CH676988A5 - - Google Patents
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- Publication number
- CH676988A5 CH676988A5 CH157/88A CH15788A CH676988A5 CH 676988 A5 CH676988 A5 CH 676988A5 CH 157/88 A CH157/88 A CH 157/88A CH 15788 A CH15788 A CH 15788A CH 676988 A5 CH676988 A5 CH 676988A5
- Authority
- CH
- Switzerland
- Prior art keywords
- amido
- cyclohexyl
- boc
- norleucyl
- hydroxy
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims abstract description 141
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 20
- 206010019280 Heart failures Diseases 0.000 claims abstract description 8
- 206010020772 Hypertension Diseases 0.000 claims abstract description 7
- 108090000783 Renin Proteins 0.000 claims abstract description 4
- 102100028255 Renin Human genes 0.000 claims abstract description 4
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 4
- 125000002252 acyl group Chemical group 0.000 claims abstract 3
- -1 Bis (1-naphthylmethyl) acetyl Chemical group 0.000 claims description 281
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 claims description 76
- 238000000034 method Methods 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 27
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- IVXQBCUBSIPQGU-UHFFFAOYSA-N piperazine-1-carboxamide Chemical compound NC(=O)N1CCNCC1 IVXQBCUBSIPQGU-UHFFFAOYSA-N 0.000 claims description 12
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-butanol Substances CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 11
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- JSPCTNUQYWIIOT-UHFFFAOYSA-N piperidine-1-carboxamide Chemical compound NC(=O)N1CCCCC1 JSPCTNUQYWIIOT-UHFFFAOYSA-N 0.000 claims description 6
- 150000003254 radicals Chemical class 0.000 claims description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- VKLQCYWNMZXXJB-UHFFFAOYSA-N 2,2-diamino-5-cyclohexyl-3-hydroxy-N-propan-2-ylpentanamide Chemical compound NC(C(CCC1CCCCC1)O)(C(NC(C)C)=O)N VKLQCYWNMZXXJB-UHFFFAOYSA-N 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 claims description 3
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 claims description 3
- ZKWFSTHEYLJLEL-UHFFFAOYSA-N morpholine-4-carboxamide Chemical compound NC(=O)N1CCOCC1 ZKWFSTHEYLJLEL-UHFFFAOYSA-N 0.000 claims description 3
- LCDCPQHFCOBUEF-UHFFFAOYSA-N pyrrolidine-1-carboxamide Chemical compound NC(=O)N1CCCC1 LCDCPQHFCOBUEF-UHFFFAOYSA-N 0.000 claims description 3
- 239000002461 renin inhibitor Substances 0.000 claims description 3
- 229940086526 renin-inhibitors Drugs 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 16
- 125000004434 sulfur atom Chemical group 0.000 claims 16
- 229910052799 carbon Inorganic materials 0.000 claims 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 8
- 229910052760 oxygen Inorganic materials 0.000 claims 8
- 239000001301 oxygen Substances 0.000 claims 8
- 125000004430 oxygen atom Chemical group O* 0.000 claims 8
- 229910052717 sulfur Inorganic materials 0.000 claims 8
- 150000005840 aryl radicals Chemical class 0.000 claims 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 2
- 229910014033 C-OH Inorganic materials 0.000 claims 2
- 229910014570 C—OH Inorganic materials 0.000 claims 2
- YMXRITGINSETDO-UHFFFAOYSA-N N,N-dimethylheptane-2-sulfonamide Chemical compound CCCCCC(C)S(=O)(=O)N(C)C YMXRITGINSETDO-UHFFFAOYSA-N 0.000 claims 2
- 125000003282 alkyl amino group Chemical group 0.000 claims 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 2
- 125000003277 amino group Chemical group 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 239000003085 diluting agent Substances 0.000 claims 2
- 229910052736 halogen Inorganic materials 0.000 claims 2
- 125000005843 halogen group Chemical group 0.000 claims 2
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical group [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 125000000963 oxybis(methylene) group Chemical group [H]C([H])(*)OC([H])([H])* 0.000 claims 2
- 150000001413 amino acids Chemical class 0.000 abstract description 4
- 125000004423 acyloxy group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 174
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 102
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 82
- 239000000243 solution Substances 0.000 description 72
- 239000000543 intermediate Substances 0.000 description 67
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 65
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 63
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 51
- 239000000203 mixture Substances 0.000 description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 35
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- 239000000741 silica gel Substances 0.000 description 31
- 229910002027 silica gel Inorganic materials 0.000 description 31
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- 238000004587 chromatography analysis Methods 0.000 description 18
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 18
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 13
- 239000012043 crude product Substances 0.000 description 13
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- 239000007858 starting material Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 235000011152 sodium sulphate Nutrition 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 229960000583 acetic acid Drugs 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- WCFDSGHAIGTEKL-UHFFFAOYSA-N n,n-dimethylmethanesulfonamide Chemical compound CN(C)S(C)(=O)=O WCFDSGHAIGTEKL-UHFFFAOYSA-N 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- 239000013067 intermediate product Substances 0.000 description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 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 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000006260 foam Substances 0.000 description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-M oxalate(1-) Chemical compound OC(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-M 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 5
- 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 5
- 239000008346 aqueous phase Substances 0.000 description 5
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- 230000000694 effects Effects 0.000 description 5
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- 235000002906 tartaric acid Nutrition 0.000 description 5
- 239000011975 tartaric acid Substances 0.000 description 5
- CVXUYYULENWBTP-NSHDSACASA-N tert-butyl n-cyclohexyl-n-[(2s)-1-oxopropan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N([C@H](C=O)C)C1CCCCC1 CVXUYYULENWBTP-NSHDSACASA-N 0.000 description 5
- RDBGTZORXXSAAR-ZDUSSCGKSA-N (2S)-2-(3-cyclohexylpropanoylamino)hexanoic acid Chemical compound C1(CCCCC1)CCC(=O)N[C@@H](CCCC)C(=O)O RDBGTZORXXSAAR-ZDUSSCGKSA-N 0.000 description 4
- GSLTVFIVJMCNBH-UHFFFAOYSA-N 2-isocyanatopropane Chemical compound CC(C)N=C=O GSLTVFIVJMCNBH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 4
- FHHZOYXKOICLGH-UHFFFAOYSA-N dichloromethane;ethanol Chemical compound CCO.ClCCl FHHZOYXKOICLGH-UHFFFAOYSA-N 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 4
- 239000000155 melt Substances 0.000 description 4
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- HDNXGFGVFDEIJW-HOTGVXAUSA-N (2s)-3-(1h-imidazol-5-yl)-2-[[(2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoyl]amino]propanoic acid Chemical compound C([C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(O)=O)C1=CC=CC=C1 HDNXGFGVFDEIJW-HOTGVXAUSA-N 0.000 description 3
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 3
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- RMTCEQSLPGEKAH-UHFFFAOYSA-N 3-naphthalen-1-yl-2-(naphthalen-1-ylmethyl)propanoic acid Chemical compound C1=CC=C2C(CC(CC=3C4=CC=CC=C4C=CC=3)C(=O)O)=CC=CC2=C1 RMTCEQSLPGEKAH-UHFFFAOYSA-N 0.000 description 2
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- 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 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([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
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- RCCPEORTSYDPMB-UHFFFAOYSA-N hydroxy benzenecarboximidothioate Chemical compound OSC(=N)C1=CC=CC=C1 RCCPEORTSYDPMB-UHFFFAOYSA-N 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- TVZNFYXAPXOARC-LURJTMIESA-N methyl (2s)-2-aminohexanoate Chemical compound CCCC[C@H](N)C(=O)OC TVZNFYXAPXOARC-LURJTMIESA-N 0.000 description 1
- MXPYSKPNTBRJHD-UHFFFAOYSA-N n,n,2-trimethylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N(C)C MXPYSKPNTBRJHD-UHFFFAOYSA-N 0.000 description 1
- HNHVTXYLRVGMHD-UHFFFAOYSA-N n-butyl isocyanate Chemical compound CCCCN=C=O HNHVTXYLRVGMHD-UHFFFAOYSA-N 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000005245 sintering Methods 0.000 description 1
- 229960001922 sodium perborate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- NOHJNTNGGFOHFG-JKSUJKDBSA-N tert-butyl (2S,3R)-4,4-diamino-5-(butylamino)-2-(cyclohexylmethyl)-3-hydroxy-5-oxopentanoate Chemical compound C(=O)(OC(C)(C)C)[C@H]([C@H](C(C(NCCCC)=O)(N)N)O)CC1CCCCC1 NOHJNTNGGFOHFG-JKSUJKDBSA-N 0.000 description 1
- GEJXYTQIQZSRFZ-GJZGRUSLSA-N tert-butyl (2S,3S)-4,4-diamino-2-(cyclohexylmethyl)-3-hydroxy-5-oxo-5-(propan-2-ylamino)pentanoate Chemical compound C(=O)(OC(C)(C)C)[C@H]([C@@H](C(C(NC(C)C)=O)(N)N)O)CC1CCCCC1 GEJXYTQIQZSRFZ-GJZGRUSLSA-N 0.000 description 1
- NOHJNTNGGFOHFG-HOTGVXAUSA-N tert-butyl (2S,3S)-4,4-diamino-5-(butylamino)-2-(cyclohexylmethyl)-3-hydroxy-5-oxopentanoate Chemical compound C(=O)(OC(C)(C)C)[C@H]([C@@H](C(C(NCCCC)=O)(N)N)O)CC1CCCCC1 NOHJNTNGGFOHFG-HOTGVXAUSA-N 0.000 description 1
- FXTYBGBBXMIZEN-HOTGVXAUSA-N tert-butyl N-[(2S,3S)-1-cyclohexyl-5-(dimethylsulfamoyl)-3-hydroxypentan-2-yl]carbamate Chemical compound CN(S(=O)(=O)CC[C@@H]([C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)O)C FXTYBGBBXMIZEN-HOTGVXAUSA-N 0.000 description 1
- VGKAMZZIVKEOMD-UHFFFAOYSA-N tert-butyl N-[2-[2-(oxiran-2-yl)ethyl]cyclohexyl]carbamate Chemical compound C(C)(C)(C)OC(=O)NC1CCCCC1CCC1OC1 VGKAMZZIVKEOMD-UHFFFAOYSA-N 0.000 description 1
- AAJVCQPQGWUYMD-QMMMGPOBSA-N tert-butyl n-[(2s)-4-methylsulfanyl-1-oxobutan-2-yl]carbamate Chemical compound CSCC[C@@H](C=O)NC(=O)OC(C)(C)C AAJVCQPQGWUYMD-QMMMGPOBSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- VFJYIHQDILEQNR-UHFFFAOYSA-M trimethylsulfanium;iodide Chemical compound [I-].C[S+](C)C VFJYIHQDILEQNR-UHFFFAOYSA-M 0.000 description 1
- ORQXBVXKBGUSBA-QMMMGPOBSA-N β-cyclohexyl-alanine Chemical compound OC(=O)[C@@H](N)CC1CCCCC1 ORQXBVXKBGUSBA-QMMMGPOBSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
-
- 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
- C07D233/64—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 substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0227—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the (partial) peptide sequence -Phe-His-NH-(X)2-C(=0)-, e.g. Renin-inhibitors with n = 2 - 6; for n > 6 see C07K5/06 - C07K5/10
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Cardiology (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3701526 | 1987-01-21 | ||
| DE3707339 | 1987-03-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH676988A5 true CH676988A5 (fi) | 1991-03-28 |
Family
ID=25851692
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH157/88A CH676988A5 (fi) | 1987-01-21 | 1988-01-18 |
Country Status (13)
| Country | Link |
|---|---|
| JP (1) | JPS6419053A (fi) |
| KR (1) | KR880009041A (fi) |
| AU (1) | AU1037588A (fi) |
| BE (1) | BE1002212A5 (fi) |
| CH (1) | CH676988A5 (fi) |
| DK (1) | DK22588A (fi) |
| FR (1) | FR2609716A1 (fi) |
| GB (1) | GB2200115B (fi) |
| IL (1) | IL85136A0 (fi) |
| IT (1) | IT1219811B (fi) |
| MY (1) | MY102311A (fi) |
| NL (1) | NL8800100A (fi) |
| SE (1) | SE8800169L (fi) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002011714A2 (en) * | 2000-08-09 | 2002-02-14 | Magnesium Diagnostics, Inc. | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
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|---|---|---|---|---|
| US6878728B1 (en) | 1999-06-11 | 2005-04-12 | Vertex Pharmaceutical Incorporated | Inhibitors of aspartyl protease |
| US20040122000A1 (en) | 1981-01-07 | 2004-06-24 | Vertex Pharmaceuticals Incorporated. | Inhibitors of aspartyl protease |
| DE3732971A1 (de) * | 1987-09-30 | 1989-04-20 | Hoechst Ag | Renin-hemmende dipeptide, verfahren zu deren herstellung, diese enthaltende mittel und ihre verwendung |
| DE3733296A1 (de) * | 1987-10-02 | 1989-04-20 | Merck Patent Gmbh | Aminosaeurederivate |
| EP0329295A1 (en) * | 1988-02-01 | 1989-08-23 | The Upjohn Company | Renin inhibiting peptides with polar end groups |
| JP2524814B2 (ja) * | 1988-08-25 | 1996-08-14 | キッセイ薬品工業株式会社 | α―ヒドロキシ―β―アミノ酸の製造方法 |
| CA2010531A1 (en) * | 1989-03-06 | 1990-09-06 | Werner Neidhart | Amino acid derivatives |
| US5185284A (en) * | 1989-05-22 | 1993-02-09 | Mitsubishi Denki Kabushiki Kaisha | Method of making a semiconductor memory device |
| US5098924A (en) * | 1989-09-15 | 1992-03-24 | E. R. Squibb & Sons, Inc. | Diol sulfonamide and sulfinyl renin inhibitors |
| TW225540B (fi) * | 1990-06-28 | 1994-06-21 | Shionogi & Co | |
| US5614522A (en) * | 1990-11-19 | 1997-03-25 | G.D. Searle & Co. | Retroviral protease inhibitors |
| JPH06502859A (ja) * | 1990-11-19 | 1994-03-31 | モンサント カンパニー | レトロウイルスプロテアーゼ阻害剤 |
| ES2059295T3 (es) * | 1990-11-19 | 1998-06-01 | Monsanto Co | Inhibidores de las proteasas retrovirales. |
| US5475013A (en) * | 1990-11-19 | 1995-12-12 | Monsanto Company | Retroviral protease inhibitors |
| US5510378A (en) * | 1990-11-19 | 1996-04-23 | G.D. Searle & Co. | Retroviral protease inhibitors |
| US5482947A (en) * | 1990-11-19 | 1996-01-09 | Talley; John J. | Retroviral protease inhibitors |
| US5475027A (en) * | 1990-11-19 | 1995-12-12 | G.D. Searle & Co. | Retroviral protease inhibitors |
| ATE196759T1 (de) | 1990-11-19 | 2000-10-15 | Monsanto Co | Inhibitoren retroviraler proteasen |
| AU4253193A (en) * | 1992-05-20 | 1993-12-13 | G.D. Searle & Co. | Urea-containing hydroxyethylamine compounds as retroviral protease inhibitors |
| EP0641325B1 (en) | 1992-05-21 | 2001-03-07 | Monsanto Company | Retroviral protease inhibitors |
| US7141609B2 (en) | 1992-08-25 | 2006-11-28 | G.D. Searle & Co. | α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
| AU669223B2 (en) * | 1992-08-25 | 1996-05-30 | G.D. Searle & Co. | Sulfonylalkanoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
| ATE154800T1 (de) * | 1992-08-25 | 1997-07-15 | Searle & Co | N-(alkanoylamino-2-hydroxypropyl)-sulfonamide verwendbar als retrovirale proteaseninhibitoren |
| US6046190A (en) * | 1992-08-25 | 2000-04-04 | G.D. Searle & Co. | Hydroxyethylamino sulphonamides useful as retroviral protease inhibitors |
| US6743929B1 (en) | 1992-08-25 | 2004-06-01 | G. D. Searle & Co. | Sulfonylalkanoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
| KR100296463B1 (ko) | 1992-08-25 | 2001-10-24 | 죤 에이치. 뷰센 | 레트로바이러스프로테아제저해제로서유용한히드록시에틸아미노술폰아미드 |
| US5968942A (en) | 1992-08-25 | 1999-10-19 | G. D. Searle & Co. | α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
| US6022994A (en) * | 1992-08-25 | 2000-02-08 | G. D. Searle &. Co. | Succinoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
| US5830897A (en) * | 1992-08-27 | 1998-11-03 | G. D. Searle & Co. | α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
| US5723490A (en) * | 1992-09-08 | 1998-03-03 | Vertex Pharmaceuticals Incorporated | THF-containing sulfonamide inhibitors of aspartyl protease |
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| IS2334B (is) * | 1992-09-08 | 2008-02-15 | Vertex Pharmaceuticals Inc., (A Massachusetts Corporation) | Aspartyl próteasi hemjari af nýjum flokki súlfonamíða |
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| JPH11324710A (ja) | 1998-05-20 | 1999-11-26 | Hitachi Ltd | ガスタービン発電プラント |
| BR9912169A (pt) | 1998-06-19 | 2001-04-10 | Vertex Pharma | Inibidores de sulfonamida de protease de aspartil |
| US6538006B1 (en) | 1998-07-08 | 2003-03-25 | Pharmacia Corporation | Retroviral protease inhibitors |
| JP3888095B2 (ja) | 2001-07-26 | 2007-02-28 | 株式会社日立製作所 | ガスタービン設備 |
| US7251926B2 (en) | 2001-07-26 | 2007-08-07 | Hitachi, Ltd. | Gas turbine installation |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1245217A (en) * | 1981-12-10 | 1988-11-22 | Joshua S. Boger | Renin inhibitory peptides having phe su13 xx deletion |
| JPS60163899A (ja) * | 1984-02-03 | 1985-08-26 | Sankyo Co Ltd | レニン阻害ペプチド類 |
| EP0163237A3 (en) * | 1984-05-29 | 1988-04-27 | Merck & Co. Inc. | Di- and tri-peptidal renin inhibitors |
| US4645759A (en) * | 1984-06-22 | 1987-02-24 | Abbott Laboratories | Renin inhibiting compounds |
| DK356085A (da) * | 1984-08-06 | 1986-02-07 | Upjohn Co | Reninhaemmende peptid eller et farmaceutisk acceptabelt syreadditionssalt deraf |
| US4727060A (en) * | 1984-11-13 | 1988-02-23 | Ciba-Geigy Corporation | Novel 5-amino-4-hydroxyvaleryl derivatives |
| EP0184855A3 (en) * | 1984-12-14 | 1989-05-03 | Abbott Laboratories | Resin inhibiting compounds |
| KR870005013A (ko) * | 1985-11-29 | 1987-06-04 | 가와무라 요시부미 | 레닌-억제 올리고펩티드, 그의 제조방법 및 용도 |
| DE3601248A1 (de) * | 1986-01-17 | 1987-07-23 | Hoechst Ag | Substituierte 4-amino-3-hydroxybuttersaeure-derivate, verfahren zu deren herstellung, diese enthaltende mittel und ihre verwendung |
-
1988
- 1988-01-18 GB GB8801040A patent/GB2200115B/en not_active Expired - Lifetime
- 1988-01-18 NL NL8800100A patent/NL8800100A/nl not_active Application Discontinuation
- 1988-01-18 CH CH157/88A patent/CH676988A5/de not_active IP Right Cessation
- 1988-01-19 IL IL85136A patent/IL85136A0/xx unknown
- 1988-01-19 BE BE8800067A patent/BE1002212A5/fr not_active IP Right Cessation
- 1988-01-19 AU AU10375/88A patent/AU1037588A/en not_active Abandoned
- 1988-01-19 FR FR8800636A patent/FR2609716A1/fr not_active Withdrawn
- 1988-01-19 MY MYPI88000039A patent/MY102311A/en unknown
- 1988-01-19 DK DK022588A patent/DK22588A/da not_active Application Discontinuation
- 1988-01-20 JP JP63010571A patent/JPS6419053A/ja active Pending
- 1988-01-20 SE SE8800169A patent/SE8800169L/xx not_active Application Discontinuation
- 1988-01-20 KR KR1019880000498A patent/KR880009041A/ko not_active Application Discontinuation
- 1988-01-21 IT IT47556/88A patent/IT1219811B/it active
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002011714A2 (en) * | 2000-08-09 | 2002-02-14 | Magnesium Diagnostics, Inc. | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
| WO2002011714A3 (en) * | 2000-08-09 | 2003-08-14 | Magnesium Diagnostics Inc | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
| US6664420B2 (en) | 2000-08-09 | 2003-12-16 | Magnesium Diagnostics, Inc. | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
| US6855826B2 (en) | 2000-08-09 | 2005-02-15 | Magnesium Diagnostics, Inc. | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
| US7041829B2 (en) | 2000-08-09 | 2006-05-09 | Magnesium Diagnostics, Inc. | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
| US7132537B2 (en) | 2000-08-09 | 2006-11-07 | Magnesium Diagnostics, Inc. | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
| US7211667B2 (en) | 2000-08-09 | 2007-05-01 | Magnesium Diagnostics, Inc. | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
| US7405311B2 (en) | 2000-08-09 | 2008-07-29 | Magnesium Diagnostics, Inc. | Antagonist of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
| US7619097B2 (en) | 2000-08-09 | 2009-11-17 | Magnesium Diagnostics, Inc. | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
| US7795450B2 (en) | 2000-08-09 | 2010-09-14 | Magnesium Diagnostics, Inc. | Antagonist of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
| US7982048B2 (en) | 2000-08-09 | 2011-07-19 | Magnesium Diagnostics, Inc. | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
| US8129545B2 (en) | 2000-08-09 | 2012-03-06 | Magnesium Diagnostics, Inc. | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2609716A1 (fr) | 1988-07-22 |
| DK22588D0 (da) | 1988-01-19 |
| SE8800169D0 (sv) | 1988-01-20 |
| GB2200115A (en) | 1988-07-27 |
| GB2200115B (en) | 1990-11-14 |
| DK22588A (da) | 1988-07-22 |
| IL85136A0 (en) | 1988-06-30 |
| AU1037588A (en) | 1988-09-01 |
| BE1002212A5 (fr) | 1990-10-16 |
| KR880009041A (ko) | 1988-09-13 |
| JPS6419053A (en) | 1989-01-23 |
| MY102311A (en) | 1992-05-28 |
| IT1219811B (it) | 1990-05-24 |
| NL8800100A (nl) | 1988-08-16 |
| SE8800169L (sv) | 1988-07-22 |
| GB8801040D0 (en) | 1988-02-17 |
| IT8847556A0 (it) | 1988-01-21 |
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| PL | Patent ceased | ||
| PL | Patent ceased |