CA2026038A1 - 4-substituted 2-aminoalk-3-enoic acids - Google Patents
4-substituted 2-aminoalk-3-enoic acidsInfo
- Publication number
- CA2026038A1 CA2026038A1 CA002026038A CA2026038A CA2026038A1 CA 2026038 A1 CA2026038 A1 CA 2026038A1 CA 002026038 A CA002026038 A CA 002026038A CA 2026038 A CA2026038 A CA 2026038A CA 2026038 A1 CA2026038 A1 CA 2026038A1
- Authority
- CA
- Canada
- Prior art keywords
- substituted
- c7alkyl
- amino
- hydroxy
- salt
- 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
- 239000002253 acid Substances 0.000 title claims abstract description 28
- 150000007513 acids Chemical class 0.000 title abstract description 6
- -1 amino, protected amino Chemical group 0.000 claims abstract description 353
- 239000000203 mixture Substances 0.000 claims abstract description 111
- 150000003839 salts Chemical class 0.000 claims abstract description 90
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 44
- 150000002367 halogens Chemical class 0.000 claims abstract description 44
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 41
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 36
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 32
- 150000001721 carbon Chemical group 0.000 claims abstract description 31
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 26
- 239000004215 Carbon black (E152) Substances 0.000 claims abstract description 19
- 229930195733 hydrocarbon Natural products 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000000470 constituent Substances 0.000 claims abstract description 10
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 57
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 35
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 27
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 22
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 20
- 239000000460 chlorine Substances 0.000 claims description 20
- 229910052801 chlorine Inorganic materials 0.000 claims description 20
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 19
- 239000011737 fluorine Substances 0.000 claims description 19
- 229910052731 fluorine Inorganic materials 0.000 claims description 19
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 15
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 9
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 claims description 8
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 8
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 7
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 6
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 6
- CTVZYLFMXUAAQZ-UHFFFAOYSA-N 2-amino-6-hydroxy-4-(phosphonomethyl)hex-3-enoic acid Chemical compound OC(=O)C(N)C=C(CCO)CP(O)(O)=O CTVZYLFMXUAAQZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 3
- 208000019695 Migraine disease Diseases 0.000 claims description 3
- BDIISILJKJGWEW-UHFFFAOYSA-N [4-amino-5-ethoxy-2-(2-fluoroethyl)-5-oxopent-2-enyl]phosphonic acid Chemical compound CCOC(=O)C(N)C=C(CCF)CP(O)(O)=O BDIISILJKJGWEW-UHFFFAOYSA-N 0.000 claims description 3
- DNMKUTJZKQHZJX-UHFFFAOYSA-N [4-amino-5-ethoxy-2-(2-hydroxyethyl)-5-oxopent-2-enyl]phosphonic acid Chemical compound CCOC(=O)C(N)C=C(CCO)CP(O)(O)=O DNMKUTJZKQHZJX-UHFFFAOYSA-N 0.000 claims description 3
- FDAGOTTWUNLLOP-UHFFFAOYSA-N [4-amino-5-ethoxy-2-(2-methoxyethyl)-5-oxopent-2-enyl]phosphonic acid Chemical compound CCOC(=O)C(N)C=C(CP(O)(O)=O)CCOC FDAGOTTWUNLLOP-UHFFFAOYSA-N 0.000 claims description 3
- BCSPXGHLTKQWAB-UHFFFAOYSA-N 2,10-diamino-4-(phosphonomethyl)dec-3-enoic acid Chemical compound NCCCCCCC(CP(O)(O)=O)=CC(N)C(O)=O BCSPXGHLTKQWAB-UHFFFAOYSA-N 0.000 claims description 2
- YOOOMZRMCBKOPS-UHFFFAOYSA-N 2-amino-6-fluoro-4-(phosphonomethyl)hex-3-enoic acid Chemical compound OC(=O)C(N)C=C(CCF)CP(O)(O)=O YOOOMZRMCBKOPS-UHFFFAOYSA-N 0.000 claims description 2
- PTYIQTMXSJCCIC-UHFFFAOYSA-N 2-amino-7-hydroxy-4-(phosphonomethyl)hept-3-enoic acid Chemical compound OC(=O)C(N)C=C(CP(O)(O)=O)CCCO PTYIQTMXSJCCIC-UHFFFAOYSA-N 0.000 claims description 2
- DTRJVCAKYINYSZ-UHFFFAOYSA-N [2-(2-amino-3-ethoxy-3-oxopropylidene)-8-hydroxyoctyl]phosphonic acid Chemical compound CCOC(=O)C(N)C=C(CP(O)(O)=O)CCCCCCO DTRJVCAKYINYSZ-UHFFFAOYSA-N 0.000 claims description 2
- RJNVBXBIQHJTNP-UHFFFAOYSA-N [4-amino-2-(1,3-dihydroxypropan-2-yl)-5-ethoxy-5-oxopent-2-enyl]phosphonic acid Chemical compound CCOC(=O)C(N)C=C(CP(O)(O)=O)C(CO)CO RJNVBXBIQHJTNP-UHFFFAOYSA-N 0.000 claims description 2
- ZWECDLATICDICM-UHFFFAOYSA-N [4-amino-5-ethoxy-2-(3-hydroxypropyl)-5-oxopent-2-enyl]phosphonic acid Chemical compound CCOC(=O)C(N)C=C(CP(O)(O)=O)CCCO ZWECDLATICDICM-UHFFFAOYSA-N 0.000 claims description 2
- WKCQTPLGPMICCC-UHFFFAOYSA-N [4-amino-5-ethoxy-2-(ethoxymethyl)-5-oxopent-2-enyl]phosphonic acid Chemical compound CCOCC(CP(O)(O)=O)=CC(N)C(=O)OCC WKCQTPLGPMICCC-UHFFFAOYSA-N 0.000 claims description 2
- 206010015037 epilepsy Diseases 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 7
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 7
- NLJNFDNPFYBQRE-UHFFFAOYSA-N 2,8-diamino-4-(phosphonomethyl)oct-3-enoic acid Chemical compound NCCCCC(CP(O)(O)=O)=CC(N)C(O)=O NLJNFDNPFYBQRE-UHFFFAOYSA-N 0.000 claims 1
- NBPWJAAXBIRKQO-UHFFFAOYSA-N 2-amino-4-(hydroxymethyl)-5-phosphonopent-3-enoic acid Chemical compound OC(=O)C(N)C=C(CO)CP(O)(O)=O NBPWJAAXBIRKQO-UHFFFAOYSA-N 0.000 claims 1
- RFPJMDKTBMDVFE-UHFFFAOYSA-N 2-amino-6-methoxy-4-(phosphonomethyl)hex-3-enoic acid Chemical compound COCCC(CP(O)(O)=O)=CC(N)C(O)=O RFPJMDKTBMDVFE-UHFFFAOYSA-N 0.000 claims 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical class NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims 1
- VYQKONACMHXMLZ-UHFFFAOYSA-N [2-(2-amino-3-ethoxy-3-oxopropylidene)-6-hydroxyhexyl]phosphonic acid Chemical compound CCOC(=O)C(N)C=C(CP(O)(O)=O)CCCCO VYQKONACMHXMLZ-UHFFFAOYSA-N 0.000 claims 1
- WDNUXVXTSKURHQ-UHFFFAOYSA-N [4-amino-5-ethoxy-2-(hydroxymethyl)-5-oxopent-2-enyl]phosphonic acid Chemical compound CCOC(=O)C(N)C=C(CO)CP(O)(O)=O WDNUXVXTSKURHQ-UHFFFAOYSA-N 0.000 claims 1
- 208000028867 ischemia Diseases 0.000 claims 1
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 abstract description 7
- 102000018899 Glutamate Receptors Human genes 0.000 abstract description 2
- 108010027915 Glutamate Receptors Proteins 0.000 abstract description 2
- HOKKHZGPKSLGJE-UHFFFAOYSA-N N-methyl-D-aspartic acid Natural products CNC(C(O)=O)CC(O)=O HOKKHZGPKSLGJE-UHFFFAOYSA-N 0.000 abstract description 2
- 230000003042 antagnostic effect Effects 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 153
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 105
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 99
- 238000001704 evaporation Methods 0.000 description 90
- 230000008020 evaporation Effects 0.000 description 90
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 82
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 69
- 235000002639 sodium chloride Nutrition 0.000 description 61
- 239000000243 solution Substances 0.000 description 49
- 239000003921 oil Substances 0.000 description 41
- 235000019198 oils Nutrition 0.000 description 41
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- 239000000741 silica gel Substances 0.000 description 32
- 229910002027 silica gel Inorganic materials 0.000 description 32
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 30
- 239000012074 organic phase Substances 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
- 229940093499 ethyl acetate Drugs 0.000 description 27
- 235000019439 ethyl acetate Nutrition 0.000 description 27
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(i) oxide Chemical compound [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 24
- 238000004587 chromatography analysis Methods 0.000 description 23
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 19
- SJHCUXCOGGKFAI-UHFFFAOYSA-N tripropan-2-yl phosphite Chemical compound CC(C)OP(OC(C)C)OC(C)C SJHCUXCOGGKFAI-UHFFFAOYSA-N 0.000 description 19
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 17
- 239000007858 starting material Substances 0.000 description 17
- 239000000725 suspension Substances 0.000 description 17
- 238000002844 melting Methods 0.000 description 16
- 230000008018 melting Effects 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000004480 active ingredient Substances 0.000 description 15
- 235000019341 magnesium sulphate Nutrition 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- 239000001602 (E)-hex-3-enoic acid Substances 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- 150000003254 radicals Chemical class 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- 239000002585 base Substances 0.000 description 13
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 11
- 238000001035 drying Methods 0.000 description 11
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 11
- 229910052938 sodium sulfate Inorganic materials 0.000 description 11
- 235000011152 sodium sulphate Nutrition 0.000 description 11
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- FPULFENIJDPZBX-UHFFFAOYSA-N ethyl 2-isocyanoacetate Chemical compound CCOC(=O)C[N+]#[C-] FPULFENIJDPZBX-UHFFFAOYSA-N 0.000 description 9
- 239000008098 formaldehyde solution Substances 0.000 description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 8
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 7
- 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 7
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 7
- 239000008101 lactose Substances 0.000 description 7
- 229910052751 metal Inorganic materials 0.000 description 7
- 239000002184 metal Substances 0.000 description 7
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 7
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- SXIFAEWFOJETOA-UHFFFAOYSA-N 4-hydroxy-butyl Chemical group [CH2]CCCO SXIFAEWFOJETOA-UHFFFAOYSA-N 0.000 description 5
- 108010010803 Gelatin Proteins 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000008273 gelatin Substances 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 235000011852 gelatine desserts Nutrition 0.000 description 5
- 125000004970 halomethyl group Chemical group 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 5
- 239000011736 potassium bicarbonate Substances 0.000 description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 125000006534 ethyl amino methyl group Chemical group [H]N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- 229920005555 halobutyl Polymers 0.000 description 4
- 235000012907 honey Nutrition 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 description 4
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 3
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 3
- YSMODUONRAFBET-UHFFFAOYSA-N 5-hydroxylysine Chemical group NCC(O)CCC(N)C(O)=O YSMODUONRAFBET-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 206010010904 Convulsion Diseases 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 150000003973 alkyl amines Chemical class 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 3
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 3
- 229940078456 calcium stearate Drugs 0.000 description 3
- 235000013539 calcium stearate Nutrition 0.000 description 3
- 239000008116 calcium stearate Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 230000036461 convulsion Effects 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 125000006264 diethylaminomethyl group Chemical group [H]C([H])([H])C([H])([H])N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
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- CRXFROMHHBMNAB-UHFFFAOYSA-N methyl 2-isocyanoacetate Chemical compound COC(=O)C[N+]#[C-] CRXFROMHHBMNAB-UHFFFAOYSA-N 0.000 description 1
- KKCWWMUENDLPST-UHFFFAOYSA-N methyl 5-[6-(phenylmethoxycarbonylamino)hex-1-en-2-yl]-4,5-dihydro-1,3-oxazole-4-carboxylate Chemical compound COC(=O)C1N=COC1C(=C)CCCCNC(=O)OCC1=CC=CC=C1 KKCWWMUENDLPST-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 125000006203 morpholinoethyl group Chemical group [H]C([H])(*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000004894 pentylamino group Chemical group C(CCCC)N* 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 229950008352 promoxolane Drugs 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 208000018198 spasticity Diseases 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid group Chemical class S(N)(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/44—Amides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3826—Acyclic unsaturated acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/59—Hydrogenated pyridine rings
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- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Hydrogenated Pyridines (AREA)
Abstract
CA- 4-17759/+
4-Substituted 2-aminoalk-3-enoic acids Abstract Substituted 2-aminoalk-3-enoic acid derivatives of formula I
(I), wherein R1 is an aliphatic hydrocarbon radical that is substituted by optionally acylated or aliphatically or araliphatically etherified hydroxy, by halogen, by optionally acylated and/or aliphatically substituted amino or by an aza-, diaza-, azoxa- or oxa-cycloaliphatic radical, or is an oxacycloaliphatic hydrocarbon radical bonded via a carbon atom, or is an optionally aliphatically N-substituted or N-acylated azacycloaliphatic hydrocarbon radical, and R2 is free or esterified carboxy, and their salts have a pronounced and selective antagonistic activity towards N-methyl-D-aspartic acid-sensitive (NMDA-sensitive) excitatory amino acid receptors. They are prepared, for example, as follows:
in a compound of formula II
4-Substituted 2-aminoalk-3-enoic acids Abstract Substituted 2-aminoalk-3-enoic acid derivatives of formula I
(I), wherein R1 is an aliphatic hydrocarbon radical that is substituted by optionally acylated or aliphatically or araliphatically etherified hydroxy, by halogen, by optionally acylated and/or aliphatically substituted amino or by an aza-, diaza-, azoxa- or oxa-cycloaliphatic radical, or is an oxacycloaliphatic hydrocarbon radical bonded via a carbon atom, or is an optionally aliphatically N-substituted or N-acylated azacycloaliphatic hydrocarbon radical, and R2 is free or esterified carboxy, and their salts have a pronounced and selective antagonistic activity towards N-methyl-D-aspartic acid-sensitive (NMDA-sensitive) excitatory amino acid receptors. They are prepared, for example, as follows:
in a compound of formula II
Description
~2~3~
4-17759/+
.
4-Substituted 2-ammoalk-3-enoic acids The invention relates to substituted 2-aminoalk-3-enoic acid derivatives of formula I
HO~ P /\~ R2 wherein Rl is an aliphatic hydrocarbon radical that is substituted by optionally acyla~ed or aliphatically or araliphatically etheri~led hydroxy, by halogen, by optionally acylated and/or aliphatically substituted amino or by an aza-, diaza-, azoxa- or oxa-cycloaliphatic radical, or is an oxacycloaliphatic hydrocarbon radical bonded via a carbon atom, or is an optionally aliphatically N-substituted or N-acylated azacycloaliphatic hydrocarbon radical, and R2 is free or esterifîed carboxy, and their salts, to processes for the preparation of the compounds according to the invention, to pharmaceutical preparations containing them, and to their use as active ingredients in medicaments.
- .
Aliphatic hydrocarbon radicals are, ~or example, aL1~yl radicals having up to and including 10, especlally up to and including 8, carbon atoms, preferably lower aL~cyl radicals.
Hydroxy-substituted aliphatic hydrocarbon radicals are, for example, mono- or di-hydroxy-lower alkyl. ~ -Acylated hydroxy is, for example, lower aLIcanoyloxy or benzoyloxy that is unsubstitutedor substituted in the phenyl moiety. Accordingly, an aliphatic hydrocarbon radical that is substituted by acylated hydroxy shall be understood as being,~ for example, lower alkanoyloxy-lower alkyl or benzoyloxy-lower aLt~yl that is unsubstituted or substituted in the phenyl moiety.
.
.
:
4-17759/+
.
4-Substituted 2-ammoalk-3-enoic acids The invention relates to substituted 2-aminoalk-3-enoic acid derivatives of formula I
HO~ P /\~ R2 wherein Rl is an aliphatic hydrocarbon radical that is substituted by optionally acyla~ed or aliphatically or araliphatically etheri~led hydroxy, by halogen, by optionally acylated and/or aliphatically substituted amino or by an aza-, diaza-, azoxa- or oxa-cycloaliphatic radical, or is an oxacycloaliphatic hydrocarbon radical bonded via a carbon atom, or is an optionally aliphatically N-substituted or N-acylated azacycloaliphatic hydrocarbon radical, and R2 is free or esterifîed carboxy, and their salts, to processes for the preparation of the compounds according to the invention, to pharmaceutical preparations containing them, and to their use as active ingredients in medicaments.
- .
Aliphatic hydrocarbon radicals are, ~or example, aL1~yl radicals having up to and including 10, especlally up to and including 8, carbon atoms, preferably lower aL~cyl radicals.
Hydroxy-substituted aliphatic hydrocarbon radicals are, for example, mono- or di-hydroxy-lower alkyl. ~ -Acylated hydroxy is, for example, lower aLIcanoyloxy or benzoyloxy that is unsubstitutedor substituted in the phenyl moiety. Accordingly, an aliphatic hydrocarbon radical that is substituted by acylated hydroxy shall be understood as being,~ for example, lower alkanoyloxy-lower alkyl or benzoyloxy-lower aLt~yl that is unsubstituted or substituted in the phenyl moiety.
.
.
:
2 ~ 2 ~
Aliphatically etherified hydroxy is, for example, lower alkoxy; araliphatically etherified hydroxy is, for example, unsubstituted or substituted phenyl-lower alkoxy. Accordingly, an aliphatic hydrocarbon radical that is substituted by aliphatically etherified hydroxy shall be understood as being, for example, lower alkoxy-lower alkyl, and an aliphatic hydrocarbon radical that is substituted by araliphatically etherified hydroxy shall be understood as being, for example, unsubstituted or substituted phenyl-lower alkoxy- lower alkyl.
A halo-substituted aliphatic hydrocarbon radical is, for example, halo-lower alkyl.
Optionally acylated andlor aliphatically substituted amino is, for example, amino, N-mono- or N,N-di-lower alkylamino, N-lower aLI~anoylamino, N-benzoylamino that is unsubstituted or substituted in the phenyl moiety, or N-lower aLkanoyl-N-lower alkyl-amino. Accordingly, aliphatic hydrocarbon radicals that are substituted by optionally acylated and/or aliphatically substituted amino are, for example, amino-lower alkyl, lower alkylamino-lower alkyl, lower aL~anoylamino-lower aL~cyl, benzoylamino-lower aLkyl that is unsubstituted or substituted in the phenyl moiety, di-lower aLtcylamino-lower aL1cyl or N-lower aL~canoyl-N-lower alkylamino-lower aL~cyl.
Aliphatic hydrocarbon radicals that are substituted by an azacycloaliphatic radical are, for example, 4- to 7-membered azacycloaLlcyl-lower aLlcyl radicals whose azacycloaLkyl moiety may be bonded via the N atom or a carbon atom and, in ~he latter case, may be N-lower aLIcylated, N-lower aLIcanoylated or N-substituted by a benzoyl group that is unsubstituted or substituted in the phenyl moiety. 4- ~o 7-membered azacycloalkyl-lower aLkyl whose azacycloaLIcyl moiety is bonded via the N atom is, for example, N,N-lower alkyleneamino-Cl-C7allcyl, i.e. azacycloaLIc~l-yl-Cl-C7aLkyl. 4- to 7-membered azacycloalkyl-lower alkyl whose azacycloaLlcyl moiety is bonded via a carbon atom and is optionally N-lower aLlcylated, N-lower aLkanoylated or N-substituted by a benzoyl group that is unsubs~ituted or substituted in the phenyl moiety is, for example, ~- to 7-membered azacycloalkyl-Cl-qalkyl or N-C2-C7aL1canoylazacycloalkyl-Cl-C7aL~cyl, also N-Cl-C4aLI~ylæacycloalkyl-Cl-C7alkyl or N-benzoylazacycloaL~cyl-Cl-C7alkyl that is unsubstituted or substituted in the phenyl moiety, each of which is bonded via a carbon atom.
Aliphatic hydrocarbon radicals that are substituted by a diazacycloaliphatic radical are, for 2 ~ 2 ~
Aliphatically etherified hydroxy is, for example, lower alkoxy; araliphatically etherified hydroxy is, for example, unsubstituted or substituted phenyl-lower alkoxy. Accordingly, an aliphatic hydrocarbon radical that is substituted by aliphatically etherified hydroxy shall be understood as being, for example, lower alkoxy-lower alkyl, and an aliphatic hydrocarbon radical that is substituted by araliphatically etherified hydroxy shall be understood as being, for example, unsubstituted or substituted phenyl-lower alkoxy- lower alkyl.
A halo-substituted aliphatic hydrocarbon radical is, for example, halo-lower alkyl.
Optionally acylated andlor aliphatically substituted amino is, for example, amino, N-mono- or N,N-di-lower alkylamino, N-lower aLI~anoylamino, N-benzoylamino that is unsubstituted or substituted in the phenyl moiety, or N-lower aLkanoyl-N-lower alkyl-amino. Accordingly, aliphatic hydrocarbon radicals that are substituted by optionally acylated and/or aliphatically substituted amino are, for example, amino-lower alkyl, lower alkylamino-lower alkyl, lower aL~anoylamino-lower aL~cyl, benzoylamino-lower aLkyl that is unsubstituted or substituted in the phenyl moiety, di-lower aLtcylamino-lower aL1cyl or N-lower aL~canoyl-N-lower alkylamino-lower aL~cyl.
Aliphatic hydrocarbon radicals that are substituted by an azacycloaliphatic radical are, for example, 4- to 7-membered azacycloaLlcyl-lower aLlcyl radicals whose azacycloaLkyl moiety may be bonded via the N atom or a carbon atom and, in ~he latter case, may be N-lower aLIcylated, N-lower aLIcanoylated or N-substituted by a benzoyl group that is unsubstituted or substituted in the phenyl moiety. 4- ~o 7-membered azacycloalkyl-lower aLkyl whose azacycloaLIcyl moiety is bonded via the N atom is, for example, N,N-lower alkyleneamino-Cl-C7allcyl, i.e. azacycloaLIc~l-yl-Cl-C7aLkyl. 4- to 7-membered azacycloalkyl-lower alkyl whose azacycloaLlcyl moiety is bonded via a carbon atom and is optionally N-lower aLlcylated, N-lower aLkanoylated or N-substituted by a benzoyl group that is unsubs~ituted or substituted in the phenyl moiety is, for example, ~- to 7-membered azacycloalkyl-Cl-qalkyl or N-C2-C7aL1canoylazacycloalkyl-Cl-C7aL~cyl, also N-Cl-C4aLI~ylæacycloalkyl-Cl-C7alkyl or N-benzoylazacycloaL~cyl-Cl-C7alkyl that is unsubstituted or substituted in the phenyl moiety, each of which is bonded via a carbon atom.
Aliphatic hydrocarbon radicals that are substituted by a diazacycloaliphatic radical are, for 2 ~ 2 ~
example, 4- tO 7-membered diazacycloalkyl-lower alkyl radicals whose diazacycloalkyl moiety is bonded via one N atom and may, at the other N atom, optionally be lower alkylated, lower alkanoylated or substituted by a benzoyl group that is unsubstituted or substituted in the phenyl moiety, such as 4- to 7-membered diazacycloalkyl-lower alkyl radicals that are bonded via an N atom and are optionally N'-lower alkylated, N'-lower alkanoylated or N'-substituted by a benzoyl group that is unsubstituted or substituted in the phenyl moiety, especially 5- to 7-membered diazacycloalk-1-yl-Cl-C7alkyl.
Aliphatic hydrocarbon radicals that are substituted by an azoxacycloaliphatic radical are, for example, 4- to 7-membered azoxacycloaLIcyl-lower alkyl radicals whose azoxacyclo-al~cyl moiety is bonded via the N atom, such as 4- to 7-membered azoxacycloalkyl-lower alkyl radicals bonded via the N atom, especially 5- to 7-membered N,N-(oxa-loweralkylene)amino-Cl-qalkyl, i.e. azoxacycloalk-l-yl-Cl-qalkyl.
Aliphatic hydrocarbon radicals that are substituted by an oxacycloaliphatic radical are, for example, 4- to 7-membered oxacycloalkyl-lower alkyl radicals whose oxacycloalkylmoiety is bonded via a carbon atom, such as 5- to 7-membered oxacycloalkyl-Cl-C7alkyl bonded via a carbon atom.
Oxacycloaliphatic hydrocarbon radicals that are bonded via a carbon atom are, for example, 5- to 7-membered oxacycloalkyl groups bonded via a carbon atom.
Azacycloaliphatic hydrocarbon radicals that are bonded via a carbon atom and areoptionally aliphatically N-substituted or N-acylated are azacycloaL~cyl radicals that are bonded via a carbon atom and are optionally N-lower alkylated, N-lower alkanoylated or N-substituted by benzoyl that is unsubstituted or substituted in the phenyl moiety, such as 5- to 7-membered azacycloaLIcyl or N-C2-C7aL~canoylazacycloaL~yl, also N-Cl-(:~4aLIcyl-azacycloallcyl or unsubstituted or substituted N-benzoylazacycloaLIcyl, each of which is bonded via a carbon atom.
Esterified carboxy is, for example, carboxy esterified by an aliphatic, cycloaliphatic or araliphatic alcohol, such as lower alkoxycarbonyl, 4- up to and including 7-membered, especially 5- or ~membered, cycloaLkoxycarbonyl, such as cyclopentyloxy- or cyclohexyloxy-carbonyl, or unsubstituted or substituted phenyl-lower aL~oxycarbonyl.
In the groups mentioned above, phenyl radicals may be unsubstitutFd or mono-, di- or tri-subs~ituted, especially mono- or di-substituted, in customary manner, for example by lower aLlcyl, lower alkoxy, halogen, cyaDo and/or by trifluoromethyl.
Hereinbefore and hereinafter, "lower" radicals and compounds shall be understood as being, for example, radicals and compounds containing up to and including 7, preferably up to and including 4, carbon atoms (C atoms).
Lower alkyl is, for example, Cl-C7aLlcyl, preferably Cl-C4aL~cyl, such as methyl, ethyl, propyl, isopropyl or butyl, but may also be isobutyl, sec.-butyl, tert.-butyl or a pentyl, hexyl or heptyl group.
Mono- or di-hydroxy-lower alkyl is, for example, hydroxy-Cl-C7aL~cyl, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, S-hydroxypentyl or 6-hydroxyhexyl, or dihydroxy-C2-C7aLI~yl in which the hydroxy groups are bonded to different carbon atoms, such as 1,2-dihydroxyethyl or, especially, 1,3-dihydroxyprop-2-yl.
Lower alkanoyl is, ~or example, C2-C7aL~anoyl, especially C2-C4aL~anoyl, such as acetyl, propionyl or butyryl, but may also be a Cs-C6alkanoyl group, such as pivaloyl. Accor-dingly, lower alkanoyloxy-lower alkyl is especially C2-C7aLtcanoyloxy-Cl-qaLlcyl, such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl, 2-acetoxyethyl, 3-acetoxy-propyl, 4-acetoxybutyl, S-acetoxypentyl or 6-acetoxyhexyl. By analogy, benzoyloxy-lower alkyl shall be understood as being, for exarnple, benzoyloxy-Cl-q-aLIcyl that is unsubstituted or substituted in the phenyl moiety, such as benzoyloxymethyl, 2-benzoyloxyethyl, 3-benzoyloxypropyl, 4-benzoyloxybutyl, 5-benzoyloxypentyl or 6-benzoyloxyhexyl.
Lower alkoxy is, for example, Cl-C7aLlcoxy, preferably Cl-C4aL~oxy, such as methoxy, ethoxy, propoxy, isopropoxy or butoxy, but may also be isobutoxy, sec.-butoxy, tert.-butoxy or a pentyloxy, hexyloxy or heptyloxy group. Accordingly, lower aL1coxy-lower aLIcyl is, for example, Cl-C4aLkoxy-Cl-C7aL~yl, such as methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypentyl or 6-methoxyhexyl.
Phenyl-lower aLtcoxy is, for example, phenyl-Cl-C4alkoxy that is unsubstituted or substituted as indicated, such as benzyloxy, 2-phenylethoxy or 3-phenylpropoxy.
Accordingly, phenyl-lower alkoxy-lower alkyl is, for example, a phenyl-Cl-C4-alkoxy-Cl-C7alkyl radical that is unsubstituted or substituted as indicated, such as a benzyloxymethyl, 2-phenylethoxymethyl, 2-benzyloxyethyl, 3-benzyloxypropyl, 4-benzyloxybutyl, 5-benzyloxypentyl or 6-benzyloxyhexyl radical.
Halo-lower alkyl is, for example, halo-Cl-C7allcyl, such as halomethyl, 2-haloethyl, 3-halopropyl, 4-halobutyl, 5-halopentyl or 6-halohexyl, in which halogen is chlorine or, especially, fluoline.
Amino-lower alkyl is, for example, amino-Cl-C7alkyl, such as aminomethyl, 2-aminoethyl, 3-aminopropyl7 4-aminobutyl, 5-aminopentyl or 6-aminohexyl.
Lower alkylamino is, for example, Cl-C7aLkylamino, especially Cl-C4alkylamino, such as methylamino, ethylamino, propylamino or butylamino, but may also be a Cs-C6alkyl-amino group, such as a pentylamino or hexylamino group. Accordingly, lower alkyl-amino-lower alkyl is especially Cl-C4alkylamino-Cl-C7alkyl, such as methylaminomethyl, ethylaminomethyl, propylaminomethyl, butylaminomethyl, 2-methylaminoethyl, 3-methylarninopropyl, 4-methylaminobutyl, 5-methylaminopentyl or 6-methylaminohexyl .
:
Lower alkanoylamino is, for example, C2-qaL~sanoylamino, especially C2-C4alkanoyl-amino, such as acetylamino, propionylamino or butyrylamino, but may also be Cs-C6-alkanoylamino, such as pivaloylamino. Accordingly, lower alkanoylamin~lower alkyl is especially C2-qalkanoylamino-Cl-qaLIcyl, such as acetylaminomethyl, propionylaminomethyl, butyrylaminomethyl, 2-acetylaminoethyl, 3-acetylaminopropyl, 4-acetylaminobutyl, 5-acetylaminopentyl or ~acetylaminohexyl. By analogy, benzoylamino-lower aLtcyl shall be unders~ood as being, for example, benzoylamino-Cl-C?alkyl that is unsubstituted or substituted in the phenyl moiety, such as benzoylaminomethyl, 2-benzoylaminoethyl, 3-benzoylaminopropyl, 4-benzoylaminobutyl, 5-ben~oylaminopentyl or 6-ben~oylaminohexyl.
.
Di-lower aLkylalIuno is, for example, di-Cl-C7aL~cylamino, especially di-Cl-C4-alkylarnino, such as dimethylamino, diethylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, dipropylamino or dibutylamino. Accordingly, di-lower aLIcylamino-lower alkyl is especially di-Cl-C4alkylamino-Cl-qalkyl, such as dimethylaminomethyl, diethylaminomethyl, N-ethyl-N-methylaminomethyl, N-methyl-N-propylaminomethyl, dipropylaminomethyl, dibutylaminomethyl, 2-dimethylaminoethyl, ~ ~ 2 ~ 8 3-dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl or 6-dimethyl-aminohexyl.
N-lower alkanoyl-N-lower aL~cylamino-lower alkyl is, for example, N-C2-C7-alkanoyl-N-Cl-C4alkylamino-Cl-C7aL~cyl, such as N-acetyl-N-methylaminomethyl, N-acetyl-N-ethylaminomethyl, N-propionyl-N-methylaminomethyl, N-butyIyl-N-methylaminomethyl, 2-(N-acetyl-N-methylamino)ethyl, 2-(N-propionyl-N-methyl-arnino)ethyl, 2-(N-acetyl-N-ethylarnino)ethyl, 3-(N-acetyl-N-methylamino)propyl,4-(N-acetyl-N-methylamino)butyl, 5-(N-acetyl-N-methylamino)pentyl or 6-(N-acetyl-N-methylamino)hexyl.
4- to 7-membered azacycloaL~cyl-C1-C7aLkyl bonded via an N atom is preferably N,N-lower alkylenearnino-Cl-C7alkyl, i.e. azacycloalk-1-yl-Cl-C7alkyl, for example pyrrolidinomethyl, piperidinomethyl, morpholinomethyl, 2-pyrrolidinoethyl, 2-piperidinoethyl, 3-pyrrolidinopropyl, 3-p;peridinopropyl, 4-pyrrolidinobutyl, 4-piperidinobutyl, S-pyrrolidinopentyl, 5-piperidinopentyl, 6-pyrrolidinohexyl or 6-piperi-dinohexyl.
4- to 7-membered azacycloaL~cyl-cl-qaLlcyl bonded via a carbon atom is preferably azacycloaLk-3-yl-C1-qalkyl or -4-yl-cl-qaL~yl~ for example piperidin-4-ylmethyl,2-(piperidin-4-yl)ethyl, 3-(piperidin-4-yl)propyl or 4-(piperidin-4-yl)butyl.
5- to 7-membered N-c2-qaL~anoylazacycloaLl~yl-cl-qallcyl bonded via a carbon atom is preferably 1-c2-c7alkanoylazacycloallc-3-yl-cl-qalkyl or -4-yl-C1-C7aLIcyl, for example 1-acetylpiperidin-4-ylmethyl, 2-(1-acetylpiperidin-4-yljethyl, 3-(1-acetylpiperidin-4-yl)propyl or 4-(1-acetylpiperidin-4-yl)butyl.
5- to 7-membered N-cl-c4aL~cylazacycloaLlcyl-cl-qaLkyl bonded via a carbon atom is preferably N-C1-C4aLIcylazacycloaLk-3-yl-Cl-C7aLlcyl or -4-yl-Cl-C7alkyl, for example 1-methylpiperidin-4-ylmethyl, 1-ethylpiperidin-4-ylmethyl, 2-(1-methyl-piperidin-4-yl)ethyl, 2-(1-ethylpiperidin-4-yl)ethyl, 3-(1-methylpiperidin-4-yl~propyl, 3-(1-ethylpiperidin-4-yl)propyl, 4-(1-methylpiperidin-4-yl)butyl or 4-(1-ethylpiperidin-4-yl)butyl.
5- to 7-membered N-benzoylazacycls)alkyl-C1-C7aLtcyl that is bonded via a carbon atom and unsubstituted or substituted in the phenyl moiety is preferably N-C1-C4benzoyl-azacycloaLlc-3-yl-Cl-C7alkyl or -4-yl-Cl-C7alkyl, for example l-benzoyl-piperidin-4-ylmethyl, 2-(1-benzoylpiperidin-4-yl)ethyl, 3-(1-benzoylpiperi~lin-4-yl)propyl or 4-tl-benzoylpiperidin-4-yl)butyl.
5- to 7-membered diazacycloalk-1-yl-Cl-C7alkyl that is bonded vla an N atom and is optionally N'-lower alkylated, N'-lower alkanoylated or N'-substituted by a benzoyl group that is unsubstituted or substituted in the phenyl moiety is, for example,N,N-(aza-lower alkylene)amino-Cl-C7alkyl, i.e. diazacycloalk-1-yl-Cl-C7alkyl, N'-Cl-C4alkyldiazacycloalk-1-yl-Cl-C7alkyl or N'-C2-C7alkanoylazacycloaL~c-l-yl-Cl-C7alkyl, for e:carnple piperazino- or N'-methyl- or N'-acetyl-piperazino-methyl, 2-(piperazino- or N'-methyl- or N'-acetyl-piperazino)-ethyl, 3-(piperazino- or N'-methyl-or N'-acetyl-piyerazino)-propyl or 4-(piperazino- or N'-methyl- or N'-ace~yl-piperazino)-butyl.
5- to 7-rnembered N,N-(oxa-lower alkylene)amino-Cl-C7alkyl, i.e. azoxacycloaL~c-l-yl-Cl-C7aLtcyl, is, for exarnple, morpholinomethyl, 2-morpholinoethyl, 3-morpholino-propyl or 4-morpholinobutyl.
5- to 7-membered oxacycloalkyl-Cl-qalkyl bonded via a carbon atom is especially 5- to 7-membered oxacycloalk-3-yl-Cl-C7alkyl or oxacycloalk-4-yl-Cl-C7aLlcyl, such as tetra-hydropyran-4-ylmethyl, 2-~tetrahydropyran-4-yl)ethyl, 3-(tetrahydropyran-4-yl)propyl or 4-(tetrahydropyran-4-yl)butyl.
S- to 7-membered oxacycloalkyl bonded via a carbon atorn is especially corresponding oxacycloalk-3-yl or -4-yl, for example tetrahydropyran-4-yl.
5- to 7-membered azacycloaLIcyl, N-Cl-C4alkylazacycloalkyl or N-C2-C7-alkanoylazacycloaLkyl bonded via a carbon atom is preferably azacycloaLlc-3-yl or -4-yl or l-C2-C7aLIcanoylazacycloaL~c-3-yl or -4-yl, for example piperidin-4-yl or l-acetyl-piperidin-4-yl, and also M-Cl C4aLI~ylazacycloaLlc-3-yl or -4-yl or N-benzoylazacycloaLI~-3-yl or -4-yl that is unsubstituted or substituted in the phenyl moiety, for example l-methylpiperidin-4-yl or 1-benzoylpiperidin-4-yl.
Lower alkoxycarbonyl is, for example, Cl-C7aL~oxycarbonyl, especially Cl-C4alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or butoxycarbonyl, but may also be a Cs-C7allcoxycarbonyl group, ~2~3~
such as a pentyloxycarbonyl, hexyloxycarbonyl or heptyloxycarbonyl group.
Phenyl-lower alkoxycarbonyl is, for example, phenyl-Cl-C4alkoxycarbonyl, such asbenzyloxycarbonyl, 2-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl or 4-phenylbutoxycarbonyl .
On account of their amphoteric nature, the compounds of formula I are in the form of internal salts and can form both acid addition salts and salts with bases.
Acid addition salts of compounds of formula I are, for example, pharmaceuticallyacceptable salts thereof with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, for example hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates, or salts with suitable aliphatic or aromatic sulfonic acids or N-sub-stituted sulfamic acids, for example methanesulfonates, benzenesulfonates, p-toluenesulfonates or N-cyclohexyl sulfamates (cyclamates).
Salts of compounds of formula I with bases are, for example, salts thereof with pharmaceutically acceptable bases, such as non-toxic metal salts derived from groups Ia, Ib, IIa and IIb, for example aLtcali metal salts, especially sodium or potassium salts, alkaline earth metal salts, especially calcium or magnesium salts, and also ammonium salts with ammonia or organic amines or quaternary amrnonium bases, such as unsubstituted or C-hydroxylated aliphatic amines, especially mono-, di- or tri-lower alkylamines, for example methyl-, ethyl- or diethyl-amine, mono-, di- or ~i-(hydroxy-lower alkyl)amines, such as ethanol-, die~hanol- or ~riethanol-amine, tris-(hydroxymethyl)methylamine or 2-hydroxy-tert.-butylamine, or N-(hydroxy-lower alkyl)-N,N-di-lower aLkylamines or N-(polyhydroxy-lower alkyl)-N-lower alkylamines, such as 2-(dimethylarnino)ethanol or D-glucamine, or quatemary aliphatic ammonium hydroxides, for example ~etrabutylammonium hydroxide.
:' For isolation or purification puIposes it is also possible to use phannaceutically unsuitable salts. Only the pharmaceutically acceptable, non-toxic salts are used therapeudcally, and these salts are therefore preferred.
The invention relates, for example, to compounds of formula I wherein Rl is an aliphatic hydrocarbon radical that is substituted by optionally aliphatically s~r araliphatically etherified hydroxy, optionally aliphatically substituted amino or by halogen, and R2 is free or esterified carboxy, and ~heir salts.
The compounds of formula I have valuable pharrnacological properties. In particular, they have a pronounced and selective antagonistic activity towards N-methyl-D-aspartic acid-sensitive (NMDA-sensitive) excitatory amino acid receptors in warm-blooded animals.
This can be demonstrated in vitro, for example, in the experimental procedure according to G. Fagg and A. Matus, Proc. Nat. Acad. Sci., USA, 81, 6876-6880 (1984). This procedure determines the extent to which the binding of L-3H-glutarnic acid to NMDA-sensitive receptors is inhibited. The NMDA-antagonistic properties of the novel compounds can also be demonstrated in vivo, however, for example in mice, by theinhibiting effçct on NMDA-induced convulsions.
On account of these properties, the compounds of formula I and their pharmaceutically acceptable salts are erninently suitable for the treatment of pathological conditions respon-sive to a blocking of NMDA-sensitive receptors, for exarnple ischaemic disorders, such as cerebral ischaemia and ischaemic disorders of the eye, vascular and muscular spasms, such as migraines, or local or general spasticity and, especially, convulsions, such as epilepsy.
The anti-convulsive properties of the compounds of the invention can be demonstrated, for example, in mice by their pronounced protective effect against convulsions triggered by electric shock or induced audiogenically, it being possible to make use, for example, of the established electric shock rnouse model or of the experimental procedure according to Chapman et aL, Arzneimittel-Forsch. 34, 1251 (1984). The compounds of the invention are distinguished, especially in the electric shock mouse model, by improved action as compared with structurally related compounds.
The anti-spastic properties that render the compounds provided according to the invention suitable for the treatment of migraines can be demonstrated, for example, in rats by their depression-inhibiting action in the frontal cortex in accordance with the experimental procedure of R. Marannes et aL, Brain Res. 457, 226 (1988). In this model9 at doses in the range of approximately from 3 to 30 mg/kg i.p., the compounds provided according to the invention lower the threshold value of spreading depression and shorten the duration thereof.
The invention relates especially to compounds of forrnula I wherein Rl is mono- or 2~2~
di-hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, benzoyloxy-lower alkyl, lower alkoxy-lower alkyl, phenyl-lower alkoxy-lower alkyl, halo-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, lower alkanoylamino-lower alkyl, di-lower alkylamino-lower alkyl, N-lower alkyl-N-lower alkanoylamino-lower alkyl, 5- to 7-mernbered azacycloalkyl-lower alkyl whose azacycloalkyl moiety is bonded via the N
atom or a carbon atom and, in the latter case, may be N-lower alkylated, N-loweralkanoylated or N-substituted by a benzoyl group that is unsubstituted or substituted in the phenyl moiety, 5- to 7-membered diazacycloaLkyl-lower alkyl whose diazacycloalkyl moiety is bonded via an N atom and is optionally N'-lower aL~cylated, N'-lower alkanoylated or N'-substituted by a benzoyl group that is unsubstituted or substituted in the phenyl moiety, 5- to 7-membered azoxacycloaLkyl-lower alkyl bonded via the N atom, 5- to 7-membered oxacycloalkyl-lower alkyl bonded via a carbon atom, 5- to 7-membered azacycloaLkyl that is bonded via a carbon atom and is optionally N-lower aLkylated, N-lower alkanoylated or N-substituted by a benzoyl group that is unsubstituted or substituted in the phenyl moiety, or 5- to 7-membered oxacycloalkyl bonded via a carbon atom, and R2 is carboxy, lower aLcoxycarbonyl, 4- up to and including 7-membered cyclo-alkoxycarbonyl or phenyl-lower aL~coxycarbonyl, any phenyl radicals ;n the mentioned groups R1 and/or R2 being unsubstituted or mono-, di- or tri-substituted by lower aLkyl, lower aLlcoxy, halogen, cyano and/or by trifluoromethyl, and their salts.
The invention relates especially, for example, to compounds of formula I wherein R1 is hydroxy-lower alkyl, lower alkoxy-lower alkyl, phenyl-lower alkoxy-lower aL~cyL amino-lower aL~cyl, lower aL~cylarnino-lower aLkyl, di-lower aLkylamino-lower aL~cyl, N,N-lower alkyleneamin~ or N,N-(aza- or oxa-lower aLkylene)amin~lower aLkyl, or halo-loweraLlcyl, and R2 is carboxy, lower alkoxycarbonyl, 4- up to and including 7-membered cyclo-alkoxycarbonyl or phenyl-lower aLlcoxycarbonyl, any phenyl radicals in the mentioned groups R1 andlor R2 being unsubstituted or mon~, di- or tri-subs~ituted by lower aL~cyl, lower aLkoxy, halogen, cyano andlor by ~ifluoromethyl, and their salts.
The invention relates especially to compounds of formula I wherein R1 is hydroxy-C1-C7alkyl, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl, dihydroxy-C2-C7alkyl, such as 1,3-dihydroxyprop-2-yl, C2-C7-alkanoyloxy-C1-C7aLI~yl, such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl, 2-acetyloxyethyl, 3-acetyloxypropyl, 4-acetyloxybutyl, 5-acetyloxypentyl or ~acetyloxy-hexyl, benzoyloxy-C1-C7alkyl that is unsubstituted or mono- or di-substituted in the phenyl moiety by Cl-C4altcyl, such as methyl, Cl-C~ coxy, such as methoxy, halogen 2~2~3~
having an atomic number of up to and including 35, such as fluorine or chlorine, cyano andlor by trifluoromethyl, such as benzoyloxymethyl, 2-benzoyloxyethyl, 3-benzoyloxypropyl, 4-benzoyloxybutyl, S-benzoyloxypentyl or 6-benzoyloxyhexyl, Cl-C4allcoxy-Cl-C7alkyl, such as methoxymethyl, ethoxymethyl, 2-methoxyethyl, 3-methoxypropyl or 4-methoxybutyl, a phenyl-Cl-C4alkoxy-Cl-C7alkyl group that isunsubstituted or mono- or di-substituted in the phenyl moiety by Cl-C4alkyl, such as methyl, Cl-C4alkoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano and/or by trifluoromethyl, such as benzyloxymethyl, 2-benzyloxyethyl, 3-benzyloxypropyl or 4-benzyloxybutyl, halo-Cl-qaLI~yl, such as halomethyl, 2-haloethyl, 3-halopropyl, 4-halobutyl, 5-halopentyl or 6-halohexyl, in which halogen is chlorine or, especially, fluorine, amino-Cl-C7alkyl, such as aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl or 6-amunohexyl, Cl-C4alkylamino-CI-C7all~yl, such as methylaminomethyl, ethylamino-methyl, propylaminomethyl, butylarninomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl or 6-methylaminohexyl, C2-C7alkanoylamino-Cl-~7alkyl, such as acetylaminomethyl, propionylaminomethyl, butyrylarninomethyl, 2-acetylaminoethyl, 3-acetylaminopropyl, 4-acetylaminobutyl, 5-acetylaminopentyl or 6-acetylaminohexyl, N-C2-C7aL1canoyl-N-Cl-C4alkyl-amino-Cl-C7alkyl, such as N-acetyl-N-methylarninomethyl, N-acetyl-N-ethyl-aminomethyl, N-propionyl-N-methylaminomethyl, N-butyryl-N-methylaminomethyl, 2-(N-acetyl-N-methylamino)ethyl, 2-(N-propionyl-N-methylamino)ethyl, 2-(N-acetyl-N-ethylamino)ethyl, 3-(N-acetyl-N-methylamino)propyl, 4-(N-acetyl-N-methyl-amino)butyl, 5-(N-acetyl-N-methylamino)pentyl or 6-(N-acetyl-N-methylamino)hexyl, di-Cl-C7alkylamino-Cl-C7aLIcyl, such as dimethylaminomethyl, diethylaminomethyl,N-ethyl-N-methylaminomethyl, N-methyl-N-propylaminomethyl, dipropylaminomethyl, dibutylaminomethyl, 2-dimethylarrunoethyl, 3-dimethylaminopropyl, 4-dimethyl-aminobutyl, S-dimethylaminopentyl or 6-dimethylaminohexyl, azacycloalk-l-yl-CI-C7aLlsyl, such as pyrrolidinomethyl, piperidinome~hyl, 2-pyrrolidinoethyl, 2-piperidinoethyl, 3-py~rolidinopropyl, 3-piperidinopropyl, 4-pyrroli-dinobutyl, 4-piperidinobutyl, S-pyrrolidinopentyl, S-piperidinopentyl, ~pyIrolidinohexyl or ~piperidinohexyl, azacycloaL~c-3-yl-Cl-C7aLkyl or -4-yl-Cl-C7aL~cyl, for exarnple piperidin-4-ylmethyl, 2-(piperidin-4-yl~ethyl, 3-(piperidin-4-yl)propyl or 4-(piperidin-4-yl)butyl, l-C2-C7aL1canoylazacycloaLlc-3-yl-Cl-qalkyl or -4-yl-C1-C7alkyl, for example 1-acetylpiperidin-4-ylmethyl, 2-(1-acetylpiperidin-4-yl)-ethyl, 3-(1-acetylpiperidin-4-yl)propyl or 4-(1-acetylpiperidin-4-yl)butyl, N-Cl-C4alkylazacycloalk-3-yl-Cl-qaLtcyl or -4-yl-Cl-qalkyl, for example ~2~3~,~
l-methylpiperidin-4-ylmethyl, 1-ethylpiperidin-4-ylmethyl, 2-(1-methylpiperidin-4-yl)ethyl, 2-(1-ethylpiperidin-4-yl)ethyl, 3-(1-methylpiperidin-4-yl)propyl, 3-(1-ethylpiperidin-4-yl)propyl, 4-(1-methylpiperidin-4-yl)butyl or 4-(1-ethyl-piperidin-4-yl)butyl, N-Cl-C4benzoylazacycloalk-3-yl-Cl-C7alkyl or -4-yl-Cl-C7alkyl, for example l-benzoylpiperidin-4-ylmethyl, 2-(1-benzoylpiperidin-4-yl)ethyl, 3-(1-benzoylpiperidin-4-yl)propyl or 4-(1-benzoylpiperidin-4-yl)butyl, diazacycloalk-l-yl-Cl-C7alkyl, N'-Cl-C4aL~cyldiazacycloalk-l-yl-Cl-C7alkyl or N'-C2-qalkanoylazacycloalk-1-yl-Cl-qalkyl, for example piperazino- or N'-methyl- or N'-acetyl-piperazino-methyl, 2-(pipcrazino- or N'-methyl- or N'-acetyl-piperazino)-ethyl, 3-(piperazino- or N'-methyl- or N'-acetyl-piperazino)-propyl or 4-(piperazino- or N'-methyl- or N'-acetyl-piperazino)-butyl, azoxacycloalk- l-yl-Cl-C7aLtcyl, for example morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl or 4-morpholinobutyl, 5- to 7-membered oxacycloalk-3-yl-Cl-qalkyl or -4-yl-Cl-C7aL~cyl, such as tetrahydropyran-4-ylmethyl, 2-(tetrahydropyran-4-yl)ethyl, 3-~tetrahydropyran-4-yl)propyl or 4-(tetrahydropyran-4-yl)butyl, S- to 7-membered azacycloalk-3-yl or -4-yl or 1-C2-q-alkanoylazacycloalk-3-yl or -4-yl, ~or exarnple piperidin-4-yl or 1-acetylpiperidin-4-yl, N-Cl-C4aLIcylazacycloalk-3-yl or -4-yl or N-benzoylazacycloalk-3-yl or -4-yl that is unsubstituted or substituted in the phenyl moiety, for example l-methylpipeAdin-4-yl or l-benzoylpiperidin-4-yl, or 5- to 7-membered oxacycloalk-3-yl or -4-yl, for example tetra-hydropyran-4-yl, and R2 is carboxy, Cl-C4alkoxycarbonyl, such as me~hoxycarbonyl or ethoxycarbonyl, 5- to 7-membered cycloaLIcoxycarbonyl, such as cyclopentyloxy- or cyclohexyloxy-carbonyl, or phenyl-Cl-C4aLIcoxycarbonyl that is unsubstituted or mono-or di-substituted by Cl-C4aLlcyl, such as methyl, Cl-C4alkoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlo~ne, cyano and/or by trifluoromethyl, such ~s benzyloxycarbonyl or 2-phenylcthoxycarbonyl, and their salts, especially their pharmaceutically acceptable salts.
~he invention relates especially, for example~ to compounds of formula I wherein Rl is hydroxy-Cl-C7aL~cyl, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl, Cl-C4aL~coxy-Cl-qalkyl, such as methoxymethyl, ethoxyme~hyl, 2-methoxyethyl, 2-ethoxye~hyl, 3-methoxypropyl or 4-methoxybutyl, a phenyl-Cl-C4aLIcoxy-Cl-C7allcyl group that is unsubstituted or mon~, di- or tri-substituted in the phenyl moiety by Cl-C4alkyl, such as methyl, Cl-C4aLkoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluoline or chlorine, cyano andlor by trifluoromethyl, such as a benzyloxymethyl, 2-benzyloxyethyl, 3-benzyloxypropyl or 4-benzyloxybutyl group, amino-Cl-C7alkyl, such as an~inomethyl, ~ ~ 2 ;, ~
2-arninoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl or 6-aminohexyl, Cl-C4aL~ylamino-Cl-C7aL~cyl, such as methylaminomethyl, ethylaminomethyl, propylaminomethyl, butylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl or 6-methylaminohexyl, C2-C7alkanoylamino-Cl-C7alkyl, such as acetylaminomethyl, propionylaminomethyl, butyrylaminomethyl, 2-acetylaminoethyl, 3-acetylaminopropyl, 4-acetylaminobutyl, 5-acetylaminopentyl or 6-acetylaminohexyl, di-Cl-C7alkylamino-Cl-C7alkyl, such as dimethylaminomethyl, diethylaminomethyl, N-ethyl-N-methylaminomethyl, N-methyl-N-propylaminomethyl, dipropylaminomethyl, dibutylaminomethyl, 2-dimethylaminoethyl, 3-di-methylaminopropyl, 4-dimethylaminobutyl, 5-dimethylarninopentyl or 6-dimethylaminohexyl, 5- to 7-membered N,N-(aza- or s:~xa-alkylene)amino-Cl-C7aL~yl, such as pyrrolidinomethyl, piperidinomethyl, morpholinomethyl, piperazino- or N'-methyl- or N'-acetyl-piperazino-methyl, 2-pyrrolidinoethyl, 2-piperidinoethyl, 2-morpholinoethyl, 3-pyrrolidinopropyl, 3-piperidinopropyl, 3-morpholinopropyl, 4-pyrro-lidinobutyl, 4-piperidinobutyl, 5-pyrrolidinopentyl, 5-piperidinopentyl or 6-piperidinohexyl, or halo-Cl-C7aL~cyl, such as halomethyl, 2-haloethyl, 3-halopropyl, 4-halobutyl, S-halopentyl or 6-halohexyl, in which halogerl is chlorine or, especially, fluorine, and R2 is carboxy, Cl-C4alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, 5- to 7-membered cycloaL1coxycarbonyl, such as cyclopentyloxy- or cyclohexyloxy-carbonyl, or phenyl-C~l-C4aLtcoxycarbonyl that is unsubstituted or mono-or di-substituted by Cl-C4aL~cyl, such as methyl, Cl-C4aLtcoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano and/or by trifluoromethyl, such as benzyloxycarbonyl or 2-phenylethoxycarbonyl, and their salts, especially their pharmaceutically acceptable salts.
.
The invention relates preferably to compounds of formula I whe~ein Rl is hydroxy-Cl-qalkyl, such as hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl, benzoyloxy-Cl-qaLlcyl that is unsubstituted or mono- or di-substi~uted in the phenyl moiety by Cl-C4alkyl, such as methyl, Cl-C~ oxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano andlor by tri-fluoromethyl, such as 2-benzoyloxyethyl, Cl-C4alkoxy-Cl-C7alkyl, such as ethoxymethyl or 2-methoxyethyl, phenyl-Cl-C4aLIcoxy-Cl-C7aL~yl that is unsubstituted or mono- or di-substituted in the phenyl moiety by Cl-C4aL~yl, such as methyl,( Cl-C4alkoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano and/or by tri~luoromethyl, such as benzyloxymethyl or 2-benzyloxyethyl, halo-Cl-C7alkyl, such as halomethyl or 2-haloethyl, in which 2l~2~g halogen is chlorine or, especially, fluorine, amino-C4-qalkyl, such as 4-aminobutyl or 6-aminohexyl, N-C2-C7aLkanoyl-N-Cl-C4aLkylarnino-Cl-C7alkyl, such as N-acetyl-N-methylaminometllyl, 5- to 7-membered azacycloalk-3-yl or -4-yl or 1-C2-C7-alk~moylazacycloalk-3-yl or -4-yl, for example piperidin-4-yl or 1-acetylpiperidin-4-yl, and R2 is carboxy, Cl-C4aLkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, or phenyl-Cl-C4aLkoxycarbonyl that is unsubstituted or mono- or di-substituted by Cl-C4aLkyl, such as methyl, Cl-C4aLkoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano and/or by trifluoro-methyl, such as benzyloxycarbonyl or 2-phenylethoxycarbonyl, and their salts, especially their pharmaceutically acceptable salts.
The invention relates especially, on the one hand, to compounds of formula I wherein R
is hydroxy-Cl-C4alkyl, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl, Cl-C4aLkoxy-Cl-C4alkyl, such as methoxymethyl, ethoxymethyl, 2-methoxyethyl, 3-methoxypropyl or 4-methoxybutyl, a phenyl-Cl-C4aLkoxy-Cl-C~aL~yl group that is unsubstituted or mono-, di- or tri-substituted in the phenyl moiety by Cl-C4-aLkyl, such as methyl, Cl-C4aLkoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano andlor by tri~luoromethyl, such as a benzyloxymethyl, 2-benzyloxyethyl, 3-benzyloxypropyl or 4-benzyloxybutyl group, or halo-Cl-C4aLlcyl, such as halomethyl, 2-haloethyl, 3-halopropyl, 4-halobutyl, 5-halopentyl or 6-halohexyl, in which halogen is chlorine or, especially, fluorine, and R2 is carboxy, Cl-~4aLIcoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, 5- to 7-membered cycloaLkoxycarbonyl, such as cyclopentyloxy- or cyclohexyloxy-carbonyl, or phenyl-Cl-C4aL~coxycarbonyl that is unsubstituted or mono- or di-substituted by Cl-C4alkyl, such as methyl, Cl-C4aL~coxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chloline, cyano and/or by trifluoromethyl, such as benzyloxycarbonyl or 2-phenylethoxycarbonyl, and their salts, especially their pharmaceutically acceptable salts.
The invention relates especially, on the other hand, to compounds of formula I wherein R
is amino-Cl-C7aL~cyl, such as aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl or 7-arninoheptyl, Cl-C4aL~ylamino-Cl-qalkyl, such as methylarninomethyl, ethylaminomethyl, propylaminomethyl, butylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl or ~methylaminohexyl, C2-c7aL~canoylamino-ci-qaLlcyl~ such as acetylaminomethyl, propionylaminomethyl, butyrylaminomethyl, 2-acetylaminoethyl, 3-acetylaminopropyl, 2~
4-acetylaminobutyl, 5-acetylaminopentyl or 6-acetylaminohexyl, di-C1-C4alkyl-amino-C1-qalkyl, such as dimethylarninomethyl, diethylaminomethyl, N-ethyl-N-methylaminomethyl, N-methyl-N-propylarninomethyl, dipropylaminomethyl, dibutyl-aminomethyl, 2-dimethylaminoethyl, 3-dimethylan~inopropyl, 4-dimethylaminobutyl,5-dimethylaminopentyl or 6-dimethylaminohexyl, 5- to 7-membered N,N-(aza- or oxa-alkylene)amino-Cl-C7alkyl, such as pyrrolidinomethyl, piperidinomethyl, morpholinomethyl, piperazino- or N'-rnethyl- or N'-acetyl-piperazino-methyl, pyrrolidinoethyl, piperidinoethyl, morpholinoethyl, pyrrolidinopropyl, piperidinopropyl, morpholinopropyl, pyrrolidinobutyl, piperidinobutyl, pyrrolidinopentyl, piperidinopentyl or piperidinohexyl, and R2 is carboxy, Cl-C4aLtcoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, 5- to 7-membered cycloalkoxycarbonyl, such as cyclopentyloxy- orcyclohexyloxy-carbonyl, or phenyl-Cl-C4aL~coxycarbonyl that is unsubstituted or mono-or di-substituted by C1-C4aL~yl, such as methyl, C1-C4aL~coxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano andlor by trifluoromethyl, such as benzyloxycarbonyl or 2-phenylethoxycarbonyl, and their salts, especially their pharmaceutically acceptable salts.
The invention relates more especially to compounds of formula I wherein R1 is hydroxy-Cl-C7aLtcyl, such as hydroxymethyl, Cl-C4alkoxy-Cl-C7alkyl, such as methoxymethyl, ethoxymethyl or 2-methoxyethyl, benzoyloxy-Cl-C4alkyl, such as 2-benzoyloxyethyl, phenyl-C1-C4aL~coxy-C1-C7a1kyl, such as benzyloxymethyl or 2-benzyloxyethyl, amino-c4-qaLlcyl~ such as 4-aminobutyl or 6-arninohexyl, N-C2-C7-alkanoyl-N-cl-c4allcylamino-c2-qaLkyl~ such as 2-(N-acetyl-N-methylamino)ethyl, 5-to 7-membered azacycloaLl~-3-yl or -4-yl or 1-C2-C7aL~canoylazacycloaLIc-3-yl or -4-yl, such as piperidin-4-yl or 1-acetylpipelidin-4-yl, or halo-C1-C4aL~cyl, in which halogen is chlorine or, especially, ~luorine, such as 2-haloethyl, and R2 is carboxy or Cl-C4aLIcoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, and their salts, especially their pha~maceutically acceptable salts.
The invention relates preferably, on the one hand, to compounds of formula I wherein R
is amino-C4-qaL~cyl, such as 4-arninobutyl or ~aminohexyl, N-Cl-C4-alkanoyl-N-Cl-C4alkylamino-Cl-qaL~yl, pipe~idin-4-yl or 1-C 2-C7aLlsanoyl-piperidin-4-yl, such as 1-acetylpiperidin-4-yl, and R2 is carboxy or C1-C4alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, and their salts.
The invention relates preferably, on the other hand, to compounds of formula I wherein R
is Cl-C4alkoxy-Cl-C4alkyl, such as methoxymethyl, ethoxymetllyl or 2-methoxyethyl, phenyl-Cl-C4alkoxy-Cl-C4alkyl7 such as benzyloxymethyl or 2-benzyloxyethyl, benzoyloxy-Cl-C4alkyl, such as 2-benzoyloxyethyl, hydroxy-Cl-C4alkyl, such as hydroxymethyl or 2-hydroxyethyl, or halo-C2-C4allcyl, such as 2-fluoroethyl, and R2 is carboxy or Cl-C4alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, and their s~llts.
The invention relates very especially, on the one hand, to compounds of ~ormula I wherein Rl is amino-C4-qalkyl, such as 4-aminobutyl, S-aminopentyl, ~aminohexyl or 7-amino-heptyl, and R2 is carboxy, Cl-C4aLkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, or a phenyl-Cl-C4aLkoxycarbonyl group that is unsubstituted or mono- or di-substi~uted by Cl-C4aLkyl, such as methyl, Cl-C4aL~coxy, such as me~hoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano andJor by trifluoromethyl, such as a benzyloxycarbonyl or 2-phenylethoxycarbonyl group, and their salts, especially their pharmaceutically acceptable salts.
The invention relates very especially, on the other hand, to compounds of formula I
wherein Rl is Cl-C4aLkoxy-C2-C4aLI<yl, such as 2-methoxyethyl, 2-ethoxyethyl, 3-meehoxypropyl or 4-methoxybutyl, hydroxy-C2-C4aLkyl, such as 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl, or halo-C2-C4aLlcyl, such as 2-fluoroethyl, 2-chloroethyl, 3-fluoropropyl or 4-fluorobutyl, and R2 is carboxy, Cl-C4aLIcoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, or a phenyl-Cl-C4aLkoxycarbonyl group that is unsubstituted or mono- or di-substituted by Cl-C4aLlcyl, such as methyl, Cl-C4aLlcoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano and/or by trifluoromethyl, such as a benzyloxycarbonyl or 2-phenylethoxycarbonyl group, and their salts, especially their pharmaceuticallyacceptable salts.
The invention relates specifically to the compounds of formula I mentioned in the Examples and their salts, especially their pharmaceutically acceptable salts.
The process for the preparation of the compounds according to the invention is as follows:
in a compound of formula II
.
2 ~ 2 ~
Z~ /~ R2 wherein Zl. Z2 are optionally protected hydroxy, Z3 is an aliphatic hydrocarbon radical that is substituted by optionally protected or acylated or aliphatically or araliphatically etherified hydroxy, by halogen, by optionally protected or acylated and/or aliphatically substituted amino or by an aza-, diaza-, azoxa- or oxa-cycloaliphatic radical, or is an oxacycloaliphatic hydrocarbon radical bonded via a carbon atom, or is an optionally protected or aliphatically N-substituted or N-acylated azacycloaliphatic hydrocarbon radical, and Z4 is protected arnino, protected amino Z4 and, if present, protected amino as a constituent of Z3 is converted into amino and, if present, protected hydroxy Zl. Z2 and/or protected hydroxy as a constituent of :Z3 is converted into hydroxy and, if present, a protected azacycloaliphatic hydrocarbon radical Z3 is freed and, if desired, a resulting compound is converted into a different compound of formula I, an isomeric rnixture obtainable in accordance with the process is separated into its components and the preferred isomer is separated, andlor a free compound obtainable in accordance with the process is converted into a salt or a salt obtainable in accordance with the process is converted into the corresponding free compound.
In starting materials of formula II, protected hydroxy Zl andJor Z2 is, for example, etheri~led, especially aliphatically or aromatically etheri~led, hydroxy, protected hydroxy Z3 is, for exarnple, acylated or silylated hydroxy, and protected amino Z4 and, if present, protected amino as a constituent of Z3 is, for exarnple, acylated amino.
Aliphatically etheriffed hydroxy is, for example, iower aLtcoxy, such as me~hoxy, ethoxy or, especially, isopropoxy. Aromatically etherified hydroxy is, for example, phenoxy that is unsubstituted or substituted by lower aLkyl, lower alkoxy, halogen, cyano andlor by nitro.
Acylated hydroxy contains as the acyl group, for example, the acyl radical of anaraliphatic carboxylic acid or of a semi-ester of carbonic acid and is, for example, lower alkanoyloxy or a phenyl-lower aLlcanoyloxy or phenyl-lower aLlcoxycarbonyloxy group ~hat is unsubstituted or substituted in the phenyl moiety by lower aLIcyl, lower aL~coxy, halogen, cyano and/or by trifluoromethyl, for example benzyloxycarbonyloxy.
2 ~
Silylated hydroxy is, for example, tri-lower alkylsilyloxy, for example trimethyl- or tributyl-silyloxy.
Acylated amino contains as the acyl group, for example, acyl derived from a suitable organic acid, such as forrnic acid, or from an araliphatic or aromatic semi-ester of carbonic acid. Accordingly, acylated amino is, for exarnple, formylamino, lower alkoxycarbonylamino, such as methoxy-, ethoxy- or tert.-butoxy-carbonylamino, or a phenyl-lower aL'coxycarbonylamino or or phenoxycarbonylamino group that is unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, halogen, cyano and/or by nitro, such as benzyloxycarbonylamino, substituted by lower aLIcyl, lower alkoxy, halogen, cyano and/or by nitro.
The freeing of the protected groups ~rom compounds of formula II, i.e. of hydroxy from protected hydroxy groups Zl, Z2 and/or from protected hydroxy groups as a constituent of Z3, or of amino from protected amino groups ~4 and, if present, from protected amino groups as a constituent of Z3, is carried out, for example, by treatment with an acidic agent, for example with a tri-lower aLkylhalosilane, such as trimethylbromosilane, tributylbromosilane or trimethyliodosilane. The operation is preferably carried out in an inert solvent, such as a halogenated aliphatic hydrocarbon, for example dichloromethane or, secondly, tri- or tetra-chloromethane, trichloroethane or tetrachloroethane, for example in a temperature range of frorn approximately -25 ~o approximately +50C, preferably of approximately from 0 to 30C, for example at room temperature, i.e. at approximately from 15 to 25C, advantageously under substantially anhydrous condi~ions and under an inert gas, such as argon or nitrogen. Working up is preferably carried out with the addition of a hydrogen halide acceptor, especially an aliphatic epoxy compound, such as an `epoxy-lower aLIcane, for example propylene oxide in a lower aL4anol, such as ethanol.
In a prefelred form, for example compounds of formula II wherein Zl and Z2 are lower alkoxy, for example isopropoxy, and Z4 is lower aLkanoylamino, such as formylamino, are used as starting materials and are treated in an aliphatic halogenated hydrocarbon, such as dichloromethane, at from approximately 15 to approxirnately 25C, with a tri-lower alkylbromosilane, such as ~imethylbromosilane or tributylbromosilane; the rnixture is left for a time, for example from 2 to 30 hours, to complete the reaction, and then an ethanolic solution of propylene oxide is added and the product is removed by filtration.
~2.~u~
Starting materials of formula II are prepared, for example, by reacting an a,~-unsaturated aldehyde of forrnula IIa ~0 z~ (IIa) with an (x-isocyanoacetic acid ester of forrnula IIb :C~ N ~- R2 (IIb) in a manner known Per se9 for example in the presence of a copper or gold catalyst, for example copper(I) oxide or bis(cyclohexylisocyanide)gold(I) tetrafluoroborate, to give the corresponding S-substituted 2-oxazoline-4-carboxylic acid ester of forrnula IIc z3 =< ~J?2 ---~ (IIc) O~N
conYerting the ester of formula IIc by hydrolysis, for example in aqueous tetrahydrofuran, into the corresponding open-chained ester of formula IId OH
"R2 (IId~, NHCH=O
converting the ester of formula IId by treatment with thionyl brornide in a manner known per se into the corresponding ~bromic ester of formula IIe B r CH2 ~R2 (~e) Z3 NHC~=O
~a2~?s and reacting the ester of formula IIe further in a manner known ~ se with a phosphorous acid triester of the formula P(Za)(Zb)(ZC), wherein Za. Zb and ~c are identical or different hydroxy groups protected in an ether form, such as a tri-lower alkyl phosphite, for example triisopropyl phosphite, to give the corresponding compound of formula II' o Z \ ~ R2 Z3 NHCH=O
Compounds obtainable in accordance with the process can be converted in customary manner into different compounds of formula I.
For example, free and esterified carboxy groups R2 can be converted in customary manner into one another. In particular, esterified carboxy R~ can be converted into carboxy by hydrolysis, or free carboxy R2 can be converted into esterified carboxy by reaction with an alcohol. Furthermore, esterified carboxy R2 can be transesterified to form a different esterified carboxy group. These transesterification reactions are carried out in customary manner under hydrolytic, alcoholytic or transesterifying conditions.
The hydrolysis of carboxylic acid esters (I; R2 = esterified carboxy) is carried out in customary manner, if necessary in the presence of an acidic or basic agent, such as a mineral acid, for example hydrochloric acid or sulfuric acid, or a base, such as an aLlcali metal hydroxide, for example sodium hydroxide.
The transesterification of esters (I; R2 = esterified carboxy) with alcohols is usually carried out under conditions of acid-catalysis or base-catalysis, fo} example in the presence of a catalytic amount of a mineral acid, such as hydrochloric acid or sulfuric acid, or of a metal base, such as sodium hydroxide, or by employing the alcohol component in the form of a metal alcoholate, for example an aLkali metal alcoholate.
Furthermore, in aliphatic hydrocarbon radicals substituted by araliphatically etherified hydroxy, such as a-phenyl-lower aL~coxy-lower aLIcyl radicals Rl, the a-phenyl-lower alkoxy group can be converted into hydroxy by reduction, for example by treatment wi~
hydrogen in the presence of a hydrogenation catalyst, such as palladium-on-carbon or Raney nickel.
-21- 202~
Resulting salts can be converted into the free compounds in a manner known Per se, for example by treatment with a base, such as an aLkali metal hydroxide, a metal carbonate, a metal hydrogen carbonate or ammonia, or with another salt-forming base mentioned at the beginning, or with an acid, such as a mineral acid, for example hydrochloric acid, or another salt-forming acid mentioned at the beginning.
Resulting salts can be converted into different salts in a manner known 1~ se, in the case of acid addition sal~s, for example, by treatment with a suitable metal salt, such as a sodium, barium or silver salt, of a different acid in a suitable solvent in which an inorganic salt being formed is insoluble and therefore is eliminated from the reaction equilibrium, and in the case of base salts, by freeing the free acid and converting it into a salt again.
The compounds of formula I, including their salts, may also be obtained in the form of hydrates or include the solvent used for crystallisation.
In view of the close relationship between the novel compounds in free form and in the form of their salts, hereinbefore and hereinafter any reference to the free compounds or their salts should be understood as including also the corresponding salts or free compounds, respectively, where appropriate and expedient.
Resulting diastereoisomeric mixtures and mibctures of racemates can be separated into the pure diastereoisomers and racemates in known manner on the basis of the physicochemical differences between the constituents, for example by chromatography and/or fractional crystallisation. -Furthermore, resulting racemates can be separated into the optical antipodes by knownmethods, for example by recrystallisation from an optically active solvent, with the aid of microorganisms, or by reaction of the resulting diastereoisomeric mixture or racemate with an optically active auxiliary compound, for example, according to the acid, basic or functionally modifiable groups contained in compounds of formula I, with an optically active ~cid, base or an optically active alcohol, ~o form mixtures of diastereoisomeric salts or functional derivatives, such as esters, and separation thereof into the diastereoisomers from which the desired enantiomer can be freed in the customary manner. Suitable bases, acids and alcohols are, for example~ amino acids, especially lysine, optically active alkaloid bases, such as strychnine, cinchonine or brucine, or ~ or L-(1-phenyl)ethylarnine, 2 ~
3-pipecoline, ephedrine, amphetamine and similar synthetically obtainable bases, optically active carboxylic or sulfonic acids, such as quinic acid or ~ or L-tartaric acid, D- or L-di-o-toluyltartaric acid, D- or L-malic acid, ~ or L-mandelic acid or D- or L-camphor-sulfonic acid, and optically active alcohols, such as borneol or ~ or L-~l-phenyl)ethanol.
The invention relates also to those forms of the process in which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaiDing steps are carried out, or in which a starting material is used in the form of a salt or, especially, is formed under the reaction conditions.
The invention relates also to the novel starting materials developed specifically for the preparation of the compounds according to the invention, especially to those starting materials resulting in the compounds of forrnula I that were described at the beginning as being preferred, to processes for the preparation thereof and to their use as interrnediates.
The novel compounds of folmula I can be used, for example, in the form of pharmaceutical preparations that contain a therapeutically effective amount of the active ingredient, optionally together with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers, which are suitable for enteral, e.g. oral, or parenteral administration.
There are used, for example, tablets or gelatin capsules that contain the active ingredient together with diluents, for exarnple lactose, dextrose, saccharose, mannitol, sorbitol, cellulose, and/or lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Tablets can also contaun binders, for example magnesium aluminium silicate, starches, such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, for example sodium alginate, and/or effervescent mixtures, or absorbents, colouring agents, flavourings and sweeteners. The novel compounds offormula 1 can also be used in the form of parenterally administrable preparations or in the form of infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions which, for example in the case of lyophilised preparations that con~ain the active ingredient on its own or together with a calTier, for example mannitol, can be prepared before use. The pharmaceutical preparations may be sterilised and/or may contain adjuncts, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers. The pharmaceutical preparations in question, which, if desired, may contain further pharmacologically active 2Q2~
su~stances, are prepared in a manner known ~ se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes, and contain approximately from 0.1 % to 100 %, especially from approximately 1 % to approximately 50 %, in the case of lyophilisates up to approximately 100 %, active ingredient.
The invention relates also to the use of the compounds of formula I, preferably in the form of pharmaceutical preparatiolls. The dosage may depend on various factors, such as the mode of administration and the species, age and/or individual condition. The daily doses are, in the case of oral administration, from approximately 0.25 to approximately 10 mg/kg, and in the case of warm-blooded animals having a body weight of approximately 70 kg, they are preferably from approximately 20 mg to approximately 500 mg.
The following Exarnples illustrate the invention; temperatures are given in degrees Celsius and pressures in mbar.
Example 1: 3.57 g (8.5 mrnol) of 6-acetoxy-4-diisopropylphosphono-methyl-2-forrnylamino-hex-3-enoic acid ethyl ester are dissolved in 22 ml of dichloro-methane, and 4.4 ml (34 mmol) of trimethylbromosilane are added dropwise at roomtemperature. The mix~ure is left to stand at room temperature for 22 hours, ~2 ml of ethanol are added dropwise, the mixture is left to stand for a further 22 hours and is con-centrated by evaporation in a rotary evaporator, the residue is dissolved in 22 ml of ethanol, and a mixture of 22 ml of propylene oxide and 22 rrl of ethanol is added drop-wise. A suspension forms, which is stirred for a fu~ther 90 rninutes and then filtered with suction. 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester having a melting point of 195 (decomp.) is obtained.
The starting material can be prepared, for example, as follows:
13.0 g (100 mmol) of acetic acid (4-oxo)bu~yl ester, 92.0 g (112.6 mmol) of dimethylammonium chloride and 10.8 ml (117 mmol) of 37 % formaldehyde solution are heated at 100 ~or one hour with stirring. The mixture is allowed to cool and is extracted 3 times with 30 ml of diethyl ether each time. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness by evaporation. Acetic acid (3-formyl)but-3-enyl ester is obtained in the form of a colourless oil which can be reacted further without further purification.
2 ~ 2 ~
13.5 g (95 mmol) o~ acetic acid (3-formyl)but-3-enyl ester and 10.4 g (9S mmol) of isocyanoacetic acid ethyl ester are added dropwise to a suspension of 0.38 g of copper(I) oxide in S0 ml of benzene. When the exothermic reaction has subsided, the mixture is stirred at room temperature for a further 45 minutes, filtered over Hyflo(~ and concentrated to dryness by evaporation. The residue is taken up in 75 ml of tetrahydro-furan, 25 ml of water are added, and the mixture is heated under reflux for 4 hours with stirnng. The mixture is concentrated to dryness by evaporadon and chromatographed on silica gel with toluene/isopropanol (9:1) as eluant.
6-acetoxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester is obtained in the form of a brownish oil.
9.19 g (35.9 mmol) of 6-acetoxy-2-formylamino-3-hydroxy-4-methylene-hexanoi~ acid ethyl ester are dissolved in 100 ml of dichloromethane, and 3.34 ml (43.1 mmol) of thionyl bromide are added dropwise at room temperature. After one hour, 10 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, saturated potassium hydrogen carbonate solution and again with water, dried over magnesium sulfate, filtered and concentrated by evaporation. 6-acetoxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a brownish oil.
Aliphatic hydrocarbon radicals that are substituted by an azoxacycloaliphatic radical are, for example, 4- to 7-membered azoxacycloaLIcyl-lower alkyl radicals whose azoxacyclo-al~cyl moiety is bonded via the N atom, such as 4- to 7-membered azoxacycloalkyl-lower alkyl radicals bonded via the N atom, especially 5- to 7-membered N,N-(oxa-loweralkylene)amino-Cl-qalkyl, i.e. azoxacycloalk-l-yl-Cl-qalkyl.
Aliphatic hydrocarbon radicals that are substituted by an oxacycloaliphatic radical are, for example, 4- to 7-membered oxacycloalkyl-lower alkyl radicals whose oxacycloalkylmoiety is bonded via a carbon atom, such as 5- to 7-membered oxacycloalkyl-Cl-C7alkyl bonded via a carbon atom.
Oxacycloaliphatic hydrocarbon radicals that are bonded via a carbon atom are, for example, 5- to 7-membered oxacycloalkyl groups bonded via a carbon atom.
Azacycloaliphatic hydrocarbon radicals that are bonded via a carbon atom and areoptionally aliphatically N-substituted or N-acylated are azacycloaL~cyl radicals that are bonded via a carbon atom and are optionally N-lower alkylated, N-lower alkanoylated or N-substituted by benzoyl that is unsubstituted or substituted in the phenyl moiety, such as 5- to 7-membered azacycloaLIcyl or N-C2-C7aL~canoylazacycloaL~yl, also N-Cl-(:~4aLIcyl-azacycloallcyl or unsubstituted or substituted N-benzoylazacycloaLIcyl, each of which is bonded via a carbon atom.
Esterified carboxy is, for example, carboxy esterified by an aliphatic, cycloaliphatic or araliphatic alcohol, such as lower alkoxycarbonyl, 4- up to and including 7-membered, especially 5- or ~membered, cycloaLkoxycarbonyl, such as cyclopentyloxy- or cyclohexyloxy-carbonyl, or unsubstituted or substituted phenyl-lower aL~oxycarbonyl.
In the groups mentioned above, phenyl radicals may be unsubstitutFd or mono-, di- or tri-subs~ituted, especially mono- or di-substituted, in customary manner, for example by lower aLlcyl, lower alkoxy, halogen, cyaDo and/or by trifluoromethyl.
Hereinbefore and hereinafter, "lower" radicals and compounds shall be understood as being, for example, radicals and compounds containing up to and including 7, preferably up to and including 4, carbon atoms (C atoms).
Lower alkyl is, for example, Cl-C7aLlcyl, preferably Cl-C4aL~cyl, such as methyl, ethyl, propyl, isopropyl or butyl, but may also be isobutyl, sec.-butyl, tert.-butyl or a pentyl, hexyl or heptyl group.
Mono- or di-hydroxy-lower alkyl is, for example, hydroxy-Cl-C7aL~cyl, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, S-hydroxypentyl or 6-hydroxyhexyl, or dihydroxy-C2-C7aLI~yl in which the hydroxy groups are bonded to different carbon atoms, such as 1,2-dihydroxyethyl or, especially, 1,3-dihydroxyprop-2-yl.
Lower alkanoyl is, ~or example, C2-C7aL~anoyl, especially C2-C4aL~anoyl, such as acetyl, propionyl or butyryl, but may also be a Cs-C6alkanoyl group, such as pivaloyl. Accor-dingly, lower alkanoyloxy-lower alkyl is especially C2-C7aLtcanoyloxy-Cl-qaLlcyl, such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl, 2-acetoxyethyl, 3-acetoxy-propyl, 4-acetoxybutyl, S-acetoxypentyl or 6-acetoxyhexyl. By analogy, benzoyloxy-lower alkyl shall be understood as being, for exarnple, benzoyloxy-Cl-q-aLIcyl that is unsubstituted or substituted in the phenyl moiety, such as benzoyloxymethyl, 2-benzoyloxyethyl, 3-benzoyloxypropyl, 4-benzoyloxybutyl, 5-benzoyloxypentyl or 6-benzoyloxyhexyl.
Lower alkoxy is, for example, Cl-C7aLlcoxy, preferably Cl-C4aL~oxy, such as methoxy, ethoxy, propoxy, isopropoxy or butoxy, but may also be isobutoxy, sec.-butoxy, tert.-butoxy or a pentyloxy, hexyloxy or heptyloxy group. Accordingly, lower aL1coxy-lower aLIcyl is, for example, Cl-C4aLkoxy-Cl-C7aL~yl, such as methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypentyl or 6-methoxyhexyl.
Phenyl-lower aLtcoxy is, for example, phenyl-Cl-C4alkoxy that is unsubstituted or substituted as indicated, such as benzyloxy, 2-phenylethoxy or 3-phenylpropoxy.
Accordingly, phenyl-lower alkoxy-lower alkyl is, for example, a phenyl-Cl-C4-alkoxy-Cl-C7alkyl radical that is unsubstituted or substituted as indicated, such as a benzyloxymethyl, 2-phenylethoxymethyl, 2-benzyloxyethyl, 3-benzyloxypropyl, 4-benzyloxybutyl, 5-benzyloxypentyl or 6-benzyloxyhexyl radical.
Halo-lower alkyl is, for example, halo-Cl-C7allcyl, such as halomethyl, 2-haloethyl, 3-halopropyl, 4-halobutyl, 5-halopentyl or 6-halohexyl, in which halogen is chlorine or, especially, fluoline.
Amino-lower alkyl is, for example, amino-Cl-C7alkyl, such as aminomethyl, 2-aminoethyl, 3-aminopropyl7 4-aminobutyl, 5-aminopentyl or 6-aminohexyl.
Lower alkylamino is, for example, Cl-C7aLkylamino, especially Cl-C4alkylamino, such as methylamino, ethylamino, propylamino or butylamino, but may also be a Cs-C6alkyl-amino group, such as a pentylamino or hexylamino group. Accordingly, lower alkyl-amino-lower alkyl is especially Cl-C4alkylamino-Cl-C7alkyl, such as methylaminomethyl, ethylaminomethyl, propylaminomethyl, butylaminomethyl, 2-methylaminoethyl, 3-methylarninopropyl, 4-methylaminobutyl, 5-methylaminopentyl or 6-methylaminohexyl .
:
Lower alkanoylamino is, for example, C2-qaL~sanoylamino, especially C2-C4alkanoyl-amino, such as acetylamino, propionylamino or butyrylamino, but may also be Cs-C6-alkanoylamino, such as pivaloylamino. Accordingly, lower alkanoylamin~lower alkyl is especially C2-qalkanoylamino-Cl-qaLIcyl, such as acetylaminomethyl, propionylaminomethyl, butyrylaminomethyl, 2-acetylaminoethyl, 3-acetylaminopropyl, 4-acetylaminobutyl, 5-acetylaminopentyl or ~acetylaminohexyl. By analogy, benzoylamino-lower aLtcyl shall be unders~ood as being, for example, benzoylamino-Cl-C?alkyl that is unsubstituted or substituted in the phenyl moiety, such as benzoylaminomethyl, 2-benzoylaminoethyl, 3-benzoylaminopropyl, 4-benzoylaminobutyl, 5-ben~oylaminopentyl or 6-ben~oylaminohexyl.
.
Di-lower aLkylalIuno is, for example, di-Cl-C7aL~cylamino, especially di-Cl-C4-alkylarnino, such as dimethylamino, diethylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, dipropylamino or dibutylamino. Accordingly, di-lower aLIcylamino-lower alkyl is especially di-Cl-C4alkylamino-Cl-qalkyl, such as dimethylaminomethyl, diethylaminomethyl, N-ethyl-N-methylaminomethyl, N-methyl-N-propylaminomethyl, dipropylaminomethyl, dibutylaminomethyl, 2-dimethylaminoethyl, ~ ~ 2 ~ 8 3-dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl or 6-dimethyl-aminohexyl.
N-lower alkanoyl-N-lower aL~cylamino-lower alkyl is, for example, N-C2-C7-alkanoyl-N-Cl-C4alkylamino-Cl-C7aL~cyl, such as N-acetyl-N-methylaminomethyl, N-acetyl-N-ethylaminomethyl, N-propionyl-N-methylaminomethyl, N-butyIyl-N-methylaminomethyl, 2-(N-acetyl-N-methylamino)ethyl, 2-(N-propionyl-N-methyl-arnino)ethyl, 2-(N-acetyl-N-ethylarnino)ethyl, 3-(N-acetyl-N-methylamino)propyl,4-(N-acetyl-N-methylamino)butyl, 5-(N-acetyl-N-methylamino)pentyl or 6-(N-acetyl-N-methylamino)hexyl.
4- to 7-membered azacycloaL~cyl-C1-C7aLkyl bonded via an N atom is preferably N,N-lower alkylenearnino-Cl-C7alkyl, i.e. azacycloalk-1-yl-Cl-C7alkyl, for example pyrrolidinomethyl, piperidinomethyl, morpholinomethyl, 2-pyrrolidinoethyl, 2-piperidinoethyl, 3-pyrrolidinopropyl, 3-p;peridinopropyl, 4-pyrrolidinobutyl, 4-piperidinobutyl, S-pyrrolidinopentyl, 5-piperidinopentyl, 6-pyrrolidinohexyl or 6-piperi-dinohexyl.
4- to 7-membered azacycloaL~cyl-cl-qaLlcyl bonded via a carbon atom is preferably azacycloaLk-3-yl-C1-qalkyl or -4-yl-cl-qaL~yl~ for example piperidin-4-ylmethyl,2-(piperidin-4-yl)ethyl, 3-(piperidin-4-yl)propyl or 4-(piperidin-4-yl)butyl.
5- to 7-membered N-c2-qaL~anoylazacycloaLl~yl-cl-qallcyl bonded via a carbon atom is preferably 1-c2-c7alkanoylazacycloallc-3-yl-cl-qalkyl or -4-yl-C1-C7aLIcyl, for example 1-acetylpiperidin-4-ylmethyl, 2-(1-acetylpiperidin-4-yljethyl, 3-(1-acetylpiperidin-4-yl)propyl or 4-(1-acetylpiperidin-4-yl)butyl.
5- to 7-membered N-cl-c4aL~cylazacycloaLlcyl-cl-qaLkyl bonded via a carbon atom is preferably N-C1-C4aLIcylazacycloaLk-3-yl-Cl-C7aLlcyl or -4-yl-Cl-C7alkyl, for example 1-methylpiperidin-4-ylmethyl, 1-ethylpiperidin-4-ylmethyl, 2-(1-methyl-piperidin-4-yl)ethyl, 2-(1-ethylpiperidin-4-yl)ethyl, 3-(1-methylpiperidin-4-yl~propyl, 3-(1-ethylpiperidin-4-yl)propyl, 4-(1-methylpiperidin-4-yl)butyl or 4-(1-ethylpiperidin-4-yl)butyl.
5- to 7-membered N-benzoylazacycls)alkyl-C1-C7aLtcyl that is bonded via a carbon atom and unsubstituted or substituted in the phenyl moiety is preferably N-C1-C4benzoyl-azacycloaLlc-3-yl-Cl-C7alkyl or -4-yl-Cl-C7alkyl, for example l-benzoyl-piperidin-4-ylmethyl, 2-(1-benzoylpiperidin-4-yl)ethyl, 3-(1-benzoylpiperi~lin-4-yl)propyl or 4-tl-benzoylpiperidin-4-yl)butyl.
5- to 7-membered diazacycloalk-1-yl-Cl-C7alkyl that is bonded vla an N atom and is optionally N'-lower alkylated, N'-lower alkanoylated or N'-substituted by a benzoyl group that is unsubstituted or substituted in the phenyl moiety is, for example,N,N-(aza-lower alkylene)amino-Cl-C7alkyl, i.e. diazacycloalk-1-yl-Cl-C7alkyl, N'-Cl-C4alkyldiazacycloalk-1-yl-Cl-C7alkyl or N'-C2-C7alkanoylazacycloaL~c-l-yl-Cl-C7alkyl, for e:carnple piperazino- or N'-methyl- or N'-acetyl-piperazino-methyl, 2-(piperazino- or N'-methyl- or N'-acetyl-piperazino)-ethyl, 3-(piperazino- or N'-methyl-or N'-acetyl-piyerazino)-propyl or 4-(piperazino- or N'-methyl- or N'-ace~yl-piperazino)-butyl.
5- to 7-rnembered N,N-(oxa-lower alkylene)amino-Cl-C7alkyl, i.e. azoxacycloaL~c-l-yl-Cl-C7aLtcyl, is, for exarnple, morpholinomethyl, 2-morpholinoethyl, 3-morpholino-propyl or 4-morpholinobutyl.
5- to 7-membered oxacycloalkyl-Cl-qalkyl bonded via a carbon atom is especially 5- to 7-membered oxacycloalk-3-yl-Cl-C7alkyl or oxacycloalk-4-yl-Cl-C7aLlcyl, such as tetra-hydropyran-4-ylmethyl, 2-~tetrahydropyran-4-yl)ethyl, 3-(tetrahydropyran-4-yl)propyl or 4-(tetrahydropyran-4-yl)butyl.
S- to 7-membered oxacycloalkyl bonded via a carbon atorn is especially corresponding oxacycloalk-3-yl or -4-yl, for example tetrahydropyran-4-yl.
5- to 7-membered azacycloaLIcyl, N-Cl-C4alkylazacycloalkyl or N-C2-C7-alkanoylazacycloaLkyl bonded via a carbon atom is preferably azacycloaLlc-3-yl or -4-yl or l-C2-C7aLIcanoylazacycloaL~c-3-yl or -4-yl, for example piperidin-4-yl or l-acetyl-piperidin-4-yl, and also M-Cl C4aLI~ylazacycloaLlc-3-yl or -4-yl or N-benzoylazacycloaLI~-3-yl or -4-yl that is unsubstituted or substituted in the phenyl moiety, for example l-methylpiperidin-4-yl or 1-benzoylpiperidin-4-yl.
Lower alkoxycarbonyl is, for example, Cl-C7aL~oxycarbonyl, especially Cl-C4alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or butoxycarbonyl, but may also be a Cs-C7allcoxycarbonyl group, ~2~3~
such as a pentyloxycarbonyl, hexyloxycarbonyl or heptyloxycarbonyl group.
Phenyl-lower alkoxycarbonyl is, for example, phenyl-Cl-C4alkoxycarbonyl, such asbenzyloxycarbonyl, 2-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl or 4-phenylbutoxycarbonyl .
On account of their amphoteric nature, the compounds of formula I are in the form of internal salts and can form both acid addition salts and salts with bases.
Acid addition salts of compounds of formula I are, for example, pharmaceuticallyacceptable salts thereof with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, for example hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates, or salts with suitable aliphatic or aromatic sulfonic acids or N-sub-stituted sulfamic acids, for example methanesulfonates, benzenesulfonates, p-toluenesulfonates or N-cyclohexyl sulfamates (cyclamates).
Salts of compounds of formula I with bases are, for example, salts thereof with pharmaceutically acceptable bases, such as non-toxic metal salts derived from groups Ia, Ib, IIa and IIb, for example aLtcali metal salts, especially sodium or potassium salts, alkaline earth metal salts, especially calcium or magnesium salts, and also ammonium salts with ammonia or organic amines or quaternary amrnonium bases, such as unsubstituted or C-hydroxylated aliphatic amines, especially mono-, di- or tri-lower alkylamines, for example methyl-, ethyl- or diethyl-amine, mono-, di- or ~i-(hydroxy-lower alkyl)amines, such as ethanol-, die~hanol- or ~riethanol-amine, tris-(hydroxymethyl)methylamine or 2-hydroxy-tert.-butylamine, or N-(hydroxy-lower alkyl)-N,N-di-lower aLkylamines or N-(polyhydroxy-lower alkyl)-N-lower alkylamines, such as 2-(dimethylarnino)ethanol or D-glucamine, or quatemary aliphatic ammonium hydroxides, for example ~etrabutylammonium hydroxide.
:' For isolation or purification puIposes it is also possible to use phannaceutically unsuitable salts. Only the pharmaceutically acceptable, non-toxic salts are used therapeudcally, and these salts are therefore preferred.
The invention relates, for example, to compounds of formula I wherein Rl is an aliphatic hydrocarbon radical that is substituted by optionally aliphatically s~r araliphatically etherified hydroxy, optionally aliphatically substituted amino or by halogen, and R2 is free or esterified carboxy, and ~heir salts.
The compounds of formula I have valuable pharrnacological properties. In particular, they have a pronounced and selective antagonistic activity towards N-methyl-D-aspartic acid-sensitive (NMDA-sensitive) excitatory amino acid receptors in warm-blooded animals.
This can be demonstrated in vitro, for example, in the experimental procedure according to G. Fagg and A. Matus, Proc. Nat. Acad. Sci., USA, 81, 6876-6880 (1984). This procedure determines the extent to which the binding of L-3H-glutarnic acid to NMDA-sensitive receptors is inhibited. The NMDA-antagonistic properties of the novel compounds can also be demonstrated in vivo, however, for example in mice, by theinhibiting effçct on NMDA-induced convulsions.
On account of these properties, the compounds of formula I and their pharmaceutically acceptable salts are erninently suitable for the treatment of pathological conditions respon-sive to a blocking of NMDA-sensitive receptors, for exarnple ischaemic disorders, such as cerebral ischaemia and ischaemic disorders of the eye, vascular and muscular spasms, such as migraines, or local or general spasticity and, especially, convulsions, such as epilepsy.
The anti-convulsive properties of the compounds of the invention can be demonstrated, for example, in mice by their pronounced protective effect against convulsions triggered by electric shock or induced audiogenically, it being possible to make use, for example, of the established electric shock rnouse model or of the experimental procedure according to Chapman et aL, Arzneimittel-Forsch. 34, 1251 (1984). The compounds of the invention are distinguished, especially in the electric shock mouse model, by improved action as compared with structurally related compounds.
The anti-spastic properties that render the compounds provided according to the invention suitable for the treatment of migraines can be demonstrated, for example, in rats by their depression-inhibiting action in the frontal cortex in accordance with the experimental procedure of R. Marannes et aL, Brain Res. 457, 226 (1988). In this model9 at doses in the range of approximately from 3 to 30 mg/kg i.p., the compounds provided according to the invention lower the threshold value of spreading depression and shorten the duration thereof.
The invention relates especially to compounds of forrnula I wherein Rl is mono- or 2~2~
di-hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, benzoyloxy-lower alkyl, lower alkoxy-lower alkyl, phenyl-lower alkoxy-lower alkyl, halo-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, lower alkanoylamino-lower alkyl, di-lower alkylamino-lower alkyl, N-lower alkyl-N-lower alkanoylamino-lower alkyl, 5- to 7-mernbered azacycloalkyl-lower alkyl whose azacycloalkyl moiety is bonded via the N
atom or a carbon atom and, in the latter case, may be N-lower alkylated, N-loweralkanoylated or N-substituted by a benzoyl group that is unsubstituted or substituted in the phenyl moiety, 5- to 7-membered diazacycloaLkyl-lower alkyl whose diazacycloalkyl moiety is bonded via an N atom and is optionally N'-lower aL~cylated, N'-lower alkanoylated or N'-substituted by a benzoyl group that is unsubstituted or substituted in the phenyl moiety, 5- to 7-membered azoxacycloaLkyl-lower alkyl bonded via the N atom, 5- to 7-membered oxacycloalkyl-lower alkyl bonded via a carbon atom, 5- to 7-membered azacycloaLkyl that is bonded via a carbon atom and is optionally N-lower aLkylated, N-lower alkanoylated or N-substituted by a benzoyl group that is unsubstituted or substituted in the phenyl moiety, or 5- to 7-membered oxacycloalkyl bonded via a carbon atom, and R2 is carboxy, lower aLcoxycarbonyl, 4- up to and including 7-membered cyclo-alkoxycarbonyl or phenyl-lower aL~coxycarbonyl, any phenyl radicals ;n the mentioned groups R1 and/or R2 being unsubstituted or mono-, di- or tri-substituted by lower aLkyl, lower aLlcoxy, halogen, cyano and/or by trifluoromethyl, and their salts.
The invention relates especially, for example, to compounds of formula I wherein R1 is hydroxy-lower alkyl, lower alkoxy-lower alkyl, phenyl-lower alkoxy-lower aL~cyL amino-lower aL~cyl, lower aL~cylarnino-lower aLkyl, di-lower aLkylamino-lower aL~cyl, N,N-lower alkyleneamin~ or N,N-(aza- or oxa-lower aLkylene)amin~lower aLkyl, or halo-loweraLlcyl, and R2 is carboxy, lower alkoxycarbonyl, 4- up to and including 7-membered cyclo-alkoxycarbonyl or phenyl-lower aLlcoxycarbonyl, any phenyl radicals in the mentioned groups R1 andlor R2 being unsubstituted or mon~, di- or tri-subs~ituted by lower aL~cyl, lower aLkoxy, halogen, cyano andlor by ~ifluoromethyl, and their salts.
The invention relates especially to compounds of formula I wherein R1 is hydroxy-C1-C7alkyl, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl, dihydroxy-C2-C7alkyl, such as 1,3-dihydroxyprop-2-yl, C2-C7-alkanoyloxy-C1-C7aLI~yl, such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl, 2-acetyloxyethyl, 3-acetyloxypropyl, 4-acetyloxybutyl, 5-acetyloxypentyl or ~acetyloxy-hexyl, benzoyloxy-C1-C7alkyl that is unsubstituted or mono- or di-substituted in the phenyl moiety by Cl-C4altcyl, such as methyl, Cl-C~ coxy, such as methoxy, halogen 2~2~3~
having an atomic number of up to and including 35, such as fluorine or chlorine, cyano andlor by trifluoromethyl, such as benzoyloxymethyl, 2-benzoyloxyethyl, 3-benzoyloxypropyl, 4-benzoyloxybutyl, S-benzoyloxypentyl or 6-benzoyloxyhexyl, Cl-C4allcoxy-Cl-C7alkyl, such as methoxymethyl, ethoxymethyl, 2-methoxyethyl, 3-methoxypropyl or 4-methoxybutyl, a phenyl-Cl-C4alkoxy-Cl-C7alkyl group that isunsubstituted or mono- or di-substituted in the phenyl moiety by Cl-C4alkyl, such as methyl, Cl-C4alkoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano and/or by trifluoromethyl, such as benzyloxymethyl, 2-benzyloxyethyl, 3-benzyloxypropyl or 4-benzyloxybutyl, halo-Cl-qaLI~yl, such as halomethyl, 2-haloethyl, 3-halopropyl, 4-halobutyl, 5-halopentyl or 6-halohexyl, in which halogen is chlorine or, especially, fluorine, amino-Cl-C7alkyl, such as aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl or 6-amunohexyl, Cl-C4alkylamino-CI-C7all~yl, such as methylaminomethyl, ethylamino-methyl, propylaminomethyl, butylarninomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl or 6-methylaminohexyl, C2-C7alkanoylamino-Cl-~7alkyl, such as acetylaminomethyl, propionylaminomethyl, butyrylarninomethyl, 2-acetylaminoethyl, 3-acetylaminopropyl, 4-acetylaminobutyl, 5-acetylaminopentyl or 6-acetylaminohexyl, N-C2-C7aL1canoyl-N-Cl-C4alkyl-amino-Cl-C7alkyl, such as N-acetyl-N-methylarninomethyl, N-acetyl-N-ethyl-aminomethyl, N-propionyl-N-methylaminomethyl, N-butyryl-N-methylaminomethyl, 2-(N-acetyl-N-methylamino)ethyl, 2-(N-propionyl-N-methylamino)ethyl, 2-(N-acetyl-N-ethylamino)ethyl, 3-(N-acetyl-N-methylamino)propyl, 4-(N-acetyl-N-methyl-amino)butyl, 5-(N-acetyl-N-methylamino)pentyl or 6-(N-acetyl-N-methylamino)hexyl, di-Cl-C7alkylamino-Cl-C7aLIcyl, such as dimethylaminomethyl, diethylaminomethyl,N-ethyl-N-methylaminomethyl, N-methyl-N-propylaminomethyl, dipropylaminomethyl, dibutylaminomethyl, 2-dimethylarrunoethyl, 3-dimethylaminopropyl, 4-dimethyl-aminobutyl, S-dimethylaminopentyl or 6-dimethylaminohexyl, azacycloalk-l-yl-CI-C7aLlsyl, such as pyrrolidinomethyl, piperidinome~hyl, 2-pyrrolidinoethyl, 2-piperidinoethyl, 3-py~rolidinopropyl, 3-piperidinopropyl, 4-pyrroli-dinobutyl, 4-piperidinobutyl, S-pyrrolidinopentyl, S-piperidinopentyl, ~pyIrolidinohexyl or ~piperidinohexyl, azacycloaL~c-3-yl-Cl-C7aLkyl or -4-yl-Cl-C7aL~cyl, for exarnple piperidin-4-ylmethyl, 2-(piperidin-4-yl~ethyl, 3-(piperidin-4-yl)propyl or 4-(piperidin-4-yl)butyl, l-C2-C7aL1canoylazacycloaLlc-3-yl-Cl-qalkyl or -4-yl-C1-C7alkyl, for example 1-acetylpiperidin-4-ylmethyl, 2-(1-acetylpiperidin-4-yl)-ethyl, 3-(1-acetylpiperidin-4-yl)propyl or 4-(1-acetylpiperidin-4-yl)butyl, N-Cl-C4alkylazacycloalk-3-yl-Cl-qaLtcyl or -4-yl-Cl-qalkyl, for example ~2~3~,~
l-methylpiperidin-4-ylmethyl, 1-ethylpiperidin-4-ylmethyl, 2-(1-methylpiperidin-4-yl)ethyl, 2-(1-ethylpiperidin-4-yl)ethyl, 3-(1-methylpiperidin-4-yl)propyl, 3-(1-ethylpiperidin-4-yl)propyl, 4-(1-methylpiperidin-4-yl)butyl or 4-(1-ethyl-piperidin-4-yl)butyl, N-Cl-C4benzoylazacycloalk-3-yl-Cl-C7alkyl or -4-yl-Cl-C7alkyl, for example l-benzoylpiperidin-4-ylmethyl, 2-(1-benzoylpiperidin-4-yl)ethyl, 3-(1-benzoylpiperidin-4-yl)propyl or 4-(1-benzoylpiperidin-4-yl)butyl, diazacycloalk-l-yl-Cl-C7alkyl, N'-Cl-C4aL~cyldiazacycloalk-l-yl-Cl-C7alkyl or N'-C2-qalkanoylazacycloalk-1-yl-Cl-qalkyl, for example piperazino- or N'-methyl- or N'-acetyl-piperazino-methyl, 2-(pipcrazino- or N'-methyl- or N'-acetyl-piperazino)-ethyl, 3-(piperazino- or N'-methyl- or N'-acetyl-piperazino)-propyl or 4-(piperazino- or N'-methyl- or N'-acetyl-piperazino)-butyl, azoxacycloalk- l-yl-Cl-C7aLtcyl, for example morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl or 4-morpholinobutyl, 5- to 7-membered oxacycloalk-3-yl-Cl-qalkyl or -4-yl-Cl-C7aL~cyl, such as tetrahydropyran-4-ylmethyl, 2-(tetrahydropyran-4-yl)ethyl, 3-~tetrahydropyran-4-yl)propyl or 4-(tetrahydropyran-4-yl)butyl, S- to 7-membered azacycloalk-3-yl or -4-yl or 1-C2-q-alkanoylazacycloalk-3-yl or -4-yl, ~or exarnple piperidin-4-yl or 1-acetylpiperidin-4-yl, N-Cl-C4aLIcylazacycloalk-3-yl or -4-yl or N-benzoylazacycloalk-3-yl or -4-yl that is unsubstituted or substituted in the phenyl moiety, for example l-methylpipeAdin-4-yl or l-benzoylpiperidin-4-yl, or 5- to 7-membered oxacycloalk-3-yl or -4-yl, for example tetra-hydropyran-4-yl, and R2 is carboxy, Cl-C4alkoxycarbonyl, such as me~hoxycarbonyl or ethoxycarbonyl, 5- to 7-membered cycloaLIcoxycarbonyl, such as cyclopentyloxy- or cyclohexyloxy-carbonyl, or phenyl-Cl-C4aLIcoxycarbonyl that is unsubstituted or mono-or di-substituted by Cl-C4aLlcyl, such as methyl, Cl-C4alkoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlo~ne, cyano and/or by trifluoromethyl, such ~s benzyloxycarbonyl or 2-phenylcthoxycarbonyl, and their salts, especially their pharmaceutically acceptable salts.
~he invention relates especially, for example~ to compounds of formula I wherein Rl is hydroxy-Cl-C7aL~cyl, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl, Cl-C4aL~coxy-Cl-qalkyl, such as methoxymethyl, ethoxyme~hyl, 2-methoxyethyl, 2-ethoxye~hyl, 3-methoxypropyl or 4-methoxybutyl, a phenyl-Cl-C4aLIcoxy-Cl-C7allcyl group that is unsubstituted or mon~, di- or tri-substituted in the phenyl moiety by Cl-C4alkyl, such as methyl, Cl-C4aLkoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluoline or chlorine, cyano andlor by trifluoromethyl, such as a benzyloxymethyl, 2-benzyloxyethyl, 3-benzyloxypropyl or 4-benzyloxybutyl group, amino-Cl-C7alkyl, such as an~inomethyl, ~ ~ 2 ;, ~
2-arninoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl or 6-aminohexyl, Cl-C4aL~ylamino-Cl-C7aL~cyl, such as methylaminomethyl, ethylaminomethyl, propylaminomethyl, butylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl or 6-methylaminohexyl, C2-C7alkanoylamino-Cl-C7alkyl, such as acetylaminomethyl, propionylaminomethyl, butyrylaminomethyl, 2-acetylaminoethyl, 3-acetylaminopropyl, 4-acetylaminobutyl, 5-acetylaminopentyl or 6-acetylaminohexyl, di-Cl-C7alkylamino-Cl-C7alkyl, such as dimethylaminomethyl, diethylaminomethyl, N-ethyl-N-methylaminomethyl, N-methyl-N-propylaminomethyl, dipropylaminomethyl, dibutylaminomethyl, 2-dimethylaminoethyl, 3-di-methylaminopropyl, 4-dimethylaminobutyl, 5-dimethylarninopentyl or 6-dimethylaminohexyl, 5- to 7-membered N,N-(aza- or s:~xa-alkylene)amino-Cl-C7aL~yl, such as pyrrolidinomethyl, piperidinomethyl, morpholinomethyl, piperazino- or N'-methyl- or N'-acetyl-piperazino-methyl, 2-pyrrolidinoethyl, 2-piperidinoethyl, 2-morpholinoethyl, 3-pyrrolidinopropyl, 3-piperidinopropyl, 3-morpholinopropyl, 4-pyrro-lidinobutyl, 4-piperidinobutyl, 5-pyrrolidinopentyl, 5-piperidinopentyl or 6-piperidinohexyl, or halo-Cl-C7aL~cyl, such as halomethyl, 2-haloethyl, 3-halopropyl, 4-halobutyl, S-halopentyl or 6-halohexyl, in which halogerl is chlorine or, especially, fluorine, and R2 is carboxy, Cl-C4alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, 5- to 7-membered cycloaL1coxycarbonyl, such as cyclopentyloxy- or cyclohexyloxy-carbonyl, or phenyl-C~l-C4aLtcoxycarbonyl that is unsubstituted or mono-or di-substituted by Cl-C4aL~cyl, such as methyl, Cl-C4aLtcoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano and/or by trifluoromethyl, such as benzyloxycarbonyl or 2-phenylethoxycarbonyl, and their salts, especially their pharmaceutically acceptable salts.
.
The invention relates preferably to compounds of formula I whe~ein Rl is hydroxy-Cl-qalkyl, such as hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl, benzoyloxy-Cl-qaLlcyl that is unsubstituted or mono- or di-substi~uted in the phenyl moiety by Cl-C4alkyl, such as methyl, Cl-C~ oxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano andlor by tri-fluoromethyl, such as 2-benzoyloxyethyl, Cl-C4alkoxy-Cl-C7alkyl, such as ethoxymethyl or 2-methoxyethyl, phenyl-Cl-C4aLIcoxy-Cl-C7aL~yl that is unsubstituted or mono- or di-substituted in the phenyl moiety by Cl-C4aL~yl, such as methyl,( Cl-C4alkoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano and/or by tri~luoromethyl, such as benzyloxymethyl or 2-benzyloxyethyl, halo-Cl-C7alkyl, such as halomethyl or 2-haloethyl, in which 2l~2~g halogen is chlorine or, especially, fluorine, amino-C4-qalkyl, such as 4-aminobutyl or 6-aminohexyl, N-C2-C7aLkanoyl-N-Cl-C4aLkylarnino-Cl-C7alkyl, such as N-acetyl-N-methylaminometllyl, 5- to 7-membered azacycloalk-3-yl or -4-yl or 1-C2-C7-alk~moylazacycloalk-3-yl or -4-yl, for example piperidin-4-yl or 1-acetylpiperidin-4-yl, and R2 is carboxy, Cl-C4aLkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, or phenyl-Cl-C4aLkoxycarbonyl that is unsubstituted or mono- or di-substituted by Cl-C4aLkyl, such as methyl, Cl-C4aLkoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano and/or by trifluoro-methyl, such as benzyloxycarbonyl or 2-phenylethoxycarbonyl, and their salts, especially their pharmaceutically acceptable salts.
The invention relates especially, on the one hand, to compounds of formula I wherein R
is hydroxy-Cl-C4alkyl, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl, Cl-C4aLkoxy-Cl-C4alkyl, such as methoxymethyl, ethoxymethyl, 2-methoxyethyl, 3-methoxypropyl or 4-methoxybutyl, a phenyl-Cl-C4aLkoxy-Cl-C~aL~yl group that is unsubstituted or mono-, di- or tri-substituted in the phenyl moiety by Cl-C4-aLkyl, such as methyl, Cl-C4aLkoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano andlor by tri~luoromethyl, such as a benzyloxymethyl, 2-benzyloxyethyl, 3-benzyloxypropyl or 4-benzyloxybutyl group, or halo-Cl-C4aLlcyl, such as halomethyl, 2-haloethyl, 3-halopropyl, 4-halobutyl, 5-halopentyl or 6-halohexyl, in which halogen is chlorine or, especially, fluorine, and R2 is carboxy, Cl-~4aLIcoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, 5- to 7-membered cycloaLkoxycarbonyl, such as cyclopentyloxy- or cyclohexyloxy-carbonyl, or phenyl-Cl-C4aL~coxycarbonyl that is unsubstituted or mono- or di-substituted by Cl-C4alkyl, such as methyl, Cl-C4aL~coxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chloline, cyano and/or by trifluoromethyl, such as benzyloxycarbonyl or 2-phenylethoxycarbonyl, and their salts, especially their pharmaceutically acceptable salts.
The invention relates especially, on the other hand, to compounds of formula I wherein R
is amino-Cl-C7aL~cyl, such as aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl or 7-arninoheptyl, Cl-C4aL~ylamino-Cl-qalkyl, such as methylarninomethyl, ethylaminomethyl, propylaminomethyl, butylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl or ~methylaminohexyl, C2-c7aL~canoylamino-ci-qaLlcyl~ such as acetylaminomethyl, propionylaminomethyl, butyrylaminomethyl, 2-acetylaminoethyl, 3-acetylaminopropyl, 2~
4-acetylaminobutyl, 5-acetylaminopentyl or 6-acetylaminohexyl, di-C1-C4alkyl-amino-C1-qalkyl, such as dimethylarninomethyl, diethylaminomethyl, N-ethyl-N-methylaminomethyl, N-methyl-N-propylarninomethyl, dipropylaminomethyl, dibutyl-aminomethyl, 2-dimethylaminoethyl, 3-dimethylan~inopropyl, 4-dimethylaminobutyl,5-dimethylaminopentyl or 6-dimethylaminohexyl, 5- to 7-membered N,N-(aza- or oxa-alkylene)amino-Cl-C7alkyl, such as pyrrolidinomethyl, piperidinomethyl, morpholinomethyl, piperazino- or N'-rnethyl- or N'-acetyl-piperazino-methyl, pyrrolidinoethyl, piperidinoethyl, morpholinoethyl, pyrrolidinopropyl, piperidinopropyl, morpholinopropyl, pyrrolidinobutyl, piperidinobutyl, pyrrolidinopentyl, piperidinopentyl or piperidinohexyl, and R2 is carboxy, Cl-C4aLtcoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, 5- to 7-membered cycloalkoxycarbonyl, such as cyclopentyloxy- orcyclohexyloxy-carbonyl, or phenyl-Cl-C4aL~coxycarbonyl that is unsubstituted or mono-or di-substituted by C1-C4aL~yl, such as methyl, C1-C4aL~coxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano andlor by trifluoromethyl, such as benzyloxycarbonyl or 2-phenylethoxycarbonyl, and their salts, especially their pharmaceutically acceptable salts.
The invention relates more especially to compounds of formula I wherein R1 is hydroxy-Cl-C7aLtcyl, such as hydroxymethyl, Cl-C4alkoxy-Cl-C7alkyl, such as methoxymethyl, ethoxymethyl or 2-methoxyethyl, benzoyloxy-Cl-C4alkyl, such as 2-benzoyloxyethyl, phenyl-C1-C4aL~coxy-C1-C7a1kyl, such as benzyloxymethyl or 2-benzyloxyethyl, amino-c4-qaLlcyl~ such as 4-aminobutyl or 6-arninohexyl, N-C2-C7-alkanoyl-N-cl-c4allcylamino-c2-qaLkyl~ such as 2-(N-acetyl-N-methylamino)ethyl, 5-to 7-membered azacycloaLl~-3-yl or -4-yl or 1-C2-C7aL~canoylazacycloaLIc-3-yl or -4-yl, such as piperidin-4-yl or 1-acetylpipelidin-4-yl, or halo-C1-C4aL~cyl, in which halogen is chlorine or, especially, ~luorine, such as 2-haloethyl, and R2 is carboxy or Cl-C4aLIcoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, and their salts, especially their pha~maceutically acceptable salts.
The invention relates preferably, on the one hand, to compounds of formula I wherein R
is amino-C4-qaL~cyl, such as 4-arninobutyl or ~aminohexyl, N-Cl-C4-alkanoyl-N-Cl-C4alkylamino-Cl-qaL~yl, pipe~idin-4-yl or 1-C 2-C7aLlsanoyl-piperidin-4-yl, such as 1-acetylpiperidin-4-yl, and R2 is carboxy or C1-C4alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, and their salts.
The invention relates preferably, on the other hand, to compounds of formula I wherein R
is Cl-C4alkoxy-Cl-C4alkyl, such as methoxymethyl, ethoxymetllyl or 2-methoxyethyl, phenyl-Cl-C4alkoxy-Cl-C4alkyl7 such as benzyloxymethyl or 2-benzyloxyethyl, benzoyloxy-Cl-C4alkyl, such as 2-benzoyloxyethyl, hydroxy-Cl-C4alkyl, such as hydroxymethyl or 2-hydroxyethyl, or halo-C2-C4allcyl, such as 2-fluoroethyl, and R2 is carboxy or Cl-C4alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, and their s~llts.
The invention relates very especially, on the one hand, to compounds of ~ormula I wherein Rl is amino-C4-qalkyl, such as 4-aminobutyl, S-aminopentyl, ~aminohexyl or 7-amino-heptyl, and R2 is carboxy, Cl-C4aLkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, or a phenyl-Cl-C4aLkoxycarbonyl group that is unsubstituted or mono- or di-substi~uted by Cl-C4aLkyl, such as methyl, Cl-C4aL~coxy, such as me~hoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano andJor by trifluoromethyl, such as a benzyloxycarbonyl or 2-phenylethoxycarbonyl group, and their salts, especially their pharmaceutically acceptable salts.
The invention relates very especially, on the other hand, to compounds of formula I
wherein Rl is Cl-C4aLkoxy-C2-C4aLI<yl, such as 2-methoxyethyl, 2-ethoxyethyl, 3-meehoxypropyl or 4-methoxybutyl, hydroxy-C2-C4aLkyl, such as 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl, or halo-C2-C4aLlcyl, such as 2-fluoroethyl, 2-chloroethyl, 3-fluoropropyl or 4-fluorobutyl, and R2 is carboxy, Cl-C4aLIcoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, or a phenyl-Cl-C4aLkoxycarbonyl group that is unsubstituted or mono- or di-substituted by Cl-C4aLlcyl, such as methyl, Cl-C4aLlcoxy, such as methoxy, halogen having an atomic number of up to and including 35, such as fluorine or chlorine, cyano and/or by trifluoromethyl, such as a benzyloxycarbonyl or 2-phenylethoxycarbonyl group, and their salts, especially their pharmaceuticallyacceptable salts.
The invention relates specifically to the compounds of formula I mentioned in the Examples and their salts, especially their pharmaceutically acceptable salts.
The process for the preparation of the compounds according to the invention is as follows:
in a compound of formula II
.
2 ~ 2 ~
Z~ /~ R2 wherein Zl. Z2 are optionally protected hydroxy, Z3 is an aliphatic hydrocarbon radical that is substituted by optionally protected or acylated or aliphatically or araliphatically etherified hydroxy, by halogen, by optionally protected or acylated and/or aliphatically substituted amino or by an aza-, diaza-, azoxa- or oxa-cycloaliphatic radical, or is an oxacycloaliphatic hydrocarbon radical bonded via a carbon atom, or is an optionally protected or aliphatically N-substituted or N-acylated azacycloaliphatic hydrocarbon radical, and Z4 is protected arnino, protected amino Z4 and, if present, protected amino as a constituent of Z3 is converted into amino and, if present, protected hydroxy Zl. Z2 and/or protected hydroxy as a constituent of :Z3 is converted into hydroxy and, if present, a protected azacycloaliphatic hydrocarbon radical Z3 is freed and, if desired, a resulting compound is converted into a different compound of formula I, an isomeric rnixture obtainable in accordance with the process is separated into its components and the preferred isomer is separated, andlor a free compound obtainable in accordance with the process is converted into a salt or a salt obtainable in accordance with the process is converted into the corresponding free compound.
In starting materials of formula II, protected hydroxy Zl andJor Z2 is, for example, etheri~led, especially aliphatically or aromatically etheri~led, hydroxy, protected hydroxy Z3 is, for exarnple, acylated or silylated hydroxy, and protected amino Z4 and, if present, protected amino as a constituent of Z3 is, for exarnple, acylated amino.
Aliphatically etheriffed hydroxy is, for example, iower aLtcoxy, such as me~hoxy, ethoxy or, especially, isopropoxy. Aromatically etherified hydroxy is, for example, phenoxy that is unsubstituted or substituted by lower aLkyl, lower alkoxy, halogen, cyano andlor by nitro.
Acylated hydroxy contains as the acyl group, for example, the acyl radical of anaraliphatic carboxylic acid or of a semi-ester of carbonic acid and is, for example, lower alkanoyloxy or a phenyl-lower aLlcanoyloxy or phenyl-lower aLlcoxycarbonyloxy group ~hat is unsubstituted or substituted in the phenyl moiety by lower aLIcyl, lower aL~coxy, halogen, cyano and/or by trifluoromethyl, for example benzyloxycarbonyloxy.
2 ~
Silylated hydroxy is, for example, tri-lower alkylsilyloxy, for example trimethyl- or tributyl-silyloxy.
Acylated amino contains as the acyl group, for example, acyl derived from a suitable organic acid, such as forrnic acid, or from an araliphatic or aromatic semi-ester of carbonic acid. Accordingly, acylated amino is, for exarnple, formylamino, lower alkoxycarbonylamino, such as methoxy-, ethoxy- or tert.-butoxy-carbonylamino, or a phenyl-lower aL'coxycarbonylamino or or phenoxycarbonylamino group that is unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, halogen, cyano and/or by nitro, such as benzyloxycarbonylamino, substituted by lower aLIcyl, lower alkoxy, halogen, cyano and/or by nitro.
The freeing of the protected groups ~rom compounds of formula II, i.e. of hydroxy from protected hydroxy groups Zl, Z2 and/or from protected hydroxy groups as a constituent of Z3, or of amino from protected amino groups ~4 and, if present, from protected amino groups as a constituent of Z3, is carried out, for example, by treatment with an acidic agent, for example with a tri-lower aLkylhalosilane, such as trimethylbromosilane, tributylbromosilane or trimethyliodosilane. The operation is preferably carried out in an inert solvent, such as a halogenated aliphatic hydrocarbon, for example dichloromethane or, secondly, tri- or tetra-chloromethane, trichloroethane or tetrachloroethane, for example in a temperature range of frorn approximately -25 ~o approximately +50C, preferably of approximately from 0 to 30C, for example at room temperature, i.e. at approximately from 15 to 25C, advantageously under substantially anhydrous condi~ions and under an inert gas, such as argon or nitrogen. Working up is preferably carried out with the addition of a hydrogen halide acceptor, especially an aliphatic epoxy compound, such as an `epoxy-lower aLIcane, for example propylene oxide in a lower aL4anol, such as ethanol.
In a prefelred form, for example compounds of formula II wherein Zl and Z2 are lower alkoxy, for example isopropoxy, and Z4 is lower aLkanoylamino, such as formylamino, are used as starting materials and are treated in an aliphatic halogenated hydrocarbon, such as dichloromethane, at from approximately 15 to approxirnately 25C, with a tri-lower alkylbromosilane, such as ~imethylbromosilane or tributylbromosilane; the rnixture is left for a time, for example from 2 to 30 hours, to complete the reaction, and then an ethanolic solution of propylene oxide is added and the product is removed by filtration.
~2.~u~
Starting materials of formula II are prepared, for example, by reacting an a,~-unsaturated aldehyde of forrnula IIa ~0 z~ (IIa) with an (x-isocyanoacetic acid ester of forrnula IIb :C~ N ~- R2 (IIb) in a manner known Per se9 for example in the presence of a copper or gold catalyst, for example copper(I) oxide or bis(cyclohexylisocyanide)gold(I) tetrafluoroborate, to give the corresponding S-substituted 2-oxazoline-4-carboxylic acid ester of forrnula IIc z3 =< ~J?2 ---~ (IIc) O~N
conYerting the ester of formula IIc by hydrolysis, for example in aqueous tetrahydrofuran, into the corresponding open-chained ester of formula IId OH
"R2 (IId~, NHCH=O
converting the ester of formula IId by treatment with thionyl brornide in a manner known per se into the corresponding ~bromic ester of formula IIe B r CH2 ~R2 (~e) Z3 NHC~=O
~a2~?s and reacting the ester of formula IIe further in a manner known ~ se with a phosphorous acid triester of the formula P(Za)(Zb)(ZC), wherein Za. Zb and ~c are identical or different hydroxy groups protected in an ether form, such as a tri-lower alkyl phosphite, for example triisopropyl phosphite, to give the corresponding compound of formula II' o Z \ ~ R2 Z3 NHCH=O
Compounds obtainable in accordance with the process can be converted in customary manner into different compounds of formula I.
For example, free and esterified carboxy groups R2 can be converted in customary manner into one another. In particular, esterified carboxy R~ can be converted into carboxy by hydrolysis, or free carboxy R2 can be converted into esterified carboxy by reaction with an alcohol. Furthermore, esterified carboxy R2 can be transesterified to form a different esterified carboxy group. These transesterification reactions are carried out in customary manner under hydrolytic, alcoholytic or transesterifying conditions.
The hydrolysis of carboxylic acid esters (I; R2 = esterified carboxy) is carried out in customary manner, if necessary in the presence of an acidic or basic agent, such as a mineral acid, for example hydrochloric acid or sulfuric acid, or a base, such as an aLlcali metal hydroxide, for example sodium hydroxide.
The transesterification of esters (I; R2 = esterified carboxy) with alcohols is usually carried out under conditions of acid-catalysis or base-catalysis, fo} example in the presence of a catalytic amount of a mineral acid, such as hydrochloric acid or sulfuric acid, or of a metal base, such as sodium hydroxide, or by employing the alcohol component in the form of a metal alcoholate, for example an aLkali metal alcoholate.
Furthermore, in aliphatic hydrocarbon radicals substituted by araliphatically etherified hydroxy, such as a-phenyl-lower aL~coxy-lower aLIcyl radicals Rl, the a-phenyl-lower alkoxy group can be converted into hydroxy by reduction, for example by treatment wi~
hydrogen in the presence of a hydrogenation catalyst, such as palladium-on-carbon or Raney nickel.
-21- 202~
Resulting salts can be converted into the free compounds in a manner known Per se, for example by treatment with a base, such as an aLkali metal hydroxide, a metal carbonate, a metal hydrogen carbonate or ammonia, or with another salt-forming base mentioned at the beginning, or with an acid, such as a mineral acid, for example hydrochloric acid, or another salt-forming acid mentioned at the beginning.
Resulting salts can be converted into different salts in a manner known 1~ se, in the case of acid addition sal~s, for example, by treatment with a suitable metal salt, such as a sodium, barium or silver salt, of a different acid in a suitable solvent in which an inorganic salt being formed is insoluble and therefore is eliminated from the reaction equilibrium, and in the case of base salts, by freeing the free acid and converting it into a salt again.
The compounds of formula I, including their salts, may also be obtained in the form of hydrates or include the solvent used for crystallisation.
In view of the close relationship between the novel compounds in free form and in the form of their salts, hereinbefore and hereinafter any reference to the free compounds or their salts should be understood as including also the corresponding salts or free compounds, respectively, where appropriate and expedient.
Resulting diastereoisomeric mixtures and mibctures of racemates can be separated into the pure diastereoisomers and racemates in known manner on the basis of the physicochemical differences between the constituents, for example by chromatography and/or fractional crystallisation. -Furthermore, resulting racemates can be separated into the optical antipodes by knownmethods, for example by recrystallisation from an optically active solvent, with the aid of microorganisms, or by reaction of the resulting diastereoisomeric mixture or racemate with an optically active auxiliary compound, for example, according to the acid, basic or functionally modifiable groups contained in compounds of formula I, with an optically active ~cid, base or an optically active alcohol, ~o form mixtures of diastereoisomeric salts or functional derivatives, such as esters, and separation thereof into the diastereoisomers from which the desired enantiomer can be freed in the customary manner. Suitable bases, acids and alcohols are, for example~ amino acids, especially lysine, optically active alkaloid bases, such as strychnine, cinchonine or brucine, or ~ or L-(1-phenyl)ethylarnine, 2 ~
3-pipecoline, ephedrine, amphetamine and similar synthetically obtainable bases, optically active carboxylic or sulfonic acids, such as quinic acid or ~ or L-tartaric acid, D- or L-di-o-toluyltartaric acid, D- or L-malic acid, ~ or L-mandelic acid or D- or L-camphor-sulfonic acid, and optically active alcohols, such as borneol or ~ or L-~l-phenyl)ethanol.
The invention relates also to those forms of the process in which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaiDing steps are carried out, or in which a starting material is used in the form of a salt or, especially, is formed under the reaction conditions.
The invention relates also to the novel starting materials developed specifically for the preparation of the compounds according to the invention, especially to those starting materials resulting in the compounds of forrnula I that were described at the beginning as being preferred, to processes for the preparation thereof and to their use as interrnediates.
The novel compounds of folmula I can be used, for example, in the form of pharmaceutical preparations that contain a therapeutically effective amount of the active ingredient, optionally together with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers, which are suitable for enteral, e.g. oral, or parenteral administration.
There are used, for example, tablets or gelatin capsules that contain the active ingredient together with diluents, for exarnple lactose, dextrose, saccharose, mannitol, sorbitol, cellulose, and/or lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Tablets can also contaun binders, for example magnesium aluminium silicate, starches, such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, for example sodium alginate, and/or effervescent mixtures, or absorbents, colouring agents, flavourings and sweeteners. The novel compounds offormula 1 can also be used in the form of parenterally administrable preparations or in the form of infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions which, for example in the case of lyophilised preparations that con~ain the active ingredient on its own or together with a calTier, for example mannitol, can be prepared before use. The pharmaceutical preparations may be sterilised and/or may contain adjuncts, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers. The pharmaceutical preparations in question, which, if desired, may contain further pharmacologically active 2Q2~
su~stances, are prepared in a manner known ~ se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes, and contain approximately from 0.1 % to 100 %, especially from approximately 1 % to approximately 50 %, in the case of lyophilisates up to approximately 100 %, active ingredient.
The invention relates also to the use of the compounds of formula I, preferably in the form of pharmaceutical preparatiolls. The dosage may depend on various factors, such as the mode of administration and the species, age and/or individual condition. The daily doses are, in the case of oral administration, from approximately 0.25 to approximately 10 mg/kg, and in the case of warm-blooded animals having a body weight of approximately 70 kg, they are preferably from approximately 20 mg to approximately 500 mg.
The following Exarnples illustrate the invention; temperatures are given in degrees Celsius and pressures in mbar.
Example 1: 3.57 g (8.5 mrnol) of 6-acetoxy-4-diisopropylphosphono-methyl-2-forrnylamino-hex-3-enoic acid ethyl ester are dissolved in 22 ml of dichloro-methane, and 4.4 ml (34 mmol) of trimethylbromosilane are added dropwise at roomtemperature. The mix~ure is left to stand at room temperature for 22 hours, ~2 ml of ethanol are added dropwise, the mixture is left to stand for a further 22 hours and is con-centrated by evaporation in a rotary evaporator, the residue is dissolved in 22 ml of ethanol, and a mixture of 22 ml of propylene oxide and 22 rrl of ethanol is added drop-wise. A suspension forms, which is stirred for a fu~ther 90 rninutes and then filtered with suction. 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester having a melting point of 195 (decomp.) is obtained.
The starting material can be prepared, for example, as follows:
13.0 g (100 mmol) of acetic acid (4-oxo)bu~yl ester, 92.0 g (112.6 mmol) of dimethylammonium chloride and 10.8 ml (117 mmol) of 37 % formaldehyde solution are heated at 100 ~or one hour with stirring. The mixture is allowed to cool and is extracted 3 times with 30 ml of diethyl ether each time. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness by evaporation. Acetic acid (3-formyl)but-3-enyl ester is obtained in the form of a colourless oil which can be reacted further without further purification.
2 ~ 2 ~
13.5 g (95 mmol) o~ acetic acid (3-formyl)but-3-enyl ester and 10.4 g (9S mmol) of isocyanoacetic acid ethyl ester are added dropwise to a suspension of 0.38 g of copper(I) oxide in S0 ml of benzene. When the exothermic reaction has subsided, the mixture is stirred at room temperature for a further 45 minutes, filtered over Hyflo(~ and concentrated to dryness by evaporation. The residue is taken up in 75 ml of tetrahydro-furan, 25 ml of water are added, and the mixture is heated under reflux for 4 hours with stirnng. The mixture is concentrated to dryness by evaporadon and chromatographed on silica gel with toluene/isopropanol (9:1) as eluant.
6-acetoxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester is obtained in the form of a brownish oil.
9.19 g (35.9 mmol) of 6-acetoxy-2-formylamino-3-hydroxy-4-methylene-hexanoi~ acid ethyl ester are dissolved in 100 ml of dichloromethane, and 3.34 ml (43.1 mmol) of thionyl bromide are added dropwise at room temperature. After one hour, 10 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, saturated potassium hydrogen carbonate solution and again with water, dried over magnesium sulfate, filtered and concentrated by evaporation. 6-acetoxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a brownish oil.
8.7 g (25 mmol) of 6-acetoxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester and 21 ml (75 mmol) of triisopropyl phosphite (90 %) are heated to from 80 to 90C and stirred for 19 hours under a pressure of approximately 100 mbar. The excess triisopropyl phosphite is distilled off and the evaporation residue is chromatographed on 150 g of silica gel with first ethyl acetate and then ethyl acetate/ethallol (9:1) as eluants. 6-acetoxy-4-diisopropylphosphonomethyl-2-formylamin~hex-3-enoic acid ethyl ester is obtained in the form of a yellowish oil.
ExamDle 2: 0.415 g (1.55 mmul) of 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester is heated under reflux in 3 ml of water for 24 hours. The reaction mixture is concentrated by evaporation, purified by chromatography on 10 g of silica gel with ethanoVwater (1:1) as eluant, and crystallised from e~hanol.
2-arnino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid having a melting point >300 is obtained.
2~2~v~
Example 3: 0.5 g (1.0 mmol) of 8-(N-benzyloxycarbonylamino)-4-diethylphosphonomethyl-2-formylamino-oct-3-enoic acid methyl ester is heated under reflux in 5.0 ml of 6N hydrochloric acid for 6 hours. Concentration to dryness by evapora-tion yields 2,8-diamino-4-phosphonomethyl-oct-3-enoic acid dihydrochloride in the form of a rubber-like solid which is recrystallised from acetonitrile; m.p. 128 (decomp.).
The starting rmaterial can be prepared as follows:
7.06 ml (47 mmol) of chloroformic acid benzyl ester are added dropwise to a solution of 5.52 g (47 mmol) of 6-aminohexan-1-ol and 3.95 g (47 mrnol) of sodium hydrogen caIbonate in 100 ml of acetone and SU ml of water. The mixture is stirred at room temperature for 18 hours and concentrated to approximately 70 ml, and the white precipitate is filtered off, washed with approximately 20 ml of water, taken up in 250 ml of methylene chloride and dried over magnesium sulfate; the magnesium sulfate is filtered off and the residue is concentrated to dryness by evaporation. 6-(N-benzyloxyca~bonyl-amino)hexan-l-ol is obtained in the form of white crystals having a melting point of 58-60.
0.32 ml (4.40 mrnol) of dimethyl sulfoxide is added dropwise under nitrogen to a solution of 0.19 ml (2.20 mmol) of oxalyl chloride in 10 ml of methylene chloride which is being stirred at -50. The mixture is stirred for 15 minutes, and then 0.5 g (2 mrnol) of 6-(N-benzyloxycarbonylamino)hexan-l-ol is added. Stirring is continued at -50 for 25 minutes, 1.78 ml ~10 mmol) of N-ethyl-N,N-diisopropylamine are added dropwise and the mixture is poured into 10 ml of ice-water. The organic phase is separated off and the aqueous phase is extracted with 10 ml of methylene chlonde. The organic phases are combined, washed twice with S ml of N-hydrochloric acid each time and once with 10 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness by evaporation. The resulting oil is purified by chromatography on silica gel with hexanelethyl acetate (1:1) as eluant. 6-(N-benzyloxycarbonylamino)hexanal is obtained.
2.44 g (30 mmol) of 37 % aqueous formaldehyde solution are added to a solution of 1.5 g (17 mmol) of anhydrous piperazine and 2.03 g (34 mmol) of acetic acid in 18.7 ml of water. The mixture is sti~red at 25 for 15 minutes, and then 7.48 g (30 mmol) of 6-(N-benzyloxycarbonylamino)hexanal are added thereto. The reaction mixture is heated under reflux for 2 hours and then cooled with ice-water and extracted twice with 50 ml of methylene chloride each time. The extracts are combined, washed twice with 25 ml of ~ 3 ~J .~
saturated sodium hydrogen carbonate solution each eime and with 25 ml of saturated sodium chloride solution, dried and concentrated to dryness by evaporation.
6-(N-benzyloxycarbonylarnino)-2-methylene-hexanal is obtained in the form of a yellowish liquid.
4.0 g (15.3 mmol) of 6-(N-benzyloxycarbonylamino)-2-methylene-hexanal and 1.62 ml (16.8 mmol) of isocyanoacetic acid methyl ester are dissolved in 50 ml of toluene and added dropwise at 40 to a suspension of 0.12 g of 96.4 % copper(I) oxide in 50 ml of toluene. The mixture is then stirred at room temperature for 2.5 hours, filtered, introduced into a column filled with 6û g of silica gel and extracted first with hexane/ethyl acetate (1:1) and then with ethyl acetate.
5-[6-(N-benzyloxycarbonylamino)hex-l-en-2-yl]-oxazoline-4-carboxylic acid methyl ester is obtained; oil.
ExamDle 2: 0.415 g (1.55 mmul) of 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester is heated under reflux in 3 ml of water for 24 hours. The reaction mixture is concentrated by evaporation, purified by chromatography on 10 g of silica gel with ethanoVwater (1:1) as eluant, and crystallised from e~hanol.
2-arnino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid having a melting point >300 is obtained.
2~2~v~
Example 3: 0.5 g (1.0 mmol) of 8-(N-benzyloxycarbonylamino)-4-diethylphosphonomethyl-2-formylamino-oct-3-enoic acid methyl ester is heated under reflux in 5.0 ml of 6N hydrochloric acid for 6 hours. Concentration to dryness by evapora-tion yields 2,8-diamino-4-phosphonomethyl-oct-3-enoic acid dihydrochloride in the form of a rubber-like solid which is recrystallised from acetonitrile; m.p. 128 (decomp.).
The starting rmaterial can be prepared as follows:
7.06 ml (47 mmol) of chloroformic acid benzyl ester are added dropwise to a solution of 5.52 g (47 mmol) of 6-aminohexan-1-ol and 3.95 g (47 mrnol) of sodium hydrogen caIbonate in 100 ml of acetone and SU ml of water. The mixture is stirred at room temperature for 18 hours and concentrated to approximately 70 ml, and the white precipitate is filtered off, washed with approximately 20 ml of water, taken up in 250 ml of methylene chloride and dried over magnesium sulfate; the magnesium sulfate is filtered off and the residue is concentrated to dryness by evaporation. 6-(N-benzyloxyca~bonyl-amino)hexan-l-ol is obtained in the form of white crystals having a melting point of 58-60.
0.32 ml (4.40 mrnol) of dimethyl sulfoxide is added dropwise under nitrogen to a solution of 0.19 ml (2.20 mmol) of oxalyl chloride in 10 ml of methylene chloride which is being stirred at -50. The mixture is stirred for 15 minutes, and then 0.5 g (2 mrnol) of 6-(N-benzyloxycarbonylamino)hexan-l-ol is added. Stirring is continued at -50 for 25 minutes, 1.78 ml ~10 mmol) of N-ethyl-N,N-diisopropylamine are added dropwise and the mixture is poured into 10 ml of ice-water. The organic phase is separated off and the aqueous phase is extracted with 10 ml of methylene chlonde. The organic phases are combined, washed twice with S ml of N-hydrochloric acid each time and once with 10 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness by evaporation. The resulting oil is purified by chromatography on silica gel with hexanelethyl acetate (1:1) as eluant. 6-(N-benzyloxycarbonylamino)hexanal is obtained.
2.44 g (30 mmol) of 37 % aqueous formaldehyde solution are added to a solution of 1.5 g (17 mmol) of anhydrous piperazine and 2.03 g (34 mmol) of acetic acid in 18.7 ml of water. The mixture is sti~red at 25 for 15 minutes, and then 7.48 g (30 mmol) of 6-(N-benzyloxycarbonylamino)hexanal are added thereto. The reaction mixture is heated under reflux for 2 hours and then cooled with ice-water and extracted twice with 50 ml of methylene chloride each time. The extracts are combined, washed twice with 25 ml of ~ 3 ~J .~
saturated sodium hydrogen carbonate solution each eime and with 25 ml of saturated sodium chloride solution, dried and concentrated to dryness by evaporation.
6-(N-benzyloxycarbonylarnino)-2-methylene-hexanal is obtained in the form of a yellowish liquid.
4.0 g (15.3 mmol) of 6-(N-benzyloxycarbonylamino)-2-methylene-hexanal and 1.62 ml (16.8 mmol) of isocyanoacetic acid methyl ester are dissolved in 50 ml of toluene and added dropwise at 40 to a suspension of 0.12 g of 96.4 % copper(I) oxide in 50 ml of toluene. The mixture is then stirred at room temperature for 2.5 hours, filtered, introduced into a column filled with 6û g of silica gel and extracted first with hexane/ethyl acetate (1:1) and then with ethyl acetate.
5-[6-(N-benzyloxycarbonylamino)hex-l-en-2-yl]-oxazoline-4-carboxylic acid methyl ester is obtained; oil.
9.4 g (26.1 mmol) of 5-[6-(N-benzyloxycarbonylarnino)hex-l-en-2-yl]-oxazoline-4-carboxylic acid methyl ester are dissolved in 40 ml of tetrahydrofuran and 20 ml of water, a few drops of triethylamine are added and the mixture is heated under reflux for 18 hours. The solvent is removed under reduced pressure and the oil that remains is taken up in a total of 125 ml of methylene chloride, dried ovçr magnesium sulfate and concentrated to dryness by evaporation. 8-(N-benzyloxycarbonylarn~no)-2-formylamino-3-hydroxy-4-methylene-octanoic acid methyl ester is obtained.
To 2.46 g (6.5 mmol) of 8-(N-benzyloxycarbonylarnino)-2-formyl-amino-3-hydroxy-4-methylene-octanoic acid methyl ester in 25 ml of tetrahydrofuran there are added S.S ml (46 mmol) of hexa-1,5-diene and then, dropwise at -50, 2.6 ml (32.5 mmol) of thionyl bron~ide. The mixture is stirred at from 0 to 5 for 2 hours, poured into 25 ml of ice-cold saturated sodium hydrogen carbonate solution and extracted twice with 20 ml of methylene chloride each time. The organic phase is washed with 10 ~nl of saturated sodium chloride solution, dried over magnesium sulfate and concen-trated to dryness by evaporation. The resulting oil is purified by chromatography on silica gel with hexane/ethyl acetate (3:1). 8-(N-benzyloxycarbonylamino~-4-bromomethyl-2-formylamino-oct-3-enoic acid methyl ester is obtained.
5 ml of triethyl phosphite are added to 1.45 g (3.3 mmol) of 8-(N-benzyloxycarbonylamino)-4-bromomethyl-2-formylamino-oct-3-enoic acid methyl 2 3 ~
ester, and the mixture is heated at 75 for 8 hours with stirring. The excess triethyl phosphite is distilled off under reduced pressure to give an oily residue which is purified by chromatography on a silica gel column with first ethyl acetate and then ethylacetate/methanol (9:1). 8-(N-benzyloxycarbonylamino)-4-diethylphosphonomethyl-2-formylamino-oct-3-enoic acid methyl ester is obtained.
Exarnple 4: 1.77 g (4.5 mmol) of 4-diisopropylphosphonomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester are dissolved in 12 ml of dichloromethane, and 2.32 ml (18.0 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 22 hours, 12 ml of ethanol are added dropwise, the mixture is left to stand for a furiher 24 hours and is concentrated by evaporation in a rotary evaporator, the residue is dissolved in 10 ml of ethanol, and a mixture of 2 ml of propylene oxide and 2 ml of ethanol is added. A
suspension forms, which is s~irred for a fur~her 2 hours at room temperature and for 2 hours wi~h ice cooling, and is then filtered with suction. 2-amino-6-methoxy-4-phos-phonomethyl-hex-3-enoic acid ethyl ester having a melting point of 242 (decomp.) is obtained.
The starting material can be prepared, for exarnple, as follows:
19.7 g (193 mmol) of 4-methoxybutanal, 17.7 g (217 mmol) of dimethylammonium chloride and 17.0 ml (226 mmol) of 37 % formaldehyde solution are heated at 100 for 3 hours with stirring. The mixture is allowed to cool and is extracted 3 times with diethyl ether. The organic phases are washed with saturated sodium chloride solution, combined, dried over sodium sulfate, filtered and concentrated to dryness by evaporation.
4-methoxy-2-methylenebutanal is obtained in ~he form of a yellowish oil which can be further reacted without further purification.
16.5 g (144.5 mmol) of 4-methoxy-2-methylenebutanal and 15.8 ml (144.5 mmol) of isocyanoacetic acid ethyl ester are dissolved in 145 ml of toluene, and 400 mg of copper(I) oxide are added. When the exothermic reaction has subsided, the mixture is stirred for a further 2 hours, filtered over Hyflo~) and concentrated to dryness by evaporation. The residue is talcen up in 145 ml of tetrahydrofuran, 33 ml of water are added, and the mixture is heated under reflux for 2 hours with stirring. The mixture is concentrated to dryness by evaporation, toluene is added, and the mixture is again concentrated by evaporation.
Chromatography on silica gel with toluene/ethanol ~95:5) as eluant yields 2-formyl-.
~ 3 ~ 1j v ~J ,~
amino-3-hydroxy-S-methoxy-4-methylene-hexanoic acid ethyl ester in the form of areddish-brown oil.
19.0 g (77.5 mmol) of 2-formylamino-3-hydroxy-6-methoxy-4-methylene-hexanoic acid ethyl ester are dissolved in 190 ml of 1,2-dichloroethane, ~md 7.20 ml (93.0 mmol) of thionyl bromide are added dropwise at room temperature. After 45 minutes, 100 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, lN potassium hydrogen carbonate solution and again with water, dried over sodium sulfate, ~lltered and concentrated by evaporation. 4-bromomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester is obtained in the form of a reddish-brown oil.
3.38 g (11.0 mmol) of 4-bromomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester and 12.0 ml (44 mmol) of triisopropyl phosphite (96 %) are heated to 80 and stirred under a pressure of approximately 130 m~ar ~or 18 hours. The excess triisopropylphosphite is distilled off under reduced pressure and the evaporation residue is purified by chromatography on silica gel with ethyl acetate. 4-diisopropylphosphonomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish oil.
Exam~le S: 0.98 g (3.5 rnmol) of 2-amino-6-methoxy-4-phosphonomethyl-hex-3-enoicacid ethyl ester is heated under reflux in ? ml of water for 17 hours. The Teaction mixture is concentrated by evaporation and crystallised from a mixture of water and ethanol.
2-amino-~methoxy-4-phosphonomethyl-hex-3-enoic acid having a melting point of 214C (decomp.) is obtained.
Example 6: 0.52 g (1.36 rnmol) of 4-diisopropylphosphono-methyl-6-fluoro-2-formylarnino-hex-3-enoic acid ethyl ester is dissolved in 3.5 ml of dichloromethane, and 0.7 ml (5.45 mmol) of trimethylbromosilane is added dropwise at room temperaturç. The mixture is left to stand at room temperature for 24 hours, 3.5 ml of ethanol are added dropwise, the mixture is left to stand for a further 24 hours and is con-centrated by evaporation in a rotary evaporator, the residue is dissolved in 2.4 ml of ethanol, and a mixture of 0.6 ml of propylene oxide and 0.6 ml of ethanol is added. A
suspension forms, which is stirred for a further 2 hours at room temperature and for 2 hours with ice cooling and is then ~lltered with suction. 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid ethyl ester having a melting point of 222 (decomp.) 2~2~
is obtained.
The starting material can be prepared, for example, as follows:
2.4 g (26.6 rnrnol) of 4-fluorobutanal, 2.44 g (30.0 mmol) of dimethylammonium chloride and 2.34 ml (31.1 mrnol) of 37 % forrnaldehyde solution are heated at 100 for 2 hours with stirring. The mixture is allowed to cool and is extracted 3 times with diethyl ether.
The organic phases are washed with saturated sodium chloride solution, combined, dried over sodium sulfate, filtered and concentrated to dryness by evaporat;on.
4-fluoro-2-methylenebutanal is obtained in the form of a yellowish oil which can be reacted further without further purification.
1.43 g (14.0 mrnol) of 4-fluoro-2-methylenebutanal and 1.53 ml (14.0 mmol) of isocyanoacetic acid ethyl ester are dissolved in 14 ml of toluene, and 40 mg of coppera) oxide are added. When the exotherrnic reaction has subsided, the rnixture is stirred for a further 2 hours, filtered over Hyflo~ and concentrated to dryness by evaporation. The residue is taken up in 14 rnl of tetrahydrofuran, 3.1 rnl of water are added, and the mixture is heated under reflux for 2 hours with stirring. The mixture is concentrated to dryness by evaporation, toluene is added, and the rnixture is again concentrated by evaporation.
Chromatography on silica gel with toluene/ethyl acetate (1:1) as eluant yields 6-fluoro-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester in the form of a dark-yellow oil.
1.40 g (6.0 mmol) of 6-fluoro-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 14 ml of 1,2-dichloroethane, and 0.56 ml (7.2 mmol) of thionyl bromide is added dropwise at room temperature. After 45 minutes, 12 ml of water are added and the mixh~e is stirred vigorously for 15 minutes. The organic phase is separated off, washed in succession with water, lN potassium hydrogen carbonate solution and again with water, dried over sodium sulfate, filtered and concentrated by evaporation.
4-bromomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl es~er is obtained in the form of a brownish-yellow oil.
1.43 g (4.82 mrnol) of 4-bromomethyl-6-fluoro~2-formylamino-hex-3-enoic acid ethyl ester and 5.3 ml ~19 mmol) of triisopropyl phosphite (96 %) are heated to 80 and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropylphosphite is distilled off under reduced pressure and the evaporation residue is purified by ~2~
chromatography on silica gel with ethyl acetate. 4-diisopropylphosphonomethyl-6-fluoro-2-formylalr~ino-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish oil.
Example 7: 0.5 g (1.86 mrnol) of 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid ethyl ester are heated under reflux ;n 4 ml of water for 17 hours. The reaction mixture is concentrated by evaporation and separated with water on a strongly acidic ion-exchanger (Dowex 50Wx8; H0 form). 2-amino-6-fluoro 4-phosphonomethyl-hex-3-enoic acid having a melting point of 160-162C (decomp.) is obtained.
~xample 8: In a manner analogous to that described in Example 3, 2,10-diarnino-4-phosphonomethyl-dec-3-enoic acid dihydrochloride, m.p. 126, is obtained, starting from 8-aminooctan-1-ol.
Example 9: 8.63 g (15.2 mmol) of 10-~N-benzyloxycarbonyl-amino)-4-diisopropylphosphonomethyl-2-formylamino-dec-3-enoic acid ethyl ester are dissolved in 22 ml of dichloromethane, and 9.82 ml (75.9 mmol) of trimethylbromosilane are added dropwise at room temperature. The rr~ixture is s~red at room temperature for 22 hours, 22 ml of absolute ethanol are then added dropwise, and the mixture is stirred for a further 22 hours and concentrated by evaporation in a rotary evaporator. 20 ml of toluene are poured over the residue, and the mixture is concentrated by evaporation in vacuo. This operation is repeated a further three times. The resulting pale yellow foam is dissolved in 150 ml of absolute ethanol, and a solution of 7.5 ml of propylene oxide in 7.5 ml of ethanol is added dropwise within a period of 90 minutes. A crystallinesuspension forms, which is stiIred overnight at room temperature. The product is filtered off and washed with ethanol and ether. Drying under a high vacuum at room temperature yields 4~70 g of crude product in the form of pale yellow crystals. For further purification, the product is stirred with 46 rnl of water. After a small amount (0.33 g) of undissolved material has been filtered off, the clear pale yellow filtrate is completely concentrated by evaporation in vacuo. 20 ml of ethanol and 20 ml of toluene are added to the residue, and the mixture is again concentrated to dIyness by evaporation. This operation is repeated twice more using toluene. After drying under a high vacuum, the residue is suspended in 150 ml of absolute ethanol, and a S-normal solution of hydrogen chloride gas in ethanol is added dropwise, with stirring, until the rnixture gives an acid reaction to Congo red. A
mixture of 7.4 ml of propylene oxide in 7.4 ml of ethanol is added dropwise to the resulting clear solution within a period of one hour. A crystalline suspension forms, which . .
2 J~ ~ 3~
is stirred for a further 15 hours and then filtered with suction. After washing with ethanol and ether, the product is dried under a high vacuum at 50 for 48 hours, yielding 2.86 g of 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid ethyl ester, which begins to sinter at 157 and melts at 194 with decomposition.
This product contains as impurities approximately from 5 to 10 % by weight of the corresponding compound that is N-benzylated in the 10-position and of the N-(2-hydroxy)propylated compound.
The starting material is prepared as follows:
In a manner analogous to that described in Example 3, 8-(N-benzyloxycarbonylamino)-2-methyleneoctanal is obtained, starting from 8-aminooctan-1-ol, via 8-(N-ben~yloxycarbonylamino)octan-l-ol and 8-~N-benzyloxycarbonylamino)octanal.
15.30 g (52.9 mmol) of 8-(N-benzyloxycarbonylamino)-2-methyleneoctanal and 7.37 ml (67.4 mmol) of isocyanoacetic acid ethyl ester are dissolved in 78 ml of toluene and added dropwise under argon, within a period of 75 minutes, to a suspension of 0.30 g of copper(I) oxide in 76 ml of toluene. The mixture is then stirred for 90 minutes at 30, cooled to room temperature and filtered, and the clear, bright red filtrate is introduced into a column filled with 250 g of silica gel (particle size 0.04-0.063 mrn) and eluted with hexane/ethyl acetate (2:1). Concentration of the suitable fractions by evaporation yields 8.15 g of 5-[8-(N-benzyloxycarbonylamino)oct-l-en-2-yl]-oxazoline-4-carboxylic acid ethyl ester in the form of a colourless honey.
8.15 g (20.25 mmol) of 5-[8-(N-benzyloxycarbonylamino)oct-l-en-2-ylJ-oxazoline-4-carboxylic acid ethyl ester are heated under reflux in 40 ml of tetrahydrofuran and 20 ml of water for 4 hours with stirring. The reaction mixture is concentrated to dryness by evaporation in vacuo at 45, and the honey-like residue is concentrated by evaporation twice more after the addition of toluene. The crude produ~t is dissolved in dichloromethane, dried with sodium sulfate, filtered and concentrated by evaporation. Drying under a high vacuum at room temperature yields 9.03 g of 10-(N-benzyloxycarbonylamino)-2-fo~mylamino-3-hydroxy-4-methylene-decanoic acid ethyl ester in the form of a yellowish honey.
To 13,70 g (32.60 mmol) of crude 10-(N-benzyloxycarbonyl-arnino)-2-formylamino-3-hydroxy-4-methylene-decanoic acid ethyl ester in 137 ml of tetrahydrofuran there are added, under argon, 18.5 ml (156.4 mmol) of hexa-1,5-diene and then, dropwise at 10 within a period of 15 minutes, 6.1 ml (78.2 mmol) of thionyl bromide. The mixture is stirred for one hour at 10 and for 2 hours at room temperature and is then poured into 200 ml of ice-cold saturated sodium hydrogen carbonate solution;
the organic phase is separated off and re-extracted once with dichloromethane. The organic phases are washed with ice-cold O.S-norrnal sodium hydrogen carbonate solution and then with saturated sodium chloride solution, dri~d over sodium sulfate and concentrated to dryness by evaporation in vacuo at 40. 64 ml (260 mmol) of triisopropyl phosphite (96 %) are added immediately to the resulting crude 10-(N-benzyloxycarbonylam~no)-4-bromomethyl-2-forrnylamino-dec-3-enoic acid ethyl es~er (27 g, yellow honey), and the mixture is stirred for 17 hours at 80 under a pressure of approximately 100 mbar, the isopropyl bromide that forrns being captured in a cold trap (CO2). The excess triisopropyl phosphite is then distilled off under reduced pressure and the evaporation residue (23 g) is purified by chromatography on a column filled with 650 mg of silica gel (0.04-0.063 mm) with ethyl acetate/methanol (95:5). 8.73 g of 10-(N-benzyloxycarbonylamino)-4-diisopropylphosphonomethyl-2-formylamino-dec-3-enoic acid ethyl ester are obtained in the form of a yellowish honey.
Example 10: 2.25 g (6.98 mmol) of 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid ethyl ester are dissolved under argon in 45 ml of 2-normal hydrochloric acid and stirred for 17 hours at a bath temperature of 120. The clear, pale brown solution is concentrated by evaporation in a rotary evaporator. The residue is dissolved in 20 ml of ethanol and, after the addition of 30 ml of toluene, concentrated by evaporation in vacuo. This operation is repeated a further three times. The resulting beige foam is dissolved in 75 ml of absolute ethanol, and a solution of 15 ml of propylene oxide in 15 ml of ethanol is added dropwise within a period of 35 minutes. The crystalline suspension that forrns, which has a pH of 3, is filtered off after 1~ hours' stirring and washed thoroughly with ethanol and ether. Drying in vacuo yields 1.65 g of beige crude product, which is dissolved in the rninimum arnount of water (about 2 ml) and chrornatographed on a column filled with 67 g of reversed-phase silica gel (Opti-Up Cl2, particle size 40 ~,lm), using pure water as eluant, at a slight ove~pressure (0.2 bar). A pure fraction, Rf value on silica gel = 0.37 with n-propanoVwater/pyridine/acetic acid (15:12:10:3) as eluant, and several n~ixed fractions containing a by-product of Rf value = 0.48 are obtained.
Chromatography of those mixed fractions again and purification of the pure fractions, l ~2~r,~,~
followed by Iyophilisation from water, yield 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid hemi-hydrochloride hydrate in the form of an amorphous glass which slowly sinters at 134 and above and decomposes at 149 with foaming.
Example 11: 4.3 g (9.9 mmol) of 7-acetoxy-4-diisopropylphos-phonomethyl-2-formylamino-hept-3-enoic acid ethyl ester are dissolved in 25 ml of dichloromethane, and 5.1 ml (39.5 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 24 hours, 25 ml of ethanol are added dropwise, the rnixture is left to stand for a further 24 hours and is concentrated by evaporation, the residue is dissolved in 25 ml of ethanol, and a mixture of 25 ml of propylene oxide and 25 ml of ethanol is added dropwise. A suspension forrns, which is stirred for one hour at room temperature and for one hour in an ice bath and is then filtered with suction. Drying yields 2-amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid ethyl ester having a melting point of 210C (decomp.).
The starting material can be prepared, for example, as follows:
10 g (69.4 rnmol) of 5-acetoxypentanal, 6.37 g (78.~ mmol) of dimethylammonium chloride and 6.1 ml (81.2 mmol) of 37 % formaldehyde solution are refluxed for 1 -~ hours (bath temperature ~110C) with stirring. The mixture is allowed to cool and is extracted three tirnes with ether; the organic phases are combined, dried over MgSO4, filtered and concentrated by evaporation. 5-acetoxy-2-methylenepentanal is obtained in the forrn of a yellowlsh oil which can be reac~od without further purification.
9.6 g (61.5 rnmol) of 5-acetoxy-2-methylenepentanal and 7.38 rnl (67.6 rnmol) ofisocyanoacetic acid ethyl ester are placed in 70 ml of toluene at room temperature, and 250 mg of copper(I) oxide are added. When the exothermic reaction has subsided, the rnixture is stirred for a further one hour and is filtered over Hyflo~3) and concentrated by evaporation. The residue is taken up in 50 ml of tetrahydrofuran, 10 ml of water are added, and the mixture is refluxed for 3 hours. The mixture is concen~rated to dryness by evaporation, toluene is added, and the rnixture is again concentrated by evaporation.
Chromatography on silica gel with toluene/ethyl acetate (4:1) yields 7-acetoxy-2-formylarnino-3-hydroxy-4-methylene-heptanoic acid ethyl ester in the form of an orange oil.
2 ~ 3 ~
5.9 g (20.5 mmol) of 7-acetoxy-2-formylamino-3-hydroxy-4-methylene-heptanoic acid ethyl ester are dissolved in 60 ml of dichloromethane, and 1.9 ml (24.6 mmol) of thionyl bromide are added dropwise at room temperature. After one hour, 40 ml of water are added asld the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession Wit}l water, lN KHC03 solution and again with water, dried over MgS04, filtered and concentrated by evaporation.
7-acetoxy-4-bromomethyl-2-formylamino-hept-3-enoic acid ethyl ester is obtained in the form of a b;own oil, which is reacted further in the crude state.
6.1 g (17.4 mmol) of 7-acetoxy-4-bromomethyl-2-formylaminohept-3-enoic acid ethyl ester and 19.1 rïll (69.6 mmol) of tIiisopropyl phosphite (90 %) are heated to 80C and stirred under a pressure of approximately 130 mbar for 18 hours. The excess trusopropyl phosphite is distilled off and the residue is purified on silica gel with ethyl acetate. 7-acetoxy4-diisopropylphosphonomethyl-2-formylamino-hept-3-enoic acid ethyl ester is obtained in the form of a yellow oil.
Example 12: 1.1 g (3.9 mmol) of 2-asnino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid ethyl ester in 8 ml of water are stirred at 13ûC for 18 hours in a bomb tube. The dark reaction solution is treated with activated carbon and filtered over Hyflo~. The colourless filtrate is concentrated to ~3 ml, and ~25 ml of ethanol are added. The resul-ting suspension is filtered with suction and dried under a high vacuum at 50C.
2-amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid having a melting point from 190C and above (decomp.) is obtained.
Example 13: 8.2 g (18.9 mmol) of 6-(N-acetyl-N-methylan~ino)-4-diisopropylphosphonomethyl-2-formylanino-hex-3-enoic acid ethyl ester are dissolved in 40 ml of dichloromethane, and 9.8 ml (75.6 mmol) of trimethylbromosilane are added dropwise at room temperatlLre. The mixture is left to stand at room temperature for 24 hours, 40 ml of ethanol are added dropwise, tne mixture is left to stand for a fur~er 24 hours and is concentrated by evaporation, the residue is dissolved in 40 ml of ethanol, and a nixture of 40 ml of propylene oxide and 40 rnl of ethanol is added dropwise. A
suspension forms, which is stirred for a further one hour at room te nperature and for one hour at 0 and is then filtered with suction. Drying yields 6-(N-acetyl-N-methylamino)-2-amino-4-phosphonomethyl-hex-3-enoic acid ethyl ester having a melting point of 222-223C ~decomp.).
~, 35 ~2~a~
The starting material can be prepared, for example, as follows:
35.8 g (0.2 mol) of 4-aminobutyraldehyde-diethylacetal (90 %) are dissolved in 600 ml of dichloromethaule, 300 ml of saturated sodium hydrogen carbonate solution are added, and the mixture is cooled to 0C. 17 ml (0.24 mol) of acetyl chloride are added dropwise at 0-5C, and the mixture is stirred for a further 6 hours at 0-5C. The organic phase is separated off and the aqueous phase is extracted twice more with dichloromethane. The organic phases are combined, dried over MgS04, filtered and concentrated by evaporation in a rotary evaporator. The residue is purified by chromatography on silica gel with ethyl acetate. 4-(N-acetylamino)butyraldehyde-diethylacetal is obtained in the form of a yellowish oil.
35 g (172.2 mmol) of 4-(N-acetylamino)butyraldehyde-diethylacetal are dissolved in 180 ml of dimethylforrnarnide, 8.3 g (206.6 mmol) of sodium hydride dispersion (60 % in mineral oil) are added in portions, and the rnixture is stirred at room temperature for 45 minutes. 12.9 ml (206.6 mmol) of methyl iodide in 20 ml of dimethylformamide are then added, and the mixture is subsequently stirred at room temperature for 4 hours.
Water/ice is added to the reaction mixture, and the batch is extracted three times with ethyl acetate. The organic phases are washed with water and saturated sodium chloride solution, combined, dried over MgSO4, filtered and concentrated by evaporation. The residue is distilled under a high vacuum. 4-(N-acetyl-N-methylamino)butyraldehyde~
diethylacetal is obtained in the form of a colourless oil9 b.p.o I = 92-94.
30 g (138.2 mmol) of 4-(N-acetyl-N-methylamino)butyraldehydedlethylacetal, 12.6 g (154.4 mmol) of dimethylammonium chloride and 12.1 ml (161.7 mmol) of 37 %
formaldehyde solution are refluxed for 45 minutes with st-irring. I he mixture is allowed to cool and is extracted three times with dichloromethane. The organic phases are combined, dried over MgSO4, filtered and concentrated by evaporation. 4-(N-acetyl-N-methylamino)-2-methylene-butyraldehyde is obtained in the form of a yellowish oil which can be reacted without further purification.
19.9 g (128.3 mmol) of 4-(N-acetyl-N-methylamino)-2-methylene-butanal and 15.4 ml (141.1 mmol) of isocyanoacetic acid ethyl ester are placed at room temperature in ~0 ml of toluene, and 500 mg of copper(I) oxide are added. When the exothermic reaction has subsided, the mixture is stirred for a further one hour at room temperature, filtered over Hyflo(g) and concentrated by evaporation. The residue is taken up in 60 ml of 2 ~ J '~3 ~ 3 tetrahydrofuran, 20 ml of water are added, and the mixture is refluxed for 4 hours. The mixture is concentrated by evaporation, toluene is added, and the rnixture is again concentrated by evapor~tion. Chromatography on sllica gel with ethyl acetate/isopropanol (7:1) yields 6-(N-acetyl-N-methylamino)-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester in the forrn of a yellowish oil.
15.8 g (55.2 mmol) of 6-(N-acetyl-N-methylamino)-2-formyl-amino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 150 ml ofdichloromethane, and 5.1 ml (66.2 mmol) of thionyl bromide are added dropwise at room temperature. After one hour, 100 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, lN KHCO3 solution and again with water, dried over MgSO4, filtered and concentrated by evaporation. 6-(N-acetyl-N-methylamino)-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish-orange oil which is reacted further in the crude state.
16.0 g (45.8 mmol) of 6-(N-acetyl-N-methylamino)-4-bromo-methyl-2-formylamino-hex-3-enoic acid ethyl ester and 50~3 ml (183.3 mmol) of triisopropyl phosphite (90 %) are heated to 80 and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off and the residue is purified by chromatography on silica gel with ethyl acetate~lsopropanol (7:2). 6-(N-acetyl-N-methylamino)-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a yellow oil.
Example 14: 3.3 g (6.82 mrnol) of 6-benzoyloxy-4-diisopropyl-phosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester are dissolved in 20 ml of dichloromethane, and 3.52 ml (27.3 rnmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 22 hours, 20 ml of ethanol are added dropwise, the mixture is left to stand for a further 22 hours and is concentrated by evaporation, the residue is dissolved in 20 ml of ethanol, and a r~ixture of 20 ml of propylene oxide and 20 rlll of ethanol is added dropwise. A suspension forms, which is stirred for one hour at room temperature and for one hour at 0C and is then filtered with suction. Drying yields 2-arnino-6-benzoyloxy-2-amino-4-phos-phonom~thyl-hex-3-enoic acid ethyl ester having a melting point of 236-237C (decomp.).
The starting material can be prepared, for example, as follows:
~ ,323 v3~
10 g (52 mmol) of 4-benzoyloxybutanal, 4.78 g (58.6 mmol) of dimethylammonium chloride and 4.6 ml (60.8 mmol) of formaldehyde solution (37 %) are refluxed for one hour with stirring (bath temperature ~110C). The rnixture is allowed to cool and is extracted three times with ether; the organic phases are combined, washed with saturated sodium chloride solution, dried over MgS04, filtered and concentrated by evaporation.
4-benzoyloxy-2-methylenebutanal is obtained in the form of a yellowish oil which can be reacted without further purification.
10 g (49 mmol) of 4-benzoyloxy-2-methylenebutanal and 5.3 ml (49 mmol) of isocyanoacetic acid ethyl ester are placed at room temperature in 70 ml of toluene, and 200 mg of copper(I) oxide are added. When the exothermic reaction has subsided, the mixture is stirred for a further one hour, filtered over Hyflo(~) and concentrated by evaporation. The residue is taken up in 50 ml of tetrahydrofuran, 10 ml of water are added, and the rnixture is refluxed for 3 hours. The mixture is concentrated by evaporation, toluene is again added, and the rnixture is again concentrated by evaporation.
Chrornatography on silica gel with toluene/ethyl acetate (3:2) yields ~benzoyloxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester in theform of a brown oil.
8 g (23.9 rnmol) of 6-benzoyl-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 80 ml of dichloromethane, and 2.22 ml (28.6 mmol) of thionyl bromide are added dropwise at room temperature. After 2 hours, 60 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, lN KHCS)3 solution and again with water, dried over MgSO4, filtered and concentrated by evaporation.
6-benzoyloxy-4-bromomethyl-2-forrnyIarninc~hex-3-enoic acid ethyl ester is obtained in the form of a brown oil which is reacted fur~er in the crude state.
8.4 g (21 mrnol) of 6-benzoyloxy-4-bromomethyl-2-formylamino-hex-3-enoic asid ethyl -ester and 23 ml (84 mmol) of triisopropyl phosphite (90 %) are heated to 80C and stirred under a pressure of ~130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off and the residue is purified by chromatography on silica gel with ethyl acetate. 6-benzoyloxy-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a brown oil.
2 ~ 2 ~
Example 15: 4.0 g (8.51 mmol) of 6-ben~yloxy-4-diisopropyl-phosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester are dissolved in 24 ml of dichloromethane, and 4.4 ml (34 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 22 hours, 24 ml of ethanol are added dropwise and the mixture is left to stand for a further 24 hours and is concentrated by evaporation in a rotary evaporator, the residue is dissolved in 24 ml of ethanol, and a mixture of 24 ml of propylene oxide and 24 ml of ethanol is added drop-wise. ~ suspension forms, which is stirred for a further one hour at room temperature and for one hour at 0 and is then filtered with suction. Drying yields 2.2 g of a white crys-talline product which is a mixture of 2-amino-6-benzyloxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester and 2-amin~
6-benzyloxy-4-phosphonomethyl-hex-3-enoic acid. To obtain a uniform product, that mixture is hydrolysed overnight at room temperature with 20 ml of N-sodium hydroxide solution in 30 ml of ethanol, acidified with N-hydrochloric acid and neutralised with propylene oxide. Since the product crystallises poorly, it is concentrated by evaporation in a rotary evaporator, the residue is filtered in water over 20 g of silica gel, and the fractions containing the desired product are concentrated by evaporation in a rotary evaporator. The residue is dissolved with 10 ml of tert.-butanoVwater (1:1) and freeze-dried.
2-amino-6-benzyloxy-4-phosphonomethyl-hex-3-enoic acid is obtained in the form of a lyophilisate.
The starting material can be prepared, for example, as follows:
6 g (0.2 mol) of a sodium hydride dispersion (80 % in white oil) are placed at room temperature in 120 ml of absolute dimethylformamide, and 22.2 ml (0.25 mol) of 1,4-butanediol are added dropwise. When the addition is complete, the mixture is stirred for a further 30 minutes at room ~emperature. 23.1 rnl (0.2 mol) of benzyl chloride are then slowly added dropwise, a slight exothermic reaction being observed. The reaction mixture is stirred overnight at room temperature, water/ice is added, and the mixture is extracted twice with ether. The organic phases are washed with water and with saturated sodium chloride solution, combined, dried over MgSO4, filtered and concentrated by evaporation. The residue is subjected to fractional distillation under a waterjet vacuum over a 10 cm Yigreux column. 4-benzyloxybu~anol is obtained, b.p.22 = 161-162.
36.6 g (170 mmol) of pyridinium chlorochromate are placed at room temperature in120 ml of dichloromethane under N2, and a solution of 20.4 g (113 mmol) of ., ~ ~ 2 s3 ~3 ~ ~
4-benzyloxybutanol in 20 ml of dichloromethane is added. The reaction mixture rapidly becomes dark and the reaction is slightly exothermic. The reaction mixture is stirred at room temperature for 3~ hours. The supernatant dichloromethane phase is decanted off and concentrated by evaporation in a rotary evaporator. The residue is filtered over 100 g of silica gel. The product fractions are concentrated by evaporation in a rotary evaporator and distilled under a high vacuum over a 10 cm Vigreux column. 4-benzyloxybutanal is obtained, b.p.o I = 72-73.
8.0 g (44.9 mmol) of 4-benzyloxybutanal, 4.12 g (50.6 mmol) of dimethylammonium chloride and 3.95 ml (52.6 rnrnol) of 37 % formaldehyde solution are kept at a bath temperature of 110 for one hour with stirring. The mixture is allowed to cool and is extracted ~hree times with ether. The organic phases are washed with saturated sodium chloride solution, combined, dried over MgSO4, filtered and concentrated by evaporation.
4-benzyloxy-2-methylenebutanal is obtained in ~he form of a yellowish oil which can be reacted further without further purification.
.
8.0 g (42 mrnol) of 4-benzyloxy-2-methylenebutanal and 4.57 ml (42 rnmol) of isocyanoacetic acid ethyl ester are placed in 60 ml of toluene, and 200 mg of copper(I) oxide are added. When the exothermic reaction has subsided, the mixture is sti~red for a further 2 hours, filtered over Hyflo~ and concentrated by evaporation. The residue is taken up in 50 ml of tetrahydrofuran, 10 ml of water are added, and the mixture is refluxed for 3 hours. The mixture is concentrated to dryness by evaporation, toluene is added, and the mixture is again concentrated by evaporation. Chromatography on silica gel with toluene/ethyl acetate (3:2) as eluant yields ~benzyloxy-2-formylarnino-3-hydroxy-4-methylene-hexanoic acid ethyl ester in the form of a reddish-brown oil.
7.0 g (21.8 mmol) of 6-benzyloxy-2-formylamin~3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 70 ml of dichloromethane, and 2.0 ml (26.1 mmol) of thionyl bromide are added dropwise at room temperature. After 2 hours, 40 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, N-KHC03 solution and again with water, dlied over MgSO4, filtered and concentrated by evaporation.
~benzyloxy-4-bromomethyl-2-formylarnino-hex-3-enoic acid ethyl ester is obtained in the form of a reddish-brown oil which can be reacted further without purification.
7.9 g (20.5 mmol) of 6-benzyloxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ,, ~2w~
ester and 22.5 ml (82.2 mmol) of ~iisopropyl phosphite (90 %) are heated to 80 and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off in a rotary evaporator and the residue is puri~led bychromatography on silica gel with ethyl acetate. 6-benzoyl-4-diisopropyl-phosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish oil.
Example 16: 3.15 g (6.84 mmol) of 4-(1-acetylpiperidin-4-yl)-5-diisopropylphosphono-2-formylamino-pent-3-enoic acid ethyl ester are dissolved in 17 ml of dichloromethane, and 3.54 ml (27.3 mmol) of trimethylbromosilane are added dropwise at room temperature. The rnixture is left to stand at room temperature for 16 hours, 17 ml of ethanol are added dropwise, the mixture is left to stand for a further 18 hours and is concentrated by evaporation in a rotary evaporator, the residue is dissolved in 12 ml of ethanol, and a mixture of 3 ml of propylene oxide and 3 ml of ethanol is added.
A suspension forms, which is stirred for a further 2 hours at room temperature and for 2 hours with ice cooling and is then filtered with suction. 2-amino-4-(1-acetyl-piperidin-4-yl)-5-phosphono-pent-3-enoic acid ethyl ester having a melting point of 225 (decomp.) is obtained.
The starting material can be prepared, for example, as follows:
3.95 g (23.3 mmol) of 2-(1-acetylpiperidin-4-yl)ethanol, 2.12 g (26.3 mmol) of dimethylammonium chloride and 3 ml (40 mmol) of 37 % formaldehyde solution are heated at 110C for 2 hours with sti~ing. The mixture is allowed to cool and is extracted several times with diethyl ether. The organic phases are combined, washed with saturated sodium ch!oride solution, d~ied over sodium sulfate, filtered and concentrated to dryness by evaporation. 2-(1-acetylpiperidin-4-yl)propenal is obtained in the foml of a yellowish oil which can be further reas~ted without further purification.
2.9 g (16.0 mmol) of 2-(1-acetylpiperidin-4-yl)propenal and 1.75 ml (16 mmol) ofisocyanoacetic acid ethyl ester are dissolved in 13 ml of toluene, and 46 mg of copper(I) oxide are added. When the exotherrnic reaction has subsided, the mixture is stiIred for a further 2 hours, filtered over Hyflo~) and concentrated to dryness by evaporation. The residue is taken up in 13 ml of tetrahydrofuran, 6 rnl of water are added, and the rnixture is heated under reflux for 2 hours with stirling. The mixture is concentrated to dryness by evaporation, toluene is added, and the mixture is again concentrated by evaporation.
~2~
Chromatography on silica gel with ethyl acetate/methanol (9:1) as eluant yields 4-(1-acetylpiperidin-4-yl)-2-formylarnino-3-hydroxy-pent-4-enoic acid ethyl ester in the form of a yellowish-brown oil.
3.3 g (10.5 mmol) of 4-(1-acetylpiperidin-4-yl)-2-formylamino-3-hydroxy-pent-4-enoic acid ethyl ester are dissolved in 25 ml of 1,2-dichloroethane, and 0.98 ml (12.6 mmol) of thionyl bromide are added dropwise at room temperature. After 1~ hours, 20 ml of water are added and the mixture is stirred vigorously for 15 minutes. The organic phase is separated off, washed in succession with water, N-potassium hydrogen carbonate solution and again with water, dried over sodium sulfate, filtered and concentrated by evaporation.
4-(1-acetylpiperidin-4-yl)-5-bromo-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a reddish-brown oil.
2.68 g (7.14 mmol) of 4-(1-acetylpiperidin-4-yl)-5-bromo-2-formylamino-pent-3-enoic acid ethyl ester and 7.5 ml (28.5 mmol) of triisopropyl phosphite (90 %) aIe heated to 80 and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off under reduced pressure and the evaporation residue is purified by chromatography on silica gel with ethyl acetate/methanol (9:1).
4-(1-acetylpiperidin-4-yl)-5-diisopropylphosphono-2-forrnylamino-pent-3-enoic acid ethyl ester is obtained in the form of a yellowish oil.
Example 17: 1 g (2.17 mrnol) of 4-(1-acetylpiperidin-4-yl)-5-diisopropylphosphono-2-formylamino-pent-3-enoic acid ethyl ester is heated under re~lux in 20 ml of 6N hydrochloric acid for 8 hours. After concentration by evaporation, the residue is dissolved in 25 ml of ethanol. 3 ml of propylene oxide are then added, ~e mixture is stirred for 2 hours at room temperature and for one hour with ice cooling, and then the suspension that has formed is filtered off with suction.
2-amino-4-(piperidin-4-yl)-5-phosphono-pent-3-enoic acid having a melting point of 212 (decomp.) is obtained.
Example 18: 0.68 g (1.49 mmol) of 5-benzyloxy-4-diisopropyl-phosphonomethyl-2-formylamino-pent-3-enoic acid ethyl ester is dissolved in 10 ml of dichloromethane, and 0.8 ml (~ mmol) of trimethylbromosilane is added dropwise at room temperature. The mixture is left to stand at room temperature for 6 hours, I0 ml of ethanol are added dropwise, the mixture is left to stand for a further 18 hours and is concent~ated by evaporation, the residue is dissolved in 5 ml of ethanol, and a rnixture of ~2~ 38 S ml of propylene oxide and S ml of ethanol is added dropwise. A suspension forms, which is stirred at room temperature for 2 hours and is then filtered with suction. Drying yields 2-amino-5-benzyloxy-4-phosphonomethyl-pent-3-enoic acid ethyl ester having a melting point of 218-220 (decomp.).
The starting material can be prepared, for example, as follows:
3.0 g (62.4 mmol) of 50 % sodism hydride dispersion in mineral oil are placed in 50 ml of tetrahydrofuran and 40 ml of dimethylformarnide, a solution of 10.0 g (62.4 mrnol) of 3-hydroxy-2-methylenepropionaldehyde-diethylacetal in 10 ml of tetrahydrofuran is slowly added dropwise at 0, and the mixture is stirred at 0 for 2 hours. The mixture is diluted with 15 rnl of tetrahydrofuran and 10 ml of dimethylformamide and stiIred at room temperature for a further 2 hours. 7.2 ml (62.4 mmol) of benzyl chlolide in 10 ml of dimethylformamide are then added at 0, and the mixture is stirred at room temperature for 18 hours. Water is added to the reaction mixture, which is then extracted three times with ethyl acetate, and the organic phases are washed with saturated sodium chloride solution. The organic phases are combined, dlied over Na2S04, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with methylene chloride, yielding 3-benzyloxy-2-methylenepropionaldehyde-diethylacetal in the form of a pale yellowish liquid.
4.8 g (1~.1 mmol) of 3-benzyloxy-2-methylenepropionaldehyde-diethylacetal and 0.36 g (1.9 mmol) of p-toluenesulfonic acid monohydrate are stiITed for 3 hours in 60 ml of acetone. The mixture is diluted with 400 ml of methylene chloride, extracted with N-KHC03 solution and saturated sodium chloride solution, dried over Na2S04, filtered and concentrated by evaporation. The 3-benzyloxy-2-methylenepropanol that remains (yellow liquid) is placed at room temperature, without further purification, together with 2.1 ml (19 mmol) of isocyanoacetic acid ethyl ester, in 25 rnl of toluene, and 50 mg of copper(I) oxide are added. When the exothermic reaction has subsided, the rnixture is stirred for a further one hour at room temperature, filtered over Hyllo~) and concentrated by evaporation. The residue is taken up in 25 ml of tetrahydrofuran, 5 ml of water are added, and the rIuxture is refluxed for 4 hours. The mixture is concentrated by evaporation, toluene is added, and the rnixture is again concentrated by evaporation.
Chromatography on silica gel with toluene/ethyl acetate (1:1) and subsequent crystal-Iisation from diethyl eth~r yield S-benzyloxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid ethyl ester having a melting point of 112-114C.
~J~
1.0 g (3.25 mmol) of S-benzyloxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid ethyl ester are suspended in 30 ml of 1,2-dichloroethane, and 0.38 ml (4.9 mmol) of thionyl chloride is added dropwise at room temperature. After 45 minutes, 20 ml of water are added to the yellow solution, and the mixture is stirred vigorously for 15 minutes. The organic phase is separated off, washed with saturated sodium chloride solution, dried over Na2SO4, filtered and concentrated by evaporation.
S-benzyloxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a yellowish oil which is reacted further in the crude state.
1.14 g (3.1 mmol) of S-benzyloxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester and 10 rnl (38.5 mmol) of triisopropyl phosphite (95 %) are heated to 80C and stirred under a pressure of approximately 130 mbar for 3~ hours. The excess triisopropyl phosphite is distilled off and the residue is purified by chromatography on silica gel with ethyl acetate. S-benzyloxy-4~iisopropylphosphonomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a yellowish oil.
Example 19: 1.10 g (2.8 mrnol) of S-ethoxy-4-diisopropylphos-phonomethyl-2-forrnylamino-pent-3-enoic acid ethyl ester are dissolved in 20 ml of dichloromethane, and 1.6 ml (12.3 mmol) of trimethylsilane are added dropwise at room temperature. The rnixeure is left to stand at room temperature for 7 hours, 20 rnl of ethanol are added, the mixture is left to stand for a further 15 hours and is concentrated by evaporation, the residue is dissolved in 10 rnl of ethanol, and a mixture of 10 ml of propylene oxide and 10 ml of ethanol is added dropwise. A suspension folms, which is stirred at room temperature for 2 hours and is then ~lltered with suction. Drying yields 5-ethoxy-2-amino-4-phosphonomethyl-pent-3-enoic acid ethyl ester having a melting point of 217-218C (decomp.).
The starting matenal can be prepared, for example, as follows:
50 g (283 mmol) of 3-ethoxypropionaldehyde-diethylacetal, 27.3 g (335 mmol) of dimethylammonium chloride and 30 ml (392 mmol) of 36 % formaldehyde solution areheated at 110C for 2 hours with stirring. The mixture is allowed to cool and is extracted ~hree times with diethyl ether. The organic phases are washed with saturated sodium chloride solution, combined, dried over sodium sulfate, filtered and concentrated to dryness by evaporation. 2-ethoxypropanol is obtained in the form of a yellow liquid 3 rJ ,~
which can be reacted -further without further purification.
4.2 g (36.1 mmol) of 2-ethoxypropanol and 4.4 ml (40 mmol) of isocyanoacetic acid ethyl ester are dissolved in 50 ml of toluene, and 200 mg of copper(I) oxide are added. When the exotherrnic reaction has subsided, the mixture is stirred for a further one hour, filtered over Hyflo(~) and concentrated to dryness by evaporation. The residue is taken up in 50 ml of tetrahydrofuran, 12 ml of water are added, and the mixture is heated under reflux for one hour with stirring. The mixture is concentrated to dryness by evaporation, toluene is added, and the mixture is again concentr~ted by evaporation. Chromatography on silica gel with toluene/isopropanol (9:1) as eluant yields 5-ethoxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid ethyl ester in the form of a yellow oil.
3.70 g (15.1 mrnol) of 5-ethoxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid ethyl ester are dissolved in 100 ml of 1,2-dichloroethane, and 1.8 rnl (22.8 mmol) of thionyl bromide are added dropwise at room temperature. After one hour, 100 ml of water are added and the rnixture is stirred vigorously for 15 minutes. The organic phase is separated off, washed in succession with lN potassium hydrogen carbonate solution and with brine, dried over sodium sulfate, filtered and concentrated by evaporation.5-ethoxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a yellowish-brown oil which is reacted further in the crude state.
3.12 g (10.1 mmol) of 5-ethoxy-4-bromomethyl-2-formylanuno-pent-3-enoic acid ethyl ester and 30 ml (118 mmol) of triisopropyl phosphite (90 %) are heated to 80C and stirred under a pressure of approximately 130 mbar for 7 hours. The excess ~iisopropyl phosphite is distilled off and the residue is purified by chromatography on silica gel with methylene oxide/methanol (97:3 to 9S:S). 5-ethoxy-4-dihydropropylphos-phonomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a yellow oil.
Example 20: Tablets, each containing 50 mg of 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or a salt, for example the sodium salt, thereof, can L~ prepared as follows:
Composi~ion (10LOOO tablets) active ingredient 500.0 g ~; ~ 2 ~ 3 eJ ~
lactose 500.0 g potato starch 352.0 g gelatin 8.0 g talcurn 60.0 g magnesium stearate 10.0 g silica (highly disperse) 20.0 g ethanol q.s.
The active ingredient is mixed with the lactose and 292 g of potato starch, and the mixture is moistened with an ethanolic solution of the gelatin and granulated through a sieve.
After drying, the remaining potato starch, the magnesium stearate, the talsum and the silica are mixed in and the mixture is compressed to form tablets which each weigh 145.0 mg and contain 50.0 mg of active ingredient, and which may, if desired, be provided with dividing notches for finer adaptation of the dose.
Example 21. Coa~ed tablets, each containing 100 mg of 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or a salt, for example the sodium salt, thereof, can be prepared as follows:
Composition (for 1.000 coated tablets) activeingredient 100.0 g lactose 100.0 g com starch ~0.0 g talcum ~ 8.5 g calciumstearate 1.5 g hydroxypropylmethylcellulose 2.36 g shellac 0.64 g water q.s.
methylene chloride q.s.
The active ingredient, the lactose and 40 g of the corn starch are mixed, and the mixture is moistened with a paste, prepared from 15 g of the corn starch and water (with heating), and granulated. The granulate is dried, the remaining corn starch, the talcum and the calcium stearate are added and mixed with the granulate. The rnixture is compressed to fonn tablets (weight: 280 mg), which are coated with a solution of the 2~2~3~
hydroxypropylmethylcellulose and the shellac in methylene chloride. Final weight of the coated tablet: 283 mg.
Example 22- Gelatin dry-filled capsules, containing 100 mg of active ingredient, for example 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or a salt, for example the sodium salt, thereof, can be prepared, for exarnple, as follows:
Composition (for 1~000 capsules) activeingredierlt 100.0 g lactose 250.0 g microcrystalline cellulose 30.0 g sodiumlaurylsulfate 2.0 g magnesium stearate 8.0 g The sodium lauryl sulfate is added to the Iyophilised active ingredient through a sieve having a mesh size of 0.2 mm. The two components are intimately mixed. Then, first the lactose is added through a sieve having a mesh size of 0.6 mm and then the microcrystalline cellulose through a sieve having a mesh size of 0.9 mm. The mixture is again intimately mixed for 10 minutes. Finally, the magnesium stearate is added through a sieve having a mesh size of 0.8 mm. After further mixing for 3 minutes, size 0 gelatin dry-fill capsules are each filled with 390 mg of the resulting formulation.
Example 23: A 0.2 % injection or infusion solution of 2-amino-~hydroxy-4-phosphonomethyl-hex-3-enoic acid or of a salt, for example the sodium salt, thereof can be prepared, for example, as follows:
.
Composit on (for 11000 ampoules) active ingredient 5.0 g sodium chloride 22.5 g phosphate buffer pH = 7.4 300.0 g dernineralised water ad 2500.0 ml The active ingredient and the sodium chloride are dissolved in 1000 ml of water and filtered through a micro-filter. The buffer solution is added, and the mixture is made up to , .
2~2~3~
2500 ml with water. To prepare dosage unit forms, 1.0 or 2.5 ml are introduced into each glass ampoule, which then contains 2.0 or 5.0 mg, respectively, of active ingredient.
Example 24: In a manner analogous to that described in Examples 1 to 10 also thefollowing compound can be m~nufactured:
2-amino-8-hydroxy-4-phosphonomethyl-oct-3-enoic acid e~hyl ester, m.p. 230-233 (decomp.);
2-amino-6-hydroxy-5-hydroxymethyl-4-phosphonomethyl-hex-3-enoic acid ethyl ester, m.p. 177-180, and 2-amino-10-hydroxy-4-phosphonomethyl-dec-3-enoic acid ethyl ester, m.p. 243-244(decomp.).
Example 25: In a manner analogous to that described in Examples 20 to 23, it is also possible to prepare pharmaceutical preparations containing a different compound of formula I according to any one of Examples 1 to 19. and 24
To 2.46 g (6.5 mmol) of 8-(N-benzyloxycarbonylarnino)-2-formyl-amino-3-hydroxy-4-methylene-octanoic acid methyl ester in 25 ml of tetrahydrofuran there are added S.S ml (46 mmol) of hexa-1,5-diene and then, dropwise at -50, 2.6 ml (32.5 mmol) of thionyl bron~ide. The mixture is stirred at from 0 to 5 for 2 hours, poured into 25 ml of ice-cold saturated sodium hydrogen carbonate solution and extracted twice with 20 ml of methylene chloride each time. The organic phase is washed with 10 ~nl of saturated sodium chloride solution, dried over magnesium sulfate and concen-trated to dryness by evaporation. The resulting oil is purified by chromatography on silica gel with hexane/ethyl acetate (3:1). 8-(N-benzyloxycarbonylamino~-4-bromomethyl-2-formylamino-oct-3-enoic acid methyl ester is obtained.
5 ml of triethyl phosphite are added to 1.45 g (3.3 mmol) of 8-(N-benzyloxycarbonylamino)-4-bromomethyl-2-formylamino-oct-3-enoic acid methyl 2 3 ~
ester, and the mixture is heated at 75 for 8 hours with stirring. The excess triethyl phosphite is distilled off under reduced pressure to give an oily residue which is purified by chromatography on a silica gel column with first ethyl acetate and then ethylacetate/methanol (9:1). 8-(N-benzyloxycarbonylamino)-4-diethylphosphonomethyl-2-formylamino-oct-3-enoic acid methyl ester is obtained.
Exarnple 4: 1.77 g (4.5 mmol) of 4-diisopropylphosphonomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester are dissolved in 12 ml of dichloromethane, and 2.32 ml (18.0 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 22 hours, 12 ml of ethanol are added dropwise, the mixture is left to stand for a furiher 24 hours and is concentrated by evaporation in a rotary evaporator, the residue is dissolved in 10 ml of ethanol, and a mixture of 2 ml of propylene oxide and 2 ml of ethanol is added. A
suspension forms, which is s~irred for a fur~her 2 hours at room temperature and for 2 hours wi~h ice cooling, and is then filtered with suction. 2-amino-6-methoxy-4-phos-phonomethyl-hex-3-enoic acid ethyl ester having a melting point of 242 (decomp.) is obtained.
The starting material can be prepared, for exarnple, as follows:
19.7 g (193 mmol) of 4-methoxybutanal, 17.7 g (217 mmol) of dimethylammonium chloride and 17.0 ml (226 mmol) of 37 % formaldehyde solution are heated at 100 for 3 hours with stirring. The mixture is allowed to cool and is extracted 3 times with diethyl ether. The organic phases are washed with saturated sodium chloride solution, combined, dried over sodium sulfate, filtered and concentrated to dryness by evaporation.
4-methoxy-2-methylenebutanal is obtained in ~he form of a yellowish oil which can be further reacted without further purification.
16.5 g (144.5 mmol) of 4-methoxy-2-methylenebutanal and 15.8 ml (144.5 mmol) of isocyanoacetic acid ethyl ester are dissolved in 145 ml of toluene, and 400 mg of copper(I) oxide are added. When the exothermic reaction has subsided, the mixture is stirred for a further 2 hours, filtered over Hyflo~) and concentrated to dryness by evaporation. The residue is talcen up in 145 ml of tetrahydrofuran, 33 ml of water are added, and the mixture is heated under reflux for 2 hours with stirring. The mixture is concentrated to dryness by evaporation, toluene is added, and the mixture is again concentrated by evaporation.
Chromatography on silica gel with toluene/ethanol ~95:5) as eluant yields 2-formyl-.
~ 3 ~ 1j v ~J ,~
amino-3-hydroxy-S-methoxy-4-methylene-hexanoic acid ethyl ester in the form of areddish-brown oil.
19.0 g (77.5 mmol) of 2-formylamino-3-hydroxy-6-methoxy-4-methylene-hexanoic acid ethyl ester are dissolved in 190 ml of 1,2-dichloroethane, ~md 7.20 ml (93.0 mmol) of thionyl bromide are added dropwise at room temperature. After 45 minutes, 100 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, lN potassium hydrogen carbonate solution and again with water, dried over sodium sulfate, ~lltered and concentrated by evaporation. 4-bromomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester is obtained in the form of a reddish-brown oil.
3.38 g (11.0 mmol) of 4-bromomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester and 12.0 ml (44 mmol) of triisopropyl phosphite (96 %) are heated to 80 and stirred under a pressure of approximately 130 m~ar ~or 18 hours. The excess triisopropylphosphite is distilled off under reduced pressure and the evaporation residue is purified by chromatography on silica gel with ethyl acetate. 4-diisopropylphosphonomethyl-2-formylamino-6-methoxy-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish oil.
Exam~le S: 0.98 g (3.5 rnmol) of 2-amino-6-methoxy-4-phosphonomethyl-hex-3-enoicacid ethyl ester is heated under reflux in ? ml of water for 17 hours. The Teaction mixture is concentrated by evaporation and crystallised from a mixture of water and ethanol.
2-amino-~methoxy-4-phosphonomethyl-hex-3-enoic acid having a melting point of 214C (decomp.) is obtained.
Example 6: 0.52 g (1.36 rnmol) of 4-diisopropylphosphono-methyl-6-fluoro-2-formylarnino-hex-3-enoic acid ethyl ester is dissolved in 3.5 ml of dichloromethane, and 0.7 ml (5.45 mmol) of trimethylbromosilane is added dropwise at room temperaturç. The mixture is left to stand at room temperature for 24 hours, 3.5 ml of ethanol are added dropwise, the mixture is left to stand for a further 24 hours and is con-centrated by evaporation in a rotary evaporator, the residue is dissolved in 2.4 ml of ethanol, and a mixture of 0.6 ml of propylene oxide and 0.6 ml of ethanol is added. A
suspension forms, which is stirred for a further 2 hours at room temperature and for 2 hours with ice cooling and is then ~lltered with suction. 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid ethyl ester having a melting point of 222 (decomp.) 2~2~
is obtained.
The starting material can be prepared, for example, as follows:
2.4 g (26.6 rnrnol) of 4-fluorobutanal, 2.44 g (30.0 mmol) of dimethylammonium chloride and 2.34 ml (31.1 mrnol) of 37 % forrnaldehyde solution are heated at 100 for 2 hours with stirring. The mixture is allowed to cool and is extracted 3 times with diethyl ether.
The organic phases are washed with saturated sodium chloride solution, combined, dried over sodium sulfate, filtered and concentrated to dryness by evaporat;on.
4-fluoro-2-methylenebutanal is obtained in the form of a yellowish oil which can be reacted further without further purification.
1.43 g (14.0 mrnol) of 4-fluoro-2-methylenebutanal and 1.53 ml (14.0 mmol) of isocyanoacetic acid ethyl ester are dissolved in 14 ml of toluene, and 40 mg of coppera) oxide are added. When the exotherrnic reaction has subsided, the rnixture is stirred for a further 2 hours, filtered over Hyflo~ and concentrated to dryness by evaporation. The residue is taken up in 14 rnl of tetrahydrofuran, 3.1 rnl of water are added, and the mixture is heated under reflux for 2 hours with stirring. The mixture is concentrated to dryness by evaporation, toluene is added, and the rnixture is again concentrated by evaporation.
Chromatography on silica gel with toluene/ethyl acetate (1:1) as eluant yields 6-fluoro-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester in the form of a dark-yellow oil.
1.40 g (6.0 mmol) of 6-fluoro-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 14 ml of 1,2-dichloroethane, and 0.56 ml (7.2 mmol) of thionyl bromide is added dropwise at room temperature. After 45 minutes, 12 ml of water are added and the mixh~e is stirred vigorously for 15 minutes. The organic phase is separated off, washed in succession with water, lN potassium hydrogen carbonate solution and again with water, dried over sodium sulfate, filtered and concentrated by evaporation.
4-bromomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl es~er is obtained in the form of a brownish-yellow oil.
1.43 g (4.82 mrnol) of 4-bromomethyl-6-fluoro~2-formylamino-hex-3-enoic acid ethyl ester and 5.3 ml ~19 mmol) of triisopropyl phosphite (96 %) are heated to 80 and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropylphosphite is distilled off under reduced pressure and the evaporation residue is purified by ~2~
chromatography on silica gel with ethyl acetate. 4-diisopropylphosphonomethyl-6-fluoro-2-formylalr~ino-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish oil.
Example 7: 0.5 g (1.86 mrnol) of 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid ethyl ester are heated under reflux ;n 4 ml of water for 17 hours. The reaction mixture is concentrated by evaporation and separated with water on a strongly acidic ion-exchanger (Dowex 50Wx8; H0 form). 2-amino-6-fluoro 4-phosphonomethyl-hex-3-enoic acid having a melting point of 160-162C (decomp.) is obtained.
~xample 8: In a manner analogous to that described in Example 3, 2,10-diarnino-4-phosphonomethyl-dec-3-enoic acid dihydrochloride, m.p. 126, is obtained, starting from 8-aminooctan-1-ol.
Example 9: 8.63 g (15.2 mmol) of 10-~N-benzyloxycarbonyl-amino)-4-diisopropylphosphonomethyl-2-formylamino-dec-3-enoic acid ethyl ester are dissolved in 22 ml of dichloromethane, and 9.82 ml (75.9 mmol) of trimethylbromosilane are added dropwise at room temperature. The rr~ixture is s~red at room temperature for 22 hours, 22 ml of absolute ethanol are then added dropwise, and the mixture is stirred for a further 22 hours and concentrated by evaporation in a rotary evaporator. 20 ml of toluene are poured over the residue, and the mixture is concentrated by evaporation in vacuo. This operation is repeated a further three times. The resulting pale yellow foam is dissolved in 150 ml of absolute ethanol, and a solution of 7.5 ml of propylene oxide in 7.5 ml of ethanol is added dropwise within a period of 90 minutes. A crystallinesuspension forms, which is stiIred overnight at room temperature. The product is filtered off and washed with ethanol and ether. Drying under a high vacuum at room temperature yields 4~70 g of crude product in the form of pale yellow crystals. For further purification, the product is stirred with 46 rnl of water. After a small amount (0.33 g) of undissolved material has been filtered off, the clear pale yellow filtrate is completely concentrated by evaporation in vacuo. 20 ml of ethanol and 20 ml of toluene are added to the residue, and the mixture is again concentrated to dIyness by evaporation. This operation is repeated twice more using toluene. After drying under a high vacuum, the residue is suspended in 150 ml of absolute ethanol, and a S-normal solution of hydrogen chloride gas in ethanol is added dropwise, with stirring, until the rnixture gives an acid reaction to Congo red. A
mixture of 7.4 ml of propylene oxide in 7.4 ml of ethanol is added dropwise to the resulting clear solution within a period of one hour. A crystalline suspension forms, which . .
2 J~ ~ 3~
is stirred for a further 15 hours and then filtered with suction. After washing with ethanol and ether, the product is dried under a high vacuum at 50 for 48 hours, yielding 2.86 g of 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid ethyl ester, which begins to sinter at 157 and melts at 194 with decomposition.
This product contains as impurities approximately from 5 to 10 % by weight of the corresponding compound that is N-benzylated in the 10-position and of the N-(2-hydroxy)propylated compound.
The starting material is prepared as follows:
In a manner analogous to that described in Example 3, 8-(N-benzyloxycarbonylamino)-2-methyleneoctanal is obtained, starting from 8-aminooctan-1-ol, via 8-(N-ben~yloxycarbonylamino)octan-l-ol and 8-~N-benzyloxycarbonylamino)octanal.
15.30 g (52.9 mmol) of 8-(N-benzyloxycarbonylamino)-2-methyleneoctanal and 7.37 ml (67.4 mmol) of isocyanoacetic acid ethyl ester are dissolved in 78 ml of toluene and added dropwise under argon, within a period of 75 minutes, to a suspension of 0.30 g of copper(I) oxide in 76 ml of toluene. The mixture is then stirred for 90 minutes at 30, cooled to room temperature and filtered, and the clear, bright red filtrate is introduced into a column filled with 250 g of silica gel (particle size 0.04-0.063 mrn) and eluted with hexane/ethyl acetate (2:1). Concentration of the suitable fractions by evaporation yields 8.15 g of 5-[8-(N-benzyloxycarbonylamino)oct-l-en-2-yl]-oxazoline-4-carboxylic acid ethyl ester in the form of a colourless honey.
8.15 g (20.25 mmol) of 5-[8-(N-benzyloxycarbonylamino)oct-l-en-2-ylJ-oxazoline-4-carboxylic acid ethyl ester are heated under reflux in 40 ml of tetrahydrofuran and 20 ml of water for 4 hours with stirring. The reaction mixture is concentrated to dryness by evaporation in vacuo at 45, and the honey-like residue is concentrated by evaporation twice more after the addition of toluene. The crude produ~t is dissolved in dichloromethane, dried with sodium sulfate, filtered and concentrated by evaporation. Drying under a high vacuum at room temperature yields 9.03 g of 10-(N-benzyloxycarbonylamino)-2-fo~mylamino-3-hydroxy-4-methylene-decanoic acid ethyl ester in the form of a yellowish honey.
To 13,70 g (32.60 mmol) of crude 10-(N-benzyloxycarbonyl-arnino)-2-formylamino-3-hydroxy-4-methylene-decanoic acid ethyl ester in 137 ml of tetrahydrofuran there are added, under argon, 18.5 ml (156.4 mmol) of hexa-1,5-diene and then, dropwise at 10 within a period of 15 minutes, 6.1 ml (78.2 mmol) of thionyl bromide. The mixture is stirred for one hour at 10 and for 2 hours at room temperature and is then poured into 200 ml of ice-cold saturated sodium hydrogen carbonate solution;
the organic phase is separated off and re-extracted once with dichloromethane. The organic phases are washed with ice-cold O.S-norrnal sodium hydrogen carbonate solution and then with saturated sodium chloride solution, dri~d over sodium sulfate and concentrated to dryness by evaporation in vacuo at 40. 64 ml (260 mmol) of triisopropyl phosphite (96 %) are added immediately to the resulting crude 10-(N-benzyloxycarbonylam~no)-4-bromomethyl-2-forrnylamino-dec-3-enoic acid ethyl es~er (27 g, yellow honey), and the mixture is stirred for 17 hours at 80 under a pressure of approximately 100 mbar, the isopropyl bromide that forrns being captured in a cold trap (CO2). The excess triisopropyl phosphite is then distilled off under reduced pressure and the evaporation residue (23 g) is purified by chromatography on a column filled with 650 mg of silica gel (0.04-0.063 mm) with ethyl acetate/methanol (95:5). 8.73 g of 10-(N-benzyloxycarbonylamino)-4-diisopropylphosphonomethyl-2-formylamino-dec-3-enoic acid ethyl ester are obtained in the form of a yellowish honey.
Example 10: 2.25 g (6.98 mmol) of 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid ethyl ester are dissolved under argon in 45 ml of 2-normal hydrochloric acid and stirred for 17 hours at a bath temperature of 120. The clear, pale brown solution is concentrated by evaporation in a rotary evaporator. The residue is dissolved in 20 ml of ethanol and, after the addition of 30 ml of toluene, concentrated by evaporation in vacuo. This operation is repeated a further three times. The resulting beige foam is dissolved in 75 ml of absolute ethanol, and a solution of 15 ml of propylene oxide in 15 ml of ethanol is added dropwise within a period of 35 minutes. The crystalline suspension that forrns, which has a pH of 3, is filtered off after 1~ hours' stirring and washed thoroughly with ethanol and ether. Drying in vacuo yields 1.65 g of beige crude product, which is dissolved in the rninimum arnount of water (about 2 ml) and chrornatographed on a column filled with 67 g of reversed-phase silica gel (Opti-Up Cl2, particle size 40 ~,lm), using pure water as eluant, at a slight ove~pressure (0.2 bar). A pure fraction, Rf value on silica gel = 0.37 with n-propanoVwater/pyridine/acetic acid (15:12:10:3) as eluant, and several n~ixed fractions containing a by-product of Rf value = 0.48 are obtained.
Chromatography of those mixed fractions again and purification of the pure fractions, l ~2~r,~,~
followed by Iyophilisation from water, yield 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid hemi-hydrochloride hydrate in the form of an amorphous glass which slowly sinters at 134 and above and decomposes at 149 with foaming.
Example 11: 4.3 g (9.9 mmol) of 7-acetoxy-4-diisopropylphos-phonomethyl-2-formylamino-hept-3-enoic acid ethyl ester are dissolved in 25 ml of dichloromethane, and 5.1 ml (39.5 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 24 hours, 25 ml of ethanol are added dropwise, the rnixture is left to stand for a further 24 hours and is concentrated by evaporation, the residue is dissolved in 25 ml of ethanol, and a mixture of 25 ml of propylene oxide and 25 ml of ethanol is added dropwise. A suspension forrns, which is stirred for one hour at room temperature and for one hour in an ice bath and is then filtered with suction. Drying yields 2-amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid ethyl ester having a melting point of 210C (decomp.).
The starting material can be prepared, for example, as follows:
10 g (69.4 rnmol) of 5-acetoxypentanal, 6.37 g (78.~ mmol) of dimethylammonium chloride and 6.1 ml (81.2 mmol) of 37 % formaldehyde solution are refluxed for 1 -~ hours (bath temperature ~110C) with stirring. The mixture is allowed to cool and is extracted three tirnes with ether; the organic phases are combined, dried over MgSO4, filtered and concentrated by evaporation. 5-acetoxy-2-methylenepentanal is obtained in the forrn of a yellowlsh oil which can be reac~od without further purification.
9.6 g (61.5 rnmol) of 5-acetoxy-2-methylenepentanal and 7.38 rnl (67.6 rnmol) ofisocyanoacetic acid ethyl ester are placed in 70 ml of toluene at room temperature, and 250 mg of copper(I) oxide are added. When the exothermic reaction has subsided, the rnixture is stirred for a further one hour and is filtered over Hyflo~3) and concentrated by evaporation. The residue is taken up in 50 ml of tetrahydrofuran, 10 ml of water are added, and the mixture is refluxed for 3 hours. The mixture is concen~rated to dryness by evaporation, toluene is added, and the rnixture is again concentrated by evaporation.
Chromatography on silica gel with toluene/ethyl acetate (4:1) yields 7-acetoxy-2-formylarnino-3-hydroxy-4-methylene-heptanoic acid ethyl ester in the form of an orange oil.
2 ~ 3 ~
5.9 g (20.5 mmol) of 7-acetoxy-2-formylamino-3-hydroxy-4-methylene-heptanoic acid ethyl ester are dissolved in 60 ml of dichloromethane, and 1.9 ml (24.6 mmol) of thionyl bromide are added dropwise at room temperature. After one hour, 40 ml of water are added asld the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession Wit}l water, lN KHC03 solution and again with water, dried over MgS04, filtered and concentrated by evaporation.
7-acetoxy-4-bromomethyl-2-formylamino-hept-3-enoic acid ethyl ester is obtained in the form of a b;own oil, which is reacted further in the crude state.
6.1 g (17.4 mmol) of 7-acetoxy-4-bromomethyl-2-formylaminohept-3-enoic acid ethyl ester and 19.1 rïll (69.6 mmol) of tIiisopropyl phosphite (90 %) are heated to 80C and stirred under a pressure of approximately 130 mbar for 18 hours. The excess trusopropyl phosphite is distilled off and the residue is purified on silica gel with ethyl acetate. 7-acetoxy4-diisopropylphosphonomethyl-2-formylamino-hept-3-enoic acid ethyl ester is obtained in the form of a yellow oil.
Example 12: 1.1 g (3.9 mmol) of 2-asnino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid ethyl ester in 8 ml of water are stirred at 13ûC for 18 hours in a bomb tube. The dark reaction solution is treated with activated carbon and filtered over Hyflo~. The colourless filtrate is concentrated to ~3 ml, and ~25 ml of ethanol are added. The resul-ting suspension is filtered with suction and dried under a high vacuum at 50C.
2-amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid having a melting point from 190C and above (decomp.) is obtained.
Example 13: 8.2 g (18.9 mmol) of 6-(N-acetyl-N-methylan~ino)-4-diisopropylphosphonomethyl-2-formylanino-hex-3-enoic acid ethyl ester are dissolved in 40 ml of dichloromethane, and 9.8 ml (75.6 mmol) of trimethylbromosilane are added dropwise at room temperatlLre. The mixture is left to stand at room temperature for 24 hours, 40 ml of ethanol are added dropwise, tne mixture is left to stand for a fur~er 24 hours and is concentrated by evaporation, the residue is dissolved in 40 ml of ethanol, and a nixture of 40 ml of propylene oxide and 40 rnl of ethanol is added dropwise. A
suspension forms, which is stirred for a further one hour at room te nperature and for one hour at 0 and is then filtered with suction. Drying yields 6-(N-acetyl-N-methylamino)-2-amino-4-phosphonomethyl-hex-3-enoic acid ethyl ester having a melting point of 222-223C ~decomp.).
~, 35 ~2~a~
The starting material can be prepared, for example, as follows:
35.8 g (0.2 mol) of 4-aminobutyraldehyde-diethylacetal (90 %) are dissolved in 600 ml of dichloromethaule, 300 ml of saturated sodium hydrogen carbonate solution are added, and the mixture is cooled to 0C. 17 ml (0.24 mol) of acetyl chloride are added dropwise at 0-5C, and the mixture is stirred for a further 6 hours at 0-5C. The organic phase is separated off and the aqueous phase is extracted twice more with dichloromethane. The organic phases are combined, dried over MgS04, filtered and concentrated by evaporation in a rotary evaporator. The residue is purified by chromatography on silica gel with ethyl acetate. 4-(N-acetylamino)butyraldehyde-diethylacetal is obtained in the form of a yellowish oil.
35 g (172.2 mmol) of 4-(N-acetylamino)butyraldehyde-diethylacetal are dissolved in 180 ml of dimethylforrnarnide, 8.3 g (206.6 mmol) of sodium hydride dispersion (60 % in mineral oil) are added in portions, and the rnixture is stirred at room temperature for 45 minutes. 12.9 ml (206.6 mmol) of methyl iodide in 20 ml of dimethylformamide are then added, and the mixture is subsequently stirred at room temperature for 4 hours.
Water/ice is added to the reaction mixture, and the batch is extracted three times with ethyl acetate. The organic phases are washed with water and saturated sodium chloride solution, combined, dried over MgSO4, filtered and concentrated by evaporation. The residue is distilled under a high vacuum. 4-(N-acetyl-N-methylamino)butyraldehyde~
diethylacetal is obtained in the form of a colourless oil9 b.p.o I = 92-94.
30 g (138.2 mmol) of 4-(N-acetyl-N-methylamino)butyraldehydedlethylacetal, 12.6 g (154.4 mmol) of dimethylammonium chloride and 12.1 ml (161.7 mmol) of 37 %
formaldehyde solution are refluxed for 45 minutes with st-irring. I he mixture is allowed to cool and is extracted three times with dichloromethane. The organic phases are combined, dried over MgSO4, filtered and concentrated by evaporation. 4-(N-acetyl-N-methylamino)-2-methylene-butyraldehyde is obtained in the form of a yellowish oil which can be reacted without further purification.
19.9 g (128.3 mmol) of 4-(N-acetyl-N-methylamino)-2-methylene-butanal and 15.4 ml (141.1 mmol) of isocyanoacetic acid ethyl ester are placed at room temperature in ~0 ml of toluene, and 500 mg of copper(I) oxide are added. When the exothermic reaction has subsided, the mixture is stirred for a further one hour at room temperature, filtered over Hyflo(g) and concentrated by evaporation. The residue is taken up in 60 ml of 2 ~ J '~3 ~ 3 tetrahydrofuran, 20 ml of water are added, and the mixture is refluxed for 4 hours. The mixture is concentrated by evaporation, toluene is added, and the rnixture is again concentrated by evapor~tion. Chromatography on sllica gel with ethyl acetate/isopropanol (7:1) yields 6-(N-acetyl-N-methylamino)-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester in the forrn of a yellowish oil.
15.8 g (55.2 mmol) of 6-(N-acetyl-N-methylamino)-2-formyl-amino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 150 ml ofdichloromethane, and 5.1 ml (66.2 mmol) of thionyl bromide are added dropwise at room temperature. After one hour, 100 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, lN KHCO3 solution and again with water, dried over MgSO4, filtered and concentrated by evaporation. 6-(N-acetyl-N-methylamino)-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish-orange oil which is reacted further in the crude state.
16.0 g (45.8 mmol) of 6-(N-acetyl-N-methylamino)-4-bromo-methyl-2-formylamino-hex-3-enoic acid ethyl ester and 50~3 ml (183.3 mmol) of triisopropyl phosphite (90 %) are heated to 80 and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off and the residue is purified by chromatography on silica gel with ethyl acetate~lsopropanol (7:2). 6-(N-acetyl-N-methylamino)-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a yellow oil.
Example 14: 3.3 g (6.82 mrnol) of 6-benzoyloxy-4-diisopropyl-phosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester are dissolved in 20 ml of dichloromethane, and 3.52 ml (27.3 rnmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 22 hours, 20 ml of ethanol are added dropwise, the mixture is left to stand for a further 22 hours and is concentrated by evaporation, the residue is dissolved in 20 ml of ethanol, and a r~ixture of 20 ml of propylene oxide and 20 rlll of ethanol is added dropwise. A suspension forms, which is stirred for one hour at room temperature and for one hour at 0C and is then filtered with suction. Drying yields 2-arnino-6-benzoyloxy-2-amino-4-phos-phonom~thyl-hex-3-enoic acid ethyl ester having a melting point of 236-237C (decomp.).
The starting material can be prepared, for example, as follows:
~ ,323 v3~
10 g (52 mmol) of 4-benzoyloxybutanal, 4.78 g (58.6 mmol) of dimethylammonium chloride and 4.6 ml (60.8 mmol) of formaldehyde solution (37 %) are refluxed for one hour with stirring (bath temperature ~110C). The rnixture is allowed to cool and is extracted three times with ether; the organic phases are combined, washed with saturated sodium chloride solution, dried over MgS04, filtered and concentrated by evaporation.
4-benzoyloxy-2-methylenebutanal is obtained in the form of a yellowish oil which can be reacted without further purification.
10 g (49 mmol) of 4-benzoyloxy-2-methylenebutanal and 5.3 ml (49 mmol) of isocyanoacetic acid ethyl ester are placed at room temperature in 70 ml of toluene, and 200 mg of copper(I) oxide are added. When the exothermic reaction has subsided, the mixture is stirred for a further one hour, filtered over Hyflo(~) and concentrated by evaporation. The residue is taken up in 50 ml of tetrahydrofuran, 10 ml of water are added, and the rnixture is refluxed for 3 hours. The mixture is concentrated by evaporation, toluene is again added, and the rnixture is again concentrated by evaporation.
Chrornatography on silica gel with toluene/ethyl acetate (3:2) yields ~benzoyloxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester in theform of a brown oil.
8 g (23.9 rnmol) of 6-benzoyl-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 80 ml of dichloromethane, and 2.22 ml (28.6 mmol) of thionyl bromide are added dropwise at room temperature. After 2 hours, 60 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, lN KHCS)3 solution and again with water, dried over MgSO4, filtered and concentrated by evaporation.
6-benzoyloxy-4-bromomethyl-2-forrnyIarninc~hex-3-enoic acid ethyl ester is obtained in the form of a brown oil which is reacted fur~er in the crude state.
8.4 g (21 mrnol) of 6-benzoyloxy-4-bromomethyl-2-formylamino-hex-3-enoic asid ethyl -ester and 23 ml (84 mmol) of triisopropyl phosphite (90 %) are heated to 80C and stirred under a pressure of ~130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off and the residue is purified by chromatography on silica gel with ethyl acetate. 6-benzoyloxy-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a brown oil.
2 ~ 2 ~
Example 15: 4.0 g (8.51 mmol) of 6-ben~yloxy-4-diisopropyl-phosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester are dissolved in 24 ml of dichloromethane, and 4.4 ml (34 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 22 hours, 24 ml of ethanol are added dropwise and the mixture is left to stand for a further 24 hours and is concentrated by evaporation in a rotary evaporator, the residue is dissolved in 24 ml of ethanol, and a mixture of 24 ml of propylene oxide and 24 ml of ethanol is added drop-wise. ~ suspension forms, which is stirred for a further one hour at room temperature and for one hour at 0 and is then filtered with suction. Drying yields 2.2 g of a white crys-talline product which is a mixture of 2-amino-6-benzyloxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester and 2-amin~
6-benzyloxy-4-phosphonomethyl-hex-3-enoic acid. To obtain a uniform product, that mixture is hydrolysed overnight at room temperature with 20 ml of N-sodium hydroxide solution in 30 ml of ethanol, acidified with N-hydrochloric acid and neutralised with propylene oxide. Since the product crystallises poorly, it is concentrated by evaporation in a rotary evaporator, the residue is filtered in water over 20 g of silica gel, and the fractions containing the desired product are concentrated by evaporation in a rotary evaporator. The residue is dissolved with 10 ml of tert.-butanoVwater (1:1) and freeze-dried.
2-amino-6-benzyloxy-4-phosphonomethyl-hex-3-enoic acid is obtained in the form of a lyophilisate.
The starting material can be prepared, for example, as follows:
6 g (0.2 mol) of a sodium hydride dispersion (80 % in white oil) are placed at room temperature in 120 ml of absolute dimethylformamide, and 22.2 ml (0.25 mol) of 1,4-butanediol are added dropwise. When the addition is complete, the mixture is stirred for a further 30 minutes at room ~emperature. 23.1 rnl (0.2 mol) of benzyl chloride are then slowly added dropwise, a slight exothermic reaction being observed. The reaction mixture is stirred overnight at room temperature, water/ice is added, and the mixture is extracted twice with ether. The organic phases are washed with water and with saturated sodium chloride solution, combined, dried over MgSO4, filtered and concentrated by evaporation. The residue is subjected to fractional distillation under a waterjet vacuum over a 10 cm Yigreux column. 4-benzyloxybu~anol is obtained, b.p.22 = 161-162.
36.6 g (170 mmol) of pyridinium chlorochromate are placed at room temperature in120 ml of dichloromethane under N2, and a solution of 20.4 g (113 mmol) of ., ~ ~ 2 s3 ~3 ~ ~
4-benzyloxybutanol in 20 ml of dichloromethane is added. The reaction mixture rapidly becomes dark and the reaction is slightly exothermic. The reaction mixture is stirred at room temperature for 3~ hours. The supernatant dichloromethane phase is decanted off and concentrated by evaporation in a rotary evaporator. The residue is filtered over 100 g of silica gel. The product fractions are concentrated by evaporation in a rotary evaporator and distilled under a high vacuum over a 10 cm Vigreux column. 4-benzyloxybutanal is obtained, b.p.o I = 72-73.
8.0 g (44.9 mmol) of 4-benzyloxybutanal, 4.12 g (50.6 mmol) of dimethylammonium chloride and 3.95 ml (52.6 rnrnol) of 37 % formaldehyde solution are kept at a bath temperature of 110 for one hour with stirring. The mixture is allowed to cool and is extracted ~hree times with ether. The organic phases are washed with saturated sodium chloride solution, combined, dried over MgSO4, filtered and concentrated by evaporation.
4-benzyloxy-2-methylenebutanal is obtained in ~he form of a yellowish oil which can be reacted further without further purification.
.
8.0 g (42 mrnol) of 4-benzyloxy-2-methylenebutanal and 4.57 ml (42 rnmol) of isocyanoacetic acid ethyl ester are placed in 60 ml of toluene, and 200 mg of copper(I) oxide are added. When the exothermic reaction has subsided, the mixture is sti~red for a further 2 hours, filtered over Hyflo~ and concentrated by evaporation. The residue is taken up in 50 ml of tetrahydrofuran, 10 ml of water are added, and the mixture is refluxed for 3 hours. The mixture is concentrated to dryness by evaporation, toluene is added, and the mixture is again concentrated by evaporation. Chromatography on silica gel with toluene/ethyl acetate (3:2) as eluant yields ~benzyloxy-2-formylarnino-3-hydroxy-4-methylene-hexanoic acid ethyl ester in the form of a reddish-brown oil.
7.0 g (21.8 mmol) of 6-benzyloxy-2-formylamin~3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 70 ml of dichloromethane, and 2.0 ml (26.1 mmol) of thionyl bromide are added dropwise at room temperature. After 2 hours, 40 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, N-KHC03 solution and again with water, dlied over MgSO4, filtered and concentrated by evaporation.
~benzyloxy-4-bromomethyl-2-formylarnino-hex-3-enoic acid ethyl ester is obtained in the form of a reddish-brown oil which can be reacted further without purification.
7.9 g (20.5 mmol) of 6-benzyloxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ,, ~2w~
ester and 22.5 ml (82.2 mmol) of ~iisopropyl phosphite (90 %) are heated to 80 and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off in a rotary evaporator and the residue is puri~led bychromatography on silica gel with ethyl acetate. 6-benzoyl-4-diisopropyl-phosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish oil.
Example 16: 3.15 g (6.84 mmol) of 4-(1-acetylpiperidin-4-yl)-5-diisopropylphosphono-2-formylamino-pent-3-enoic acid ethyl ester are dissolved in 17 ml of dichloromethane, and 3.54 ml (27.3 mmol) of trimethylbromosilane are added dropwise at room temperature. The rnixture is left to stand at room temperature for 16 hours, 17 ml of ethanol are added dropwise, the mixture is left to stand for a further 18 hours and is concentrated by evaporation in a rotary evaporator, the residue is dissolved in 12 ml of ethanol, and a mixture of 3 ml of propylene oxide and 3 ml of ethanol is added.
A suspension forms, which is stirred for a further 2 hours at room temperature and for 2 hours with ice cooling and is then filtered with suction. 2-amino-4-(1-acetyl-piperidin-4-yl)-5-phosphono-pent-3-enoic acid ethyl ester having a melting point of 225 (decomp.) is obtained.
The starting material can be prepared, for example, as follows:
3.95 g (23.3 mmol) of 2-(1-acetylpiperidin-4-yl)ethanol, 2.12 g (26.3 mmol) of dimethylammonium chloride and 3 ml (40 mmol) of 37 % formaldehyde solution are heated at 110C for 2 hours with sti~ing. The mixture is allowed to cool and is extracted several times with diethyl ether. The organic phases are combined, washed with saturated sodium ch!oride solution, d~ied over sodium sulfate, filtered and concentrated to dryness by evaporation. 2-(1-acetylpiperidin-4-yl)propenal is obtained in the foml of a yellowish oil which can be further reas~ted without further purification.
2.9 g (16.0 mmol) of 2-(1-acetylpiperidin-4-yl)propenal and 1.75 ml (16 mmol) ofisocyanoacetic acid ethyl ester are dissolved in 13 ml of toluene, and 46 mg of copper(I) oxide are added. When the exotherrnic reaction has subsided, the mixture is stiIred for a further 2 hours, filtered over Hyflo~) and concentrated to dryness by evaporation. The residue is taken up in 13 ml of tetrahydrofuran, 6 rnl of water are added, and the rnixture is heated under reflux for 2 hours with stirling. The mixture is concentrated to dryness by evaporation, toluene is added, and the mixture is again concentrated by evaporation.
~2~
Chromatography on silica gel with ethyl acetate/methanol (9:1) as eluant yields 4-(1-acetylpiperidin-4-yl)-2-formylarnino-3-hydroxy-pent-4-enoic acid ethyl ester in the form of a yellowish-brown oil.
3.3 g (10.5 mmol) of 4-(1-acetylpiperidin-4-yl)-2-formylamino-3-hydroxy-pent-4-enoic acid ethyl ester are dissolved in 25 ml of 1,2-dichloroethane, and 0.98 ml (12.6 mmol) of thionyl bromide are added dropwise at room temperature. After 1~ hours, 20 ml of water are added and the mixture is stirred vigorously for 15 minutes. The organic phase is separated off, washed in succession with water, N-potassium hydrogen carbonate solution and again with water, dried over sodium sulfate, filtered and concentrated by evaporation.
4-(1-acetylpiperidin-4-yl)-5-bromo-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a reddish-brown oil.
2.68 g (7.14 mmol) of 4-(1-acetylpiperidin-4-yl)-5-bromo-2-formylamino-pent-3-enoic acid ethyl ester and 7.5 ml (28.5 mmol) of triisopropyl phosphite (90 %) aIe heated to 80 and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off under reduced pressure and the evaporation residue is purified by chromatography on silica gel with ethyl acetate/methanol (9:1).
4-(1-acetylpiperidin-4-yl)-5-diisopropylphosphono-2-forrnylamino-pent-3-enoic acid ethyl ester is obtained in the form of a yellowish oil.
Example 17: 1 g (2.17 mrnol) of 4-(1-acetylpiperidin-4-yl)-5-diisopropylphosphono-2-formylamino-pent-3-enoic acid ethyl ester is heated under re~lux in 20 ml of 6N hydrochloric acid for 8 hours. After concentration by evaporation, the residue is dissolved in 25 ml of ethanol. 3 ml of propylene oxide are then added, ~e mixture is stirred for 2 hours at room temperature and for one hour with ice cooling, and then the suspension that has formed is filtered off with suction.
2-amino-4-(piperidin-4-yl)-5-phosphono-pent-3-enoic acid having a melting point of 212 (decomp.) is obtained.
Example 18: 0.68 g (1.49 mmol) of 5-benzyloxy-4-diisopropyl-phosphonomethyl-2-formylamino-pent-3-enoic acid ethyl ester is dissolved in 10 ml of dichloromethane, and 0.8 ml (~ mmol) of trimethylbromosilane is added dropwise at room temperature. The mixture is left to stand at room temperature for 6 hours, I0 ml of ethanol are added dropwise, the mixture is left to stand for a further 18 hours and is concent~ated by evaporation, the residue is dissolved in 5 ml of ethanol, and a rnixture of ~2~ 38 S ml of propylene oxide and S ml of ethanol is added dropwise. A suspension forms, which is stirred at room temperature for 2 hours and is then filtered with suction. Drying yields 2-amino-5-benzyloxy-4-phosphonomethyl-pent-3-enoic acid ethyl ester having a melting point of 218-220 (decomp.).
The starting material can be prepared, for example, as follows:
3.0 g (62.4 mmol) of 50 % sodism hydride dispersion in mineral oil are placed in 50 ml of tetrahydrofuran and 40 ml of dimethylformarnide, a solution of 10.0 g (62.4 mrnol) of 3-hydroxy-2-methylenepropionaldehyde-diethylacetal in 10 ml of tetrahydrofuran is slowly added dropwise at 0, and the mixture is stirred at 0 for 2 hours. The mixture is diluted with 15 rnl of tetrahydrofuran and 10 ml of dimethylformamide and stiIred at room temperature for a further 2 hours. 7.2 ml (62.4 mmol) of benzyl chlolide in 10 ml of dimethylformamide are then added at 0, and the mixture is stirred at room temperature for 18 hours. Water is added to the reaction mixture, which is then extracted three times with ethyl acetate, and the organic phases are washed with saturated sodium chloride solution. The organic phases are combined, dlied over Na2S04, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with methylene chloride, yielding 3-benzyloxy-2-methylenepropionaldehyde-diethylacetal in the form of a pale yellowish liquid.
4.8 g (1~.1 mmol) of 3-benzyloxy-2-methylenepropionaldehyde-diethylacetal and 0.36 g (1.9 mmol) of p-toluenesulfonic acid monohydrate are stiITed for 3 hours in 60 ml of acetone. The mixture is diluted with 400 ml of methylene chloride, extracted with N-KHC03 solution and saturated sodium chloride solution, dried over Na2S04, filtered and concentrated by evaporation. The 3-benzyloxy-2-methylenepropanol that remains (yellow liquid) is placed at room temperature, without further purification, together with 2.1 ml (19 mmol) of isocyanoacetic acid ethyl ester, in 25 rnl of toluene, and 50 mg of copper(I) oxide are added. When the exothermic reaction has subsided, the rnixture is stirred for a further one hour at room temperature, filtered over Hyllo~) and concentrated by evaporation. The residue is taken up in 25 ml of tetrahydrofuran, 5 ml of water are added, and the rIuxture is refluxed for 4 hours. The mixture is concentrated by evaporation, toluene is added, and the rnixture is again concentrated by evaporation.
Chromatography on silica gel with toluene/ethyl acetate (1:1) and subsequent crystal-Iisation from diethyl eth~r yield S-benzyloxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid ethyl ester having a melting point of 112-114C.
~J~
1.0 g (3.25 mmol) of S-benzyloxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid ethyl ester are suspended in 30 ml of 1,2-dichloroethane, and 0.38 ml (4.9 mmol) of thionyl chloride is added dropwise at room temperature. After 45 minutes, 20 ml of water are added to the yellow solution, and the mixture is stirred vigorously for 15 minutes. The organic phase is separated off, washed with saturated sodium chloride solution, dried over Na2SO4, filtered and concentrated by evaporation.
S-benzyloxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a yellowish oil which is reacted further in the crude state.
1.14 g (3.1 mmol) of S-benzyloxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester and 10 rnl (38.5 mmol) of triisopropyl phosphite (95 %) are heated to 80C and stirred under a pressure of approximately 130 mbar for 3~ hours. The excess triisopropyl phosphite is distilled off and the residue is purified by chromatography on silica gel with ethyl acetate. S-benzyloxy-4~iisopropylphosphonomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a yellowish oil.
Example 19: 1.10 g (2.8 mrnol) of S-ethoxy-4-diisopropylphos-phonomethyl-2-forrnylamino-pent-3-enoic acid ethyl ester are dissolved in 20 ml of dichloromethane, and 1.6 ml (12.3 mmol) of trimethylsilane are added dropwise at room temperature. The rnixeure is left to stand at room temperature for 7 hours, 20 rnl of ethanol are added, the mixture is left to stand for a further 15 hours and is concentrated by evaporation, the residue is dissolved in 10 rnl of ethanol, and a mixture of 10 ml of propylene oxide and 10 ml of ethanol is added dropwise. A suspension folms, which is stirred at room temperature for 2 hours and is then ~lltered with suction. Drying yields 5-ethoxy-2-amino-4-phosphonomethyl-pent-3-enoic acid ethyl ester having a melting point of 217-218C (decomp.).
The starting matenal can be prepared, for example, as follows:
50 g (283 mmol) of 3-ethoxypropionaldehyde-diethylacetal, 27.3 g (335 mmol) of dimethylammonium chloride and 30 ml (392 mmol) of 36 % formaldehyde solution areheated at 110C for 2 hours with stirring. The mixture is allowed to cool and is extracted ~hree times with diethyl ether. The organic phases are washed with saturated sodium chloride solution, combined, dried over sodium sulfate, filtered and concentrated to dryness by evaporation. 2-ethoxypropanol is obtained in the form of a yellow liquid 3 rJ ,~
which can be reacted -further without further purification.
4.2 g (36.1 mmol) of 2-ethoxypropanol and 4.4 ml (40 mmol) of isocyanoacetic acid ethyl ester are dissolved in 50 ml of toluene, and 200 mg of copper(I) oxide are added. When the exotherrnic reaction has subsided, the mixture is stirred for a further one hour, filtered over Hyflo(~) and concentrated to dryness by evaporation. The residue is taken up in 50 ml of tetrahydrofuran, 12 ml of water are added, and the mixture is heated under reflux for one hour with stirring. The mixture is concentrated to dryness by evaporation, toluene is added, and the mixture is again concentr~ted by evaporation. Chromatography on silica gel with toluene/isopropanol (9:1) as eluant yields 5-ethoxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid ethyl ester in the form of a yellow oil.
3.70 g (15.1 mrnol) of 5-ethoxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid ethyl ester are dissolved in 100 ml of 1,2-dichloroethane, and 1.8 rnl (22.8 mmol) of thionyl bromide are added dropwise at room temperature. After one hour, 100 ml of water are added and the rnixture is stirred vigorously for 15 minutes. The organic phase is separated off, washed in succession with lN potassium hydrogen carbonate solution and with brine, dried over sodium sulfate, filtered and concentrated by evaporation.5-ethoxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a yellowish-brown oil which is reacted further in the crude state.
3.12 g (10.1 mmol) of 5-ethoxy-4-bromomethyl-2-formylanuno-pent-3-enoic acid ethyl ester and 30 ml (118 mmol) of triisopropyl phosphite (90 %) are heated to 80C and stirred under a pressure of approximately 130 mbar for 7 hours. The excess ~iisopropyl phosphite is distilled off and the residue is purified by chromatography on silica gel with methylene oxide/methanol (97:3 to 9S:S). 5-ethoxy-4-dihydropropylphos-phonomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a yellow oil.
Example 20: Tablets, each containing 50 mg of 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or a salt, for example the sodium salt, thereof, can L~ prepared as follows:
Composi~ion (10LOOO tablets) active ingredient 500.0 g ~; ~ 2 ~ 3 eJ ~
lactose 500.0 g potato starch 352.0 g gelatin 8.0 g talcurn 60.0 g magnesium stearate 10.0 g silica (highly disperse) 20.0 g ethanol q.s.
The active ingredient is mixed with the lactose and 292 g of potato starch, and the mixture is moistened with an ethanolic solution of the gelatin and granulated through a sieve.
After drying, the remaining potato starch, the magnesium stearate, the talsum and the silica are mixed in and the mixture is compressed to form tablets which each weigh 145.0 mg and contain 50.0 mg of active ingredient, and which may, if desired, be provided with dividing notches for finer adaptation of the dose.
Example 21. Coa~ed tablets, each containing 100 mg of 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or a salt, for example the sodium salt, thereof, can be prepared as follows:
Composition (for 1.000 coated tablets) activeingredient 100.0 g lactose 100.0 g com starch ~0.0 g talcum ~ 8.5 g calciumstearate 1.5 g hydroxypropylmethylcellulose 2.36 g shellac 0.64 g water q.s.
methylene chloride q.s.
The active ingredient, the lactose and 40 g of the corn starch are mixed, and the mixture is moistened with a paste, prepared from 15 g of the corn starch and water (with heating), and granulated. The granulate is dried, the remaining corn starch, the talcum and the calcium stearate are added and mixed with the granulate. The rnixture is compressed to fonn tablets (weight: 280 mg), which are coated with a solution of the 2~2~3~
hydroxypropylmethylcellulose and the shellac in methylene chloride. Final weight of the coated tablet: 283 mg.
Example 22- Gelatin dry-filled capsules, containing 100 mg of active ingredient, for example 2-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or a salt, for example the sodium salt, thereof, can be prepared, for exarnple, as follows:
Composition (for 1~000 capsules) activeingredierlt 100.0 g lactose 250.0 g microcrystalline cellulose 30.0 g sodiumlaurylsulfate 2.0 g magnesium stearate 8.0 g The sodium lauryl sulfate is added to the Iyophilised active ingredient through a sieve having a mesh size of 0.2 mm. The two components are intimately mixed. Then, first the lactose is added through a sieve having a mesh size of 0.6 mm and then the microcrystalline cellulose through a sieve having a mesh size of 0.9 mm. The mixture is again intimately mixed for 10 minutes. Finally, the magnesium stearate is added through a sieve having a mesh size of 0.8 mm. After further mixing for 3 minutes, size 0 gelatin dry-fill capsules are each filled with 390 mg of the resulting formulation.
Example 23: A 0.2 % injection or infusion solution of 2-amino-~hydroxy-4-phosphonomethyl-hex-3-enoic acid or of a salt, for example the sodium salt, thereof can be prepared, for example, as follows:
.
Composit on (for 11000 ampoules) active ingredient 5.0 g sodium chloride 22.5 g phosphate buffer pH = 7.4 300.0 g dernineralised water ad 2500.0 ml The active ingredient and the sodium chloride are dissolved in 1000 ml of water and filtered through a micro-filter. The buffer solution is added, and the mixture is made up to , .
2~2~3~
2500 ml with water. To prepare dosage unit forms, 1.0 or 2.5 ml are introduced into each glass ampoule, which then contains 2.0 or 5.0 mg, respectively, of active ingredient.
Example 24: In a manner analogous to that described in Examples 1 to 10 also thefollowing compound can be m~nufactured:
2-amino-8-hydroxy-4-phosphonomethyl-oct-3-enoic acid e~hyl ester, m.p. 230-233 (decomp.);
2-amino-6-hydroxy-5-hydroxymethyl-4-phosphonomethyl-hex-3-enoic acid ethyl ester, m.p. 177-180, and 2-amino-10-hydroxy-4-phosphonomethyl-dec-3-enoic acid ethyl ester, m.p. 243-244(decomp.).
Example 25: In a manner analogous to that described in Examples 20 to 23, it is also possible to prepare pharmaceutical preparations containing a different compound of formula I according to any one of Examples 1 to 19. and 24
Claims (28)
1. A substituted 2-aminoalk-3-enoic acid derivative of formula I
(I) wherein R1 is an aliphatic hydrocarbon radical that is substituted by optionally acylated or aliphatically or araliphatically etherified hydroxy, by halogen, by optionally acylated and/or aliphatically substituted amino or by an aza-, diaza-, azoxa- or oxa-cycloaliphatic radical, or is an oxacycloaliphatic hydrocarbon radical bonded via a carbon atom, or is an optionally aliphatically N-substituted or N-acylated azacycloaliphatic hydrocarbon radical, and R2 is free or esterified carboxy, or a salt thereof.
(I) wherein R1 is an aliphatic hydrocarbon radical that is substituted by optionally acylated or aliphatically or araliphatically etherified hydroxy, by halogen, by optionally acylated and/or aliphatically substituted amino or by an aza-, diaza-, azoxa- or oxa-cycloaliphatic radical, or is an oxacycloaliphatic hydrocarbon radical bonded via a carbon atom, or is an optionally aliphatically N-substituted or N-acylated azacycloaliphatic hydrocarbon radical, and R2 is free or esterified carboxy, or a salt thereof.
2. A compound according to claim 1 of formula I, wherein R1 is mono- or di-hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, benzoyloxy-lower alkyl, lower alkoxy-lower alkyl, phenyl-lower alkoxy-lower alkyl, halo-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, lower alkanoylamino-lower alkyl, di-lower alkylamino-lower alkyl, N-lower alkyl-N-lower alkanoylamino-lower alkyl, 5- to 7-membered azacycloalkyl-lower alkyl whose azacycloalkyl moiety is bonded via the N
atom or a carbon atom and, in the latter case, may be N-lower alkylated, N-loweralkanoylated or N-substituted by a benzoyl group that is unsubstituted or substituted in the phenyl moiety, 5- to 7-membered diazacycloalkyl-lower alkyl whose diazacycloalkyl moiety is bonded via an N atom and is optionally N'-lower alkylated, N'-lower alkanoylated or N'-substituted by a benzoyl group that is unsubstituted or substituted in the phenyl moiety, 5- to 7-membered azoxacycloalkyl-lower alkyl bonded via the N atom, 5- to 7-membered oxacycloalkyl-lower alkyl bonded via a carbon atom, 5- to 7-membered azacycloalkyl that is bonded via a carbon atom and is optionally N-lower alkylated, N-lower alkanoylated or N-substituted by a benzoyl group that is unsubstituted or substituted in the phenyl moiety, or 5- to 7-membered oxaacycloalkyl bonded via a carbon atom, and R2 is carboxy, lower alkoxycarbonyl, 4- up to and including 7-membered cyclo-alkoxycarbonyl or phenyl-lower alkoxycarbonyl, any phenyl radicals in the mentioned groups R1 and/or R2 being unsubstituted or mono-, di- or tri-substituted by lower alkyl, lower alkoxy, halogen, cyano and/or by trifluoromethyl, or a salt thereof.
atom or a carbon atom and, in the latter case, may be N-lower alkylated, N-loweralkanoylated or N-substituted by a benzoyl group that is unsubstituted or substituted in the phenyl moiety, 5- to 7-membered diazacycloalkyl-lower alkyl whose diazacycloalkyl moiety is bonded via an N atom and is optionally N'-lower alkylated, N'-lower alkanoylated or N'-substituted by a benzoyl group that is unsubstituted or substituted in the phenyl moiety, 5- to 7-membered azoxacycloalkyl-lower alkyl bonded via the N atom, 5- to 7-membered oxacycloalkyl-lower alkyl bonded via a carbon atom, 5- to 7-membered azacycloalkyl that is bonded via a carbon atom and is optionally N-lower alkylated, N-lower alkanoylated or N-substituted by a benzoyl group that is unsubstituted or substituted in the phenyl moiety, or 5- to 7-membered oxaacycloalkyl bonded via a carbon atom, and R2 is carboxy, lower alkoxycarbonyl, 4- up to and including 7-membered cyclo-alkoxycarbonyl or phenyl-lower alkoxycarbonyl, any phenyl radicals in the mentioned groups R1 and/or R2 being unsubstituted or mono-, di- or tri-substituted by lower alkyl, lower alkoxy, halogen, cyano and/or by trifluoromethyl, or a salt thereof.
3. A compound according to claim 1 of formula I, wherein R1 is hydroxy-C1-C7alkyl, dihydroxy-C2-C7alkyl, C2-C7alkanoyloxy-C1-C7alkyl, benzoyloxy-C1-C7alkyl that isunsubstituted or mono- or di-substituted in the phenyl moiety by C1-C4alkyl, C1-C4alkoxy, halogen having an atomic number of up to and including 35, cyano and/or by trifluoromethyl, C1-C4alkoxy-C1-C7alkyl, a phenyl-C1-C4alkoxy-C1-C7alkyl group that is unsubstituted or mono- or di-substituted in the phenyl moiety by C1-C4alkyl, C1-C4alkoxy, halogen having an atomic number of up to and including 35, cyano and/or by trifluoromethyl, halo-C1-C7alkyl, in which halogen is chlorine or fluorine, amino-C1-C7alkyl, C1-C4alkylamino-C1-C7-alkyl, C2-C7alkanoylamino-C1-C7alkyl, N-C2-C7alkanoyl-N-C1-C4alkylamino-C1-C7-alkyl, di-C1-C7alkylamino-C1-C7alkyl, azacycloalk-1-yl-C1-C7alkyl, azacycloalk-3-yl-C1-C7alkyl or-4-yl-C1-C7alkyl, 1-C2-C7alkanoylazacycloalk-3-yl-C1-C7alkyl or -4-yl-C1-C7alkyl, N-C1-C4-alkylazacycloalk-3-yl-C1-C7alkyl or-4-yl-C1-C7alkyl, N-C1-C4benzoylaza-cycloalk-3-yl-C1-C7alkyl or -4-yl-C1-C7alkyl, diazacycloalk-1-yl-C1-C7alkyl, N'-C1-C4alkyldiazacycloalk-1-yl-C1-C7alkyl, N'-C2-C7alkanoylazacycloalk-1-yl-C1-C7alkyl, azoxacycloalk-1-yl-C1-C7alkyl, 5- to 7-membered oxacycloalk-3-yl-C1-C7alkyl or -4-yl-C1-C7alkyl, 5- to 7-membered azacycloalk-3-yl or -4-yl or 1-C2-C7alkanoylazacycloalk-3-yl or -4-yl, N-C1-C4alkylazacycloalk-3-yl or -4-yl, or N-benzoylazacycloalk-3-yl or -4-yl that is unsubstituted or substituted in the phenyl moiety, or 5- to 7-membered oxacycloalk-3-yl or -4-yl, and R2 is carboxy, C1-C4-alkoxycarbonyl, 5- to 7-membered cyclolakoxycarbonyl, or phenyl-C1-C4alkoxycarbonyl that is unsubstituted or mono- or di-substituted by C1-C4alkyl, C1-C4alkoxy, halogen having an atomic number of up to and including 35, cyano and/or by trifluoromethyl, or a salt thereof.
4. A compound according to claim 1 of formula I, wherein R1 is hydroxy-C1-C7alkyl, benzoyloxy-C1-C7alkyl that is unsubstituted or mono- or di-substituted in the phenyl moiety by C1-C4alkyl, C1-C4alkoxy, halogen having an atomic number of up to and including 35, cyano and/or by trifluoromethyl, phenyl-C1-C4alkoxy-C1-C7alkyl that is unsubstituted or mono- or di-substituted in the phenyl moiety by C1-C4alkyl, C1-C4-alkoxy, halogen having an atomic number of up to and including 35, cyano and/or by trifluoromethyl, halo-C1-C7alkyl, in which halogen is chlorine or fluorine, amino-C4-C7alkyl, N-C2-C7alkanoyl-N-C1-C4alkylamino-C1-C7alkyl or 5- to 7-membered azacycloalk-3-yl or -4-yl or 1-C2-C7alkanoylazacycloalk-3-yl or -4-yl, and R2 is carboxy, C1-C4alkoxycarbonyl or phenyl-C1-C4alkoxycarbonyl that is unsubstituted or mono- or di-substituted by C1-C4alkyl, C1-C4alkoxy, halogen having an atomic number of up to and including 35, cyano and/or by trifluoromethyl, or a salt thereof.
5. A compound according to claim 1 of formula I, wherein R1 is hydroxy-C1-C7alkyl, C1-C4alkoxy-C1-C7alkyl, benzoyloxy-C1-C4alkyl, amino-C4-C7alkyl, N-C2-C7-alkanoyl-N-C1-C4alkylamino-C2-C7alkyl, 5- to 7-membered azacycloalk-3-yl or -4-yl or 1-C2-C7alkanoylazacycloalk-3-yl or -4-yl, or halo-C1-C4alkyl, in which halogen is chlorine or fluorine, and R2 is carboxy or C1-C4alkoxycarbonyl, or a salt thereof.
6. A compound according to claim 1 of formula I, wherein R1 is hydroxymethyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-benzoyloxyethyl, benzyloxymethyl,2-benzyloxyethyl, 4-aminobutyl, 6-aminohexyl, 2-(N-acetyl-N-methylamino)ethyl, piperidin-4-yl, 1-acetylpiperidin-4-yl or 2-fluoroethyl, and R2 is carboxy or C1-C4alkoxycarbonyl, or a salt thereof.
7. A compound according to claim 1 of formula I, wherein R1 is amino-C4-C7alkyl,N-C1-C4alkanoyl-N-C1-C4alkylamino-C1-C7alkyl, piperidin-4-yl or 1-C2-C7-alkanoylpiperidin-4-yl, and R2 is carboxy or C1-C4alkoxycarbonyl, or a salt thereof.
8. A compound according to claim 1 of formula I, wherein R1 is hydroxy-C1-C4alkyl, C1-C4alkoxy-C1-C4alkyl, phenyl-C1-C4alkoxy-C1-C4alkyl, benzoyloxy-C1-C4alkyl or halo-C2-C4alkyl, and R2 is carboxy or C1-C4alkoxycarbonyl, or a salt thereof.
9. A compound according to claim 1 of formula I, wherein R1 is C1-C4alkoxy-C2-C4alkyl, hydroxy-C2-C4alkyl or halo-C2-C4alkyl, and R2 is carboxy, C1-C4alkoxycarbonyl or a phenyl-C1-C4alkoxycarbonyl group that is unsubstituted or mono- or di-substituted by C1-C4alkyl, C1-C4alkoxy, halogen having an atomic number of up to and including 35, cyano and/or by trifluoromethyl, or a salt thereof.
10. 2-Amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester or a salt thereof.
11. 2-Amino-6-hydroxy-4-phosphonomethyl-hex-3-enoic acid or a salt thereof.
12. 2,10-Diamino-4-phosphonomethyl-dec-3-enoic acid or a salt thereof.
13. 2,8-Diamino-4-phosphonomethyl-oct-3-enoic acid or a salt thereof.
14. 2-Amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester or a salt thereof.
15. 2-Amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid ethyl ester or a salt thereof.
16. 2-Amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid or a salt thereof.
17. 2-Amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid ethyl ester or a salt thereof.
18. 2-Amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid or a salt thereof.
19. 2-Amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid or a salt thereof.
20. 2-Amino-5-hydroxy-4-phosphonomethyl-pent-3-enoic acid ethyl ester or a salt thereof.
21. 2-Amino-5-hydroxy-4-phosphonomethyl-pent-3-enoic acid or a salt thereof.
22. 5-Ethoxy-2-amino-4-phosphonomethyl-pent-3-enoic acid ethyl ester or a salt thereof.
23. 2-Amino-8-hydroxy-4-phosphonomethyl-oct-3-enoic acid ethyl ester or a salt thereof.
24. 2-Amino-6-hydroxy-5-hydroxymethyl-4-phosphonomethyl-hex-3-enoic acid ethyl ester or a salt thereof.
25. 2-Amino-10-hydroxy-4-phosphonomethyl-dec-3-enoic acid ethyl ester or a salt thereof.
26. A pharmaceutical preparation containing an therapeutically effective amount of a compound according to any one of claims 1 to 25 in the free form or in the form of a pharmaceutically acceptable salt in admixture to conventional pharmaceutical auxiliaries.
27. A process for the preparation of unsaturated aminocarboxylic acid derivatives of formula I
(I), wherein R1 is an aliphatic hydrocarbon radical that is substituted by optionally acylated or aliphatically or araliphatically etherified hydroxy, by halogen, by optionally acylated and/or aliphatically substituted amino or by an aza-, diaza-, azoxa- or oxa-cycloaliphatic radical, or is an oxacycloaliphatic hydrocarbon radical bonded via a carbon atom, or is an optionally aliphatically N-substituted or N-acylated azacycloaliphatic hydrocarbon radical, and R2 is free or esterified carboxy, and their salts, which comprises in a compound of formula II
(II), wherein Z1, Z2 are optionally protected hydroxy, Z3 is an aliphatic hydrocarbon radical that is substituted by optionally protected or acylated or aliphatically or araliphatically etherified hydroxy, by halogen, by optionally protected or acylated and/or aliphatically substituted amino or by an aza-, diaza-, azoxa- or oxa-cycloaliphatic radical, or is an oxacycloaliphatic hydrocarbon radical bonded via a carbon atom, or is an optionally protected or aliphatically N-substituted or N-acylated azacycloaliphatic hydrocarbon radical, and Z4 is protected amino, converting protected amino Z4 and, if present, protected amino as a constituent of Z3 into amino and, if present, converting protected hydroxy Z1, Z2 and/or protected hydroxy as a constituent of Z3 into hydroxy and, if present, freeing a protected azacycloaliphatic hydrocarbon radical Z3 and, if desired, converting a resulting compound into a different compound of formula I, separating an isomeric mixture obtainable in accordance with the process into its components and separating the preferred isomer, and/or converting a free compound obtainable in accor-dance with the process into a salt or converting a salt obtainable in accordance with the process into the corresponding free compound.
(I), wherein R1 is an aliphatic hydrocarbon radical that is substituted by optionally acylated or aliphatically or araliphatically etherified hydroxy, by halogen, by optionally acylated and/or aliphatically substituted amino or by an aza-, diaza-, azoxa- or oxa-cycloaliphatic radical, or is an oxacycloaliphatic hydrocarbon radical bonded via a carbon atom, or is an optionally aliphatically N-substituted or N-acylated azacycloaliphatic hydrocarbon radical, and R2 is free or esterified carboxy, and their salts, which comprises in a compound of formula II
(II), wherein Z1, Z2 are optionally protected hydroxy, Z3 is an aliphatic hydrocarbon radical that is substituted by optionally protected or acylated or aliphatically or araliphatically etherified hydroxy, by halogen, by optionally protected or acylated and/or aliphatically substituted amino or by an aza-, diaza-, azoxa- or oxa-cycloaliphatic radical, or is an oxacycloaliphatic hydrocarbon radical bonded via a carbon atom, or is an optionally protected or aliphatically N-substituted or N-acylated azacycloaliphatic hydrocarbon radical, and Z4 is protected amino, converting protected amino Z4 and, if present, protected amino as a constituent of Z3 into amino and, if present, converting protected hydroxy Z1, Z2 and/or protected hydroxy as a constituent of Z3 into hydroxy and, if present, freeing a protected azacycloaliphatic hydrocarbon radical Z3 and, if desired, converting a resulting compound into a different compound of formula I, separating an isomeric mixture obtainable in accordance with the process into its components and separating the preferred isomer, and/or converting a free compound obtainable in accor-dance with the process into a salt or converting a salt obtainable in accordance with the process into the corresponding free compound.
28. Method for the treatment of epilepsy, ischaemias and/or migraines, wherein acompound according to any one of claims 1 to 25 or a pharmaceutical preparation according to claim 26 is administered to a warm-blooded organism in need of suchtreatment.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH3479/89-6 | 1989-09-26 | ||
CH347989 | 1989-09-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2026038A1 true CA2026038A1 (en) | 1991-03-27 |
Family
ID=4256862
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002026038A Abandoned CA2026038A1 (en) | 1989-09-26 | 1990-09-24 | 4-substituted 2-aminoalk-3-enoic acids |
Country Status (19)
Country | Link |
---|---|
EP (1) | EP0420806B1 (en) |
JP (1) | JPH03130296A (en) |
KR (1) | KR910006312A (en) |
AT (1) | ATE124700T1 (en) |
AU (1) | AU638057B2 (en) |
CA (1) | CA2026038A1 (en) |
DD (1) | DD298105A5 (en) |
DE (1) | DE59009368D1 (en) |
DK (1) | DK0420806T3 (en) |
ES (1) | ES2074153T3 (en) |
FI (1) | FI97231C (en) |
HU (1) | HUT56110A (en) |
IE (1) | IE67873B1 (en) |
IL (1) | IL95729A (en) |
MX (1) | MX22528A (en) |
NO (1) | NO179450C (en) |
NZ (1) | NZ235427A (en) |
PT (1) | PT95401B (en) |
ZA (1) | ZA907641B (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK0391850T3 (en) * | 1989-04-07 | 1994-10-24 | Ciba Geigy Ag | Unsaturated aminodicarboxylic acid derivatives |
GB9022785D0 (en) * | 1990-10-19 | 1990-12-05 | Merck Sharp & Dohme | Therapeutic agents |
US5464843A (en) * | 1992-06-23 | 1995-11-07 | G.D. Searle & Co. | Imidazo[1,2-a]pyridinyldiacid compounds for cognitive enhancement and for treatment of cognitive disorders and neutrotoxic injury |
WO2018193999A1 (en) * | 2017-04-17 | 2018-10-25 | 国立大学法人京都大学 | Optically-active 2-amino-phosphonoalkane acid, optically-active 2-amino-phosphonoalkane acid salt, and hydrates of these |
EP3427729A1 (en) | 2017-07-13 | 2019-01-16 | Paris Sciences et Lettres - Quartier Latin | Probenecid for use in treating epileptic diseases, disorders or conditions |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0233154B1 (en) * | 1986-02-13 | 1991-12-18 | Ciba-Geigy Ag | Unsaturated amino-acids |
EP0302826A3 (en) * | 1987-08-04 | 1991-04-03 | Ciba-Geigy Ag | Process for the preparation of unsaturated amino acid compounds |
-
1990
- 1990-09-18 EP EP90810712A patent/EP0420806B1/en not_active Expired - Lifetime
- 1990-09-18 IL IL95729A patent/IL95729A/en not_active IP Right Cessation
- 1990-09-18 ES ES90810712T patent/ES2074153T3/en not_active Expired - Lifetime
- 1990-09-18 AT AT90810712T patent/ATE124700T1/en not_active IP Right Cessation
- 1990-09-18 DK DK90810712.1T patent/DK0420806T3/en not_active Application Discontinuation
- 1990-09-18 DE DE59009368T patent/DE59009368D1/en not_active Expired - Fee Related
- 1990-09-24 CA CA002026038A patent/CA2026038A1/en not_active Abandoned
- 1990-09-24 NZ NZ235427A patent/NZ235427A/en unknown
- 1990-09-24 FI FI904690A patent/FI97231C/en not_active IP Right Cessation
- 1990-09-24 PT PT95401A patent/PT95401B/en not_active IP Right Cessation
- 1990-09-24 MX MX2252890A patent/MX22528A/en unknown
- 1990-09-25 DD DD90344183A patent/DD298105A5/en not_active IP Right Cessation
- 1990-09-25 KR KR1019900015186A patent/KR910006312A/en not_active Application Discontinuation
- 1990-09-25 HU HU906210A patent/HUT56110A/en unknown
- 1990-09-25 JP JP2252073A patent/JPH03130296A/en active Pending
- 1990-09-25 AU AU63152/90A patent/AU638057B2/en not_active Ceased
- 1990-09-25 ZA ZA907641A patent/ZA907641B/en unknown
- 1990-09-25 NO NO904169A patent/NO179450C/en unknown
- 1990-09-25 IE IE345290A patent/IE67873B1/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
NO179450B (en) | 1996-07-01 |
IE67873B1 (en) | 1996-05-01 |
IL95729A (en) | 1998-02-22 |
HUT56110A (en) | 1991-07-29 |
AU638057B2 (en) | 1993-06-17 |
EP0420806B1 (en) | 1995-07-05 |
DE59009368D1 (en) | 1995-08-10 |
DK0420806T3 (en) | 1995-10-16 |
NO904169L (en) | 1991-03-27 |
HU906210D0 (en) | 1991-03-28 |
IL95729A0 (en) | 1991-06-30 |
AU6315290A (en) | 1991-04-11 |
FI97231B (en) | 1996-07-31 |
IE903452A1 (en) | 1991-04-10 |
NO179450C (en) | 1996-10-09 |
EP0420806A1 (en) | 1991-04-03 |
MX22528A (en) | 1994-02-28 |
ATE124700T1 (en) | 1995-07-15 |
FI97231C (en) | 1996-11-11 |
DD298105A5 (en) | 1992-02-06 |
ES2074153T3 (en) | 1995-09-01 |
ZA907641B (en) | 1991-05-29 |
NO904169D0 (en) | 1990-09-25 |
FI904690A0 (en) | 1990-09-24 |
NZ235427A (en) | 1992-10-28 |
JPH03130296A (en) | 1991-06-04 |
PT95401A (en) | 1991-05-22 |
PT95401B (en) | 1997-07-31 |
KR910006312A (en) | 1991-04-29 |
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FZDE | Discontinued |