NO860483L - NEW CEPHALOSPORINES AND PROCEDURES FOR PRODUCING THEREOF. - Google Patents
NEW CEPHALOSPORINES AND PROCEDURES FOR PRODUCING THEREOF.Info
- Publication number
- NO860483L NO860483L NO860483A NO860483A NO860483L NO 860483 L NO860483 L NO 860483L NO 860483 A NO860483 A NO 860483A NO 860483 A NO860483 A NO 860483A NO 860483 L NO860483 L NO 860483L
- Authority
- NO
- Norway
- Prior art keywords
- stands
- atoms
- alkyl
- group
- branched
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 164
- 125000000217 alkyl group Chemical group 0.000 claims description 57
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 55
- 229910052739 hydrogen Inorganic materials 0.000 claims description 51
- 239000001257 hydrogen Substances 0.000 claims description 50
- 229920006395 saturated elastomer Polymers 0.000 claims description 50
- -1 hydroxy, carboxy Chemical group 0.000 claims description 48
- 125000003118 aryl group Chemical group 0.000 claims description 45
- 150000001875 compounds Chemical class 0.000 claims description 42
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 40
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 40
- 125000004122 cyclic group Chemical group 0.000 claims description 35
- 150000002431 hydrogen Chemical class 0.000 claims description 34
- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 150000002367 halogens Chemical class 0.000 claims description 28
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 27
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 26
- 125000001424 substituent group Chemical group 0.000 claims description 23
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 239000000460 chlorine Chemical group 0.000 claims description 22
- 229910052801 chlorine Inorganic materials 0.000 claims description 22
- 239000011737 fluorine Chemical group 0.000 claims description 22
- 229910052731 fluorine Inorganic materials 0.000 claims description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 21
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 20
- 241001465754 Metazoa Species 0.000 claims description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 18
- 125000005842 heteroatom Chemical group 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 18
- 239000001301 oxygen Substances 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- 239000011593 sulfur Substances 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 229930186147 Cephalosporin Natural products 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 15
- 229940124587 cephalosporin Drugs 0.000 claims description 15
- 150000001780 cephalosporins Chemical class 0.000 claims description 15
- 150000001412 amines Chemical class 0.000 claims description 14
- 229910006069 SO3H Inorganic materials 0.000 claims description 13
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 13
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 13
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
- 125000004414 alkyl thio group Chemical group 0.000 claims description 12
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 125000006239 protecting group Chemical group 0.000 claims description 11
- 125000005110 aryl thio group Chemical group 0.000 claims description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- 125000004104 aryloxy group Chemical group 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052794 bromium Chemical group 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 150000001735 carboxylic acids Chemical class 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 125000000335 thiazolyl group Chemical group 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 7
- 125000001153 fluoro group Chemical group F* 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 6
- 230000004913 activation Effects 0.000 claims description 6
- 150000008064 anhydrides Chemical class 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- 125000002971 oxazolyl group Chemical group 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 238000011282 treatment Methods 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
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 101100134922 Gallus gallus COR5 gene Proteins 0.000 claims description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 2
- 125000006242 amine protecting group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical class OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 claims description 2
- 150000003458 sulfonic acid derivatives Chemical class 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims 1
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 1
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims 1
- 239000005864 Sulphur Substances 0.000 claims 1
- 235000019728 animal nutrition Nutrition 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims 1
- 229940126601 medicinal product Drugs 0.000 claims 1
- 239000013543 active substance Substances 0.000 description 38
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- 229910001868 water Inorganic materials 0.000 description 17
- HQOQSFITXGQQDM-SSDOTTSWSA-N methyl (6R)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound COC(=O)C1=CCS[C@@H]2CC(=O)N12 HQOQSFITXGQQDM-SSDOTTSWSA-N 0.000 description 16
- 239000000126 substance Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 239000011347 resin Substances 0.000 description 11
- 229920005989 resin Polymers 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 108010073038 Penicillin Amidase Proteins 0.000 description 8
- 239000000969 carrier Substances 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- NLARCUDOUOQRPB-WTKPLQERSA-N (2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetic acid Chemical compound CO\N=C(/C(O)=O)C1=CSC(N)=N1 NLARCUDOUOQRPB-WTKPLQERSA-N 0.000 description 7
- 238000003776 cleavage reaction Methods 0.000 description 7
- 239000000825 pharmaceutical preparation Substances 0.000 description 7
- 230000007017 scission Effects 0.000 description 7
- 235000002639 sodium chloride Nutrition 0.000 description 7
- 239000003651 drinking water Substances 0.000 description 6
- 235000020188 drinking water Nutrition 0.000 description 6
- 238000006884 silylation reaction Methods 0.000 description 6
- 235000013343 vitamin Nutrition 0.000 description 6
- 229940088594 vitamin Drugs 0.000 description 6
- 239000011782 vitamin Substances 0.000 description 6
- 229930003231 vitamin Natural products 0.000 description 6
- 241000287828 Gallus gallus Species 0.000 description 5
- 235000013330 chicken meat Nutrition 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000003925 fat Substances 0.000 description 5
- 235000019197 fats Nutrition 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- MSPCIZMDDUQPGJ-UHFFFAOYSA-N N-methyl-N-(trimethylsilyl)trifluoroacetamide Chemical compound C[Si](C)(C)N(C)C(=O)C(F)(F)F MSPCIZMDDUQPGJ-UHFFFAOYSA-N 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000009395 breeding Methods 0.000 description 4
- 230000001488 breeding effect Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- 239000008298 dragée Substances 0.000 description 4
- 235000013312 flour Nutrition 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 4
- 239000002699 waste material Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 235000010469 Glycine max Nutrition 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 241000282887 Suidae Species 0.000 description 3
- 240000008042 Zea mays Species 0.000 description 3
- 235000016383 Zea mays subsp huehuetenangensis Nutrition 0.000 description 3
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 235000009973 maize Nutrition 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 150000003722 vitamin derivatives Chemical class 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 2
- 241000272517 Anseriformes Species 0.000 description 2
- 239000004470 DL Methionine Substances 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- XCOBLONWWXQEBS-KPKJPENVSA-N N,O-bis(trimethylsilyl)trifluoroacetamide Chemical compound C[Si](C)(C)O\C(C(F)(F)F)=N\[Si](C)(C)C XCOBLONWWXQEBS-KPKJPENVSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 241000588769 Proteus <enterobacteria> Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 241000209140 Triticum Species 0.000 description 2
- 235000021307 Triticum Nutrition 0.000 description 2
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 2
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000013339 cereals Nutrition 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- FFEARJCKVFRZRR-UHFFFAOYSA-N methionine Chemical compound CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 235000006109 methionine Nutrition 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000005051 trimethylchlorosilane Substances 0.000 description 2
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 2
- 235000019155 vitamin A Nutrition 0.000 description 2
- 239000011719 vitamin A Substances 0.000 description 2
- 229940045997 vitamin a Drugs 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- MASDFXZJIDNRTR-UHFFFAOYSA-N 1,3-bis(trimethylsilyl)urea Chemical compound C[Si](C)(C)NC(=O)N[Si](C)(C)C MASDFXZJIDNRTR-UHFFFAOYSA-N 0.000 description 1
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- NFTWWHSKWXOTLL-UHFFFAOYSA-N 1,4-dimethylpiperazin-2-one Chemical compound CN1CCN(C)C(=O)C1 NFTWWHSKWXOTLL-UHFFFAOYSA-N 0.000 description 1
- YSDBJKNOEWSFGA-UHFFFAOYSA-N 1-(4-methylpiperazin-1-yl)ethanone Chemical compound CN1CCN(C(C)=O)CC1 YSDBJKNOEWSFGA-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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Description
, ;Foreliggende oppfinnelse vedrører nye cefalosporiner, fremgangsmåter til fremstilling derav, samt anvendelse av forbindelsene som legemidler, spesielt innenfor den antibakterielle terapi. , ;The present invention relates to new cephalosporins, methods for their production, and the use of the compounds as pharmaceuticals, especially within antibacterial therapy.
Cef alosporiner som, som acylsidek jeder bærer en .. 2-( 2-aminotiazol-4-yl)-2-alkoksyiminoeddiksyrerest og i 3-stilling en pyridiniummetylrest, er kjent fra EP 64.740. Cephalosporins which, as acyl side chains, carry a .. 2-(2-aminothiazol-4-yl)-2- alkoxyiminoacetic acid residue and in the 3-position a pyridinium methyl residue are known from EP 64,740.
Foreliggende oppfinnelse vedrører nye cefalosporinger av generelle formel (I) The present invention relates to new cephalosporins of general formula (I)
hvori in which
R"<*>" står for rettkjedet eller forgrenet, mettet eller umettet, eventuelt med karboksy substituert alkyl med inntil 6 C-atomer, R"<*>" stands for straight-chain or branched, saturated or unsaturated, possibly carboxy-substituted alkyl with up to 6 C atoms,
R 2 ståor for rettkjedet eller forgrenet alkyl med inntil R 2 stands for straight-chain or branched alkyl with up to
6 C-atomer, som eventuelt er substituert med hydroksy, karboksy, alkoksy, alkoksykarbonyl med inntil 3 C-atomer, halogen eller cyano, Resten 6 C atoms, which are optionally substituted with hydroxy, carboxy, alkoxy, alkoxycarbonyl with up to 3 C atoms, halogen or cyano, The remainder
for de eventuelt på ringmetylengruppen substituerte gruppene, for the optionally substituted groups on the ring methylene group,
R 3 ståor for rettkjedet, forgrenet eller cyklisk, mettet eller umettet'alkyl med inntil 10 C-atomer som eventuelt er substituert R 3 stands for straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 10 C atoms which are optionally substituted
- med -OH, CHO, OCONH„, NHC0NH9 - with -OH, CHO, OCONH„, NHC0NH9
5 5 " 5 5 5 " 5
- med gruppene COOR , NHCOR , COR hvori - with the groups COOR , NHCOR , COR in which
R 5 står for hydrogen, alkyl med inntil 8 C-atomer, aryl R 5 stands for hydrogen, alkyl with up to 8 C atoms, aryl
med 6-10 C-atomer, eller C7-C14-aralkyl, with 6-10 C atoms, or C7-C14 aralkyl,
- med halogen, cyano, SO-.H, - with halogen, cyano, SO-.H,
hvor where
R 6 og R 7 uavhengig av hverandre stå°r for hydrogen eller til sammen eller hver for seg for C-^-Cg-alkyl, C^- C^-alkenyl eller fenyl, eller hvor substituentene R^, R^ eventuelt med nitrogenatomet danner en 5- til 7-leddet ring, som, som ytterligere hetereoatomer kan inneholde et oksygen-, svovel- og/eller 1-2 nitrogenatomer og som R 6 and R 7 independently of each other stand for hydrogen or together or individually for C-C-C-alkyl, C-C-C-alkenyl or phenyl, or where the substituents R^, R^ optionally with the nitrogen atom forms a 5- to 7-membered ring, which, as further heteroatoms, may contain an oxygen, sulfur and/or 1-2 nitrogen atoms and which
eventuelt er substituert med C^-C^-alkyl, eller is optionally substituted with C 1 -C 4 -alkyl, or
- med gruppene -SC^-Y eller -O-Y, hvor - with the groups -SC^-Y or -O-Y, where
Y står for C^-Cg-alkyl, aryl med 6-10 C-atomer eller står for C7-C14~aralkyl, og Y stands for C 1 -C 8 -alkyl, aryl with 6-10 C atoms or stands for C 7 -C 14 -aralkyl, and
R^ a) står for rettkjedet, forgrenet eller cyklisk, mettet eller umettet alkyl med inntil 10 C-atomer, som minst er enkelt substituert R^ a) stands for straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 10 C atoms, which is at least singly substituted
- med OH, CHO, OCONH2, -NHCONH2, - with OH, CHO, OCONH2, -NHCONH2,
- med gruppene COOR5, NHCOR5, COR5, - with the groups COOR5, NHCOR5, COR5,
hvor where
R<5>står for hydrogen, alkyl med inntil 8 C-atomer, aryl med 6-10 C-atomer eller C7~C14-aralkyl, R<5> stands for hydrogen, alkyl with up to 8 C atoms, aryl with 6-10 C atoms or C7~C14 aralkyl,
- med halogen, cyano, SO-.H, - with halogen, cyano, SO-.H,
- med gruppene - with the groups
hvor where
R 6 :og R 7 uavhengig.av hverandre ståor for hydrogen eller sammen eller hver for seg står for ci~C6~alkyl, C~-C,-alkenyl eller fenyl eller hvor substituentene R 6 , R 7eventuelt med nitrogenatomet danner en 5- til 7-leddet ring, som, som ytterligere heteroatomer, kan inneholde et oksygen-, svovel- og/eller 1-2 nitrogenatomer og som eventuelt er substituert med C1-C4-alkyl eller R 6 : and R 7 independently of each other stand for hydrogen or together or individually stand for C 1 -C 6 -alkyl, C -C 1 -alkenyl or phenyl or where the substituents R 6 , R 7 optionally with the nitrogen atom form a 5- to 7-membered ring, which, as further heteroatoms, may contain an oxygen, sulfur and/or 1-2 nitrogen atoms and which is optionally substituted with C1-C4 alkyl or
- med gruppen -S02~Y eller -0-Y - with the group -S02~Y or -0-Y
hvor where
Y står for C^-Cg-alkyl, aryl med 6-10 C-atomer Y stands for C 1 -C 8 alkyl, aryl with 6-10 C atoms
eller or
står for C^-C^-aralkyl, stands for C^-C^-aralkyl,
AA
b) star for CHO, S03H, b) stands for CHO, SO3H,
c) stå° r for COOR 5 , hvor R 5 har den ovenfor angitte betydning eller c) r stands for COOR 5 , where R 5 has the above meaning or
d) ståo r for gruppen -Z-R 8 d) stands for the group -Z-R 8
hvor where
Z står for Z stands for
eller -S02- og R 8 ståor for rettkjedet, forgrenet eller cyklisk, mettet eller umettet alkyl med inntil 8 C-atomer, som eventuelt er substituert med halogen, hydroksy, cyano, alkoksy, aryltio med i ethvert tilfelle inntil 6 C-atomer, aryloksy, aryltio med inntil 10 C-atomer, karboksy, C-^-Cg-alkoksykarbonyl, -OCONH2, -NHCONH,,, S03H eller or -SO2- and R 8 stand for straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 8 C atoms, which is optionally substituted with halogen, hydroxy, cyano, alkoxy, arylthio with in any case up to 6 C atoms, aryloxy, arylthio with up to 10 C-atoms, carboxy, C-^-C 8 -alkoxycarbonyl, -OCONH2, -NHCONH,,, SO3H or
hvor R^, R^ har de ovenfor angitte betydninger, where R^, R^ have the meanings indicated above,
- står for aryl med 6-10 C-atomer, - stands for aryl with 6-10 C atoms,
- står for C7-C14~aralkyl, - stands for C7-C14~aralkyl,
- for heterocyklyl eller - for heterocyclyl or
- for gruppen - for the group
hvor where
6 7 6 7
R , R har den ovenfor angitte betydning. R , R has the meaning given above.
Når restene When the remains
er substituert på ringmetylengruppen, er dette med inntil fire, fortrinnsvis inntil to like eller forskjellige substituenter som: a) rettkjedet, forgrenet eller cyklisk, mettet eller umettet alkyl med inntil 10 C-atomer, som eventuelt er videre is substituted on the ring methylene group, this is with up to four, preferably up to two identical or different substituents such as: a) straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 10 C atoms, which is optionally further
substituert substituted
- med -OH, CHO, -OCONHp, -NHCONH- - with -OH, CHO, -OCONHp, -NHCONH-
5 5 5 5 5 5
- med gruppene COOR , NHCOR , COR , hvor - with the groups COOR , NHCOR , COR , where
R 5 står for hydrogen, alkyl med inntil 8 C-atomer, R 5 stands for hydrogen, alkyl with up to 8 C atoms,
aryl med 6-10 C-atomer eller C^-C^-aralkyl, aryl with 6-10 C atoms or C 1 -C 2 -aralkyl,
- med halogen, cyano, SO^H, - with halogen, cyano, SO^H,
- med gruppene - with the groups
hvor where
R 6 og R 7 uavhengig av hverandre stå°r for hydrogen eller sammen eller hver for seg for C^-C^-alkyl, e^-Cg-alkenyl eller fenyl eller hvor substituentene R .■> R eventuelt med nitrogenatomet danner en 5- til 7-leddet'ring, som, som ytterligere heteroatom kan inneholde et oksygen-, svovel- og/eller 1-2 nitrogen-atoraer, og som eventuelt er substituert med C-^-C^-alkyl, eller R 6 and R 7 independently of each other stand for hydrogen or together or separately for C₁-C₂-alkyl, C₁-C₂-alkenyl or phenyl or where the substituents R .■> R optionally with the nitrogen atom form a 5 - to a 7-membered ring, which, as an additional heteroatom, may contain an oxygen, sulfur and/or 1-2 nitrogen atoms, and which is optionally substituted with C-^-C^-alkyl, or
- med gruppene -S02~Y eller -0-Y - with the groups -S02~Y or -0-Y
hvor where
Y står for C-^-Cg-alkyl, aryl med 6-10 C-atomer eller for C^-C-^-aralkyl, eller Y stands for C-^-Cg-alkyl, aryl with 6-10 C atoms or for C^-C-^-aralkyl, or
g g
b) gruppen -Z-R , b) the group -Z-R ,
hvor where
Z står for Z stands for
eller -SO.,- og or -SO.,- and
R 8 ståor for rettkjedet, forgrenet eller cyklisk, mettet eller umettet alkyl med inntil 6 C-atomer, som eventuelt er substituert med halogen, hydroksy, cyano, alkoksy, alkyltio alle med 6 C-atomer, aryloksy, aryltio (6-10 C-atomer), karboksy, C-^-Cg-alkoksykarbonyl, R 8 stands for straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 6 C atoms, which is optionally substituted with halogen, hydroxy, cyano, alkoxy, alkylthio all with 6 C atoms, aryloxy, arylthio (6-10 C -atoms), carboxy, C 1 -C 8 -alkyloxycarbonyl,
-OCONH2-, -NHCONH2, -SC^H, -OCONH2-, -NHCONH2, -SC^H,
6 7 6 7
hvor R , R har den ovenfor angitte betydning where R , R has the meaning stated above
- står for aryl med 6-10 C-atomer - stands for aryl with 6-10 C atoms
- står for Cy-C^-aralkyl - stands for Cy-C4-aralkyl
- for heterocyklyl eller - for heterocyclyl or
- for gruppen - 6 7 hvor R , R igjen har den ovenfor angitte betydning, - for the group - 6 7 where R , R again has the meaning stated above,
C) -OH, CHO, OCONH2, NHCONH-j, C) -OH, CHO, OCONH2, NHCONH-j,
d) gruppene COOR<5>, NHCOR<5>, COR<5>, d) the groups COOR<5>, NHCOR<5>, COR<5>,
hvor where
i R<5>står for hydrogen, alkyl med inntil 8 C-atomer, aryl med 6-10 C-atomer, eller G.,-C, .-aralkyl, in R<5> stands for hydrogen, alkyl with up to 8 C atoms, aryl with 6-10 C atoms, or G.,-C,.-aralkyl,
e) halogen, cyano, SO^H, e) halogen, cyano, SO^H,
f) gruppen f) the group
hvor where
6 7 6 7
R og R har den ovenfor angitte betydning, R and R have the meaning given above,
g) gruppen -O-Y, hvor g) the group -O-Y, where
Y står for C^-C^-alkyl, aryl med 6-10 C-atomer eller Y stands for C^-C^-alkyl, aryl with 6-10 C atoms or
- for C^-C-^-aralkyl.- for C 1 -C 2 -aralkyl.
Foretrukne forbindelser av den generelle formel I er forbindelser hvori Preferred compounds of the general formula I are compounds wherein
R"*" står for rettkjedet, forgrenet, mettet eller umettet, eventuelt med karboksy substituert alkyl med inntil 4 C-atomer, R"*" stands for straight-chain, branched, saturated or unsaturated, possibly carboxy-substituted alkyl with up to 4 C atoms,
R står for rettkjedet eller forgrenet alkyl med inntil R stands for straight chain or branched alkyl with up to
4 C-atomer, som eventuelt er substituert med hydroksy, karboksy, metoksy, metoksykarbonyl, fluor, klor eller brom, resten 4 C atoms, which are optionally substituted with hydroxy, carboxy, methoxy, methoxycarbonyl, fluorine, chlorine or bromine, the rest
står for de eventuelt substituerte restene stands for those possibly substituted the remains
hvori in which
R 3 stå°r for rettkjedet, forgrenet eller cyklisk, mettet eller umettet alkyl med inntil 8 C-atomer, som eventuelt er substituert R 3 stands for straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 8 C atoms, which is optionally substituted
- med OH, CHO, OCONH-, NHCONH- - with OH, CHO, OCONH-, NHCONH-
5 5 5 5 5 5
- med gruppene COOR , NHCOR , COR - with the groups COOR, NHCOR, COR
hvori in which
/' /'
R 5i står for hydrogen, alkyl med inntil v. 6 C-atomer, R 5i stands for hydrogen, alkyl with up to v. 6 C atoms,
fenyl eller benzyl, phenyl or benzyl,
- med fluor, klor, brom eller SO^H, - with fluorine, chlorine, bromine or SO^H,
- med gruppene - with the groups
hvori in which
R 6 og R 7uavhengig av hverandre står for hydrogen, for C^-C-j-alkyl eller fenyl eller hvor substituentene R , R eventuelt med nitrogenatomet danner en 5- eller 6-leddet ring, som, som ytterligere heteroatomer, kan inneholde et oksygen-, svovel- og/eller 1-2 nitrogenatomer og som eventuelt er substituert med C^-C2_alkyl, eller R 6 and R 7 independently of each other stand for hydrogen, for C 1 -C 1 -alkyl or phenyl or where the substituents R , R optionally with the nitrogen atom form a 5- or 6-membered ring, which, as further heteroatoms, may contain an oxygen , sulfur and/or 1-2 nitrogen atoms and which is optionally substituted with C₁-C₂_alkyl, or
- med gruppen -SC^-Y eller -0-Y, - with the group -SC^-Y or -0-Y,
hvor where
Y står for C-^-Cg-alkyl, fenyl eller benzyl, Y stands for C--C8-alkyl, phenyl or benzyl,
R^ a) står for rettkjedet, forgrenet eller cyklisk, mettet eller umettet alkyl med inntil 8 C-atomer, som minst er enkeltsubstituert, R^ a) stands for straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 8 C atoms, which is at least singly substituted,
- med OH, CHO, OCONH-,, NHCONH-, - with OH, CHO, OCONH-,, NHCONH-,
5 5 5 5 5 5
- med gruppene COOR , NHCOR , COR - with the groups COOR, NHCOR, COR
hvor where
R<5>står for hydrogen, alkyl med inntil 6 C-atomer, R<5> stands for hydrogen, alkyl with up to 6 C atoms,
fenyl eller benzyl, phenyl or benzyl,
- med fluor, klor, brom eller SO^H, - with fluorine, chlorine, bromine or SO^H,
- med gruppene eller - with the groups or
6 7 6 7
hvor R og R har den ovenfor angitte betydning, where R and R have the above meaning,
-.med gruppene -SO2-Y eller -0-Y -.with the groups -SO2-Y or -0-Y
hvor where
Y står for C-^-Cg-alkyl, fenyl eller benzyl, eller Y stands for C 1 -C 8 alkyl, phenyl or benzyl, or
b) står for CHO eller S03H, b) stands for CHO or SO3H,
c) står for COOR<5>, c) stands for COOR<5>,
hvor where
R<5>har den ovenfor angitte betydning, eller R<5> has the meaning indicated above, or
d) stå a r for gruppen -Z-R<8>, d) stand for the group -Z-R<8>,
hvor where
Z står for Z stands for
eller _S02- og R 8 ståor for rettkjedet, forgrenet eller cyklisk, mettet eller umettet alkyl med inntil 6 C-atomer, som eventuelt er substituert med fluor, klor, brom, hydroksy, karboksy, alkoksy eller alkyltio med inntil 3 C-atomer, fenyloksy, fenyltio, alkoksykarbonyl med inntil 3 C-atomer, med OCONH2, or _SO2 and R 8 stand for straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 6 C atoms, which is optionally substituted with fluorine, chlorine, bromine, hydroxy, carboxy, alkoxy or alkylthio with up to 3 C atoms, phenyloxy, phenylthio, alkoxycarbonyl with up to 3 C atoms, with OCONH2,
hvor R^ og R^ har den ovenfor angitte betydning, where R^ and R^ have the above meaning,
- for fenyl, - for phenyl,
- for benzyl, - for benzyl,
- for pyridyl, furyl, tienyl, tiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoksazolyl, oksazolyl, morfolinyl, piperidinyl, imidazolyl, pyrazolyl, tiazolyl eller piperazinyl, eller - står for gruppen - for pyridyl, furyl, thienyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, oxazolyl, morpholinyl, piperidinyl, imidazolyl, pyrazolyl, thiazolyl or piperazinyl, or - represents the group
hvor where
6 7 6 7
R og R har den ovenvor angitte betydning. R and R have the above meaning.
Spesielt foretrukne forbindelser av formel I er forbindelser hvori Particularly preferred compounds of formula I are compounds wherein
R"*", står for metyl, etyl, allyl eller 1-karboksy-l-metyletyl, R"*", stands for methyl, ethyl, allyl or 1-carboxy-1-methylethyl,
R 2 star for metyl, etyl, 2-hydroksyetyl eller karboksy- R 2 stands for methyl, ethyl, 2-hydroxyethyl or carboxy-
metyl, methyl,
resten the rest
står for de eventuelt substituerte gruppene stands for the optionally substituted groups
hvori in which
R 3 står for rettekjedet, forgrenet eller cyklisk, mettet eller umettet alkyl med inntil 6 C-atomer, som eventuelt er substituert R 3 stands for straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 6 C atoms, which is optionally substituted
- med OH, CHO, OCONH-, NHCONH-, - with OH, CHO, OCONH-, NHCONH-,
5 5 5 5 5 5
- med gruppene COOR , NHCOR eller COR , hvori - with the groups COOR , NHCOR or COR , in which
R står for hydrogen, alkyl med inntil 4 C-atomer, fenyl eller benzyl, R stands for hydrogen, alkyl with up to 4 C atoms, phenyl or benzyl,
- med fluor, klor eller SO^H, - with fluorine, chlorine or SO^H,
- med gruppene - with the groups
hvor R 6 , R 7 uavhengig av hverandre står for hydrogen, metyl, etyl, fenyl eller med nitrogenatomet danner en ring som pyrrolidin, piperazin, piperidin, morfolin eller tiomorfolin, eller where R 6 , R 7 independently of each other stand for hydrogen, methyl, ethyl, phenyl or with the nitrogen atom form a ring such as pyrrolidine, piperazine, piperidine, morpholine or thiomorpholine, or
- står for gruppen -S02~Y eller -0-Y, hvori - stands for the group -S02~Y or -0-Y, in which
Y står for alkyl (inntil C4), fenyl eller benzyl, Y stands for alkyl (up to C4), phenyl or benzyl,
og and
R^ a) står for rettkjedet, forgrenet eller cyklisk, mettet eller umettet alkyl med inntil 6 C-atomer, som minst er enkeltsubstituert R^ a) stands for straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 6 C atoms, which is at least singly substituted
- med OH, CHO, OCONH-,, NHCONH-,, - with OH, CHO, OCONH-,, NHCONH-,,
5 5 5 5 5 5
- med gruppene COOR , NHCOR , COR - with the groups COOR, NHCOR, COR
hvori in which
5 5
R star for hydrogen, alkyl (inntil:C4), fenyl eller benzyl, R stands for hydrogen, alkyl (up to: C4), phenyl or benzyl,
■• - med fluor, klor eller SO^H, ■• - with fluorine, chlorine or SO^H,
- med gruppene - with the groups
eller or
hvori in which
R^ og R^ har den ovenfor angitte betydning eller R^ and R^ have the meaning indicated above or
- med gruppene -SC^-Y eller -0-Y, - with the groups -SC^-Y or -0-Y,
hvori in which
Y står for alkyl med inntil 4 C-atomer, fenyl eller benzyl, Y stands for alkyl with up to 4 C atoms, phenyl or benzyl,
eller or
b) står for CHO eller SO^H, b) stands for CHO or SO^H,
c) står for COOR c) stands for COOR
hvori in which
5 5
R har den ovenfor angitte betydning, eller R has the above meaning, or
d) ståo r for gruppen -Z-R 8 d) stands for the group -Z-R 8
hvori in which
Z står for Z stands for
eller -SO2- og or -SO2- and
R 8 ståor for rettkjedet eller forgrenet, mettet eller umettet alkyl med inntil 4 C-atomer, som eventuelt er substituert med klor, fluor, hydroksy, karboksy, R 8 stands for straight-chain or branched, saturated or unsaturated alkyl with up to 4 C atoms, which is optionally substituted with chlorine, fluorine, hydroxy, carboxy,
OCONH2, NHCONH2, SO-^H, OCONH 2 , NHCONH 2 , SO-^H,
6 7 6 7
hvor R og R har den ovenfor angitte betydning, where R and R have the above meaning,
- står for fenyl, - stands for phenyl,
- står for benzyl, - stands for benzyl,
- for pyridyl, furyl, tienyl, tiazolyl, isoksazolyl, imidazolyl, pyrazolyl eller - for gruppen - for pyridyl, furyl, thienyl, thiazolyl, isoxazolyl, imidazolyl, pyrazolyl or - for the group
hvor where
R 6 , R 7igjen har den ovenfor angitte betydning. R 6 , R 7 again have the meaning indicated above.
Når restene When the remains
er substituert, kan dette både ved de foretrukne og også ved de spesielt foretrukne forbindelsene av generell formel I være substituert med en substituent som: a) rettkjedet, forgrenet eller cyklisk, mettet eller umettet alkyl med inntil 6 C-atomer, som igjen videre er substituert is substituted, this can both in the preferred and also in the particularly preferred compounds of general formula I be substituted with a substituent such as: a) straight-chain, branched or cyclic, saturated or unsaturated alkyl with up to 6 C atoms, which in turn is further substituted
- med OH, CHO, OCONH-, NHCONH-, - with OH, CHO, OCONH-, NHCONH-,
5 5 5 5 5 5
- med gruppene COOR , NHCOR , COR - with the groups COOR, NHCOR, COR
hvori in which
R 5 ståor for hydrogen, alkyl med inntil 4 C-atomer, fenyl eller benzyl, R 5 stands for hydrogen, alkyl with up to 4 C atoms, phenyl or benzyl,
- med fluor, klor, SO^H, - with fluorine, chlorine, SO^H,
- med gruppene - with the groups
hvori R<6>og R<7>uavhengig av hverandre står for hydrogen, metyl, etyl, fenyl eller hvor R 6 , R 7 sammen med nitrogenatomet danner en ring som pyrrolidin, piperidin, piperazin, morfolin eller tiomorfolin, eller in which R<6> and R<7> independently of each other stand for hydrogen, methyl, ethyl, phenyl or where R 6 , R 7 together with the nitrogen atom form a ring such as pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, or
- med gruppen -SO2-Y eller -0-Y, - with the group -SO2-Y or -0-Y,
hvor where
Y står for alkyl med inntl 4 C-atomer, fenyl eller benzyl, Y stands for alkyl with intl 4 C atoms, phenyl or benzyl,
g g
b) gruppen -Z-R b) the group -Z-R
hvori in which
Z står for Z stands for
eller -S02~, og R 8 ståor for rettkjedet, forgrenet, mettet eller umettet alkyl med inntil 4 C-atomer, som eventuelt er substituert med fluor, klor, hydroksy, karboksy, OCONH2, NHCONH2, S03H, or -S02~, and R 8 stands for straight-chain, branched, saturated or unsaturated alkyl with up to 4 C atoms, which is optionally substituted with fluorine, chlorine, hydroxy, carboxy, OCONH2, NHCONH2, SO3H,
6 7 6 7
hvor R , R har den ovenfor angitte betydning, where R , R has the above meaning,
- står for fenyl, - stands for phenyl,
- står for benzyl, - stands for benzyl,
- for pyridyl, tienyl, furyl, tiazolyl, oksazolyl, isoksazolyl, imidazolyl, pyrimidyl, morfolinyl, piperidinyl eller - for gruppen - for pyridyl, thienyl, furyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrimidyl, morpholinyl, piperidinyl or - for the group
hvor where
R^, R7 igjen har den ovenfor angitte betydning, R^, R7 again have the meaning indicated above,
c) OH, CHO, OCONH2, NHCONH2, c) OH, CHO, OCONH2, NHCONH2,
5 5 5 5 5 5
d) gruppene COOR , NHCOR , COR , d) the groups COOR , NHCOR , COR ,
hvor where
R 5 har den ovenfor angitte betydning, R 5 has the above meaning,
e) fluor, klor, SO^H, e) fluorine, chlorine, SO^H,
f) gruppene f) the groups
hvor R 6 , R 7igjen har den ovenfor angitte betydningen, where R 6 , R 7 again have the meaning given above,
eller or
g)i gruppen -0-Y g) in the group -0-Y
hvori in which
Y står for alkyl med inntil 4 C-atomer, fenyl eller benzyl. Y stands for alkyl with up to 4 C atoms, phenyl or benzyl.
Av forbindelsene av formel I ifølge oppfinnelsen kan det opp-stå flere isomerer, som alle er antibiotisk virksomme og om nødvendig kan adskilles ved kromatografi eller krystalli-sasjon . From the compounds of formula I according to the invention, several isomers can arise, all of which are antibiotically active and, if necessary, can be separated by chromatography or crystallization.
Forbindelsene av den generelle formel I kan fremstilles ved at man omsetter forbindelser av den generelle formel II The compounds of the general formula I can be prepared by reacting compounds of the general formula II
hvori in which
R"*" har den ovenfor angitte betydning, R"*" has the above meaning,
hvori aminogruppen kan foreligge beskyttet eller ubeskyttet, etter aktivering av karboksylgruppen ved overføring i et blandet anhydrid, eksempelvis med klormaursyreetylester eller metansulfonsyreklorid ved overføring i syrehalogenidet eller ved overføring i en aktivert ester med eksempelvis N-hydroksybenztriazol eller dicykloheksylkarbodiimid, med forbindelser av generell formel III, in which the amino group can be protected or unprotected, after activation of the carboxyl group by transfer in a mixed anhydride, for example with chloroformate ethyl ester or methanesulfonic acid chloride by transfer in the acid halide or by transfer in an activated ester with for example N-hydroxybenztriazole or dicyclohexylcarbodiimide, with compounds of general formula III,
hvori in which
har"den ovenfor angitte betydning, der- has" the above meaning, where-
etter eventuelt avspaltes beskyttelsesgruppen og de ønskede saltene eller fra saltene, de frie syrene, fremstilles. after, if necessary, the protecting group is removed and the desired salts or from the salts, the free acids, are produced.
For koplingen av karboksylsyrene (II) til B-laktamer av formelen (III) kan et stort antall av de kjente fremgangs-måtene fra cefalosporin- hhv. penicillinkjemien anvendes. Det har vist seg fordelaktig å aktivere karboksylsyrene For the coupling of the carboxylic acids (II) to B-lactams of the formula (III), a large number of the known methods from cephalosporins or penicillin chemistry is used. It has proven beneficial to activate the carboxylic acids
av generell formel (II) uten aminbeskyttelsesgruppe og deretter kople dem med 8-laktamene av formel (III), som of general formula (II) without an amine protecting group and then coupling them with the 8-lactams of formula (III), which
er brakt i oppløsning med et amin. is brought into solution with an amine.
Spesielt fordelaktig er aktiveringen med sulfonsyrederivater av formelen V til anhydrider av formelen IV Particularly advantageous is the activation with sulfonic acid derivatives of the formula V to anhydrides of the formula IV
hvori in which
T står for resten R 9-SO^-O- eller halogen, og T stands for the residue R 9-SO^-O- or halogen, and
R står for alkyl med inntil 10 C-atomer, som eventuelt er substituert med fluor, klor, cyano, fenyl, alkoksykarbonyl, alkoksy eller alkyl alle med inntil 4 C-atomer, eller - står for fenyl, som eventuelt er substituert med fluor, klor, brom, cyano, alkyl, alkoksy, alkyltio, alkoksykarbonyl alle med inntil 4 C-atomer, nitro, trifluormetyl eller fenyl. R stands for alkyl with up to 10 C atoms, which is optionally substituted with fluorine, chlorine, cyano, phenyl, alkoxycarbonyl, alkoxy or alkyl all with up to 4 C atoms, or - stands for phenyl, which is optionally substituted with fluorine, chlorine, bromine, cyano, alkyl, alkoxy, alkylthio, alkoxycarbonyl all with up to 4 C atoms, nitro, trifluoromethyl or phenyl.
Nåo r R 9er substituert, er fortrinnsvis 1-3 substituenter tilstede, spesielt foretrukket de ovenfor nevnte. When R 9 is substituted, preferably 1-3 substituents are present, particularly preferred are those mentioned above.
Spesielt foretrukket utgjør R gen metyl- eller p-tolylrest. Particularly preferably, R is a methyl or p-tolyl residue.
De blandede, anhydridene av formelen (IV) fremstilles ved The mixed anhydrides of the formula (IV) are prepared by
at man oppløser karboksylsyrene av formel (II) og 1-1,4 ekvivalenter av et amin i et oppløsningsmiddel og lar blandingen reagere med 1-1,2 ekvivalenter av et sulfonsyrederivat av formelen (V). that one dissolves the carboxylic acids of formula (II) and 1-1.4 equivalents of an amine in a solvent and allows the mixture to react with 1-1.2 equivalents of a sulphonic acid derivative of formula (V).
Som oppløsningsmiddel egner seg alle oppløsningsmidler Any solvent is suitable as a solvent
som er stabile under reaksjonsbetingelsene, som f.eks. dietyleter, tetrahydrofuran, acetonitril, aceton, metylenklorid, kloroform eller dimetylformamid. which are stable under the reaction conditions, such as e.g. diethyl ether, tetrahydrofuran, acetonitrile, acetone, methylene chloride, chloroform or dimethylformamide.
Som aminer egner seg tertiære aminer som f.eks. trietylamin eller tributylamin, men også sterisk hindrede sekundære aminer som f.eks. diisopropylamin, eller blandinger av disse aminene. As amines, tertiary amines such as e.g. triethylamine or tributylamine, but also sterically hindered secondary amines such as e.g. diisopropylamine, or mixtures of these amines.
Omsetningen kan gjennomføres ved temperaturer mellom -80°C og romtemperatur. Fortrinnsvis gjennomføres aktiveringen med C1-S02CH3, i dimetylformamid ved -40°C til -60°C i The conversion can be carried out at temperatures between -80°C and room temperature. Preferably, the activation is carried out with C1-SO2CH3, in dimethylformamide at -40°C to -60°C in
løpet av 0,2 til 24 timer, fortrinnsvis 0,5 til 5 timer. during 0.2 to 24 hours, preferably 0.5 to 5 hours.
Til oppløsning av forbindelsene av formel (III) kan de For dissolving the compounds of formula (III) they can
ved fremstillingen av forbindelsene av formel (IV) nevnte oppløsningsmidlene eller vann samt som baser de ovenfor nevnte aminene anvendes. in the preparation of the compounds of formula (IV) the mentioned solvents or water and as bases the above-mentioned amines are used.
Spesielt fordelaktig er også en aktivering av karboksylsyrene av generell formel (II) ved overføring i en aktivert ester med eksempelvis N-hydroksysuccinimid og dicykloheksylkarbodiimid eller 1-hydroksybenztriazol og dicykloheksylkarbodiimid. Activation of the carboxylic acids of general formula (II) by transfer into an activated ester with, for example, N-hydroxysuccinimide and dicyclohexylcarbodiimide or 1-hydroxybenztriazole and dicyclohexylcarbodiimide is also particularly advantageous.
Som oppløsningsmiddel egner seg alle oppløsningsmidler Any solvent is suitable as a solvent
som også er egnet for fremstilling av anhydridene av formel which is also suitable for the preparation of the anhydrides of formula
(IV) . (IV).
Omsetningene kan gjennomføres' ved temperaturer mellom • -30°C og +100°C. Fortrinnsvis aktiveres med l-'hydroksybenztriazol og dicykloheksylkarbodiimid i .dimetylformamid ved romtemperatur 2-6 timer, deretter frafiltreres fra utfelt dicykloheksylurinstoff og;omsettesirned en forbindelse av formel (III) i form av en oppløsning av aminsaltet i løpet av 2-24 timer. Til oppløsning av forbindelsene av formel (III) kan de ved fremstillingen av forbindelsene av formel (IV) nevnte oppløsningenemidlene, samt som baser de på samme sted omtalte aminene anvendes. The conversions can be carried out at temperatures between • -30°C and +100°C. Preferably activated with 1-hydroxybenztriazole and dicyclohexylcarbodiimide in dimethylformamide at room temperature for 2-6 hours, then filtered off from precipitated dicyclohexylurea and reacted with a compound of formula (III) in the form of a solution of the amine salt within 2-24 hours. To dissolve the compounds of formula (III), the solvents mentioned in the preparation of the compounds of formula (IV) can be used, as well as the amines mentioned in the same place as bases.
Forbindelsene av formelen (III) får man ved at man avspalter aminobeskyttelsesgruppene R"1"0 fra formelen (VI). The compounds of the formula (III) are obtained by cleaving the amino protecting groups R"1"0 from the formula (VI).
Herved kan R"*"^ enten være en syrelabil beskyttelsesgruppe som t-butyloksykarbonylgruppen eller fortrinnsvis en enzymatisk avspaltbar beskyttelsesgruppe. Foretrukne enzymatisk avspaltbare beskyttelsesgrupper er fenylacetyl eller 2-tienylacetyl. Hereby, R"*"^ can either be an acid-labile protecting group such as the t-butyloxycarbonyl group or preferably an enzymatically cleavable protecting group. Preferred enzymatically cleavable protecting groups are phenylacetyl or 2-thienylacetyl.
Den enzymatisk avspaltningen foregår ved romtemperatur The enzymatic cleavage takes place at room temperature
i vann eller en blanding av vann og et polart organisk oppløsningsmiddel, som f.eks. acetonitril eller tetrahydrofuran, med immobilisert penicillin G-acylase ved pH 7-8, fortrinnsvis ved pH 7,5-7,8. in water or a mixture of water and a polar organic solvent, such as e.g. acetonitrile or tetrahydrofuran, with immobilized penicillin G-acylase at pH 7-8, preferably at pH 7.5-7.8.
Under den enzymatisk spaltningen holdes pH-verdien konstant ved tilsats av en base som litiumhydroksyd, natriumhydroksyd, kaliumhydroksyd eller et tert.amin som f.eks. trietylamin, tripropylamin, tributylamin eller pyridin. During the enzymatic cleavage, the pH value is kept constant by adding a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide or a tert.amine such as e.g. triethylamine, tripropylamine, tributylamine or pyridine.
Forbindelsene rav formelen (VI) lar seg fremstille fra estere av formelen- (VII) over mellomforbindelser:av formelen (VIII). The compounds of the formula (VI) can be prepared from esters of the formula (VII) via intermediate compounds of the formula (VIII).
I estrene av formelen (VII) utgjør X en avspaltbar gruppe som mesylat, tosylat, brosylat, triflat, nonaflat, jodid, bromid, klorid og R en i cefalosporinkjemien vanlig syre-beskyttelsesgruppe, fortrinnsvis en sur avspaltbar beskyttelsesgruppe, som f.eks. benzhydryl, 4-metoksydifenylmetyl, t-butyl. In the esters of the formula (VII), X is a cleavable group such as mesylate, tosylate, brosylate, triflate, nonaflate, iodide, bromide, chloride and R is an acid protecting group common in cephalosporin chemistry, preferably an acidic cleavable protecting group, such as e.g. benzhydryl, 4-methoxydiphenylmethyl, t-butyl.
Forbindelsene av formelen (VII) overføres ved avspaltning av syrebeskyttelsesgruppen R til de reaktive frie syrene av formelen (VIII). Ved de foretrukne syrelabile beskyt-telsesgruppene R avspaltes beskyttelsesgruppen i et organisk oppløsningsmiddel. Foretrukket er avspaltningen av benzhydrylbeskyttelsesgruppen i metylenklorid med trifluor-eddiksyre eventuelt under tilsats av en alkoksybenzol, fortrinnsvis metoksybenzol. Avspaltningen foregår ved -20°C til +30°C, fortrinnsvis ved 0°C i løpet av 5 minutter til en time, fortrinnsvis i løpet av 20 minutter. The compounds of the formula (VII) are transferred by cleavage of the acid protecting group R to the reactive free acids of the formula (VIII). In the case of the preferred acid-labile protecting groups R, the protecting group is split off in an organic solvent. The cleavage of the benzhydryl protecting group in methylene chloride with trifluoroacetic acid is preferred, possibly with the addition of an alkoxybenzene, preferably methoxybenzene. The cleavage takes place at -20°C to +30°C, preferably at 0°C within 5 minutes to an hour, preferably within 20 minutes.
Syren-av formelen (VIII) kan isoleres etter'avspaltning The acid of formula (VIII) can be isolated after cleavage
av beskyttelsesgruppen. Det er imidlertid fordelaktig ikke of the protection group. However, it is not beneficial
-å isolere, men dérimot direkte og uten rensing å omsette -forbindelsen av formel (VI). Herved avdåmpes skånsomt den ^oppløsningen av (VIII) som oppstår ved reaksjonen (VII) —> - to isolate, but on the other hand directly and without purification to react - the compound of formula (VI). In this way, the ^solution of (VIII) that occurs during the reaction (VII) is gently evaporated —>
(VIII) i vakuum. Den tilbakeblevne råe syren opptas i (VIII) in vacuum. The remaining crude acid is taken up
et organisk oppløsningsmiddel, fortrinnsvis i tetrahydrofuran, og omsettes med 2-50 ekvivalenter, fortrinnsvis med 5-20 ekvivalenter av et tert.amin av formelen an organic solvent, preferably in tetrahydrofuran, and is reacted with 2-50 equivalents, preferably with 5-20 equivalents of a tert.amine of the formula
hvor where
har den ovenfor angitte betydning, til forbin- has the meaning stated above, in connection with
delser av formel (VI). moieties of formula (VI).
Omsetningen gjennomføres ved temperaturer mellom -20°C The turnover is carried out at temperatures between -20°C
og 40°C, fortrinnsvis ved 25°C, i løpet av 10 minutter til 2 timer, fortrinnsvis i løpet av 30 minutter. Produktet kan etter avsluttet reaksjon utfelles ved tilsats av dietyleter. Det fremstilte råproduktet kan renses på en harpiks som "Diaion HP 20" eller "XAD 7". Det er også fordelaktig og mulig å omsette råproduktet direkte videre til forbindelser av formelen (III). and 40°C, preferably at 25°C, within 10 minutes to 2 hours, preferably within 30 minutes. After the reaction has finished, the product can be precipitated by adding diethyl ether. The prepared crude product can be purified on a resin such as "Diaion HP 20" or "XAD 7". It is also advantageous and possible to convert the crude product directly further into compounds of the formula (III).
Forbindelsene av formel (VI) lar seg alternativt fremstille fra syrer av formel (IX), hvori R har den ovenfor angitte The compounds of formula (VI) can alternatively be prepared from acids of formula (IX), in which R has the above-mentioned
12 12
betydning og R er eventuelt substituert alkyl eller aryl, som metyl, etyl, propyl, klormetyl, diklormetyl, triklor-metyl, trifluormetyl, fenyl. Spesielt foretrukket utgjør R"*"^ en metylgruppe . meaning and R is optionally substituted alkyl or aryl, such as methyl, ethyl, propyl, chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, phenyl. Particularly preferably, R"*"^ constitutes a methyl group.
Utgangsforbindelsene av formelen (IX) suspenderes i et egnet organisk opplsningsmiddel og bringes i oppløsning ved silylering til silylester X. Spesielt egnede organiske oppløsnings-midler er kloroform, metylenklorid, dikloretan. Silyleringen gjennomføres med et vanlig silyleringsmiddel som trimetyl-klorsilan (TMCS), heksametyldisilazan (HMDS), N,0-bis-(trimetylsilyl)acetamid (BSA), N,O-bis(trimetylsilyl)-trifluor-acetamid (BSTFA), N-metyl-N-trimetylsilylacetamid (MSA), N-metyl-N-trimetyl-silyltrifluoracetamid (MSTFA), 1,3-bis-(trimetylsilyl)urinstoff eller trimetylsilyltrifluormetan-sulfonat. The starting compounds of the formula (IX) are suspended in a suitable organic solvent and brought into solution by silylation to silyl ester X. Particularly suitable organic solvents are chloroform, methylene chloride, dichloroethane. The silylation is carried out with a common silylation agent such as trimethylchlorosilane (TMCS), hexamethyldisilazane (HMDS), N,0-bis-(trimethylsilyl)acetamide (BSA), N,O-bis(trimethylsilyl)-trifluoroacetamide (BSTFA), N -methyl-N-trimethylsilylacetamide (MSA), N-methyl-N-trimethylsilyltrifluoroacetamide (MSTFA), 1,3-bis-(trimethylsilyl)urea or trimethylsilyltrifluoromethanesulfonate.
Herved kan også flere silyleringsmidler anvendes i blanding. In this way, several silylation agents can also be used in a mixture.
Silyleringen foregår ved -30°C til +70°C, fortrinnsvis The silylation takes place at -30°C to +70°C, preferably
ved -10°C til +10°C, i løpet av 5 minutter til 30 minutter. Fortrinnsvis anvendes et to til ti gangers overskudd av at -10°C to +10°C, within 5 minutes to 30 minutes. Preferably, a two to ten times excess of is used
■.silyléxihgsmidlet, f ortrinnsvi-s et to til fem gangers overskudd. ■.silyléxihgsmidtel, f ortrnnnvi-s a two to five times excess.
'.Derti slik oppnådde oppløsningen av trimetylsilylesteren av formelen (X) omsettes ved -40°C til +30°C, <fortrinnsvis med 3-4 ekvivalenter av et trialkylsilyljodid, spesielt foretrukket trimetylsilyljodid, i løpet av 15 minutter til 2 timer, fortrinnsvis i løpet av 30 minutter til 1 time, til forbindelser av formelen (XI). The thus obtained solution of the trimethylsilyl ester of the formula (X) is reacted at -40°C to +30°C, <preferably with 3-4 equivalents of a trialkylsilyl iodide, particularly preferred trimethylsilyl iodide, during 15 minutes to 2 hours, preferably within 30 minutes to 1 hour, to compounds of formula (XI).
Forbindelsene av formelen (XI) isoleres med fordel ikke, men omsettes derimot direkte uten rensing med aminer The compounds of the formula (XI) are advantageously not isolated, but reacted directly without purification with amines
til forbindelsene av formel (VI). to the compounds of formula (VI).
Forbindelsene av generell formel I kan alternativt også fremstilles ved at man omsetter forbindelser av formelen The compounds of general formula I can alternatively also be prepared by reacting compounds of the formula
(XII) (XII)
1 12 hvori R og R har den ovenfor angitte betydning, som tidligere beskrevet for omsetningen av forbindelsene av formel (VI) direkte uten isolering av mellomtrinnene etter silylering og overføring til jodid med aminer 1 12 wherein R and R have the above meaning, as previously described for the reaction of the compounds of formula (VI) directly without isolation of the intermediate steps after silylation and transfer to iodide with amines
til forbindelser av formel (I). to compounds of formula (I).
Forbindelsene ifølge oppfinnelsen oppviser enr-sterk og The compounds according to the invention exhibit enr-strong and
bred antimikrobiell-virksomhet, spesielt mot gram-negative broad antimicrobial activity, especially against gram-negatives
n og gram-positive bakterier. Disse egenskapene muliggjør anvendelse som kjemoterapeutisk virksomme stoffer innen medisinen. n and gram-positive bacteria. These properties enable use as chemotherapeutically active substances in medicine.
Spesielt virksomme er forbindelsene ifølge oppfinnelsen The compounds according to the invention are particularly effective
mot bakterier og bakterieliknende mikroorganismer. Det egner seg følgelig spesielt godt til profylakse og kjemoterapi ved lokale og systemiske infeksjoner innen human- og veterinær-medisin, som er fremkalt av disse organismene. against bacteria and bacteria-like microorganisms. It is therefore particularly suitable for prophylaxis and chemotherapy in local and systemic infections in human and veterinary medicine, which are caused by these organisms.
Eksempelvis kan lokale og/eller systemiske sykdomstilstander behandles og/eller forhindres, som er forårsaket av følgende sykdomsfremkallere eller blandinger av følgende sykdomsfremkallere: Micrococcaceae, som stafylokokker, f.eks. Staphylococcus aureus, Staphylococcus épidermidis, Staphylococcus aerogenes og Graffkya tetragena; For example, local and/or systemic disease states can be treated and/or prevented, which are caused by the following pathogens or mixtures of the following pathogens: Micrococcaceae, such as staphylococci, e.g. Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus aerogenes and Graffkya tetragena;
Lactobacteriaceae som streptokokker, f.eks. Streptococcus pyogenes, a- hhv. B-hemolyserende streptokokker, ikke hemolyserende streptokokker, Streptococcus viridans, Streptococcus faecalis (enterokokker) og Dipolococcus pneumoniae (pneumo-kokker); Lactobacteriaceae such as streptococci, e.g. Streptococcus pyogenes, a- or B-hemolytic streptococci, non-hemolytic streptococci, Streptococcus viridans, Streptococcus faecalis (enterococci) and Dipolococcus pneumoniae (pneumococci);
Enterobacteriaceae, som Escherichie-bakterier av coli-gruppen: Escherichia-bakterier, f.eks. Escherichia coli, Enterobacter-bakterier, f.eks. Enterobacter-Aerogenes, Enterobacter-Cloacae, Klebsiella-bakterier, f.eks. Klebsiella pneumoniae, Serratia, f.eks. Serratia marcescens, Proteae-bakterier Enterobacteriaceae, such as Escherichie bacteria of the coli group: Escherichia bacteria, e.g. Escherichia coli, Enterobacter bacteria, e.g. Enterobacter-Aerogenes, Enterobacter-Cloacae, Klebsiella bacteria, e.g. Klebsiella pneumoniae, Serratia, e.g. Serratia marcescens, Proteae bacteria
av Proteus-gruppen: f.eks. Proteus vulgaris, Proteus morganii, • Proteus rettgeri, Proteus mitabilis; of the Proteus group: e.g. Proteus vulgaris, Proteus morganii, • Proteus rettgeri, Proteus mitabilis;
Pseudomonadaceae, som Pseudomonas-bakterier, f.eks. Pseudomonas aeruginosa; Pseudomonadaceae, such as Pseudomonas bacteria, e.g. Pseudomonas aeruginosa;
Bacteroidaceae, som Baeteroides-bakterier, f.eks. Bacteroides fragilis. Bacteroidaceae, such as Baeteroides bacteria, e.g. Bacteroides fragilis.
Liten ovenfor over rsykdomsfremkallere er ment som eksempler og skal ikke virke-begrensende. The above list of disease-causing agents is intended as examples and should not be restrictive.
Som sykdommer som kan forebygges, forbedres og/eller helbredes ved forbindelsene ifølge oppfinnelsen kan eksempelvis nevnes: Sykdomstilstander i luftveiene og struperommet; ørebetennelse, faryngitt: lungebetennelse; bukhinnebetennelse, nyrebekken-betennelse; cystitt, endokarditt, systeminfeksjoner, bronkitt, artritt, lokale infeksjoner. Diseases that can be prevented, improved and/or cured by the compounds according to the invention can for example be mentioned: Disease states in the respiratory tract and larynx; ear infection, pharyngitis: pneumonia; peritonitis, pyelonephritis; cystitis, endocarditis, systemic infections, bronchitis, arthritis, local infections.
Til foreliggende oppfinnelse hører farmasøytiske preparater som ved siden av ikke-toksiske, inerte farmasøytisk egnede bærerstoffer inneholder en eller flere forbindelser ifølge oppfinnelsen eller som består av et eller flere virksomme stoff ifølge oppfinnelsen, samt fremgangsmåter til fremstilling av disse preparatene. The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable carriers, contain one or more compounds according to the invention or which consist of one or more active substances according to the invention, as well as methods for producing these preparations.
Til foreliggende oppfinnelse hører også farmasøytiske preparater i doseringsenheter. Dette betyr at preparatene forelig-ger i form av enkelte deler, f.eks. tabletter, dragéer, kapsler, piller, suppositorier og ampuller, hvis innhold av virksomt stoff utgjør en brøkdel eller et multiplum av en enkelt dose. Doseringsenhetene kan f.eks. inneholde 1, 2, 3 eller 4 enkeltdoser eller h, 1/3 eller 1/4 enkeltdose. En enkeltdose inneholder fortrinnsvis den mengden virksomt stoff som administreres ved en tilførsel og som vanligvis tilsvarer en hel, en halv eller en tredjedel eller en fjerde-del av en dagsdose. The present invention also includes pharmaceutical preparations in dosage units. This means that the preparations are available in the form of individual parts, e.g. tablets, dragées, capsules, pills, suppositories and ampoules, whose content of active substance constitutes a fraction or a multiple of a single dose. The dosage units can e.g. contain 1, 2, 3 or 4 single doses or h, 1/3 or 1/4 single dose. A single dose preferably contains the amount of active substance that is administered in one supply and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.
Under ikke-toksiske, inerte farmasøytisk egnede bærerstoffer forstås faste, halvfaste eller flytende fortynningsmidler, fyllstoffer og sammensetningshjelpemidler av enhver art. Non-toxic, inert pharmaceutically suitable carriers are understood to mean solid, semi-solid or liquid diluents, fillers and composition aids of any kind.
Som foretrukne farmasøytiske preparater kan nevnes■tabletter, dragéer; kapsler, piller, granulater, suppositorier, oppløs-ninger, suspensjoner og emulsjoner, pastaer, salver, geleer, kremer, lotions, pudder og spray. As preferred pharmaceutical preparations can be mentioned■tablets, dragées; capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays.
Tabletter, dragéer, kapsler, piller og granulater kan inneholde det eller de virksomme stoffene ved siden av de vanlige bærestoffene som (a) fylle- og drøyemidler, f.eks. stivelse, melkesukker, rørsukker, glukose, mannitt og kiselsyre. (b) bindemidler, f.eks. karboksymetylcellulose, alginat, gelatin, polyvinylpyrrolidon, (c) midler som holder på fuktigheten, f.eks. glycerin, (d) sprengmidler, f.eks. agar-agar, kalsiumkarbonat og natriumkarbonat, (e) oppløsnings-forsinkere, f.eks. parafin og (f) resorpsjonsakseleratorer, f.eks. kvaternære ammoniumforbindelser, (g) fuktemidler, Tablets, dragées, capsules, pills and granules may contain the active substance(s) in addition to the usual carriers such as (a) bulking and thickening agents, e.g. starch, milk sugar, cane sugar, glucose, mannitol and silicic acid. (b) binders, e.g. carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, (c) humectants, e.g. glycerin, (d) explosives, e.g. agar-agar, calcium carbonate and sodium carbonate, (e) dissolution retarders, e.g. paraffin and (f) resorption accelerators, e.g. quaternary ammonium compounds, (g) wetting agents,
f.eks. cetylalkohol, glycerinmonostearat, (h) adsorpsjons-midler, f.eks. kaolin og bentonitt og (i) glidemidler, e.g. cetyl alcohol, glycerin monostearate, (h) adsorbents, e.g. kaolin and bentonite and (i) lubricants,
f.eks. talkum, kalsium- eller magnesiumstearat og faste polyetylenglykoler eller blandinger av de under (a) til (i) angitte stoffene. e.g. talc, calcium or magnesium stearate and solid polyethylene glycols or mixtures of the substances specified under (a) to (i).
Tablettene, dragéene, kapslene, pillene og granulatene kan eventuelt være utstyrt med vanlige, eventulet opakiser-ingsmiddelholdige overtrekk eller omhyllinger, og også The tablets, dragées, capsules, pills and granules may optionally be equipped with ordinary, possibly opacifying agent-containing covers or covers, and also
være slik sammensatt at de avgir det eller de virksomme stoffene bare, eller foretrukket, i en bestemt del av intesti-naltrakten, eventuelt med forsinket avgivelse, hvorved det som innstøpningsmasser f.eks. kan anvendes polymerstoffer og vokser. be composed in such a way that they release the active substance(s) only, or preferentially, in a specific part of the intestinal tract, possibly with delayed release, whereby as embedding masses e.g. polymer substances and waxes can be used.
Det eller de virksomme stoffene kan eventuelt også foreligge The active substance(s) may also be present
i mikroinnkapselform med et eller flere av de ovenfor angitte bærestoffene. in micro-encapsulated form with one or more of the carriers specified above.
Suppositorier kan ved siden av det eller de virksomme stoffene inneholde vanlige vannoppløselige eller vannuoppløselige Suppositories can contain normal water-soluble or water-insoluble substances in addition to the active substance(s).
bærestoffer, f.eks. polyetylenglykoler, fett, f.eks. kakao- carriers, e.g. polyethylene glycols, fats, e.g. cocoa
j fett og høyere estere .(f .eks. C^^-alkohol med C-^g-f ettsyre) eller blandinger av disse.stoffene. j fats and higher esters (e.g. C^^-alcohol with C-^g-f acetic acid) or mixtures of these substances.
For parenteral tilførsel kan oppløsningene også foreligge For parenteral administration, the solutions may also be available
i steril og blodisotonisk form. in sterile and blood isotonic form.
De terapeutisk virksomme forbindelsene skal i de ovenfor angitte farmasøytiske preparatene fortrinnsvis være tilstede i en konsentrasjon på ca. 0,1 til 99,5, fortrinnsvis fra ca. 0,5 til 95 vekt-% av totalblandingen. The therapeutically active compounds should preferably be present in the above-mentioned pharmaceutical preparations in a concentration of approx. 0.1 to 99.5, preferably from approx. 0.5 to 95% by weight of the total mixture.
De ovenfor angitte- farmasøytiske preparatene kan foruten forbindelsene ifølge oppfinnelsen også inneholde andre farmasøytisk virksomme stoffer. In addition to the compounds according to the invention, the above-mentioned pharmaceutical preparations may also contain other pharmaceutically active substances.
Fremstillingen av de ovenfor angitte farmasøytiske preparatene foregår på vanlig måte ved kjente fremgangsmåter, f.eks. The production of the above-mentioned pharmaceutical preparations takes place in the usual way by known methods, e.g.
ved blanding av det eller de virksomme stoffene med bærestof-fet eller -stoffene. by mixing the active substance or substances with the carrier fat or substances.
Det virksomme stoffet eller de farmasøytiske preparatene kan anvendes lokalt, oralt, parenteralt, intraperitonealt og/eller rektalt, fortrinnsvis oralt eller parenteralt som intravenøst eller intramuskulært. The active substance or the pharmaceutical preparations can be used locally, orally, parenterally, intraperitoneally and/or rectally, preferably orally or parenterally as intravenously or intramuscularly.
Generelt har det både innen human- og også innenfor veterinær-medisinen vist seg fordelaktig å anvende det eller de virksomme stoffene ifølge oppfinnelsen i totalmengder på ca. In general, both within human and also within veterinary medicine, it has proven advantageous to use the active substance(s) according to the invention in total amounts of approx.
1 til ca. 1000, fortrinnsvis 1 til 200 mg/kg legemsvekt 1 to approx. 1000, preferably 1 to 200 mg/kg body weight
pr. døgn, eventuelt i form av flere enkelttilførsler for å oppnå det ønskede resultatet. En enkelttilførsel inneholder det eller de virksomme stoffene ifølge oppfinnelsen fortrinnsvis i mengder fra 1 til 250, spesielt 1 til 60 mg/kg legemsvekt. Det kan likevel være påkrevet å avvike fra de nevnte per day, possibly in the form of several individual injections to achieve the desired result. A single supply contains the active substance(s) according to the invention preferably in amounts from 1 to 250, especially 1 to 60 mg/kg body weight. It may still be required to deviate from those mentioned
doseringene, i avhengighet av typen og legemsvekten for the dosages, depending on the type and body weight of
\behandlingsobjektet, typen og alvoret'av sykdomstilstanden, typen, og preparatet og tilførselsformen for■legemidlet \the object of treatment, the type and severity' of the disease state, the type, and the preparation and the administration form of the medicine
samt det tidsrommet hhv. intervallet innenfor hvilket administreringen skal foregå. Følgelig kan det i enkelte tilfeller være tilstrekkelig å anvende mindre enn den ovenfor angitte mengden virksomt stoff, mens den ovenfor angitte mengden virksomt stoff i andre tilfeller må overskrides. Fastleggel- as well as that time period or the interval within which the administration is to take place. Consequently, in some cases it may be sufficient to use less than the amount of active substance stated above, while the amount of active substance stated above must be exceeded in other cases. Determining
sen av i ethvert tilfelle påkrevde optimale doseringen og tilførselsarten for det virksomme stoffet kan lett avgjøres av fagmannen på grunnlag av hans fagkunnskap. in any case, the optimal dosage required and the mode of delivery of the active substance can be easily determined by the person skilled in the art on the basis of his professional knowledge.
Forbindelsene ifølge oppfinnelsen kan for å oppnå en utvidelse The compounds according to the invention can to achieve an expansion
av virkningsspekteret kombineres med et annet -laktamantibio-tika eller også med aminoglykosidantibiotika, som f.eks. gentamycin, sisomycin, kanamycin, amikacin eller tobramycin. of the spectrum of action is combined with another -lactam antibiotic or also with aminoglycoside antibiotics, such as e.g. gentamycin, sisomycin, kanamycin, amikacin or tobramycin.
De virksomme stoffene ifølge oppfinnelsen kan anvendes The active substances according to the invention can be used
innenfor alle områdene av dyreoppdrett som middel for å within all areas of animal husbandry as a means of
fremme og akselerere veksten og til forbedring av forutnyttelsen hos sunne og syke dyr. promote and accelerate growth and improve utilization in healthy and diseased animals.
Virksomheten av det virksomme stoffet er herved i stor The activity of the active substance is thereby great
grad uavhengig av dyrets type og stamme. Spesielt verdifulle har de virksomme forbindelsene vist seg å være ved oppdrett av ung- og gjødyr. Som dyr for hvilke de virksomme stoffene kan anvendes for å fremme og akselerere veksten og forbedre forutnyttelsen kan eksempelvis følgende nytte- og selskapsdyr nevnes: degree regardless of the animal's type and strain. The active compounds have proven to be particularly valuable when breeding young and fattening animals. As animals for which the active substances can be used to promote and accelerate growth and improve utilization, the following useful and companion animals can be mentioned, for example:
Varmblodige dyr som okser, svin, hester, sauer, geiter, Warm-blooded animals such as oxen, pigs, horses, sheep, goats,
katter, hunder, kaniner; pelsdyr f.eks. nerts og chinchilla; fjærkre, f.eks. høns, gjess, ender, kalkuner, duer, papegøyer og kanarifugler, og kaldblodige dyr som fisker, f.eks. cats, dogs, rabbits; fur animals e.g. mink and chinchilla; poultry, e.g. chickens, geese, ducks, turkeys, pigeons, parrots and canaries, and cold-blooded animals such as fish, e.g.
karper, og reptiler, f.eks. slanger. carp, and reptiles, e.g. snakes.
Mengden av de virksomme stoffene som administreres til The amount of the active substances administered to
dyr for å oppnå den ønskede effekten, kan på grunn av de animals to achieve the desired effect, can because of the
gunstige egenskapene for det virksomme stoffet varieres innenfor vide grenser. Den ligger fortrinnsvis på ca. the favorable properties of the active substance are varied within wide limits. It is preferably located at approx.
0,01 til 50, spesielt 0,1 til.10 mg/kg legemsvekt pr. dag. Varigheten av administreringen kan utgjøre fra få timer 0.01 to 50, especially 0.1 to 10 mg/kg body weight per day. The duration of administration can range from a few hours
eller dager til flere år. Den mengden,av det virksomme stoffet som administreres, samt varigheten av administreringen avhenger spesielt av typen, stammen, sunnhetstilstanden og typen hold og foring for dyret og kan lett bestemmes av fagmannen. or days to several years. The amount of the active substance that is administered, as well as the duration of the administration, depends in particular on the type, the strain, the state of health and the type of housing and feeding for the animal and can be easily determined by the person skilled in the art.
Det virksomme stoffet administreres til dyrene ved vanlige fremgangsmåter. Typen administrering avhenger spesielt av typen, forholdene og sunnhetstilstanden for dyret. Følgelig kan administreringen foregå en eller flere ganger daglig med regelmessige eller uregelmessige intervaller, oralt The active substance is administered to the animals by usual procedures. The type of administration depends in particular on the type, conditions and state of health of the animal. Consequently, the administration can take place once or more times a day at regular or irregular intervals, orally
eller parenteralt. Av hensiktsmessighetsgrunner foretrekkes i de fleste tilfeller en oral administrering, spesielt i rytmen for dyrets nærings- og/eller væskeinntak. Med "næring" forstås innenfor rammen av foreliggende oppfinnelse både fast og flytende næring og også drikker og vann. or parenterally. For reasons of expediency, oral administration is preferred in most cases, especially in the rhythm of the animal's food and/or fluid intake. Within the scope of the present invention, "food" means both solid and liquid food as well as drinks and water.
De virksomme stoffene kan administreres som rene stoffer eller i sammensatt form, dvs. i blanding med ikke-toksiske, inerte bærestoffer av en hvilken som helst type, f.eks. The active substances can be administered as pure substances or in compound form, i.e. in admixture with non-toxic, inert carriers of any type, e.g.
med bærestoffer og i sammensetninger som er vanlige ved næringsmessige preparater. with carriers and in compositions that are common in nutritional preparations.
De virksomme stoffene administreres eventuelt i sammensatt form sammen med farmasøytisk virksomme stoffer, mineralsalter, sporelementer, vitaminer, eggehvitestoffer, fettstoffer, fargestoffer og/eller smaksstoffer på egnet form. The active substances are optionally administered in compound form together with pharmaceutically active substances, mineral salts, trace elements, vitamins, egg whites, fats, dyes and/or flavorings in a suitable form.
Anbefalelsesverdig er oral administrering sammen med foret og/eller drikkevannet, hvor man etter behov tilsetter det virksomme stoffet i den samlede mengden eller bare i deler Oral administration together with the feed and/or drinking water is recommended, where the active substance is added as needed in the total amount or only in parts
av foret og/eller drikkevannet. of the feed and/or drinking water.
Det virksomme stoffet tilsettes ved vanlige, fremgangsmåter ved enkel blanding som renstoffblanding, fortrinnsvis i finfordelt form eller i sammensatt form i blanding med spisbare, 'ikke-toksiske bærestoffer, eventuelt i form av The active substance is added by usual, methods by simple mixing as pure substance mixture, preferably in finely divided form or in compound form in a mixture with edible, non-toxic carriers, possibly in the form of
en forblanding eller et forkonsentrat til foret og/eller drikkevannet. a premix or a preconcentrate for the feed and/or drinking water.
Foret og/eller drikkevannet kan eventuelt inneholde det virksomme stoffet i en vektkonsentrasjon på ca. 0,01 til The feed and/or drinking water may possibly contain the active substance in a weight concentration of approx. 0.01 more
50, spesielt 0,1 til 10 ppm. Den optimale størrelsen av konsentrasjonen av det virksomme stoffet i foret og/eller drikkevannet er spesielt avhengig av omfanget av for og/eller drikkevanninntak for dyret og kan lett bestemmes av enhver fagmann. 50, especially 0.1 to 10 ppm. The optimal size of the concentration of the active substance in the feed and/or drinking water is particularly dependent on the extent of feed and/or drinking water intake for the animal and can be easily determined by any person skilled in the art.
Typen av foret og dets sammensetning er her uten betydning. Alle vanlige eller spesielle forsammensetninger kan anvendes som fortrinnsvis inneholder den vanlige, for en avbalansert ernæring nødvendige likevekten mellom energi- og oppbygnings-stoffer. Foret kan eksempelvis være sammensatt av vegetabilske stoffer, f.eks. høy, røtter, korn, kornprodukter, animalske stoffer, f.eks. kjøtt, fett, benmel, fiskeprodukter, vitaminer, f.eks. vitamin A, D-kompleks og B-kompleks, proteiner, aminosyrer, f.eks. DL-metionin og uorganiske stoffer, f.eks. kalk og koksalt. The type of lining and its composition are irrelevant here. All common or special pre-compositions can be used which preferably contain the usual equilibrium between energy and structural substances necessary for balanced nutrition. The lining can, for example, be composed of vegetable substances, e.g. hay, roots, grains, grain products, animal substances, e.g. meat, fat, bone meal, fish products, vitamins, e.g. vitamin A, D-complex and B-complex, proteins, amino acids, e.g. DL-methionine and inorganic substances, e.g. lime and table salt.
Forkonsentrater inneholder de virksomme stoffene ved siden Pre-concentrates contain the active substances on the side
av spiselige stoffer, f.eks. rugmel, maismel, soyabønnemel eller kalk, eventuelt med ytterligere nærings- og oppbygnings-stoffer som proteiner, mineralsalter og vitaminer. De kan være fremstilt ved de vanlige blandefremgangsmåtene. of edible substances, e.g. rye flour, maize flour, soya bean flour or lime, possibly with additional nutritional and structural substances such as proteins, mineral salts and vitamins. They can be prepared by the usual mixing methods.
Fortrinnsvis i forblandinger og forkonsentrater kan de virksomme stoffene være beskyttet mot luft, lys og/eller fuktighet, eventuelt med egnede midler som dekker overflaten, f.eks. med ikke-toksiske vokser eller gelatin. .Eksempel på sammensetningen av et kyllingoppdrettsfor som"inneholder et uvirksomt stoff ifølge oppfinnelsen: Preferably in premixes and preconcentrates, the active substances can be protected from air, light and/or moisture, possibly with suitable means that cover the surface, e.g. with non-toxic waxes or gelatin. .Example of the composition of a chicken rearing feed which "contains an inactive substance according to the invention:
200 g hvete, .340 g .mais, 361 g soyaavfall, 60 g oksetalg, 200 g wheat, .340 g .maize, 361 g soy waste, 60 g beef tallow,
15 g dikalsiumfosfat, 10 g kalsiumkarbonat, 4 g jodert koksalt, 7,5 g vitamin-mineralblanding og 2,5 g forblanding av virksomt stoff gir etter omhyggelig blanding 1 kg for. 15 g of dicalcium phosphate, 10 g of calcium carbonate, 4 g of iodized table salt, 7.5 g of vitamin-mineral mixture and 2.5 g of premix of active substance after careful mixing give 1 kg for.
I 1 kg forblanding inneholdes: 1 kg of premix contains:
600 I.E. vitamin A, 100 I.E. vitamin , 10 mg vitamin E, 1 mg vitamin , 3 mg riboflavin, 2 mg pyridoksin, 20 ug vitamin B^2, 5 mg kalsiumpantotenat, 30 mg nikotinsyre, 600 I.E. vitamin A, 100 I.E. vitamin , 10 mg vitamin E, 1 mg vitamin , 3 mg riboflavin, 2 mg pyridoxine, 20 ug vitamin B^2, 5 mg calcium pantothenate, 30 mg nicotinic acid,
200 mg kolinklorid, 200 mg MnS04x H20, 140 mg ZnS04x 7H20, 100 mg FeS04x 7H20 og 20 mg CuS04x 5H20. 200 mg choline chloride, 200 mg MnS04x H20, 140 mg ZnS04x 7H20, 100 mg FeS04x 7H20 and 20 mg CuS04x 5H20.
Forblandingen av det virksomme stoffet inneholder de virksomme stoffet i den ønskede mengde, f.eks. 10 mg og i til-legg 1 g DL-metionin samt så mye soyabønnemel at 2,5 g forblanding oppstår. The premix of the active substance contains the active substance in the desired amount, e.g. 10 mg and in addition 1 g of DL-methionine as well as so much soybean meal that 2.5 g of premix is produced.
Eksempel på sammensetningen av svineoppdretssfor som inneholder et virksomt stoff ifølge oppfinnelsen: 630 g forkornavfall (sammensatt av 200 g mais, 150 g byggkorn-150 g havre- og 130 g hveteavfall), 80 g fiskemel, 60 g soyaavfall, 60 g tapiokamel, 38 g ølgjær, 50 g vitamin-mineral-blanding for svin (sammensetning f.eks. som ved kyllingforet), 30 g sukkerrørmelasse og 2 g forblanding av virksomt stoff (sammensetning f.eks. som ved kyllingforet) gir etter omhyggelig blanding 1 kg for. Example of the composition of pig breeding feed containing an active substance according to the invention: 630 g pre-grain waste (composed of 200 g maize, 150 g barley grain-150 g oat and 130 g wheat waste), 80 g fish meal, 60 g soy waste, 60 g tapioca flour, 38 g brewer's yeast, 50 g vitamin-mineral mixture for pigs (composition e.g. as for chicken feed), 30 g sugar cane molasses and 2 g premix of active substance (composition e.g. as for chicken feed) gives, after careful mixing, 1 kg for .
De angitte forblandingene er fortrinnsvis til oppdrett The indicated premixes are preferably for breeding
og gjøing av kyllinger hhv. svin, de kan likevel anvendes i den samme eller liknende sammensetning også til oppdrett og gjøing av andre dyr. and brooding of chickens respectively. pigs, they can still be used in the same or similar composition also for breeding and fattening other animals.
Fremstillingseksempler Eksempel 1 Production examples Example 1
a) - 3 - [ 1, 4- dimetyl- 3-okso-plpe razinium] metyl- 7g" - f enyl-acetamido- 3- cefem- 4- karboksylat a) - 3 - [ 1, 4- dimethyl- 3-oxo-plpe razinium] methyl- 7g" - phenyl-acetamido- 3- cephem- 4- carboxylate
Under nitrogen oppslemmes 9,36 g (24 mmol) 3-acetoksy-metyl-7e-fenylacetamido-3-cefem-4-karboksylsyre ved romtemperatur i 100 ml absolutt metylenklorid og bringes i oppløsning ved tilsats av 15,2 ml (72 mmol) N-metyl-N-trimetylsilyl-trifluoracetamid (MSTFA). Etter avkjøling til 0°C tilsettes 14 ml (96 mmol) trimetylsilyljodid og reaksjonsoppløsningen omrøres deretter i en time ved 0°C. Deretter tilsettes 15,3 g (120 mmol) 1,4-dimetyl-3-okso-piperazin og oppløs-ningen etteromrøres i 30 minutter. Deretter tilsettes 4,8 ml vann og etter ytterligere 5 minutter helles blandingen på 400 ml eter. Eteren fradekanteres fra den oljeformige resten, resten røres nok en gang ut med eter og etter for-nyet dekantering opptas den i vann og kromatograferes over absorberharpiks "HP 20" (elueringsmiddel: acetonitril/vann 5/95). Utbytte: 5,3 g av en blanding av 2 isomerer. Under nitrogen, 9.36 g (24 mmol) of 3-acetoxy-methyl-7e-phenylacetamido-3-cephem-4-carboxylic acid are suspended at room temperature in 100 ml of absolute methylene chloride and dissolved by the addition of 15.2 ml (72 mmol) N-methyl-N-trimethylsilyl-trifluoroacetamide (MSTFA). After cooling to 0°C, 14 ml (96 mmol) of trimethylsilyl iodide are added and the reaction solution is then stirred for one hour at 0°C. 15.3 g (120 mmol) of 1,4-dimethyl-3-oxo-piperazine are then added and the solution is stirred for 30 minutes. 4.8 ml of water are then added and after a further 5 minutes the mixture is poured into 400 ml of ether. The ether is decanted from the oily residue, the residue is stirred out once more with ether and after renewed decantation it is taken up in water and chromatographed over absorbent resin "HP 20" (eluent: acetonitrile/water 5/95). Yield: 5.3 g of a mixture of 2 isomers.
<1>H-NMR (D--DMSO) <1>H-NMR (D--DMSO)
6 6
6(ppm) = 9,20 (l)bd, J = 7 Hz, 7,32 (5)m, 5,61 (l)dd, 6(ppm) = 9.20 (l)bd, J = 7 Hz, 7.32 (5)m, 5.61 (l)dd,
J = 7 Hz, J = 5 Hz, 5,12 og 5,10 (l)d, J = 5 Hz, J = 7 Hz, J = 5 Hz, 5.12 and 5.10 (l)d, J = 5 Hz,
5,02 (l)bd, J = 13 Hz, 4,33 og 4,18 (l)d, J = 5.02 (l)bd, J = 13 Hz, 4.33 and 4.18 (l)d, J =
13 Hz, 3,34-4,24 (10)m, 3,10 (3)s, 2,92 (3)s. 13 Hz, 3.34-4.24 (10)m, 3.10 (3)s, 2.92 (3)s.
b) 7- amino- 3-( 1f4- dimetyl- 3- oksopiperazinium) metyl- 3- cefem-4- karboksylat b) 7- amino- 3-( 1f4- dimethyl- 3- oxopiperazinium) methyl- 3- cephem-4- carboxylate
5,0 g 3-(1,4-dimetyl-3-oksopiperazinium)metyl-7e-fenylacet- - amido-3-cefem-4-karboksylat oppløses i 100 ml vann. Det innstilles på pH 7,8 med 4N trietylamin i etanol. Deretter tilsettes 6 g penicillin-G-acylase og pH'en holdes konstant ved tilsats av trietylamin. Etter avslutning av den enzyma-tiske spaltningen frafiltreres acylasen og filtratet innstilles på pH 2 med konsentrert saltsyre. Fra bunnfallet som oppstår frasuges den flytende fasen over kiselgelgur og filtratet tilsettes til 2 liter aceton. Det ønskede Dissolve 5.0 g of 3-(1,4-dimethyl-3-oxopiperazinium)methyl-7e-phenylacet--amido-3-cephem-4-carboxylate in 100 ml of water. It is adjusted to pH 7.8 with 4N triethylamine in ethanol. 6 g of penicillin-G-acylase are then added and the pH is kept constant by the addition of triethylamine. After completion of the enzymatic cleavage, the acylase is filtered off and the filtrate is adjusted to pH 2 with concentrated hydrochloric acid. From the precipitate that occurs, the liquid phase is suctioned off over silica gel and the filtrate is added to 2 liters of acetone. The desired
produktet utkrystalliseres som■hydroklorid og frasuges og tørkes. Utbytte: 3,3 g (x HC1 x H20) som blanding av to Isomerer. the product crystallizes out as ■hydrochloride and is filtered off with suction and dried. Yield: 3.3 g (x HC1 x H2O) as a mixture of two isomers.
^H-NMR (D20) ^H-NMR (D20)
6 (ppm) = 5,40 og 5,39 (l)d, J = 5 Hz, 5,19 og 5,18 (l)d, 6 (ppm) = 5.40 and 5.39 (l)d, J = 5 Hz, 5.19 and 5.18 (l)d,
J = 5 Hz, 4,86 og 4,76 (l)d, J = 13 Hz, 4,24 J = 5 Hz, 4.86 and 4.76 (l)d, J = 13 Hz, 4.24
og 4,21 (l)d, J = 13 Hz, 4,24 (l)d, J = 18 Hz, 4,06 (l)m, 3,62 - 4,00 (5)m, 3,56 og 3,54 (l)d, and 4.21 (l)d, J = 13 Hz, 4.24 (l)d, J = 18 Hz, 4.06 (l)m, 3.62 - 4.00 (5)m, 3.56 and 3.54 (l)d,
J = 18 Hz, 3,17 og 3,15 (3)s, 2,98 (3)s. J = 18 Hz, 3.17 and 3.15 (3)s, 2.98 (3)s.
c) 78 -[ ( Z)- 2-( 2- aminotiazol- 4- yl)- 2- metoksyiminoacetamido]-3-( 1, 4- dimetyl- 3- oksopiperazinium) metyl- 3- cefem- 4- karboksylat c) 78 -[ ( Z )- 2-( 2- aminothiazol-4- yl)- 2- methoxyiminoacetamido]-3-( 1, 4- dimethyl- 3- oxopiperazinium) methyl- 3- cephem- 4- carboxylate
1,1 g (5,3 mmol) (Z)-2-(2-aminotiazol-4-yl)-2-metoksyimino-eddiksyre oppløses under nitrogen ved romtemperatur i 8,1 1.1 g (5.3 mmol) (Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino-acetic acid is dissolved under nitrogen at room temperature for 8.1
ml absolutt dimetylformamid. Etter tilsats av 339 ul N-etyl-diisopropylamin, 369 ul tripropylamin og 456 ul tributylamin avkjøles til -50°C. Deretter tilsettes denne oppløsningen raskt til en til 0°C avkjølt oppløsning av 1,6 g (4,0 mmol) 7-amino-3-(1,4-dimetyl-3-oksopiperazinium)metyl-3-cefem-4-karboksylat (x HC1 x H20) i 2,55 ml vann og 2,1 ml trietylamin. Etter 5 minutter helles reaksjonsoppløsningen på ml of absolute dimethylformamide. After adding 339 µl of N-ethyl-diisopropylamine, 369 µl of tripropylamine and 456 µl of tributylamine, cool to -50°C. This solution is then quickly added to a solution of 1.6 g (4.0 mmol) 7-amino-3-(1,4-dimethyl-3-oxopiperazinium)methyl-3-cephem-4-carboxylate cooled to 0°C (x HC1 x H2O) in 2.55 mL of water and 2.1 mL of triethylamine. After 5 minutes, the reaction solution is poured on
500 ml aceton. Det opptredende bunnfallet suges fra, tørkes og kromatograferes over adsorberharpiks "HP 20" (elueringsmiddel:. acetonitril/vann 5/95). Utbytte: 700 mg av en blanding av to isomerer. 500 ml of acetone. The resulting precipitate is suctioned off, dried and chromatographed over adsorber resin "HP 20" (eluent: acetonitrile/water 5/95). Yield: 700 mg of a mixture of two isomers.
<1>H-NMR (D,-DMS0) <1>H-NMR (D,-DMSO)
b b
5 (ppm) = 9,63 (l)bd, J = 7 Hz, 7,26 (2)bs, 6,76 (l)s, 5 (ppm) = 9.63 (l)bd, J = 7 Hz, 7.26 (2)bs, 6.76 (l)s,
5,71 (l)dd, y = 7 Hz, J = 5 Hz, 5,17/5,15 (l)d, 5.71 (l)dd, y = 7 Hz, J = 5 Hz, 5.17/5.15 (l)d,
J = 5 Hz, 5,08/5,03 (l)d, J = 12 Hz, 4,32 (l)d, J = 5 Hz, 5.08/5.03 (l)d, J = 12 Hz, 4.32 (l)d,
J = 16 Hz, 4,13 (l)d, J = 16 Hz, 4,13/4,07 (l)d, J = 16 Hz, 4.13 (l)d, J = 16 Hz, 4.13/4.07 (l)d,
J = 12 Hz, 3,87 (3)s, 3,30 - 4,00 (6)m, 3,09 (3)bs, 2,92 (3)s. J = 12 Hz, 3.87 (3)s, 3.30 - 4.00 (6)m, 3.09 (3)bs, 2.92 (3)s.
Eksempel 2 Example 2
a) 7- amino- 3-( 4- metylsulfonyl- l- metylpiperazinium)- metyl-3- cefem- 4- karboksylat a) 7- amino- 3-( 4- methylsulfonyl- 1- methylpiperazinium)- methyl 3- cephem- 4- carboxylate
Analogt eksempel la omsettes 4,6,8 g 3-acetoksymetyl-7-B-fenylacetamido-3-cefem-4-karboksylsyre med 21 g 4-metyl-sulf onyl-l-metylpiperazin . Produktet utfelles fra aceton og spaltes og opparbeides analogt eksempel lb med penicillin G-acylase. In an analogous example, 4,6,8 g of 3-acetoxymethyl-7-B-phenylacetamido-3-cephem-4-carboxylic acid was reacted with 21 g of 4-methyl-sulfonyl-1-methylpiperazine. The product is precipitated from acetone and cleaved and worked up analogously to example 1b with penicillin G-acylase.
Utbytte: 1,05 g (x HC1 x H20). Yield: 1.05 g (x HC 1 x H 2 O).
<1>H-NMR (D20) <1>H-NMR (D20)
(ppm) = 5,39 (l)d, J = 5 Hz, 5,17 (l)d, J =5 Hz, 4,78 (l)d, J---= 13 Hz, 4,14 (l)d, J = 13 Hz, 3,92 (l)d, J = 18 Hz, 3,40 - 3,80 (9)m, 3,10 (3)s, 3,06 (3)s. (ppm) = 5.39 (l)d, J = 5 Hz, 5.17 (l)d, J =5 Hz, 4.78 (l)d, J---= 13 Hz, 4.14 ( l)d, J = 13 Hz, 3.92 (l)d, J = 18 Hz, 3.40 - 3.80 (9)m, 3.10 (3)s, 3.06 (3)s.
b) 7B-[ Z- 2-( aminotiazol- 4- yl)- 2- metoksyiminoacetamido]-3- ( 4- metylsulfonyl- l- metylpiperazinium) mety1- 3- cefem-4- karboksylat b) 7B-[ Z- 2-( aminothiazol-4-yl)- 2- methoxyiminoacetamido]-3-( 4- methylsulfonyl- 1- methylpiperazinium) methyl 1- 3- cephem-4- carboxylate
Analogt eksempel 1c omsettes 0,5 g av produktet fra eksempel 2a med 0,34 g Z-2-(2-aminotiazol-4-yl)-2-metoksyiminoeddik-syre. Utbytte etter kromatografi på adsorberharpiks "HP 20": 0,56 g. Analogously to example 1c, 0.5 g of the product from example 2a is reacted with 0.34 g of Z-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid. Yield after chromatography on adsorber resin "HP 20": 0.56 g.
<1>H-NMR (D,-DMS0) <1>H-NMR (D,-DMSO)
5(ppm) = 9,55 (l)d, J = 7 Hz, 7,25 (2)bs, 6,73 (l)s, 5(ppm) = 9.55 (l)d, J = 7 Hz, 7.25 (2)bs, 6.73 (l)s,
5,66 (l)dd, J = 7 Hz, J = 5 Hz, 5,13 (l)d, 5.66 (l)dd, J = 7 Hz, J = 5 Hz, 5.13 (l)d,
J = 5 Hz, 5,14 (l)bd, J = 13 Hz, 4,06 (l)bd, J = 5 Hz, 5.14 (l)bd, J = 13 Hz, 4.06 (l)bd,
J = 13 Hz, 3,83 (3)s, 3,26 (3)s, 3,20 - 4,00 (10)m, 3,04 (3)s. J = 13 Hz, 3.83 (3)s, 3.26 (3)s, 3.20 - 4.00 (10)m, 3.04 (3)s.
Eksempel 3 Example 3
a) 7- amino- 3-( 4- formyl- l- metylpiperazinium) metyl- 3- cefem-4- karboksylat a) 7- amino- 3-( 4-formyl-1- methylpiperazinium) methyl- 3- cephem-4- carboxylate
Analogt eksempel la omsettes 4,68 g 3-acetoksymetyl-7-B-fenylacetamido-3-cefem-4-karboksylsyre med 15 g 4-formyl-1-metyl-piperazin. Produktet utfelles fra aceton og spaltes og opparbeides analogt eksempel lb med penicillin G-acylase. Utbytte: 1,2 g (x HC1 x H20). In an analogous example, 4.68 g of 3-acetoxymethyl-7-B-phenylacetamido-3-cephem-4-carboxylic acid was reacted with 15 g of 4-formyl-1-methyl-piperazine. The product is precipitated from acetone and cleaved and worked up analogously to example 1b with penicillin G-acylase. Yield: 1.2 g (x HC1 x H2O).
<1>H-NMR (D20) <1>H-NMR (D20)
6 (ppm) = 8,02.(l)s, 5,38 (l)d, J = 5 Hz, 5,17 (l)d, J = 6 (ppm) = 8.02.(l)s, 5.38 (l)d, J = 5 Hz, 5.17 (l)d, J =
5 Hz,l 4,78 (Dd, J = 13 Hz, 4,14 (2)d, J = 13 Hz, 3,70 - 3,98 (3)m, 3,30 - 3,64 (6)m, 3,13 (3)s. 5 Hz,l 4.78 (Dd, J = 13 Hz, 4.14 (2)d, J = 13 Hz, 3.70 - 3.98 (3)m, 3.30 - 3.64 (6) m, 3.13 (3) p.
b) 76 -[ Z- 2-( 2- aminotiazol- 4- yl)- 2- metoksyiminoacetamido]-3-( 4- formyl- l- metylpiperazinium) metyl- 3- cefem- 4- karboksylat b) 76 -[ Z- 2-( 2- aminothiazol-4- yl)- 2- methoxyiminoacetamido]-3-( 4- formyl-1- methylpiperazinium) methyl- 3- cephem- 4- carboxylate
Analogt eksempel lc omsettes 0,6 g av produktet fra eksempel 3a med 0,47 g Z-2-(2-aminotiazol-4-yl)-2-metoksyiminoeddik-syre. Utbytte etter rensing over adsorberharpiks "HP 20": 0,2 g. Analogously to example 1c, 0.6 g of the product from example 3a is reacted with 0.47 g of Z-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid. Yield after purification over adsorber resin "HP 20": 0.2 g.
<1>H-NMR (D,-DMSO) <1>H-NMR (D,-DMSO)
6 6
<5(ppm) = 9,62 (l)d, J = 7 Hz, 8,12 (l)s, 7,26 (2)bs, <5(ppm) = 9.62 (l)d, J = 7 Hz, 8.12 (l)s, 7.26 (2)bs,
6,77 (l)s, 5,20 (l)dd, J = 7 Hz, J = 5 Hz, 6.77 (l)s, 5.20 (l)dd, J = 7 Hz, J = 5 Hz,
5,17 (l)d, J = 5 Hz, 5,14 (l)bd, J = 13 Hz, 5.17 (l)d, J = 5 Hz, 5.14 (l)bd, J = 13 Hz,
4,07 (l)bd, J = 13 Hz, 3,87 (3)s, 3,10 (3)s, 4.07 (l)bd, J = 13 Hz, 3.87 (3)s, 3.10 (3)s,
3,00 - 4,00 (8)m. 3.00 - 4.00 (8)m.
Eksempel 4 Example 4
a) 7- amino- 3-( 4- aminokarbonyl- l- metylpiperazinium) metyl-3- cefem- 4- karboksylat a) 7- amino- 3-( 4- aminocarbonyl- 1- methylpiperazinium) methyl 3- cephem- 4- carboxylate
Analaogt eksempel la omsettes 9,4 g 3-acetoksymetyl-7-B-fenylacetamido-3-cefem-4-karboksylsyre med en oppløsning av 34 g l-aminokarbonyl-4-metylpiperazin i 150 ml dimetylformamid. Produktet utfelles fra eter og spaltes og opparbeides analogt eksempel lb med penicillin-G-acylase. Utbytte 3,1 g (x HC1 x H20). Analogously to the example, 9.4 g of 3-acetoxymethyl-7-B-phenylacetamido-3-cephem-4-carboxylic acid was reacted with a solution of 34 g of 1-aminocarbonyl-4-methylpiperazine in 150 ml of dimethylformamide. The product is precipitated from ether and cleaved and worked up analogously to example 1b with penicillin G-acylase. Yield 3.1 g (x HC1 x H2O).
<1>H-NMR (D20) <1>H-NMR (D20)
6(ppm) - 5,39 (l)d, J =5 Hz, 5,16 (l)d, J = 5 Hz, 4,80 (l)d, J = 13 Hz, 4,14 (l)d, J = 13 Hz, 3,85 - 4,02 (3)m, 3,35 - 3,72 (7)m, 3,22 (3)s. 6(ppm) - 5.39 (l)d, J =5 Hz, 5.16 (l)d, J = 5 Hz, 4.80 (l)d, J = 13 Hz, 4.14 (l) d, J = 13 Hz, 3.85 - 4.02 (3)m, 3.35 - 3.72 (7)m, 3.22 (3)s.
b) 7;b'- [ Z- 2- ( 2;- amiinotiazol- 4- yl) -- 2- metoksyimin. oace tamido] - 3- ( 4- amin6karbonyl- l- metylpiperazinium) metyl- 3- cefem-4- karboksylat b) 7;b'- [ Z- 2-( 2;- aminothiazol-4-yl) -- 2- methoxyimine. oace tamido] - 3-( 4- amino6carbonyl-1- methylpiperazinium) methyl- 3- cephem-4- carboxylate
Analogt eksempel lc omsettes 0,98 g av produktet fra eksempel 4a med 0,68 g Z-2-(2-aminotiazol-4-yl)-2-metoksy-iminoeddiksyre. Utbytte etter kromatografi på adsorberharpiks "HP 20": 0,9 g. Analogous to example 1c, 0.98 g of the product from example 4a is reacted with 0.68 g of Z-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid. Yield after chromatography on adsorber resin "HP 20": 0.9 g.
<1>H-NMR (Dg-DMSO) <1>H-NMR (Dg-DMSO)
(ppm) = 9,58 (l)d, J = 7 Hz, 7,53 (2)bs, 6,72 (l)s, 6,29 (2) bs, 5,66 (l)dd, J = 7 Hz, J = 5 Hz, 5,13 (l)d, (ppm) = 9.58 (l)d, J = 7 Hz, 7.53 (2)bs, 6.72 (l)s, 6.29 (2)bs, 5.66 (l)dd, J = 7 Hz, J = 5 Hz, 5.13 (l)d,
J = 5 Hz, 5,09 (l)bd, J = 13 Hz, 3,99 (l)bd, J = 5 Hz, 5.09 (l)bd, J = 13 Hz, 3.99 (l)bd,
J = 13 Hz, 3,82 (3)s, 3,18 - 3,92 (10)m, 3,00 (3) s. J = 13 Hz, 3.82 (3)s, 3.18 - 3.92 (10)m, 3.00 (3)s.
Eksempel 5 Example 5
a) 7- amino- 3-( 4- dimetylaminosulfonyl- l- metylpiperazinium)-metyl- 3- cefem- 4- karboksylat a) 7-amino- 3-( 4- dimethylaminosulfonyl- 1- methylpiperazinium)-methyl- 3- cephem- 4- carboxylate
Analogt eksempel la omsettes 9,4 g 3-acetoksymetyl-7-B-fenylacetamido-3-cefem-4-karboksylsyre med 49 g 1-dimetylaminosulfonyl-4-metyl-piperazin. Råproduktet spaltes analogt eksempel lb med penicillin G-acylase. Analogously to the example, 9.4 g of 3-acetoxymethyl-7-B-phenylacetamido-3-cephem-4-carboxylic acid was reacted with 49 g of 1-dimethylaminosulfonyl-4-methyl-piperazine. The crude product is cleaved analogously to example 1b with penicillin G-acylase.
Utbytte 2,0 g (x HC1 x H20). Yield 2.0 g (x HC1 x H2O).
<1>H-NMR (D20) <1>H-NMR (D20)
6(ppm) = 5,39 (l)d, J = 5 Hz, 5,96 (l)d, J = 5 Hz, 4,82 (l)d, J = 13 Hz, 4,18 (l)d, J = 13 Hz, 3,98 (l)d, J = 18 Hz, 3,48 - 3,80 (9)m, 3,13 (3)s, 2,89 (6)s. 6(ppm) = 5.39 (l)d, J = 5 Hz, 5.96 (l)d, J = 5 Hz, 4.82 (l)d, J = 13 Hz, 4.18 (l) d, J = 13 Hz, 3.98 (l)d, J = 18 Hz, 3.48 - 3.80 (9)m, 3.13 (3)s, 2.89 (6)s.
b) 7 B-[ Z- 2-( 2- aminotiazol- 4- yl)- 2- metoksyiminoacetamido]-3-( 4- dimetylaminosulfonyl- l- metylpiperazinium) metyl-3- cefem- 4- karboksylat b) 7 B-[ Z- 2-( 2- aminothiazol-4- yl)- 2- methoxyiminoacetamido]-3-( 4- dimethylaminosulfonyl- 1- methylpiperazinium) methyl-3- cephem- 4- carboxylate
Analogt eksempel lc omsettes 0,9 g av produktet fra eksempel 5a med 0,55 g Z-[2-(2-aminotiazol-4-yl)-2-metoksyimino-eddiksyre. Utbytte etter kromatografi på adsorberharpiks "HP 20": 0,4 5 g. Analogously to example 1c, 0.9 g of the product from example 5a is reacted with 0.55 g of Z-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetic acid. Yield after chromatography on adsorber resin "HP 20": 0.45 g.
1H-NMR (Dr-DMSO) 1H-NMR (Dr-DMSO)
b b
(ppm) = 9,59 (l)d, J =7 Hz, 7,24 (2)bs, 6,74 (l)s, (ppm) = 9.59 (l)d, J =7 Hz, 7.24 (2)bs, 6.74 (l)s,
5-, 6 7 (l)dd, j ■= 7 Hz, J = 5 Hz, 5,13 (l)d, J = 5-, 6 7 (l)dd, j ■= 7 Hz, J = 5 Hz, 5.13 (l)d, J =
5 Hz, 5,14 (l)bd, J - 13 Hz, 4,03 (l)bd, J = 5 Hz, 5.14 (l)bd, J - 13 Hz, 4.03 (l)bd, J =
13 Hz, 3.,84 (3)s, 3,81 (l)d, J = 18 Hz, 3,20 - 3,60 (9)m, 3,04 (3)s, 2,82 (6)s. 13 Hz, 3.84 (3)s, 3.81 (l)d, J = 18 Hz, 3.20 - 3.60 (9)m, 3.04 (3)s, 2.82 (6 )p.
Eksempel 6 Example 6
a) 7- amino- 3-( 4- acetyl- l- metylpiperazinium) mety1- 3- cefem-4- karboksylat a) 7- amino- 3-( 4- acetyl- 1- methylpiperazinium) methyl 1- 3- cephem-4- carboxylate
Analogt eksempel la omsettes 9,4 g 3-acetoksymetyl-7-B-fenylacetamido-3-cefem-4-karboksylat med 34 g 1-acetyl-4-metyl-piperazin. Etter kromatografi av råproduktet som er utfelt fra eter på adsorberharpiks "HP 20" får man 7,5 In an analogous example, 9.4 g of 3-acetoxymethyl-7-B-phenylacetamido-3-cephem-4-carboxylate were reacted with 34 g of 1-acetyl-4-methyl-piperazine. After chromatography of the crude product which is precipitated from ether on adsorber resin "HP 20", 7.5
g 3-(4-acetyl-l-metylpiperazinium)metyl-7-B-fenylacetmido-3-cefem-4-karboksylat, som analogt eksempel lb spaltes med penicillin G-acylase. g 3-(4-acetyl-1-methylpiperazinium)methyl-7-B-phenylacetmido-3-cephem-4-carboxylate, which is cleaved analogously to example 1b with penicillin G-acylase.
Utbytte 3,2 g (x HC1 x H20). Yield 3.2 g (x HC1 x H2O).
<1>H-NMR (D20) <1>H-NMR (D20)
5 (ppm) = 5,31 (l)d, J = 5 Hz, 5,08 (l)d, J = 5 Hz, 4,80 (l)d, J = 13 Hz, 4,10 (l)d, J = 13 Hz, 3,20 - 4,00 (10)m, 3,05 (3)s, 2,03 (3)s. 5 (ppm) = 5.31 (l)d, J = 5 Hz, 5.08 (l)d, J = 5 Hz, 4.80 (l)d, J = 13 Hz, 4.10 (l) d, J = 13 Hz, 3.20 - 4.00 (10)m, 3.05 (3)s, 2.03 (3)s.
b) 7B-[ Z- 2-( 2- aminotiazol- 4- yl)- 2- metoksyiminoacetamido]-3-( 4- acetyl- l- metylpiperazinium) metyl- 3- cefem- 4- karboksylat b) 7B-[ Z- 2-( 2- aminothiazol-4- yl)- 2- methoxyiminoacetamido]-3-( 4- acetyl- 1- methylpiperazinium) methyl- 3- cephem- 4- carboxylate
Analogt eksempel lc omsettes 1,59 g av produktet fra eksempel 6a med 1,24 g Z-2-(2-aminotiazol-4-yl)-2-metoksyimino-eddiksyre. Utbytte etter kromatografi på adsorberharpiks "HP 20": 0,8 g. Analogously to example 1c, 1.59 g of the product from example 6a is reacted with 1.24 g of Z-2-(2-aminothiazol-4-yl)-2-methoxyimino-acetic acid. Yield after chromatography on adsorber resin "HP 20": 0.8 g.
1H-NMR (D,-DMSO) 1H-NMR (D,-DMSO)
D D
(ppm) = 9,61 (l)d, J = 7 Hz, 7,26 (2)bs, 6,75 (l)s, 5,69 (l)dd, J = 7 Hz, J = 5 Hz, 5,16 (l)d, J = 5 Hz, 5,15 (l)bd, J = 13 Hz, 4,03 (l)bd, J = 13 Hz, (ppm) = 9.61 (l)d, J = 7 Hz, 7.26 (2)bs, 6.75 (l)s, 5.69 (l)dd, J = 7 Hz, J = 5 Hz , 5.16 (l)d, J = 5 Hz, 5.15 (l)bd, J = 13 Hz, 4.03 (l)bd, J = 13 Hz,
3,86 (3)s, 3,2 - 4,0 (10)m, 3,07 (3)s, 2,07 (3)s. 3.86 (3)s, 3.2 - 4.0 (10)m, 3.07 (3)s, 2.07 (3)s.
Eksempel 7 Example 7
a) 7- amino- 3-( 4- tert- butoksykarbonyl- l- metylpiperazinium)-_v . metyl- 3- cefem- 4- karboksylat a) 7-amino-3-(4-tert-butoxycarbonyl-1-methylpiperazinium)-_v . methyl- 3- cephem- 4- carboxylate
Analogt eksempel la omsettes 9,4 g 3-acetoksymetyl-7-B-fenylacetamido-3-cefem-4-karboksylat med 48 g l-metyl-4-tert-butoksykarbonylpiperazin. Råproduktet spaltes analogt eksempel lb med penicillin G-acylase. Utbytte 1,9 g (x HC1 In an analogous example, 9.4 g of 3-acetoxymethyl-7-B-phenylacetamido-3-cephem-4-carboxylate were reacted with 48 g of 1-methyl-4-tert-butoxycarbonylpiperazine. The crude product is cleaved analogously to example 1b with penicillin G-acylase. Yield 1.9 g (x HC1
x H20) . x H 2 O).
"""H-NMR (D20) """H-NMR (D20)
6 (ppm) = 5,29 (l)d, J = 5 Hz, 5,06 (l)d, J = 5 Hz, 6 (ppm) = 5.29 (l)d, J = 5 Hz, 5.06 (l)d, J = 5 Hz,
4,64 (l)d, J = 13 Hz, 4,00 (l)d, J = 13 Hz, 3,75-4,00 (3)m, 3,20 - 3,55 (7)m, 2,98 (3)s, 1,32 4.64 (l)d, J = 13 Hz, 4.00 (l)d, J = 13 Hz, 3.75-4.00 (3)m, 3.20 - 3.55 (7)m, 2.98 (3)s, 1.32
(9)s. (9)p.
b) 7- 8 -[ Z- 2-( 2- aminotiazol- 4- yl)- 2- metoksyiminoacetamido]-3-( 4- tert- butoksykarbonyl- l- metylpiperazinium) metyl-3- cefem- 4- karboksylat b) 7- 8 -[ Z- 2-( 2- aminothiazol-4-yl)- 2- methoxyiminoacetamido]-3-( 4- tert- butoxycarbonyl- 1- methylpiperazinium) methyl-3- cephem- 4- carboxylate
Analogt eksempel lc omsettes 0,85 g av produktet fra eksempel 7a med 0,52 g Z-2-(2-aminotiazol-4-yl)-2-metoksyiminoeddik-syre. Utbytte etter kromatografi på adsorberharpiks "HP 20" 0,2 g. Analogously to example 1c, 0.85 g of the product from example 7a is reacted with 0.52 g of Z-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid. Yield after chromatography on adsorber resin "HP 20" 0.2 g.
<1>H-NMR (Dg-DMSO) <1>H-NMR (Dg-DMSO)
(ppm) = 9,64 (l)d, J = 7 Hz, 7,30 (2)bs, 6,77 (l)s, (ppm) = 9.64 (l)d, J = 7 Hz, 7.30 (2)bs, 6.77 (l)s,
5,70 (l)dd, J = 7 Hz, J = 5 Hz, 5,17 (l)d, J 5.70 (l)dd, J = 7 Hz, J = 5 Hz, 5.17 (l)d, J
= 5 Hz, 5,14 (l)bd, J =. 13 Hz, 4,03 (l)bd, J = = 5 Hz, 5.14 (l)bd, J =. 13 Hz, 4.03 (l)bd, J =
13 Hz, 3,87 (3)s, 3,24 - 3,95 (10)m, 3,05 (3)s, 1,45 (9)s. 13 Hz, 3.87 (3)s, 3.24 - 3.95 (10)m, 3.05 (3)s, 1.45 (9)s.
Eksempel 8 Example 8
a) 7- amino- 3-[ 4-( 3- hydroksypropyl)- 1- metylpiperazinium]-metyl- 3- cefem- 4- karboksylat a) 7-amino- 3-[ 4-( 3- hydroxypropyl)- 1- methylpiperazinium]-methyl- 3- cephem- 4- carboxylate
Analogt eksempel la omsettes 4,68 g 3-acetoksymetyl-7B-fenylacetamido-3-cefem-4-karboksylsyre med 19 g 4-(3-hydroksy-propyl)-1-metyl-piperazin. Produktet utfelles fra aceton og spaltes og opparbeides analogt eksempel lb med penicillin In an analogous example, 4.68 g of 3-acetoxymethyl-7B-phenylacetamido-3-cephem-4-carboxylic acid was reacted with 19 g of 4-(3-hydroxy-propyl)-1-methyl-piperazine. The product is precipitated from acetone and split and worked up analogously to example 1b with penicillin
G-acylase. G-acylase.
Utbytte: 2,3 g (x HCI x H20). Yield: 2.3 g (x HCl x H 2 O).
<1>H-NMR (D20) <1>H-NMR (D20)
(ppm) = 5,47 (l)d, J = 5 Hz, 5,26 (l)d, J = 5 Hz, (ppm) = 5.47 (l)d, J = 5 Hz, 5.26 (l)d, J = 5 Hz,
4,97 (l)d, J - 15 Hz, 4,37 (l)d, J .= 15 Hz, 4.97 (l)d, J - 15 Hz, 4.37 (l)d, J .= 15 Hz,
4,02 (l)d, J =18 Hz, 3,70-3,90 (10)m, 3,64 (1) d, J = 18 Hz, 3,45 (2)m, 3,33 (3)s, 2,04 4.02 (l)d, J =18 Hz, 3.70-3.90 (10)m, 3.64 (1) d, J = 18 Hz, 3.45 (2)m, 3.33 ( 3)s, 2.04
(2) m. (2) m.
b) 7B-[ Z- 2-( 2- aminotiazol- 4- yl)- 2- metoksyiminoacetamido]-3- 4-( 3- hydroksypropyl)- 1- metylpiperazinium - metyl- 3-cefem- 4- karboksylat b) 7B-[ Z- 2-( 2- aminothiazol-4- yl)- 2- methoxyiminoacetamido]-3- 4-( 3- hydroxypropyl)- 1- methyl piperazinium - methyl- 3- cephem- 4- carboxylate
Analogt eksempel lc omsettes 1,0 g av produktet fra eksempel 8a med 0,66 g Z-2-(2-aminotiazol-4-yl)-2-metoksyimino-eddiksyre. Utbytte etter kromatografi på adsorberharpiks "HP 20": 0,68 g. Analogously to example 1c, 1.0 g of the product from example 8a is reacted with 0.66 g of Z-2-(2-aminothiazol-4-yl)-2-methoxyimino-acetic acid. Yield after chromatography on adsorber resin "HP 20": 0.68 g.
<1>H-NMR (D,-DMSO) <1>H-NMR (D,-DMSO)
6 6
(ppm) = 9,60 (l)d, J = 7 Hz, 7,27 (2)bs, 6,74 (l)s, (ppm) = 9.60 (l)d, J = 7 Hz, 7.27 (2)bs, 6.74 (l)s,
5,66 (l)dd, J = 7 Hz, J = 5 Hz, 5,15 (l)d, 5.66 (l)dd, J = 7 Hz, J = 5 Hz, 5.15 (l)d,
J = 5 Hz, 5,08 (l)d, J = 14 Ha, 4,02 (l)d, J = 5 Hz, 5.08 (l)d, J = 14 Ha, 4.02 (l)d,
J = 14 Hz, 3,83 (3)s, 3,81 (l)d, J = 18 Hz, J = 14 Hz, 3.83 (3)s, 3.81 (l)d, J = 18 Hz,
3,30 - 3,50 (7)m, 2,97 (3)s, 2,40 - 2,80 (6)m, 1,55 (2)m. 3.30 - 3.50 (7)m, 2.97 (3)s, 2.40 - 2.80 (6)m, 1.55 (2)m.
Eksempel 9 Example 9
7B-[ Z- 2-( 2- aminotiazol- 4- yl)- 2- metoksyimnoacetamido]- 3-( 4- aminokarbonyl- l- etylpiperazinium) metyl- 3- cefem- 4-karboksylat 7B-[ Z- 2-( 2- aminothiazol-4- yl)- 2- methoxyimnoacetamido]- 3-( 4- aminocarbonyl- 1- ethylpiperazinium) methyl- 3- cephem- 4-carboxylate
<1>H-NMR (D,-DMSO) <1>H-NMR (D,-DMSO)
6 6
(ppm) = 9,64 (l)d, J = 7 Hz, 7,29 (2)bs, 6,77 (l)s, (ppm) = 9.64 (l)d, J = 7 Hz, 7.29 (2)bs, 6.77 (l)s,
6,33 (2)bs, 5,68 (l)dd, J = 7 Hz, J = 5 Hz, 6.33 (2)bs, 5.68 (l)dd, J = 7 Hz, J = 5 Hz,
5,10 (l)d, J = 13 Hz, 5,08 (l)d, J = 5 Hz, 5.10 (l)d, J = 13 Hz, 5.08 (l)d, J = 5 Hz,
3,96 (l)d, J = 13 Hz, 3,88 (3)s, 3,20 - 3,92 (12)m, 1,26 (3)m. 3.96 (l)d, J = 13 Hz, 3.88 (3)s, 3.20 - 3.92 (12)m, 1.26 (3)m.
' Eksempel 10 ' Example 10
7B - [ Z-2 - ( 2- aminotiåzol- 4- yl ).- 2- metoksyiminoacetamido] - 3-[ 4- ( 2-- hydroksyetyl) - l- metylpiperazinium] metyl- 3- cefem-4- karboksylat 7B - [ Z-2 - ( 2- aminothiazol-4-yl ).- 2- methoxyiminoacetamido] - 3-[ 4-( 2-- hydroxyethyl) - 1- methylpiperazinium] methyl- 3- cephem-4- carboxylate
—H-NMR ,(D -DMSO) —H-NMR, (D-DMSO)
D D
6 (ppm) = 9,64 (l)d, J = 7 Hz, 7,30 (2)bs, 6,78 (l)s, 6 (ppm) = 9.64 (l)d, J = 7 Hz, 7.30 (2)bs, 6.78 (l)s,
5,70 (l)dd, J = 7 Hz, J = 5 Hz, 5,18 (l)d, J = 5.70 (l)dd, J = 7 Hz, J = 5 Hz, 5.18 (l)d, J =
5 Hz, 5,12 (l)d, J = 13 Hz, 4,01 (l)d, J = 13 5 Hz, 5.12 (l)d, J = 13 Hz, 4.01 (l)d, J = 13
Hz, 3,88 (3)s, 3,85 (l)d, J = 18 Hz, 3,20 - Hz, 3.88 (3)s, 3.85 (l)d, J = 18 Hz, 3.20 -
360, (7)m, 3,01 (3)s, 2,40 - 280 (6)m. 360, (7)m, 3.01 (3)s, 2.40 - 280 (6)m.
Eksempel 11 Example 11
76-[ Z- 2-( 2- aminotiazol- 4- yl)- 2- metoksyiminoacetamido]-3-[ l- metyl- 4-( 2- oksoimidazolidino) karbonylpiperazinium]- metyl-3- cefem- 4- karboksylat 76-[ Z- 2-( 2- aminothiazol-4-yl)- 2- methoxyiminoacetamido]-3-[ 1- methyl- 4-( 2- oxoimidazolidino) carbonylpiperazinium]- methyl-3- cephem- 4- carboxylate
<1>H-NMR (D.--DMSO) <1>H-NMR (D.--DMSO)
(ppm) = 9,61 (l)d, J = 7 Hz, 7,50 (l)bs, 7,28 (2)bs, (ppm) = 9.61 (l)d, J = 7 Hz, 7.50 (l)bs, 7.28 (2)bs,
6,76 (l)s, 5,69 (l)dd, J = 7 Hz, J = 5 Hz, 6.76 (l)s, 5.69 (l)dd, J = 7 Hz, J = 5 Hz,
5,16 (l)d, J = 13 Hz, 5,15 (l)d, J = 5 Hz, 5.16 (l)d, J = 13 Hz, 5.15 (l)d, J = 5 Hz,
4,05 (l)d, J = 13 Hz, 3,88 (3)s, 3,20 - 3,96 (14)m, 3,08 (3)s. 4.05 (l)d, J = 13 Hz, 3.88 (3)s, 3.20 - 3.96 (14)m, 3.08 (3)s.
Eksempel 12 Example 12
7g-[ Z- 2-( 2- aminotiazol- 4- yl)- 2- metoksyiminoacetamido]- 3-[ l- metyl- 4-( 3- metylsulfonyl- 2- oksoimidazolidino) karbonyl-piperazinium] metyl- 3- cefem- 4- karboksylat 7g-[ Z- 2-( 2- aminothiazol- 4- yl)- 2- methoxyiminoacetamido]- 3-[ 1- methyl- 4-( 3- methylsulfonyl- 2- oxoimidazolidino) carbonyl-piperazinium] methyl- 3- cephem- 4- carboxylate
-H-NMR (Dg-DMSO) -H-NMR (Dg-DMSO)
(ppm) = 9,58 (l)d, J = 7 Hz, 7,24 (2)bs, 6,73 (l)s, (ppm) = 9.58 (l)d, J = 7 Hz, 7.24 (2)bs, 6.73 (l)s,
5)67 (l)dd, J = 7 Hz, J = 5 Hz, 5,15 (l)d, 5)67 (l)dd, J = 7 Hz, J = 5 Hz, 5.15 (l)d,
J = 13 Hz, 5,12 (l)d, J = 5 Hz, 4,04 (l)d, J = 13 Hz, 5.12 (l)d, J = 5 Hz, 4.04 (l)d,
J = 13 Hz, 3,84 (3)s, 3,20 - 3,98 (14)m, J = 13 Hz, 3.84 (3)s, 3.20 - 3.98 (14)m,
3,35 (3)s, 3,08 (3)s. 3.35 (3)s, 3.08 (3)s.
Claims (19)
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DE19853506159 DE3506159A1 (en) | 1985-02-22 | 1985-02-22 | NEW CEPHALOSPORINE, METHOD FOR THEIR PRODUCTION AND THEIR USE IN MEDICINAL PRODUCTS |
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EP (1) | EP0192176A3 (en) |
JP (1) | JPS61194088A (en) |
KR (1) | KR860006472A (en) |
CN (1) | CN86100820A (en) |
AU (1) | AU591649B2 (en) |
DD (1) | DD263064A5 (en) |
DE (1) | DE3506159A1 (en) |
DK (1) | DK82186A (en) |
ES (1) | ES8707734A1 (en) |
FI (1) | FI860746A (en) |
GR (1) | GR860486B (en) |
HU (1) | HU200778B (en) |
NO (1) | NO860483L (en) |
PT (1) | PT82063B (en) |
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US5147871A (en) * | 1986-07-03 | 1992-09-15 | Hoffmann La-Roche, Inc. | Anti-bacterial cephalosporin compounds |
DE3711343A1 (en) * | 1987-04-03 | 1988-10-20 | Bayer Ag | CEPHALOSPORINE DERIVATIVES, METHOD FOR THEIR PRODUCTION AND THEIR USE IN MEDICINAL PRODUCTS |
EP0300546B1 (en) * | 1987-07-10 | 1995-08-09 | Gist-Brocades N.V. | Process for the preparation of cephem compounds and cephalosporin derivatives |
US5336768A (en) * | 1988-05-24 | 1994-08-09 | Hoffmann-La Roche Inc. | Antibacterial cephalosporin compounds |
YU63689A (en) * | 1988-03-31 | 1991-06-30 | Hoffmann La Roche | Acyl derivatives |
PH25965A (en) * | 1988-06-06 | 1992-01-13 | Fujisawa Pharmaceutical Co | New cephem compounds which have antimicrobial activities |
US5162523A (en) * | 1989-07-21 | 1992-11-10 | Hoffmann-La Roche Inc. | Cephalosporin antibacterial compounds |
US5159077A (en) * | 1989-07-21 | 1992-10-27 | Hoffmann-La Roche Inc. | Penam antibacterial compounds |
US5143910A (en) * | 1989-09-07 | 1992-09-01 | Shionogi & Co., Ltd. | Piperaziniocephalosporins |
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US4525473A (en) * | 1983-03-30 | 1985-06-25 | Bristol-Myers Company | Cephalosporins |
DE3409431A1 (en) * | 1983-10-08 | 1985-04-18 | Hoechst Ag, 6230 Frankfurt | CEPHALOSPORINE DERIVATIVES AND METHOD FOR THEIR PRODUCTION |
DE3419013A1 (en) * | 1984-05-22 | 1985-11-28 | Bayer Ag, 5090 Leverkusen | NEW CEPHALOSPORINE AND METHOD FOR THEIR PRODUCTION |
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1985
- 1985-02-22 DE DE19853506159 patent/DE3506159A1/en not_active Withdrawn
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1986
- 1986-02-05 AU AU53295/86A patent/AU591649B2/en not_active Ceased
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- 1986-02-12 EP EP86101752A patent/EP0192176A3/en not_active Withdrawn
- 1986-02-20 FI FI860746A patent/FI860746A/en not_active Application Discontinuation
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- 1986-02-20 GR GR860486A patent/GR860486B/en unknown
- 1986-02-20 PT PT82063A patent/PT82063B/en unknown
- 1986-02-21 KR KR1019860001217A patent/KR860006472A/en not_active Application Discontinuation
- 1986-02-21 HU HU86737A patent/HU200778B/en not_active IP Right Cessation
- 1986-02-21 DK DK82186A patent/DK82186A/en not_active Application Discontinuation
- 1986-02-21 ES ES552282A patent/ES8707734A1/en not_active Expired
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AU591649B2 (en) | 1989-12-14 |
HU200778B (en) | 1990-08-28 |
GR860486B (en) | 1986-06-18 |
KR860006472A (en) | 1986-09-11 |
EP0192176A3 (en) | 1988-03-16 |
DD263064A5 (en) | 1988-12-21 |
EP0192176A2 (en) | 1986-08-27 |
DE3506159A1 (en) | 1986-08-28 |
FI860746A0 (en) | 1986-02-20 |
DK82186A (en) | 1986-08-23 |
PT82063B (en) | 1987-12-18 |
ES552282A0 (en) | 1987-08-16 |
JPS61194088A (en) | 1986-08-28 |
FI860746A (en) | 1986-08-23 |
HUT41801A (en) | 1987-05-28 |
CN86100820A (en) | 1986-10-01 |
PT82063A (en) | 1986-03-01 |
ES8707734A1 (en) | 1987-08-16 |
AU5329586A (en) | 1986-08-28 |
ZA861307B (en) | 1986-10-29 |
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