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
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- 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)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Indole Compounds (AREA)
Abstract
HA362a ABSTRACT
UREIDO RENIN INHIBITORS
Compounds of the formula
UREIDO RENIN INHIBITORS
Compounds of the formula
Description
HA362a U9~
Jones et al. in WO 84/03044 published in 1984 disclose renin inhibiting tetra-, penta- or hexapeptide analogues of the formula X-D-E-A-B-Z-W
where X and W are terminal groups; D, E, B and Z, of which any one or, except with reduced analogues, two may be absent, are aromatic, lipo-philic or (in the case of E) aromatic, lipophilic,or basic amino acid or amino acid analogue : residues, and A is an analogue of a lipophilic or aromatic dipeptide residue wherein the peptide link is replaced by one to four-atom carbon or carbon-nitrogen link which as such or in hydrated form is an unhydrolyzable tetrahedral analogue of the transition state of the peptide bond as given above. In particula., A is defined as R4 Rl R2 ~;~ 25 -N - C - M - C -', ' ":
Jones et al. in WO 84/03044 published in 1984 disclose renin inhibiting tetra-, penta- or hexapeptide analogues of the formula X-D-E-A-B-Z-W
where X and W are terminal groups; D, E, B and Z, of which any one or, except with reduced analogues, two may be absent, are aromatic, lipo-philic or (in the case of E) aromatic, lipophilic,or basic amino acid or amino acid analogue : residues, and A is an analogue of a lipophilic or aromatic dipeptide residue wherein the peptide link is replaced by one to four-atom carbon or carbon-nitrogen link which as such or in hydrated form is an unhydrolyzable tetrahedral analogue of the transition state of the peptide bond as given above. In particula., A is defined as R4 Rl R2 ~;~ 25 -N - C - M - C -', ' ":
-2- HA362a wherein M can be -CH-OH.
Szelke et al. in European Patent Application 104,041 published in 1984 disclose renin inhibitory polypeptides including the partial sequence X- A -B - Z- W and X-Phe-His-A-B-Z-W
10 wherein A is Rl R3 R2 0 -NH-CH - G- N - C~ - C-and G is OH
-CH - C~2 X is hydrogen, protecting group, or an amino acyl residue, B is a lipophilic amino acyl residue, and Z plu~ W are an amino alcohol residue or Z is aminoacyl and W i8 hydroxy, ester, amide, etc.
Matsueda et al. in United States Patent 4,548,926 disclose renin inhibiting peptides of the formula ~; 25 NH
2 But Rl-- C~ - C~ X
~' ~, , .~.. .. .. .
129763~
HA362a wherein But represents an isobutyl or sec-butyl group and X includes a group of the formula -CH(R2)_y Gordon et al. in IJ.S. Patent 4,514,391 disclose hydroxy substituted peptide compounds of the formula OH R Rl O
l l 11 which possess angiotensin converting enzyme or enkephalinase inhibition activity.
This invention is directed to new hydroxy containing ureido renin inhibitors of formula I
including pharmaceutically acceptable salts thereof (I) 11 ~ R2 Rl Rg O
X-NH-CH--C-NH-CH--CH-CH2-N--C-NH-CH--C ( NH-CH--C ) Rlo 30 X is R6-~CH2)m-~ NH CH ~p Il l 11 R6-(cH2)m-c-t ~H - CH -C ~-p , , .. ..
HA362a R6 ( CH2 )m ~ C ~ NH--CH--C--R6----(CH2)n C~ NH--CH--C tp Il I 11 R6--(CH2)m NH--C~ NH--CH- C~
l 11 6--(CH2 )m S02~ NH--CH--C
Il l 11 or R6-(CH2)m CH-C-(NH-CH--C ~p I
(CH2) R' Rl, R3, R4, R5, and Rg are independently select-30 ed from hydrogen, lower alkyl, halo substituted lower alkyl, -(CH2)n-aryl, -(CH2)n-heterocyclo, -(CH2)n-OH, ( 2 )n H2, (CH2)n-SH~ -(CH2)n-S-lower alkyl, -(CH2)n-0-lower alkyl, ~(CH2)n~0~(CH2)g~0H~
- ( CH2 ) ~- ( CH2 ) g~NH2 ~ ~ ( CH2 ) n ( 2 ,.
~ ,~
~.. . . .
-~` 129763~
_5_ HA362a NH
.~
(CH ) ~S~(CH2)g~NH2~ -(CH2)n ( 2)n C NH2 , ~(CH2)n ~ J~R7' (CH)n P~8 and -(CH2)n-cycloalkyl.
R2 is hydrogen, lower alkyl, -(CH2)m-aryl, -(CH2)m-cycloalkyl, or -(CH2)n-heterocyclo.
R6 and R'6 are independently selected from lower alkyl, cycloalkyl, aryl and heterocyclo.
p is zero or one.
m and m' are independently selected from zero and an integer from 1 to 5.
n is an integer from 1 to 5.
g is an integer from 2 to 5.
7 CH2 0 CH2 ~ or -CH2 ~ .
R8 is 2,4-dinitrophenyl, _1_0_CF72~ , -SO ~ H3 ~ or -CH -O-CH
q is zero or one.
R1o is hydroxy, -O-lower alkyl, : -O-(CH2)m-cycloalkyl, -O-(CH2)m-aryl, -O-(CH2)n-heterocyclo, -NH2, or -O-salt forming ion.
..~
" .,~, . ,.~ ., .. ~ . . , HA362a This invention in its broadest aspects relates to the compounds of formula I above, to compositions and the method of using such compounds as antihypertensive agents.
The term lower alkyl used in defining various symbols refers to straight or branched chain radicals having up to seven carbons.
The term cycloalkyl refers to saturated rings of 4 to 7 carbon atoms with cyclopentyl and cyclohexyl being most preferred.
The term halogen refers to chloro, bromo and fluoro.
The term halo substituted lower alkyl refers to such lower alkyl groups described above in which one or more hydrogens have been replaced by chloro, bromo or fluoro groups such as trifluoro-methyl, which is preferred, pentafluoroethyl, 2,2,2-trichloroethyl, chloromethyl, bromomethyl, etc.
The term aryl refers to phenyl, l-naphthyl, 2-naphthyl, mono substituted phenyl, 1-naphthyl, or 2-naphthyl wherein said substituent is lower alkyl of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, halogen, hydroxy, amino, -NH-alkyl wherein alkyl is of 1 to 4 carbons, or -N(alkyl)2 wherein alkyl is of 1 to 4 carbons, di or tri substituted phenyl, 1-naphthyl or 2-naphthyl wherein said substituents are selected from methyl, methoxy, methylthio, halogen, and hydroxy.
~. ~
-HA362a The term heterocyclo refers to fully saturated or unsaturated rings of 5 or 6 atoms containing one or two O and S atoms and/or one to four N atoms provided that the total number of hetero atoms in the ring is 4 or less. The heterocyclo ring is attached by way of an available carbon atom.
Preferred heterocyclo groups include 2- and 3-thienyl, 2- and 3-furyl, 2-, 3- and 4-pyridyl, and imidazolyl. The term heterocyclo also includes bicyclic rings wherein the five or six membered ring containing O, S and N atoms as defined above is fused to a benzene ring. The preferred bicyclic ring is indolyl.
The compounds of formula I wherein Il l 11 X iS R6-(cH2)m-o-c-t NH- CH - C~p can be prepared by coupling an alcohol of the formula (II) R3 R2 o R1 o Rg O
l 11 1 11 1 ll H2N-CH- CH - CH2- N - C-NH-CH-C -(NH-CH-C ~ R1o OH
with a peptide of the formula (III) R6-(CH2)m-O-C-~-NH -CH - C ~-p NH -CH - COOH
~,~
.:..... .
~297631 HA362a This reaction is preferably performed in a solvent such as dimethylformamide and in the presence of hydroxybenzotriazole, diisopropylethylamine, and a coupling agent such as dicyclohexylcarbodiimide.
The corresponding compounds of formula I
wherein p is zero can be prepared by coupling the alcohol of formula II with the amino acid of the formula (IV) Il I
R6-(CH2)m-0-C-NH-CH -COOH
to yield the products of the formula (V) ll 1 4 ll 1 3 1 2 ~ 9 11 R6-~CH2)m-O-C-NH-CH- C-NH-CH-CH-CH2-N- C-NH-CH-C-~ NH-CH-C ~- Rlo .
OH
When R6-(CH2)m~ is t-butyl or benzyl, then the product of formula V can be treated so as to remove the t-butoxycarbonyl or benzyloxycarbonyl group such as by the use of hydrochloric acid when R6 is t-butyl to yield the amine of the formula (Vl) R O R R O R O R O
14 11 13 12 ~ 19 11 H2N-CH-C-NH-CH-CH-CH2-N- C-NH-CH-C-~NH-CH-C ~ Rlo OH
HA362a Coupling with the amino acid of the formula (VII) Il I
S R6-(CH2)m~O~C - NH - CH -COOR
yields the products of formula I wherein p is one.
The compounds of formula I wherein X is other than R6-(CH2)m~O~C-~ NH -CH- C tp can be prepared by treating the product of formula I wherein R6 is Il 11 C O C(CH3)3 or C O CH2 ~ and m is zero to remove the t-butoxycarbonyl or benzyloxycarbonyl group and yield the intermediates of the formula (VIII) R5 R4 1l 13 12 h 1 ll Rg O
H2N-CH-C-NH-CH C-NH-CH-CH-CH2-N- C-NH-CH-C-~-NH-CH-C ~ Rlo OH
: The amine of formula VIII or formula VI is treated with the halide of the formula (IX) R6 ( CH2 )m-halo :~
, ., ~
~
.
~.,..... , ~ .. ......
.
HA362a particularly where halo is Br to give the products of formula I wherein X is R6-(CH2)m ( NH -CH- C tp The amine of formula VIII or VI is treated with the acid chloride of the formula 10 (X) o Il .
R6~CH2)m~C~Cl or l5 (XI) o R6 (CH2)n C Cl 20 in the presence of triethylamine to yield the products of formula I wherein O R O
~ 5 11 X iS R6 (CH2)m C ~ NH CH C~p or o R O
R6-0-(CH2)n-C ~ NH-CH - C-t-p ~ 30The amine of formula VIII or VI is treated '~ with the substituted sulfonyl chloride of the formula (XII) ~ ~ R6 ( CH2 )m-S02-C
,~' .~
~'''''': '` ' ' , ~ ' .
: ' ' ' ' ' ' , .
129763~
HA362a to yield the products of formula I wherein X is R o R6-(CH2)m- So2-~ NH-CH - C-~ .
The amine of formula VIII or VI is treated with phosgene and the resulting acid chloride is treated with the substituted amine of the formula (XIII) R6-(CH2)m NH2 to yield the products of formula I wherein X is R6-(CH2)m-NH-C-~ NH-CH C +p The products of formula I wherein Il l 11 X is R6-(CH2)m- G~-c-~NH--CH--C ~
I
(CH2) R'6 can be prepared by coupling the carboxylic acid of the formula :
. ~.
' ;
...... ..
HA362a (XIV) o Il R6 (CH2)m CH C OH
S
( CH2 ) I
R~6 to the amine of formula VI or VIII in the presence of dicyclohexylcarbodiimide and l-hydroxybenzo-triazole hydrate. Alternatively, the acid of formula XIV can be converted to the acid chloride and this acid chloride can then be coupled to the amine of formula VI or VIII in the presence of triethyl-amine and tetrahydrofuran or water and sodium bicarbonate.
The alcohol of formula II can be prepared by reacting an alcohol of the formula (XV) Prot-NH-CH -CH - CH2-N -H
I
OH
preferably the hydrochloride salt thereof, with the carbamoyl chloride of the formula .,~
... .
HA362a (XVI) O Rl O
Il 1 ~1 Cl- C- NH - CH- C- 0 - CH
to give (XVII) R R2 I Rl Prot-NH-C3-CH-CH2-N--C-NH-CH--C-O-CH
OH
wherein Prot is an amino protecting group such as t-butoxycarbonyl. Removal of the benzyl group from the intermediate of formula XVII such as by hydrogenation yields the acid of the formula (XVIII) ~ R R O R O
~ 25 13 l2 ~
Prot-NH-CH -FH-CH -N -C NH-CH-C-OH
OH
` ~ :
~: 30 .,~ 3S
.~
,::
.,.... ~
~297631 HA362a Removal of the t-butoxycarbonyl amino protecting group such as by treatment with hydrochloric acid gives the alcohol of formula II wherein q is zero and Rlo is hydroxy. When q is zero and Rlo is other than hydroxy, the acid of formula XVIII is treated to introduce the R1o group, for example, treatment with diazomethane where R1o is methoxy, followed by removal of the t-butoxycarbonyl protecting group. Of course, where final products are desired having Rlo as then the benzyl -O-CH2~
group is not removed from the intermediate of formula XVII.
When ~ is one, then the acid of formula XVIII
is treated with the amino acid of the formula (XIX) Rg 0 H2N CH -C Rlo in the presence of a coupling reagent such as dicyclohexylcarbodiimide to give (XX) R R O R O R O
13 12 ~ 19 11 Prot-NH-CH-CH-CH2-N-- C-NH-CH-- C-NH-CH-C-Rlo OH
Removal of the t-butoxycarbonyl amino protecting group as described above gives the alcohol of formula II.
. . .
~ ,;
12g7631 HA362a The alcohol starting compound of XV can be prepared by treating the ketone of the formula (XXI) I
Prot- NH -CH - C -CH2- N - CH2 ~
with a conventional reducing agent such as sodium borohydride followed by hydrogenation using palladium hydroxide on carbon catalyst.
The ketone of formula XXI can be prepared by treating the ketone of the formula 15 (XXI I ) I
Prot-NH -CH -C- CH2- Cl ll o with an amine of the formula (~XIII) H
in the presence of sodium iodide and sodium bicar-bonate in a solvent such as dimethylformamide.
When R2 is hydrogen, the ketone of formula XXII is reacted with dibenzylamine. After reduction to the alcohol, both benzyl groups are removed by "..;
~.
12g~631 HA362a hydrogenation.
In the above reactions, if any of Rl, R2, R3, R4, R5, and Rg are -(CH2)n-aryl wherein aryl is phenyl, l-naphthyl, 2-naphthyl substituted with one or more hydroxy or amino groups, -(CH2)n-heterocyclo wherein heterocyclo is an imidazolyl, -(CH2)n-NH2, ~ NH
-(CH2) -SH, -(CH2) -OH, or -(CH2) -NH-C
then the hydroxyl, amino, imidazolyl, mercaptan, or guanidinyl function should be protected during the reaction. Suitable protecting groups include benzyloxycarbonyl, t-butoxycarbonyl, benzyl, benz-hydryl, trityl, etc., and nitro in the case of guanidinyl. The protecting group is removed by hydrogenation, treatment with acid, or by other known means following completion of the reaction.
The various peptide intermediates employed in above procedures are known in the literature or can be readily prepared by known methods. See for example, The Peptides, Volume 1, "Major Methods Of Peptide Bond Formation", Academic Press (1979).
Preferred compounds of this invention are those of formula I wherein:
O R O
Il 15 1l X is lower alkyl-O-C-NH-CH -C- , 7~
HA362a - CH2-0-C-NH -CH - C- , or ~ 11 ~ ~ C~2,2 CH-C-Rl is lower alkyl of 3 to 5 carbons -(CH2)m-cyclopentyl, -(CH2)m-cyclohexyl, -(CH2)m ~ , or ~(CH2)m- ~
wherein m is an integer from 1 to 3.
22 is hydrogen, lower alkyl of 3 to 5 carbons, -(CH2)m-cyclopentyl, -(CH2)m-cyclohexyl, (CH2)m ~ or -(CH2)m ~ wherein m is an integer from 1 to 3.
R3 is lower alkyl of 3 to 5 carbons, -(CH2)m~cyclopentyl, -(CH2)m-cyclohexyl or ~(CH2)m ~ wherein m is an integer from 1 to 3.
~297631 HA362a 4 -CH2 ~ JNH , -CH2 ~ N-CH2-0-CH2 ~ , -CH2 ~ -CH2 ~ ' -CH2 ~ 0H
-CH2 ~ ' -CH2--@ N , CH2 -(CH2)2 ~ ' or -CH2 ~ N02 R5 and Rg are independently selected from -CH2 ~ , -(CH2) ~ , -CH2-(~-naphthyl), -CH2-(~-naphthyl), -CH2 ~ OH , -CH2-cyclopentyl, , . ' 129763~
HA362a -CH2-cyclohexyl, _[~) , -CH~N
5 --CH2~ , -CH2~ JNH , -CH2~JH
and -CH ~ O
H
Rlo iS--o-CH3 ~ -0-C2H5, -0-CH2~>, -0-CH2 ~ or hydroxy.
Moæt preferred are the above compounds wherein O R O
Il 15 11 X is (H3C)3-C-O-C-NH-CH- C-Rl is -CH- CH2- CH3 or -CH-(CH3)2, especially -CH - CH2- CH3 I
~2g763~
HA362a -20~
R2 is hydrogen, -CH2-CH(CH3)2 or -CH(CH3)2 , especially hydrogen.
R5 is -CH2 ~
R4 is ~N J
R3 is -CH2-CH(CH3)2 q is zero or one, especially one.
R9 is -CH2 ~ TN~J
especially -CH2 ~ NH
Rlo is -O CH3 The compounds of formula I form salts with a variety of inorganic and organic acids. The non-toxic pharmaceutically acceptable salts arepreferred, although other salts are also useful in isolating or purifying the product. Such pharmaceutically acceptable salts include those formed with hydrochloric acid, methanesulfonic acid, sulfuric acid, acetic acid, maleic acid, etc.
The salts are obtained by reacting the product ' ,'~ `' , - ;.
~2g7~
HA362a with an equivalent amount of the acid in a medium in which the salt precipitates.
The compounds of formula I contain asymmetric centers when any or all of Rl, R3, R4, R5, and Rg are other than hydrogen and at the carbon to which the -OH group is attached.
Thus, the compounds of formula I can exist in diasteroisomeric forms or in mixtures thereof.
The above described processes can utilize racemates, enantiomers or diastereomers as starting materials. When diastereomeric products are prepared, they can be separated by conventional chromatographic or fractional crystallization methods.
The compounds of formula I, and the pharma-ceutically acceptable salts thereof, are anti-hypertensive agents. They inhibit the conversion of angiotensinogen to angiotensin I and therefore, are useful in reducing or relieving angiotensin related hypertension. The action of the enzyme renin on angiotensinogen, a pseudoglobulin in blood plasma, produces angiotensin I.
Angiotensin I is converted by angiotensin converting enzyme (ACE) to angiotensin II. The latter is an active pressor substance which has been implicated as the causative agent in several forms of hypertension in various mammalian species, e.g., humans. The compounds of this invention intervene in the angiotensinogen ~
(renin) ~ angiotensin I ~ (ACE) ~ angiotensin II
sequence by inhibiting renin and reducing or ~2g7~31 -22- HA362a eliminating the formation of the pressor substance angiotensin II. Thus by the administration of a composition containing one (or a combination) of the compounds of this i~vention, angiotensin dependent hypertension in a species of mammal (e.g., humans) suffering therefrom is alleviated.
A single dose, or preferably two to four divided daily doses, provided on a basis of about 100 to 1000 mg., preferably about 250 to 500 mg. per kg. of body weight per day is appropriate to reduce blood pressure. The substance is preferably administered orally, but parenteral routes such as the subcutaneous, intramuscular, intraveneous or intraperitoneal routes can also be employed.
The compounds of this invention can also be formulated in combination with a diuretic for the treatment of hypertension.
A combination product comprising a compound of this invention and a diuretic can be administered in an effective amount which comprises a total daily dosage of about 1000 to 6000 mg., preferably about 3000 to 4000 mg. of a compound of this invention, and about 15 to 300 mg., preferably about 15 to 200 mg. of the diuretic, to a mammalian species in need thereof.
Exemplary of the diuretics contemplated for use in combination with a compound of this invention are the thiazide diuretics, e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflu-methiazide, bendroflumethiazide, methyclothiazide,trichloromethiazide, polythiazide or benzthiazide - , .
. ' :.' . ' ' `- 12g763~
HA362a as well as ethacrynic acid, ticrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride and spironolactone and salts of such compounds.
The compounds of formula I can be for~.ulated for use in the reduction of blood pressure in compositions such as tablets, capsules or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration.
About 100 to 500 mg. of a compound of formula I is compounded with physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice.
The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.
The following examples are illustrative of the invention. Temperatures are given in degrees centigrade.
lZ~7~9~
HA362a Example 1 N-[[[(3S)-3-[[N-[N-[(l,l-Dimethylethoxy)carbonyl]-L-phenYlalanyl]-L-histidyl]amino]-2-hydroxY-5-methylhexvl](2-methYlpropyl)amino]carbonyl]-L-valine, methyl ester, monohydrochloride (isomer A)a) (S)-[3-Methvl-1-[[(2-methylPropyl)(phenyl-methyl)amino]acetyl]butyl]carbamic acid, 1,1-dimethYlethyl ester,4-methylbenzenesulfonic acid salt (1:1) N-Methyl morpholine (16.5 ml., 150 mmole) is added to a stirred solution of N-[(l,1-dimethyl-ethoxy)carbonyl]-L-leucine (34.67., 150 mmole) in dry tetrahydrofuran (135 ml.) at ~15 followed by the dropwise addition of isobutyl chloroformate (19.5 ml., 150 mmole). After stirring at -15 for twenty minutes, it is filtered and diluted with ether (4~0 ml.) kept at -20. This is added dropwise over 15 minutes to an ethereal solution of diazomethane (600 ml., generated from 60 g. of N-methyl-N'-nitro-N-nitrosoguanidine). After the addition is over the reaction is allowed to run at ; room temperature for two hours. Excess diazomethane is blown off by a stream of nitrogen. The ethereal solution is washed with saturated aqueous sodium bicarbonate and saturated sodium chloride solutions. The ethereal solution is concentrated ln vacuo and the residue is dissolved in hexane. On cooling, 27.7 g. of (S)-[3-methyl-1-[(diazomethyl)carbonyl]butyl]-carbamic acid, 1,1-dimethylethyl ester is obtained as a crystalline material; m.p. (88) 89 - g0.
.
~, , . . .
.
.
12g7631 HA362a Hydrochloric acid in acetic acid (2.2 N, 94 mmole) is added dropwise to a stirred (ice-bath) solution of the above diazo product (24 g., 94 mmole) in ether (470 ml.). After stirring for 10 minutes the solution is evaporated ln vacuo.
The residue is dissolved in ethyl acetate:hexane (1:3) and passed through a small column of silica gel (400 g.) using ethyl acetate:hexane (1:3) for elution. A homogeneous material is obtained (23.2 g.). On crystallization from a mixture of ether and hexane fine crystalline (S)-[3-methyl-l-[(chloromethyl)carbonyl]butyl]carbamic acid, 1,1-dimethylethyl ester is obtained; m.p. 66-68.
A solution of (phenylmethyl)(2-methylpropyl)-amine (8.16 g., 50 ml.), (S)-[3-methyl-1-[(chloro-methyl)carbonyl]butyl]carbamic acid, l,l-dimethyl-ethyl ester (13.19 g., 50 mmole), sodium bicarbonate (6.3 g., 75 mmole), sodium iodide (3.74 g., 25 mmole) and dimethylformamide (100 ml.) is stirred at room temperature for 4 hours. It is then evaporated, taken into ethyl acetate and washed with water. The ethyl acetate solution is evaporated and the residue dissolved in ether.
The ethereal solution is filtered to remove a very small amount of insoluble material. The ethereal solution is evaporated and the residue is chromato-graphed over a small column of silica gel (350 g.) using the solvent system ethyl acetate:hexane (1:4). The homogeneous fractions are pooled and evaporated. The residue (17.62 g.) is dissolved in ether and an ethyl acetate solution of `", HA362a p-toluenesulfonic acid (8.6 g., 45.2 mmole) is added. The crystallized salt is filtered to give 18.72 g. of (S)-[3-methyl-1-[[(2-methylpropyl) (phenylmethyl)amino]acetyl]butyl]carbamic acid, l,l-dimethylethyl ester, 4-methylbenzenesulfonic acid salt (1:1); m.p. (140) 143; [~]D = -38.9 (c = 2.2, methanol). TLC (silica gel; n-propanol:
NH40H, 98:2) Rf = 0.8.
Anal. calc'd. for C30H46N26S C7H83 C, 64.03; H, 8.24; N, 4.98; S, 5.70 Found: C, 63.83; H, 8.00; N, 4.97; S, 5.78.
b) (S)-~l-[tRS)-l-HydroxY-2-[(2-methylpro~yl) (~henvlmethYlLamino~ethyll-3-methylbutyl]carbamic acid, 1,1-dimethYlethyl ester, monohydrochloride The 4-methylbenzenesulfonic acid salt product from part (b) (5.62 g., 10 mmole) is taken into ethyl acetate and shook with saturated sodium bicarbonate solution. The ethyl acetate layer is dried over magnesium sulfate and evaporated in vacuo. The resulting free base (3.9 g.) is dissolved in ethanol (35 ml.). Sodium borohydride (400 mg., 10.4 mmole) is added to the stirring ethanolic solution at room temperature. After one hour the solution is evaporated and the residue is suspended in ethyl acetate and water and acidified to pH 2.0 using dilute hydrochloric acid. Then saturated sodium bicarbonate solution is added until the ethyl acetate solution is slightly basic. The ethyl acetate layer is dried over magnesium sulfate and evaporated to give 3.91 g.
of alcohol product. An analytical sample of this alcohol is prepared as the hydrochloride salt as follows. Hydrochloric acid in dioxane ~1 ...
, . " ~ , . .. .
lZg76~1 HA362a solution (5N, 0.28 ml.) is added to an ethereal solution of an aliquot of the above alcohol (O.S59 g., 1.42 mmole). The solution is concentrated and dried in high vacuum tc give (S)-[1-[(RS)-l-hydroxy-2-[(2-methylpropyl)(phenylmethyl)amino]ethyl]-3-methylbutyl]carbamic acid, l,1-dimethylethyl ester, monohydrochloride as a crisp solid; m.p. 50 - 65 [a]D = -29.8 (c = 1.54, methanol). TLC (silica gel, ethyl acetate:hexane, 1:4) Rf = 0.47.
Anal- calc'd- for C23H40N23 HCl 0-44 H2O
C, 63.21; H, 9.68; N, 6.41; Cl, 8.11 Found: C, 63.21; H, 9.49; N, 6.05; Cl, 7.88.
c) (S)-[1-[(RS)-l-HYdroxy-2-[(2-methylpro~yl)-amino]ethyll-3-methylbutyl~carbamic acid,l,1-dimethYlethyl ester, monohydrochloride The alcohol product from part (b) (1.67 g.,4.25 mmole) is dissolved in methanol (50 ml.) and aqueous hydrochloric acid (lN, 4.25 ml.) is added.
The solution is stirred under an atmosphere of hydrogen in the presence of palladium hydroxide on carbon catalyst (0.36 g.) for two hours. It is filtered through hyflo and concentrated to dryness ln vacuo to give 1.31 g. of (S)-[l-[(RS)-l-hydroxy-2-[(2-methylpropyl)amino]ethyl]-3-methylbutyl]-carbamic acid, l,l-dimethylethyl ester, monohydro-chloride; m.p. 138 - 150; [~]22 = -29.0 (c = 1.2, methanol). TLC (silica gel; chloroform:methanol:
acetic acid, 9:1:1) Rf = 0.73.
r C16H34N23 HCl 0.2 H2O:
C, 56.21; H, 10.41; N, 8.20; Cl, 10.37 Found: C, 56.21; H, 10.41; N, 8.14; Cl, 10.41.
HA362a d) N-[[[(3S)-3-[[(1,1-DimethYlethoxy)carbonyl]-amino]-2-hYdroxy-5-methylhexvl](2-methyl~ropyl)-amino]carbonylL-L-valine, phenylmethyl ester L-Valine, phenylmethyl ester, benzene sulfonic acid salt (8.38 g., 23 mmole) is dissolved in methylene chloride (100 ml.) and the solution is cooled to -30. N-Methyl morpholine (6.33 ml., 57.5 mmole) is added followed by a solution of phosgene in benzene (12.5% solution, 27.4 ml., 34.5 mmole). The reaction mixture is stirred at -20 for 30 minutes. It is then evaporated ln vacuo. A suspension of (S)-l-[l-hydroxy-2-[(2-methylpropyl)amino]ethyl]-3-methylbutyl]carbamic acid, l,l-dimethylethyl ester, monohydrochloride (8.0 g., 23.6 mmole) in methylene chloride (50 ml.) and N-methyl morpholine (5.05 g., 46 mmole) are added to the above residue. The reaction mixture is stirred in an ice-bath for 2 hours and then at room temperature overnight. It is evaporated and the residue is taken into ethyl acetate and washed with water, saturated sodium bicarbonate solution, and 10% potassium hydrogen sulfate solution. The ethyl acetate extract is dried and evaporated.
The crude product is chromatographed over silica gel (500 g.) using the solvent system ethyl acetate:hexane (1:2) to give 7.7 g., of N-[[[(3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)amino]carbonyl]-L-valine, phenylmethyl ester as a gummy solid; m.p.
40 _ 49; [~]2D2 = -41.4 (c = 1.5, methanol).
TLC (silica gel; ethyl acetate:hexane, 1:2) Rf = 0.37.
129763i HA362a Anal. calc'd. for C29H49N3O6:
C, 65.01; H, 9.22; N, 7.84 Found: C, 64.64; H, 9.14; N, 7.91.
e) N-[[[(3S)-3-[[(1,1-Dimethylethoxv)carbonYll-amino]-2-hYdroxY-5-methYlhexyl](2-methylproPyl)-amino]carbonyl]-L-valine, methyl ester(isomer A) The phenylmethyl ester product from part (d) (2.2 g., 4.1 mmole) is dissolved in methanol (75 ml.) and stirred under an atmosphere of hydrogen in the presence of palladium hydroxide on carbon catalyst for 16 hours. The catalyst is filtered through hyflo and the methanolic solution is evaporated to give 1.8 g. of N-[[[(3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)amino]carbonyl]-L-valine.
N-[[[(3S)-3-[[(1,1-Dimethylethoxy)carbonyl]-amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)amino]-carbonyl]-L-valine (3.0 g., 6.73 mmole) is dissolved in an ethereal solution of diazomethane generated from 2.67 g. (17.7 mmole) of N-methyl-N'-nitro-N-nitrosoguanidine reagent.
After keeping the solution at room temperature for one hour it is evaporated. The crude methyl ester product is chromatographed over silica gel (300 g.) using the solvent system ethyl acetate:hexane(2:5).
The earlier fractions (36 - 68, each 35 ml.
fractions) contain the faster moving isomer. They ; are pooled and evaporated to give 1.2 g. of N-[[[(3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)amino]-.~ , ~Z97631 HA362a carbonyl]-L-valine, methyl ester (isomer A);
m.p. 40 -49; [~]D22 = +7.2 (c = 1.5, methamol).
d. for C23H45N306 0-25 H20 C, 59.52; H, 9.88; N, 9.05 Found: C, 59.50; H, 9.78; N, 8.97.
f) N-~ L( 3S)-3-Amino-2-hydroxy-5-methylhexyl]-(2-methylproPyl)amino]carbonyl]-L-valiner methyl ester! monohydrochloride (isomer A) The methyl ester (isomer A) product from part (e) (0.4 g., 0.87 mmole) is dissolved in a solution of hydrochloric acid in dioxane (5 ml., 4.9 N) and allowed to stand at room temperature for 40 minutes. It is then evaporated and re-evaporated from methanol and ether. The residue is dissolved in water, millipore filtered, and lyophilized to give 0.29 g. of N-[[[(3S)-3-amino-2-hydroxy-5-methylhexyl](2-methylpropyl)amino]-carbonyl]-L-valine, methyl ester, monohydrochloride (isomer A); m.p. 41 - 61; [a]22 = -2.94~
(c = 1, methanol). TLC (silica gel; chloroform:
methanol:acetic acid, 8:1:1) Rf = 0.61.
Anal. calc'd. for C18H37N3O4- HCl 0.7 H2O:
C, 52.88; H, 9.72; N, 10.28; Cl, 8.67 Found: C, 52.88; H, 9.42; N, 10.38; Cl, 8.41.
g) N-[N-[(1,1-Dimethvlethoxv)carbonyl3-L-phenvl-`
alanyl]-l'-~(Dhenylmethoxy)methyll-L-histidine Thionyl chloride (27.2 ml., 375 mmole) is added in drops to a stirred solution in an ice-bath of L-histidine (38.75 g., 240 mmole) in methanol (500 ml.). After 15 minutes the ice-bath is removed and the reaction mixture is stirred at ..,~
.. . .
~7631 HA362a room temperature for one hour. After refluxing for 48 hours, it is concentrated ln vacuo. The separated crystals are filtered using methanol for washings to give 48.93 g. of L-histidine, methyl ester, dihydrochloride. The methanolic solution on dilution with ether affords an additional 10 g. of product; m.p. 208 - 209; ~]2D2 = +10.1 (c = 1.8, water).
Triethylamine (28 ml., 200 ml.) and di-tert-butyl dicarbonate (48 g., 220 mmole) are added to a suspension of L-histidine, methyl ester (24.2 g., 100 mmole) in methanol (80 ml.). After 3.5 hours, the mixture is filtered and the methanolic solution is concentrated ln vacuo. The residue is taken into chloroform and washed with 10% citric acid. The crude product on crystallization from isopropyl ether affords 23.1 g. of N,1'-bis[(1,1-dimethylethoxy)carbonyl]-L-histidine, methyl ester;
m.p. (62) 88 _ 95; [~]2D2 = +25.4 (c = 1.1, carbon tetrachloride).
Benzylchloromethyl ether (11.6 ml., 83.6 mmole) is added to a solution of N,1'-bis[(1,1-dimethyl-ethoxy)carbonyl]-L-histidine, methyl ester (24.7 g., 66.9 mmole) in dry methylene chloride (156 ml.) and the reaction mixture is stirred at room temperature for 5 hours. After concentrating in vacuo and on dissolution in ethyl acetate 17.85 g.
of N-[(l,1-dimethylethoxy)carbonyl]-1'-[(phenyl-methoxy)methyl]-L-histidine, methyl ester, mono-';
-`~ 1297631 HA362a hydrochloride crystallizes out; m.p. (148) 152 -153; [a]22 = -19.5 (c = 1.8, methanol). This methyl ester product is dissolved in hydrogen chloride in acetic acid solution (60 ml., 1.5 N) and kept at room temperture for 15 minutes. It is then evaporated ln vacuo and the residue is dissolved in hot isopropanol. After cooling, the separated crystals are filtered to yield 7.08 g.
of l-[(phenylmethoxy)methyl]-L-histidine, methyl ester, dihydrochloride; m.p. (170) 173 - 174.
l-[(Phenylmethoxy)methyl]-L-histidine, methyl ester, dihydrochloride (1.79 g., 4.94 mmole), l-hydroxybenzotriazole (0.756 g., 4.94 mmole), and N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine (1.31 g., 4.94 mmole) are dissolved in dimethyl-formamide (16 ml.). While stirring the above solution in an ice-bath, dicyclohexylcarbodiimide (1.02 g~, 4.94 mmole) and N,N-diisopropylethylamine (1.72 ml., 10 mmole) are added. After 3 hours the ice-bath is removed and the relction mixture is stirred at room temperature overnight. It is then concentrated to dryness and the residue is tritura-ted with ethyl acetate. The separated urea is filtered off. The ethyl acetate solution is washed with saturated sodium bicarbonate and then it is evaporated. The residue upon crystallization from ethyl acetate gives 1.97 g. of N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-1'-[(phenylmethoxy)methyl]-L-histidine, methyl ester;
m.p. (165) 166 - lfi8.
., ~ .. . ..
HA362a N-[N-[(1,1-Dimethylethoxy)carbonyl]-L-phenylalanyl]-1'-[(phenylmethoxy)methyl]~L-histidine, methyl ester (4.5 g., 8.4 mmole) is dissolved in hot methanol (25 ml.~. After cooling to room temperature aqueous sodium hydroxide solution (9.24 ml., lN) is added and the mixture is stirred at room temperature for 3 hours. It is then concentrated in vacuo and water (60 ml.) is added to the residue. After cooling the aqueous solution in an ice-bath, it is acidified to pH 4.5 using aqueous hydrochloric acid. It is then extracted with ~thyl acetate to yield 3.95 g. of crystalline N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-l'-[(phenylmethoxy)methyl]-L-histidine; m.p. 193 - 194; [~]22 = -4.8 (c = 1.1, dimethylformamide).
h) N-[[[(3S)-3-[[N-[N-[(l,l-Dimethylethoxy)-carbonyl]-L-phenylalanyl]-1'-[(phenylmethoxy)-methyl]-L-histidinyl]amino]-2-hydroxy-5-methyl-hexyll(2-methylpropyl)amino]carbonyl]-L-valine~
methyl ester (isomer A) N-~[[(3S)-3-Amino-2-hydroxy-5-methylhexyl]-(2-methylpropyl)amino~carbonyl]-L-valine, methyl ester, monohydrochloride (isomer A) (0.396 g., 1 mmole~, N-[N-[(1,1-dime-thylethoxy)carbonyl]-L-phenylalanyl]-1'-[(phPnylmethoxy)methyl] L-histidine (0.522 g~, 1 mmole) and 1-hydroxybenzo-triazole hydrate (0.153 g., 1 mmole) are dissolve~
in dimethylformamide (6 ml.). Diisopropylethyl amine (0.21 ml., 1.3 mmole) is added and the solution is cooled to -10. While stirring under a , ` ~
..~
-` 1297631 HA362a gentle flow of nitrogen, dicyclohexylcarbodiimide (0.206 g., 1 mmole) is added. After stirring for one hour between -10 and 0, the reaction mixture is then stirred in an ice-bath for 2 hours and then stirring is continued at ambient temperature overnight.
The separated dicyclohexyl urea is filtered off and the dimethylformamide solution is evaporated.
The residue is taken into ethyl acetate and washed with saturated sodium bicarbonate solution. The ethyl acetate extract after concentration is chromatographed over silica gel (45 g.) using the solvent system chloroform:methanol:acetic acid (9:0.5:0.5). Homogeneous fractions containing the product are pooled, evaporated, and the residue taken into ethyl acetate and washed with saturat~d sodium bicarbonate. The ethyl acetate extract is dried and evaporated to give 0.61 g. of N-[[[(3S)-3-~[N-LN-[(1,1-dimethylethoxy)carbonyl]-L-phenyl-alanyl]-1'-[(phenylmethoxy~methyl]-L-histidyl]-amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)-amino]carbonyl]-L-valine, methyl ester (isomer A).
i) N-[~ f ( 3S)-3-[[N-[N-~(l,1-Dimethylethoxy)-carbonyll-L-Phenvlalanyll-L-histidyllaminol-2 hydroxv-5-methylhexvll(2-methYlpropyl)amino]-carbonYll-L-valine, methYl ester, monohvdrochloride (isomer A~
The methyl ester product from part (h) (0.3 g., 0.35 mmole) is dissolved in methanol (25 ml.). Aqueous hydrochloric acid (lN, 0.35 ml.) is added and the solution is stirred under an atmosphere of hydrogen in the presence of palladium :
;
,~"
1~
, _35_ HA362a hydroxide on carbon catalyst (0.1 g.) for 15 hours. It is then filtered through hyflo and evaporated to dryness. The residue is triturated with ether and filtered to give 0.22 g. of S N- [ [ [ ( 3S ) -3-[[N-[N-[(l,l-dimethylethoxy)carbonyl]-L-phenylalanyl~-L-histidyl]amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)amino3carbonyl~-L-valine, methyl ester, monohydrochloride (isomer A);
m.p. 125 - 137; [a]2D2 = -2.9 (c = 1, methanol). TLC (silica gel, chloroform:methanol:
acetic acid, 15:1:1) Rf = 0.23.
38H61N78 HCl- 1.1 H2O:
C, 57.02; H, 8.06; N, 12.25; Cl, 4.43 Found: C, 57.02; H, 7.89; N, 12.12; Cl, 4.99.
Example 2 N-~[(3S)-3-[[N-[~-[(l,l-DimethYlethoxY)carbonvl~-L-~henYlalanYll-L-histidy~laminol-2-hYdroxy-5-methylhexYl](2-methylpropyl2aminolcarbonYl]-L-valine, methyl ester~ monohYdrochloride (isomer B) a) N-[[ L ( 3S?-3 - r [ ( 1, 1 -DimethylethoxY ) carbonYl ] -amino]-2-hydroxy-S-methvlhexYll(2-methylro~yl) amino]carbonYll-L-valine, methYl ester (isomer B) Following the chromatographic procedure described in Example 1 (e), fractions 70 - 90 (50 ml. fractions) contain the slow moving isomer.
These fractions are pooled and evaporated to give 1.25 g. of N-~[[(3S)-3-~[(1,1-dimethylethoxy)-carbonyl]amino]-2-hydroxy-5-methylhexyl](2-methyl-propyl)amino]carbonyl]-L-valine, methyl ester (isomer B); m.p. 44 - 55; [a]2D2 = -78 (c = 1, 1297~
HA362a methanol). TLC (silica gel; ethyl acetate:
hexane 1:1) Rf = 0.38.
Anal- calc~d. for C23H45N3O6 C, 60.10; H, 9.87; N, 9.14;
S Found: C, 59.84; H, 9.82; N, 9.00.
b) N-[ r r ( 3S)-3-Amino-2-hydroxy-5-methylhexYll-(2-methyl~ro~Yl)aminolcarbonyll-L-valine, methyl ester, monohYdrochloride (isomer B) The methyl ester (isomer B) product from part (a) (0.35 g., 0.76 mmole) is dissolved in a solution of hydrochoric acid in dioxane (4 ml., 4.9 N) and allowed to stand at room temperature for 50 minutes. It is then evaporated and reevaporated from methanol and ether. The crude residue is dissolved in water, millipore filtered, and lyophilized to give 0.27 g. of N-[t[(3S)-3-amino-2-hydroxy-S-methylhexyl]~2-methylpropyl)amino]-carbonyl]-L-valine, methyl ester, monohydrochloride (isomer B).
c) N-[[~(3S)-3-r[N-[N-[(1,1-DimethYlethoxv2-carbonyl]-L-phenYlalanyl~ henylmethoxy)methyl]
L-histidYl]aminol-2-hvdroxy-5-methYlhexvll(2-methYl-proyl)aminolcarbonvll-L-valine, methyl ester (isomer Al N-[[[(3S)-3-Amino-2-hydroxy-5-methylhexyl]-(2-methylpropyl)amino]carbonyl]-L-valine, methyl ester, monohydrochloride (isomer B) (0.36 g., 0.91 mmole), N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-l'-[(phenylmethoxy)methyl]-L-histidine (0.475 g., 0.91 mmole) and 1-hydroxybenzotriazole ~.
'.
-`` 1297631 HA362a hydrate (0.139 g., 0.91 mmole) are dissolved in dimethylformamide (6.5 ml.). Diisopropylethylamine (0.21 ml., 1.3 mmole) is added and the solution is stirred in an ice-bath. Dicyclohexylcarbodiimide (0.188 g., 0.91 mmole) is added and the stirring of the reaction mixture is continued at ambient temperature overnight. Dicyclohexylurea is filtered off and the dimethylformamide solution is evaporated. The residue is taken into ethyl acetate and washed with saturated sodium bicarbonate solution. The ethyl acetate extract after concentration is chromatographed over silica gel (50 g.) using the solvent system chloroform:
methanol:acetic acid, 10:0.5:0.5. Homogeneous fractions containing the product are pooled, evaporated, and the residue taken into ethyl acetate and washed with saturated sodium bicarbonate. The ethyl acetate extract is dried and evaporated to give 0.62 g. of N-[[[(3S)-3-[[N-rN-[(1,1-dimethylethoxy)carbonyl]-L-phenyl-alanyl]-1'-[(phenylmethoxy)methyl}-L-histidyl]-amino]-2-hydroxy-5-methylhexyl](2-methoxypropyl)-amino]carbonyl]-L-valine, methyl ester (isomer A).
d) N-~LL~3S)-3-rrN-[N-[(1,1-Dimethvlethoxy)-carbonvll-L-phenvlalanYl]-L-histidyl]amino]-2-hydroxy-5-methvlhexyll(2-methyl~ro~yl)amino]-carbonvl]-L-valine, methyl ester,monohvdrochloride (isomer B) The methyl ester (isomer B) product from part (c) (0.32 g., 0.37 mmole) is dissolved in . ,~ . ..... . .. . . .
.
HA362a methanol (25 ml.). Aqueous hydrochloric acid (1 N, 0.37 mmole) is added and the solution is stirred under an atmosphere of hydrogen in the presence of palladium hydroxide on carbon catalyst (0.1 g.) for 18 hours. It is then filtered through hyflo and evaporated to dryness. The residue is dissolved in isopropanol (3 ml.) and while shaking vigorously isopropyl ether (35 ml.) is added. The resulting precipitate is filtered and dried to give 0.184 g. of N-[[[(3S)-3-[[N-[N-[(l,l-dimethylethoxy)carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl](2-methyl-propyl)amino]carbonyl]-L-valine, methyl ester monohydrochloride (isomer B); m.p. 115 - 140;
[a]2D2 = -36.9 (c = l.l, methanol). TLC (silica gel; chloroform:methanol:acetic acid, 15:1:1) Rf = 0.20.
38H61N708 HCl 1.34 H20:
C, 56.73; H, 8.10; N, 12.19; Cl, 4.41 Found: C, 56.73; H, 7.99; N, 12.28; Cl, 4.66.
Exam~le 3 N-[N-[r[(3S)-3-[[N-rN-[(1,1-Dimethvlethoxv)-carbonyll-L-phenylalanvll-L-histidyl]aminol-2-hvdroxY-5-methYlhexY1](2-methvl~ro~Yl)amino]
carbonyll-L-valvl]-L-~henylalanine, methyl ester, monohvdrochloride a~ N-[[[(3S)-3-[[(l,l-Dimethylethoxv)carbonyl]-aminol-2-hvdroxv-5-methylhexyll(2-methYl~ropyl)-amino]carbonvll-L-valine N-[[[(3S)-3-[[(1,1-Dimethylethoxy)carbonyl]-HA362a amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)-amino]carbonyl]-L-valine, phenylmethyl ester (2.0 g., 3.73 mmole), prepared as set forth in Example l(d), is dissolved in methanol (100 ml.) and stirred under an atmosphere of hydrogen for 16 hours in the presence of palladium hydroxide on carbon catalyst (400 mg.). It is filtered and the methanolic solution is evaporated to give 1.66 g.
of N-[[[(3S)-3-[[(l,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)amino]carbonyl]-L-valine as a foamy solid.
b) N-[N- L[ [ ( 3S)-3-[[(l,1-DimethYlethoxY)carbonyl]-amino]-2-hydroxv-5-methvlhexvl](2-methylDropYl)amino]
carbonyl]-L-valyl]-L-phenvlala-nlne~ methyl ester N-[[[(3S)-3-[[(1,1-Dimethylethoxy)carbonyl]-amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)amino]-carbonyl]-L-valine (1.62 g., 3.63 mmole), L-phenyl-alanine, methyl ester, monohydrochloride (0.94 g., 4.36 mmole) and N-hydroxy succinimide (0.42 g., 3.63 mmole) are dissolved in dimethylformamide (13 ml.). While stirring the above solution in an ice-bath, dicyclohexylcarbodiimide (0.75 g., 3.63 mmole) and diisopropylethyl amine (0.85 ml.
Szelke et al. in European Patent Application 104,041 published in 1984 disclose renin inhibitory polypeptides including the partial sequence X- A -B - Z- W and X-Phe-His-A-B-Z-W
10 wherein A is Rl R3 R2 0 -NH-CH - G- N - C~ - C-and G is OH
-CH - C~2 X is hydrogen, protecting group, or an amino acyl residue, B is a lipophilic amino acyl residue, and Z plu~ W are an amino alcohol residue or Z is aminoacyl and W i8 hydroxy, ester, amide, etc.
Matsueda et al. in United States Patent 4,548,926 disclose renin inhibiting peptides of the formula ~; 25 NH
2 But Rl-- C~ - C~ X
~' ~, , .~.. .. .. .
129763~
HA362a wherein But represents an isobutyl or sec-butyl group and X includes a group of the formula -CH(R2)_y Gordon et al. in IJ.S. Patent 4,514,391 disclose hydroxy substituted peptide compounds of the formula OH R Rl O
l l 11 which possess angiotensin converting enzyme or enkephalinase inhibition activity.
This invention is directed to new hydroxy containing ureido renin inhibitors of formula I
including pharmaceutically acceptable salts thereof (I) 11 ~ R2 Rl Rg O
X-NH-CH--C-NH-CH--CH-CH2-N--C-NH-CH--C ( NH-CH--C ) Rlo 30 X is R6-~CH2)m-~ NH CH ~p Il l 11 R6-(cH2)m-c-t ~H - CH -C ~-p , , .. ..
HA362a R6 ( CH2 )m ~ C ~ NH--CH--C--R6----(CH2)n C~ NH--CH--C tp Il I 11 R6--(CH2)m NH--C~ NH--CH- C~
l 11 6--(CH2 )m S02~ NH--CH--C
Il l 11 or R6-(CH2)m CH-C-(NH-CH--C ~p I
(CH2) R' Rl, R3, R4, R5, and Rg are independently select-30 ed from hydrogen, lower alkyl, halo substituted lower alkyl, -(CH2)n-aryl, -(CH2)n-heterocyclo, -(CH2)n-OH, ( 2 )n H2, (CH2)n-SH~ -(CH2)n-S-lower alkyl, -(CH2)n-0-lower alkyl, ~(CH2)n~0~(CH2)g~0H~
- ( CH2 ) ~- ( CH2 ) g~NH2 ~ ~ ( CH2 ) n ( 2 ,.
~ ,~
~.. . . .
-~` 129763~
_5_ HA362a NH
.~
(CH ) ~S~(CH2)g~NH2~ -(CH2)n ( 2)n C NH2 , ~(CH2)n ~ J~R7' (CH)n P~8 and -(CH2)n-cycloalkyl.
R2 is hydrogen, lower alkyl, -(CH2)m-aryl, -(CH2)m-cycloalkyl, or -(CH2)n-heterocyclo.
R6 and R'6 are independently selected from lower alkyl, cycloalkyl, aryl and heterocyclo.
p is zero or one.
m and m' are independently selected from zero and an integer from 1 to 5.
n is an integer from 1 to 5.
g is an integer from 2 to 5.
7 CH2 0 CH2 ~ or -CH2 ~ .
R8 is 2,4-dinitrophenyl, _1_0_CF72~ , -SO ~ H3 ~ or -CH -O-CH
q is zero or one.
R1o is hydroxy, -O-lower alkyl, : -O-(CH2)m-cycloalkyl, -O-(CH2)m-aryl, -O-(CH2)n-heterocyclo, -NH2, or -O-salt forming ion.
..~
" .,~, . ,.~ ., .. ~ . . , HA362a This invention in its broadest aspects relates to the compounds of formula I above, to compositions and the method of using such compounds as antihypertensive agents.
The term lower alkyl used in defining various symbols refers to straight or branched chain radicals having up to seven carbons.
The term cycloalkyl refers to saturated rings of 4 to 7 carbon atoms with cyclopentyl and cyclohexyl being most preferred.
The term halogen refers to chloro, bromo and fluoro.
The term halo substituted lower alkyl refers to such lower alkyl groups described above in which one or more hydrogens have been replaced by chloro, bromo or fluoro groups such as trifluoro-methyl, which is preferred, pentafluoroethyl, 2,2,2-trichloroethyl, chloromethyl, bromomethyl, etc.
The term aryl refers to phenyl, l-naphthyl, 2-naphthyl, mono substituted phenyl, 1-naphthyl, or 2-naphthyl wherein said substituent is lower alkyl of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, halogen, hydroxy, amino, -NH-alkyl wherein alkyl is of 1 to 4 carbons, or -N(alkyl)2 wherein alkyl is of 1 to 4 carbons, di or tri substituted phenyl, 1-naphthyl or 2-naphthyl wherein said substituents are selected from methyl, methoxy, methylthio, halogen, and hydroxy.
~. ~
-HA362a The term heterocyclo refers to fully saturated or unsaturated rings of 5 or 6 atoms containing one or two O and S atoms and/or one to four N atoms provided that the total number of hetero atoms in the ring is 4 or less. The heterocyclo ring is attached by way of an available carbon atom.
Preferred heterocyclo groups include 2- and 3-thienyl, 2- and 3-furyl, 2-, 3- and 4-pyridyl, and imidazolyl. The term heterocyclo also includes bicyclic rings wherein the five or six membered ring containing O, S and N atoms as defined above is fused to a benzene ring. The preferred bicyclic ring is indolyl.
The compounds of formula I wherein Il l 11 X iS R6-(cH2)m-o-c-t NH- CH - C~p can be prepared by coupling an alcohol of the formula (II) R3 R2 o R1 o Rg O
l 11 1 11 1 ll H2N-CH- CH - CH2- N - C-NH-CH-C -(NH-CH-C ~ R1o OH
with a peptide of the formula (III) R6-(CH2)m-O-C-~-NH -CH - C ~-p NH -CH - COOH
~,~
.:..... .
~297631 HA362a This reaction is preferably performed in a solvent such as dimethylformamide and in the presence of hydroxybenzotriazole, diisopropylethylamine, and a coupling agent such as dicyclohexylcarbodiimide.
The corresponding compounds of formula I
wherein p is zero can be prepared by coupling the alcohol of formula II with the amino acid of the formula (IV) Il I
R6-(CH2)m-0-C-NH-CH -COOH
to yield the products of the formula (V) ll 1 4 ll 1 3 1 2 ~ 9 11 R6-~CH2)m-O-C-NH-CH- C-NH-CH-CH-CH2-N- C-NH-CH-C-~ NH-CH-C ~- Rlo .
OH
When R6-(CH2)m~ is t-butyl or benzyl, then the product of formula V can be treated so as to remove the t-butoxycarbonyl or benzyloxycarbonyl group such as by the use of hydrochloric acid when R6 is t-butyl to yield the amine of the formula (Vl) R O R R O R O R O
14 11 13 12 ~ 19 11 H2N-CH-C-NH-CH-CH-CH2-N- C-NH-CH-C-~NH-CH-C ~ Rlo OH
HA362a Coupling with the amino acid of the formula (VII) Il I
S R6-(CH2)m~O~C - NH - CH -COOR
yields the products of formula I wherein p is one.
The compounds of formula I wherein X is other than R6-(CH2)m~O~C-~ NH -CH- C tp can be prepared by treating the product of formula I wherein R6 is Il 11 C O C(CH3)3 or C O CH2 ~ and m is zero to remove the t-butoxycarbonyl or benzyloxycarbonyl group and yield the intermediates of the formula (VIII) R5 R4 1l 13 12 h 1 ll Rg O
H2N-CH-C-NH-CH C-NH-CH-CH-CH2-N- C-NH-CH-C-~-NH-CH-C ~ Rlo OH
: The amine of formula VIII or formula VI is treated with the halide of the formula (IX) R6 ( CH2 )m-halo :~
, ., ~
~
.
~.,..... , ~ .. ......
.
HA362a particularly where halo is Br to give the products of formula I wherein X is R6-(CH2)m ( NH -CH- C tp The amine of formula VIII or VI is treated with the acid chloride of the formula 10 (X) o Il .
R6~CH2)m~C~Cl or l5 (XI) o R6 (CH2)n C Cl 20 in the presence of triethylamine to yield the products of formula I wherein O R O
~ 5 11 X iS R6 (CH2)m C ~ NH CH C~p or o R O
R6-0-(CH2)n-C ~ NH-CH - C-t-p ~ 30The amine of formula VIII or VI is treated '~ with the substituted sulfonyl chloride of the formula (XII) ~ ~ R6 ( CH2 )m-S02-C
,~' .~
~'''''': '` ' ' , ~ ' .
: ' ' ' ' ' ' , .
129763~
HA362a to yield the products of formula I wherein X is R o R6-(CH2)m- So2-~ NH-CH - C-~ .
The amine of formula VIII or VI is treated with phosgene and the resulting acid chloride is treated with the substituted amine of the formula (XIII) R6-(CH2)m NH2 to yield the products of formula I wherein X is R6-(CH2)m-NH-C-~ NH-CH C +p The products of formula I wherein Il l 11 X is R6-(CH2)m- G~-c-~NH--CH--C ~
I
(CH2) R'6 can be prepared by coupling the carboxylic acid of the formula :
. ~.
' ;
...... ..
HA362a (XIV) o Il R6 (CH2)m CH C OH
S
( CH2 ) I
R~6 to the amine of formula VI or VIII in the presence of dicyclohexylcarbodiimide and l-hydroxybenzo-triazole hydrate. Alternatively, the acid of formula XIV can be converted to the acid chloride and this acid chloride can then be coupled to the amine of formula VI or VIII in the presence of triethyl-amine and tetrahydrofuran or water and sodium bicarbonate.
The alcohol of formula II can be prepared by reacting an alcohol of the formula (XV) Prot-NH-CH -CH - CH2-N -H
I
OH
preferably the hydrochloride salt thereof, with the carbamoyl chloride of the formula .,~
... .
HA362a (XVI) O Rl O
Il 1 ~1 Cl- C- NH - CH- C- 0 - CH
to give (XVII) R R2 I Rl Prot-NH-C3-CH-CH2-N--C-NH-CH--C-O-CH
OH
wherein Prot is an amino protecting group such as t-butoxycarbonyl. Removal of the benzyl group from the intermediate of formula XVII such as by hydrogenation yields the acid of the formula (XVIII) ~ R R O R O
~ 25 13 l2 ~
Prot-NH-CH -FH-CH -N -C NH-CH-C-OH
OH
` ~ :
~: 30 .,~ 3S
.~
,::
.,.... ~
~297631 HA362a Removal of the t-butoxycarbonyl amino protecting group such as by treatment with hydrochloric acid gives the alcohol of formula II wherein q is zero and Rlo is hydroxy. When q is zero and Rlo is other than hydroxy, the acid of formula XVIII is treated to introduce the R1o group, for example, treatment with diazomethane where R1o is methoxy, followed by removal of the t-butoxycarbonyl protecting group. Of course, where final products are desired having Rlo as then the benzyl -O-CH2~
group is not removed from the intermediate of formula XVII.
When ~ is one, then the acid of formula XVIII
is treated with the amino acid of the formula (XIX) Rg 0 H2N CH -C Rlo in the presence of a coupling reagent such as dicyclohexylcarbodiimide to give (XX) R R O R O R O
13 12 ~ 19 11 Prot-NH-CH-CH-CH2-N-- C-NH-CH-- C-NH-CH-C-Rlo OH
Removal of the t-butoxycarbonyl amino protecting group as described above gives the alcohol of formula II.
. . .
~ ,;
12g7631 HA362a The alcohol starting compound of XV can be prepared by treating the ketone of the formula (XXI) I
Prot- NH -CH - C -CH2- N - CH2 ~
with a conventional reducing agent such as sodium borohydride followed by hydrogenation using palladium hydroxide on carbon catalyst.
The ketone of formula XXI can be prepared by treating the ketone of the formula 15 (XXI I ) I
Prot-NH -CH -C- CH2- Cl ll o with an amine of the formula (~XIII) H
in the presence of sodium iodide and sodium bicar-bonate in a solvent such as dimethylformamide.
When R2 is hydrogen, the ketone of formula XXII is reacted with dibenzylamine. After reduction to the alcohol, both benzyl groups are removed by "..;
~.
12g~631 HA362a hydrogenation.
In the above reactions, if any of Rl, R2, R3, R4, R5, and Rg are -(CH2)n-aryl wherein aryl is phenyl, l-naphthyl, 2-naphthyl substituted with one or more hydroxy or amino groups, -(CH2)n-heterocyclo wherein heterocyclo is an imidazolyl, -(CH2)n-NH2, ~ NH
-(CH2) -SH, -(CH2) -OH, or -(CH2) -NH-C
then the hydroxyl, amino, imidazolyl, mercaptan, or guanidinyl function should be protected during the reaction. Suitable protecting groups include benzyloxycarbonyl, t-butoxycarbonyl, benzyl, benz-hydryl, trityl, etc., and nitro in the case of guanidinyl. The protecting group is removed by hydrogenation, treatment with acid, or by other known means following completion of the reaction.
The various peptide intermediates employed in above procedures are known in the literature or can be readily prepared by known methods. See for example, The Peptides, Volume 1, "Major Methods Of Peptide Bond Formation", Academic Press (1979).
Preferred compounds of this invention are those of formula I wherein:
O R O
Il 15 1l X is lower alkyl-O-C-NH-CH -C- , 7~
HA362a - CH2-0-C-NH -CH - C- , or ~ 11 ~ ~ C~2,2 CH-C-Rl is lower alkyl of 3 to 5 carbons -(CH2)m-cyclopentyl, -(CH2)m-cyclohexyl, -(CH2)m ~ , or ~(CH2)m- ~
wherein m is an integer from 1 to 3.
22 is hydrogen, lower alkyl of 3 to 5 carbons, -(CH2)m-cyclopentyl, -(CH2)m-cyclohexyl, (CH2)m ~ or -(CH2)m ~ wherein m is an integer from 1 to 3.
R3 is lower alkyl of 3 to 5 carbons, -(CH2)m~cyclopentyl, -(CH2)m-cyclohexyl or ~(CH2)m ~ wherein m is an integer from 1 to 3.
~297631 HA362a 4 -CH2 ~ JNH , -CH2 ~ N-CH2-0-CH2 ~ , -CH2 ~ -CH2 ~ ' -CH2 ~ 0H
-CH2 ~ ' -CH2--@ N , CH2 -(CH2)2 ~ ' or -CH2 ~ N02 R5 and Rg are independently selected from -CH2 ~ , -(CH2) ~ , -CH2-(~-naphthyl), -CH2-(~-naphthyl), -CH2 ~ OH , -CH2-cyclopentyl, , . ' 129763~
HA362a -CH2-cyclohexyl, _[~) , -CH~N
5 --CH2~ , -CH2~ JNH , -CH2~JH
and -CH ~ O
H
Rlo iS--o-CH3 ~ -0-C2H5, -0-CH2~>, -0-CH2 ~ or hydroxy.
Moæt preferred are the above compounds wherein O R O
Il 15 11 X is (H3C)3-C-O-C-NH-CH- C-Rl is -CH- CH2- CH3 or -CH-(CH3)2, especially -CH - CH2- CH3 I
~2g763~
HA362a -20~
R2 is hydrogen, -CH2-CH(CH3)2 or -CH(CH3)2 , especially hydrogen.
R5 is -CH2 ~
R4 is ~N J
R3 is -CH2-CH(CH3)2 q is zero or one, especially one.
R9 is -CH2 ~ TN~J
especially -CH2 ~ NH
Rlo is -O CH3 The compounds of formula I form salts with a variety of inorganic and organic acids. The non-toxic pharmaceutically acceptable salts arepreferred, although other salts are also useful in isolating or purifying the product. Such pharmaceutically acceptable salts include those formed with hydrochloric acid, methanesulfonic acid, sulfuric acid, acetic acid, maleic acid, etc.
The salts are obtained by reacting the product ' ,'~ `' , - ;.
~2g7~
HA362a with an equivalent amount of the acid in a medium in which the salt precipitates.
The compounds of formula I contain asymmetric centers when any or all of Rl, R3, R4, R5, and Rg are other than hydrogen and at the carbon to which the -OH group is attached.
Thus, the compounds of formula I can exist in diasteroisomeric forms or in mixtures thereof.
The above described processes can utilize racemates, enantiomers or diastereomers as starting materials. When diastereomeric products are prepared, they can be separated by conventional chromatographic or fractional crystallization methods.
The compounds of formula I, and the pharma-ceutically acceptable salts thereof, are anti-hypertensive agents. They inhibit the conversion of angiotensinogen to angiotensin I and therefore, are useful in reducing or relieving angiotensin related hypertension. The action of the enzyme renin on angiotensinogen, a pseudoglobulin in blood plasma, produces angiotensin I.
Angiotensin I is converted by angiotensin converting enzyme (ACE) to angiotensin II. The latter is an active pressor substance which has been implicated as the causative agent in several forms of hypertension in various mammalian species, e.g., humans. The compounds of this invention intervene in the angiotensinogen ~
(renin) ~ angiotensin I ~ (ACE) ~ angiotensin II
sequence by inhibiting renin and reducing or ~2g7~31 -22- HA362a eliminating the formation of the pressor substance angiotensin II. Thus by the administration of a composition containing one (or a combination) of the compounds of this i~vention, angiotensin dependent hypertension in a species of mammal (e.g., humans) suffering therefrom is alleviated.
A single dose, or preferably two to four divided daily doses, provided on a basis of about 100 to 1000 mg., preferably about 250 to 500 mg. per kg. of body weight per day is appropriate to reduce blood pressure. The substance is preferably administered orally, but parenteral routes such as the subcutaneous, intramuscular, intraveneous or intraperitoneal routes can also be employed.
The compounds of this invention can also be formulated in combination with a diuretic for the treatment of hypertension.
A combination product comprising a compound of this invention and a diuretic can be administered in an effective amount which comprises a total daily dosage of about 1000 to 6000 mg., preferably about 3000 to 4000 mg. of a compound of this invention, and about 15 to 300 mg., preferably about 15 to 200 mg. of the diuretic, to a mammalian species in need thereof.
Exemplary of the diuretics contemplated for use in combination with a compound of this invention are the thiazide diuretics, e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflu-methiazide, bendroflumethiazide, methyclothiazide,trichloromethiazide, polythiazide or benzthiazide - , .
. ' :.' . ' ' `- 12g763~
HA362a as well as ethacrynic acid, ticrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride and spironolactone and salts of such compounds.
The compounds of formula I can be for~.ulated for use in the reduction of blood pressure in compositions such as tablets, capsules or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration.
About 100 to 500 mg. of a compound of formula I is compounded with physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice.
The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.
The following examples are illustrative of the invention. Temperatures are given in degrees centigrade.
lZ~7~9~
HA362a Example 1 N-[[[(3S)-3-[[N-[N-[(l,l-Dimethylethoxy)carbonyl]-L-phenYlalanyl]-L-histidyl]amino]-2-hydroxY-5-methylhexvl](2-methYlpropyl)amino]carbonyl]-L-valine, methyl ester, monohydrochloride (isomer A)a) (S)-[3-Methvl-1-[[(2-methylPropyl)(phenyl-methyl)amino]acetyl]butyl]carbamic acid, 1,1-dimethYlethyl ester,4-methylbenzenesulfonic acid salt (1:1) N-Methyl morpholine (16.5 ml., 150 mmole) is added to a stirred solution of N-[(l,1-dimethyl-ethoxy)carbonyl]-L-leucine (34.67., 150 mmole) in dry tetrahydrofuran (135 ml.) at ~15 followed by the dropwise addition of isobutyl chloroformate (19.5 ml., 150 mmole). After stirring at -15 for twenty minutes, it is filtered and diluted with ether (4~0 ml.) kept at -20. This is added dropwise over 15 minutes to an ethereal solution of diazomethane (600 ml., generated from 60 g. of N-methyl-N'-nitro-N-nitrosoguanidine). After the addition is over the reaction is allowed to run at ; room temperature for two hours. Excess diazomethane is blown off by a stream of nitrogen. The ethereal solution is washed with saturated aqueous sodium bicarbonate and saturated sodium chloride solutions. The ethereal solution is concentrated ln vacuo and the residue is dissolved in hexane. On cooling, 27.7 g. of (S)-[3-methyl-1-[(diazomethyl)carbonyl]butyl]-carbamic acid, 1,1-dimethylethyl ester is obtained as a crystalline material; m.p. (88) 89 - g0.
.
~, , . . .
.
.
12g7631 HA362a Hydrochloric acid in acetic acid (2.2 N, 94 mmole) is added dropwise to a stirred (ice-bath) solution of the above diazo product (24 g., 94 mmole) in ether (470 ml.). After stirring for 10 minutes the solution is evaporated ln vacuo.
The residue is dissolved in ethyl acetate:hexane (1:3) and passed through a small column of silica gel (400 g.) using ethyl acetate:hexane (1:3) for elution. A homogeneous material is obtained (23.2 g.). On crystallization from a mixture of ether and hexane fine crystalline (S)-[3-methyl-l-[(chloromethyl)carbonyl]butyl]carbamic acid, 1,1-dimethylethyl ester is obtained; m.p. 66-68.
A solution of (phenylmethyl)(2-methylpropyl)-amine (8.16 g., 50 ml.), (S)-[3-methyl-1-[(chloro-methyl)carbonyl]butyl]carbamic acid, l,l-dimethyl-ethyl ester (13.19 g., 50 mmole), sodium bicarbonate (6.3 g., 75 mmole), sodium iodide (3.74 g., 25 mmole) and dimethylformamide (100 ml.) is stirred at room temperature for 4 hours. It is then evaporated, taken into ethyl acetate and washed with water. The ethyl acetate solution is evaporated and the residue dissolved in ether.
The ethereal solution is filtered to remove a very small amount of insoluble material. The ethereal solution is evaporated and the residue is chromato-graphed over a small column of silica gel (350 g.) using the solvent system ethyl acetate:hexane (1:4). The homogeneous fractions are pooled and evaporated. The residue (17.62 g.) is dissolved in ether and an ethyl acetate solution of `", HA362a p-toluenesulfonic acid (8.6 g., 45.2 mmole) is added. The crystallized salt is filtered to give 18.72 g. of (S)-[3-methyl-1-[[(2-methylpropyl) (phenylmethyl)amino]acetyl]butyl]carbamic acid, l,l-dimethylethyl ester, 4-methylbenzenesulfonic acid salt (1:1); m.p. (140) 143; [~]D = -38.9 (c = 2.2, methanol). TLC (silica gel; n-propanol:
NH40H, 98:2) Rf = 0.8.
Anal. calc'd. for C30H46N26S C7H83 C, 64.03; H, 8.24; N, 4.98; S, 5.70 Found: C, 63.83; H, 8.00; N, 4.97; S, 5.78.
b) (S)-~l-[tRS)-l-HydroxY-2-[(2-methylpro~yl) (~henvlmethYlLamino~ethyll-3-methylbutyl]carbamic acid, 1,1-dimethYlethyl ester, monohydrochloride The 4-methylbenzenesulfonic acid salt product from part (b) (5.62 g., 10 mmole) is taken into ethyl acetate and shook with saturated sodium bicarbonate solution. The ethyl acetate layer is dried over magnesium sulfate and evaporated in vacuo. The resulting free base (3.9 g.) is dissolved in ethanol (35 ml.). Sodium borohydride (400 mg., 10.4 mmole) is added to the stirring ethanolic solution at room temperature. After one hour the solution is evaporated and the residue is suspended in ethyl acetate and water and acidified to pH 2.0 using dilute hydrochloric acid. Then saturated sodium bicarbonate solution is added until the ethyl acetate solution is slightly basic. The ethyl acetate layer is dried over magnesium sulfate and evaporated to give 3.91 g.
of alcohol product. An analytical sample of this alcohol is prepared as the hydrochloride salt as follows. Hydrochloric acid in dioxane ~1 ...
, . " ~ , . .. .
lZg76~1 HA362a solution (5N, 0.28 ml.) is added to an ethereal solution of an aliquot of the above alcohol (O.S59 g., 1.42 mmole). The solution is concentrated and dried in high vacuum tc give (S)-[1-[(RS)-l-hydroxy-2-[(2-methylpropyl)(phenylmethyl)amino]ethyl]-3-methylbutyl]carbamic acid, l,1-dimethylethyl ester, monohydrochloride as a crisp solid; m.p. 50 - 65 [a]D = -29.8 (c = 1.54, methanol). TLC (silica gel, ethyl acetate:hexane, 1:4) Rf = 0.47.
Anal- calc'd- for C23H40N23 HCl 0-44 H2O
C, 63.21; H, 9.68; N, 6.41; Cl, 8.11 Found: C, 63.21; H, 9.49; N, 6.05; Cl, 7.88.
c) (S)-[1-[(RS)-l-HYdroxy-2-[(2-methylpro~yl)-amino]ethyll-3-methylbutyl~carbamic acid,l,1-dimethYlethyl ester, monohydrochloride The alcohol product from part (b) (1.67 g.,4.25 mmole) is dissolved in methanol (50 ml.) and aqueous hydrochloric acid (lN, 4.25 ml.) is added.
The solution is stirred under an atmosphere of hydrogen in the presence of palladium hydroxide on carbon catalyst (0.36 g.) for two hours. It is filtered through hyflo and concentrated to dryness ln vacuo to give 1.31 g. of (S)-[l-[(RS)-l-hydroxy-2-[(2-methylpropyl)amino]ethyl]-3-methylbutyl]-carbamic acid, l,l-dimethylethyl ester, monohydro-chloride; m.p. 138 - 150; [~]22 = -29.0 (c = 1.2, methanol). TLC (silica gel; chloroform:methanol:
acetic acid, 9:1:1) Rf = 0.73.
r C16H34N23 HCl 0.2 H2O:
C, 56.21; H, 10.41; N, 8.20; Cl, 10.37 Found: C, 56.21; H, 10.41; N, 8.14; Cl, 10.41.
HA362a d) N-[[[(3S)-3-[[(1,1-DimethYlethoxy)carbonyl]-amino]-2-hYdroxy-5-methylhexvl](2-methyl~ropyl)-amino]carbonylL-L-valine, phenylmethyl ester L-Valine, phenylmethyl ester, benzene sulfonic acid salt (8.38 g., 23 mmole) is dissolved in methylene chloride (100 ml.) and the solution is cooled to -30. N-Methyl morpholine (6.33 ml., 57.5 mmole) is added followed by a solution of phosgene in benzene (12.5% solution, 27.4 ml., 34.5 mmole). The reaction mixture is stirred at -20 for 30 minutes. It is then evaporated ln vacuo. A suspension of (S)-l-[l-hydroxy-2-[(2-methylpropyl)amino]ethyl]-3-methylbutyl]carbamic acid, l,l-dimethylethyl ester, monohydrochloride (8.0 g., 23.6 mmole) in methylene chloride (50 ml.) and N-methyl morpholine (5.05 g., 46 mmole) are added to the above residue. The reaction mixture is stirred in an ice-bath for 2 hours and then at room temperature overnight. It is evaporated and the residue is taken into ethyl acetate and washed with water, saturated sodium bicarbonate solution, and 10% potassium hydrogen sulfate solution. The ethyl acetate extract is dried and evaporated.
The crude product is chromatographed over silica gel (500 g.) using the solvent system ethyl acetate:hexane (1:2) to give 7.7 g., of N-[[[(3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)amino]carbonyl]-L-valine, phenylmethyl ester as a gummy solid; m.p.
40 _ 49; [~]2D2 = -41.4 (c = 1.5, methanol).
TLC (silica gel; ethyl acetate:hexane, 1:2) Rf = 0.37.
129763i HA362a Anal. calc'd. for C29H49N3O6:
C, 65.01; H, 9.22; N, 7.84 Found: C, 64.64; H, 9.14; N, 7.91.
e) N-[[[(3S)-3-[[(1,1-Dimethylethoxv)carbonYll-amino]-2-hYdroxY-5-methYlhexyl](2-methylproPyl)-amino]carbonyl]-L-valine, methyl ester(isomer A) The phenylmethyl ester product from part (d) (2.2 g., 4.1 mmole) is dissolved in methanol (75 ml.) and stirred under an atmosphere of hydrogen in the presence of palladium hydroxide on carbon catalyst for 16 hours. The catalyst is filtered through hyflo and the methanolic solution is evaporated to give 1.8 g. of N-[[[(3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)amino]carbonyl]-L-valine.
N-[[[(3S)-3-[[(1,1-Dimethylethoxy)carbonyl]-amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)amino]-carbonyl]-L-valine (3.0 g., 6.73 mmole) is dissolved in an ethereal solution of diazomethane generated from 2.67 g. (17.7 mmole) of N-methyl-N'-nitro-N-nitrosoguanidine reagent.
After keeping the solution at room temperature for one hour it is evaporated. The crude methyl ester product is chromatographed over silica gel (300 g.) using the solvent system ethyl acetate:hexane(2:5).
The earlier fractions (36 - 68, each 35 ml.
fractions) contain the faster moving isomer. They ; are pooled and evaporated to give 1.2 g. of N-[[[(3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)amino]-.~ , ~Z97631 HA362a carbonyl]-L-valine, methyl ester (isomer A);
m.p. 40 -49; [~]D22 = +7.2 (c = 1.5, methamol).
d. for C23H45N306 0-25 H20 C, 59.52; H, 9.88; N, 9.05 Found: C, 59.50; H, 9.78; N, 8.97.
f) N-~ L( 3S)-3-Amino-2-hydroxy-5-methylhexyl]-(2-methylproPyl)amino]carbonyl]-L-valiner methyl ester! monohydrochloride (isomer A) The methyl ester (isomer A) product from part (e) (0.4 g., 0.87 mmole) is dissolved in a solution of hydrochloric acid in dioxane (5 ml., 4.9 N) and allowed to stand at room temperature for 40 minutes. It is then evaporated and re-evaporated from methanol and ether. The residue is dissolved in water, millipore filtered, and lyophilized to give 0.29 g. of N-[[[(3S)-3-amino-2-hydroxy-5-methylhexyl](2-methylpropyl)amino]-carbonyl]-L-valine, methyl ester, monohydrochloride (isomer A); m.p. 41 - 61; [a]22 = -2.94~
(c = 1, methanol). TLC (silica gel; chloroform:
methanol:acetic acid, 8:1:1) Rf = 0.61.
Anal. calc'd. for C18H37N3O4- HCl 0.7 H2O:
C, 52.88; H, 9.72; N, 10.28; Cl, 8.67 Found: C, 52.88; H, 9.42; N, 10.38; Cl, 8.41.
g) N-[N-[(1,1-Dimethvlethoxv)carbonyl3-L-phenvl-`
alanyl]-l'-~(Dhenylmethoxy)methyll-L-histidine Thionyl chloride (27.2 ml., 375 mmole) is added in drops to a stirred solution in an ice-bath of L-histidine (38.75 g., 240 mmole) in methanol (500 ml.). After 15 minutes the ice-bath is removed and the reaction mixture is stirred at ..,~
.. . .
~7631 HA362a room temperature for one hour. After refluxing for 48 hours, it is concentrated ln vacuo. The separated crystals are filtered using methanol for washings to give 48.93 g. of L-histidine, methyl ester, dihydrochloride. The methanolic solution on dilution with ether affords an additional 10 g. of product; m.p. 208 - 209; ~]2D2 = +10.1 (c = 1.8, water).
Triethylamine (28 ml., 200 ml.) and di-tert-butyl dicarbonate (48 g., 220 mmole) are added to a suspension of L-histidine, methyl ester (24.2 g., 100 mmole) in methanol (80 ml.). After 3.5 hours, the mixture is filtered and the methanolic solution is concentrated ln vacuo. The residue is taken into chloroform and washed with 10% citric acid. The crude product on crystallization from isopropyl ether affords 23.1 g. of N,1'-bis[(1,1-dimethylethoxy)carbonyl]-L-histidine, methyl ester;
m.p. (62) 88 _ 95; [~]2D2 = +25.4 (c = 1.1, carbon tetrachloride).
Benzylchloromethyl ether (11.6 ml., 83.6 mmole) is added to a solution of N,1'-bis[(1,1-dimethyl-ethoxy)carbonyl]-L-histidine, methyl ester (24.7 g., 66.9 mmole) in dry methylene chloride (156 ml.) and the reaction mixture is stirred at room temperature for 5 hours. After concentrating in vacuo and on dissolution in ethyl acetate 17.85 g.
of N-[(l,1-dimethylethoxy)carbonyl]-1'-[(phenyl-methoxy)methyl]-L-histidine, methyl ester, mono-';
-`~ 1297631 HA362a hydrochloride crystallizes out; m.p. (148) 152 -153; [a]22 = -19.5 (c = 1.8, methanol). This methyl ester product is dissolved in hydrogen chloride in acetic acid solution (60 ml., 1.5 N) and kept at room temperture for 15 minutes. It is then evaporated ln vacuo and the residue is dissolved in hot isopropanol. After cooling, the separated crystals are filtered to yield 7.08 g.
of l-[(phenylmethoxy)methyl]-L-histidine, methyl ester, dihydrochloride; m.p. (170) 173 - 174.
l-[(Phenylmethoxy)methyl]-L-histidine, methyl ester, dihydrochloride (1.79 g., 4.94 mmole), l-hydroxybenzotriazole (0.756 g., 4.94 mmole), and N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine (1.31 g., 4.94 mmole) are dissolved in dimethyl-formamide (16 ml.). While stirring the above solution in an ice-bath, dicyclohexylcarbodiimide (1.02 g~, 4.94 mmole) and N,N-diisopropylethylamine (1.72 ml., 10 mmole) are added. After 3 hours the ice-bath is removed and the relction mixture is stirred at room temperature overnight. It is then concentrated to dryness and the residue is tritura-ted with ethyl acetate. The separated urea is filtered off. The ethyl acetate solution is washed with saturated sodium bicarbonate and then it is evaporated. The residue upon crystallization from ethyl acetate gives 1.97 g. of N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-1'-[(phenylmethoxy)methyl]-L-histidine, methyl ester;
m.p. (165) 166 - lfi8.
., ~ .. . ..
HA362a N-[N-[(1,1-Dimethylethoxy)carbonyl]-L-phenylalanyl]-1'-[(phenylmethoxy)methyl]~L-histidine, methyl ester (4.5 g., 8.4 mmole) is dissolved in hot methanol (25 ml.~. After cooling to room temperature aqueous sodium hydroxide solution (9.24 ml., lN) is added and the mixture is stirred at room temperature for 3 hours. It is then concentrated in vacuo and water (60 ml.) is added to the residue. After cooling the aqueous solution in an ice-bath, it is acidified to pH 4.5 using aqueous hydrochloric acid. It is then extracted with ~thyl acetate to yield 3.95 g. of crystalline N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-l'-[(phenylmethoxy)methyl]-L-histidine; m.p. 193 - 194; [~]22 = -4.8 (c = 1.1, dimethylformamide).
h) N-[[[(3S)-3-[[N-[N-[(l,l-Dimethylethoxy)-carbonyl]-L-phenylalanyl]-1'-[(phenylmethoxy)-methyl]-L-histidinyl]amino]-2-hydroxy-5-methyl-hexyll(2-methylpropyl)amino]carbonyl]-L-valine~
methyl ester (isomer A) N-~[[(3S)-3-Amino-2-hydroxy-5-methylhexyl]-(2-methylpropyl)amino~carbonyl]-L-valine, methyl ester, monohydrochloride (isomer A) (0.396 g., 1 mmole~, N-[N-[(1,1-dime-thylethoxy)carbonyl]-L-phenylalanyl]-1'-[(phPnylmethoxy)methyl] L-histidine (0.522 g~, 1 mmole) and 1-hydroxybenzo-triazole hydrate (0.153 g., 1 mmole) are dissolve~
in dimethylformamide (6 ml.). Diisopropylethyl amine (0.21 ml., 1.3 mmole) is added and the solution is cooled to -10. While stirring under a , ` ~
..~
-` 1297631 HA362a gentle flow of nitrogen, dicyclohexylcarbodiimide (0.206 g., 1 mmole) is added. After stirring for one hour between -10 and 0, the reaction mixture is then stirred in an ice-bath for 2 hours and then stirring is continued at ambient temperature overnight.
The separated dicyclohexyl urea is filtered off and the dimethylformamide solution is evaporated.
The residue is taken into ethyl acetate and washed with saturated sodium bicarbonate solution. The ethyl acetate extract after concentration is chromatographed over silica gel (45 g.) using the solvent system chloroform:methanol:acetic acid (9:0.5:0.5). Homogeneous fractions containing the product are pooled, evaporated, and the residue taken into ethyl acetate and washed with saturat~d sodium bicarbonate. The ethyl acetate extract is dried and evaporated to give 0.61 g. of N-[[[(3S)-3-~[N-LN-[(1,1-dimethylethoxy)carbonyl]-L-phenyl-alanyl]-1'-[(phenylmethoxy~methyl]-L-histidyl]-amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)-amino]carbonyl]-L-valine, methyl ester (isomer A).
i) N-[~ f ( 3S)-3-[[N-[N-~(l,1-Dimethylethoxy)-carbonyll-L-Phenvlalanyll-L-histidyllaminol-2 hydroxv-5-methylhexvll(2-methYlpropyl)amino]-carbonYll-L-valine, methYl ester, monohvdrochloride (isomer A~
The methyl ester product from part (h) (0.3 g., 0.35 mmole) is dissolved in methanol (25 ml.). Aqueous hydrochloric acid (lN, 0.35 ml.) is added and the solution is stirred under an atmosphere of hydrogen in the presence of palladium :
;
,~"
1~
, _35_ HA362a hydroxide on carbon catalyst (0.1 g.) for 15 hours. It is then filtered through hyflo and evaporated to dryness. The residue is triturated with ether and filtered to give 0.22 g. of S N- [ [ [ ( 3S ) -3-[[N-[N-[(l,l-dimethylethoxy)carbonyl]-L-phenylalanyl~-L-histidyl]amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)amino3carbonyl~-L-valine, methyl ester, monohydrochloride (isomer A);
m.p. 125 - 137; [a]2D2 = -2.9 (c = 1, methanol). TLC (silica gel, chloroform:methanol:
acetic acid, 15:1:1) Rf = 0.23.
38H61N78 HCl- 1.1 H2O:
C, 57.02; H, 8.06; N, 12.25; Cl, 4.43 Found: C, 57.02; H, 7.89; N, 12.12; Cl, 4.99.
Example 2 N-~[(3S)-3-[[N-[~-[(l,l-DimethYlethoxY)carbonvl~-L-~henYlalanYll-L-histidy~laminol-2-hYdroxy-5-methylhexYl](2-methylpropyl2aminolcarbonYl]-L-valine, methyl ester~ monohYdrochloride (isomer B) a) N-[[ L ( 3S?-3 - r [ ( 1, 1 -DimethylethoxY ) carbonYl ] -amino]-2-hydroxy-S-methvlhexYll(2-methylro~yl) amino]carbonYll-L-valine, methYl ester (isomer B) Following the chromatographic procedure described in Example 1 (e), fractions 70 - 90 (50 ml. fractions) contain the slow moving isomer.
These fractions are pooled and evaporated to give 1.25 g. of N-~[[(3S)-3-~[(1,1-dimethylethoxy)-carbonyl]amino]-2-hydroxy-5-methylhexyl](2-methyl-propyl)amino]carbonyl]-L-valine, methyl ester (isomer B); m.p. 44 - 55; [a]2D2 = -78 (c = 1, 1297~
HA362a methanol). TLC (silica gel; ethyl acetate:
hexane 1:1) Rf = 0.38.
Anal- calc~d. for C23H45N3O6 C, 60.10; H, 9.87; N, 9.14;
S Found: C, 59.84; H, 9.82; N, 9.00.
b) N-[ r r ( 3S)-3-Amino-2-hydroxy-5-methylhexYll-(2-methyl~ro~Yl)aminolcarbonyll-L-valine, methyl ester, monohYdrochloride (isomer B) The methyl ester (isomer B) product from part (a) (0.35 g., 0.76 mmole) is dissolved in a solution of hydrochoric acid in dioxane (4 ml., 4.9 N) and allowed to stand at room temperature for 50 minutes. It is then evaporated and reevaporated from methanol and ether. The crude residue is dissolved in water, millipore filtered, and lyophilized to give 0.27 g. of N-[t[(3S)-3-amino-2-hydroxy-S-methylhexyl]~2-methylpropyl)amino]-carbonyl]-L-valine, methyl ester, monohydrochloride (isomer B).
c) N-[[~(3S)-3-r[N-[N-[(1,1-DimethYlethoxv2-carbonyl]-L-phenYlalanyl~ henylmethoxy)methyl]
L-histidYl]aminol-2-hvdroxy-5-methYlhexvll(2-methYl-proyl)aminolcarbonvll-L-valine, methyl ester (isomer Al N-[[[(3S)-3-Amino-2-hydroxy-5-methylhexyl]-(2-methylpropyl)amino]carbonyl]-L-valine, methyl ester, monohydrochloride (isomer B) (0.36 g., 0.91 mmole), N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-l'-[(phenylmethoxy)methyl]-L-histidine (0.475 g., 0.91 mmole) and 1-hydroxybenzotriazole ~.
'.
-`` 1297631 HA362a hydrate (0.139 g., 0.91 mmole) are dissolved in dimethylformamide (6.5 ml.). Diisopropylethylamine (0.21 ml., 1.3 mmole) is added and the solution is stirred in an ice-bath. Dicyclohexylcarbodiimide (0.188 g., 0.91 mmole) is added and the stirring of the reaction mixture is continued at ambient temperature overnight. Dicyclohexylurea is filtered off and the dimethylformamide solution is evaporated. The residue is taken into ethyl acetate and washed with saturated sodium bicarbonate solution. The ethyl acetate extract after concentration is chromatographed over silica gel (50 g.) using the solvent system chloroform:
methanol:acetic acid, 10:0.5:0.5. Homogeneous fractions containing the product are pooled, evaporated, and the residue taken into ethyl acetate and washed with saturated sodium bicarbonate. The ethyl acetate extract is dried and evaporated to give 0.62 g. of N-[[[(3S)-3-[[N-rN-[(1,1-dimethylethoxy)carbonyl]-L-phenyl-alanyl]-1'-[(phenylmethoxy)methyl}-L-histidyl]-amino]-2-hydroxy-5-methylhexyl](2-methoxypropyl)-amino]carbonyl]-L-valine, methyl ester (isomer A).
d) N-~LL~3S)-3-rrN-[N-[(1,1-Dimethvlethoxy)-carbonvll-L-phenvlalanYl]-L-histidyl]amino]-2-hydroxy-5-methvlhexyll(2-methyl~ro~yl)amino]-carbonvl]-L-valine, methyl ester,monohvdrochloride (isomer B) The methyl ester (isomer B) product from part (c) (0.32 g., 0.37 mmole) is dissolved in . ,~ . ..... . .. . . .
.
HA362a methanol (25 ml.). Aqueous hydrochloric acid (1 N, 0.37 mmole) is added and the solution is stirred under an atmosphere of hydrogen in the presence of palladium hydroxide on carbon catalyst (0.1 g.) for 18 hours. It is then filtered through hyflo and evaporated to dryness. The residue is dissolved in isopropanol (3 ml.) and while shaking vigorously isopropyl ether (35 ml.) is added. The resulting precipitate is filtered and dried to give 0.184 g. of N-[[[(3S)-3-[[N-[N-[(l,l-dimethylethoxy)carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl](2-methyl-propyl)amino]carbonyl]-L-valine, methyl ester monohydrochloride (isomer B); m.p. 115 - 140;
[a]2D2 = -36.9 (c = l.l, methanol). TLC (silica gel; chloroform:methanol:acetic acid, 15:1:1) Rf = 0.20.
38H61N708 HCl 1.34 H20:
C, 56.73; H, 8.10; N, 12.19; Cl, 4.41 Found: C, 56.73; H, 7.99; N, 12.28; Cl, 4.66.
Exam~le 3 N-[N-[r[(3S)-3-[[N-rN-[(1,1-Dimethvlethoxv)-carbonyll-L-phenylalanvll-L-histidyl]aminol-2-hvdroxY-5-methYlhexY1](2-methvl~ro~Yl)amino]
carbonyll-L-valvl]-L-~henylalanine, methyl ester, monohvdrochloride a~ N-[[[(3S)-3-[[(l,l-Dimethylethoxv)carbonyl]-aminol-2-hvdroxv-5-methylhexyll(2-methYl~ropyl)-amino]carbonvll-L-valine N-[[[(3S)-3-[[(1,1-Dimethylethoxy)carbonyl]-HA362a amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)-amino]carbonyl]-L-valine, phenylmethyl ester (2.0 g., 3.73 mmole), prepared as set forth in Example l(d), is dissolved in methanol (100 ml.) and stirred under an atmosphere of hydrogen for 16 hours in the presence of palladium hydroxide on carbon catalyst (400 mg.). It is filtered and the methanolic solution is evaporated to give 1.66 g.
of N-[[[(3S)-3-[[(l,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)amino]carbonyl]-L-valine as a foamy solid.
b) N-[N- L[ [ ( 3S)-3-[[(l,1-DimethYlethoxY)carbonyl]-amino]-2-hydroxv-5-methvlhexvl](2-methylDropYl)amino]
carbonyl]-L-valyl]-L-phenvlala-nlne~ methyl ester N-[[[(3S)-3-[[(1,1-Dimethylethoxy)carbonyl]-amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)amino]-carbonyl]-L-valine (1.62 g., 3.63 mmole), L-phenyl-alanine, methyl ester, monohydrochloride (0.94 g., 4.36 mmole) and N-hydroxy succinimide (0.42 g., 3.63 mmole) are dissolved in dimethylformamide (13 ml.). While stirring the above solution in an ice-bath, dicyclohexylcarbodiimide (0.75 g., 3.63 mmole) and diisopropylethyl amine (0.85 ml.
5.3 mmole) are added. The reaction is continued in the ice-bath for two hours and then at ambient temperture overnight. It is filtered and the dimethylformamide solution is evaporated ln vacuo. The residue is taken into ethyl acetate and washed with saturated sodium bicarbonate, :
, , HA362a water, and aqueous hydrochloric acid (0. 25 N) solutions. The ethyl acetate solution is dried and then evaporated. The crude product is chromatographed over silica gel (100 g.) eluting with ethyl acetate:hexane (1:1) to give 1.4 g. of N-[N-[[[(3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2 -hydroxy-5-methylhexyl](2-methylpropyl)amino]-carbonyl]-L-valyl]-L-phenylalanine, methyl ester;
m.p. (52) 63 - 74; [a]2D2 = -26 4 (c = 1 2 methanol). TLC (silica gel, ethyl acetate:
hexane, 4:6) Rf = 0.4 and 0.44.
Anal. calc'd. for C32H54N4O7:
C, 63.34; H, 8.97; N, 9.23 Found: C, 63.04; H, 8.87; N, 9.17.
c) N-rN-[[[(3S)-3-Amino-2-hvdroxy-5-methylhexyll-~methyl~ropvl)amino]carbonYl1-L-valYll-L-~henyl-alanine, methYl ester, monohYdrochloride The methyl ester product from part ~b) (0.92 g., 1.502 mmole) is dissolved in a solution of hydrochloric acid in dioxane (4.9 N, 8 ml.).
; After keeping the solution at room temperature for 45 minutes it is evaporated. The residue is chromatographed over silica gel (100 g.) eluting with chloroform:methanol:acetic acid (12:0.9:0.9).
Fractions containing homogeneous material are pooled and evaporated (0.49 g.). The impuxe fractions are pooled, evaporated and rechromatographed over silica gel (20 g.) eluting with the solvent system chloroform:methanol:acetic acid (12:1:1) to give an additional amount (0.15 g.) of product resulting in a total yield of , _41_ HA362a 0.64 g. of N-[N-[[[(3S)-3-amino-2-hydroxy-5-methyl-hexyl](2-methylpropyl)amino]carbonyl]-L-valyl]-L-phenylalanine, methyl ester, monohydrochloride.
d) N-[N-[[[(3S)-3-LLN-~N-[(l,l-Dimethylethox~)-carbonyll-L-~henylalanyl]-ll-[(phenylmethoxy)methyl]
L-histidyllamino]-2-hydroxy-5-methylhexYl](2-methYl-proPyl)amino~carbonvll-L-valYl]-L-phenYlalanine, methvl ester N-[N-[[[(3S)-3-Amino-2-hydroxy-S-methylhexyl]-(2-methylpropyl)amino]carbonyl]-L-valyl]-L-phenyl-alanine, methyl ester, monohydrochloride (0.32 g., 0.59 mmole), N-[N-~l,1-dimethylethoxy)carbonyl~-L-phenylalanyl]-1'-[(phenylmethoxy)methyl]-L-histidine (0.309 g., 0.59 mmole), and l-hydroxybenzotriazole hydrate (0.09lg., 0.59 mmole) are dissolved in dimethylformamide (3 ml.). A small amount of benzene (3 ml.) is used for the washings and then it is evaporated off. While stirring the above solution at -10 under a gentle flow of nitrogen, dicyclohexylcarbodiimide (0.122 g., 0.59 mmole) and diisopropylethylamine (0.145 ml., 0.9 mmole) are added. After stirring at -10 for two hours, it is then stirred in an ice-bath for one hour, and stirring is then continued at ambient temperature overnight. The reaction mixture is then evaporated, diluted with ethyl acetate, and filtered to remove dicyclohexyl urea. The ethyl acetate solution is washed with saturated sodium bicarbonate and water and then evaporated. The residue is chromatographed over silica gel (35 g.) ~297631 HA362a eluting with the solvent system chloroform:methanol:acetic acid (10:0:5:0.5). The fractions containing the desired product are pooled, evaporated, and the residue is dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The ethyl acetate solution is then evaporated to give 0.48 g. of N-[N-~[[(3S)-3-~[N-[N-~(1,1-dimethylethoxy)carbonyl3-L-phenyl-alanyl]-l'-[(phenylmethoxy)methyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)amino]-carbonyl]-L-valyl]-L-phenylalanine, methyl ester.
e) N-~N-[[[(3S)-3-~[N-[N-[(1,1-Dimethylethoxy)-carbonvl]-L-phenvlalanvl]-L-histidYl]aminol-2-hvdroxv-5-methYlhexyll(2-methylpro~Yl)amino]-carbonyll-L-valYll-L-Dhenylalanine, methYl ester, monohvdrochloride The methyl ester product from part (d) (0.195 g., 0.193 mmole) is dissolved in methanol (25 ml.). Aqueous hydrochloric acid (lN, 0.2 ml.) is added and the solution is stirred under an atmosphere of hydrogen in the presence of palladium hydroxide on carbon catalyst (0.1 g.) for 18 hours. It is then filtered through hyflo and evaporated to dryness. The residue (0.16 g.) ; 25 is stirred with ether and filtered. The solid (0.145 g.) is dissolved in isopropanol (0.5 ml.) and diluted with isopropyl ether (35 ml.). This sample (120 mg.) is again precipitated from iso-propanol-isopropyl ether to give 105 mg. of N-[N-t[[(3S)-3-[[N-[N-[(1,1-dimethylethoxy)-"` ,;
- 1~97631 HA362a carbonyl]-2-phenylalanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)amino]-carbonyl]-L-valyl]-L-phenylalanine, methyl ester, monohydrochloride; m.p. (129) 135 - 145;
[~]D2 = -13.5 (c = 1, methanol). TLC (silica gel; chloroform:methanol:acetic acid, 15:1:1) Rf = 0.31.
Anal- calc'd- for C47H70N89 HCl 2.42 H2O:
C, 58.12; H, 7.87; N, 11.54; Cl, 3.65 Found: C, 58.12; H, 7.60; N, 11.50; Cl, 4.76.
Example 4 N-~N-~[(3S)-3-r[N-[N-[~1,1-DimethylethoxY)carbonyl]-L-phenylalanyll-L-histidinYllamino]-2-hYdroxy-5-methYlhexyl](l-methylethvl)aminolcarbonyl]-L-iso-leucYll-L-histidine, methylester, dihYdrochloride a) (S)-[3-Methyl-l-[[(1-methvlethYl)(~henYlmethvl)-aminolacetYllbutyl]carbamic acid, l,1-dimethYlethYl ester A solution of (S)-[3-methyl-1-[(chloromethyl)-carbonyl3butyl]carbamic acid, 1,1-dimethylethyl ester (6.6 g., 25 mmole), N-isopropylbenzylamine (4.182 ml., 25 mmole), sodium bicarbonate (3.15 g., 37.5 mmole), sodium iodide (1.875 g., 12.5 mmole), and dimethylformamide (80 ml.) are stirred at room temperature for 7.5 hours.
The reaction mixture is then evaporated ln vacuo and the residue is taken into ethyl acetate and washed with water to give 9.4 g. of (S)-[3-methyl-1-[[(1-methylethyl)(phenylmethyl)amino]-acetyl]butyl]carbamic acid, l,l-dimethylethyl `.~ ....
" ~Z97631 HA362a ester.
b) (3S)-[l-[(R,S)-l-HYdroxy-2-[(1-methYlethyl)-(~henylmethyl)amino]ethyll-3-methvlbutvl]carbamic acid,l,l-dimethylethyl ester Sodium borohydride (1 g., 26.3 mmole) is added to a solution of (S)-[3-methyl-1-[[(1-methyl-ethyl)(phenylmethyl~amino]acetyl~butyl]carbamic acid, l,l-dimethylethyl ester (9.4 g., 25 mmole) in ethanol (75 ml.). The solution is stirred at room temperture for one hour. It is then concen-trated to dryness ln vacuo. The residue is suspended in ethyl acetate/water and acidified to pH 2.0 by adding dilute hydrochloric acid. The aqueous layer is then made basic by adding saturated sodium bicarbonate. The aqueous layer is then extracted with ethyl acetate. The ethyl acetate solution on evaporation and redissolution in a mixture of ethyl acetate:hexane (1:3) deposits 2.526 g. of a crystalline material which is found to be one of the isomeric alcohols. The mother liquor is then chromatographed over silica gel (300 g.) using the solvent system ethyl acetate:hexane (1:3). The purified isomeric alcohol derivatives are pooled to give 7.0 g. of 25 (3S)-[1-[(R,S)-1-hydroxy-2-[(1-methylethyl)(phenyl-methyl)amino]ethyl]-3-methylbutyl]carbamic acid, 1,1-dimethylethyl ester.
c) (3S)-[1-[(R,S)-1-HvdroxY-2-[(1-methvlethvl)-amino]ethyl]-3-methylbutyl]carbamic acid, 1,1-dimethvlethvl ester, monohYdrochloride ., ~297631 HA362a A solution of the carbamic acid, 1,1-dimethylethyl ester product from part (b) (2.27 g., 6 mmole) in methanol (40 ml.) and aqueous hydro-chloric acid (lN, 6 ml.) is stirred under an atmosphere of hydrogen in the presence of palladium hydroxide on carbon catalyst (460 mg.) for 3.5 hours. The mixture is then filtered through hyflo and evaporated to give 1.87 g. of (3S)-l-[~R,S)-l-hydroxy-2-[(1-methylethyl)amino]ethyl]-3-methylbutyl]-carbamic acid, l,l-dimethylethyl ester, monohydro-chloride.
d) N-[[t~3S)-3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxY-5-methylhexyl](l-methylethYl)aminolcarbonYl]-L-isoleucine, ~henylmethYl ester N-Methylmorpholine (0.74 ml., 6.7 mmole) is added to a stirred solution of L-isoleucine, phenylmethyl ester, hydrochloride (1.06 g., 2.7 mmole) in methylene chloride (12 ml.) at -30 followed by the dropwise addition of a solution of phosgene in benzene (12.5%, 3.2 ml., 4.032 mmole).
After stirring for 30 minutes at -20, the mixture is concentrated to dryness ln vacuo. A solution of (3S)-[l-[(R,S)-1-hydroxy-2-[(1-methylethyl)amino]-ethyl]-3-methylbutyl]carbamic acid, 1,1-dimethylethyl ester, monohydrochloride (0.9 g., 2.77 mmole) in methylene chloride (6 ml.) is added to the above residue. While stirring the above solution in an ice-bath, N-methylmorpholine (0.59 ml., 5.36 mmole) is added and the stirring is continued for 2 hourc in the ice-bath and then overnight at -HA362a room temperature. The reaction mixtur~ is then evaporated to dryness, the residue is taken up in ethyl acetate and washed neutral with saturated sodium bicarbonate and 10% potassium bisulfate.
The ethyl acetate extract after drying is chroma-tographed (silica gel, 75 g.) using the solvent system ethyl acetate:hexane (1:1) to give 0.78 g.
of N-[[[(3S)-3-[[(1,1-dimethylethoxy)carbonyl]-amino]-2-hydroxy-5-methylhexyl](l-methylethyl)-amino]carbonyl]-L-isoleucine, phenylmethyl ester.
e) N-[[[(3S)-3-[[(1,1-Dimethylethoxv)carbonyl]-amino]-2-hydroxy-5-methylhexYl](l-methylethyl)-amino]carbonvl]-L-isoleucine A solution of the phenylmethyl ester product from part (d) (0.78 g., 1.45 mmole) in methanol (40 ml.) is stirred under an atmosphere of hydrogen overnight in the presence of palladium hydroxide on carbon catalyst (0.15 g.). The mixture is then filtered through hyflo and concentrated to dryness to give 0.6 g. of N-[[[(3S)-3-[[(1,1-dimethylethoxy)carbonyl]-amino]-2-hydroxy-5-methylhexyl](l-methylethyl)-amino]carbonyl]-L-isoleucine.
f) N-[N-[[1(3S)-3-[ r ( 1, 1-DimethYlethOxY ) carbonYl 1 -amino]-2-hYdroxY-5-methYlhexY~ -methylethyl)amino]
carbonyl]-L-isoleucvl]-1'-[(DhenYlmethoxY)methyl]-L-histidine, methYl ester Dicyclohexylcarbodiimide (0.277 g., 1.35 mmole) is added to a stirred (ice-bath) mixture of the L-isoleucine product from part (e) (0.6 g., HA362a 1.35 mmole), N-hydroxy succinimide ~0.155 g., 1.35 mmole), l'-[(phenylmethoxy)methyl]-L-histidine, methyl ester, monohydrochloride (0.488 g., 1.35 mmole), diisopropylethylamine (0.47 ml., 2.76 mmole), and dimethylformamide (5 ml.).
Stirring is continued at 5 (cold room) overnight.
The reaction mixture is then evaporated and the residue is taken up in ethyl acetate. The separated dicyclohexyl urea is filtered off and then the ethyl acetate solution is washed with saturated sodium bicarbonate. After evaporation of the ethyl acetate extract, the residue is chromatographed (silica gel, 75 g.) using the solvent system ethyl acetate:methanol (9:1) to give 0.54 g. of N-[N-[[[(3S)-3-[[(1,1-dimethyl-ethoxy)carbonyl]amino]-2-hydroxy-5-methylhexyl]-(1-methylethyl)amino]carbonyl]-L-isoleucyl]-l'-[(phenylmethoxy)methyl]-L-histidine, methyl ester.
g) N-~N-[~[(3S)-3-Amino-2-hYdroxv-5-methvlhexvll-(1-methYlethyl)aminolcarbonvll-L-isoleucyl]-1'-[(~henylmethoxY)methYll-L-histidine, methYl ester, dihvdrochloride The L-histidine, methyl ester product from part (f) (0.545 g., 0.76 mmole) is dissolved in a solution of hydrochloric acid in dioxane (2N, 12 ml.) and kept at room temperature for 3.5 hours. It is then concentrated to dryness in vacuo to give 0.53 g. of N-[N-[[[(3S)-3-amino-2-hydroxy-5-methylhexyl](1-methylethyl)amino]carbonyl]-L-isoleucyl]-l'-[(phenylmethoxy)me-hyl]-L--, .
, .
~297631 HA362a histidine, methyl ester, dihydrochloride.
h) N-[N-[~[(3S)-3-[[N-[N-[(l,l-(DimethYlethoxy)-carbonyll-L-PhenYlalanYl]-l'-~(phenylm-ethoxy)methyl]-L-histidinyllamino]-2-hYdroxY-5-methylhexyl](1-methylethyl-2amino]carbonyl]-L-isoleucyl]-ll-[(phenYlmethoxy)methyll-L-histidine, methyl ester Dicyclohexylcarbodiimide (0.156 g., 0.76 mmole) is added to a stirred (ice-bath) solution of the L-histidine, methyl ester, dihydro-chloride product from part (g) (0.53 g., 0.76 mmole), l-hydroxybenzotriazole hydrate (0.116 g., 0.76 mmole), N-[N-[(l,l-dimethylethoxy)carbonyl]-L-phenylalanyl]-l'-[(phenylmethoxy)methyl]-L-histidine (0.396 g., 0.76 mmole), diisopropyl-ethylamine (0.264 ml., 1.51 mmole) and dimethyl-formamide (4 ml.). Stirring is continued at 5 (cold room) overnight. The reaction mixture is then concentrated to dryness ln vacuo. The residue is taken into ethyl acetate, separated dicyclohexyl urea is filtered off, and the ethyl acetate solution is washed with saturated sodium bicarbonate. The ethyl acetate solution after evaporation is chromatographed (silica gel, 75 g.) using the solv~nt system ethyl acetate:methanol (8.5:1.5) to give 0.48 g. of N-[N-[[[(3S)-3-[[N-[N-[(l,1-dimethylethoxy)carbonyl]-L-phenyl-alanyl]-1'-[(phenylmethoxy)methyl]-L-histidinyl]-amino]-2-hydroxy-5-methylhexyl](1-methylethyl)-amino]carbonyl]-L-isoleucyl]-l'-[(phenylmethoxy)-methyl]-L-histidine, methyl ester.
lZg763i HA362a i) N-[N-[~[(3S)-3-[[N-[N-[(l,l-Dimethylethoxy)-carbonYl1-L-phenYlalanyll~L-histidinyllamino~-2-hydroxY-S-methYlhexyl](l-methYlethyl)amino]carbon~l]-L-isoleucvl~-L-histidine, methyl ester, dihvdrochloride The L-histidine, methyl ester product from part (h) (0.466 g., 0.415 mmole) is dissolved in methanol (25 ml.) and aqueous hydrochloric acid (lN, 0.79 ml.). The mixture is stirred under an atmosphere of hydrogen in the presence of palladium hydroxide on carbon catalyst (0.1 g.) for 48 hours. The solution is filtered through hyflo and concentrated to dryness ln vacuo. The residue is chromatographed (silica gel, 39 ~.) using the solvent system ethyl acetate:acetic acid:water (4:1:1). The fractions containing the product are pooled and evaporated. The residue is dissolved in methanol and aqueous hydrochloric acid (lN, 0.52 ml.) is added. The mixture is then evaporated, the residue is dissolved in a minimum amount of methanol, and passed through a column of LH-20 using methanol for elution to give 0.224 g.
of product. 174 mg. of the above solid is dissolved in methanol and aqueous hydrochloric acid (lN, 0.047 ml.) is added and the solution is evaporated to dryness to give 0.171 g. of N-[N-[[[(3S)-3-[[N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-L-histidinyl]amino~-2-hydroxy-5-methylhexyl](1-methylethyl)amino]carbonyl]-L-isoleucyl]-L-histidine, methyl ester, dihydro-.
~2~7631 HA362a chloride; m.p. (115) 148 - 168; [~]22 = -7.8 (c = 1.2, methanol). TLC (silica gel; ethyl acetate:acetic acid:water, 4:1:1) Rf = 0.45.
Anal. calc'd. for C44H6809N1o 2 C, 52.90; H, 7.57; N, 14.02; Cl, 7.10 Found: C, 52.86; H, 7.24; N, 13.73; Cl, 6.97.
Example 5 N-[[[(3S)-3-[[N-[N-[(1,1-Dimethylethoxy)carbonyl]-L-Pheny~lalanYl]-L-histidYl]amino]-2-hydroxY-5-methylhexyl~ methYlethYl)amino]carbonyl]-L-isoleucine, methyl ester, isomer A, monohYdrochloride a) N-r~[(3S)-3-[[(1,1-DimethYlethoxy)carbonYl]-aminol-2-hYdroxy-5-methYlhexyll(l-methylethyl)-amino]carbonYll-L-isoleucine, methyl ester, isomer A
N-Methylmorpholine (0.79 ml., 7.1 mmole) is added to a stirred solution of L-isoleucine, methyl ester, monohydrochloride (0.442 g., 2.43 mmole) in methylene chloride (10 ml.) at -30 followed by the dropwise addition of a solution of phosgene in benzene (12.5%, 2.94 ml., 3.7 mmole). After stirring for 20 minutes at -20, the mixture is concentrated to dryness ln vacuo. An ice-cold solution of (3S)-[1-[(R,S)-1-hydroxy-2-[(1-methylethyl)amino]ethyl]-3-methyl-butyl]carbamic acid, 1,1-dimethylethyl ester, monohydrochloride (0.79 g., 2.43 mmole) in methylene chloride (10 ml.) and N-methylmorpholine (0.54 ml., 4.86 mmole) is added to the above residue. The reaction mixture is stirred in an ' ' ....
~ ~ .
~297631 HA362a ice-bath for 6 hours and at room temperature overnight. It is then evaporated to dryness, the residue is taken up in ethyl acetate and washed with saturated sodium bicarbonate solution and 10%
potassium bisulfate solution. The ethyl acetate extract after evaporation is chromatographed (silica gel, 125 g.) using the solvent system ethyl acetate:hexane (4:3). In this chromatography the two diastereoisomers are separated giving 0.26 g. of N-[[[(3S)-3-[[(1,1-dimethylethoxy)-carbonyl]amino]-2-hydroxy-5-methylhexyl](l-methyl-ethyl)amino]carbonyl]-L-isoleucine, methyl ester, isomer A and 0.448 g. of N-[[[(3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-5-methylhexyl](l-methylethyl)amino]carbonyl]-L-isoleucine, methyl ester, isomer B.
b) N- r [ ~ ( 3S)-3-Amino-2-hYdroxY-5-methylhexYll-(l-methylethyl)aminolcarbonYll-L-isoleucine, methvl ester, isomer A
The L-isoleucine,methyl ester, isomer A
product from part (a) (0.25 g., 0.544 mmole) is dissolved in a solution of hydrochloric acid in dioxane (2N, 2.25 ml.). After keeping the solution at room temperature for 4 hours, it is evaporated ln vacuo to give N-[[[(3S)-3-amino-2-hydroxy-5-methylhexyl](1-methylethyl)amino]-carbonyl]-L-isoleucine, methyl ester, isomer A.
c) N-[[[(3S)-3-[[N-[N-[(l,l-Dimethvlethoxy)-carbonYl1-L-phenylalanY13-1'-[(phenYlmethoxv)-methyl]-L-histidyllaminol-2-hYdroxv-5-methY1-.' , . ~.
:
lZ97631 HA362a hexyl](l-methYlethvl)amino]carbonYl]-L-isoleucine, methyl ester' isomer A
Dicyclohexylcarbodiimide (0.109 g., 0.59 mmole) is added to a stirred (ice-bath) solution of N-[[[(3S)-3-amino-2-hydroxy-5-methyl-hexyl](l-methylethyl)amino]carbonyl]-L-isoleucine, methyl ester, isomer A from part (b), l-hydroxy-benzotriazole hydrate (0.081 g., 0.53 mmole), N-[N-[(l,l-dimethylethoxy)carbonyl]-L-phenylalanyl]-l'-[(phenylmethoxy)methyl]-L-histidine (0.277 g., 0.53 mmole), diisopropylethylamine (0.15 ml., 0.885 mmole), and dimethylformamide (3 ml.).
Stirring is continued at 5 (cold room) overnight.
It is then concentrated to dryness in vacuo and the residue is triturated with ethyl acetate and the separated dicyclohexyl urea is filtered off.
The eth~l acetate solution is washed with saturated sodium bicarbonate solution and water.
It is then evaporated in vacuo and the residue chromatographed (silica gel, 75 g.) using the solvent system chloroform:methanol:acetic acid (10:0.5:0.5). The product containing fractions are pooled, evaporated, and the residue is dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The ethyl acetate solution is dried over magnesium sulfate and evaporated in vacuo to give 0.26 g. of N-[[[(3Sj-3-[[N-[N-[(l,l-dimethylethoxy)carbonyl]-L-phenylalanyl]-l'-[(phenylmethoxy)methyl]-L-histidinyl]amino]-2-hydroxy-5-methylhexyl](1-' .~
,,"
!
129~631 HA362a methylethyl)amino]carbonyl~-L-isoleucine, methyl ester, isomer A.
d) N-[[[(3S)-3-[[N-[N-[(1,1-DimethYlethoxY)-carbonYll-L-~henYlalanYll-L-histidyllaminol-2 hYdroxY-5-methYlhexYll(l-methylethyl)aminol-carbonYl]-L-isoleucine, methYl ester, isomer A, monohYdrochloride The L-isoleucine, methyl ester, isomer A
product from part (c) (0.237 g., 0.274 mmole) is dissolved in methanol (3 ml.). Hydrochloric acid (0.1 N, 2.3 ml., prepared by diluting lN
aqueous hydrochloric acid with methanol) is added and the solution is stirred under an atmosphere of hydrogen in the presence of palladium hydroxide on carbon catalyst (65 mg.) for 18 hours. The mixture is then filtered through Celite and evaporated. The residue is stirred with isopropyl ether and filtered to give 0.165 g. of N-[~[(3S)-3-[[N-[N-[(l,l-dimethylethoxy)carbonyl]-L-phenyl-alanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]-(l-methylethyl)amino]carbonyl]-L-isoleucine, methyl ester, isomer A, monohydrochloride; m.p. 101 - 116;
[a]2D0 = ~11.65 (c = 1, methanol). TLC (silica gel; ethyl acetate:acetic acid:water, 12:1:1) Rf = 0.28.
Anal. calc'd. for C38H61N708 2 C, 56.52; H, 8.11; N, 12.14; Cl, 4.39 ~ound: C, 56.65; H, 8.00; N, 11.73; C1, 4.48.
~ * Trade Mark :
i lZ97631 HA362a Example 6 N-[[[(3S)-3-[[N-[N-[(1,1-Dimethylethoxy)carbonyl]-L-Phenylalanyll-L-histidyl]amino]-2-hydroxy-5-methylhexyl](1-methYlethyl)amino]carbonYl]-L-isoleucine, methYl ester, isomer B, monohydrochloridea) N-[[[(3S)-3-Amino-2-hYdroxy-5-methylhexyl](l-methylethYl)aminolcarbonyll-L-isoleucine, methyl ester, isomer B
The L-isoleucine, methyl ester, isomer B
product from Example 5(a) (0.35 g., 0.76 mmole) is dissolved in a solution of hydrochloric acid in dioxane (4 N, 3 ml.). After keeping the solution at room temperature for two hours, it is evaporated in vacuo to give N-[[[(3S)-3-amino-2-hydroxy-5-methylhexyl](1-methylethyl)amino]-carbonyl]-L-isoleucine, methyl ester, isomer B.
b) N-[[[(3S)-3-[[N-[N-[(1,1-DimethYlethoxY)-carbonYll-L-PhenYlalanyll-l'-[(Phenylmethoxv)-methYll-L-histidyl]aminol-2-hydroxy-5-methylhexyl]
(1-methYlethYl)aminolcarbonYl]-L-isoleucine, methYl ester, isomer B
Dicyclohexylcarbodiimide (0.161 g., 0.783 mmole) is added to a stirred (ice-bath) solution of N-[[[(3S)-3-amino-2-hydroxy-5-methyl-hexyl](1-methylethyl)amino]carbonyl]-L-isoleucine, methyl ester, isomer B from part (a), l-hydroxy-benzotriazole hydrate (0.12 g., 0.783 mmole), N-[N-[(1,1-dimethy7ethoxy)carbonyl]-L-phenylalanyl]-1'-[(phenylmethoxy)methyl]-L-histidine (0.409 g., 0.783 mmole), diisopropylethylamine (0.17 ml., '' ~297631 HA362a 1.0 mmole), and dimethylformamide (2 ml.).
Stirring is continued at 5 (cold room) overnight.
It is then concentrated to dryness in vacuo and the residue is triturated with ethyl acetate and the separated dicyclohexyl urea is filtered off.
The ethyl acetate solution is washed with saturated sodium bicarbonate solution and water.
It is then evaporated in vacuo and the residue chromatographed (silica gel, 120 g.) using the solvent system chloroform:methanol:acetic acid (10:0.5:0.5). The product containing fractions are pooled, evaporated, and the residue is dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The ethyl acetate solution is dried over magnesium sulfate and evaporated ln vacuo to give 0.37 g. of N-[[[(3S)-3-[[N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-1'-[(phenylmethoxy)methyl]-L-histidinyl]-amino]-2-hydroxy-5-methylhexyl](1-methylethyl)amino]-carbonyl]-L-isoleucine, methyl ester, isomer B.
c) N-[[[(3S)-3-[[N-LN-[(1,1-DimethvlethoxY)carbonYll-L-phenvlalanyll-L-histidyl]amino]-2-hydroxy-5-methyl-hexyl](1-methYlethyl)amino]carbonyll-L-isoleucine, methYl ester, isomer B, monohYdrochloride The L-isoleucine, methyl ester, isomer B
product from part (b) (0.363 g., 0.42 mmole) is dissolved in methanol (10 ml.). Hydrochloric acid (0.1 N, 3.6 ml., prepared by diluting lN aqueous hydrochloric acid with methanol) is added and the solution is stirred under an atmosphere of ~297631 HA362a hydrogen in the presence of palladium hydroxide on carbon catalyst (lO0 mg.) for 18 hours. The mixture is then filtered through Celite and evaporated. After reevaporation from benzene, the residue is triturated and stirred with isopropyl ether and then filtered to give 0.30 g. of N-[[[(3S)-3-[[N-[(l,l-dimethylethoxy)carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl](l-methylethyl)amino]carbonyl]-L-isoleucine, methyl ester, isomer B, monohydro-chloride; m.p. 118-128; [~]2D0 = -50.5 (c = 1.1, methanol). TLC (silica gel; ethyl acetate:acetic acid:water, 12:1:1) Rf = 0.2.
Anal. calc'd. for C38H61H7O8 2 C, 57.03; H, 8.06; N, 12.25; Cl, 4.43 Found: C, 57.03; H, 7.88; N, 12.04; Cl, 4.32.
Exam~le 7 N-[[[(3S)-3-[LN-[N-[(l,l-Dimethvlethoxy)carbonyl]-L-~henvlalanvl]-L-histidvllaminol-2-hYdroxv-5-methYlhexYllamino]carbonYl]-L-isoleucine, methYl ester, monohydrochloride a) (S)-[3-MethYl-l-[[bis(~henYlmethYl)amino]-acetyl]butYllcarbamic acid, 1,1-dimethYlethyl ester A solution of (S)-[3-methyl-1-[(chloro-methyl)carbonyl]butyl]carbamic acid, 1,l-dimethyl-ethyl ester (3.165 g., 12 mmole), dibenzylamine (2.31 ml., 12 mmole), sodium bicarbonate (1.52 g., 18 mmole), sodium iodide (0.9 g., 6 mmole), and 30~ dimethylformamide (24 ml.) are stirred at room temperature for one hour. An additional amount of 1~97631 HA362a dibenzylamine (0.23 ml., 1.2 mmole) is added and the stirring is continued for another 2.5 hours.
The reaction mixture is then concentrated to dryness. The residue is taken into ethyl acetate and washed with water. The ethyl acetate solution is concentrated and on dissolution in benzene a small amount of insoluble material separates. The solution is filtered and the benzene evaporated.
The residue is dissolved in ethyl acetate and passed through a small column of silica gel. The ethyl acetate solution is evaporated and the residue crystallized from hexane to give 3.603 g.
of (S)-[3-methyl-1-[[bis(phenylmethyl)amino]acetyl]-butyl]carbamic acid, 1,1-dimethylethyl ester; m.p.
(72) 75 - 77.
b) (3S)-L1-[(R,S)-1-HYdroxv-2-~bis(~henYlmethYl)-amino]ethY11-3-methYlbutYllcarbamic acid, 1,1-dimethylethyl ester Sodium borohydride (0.354 g., 9.3 mmole) is added to a solution of (S)-[3-methyl-1-[[bis(phenyl-methyl)amino]acetyl]butyl]carbamic acid, l,l-dimethyl-ethyl ester (3.59 g., 8.45 mmole) in ethanol (25 ml.).
The solution is stirred at room temperature for one hour and then concentrated to dryness ln vacuo.
The residue is suspended in ethyl acetate/water and acidified to pH 2.0 using dilute hydrochloric acid. The aqueous layer is then made basic using solid sodium bicarbonate and it is extracted with ethyl acetate to give 3.65 g. of (3S)-[l-[(R,S)-1-hydroxy-2-[bis(phenylmethyl)amino]-ethyl]-3-methylbutyl]carbamic acid, l,l-dimethyl-ethyl ester.
~ 12~7631 HA362a c) (3S)-[l-[(R,S)-2-Amino-l-hydroxyethyl~-3-methylbutYl]carbamic acid, l,l-dimethylethyl ester, monohydrochloride (3S~-[l-(R,S)-l-~ydroxy-2-[bis(phenylmethyl)-amino]ethyl]-3-methylbutyl]carbamic acid, 1,1-dimethylethyl ester (4.25 g., 9.96 mmole) is dissolved in methanol (80 ml.). Aqueous hydro-chloric acid (lN, 9.96 ml.) is added followed by palladium hydroxide on carbon catalyst (0.85 g.).
The mixture is then stirred under an atmosphere of hydrogen for 24 hours. It is then filtered through hyflo and the solution is concentrated to dryness to give 2.62 g. of (3S)-[l-[(R,S)-2-amino-l-hydroxyethyl]-3-methylbutyl]carbamic acid, 1,1-dimethylethyl ester, monohydrochloride.d) N-[[[(3S)-3-[[(1,1-DimethylethoxY)carbonyl]-aminol-2-hvdroxy-5-methvlhexyllaminolcarbonYl]-L-isoleucine, methyl ester N-Methylmorpholine (0.588 ml., 5.33 mmole) is added to a stirred solution of L-isoleucine, methyl ester, monohydrochloride (0.385 g., 2.12 mmole) in methylene chloride (8 ml.) at -30 followed by the dropwise addition of a solution of phosgene in benzene (12.5%, 3.18 mmole, 2.52 ml.). After stirring for 30 minutes at -20, the mixture is concentrated to dryness ln vacuo.
An ice-cold solution of (3S)-[1-[(R,S)-2-amino-1-hydroxyethyl]-3-methylbutyl]carbamic acid, 1,1-dimethylethyl ester, monohydrochloride (0.6 g., 2.12 mmole) in methylene chloride (6 ml.) and N-methylmorpholine (0.47 ml., 4.24 mmole) are ~., 1297~`3~
HA362a added to the above residue. An additional 3 ml.
of methylene chloride is used for washings. The reaction mixture is stirred in an ice-bath for 2 hours and at room temperature overnight. It is then evaporated to dryness, the residue is taken up in ethyl acetate and washed with saturated sodium bicarbonate and 10% potassium bisulfate solution. The ethyl acetate extract after evaporation is chromatographed over silica gel (60 g.) using the solvent system ethyl acetate:
hexane (2:1) to give 0.48 g. of N-[[[(3S~-3-[[(l,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-5-methylhexyl]amino]carbonyl]-L-isoleucine, methyl ester.
e) N-[[r(3S)-3-Amino-2-hvdroxv-5-methvlheXYll-aminolcarbonvll-L-isoleucine, methYl ester, mono-The isoleucine, methyl ester product frompart (d) (0.43 g., 1.03 mmole) is dissolved in a solution of hydrochloric acid in dioxane (2N, 3ml.) and kept at room temperature for 2.5 hours. The mixture is then concentrated to dryness ln vacuo to give N-[[[(3S)-3-amino-2-hydroxy-5-methylhexyl]-amino]carbonyl]-L-isoleucine, methyl ester, mono-hydrochloride.
f) N-[[~(3S)-3-[[N-[N-[(1,1-DimethylethoxY)-carbonyl]-L-~henylalanvl]-1'-[(~henvlmethoxy)-methvll-L-histidvllaminol-2-hvdroxv-5-methYlhexvll-amino]carbonYl]-L-isoleucine, methyl ester Dicyclohexylcarbodiimide (0.212 g., 1.03 mmole) is added to a stirred (ice-bath) solution of ;
' , HA362a the L-isoleucine, methyl ester, monohydrochloride product from part (e), l-hydroxybenzotriazole hydrate (0.158g., 1.03 mmole), N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-l'-[(phenyl-methoxy)methyl]-L-histidine (0.538 g., 1.03 mmole) diisopropylethylamine (O.22 ml., 1.29 mmole), and dimethylformamide (4 ml.). Stirring is continued at 5 (cold room) overnight. The mixture is then concentrated to dryness ln vacuo The residue is triturated with ethyl acetate and the separated dicyclohexyl urea is filtered off. The ethyl acetate solution is washed with saturated sodium bicarbonate solution and water. It is then evaporated ln vacuo and the residue is chromatographed over silica gel (65 g.) using the solvent system chloroform:methanol:acetic acid (10:0.75:0.75). The product containing fractions are pooled, evaporated, and the residue is dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The ethyl acetate solution after drying over anhydrous magnesium sulfate is evaporated 1n vacuo to give 0.57 g. of N-[[[(3S)-3-[[N-[N-[(1,1-dimethylethoxy)-carbonyl]-L-phenylalanyl]-1'-[(phenylmethoxy)methyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]amino~-carbonyl]-L-isoleucine, methyl ester.
g) N-[[[(3S)-3-[[N-[N-[(l,1-Dimethylethoxv)-carbonyl]-L-phenvlalanyl]-L-histidvl]aminol-2-hydroxv-5-methYlhexyl]aminolcarbonyl]-L-isoleucine~
methvl ester, monohvdrochloride The L-isoleucine, methyl ester product from part (f) (0.37 g., 0.45 mmole) is dissolved in 12~7631 HA362a methanol (20 ml.). Hydrochloric acid (O.lN, 4.05 ml., prepared by diluting lN aqueous hydro-chloric acid with methanol) is added and the solution is stirred under an atmosphere of hydrogen in the presence of palladium hydroxide on carbon catalyst (125 mg.) for 18 hours. The mixture is then filtered through Celite and evaporated. The residue is dissolved in iso-propanol and diluted with isopropyl ether. The separated solid is filtered to give 0.27 g. of N-[[[(3S)-3-[[N-[N-[(l,l-dimethylethoxy)carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]amino]carbonyl]-L-isoleucine, methyl ester, monohydrochloride, m.p. 133 - 158;
[~]D0 = -8.0 (c = 1.2, methanoll. TLC (silica gel; ethyl acetate:acetic acid:water, lZ:l:l) Rf =
0.16.
Anal. calc'd. for C35H55N7O8 2 C, 54.93; H, 7.77; N, 12.82; Cl, 4.63 Found: C, 54.93; H, 7.66; N, 12.46; Cl, 4.82.
Examule 8 N-[N-[[[(3S)-3-[[N-[N-[(1,1-DimethYlethoxv)carbonYll-L-~henYlalanYl]-L-histidYl]aminol-2-hYdroxy-5-meth hexyl]amino]carbonyl]-L-isoleucyl]-L-histine, methyl ester, dihydrochloride a) N-[[[(3S)-3-[[(1,1-Dimethylethoxv)carbonyll-amino]-2-hYdroxY-5-methYlhexyl]aminolcarbonYl]-L-isoleucine, phenYlmethyl ester N-Methylmorpholine (2.5 ml., 22.73 mmole) is added to a stirred solution of L-isoleucine, phenylmethyl ester, monohydrochloride (3.56 g., HA362a 9.264 mmole) in methylene chloride (38 ml.) at -30 followed by the dropwise addition of a solution of phosgene in benzene (12.5%, 10.8 ml., 13.608 mmole). After stirring for 30 minutes at -20, the mixture is concentrated to dryness ln vacuo. A solution of (3S)-[l-[(R,S)-2-amino-1-hydroxyethyl]-3-methylbutyl]carbamic acid, 1,1-dimethylethyl ester, monohydrochloride (2.62 g., 9.264 mmole) in methylene chloride (20 ml.) is added to the above residue. While stirring th~
above solution in an ice-bath, N-methylmorpholine (2.0 g., 18.18 mmole) is added and the stirring is continued for 2 hours in the ice-bath and then overnight at room temperature. The mixture is then evaporated to dryness. The residue is taken up in ethyl acetate and washed neutral with sodium bicarbonate and 10% potassium bisulfate. The ethyl acetate extract after drying is chromatographed over silica gel (250 g.) using the solvent system ethyl acetate:hexane (1:1) to give 1.92 g. of N-[[[(3S)-3-[[(1,1-dimethylethoxy)-carbonyl]amino]-2-hydroxy-5-methylhexyl]amino]-carbonyl]-L-isoleucine, phenylmethyl ester.
b) N-[[[(3S)-3-[[~1,1-Dimethylethoxy)carbonyl]-aminol-2-hydroxy-5-methylhexyllamino]carbonyll-L-isoleucine ~ A solution of the L-isoleucine, phenylmethyl ; ester from part (a) (1.92 g., 3.89 mmole) in methanol (50 ml.) is stirred under an atmosphere of hydrogen for 2 hours in the presence of palladium hydroxide on carbon catalyst (0.4 g.).
1297~
HA362a The mixture is then filtered through hyflo and concentrated to dryness to give 1.51 g. of N-[[[~3S)-3-[[(1,1-dimethylethoxy)carbonyl]-amino]-2-hydroxy-5-methylhexyl]amino]carbonyl]~
L-isoleucine.
c) N-[N-[(l,1-DimethylethoxY)carbonyl~-L-Phenvlalanyl]-3'-[(phenYlmethoxy)carbonyl]-L-histidine A solution of N-[N-[(1,1-dimethylethoxy) carbonyl]-L-phenylalanyl]-l'-[(phenylmethoxy)-methyl]-L-histidine in a mixture of methanol:
acetic acid (8:2, 200 ml.) is stirred under an atmosphere of hydrogen overnight in the presence of palladium hydroxide on carbon catalyst (2.6 g.).
The mixture is filtered through hyflo and concentrated to dryness. The residue on crystalli-zation from hot acetonitrile (150 ml.) gives 6.01 g. of N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-L-histidine; m.p. (192) 197 - 198.
To a stirred (ice-bath) solution of N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-L-histidine (3.68 g., 10 mmole) in dimethylformamide (20 ml.) and diisopropylethylamine (1.74 ml., 10 mmole) is added N-carbobenzyloxysuccinimide (3.0 g., 12 mmole). (This latter reagent is added in 4 portions at intervals of 15 minutes.) After stirring for 90 minutes, the mixture is evaporated in vacuo. The residue is taken up in ethyl acetate and washed with 10% citric acid.
After evaporation of the ethyl acetate solution, the residue is chromatographed over silica gel using the solvent system chloroform:methanol:acetic 1297~31 HA362a acid (90:3:3) to give 3.2 g. of N-[N-[(1,1-dimethyl-ethoxy)carbonyl]-L-phenylalanyl]-3'-[(phenyl-methoxy)carbonyl]-L-histidine.
d) 3'-[(Phenylmethoxv)carbonyl]-L-histidine, methyl ester, monohYdrochloride N-[(1,1-Dimethylethoxy)carbonyl]-L-histidine, methyl ester (2.42 g., 9 mmole) [prepared as set forth by Hanford et al., J. Org. Chem., Vol. 33, p. 4251 (1968)] is dissolved in tetrahydrofuran (40 ml.) and diisopropylethylamine (1.74 ml., 9.9 mmole) is added. While stirring the above solution at room temperature, benzyloxycarbonyl chloride (1.42 ml., 9.9 mmole) is added. After a period of 90 minutes, the mixture is concentrated to dryness. The residue is taken up in ethyl acetate and washed with water. The ethyl acetate extract after evaporation is crystallized from ethyl acetate:hexane (1:1) to give 2.07 g. of N-[(1,1-dimethylethoxy)carbonyl]-3'-[(phenyl-methoxy)carbonyl]-L-histidine, methyl ester.
This N-[(1,1-dimethylethoxy)carbonyl]-3'-[(phenylmethoxy)carbonyl]-L-histidine, methyl ester (1.09 g., 2.7 mmole) is dissolved in a solution of hydrochloric acid in acetic acid (2N, 24 ml.). After keeping the mixture at room ~ temperature for 10 minutes, it is concentrated ; in vacuo. The residue is reevaporated from benzene and acetonitrile several times to give ; 30 3'-[(phenylmethoxy)carbonyl]-L-histidine, methyl ester, monohydrochloride.
129763~
HA362a e) N-[N-[[[(3S)-3-[[(1,1-Dimethylethoxy)carbonyl]-aminol-2-hYdroxY-5-methylhexyl1amino]carbonyl]-L-isoleucYl]-3'-[(phenYlmethoxy)carbonyl]-L-histidine, methvl ester Dicyclohexylcarbodiimide (0.556 g., 2.7 mmole) is added to a stirred (ice-bath) solution of N-[[[(3S)-3-[[(1,1-dimethylethoxy)-carbonyl]amino]-2-hydroxy-5-methylhexyl]amino]-carbonyl]-L-isoleucine (l.09 g., 2.7 mmole), 1-hydroxybenzotriazole hydrate (0.413 g., 2.7 mmole), 3'-[(phenylmethoxy)carbonyl]-L-histidine, methyl ester, monohydrochloride (2.7 mmole), and diisopropylethylamine (0.47 ml., 2.7 mmole) in dimethylformamide (12 ml.). The reaction mixture is stirred at 5 (cold room) overnight. It is then concentrated to dryness.
The residue is triturated with ethyl acetate and filtered to remove dicyclohexyl urea. The ethyl acetate solution is washed with saturated sodium bicarbonate and then evaporated. The residue is chromatographed over silica gel (200 g.) using the solvent system chloroform:methanol (95:5) to give 1.022 g. of N-[N-[[[(3S)-3-[[(1,1-dimethylethoxy) carbonyl]amino]-2-hydroxy-5-methylhexyl]amino]-carbonyl]-L-isoleucyl]-3'-[(phenylmethoxy)carbonyl]-L-histidine, methyl ester.
f) N-[N-[[[(3S)-3-Amino-2-hydroxy-5-methYlhexyl]-aminolcarbonyl]-L-isoleucvll-3'-[(phenvlmethoxY)-carbonvll-L-histine, methvl ester, monohvdrochloride The L-histidine, methyl ester product from part (e) (0.62 g., 0.9 mmole) is dissolved in a . , ,. ,.... , .. ~ . . - .
. ' ' ' , ' ' : '' ' .' ~Z9763~
HA362a solution of hydrochloric acid in dioxane (4N, 10.2 ml.). After keeping the mixture at room temperature for 20 minutes, it is concentrated to dryness in vacuo to give N-[N-[~[(3S)-3-amino-2-hydroxy-5-methylhexyl]amino]carbonyl]-L-iso-leucyl]-3'-[(phenylmethoxy)carbonyl]-L-histidine, methyl ester, monohydrochloride.
g) N-[N-[[[(3S)-3-[[N-[N-~(l,l-Dimethylethoxv)-carbonyll-L-~henylalanyl]-3'-[(Phenylmethoxy)-carbonyl]-L-histidyl]amino]-2-hydroxY-5-methyl-hexyllaminolcarbonvl]-L-isoleucyl]-3'-[(phenYl-methoxy)carbonYl]-L-histidine, methvl ester Dicyclohexylcarbodiimide (0.185 g., 0.9 mmole) is added to a stirred (ice-bath) solution of the L-histidine, methyl ester, mono-hydrochloride product from part (f) (O.9 mmole), 1-hydroxybenzotriazole hydrate (0.138 g., 0.9 mmnole), N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-3'-[(phenylmethoxy)carbonyl]-L-histidine (0.483 g., 0.9 mmole), and diisopropyl-ethylamine (0.16 ml., 0.94 mmole) in dimethyl-formamide (3 ml.). The reaction mixture is stirred at 5 (cold room) overnight. It is then concen-trated to dryness, triturated with ethyl acetate 2S and the separated dicyclohexyl urea is filtered off.
The ethyl acetate solution is washed with saturated sodium bicarbonate and then evaporated. The residue is chromatographed over silica gel (80 g.) using the solvent system ethyl acetate:methanol (95:5) to give 0.266 g. of N-[N-[[[(3S~-3-[[N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-3'-.
~Z9763i HA362a [(phenylmethoxy)carbonyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]amino]carbonyl]-L-iso-leucyl]-3'-[(phenylmethoxy)carbonyl~-L-histidine, methyl ester.
h) N-[N-~[[(3S)-3-[[N-[N-[(1,1-DimethYlethoxy)-carbonyll-L-DhenvlalanYl~-L-histidyl]amino]-2 hvdroxy-5-methylhexYllamino]carbonyl]-L-iso-leucvll-L-histidine, methYl ester, dihydrochloride The L-histidine, methyl ester product from part (g) (250 mg., 0.23 mmole) is dissolved in methanol (10 ml.). After adding aqueous hydro-chloric acid (lN, 0.41 ml.) and palladium hydroxide on carbon catalyst (50 mg.), the solution is stirred under an atmosphere of hydrogen for 4 hours. It is then filtered through hyflo and evaporated to dryness to give 0.187 g. of N-[N-[[[(3S)-3-[[N-[N-[(1,1-dimethylethoxy)-carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]amino]carbonyl]-L-isoleucyl]-Z0 L-histidine, methyl ester, dihydrochloride; m.p.
75 - 170; [~]2D0 = -7.8 (c = 1.7, methanol).
TLC (silica gel; chloroform:methanol:acetic acid, 6:4:2) Rf = 0.7.
Anal. cal'd. for C41H62OgNlo 2 C, 50.28; H, 7.36; N, 14.30; Cl, 7.24 Found: C, 50.30; H, 7.43; N, 14.00; Cl, 7.25.
" . ~
~,, " 1297~31 HA362a Exam~les 9 - 29 Following the procedure of Examples 1 to 8, additional compounds within the scope of this invention can be prepared having the formula R4 R3 R2 o R1 I 11 I j I I i X-NH-CH- C -NH - CH - CH ~ CH2--N -C-NH - CH - C-A
I
OH
wherein the substituents are as defined below.
~:;
... .
Z~7~3~
-69- HA362a _~ Y
o=u O=~ ~z N _N
O
_ -- I -- _, _ N
? I -. _ Z
t, ~, ~ N~
; I Y Y
O = U = ~J
U ~ -- I N
O=U = U ~--X I _ _ ~
O ,_1 ' ~' ', ~',,i ', 1297~31 .., -7 O- HA362 a "~ Z2 s ~ U ~Z-= $1 a,--a 'a-a aN
C I Z Z
~ I -~ ;~ ~
~N ¦ _ _ _ N N
~ _ ~ I , _ _ ~5-= Z~Z ~) ,' N N N
~c I ,a ,a ;.
O_~ ~
~~-, ~aN ~ o=$_~
( Z Z
~ o= U o=~ o =~
~ o - ol ,o ., . , ~, ~, ~!' X I -- 2 'r 'l ~ ,D
', `l ~
~1~
:r 1297~3i H~362a ~~
t~Z~ o=u ~
o = ~, o = t~ ~ o = ~. ~ _ z z ^r U ~
J
_~ O ~_ ~ U
X
.~ .
.,,j,.~,", .. . . .
~29763~
-72- HA362a o=u ~ o=u ~ o=y~
c I z z z , ~ ~. ^
, z_~ ' z \\ I z _ = _ 8-- N _ ~ -- O ~ U
O = U Z U"
, ~ X ~\ ON ~
~ , .,1 .-- : '' '"'' ' ' 1297~i31 ~ .~
_73_ HA362a 0='~ ~ 0=~ ~ 0=o ~
V --;~
I Z Z Z
_ _ .'. `, `, _ _ _ ~ ~z-= z~z q o = ~
~ U--o = ~ U--y : ' o~ " ~ N
~ . X' I
N N ~r ,1, " i '.' ~ * ~",.. ..... .. .
' `~ 1Z97~31 74 HA362a _~z ~ o ~ o ~
N
C ! Z _ _ ^_^_ /~
_ Z 1~=-'J
;~
I ~
O =t~ ~
O ~ ~ Z ~,~
U y U ~
W ¦ ~ N
., . ~ .
~, .
lZ97~31 HA362a ExamPle 30 looo tablets each containing the following ingrdients N-[N-[[[(3s)-3-[[N-[N-[(~
5 Dimethylethoxy)carbonyl]-L-phenyl-alanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]amino]carbonyl]-L-isoleucyl]-L-histidine, methyl ester, dihydrochloride 250 mg.
10 Cornstarch 100 mg.
Gelatin 20 mg.
Avicel(microcrystalline cellulose) 50 mg.
Magnesium stearate 5 mg.
425 mg.
are preapred from sufficient bulk quantities by mixing the N-[N-[[[(3S)-3-[[N-[N-[(1,1-dimethyl-ethoxy)carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]amino]carbonyl]-L-isoleucyl]-L-histidine, methyl ester, dihydrochloride and corn-starch with an aqueous solution of the gelatin. Themixture is dried and ground to a fine powder. The Avicel and then the magnesium stearate are admixed with granulation. This mixture is then compressed in a tablet press to form 1000 tablets each containing 250 mg. of active ingredient.
In a simi}ar manner, tablets containing 250 mg.
of the product of any of Examples 1 to 7 and 9 to 29 can be prepared.
A similar procedure can be employed to form tablets containing 500 mg. of active ingredient.
~' ;
~'' ~.
A * Trade Mark ~' ~, ......
12~7~31 HA362a Example 31 An injectable solution is prepared as follows:
N-[[[(3S)-3-[[N-[N-[(l,l-Dimethyl-5 ethoxy)carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)-amino]carbonyl]-L-valine, methyl ester,monohydrochloride (isomer A) lO00 g.
10 Methyl paraben 5 g.
Propyl paraben l g.
Sodium chloride 5 g.
The active substance, preservatives, and sodium chloride are dissolved in 3 liters of water for injection and then the volume is brought up to 5 liters. The solution is filtered through a sterile filter and aseptically filled into pre-sterilized vials which are closed with presteri-lized rubber closures. Each vial contains 5 ml.
of solution in a concentration of 200 mg. of active ingredient per ml. of solution for injection.
In a similar manner, an injectable solution containing 200 mg. of active ingredient per ml. of solution can be prepared for the product of any of Examples 2 to 29.
.. ... .
~zg7~3i HA362a Example 32 1000 Tablets each containing the following ingredients:
N-[N-[[[(3s)-3-[[N-[N-~
5 Dimethylethoxy)carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]amino]-carbonyl]-L-isoleucyl]-L-histidine, methyl ester, dihydrochloride 500 mg.
10 Avicel 300 mg.
Hydrochlorothiazide 14.5 mg.
Lactose 113 mg.
Cornstarch 15.5 mg.
Stearic acid 7 mg.
950 mg.
are prepared from sufficient bulk ~uantities by slugging the N-[N-[[[(3S)-3-[[N-[N-[(l,l-dimethyl-ethoxy)carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]amino]carbonyl]-L-isoleucyl]-L-histidine, methyl ester, dihydrochloride, Avicel, and a poriton of the stearic acid. The slugs are ground and passed through a #2 screen, then mixed with the hydrochlorothiazide, lactose, cornstarch, and remainder of the strearic acid. The mixture i~ compressed into 950 mg. capsule shaped tablets in a tablet press. The tablets are scored for dividing in half.
In a similar manner, tablets can be prepared containing 500 mg. of the product of any of 30 Examples 1 to 7 and 9 to 29.
:, . . ,
, , HA362a water, and aqueous hydrochloric acid (0. 25 N) solutions. The ethyl acetate solution is dried and then evaporated. The crude product is chromatographed over silica gel (100 g.) eluting with ethyl acetate:hexane (1:1) to give 1.4 g. of N-[N-[[[(3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2 -hydroxy-5-methylhexyl](2-methylpropyl)amino]-carbonyl]-L-valyl]-L-phenylalanine, methyl ester;
m.p. (52) 63 - 74; [a]2D2 = -26 4 (c = 1 2 methanol). TLC (silica gel, ethyl acetate:
hexane, 4:6) Rf = 0.4 and 0.44.
Anal. calc'd. for C32H54N4O7:
C, 63.34; H, 8.97; N, 9.23 Found: C, 63.04; H, 8.87; N, 9.17.
c) N-rN-[[[(3S)-3-Amino-2-hvdroxy-5-methylhexyll-~methyl~ropvl)amino]carbonYl1-L-valYll-L-~henyl-alanine, methYl ester, monohYdrochloride The methyl ester product from part ~b) (0.92 g., 1.502 mmole) is dissolved in a solution of hydrochloric acid in dioxane (4.9 N, 8 ml.).
; After keeping the solution at room temperature for 45 minutes it is evaporated. The residue is chromatographed over silica gel (100 g.) eluting with chloroform:methanol:acetic acid (12:0.9:0.9).
Fractions containing homogeneous material are pooled and evaporated (0.49 g.). The impuxe fractions are pooled, evaporated and rechromatographed over silica gel (20 g.) eluting with the solvent system chloroform:methanol:acetic acid (12:1:1) to give an additional amount (0.15 g.) of product resulting in a total yield of , _41_ HA362a 0.64 g. of N-[N-[[[(3S)-3-amino-2-hydroxy-5-methyl-hexyl](2-methylpropyl)amino]carbonyl]-L-valyl]-L-phenylalanine, methyl ester, monohydrochloride.
d) N-[N-[[[(3S)-3-LLN-~N-[(l,l-Dimethylethox~)-carbonyll-L-~henylalanyl]-ll-[(phenylmethoxy)methyl]
L-histidyllamino]-2-hydroxy-5-methylhexYl](2-methYl-proPyl)amino~carbonvll-L-valYl]-L-phenYlalanine, methvl ester N-[N-[[[(3S)-3-Amino-2-hydroxy-S-methylhexyl]-(2-methylpropyl)amino]carbonyl]-L-valyl]-L-phenyl-alanine, methyl ester, monohydrochloride (0.32 g., 0.59 mmole), N-[N-~l,1-dimethylethoxy)carbonyl~-L-phenylalanyl]-1'-[(phenylmethoxy)methyl]-L-histidine (0.309 g., 0.59 mmole), and l-hydroxybenzotriazole hydrate (0.09lg., 0.59 mmole) are dissolved in dimethylformamide (3 ml.). A small amount of benzene (3 ml.) is used for the washings and then it is evaporated off. While stirring the above solution at -10 under a gentle flow of nitrogen, dicyclohexylcarbodiimide (0.122 g., 0.59 mmole) and diisopropylethylamine (0.145 ml., 0.9 mmole) are added. After stirring at -10 for two hours, it is then stirred in an ice-bath for one hour, and stirring is then continued at ambient temperature overnight. The reaction mixture is then evaporated, diluted with ethyl acetate, and filtered to remove dicyclohexyl urea. The ethyl acetate solution is washed with saturated sodium bicarbonate and water and then evaporated. The residue is chromatographed over silica gel (35 g.) ~297631 HA362a eluting with the solvent system chloroform:methanol:acetic acid (10:0:5:0.5). The fractions containing the desired product are pooled, evaporated, and the residue is dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The ethyl acetate solution is then evaporated to give 0.48 g. of N-[N-~[[(3S)-3-~[N-[N-~(1,1-dimethylethoxy)carbonyl3-L-phenyl-alanyl]-l'-[(phenylmethoxy)methyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)amino]-carbonyl]-L-valyl]-L-phenylalanine, methyl ester.
e) N-~N-[[[(3S)-3-~[N-[N-[(1,1-Dimethylethoxy)-carbonvl]-L-phenvlalanvl]-L-histidYl]aminol-2-hvdroxv-5-methYlhexyll(2-methylpro~Yl)amino]-carbonyll-L-valYll-L-Dhenylalanine, methYl ester, monohvdrochloride The methyl ester product from part (d) (0.195 g., 0.193 mmole) is dissolved in methanol (25 ml.). Aqueous hydrochloric acid (lN, 0.2 ml.) is added and the solution is stirred under an atmosphere of hydrogen in the presence of palladium hydroxide on carbon catalyst (0.1 g.) for 18 hours. It is then filtered through hyflo and evaporated to dryness. The residue (0.16 g.) ; 25 is stirred with ether and filtered. The solid (0.145 g.) is dissolved in isopropanol (0.5 ml.) and diluted with isopropyl ether (35 ml.). This sample (120 mg.) is again precipitated from iso-propanol-isopropyl ether to give 105 mg. of N-[N-t[[(3S)-3-[[N-[N-[(1,1-dimethylethoxy)-"` ,;
- 1~97631 HA362a carbonyl]-2-phenylalanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)amino]-carbonyl]-L-valyl]-L-phenylalanine, methyl ester, monohydrochloride; m.p. (129) 135 - 145;
[~]D2 = -13.5 (c = 1, methanol). TLC (silica gel; chloroform:methanol:acetic acid, 15:1:1) Rf = 0.31.
Anal- calc'd- for C47H70N89 HCl 2.42 H2O:
C, 58.12; H, 7.87; N, 11.54; Cl, 3.65 Found: C, 58.12; H, 7.60; N, 11.50; Cl, 4.76.
Example 4 N-~N-~[(3S)-3-r[N-[N-[~1,1-DimethylethoxY)carbonyl]-L-phenylalanyll-L-histidinYllamino]-2-hYdroxy-5-methYlhexyl](l-methylethvl)aminolcarbonyl]-L-iso-leucYll-L-histidine, methylester, dihYdrochloride a) (S)-[3-Methyl-l-[[(1-methvlethYl)(~henYlmethvl)-aminolacetYllbutyl]carbamic acid, l,1-dimethYlethYl ester A solution of (S)-[3-methyl-1-[(chloromethyl)-carbonyl3butyl]carbamic acid, 1,1-dimethylethyl ester (6.6 g., 25 mmole), N-isopropylbenzylamine (4.182 ml., 25 mmole), sodium bicarbonate (3.15 g., 37.5 mmole), sodium iodide (1.875 g., 12.5 mmole), and dimethylformamide (80 ml.) are stirred at room temperature for 7.5 hours.
The reaction mixture is then evaporated ln vacuo and the residue is taken into ethyl acetate and washed with water to give 9.4 g. of (S)-[3-methyl-1-[[(1-methylethyl)(phenylmethyl)amino]-acetyl]butyl]carbamic acid, l,l-dimethylethyl `.~ ....
" ~Z97631 HA362a ester.
b) (3S)-[l-[(R,S)-l-HYdroxy-2-[(1-methYlethyl)-(~henylmethyl)amino]ethyll-3-methvlbutvl]carbamic acid,l,l-dimethylethyl ester Sodium borohydride (1 g., 26.3 mmole) is added to a solution of (S)-[3-methyl-1-[[(1-methyl-ethyl)(phenylmethyl~amino]acetyl~butyl]carbamic acid, l,l-dimethylethyl ester (9.4 g., 25 mmole) in ethanol (75 ml.). The solution is stirred at room temperture for one hour. It is then concen-trated to dryness ln vacuo. The residue is suspended in ethyl acetate/water and acidified to pH 2.0 by adding dilute hydrochloric acid. The aqueous layer is then made basic by adding saturated sodium bicarbonate. The aqueous layer is then extracted with ethyl acetate. The ethyl acetate solution on evaporation and redissolution in a mixture of ethyl acetate:hexane (1:3) deposits 2.526 g. of a crystalline material which is found to be one of the isomeric alcohols. The mother liquor is then chromatographed over silica gel (300 g.) using the solvent system ethyl acetate:hexane (1:3). The purified isomeric alcohol derivatives are pooled to give 7.0 g. of 25 (3S)-[1-[(R,S)-1-hydroxy-2-[(1-methylethyl)(phenyl-methyl)amino]ethyl]-3-methylbutyl]carbamic acid, 1,1-dimethylethyl ester.
c) (3S)-[1-[(R,S)-1-HvdroxY-2-[(1-methvlethvl)-amino]ethyl]-3-methylbutyl]carbamic acid, 1,1-dimethvlethvl ester, monohYdrochloride ., ~297631 HA362a A solution of the carbamic acid, 1,1-dimethylethyl ester product from part (b) (2.27 g., 6 mmole) in methanol (40 ml.) and aqueous hydro-chloric acid (lN, 6 ml.) is stirred under an atmosphere of hydrogen in the presence of palladium hydroxide on carbon catalyst (460 mg.) for 3.5 hours. The mixture is then filtered through hyflo and evaporated to give 1.87 g. of (3S)-l-[~R,S)-l-hydroxy-2-[(1-methylethyl)amino]ethyl]-3-methylbutyl]-carbamic acid, l,l-dimethylethyl ester, monohydro-chloride.
d) N-[[t~3S)-3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-hydroxY-5-methylhexyl](l-methylethYl)aminolcarbonYl]-L-isoleucine, ~henylmethYl ester N-Methylmorpholine (0.74 ml., 6.7 mmole) is added to a stirred solution of L-isoleucine, phenylmethyl ester, hydrochloride (1.06 g., 2.7 mmole) in methylene chloride (12 ml.) at -30 followed by the dropwise addition of a solution of phosgene in benzene (12.5%, 3.2 ml., 4.032 mmole).
After stirring for 30 minutes at -20, the mixture is concentrated to dryness ln vacuo. A solution of (3S)-[l-[(R,S)-1-hydroxy-2-[(1-methylethyl)amino]-ethyl]-3-methylbutyl]carbamic acid, 1,1-dimethylethyl ester, monohydrochloride (0.9 g., 2.77 mmole) in methylene chloride (6 ml.) is added to the above residue. While stirring the above solution in an ice-bath, N-methylmorpholine (0.59 ml., 5.36 mmole) is added and the stirring is continued for 2 hourc in the ice-bath and then overnight at -HA362a room temperature. The reaction mixtur~ is then evaporated to dryness, the residue is taken up in ethyl acetate and washed neutral with saturated sodium bicarbonate and 10% potassium bisulfate.
The ethyl acetate extract after drying is chroma-tographed (silica gel, 75 g.) using the solvent system ethyl acetate:hexane (1:1) to give 0.78 g.
of N-[[[(3S)-3-[[(1,1-dimethylethoxy)carbonyl]-amino]-2-hydroxy-5-methylhexyl](l-methylethyl)-amino]carbonyl]-L-isoleucine, phenylmethyl ester.
e) N-[[[(3S)-3-[[(1,1-Dimethylethoxv)carbonyl]-amino]-2-hydroxy-5-methylhexYl](l-methylethyl)-amino]carbonvl]-L-isoleucine A solution of the phenylmethyl ester product from part (d) (0.78 g., 1.45 mmole) in methanol (40 ml.) is stirred under an atmosphere of hydrogen overnight in the presence of palladium hydroxide on carbon catalyst (0.15 g.). The mixture is then filtered through hyflo and concentrated to dryness to give 0.6 g. of N-[[[(3S)-3-[[(1,1-dimethylethoxy)carbonyl]-amino]-2-hydroxy-5-methylhexyl](l-methylethyl)-amino]carbonyl]-L-isoleucine.
f) N-[N-[[1(3S)-3-[ r ( 1, 1-DimethYlethOxY ) carbonYl 1 -amino]-2-hYdroxY-5-methYlhexY~ -methylethyl)amino]
carbonyl]-L-isoleucvl]-1'-[(DhenYlmethoxY)methyl]-L-histidine, methYl ester Dicyclohexylcarbodiimide (0.277 g., 1.35 mmole) is added to a stirred (ice-bath) mixture of the L-isoleucine product from part (e) (0.6 g., HA362a 1.35 mmole), N-hydroxy succinimide ~0.155 g., 1.35 mmole), l'-[(phenylmethoxy)methyl]-L-histidine, methyl ester, monohydrochloride (0.488 g., 1.35 mmole), diisopropylethylamine (0.47 ml., 2.76 mmole), and dimethylformamide (5 ml.).
Stirring is continued at 5 (cold room) overnight.
The reaction mixture is then evaporated and the residue is taken up in ethyl acetate. The separated dicyclohexyl urea is filtered off and then the ethyl acetate solution is washed with saturated sodium bicarbonate. After evaporation of the ethyl acetate extract, the residue is chromatographed (silica gel, 75 g.) using the solvent system ethyl acetate:methanol (9:1) to give 0.54 g. of N-[N-[[[(3S)-3-[[(1,1-dimethyl-ethoxy)carbonyl]amino]-2-hydroxy-5-methylhexyl]-(1-methylethyl)amino]carbonyl]-L-isoleucyl]-l'-[(phenylmethoxy)methyl]-L-histidine, methyl ester.
g) N-~N-[~[(3S)-3-Amino-2-hYdroxv-5-methvlhexvll-(1-methYlethyl)aminolcarbonvll-L-isoleucyl]-1'-[(~henylmethoxY)methYll-L-histidine, methYl ester, dihvdrochloride The L-histidine, methyl ester product from part (f) (0.545 g., 0.76 mmole) is dissolved in a solution of hydrochloric acid in dioxane (2N, 12 ml.) and kept at room temperature for 3.5 hours. It is then concentrated to dryness in vacuo to give 0.53 g. of N-[N-[[[(3S)-3-amino-2-hydroxy-5-methylhexyl](1-methylethyl)amino]carbonyl]-L-isoleucyl]-l'-[(phenylmethoxy)me-hyl]-L--, .
, .
~297631 HA362a histidine, methyl ester, dihydrochloride.
h) N-[N-[~[(3S)-3-[[N-[N-[(l,l-(DimethYlethoxy)-carbonyll-L-PhenYlalanYl]-l'-~(phenylm-ethoxy)methyl]-L-histidinyllamino]-2-hYdroxY-5-methylhexyl](1-methylethyl-2amino]carbonyl]-L-isoleucyl]-ll-[(phenYlmethoxy)methyll-L-histidine, methyl ester Dicyclohexylcarbodiimide (0.156 g., 0.76 mmole) is added to a stirred (ice-bath) solution of the L-histidine, methyl ester, dihydro-chloride product from part (g) (0.53 g., 0.76 mmole), l-hydroxybenzotriazole hydrate (0.116 g., 0.76 mmole), N-[N-[(l,l-dimethylethoxy)carbonyl]-L-phenylalanyl]-l'-[(phenylmethoxy)methyl]-L-histidine (0.396 g., 0.76 mmole), diisopropyl-ethylamine (0.264 ml., 1.51 mmole) and dimethyl-formamide (4 ml.). Stirring is continued at 5 (cold room) overnight. The reaction mixture is then concentrated to dryness ln vacuo. The residue is taken into ethyl acetate, separated dicyclohexyl urea is filtered off, and the ethyl acetate solution is washed with saturated sodium bicarbonate. The ethyl acetate solution after evaporation is chromatographed (silica gel, 75 g.) using the solv~nt system ethyl acetate:methanol (8.5:1.5) to give 0.48 g. of N-[N-[[[(3S)-3-[[N-[N-[(l,1-dimethylethoxy)carbonyl]-L-phenyl-alanyl]-1'-[(phenylmethoxy)methyl]-L-histidinyl]-amino]-2-hydroxy-5-methylhexyl](1-methylethyl)-amino]carbonyl]-L-isoleucyl]-l'-[(phenylmethoxy)-methyl]-L-histidine, methyl ester.
lZg763i HA362a i) N-[N-[~[(3S)-3-[[N-[N-[(l,l-Dimethylethoxy)-carbonYl1-L-phenYlalanyll~L-histidinyllamino~-2-hydroxY-S-methYlhexyl](l-methYlethyl)amino]carbon~l]-L-isoleucvl~-L-histidine, methyl ester, dihvdrochloride The L-histidine, methyl ester product from part (h) (0.466 g., 0.415 mmole) is dissolved in methanol (25 ml.) and aqueous hydrochloric acid (lN, 0.79 ml.). The mixture is stirred under an atmosphere of hydrogen in the presence of palladium hydroxide on carbon catalyst (0.1 g.) for 48 hours. The solution is filtered through hyflo and concentrated to dryness ln vacuo. The residue is chromatographed (silica gel, 39 ~.) using the solvent system ethyl acetate:acetic acid:water (4:1:1). The fractions containing the product are pooled and evaporated. The residue is dissolved in methanol and aqueous hydrochloric acid (lN, 0.52 ml.) is added. The mixture is then evaporated, the residue is dissolved in a minimum amount of methanol, and passed through a column of LH-20 using methanol for elution to give 0.224 g.
of product. 174 mg. of the above solid is dissolved in methanol and aqueous hydrochloric acid (lN, 0.047 ml.) is added and the solution is evaporated to dryness to give 0.171 g. of N-[N-[[[(3S)-3-[[N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-L-histidinyl]amino~-2-hydroxy-5-methylhexyl](1-methylethyl)amino]carbonyl]-L-isoleucyl]-L-histidine, methyl ester, dihydro-.
~2~7631 HA362a chloride; m.p. (115) 148 - 168; [~]22 = -7.8 (c = 1.2, methanol). TLC (silica gel; ethyl acetate:acetic acid:water, 4:1:1) Rf = 0.45.
Anal. calc'd. for C44H6809N1o 2 C, 52.90; H, 7.57; N, 14.02; Cl, 7.10 Found: C, 52.86; H, 7.24; N, 13.73; Cl, 6.97.
Example 5 N-[[[(3S)-3-[[N-[N-[(1,1-Dimethylethoxy)carbonyl]-L-Pheny~lalanYl]-L-histidYl]amino]-2-hydroxY-5-methylhexyl~ methYlethYl)amino]carbonyl]-L-isoleucine, methyl ester, isomer A, monohYdrochloride a) N-r~[(3S)-3-[[(1,1-DimethYlethoxy)carbonYl]-aminol-2-hYdroxy-5-methYlhexyll(l-methylethyl)-amino]carbonYll-L-isoleucine, methyl ester, isomer A
N-Methylmorpholine (0.79 ml., 7.1 mmole) is added to a stirred solution of L-isoleucine, methyl ester, monohydrochloride (0.442 g., 2.43 mmole) in methylene chloride (10 ml.) at -30 followed by the dropwise addition of a solution of phosgene in benzene (12.5%, 2.94 ml., 3.7 mmole). After stirring for 20 minutes at -20, the mixture is concentrated to dryness ln vacuo. An ice-cold solution of (3S)-[1-[(R,S)-1-hydroxy-2-[(1-methylethyl)amino]ethyl]-3-methyl-butyl]carbamic acid, 1,1-dimethylethyl ester, monohydrochloride (0.79 g., 2.43 mmole) in methylene chloride (10 ml.) and N-methylmorpholine (0.54 ml., 4.86 mmole) is added to the above residue. The reaction mixture is stirred in an ' ' ....
~ ~ .
~297631 HA362a ice-bath for 6 hours and at room temperature overnight. It is then evaporated to dryness, the residue is taken up in ethyl acetate and washed with saturated sodium bicarbonate solution and 10%
potassium bisulfate solution. The ethyl acetate extract after evaporation is chromatographed (silica gel, 125 g.) using the solvent system ethyl acetate:hexane (4:3). In this chromatography the two diastereoisomers are separated giving 0.26 g. of N-[[[(3S)-3-[[(1,1-dimethylethoxy)-carbonyl]amino]-2-hydroxy-5-methylhexyl](l-methyl-ethyl)amino]carbonyl]-L-isoleucine, methyl ester, isomer A and 0.448 g. of N-[[[(3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-5-methylhexyl](l-methylethyl)amino]carbonyl]-L-isoleucine, methyl ester, isomer B.
b) N- r [ ~ ( 3S)-3-Amino-2-hYdroxY-5-methylhexYll-(l-methylethyl)aminolcarbonYll-L-isoleucine, methvl ester, isomer A
The L-isoleucine,methyl ester, isomer A
product from part (a) (0.25 g., 0.544 mmole) is dissolved in a solution of hydrochloric acid in dioxane (2N, 2.25 ml.). After keeping the solution at room temperature for 4 hours, it is evaporated ln vacuo to give N-[[[(3S)-3-amino-2-hydroxy-5-methylhexyl](1-methylethyl)amino]-carbonyl]-L-isoleucine, methyl ester, isomer A.
c) N-[[[(3S)-3-[[N-[N-[(l,l-Dimethvlethoxy)-carbonYl1-L-phenylalanY13-1'-[(phenYlmethoxv)-methyl]-L-histidyllaminol-2-hYdroxv-5-methY1-.' , . ~.
:
lZ97631 HA362a hexyl](l-methYlethvl)amino]carbonYl]-L-isoleucine, methyl ester' isomer A
Dicyclohexylcarbodiimide (0.109 g., 0.59 mmole) is added to a stirred (ice-bath) solution of N-[[[(3S)-3-amino-2-hydroxy-5-methyl-hexyl](l-methylethyl)amino]carbonyl]-L-isoleucine, methyl ester, isomer A from part (b), l-hydroxy-benzotriazole hydrate (0.081 g., 0.53 mmole), N-[N-[(l,l-dimethylethoxy)carbonyl]-L-phenylalanyl]-l'-[(phenylmethoxy)methyl]-L-histidine (0.277 g., 0.53 mmole), diisopropylethylamine (0.15 ml., 0.885 mmole), and dimethylformamide (3 ml.).
Stirring is continued at 5 (cold room) overnight.
It is then concentrated to dryness in vacuo and the residue is triturated with ethyl acetate and the separated dicyclohexyl urea is filtered off.
The eth~l acetate solution is washed with saturated sodium bicarbonate solution and water.
It is then evaporated in vacuo and the residue chromatographed (silica gel, 75 g.) using the solvent system chloroform:methanol:acetic acid (10:0.5:0.5). The product containing fractions are pooled, evaporated, and the residue is dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The ethyl acetate solution is dried over magnesium sulfate and evaporated in vacuo to give 0.26 g. of N-[[[(3Sj-3-[[N-[N-[(l,l-dimethylethoxy)carbonyl]-L-phenylalanyl]-l'-[(phenylmethoxy)methyl]-L-histidinyl]amino]-2-hydroxy-5-methylhexyl](1-' .~
,,"
!
129~631 HA362a methylethyl)amino]carbonyl~-L-isoleucine, methyl ester, isomer A.
d) N-[[[(3S)-3-[[N-[N-[(1,1-DimethYlethoxY)-carbonYll-L-~henYlalanYll-L-histidyllaminol-2 hYdroxY-5-methYlhexYll(l-methylethyl)aminol-carbonYl]-L-isoleucine, methYl ester, isomer A, monohYdrochloride The L-isoleucine, methyl ester, isomer A
product from part (c) (0.237 g., 0.274 mmole) is dissolved in methanol (3 ml.). Hydrochloric acid (0.1 N, 2.3 ml., prepared by diluting lN
aqueous hydrochloric acid with methanol) is added and the solution is stirred under an atmosphere of hydrogen in the presence of palladium hydroxide on carbon catalyst (65 mg.) for 18 hours. The mixture is then filtered through Celite and evaporated. The residue is stirred with isopropyl ether and filtered to give 0.165 g. of N-[~[(3S)-3-[[N-[N-[(l,l-dimethylethoxy)carbonyl]-L-phenyl-alanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]-(l-methylethyl)amino]carbonyl]-L-isoleucine, methyl ester, isomer A, monohydrochloride; m.p. 101 - 116;
[a]2D0 = ~11.65 (c = 1, methanol). TLC (silica gel; ethyl acetate:acetic acid:water, 12:1:1) Rf = 0.28.
Anal. calc'd. for C38H61N708 2 C, 56.52; H, 8.11; N, 12.14; Cl, 4.39 ~ound: C, 56.65; H, 8.00; N, 11.73; C1, 4.48.
~ * Trade Mark :
i lZ97631 HA362a Example 6 N-[[[(3S)-3-[[N-[N-[(1,1-Dimethylethoxy)carbonyl]-L-Phenylalanyll-L-histidyl]amino]-2-hydroxy-5-methylhexyl](1-methYlethyl)amino]carbonYl]-L-isoleucine, methYl ester, isomer B, monohydrochloridea) N-[[[(3S)-3-Amino-2-hYdroxy-5-methylhexyl](l-methylethYl)aminolcarbonyll-L-isoleucine, methyl ester, isomer B
The L-isoleucine, methyl ester, isomer B
product from Example 5(a) (0.35 g., 0.76 mmole) is dissolved in a solution of hydrochloric acid in dioxane (4 N, 3 ml.). After keeping the solution at room temperature for two hours, it is evaporated in vacuo to give N-[[[(3S)-3-amino-2-hydroxy-5-methylhexyl](1-methylethyl)amino]-carbonyl]-L-isoleucine, methyl ester, isomer B.
b) N-[[[(3S)-3-[[N-[N-[(1,1-DimethYlethoxY)-carbonYll-L-PhenYlalanyll-l'-[(Phenylmethoxv)-methYll-L-histidyl]aminol-2-hydroxy-5-methylhexyl]
(1-methYlethYl)aminolcarbonYl]-L-isoleucine, methYl ester, isomer B
Dicyclohexylcarbodiimide (0.161 g., 0.783 mmole) is added to a stirred (ice-bath) solution of N-[[[(3S)-3-amino-2-hydroxy-5-methyl-hexyl](1-methylethyl)amino]carbonyl]-L-isoleucine, methyl ester, isomer B from part (a), l-hydroxy-benzotriazole hydrate (0.12 g., 0.783 mmole), N-[N-[(1,1-dimethy7ethoxy)carbonyl]-L-phenylalanyl]-1'-[(phenylmethoxy)methyl]-L-histidine (0.409 g., 0.783 mmole), diisopropylethylamine (0.17 ml., '' ~297631 HA362a 1.0 mmole), and dimethylformamide (2 ml.).
Stirring is continued at 5 (cold room) overnight.
It is then concentrated to dryness in vacuo and the residue is triturated with ethyl acetate and the separated dicyclohexyl urea is filtered off.
The ethyl acetate solution is washed with saturated sodium bicarbonate solution and water.
It is then evaporated in vacuo and the residue chromatographed (silica gel, 120 g.) using the solvent system chloroform:methanol:acetic acid (10:0.5:0.5). The product containing fractions are pooled, evaporated, and the residue is dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The ethyl acetate solution is dried over magnesium sulfate and evaporated ln vacuo to give 0.37 g. of N-[[[(3S)-3-[[N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-1'-[(phenylmethoxy)methyl]-L-histidinyl]-amino]-2-hydroxy-5-methylhexyl](1-methylethyl)amino]-carbonyl]-L-isoleucine, methyl ester, isomer B.
c) N-[[[(3S)-3-[[N-LN-[(1,1-DimethvlethoxY)carbonYll-L-phenvlalanyll-L-histidyl]amino]-2-hydroxy-5-methyl-hexyl](1-methYlethyl)amino]carbonyll-L-isoleucine, methYl ester, isomer B, monohYdrochloride The L-isoleucine, methyl ester, isomer B
product from part (b) (0.363 g., 0.42 mmole) is dissolved in methanol (10 ml.). Hydrochloric acid (0.1 N, 3.6 ml., prepared by diluting lN aqueous hydrochloric acid with methanol) is added and the solution is stirred under an atmosphere of ~297631 HA362a hydrogen in the presence of palladium hydroxide on carbon catalyst (lO0 mg.) for 18 hours. The mixture is then filtered through Celite and evaporated. After reevaporation from benzene, the residue is triturated and stirred with isopropyl ether and then filtered to give 0.30 g. of N-[[[(3S)-3-[[N-[(l,l-dimethylethoxy)carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl](l-methylethyl)amino]carbonyl]-L-isoleucine, methyl ester, isomer B, monohydro-chloride; m.p. 118-128; [~]2D0 = -50.5 (c = 1.1, methanol). TLC (silica gel; ethyl acetate:acetic acid:water, 12:1:1) Rf = 0.2.
Anal. calc'd. for C38H61H7O8 2 C, 57.03; H, 8.06; N, 12.25; Cl, 4.43 Found: C, 57.03; H, 7.88; N, 12.04; Cl, 4.32.
Exam~le 7 N-[[[(3S)-3-[LN-[N-[(l,l-Dimethvlethoxy)carbonyl]-L-~henvlalanvl]-L-histidvllaminol-2-hYdroxv-5-methYlhexYllamino]carbonYl]-L-isoleucine, methYl ester, monohydrochloride a) (S)-[3-MethYl-l-[[bis(~henYlmethYl)amino]-acetyl]butYllcarbamic acid, 1,1-dimethYlethyl ester A solution of (S)-[3-methyl-1-[(chloro-methyl)carbonyl]butyl]carbamic acid, 1,l-dimethyl-ethyl ester (3.165 g., 12 mmole), dibenzylamine (2.31 ml., 12 mmole), sodium bicarbonate (1.52 g., 18 mmole), sodium iodide (0.9 g., 6 mmole), and 30~ dimethylformamide (24 ml.) are stirred at room temperature for one hour. An additional amount of 1~97631 HA362a dibenzylamine (0.23 ml., 1.2 mmole) is added and the stirring is continued for another 2.5 hours.
The reaction mixture is then concentrated to dryness. The residue is taken into ethyl acetate and washed with water. The ethyl acetate solution is concentrated and on dissolution in benzene a small amount of insoluble material separates. The solution is filtered and the benzene evaporated.
The residue is dissolved in ethyl acetate and passed through a small column of silica gel. The ethyl acetate solution is evaporated and the residue crystallized from hexane to give 3.603 g.
of (S)-[3-methyl-1-[[bis(phenylmethyl)amino]acetyl]-butyl]carbamic acid, 1,1-dimethylethyl ester; m.p.
(72) 75 - 77.
b) (3S)-L1-[(R,S)-1-HYdroxv-2-~bis(~henYlmethYl)-amino]ethY11-3-methYlbutYllcarbamic acid, 1,1-dimethylethyl ester Sodium borohydride (0.354 g., 9.3 mmole) is added to a solution of (S)-[3-methyl-1-[[bis(phenyl-methyl)amino]acetyl]butyl]carbamic acid, l,l-dimethyl-ethyl ester (3.59 g., 8.45 mmole) in ethanol (25 ml.).
The solution is stirred at room temperature for one hour and then concentrated to dryness ln vacuo.
The residue is suspended in ethyl acetate/water and acidified to pH 2.0 using dilute hydrochloric acid. The aqueous layer is then made basic using solid sodium bicarbonate and it is extracted with ethyl acetate to give 3.65 g. of (3S)-[l-[(R,S)-1-hydroxy-2-[bis(phenylmethyl)amino]-ethyl]-3-methylbutyl]carbamic acid, l,l-dimethyl-ethyl ester.
~ 12~7631 HA362a c) (3S)-[l-[(R,S)-2-Amino-l-hydroxyethyl~-3-methylbutYl]carbamic acid, l,l-dimethylethyl ester, monohydrochloride (3S~-[l-(R,S)-l-~ydroxy-2-[bis(phenylmethyl)-amino]ethyl]-3-methylbutyl]carbamic acid, 1,1-dimethylethyl ester (4.25 g., 9.96 mmole) is dissolved in methanol (80 ml.). Aqueous hydro-chloric acid (lN, 9.96 ml.) is added followed by palladium hydroxide on carbon catalyst (0.85 g.).
The mixture is then stirred under an atmosphere of hydrogen for 24 hours. It is then filtered through hyflo and the solution is concentrated to dryness to give 2.62 g. of (3S)-[l-[(R,S)-2-amino-l-hydroxyethyl]-3-methylbutyl]carbamic acid, 1,1-dimethylethyl ester, monohydrochloride.d) N-[[[(3S)-3-[[(1,1-DimethylethoxY)carbonyl]-aminol-2-hvdroxy-5-methvlhexyllaminolcarbonYl]-L-isoleucine, methyl ester N-Methylmorpholine (0.588 ml., 5.33 mmole) is added to a stirred solution of L-isoleucine, methyl ester, monohydrochloride (0.385 g., 2.12 mmole) in methylene chloride (8 ml.) at -30 followed by the dropwise addition of a solution of phosgene in benzene (12.5%, 3.18 mmole, 2.52 ml.). After stirring for 30 minutes at -20, the mixture is concentrated to dryness ln vacuo.
An ice-cold solution of (3S)-[1-[(R,S)-2-amino-1-hydroxyethyl]-3-methylbutyl]carbamic acid, 1,1-dimethylethyl ester, monohydrochloride (0.6 g., 2.12 mmole) in methylene chloride (6 ml.) and N-methylmorpholine (0.47 ml., 4.24 mmole) are ~., 1297~`3~
HA362a added to the above residue. An additional 3 ml.
of methylene chloride is used for washings. The reaction mixture is stirred in an ice-bath for 2 hours and at room temperature overnight. It is then evaporated to dryness, the residue is taken up in ethyl acetate and washed with saturated sodium bicarbonate and 10% potassium bisulfate solution. The ethyl acetate extract after evaporation is chromatographed over silica gel (60 g.) using the solvent system ethyl acetate:
hexane (2:1) to give 0.48 g. of N-[[[(3S~-3-[[(l,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-5-methylhexyl]amino]carbonyl]-L-isoleucine, methyl ester.
e) N-[[r(3S)-3-Amino-2-hvdroxv-5-methvlheXYll-aminolcarbonvll-L-isoleucine, methYl ester, mono-The isoleucine, methyl ester product frompart (d) (0.43 g., 1.03 mmole) is dissolved in a solution of hydrochloric acid in dioxane (2N, 3ml.) and kept at room temperature for 2.5 hours. The mixture is then concentrated to dryness ln vacuo to give N-[[[(3S)-3-amino-2-hydroxy-5-methylhexyl]-amino]carbonyl]-L-isoleucine, methyl ester, mono-hydrochloride.
f) N-[[~(3S)-3-[[N-[N-[(1,1-DimethylethoxY)-carbonyl]-L-~henylalanvl]-1'-[(~henvlmethoxy)-methvll-L-histidvllaminol-2-hvdroxv-5-methYlhexvll-amino]carbonYl]-L-isoleucine, methyl ester Dicyclohexylcarbodiimide (0.212 g., 1.03 mmole) is added to a stirred (ice-bath) solution of ;
' , HA362a the L-isoleucine, methyl ester, monohydrochloride product from part (e), l-hydroxybenzotriazole hydrate (0.158g., 1.03 mmole), N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-l'-[(phenyl-methoxy)methyl]-L-histidine (0.538 g., 1.03 mmole) diisopropylethylamine (O.22 ml., 1.29 mmole), and dimethylformamide (4 ml.). Stirring is continued at 5 (cold room) overnight. The mixture is then concentrated to dryness ln vacuo The residue is triturated with ethyl acetate and the separated dicyclohexyl urea is filtered off. The ethyl acetate solution is washed with saturated sodium bicarbonate solution and water. It is then evaporated ln vacuo and the residue is chromatographed over silica gel (65 g.) using the solvent system chloroform:methanol:acetic acid (10:0.75:0.75). The product containing fractions are pooled, evaporated, and the residue is dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The ethyl acetate solution after drying over anhydrous magnesium sulfate is evaporated 1n vacuo to give 0.57 g. of N-[[[(3S)-3-[[N-[N-[(1,1-dimethylethoxy)-carbonyl]-L-phenylalanyl]-1'-[(phenylmethoxy)methyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]amino~-carbonyl]-L-isoleucine, methyl ester.
g) N-[[[(3S)-3-[[N-[N-[(l,1-Dimethylethoxv)-carbonyl]-L-phenvlalanyl]-L-histidvl]aminol-2-hydroxv-5-methYlhexyl]aminolcarbonyl]-L-isoleucine~
methvl ester, monohvdrochloride The L-isoleucine, methyl ester product from part (f) (0.37 g., 0.45 mmole) is dissolved in 12~7631 HA362a methanol (20 ml.). Hydrochloric acid (O.lN, 4.05 ml., prepared by diluting lN aqueous hydro-chloric acid with methanol) is added and the solution is stirred under an atmosphere of hydrogen in the presence of palladium hydroxide on carbon catalyst (125 mg.) for 18 hours. The mixture is then filtered through Celite and evaporated. The residue is dissolved in iso-propanol and diluted with isopropyl ether. The separated solid is filtered to give 0.27 g. of N-[[[(3S)-3-[[N-[N-[(l,l-dimethylethoxy)carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]amino]carbonyl]-L-isoleucine, methyl ester, monohydrochloride, m.p. 133 - 158;
[~]D0 = -8.0 (c = 1.2, methanoll. TLC (silica gel; ethyl acetate:acetic acid:water, lZ:l:l) Rf =
0.16.
Anal. calc'd. for C35H55N7O8 2 C, 54.93; H, 7.77; N, 12.82; Cl, 4.63 Found: C, 54.93; H, 7.66; N, 12.46; Cl, 4.82.
Examule 8 N-[N-[[[(3S)-3-[[N-[N-[(1,1-DimethYlethoxv)carbonYll-L-~henYlalanYl]-L-histidYl]aminol-2-hYdroxy-5-meth hexyl]amino]carbonyl]-L-isoleucyl]-L-histine, methyl ester, dihydrochloride a) N-[[[(3S)-3-[[(1,1-Dimethylethoxv)carbonyll-amino]-2-hYdroxY-5-methYlhexyl]aminolcarbonYl]-L-isoleucine, phenYlmethyl ester N-Methylmorpholine (2.5 ml., 22.73 mmole) is added to a stirred solution of L-isoleucine, phenylmethyl ester, monohydrochloride (3.56 g., HA362a 9.264 mmole) in methylene chloride (38 ml.) at -30 followed by the dropwise addition of a solution of phosgene in benzene (12.5%, 10.8 ml., 13.608 mmole). After stirring for 30 minutes at -20, the mixture is concentrated to dryness ln vacuo. A solution of (3S)-[l-[(R,S)-2-amino-1-hydroxyethyl]-3-methylbutyl]carbamic acid, 1,1-dimethylethyl ester, monohydrochloride (2.62 g., 9.264 mmole) in methylene chloride (20 ml.) is added to the above residue. While stirring th~
above solution in an ice-bath, N-methylmorpholine (2.0 g., 18.18 mmole) is added and the stirring is continued for 2 hours in the ice-bath and then overnight at room temperature. The mixture is then evaporated to dryness. The residue is taken up in ethyl acetate and washed neutral with sodium bicarbonate and 10% potassium bisulfate. The ethyl acetate extract after drying is chromatographed over silica gel (250 g.) using the solvent system ethyl acetate:hexane (1:1) to give 1.92 g. of N-[[[(3S)-3-[[(1,1-dimethylethoxy)-carbonyl]amino]-2-hydroxy-5-methylhexyl]amino]-carbonyl]-L-isoleucine, phenylmethyl ester.
b) N-[[[(3S)-3-[[~1,1-Dimethylethoxy)carbonyl]-aminol-2-hydroxy-5-methylhexyllamino]carbonyll-L-isoleucine ~ A solution of the L-isoleucine, phenylmethyl ; ester from part (a) (1.92 g., 3.89 mmole) in methanol (50 ml.) is stirred under an atmosphere of hydrogen for 2 hours in the presence of palladium hydroxide on carbon catalyst (0.4 g.).
1297~
HA362a The mixture is then filtered through hyflo and concentrated to dryness to give 1.51 g. of N-[[[~3S)-3-[[(1,1-dimethylethoxy)carbonyl]-amino]-2-hydroxy-5-methylhexyl]amino]carbonyl]~
L-isoleucine.
c) N-[N-[(l,1-DimethylethoxY)carbonyl~-L-Phenvlalanyl]-3'-[(phenYlmethoxy)carbonyl]-L-histidine A solution of N-[N-[(1,1-dimethylethoxy) carbonyl]-L-phenylalanyl]-l'-[(phenylmethoxy)-methyl]-L-histidine in a mixture of methanol:
acetic acid (8:2, 200 ml.) is stirred under an atmosphere of hydrogen overnight in the presence of palladium hydroxide on carbon catalyst (2.6 g.).
The mixture is filtered through hyflo and concentrated to dryness. The residue on crystalli-zation from hot acetonitrile (150 ml.) gives 6.01 g. of N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-L-histidine; m.p. (192) 197 - 198.
To a stirred (ice-bath) solution of N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-L-histidine (3.68 g., 10 mmole) in dimethylformamide (20 ml.) and diisopropylethylamine (1.74 ml., 10 mmole) is added N-carbobenzyloxysuccinimide (3.0 g., 12 mmole). (This latter reagent is added in 4 portions at intervals of 15 minutes.) After stirring for 90 minutes, the mixture is evaporated in vacuo. The residue is taken up in ethyl acetate and washed with 10% citric acid.
After evaporation of the ethyl acetate solution, the residue is chromatographed over silica gel using the solvent system chloroform:methanol:acetic 1297~31 HA362a acid (90:3:3) to give 3.2 g. of N-[N-[(1,1-dimethyl-ethoxy)carbonyl]-L-phenylalanyl]-3'-[(phenyl-methoxy)carbonyl]-L-histidine.
d) 3'-[(Phenylmethoxv)carbonyl]-L-histidine, methyl ester, monohYdrochloride N-[(1,1-Dimethylethoxy)carbonyl]-L-histidine, methyl ester (2.42 g., 9 mmole) [prepared as set forth by Hanford et al., J. Org. Chem., Vol. 33, p. 4251 (1968)] is dissolved in tetrahydrofuran (40 ml.) and diisopropylethylamine (1.74 ml., 9.9 mmole) is added. While stirring the above solution at room temperature, benzyloxycarbonyl chloride (1.42 ml., 9.9 mmole) is added. After a period of 90 minutes, the mixture is concentrated to dryness. The residue is taken up in ethyl acetate and washed with water. The ethyl acetate extract after evaporation is crystallized from ethyl acetate:hexane (1:1) to give 2.07 g. of N-[(1,1-dimethylethoxy)carbonyl]-3'-[(phenyl-methoxy)carbonyl]-L-histidine, methyl ester.
This N-[(1,1-dimethylethoxy)carbonyl]-3'-[(phenylmethoxy)carbonyl]-L-histidine, methyl ester (1.09 g., 2.7 mmole) is dissolved in a solution of hydrochloric acid in acetic acid (2N, 24 ml.). After keeping the mixture at room ~ temperature for 10 minutes, it is concentrated ; in vacuo. The residue is reevaporated from benzene and acetonitrile several times to give ; 30 3'-[(phenylmethoxy)carbonyl]-L-histidine, methyl ester, monohydrochloride.
129763~
HA362a e) N-[N-[[[(3S)-3-[[(1,1-Dimethylethoxy)carbonyl]-aminol-2-hYdroxY-5-methylhexyl1amino]carbonyl]-L-isoleucYl]-3'-[(phenYlmethoxy)carbonyl]-L-histidine, methvl ester Dicyclohexylcarbodiimide (0.556 g., 2.7 mmole) is added to a stirred (ice-bath) solution of N-[[[(3S)-3-[[(1,1-dimethylethoxy)-carbonyl]amino]-2-hydroxy-5-methylhexyl]amino]-carbonyl]-L-isoleucine (l.09 g., 2.7 mmole), 1-hydroxybenzotriazole hydrate (0.413 g., 2.7 mmole), 3'-[(phenylmethoxy)carbonyl]-L-histidine, methyl ester, monohydrochloride (2.7 mmole), and diisopropylethylamine (0.47 ml., 2.7 mmole) in dimethylformamide (12 ml.). The reaction mixture is stirred at 5 (cold room) overnight. It is then concentrated to dryness.
The residue is triturated with ethyl acetate and filtered to remove dicyclohexyl urea. The ethyl acetate solution is washed with saturated sodium bicarbonate and then evaporated. The residue is chromatographed over silica gel (200 g.) using the solvent system chloroform:methanol (95:5) to give 1.022 g. of N-[N-[[[(3S)-3-[[(1,1-dimethylethoxy) carbonyl]amino]-2-hydroxy-5-methylhexyl]amino]-carbonyl]-L-isoleucyl]-3'-[(phenylmethoxy)carbonyl]-L-histidine, methyl ester.
f) N-[N-[[[(3S)-3-Amino-2-hydroxy-5-methYlhexyl]-aminolcarbonyl]-L-isoleucvll-3'-[(phenvlmethoxY)-carbonvll-L-histine, methvl ester, monohvdrochloride The L-histidine, methyl ester product from part (e) (0.62 g., 0.9 mmole) is dissolved in a . , ,. ,.... , .. ~ . . - .
. ' ' ' , ' ' : '' ' .' ~Z9763~
HA362a solution of hydrochloric acid in dioxane (4N, 10.2 ml.). After keeping the mixture at room temperature for 20 minutes, it is concentrated to dryness in vacuo to give N-[N-[~[(3S)-3-amino-2-hydroxy-5-methylhexyl]amino]carbonyl]-L-iso-leucyl]-3'-[(phenylmethoxy)carbonyl]-L-histidine, methyl ester, monohydrochloride.
g) N-[N-[[[(3S)-3-[[N-[N-~(l,l-Dimethylethoxv)-carbonyll-L-~henylalanyl]-3'-[(Phenylmethoxy)-carbonyl]-L-histidyl]amino]-2-hydroxY-5-methyl-hexyllaminolcarbonvl]-L-isoleucyl]-3'-[(phenYl-methoxy)carbonYl]-L-histidine, methvl ester Dicyclohexylcarbodiimide (0.185 g., 0.9 mmole) is added to a stirred (ice-bath) solution of the L-histidine, methyl ester, mono-hydrochloride product from part (f) (O.9 mmole), 1-hydroxybenzotriazole hydrate (0.138 g., 0.9 mmnole), N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-3'-[(phenylmethoxy)carbonyl]-L-histidine (0.483 g., 0.9 mmole), and diisopropyl-ethylamine (0.16 ml., 0.94 mmole) in dimethyl-formamide (3 ml.). The reaction mixture is stirred at 5 (cold room) overnight. It is then concen-trated to dryness, triturated with ethyl acetate 2S and the separated dicyclohexyl urea is filtered off.
The ethyl acetate solution is washed with saturated sodium bicarbonate and then evaporated. The residue is chromatographed over silica gel (80 g.) using the solvent system ethyl acetate:methanol (95:5) to give 0.266 g. of N-[N-[[[(3S~-3-[[N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-3'-.
~Z9763i HA362a [(phenylmethoxy)carbonyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]amino]carbonyl]-L-iso-leucyl]-3'-[(phenylmethoxy)carbonyl~-L-histidine, methyl ester.
h) N-[N-~[[(3S)-3-[[N-[N-[(1,1-DimethYlethoxy)-carbonyll-L-DhenvlalanYl~-L-histidyl]amino]-2 hvdroxy-5-methylhexYllamino]carbonyl]-L-iso-leucvll-L-histidine, methYl ester, dihydrochloride The L-histidine, methyl ester product from part (g) (250 mg., 0.23 mmole) is dissolved in methanol (10 ml.). After adding aqueous hydro-chloric acid (lN, 0.41 ml.) and palladium hydroxide on carbon catalyst (50 mg.), the solution is stirred under an atmosphere of hydrogen for 4 hours. It is then filtered through hyflo and evaporated to dryness to give 0.187 g. of N-[N-[[[(3S)-3-[[N-[N-[(1,1-dimethylethoxy)-carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]amino]carbonyl]-L-isoleucyl]-Z0 L-histidine, methyl ester, dihydrochloride; m.p.
75 - 170; [~]2D0 = -7.8 (c = 1.7, methanol).
TLC (silica gel; chloroform:methanol:acetic acid, 6:4:2) Rf = 0.7.
Anal. cal'd. for C41H62OgNlo 2 C, 50.28; H, 7.36; N, 14.30; Cl, 7.24 Found: C, 50.30; H, 7.43; N, 14.00; Cl, 7.25.
" . ~
~,, " 1297~31 HA362a Exam~les 9 - 29 Following the procedure of Examples 1 to 8, additional compounds within the scope of this invention can be prepared having the formula R4 R3 R2 o R1 I 11 I j I I i X-NH-CH- C -NH - CH - CH ~ CH2--N -C-NH - CH - C-A
I
OH
wherein the substituents are as defined below.
~:;
... .
Z~7~3~
-69- HA362a _~ Y
o=u O=~ ~z N _N
O
_ -- I -- _, _ N
? I -. _ Z
t, ~, ~ N~
; I Y Y
O = U = ~J
U ~ -- I N
O=U = U ~--X I _ _ ~
O ,_1 ' ~' ', ~',,i ', 1297~31 .., -7 O- HA362 a "~ Z2 s ~ U ~Z-= $1 a,--a 'a-a aN
C I Z Z
~ I -~ ;~ ~
~N ¦ _ _ _ N N
~ _ ~ I , _ _ ~5-= Z~Z ~) ,' N N N
~c I ,a ,a ;.
O_~ ~
~~-, ~aN ~ o=$_~
( Z Z
~ o= U o=~ o =~
~ o - ol ,o ., . , ~, ~, ~!' X I -- 2 'r 'l ~ ,D
', `l ~
~1~
:r 1297~3i H~362a ~~
t~Z~ o=u ~
o = ~, o = t~ ~ o = ~. ~ _ z z ^r U ~
J
_~ O ~_ ~ U
X
.~ .
.,,j,.~,", .. . . .
~29763~
-72- HA362a o=u ~ o=u ~ o=y~
c I z z z , ~ ~. ^
, z_~ ' z \\ I z _ = _ 8-- N _ ~ -- O ~ U
O = U Z U"
, ~ X ~\ ON ~
~ , .,1 .-- : '' '"'' ' ' 1297~i31 ~ .~
_73_ HA362a 0='~ ~ 0=~ ~ 0=o ~
V --;~
I Z Z Z
_ _ .'. `, `, _ _ _ ~ ~z-= z~z q o = ~
~ U--o = ~ U--y : ' o~ " ~ N
~ . X' I
N N ~r ,1, " i '.' ~ * ~",.. ..... .. .
' `~ 1Z97~31 74 HA362a _~z ~ o ~ o ~
N
C ! Z _ _ ^_^_ /~
_ Z 1~=-'J
;~
I ~
O =t~ ~
O ~ ~ Z ~,~
U y U ~
W ¦ ~ N
., . ~ .
~, .
lZ97~31 HA362a ExamPle 30 looo tablets each containing the following ingrdients N-[N-[[[(3s)-3-[[N-[N-[(~
5 Dimethylethoxy)carbonyl]-L-phenyl-alanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]amino]carbonyl]-L-isoleucyl]-L-histidine, methyl ester, dihydrochloride 250 mg.
10 Cornstarch 100 mg.
Gelatin 20 mg.
Avicel(microcrystalline cellulose) 50 mg.
Magnesium stearate 5 mg.
425 mg.
are preapred from sufficient bulk quantities by mixing the N-[N-[[[(3S)-3-[[N-[N-[(1,1-dimethyl-ethoxy)carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]amino]carbonyl]-L-isoleucyl]-L-histidine, methyl ester, dihydrochloride and corn-starch with an aqueous solution of the gelatin. Themixture is dried and ground to a fine powder. The Avicel and then the magnesium stearate are admixed with granulation. This mixture is then compressed in a tablet press to form 1000 tablets each containing 250 mg. of active ingredient.
In a simi}ar manner, tablets containing 250 mg.
of the product of any of Examples 1 to 7 and 9 to 29 can be prepared.
A similar procedure can be employed to form tablets containing 500 mg. of active ingredient.
~' ;
~'' ~.
A * Trade Mark ~' ~, ......
12~7~31 HA362a Example 31 An injectable solution is prepared as follows:
N-[[[(3S)-3-[[N-[N-[(l,l-Dimethyl-5 ethoxy)carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)-amino]carbonyl]-L-valine, methyl ester,monohydrochloride (isomer A) lO00 g.
10 Methyl paraben 5 g.
Propyl paraben l g.
Sodium chloride 5 g.
The active substance, preservatives, and sodium chloride are dissolved in 3 liters of water for injection and then the volume is brought up to 5 liters. The solution is filtered through a sterile filter and aseptically filled into pre-sterilized vials which are closed with presteri-lized rubber closures. Each vial contains 5 ml.
of solution in a concentration of 200 mg. of active ingredient per ml. of solution for injection.
In a similar manner, an injectable solution containing 200 mg. of active ingredient per ml. of solution can be prepared for the product of any of Examples 2 to 29.
.. ... .
~zg7~3i HA362a Example 32 1000 Tablets each containing the following ingredients:
N-[N-[[[(3s)-3-[[N-[N-~
5 Dimethylethoxy)carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]amino]-carbonyl]-L-isoleucyl]-L-histidine, methyl ester, dihydrochloride 500 mg.
10 Avicel 300 mg.
Hydrochlorothiazide 14.5 mg.
Lactose 113 mg.
Cornstarch 15.5 mg.
Stearic acid 7 mg.
950 mg.
are prepared from sufficient bulk ~uantities by slugging the N-[N-[[[(3S)-3-[[N-[N-[(l,l-dimethyl-ethoxy)carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]amino]carbonyl]-L-isoleucyl]-L-histidine, methyl ester, dihydrochloride, Avicel, and a poriton of the stearic acid. The slugs are ground and passed through a #2 screen, then mixed with the hydrochlorothiazide, lactose, cornstarch, and remainder of the strearic acid. The mixture i~ compressed into 950 mg. capsule shaped tablets in a tablet press. The tablets are scored for dividing in half.
In a similar manner, tablets can be prepared containing 500 mg. of the product of any of 30 Examples 1 to 7 and 9 to 29.
:, . . ,
Claims (36)
1. A compound of the formula including a pharmaceutically acceptable salt thereof wherein:
X is HA362a , , , , or ;
R1, R3, R4, R5, and R9 are independently selected from the group consisting of hydrogen, lower alkyl, halo substituted lower alkyl, -(CH2)n-aryl, -(CH2)n-heterocyclo, -(CH2)n-OH, -(CH2)n-NH2, -(CH2)n-SH, -(CH2)n-S-lower alkyl, -(CH2)n-O-lower alkyl, -(CH2)n-O-(CH2)g-OH, -(CH2)n-O-(CH2)g-NH2, -(CH2)n-S-(CH2)g-OH, HA362a , , and -(CH2)n-cycloalkyl;
R2 is hydrogen, lower alkyl, -(CH2)m-aryl, -(CH2)m-cycloalkyl, or -(CH2)n-heterocyclo;
R6 and R'6 are independently selected from the groug consisting of lower alkyl, cycloalkyl, aryl and heterocyclo;
p is zero or one;
m and m' are independently selected from the group consisting of zero and an integer from 1 to 5;
n is an integer from 1 to 5;
g is an integer from 2 to 5;
R7 is or ;
R8 is 2,4-dinitrophenyl, , , or ;
q is zero or one;
HA362a R10 is hydroxy, -O-lower alkyl, -O-(CH2)m-cycloalkyl, -O-(CH2)m-aryl, -O-(CH2)n-heterocyclo, -NH2, or -O-salt forming ion;
the term lower alkyl refers to straight or branched chain radicals having up to seven carbon atoms;
the term cycloalkyl refers to saturated rings of 4 to 7 carbon atoms;
the term halo refers to Cl, Br, and F;
the term halo substituted lower alkyl refers to such lower alkyl groups in which one or more hydrogens have been replaced by chloro, bromo or fluoro groups;
the term aryl refers to phenyl, 1-naphthyl, 2-naphthyl, mono substituted phenyl, 1-napthyl, or 2-naphthyl wherein said substituent is lower alkyl of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, halogen, hydroxy, amino, -NH-alkyl wherein alkyl is of 1 to 4 carbons, or -N(alkyl)2 wherein alkyl is of 1 to 4 carbons, di or tri substituted phenyl, 1-naphthyl or 2-naphthyl wherein said substituents are methyl, methoxy, methylthio, halogen or hydroxy; and the term heterocyclo refers to fully saturated or unsaturated rings of 5 or 6 atoms containing one or two O or S atoms and/or one to four N atoms provided that the total number of hetero atoms in the ring is 4 or less and bicyclic rings wherein the five or six membered ring containing 0, S and N atoms as defined above is fused to a benzene ring.
HA362a
X is HA362a , , , , or ;
R1, R3, R4, R5, and R9 are independently selected from the group consisting of hydrogen, lower alkyl, halo substituted lower alkyl, -(CH2)n-aryl, -(CH2)n-heterocyclo, -(CH2)n-OH, -(CH2)n-NH2, -(CH2)n-SH, -(CH2)n-S-lower alkyl, -(CH2)n-O-lower alkyl, -(CH2)n-O-(CH2)g-OH, -(CH2)n-O-(CH2)g-NH2, -(CH2)n-S-(CH2)g-OH, HA362a , , and -(CH2)n-cycloalkyl;
R2 is hydrogen, lower alkyl, -(CH2)m-aryl, -(CH2)m-cycloalkyl, or -(CH2)n-heterocyclo;
R6 and R'6 are independently selected from the groug consisting of lower alkyl, cycloalkyl, aryl and heterocyclo;
p is zero or one;
m and m' are independently selected from the group consisting of zero and an integer from 1 to 5;
n is an integer from 1 to 5;
g is an integer from 2 to 5;
R7 is or ;
R8 is 2,4-dinitrophenyl, , , or ;
q is zero or one;
HA362a R10 is hydroxy, -O-lower alkyl, -O-(CH2)m-cycloalkyl, -O-(CH2)m-aryl, -O-(CH2)n-heterocyclo, -NH2, or -O-salt forming ion;
the term lower alkyl refers to straight or branched chain radicals having up to seven carbon atoms;
the term cycloalkyl refers to saturated rings of 4 to 7 carbon atoms;
the term halo refers to Cl, Br, and F;
the term halo substituted lower alkyl refers to such lower alkyl groups in which one or more hydrogens have been replaced by chloro, bromo or fluoro groups;
the term aryl refers to phenyl, 1-naphthyl, 2-naphthyl, mono substituted phenyl, 1-napthyl, or 2-naphthyl wherein said substituent is lower alkyl of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, halogen, hydroxy, amino, -NH-alkyl wherein alkyl is of 1 to 4 carbons, or -N(alkyl)2 wherein alkyl is of 1 to 4 carbons, di or tri substituted phenyl, 1-naphthyl or 2-naphthyl wherein said substituents are methyl, methoxy, methylthio, halogen or hydroxy; and the term heterocyclo refers to fully saturated or unsaturated rings of 5 or 6 atoms containing one or two O or S atoms and/or one to four N atoms provided that the total number of hetero atoms in the ring is 4 or less and bicyclic rings wherein the five or six membered ring containing 0, S and N atoms as defined above is fused to a benzene ring.
HA362a
2. A compound of Claim 1 wherein:
X is lower alkyl , , or ;
R1 is lower alkyl of 3 to 5 carbons -(CH2)m-cyclopentyl, -(CH2)m-cyclohexyl, , or ;
m is an integer from 1 to 3;
R2 is hydrogen, lower alkyl of 3 to 5 carbons, -(CH2)m-cyclopentyl, -(CH2)m-cyclohexyl, , or ;
R3 is lower alkyl of 3 to 5 carbons, -(CH2)m-cyclopentyl, -(CH2)m-cyclohexyl or ;
HA362a R4 is , , , , , , , , , or ;
R5 and R9 are independently selected from the group consisting of , , -CH2-(.alpha.-naphthyl), -CH2-(.beta.-naphthyl), , -CH2-cyclopentyl, HA362a -CH2-cyclohexyl, , , , , , and ; and R10 is-o-CH3 , -O-C2H5, , or hydroxy.
X is lower alkyl , , or ;
R1 is lower alkyl of 3 to 5 carbons -(CH2)m-cyclopentyl, -(CH2)m-cyclohexyl, , or ;
m is an integer from 1 to 3;
R2 is hydrogen, lower alkyl of 3 to 5 carbons, -(CH2)m-cyclopentyl, -(CH2)m-cyclohexyl, , or ;
R3 is lower alkyl of 3 to 5 carbons, -(CH2)m-cyclopentyl, -(CH2)m-cyclohexyl or ;
HA362a R4 is , , , , , , , , , or ;
R5 and R9 are independently selected from the group consisting of , , -CH2-(.alpha.-naphthyl), -CH2-(.beta.-naphthyl), , -CH2-cyclopentyl, HA362a -CH2-cyclohexyl, , , , , , and ; and R10 is-o-CH3 , -O-C2H5, , or hydroxy.
3. A compound of Claim 2 wherein q is one.
4. A compound of Claim 3 wherein X is ;
R1 is or -CH-(CH3)2;
R2 is hydrogen, -CH2-CH-(CH3)2, or -CH-(CH3)2;
R5 is ;
HA362a R4 is ;
R3 is -CH2-CH-(CH3)2 ;
R9 is or ; and R10 is -O-CH3.
R1 is or -CH-(CH3)2;
R2 is hydrogen, -CH2-CH-(CH3)2, or -CH-(CH3)2;
R5 is ;
HA362a R4 is ;
R3 is -CH2-CH-(CH3)2 ;
R9 is or ; and R10 is -O-CH3.
5. The compound of Claim 4 wherein:
R10 is ;
R2 is hydrogen; and Rg is .
R10 is ;
R2 is hydrogen; and Rg is .
6. The compound of Claim 5, N-[N-[[[(3S)-3-[[N-[N-[(1, 1-dimethylethoxy)carbonyl]-L-phenyl-alanyl]-L-histidyl]amino]-2-hydroxy-5- methylhexyl]-amino]carbonyl]-L-isoleucyl]-L-histidine, methyl ester, dihydrochloride.
7. The compound of Claim 4 wherein:
R1 is - CH-(CH3)2 ;
R2 is -CH2-CH-(CH3)2; and R9 is .
R1 is - CH-(CH3)2 ;
R2 is -CH2-CH-(CH3)2; and R9 is .
8. The compound of Claim 7, N-[N-[[[(3S)-3-[[N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenyl-alanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]-(2-methylpropyl)amino]carbonyl]-L-valyl]-L-phenyl-alanine, methyl ester, monohydrochloride.
HA362a
HA362a
9. The compound of Claim 4 wherein:
R1 is ;
R2 is -CH-(CH3)2; and R9 is .
R1 is ;
R2 is -CH-(CH3)2; and R9 is .
10. The compound of Claim 9, N-[N-[[[(3S)-3-[[N-[N- [(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl](1-methylethyl)amino]carbonyl]-L-isoleucyl]-L-histidine, methyl ester, dihydrochloride.
11. A compound of Claim 2 wherein:
q is zero.
q is zero.
12. A compound of Claim 11 wherein X is ;
R1 is or -CH-(CH3)2 ;
R2 is hydrogen, -CH2-CH-(CH3)2, or -CH-(CH3)2 ;
R5 is ;
R4 is ;
R3 is -CH2-CH-(CH3)2 ; and R10 is -O-CH3.
HA362a
R1 is or -CH-(CH3)2 ;
R2 is hydrogen, -CH2-CH-(CH3)2, or -CH-(CH3)2 ;
R5 is ;
R4 is ;
R3 is -CH2-CH-(CH3)2 ; and R10 is -O-CH3.
HA362a
13. The compound of Claim 12 wherein:
R1 is -CH-(CH3)2; and R2 is -CH-CH2-CH-(CH3)2-
R1 is -CH-(CH3)2; and R2 is -CH-CH2-CH-(CH3)2-
14. The compound of Claim 13, N-[[[(3S)-3-[[N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenyl-alanyl]-L-histidyl]amino]-2-hydroxy-5-methyl-hexyl](2-methylpropyl)amino]carbonyl]-L-valine, methyl ester, monhydrochloride.
15. The compound of Claim 12 wherein:
R1 is ; and R2 is -CH-(CH3)2 .
R1 is ; and R2 is -CH-(CH3)2 .
16. The compound of Claim 15, N-[[[(3S)-3-[[N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenyl-alanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]-(1-methylethyl)amino]carbonyl]-L-isoleucine, methyl ester, monohydrochloride.
17. The compound of Claim 12 wherein:
R1 is ; and R2 is hydrogen.
R1 is ; and R2 is hydrogen.
18. The compound of Claim 17, N-[[[(3S)-3-[[N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]amino]-carbonyl]-L-isoleucine, methyl ester, monohydrochloride.
19. A pharmaceutical composition for treating hypertension in a mammalian species comprising an anti-hypertensively effective amount of a compound as defined in Claim 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier therefor.
20. A pharmaceutical composition for treating hypertension in a mammalian species comprising an anti-hypertensively effective amount of a compound as defined in Claim 2, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier therefor.
21. A composition of Claim 20 wherein q is one.
22. A composition of Claim 21 wherein X is ;
R1 is or -CH-(CH3)2;
R2 is hydrogen, -CH2-CH-(CH3)2, or -CH-(CH3)2;
R5 is ;
R4 is ;
R3 is -CH2-CH-(CH3)2;
R9 is or ;
and R10 is -O-CH3-.
R1 is or -CH-(CH3)2;
R2 is hydrogen, -CH2-CH-(CH3)2, or -CH-(CH3)2;
R5 is ;
R4 is ;
R3 is -CH2-CH-(CH3)2;
R9 is or ;
and R10 is -O-CH3-.
23. A composition of Claim 22 wherein:
R1 is ;
R2 is hydrogen; and R9 is .
R1 is ;
R2 is hydrogen; and R9 is .
24. A composition of Claim 19, wherein the compound is N-[N-[[[(3S)-3-[[N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl]am-ino]carbonyl]-L-isoleucyl]-L-histidine, methyl ester, dihydrochloride.
25. A composition of Claim 22 wherein:
R1 is -CH-(CH3)2;
R2 is -CH2-CH-(CH3)2; and R9 is .
R1 is -CH-(CH3)2;
R2 is -CH2-CH-(CH3)2; and R9 is .
26. A composition of Claim 19, wherein the compound is N-[N-[[[(3S)-3-[[N-[N-((1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl](2-methylpropyl)amino]carbonyl]-L-valyl]-L-phen-ylalanine, methyl ester, monohydrochloride.
27. A composition of Claim 22 wherein:
R1 is ;
R2 is -CH-(CH3)2; and R9 is .
R1 is ;
R2 is -CH-(CH3)2; and R9 is .
28. A composition of Claim 19, wherein the compound is N-[N-[[[(3S)-3-[[N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-hydroxy-5-methylhexyl](l-methylethyl)amino]carbonyl]-L-isoleucyl]-L-histidine, methyl ester, dihydrochloride.
29. A composition of Claim 20 wherein q is zero.
30. A composition of Claim 29 wherein X is ;
R1 is or -CH-(CH3)2;
R2 is hydrogen, -CH2-CH-(CH3)2, or -CH-(CH3)2;
R5 is ;
R4 is ;
R3 is -CH2-CH-(CH3)2; and R10 is -O-CH3-.
R1 is or -CH-(CH3)2;
R2 is hydrogen, -CH2-CH-(CH3)2, or -CH-(CH3)2;
R5 is ;
R4 is ;
R3 is -CH2-CH-(CH3)2; and R10 is -O-CH3-.
31. A composition of Claim 30 wherein:
R1 is -CH-(CH3)2; and R2 is -CH CH2-CH-(CH3)2.
R1 is -CH-(CH3)2; and R2 is -CH CH2-CH-(CH3)2.
32. A composition of Claim l9, wherein the compound is N-[[[(3S)-3-[[N-[N-[(l,l-dime-thylethoxy)carbonyl]-L-phenylalanyl]-L-histi-dyl]amino]-2-hydroxy-5-methylhexyl](2-methyl-propyl)amino]carbonyl]-L-valine, methyl ester, monohydrochloride.
33. A composition of Claim 30 wherein:
R1 is ; and R2 is -CH-(CH3)2.
R1 is ; and R2 is -CH-(CH3)2.
34. A composition of Claim l9, wherein the compound is N-[[[(3S)-3-[[N-[N-[(1,1-dime-thylethoxy)carbonyl]-L-phenylalanyl]-L-histi-dyl]amino]-2-hydroxy-5-methylhexyl](1-methyl-ethyl)amino]carbonyl]-L-isoleucine, methyl ester, monohydrochloride.
35. A composition of Claim 30 wherein:
R1 is ; and R2 is hydrogen.
R1 is ; and R2 is hydrogen.
36. A composition of Claim 19, wherein the compound is N-[[[(3S)-3-[[N-[N-[(1,1-dime-thylethoxy)carbonyl]-L-phenylalanyl]-L-histi-dyl]amino]-2-hydroxy-5-methylhexyl]amino]car-bonyl]-L-isoleucine, methyl ester, monohydro-chloride.
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 (en) |
CA (1) | CA1297631C (en) |
DE (1) | DE3643977A1 (en) |
FR (1) | FR2592048B1 (en) |
GB (1) | GB2184730B (en) |
IT (1) | IT1213574B (en) |
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ATE234279T1 (en) * | 1992-10-30 | 2003-03-15 | Searle & Co | SULFONYLALKANOYLAMINOHYDROXYETHYLAMINOSULFAMIDS URN USABLE AS RETROVIRAL PROTEASE INHIBITORS |
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US6337398B1 (en) | 1992-10-30 | 2002-01-08 | G.D. Searle & Co. | Succinoylamino hydroxyethylamino sulfonyl urea derivatives 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 |
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 |
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US6696488B2 (en) | 2000-08-11 | 2004-02-24 | The Brigham And Women's Hospital, Inc. | (Hydroxyethyl)ureas as inhibitors of alzheimer's β-amyloid production |
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DE3377497D1 (en) * | 1982-09-15 | 1988-09-01 | Haessle Ab | Enzyme inhibitors |
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/en 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/en not_active Withdrawn
- 1986-12-22 IT IT8622804A patent/IT1213574B/en active
- 1986-12-23 JP JP61316118A patent/JPS62164658A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
GB8630006D0 (en) | 1987-01-28 |
FR2592048A1 (en) | 1987-06-26 |
IT8622804A0 (en) | 1986-12-22 |
JPS62164658A (en) | 1987-07-21 |
IT1213574B (en) | 1989-12-20 |
GB2184730A (en) | 1987-07-01 |
FR2592048B1 (en) | 1995-07-07 |
GB2184730B (en) | 1990-02-07 |
DE3643977A1 (en) | 1987-07-02 |
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