropan-2-yl)oxycarbonyl]phenyl]phenyl]methyl]imidazole-4-carboxylate Chemical compound CCCCC1=NC(C(C)(C)O)=C(C(=O)OCC)N1CC1=CC=C(C=2C(=CC=CC=2)C(=O)OC(C)(C)C)C=C1 ZSANATMGGJSHMX-UHFFFAOYSA-N 0.000 description 1
- YTMSTTIEKPEEMZ-UHFFFAOYSA-N ethyl 2-butyl-5-(3-hydroxypentan-3-yl)-1h-imidazole-4-carboxylate Chemical compound CCCCC1=NC(C(O)(CC)CC)=C(C(=O)OCC)N1 YTMSTTIEKPEEMZ-UHFFFAOYSA-N 0.000 description 1
- 229960003750 ethyl chloride Drugs 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 210000003191 femoral vein Anatomy 0.000 description 1
- NJVOZLGKTAPUTQ-UHFFFAOYSA-M fentin chloride Chemical compound C=1C=CC=CC=1[Sn](C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 NJVOZLGKTAPUTQ-UHFFFAOYSA-M 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 125000003844 furanonyl group Chemical group 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 230000008571 general function Effects 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- YWGHUJQYGPDNKT-UHFFFAOYSA-N hexanoyl chloride Chemical compound CCCCCC(Cl)=O YWGHUJQYGPDNKT-UHFFFAOYSA-N 0.000 description 1
- PKHMTIRCAFTBDS-UHFFFAOYSA-N hexanoyl hexanoate Chemical compound CCCCCC(=O)OC(=O)CCCCC PKHMTIRCAFTBDS-UHFFFAOYSA-N 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 230000003284 homeostatic effect Effects 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
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- XJFQCYIFOWHHFN-PLKCGDGVSA-N hypertensinogen 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)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 XJFQCYIFOWHHFN-PLKCGDGVSA-N 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 1
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 1
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- VHRYZQNGTZXDNX-UHFFFAOYSA-N methacryloyl chloride Chemical compound CC(=C)C(Cl)=O VHRYZQNGTZXDNX-UHFFFAOYSA-N 0.000 description 1
- LFETXMWECUPHJA-UHFFFAOYSA-N methanamine;hydrate Chemical compound O.NC LFETXMWECUPHJA-UHFFFAOYSA-N 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- HQEIPVHJHZTMDP-JEDNCBNOSA-N methyl (2s)-pyrrolidine-2-carboxylate;hydrochloride Chemical compound Cl.COC(=O)[C@@H]1CCCN1 HQEIPVHJHZTMDP-JEDNCBNOSA-N 0.000 description 1
- LXNYUGNEPVCEEV-UHFFFAOYSA-N methyl 2-butyl-5-(1-hydroxy-2,2-dimethylpropyl)-3-[[4-[2-[(2-methylpropan-2-yl)oxycarbonyl]phenyl]phenyl]methyl]imidazole-4-carboxylate Chemical compound CCCCC1=NC(C(O)C(C)(C)C)=C(C(=O)OC)N1CC1=CC=C(C=2C(=CC=CC=2)C(=O)OC(C)(C)C)C=C1 LXNYUGNEPVCEEV-UHFFFAOYSA-N 0.000 description 1
- OPKIYTAEJCKVCS-UHFFFAOYSA-N methyl 2-butyl-5-(hydroxymethyl)-1h-imidazole-4-carboxylate Chemical compound CCCCC1=NC(C(=O)OC)=C(CO)N1 OPKIYTAEJCKVCS-UHFFFAOYSA-N 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- ULWOJODHECIZAU-UHFFFAOYSA-N n,n-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 description 1
- OWYKHVLWBVIMNI-UHFFFAOYSA-N n-propan-2-yl-1h-imidazole-5-carboxamide Chemical compound CC(C)NC(=O)C1=CN=CN1 OWYKHVLWBVIMNI-UHFFFAOYSA-N 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- NSNPSJGHTQIXDO-UHFFFAOYSA-N naphthalene-1-carbonyl chloride Chemical compound C1=CC=C2C(C(=O)Cl)=CC=CC2=C1 NSNPSJGHTQIXDO-UHFFFAOYSA-N 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- QMMOXUPEWRXHJS-UHFFFAOYSA-N pent-2-ene Chemical compound CCC=CC QMMOXUPEWRXHJS-UHFFFAOYSA-N 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- XGISHOFUAFNYQF-UHFFFAOYSA-N pentanoyl chloride Chemical compound CCCCC(Cl)=O XGISHOFUAFNYQF-UHFFFAOYSA-N 0.000 description 1
- DUCKXCGALKOSJF-UHFFFAOYSA-N pentanoyl pentanoate Chemical compound CCCCC(=O)OC(=O)CCCC DUCKXCGALKOSJF-UHFFFAOYSA-N 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- LZZHUQKJWKRUOS-UHFFFAOYSA-N propan-2-yl 1h-imidazole-5-carboxylate Chemical compound CC(C)OC(=O)C1=CNC=N1 LZZHUQKJWKRUOS-UHFFFAOYSA-N 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 150000003214 pyranose derivatives Chemical class 0.000 description 1
- RWRDJVNMSZYMDV-UHFFFAOYSA-L radium chloride Chemical compound [Cl-].[Cl-].[Ra+2] RWRDJVNMSZYMDV-UHFFFAOYSA-L 0.000 description 1
- 229910001630 radium chloride Inorganic materials 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 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
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- OSHAAVSJZUGIRG-UHFFFAOYSA-N sulfonylmagnesium Chemical compound S(=O)(=O)=[Mg] OSHAAVSJZUGIRG-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 150000003606 tin compounds Chemical class 0.000 description 1
- 108010021724 tonin Proteins 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- JKVRTUCVPZTEQZ-UHFFFAOYSA-N tributyltin azide Chemical compound CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-] JKVRTUCVPZTEQZ-UHFFFAOYSA-N 0.000 description 1
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- MZGUIAFRJWSYJJ-UHFFFAOYSA-M trimethylstannanylium;bromide Chemical compound C[Sn](C)(C)Br MZGUIAFRJWSYJJ-UHFFFAOYSA-M 0.000 description 1
- 238000005866 tritylation reaction Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
- 210000004127 vitreous body Anatomy 0.000 description 1
- 239000003799 water insoluble solvent Substances 0.000 description 1
- WCJYTPVNMWIZCG-UHFFFAOYSA-N xylylcarb Chemical compound CNC(=O)OC1=CC=C(C)C(C)=C1 WCJYTPVNMWIZCG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Breeding Of Plants And Reproduction By Means Of Culturing (AREA)
- Dental Preparations (AREA)
- Phenolic Resins Or Amino Resins (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Claims (1)
Applications Claiming Priority (18)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP27098/1991 | 1991-02-21 | ||
JP27098/91 | 1991-02-21 | ||
JP2709891 | 1991-02-21 | ||
JP96588/1991 | 1991-04-26 | ||
JP9658891 | 1991-04-26 | ||
JP96588/91 | 1991-04-26 | ||
JP134889/1991 | 1991-06-06 | ||
JP13488991 | 1991-06-06 | ||
JP134889/91 | 1991-06-06 | ||
JP167138/91 | 1991-07-08 | ||
JP16713891 | 1991-07-08 | ||
JP167138/1991 | 1991-07-08 | ||
JP173972/91 | 1991-07-15 | ||
JP173972/1991 | 1991-07-15 | ||
JP17397291 | 1991-07-15 | ||
JP184841/1991 | 1991-07-24 | ||
JP184841/91 | 1991-07-24 | ||
JP18484191 | 1991-07-24 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN92102075A Division CN1045770C (zh) | 1991-02-21 | 1992-02-21 | 制备1-联苯甲基咪唑衍生物的方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1188645A CN1188645A (zh) | 1998-07-29 |
CN1121859C true CN1121859C (zh) | 2003-09-24 |
Family
ID=27549327
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN92102075A Expired - Lifetime CN1045770C (zh) | 1991-02-21 | 1992-02-21 | 制备1-联苯甲基咪唑衍生物的方法 |
CN97126347A Expired - Lifetime CN1121859C (zh) | 1991-02-21 | 1997-12-24 | 用于治疗或预防高血压症的药物组合物的制备方法 |
CN97123452A Expired - Lifetime CN1101384C (zh) | 1991-02-21 | 1997-12-24 | 1-联苯甲基咪唑衍生物的制备方法 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN92102075A Expired - Lifetime CN1045770C (zh) | 1991-02-21 | 1992-02-21 | 制备1-联苯甲基咪唑衍生物的方法 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN97123452A Expired - Lifetime CN1101384C (zh) | 1991-02-21 | 1997-12-24 | 1-联苯甲基咪唑衍生物的制备方法 |
Country Status (23)
Country | Link |
---|---|
EP (2) | EP0545912B1 (zh) |
JP (1) | JPH07121918B2 (zh) |
KR (1) | KR0128289B1 (zh) |
CN (3) | CN1045770C (zh) |
AT (2) | ATE200777T1 (zh) |
CA (2) | CA2061607C (zh) |
CZ (1) | CZ289194B6 (zh) |
DE (6) | DE10299043I2 (zh) |
DK (2) | DK0545912T3 (zh) |
ES (2) | ES2156866T3 (zh) |
FI (2) | FI112942B3 (zh) |
GR (2) | GR3035906T3 (zh) |
HK (2) | HK1011361A1 (zh) |
HU (3) | HU223338B1 (zh) |
IE (1) | IE920540A1 (zh) |
IL (3) | IL114996A (zh) |
IS (1) | IS1756B (zh) |
LU (4) | LU91056I2 (zh) |
NL (3) | NL300133I2 (zh) |
NO (6) | NO304516B3 (zh) |
NZ (1) | NZ241681A (zh) |
PT (2) | PT503785E (zh) |
RU (1) | RU2128173C1 (zh) |
Families Citing this family (103)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5616599A (en) * | 1991-02-21 | 1997-04-01 | Sankyo Company, Limited | Angiotensin II antagosist 1-biphenylmethylimidazole compounds and their therapeutic use |
PT573218E (pt) * | 1992-06-02 | 2001-06-29 | Sankyo Co | 4-carbonilimidazoles como antagonistas de angiotensina ii e sua utilizacao terapeutica |
RU2109736C1 (ru) * | 1992-12-17 | 1998-04-27 | Санкио Компани Лимитед | Производные бифенила и способ их получения |
US5395844A (en) * | 1993-06-10 | 1995-03-07 | The Du Pont Merck Pharmaceutical Company | Imidazole 5-position substituted angiotensin II antagonists |
RU2123847C1 (ru) * | 1994-03-16 | 1998-12-27 | Санкио Компани Лимитед | Лекарственное средство и способ лечения повышенного глазного давления и/или глаукомы |
TW442301B (en) | 1995-06-07 | 2001-06-23 | Sanofi Synthelabo | Pharmaceutical compositions containing irbesartan |
AUPN786896A0 (en) | 1996-02-02 | 1996-02-29 | Telstra Corporation Limited | A network fault system |
RU2183128C2 (ru) | 1996-07-15 | 2002-06-10 | Санкио Компани Лимитед | Фармацевтическая композиция |
WO1998034922A1 (fr) * | 1997-02-05 | 1998-08-13 | Sankyo Company, Limited | Agent destine a la prophylaxie ou la therapie des complications diabetiques |
WO2000078727A1 (fr) * | 1999-06-22 | 2000-12-28 | Takeda Chemical Industries, Ltd. | Methode de preparation de derives d'imidazole |
SE9903028D0 (sv) | 1999-08-27 | 1999-08-27 | Astra Ab | New use |
PE20010781A1 (es) | 1999-10-22 | 2001-08-08 | Takeda Chemical Industries Ltd | Compuestos 1-(1h-imidazol-4-il)-1-(naftil-2-sustituido)etanol, su produccion y utilizacion |
JP4521844B2 (ja) * | 2000-04-18 | 2010-08-11 | 日本曹達株式会社 | 4,5−ジシアノイミダゾールの製造方法 |
AU2001284413A1 (en) * | 2000-08-30 | 2002-03-13 | Sankyo Company Limited | Medicinal compositions for preventing or treating heart failure |
US8168616B1 (en) | 2000-11-17 | 2012-05-01 | Novartis Ag | Combination comprising a renin inhibitor and an angiotensin receptor inhibitor for hypertension |
NZ525913A (en) * | 2000-11-21 | 2004-05-28 | Sankyo Co | A pharmaceutical composition |
NZ531346A (en) * | 2001-08-28 | 2005-10-28 | Sankyo Co | Medicinal compositions containing angiotensin II receptor antagonist |
KR101194453B1 (ko) | 2003-01-31 | 2012-10-24 | 다이이찌 산쿄 가부시키가이샤 | 동맥 경화 및 고혈압증의 예방 및 치료를 위한 의약 |
CN1197866C (zh) * | 2003-03-21 | 2005-04-20 | 上海医药工业研究院 | 4,6-二氢呋喃并[3,4-d]咪唑-6-酮衍生物及其盐和制备方法 |
EP1614428A4 (en) * | 2003-04-15 | 2010-01-06 | Sankyo Co | MEDICAMENT FOR THE PREVENTION OR TREATMENT OF ANGIOGENIC OCULAR DISEASES |
US7732162B2 (en) | 2003-05-05 | 2010-06-08 | Probiodrug Ag | Inhibitors of glutaminyl cyclase for treating neurodegenerative diseases |
GB0316546D0 (en) | 2003-07-15 | 2003-08-20 | Novartis Ag | Process for the manufacture of organic compounds |
EP2428516A1 (en) | 2003-11-19 | 2012-03-14 | Metabasis Therapeutics, Inc. | Novel phosphorus-containing thyromimetics |
GB0327839D0 (en) | 2003-12-01 | 2003-12-31 | Novartis Ag | Organic compounds |
JP2005206603A (ja) * | 2004-01-21 | 2005-08-04 | Teva Pharmaceutical Industries Ltd | カンデサルタンシレキセチルの調製 |
GB0402262D0 (en) | 2004-02-02 | 2004-03-10 | Novartis Ag | Process for the manufacture of organic compounds |
US7692023B2 (en) | 2004-02-11 | 2010-04-06 | Teva Pharmaceutical Industries Ltd. | Candesartan cilexetil polymorphs |
US7157584B2 (en) | 2004-02-25 | 2007-01-02 | Takeda Pharmaceutical Company Limited | Benzimidazole derivative and use thereof |
US20080161321A1 (en) | 2004-03-17 | 2008-07-03 | David Louis Feldman | Use of Renin Inhibitors in Therapy |
US7528258B2 (en) * | 2004-09-02 | 2009-05-05 | Teva Pharmaceutical Industries Ltd | Preparation of olmesartan medoxomil |
EP1799199B1 (en) | 2004-10-08 | 2012-03-28 | Novartis AG | Use of renin inhibitors for the prevention or treatment of diastolic dysfunction or diastolic heart failure |
WO2006046593A1 (ja) | 2004-10-27 | 2006-05-04 | Daiichi Sankyo Company, Limited | 2以上の置換基を有するベンゼン化合物 |
JP2007525504A (ja) * | 2004-12-30 | 2007-09-06 | テバ ファーマシューティカル インダストリーズ リミティド | 2.5よりも高いpHでオルメサルタンメドキソミルを調製するための方法 |
WO2006073519A1 (en) * | 2005-01-03 | 2006-07-13 | Teva Pharmaceutical Industries Ltd. | Olmesartan medoxomil with reduced levels of impurities |
DE602006010364D1 (de) * | 2005-04-22 | 2009-12-24 | Daiichi Sankyo Co Ltd | Pharmazeutikum zur prävention oder behandlung von metabolischer knochenkrankheit |
US7943779B2 (en) * | 2005-07-29 | 2011-05-17 | Krka | Process for the preparation of olmesartan medoxomil |
EP1816131A1 (en) * | 2006-02-06 | 2007-08-08 | KRKA, tovarna zdravil, d.d., Novo mesto | Process for the preparation of olmesartan medoxomil |
CZ299265B6 (cs) * | 2005-10-20 | 2008-05-28 | Zentiva, A. S. | Zpusob výroby 1-(cyklohexyloxykarbonyloxy)ethyl-2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)bifenyl-4-yl]methyl]benzimidazol-7-karboxylátu (candesartan cilexetilu) |
CZ299902B6 (cs) * | 2005-10-27 | 2008-12-29 | Zentiva, A. S | Zpusob odstranování trifenylmethanové chránicí skupiny u prekurzoru antihypertenzních léciv |
EP1801111B1 (en) * | 2005-12-20 | 2014-07-16 | LEK Pharmaceuticals d.d. | Novel polymorph forms of olmesartan medoxomil |
JP5047156B2 (ja) * | 2006-02-27 | 2012-10-10 | 武田薬品工業株式会社 | 医薬パッケージ |
ATE526963T1 (de) | 2006-05-04 | 2011-10-15 | Lek Pharmaceuticals | Pharmazeutische zusammensetzung mit olmesartan- medoxomil |
WO2007148344A2 (en) * | 2006-06-19 | 2007-12-27 | Matrix Laboratories Limited | Process for the preparation of olmesartan medoxomil |
US8242151B2 (en) | 2007-02-07 | 2012-08-14 | Kyowa Hakko Kirin Co., Ltd. | Tricyclic compounds |
CA2679446C (en) | 2007-03-01 | 2016-05-17 | Probiodrug Ag | New use of glutaminyl cyclase inhibitors |
EP2141160A4 (en) * | 2007-03-23 | 2011-06-29 | Daiichi Sankyo Co Ltd | GROUND CRYSTAL OLMESARTAN MEDOXOMIL |
US9656991B2 (en) | 2007-04-18 | 2017-05-23 | Probiodrug Ag | Inhibitors of glutaminyl cyclase |
TWI448284B (zh) * | 2007-04-24 | 2014-08-11 | Theravance Inc | 雙效抗高血壓劑 |
CN101311168B (zh) * | 2007-05-21 | 2010-12-08 | 上海医药工业研究院 | 4-(1-羟基-1-甲基乙基)-2-丙基咪唑-5-羧酸酯的制备方法 |
CN101311169B (zh) * | 2007-05-21 | 2011-03-16 | 上海医药工业研究院 | 4-(1-羟基-1-甲基乙基)-2-丙基咪唑-5-羧酸乙酯的制备方法 |
EP2170930B3 (en) | 2007-06-04 | 2013-10-02 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
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 |
GB0710680D0 (en) * | 2007-06-05 | 2007-07-11 | Generics Uk Ltd | Novel crystalline form of olmesartan medoxmil |
WO2009001661A1 (ja) * | 2007-06-22 | 2008-12-31 | Daiichi Sankyo Company, Limited | アルツハイマー病の予防又は治療のための医薬 |
JP2011522828A (ja) | 2008-06-04 | 2011-08-04 | シナジー ファーマシューティカルズ インコーポレイテッド | 胃腸障害、炎症、癌、およびその他の障害の治療のために有用なグアニル酸シクラーゼのアゴニスト |
ES2540062T3 (es) | 2008-06-09 | 2015-07-08 | Daiichi Sankyo Company, Limited | Procedimiento de producción de un compuesto de 1-bifenilmetilimidazol |
AU2009270833B2 (en) | 2008-07-16 | 2015-02-19 | Bausch Health Ireland Limited | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
JP5559689B2 (ja) | 2008-08-06 | 2014-07-23 | 協和発酵キリン株式会社 | 3環系化合物 |
WO2010054515A1 (zh) | 2008-11-17 | 2010-05-20 | 上海医药工业研究院 | 4-(1-羟基-1-甲基乙基)-2-丙基咪唑-5-羧酸酯的制备方法 |
JP2009102340A (ja) * | 2008-12-04 | 2009-05-14 | Daiichi Sankyo Co Ltd | イミダゾール誘導体の製造法(2) |
WO2010093601A1 (en) | 2009-02-10 | 2010-08-19 | Metabasis Therapeutics, Inc. | Novel sulfonic acid-containing thyromimetics, and methods for their use |
WO2010126014A1 (ja) | 2009-04-28 | 2010-11-04 | 第一三共株式会社 | 新規溶媒和物結晶 |
TWI539948B (zh) | 2009-04-28 | 2016-07-01 | 第一三共股份有限公司 | 奧美沙坦酯之製造方法 |
MX2012002993A (es) | 2009-09-11 | 2012-04-19 | Probiodrug Ag | Derivados heterociclicos como inhibidores de ciclasa glutaminilo. |
CN102050816A (zh) * | 2009-10-28 | 2011-05-11 | 北京万全阳光医学技术有限公司 | 一种合成奥美沙坦酯的方法 |
HUP0900788A2 (en) | 2009-12-16 | 2011-11-28 | Sanofi Aventis | Process for producing 4-bromomethyl-biphenyl derivatives |
WO2011083112A2 (en) | 2010-01-05 | 2011-07-14 | Ratiopharm Gmbh | Solid oral dosage form containing olmesartan medoxomil |
WO2011107530A2 (en) | 2010-03-03 | 2011-09-09 | Probiodrug Ag | Novel inhibitors |
JP5688745B2 (ja) | 2010-03-10 | 2015-03-25 | プロビオドルグ エージー | グルタミニルシクラーゼ(qc、ec2.3.2.5)の複素環阻害剤 |
EP2560953B1 (en) | 2010-04-21 | 2016-01-06 | Probiodrug AG | Inhibitors of glutaminyl cyclase |
JP5137996B2 (ja) * | 2010-04-28 | 2013-02-06 | 日本曹達株式会社 | 4,5−ジシアノイミダゾールの製造方法 |
IT1400311B1 (it) | 2010-05-10 | 2013-05-24 | Menarini Int Operations Lu Sa | Associazione di inibitori della xantina ossidasi e antagonisti del recettore dell'angiotensina ii e loro uso. |
EP2425859A1 (en) | 2010-08-08 | 2012-03-07 | Abdi Ibrahim Ilac Sanayi ve Ticaret Anonim Sirketi | Olmesartan formulations |
US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
CN102060778B (zh) * | 2010-12-24 | 2012-05-23 | 江苏江神药物化学有限公司 | 一种4-(1-羟基-1-甲基乙基)-2-丙基咪唑-5-羧酸乙酯的合成方法 |
CN102206208A (zh) * | 2010-12-24 | 2011-10-05 | 上海现代制药股份有限公司 | 含低水平杂质的奥美沙坦酯的制备方法 |
ES2570167T3 (es) | 2011-03-16 | 2016-05-17 | Probiodrug Ag | Derivados de benzimidazol como inhibidores de glutaminil ciclasa |
TW201311678A (zh) | 2011-08-03 | 2013-03-16 | Kyowa Hakko Kirin Co Ltd | 二苯并氧呯衍生物 |
BR112014014527A2 (pt) | 2011-12-15 | 2017-06-13 | Takeda Pharmaceuticals Usa Inc | combinações de azilsartan e clorotalidona para tratar hipertensão em pacientes negros |
CN103304550B (zh) * | 2012-03-16 | 2016-01-27 | 湖南欧亚生物有限公司 | 一种奥美沙坦酯的制备方法 |
US9624181B2 (en) | 2012-08-31 | 2017-04-18 | Api Corporation | Method for producing biaryl compound |
JP5881837B2 (ja) | 2012-09-26 | 2016-03-09 | 株式会社エーピーアイ コーポレーション | テトラゾール化合物の脱保護方法 |
JP6218084B2 (ja) | 2012-10-04 | 2017-10-25 | 国立研究開発法人国立循環器病研究センター | 悪性腫瘍転移抑制用医薬 |
CN103012382B (zh) * | 2012-12-05 | 2016-10-05 | 迪沙药业集团有限公司 | 一种奥美沙坦酯的制备方法 |
CN103044407A (zh) * | 2012-12-20 | 2013-04-17 | 安徽悦康凯悦制药有限公司 | 奥美沙坦酯的制备方法 |
CN103965167A (zh) * | 2013-01-29 | 2014-08-06 | 通化济达医药有限公司 | 咪唑羧酸衍生物 |
JP2014152127A (ja) * | 2013-02-06 | 2014-08-25 | Tokuyama Corp | オルメサルタンメドキソミルの製造方法 |
CA2905435A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
WO2014151206A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
EP3004138B1 (en) | 2013-06-05 | 2024-03-13 | Bausch Health Ireland Limited | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
EP3025711B1 (en) | 2013-07-23 | 2020-11-18 | Daiichi Sankyo Company, Limited | Medicine for preventing or treating hypertension |
CN103880825B (zh) * | 2014-03-14 | 2019-03-05 | 浙江华海药业股份有限公司 | 一种高纯的三苯甲基奥美沙坦酯的制备工艺 |
CN104356069B (zh) * | 2014-11-18 | 2016-09-14 | 黄冈鲁班药业有限公司 | 奥美沙坦酯中间体4-(1-羟基-1-甲基乙基)-2-丙基咪唑-5-羧酸乙酯的制备方法及应用 |
CN104447564B (zh) * | 2014-11-24 | 2016-08-31 | 广州天赐高新材料股份有限公司 | 高纯度4,5-二氰基-2-三氟甲基咪唑及其盐的制备方法 |
CN104402873A (zh) * | 2014-12-02 | 2015-03-11 | 千辉药业(安徽)有限责任公司 | 一种奥美沙坦酯中间体的制备方法 |
CN105481842A (zh) * | 2015-12-15 | 2016-04-13 | 江苏中邦制药有限公司 | 一种奥美沙坦酯的制备方法 |
EP3434284A4 (en) | 2016-03-24 | 2019-11-13 | Daiichi Sankyo Company, Limited | MEDICINE FOR THE TREATMENT OF KIDNEY DISEASE |
CN106749195A (zh) * | 2016-12-30 | 2017-05-31 | 青岛黄海制药有限责任公司 | 一种奥美沙坦酯中间体杂质合成、鉴定的方法 |
CN107474042A (zh) * | 2017-09-07 | 2017-12-15 | 浙江华海致诚药业有限公司 | 一种三苯甲基奥美沙坦酯的晶型h |
ES2812698T3 (es) | 2017-09-29 | 2021-03-18 | Probiodrug Ag | Inhibidores de glutaminil ciclasa |
CN109081812B (zh) * | 2018-08-30 | 2022-08-16 | 黄冈鲁班药业股份有限公司 | 4-(1-羟基-1-甲基乙基)-2-丙基咪唑-5-羧酸乙酯一水合物 |
KR102131359B1 (ko) | 2018-09-07 | 2020-07-07 | 오토텔릭바이오 주식회사 | 안정성이 향상된 의약 조성물 |
CN112778209B (zh) * | 2019-11-04 | 2024-05-14 | 宜昌东阳光长江药业股份有限公司 | 一种二酸的制备方法 |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5671074A (en) * | 1979-11-12 | 1981-06-13 | Takeda Chem Ind Ltd | 1,2-disubstituted-4-halogenoimidazole-5-acetic acid derivative |
JPS5671073A (en) * | 1979-11-12 | 1981-06-13 | Takeda Chem Ind Ltd | Imidazole derivative |
IE802177L (en) | 1980-10-21 | 1981-05-12 | Takeda Chemical Industries Ltd | Imidazol-5-ylacetic acid derivatives |
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 |
CA1338238C (en) | 1988-01-07 | 1996-04-09 | David John Carini | Angiotensin ii receptor blocking imidazoles and combinations thereof with diuretics and nsaids |
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 |
US4916129A (en) | 1989-01-19 | 1990-04-10 | E. I. Du Pont De Nemours And Company | Combination β-blocking/angiotensin II blocking antihypertensives |
CA2016710A1 (en) | 1989-05-15 | 1990-11-15 | Prasun K. Chakravarty | 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 |
US5064825A (en) * | 1989-06-01 | 1991-11-12 | Merck & Co., Inc. | Angiotensin ii antagonists |
WO1991012002A1 (en) * | 1990-02-13 | 1991-08-22 | Merck & Co., Inc. | Imidazole angiotensin ii antagonists incorporating a substituted benzyl element |
US5140037A (en) * | 1990-03-20 | 1992-08-18 | E. I. Du Pont De Nemours And Company | Treatment of central nervous system disorders with imidazole angiotensin-ii receptor antagonists |
-
1992
- 1992-02-20 CA CA002061607A patent/CA2061607C/en not_active Expired - Lifetime
- 1992-02-20 IS IS3819A patent/IS1756B/is unknown
- 1992-02-20 IE IE054092A patent/IE920540A1/en active Protection Beyond IP Right Term
- 1992-02-20 CA CA002229000A patent/CA2229000C/en not_active Expired - Lifetime
- 1992-02-20 FI FI920749A patent/FI112942B3/fi not_active IP Right Cessation
- 1992-02-21 AT AT92301449T patent/ATE200777T1/de active
- 1992-02-21 CN CN92102075A patent/CN1045770C/zh not_active Expired - Lifetime
- 1992-02-21 AT AT93200195T patent/ATE200778T1/de active
- 1992-02-21 JP JP4034970A patent/JPH07121918B2/ja not_active Expired - Lifetime
- 1992-02-21 HU HU9200578A patent/HU223338B1/hu active Protection Beyond IP Right Term
- 1992-02-21 DK DK93200195T patent/DK0545912T3/da active
- 1992-02-21 PT PT92301449T patent/PT503785E/pt unknown
- 1992-02-21 DE DE2002199043 patent/DE10299043I2/de active Active
- 1992-02-21 EP EP93200195A patent/EP0545912B1/en not_active Expired - Lifetime
- 1992-02-21 RU RU95101430A patent/RU2128173C1/ru active
- 1992-02-21 IL IL114996A patent/IL114996A/xx not_active IP Right Cessation
- 1992-02-21 PT PT93200195T patent/PT545912E/pt unknown
- 1992-02-21 IL IL10103492A patent/IL101034A/en not_active IP Right Cessation
- 1992-02-21 DE DE69231798T patent/DE69231798T3/de not_active Expired - Lifetime
- 1992-02-21 EP EP92301449A patent/EP0503785B3/en not_active Expired - Lifetime
- 1992-02-21 NO NO19920688A patent/NO304516B3/no not_active IP Right Cessation
- 1992-02-21 DE DE200512000051 patent/DE122005000051I1/de active Pending
- 1992-02-21 NZ NZ241681A patent/NZ241681A/en not_active IP Right Cessation
- 1992-02-21 DE DE69231801T patent/DE69231801T2/de not_active Expired - Lifetime
- 1992-02-21 ES ES93200195T patent/ES2156866T3/es not_active Expired - Lifetime
- 1992-02-21 DE DE122011000011C patent/DE122011000011I1/de active Pending
- 1992-02-21 DK DK92301449T patent/DK0503785T3/da active
- 1992-02-21 CZ CS1992516A patent/CZ289194B6/cs not_active IP Right Cessation
- 1992-02-21 DE DE122009000024C patent/DE122009000024I1/de active Pending
- 1992-02-21 ES ES92301449T patent/ES2157895T7/es active Active
- 1992-02-21 KR KR1019920002676A patent/KR0128289B1/ko not_active IP Right Cessation
-
1994
- 1994-10-28 HU HU9601179A patent/HU223667B1/hu active IP Right Grant
-
1995
- 1995-06-29 HU HU95P/P00605P patent/HU211934A9/hu unknown
- 1995-08-18 IL IL11499695A patent/IL114996A0/xx unknown
- 1995-11-02 FI FI955248A patent/FI112941B/fi not_active IP Right Cessation
- 1995-11-09 NO NO954507A patent/NO304517B1/no not_active IP Right Cessation
-
1997
- 1997-12-24 CN CN97126347A patent/CN1121859C/zh not_active Expired - Lifetime
- 1997-12-24 CN CN97123452A patent/CN1101384C/zh not_active Expired - Lifetime
-
1998
- 1998-11-26 HK HK98112355A patent/HK1011361A1/xx not_active IP Right Cessation
- 1998-12-09 HK HK98113006A patent/HK1011969A1/xx not_active IP Right Cessation
-
2001
- 2001-05-22 GR GR20010400760T patent/GR3035906T3/el unknown
- 2001-05-22 GR GR20010400763T patent/GR3035909T3/el unknown
-
2003
- 2003-08-01 NL NL300133C patent/NL300133I2/nl unknown
- 2003-11-27 NO NO2003009C patent/NO2003009I2/no unknown
-
2004
- 2004-01-26 LU LU91056C patent/LU91056I2/fr unknown
-
2006
- 2006-03-30 NL NL300227C patent/NL300227I1/nl unknown
- 2006-10-09 NO NO2006012C patent/NO2006012I1/no unknown
-
2007
- 2007-04-02 LU LU91330C patent/LU91330I2/fr unknown
-
2009
- 2009-02-13 NL NL300375C patent/NL300375I1/nl unknown
- 2009-05-11 LU LU91571C patent/LU91571I2/fr unknown
- 2009-09-11 NO NO2009019C patent/NO2009019I1/no unknown
-
2011
- 2011-07-26 LU LU91847C patent/LU91847I2/fr unknown
- 2011-08-10 NO NO2011013C patent/NO2011013I1/no unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1121859C (zh) | 用于治疗或预防高血压症的药物组合物的制备方法 | |
US5646171A (en) | Angiotensin II antagonist 1-biphenylmethylimidazole compounds and their therapeutic use | |
CN1225463C (zh) | 具有钾通道阻断作用的芳基化呋喃和噻吩甲酰胺 | |
CN1037102C (zh) | 含硅的杀真菌化合物的制备方法 | |
CN1280570A (zh) | 有取代稠合杂环化合物 | |
CN1056140C (zh) | 联苯衍生物,它们的制备以及它们在治疗高血压和心脏病方面的应用 | |
CN1171394A (zh) | 新的脲衍生物及其制法和医药用途 | |
CN1149214C (zh) | 三唑并衍生物和含有它们作为有效组分的趋化因子抑制剂 | |
CN1079467A (zh) | 吡咯化合物及其生产方法和应用 | |
CN101031555A (zh) | 具有vap-1抑制活性的噻唑衍生物 | |
CN1354750A (zh) | 胺衍生物化合物 | |
CN1051766C (zh) | 血管紧张素ⅱ拮抗剂咪唑衍生物,它们的制备及其治疗用途 | |
CN1042907A (zh) | 除草剂组合物 | |
CN1037511C (zh) | 1-(芳烷基-氨烷基)咪唑化合物的制备方法 | |
CN1333755A (zh) | 为玻连蛋白受体拮抗剂的苯并咪唑化合物 | |
CN1158844A (zh) | 叔胺 | |
CN1091426A (zh) | 吲唑衍生物 | |
CN1285830A (zh) | 吡啶基吡咯衍生物 | |
CN1177829C (zh) | 取代磺酰基氨基氰、其制备方法及其作为药物的应用 | |
CN101065125A (zh) | 亚胺化合物 | |
CN1918127A (zh) | 具有引入了取代或无取代氨基的4-吡啶基烷硫基的新型环状化合物 | |
CN1049663A (zh) | 吡咯并喹啉类化合物 | |
CN1040434C (zh) | 杂二环化合物 | |
CZ289244B6 (cs) | 1-Bifenylmethylimidazolové deriváty, způsob výroby a farmaceutické prostředky s jejich obsahem | |
CN1036206A (zh) | 吡咯基甲基硅烷的制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C06 | Publication | ||
PB01 | Publication | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1014879 Country of ref document: HK |
|
EE01 | Entry into force of recordation of patent licensing contract |
Assignee: Shanghai Sankyo Pharmaceutical Co. Ltd. Assignor: Sankyo Co., Ltd. Contract fulfillment period: Contract performance period from January 10, 2006 to December 7, 2009 Contract record no.: Contract filing No. 061000030018 Denomination of invention: Method for the preparation of a pharmaceutical composition for the treatment or prevention of hypertension Granted publication date: 20030924 License type: Common License Record date: 20060314 |
|
LIC | Patent licence contract for exploitation submitted for record |
Free format text: COMMON LICENCE; TIME LIMIT OF IMPLEMENTING CONTACT: 2006.1.10 TO 2009.12.7 Name of requester: SHANGHAI SANKYO PHARMACEUTICAL CO., LTD. Effective date: 20060314 |
|
C56 | Change in the name or address of the patentee |
Owner name: FIRST SANKYO CO., LTD. Free format text: FORMER NAME OR ADDRESS: SANKYO CO., LTD. |
|
CP03 | Change of name, title or address |
Address after: Tokyo, Japan, Japan Patentee after: Sankyo Co. Address before: Tokyo, Japan, Japan Patentee before: Sankyo Co., Ltd. |
|
C17 | Cessation of patent right | ||
CX01 | Expiry of patent term |
Expiration termination date: 20120221 Granted publication date: 20030924 |