CA2570920A1 - Piperidine derivatives as renin inhibitors - Google Patents

Info

Publication number

CA2570920A1

CA2570920A1 CA002570920A CA2570920A CA2570920A1 CA 2570920 A1 CA2570920 A1 CA 2570920A1 CA 002570920 A CA002570920 A CA 002570920A CA 2570920 A CA2570920 A CA 2570920A CA 2570920 A1 CA2570920 A1 CA 2570920A1

Authority

CA

Canada

Prior art keywords

alkoxy

alkyl

6alkoxy

6alkyl

hydroxy

Prior art date

2004-07-09

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.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 239000002461 renin inhibitor Substances 0.000 title abstract description 7
• 229940086526 renin-inhibitors Drugs 0.000 title abstract description 6
• 150000003053 piperidines Chemical class 0.000 title abstract description 5
• 150000001875 compounds Chemical class 0.000 claims abstract description 171
• 238000000034 method Methods 0.000 claims abstract description 80
• 238000002360 preparation method Methods 0.000 claims abstract description 7
• 239000003814 drug Substances 0.000 claims abstract description 6
• -1 3-acetamidomethylpyrrolidinyl Chemical group 0.000 claims description 269
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 62
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 36
• 229910052739 hydrogen Inorganic materials 0.000 claims description 32
• 239000001257 hydrogen Substances 0.000 claims description 31
• 229910052736 halogen Inorganic materials 0.000 claims description 22
• 150000002367 halogens Chemical class 0.000 claims description 22
• 150000003839 salts Chemical class 0.000 claims description 20
• 229920006395 saturated elastomer Polymers 0.000 claims description 20
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
• 125000003118 aryl group Chemical group 0.000 claims description 17
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
• 125000004076 pyridyl group Chemical group 0.000 claims description 15
• 229910052760 oxygen Inorganic materials 0.000 claims description 13
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
• 125000004432 carbon atom Chemical group C* 0.000 claims description 12
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
• 239000001301 oxygen Substances 0.000 claims description 11
• 239000005864 Sulphur Substances 0.000 claims description 10
• 125000002252 acyl group Chemical group 0.000 claims description 10
• 125000000623 heterocyclic group Chemical group 0.000 claims description 10
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 10
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 9
• 229910052799 carbon Inorganic materials 0.000 claims description 8
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 8
• 125000002757 morpholinyl group Chemical group 0.000 claims description 8
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
• 125000001424 substituent group Chemical group 0.000 claims description 8
• 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 claims description 8
• 125000001624 naphthyl group Chemical group 0.000 claims description 7
• 125000003386 piperidinyl group Chemical group 0.000 claims description 7
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
• 125000002971 oxazolyl group Chemical group 0.000 claims description 6
• 125000005476 oxopyrrolidinyl group Chemical group 0.000 claims description 6
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
• 125000004193 piperazinyl group Chemical group 0.000 claims description 6
• 229940002612 prodrug Drugs 0.000 claims description 6
• 239000000651 prodrug Substances 0.000 claims description 6
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 6
• 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 6
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
• 230000009471 action Effects 0.000 claims description 5
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
• 125000002541 furyl group Chemical group 0.000 claims description 5
• 125000002883 imidazolyl group Chemical group 0.000 claims description 5
• 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 5
• 125000001041 indolyl group Chemical group 0.000 claims description 5
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 5
• 125000001544 thienyl group Chemical group 0.000 claims description 5
• 206010019280 Heart failures Diseases 0.000 claims description 4
• 206010020772 Hypertension Diseases 0.000 claims description 4
• 125000004104 aryloxy group Chemical group 0.000 claims description 4
• 125000005605 benzo group Chemical group 0.000 claims description 4
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
• 125000000532 dioxanyl group Chemical group 0.000 claims description 4
• 125000005879 dioxolanyl group Chemical group 0.000 claims description 4
• 125000005883 dithianyl group Chemical group 0.000 claims description 4
• 125000005411 dithiolanyl group Chemical group S1SC(CC1)* 0.000 claims description 4
• 125000005842 heteroatom Chemical group 0.000 claims description 4
• 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 4
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
• 125000004434 sulfur atom Chemical group 0.000 claims description 4
• 125000001425 triazolyl group Chemical group 0.000 claims description 4
• 125000006625 (C3-C8) cycloalkyloxy group Chemical class 0.000 claims description 3
• 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 3
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 3
• 208000010412 Glaucoma Diseases 0.000 claims description 3
• 208000001647 Renal Insufficiency Diseases 0.000 claims description 3
• 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
• 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 claims description 3
• 230000002526 effect on cardiovascular system Effects 0.000 claims description 3
• 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 3
• 201000006370 kidney failure Diseases 0.000 claims description 3
• 208000010125 myocardial infarction Diseases 0.000 claims description 3
• 229910052757 nitrogen Inorganic materials 0.000 claims description 3
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
• 230000002265 prevention Effects 0.000 claims description 3
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
• 125000000335 thiazolyl group Chemical group 0.000 claims description 3
• 125000004306 triazinyl group Chemical group 0.000 claims description 3
• 125000006590 (C2-C6) alkenylene group Chemical group 0.000 claims description 2
• 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 2
• 125000002152 1H-pyrrolizinyl group Chemical group C1(C=CN2C=CC=C12)* 0.000 claims description 2
• 239000004480 active ingredient Substances 0.000 claims description 2
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
• 125000004429 atom Chemical group 0.000 claims description 2
• 125000005331 diazinyl group Chemical group N1=NC(=CC=C1)* 0.000 claims description 2
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 2
• 230000002285 radioactive effect Effects 0.000 claims description 2
• 150000002431 hydrogen Chemical group 0.000 claims 11
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 9
• 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims 6
• 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims 4
• 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims 2
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 2
• 125000006621 (C3-C8) cycloalkyl-(C1-C6) alkyl group Chemical group 0.000 claims 2
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 1
• 239000002552 dosage form Substances 0.000 claims 1
• 239000000825 pharmaceutical preparation Substances 0.000 claims 1
• 230000008569 process Effects 0.000 abstract description 7
• 229940079593 drug Drugs 0.000 abstract description 4
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 91
• 239000000243 solution Substances 0.000 description 91
• DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 74
• 239000003921 oil Substances 0.000 description 71
• 235000019198 oils Nutrition 0.000 description 71
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 70
• 239000000203 mixture Substances 0.000 description 60
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 58
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
• 239000011541 reaction mixture Substances 0.000 description 54
• 238000003818 flash chromatography Methods 0.000 description 53
• 229910052681 coesite Inorganic materials 0.000 description 50
• 229910052906 cristobalite Inorganic materials 0.000 description 50
• 229910052682 stishovite Inorganic materials 0.000 description 50
• 229910052905 tridymite Inorganic materials 0.000 description 50
• 229910052938 sodium sulfate Inorganic materials 0.000 description 46
• 235000011152 sodium sulphate Nutrition 0.000 description 46
• 239000012267 brine Substances 0.000 description 42
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 42
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 41
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 38
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 35
• 238000001704 evaporation Methods 0.000 description 32
• 230000008020 evaporation Effects 0.000 description 32
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
• 239000012074 organic phase Substances 0.000 description 29
• 239000007858 starting material Substances 0.000 description 28
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 27
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 26
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 25
• 235000019439 ethyl acetate Nutrition 0.000 description 25
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
• 229910021529 ammonia Inorganic materials 0.000 description 19
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 17
• 235000017557 sodium bicarbonate Nutrition 0.000 description 17
• 239000007787 solid Substances 0.000 description 17
• 239000012230 colorless oil Substances 0.000 description 16
• 238000010992 reflux Methods 0.000 description 16
• 238000006243 chemical reaction Methods 0.000 description 15
• 150000003254 radicals Chemical class 0.000 description 13
• ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 12
• 150000002148 esters Chemical class 0.000 description 12
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
• 238000007429 general method Methods 0.000 description 11
• 239000000126 substance Substances 0.000 description 10
• 239000000725 suspension Substances 0.000 description 10
• IQOIMKMZQVCXMK-UHFFFAOYSA-N 6-(chloromethyl)-4-(3-methoxypropyl)-1,4-benzoxazin-3-one Chemical compound C1=C(CCl)C=C2N(CCCOC)C(=O)COC2=C1 IQOIMKMZQVCXMK-UHFFFAOYSA-N 0.000 description 9
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
• LFWGXIVKBPLQMD-UHFFFAOYSA-N benzyl 3-hydroxy-4-(4-hydroxyphenyl)-5-tri(propan-2-yl)silyloxypiperidine-1-carboxylate Chemical compound CC(C)[Si](C(C)C)(C(C)C)OC1CN(C(=O)OCC=2C=CC=CC=2)CC(O)C1C1=CC=C(O)C=C1 LFWGXIVKBPLQMD-UHFFFAOYSA-N 0.000 description 9
• OKOSFIZVPAFSGF-UHFFFAOYSA-N benzyl 3-hydroxy-4-(4-methoxyphenyl)-5-[[4-(3-methoxypropyl)-2,3-dihydro-1,4-benzoxazin-6-yl]methoxy]piperidine-1-carboxylate Chemical compound C1=C2N(CCCOC)CCOC2=CC=C1COC1CN(C(=O)OCC=2C=CC=CC=2)CC(O)C1C1=CC=C(OC)C=C1 OKOSFIZVPAFSGF-UHFFFAOYSA-N 0.000 description 9
• 239000010410 layer Substances 0.000 description 9
• 239000012312 sodium hydride Substances 0.000 description 9
• 229910000104 sodium hydride Inorganic materials 0.000 description 9
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
• 238000012360 testing method Methods 0.000 description 8
• 239000001993 wax Substances 0.000 description 8
• 101800000734 Angiotensin-1 Proteins 0.000 description 7
• 102400000344 Angiotensin-1 Human genes 0.000 description 7
• 235000019502 Orange oil Nutrition 0.000 description 7
• 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 7
• 230000015572 biosynthetic process Effects 0.000 description 7
• 239000010502 orange oil Substances 0.000 description 7
• HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 6
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
• LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
• 239000003112 inhibitor Substances 0.000 description 6
• 229910000027 potassium carbonate Inorganic materials 0.000 description 6
• 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 6
• 239000000377 silicon dioxide Substances 0.000 description 6
• 235000012239 silicon dioxide Nutrition 0.000 description 6
• GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 5
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
• 108090000783 Renin Proteins 0.000 description 5
• 230000036772 blood pressure Effects 0.000 description 5
• 239000000706 filtrate Substances 0.000 description 5
• 239000006260 foam Substances 0.000 description 5
• 238000004128 high performance liquid chromatography Methods 0.000 description 5
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
• LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 4
• INXKVYFOWNAVMU-UHFFFAOYSA-N 2,5-difluorophenol Chemical compound OC1=CC(F)=CC=C1F INXKVYFOWNAVMU-UHFFFAOYSA-N 0.000 description 4
• YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
• 102000005862 Angiotensin II Human genes 0.000 description 4
• 101800000733 Angiotensin-2 Proteins 0.000 description 4
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
• 101000579218 Homo sapiens Renin Proteins 0.000 description 4
• CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 4
• 102100028255 Renin Human genes 0.000 description 4
• 238000005804 alkylation reaction Methods 0.000 description 4
• 229950006323 angiotensin ii Drugs 0.000 description 4
• ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 4
• 239000007903 gelatin capsule Substances 0.000 description 4
• 238000002347 injection Methods 0.000 description 4
• 239000007924 injection Substances 0.000 description 4
• 239000007788 liquid Substances 0.000 description 4
• PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 4
• 229920005862 polyol Polymers 0.000 description 4
• 150000003077 polyols Chemical class 0.000 description 4
• 230000009467 reduction Effects 0.000 description 4
• 238000000926 separation method Methods 0.000 description 4
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
• 238000004809 thin layer chromatography Methods 0.000 description 4
• OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
• WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 3
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
• 125000003545 alkoxy group Chemical group 0.000 description 3
• 230000029936 alkylation Effects 0.000 description 3
• 239000008346 aqueous phase Substances 0.000 description 3
• 229910052786 argon Inorganic materials 0.000 description 3
• HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 3
• 125000003178 carboxy group Chemical group [H]OC(*)=O 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
• 238000003776 cleavage reaction Methods 0.000 description 3
• WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 3
• 239000006185 dispersion Substances 0.000 description 3
• 239000007941 film coated tablet Substances 0.000 description 3
• 238000001914 filtration Methods 0.000 description 3
• 229960003883 furosemide Drugs 0.000 description 3
• 238000000338 in vitro Methods 0.000 description 3
• 238000001727 in vivo Methods 0.000 description 3
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
• 125000004524 naphthpyridyl group Chemical group C1(=CC=NC2=C1C1=CC=CC=C1C=C2)* 0.000 description 3
• 239000008194 pharmaceutical composition Substances 0.000 description 3
• 239000012071 phase Substances 0.000 description 3
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