SE458203B - PROCEDURES FOR THE PREPARATION OF 4-CARBAMOYLOXIAZAPHOSPHORPHINES AND PHARMACEUTICAL PREPARATIONS FOR TREATMENT OF ANALYZOUS TUMORS AND SIMILAR ORAL DISEASES - Google Patents
PROCEDURES FOR THE PREPARATION OF 4-CARBAMOYLOXIAZAPHOSPHORPHINES AND PHARMACEUTICAL PREPARATIONS FOR TREATMENT OF ANALYZOUS TUMORS AND SIMILAR ORAL DISEASESInfo
- Publication number
- SE458203B SE458203B SE8105340A SE8105340A SE458203B SE 458203 B SE458203 B SE 458203B SE 8105340 A SE8105340 A SE 8105340A SE 8105340 A SE8105340 A SE 8105340A SE 458203 B SE458203 B SE 458203B
- Authority
- SE
- Sweden
- Prior art keywords
- alkyl
- hydrogen
- mmol
- chloroethyl
- hydroxy
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 7
- 206010028980 Neoplasm Diseases 0.000 title claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 3
- 238000002360 preparation method Methods 0.000 title claims description 3
- 238000011282 treatment Methods 0.000 title claims description 3
- 201000010099 disease Diseases 0.000 title 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title 1
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 150000002431 hydrogen Chemical group 0.000 claims description 8
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- VZZWPFPWQGVAHK-UHFFFAOYSA-N 2h-oxazaphosphinin-4-yl carbamate Chemical class NC(=O)OC1=PNOC=C1 VZZWPFPWQGVAHK-UHFFFAOYSA-N 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 3
- 239000003377 acid catalyst Substances 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 230000036210 malignancy Effects 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 238000002844 melting Methods 0.000 description 19
- 230000008018 melting Effects 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- -1 alkyl ketones Chemical class 0.000 description 11
- 239000013078 crystal Substances 0.000 description 10
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- RANONBLIHMVXAJ-UHFFFAOYSA-N 4-hydroxycyclophosphamide Chemical compound OC1CCOP(=O)(N(CCCl)CCCl)N1 RANONBLIHMVXAJ-UHFFFAOYSA-N 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 229960001330 hydroxycarbamide Drugs 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- GHTXIUJUEVFYHW-NYYWCZLTSA-N (ne)-n-[3-[amino-[bis(2-chloroethyl)amino]phosphoryl]oxypropylidene]hydroxylamine Chemical compound ClCCN(CCCl)P(=O)(N)OCC\C=N\O GHTXIUJUEVFYHW-NYYWCZLTSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical class NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 239000004202 carbamide Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 4
- DRAJWRKLRBNJRQ-UHFFFAOYSA-N Hydroxycarbamic acid Chemical class ONC(O)=O DRAJWRKLRBNJRQ-UHFFFAOYSA-N 0.000 description 4
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 229960004397 cyclophosphamide Drugs 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- KMUZEPMBBDHYBC-UHFFFAOYSA-N 2-(hydroxycarbamoylamino)acetic acid Chemical compound ONC(=O)NCC(O)=O KMUZEPMBBDHYBC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 235000021395 porridge Nutrition 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- IZJCEZHCNFRDKR-UHFFFAOYSA-N 4-ethoxy-2h-oxazaphosphinine Chemical compound CCOC1=PNOC=C1 IZJCEZHCNFRDKR-UHFFFAOYSA-N 0.000 description 2
- QTALEJBFHUYLPY-UHFFFAOYSA-N C(C)(=O)O.C(C1=CC=CC=C1)N=C=O Chemical compound C(C)(=O)O.C(C1=CC=CC=C1)N=C=O QTALEJBFHUYLPY-UHFFFAOYSA-N 0.000 description 2
- 101100298295 Drosophila melanogaster flfl gene Proteins 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- FLCMCTKYSHCVAJ-UHFFFAOYSA-N OC1=PNOC=C1 Chemical class OC1=PNOC=C1 FLCMCTKYSHCVAJ-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 239000004133 Sodium thiosulphate Substances 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- BJCVXPUCICIZQC-UHFFFAOYSA-N benzyl 2-(hydroxycarbamoylamino)acetate Chemical compound ONC(=O)NCC(=O)OCC1=CC=CC=C1 BJCVXPUCICIZQC-UHFFFAOYSA-N 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229910052717 sulfur Chemical group 0.000 description 2
- 239000011593 sulfur Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 239000000052 vinegar Substances 0.000 description 2
- 235000021419 vinegar Nutrition 0.000 description 2
- NEHSQHPPBUJKKZ-UHFFFAOYSA-N 1-[2-[bis(2-chloroethyl)amino]-2-oxo-1,3,2$l^{5}-oxazaphosphinan-4-yl]-1-hydroxyurea Chemical compound NC(=O)N(O)C1CCOP(=O)(N(CCCl)CCCl)N1 NEHSQHPPBUJKKZ-UHFFFAOYSA-N 0.000 description 1
- AKGCYKHMRWIWJQ-UHFFFAOYSA-N 1-[2-[bis(2-chloroethyl)amino]-2-oxo-1,3,2$l^{5}-oxazaphosphinan-4-yl]-3-(2-bromophenyl)-1-hydroxyurea Chemical compound C=1C=CC=C(Br)C=1NC(=O)N(O)C1CCOP(=O)(N(CCCl)CCCl)N1 AKGCYKHMRWIWJQ-UHFFFAOYSA-N 0.000 description 1
- QFZCQXSJDLVPCY-UHFFFAOYSA-N 1-[2-[bis(2-chloroethyl)amino]-2-oxo-1,3,2$l^{5}-oxazaphosphinan-4-yl]-3-(4-bromophenyl)-1-hydroxyurea Chemical compound C=1C=C(Br)C=CC=1NC(=O)N(O)C1CCOP(=O)(N(CCCl)CCCl)N1 QFZCQXSJDLVPCY-UHFFFAOYSA-N 0.000 description 1
- DPSSZJQTMCEKNL-UHFFFAOYSA-N 1-[2-[bis(2-chloroethyl)amino]-2-oxo-1,3,2$l^{5}-oxazaphosphinan-4-yl]-3-cyclohexyl-1-hydroxyurea Chemical compound C1CCCCC1NC(=O)N(O)C1CCOP(=O)(N(CCCl)CCCl)N1 DPSSZJQTMCEKNL-UHFFFAOYSA-N 0.000 description 1
- CZQIJQFTRGDODI-UHFFFAOYSA-N 1-bromo-4-isocyanatobenzene Chemical compound BrC1=CC=C(N=C=O)C=C1 CZQIJQFTRGDODI-UHFFFAOYSA-N 0.000 description 1
- SXJYSIBLFGQAND-UHFFFAOYSA-N 1-isocyanato-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC(N=C=O)=C1 SXJYSIBLFGQAND-UHFFFAOYSA-N 0.000 description 1
- GFNKTLQTQSALEJ-UHFFFAOYSA-N 1-isocyanato-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(N=C=O)C=C1 GFNKTLQTQSALEJ-UHFFFAOYSA-N 0.000 description 1
- RAXABQCFPAWRSY-UHFFFAOYSA-N 2-[bis(2-chloroethyl)amino]-3-(2-chloroethyl)-2-oxo-1,3,2$l^{5}-oxazaphosphinan-4-ol Chemical compound OC1CCOP(=O)(N(CCCl)CCCl)N1CCCl RAXABQCFPAWRSY-UHFFFAOYSA-N 0.000 description 1
- ZZVDXRCAGGQFAK-UHFFFAOYSA-N 2h-oxazaphosphinine Chemical class N1OC=CC=P1 ZZVDXRCAGGQFAK-UHFFFAOYSA-N 0.000 description 1
- 241000428352 Amma Species 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- BCSPUHMNKHYRRO-UHFFFAOYSA-N ONC(=O)OCC.ONC(OCC)=O Chemical compound ONC(=O)OCC.ONC(OCC)=O BCSPUHMNKHYRRO-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- VYWQTJWGWLKBQA-UHFFFAOYSA-N [amino(hydroxy)methylidene]azanium;chloride Chemical class Cl.NC(N)=O VYWQTJWGWLKBQA-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- LURYMYITPCOQAU-UHFFFAOYSA-N benzoyl isocyanate Chemical compound O=C=NC(=O)C1=CC=CC=C1 LURYMYITPCOQAU-UHFFFAOYSA-N 0.000 description 1
- VLQHNAMRWPQWNK-UHFFFAOYSA-N benzyl 2-aminoacetate;hydron;chloride Chemical compound Cl.NCC(=O)OCC1=CC=CC=C1 VLQHNAMRWPQWNK-UHFFFAOYSA-N 0.000 description 1
- PQBSPTAPCMSZAA-UHFFFAOYSA-N benzyl n-hydroxycarbamate Chemical compound ONC(=O)OCC1=CC=CC=C1 PQBSPTAPCMSZAA-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- KQWGXHWJMSMDJJ-UHFFFAOYSA-N cyclohexyl isocyanate Chemical compound O=C=NC1CCCCC1 KQWGXHWJMSMDJJ-UHFFFAOYSA-N 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002443 hydroxylamines Chemical class 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- VFKUVJKBMUOOQX-UHFFFAOYSA-N n-hydroxymorpholine-4-carboxamide Chemical compound ONC(=O)N1CCOCC1 VFKUVJKBMUOOQX-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 231100000927 organotoxic Toxicity 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000012958 reprocessing Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
- C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
- C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
- C07F9/65846—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring the phosphorus atom being part of a six-membered ring which may be condensed with another ring system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
' 458 205 10 15 20 25 30 35 2 gruppen -N(OH)- och i detta fall Z är gruppen -NR5R7, X är syre eller svavel och R5 är väte eller C1_4-alkyl och R7 är väte, bensoyl, cykloalkyl med 3-8 kolatomer, en rak- eller grenkedjig alkyl med 1-18 kolatomer, varvid alkylgruppen även kan vara substituerad med -OH, -halogen, karboxi, karb- -Cl-C2-alkoxi, bensyloxíkarbonyl eller -P0(CH3)2 eller vari R7 betecknar fenyl-C1_4-alkyl, som eventuellt är substituerad med en karboxígrupp eller vari R7 är fenyl, varvid fenylgrup- pen kan vara osnbstituerad eller enkelt eller tváfaldigt substituerad med C1_4-alkyl, nitro, halogen eller trífluor- metyl, eller vari R5 och R7 tillsammans med kväveatomen bil- dar en píperídínring eller en morfolinríng och deras farma- ceutiska användbara salter. The group -N (OH) - and in this case Z is the group -NR 5 R 7, X is oxygen or sulfur and R 5 is hydrogen or C 1-4 alkyl and R 7 is hydrogen, benzoyl, cycloalkyl with 3 -8 carbon atoms, a straight or branched chain alkyl having 1-18 carbon atoms, wherein the alkyl group may also be substituted by -OH, -halogen, carboxy, carb-C 1 -C 2 -alkoxy, benzyloxycarbonyl or -PO (CH 3) 2 or wherein R 7 represents phenyl-C 1-4 alkyl, which is optionally substituted by a carboxy group or wherein R 7 is phenyl, wherein the phenyl group may be unsubstituted or mono- or disubstituted by C 1-4 alkyl, nitro, halogen or trifluoromethyl, or wherein R 5 and R7 together with the nitrogen atom forms a piperidine ring or a morpholine ring and their pharmaceutically usable salts.
På grund av de speciellt gynnsamma egenskaperna och lättill- gänglígheten föredras därvid de 4-karbamoyloxi-oxazafosfori- ner med den allmänna formeln I vari Z är gruppen (Rs Rv , X är syre, R4 och R5, som kan vara lika eller olika, är väte, metyl eller etyl och R7 är väte eller rak- eller grenkedjig alkyl med 1-18 kolatomer, fenyl eller bensyl.Due to the particularly favorable properties and readiness, the 4-carbamoyloxy-oxazaphosphorines of the general formula I in which Z is the group (R 5, R 6, X is oxygen, R 4 and R 5, which may be the same or different, are preferred). hydrogen, methyl or ethyl and R 7 is hydrogen or straight or branched chain alkyl of 1-18 carbon atoms, phenyl or benzyl.
En annan grupp av föredragna föreningar med formeln I är sådana, i vilka X är syre, R1, R2 och R3, som är lika eller olika, är väte eller en 2-kloretylgrupp, R4 och R5 är väte och R7 är väte, bensyl eller fenyl.Another group of preferred compounds of formula I are those in which X is oxygen, R 1, R 2 and R 3, which are the same or different, are hydrogen or a 2-chloroethyl group, R 4 and R 5 are hydrogen and R 7 is hydrogen, benzyl or phenyl.
De nya 4-karbamoyloxi-oxazafosforinerna med den allmänna for- meln I framställs medelst ett förfarande, som utmärks av att man i närvaro av ett inert lösningsmedel vid en temperatur av mellan -35°C och +50°C, eventuellt i närvaro av en sur kata- lysator, omsätter en 4-hydroxi- eller 4-metoxi eller 4-etoxi- oxazafosforín med den allmänna formeln II R OY 1:1 I: / II \ ca N N \\\ R \P/ /cuz 2 ¿á'\\ 0 0____-- CH2 10 15 20 25 30 35 458 203 3 vari R1, R2 och R3 har samma betydelser som i samband med formeln I ovan och Y är väte, metyl eller etyl, med ett hydroxikarbamatderivat med den allmänna formeln III RSH flo-xll-c-z In vari R5 är väte eller Cl-C4-alkyl, X är syre eller svavel och Z är gruppen -NRSR7 eller OR8 och R5 är väte eller CIC4- alkyl, R7 är väte, bensoyl, cykloalkyl med 3-8 kolatomer, en rak- eller grenkedjig alkyl med 1-18 kolatomer, varvid alkyl- gruppen även kan vara substituerad med -OH, -halogen, karboxi karb-Cl-C2-alkoxi, bensyloxikarbonyl eller -PO(CH3)2, eller vari R7 betecknar fenyl-Cl_4-alkyl, som eventuellt är substi- tuerad med en karboxigrupp, eller vari R7 är fenyl, varvid fenylgruppen kan vara osubstítuerad eller enkelt eller två- faldigt substituerad med C1_4-alkyl, nítro, halogen eller trifluormetyl, eller vari R5 och R7 tillsammans med kväveato- men bildar en piperidinring eller en morfolinring och Ra är en Cl-C4-alkylgrupp eller en bensylgrupp, och eventuellt överför de erhållna föreningarna till deras salter.The novel 4-carbamoyloxy-oxazaphosphorines of the general formula I are prepared by a process which is characterized in that in the presence of an inert solvent at a temperature of between -35 ° C and + 50 ° C, optionally in the presence of a acid catalyst, converts a 4-hydroxy- or 4-methoxy or 4-ethoxy-oxazaphosphorine of the general formula II R OY 1: 1 I: / II \ ca NN \\\ R \ P / / cuz 2 ¿á Wherein R 1, R 2 and R 3 have the same meanings as in connection with formula I above and Y is hydrogen, methyl or ethyl, with a hydroxycarbamate derivative of the general formula III In which R 5 is hydrogen or C 1 -C 4 alkyl, X is oxygen or sulfur and Z is the group -NRSR 7 or OR 8 and R 5 is hydrogen or C 1 -C 4 alkyl, R 7 is hydrogen, benzoyl, cycloalkyl having 3- 8 carbon atoms, a straight or branched chain alkyl having 1-18 carbon atoms, wherein the alkyl group may also be substituted by -OH, -halogen, carboxy carb-C 1 -C 2 -alkoxy, benzyloxycarbonyl or -PO (CH 3) 2, or wherein R7 bet represents phenyl-C 1-4 alkyl, which is optionally substituted by a carboxy group, or wherein R 7 is phenyl, wherein the phenyl group may be unsubstituted or mono- or disubstituted by C 1-4 alkyl, nitro, halogen or trifluoromethyl, or wherein R 5 and R 7 together with the nitrogen atom forms a piperidine ring or a morpholine ring and R a is a C 1 -C 4 alkyl group or a benzyl group, and optionally transfers the obtained compounds to their salts.
Som lämpliga lösningsmedel ifrâgakommer vatten, lägre alkyl- halogenider såsom speciellt metylenklorid, lägre alkylketo- ner såsom speciellt aceton, dietyleter, dimetylformamid (DMF), hexametylfosforsyratriamid (HMPT) och liknande lösningsmedel respektive blandningar av flera sådana lösningsmedel. Reak- tionen utförs vid temperaturer inom intervallet från -35°C till +50°C, dvs. eventuellt under kylning, vid rumstemperatur eller under uppvärmning. Omsättningen kan ske i närvaro av en sur katalysator såsom en oorganisk syra, triklorättiksyra, trifluormetansulfonsyra, p-toluensulfonsyra eller en Lewis- -syra såsom AlCl3, ZnCl2 eller TiCl4.Suitable solvents include water, lower alkyl halides such as especially methylene chloride, lower alkyl ketones such as especially acetone, diethyl ether, dimethylformamide (DMF), hexamethylphosphoric triamide (HMPT) and similar solvents or mixtures of several such solvents. The reaction is carried out at temperatures in the range from -35 ° C to + 50 ° C, i.e. possibly during cooling, at room temperature or during heating. The reaction may be in the presence of an acid catalyst such as an inorganic acid, trichloroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid or a Lewis acid such as AlCl 3, ZnCl 2 or TiCl 4.
Ett ytterligare förfarande för framställning av föreningar med R 6 med R6 = H och R är väte, utmärks formel I, vari Z är -N \R7 av att man i ett inert lösningsmedel vid en temperatur inom in- 5 tervallet från -700 till +5OOC omsätter en oxim med den allmän- na formeln IV 458 203 10 15 20 25 30 35 4 R R , =: R/\/q 2 a . . - oß\o-_-c--cfl-__c-__-_-_n-_on :v /\ I -I :<4 :<4 n4 124 __ vari Rl_4 har samma betydelse som i samband med formel I, med en förening med den allmänna formeln V V vari X och R7 har samma betydelser som i samband med formel I.A further process for the preparation of compounds of R 6 with R 6 = H and R is hydrogen, Formula I is characterized in which Z is -N 4 R 7 in an inert solvent at a temperature in the range of -700 to + 50 DEG C. converts an oxime of the general formula IV 458 203 10 15 20 25 30 35 4 RR, =: R / \ / q 2 a. . - oß \ o -_- c - c fl -__ c -__-_-_ n-_on: v / \ I -I: <4: <4 n4 124 __ wherein Rl_4 has the same meaning as in connection with formula I, with a compound of the general formula VV wherein X and R 7 have the same meanings as in connection with formula I.
Reaktionsförloppet kan vid förfarandet enligt uppfinningen följas tunnskiktskromatgrafískt. Isoleringen av tunnskikts- kromatografiskt enhetliga substanser sker medelst för dylika produkter sedvanliga upparbetningsförfaranden, speciellt ge- nom kristallisation eller kromatografisk rening. Strukturbe- stämning sker genom smältpunkt, tunnskiktskromatografi, ele- mentaranalys odh/eller»IR- och IHNMR-spektralanalys.The course of the reaction can be followed graphically graphically in the process according to the invention. The isolation of thin-layer chromatographically uniform substances takes place by means of usual reprocessing procedures for such products, especially by crystallization or chromatographic purification. Structural determination takes place by melting point, thin-layer chromatography, elemental analysis and / or »IR and IHNMR spectral analysis.
De vid förfarandet enligt uppfinningen som utgångsmaterial an- vända föreningarna är i stor utsträckning kända, kan användas i kristallin form eller som råprodukt och kan syntetiseras på i och för sig känt sätt enligt följande: 4-hydroxi-oxazafosforiner erhålls genom reduktion av 4 -hydro- peroxiderivat (exempelvis A. Takamizawa et.al _, J.Med.Chem. lå (1975) 376). 4-metoxi~ respektive 4-etoxi-oxazafosforiner er- hålls genom sur katalys utgående från 4-hydroxiderivaten i metanol respektive etanol eller i inerta lösningsmedel, som innehåller metanol respektive etanol. Hydroxikarbamidderivaten framställs genom omsättning av pâ lämpligt sätt substituerade isocyanater respektive karbamidsyraklorider med hydroxylamin respektive N-monosubstituerad hydroxylamin. Pâ liknande sätt 10 15 20 25 30 35 458 203 s kan N-hydroxi-karbamidsyraestrar (hydroxikarbamater) erhållas genom omsättning av motsvarande klorkolsyraestrar med hydrox- ylamin respektive N-monosubstituerad hydroxylamin. För syntes av hydroxikarbamid- respektive N-hydroxikarbamidsyraestrar med en ytterligare hydroxi-, karboxi- eller sulfonsyragrupp är det lämpligt att utnyttja en syntesväg med skyddsgrupp.The compounds used in the process of the invention as starting materials are widely known, can be used in crystalline form or as crude product and can be synthesized in a manner known per se as follows: 4-hydroxy-oxazaphosphorines are obtained by reduction of 4-hydro peroxide derivatives (e.g. A. Takamizawa et al., J. Med. Chem. La (1975) 376). 4-Methoxy- and 4-ethoxy-oxazaphosphorines are obtained by acid catalysis from the 4-hydroxide derivatives in methanol or ethanol or in inert solvents containing methanol and ethanol. The hydroxycarbamide derivatives are prepared by reacting appropriately substituted isocyanates and urea chlorides with hydroxylamine and N-monosubstituted hydroxylamine, respectively. Similarly, N-hydroxycarbamic acid esters (hydroxycarbamates) can be obtained by reacting the corresponding chlorocaric acid esters with hydroxylamine and N-monosubstituted hydroxylamine, respectively. For the synthesis of hydroxycarbamide or N-hydroxycarbamic acid esters with an additional hydroxy, carboxy or sulfonic acid group, it is convenient to use a synthetic route with protecting group.
Oximerna med formel IV kan erhållas på olika sätt. De kan ex- empelvis erhállas genom omsättning av motsvarande 4-hydroxi- -oxazafosforiner med hydroxylamin respektive med hydroxyl- aminsalter. pH-värdet bör om möjligt hållas mellan 2 och 7.The oximes of formula IV can be obtained in various ways. They can be obtained, for example, by reacting the corresponding 4-hydroxy-oxazaphosphorines with hydroxylamine and with hydroxylamine salts, respectively. The pH value should, if possible, be kept between 2 and 7.
Av 4-karbamoyloxi-oxazafosforinerna enligt uppfinningen kan de racemiska cis- och trans-isomererna framställas (cis = 2R, 4R / 23, 4S; trans = 2R, 4S / 2S, 4R). Numreringen är i över- ensstämmelse med IUPAC-nomenklaturreglerna och med litteratu- ren avseende motsvarande oxazafosforinderivat. Cis- respekti- ve trans-formen kan även framställas alltefter valet av reak- tionsbetingelser. Farmakologiskt sett uppvisar isomererna icke några signifikanta skillnader.From the 4-carbamoyloxy-oxazaphosphorines of the invention, the racemic cis and trans isomers can be prepared (cis = 2R, 4R / 23, 4S; trans = 2R, 4S / 2S, 4R). The numbering is in accordance with the IUPAC nomenclature rules and with the literature regarding the corresponding oxazaphosphorine derivatives. The cis- or trans-form can also be produced according to the choice of reaction conditions. Pharmacologically, the isomers do not show any significant differences.
Föreningarna enligt uppfinningen utmärks av anmärkningsvärda, kemoterapeutiskt värdefulla egenskaper. I jämförelse med den kända jämförelsesubstansen cyklofosfamid uppvisar de på expe- rimentella transplantationstumörer hos råtta en näranog lika kraftig cancerotoxisk kemoterapeutisk aktivitet. De verkar di- rekt alkylerande i vattenlösning och uppvisar in vitro hög cy- totoxicitet medan cyklofosfamid kräver en enzymatisk aktive- ring och praktiskt taget icke alls verkar cytotoxisk in vitro.The compounds of the invention are characterized by remarkable, chemotherapeutically valuable properties. In comparison with the known comparative substance cyclophosphamide, they show almost experimental cancerotoxic chemotherapeutic activity on rat experimental transplant tumors in rats. They act directly alkylating in aqueous solution and show high cytotoxicity in vitro, while cyclophosphamide requires enzymatic activation and practically do not act cytotoxically in vitro at all.
Den akuta toxiciteten hos föreningen enligt uppfinningen är ca. fyra gånger mindre än för jämförelsesubstansen cyklofosfamid, varför den terapeutiska bredden avsevärt ökas. Även med avse- ende på organotoxiska biverkningar, som leukocytdepression och immunsuppression, uppvisar föreningarna enligt uppfinningen betydande fördelar jämfört med jämförelsesubstansen cyklofos- famid. 458 203 10 15 20 25 30 35 6 Föreningarna enligt uppfinningen är lämpliga för behandling av maligna tumörer och liknande maligna sjukdomar, såsom leu- kemi, hos människor. Därvid ifrågakommer mängder av 0,01-100 mg/kg. De härvid använda farmaceutiska beredningarna fram- ställs medelst sedvanliga metoder under användning av sedvan~ liga tillsats- och bärarmaterial.The acute toxicity of the compound of the invention is approx. four times less than for the comparator cyclophosphamide, so the therapeutic range is considerably increased. Also with respect to organotoxic side effects, such as leukocyte depression and immunosuppression, the compounds of the invention show significant advantages over the comparator cyclophosphamide. The compounds of the invention are suitable for the treatment of malignant tumors and similar malignancies, such as leukemia, in humans. In this case, amounts of 0.01-100 mg / kg are in question. The pharmaceutical preparations used herein are prepared by conventional methods using conventional additive and carrier materials.
Uppfinningen åskådliggörs närmare medelst följande utförings- exempel, vari temperaturangivelserna avser Celsiusgrader.The invention is further illustrated by the following exemplary embodiments, in which the temperature indications refer to degrees Celsius.
Exempel 1 l-hvdroxi-1-f2-(bis-(2-kloretvlä-amíno)-2-oxo-tetrahvdro-2H- -1,3,2-oxazafosforin-4-vl1-karbamid 15 g (54 mol) 4-hydroxicyklofosfamid (dvs. 2-(bis-(2-kloret- yl)-amino)-4~hydroxi-tetrahydro-2H-l,3,2-oxazafosforin-2-oxid) och 4,4 g (58 mmol) hydroxikarbamid upplöstes i 70 ml DMF, surgjordes med triklorättiksyra (pH 3-4) och fick stå 20 tim~ mar vid OO i kylskåp. Därefter späddes kristallgröten med 70 ml ättikester och efter 2 timmar avsögs materialet, tvättades och torkades samt omkristalliserades ur metanol.Example 1 1-Hydroxy-1- [2- (bis- (2-chloroethylamino) -2-oxo-tetrahydro-2H--1,3,2-oxazaphosphorin-4-yl] -urea 15 g (54 mol) 4 -hydroxycyclophosphamide (ie 2- (bis- (2-chloroethyl) -amino) -4-hydroxy-tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide) and 4.4 g (58 mmol) hydroxycarbamide was dissolved in 70 ml of DMF, acidified with trichloroacetic acid (pH 3-4) and allowed to stand for 20 hours at 0 ° C in a refrigerator, then the crystal porridge was diluted with 70 ml of acetic ester and after 2 hours the material was filtered off, washed and dried and recrystallized from methanol.
Utbyte: ll,3 g (62 % av det teoretiska värdet) av cis-formen Smältpunkt: 139-1430 (sönderdelning).Yield: 11.3 g (62% of theory) of the cis form Melting point: 139-1430 (decomposition).
Exempel 2 1-hvdroxí-l-[2-(bis-(2-kloretvl)~amino)-2-oxo-tetrahvdro-2H- :ll3,2-oxazafosforin-4-vl1-karbamid, cis-formen 1,1 g (4,0 mmol) 4-hydroxicyklofosfamid upplöstes i metanol, försattes med spår av triklorättiksyra, fick stå över natten vid -25° , varefter metanolen avdrevs under skonsamma beting- elser, återstoden upptogs í en ringa mängd metylenklorid och den erhållna lösningen torkades och indunstades till 1,2 g 4-metoxícyklofosfamid (dvs. 2-(bis-(2-kloretyl)-amino)-4 toxi-tetrahydro~2H-1,3,2-oxazafosforin-2-oxíd). Därefter upp- löstes 1,2 g 4-metoxicyklofosfamid och 304 mg hydroxikarbamid 10 15 20 25 30 35 458 205 7 i 3 ml DMF och lösningen förvarades 20 timmar vid -2S° i kylskåp. Kristallgröten spâddes med 3 ml ättíkester, avsögs, tvättades, torkades och omkristalliserades ur metanol.Example 2 1-Hydroxy-1- [2- (bis- (2-chloroethyl) -amino) -2-oxo-tetrahydro-2H-: 1,3,2-oxazaphosphorin-4-yl] -urea, cis-form 1.1 g (4.0 mmol) of 4-hydroxycyclophosphamide was dissolved in methanol, added with traces of trichloroacetic acid, allowed to stand overnight at -25 °, after which the methanol was evaporated under gentle conditions, the residue was taken up in a small amount of methylene chloride and the resulting solution was dried and evaporated to 1.2 g of 4-methoxycyclophosphamide (ie 2- (bis- (2-chloroethyl) -amino) -4-toxi-tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide). Then 1.2 g of 4-methoxycyclophosphamide and 304 mg of hydroxycarbamide were dissolved in 3 ml of DMF and the solution was stored for 20 hours at -2S ° in a refrigerator. The crystalline porridge was diluted with 3 ml of acetic ester, filtered off with suction, washed, dried and recrystallized from methanol.
Utbyte: 670 mg (50 % av det teoretiska värdet) av samma produkt som i exempel 1.Yield: 670 mg (50% of theory) of the same product as in Example 1.
Exempel 3 1-hvdroxi-1-I2-(bis-(2-kloretvl)~amíno)-2-oxo-tetrahvdro-2H- -1.3.2-oxazafosforin-4-vl1-karbamid, trans-formen 16 g (58 mmol) 4-hydroxicyklofosfamid och 5,2 g (68 mmol) hydroxikarbamid upplöstes i 160 ml vatten, surgjordes med triklorättíksyra (pH 3-4) och fick stå 20 timmar vid 0° i kylskåp. Därefter avsögs kristallgröten, tvättades med vat- ten, torkades i högvakuum över fosforpentoxid och omkristal- líserades ur metanol/kloroform.Example 3 1-Hydroxy-1- [2- (bis- (2-chloroethyl) -amino) -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl] -urea, trans form 16 g (58 mmol) 4-hydroxycyclophosphamide and 5.2 g (68 mmol) of hydroxycarbamide were dissolved in 160 ml of water, acidified with trichloroacetic acid (pH 3-4) and allowed to stand for 20 hours at 0 ° in a refrigerator. The crystal porridge was then filtered off, washed with water, dried in a high vacuum over phosphorus pentoxide and recrystallized from methanol / chloroform.
Utbyte: 12,7 g (65 % av det teoretiska värdet) av trans- ~formen av produkten i exempel 1 Smältpunkt: 148° (sönderdelning) Exempel 4 1-hvdroxi-1-I3-(2-kloretvl)-2-(bis-(2'-kloretvl)-amíno)~2- oxo-tetrahvdro-ZH-1.3,2-oxazafosforin-4-vl1-karbamid 20 g (50 mmol) 4-hydroxitrofosfamid (dvs. 3-(2~kloretyl)-2- -(bis(2-kloretyl)-amino)-4-hydroxi-tetrahydro-2H-1,3,2-oxaza- fosforin-2-oxid och 5,3 g (70 mmol) hydroxikarbamid upplöstes i 100 ml DMF och kyldes till -15°. Därefter surgjordes bland- ningen med triklorättiksyra (pH 3-4) och omrördes 5 timmar vid -l5°. Efter att ha fått stà över natten vid 0° späddes reaktíonslösningen med den dubbla mängden vatten. Därefter utskakades blandningen fyra gånger med vardera 300 ml ättik- ester/metanol (l0:l), de kombinerade ättikesterfaserna tvät- tades två gånger med vatten, torkades över natriumsulfat och indunstades i vakuum till 22 g olja. Efter upptagande i ättik- ester/metanol utkristalliserade 4,2 g produkt med smältpunkten 4558 10 15 20 25 30 35 2()3 8 106-110°. Moderluten underkastades separation kolonnkro- matografískt på kíselgel med kloroform/metanol (10:1) och omkrístallíserades med det första kristallisatet ur ättik- ester/metanol.Yield: 12.7 g (65% of theory) of the transform of the product of Example 1 Melting point: 148 ° (decomposition) Example 4 1-Hydroxy-1-3-3- (2-chloroethyl) -2- ( bis- (2'-chloroethyl) -amino) -2-oxo-tetrahydro-ZH-1,3,2-oxazaphosphorin-4-yl-urea 20 g (50 mmol) of 4-hydroxythrophosphamide (ie 3- (2-chloroethyl) -2- - (bis (2-chloroethyl) -amino) -4-hydroxy-tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide and 5.3 g (70 mmol) of hydroxycarbamide were dissolved in 100 ml DMF and cooled to -15 °, then the mixture was acidified with trichloroacetic acid (pH 3-4) and stirred for 5 hours at -15 ° After standing overnight at 0 °, the reaction solution was diluted with twice the amount of water. the mixture four times with 300 ml each of ethyl acetate / methanol (10: 1), the combined acetic ester phases were washed twice with water, dried over sodium sulphate and evaporated in vacuo to 22 g of oil.After incorporation into vinegar ester / methanol crystallized out 4.2 g of product with melting point 4558 10 15 20 25 30 35 2 () 3 8 106-110 °. The mother liquor was column chromatographed on silica gel with chloroform / methanol (10: 1) and recrystallized from the first crystallizate from vinegar ester / methanol.
Utbyte: 7,0 g (35 % av det teoretiska värdet) smä1tpunkt= 115-1ee° (sönaeraelning).Yield: 7.0 g (35% of theory) melting point = 115-1ee ° (solar eclipse).
Exemgel 5 3-bensvl¿1-hvdroxí-1-f2-(bis-(2-kloretvl)-amíno)-2-oxo-tetra- hydro-ZH-1.3.2-oxazafosforin-4-vl1-karbamíd Till 900 mg (3,25 mmol) 4-hydroxicyklofosfamid i l ml metylen~ klorid sattes 540 mg (3,25 mmol) 3-bensyl-l-hydroxikarbamid i 40 ml aceton och en katalytisk mängd triklorättiksyra. Bland- ningen fick stå vid -250 över natten, varefter kristallerna avsögs, tvättades med aceton och eter och omkristalliserades ur ättikester.Example 5 3-Benzyl-1-hydroxy-1- [2- (bis- (2-chloroethyl) -amino) -2-oxo-tetrahydro-ZH-1,3,2-oxazaphosphorin-4-yl] -urea To 900 mg (3.25 mmol) 4-hydroxycyclophosphamide 1 ml of methylene chloride was added 540 mg (3.25 mmol) of 3-benzyl-1-hydroxycarbamide in 40 ml of acetone and a catalytic amount of trichloroacetic acid. The mixture was allowed to stand at -250 overnight, after which the crystals were filtered off with suction, washed with acetone and ether and recrystallized from ethyl acetate.
Utbyte: 500 mg (40 % av det teoretiska värdet).Yield: 500 mg (40% of theory).
Smältpunkt: l22~l23° (sönderdelning).Melting point: 1202 ~ 233 ° (decomposition).
Exempel 6 3-(0-bromfenvl3-1-hvdroxi-1-I2-(bis-(2-kloretyl)-amíno)-2- oxo-tetrahvdro-2H-1.3,2-oxazafosforin-4-vl1-karbamíd 560 mg (2 mmol) 4-hydroxicyklofosfamid i 10 ml aceton försattes med 460 mg 3-o-bromfenyl-l-hydroxikarbamid och en katalytisk mängd tríklorättíksyra och fick stå vid -250. Efter 2 dagar avsögs kristallerna och omkristalliserades ur aceton.Example 6 3- (O-Bromophenyl] -1-hydroxy-1- [2- (bis- (2-chloroethyl) -amino) -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl] -urea 560 mg (2 mmol) of 4-hydroxycyclophosphamide in 10 ml of acetone was added with 460 mg of 3-o-bromophenyl-1-hydroxycarbamide and a catalytic amount of trichloroacetic acid and allowed to stand at -250. After 2 days the crystals were filtered off and recrystallized from acetone.
Utbyte: Smältpunkt: 320 mg (32 % av det teoretiska värdet). 110-111° (sönaeraelning). 10 15 20 9 458 203 Exsmnall 3-Qgggggi-N-I2-(bis-(2-kloretvl3-amino)-2-oxo-tetrahvdro-2H- -1,3,2-oxazafosforin-4-yl]-N-mogfolinokarbonylamin 1,2 g (4,3 mmol) 4-hydroxicyklofosfamid i 15 ml aceton för- sattes med 630 mg (4,3 mmol) N-hydroxi-morfolino-karboxamid och spår av triklorättíksyra och fick stå vid -25°. Efter fy- ra dagar avsögs kristallerna och omkristalliseradee ur aceton Utbyte: 780 mg (45 % av det teoretiska värdet).Yield: Melting point: 320 mg (32% of theory). 110-111 ° (sunrise). 10 15 20 9 458 203 Example 3-Qgggggi-N-I2- (bis- (2-chloroethyl-3-amino) -2-oxo-tetrahydro-2H--1,3,2-oxazaphosphorin-4-yl] -N- mogfolinocarbonylamine 1.2 g (4.3 mmol) of 4-hydroxycycloposphamide in 15 ml of acetone were added with 630 mg (4.3 mmol) of N-hydroxy-morpholino-carboxamide and traces of trichloroacetic acid and allowed to stand at -25 °. for four days the crystals were filtered off and recrystallized from acetone Yield: 780 mg (45% of theory).
Smältpunkt: 123-124° (sönderdelníng).Melting point: 123-124 ° (decomposition).
Exempel 8-70 Utgående fràn motsvarande 4-hydroxi-tetrahydro-ZH-1,3,2- -oxazafosforin-2-oxider framställdes på analogt sätt de i nedanstående tabell angivna 4-ureídooxiderivaten med den på eid 10 angivna allmänna formeln. 458 203 15 vom f v Q; A mmm v mnïmvïwmufiå- .à -m -Nmuwmqvàu hmowmvflflu m _. . ä. . _ var? 1 09. ©~mu-~mu»mz..wwu.E- à Im -Nmuwmuåu -Nmvwmuåu 9 . _ _ _ ä.. _ . _ _ . v03 .. 3 wmuumu-wmu..mz-opfiêf å. .à .Nmuwmuåu -Nmuwmuinu E. . . _ :ö ._ ._ _ _. _ voi.. ®imz|æwwwêln .lm .à ...Nmuwmuåo -Nmowmuåu S. _ uøš 1 2. 96%A§öT=z-0U-3ow2- å. _ .à -Nmowmoihp -wšwmuåu Nv 000m W=UMAN=UTmZAUUAxQvšI -m -m -Nä muåu f m0 H78 I. oomm 3~=U.=u1mz»oUAxo~š- |m_ _ .à -Nmuwmuffiu -Nmowmuuflu 3 v.. E.. mmv-m=v-mz-ouåzovmz.. .à _ -m -Nmvwmuåo hmuwmuxflo m 0092. ånïmzlouäšvš- å à -Nmvwmvifiu -Nmumšnfiu w 1 .a . .az :mflumwfxmwmuawwflm _ . m dm Mm. Nm vm .fiwmsmxm .J _ O/m\ o _ _ N _ Z\ 1/ Z\ i K Å /J 458 203 1 u 019 @-š|oo z- -m -m -NmuNmUåQ -NNONNULÜU NN.Examples 8-70 Starting from the corresponding 4-hydroxy-tetrahydro-ZH-1,3,2--oxazaphosphorine-2-oxides, the 4-uride oxide derivatives of the general formula given in Eid 10 are prepared in an analogous manner. 458 203 15 vom f v Q; A mmm v mnïmvïwmu fi å- .à -m -Nmuwmqvàu hmowmv flfl u m _. . ä.. _ where? 1 09. © ~ mu- ~ mu »mz..wwu.E- à Im -Nmuwmuåu -Nmvwmuåu 9. _ _ _ ä .. _. _ _. v03 .. 3 wmuumu-wmu..mz-op fi êf å. .à .Nmuwmuåu -Nmuwmuinu E.. . _: ö ._ ._ _ _. _ voi .. ®imz | æwwwêln .lm .à ... Nmuwmuåo -Nmowmuåu S. _ uøš 1 2. 96% A§öT = z-0U-3ow2- å. _ .à -Nmowmoihp -wšwmuåu Nv 000m W = UMAN = UTmZAUUAxQvšI -m -m -Nä muåu f m0 H78 I. oomm 3 ~ = U. = u1mz »oUAxo ~ š- | m_ _ .à -Nmuwmuf fi u -Nmowmuu fl u 3 v .. E .. mmv-m = v- mz-ouåzovmz .. .à _ -m -Nmvwmuåo hmuwmux fl o m 0092. ånïmzlouäšvš- å à -Nmvwmvi fi u -Nmumšn fi u w 1 .a. .az: m fl umwfxmwmuaww fl m _. m dm Mm. Nm vm .fi wmsmxm .J _ O / m \ o _ _ N _ Z \ 1 / Z \ i K Å / J 458 203 1 u 019 @ -š | oo z- -m -m -NmuNmUåQ -NNONNULÜU NN.
. SO. uoä .. mm nmu|o|©-š..wwwål -m à .Nmuflwøtfiv lNmuNmufflu S-.. SO. uoä .. mm nmu | o | © -š..wwwål -m à .Nmu fl wøt fi v lNmuNmuf fl u S-.
. EQ . _ . .m . _ vi? | m? šwwwfiz- um. -m |NmuNmuåu lNmuNmulfiu NN EO . . . . . 00:: Nüšlou z-. å. im -NmuNmuåu 1NmuNmuåu mNw G . EQ . . uoä ømzwmwßaá; -m »m -Nmnmmuáo -NmuNmuåu NN .. EQ. _. .m. _ we? | m? šwww fi z- um. -m | NmuNmuåu lNmuNmul fi u NN EO. . . . . 00 :: Nüšlou z-. å. im -NmuNmuåu 1NmuNmuåu mNw G. EQ. . uoä ømzwmwßaá; -m »m -Nmnmmuáo -NmuNmuåu NN.
I Q? . _ N N N N vowí 8 \ šèo r à -m 1 m0 5-8 - mv mvàu .N n _ . EQ. . N N _ N N N. NN uooNf .. m2. .Hm|©.mz|mwuQE1 um -m .. mv 3-5 - m0 5-8 ON.I Q? . _ N N N N vowí 8 \ šèo r à -m 1 m0 5-8 - mv mvàu .N n _. EQ. . N N _ N N N. NN uooNf .. m2. .Hm | © .mz | mwuQE1 um -m .. mv 3-5 - m0 5-8 ON.
^IO~ f \ . uoNm ... å -mzßwfivå- -m -m hmflmmuinu -NæuNmuflfiu 9.^ IO ~ f \. uoNm ... å -mzßw fi vå- -m -m hm fl mmuinu -NæuNmu flfi u 9.
. ES. . . uowm ÛIÉHRÉÉI á »m lNmoNmoåu xNmuNmuåu m v _ EQ. _ _. _ _ _ 000m.. NAÛV mušzfxomumå; :m lm lNmuNmuffiu »Nmnmmufflo .i _23' WUuwN/Iwm .mmwH . . .MZ C »xcäfimsw m :m mm Nm Pm Hmåewxm _45s 203 '12 36 . @^nmov.z1%musz1 1m à .hmummoflflo hmuwmoåo mn % mo. _ uommf Û1U1mz11wwuwÛÅ1 1m .á hmowmuåu Nmowmuåfiu .S _ 1 . _ . äs. _ . oowo.. mmwumouhmnïmzåuo 1 1m 1m hmowmuiflo 1wmuwmu1flo mn m9 vom: 1 9; w^nmuvom1wmu1mz1wfiå1 1m 1m hmowmuflno hmumšào mn E: nnó mo1~m01~mu1æz1ou 1 1m 1m Nmuwmuåu . hæuwmuinu en IOV flf: 1 :: u mo? 1 NE. mmwuwøu1~mmuvmu1mz1oo 1 1m 1m hmuwmuåu ...hmummuiflu ...mn o EQ. 00mm flo1wmu1wmo1mz1ßåz1 1m 1m hmuwmnïfiu Rmuwmuinu Nm u om 1 å äTßwmoYmzAWwo. 1 å 1m .hmommuåo hmuwmolno å 1 . L; .S . EQ . w 0.19 .81 1mz1æwà1 à .à hmowmohfiu 1 muwmoåu om m EQ . . h . , . 1 00mm 1 ä gàzwwwumå- å å. .wmummohfiu hmowmuznv _ mw N . .EQ _ o _ . _ uowt. 1 i.. gmzwwmißy? 1m . »m 1wmummu1fiu hmuwmuåu mm 20 . vom: 1 E; moz1g1mz1wwuqå1 1m 1m hmummuåu kmuwmuåu ä 59 wwum>|wm .mwmu .A2 AP m dä mm Nm vm Hwašwxm uxcsmuflmåw Uoen _. 458 203 Nmz:oo:mz: :m :NmuNmuåu :m :NmuNmuåo mn Nïo ®:mz:mu:mz: :m :m :NmuNmoåo :NmuNmuÅu Nm Qom? /U Nmo:m.m:mo:mz: :m :m :NmoNmuflfiu ...Nmoflmuåo .h 36 mmflïmzóuàfimuvfiu :m :m :NmoNmoåo :NmuNmuÅo m; . o! . .ooNí mmHïE/ïouåmmNuV :_ :m :m :NmuNmuåu :NmuNmuLfiu we wo muïßbvmmuvzoumz. m m. .mumufiu mumu u n ooßNv : mNf nmu:Fm:oo:^nmuvzN. :m :m :NmuNmuåo :NmuNmuflß .wa 00mm : mm N.^.nmuvz:ou:mm: »m :m :NmUNmuåu :NmuNmuåu n; ooNm _ NN mmNuv måumz: .:m :m :NmuNmuåu :NmuNmuåu Nm uofNf : mi. m. zèumz: :m :m :NmuNmuåu :NmuNmoLho S :: N N N N : »m6 çñnmovzöuånmoTz: :m :m :.. mv muåu : mv mu Ü om . . v. Ola . 4 a uowNf : WN.. @:mz:ou:^nmufiz\ :m :m :NmuNmuàu :NmuNmuåu mn OI :h : .m _ .É ffiwfluwwfxflwqwfmuawßm.wmw .m JM . . Mm Nå ...N Am-Qëwxm v02 To 3 æøšzåvuwïz- å .à kñmzuxflu ..~=u~=u.äu 3 uøfivèï .@..~=u|mz..ow, z.. :m5 a: -Nmußöxflu -Nmufnïflu 3 EQ _ v03 _. znïza ...a .å -Nmuwmuinu ..~=u~=u...~u 3 v05.. ~=z-øu..=z..~wnuu.=z| .å - -m -fiöåvàu ..~=u~mu.Au S 38 ©smzn Wi z- u: u: xwmufuxflu ...Nmufiæufifiu 3 38 Eâmïuåvvåvu z.. .à .å ..~mu~mu...fiu -Nmnmmuåu 3 :Q u .u Rïw? Nšuæwoåz- hä. . à .käwmuåo .wmuwmuåo .mm _. 36 Nmånávuåsz- _ å. ..-wšwmuffiu .å -wmummukownmu .R . . . . N - :m6 NÉAö e. .à ..~mu«.mw..nomnš 1: -Nä :u S n .wm . . . N N nn 009.11.. ßcïæmo - ...m .wšmmuiuo .hä .. m0 m» 3 nu R . mo. ...N w. .. moi; Nmzuwmoäz- .à -Nmuwmuinu -mmm mv .ö .B .R wøum>|um .amma ...Hz C uxcsmufldfinw m . im mm am fm Hwmåmxm 453 203 .mcummcwcwuflw .mchfinmuwfluä mv www Eomwm mvwwxm cmwcflnwmfinwu uxmumx mummflfinwuuæ swe ..~"mv HocmumE\EuowoHoHM ßwfløwšmmcfiuwflww >m mcH:fi:w>cm Hmflcfi Hmmfimmflx wa flwmuwoumëouxwßxflxwccsu ®«> um©Hm>|mm.E0cmm mwwmnwmfinmßxwuwx 458 203 mcummcflcmumu m:«Aw2Hw mfifio cm >m Euow fl,mn .wumuwmflnuøx wxofl uw mcuwøxcømufiwëw ^~ _ . _ . 4 . uømmcnæ gås? u z. _ a: . .å -Nmuwmïflu Nmoumuaflu 2 _ EQ Qrë . 5 uumofwwow. woou.. =u|mz|ou .zn .à :m ...dmuflmonflu :Nmufvnflu ._ 3 mo _ . nom: , ©namvl~ouf~muamzpo z.. n: am :flmuamutfiu nflmuflmoaflu 3 EQ . . umnnf ficmzaou z.. .à . n: . ..~mu~mu..._..u :wmum muåu ß w . o EQ _ . uofl: |mzlwwnïza . .à . . .å .hmufoaflu .kmußfiuåu . 3 EQ _ . _ . uoíä . . flmzwow.. ©|mz|ou| z- .à um :Nmuflmuuflu xwmoumunflu. 3 EQ . . _ wwum>|wm .mmwu .uz A» uxcflmuawëw fl~ vx ~ mm Nm . va . Hmmëmxm 10 15 20 25 30 35 458 203 16 Exemoel 71 §tyl-2-(bis-(2-kloretyl)-amino-2-oxo-tetrahydro-2H-1,3,2- -oxazafosforin-4-yl-oxi-karbamat 550 mg (2 mmol) 4-hydroxicyklofosfamid och 210 mg (2 mmol) etylhydroxikarbamat (hydroxiuretan) upplöstes i 5 ml torr al- koholfri metylenklorid, försattes med en katalytisk mängd triklorättiksyra och molekylsikt 4 A och fick stå 3 dagar vid -250. Därefter avskildes molekylsikten och blandningen tvättades i separertratt en gång med utspädd natriumvâtekar- bonatlösning, den över natriumsulfat torkade metylenkloridfa- sen indunstades i vakuum och späddes med eter. Efter att ha fått stå 20 timmar vid -250 avsögs kristallerna, tvättades och torkades.. ES. . . uowm ÛIÉHRÉÉI á »m lNmoNmoåu xNmuNmuåu m v _ EQ. _ _. _ _ _ 000m .. NAÛV mušzfxomumå; : m lm lNmuNmuf fi u »Nmnmmuf fl o .i _23 'WUuwN / Iwm .mmwH. . .MZ C »xcä fi msw m: m mm Nm Pm Hmåewxm _45s 203 '12 36. @ ^ nmov.z1% musz1 1m à .hmummo flfl o hmuwmoåo mn% mo. _ uommf Û1U1mz11wwuwÛÅ1 1m .á hmowmuåu Nmowmuå fi u .S _ 1. _. äs. _. oowo .. mmwumouhmnïmzåuo 1 1m 1m hmowmui fl o 1wmuwmu1 fl o mn m9 vom: 1 9; w ^ nmuvom1wmu1mz1w fi å1 1m 1m hmowmu fl no hmumšào mn E: nnó mo1 ~ m01 ~ mu1æz1ou 1 1m 1m Nmuwmuåu. hæuwmuinu en IOV fl f: 1 :: u mo? 1 NE. mmwuwøu1 ~ mmuvmu1mz1oo 1 1m 1m hmuwmuåu ... hmummui fl u ... mn o EQ. 00mm fl o1wmu1wmo1mz1ßåz1 1m 1m hmuwmnï fi u Rmuwmuinu Nm u om 1 å äTßwmoYmzAWwo. 1 to 1m .hmommuåo hmuwmolno to 1. L; .S. EQ. w 0.19 .81 1mz1æwà1 à .à hmowmoh fi u 1 muwmoåu om m EQ. . hrs . ,. 1 00mm 1 ä gàzwwwumå- å å. .Wmummoh fi u hmowmuznv _ mw N. .EQ _ o _. _ uowt. 1 i .. gmzwwmißy? 1m. »M 1wmummu1 fi u hmuwmuåu mm 20. vom: 1 E; moz1g1mz1wwuqå1 1m 1m hmummuåu kmuwmuåu ä 59 wwum> | wm .mwmu .A2 AP m dä mm Nm vm Hwašwxm uxcsmu fl måw Uoen _. 458 203 Nmz: oo: mz:: m: NmuNmuåu: m: NmuNmuåo mn Nïo ®: mz: mu: mz:: m: m: NmuNmoåo: NmuNmuÅu Nm Qom? / U Nmo: m.m: mo: mz:: m: m: NmoNmu flfi u ... Nmo fl muåo .h 36 mm fl ïmzóuà fi muv fi u: m: m: NmoNmoåo: NmuNmuÅo m; . O! . .ooNí mmHïE / ïouåmmNuV: _: m: m: NmuNmuåu: NmuNmuL fi u we wo muïßbvmmuvzoumz. m m. .mumu fi u mumu u n ooßNv: mNf nmu: Fm: oo: ^ nmuvzN. : m: m: NmuNmuåo: NmuNmu fl ß .wa 00mm: mm N. ^. nmuvz: ou: mm: »m: m: NmUNmuåu: NmuNmuåu n; ooNm _ NN mmNuv måumz:.: m: m: NmuNmuåu: NmuNmuåu Nm uofNf: mi. m. zèumz:: m: m: NmuNmuåu: NmuNmoLho S :: N N N N: »m6 çñnmovzöuånmoTz:: m: m: .. mv muåu: mv mu Ü om. . v. Ola. 4 a uowNf: WN .. @: mz: ou: ^ nmu fi z \: m: m: NmuNmuàu: NmuNmuåu mn OI: h: .m _ .É f fi w fl uwwfx fl wqwfmuawßm.wmw .m JM. . Mm Nå ... N Am-Qëwxm v02 To 3 æøšzåvuwïz- å .à kñmzux fl u .. ~ = u ~ = u.äu 3 uø fi vèï. @ .. ~ = u | mz..ow, z ..: m5 a: -Nmußöx fl u -Nmufnï fl u 3 EQ _ v03 _. znïza ... a .å -Nmuwmuinu .. ~ = u ~ = u ... ~ u 3 v05 .. ~ = z-øu .. = z .. ~ wnuu. = z | .å - -m -fi öåvàu .. ~ = u ~ mu.Au S 38 © smzn Wi z- u: u: xwmufux fl u ... Nmu fi æu fifi u 3 38 Eâmïuåvvåvu z .. .à .å .. ~ mu ~ mu .. .fi u -Nmnmmuåu 3: Q u .u Rïw? Nšuæwoåz- hä. . à .käwmuåo .wmuwmuåo .mm _. 36 Nmånávuåsz- _ å. ..- wšwmuf fi u .å -wmummukownmu .R. . . . N -: m6 NÉAö e. .À .. ~ mu «.mw..nomnš 1: -Nä: u S n .wm. . . N N nn 009.11 .. ßcïæmo - ... m .wšmmuiuo .hä .. m0 m »3 nu R. mo. ... N w ... moi; Nmzuwmoäz- .à -Nmuwmuinu -mmm mv .ö .B .R wøum> | um .amma ... Hz C uxcsmu fl d fi nw m. im mm am fm Hwmåmxm 453,203 .mcummcwcwu al w .mch fi nmuw al UA MW www Eomwm mvwwxm cmwc al NWM fi NWU uxmumx mumm flfi nwuuæ eng .. ~ "mv HocmumE \ EuowoHoHM SSW al øwšmmc fi uw al ww> m MCH: fi: w> cm Hm f c f Hmm fi mm fl x wa al wmuwoumëouxwßx al xwccsu ®«> um © Hm> | mm .E0cmm mwwmnwm fi nmßxwuwx 458 203 mcummc fl cmumu m: «Aw2Hw m fifi o cm> m Euow fl, mn .wumuwm fl nuøx wxo fl uw mcuwøxcømu fi wëw ^ ~ _. _M. E. . 5 uumofwwow. Woou .. = u | mz | ou .zn .à: m ... dmu fl mon fl u: Nmufvn fl u ._ 3 mo _. Nom:, © namvl ~ ouf ~ muamzpo z .. n: am: fl muamut fi u n fl mu fl moa fl u 3 EQ.. Umnnf fi cmzaou z .. .à. N:. .. ~ mu ~ mu ..._ .. u: wmum muåu ß w. O EQ _. Uo fl: | mzlwwnïza. .À.. .Å .hmufoa fl u .kmuß fi uåu. 3 EQ _. _. uoíä.. fl mzwow .. © | mz | ou | z- .à um: Nmu fl muu fl u xwmoumun fl u. 3 EQ.. _ wwum> | wm .mmwu .uz A »uxc fl muawëw fl ~ vx ~ mm Excerpt 71 15 Tyl-2- (bis- (2-chloroethyl) -amino-2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorine 4-yl-oxy-carbamate 550 mg (2 mmol) 4-hydroxycyclophosphamide and 210 mg (2 mmol) l) ethyl hydroxycarbamate (hydroxyurethane) was dissolved in 5 ml of dry alcohol-free methylene chloride, added with a catalytic amount of trichloroacetic acid and molecular sieve 4 A and allowed to stand for 3 days at -250. Then the molecular sieve was separated and the mixture was washed in a separatory funnel once with dilute sodium bicarbonate solution, the methylene chloride phase dried over sodium sulfate was evaporated in vacuo and diluted with ether. After standing for 20 hours at -250, the crystals were filtered off, washed and dried.
Utbyte: ' 290 mg (40 % av det teoretiska värdet).Yield: 290 mg (40% of theory).
Smältpunkt: 960.Melting point: 960.
Exemnel 72 Bensy1-2-(bis-(2-kloretyl)-amino-2-oxo-tetrahydro-2H-1,3,2- -oxazafosforin-4fyl-oxi-karbamat 750 mg (2,7 mmol) 4-hydroxicyklofosfamid och 450 mg (2,7 mmol) bensylhydroxikarbamat upplöstes i 6 ml alkoholfri metylenklo- rid, försattes med en ringa mängd triklorättiksyra och fick stå i kylskåp vid -250. Efter 3 dagar filtrerades blandningen och moderluten späddes med 5 ml kloroform, tvättades med vat- ten, med utspädd natriumvätekarbonatlösning och ytterligare med vatten, torkades över natriumsulfat och indunstades i va- kuum. Den oljiga återstoden omkristalliserades ur ättikester/ en liten mängd metanol.Example 72 Benzyl 2- (bis- (2-chloroethyl) -amino-2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-phyl-oxy-carbamate 750 mg (2.7 mmol) 4-hydroxycyclophosphamide and 450 mg (2.7 mmol) of benzyl hydroxycarbamate were dissolved in 6 ml of non-alcoholic methylene chloride, added with a small amount of trichloroacetic acid and allowed to stand in a refrigerator at -250. After 3 days the mixture was filtered and the mother liquor was diluted with 5 ml of chloroform, washed with water The tin, with dilute sodium bicarbonate solution and further with water, was dried over sodium sulphate and evaporated in vacuo, the oily residue was recrystallized from ethyl acetate / a small amount of methanol.
Utbyte: 680 mg (59 % av det teoretiska värdet). smä1tpufikt= 112-114°. b. 10 l5 20 25 30 35 458 203 17 Exemgel 73 {3-hvdroxi-3~[2-(bis-(2-kloretvl3~amíno\-2-oxo-tetrahvdro-2H_ -1.3,2-oxazafosforin-4-vl1-ureídoï-ättíksvra-cvklohexv1amin- salt a) 3-hydroxi-ureido-ättiksyra 56,5 g (0,28 mol) glycinbensylester-hydroklorid suspenderades i 300 ml toluen och under omröring inleddes torr fosgengas tvâ timmar vid en badtemperatur av 1400. Därefter indunstades reaktionsblandningen i vakuum och återstoden destillerades i högvakuum.Yield: 680 mg (59% of theory). smä1tpu fi kt = 112-114 °. b. 10 l5 20 25 30 35 458 203 17 Exemgel 73 {3-Hydroxy-3- [2- (bis- (2-chloroethyl] -amino] -2-oxo-tetrahydro-2H_-1,3,2-oxazaphosphorin-4- v11-ureido-acetic acid-cyclohexylamine salt a) 3-hydroxy-ureido-acetic acid 56.5 g (0.28 mol) of glycine benzyl ester hydrochloride were suspended in 300 ml of toluene and with stirring dry phosgene gas was started for two hours at a bath temperature of 1400. Then the reaction mixture was evaporated in vacuo and the residue was distilled in high vacuum.
Utbyte: 51 g (95 % av det teoretiska värdet) bensyl-iso- cyanat-acetat Kokpunkt= 0,05: 100-1o2°.Yield: 51 g (95% of theory) of benzyl isocyanate acetate Boiling point = 0,05: 100-1o2 °.
Till 28,7 g (O,l5 mol) bensyl-isocyanat-acetat i 50 ml dioxan sattes droppvis under omröring och kylning då och då 6,6 g (0,2 mol) hydroxylamin i 200 ml dioxan. Efter l timmes omröring vid rumstemperatur indunstades det hela i vakuum och återstoden omkristalliserades ur ättikester.To 28.7 g (0.1 mol) of benzyl isocyanate acetate in 50 ml of dioxane was added dropwise with occasional stirring and cooling 6.6 g (0.2 mol) of hydroxylamine in 200 ml of dioxane. After stirring for 1 hour at room temperature, the whole was evaporated in vacuo and the residue was recrystallized from ethyl acetate.
Utbyte: 28,1 g (83,6 % av det teoretiska värdet) bensyl-3- -hydroxi-ureido-acetat.Yield: 28.1 g (83.6% of theory) of benzyl 3-hydroxy-ureido-acetate.
Smältpunkt: 113-1200. 22,4 g (0,1 mol) bensyl-3-hydroxi-ureido-acetat i 300 ml metan- ol försattes med S g palladiumkol och hydrerades i en skakauto- klav. Efter ca. 20 minuter hade den erforderliga vätemängden upptagits. Katalysatorn avsögs, filtratet indunstades i vakuum och den fasta återstoden omkristalliserades ur dioxan.Melting point: 113-1200. 22.4 g (0.1 mol) of benzyl 3-hydroxy-ureido-acetate in 300 ml of methanol were added with 5 g of palladium carbon and hydrogenated in a shake autoclave. After approx. 20 minutes, the required amount of hydrogen had been absorbed. The catalyst was filtered off with suction, the filtrate was evaporated in vacuo and the solid residue was recrystallized from dioxane.
Utbyte: 9,8 g (73 % av det teoretiska värdet) 3-hydroxi- -ureido-ättiksyra. smä1tpunkt= 13s°. b) 2,4 g (18 mmol) 3-hydroxi-ureido-ättiksyra i 10 ml vatten och 25 ml aceton försattes med 6,1 g (2 mmol) 4-hydroxicyklo- fosfamid och fick stå över natten vid -250. Därefter tillsattes 10 15 20 25 30 35 458 203 18 25 ml aceton och l,8 g (18 mmol) cyklohexylamin i l0 ml ace- ton, efter 2 timmar avsögs kristallerna och omkristalliserades ur aceton med en ringa mängd metanol.Yield: 9.8 g (73% of theory) of 3-hydroxy-ureido-acetic acid. melting point = 13s °. b) 2.4 g (18 mmol) of 3-hydroxy-ureido-acetic acid in 10 ml of water and 25 ml of acetone were added with 6.1 g (2 mmol) of 4-hydroxycyclophosphamide and allowed to stand overnight at -250. Then 45 ml of acetone and 1.8 g (18 mmol) of cyclohexylamine in 10 ml of acetone were added, after 2 hours the crystals were filtered off and recrystallized from acetone with a small amount of methanol.
Utbyte: 3,1 g (44 % av det teoretiska värdet). smä1tpunxc= 107-1o8°.Yield: 3.1 g (44% of theory). smä1tpunxc = 107-1o8 °.
Exempel 74 3-ÅÉ,N-(bis-(2-kloretyl)-diamino-fosfinyl-ox;7-propionaldehyd- -oxim (aldofosfamid-oxim) 4,0 g (l3,7 mmol) 4-hydroperoxicykloíosfamid suspenderades i 50 ml vatten under iskylning och försattes med 500 mg natrium- tiosulfat x 5 mol vatten. Under omröring vid 5-l0° kontrolle- rades pH-värdet med en pH-mätare och pH-värdet hölls mellan 4,5 och 5,5 med hjälp av 2 n svavelsyra och en koncentrerad lösning av natriumtiosulfat tillfördes droppvis till dess pH- -värdet icke längre steg. Man omrörde en halv timme vid ca. 100, tillsatte droppvis en vattenlösning av 950 mg hydroxyl- amin-hydroklorid, höll pH-värdet vid 5 med 2 n natronlut, lät reaktionsblandningen stå över natten i kylskåp vid So, extra- herade fyra gånger med vardera 50 ml ättikester och indunsta- de de organiska extrakten i vakuum vid 300 efter torkning över natriumsulfat. Återstoden upptogs i metylenklorid och kristal- lerna avsögs efter l dag.Example 74 3-ÅE, N- (bis- (2-chloroethyl) -diamino-phosphinyl-ox; 7-propionaldehyde-oxime (aldophosphamide-oxime) 4.0 g (13.7 mmol) of 4-hydroperoxycycloiosfamide were suspended in 50 g ml of water under ice-cooling and was added with 500 mg of sodium thiosulphate x 5 mol of water While stirring at 5-10 °, the pH was checked with a pH meter and the pH was kept between 4.5 and 5.5 using of 2 n sulfuric acid and a concentrated solution of sodium thiosulphate were added dropwise until the pH value no longer rose, stirred for half an hour at about 100, an aqueous solution of 950 mg of hydroxylamine hydrochloride was added dropwise, the pH was maintained at 5 with 2 n sodium hydroxide solution, the reaction mixture was allowed to stand overnight in a refrigerator at 50 DEG C., extracted four times with 50 ml of acetic ester each and evaporated the organic extracts in vacuo at 300 after drying over sodium sulfate. The residue was taken up in methylene chloride and crystals. sucked after 1 day.
Utbyte: 3,4 g (85 % av det teoretiska värdet). smä1tpunkt= 79-s1°.Yield: 3.4 g (85% of theory). melting point = 79 ° C.
Exempel 75 3-p-bromfenvl-1-hvdroxi-1-[2-(bis-(2-kloretvl)-amíno)-2-oxo- tetrahvdro-2H-1,3.2-oxazafosforin-4-vllkarbamid 5,8 g (20 mmol) aldofosfamidoxim i 60 ml aceton försattes med 4 g (20 mmol) p-bromfenylisocyanat i 40 ml aceton och omrördes 5 timmar under kylning. Efter 2 timmar torkades det avsugna _ _ . _ . _ -r . . o kristallisatet i varuum 1 rotationszorangare vid 40 och om- 10 15 20 25 30 35 458 203 19 kristalliserades ur metanol.Example 75 3-p-Bromophenyl-1-hydroxy-1- [2- (bis- (2-chloroethyl) -amino) -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl] urea 5.8 g (20 mmol) of aldophosphamidoxime in 60 ml of acetone was added with 4 g (20 mmol) of p-bromophenyl isocyanate in 40 ml of acetone and stirred for 5 hours under cooling. After 2 hours, the aspirated _ _ was dried. _. _ -r. . The crystallizate in the 1 rotary zorangar at 40 and recrystallized from methanol was crystallized from methanol.
Utbyte: 8,1 g (82,8 % av det teoretiska värdet).Yield: 8.1 g (82.8% of theory).
Smältpunkt: 118-l20°.Melting point: 118-120 °.
Exemgel 76 3-m-trifluormetvlfenyl-1-hvdroxi-1-I2-(bis-(2-kloretvl)-ami- no)-2-oxotetrahvdro-2H-1.3.2-oxazafosforín-4-V1lkarbamid 7,3 g (25 mmol) aldofosfamidoxim i 80 ml aceton försattes med 4,7 g (25 mmol) m-trifluormetylfenylisocyanat i 40 ml aceton, omrördes 3 timar vid 0°, fick stå över natten i kylskåp vid -25° och försattes med 150 ml petroleumeter, varefter de er- hållna kristallerna avsögs efter att ha fått stå över natten i kylskåp vid -250. Kristallisatet torkades vid 300 och om- kristalliserades ur isopropanol.Example Gel 76 3-m-Trifluoromethylphenyl-1-hydroxy-1- [2- (bis- (2-chloroethyl) -amino) -2-oxotetrahydro-2H-1,3,2-oxazaphosphorin-4-yl] urea 7.3 g ( 25 mmol) of aldophosphamidoxime in 80 ml of acetone were added with 4.7 g (25 mmol) of m-trifluoromethylphenyl isocyanate in 40 ml of acetone, stirred for 3 hours at 0 °, allowed to stand overnight in a refrigerator at -25 ° and added with 150 ml of petroleum ether. after which the crystals obtained were filtered off after being allowed to stand overnight in a refrigerator at -250. The crystallizate was dried at 300 and recrystallized from isopropanol.
Utbyte: 9,2 g (76,8 % av det teoretiska värdet).Yield: 9.2 g (76.8% of theory).
Smältpunktz 91~93O.Melting point 91 ~ 93O.
Exempel 77 3-cvklohexvl-l-hvdroxi-1-I2-(bis-(2-kloretvl)-amíno)-2-oxo- tetrahvdro-2H-1.3,2-oxazafosforin-4-vllkarbamid 5 g (18 mmol) aldofosfamid-oxim och 2,2 g cyklohexylisocyanat upplöstes vardera i 10 ml aceton och sammanfördes därefter vid OO. Efter 2 timmar avsögs kristallerna och eftertvätta- des med aceton/eter.Example 77 3-Cyclohexyl-1-hydroxy-1- [2- (bis- (2-chloroethyl) -amino) -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl] urea 5 g (18 mmol) of aldophosphamide oxime and 2.2 g of cyclohexyl isocyanate were each dissolved in 10 ml of acetone and then combined at 0 DEG. After 2 hours, the crystals were filtered off and washed with acetone / ether.
Utbyte: 4,2 g (56 % av det teoretiska Värdet). smältpunkt: 113°.Yield: 4.2 g (56% of theory). melting point: 113 °.
Exemgel 78 3-etvl-1-hvdroxi-1-I2-(bis-(2-kloretvl)-èmíno)-2-oxo-tetra- hvdro-2H-1,3.2-oxazafosforin-4-vl]-karbamid 5 g (18 mmol) aldofosfamid-oxim och 1,2 g etylísocyanat upp- 4558 10 15 20 25 30 35 2(]5 20 löstes vardera i 15 ml aceton och sammanfördes därefter vid ca. O°. Efter 5 timmar avsögs kristallisatet och eftertvätta- des med aceton/eter.Example 78 78 3-Ethyl-1-hydroxy-1- [2- (bis- (2-chloroethyl) -emino) -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl] -urea 5 g (18 mmol) of aldophosphamide oxime and 1.2 g of ethyl isocyanate were dissolved in 15 ml each of 15 ml of acetone and then combined at about 0 DEG C. After 5 hours, the crystallizate was filtered off and washed. with acetone / ether.
Utbyte: 3,5 9 (54 % av det teoretiska värdet). smä1tpunkt= 1o1°.Yield: 3.5 9 (54% of theory). melting point = 1o1 °.
Egemgel 79 §;1fluoren-2-vl)-1-hvdroxí-1-I2-(bis-(2-kloretvl)-amíno)-2- -oxo-tetrahvdro-2H-1,3.2-oxazafosforin-4-vl]-karbamid 2,9 g (10 mmol) aldofosfamid-oxim i 30 ml aceton försattes med 2,1 g (10 mmol) fluorenyl-2-isocyanat i 20 ml aceton vid Oo.Egemgel 79 §; 1fluoren-2-yl) -1-hydroxy-1- [2- (bis- (2-chloroethyl) -amino) -2--oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl] -urea 2.9 g (10 mmol) of aldophosphamide oxime in 30 ml of acetone were added with 2.1 g (10 mmol) of fluorenyl-2-isocyanate in 20 ml of acetone at 0 ° C.
Nästa dag avsögs den utfällda produkten, torkades i vakuum vid 600 och omkristalliserades ur ísopropanol/metanol.The next day, the precipitated product was filtered off, dried in vacuo at 600 and recrystallized from isopropanol / methanol.
Utbyte: 2,5 g (40,l % av det teoretiska värdet).Yield: 2.5 g (40.1% of theory).
Smältpunkt: 1140.Melting point: 1140.
Exempel 80 3-bensovl-1-hvdroxi-1-I2-(bis-(2-kloretvl5-amino)-2-oxo- tetrahvdro-2H-1,3,2-oxazafosforin-4-vl1-karbamíd 5,8 g (20 mmol) aldofosfamíd-oxim i 60 ml aceton försattes med 2,9 g (20 mmol) bensoylísocyanat i 40 ml aceton. Bland- ningen omrördes 5 timmar i isbad under kvâveatmosfär och efter ytterligare 2 timmar avsögs det fasta materialet, som torkades i rotationsindunstare vid 30° och omkristallíserades ur metanol.Example 80 3-Benzoyl-1-hydroxy-1- [2- (bis- (2-chloroethyl] -amino) -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl] -urea 5.8 g (20 mmol) of aldophosphamide oxime in 60 ml of acetone was added with 2.9 g (20 mmol) of benzoyl isocyanate in 40 ml of acetone, the mixture was stirred for 5 hours in an ice bath under a nitrogen atmosphere and after a further 2 hours the solid was filtered off. rotary evaporator at 30 ° and recrystallized from methanol.
Utbyte: 2,4 g (27,3 % av det teoretiska värdet).Yield: 2.4 g (27.3% of theory).
Smältpunkt: 124-125°. 10 15 20 458 203 21 Exemgel 81 3-p-nitrofeny1~1-hydroxi-l-[É-(bis~(2-kloretyl)-amino)-2- oxo-tetrahydro-2H-1,3,2-oxazafosforin-4-yI7-karbamid Till 5,8 g (20 mol) aldofosfamid-oxim i 60 ml aceton sattes en lösning av 3,3 g (20 mmol) p-nitrofenylisocyanat i 40 ml aceton. Efter 2 timmar avsögs den fasta produkten, som tor- kades i rotationsindunstare vid 400 och omkristalliserades ur dimetylformamid/etanol.Melting point: 124-125 °. Example 15 81 3-p-Nitrophenyl-1-hydroxy-1- [E- (bis- (2-chloroethyl) -amino) -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorine -4-yl-urea To 5.8 g (20 mol) of aldophosphamide oxime in 60 ml of acetone was added a solution of 3.3 g (20 mmol) of p-nitrophenyl isocyanate in 40 ml of acetone. After 2 hours, the solid product was filtered off with suction, dried in a rotary evaporator at 400 DEG and recrystallized from dimethylformamide / ethanol.
Utbyte: 6,7 g (73,5 % av det teoretiska värdet). smä1tpunkt= 117-11a°.Yield: 6.7 g (73.5% of theory). melting point = 117-11a °.
Claims (2)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8029222 | 1980-09-10 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| SE8105340L SE8105340L (en) | 1982-03-11 |
| SE458203B true SE458203B (en) | 1989-03-06 |
Family
ID=10515985
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SE8105340A SE458203B (en) | 1980-09-10 | 1981-09-08 | PROCEDURES FOR THE PREPARATION OF 4-CARBAMOYLOXIAZAPHOSPHORPHINES AND PHARMACEUTICAL PREPARATIONS FOR TREATMENT OF ANALYZOUS TUMORS AND SIMILAR ORAL DISEASES |
Country Status (29)
| Country | Link |
|---|---|
| JP (1) | JPS5785396A (en) |
| AR (1) | AR231989A1 (en) |
| AT (1) | AT386210B (en) |
| AU (1) | AU538275B2 (en) |
| BE (1) | BE890276A (en) |
| CA (2) | CA1161453A (en) |
| CH (1) | CH650787A5 (en) |
| CS (1) | CS227680B2 (en) |
| DD (1) | DD202166A5 (en) |
| DE (1) | DE3133309A1 (en) |
| DK (1) | DK400481A (en) |
| EG (1) | EG15392A (en) |
| ES (1) | ES8206544A1 (en) |
| FI (1) | FI70026C (en) |
| FR (1) | FR2489825A1 (en) |
| GR (1) | GR75300B (en) |
| HU (1) | HU185953B (en) |
| IE (1) | IE51784B1 (en) |
| IL (1) | IL63661A (en) |
| IT (2) | IT1198350B (en) |
| LU (1) | LU83613A1 (en) |
| NL (1) | NL8104093A (en) |
| NO (1) | NO161261C (en) |
| PL (1) | PL128627B1 (en) |
| PT (1) | PT73645B (en) |
| RO (1) | RO83972B (en) |
| SE (1) | SE458203B (en) |
| YU (1) | YU42584B (en) |
| ZA (1) | ZA815922B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA851062B (en) * | 1984-03-01 | 1985-11-27 | Asta Werke Ag Chem Fab | Salts of oxazaphosphorine derivatives and process for their production |
| DE3569737D1 (en) * | 1984-03-01 | 1989-06-01 | Asta Pharma Ag | Salts of oxazaphosphorine derivatives |
| WO2016089208A2 (en) | 2014-12-04 | 2016-06-09 | Stichting Maastricht Radiation Oncology "Maastro-Clinic" | Sulfonamide, sulfamate and sulfamide derivatives of anti-cancer agents |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA955937A (en) * | 1971-06-28 | 1974-10-08 | Shionogi And Co. Ltd. | Cyclic phosphamide derivatives |
| US3911005A (en) * | 1974-09-12 | 1975-10-07 | Monsanto Co | 1,3,2-Diazaphospholidine compounds |
| JPS5159886A (en) * | 1974-11-20 | 1976-05-25 | Shionogi Seiyaku Kk |
-
1981
- 1981-08-22 DE DE19813133309 patent/DE3133309A1/en active Granted
- 1981-08-25 IE IE1951/81A patent/IE51784B1/en unknown
- 1981-08-26 IL IL63661A patent/IL63661A/en not_active IP Right Cessation
- 1981-08-26 ZA ZA815922A patent/ZA815922B/en unknown
- 1981-08-26 AU AU74657/81A patent/AU538275B2/en not_active Ceased
- 1981-08-31 CH CH5584/81A patent/CH650787A5/en not_active IP Right Cessation
- 1981-08-31 GR GR65896A patent/GR75300B/el unknown
- 1981-09-03 NL NL8104093A patent/NL8104093A/en not_active Application Discontinuation
- 1981-09-04 CS CS816537A patent/CS227680B2/en unknown
- 1981-09-07 LU LU83613A patent/LU83613A1/en unknown
- 1981-09-07 AT AT0386481A patent/AT386210B/en not_active IP Right Cessation
- 1981-09-08 RO RO105257A patent/RO83972B/en unknown
- 1981-09-08 HU HU812580A patent/HU185953B/en unknown
- 1981-09-08 EG EG508/81A patent/EG15392A/en active
- 1981-09-08 FR FR8116999A patent/FR2489825A1/en active Granted
- 1981-09-08 SE SE8105340A patent/SE458203B/en not_active IP Right Cessation
- 1981-09-08 DD DD81233132A patent/DD202166A5/en unknown
- 1981-09-09 JP JP56141108A patent/JPS5785396A/en active Granted
- 1981-09-09 PT PT73645A patent/PT73645B/en unknown
- 1981-09-09 FI FI812798A patent/FI70026C/en not_active IP Right Cessation
- 1981-09-09 BE BE2/59345A patent/BE890276A/en not_active IP Right Cessation
- 1981-09-09 CA CA000385516A patent/CA1161453A/en not_active Expired
- 1981-09-09 PL PL1981232960A patent/PL128627B1/en unknown
- 1981-09-09 ES ES505324A patent/ES8206544A1/en not_active Expired
- 1981-09-09 DK DK400481A patent/DK400481A/en not_active Application Discontinuation
- 1981-09-09 NO NO813063A patent/NO161261C/en unknown
- 1981-09-09 IT IT23860/81A patent/IT1198350B/en active
- 1981-09-10 AR AR286736A patent/AR231989A1/en active
- 1981-09-10 YU YU2179/81A patent/YU42584B/en unknown
-
1984
- 1984-05-30 CA CA000455507A patent/CA1184563B/en not_active Expired
- 1984-06-12 IT IT21372/84A patent/IT1220985B/en active
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CZ412898A3 (en) | Substituted cyclopentane compounds usable as neuroaminidase inhibitors | |
| US3867396A (en) | Triazolyl phosphorus compounds | |
| SE446267B (en) | NEW QUINOLYLGUANIDE INGREDIENTS, PROCEDURES FOR PREPARING THEREOF, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE DERIVATIVES | |
| US4283541A (en) | Pyridylacyl-hydroxamates | |
| SE458203B (en) | PROCEDURES FOR THE PREPARATION OF 4-CARBAMOYLOXIAZAPHOSPHORPHINES AND PHARMACEUTICAL PREPARATIONS FOR TREATMENT OF ANALYZOUS TUMORS AND SIMILAR ORAL DISEASES | |
| CS195677B2 (en) | Method of producing new derivatives of alkyl-n-acyl-6,7-aziridino-6-deamino-7-deoxy-alfa-thiolincosaminide | |
| US3956500A (en) | Carbamate pesticidal compositions | |
| US3040046A (en) | Quinoxalines and processes for their production | |
| CA2122960A1 (en) | Polycyclic compounds and processes for the preparation thereof | |
| US4128581A (en) | Ketoxime carbamates | |
| GB2106896A (en) | N-substituted aziridine-2-carboxylic acid derivatives | |
| Sullivan et al. | Studies in. beta.-lactams. Synthesis of. beta.-lactams via cycloaddition of iminodithiocarbonate esters with azidoketene | |
| US4215075A (en) | Ketoxime carbamates | |
| US3632621A (en) | Novel oximecarbamates | |
| Rufer et al. | Chemotherapeutic Nitroheterocycles. 6. Substituted 5-aminomethyl-3-(5-nitro-2-imidazolylmethyleneamino)-2-oxazolidinones | |
| US3803145A (en) | Quinoxaline-di-n-oxides | |
| CA1043334A (en) | Carbamate pesticidal compositions | |
| US3980796A (en) | Substituted 2-alkoxycarbonylamine-5-(6)-phenylmercapto-benzimidazoles | |
| US3969511A (en) | Insecticidal, miticidal and lepidoptericidal active isothiuronium complex acids and free bases | |
| US3767808A (en) | Oximecarbamate pesticidal compositions and their use | |
| US3932440A (en) | P-(1H-tetrazol-1-yl)-phenylcarbamates | |
| US2728765A (en) | Penicillin salts of bis-aralkylalkenylenediamines | |
| KR840001670B1 (en) | Process for the preparation of octadecenic acid amide | |
| US4154732A (en) | Ketoxime carbamates | |
| IE58135B1 (en) | A process for the preparation of cyclic prodrugs of antiinflammatory oxicams |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| NUG | Patent has lapsed |
Ref document number: 8105340-7 Effective date: 19920408 Format of ref document f/p: F |