CA1297631C - Ureido renin inhibitors - Google Patents
Ureido renin inhibitorsInfo
- Publication number
- CA1297631C CA1297631C CA000523367A CA523367A CA1297631C CA 1297631 C CA1297631 C CA 1297631C CA 000523367 A CA000523367 A CA 000523367A CA 523367 A CA523367 A CA 523367A CA 1297631 C CA1297631 C CA 1297631C
- Authority
- CA
- Canada
- Prior art keywords
- amino
- carbonyl
- hydroxy
- compound
- methyl ester
- 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
- 239000002461 renin inhibitor Substances 0.000 title abstract description 3
- 229940086526 renin-inhibitors Drugs 0.000 title abstract description 3
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 title description 2
- -1 UREIDO Chemical class 0.000 claims abstract description 141
- 150000001875 compounds Chemical class 0.000 claims abstract description 50
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 152
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 136
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 121
- 239000000203 mixture Substances 0.000 claims description 51
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 239000001257 hydrogen Substances 0.000 claims description 35
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 24
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 15
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 7
- 206010020772 Hypertension Diseases 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 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 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- 125000002619 bicyclic group Chemical group 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 9
- 108090000783 Renin Proteins 0.000 abstract description 7
- 102100028255 Renin Human genes 0.000 abstract description 6
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 102000004881 Angiotensinogen Human genes 0.000 abstract description 4
- 108090001067 Angiotensinogen Proteins 0.000 abstract description 4
- 102000005862 Angiotensin II Human genes 0.000 abstract description 3
- 101800000733 Angiotensin-2 Proteins 0.000 abstract description 3
- 229950006323 angiotensin ii Drugs 0.000 abstract description 3
- 229940030600 antihypertensive agent Drugs 0.000 abstract description 3
- 239000002220 antihypertensive agent Substances 0.000 abstract description 3
- 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 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 255
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 189
- 239000000243 solution Substances 0.000 description 135
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 72
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 66
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 57
- 239000000047 product Substances 0.000 description 55
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 43
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 41
- 239000000741 silica gel Substances 0.000 description 40
- 229910002027 silica gel Inorganic materials 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 34
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 33
- 229960000443 hydrochloric acid Drugs 0.000 description 31
- 235000011167 hydrochloric acid Nutrition 0.000 description 31
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 30
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 30
- 229910001868 water Inorganic materials 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- 238000003756 stirring Methods 0.000 description 28
- 239000002904 solvent Substances 0.000 description 22
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 150000002148 esters Chemical class 0.000 description 20
- 229960002885 histidine Drugs 0.000 description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 18
- 239000003054 catalyst Substances 0.000 description 18
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 16
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 15
- 150000004702 methyl esters Chemical class 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 12
- 239000002024 ethyl acetate extract Substances 0.000 description 11
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 229960000310 isoleucine Drugs 0.000 description 10
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 10
- 229960004295 valine Drugs 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- YXMMTUJDQTVJEN-WDSKDSINSA-N methyl (2s,3s)-2-amino-3-methylpentanoate Chemical compound CC[C@H](C)[C@H](N)C(=O)OC YXMMTUJDQTVJEN-WDSKDSINSA-N 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 229960001407 sodium bicarbonate Drugs 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 8
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 8
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- BXRMEWOQUXOLDH-LURJTMIESA-N L-Histidine methyl ester Chemical compound COC(=O)[C@@H](N)CC1=CN=CN1 BXRMEWOQUXOLDH-LURJTMIESA-N 0.000 description 6
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 229940024606 amino acid Drugs 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 150000002431 hydrogen Chemical group 0.000 description 5
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- 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 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 4
- JTNCEQNHURODLX-UHFFFAOYSA-N 2-phenylethanimidamide Chemical compound NC(=N)CC1=CC=CC=C1 JTNCEQNHURODLX-UHFFFAOYSA-N 0.000 description 4
- 101800000734 Angiotensin-1 Proteins 0.000 description 4
- 102400000344 Angiotensin-1 Human genes 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 4
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 4
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 4
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 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 4
- 238000001816 cooling Methods 0.000 description 4
- 239000008120 corn starch Substances 0.000 description 4
- 229940099112 cornstarch Drugs 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000002934 diuretic Substances 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 229960004592 isopropanol Drugs 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 235000009518 sodium iodide Nutrition 0.000 description 4
- 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 3
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 3
- KTOQRRDVVIDEAA-UHFFFAOYSA-N 2-methylpropane Chemical group [CH2]C(C)C KTOQRRDVVIDEAA-UHFFFAOYSA-N 0.000 description 3
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 3
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 3
- 229930182844 L-isoleucine Natural products 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DWAYENIPKPKKMV-ILKKLZGPSA-N [(2s)-3-(1h-imidazol-3-ium-4-yl)-1-methoxy-1-oxopropan-2-yl]azanium;dichloride Chemical compound Cl.Cl.COC(=O)[C@@H](N)CC1=CN=CN1 DWAYENIPKPKKMV-ILKKLZGPSA-N 0.000 description 3
- DEJWJZIWIHTBES-LURJTMIESA-N [(3s)-1-chloro-5-methyl-2-oxohexan-3-yl]carbamic acid Chemical compound CC(C)C[C@H](NC(O)=O)C(=O)CCl DEJWJZIWIHTBES-LURJTMIESA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 125000000266 alpha-aminoacyl group Chemical group 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 230000001882 diuretic effect Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229960002003 hydrochlorothiazide Drugs 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 229940086542 triethylamine Drugs 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 102000015427 Angiotensins Human genes 0.000 description 2
- 108010064733 Angiotensins Proteins 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000009491 slugging Methods 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940032330 sulfuric acid Drugs 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000003451 thiazide diuretic agent Substances 0.000 description 1
- AGHANLSBXUWXTB-UHFFFAOYSA-N tienilic acid Chemical compound ClC1=C(Cl)C(OCC(=O)O)=CC=C1C(=O)C1=CC=CS1 AGHANLSBXUWXTB-UHFFFAOYSA-N 0.000 description 1
- 229960000356 tienilic acid Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229960001288 triamterene Drugs 0.000 description 1
- 229960004813 trichlormethiazide Drugs 0.000 description 1
- LMJSLTNSBFUCMU-UHFFFAOYSA-N trichlormethiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(C(Cl)Cl)NS2(=O)=O LMJSLTNSBFUCMU-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 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 1
- 239000008215 water for injection Substances 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
- C07K5/02—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
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
- C07C275/06—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
- C07C275/14—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
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)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Indole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US81256185A | 1985-12-23 | 1985-12-23 | |
| US812,561 | 1991-12-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1297631C true CA1297631C (en) | 1992-03-17 |
Family
ID=25209973
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000523367A Expired - Lifetime CA1297631C (en) | 1985-12-23 | 1986-11-19 | Ureido renin inhibitors |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JPS62164658A (de) |
| CA (1) | CA1297631C (de) |
| DE (1) | DE3643977A1 (de) |
| FR (1) | FR2592048B1 (de) |
| GB (1) | GB2184730B (de) |
| IT (1) | IT1213574B (de) |
Families Citing this family (57)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4599198A (en) * | 1985-08-02 | 1986-07-08 | Pfizer Inc. | Intermediates in polypeptide synthesis |
| US5049548A (en) * | 1989-03-03 | 1991-09-17 | Merck & Co., Inc. | Renin-inhibitory di-, tri-, and tetrapeptides |
| US5510378A (en) * | 1990-11-19 | 1996-04-23 | G.D. Searle & Co. | Retroviral protease inhibitors |
| EP0558630B1 (de) * | 1990-11-19 | 1998-04-08 | Monsanto Company | Retrovirale proteaseinhibitoren |
| US5475027A (en) * | 1990-11-19 | 1995-12-12 | G.D. Searle & Co. | Retroviral protease inhibitors |
| US5482947A (en) | 1990-11-19 | 1996-01-09 | Talley; John J. | Retroviral protease inhibitors |
| DE69126987T2 (de) * | 1990-11-19 | 1998-03-05 | Monsanto Co | Retrovirale protease-inhibitoren |
| US5648511A (en) * | 1990-11-19 | 1997-07-15 | G.D. Searle & Co. | Method for making intermediates useful in the synthesis of retroviral protease inhibitors |
| ATE196466T1 (de) | 1990-11-19 | 2000-10-15 | Monsanto Co | Inhibitoren retroviraler proteasen |
| US5614522A (en) * | 1990-11-19 | 1997-03-25 | G.D. Searle & Co. | Retroviral protease inhibitors |
| US5583238A (en) * | 1990-11-19 | 1996-12-10 | G. D. Searle & Co. | Method for making intermediates useful in synthesis of retroviral protease inhibitors |
| US5475013A (en) * | 1990-11-19 | 1995-12-12 | Monsanto Company | Retroviral protease inhibitors |
| AU4253193A (en) * | 1992-05-20 | 1993-12-13 | G.D. Searle & Co. | Urea-containing hydroxyethylamine compounds as retroviral protease inhibitors |
| EP0957093A3 (de) * | 1992-05-21 | 2000-04-12 | Monsanto Company | Retrovirusprotease Inhibitoren |
| US5760076A (en) * | 1992-08-25 | 1998-06-02 | G.D Searle & Co. | Succinoylamino 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 |
| US7141609B2 (en) | 1992-08-25 | 2006-11-28 | G.D. Searle & Co. | α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
| US5968942A (en) | 1992-08-25 | 1999-10-19 | G. D. Searle & Co. | α- and β-amino acid hydroxyethylamino sulfonamides 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 |
| US6046190A (en) * | 1992-08-25 | 2000-04-04 | G.D. Searle & Co. | Hydroxyethylamino sulphonamides useful as retroviral protease inhibitors |
| ATE218541T1 (de) * | 1992-08-25 | 2002-06-15 | Searle & Co | Hydroxyethylaminosulfonamide verwendbar als inhibitoren retroviraler proteasen |
| 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 |
| US6156768A (en) | 1992-10-30 | 2000-12-05 | G. D. Searle & Co. | Alpha- and beta-amino acid hydroxyethylamino sulfamic acid derivatives useful as retroviral protease inhibitors |
| US6337398B1 (en) | 1992-10-30 | 2002-01-08 | G.D. Searle & Co. | Succinoylamino hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors |
| US5578606A (en) | 1992-10-30 | 1996-11-26 | G. D. Searle & Co. | α- and β-amino acid hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors |
| US5756498A (en) * | 1992-10-30 | 1998-05-26 | G.D. Searle & Co. | Sulfonylalkanoylamino hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors |
| DE69326077T2 (de) * | 1992-10-30 | 2000-01-27 | Searle & Co | Sulfonylalkanoylaminohydroxyethylaminosulfaminsäuren verwendbar als inhibitoren retroviraler proteasen |
| US5514801A (en) | 1992-12-29 | 1996-05-07 | Monsanto Company | Cyclic sulfone containing retroviral protease inhibitors |
| US5830888A (en) * | 1993-04-16 | 1998-11-03 | Monsanto Company | Macrocyclic retroviral protease inhibitors |
| US5750648A (en) * | 1993-08-20 | 1998-05-12 | G.D. Searle & Co. | Retroviral protease inhibitors and combinations thereof |
| US5602119A (en) * | 1993-10-29 | 1997-02-11 | Vazquez; Michael L. | Succinoylamino hydroxyethylamino sulfamic acid derivatives useful as retroviral protease inhibitors |
| US6133444A (en) * | 1993-12-22 | 2000-10-17 | Perseptive Biosystems, Inc. | Synthons for the synthesis and deprotection of peptide nucleic acids under mild conditions |
| EP0738711B1 (de) * | 1994-11-04 | 2000-03-08 | Santen Pharmaceutical Co., Ltd. | Neue hydroxy-substituierte 1,3-dialkyl-harnstoffderivate |
| ATE382041T1 (de) * | 1995-01-20 | 2008-01-15 | Searle Llc | Bis-sulfonamid-hydroxyethylamino-derivate als inhibitoren retroviraler proteasen |
| US5831117A (en) | 1995-01-20 | 1998-11-03 | G. D. Searle & Co. | Method of preparing retroviral protease inhibitor intermediates |
| US6140505A (en) | 1995-03-10 | 2000-10-31 | G. D. Searle & Co. | Synthesis of benzo fused heterocyclic sulfonyl chlorides |
| US5756533A (en) * | 1995-03-10 | 1998-05-26 | G.D. Searle & Co. | Amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors |
| US6150556A (en) | 1995-03-10 | 2000-11-21 | G. D. Dearle & Co. | Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors |
| EP1188766A1 (de) | 1995-03-10 | 2002-03-20 | G.D. Searle & Co. | Verbindungen der Struktur bis-Aminosäure-Hydroxyethylamino-Sulfonamid als Inhibitoren der retroviralen Protease |
| US7339078B2 (en) | 1995-03-10 | 2008-03-04 | G.D. Searle Llc | Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors |
| US6169085B1 (en) | 1995-03-10 | 2001-01-02 | G. D. Searle & Company | Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors |
| AU717598B2 (en) * | 1995-03-10 | 2000-03-30 | G.D. Searle & Co. | Heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors |
| US5776971A (en) | 1995-03-10 | 1998-07-07 | G.D. Searle & Co. | Heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors |
| US5985870A (en) * | 1995-03-10 | 1999-11-16 | G.D. Searle & Co. | Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors |
| US6861539B1 (en) | 1995-03-10 | 2005-03-01 | G. D. Searle & Co. | Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors |
| US5705500A (en) * | 1995-03-10 | 1998-01-06 | G.D. Searle & Co. | Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors |
| US6407134B1 (en) | 1995-03-10 | 2002-06-18 | G. D. Searle & Co. | Heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors |
| US6667307B2 (en) | 1997-12-19 | 2003-12-23 | G.D. Searle & Co. | Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors |
| US5753660A (en) * | 1995-11-15 | 1998-05-19 | G. D. Searle & Co. | Substituted sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors |
| BR9815469A (pt) * | 1997-05-08 | 2001-03-06 | Smithkline Beecham Corp | Inibidores de protease |
| AU4862799A (en) | 1998-07-08 | 2000-02-01 | G.D. Searle & Co. | Retroviral protease inhibitors |
| AU2001281250A1 (en) | 2000-08-11 | 2002-02-25 | The Brigham And Women's Hospital, Inc. | (hydroxyethyl)ureas as inhibitors of alzheimer's beta-amyloid production |
| KR100750102B1 (ko) | 2001-06-14 | 2007-08-17 | 삼성전자주식회사 | 디스크 카트리지 |
| PL368052A1 (en) | 2001-07-11 | 2005-03-21 | Elan Pharmaceuticals, Inc. | N-(3-amino-2-hydroxy-propyl) substituted alkylamide compounds |
| AU2003293155A1 (en) * | 2002-11-27 | 2004-06-23 | Elan Pharmaceutical, Inc. | Substituted ureas and carbamates |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0104041B1 (de) * | 1982-09-15 | 1988-07-27 | Aktiebolaget Hässle | Enzyminhibitoren |
| WO1984003044A1 (en) * | 1983-02-07 | 1984-08-16 | Ferring Ab | Enzyme inhibitors |
| US4604402A (en) * | 1984-03-30 | 1986-08-05 | E. R. Squibb & Sons, Inc. | Hydroxy substituted ureido amino and imino acids |
| US4599198A (en) * | 1985-08-02 | 1986-07-08 | Pfizer Inc. | Intermediates in polypeptide synthesis |
-
1986
- 1986-11-19 CA CA000523367A patent/CA1297631C/en not_active Expired - Lifetime
- 1986-11-28 FR FR8616673A patent/FR2592048B1/fr not_active Expired - Fee Related
- 1986-12-16 GB GB8630006A patent/GB2184730B/en not_active Expired - Fee Related
- 1986-12-22 IT IT8622804A patent/IT1213574B/it active
- 1986-12-22 DE DE19863643977 patent/DE3643977A1/de not_active Withdrawn
- 1986-12-23 JP JP61316118A patent/JPS62164658A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| FR2592048B1 (fr) | 1995-07-07 |
| DE3643977A1 (de) | 1987-07-02 |
| GB2184730A (en) | 1987-07-01 |
| FR2592048A1 (fr) | 1987-06-26 |
| GB8630006D0 (en) | 1987-01-28 |
| JPS62164658A (ja) | 1987-07-21 |
| GB2184730B (en) | 1990-02-07 |
| IT8622804A0 (it) | 1986-12-22 |
| IT1213574B (it) | 1989-12-20 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed | ||
| MKLA | Lapsed |
Effective date: 19950918 |