DE2849396A1 - N-(phosphonacetyl)-l-asparaginsaeureverbindungen und verfahren zu deren herstellung - Google Patents
N-(phosphonacetyl)-l-asparaginsaeureverbindungen und verfahren zu deren herstellungInfo
- Publication number
- DE2849396A1 DE2849396A1 DE19782849396 DE2849396A DE2849396A1 DE 2849396 A1 DE2849396 A1 DE 2849396A1 DE 19782849396 DE19782849396 DE 19782849396 DE 2849396 A DE2849396 A DE 2849396A DE 2849396 A1 DE2849396 A1 DE 2849396A1
- Authority
- DE
- Germany
- Prior art keywords
- pala
- salt
- aspartic acid
- ethanol
- water
- 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.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims description 27
- 230000008569 process Effects 0.000 title claims description 19
- 238000002360 preparation method Methods 0.000 title claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 151
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 86
- 239000000243 solution Substances 0.000 claims description 82
- ZZKNRXZVGOYGJT-VKHMYHEASA-N (2s)-2-[(2-phosphonoacetyl)amino]butanedioic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)CP(O)(O)=O ZZKNRXZVGOYGJT-VKHMYHEASA-N 0.000 claims description 71
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 70
- 239000000203 mixture Substances 0.000 claims description 49
- -1 phosphonoacetyl Chemical group 0.000 claims description 43
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 36
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 34
- 229960000583 acetic acid Drugs 0.000 claims description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 31
- 229960005261 aspartic acid Drugs 0.000 claims description 30
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 claims description 30
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 27
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 claims description 23
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 claims description 23
- PEOGKOTVGUTAEM-UHFFFAOYSA-N (2-chloro-2-oxoethyl)phosphonic acid Chemical compound OP(O)(=O)CC(Cl)=O PEOGKOTVGUTAEM-UHFFFAOYSA-N 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 17
- 229910052698 phosphorus Inorganic materials 0.000 claims description 17
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 claims description 14
- 239000012362 glacial acetic acid Substances 0.000 claims description 13
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 10
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 9
- 150000003946 cyclohexylamines Chemical class 0.000 claims description 9
- HLMUYZYLPUHSNV-NTISSMGPSA-N [(2s)-1,4-dioxo-1,4-bis(phenylmethoxy)butan-2-yl]azanium;4-methylbenzenesulfonate Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.C([C@H](N)C(=O)OCC=1C=CC=CC=1)C(=O)OCC1=CC=CC=C1 HLMUYZYLPUHSNV-NTISSMGPSA-N 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 239000001632 sodium acetate Substances 0.000 claims description 5
- 235000017281 sodium acetate Nutrition 0.000 claims description 5
- 239000012535 impurity Substances 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- CYTYCFOTNPOANT-UHFFFAOYSA-N Perchloroethylene Chemical group ClC(Cl)=C(Cl)Cl CYTYCFOTNPOANT-UHFFFAOYSA-N 0.000 claims description 3
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 3
- 230000032050 esterification Effects 0.000 claims description 3
- 238000005886 esterification reaction Methods 0.000 claims description 3
- 238000005342 ion exchange Methods 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 229950011008 tetrachloroethylene Drugs 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- BQAMWLOABQRMAO-INIZCTEOSA-N dibenzyl (2s)-2-aminobutanedioate Chemical compound C([C@H](N)C(=O)OCC=1C=CC=CC=1)C(=O)OCC1=CC=CC=C1 BQAMWLOABQRMAO-INIZCTEOSA-N 0.000 claims 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims 1
- 239000000047 product Substances 0.000 description 65
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 64
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 61
- 239000007787 solid Substances 0.000 description 40
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 239000003921 oil Substances 0.000 description 27
- 235000019198 oils Nutrition 0.000 description 27
- 239000002904 solvent Substances 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 25
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 23
- 239000000706 filtrate Substances 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 17
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 15
- 238000004458 analytical method Methods 0.000 description 15
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 14
- 239000001913 cellulose Substances 0.000 description 12
- 229920002678 cellulose Polymers 0.000 description 12
- 239000011521 glass Substances 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 11
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 11
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 11
- 238000004809 thin layer chromatography Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- MHLMRBVCMNDOCW-UHFFFAOYSA-N acetic acid;butan-1-ol;hydrate Chemical compound O.CC(O)=O.CCCCO MHLMRBVCMNDOCW-UHFFFAOYSA-N 0.000 description 10
- 230000003287 optical effect Effects 0.000 description 10
- XUYJLQHKOGNDPB-UHFFFAOYSA-N phosphonoacetic acid Chemical compound OC(=O)CP(O)(O)=O XUYJLQHKOGNDPB-UHFFFAOYSA-N 0.000 description 10
- 230000003595 spectral effect Effects 0.000 description 10
- JDWFOTLBRARKLZ-UHFFFAOYSA-N azanium;ethanol;hydroxide;hydrate Chemical compound [NH4+].O.[OH-].CCO JDWFOTLBRARKLZ-UHFFFAOYSA-N 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 7
- 159000000007 calcium salts Chemical class 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 239000000470 constituent Substances 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 239000011574 phosphorus Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 239000002246 antineoplastic agent Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000007921 spray Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 238000009835 boiling Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- SZEXXTYGQYKIHJ-UHFFFAOYSA-N O.O.O.O.[Na].[Na].[Na].[Na] Chemical compound O.O.O.O.[Na].[Na].[Na].[Na] SZEXXTYGQYKIHJ-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- OLAPPGSPBNVTRF-UHFFFAOYSA-N naphthalene-1,4,5,8-tetracarboxylic acid Chemical compound C1=CC(C(O)=O)=C2C(C(=O)O)=CC=C(C(O)=O)C2=C1C(O)=O OLAPPGSPBNVTRF-UHFFFAOYSA-N 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical class C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 3
- 238000005341 cation exchange Methods 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 description 2
- GZLMFCWSEKVVGO-UHFFFAOYSA-N 3-azaniumyl-2-hydroxy-5-methylhexanoate Chemical compound CC(C)CC(N)C(O)C(O)=O GZLMFCWSEKVVGO-UHFFFAOYSA-N 0.000 description 2
- IGQGXIVCGKMRAM-UHFFFAOYSA-N 4-amino-3-methylbenzenesulfonamide Chemical compound CC1=CC(S(N)(=O)=O)=CC=C1N IGQGXIVCGKMRAM-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical group C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- 235000019502 Orange oil Nutrition 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000010502 orange oil Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 150000004885 piperazines Chemical class 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- BWAUQTFFVCLSOS-UHFFFAOYSA-N sodiosodium hydrate Chemical compound O.[Na].[Na] BWAUQTFFVCLSOS-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 150000004685 tetrahydrates Chemical class 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
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 2
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 2
- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical compound [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 description 2
- 238000012800 visualization Methods 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- DOETVZCFKJCYJV-UHFFFAOYSA-N 6-(4,5-dihydro-1h-imidazol-2-yl)-2-[4-(4,5-dihydro-1h-imidazol-2-yl)phenyl]-1h-indole Chemical compound N1CCN=C1C1=CC=C(C=2NC3=CC(=CC=C3C=2)C=2NCCN=2)C=C1 DOETVZCFKJCYJV-UHFFFAOYSA-N 0.000 description 1
- 101100286286 Dictyostelium discoideum ipi gene Proteins 0.000 description 1
- 241001235534 Graphis <ascomycete fungus> Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- FJRXGBBVWWBHMW-UHFFFAOYSA-N O.O.O.O.[Na].[Na] Chemical compound O.O.O.O.[Na].[Na] FJRXGBBVWWBHMW-UHFFFAOYSA-N 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- NDUXAYZFYGZISK-UHFFFAOYSA-N ethanol;propan-2-one;hydrate Chemical compound O.CCO.CC(C)=O NDUXAYZFYGZISK-UHFFFAOYSA-N 0.000 description 1
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000003517 fume Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 201000003866 lung sarcoma Diseases 0.000 description 1
- 238000012792 lyophilization process Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
-
- 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
- A61K31/66—Phosphorus compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US85138277A | 1977-11-14 | 1977-11-14 |
Publications (1)
Publication Number | Publication Date |
---|---|
DE2849396A1 true DE2849396A1 (de) | 1979-05-17 |
Family
ID=25310650
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE19782849396 Withdrawn DE2849396A1 (de) | 1977-11-14 | 1978-11-14 | N-(phosphonacetyl)-l-asparaginsaeureverbindungen und verfahren zu deren herstellung |
Country Status (14)
Country | Link |
---|---|
JP (1) | JPS5492920A (da) |
AT (1) | AT374485B (da) |
AU (1) | AU520966B2 (da) |
CA (1) | CA1110266A (da) |
CH (1) | CH636595A5 (da) |
DE (1) | DE2849396A1 (da) |
DK (1) | DK149134C (da) |
FI (1) | FI65261C (da) |
FR (1) | FR2408617A1 (da) |
GB (2) | GB2008118B (da) |
GR (1) | GR65247B (da) |
NL (1) | NL7811252A (da) |
NZ (1) | NZ188909A (da) |
SE (1) | SE439774B (da) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4284579A (en) * | 1979-07-17 | 1981-08-18 | The United States Of America As Represented By The Of The Department Of Health & Human Services | (N-Phosphonacetyl-L-aspartato)(1,2-diaminocyclchexane)platinum(II) or alkali metal salt |
-
1978
- 1978-11-13 AU AU41528/78A patent/AU520966B2/en not_active Expired
- 1978-11-14 CA CA316,224A patent/CA1110266A/en not_active Expired
- 1978-11-14 JP JP13947278A patent/JPS5492920A/ja active Pending
- 1978-11-14 CH CH1170578A patent/CH636595A5/fr not_active IP Right Cessation
- 1978-11-14 SE SE7811736A patent/SE439774B/sv not_active IP Right Cessation
- 1978-11-14 NL NL7811252A patent/NL7811252A/xx not_active Application Discontinuation
- 1978-11-14 AT AT0813278A patent/AT374485B/de active
- 1978-11-14 DK DK506278A patent/DK149134C/da not_active IP Right Cessation
- 1978-11-14 DE DE19782849396 patent/DE2849396A1/de not_active Withdrawn
- 1978-11-14 GB GB7844508A patent/GB2008118B/en not_active Expired
- 1978-11-14 NZ NZ188909A patent/NZ188909A/xx unknown
- 1978-11-14 GB GB8024584A patent/GB2051070B/en not_active Expired
- 1978-11-14 FR FR7832098A patent/FR2408617A1/fr active Granted
- 1978-11-14 FI FI783467A patent/FI65261C/fi not_active IP Right Cessation
- 1978-11-14 GR GR57650A patent/GR65247B/el unknown
Also Published As
Publication number | Publication date |
---|---|
SE439774B (sv) | 1985-07-01 |
AT374485B (de) | 1984-04-25 |
FI65261C (fi) | 1984-04-10 |
GB2051070A (en) | 1981-01-14 |
AU4152878A (en) | 1979-05-24 |
GB2008118B (en) | 1982-08-04 |
ATA813278A (de) | 1983-09-15 |
FI783467A (fi) | 1979-05-15 |
SE7811736L (sv) | 1979-05-15 |
JPS5492920A (en) | 1979-07-23 |
FI65261B (fi) | 1983-12-30 |
NL7811252A (nl) | 1979-05-16 |
GB2008118A (en) | 1979-05-31 |
FR2408617B1 (da) | 1983-11-18 |
GB2051070B (en) | 1982-08-04 |
DK149134B (da) | 1986-02-10 |
DK149134C (da) | 1986-07-14 |
FR2408617A1 (fr) | 1979-06-08 |
CA1110266A (en) | 1981-10-06 |
DK506278A (da) | 1979-05-15 |
CH636595A5 (fr) | 1983-06-15 |
AU520966B2 (en) | 1982-03-11 |
GR65247B (en) | 1980-07-31 |
NZ188909A (en) | 1980-10-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0001584B1 (de) | Hydroxydiphosphonsäuren, Verfahren zu ihrer Herstellung und ihre Verwendung als Komplexierungsmittel | |
DE2508895C2 (da) | ||
DE3128819C2 (da) | ||
DE69322087T2 (de) | Neues kristall von heterozyclischen bis(phosphonsäure) monohydrat-derivat | |
DE69527980T2 (de) | Chalcone und ihre ester mit antiproliferativer aktivität in gebärmutter, ovar- und brusttumoren | |
EP0170896B1 (de) | Neue 1-Hydroxy-1,1-diphosphonsäureverbindungen, Verf. zu ihrer Herstellung u. pharmakologische Zubereitungen, insb. zur Behandlung von Knochentumoren | |
EP0533790B1 (de) | Neue salzform von 5-difluormethoxy-2- [3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1h-benzimidazol | |
DE3709230A1 (de) | Neues calciumsalz der valproinsaeure | |
DE2707095C3 (de) | Isopropylaminopyrimidinorthophosphat | |
DE3016752A1 (de) | Verfahren zur herstellung von 2-isopropylaminopyrimidinhydroxy-derivaten | |
DE3720151C2 (da) | ||
DE2849396A1 (de) | N-(phosphonacetyl)-l-asparaginsaeureverbindungen und verfahren zu deren herstellung | |
DE2336671A1 (de) | Oxyessigsaeureaether von o-thymotinsaeureestern | |
DE2745084C2 (da) | ||
DE2520488A1 (de) | Verfahren zur gewinnung reiner 3alpha,7alpha-dihydroxy-5beta-cholansaeure | |
DE19820974A1 (de) | Isolierung der Salze von 1-Hydroxy-1,1-diphosphonsäureverbindungen | |
DE3102984A1 (de) | Verfahren zur herstellung von cysteamin-s-substituierten verbindungen und deren derivaten | |
DE2732144A1 (de) | Salicylsaeurederivate | |
DE3443270A1 (de) | Menadioncholinbisulfit-addukt und verfahren zu dessen herstellung | |
DE2746087A1 (de) | Cyclodextrin-einschlusskomplexe mit indomethacin, verfahren zu ihrer herstellung und pharmazeutische mittel | |
DE2636346C2 (de) | Wasserfreies acetylsalicylsaures Natrium in Form von plattenartigen Kristallen, Verfahren zu dessen Herstellung und Arzneimittel, welche dieses enthalten | |
DE2318043C3 (de) | Bis-eckige Klammer auf 4,7-dihydroxycumarinyl-(3) eckige Klammer zu- essigsäure und deren pharmakologisch verträgliche Salze sowie Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel | |
DE933030C (de) | Verfahren zur Reinigung von ª‡-Amino-ª†-methylmercapto-butyronitril | |
CH219010A (de) | Verfahren zur Herstellung einer festen quecksilberhaltigen Molekularverbindung. | |
DD201796A5 (de) | Verfahren zur herstellung von 17s,17's-bisspartein |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
8141 | Disposal/no request for examination |