CA2050092A1 - Amino acid derivatives - Google Patents
Amino acid derivativesInfo
- Publication number
- CA2050092A1 CA2050092A1 CA002050092A CA2050092A CA2050092A1 CA 2050092 A1 CA2050092 A1 CA 2050092A1 CA 002050092 A CA002050092 A CA 002050092A CA 2050092 A CA2050092 A CA 2050092A CA 2050092 A1 CA2050092 A1 CA 2050092A1
- Authority
- CA
- Canada
- Prior art keywords
- amino
- formula
- alkyl
- ala
- cyclohexyl
- 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
- 150000003862 amino acid derivatives Chemical class 0.000 title claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 108090000783 Renin Proteins 0.000 claims abstract description 9
- 102100028255 Renin Human genes 0.000 claims abstract description 9
- -1 piperazino group Chemical group 0.000 claims description 296
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 64
- 150000001875 compounds Chemical class 0.000 claims description 62
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
- 206010020772 Hypertension Diseases 0.000 claims description 5
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 5
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 5
- 206010020571 Hyperaldosteronism Diseases 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 201000009395 primary hyperaldosteronism Diseases 0.000 claims description 4
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 150000001602 bicycloalkyls Chemical group 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 230000002829 reductive effect Effects 0.000 claims description 3
- 125000000565 sulfonamide group Chemical group 0.000 claims description 3
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 2
- 230000001419 dependent effect Effects 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 229910052727 yttrium Inorganic materials 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- 239000007787 solid Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 239000000203 mixture Substances 0.000 description 21
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
- 125000006239 protecting group Chemical group 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 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 8
- 150000003254 radicals Chemical class 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 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 7
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 7
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 238000007327 hydrogenolysis reaction Methods 0.000 description 7
- 239000012442 inert solvent Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 229940024606 amino acid Drugs 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 5
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 4
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 4
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000010265 fast atom bombardment Methods 0.000 description 4
- 235000011167 hydrochloric acid Nutrition 0.000 description 4
- 229960000443 hydrochloric acid Drugs 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
- 125000006518 morpholino carbonyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])N(C(*)=O)C1([H])[H] 0.000 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 235000004279 alanine Nutrition 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000003054 catalyst Substances 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
- 238000007911 parenteral administration Methods 0.000 description 3
- 238000010647 peptide synthesis reaction Methods 0.000 description 3
- 210000002381 plasma Anatomy 0.000 description 3
- SMKRKQBMYOFFMU-UHFFFAOYSA-N prallethrin Chemical compound CC1(C)C(C=C(C)C)C1C(=O)OC1C(C)=C(CC#C)C(=O)C1 SMKRKQBMYOFFMU-UHFFFAOYSA-N 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 238000003797 solvolysis reaction Methods 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
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- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-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
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229930194542 Keto Natural products 0.000 description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 2
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 235000019759 Maize starch Nutrition 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
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- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
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- 238000010521 absorption reaction Methods 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
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- 150000008282 halocarbons Chemical class 0.000 description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
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- NIZHERJWXFHGGU-UHFFFAOYSA-N isocyanato(trimethyl)silane Chemical compound C[Si](C)(C)N=C=O NIZHERJWXFHGGU-UHFFFAOYSA-N 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 238000012423 maintenance Methods 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
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 description 1
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 description 1
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 125000001402 nonanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-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
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- DRINJBFRTLBHNF-UHFFFAOYSA-N propane-2-sulfonyl chloride Chemical compound CC(C)S(Cl)(=O)=O DRINJBFRTLBHNF-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000002461 renin inhibitor Substances 0.000 description 1
- 230000000894 saliuretic effect Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 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
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 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
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- ORQXBVXKBGUSBA-QMMMGPOBSA-N β-cyclohexyl-alanine Chemical compound OC(=O)[C@@H](N)CC1CCCCC1 ORQXBVXKBGUSBA-QMMMGPOBSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Genetics & Genomics (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Crystallography & Structural Chemistry (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A b s t r a c t Novel amino acid derivatives of the formula I
in which R1 to R5, W, X and Y have the meanings indicated in Patent Claim 1, and their salts inhibit the activity of human plasma renin.
in which R1 to R5, W, X and Y have the meanings indicated in Patent Claim 1, and their salts inhibit the activity of human plasma renin.
Description
Merck Patent Gesellschaft 2 ~3 mit beschrankter Haftung 6100 D a r m s t a d t Amino acid derivatives The invention relates to novel amino acid deriva-tives of the formula I
X-W-CR1R2-Co-Y-NH-CHR3-CR4-CooRs in which X LS H, R6-O--CmH2m-CO--I R~-CmH2m-O-CO--, R6-CmH2m-CO-, R6-SO2-, R7R3N-C~H2m-Co-, R9-NH-C(=NH)-NH-CmH2m--CO--~ R700C-CmH2m-Co--~ R703S-CmEI2m-CO--~
R7-o-(CH2CH2o)~-CmH2m-co- or A3N -CmH2m-CO- An W i8 O or NH, Y is ~Ala or Isoser, R , R
and R8 are each H or A, R , R
and R6 are each H, A, Ar, Ar-alkyl, Het, Het-alkyl, cycloal.kyl having 3-7 C atoms, which is unsub-~ti.tuted or monosubstituted or polysub~tituted by A, AO and/or Hal, cycloalkylalkyl having 4-11 C atoms, bicycloalkyl or tricycloalkyl each ha~ing 7 14 C atoms, or bicycloalkylalkyl or tri.cycloalkylalkyl each having 8-18 C atoms, R4 is (H, OH), (H, NH2) or =O, Rs is H, A or cycloalkyl having 3-7 C atoms, R7R8N is also an unsubstituted pyrrolidino, piperid-ino, morpholino or piperazino group or one which is suhstituted by A, OH, NH2~ NHAr NA2 NH~c, NH-CO-CIH2~-O-R9, NH-co-o-c~H2x-R ~
hydroxyalkyl, COOH, COOA, CONH2, aminoalkyl, HAN-alkyl, A2N-alkyl, A3N~alkyl Ane, NH-CO-NH2, NH-CO-NHA, guanidinyl or guanidinylalkyl, R is M, A, Ar-alkyl or CN, m and x are each 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, n is 0, 1, 2 or 3, - 2 ~ 2~ 2 Ax is unsubsti~uted phenyl or phenyl which is monosubstituted or polysubstituted by A, OA, Hal, CF3, OH, NO2, hydroxyalkyl, NH2, NHA, NAz, NHAc, NH-S02-A, SA, SO-A, SO2-A, SO2NH2~ S02NHA, COOH, COOAI CONH2r CN, ~ninoalkyl, HAN-alkyl, A2N-alkyl,A3N~-alkyl Aneand/orguanidinylalkyl, or is unsubstituted naphthyl, Het is a saturated or unsaturated 5- or 6-membered heterocyclic radical having 1-4 N, O andJor S
atoms, which can ~e fused to a benzene ring and/or monosubstituted or polysubstituted by A, OA, Hal, CF3, OH, NOz, carbonyl oxygen, MH2, NHA, NA2, NHAc, NH-COOA, NHCOO~r, NHCOOCH~Ar, NH-SO2-A, SA, SO-A, SO2-A, SO2NH2, SO2NHA, COOH, COOA, CONH2, CN, Ar, Ar-al~yl, Ar-alkenyl, hydroxyalkyl, aminoalkyl, HAN-alkyl, A2N-alkyl and/or A3N~-alkyl Ane and/or whose N and/or S
heteroatoms can also be oxidised, Hal is F, Cl, Br or I, Ac is A-CO-, Ar-CO , Ar-alkyl-CO- or A-NH-CO-, Ane is an anion, which can also be absent, if instead of this a carboxyl group contained in the compound of the formula I i5 present in the fo~n of a carboxylate anion, -alkyl is an alkylene group having 1-8 C atoms and A is alkyl having 1~8 C atoms, in which in addition instead of one or more ~NH-CO groups there can also be one or more -NA-CO groups, and their ~alts.
Similar compounds are disclosed in EP-A-249,096.
The invention was based on the object of finding novel compounds having useful properties, in particular those which can be used for the preparation of medica-ments.
3S It ha~ been found that the compounds of the formula I and their salts have very useful properties. In particular~ they inhibit the activity of human plasma renin. This action can be detected, for example, by the method of F. Fyhrqui~t et al., Clin. Chem. 22/ 250-256 - 3 - 2050~92 (1976). It is noteworthy that these compounds are very specific inhibitors of renin; as a rule about 100 to 1000 times as high concentrations of these compounds are necessary for the inhibition of other aspartylproteinases (for example pepsin and cathepsin D) as for renin inhi-bition. The actions of the compounds on the blood pres-sure and/or on the heart rate and the inhibition of the renin activity in the blood plasma can additionally be determined in conscious monkey~, for example female monkeys (Macaca fascicularis); in this connection blood pressure and heart rate can be measured following the method of M.J. Wood et al., J. Hypertension 4, 251-254 (1985). To stimulate renin activity, the animals are in thi~ case expediently pretreated with a saluretic. Blood ~amples for determining the plasma renin activity can be obtained by puncture of the femoral vein.
The compounds can be employed as medicament - active compounds in human and veterinary medicine, in particular for the prophylaxis and for the treatment of cardiac, circulatory and vascular diseases, in particular hypertension, cardiac insufficiency and hyperaldo-steronism. In addition, the compounds can be used for diagnostic purposes in patients with hypertension or hyperaldosteronism in order to determine the possible contribution of the renin activity to the maintenance of the pathological condition. Such diagnostic tests can be carried out in a similar manner to that given in EP-A-77,028.
The abbreviations of amino acid radicals mentioned above and below are for the radical~ -NR'-Rn-CO-, as a rule -NH-CHR-CO- (in which R, R' and R" have the specific meaning known for each amino acid), of the following amino acids:
Ada 3-(1-adamantyl)alanine Ala alanine ~Ala ~-alanine Bia 3-(2-benzimidazolyl)alanine Cal 3-cyclohexylalanine Gly glycine His histidine Hph homophenylalanine (2-amino 4-phenylbutyric acid) Ile isoleucine Leu leucine ~al 3-(p-methoxyphenyl)alanine Nle norleucine Phe phenylalanine Tia 3-~thienyl)alanine [for example 2-Tia =
3-(2-thienyl)alanine]
Tiz 3-(thiazolyl)alanine [for example 2-Tiz =
3-~2-thiazolyl)alanine]
Trp tryptophan Tyr tyrosine.
In addition, the following hav0 the meaning below:
BOC tert.-butoxycarbonyl BOM benzyloxymethyl imi-BOM benzylo~ymethyl in the l-position of the imidazole ring CBZ benzyloxycarbonyl DCCI clicyclohexylcarbodiLmide DME climethylformamide DNP 2,4-dinitrophenyl imi-DNP 2,4-dinitrophenyl in the l-position of the imidazole ring ETOC ethoxycarbonyl FMOC 'i-fluorenylmethoxycarbonyl HOBt 1-hydroxybenzotriazole IPOC isopropoxycarbonyl Pla the radical of phenyllactic acid -O-CH(CH2C6Hs)~CO- (S-form) PO~ phenoxy~cetyl THF tetrahydrofuran.
If the abovementioned amino acids can occur in several enantiomexic forms, all these forms and also their mixtures (for example the DL-forms) are included above and below, for example as constituents of the compounds of ~he formula 1. The L-forms are preferred. If _ 5 _ 2~3~9~
individual compounds are mentioned below, the abbrevia-tions of these amino acids in each case relate to the L-form, if not expressly stated otherwise.
The invention further relates to a process for the preparation of an amino acid derivative of the formula I and of its salts, characterised in that it is set free from one of its functional derivatives by treating with a solvolysing or hydrogenolysing agent or in that a carboxylic acid of the formula II
X-Gl-OH II
in which Gl (a) is absent, (b) i~ -W-CRlR2_co-~(c) is -W-CRlR2_co_y_, or one of its reactive derivatives is reacted with a compound of the formula III
H - G 2 -NH - CHR3-CR4-CooR5 III
in which G2 (a) i8 -W-CRlR2-CO-Y-, (b) is _y_, ( C ) i8 absent, and in that a functionally modified amino and/or hydroxy group i8 optionally set free in a compound of the formula I by treating with solvolysing or hydrogenolysing agents and/or a free amino group is acylated by treating with an acylating agent and/or an aminoketo acid derivative of the formula I, R4 = O, is reduced or reductively aminated to prepare a compound of the formula I, R~ = (H, OH) or (H, NH2) and/or an ester of the formula I, R5 = A is hydrolysed and/or an acid of the formula I, R5 = H is esterified and/or a compound of the formula I is conver-ted into one of its salts by treating with an acid.
Above and below, the radi-cals or parameters Rl to R~, W, X, Y, m, n, x, Ar, Het, Hal, Ac, An, A, Gl and G2 have the meanings indicated in the formulae I, II or III
- 6 - 20~0~2 unless expressly stated otherwise.
In the above formulae, A has 1-8, preferably 1, 2, 3 or 4 C atoms. A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, or tert.-butyl, additionally also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, l-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, l-ethyl-l-methylpropyl, 1-ethyl-2-methyl-propyl, 1,1,2- or 1,2,2-trLmethylpropyl, heptyl, octyl.
Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but also, for example, 1-, 2- or 3-methylcyclopentyl, or 1-, 2-, 3- or 4-methylcyclohexyl.
Accordingly, cycloalkylalkyl is preferably cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, 2-cyclobutylethyl,cyclopentylmethyl,2-cyclopentylethyl, cyclohexylmethyl, 2-cyclohexylethyl, but also, for example, 1-, 2- or 3-methylcyclopentylmethyl, or 1-, 2-, 3- or 4-methylcyclohexylmethyl.
Bicycloalkyl is preferably 1- or 2-decalyl, 2-bicyclo[2.2.1~heptyl or 6,6-dimethyl-2-bicyclot3.1.11-heptyl.
Tricycloalkyl is preferably l-adamantyl.
Hal is preferably F, Cl or Br, but also I.
Ac is preferably A-C0-, such as acetyl, propionyl or butyryl, Ar-C0- such as benzoyl, o-, m- or p-methoxy-benzoyl or 3,4-dimethoxybenzoyl, or A-NH-C0- such as N-methyl- or N-ethylcarbamoyl.
Ar is preferably phenyl, in addition preferably o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, o-, m- or p-iodophenyl, o-, m- or p-trifluoromethylphenyl, o-, m-or p-hydroxyphenyl, o-, m- or p-sulfamoylphen~l, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, o-, m-, or p-aminophenyl, o-, m-or p-aminomethylphenyl, o-, m- or p-dimethylaminomethyl-phenyl, o-, m- or p-guanidinomethylphenyl, 1- or _ 7 _ 20~92 2-naphthyl.
Accordingly, Ar-alkyl is preferably benzyl, 1- or 2-phenylethyl, o-, m- or p-methylbenzyl, 1- or 2-o-, -m-or -p-tolylethyl, o-, m- or p-ethylbenzyl, 1- or 2-o-, -m- or -p-ethylphenylethyl, o-, m- or p-methoxybenzyl, 1-or 2-o-, -m- or -p-methoxyphenylethyl, o-, m- or p-fluorobenzyl, 1- or 2-o-, -m- or -p-fluorophenylethyl, o-, m- or p-chlorobenzyl, 1- or 2-o-, -m- or -p-chloro-phenylethyl, o-, m- or p-bromobenzyl, 1- or 2-o-, -m- or -p-bromophenylethyl, o-, m- or p-iodobenzyl, 1- or 2-o-, -m- or -p-iodophenylethyl, o-, m- or p-trifluoromethyl-benzyl, o-, m- or p-hydroxybenzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxybenzyl, 3,4,5-trimethoxy-benzyl, o-, m- or p-aminobenzyl o-, m- or p-aminomethyl-benzyl, o-, m- or p-dimethylaminomethylbenzyl, o-, m- or p-guanidinomethylbenzyl, 1- or 2-naphthylmethyl.
Het is preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothi-azolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyr~midinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 2,1,5-thiadiazol-3- or -4-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzo-furyl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-iso-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benæ-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-iso-quinolyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolyl. The 8 2050~2 heterocyclic radicals can also be partially or completely hydrogenated. Het can thus also be, for example, 2,3-di-hydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4-or -5-furyl, tetrahydro-2- or -3-furyl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -S-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -S-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -S-pyrazolyl, tetra-hydro-l-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3-or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-or -6-pyridyl, 1,2,3,6-tetrahydro-1-, -2-, -3-, -4-, -5-or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-di-oxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-l-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl.
The heterocyclic radicals can also be substituted as indicated. Het can also preferably be, for example:
2-amino-4-thiazolyl, 4-carboxy-2-thiazolyl, 4-carbamoyl-2-thiazolyl, 4-(2-aminoethyl)-2-thiazolyl, 4-amino-2-methyl-5-pyrimidinyl, 2-amino-5,6-dimethyl-3-pyrazinyl, 4-carbamoylpiperidino, in addition, for example, 3-, 4-or 5-methyl-2-furyl, 2-, 4- or 5-methyl-3-furyl, 2,4-di-methyl-3-furyl, S-nitro-2-furyl, 5-styryl-2-furyl, 3-, 4-or S-methyl-2-thienyl, 2-, 4- or S-methyl-3-thienyl, 3-methyl-S-tert.-butyl-2-thienyl, S-chloro-2-thienyl, S-phenyl-2- or -3-thienyl, 1-, 3-, 4- or S-methyl-2-pyrrolyl, 1-methyl-4- or -5-nitro-2-pyrrolyl, 3,5-dimeth-yl-4-ethyl-2-pyrrolyl, 4-methyl-5-pyrazolyl, 5-methyl-3-isoxazolyl, 3,4-dimethyl-5-isoxazolyl, 4- or 5-methyl-2-thiazolyl, 2- or 5-methyl-4-thiazolyl, 2- or 4-methyl-5-thiazolyl, 2,4-dimethyl-5-thiazolyl, 3-, 4-, 5- or 6-methyl-2-pyridyl, 2-, 4-, 5- or 6-methyl-3-pyridyl, 2- or 3-methyl-4-pyridyl, 3-, 4-, 5- or 6-chloro-2-pyridyl, 2-, 4-, 5- or 6-chloro-3-pyridyl, 2- or 3-chloro-4-pyridyl, 2,6-dichloropyridyl, 2-hydroxy-3-, -4-, -5- or -6-pyridyl (= lH-2-pyridon-3-, -4-, -5- or 2~0~92 -6-yl),5-phenyl-lH-2-pyridon-3-yl,5-p-methoxyphenyl-lH-2-pyridon-3-yl, 2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl, 2-hydroxy-4-amino-6-methyl-3-pyridyl, 3-N'-methylureido-lH-4-pyridon-5-yl, 4-methyl-2-pyrimidinyl, 4,6-dimethyl-2-pyrimidinyl, 2-, 5- or 6-methyl-4-pyrimid-inyl, 2,6-dimethyl-4-pyrimidinyl, 2,6-dihydroxy-4-pyrLm-idinyl, 5-chloro-2-methyl-4-pyrimidinyl, 3-methyl-2-benzofuryl, 2-ethyl-3-benzofuryl, 7-methyl-2-benzo-thienyl, 1-, 2-, 4-, 5-, 6- or 7-methyl-3-indolyl, 1-methyl-5- or -6-benzimidazolyl, l-ethyl-S- or -6-benz-imidazolyl, 3-, 4-, 5-, 6-, 7- or 8-hydroxy-2-quinolyl, 2-oxopyrrolidino, 2-oxopiperidino, 2,5-dioxopyrrolidino or 3-benzyl-2,5-dioxopyrrolidino.
~ is generally preferably H; R6-C~H2m-O-CO- such as BOC; R6-CmH2m-CO- such as formyl or acetyl; R6-S02-, in particular A-S02- such as methylsulfonyl; R7R3N-CmH2~-Co-, in particular 4-BOC-aminopiperidinocarbonyl, 4-amino-piperidinocarbonyl, 4-hydroxypiperidinocarbonyl, 4-dimethylaminopiperidinocarbonyl, 4-ethoxycarbonylamino-piperidinocarbonyl, morpholinocarbonyl, piperazino-carbonyl or 4-BOC-piperazinocarbonyl.
The group Y is preferably ~Ala.
W i8 preferably NH.
R1, R5, R7, and R8 are each preferably H, in addi-tion preferably methyl; R5 i8 preferably al~o ethyl, propyl, i~opropyl, n-butyl, isobutyl, cyclopentyl or cyclohexyl. R7R~ is preferably also pyrrolidino, piperi-dino, morpholino, aminopiperidino such as 4-aminopiperi-dino, hydroxypiperidino such as 4-hydroxypiperidino, alkylaminopiperidino such as 4-methylaminopiperidino, dialkylaminopiperidino such a~ 4-dimethylaminopiperidino, ethoxycarbonylaminopiperidino such as 4-ethoxycarbonyl-aminopiperidino or BOC-aminopiperidino such a~ 4-BOC-aminopiperidino, morpholino or 4-BOC-piperazino.
R2 is preferably Ar-alkyl, in particular benzyl or p-methoxybenzyl; in addition preferably A, in parti-cular n-butyl or isobutyl; cycloalkylalkyl, in particular cyclohexylmethyl; or Het-alkyl, in particular 2-thienyl-methyl. The group -W-CRlR2-CO- is preferably one of the 20S0~9~
radicals Phe or Pla, in addition Ada, Bia, Cal, His, Hph, Ile, Leu, Mal, Nle, Tia, Tiz, Trp or Tyr.
R3 is preferably cycloalkylalkyl, in particular cyclohexylmethyl, in addition preferably alkyl, in particular n-butyl or isobutyl; Ar-alkyl, in particular benzyl or p-methoxybenzyl; Het-alkyl, for example 2-thienylmethyl; or cycloalkyl, in particular cyclohexyl.
R4 is preferably (H, OH).
R9 is preferably H, methyl or CN.
The parameter m is preferably 1, 2, 3, 4 or 5; n is preferably 1; x is preferably 1 or 2.
CmH~ and CrH~ are preferably straight-chain, that is to say preferably -(CH2) m~ or -(CH2)~-.
Accordin~ly, the group X i8 in particular prefer-ably H; R7R8N-(CH2)m-Co-, in particular H2N-CmH~-CO- such as aminocarbonyl, aminoacetyl (H-Gly~), 3-aminopropionyl (H-~Ala-), 4-aminobutyryl, 5-aminopentanoyl, 6-amino-hexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-amino-nonanoyl, 10-aminodecanoyl, ll-aminoundecanoyl, but also, for example, 2-aminopropionyl (Ala), 2-amino-2-methyl-propionyl, 3-amino-3-methylbutyryl; ANH-CmH~-CO- such as methylaminocarbonyl, ethylaminocarbonyl, methylamino-acetyl (sarcosyl), 3-methylaminopropionyl, 4-methylamino-butyryl, 5-methylaminopentanoyl, 6-methylaminohexanoyl, 6-ethylaminohexanoyl, 7-methylaminoheptanoyl, 8-methyl-aminooctanoyl, 9-methylaminononanoyl, 10-methylamino-decanoyl, ll-methylaminoundecanoyl; AkN-C~H~-CO- such as dimethylaminocarbonyl, dimethylaminoacetyl, 3-dimethyl-aminopropionyl, 4-dimethylaminobutyryl, 5-dimethylamino-pentanoyl, 6-dimethylaminohexanoyl, 6-diethylaminohexan-oyl, 7-dimethylaminoheptanoyl, 8-dimethylaminooctanoyl, 9-dimethylaminononanoyl, 10-dimethylaminodecanoyl, 11-dimethylaminoundecanoyl; pyrrolidino-CmH~-CO- such as pyrrolidinocarbonyl,pyrrolidinoacetyl,3-pyrrolidinopro-pionyl, 4-pyrrolidinobutyryl, S-pyrrolidinopentanoyl, 6-pyrrolidinohexanoyl, 4-pyrrolidinoheptanoyl, 8-pyrroli-dinooctanoyl,9-pyrrolidinononanoyl,10-pyrrolidinodecan-oyl; piperidino-CmH~-CO- such as piperidinocarbonyl, piperidinoacetyl, 3-piperidinopropionyl, 4-piperidino-20~0~2 butyryl, 5-piperidinopentanoyl, 6-piperidinohexanoyl, 7-piperidinoheptanoyl, 8-piperidinooctanoyl, 9-piperidino-nonanoyl, 10-piperidinodecanoyl; morpholino-CmH2m-CO- such as morpholinocarbonyl, morpholinoacetyl, 3-morpholino-propionyl, 4-morpholinobutyryl, 5-morpholinopentanoyl, 6-morpholinohexanoyl, 7-morpholinoheptanoyl, 8-morphol-inooctanoyl,9-morpholinononanoyl,10-morpholinodecanoyl;
4-hydroxypiperidino-CmH2m-CO- such as 4-hydroxypiperidino-carbonyl, 4-hydroxypiperidinoacetyl; 4-aminopiperidino-CmH2m-CO- such as 4-aminopiperidinocarbonyl, 4-amino-piperidinoacetyl, 3-(4-aminopiperidino)propionyl, 4-(4-aminopiperidinojbutyryl, 5-(4-aminopiperidino)pentanoyl, 6-(4-aminopiperidino)hexanoyl, 7-(4-aminopiperidino)hept-anoyl, 8-(4-aminopiperidino)octanoyl, 9-(4-aminopiperi-dino)nonanoyl, 10-(4-aminopiperidino)decanoyl; 4-BOC-aminopiperidino-CmH2m-CO- such as 4-BOC-aminopiperidino-carbonyl, 4-BOC-aminopiperidinoacetyl; 4-dialkylamino-piperidino-CmH2~-CO- such as 4-dimethylaminopiperidino-carbonyl, 4-dimethylaminopiperidinoacetyl; 4-alkoxycarb-onylaminopiperidino-CmH2m-CO- such as 4-ethoxycarbonyl-aminopiperidinocarbonyl, 4-methoxycarbonylaminopiperi-dinoacetyl; 4-guanidinopiperidino-C H2m-CO- such as 4-guanidinopiperidinocarbonyl, 4-guanidinopiperidinoacetyl;
4-carboxypiperidino-C H2m-CO- such as 4-carboxypiperidino-carbonyl, 4-carboxypiperidinoacetyl; 4-alkoxycarbonyl-piperidino-C~H2~-CO- such as 4-methoxycarbonylpiperidino-carbonyl, 4-ethoxycarbonylpiperidinocarbonyl, 4-methoxy-carbonylpiperidinoacetyl, 4-ethoxycarbonylpiperidino-acetyl; 4-AcNH-piperidino-C.H2.-CO- such as 4-acetamidopiperidinocarbonyl, 4-acetamidopiperidino-acetyl; morpholino-C H2m-CO- such as morpholinocarbonyl or morpholino w etyl; 4-BOC-piperazino-C H2m-CO- such as 4-BOC-piperazinocarbonyl or 4-Boc-piperazinoacetyl;
H2N-C(=NH)-NH-C H2m-CO- such as guanidinoacetyl, 3-guani-dinopropionyl, 4-guanidinobutyryl, 5-guanidinopentanoyl, 6-guanidinohexanoyl, 7-guanidinoheptanoyl, 8-guanidino-octanoyl; NC-NH-C(=NH)-NH-CmH2m-CO- such as N'-cyano-guanidinoacetyl, 3-(N'-cyanoguanidino)propionyl, 4-(N'-cyanoguanidino)butyryl, 5-(N'-cyanoguanidino)pentanoyl, 2 ~ 2 6-(N'-cyanoguanidino)hexanoyl, 7-(N~-cyanoguanidino)-heptanoyl, 8-(N'-cyanoguanidino)octanoyl; HOOC-CmH~-CO-such as malonyl, succinyl, glutaryl, adipyl, 6-carboxy-hexanoyl, 7-carboxyheptanoyl, 8-carboxyoctanoyl, 9-carb-S oxynonanoyl, l~-carboxydecanoyl, ll-carboxyundecanoyl;
AOOC-C~H~-CO- such as methoxycarbonylacetyl, 3-methoxy-carbonylpropionyl, 4-methoxycarbonylbutyryl, S-methoxy-carbonylpentanoyl, 6-methoxycarbonylhexanoyl, 7-methoxy-carbonylheptanoyl, 8-methoxycarbonyloctanoyl, 9-methoxy-carbonylnonanoyl, 10-methoxycarbonyldecanoyl, ethoxy-carbonylacetyl, 3-ethoxycarbonylpropionyl, 4-ethoxycarb-onylbutyryl,5-ethoxycarbonylpentanoyl,6-ethoxycarbonyl-hexanoyl, 7-ethoxycarbonylheptanoyl, 8-ethoxycarbonyl-octanoyl, 9-ethoxycarbonylnonanoyl, 10-ethoxycarbonyl-decanoyl; H-S03-CmHam-CO- such as sulfoacetyl, 3-sulfo-propionyl, 4-sulfobutyryl, 5-sulfopentanoyl, 6-sulfohexa-noyl, 7-sulfoheptanoyl, 8-sulfooctanoyl, 9-sulfononanoyl, 10-sulfodecanoyl; A-SO3-CmHam-CO- such as methoxysulfonyl-acetyl, 3-methoxysulfonylpropionyl, 4-methoxysulfonyl-butyryl, 5-methoxysulfonylpentanoyl, 6-methoxysulfonyl-hexanoyl, 7-methoxysulfonylheptanoyl, 8-methoxysulfonyl-octanoyl, 9-methoxysulfonylnonanoyl, 10-methoxysulfonyl-decanoyl, ethoxysulfonylacetyl, 3-ethoxysulfonyl-propionyl, 4-ethoxysulfonylbutyryl, 5-ethoxysulfonyl-pentanoyl, 6-ethoxysulfonylhexanoyl, 7-ethoxysulfonyl-heptanoyl, 8-ethoxysulfonyloctanoyl, 9-ethoxy~ulfonyl-nonanoyl, 10-ethoxysulfonyldecanoyl; Rff-CmH~-O-CO-, in particular A-O-CO- ~uch as ETOC, IPOC, BOC and also Ar-C~Ham-O-CO- such as CBZ; R5-CmHam-Co-, in particular A-CO- such as acetyl, trimethylacetyl or 3,3-dimethyl-butyryl, but also formyl; or R6-SOz- such as A-SO2-, preferably methylsulfonyl.
The compounds of the formula I can have one or more chiral centres and therefore occur in different - optically active or optically inactive - forms. The formula I includes all these forms. If R3 differs from H
and/or R4 is (H, OH) or (H, NHa), the 2R-hydroxy, 2R-amino, 3S-aminoj 2R-hydroxy-3S-amino and 2R,3S-diamino enantiomers are preferred (the C atom which carries the - 13 - 203~92 radical R4 being allocated the 2-position and the C atom which carries the radicals X-W-CRlR2-C0-Y-NH and R3 being allocated the 3-position.
The abovementioned cycloalkyl and phenyl groups are preferably unsubstituted or preferably carry 1 to 3, in particular 1 or 2 substituents.
The invention accordingly relates in particular to those compounds of the formula I in which at least one of the said radicals has one of the abovementioned preferred meanings. Some preferred groups of compounds can be expressed by the following sub-formulae Ia to Ik:
Ia H-W-CRlR2-Co-Y-NH-CHR3-CR4-CooR5;
Ib R6--O--CmH2o~--Co-W-CRlR2-Co-Y-NH-CHR3--CR4-CooR5;
IC R6-CmH2~-O-CO-W--CRlR2-CO--Y-NH-ClIR3-CR4-CoOR5;
Id R6-CmH2~-Co-W-CRlR2-Co-Y-NH-CHR3-CR4-CooR5;
Ie R7R8N--CmH2m--CO--W-CRlR2-Co-Y-NH-CHR3--CR4-CooRs;
I f R9-NH-C ( =NH ) -NH-CmH2o,-Co-W-CRlR2-Co-Y-NH-CHR3-CR4-CooR5;
Ig R700C-CmH2.-Co-W-CRlR2-Co-Y-NH-CHR3-CR4-CooR5;
Ih R703S-CmH2.-Co-W-CRlR2-Co-Y-NH-CHR3-CR4-CooR5;
I i R7-o- ( CH2CH20 ) n-CmH2",-CO--W--CRlR2-CO--Y--NH--CHR3-CR4--CooR5;
I ~ R7RaN-Co-W-CRlR2-Co-Y-NH-CHR3-CR4-CooR5;
Ik 4-Aminopiperidinocarbonyl-W-CRlR2-CO-Y-NH-CHR3-CR4-cooR5 .
~articularly preferred compounds are those of the sub-formulae:
(a) Iaa to Ika which correspond to the formulae Ia to Ik, but in which additionally -W-CRlR2-C0- is Phe, Pla, Nal or 3 0 -CH2-CH ( CH2C~Hs ) ~CO~;
(b) Iab to Ikb and also Iaab to Ikab, which correspond to the formulae Ia to Ik and also Iaa to Ika, but in which additionally Y is ~Ala. 5 (c) Iac to Ikc, Iaac to Ikac and also Iabc to Ikbc, which correspond to the formulae Ia to Ik, Iaa to Ika and also Iab to Ikb, but in which additionally - 14 - 2~992 R3 is cyclohexylmethyl.
Particularly preferred compounds are those of the sub-formulae:
I and Ia to Ik , which correspond to the formulae I and also Ia to Ik and those compounds which correspond to the other abovementioned sub-formulae, but in which additionally R4 is (H, OH);
I~ and Ia~ to Ik~, which correspond to the formulae I and also Ia to Ik and those compounds which correspond to the other abovementioned sub-formulae, but in which additionally R5 is alkyl having 1-3 C atoms.
A particularly preferred group of compounds corresponds to the formula I
in which X is H, AO-CO-, H-CO-, 4-BOC-aminopiperidinocarbonyl, 4-hydroxypiperidinocarbonyl, 4-aminopiperidinocarb-onyl, 4-A2N-piperidinocarbonyl, 4-AOOC-NH-piperi-dinocarbonyl, piperazinocarbonyl, 4-BOC-piperazino-carbonyl, morpholinocarbonyl or A-SO2-, -W-CRlRZ-cO- i8 Phe or Pla, Y i~ ~Ala or Isoser, R3 is cyclohexylmethyl, R~ is (H, OH) and R5 is alkyl having 1-3 C atoms.
The compounds of the formula I and also the starting substances for their preparation are otherwise prepared by methods known per se, such as are described in the literature (for example in the standard works such as Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart;
and in addition EP-A-45,665, EP-A-77,028, EP-A-77,029, EP-A-81,783 and EP-A-249,096), to be precise under reaction conditions which are known and suitable for the i said reactions. Use can also be made here of variants which are known per se but are not mentioned here in greater detail.
The starting substances, if desired, can also be 2 a ~ 2 formed in 8itU, such that they are not isolated from the reaction mixture, but Lmmediately reacted further to give the compounds of the formula I.
The compounds of the formula I can be obtained by setting them free from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogen-olysis.
Preferred starting substances for the solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and/or hydroxy groups contain correspondingly protected amino and/or hydroxy groups, preferably those which in~tead of an H atom which is bonded to an N atom, carry an amino protective group, for example those of the formula I, but instead of an His group contain an N(im)-R~-His group (in which R~ is an amino protective group, for example BOM or DNP), or those of the formula X-W-CR1RZ-Co-Y-NH-CHR3-CH(NHR~)-CooR5.
In addition, starting substances are preferred which instead of the H atom of a hydroxy group carry a hydroxy protective group, for example those of the formula X-~-CRlRZ-Co-Y-NH-CHR3-CHoR~-CooR5~ in which R~ is a hydroxy protective group.
Several - identical or different - protected amino and/or hydroxy groups can also be present in the molecule of the starting substance. If the protective groups present are different from one another, they can in many cases be removed selectively.
The expression ~amino protective group~ is generally known and relates to groups which are suitable for protecting an amino group from chemical reactions (for blocking), but which are easily removable after the desired chemical reaction has been carried out at another site in the molecule. Typical of such groups are in particular unsubstituted or substituted acyl, aryl (for example DNP), aralkoxymethyl (for example BOM) or aralkyl groups (for example benzyl, 4-nitrobenzyl, triphenyl-methyl). Since the amino protec~ive groups are removed 2 ~ 9 2 after the desired reaction (or reaction sequence), their nature and size is otherwise not critical; but those with 1-20 C atoms, in particular 1-8 C atoms, are preferred.
The expression ~acyl group" is to be interpreted in the widest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and also in particular alkoxycarbonyl, aryloxy-carbonyl and aralkoxycarbonyl groups. Examples of acyl groups of this type are alkanoyl such as acetyl, propion-yl or butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as POA;
alkoxycarbonyl such as methoxycarbonyl, ETOC, 2,2,2-tri-chloroethoxycarbonyl, IPOC, BOC, 2-iodoethoxycarbonyl;
aralkyloxycarbonyl such as CBZ, 4-methoxybenzyloxy-carbonyl and FMOC. Preferred amino protective groups are BOC, DNP and BOM, and in addition CBZ, FMOC, benzyl and acetyl.
The expression ~hydroxy protective group~ is likewise generally known and relates to groups which are suitable for protecting a hydroxy group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at another site in the molecule. Typical of such groups are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, and in addition also alkyl groups. The nature and size of the hydroxy protective groups is not critical, since they are removed again after the desired chemical reaction or reaction sequence; groups with 1-20 C
atoms, in particular 1-10 C atoms, are preferred.
Examples of hydroxy protective groups are, among others, tert.-butyl, benzyl, p-nitrobenzoyl, p-toluenesulfonyl and acetyl, benzyl and acetyl being particularly preferred.
The functional derivatives of the compounds of the formula I to be used as starting substances can be prepared by customary methods of amino acid and peptide synthesis, such as, for example, are described in the said standard works and patent applications, for example 2050~92 also by the solid phase method according to Merrifield.
The compounds of the formula I are set free from their functional derivatives - depending on the protec-tive group used - for example with strong acids, expedi-ently with trifluoroacetic acid or perchloric acidl butalso with other strong inorganic acids such as hydro-chloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene- or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary.
Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such a~ DMF, halogenated hydrocarbons such as dichloromethane, and in addition also alcohols such as methanol, ethanol or isopropanol and also water. In addition, mixtures of the abovementioned solvents are suitable. Trifluoroacetic acid i~ preferably used in excess without addition of a further solvent, perchloric acid in the form of a mixture of acetic acid and 70 % perchloric acid in the ratio 9;1.
The reaction temperatures for the cleavage are expedi-ently between about O and about 50; the reaction is preferably carried out between 15 and 30 (room tempera-ture).
The BOC group can, for example, preferably beremoved with 40 % trifluoroacetic acid in dichloromethane or with about 3 to 5 N HCl in dioxane at 15-30C, the FMOC group with an about 5-20 % solution of dimethyl-amine, diethylamine or piperidine in DMF at 15-30. The DNP group is also removed, for example, with an about 3-10 % solution of 2-mercaptoethanol in DMF/water at 15-30.
Protective groups which can be removed by hydro-genolysis (for example BOM, CBZ or benzyl) can be removed, for example, by treating with hydrogen in the presence of a catalyst (for example a noble metal cata-lyst such as palladium, expediently on a support such as carbon). Suitable solvents in thiY case are the 2 ~ 2 abovementioned, in particular, for example, alcohols such as methanol or ethanol or amides such as DNF. The hydro-~enolysis is as a rule carried out at temperatures between about 0 and 100 and at pressures between about 1 and 200 bar, preferably at 20-30 and at 1-10 bar. The CBZ group is easily hydrogenolysed, for example, on 5-10 ~ Pd-C in methanol at 20-30.
Compounds of the formula I can also be obtained by direct condensation (peptide synthesis) from a car-boxylic acid component (formula II) and a hydroxyl or amino component (formula III). Suitable carboxylic acid components are, for example, those of the sub-formulae (a) X-OH, (b) X-W-CRlR2-COOH or (c) X-W-CR1R2-CO-Y-OH, suitable hydroxyl or amino components are thoqe of the sub-formulae (a) HW-CRlR2-Co-Y-NH-CHR3-CR4-CooR5, (b) H-Y-NH-CHR3-CR4-CooR5 or ( c ) H2N-CHR3-CR4-CooR5 .
The reaction is expediently carried out in this case by customary methods of peptide synthesis, such as are described, for example, in Houben-Weyl, loc.cit., Volume 15/II, pages 1-806 (1974); these methods can also be transferred, if W = O, to the conden~ation according to (a)~ an ester bond being formed.
The reaction is preferably carried out in the presence of a dehydrating agent, for example of a carbo-diimide such as DCCI or dimethylaminopropylethyl-carbodiimide, and in addition propanephosphonic anhydride (cf. Angew. Chem. 92, 129 (1980)), diphenylphosphoryl azide or 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, in an inert solvent, for example a halogenated hydro-carbon such as dichloromethane, an ether such as THF or dioxane, an amide such as DMF or dimethylacetamide, or a nitrile such as acetonitrile, at temperatures between about -10 and 40, preferably between 0 and 30.
Instead of II or III, suitable reactive deriva-tives of these substances can also be employed in the reaction, for example those in which reactive groups are intermediately blocked by protective groups. The acid 19 20~0~92 derivatives II can be used, for example, in the form of their activated ester~, which are expediently formed in situ, for example by addition of HOBt or N-hydroxy-succinimide.
The starting sub~tances of the formulae II and III are for the greatest part known. If they are not known, they can be prepared by known methods, for example the abovementioned methods of condensation and removal of protective groups.
If desired, a functionally modified amino and/or hydroxy group in a compound of the formula I can be set free by solvolysi5 or hydrogenolysis according to one of the methods described above.
Thus, for example, a compound of the formula I
lS which contains an R9-C~H2~-O-CO-NH-, an AcNH- or an AOOC-group can be converted into the corresponding compound of the formula I which instead of this contains an H2N- or an HOOC-group, expediently by selective solvolysis according to one of the abovementioned methods. AOOC-groups can be hydrolysed, for example, with NaOH or KOH
in water-dioxane at temperatures between O and 40, preferably 10 and 30.
It is also possible to acylate a compound of the formula I which contains a free primary or secondary amino group. Thus, in particular, compounds of the formula I, in which X is H, can be reacted with acylating agents of the formula X-Cl or X-Br (in which X is differ-ent from H), expediently in the presence of an inert solvent such as THF and/or of a base such as pyridine or triethylamine at temperatures between -10 and +30.
Furthermore, keto compounds of the formula I
(R~ = O) can be reduced to compounds of the formula I
~R4 = (H, OH)], for example with a complex metal hydride such as NaBH4, which does not simultaneously reduce the peptide carbonyl groups, in an inert solvent such as methanol at temperature~ between about -10 and +30.
Reto compounds of the formula I (R4 = O) can also be converted into compounds of the formula I (R4 = H, NH2) by reductive amination. Reductive amination can be - 20 - 2~ 92 carried out in one or more steps. Thus, for example, the keto compound can be treated with ammonium salts, for example ammonium acetate, and NaCNBH3, preferably in an inert solvent, for example an alcohol such as methanol, at temperatures between about 0 and 50, in particular between 15 and 30. It is furthermore possible to convert the keto compound into the oxime first with hydroxylamine in a customary manner and to reduce this, for example by catalytic hydrogenation on Raney nickel, to the amine.
If desired, an ester of the formula I in which R5 = A can be hydrolysed to the corresponding acid of the formula I in which R5 = H, for example with sodium hydroxide or potassium hydroxide, in a lower alcohol such as methanol or ethanol at temperatures between about 0 and +30-. Conversely, an acid of the formula I (R5 = H) can be esterified to give the corresponding ester of the formula I (R5 = A), for example with diazoalkanes such as diazomethane in dioxane or with an alkyl halide such as methyl iodide or isopropyl bromide in an inert solvent such as DMF in the presence of a base such as potassium carbonate at temperatures between about 0 and +30.
A base of the formula I can be converted into the respective acid addition salt using an acid. Suitable acids for this reaction are in particular those which give physiologically acceptable salts, thus inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophos-phoric acid, sulfamic acid, and in addition organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, trifluoroacetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2 ~ ~ O ~ 9 2 -p-toluenesulfonic acid, naphthalenemonc- and -disulfonic acids, and laurylsulfuric acid. Salts with physiologic~
ally unacceptable acids, for example picrates, can ~e used for the isolation and/or purification of the compounds of the formula I.
The novel compounds of the formula I and their physiologically acceptable salts can be used for the production of the pharmaceutical prepaxations by bringing them into a suitable dosage form together with at least one e~cipient or auxiliary and, if desired, together with one or more other active compound(s). The preparations thus obtained can be employed as medicaments in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral or rectal) or parenteral administration or for administration in the form of an inhalation spray and do not react with the novel compounds, for example water, vegetable oils t benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty acid glycerides, gelatin, soya lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc or cellulose. For oral administration, tablets, coated tablets, capsules, syrups, juices or drops are used in particular; especi-ally of interest are coated tablets and capsules having enteric coaltings or capsule shells. Suppositories are used for rectal administration, and solutions, preferably oily or aqueous solutions, and in addition suspensions, emulsions or implants are used for parenteral admini-stration. For administration as inhalation sprays, sprays can be used which contain the active compound either dissolved or suspended in a propellant gas mixture (for example fluorochlorohydrocarbons). The active compound in this case is expediently used in micronised form, it being po~sible for one or more additional physiologically tolerable solvents to be present, for example ethanol.
Inhalation solutions can be administered with the aid of customary inhalers. The novel compounds can also be lyophilised and the lyophilisates obtained used, for ex~mple, for the production of in~ection preparations.
- 22 ~
The preparations mentioned can be sterilised and/or can contain auxiliaries such as preservatives, stabilisers and/or wetting agents, emulsifiers, s~lts for aff~cting the osmotic pressureJ buffer substances, colourants and~or flavourings. If desired, they can also contain one or more other active compounds, for example one or more vitamins.
The substances according to the invention are as a rule administered in analogy to other known commer-cially available peptides, but in particular in analogy to the compounds described in EP-A-249,096, preferably in dosages be~ween about 10 mg and 1 g, in particular between 50 and 500 mg per dosage unit. The daily dosage is preferably between about 0.2 and 20 mg/kg, in parti-cular bet~een 1 and 10 mg/kg of body weight. The specific dose for each specific patient, howe~er, depends on a wide variety of factors, for example on the activity of the ~pecific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and route of administration, and on the excretion rate, medicament combination and severity of the particular disease to which the treatment applies. Parenteral administration is preferred. Renin-dependent hypertension and hyperaldosteronism can be effectively treated by ~5 administration of dosages between, in particular, about 0.2 and 20, preferably between 1 and l0 mg/kg of body weight. For diagnostic purposes the novel compounds can expediently be administered in individual doses between about 0.1 and 10 mg/kg of body weight.
Above and below, all temperatures are indicated in C. In the following examples "customary working up"
means: water is added if necessary, the pH is adjusted to between 2 and 8, depending on the constitution of the final product, the mixture is extracted with ethyl acetate or dichloromethane, the organic phase is separ~
ated off, dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel and/or crystallisation. TFA = trifluoroacetate. FAB =
mass spectrum by the "fast atom bombardment" methodO
- 23 - 2~ 92 Example 1 1 g of isopropyl 3S-[tert.-butoxycarbonyl-L-(N-imi-benzyloxymethylhistidyl)-~-alanylamino]-4-cyclohexyl-2R-hydroxybutyrate [= I~isopropyl 3S-(BOC-(imi-BOM-His)-S ~Ala-amino)-4-cyclohexy1-2R-hydroxybutyrate~; obtainable by condensation of BOC-(imi-BOM-His)-~-Ala-OH with isopropyl 3S-amino-4-cyclohexyl-2R-hydroxybutyrate] is dissolved in 30 ml of ethanol, and hydrogenated on 0.3 g of 10% Pd-C at 20 and 1 bar until Hz absorption has stopped, the mixture is filtered and evaporated and iso-propyl 3S-(BOC-His-~Ala-amino)-4-cyclohexyl-2R-hydroxy-butyrate is obtained after chromatographic purification on silica gel.
Isopropyl 3S-(4-carboxypiperidinocarbonyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate is obtained analogously by hydrogenolysis of isopropyl 3S-(4-benzyl-oxycarbonylpiperidinocarbonyl-Phe-~Ala-amino)-4-cyclo-hexyl-2R-hydroxybutyrate.
Example 2 A mixture of 1 mmol of ethyl 3s-[Boc-(imi-DNp-His)-~Ala-amino]-4-cyclohexyl-2R-hydroxybutyrate (obtain-able by condensation of ethyl BOC-(imi-DNP-His)-~-Ala-OH
with 3S-amino-4-cyclohexyl-2R-hydroxybutyrate], 2 g of 2-mercaptoethanol, 20 ml of DMF and 20 ml of water i8 ad~usted to pH 8 with stirring at 20 using aqueous Na2CO3 solution and the mixture is stirred at 20 for a further 2 hours. Customary working-up gives ethyl 3S-(BOC-His-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate.
Example 3 A solution of 2.15 g of methyl 3S-amino-4-cyclo-hexyl-2R-hydroxybutyrate in 60 ml of dichloromethane is treated with 1.01 g of N-methylmorpholine. 4.5 g of 4-BOC-aminopiperidinocarbonyl-Phe-~Ala-OH, 1.35 g of HOBt and a solution of 2.06 g of DCCI in 50 ml of dichloro-methane are added with stirring, the mixture is ~tirred at 0-5 for 12 hours, the precipitated dicyclohexylurea is filtered off and the filtrate is evaporated. Customary working-up gives methyl 3S-(4-BOC-aminopiperidino-carbonyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate~
20~0~92 m.p. 113-114.
Example 4 Isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate, m.p. 104-105, is obtained analogously to Example 3 using iso-propyl 3S-amino-4-cyclohexy1-2R-hydroxybutyrate.
Example 5 Isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-Phe-Isoser-amino)-4-cyclohexyl-2R-hydroxybutyrate~2isomers~
m.p. 115-116 and m.p. 102-103 respectively, are obtained analogously to Example 3 using 4-BOC-amino-piperidinocarbonyl-Phe-Isoser-OH and isopropyl 3S-amino-4-cyclohexyl-2R-hydroxybutyrate.
Example 6 The following are obtained from isopropyl 3S-amino-4-cyclohexyl-2R-hydroxybutyrate analogously to Example 3 (a) isopropyl 3S-(BOC-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate, m.p. 120-122, using BOC-Phe-~Ala-OH;
(b) isopropyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxy-piperidinocarbonyl-Phe-~Ala-amino)-butyrate, m.p.
120-121-, using 4-hydroxypiperidinocarbonyl-Phe-~Ala-OH;
(c) i8opropyl 3S-(4-BOC-piperazinocarbonyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate,m.p.86-87-, using 4-BOC-piperazinocarbonyl-Phe-~Ala-OH;
(d) isopropyl 4-cyclohexyl-2R-hydroxy-3S-(morpholino-carbonyl-Phe-~Ala-amino)-butyrate, m.p. 112-113, using morpholinocarbonyl-Phe-~Ala-OH;
(e) isopropyl 4-cyclohexyl-3-(4-dimethylaminopiperidino-carbonyl-Phe-~Ala-amino)-2R-hydroxybutyrate, hydro-chloride, m.p. 219-220, using 4-dimethylamino-piperidinocarbonyl-Phe-~Ala-OH;
(f) isopropyl 4-cyclohexyl-3-(4-ethoxycarbonylamino-piperidinocarbonyl-Phe-~Ala-amino)-2R-hydroxy-butyrate using 4-ethoxycarbonylaminopiperidino-carbonyl-Phe-~Ala-OH;
2~0~92 (g) isopropyl 4-cyclohexyl-3-(4-ethoxycarbonylpiperi-dinocarbonyl-Phe-~Ala-amino)-2R-hydroxybutyrate, m.p. 117-118, using 4-ethoxycarbonylpiperidino-carbonyl-Phe-~Ala-OH; (h) isopropyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxy-piperidinocarbonyl-Phe-Isoser-amino)-butyrate using 4-hydroxypiperidinocarbonyl-Phe-Isoser-OH.
Example 7 The following are obtained from 4-hydroxypiperi-dinocarbonyl-Phe-~Ala-OH analogou~ly to Example 3 (a) methyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxypiperi-dinocarbonyl-Phe-~Ala-amino)-butyrate using methyl 3S-amino-4-cyclohexyl-2R-hydroxybutyrate;
(b) ethyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxypiperi-15dinocarbonyl-Phe-~Ala-amino)-butyrate using ethyl 3S-amino-4-cyclohexyl-2R-hydroxybutyrate;
(c) n-butyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxypiperi-dinocarbonyl-Phe-~Ala-amino)-butyrate using n_butyl 3S-amino-4-cyclohexyl-2R-hydroxybutyrate;
20(d) cyclohexyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxy-piperidinocarbonyl-Phe-~Ala-amino)-butyrate using cyclohexyl 3S-amino-4-cyclohexyl-2R-hydroxybutyrate;
(e) i80propyl 2R-hydroxy-3S-(4-hydroxypiperidino-carbonyl-Phe-~Ala-amino)-5-methylhexanoate using 25isopropyl 3S-amino-2R-hydroxy-5-methylhexanoate;
(f) isopropyl 2R-hydroxy-3S-(4-hydroxypiperidino-carbonyl~Phe-~Ala-amino)-4-phenylbutyrate using isopropyl 3S-amino-2R-hydroxy-4-phenylbutyrate;
Example 8 30The following are obtained from isopropyl 4-cyclohexyl-2R-hydroxy-3S-(H-Phe-~Ala-amino)butyrate analogously to Example 3 (a) isopropyl 3S-(3-BOC-amino-3-methylbutyryl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate using 3-BOC-35amino-3-methylbutyric acid;
(b) isopropyl 3S-(6-BOC-aminohexanoyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate using 6-BOC-amino-hexanoic acid;
.
(c~ isopropyl 4-cyclohexyl-2R-hydroxy 3S-(3,6 t 8-trioxa-nonanoyl-Phe-~Ala-amino)-butyrate using 3,6,8-trioxanonanoic acid.
Example 9 The following are obtained from isopropyl 3S- (H-~Ala-amino)-4~cyclohexy1-2R-hydroxybutyrate [FAB: M -~ 1 = 315; obtainable by condensation of CBZ-~Ala-OH with isopropyl 3S-amino~4-cyclohexyl-2R~hydroxybutyrate to ~ive isopropyl 3S-(CBZ-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate ~FAB: M + 1 = 449) and hydrogenolysis]
analogously to Example 3 (a) isopropyl 4-cyclohexyl-2R-hydroxy-3S~(H Pla-~la-amino)-butyrate, m.p. 54-55l using H-Pla-OH;
(b) isopropyl 3S-(H-CO-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyxate, m.p. 108 tdec.), using H-CO Phe~
OH;
(c) isopropyl 4-cyclohexyl-2R-hydroxy-3S-(morpholino-carbonyl-Pla-~Ala-amino)-butyrate using moxpholino-carbonyl-Pla-OH;
(d) to (m) using acids of the formula 4-~OC-aminopiperi-dinocarbonyl-Z-OH
(Z = Ada, Calf Leu, Mal, Nle, Pla, 2-Tia, 2-Tiz, Trp and Tyr respectively);
(d) isopropyl 3S (4-BOC-aminopiperidinocarbonyl-Ada-~Ala-ami.no)-4-cyclohexyl-2R-hydroxybutyrate;
(e) isopropy~l 3S-(4-BOC-aminopiperidinocarbonyl-Cal-~Ala-ami.no)-4-cyclohexyl-2R-hydroxybutyrate;
(f) isopropyl 3S-~4-BOC-aminopiperidinocarbonyl-Leu-~Ala-ami.no)-4-cyclohexyl-2R-hydroxybutyrate;
(g) isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-Mal-~Ala~amino)-4-cyclohexyl-2R-hydroxybutyrate;
(h) isopropyl 3S-(4-BOC-aminopiparidinocarbonyl-Nle-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate;
(i.) isopropyl 3S-(4-BOC-aminopiperidinocar~onyl-Pla-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate;
(~) isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-2-Tia-~Ala amino)-4-cyclohexyl-2R-hydroxybutyrate;
(k) isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-2~Tiz-~Ala-amino)-4 cyclohexyl-2R-hydroxybutyxate;
- 27 - 2 05 ~9 2 (1) isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-Trp-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate;
(m) isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-Tyr-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate.
Example 10 A mixture of 461 mg of isopropyl 4-cyclohexyl-2R-hydroxy-3S-(H-Phe-~Ala-amino)-butyrate, 115 mg of tri-methylsilyl isocyanate and 25 ml of THF is stirred at 20 for 2 hours. 2.5 ml of 1 N aqueous hydrochloric acid are added to remove the protective group, the mixture is stirred at 20 for a further 15 min, and worked up in the customary manner to give isopropyl 3S-(N-carbamoyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate.
Example 11 A mixture of 461 mg of isopropyl 4-cyclohexyl-2R-hydroxy-3S-(H-Phe-~Ala-amino)-butyrate, 71 mg of ethyl isocyanate and 25 ml of THF is stirred at 20 for 3 hours. The mixture i8 worked up in the customary manner to give isopropyl 4-cyclohexyl-3S-tN-(N-ethylcarbamoyl)-Phe-~Ala-amino~-2R-hydroxybutyrate.
Example 12 A solution of 1 g of methyl 3S-(4-~OC-amino-piperidinocarbonyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate in 20 ml of dichloromethane and 20 ml of trifluoroacetic acid i8 3tirred at 20 for 1 hour and then evaporated. Methyl 3S-(4-aminopiperidinocarbonyl-Phe-~Ala-amino)-4-cyclohexy1-2R-hydroxybutyrate, TFA, m.p. 163-164, are obtained.
The following are obtained analogously by cleav-ing the appropriate BOC derivatives with trifluoroacetic acid:
isopropyl 3S-(4-aminopiperidinocarbonyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate, TFA, m.p. 185-186, 1/3 citrate, m.p. 119-120 isopropyl 3S-(4-aminopiperidinocarbonyl-Phe-Isoser-amino)-4-cyclohexyl-2R-hydroxybutyrate~ TFA, 2-isomers, m.p. 118-119 and 155-156 re~pectively isopropyl 4-cyclohexyl-2R-hydroxy-3S-(H-Phe-~Ala-amino)-butyrate, TFA, m.p. 77-78 2 ~ ~ O ~ 9 2 isopropyl 4-cyclohexy1-2R-hydroxy-3S-(piperazinocarbonyl-Phe-~Ala-amino)-butyrate, TFA, m.p. 113-114 isopropyl 3S-~3-amino-3-methylbutyryl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate isopropyl 3S-(6-aminohexanoyl-Phe-~Ala-amino)-4-cyclo-hexyl-2R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-Ada-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-Cal-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-Leu-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-Nal-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate isopropyl 3S-~4-aminopiperidinocarbonyl-Nle-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-Pla-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-2-Tia-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-2-Tiz-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate i~opropyl 3S-(4-aminopiperidinocarbonyl-Trp-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-Tyr-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate Example 13 (a) A mixture of 1 g of methyl 3S-(4-~OC-aminopiperi-dinocarbonyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate, 50 ml of dioxane and 20 ml of 2 N
aqueous NaOH ~olution is stirred at 20 for 3 hours.
The mixture i8 worked up in the customary manner and gives 3S-(4-BOC-aminopiperidinocarbonyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyric acid.
(b) The crude acid obtained according to (a) is stirred with 25 ml of DMF, 1 ml of i80propyl iodide and 200 mg of R2C03 for 24 hours. The mixture i8 worked up in the customary manner and gives isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-Phe-~Ala-amino)-4-2~0092 cyclohexyl-2R-hydroxybutyrate, m.p. 104-105.
Example 14 Isopropyl 4-cyclohexyl-2R-hydroxy-3S-(H-Phe-~Ala-amino)-butyrate, TFA, m.p. 77-78, is obtained by hydro-genolysis of isopropyl 3S-(CBZ-Phe-~Ala-amino)-4-cyclo-hexyl-2R-hydroxybutyrate analogously to Example 1.
Example 15 (a) 449 mg of isopropyl 4-cyclohexyl-2R-hydroxy-3S-(H-Phe-~Ala-amino)butyrate are dissolved in 25 ml of THF. A solution of 117 mg of methanesulfonyl chlor-ide in 3 ml of THF is added dropwise with stirring.
The mixture is stirred at 20 for a further 3 hours, and worked up in the customary manner to give isopropyl 4-cyclohexyl-2R-hydroxy-3S-(methane-sulfonyl-Phe-~Ala-amino)butyrate, m.p. 115-116.
(b) Isopropyl 4-cyclohexyl-2R-hydroxy-3S-(isopropyl-sulfonyl-Phe-~Ala-amino)butyrate is obtained analo-gously using isopropylsulfonyl chloride.
(c) Isopropyl 3S-(acetyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate i8 obtained analogously u~ing acetyl chloride.
Example 16 (a) Isopropyl 4-cyclohexyl-3S-~4-hydroxypiperidino-carbonyl-Phe-~Ala-amino)-2-oxobutyrate is obtained from 4-hydroxypiperidinocarbonyl-Phe-~Ala-OH and isopropyl 3S-amino-4-cyclohexyl-2-oxobutyrate analogously to Example 3.
(b) A solution of 1 g of the above ketoester in 25 ml of methanol is hydrogenated on 0.1 g of 10% Pd-C at 20 and 1 bar until absorption of Hz is complete. After filtering and evaporating, a mixture of isopropyl 4-cyclohexyl-2R- and -2S-hydroxy-3S-(4-hydroxypiperi-dinocarbonyl-Phe-~Ala-amino)butyrate is obtained, which can be separated on ~ilica gel.
Example 17 A solution of 586 mg of the ketoester obtainable according to Example 16 (a) and 1.43 g of Na2CO3 10 H20 in 5 ml of methanol and 5 ml of water is treated with 70 mg of hydroxylamine hydrochloride and stirred at 20 2~0~92 for 14 hours. The precipitated oxLme is filtered off, dried, dissolved in 10 ml of methanol and hydrogenated at 20 and 5 bar on 0.4 g of Raney Ni. The catalyst is filtered off, the filtrate is evaporated and the mixture S of isopropyl 2R- and 2S-amino-4-cyclohexyl-3S-(4-hydroxy-piperidinocarbonyl-Phe-~Ala-amino)butyrate obtained is separated.
The examples below relate to pharmaceutical preparations.
Example A: Tablets A mixture of 1 kq of i~opropyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxypiperidinocarbonyl-Phe-~Ala-amino)-butyrate, 4 kg of lactose, 1.2 kg of maize starch, 200 g of talc and 100 g of magnesium stearate i8 compressed to give tablets in a customary manner in such a way that each tablet contains 100 mg of active compound.
Bxample B: Coated tablets Tablets are pressed analogously to Example A, and are then coated in a customary manner with a coating of sucrose, maize starch, talc, tragacanth and colourant.
Example C: Capsules 500 g of isopropyl 3S-(BOC-Phe-~Ala-amino)-4-cycIohexyl-2R-hydroxybutyrate are filled into hard gelatine capsules in a customary manner in such a way that each capsule contains 500 mg of active compound.
Bxample D: In~ection vials A solution of 100 g of methyl 3S-(4-aminopiperi-dinocarbonyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxy-butyrate trifluoroacetate in 4 1 of doubly distilled water is ad~usted to pH 6.5 with 2N hydrochloric acid, sterile filtered and poured into in~ection vials. The solution i8 lyophilised under sterile conditions and the vials are sterile sealed. Each in~ection vial contains 100 mg of active compound.
Example E: Suppositories A mixture of 50 g of isopropyl 4-cyclohexyl-2R-hydroxy-3S-(methanesulfonyl-phe-~Ala-amino)butyrate is fused with 10 g of soya lecithin and 140 g of cocoa - 31 - 2~
butter, poured into moulds and allowed to cool. Each Ruppository contain~ 250 mg of active compound.
X-W-CR1R2-Co-Y-NH-CHR3-CR4-CooRs in which X LS H, R6-O--CmH2m-CO--I R~-CmH2m-O-CO--, R6-CmH2m-CO-, R6-SO2-, R7R3N-C~H2m-Co-, R9-NH-C(=NH)-NH-CmH2m--CO--~ R700C-CmH2m-Co--~ R703S-CmEI2m-CO--~
R7-o-(CH2CH2o)~-CmH2m-co- or A3N -CmH2m-CO- An W i8 O or NH, Y is ~Ala or Isoser, R , R
and R8 are each H or A, R , R
and R6 are each H, A, Ar, Ar-alkyl, Het, Het-alkyl, cycloal.kyl having 3-7 C atoms, which is unsub-~ti.tuted or monosubstituted or polysub~tituted by A, AO and/or Hal, cycloalkylalkyl having 4-11 C atoms, bicycloalkyl or tricycloalkyl each ha~ing 7 14 C atoms, or bicycloalkylalkyl or tri.cycloalkylalkyl each having 8-18 C atoms, R4 is (H, OH), (H, NH2) or =O, Rs is H, A or cycloalkyl having 3-7 C atoms, R7R8N is also an unsubstituted pyrrolidino, piperid-ino, morpholino or piperazino group or one which is suhstituted by A, OH, NH2~ NHAr NA2 NH~c, NH-CO-CIH2~-O-R9, NH-co-o-c~H2x-R ~
hydroxyalkyl, COOH, COOA, CONH2, aminoalkyl, HAN-alkyl, A2N-alkyl, A3N~alkyl Ane, NH-CO-NH2, NH-CO-NHA, guanidinyl or guanidinylalkyl, R is M, A, Ar-alkyl or CN, m and x are each 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, n is 0, 1, 2 or 3, - 2 ~ 2~ 2 Ax is unsubsti~uted phenyl or phenyl which is monosubstituted or polysubstituted by A, OA, Hal, CF3, OH, NO2, hydroxyalkyl, NH2, NHA, NAz, NHAc, NH-S02-A, SA, SO-A, SO2-A, SO2NH2~ S02NHA, COOH, COOAI CONH2r CN, ~ninoalkyl, HAN-alkyl, A2N-alkyl,A3N~-alkyl Aneand/orguanidinylalkyl, or is unsubstituted naphthyl, Het is a saturated or unsaturated 5- or 6-membered heterocyclic radical having 1-4 N, O andJor S
atoms, which can ~e fused to a benzene ring and/or monosubstituted or polysubstituted by A, OA, Hal, CF3, OH, NOz, carbonyl oxygen, MH2, NHA, NA2, NHAc, NH-COOA, NHCOO~r, NHCOOCH~Ar, NH-SO2-A, SA, SO-A, SO2-A, SO2NH2, SO2NHA, COOH, COOA, CONH2, CN, Ar, Ar-al~yl, Ar-alkenyl, hydroxyalkyl, aminoalkyl, HAN-alkyl, A2N-alkyl and/or A3N~-alkyl Ane and/or whose N and/or S
heteroatoms can also be oxidised, Hal is F, Cl, Br or I, Ac is A-CO-, Ar-CO , Ar-alkyl-CO- or A-NH-CO-, Ane is an anion, which can also be absent, if instead of this a carboxyl group contained in the compound of the formula I i5 present in the fo~n of a carboxylate anion, -alkyl is an alkylene group having 1-8 C atoms and A is alkyl having 1~8 C atoms, in which in addition instead of one or more ~NH-CO groups there can also be one or more -NA-CO groups, and their ~alts.
Similar compounds are disclosed in EP-A-249,096.
The invention was based on the object of finding novel compounds having useful properties, in particular those which can be used for the preparation of medica-ments.
3S It ha~ been found that the compounds of the formula I and their salts have very useful properties. In particular~ they inhibit the activity of human plasma renin. This action can be detected, for example, by the method of F. Fyhrqui~t et al., Clin. Chem. 22/ 250-256 - 3 - 2050~92 (1976). It is noteworthy that these compounds are very specific inhibitors of renin; as a rule about 100 to 1000 times as high concentrations of these compounds are necessary for the inhibition of other aspartylproteinases (for example pepsin and cathepsin D) as for renin inhi-bition. The actions of the compounds on the blood pres-sure and/or on the heart rate and the inhibition of the renin activity in the blood plasma can additionally be determined in conscious monkey~, for example female monkeys (Macaca fascicularis); in this connection blood pressure and heart rate can be measured following the method of M.J. Wood et al., J. Hypertension 4, 251-254 (1985). To stimulate renin activity, the animals are in thi~ case expediently pretreated with a saluretic. Blood ~amples for determining the plasma renin activity can be obtained by puncture of the femoral vein.
The compounds can be employed as medicament - active compounds in human and veterinary medicine, in particular for the prophylaxis and for the treatment of cardiac, circulatory and vascular diseases, in particular hypertension, cardiac insufficiency and hyperaldo-steronism. In addition, the compounds can be used for diagnostic purposes in patients with hypertension or hyperaldosteronism in order to determine the possible contribution of the renin activity to the maintenance of the pathological condition. Such diagnostic tests can be carried out in a similar manner to that given in EP-A-77,028.
The abbreviations of amino acid radicals mentioned above and below are for the radical~ -NR'-Rn-CO-, as a rule -NH-CHR-CO- (in which R, R' and R" have the specific meaning known for each amino acid), of the following amino acids:
Ada 3-(1-adamantyl)alanine Ala alanine ~Ala ~-alanine Bia 3-(2-benzimidazolyl)alanine Cal 3-cyclohexylalanine Gly glycine His histidine Hph homophenylalanine (2-amino 4-phenylbutyric acid) Ile isoleucine Leu leucine ~al 3-(p-methoxyphenyl)alanine Nle norleucine Phe phenylalanine Tia 3-~thienyl)alanine [for example 2-Tia =
3-(2-thienyl)alanine]
Tiz 3-(thiazolyl)alanine [for example 2-Tiz =
3-~2-thiazolyl)alanine]
Trp tryptophan Tyr tyrosine.
In addition, the following hav0 the meaning below:
BOC tert.-butoxycarbonyl BOM benzyloxymethyl imi-BOM benzylo~ymethyl in the l-position of the imidazole ring CBZ benzyloxycarbonyl DCCI clicyclohexylcarbodiLmide DME climethylformamide DNP 2,4-dinitrophenyl imi-DNP 2,4-dinitrophenyl in the l-position of the imidazole ring ETOC ethoxycarbonyl FMOC 'i-fluorenylmethoxycarbonyl HOBt 1-hydroxybenzotriazole IPOC isopropoxycarbonyl Pla the radical of phenyllactic acid -O-CH(CH2C6Hs)~CO- (S-form) PO~ phenoxy~cetyl THF tetrahydrofuran.
If the abovementioned amino acids can occur in several enantiomexic forms, all these forms and also their mixtures (for example the DL-forms) are included above and below, for example as constituents of the compounds of ~he formula 1. The L-forms are preferred. If _ 5 _ 2~3~9~
individual compounds are mentioned below, the abbrevia-tions of these amino acids in each case relate to the L-form, if not expressly stated otherwise.
The invention further relates to a process for the preparation of an amino acid derivative of the formula I and of its salts, characterised in that it is set free from one of its functional derivatives by treating with a solvolysing or hydrogenolysing agent or in that a carboxylic acid of the formula II
X-Gl-OH II
in which Gl (a) is absent, (b) i~ -W-CRlR2_co-~(c) is -W-CRlR2_co_y_, or one of its reactive derivatives is reacted with a compound of the formula III
H - G 2 -NH - CHR3-CR4-CooR5 III
in which G2 (a) i8 -W-CRlR2-CO-Y-, (b) is _y_, ( C ) i8 absent, and in that a functionally modified amino and/or hydroxy group i8 optionally set free in a compound of the formula I by treating with solvolysing or hydrogenolysing agents and/or a free amino group is acylated by treating with an acylating agent and/or an aminoketo acid derivative of the formula I, R4 = O, is reduced or reductively aminated to prepare a compound of the formula I, R~ = (H, OH) or (H, NH2) and/or an ester of the formula I, R5 = A is hydrolysed and/or an acid of the formula I, R5 = H is esterified and/or a compound of the formula I is conver-ted into one of its salts by treating with an acid.
Above and below, the radi-cals or parameters Rl to R~, W, X, Y, m, n, x, Ar, Het, Hal, Ac, An, A, Gl and G2 have the meanings indicated in the formulae I, II or III
- 6 - 20~0~2 unless expressly stated otherwise.
In the above formulae, A has 1-8, preferably 1, 2, 3 or 4 C atoms. A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, or tert.-butyl, additionally also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, l-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, l-ethyl-l-methylpropyl, 1-ethyl-2-methyl-propyl, 1,1,2- or 1,2,2-trLmethylpropyl, heptyl, octyl.
Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but also, for example, 1-, 2- or 3-methylcyclopentyl, or 1-, 2-, 3- or 4-methylcyclohexyl.
Accordingly, cycloalkylalkyl is preferably cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, 2-cyclobutylethyl,cyclopentylmethyl,2-cyclopentylethyl, cyclohexylmethyl, 2-cyclohexylethyl, but also, for example, 1-, 2- or 3-methylcyclopentylmethyl, or 1-, 2-, 3- or 4-methylcyclohexylmethyl.
Bicycloalkyl is preferably 1- or 2-decalyl, 2-bicyclo[2.2.1~heptyl or 6,6-dimethyl-2-bicyclot3.1.11-heptyl.
Tricycloalkyl is preferably l-adamantyl.
Hal is preferably F, Cl or Br, but also I.
Ac is preferably A-C0-, such as acetyl, propionyl or butyryl, Ar-C0- such as benzoyl, o-, m- or p-methoxy-benzoyl or 3,4-dimethoxybenzoyl, or A-NH-C0- such as N-methyl- or N-ethylcarbamoyl.
Ar is preferably phenyl, in addition preferably o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, o-, m- or p-iodophenyl, o-, m- or p-trifluoromethylphenyl, o-, m-or p-hydroxyphenyl, o-, m- or p-sulfamoylphen~l, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, o-, m-, or p-aminophenyl, o-, m-or p-aminomethylphenyl, o-, m- or p-dimethylaminomethyl-phenyl, o-, m- or p-guanidinomethylphenyl, 1- or _ 7 _ 20~92 2-naphthyl.
Accordingly, Ar-alkyl is preferably benzyl, 1- or 2-phenylethyl, o-, m- or p-methylbenzyl, 1- or 2-o-, -m-or -p-tolylethyl, o-, m- or p-ethylbenzyl, 1- or 2-o-, -m- or -p-ethylphenylethyl, o-, m- or p-methoxybenzyl, 1-or 2-o-, -m- or -p-methoxyphenylethyl, o-, m- or p-fluorobenzyl, 1- or 2-o-, -m- or -p-fluorophenylethyl, o-, m- or p-chlorobenzyl, 1- or 2-o-, -m- or -p-chloro-phenylethyl, o-, m- or p-bromobenzyl, 1- or 2-o-, -m- or -p-bromophenylethyl, o-, m- or p-iodobenzyl, 1- or 2-o-, -m- or -p-iodophenylethyl, o-, m- or p-trifluoromethyl-benzyl, o-, m- or p-hydroxybenzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxybenzyl, 3,4,5-trimethoxy-benzyl, o-, m- or p-aminobenzyl o-, m- or p-aminomethyl-benzyl, o-, m- or p-dimethylaminomethylbenzyl, o-, m- or p-guanidinomethylbenzyl, 1- or 2-naphthylmethyl.
Het is preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothi-azolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyr~midinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 2,1,5-thiadiazol-3- or -4-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzo-furyl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-iso-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benæ-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-iso-quinolyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolyl. The 8 2050~2 heterocyclic radicals can also be partially or completely hydrogenated. Het can thus also be, for example, 2,3-di-hydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4-or -5-furyl, tetrahydro-2- or -3-furyl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -S-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -S-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -S-pyrazolyl, tetra-hydro-l-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3-or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-or -6-pyridyl, 1,2,3,6-tetrahydro-1-, -2-, -3-, -4-, -5-or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-di-oxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-l-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl.
The heterocyclic radicals can also be substituted as indicated. Het can also preferably be, for example:
2-amino-4-thiazolyl, 4-carboxy-2-thiazolyl, 4-carbamoyl-2-thiazolyl, 4-(2-aminoethyl)-2-thiazolyl, 4-amino-2-methyl-5-pyrimidinyl, 2-amino-5,6-dimethyl-3-pyrazinyl, 4-carbamoylpiperidino, in addition, for example, 3-, 4-or 5-methyl-2-furyl, 2-, 4- or 5-methyl-3-furyl, 2,4-di-methyl-3-furyl, S-nitro-2-furyl, 5-styryl-2-furyl, 3-, 4-or S-methyl-2-thienyl, 2-, 4- or S-methyl-3-thienyl, 3-methyl-S-tert.-butyl-2-thienyl, S-chloro-2-thienyl, S-phenyl-2- or -3-thienyl, 1-, 3-, 4- or S-methyl-2-pyrrolyl, 1-methyl-4- or -5-nitro-2-pyrrolyl, 3,5-dimeth-yl-4-ethyl-2-pyrrolyl, 4-methyl-5-pyrazolyl, 5-methyl-3-isoxazolyl, 3,4-dimethyl-5-isoxazolyl, 4- or 5-methyl-2-thiazolyl, 2- or 5-methyl-4-thiazolyl, 2- or 4-methyl-5-thiazolyl, 2,4-dimethyl-5-thiazolyl, 3-, 4-, 5- or 6-methyl-2-pyridyl, 2-, 4-, 5- or 6-methyl-3-pyridyl, 2- or 3-methyl-4-pyridyl, 3-, 4-, 5- or 6-chloro-2-pyridyl, 2-, 4-, 5- or 6-chloro-3-pyridyl, 2- or 3-chloro-4-pyridyl, 2,6-dichloropyridyl, 2-hydroxy-3-, -4-, -5- or -6-pyridyl (= lH-2-pyridon-3-, -4-, -5- or 2~0~92 -6-yl),5-phenyl-lH-2-pyridon-3-yl,5-p-methoxyphenyl-lH-2-pyridon-3-yl, 2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl, 2-hydroxy-4-amino-6-methyl-3-pyridyl, 3-N'-methylureido-lH-4-pyridon-5-yl, 4-methyl-2-pyrimidinyl, 4,6-dimethyl-2-pyrimidinyl, 2-, 5- or 6-methyl-4-pyrimid-inyl, 2,6-dimethyl-4-pyrimidinyl, 2,6-dihydroxy-4-pyrLm-idinyl, 5-chloro-2-methyl-4-pyrimidinyl, 3-methyl-2-benzofuryl, 2-ethyl-3-benzofuryl, 7-methyl-2-benzo-thienyl, 1-, 2-, 4-, 5-, 6- or 7-methyl-3-indolyl, 1-methyl-5- or -6-benzimidazolyl, l-ethyl-S- or -6-benz-imidazolyl, 3-, 4-, 5-, 6-, 7- or 8-hydroxy-2-quinolyl, 2-oxopyrrolidino, 2-oxopiperidino, 2,5-dioxopyrrolidino or 3-benzyl-2,5-dioxopyrrolidino.
~ is generally preferably H; R6-C~H2m-O-CO- such as BOC; R6-CmH2m-CO- such as formyl or acetyl; R6-S02-, in particular A-S02- such as methylsulfonyl; R7R3N-CmH2~-Co-, in particular 4-BOC-aminopiperidinocarbonyl, 4-amino-piperidinocarbonyl, 4-hydroxypiperidinocarbonyl, 4-dimethylaminopiperidinocarbonyl, 4-ethoxycarbonylamino-piperidinocarbonyl, morpholinocarbonyl, piperazino-carbonyl or 4-BOC-piperazinocarbonyl.
The group Y is preferably ~Ala.
W i8 preferably NH.
R1, R5, R7, and R8 are each preferably H, in addi-tion preferably methyl; R5 i8 preferably al~o ethyl, propyl, i~opropyl, n-butyl, isobutyl, cyclopentyl or cyclohexyl. R7R~ is preferably also pyrrolidino, piperi-dino, morpholino, aminopiperidino such as 4-aminopiperi-dino, hydroxypiperidino such as 4-hydroxypiperidino, alkylaminopiperidino such as 4-methylaminopiperidino, dialkylaminopiperidino such a~ 4-dimethylaminopiperidino, ethoxycarbonylaminopiperidino such as 4-ethoxycarbonyl-aminopiperidino or BOC-aminopiperidino such a~ 4-BOC-aminopiperidino, morpholino or 4-BOC-piperazino.
R2 is preferably Ar-alkyl, in particular benzyl or p-methoxybenzyl; in addition preferably A, in parti-cular n-butyl or isobutyl; cycloalkylalkyl, in particular cyclohexylmethyl; or Het-alkyl, in particular 2-thienyl-methyl. The group -W-CRlR2-CO- is preferably one of the 20S0~9~
radicals Phe or Pla, in addition Ada, Bia, Cal, His, Hph, Ile, Leu, Mal, Nle, Tia, Tiz, Trp or Tyr.
R3 is preferably cycloalkylalkyl, in particular cyclohexylmethyl, in addition preferably alkyl, in particular n-butyl or isobutyl; Ar-alkyl, in particular benzyl or p-methoxybenzyl; Het-alkyl, for example 2-thienylmethyl; or cycloalkyl, in particular cyclohexyl.
R4 is preferably (H, OH).
R9 is preferably H, methyl or CN.
The parameter m is preferably 1, 2, 3, 4 or 5; n is preferably 1; x is preferably 1 or 2.
CmH~ and CrH~ are preferably straight-chain, that is to say preferably -(CH2) m~ or -(CH2)~-.
Accordin~ly, the group X i8 in particular prefer-ably H; R7R8N-(CH2)m-Co-, in particular H2N-CmH~-CO- such as aminocarbonyl, aminoacetyl (H-Gly~), 3-aminopropionyl (H-~Ala-), 4-aminobutyryl, 5-aminopentanoyl, 6-amino-hexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-amino-nonanoyl, 10-aminodecanoyl, ll-aminoundecanoyl, but also, for example, 2-aminopropionyl (Ala), 2-amino-2-methyl-propionyl, 3-amino-3-methylbutyryl; ANH-CmH~-CO- such as methylaminocarbonyl, ethylaminocarbonyl, methylamino-acetyl (sarcosyl), 3-methylaminopropionyl, 4-methylamino-butyryl, 5-methylaminopentanoyl, 6-methylaminohexanoyl, 6-ethylaminohexanoyl, 7-methylaminoheptanoyl, 8-methyl-aminooctanoyl, 9-methylaminononanoyl, 10-methylamino-decanoyl, ll-methylaminoundecanoyl; AkN-C~H~-CO- such as dimethylaminocarbonyl, dimethylaminoacetyl, 3-dimethyl-aminopropionyl, 4-dimethylaminobutyryl, 5-dimethylamino-pentanoyl, 6-dimethylaminohexanoyl, 6-diethylaminohexan-oyl, 7-dimethylaminoheptanoyl, 8-dimethylaminooctanoyl, 9-dimethylaminononanoyl, 10-dimethylaminodecanoyl, 11-dimethylaminoundecanoyl; pyrrolidino-CmH~-CO- such as pyrrolidinocarbonyl,pyrrolidinoacetyl,3-pyrrolidinopro-pionyl, 4-pyrrolidinobutyryl, S-pyrrolidinopentanoyl, 6-pyrrolidinohexanoyl, 4-pyrrolidinoheptanoyl, 8-pyrroli-dinooctanoyl,9-pyrrolidinononanoyl,10-pyrrolidinodecan-oyl; piperidino-CmH~-CO- such as piperidinocarbonyl, piperidinoacetyl, 3-piperidinopropionyl, 4-piperidino-20~0~2 butyryl, 5-piperidinopentanoyl, 6-piperidinohexanoyl, 7-piperidinoheptanoyl, 8-piperidinooctanoyl, 9-piperidino-nonanoyl, 10-piperidinodecanoyl; morpholino-CmH2m-CO- such as morpholinocarbonyl, morpholinoacetyl, 3-morpholino-propionyl, 4-morpholinobutyryl, 5-morpholinopentanoyl, 6-morpholinohexanoyl, 7-morpholinoheptanoyl, 8-morphol-inooctanoyl,9-morpholinononanoyl,10-morpholinodecanoyl;
4-hydroxypiperidino-CmH2m-CO- such as 4-hydroxypiperidino-carbonyl, 4-hydroxypiperidinoacetyl; 4-aminopiperidino-CmH2m-CO- such as 4-aminopiperidinocarbonyl, 4-amino-piperidinoacetyl, 3-(4-aminopiperidino)propionyl, 4-(4-aminopiperidinojbutyryl, 5-(4-aminopiperidino)pentanoyl, 6-(4-aminopiperidino)hexanoyl, 7-(4-aminopiperidino)hept-anoyl, 8-(4-aminopiperidino)octanoyl, 9-(4-aminopiperi-dino)nonanoyl, 10-(4-aminopiperidino)decanoyl; 4-BOC-aminopiperidino-CmH2m-CO- such as 4-BOC-aminopiperidino-carbonyl, 4-BOC-aminopiperidinoacetyl; 4-dialkylamino-piperidino-CmH2~-CO- such as 4-dimethylaminopiperidino-carbonyl, 4-dimethylaminopiperidinoacetyl; 4-alkoxycarb-onylaminopiperidino-CmH2m-CO- such as 4-ethoxycarbonyl-aminopiperidinocarbonyl, 4-methoxycarbonylaminopiperi-dinoacetyl; 4-guanidinopiperidino-C H2m-CO- such as 4-guanidinopiperidinocarbonyl, 4-guanidinopiperidinoacetyl;
4-carboxypiperidino-C H2m-CO- such as 4-carboxypiperidino-carbonyl, 4-carboxypiperidinoacetyl; 4-alkoxycarbonyl-piperidino-C~H2~-CO- such as 4-methoxycarbonylpiperidino-carbonyl, 4-ethoxycarbonylpiperidinocarbonyl, 4-methoxy-carbonylpiperidinoacetyl, 4-ethoxycarbonylpiperidino-acetyl; 4-AcNH-piperidino-C.H2.-CO- such as 4-acetamidopiperidinocarbonyl, 4-acetamidopiperidino-acetyl; morpholino-C H2m-CO- such as morpholinocarbonyl or morpholino w etyl; 4-BOC-piperazino-C H2m-CO- such as 4-BOC-piperazinocarbonyl or 4-Boc-piperazinoacetyl;
H2N-C(=NH)-NH-C H2m-CO- such as guanidinoacetyl, 3-guani-dinopropionyl, 4-guanidinobutyryl, 5-guanidinopentanoyl, 6-guanidinohexanoyl, 7-guanidinoheptanoyl, 8-guanidino-octanoyl; NC-NH-C(=NH)-NH-CmH2m-CO- such as N'-cyano-guanidinoacetyl, 3-(N'-cyanoguanidino)propionyl, 4-(N'-cyanoguanidino)butyryl, 5-(N'-cyanoguanidino)pentanoyl, 2 ~ 2 6-(N'-cyanoguanidino)hexanoyl, 7-(N~-cyanoguanidino)-heptanoyl, 8-(N'-cyanoguanidino)octanoyl; HOOC-CmH~-CO-such as malonyl, succinyl, glutaryl, adipyl, 6-carboxy-hexanoyl, 7-carboxyheptanoyl, 8-carboxyoctanoyl, 9-carb-S oxynonanoyl, l~-carboxydecanoyl, ll-carboxyundecanoyl;
AOOC-C~H~-CO- such as methoxycarbonylacetyl, 3-methoxy-carbonylpropionyl, 4-methoxycarbonylbutyryl, S-methoxy-carbonylpentanoyl, 6-methoxycarbonylhexanoyl, 7-methoxy-carbonylheptanoyl, 8-methoxycarbonyloctanoyl, 9-methoxy-carbonylnonanoyl, 10-methoxycarbonyldecanoyl, ethoxy-carbonylacetyl, 3-ethoxycarbonylpropionyl, 4-ethoxycarb-onylbutyryl,5-ethoxycarbonylpentanoyl,6-ethoxycarbonyl-hexanoyl, 7-ethoxycarbonylheptanoyl, 8-ethoxycarbonyl-octanoyl, 9-ethoxycarbonylnonanoyl, 10-ethoxycarbonyl-decanoyl; H-S03-CmHam-CO- such as sulfoacetyl, 3-sulfo-propionyl, 4-sulfobutyryl, 5-sulfopentanoyl, 6-sulfohexa-noyl, 7-sulfoheptanoyl, 8-sulfooctanoyl, 9-sulfononanoyl, 10-sulfodecanoyl; A-SO3-CmHam-CO- such as methoxysulfonyl-acetyl, 3-methoxysulfonylpropionyl, 4-methoxysulfonyl-butyryl, 5-methoxysulfonylpentanoyl, 6-methoxysulfonyl-hexanoyl, 7-methoxysulfonylheptanoyl, 8-methoxysulfonyl-octanoyl, 9-methoxysulfonylnonanoyl, 10-methoxysulfonyl-decanoyl, ethoxysulfonylacetyl, 3-ethoxysulfonyl-propionyl, 4-ethoxysulfonylbutyryl, 5-ethoxysulfonyl-pentanoyl, 6-ethoxysulfonylhexanoyl, 7-ethoxysulfonyl-heptanoyl, 8-ethoxysulfonyloctanoyl, 9-ethoxy~ulfonyl-nonanoyl, 10-ethoxysulfonyldecanoyl; Rff-CmH~-O-CO-, in particular A-O-CO- ~uch as ETOC, IPOC, BOC and also Ar-C~Ham-O-CO- such as CBZ; R5-CmHam-Co-, in particular A-CO- such as acetyl, trimethylacetyl or 3,3-dimethyl-butyryl, but also formyl; or R6-SOz- such as A-SO2-, preferably methylsulfonyl.
The compounds of the formula I can have one or more chiral centres and therefore occur in different - optically active or optically inactive - forms. The formula I includes all these forms. If R3 differs from H
and/or R4 is (H, OH) or (H, NHa), the 2R-hydroxy, 2R-amino, 3S-aminoj 2R-hydroxy-3S-amino and 2R,3S-diamino enantiomers are preferred (the C atom which carries the - 13 - 203~92 radical R4 being allocated the 2-position and the C atom which carries the radicals X-W-CRlR2-C0-Y-NH and R3 being allocated the 3-position.
The abovementioned cycloalkyl and phenyl groups are preferably unsubstituted or preferably carry 1 to 3, in particular 1 or 2 substituents.
The invention accordingly relates in particular to those compounds of the formula I in which at least one of the said radicals has one of the abovementioned preferred meanings. Some preferred groups of compounds can be expressed by the following sub-formulae Ia to Ik:
Ia H-W-CRlR2-Co-Y-NH-CHR3-CR4-CooR5;
Ib R6--O--CmH2o~--Co-W-CRlR2-Co-Y-NH-CHR3--CR4-CooR5;
IC R6-CmH2~-O-CO-W--CRlR2-CO--Y-NH-ClIR3-CR4-CoOR5;
Id R6-CmH2~-Co-W-CRlR2-Co-Y-NH-CHR3-CR4-CooR5;
Ie R7R8N--CmH2m--CO--W-CRlR2-Co-Y-NH-CHR3--CR4-CooRs;
I f R9-NH-C ( =NH ) -NH-CmH2o,-Co-W-CRlR2-Co-Y-NH-CHR3-CR4-CooR5;
Ig R700C-CmH2.-Co-W-CRlR2-Co-Y-NH-CHR3-CR4-CooR5;
Ih R703S-CmH2.-Co-W-CRlR2-Co-Y-NH-CHR3-CR4-CooR5;
I i R7-o- ( CH2CH20 ) n-CmH2",-CO--W--CRlR2-CO--Y--NH--CHR3-CR4--CooR5;
I ~ R7RaN-Co-W-CRlR2-Co-Y-NH-CHR3-CR4-CooR5;
Ik 4-Aminopiperidinocarbonyl-W-CRlR2-CO-Y-NH-CHR3-CR4-cooR5 .
~articularly preferred compounds are those of the sub-formulae:
(a) Iaa to Ika which correspond to the formulae Ia to Ik, but in which additionally -W-CRlR2-C0- is Phe, Pla, Nal or 3 0 -CH2-CH ( CH2C~Hs ) ~CO~;
(b) Iab to Ikb and also Iaab to Ikab, which correspond to the formulae Ia to Ik and also Iaa to Ika, but in which additionally Y is ~Ala. 5 (c) Iac to Ikc, Iaac to Ikac and also Iabc to Ikbc, which correspond to the formulae Ia to Ik, Iaa to Ika and also Iab to Ikb, but in which additionally - 14 - 2~992 R3 is cyclohexylmethyl.
Particularly preferred compounds are those of the sub-formulae:
I and Ia to Ik , which correspond to the formulae I and also Ia to Ik and those compounds which correspond to the other abovementioned sub-formulae, but in which additionally R4 is (H, OH);
I~ and Ia~ to Ik~, which correspond to the formulae I and also Ia to Ik and those compounds which correspond to the other abovementioned sub-formulae, but in which additionally R5 is alkyl having 1-3 C atoms.
A particularly preferred group of compounds corresponds to the formula I
in which X is H, AO-CO-, H-CO-, 4-BOC-aminopiperidinocarbonyl, 4-hydroxypiperidinocarbonyl, 4-aminopiperidinocarb-onyl, 4-A2N-piperidinocarbonyl, 4-AOOC-NH-piperi-dinocarbonyl, piperazinocarbonyl, 4-BOC-piperazino-carbonyl, morpholinocarbonyl or A-SO2-, -W-CRlRZ-cO- i8 Phe or Pla, Y i~ ~Ala or Isoser, R3 is cyclohexylmethyl, R~ is (H, OH) and R5 is alkyl having 1-3 C atoms.
The compounds of the formula I and also the starting substances for their preparation are otherwise prepared by methods known per se, such as are described in the literature (for example in the standard works such as Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart;
and in addition EP-A-45,665, EP-A-77,028, EP-A-77,029, EP-A-81,783 and EP-A-249,096), to be precise under reaction conditions which are known and suitable for the i said reactions. Use can also be made here of variants which are known per se but are not mentioned here in greater detail.
The starting substances, if desired, can also be 2 a ~ 2 formed in 8itU, such that they are not isolated from the reaction mixture, but Lmmediately reacted further to give the compounds of the formula I.
The compounds of the formula I can be obtained by setting them free from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogen-olysis.
Preferred starting substances for the solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and/or hydroxy groups contain correspondingly protected amino and/or hydroxy groups, preferably those which in~tead of an H atom which is bonded to an N atom, carry an amino protective group, for example those of the formula I, but instead of an His group contain an N(im)-R~-His group (in which R~ is an amino protective group, for example BOM or DNP), or those of the formula X-W-CR1RZ-Co-Y-NH-CHR3-CH(NHR~)-CooR5.
In addition, starting substances are preferred which instead of the H atom of a hydroxy group carry a hydroxy protective group, for example those of the formula X-~-CRlRZ-Co-Y-NH-CHR3-CHoR~-CooR5~ in which R~ is a hydroxy protective group.
Several - identical or different - protected amino and/or hydroxy groups can also be present in the molecule of the starting substance. If the protective groups present are different from one another, they can in many cases be removed selectively.
The expression ~amino protective group~ is generally known and relates to groups which are suitable for protecting an amino group from chemical reactions (for blocking), but which are easily removable after the desired chemical reaction has been carried out at another site in the molecule. Typical of such groups are in particular unsubstituted or substituted acyl, aryl (for example DNP), aralkoxymethyl (for example BOM) or aralkyl groups (for example benzyl, 4-nitrobenzyl, triphenyl-methyl). Since the amino protec~ive groups are removed 2 ~ 9 2 after the desired reaction (or reaction sequence), their nature and size is otherwise not critical; but those with 1-20 C atoms, in particular 1-8 C atoms, are preferred.
The expression ~acyl group" is to be interpreted in the widest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and also in particular alkoxycarbonyl, aryloxy-carbonyl and aralkoxycarbonyl groups. Examples of acyl groups of this type are alkanoyl such as acetyl, propion-yl or butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as POA;
alkoxycarbonyl such as methoxycarbonyl, ETOC, 2,2,2-tri-chloroethoxycarbonyl, IPOC, BOC, 2-iodoethoxycarbonyl;
aralkyloxycarbonyl such as CBZ, 4-methoxybenzyloxy-carbonyl and FMOC. Preferred amino protective groups are BOC, DNP and BOM, and in addition CBZ, FMOC, benzyl and acetyl.
The expression ~hydroxy protective group~ is likewise generally known and relates to groups which are suitable for protecting a hydroxy group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at another site in the molecule. Typical of such groups are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, and in addition also alkyl groups. The nature and size of the hydroxy protective groups is not critical, since they are removed again after the desired chemical reaction or reaction sequence; groups with 1-20 C
atoms, in particular 1-10 C atoms, are preferred.
Examples of hydroxy protective groups are, among others, tert.-butyl, benzyl, p-nitrobenzoyl, p-toluenesulfonyl and acetyl, benzyl and acetyl being particularly preferred.
The functional derivatives of the compounds of the formula I to be used as starting substances can be prepared by customary methods of amino acid and peptide synthesis, such as, for example, are described in the said standard works and patent applications, for example 2050~92 also by the solid phase method according to Merrifield.
The compounds of the formula I are set free from their functional derivatives - depending on the protec-tive group used - for example with strong acids, expedi-ently with trifluoroacetic acid or perchloric acidl butalso with other strong inorganic acids such as hydro-chloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene- or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary.
Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such a~ DMF, halogenated hydrocarbons such as dichloromethane, and in addition also alcohols such as methanol, ethanol or isopropanol and also water. In addition, mixtures of the abovementioned solvents are suitable. Trifluoroacetic acid i~ preferably used in excess without addition of a further solvent, perchloric acid in the form of a mixture of acetic acid and 70 % perchloric acid in the ratio 9;1.
The reaction temperatures for the cleavage are expedi-ently between about O and about 50; the reaction is preferably carried out between 15 and 30 (room tempera-ture).
The BOC group can, for example, preferably beremoved with 40 % trifluoroacetic acid in dichloromethane or with about 3 to 5 N HCl in dioxane at 15-30C, the FMOC group with an about 5-20 % solution of dimethyl-amine, diethylamine or piperidine in DMF at 15-30. The DNP group is also removed, for example, with an about 3-10 % solution of 2-mercaptoethanol in DMF/water at 15-30.
Protective groups which can be removed by hydro-genolysis (for example BOM, CBZ or benzyl) can be removed, for example, by treating with hydrogen in the presence of a catalyst (for example a noble metal cata-lyst such as palladium, expediently on a support such as carbon). Suitable solvents in thiY case are the 2 ~ 2 abovementioned, in particular, for example, alcohols such as methanol or ethanol or amides such as DNF. The hydro-~enolysis is as a rule carried out at temperatures between about 0 and 100 and at pressures between about 1 and 200 bar, preferably at 20-30 and at 1-10 bar. The CBZ group is easily hydrogenolysed, for example, on 5-10 ~ Pd-C in methanol at 20-30.
Compounds of the formula I can also be obtained by direct condensation (peptide synthesis) from a car-boxylic acid component (formula II) and a hydroxyl or amino component (formula III). Suitable carboxylic acid components are, for example, those of the sub-formulae (a) X-OH, (b) X-W-CRlR2-COOH or (c) X-W-CR1R2-CO-Y-OH, suitable hydroxyl or amino components are thoqe of the sub-formulae (a) HW-CRlR2-Co-Y-NH-CHR3-CR4-CooR5, (b) H-Y-NH-CHR3-CR4-CooR5 or ( c ) H2N-CHR3-CR4-CooR5 .
The reaction is expediently carried out in this case by customary methods of peptide synthesis, such as are described, for example, in Houben-Weyl, loc.cit., Volume 15/II, pages 1-806 (1974); these methods can also be transferred, if W = O, to the conden~ation according to (a)~ an ester bond being formed.
The reaction is preferably carried out in the presence of a dehydrating agent, for example of a carbo-diimide such as DCCI or dimethylaminopropylethyl-carbodiimide, and in addition propanephosphonic anhydride (cf. Angew. Chem. 92, 129 (1980)), diphenylphosphoryl azide or 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, in an inert solvent, for example a halogenated hydro-carbon such as dichloromethane, an ether such as THF or dioxane, an amide such as DMF or dimethylacetamide, or a nitrile such as acetonitrile, at temperatures between about -10 and 40, preferably between 0 and 30.
Instead of II or III, suitable reactive deriva-tives of these substances can also be employed in the reaction, for example those in which reactive groups are intermediately blocked by protective groups. The acid 19 20~0~92 derivatives II can be used, for example, in the form of their activated ester~, which are expediently formed in situ, for example by addition of HOBt or N-hydroxy-succinimide.
The starting sub~tances of the formulae II and III are for the greatest part known. If they are not known, they can be prepared by known methods, for example the abovementioned methods of condensation and removal of protective groups.
If desired, a functionally modified amino and/or hydroxy group in a compound of the formula I can be set free by solvolysi5 or hydrogenolysis according to one of the methods described above.
Thus, for example, a compound of the formula I
lS which contains an R9-C~H2~-O-CO-NH-, an AcNH- or an AOOC-group can be converted into the corresponding compound of the formula I which instead of this contains an H2N- or an HOOC-group, expediently by selective solvolysis according to one of the abovementioned methods. AOOC-groups can be hydrolysed, for example, with NaOH or KOH
in water-dioxane at temperatures between O and 40, preferably 10 and 30.
It is also possible to acylate a compound of the formula I which contains a free primary or secondary amino group. Thus, in particular, compounds of the formula I, in which X is H, can be reacted with acylating agents of the formula X-Cl or X-Br (in which X is differ-ent from H), expediently in the presence of an inert solvent such as THF and/or of a base such as pyridine or triethylamine at temperatures between -10 and +30.
Furthermore, keto compounds of the formula I
(R~ = O) can be reduced to compounds of the formula I
~R4 = (H, OH)], for example with a complex metal hydride such as NaBH4, which does not simultaneously reduce the peptide carbonyl groups, in an inert solvent such as methanol at temperature~ between about -10 and +30.
Reto compounds of the formula I (R4 = O) can also be converted into compounds of the formula I (R4 = H, NH2) by reductive amination. Reductive amination can be - 20 - 2~ 92 carried out in one or more steps. Thus, for example, the keto compound can be treated with ammonium salts, for example ammonium acetate, and NaCNBH3, preferably in an inert solvent, for example an alcohol such as methanol, at temperatures between about 0 and 50, in particular between 15 and 30. It is furthermore possible to convert the keto compound into the oxime first with hydroxylamine in a customary manner and to reduce this, for example by catalytic hydrogenation on Raney nickel, to the amine.
If desired, an ester of the formula I in which R5 = A can be hydrolysed to the corresponding acid of the formula I in which R5 = H, for example with sodium hydroxide or potassium hydroxide, in a lower alcohol such as methanol or ethanol at temperatures between about 0 and +30-. Conversely, an acid of the formula I (R5 = H) can be esterified to give the corresponding ester of the formula I (R5 = A), for example with diazoalkanes such as diazomethane in dioxane or with an alkyl halide such as methyl iodide or isopropyl bromide in an inert solvent such as DMF in the presence of a base such as potassium carbonate at temperatures between about 0 and +30.
A base of the formula I can be converted into the respective acid addition salt using an acid. Suitable acids for this reaction are in particular those which give physiologically acceptable salts, thus inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophos-phoric acid, sulfamic acid, and in addition organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, trifluoroacetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2 ~ ~ O ~ 9 2 -p-toluenesulfonic acid, naphthalenemonc- and -disulfonic acids, and laurylsulfuric acid. Salts with physiologic~
ally unacceptable acids, for example picrates, can ~e used for the isolation and/or purification of the compounds of the formula I.
The novel compounds of the formula I and their physiologically acceptable salts can be used for the production of the pharmaceutical prepaxations by bringing them into a suitable dosage form together with at least one e~cipient or auxiliary and, if desired, together with one or more other active compound(s). The preparations thus obtained can be employed as medicaments in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral or rectal) or parenteral administration or for administration in the form of an inhalation spray and do not react with the novel compounds, for example water, vegetable oils t benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty acid glycerides, gelatin, soya lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc or cellulose. For oral administration, tablets, coated tablets, capsules, syrups, juices or drops are used in particular; especi-ally of interest are coated tablets and capsules having enteric coaltings or capsule shells. Suppositories are used for rectal administration, and solutions, preferably oily or aqueous solutions, and in addition suspensions, emulsions or implants are used for parenteral admini-stration. For administration as inhalation sprays, sprays can be used which contain the active compound either dissolved or suspended in a propellant gas mixture (for example fluorochlorohydrocarbons). The active compound in this case is expediently used in micronised form, it being po~sible for one or more additional physiologically tolerable solvents to be present, for example ethanol.
Inhalation solutions can be administered with the aid of customary inhalers. The novel compounds can also be lyophilised and the lyophilisates obtained used, for ex~mple, for the production of in~ection preparations.
- 22 ~
The preparations mentioned can be sterilised and/or can contain auxiliaries such as preservatives, stabilisers and/or wetting agents, emulsifiers, s~lts for aff~cting the osmotic pressureJ buffer substances, colourants and~or flavourings. If desired, they can also contain one or more other active compounds, for example one or more vitamins.
The substances according to the invention are as a rule administered in analogy to other known commer-cially available peptides, but in particular in analogy to the compounds described in EP-A-249,096, preferably in dosages be~ween about 10 mg and 1 g, in particular between 50 and 500 mg per dosage unit. The daily dosage is preferably between about 0.2 and 20 mg/kg, in parti-cular bet~een 1 and 10 mg/kg of body weight. The specific dose for each specific patient, howe~er, depends on a wide variety of factors, for example on the activity of the ~pecific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and route of administration, and on the excretion rate, medicament combination and severity of the particular disease to which the treatment applies. Parenteral administration is preferred. Renin-dependent hypertension and hyperaldosteronism can be effectively treated by ~5 administration of dosages between, in particular, about 0.2 and 20, preferably between 1 and l0 mg/kg of body weight. For diagnostic purposes the novel compounds can expediently be administered in individual doses between about 0.1 and 10 mg/kg of body weight.
Above and below, all temperatures are indicated in C. In the following examples "customary working up"
means: water is added if necessary, the pH is adjusted to between 2 and 8, depending on the constitution of the final product, the mixture is extracted with ethyl acetate or dichloromethane, the organic phase is separ~
ated off, dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel and/or crystallisation. TFA = trifluoroacetate. FAB =
mass spectrum by the "fast atom bombardment" methodO
- 23 - 2~ 92 Example 1 1 g of isopropyl 3S-[tert.-butoxycarbonyl-L-(N-imi-benzyloxymethylhistidyl)-~-alanylamino]-4-cyclohexyl-2R-hydroxybutyrate [= I~isopropyl 3S-(BOC-(imi-BOM-His)-S ~Ala-amino)-4-cyclohexy1-2R-hydroxybutyrate~; obtainable by condensation of BOC-(imi-BOM-His)-~-Ala-OH with isopropyl 3S-amino-4-cyclohexyl-2R-hydroxybutyrate] is dissolved in 30 ml of ethanol, and hydrogenated on 0.3 g of 10% Pd-C at 20 and 1 bar until Hz absorption has stopped, the mixture is filtered and evaporated and iso-propyl 3S-(BOC-His-~Ala-amino)-4-cyclohexyl-2R-hydroxy-butyrate is obtained after chromatographic purification on silica gel.
Isopropyl 3S-(4-carboxypiperidinocarbonyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate is obtained analogously by hydrogenolysis of isopropyl 3S-(4-benzyl-oxycarbonylpiperidinocarbonyl-Phe-~Ala-amino)-4-cyclo-hexyl-2R-hydroxybutyrate.
Example 2 A mixture of 1 mmol of ethyl 3s-[Boc-(imi-DNp-His)-~Ala-amino]-4-cyclohexyl-2R-hydroxybutyrate (obtain-able by condensation of ethyl BOC-(imi-DNP-His)-~-Ala-OH
with 3S-amino-4-cyclohexyl-2R-hydroxybutyrate], 2 g of 2-mercaptoethanol, 20 ml of DMF and 20 ml of water i8 ad~usted to pH 8 with stirring at 20 using aqueous Na2CO3 solution and the mixture is stirred at 20 for a further 2 hours. Customary working-up gives ethyl 3S-(BOC-His-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate.
Example 3 A solution of 2.15 g of methyl 3S-amino-4-cyclo-hexyl-2R-hydroxybutyrate in 60 ml of dichloromethane is treated with 1.01 g of N-methylmorpholine. 4.5 g of 4-BOC-aminopiperidinocarbonyl-Phe-~Ala-OH, 1.35 g of HOBt and a solution of 2.06 g of DCCI in 50 ml of dichloro-methane are added with stirring, the mixture is ~tirred at 0-5 for 12 hours, the precipitated dicyclohexylurea is filtered off and the filtrate is evaporated. Customary working-up gives methyl 3S-(4-BOC-aminopiperidino-carbonyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate~
20~0~92 m.p. 113-114.
Example 4 Isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate, m.p. 104-105, is obtained analogously to Example 3 using iso-propyl 3S-amino-4-cyclohexy1-2R-hydroxybutyrate.
Example 5 Isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-Phe-Isoser-amino)-4-cyclohexyl-2R-hydroxybutyrate~2isomers~
m.p. 115-116 and m.p. 102-103 respectively, are obtained analogously to Example 3 using 4-BOC-amino-piperidinocarbonyl-Phe-Isoser-OH and isopropyl 3S-amino-4-cyclohexyl-2R-hydroxybutyrate.
Example 6 The following are obtained from isopropyl 3S-amino-4-cyclohexyl-2R-hydroxybutyrate analogously to Example 3 (a) isopropyl 3S-(BOC-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate, m.p. 120-122, using BOC-Phe-~Ala-OH;
(b) isopropyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxy-piperidinocarbonyl-Phe-~Ala-amino)-butyrate, m.p.
120-121-, using 4-hydroxypiperidinocarbonyl-Phe-~Ala-OH;
(c) i8opropyl 3S-(4-BOC-piperazinocarbonyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate,m.p.86-87-, using 4-BOC-piperazinocarbonyl-Phe-~Ala-OH;
(d) isopropyl 4-cyclohexyl-2R-hydroxy-3S-(morpholino-carbonyl-Phe-~Ala-amino)-butyrate, m.p. 112-113, using morpholinocarbonyl-Phe-~Ala-OH;
(e) isopropyl 4-cyclohexyl-3-(4-dimethylaminopiperidino-carbonyl-Phe-~Ala-amino)-2R-hydroxybutyrate, hydro-chloride, m.p. 219-220, using 4-dimethylamino-piperidinocarbonyl-Phe-~Ala-OH;
(f) isopropyl 4-cyclohexyl-3-(4-ethoxycarbonylamino-piperidinocarbonyl-Phe-~Ala-amino)-2R-hydroxy-butyrate using 4-ethoxycarbonylaminopiperidino-carbonyl-Phe-~Ala-OH;
2~0~92 (g) isopropyl 4-cyclohexyl-3-(4-ethoxycarbonylpiperi-dinocarbonyl-Phe-~Ala-amino)-2R-hydroxybutyrate, m.p. 117-118, using 4-ethoxycarbonylpiperidino-carbonyl-Phe-~Ala-OH; (h) isopropyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxy-piperidinocarbonyl-Phe-Isoser-amino)-butyrate using 4-hydroxypiperidinocarbonyl-Phe-Isoser-OH.
Example 7 The following are obtained from 4-hydroxypiperi-dinocarbonyl-Phe-~Ala-OH analogou~ly to Example 3 (a) methyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxypiperi-dinocarbonyl-Phe-~Ala-amino)-butyrate using methyl 3S-amino-4-cyclohexyl-2R-hydroxybutyrate;
(b) ethyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxypiperi-15dinocarbonyl-Phe-~Ala-amino)-butyrate using ethyl 3S-amino-4-cyclohexyl-2R-hydroxybutyrate;
(c) n-butyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxypiperi-dinocarbonyl-Phe-~Ala-amino)-butyrate using n_butyl 3S-amino-4-cyclohexyl-2R-hydroxybutyrate;
20(d) cyclohexyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxy-piperidinocarbonyl-Phe-~Ala-amino)-butyrate using cyclohexyl 3S-amino-4-cyclohexyl-2R-hydroxybutyrate;
(e) i80propyl 2R-hydroxy-3S-(4-hydroxypiperidino-carbonyl-Phe-~Ala-amino)-5-methylhexanoate using 25isopropyl 3S-amino-2R-hydroxy-5-methylhexanoate;
(f) isopropyl 2R-hydroxy-3S-(4-hydroxypiperidino-carbonyl~Phe-~Ala-amino)-4-phenylbutyrate using isopropyl 3S-amino-2R-hydroxy-4-phenylbutyrate;
Example 8 30The following are obtained from isopropyl 4-cyclohexyl-2R-hydroxy-3S-(H-Phe-~Ala-amino)butyrate analogously to Example 3 (a) isopropyl 3S-(3-BOC-amino-3-methylbutyryl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate using 3-BOC-35amino-3-methylbutyric acid;
(b) isopropyl 3S-(6-BOC-aminohexanoyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate using 6-BOC-amino-hexanoic acid;
.
(c~ isopropyl 4-cyclohexyl-2R-hydroxy 3S-(3,6 t 8-trioxa-nonanoyl-Phe-~Ala-amino)-butyrate using 3,6,8-trioxanonanoic acid.
Example 9 The following are obtained from isopropyl 3S- (H-~Ala-amino)-4~cyclohexy1-2R-hydroxybutyrate [FAB: M -~ 1 = 315; obtainable by condensation of CBZ-~Ala-OH with isopropyl 3S-amino~4-cyclohexyl-2R~hydroxybutyrate to ~ive isopropyl 3S-(CBZ-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate ~FAB: M + 1 = 449) and hydrogenolysis]
analogously to Example 3 (a) isopropyl 4-cyclohexyl-2R-hydroxy-3S~(H Pla-~la-amino)-butyrate, m.p. 54-55l using H-Pla-OH;
(b) isopropyl 3S-(H-CO-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyxate, m.p. 108 tdec.), using H-CO Phe~
OH;
(c) isopropyl 4-cyclohexyl-2R-hydroxy-3S-(morpholino-carbonyl-Pla-~Ala-amino)-butyrate using moxpholino-carbonyl-Pla-OH;
(d) to (m) using acids of the formula 4-~OC-aminopiperi-dinocarbonyl-Z-OH
(Z = Ada, Calf Leu, Mal, Nle, Pla, 2-Tia, 2-Tiz, Trp and Tyr respectively);
(d) isopropyl 3S (4-BOC-aminopiperidinocarbonyl-Ada-~Ala-ami.no)-4-cyclohexyl-2R-hydroxybutyrate;
(e) isopropy~l 3S-(4-BOC-aminopiperidinocarbonyl-Cal-~Ala-ami.no)-4-cyclohexyl-2R-hydroxybutyrate;
(f) isopropyl 3S-~4-BOC-aminopiperidinocarbonyl-Leu-~Ala-ami.no)-4-cyclohexyl-2R-hydroxybutyrate;
(g) isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-Mal-~Ala~amino)-4-cyclohexyl-2R-hydroxybutyrate;
(h) isopropyl 3S-(4-BOC-aminopiparidinocarbonyl-Nle-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate;
(i.) isopropyl 3S-(4-BOC-aminopiperidinocar~onyl-Pla-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate;
(~) isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-2-Tia-~Ala amino)-4-cyclohexyl-2R-hydroxybutyrate;
(k) isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-2~Tiz-~Ala-amino)-4 cyclohexyl-2R-hydroxybutyxate;
- 27 - 2 05 ~9 2 (1) isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-Trp-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate;
(m) isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-Tyr-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate.
Example 10 A mixture of 461 mg of isopropyl 4-cyclohexyl-2R-hydroxy-3S-(H-Phe-~Ala-amino)-butyrate, 115 mg of tri-methylsilyl isocyanate and 25 ml of THF is stirred at 20 for 2 hours. 2.5 ml of 1 N aqueous hydrochloric acid are added to remove the protective group, the mixture is stirred at 20 for a further 15 min, and worked up in the customary manner to give isopropyl 3S-(N-carbamoyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate.
Example 11 A mixture of 461 mg of isopropyl 4-cyclohexyl-2R-hydroxy-3S-(H-Phe-~Ala-amino)-butyrate, 71 mg of ethyl isocyanate and 25 ml of THF is stirred at 20 for 3 hours. The mixture i8 worked up in the customary manner to give isopropyl 4-cyclohexyl-3S-tN-(N-ethylcarbamoyl)-Phe-~Ala-amino~-2R-hydroxybutyrate.
Example 12 A solution of 1 g of methyl 3S-(4-~OC-amino-piperidinocarbonyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate in 20 ml of dichloromethane and 20 ml of trifluoroacetic acid i8 3tirred at 20 for 1 hour and then evaporated. Methyl 3S-(4-aminopiperidinocarbonyl-Phe-~Ala-amino)-4-cyclohexy1-2R-hydroxybutyrate, TFA, m.p. 163-164, are obtained.
The following are obtained analogously by cleav-ing the appropriate BOC derivatives with trifluoroacetic acid:
isopropyl 3S-(4-aminopiperidinocarbonyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate, TFA, m.p. 185-186, 1/3 citrate, m.p. 119-120 isopropyl 3S-(4-aminopiperidinocarbonyl-Phe-Isoser-amino)-4-cyclohexyl-2R-hydroxybutyrate~ TFA, 2-isomers, m.p. 118-119 and 155-156 re~pectively isopropyl 4-cyclohexyl-2R-hydroxy-3S-(H-Phe-~Ala-amino)-butyrate, TFA, m.p. 77-78 2 ~ ~ O ~ 9 2 isopropyl 4-cyclohexy1-2R-hydroxy-3S-(piperazinocarbonyl-Phe-~Ala-amino)-butyrate, TFA, m.p. 113-114 isopropyl 3S-~3-amino-3-methylbutyryl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate isopropyl 3S-(6-aminohexanoyl-Phe-~Ala-amino)-4-cyclo-hexyl-2R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-Ada-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-Cal-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-Leu-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-Nal-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate isopropyl 3S-~4-aminopiperidinocarbonyl-Nle-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-Pla-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-2-Tia-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-2-Tiz-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate i~opropyl 3S-(4-aminopiperidinocarbonyl-Trp-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-Tyr-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate Example 13 (a) A mixture of 1 g of methyl 3S-(4-~OC-aminopiperi-dinocarbonyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate, 50 ml of dioxane and 20 ml of 2 N
aqueous NaOH ~olution is stirred at 20 for 3 hours.
The mixture i8 worked up in the customary manner and gives 3S-(4-BOC-aminopiperidinocarbonyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyric acid.
(b) The crude acid obtained according to (a) is stirred with 25 ml of DMF, 1 ml of i80propyl iodide and 200 mg of R2C03 for 24 hours. The mixture i8 worked up in the customary manner and gives isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-Phe-~Ala-amino)-4-2~0092 cyclohexyl-2R-hydroxybutyrate, m.p. 104-105.
Example 14 Isopropyl 4-cyclohexyl-2R-hydroxy-3S-(H-Phe-~Ala-amino)-butyrate, TFA, m.p. 77-78, is obtained by hydro-genolysis of isopropyl 3S-(CBZ-Phe-~Ala-amino)-4-cyclo-hexyl-2R-hydroxybutyrate analogously to Example 1.
Example 15 (a) 449 mg of isopropyl 4-cyclohexyl-2R-hydroxy-3S-(H-Phe-~Ala-amino)butyrate are dissolved in 25 ml of THF. A solution of 117 mg of methanesulfonyl chlor-ide in 3 ml of THF is added dropwise with stirring.
The mixture is stirred at 20 for a further 3 hours, and worked up in the customary manner to give isopropyl 4-cyclohexyl-2R-hydroxy-3S-(methane-sulfonyl-Phe-~Ala-amino)butyrate, m.p. 115-116.
(b) Isopropyl 4-cyclohexyl-2R-hydroxy-3S-(isopropyl-sulfonyl-Phe-~Ala-amino)butyrate is obtained analo-gously using isopropylsulfonyl chloride.
(c) Isopropyl 3S-(acetyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate i8 obtained analogously u~ing acetyl chloride.
Example 16 (a) Isopropyl 4-cyclohexyl-3S-~4-hydroxypiperidino-carbonyl-Phe-~Ala-amino)-2-oxobutyrate is obtained from 4-hydroxypiperidinocarbonyl-Phe-~Ala-OH and isopropyl 3S-amino-4-cyclohexyl-2-oxobutyrate analogously to Example 3.
(b) A solution of 1 g of the above ketoester in 25 ml of methanol is hydrogenated on 0.1 g of 10% Pd-C at 20 and 1 bar until absorption of Hz is complete. After filtering and evaporating, a mixture of isopropyl 4-cyclohexyl-2R- and -2S-hydroxy-3S-(4-hydroxypiperi-dinocarbonyl-Phe-~Ala-amino)butyrate is obtained, which can be separated on ~ilica gel.
Example 17 A solution of 586 mg of the ketoester obtainable according to Example 16 (a) and 1.43 g of Na2CO3 10 H20 in 5 ml of methanol and 5 ml of water is treated with 70 mg of hydroxylamine hydrochloride and stirred at 20 2~0~92 for 14 hours. The precipitated oxLme is filtered off, dried, dissolved in 10 ml of methanol and hydrogenated at 20 and 5 bar on 0.4 g of Raney Ni. The catalyst is filtered off, the filtrate is evaporated and the mixture S of isopropyl 2R- and 2S-amino-4-cyclohexyl-3S-(4-hydroxy-piperidinocarbonyl-Phe-~Ala-amino)butyrate obtained is separated.
The examples below relate to pharmaceutical preparations.
Example A: Tablets A mixture of 1 kq of i~opropyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxypiperidinocarbonyl-Phe-~Ala-amino)-butyrate, 4 kg of lactose, 1.2 kg of maize starch, 200 g of talc and 100 g of magnesium stearate i8 compressed to give tablets in a customary manner in such a way that each tablet contains 100 mg of active compound.
Bxample B: Coated tablets Tablets are pressed analogously to Example A, and are then coated in a customary manner with a coating of sucrose, maize starch, talc, tragacanth and colourant.
Example C: Capsules 500 g of isopropyl 3S-(BOC-Phe-~Ala-amino)-4-cycIohexyl-2R-hydroxybutyrate are filled into hard gelatine capsules in a customary manner in such a way that each capsule contains 500 mg of active compound.
Bxample D: In~ection vials A solution of 100 g of methyl 3S-(4-aminopiperi-dinocarbonyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxy-butyrate trifluoroacetate in 4 1 of doubly distilled water is ad~usted to pH 6.5 with 2N hydrochloric acid, sterile filtered and poured into in~ection vials. The solution i8 lyophilised under sterile conditions and the vials are sterile sealed. Each in~ection vial contains 100 mg of active compound.
Example E: Suppositories A mixture of 50 g of isopropyl 4-cyclohexyl-2R-hydroxy-3S-(methanesulfonyl-phe-~Ala-amino)butyrate is fused with 10 g of soya lecithin and 140 g of cocoa - 31 - 2~
butter, poured into moulds and allowed to cool. Each Ruppository contain~ 250 mg of active compound.
Claims (7)
1. Amino acid derivatives of the formula I
in which X is H, R6-O-CmH2m-CO-, R6-CmH2m-O-CO-, R6-CmH2m-CO-, R6-SO2-, R7R8N-CmH2m-CO-, R9-NH-C(=NH)-NH-CmH2m-CO-, R7OOC-CmH2m-CO-, R7O3S-CmH2m-CO-, R7-O-(CH2CH2O)n-CmH2m-CO- or A3N+-CmH2m-CO- An-, W is O or NH, Y is .beta.Ala or Isoser, R1, R7 and R8 are each H or A, R2, R3 and R6 are each H, A, Ar, Ar-alkyl, Het, Het-alkyl, cycloalkyl having 3-7 C atoms, which is unsub-stituted or monosubstituted or polysubstituted by A, AO and/or Hal, cycloalkylalkyl having 4-11 C atoms, bicycloalkyl or tricycloalkyl each having 7-14 C atoms, or bicycloalkylalkyl or tricycloalkylalkyl each having 8-18 C atoms, R4 is (H, OH), (H, NH2) or =O, R5 is H, A or cycloalkyl having 3-7 C atoms, R7R8N is also an unsubstituted pyrrolidino, piperid-ino, morpholino or piperazino group or one which is substituted by A, OH, NH2, NHA, NA2, NHAc, NH-CO-CxH2x-O-R9, NH-CO-O-CxH2x-R9, hydroxyalkyl, COOH, COOA, CONH2, aminoalkyl, HAN-alkyl, A2N-alkyl, A3N~alkyl Ane, NH-CO-NH2, NH-CO-NHA, guanidinyl or guanidinylalkyl, R9 is H, A, Ar-alkyl or CN, m and x are each 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, n is 0, 1, 2 or 3, Ar is unsubstituted phenyl or phenyl which is monosubstituted or polysubstituted by A, OA, Hal, CF3, OH, NO2, hydroxyalkyl, NH2, NHA, NA2, NHAc, NH-SO2-A, SA, SO-A, SO2-A, SO2NHa, SO2NHA, COOH, COOA, CONH2, CN, aminoalkyl, HAN-alkyl, A2N-alkyl,A3N?-alkyl An? and/or guanidinylalkyl, or is unsubstituted naphthyl, Het is a saturated or unsaturated 5- or 6-membered heterocyclic radical having 1-4 N, O and/or S
atoms, which can be fused to a benzene ring and/or monosubstituted or polysubstituted by A, OA, Hal, CF3, OH, NO2, carbonyl oxygen, NH2, NHA, NA2, NHAc, NH-COOA, NHCOOAr, NHCOOCH2Ar, NH-SO2-A, SA, SO-A, SO2-A, SO2NH2, SO2NHA, COOH, COOA, CONH2, CN, Ar, Ar-alkyl, Ar-alkenyl, hydroxyalkyl, aminoalkyl, HAN-alkyl, A2N-alkyl and/or A3N?-alkyl An? and/or whose N and/or S
heteroatoms can also be oxidised, Hal is F, Cl, Br or I, Ac is A-CO-, Ar-CO-, Ar-alkyl-CO- or A-NH-CO-, Ane is an anion, which can also be absent, if instead of this a carboxyl group contained in the compound of the formula I is present in the form of a carboxylate anion, -alkyl is an alkylene group having 1-8 C atoms and A is alkyl having 1-8 C atoms, in which in addition instead of one or more -NH-CO groups there can also be one or more -NA-CO groups, and their salts.
in which X is H, R6-O-CmH2m-CO-, R6-CmH2m-O-CO-, R6-CmH2m-CO-, R6-SO2-, R7R8N-CmH2m-CO-, R9-NH-C(=NH)-NH-CmH2m-CO-, R7OOC-CmH2m-CO-, R7O3S-CmH2m-CO-, R7-O-(CH2CH2O)n-CmH2m-CO- or A3N+-CmH2m-CO- An-, W is O or NH, Y is .beta.Ala or Isoser, R1, R7 and R8 are each H or A, R2, R3 and R6 are each H, A, Ar, Ar-alkyl, Het, Het-alkyl, cycloalkyl having 3-7 C atoms, which is unsub-stituted or monosubstituted or polysubstituted by A, AO and/or Hal, cycloalkylalkyl having 4-11 C atoms, bicycloalkyl or tricycloalkyl each having 7-14 C atoms, or bicycloalkylalkyl or tricycloalkylalkyl each having 8-18 C atoms, R4 is (H, OH), (H, NH2) or =O, R5 is H, A or cycloalkyl having 3-7 C atoms, R7R8N is also an unsubstituted pyrrolidino, piperid-ino, morpholino or piperazino group or one which is substituted by A, OH, NH2, NHA, NA2, NHAc, NH-CO-CxH2x-O-R9, NH-CO-O-CxH2x-R9, hydroxyalkyl, COOH, COOA, CONH2, aminoalkyl, HAN-alkyl, A2N-alkyl, A3N~alkyl Ane, NH-CO-NH2, NH-CO-NHA, guanidinyl or guanidinylalkyl, R9 is H, A, Ar-alkyl or CN, m and x are each 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, n is 0, 1, 2 or 3, Ar is unsubstituted phenyl or phenyl which is monosubstituted or polysubstituted by A, OA, Hal, CF3, OH, NO2, hydroxyalkyl, NH2, NHA, NA2, NHAc, NH-SO2-A, SA, SO-A, SO2-A, SO2NHa, SO2NHA, COOH, COOA, CONH2, CN, aminoalkyl, HAN-alkyl, A2N-alkyl,A3N?-alkyl An? and/or guanidinylalkyl, or is unsubstituted naphthyl, Het is a saturated or unsaturated 5- or 6-membered heterocyclic radical having 1-4 N, O and/or S
atoms, which can be fused to a benzene ring and/or monosubstituted or polysubstituted by A, OA, Hal, CF3, OH, NO2, carbonyl oxygen, NH2, NHA, NA2, NHAc, NH-COOA, NHCOOAr, NHCOOCH2Ar, NH-SO2-A, SA, SO-A, SO2-A, SO2NH2, SO2NHA, COOH, COOA, CONH2, CN, Ar, Ar-alkyl, Ar-alkenyl, hydroxyalkyl, aminoalkyl, HAN-alkyl, A2N-alkyl and/or A3N?-alkyl An? and/or whose N and/or S
heteroatoms can also be oxidised, Hal is F, Cl, Br or I, Ac is A-CO-, Ar-CO-, Ar-alkyl-CO- or A-NH-CO-, Ane is an anion, which can also be absent, if instead of this a carboxyl group contained in the compound of the formula I is present in the form of a carboxylate anion, -alkyl is an alkylene group having 1-8 C atoms and A is alkyl having 1-8 C atoms, in which in addition instead of one or more -NH-CO groups there can also be one or more -NA-CO groups, and their salts.
2. a) Methyl 3S-(4-aminopiperidinocarbonyl-Phe-.beta.Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate;
b) isopropyl 3S-(4-aminopiperidinocarbonyl-Phe-.beta.Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate;
c) isopropyl 3S-(4-aminopiperidinocarbonyl-Phe-Isoser-amino)-4-cyclohexyl-2R-hydroxybutyrate.
b) isopropyl 3S-(4-aminopiperidinocarbonyl-Phe-.beta.Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate;
c) isopropyl 3S-(4-aminopiperidinocarbonyl-Phe-Isoser-amino)-4-cyclohexyl-2R-hydroxybutyrate.
3. Process for the preparation of an amino acid derivative of the formula I and of its salts, charac-terised in that it is set free from one of its functional derivatives by treating with a solvolysing or hydrogen-olysing agent or in that a carboxylic acid of the formula II
in which (a) is absent, (b) is -W-CR1R2-CO-, (c) iS -W-CR1R2-CO-Y-, or one of its reactive derivatives is reacted with a compound of the formula III
in which G2 (a) is -W-CR1R2-CO-Y-, (b) is -Y-, (c) is absent, and in that a functionally modified amino and/or hydroxy group is optionally set free in a compound of the formula I by treating with solvolysing or hydrogenolysing agents and/or a free amino group is acylated by treating with an acylating agent and/or an aminoketo acid derivative of the formula I, R4 = O, is reduced or reductively aminated to prepare a compound of the formula I, R4 - (H, OH) or (H, NH2) and/or an ester of the formula I, R5 = A is hydrolysed and/or an acid of the formula I, R5 = H is esterified and/or a compound of the formula I is con-verted into one of its salts by treating with an acid.
in which (a) is absent, (b) is -W-CR1R2-CO-, (c) iS -W-CR1R2-CO-Y-, or one of its reactive derivatives is reacted with a compound of the formula III
in which G2 (a) is -W-CR1R2-CO-Y-, (b) is -Y-, (c) is absent, and in that a functionally modified amino and/or hydroxy group is optionally set free in a compound of the formula I by treating with solvolysing or hydrogenolysing agents and/or a free amino group is acylated by treating with an acylating agent and/or an aminoketo acid derivative of the formula I, R4 = O, is reduced or reductively aminated to prepare a compound of the formula I, R4 - (H, OH) or (H, NH2) and/or an ester of the formula I, R5 = A is hydrolysed and/or an acid of the formula I, R5 = H is esterified and/or a compound of the formula I is con-verted into one of its salts by treating with an acid.
4. Process for the production of pharmaceutical preparations, characterised in that a compound of the formula I and/or one of its physiologically acceptable salts is brought into a suitable dosage form together with at least onw solid, liquid or semi-liquid excipient or auxiliary.
5. Pharmaceutical preparation, characterised in that it contains at least one compound of the formula I and/or one of its physiologically acceptable salts.
6. Use of compounds of the formula I or of their physiologically acceptable salts for the production of a medicament.
7. Use of compounds of the formula I or of their physiologically acceptable salts in the control of renin-dependent hypertension or hyperaldosteronism.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DEP4027457.8 | 1990-08-30 | ||
DE4027457A DE4027457A1 (en) | 1990-08-30 | 1990-08-30 | AMINO ACID DERIVATIVES |
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CA2050092A1 true CA2050092A1 (en) | 1992-03-01 |
Family
ID=6413247
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CA002050092A Abandoned CA2050092A1 (en) | 1990-08-30 | 1991-08-28 | Amino acid derivatives |
Country Status (12)
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EP (1) | EP0474008A1 (en) |
JP (1) | JPH04297447A (en) |
KR (1) | KR920004413A (en) |
AU (1) | AU8352791A (en) |
CA (1) | CA2050092A1 (en) |
CS (1) | CS259991A3 (en) |
DE (1) | DE4027457A1 (en) |
HU (1) | HUT62603A (en) |
IE (1) | IE913050A1 (en) |
PT (1) | PT98822A (en) |
TW (1) | TW198009B (en) |
ZA (1) | ZA916861B (en) |
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EP1634018B1 (en) | 2003-06-19 | 2012-08-01 | Worgas Bruciatori S.R.L. | Burner with diffuser resistant to high operating temperatures |
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Publication number | Priority date | Publication date | Assignee | Title |
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ATE116994T1 (en) * | 1986-06-10 | 1995-01-15 | Merck Patent Gmbh | RENIN-INHIBITING AMINO ACID DERIVATIVES. |
-
1990
- 1990-08-30 DE DE4027457A patent/DE4027457A1/en not_active Withdrawn
-
1991
- 1991-08-19 EP EP91113841A patent/EP0474008A1/en not_active Withdrawn
- 1991-08-22 CS CS912599A patent/CS259991A3/en unknown
- 1991-08-26 KR KR1019910014764A patent/KR920004413A/en not_active Application Discontinuation
- 1991-08-27 TW TW080106793A patent/TW198009B/zh active
- 1991-08-28 CA CA002050092A patent/CA2050092A1/en not_active Abandoned
- 1991-08-29 IE IE305091A patent/IE913050A1/en unknown
- 1991-08-29 PT PT98822A patent/PT98822A/en not_active Application Discontinuation
- 1991-08-29 ZA ZA916861A patent/ZA916861B/en unknown
- 1991-08-30 AU AU83527/91A patent/AU8352791A/en not_active Abandoned
- 1991-08-30 JP JP3298603A patent/JPH04297447A/en active Pending
- 1991-08-30 HU HU912826A patent/HUT62603A/en unknown
Also Published As
Publication number | Publication date |
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HU912826D0 (en) | 1992-01-28 |
ZA916861B (en) | 1992-05-27 |
CS259991A3 (en) | 1992-03-18 |
DE4027457A1 (en) | 1992-03-05 |
IE913050A1 (en) | 1992-03-11 |
AU8352791A (en) | 1993-04-08 |
EP0474008A1 (en) | 1992-03-11 |
PT98822A (en) | 1992-07-31 |
TW198009B (en) | 1993-01-11 |
HUT62603A (en) | 1993-05-28 |
JPH04297447A (en) | 1992-10-21 |
KR920004413A (en) | 1992-03-27 |
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