PT1776359E - Derivados de piperidina como inibidores da renina - Google Patents
Derivados de piperidina como inibidores da renina Download PDFInfo
- Publication number
- PT1776359E PT1776359E PT05761185T PT05761185T PT1776359E PT 1776359 E PT1776359 E PT 1776359E PT 05761185 T PT05761185 T PT 05761185T PT 05761185 T PT05761185 T PT 05761185T PT 1776359 E PT1776359 E PT 1776359E
- Authority
- PT
- Portugal
- Prior art keywords
- formula
- compound
- phenyl
- benzo
- oxazin
- Prior art date
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- 239000002461 renin inhibitor Substances 0.000 title description 7
- 229940086526 renin-inhibitors Drugs 0.000 title description 7
- 150000003053 piperidines Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 224
- 150000003839 salts Chemical class 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 206010019280 Heart failures Diseases 0.000 claims description 3
- 206010020772 Hypertension Diseases 0.000 claims description 3
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 2
- 208000010412 Glaucoma Diseases 0.000 claims description 2
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 2
- 201000006370 kidney failure Diseases 0.000 claims description 2
- 208000010125 myocardial infarction Diseases 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- -1 invert sugar Substances 0.000 description 157
- 239000000243 solution Substances 0.000 description 101
- 238000000034 method Methods 0.000 description 79
- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 76
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 68
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 66
- 239000000203 mixture Substances 0.000 description 60
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
- 239000011541 reaction mixture Substances 0.000 description 55
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- 238000003818 flash chromatography Methods 0.000 description 53
- 239000003921 oil Substances 0.000 description 48
- 235000019198 oils Nutrition 0.000 description 48
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 47
- 229910052938 sodium sulfate Inorganic materials 0.000 description 47
- 235000011152 sodium sulphate Nutrition 0.000 description 47
- 239000012074 organic phase Substances 0.000 description 46
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 38
- 229910052681 coesite Inorganic materials 0.000 description 37
- 229910052906 cristobalite Inorganic materials 0.000 description 37
- 229910052682 stishovite Inorganic materials 0.000 description 37
- 229910052905 tridymite Inorganic materials 0.000 description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- 239000012230 colorless oil Substances 0.000 description 36
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 35
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 238000001704 evaporation Methods 0.000 description 32
- 230000008020 evaporation Effects 0.000 description 32
- 239000012267 brine Substances 0.000 description 30
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 30
- 239000007858 starting material Substances 0.000 description 30
- 239000000377 silicon dioxide Substances 0.000 description 29
- 235000012239 silicon dioxide Nutrition 0.000 description 29
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- 229920006395 saturated elastomer Polymers 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 24
- 235000019439 ethyl acetate Nutrition 0.000 description 23
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 21
- 239000007787 solid Substances 0.000 description 19
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 18
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 17
- 235000017557 sodium bicarbonate Nutrition 0.000 description 17
- 238000010992 reflux Methods 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 13
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 12
- 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 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 239000011780 sodium chloride Substances 0.000 description 12
- 238000007429 general method Methods 0.000 description 11
- 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-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
- 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
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 6
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 108090000783 Renin Proteins 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-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
- 230000036772 blood pressure Effects 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- PWUCNIRAAUZWGV-UHFFFAOYSA-N 3-hydroxy-4-(4-methoxyphenyl)-5-[[4-(3-methoxypropyl)-2,3-dihydro-1,4-benzoxazin-6-yl]methoxy]piperidine-1-carboxylic acid Chemical compound C1=C2N(CCCOC)CCOC2=CC=C1COC1CN(C(O)=O)CC(O)C1C1=CC=C(OC)C=C1 PWUCNIRAAUZWGV-UHFFFAOYSA-N 0.000 description 5
- 102100028255 Renin Human genes 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
- 239000003112 inhibitor Substances 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
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-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
- 235000019502 Orange oil Nutrition 0.000 description 4
- 229950006323 angiotensin ii Drugs 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 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
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection 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
- 239000010502 orange oil Substances 0.000 description 4
- 229920005862 polyol Polymers 0.000 description 4
- 150000003077 polyols Chemical class 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
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical class C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 241000288906 Primates Species 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 239000012223 aqueous fraction Substances 0.000 description 3
- 239000007864 aqueous solution 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
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 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
- 239000008298 dragée 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
- 239000007903 gelatin capsule Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000007940 sugar coated tablet Substances 0.000 description 3
- 239000003826 tablet Substances 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
- DGKGLCQTCLFVFM-SSDOTTSWSA-N (3r)-3-(2,5-difluorophenoxy)butan-1-ol Chemical compound OCC[C@@H](C)OC1=CC(F)=CC=C1F DGKGLCQTCLFVFM-SSDOTTSWSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- BJLJWRKPOCAYPY-UHFFFAOYSA-N 1-(1-phenylethyl)-4-(4-phenylmethoxyphenyl)-5-tri(propan-2-yl)silyloxypiperidin-3-ol Chemical compound CC(C)[Si](C(C)C)(C(C)C)OC1CN(C(C)C=2C=CC=CC=2)CC(O)C1C(C=C1)=CC=C1OCC1=CC=CC=C1 BJLJWRKPOCAYPY-UHFFFAOYSA-N 0.000 description 2
- GRPVXZDDHARJSD-UHFFFAOYSA-N 1-(3-bromopropoxy)-2-chlorobenzene Chemical compound ClC1=CC=CC=C1OCCCBr GRPVXZDDHARJSD-UHFFFAOYSA-N 0.000 description 2
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 2
- CQMJEZQEVXQEJB-UHFFFAOYSA-N 1-hydroxy-1,3-dioxobenziodoxole Chemical compound C1=CC=C2I(O)(=O)OC(=O)C2=C1 CQMJEZQEVXQEJB-UHFFFAOYSA-N 0.000 description 2
- JKIPXZABCHFCTD-UHFFFAOYSA-N 1-prop-2-enoxyadamantane Chemical compound C1C(C2)CC3CC2CC1(OCC=C)C3 JKIPXZABCHFCTD-UHFFFAOYSA-N 0.000 description 2
- FJYVXYMRSUFESD-UHFFFAOYSA-N 2-(2,5-difluorophenoxy)ethanol Chemical compound OCCOC1=CC(F)=CC=C1F FJYVXYMRSUFESD-UHFFFAOYSA-N 0.000 description 2
- XVDMRLUZDUUXJV-UHFFFAOYSA-N 2-(3-bromopropoxy)-1,4-difluorobenzene Chemical compound FC1=CC=C(F)C(OCCCBr)=C1 XVDMRLUZDUUXJV-UHFFFAOYSA-N 0.000 description 2
- PJWBNHPIMROMAC-UHFFFAOYSA-N 2-[(2-chlorophenyl)methoxy]ethanol Chemical compound OCCOCC1=CC=CC=C1Cl PJWBNHPIMROMAC-UHFFFAOYSA-N 0.000 description 2
- QNTPWFDJZDQATN-UHFFFAOYSA-N 2-[(3-fluorophenyl)methoxy]ethanol Chemical compound OCCOCC1=CC=CC(F)=C1 QNTPWFDJZDQATN-UHFFFAOYSA-N 0.000 description 2
- HPBQZTVKXNNOSF-UHFFFAOYSA-N 2-[methyl-(4-methylphenyl)sulfonylamino]ethyl 4-methylbenzenesulfonate Chemical compound C=1C=C(C)C=CC=1S(=O)(=O)N(C)CCOS(=O)(=O)C1=CC=C(C)C=C1 HPBQZTVKXNNOSF-UHFFFAOYSA-N 0.000 description 2
- NCRMNHSZPLHRRW-UHFFFAOYSA-N 2-iodoethoxy-tri(propan-2-yl)silane Chemical compound CC(C)[Si](C(C)C)(C(C)C)OCCI NCRMNHSZPLHRRW-UHFFFAOYSA-N 0.000 description 2
- PPYVNZZBCCTEBD-UHFFFAOYSA-N 3-(2,5-difluorophenyl)propan-1-ol Chemical compound OCCCC1=CC(F)=CC=C1F PPYVNZZBCCTEBD-UHFFFAOYSA-N 0.000 description 2
- DURXQDAFKSWAES-UHFFFAOYSA-N 3-(2,5-difluorophenyl)propanoic acid Chemical compound OC(=O)CCC1=CC(F)=CC=C1F DURXQDAFKSWAES-UHFFFAOYSA-N 0.000 description 2
- YEYSOEFOGRDVJM-UHFFFAOYSA-N 3-[(2-fluorophenyl)methoxy]propan-1-ol Chemical compound OCCCOCC1=CC=CC=C1F YEYSOEFOGRDVJM-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
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- 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
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- 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
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- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Ophthalmology & Optometry (AREA)
- Hospice & Palliative Care (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Applications Claiming Priority (1)
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| CH11582004 | 2004-07-09 |
Publications (1)
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| PT1776359E true PT1776359E (pt) | 2011-12-15 |
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| ATE462703T1 (de) | 2004-08-25 | 2010-04-15 | Actelion Pharmaceuticals Ltd | Bicyclononen-derivate als renin-inhibitoren |
| GB0428526D0 (en) | 2004-12-30 | 2005-02-09 | Novartis Ag | Organic compounds |
| EP1707202A1 (de) * | 2005-03-31 | 2006-10-04 | Speedel Experimenta AG | Organische Verbindungen |
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| TW200722424A (en) | 2005-03-31 | 2007-06-16 | Speedel Experimenta Ag | Substituted piperidines |
| GB0508992D0 (en) * | 2005-05-03 | 2005-06-08 | Novartis Ag | Organic compounds |
| GB0510810D0 (en) * | 2005-05-26 | 2005-06-29 | Novartis Ag | Organic compounds |
| JP4297972B2 (ja) | 2005-05-27 | 2009-07-15 | アクテリオン ファーマシューティカルズ リミテッド | 新規なピペリジンカルボン酸アミド誘導体 |
| GB0514203D0 (en) | 2005-07-11 | 2005-08-17 | Novartis Ag | Organic compounds |
| AR058885A1 (es) | 2005-12-30 | 2008-02-27 | Novartis Ag | Compuestos de piperidina 3,5-sustituidos |
| TW200804359A (en) * | 2006-01-19 | 2008-01-16 | Speedel Experimenta Ag | Substituted 4-phenylpiperidines |
| EP1816122A3 (en) * | 2006-01-19 | 2007-09-19 | Speedel Experimenta AG | 3,4,5-substituted piperidines as therapeutic compounds |
| TW200821303A (en) * | 2006-08-08 | 2008-05-16 | Speedel Experimenta Ag | Organic compounds |
| EP1911758A1 (en) * | 2006-10-04 | 2008-04-16 | Speedel Experimenta AG | Phenyl piperidine derivatives for use as renin inhibitors |
| EP1908761A1 (en) * | 2006-10-04 | 2008-04-09 | Speedel Experimenta AG | Organic compounds |
| WO2008074450A2 (en) * | 2006-12-20 | 2008-06-26 | Nicox S.A. | Non-peptidic renin inhibitors nitroderivatives |
| TWI452044B (zh) | 2007-06-15 | 2014-09-11 | Mitsubishi Tanabe Pharma Corp | 嗎啉衍生物 |
| ES2541107T3 (es) | 2007-06-25 | 2015-07-16 | Novartis Ag | Derivados de N5-(2-etoxietil)-N3-(2-piridinil)-3,5-piperidindicarboxamida para su uso como inhibidores de renina |
| AR069005A1 (es) * | 2007-10-25 | 2009-12-23 | Speedel Experimenta Ag | Piperidinas 4,4-disustituidas |
| TW200932241A (en) | 2007-12-05 | 2009-08-01 | Speedel Experimenta Ag | Organic compounds |
| BRPI0907933A2 (pt) | 2008-02-08 | 2015-07-28 | Novartis Ag | Pepiridinas substituídas como inibidoras da renina |
| WO2009098275A1 (en) * | 2008-02-08 | 2009-08-13 | Novartis Ag | Substituted piperidines as renin inhibitors |
| WO2009106599A2 (en) * | 2008-02-29 | 2009-09-03 | Novartis Ag | Substituted piperidines as therapeutic compounds |
| WO2009127251A1 (en) * | 2008-04-16 | 2009-10-22 | Novartis Ag | Combinations comprising a renin inhibitor |
| PL2274295T3 (pl) * | 2008-05-05 | 2016-01-29 | Idorsia Pharmaceuticals Ltd | 3,4–podstawione pochodne piperydyny jako inhibitory reniny |
| AR072166A1 (es) | 2008-06-19 | 2010-08-11 | Takeda Pharmaceutical | Derivado de piperidina y su uso como inhibidor de renina superior |
| EP2163245A1 (en) | 2008-09-10 | 2010-03-17 | Novartis Ag | Renin inhibitors for the treatment of psoriasis |
| WO2010032856A1 (ja) | 2008-09-19 | 2010-03-25 | 武田薬品工業株式会社 | 含窒素複素環化合物およびその用途 |
| WO2010114978A1 (en) * | 2009-04-03 | 2010-10-07 | Merck Sharp & Dohme Corp. | Renin inhibitors |
| US8563035B2 (en) | 2010-05-05 | 2013-10-22 | Sanovel Ilac Sanayi Ve Ticaret Anomin Sirketi | Oral tablet compositions of dexlansoprazole |
| EP2384745A3 (en) * | 2010-05-05 | 2012-01-18 | Sanovel Ilac Sanayi ve Ticaret A.S. | Modified release pharmaceutical compositions of dexlansoprazole |
| EP2384746A3 (en) | 2010-05-05 | 2012-03-07 | Sanovel Ilac Sanayi ve Ticaret A.S. | Dual release oral tablet compositions of dexlansoprazole |
| EP4255909A1 (en) * | 2020-12-02 | 2023-10-11 | Qurient Co. Ltd. | Compounds having cyclin-dependent kinase(cdk)-inhibitory function |
| US20250214980A1 (en) | 2022-03-14 | 2025-07-03 | Slap Pharmaceuticals Llc | Multicyclic compounds |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2167865C2 (ru) * | 1995-09-07 | 2001-05-27 | Ф. Хоффманн-Ля Рош Аг | Производные пиперидина, способ их получения, фармацевтическая композиция на их основе и промежуточные вещества |
| US6197959B1 (en) * | 1999-04-27 | 2001-03-06 | Hoffmann-La Roche Inc. | Piperidine derivatives |
| US6376672B1 (en) * | 1999-04-27 | 2002-04-23 | Hoffmann-La Roche Inc. | Naphthalenylmethoxypiperidines as renin inhibitors |
| JP2004534017A (ja) * | 2001-04-27 | 2004-11-11 | バーテックス ファーマシューティカルズ インコーポレイテッド | Ｂａｃｅのインヒビター |
| US20040204455A1 (en) * | 2003-04-10 | 2004-10-14 | Cody Wayne Livingston | Piperidine derivative rennin inhibitors |
-
2005
- 2005-07-08 TW TW094123146A patent/TW200613274A/zh unknown
- 2005-07-08 AR ARP050102851A patent/AR053406A1/es not_active Application Discontinuation
- 2005-07-11 US US11/631,777 patent/US20080076766A1/en not_active Abandoned
- 2005-07-11 CA CA002570920A patent/CA2570920A1/en not_active Abandoned
- 2005-07-11 WO PCT/EP2005/053306 patent/WO2006005741A2/en not_active Ceased
- 2005-07-11 BR BRPI0513199-5A patent/BRPI0513199A/pt not_active IP Right Cessation
- 2005-07-11 JP JP2007519812A patent/JP4842262B2/ja not_active Expired - Fee Related
- 2005-07-11 AT AT05761185T patent/ATE521607T1/de active
- 2005-07-11 ES ES05761185T patent/ES2372502T3/es not_active Expired - Lifetime
- 2005-07-11 PL PL05761185T patent/PL1776359T3/pl unknown
- 2005-07-11 CN CNA2005800227495A patent/CN101014594A/zh active Pending
- 2005-07-11 PT PT05761185T patent/PT1776359E/pt unknown
- 2005-07-11 EP EP05761185A patent/EP1776359B1/en not_active Expired - Lifetime
-
2006
- 2006-12-21 IL IL180242A patent/IL180242A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL180242A0 (en) | 2007-07-04 |
| ATE521607T1 (de) | 2011-09-15 |
| CN101014594A (zh) | 2007-08-08 |
| US20080076766A1 (en) | 2008-03-27 |
| WO2006005741A3 (en) | 2006-07-06 |
| TW200613274A (en) | 2006-05-01 |
| EP1776359B1 (en) | 2011-08-24 |
| CA2570920A1 (en) | 2006-01-19 |
| EP1776359A2 (en) | 2007-04-25 |
| JP4842262B2 (ja) | 2011-12-21 |
| JP2008505871A (ja) | 2008-02-28 |
| HK1104037A1 (en) | 2008-01-04 |
| AR053406A1 (es) | 2007-05-09 |
| WO2006005741A2 (en) | 2006-01-19 |
| PL1776359T3 (pl) | 2012-01-31 |
| ES2372502T3 (es) | 2012-01-20 |
| BRPI0513199A (pt) | 2008-04-29 |
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