CA1297631C - Inhibiteurs de la renine a groupement ureido - Google Patents

Inhibiteurs de la renine a groupement ureido

Info

Publication number: CA1297631C
Authority: CA; Canada
Prior art keywords: amino; carbonyl; hydroxy; compound; methyl ester
Prior art date: 1985-12-23
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

Application number

CA000523367A

Other languages

English (en)

Inventor

Sesha I. Natarajan

Denis E. Ryono

Edward W. Petrillo, Jr.

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

ER Squibb and Sons LLC

Original Assignee

ER Squibb and Sons LLC

Priority date (The priority date 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 date listed.)

1985-12-23

Filing date

1986-11-19

Publication date

1992-03-17

1986-11-19 Application filed by ER Squibb and Sons LLC filed Critical ER Squibb and Sons LLC

1992-03-17 Application granted granted Critical

1992-03-17 Publication of CA1297631C publication Critical patent/CA1297631C/fr

2009-03-17 Anticipated expiration legal-status Critical

Status Expired - Lifetime legal-status Critical Current

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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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)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Peptides Or Proteins (AREA)
Indole Compounds (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

CA000523367A 1985-12-23 1986-11-19 Inhibiteurs de la renine a groupement ureido Expired - Lifetime CA1297631C (fr)

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 (fr)	1992-03-17

Family

ID=25209973

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA000523367A Expired - Lifetime CA1297631C (fr)	1985-12-23	1986-11-19	Inhibiteurs de la renine a groupement ureido

Country Status (6)

Country	Link
JP (1)	JPS62164658A (fr)
CA (1)	CA1297631C (fr)
DE (1)	DE3643977A1 (fr)
FR (1)	FR2592048B1 (fr)
GB (1)	GB2184730B (fr)
IT (1)	IT1213574B (fr)

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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
EP0813868B1 (fr) *	1990-11-19	2005-06-01	Monsanto Company	Inhibiteurs de protéases rétrovirales
US5648511A (en) *	1990-11-19	1997-07-15	G.D. Searle & Co.	Method for making intermediates useful in the synthesis of retroviral protease inhibitors
US5475027A (en) *	1990-11-19	1995-12-12	G.D. Searle & Co.	Retroviral protease inhibitors
US5614522A (en) *	1990-11-19	1997-03-25	G.D. Searle & Co.	Retroviral protease inhibitors
US5708004A (en) *	1990-11-19	1998-01-13	Monsanto Company	Retroviral protease inhibitors
DK0558657T3 (da)	1990-11-19	1997-07-07	Monsanto Co	Retrovirale proteaseinhibitorer
CA2096408C (fr) *	1990-11-19	2005-02-08	Gary Anthony Decrescenzo	Inhibiteurs de la protease des retrovirus
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
US5482947A (en) *	1990-11-19	1996-01-09	Talley; John J.	Retroviral protease inhibitors
WO1993023368A1 (fr) *	1992-05-20	1993-11-25	G.D. Searle & Co.	Composes d'hydroxyethylamine contenant de l'uree utilises comme inhibiteurs de proteases retrovirales
AU667376B2 (en) *	1992-05-21	1996-03-21	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
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
JP4091654B2 (ja) *	1992-08-25	2008-05-28	ジー．ディー．サール、リミテッド、ライアビリティ、カンパニー	レトロウイルスプロテアーゼ阻害剤として有用なスルホニルアルカノイルアミノヒドロキシエチルアミノスルホンアミド
US6743929B1 (en)	1992-08-25	2004-06-01	G. D. Searle & Co.	Sulfonylalkanoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US5760076A (en) *	1992-08-25	1998-06-02	G.D Searle & Co.	Succinoylamino 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
WO1994004491A1 (fr) *	1992-08-25	1994-03-03	G.D. Searle & Co.	N-(alcanoylamino)-2-hydroxypropyl)-sulfamides utiles comme inhibiteurs de proteases retrovirales
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
US5583132A (en) *	1992-10-30	1996-12-10	Vazquez; Michael L.	Sulfonylalkanoylamino hydroxyethylamino sulfamic acids 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
DE69319351T2 (de) *	1992-10-30	1998-11-19	Monsanto Co	Hydroxyethylaminosulfamidsäure-derivate verwendbar als inhibitoren retroviraler proteasen
US5756498A (en) *	1992-10-30	1998-05-26	G.D. Searle & Co.	Sulfonylalkanoylamino 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
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
WO1996014293A1 (fr) *	1994-11-04	1996-05-17	Santen Pharmaceutical Co., Ltd.	Nouveau derive de 1,3-dialkyluree ayant un groupe hydroxyle
US5831117A (en)	1995-01-20	1998-11-03	G. D. Searle & Co.	Method of preparing retroviral protease inhibitor intermediates
US6143747A (en)	1995-01-20	2000-11-07	G. D. Searle & Co.	Bis-sulfonamide hydroxyethylamino retroviral protease inhibitors
US5756533A (en) *	1995-03-10	1998-05-26	G.D. Searle & Co.	Amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US6140505A (en)	1995-03-10	2000-10-31	G. D. Searle & Co.	Synthesis of benzo fused heterocyclic sulfonyl chlorides
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
CN1530372A (zh)	1995-03-10	2004-09-22	G.D.ɪ��˾	杂环羰基氨基酸羟乙氨基磺酰胺逆转录病毒蛋白酶抑制剂
US7339078B2 (en)	1995-03-10	2008-03-04	G.D. Searle Llc	Bis-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
US6150556A (en) *	1995-03-10	2000-11-21	G. D. Dearle & Co.	Bis-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
US5985870A (en) *	1995-03-10	1999-11-16	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
US6169085B1 (en)	1995-03-10	2001-01-02	G. D. Searle & Company	Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors
EP1188766A1 (fr)	1995-03-10	2002-03-20	G.D. Searle & Co.	Hydroxyethylamino sulfonamide de bis-aminoacide comme inhibiteurs de proteases de retrovirus
AU7722296A (en) *	1995-11-15	1997-06-05	G.D. Searle & Co.	Substituted sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors
CA2289602A1 (fr) *	1997-05-08	1998-11-12	William Edward Bondinell	Inhibiteurs de proteases
US6538006B1 (en)	1998-07-08	2003-03-25	Pharmacia Corporation	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
WO2003006423A1 (fr) *	2001-07-11	2003-01-23	Elan Pharmaceuticals, Inc.	Composes de n-(3-amino-2-hydroxy-propyl) alkylamide substitues
US7351738B2 (en) *	2002-11-27	2008-04-01	Elan Pharmaceuticals, Inc.	Substituted ureas and carbamates

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* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP0104041B1 (fr) *	1982-09-15	1988-07-27	Aktiebolaget Hässle	Inhibiteurs d'enzyme
EP0316965A3 (fr) *	1983-02-07	1989-08-09	Aktiebolaget Hässle	Inhibiteurs d'enzymes
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/fr 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 DE DE19863643977 patent/DE3643977A1/de not_active Withdrawn
- 1986-12-22 IT IT8622804A patent/IT1213574B/it active
- 1986-12-23 JP JP61316118A patent/JPS62164658A/ja active Pending

Also Published As

Publication number	Publication date
IT8622804A0 (it)	1986-12-22
GB2184730B (en)	1990-02-07
IT1213574B (it)	1989-12-20
JPS62164658A (ja)	1987-07-21
DE3643977A1 (de)	1987-07-02
GB8630006D0 (en)	1987-01-28
FR2592048B1 (fr)	1995-07-07
GB2184730A (en)	1987-07-01
FR2592048A1 (fr)	1987-06-26

Legal Events

Date	Code	Title	Description
1995-09-18	MKLA	Lapsed
2023-05-26	MKLA	Lapsed	Effective date: 19950918

Publication	Publication Date	Title
CA1297631C (fr)	1992-03-17	Inhibiteurs de la renine a groupement ureido
US4757050A (en)	1988-07-12	Ureido renin inhibitors
EP0132304B1 (fr)	1989-06-07	Composés peptides hydroxy substitués
CA1269497A (fr)	1990-05-22	Ester et amide d'acides amines inhibiteurs de la renine
CA1282549C (fr)	1991-04-02	Inhibiteurs de l'aminocarbonyl resine
EP1391461B1 (fr)	2010-04-14	Inhibiteurs de l'enzyme de conversion de l'interleukine-1-beta comprenant un lactame bicyclique
US4885292A (en)	1989-12-05	N-heterocyclic alcohol renin inhibitors
EP0231919B1 (fr)	1993-01-20	Inhibiteurs de la rénine alcool-hétérocycliques
CA1274346A (fr)	1990-09-18	Derives amides et esters d'acides amines inhibant la resine
US4820691A (en)	1989-04-11	Amino acid 1,2-diketo derivatives as renin inhibitors
CA2207874A1 (fr)	1996-06-13	Nouveaux p-amidinobenzylamides dipeptidiques a restes n-terminaux sulfonyle ou aminosulfonyle
EP0159156A1 (fr)	1985-10-23	Uréidoamino- et -imino-acides hydroxy substitués
EP0103496A1 (fr)	1984-03-21	Dérivés aminés et iminés d'acides acylalkylamino-carbonyl substitués
US5843905A (en)	1998-12-01	Peptidic phosphinyloxymethyl ketones as interleukin-1β-converting enzyme inhibitors
EP0158947B1 (fr)	1991-02-06	Dérivé de p-aminophénol ayant une activité mucrosecrétolytique fluide et antipyrétique, son procédé de préparation et ses compositions pharmaceutiques
CA2017552A1 (fr)	1990-11-26	Heterocycles amino-substitues en tant qu'inhibiteurs de la renine
HU208427B (en)	1993-10-28	Process for producing renine-inhibiting amino-acid derivatives and pharmaceutical compositions containing them
GB2123834A (en)	1984-02-08	Substituted peptide compounds
US4749781A (en)	1988-06-07	Aminocarbonyl renin inhibitors
HU198077B (en)	1989-07-28	Process for producing substituted aminoalkanoyl aminoalkylphosphonates
CA1310792C (fr)	1992-11-24	Inhibiteurs de la renine de type alcool n-heterocyclique
HK1064102B (en)	2010-08-20	Bicyclic lactam inhibitors of interleukin-1-beta coverting enzyme
HK1012630B (en)	2004-10-15	Bicycling lactam inhibitor of interleukin-1-beta converting enzyme
MXPA96006192A (en)	1998-10-30	Inhibitors of lactama biciclica de la enzima queconvierte la interleucina-1-b