CA2003091A1 - Substituted oxadiaminobutanes - Google Patents
Substituted oxadiaminobutanesInfo
- Publication number
- CA2003091A1 CA2003091A1 CA002003091A CA2003091A CA2003091A1 CA 2003091 A1 CA2003091 A1 CA 2003091A1 CA 002003091 A CA002003091 A CA 002003091A CA 2003091 A CA2003091 A CA 2003091A CA 2003091 A1 CA2003091 A1 CA 2003091A1
- Authority
- CA
- Canada
- Prior art keywords
- lower alkyl
- hydrogen
- hydroxy
- formula
- phenyl
- 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
- 150000001875 compounds Chemical class 0.000 claims abstract description 139
- 125000000217 alkyl group Chemical group 0.000 claims description 168
- 229910052739 hydrogen Inorganic materials 0.000 claims description 130
- 239000001257 hydrogen Substances 0.000 claims description 130
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 116
- -1 phenylsulfonyloxy Chemical group 0.000 claims description 114
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 94
- 150000002431 hydrogen Chemical class 0.000 claims description 86
- 239000000203 mixture Substances 0.000 claims description 66
- 229910021529 ammonia Inorganic materials 0.000 claims description 58
- 150000003839 salts Chemical class 0.000 claims description 54
- 229910052736 halogen Inorganic materials 0.000 claims description 35
- 238000000034 method Methods 0.000 claims description 35
- 150000002367 halogens Chemical group 0.000 claims description 34
- 125000003545 alkoxy group Chemical group 0.000 claims description 31
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 238000002360 preparation method Methods 0.000 claims description 19
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 18
- 125000003342 alkenyl group Chemical group 0.000 claims description 17
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 17
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- 125000004423 acyloxy group Chemical group 0.000 claims description 16
- 125000000304 alkynyl group Chemical group 0.000 claims description 16
- 239000000460 chlorine Chemical group 0.000 claims description 16
- 229910052801 chlorine Inorganic materials 0.000 claims description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 14
- 239000011737 fluorine Substances 0.000 claims description 14
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 13
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 12
- 125000001153 fluoro group Chemical group F* 0.000 claims description 10
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 10
- KZCFCFDOYOJTOF-UHFFFAOYSA-N o-(3-amino-2-fluoropropyl)hydroxylamine Chemical compound NCC(F)CON KZCFCFDOYOJTOF-UHFFFAOYSA-N 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 102000052812 Ornithine decarboxylases Human genes 0.000 claims description 9
- 108700005126 Ornithine decarboxylases Proteins 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 4
- UFOZXNZOYKGSQO-UHFFFAOYSA-N 1-amino-3-aminooxypropan-2-ol Chemical compound NCC(O)CON UFOZXNZOYKGSQO-UHFFFAOYSA-N 0.000 claims description 4
- 125000006290 2-hydroxybenzyl group Chemical group [H]OC1=C(C([H])=C([H])C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 230000002140 halogenating effect Effects 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 230000005764 inhibitory process Effects 0.000 claims description 4
- XISRILLATOFWFK-UHFFFAOYSA-N 1-amino-3-(cyclopentylideneamino)oxypropan-2-ol Chemical compound NCC(O)CON=C1CCCC1 XISRILLATOFWFK-UHFFFAOYSA-N 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- AQURQPCATLDLDB-UHFFFAOYSA-N 2-fluoro-3-(quinolin-4-ylmethylideneamino)oxypropan-1-amine Chemical compound C1=CC=C2C(C=NOCC(F)CN)=CC=NC2=C1 AQURQPCATLDLDB-UHFFFAOYSA-N 0.000 claims description 2
- WEELKHULXWGQCP-UHFFFAOYSA-N 3-(benzylideneamino)oxy-2-fluoropropan-1-amine Chemical compound NCC(F)CON=CC1=CC=CC=C1 WEELKHULXWGQCP-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 229910052727 yttrium Inorganic materials 0.000 claims description 2
- 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 2
- ZSNNANKILXFOFC-UHFFFAOYSA-N (1-amino-3-aminooxypropan-2-yl) methanesulfonate Chemical compound CS(=O)(=O)OC(CN)CON ZSNNANKILXFOFC-UHFFFAOYSA-N 0.000 claims 1
- IGLMRXRQKOEYDO-UHFFFAOYSA-N 1-amino-3-(butan-2-ylideneamino)oxypropan-2-ol Chemical compound CCC(C)=NOCC(O)CN IGLMRXRQKOEYDO-UHFFFAOYSA-N 0.000 claims 1
- DBIPKYHLWLWWQA-UHFFFAOYSA-N 2-[(3-amino-2-fluoropropoxy)iminomethyl]phenol Chemical compound NCC(F)CON=CC1=C(O)C=CC=C1 DBIPKYHLWLWWQA-UHFFFAOYSA-N 0.000 claims 1
- CLCHQKHFRSVCLB-UHFFFAOYSA-N 3-[(2,2-difluoro-1-phenylethylidene)amino]oxy-2-fluoropropan-1-amine Chemical compound NCC(F)CON=C(C(F)F)C1=CC=CC=C1 CLCHQKHFRSVCLB-UHFFFAOYSA-N 0.000 claims 1
- BNGYJUNLWMRJFY-UHFFFAOYSA-N C1=C(C(=C(C(=N1)C=NOCC(CN)F)O)C=O)COP(=O)(O)O Chemical compound C1=C(C(=C(C(=N1)C=NOCC(CN)F)O)C=O)COP(=O)(O)O BNGYJUNLWMRJFY-UHFFFAOYSA-N 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 180
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 144
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 141
- 239000000243 solution Substances 0.000 description 111
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 104
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 103
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 98
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 84
- 238000001704 evaporation Methods 0.000 description 74
- 230000008020 evaporation Effects 0.000 description 74
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 65
- 239000000741 silica gel Substances 0.000 description 65
- 229910002027 silica gel Inorganic materials 0.000 description 65
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 49
- 235000002639 sodium chloride Nutrition 0.000 description 40
- 239000011541 reaction mixture Substances 0.000 description 34
- 150000003254 radicals Chemical class 0.000 description 33
- 235000011121 sodium hydroxide Nutrition 0.000 description 32
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 31
- 239000007858 starting material Substances 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 27
- 239000003921 oil Substances 0.000 description 24
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 22
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 22
- 229940083608 sodium hydroxide Drugs 0.000 description 18
- 239000004480 active ingredient Substances 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- 229960001171 acetohydroxamic acid Drugs 0.000 description 15
- 235000011167 hydrochloric acid Nutrition 0.000 description 14
- 229960000443 hydrochloric acid Drugs 0.000 description 14
- 239000012071 phase Substances 0.000 description 14
- 239000000843 powder Substances 0.000 description 14
- 238000010992 reflux Methods 0.000 description 14
- AYBVSMLMXOSFSL-UHFFFAOYSA-N 1-amino-3-aminooxypropan-2-ol;dihydrochloride Chemical compound Cl.Cl.NCC(O)CON AYBVSMLMXOSFSL-UHFFFAOYSA-N 0.000 description 13
- XWXPEUDSUNQSQL-UHFFFAOYSA-N o-(3-amino-2-fluoropropyl)hydroxylamine;dihydrochloride Chemical compound Cl.Cl.NCC(F)CON XWXPEUDSUNQSQL-UHFFFAOYSA-N 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 239000011780 sodium chloride Substances 0.000 description 11
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 11
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 239000000377 silicon dioxide Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 7
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 125000001589 carboacyl group Chemical group 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 150000002500 ions Chemical class 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000011589 pyridoxal 5'-phosphate Substances 0.000 description 6
- 229960001327 pyridoxal phosphate Drugs 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 230000007717 exclusion Effects 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 229920000768 polyamine Polymers 0.000 description 5
- 235000007682 pyridoxal 5'-phosphate Nutrition 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 5
- QHMQWEPBXSHHLH-UHFFFAOYSA-N sulfur tetrafluoride Chemical compound FS(F)(F)F QHMQWEPBXSHHLH-UHFFFAOYSA-N 0.000 description 5
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- RADKZDMFGJYCBB-UHFFFAOYSA-N Pyridoxal Chemical compound CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 4
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 4
- 239000008298 dragée Substances 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 4
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000007911 parenteral administration Methods 0.000 description 4
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 4
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 239000001828 Gelatine Substances 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- SJSWRKNSCWKNIR-UHFFFAOYSA-N azane;dihydrochloride Chemical compound N.Cl.Cl SJSWRKNSCWKNIR-UHFFFAOYSA-N 0.000 description 3
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 239000000155 melt Substances 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- MFSUKOCGNJOMDD-UHFFFAOYSA-N n-ethoxyacetamide Chemical compound CCONC(C)=O MFSUKOCGNJOMDD-UHFFFAOYSA-N 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 3
- 235000006408 oxalic acid Nutrition 0.000 description 3
- 229940116315 oxalic acid Drugs 0.000 description 3
- NOQXXYIGRPAZJC-UHFFFAOYSA-N oxiran-2-ylmethyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCC1OC1 NOQXXYIGRPAZJC-UHFFFAOYSA-N 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
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- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000000369 oxido group Chemical group [*]=O 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 125000005544 phthalimido group Chemical group 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 1
- MTURGQJJIULABB-UHFFFAOYSA-N propan-1-amine;dihydrochloride Chemical compound Cl.Cl.CCCN MTURGQJJIULABB-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- MGCGJBXTNWUHQE-UHFFFAOYSA-N quinoline-4-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CC=NC2=C1 MGCGJBXTNWUHQE-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 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
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 150000003538 tetroses Chemical class 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- KRVIQSHPVVXYIT-UHFFFAOYSA-N trifluoro(piperidin-1-yl)-$l^{4}-sulfane Chemical compound FS(F)(F)N1CCCCC1 KRVIQSHPVVXYIT-UHFFFAOYSA-N 0.000 description 1
- WRTMQOHKMFDUKX-UHFFFAOYSA-N triiodide Chemical compound I[I-]I WRTMQOHKMFDUKX-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 201000002311 trypanosomiasis Diseases 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
- C07C239/08—Hydroxylamino compounds or their ethers or esters
- C07C239/20—Hydroxylamino compounds or their ethers or esters having oxygen atoms of hydroxylamino groups etherified
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
- C07C247/04—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/32—Oximes
- C07C251/50—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals
- C07C251/58—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/63—Carboxylic acid nitriles containing cyano groups and nitrogen atoms further bound to other hetero atoms, other than oxygen atoms of nitro or nitroso groups, bound to the same carbon skeleton
- C07C255/64—Carboxylic acid nitriles containing cyano groups and nitrogen atoms further bound to other hetero atoms, other than oxygen atoms of nitro or nitroso groups, bound to the same carbon skeleton with the nitrogen atoms further bound to oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
- C07C309/66—Methanesulfonates
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- 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
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- C07F9/58—Pyridine rings
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- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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- Saccharide Compounds (AREA)
Abstract
Substituted oxadiaminobutanes Abstract of the Disclosure Compounds of formula I
Description
2~)0:~091 , :
4-17327/+
Substituted oxadiaminobutanes The invention relates to the use of compounds of formula I
~C ,~
Rl ~ O~ ~ H~ ~ H~
2 :~
wherein X is halogen, hydroxy, lower alkoxy, acyloxy, lower alkyl-sulfonyloxy or arylsulfonyloxy; each of Rl and R2, independently of the ~ ., .
other, is hydrogen, lower alkyl, cycloalkyl, aryl-lower alkyl or hetaryl-lower alkyl, or Rl and R2 together are a radical ~ :
C=
Rs/ - ~;~
wherein each of R4 and Rs, independently of the other, is hydrogen, lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, lower alkoxy-lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl-lower alkyl, .
hetaryl-lower alkyl, aryl, hetaryl, carboxy or lower alkoxycarbonyl, or wherein R4 is polyhydroxy-lower alkyl and Rs is hydrogen or hydroxy-methyl, or wherein R4 and Rs together are C2-C7alkylene or unsub-stituted or substituted benzo-C4-C6alkylene; and R3 is hydrogen, un-substituted or hydroxy- or halogen- and/or aminoxy-substituted lower alkyl, lower alkenyl, lower alkynyl or free or etherified hydroxy; and pharmaceutically acceptable salts thereof, (for the manufacture of pharmaceutical preparationsj Ifor the therapeutic treatment of diseases of the human or animal body that respond to inhibition of ornithine de-carboxylase, for example tumours or protozoa infections, and also to novel compounds of formula I.
' ''.' : ~ "',.'" ',' '' 09~
The invention relates also to compounds of formula I
1 ~ \CH / ~CH ~ ~R (I), z wherein X is halogen, hydroxy, lower alkoxy, acyloxy, lower alkyl-sulfonyloxy or arylsulfonyloxy; each of R1 and R2, independently of the other, is hydrogen, lower alkyl, cycloalkyl, aryl-lower alkyl or hetaryl-lower alkyl, or Rl and R2 together are a radical -R4\ . -~C= , . . , ~ , , wherein each of R4 and Rs, independently of the other, is hydrogen, lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, lower alkoxy-lower .
alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl-lower alkyl, hetaryl-lower alkyl, aryl, hetaryl, carboxy or lower alkoxycarbonyl, or wherein R4 is polyhydroxy-lower alkyl and Rs is hydrogen or hydroxy- .
methyl, or wherein R4 and Rs together are C2-C7alkylene or unsub-stituted or substituted benzo-C4-C6alkylene; and R3 is hydrogen, un- :
substituted or hydroxy- or halogen- and/or aminoxy-substituted lower alkyl, lower alkenyl, lower alkynyl or free or etherified hydroxy; with the proviso tha~ when X is hydroxy and Rl and R2 together are a radical R4\
/C= , R3 is hydrogen; with the proviso that when X is hydroxy and R3 is hydrogen, the radicals Rl and R2 cannot together be l,l-dimèthyl-methylidene, l-n-butylidene or nitro-(furanyl or imidazolyl)-methylidene;
with the proviso that when X is hydroxy and R3 is hydrogen, hydroxy or lower alkyl, the radicals Rl and R2 cannot both be hydrogen; and with the proviso that when X iS hydroxy and Rl and Rz are each independently hydrogen, lower alkyl, cycloalkyl, aryl-lower alkyl or hetaryl-lower .:
alkyl but are not both hydrogen, R3 is hydrogen, methyl, ethyl or n-propyl; and salts thereof, to processes for the preparation of these compounds, to pharmaceutical preparations containing these compounds, to ::
the use of these compounds for the therapeutic treatment of the human or . :
animal body or for the manufacture of pharmaceutical preparations.
~ -` 2~0~.~9~.
The general terms used hereinbefore and hereinafter have the following meanings in the context of this application:
The prefix "lower" denotes a radical having up to and including 7 and especially up to and including 4 carbon atoms.
Lower alkyl is, for example, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, :~ -preferably ethyl and especially methyl.
:: ""' " ~, Lower alkenyl is, for example, vinyl, allyl, l-propenyl, isopropenyl, 2 or 3-methallyl or 3-butenyl.
Lower alkynyl is, for example, ethynyl or 2-butynyl and especially propargyl.
Cycloalkyl contains, for example, from 3 to 8 and especially 5 or 6 ring carbon atoms and is, for example, cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl.
Etherified hydroxy is, for example, lower alkoxy or phenyl-lower alkoxy.
Lower alkoxy is, for example, n-propoxy, isopropoxy, n-butoxy or tert.-butoxy, preferably ethoxy and especially methoxy, whilst phenyl-lower alkoxy is, for example, benzyloxy.
Acyloxy is preferably lower alkanoyloxy, but also, for example, aryl-carbonyloxy (= aroyloxy) or hetarylcarbonyloxy (z hetaroyloxy).
Arylcarbonyloxy is, for example, benzoyloxy.
Hetarylcarbonyloxy is, for example, pyridoyloxy or thienoyloxy.
Lower alkylsulfonyloxy is, for example, methylsulfonyloxy. -: : ~,,:
, ~
'''~
. ._ ,, ` ,, i"' "' ~ ~
zoo~o~
Arylsulfonyloxy is, for example, phenylsulfonyloxy that is unsubstituted or substituted by lower alkyl or by halogen, such as phenyl- or 4-methyl-phenyl-sulfonyloxy.
Lower alkoxycarbonyl is, for example, propoxycarbonyl or butoxycarbonyl, preferably methoxycarbonyl or ethoxycarbonyl.
Halogen is generally, for example, fluorine or iodine, especially bromine and more especially chlorine.
A halogen radical X in a compound of formula I is especially chlorine and more especially fluorine, but may also be, for example, bromine or iodine.
Halo-lower alkyl is, for example, difluoromethyl or trifluoromethyl, also l-chloroethyl.
Hydroxy-lower alkyl is, for example, hydroxymethyl or 2-hydroxyethyl.
Lower alkoxy-lower alkyl is, for example, methoxymethyl.
Polyhydroxy-lower alkyl is, for example, 1,2-dihydroxyethyl or 1,2,3-tri-hydroxypropyl, preferably 1,2,3,4-tetrahydroxybutyl and especially 1,2,3,4,5~pentahydroxypentyl. ;~
Lower alkyl substituted by hydroxy or halogen and/or by aminoxy is, for example, hydroxy-lower alkyl or halo-lower alkyl, also hydroxyaminoxy-lower alkyl, for example 3-aminoxy-2-hydroxypropyl, or hydroxyhalo-lower ~ ~ - alkyl, for example 3-aminoxy-2-fluoropropyl.
Compounds of formula I wherein R1 and Rz together are a radical -~
RsR4C=, R4 is polyhydroxy-lower alkyl and Rs is hydrogen or hydroxy-methyl, are preferably derived from sugars, especially from aldo- or keto-(trioses, tetroses, pentoses or hexoses). The radical RsR4C=
wherein R4 is 1,2,3,4,5-pentahydroxypentyl (derived from D-glucose) and ~ `
Rs is hydrogen is especially preferred. ~-...
,: ' -, : ~-':
20~:~0g~
Lower alkanoyl is, for example, formyl, propionyl or butyryl, and especially acetyl. ;
Lower alkanoyloxy is, for example, formyloxy, propionyloxy or butyryloxy, and especially acetoxy.
Aryl is, for example, phenyl or naphthyl, such as 1- or 2-naphthyl. The ~j phenyl or naphthyl radicals can be unsubstituted or substituted. Aryl is preferably phenyl that is unsubstituted or substituted by lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, halogen, hydroxy, lower alkoxy, lower alkanoyloxy and/or by nitro, and is especially phenyl.
Aryl-lower alkyl is preferably phenyl-lower alkyl and especially benzyl.
Hetaryl, as such or in composite terms, such as, for example, hetaryl-lower alkyl, is to be understood as being especially a monocyclic but also a bi- or poly-cyclic, heterocyclic radical of aromatic character. .
Bi- and poly-cyclic hetaryl can be composed of several heterocyclic rings or, preferably, of one heterocycle and one or more, for example one or two and especi~lly one, fused carbocyclic ring, especially a benzo ring.
Each individual ring contains, for example, 3, 5, 6 or 7 and especially 5 or 6 ring members. Hetaryl is especially an aza-, thia-, oxa-, thiaza-, thiadiaza-, oxaza-, diaza-, triaza- or tetraza-cyclic radical.
Hetaryl is especially a monocyclic monoaza-, monothia- or monooxa-cyclic -radical, such as pyrryl, for example 2-pyrryl or 3-pyrryl, pyridyl, for ~
example 2-, 3- or 4-pyridyl, thienyl, for example 2- or 3-thienyl, or ~ ;
furyl, for example 2-furyl; a bicyclic monoaza-, monooxa- or monothia~
cyclic radical, such as indolyl, for example 2- or 3-indolyl, quinolinyl, for example 2- or 4-quinolinyl, isoquinolinyl, for example 1-isoquinolin-yl, benzofuranyl, for example 2- or 3-benzofuranyl, or benzothienyl, for example 2- or 3-benzothienyl; a monocyclic diaza-, triaza-, tetraza-, oxaza-, thiaza- or thiadiaza-cyclic radical, such as imidazolyl, for `~ `
example 2-imidazolyl, pyrimidinyl, for example 2- or 4-pyrimidinyl, tri- ~ ~
09~1.
.
azolyl, for example l,2,4-triazol-3-yl, tetrazolyl, for example 1- or 5-tetrazolyl, oxazolyl, for example 2-oxazolyl, isoxazolyl, for example 3- or 4-isoxazolyl, thiazolyl, for example 2-thiazolyl, isothiazolyl, for example 3- or 4-isothiazolyl or 1,2,4- or 1,3,4-thiadiazolyl, for example 1,2,4-thiadiazol-3-yl or 1,3,4-thiadiazol-2-yl; or a bicyclic diaza-, oxaza- or thiaza-cyclic radical, such as benzimidazolyl, for example 2-benzimidazolyl, benzoxazolyl, for example 2-benzoxazolyl, or benzo-thiazolyl, for example 2-benzothiazolyl.
Hetaryl radicals are unsubstituted or carry substituents. Suitable sub-stituents at ring carbon atoms are, for example, the substituents indicated above for aryl radicals and, in addition, phosphonooxymethyl-E_CH2_0_P(=O)(OH)2], and also oxo (=O). Ring nitrogen atoms can be substituted, for example, by lower alkyl, aryl-lower alkyl, lower alkanoyl, benzoyl, carboxy, lower alkoxycarbonyl, hydroxy, lower alkoxy, lower alkanoyloxy or by oxido ( - I ) Hetaryl is especially pyridyl, quinolinyl, thienyl, pyrryl or imidazolyl.
Hetaryl-lower alkyl is especially pyridyl-, thienyl-, pyrryl-or -imidazolyl-methyl.
A radical RsR4C= wherein R4 and Rs together are C2-C7alkylene is to be understood as being cycloalkylidene having from 3 to 8 ring carbon atoms, for example cyclopropylldene, cyclopentylidene or cyclohexylidene.
A r~dical RsR4C= wherein R4 and Rs together are unsubstituted or substituted benzo-C4-C6alkylene is to be understood as being, for -~
example, cyclopentylidene or cyclohexylidene each of which carries a fused benzo ring that is unsubstituted or substituted by lower alkyl, ~
lower alkoxy, carboxy, lower alkoxycarbonyl, carbamoyl and/or by cyano. -~ `
Examples of such radicals are indan-l-ylidene, 4-cyano-indan-1-ylidene and 1,2,3,4-tetrahydro-1-naphthylidene.
~ `
2~0309~.
-: -_ 7 _ A radical RsR4C= wherein R4 is 3-hydroxy-5-(hydroxymethyl or phos-phonooxymethyl)-2-methyl-4-pyridyl and Rs is hydrogen, or a 3-hydroxy-5-(hydroxymethyl or phosphonooxymethyl)-2-methyl-4-pyridylmethylidene radical formed by Rl and R2 together, is derived from pyridoxal or pyridoxal 5-phosphate, respectively. A phosphono radical corresponds to the group -P(=O)(OH)2.
Cl-C4alkylidene is preferably ethylidene or 1,1-dimethylmethylidene [=C(CH3)2], and also, for example, l-n-butylidene [=CH-CH2-CH2-CH3]
or 2-n-butylidene [CH3-C(=)-CHz-CH3].
Salts of compounds according to the invention are especially pharma-ceutically acceptable, non-toxic salts. For example, compounds of ~ormula I having basic groups may form acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example acetic-acid, fumaric acid, oxalic acid or methanesulfonic acid, or, for example, with amino acids, such as arginine or lysine. If several basic groups are present, mono- or poly-salts may be formed. Compounds of formula I having an acidic group, for example carboxy, and a basic group, for example amino, can be, for example, in the form of internal salts, that is to say in zwitterionic form, or one part of the molecule may be in the form of an internal salt and another part may be in the form of a ~ ~
normal salt. -;:
~ ;,:~',",',' For isolation or purification purposes it is also possible to use pharma~
ceutically unacceptable salts, for example picrates or perchlorates. Only pharmaceutically acceptable, non-toxic salts are used therapeutically and these are therefore preferreq.
Depending upon the structural factors, the compounds of the present invention may be in the form of isomeric mixtures or in the form of pure isom-rs.
':
~ - ' ' ;'~, Z00309~
.
':
The compounds according to the invention have valuable, especially pharmacologically useful, properties. In particular, they have a strong specific inhibitory action on the enzyme ornithine decarboxylase (ODC).
ODC as a key enzyme plays an important part in the polyamine synthesis which takes place in virtually all cells of mammals, including humans.
The polyamine concentration in the cell is regulated by ODC. Inhibition of the ODC enzyme results in a reduction in the polyamine concentration.
Since a reduction in the polyamine concentration effects inhibition of cell growth, it is possible by administering ODC-inhibiting substances to inhibit the growth of both eukaryotic and prokaryotic cells, and especially of cells undergoing rapid or uncontrollable growth, and even to kill cells or to inhibit the onset of cell differentiation.
The inhibition of the ODC enzyme can be demonstrated, for example, using the method of J.E. Seely and A.E. Pegg, Ornithine decarboxylase (mouse -kidney), pages 158-161, in H. Tabor and C. ~hite Tabor (Eds.): Methods in enzymology, Vol. 94: Polyamines, Academic Press, New York, 1983. The compounds of the invention exhibit ICso values of about 0.01 ~mol minimum. `` -The compounds of formula I have anti-proliferative properties which may - -be demonstrated directly, for example, in the following test in which the inhibitory action of the compounds of formula I on the growth of human TZ4 bladder carcinoma cells is determined. These cells are incubated in "Eagle's minimal essential medium" to which 5 % (v/v) of foetal calf ' serum has been added, in a humidified incubator at 37C and 5 % by volume CO2 in the air. The carcinoma cells (1000-1500) are inoculated into 96-hole microtitre plates and incubated overnight under the above- ; ~;
mentioned conditions. The test co,mpound is added in serial dilutions on day 1. The plates are incubated for 5 days under the above-mentioned ;
conditions. During this period, the control cultures undergo at least 4 cell divisions. After incubation the cells are fixed with 3.3 %
(weight/volume) aqueous glutaraldehyde solution, washed with water and stained with 0.05 % (w/v) aqueous methylene blue solution. After washing, - -the dye is eluted with 3 % (w/v) aqueous hydrochloric acid. The optical density (OD) per hole, which is directly proportional to the number of -", -.;
:, '': :` ' 20030~1 cells, is then measured using a photometer (Titertek multiskan) at 665 nm. The ICso values are calculated with a computer system using the formula OD66s (test) - OD66s (start) x 100 OD66s (test) - OD66s (start) Ths ICso values are defined as that active ingredient concentration at which the number of cells per hole at the end of the incubation period constitutes only 50 % of the number of cells in the control cultures. The resulting ICso values for the compounds of formula I are about 1 ~mol minimum.
The compounds of formula I are therefore, for example, useful for the treatment of benign and malign`ant tumours. They can bring about the regression of tumours and also prevent the spread of tumour cells and the ~
growth of micrometastases. Furthermore, they can be used, for example, -for the treatment of protozoa infections, for example trypanosomiasis, malaria or pulmonary inflammation caused by Pneumocystis carinii. - ;
The invention relates preferably to the above-mentioned use of compounds of formula I wherein X is halogen, hydroxy, lower alkoxy, lower alkyl~
sulfonyloxy or phenylsulfonyloxy; each of R1 and Rz, independently of ~ ~;
the other, is hydrogen, lower alkyl, C3-Cgcycloalkyl or phenyl-lower alkyl, or R1 and R2 together are a radical R4\ ~;~
/C= ,. ~ : -Rs wherein each of R4 and Rs, independently of the other, is hydrogen, lowér alkyl, halo-lower~alkyl, C3'C8'cycloalkyl, phenyl-lower alkyl or ! ' ; .
phenyl, or wherein R4 is 3-hydroxy-5-(hydroxymethyl or phosphonooxy-methyl)-2-methyl-4-pyridyl and Rs is hydrogen, or wherein R4 is 1,2,3,4-tetrahydroxybutyl or 1,2,3,4,5-pentahydroxypentyl and Rs is hydrogen or hydroxymethyl, or wherein R4 is quinolinyl, carboxy or lower alkoxycarbonyl and Rs is hydrogen or lower alkyl, or wherein R4 and Rs together are Cz-C7alkylene or unsubstituted or cyano-substituted ~ ~
: ' ~ ,.i; ' '. ., ; , . .,., ', '.` ., 200309~
benzo-C4-Csalkylene; and R3 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, benzyloxy or hydroxy; phenyl groups being unsubstituted or substituted by lower alkyl, halo-lower alkyl, halogen, hydroxy, lower alkoxy, lower alkanoyloxy and/or by nitro; and pharma-ceutically acceptable salts thereof.
The invention relates especially to the above-mentioned use of compounds of formula I wherein X is fluorine, chlorine, hydroxy, lower alkyl-sulfonyloxy or phenylsulfonyloxy; each of R1 and R2, independently of the other, is hydrogen, lower alkyl, C3-C~cycloalkyl or phenyl-lower .:.alkyl, or Rl and R2 together are a radical . :
R4\
~C= , ' `
wherein each of R4 and Rs, independently of the other, is hydrogen, lower alkyl, halo-lower alkyl, C3-C7cycloalkyl, phenyl-lower alkyl or phenyl, or wherein R4 is quinolinyl, 3-hydroxy-5-(hydroxymethyl or phos-phonooxymethyl)-2-methyl-4-pyridyl and Rs is hydrogen, or wherein R4 is -~
carboxy or lower alkoxycarbonyl and Rs is lower alkyl, or wherein R4 and Rs together are -(CH2)4- or -(CNZ)s- ; and R3 is hydrogen, ;-~
lower alkyl, lower alkenyl, lower alkynyl or hydroxy; phenyl groups being unsubstituted or substituted by lower alkyl, trifluoromethyl, halogen, hydroxy, lower alkoxy and/or by nitro; and pharmaceutically acceptable sàlts thereof.
"~
The invention relates especially to the above-mentioned use of compounds of formula I wherein X is fluorine, chlorine, hydroxy or methylsulfonyl- ;~
oxy, R1 is hydrogen, R2 is hydrogen, C1-C4alkyl, benzyl or 2-hydroxy-benzyl, or R1 and R2 together are C7-C6cycloalkylidene~ C1-C4-alkylidene, benzylidene, 2-hydroxybenzylidene or 3-hydroxy-S-(hydroxy-methyl or phosphonooxymethyl)-2-methyl-4-pyridylmethylidene, and R3 is hydrogen, Cl-C4alkyl, C2-C4alkynyl or hydroxy; and pharmaceutically .-acceptable salts thereof. :: : :
' 2003091l The invention relates especially to the above-mentioned use of 3-aminoxy-2-hydroxypropylamine and 3-aminoxy-2-fluoropropylamine and pharma-ceutically acceptable salts thereof.
The invention relates preferably to compounds of formula I wherein X is halogen, hydroxy, lower alkoxy, lower alkylsulfonyloxy or phenylsulfonyl-oxy; each of Rl and R2, independently of the other, is hydrogen, lower alkyl, C3-C8cycloalkyl or phenyl-lower alkyl, or Rl and Rz together are a radical ~C= , ,, ~, .. .
Rs wherein each of R4 and Rs~ independently of the other, is hydrogen, lower alkyl, halo-lower alkyl,. C3-Cacycloalkyl, phenyl-lower alkyl or phenyl, or wherein R4 is 3-hydroxy-5-(hydroxymethyl or phosphonooxy-methyl)-2-methyl-4-pyridyl and Rs is hydrogen, or wherein R4 is .~ ;
1,2,3,4-tetrahydroxybutyl or 1,2,3,4,5-pentahydroxypentyl and Rs is . ~ ~:
hydrogen or hydroxymethyl, or wherein R4 is quinolinyl, carboxy or lower .:... :
alkoxycarbonyl and Rs is hydrogen or lower alkyl, or wherein R4 and Rs together are Cz-C7alkylene or unsubstituted or cyano-substituted benzo-C4-C6alkylene; and R3 is hydrogen, lower alkyl, lower alkenyl, lower a.lkynyl, lower alkoxy, benzyloxy or hydroxy; with the proviso that .
when X is hydroxy and Rl and R2 eogether are a radical /C= , R3 is :
hydrogen; with the proviso that when X is hydroxy and R3 is hydrogen, . ::
the radicals Rl and R2 cannot together be 1,1-dimethylmethylidene or l-n-butylidene; with the proviso that when X is hydroxy and R3 is hydrogen, hydroxy or lower alkyl, the radicals Rl and R2 cannot both be hydrogen; and with the provi$o that;when X is hydroxy and Rl and R2 are each independently hydrogen, lower alkyl, cycloalkyl or phenyl-lower ~ ~ :
alkyl but are not both hydrogen, R3 is hydrogen, methyl, ethyl or n-propyl; phenyl groups being unsubstituted or substituted by lower alkyl, halo-lower alkyl, halogen, hydroxy, iower.alkoxy, lower alkanoyl-oxy andtor by nitro; and salts thereof.
,~ . , .
. , .
' ~ :: ~ ~,,-.~ . : :.
,: ~ :,:
::
200309~
The invention relates preferably to compounds of formula I wherein X is .
fluorine, chlorine, hydroxy, lower alkylsulfonyloxy or phenylsulfonyloxy;
each of R1 and Rz, independently of the other, is hydrogen, lower alkyl, C3-C7cycloalkyl or phenyl-lower alkyl, with the proviso that the radicals R1 and R2 cannot both be hydrogen when X is hydroxy, or wherein R1 and Rz together are a radical ~ ; .
R4\ -~
~C= :, ~
wherein each of R4 and Rs, independently of the other, is hydrogen, :
lower alkyl, halo-lower alkyl, C3-C7cycloalkyl, phenyl-lower alkyl or -phenyl, or wherein R4 is quinolinyl, 3-hydroxy-5-(hydroxymethyl or phosphonooxymethyl)-2-methyl-4-pyridyl and Rs is hydrogen, or wherein i ~.
R4 is carboxy or lower alkoxycarbonyl and Rs is lower alkyl, or wherein ~
R4 and Rs together are -(CHz)4- or -(CHz)s- ; and R3 is hydrogen; -: -with the proviso that when X is hydroxy, the radicals R1 and Rz cannot together be 1,1-dimethylmethylidene or 1-n-butylidene; phenyl groups being unsubstituted or substituted by lower alkyl, trifluoromethyl, halogen, hydroxy, lower alkoxy or by lower alkanoyloxy; and salts thereof. :~
The invention relates especially to compounds of formula I wherein X is fluorine, chlorine or methylsulfonyloxy; each of R1 and R2, independently of the other, is hydrogen, lower alkyl, C3-C7cycloalkyl :-or phenyl-lower alkyl, or R1 and R2 together are a radical -: R4 ~C= ' :;,'' wherein each of R4 and Rst indepen,dqntly of thq;other, is hydrogen, `
lower alkyl, halo-lower alkyl, C3-C7cycloalkyl, phenyl-lower alkyl or phenyl, or wherein R4 is quinolinyl, 3-hydroxy-S-(hydroxymethyl or phos-phonooxymethyl)-2-methyl-4-pyridyl and R5 is hydrogen, or wherein R4 is carboxy or lower alkoxycarbonyl and Rs is lower alkyl, or wherein R4 ~ ~
: ~ and Rs together are -(C~2)4- or -(CH2)s- ; and R3 is hydrogen, . :
200~091 lower alkyl, lower alkenyl, lower alkynyl or hydroxy; phenyl groups being unsubstituted or substituted by lower alkyl, trifluoromethyl, halogen, hydroxy, lower alkoxy and/or by nitro; and salts thereof.
The invention relates more especially to compounds of formula I wherein X
is fluorine, chlorine or methylsulfonyloxy, R1 is hydrogen, Rz is hydrogen, Cl-C4alkyl, benzyl or 2-hydroxybenzyl, or R1 and R2 ~~ ;
together are C5-C6cycloalkylidene, C1-C4alkylidene, benzylidene, ~ ~
2-'nydroxybenzylidene or 3-hydroxy-5-(hydroxymethyl or phosphonooxy- `
methyl)-2-methyl-4-pyridylmethylidene, and R3 is hydrogen, C1-C4alkyl, C2-C4alkynyl or hydroxy; and salts thereof. ;~ ~
;.. :' The following sub-groups of a group of compounds of formula I are each to -;
be given special mention~
~ .,. :
(a) compounds of formula I wherein R1 and Rz are hydrogen and X is - ~
halogen; (b) compounds of formula I wherein R1 and Rz together are a~ - radical \C=
Rs (c) compounds of formula I wherein R3 is hydrogen.
~,,, The invention relates especially to the specific compounds described in the Examples and pharmaceutically acceptable salts thereof. ~
- ~, ':
The novel compounds of formula I can be prepared in a manner known Per se, for example as follows:
(a) for the preparation of compounds of formula I wherein X is halogen, a ~compoùnd of formula II
~, Rl ~ o\~ / H\cH ~ \R3 (II) -.. ~ ' .::
: ~ ::
: , ~ . :.
- 14 - .
wherein R1, R2 and R3 are as defined under formula I and Y is a group that can be converted into halogen or replaced by halogen, is reacted with a halogenating agent, or (b) for the preparation of compounds of formula I wherein X is hydroxy, a compound of formula III .
\CH / \~H (III) z wherein Rl and R2 are as defined under formula I, is reacted with ammonia or with an amine of formula NH2R3 wherein R3 is as defined : -~
under formula I, or ~::
':
(c) for the preparation of compounds of formula I wherein R1 is hydrogen, in a compound of formula IV
1' \CH / ~CH ~ ~ (IV) -~-wherein R2 and R3 are as defined under formula I and each of S and S', . ~.
indepsndently of the other, is an amino-protecting group or hydrogen, at least one of the groups S and S' being an amino-protecting group, or wherein S and R2 together or S' and R3 together are a bivalent amino-prctecting group, the amino-protecting group(s) is(are) removed, or (d) a compound of formula V
Rl OH
Y (V) :
. , . !.R2 ~
wherein R1 and R2 are as defined under formula I, is reacted with a compound of formula VI .
CH2/ \CH2~ \R3 (VI) -2(~0309~
wherein R3 and X are as defined under formula I, Z is hydroxy or a nuclsofugal leaving group and S is an amino-protecting group or hydrogen and, where applicable, the amino-protec~ing group is removed, or (e) for the preparation of compounds of formula I wherein R3 is hydrogen, in a compound of formula VII
1 ~ \CH / ~CH -W (VII) wherein Rl, R2 and X are as defined under formula I and W is a radical that can be converted into amino, the radical W is converted into amino;
or (f) for the preparation of compounds of formula I wherein R3 is hydrogen or especially hydroxy or lower alkyl, a compound of formula VIII
Rl ~ 0\ /CH\ (VIII) wherein Rl, R2 and X are as defined under formula I and R3 is hydrogen, hydroxy or lower alkyl, is reduced; andtor, if desired, a resulting compound of formula I is converted into a different compound of formula I and/or, if desired, a resulting salt is converted into the free compound or into a different salt and/or, if desired, a resulting free compound is converted into a salt and/or a resulting mixture of isomeric compounds of formula I is separated into the individual isomers.
In the more specific description of processes (a) to (f) that follows, ~ ;~
unlessiotherwisç indicared~ the symbdls X, Rl, R2 and R3 are each as ! " ' ~'`' defined under formula I.
:' Process (a): A group Y that can be converted into halogen or replaced by halogen is, for example, hydroxy or aliphatically or aromatically ;~
substituted sulfonyloxy, for example methylsulfonyloxy or 4-methylphenyl~
sulfonyloxy (tosyloxy). Preferably Y is hydroxy.
,~ `,'' .,.,''' ', 20~309~
Halogenating agents that are suitable for the conversion of Y = for example hydroxy into X = fluorine are, for example, hydrogen fluoride, sulfur tetrafluoride, especially a mixture of hydrogen fluoride and sulfur tetrafluoride and also, for example, substituted amino-sulfur trifluorides, such as diethylamino-sulfur trifluoride (DAST) or piperidino-sulfur trifluoride.
:
Halogenating agents that are suitable for the conversion of Y = for example hydroxy into X = chlorine, bromine or iodine are, for example, hydrogen halides, for example hydrogen chloride, bromide or iodide, thionyl halides, for example thionyl chloride or bromide, sulfuryl halides, for example sulfuryl chloride or bromide, or phosphorus halides, for example phosphorus tribromide, triiodide, pentabromide, pentaiodide, trichloride or pentachloride.
Compounds of formula II wherein Y is arylsulfonyloxy, for example tosyloxy, can be converted by reaction with alkali metal halides, -~
especially alkali metal chlorides, bromides or iodides, preferably in dimethylformamide, into compounds of formula I wherein X is chlorine, bromine or iodine.
Compounds of formula II wherein Y is arylsulfonyloxy, for example tosyl-oxy, can also be converted into compounds of formula I wherein X is fluorine, for example by reaction with KHFz, for example in 1,2-di-hydroxyethane.
Particularly in the case of the last two reactions it may be necessary before the reaction is carried out to protect the amino groups in the compounds of~formula II~by amino-protecting groups, for example those mentioned below. After the reaction, the amino-protecting groups are removed again in a manner known per se.
The starting compounds of formula II wherein Y is hydroxy are prepared,for example, according to process (b), see below. The starting compounds of formula II wherein Y is aliphatically or aromatically substituted sulfonyloxy are preferably prepared in a manner known per se from -compounds of formula II wherein Y is hydroxy, for example by reaction with lower alkylsulfonyl or arylsulfonyl chlorides.
Process (b~: The nucleophilic substitution reaction according to process (b) is carried out without a solvent or in the presence of a solvent, for example a lower alkanol or ether, such as isopropanol or tetrahydrofuran, and optionally under elevated pressure and takes place selectively at the terminal carbon atom of the oxiranyl radical.
The starting compounds of formula III are obtained, for example, by reacting a hydroxylamine or oxime of formula V with, for example, epichlorohydrin, epibromohydrin or 3-tosyloxy-1,2-epoxypropane. This reaction is preferably carrie~ out in the presence of a base, for example sodium hydroxide, and without a solvent or in the presence of a solvent, for example acetone or acetonitrile.
If optically active epichlorohydrin, epibromohydrin or especially 3-tosyloxy-1,2-epoxypropane is used in the preparation of compounds of formula III, then there are obtained stereoselectively the corresponding optically active compounds of formula III. If the latter are used in process (b), then optically active compounds of formula I are obtained.
The compounds of formula III can also be obtained from compounds of formula VII wherein X is hydroxy and U is, for example, chlorine, by closing the epoxy ring in the presence of a base.
Process (c): Preferred monovalent amino-protecting groups S and S' are -~
ester groups, for example lower~alkyl esters and especially tert.-butoxy-carbonyl ~BOC), or acyl radicals, for example lower alkanoyl or halo-lower alkanoyl, such as especially acetyl, chloroacetyl or trifluoro- ~
acetyl. ~ ~ ;
Preferred bivalent amino-protecting groups, formed by the radicals S and Rz or S' and R3, are mono- or di-substituted methylidene groups, such as 1-lower alkoxy-lower alkylidene groups, for example =C(CH3)(0C2Hs), ~ , :
'' ` ' ` ~ ~:
' ' , ~,; ~ ''`'';:'':`
- ~ ~
- 18 - ~
and also, for example, =C(CH3)2 or =CH-phenyl, all of which are prefer- -ably used for the protection of the nitrogen atom in the N-O grouping, and bisacyl radicals, for example that of phthalic acid, which forms a phthalimido group together with the nitrogen atom to be protected.
The mode of action of protecting groups, for example amino-protecting groups t and the methods by which they can be introduced and removed are known per se and are described, for example, in J.F.W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, and T.W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York 1984. ;~
The removal of thP amino-protecting groups can be effected, for example, -by hydrolysis, especially in an acidis medium, for example with hydrogen chloride, dilute sulfuric acid, oxalic acid, organic sulfonic acids, for example toluene-4-sulfonic acid, or trifluoroacetic acid.
Certain amino-protecting groups, for example mono- or di-substituted methylidene groups and lower alkanoyl, can be converted by reduction, for example with complex hydrides, for example LiAlH4 or NaBH3CN, into a group Rl or R3 in formula I, for example =C(CH3)2 can be converted into isopropyl or acetyl into ethyl.
Compounds of formula IV are prepared, for example, by carrying out one of processes (a), (b), (d), (e) and (f) with protected amino group(s). The compounds of formula IV can also be prepared from compounds of formula I, ~ -for example for purification purposes. ~-Process (d): In the compounds of formula VI the nucleofugal leaving ~-group Z has exactly the same definition as a nucleofugal leaving group W
in the compounds of formula VII under process (e). The amino-protecting groups S in a compound of formula VI correspond to the amino-protecting groups 5 or S' defined in compounds of formula IV under process (c).
~ `'~,`'~' ', 200309~
If, in a compound of formula VI, Z is hydroxy, then it is possible to carry out, for example, an intermolecular dehydrating reaction.
Especially suitable for this purpose is the Mitsunobu reaction [see Bull.
Chem. Soc. Japan 40, 2380 (1967)] in which the compounds of formulae V
and VI are reacted with, for example, triphenylphosphine and N,N'-azodi-carboxylic acid ethyl ester.
If, in a compound of formula VI, Z is a nucleofugal leaving group, then process (d) corresponds to a simple nucleophilic substitution (0-alkyla-tion).
If, in a compound of formula VI, X is hydroxy, then it may be advisable -before process (d) is carried out to protect that hydroxy group with a hydroxy-protecting group which is removed again when the reaction accord-ing to process (d) is complete. Suitable hydroxy-protecting groups are, for example, acyl derivatives (esters), for example lower alkanoyl, benzoyl, benzyloxycarbonyl or lower alkoxycarbonyl, or alkyl derivatives -(ethers), for example lower alkoxy-lower alkyl, 2-tetrahydropyranyl, trityl or benzyl, and also tri-lower alkylsilyl.
If, in a compound of formula VI, X is hydroxy, then that hydroxy group may also be protected together with the amino group -NSR3. This can be `~ ~ -effected, for example, by the radicals X and S in a compound of formula VI together forming a group -0-CH2-, an oxazolidine ring being formed. A ;~
compound protected in this manner is obtained, for example, from the free hydroxyamino compound by condensation with formaldehyde in a manner known E~ se. This protecting group is removed again in an acidic ~ ~-medium after process (d) has been carried out.
.
Compounds of formula VI wherein X and Z are hydroxy are prepared, for example, by reacting 2,3-epoxypropanol with ammonia or an amine of `;
formula NHz~3 and then, if required, introducing a hydroxy- and/or ; k amino-protecting group. ;
.. ~ ~ . :-, , - , , .,~:
:~ : , '". ~.
~: ~ - ' " :.
,, :
20~)31)91 -Process (e): In a compound of formula VII, a radical ~ that can be converted into amino is, for example, an azido group (-N3~ that can be converted into amino by reduction, for example with complex metal hydrides, for example LiAlH4, tin(II) chloride or with hydrogen in the presence of a catalyst, for example palladium-on-carbon. It may be , advisable before process (e) is carried out to protect a hydroxy group X
and/or the amino group RlRzN- in the compound of formula VII with a hydroxy- and/or amino-protecting group. Such protecting groups are removed again after process (e) has been carried out.
Compounds of formula VII wherein W is azido can be obtained, for example, by the reaction of compounds of formula III or IIIa with, for example, sodium or ammonium azide.
The radical W in a compound of formula VII can also be, for example, a nucleofugal leaving group. Such a nucleofugal leaving group W is prefer-ably halogen, for example chlorine, bromine or iodine, but also, for example, aliphatically or aromatically substituted sulfonyloxy, for example methylsulfonyloxy or 4-methylphenylsulfonyloxy.
Such a compound of formula VII can be converted into a compound of formula I by reaction with ammonia or an amine of formula NHzR3 in the -~
manner of a nucleophilic substitution reaction.
Starting compounds of formula VII are prepared, for example, from com-pounds of formula III or from compounds of formula IX
R 0 ~CH (IX) ~ ~ 2 by reaction with the corresponding nucleophiles, for example halide, methanesulfonate or p-toluenesulfonate.
~ `': `~``''``' 200309~
- 21 ~
Compounds of formula VII wherein X is hydroxy and W is, for example, halogen or tosyloxy, can also be obtained by reaction of compounds of formula V with epihalohydrin or 3-tosyloxy-1,2-epoxypropane, especially in an acidic medium.
Compounds of formula IX wherein X is hydroxy can be obtained analogously from compounds of formula V by reaction with 2,3-epoxypropanol.
Compounds of formula IX can also be obtained, for example, starting from compounds of formula V with, for example, 3-halo-2-X-propanols, wherein the hydroxy group is, if appropriate, in protected form.
Process (f): The reduction can be carried out, for example, using the same reducing agents as those 1ndicated in process (e) for the reduction of azido groups.
The starting compounds of formula VIII can be prepared, for example, from -the analogous aldehydes (=O instead of =NR3 in formula VIII) by reaction with ammonia, hydroxylamine or lower alkylamines. ~ ;
The mentioned aldehydes analogous to formula VIII can be prepared from ; ; ; ;`
corresponding hydroxymethyl compounds, for example, by oxidation, for ~
exampls with pyridinium chlorochromate [see J. Org. Chem. 46, 4797 ~ ~;
(1981)]. They may also be obtained by reduction of corresponding lower alkyl esters, for example with diisobutylaluminium hydride [see Chem.
Pharm. Bull. 23, 3081 (1975)] or by reduction of corresponding acid chlorides, for example with tri-n-butyltin hydride [see J. Org. Chem.
25, 284 (1961) or J. Amer. Chem. Soc. ô8, 571 (1966)].
:, '~
: .
The mentioned aidehydes analogous to formula VIII can also be obtained -; ;~
especially by the following reaction sequence:
(1) Reaction of 3,4-0,0-isopropylidene-3,4-dihydroxy-1,2-epoxybutane [see J. Org. Chem. 52, 2841 (1987) or DE-A-3 150 917] with acetohydroxamic acid ethyl ester to form 3,4-0,0-isopropylidene-2,3,4-trihydroxy-1 ethoxyethylideneaminoxy)-butane. In the latter compound the 2-hydroxy group may optionally be converted in a manner known per se into a ~ ~ '' ' .' '" ' "' :
different radical X in formula I, for example halogen, or be protscted by a protecting group. (2) Removal of the isopropylidene group, for example by treatment with dilute acid. (3) Glycol cleavage of the terminal a,~-dihydroxyethyl group to formyl by reaction of NaIO4 or Pb(OCOCH3)4. (4) Removal of the l-ethoxyethylidene group, for example by treatment with acid.
Compounds of formùla I can be converted into different compounds of formula I.
Compounds of formula I wherein X is hydroxy can be converted in a manner known per se into compounds of formula I wherein X is lower alkoxy, acyloxy, lower alkylsulfonyloxy or arylsulfonyloxy by reacting the former with lower alkylating agents, for example lower alkyl halides, tosylates or mesylates, or di-lower alkyl sulfates, or acylating agents, for example acid anhydrides or halides, or lower alkylsulfonyl halides or arylsulfonyl halides, for example 4-methylphenylsulfonyl chloride. In these reactions the two amino groups in the compounds of formula I are ~ -preferably protected. ;-When carrying out an above-mentioned alkylation of X = OH into X z lower ;
alkoxy, the amino group -NRlR2 (Rl and R2 are hydrogen) may also be -lower alkylated at the same time even though it has been protected by an amino-protecting group, for example BOC. - ;-~
Compounds of formula I wherein Rl and Rz together are a radical ;~ ~ fRsR4C= can be converted into different compounds of formula I wherein Rl is hydrogen and R2 is a radical -CHR4Rs by reduction, for example `-- `
with sod~um yanoborohydride.
Compounds of formula I wherein Rl and R2 are hydrogen can be converted into different compounds of formula I wherein the radicals Rl and Rz together are a group RsR4C= by reaction with a carbonyl compound --~
RsR4C=O in which the carbonyl group may also be in masked form, for example in acetal or ketal form.
~.
Z00309~
Conversely, it is also possible for compounds of formula I wherein R
and R2 together are a group RsR4C= to be converted into compounds of formula I wherein R1 and R2 are hydrogen, for example by acidic hydrolysis.
Free compounds of formula I having salt-forming properties obtainable in accordance with the process can be converted into their salts in a manner known per se; compounds having basic properties can be converted by treatment with acids or suitable derivatives thereof.
:',"
The compounds, including their salts, can also be obtained in the form of their hydrates, or their crystals may include, for example, the solvent ~ ~-used for crystallisation. -Mixtures of isomers obtainable according to the invention can be ~ ~
separated into the individual isomers in a manner known per se; ~ ;
racemates can be separated, for example, by forming salts with optically pure salt-forming reagents and separating the resulting mixture of di-astereoisomers, for example by means of fractional crystallisation. ;
The reactions mentioned above can be carried out under reaction condi~
tions known per se, in the absence or, usually, in the presence of ;
solvents or diluents, preferably those solvents or diluents which are inert towards the reagents used and are solvents therefor, in the absence -or presence of catalysts, condensation agents or neutralising agents and, depending upon the nature of the reaction and/or the reactants, at reduced, normal or elevated temperature, for example in a temperature range of from approximately -80C to approximately 190C, preferably from`;~
approximately -20C to approximately 150C, for example at the boiling -point of the solvent used, under atmospheric pressure or in a closed vessel, optionally under pressure, and/or in an inert atmosphere, for example under a nitrogen atmosphere.
., ~ .. ' -:
The starting materials used in the process of the present invention are ; preferably those which result in the compounds described at the beginning as being especially valuable. - ;
': ': ' ' : .
The invention relates also to those forms of the process in which a com-pound obtainable as intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example a salt thereof.
The prasent invention relates also to pharmaceutical preparations that contain one of the pharmacologically active compounds of formula I as active ingredient. Preparations for enteral, especially oral, and ~ ~;
parenteral administration are especially preferred. The preparations contain the active ingredient on its own or, preferably, together with a pharmaceutically acceptable carrier. The dosage of the active ingredient -depends upon ~he disease to be treated, and upon the species, its age, weight and individuai condition, and upon the mode of administration. -The pharmaceutical preparations contain from approximately 5 % to approximately 95 % active ingredient, forms of administration that are in single dose form preferably containing from approximately 20 % to approximately 90 % active ingredient, and forms of administration that are not in single dose form preferably containing from approximately 5 %
to approximately 20 % active ingredient. Dosage unit forms, such as dragées, tablets or capsules, contain from approximately 0.05 g to approximately 1.0 g of active ingredient.
The pharmaceutical preparations of the present invention are manufactured in a manner known ~ se, for example by means of conventional mix~
ing, granulating, confectioning, dissolving or lyophilising processes. ~i ;
! ~
For`example, pharmaceutical compositions for oral administration can be ~
obtained by combining the active ingredient with one or more solid ~ - -carriers, optionally granulating a resulting mixture and processing the - -~
mixture or granulate, if desired and/or appropriate, with the addition of ~
additional adjuncts, to form tablets or dragée cores. ~ - `
:-. - ~, : :-Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropylmethylcellulose. sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, cross-linked polyvinylpyrrolidone. alginic acid or a salt thereof, such as sodium alginate. Additional adjuncts are especially flow-regulating agents and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
Dragée cores can be provided with suitable coatings which may be resistant to gastric juices, there being used inter alia concentrated sugar solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or lacquer solutions in suitable organic solvents or solvent mixtures or, for the preparation of coatings that are resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxy-propylmethylcellulose phthalate. Colourings or pigments may be added to the tablets or dragée coatings, for example for identification purposes or to indicate different doses of active ingredient. ~
~. . ,'..
Pharmaceutical compositions for oral administration are also dry-fill capsules consisting of gelatine, and soft sealed capsules consisting of ~ ~
gelatine and a p.lasticiser, such as glycerine or sorbitol. The dry-fill -capsules may contain the active ingredient in the form of a granulate, for example in admixture with fillers, such as corn starch, binders , . ' . i ! , . I ~ i ! . ' ' and/or glidants, such as talc or magnesium stearate, and optionally stabilisers. In soft capsules the active ingredient is preferably dissolved or suspended in suitable liquid adjuncts, such as fatty oils, paraffin oil or liquid polyethylene glycols, it likewise being possible to add stabilisers.
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Other oral forms of administration are, for example, syrups prepared incustomary manner which contain the active ingredient, for example, in suspended form and in a concentration of approximately from 5 ~/O to 20 %, preferably about 10 %, or in a similar concentration that provides a suitable single dose when administered, for example, in measures of 5 or 10 ml. Also suitable are, for example, powdered or liquid concentrates for the preparation of shakes, for example in milk. Such concentrates may also be packed in single dose quantities.
Suitable rectally administrable pharmaceutical preparations are, for example, suppositories that consist of a combination of the active ingredient with a suppository base material. Suitable suppository base materials are, for example, natural or synthetic triglycerides, paraffin ~-hydrocarbons, polyethylene glxcols or higher alkanols.
For parenteral administration there are suitable, especially, aqueous solutions of an active ingredient in water-soluble form, for example in the form of a water-soluble salt, or aqueous injection suspensions that ~ -contain viscosity- increasing substances~ for example sodium carboxy~
methylcellulose, sorbitol and/or dextran and, if desired, stabilisers.
The active ingredient, optionally together with adjuncts, can also be in the form of a lyophilisate and can be made into a solution prior to ;~ -parenteral administration by the addition of suitable solvents.- ~ `
The solutions used, for example, for parenteral administration can alsobe used as infusion solutions.
The invention relates also to a method of treating the pathological - ~-conditions mentioned above. The!compounds of the present invention can be administered prophylactically or therapeutically, and are preferably administered in the form of pharmaceutical preparations. A daily dose of ;~
from approximately 0.3 g to approximately 15 g, preferably from approximately 0.5 g to approximately 5 g, of a compound of the present invention will be administered in the case of a body weight of approxlmately 70 kg.
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The following Examples illustrate the present invention; temperatures are given in degrees Celsius. The following abbreviations are used: BOC ~
tert.-butoxycarbonyl; THF - tetrahydrofuran; hexane = n-hexane;
ether - diethyl ether; mesyl - methylsulfonyl.
Example 1: In a gold-coated 50 ml autoclave, 3.2 g of N-(3-aminoxy-2-hydroxypropyl)-isopropylamine are dissolved at -78 in 20 g of anhydrous ~ -hydrogen fluoride, and 5.4 g of sulfur tetrafluoride are added thereto.
The autoclave is sealed, stirred with a magnetic rod for 3 hours at -78, heated to 0 and after a further 24 hours degassed. The residue is taken ~-up in 30 ml of 2N hydrochloric acid, filtered and applied to a 35 x 270 mm column with slightly basic ion exchanger MWA-1 (Dow Chemicals).
The column is washed with water. The ninhydrin-positive fractions are combined, neutralised with hydrochloric acid and concentrated by evapora-tion. The hygroscopic residue corresponds to N-(3-aminoxy-2-fluoro-propyl)-isopropylamine dihydrochloride; it is crystallised from ethyl acetate and dried over phosphorus pentoxide; Rf value = 0.55 (silica gellmethylene chloride:methanol:concentrated ammonia 150:50:1).
The N-(3-aminoxy-2-hydroxypropyl)-isopropylamine used as starting material is freed from the corresponding dihydrochloride (see DE-C-2 651 033) by filtration over a strongly basic ion exchanger, for example 50 times the amount of DOWEX 1x4 (OH).
Example 2: 30 ml of an approximately 2N solution of hydrogen chloride in ethyl acetate are atted to a solution of 3 g of N,N'-di-BOC-N-(3-aminoxy-2-fluoropropyl)-isopropylamine in 30 ml of ethyl acetate and the mixture is stirred at room temperature for lô hours with the exclusion of moisture. The precipitated product, is filtered with suction, washed with ethyl acetate ant ether and dried, yielding N-(3-aminoxy-2-fluoropropyl)-isopropylamine dihydrochloride in the form of a white hygroscopic powder, Rf value s 0.55 (silica gel/methylene chloride:methanol:concentrated ammonia 150:50:1).
The starting material is prepared as follows:
; ' ` , ~.,;
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-- .:
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The crude product from the fluorination batch described in Example 1, starting from 20 mmol of N-(3-aminoxy-2-fluoroproPYl)-isoPropylamine, is dissolved in 30 ml of 2N hydrochloric acid. This solution is diluted with 50 ml of water and 50 ml of THF and neutralised in portions with solid sodium hydrogen carbonate. This mixture is then treated dropwise with a solution of 12 g of di-tert.-butyl dicarbonate (FluXa) in 50 ml o THF
while cooling with ice and is then stirred at room temperature for 20 hours. The reaction mixture is diluted with 250 ml of ether. The upper layer is washed with water and a saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. The oil that remains is chromatographed over silica gel with a mixture of hexane/ethyl acetate (1:1), yielding N,N'-di-BOC-N-(3-aminoxy-2-fluoro-propyl)-isopropylamine in the form of a colourless oil, Rf value = 0.32 (silica gel/hexane:ethyl acetate 2:1). ~
. :,;
Example 32: 2 ml of lN sodium hydroxide solution and 0.2 ml (2 mmol) of ~ -benzaldehyde are added to a solution of 360 mg (2 mmol) of 3-aminoxy-2-hydroxypropylamine dihydrochloride in 5 ml of ethanol and the mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated by evaporation, 10 ml of water and 1 ml of 2N sodium hydroxide solution are added and the mixture is extracted twice with SO ml of ether. The ether phases are washed with dilute sodium chloride solution, combined, filtered and concentrated by evaporation. The residue is crystallised from a small amount of ether and corresponds to 3-benzylideneaminoxy-2-hydroxypropylamine, m.p. 65, Rf value = 0.32 Ssilica gel/methylene chloride:methanol:concentrated ammonia 40:10:1).
Example 3a: 40 ml of concentrated ammonia are added to a solution of 1.77 g (10 mmol? of 1-benzylidene,aminoxy-2,3-epoxypropane [see, for example, Zh. Org. Khimii 5, 1353 (1969)] in 10 ml of THF and the mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated by evaporation and taken up in 100 ml of ether. This solution is dried over sodium sulfate, filtered and concentrated, and the 3-benzylideneaminoxy-2-hydroxypropylamine crystallises out after cooling, m.p. 65.
.~ :
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2003iO9l Example 4- Analogously to the process described in Example 3, 3-aminoxy-2-hydroxypropylamine dihydrochloride is reacted with cyclo-pentanone, yielding 3-cyclopentylideneaminoxy-2-hydroxypropylamine in the form of a wax, Rf value = 0.33 (silica gel/methylene chloride:methanol:concentrated ammonia 40:10:1).
Example 4a: Analogously to Example 3a, 1-cyclopentylideneaminoxy-2,3-epoxypropane [see J. Med. Chem. 28, 153 (1985)] is reacted with concentrated ammonia and worked up. The crude product is chromatographed with the system methylene chloride/methanol/concentrated ammonia (40:10:1), yielding 3-cyclopentylideneaminoxy-2-hydroxypropylamine in the form of a wax, Rf value = 0.33 (silica gel/methylene chloride:methanol:concentrated ammonia 40:10:1).
Example 5: In a 200 ml Teflon reactor, 2.5 g of 3-aminoxy-2-hydroxy- ~;
propylamine (see DE-C-2 651 083) are dissolved at -78 in 40 g of liquid hydrogen fluoride (HF). A further 5.6 g of sulfur tetrafluoride are then -introduced. The mixture in the reactor is sealed and stirred with a magnetic rod for 3 hours at -78, heated to 0 and after a further 24 hours degassed, yielding crude 3-aminoxy-2-fluoropropylamine in the form of the hydrofluoride which is converted into the corresponding pure dihydrochloride using one of the following two methods:
a)- Th~P residue is taken up in 50 ml of 2N HCl, filtered and applied to a 35 x 270 mm column with slightly basic ion exchanger MWA-1 (Dow Chemicals). The column is washed with water. The ninhydrin-positive fractions are combined, neutralised with lN HCl and concentrated by evaporation. The residue is crystallised from ethyl acetate, yielding 3-aminoxy-2-fluoropropylamine dihydrochloride having a melting point of 204-207. ~ ~;
b) The residue is taken up in 50 ml of 2N HCl and 100 ml of water, filtered and diluted with 100 ml of THF. This mixture is neutralised to pH 7.5 in por~ions with solid sodium hydrogen carbonate while cooling -with ice, and then a solution of 13.0 g of di-tert.-butyl dicarbonate (Fluka) in 70 ml of THF is added dropwise thereto. The two-phase reaction ~ -200~0~
mixture is stirred at room temperature for 16 hours and then diluted with 100 ml of ether. The organic phase is separated off, washed with ]00 ml of water and 50 ml of a saturated sodium chloride solution, dried over magnesium sulfate and, after the drying agent has been separated off, concentrated by evaporation. The residue is crystallised from ether and hexane and corresponds to N,N'-di-BOC-3-aminoxy-2-fluoropropylamine having a melting point of 67-69.
20 ml of a 1.8N solution of hydrogen chloride in ethyl acetate are added to a solution of 1.8 g of N,N'-di-BOC-3-aminoxy-2-fluoropropylamine in -~
10 ml of ethyl acetate and the mixture is stirred at room temperature for 18 hours. The product that crystallises out is filtered with suction, washed with ether and dried. It corresponds to 3-aminoxy-2-fluoropropyl- ~- ~amine dihydrochloride having a melting point of 204-207. -Example 6: Analogously to Example 2, 3.4 g of N,N'-di-BOC-3-aminoxy-2-mesyloxypropylamine are treated with 30 ml of an approximately 1.5N
solution of hydrogen chloride in ethyl acetate and worked up, yielding 3-aminoxy-2-methylsulfonyloxypropylamine dihydrochloride in the form of white hygroscopic crystals, Rf value = 0.37 (silica gel/methylene chloride:methanol:concentrated ammonia 40:10:1).
.
The starting material is prepared as follows:
While cooling with ice-water, a solution of 48 g (0.22 mol) of di-tert.-butyl dicarbonate (Fluka) in 100 ml of THF is added dropwise, with stirr-ing, to a solution of 18 g (0.1 mol) of 3-aminoxy-2-hydroxypropylamine dihydrochloride and 21.2 g (0.2 mol) of anhydrous sodium carbonate in 100 ml of water~and 100 ml of!THF~and the mixtu~re is stirred at room temperature for 4 hours. The reaction mixture is diluted with 250 ml of ether. The upper layer is separated off, washed with water and a saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. The N,N'-di-BOC-3-aminoxy-2-hydroxypropyl-amine that remains behind is crystallised from ether/petroleum ether, m.p. 106-108. ;
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:::::
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~UUW~l While cooling with ice-water and with the exclusion of moisture, 1.26 g(ll mmol) of methanesulfochloride are added, with stirring, to a solution of 2.75 g (9 mmol) of N,N'-di-BOC-3-aminoxy-2-hydroxypropylamine in 10 ml of pyridine and the mixture is stirred at room temperature for 16 hours.
2 ml of water are then added and the reaction mixture is concentrated by evaporation. 100 ml of ether and 50 ml of water are added to the residue.
The upper layer is separated off, washed in succession with a diluted sodium hydrogen sulfate solution, water, a saturated sodium hydrogen carbonate solution and again with water and, after drying over magnesium suifate, concentrated by evaporation, yielding N,N'-di-BOC-3-aminoxy-2-mesyloxypropylamine in the form of a yellow oil. Rf value = 0.28 (silica gel/hexane:ethyl acetate l:l).
Example 7: Analogously to Example 2, 1.3 g of N,N'-di-BOC-3-methyl-aminoxy-2-methoxypropylamine are treated with 20 ml of an approximately 1.5N solution of hydrogen chloride in ethyl acetate and worked up. The crude product is dissolved in a small amount of water, and filtered over 100 ml of DOWEX lx4 (OH form). The filtrate is concentrated by evaporation and the residue is crystallised from 10 ml of methanol with the addition of 700 mg of oxalic acid, yielding 3-methylaminoxy-2-methoxypropylamine dioxalate, m.p. 153-155.
The starting material is prepared as follows:
Uith stirring and with the exclusion of moisture, 1.7 g (40 mmol) of a 55-60 % NaH dispersion in oil are added to a solution of 3.06 g (10 mmol) of N,N'-di-BOC-3-aminoxy-2-hydroxypropylamine in 100 ml of THF. A solu- ;
tion of l.9 ml (~0 mmol) of dimethyl sulfate in 10 ml of THF is then added dropwise thereto and the mixture is stirred at room temperature for `
15 hours. The reaction mixture is concentrated by evaporation and the -residue is taken up in ether, washed with water, dried over magnesium ~ `
sulfate and again concentrated by evaporation. The oil that remains is ~ :
chromatographed over silica gel with a mixture of hexane/ethyl acetate (l:l), yielding N,N'-di-BOC-3-methylaminoxy-2-methoxypropylamine in the - -~form of a pale yellow oil, Rf value = 0.36 (silica gel/hexane:ethyl acetate l:l). 1`
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- .
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Example 8: Analogously to Example 3, 3-aminoxy-2-hydroxypropylamine -dihydrochloride is reacted with salicylaldehyde, yielding 3-salicylidene-aminoxy-2-hydroxypropylamine [- 3-(2-hydroxybenzylideneaminoxy)-2-hydroxypropylamine] in the form of yellow crystals having a melting point of 94-97.
,~
Examp]e 9: Analogously to Example 3, 3-aminoxy-2-hydroxypropylamine dihydrochloride is reacted with acetone, yielding 3-isopropylidene-aminoxy-2-hydroxypropylamine which is crystallised in hydrochloride form from isopropanol/ether. The white hygroscopic crystals are dried over phosphorus pentoxide, Rf value = 0.1 (silica gel/methylene chloride:methanol:concentrated ammonia 150:50:1). ~
~ : '' :, Example 9a: Analogously to Example 3a, 1-isopropylideneaminoxy-2,3-epoxypropane [see Zh. Org. Khimii 5, 1353 (1969)] is reacted with concentrated ammonia. The reaction mixture is concentrated to dryness by evaporation, yielding 3-isopropylideneaminoxy-2-hydroxypropylamine in the form of a pale yellow oil, Rf value = 0.1 (silica gel/methylene chloride:methanol:concentrated ammonia 150:50:1).
Example 10: Analogously to Example 2, 4.5 g of N-BOC-(3-isopropyl-aminoxy-2-hydroxypropyl)-amine are treated with 50 ml of an approximately 1.5N solution of hydrogen chloride in ethyl acetate. The reaction mixture is concentrated by evaporation and the crude product is dissolved in a small amount of water and filtered over 200 ml of DOWEX lx4 (OH form).
The filtrate is concentrated by evaporation and the oily residue is taken up in ethyl acetate, dried over sodium sulfate and freed of solvent again. The 3-isopropylaminoxy-2-hydroxypropylamine, which slowly crystallises, is sublimed at 50/0.1 mbar.
The starting material is prepared as follows:
A solution of 28 g of di-tert.-butyl dicarbonate (Fluka) in 150 ml of THF
is added dropwise, with stirring and while cooling with ice-water, to a ~
solution of 13.48 g of 3-isopropylideneaminoxy-2-hydroxypropylamine in `~ ;
- '::`''. ~
' ~:'` ;, ,, 150 ml of THF and 150 ml of water and the mixture is stirred at room temperature for 16 hours. The reaction mixture is freed of THF in vacuo and extracted with ether. The organic phase is washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. The residue is chromatographed over silica gel with a mixture of hexane/ethyl acetate (1:1), yielding N-BOC-3-iso-propylideneaminoxy-2-hydroxypropylamine in the form of a pale yellow oil, Rf value = 0.16 (silica gel/hexane:ethyl acetate 1:1).
17.3 ml (304 mmol) of glacial acetic acid and 9.6 g (152 mmol) of sodium cyanoborohydride are added to a solution of 10.32 g (41.95 mmol) of N-BOC-3-isopropylideneaminoxy-2-hydroxypropylamine in 230 ml of THF and the mixture is stirred at room temperature for 16 hours. 10.32 g of sodium hydrogen carbonate are added to the reaction mixture which is then stirred for 30 minutes and concentrated by evaporation. The residue is taken up in ether, washed with water, dried over magnesium sulfate and freed of solvent. The product is chromatographed over silica gel with a mixture of hexane/ethyl acetate (1:1), yielding N-BOC-(3-isopropyl-aminoxy-2-hydroxypropyl)-amine in the form of a pale yellow oil, Rf value = 0.05 (silica gel/hexane:ethyl acetate 1:1).
:, ~.
Example 11: 10 ml of an approximately 5.5N solution of HCl in ethanol -are added to a solution of 2.6 g of N-BOC-(3-isopropylaminoxy-2-fluoro-propyl)-amine in 25 ml of ethanol and the mixture is left to stand at ~
room temperature for 18 hours with the exclusion of moisture and then ~ -concentrated to dryness by evaporation. The residue is dissolved in water ~ ~
and extracted once with ether. The aqueous phase is filtered with -; -activated carbon and lyophilised, yielding 3-isopropylaminoxy-2-fluoro-propylamine dihydrochloride in the form of a yellowish hygroscopic powder, Rf value = 0.59 (silica gel/methylene chloride:methanol:concentrated ammonia 40:10:1). -~
The starting material is prepared as follows: ~ ~
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200309~
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Analogously to Example 5, 2.65 g (17.9 mmol) of 3-isopropylaminoxy-2-hydroxypropylamine in 20 ml of anhydrous hydrogen fluoride are ~ -fluorinated with 4.2 g (40 mmol) of sulfur tetrafluoride and converted into a corresponding (mono-)BOC-derivative with 10 g of di-tert.-butyl dicarbonate (Fluka). The crude product is chromatographed over silica gel with a mixture: of hexane/ethyl acetate (2:1), yielding N-BoC-(3-iso-propylaminoxy-2-fluoropropyl)-amine in the form of a pale yellow oil, Rf value = 0.12 (silica gel/hexane:ethyl acetate 2:1).
Example 12: Analogously to Example 3, 537 mg (3 mmol) of 3-aminoxy-2-hydroxypropylamine dihydrochloride in 10 ml of ethanol and 3 ml of lN
sodium hydroxide solution are reacted with 0.61 g (3 mmol) of pyridoxal hydrochloride. The reaction mixture is concentrated by evaporation and the crystalline residue is recrystallised from methanol, yielding 3-pyridoxalaminoxy-2-hydroxypropylamine dihydrochloride in the form of white crystals, m.p. >185 (decomposition), Rf value = 0.11 (silica geltmethylene chloride:methanol:concentrated ammonia 40:10:1).
Example 13: 0.14 ml of acetaldehyde is added to a solution of 450 mg (2.5 mmol) of 3-aminoxy-2-fluoropropylamine dihydrochloride (see Example 5! in 5 ml of ethanol and 2.5 ml of lN sodium hydroxide solution and the mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated by evaporation and the residue is partitioned between water and ether. The lower phase is concentrated and lyophilised, yielding 3-ethylideneaminoxy-2-fluoropropylamine hydrochloride in the ; - -form of a white powder containing 1 mol of sodium chloride, Rf value --0.27 (silica gel/methylene chloride:methanol:concentrated ammonia 300:50:1). - ;~
Exam~le 14: 3-ethylideneaminoxy-2-fluoropropylamine (see Example 13) is reduced with sodium cyanoborohydride in a manner analogous to that ;;
described in Example 10 to form 3-ethylaminoxy-2-fluoropropylamine, R
value 0.2 (silica geltmethylene chloride:methanol:concentrated ammonia 40:10:1).
' ' .
- 200309~L
. . .
Example lS: 0.44 ml (6 mmol) of acetone is added to a solution of 900 mg (5.0 mmol) of 3-aminoxy-2-fluoropropylamine dihydrochloride (see Example 5) in 10 ml of ethanol and 5.0 ml of lN sodium hydroxide solution and the mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated by evaporation and the residue is partitioned between water and ether. The lower phase is concentrated and lyophilised, yield-ing 3-isopropylideneaminoxy-2-fluoropropylamine hydrochloride in the form of a white powder containing 1 mol of sodium chloride, m.p. 90, Rf value 0.30 (silica gellmethylene chloride:methanol:concentrated ammonia 300:50:1).
Example 16: 3-isopropylideneaminoxy-2-fluoropropylamine (see Example 15) is reduced with sodium cyanoborohydride in a manner analogous to that described in Example 10 to form 3-isopropylaminoxy-2-fluoropropylamine.
The dihydrochloride salt is obtained in the form of a yellowish powder, Rf value = 0.59 (silica gel/methylene chloride:methanol:ammonia 40:10:1).
The product is identical to that of Example 11.
Example 17: 0.4 ml of benzaldehyde is added to a solution of 724 mg - -(4 mmol) of 3-aminoxy-2-fluoropropylamine dihydrochloride (see Example 5) :
in 10 ml of ethanol and 4 ml of lN sodium hydroxide solution and the mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated by evaporation and the residue is partitioned between -4 ml of lN sodium hydroxide solution and 100 ml of ether. The ether phase is washed with 10 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness by evaporation. The oily residue is taken up in 7 ml of ethyl acetate, and 3.7 ml of a lN solution of HCl gas in ethyl acetate are added. The 3-benzylideneaminoxy-2-fluoro-propylamine hydrochloride that crystallises out is filtered with suction and dried, m.p. 150-152, Rf value 0.46 (silica gel/methylene chloride:methanol:concentrated ammonia 300:50:1). ~ ~ -~,.:
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Example 18: 3-benzylideneaminoxy-2-fluoropropylamine (see Example 17) is reduced with sodium cyanoborohydride in a manner analogous to that described in Example 10 to form 3-benzylaminoxy-2-fluoropropylamine, Rf value 0.35 (silica gel/methylene chloride:methanol:concentrated ammonia 40:10:1).
Example 19: 3.2 ml of salicylaldehyde are added to a solution of 5.43 g(30 mmol) of 3-aminoxy-2-fluoropropylamine dihydrochloride (see Example 5) in 60 ml of ethanol and 30 ml of lN sodium hydroxide solution and the mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated by evaporation a~d the residue is partitioned between 30 ml of lN sodium hydroxide solution and 100 ml of ether. The ether phase is washed with 30 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness by evaporation. The oily residue is taken up in 70 ml of ethyl acetate, and 14 ml of a 2.2N
solution of HCl gas in ethyl acetate are added. The 3-(2-hydroxy-benzylideneaminoxy)-2-fluoropropylamine hydrochloride that crystallises out is filtered with suction and dried, m.p. 174-175, Rf value 0.33 ;~
(silica gel/methylene chloride:methanol:concentrated ammonia 300:50:1).
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Example 20: 2.7 g (13 mmol) of phosphorus pentachloride are added in ~` -portions over a period of 15 minutes to a suspension of 2.1 g (lO mmol) of 3-(l-ethoxyethylideneaminoxy)-2-hydroxypropylamine hydrochloride ;~
(U.S. Patent No. 4 404 384) in 20 ml of methylene chloride and the mixture is stirred at room temperature for 2 hours. After the addition of 2 ml of water, the reaction mixture is stirred for a further 2 hours at ~
, . .,: , room temperature and then concentrated by evaporation. The residue is treated with strDngly basic ion exchanger M~'A-l (Dow Chemicals) analogously to Example 1, yielding 3-aminoxy-2-chloropropylamine dihydrochloride, Rf value 0.31 (silica gel/methylene chloride:methanol:concentrated ammonia 40:10:1).
Example 20a: Analogously to Example 2, N,N'-di-BOC-3-aminoxy-2-chloro-propylamine is treated with hydrogen chloride in ethyl acetate, yielding 3-aminoxy-2-chloropropylamine dihydrochloride, Rf value 0.31 (silica gel/methylene chloride:methanol:concentrated ammonia 40:10:1).
~.
:
200:~09~. :
The starting material is prepared as follows:
The reaction mixture from Example 20, after hydrolysis by the addition of water, is carefully treated with 10 g of sodium hydrogen carbonate and then reacted with 2.5 g of di-tert.-butyl dicarbonate analogously to Example 2 to form N,N'-di-BOC-3-aminoxy-2-chloropropylamine. The pure substance is isolated in the form of colourless crystals having a melting -point of 111-113.
', .:
Example 21: 0.4 ml of 2-oxopropionic acid ethyl ester is added to a solution of 450 mg (2.5 mmol) of 3-aminoxy-2-fluoropropylamine dihydro-chloride (see Example 5) in 5 ml of ethanol and 2.5 ml of lN sodium hydroxide solution and the mi~ture is stirred at room temperature for - ;
16 hours. The reaction mixture is concentrated by evaporation and the residue is partitioned between water and ether. The lower phase is concentrated and lyophilised, yielding 3-(1-ethoxycarbonylethylidene- -aminoxy)-2-fluoropropylamine hydrochloride in the form of a white powder containing 1 mol of sodium chloride, Rf value 0.30 (silica gel/methylene chloride:methanol:concentrated ammonia 300:50:1).
~ i ' ,. -,, Example 21a: 450 mg (2.5 mmol) of 3-aminoxy-2-fluoropropylamine di-hydrochloride are reacted in a manner analogous to that described in Example 21 with 0.5 ml of 2-oxopropionic acid methyl ester, yielding 3-(1-methoxycarbonylethylideneaminoxy)-2-fluoropropylamine hydrochloride ~ -in the form of a white powder, m.p. 150 (decomposition).
:~ , ` ~: .,-Example 22: 3-aminoxy-2-fluoropropylamine (see Example 5) is reacted with 2-oxopropionic acit i,n ajmannerjanalogous to that described in Example 3, yielding 3-(1-carboxyethylideneaminoxy)-2-fluoropropylamine.
.
~: :
: ..:; -....,,.,~.::
-Example 23: 3-aminoxy-2-fluoropropylamine (see Example 5) is reacted with methoxyacetone in a manner analogous to that described in Example 21, yielding 3-(l-methoxymethylethylideneaminoxy)-2-fluoropropylamine, m.p. 70, Rf value 0.33 (silica gel/methylene chloride:methanol:concentrated ammonia 300:50:1).
Example 24: 3-aminoxy-2-fluoropropylamine (see Example 5) is reacted with acrolein in a manner analogous to that described in Example 3, yielding 3-(prop-2-en-1-ylideneaminoxy)-2-fluoropropylamine, Rf value 0.35 (silica gel!methylene chloride:methanol:concentrated ammonia 300:50:1).
Example 24a: 3-aminoxy-2-hydroxypropylamine dihydrochloride is reacted ~ ;
with acrolein in a manner analogous to that described in Example 21, --~ -yielding 3-(2-propenylideneaminoxy)-2-hydroxypropylamine hydrochloride, .. . ..
Rf value 0.23 (silica gel/methylene chloride:methanol:concentrated ammonia 40:10:1).
ExamPle 25: 3-aminoxy-2-fluoropropylamine (see Example 5) is reacted with methyl vinyl ketone in a manner analogous to that described in ;
Example 3, yielding 3-(1-methylprop-2-en-1-ylideneaminoxy)-2-fluoro-propylamine, Rf value 0.35 (silica gel/methylene chloride:methanol:concentrated ammonia 300:50:1).
Example 26: 0.5 ml (5.5 mmol) of ethyl methyl ketone is added to a solution of 900 mg (5.0 mmol) of 3-aminoxy-2-fluoropropylamine dihydro-chloride (see Example 5) in 10 ml of ethanol and 5.0 ml of lN sodium -hydroxide solution and the mixture is stirred at room temperature for 16 hours. The reaction mix,turle islcqncentrated by evaporation and the residue is partitioned between water and ether. The lower phase is concentrated and lyophilised, yielding 3-(1-methyl-1-propylideneamin-oxy)-2-fluoropropylamine hydrochloride in the form of a white powder containing 1 mol of sodium chloride, Rf value 0.31 (silica gel/methylene chloride:-ethanol:concentrated a _onia 300:50:1).
".
. ~
Example 26a: A solution of 1.8 g (10 mmol) of 3-aminoxy-2-hydroxypropyl-amine dihydrochloride in 20 ml of ethanol is reacted in a manner analogous to that described in Example 21 with 10 ml of lN NaOH and 0.99 ml (11 mmol) of ethyl methyl ketone, yielding 3-(1-methyl-1-propylideneaminoxy)-2-hydroxypropylamine hydrochloride in the form of a white powder containing 1 mol of sodium chloride, Rf value 0.29 (silica gel/methylene chloride:methanol:concentrated ammonia 150:50:1).
... -.
Example 27: A solution of 850 mg of N-BOC-N-propargyl-3-(1-ethoxy-ethylideneaminoxy)-2-hydroxypropylamine in 5 ml of dioxane and 5 ml of 2N
hydrochloric acid is boiled under reflux for 30 minutes and then concentrated by evaporation. The residue is dissolved in a small amount -- -~
of water, filtered until clear and free~e-dried, yielding N-propargyl-3-aminoxy-2-hydroxypropylamine dihydrochloride in the form of a brown amorphous powder, Rf value = 0.3 (silica gel/methylene ;~
chloride:methanol:concentrated ammonia 150:50:1). - ;
The starting material is prepared as follows:
8.5 ml (133.3 mmol) of propargylamine are added to a solution of 2.12 g (13.3 mmol) of 0-2,3-epoxypropyl-acetohydroxamic acid ethyl ester in 10.5 ml of isopropanol and the mixture is left to stand at room tempera- ;~
ture for 3 days. The reaction mixture is concentrated by evaporation and ~ ~then taken up in 30 ml of methylene chloride. While cooling with ice, a ;
solution of 16.6 g of di-tert.-butyl dicarbonate in 30 ml of methylene ;~
chloride is then added dropwise thereto and the mixture is left to react at room temperature for 24 hours. Uorking up in a manner analogous to that described in Example 2 and chromatography on silica gel in methylene chloride/ethyl acetate (8l5:15) yield~ N-~OC-N-propargyl-3-(1-ethoxyethyl-ideneaminoxy)-2-hydroxypropyIamine in the form of a yellow oil, Rf value - -= 0.38 (silica gel/methylene chloride:ethyl acetate 85:15).
Example 27a: A solution of 1.15 g (5 mmol) of N-methallyl-3-(1-ethoxy-ethylideneaminoxy)-2-hydroxypropylamine in 9 ml of dioxane and 9 ml of 2N
~; hydrochloric acid is boiled under reflux for 30 minutes, filtered and concentrated to dryness by evaporation. The residue is crystallised from : ~ - .
~ .
2003iO9~
ethanol/ether, yielding N-methallyl-3-aminoxy-2-hydroxypropylamine di-hydrochloride in the form of a white hygroscopic powder, Rf value = 0.33 (silica gel/methylene chloride:methanol:concentrated ammonia 40:10:1).
The starting material is prepared as follows:
8.8 g of 2-methallylamine hydrochloride and 74.4 ml of 1.lN sodium methanolate solution are added to a solution of 2.82 g (17.5 mmol) of 0-2,3-epoxypropyl-acetohydroxamic acid ethyl ester in 20 ml of methanol and the mixture is boiled under reflux for 5 hours. The reaction mixture f is filtered and concentrated by evaporation. The residue is chromato-graphed over 250 g of silica gel with methylene ~`
chloride:methanol:concentrated ammonia 150:50:1, yielding N-methallyl-3-(l-ethoxyethylideneaminoxy)-2-hydroxypropylamine, Rf value 0.45 (silica gel/methylene chloride:methanol:concentrated ammonia 300:50:1).
Example 27b: A solution of 2.75 g (12.5 mmol) of N-allyl-3-(1-ethoxy-ethylideneaminoxy)-2-hydroxypropylamine in 30 ml of 2N hydrochloric acid is boiled under reflux for 40 minutes, filtered and concentrated to -~
dryness by evaporation, yielding N-allyl-3-aminoxy-2-hydroxypropylamine dihydrochloride in the form of a yellow oil, Rf value = 0.23 (silica `~
gel~methylene chloride:methanol:concentrated ammonia 40:10:1).
Th`e starting material is prepared as follows:
6.1 ml (81.8 mmol) of allylamine are added to a solution of 2.82 g ~
(17.5 mmol) of 0-2,3-epoxypropyl-acetohydroxamic acid ethyl ester in 35 ~ -ml of methanol and the mixture is stirred at 50 for 16 hours. The -reactjion mixture is concentrated by~evaporation and the residue is chromatographed over 250 g of silica gel with methylene chIoride:methanol:concentrated ammonia 150:50:1, yielding N-allyl-3-(1-ethoxyethylideneaminoxy)-2-hydroxypropylamine, Rf value 0.60 (silica ~-~
gel/methylene chloride:methanol:concentrated ammonia 150:50:1).
,~ .. :
~: :
- 200:}091 Example 28: 3 ml of lN NaOH and 0.54 g (3 mmol) of glucose are added to a solution of 543 mg (3 mmol) of 3-aminoxy-2-fluoropropylamine dihydro-chloride in 8 ml of ethanol and the mixture is left to stand at room temperature for 16 hours and then concentrated to dryness by evaporation.
The residue is taken up in 10 ml of water, filtered and lyophilised, yielding 0-(3-amino-2-fluoropropyl)-glucose oxime hydrochloride, Rf value 0.16 (silica gel/n-butanol:pyridine:concentrated ammonia:water 200:120:30:150).
Example 29: A solution of 212 mg (1 mmol) of 3-(1-ethoxyethylidene-aminoxy)-2S-hydroxypropylamine hydrochloride in 3 ml of lN hydrochloric acid is boiled under reflux for 1 hour and then concentrated by evapora~
tion. The residue is crystallised from ethanol/ether, yielding 3-aminoxy-2S-hydroxypropylamine dihydrochloride, m.p. 150-155, [~]D +3 0 (c - 1.009 in water).
The starting compounds are prepared as follows:
4.4 ml of 5N sodium hydroxide solution are added dropwise at 55 to a solution of 2.25 g (22 mmol) of acetohydroxamic acid ethyl ester and 5.0 g (22 mmol~ of 2R-p-toluenesulfonic acid glycidyl ester (- 3-tosyl-oxy-1,2R-epoxypropane) in 50 ml of acetone and the mixture is boiled under reflux for 1 hour. After cooling, the mixture is filtered and the filtrate is concentrated by evaporation in vacuo. The residue is taken up ~ -in 50 ml of ether. This solution is washed twice with 10 ml of water, - ;
dried over magnesium sulfate and again concentrated by evaporation. The ,-resulting oily 0-2S,3-epoxypropylacetohydroxamic acid ethyl ester is ;~
distilled in vacuo, b.p. 85-90/18 mbar.
, -100 ml of concentrated ammonia are added to 3.2 g (20 mmol) of O-2S,3-epoxypropylacetohydroxamic acid ethyl ester and the mixture is stirred in a closéd vessel at room temperature for 16 hours and then concentrated to dryness by evaporation. The residue is again taken up in 50 ml of water and adjusted to pH 5.5 with lN hydrochloric acid. The solution is ' ~
:
:--200309~.
concentrated by evaporation and the crystalline residue of 3-(1-ethoxy-ethylideneaminoxy)-2S-hydroxypropylamine hydrochloride is recrystallised -from ethanol/ethyl acetate, m.p. 103-106. -Example 30: Analogously to Example 29, starting from acetohydroxamic acid ethyl ester and 25-p-toluenesulfonic acid glycidyl ether (- 3-tosyloxy-1,2S-epoxypropane), 3-aminoxy-2R-hydroxypropylamine dihydrochloride is obtained, m.p. 157-158; []D~ ~3 0 (c = 1.039 in water).
, .
Example 31: A solution of 1.2 g (4.1 mmol) of N-[3-(1-ethoxyethylidene~
aminoxy)-2-hydroxypropyl]-N-BOC-hydroxylamine in 10 ml of dioxane and -5 ml of 2N HCl is boiled under reflux for 1 hour and then concentrated to - ~
dryness by evaporation, yielding N-~3-aminoxy-2-hydroxypropyl)-hydroxyl- ~ ;
amine dihydrochloride, Rf value 0.05 (silica gel/methylene ;~
chloride:methanol:concentrated ammonia 40:10:1).
The starting materiai iF prepared as follows:
A solution of 4.8 g (30 mmol) of 0-(2,3-epoxypropyl)-acetohydroxamic acid ethyl ester in 40 ml of methanol is added to a mixture of 10.4 g (0.15 mol) of hydroxylamine hydrochloride and S.9 g of sodium hydroxide solution in 40 ml of methanol and the mixture is stirred at room tempera- ;~
ture for 24 hours. The reaction mixture is concentrated by evaporation, taken up in 25 ml each of water and THF and reacted with 8.0 g of di-tert.-butyl-dicarbonate (Fluka) in 40 ml of THF. Working up and purifica-tion by chromatography over 250 g of silica gel with hexane:ethyl acetate 1:1 yields N-[3-(1-ethoxyethylideneaminoxy)-2-hydroxypropyl]-N-BOC-hydroxylamine in the form of a pale yellow oil, Rf value 0.05 (silica gelihexane:ethyl;acetate l:l) ExamDle 32: 2.54 g (11.53 mmol) of 0-[3-(2-hydroxyethylamino)-2-hydroxypropyl]-acetohydroxamic acid ethyl ester in 50 ml of 2N hydro-chloric acid are boiled under reflux, with stirring, for 3 hours. After cooling, the reaction mixture is concentrated to dryness by evaporation -under a water-jet vacuum, yielding 0-[3-(2-hydroxyethylamino)-2-hydroxy-,.~
~. :,: . . :.
:, : :, :-: ~:~.
- , . :;.
'~.'. ;'.~"'.'.,'"
- -: ~ - -- ~00:~09~ -,: ,-, propyl]-hydroxylamine dihydrochloride in the form of a pale yellow oil, -Rf value 0.43 (silica gel/methylene chloride:methanol:concentrated ammonia 5:3:1).
" ~
The starting material is prepared as follows:
A solution of 6.4 g (40 mmol) of 0-(2,3-epoxypropyl)-acetohydroxamic acid ~
ethyl ester and 8 ml of ethanolamine in 80 ml of isopropanol is stirred - -at 60 for 18 hours and then concentrated to dryness by evaporation. The resulting residue is chromatographed over 250 g of silica gel UsiDg the system methylene chloride:methanol:concentrated ammonia 300:50:1. The fractions having an Rf value of 0.1 (in the same system) are combined and concentrated by evaporation. The yellow oil that remains is o-[3-(2-hydroxyethylamino)-2-hydroxypropyl]-acetohydroxamic acid ethyl ester.
Example 33: A mixture of 6.5 g (34 mmol) of 0-(3-methylamino-2-hydroxy-propyl)-acetohydroxamic acid ethyl ester in 150 ml of 2N hydrochloric acid is boiled under reflux for 4 hours and then concentrated to dryness -by evaporation. The wax-like residue of N-(3-aminoxy-2-hydroxypropyl)- -methylamine dihydrochloride is taken up in a small amount of water, ' converted into the free base by filtration over 150 ml of Dowex lx4 ion ;
exchanger resin (in basic form) and crystallised in oxalate salt form, m.p. 130-133 (from methanol), Rf value 0.43 (silica gel/methylene chloride:methanol:concentrated ammonia 40:10:1).
The starting material is prepared as follows:
A solution of 8.0 g (50 mmol) of 0-(2,3-epoxypropyl)-acetohydroxamic acid ethyl ester and 50 ml of a 33 % ethanolic methylamine solution in 100 ml of isopropanol is stirred at 85 for 4 hours and then concentrated to I dryness by evaporation. The resulting residue is chromatographed over 250 g of silica gel with ethyl acetate. The fractions having an Rf value of 0.21 (silica gel/methylene chloride:methanol:concentrated ammonia 150:50:1) are combined and concentrated by evaporation. The yellow oil that remains is 0-(3-methylamino-2-hydroxypropyl)-acetohydroxamic acid ethyl ester.
200~0~
- 44 - ~
, .
Example 34: A mixture of 0.8 g of bis-1,7-ethoxyethylideneaminoxY~4~
aza-2,6-dihydroxyheptane in 20 ml of 2N hydrochloric acid is boiled under reflux for 0.5 hour and then concentrated to dryness by evaporation. The wax-like hygroscopic residue of bis-1,7-aminoxy-4-aza-2,6-dihydroxy-heptane trihydrochloride is crystallised from methanol/ether, Rf value 0.44 (silica gel/methylene chloride:methanol:concentrated ammonia 5:3:1).
The starting material is prepared as follows:
A solution of 6.4 g (40 mmol) of 0-(2,3-epoxypropyl)-acetohydroxamic acid ethyl ester and 7.04 g of 0-(3-amino-2-hydroxypropyl)-acetohydroxamic acid ethyl ester in 100 ml of isopropanol is stirred at 70 for 3.5 hours and then concentrated to dryness by evaporation. The resulting residue is chromatographed over 700 g of silica gel with ethyl acetate. The fractions having an Rf value of 0.30 (silica gel/ethyl acetate) are combined and concentrated by evaporation. The yellow oil that remains is bis-1,7-ethoxyethylideneaminoxy-4-aza-2,6-dihydroxyheptane.
Example 35: 0.26 ml of cyclopentanone is added to a solution of 0.54 g (3 mmol) of 3-aminoxy-2-fluoropropylamine dihydrochloride (see Example 5) in ô ml of ethanol and 3 ml of lN sodium hydroxide solution and the mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated by evaporation and the residue is partitioned between 3 ml ;
of lN sodium hydroxide solution and 10 ml of ether. The ether phase is washed with saturated sodium chloride solution, dried over sodium sulfate -and concentrated to dryness by evaporation. The oily residue is taken up in lO ml of ethyl acetate, and 2.5 ml of a lN solution of HCl gas in ethyl acetatq are added. Thel3-(cyclopentylideneaminoxy)-2-fluoropropyl-amine hydrochloride that crystallises out is filtered with suction and dried, m.p. 109-112.
~ '; ' ,, , , , .~ ~ :`~''' ' 200309~ ' Example 36: 5 ml of 6N methanolic HCl are added to a solution of 2.43 g of N-BOC-3-pyridoxalaminoxy-2-fluoropropylamine in 10 ml of methanol and left to stand with the exclusion of moisture. The 3-pyridoxalaminoxy-2-fluoropropylamine dihydrochloride that crystallises out is filtered with suction, washed with ethyl acetate and dried, m.p. 210-213.
The starting material is prepared as follows:
814 mg (4 mmol) of pyridoxal hydrochloride and 8 ml of lN sodium hydroxide solution are added to a solution of 724 mg (4 mmol) of 3-aminoxy-2-fluoropropylamine dihydrochloride (see Example 5) in 13 ml of ethanol and the mixture is stirred at room temperature for 16 hours. A - - -;
further 4 ml of lN sodium hydroxide solution and a solution of 1.08 g of di-tert.-butyl dicarbonate in 20 ml of THF are added to the reaction mixture. After conventional working up and purification by chromato-graphy. the reaction mixture yields N-BOC-3-pyridoxalaminoxy-2-fluoro-propylamine in the form of a yellow foam, Rf value 0.25 (silica gel/methylene chloride:methanol 10:1).
Example 37: A solution of l.ô g (10 mmGl) of 3-aminoxy-2-hydroxypropyl-amine dihydrochloride in 20 ml of ethanol is reacted with 10 ml of lN --NaOH and 1.02 ml (11 mmol) of methoxyacetone. The reaction mixture is concentrated by evaporation and the residue is partitioned between water and ether. The lower phase is concentrated and lyophilised, yielding 3-(1-methyl-2-methoxyethylideneaminoxy)-2-hydroxypropylamine hydro-chloride in the form of a white powder containing 1 mol of sodium chloride, Rf value 0.2 (silica gel/methylene chloride:methanol:concentrated ammonia 150:50:1).
Example 30: A solution of l.ô g (10 mmol) of 3-aminoxy-2-hydroxypropyl- - -amine dihydrochloride in 20 ml of ethanol is reacted with 10 ml of lN
NaOH and 0.72 ml (10 mmol) of pyruvic acid methyl ester. The reaction mixture is concentrated by evaporation and the residue is partitioned between water and ether. The lower phase is concentrated and lyophilised, yielding 3-(1-methoxycarbonylethylideneaminoxy)-2-hydroxypropylamine ' ~ ~ '''~"' '''' 200:~09~
hydrochloride in the form of a white powder containing 1 mol of sodium chloride; m.p. 136-140, Rf value 0.38 (silica gel/methylene chloride:methanol:concentrated ammonia 40:10:1).
Example 39: 4 ml of lN NaOH and 0.72 g (4 mmol) of glucose are added to a solution of 0.72 g (4 mmol) of 3-aminoxy-2-hydroxypropylamine dihydro-chloride in 10 ml of ethanol and the mixture is left to stand at room temperature for 16 hours and then concentrated to dryness by evaporation.
The residue is taken up in 10 ml of water, filtered and lyophilised, yielding 0-(3-amino-2-hydroxypropyl)-glucose oxime hydrochloride, Rf value 0.05 (silica gel/n-butanol:pyridine:concentrated ammonia:water 200:120:30:150).
Example 40: 5 ml of 5.5N HCl/EtOH are added to a solution of 750 mg of 3-(2~butylaminoxy)-2-hydroxy-N-BOC-propylamine in 10 ml of ethanol and the mixture is left to stand at room temperature for 16 hours and then concentrated to dryness by evaporation, yielding 3-(2-butylaminoxy)-2-hydroxypropylamine dihydrochloride in the form of a light-yellow viscous oil, Rf value 0.14 (silica gel/methylene chloride:methanol:concentrated ammonia 40:10:1).
Th- starting material is prepared as follows:
2.5 ml of glacial acetic acid and 0.27 g (3.9 mmol) of sodium cyanoboro-hydride are added to a solution of 1.05 g (3.9 mmol) of 3-(1-methyl- ~-propylideneaminoxy)-2-hydroxy-N-BOC-propylamine in 25 ml of THF and the mixture is stirred at room temperature for 48 hours. After the addition of 4 g of sodium hydrogen carbonate, the reaction mixture is concentrated to dryness by evaporation and the re,sidue is partitioned bstween water and ether. The organic phase is dried over magnesium sulfate, con- -centrated by evaporation and chromatographed over 75 g of silica gel with hexane:ethyl acetate 1:1, yielding 3-(2-butylaminoxy)-2-hydroxy-N-BOC- ;
propylamine in the form of a pale yellow oil, Rf value 0.10 (silica ;
gel/hexane/ethyl acetate 1:1). ;~
~ " .
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~ : . " ;'':' 2003~
Example 41: 4 ml of lN NaOH and 0.53 g (4 mmol) of indanone are added to a solution of 0.72 g (4 mmol) of 3-aminoxy-2-hydroxypropylamine di-hydrochloride in 10 ml of ethanol and the mixture is stirred at 50 for 16 hours and then concentrated to dryness by evaporation. The residue is dissolved in 10 ml of water and, after the addition of 4 ml of lN NaOH, extracted with ether. The ether phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evapora-tion. The resulting 0-(3-amino-2-hydroxypropyl)-indanone oxime is crystallised from ethertpetroleum ether, m.p. 88-92, Rf value 0.10 (silica gel/methylene chloride:methanol:concentrated ammonia 300:50:1). -Example 42: 3 ml of lN NaOH and 471 mg (3 mmol) of 4-cyanoindanone are added to a solution of 543 mg (3 mmol) of 3-aminoxy-2-fluoropropylamine dihydrochloride in 8 ml of ethanol and the mixture is stirred at 50 for 16 hours and then concentrated to dryness by evaporation. The residue is dissolved in 10 ml of water and, after the addition of 3 ml of lN NaOH, extracted with ether. The ether phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evapora-tion. The resulting 0-(3-amino-2-fluoropropyl)-4-cyanoindanone oxime is crystallised from ether/petroleum ether, m.p. 90-92, Rf value 0.46 (silica gel/methylene chloride:methanol:concentrated ammonia 300:50:1).
'~
Example 43: A solution of 720 mg (4 mmol) of 3-aminoxy-2-hydroxypropyl-amine dihydrochloride in 10 ml of ethanol is reacted with 4 ml of lN
NaOH and 0.22 ml (4.4 mmol) of hydroxyacetone. The reaction mixture is concentrated by evaporation and the residue is partitioned between water and ether. The lower phase is concentrated and lyophilised, yielding 3-(1-hydroxymethylethylideneaminoxy)-2-hydroxypropylamine hydrochloride in the~form of a brown oil cqntai~ing 1 mol of sodium chloride, Rf value -~
0.10 (silica gel/methylene chloride:methanol:concentrated ammonia ~ -40:10:1).
Example 44: A solution of 1.22 g (3.2 mmol) of 3-(1-ethoxyethylidene- - -~
: .~. . . ~
~ aminoxy)-2-hydroxy-N-BOC-N-benzyloxypropylamine in 30 ml of lN HCl is ; - boiled under reflux for 1 hour and concentrated to dryness by evapora-, ~ . -, . .. - .
tion. The residue is crystallised from ethyl acetate, washed with ethyl acetate/ether and dried, yielding 3-aminoxy-2-hydroxy-N-benzyloxypropyl-amine dihydrochloride, m.p. 140-143.
The starting material is prepared as follows:
A solution of 1.6 g (10 mmol) of 0-(2,3-epoxypropyl)-acetohydroxamic acid ethyl ester in 16 ml of methanol is added dropwise to a solution of 16 g (0.1 mol) of O-benzylhydroxylamine hydrochloride in 70 ml of methanol and 90 ml of 1.2N sodium methanolate and the mixture is stirred at room temperature for 24 hours. The reaction mixture is concentrated by ;
evaporation, taken up in 100 ml of THF and reacted with 28.8 g of di-tert.-butyl dicarbonate (Fluka) in 100 ml of THF. Conventional working up -and purification by chromatography over 700 g of silica gel with hexane:ethyl acetate 2:1 yields 3-(1-ethoxyethylideneaminoxy)-2-hydroxy-N-BOC-N-benzyloxypropylamine in the form of a pale yellow oil, Rf value 0.41 (silica gellhexane:ethyl acetate 2:1).
Example 45: 530 mg (2 mmol) of pyridoxal phosphate are added to a solu-tion of 362 mg (2 mmol) of 3-aminoxy-2-fluoropropylamine dihydrochloride (see Example 5) in 20 ml of 0.1N NaOH and the mixture is stirred at room temperature for 30 minutes, then filtered and lyophilised. The resulting hygroscopic lyophilisate is 3-amino-2-fluoropropoxyimino-pyridoxal phos-phate hydrochloride containing 1 mol of sodium chloride, Rf value 0.13 (silica`gel/methyl ethyl ketone:ethanol:water:concentrated ammonia 15:5:5:5; pyridoxal phosphate Rf value 0.26).
:: '. . ~:, .: - .
Example 46: 265 mg (1 mmol) of pyridoxal phosphate are added to a ~`solution of ~ôO mg (l mmol) of 3-!aminoxy-2-hydroxypropylamine dihydro- ~ ~;
chloride in 10 ml of O.lN NaOH and the mixture is stirred at room -~ i temperature for 30 minutes, then filtered and lyophilised. The resulting 5 hygroscop1c lyophilisate is 3-amino-2-hydroxypropoxyimino-pyridoxal ;~
~phosphate hydrochloride containing 1 mol of sodium chloride, Rf value ;
0.10 (silica~gel/methyl ethyl ketone:ethanol:water:concentrated ammonia ~ `
15:5:5:5; pyrldoxal phosphate Rf value 0.26).
: ::: ;,:.
;. :-. .:
:.~
200309~
Example 47: A solution of 4.21 g (13.7 mmol) of 3-(1-ethoxyethylidene-aminoxy)-2-hydroxy-N-goc-N-methoxypropylamine in 130 ml of lN HCl is boiled under reflux for 1 hour and then concentrated to dryness by evaporation. The residue is crystallised from ethanol, washed with ethyl acetate/ether and dried, yielding 3-aminoxy-2-hydroxy-N-methoxypropyl~
amine dihydrochloride, m.p. 142-152.
The starting material is prepared as follows:
A solution of 3.2 g (20 mmol) of 0-(2,3-epoxypropyl)-acetohydroxamic acid ethyl ester in 30 ml of methanol is added dropwise to a solution of 25 g (0.3 mol) of O-methylhydroxylamine hydrochloride in 100 ml of methanol and 300 ml of lN sodium methanolate and the mixture is stirred at room temperature for 24 hours. The reaction mixture is concentrated by evaporation, taken up in 150 ml each of water and THF and reacted with 50 g of di-tert.-butyl dicarbonate in 150 ml of THF. Working up and purification by chromatography over 750 g of silica gel with hexane:ethyl acetate 3:1 yields 3-(1-ethoxyethylideneaminoxy)-2-hydroxy-N-BOC-N-methoxypropylamine in the form of a pale yellow oil, Rf value 0.2 (silica gel/hexane:ethyl acetate 3:1).
Exam~le 48: A solution of 5.0 g (24.7 mmol) of 3-(1-ethoxyethylidene-aminoxy)-1-azidoisopropanol in 50 ml of 2N HCl is boiled under reflux for 1 hour and then concentrated to dryness by evaporation, yielding 3-aminoxy-1-azidoisopropanol hydrochloride in the form of a yellowish-brown oil, Rf value 0.35 (silica gel/methylene chloride:methanol 10:1), IR (methylene chloride): 2100 cm 1. ~ ~
:~:, ~; - :"
The~starting material is Rrepared,as f!ollows:
3.25 g (50 mmol) of sodium azide and 1.35 g (25 mmol) of ammonium chloride are added to a solution of 4.0 g (25 mmol) of 0-~2,3-epoxy-propyl)-acetohydroxamic acid ethyl ester in -50 ml of ethylene glycol monomethyl ether and 2.5 ml of water and the mixture is stirred at 130 for 12 hours. After cooling, the reaction mixture is diluted with 500 ml of ethyl acetate, filtered and concentrated by evaporation. The residue ;: '.:,~`.
' " '.'.
' ',`~' ,'' 200309~
, .
is taken up in 300 ml of ether, washed with water, dried over magnesium sulfate and freed of solvent, yielding 3-(1-ethoxyethylideneaminoxy)-1-azidoisopropanol in the form of a yellow oil, Rf value 0.05 (silica gel/hexane:ethyl acetate 1:1); IR (methylene chloride): 2100, 3200-3650 cm Example 49: A solution of 0.84 g (5 mmol) of 3-aminoxy-1-azidoiso-propanol hydrochloride in 5 ml of ethanol and 5 ml of lN alcoholic HCl is hydrogenated with hydrogen in the presence of 0.1 g of 5 % Pd/C. When the reduction is complete and the catalyst has been separated off, the filtrate is concentrated by evaporation and the residue is crystallised from alcohol/ether, yielding 3-aminoxy-2-hydroxypropylamine dihydro-chloride, m.p. 153-156.
. ~
Example 50: 180 mg (1.15 mmol) of quinoline-4-aldehyde are added to ~ --200 mg (1.1 mmol) of 3-aminoxy-2-fluoropropylamine dihydrochloride in 1.1 ml of lN NaOH and 4 ml of ethanol and the mixture is then stirred at 50 for 22 hours. The solution is concentrated and the residue is -chromatographed with water on Opti-Up C-12. The fractions containing the -~ ;~
product are combined and concentrated to dryness. The residue is triturated with ether and left to stand overnight in a refrigerator, and the precipitate is filtered off with suction, yielding 4-(3-amino-2-fluoropropoxyiminomethyl)-quinoline in the form of a colourless powder.
FAB-MS: (M+H) = 248. IR (KBr) inter alia: 1625, 15g8, 1570 cm 1.
', '''.:~''' ~
Example 51: 0.64 ml of lN NaOH followed by 100 mg of difluoromethyl phenyl ketone (see EP 298 478) are added to 114.7 mg (0.64 mmol) of 3-aminoxy-2-hydroxypropylamine dihydrochloride in 1 ml of ethanol. After stirring for 20 hours at 50, a further 28.7 mg of 3-aminoxy-2-hydroxy- ~
propylamine dihydrochloride are added, followed by 0.16 ml of lN NaOH and ~ ;
1 ml of ethanol. The reaction mixture is heated at 80 for a further 2.5 hours, then concentrated in a rotary evaporator, and the residue is chromatographed on Opti-Up C-12-silica gel (eluant: water). The fractions containing the product 3-(2,2-difluoro-1-phenylethylideneaminoxy)-2-,:~ ..:.
~: . ' .
. . .
hydroxypropylamine hydrochloride are concentrated and dried under a high vacuum. FAB-MS: (M+H) = 245. IR (KBr) inter alia: 1604, 1526, 1488, 1457 cm 1.
Example 52: In a manner analogous to that described in Example 51, starting from 3-aminoxy-2-fluoropropylamine dihydrochloride and difluoro-methyl phenyl ketone there is obtained 3-(2,2-difluoro-1-phenylethyl-ideneaminoxy)-2-fluoropropylamine hydrochloride.
FAB-MS: (M+H) = 247. IR ~Nujol) inter alia: 1600, 1496, 1446, 1369 cm Example 53: 3-aminoxy-2-fluoropropylamine dihydrochloride can also be prepared as follows:
A mixture of 0.25 g (0.68 mmol) of N-[2-fluoro-3-phthalimidopropoxy]- ~-phthalimide, 2 ml of water and 2 ml of concentrated hydrochloric acid is heated under reflux for 2 hours, then cooled to 0 and filtered with suction, and the filtration residue is washed with a small amount of water and the filtrate is concentrated by evaporation in vacuo. The crystalline residue is concentrated to dryness by evaporation twice using ~ - -10 ml of ethanol each time and then suspended in 10 ml of ethanol. The - suspension is filtered and the crystals are washed with ether and dried at 70 under a high vacuum. The resulting title compound melts at 206-207.
The starting material is prepared as follows:
a) N-(3-hydroxY-2-fluoroProPYl)-phthalimide A mixture of 2.5 g (0.0151 mol) of 3-bromo-2-fluoropropan-1-ol (95 %) [Foster et al., J. Med. Chem. 24, 1399 (1981) and I. Chehidi et al., Tetrahedron Lettersj, 30~! 3167 (ll9~9)] and 3.243 g (0.0175 mol) : ;-of phthalimide-potassium in 10 ml of dimethylformamide is stirred at 100 -"
for 6 hours. The mixture is cooled to room temperature and filtered, the filtrate is concentrated by evaporation in vacuo and the oily residue ~ ~ "
is partitioned between water and methylene chloride. The organic phase is dried over sodium sulfate and then concentrated by evaporation and the residue is crystallised from ethyl acetate/hexane. The resulting title ~ ~;
compound melts at 97-99. ~ ~
~: :
200:~091 b) N-[2-fluoro-3-phthalimidopropoxy]-phthalimide 0.273 g (0.00157 mol) of azodicarboxylic acid diethyl ester is added, with stirring, to a solution of 0.335 g (0.0015 mol) of N-(3-hydroxy-2-fluoropropyl)-phthalimide, 0.245 g (0.0015 mol) of N-hydroxyphthalimide and 0.394 g (0.0015 mol) of triphenylphosphine in 5 ml of tetrahydro-furan. The mixture is stirred at room temperature for 2 hours and the resulting suspension is diluted with approximately 5 ml of tetrahydro-furan, cooled to 0 and filtered, and the crystals are washed with tetra- -~
hydrofuran. After drying under a high vacuum, the resulting ~itle com-pound melts at 134-185.
Example 54: Capsules containing 0.25 g of active ingredient, for example one of the compounds of Examples l to 53, can be prepared as follows: ~
~'., ~-: :-Composition (for 5000 capsules) active ingredient1250 g -talc 180 g wheat starch 120 g magnesium stearate 80 g lactose 20 g The pulverulent substances are forced through a sieve of 0.6 mm mesh size -and mixed together. 0.33 g portions of the mixture are introduced into gelatine capsules using a capsule-filling machine.
~.": '',"':'' ,' ., :' .
" :, , , ~:
: .
: .
4-17327/+
Substituted oxadiaminobutanes The invention relates to the use of compounds of formula I
~C ,~
Rl ~ O~ ~ H~ ~ H~
2 :~
wherein X is halogen, hydroxy, lower alkoxy, acyloxy, lower alkyl-sulfonyloxy or arylsulfonyloxy; each of Rl and R2, independently of the ~ ., .
other, is hydrogen, lower alkyl, cycloalkyl, aryl-lower alkyl or hetaryl-lower alkyl, or Rl and R2 together are a radical ~ :
C=
Rs/ - ~;~
wherein each of R4 and Rs, independently of the other, is hydrogen, lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, lower alkoxy-lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl-lower alkyl, .
hetaryl-lower alkyl, aryl, hetaryl, carboxy or lower alkoxycarbonyl, or wherein R4 is polyhydroxy-lower alkyl and Rs is hydrogen or hydroxy-methyl, or wherein R4 and Rs together are C2-C7alkylene or unsub-stituted or substituted benzo-C4-C6alkylene; and R3 is hydrogen, un-substituted or hydroxy- or halogen- and/or aminoxy-substituted lower alkyl, lower alkenyl, lower alkynyl or free or etherified hydroxy; and pharmaceutically acceptable salts thereof, (for the manufacture of pharmaceutical preparationsj Ifor the therapeutic treatment of diseases of the human or animal body that respond to inhibition of ornithine de-carboxylase, for example tumours or protozoa infections, and also to novel compounds of formula I.
' ''.' : ~ "',.'" ',' '' 09~
The invention relates also to compounds of formula I
1 ~ \CH / ~CH ~ ~R (I), z wherein X is halogen, hydroxy, lower alkoxy, acyloxy, lower alkyl-sulfonyloxy or arylsulfonyloxy; each of R1 and R2, independently of the other, is hydrogen, lower alkyl, cycloalkyl, aryl-lower alkyl or hetaryl-lower alkyl, or Rl and R2 together are a radical -R4\ . -~C= , . . , ~ , , wherein each of R4 and Rs, independently of the other, is hydrogen, lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, lower alkoxy-lower .
alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl-lower alkyl, hetaryl-lower alkyl, aryl, hetaryl, carboxy or lower alkoxycarbonyl, or wherein R4 is polyhydroxy-lower alkyl and Rs is hydrogen or hydroxy- .
methyl, or wherein R4 and Rs together are C2-C7alkylene or unsub-stituted or substituted benzo-C4-C6alkylene; and R3 is hydrogen, un- :
substituted or hydroxy- or halogen- and/or aminoxy-substituted lower alkyl, lower alkenyl, lower alkynyl or free or etherified hydroxy; with the proviso tha~ when X is hydroxy and Rl and R2 together are a radical R4\
/C= , R3 is hydrogen; with the proviso that when X is hydroxy and R3 is hydrogen, the radicals Rl and R2 cannot together be l,l-dimèthyl-methylidene, l-n-butylidene or nitro-(furanyl or imidazolyl)-methylidene;
with the proviso that when X is hydroxy and R3 is hydrogen, hydroxy or lower alkyl, the radicals Rl and R2 cannot both be hydrogen; and with the proviso that when X iS hydroxy and Rl and Rz are each independently hydrogen, lower alkyl, cycloalkyl, aryl-lower alkyl or hetaryl-lower .:
alkyl but are not both hydrogen, R3 is hydrogen, methyl, ethyl or n-propyl; and salts thereof, to processes for the preparation of these compounds, to pharmaceutical preparations containing these compounds, to ::
the use of these compounds for the therapeutic treatment of the human or . :
animal body or for the manufacture of pharmaceutical preparations.
~ -` 2~0~.~9~.
The general terms used hereinbefore and hereinafter have the following meanings in the context of this application:
The prefix "lower" denotes a radical having up to and including 7 and especially up to and including 4 carbon atoms.
Lower alkyl is, for example, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, :~ -preferably ethyl and especially methyl.
:: ""' " ~, Lower alkenyl is, for example, vinyl, allyl, l-propenyl, isopropenyl, 2 or 3-methallyl or 3-butenyl.
Lower alkynyl is, for example, ethynyl or 2-butynyl and especially propargyl.
Cycloalkyl contains, for example, from 3 to 8 and especially 5 or 6 ring carbon atoms and is, for example, cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl.
Etherified hydroxy is, for example, lower alkoxy or phenyl-lower alkoxy.
Lower alkoxy is, for example, n-propoxy, isopropoxy, n-butoxy or tert.-butoxy, preferably ethoxy and especially methoxy, whilst phenyl-lower alkoxy is, for example, benzyloxy.
Acyloxy is preferably lower alkanoyloxy, but also, for example, aryl-carbonyloxy (= aroyloxy) or hetarylcarbonyloxy (z hetaroyloxy).
Arylcarbonyloxy is, for example, benzoyloxy.
Hetarylcarbonyloxy is, for example, pyridoyloxy or thienoyloxy.
Lower alkylsulfonyloxy is, for example, methylsulfonyloxy. -: : ~,,:
, ~
'''~
. ._ ,, ` ,, i"' "' ~ ~
zoo~o~
Arylsulfonyloxy is, for example, phenylsulfonyloxy that is unsubstituted or substituted by lower alkyl or by halogen, such as phenyl- or 4-methyl-phenyl-sulfonyloxy.
Lower alkoxycarbonyl is, for example, propoxycarbonyl or butoxycarbonyl, preferably methoxycarbonyl or ethoxycarbonyl.
Halogen is generally, for example, fluorine or iodine, especially bromine and more especially chlorine.
A halogen radical X in a compound of formula I is especially chlorine and more especially fluorine, but may also be, for example, bromine or iodine.
Halo-lower alkyl is, for example, difluoromethyl or trifluoromethyl, also l-chloroethyl.
Hydroxy-lower alkyl is, for example, hydroxymethyl or 2-hydroxyethyl.
Lower alkoxy-lower alkyl is, for example, methoxymethyl.
Polyhydroxy-lower alkyl is, for example, 1,2-dihydroxyethyl or 1,2,3-tri-hydroxypropyl, preferably 1,2,3,4-tetrahydroxybutyl and especially 1,2,3,4,5~pentahydroxypentyl. ;~
Lower alkyl substituted by hydroxy or halogen and/or by aminoxy is, for example, hydroxy-lower alkyl or halo-lower alkyl, also hydroxyaminoxy-lower alkyl, for example 3-aminoxy-2-hydroxypropyl, or hydroxyhalo-lower ~ ~ - alkyl, for example 3-aminoxy-2-fluoropropyl.
Compounds of formula I wherein R1 and Rz together are a radical -~
RsR4C=, R4 is polyhydroxy-lower alkyl and Rs is hydrogen or hydroxy-methyl, are preferably derived from sugars, especially from aldo- or keto-(trioses, tetroses, pentoses or hexoses). The radical RsR4C=
wherein R4 is 1,2,3,4,5-pentahydroxypentyl (derived from D-glucose) and ~ `
Rs is hydrogen is especially preferred. ~-...
,: ' -, : ~-':
20~:~0g~
Lower alkanoyl is, for example, formyl, propionyl or butyryl, and especially acetyl. ;
Lower alkanoyloxy is, for example, formyloxy, propionyloxy or butyryloxy, and especially acetoxy.
Aryl is, for example, phenyl or naphthyl, such as 1- or 2-naphthyl. The ~j phenyl or naphthyl radicals can be unsubstituted or substituted. Aryl is preferably phenyl that is unsubstituted or substituted by lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, halogen, hydroxy, lower alkoxy, lower alkanoyloxy and/or by nitro, and is especially phenyl.
Aryl-lower alkyl is preferably phenyl-lower alkyl and especially benzyl.
Hetaryl, as such or in composite terms, such as, for example, hetaryl-lower alkyl, is to be understood as being especially a monocyclic but also a bi- or poly-cyclic, heterocyclic radical of aromatic character. .
Bi- and poly-cyclic hetaryl can be composed of several heterocyclic rings or, preferably, of one heterocycle and one or more, for example one or two and especi~lly one, fused carbocyclic ring, especially a benzo ring.
Each individual ring contains, for example, 3, 5, 6 or 7 and especially 5 or 6 ring members. Hetaryl is especially an aza-, thia-, oxa-, thiaza-, thiadiaza-, oxaza-, diaza-, triaza- or tetraza-cyclic radical.
Hetaryl is especially a monocyclic monoaza-, monothia- or monooxa-cyclic -radical, such as pyrryl, for example 2-pyrryl or 3-pyrryl, pyridyl, for ~
example 2-, 3- or 4-pyridyl, thienyl, for example 2- or 3-thienyl, or ~ ;
furyl, for example 2-furyl; a bicyclic monoaza-, monooxa- or monothia~
cyclic radical, such as indolyl, for example 2- or 3-indolyl, quinolinyl, for example 2- or 4-quinolinyl, isoquinolinyl, for example 1-isoquinolin-yl, benzofuranyl, for example 2- or 3-benzofuranyl, or benzothienyl, for example 2- or 3-benzothienyl; a monocyclic diaza-, triaza-, tetraza-, oxaza-, thiaza- or thiadiaza-cyclic radical, such as imidazolyl, for `~ `
example 2-imidazolyl, pyrimidinyl, for example 2- or 4-pyrimidinyl, tri- ~ ~
09~1.
.
azolyl, for example l,2,4-triazol-3-yl, tetrazolyl, for example 1- or 5-tetrazolyl, oxazolyl, for example 2-oxazolyl, isoxazolyl, for example 3- or 4-isoxazolyl, thiazolyl, for example 2-thiazolyl, isothiazolyl, for example 3- or 4-isothiazolyl or 1,2,4- or 1,3,4-thiadiazolyl, for example 1,2,4-thiadiazol-3-yl or 1,3,4-thiadiazol-2-yl; or a bicyclic diaza-, oxaza- or thiaza-cyclic radical, such as benzimidazolyl, for example 2-benzimidazolyl, benzoxazolyl, for example 2-benzoxazolyl, or benzo-thiazolyl, for example 2-benzothiazolyl.
Hetaryl radicals are unsubstituted or carry substituents. Suitable sub-stituents at ring carbon atoms are, for example, the substituents indicated above for aryl radicals and, in addition, phosphonooxymethyl-E_CH2_0_P(=O)(OH)2], and also oxo (=O). Ring nitrogen atoms can be substituted, for example, by lower alkyl, aryl-lower alkyl, lower alkanoyl, benzoyl, carboxy, lower alkoxycarbonyl, hydroxy, lower alkoxy, lower alkanoyloxy or by oxido ( - I ) Hetaryl is especially pyridyl, quinolinyl, thienyl, pyrryl or imidazolyl.
Hetaryl-lower alkyl is especially pyridyl-, thienyl-, pyrryl-or -imidazolyl-methyl.
A radical RsR4C= wherein R4 and Rs together are C2-C7alkylene is to be understood as being cycloalkylidene having from 3 to 8 ring carbon atoms, for example cyclopropylldene, cyclopentylidene or cyclohexylidene.
A r~dical RsR4C= wherein R4 and Rs together are unsubstituted or substituted benzo-C4-C6alkylene is to be understood as being, for -~
example, cyclopentylidene or cyclohexylidene each of which carries a fused benzo ring that is unsubstituted or substituted by lower alkyl, ~
lower alkoxy, carboxy, lower alkoxycarbonyl, carbamoyl and/or by cyano. -~ `
Examples of such radicals are indan-l-ylidene, 4-cyano-indan-1-ylidene and 1,2,3,4-tetrahydro-1-naphthylidene.
~ `
2~0309~.
-: -_ 7 _ A radical RsR4C= wherein R4 is 3-hydroxy-5-(hydroxymethyl or phos-phonooxymethyl)-2-methyl-4-pyridyl and Rs is hydrogen, or a 3-hydroxy-5-(hydroxymethyl or phosphonooxymethyl)-2-methyl-4-pyridylmethylidene radical formed by Rl and R2 together, is derived from pyridoxal or pyridoxal 5-phosphate, respectively. A phosphono radical corresponds to the group -P(=O)(OH)2.
Cl-C4alkylidene is preferably ethylidene or 1,1-dimethylmethylidene [=C(CH3)2], and also, for example, l-n-butylidene [=CH-CH2-CH2-CH3]
or 2-n-butylidene [CH3-C(=)-CHz-CH3].
Salts of compounds according to the invention are especially pharma-ceutically acceptable, non-toxic salts. For example, compounds of ~ormula I having basic groups may form acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example acetic-acid, fumaric acid, oxalic acid or methanesulfonic acid, or, for example, with amino acids, such as arginine or lysine. If several basic groups are present, mono- or poly-salts may be formed. Compounds of formula I having an acidic group, for example carboxy, and a basic group, for example amino, can be, for example, in the form of internal salts, that is to say in zwitterionic form, or one part of the molecule may be in the form of an internal salt and another part may be in the form of a ~ ~
normal salt. -;:
~ ;,:~',",',' For isolation or purification purposes it is also possible to use pharma~
ceutically unacceptable salts, for example picrates or perchlorates. Only pharmaceutically acceptable, non-toxic salts are used therapeutically and these are therefore preferreq.
Depending upon the structural factors, the compounds of the present invention may be in the form of isomeric mixtures or in the form of pure isom-rs.
':
~ - ' ' ;'~, Z00309~
.
':
The compounds according to the invention have valuable, especially pharmacologically useful, properties. In particular, they have a strong specific inhibitory action on the enzyme ornithine decarboxylase (ODC).
ODC as a key enzyme plays an important part in the polyamine synthesis which takes place in virtually all cells of mammals, including humans.
The polyamine concentration in the cell is regulated by ODC. Inhibition of the ODC enzyme results in a reduction in the polyamine concentration.
Since a reduction in the polyamine concentration effects inhibition of cell growth, it is possible by administering ODC-inhibiting substances to inhibit the growth of both eukaryotic and prokaryotic cells, and especially of cells undergoing rapid or uncontrollable growth, and even to kill cells or to inhibit the onset of cell differentiation.
The inhibition of the ODC enzyme can be demonstrated, for example, using the method of J.E. Seely and A.E. Pegg, Ornithine decarboxylase (mouse -kidney), pages 158-161, in H. Tabor and C. ~hite Tabor (Eds.): Methods in enzymology, Vol. 94: Polyamines, Academic Press, New York, 1983. The compounds of the invention exhibit ICso values of about 0.01 ~mol minimum. `` -The compounds of formula I have anti-proliferative properties which may - -be demonstrated directly, for example, in the following test in which the inhibitory action of the compounds of formula I on the growth of human TZ4 bladder carcinoma cells is determined. These cells are incubated in "Eagle's minimal essential medium" to which 5 % (v/v) of foetal calf ' serum has been added, in a humidified incubator at 37C and 5 % by volume CO2 in the air. The carcinoma cells (1000-1500) are inoculated into 96-hole microtitre plates and incubated overnight under the above- ; ~;
mentioned conditions. The test co,mpound is added in serial dilutions on day 1. The plates are incubated for 5 days under the above-mentioned ;
conditions. During this period, the control cultures undergo at least 4 cell divisions. After incubation the cells are fixed with 3.3 %
(weight/volume) aqueous glutaraldehyde solution, washed with water and stained with 0.05 % (w/v) aqueous methylene blue solution. After washing, - -the dye is eluted with 3 % (w/v) aqueous hydrochloric acid. The optical density (OD) per hole, which is directly proportional to the number of -", -.;
:, '': :` ' 20030~1 cells, is then measured using a photometer (Titertek multiskan) at 665 nm. The ICso values are calculated with a computer system using the formula OD66s (test) - OD66s (start) x 100 OD66s (test) - OD66s (start) Ths ICso values are defined as that active ingredient concentration at which the number of cells per hole at the end of the incubation period constitutes only 50 % of the number of cells in the control cultures. The resulting ICso values for the compounds of formula I are about 1 ~mol minimum.
The compounds of formula I are therefore, for example, useful for the treatment of benign and malign`ant tumours. They can bring about the regression of tumours and also prevent the spread of tumour cells and the ~
growth of micrometastases. Furthermore, they can be used, for example, -for the treatment of protozoa infections, for example trypanosomiasis, malaria or pulmonary inflammation caused by Pneumocystis carinii. - ;
The invention relates preferably to the above-mentioned use of compounds of formula I wherein X is halogen, hydroxy, lower alkoxy, lower alkyl~
sulfonyloxy or phenylsulfonyloxy; each of R1 and Rz, independently of ~ ~;
the other, is hydrogen, lower alkyl, C3-Cgcycloalkyl or phenyl-lower alkyl, or R1 and R2 together are a radical R4\ ~;~
/C= ,. ~ : -Rs wherein each of R4 and Rs, independently of the other, is hydrogen, lowér alkyl, halo-lower~alkyl, C3'C8'cycloalkyl, phenyl-lower alkyl or ! ' ; .
phenyl, or wherein R4 is 3-hydroxy-5-(hydroxymethyl or phosphonooxy-methyl)-2-methyl-4-pyridyl and Rs is hydrogen, or wherein R4 is 1,2,3,4-tetrahydroxybutyl or 1,2,3,4,5-pentahydroxypentyl and Rs is hydrogen or hydroxymethyl, or wherein R4 is quinolinyl, carboxy or lower alkoxycarbonyl and Rs is hydrogen or lower alkyl, or wherein R4 and Rs together are Cz-C7alkylene or unsubstituted or cyano-substituted ~ ~
: ' ~ ,.i; ' '. ., ; , . .,., ', '.` ., 200309~
benzo-C4-Csalkylene; and R3 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, benzyloxy or hydroxy; phenyl groups being unsubstituted or substituted by lower alkyl, halo-lower alkyl, halogen, hydroxy, lower alkoxy, lower alkanoyloxy and/or by nitro; and pharma-ceutically acceptable salts thereof.
The invention relates especially to the above-mentioned use of compounds of formula I wherein X is fluorine, chlorine, hydroxy, lower alkyl-sulfonyloxy or phenylsulfonyloxy; each of R1 and R2, independently of the other, is hydrogen, lower alkyl, C3-C~cycloalkyl or phenyl-lower .:.alkyl, or Rl and R2 together are a radical . :
R4\
~C= , ' `
wherein each of R4 and Rs, independently of the other, is hydrogen, lower alkyl, halo-lower alkyl, C3-C7cycloalkyl, phenyl-lower alkyl or phenyl, or wherein R4 is quinolinyl, 3-hydroxy-5-(hydroxymethyl or phos-phonooxymethyl)-2-methyl-4-pyridyl and Rs is hydrogen, or wherein R4 is -~
carboxy or lower alkoxycarbonyl and Rs is lower alkyl, or wherein R4 and Rs together are -(CH2)4- or -(CNZ)s- ; and R3 is hydrogen, ;-~
lower alkyl, lower alkenyl, lower alkynyl or hydroxy; phenyl groups being unsubstituted or substituted by lower alkyl, trifluoromethyl, halogen, hydroxy, lower alkoxy and/or by nitro; and pharmaceutically acceptable sàlts thereof.
"~
The invention relates especially to the above-mentioned use of compounds of formula I wherein X is fluorine, chlorine, hydroxy or methylsulfonyl- ;~
oxy, R1 is hydrogen, R2 is hydrogen, C1-C4alkyl, benzyl or 2-hydroxy-benzyl, or R1 and R2 together are C7-C6cycloalkylidene~ C1-C4-alkylidene, benzylidene, 2-hydroxybenzylidene or 3-hydroxy-S-(hydroxy-methyl or phosphonooxymethyl)-2-methyl-4-pyridylmethylidene, and R3 is hydrogen, Cl-C4alkyl, C2-C4alkynyl or hydroxy; and pharmaceutically .-acceptable salts thereof. :: : :
' 2003091l The invention relates especially to the above-mentioned use of 3-aminoxy-2-hydroxypropylamine and 3-aminoxy-2-fluoropropylamine and pharma-ceutically acceptable salts thereof.
The invention relates preferably to compounds of formula I wherein X is halogen, hydroxy, lower alkoxy, lower alkylsulfonyloxy or phenylsulfonyl-oxy; each of Rl and R2, independently of the other, is hydrogen, lower alkyl, C3-C8cycloalkyl or phenyl-lower alkyl, or Rl and Rz together are a radical ~C= , ,, ~, .. .
Rs wherein each of R4 and Rs~ independently of the other, is hydrogen, lower alkyl, halo-lower alkyl,. C3-Cacycloalkyl, phenyl-lower alkyl or phenyl, or wherein R4 is 3-hydroxy-5-(hydroxymethyl or phosphonooxy-methyl)-2-methyl-4-pyridyl and Rs is hydrogen, or wherein R4 is .~ ;
1,2,3,4-tetrahydroxybutyl or 1,2,3,4,5-pentahydroxypentyl and Rs is . ~ ~:
hydrogen or hydroxymethyl, or wherein R4 is quinolinyl, carboxy or lower .:... :
alkoxycarbonyl and Rs is hydrogen or lower alkyl, or wherein R4 and Rs together are Cz-C7alkylene or unsubstituted or cyano-substituted benzo-C4-C6alkylene; and R3 is hydrogen, lower alkyl, lower alkenyl, lower a.lkynyl, lower alkoxy, benzyloxy or hydroxy; with the proviso that .
when X is hydroxy and Rl and R2 eogether are a radical /C= , R3 is :
hydrogen; with the proviso that when X is hydroxy and R3 is hydrogen, . ::
the radicals Rl and R2 cannot together be 1,1-dimethylmethylidene or l-n-butylidene; with the proviso that when X is hydroxy and R3 is hydrogen, hydroxy or lower alkyl, the radicals Rl and R2 cannot both be hydrogen; and with the provi$o that;when X is hydroxy and Rl and R2 are each independently hydrogen, lower alkyl, cycloalkyl or phenyl-lower ~ ~ :
alkyl but are not both hydrogen, R3 is hydrogen, methyl, ethyl or n-propyl; phenyl groups being unsubstituted or substituted by lower alkyl, halo-lower alkyl, halogen, hydroxy, iower.alkoxy, lower alkanoyl-oxy andtor by nitro; and salts thereof.
,~ . , .
. , .
' ~ :: ~ ~,,-.~ . : :.
,: ~ :,:
::
200309~
The invention relates preferably to compounds of formula I wherein X is .
fluorine, chlorine, hydroxy, lower alkylsulfonyloxy or phenylsulfonyloxy;
each of R1 and Rz, independently of the other, is hydrogen, lower alkyl, C3-C7cycloalkyl or phenyl-lower alkyl, with the proviso that the radicals R1 and R2 cannot both be hydrogen when X is hydroxy, or wherein R1 and Rz together are a radical ~ ; .
R4\ -~
~C= :, ~
wherein each of R4 and Rs, independently of the other, is hydrogen, :
lower alkyl, halo-lower alkyl, C3-C7cycloalkyl, phenyl-lower alkyl or -phenyl, or wherein R4 is quinolinyl, 3-hydroxy-5-(hydroxymethyl or phosphonooxymethyl)-2-methyl-4-pyridyl and Rs is hydrogen, or wherein i ~.
R4 is carboxy or lower alkoxycarbonyl and Rs is lower alkyl, or wherein ~
R4 and Rs together are -(CHz)4- or -(CHz)s- ; and R3 is hydrogen; -: -with the proviso that when X is hydroxy, the radicals R1 and Rz cannot together be 1,1-dimethylmethylidene or 1-n-butylidene; phenyl groups being unsubstituted or substituted by lower alkyl, trifluoromethyl, halogen, hydroxy, lower alkoxy or by lower alkanoyloxy; and salts thereof. :~
The invention relates especially to compounds of formula I wherein X is fluorine, chlorine or methylsulfonyloxy; each of R1 and R2, independently of the other, is hydrogen, lower alkyl, C3-C7cycloalkyl :-or phenyl-lower alkyl, or R1 and R2 together are a radical -: R4 ~C= ' :;,'' wherein each of R4 and Rst indepen,dqntly of thq;other, is hydrogen, `
lower alkyl, halo-lower alkyl, C3-C7cycloalkyl, phenyl-lower alkyl or phenyl, or wherein R4 is quinolinyl, 3-hydroxy-S-(hydroxymethyl or phos-phonooxymethyl)-2-methyl-4-pyridyl and R5 is hydrogen, or wherein R4 is carboxy or lower alkoxycarbonyl and Rs is lower alkyl, or wherein R4 ~ ~
: ~ and Rs together are -(C~2)4- or -(CH2)s- ; and R3 is hydrogen, . :
200~091 lower alkyl, lower alkenyl, lower alkynyl or hydroxy; phenyl groups being unsubstituted or substituted by lower alkyl, trifluoromethyl, halogen, hydroxy, lower alkoxy and/or by nitro; and salts thereof.
The invention relates more especially to compounds of formula I wherein X
is fluorine, chlorine or methylsulfonyloxy, R1 is hydrogen, Rz is hydrogen, Cl-C4alkyl, benzyl or 2-hydroxybenzyl, or R1 and R2 ~~ ;
together are C5-C6cycloalkylidene, C1-C4alkylidene, benzylidene, ~ ~
2-'nydroxybenzylidene or 3-hydroxy-5-(hydroxymethyl or phosphonooxy- `
methyl)-2-methyl-4-pyridylmethylidene, and R3 is hydrogen, C1-C4alkyl, C2-C4alkynyl or hydroxy; and salts thereof. ;~ ~
;.. :' The following sub-groups of a group of compounds of formula I are each to -;
be given special mention~
~ .,. :
(a) compounds of formula I wherein R1 and Rz are hydrogen and X is - ~
halogen; (b) compounds of formula I wherein R1 and Rz together are a~ - radical \C=
Rs (c) compounds of formula I wherein R3 is hydrogen.
~,,, The invention relates especially to the specific compounds described in the Examples and pharmaceutically acceptable salts thereof. ~
- ~, ':
The novel compounds of formula I can be prepared in a manner known Per se, for example as follows:
(a) for the preparation of compounds of formula I wherein X is halogen, a ~compoùnd of formula II
~, Rl ~ o\~ / H\cH ~ \R3 (II) -.. ~ ' .::
: ~ ::
: , ~ . :.
- 14 - .
wherein R1, R2 and R3 are as defined under formula I and Y is a group that can be converted into halogen or replaced by halogen, is reacted with a halogenating agent, or (b) for the preparation of compounds of formula I wherein X is hydroxy, a compound of formula III .
\CH / \~H (III) z wherein Rl and R2 are as defined under formula I, is reacted with ammonia or with an amine of formula NH2R3 wherein R3 is as defined : -~
under formula I, or ~::
':
(c) for the preparation of compounds of formula I wherein R1 is hydrogen, in a compound of formula IV
1' \CH / ~CH ~ ~ (IV) -~-wherein R2 and R3 are as defined under formula I and each of S and S', . ~.
indepsndently of the other, is an amino-protecting group or hydrogen, at least one of the groups S and S' being an amino-protecting group, or wherein S and R2 together or S' and R3 together are a bivalent amino-prctecting group, the amino-protecting group(s) is(are) removed, or (d) a compound of formula V
Rl OH
Y (V) :
. , . !.R2 ~
wherein R1 and R2 are as defined under formula I, is reacted with a compound of formula VI .
CH2/ \CH2~ \R3 (VI) -2(~0309~
wherein R3 and X are as defined under formula I, Z is hydroxy or a nuclsofugal leaving group and S is an amino-protecting group or hydrogen and, where applicable, the amino-protec~ing group is removed, or (e) for the preparation of compounds of formula I wherein R3 is hydrogen, in a compound of formula VII
1 ~ \CH / ~CH -W (VII) wherein Rl, R2 and X are as defined under formula I and W is a radical that can be converted into amino, the radical W is converted into amino;
or (f) for the preparation of compounds of formula I wherein R3 is hydrogen or especially hydroxy or lower alkyl, a compound of formula VIII
Rl ~ 0\ /CH\ (VIII) wherein Rl, R2 and X are as defined under formula I and R3 is hydrogen, hydroxy or lower alkyl, is reduced; andtor, if desired, a resulting compound of formula I is converted into a different compound of formula I and/or, if desired, a resulting salt is converted into the free compound or into a different salt and/or, if desired, a resulting free compound is converted into a salt and/or a resulting mixture of isomeric compounds of formula I is separated into the individual isomers.
In the more specific description of processes (a) to (f) that follows, ~ ;~
unlessiotherwisç indicared~ the symbdls X, Rl, R2 and R3 are each as ! " ' ~'`' defined under formula I.
:' Process (a): A group Y that can be converted into halogen or replaced by halogen is, for example, hydroxy or aliphatically or aromatically ;~
substituted sulfonyloxy, for example methylsulfonyloxy or 4-methylphenyl~
sulfonyloxy (tosyloxy). Preferably Y is hydroxy.
,~ `,'' .,.,''' ', 20~309~
Halogenating agents that are suitable for the conversion of Y = for example hydroxy into X = fluorine are, for example, hydrogen fluoride, sulfur tetrafluoride, especially a mixture of hydrogen fluoride and sulfur tetrafluoride and also, for example, substituted amino-sulfur trifluorides, such as diethylamino-sulfur trifluoride (DAST) or piperidino-sulfur trifluoride.
:
Halogenating agents that are suitable for the conversion of Y = for example hydroxy into X = chlorine, bromine or iodine are, for example, hydrogen halides, for example hydrogen chloride, bromide or iodide, thionyl halides, for example thionyl chloride or bromide, sulfuryl halides, for example sulfuryl chloride or bromide, or phosphorus halides, for example phosphorus tribromide, triiodide, pentabromide, pentaiodide, trichloride or pentachloride.
Compounds of formula II wherein Y is arylsulfonyloxy, for example tosyloxy, can be converted by reaction with alkali metal halides, -~
especially alkali metal chlorides, bromides or iodides, preferably in dimethylformamide, into compounds of formula I wherein X is chlorine, bromine or iodine.
Compounds of formula II wherein Y is arylsulfonyloxy, for example tosyl-oxy, can also be converted into compounds of formula I wherein X is fluorine, for example by reaction with KHFz, for example in 1,2-di-hydroxyethane.
Particularly in the case of the last two reactions it may be necessary before the reaction is carried out to protect the amino groups in the compounds of~formula II~by amino-protecting groups, for example those mentioned below. After the reaction, the amino-protecting groups are removed again in a manner known per se.
The starting compounds of formula II wherein Y is hydroxy are prepared,for example, according to process (b), see below. The starting compounds of formula II wherein Y is aliphatically or aromatically substituted sulfonyloxy are preferably prepared in a manner known per se from -compounds of formula II wherein Y is hydroxy, for example by reaction with lower alkylsulfonyl or arylsulfonyl chlorides.
Process (b~: The nucleophilic substitution reaction according to process (b) is carried out without a solvent or in the presence of a solvent, for example a lower alkanol or ether, such as isopropanol or tetrahydrofuran, and optionally under elevated pressure and takes place selectively at the terminal carbon atom of the oxiranyl radical.
The starting compounds of formula III are obtained, for example, by reacting a hydroxylamine or oxime of formula V with, for example, epichlorohydrin, epibromohydrin or 3-tosyloxy-1,2-epoxypropane. This reaction is preferably carrie~ out in the presence of a base, for example sodium hydroxide, and without a solvent or in the presence of a solvent, for example acetone or acetonitrile.
If optically active epichlorohydrin, epibromohydrin or especially 3-tosyloxy-1,2-epoxypropane is used in the preparation of compounds of formula III, then there are obtained stereoselectively the corresponding optically active compounds of formula III. If the latter are used in process (b), then optically active compounds of formula I are obtained.
The compounds of formula III can also be obtained from compounds of formula VII wherein X is hydroxy and U is, for example, chlorine, by closing the epoxy ring in the presence of a base.
Process (c): Preferred monovalent amino-protecting groups S and S' are -~
ester groups, for example lower~alkyl esters and especially tert.-butoxy-carbonyl ~BOC), or acyl radicals, for example lower alkanoyl or halo-lower alkanoyl, such as especially acetyl, chloroacetyl or trifluoro- ~
acetyl. ~ ~ ;
Preferred bivalent amino-protecting groups, formed by the radicals S and Rz or S' and R3, are mono- or di-substituted methylidene groups, such as 1-lower alkoxy-lower alkylidene groups, for example =C(CH3)(0C2Hs), ~ , :
'' ` ' ` ~ ~:
' ' , ~,; ~ ''`'';:'':`
- ~ ~
- 18 - ~
and also, for example, =C(CH3)2 or =CH-phenyl, all of which are prefer- -ably used for the protection of the nitrogen atom in the N-O grouping, and bisacyl radicals, for example that of phthalic acid, which forms a phthalimido group together with the nitrogen atom to be protected.
The mode of action of protecting groups, for example amino-protecting groups t and the methods by which they can be introduced and removed are known per se and are described, for example, in J.F.W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, and T.W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York 1984. ;~
The removal of thP amino-protecting groups can be effected, for example, -by hydrolysis, especially in an acidis medium, for example with hydrogen chloride, dilute sulfuric acid, oxalic acid, organic sulfonic acids, for example toluene-4-sulfonic acid, or trifluoroacetic acid.
Certain amino-protecting groups, for example mono- or di-substituted methylidene groups and lower alkanoyl, can be converted by reduction, for example with complex hydrides, for example LiAlH4 or NaBH3CN, into a group Rl or R3 in formula I, for example =C(CH3)2 can be converted into isopropyl or acetyl into ethyl.
Compounds of formula IV are prepared, for example, by carrying out one of processes (a), (b), (d), (e) and (f) with protected amino group(s). The compounds of formula IV can also be prepared from compounds of formula I, ~ -for example for purification purposes. ~-Process (d): In the compounds of formula VI the nucleofugal leaving ~-group Z has exactly the same definition as a nucleofugal leaving group W
in the compounds of formula VII under process (e). The amino-protecting groups S in a compound of formula VI correspond to the amino-protecting groups 5 or S' defined in compounds of formula IV under process (c).
~ `'~,`'~' ', 200309~
If, in a compound of formula VI, Z is hydroxy, then it is possible to carry out, for example, an intermolecular dehydrating reaction.
Especially suitable for this purpose is the Mitsunobu reaction [see Bull.
Chem. Soc. Japan 40, 2380 (1967)] in which the compounds of formulae V
and VI are reacted with, for example, triphenylphosphine and N,N'-azodi-carboxylic acid ethyl ester.
If, in a compound of formula VI, Z is a nucleofugal leaving group, then process (d) corresponds to a simple nucleophilic substitution (0-alkyla-tion).
If, in a compound of formula VI, X is hydroxy, then it may be advisable -before process (d) is carried out to protect that hydroxy group with a hydroxy-protecting group which is removed again when the reaction accord-ing to process (d) is complete. Suitable hydroxy-protecting groups are, for example, acyl derivatives (esters), for example lower alkanoyl, benzoyl, benzyloxycarbonyl or lower alkoxycarbonyl, or alkyl derivatives -(ethers), for example lower alkoxy-lower alkyl, 2-tetrahydropyranyl, trityl or benzyl, and also tri-lower alkylsilyl.
If, in a compound of formula VI, X is hydroxy, then that hydroxy group may also be protected together with the amino group -NSR3. This can be `~ ~ -effected, for example, by the radicals X and S in a compound of formula VI together forming a group -0-CH2-, an oxazolidine ring being formed. A ;~
compound protected in this manner is obtained, for example, from the free hydroxyamino compound by condensation with formaldehyde in a manner known E~ se. This protecting group is removed again in an acidic ~ ~-medium after process (d) has been carried out.
.
Compounds of formula VI wherein X and Z are hydroxy are prepared, for example, by reacting 2,3-epoxypropanol with ammonia or an amine of `;
formula NHz~3 and then, if required, introducing a hydroxy- and/or ; k amino-protecting group. ;
.. ~ ~ . :-, , - , , .,~:
:~ : , '". ~.
~: ~ - ' " :.
,, :
20~)31)91 -Process (e): In a compound of formula VII, a radical ~ that can be converted into amino is, for example, an azido group (-N3~ that can be converted into amino by reduction, for example with complex metal hydrides, for example LiAlH4, tin(II) chloride or with hydrogen in the presence of a catalyst, for example palladium-on-carbon. It may be , advisable before process (e) is carried out to protect a hydroxy group X
and/or the amino group RlRzN- in the compound of formula VII with a hydroxy- and/or amino-protecting group. Such protecting groups are removed again after process (e) has been carried out.
Compounds of formula VII wherein W is azido can be obtained, for example, by the reaction of compounds of formula III or IIIa with, for example, sodium or ammonium azide.
The radical W in a compound of formula VII can also be, for example, a nucleofugal leaving group. Such a nucleofugal leaving group W is prefer-ably halogen, for example chlorine, bromine or iodine, but also, for example, aliphatically or aromatically substituted sulfonyloxy, for example methylsulfonyloxy or 4-methylphenylsulfonyloxy.
Such a compound of formula VII can be converted into a compound of formula I by reaction with ammonia or an amine of formula NHzR3 in the -~
manner of a nucleophilic substitution reaction.
Starting compounds of formula VII are prepared, for example, from com-pounds of formula III or from compounds of formula IX
R 0 ~CH (IX) ~ ~ 2 by reaction with the corresponding nucleophiles, for example halide, methanesulfonate or p-toluenesulfonate.
~ `': `~``''``' 200309~
- 21 ~
Compounds of formula VII wherein X is hydroxy and W is, for example, halogen or tosyloxy, can also be obtained by reaction of compounds of formula V with epihalohydrin or 3-tosyloxy-1,2-epoxypropane, especially in an acidic medium.
Compounds of formula IX wherein X is hydroxy can be obtained analogously from compounds of formula V by reaction with 2,3-epoxypropanol.
Compounds of formula IX can also be obtained, for example, starting from compounds of formula V with, for example, 3-halo-2-X-propanols, wherein the hydroxy group is, if appropriate, in protected form.
Process (f): The reduction can be carried out, for example, using the same reducing agents as those 1ndicated in process (e) for the reduction of azido groups.
The starting compounds of formula VIII can be prepared, for example, from -the analogous aldehydes (=O instead of =NR3 in formula VIII) by reaction with ammonia, hydroxylamine or lower alkylamines. ~ ;
The mentioned aldehydes analogous to formula VIII can be prepared from ; ; ; ;`
corresponding hydroxymethyl compounds, for example, by oxidation, for ~
exampls with pyridinium chlorochromate [see J. Org. Chem. 46, 4797 ~ ~;
(1981)]. They may also be obtained by reduction of corresponding lower alkyl esters, for example with diisobutylaluminium hydride [see Chem.
Pharm. Bull. 23, 3081 (1975)] or by reduction of corresponding acid chlorides, for example with tri-n-butyltin hydride [see J. Org. Chem.
25, 284 (1961) or J. Amer. Chem. Soc. ô8, 571 (1966)].
:, '~
: .
The mentioned aidehydes analogous to formula VIII can also be obtained -; ;~
especially by the following reaction sequence:
(1) Reaction of 3,4-0,0-isopropylidene-3,4-dihydroxy-1,2-epoxybutane [see J. Org. Chem. 52, 2841 (1987) or DE-A-3 150 917] with acetohydroxamic acid ethyl ester to form 3,4-0,0-isopropylidene-2,3,4-trihydroxy-1 ethoxyethylideneaminoxy)-butane. In the latter compound the 2-hydroxy group may optionally be converted in a manner known per se into a ~ ~ '' ' .' '" ' "' :
different radical X in formula I, for example halogen, or be protscted by a protecting group. (2) Removal of the isopropylidene group, for example by treatment with dilute acid. (3) Glycol cleavage of the terminal a,~-dihydroxyethyl group to formyl by reaction of NaIO4 or Pb(OCOCH3)4. (4) Removal of the l-ethoxyethylidene group, for example by treatment with acid.
Compounds of formùla I can be converted into different compounds of formula I.
Compounds of formula I wherein X is hydroxy can be converted in a manner known per se into compounds of formula I wherein X is lower alkoxy, acyloxy, lower alkylsulfonyloxy or arylsulfonyloxy by reacting the former with lower alkylating agents, for example lower alkyl halides, tosylates or mesylates, or di-lower alkyl sulfates, or acylating agents, for example acid anhydrides or halides, or lower alkylsulfonyl halides or arylsulfonyl halides, for example 4-methylphenylsulfonyl chloride. In these reactions the two amino groups in the compounds of formula I are ~ -preferably protected. ;-When carrying out an above-mentioned alkylation of X = OH into X z lower ;
alkoxy, the amino group -NRlR2 (Rl and R2 are hydrogen) may also be -lower alkylated at the same time even though it has been protected by an amino-protecting group, for example BOC. - ;-~
Compounds of formula I wherein Rl and Rz together are a radical ;~ ~ fRsR4C= can be converted into different compounds of formula I wherein Rl is hydrogen and R2 is a radical -CHR4Rs by reduction, for example `-- `
with sod~um yanoborohydride.
Compounds of formula I wherein Rl and R2 are hydrogen can be converted into different compounds of formula I wherein the radicals Rl and Rz together are a group RsR4C= by reaction with a carbonyl compound --~
RsR4C=O in which the carbonyl group may also be in masked form, for example in acetal or ketal form.
~.
Z00309~
Conversely, it is also possible for compounds of formula I wherein R
and R2 together are a group RsR4C= to be converted into compounds of formula I wherein R1 and R2 are hydrogen, for example by acidic hydrolysis.
Free compounds of formula I having salt-forming properties obtainable in accordance with the process can be converted into their salts in a manner known per se; compounds having basic properties can be converted by treatment with acids or suitable derivatives thereof.
:',"
The compounds, including their salts, can also be obtained in the form of their hydrates, or their crystals may include, for example, the solvent ~ ~-used for crystallisation. -Mixtures of isomers obtainable according to the invention can be ~ ~
separated into the individual isomers in a manner known per se; ~ ;
racemates can be separated, for example, by forming salts with optically pure salt-forming reagents and separating the resulting mixture of di-astereoisomers, for example by means of fractional crystallisation. ;
The reactions mentioned above can be carried out under reaction condi~
tions known per se, in the absence or, usually, in the presence of ;
solvents or diluents, preferably those solvents or diluents which are inert towards the reagents used and are solvents therefor, in the absence -or presence of catalysts, condensation agents or neutralising agents and, depending upon the nature of the reaction and/or the reactants, at reduced, normal or elevated temperature, for example in a temperature range of from approximately -80C to approximately 190C, preferably from`;~
approximately -20C to approximately 150C, for example at the boiling -point of the solvent used, under atmospheric pressure or in a closed vessel, optionally under pressure, and/or in an inert atmosphere, for example under a nitrogen atmosphere.
., ~ .. ' -:
The starting materials used in the process of the present invention are ; preferably those which result in the compounds described at the beginning as being especially valuable. - ;
': ': ' ' : .
The invention relates also to those forms of the process in which a com-pound obtainable as intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example a salt thereof.
The prasent invention relates also to pharmaceutical preparations that contain one of the pharmacologically active compounds of formula I as active ingredient. Preparations for enteral, especially oral, and ~ ~;
parenteral administration are especially preferred. The preparations contain the active ingredient on its own or, preferably, together with a pharmaceutically acceptable carrier. The dosage of the active ingredient -depends upon ~he disease to be treated, and upon the species, its age, weight and individuai condition, and upon the mode of administration. -The pharmaceutical preparations contain from approximately 5 % to approximately 95 % active ingredient, forms of administration that are in single dose form preferably containing from approximately 20 % to approximately 90 % active ingredient, and forms of administration that are not in single dose form preferably containing from approximately 5 %
to approximately 20 % active ingredient. Dosage unit forms, such as dragées, tablets or capsules, contain from approximately 0.05 g to approximately 1.0 g of active ingredient.
The pharmaceutical preparations of the present invention are manufactured in a manner known ~ se, for example by means of conventional mix~
ing, granulating, confectioning, dissolving or lyophilising processes. ~i ;
! ~
For`example, pharmaceutical compositions for oral administration can be ~
obtained by combining the active ingredient with one or more solid ~ - -carriers, optionally granulating a resulting mixture and processing the - -~
mixture or granulate, if desired and/or appropriate, with the addition of ~
additional adjuncts, to form tablets or dragée cores. ~ - `
:-. - ~, : :-Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropylmethylcellulose. sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, cross-linked polyvinylpyrrolidone. alginic acid or a salt thereof, such as sodium alginate. Additional adjuncts are especially flow-regulating agents and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
Dragée cores can be provided with suitable coatings which may be resistant to gastric juices, there being used inter alia concentrated sugar solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or lacquer solutions in suitable organic solvents or solvent mixtures or, for the preparation of coatings that are resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxy-propylmethylcellulose phthalate. Colourings or pigments may be added to the tablets or dragée coatings, for example for identification purposes or to indicate different doses of active ingredient. ~
~. . ,'..
Pharmaceutical compositions for oral administration are also dry-fill capsules consisting of gelatine, and soft sealed capsules consisting of ~ ~
gelatine and a p.lasticiser, such as glycerine or sorbitol. The dry-fill -capsules may contain the active ingredient in the form of a granulate, for example in admixture with fillers, such as corn starch, binders , . ' . i ! , . I ~ i ! . ' ' and/or glidants, such as talc or magnesium stearate, and optionally stabilisers. In soft capsules the active ingredient is preferably dissolved or suspended in suitable liquid adjuncts, such as fatty oils, paraffin oil or liquid polyethylene glycols, it likewise being possible to add stabilisers.
200309~
Other oral forms of administration are, for example, syrups prepared incustomary manner which contain the active ingredient, for example, in suspended form and in a concentration of approximately from 5 ~/O to 20 %, preferably about 10 %, or in a similar concentration that provides a suitable single dose when administered, for example, in measures of 5 or 10 ml. Also suitable are, for example, powdered or liquid concentrates for the preparation of shakes, for example in milk. Such concentrates may also be packed in single dose quantities.
Suitable rectally administrable pharmaceutical preparations are, for example, suppositories that consist of a combination of the active ingredient with a suppository base material. Suitable suppository base materials are, for example, natural or synthetic triglycerides, paraffin ~-hydrocarbons, polyethylene glxcols or higher alkanols.
For parenteral administration there are suitable, especially, aqueous solutions of an active ingredient in water-soluble form, for example in the form of a water-soluble salt, or aqueous injection suspensions that ~ -contain viscosity- increasing substances~ for example sodium carboxy~
methylcellulose, sorbitol and/or dextran and, if desired, stabilisers.
The active ingredient, optionally together with adjuncts, can also be in the form of a lyophilisate and can be made into a solution prior to ;~ -parenteral administration by the addition of suitable solvents.- ~ `
The solutions used, for example, for parenteral administration can alsobe used as infusion solutions.
The invention relates also to a method of treating the pathological - ~-conditions mentioned above. The!compounds of the present invention can be administered prophylactically or therapeutically, and are preferably administered in the form of pharmaceutical preparations. A daily dose of ;~
from approximately 0.3 g to approximately 15 g, preferably from approximately 0.5 g to approximately 5 g, of a compound of the present invention will be administered in the case of a body weight of approxlmately 70 kg.
~00309~
The following Examples illustrate the present invention; temperatures are given in degrees Celsius. The following abbreviations are used: BOC ~
tert.-butoxycarbonyl; THF - tetrahydrofuran; hexane = n-hexane;
ether - diethyl ether; mesyl - methylsulfonyl.
Example 1: In a gold-coated 50 ml autoclave, 3.2 g of N-(3-aminoxy-2-hydroxypropyl)-isopropylamine are dissolved at -78 in 20 g of anhydrous ~ -hydrogen fluoride, and 5.4 g of sulfur tetrafluoride are added thereto.
The autoclave is sealed, stirred with a magnetic rod for 3 hours at -78, heated to 0 and after a further 24 hours degassed. The residue is taken ~-up in 30 ml of 2N hydrochloric acid, filtered and applied to a 35 x 270 mm column with slightly basic ion exchanger MWA-1 (Dow Chemicals).
The column is washed with water. The ninhydrin-positive fractions are combined, neutralised with hydrochloric acid and concentrated by evapora-tion. The hygroscopic residue corresponds to N-(3-aminoxy-2-fluoro-propyl)-isopropylamine dihydrochloride; it is crystallised from ethyl acetate and dried over phosphorus pentoxide; Rf value = 0.55 (silica gellmethylene chloride:methanol:concentrated ammonia 150:50:1).
The N-(3-aminoxy-2-hydroxypropyl)-isopropylamine used as starting material is freed from the corresponding dihydrochloride (see DE-C-2 651 033) by filtration over a strongly basic ion exchanger, for example 50 times the amount of DOWEX 1x4 (OH).
Example 2: 30 ml of an approximately 2N solution of hydrogen chloride in ethyl acetate are atted to a solution of 3 g of N,N'-di-BOC-N-(3-aminoxy-2-fluoropropyl)-isopropylamine in 30 ml of ethyl acetate and the mixture is stirred at room temperature for lô hours with the exclusion of moisture. The precipitated product, is filtered with suction, washed with ethyl acetate ant ether and dried, yielding N-(3-aminoxy-2-fluoropropyl)-isopropylamine dihydrochloride in the form of a white hygroscopic powder, Rf value s 0.55 (silica gel/methylene chloride:methanol:concentrated ammonia 150:50:1).
The starting material is prepared as follows:
; ' ` , ~.,;
~ '`- ', ':
-- .:
200309~
The crude product from the fluorination batch described in Example 1, starting from 20 mmol of N-(3-aminoxy-2-fluoroproPYl)-isoPropylamine, is dissolved in 30 ml of 2N hydrochloric acid. This solution is diluted with 50 ml of water and 50 ml of THF and neutralised in portions with solid sodium hydrogen carbonate. This mixture is then treated dropwise with a solution of 12 g of di-tert.-butyl dicarbonate (FluXa) in 50 ml o THF
while cooling with ice and is then stirred at room temperature for 20 hours. The reaction mixture is diluted with 250 ml of ether. The upper layer is washed with water and a saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. The oil that remains is chromatographed over silica gel with a mixture of hexane/ethyl acetate (1:1), yielding N,N'-di-BOC-N-(3-aminoxy-2-fluoro-propyl)-isopropylamine in the form of a colourless oil, Rf value = 0.32 (silica gel/hexane:ethyl acetate 2:1). ~
. :,;
Example 32: 2 ml of lN sodium hydroxide solution and 0.2 ml (2 mmol) of ~ -benzaldehyde are added to a solution of 360 mg (2 mmol) of 3-aminoxy-2-hydroxypropylamine dihydrochloride in 5 ml of ethanol and the mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated by evaporation, 10 ml of water and 1 ml of 2N sodium hydroxide solution are added and the mixture is extracted twice with SO ml of ether. The ether phases are washed with dilute sodium chloride solution, combined, filtered and concentrated by evaporation. The residue is crystallised from a small amount of ether and corresponds to 3-benzylideneaminoxy-2-hydroxypropylamine, m.p. 65, Rf value = 0.32 Ssilica gel/methylene chloride:methanol:concentrated ammonia 40:10:1).
Example 3a: 40 ml of concentrated ammonia are added to a solution of 1.77 g (10 mmol? of 1-benzylidene,aminoxy-2,3-epoxypropane [see, for example, Zh. Org. Khimii 5, 1353 (1969)] in 10 ml of THF and the mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated by evaporation and taken up in 100 ml of ether. This solution is dried over sodium sulfate, filtered and concentrated, and the 3-benzylideneaminoxy-2-hydroxypropylamine crystallises out after cooling, m.p. 65.
.~ :
: ' ': :.: . ' . :~
2003iO9l Example 4- Analogously to the process described in Example 3, 3-aminoxy-2-hydroxypropylamine dihydrochloride is reacted with cyclo-pentanone, yielding 3-cyclopentylideneaminoxy-2-hydroxypropylamine in the form of a wax, Rf value = 0.33 (silica gel/methylene chloride:methanol:concentrated ammonia 40:10:1).
Example 4a: Analogously to Example 3a, 1-cyclopentylideneaminoxy-2,3-epoxypropane [see J. Med. Chem. 28, 153 (1985)] is reacted with concentrated ammonia and worked up. The crude product is chromatographed with the system methylene chloride/methanol/concentrated ammonia (40:10:1), yielding 3-cyclopentylideneaminoxy-2-hydroxypropylamine in the form of a wax, Rf value = 0.33 (silica gel/methylene chloride:methanol:concentrated ammonia 40:10:1).
Example 5: In a 200 ml Teflon reactor, 2.5 g of 3-aminoxy-2-hydroxy- ~;
propylamine (see DE-C-2 651 083) are dissolved at -78 in 40 g of liquid hydrogen fluoride (HF). A further 5.6 g of sulfur tetrafluoride are then -introduced. The mixture in the reactor is sealed and stirred with a magnetic rod for 3 hours at -78, heated to 0 and after a further 24 hours degassed, yielding crude 3-aminoxy-2-fluoropropylamine in the form of the hydrofluoride which is converted into the corresponding pure dihydrochloride using one of the following two methods:
a)- Th~P residue is taken up in 50 ml of 2N HCl, filtered and applied to a 35 x 270 mm column with slightly basic ion exchanger MWA-1 (Dow Chemicals). The column is washed with water. The ninhydrin-positive fractions are combined, neutralised with lN HCl and concentrated by evaporation. The residue is crystallised from ethyl acetate, yielding 3-aminoxy-2-fluoropropylamine dihydrochloride having a melting point of 204-207. ~ ~;
b) The residue is taken up in 50 ml of 2N HCl and 100 ml of water, filtered and diluted with 100 ml of THF. This mixture is neutralised to pH 7.5 in por~ions with solid sodium hydrogen carbonate while cooling -with ice, and then a solution of 13.0 g of di-tert.-butyl dicarbonate (Fluka) in 70 ml of THF is added dropwise thereto. The two-phase reaction ~ -200~0~
mixture is stirred at room temperature for 16 hours and then diluted with 100 ml of ether. The organic phase is separated off, washed with ]00 ml of water and 50 ml of a saturated sodium chloride solution, dried over magnesium sulfate and, after the drying agent has been separated off, concentrated by evaporation. The residue is crystallised from ether and hexane and corresponds to N,N'-di-BOC-3-aminoxy-2-fluoropropylamine having a melting point of 67-69.
20 ml of a 1.8N solution of hydrogen chloride in ethyl acetate are added to a solution of 1.8 g of N,N'-di-BOC-3-aminoxy-2-fluoropropylamine in -~
10 ml of ethyl acetate and the mixture is stirred at room temperature for 18 hours. The product that crystallises out is filtered with suction, washed with ether and dried. It corresponds to 3-aminoxy-2-fluoropropyl- ~- ~amine dihydrochloride having a melting point of 204-207. -Example 6: Analogously to Example 2, 3.4 g of N,N'-di-BOC-3-aminoxy-2-mesyloxypropylamine are treated with 30 ml of an approximately 1.5N
solution of hydrogen chloride in ethyl acetate and worked up, yielding 3-aminoxy-2-methylsulfonyloxypropylamine dihydrochloride in the form of white hygroscopic crystals, Rf value = 0.37 (silica gel/methylene chloride:methanol:concentrated ammonia 40:10:1).
.
The starting material is prepared as follows:
While cooling with ice-water, a solution of 48 g (0.22 mol) of di-tert.-butyl dicarbonate (Fluka) in 100 ml of THF is added dropwise, with stirr-ing, to a solution of 18 g (0.1 mol) of 3-aminoxy-2-hydroxypropylamine dihydrochloride and 21.2 g (0.2 mol) of anhydrous sodium carbonate in 100 ml of water~and 100 ml of!THF~and the mixtu~re is stirred at room temperature for 4 hours. The reaction mixture is diluted with 250 ml of ether. The upper layer is separated off, washed with water and a saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. The N,N'-di-BOC-3-aminoxy-2-hydroxypropyl-amine that remains behind is crystallised from ether/petroleum ether, m.p. 106-108. ;
-,:,, . ,:
~, :, :-.
': ~ ;. . .,:
:::::
: .
~UUW~l While cooling with ice-water and with the exclusion of moisture, 1.26 g(ll mmol) of methanesulfochloride are added, with stirring, to a solution of 2.75 g (9 mmol) of N,N'-di-BOC-3-aminoxy-2-hydroxypropylamine in 10 ml of pyridine and the mixture is stirred at room temperature for 16 hours.
2 ml of water are then added and the reaction mixture is concentrated by evaporation. 100 ml of ether and 50 ml of water are added to the residue.
The upper layer is separated off, washed in succession with a diluted sodium hydrogen sulfate solution, water, a saturated sodium hydrogen carbonate solution and again with water and, after drying over magnesium suifate, concentrated by evaporation, yielding N,N'-di-BOC-3-aminoxy-2-mesyloxypropylamine in the form of a yellow oil. Rf value = 0.28 (silica gel/hexane:ethyl acetate l:l).
Example 7: Analogously to Example 2, 1.3 g of N,N'-di-BOC-3-methyl-aminoxy-2-methoxypropylamine are treated with 20 ml of an approximately 1.5N solution of hydrogen chloride in ethyl acetate and worked up. The crude product is dissolved in a small amount of water, and filtered over 100 ml of DOWEX lx4 (OH form). The filtrate is concentrated by evaporation and the residue is crystallised from 10 ml of methanol with the addition of 700 mg of oxalic acid, yielding 3-methylaminoxy-2-methoxypropylamine dioxalate, m.p. 153-155.
The starting material is prepared as follows:
Uith stirring and with the exclusion of moisture, 1.7 g (40 mmol) of a 55-60 % NaH dispersion in oil are added to a solution of 3.06 g (10 mmol) of N,N'-di-BOC-3-aminoxy-2-hydroxypropylamine in 100 ml of THF. A solu- ;
tion of l.9 ml (~0 mmol) of dimethyl sulfate in 10 ml of THF is then added dropwise thereto and the mixture is stirred at room temperature for `
15 hours. The reaction mixture is concentrated by evaporation and the -residue is taken up in ether, washed with water, dried over magnesium ~ `
sulfate and again concentrated by evaporation. The oil that remains is ~ :
chromatographed over silica gel with a mixture of hexane/ethyl acetate (l:l), yielding N,N'-di-BOC-3-methylaminoxy-2-methoxypropylamine in the - -~form of a pale yellow oil, Rf value = 0.36 (silica gel/hexane:ethyl acetate l:l). 1`
'; `' . .`
- .
200309~
Example 8: Analogously to Example 3, 3-aminoxy-2-hydroxypropylamine -dihydrochloride is reacted with salicylaldehyde, yielding 3-salicylidene-aminoxy-2-hydroxypropylamine [- 3-(2-hydroxybenzylideneaminoxy)-2-hydroxypropylamine] in the form of yellow crystals having a melting point of 94-97.
,~
Examp]e 9: Analogously to Example 3, 3-aminoxy-2-hydroxypropylamine dihydrochloride is reacted with acetone, yielding 3-isopropylidene-aminoxy-2-hydroxypropylamine which is crystallised in hydrochloride form from isopropanol/ether. The white hygroscopic crystals are dried over phosphorus pentoxide, Rf value = 0.1 (silica gel/methylene chloride:methanol:concentrated ammonia 150:50:1). ~
~ : '' :, Example 9a: Analogously to Example 3a, 1-isopropylideneaminoxy-2,3-epoxypropane [see Zh. Org. Khimii 5, 1353 (1969)] is reacted with concentrated ammonia. The reaction mixture is concentrated to dryness by evaporation, yielding 3-isopropylideneaminoxy-2-hydroxypropylamine in the form of a pale yellow oil, Rf value = 0.1 (silica gel/methylene chloride:methanol:concentrated ammonia 150:50:1).
Example 10: Analogously to Example 2, 4.5 g of N-BOC-(3-isopropyl-aminoxy-2-hydroxypropyl)-amine are treated with 50 ml of an approximately 1.5N solution of hydrogen chloride in ethyl acetate. The reaction mixture is concentrated by evaporation and the crude product is dissolved in a small amount of water and filtered over 200 ml of DOWEX lx4 (OH form).
The filtrate is concentrated by evaporation and the oily residue is taken up in ethyl acetate, dried over sodium sulfate and freed of solvent again. The 3-isopropylaminoxy-2-hydroxypropylamine, which slowly crystallises, is sublimed at 50/0.1 mbar.
The starting material is prepared as follows:
A solution of 28 g of di-tert.-butyl dicarbonate (Fluka) in 150 ml of THF
is added dropwise, with stirring and while cooling with ice-water, to a ~
solution of 13.48 g of 3-isopropylideneaminoxy-2-hydroxypropylamine in `~ ;
- '::`''. ~
' ~:'` ;, ,, 150 ml of THF and 150 ml of water and the mixture is stirred at room temperature for 16 hours. The reaction mixture is freed of THF in vacuo and extracted with ether. The organic phase is washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. The residue is chromatographed over silica gel with a mixture of hexane/ethyl acetate (1:1), yielding N-BOC-3-iso-propylideneaminoxy-2-hydroxypropylamine in the form of a pale yellow oil, Rf value = 0.16 (silica gel/hexane:ethyl acetate 1:1).
17.3 ml (304 mmol) of glacial acetic acid and 9.6 g (152 mmol) of sodium cyanoborohydride are added to a solution of 10.32 g (41.95 mmol) of N-BOC-3-isopropylideneaminoxy-2-hydroxypropylamine in 230 ml of THF and the mixture is stirred at room temperature for 16 hours. 10.32 g of sodium hydrogen carbonate are added to the reaction mixture which is then stirred for 30 minutes and concentrated by evaporation. The residue is taken up in ether, washed with water, dried over magnesium sulfate and freed of solvent. The product is chromatographed over silica gel with a mixture of hexane/ethyl acetate (1:1), yielding N-BOC-(3-isopropyl-aminoxy-2-hydroxypropyl)-amine in the form of a pale yellow oil, Rf value = 0.05 (silica gel/hexane:ethyl acetate 1:1).
:, ~.
Example 11: 10 ml of an approximately 5.5N solution of HCl in ethanol -are added to a solution of 2.6 g of N-BOC-(3-isopropylaminoxy-2-fluoro-propyl)-amine in 25 ml of ethanol and the mixture is left to stand at ~
room temperature for 18 hours with the exclusion of moisture and then ~ -concentrated to dryness by evaporation. The residue is dissolved in water ~ ~
and extracted once with ether. The aqueous phase is filtered with -; -activated carbon and lyophilised, yielding 3-isopropylaminoxy-2-fluoro-propylamine dihydrochloride in the form of a yellowish hygroscopic powder, Rf value = 0.59 (silica gel/methylene chloride:methanol:concentrated ammonia 40:10:1). -~
The starting material is prepared as follows: ~ ~
:~ ;: "-"'-::
~'~ ' ' . .~ - '' '',:
: , ' ` ':' . . :
200309~
.. . :.
- 34 - ~
. -: - .:
Analogously to Example 5, 2.65 g (17.9 mmol) of 3-isopropylaminoxy-2-hydroxypropylamine in 20 ml of anhydrous hydrogen fluoride are ~ -fluorinated with 4.2 g (40 mmol) of sulfur tetrafluoride and converted into a corresponding (mono-)BOC-derivative with 10 g of di-tert.-butyl dicarbonate (Fluka). The crude product is chromatographed over silica gel with a mixture: of hexane/ethyl acetate (2:1), yielding N-BoC-(3-iso-propylaminoxy-2-fluoropropyl)-amine in the form of a pale yellow oil, Rf value = 0.12 (silica gel/hexane:ethyl acetate 2:1).
Example 12: Analogously to Example 3, 537 mg (3 mmol) of 3-aminoxy-2-hydroxypropylamine dihydrochloride in 10 ml of ethanol and 3 ml of lN
sodium hydroxide solution are reacted with 0.61 g (3 mmol) of pyridoxal hydrochloride. The reaction mixture is concentrated by evaporation and the crystalline residue is recrystallised from methanol, yielding 3-pyridoxalaminoxy-2-hydroxypropylamine dihydrochloride in the form of white crystals, m.p. >185 (decomposition), Rf value = 0.11 (silica geltmethylene chloride:methanol:concentrated ammonia 40:10:1).
Example 13: 0.14 ml of acetaldehyde is added to a solution of 450 mg (2.5 mmol) of 3-aminoxy-2-fluoropropylamine dihydrochloride (see Example 5! in 5 ml of ethanol and 2.5 ml of lN sodium hydroxide solution and the mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated by evaporation and the residue is partitioned between water and ether. The lower phase is concentrated and lyophilised, yielding 3-ethylideneaminoxy-2-fluoropropylamine hydrochloride in the ; - -form of a white powder containing 1 mol of sodium chloride, Rf value --0.27 (silica gel/methylene chloride:methanol:concentrated ammonia 300:50:1). - ;~
Exam~le 14: 3-ethylideneaminoxy-2-fluoropropylamine (see Example 13) is reduced with sodium cyanoborohydride in a manner analogous to that ;;
described in Example 10 to form 3-ethylaminoxy-2-fluoropropylamine, R
value 0.2 (silica geltmethylene chloride:methanol:concentrated ammonia 40:10:1).
' ' .
- 200309~L
. . .
Example lS: 0.44 ml (6 mmol) of acetone is added to a solution of 900 mg (5.0 mmol) of 3-aminoxy-2-fluoropropylamine dihydrochloride (see Example 5) in 10 ml of ethanol and 5.0 ml of lN sodium hydroxide solution and the mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated by evaporation and the residue is partitioned between water and ether. The lower phase is concentrated and lyophilised, yield-ing 3-isopropylideneaminoxy-2-fluoropropylamine hydrochloride in the form of a white powder containing 1 mol of sodium chloride, m.p. 90, Rf value 0.30 (silica gellmethylene chloride:methanol:concentrated ammonia 300:50:1).
Example 16: 3-isopropylideneaminoxy-2-fluoropropylamine (see Example 15) is reduced with sodium cyanoborohydride in a manner analogous to that described in Example 10 to form 3-isopropylaminoxy-2-fluoropropylamine.
The dihydrochloride salt is obtained in the form of a yellowish powder, Rf value = 0.59 (silica gel/methylene chloride:methanol:ammonia 40:10:1).
The product is identical to that of Example 11.
Example 17: 0.4 ml of benzaldehyde is added to a solution of 724 mg - -(4 mmol) of 3-aminoxy-2-fluoropropylamine dihydrochloride (see Example 5) :
in 10 ml of ethanol and 4 ml of lN sodium hydroxide solution and the mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated by evaporation and the residue is partitioned between -4 ml of lN sodium hydroxide solution and 100 ml of ether. The ether phase is washed with 10 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness by evaporation. The oily residue is taken up in 7 ml of ethyl acetate, and 3.7 ml of a lN solution of HCl gas in ethyl acetate are added. The 3-benzylideneaminoxy-2-fluoro-propylamine hydrochloride that crystallises out is filtered with suction and dried, m.p. 150-152, Rf value 0.46 (silica gel/methylene chloride:methanol:concentrated ammonia 300:50:1). ~ ~ -~,.:
200309~
Example 18: 3-benzylideneaminoxy-2-fluoropropylamine (see Example 17) is reduced with sodium cyanoborohydride in a manner analogous to that described in Example 10 to form 3-benzylaminoxy-2-fluoropropylamine, Rf value 0.35 (silica gel/methylene chloride:methanol:concentrated ammonia 40:10:1).
Example 19: 3.2 ml of salicylaldehyde are added to a solution of 5.43 g(30 mmol) of 3-aminoxy-2-fluoropropylamine dihydrochloride (see Example 5) in 60 ml of ethanol and 30 ml of lN sodium hydroxide solution and the mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated by evaporation a~d the residue is partitioned between 30 ml of lN sodium hydroxide solution and 100 ml of ether. The ether phase is washed with 30 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness by evaporation. The oily residue is taken up in 70 ml of ethyl acetate, and 14 ml of a 2.2N
solution of HCl gas in ethyl acetate are added. The 3-(2-hydroxy-benzylideneaminoxy)-2-fluoropropylamine hydrochloride that crystallises out is filtered with suction and dried, m.p. 174-175, Rf value 0.33 ;~
(silica gel/methylene chloride:methanol:concentrated ammonia 300:50:1).
~,:: : ,,::-:
Example 20: 2.7 g (13 mmol) of phosphorus pentachloride are added in ~` -portions over a period of 15 minutes to a suspension of 2.1 g (lO mmol) of 3-(l-ethoxyethylideneaminoxy)-2-hydroxypropylamine hydrochloride ;~
(U.S. Patent No. 4 404 384) in 20 ml of methylene chloride and the mixture is stirred at room temperature for 2 hours. After the addition of 2 ml of water, the reaction mixture is stirred for a further 2 hours at ~
, . .,: , room temperature and then concentrated by evaporation. The residue is treated with strDngly basic ion exchanger M~'A-l (Dow Chemicals) analogously to Example 1, yielding 3-aminoxy-2-chloropropylamine dihydrochloride, Rf value 0.31 (silica gel/methylene chloride:methanol:concentrated ammonia 40:10:1).
Example 20a: Analogously to Example 2, N,N'-di-BOC-3-aminoxy-2-chloro-propylamine is treated with hydrogen chloride in ethyl acetate, yielding 3-aminoxy-2-chloropropylamine dihydrochloride, Rf value 0.31 (silica gel/methylene chloride:methanol:concentrated ammonia 40:10:1).
~.
:
200:~09~. :
The starting material is prepared as follows:
The reaction mixture from Example 20, after hydrolysis by the addition of water, is carefully treated with 10 g of sodium hydrogen carbonate and then reacted with 2.5 g of di-tert.-butyl dicarbonate analogously to Example 2 to form N,N'-di-BOC-3-aminoxy-2-chloropropylamine. The pure substance is isolated in the form of colourless crystals having a melting -point of 111-113.
', .:
Example 21: 0.4 ml of 2-oxopropionic acid ethyl ester is added to a solution of 450 mg (2.5 mmol) of 3-aminoxy-2-fluoropropylamine dihydro-chloride (see Example 5) in 5 ml of ethanol and 2.5 ml of lN sodium hydroxide solution and the mi~ture is stirred at room temperature for - ;
16 hours. The reaction mixture is concentrated by evaporation and the residue is partitioned between water and ether. The lower phase is concentrated and lyophilised, yielding 3-(1-ethoxycarbonylethylidene- -aminoxy)-2-fluoropropylamine hydrochloride in the form of a white powder containing 1 mol of sodium chloride, Rf value 0.30 (silica gel/methylene chloride:methanol:concentrated ammonia 300:50:1).
~ i ' ,. -,, Example 21a: 450 mg (2.5 mmol) of 3-aminoxy-2-fluoropropylamine di-hydrochloride are reacted in a manner analogous to that described in Example 21 with 0.5 ml of 2-oxopropionic acid methyl ester, yielding 3-(1-methoxycarbonylethylideneaminoxy)-2-fluoropropylamine hydrochloride ~ -in the form of a white powder, m.p. 150 (decomposition).
:~ , ` ~: .,-Example 22: 3-aminoxy-2-fluoropropylamine (see Example 5) is reacted with 2-oxopropionic acit i,n ajmannerjanalogous to that described in Example 3, yielding 3-(1-carboxyethylideneaminoxy)-2-fluoropropylamine.
.
~: :
: ..:; -....,,.,~.::
-Example 23: 3-aminoxy-2-fluoropropylamine (see Example 5) is reacted with methoxyacetone in a manner analogous to that described in Example 21, yielding 3-(l-methoxymethylethylideneaminoxy)-2-fluoropropylamine, m.p. 70, Rf value 0.33 (silica gel/methylene chloride:methanol:concentrated ammonia 300:50:1).
Example 24: 3-aminoxy-2-fluoropropylamine (see Example 5) is reacted with acrolein in a manner analogous to that described in Example 3, yielding 3-(prop-2-en-1-ylideneaminoxy)-2-fluoropropylamine, Rf value 0.35 (silica gel!methylene chloride:methanol:concentrated ammonia 300:50:1).
Example 24a: 3-aminoxy-2-hydroxypropylamine dihydrochloride is reacted ~ ;
with acrolein in a manner analogous to that described in Example 21, --~ -yielding 3-(2-propenylideneaminoxy)-2-hydroxypropylamine hydrochloride, .. . ..
Rf value 0.23 (silica gel/methylene chloride:methanol:concentrated ammonia 40:10:1).
ExamPle 25: 3-aminoxy-2-fluoropropylamine (see Example 5) is reacted with methyl vinyl ketone in a manner analogous to that described in ;
Example 3, yielding 3-(1-methylprop-2-en-1-ylideneaminoxy)-2-fluoro-propylamine, Rf value 0.35 (silica gel/methylene chloride:methanol:concentrated ammonia 300:50:1).
Example 26: 0.5 ml (5.5 mmol) of ethyl methyl ketone is added to a solution of 900 mg (5.0 mmol) of 3-aminoxy-2-fluoropropylamine dihydro-chloride (see Example 5) in 10 ml of ethanol and 5.0 ml of lN sodium -hydroxide solution and the mixture is stirred at room temperature for 16 hours. The reaction mix,turle islcqncentrated by evaporation and the residue is partitioned between water and ether. The lower phase is concentrated and lyophilised, yielding 3-(1-methyl-1-propylideneamin-oxy)-2-fluoropropylamine hydrochloride in the form of a white powder containing 1 mol of sodium chloride, Rf value 0.31 (silica gel/methylene chloride:-ethanol:concentrated a _onia 300:50:1).
".
. ~
Example 26a: A solution of 1.8 g (10 mmol) of 3-aminoxy-2-hydroxypropyl-amine dihydrochloride in 20 ml of ethanol is reacted in a manner analogous to that described in Example 21 with 10 ml of lN NaOH and 0.99 ml (11 mmol) of ethyl methyl ketone, yielding 3-(1-methyl-1-propylideneaminoxy)-2-hydroxypropylamine hydrochloride in the form of a white powder containing 1 mol of sodium chloride, Rf value 0.29 (silica gel/methylene chloride:methanol:concentrated ammonia 150:50:1).
... -.
Example 27: A solution of 850 mg of N-BOC-N-propargyl-3-(1-ethoxy-ethylideneaminoxy)-2-hydroxypropylamine in 5 ml of dioxane and 5 ml of 2N
hydrochloric acid is boiled under reflux for 30 minutes and then concentrated by evaporation. The residue is dissolved in a small amount -- -~
of water, filtered until clear and free~e-dried, yielding N-propargyl-3-aminoxy-2-hydroxypropylamine dihydrochloride in the form of a brown amorphous powder, Rf value = 0.3 (silica gel/methylene ;~
chloride:methanol:concentrated ammonia 150:50:1). - ;
The starting material is prepared as follows:
8.5 ml (133.3 mmol) of propargylamine are added to a solution of 2.12 g (13.3 mmol) of 0-2,3-epoxypropyl-acetohydroxamic acid ethyl ester in 10.5 ml of isopropanol and the mixture is left to stand at room tempera- ;~
ture for 3 days. The reaction mixture is concentrated by evaporation and ~ ~then taken up in 30 ml of methylene chloride. While cooling with ice, a ;
solution of 16.6 g of di-tert.-butyl dicarbonate in 30 ml of methylene ;~
chloride is then added dropwise thereto and the mixture is left to react at room temperature for 24 hours. Uorking up in a manner analogous to that described in Example 2 and chromatography on silica gel in methylene chloride/ethyl acetate (8l5:15) yield~ N-~OC-N-propargyl-3-(1-ethoxyethyl-ideneaminoxy)-2-hydroxypropyIamine in the form of a yellow oil, Rf value - -= 0.38 (silica gel/methylene chloride:ethyl acetate 85:15).
Example 27a: A solution of 1.15 g (5 mmol) of N-methallyl-3-(1-ethoxy-ethylideneaminoxy)-2-hydroxypropylamine in 9 ml of dioxane and 9 ml of 2N
~; hydrochloric acid is boiled under reflux for 30 minutes, filtered and concentrated to dryness by evaporation. The residue is crystallised from : ~ - .
~ .
2003iO9~
ethanol/ether, yielding N-methallyl-3-aminoxy-2-hydroxypropylamine di-hydrochloride in the form of a white hygroscopic powder, Rf value = 0.33 (silica gel/methylene chloride:methanol:concentrated ammonia 40:10:1).
The starting material is prepared as follows:
8.8 g of 2-methallylamine hydrochloride and 74.4 ml of 1.lN sodium methanolate solution are added to a solution of 2.82 g (17.5 mmol) of 0-2,3-epoxypropyl-acetohydroxamic acid ethyl ester in 20 ml of methanol and the mixture is boiled under reflux for 5 hours. The reaction mixture f is filtered and concentrated by evaporation. The residue is chromato-graphed over 250 g of silica gel with methylene ~`
chloride:methanol:concentrated ammonia 150:50:1, yielding N-methallyl-3-(l-ethoxyethylideneaminoxy)-2-hydroxypropylamine, Rf value 0.45 (silica gel/methylene chloride:methanol:concentrated ammonia 300:50:1).
Example 27b: A solution of 2.75 g (12.5 mmol) of N-allyl-3-(1-ethoxy-ethylideneaminoxy)-2-hydroxypropylamine in 30 ml of 2N hydrochloric acid is boiled under reflux for 40 minutes, filtered and concentrated to -~
dryness by evaporation, yielding N-allyl-3-aminoxy-2-hydroxypropylamine dihydrochloride in the form of a yellow oil, Rf value = 0.23 (silica `~
gel~methylene chloride:methanol:concentrated ammonia 40:10:1).
Th`e starting material is prepared as follows:
6.1 ml (81.8 mmol) of allylamine are added to a solution of 2.82 g ~
(17.5 mmol) of 0-2,3-epoxypropyl-acetohydroxamic acid ethyl ester in 35 ~ -ml of methanol and the mixture is stirred at 50 for 16 hours. The -reactjion mixture is concentrated by~evaporation and the residue is chromatographed over 250 g of silica gel with methylene chIoride:methanol:concentrated ammonia 150:50:1, yielding N-allyl-3-(1-ethoxyethylideneaminoxy)-2-hydroxypropylamine, Rf value 0.60 (silica ~-~
gel/methylene chloride:methanol:concentrated ammonia 150:50:1).
,~ .. :
~: :
- 200:}091 Example 28: 3 ml of lN NaOH and 0.54 g (3 mmol) of glucose are added to a solution of 543 mg (3 mmol) of 3-aminoxy-2-fluoropropylamine dihydro-chloride in 8 ml of ethanol and the mixture is left to stand at room temperature for 16 hours and then concentrated to dryness by evaporation.
The residue is taken up in 10 ml of water, filtered and lyophilised, yielding 0-(3-amino-2-fluoropropyl)-glucose oxime hydrochloride, Rf value 0.16 (silica gel/n-butanol:pyridine:concentrated ammonia:water 200:120:30:150).
Example 29: A solution of 212 mg (1 mmol) of 3-(1-ethoxyethylidene-aminoxy)-2S-hydroxypropylamine hydrochloride in 3 ml of lN hydrochloric acid is boiled under reflux for 1 hour and then concentrated by evapora~
tion. The residue is crystallised from ethanol/ether, yielding 3-aminoxy-2S-hydroxypropylamine dihydrochloride, m.p. 150-155, [~]D +3 0 (c - 1.009 in water).
The starting compounds are prepared as follows:
4.4 ml of 5N sodium hydroxide solution are added dropwise at 55 to a solution of 2.25 g (22 mmol) of acetohydroxamic acid ethyl ester and 5.0 g (22 mmol~ of 2R-p-toluenesulfonic acid glycidyl ester (- 3-tosyl-oxy-1,2R-epoxypropane) in 50 ml of acetone and the mixture is boiled under reflux for 1 hour. After cooling, the mixture is filtered and the filtrate is concentrated by evaporation in vacuo. The residue is taken up ~ -in 50 ml of ether. This solution is washed twice with 10 ml of water, - ;
dried over magnesium sulfate and again concentrated by evaporation. The ,-resulting oily 0-2S,3-epoxypropylacetohydroxamic acid ethyl ester is ;~
distilled in vacuo, b.p. 85-90/18 mbar.
, -100 ml of concentrated ammonia are added to 3.2 g (20 mmol) of O-2S,3-epoxypropylacetohydroxamic acid ethyl ester and the mixture is stirred in a closéd vessel at room temperature for 16 hours and then concentrated to dryness by evaporation. The residue is again taken up in 50 ml of water and adjusted to pH 5.5 with lN hydrochloric acid. The solution is ' ~
:
:--200309~.
concentrated by evaporation and the crystalline residue of 3-(1-ethoxy-ethylideneaminoxy)-2S-hydroxypropylamine hydrochloride is recrystallised -from ethanol/ethyl acetate, m.p. 103-106. -Example 30: Analogously to Example 29, starting from acetohydroxamic acid ethyl ester and 25-p-toluenesulfonic acid glycidyl ether (- 3-tosyloxy-1,2S-epoxypropane), 3-aminoxy-2R-hydroxypropylamine dihydrochloride is obtained, m.p. 157-158; []D~ ~3 0 (c = 1.039 in water).
, .
Example 31: A solution of 1.2 g (4.1 mmol) of N-[3-(1-ethoxyethylidene~
aminoxy)-2-hydroxypropyl]-N-BOC-hydroxylamine in 10 ml of dioxane and -5 ml of 2N HCl is boiled under reflux for 1 hour and then concentrated to - ~
dryness by evaporation, yielding N-~3-aminoxy-2-hydroxypropyl)-hydroxyl- ~ ;
amine dihydrochloride, Rf value 0.05 (silica gel/methylene ;~
chloride:methanol:concentrated ammonia 40:10:1).
The starting materiai iF prepared as follows:
A solution of 4.8 g (30 mmol) of 0-(2,3-epoxypropyl)-acetohydroxamic acid ethyl ester in 40 ml of methanol is added to a mixture of 10.4 g (0.15 mol) of hydroxylamine hydrochloride and S.9 g of sodium hydroxide solution in 40 ml of methanol and the mixture is stirred at room tempera- ;~
ture for 24 hours. The reaction mixture is concentrated by evaporation, taken up in 25 ml each of water and THF and reacted with 8.0 g of di-tert.-butyl-dicarbonate (Fluka) in 40 ml of THF. Working up and purifica-tion by chromatography over 250 g of silica gel with hexane:ethyl acetate 1:1 yields N-[3-(1-ethoxyethylideneaminoxy)-2-hydroxypropyl]-N-BOC-hydroxylamine in the form of a pale yellow oil, Rf value 0.05 (silica gelihexane:ethyl;acetate l:l) ExamDle 32: 2.54 g (11.53 mmol) of 0-[3-(2-hydroxyethylamino)-2-hydroxypropyl]-acetohydroxamic acid ethyl ester in 50 ml of 2N hydro-chloric acid are boiled under reflux, with stirring, for 3 hours. After cooling, the reaction mixture is concentrated to dryness by evaporation -under a water-jet vacuum, yielding 0-[3-(2-hydroxyethylamino)-2-hydroxy-,.~
~. :,: . . :.
:, : :, :-: ~:~.
- , . :;.
'~.'. ;'.~"'.'.,'"
- -: ~ - -- ~00:~09~ -,: ,-, propyl]-hydroxylamine dihydrochloride in the form of a pale yellow oil, -Rf value 0.43 (silica gel/methylene chloride:methanol:concentrated ammonia 5:3:1).
" ~
The starting material is prepared as follows:
A solution of 6.4 g (40 mmol) of 0-(2,3-epoxypropyl)-acetohydroxamic acid ~
ethyl ester and 8 ml of ethanolamine in 80 ml of isopropanol is stirred - -at 60 for 18 hours and then concentrated to dryness by evaporation. The resulting residue is chromatographed over 250 g of silica gel UsiDg the system methylene chloride:methanol:concentrated ammonia 300:50:1. The fractions having an Rf value of 0.1 (in the same system) are combined and concentrated by evaporation. The yellow oil that remains is o-[3-(2-hydroxyethylamino)-2-hydroxypropyl]-acetohydroxamic acid ethyl ester.
Example 33: A mixture of 6.5 g (34 mmol) of 0-(3-methylamino-2-hydroxy-propyl)-acetohydroxamic acid ethyl ester in 150 ml of 2N hydrochloric acid is boiled under reflux for 4 hours and then concentrated to dryness -by evaporation. The wax-like residue of N-(3-aminoxy-2-hydroxypropyl)- -methylamine dihydrochloride is taken up in a small amount of water, ' converted into the free base by filtration over 150 ml of Dowex lx4 ion ;
exchanger resin (in basic form) and crystallised in oxalate salt form, m.p. 130-133 (from methanol), Rf value 0.43 (silica gel/methylene chloride:methanol:concentrated ammonia 40:10:1).
The starting material is prepared as follows:
A solution of 8.0 g (50 mmol) of 0-(2,3-epoxypropyl)-acetohydroxamic acid ethyl ester and 50 ml of a 33 % ethanolic methylamine solution in 100 ml of isopropanol is stirred at 85 for 4 hours and then concentrated to I dryness by evaporation. The resulting residue is chromatographed over 250 g of silica gel with ethyl acetate. The fractions having an Rf value of 0.21 (silica gel/methylene chloride:methanol:concentrated ammonia 150:50:1) are combined and concentrated by evaporation. The yellow oil that remains is 0-(3-methylamino-2-hydroxypropyl)-acetohydroxamic acid ethyl ester.
200~0~
- 44 - ~
, .
Example 34: A mixture of 0.8 g of bis-1,7-ethoxyethylideneaminoxY~4~
aza-2,6-dihydroxyheptane in 20 ml of 2N hydrochloric acid is boiled under reflux for 0.5 hour and then concentrated to dryness by evaporation. The wax-like hygroscopic residue of bis-1,7-aminoxy-4-aza-2,6-dihydroxy-heptane trihydrochloride is crystallised from methanol/ether, Rf value 0.44 (silica gel/methylene chloride:methanol:concentrated ammonia 5:3:1).
The starting material is prepared as follows:
A solution of 6.4 g (40 mmol) of 0-(2,3-epoxypropyl)-acetohydroxamic acid ethyl ester and 7.04 g of 0-(3-amino-2-hydroxypropyl)-acetohydroxamic acid ethyl ester in 100 ml of isopropanol is stirred at 70 for 3.5 hours and then concentrated to dryness by evaporation. The resulting residue is chromatographed over 700 g of silica gel with ethyl acetate. The fractions having an Rf value of 0.30 (silica gel/ethyl acetate) are combined and concentrated by evaporation. The yellow oil that remains is bis-1,7-ethoxyethylideneaminoxy-4-aza-2,6-dihydroxyheptane.
Example 35: 0.26 ml of cyclopentanone is added to a solution of 0.54 g (3 mmol) of 3-aminoxy-2-fluoropropylamine dihydrochloride (see Example 5) in ô ml of ethanol and 3 ml of lN sodium hydroxide solution and the mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated by evaporation and the residue is partitioned between 3 ml ;
of lN sodium hydroxide solution and 10 ml of ether. The ether phase is washed with saturated sodium chloride solution, dried over sodium sulfate -and concentrated to dryness by evaporation. The oily residue is taken up in lO ml of ethyl acetate, and 2.5 ml of a lN solution of HCl gas in ethyl acetatq are added. Thel3-(cyclopentylideneaminoxy)-2-fluoropropyl-amine hydrochloride that crystallises out is filtered with suction and dried, m.p. 109-112.
~ '; ' ,, , , , .~ ~ :`~''' ' 200309~ ' Example 36: 5 ml of 6N methanolic HCl are added to a solution of 2.43 g of N-BOC-3-pyridoxalaminoxy-2-fluoropropylamine in 10 ml of methanol and left to stand with the exclusion of moisture. The 3-pyridoxalaminoxy-2-fluoropropylamine dihydrochloride that crystallises out is filtered with suction, washed with ethyl acetate and dried, m.p. 210-213.
The starting material is prepared as follows:
814 mg (4 mmol) of pyridoxal hydrochloride and 8 ml of lN sodium hydroxide solution are added to a solution of 724 mg (4 mmol) of 3-aminoxy-2-fluoropropylamine dihydrochloride (see Example 5) in 13 ml of ethanol and the mixture is stirred at room temperature for 16 hours. A - - -;
further 4 ml of lN sodium hydroxide solution and a solution of 1.08 g of di-tert.-butyl dicarbonate in 20 ml of THF are added to the reaction mixture. After conventional working up and purification by chromato-graphy. the reaction mixture yields N-BOC-3-pyridoxalaminoxy-2-fluoro-propylamine in the form of a yellow foam, Rf value 0.25 (silica gel/methylene chloride:methanol 10:1).
Example 37: A solution of l.ô g (10 mmGl) of 3-aminoxy-2-hydroxypropyl-amine dihydrochloride in 20 ml of ethanol is reacted with 10 ml of lN --NaOH and 1.02 ml (11 mmol) of methoxyacetone. The reaction mixture is concentrated by evaporation and the residue is partitioned between water and ether. The lower phase is concentrated and lyophilised, yielding 3-(1-methyl-2-methoxyethylideneaminoxy)-2-hydroxypropylamine hydro-chloride in the form of a white powder containing 1 mol of sodium chloride, Rf value 0.2 (silica gel/methylene chloride:methanol:concentrated ammonia 150:50:1).
Example 30: A solution of l.ô g (10 mmol) of 3-aminoxy-2-hydroxypropyl- - -amine dihydrochloride in 20 ml of ethanol is reacted with 10 ml of lN
NaOH and 0.72 ml (10 mmol) of pyruvic acid methyl ester. The reaction mixture is concentrated by evaporation and the residue is partitioned between water and ether. The lower phase is concentrated and lyophilised, yielding 3-(1-methoxycarbonylethylideneaminoxy)-2-hydroxypropylamine ' ~ ~ '''~"' '''' 200:~09~
hydrochloride in the form of a white powder containing 1 mol of sodium chloride; m.p. 136-140, Rf value 0.38 (silica gel/methylene chloride:methanol:concentrated ammonia 40:10:1).
Example 39: 4 ml of lN NaOH and 0.72 g (4 mmol) of glucose are added to a solution of 0.72 g (4 mmol) of 3-aminoxy-2-hydroxypropylamine dihydro-chloride in 10 ml of ethanol and the mixture is left to stand at room temperature for 16 hours and then concentrated to dryness by evaporation.
The residue is taken up in 10 ml of water, filtered and lyophilised, yielding 0-(3-amino-2-hydroxypropyl)-glucose oxime hydrochloride, Rf value 0.05 (silica gel/n-butanol:pyridine:concentrated ammonia:water 200:120:30:150).
Example 40: 5 ml of 5.5N HCl/EtOH are added to a solution of 750 mg of 3-(2~butylaminoxy)-2-hydroxy-N-BOC-propylamine in 10 ml of ethanol and the mixture is left to stand at room temperature for 16 hours and then concentrated to dryness by evaporation, yielding 3-(2-butylaminoxy)-2-hydroxypropylamine dihydrochloride in the form of a light-yellow viscous oil, Rf value 0.14 (silica gel/methylene chloride:methanol:concentrated ammonia 40:10:1).
Th- starting material is prepared as follows:
2.5 ml of glacial acetic acid and 0.27 g (3.9 mmol) of sodium cyanoboro-hydride are added to a solution of 1.05 g (3.9 mmol) of 3-(1-methyl- ~-propylideneaminoxy)-2-hydroxy-N-BOC-propylamine in 25 ml of THF and the mixture is stirred at room temperature for 48 hours. After the addition of 4 g of sodium hydrogen carbonate, the reaction mixture is concentrated to dryness by evaporation and the re,sidue is partitioned bstween water and ether. The organic phase is dried over magnesium sulfate, con- -centrated by evaporation and chromatographed over 75 g of silica gel with hexane:ethyl acetate 1:1, yielding 3-(2-butylaminoxy)-2-hydroxy-N-BOC- ;
propylamine in the form of a pale yellow oil, Rf value 0.10 (silica ;
gel/hexane/ethyl acetate 1:1). ;~
~ " .
'~: ;, ~ : : .
~ : . " ;'':' 2003~
Example 41: 4 ml of lN NaOH and 0.53 g (4 mmol) of indanone are added to a solution of 0.72 g (4 mmol) of 3-aminoxy-2-hydroxypropylamine di-hydrochloride in 10 ml of ethanol and the mixture is stirred at 50 for 16 hours and then concentrated to dryness by evaporation. The residue is dissolved in 10 ml of water and, after the addition of 4 ml of lN NaOH, extracted with ether. The ether phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evapora-tion. The resulting 0-(3-amino-2-hydroxypropyl)-indanone oxime is crystallised from ethertpetroleum ether, m.p. 88-92, Rf value 0.10 (silica gel/methylene chloride:methanol:concentrated ammonia 300:50:1). -Example 42: 3 ml of lN NaOH and 471 mg (3 mmol) of 4-cyanoindanone are added to a solution of 543 mg (3 mmol) of 3-aminoxy-2-fluoropropylamine dihydrochloride in 8 ml of ethanol and the mixture is stirred at 50 for 16 hours and then concentrated to dryness by evaporation. The residue is dissolved in 10 ml of water and, after the addition of 3 ml of lN NaOH, extracted with ether. The ether phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evapora-tion. The resulting 0-(3-amino-2-fluoropropyl)-4-cyanoindanone oxime is crystallised from ether/petroleum ether, m.p. 90-92, Rf value 0.46 (silica gel/methylene chloride:methanol:concentrated ammonia 300:50:1).
'~
Example 43: A solution of 720 mg (4 mmol) of 3-aminoxy-2-hydroxypropyl-amine dihydrochloride in 10 ml of ethanol is reacted with 4 ml of lN
NaOH and 0.22 ml (4.4 mmol) of hydroxyacetone. The reaction mixture is concentrated by evaporation and the residue is partitioned between water and ether. The lower phase is concentrated and lyophilised, yielding 3-(1-hydroxymethylethylideneaminoxy)-2-hydroxypropylamine hydrochloride in the~form of a brown oil cqntai~ing 1 mol of sodium chloride, Rf value -~
0.10 (silica gel/methylene chloride:methanol:concentrated ammonia ~ -40:10:1).
Example 44: A solution of 1.22 g (3.2 mmol) of 3-(1-ethoxyethylidene- - -~
: .~. . . ~
~ aminoxy)-2-hydroxy-N-BOC-N-benzyloxypropylamine in 30 ml of lN HCl is ; - boiled under reflux for 1 hour and concentrated to dryness by evapora-, ~ . -, . .. - .
tion. The residue is crystallised from ethyl acetate, washed with ethyl acetate/ether and dried, yielding 3-aminoxy-2-hydroxy-N-benzyloxypropyl-amine dihydrochloride, m.p. 140-143.
The starting material is prepared as follows:
A solution of 1.6 g (10 mmol) of 0-(2,3-epoxypropyl)-acetohydroxamic acid ethyl ester in 16 ml of methanol is added dropwise to a solution of 16 g (0.1 mol) of O-benzylhydroxylamine hydrochloride in 70 ml of methanol and 90 ml of 1.2N sodium methanolate and the mixture is stirred at room temperature for 24 hours. The reaction mixture is concentrated by ;
evaporation, taken up in 100 ml of THF and reacted with 28.8 g of di-tert.-butyl dicarbonate (Fluka) in 100 ml of THF. Conventional working up -and purification by chromatography over 700 g of silica gel with hexane:ethyl acetate 2:1 yields 3-(1-ethoxyethylideneaminoxy)-2-hydroxy-N-BOC-N-benzyloxypropylamine in the form of a pale yellow oil, Rf value 0.41 (silica gellhexane:ethyl acetate 2:1).
Example 45: 530 mg (2 mmol) of pyridoxal phosphate are added to a solu-tion of 362 mg (2 mmol) of 3-aminoxy-2-fluoropropylamine dihydrochloride (see Example 5) in 20 ml of 0.1N NaOH and the mixture is stirred at room temperature for 30 minutes, then filtered and lyophilised. The resulting hygroscopic lyophilisate is 3-amino-2-fluoropropoxyimino-pyridoxal phos-phate hydrochloride containing 1 mol of sodium chloride, Rf value 0.13 (silica`gel/methyl ethyl ketone:ethanol:water:concentrated ammonia 15:5:5:5; pyridoxal phosphate Rf value 0.26).
:: '. . ~:, .: - .
Example 46: 265 mg (1 mmol) of pyridoxal phosphate are added to a ~`solution of ~ôO mg (l mmol) of 3-!aminoxy-2-hydroxypropylamine dihydro- ~ ~;
chloride in 10 ml of O.lN NaOH and the mixture is stirred at room -~ i temperature for 30 minutes, then filtered and lyophilised. The resulting 5 hygroscop1c lyophilisate is 3-amino-2-hydroxypropoxyimino-pyridoxal ;~
~phosphate hydrochloride containing 1 mol of sodium chloride, Rf value ;
0.10 (silica~gel/methyl ethyl ketone:ethanol:water:concentrated ammonia ~ `
15:5:5:5; pyrldoxal phosphate Rf value 0.26).
: ::: ;,:.
;. :-. .:
:.~
200309~
Example 47: A solution of 4.21 g (13.7 mmol) of 3-(1-ethoxyethylidene-aminoxy)-2-hydroxy-N-goc-N-methoxypropylamine in 130 ml of lN HCl is boiled under reflux for 1 hour and then concentrated to dryness by evaporation. The residue is crystallised from ethanol, washed with ethyl acetate/ether and dried, yielding 3-aminoxy-2-hydroxy-N-methoxypropyl~
amine dihydrochloride, m.p. 142-152.
The starting material is prepared as follows:
A solution of 3.2 g (20 mmol) of 0-(2,3-epoxypropyl)-acetohydroxamic acid ethyl ester in 30 ml of methanol is added dropwise to a solution of 25 g (0.3 mol) of O-methylhydroxylamine hydrochloride in 100 ml of methanol and 300 ml of lN sodium methanolate and the mixture is stirred at room temperature for 24 hours. The reaction mixture is concentrated by evaporation, taken up in 150 ml each of water and THF and reacted with 50 g of di-tert.-butyl dicarbonate in 150 ml of THF. Working up and purification by chromatography over 750 g of silica gel with hexane:ethyl acetate 3:1 yields 3-(1-ethoxyethylideneaminoxy)-2-hydroxy-N-BOC-N-methoxypropylamine in the form of a pale yellow oil, Rf value 0.2 (silica gel/hexane:ethyl acetate 3:1).
Exam~le 48: A solution of 5.0 g (24.7 mmol) of 3-(1-ethoxyethylidene-aminoxy)-1-azidoisopropanol in 50 ml of 2N HCl is boiled under reflux for 1 hour and then concentrated to dryness by evaporation, yielding 3-aminoxy-1-azidoisopropanol hydrochloride in the form of a yellowish-brown oil, Rf value 0.35 (silica gel/methylene chloride:methanol 10:1), IR (methylene chloride): 2100 cm 1. ~ ~
:~:, ~; - :"
The~starting material is Rrepared,as f!ollows:
3.25 g (50 mmol) of sodium azide and 1.35 g (25 mmol) of ammonium chloride are added to a solution of 4.0 g (25 mmol) of 0-~2,3-epoxy-propyl)-acetohydroxamic acid ethyl ester in -50 ml of ethylene glycol monomethyl ether and 2.5 ml of water and the mixture is stirred at 130 for 12 hours. After cooling, the reaction mixture is diluted with 500 ml of ethyl acetate, filtered and concentrated by evaporation. The residue ;: '.:,~`.
' " '.'.
' ',`~' ,'' 200309~
, .
is taken up in 300 ml of ether, washed with water, dried over magnesium sulfate and freed of solvent, yielding 3-(1-ethoxyethylideneaminoxy)-1-azidoisopropanol in the form of a yellow oil, Rf value 0.05 (silica gel/hexane:ethyl acetate 1:1); IR (methylene chloride): 2100, 3200-3650 cm Example 49: A solution of 0.84 g (5 mmol) of 3-aminoxy-1-azidoiso-propanol hydrochloride in 5 ml of ethanol and 5 ml of lN alcoholic HCl is hydrogenated with hydrogen in the presence of 0.1 g of 5 % Pd/C. When the reduction is complete and the catalyst has been separated off, the filtrate is concentrated by evaporation and the residue is crystallised from alcohol/ether, yielding 3-aminoxy-2-hydroxypropylamine dihydro-chloride, m.p. 153-156.
. ~
Example 50: 180 mg (1.15 mmol) of quinoline-4-aldehyde are added to ~ --200 mg (1.1 mmol) of 3-aminoxy-2-fluoropropylamine dihydrochloride in 1.1 ml of lN NaOH and 4 ml of ethanol and the mixture is then stirred at 50 for 22 hours. The solution is concentrated and the residue is -chromatographed with water on Opti-Up C-12. The fractions containing the -~ ;~
product are combined and concentrated to dryness. The residue is triturated with ether and left to stand overnight in a refrigerator, and the precipitate is filtered off with suction, yielding 4-(3-amino-2-fluoropropoxyiminomethyl)-quinoline in the form of a colourless powder.
FAB-MS: (M+H) = 248. IR (KBr) inter alia: 1625, 15g8, 1570 cm 1.
', '''.:~''' ~
Example 51: 0.64 ml of lN NaOH followed by 100 mg of difluoromethyl phenyl ketone (see EP 298 478) are added to 114.7 mg (0.64 mmol) of 3-aminoxy-2-hydroxypropylamine dihydrochloride in 1 ml of ethanol. After stirring for 20 hours at 50, a further 28.7 mg of 3-aminoxy-2-hydroxy- ~
propylamine dihydrochloride are added, followed by 0.16 ml of lN NaOH and ~ ;
1 ml of ethanol. The reaction mixture is heated at 80 for a further 2.5 hours, then concentrated in a rotary evaporator, and the residue is chromatographed on Opti-Up C-12-silica gel (eluant: water). The fractions containing the product 3-(2,2-difluoro-1-phenylethylideneaminoxy)-2-,:~ ..:.
~: . ' .
. . .
hydroxypropylamine hydrochloride are concentrated and dried under a high vacuum. FAB-MS: (M+H) = 245. IR (KBr) inter alia: 1604, 1526, 1488, 1457 cm 1.
Example 52: In a manner analogous to that described in Example 51, starting from 3-aminoxy-2-fluoropropylamine dihydrochloride and difluoro-methyl phenyl ketone there is obtained 3-(2,2-difluoro-1-phenylethyl-ideneaminoxy)-2-fluoropropylamine hydrochloride.
FAB-MS: (M+H) = 247. IR ~Nujol) inter alia: 1600, 1496, 1446, 1369 cm Example 53: 3-aminoxy-2-fluoropropylamine dihydrochloride can also be prepared as follows:
A mixture of 0.25 g (0.68 mmol) of N-[2-fluoro-3-phthalimidopropoxy]- ~-phthalimide, 2 ml of water and 2 ml of concentrated hydrochloric acid is heated under reflux for 2 hours, then cooled to 0 and filtered with suction, and the filtration residue is washed with a small amount of water and the filtrate is concentrated by evaporation in vacuo. The crystalline residue is concentrated to dryness by evaporation twice using ~ - -10 ml of ethanol each time and then suspended in 10 ml of ethanol. The - suspension is filtered and the crystals are washed with ether and dried at 70 under a high vacuum. The resulting title compound melts at 206-207.
The starting material is prepared as follows:
a) N-(3-hydroxY-2-fluoroProPYl)-phthalimide A mixture of 2.5 g (0.0151 mol) of 3-bromo-2-fluoropropan-1-ol (95 %) [Foster et al., J. Med. Chem. 24, 1399 (1981) and I. Chehidi et al., Tetrahedron Lettersj, 30~! 3167 (ll9~9)] and 3.243 g (0.0175 mol) : ;-of phthalimide-potassium in 10 ml of dimethylformamide is stirred at 100 -"
for 6 hours. The mixture is cooled to room temperature and filtered, the filtrate is concentrated by evaporation in vacuo and the oily residue ~ ~ "
is partitioned between water and methylene chloride. The organic phase is dried over sodium sulfate and then concentrated by evaporation and the residue is crystallised from ethyl acetate/hexane. The resulting title ~ ~;
compound melts at 97-99. ~ ~
~: :
200:~091 b) N-[2-fluoro-3-phthalimidopropoxy]-phthalimide 0.273 g (0.00157 mol) of azodicarboxylic acid diethyl ester is added, with stirring, to a solution of 0.335 g (0.0015 mol) of N-(3-hydroxy-2-fluoropropyl)-phthalimide, 0.245 g (0.0015 mol) of N-hydroxyphthalimide and 0.394 g (0.0015 mol) of triphenylphosphine in 5 ml of tetrahydro-furan. The mixture is stirred at room temperature for 2 hours and the resulting suspension is diluted with approximately 5 ml of tetrahydro-furan, cooled to 0 and filtered, and the crystals are washed with tetra- -~
hydrofuran. After drying under a high vacuum, the resulting ~itle com-pound melts at 134-185.
Example 54: Capsules containing 0.25 g of active ingredient, for example one of the compounds of Examples l to 53, can be prepared as follows: ~
~'., ~-: :-Composition (for 5000 capsules) active ingredient1250 g -talc 180 g wheat starch 120 g magnesium stearate 80 g lactose 20 g The pulverulent substances are forced through a sieve of 0.6 mm mesh size -and mixed together. 0.33 g portions of the mixture are introduced into gelatine capsules using a capsule-filling machine.
~.": '',"':'' ,' ., :' .
" :, , , ~:
: .
: .
Claims (23)
1. Pharmaceutical composition comprising a compound of the formula I
(I) wherein X is halogen, hydroxy, lower alkoxy, acyloxy, lower alkyl-sulfonyloxy or arylsulfonyloxy; each of R1 and R2, independently of the other, is hydrogen, lower alkyl, cycloalkyl, aryl-lower alkyl or hetaryl-lower alkyl, or R1 and R2 together are a radical wherein each of R4 and R5, independently of the other, is hydrogen, lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, lower alkoxy-lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl-lower alkyl, hetaryl-lower alkyl, aryl, hetaryl, carboxy or lower alkoxycarbonyl, or wherein R4 is polyhydroxy-lower alkyl and R5 is hydrogen or hydroxymethyl, or wherein R4 and R5 together are C2-C7alkylene or unsubstituted or substituted benzo-C4-C6alkylene; and R3 is hydrogen, unsubstituted or hydroxy- or halogen- and/or aminoxy-substituted lower alkyl, lower alkenyl, lower alkynyl or free or etherified hydroxy; or pharmaceutically acceptable salts thereof, for the therapeutic treatment of diseases of the human or animal body that respond to inhibition of ornithine decarboxylase.
(I) wherein X is halogen, hydroxy, lower alkoxy, acyloxy, lower alkyl-sulfonyloxy or arylsulfonyloxy; each of R1 and R2, independently of the other, is hydrogen, lower alkyl, cycloalkyl, aryl-lower alkyl or hetaryl-lower alkyl, or R1 and R2 together are a radical wherein each of R4 and R5, independently of the other, is hydrogen, lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, lower alkoxy-lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl-lower alkyl, hetaryl-lower alkyl, aryl, hetaryl, carboxy or lower alkoxycarbonyl, or wherein R4 is polyhydroxy-lower alkyl and R5 is hydrogen or hydroxymethyl, or wherein R4 and R5 together are C2-C7alkylene or unsubstituted or substituted benzo-C4-C6alkylene; and R3 is hydrogen, unsubstituted or hydroxy- or halogen- and/or aminoxy-substituted lower alkyl, lower alkenyl, lower alkynyl or free or etherified hydroxy; or pharmaceutically acceptable salts thereof, for the therapeutic treatment of diseases of the human or animal body that respond to inhibition of ornithine decarboxylase.
2. Pharmaceutical composition according to claim 1 comprising a compound of the formula I wherein X is halogen, hydroxy, lower alkoxy, lower alkylsulfonyloxy or phenylsulfonyloxy; each of R1 and R2, independently of the other, is hydrogen, lower alkyl, C3-C8cycloalkyl or phenyl-lower alkyl, or R1 and R2 together are a radical (I), wherein each of R4 and R5, independently of the other, is hydrogen, lower alkyl, halo-lower alkyl, C3-C8cycloalkyl, phenyl-lower alkyl or phenyl, or wherein R4 is 3-hydroxy-5-(hydroxymethyl or phosphonooxy-methyl)-2-methyl-4-pyridyl and R5 is hydrogen, or wherein R4 is 1,2,3,4-tetrahydroxybutyl or 1,2,3,4,5-pentahydroxypentyl and R5 is hydrogen or hydroxymethyl, or wherein R4 is quinolinyl, carboxy or lower alkoxycarbonyl and R5 is hydrogen or lower alkyl, or wherein R4 and R5 together are C2-C7alkylene or unsubstituted or cyano-substituted benzo-C4-C5-alkylene; and R3 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, benzyloxy or hydroxy; phenyl groups being unsubstituted or substituted by lower alkyl, halo-lower alkyl, halogen, hydroxy, lower alkoxy, lower alkanoyloxy and/or by nitro or pharma-ceutically acceptable salts thereof.
3. Pharmaceutical composition according to claim 1 comprising a compound of the formula I wherein X is fluorine, chlorine, hydroxy, lower alkyl-sulfonyloxy or phenylsulfonyloxy each of R1 and R2, independently of the other, is hydrogen, lower alkyl, C3-C7cycloalkyl or phenyl-lower alkyl, or R1 and R2 together are a radical wherein each of R4 and R5, independently of the other, is hydrogen, lower alkyl, halo-lower alkyl, C3-C7cycloalkyl, phenyl-lower alkyl or phenyl, or wherein R4 is quinolinyl, 3-hydroxy-5-(hydroxymethyl or phosphonooxymethyl)-2-methyl-4-pyridyl and R5 is hydrogen, or wherein R4 is carboxy or lower alkoxycarbonyl and R5 is lower alkyl, or wherein R4 and R5 together are -(CH2)4- or -(CH2)5- ; and R3 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl or hydroxy; phenyl groups being unsubstituted or substituted by lower alkyl, trifluoromethyl, halogen, hydroxy, lower alkoxy and/or by nitro; or pharmaceutically acceptable salts thereof.
4. Pharmaceutical composition according to claim 1 comprising a compound of the formula I wherein X is fluorine, chlorine, hydroxy or methyl-sulfonyloxy, R1 is hydrogen, R2 is hydrogen, C1-C4alkyl, benzyl or 2-hydroxybenzyl, or R1 and R2 together are C5-C6cycloalkylidene, C1-C4-alkylidene, benzylidene, 2-hydroxybenzylidene or 3-hydroxy-5-(hydroxy-methyl or phosphonooxymethyl)-2-methyl-4-pyridylmethylidene, and R3 is hydrogen, C1-C4alkyl, C2-C4alkynyl or hydroxy; or pharmaceutically acceptable salts thereof.
5. Pharmaceutical composition according to claim 1 comprising 3-aminoxy-2-hydroxypropylamine or pharmaceutically acceptable salts thereof.
6. Compounds of formula I
(I), wherein X is halogen, hydroxy, lower alkoxy, acyloxy, lower alkyl-sulfonyloxy or arylsulfonyloxy; each of R1 and R2, independently of the other, is hydrogen, lower alkyl, cycloalkyl, aryl-lower alkyl or hetaryl-lower alkyl, or R1 and R2 together are a radical wherein each of R4 and R5, independently of the other, is hydrogen, lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, lower alkoxy-lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl-lower alkyl, hetaryl-lower alkyl, aryl, hetaryl, carboxy or lower alkoxycarbonyl, or wherein R4 is polyhydroxy-lower alkyl and R5 is hydrogen or hydroxy-methyl, or wherein R4 and R5 together are C2-C7alkylene or unsub-stituted or substituted benzo-C4-C6alkylene; and R3 is hydrogen, un-substituted or hydroxy- or halogen- and/or aminoxy-substituted lower alkyl, lower alkenyl, lower alkynyl or free or etherified hydroxy; with the proviso that when X is hydroxy and R1 and R2 together are a radical ,- R3 is hydrogen; with the proviso that when X is hydroxy and R3 is hydrogen, the radicals R1 and R2 cannot together be 1,1-dimethyl-methylidene, 1-n-butylidene or nitro-(furanyl or imidazolyl)-methylidene;
with the proviso that when X is hydroxy and R3 is hydrogen, hydroxy or lower alkyl, the radicals R1 and R2 cannot both be hydrogen; and with the proviso that when X is hydroxy and R1 and R2 are each independently hydrogen, lower alkyl, cycloalkyl, aryl-lower alkyl or hetaryl-lower alkyl but are not both hydrogen, R3 is hydrogen, methyl, ethyl or n-propyl; and salts thereof.
(I), wherein X is halogen, hydroxy, lower alkoxy, acyloxy, lower alkyl-sulfonyloxy or arylsulfonyloxy; each of R1 and R2, independently of the other, is hydrogen, lower alkyl, cycloalkyl, aryl-lower alkyl or hetaryl-lower alkyl, or R1 and R2 together are a radical wherein each of R4 and R5, independently of the other, is hydrogen, lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, lower alkoxy-lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl-lower alkyl, hetaryl-lower alkyl, aryl, hetaryl, carboxy or lower alkoxycarbonyl, or wherein R4 is polyhydroxy-lower alkyl and R5 is hydrogen or hydroxy-methyl, or wherein R4 and R5 together are C2-C7alkylene or unsub-stituted or substituted benzo-C4-C6alkylene; and R3 is hydrogen, un-substituted or hydroxy- or halogen- and/or aminoxy-substituted lower alkyl, lower alkenyl, lower alkynyl or free or etherified hydroxy; with the proviso that when X is hydroxy and R1 and R2 together are a radical ,- R3 is hydrogen; with the proviso that when X is hydroxy and R3 is hydrogen, the radicals R1 and R2 cannot together be 1,1-dimethyl-methylidene, 1-n-butylidene or nitro-(furanyl or imidazolyl)-methylidene;
with the proviso that when X is hydroxy and R3 is hydrogen, hydroxy or lower alkyl, the radicals R1 and R2 cannot both be hydrogen; and with the proviso that when X is hydroxy and R1 and R2 are each independently hydrogen, lower alkyl, cycloalkyl, aryl-lower alkyl or hetaryl-lower alkyl but are not both hydrogen, R3 is hydrogen, methyl, ethyl or n-propyl; and salts thereof.
7. Compounds of formula I according to claim 6, wherein X is halogen, hydroxy, lower alkoxy, lower alkylsulfonyloxy or phenylsulfonyloxy; each of R1 and R2, independently of the other, is hydrogen, lower alkyl, C3-C8cycloalkyl or phenyl-lower alkyl, or R1 and R2 together are a radical wherein each of R4 and R5, independently of the other, is hydrogen, lower alkyl, halo-lower alkyl, C3-C8cycloalkyl, phenyl-lower alkyl or phenyl, or wherein R4 is 3-hydroxy-5-(hydroxymethyl or phosphonooxy-methyl)-2-methyl-4-pyridyl and R5 is hydrogen, or wherein R4 is 1,2,3,4-tetrahydroxybutyl or 1,2,3,4,5-pentahydroxypentyl and R5 is hydrogen or hydroxymethyl, or wherein R4 is quinolinyl, carboxy or lower alkoxycarbonyl and R5 is hydrogen or lower alkyl, or wherein R4 and R5 together are C2-C7alkylene or unsubstituted or cyano-substituted benzo-C4-C6alkylene; and R3 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, benzyloxy or hydroxy; with the proviso that when X is hydroxy and R1 and R2 together are a radical , R3 is hydrogen; with the proviso that when X is hydroxy and R3 is hydrogen, the radicals R1 and R2 cannot together be 1,1-dimethylmethylidene or 1-n-butylidene; with the proviso that when X is hydroxy and R3 is hydrogen, hydroxy or lower alkyl, the radicals R1 and R2 cannot both be hydrogen; and with the proviso that when X is hydroxy and R1 and R2 are each independently hydrogen, lower alkyl, cycloalkyl or phenyl-lower alkyl but are not both hydrogen, R3 is hydrogen, methyl, ethyl or n-propyl; phenyl groups being unsubstituted or substituted by lower alkyl, halo-lower alkyl, halogen, hydroxy, lower alkoxy, lower alkanoyl-oxy and/or by nitro; and salts thereof.
8. Compounds of formula I according to claim 6, wherein X is fluorine, chlorine, hydroxy, lower alkylsulfonyloxy or phenylsulfonyloxy; each of R1 and R2, independently of the other, is hydrogen, lower alkyl, C3-C7cycloalkyl or phenyl-lower alkyl, with the proviso that the radicals R1 and R2 cannot both be hydrogen when X is hydroxy, or wherein R1 and R2 together are a radical wherein each of R4 and R5, independently of the other, is hydrogen, lower alkyl, halo-lower alkyl, C3-C7cycloalkyl, phenyl-lower alkyl or phenyl, or wherein R4 is quinolinyl, 3-hydroxy-5-(hydroxymethyl or phosphonooxymethyl)-2-methyl-4-pyridyl and R5 is hydrogen, or wherein R4 is carboxy or lower alkoxycarbonyl and R5 is lower alkyl, or wherein R4 and R5 together are -(CH2)4- or -(CH2)5-; and R3 is hydrogen;
with the proviso that when X is hydroxy, the radicals R1 and R2 cannot together be 1,1-dimethylmethylidene or 1-n-butylidene; phenyl groups being unsubstituted or substituted by lower alkyl, trifluoromethyl, halogen, hydroxy, lower alkoxy or by lower alkanoyloxy; and salts thereof.
with the proviso that when X is hydroxy, the radicals R1 and R2 cannot together be 1,1-dimethylmethylidene or 1-n-butylidene; phenyl groups being unsubstituted or substituted by lower alkyl, trifluoromethyl, halogen, hydroxy, lower alkoxy or by lower alkanoyloxy; and salts thereof.
9. Compounds of formula I according to claim 6, wherein X is fluorine, chlorine or methylsulfonyloxy; each of R1 and R2, independently of the other, is hydrogen, lower alkyl, C3-C7cycloalkyl or phenyl-lower alkyl, or R1 and R2 together are a radical wherein each of R4 and R5, independently of the other, is hydrogen, lower alkyl, halo-lower alkyl, C3-C7cycloalkyl, phenyl-lower alkyl or phenyl, or wherein R4 is quinolinyl, 3-hydroxy-5-(hydroxymethyl or phosphonooxymethyl)-2-methyl-4-pyridyl and R5 is hydrogen, or wherein R4 is carboxy or lower alkoxycarbonyl and R5 is lower alkyl, or wherein R4 and R5 together are -(CH2)4- or -(CH2)5- ; and R3 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl or hydroxy; phenyl groups being unsubstituted or substituted by lower alkyl, trifluoromethyl, halogen, hydroxy, lower alkoxy and/or by nitro; and salts thereof.
10. Compounds of formula I according to claim 6, wherein X is fluorine, chlorine or methylsulfonyloxy, R1 is hydrogen, R2 is hydrogen, C1-C4-alkyl, benzyl or 2-hydroxybenzyl, or R1 and R2 together are C5-C6-cycloalkylidene, C1-C4alkylidene, benzylidene, 2-hydroxybenzylidene or 3-hydroxy-5-(hydroxymethyl or phosphonooxymethyl)-2-methyl-4-pyridyl-methylidene, and R3 is hydrogen, C1-C4alkyl, C2-C4alkynyl or hydroxy; and salts thereof.
11. 3-Benzylideneaminoxy-2-fluoropropylamine according to claim 6 and pharmaceutically acceptable salts thereof.
12. 3-Cyclopentylideneaminoxy-2-hydroxypropylamine according to claim 6 and pharmaceutically acceptable salts thereof.
13. 3-Aminoxy-2-fluoropropylamine according to claim 6 and pharma-ceutically acceptable salts thereof.
14. 3-Pyridoxalaminoxy-2-fluoropropylamine according to claim 6 and pharmaceutically acceptable salts thereof.
15. 3-Amino-2-fluoropropoxyimino-pyridoxal phosphate according to claim 6 and pharmaceutically acceptable salts thereof.
16. 3-Aminoxy-2-methylsulfonyloxypropylamine according to claim 6 and pharmaceutically acceptable salts thereof.
17. 3-(2-Hydroxybenzylideneaminoxy)-2-fluoropropylamine according to claim 6 and pharmaceutically acceptable salts thereof.
18. 3-(1-Hethoxymethylethylideneaminoxy)-2-fluoropropylamine according to claim 6 and pharmaceutically acceptable salts thereof.
19. 3-(1-Methylpropylideneaminoxy)-2-hydroxypropylamine according to claim 6 and pharmaceutically acceptable salts thereof.
20. 3-(2,2-Difluoro-1-phenylethylideneaminoxy)-2-fluoropropylamine according to claim 6 and pharmaceutically acceptable salts thereof.
21. 4-(3-Amino-2-fluoropropoxyiminomethyl)-quinoline according to claim 6 and pharmaceutically acceptable salts thereof.
22. A pharmaceutical preparation containing a compound according to claim 6 and at least one pharmaceutically acceptable carrier.
23. A process for the preparation of a compound of formula I according to claim 6, which process comprises (a) for the preparation of compounds of formula I wherein X is halogen,reacting a compound of formula II
(II) wherein R1, R2 and R3 are as defined under formula I and Y is a group that can be converted into halogen or replaced by halogen, with a halogenating agent, or (b) for the preparation of compounds of formula I wherein X is hydroxy,reacting a compound of formula III
(III) wherein R1 and R2 are as defined under formula I, with ammonia or with an amine of formula NH2R3 wherein R3 is as defined under formula I, or (c) for the preparation of compounds of formula I wherein R1 is hydrogen, in a compound of formula IV
(IV) wherein R2 and R3 are as defined under formula I and each of S and S', independently of the other, is an amino-protecting group or hydrogen, at least one of the groups S and S' being an amino-protecting group, or wherein S and R2 together or S' and R3 together are a bivalent amino-protecting group, removing the amino-protecting group(s), or (d) reacting a compound of formula V
(V) wherein R1 and R2 are as defined under formula I, with a compound of formula VI
(VI) wherein R3 and X are as defined under formula I, Z is hydroxy or a nucleofugal leaving group and S is an amino-protecting group or hydrogen and, where applicable, removing the amino-protecting group, or (e) for the preparation of compounds of formula I wherein R3 is hydrogen, in a compound of formula VII
(VII) wherein R1, R2 and X are as defined under formula I and W is a radical that can be converted into amino, converting the radical W into amino; or (f) for the preparation of compounds of formula I wherein R3 is hydrogen or especially hydroxy or lower alkyl, reducing a compound of formula VIII
(VIII) wherein R1, R2 and X are as defined under formula I and R3 is hydrogen, hydroxy or lower alkyl and/or, if desired, converting a resulting compound of formula I into a different compound of formula I
and/or, if desired, converting a resulting salt into the free compound or into a different salt and/or, if desired, converting a resulting free compound into a salt and/or separating a resulting mixture of isomeric compound of formula I into the individual isomers.
(II) wherein R1, R2 and R3 are as defined under formula I and Y is a group that can be converted into halogen or replaced by halogen, with a halogenating agent, or (b) for the preparation of compounds of formula I wherein X is hydroxy,reacting a compound of formula III
(III) wherein R1 and R2 are as defined under formula I, with ammonia or with an amine of formula NH2R3 wherein R3 is as defined under formula I, or (c) for the preparation of compounds of formula I wherein R1 is hydrogen, in a compound of formula IV
(IV) wherein R2 and R3 are as defined under formula I and each of S and S', independently of the other, is an amino-protecting group or hydrogen, at least one of the groups S and S' being an amino-protecting group, or wherein S and R2 together or S' and R3 together are a bivalent amino-protecting group, removing the amino-protecting group(s), or (d) reacting a compound of formula V
(V) wherein R1 and R2 are as defined under formula I, with a compound of formula VI
(VI) wherein R3 and X are as defined under formula I, Z is hydroxy or a nucleofugal leaving group and S is an amino-protecting group or hydrogen and, where applicable, removing the amino-protecting group, or (e) for the preparation of compounds of formula I wherein R3 is hydrogen, in a compound of formula VII
(VII) wherein R1, R2 and X are as defined under formula I and W is a radical that can be converted into amino, converting the radical W into amino; or (f) for the preparation of compounds of formula I wherein R3 is hydrogen or especially hydroxy or lower alkyl, reducing a compound of formula VIII
(VIII) wherein R1, R2 and X are as defined under formula I and R3 is hydrogen, hydroxy or lower alkyl and/or, if desired, converting a resulting compound of formula I into a different compound of formula I
and/or, if desired, converting a resulting salt into the free compound or into a different salt and/or, if desired, converting a resulting free compound into a salt and/or separating a resulting mixture of isomeric compound of formula I into the individual isomers.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH4276/88-1 | 1988-11-18 | ||
CH427688 | 1988-11-18 |
Publications (1)
Publication Number | Publication Date |
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CA2003091A1 true CA2003091A1 (en) | 1990-05-18 |
Family
ID=4273087
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CA002003091A Abandoned CA2003091A1 (en) | 1988-11-18 | 1989-11-16 | Substituted oxadiaminobutanes |
Country Status (12)
Country | Link |
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EP (1) | EP0369944A1 (en) |
JP (1) | JPH02188563A (en) |
KR (1) | KR900007409A (en) |
AU (1) | AU4471189A (en) |
CA (1) | CA2003091A1 (en) |
DK (1) | DK578389A (en) |
FI (1) | FI895446A0 (en) |
HU (1) | HUT51598A (en) |
IL (1) | IL92326A0 (en) |
NO (1) | NO894589L (en) |
PT (1) | PT92324A (en) |
ZA (1) | ZA898779B (en) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
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HU207988B (en) * | 1988-10-20 | 1993-07-28 | Biorex Kutato Fejlesztoe Kft | Process for producing halogenides of o-/3-amino-2-hydroxy-propyl/hydroximic acid and pharmaceutical compositions containing them as active components |
EP0452264A1 (en) * | 1990-04-11 | 1991-10-16 | Ciba-Geigy Ag | Hydroxylamine compounds |
EP0495750A3 (en) * | 1991-01-14 | 1992-09-16 | Ciba-Geigy Ag | Heterocyclic hydroxylamine |
TW214545B (en) * | 1992-02-17 | 1993-10-11 | Ciba Geigy Ag | |
DE4306392A1 (en) * | 1993-03-02 | 1994-09-08 | Basf Ag | β-hydroxyoxime ether and dispersions or solutions which can be crosslinked at room temperature with β-hydroxyoxime ethers |
EP0644872B1 (en) * | 1993-04-13 | 1997-03-19 | Ciba-Geigy Ag | Ornithine decarboxylase inhibiting cyclic aminooxy compounds |
US5610195A (en) * | 1993-04-13 | 1997-03-11 | Ciba-Geigy Corporation | Ornithine decarboxylase inhibiting branched aminooxy amino alkane derivatives |
HU218480B (en) * | 1995-06-15 | 2000-09-28 | BIOREX Kutató és Fejlesztő Rt. | Hydroxylamine derivatives, process for producing them and pharmaceutical compositions containing them |
WO2003057664A1 (en) | 2002-01-11 | 2003-07-17 | Biorex Kutató És Fejlesztö Rt. | Carboxamidine derivatives and their use in the treatment of vascular diseases |
Family Cites Families (5)
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DE2651083A1 (en) * | 1976-11-09 | 1978-05-18 | Hoechst Ag | NEW O-ALKYLATED HYDROXYLAMINE, METHOD FOR THEIR PRODUCTION AND THEIR USE |
FR2539413A1 (en) * | 1983-01-17 | 1984-07-20 | Pos Lab | CARBOSTYRILOXIMINOPROPANOLAMINES USEFUL AS MEDICAMENTS AND PROCESS FOR THEIR PREPARATION |
EP0184112B1 (en) * | 1984-11-27 | 1990-05-09 | Chugai Seiyaku Kabushiki Kaisha | Novel vitamin d derivatives and process for producing the same |
US4707498A (en) * | 1986-01-14 | 1987-11-17 | Merrell Dow Pharmaceuticals Inc. | Fluorinated diaminoalkyne derivatives |
ZA882719B (en) * | 1987-04-23 | 1988-10-17 | Merrell Dow Pharmaceuticals Inc. | Use of odc inhibitors,dacarbazine,and interferon in the treatment of malignant melanoma |
-
1989
- 1989-11-09 EP EP89810859A patent/EP0369944A1/en not_active Withdrawn
- 1989-11-15 AU AU44711/89A patent/AU4471189A/en not_active Abandoned
- 1989-11-15 FI FI895446A patent/FI895446A0/en not_active Application Discontinuation
- 1989-11-16 IL IL92326A patent/IL92326A0/en unknown
- 1989-11-16 CA CA002003091A patent/CA2003091A1/en not_active Abandoned
- 1989-11-16 JP JP1296293A patent/JPH02188563A/en active Pending
- 1989-11-16 PT PT92324A patent/PT92324A/en not_active Application Discontinuation
- 1989-11-17 HU HU895959A patent/HUT51598A/en unknown
- 1989-11-17 NO NO89894589A patent/NO894589L/en unknown
- 1989-11-17 ZA ZA898779A patent/ZA898779B/en unknown
- 1989-11-17 DK DK578389A patent/DK578389A/en not_active Application Discontinuation
- 1989-11-17 KR KR1019890016678A patent/KR900007409A/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
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EP0369944A1 (en) | 1990-05-23 |
NO894589D0 (en) | 1989-11-17 |
AU4471189A (en) | 1990-05-24 |
FI895446A0 (en) | 1989-11-15 |
HUT51598A (en) | 1990-05-28 |
NO894589L (en) | 1990-05-21 |
PT92324A (en) | 1990-05-31 |
JPH02188563A (en) | 1990-07-24 |
DK578389D0 (en) | 1989-11-17 |
DK578389A (en) | 1990-05-19 |
HU895959D0 (en) | 1990-02-28 |
KR900007409A (en) | 1990-06-01 |
IL92326A0 (en) | 1990-07-26 |
ZA898779B (en) | 1990-07-25 |
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