CA2081236A1 - Amino acid derivatives - Google Patents
Amino acid derivativesInfo
- Publication number
- CA2081236A1 CA2081236A1 CA002081236A CA2081236A CA2081236A1 CA 2081236 A1 CA2081236 A1 CA 2081236A1 CA 002081236 A CA002081236 A CA 002081236A CA 2081236 A CA2081236 A CA 2081236A CA 2081236 A1 CA2081236 A1 CA 2081236A1
- Authority
- CA
- Canada
- Prior art keywords
- cyclopropyl
- signifies
- pyridyl
- triazolo
- acetamide
- 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 description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 239000000203 mixture Substances 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 206010020772 Hypertension Diseases 0.000 claims abstract description 8
- 230000002265 prevention Effects 0.000 claims abstract description 8
- 206010019280 Heart failures Diseases 0.000 claims abstract description 7
- -1 alkylsulphonylalkyl Chemical group 0.000 claims description 26
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 8
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 8
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 7
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 7
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 125000005302 thiazolylmethyl group Chemical group [H]C1=C([H])N=C(S1)C([H])([H])* 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 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 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- 239000013543 active substance Substances 0.000 claims 1
- HEJWXWCEUGXMNO-NJTBCWBZSA-N n-[(2s,3r,4s)-1-cyclohexyl-4-cyclopropyl-3,4-dihydroxybutan-2-yl]-2-(8-cyclopropyl-6-pyridin-3-yl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)acetamide Chemical compound C([C@@H]([C@@H](O)[C@@H](O)C1CC1)NC(=O)CC=1N2C=C(N=C(C2=NN=1)C1CC1)C=1C=NC=CC=1)C1CCCCC1 HEJWXWCEUGXMNO-NJTBCWBZSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 abstract description 9
- 108090000783 Renin Proteins 0.000 abstract description 7
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 4
- 230000009471 action Effects 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 78
- 239000000243 solution Substances 0.000 description 36
- 239000000843 powder Substances 0.000 description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 18
- 235000002639 sodium chloride Nutrition 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- 239000006260 foam Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 238000009833 condensation Methods 0.000 description 12
- 230000005494 condensation Effects 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 11
- 235000019341 magnesium sulphate Nutrition 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- PSDADIDIQCPEQC-UHFFFAOYSA-N 2-pyrazin-2-ylacetic acid Chemical compound OC(=O)CC1=CN=CC=N1 PSDADIDIQCPEQC-UHFFFAOYSA-N 0.000 description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 8
- 238000007127 saponification reaction Methods 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 239000007858 starting material Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 101800000734 Angiotensin-1 Proteins 0.000 description 6
- 102400000344 Angiotensin-1 Human genes 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 6
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 5
- 102100028255 Renin Human genes 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 5
- 235000011167 hydrochloric acid Nutrition 0.000 description 5
- 229960000443 hydrochloric acid Drugs 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 239000001828 Gelatine Substances 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 238000005660 chlorination reaction Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- GBCNXGKAGMMHMV-UHFFFAOYSA-N diethyl 2-(pyridin-3-ylmethyl)propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)CC1=CC=CN=C1 GBCNXGKAGMMHMV-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 239000003112 inhibitor Substances 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 4
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 229920005862 polyol Polymers 0.000 description 4
- 150000003077 polyols Chemical class 0.000 description 4
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 4
- 229910021653 sulphate ion Inorganic materials 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- HUTNOYOBQPAKIA-UHFFFAOYSA-N 1h-pyrazin-2-one Chemical compound OC1=CN=CC=N1 HUTNOYOBQPAKIA-UHFFFAOYSA-N 0.000 description 3
- HFBHPHBIBAUDNE-UHFFFAOYSA-N 2h-1,2,4-triazin-3-one Chemical class O=C1N=CC=NN1 HFBHPHBIBAUDNE-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 102000005862 Angiotensin II Human genes 0.000 description 3
- 101800000733 Angiotensin-2 Proteins 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229950006323 angiotensin ii Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000003795 chemical substances by application 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
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229960002668 sodium chloride Drugs 0.000 description 3
- 239000011780 sodium chloride Substances 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
- QCHGPWDFRLYQLQ-RWMBFGLXSA-N (1s,2r,3s)-3-amino-4-cyclohexyl-1-cyclopropylbutane-1,2-diol Chemical compound C([C@H](N)[C@@H](O)[C@@H](O)C1CC1)C1CCCCC1 QCHGPWDFRLYQLQ-RWMBFGLXSA-N 0.000 description 2
- UVJGDBNDVRWKTG-UHFFFAOYSA-N (3-cyclopropyl-5-pyridin-3-ylpyrazin-2-yl)hydrazine Chemical compound NNC1=NC=C(C=2C=NC=CC=2)N=C1C1CC1 UVJGDBNDVRWKTG-UHFFFAOYSA-N 0.000 description 2
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 108090001067 Angiotensinogen Proteins 0.000 description 2
- 102000004881 Angiotensinogen Human genes 0.000 description 2
- 108010064733 Angiotensins Proteins 0.000 description 2
- 102000015427 Angiotensins Human genes 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 229960004977 anhydrous lactose Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- RCJVRSBWZCNNQT-UHFFFAOYSA-N dichloridooxygen Chemical compound ClOCl RCJVRSBWZCNNQT-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 2
- 229960002216 methylparaben Drugs 0.000 description 2
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 2
- 239000003791 organic solvent mixture Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 235000014786 phosphorus Nutrition 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 2
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 2
- 229960003415 propylparaben Drugs 0.000 description 2
- 238000003127 radioimmunoassay Methods 0.000 description 2
- 239000002461 renin inhibitor Substances 0.000 description 2
- 229940086526 renin-inhibitors Drugs 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
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Classifications
-
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
Abstract The compounds of the formula I
wherein X, R1, R2, R3, R4 and R6 have the significance given in claim 1, in the form of optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates as well as pharmaceutically usable salts thereof inhibit the action of the natural enzyme renin and can accordingly be used in the form of pharmaceutical preparations for the control or prevention of high blood pressure and cardiac insufficiency. They can be manufactured by reacting an aminodiol of the formula II
with a corresponding acid or an activated derivative thereof.
wherein X, R1, R2, R3, R4 and R6 have the significance given in claim 1, in the form of optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates as well as pharmaceutically usable salts thereof inhibit the action of the natural enzyme renin and can accordingly be used in the form of pharmaceutical preparations for the control or prevention of high blood pressure and cardiac insufficiency. They can be manufactured by reacting an aminodiol of the formula II
with a corresponding acid or an activated derivative thereof.
Description
2~236 RA~4Q19111 The present invention is conce~ed with amino acid derivatives.
6 In particular, it is concemed with amino acid derivatives of the general formula N~N O R4 OH
~N~NH~R5 N~f~X R3 OH
1D wherein X signifies a nitrogen atom ol -CH-, Rl signifies phellyl, pyridyl or isoquinolinyl, R2 signif;es cycloal:kyl, cycloalkylalkyl, alkylthioalkyl, alkylsulphonylalkyl, alkenyl or, where X signifies a nitrogen atom and/or Rl signifies isoquinolinyl and/or R3 signifies alkenyl, also alkyl, :R3 signi~ies hydrogen, alkyl, alkenyl, imidazolylmethyl, pyridylmethyl, t~ia~olylmethyl or benzyl, R4 signifies cyclohe~ylmethyl or benzyl and :R5 signifies cycloalkyl, alkyl or heterocyclylalkyl, in the form of optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates as 2~) well as pharmaceutically usable salts of these compounds.
These compounds are novel and are distinguished by valuable pharmacodynamic prop~rties.
Objects of the present invention are the compounds of formula I
and their pharmaceutically usable salts per se and for use as thera-peutically active s~bstances, the manufacture of these compounds, medicaments containing these and the manufacture of such medica-ments as well as the use of compounds of formula I and their pharma-ceutically usable salts in the control or prevention of illnesses or in the improvement of health, especially in the control or prevention of high blood pressure and cardiac insufficiency.
:Kbr/08.û9.92 208123b The term "alkyl" used in the present description, alone or in combination, signifies straight-chain and branched, saturated hy-drocarbon residues with 1-8, preferably 1-4, car~on atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, t-butyl, pentyl, he~yl and the like. The term "cycloalkyl" signifies saturated, cyclic hydrocarbon residues with 3-8, preferably 3-6, carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term ~'alkenyl" relates to straight-chain ana branched, unsaturated hydrocarbon residues with 2-8, preferably 2-4, carbon atoms such as 10 vinyl, allyl, 2-butenyl, 3-butenyl and the like. The term "heterocyclyl"
signifies a saturated 5- or 6-membered heterocycle with at least one nitrogen atom and optionally an additional oxygen, nitrogen or sulphur atom as a Iing member, which is attached to ~he -CH(O~I)- group via a nitrogen atom and in which the additional nitrogen atom can be alkyl-15 ated, such as morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, S-oxothiomorpholinyl, S,S-dio~othiomorpholinyl, pyrrolidinyl, thiazolidinyl, irnidazolidinyl, oxazolidinyl, N-methylpiperidinyl and the like.
aD The term "pharmaceutically usable salts" embraces salts with inorganic or organic acids such as hydrochloric acid, hydro- bromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulphonic acid, p-toluenesulphonic acid and the like. Such salts can be manufactured readily by any person skilled in the art having regard to the state of the art and taking into consideration the nature of the compound to be converted into a salt.
The compounds of formula I have at least three asymmetric carbon atoms and are therefore present in the form of optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereome~c racemates. The present invention embraces all forms. M[ixtures of diasteromers, diastereomeric racemates or mixtures of diastereomeric racemates can be separated according to 3~ usual methods, e.g. by column chromatography, thin-layer chromato-graphy, HPLC and the like.
2~8~ 236 A particular group of compounds of formula I comprises those in which R2 signifies cycloalkyl, cycloalkylalkyl, alkylthioalkyl, alkylsul-phonylalkyl, alkenyl or, where X signifies a nitrogen atom and/or Rl signifies isoquinolinyl, also alkyl.
Those compounds of formula I in which X signifies -CH- are prefer.red. Compounds of formula I in which Rl signifies pyridyl, especially 3-pyridyl, are`also preferred.~ R2 pre~erably sigDifies cycloalkyl or cycloalkylalkyl, especially cycloalkyl, particularly cyclopropyl. The preferred significance of R3 is imidazolylmethyl, pyridylmethyl or thiazolylmethyl, especially pyIidylrnethyl or thiazolylmethyl, par-ticularly 4-thiazolylmethyl. Cyclohexylmethyl is the preferred si~ifi-cance for R4. R~ preferably signifies cycloalkyl or alkyl, especially cycloalkyl, particularly cyclopropyl.
~5 :From the above it will be evident ~at those compounds of formula I in whic~ X signifies -CH, Rl signifies 3-pyridyl, R2 signifies cyclo-propyl, R3 signifies 4-thiazolylmethyl, R4 signifies cyclohexylmethyl and R5 signifies cyclopropyl are particularly preferred.
aD
Especially preferred compolmds of formula I are:
(R or S)-N-[(1S,2R,3S)-1-(Cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-cyclopropyl-6-(3-pyridyl)- a-(3-pyridylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetamide, N-~(1$,2R,3S)-1-(cyclohe:~ylmethyl)-3-cyclopropyl-2,3-di-hydroxypropyl]-8-cyclopropyl-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetamide, (R or S~N-~(1S,2R,3$)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-cyclopropyl-6-(3-pyridyl)-a-(4-thiazolylmethyl)-s-triazolo[4,3-a]pyrazine-3-a~etamide, (R,S)-N-[(1S,2R,3$)-1-benzyl-3-cyclopropyl-2,3-dihydro~ypropyU-8-cyclopropyl-6-(3-pyridyl)-a-(3-pyridyl- methyl)-s-triazolo[4,3-a]pyrazine-3-acetamide, (R or S)-N-[(1$,2R,3$)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-(cyclopropylmethyl)-6-(3-pyridyl)-a-(3-pyridylmethyl)-~-triazolo[4,3-a~pyrazine-3-acetamide, (R or S~N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopIopyl-2,3-2~23~
dihydro~ypropyl]-8-(cyclopropylmethyl)-6-(3-pyridyl)-a-(4-thiazol-ylmethyl)-~-triazolo~4,3-a~pyrazin0-3-acetamide and tR9S)-a-allyl-N-[(1S.2R,3S)-1-(cyclohe~ylDnethyl)-3-cyclopropyl-2,3-d:ihydro~ypropyl]-8-propyl-6-(3-pyridyl)-s-triazolo[4 ,3-a]pyrazine-3-acetamide.
Further ~specially preferred compounds of formula I are:
N-[(lS,2R,3S)-1-(Cyclohe~ylmethyU-3-cyclopropyl-2,3-dihy-10 drn~ypropyl]-6-(4-isoql~inolinyl)-8-propyl-s-triazolo[4,3-a]pyrazine-3-acetamide, (S or R~-N-[(1S,2R,3S)-1-(cyclohexyl~ethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-ff-(4-isoquinolinyl)-8-propyl-a-(3-pyridylmethyl)-s-triazolo[4,3-a~pyrazine-3-acetamide and 16 (R or S)-N-[(1S,2R,3$)-1-(cyclohex~lmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-6-(4-isoquinolinyl)-8-pl opyl-a-(3-pyridylmethyl)-s-triazolo[4,3-a~pyrazine-3-acet~de.
Further e~amples of prefelTed compounds of formula I are:
ao N-[(1S,2R,3S)-1-(Cyclohe~ylmethyl)-3-cyclopropyl-2,3-dihy-droxypropyl]-8-propyl-6-(3-pyridyl~s-triazolo[3,4-~[1,2,4]triazine-3-acetamide, (R or S)-N-[(lS,2R,3S)-1-(cyclohexylmethyl)-3-cycloprnpyl-2,3-dihydroxypropyl~-8-propyl-6-(3-pyridyl)-a t3-:pyridylmethyl)-s-triazolo [3,4-f~[1,2,4]triazine-3-acetamide, (S or R)-N-[(lS,2:E~,3S)-1-(cyclohexylmethyl)-3-cyclo propyl-2,3-dihydroxypropyl]-8-propyl-B-(3-pyridyl)-a-(3-pyridylmethyl)-s-triazolo [3,4-~[1,2,4]triazine-3-acetaunide, tS or R~N-C(1S92R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3 dihydro~ypropyl]-8-isobutyl-6-(3-pyridyl)-a-(3-pyxidylmethyl)-s-triazolo[3,4-fl[1,2,4]triazine-3-acetamide and (R or S~N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-isobutyl-6-(3-pyridyl)-a-(3-pyridylmethyl)-s-36 triazolo[3,4-f~[1,2,4]t~azine-3-acetamide.
The compouIlds of formula I in the form of optically pure dia-stereomers, mixtures of diastereomers, diastereomeric racemates or - 5 ~ 2 ~ ~
mi~tures of diastereomeric racemates as well as pharmaceutically usable salt~ thereof can be manufactured by a~ reaclting a compolmd of the general ~ormula - H2N--~J~ Rs OH
wherein R4 and R5 have the significance given above, with a compound of the general formula N--N O
J~OH III
l~X R3 wherein X, Rl, R2 and R3 haYe the significance given above, or an activated derivat*e thereof, and b) if desired, oxidizing a compound of forrnula I obtained in which R2 æignifies alkylthioalkyl to the corresponding compound of formula I
in which 1~2 signifies alkylsulphonylal~yl, and/or ~D c) if desired, separating a mixture of diastereomeric racemates into the diastereomeric race:mates or optically pure diastereomers, and/or d) if desired, separating a mi~ture of diastereomers into the optically pure diastereomers, and/or e) if desired, converting a compolmd obtained into a pharmaceu-tically usable salt.
The acylation of a compo~Lnd of formula II is effected according to 30 methods known per se. Especially suitable acylating agents are activated.
acid derivatives such as esters, mixed esl;ers, acid halides, acid anhy-.
-6- 2~8123~
drides or mi~ed acid anhydlides. The reaction is carried out in an orga-nic solvent or solvent mixture which is inert under the reaction condi-tions at a temperature between about 0C and room temperature. As sol-vents there come ;nto consideration especially aromatic hydrocarbons 5 such as benzene, toluene or ~ylene, chlorinated hydrocarbons such as methylene chlolLide or chlo3: oi~orm, ethers such a~ diethyl ether, tetra-hydrofilran or dioxan, and the like. The reaction is e~ected under re-action conditions which are usual in peptide chemistry, i.e. preferably in the presence of a condensation agent such as HBTU (O-benzotriazolyl-10 N,N,N',N'-tetramethyluronium hexaIluorophosphate), BOP (benzotria-zol- 1-ylo~y-tris-(dimethylamino)phosphonium hexafluol ophosphate), BOPC (bis(2-oxo-3-oxazolidinyl)phosphinic chloride), HOBT (N-hydroxy-benzotriazole), DCC (dicy~lohe~ylcarbodiimide), EDC (N-ethyl-N'-(3-dimethylaminopropyl)car~odiimide hydrochloride), and the like. The 15 reaction iB conveniently carried out in an organic solvent or solvent mi:Rture which is inert under the reaction conditions at a temperature between about 0 and 50C, preferably at about room temperature. As solvents there come into consideration especially dimethylformamide, methylene chloride, acetonitrile, tetrahydrofùran and the like.
ao The oxidation of a compound OI formula I in which R2 signiies alkylthioalkyl is also carried out according to methods known per se.
The oxidation can be carried out e.g~ by reaction with hydrogen peroxide, an organic peracid such as peracetic acid, perbenzoic acid, perphthalic 25 acid and the like, a perester, sodium periodate, potassium peroxomono-sulphate in alkanoVwater and the like. The oxidation is conveniently carried out in an inert organic solven~ ~uch as a halogenated hydrocar-bon, e.g. chloroform, methylene chloride~ dichloroethane and the like.
When hydrogen peroxide is used as the oxidation agent, the reaction can 30 also be carried out in acetic acid and the like. Conveniently, the oxida-tion i8 carried out at a temperature between about 0 and 30C, prefiera-bly at about 0C
The starting materials of formula II are known or can be obtained 35 in analogy to the preparation of the known compounds.
- 7 - 2 ~ 3 $
The starting materials of formula III in which ~ signifies -CH-are known fi om EP-A 0,36g,743 or can be obtained in analogy to the preparation of the known cQmpounds.
6 The remaining compounds of formula III are novel and are an object of the present invention. They can be prepared starting ~rom corresponding 1,2,4-triazinones according to va~ous methods which are known per se and which are ~ some e~tent analogous to the procedure described in EP-A 0,369,743. These preparative procedures as well as the procedure in accordance with :EP-A 0,369,743 are compiled in the following Schemes I and II. In these Schemes R signifies alkyl and Rl, R2 and R3 have the signilScance given above. The 1,2,4-triazinones of formula IX in Scheme II can be obtained in analogy to the preparation of 1,2,4-triazinones described in J. Heterocyclic Chem., 15, 1271(1978).
~12~
Scheme 1 ~NH
N~
Rl n - t ~1 R ~N
N~
R1 V .:
~2~N
N~J
R~
HN--NH N--N
R2~ C~COOR P~2~ COOR
R1 V:~ F11 VIII
N--N
R2~ COOH
R1 m~, ,.
;: . ~ , .
.
' 2~8~3~
Scheme 2 N~N
t Cl R2~N
N~,N
HN~NH2 R2~NI
N,~N
HN--NH N--N
R2~ C~X~COOR _ ~ R2~ COOR
N--N
R2~l~ J 3~CC)OH
~N R3 R1 mb -lo- 2~8~3~
The compounds of ~orlmula I and their pharmaceutically usable salts have an inhibitory activity on the natural enzyme renin. The latter passes ~om the ~idneys into the blood and ~ere brings about the cleavage of angiotensinogen wi~h the formation of the decapeptide 5 angiotensin I which is then cleaved in the llmgs, the kidneys and other o-rgans to the octapeptide angiotensin II. AngiotensiIl II increases the blood pressure not only directly by arte~al constriction, but also indi-rectly by the liberation o`f the so~ium ion-retaining hormone aldosterone from the adrenal gland, Wit~L which is associated an increase in the 10 extracellular fluid volume. This increase is attributed to the action of angiotensin II itself or to the heptapeptide angiotensin III which is formed therefrom as a cleavage product. Inhibitors of the en~ymatic activity of renin brings about a decrease in the formation of ang~otensin I and as a consequence thereof the formation of a smaller amount of 15 angiotensin II. The reduced concentration of $his act*e peptide hor-mone is the actual reason fior the blood pressure-lowering activity of renin inhibitors.
The activity of renin inhibitors can be demonstrated experiment-2D ally by means of the in vitro test described hereinafter:
In vitro test with l2ur_human reni~
The test is carried out in Eppendorf` te~t tubes. The incubation 25 mixture consists of (1) 100 ml of human reni]~l in buf~er A (O.lM sodiumphosphate solution, pH 7.4, containing 0.1% bovine serum albumin, O.l~o ~odium azide and 1~ ethylenediamine-tetraacetic acid), suflEicient ~or a renin activity of 2-3 ng of angiotensin Vml/hr.; (2) 145 ml of buf~er A: (3) 30 ml of 10 mM human tetradecapeptide renin substrate 30 (hTD) in 10 mM hydro- chloric acid: (4) 15 ml of dimethyl sulphoxide with or wi~hout inhibitor and (5) 10 ml of a 0.03 molar solution of hydro-xyquinoline sulphate in water.
The samples are incubated for three hours at 37C and, respect-35 *ely, 4~ in triplicate. 2 ~100 ml samples per e~perimental test tubeare used in order to measure the production of angiotensin I via RIA
(standard radioimmunoassay; clinical assay solid phase kit). Cross reactivities of the ant;body used in the RIA are: angiotensin I 100%;
2~8~23~
angiotenæin II 0.0013%; hTD (angiotensin I-Val-Ile-His-Ser-VH 0.09%.
The production of angiotensin I is dete~nined by the dif~erence between ~e experiment at 37C and that at 4C.
The following coIltrols are carried out:
(a) incubation of hTD samples without renin and without inhibitor at ~ -37C an'd'4C.~''The ai~erence''bet'ween these'two values gives the base value of the ang~otensin I production.
(b) Incubation OI hTD samples with renin, but without inhibitsr at 37C and 4C. The difference between these values gives the maximal value of angiot~nsin I production.
~5 In each sample the base value of the angiotensin I production is subtracted from the angiotensin I production which is determined. The dif~erence between the ma~imal value and the base value gives the value of the ma~imal substrate hydrolysis (- 100%) by renin.
The results are given as ICso values ~which denote that concen-tration of the inhibitor at which the enzymatic activity is inhibited by 50%. The IC~o values are determined from a linear regression curve from a logit-log plot.
The results obtained in this test are compiled in the following Table:
Table ~ I~50 v~1ues in nmol/lt B 2.0 D 2.3 F
-~2- 2~ 23~
A = (R or S)-N-[(1S,2R,3~;~1-(Cyclohe~ylmethyl~-3-cyclQpropyl-2,3-dihydro~ypropyl]-8-cyclopropyl-6-(3-pylidyl)-a-(3-pyridylmethyl~-s-triazolo[4,3-a]pyrazine-3-acetamide B = (R or S)-N-r(1S,2R,3S}1-(Cyclohe~ylmethyl)-3-oyclopropyl-2,3-dihydrogypropyl]-8-cyclopropyl-6-(3-pyridyl) o~{4-thiazolylmethyl)-s-triazolo[4 ,3-a]pyrazine-3-acetamide C = (R or S)-N-[(1S,2iR,3S~1-(Cyclohe~ylmethyl)-3-cyclopropyl-2,3-dihydro~ypropyl]-8-(cyclopropylmethyl)-6-(3-pyridyl)-a-(3-pyri-dylmethyl)-s-triazolo[4 ,3-a]pyrazine-3-acetamide D = ~R or S)-N-[(1S,2R,3S~1-(Cyclohe~ylmethyl)-3-cyclopropyl-2,3-dihydro~ypropyl]-8-(cyclopropylmethyl)~6-(3-pyridyl)-a-(4-thia-1~ zolylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetamide E = (R,S)-N-~(1S,2R,3S)-1-Benzyl-3-cyclopropyl-2,3-dihydroa;y- propyl]-8-cyclopropyl-6-(3-pyridyl)-a-(3-py~idylrnethyl)-s-triazolo[4,3-a]pyra-zine-3-acetamide aD
F = (R or S)-N-[(1S,2R,3S)-1-(Cyclohexylmethyl~-3-cycloproyl-2,3-dihydroxypropyl~-8-isobutyl-6-(3-pyridyl)-a-(3-pyridylmethyl,)-s-triazolo[3 ,4-~[1,2,4]triazine-3-acetamide 25 G = (R,S)-a-Allyl-N-~(1S,2R,3S)-1-(cyclohe~ylmethyl)-3-cyclopropyl-2,3-dihydro~ypropyl~-8-propyl~6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetamide The compounds of formula I as well as their pharmaceutically 30 usable salts can be used as medicaments, e.g. in the form of pharma-ceutical preparations. Ihe pharmaceutical preparations can be ad-ministered enterally su~h as orally, e.g. in the ~orm of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions, nasally, e.g. in the form of nasal sprays, or rectally, e.g.
35 in the form of ~uppositories. However, the administration can also be ef~ected parenterally such as intramuscularly or intravenously, e.g. in the folm of injection solutions.
-13- 2~8~2~6 The compounds of fo~nula I as well as their pharmlaceutically usable SaltB can be processed with pharmaceutically inert, inorganic or organic e~cipients for the manu~acture OI tablets, coated tablets, dragées and hard gelatine capsules. Lactose, corn starch or derivatives thereo~, 5 tal~, stearic acid or its salts e~ can be used e.g. as such excipients for ta~lets, dragées and hard gelatine cap~ule~.
- Suitable excipients ~or soft gelatine capsules are e.g. vegetable oils, wa~es, fats, semi-solid and liquid polyols etc.
Suitable exci~ients for the mallufacture of solutions and syr~lps are eg. water, polyols, saccharose, invert sugar, glucose etc.
Suitable excipients for injection solutions are e.g. water, alcohols, 15 polyols, glycerol, vegetable oils etc.
Suitable excipients for auppositones are e.g. natural or hardened oils, wa~e~, fats, semi~ uid or liquid polyols etc.
~0 Moreover, the pharmaceutical preparations can contain preser-vatives, solubili~ers, viscosity-increasing substances, stabilizers, wet-ting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buf~ers, coating agents or antioxidants.
They can also contain still other therapeutically valuable substances.
~5 In accordance with the inveIltion ~e compounds of general formula I as well a~ their pharmaceutically usable salts can be used in the control or prevention of high blood pressure and cardiac insu~-ficiency. The dosage can vary within wide limits and will, QI course, be 30 fitted to the individual requirements in each particular case. In general, in the case of oral admir istration there should suffice a daily dosage of about 3 mg to about 3 g, preferably about 10 mg to about 1 g, e.g. approxi-mately 300 mg per person, divided in preferably 1-3 ~t doses, which can e.g. be of the same amount, whereby, however9 the upper limit just 36 given can also be exceeded when this is found to be indicated. Usually, children receive half of the adult dosage.
-14- 20~2~6 The following E~amples are intended to illustrate the present invention, but are ~IOt intended to be lir~iting in any manner. All temperatures are given in degrees Celsius.
S ~
0.587 g (1.55 mmol) of HBTU and 0.21~ ml (1.5~ mmol~ of triet~iylamine were added to a 801u~ion ~ 0;600 g rl;56 mmol) of rac-8-cyclopropyl-6-(3-pyridyl)--(3 pyridylmethyl)-s-triazolor4,3-a]pyraziIle-3-acetic acid and 0.352 g (1~55 mmol) of (lS,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butarledio~ ~EP-A 0,332,008) in 30 ml of acetonitrile and the resulting suspension was stirred at room temperature for 12 hours.
Af~er the addition of saturated sodi~n chlolide solution the mixture was extracted three times with ethyl acetate. The orgarlic phase was washed ~5 with æaturated sodium hydrogen carbonate solution, water arld ~aturated sodium chloride ~olution, dried over magnesium sulphate, Sltered and evaporated under reduced presæure. ~er chromatography on silica gel (methylene chloride/methanol 9:1) there were obtained 0.240 g of the pure, less polar epimer (R or ~;~N-r(1S,2R,3S)-l-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydrc)xypropyl]-8-cyclopropyl-6-(3-pyridyl)-a-(3-pyridylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetamide, MS:
tFAB) 596 (M+H)~, and 0.160 g of th~ pure, ]more polar (S or O-N-[(lS,2R,3S~-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-cyclopropyl-6-(3-pyridyl)-a-(3-pyridylmethyl~-s-triazoloL4,3-a]pyrazine-3-acetarnide? MS: (FAB) 596 (M~H)~, each as a colourless foam.
The rac-8-cyclopropyl-6-(3-pyridyl)-a-(3-pyridylmethyl)-s-t~iazolo~4,3-a]pyrazine-3-acetic acid used as the starting material was prepared as follows:
(a) 49 g (240 mmol) of DCC were added at 10 to a suspension of 25.18 g (18S ~nol) of the sodium salt of 2-cyclopropyl-2-oxo acetic acid (Colle t.
Czech. Chem. Commun. 40, 1038 ~1975)), 38.28 g (185 mmol) of 3-(aminoacetyl)pyridine dihydrochloride (J. Chem. Soc. 1938, 7~3) and 25.34 g (185 mmol) of HOBT in 750 ml of methylene chloride and the mixture wa~ stirred at room temperature overnight. The resulting urea was filtered of~, the ~ltrate was washed with saturated sodi~n hytlrogen carbonate solution and subsequently with saturated sodium chloride 3 ~
~olution, dried over magnesium sulphate, filteled and evaporated under reduced pressure. Chromatography on silica gel (methylene chloride/-methanol 97:3) yielded 21 g of N-~2-o~o-2-(3-pyridyl)ethyl]-~-oxocyclo-propylaretamide as colourless crystals, M~: (EI) 233 (M+H)+.
(b) A solution of 9.00 g (38.76 mmol) of N-[2-oxo-2-(3-pyridyl)ethyl]-oc-oxocyclopropylacetamide in 80 ml of ethanol was treated wit~ 8.90 g (116 mr~ol) of ammonium acetate and the mi~:ture was heated at reflu~
for 2 hours. The solvent was evaporated and the residue was dissolved 10 in methylene chloride. The æolution was wa~hed in succession with water, ~aturated sodium hydrogen carhonate solution, water and saturated sodium chloride sollltion, dried over magnesium sulphate, Sltered and evaporated under reduced pressure. Af~cer chromatography on silica gel (methylene chlo~de/methanol, ~:1) and recrystalliza~on from diethyl et~er there vvere obtained 6.û0 g of 3-cyclopropyl-5-(3-pyridyl)-2(1H)-pyrazinone as a yellow powder, m.p. 168-170, MS: (EI) 213 M+.
(c) A solution of 6.00 g (28.13 mmol~ of 3-cyclopropyl-5-(3-py~idyl)-aD 2(1H)-pyrazinone in 50 of phosphorus oxychloride was heated to reflu~
for 2 hours. The pale brown solution was evaporated on a rotary evapo-rator under reduced pressure and the residue was poured into ice-water. Af~Ger e~traction with methylene chloride, drying o~er sodium sulphate, filtration and evaporation under r~duced pressure there were 25 obtained 5.20 g of 2-chloro-3-cyclopropyl-5-(3-pyIidyl)pyrazine as a colourless powder, MS: (EI) 230 Mf.
(d) A 601uti0n of 5.20 g (22.4 mmol) of 2-chloro-3-cyclopropyl-5-(3-py~dyl)pyrazine in 50 ml of ethanol was treated with 7 ml (140 mmol) of 30 hydrazine hydrate and the mixture was heated to reflux ~or 7 hours.
After cooling to room temperature the precipitated product was filtered o~ under suction and there were thus obtained 2.70 g of 3-cyclopropyl-2-hydrazino-5-(3-pyridyl)pyrazine as yellow glistening platelets, m.p. 179-181, MS: OEI) 227 M~.
~e) 0.760 g (4 ~nol) of p-toluenesulphonic acid was added to a solution of 0.900 g (4 mmol) of 3-cyclopropyl-2-hydrazino-5-(3 pyri-dyl)pyrazine and 1.5 g (6 mmol) of diethyl (3-py~dylmethyl)malonate -16- ~8~3~
(Arch. Pharm. 308, 663 (1975)) in 70 ml of ~ylene and the mixture was heated to reflux ~or 2 hours on a water separa~r. Af~er distilling OI the ~ylene under reduced pressure the residue was dissolved in methylene chloride. The organic phase was washed with saturated sodium bicar-bonate solution and ~ubsequently with satura$ed sodium chloride solu-tion, dried over magnesium sulphate, filtered and evaporated under reduced pressure. Chromatography on silica gel (methylene chloride/-methanol~3:1) yielde~`O.B00 g~of ethyl rac-8-cyclopropyl-6-(3-pyridyl)-oc-(3-pyridylmethyl)-s-t~iazolo~4,3-a]pyrazine-3-acetate as a colourless oil (Rf:
0.33, silica gel, methylene chloride/methanol, 9:1).
(f~ A solution of 0.300 g (0.724 mmol) of ethyl rac-8-cyclopropyl-6-(3-pyridyl~-oc-(3-pyridylmethyl)-s-triazolo[4,3-a]pyra~ e-3-aceta$e in 20 ml of ethanol was treated with 10 ml of 2N sodium hydro~ide solution and 15 the mixture was stirred at room temperature for 6 hours. Ihereafter, 10 ml of 2N hydrochloric acid were added thereto, the mi~ture was evaporated and the residue was partitioned between 10 ml of water and 50 ml of a 10:1 mixture of methylene chloride and methanol. The organic phase was dried over sodium sulphate, filtered and evaporated under reduced pressure. There was thus obtained 0.258 g of rac-8-cyclopropyl-6-(3-pyridyl)-a-(3-pyridylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetic acid as a colourless, amorphous powder, MS: (EI) 342 (M-C02)+.
Example 2 The ~ollowing compounds were manufactured in an analogous manner ~o that described in Example 1:
- From rac-8-cyclopropyl-6-(3-pyridyl)-a-(4-thiazolylmethyl)-s-triazolo 30 [4,3-alpyrazine-3-acetic acid and (lS,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol the (lR or S~N-~(1S,2R,3S)-1-(cyclohexyl-methyl~3-cyclopropyl-2,3-dihydroxypropyl]-8-cyclopropyl-/3-(3-pyridyl)-a-(4-thiazolylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetamide, MS: ~FAB) 602 (M+H)~, and the (S or R)-N-[(lS,2R,3S~1-(cyclohexylmethyl)-3-cyclo~
35 propyl-2,3-dihydroxypropyl]-8-cycloprop;y1-6-(3-pyridyl)-a-(4-thiazolyl-methyl)-s-triazolo[4,3-a]pyrazine-3-acetamide, MS: (FAB) 602 (M~H)+, each as a colourless foam;
-17- ~81236 - from 8-cyclopropyl-6-(3-pyridyl~s-triazolo[4,3-a3pyrazine-3-acetic acid and (1S,2R,3S~-3-amino-4-cyclohe~yl-1-cyclQpropyl-1,2-butanediol the N-[(1S,2R,3S)-1-(cyclohe~ylmethyl3-3-cyclopropyl-2,3-dihydroxypropyl]-8-cyclopropyl-6-(3-py~idyl)-s-triazolo[d~,3-a]pyrazine-3-acetamide, MS:
5 (FAB) ~05 (M-~H)~, as a colourless foam;
- from rac-8-(cyclopropylmethyl)-6-(3-pyridyl)-a~3-pyridylmethyl)-s-triazolor;~,3-a]pyTazine:3-acetic acid ana ~1$,2R;3S)~3-amino-4-cyclohe~yl-1-cyclopropyl-1,2-butanediol ~he (R or S)-N-[(lS,2R,3S)-1-10 (cyclohe~ylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-(cycloprQ-pylmethyl)-6-(3-py~idyl)-o~-(3-pyFidylmethyl)-s-t~azolo[4,3-a]pyrazine-3-acetamide, MS: (FAB) 610 (M+H)+, and the (S or R)-N-[(1S,2R,3O-1-(cyclohe~ylmethyl~-3-cyclopropyl-2,3-dihydro~ypropyl]-8-(cyclopro-pylmethyl)-6-(3-pyridyl)-a-(3-pyridylmethyl)-s-tliazolo[4,3-a~pyI azine-3-15 acetamide, MS: (FAB) 61Q (M+H)+, each as a colourless foam;
- from rac-8-(cyclopropylmethyl)-6^(3-pyridyl)-a-(4-thiazolylmethyl)-s-triaæolo[4,33pyrazine-3-acetic acid and (1S,2R,3$)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butaIIediol the (R or S~-N-[(1S,2R,3S)-1-(cyclohexyl-20 methyl~-3-cyclopropyl-2,3-dihydroxypropyll-8-(cyclopropylmethyl)-6-(35-pyridyl)-a-(4-thiazolylmethyl)-s-tIiazolo[4,3-;3]pyrazine-3-acetamide, MS:
(ISP) 616 (M~E)+, and the (S or R)-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-~cyclopropylmethyl)-8-(3-pyridyl)-a-(4-thiazolylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetamide, MS: (ISP) 616 25 (M~H)~, each as a colourless foam;
- from 8-(cyclopropylmethyl)-6-(3-pyridyl)-s-triasolo[4,~-a]pyrazine-3-acetic acid and (lS,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-~utanediol the N-C(lS,2R,3S)-1-~cyclohexylmethyl)-3-cyclopropyl-2,3-30 dihydroxypropyl]-8-(cyclopropylmethyl)-6-(3-pyridyl)-s-triazolo[4,3-a]-pyrazine-3-acetamide, MS: (ISP) 519 (M~H)~, as a colourless foam;
- from rac-6-(4-isoquinolinyl)-8-propyl-a-(3-pyridylmethyl)-s-tr~azolo [4,3-a]pyrazine-3~acetic acid and (1S,2R,3S)-3-amino-4-cyclohexyl-1-35 cyclopropyl-1,2-butanediol the (R or S)-N-[(1S,2R,3$)-1-(cyclohexyl-methyl)-3-cyclopropyl-2,3-dihydroxypropyl]-6-(4-isoquinolinyl)-8-propyl-o~-(3-pyridylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetam;de, MS: (FAB) 648 (M+H)f, and the (~3 or R)-N-[(1S,2R,3$}1-(cyclohexylmethyl)-3-cyclopro--18- 2~23fi pyl-2,3-dihydroxypropyl]-6-(4-isoquinolinyl)-8-propyl-a-(3-pyridylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetamide, M[S: (FAB) 648 (M~H~, each as a colourless foam;
- from 6-(4-isoquinolinyl~-8-propyl-s-triazolo[4,3-aJpyrazine-3-acetic acid and (1S,2R,30-3-amino-4-cyclohe2~yl-1-c~rclopropy~-1,2-butanediol the N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydro:gypropyU-6-(ds-isoquinolinyl)~8-propyl s-ti~iazolo[4,3-~})yrazine-3-acetamide, MS: (EI~
556 M+, as a colourless foam;
- ~rom rac-8-cyclopropyl-6-(3-pyridyl)-oc-(3-pyridylmethyl)-s-1triazolo[4,3-a]pyrazine-3-acetic acid and (1S,2R,30-3-amino-1-cyclopropyl-4-phenyl-1,2-butanediol the (R,S)-N-[(lS,2R,3S)-1-benzyl-3-cyclopropyl-2,3-dihydro~ypropyl]-8-cyclopropyl-6-(3-pyridyl)-a-(3-pyridylmethyl)-s-15 triazolo[4,3-a]pyrazine-3-acetamide, MS: (FAB) 590 (M+H~+, as a colourless foam (1:1 epimer mixture);
- from 8-propyl-6-(3-pyridyl)-s-triazolo[3,4-f~[1,2,4]~iazine-3-acetic acid and (lS,2R,3S)-3-arnino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol the N-ao [(1$,2R,3$)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-propyl-6-(3-pyridyl)-s-triazolo[3,4-f~[1,2,4]triazine-3-acetamide, MS:
(FAB) 508 (M~H)~, as a colourless foam;
- frcm rac-8-propyl-6-(3-pylidyl)-a-(3-pyridylmethyl)-s-triazolo[3,4-f~-25 [1,2,4]triazine-3-acetic acid and (lS,2R,3S)-3-amino-4-cyclohexyl-:l-cyclopropyl-1,2-butanediol the (R or S~N-[(1S,2R,3S)-1-(cyclohexyl-methy~)-3-cyc~opropyl-2,3-dihydro:~ypropyl]-8-propyl-6-(3-pyridylhc-~3-pyridylmethyl)-s-triazolo[394~f~[1,2,4]triazine-3-acetamide, MS: (FAB) 599 (M+H)~, and the (S or R)-N-[(1S,2R,3S)-1 (cyclohexylmethyl)-3-cyclopro-30 pyl-2,3-dihydro~ypropyl]-8-propyl-6-(3-pyridyl)-a-(3-pyridylmethyl)-s-triazolo[3,4-f 1[1,2,4]triazine-3-acetamide, MS: (FAB) 599 (M+H)+, each as a colourless foam;
- from rae-8-isobutyl-6-(3-pyridyl)-a-(3-pyIidylmethyl~s-triazolo[3,4-f~-36 ~1,2,4Jtriazine-3-acetic acid and (1S,2R,3$)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol the (R or S~-N-[(1S,2R,3S)-1-(cyclohe~yl-methyl)-3-cyclopropyl-2,3-dihydro~ypropyl]-8-isobutyl-6~(3-pyridyl)-os-(3-pyridylme~hyl)-s-triazolo[3,4-f~[1,2,4]triazine-3-acetamide, MS: (FAB) 6:13 2~23~
(M~H)~, and the (S or ~ -N-[(1S,2R,3S~1-(cyclohexylmethyl)-3-cyclopro-pyl-2 ,3-dihydroxypropyl]-8-isobutyl-8-(3-pyridyl)-a-(3-pyridylmethyl)-s-tria~olo[3,4-f 1[l~2~43triazine-3-acetamide~ MS: (FAB) 613 (M+H)~, each as a colourless foam.
The acids used as starting mate~als were prepared as ~ollows:
~ 1:6-~3-pv~.~Yl2-a-r4-thiazQl~lm~thYl2 ~z~[~
~razin~ ~ ~cetic ~cid In an analogous mamler to ~at described in E~ample 1 (e,f), by the condensation of 3-cyclopropyl-2-hydrazino-5-(3-pyridyl)pyrazine with die$hyl (4-thiazolylmethyl)malonate (EP-A 0,307,837) and subsequent basic saponifioation there was obtained rac-8-cyclopropyl-6-(3-pyridyl)-a-1~ ~4-thiazolylmethyl)-s-t~iazolo[4,3-a]pyrazine-3-acetic acid as a colourless powder (Rf: 0.161, silica gel, methylene chloride/methanol, 4:13.
~0 In an analogous manner to that described in Example 1 (e,f~, by the condensation of 3-cyclopropyl-2-hydrazirlo-5-(3-pyridyl)pyrazine with diethyl malonate and subsequent basic saponification there was obtained 8-cyclopropyl-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetic acid as a colourless powder, MS: (EI) 251 (M-CO~)+.
ra&-8-(~vclolpropylmethv!)-6-(3-pvri~vl)-a-(3-pYridvlmethyl)-s-~riazo-lor~.~-a~yrazine-~-acetic ~d In an analogous manner to that described in Example 1 (a-f~, by 30 the coupling of 2-oxo-3-cyclopropylpropioI~ic acid (J. Med. Chem. 30, 1074 (1987)) with 3-(an~inoacetyl)pyridille dihydrochloride there was obtained N-[2-oxo-2-(3-pyridyl)ethyl]~ oxo-3-cylopropylpropionamide as a colourless powder, MS: (EI) 218 (M-CO)+, which with ammonium chloride in ethanol gave 3-(syclopropylmethyl)-5-(3-p~dyl)-2(1H)-.~ pyrazinone, MS: (EI) 227 M+, as a colourless powder. Chlorination wi~hphosphorus oxychloride yielded 2-chloro-3-(cyclopropylme~hyl)-~-(3-pyri-dyl)pyrazine as a beige powder, MS: (EI) 245 M~, which by reaction with hydrazine hydrate yielded 3-(cyclopropylmethyl)-2-hydrazino-5-~3-pyr~-3 ~
dyl)pyrazine as a yellowish powder, m.p. 161-163, MS: (EI~ 241 M~.
Condensation w;~ diethyl (3-pyridylmethyl~malonate and suhsequent basic sapo}~ification then yielded rac-8-(cyclopropylmethyl)-6-(3-pyridyl)-a-(3-pyridylmethyl~-s-triazolo[4,3-a]pyrazirle-3-acetic acid as a colourle~;s 5 powder, MS: (ISN~ 400 (M-H~-.
In an analogous manner to that described in E~ample 1 (e,f), by the condensation of 3-(i~yclopropylmethyl~ 2-hydrazino 5 (3 pyridyl~pyra-zine with diethyl (4-thiazolylmethyl)malonate and subsequent basic saponification there was obtained rac-8-(cyclopropylmethyl~-6-(3-pyri-dyl)-a-(4-thiazolylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetic acid as a 15 colourless powder, MS: (ISN) 40~ (M-H)-.
8-(CvclQlpFQl?vlme~hyl)-~-(3-~)-s-triazQlQL4~^al~zin~-~ace~ acid In an analogous marmer to that described in Example 1 (e,f~, by aD the condensation of 3-(cyclopropylmethyl~2-hydrazino-5-(3-pyridyl)-pyrazine with die~yl malonate there was obkained ethyl 8-(cyclopropyl-methyl~6-(3-pyridyl~s-triazolo[4,3-a]pyraziIle-3-acetate as a colourless powder, m.p. 140-141, MS: (EI) 337 M~. Subsequent basic saponifica-tion gave 8-(cyclopropylmethyl)-6-(3-pyridyl)-s-triazolo~4,3-a]pyrazirle-3-25 acetic acid as a colourless powder (Rf: 0.12, methylene chloride/-methanol, 4:1).
~zine-3-ac~ a~i~
In an analogous manner to that described in 13xample 1 (b-f~, by the reaction OI N-[(isoql~inolinylcarbonyl)methyl]-2-o~opentanamide with ammonium chloride in ethanol there was obtained 5-(4-isoquino-linyl~3-propyl-2(1H}pyrazinone as a colourless powder, MS: (EI) 265 35 M+. Chlorination with phosphorus o~ychloride yielded 4-(5-chloro-6-propyl-2-pyrazinyl)isoquinoline, MS: (El:) 283 M+, as a colourless powder which by reaction with hydrazine hydrate yielded 4-(5-hydrazino-6-pro-pyl-2-pyrazinyl)isoquinoline as a yellowish powder, m.p. 161-163, MS:
-21- 2~ 3~
(EI) 279 M~. Condensation wi~h diethyl (3 pyridylmethyl)malonate and subsequent basic saponification then yielded rac-6-(4-isoquinolinyl3-8-propyl-a-(3-pyridylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetic acid as a colourless powder, MS: (EI) 394 (M-C02)+.
In an analogous manner to tha~ ~esc~bed in E~ample 1 (e,i~, by the condensation OI 4-(5-hydrazino-6-propyl-2-pyrazinyl)isoquinoline 10 with die~yl malonate and 6ubsequent basic saponification there was obtained rac-6-(4-isoquinolinyl)-8-propyl-s-triazolo[4,3-a]pyrazine-3-acetic aoid as a colourless powder, MS: (EI) 303 (M-CO2)+.
The N-[(isoquinolinylcarbonyl)methyU-2-oxopentanamide used as ~5 the starting material was prepared as follows:
In an analogous manner to that described in Org. Synth. 64, 19 (1986) for 2,2-diethoxy-2-(4-pyridylethyl)diarnine, starting from 4-acetyl-isoqLuinoline (J. Am. Chem. Soc. 67, 1268 (1945)) by reaction with hydro-20 xylamine, preparation of the tosylate and subsequent rearrangementwith sodiurn ethanolate there was obtained 2,2-diethoxy-2-(4-isoquino-linyl)ethylamine, m.p. 236 (decomposition).
0.8 ml of 2-oxo-n-valeric acid, 2.7 ml (15.5 mol3 of triethylamine 25 and 1.07 g (7.8 mmol) of EOBT were added to a suspension of 2.6 g (7.8 mmol) of 2,2-diethoxy-2-(4-isoquinolinyl)ethylamiIle in 40 ml of methylene chloride and the reaction mixture was subseqllently treated with 1.59 g of DCC in i3 ml of methylene chloride. A~ter 24 hours ~le resulting urea w~s f;ltered of~ e filtrate was washed with saturated 30 sodium hydrogen carbonate solution and saturated sodiuxn chloride eolution, d~ied over magnesium sulphate, filtered and evaporated under reduced pressur~. Chromatography on silica gel (methylene chloridel-ether, 9:1) yielded 1.5 g of a yellow oil which was dissolved in 50 ml of 2N
hydrochloric acid and stirred at room temperature for 24 hours. The 35 solvent was evaporated under reduced pressure and the thus-obtained residue was dried azeotropically with toluene several times. There were thus obtained 1.1 g of N-[(4-isoquinolinylcarbonyl)methyl]-2-oxopentan-amide hydrochloride as a pale brown powder, MS: (EI) 256 (M-CO)+.
, 2~8~3~
In an analogous manner to that de~clibed in Example 1 (c-f~, from ~-propyl-3-~3-pylidyl)-as-l;riazin-6~1H)-orle by clhlorination with phos-phorus oxychloride there wa~ obtained 6-chloro-~-propyl-3-(3-pyridyl)-as-triazine as a colourless powder, m~.p;74-76, MS: IEI) 234 M+, which by reaction with hydrazine yielded 6-hydrazino-5-propyl-3-(3-pyndyl)-as-triazine as a yellow powder, M~: (EI) 230 M+. Condensation with diethyl (3-pyridylmethyl)malonate and subsequent basic saponification gave rac-8-propyl-6-(3-pyridyl~a-~3-pyridylmethyl~6-triazolo[3,4-~1[1,2,4]triazine-3-acetic acid as a colourless powder, MS: (Fl~B) 346 (M-C02~H)+.
,5 ~
In an analogous manner to ~at desc~ibed in E~ample 1 (e,f), by the condensation of 6-hydrazino-5-propyl-3-(3-pyridyl)-as-tIiazine with diethyl malonate and subsequent basic saponification there was obtain0d 8-propyl-6-(3-py~idyl)-s-triazolo[3,4-f~[1,2,4]tr;azine-3-acetic acid QS a colourless powder, MS: (FA33) 299 (M+H)+.
The 5-propyl-3-(3-pyIidyl)-as-triazin-6(ïH)-one used as the starting material was prepared as follows:
'' 6.50 g (36 mmol) of D,L-norvaline ethyl e~ter hydrochloride in 10 ml of water were added to a euspension of 6.40 g (36 mmol) of methyl pyridine-3-carbo~midate (J. Org. Chem ~, 41~ (1961) in 10 ml of ether and the m~ture was stirrsd at room temperature for 3 hours. Af~er the addition of 50 ml of methylene chloride the organic phase wa~ separated, dried over 80ditlm sulphate, filtered and evaporated under reduced pressure. The thus-obtained pale yellow oil (6.05 g) was heated to reflux for 2 hour3 with 1.6 ml (30 mmol) of hydrazine hydrate in 20 ml of isopro-panol. APcer cooling to room temperatllre the rnixture wa~ treated with 10 ml of water and e~tracted with methylene chloride. The organic phases were dried over magnesium sulphate, filtered and evaporated under reduced pressure. After chromatography on silica gel (methylene chloride/methanol, 9:1) there were obtained 2.50 g of rac-2,5-dihydIo-5-~08123~
propyl-3-(3-pyridyl)-as-triazin-6(1H)-one as a colourless powder, m.p.
144-146, MS: OEI) 218 M-~.
6.4 ml (10.5 mmol) of 10% Javelle water were added to a solution of 1.09 g (5 mmol) of rac-2,5-dihydro-5-propyl-3-(3-pyridyl~as-triazin-6(1H)-one in 10 ml of lN sodium hydrogide solution while cooling with ice and the mi~ture was subsequently stirred at room te3nper~ure ~or 12 hours.
:E:~tractio~ methylene chloride, drying over sodiilm sulphate, filtration and evaporation under reduced pressure yielded 0.58 g of 5-propyl-3-(3-pyridyl)-as tria~in-6(1H)-one as a colourless powder, m.p.
160-162, MS: (EI) 216 M+.
~r In an analogous manner to that desc~bed in Example 1 (c-f~, from 5-isobutyl-3-(3-pyIidyl)-as-triazin-6(1H)-one by chlorination with phos-phorus o~ychloride there was obtained 6-chloro-5-isobutyl-3-(3-pyrid~
as-triazine as a colourless powder, m.p. 63-65, MS: (:3I) 248 M~, which by reaction with hydrazine yielded 6-hydrazino-5-isobutyl-3-(3-pyridyl~
as-t~azine as a yellow powder, m.p. 126-129, MS: (EI) 244 M+. Conden-sation with diethyl (3-pyridylmethyl)malonate and subsequent basic saponification gave rac-8-isobutyl-6-(3-pyridyl)-a-(3-pyridylmethyl)-s-tIiazolo[3,4-f~[1,2,4]triazine-3-acetic acid as a colourless powder, MS:
(lFAB) 359 (M-C02+H)+.
The 5-isobutyl-3-(3-pyridyl~as-triazin-6(1H~one used as the starting material was prepared as follows:
In an analogous manner to that described for 5-propyl-3-(3-pyri-. dyl)-as-triazin-6(1H~one using D,L-leucine ethyl ester hydrochloride in place of D,L-norvaline ethyl ester hydrochlonde there was obtained 5-iso-butyl-3-(3-pyridyl~as-triazin-6(1H)-one as a colourless powder, m.p. 141-144C, MS: (EI) 230 M~.
The (lS,2R,3S)-3-~nino-1-cyclopropyl-4-phenyl-1,2-blltanediol used as the starting material was prepared as ~ollows:
2~1236 9.96 ml (124.5 mmQl) of cyclopropyl bromide in 100 ml of ether were added dropwise wi~in 30 mimltes under slight reflu~ to 3.03 g 5 (124.5 ~nol) of magnesium ir3 10 ml of abs. ether and the mi~ture was ~ubsequently heated to reflu~ for 2 1/2 hDul s. Sub~equent Iy, 6.25 g (22.63 mmol) oftert.-butyl [1S~2R~1-bemzyl-2-cyano-2-hydroxyethyl]-carbamate (EP-~i 0,266,960) were added dropwise thereto under re~
within 4~ minutes and t~e migture was heated to reflu~ for a further 2 lJ2 hours. Finally, t~e mixture wa~ lel~ to cool (10), 10% citric aeid was added dropwise thereto and the mi~ture wa~ e~tracted twice with ether.
The organic phase was washed with water and saturated sodium chlor-ide solution, d2ied over magnesium sulphate, ISltered and evaporated under reduced pressure. Chromatography on silica gel (toluene/ethyl 15 acetate, 9:1) yielded tert-butyl [(1S,2R~1-benzyl-2-(cyclopropylcar~oIlyl)-2- hydroxyethyl~carb~ate as a pale yellow solid, MS: (EI) 246 (M-C3HgO)+.
A solution of 2.83 g (8.77 mmol) of tert-butyl [(lS,2R)-1-benzyl-2-a~ (cyclopropylcarbonyl)-2-hydroxyethyl]carbarnate was dissolved in 130 ml of methylene chloride, 3 ml of acetic acid were added thereto and the mixture was finally treated portionwise at 0 10 with 0.332 mg (8.78 mmol) of sodium borohydride. The reaction solution was stirred at ~
for a further 2 hours and partitioned between 2N sodium hydrogen 25 carbonate solution and methylene chloride. The organic phase was æeparated> washed with water and with saturat~d sodium chloride solution, dried over magnesium sulphate> filtered and evaporated under reduced pressure. Crystalligatiorl of the residue fi~om etherlhe~ane yielded 2.1 g of tert-butyl [(1S>2R>3$)-1-benzyl-3-cyclopropyl-2>3-dihydroxy-30 propyl]car~amate as colourless needles> m.p. 83-85.
~ A solution of 2.0 g (6.23 mmol) of tert-butyl [(lS>2R>3S~1-benzyl-3-cyclopropyl-2>3-dihydroxypropyl]carbamate in 2û ml of methanol was treated with 20 ml of 2N hydrochloric acid and the solution was heated to 35 50 for 9û minutes. Af'cer cooling the mixture was neutralized by the addition of 40 ml of lN sodi~ hydroxide solution and concentrated to dryness on a rotary evaporator under reduced pressure. The residue was partitioned between water and methylene chloride. The organic 2~8123~
phase was washed ~nth water and saturated sodivln chlo~de solu~on, d~ed over magnesium sulphate, ~ltered and evaporated ~ der redured pressure. There wasthus ob ~ ned (1S,2R,3S)-3-~nino-1-cyclopropyl-4-phenyl-1,2-blltanediol a~ a white, crystalline 60lid, MS: (EI~ 150 ~M-C4~I8O+-~Q~
The following compo~ds were mar~ actured in an analogous 1D mannerto that desc~bedin E~al~ple 1:
- From rac-8-(3-methylsulphanylpropyl)-6-(3-pyridyl)-a-(3-pyridyl-methyl)-s-triazolo[4,3-a~pyrazine-3-acetic acid and (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol the (R or S)-N-[(1S,2R,3S)-1-(cy-15 clohe~ylmethyl)-3-cyclopropyl-2,3-dihydro:~ypropyl~-8-(3-methylsulpha-nylpropyl)-6-(3-pyridyl)-a-t3-pyridylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetamide, MS: (FAB) 644 (I!~H)~, and the (S or R)-N-[(lS,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dih,ydroxypropyl]-8-(3-methylsul-phanylpropyl)-6-(3-pyridyl)-oc-(3-pyridylmethyl)-s-triazolo[4,3-a~pyrazine-~0 3-acetamide, MS: (FAB) 644 (M+H)+, each as a colourless foam;
- from rac-a-allyl-8-propyl-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetic acid and (lS,2R,3S)-3-amino-4-cyclohe~yl-1-cyclopropyl-1,2-butanediol the (R,S~a-allyl-N-[(1S,2R,3S)~1-(cyclohexylmethyl)-3-cyclopropyl-2,3-25 dihydroxypropyl]-8-propyl-6-(3-pyndyl)-s-triazolo[d~,3-a]pyraz;ne-3-acetamide, MS: (FAB) 547, (M+H)+, as a colourless foam.
The aMds used as starting matenals were prepared as follows:
In an analogous manner to that desc~bed in Example 1 (a-f~, by the coupling of 5-(methylsulphanyl)-2-oxopentanoic acid (J. Med. Chem.
3S 80, 1074 (1987)) with 3-(aminoacetyl)py~idine dihydroc~loride there was obtained N-[2-oxo-2-(3-pyridyl)ethyl]-oc-oxo-5-methanesulphanylpentan-amide as a colourless powder, MS: (EI) 280 M+, which with ammonium 3 ~
chloride in ethanol gave 3-(3-methylsulphanylpropyl)-5-(3-pyridyl)-2(1H)-pyrazinone, MS (EI) 261 M~, as a colourless powder. Chlorination with phosphorlls oxychloride yielded 2-chloro-3-(3-methylsulphanylpropyl)-~-(3-pyridyl)pyrazine as a beige powder) M~3: (EI) 244 (M-Cl)~, which by 5 reaction with hydrazine hydrate yielded 2-hydrazino-3-(3-methyl~ul-phanylpropyl)-5-(3-pyridyl)pyrazine as a yellowish powder, MS: (EI) 275 M~. Condensation with diethyl (3-pyridylmethyl)malonate and su~-sequent basic saponilScation t~en`yielded rac-8-(3-methylsulphanyl-propyl)-6-(3-pyridyl~-a-(3-pyridylmethyl~s-triazolo[4,3-a]pyrazine-3-1D acetic acid as a colourless foam, MS: (EI) 390 (M[-C02)~.
ra~-a-AllYl-8-~ropvl-6-(~i~yl)-s-tria~olo[4~-al;pyrazine-3-acetic açid 135 mg (3.1 mmol) of sodium hydride were added in one portion to a solution of 975 mg (3 mmol) of ethyl 8-propyl-6-(3-pyridyl)-s-triazolo~4,3-a]pyrazine-3-acetate (EP-A 0,369,743) in 25 ml of dimethylformamide at 0. After the evolution of hydrogen had finished 0.25 ml (3 mmol) of allyl bromide in S ml of dimethylformamide were slowly added Idropwise and the resulting solution was stirred for 2 hours. The reaction solution was 20 poured on to ice-water and e~tracted three times with methylene chloride. The organic phase was dried over magnesium sulphate, filtered and evaporated under reduced pressure. Chromatography on silica gel (methylene chloride/ methanol 25:1~ yielded 800 mg of ~thyl rac-oc-allyl-8-propyl-6-t3-pyridyl)-s-triazolo[4,,3-a]pyrazine-3-acetate as a 25 colourless oil, MS: (EI) 365 M+, which was saponified in an analogous manner to that described in Ea~ample 1(f) and then yielded rac-oc-allyl-8-propyl-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetic acid, MS: (EI) 293 (M-C02)+, as a colourless powder.
Example 4 62.9 mg (0.311 mmol) of m-chloroperbenzoic acid (85%) were added to a solution of 100 mg (0.155 rnmol) of (R or S)-N-[(lS,2:E~,3S)-1-(cyclo-hexylmethyl)-3-cyclopropyl-2,3-dihydroxy-propyl]-8-(3-methylsulpha-35 nylpropyl)-6-(3-pyridyl)-a-(3-pyridylmethyl)-s-triazolo[4~3-a]pyrazine-3 acetamide in 2 ml of methylene chloride at 0 and the mi~ture was stirred at room temperature for 12 hours. The reaction solution was diluted with 10 ml of methylene chloride and subsequently washed with -~7~ 123~
10% sod~ ulphite solution, saturated sodium bicarbonate solution and water. The organic phase was dried over magnesium sulphate, filtered and evaporated und~r reduced pressure. Chromatography on silica gel (methylene chlo~de/m~thanol/ ammonia 110:10:1) yielded ~0 mg of (R~ or S)-N-[(1S,2R,3S)-1-(cyclohexylme~hyl)-3-cyclopropyl-2,3-dihydroxypropyl~-8-(3-methylsulphonylpropyl)-6-(3-pyridyl) c~-(3-pyridylmethyl)-s-triazolo[4,3-a~pyrazine-3-acetamide as colourless crystals,~S -~ISP) 676 ~M~H~+.
In an analogous manner to that described above, from (S or R)-N-[(lS,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydro:~ypropyl]-8-(3-methylsulphanylpropyl)-6-(3-pyridyl)-oc-(3-pyridylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetamide there was l)btained (S or R~N-[(lS,2R,3.$)-1-(cyclohe~ylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-(3-methylsul-~5 phonylpropyl)-6-(3-pyridyl)-oc-(3-pyridylmethyl)-s-triazolo~4,3-a]pyrazine-3-acetamide as colourles~ crystale, MS: (ISP) 676 (M+H)~.
~m~DlQA
2D Qral ag~eous suspQnsi Composition:
(R or S)-N-~(1S,2R,3S)-1-(Cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-cyclopropyl-6-(3-pyridyl)-oc-(4-thiazolyl-methyl)-s-triazolo[4,3-a]pyrazine-3-acetamide micronized 5.0 g Polysorbate 80 0.3 g Hydroxypropylmethylcellulose 1.0 g Flavouring q.s Methylparaben 0.2 g Propylparaben 0.04 g Water ad 100.0 ml ~8~L236 ExaLm~l~
~Qm~L
(R or 0-N-[(1S,2R,3S)-1-(Cyclohe~ylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-cyclopropyl-6-(3-pyridyl)-o~-(4-thiazolyl-methyl)-s-triazolo[4,3-a]pyrazine-3-acetamide methane-sulphonate 1.0 g Methylparaben û.2 g Propylparaben 0.04 g Flavouring q.s.
Water ad 100.0 ml E~ample~
1) (R or S)-N-[(lS,2R,3S)-1-(Cyclohexylme$hyl)-3-cyclopro-pyl-2,3-dihydroxypropyl:l-8-cyclopropyl-6-(3-pyridyl)-a-(4-thiazolylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetamide methanesulphonate ~00 mg 2) Anhydrous lactose 160 mg 3) Hydroxypropylmethylcellulose 18 mg 4) Sodium carboxymethylcellulose 20 mg 5) Magnesium stearate 2m~
Tablet weig~ 400 mg Y_ 1) and 2) are mixed intensively. The mixture is thereafter moistened with an aqueous solution of 3) and kneaded, and the resulting 15 mass is granulated, dried and sieved. The granulate is mixed with 4) and 5) and pressed to tablets of suitable si~e.
2~123~
~am~
~i~
1) (R or S)-N-[(1S,2R,30-1-(CycJohe~ylmethyl~3-cyclopro-- pyl-2,3-dihydro~ypropyl3-8-cy~opropyl-6-(3-pyri~yl)-a-(4-thiazolylmethyl)-s-tria~olo~4,3-a]pyrazine-3-acetamide methane~ulphonate 200 mg 2) Anhydrous lactose 16ûmg 3) Hydro~ypropylmethylcellulose 18 mg 4) Sodium carboxymethylcellulose 20 mg 5) Magnesium stearate 2 m~
Capsule fill weight 400 mg 1) and 2) are mixed int0nsively. The mixture is thereafter moistened with an aqueous solution of 3) and kIleaded, and the resulting ma6s is granulated, dried and sieved. The granulate is mi~ed with 4) and ~), the mixture is filled into capsules of suitable size.
E~ample E
~Q~
1 ml (R or S)-N-[(1$,2R,3S)-1-(Cyclohe~ylmethyl)-3-cyclopropyl-2,3-dihydro~ypropyl]-8-cyclopropyl-6-(3-py~dyl)-a-(4-thiazolyl-methyl)-s-triazolo[4,3-a]pyrazine-3-acetamide methane-sulphonate 20 mg Pyrogen-free D-mannitol 10 mg Water for injection ad 1.0 ml The ac~;ive subst~Lnce and the mannitol are dissolved in nitrogen-5 gassed water and subsequently lyophilized according to a con~entional procedure.
''E~.E
When the procedures desc~bed in ~ amples A-E are followed, corr~spomding galenical preparations can be manufacturedl ~rom the following, likewise pre~erred compounds and their pharmaceutically usable salts:
1~ (R or S)-N-[~lS,2R,3S) l-(Cyclohe:~ylmethyl~3-cyclopropyl-2,3-dihydroxypropyl]-8-c~c~opropyl-6-(3-pyridyl)-a-~3-pyridyl-methyl)-s-triazolo[4 ,3-a]pyrazine-3-acetamide~
- (:R or S)-N-[(1$,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-(cyclopropylmethyl)-6-(3-pyridyl)-oc-(3-pylidylmethyl~-s-triazolo[4,3-a~pyrazine-3-acetamide, - (R or S)-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-(cyclopropylmethyl)-6-(3-pyridyl)-a-(4-thiazolylmethyl)-s-triazolo[4,3-a~pyraz;ne-3-acetamide.
6 In particular, it is concemed with amino acid derivatives of the general formula N~N O R4 OH
~N~NH~R5 N~f~X R3 OH
1D wherein X signifies a nitrogen atom ol -CH-, Rl signifies phellyl, pyridyl or isoquinolinyl, R2 signif;es cycloal:kyl, cycloalkylalkyl, alkylthioalkyl, alkylsulphonylalkyl, alkenyl or, where X signifies a nitrogen atom and/or Rl signifies isoquinolinyl and/or R3 signifies alkenyl, also alkyl, :R3 signi~ies hydrogen, alkyl, alkenyl, imidazolylmethyl, pyridylmethyl, t~ia~olylmethyl or benzyl, R4 signifies cyclohe~ylmethyl or benzyl and :R5 signifies cycloalkyl, alkyl or heterocyclylalkyl, in the form of optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates as 2~) well as pharmaceutically usable salts of these compounds.
These compounds are novel and are distinguished by valuable pharmacodynamic prop~rties.
Objects of the present invention are the compounds of formula I
and their pharmaceutically usable salts per se and for use as thera-peutically active s~bstances, the manufacture of these compounds, medicaments containing these and the manufacture of such medica-ments as well as the use of compounds of formula I and their pharma-ceutically usable salts in the control or prevention of illnesses or in the improvement of health, especially in the control or prevention of high blood pressure and cardiac insufficiency.
:Kbr/08.û9.92 208123b The term "alkyl" used in the present description, alone or in combination, signifies straight-chain and branched, saturated hy-drocarbon residues with 1-8, preferably 1-4, car~on atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, t-butyl, pentyl, he~yl and the like. The term "cycloalkyl" signifies saturated, cyclic hydrocarbon residues with 3-8, preferably 3-6, carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term ~'alkenyl" relates to straight-chain ana branched, unsaturated hydrocarbon residues with 2-8, preferably 2-4, carbon atoms such as 10 vinyl, allyl, 2-butenyl, 3-butenyl and the like. The term "heterocyclyl"
signifies a saturated 5- or 6-membered heterocycle with at least one nitrogen atom and optionally an additional oxygen, nitrogen or sulphur atom as a Iing member, which is attached to ~he -CH(O~I)- group via a nitrogen atom and in which the additional nitrogen atom can be alkyl-15 ated, such as morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, S-oxothiomorpholinyl, S,S-dio~othiomorpholinyl, pyrrolidinyl, thiazolidinyl, irnidazolidinyl, oxazolidinyl, N-methylpiperidinyl and the like.
aD The term "pharmaceutically usable salts" embraces salts with inorganic or organic acids such as hydrochloric acid, hydro- bromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulphonic acid, p-toluenesulphonic acid and the like. Such salts can be manufactured readily by any person skilled in the art having regard to the state of the art and taking into consideration the nature of the compound to be converted into a salt.
The compounds of formula I have at least three asymmetric carbon atoms and are therefore present in the form of optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereome~c racemates. The present invention embraces all forms. M[ixtures of diasteromers, diastereomeric racemates or mixtures of diastereomeric racemates can be separated according to 3~ usual methods, e.g. by column chromatography, thin-layer chromato-graphy, HPLC and the like.
2~8~ 236 A particular group of compounds of formula I comprises those in which R2 signifies cycloalkyl, cycloalkylalkyl, alkylthioalkyl, alkylsul-phonylalkyl, alkenyl or, where X signifies a nitrogen atom and/or Rl signifies isoquinolinyl, also alkyl.
Those compounds of formula I in which X signifies -CH- are prefer.red. Compounds of formula I in which Rl signifies pyridyl, especially 3-pyridyl, are`also preferred.~ R2 pre~erably sigDifies cycloalkyl or cycloalkylalkyl, especially cycloalkyl, particularly cyclopropyl. The preferred significance of R3 is imidazolylmethyl, pyridylmethyl or thiazolylmethyl, especially pyIidylrnethyl or thiazolylmethyl, par-ticularly 4-thiazolylmethyl. Cyclohexylmethyl is the preferred si~ifi-cance for R4. R~ preferably signifies cycloalkyl or alkyl, especially cycloalkyl, particularly cyclopropyl.
~5 :From the above it will be evident ~at those compounds of formula I in whic~ X signifies -CH, Rl signifies 3-pyridyl, R2 signifies cyclo-propyl, R3 signifies 4-thiazolylmethyl, R4 signifies cyclohexylmethyl and R5 signifies cyclopropyl are particularly preferred.
aD
Especially preferred compolmds of formula I are:
(R or S)-N-[(1S,2R,3S)-1-(Cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-cyclopropyl-6-(3-pyridyl)- a-(3-pyridylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetamide, N-~(1$,2R,3S)-1-(cyclohe:~ylmethyl)-3-cyclopropyl-2,3-di-hydroxypropyl]-8-cyclopropyl-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetamide, (R or S~N-~(1S,2R,3$)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-cyclopropyl-6-(3-pyridyl)-a-(4-thiazolylmethyl)-s-triazolo[4,3-a]pyrazine-3-a~etamide, (R,S)-N-[(1S,2R,3$)-1-benzyl-3-cyclopropyl-2,3-dihydro~ypropyU-8-cyclopropyl-6-(3-pyridyl)-a-(3-pyridyl- methyl)-s-triazolo[4,3-a]pyrazine-3-acetamide, (R or S)-N-[(1$,2R,3$)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-(cyclopropylmethyl)-6-(3-pyridyl)-a-(3-pyridylmethyl)-~-triazolo[4,3-a~pyrazine-3-acetamide, (R or S~N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopIopyl-2,3-2~23~
dihydro~ypropyl]-8-(cyclopropylmethyl)-6-(3-pyridyl)-a-(4-thiazol-ylmethyl)-~-triazolo~4,3-a~pyrazin0-3-acetamide and tR9S)-a-allyl-N-[(1S.2R,3S)-1-(cyclohe~ylDnethyl)-3-cyclopropyl-2,3-d:ihydro~ypropyl]-8-propyl-6-(3-pyridyl)-s-triazolo[4 ,3-a]pyrazine-3-acetamide.
Further ~specially preferred compounds of formula I are:
N-[(lS,2R,3S)-1-(Cyclohe~ylmethyU-3-cyclopropyl-2,3-dihy-10 drn~ypropyl]-6-(4-isoql~inolinyl)-8-propyl-s-triazolo[4,3-a]pyrazine-3-acetamide, (S or R~-N-[(1S,2R,3S)-1-(cyclohexyl~ethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-ff-(4-isoquinolinyl)-8-propyl-a-(3-pyridylmethyl)-s-triazolo[4,3-a~pyrazine-3-acetamide and 16 (R or S)-N-[(1S,2R,3$)-1-(cyclohex~lmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-6-(4-isoquinolinyl)-8-pl opyl-a-(3-pyridylmethyl)-s-triazolo[4,3-a~pyrazine-3-acet~de.
Further e~amples of prefelTed compounds of formula I are:
ao N-[(1S,2R,3S)-1-(Cyclohe~ylmethyl)-3-cyclopropyl-2,3-dihy-droxypropyl]-8-propyl-6-(3-pyridyl~s-triazolo[3,4-~[1,2,4]triazine-3-acetamide, (R or S)-N-[(lS,2R,3S)-1-(cyclohexylmethyl)-3-cycloprnpyl-2,3-dihydroxypropyl~-8-propyl-6-(3-pyridyl)-a t3-:pyridylmethyl)-s-triazolo [3,4-f~[1,2,4]triazine-3-acetamide, (S or R)-N-[(lS,2:E~,3S)-1-(cyclohexylmethyl)-3-cyclo propyl-2,3-dihydroxypropyl]-8-propyl-B-(3-pyridyl)-a-(3-pyridylmethyl)-s-triazolo [3,4-~[1,2,4]triazine-3-acetaunide, tS or R~N-C(1S92R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3 dihydro~ypropyl]-8-isobutyl-6-(3-pyridyl)-a-(3-pyxidylmethyl)-s-triazolo[3,4-fl[1,2,4]triazine-3-acetamide and (R or S~N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-isobutyl-6-(3-pyridyl)-a-(3-pyridylmethyl)-s-36 triazolo[3,4-f~[1,2,4]t~azine-3-acetamide.
The compouIlds of formula I in the form of optically pure dia-stereomers, mixtures of diastereomers, diastereomeric racemates or - 5 ~ 2 ~ ~
mi~tures of diastereomeric racemates as well as pharmaceutically usable salt~ thereof can be manufactured by a~ reaclting a compolmd of the general ~ormula - H2N--~J~ Rs OH
wherein R4 and R5 have the significance given above, with a compound of the general formula N--N O
J~OH III
l~X R3 wherein X, Rl, R2 and R3 haYe the significance given above, or an activated derivat*e thereof, and b) if desired, oxidizing a compound of forrnula I obtained in which R2 æignifies alkylthioalkyl to the corresponding compound of formula I
in which 1~2 signifies alkylsulphonylal~yl, and/or ~D c) if desired, separating a mixture of diastereomeric racemates into the diastereomeric race:mates or optically pure diastereomers, and/or d) if desired, separating a mi~ture of diastereomers into the optically pure diastereomers, and/or e) if desired, converting a compolmd obtained into a pharmaceu-tically usable salt.
The acylation of a compo~Lnd of formula II is effected according to 30 methods known per se. Especially suitable acylating agents are activated.
acid derivatives such as esters, mixed esl;ers, acid halides, acid anhy-.
-6- 2~8123~
drides or mi~ed acid anhydlides. The reaction is carried out in an orga-nic solvent or solvent mixture which is inert under the reaction condi-tions at a temperature between about 0C and room temperature. As sol-vents there come ;nto consideration especially aromatic hydrocarbons 5 such as benzene, toluene or ~ylene, chlorinated hydrocarbons such as methylene chlolLide or chlo3: oi~orm, ethers such a~ diethyl ether, tetra-hydrofilran or dioxan, and the like. The reaction is e~ected under re-action conditions which are usual in peptide chemistry, i.e. preferably in the presence of a condensation agent such as HBTU (O-benzotriazolyl-10 N,N,N',N'-tetramethyluronium hexaIluorophosphate), BOP (benzotria-zol- 1-ylo~y-tris-(dimethylamino)phosphonium hexafluol ophosphate), BOPC (bis(2-oxo-3-oxazolidinyl)phosphinic chloride), HOBT (N-hydroxy-benzotriazole), DCC (dicy~lohe~ylcarbodiimide), EDC (N-ethyl-N'-(3-dimethylaminopropyl)car~odiimide hydrochloride), and the like. The 15 reaction iB conveniently carried out in an organic solvent or solvent mi:Rture which is inert under the reaction conditions at a temperature between about 0 and 50C, preferably at about room temperature. As solvents there come into consideration especially dimethylformamide, methylene chloride, acetonitrile, tetrahydrofùran and the like.
ao The oxidation of a compound OI formula I in which R2 signiies alkylthioalkyl is also carried out according to methods known per se.
The oxidation can be carried out e.g~ by reaction with hydrogen peroxide, an organic peracid such as peracetic acid, perbenzoic acid, perphthalic 25 acid and the like, a perester, sodium periodate, potassium peroxomono-sulphate in alkanoVwater and the like. The oxidation is conveniently carried out in an inert organic solven~ ~uch as a halogenated hydrocar-bon, e.g. chloroform, methylene chloride~ dichloroethane and the like.
When hydrogen peroxide is used as the oxidation agent, the reaction can 30 also be carried out in acetic acid and the like. Conveniently, the oxida-tion i8 carried out at a temperature between about 0 and 30C, prefiera-bly at about 0C
The starting materials of formula II are known or can be obtained 35 in analogy to the preparation of the known compounds.
- 7 - 2 ~ 3 $
The starting materials of formula III in which ~ signifies -CH-are known fi om EP-A 0,36g,743 or can be obtained in analogy to the preparation of the known cQmpounds.
6 The remaining compounds of formula III are novel and are an object of the present invention. They can be prepared starting ~rom corresponding 1,2,4-triazinones according to va~ous methods which are known per se and which are ~ some e~tent analogous to the procedure described in EP-A 0,369,743. These preparative procedures as well as the procedure in accordance with :EP-A 0,369,743 are compiled in the following Schemes I and II. In these Schemes R signifies alkyl and Rl, R2 and R3 have the signilScance given above. The 1,2,4-triazinones of formula IX in Scheme II can be obtained in analogy to the preparation of 1,2,4-triazinones described in J. Heterocyclic Chem., 15, 1271(1978).
~12~
Scheme 1 ~NH
N~
Rl n - t ~1 R ~N
N~
R1 V .:
~2~N
N~J
R~
HN--NH N--N
R2~ C~COOR P~2~ COOR
R1 V:~ F11 VIII
N--N
R2~ COOH
R1 m~, ,.
;: . ~ , .
.
' 2~8~3~
Scheme 2 N~N
t Cl R2~N
N~,N
HN~NH2 R2~NI
N,~N
HN--NH N--N
R2~ C~X~COOR _ ~ R2~ COOR
N--N
R2~l~ J 3~CC)OH
~N R3 R1 mb -lo- 2~8~3~
The compounds of ~orlmula I and their pharmaceutically usable salts have an inhibitory activity on the natural enzyme renin. The latter passes ~om the ~idneys into the blood and ~ere brings about the cleavage of angiotensinogen wi~h the formation of the decapeptide 5 angiotensin I which is then cleaved in the llmgs, the kidneys and other o-rgans to the octapeptide angiotensin II. AngiotensiIl II increases the blood pressure not only directly by arte~al constriction, but also indi-rectly by the liberation o`f the so~ium ion-retaining hormone aldosterone from the adrenal gland, Wit~L which is associated an increase in the 10 extracellular fluid volume. This increase is attributed to the action of angiotensin II itself or to the heptapeptide angiotensin III which is formed therefrom as a cleavage product. Inhibitors of the en~ymatic activity of renin brings about a decrease in the formation of ang~otensin I and as a consequence thereof the formation of a smaller amount of 15 angiotensin II. The reduced concentration of $his act*e peptide hor-mone is the actual reason fior the blood pressure-lowering activity of renin inhibitors.
The activity of renin inhibitors can be demonstrated experiment-2D ally by means of the in vitro test described hereinafter:
In vitro test with l2ur_human reni~
The test is carried out in Eppendorf` te~t tubes. The incubation 25 mixture consists of (1) 100 ml of human reni]~l in buf~er A (O.lM sodiumphosphate solution, pH 7.4, containing 0.1% bovine serum albumin, O.l~o ~odium azide and 1~ ethylenediamine-tetraacetic acid), suflEicient ~or a renin activity of 2-3 ng of angiotensin Vml/hr.; (2) 145 ml of buf~er A: (3) 30 ml of 10 mM human tetradecapeptide renin substrate 30 (hTD) in 10 mM hydro- chloric acid: (4) 15 ml of dimethyl sulphoxide with or wi~hout inhibitor and (5) 10 ml of a 0.03 molar solution of hydro-xyquinoline sulphate in water.
The samples are incubated for three hours at 37C and, respect-35 *ely, 4~ in triplicate. 2 ~100 ml samples per e~perimental test tubeare used in order to measure the production of angiotensin I via RIA
(standard radioimmunoassay; clinical assay solid phase kit). Cross reactivities of the ant;body used in the RIA are: angiotensin I 100%;
2~8~23~
angiotenæin II 0.0013%; hTD (angiotensin I-Val-Ile-His-Ser-VH 0.09%.
The production of angiotensin I is dete~nined by the dif~erence between ~e experiment at 37C and that at 4C.
The following coIltrols are carried out:
(a) incubation of hTD samples without renin and without inhibitor at ~ -37C an'd'4C.~''The ai~erence''bet'ween these'two values gives the base value of the ang~otensin I production.
(b) Incubation OI hTD samples with renin, but without inhibitsr at 37C and 4C. The difference between these values gives the maximal value of angiot~nsin I production.
~5 In each sample the base value of the angiotensin I production is subtracted from the angiotensin I production which is determined. The dif~erence between the ma~imal value and the base value gives the value of the ma~imal substrate hydrolysis (- 100%) by renin.
The results are given as ICso values ~which denote that concen-tration of the inhibitor at which the enzymatic activity is inhibited by 50%. The IC~o values are determined from a linear regression curve from a logit-log plot.
The results obtained in this test are compiled in the following Table:
Table ~ I~50 v~1ues in nmol/lt B 2.0 D 2.3 F
-~2- 2~ 23~
A = (R or S)-N-[(1S,2R,3~;~1-(Cyclohe~ylmethyl~-3-cyclQpropyl-2,3-dihydro~ypropyl]-8-cyclopropyl-6-(3-pylidyl)-a-(3-pyridylmethyl~-s-triazolo[4,3-a]pyrazine-3-acetamide B = (R or S)-N-r(1S,2R,3S}1-(Cyclohe~ylmethyl)-3-oyclopropyl-2,3-dihydrogypropyl]-8-cyclopropyl-6-(3-pyridyl) o~{4-thiazolylmethyl)-s-triazolo[4 ,3-a]pyrazine-3-acetamide C = (R or S)-N-[(1S,2iR,3S~1-(Cyclohe~ylmethyl)-3-cyclopropyl-2,3-dihydro~ypropyl]-8-(cyclopropylmethyl)-6-(3-pyridyl)-a-(3-pyri-dylmethyl)-s-triazolo[4 ,3-a]pyrazine-3-acetamide D = ~R or S)-N-[(1S,2R,3S~1-(Cyclohe~ylmethyl)-3-cyclopropyl-2,3-dihydro~ypropyl]-8-(cyclopropylmethyl)~6-(3-pyridyl)-a-(4-thia-1~ zolylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetamide E = (R,S)-N-~(1S,2R,3S)-1-Benzyl-3-cyclopropyl-2,3-dihydroa;y- propyl]-8-cyclopropyl-6-(3-pyridyl)-a-(3-py~idylrnethyl)-s-triazolo[4,3-a]pyra-zine-3-acetamide aD
F = (R or S)-N-[(1S,2R,3S)-1-(Cyclohexylmethyl~-3-cycloproyl-2,3-dihydroxypropyl~-8-isobutyl-6-(3-pyridyl)-a-(3-pyridylmethyl,)-s-triazolo[3 ,4-~[1,2,4]triazine-3-acetamide 25 G = (R,S)-a-Allyl-N-~(1S,2R,3S)-1-(cyclohe~ylmethyl)-3-cyclopropyl-2,3-dihydro~ypropyl~-8-propyl~6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetamide The compounds of formula I as well as their pharmaceutically 30 usable salts can be used as medicaments, e.g. in the form of pharma-ceutical preparations. Ihe pharmaceutical preparations can be ad-ministered enterally su~h as orally, e.g. in the ~orm of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions, nasally, e.g. in the form of nasal sprays, or rectally, e.g.
35 in the form of ~uppositories. However, the administration can also be ef~ected parenterally such as intramuscularly or intravenously, e.g. in the folm of injection solutions.
-13- 2~8~2~6 The compounds of fo~nula I as well as their pharmlaceutically usable SaltB can be processed with pharmaceutically inert, inorganic or organic e~cipients for the manu~acture OI tablets, coated tablets, dragées and hard gelatine capsules. Lactose, corn starch or derivatives thereo~, 5 tal~, stearic acid or its salts e~ can be used e.g. as such excipients for ta~lets, dragées and hard gelatine cap~ule~.
- Suitable excipients ~or soft gelatine capsules are e.g. vegetable oils, wa~es, fats, semi-solid and liquid polyols etc.
Suitable exci~ients for the mallufacture of solutions and syr~lps are eg. water, polyols, saccharose, invert sugar, glucose etc.
Suitable excipients for injection solutions are e.g. water, alcohols, 15 polyols, glycerol, vegetable oils etc.
Suitable excipients for auppositones are e.g. natural or hardened oils, wa~e~, fats, semi~ uid or liquid polyols etc.
~0 Moreover, the pharmaceutical preparations can contain preser-vatives, solubili~ers, viscosity-increasing substances, stabilizers, wet-ting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buf~ers, coating agents or antioxidants.
They can also contain still other therapeutically valuable substances.
~5 In accordance with the inveIltion ~e compounds of general formula I as well a~ their pharmaceutically usable salts can be used in the control or prevention of high blood pressure and cardiac insu~-ficiency. The dosage can vary within wide limits and will, QI course, be 30 fitted to the individual requirements in each particular case. In general, in the case of oral admir istration there should suffice a daily dosage of about 3 mg to about 3 g, preferably about 10 mg to about 1 g, e.g. approxi-mately 300 mg per person, divided in preferably 1-3 ~t doses, which can e.g. be of the same amount, whereby, however9 the upper limit just 36 given can also be exceeded when this is found to be indicated. Usually, children receive half of the adult dosage.
-14- 20~2~6 The following E~amples are intended to illustrate the present invention, but are ~IOt intended to be lir~iting in any manner. All temperatures are given in degrees Celsius.
S ~
0.587 g (1.55 mmol) of HBTU and 0.21~ ml (1.5~ mmol~ of triet~iylamine were added to a 801u~ion ~ 0;600 g rl;56 mmol) of rac-8-cyclopropyl-6-(3-pyridyl)--(3 pyridylmethyl)-s-triazolor4,3-a]pyraziIle-3-acetic acid and 0.352 g (1~55 mmol) of (lS,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butarledio~ ~EP-A 0,332,008) in 30 ml of acetonitrile and the resulting suspension was stirred at room temperature for 12 hours.
Af~er the addition of saturated sodi~n chlolide solution the mixture was extracted three times with ethyl acetate. The orgarlic phase was washed ~5 with æaturated sodium hydrogen carbonate solution, water arld ~aturated sodium chloride ~olution, dried over magnesium sulphate, Sltered and evaporated under reduced presæure. ~er chromatography on silica gel (methylene chloride/methanol 9:1) there were obtained 0.240 g of the pure, less polar epimer (R or ~;~N-r(1S,2R,3S)-l-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydrc)xypropyl]-8-cyclopropyl-6-(3-pyridyl)-a-(3-pyridylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetamide, MS:
tFAB) 596 (M+H)~, and 0.160 g of th~ pure, ]more polar (S or O-N-[(lS,2R,3S~-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-cyclopropyl-6-(3-pyridyl)-a-(3-pyridylmethyl~-s-triazoloL4,3-a]pyrazine-3-acetarnide? MS: (FAB) 596 (M~H)~, each as a colourless foam.
The rac-8-cyclopropyl-6-(3-pyridyl)-a-(3-pyridylmethyl)-s-t~iazolo~4,3-a]pyrazine-3-acetic acid used as the starting material was prepared as follows:
(a) 49 g (240 mmol) of DCC were added at 10 to a suspension of 25.18 g (18S ~nol) of the sodium salt of 2-cyclopropyl-2-oxo acetic acid (Colle t.
Czech. Chem. Commun. 40, 1038 ~1975)), 38.28 g (185 mmol) of 3-(aminoacetyl)pyridine dihydrochloride (J. Chem. Soc. 1938, 7~3) and 25.34 g (185 mmol) of HOBT in 750 ml of methylene chloride and the mixture wa~ stirred at room temperature overnight. The resulting urea was filtered of~, the ~ltrate was washed with saturated sodi~n hytlrogen carbonate solution and subsequently with saturated sodium chloride 3 ~
~olution, dried over magnesium sulphate, filteled and evaporated under reduced pressure. Chromatography on silica gel (methylene chloride/-methanol 97:3) yielded 21 g of N-~2-o~o-2-(3-pyridyl)ethyl]-~-oxocyclo-propylaretamide as colourless crystals, M~: (EI) 233 (M+H)+.
(b) A solution of 9.00 g (38.76 mmol) of N-[2-oxo-2-(3-pyridyl)ethyl]-oc-oxocyclopropylacetamide in 80 ml of ethanol was treated wit~ 8.90 g (116 mr~ol) of ammonium acetate and the mi~:ture was heated at reflu~
for 2 hours. The solvent was evaporated and the residue was dissolved 10 in methylene chloride. The æolution was wa~hed in succession with water, ~aturated sodium hydrogen carhonate solution, water and saturated sodium chloride sollltion, dried over magnesium sulphate, Sltered and evaporated under reduced pressure. Af~cer chromatography on silica gel (methylene chlo~de/methanol, ~:1) and recrystalliza~on from diethyl et~er there vvere obtained 6.û0 g of 3-cyclopropyl-5-(3-pyridyl)-2(1H)-pyrazinone as a yellow powder, m.p. 168-170, MS: (EI) 213 M+.
(c) A solution of 6.00 g (28.13 mmol~ of 3-cyclopropyl-5-(3-py~idyl)-aD 2(1H)-pyrazinone in 50 of phosphorus oxychloride was heated to reflu~
for 2 hours. The pale brown solution was evaporated on a rotary evapo-rator under reduced pressure and the residue was poured into ice-water. Af~Ger e~traction with methylene chloride, drying o~er sodium sulphate, filtration and evaporation under r~duced pressure there were 25 obtained 5.20 g of 2-chloro-3-cyclopropyl-5-(3-pyIidyl)pyrazine as a colourless powder, MS: (EI) 230 Mf.
(d) A 601uti0n of 5.20 g (22.4 mmol) of 2-chloro-3-cyclopropyl-5-(3-py~dyl)pyrazine in 50 ml of ethanol was treated with 7 ml (140 mmol) of 30 hydrazine hydrate and the mixture was heated to reflux ~or 7 hours.
After cooling to room temperature the precipitated product was filtered o~ under suction and there were thus obtained 2.70 g of 3-cyclopropyl-2-hydrazino-5-(3-pyridyl)pyrazine as yellow glistening platelets, m.p. 179-181, MS: OEI) 227 M~.
~e) 0.760 g (4 ~nol) of p-toluenesulphonic acid was added to a solution of 0.900 g (4 mmol) of 3-cyclopropyl-2-hydrazino-5-(3 pyri-dyl)pyrazine and 1.5 g (6 mmol) of diethyl (3-py~dylmethyl)malonate -16- ~8~3~
(Arch. Pharm. 308, 663 (1975)) in 70 ml of ~ylene and the mixture was heated to reflux ~or 2 hours on a water separa~r. Af~er distilling OI the ~ylene under reduced pressure the residue was dissolved in methylene chloride. The organic phase was washed with saturated sodium bicar-bonate solution and ~ubsequently with satura$ed sodium chloride solu-tion, dried over magnesium sulphate, filtered and evaporated under reduced pressure. Chromatography on silica gel (methylene chloride/-methanol~3:1) yielde~`O.B00 g~of ethyl rac-8-cyclopropyl-6-(3-pyridyl)-oc-(3-pyridylmethyl)-s-t~iazolo~4,3-a]pyrazine-3-acetate as a colourless oil (Rf:
0.33, silica gel, methylene chloride/methanol, 9:1).
(f~ A solution of 0.300 g (0.724 mmol) of ethyl rac-8-cyclopropyl-6-(3-pyridyl~-oc-(3-pyridylmethyl)-s-triazolo[4,3-a]pyra~ e-3-aceta$e in 20 ml of ethanol was treated with 10 ml of 2N sodium hydro~ide solution and 15 the mixture was stirred at room temperature for 6 hours. Ihereafter, 10 ml of 2N hydrochloric acid were added thereto, the mi~ture was evaporated and the residue was partitioned between 10 ml of water and 50 ml of a 10:1 mixture of methylene chloride and methanol. The organic phase was dried over sodium sulphate, filtered and evaporated under reduced pressure. There was thus obtained 0.258 g of rac-8-cyclopropyl-6-(3-pyridyl)-a-(3-pyridylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetic acid as a colourless, amorphous powder, MS: (EI) 342 (M-C02)+.
Example 2 The ~ollowing compounds were manufactured in an analogous manner ~o that described in Example 1:
- From rac-8-cyclopropyl-6-(3-pyridyl)-a-(4-thiazolylmethyl)-s-triazolo 30 [4,3-alpyrazine-3-acetic acid and (lS,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol the (lR or S~N-~(1S,2R,3S)-1-(cyclohexyl-methyl~3-cyclopropyl-2,3-dihydroxypropyl]-8-cyclopropyl-/3-(3-pyridyl)-a-(4-thiazolylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetamide, MS: ~FAB) 602 (M+H)~, and the (S or R)-N-[(lS,2R,3S~1-(cyclohexylmethyl)-3-cyclo~
35 propyl-2,3-dihydroxypropyl]-8-cycloprop;y1-6-(3-pyridyl)-a-(4-thiazolyl-methyl)-s-triazolo[4,3-a]pyrazine-3-acetamide, MS: (FAB) 602 (M~H)+, each as a colourless foam;
-17- ~81236 - from 8-cyclopropyl-6-(3-pyridyl~s-triazolo[4,3-a3pyrazine-3-acetic acid and (1S,2R,3S~-3-amino-4-cyclohe~yl-1-cyclQpropyl-1,2-butanediol the N-[(1S,2R,3S)-1-(cyclohe~ylmethyl3-3-cyclopropyl-2,3-dihydroxypropyl]-8-cyclopropyl-6-(3-py~idyl)-s-triazolo[d~,3-a]pyrazine-3-acetamide, MS:
5 (FAB) ~05 (M-~H)~, as a colourless foam;
- from rac-8-(cyclopropylmethyl)-6-(3-pyridyl)-a~3-pyridylmethyl)-s-triazolor;~,3-a]pyTazine:3-acetic acid ana ~1$,2R;3S)~3-amino-4-cyclohe~yl-1-cyclopropyl-1,2-butanediol ~he (R or S)-N-[(lS,2R,3S)-1-10 (cyclohe~ylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-(cycloprQ-pylmethyl)-6-(3-py~idyl)-o~-(3-pyFidylmethyl)-s-t~azolo[4,3-a]pyrazine-3-acetamide, MS: (FAB) 610 (M+H)+, and the (S or R)-N-[(1S,2R,3O-1-(cyclohe~ylmethyl~-3-cyclopropyl-2,3-dihydro~ypropyl]-8-(cyclopro-pylmethyl)-6-(3-pyridyl)-a-(3-pyridylmethyl)-s-tliazolo[4,3-a~pyI azine-3-15 acetamide, MS: (FAB) 61Q (M+H)+, each as a colourless foam;
- from rac-8-(cyclopropylmethyl)-6^(3-pyridyl)-a-(4-thiazolylmethyl)-s-triaæolo[4,33pyrazine-3-acetic acid and (1S,2R,3$)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butaIIediol the (R or S~-N-[(1S,2R,3S)-1-(cyclohexyl-20 methyl~-3-cyclopropyl-2,3-dihydroxypropyll-8-(cyclopropylmethyl)-6-(35-pyridyl)-a-(4-thiazolylmethyl)-s-tIiazolo[4,3-;3]pyrazine-3-acetamide, MS:
(ISP) 616 (M~E)+, and the (S or R)-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-~cyclopropylmethyl)-8-(3-pyridyl)-a-(4-thiazolylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetamide, MS: (ISP) 616 25 (M~H)~, each as a colourless foam;
- from 8-(cyclopropylmethyl)-6-(3-pyridyl)-s-triasolo[4,~-a]pyrazine-3-acetic acid and (lS,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-~utanediol the N-C(lS,2R,3S)-1-~cyclohexylmethyl)-3-cyclopropyl-2,3-30 dihydroxypropyl]-8-(cyclopropylmethyl)-6-(3-pyridyl)-s-triazolo[4,3-a]-pyrazine-3-acetamide, MS: (ISP) 519 (M~H)~, as a colourless foam;
- from rac-6-(4-isoquinolinyl)-8-propyl-a-(3-pyridylmethyl)-s-tr~azolo [4,3-a]pyrazine-3~acetic acid and (1S,2R,3S)-3-amino-4-cyclohexyl-1-35 cyclopropyl-1,2-butanediol the (R or S)-N-[(1S,2R,3$)-1-(cyclohexyl-methyl)-3-cyclopropyl-2,3-dihydroxypropyl]-6-(4-isoquinolinyl)-8-propyl-o~-(3-pyridylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetam;de, MS: (FAB) 648 (M+H)f, and the (~3 or R)-N-[(1S,2R,3$}1-(cyclohexylmethyl)-3-cyclopro--18- 2~23fi pyl-2,3-dihydroxypropyl]-6-(4-isoquinolinyl)-8-propyl-a-(3-pyridylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetamide, M[S: (FAB) 648 (M~H~, each as a colourless foam;
- from 6-(4-isoquinolinyl~-8-propyl-s-triazolo[4,3-aJpyrazine-3-acetic acid and (1S,2R,30-3-amino-4-cyclohe2~yl-1-c~rclopropy~-1,2-butanediol the N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydro:gypropyU-6-(ds-isoquinolinyl)~8-propyl s-ti~iazolo[4,3-~})yrazine-3-acetamide, MS: (EI~
556 M+, as a colourless foam;
- ~rom rac-8-cyclopropyl-6-(3-pyridyl)-oc-(3-pyridylmethyl)-s-1triazolo[4,3-a]pyrazine-3-acetic acid and (1S,2R,30-3-amino-1-cyclopropyl-4-phenyl-1,2-butanediol the (R,S)-N-[(lS,2R,3S)-1-benzyl-3-cyclopropyl-2,3-dihydro~ypropyl]-8-cyclopropyl-6-(3-pyridyl)-a-(3-pyridylmethyl)-s-15 triazolo[4,3-a]pyrazine-3-acetamide, MS: (FAB) 590 (M+H~+, as a colourless foam (1:1 epimer mixture);
- from 8-propyl-6-(3-pyridyl)-s-triazolo[3,4-f~[1,2,4]~iazine-3-acetic acid and (lS,2R,3S)-3-arnino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol the N-ao [(1$,2R,3$)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-propyl-6-(3-pyridyl)-s-triazolo[3,4-f~[1,2,4]triazine-3-acetamide, MS:
(FAB) 508 (M~H)~, as a colourless foam;
- frcm rac-8-propyl-6-(3-pylidyl)-a-(3-pyridylmethyl)-s-triazolo[3,4-f~-25 [1,2,4]triazine-3-acetic acid and (lS,2R,3S)-3-amino-4-cyclohexyl-:l-cyclopropyl-1,2-butanediol the (R or S~N-[(1S,2R,3S)-1-(cyclohexyl-methy~)-3-cyc~opropyl-2,3-dihydro:~ypropyl]-8-propyl-6-(3-pyridylhc-~3-pyridylmethyl)-s-triazolo[394~f~[1,2,4]triazine-3-acetamide, MS: (FAB) 599 (M+H)~, and the (S or R)-N-[(1S,2R,3S)-1 (cyclohexylmethyl)-3-cyclopro-30 pyl-2,3-dihydro~ypropyl]-8-propyl-6-(3-pyridyl)-a-(3-pyridylmethyl)-s-triazolo[3,4-f 1[1,2,4]triazine-3-acetamide, MS: (FAB) 599 (M+H)+, each as a colourless foam;
- from rae-8-isobutyl-6-(3-pyridyl)-a-(3-pyIidylmethyl~s-triazolo[3,4-f~-36 ~1,2,4Jtriazine-3-acetic acid and (1S,2R,3$)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol the (R or S~-N-[(1S,2R,3S)-1-(cyclohe~yl-methyl)-3-cyclopropyl-2,3-dihydro~ypropyl]-8-isobutyl-6~(3-pyridyl)-os-(3-pyridylme~hyl)-s-triazolo[3,4-f~[1,2,4]triazine-3-acetamide, MS: (FAB) 6:13 2~23~
(M~H)~, and the (S or ~ -N-[(1S,2R,3S~1-(cyclohexylmethyl)-3-cyclopro-pyl-2 ,3-dihydroxypropyl]-8-isobutyl-8-(3-pyridyl)-a-(3-pyridylmethyl)-s-tria~olo[3,4-f 1[l~2~43triazine-3-acetamide~ MS: (FAB) 613 (M+H)~, each as a colourless foam.
The acids used as starting mate~als were prepared as ~ollows:
~ 1:6-~3-pv~.~Yl2-a-r4-thiazQl~lm~thYl2 ~z~[~
~razin~ ~ ~cetic ~cid In an analogous mamler to ~at described in E~ample 1 (e,f), by the condensation of 3-cyclopropyl-2-hydrazino-5-(3-pyridyl)pyrazine with die$hyl (4-thiazolylmethyl)malonate (EP-A 0,307,837) and subsequent basic saponifioation there was obtained rac-8-cyclopropyl-6-(3-pyridyl)-a-1~ ~4-thiazolylmethyl)-s-t~iazolo[4,3-a]pyrazine-3-acetic acid as a colourless powder (Rf: 0.161, silica gel, methylene chloride/methanol, 4:13.
~0 In an analogous manner to that described in Example 1 (e,f~, by the condensation of 3-cyclopropyl-2-hydrazirlo-5-(3-pyridyl)pyrazine with diethyl malonate and subsequent basic saponification there was obtained 8-cyclopropyl-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetic acid as a colourless powder, MS: (EI) 251 (M-CO~)+.
ra&-8-(~vclolpropylmethv!)-6-(3-pvri~vl)-a-(3-pYridvlmethyl)-s-~riazo-lor~.~-a~yrazine-~-acetic ~d In an analogous manner to that described in Example 1 (a-f~, by 30 the coupling of 2-oxo-3-cyclopropylpropioI~ic acid (J. Med. Chem. 30, 1074 (1987)) with 3-(an~inoacetyl)pyridille dihydrochloride there was obtained N-[2-oxo-2-(3-pyridyl)ethyl]~ oxo-3-cylopropylpropionamide as a colourless powder, MS: (EI) 218 (M-CO)+, which with ammonium chloride in ethanol gave 3-(syclopropylmethyl)-5-(3-p~dyl)-2(1H)-.~ pyrazinone, MS: (EI) 227 M+, as a colourless powder. Chlorination wi~hphosphorus oxychloride yielded 2-chloro-3-(cyclopropylme~hyl)-~-(3-pyri-dyl)pyrazine as a beige powder, MS: (EI) 245 M~, which by reaction with hydrazine hydrate yielded 3-(cyclopropylmethyl)-2-hydrazino-5-~3-pyr~-3 ~
dyl)pyrazine as a yellowish powder, m.p. 161-163, MS: (EI~ 241 M~.
Condensation w;~ diethyl (3-pyridylmethyl~malonate and suhsequent basic sapo}~ification then yielded rac-8-(cyclopropylmethyl)-6-(3-pyridyl)-a-(3-pyridylmethyl~-s-triazolo[4,3-a]pyrazirle-3-acetic acid as a colourle~;s 5 powder, MS: (ISN~ 400 (M-H~-.
In an analogous manner to that described in E~ample 1 (e,f), by the condensation of 3-(i~yclopropylmethyl~ 2-hydrazino 5 (3 pyridyl~pyra-zine with diethyl (4-thiazolylmethyl)malonate and subsequent basic saponification there was obtained rac-8-(cyclopropylmethyl~-6-(3-pyri-dyl)-a-(4-thiazolylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetic acid as a 15 colourless powder, MS: (ISN) 40~ (M-H)-.
8-(CvclQlpFQl?vlme~hyl)-~-(3-~)-s-triazQlQL4~^al~zin~-~ace~ acid In an analogous marmer to that described in Example 1 (e,f~, by aD the condensation of 3-(cyclopropylmethyl~2-hydrazino-5-(3-pyridyl)-pyrazine with die~yl malonate there was obkained ethyl 8-(cyclopropyl-methyl~6-(3-pyridyl~s-triazolo[4,3-a]pyraziIle-3-acetate as a colourless powder, m.p. 140-141, MS: (EI) 337 M~. Subsequent basic saponifica-tion gave 8-(cyclopropylmethyl)-6-(3-pyridyl)-s-triazolo~4,3-a]pyrazirle-3-25 acetic acid as a colourless powder (Rf: 0.12, methylene chloride/-methanol, 4:1).
~zine-3-ac~ a~i~
In an analogous manner to that described in 13xample 1 (b-f~, by the reaction OI N-[(isoql~inolinylcarbonyl)methyl]-2-o~opentanamide with ammonium chloride in ethanol there was obtained 5-(4-isoquino-linyl~3-propyl-2(1H}pyrazinone as a colourless powder, MS: (EI) 265 35 M+. Chlorination with phosphorus o~ychloride yielded 4-(5-chloro-6-propyl-2-pyrazinyl)isoquinoline, MS: (El:) 283 M+, as a colourless powder which by reaction with hydrazine hydrate yielded 4-(5-hydrazino-6-pro-pyl-2-pyrazinyl)isoquinoline as a yellowish powder, m.p. 161-163, MS:
-21- 2~ 3~
(EI) 279 M~. Condensation wi~h diethyl (3 pyridylmethyl)malonate and subsequent basic saponification then yielded rac-6-(4-isoquinolinyl3-8-propyl-a-(3-pyridylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetic acid as a colourless powder, MS: (EI) 394 (M-C02)+.
In an analogous manner to tha~ ~esc~bed in E~ample 1 (e,i~, by the condensation OI 4-(5-hydrazino-6-propyl-2-pyrazinyl)isoquinoline 10 with die~yl malonate and 6ubsequent basic saponification there was obtained rac-6-(4-isoquinolinyl)-8-propyl-s-triazolo[4,3-a]pyrazine-3-acetic aoid as a colourless powder, MS: (EI) 303 (M-CO2)+.
The N-[(isoquinolinylcarbonyl)methyU-2-oxopentanamide used as ~5 the starting material was prepared as follows:
In an analogous manner to that described in Org. Synth. 64, 19 (1986) for 2,2-diethoxy-2-(4-pyridylethyl)diarnine, starting from 4-acetyl-isoqLuinoline (J. Am. Chem. Soc. 67, 1268 (1945)) by reaction with hydro-20 xylamine, preparation of the tosylate and subsequent rearrangementwith sodiurn ethanolate there was obtained 2,2-diethoxy-2-(4-isoquino-linyl)ethylamine, m.p. 236 (decomposition).
0.8 ml of 2-oxo-n-valeric acid, 2.7 ml (15.5 mol3 of triethylamine 25 and 1.07 g (7.8 mmol) of EOBT were added to a suspension of 2.6 g (7.8 mmol) of 2,2-diethoxy-2-(4-isoquinolinyl)ethylamiIle in 40 ml of methylene chloride and the reaction mixture was subseqllently treated with 1.59 g of DCC in i3 ml of methylene chloride. A~ter 24 hours ~le resulting urea w~s f;ltered of~ e filtrate was washed with saturated 30 sodium hydrogen carbonate solution and saturated sodiuxn chloride eolution, d~ied over magnesium sulphate, filtered and evaporated under reduced pressur~. Chromatography on silica gel (methylene chloridel-ether, 9:1) yielded 1.5 g of a yellow oil which was dissolved in 50 ml of 2N
hydrochloric acid and stirred at room temperature for 24 hours. The 35 solvent was evaporated under reduced pressure and the thus-obtained residue was dried azeotropically with toluene several times. There were thus obtained 1.1 g of N-[(4-isoquinolinylcarbonyl)methyl]-2-oxopentan-amide hydrochloride as a pale brown powder, MS: (EI) 256 (M-CO)+.
, 2~8~3~
In an analogous manner to that de~clibed in Example 1 (c-f~, from ~-propyl-3-~3-pylidyl)-as-l;riazin-6~1H)-orle by clhlorination with phos-phorus oxychloride there wa~ obtained 6-chloro-~-propyl-3-(3-pyridyl)-as-triazine as a colourless powder, m~.p;74-76, MS: IEI) 234 M+, which by reaction with hydrazine yielded 6-hydrazino-5-propyl-3-(3-pyndyl)-as-triazine as a yellow powder, M~: (EI) 230 M+. Condensation with diethyl (3-pyridylmethyl)malonate and subsequent basic saponification gave rac-8-propyl-6-(3-pyridyl~a-~3-pyridylmethyl~6-triazolo[3,4-~1[1,2,4]triazine-3-acetic acid as a colourless powder, MS: (Fl~B) 346 (M-C02~H)+.
,5 ~
In an analogous manner to ~at desc~ibed in E~ample 1 (e,f), by the condensation of 6-hydrazino-5-propyl-3-(3-pyridyl)-as-tIiazine with diethyl malonate and subsequent basic saponification there was obtain0d 8-propyl-6-(3-py~idyl)-s-triazolo[3,4-f~[1,2,4]tr;azine-3-acetic acid QS a colourless powder, MS: (FA33) 299 (M+H)+.
The 5-propyl-3-(3-pyIidyl)-as-triazin-6(ïH)-one used as the starting material was prepared as follows:
'' 6.50 g (36 mmol) of D,L-norvaline ethyl e~ter hydrochloride in 10 ml of water were added to a euspension of 6.40 g (36 mmol) of methyl pyridine-3-carbo~midate (J. Org. Chem ~, 41~ (1961) in 10 ml of ether and the m~ture was stirrsd at room temperature for 3 hours. Af~er the addition of 50 ml of methylene chloride the organic phase wa~ separated, dried over 80ditlm sulphate, filtered and evaporated under reduced pressure. The thus-obtained pale yellow oil (6.05 g) was heated to reflux for 2 hour3 with 1.6 ml (30 mmol) of hydrazine hydrate in 20 ml of isopro-panol. APcer cooling to room temperatllre the rnixture wa~ treated with 10 ml of water and e~tracted with methylene chloride. The organic phases were dried over magnesium sulphate, filtered and evaporated under reduced pressure. After chromatography on silica gel (methylene chloride/methanol, 9:1) there were obtained 2.50 g of rac-2,5-dihydIo-5-~08123~
propyl-3-(3-pyridyl)-as-triazin-6(1H)-one as a colourless powder, m.p.
144-146, MS: OEI) 218 M-~.
6.4 ml (10.5 mmol) of 10% Javelle water were added to a solution of 1.09 g (5 mmol) of rac-2,5-dihydro-5-propyl-3-(3-pyridyl~as-triazin-6(1H)-one in 10 ml of lN sodium hydrogide solution while cooling with ice and the mi~ture was subsequently stirred at room te3nper~ure ~or 12 hours.
:E:~tractio~ methylene chloride, drying over sodiilm sulphate, filtration and evaporation under reduced pressure yielded 0.58 g of 5-propyl-3-(3-pyridyl)-as tria~in-6(1H)-one as a colourless powder, m.p.
160-162, MS: (EI) 216 M+.
~r In an analogous manner to that desc~bed in Example 1 (c-f~, from 5-isobutyl-3-(3-pyIidyl)-as-triazin-6(1H)-one by chlorination with phos-phorus o~ychloride there was obtained 6-chloro-5-isobutyl-3-(3-pyrid~
as-triazine as a colourless powder, m.p. 63-65, MS: (:3I) 248 M~, which by reaction with hydrazine yielded 6-hydrazino-5-isobutyl-3-(3-pyridyl~
as-t~azine as a yellow powder, m.p. 126-129, MS: (EI) 244 M+. Conden-sation with diethyl (3-pyridylmethyl)malonate and subsequent basic saponification gave rac-8-isobutyl-6-(3-pyridyl)-a-(3-pyridylmethyl)-s-tIiazolo[3,4-f~[1,2,4]triazine-3-acetic acid as a colourless powder, MS:
(lFAB) 359 (M-C02+H)+.
The 5-isobutyl-3-(3-pyridyl~as-triazin-6(1H~one used as the starting material was prepared as follows:
In an analogous manner to that described for 5-propyl-3-(3-pyri-. dyl)-as-triazin-6(1H~one using D,L-leucine ethyl ester hydrochloride in place of D,L-norvaline ethyl ester hydrochlonde there was obtained 5-iso-butyl-3-(3-pyridyl~as-triazin-6(1H)-one as a colourless powder, m.p. 141-144C, MS: (EI) 230 M~.
The (lS,2R,3S)-3-~nino-1-cyclopropyl-4-phenyl-1,2-blltanediol used as the starting material was prepared as ~ollows:
2~1236 9.96 ml (124.5 mmQl) of cyclopropyl bromide in 100 ml of ether were added dropwise wi~in 30 mimltes under slight reflu~ to 3.03 g 5 (124.5 ~nol) of magnesium ir3 10 ml of abs. ether and the mi~ture was ~ubsequently heated to reflu~ for 2 1/2 hDul s. Sub~equent Iy, 6.25 g (22.63 mmol) oftert.-butyl [1S~2R~1-bemzyl-2-cyano-2-hydroxyethyl]-carbamate (EP-~i 0,266,960) were added dropwise thereto under re~
within 4~ minutes and t~e migture was heated to reflu~ for a further 2 lJ2 hours. Finally, t~e mixture wa~ lel~ to cool (10), 10% citric aeid was added dropwise thereto and the mi~ture wa~ e~tracted twice with ether.
The organic phase was washed with water and saturated sodium chlor-ide solution, d2ied over magnesium sulphate, ISltered and evaporated under reduced pressure. Chromatography on silica gel (toluene/ethyl 15 acetate, 9:1) yielded tert-butyl [(1S,2R~1-benzyl-2-(cyclopropylcar~oIlyl)-2- hydroxyethyl~carb~ate as a pale yellow solid, MS: (EI) 246 (M-C3HgO)+.
A solution of 2.83 g (8.77 mmol) of tert-butyl [(lS,2R)-1-benzyl-2-a~ (cyclopropylcarbonyl)-2-hydroxyethyl]carbarnate was dissolved in 130 ml of methylene chloride, 3 ml of acetic acid were added thereto and the mixture was finally treated portionwise at 0 10 with 0.332 mg (8.78 mmol) of sodium borohydride. The reaction solution was stirred at ~
for a further 2 hours and partitioned between 2N sodium hydrogen 25 carbonate solution and methylene chloride. The organic phase was æeparated> washed with water and with saturat~d sodium chloride solution, dried over magnesium sulphate> filtered and evaporated under reduced pressure. Crystalligatiorl of the residue fi~om etherlhe~ane yielded 2.1 g of tert-butyl [(1S>2R>3$)-1-benzyl-3-cyclopropyl-2>3-dihydroxy-30 propyl]car~amate as colourless needles> m.p. 83-85.
~ A solution of 2.0 g (6.23 mmol) of tert-butyl [(lS>2R>3S~1-benzyl-3-cyclopropyl-2>3-dihydroxypropyl]carbamate in 2û ml of methanol was treated with 20 ml of 2N hydrochloric acid and the solution was heated to 35 50 for 9û minutes. Af'cer cooling the mixture was neutralized by the addition of 40 ml of lN sodi~ hydroxide solution and concentrated to dryness on a rotary evaporator under reduced pressure. The residue was partitioned between water and methylene chloride. The organic 2~8123~
phase was washed ~nth water and saturated sodivln chlo~de solu~on, d~ed over magnesium sulphate, ~ltered and evaporated ~ der redured pressure. There wasthus ob ~ ned (1S,2R,3S)-3-~nino-1-cyclopropyl-4-phenyl-1,2-blltanediol a~ a white, crystalline 60lid, MS: (EI~ 150 ~M-C4~I8O+-~Q~
The following compo~ds were mar~ actured in an analogous 1D mannerto that desc~bedin E~al~ple 1:
- From rac-8-(3-methylsulphanylpropyl)-6-(3-pyridyl)-a-(3-pyridyl-methyl)-s-triazolo[4,3-a~pyrazine-3-acetic acid and (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol the (R or S)-N-[(1S,2R,3S)-1-(cy-15 clohe~ylmethyl)-3-cyclopropyl-2,3-dihydro:~ypropyl~-8-(3-methylsulpha-nylpropyl)-6-(3-pyridyl)-a-t3-pyridylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetamide, MS: (FAB) 644 (I!~H)~, and the (S or R)-N-[(lS,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dih,ydroxypropyl]-8-(3-methylsul-phanylpropyl)-6-(3-pyridyl)-oc-(3-pyridylmethyl)-s-triazolo[4,3-a~pyrazine-~0 3-acetamide, MS: (FAB) 644 (M+H)+, each as a colourless foam;
- from rac-a-allyl-8-propyl-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetic acid and (lS,2R,3S)-3-amino-4-cyclohe~yl-1-cyclopropyl-1,2-butanediol the (R,S~a-allyl-N-[(1S,2R,3S)~1-(cyclohexylmethyl)-3-cyclopropyl-2,3-25 dihydroxypropyl]-8-propyl-6-(3-pyndyl)-s-triazolo[d~,3-a]pyraz;ne-3-acetamide, MS: (FAB) 547, (M+H)+, as a colourless foam.
The aMds used as starting matenals were prepared as follows:
In an analogous manner to that desc~bed in Example 1 (a-f~, by the coupling of 5-(methylsulphanyl)-2-oxopentanoic acid (J. Med. Chem.
3S 80, 1074 (1987)) with 3-(aminoacetyl)py~idine dihydroc~loride there was obtained N-[2-oxo-2-(3-pyridyl)ethyl]-oc-oxo-5-methanesulphanylpentan-amide as a colourless powder, MS: (EI) 280 M+, which with ammonium 3 ~
chloride in ethanol gave 3-(3-methylsulphanylpropyl)-5-(3-pyridyl)-2(1H)-pyrazinone, MS (EI) 261 M~, as a colourless powder. Chlorination with phosphorlls oxychloride yielded 2-chloro-3-(3-methylsulphanylpropyl)-~-(3-pyridyl)pyrazine as a beige powder) M~3: (EI) 244 (M-Cl)~, which by 5 reaction with hydrazine hydrate yielded 2-hydrazino-3-(3-methyl~ul-phanylpropyl)-5-(3-pyridyl)pyrazine as a yellowish powder, MS: (EI) 275 M~. Condensation with diethyl (3-pyridylmethyl)malonate and su~-sequent basic saponilScation t~en`yielded rac-8-(3-methylsulphanyl-propyl)-6-(3-pyridyl~-a-(3-pyridylmethyl~s-triazolo[4,3-a]pyrazine-3-1D acetic acid as a colourless foam, MS: (EI) 390 (M[-C02)~.
ra~-a-AllYl-8-~ropvl-6-(~i~yl)-s-tria~olo[4~-al;pyrazine-3-acetic açid 135 mg (3.1 mmol) of sodium hydride were added in one portion to a solution of 975 mg (3 mmol) of ethyl 8-propyl-6-(3-pyridyl)-s-triazolo~4,3-a]pyrazine-3-acetate (EP-A 0,369,743) in 25 ml of dimethylformamide at 0. After the evolution of hydrogen had finished 0.25 ml (3 mmol) of allyl bromide in S ml of dimethylformamide were slowly added Idropwise and the resulting solution was stirred for 2 hours. The reaction solution was 20 poured on to ice-water and e~tracted three times with methylene chloride. The organic phase was dried over magnesium sulphate, filtered and evaporated under reduced pressure. Chromatography on silica gel (methylene chloride/ methanol 25:1~ yielded 800 mg of ~thyl rac-oc-allyl-8-propyl-6-t3-pyridyl)-s-triazolo[4,,3-a]pyrazine-3-acetate as a 25 colourless oil, MS: (EI) 365 M+, which was saponified in an analogous manner to that described in Ea~ample 1(f) and then yielded rac-oc-allyl-8-propyl-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetic acid, MS: (EI) 293 (M-C02)+, as a colourless powder.
Example 4 62.9 mg (0.311 mmol) of m-chloroperbenzoic acid (85%) were added to a solution of 100 mg (0.155 rnmol) of (R or S)-N-[(lS,2:E~,3S)-1-(cyclo-hexylmethyl)-3-cyclopropyl-2,3-dihydroxy-propyl]-8-(3-methylsulpha-35 nylpropyl)-6-(3-pyridyl)-a-(3-pyridylmethyl)-s-triazolo[4~3-a]pyrazine-3 acetamide in 2 ml of methylene chloride at 0 and the mi~ture was stirred at room temperature for 12 hours. The reaction solution was diluted with 10 ml of methylene chloride and subsequently washed with -~7~ 123~
10% sod~ ulphite solution, saturated sodium bicarbonate solution and water. The organic phase was dried over magnesium sulphate, filtered and evaporated und~r reduced pressure. Chromatography on silica gel (methylene chlo~de/m~thanol/ ammonia 110:10:1) yielded ~0 mg of (R~ or S)-N-[(1S,2R,3S)-1-(cyclohexylme~hyl)-3-cyclopropyl-2,3-dihydroxypropyl~-8-(3-methylsulphonylpropyl)-6-(3-pyridyl) c~-(3-pyridylmethyl)-s-triazolo[4,3-a~pyrazine-3-acetamide as colourless crystals,~S -~ISP) 676 ~M~H~+.
In an analogous manner to that described above, from (S or R)-N-[(lS,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydro:~ypropyl]-8-(3-methylsulphanylpropyl)-6-(3-pyridyl)-oc-(3-pyridylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetamide there was l)btained (S or R~N-[(lS,2R,3.$)-1-(cyclohe~ylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-(3-methylsul-~5 phonylpropyl)-6-(3-pyridyl)-oc-(3-pyridylmethyl)-s-triazolo~4,3-a]pyrazine-3-acetamide as colourles~ crystale, MS: (ISP) 676 (M+H)~.
~m~DlQA
2D Qral ag~eous suspQnsi Composition:
(R or S)-N-~(1S,2R,3S)-1-(Cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-cyclopropyl-6-(3-pyridyl)-oc-(4-thiazolyl-methyl)-s-triazolo[4,3-a]pyrazine-3-acetamide micronized 5.0 g Polysorbate 80 0.3 g Hydroxypropylmethylcellulose 1.0 g Flavouring q.s Methylparaben 0.2 g Propylparaben 0.04 g Water ad 100.0 ml ~8~L236 ExaLm~l~
~Qm~L
(R or 0-N-[(1S,2R,3S)-1-(Cyclohe~ylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-cyclopropyl-6-(3-pyridyl)-o~-(4-thiazolyl-methyl)-s-triazolo[4,3-a]pyrazine-3-acetamide methane-sulphonate 1.0 g Methylparaben û.2 g Propylparaben 0.04 g Flavouring q.s.
Water ad 100.0 ml E~ample~
1) (R or S)-N-[(lS,2R,3S)-1-(Cyclohexylme$hyl)-3-cyclopro-pyl-2,3-dihydroxypropyl:l-8-cyclopropyl-6-(3-pyridyl)-a-(4-thiazolylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetamide methanesulphonate ~00 mg 2) Anhydrous lactose 160 mg 3) Hydroxypropylmethylcellulose 18 mg 4) Sodium carboxymethylcellulose 20 mg 5) Magnesium stearate 2m~
Tablet weig~ 400 mg Y_ 1) and 2) are mixed intensively. The mixture is thereafter moistened with an aqueous solution of 3) and kneaded, and the resulting 15 mass is granulated, dried and sieved. The granulate is mixed with 4) and 5) and pressed to tablets of suitable si~e.
2~123~
~am~
~i~
1) (R or S)-N-[(1S,2R,30-1-(CycJohe~ylmethyl~3-cyclopro-- pyl-2,3-dihydro~ypropyl3-8-cy~opropyl-6-(3-pyri~yl)-a-(4-thiazolylmethyl)-s-tria~olo~4,3-a]pyrazine-3-acetamide methane~ulphonate 200 mg 2) Anhydrous lactose 16ûmg 3) Hydro~ypropylmethylcellulose 18 mg 4) Sodium carboxymethylcellulose 20 mg 5) Magnesium stearate 2 m~
Capsule fill weight 400 mg 1) and 2) are mixed int0nsively. The mixture is thereafter moistened with an aqueous solution of 3) and kIleaded, and the resulting ma6s is granulated, dried and sieved. The granulate is mi~ed with 4) and ~), the mixture is filled into capsules of suitable size.
E~ample E
~Q~
1 ml (R or S)-N-[(1$,2R,3S)-1-(Cyclohe~ylmethyl)-3-cyclopropyl-2,3-dihydro~ypropyl]-8-cyclopropyl-6-(3-py~dyl)-a-(4-thiazolyl-methyl)-s-triazolo[4,3-a]pyrazine-3-acetamide methane-sulphonate 20 mg Pyrogen-free D-mannitol 10 mg Water for injection ad 1.0 ml The ac~;ive subst~Lnce and the mannitol are dissolved in nitrogen-5 gassed water and subsequently lyophilized according to a con~entional procedure.
''E~.E
When the procedures desc~bed in ~ amples A-E are followed, corr~spomding galenical preparations can be manufacturedl ~rom the following, likewise pre~erred compounds and their pharmaceutically usable salts:
1~ (R or S)-N-[~lS,2R,3S) l-(Cyclohe:~ylmethyl~3-cyclopropyl-2,3-dihydroxypropyl]-8-c~c~opropyl-6-(3-pyridyl)-a-~3-pyridyl-methyl)-s-triazolo[4 ,3-a]pyrazine-3-acetamide~
- (:R or S)-N-[(1$,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-(cyclopropylmethyl)-6-(3-pyridyl)-oc-(3-pylidylmethyl~-s-triazolo[4,3-a~pyrazine-3-acetamide, - (R or S)-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-(cyclopropylmethyl)-6-(3-pyridyl)-a-(4-thiazolylmethyl)-s-triazolo[4,3-a~pyraz;ne-3-acetamide.
Claims (30)
1. Amino acid derivatives of the general formula I
wherein X signifies a nitrogen atom or -CH-, R1 signifies phenyl, pyridyl or isoquinolinyl, R2 signifies cycloalkyl, cycloalkylalkyl, alkylthioalkyl, alkylsulphonylalkyl, alkenyl or, where X signifies a nitrogen atom and/or R1 signifies isoquinolinyl and/or R3 signifies alkenyl, also alkyl, R3 signifies hydrogen, alkyl, alkenyl, imidazolylmethyl, pyridylmethyl, thiazolylmethyl or benzyl, R4 signifies cyclohexylmethyl or benzyl and R6 signifies cycloalkyl, alkyl or heterocyclyalkyl, in the form of optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates as well as pharmaceutically usable salts of these compounds.
wherein X signifies a nitrogen atom or -CH-, R1 signifies phenyl, pyridyl or isoquinolinyl, R2 signifies cycloalkyl, cycloalkylalkyl, alkylthioalkyl, alkylsulphonylalkyl, alkenyl or, where X signifies a nitrogen atom and/or R1 signifies isoquinolinyl and/or R3 signifies alkenyl, also alkyl, R3 signifies hydrogen, alkyl, alkenyl, imidazolylmethyl, pyridylmethyl, thiazolylmethyl or benzyl, R4 signifies cyclohexylmethyl or benzyl and R6 signifies cycloalkyl, alkyl or heterocyclyalkyl, in the form of optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates as well as pharmaceutically usable salts of these compounds.
2. Compounds in accordance with claim 1 or 2, wherein R2 signifies cycloalkyl, cycloalkylalkyl, alkylthioalkyl, alkylsulphonylalkyl, alkenyl or, where X signifies a nitrogen atom and/or R1 signifies iso-quinolinyl, also alkyl.
3. Compounds in accordance with claim 1 or 2, wherein X
signifies -CH-.
signifies -CH-.
4. Compounds in accordance with any one of claims 1-3, wherein R1 signifies pyridyl, preferably 3-pyridyl.
5. Compounds in accordance with any one of claims 1-4, wherein R2 signifies cycloalkyl or cycloalkylalkyl, preferably cycloalkyl, especially cyclopropyl.
6. Compounds in accordance with any one of claims 1-57 wherein R3 signifies imidazolylmethyl, pyridylmethyl or thiazol-ylmethyl, preferably pyridylmethyl or thiazolylmethyl, especially 4-thiazolylmethyl.
7. Compounds in accordance with any one of claims 1-6, wherein R4 signifies cyclohexylmethyl.
8. Compounds in accordance with any one of claims 1-7, wherein R5 signifies cycloalkyl or alkyl, preferably cycloalkyl, especially cyclopropyl.
9. Compounds in accordance with any one of claims 1-8, wherein X signifies -CH-, R1 signifies 3-pyridyl, R2 signifies cyclopropyl, R3 signifies 4-thiazolylmethyl, R4 signifies cyclohexylmethyl and R5 signifies cyclopropyl.
10. (R or S)-N-r(1S,2R,3S)-1-(Cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-cyclopropyl-6-(3-pyrdyl)-.alpha.-(3-pyridylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetamide.
11. N-[(1S,2R,3S)-1-(Cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-cyclopropyl-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetamide.
12. (R or S) N-[(1S,2R,3S)-1-(Cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-cyclopropyl-6-(3-pyridyl)-.alpha.-(4-thiazolylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetamide.
13. (R,S)-N-[(1S,2R,3S)-1-Benzyl-3-cyclopropyl-2,3-dihydroxy-propyl]-8-cyclopropyl-6-(3-pyridyl)-.alpha.-(3-pyridylmethyl)-s-triazolo[4,3-a]-pyrazine-3-acetamide.
14. (R or S)-N-[(1S,2R,3S)-1-(Cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-(cyclopropylmethyl)-6-(3-pyridyl)-.alpha.-(3-pyridyl-methyl)-s-triazolo[4,3-a]pyrazine-3-acetamide.
15. (R or S)-N-[(1S,2R,3S)-1-(Cyclohexylmethyl)3-cyclopropyl-2,3-dihydroxypropyl]-8-(cyclopropylmethyl)-6-(3-pyridyl)-.alpha.-(4-thiazolyl-methyl)-s-triazolo[4,3-a]pyrazine-3-acetamide.
16. (R,S)-.alpha.-Allyl-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclo-propyl-2,3-dihydroxypropyl]-8-propyl-6-(3-pyridyl)-s-triazolo[4,3-a]-pyrazine-3-acetamide.
17. N-[(1S,2R,3S)-1-(Cyclohexylmethyl)-3-cyclopropyl-2,3-dihy-droxypropyl]-6-(4-isoquinolinyl)-8-propyl-s-triazolo [4,3-a]pyrazine-3-acetamide, (S or R)-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-6-(4-isoquinolinyl)-8-propyl-.alpha.-(3-pyridylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetamide or (R or S)-N-[(1S,2R,3S)-1-(cyclo-hexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-6-(4-isoquinolinyl)-8-propyl-.alpha.-(3-pyridylmethyl)-s-triazolo[4,3-a]pyrazine-3-acetamide.
18. N-[(1S,2R,3S)-1-(Cyclohexylmethyl)-3-cyclopropyl-2,3-dihy-droxypropyl]-8-propyl-6-(3-pyridyl)-s-triazolo[3,4-f][1.2.4]triazine-3-acet-amide, (R or S)-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-propyl-6-(3-pyridyl)-.alpha.-(3-pyridylmethyl)-s-triazolo [3,4-f][1.2.4]triazine-3-acetamide, (S or R)-N-[(1S,2R,3S)-1-(cyclohexyl-methyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-propyl-6-(3-pyridyl)-.alpha.-(3-pyridylmethyl)-s-triazolo[3,4-f][1.2.4]triazine-3-acetamide, (S or R)-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-isobutyl-6-(3-pyridyl)-.alpha.-(3-pyridylmethyl)-s-triazolo[3,4-f][1.2.4]triazine-3-acetamide or (R or S)-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-8-isobutyl-6-(3-pyridyl)-.alpha.-(3-pyridylmethyl)-s-triazolo[3,4-f][1.2.4]triazine-3-acetamide.
19. Compounds of the general formula IIIb wherein R1 signifies phenyl, pyridyl or isoquinolinyl, R2 signifies cycloalkyl, cycloalkylalkyl, alkylthioalkyl, alkylsulphonylalkyl, alkenyl or alkyl and R3 signifies hydrogen, alkyl, alkenyl, imidazolylmethyl, pyridylmethyl, thiazolylmethyl or benzyl.
20. Amino acid derivatives in accordance with any one of claims 1-18 for use as therapeutically active substances.
21. Amino acid derivatives in accorclance with any one of claims 1-18 for use in the control or prevention of high blood pressure and cardiac insufficiency.
22. A process for the manufacture of a compound in accordance with any one of claims 1-18, which process comprises a) reacting a compound of the general formula II
wherein R4 and R5 have the significance given in claim 1, with a compound of the general formula III
wherein X, R1, R2 and R3 have the significance given in claim 1, or an activated derivative thereof, and b) if desired, oxidizing a compound of formula I obtained in which R2 signifies alkylthioalkyl to the corresponding compound of formula I
in which R2 signifies alkylsulphonylalkyl, and/or c) if desired, separating a mixture of diastereomeric racemates into the diastereomeric racemates or optically pure diastereomers, and/or d) if desired, separating a mixture of diastereomers into the optically pure diastereomers, and/or e) if desired, converting a compound obtained into a pharmaceutically usable salt.
wherein R4 and R5 have the significance given in claim 1, with a compound of the general formula III
wherein X, R1, R2 and R3 have the significance given in claim 1, or an activated derivative thereof, and b) if desired, oxidizing a compound of formula I obtained in which R2 signifies alkylthioalkyl to the corresponding compound of formula I
in which R2 signifies alkylsulphonylalkyl, and/or c) if desired, separating a mixture of diastereomeric racemates into the diastereomeric racemates or optically pure diastereomers, and/or d) if desired, separating a mixture of diastereomers into the optically pure diastereomers, and/or e) if desired, converting a compound obtained into a pharmaceutically usable salt.
23. A medicament containing an amino acid derivative in accordance with any one of claims 1-18 and a therapeutically inert excipient.
24. A medicament for the control or prevention of high blood pressure and cardiac insufficiency, containing an amino acid derivative in accordance with any one of claims 1-18 and a therapeutically inert excipient.
25. The use of an amino acid derivative in accordance with any one of claims 1-18 in the control or prevention of illnesses.
26. The use of an amino acid derivative in accordance with any one of claims 1-18 in the control or prevention of high blood pressure and cardiac insufficiency.
27. The use of an amino acid derivative in accordance with any one of claims 1-18 for the manufacture of medicaments against high blood pressure and/or cardiac insufficiency.
28. Amino acid derivatives in accordance with any one of claims 1-18, whenever prepared according to the process as claimed in claim 22 or by an obvious chemical equivalent thereof.
29. The invention as hereinbefore described.
30. A method of treating or preventing high blood pressure and/or cardiac insufficiency which comprises administering to a patient requiring such a treatment an effective amount of an amino acid derivative in accordance with any one of claims 1-18.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH337491 | 1991-11-19 | ||
| CH3374/91 | 1991-11-19 | ||
| CH2665/92 | 1992-08-28 | ||
| CH266592 | 1992-08-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2081236A1 true CA2081236A1 (en) | 1993-04-24 |
Family
ID=25691089
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002081236A Abandoned CA2081236A1 (en) | 1991-11-19 | 1992-10-23 | Amino acid derivatives |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0543245A1 (en) |
| JP (1) | JPH05239059A (en) |
| CN (1) | CN1072413A (en) |
| AU (1) | AU2841392A (en) |
| BG (1) | BG97094A (en) |
| CA (1) | CA2081236A1 (en) |
| FI (1) | FI925068A (en) |
| HU (1) | HU9203580D0 (en) |
| IL (1) | IL103743A0 (en) |
| IS (1) | IS3947A (en) |
| NO (1) | NO924423L (en) |
| TW (1) | TW275630B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2615284B2 (en) * | 1991-08-19 | 1997-05-28 | 三菱重工業 株式会社 | Manufacturing method of aluminum composite products |
| US5481008A (en) * | 1993-09-13 | 1996-01-02 | Hoffmann-La Roche Inc. | Process for the preparation of optically active compounds |
| CA2539479C (en) * | 2003-09-23 | 2010-07-06 | Merck & Co., Inc. | Isoquinoline potassium channel inhibitors |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1328333C (en) * | 1988-03-04 | 1994-04-05 | Quirico Branca | Amino acid derivatives |
| AU629867B2 (en) * | 1988-11-17 | 1992-10-15 | Imperial Chemical Industries Plc | Triazolo (4,3a) pyrazine derivatives |
| CA2044564A1 (en) * | 1990-06-28 | 1991-12-29 | Quirico Branca | Amino acid derivatives |
-
1992
- 1992-10-16 TW TW081108228A patent/TW275630B/zh active
- 1992-10-23 CA CA002081236A patent/CA2081236A1/en not_active Abandoned
- 1992-11-09 FI FI925068A patent/FI925068A/en not_active Application Discontinuation
- 1992-11-09 EP EP92119128A patent/EP0543245A1/en not_active Withdrawn
- 1992-11-13 IL IL103743A patent/IL103743A0/en unknown
- 1992-11-16 AU AU28413/92A patent/AU2841392A/en not_active Abandoned
- 1992-11-16 HU HU9203580A patent/HU9203580D0/en unknown
- 1992-11-17 NO NO92924423A patent/NO924423L/en unknown
- 1992-11-17 BG BG097094A patent/BG97094A/en unknown
- 1992-11-18 CN CN92113665A patent/CN1072413A/en active Pending
- 1992-11-18 IS IS3947A patent/IS3947A/en unknown
- 1992-11-18 JP JP4331267A patent/JPH05239059A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| AU2841392A (en) | 1993-05-20 |
| FI925068A0 (en) | 1992-11-09 |
| CN1072413A (en) | 1993-05-26 |
| BG97094A (en) | 1993-12-24 |
| NO924423D0 (en) | 1992-11-17 |
| JPH05239059A (en) | 1993-09-17 |
| IS3947A (en) | 1993-05-20 |
| EP0543245A1 (en) | 1993-05-26 |
| IL103743A0 (en) | 1993-04-04 |
| FI925068A (en) | 1993-05-20 |
| HU9203580D0 (en) | 1993-01-28 |
| NO924423L (en) | 1993-05-20 |
| TW275630B (en) | 1996-05-11 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |