CA1165328A - Preparation of amino-acid derivatives useful as pharmaceuticals - Google Patents
Preparation of amino-acid derivatives useful as pharmaceuticalsInfo
- Publication number
- CA1165328A CA1165328A CA000373489A CA373489A CA1165328A CA 1165328 A CA1165328 A CA 1165328A CA 000373489 A CA000373489 A CA 000373489A CA 373489 A CA373489 A CA 373489A CA 1165328 A CA1165328 A CA 1165328A
- Authority
- CA
- Canada
- Prior art keywords
- group
- carbon atoms
- alkyl
- formula
- substituted
- 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.)
- Expired
Links
- 150000003862 amino acid derivatives Chemical class 0.000 title abstract description 8
- 238000002360 preparation method Methods 0.000 title description 8
- 239000003814 drug Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 91
- -1 hydroxylamino group Chemical group 0.000 claims abstract description 75
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 70
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 42
- 125000005843 halogen group Chemical group 0.000 claims abstract description 32
- 125000003277 amino group Chemical group 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 27
- 125000003118 aryl group Chemical group 0.000 claims abstract description 26
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 239000002253 acid Substances 0.000 claims abstract description 18
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 18
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims abstract description 10
- 125000004001 thioalkyl group Chemical group 0.000 claims abstract description 10
- SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 claims abstract description 9
- 239000005864 Sulphur Substances 0.000 claims abstract description 8
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 7
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- 125000000033 alkoxyamino group Chemical group 0.000 claims abstract description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 5
- 125000004966 cyanoalkyl group Chemical group 0.000 claims abstract description 5
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 5
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 5
- 125000005358 mercaptoalkyl group Chemical group 0.000 claims abstract description 5
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims abstract description 4
- 125000003396 thiol group Chemical group [H]S* 0.000 claims abstract description 4
- 238000004519 manufacturing process Methods 0.000 claims abstract 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 68
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- 239000000460 chlorine Substances 0.000 claims description 27
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 15
- 150000004702 methyl esters Chemical class 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 235000004279 alanine Nutrition 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 7
- YUHPULRMJRQVME-SSDOTTSWSA-N methyl (2r)-2-amino-4-cyano-2-methylbutanoate Chemical compound COC(=O)[C@](C)(N)CCC#N YUHPULRMJRQVME-SSDOTTSWSA-N 0.000 claims description 7
- 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 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000011591 potassium Substances 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- OLTHLMNHOYRUKO-CYBMUJFWSA-N (2r)-2-[(4-chlorobenzoyl)amino]-4-cyano-2-methylbutanoic acid Chemical compound N#CCC[C@](C)(C(O)=O)NC(=O)C1=CC=C(Cl)C=C1 OLTHLMNHOYRUKO-CYBMUJFWSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 159000000007 calcium salts Chemical class 0.000 claims description 3
- DOTDXLDEDCAPJU-CQSZACIVSA-N methyl (2r)-2-[(4-chlorobenzoyl)amino]-4-cyano-2-methylbutanoate Chemical compound N#CCC[C@](C)(C(=O)OC)NC(=O)C1=CC=C(Cl)C=C1 DOTDXLDEDCAPJU-CQSZACIVSA-N 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims 6
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 3
- 229910052736 halogen Inorganic materials 0.000 claims 3
- 125000003282 alkyl amino group Chemical group 0.000 claims 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 2
- 150000002367 halogens Chemical class 0.000 claims 2
- 125000004442 acylamino group Chemical group 0.000 abstract description 3
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 125000003710 aryl alkyl group Chemical group 0.000 abstract description 3
- 125000004443 haloalkoxycarbonylamino group Chemical group 0.000 abstract description 3
- 229940034982 antineoplastic agent Drugs 0.000 abstract description 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 2
- 238000002844 melting Methods 0.000 description 56
- 230000008018 melting Effects 0.000 description 56
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000002904 solvent Substances 0.000 description 34
- 238000006243 chemical reaction Methods 0.000 description 31
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- 239000000047 product Substances 0.000 description 29
- 239000000203 mixture Substances 0.000 description 27
- 239000000243 solution Substances 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- 238000004458 analytical method Methods 0.000 description 16
- 206010028980 Neoplasm Diseases 0.000 description 15
- 239000000843 powder Substances 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 7
- 229910052794 bromium Inorganic materials 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- DWKPPFQULDPWHX-VKHMYHEASA-N l-alanyl ester Chemical compound COC(=O)[C@H](C)N DWKPPFQULDPWHX-VKHMYHEASA-N 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 238000011084 recovery Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 241001467552 Mycobacterium bovis BCG Species 0.000 description 5
- 229960000190 bacillus calmette–guérin vaccine Drugs 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 230000028993 immune response Effects 0.000 description 5
- 230000004957 immunoregulator effect Effects 0.000 description 5
- 238000002513 implantation Methods 0.000 description 5
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 5
- 150000007530 organic bases Chemical class 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 230000008961 swelling Effects 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 4
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 150000008282 halocarbons Chemical class 0.000 description 4
- 229940102223 injectable solution Drugs 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 229960001614 levamisole Drugs 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 3
- NGTORYSYDRDVFM-UHFFFAOYSA-N 2-(2-cyanoethylamino)propanoic acid Chemical compound OC(=O)C(C)NCCC#N NGTORYSYDRDVFM-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- WOVMXLQMZGWABP-UHFFFAOYSA-L disodium;2-[(4-chlorobenzoyl)amino]-2-(2-cyanoethyl)propanedioate;dihydrate Chemical compound O.O.[Na+].[Na+].N#CCCC(C(=O)[O-])(C([O-])=O)NC(=O)C1=CC=C(Cl)C=C1 WOVMXLQMZGWABP-UHFFFAOYSA-L 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- 230000003053 immunization Effects 0.000 description 3
- 238000002649 immunization Methods 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 230000000707 stereoselective effect Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 229910021653 sulphate ion Inorganic materials 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- MPMFCABZENCRHV-UHFFFAOYSA-N tilorone Chemical compound C1=C(OCCN(CC)CC)C=C2C(=O)C3=CC(OCCN(CC)CC)=CC=C3C2=C1 MPMFCABZENCRHV-UHFFFAOYSA-N 0.000 description 3
- 229950006823 tilorone Drugs 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 2
- NUMYEJKCZXZPGY-UHFFFAOYSA-N 2-[(4-chlorobenzoyl)amino]-4-cyanobutanoic acid Chemical compound N#CCCC(C(=O)O)NC(=O)C1=CC=C(Cl)C=C1 NUMYEJKCZXZPGY-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- 208000001792 Sarcoma 37 Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 2
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 description 2
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 2
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- CBYYFYSTWCDRFD-UHFFFAOYSA-N diethyl 2-[(4-chlorobenzoyl)-(2-cyanoethyl)amino]propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)N(CCC#N)C(=O)C1=CC=C(Cl)C=C1 CBYYFYSTWCDRFD-UHFFFAOYSA-N 0.000 description 2
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
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- JINBYESILADKFW-UHFFFAOYSA-N aminomalonic acid Chemical compound OC(=O)C(N)C(O)=O JINBYESILADKFW-UHFFFAOYSA-N 0.000 description 1
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- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- IBNYJZJSXDGJNG-NSHDSACASA-N benzyl (2s)-2-carbonochloridoylpyrrolidine-1-carboxylate Chemical compound ClC(=O)[C@@H]1CCCN1C(=O)OCC1=CC=CC=C1 IBNYJZJSXDGJNG-NSHDSACASA-N 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
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- 239000011575 calcium Substances 0.000 description 1
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- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
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- PAFZNILMFXTMIY-UHFFFAOYSA-O cyclohexylammonium Chemical compound [NH3+]C1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-O 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- NMSZTQWZINJIMY-UHFFFAOYSA-N diethyl 2-benzamidopropanedioate Chemical compound CCOC(=O)C(C(=O)OCC)NC(=O)C1=CC=CC=C1 NMSZTQWZINJIMY-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
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- 150000002170 ethers Chemical class 0.000 description 1
- JWNSMRQPYJVPDJ-UHFFFAOYSA-N ethyl 2-benzamido-2-[2-(2-cyanopropyl)phenyl]acetate Chemical compound C(C)OC(C(NC(C1=CC=CC=C1)=O)C1=C(C=CC=C1)CC(C)C#N)=O JWNSMRQPYJVPDJ-UHFFFAOYSA-N 0.000 description 1
- GYEKVSOESPZWDI-UHFFFAOYSA-N ethyl 2-benzamido-2-phenylacetate Chemical compound C=1C=CC=CC=1C(C(=O)OCC)NC(=O)C1=CC=CC=C1 GYEKVSOESPZWDI-UHFFFAOYSA-N 0.000 description 1
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- CATSNJVOTSVZJV-UHFFFAOYSA-N heptan-2-one Chemical compound CCCCCC(C)=O CATSNJVOTSVZJV-UHFFFAOYSA-N 0.000 description 1
- MRRTYRPSTAHYCQ-GDLZYMKVSA-N hexadecyl (2R)-2-[(4-chlorobenzoyl)amino]-4-cyano-2-methylbutanoate Chemical compound C(CCCCCCCCCCCCCCC)OC([C@@](NC(C1=CC=C(C=C1)Cl)=O)(C)CCC#N)=O MRRTYRPSTAHYCQ-GDLZYMKVSA-N 0.000 description 1
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- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000006316 iso-butyl amino group Chemical group [H]N(*)C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940041476 lactose 100 mg Drugs 0.000 description 1
- 229960003136 leucine Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- IPCPTKMULHIADB-CQSZACIVSA-N methyl (2R)-2-[(4-chloro-2-hydroxybenzoyl)amino]-4-cyano-2-methylbutanoate Chemical compound COC([C@@](NC(C1=C(C=C(C=C1)Cl)O)=O)(C)CCC#N)=O IPCPTKMULHIADB-CQSZACIVSA-N 0.000 description 1
- HFDCNPDZSJUAIA-OAHLLOKOSA-N methyl (2R)-4-cyano-2-[(3-fluoro-4-methylbenzoyl)amino]-2-methylbutanoate Chemical compound COC([C@@](NC(C1=CC(=C(C=C1)C)F)=O)(C)CCC#N)=O HFDCNPDZSJUAIA-OAHLLOKOSA-N 0.000 description 1
- RASDXTSOKNMENP-OAHLLOKOSA-N methyl (2R)-4-cyano-2-[(4-cyanobenzoyl)amino]-2-methylbutanoate Chemical compound COC([C@@](NC(C1=CC=C(C=C1)C#N)=O)(C)CCC#N)=O RASDXTSOKNMENP-OAHLLOKOSA-N 0.000 description 1
- GKBJHBPYGVZURU-OAHLLOKOSA-N methyl (2R)-4-cyano-2-methyl-2-[(4-methylbenzoyl)amino]butanoate Chemical compound COC([C@@](NC(=O)C1=CC=C(C=C1)C)(C)CCC#N)=O GKBJHBPYGVZURU-OAHLLOKOSA-N 0.000 description 1
- SFPJHXZVNIVXLT-CQSZACIVSA-N methyl (2r)-2-[(2-chlorobenzoyl)amino]-4-cyano-2-methylbutanoate Chemical compound N#CCC[C@](C)(C(=O)OC)NC(=O)C1=CC=CC=C1Cl SFPJHXZVNIVXLT-CQSZACIVSA-N 0.000 description 1
- ACEABNDEUFDYIV-CQSZACIVSA-N methyl (2r)-2-[(4-bromobenzoyl)amino]-4-cyano-2-methylbutanoate Chemical compound N#CCC[C@](C)(C(=O)OC)NC(=O)C1=CC=C(Br)C=C1 ACEABNDEUFDYIV-CQSZACIVSA-N 0.000 description 1
- HFCLJJPMEHHKHD-KRWDZBQOSA-N methyl (2s)-2-[(4-chlorobenzoyl)amino]-2-(2-cyanoethyl)-4-methylpentanoate Chemical compound N#CCC[C@@](C(=O)OC)(CC(C)C)NC(=O)C1=CC=C(Cl)C=C1 HFCLJJPMEHHKHD-KRWDZBQOSA-N 0.000 description 1
- KTSXOJNXFGFYSR-UHFFFAOYSA-N methyl 2-[(4-chlorobenzoyl)amino]-2-[2-(2-cyanoethyl)phenyl]acetate Chemical compound C=1C=CC=C(CCC#N)C=1C(C(=O)OC)NC(=O)C1=CC=C(Cl)C=C1 KTSXOJNXFGFYSR-UHFFFAOYSA-N 0.000 description 1
- FHWIKZKVYLCJFY-UHFFFAOYSA-N methyl 2-[(4-chlorobenzoyl)amino]-4-cyanobutanoate Chemical compound N#CCCC(C(=O)OC)NC(=O)C1=CC=C(Cl)C=C1 FHWIKZKVYLCJFY-UHFFFAOYSA-N 0.000 description 1
- SZJUWKPNWWCOPG-UHFFFAOYSA-N methyl 2-anilinoacetate Chemical compound COC(=O)CNC1=CC=CC=C1 SZJUWKPNWWCOPG-UHFFFAOYSA-N 0.000 description 1
- 125000004372 methylthioethyl group Chemical group [H]C([H])([H])SC([H])([H])C([H])([H])* 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000001446 muramyl group Chemical group N[C@@H](C=O)[C@@H](O[C@@H](C(=O)*)C)[C@H](O)[C@H](O)CO 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000005951 type IV hypersensitivity Effects 0.000 description 1
- 208000027930 type IV hypersensitivity disease Diseases 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Immunology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP55-36562 | 1980-03-22 | ||
| JP3656280A JPS56147753A (en) | 1980-03-22 | 1980-03-22 | Amino acid derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1165328A true CA1165328A (en) | 1984-04-10 |
Family
ID=12473192
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000373489A Expired CA1165328A (en) | 1980-03-22 | 1981-03-20 | Preparation of amino-acid derivatives useful as pharmaceuticals |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US4545942A (enExample) |
| JP (1) | JPS56147753A (enExample) |
| BE (1) | BE888057A (enExample) |
| CA (1) | CA1165328A (enExample) |
| CH (1) | CH651820A5 (enExample) |
| DE (1) | DE3111025A1 (enExample) |
| ES (1) | ES500585A0 (enExample) |
| FR (1) | FR2478629A1 (enExample) |
| GB (1) | GB2072173B (enExample) |
| IT (1) | IT1172237B (enExample) |
| NL (1) | NL8101439A (enExample) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3416120A1 (de) * | 1984-04-30 | 1985-10-31 | Henkel KGaA, 4000 Düsseldorf | Benzoylalanine und ihre verwendung als korrosionsinhibitoren fuer waessrige systeme |
| CN104800228B (zh) * | 2014-01-28 | 2019-04-12 | 杭州民生药物研究院有限公司 | 一种o-苯甲酰-(4-三氟甲基)水杨酰胺类化合物在制备治疗肠癌药物中的应用 |
| CN104803877B (zh) * | 2014-01-28 | 2018-02-02 | 杭州民生药业有限公司 | 一种o‑苯乙酰‑(4‑三氟甲基)水杨酰胺类化合物及其应用 |
| CN104803876B (zh) * | 2014-01-28 | 2018-02-02 | 杭州民生药业有限公司 | 一种o‑肉桂酰‑(4‑三氟甲基)水杨酰胺类化合物及其应用 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3125583A (en) * | 1964-03-17 | Hjnc oxchaxohxchc o oh | ||
| US2553737A (en) * | 1945-06-16 | 1951-05-22 | Winthrop Stearns Inc | Lower alkyl (beta-cyanoalkyl)-(lower acyl) aminomalonates |
| US2847451A (en) * | 1954-10-01 | 1958-08-12 | Nat Distillers Chem Corp | Growth accelerator |
| US2891053A (en) * | 1955-12-20 | 1959-06-16 | Bayer Ag | Therapeutically valuable calcium salts |
| JPS5569552A (en) * | 1978-11-20 | 1980-05-26 | Dai Ichi Pure Chem Co Ltd | Optically active alpha-acylamino-gamma-cyanobutyric acid ester |
-
1980
- 1980-03-22 JP JP3656280A patent/JPS56147753A/ja active Granted
-
1981
- 1981-03-12 GB GB8107862A patent/GB2072173B/en not_active Expired
- 1981-03-20 BE BE0/204213A patent/BE888057A/fr not_active IP Right Cessation
- 1981-03-20 DE DE19813111025 patent/DE3111025A1/de active Granted
- 1981-03-20 FR FR8105597A patent/FR2478629A1/fr active Granted
- 1981-03-20 ES ES500585A patent/ES500585A0/es active Granted
- 1981-03-20 IT IT67391/81A patent/IT1172237B/it active
- 1981-03-20 CA CA000373489A patent/CA1165328A/en not_active Expired
- 1981-03-20 CH CH1912/81A patent/CH651820A5/de not_active IP Right Cessation
- 1981-03-23 NL NL8101439A patent/NL8101439A/nl not_active Application Discontinuation
-
1984
- 1984-04-09 US US06/597,817 patent/US4545942A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| IT8167391A0 (it) | 1981-03-20 |
| IT1172237B (it) | 1987-06-18 |
| JPS56147753A (en) | 1981-11-16 |
| CH651820A5 (de) | 1985-10-15 |
| ES8306099A1 (es) | 1983-05-01 |
| BE888057A (fr) | 1981-09-21 |
| FR2478629B1 (enExample) | 1983-06-24 |
| JPS6332780B2 (enExample) | 1988-07-01 |
| GB2072173A (en) | 1981-09-30 |
| GB2072173B (en) | 1984-07-25 |
| DE3111025C2 (enExample) | 1989-12-07 |
| NL8101439A (nl) | 1981-10-16 |
| DE3111025A1 (de) | 1982-01-14 |
| ES500585A0 (es) | 1983-05-01 |
| US4545942A (en) | 1985-10-08 |
| FR2478629A1 (fr) | 1981-09-25 |
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Legal Events
| Date | Code | Title | Description |
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| MKEX | Expiry |