CA2071743A1 - Heterocyclic compounds with renin-inhibiting properties, a process for the preparation thereof and the use thereof - Google Patents
Heterocyclic compounds with renin-inhibiting properties, a process for the preparation thereof and the use thereofInfo
- Publication number
- CA2071743A1 CA2071743A1 CA002071743A CA2071743A CA2071743A1 CA 2071743 A1 CA2071743 A1 CA 2071743A1 CA 002071743 A CA002071743 A CA 002071743A CA 2071743 A CA2071743 A CA 2071743A CA 2071743 A1 CA2071743 A1 CA 2071743A1
- Authority
- CA
- Canada
- Prior art keywords
- formula
- alkyl
- pyridyl
- radical
- hydrogen
- 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.)
- Abandoned
Links
- 150000002391 heterocyclic compounds Chemical class 0.000 title claims abstract description 10
- 238000000034 method Methods 0.000 title claims description 14
- 230000008569 process Effects 0.000 title claims description 7
- 108090000783 Renin Proteins 0.000 title abstract description 15
- 102100028255 Renin Human genes 0.000 title abstract description 13
- 230000002401 inhibitory effect Effects 0.000 title abstract description 8
- 238000002360 preparation method Methods 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 19
- 239000001257 hydrogen Substances 0.000 claims abstract description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 8
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims abstract description 7
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 5
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims abstract description 3
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 6
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- 239000013543 active substance Substances 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 239000012634 fragment Substances 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 229910052731 fluorine Chemical group 0.000 claims description 5
- 239000011737 fluorine Chemical group 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 238000011282 treatment Methods 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
- 125000005493 quinolyl group Chemical group 0.000 claims description 3
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- 239000005977 Ethylene Substances 0.000 claims description 2
- 206010020772 Hypertension Diseases 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 125000000524 functional group Chemical group 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 abstract 2
- 230000003389 potentiating effect Effects 0.000 abstract 1
- -1 amino diol Chemical class 0.000 description 39
- 239000000203 mixture Substances 0.000 description 15
- 150000003254 radicals Chemical class 0.000 description 15
- 101800000734 Angiotensin-1 Proteins 0.000 description 12
- 102400000344 Angiotensin-1 Human genes 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 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 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 210000002381 plasma Anatomy 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 6
- 239000002461 renin inhibitor Substances 0.000 description 6
- 229940086526 renin-inhibitors Drugs 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000011534 incubation Methods 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 230000036772 blood pressure Effects 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- 102000005862 Angiotensin II Human genes 0.000 description 3
- 101800000733 Angiotensin-2 Proteins 0.000 description 3
- 102000004881 Angiotensinogen Human genes 0.000 description 3
- 108090001067 Angiotensinogen Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 108010010369 HIV Protease Proteins 0.000 description 3
- 101000579218 Homo sapiens Renin Proteins 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229950006323 angiotensin ii Drugs 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000003127 radioimmunoassay Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 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 2
- 125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 2
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
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- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
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- 150000002148 esters Chemical class 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
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- 239000007858 starting material Substances 0.000 description 2
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- 125000001424 substituent group Chemical group 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 1
- LLUBVCCZUMPBMI-UHFFFAOYSA-N 1-[[ethyl(methyl)phosphoryl]oxy-methylphosphoryl]ethane Chemical compound CCP(C)(=O)OP(C)(=O)CC LLUBVCCZUMPBMI-UHFFFAOYSA-N 0.000 description 1
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 description 1
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- YPMJZJQSSFVMPK-UHFFFAOYSA-N 2-(8-propyl-6-pyridin-3-yl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3-(1-tritylimidazol-4-yl)propanoic acid Chemical compound N=1N=C2C(CCC)=NC(C=3C=NC=CC=3)=CN2C=1C(C(O)=O)CC(N=C1)=CN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 YPMJZJQSSFVMPK-UHFFFAOYSA-N 0.000 description 1
- WVDXXKXKKRPDLX-UHFFFAOYSA-N 2-(8-propyl-6-pyridin-3-yl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3-pyridin-3-ylpropanoic acid Chemical compound N=1N=C2C(CCC)=NC(C=3C=NC=CC=3)=CN2C=1C(C(O)=O)CC1=CC=CN=C1 WVDXXKXKKRPDLX-UHFFFAOYSA-N 0.000 description 1
- HOYGHJHBRWIPPE-UHFFFAOYSA-N 2-[8-(2-methylpropyl)-6-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]-3-pyridin-3-ylpropanoic acid Chemical compound N=1N=C2C(CC(C)C)=NC(C=3C=CC=CC=3)=CN2C=1C(C(O)=O)CC1=CC=CN=C1 HOYGHJHBRWIPPE-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
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- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- MSWIFFGHKBTPMY-VFUQPONKSA-L magnesium;(e)-4-octadecoxy-4-oxobut-2-enoate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O.CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O MSWIFFGHKBTPMY-VFUQPONKSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical compound CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000004944 pyrazin-3-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- KEDYTOTWMPBSLG-HILJTLORSA-N ramiprilat Chemical compound C([C@H](N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)C(O)=O)CC1=CC=CC=C1 KEDYTOTWMPBSLG-HILJTLORSA-N 0.000 description 1
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- 229910002027 silica gel Inorganic materials 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 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
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Abstract of the disclosure Heterocyclic compounds of the formula (I) ( I ) in which the radicals have the following meanings:
R1 for example propyl and isobutyl R2 for example phenyl or pyridyl R3 for example hydrogen, R4 for example cyclohexylmethyl R5 for example hydrogen or hydroxyl R6 a radical of the formula (II) (CH2)s-CHR7-z (II) where R7 is for example hydrogen, z is a 5- to 7-membered heterocyclic ring and s is 0, 1, 2, 3 or 4;
are potent renin-inhibiting compounds.
R1 for example propyl and isobutyl R2 for example phenyl or pyridyl R3 for example hydrogen, R4 for example cyclohexylmethyl R5 for example hydrogen or hydroxyl R6 a radical of the formula (II) (CH2)s-CHR7-z (II) where R7 is for example hydrogen, z is a 5- to 7-membered heterocyclic ring and s is 0, 1, 2, 3 or 4;
are potent renin-inhibiting compounds.
Description
~r~
HOECHST AKTI3NGESELLSCHAFT HOE 91/F 187 Dr.JA/fe Description Heterocyclic compounds with renin-inhibiting properties, a process for the preparation thereof and the use thereof EP-A 370 454, EP-A 373 497, EP-A 394 853 and EP-A 417 698 disclose amino diol derivatives which have C-terminal heterocyclic substituents and a renin-inhibitory action.
EP-A 369 743 and J. Med. Chem. 33 (1990~, 2326-2334, J. Med. Chem. 33 (1990), 2335-2342 and J. Med. Chem. 34 (1991), 151-157 describe alkyl alcohol and statin derivatives which contain two heterocyclic systems linked via an alkylamino bridge.
It has now been found, surprisingly, that compounds which contain two heterocyclic systems linked via an alkylamino bridge are exceptionally active and highly specific renin inhibitors which have a substantially improved action in vivo and a considerably enhanced absorption in the gastrointestinal tract.
The invention therefore relates to compounds of the formula I
R~ N--CH--CH CH--R~ t I ) in which the radicals have the following meanings:
Rl ( Cl-C8 ) -alkyl or phenyl;
R2 phenyl or pyridyl, where the pyridyl radical optionally carries a (cl-c4)-alkyl substituent;
R3 hydrogen or a group of the formula Q-A in which Q is pyridyl, imidazolyl, thiazolyl and pyrazolyl, and A
HOECHST AKTI3NGESELLSCHAFT HOE 91/F 187 Dr.JA/fe Description Heterocyclic compounds with renin-inhibiting properties, a process for the preparation thereof and the use thereof EP-A 370 454, EP-A 373 497, EP-A 394 853 and EP-A 417 698 disclose amino diol derivatives which have C-terminal heterocyclic substituents and a renin-inhibitory action.
EP-A 369 743 and J. Med. Chem. 33 (1990~, 2326-2334, J. Med. Chem. 33 (1990), 2335-2342 and J. Med. Chem. 34 (1991), 151-157 describe alkyl alcohol and statin derivatives which contain two heterocyclic systems linked via an alkylamino bridge.
It has now been found, surprisingly, that compounds which contain two heterocyclic systems linked via an alkylamino bridge are exceptionally active and highly specific renin inhibitors which have a substantially improved action in vivo and a considerably enhanced absorption in the gastrointestinal tract.
The invention therefore relates to compounds of the formula I
R~ N--CH--CH CH--R~ t I ) in which the radicals have the following meanings:
Rl ( Cl-C8 ) -alkyl or phenyl;
R2 phenyl or pyridyl, where the pyridyl radical optionally carries a (cl-c4)-alkyl substituent;
R3 hydrogen or a group of the formula Q-A in which Q is pyridyl, imidazolyl, thiazolyl and pyrazolyl, and A
is methylene or ethylene, R4 hydrogen~ (Cl-C10)-alkyl~ (C3-C3)-cycloalkyl~ (C3-C8)-cycloalkyl-(C1-C4)-alkyl, (c6-cl2)-aryl or ~C6-C12)-aryl-( Cl-C4 ) -alkyl;
Rs hydrogen, (C1-C10)-alkyl~ (C6 Cl2)-aryl, (C6-C12)-arYl-(Cl-C4)-alkyl, hydroxyl or amino;
R6 a radical of the formula (II) (CH2)~-CHR7-Z (II) where R7 i8 hydrogen, (Cl-C7)-alkyl, (C1-C4)-alkoxy, (Cl-C4)-alkylthio, (Cl-C4)-alkylamino, hydroxyl, azido or halogen, and Z is a 5- to 7-membered heterocyclic ring which can be benzo-fused, aromatic, partially hydrogenated or lS completely hydrogenated and which can contain as hetero atoms one or two identical or different radicals from the group comprising N, O, S, NO, SO, SO2 and which can be substituted by one or two identical or different radicals from the series comprising (C1-C4)-alkyl, allyl, (Cl-C4)-alkoxy, hydroxyl, halogen, amino, mono- or di-(Cl-C4)-alkyl-amino and CF3; and where s is 0, 1, 2, 3 or 4; and the physiologially tolerated salts thereof.
25 Preferred in this connection are heterocyclic compounds in which the radicals in formula (I) have the following meanings:
R4 isobutyl, benzyl or cyclohexylmethyl;
Rs hydrogen, (C1-C5)-alkyl, (C6-C10)-aryl, (C6-C10)-aryl-(C1-C4)-alkyl or hydroxylr R5 a radical of the formula (II) in which R7is hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (Cl-C4)-alkylamino, hydroxyl, azido or halogen, 35 s is 0, 1 or 2, and Z is a heteroaryl radical from the group comprising pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, ~7~L7~3 oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, ~-carbolinyl or a benzo-fused, cyclopenta-, cyclohexa- or cyclohept~-fused derivative from this group, and the other radicals are defined as in claim 1, and the physiologically tolerated salts thereof.
Very particularly preferred compounds of the formula (I) are those in which the radicals have the following meaning:
R1 methyl, ethyl, propyl, i-propyl, butyl, i-butyl or pentyl;
RZ phenyl or 3-pyridyl, where the pyridyl radical optionally carries a methyl or ethyl substituent;
R4 isobutyl, benzyl or cyclohexylmethyl;
Rs hydrogen or hydroxyl;
R6 a radical of the formula (II~, in which R7 is hydrogen or fluorine, Z is a 2-, 3- or 4-pyridyl radical, a 2-, 4- or 5-imidazolyl radical or a 2-oxazolinyl radical, where said heterocycles can each be substituted by one or two identical or different radicals from the series comprising methyl, ethyl, propyl, allyl, fluorine, chlorine, bromine, CF3 and methoxy, and s is 0, 1 or 2.
The chirality centers in the compounds of the formula (I) can have the ~ or S configuration.
The term "aryl" means, for example, mono- or bicyclic hydrocarbon ring systems with one or more aromatic rings such as phenyl, naphthyl, tetrahydronaphthyl, indanyl and the like. Aryl radicals can moreover be unsubstituted or substituted by 1, 2 or 3 substituents which can be, independently of one another, (Cl-C7)-alkyl, halogeno-alkyl, alkoxy, alkylthio, amino, alkylamino, hydroxyl, halogen, mercapto, nitro, formyl, carboxyl and carbamoylO
Halogen is fluorine, chlorine, bromine or iodine.
(C,-C10)-Alkyl means an alkyl radical or a corresponding unsaturated radical with 1-10 carbon atoms. The radical can be straight-chain or branched. Corresponding state-ments apply to radicals derived therefrom, such as, for example, alkoxy, alkylthio, alkylamino, alkanoyl and aralkyl.
(C3-C8)-Cycloalkyl preferably means cyclopropyl, cyclo-butyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclo-oc~yl. If these cyclic radicals carry more than one substituent, these can be bo~h cis and trans with respect to one another.
The radical Z is, for example, a heteroaryl radical such as pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, ~-carbolinyl or a benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative of these radicals. This heterocycle can be up to trisubstituted on a nitrogen atom by oxide, (C1-C6)-alkyl, preferably methyl or ethyl, phenyl or phenyl-(C1-C4)-alkyl, for example benzyl, and/or on one or more carbon atoms by (C1-C4)-alkyl such as, for example, methyl, phenyl, phenyl-(C1-C4)-alkyl such as, for example, benzyl, halogen such asl for 0xample, chlorine, hydroxyl, (C1-C4)-alkoxy such as, for example, methoxy, phenyl-(C1-C4)-alkoxy such as, for example, benzyloxy, or oxo, and can be partially saturated. Z preferably means one of the following groups: 2- or 3-pyrrolyl, phenyl-pyrrolyl, for example 4- or 5-phenyl-2-pyrrolyl, 2-furyl, 2-thienyl, 4-imidazolyl, methylimidazolyl, for example 1-methyl-2-, -4- or -5-imidazolyl, 1,3-thiazol-2-yl, 2-, 3- or 4-pyridyl, 2-, 3- or 4-pyridyl 1-oxide, 2-pyrazinyl, 2-, 4- or 5-pyrimidyl, 2-, 3- or 5-indolyl, substituted 2-indolyl, for example 1-methyl-, 5-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro- or 4,5-dimethyl-2-indolyl, 1-benzyl-2- or -3-indolyl, -- 5 ~
Rs hydrogen, (C1-C10)-alkyl~ (C6 Cl2)-aryl, (C6-C12)-arYl-(Cl-C4)-alkyl, hydroxyl or amino;
R6 a radical of the formula (II) (CH2)~-CHR7-Z (II) where R7 i8 hydrogen, (Cl-C7)-alkyl, (C1-C4)-alkoxy, (Cl-C4)-alkylthio, (Cl-C4)-alkylamino, hydroxyl, azido or halogen, and Z is a 5- to 7-membered heterocyclic ring which can be benzo-fused, aromatic, partially hydrogenated or lS completely hydrogenated and which can contain as hetero atoms one or two identical or different radicals from the group comprising N, O, S, NO, SO, SO2 and which can be substituted by one or two identical or different radicals from the series comprising (C1-C4)-alkyl, allyl, (Cl-C4)-alkoxy, hydroxyl, halogen, amino, mono- or di-(Cl-C4)-alkyl-amino and CF3; and where s is 0, 1, 2, 3 or 4; and the physiologially tolerated salts thereof.
25 Preferred in this connection are heterocyclic compounds in which the radicals in formula (I) have the following meanings:
R4 isobutyl, benzyl or cyclohexylmethyl;
Rs hydrogen, (C1-C5)-alkyl, (C6-C10)-aryl, (C6-C10)-aryl-(C1-C4)-alkyl or hydroxylr R5 a radical of the formula (II) in which R7is hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (Cl-C4)-alkylamino, hydroxyl, azido or halogen, 35 s is 0, 1 or 2, and Z is a heteroaryl radical from the group comprising pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, ~7~L7~3 oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, ~-carbolinyl or a benzo-fused, cyclopenta-, cyclohexa- or cyclohept~-fused derivative from this group, and the other radicals are defined as in claim 1, and the physiologically tolerated salts thereof.
Very particularly preferred compounds of the formula (I) are those in which the radicals have the following meaning:
R1 methyl, ethyl, propyl, i-propyl, butyl, i-butyl or pentyl;
RZ phenyl or 3-pyridyl, where the pyridyl radical optionally carries a methyl or ethyl substituent;
R4 isobutyl, benzyl or cyclohexylmethyl;
Rs hydrogen or hydroxyl;
R6 a radical of the formula (II~, in which R7 is hydrogen or fluorine, Z is a 2-, 3- or 4-pyridyl radical, a 2-, 4- or 5-imidazolyl radical or a 2-oxazolinyl radical, where said heterocycles can each be substituted by one or two identical or different radicals from the series comprising methyl, ethyl, propyl, allyl, fluorine, chlorine, bromine, CF3 and methoxy, and s is 0, 1 or 2.
The chirality centers in the compounds of the formula (I) can have the ~ or S configuration.
The term "aryl" means, for example, mono- or bicyclic hydrocarbon ring systems with one or more aromatic rings such as phenyl, naphthyl, tetrahydronaphthyl, indanyl and the like. Aryl radicals can moreover be unsubstituted or substituted by 1, 2 or 3 substituents which can be, independently of one another, (Cl-C7)-alkyl, halogeno-alkyl, alkoxy, alkylthio, amino, alkylamino, hydroxyl, halogen, mercapto, nitro, formyl, carboxyl and carbamoylO
Halogen is fluorine, chlorine, bromine or iodine.
(C,-C10)-Alkyl means an alkyl radical or a corresponding unsaturated radical with 1-10 carbon atoms. The radical can be straight-chain or branched. Corresponding state-ments apply to radicals derived therefrom, such as, for example, alkoxy, alkylthio, alkylamino, alkanoyl and aralkyl.
(C3-C8)-Cycloalkyl preferably means cyclopropyl, cyclo-butyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclo-oc~yl. If these cyclic radicals carry more than one substituent, these can be bo~h cis and trans with respect to one another.
The radical Z is, for example, a heteroaryl radical such as pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, ~-carbolinyl or a benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative of these radicals. This heterocycle can be up to trisubstituted on a nitrogen atom by oxide, (C1-C6)-alkyl, preferably methyl or ethyl, phenyl or phenyl-(C1-C4)-alkyl, for example benzyl, and/or on one or more carbon atoms by (C1-C4)-alkyl such as, for example, methyl, phenyl, phenyl-(C1-C4)-alkyl such as, for example, benzyl, halogen such asl for 0xample, chlorine, hydroxyl, (C1-C4)-alkoxy such as, for example, methoxy, phenyl-(C1-C4)-alkoxy such as, for example, benzyloxy, or oxo, and can be partially saturated. Z preferably means one of the following groups: 2- or 3-pyrrolyl, phenyl-pyrrolyl, for example 4- or 5-phenyl-2-pyrrolyl, 2-furyl, 2-thienyl, 4-imidazolyl, methylimidazolyl, for example 1-methyl-2-, -4- or -5-imidazolyl, 1,3-thiazol-2-yl, 2-, 3- or 4-pyridyl, 2-, 3- or 4-pyridyl 1-oxide, 2-pyrazinyl, 2-, 4- or 5-pyrimidyl, 2-, 3- or 5-indolyl, substituted 2-indolyl, for example 1-methyl-, 5-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro- or 4,5-dimethyl-2-indolyl, 1-benzyl-2- or -3-indolyl, -- 5 ~
4,5,6,7-tetrahydro-2-indolyl, cyclohepta[b]-5-pyrrolyl, 2-, 3- or 4-quinolyl, 4-hydroxy-2-quinolyl, 1-, 3- or 4-isoquinolyl, 1-oxo-1,2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzofuranyl, 2-benzoxalolyl, 2-benzo-thiazolyl, benzo[e]-2-indolyl or ~-carbolin-3-yl.
Partially hydrogenated or completely hydrogenated heterocyclic rings are, for example, dihydropyridinyl, pyrrolidinyl, for example 2-, 3- or 4-N-~ethylpyr-rolidinyl, piperidinyl, piperazinyl, morpholino, thio-morpholino or tetrahydrothienyl.
Salts of compounds of the formula (I) mean, inparticular, pharmaceutically utilizable and non-toxic salts.
Salts of this type are formed~ for example, by compounds of the formula (I) which contain acidic groups, for example carhoxyl, with alkali metals or alkaline earth metals such as Na, K, Mg and Ca, and with physiologically tolerated organic amines such as, for example, triethylamine.
Compounds of the formula (I) which contain basic groups, for example an amino group or a guanidino group, form salts with inorganic acids such as, for example, hydro-chloric acid, sulfuric acid or phosphoric acid and with organic carboxylic or sulfonic acids such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid or p-toluenesulfonic acid.
The invention furthermore relates to a process for preparing compounds of the formula tI), wherein a fragment with a terminal carboxyl group or its reactive derivative is coupled to a corresponding fragment with a free amino group, where appropriate protective group( 8 ) temporarily introduced to protect other functional groups are eliminated, and the compound obtained in this way is, ~17~ ~
where appropriate, converted into a physiologically tolerated salt.
Fragments of a compound of the formula (I) with a terminal carboxyl group have the following formula (III) ~ N ~ 0H (~
N~J
Fragments of a compound of the formula (I) with a terminal amino group have the following formula (IV) R~ R~
H2N-Cil--CH--CH-R~ ( I V ) OH
Methods suitable for producing an amide linkage are described, for example, in Houben-Weyl (Methoden der organischen Chemie [Methods of Organic Chemistry], volume 15t2), Bodanszky et al. (Peptide Synthesis, 2nd ed.
(Wiley & Sons; New York 1976)) or Gross, Meienhofer (The Peptides-Analysis, Synthesis, ~iology (Academic Press, New York 1979)).
The following methods are preferably used: active ester method with N-hydroxysuccinimide or 1-hydroxybenzo-triazole as ester component, coupling with a carbodiimide such as dicyclohexylcarbodiimide or with propane-phosphonic anhydride or methylethylphosphinic anhydride,and the mixed anhydride method with pivaloyl chloride (M. Zaoral, Coll. Czech. Chem. Commun., 1962, 27, 1273).
The reaction is carried out in an inert solvent or mixture of solvents, preferably at a temperature between -20C and the boiling point of the reaction mixture.
~7~7 Carhoxylic acids of the formula (III) were prepared by the methods of R. H. Bradbury et al. (EP-A 369 743), D. A. Roberts et al. (J. Med. Chem. 33 (1990), 2326-2334), R. H. Bradbury et al. (J. Med. Chem. 33 (1990), - 5 2335-2342) and R. H. Bradbury et al. (J. Med. Chem. 34 (1991), 151-157).
The preparation of the optically active amines of the formula (IV) in which R4, Rs and R6 are as defined above and which are used as starting compounds starts from optically active ~-amino acids, whose center of asymmetry is retained. For this purpose, an N-protected amino aldehyde is prepared in a known manner and i8 coupled in an aldol-analogous addition onto a corresponding hetero-arylalkyl building block and, after elimination of the N-protective groups, gives amino alcohols of the formula (IV). When Rs = OH, an N-protected amino aldehyde is likewise used as starting material and is converted into the required intermediates for example by aldol-analogous addition of unsaturated compounds, introduction of suitable protective groups and subsequent epoxidation.
Mixtures of diastereomers with regard to the OH-carrying center are obtained and are separated in a manner known per se, for example by ~ractional crystallization or by chromatography. The diastereomeric purity is checked, for example, by HPLC; the enantiomeric purity can be checked in a known manner by conversion into Nosher derivatives (H. S. Mosher et al., J. Org. Chem. 34 (1969) 2543).
N-Protected amino aldehydes are prepared by the method of B. Castro et al. (Synthesis 1983, 676).
The aldol-analogous addition onto N-protected amino aldehydes (preferably N-tert-butyloxycarbonyl and benzyl-oxycarbonyl protective groups) is carried out in a solvent which is inert to bases, such as ether, THF, toluene, DMF, DMSO or dimethoxyethane.
Bases which can be used for the deprotonation of the heteroarylalkyl component are alkali metal alcoholates such as potassium tert-butylate, sodium methylate, alkali metal hydrides such as sodium or potassium hydride, organometallic bases such as n-butyllithium, s-butyl-lithium, methyllithium or phenyllithium, sodamide andalkali metal salts of organic ni~rogen bases such as lithium diisopropylamide.
The necessary operations preceding and following the preparation of compounds of the formula (I), such as introduction and elimination of protective groups, are known from the literature and are described~ for example, in T. W. Greene, "Protective Groupæ Synthesis". Salts of compounds of the formula (I~ with salt-forming groups are prepared in a manner known per se by, for example, reacting a compound of the formula (I) with a basic group with a stoichiometric amount of a suitable acid.
Mixtures of stereoisomers, in particular mixtures of diastereomers, which are produced when racemic carboxylic acid derivatives are used, can be separated in a manner known per se by fractional crystallization or by chromatography.
The compounds of the formula (I) according to the invention have enzyme-inhibiting properties, in particular they inhibit the action of the natural enzyme renin. Renin is a proteolytic enzyme from the class of aspartyl proteases which is secreted as a consequence of various stimuli (volume depletion, sodium deficiency, ~-receptor stimulation) by the juxtaglomerular cells of the kidney into the bloodstream. There it cleaves the decapeptide angiotensin I off the angiotensinogen which is secreted by the liver. Angiotensin I is converted by angiotensin converting enzyme (ACE) into angiotensin II.
Angiotensin II plays an essential part in the regulation of blood pressure because it increases the blood pressure directly by vasoconstriction. In addition, it stimulates the secretion of aldosterone from the adrenal and in this 9 ~ 7~
way increases, via inhibition of sodium excretion, the extracellular fluid volume, which in turn contributes to increasing the blood pressure. Inhibitors of the enzyme activity of renin bring about a reduced formation of angiotensin I, which results in a reduced formation of angiotensin II. The reduction in the concentration of this active peptide hormone is the direct reason for the blood pressure-lowering action of renin inhibitors.
The activity of renin inhibitors can be checked by in vitro tests. This entails measuring the reduction in the formation of angiotensin I in various systems (human plasma, purified human renin).
1. Principle of the test For example, human plasma which contains both renin and angiotensinogen is incubated with the compound to be tested at 37C. During this, angiotensin I is liberated from angiotensinogen due to the action of renin and can subsequently be measured in a commercially available radioimmunoassay. This angiotensin release is inhibited by renin inhibitors.
2. Obtaining the plasma The blood is obtained from volunteer subjects ~about 0.5 1 per person; Bluko sampler (supplied by ASID ~onz und Sohn, Unterschlei~heim)) and collected in partially evacuated bottles while cooling in ice. Coagulation is prevented by addition of EDTA (final concentration 10 mM). After centrifugation (HS 4 rotor (Sorv~ll), 3,500 rpm, 0-4C, 15 min; repeat if necessary), the plasma is carefully removed by pipette and frozen in suitable proportions at -30C. Only pla~mas with sufficiently high renin activity are used for the test.
Plasmas with low renin activity are activated (prorenin ~ renin) by a cold treatment (-4C, 3 days).
- 10 - 2~
3. Test procedure Angiotensin I is determined using the Renin-Maia- kit (Serono Diagnostics S.A., Coinsins, ~witzerland~. The plasma is incubated in accordance with the instructions given there with:
Incubation mixture: 1000 ~1 of plasma (thawed at 0-4C) 100 ~1 of phosphate buffer (pH 7.4) (addition of 10-~ M
ramiprilat) 10 ~1 of PMSF solution 10 ~1 of 0.1% Genapol PFIC
12 ~1 of DMSO or test product The test products are generally dissolved Io-2 M in 100~
dimethyl sulfoxide (DMSO) and appropriately diluted with DMSO; the maximum content of DMSO in the incubation mixture is 1~.
The mixtures are mixed in ice and, for the incubation, placed in a waterbath (37C) for 1 hour. A total of 6 samples (each 100 ~1) are taken from an additional mixture without inhibitor and without further incubation for determination of the initial angiotensin I content of the plasma used.
The concentrations of the test products are chosen so that approximately the range of 10-90~ enzyme inhibition is covered (at least five concentrations~. At the end of the incubation time, three 100 ~1 samples from each mixture are frozen in precooled Eppendorf tubes on dry ice and stored at about -25C for the angiotensin I
determination (mean of three single samples).
Angiotensin I radioimmunoassay (RIA) The instructions for use of the RIA kit (Renin-Maia kit, Serono Diagnostics S.A., Coinsins, Switzerland) are followed exactly.
The calibration plot covers the range from 0.2 to 25.0 ng of angiotensin I per ml. The baseline angiotensin I
content of the plasma is subtracted from all the measure-ments. The plasma renin activity (PRA) is reported as ng of ang I/ml x hour. PRA values in the presence of the test substances are related to a mixture without inhibitor (= 100~) and the ICso is read off as % remaining activity against the concentration (M) of the test product (logarithmic scale).
The compounds of the formula (I) described in the present invention show inhibitory actions in the in vitro test at concentrations of about 10-5 to 10-1 mol/l.
Renin inhibitors bring about a lowering of blood pressure in animals deprived of salt. Since human renin differs from the renin of other species, primates (marmosets, rhesus monkeys) are used for the in vivo test of renin inhibitors. Primate renin and human renin are substan-tially homologous in their sequence. Endogenous reninsecretion is stimulated by i.v. injection of furosemide.
The test compounds are subsequently administered and their action on blood pressure and heart rate is measured. ~he compounds of the present invention are active in this test in an i.v. dose range of about 0.1-5 mg/kg and on intraduodenal administration by gastroscope in the dose range of about 1-50 mg/kg. The compounds of the formula (I) described in the present invention can be used as antih~pertensives and for the treatment of heart failure.
HIV protease is cut autocatalytically out of the GAG-POL
polypeptide and subsequently cleaves the precursor peptide p5S into the core antigens pl7, p24 and pl4. It is thus an essential enzyme whose inhibition interrupts the life cycle of the virus and suppresses its growth.
12 ~ ~ i d Biological tests showed that the compounds according to the invention have an enzyme inhibitory action and inhibit viral enzymes such as HIV protease too. The HIV
protease inhibiting action has particular importance and S qualifies the compounds according to the invention in particular for the therapy and prophylaxis of diseases caused by infection with HIV. The compounds of the formula (I) according to the invention show inhibitory actions in the in vitro tests used at concentrations of about 10-4 to 10-~ mol/l.
The present invention also relates to the use of com-pounds of the formula (I) for producing pharmaceuticals for the therapy of high blood pressure and the treatment of congestive heart failure, and for the therapy and prophylaxis of viral diseases, in particular of diseases caused by HIV, and to said pharmaceuticals.
Pharmaceutical products contain an effective amount of the active substance of the formula (I), preferably together with an inorganic or organic pharmaceutically utilizable excipient. Administration can be intranasally, intravenously, subcutaneously or orally. The dosage of the active substance depends on the warm blooded species, the body weight, age and on the mode of administration.
The pharmaceutical products of the present invention are produced in dissolving, mixing, granulating or coating processes known per se.
For a form for oral administration, the active compounds are mixed with the additives customary for this purpose, such as excipient, stabilizers or inert diluents, and converted by conventional methods into suitable dosage forms such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily solutions. Examples of inert vehicles which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, magnesium stearyl fumarate or starch, in particular corn starch. This preparation can be carried out both as dry and wet granules. Examples of suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil and fish liver oil.
For subcutaneous or intravenous administration, the active compounds or the physiologically tolerated salts thereof are converted, if required with the substances customary for this purpose, such as solubilizers, emulsi-fiers or other auxiliaries, into solutions, suspensions or emulsions. Examples of suitable solvents are: water, physiological saline solutions or alcohols, for example ethanol, propanediol or glycerol, as well as sugar solutions such as glucose or mannitol solutions, or else a mixture of the various solvents mentioned.
15 List of abbreviations used:
Boc tert.-Butoxycarbonyl BuLi n-Butyllithium DCC Dicyclohexylcarbodiimide DCI Desorption Chemical Ionisation DNP 2,4-Dinitrophenyl DME Dimethoxyethane DMF Dimethylformamide EA Ethyl acetate FAB Fast atom bombardment h Hour HOBt l-Hydroxybenzotriazole M Molecular peak MS Mass spectrum min Minutes NEM N-Ethylmorpholine RT Room temperature THF Tetrahydrofuran Trt Triphenylmethyl The following examples illustrate the preparation of the compounds according to the invention.
Example 1 N-[2-(8-Isobutyl-6-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3-yl)ethanoyl]-(2S,3R,4S)-l-cyclohexyl-3,4-dihydroxy-~-(2-pyridyl)-2-hexylamine la) (2S,3R,4S)-2-tert.-Butyloxycarbonylamino-l-cyclo-hexyl-3,4-dihydroxy-6-(2-pyridyl)-hexane 2.8 ml of n-butyllithium are added to 186 mg of 2-picoline in 20 ml of THF at -78C. After the mixture has warmed up to room temperature it is stirred for 30 min and then cooled to -40C. 2 mmol of (2RS,3R,4S)-3-tert . -butyldimethylsilyloxy-4-tert . -butyloxycarbonylamino-5-cyclohexyl-1,2-epoxypentane (disclosed in EP-A 189 203, Example 6) are added (dissolved in 10 ml of THF). The mixture is stirred at room temperature for 10 h and then diluted with water and extracted with methyl tert.-butyl ether. The crude product after concentration is dissolved in THF and stirred with 10 ml of a 1 M solution of tetrabutylammonium fluoride in THF at 0C for 1 h.
Dilution with water, extraction with EA and concentration result in 300 mg of the (2S,3R,4S) isomer (MS (FAB): 393 (M+H)) and 240 mg of the (2S,3S,4S) isomer (MS (FAB): 393 (M~H)) after separation by chromatography on silica gel.
lb) N-[2-(8-Isobutyl-6-phenyl-1,2,4-triazolo[4,3-a]-pyrazin-3-yl)-ethanoyl]-(2S,3R,4S)-l-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)-2~hexylamine 400 mg of (2S,3R,4S)-2-tert.-butyloxycarbonylamino-1-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)hexane (compound from Example la) are dissolved in 5 ml of abs. CH2Cl2, 5 ml of trifluoroacetic acid are added and the resulting solution is stirred at room temperature for 3 h. The residue obtained after concentration is taken up in 1 M
NaHCO3 solution, the mixture is extracted three times with EA, and the combined EA phases are dried over Na2SO~.
- 15 _ 2~r'~
The residue after concentration is dissolved in 5 ml of absolute DMF, 3l6.6 mg of 2-(8-isobutyl-6-phenyl-l,2,4-triazolo[413-a]pyrazin-3-yl)acetic acid (disclosed in EP-A 369,743, Example l), 208.4 mg of N,N-dicyclohexyl-carbodiimide and 206.8 mg of l-hydroxybenzotriazole are addedl the pH of the solution is adjusted to 9 with N-ethylmorpholinel and it is ~tirred at room temperature for 50 h. Filtration is followed by dilution with EA and washing once each with saturated NaHCO3 solutionl water and saturated brinel and chromatography with a CH2Cl2/CH3OH mixture as mobile phase yields 207.4 mg of the title compound.
MS(FAB):585 (M+H) Example 2 N-[2-(8-Isobutyl-6-phenyl-ll2,4-triazolo[4,3-a]pyrazin-3-yl)-3-(3-pyridyl)propionyl]-(2S,3R,4S)-l-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)-2-hexylamine The title compound results from reaction of 2-[8-iso-butyl-6-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3-yl]-3-(3-pyridyl)propionic acid (disclosed in EP-A 369 743, Example 3) with the compound from Example la by the process of Example lb.
MS (FAB):676 (M+H) Example 3 N-[2-(8-Propyl-6-(3-pyridyl)-l,2,4-triazolo[4,3-a]-pyrazin-3-yl)ethanoyl]-(2S,3R,4S)-l-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)-2-hexylamine The title compound is prepared from 8-propyl-6-(3-pyridyl)-ll214-triazolo[4l3-a]pyrazin-3-yl-acetic acid (disclosed in EP-A 369 7431 Example 4) and the compound from Example la by the process detailed in Example lb.
MS (FAB): 572 (M+H) 16 2~ 3 Example 4 N-[2-(8-Propyl-6-(3-pyridyl)-1,2,4-triazolo[4,3-a]-pyrazin-3-yl)-3-(3-pyridyl)-propionyl]-t2S,3R,4S)-l-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)-2-hexylamine The title compound is prepared from 2-[8-propyl-6-(3-pyridyl)-1,2,4-triazolo[4,3-a]pyrazin-3-yl]-3-(3-pyridyl)propionic acid (disclosed in EP-A 369 743, Example 6) and the compound from Example la by the process of Example lb.
10 MS tFAB): 663 (M+H) Example 5 N-[3-Imidazol-4-yl)-(2RS)-2-(8-propyl-6-(3-pyridyl)-1,2,4-triazolo[4,3-a]pyrazin-3-yl)-propionyl]-(2S,3R,4S)-l-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)-2-hexylamine The title compound is prepared from 3-(1-triphenylmethyl-imidazol-4-yl)-2-[8-propyl-6-(3-pyridyl)-1,2,4-triazolo-[4,3-a]pyrazin-3-yl]-propionic acid (disclosed in EP-A
369 743, Example 27) and the compound from Example la by the process of Example lb and subsequent elimination of the Ni~-Trt protective group with 90~ strength trifluoro-acetic acid and working up by extraction.
MS (FAB): 652 (M+H)
Partially hydrogenated or completely hydrogenated heterocyclic rings are, for example, dihydropyridinyl, pyrrolidinyl, for example 2-, 3- or 4-N-~ethylpyr-rolidinyl, piperidinyl, piperazinyl, morpholino, thio-morpholino or tetrahydrothienyl.
Salts of compounds of the formula (I) mean, inparticular, pharmaceutically utilizable and non-toxic salts.
Salts of this type are formed~ for example, by compounds of the formula (I) which contain acidic groups, for example carhoxyl, with alkali metals or alkaline earth metals such as Na, K, Mg and Ca, and with physiologically tolerated organic amines such as, for example, triethylamine.
Compounds of the formula (I) which contain basic groups, for example an amino group or a guanidino group, form salts with inorganic acids such as, for example, hydro-chloric acid, sulfuric acid or phosphoric acid and with organic carboxylic or sulfonic acids such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid or p-toluenesulfonic acid.
The invention furthermore relates to a process for preparing compounds of the formula tI), wherein a fragment with a terminal carboxyl group or its reactive derivative is coupled to a corresponding fragment with a free amino group, where appropriate protective group( 8 ) temporarily introduced to protect other functional groups are eliminated, and the compound obtained in this way is, ~17~ ~
where appropriate, converted into a physiologically tolerated salt.
Fragments of a compound of the formula (I) with a terminal carboxyl group have the following formula (III) ~ N ~ 0H (~
N~J
Fragments of a compound of the formula (I) with a terminal amino group have the following formula (IV) R~ R~
H2N-Cil--CH--CH-R~ ( I V ) OH
Methods suitable for producing an amide linkage are described, for example, in Houben-Weyl (Methoden der organischen Chemie [Methods of Organic Chemistry], volume 15t2), Bodanszky et al. (Peptide Synthesis, 2nd ed.
(Wiley & Sons; New York 1976)) or Gross, Meienhofer (The Peptides-Analysis, Synthesis, ~iology (Academic Press, New York 1979)).
The following methods are preferably used: active ester method with N-hydroxysuccinimide or 1-hydroxybenzo-triazole as ester component, coupling with a carbodiimide such as dicyclohexylcarbodiimide or with propane-phosphonic anhydride or methylethylphosphinic anhydride,and the mixed anhydride method with pivaloyl chloride (M. Zaoral, Coll. Czech. Chem. Commun., 1962, 27, 1273).
The reaction is carried out in an inert solvent or mixture of solvents, preferably at a temperature between -20C and the boiling point of the reaction mixture.
~7~7 Carhoxylic acids of the formula (III) were prepared by the methods of R. H. Bradbury et al. (EP-A 369 743), D. A. Roberts et al. (J. Med. Chem. 33 (1990), 2326-2334), R. H. Bradbury et al. (J. Med. Chem. 33 (1990), - 5 2335-2342) and R. H. Bradbury et al. (J. Med. Chem. 34 (1991), 151-157).
The preparation of the optically active amines of the formula (IV) in which R4, Rs and R6 are as defined above and which are used as starting compounds starts from optically active ~-amino acids, whose center of asymmetry is retained. For this purpose, an N-protected amino aldehyde is prepared in a known manner and i8 coupled in an aldol-analogous addition onto a corresponding hetero-arylalkyl building block and, after elimination of the N-protective groups, gives amino alcohols of the formula (IV). When Rs = OH, an N-protected amino aldehyde is likewise used as starting material and is converted into the required intermediates for example by aldol-analogous addition of unsaturated compounds, introduction of suitable protective groups and subsequent epoxidation.
Mixtures of diastereomers with regard to the OH-carrying center are obtained and are separated in a manner known per se, for example by ~ractional crystallization or by chromatography. The diastereomeric purity is checked, for example, by HPLC; the enantiomeric purity can be checked in a known manner by conversion into Nosher derivatives (H. S. Mosher et al., J. Org. Chem. 34 (1969) 2543).
N-Protected amino aldehydes are prepared by the method of B. Castro et al. (Synthesis 1983, 676).
The aldol-analogous addition onto N-protected amino aldehydes (preferably N-tert-butyloxycarbonyl and benzyl-oxycarbonyl protective groups) is carried out in a solvent which is inert to bases, such as ether, THF, toluene, DMF, DMSO or dimethoxyethane.
Bases which can be used for the deprotonation of the heteroarylalkyl component are alkali metal alcoholates such as potassium tert-butylate, sodium methylate, alkali metal hydrides such as sodium or potassium hydride, organometallic bases such as n-butyllithium, s-butyl-lithium, methyllithium or phenyllithium, sodamide andalkali metal salts of organic ni~rogen bases such as lithium diisopropylamide.
The necessary operations preceding and following the preparation of compounds of the formula (I), such as introduction and elimination of protective groups, are known from the literature and are described~ for example, in T. W. Greene, "Protective Groupæ Synthesis". Salts of compounds of the formula (I~ with salt-forming groups are prepared in a manner known per se by, for example, reacting a compound of the formula (I) with a basic group with a stoichiometric amount of a suitable acid.
Mixtures of stereoisomers, in particular mixtures of diastereomers, which are produced when racemic carboxylic acid derivatives are used, can be separated in a manner known per se by fractional crystallization or by chromatography.
The compounds of the formula (I) according to the invention have enzyme-inhibiting properties, in particular they inhibit the action of the natural enzyme renin. Renin is a proteolytic enzyme from the class of aspartyl proteases which is secreted as a consequence of various stimuli (volume depletion, sodium deficiency, ~-receptor stimulation) by the juxtaglomerular cells of the kidney into the bloodstream. There it cleaves the decapeptide angiotensin I off the angiotensinogen which is secreted by the liver. Angiotensin I is converted by angiotensin converting enzyme (ACE) into angiotensin II.
Angiotensin II plays an essential part in the regulation of blood pressure because it increases the blood pressure directly by vasoconstriction. In addition, it stimulates the secretion of aldosterone from the adrenal and in this 9 ~ 7~
way increases, via inhibition of sodium excretion, the extracellular fluid volume, which in turn contributes to increasing the blood pressure. Inhibitors of the enzyme activity of renin bring about a reduced formation of angiotensin I, which results in a reduced formation of angiotensin II. The reduction in the concentration of this active peptide hormone is the direct reason for the blood pressure-lowering action of renin inhibitors.
The activity of renin inhibitors can be checked by in vitro tests. This entails measuring the reduction in the formation of angiotensin I in various systems (human plasma, purified human renin).
1. Principle of the test For example, human plasma which contains both renin and angiotensinogen is incubated with the compound to be tested at 37C. During this, angiotensin I is liberated from angiotensinogen due to the action of renin and can subsequently be measured in a commercially available radioimmunoassay. This angiotensin release is inhibited by renin inhibitors.
2. Obtaining the plasma The blood is obtained from volunteer subjects ~about 0.5 1 per person; Bluko sampler (supplied by ASID ~onz und Sohn, Unterschlei~heim)) and collected in partially evacuated bottles while cooling in ice. Coagulation is prevented by addition of EDTA (final concentration 10 mM). After centrifugation (HS 4 rotor (Sorv~ll), 3,500 rpm, 0-4C, 15 min; repeat if necessary), the plasma is carefully removed by pipette and frozen in suitable proportions at -30C. Only pla~mas with sufficiently high renin activity are used for the test.
Plasmas with low renin activity are activated (prorenin ~ renin) by a cold treatment (-4C, 3 days).
- 10 - 2~
3. Test procedure Angiotensin I is determined using the Renin-Maia- kit (Serono Diagnostics S.A., Coinsins, ~witzerland~. The plasma is incubated in accordance with the instructions given there with:
Incubation mixture: 1000 ~1 of plasma (thawed at 0-4C) 100 ~1 of phosphate buffer (pH 7.4) (addition of 10-~ M
ramiprilat) 10 ~1 of PMSF solution 10 ~1 of 0.1% Genapol PFIC
12 ~1 of DMSO or test product The test products are generally dissolved Io-2 M in 100~
dimethyl sulfoxide (DMSO) and appropriately diluted with DMSO; the maximum content of DMSO in the incubation mixture is 1~.
The mixtures are mixed in ice and, for the incubation, placed in a waterbath (37C) for 1 hour. A total of 6 samples (each 100 ~1) are taken from an additional mixture without inhibitor and without further incubation for determination of the initial angiotensin I content of the plasma used.
The concentrations of the test products are chosen so that approximately the range of 10-90~ enzyme inhibition is covered (at least five concentrations~. At the end of the incubation time, three 100 ~1 samples from each mixture are frozen in precooled Eppendorf tubes on dry ice and stored at about -25C for the angiotensin I
determination (mean of three single samples).
Angiotensin I radioimmunoassay (RIA) The instructions for use of the RIA kit (Renin-Maia kit, Serono Diagnostics S.A., Coinsins, Switzerland) are followed exactly.
The calibration plot covers the range from 0.2 to 25.0 ng of angiotensin I per ml. The baseline angiotensin I
content of the plasma is subtracted from all the measure-ments. The plasma renin activity (PRA) is reported as ng of ang I/ml x hour. PRA values in the presence of the test substances are related to a mixture without inhibitor (= 100~) and the ICso is read off as % remaining activity against the concentration (M) of the test product (logarithmic scale).
The compounds of the formula (I) described in the present invention show inhibitory actions in the in vitro test at concentrations of about 10-5 to 10-1 mol/l.
Renin inhibitors bring about a lowering of blood pressure in animals deprived of salt. Since human renin differs from the renin of other species, primates (marmosets, rhesus monkeys) are used for the in vivo test of renin inhibitors. Primate renin and human renin are substan-tially homologous in their sequence. Endogenous reninsecretion is stimulated by i.v. injection of furosemide.
The test compounds are subsequently administered and their action on blood pressure and heart rate is measured. ~he compounds of the present invention are active in this test in an i.v. dose range of about 0.1-5 mg/kg and on intraduodenal administration by gastroscope in the dose range of about 1-50 mg/kg. The compounds of the formula (I) described in the present invention can be used as antih~pertensives and for the treatment of heart failure.
HIV protease is cut autocatalytically out of the GAG-POL
polypeptide and subsequently cleaves the precursor peptide p5S into the core antigens pl7, p24 and pl4. It is thus an essential enzyme whose inhibition interrupts the life cycle of the virus and suppresses its growth.
12 ~ ~ i d Biological tests showed that the compounds according to the invention have an enzyme inhibitory action and inhibit viral enzymes such as HIV protease too. The HIV
protease inhibiting action has particular importance and S qualifies the compounds according to the invention in particular for the therapy and prophylaxis of diseases caused by infection with HIV. The compounds of the formula (I) according to the invention show inhibitory actions in the in vitro tests used at concentrations of about 10-4 to 10-~ mol/l.
The present invention also relates to the use of com-pounds of the formula (I) for producing pharmaceuticals for the therapy of high blood pressure and the treatment of congestive heart failure, and for the therapy and prophylaxis of viral diseases, in particular of diseases caused by HIV, and to said pharmaceuticals.
Pharmaceutical products contain an effective amount of the active substance of the formula (I), preferably together with an inorganic or organic pharmaceutically utilizable excipient. Administration can be intranasally, intravenously, subcutaneously or orally. The dosage of the active substance depends on the warm blooded species, the body weight, age and on the mode of administration.
The pharmaceutical products of the present invention are produced in dissolving, mixing, granulating or coating processes known per se.
For a form for oral administration, the active compounds are mixed with the additives customary for this purpose, such as excipient, stabilizers or inert diluents, and converted by conventional methods into suitable dosage forms such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily solutions. Examples of inert vehicles which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, magnesium stearyl fumarate or starch, in particular corn starch. This preparation can be carried out both as dry and wet granules. Examples of suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil and fish liver oil.
For subcutaneous or intravenous administration, the active compounds or the physiologically tolerated salts thereof are converted, if required with the substances customary for this purpose, such as solubilizers, emulsi-fiers or other auxiliaries, into solutions, suspensions or emulsions. Examples of suitable solvents are: water, physiological saline solutions or alcohols, for example ethanol, propanediol or glycerol, as well as sugar solutions such as glucose or mannitol solutions, or else a mixture of the various solvents mentioned.
15 List of abbreviations used:
Boc tert.-Butoxycarbonyl BuLi n-Butyllithium DCC Dicyclohexylcarbodiimide DCI Desorption Chemical Ionisation DNP 2,4-Dinitrophenyl DME Dimethoxyethane DMF Dimethylformamide EA Ethyl acetate FAB Fast atom bombardment h Hour HOBt l-Hydroxybenzotriazole M Molecular peak MS Mass spectrum min Minutes NEM N-Ethylmorpholine RT Room temperature THF Tetrahydrofuran Trt Triphenylmethyl The following examples illustrate the preparation of the compounds according to the invention.
Example 1 N-[2-(8-Isobutyl-6-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3-yl)ethanoyl]-(2S,3R,4S)-l-cyclohexyl-3,4-dihydroxy-~-(2-pyridyl)-2-hexylamine la) (2S,3R,4S)-2-tert.-Butyloxycarbonylamino-l-cyclo-hexyl-3,4-dihydroxy-6-(2-pyridyl)-hexane 2.8 ml of n-butyllithium are added to 186 mg of 2-picoline in 20 ml of THF at -78C. After the mixture has warmed up to room temperature it is stirred for 30 min and then cooled to -40C. 2 mmol of (2RS,3R,4S)-3-tert . -butyldimethylsilyloxy-4-tert . -butyloxycarbonylamino-5-cyclohexyl-1,2-epoxypentane (disclosed in EP-A 189 203, Example 6) are added (dissolved in 10 ml of THF). The mixture is stirred at room temperature for 10 h and then diluted with water and extracted with methyl tert.-butyl ether. The crude product after concentration is dissolved in THF and stirred with 10 ml of a 1 M solution of tetrabutylammonium fluoride in THF at 0C for 1 h.
Dilution with water, extraction with EA and concentration result in 300 mg of the (2S,3R,4S) isomer (MS (FAB): 393 (M+H)) and 240 mg of the (2S,3S,4S) isomer (MS (FAB): 393 (M~H)) after separation by chromatography on silica gel.
lb) N-[2-(8-Isobutyl-6-phenyl-1,2,4-triazolo[4,3-a]-pyrazin-3-yl)-ethanoyl]-(2S,3R,4S)-l-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)-2~hexylamine 400 mg of (2S,3R,4S)-2-tert.-butyloxycarbonylamino-1-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)hexane (compound from Example la) are dissolved in 5 ml of abs. CH2Cl2, 5 ml of trifluoroacetic acid are added and the resulting solution is stirred at room temperature for 3 h. The residue obtained after concentration is taken up in 1 M
NaHCO3 solution, the mixture is extracted three times with EA, and the combined EA phases are dried over Na2SO~.
- 15 _ 2~r'~
The residue after concentration is dissolved in 5 ml of absolute DMF, 3l6.6 mg of 2-(8-isobutyl-6-phenyl-l,2,4-triazolo[413-a]pyrazin-3-yl)acetic acid (disclosed in EP-A 369,743, Example l), 208.4 mg of N,N-dicyclohexyl-carbodiimide and 206.8 mg of l-hydroxybenzotriazole are addedl the pH of the solution is adjusted to 9 with N-ethylmorpholinel and it is ~tirred at room temperature for 50 h. Filtration is followed by dilution with EA and washing once each with saturated NaHCO3 solutionl water and saturated brinel and chromatography with a CH2Cl2/CH3OH mixture as mobile phase yields 207.4 mg of the title compound.
MS(FAB):585 (M+H) Example 2 N-[2-(8-Isobutyl-6-phenyl-ll2,4-triazolo[4,3-a]pyrazin-3-yl)-3-(3-pyridyl)propionyl]-(2S,3R,4S)-l-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)-2-hexylamine The title compound results from reaction of 2-[8-iso-butyl-6-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3-yl]-3-(3-pyridyl)propionic acid (disclosed in EP-A 369 743, Example 3) with the compound from Example la by the process of Example lb.
MS (FAB):676 (M+H) Example 3 N-[2-(8-Propyl-6-(3-pyridyl)-l,2,4-triazolo[4,3-a]-pyrazin-3-yl)ethanoyl]-(2S,3R,4S)-l-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)-2-hexylamine The title compound is prepared from 8-propyl-6-(3-pyridyl)-ll214-triazolo[4l3-a]pyrazin-3-yl-acetic acid (disclosed in EP-A 369 7431 Example 4) and the compound from Example la by the process detailed in Example lb.
MS (FAB): 572 (M+H) 16 2~ 3 Example 4 N-[2-(8-Propyl-6-(3-pyridyl)-1,2,4-triazolo[4,3-a]-pyrazin-3-yl)-3-(3-pyridyl)-propionyl]-t2S,3R,4S)-l-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)-2-hexylamine The title compound is prepared from 2-[8-propyl-6-(3-pyridyl)-1,2,4-triazolo[4,3-a]pyrazin-3-yl]-3-(3-pyridyl)propionic acid (disclosed in EP-A 369 743, Example 6) and the compound from Example la by the process of Example lb.
10 MS tFAB): 663 (M+H) Example 5 N-[3-Imidazol-4-yl)-(2RS)-2-(8-propyl-6-(3-pyridyl)-1,2,4-triazolo[4,3-a]pyrazin-3-yl)-propionyl]-(2S,3R,4S)-l-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)-2-hexylamine The title compound is prepared from 3-(1-triphenylmethyl-imidazol-4-yl)-2-[8-propyl-6-(3-pyridyl)-1,2,4-triazolo-[4,3-a]pyrazin-3-yl]-propionic acid (disclosed in EP-A
369 743, Example 27) and the compound from Example la by the process of Example lb and subsequent elimination of the Ni~-Trt protective group with 90~ strength trifluoro-acetic acid and working up by extraction.
MS (FAB): 652 (M+H)
Claims (8)
1. A heterocyclic compound of the formula (I) (I) in which the radicals have the following meanings:
R1 (C1-C8) -alkyl or phenyl;
R2 phenyl or pyridyl, where the pyridyl radical optionally carries a (C1-C4)-alkyl substituent;
R3 hydrogen or a group of the formula Q-A in which Q is pyridyl, imidazolyl, thiazolyl and pyrazolyl, and A is methylene or ethylene;
R4 hydrogen, (C1-C10)-alkyl, (C3-Cs)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C4)-alkyl, (C6-C12)-aryl or (C6-C12)-aryl-(C1-C4)-alkyl;
R5 hydrogen, (C1-C10)-alkyl, (C6-C12)-aryl, (C6-C12)-aryl-(C1-C4)-alkyl, hydroxyl or amino;
R6 a radical of the formula (II) (CH2)s-CHR7-Z (II) where R7 is hydrogen, (C1-C7)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylamino, hydroxyl, azido or halogen, and Z is a 5- to 7-membered heterocyclic ring which can be benzo-fused, aromatic, partially hydro-genated or completely hydrogenated and which can contain as hetero atoms one or two identical or different radicals from the group comprising N, O, S, NO, SO, SO2 and which can be substituted by one or two identical or different radicals from the series comprising (C1-C4)-alkyl, allyl, (C1-C4)-alkoxy, hydroxyl, halogen, amino, mono-or di-(C1-C4)-alkylamino and CF3; and where s is 0, 1, 2, 3 or 4;
and the physiologially tolerated salts thereof.
R1 (C1-C8) -alkyl or phenyl;
R2 phenyl or pyridyl, where the pyridyl radical optionally carries a (C1-C4)-alkyl substituent;
R3 hydrogen or a group of the formula Q-A in which Q is pyridyl, imidazolyl, thiazolyl and pyrazolyl, and A is methylene or ethylene;
R4 hydrogen, (C1-C10)-alkyl, (C3-Cs)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C4)-alkyl, (C6-C12)-aryl or (C6-C12)-aryl-(C1-C4)-alkyl;
R5 hydrogen, (C1-C10)-alkyl, (C6-C12)-aryl, (C6-C12)-aryl-(C1-C4)-alkyl, hydroxyl or amino;
R6 a radical of the formula (II) (CH2)s-CHR7-Z (II) where R7 is hydrogen, (C1-C7)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylamino, hydroxyl, azido or halogen, and Z is a 5- to 7-membered heterocyclic ring which can be benzo-fused, aromatic, partially hydro-genated or completely hydrogenated and which can contain as hetero atoms one or two identical or different radicals from the group comprising N, O, S, NO, SO, SO2 and which can be substituted by one or two identical or different radicals from the series comprising (C1-C4)-alkyl, allyl, (C1-C4)-alkoxy, hydroxyl, halogen, amino, mono-or di-(C1-C4)-alkylamino and CF3; and where s is 0, 1, 2, 3 or 4;
and the physiologially tolerated salts thereof.
2. A heterocyclic compound as claimed in claim 1, wherein the radicals in the formula (I) have the following meanings:
R4 isobutyl, benzyl or cyclohexylmethyl;
R5 hydrogen, (C1-C5)-alkyl, (C6-C10)-aryl, (C6-C10)-aryl-(C1-C4) -alkyl or hydroxyl;
R6 a radical of the formula (II) in which R7 is hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylamino, hydroxyl, azido or halogen, s is 0, 1 or 2, and Z is a heteroaryl radical from the group comprising pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, .beta.-carbolinyl or a benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative from this group, and the other radicals are defined as in claim 1, and the physiologically tolerated salts thereof.
R4 isobutyl, benzyl or cyclohexylmethyl;
R5 hydrogen, (C1-C5)-alkyl, (C6-C10)-aryl, (C6-C10)-aryl-(C1-C4) -alkyl or hydroxyl;
R6 a radical of the formula (II) in which R7 is hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylamino, hydroxyl, azido or halogen, s is 0, 1 or 2, and Z is a heteroaryl radical from the group comprising pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, .beta.-carbolinyl or a benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative from this group, and the other radicals are defined as in claim 1, and the physiologically tolerated salts thereof.
3. A heterocyclic compound as claim in claim 1, wherein the radicals in the formula (I) have the following meanings:
R1 methyl, ethyl, propyl, i-propyl, butyl, i-butyl or pentyl;
R2 phenyl or 3-pyridyl, where the pyridyl radical optionally carries a methyl or ethyl substituent;
R4 isobutyl, benzyl or cyclohexylmethyl;
R5 hydrogen or hydroxyl;
R6 a radical of the formula (II), in which R7 is hydrogen or fluorine, Z is a 2-, 3- or 4-pyridyl radical, a 2-, 4- or 5-imidazolyl radical or a 2-oxazolinyl radical, where said heterocycles can each be substituted by one or two identical or different radicals from the series comprising methyl, ethyl, propyl, allyl, fluorine, chlorine, bromine, CF3 and methoxy, and s is 0, 1 or 2;
and the other radicals are as defined in claim 1, and the physiologically tolerated salts thereof.
R1 methyl, ethyl, propyl, i-propyl, butyl, i-butyl or pentyl;
R2 phenyl or 3-pyridyl, where the pyridyl radical optionally carries a methyl or ethyl substituent;
R4 isobutyl, benzyl or cyclohexylmethyl;
R5 hydrogen or hydroxyl;
R6 a radical of the formula (II), in which R7 is hydrogen or fluorine, Z is a 2-, 3- or 4-pyridyl radical, a 2-, 4- or 5-imidazolyl radical or a 2-oxazolinyl radical, where said heterocycles can each be substituted by one or two identical or different radicals from the series comprising methyl, ethyl, propyl, allyl, fluorine, chlorine, bromine, CF3 and methoxy, and s is 0, 1 or 2;
and the other radicals are as defined in claim 1, and the physiologically tolerated salts thereof.
4. A process for preparing a heterocyclic compound of the formula (I) as claimed in claim 1, wherein a fragment of the formula (III) with a terminal carboxyl group or its reactive derivative is coupled to a fragment of the formula (IV) with a free amino group, (III) (IV) where appropriate protective group(s) temporarily introduced to protect other functional groups are eliminated, and the compound obtained in this way is, where appropriate, converted into a physio-logically tolerated salt.
5. A heterocyclic compound of the formula (I) as claimed in any of claims 1 to 3 for use as medicine.
6. A heterocyclic compound of the formula (I) as claimed in any of claims 1 to 3 for use as medicine for the treatment of high blood pressure.
7. A pharmaceutical composition containing an active substance and, where appropriate, excipients and further additives, which contains as active substance at least one compound of the formula (I) as claimed in claim 1.
8. A process for the production of a pharmaceutical composition as claimed in claim 7, which comprises converting the active substance or substances together with a physiologically acceptable vehicle and, where appropriate, other additives into a suitable dosage form.
Applications Claiming Priority (2)
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DEP4120494.8 | 1991-06-21 | ||
DE4120494 | 1991-06-21 |
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CA002071743A Abandoned CA2071743A1 (en) | 1991-06-21 | 1992-06-19 | Heterocyclic compounds with renin-inhibiting properties, a process for the preparation thereof and the use thereof |
Country Status (15)
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EP (1) | EP0519434A3 (en) |
JP (1) | JPH05170768A (en) |
KR (1) | KR930000516A (en) |
CN (1) | CN1068117A (en) |
AU (1) | AU1835592A (en) |
BR (1) | BR9202327A (en) |
CA (1) | CA2071743A1 (en) |
CZ (1) | CZ187992A3 (en) |
FI (1) | FI922876A (en) |
HU (1) | HU9202064D0 (en) |
IE (1) | IE921996A1 (en) |
MX (1) | MX9203076A (en) |
NO (1) | NO922428L (en) |
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ZA (1) | ZA924521B (en) |
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NZ249789A (en) * | 1992-03-11 | 1997-07-27 | Narhex Ltd | Hydrazine, carbazate and 1,2-diazacyclic derivatives and pharmaceutical compositions |
US6071895A (en) * | 1992-03-11 | 2000-06-06 | Narhex Limited | Polar-substituted hydrocarbons |
DE69333270T2 (en) | 1992-03-11 | 2004-08-05 | Narhex Ltd. | AMINE DERIVATIVES OF OXO AND HYDROXY SUBSTITUTED CARBON HYDROGEN |
US5888992A (en) * | 1992-03-11 | 1999-03-30 | Narhex Limited | Polar substituted hydrocarbons |
IL110898A0 (en) * | 1993-09-10 | 1994-11-28 | Narhex Australia Pty Ltd | Polar-substituted hydrocarbons |
MXPA05011497A (en) * | 2003-04-30 | 2005-12-15 | Actelion Pharmaceuticals Ltd | Tropane derivatives and their use as ace inhibitors. |
CN1780837A (en) * | 2003-04-30 | 2006-05-31 | 埃科特莱茵药品有限公司 | Azabicyclononene derivatives |
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DE3841732A1 (en) * | 1988-12-10 | 1990-06-13 | Hoechst Ag | DIPEPTIDE DERIVATIVES WITH ENZYME-INHIBITOR EFFECT |
DE3913272A1 (en) * | 1989-04-22 | 1990-10-25 | Hoechst Ag | DIPEPTIDE DERIVATIVES WITH ENZYME-INHIBITOR EFFECT |
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1992
- 1992-06-11 PL PL29486692A patent/PL294866A1/en unknown
- 1992-06-17 EP EP19920110245 patent/EP0519434A3/en not_active Withdrawn
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- 1992-06-18 CZ CS921879A patent/CZ187992A3/en unknown
- 1992-06-19 BR BR929202327A patent/BR9202327A/en not_active Application Discontinuation
- 1992-06-19 HU HU9202064A patent/HU9202064D0/en unknown
- 1992-06-19 CA CA002071743A patent/CA2071743A1/en not_active Abandoned
- 1992-06-19 AU AU18355/92A patent/AU1835592A/en not_active Abandoned
- 1992-06-19 NO NO92922428A patent/NO922428L/en unknown
- 1992-06-19 KR KR1019920010652A patent/KR930000516A/en not_active Application Discontinuation
- 1992-06-19 JP JP4160477A patent/JPH05170768A/en active Pending
- 1992-06-19 ZA ZA924521A patent/ZA924521B/en unknown
- 1992-06-19 MX MX9203076A patent/MX9203076A/en unknown
- 1992-06-20 CN CN92104867A patent/CN1068117A/en active Pending
- 1992-07-01 IE IE199692A patent/IE921996A1/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
AU1835592A (en) | 1992-12-24 |
PL294866A1 (en) | 1993-05-31 |
EP0519434A3 (en) | 1993-04-14 |
IE921996A1 (en) | 1992-12-30 |
JPH05170768A (en) | 1993-07-09 |
NO922428L (en) | 1992-12-22 |
BR9202327A (en) | 1993-01-19 |
HU9202064D0 (en) | 1992-09-28 |
FI922876A (en) | 1992-12-22 |
CZ187992A3 (en) | 1993-01-13 |
FI922876A0 (en) | 1992-06-18 |
CN1068117A (en) | 1993-01-20 |
ZA924521B (en) | 1993-02-24 |
EP0519434A2 (en) | 1992-12-23 |
KR930000516A (en) | 1993-01-15 |
NO922428D0 (en) | 1992-06-19 |
MX9203076A (en) | 1992-12-01 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
FZDE | Discontinued |