NO883287L - Cephalosporins. - Google Patents
Cephalosporins.Info
- Publication number
- NO883287L NO883287L NO883287A NO883287A NO883287L NO 883287 L NO883287 L NO 883287L NO 883287 A NO883287 A NO 883287A NO 883287 A NO883287 A NO 883287A NO 883287 L NO883287 L NO 883287L
- Authority
- NO
- Norway
- Prior art keywords
- group
- carboxy
- methyl
- toxic salts
- amino
- Prior art date
Links
- 229930186147 Cephalosporin Natural products 0.000 title claims description 36
- 229940124587 cephalosporin Drugs 0.000 title claims description 36
- 150000001780 cephalosporins Chemical class 0.000 title claims description 28
- 150000001875 compounds Chemical class 0.000 claims description 160
- -1 Cephalosporin compound Chemical class 0.000 claims description 89
- 150000003839 salts Chemical class 0.000 claims description 73
- 239000000203 mixture Substances 0.000 claims description 52
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 48
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 46
- 239000000243 solution Substances 0.000 claims description 45
- 239000012453 solvate Substances 0.000 claims description 45
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 41
- 238000000034 method Methods 0.000 claims description 39
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 36
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 35
- 231100000252 nontoxic Toxicity 0.000 claims description 32
- 230000003000 nontoxic effect Effects 0.000 claims description 32
- 238000002360 preparation method Methods 0.000 claims description 30
- 235000019253 formic acid Nutrition 0.000 claims description 25
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 claims description 24
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 23
- SCNWTQPZTZMXBG-UHFFFAOYSA-N 2-methyloct-2-enoic acid Chemical compound CCCCCC=C(C)C(O)=O SCNWTQPZTZMXBG-UHFFFAOYSA-N 0.000 claims description 22
- 125000006239 protecting group Chemical group 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 150000004677 hydrates Chemical class 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 238000002441 X-ray diffraction Methods 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 125000003277 amino group Chemical group 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 2
- 230000009102 absorption Effects 0.000 claims 2
- 238000010521 absorption reaction Methods 0.000 claims 2
- 238000000862 absorption spectrum Methods 0.000 claims 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims 1
- 235000014113 dietary fatty acids Nutrition 0.000 claims 1
- 229930195729 fatty acid Natural products 0.000 claims 1
- 239000000194 fatty acid Substances 0.000 claims 1
- 150000004665 fatty acids Chemical class 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 description 81
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 239000013078 crystal Substances 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- 239000003960 organic solvent Substances 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
- 235000017557 sodium bicarbonate Nutrition 0.000 description 11
- 239000002253 acid Substances 0.000 description 10
- 230000000844 anti-bacterial effect Effects 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- 241000894006 Bacteria Species 0.000 description 8
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 150000001782 cephems Chemical group 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 208000035473 Communicable disease Diseases 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 229940125904 compound 1 Drugs 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 241000192125 Firmicutes Species 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 241000191967 Staphylococcus aureus Species 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical group NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000002198 insoluble material Substances 0.000 description 3
- 229960003085 meticillin Drugs 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- YWBFPKPWMSWWEA-UHFFFAOYSA-O triazolopyrimidine Chemical group BrC1=CC=CC(C=2N=C3N=CN[N+]3=C(NCC=3C=CN=CC=3)C=2)=C1 YWBFPKPWMSWWEA-UHFFFAOYSA-O 0.000 description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- YILWZCATAFPDRY-HAHDFKILSA-N (2z)-2-(2-amino-1,3-thiazol-4-yl)-2-[[2,2-dimethyl-6-[(2-methylpropan-2-yl)oxycarbonyl]-1,3-benzodioxol-5-yl]methoxyimino]acetic acid Chemical compound CC(C)(C)OC(=O)C1=CC=2OC(C)(C)OC=2C=C1CO\N=C(/C(O)=O)C1=CSC(N)=N1 YILWZCATAFPDRY-HAHDFKILSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241000588747 Klebsiella pneumoniae Species 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
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- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000032536 Pseudomonas Infections Diseases 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
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- 150000007513 acids Chemical class 0.000 description 2
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- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 125000000637 arginyl group Chemical class N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
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- 159000000001 potassium salts Chemical class 0.000 description 2
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- OBSLWIKITOYASJ-YDEIVXIUSA-N (3r,4r,5s,6r)-6-(hydroxymethyl)-3-(methylamino)oxane-2,4,5-triol Chemical class CN[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OBSLWIKITOYASJ-YDEIVXIUSA-N 0.000 description 1
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- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
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- 239000002841 Lewis acid Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
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- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
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- 241000588770 Proteus mirabilis Species 0.000 description 1
- 241000607715 Serratia marcescens Species 0.000 description 1
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- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
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- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-L aspartate group Chemical class N[C@@H](CC(=O)[O-])C(=O)[O-] CKLJMWTZIZZHCS-REOHCLBHSA-L 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- UPABQMWFWCMOFV-UHFFFAOYSA-N benethamine Chemical class C=1C=CC=CC=1CNCCC1=CC=CC=C1 UPABQMWFWCMOFV-UHFFFAOYSA-N 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical class C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
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- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
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- 150000003857 carboxamides Chemical class 0.000 description 1
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- 229960000484 ceftazidime Drugs 0.000 description 1
- NMVPEQXCMGEDNH-TZVUEUGBSA-N ceftazidime pentahydrate Chemical compound O.O.O.O.O.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 NMVPEQXCMGEDNH-TZVUEUGBSA-N 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
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- 238000009833 condensation Methods 0.000 description 1
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- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 150000005332 diethylamines Chemical class 0.000 description 1
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- 238000003113 dilution method Methods 0.000 description 1
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- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical class CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 208000027136 gram-positive bacterial infections Diseases 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- JBFYUZGYRGXSFL-UHFFFAOYSA-N imidazolide Chemical compound C1=C[N-]C=N1 JBFYUZGYRGXSFL-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
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- 239000008101 lactose Substances 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
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- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
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- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Chemical group O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
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- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- BLUBMEHKTZJCFB-UHFFFAOYSA-N tert-butyl 2,2,6-trimethyl-1,3-benzodioxole-5-carboxylate Chemical compound C1=C(C(=O)OC(C)(C)C)C(C)=CC2=C1OC(C)(C)O2 BLUBMEHKTZJCFB-UHFFFAOYSA-N 0.000 description 1
- XGXCHYSRSHNKIR-UHFFFAOYSA-N tert-butyl 6-(aminooxymethyl)-2,2-dimethyl-1,3-benzodioxole-5-carboxylate Chemical compound C1=C(CON)C(C(=O)OC(C)(C)C)=CC2=C1OC(C)(C)O2 XGXCHYSRSHNKIR-UHFFFAOYSA-N 0.000 description 1
- GLAHRXQYMBCKNY-UHFFFAOYSA-N tert-butyl 6-(bromomethyl)-2,2-dimethyl-1,3-benzodioxole-5-carboxylate Chemical compound C1=C(CBr)C(C(=O)OC(C)(C)C)=CC2=C1OC(C)(C)O2 GLAHRXQYMBCKNY-UHFFFAOYSA-N 0.000 description 1
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- 230000001225 therapeutic effect Effects 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical class C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
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- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical class [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 description 1
Description
Foreliggende oppfinnelse omhandler cefalosporinderivater og deres krystallinske form, fremgangsmåter for fremstilling av disse, samt farmasøytiske blandinger inneholdende disse for behandling og/eller forhindring av smittsomme sykdommer. The present invention relates to cephalosporin derivatives and their crystalline form, methods for producing these, as well as pharmaceutical mixtures containing these for the treatment and/or prevention of infectious diseases.
Utviklingen av cefalosporinderivater har vært bemerkelses-verdig. Enkelte cefalosporinderivater er blitt utviklet som har utmerket antibakteriell aktivitet mot gramnegative bakterier innbefattende Pseudomonas aeruginosa. Imidlertid er den antibakterielle aktivitet av disse cefalosporinderivater relativt dårlig mot grampositive bakterier. Flere cefalosporinantistoffer er blitt brukt for behandling av grampositive bakterieinfeksjoner, og økningen av grampositive bakterier som er motstandsdyktige mot cefalosporin-antistof f er, f.eks. meticillinresistente Staphylococcus aureus (MRSA), er blitt godt kjent gjennom årenes løp. The development of cephalosporin derivatives has been remarkable. Certain cephalosporin derivatives have been developed that have excellent antibacterial activity against Gram-negative bacteria including Pseudomonas aeruginosa. However, the antibacterial activity of these cephalosporin derivatives is relatively poor against Gram-positive bacteria. Several cephalosporin antibodies have been used for the treatment of gram-positive bacterial infections, and the increase in gram-positive bacteria that are resistant to cephalosporin antibodies is, e.g. methicillin-resistant Staphylococcus aureus (MRSA), has become well known over the years.
På nevnte bakgrunn har det vært ønskelig å utvikle cefalosporinderivater med en sterk antibakteriell aktivitet mot grampositive bakterier mens de opprettholder en tilstrekkelig antibakteriell aktivitet mot gramnegative bakterier, innbefattende Pseudomonas aeruginosa. On the aforementioned background, it has been desirable to develop cephalosporin derivatives with a strong antibacterial activity against Gram-positive bacteria while maintaining a sufficient antibacterial activity against Gram-negative bacteria, including Pseudomonas aeruginosa.
Oppsummering av oppfinnelsenSummary of the invention
Et mål for foreliggende oppfinnelse er å fremskaffe nye cefalosporinderivater samt salter, solvater og salter av solvater derav og krystallinske former av disse. An aim of the present invention is to provide new cephalosporin derivatives as well as salts, solvates and salts of solvates thereof and crystalline forms thereof.
Et annet mål for foreliggende oppfinnelse er å fremskaffe fremgangsmåter for fremstilling av nye cefalosporinderivater samt deres krystallinske form. Another aim of the present invention is to provide methods for the production of new cephalosporin derivatives as well as their crystalline form.
Et ytterligere mål for foreliggende oppfinnelse er å fremskaffe blandinger for å forhindre og/eller behandle smittsomme sykdommer, og som omfatter nye cefalosporinderivater som aktive komponenter. A further aim of the present invention is to provide compositions to prevent and/or treat infectious diseases, and which comprise new cephalosporin derivatives as active components.
Et ytterligere mål for foreliggende oppfinnelse er å fremskaffe mellomprodukter ved syntesen av cefalosporinderivater samt fremgangsmåter for fremstilling av slike mellomprodukter . A further aim of the present invention is to provide intermediate products in the synthesis of cephalosporin derivatives as well as methods for the production of such intermediate products.
Foreliggende oppfinnelse er basert på utvelgelsen av en triazolopyrimidinring som substituent ved 3-posisjonen til cefemskjelettet og en 2-karboksy-4,5-dihydroksyfenylmetyl-oksyiminoenhet som substituent ved 7-posisjonen av cefemskjelettet . The present invention is based on the selection of a triazolopyrimidine ring as a substituent at the 3-position of the cephem skeleton and a 2-carboxy-4,5-dihydroxyphenylmethyl-oxyimino unit as a substituent at the 7-position of the cephem skeleton.
Forbindelsene ifølge foreliggende oppfinnelse inneholdende disse substituenter har et bredt antibakterielt spektrum mot gramnegative bakterier, innbefattende Pseudomonas aeruginosa samt grampositive bakterier, innbefattende meticillinresistente Staphylococcus aureus. Disse forbindelser er spesielt anvendelige ved behandling av smittsomme sykdommer. The compounds according to the present invention containing these substituents have a broad antibacterial spectrum against gram-negative bacteria, including Pseudomonas aeruginosa as well as gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. These compounds are particularly useful in the treatment of infectious diseases.
Trinatriumsaltet av forbindelsene ifølge foreliggende oppfinnelse er generelt et amorft, fast stoff og har en utmerket oppløselighet som er sterkt påkrevet for parenteral bruk. Imidlertid er stabiliteten til saltet ikke nødvendig-vis tilstrekkelig for farmasøytisk bruk som bulkmaterialer eller som parenterale preparater. Som et resultat av utstrakte studier for å forbedre stabiliteten til forbindelsene, har nærværende oppfinnere nå funnet at meget rene og stabile krystallinske former av forbindelsene ifølge oppfinnelsen fordelaktig og konsistent kan fremstilles og isoleres. The trisodium salt of the compounds of the present invention is generally an amorphous solid and has an excellent solubility which is highly required for parenteral use. However, the stability of the salt is not necessarily sufficient for pharmaceutical use as bulk materials or as parenteral preparations. As a result of extensive studies to improve the stability of the compounds, the present inventors have now found that very pure and stable crystalline forms of the compounds of the invention can be advantageously and consistently prepared and isolated.
Detaljert beskriveles av oppfinnelsenThe invention is described in detail
Som et resultat av utstrakt forskning i forbindelse med utvikling av cefalosporinderivater med tilfredsstillende antibakteriell aktivitet mot gramnegative bakterier, innbefattende Pseudomonas aeruginosa, og som også har sterk antibakteriell aktivitet mot grampositive bakterier, har nærværende oppfinnere funnet at cefalosporinderivater representert ved den generelle formel (I) som vist nedenfor, for, tilfredsstiller disse krav og har oppnådd foreliggende oppfinnelse. As a result of extensive research in connection with the development of cephalosporin derivatives with satisfactory antibacterial activity against gram-negative bacteria, including Pseudomonas aeruginosa, and which also have strong antibacterial activity against gram-positive bacteria, the present inventors have found that cephalosporin derivatives represented by the general formula (I) which shown below, for, satisfy these requirements and have achieved the present invention.
Foreliggende oppfinnelse er basert på utvelgelsen av en triazolopyrimidinring som substituenter ved 3-posisjonen av cefemskjelettet og av en en 2-karboksy-4,5-dihydroksyfenyl-metyloksyiminoenhet som substituent ved 7-posisjonen av cefemskj elettet. The present invention is based on the selection of a triazolopyrimidine ring as substituents at the 3-position of the cephem skeleton and of a 2-carboxy-4,5-dihydroxyphenyl-methyloxyimino unit as a substituent at the 7-position of the cephem skeleton.
Foreliggende oppfinnelse er rettet mot cefalosporinderivater representert ved den generelle formel (I): The present invention is directed to cephalosporin derivatives represented by the general formula (I):
samt salter, solvater og salter av solvater derav, hvor R-^ representerer et hydrogenatom eller en aminobeskyttende gruppe,R^ og R-* representerer uavhengig av hverandre et hydyrogenatom eller en karboksybeskyttende gruppe, R^ representerer et hydrogenatom, en hydroksygruppe, en aminogruppe, en sulfogruppe, en karboksygruppe eller en beskyttet karboksygruppe, R<5>representerer et hydrogenatom, en metylgruppe, en karboksygruppe, en beskyttet karboksygruppe, en karboksymetylgruppe eller en beskyttet karboksymetylgruppe, og bindingen vist ved den buede linjen representerer en binding av antiform eller synform. as well as salts, solvates and salts of solvates thereof, where R-^ represents a hydrogen atom or an amino-protecting group, R^ and R-* independently represent a hydrogen atom or a carboxy-protecting group, R^ represents a hydrogen atom, a hydroxy group, an amino group , a sulfo group, a carboxy group, or a protected carboxy group, R<5>represents a hydrogen atom, a methyl group, a carboxy group, a protected carboxy group, a carboxymethyl group, or a protected carboxymethyl group, and the bond shown by the curved line represents a bond of anti form or syn form .
Foreliggende oppfinnelse er også rettet mot krystallinske former av et cefalosporinderivat representert ved formelen The present invention is also directed to crystalline forms of a cephalosporin derivative represented by the formula
(I' ) :(I' ) :
samt salter, solvater, spesielt hydrater, og salter av solvater derav. as well as salts, solvates, especially hydrates, and salts of solvates thereof.
Foreliggende oppfinnelse er også rettet mot fremgangsmåter ved fremstilling av ovenfor nevnte cefalosporinderivater og deres krystallinske former. Foreliggende oppfinnelse er ytterligere rettet mot farmasøytiske blandinger for behandling og/eller forhindring av smittsomme sykdommer,karakterisert vedå innbefatte disse cefalosporinderivater som aktive komponenter. The present invention is also directed to methods for the production of the above-mentioned cephalosporin derivatives and their crystalline forms. The present invention is further directed to pharmaceutical mixtures for the treatment and/or prevention of infectious diseases, characterized by including these cephalosporin derivatives as active components.
I cefalosporinderivatene ifølge foreliggende oppfinnelse, representert ved den generelle formel (I), er det kjent at aminotiazolenheten som substituent ved 7-posisjonen derav oppviser tautomeri som vist nedenfor: In the cephalosporin derivatives according to the present invention, represented by the general formula (I), it is known that the aminothiazole unit as a substituent at the 7-position thereof exhibits tautomerism as shown below:
hvor r<1>, r<2>og bindingen vist med en bølget linje har samme betydning som angitt ovenfor. I foreliggende oppfinnelse er where r<1>, r<2> and the bond shown with a wavy line have the same meaning as indicated above. In the present invention is
aminotiazolenheten uttrykt som å innbefatte begge isomerer, siden begge generelt er ansett for å være samme substans. Følgelig innbefatter forbindelsene ifølge foreliggende oppfinnelse, representert ved den generelle formel (I), også begge av disse tautomere isomerer. the aminothiazole moiety expressed as including both isomers, since both are generally considered to be the same substance. Consequently, the compounds according to the present invention, represented by the general formula (I), also include both of these tautomeric isomers.
Forbindelsene representert ved den generelle formel (I) kan danne base eller syreaddisjonssalter. Typiske eksempler på basesalter av forbindelsene representert ved den generelle formel (I), innbefatter farmasøytisk akseptable salter, så som alkalimetallsalter (natriumsalter, kaliumsalter osv.), jordalkalimetallsalter (kalsiumsalter osv.), salter av organiske baser (ammoniumsalter, benzylaminsalter, dietylam-insalter osv.) og salter av aminosyrer (argininsalter, lysinsalter osv.). Disse salter av forbindelsene kan være monosalter, disalter eller trisalter. I tilfelle monosalter eller disalter kan saltene være salter av karboksygruppen ved 2-posisjonen og/eller salter av karboksy- eller sulfogr-uppen inneholdt i substituentene ved 3-posisjonen og/eller salter av karboksygruppen i acylgruppen ved 7-posisjonen av cefemskjelettet. The compounds represented by the general formula (I) can form base or acid addition salts. Typical examples of base salts of the compounds represented by the general formula (I) include pharmaceutically acceptable salts, such as alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts, etc.), salts of organic bases (ammonium salts, benzylamine salts, diethylamine salts etc.) and salts of amino acids (arginine salts, lysine salts, etc.). These salts of the compounds may be monosalts, disalts or trisalts. In the case of monosalts or disalts, the salts can be salts of the carboxy group at the 2-position and/or salts of the carboxy or sulfo group contained in the substituents at the 3-position and/or salts of the carboxy group of the acyl group at the 7-position of the cephem skeleton.
Typiske eksempler på syreaddisjonssalter av forbindelsene representert av den generelle formel (I), innbefatter farma-søytisk akseptable salter, så som salter av uorganiske syrer (hydroklorider, hydrobromider, sulfater, fosfater osv.), salter av organiske syrer (acetater, sitrater, maleater, tartrater, benzoater, askorbater, etansulfonater, toluen-sulfonater osv.) og salter av aminosyrer (aspartater, gluta-mater osv.). Disse salter av forbindelsene kan være monosalter eller disalter. I tilfelle monosalter kan saltene dannes i aminotiazolringen som substituent ved 7-posisjonen av cefemskjelettet eller i triazolopyrimidinringen som substituent ved 3-posisjonen av cefemskjelettet. Typical examples of acid addition salts of the compounds represented by the general formula (I) include pharmaceutically acceptable salts, such as salts of inorganic acids (hydrochlorides, hydrobromides, sulfates, phosphates, etc.), salts of organic acids (acetates, citrates, maleates , tartrates, benzoates, ascorbates, ethane sulfonates, toluene sulfonates, etc.) and salts of amino acids (aspartates, glutamaters, etc.). These salts of the compounds can be monosalts or disalts. In the case of monosalts, the salts can be formed in the aminothiazole ring as a substituent at the 7-position of the cephem skeleton or in the triazolopyrimidine ring as a substituent at the 3-position of the cephem skeleton.
Forbindelsene representert ved den generelle formel (I) kan danne solvater, spesielt maursyresolvater eller hydrater. Forbindelsene ifølge foreliggende oppfinnelse, representert ved den generelle formel (I), kan være til stede som en synisomer vist nedenfor: hvor R-<*->og R^ har samme betydning som definert ovenfor, eller som en antiisomer vist nedenfor: The compounds represented by the general formula (I) can form solvates, especially formic acid solvates or hydrates. The compounds according to the present invention, represented by the general formula (I), can be present as a synisomer shown below: where R-<*-> and R^ have the same meaning as defined above, or as an antiisomer shown below:
hvor r! og R^ har samme betydning som definert ovenfor, eller som en blanding av disse isomerer. Blant disse er synisomeren spesielt foretrukket, og blandinger i hovedsak bestående av synisomeren er også foretrukket. where r! and R 1 has the same meaning as defined above, or as a mixture of these isomers. Among these, the syn isomer is particularly preferred, and mixtures essentially consisting of the syn isomer are also preferred.
I forbindelsene ifølge foreliggende oppfinnelse, representert ved den generelle formel (I), kan de aminobeskyttende grupper være valgt fra acylgrupper, så som formyl, acetyl, kloracetyl, t-butoksykarbonyl, benzyloksykarbonyl osv., eller aralkylgrupper, så som benzyl, difenylmetyl, trifenyl-metyl osv. Trimetylsilylgrupper kan også bli brukt som en aminobeskyttende gruppe. Karboksybeskyttende grupper kan være valgt fra alkylestere, så som metylester, etylester, t-butylester osv., eller aralkylestere, så som benzylester, difenylmetylester, trifenylmetylester osv., eller trialkyl-silylestere, så som trimetylsilylester osv. Uorganiske eller organiske baser kan også bli brukt som karboksybeskyttende grupper. Ved samlet å ta i betraktning forskjellige operasjoner, syntese av således beskyttede produkter samt betingelser for fjerning av beskyttende grupper, er det foretrukket å bruke en trifenylmetylgruppe som aminobeskyttende gruppe og en difenylmetylgruppe som karboksybeskyttende gruppe. In the compounds of the present invention, represented by the general formula (I), the amino protecting groups can be selected from acyl groups, such as formyl, acetyl, chloroacetyl, t-butoxycarbonyl, benzyloxycarbonyl, etc., or aralkyl groups, such as benzyl, diphenylmethyl, triphenyl -methyl etc. Trimethylsilyl groups can also be used as an amino protecting group. Carboxy-protecting groups may be selected from alkyl esters, such as methyl ester, ethyl ester, t-butyl ester, etc., or aralkyl esters, such as benzyl ester, diphenyl methyl ester, triphenyl methyl ester, etc., or trialkyl silyl esters, such as trimethyl silyl ester, etc. Inorganic or organic bases may also be used as carboxy protecting groups. Taking into account different operations, synthesis of thus protected products and conditions for removing protective groups, it is preferred to use a triphenylmethyl group as an amino-protecting group and a diphenylmethyl group as a carboxy-protecting group.
Forbindelsene ifølge foreliggende oppfinnelse, representert ved den generelle formel (I), kan bli fremstilt som følger, nemlig: The compounds according to the present invention, represented by the general formula (I), can be prepared as follows, namely:
Fremgangsmåte AProcedure A
Forbindelsene ifølge foreliggende oppfinnelse, representert ved den generelle formel (I), kan bli fremstilt ved å omsette forbindelser representert ved den generelle formel The compounds according to the present invention, represented by the general formula (I), can be prepared by reacting compounds represented by the general formula
(II) : (II) :
hvorR^, r<4>og R^ har samme betydning som definert ovenfor, med forbindelser representert ved den generelle formel wherein R^, r<4> and R^ have the same meaning as defined above, with compounds represented by the general formula
(III): (III):
hvor R-'-,R^ og bindingen vist ved den bølgede linje har samme betydning som definert ovenfor, og R^ og R^ er like where R-'-,R^ and the bond shown by the wavy line have the same meaning as defined above, and R^ and R^ are equal
eller forskjellige og representerer, uavhengig av hverandre, et hydrogenatom eller en hydroksybeskyttende gruppe, eller representerer sammen en isopropylidengruppe. or different and independently represent a hydrogen atom or a hydroxy protecting group, or together represent an isopropylidene group.
Om nødvendig og ønsket kan forbindelsene representert ved den generelle formel (II), omsettes til rekative derivater ved aminogruppen derav. If necessary and desired, the compounds represented by the general formula (II) can be converted into reactive derivatives at the amino group thereof.
Forbindelsene representert ved den generelle formel (II), kan omsettes med forbindelsene representert ved den generelle formel (III) ved å bruke egnede kondenseringsmidler, så som N,N'-dicykloheksylkarbodiimid, N-etyl-5-fenylisoksaz-olium-3'-sulfonat osv. Alternativt kan forbindelsene representert ved den generelle formel (III), omsettes til passende reaktive derivater før reaksjonen med forbindelsene representert ved den generelle formel (II). Passende reaktive derivater kan f.eks. være syrehalider (syreklorider osv.), azider, syreanhydrider, spesielt blandet syreanhydrid med sterke baser, aktive estere (N-hydroksysuccinimidester osv.), eller aktive amider (imidazolid, triazolid osv.). The compounds represented by the general formula (II) can be reacted with the compounds represented by the general formula (III) using suitable condensing agents, such as N,N'-dicyclohexylcarbodiimide, N-ethyl-5-phenylisoxazolium-3'- sulfonate, etc. Alternatively, the compounds represented by the general formula (III) may be converted into suitable reactive derivatives prior to the reaction with the compounds represented by the general formula (II). Suitable reactive derivatives can e.g. be acid halides (acid chlorides, etc.), azides, acid anhydrides, especially mixed acid anhydrides with strong bases, active esters (N-hydroxysuccinimide esters, etc.), or active amides (imidazolide, triazolide, etc.).
Reaksjonen mellom forbindelsene representert ved den generelle formel (II) og forbindelsene representert ved den generelle formel (III), kan utføres generelt i et inert organisk oppløsningsmiddel, så som dioksan, tetrahydrofuran, acetonitril, kloroform, metylenklorid, etylacetat, dimetylformamid osv., om nødvendig og ønsket i nærvær av avsuringsmidler. Reaksjonen kan også utføres i en vandig oppløsning, fortrinnsvis i nærvær av avsuringsmidler. Som avsuringsmidler kan trietylamin, dietylanilin o.l. bli brukt i det organiske oppløsningsmiddelsystem, og vandige alkaliforbin-delser, spesielt natriumhydroksyd, natriumhydrogenkarbonat, kaliumkarbonat o.l., kan bli brukt i det vandige system. The reaction between the compounds represented by the general formula (II) and the compounds represented by the general formula (III) can be generally carried out in an inert organic solvent, such as dioxane, tetrahydrofuran, acetonitrile, chloroform, methylene chloride, ethyl acetate, dimethylformamide, etc., if necessary and desired in the presence of deacidifying agents. The reaction can also be carried out in an aqueous solution, preferably in the presence of deacidifying agents. As deacidifying agents, triethylamine, diethylaniline and the like can be used. be used in the organic solvent system, and aqueous alkali compounds, especially sodium hydroxide, sodium hydrogen carbonate, potassium carbonate and the like, may be used in the aqueous system.
Reaksjonen kan utføres ved temperaturer som ligger i området fra ca. +30°C til romtemperatur og fortrinnsvis fra -s-10°C til 10°C. Under betingelsene beskrevet ovenfor, opprettholdes bindingen representert ved en bølget linje i den gene- The reaction can be carried out at temperatures in the range from approx. +30°C to room temperature and preferably from -s-10°C to 10°C. Under the conditions described above, the bond is maintained represented by a wavy line in the gene-
reile formel (III).proper formula (III).
Forbindelsene representert ved den generelle formel (II), brukt i fremgangsmåten ifølge foreliggende oppfinnelse, kan bli fremstilt ved metodene beskrevet i japansk patent Kokai 142987 (1985). Forbindelsene representert ved den generelle formel (III), kan generelt fremstilles ved metodene D, E og F beskrevet nedenfor. The compounds represented by the general formula (II), used in the method according to the present invention, can be prepared by the methods described in Japanese patent Kokai 142987 (1985). The compounds represented by the general formula (III) can generally be prepared by the methods D, E and F described below.
Om nødvendig og ønsket kan de beskyttende grupper bli fjernet fra således erholdte cefalosporinderivater representert ved den generelle formel (I). If necessary and desired, the protective groups can be removed from the thus obtained cephalosporin derivatives represented by the general formula (I).
Fremgangsmåte BProcedure B
Forbindelsene representert ved den generelle formel (I), kan fremstilles ved å omsette forbindelser representert ved den generelle formel (IV): hvor r<1>,R<3>,R<4>, r<5>og bindingen vist med en bølget linje har samme betydning som definert ovenfor, med forbindelser representert ved den generelle formel (V): The compounds represented by the general formula (I) can be prepared by reacting compounds represented by the general formula (IV): where r<1>,R<3>,R<4>, r<5> and the bond shown with a wavy line has the same meaning as defined above, with compounds represented by the general formula (V):
hvorR<2>,R<6>ogR<7>har samme betydning som definert ovenfor, og X representerer et halogenatom eller en hydroksygruppe. Når forbindelsene representert ved den generelle formel (V) er alkoholer, kan de enten omsettes direkte med forbindelsene representert ved den generelle formel (IV), ved til- where R<2>, R<6> and R<7> have the same meaning as defined above, and X represents a halogen atom or a hydroxy group. When the compounds represented by the general formula (V) are alcohols, they can either be reacted directly with the compounds represented by the general formula (IV), by adding
stedeværelse av passende kondenseringsmidler, så som trifenylfosfin eller dietylazodikarboksylat, eller omsettes til passende reaktive derivater, så som tosylat, og så omsettes med forbindelsene representert ved den generelle formel (IV). Imidlertid - med hensyn til reaktiviteten og anvendeligheten - er halider foretrukket for forbindelsene representert ved den generelle formel (V) for å omsettes med forbindelsene representert ved den generelle formel (IV). presence of suitable condensing agents, such as triphenylphosphine or diethylazodicarboxylate, or reacted to suitable reactive derivatives, such as tosylate, and then reacted with the compounds represented by the general formula (IV). However - in terms of reactivity and applicability - halides are preferred for the compounds represented by the general formula (V) to react with the compounds represented by the general formula (IV).
Reaksjonen mellom forbindelsene representert ved den generelle formel (IV) og forbindelsene representert ved den generelle formel (V), kan utføres i et inert organisk opp-løsningsmiddel, så som dioksan, tetrahydrofuran, acetonitril, kloroform, metylenklorid, etylacetat, dimetylformamid osv. eller blandinger derav, eller om nødvendig og ønsket i vann eller en blanding av vann og organiske opp-løsningsmidler, fortrinnsvis i nærvær av avsuringsmidler. Som avsuringsmidler kan trietylamin, dietylanilin o.l. bli brukt i organiske oppløsningsmidler, og vandige alkali-forbindelser, fortrinnsvis natriumhydroksyd, natriumhydrogenkarbonat, kaliumkarbonat o.l., kan bli brukt i vandige oppløsningsmidler. The reaction between the compounds represented by the general formula (IV) and the compounds represented by the general formula (V) can be carried out in an inert organic solvent, such as dioxane, tetrahydrofuran, acetonitrile, chloroform, methylene chloride, ethyl acetate, dimethylformamide, etc. or mixtures thereof, or if necessary and desired in water or a mixture of water and organic solvents, preferably in the presence of deacidifying agents. As deacidifying agents, triethylamine, diethylaniline and the like can be used. be used in organic solvents, and aqueous alkali compounds, preferably sodium hydroxide, sodium hydrogen carbonate, potassium carbonate and the like, may be used in aqueous solvents.
Reaksjonen mellom forbindelsene representert ved den generelle formel (IV) og forbindelsene representert ved den generelle formel (V), kan utføres ved temperaturer i området fra ca. -s-30°C til romtemperatur og fortrinnsvis fra -J-10°C til 10°C. Under betingelsene beskrevet ovenfor, opprettholdes bindingen representert ved en bølget linje i den generelle formel (IV). The reaction between the compounds represented by the general formula (IV) and the compounds represented by the general formula (V) can be carried out at temperatures in the range from approx. -s-30°C to room temperature and preferably from -J-10°C to 10°C. Under the conditions described above, the bond represented by a wavy line in the general formula (IV) is maintained.
Forbindelsene representert ved den generelle formel (IV), kan fremstilles ved metoden beskrevet i japansk ansøkning 249193 (1984). The compounds represented by the general formula (IV) can be prepared by the method described in Japanese application 249193 (1984).
Forbindelsene representert ved den generelle formel (V), i tilfelle med halidform, kan fremstilles fra 4-metylkatechol ved den følgende fremgangsmåte; for det første beskyttelse av hydroksygruppene, derpå halogenering av 5-posisjonen på vanlig måte, derpå erstatning av halogenatomet med en karboksylgruppe, så beskyttelse av karboksylgruppen ved esterifisering og endelig halogenering av benzylenden ved vanlig metode. Derpå, om nødvendig og ønsket kan de resulterende halider hydrolyseres for å gi hydroksyformen av forbindelsene representert ved den generelle formel (V). The compounds represented by the general formula (V), in the case of the halide form, can be prepared from 4-methylcatechol by the following procedure; first, protection of the hydroxy groups, then halogenation of the 5-position in the usual way, then replacement of the halogen atom with a carboxyl group, then protection of the carboxyl group by esterification and finally halogenation of the benzyl end by the usual method. Then, if necessary and desired, the resulting halides can be hydrolyzed to give the hydroxy form of the compounds represented by the general formula (V).
Om nødvendig og ønsket kan beskyttelsesgrupper fjernes fra således erholdte cefalosporinderivater, representert ved den generelle formel (I). If necessary and desired, protective groups can be removed from cephalosporin derivatives thus obtained, represented by the general formula (I).
Fremgangsmåte CProcedure C
Forbindelsene representert ved den generelle formel (I), kan fremstilles ved å omsette forbindelser representert ved den generelle formel (VI): hvorR<1>,R<2>,R<3>, R**, r<7>og bindingen vist med en buet linje har samme betydning som definert ovenfor, og Y representerer en acetoksygruppe eller et halogenatom, med forbindelser representert ved den generelle formel (VII): The compounds represented by the general formula (I) can be prepared by reacting compounds represented by the general formula (VI): where R<1>, R<2>, R<3>, R**, r<7> and the bond shown by a curved line has the same meaning as defined above, and Y represents an acetoxy group or a halogen atom, with compounds represented by the general formula (VII):
hvorR<4>og R^ har samme betydning som definert ovenfor. where R<4> and R^ have the same meaning as defined above.
Reaksjonen kan utføres ved å omsette forbindelsene representert ved den generelle formel (VI) med forbindelsene representert ved den generelle formel (VII) i et organisk oppløsningsmiddel, så som alkoholer, dimetylformamid, acetonitril osv. eller blandinger derav, eller i et vandig system. Reaksjonen mellom forbindelsene representert ved den generelle formel (IV) og forbindelsene representert ved den generelle formel (V), kan utføres i et organisk oppløs-ningsmiddel, fortrinnsvis i nærvær av en Lewis-syre, så som bortrifluorid-eterkompleks o.l. eller i et vandig system i nærvær av en passende mengde vandig alkali, så som natriumhydrogenkarbonat eller kaliumkarbonat, fortrinnsvis i en bufferoppløsning ved en pH i området fra 6,0 til 7,8, ved temperaturer i området fra ca. 40°C til ca. 80°C, fortrinnsvis ved fra 55 til 65°C. Under betingelsene beskrevet ovenfor, opprettholdes bindingen representert ved en buet linje i den generelle formel (VI). Forbindelsene representert ved den generelle formel (VI), kan fremstilles fra forbindelsene representert ved den generelle formel (III) og kjente 7-aminocefalosporansyrer eller derivater derav ved konvensjo-nelle kondensasjonsreaksjoner. Forbindelsene representert ved den generelle formel (VII), kan fremstilles ved metoden beskrevet i japansk patent Kokai 142987 (1985). The reaction can be carried out by reacting the compounds represented by the general formula (VI) with the compounds represented by the general formula (VII) in an organic solvent, such as alcohols, dimethylformamide, acetonitrile, etc. or mixtures thereof, or in an aqueous system. The reaction between the compounds represented by the general formula (IV) and the compounds represented by the general formula (V) can be carried out in an organic solvent, preferably in the presence of a Lewis acid, such as boron trifluoride ether complex and the like. or in an aqueous system in the presence of a suitable amount of aqueous alkali, such as sodium bicarbonate or potassium carbonate, preferably in a buffer solution at a pH in the range of 6.0 to 7.8, at temperatures in the range of about 40°C to approx. 80°C, preferably at from 55 to 65°C. Under the conditions described above, the bond represented by a curved line in the general formula (VI) is maintained. The compounds represented by the general formula (VI) can be prepared from the compounds represented by the general formula (III) and known 7-aminocephalosporanic acids or derivatives thereof by conventional condensation reactions. The compounds represented by the general formula (VII) can be prepared by the method described in Japanese patent Kokai 142987 (1985).
Om nøvendig og ønsket kan de beskyttende grupper bli fjernet fra således erholdte cefalosporinderivater, representert ved den generelle formel (I). If necessary and desired, the protective groups can be removed from the cephalosporin derivatives thus obtained, represented by the general formula (I).
Forbindelsene representert ved den generelle formel (III): hvorR<1>,R<2>,R<6>,R<7>og bindingen vist med en buet linje har samme betydning som definert ovenfor, kan passende bli fremstilt fra forbindelsene representert ved den generelle formel (VIII): hvor R<1>,R<2>og bindingen vist med en krum linje har samme betydning som definert ovenfor, og R<8>representerer et hydrogenatom eller en karboksybeskyttende gruppe. The compounds represented by the general formula (III): where R<1>,R<2>,R<6>,R<7>and the bond shown by a curved line have the same meaning as defined above, can be suitably prepared from the compounds represented by the general formula (VIII): where R<1>, R<2> and the bond shown with a curved line have the same meaning as defined above, and R<8> represents a hydrogen atom or a carboxy protecting group.
Forbindelsene representert ved den generelle formel (VIII), kan generelt fremstilles ved metodene beskrevet nedenfor. The compounds represented by the general formula (VIII) can generally be prepared by the methods described below.
Fremgangsmåte DProcedure D
Forbindelsene representert ved den generelle formel (VIII), kan fremstilles ved å omsette de kjente forbindelser representert ved den generelle formel (IX): The compounds represented by the general formula (VIII) can be prepared by reacting the known compounds represented by the general formula (IX):
hvorR<1>,R<8>og bindingen vist med en krum linje har samme betydning som definert ovenfor, med forbindelsene representert ved den generelle formel (V): hvor R<2>og X har samme betydning som definert ovenfor. Når forbindelsene representert ved den generelle formel (V) er alkoholer, kan de enten omsettes direkte med forbindelsene representert ved den generelle formel (IX), i nærvær av passende kondenseringsmidler, så som trifenylfosfin eller etylazodikarboksylat, eller omsettes til passende reaktive derivater, så som tosylat, og derpå omsettes med forbindelsene representert ved den generelle formel (IX). Imidlertid - med hensyn til reaktivitet og anvendelighet - er halider foretrukket for forbindelsene representert ved den generelle formel (V) og blir omsatt med forbindelsene representert ved den generelle formel (IX). where R<1>, R<8> and the bond shown by a curved line have the same meaning as defined above, with the compounds represented by the general formula (V): where R<2> and X have the same meaning as defined above. When the compounds represented by the general formula (V) are alcohols, they can either be reacted directly with the compounds represented by the general formula (IX), in the presence of suitable condensing agents, such as triphenylphosphine or ethyl azodicarboxylate, or be reacted to suitable reactive derivatives, such as tosylate, and then reacted with the compounds represented by the general formula (IX). However - with regard to reactivity and applicability - halides are preferred for the compounds represented by the general formula (V) and are reacted with the compounds represented by the general formula (IX).
Reaksjonen mellom forbindelsene representert ved den generelle formel (IX) og forbindelsene representert ved den generelle formel (V), kan utføres i et inert organisk opp-løsningsmiddel, så som dioksan, tetrahydrofuran, acetonitril, kloroform, metylenklorid, etylacetat, dimetylformamid osv. eller blandinger derav, eller om nødvendig og ønsket i vann eller blandinger av vann og organiske opp-løsningsmidler, fortrinnsvis i nærvær av avsuringsmidler. Som avsuringsmidler kan trietylamin, dietylanilin o.l. bli brukt i organiske oppløsningsmidler, og vandige alkali-forbindelser, fortrinnsvis natriumhydroksyd, natriumhydrogenkarbonat, kaliumkarbonat o.l., kan bli brukt i vandige oppløsningsmidler. The reaction between the compounds represented by the general formula (IX) and the compounds represented by the general formula (V) can be carried out in an inert organic solvent such as dioxane, tetrahydrofuran, acetonitrile, chloroform, methylene chloride, ethyl acetate, dimethylformamide, etc. or mixtures thereof, or if necessary and desired in water or mixtures of water and organic solvents, preferably in the presence of deacidifying agents. As deacidifying agents, triethylamine, diethylaniline and the like can be used. be used in organic solvents, and aqueous alkali compounds, preferably sodium hydroxide, sodium hydrogen carbonate, potassium carbonate and the like, may be used in aqueous solvents.
Reaksjonen mellom forbindelsene representert ved den generelle formel (IX) og forbindelsene representert ved den generelle formel (V), kan utføres ved temperaturer i området fra ca. +30°C til romtemperatur og fortrinnsvis fra -MO°C til 10°C. Under betingelsene beskrevet ovenfor, opprettholdes bindingen representert ved en krum linje i den generelle formel (IX). The reaction between the compounds represented by the general formula (IX) and the compounds represented by the general formula (V) can be carried out at temperatures in the range from approx. +30°C to room temperature and preferably from -MO°C to 10°C. Under the conditions described above, the bond represented by a curved line in the general formula (IX) is maintained.
Forbindelsene representert ved den generelle formel (V), kan fremstilles fra 2,2,6-trimetylbenzodioksol ved metoden beskrevet ovenfor for forbindelsene representert ved den generelle formel (V). The compounds represented by the general formula (V) can be prepared from 2,2,6-trimethylbenzodioxole by the method described above for the compounds represented by the general formula (V).
Om nødvendig og ønsket kan beskyttelsesgruppene bli fjernet fra således erholdte forbindelser, representert ved den generelle formel (VIII). If necessary and desired, the protecting groups can be removed from compounds thus obtained, represented by the general formula (VIII).
Fremgangsmåte EProcedure E
Forbindelsene representert ved den generelle formel (VIII), kan fremstilles ved å omsette de kjente forbindelser representert ved den generelle formel (X): hvor r! og R<8>har samme betydning som definert ovenfor, med forbindelser representert ved den generelle formel (XI): The compounds represented by the general formula (VIII) can be prepared by reacting the known compounds represented by the general formula (X): where r! and R<8> has the same meaning as defined above, with compounds represented by the general formula (XI):
hvor R<2>har samme betydning som definert ovenfor, i et organisk oppløsningsmiddel, så som metanol, etanol, dioksan, tetrahydrofuran, metylenklorid og etylacetat, og om nødven-dig og ønsket i nærvær av dehydreringsmidler, så som mole-kylsikt, ved temperaturer i området fra ca. -s-30°C til ca. 100°C, fortrinnsvis fra -M0°C til 30°C. where R<2> has the same meaning as defined above, in an organic solvent, such as methanol, ethanol, dioxane, tetrahydrofuran, methylene chloride and ethyl acetate, and if necessary and desired in the presence of dehydrating agents, such as molecular sieves, by temperatures in the area from approx. -s-30°C to approx. 100°C, preferably from -M0°C to 30°C.
Forbindelsene representert ved den generelle formel (XI), kan fremstilles fra en halidform av ovenfor nevnte forbindelser representert ved den generelle formel (V) ved ftalimidoksylering fulgt av deftaloylering, hvorav begge reaksjoner kan utføres ved vanlige metoder. The compounds represented by the general formula (XI) can be prepared from a halide form of the above-mentioned compounds represented by the general formula (V) by phthalimidoxylation followed by dephthaloylation, both of which reactions can be carried out by conventional methods.
Om nødvendig og ønsket kan beskyttelsesgruppene bli fjernet fra således erholdte forbindelser, representert ved den generelle formel (VIII). If necessary and desired, the protecting groups can be removed from compounds thus obtained, represented by the general formula (VIII).
Fremgangsmåte FProcedure F
Forbindelsene representert ved den generelle formel (VIII) kan fremstilles ved å omsette de kjente forbindelser representert ved den generelle formel (XII): The compounds represented by the general formula (VIII) can be prepared by reacting the known compounds represented by the general formula (XII):
hvor R<9>representerer et hydrogenatom eller en karboksybeskyttende gruppe, og Z representerer et halogenatom, med forbindelsene representert ved den generelle formel (V): hvor R<2>og X har samme betydning som definert ovenfor, ved metoden som er lik ovenfor nevnte fremgangsmåte D, og derpå ved å kondensere produktet med tioureaderivatene representert ved den generelle formel (XIII): where R<9> represents a hydrogen atom or a carboxy protecting group, and Z represents a halogen atom, with the compounds represented by the general formula (V): where R<2> and X have the same meaning as defined above, by the method similar to the above said method D, and then by condensing the product with the thiourea derivatives represented by the general formula (XIII):
hvor r<1>har samme betydning som definert ovenfor. Under betingelsene beskrevet ovenfor, opprettholdes bindingen representert ved en bølget linje i den generelle formel (XII). Med hensyn til reaktivitet og anvendelighet er det ønskelig å reagere en alkoholform av forbindelsene representert ved den generelle formel (V) med forbindelsene representert ved den generelle formel (XII). where r<1> has the same meaning as defined above. Under the conditions described above, the bond represented by a wavy line in the general formula (XII) is maintained. With regard to reactivity and applicability, it is desirable to react an alcohol form of the compounds represented by the general formula (V) with the compounds represented by the general formula (XII).
I foreliggende fremgangsmåte kan kondensasjonen med tioureaderivatene utføres i et organisk oppløsningsmiddel, så som metanol, etanol, dioksan, tetrahydrofuran, metylenklorid og etylacetat eller blandinger derav, og fortrinnsvis i nærvær av et avsuringsmiddel, så som trietylamin, dietylanilin, natriumhydrogenkarbonat og kaliumkarbonat ved temperaturer i området fra ca. -s-30°Ctil ca. 100°C, foretrukket fra +10°C til 30°C. In the present process, the condensation with the thiourea derivatives can be carried out in an organic solvent, such as methanol, ethanol, dioxane, tetrahydrofuran, methylene chloride and ethyl acetate or mixtures thereof, and preferably in the presence of a deacidifying agent, such as triethylamine, diethylaniline, sodium bicarbonate and potassium carbonate at temperatures in the area from approx. -s-30°C to approx. 100°C, preferably from +10°C to 30°C.
Om nødvendig og ønsket kan de beskyttende grupper bli fjernet fra således erholdte forbindelser, representert ved den generelle formel (VIII). If necessary and desired, the protective groups can be removed from compounds thus obtained, represented by the general formula (VIII).
Trinatriumsaltet av forbindelsen ifølge foreliggende oppfinnelse, representert ved formelen (I'), er generelt et amorft, fast stoff. Saltet har en utmerket oppløselighet som er meget påkrevet for parenteral bruk, men stabiliteten til saltet er ikke nødvendigvis tilstrekkelig for farma-søytisk bruk som bulkmaterialer eller som parenterale preparater. Som et resultat av utstrakte studier for å forbedre stabiliteten til forbindelsen, har nærværende oppfinnere nå funnet at svært rene krystallinske forbindelser ifølge foreliggende oppfinnelse, representert ved formelen (I'), (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy-4,5-di-hydroksyfenyl)metyl]oksyimino]acetamido]-3-[(2-karboksy-5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tiometyl]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre, fordelaktig og konsistent kan fremstilles og isoleres. Spesielt har nærværende oppfinnere fremstilt og isolert krystallinsk, hydrert (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy- 4,5-dihydroksyfenyl)metyl]oksyimino]acetamido]-3-[(2-karboksy-5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tiometyl]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre. Denne nye krystallinske, hydrerte forbindelse er overlegen, ikke bare ved sin krystallinitet og økte renhet, men erhol-des også i høyt utbytte og har økt stabilitet ved lagring. Disse egenskaper til det krystallinske materiale gir det spesiell verdi ved farmasøytisk bruk. The trisodium salt of the compound of the present invention, represented by formula (I'), is generally an amorphous solid. The salt has an excellent solubility which is very much required for parenteral use, but the stability of the salt is not necessarily sufficient for pharmaceutical use as bulk materials or as parenteral preparations. As a result of extensive studies to improve the stability of the compound, the present inventors have now found that highly pure crystalline compounds of the present invention, represented by the formula (I'), (6R,7R)-7-[2-(2-amino -4-thiazolyl)-2-[Z-[(2-carboxy-4,5-di-hydroxyphenyl)methyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1, 5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid can advantageously and consistently be prepared and isolated. In particular, the present inventors have prepared and isolated crystalline, hydrated (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl] oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4, 2,0]oct-2-ene-2-carboxylic acid. This new crystalline, hydrated compound is superior, not only in its crystallinity and increased purity, but is also obtained in high yield and has increased stability during storage. These properties of the crystalline material give it special value in pharmaceutical use.
Det ovenfor nevnte hydrerte, krystallinske materiale blekarakterisert vedsitt infrarøde spektrum og for røntgen-strålepulverdiffraksjonsmønstret. The above-mentioned hydrated crystalline material was characterized by its infrared spectrum and X-ray powder diffraction pattern.
IR-spektrum (Nujol): V maks 3600-2200, 3275, 1769, 1652, 1596, 1542, 1521, 1519, 1307, 1272, 1190, 1160, 1103, 1064, 1026, 964, 901, 854, 795, 770 cm"<1>. IR spectrum (Nujol): V max 3600-2200, 3275, 1769, 1652, 1596, 1542, 1521, 1519, 1307, 1272, 1190, 1160, 1103, 1064, 1026, 964, 901, 854, 7095, 777 cm"<1>.
Røntgenstrålediffraksjonsmønster (gitt som d-avstander i Ångstrøm-enheter og prosentvise intensiteter): X-ray diffraction pattern (given as d-spacings in Angstrom units and percentage intensities):
Den krystallinske, hydrerte forbindelse representert ved formel (I'), kan passende fremstilles fra en oppløsning av et solvat eller et salt av nevnte forbindelse. Således - i henhold til en ytterligere utførelsesform av oppfinnelsen - er det fremskaffet en fremgangsmåte for å fremstille krystallinsk, hydrert (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy-4,5-dihydroksyfenyl)metyl]oksyimino]acetamido]-3-[(2-karboksy-5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)-tio-metyl]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre ved å justere pH til et solvat (eddiksyre-solvat, maursyresolvat osv.), et syreaddisjonssalt (trifluoreddiksyresalt osv.) eller et basesalt (trinatriumsalt osv.) av nevnte syre i et passende vandig medium til en pH i området på fra 1,0 til 4,0, fortrinnsvis fra 1,5 til 2,5, og ved en temperatur i området fra -s-40°C til 80°C, fortrinnsvis fra 15°C til 50°C. Justeringen av pH kan utføres ved å bruke en uorganisk syre, så som saltsyre, svovelsyre eller fosforsyre eller en blanding derav. Om nødvendig og ønsket kan krystallisering utføres ved å bruke en kjernekrystall, og rekrystallisering kan utføres i et passende surt oppløs-ningsmiddel på vanlig måte. Oppløsningsmidlet kan inneholde vann, lavere alifatiske alkoholer, så som metanol, etanol, isopropanol, vandige karbonsyrer, lavere alifatiske kar-boksylsyrer, så som maursyre, eddiksyre, organiske amider, så som N,N-dimetylformamid, N,N-dimetylacetamid, N-metyl-pyrrolidon, etere, så som monoglym, diglym, tetrahydrofuran eller en blanding derav.Blandede oppløsningsmidler, så som 50 % aceton-vann eller 30 % metanol-vann, kan også bli brukt. Ikke-toksiske salter ved karboksylgruppene av forbindelsene representert ved formel (I')/kan innbefatte uorganiske salter, så som alkalimetallsalter (natriumsalter, kaliumsalter osv.), jordalkalimetallsalter (kalsiumsalter osv.), aminosyresalter (lysinsalter, argininsalter osv.) og organiske basesalter (prokainsalter, fenyletylbenzylamin-salter, dibenzyletylendiaminsalter, dietanolaminsalter, N-metylglukosaminsalter osv.), mest foretrukket natriumsalter. Andre ikke-toksiske salter kan innbefatte syreaddisjonssalter dannet med f.eks. saltsyre, hydrobromsyre, svovelsyre, salpetersyre, maursyre og trifluoreddiksyre. The crystalline, hydrated compound represented by formula (I') may conveniently be prepared from a solution of a solvate or salt of said compound. Thus - according to a further embodiment of the invention - a method has been provided for preparing crystalline, hydrogenated (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[( 2-carboxy-4,5-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)-thio-methyl] -8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid by adjusting the pH of a solvate (acetic acid solvate, formic acid solvate, etc.), an acid addition salt (trifluoroacetic acid salt, etc. .) or a base salt (trisodium salt, etc.) of said acid in a suitable aqueous medium to a pH in the range of from 1.0 to 4.0, preferably from 1.5 to 2.5, and at a temperature in the range of -s-40°C to 80°C, preferably from 15°C to 50°C. The adjustment of pH can be carried out by using an inorganic acid, such as hydrochloric acid, sulfuric acid or phosphoric acid or a mixture thereof. If necessary and desired, crystallization can be carried out using a core crystal, and recrystallization can be carried out in a suitable acidic solvent in the usual way. The solvent may contain water, lower aliphatic alcohols such as methanol, ethanol, isopropanol, aqueous carboxylic acids, lower aliphatic carboxylic acids such as formic acid, acetic acid, organic amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N -methyl-pyrrolidone, ethers, such as monoglyme, diglyme, tetrahydrofuran or a mixture thereof. Mixed solvents, such as 50% acetone-water or 30% methanol-water, can also be used. Non-toxic salts at the carboxyl groups of the compounds represented by formula (I') may include inorganic salts such as alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts, etc.), amino acid salts (lysine salts, arginine salts, etc.) and organic base salts (procaine salts, phenylethylbenzylamine salts, dibenzylethylenediamine salts, diethanolamine salts, N-methylglucosamine salts, etc.), most preferably sodium salts. Other non-toxic salts may include acid addition salts formed with e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, formic acid and trifluoroacetic acid.
Ved fremstillingen av krystallinsk, hydrert form av forbindelsene representert ved formel (I'), (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy-4,5-dihydroksyfenyl)-metyl]-oksyimino]acetamido]-3-[(2-karboksy-5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tiometyl]-8-okso-5-tia-l-azabicyklo[4,2,0]-okt-2-en-2-karboksylsyre, er dets maursyresolvat spesielt foretrukket som utgangsmateriale. Maursyresolvatet i seg selv kan også krystalliseres, og det krystalliserte solvat, så vel som fremgangsmåten for fremstilling av nevnte krystalliserte solvat, er også innbefattet i foreliggende oppfinnelse. In the preparation of the crystalline, hydrated form of the compounds represented by formula (I'), (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4 ,5-dihydroxyphenyl)-methyl]-oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5 -thia-1-azabicyclo[4,2,0]-oct-2-ene-2-carboxylic acid, its formic acid solvate is particularly preferred as starting material. The formic acid solvate itself can also be crystallized, and the crystallized solvate, as well as the method for producing said crystallized solvate, are also included in the present invention.
Det krystalliserte maursyresolvat av forbindelsen representert ved formel (I'), blekarakterisert vedsitt infrarøde spektrum (og for røntgenstrålepulverdiffraksjonsmønstret). The crystallized formic acid solvate of the compound represented by formula (I') was characterized by its infrared spectrum (and by its X-ray powder diffraction pattern).
IR spektrum (Nujol): Vmaks 3600-2200, 3269, 1770, 1654, 1596, 1517, 1509, 1303, 1188, 1159, 1101, 1061, 1025, 962, 904, 853, 794, 770 cm"<1>. IR spectrum (Nujol): Vmax 3600-2200, 3269, 1770, 1654, 1596, 1517, 1509, 1303, 1188, 1159, 1101, 1061, 1025, 962, 904, 853, 794, 770 cm"<1>.
Røntgenstrålediffraksjonsmønster (gitt som d-avstander i Ångstrøm-enheter og prosentvise intensiteter): X-ray diffraction pattern (given as d-spacings in Angstrom units and percentage intensities):
Krystallinsk maursyresolvat av (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy-4,5-dihydroksyfenyl)metyl]oksy-imino]acetamido]-3-[(2-karboksy-5-metyl-s-triazolo[1,5-a]-pyrimidin-7-yl)tiometyl]-8-okso-5-tia-l-azabicyklo[4,2,0]-okt-2-en-2-karboksylsyre kan generelt fremstilles fra dets amorfe basesalter, så som trinatriumsalter eller fra syreaddisjonssalter, så som saltsyresalter eller trifluoreddik-syresalter. Således kan tilsvarende cefalosporinderivater eller dets salter effektivt krystalliseres fra maursyre ved en temperatur i området fra 0°C til 60°C, fortrinnsvis fra 15°C til 50°C, og om nødvendig og ønsket ved å bruke syrer, så som saltsyre. Krystalliseringen kan også lettes ved å tilsette vann til oppløsningen eller ved bruk av kjernekrystaller. Crystalline formic acid solvate of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxy-imino]acetamido]- 3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]-pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4,2,0] -oct-2-ene-2-carboxylic acid can generally be prepared from its amorphous base salts, such as trisodium salts or from acid addition salts, such as hydrochloric acid salts or trifluoroacetic acid salts. Thus, corresponding cephalosporin derivatives or its salts can be effectively crystallized from formic acid at a temperature in the range from 0°C to 60°C, preferably from 15°C to 50°C, and if necessary and desired by using acids, such as hydrochloric acid. The crystallization can also be facilitated by adding water to the solution or by using core crystals.
Forbindelsene ifølge foreliggende oppfinnelse viser en kraftig antibakteriell aktivitet mot et bredt område av bakterier, innbefattende grampositive og gramnegative bakterier, spesielt mot meticillinresistente Staphylococcus aureus og Pseudomonas aeruginosa, og er meget anvendelige som terapeutiske midler mot smittsomme sykdommer. The compounds according to the present invention show a strong antibacterial activity against a wide range of bacteria, including gram-positive and gram-negative bacteria, especially against methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa, and are very useful as therapeutic agents against infectious diseases.
For å vise anvendeligheten av forbindelsene ifølge foreliggende oppfinnelse, er data angående antibakteriell aktivitet til en representativ forbindelse (referert til som forbindelse 1) vist nedenfor. En forbindelse beskrevet i en annen oppfinnelse av nærværende oppfinnere, japansk ansøkning 147359 (1985), er brukt som en sammenligningsforbindelse. To demonstrate the utility of the compounds of the present invention, data regarding antibacterial activity of a representative compound (referred to as compound 1) are shown below. A compound described in another invention of the present inventors, Japanese Application 147359 (1985), is used as a comparison compound.
Forbindelse 1: (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy-4,5-dihydroksyfenyl)metyl]oksy-imino]-acetamido]-3-[(2-karboksy-5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tiometyl]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre Compound 1: (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxy-imino]-acetamido] -3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4,2,0] oct-2-ene-2-carboxylic acid
Sammenlignings-comparative
forbindelse: (6R,7R) -7-[2-(2-amino-4-tiazolyl)-2-[Z-[ ( 4-acetoxy-2-karboksy-5-hydroksyfenyl)metyl]-oksyimino]acetamido]-3-[(2-karboksy-5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tiometyl]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre. compound: (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(4-acetoxy-2-carboxy-5-hydroxyphenyl)methyl]-oxyimino]acetamido]- 3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct -2-ene-2-carboxylic acid.
Eksperimentelt eksempel 1Experimental example 1
Antibakteriell aktivitet in vitro ble bestemt i samsvar med agarplate-fortynningsmetoden. Antibacterial activity in vitro was determined according to the agar plate dilution method.
En platinaløkke, hver med forsøksbakterier (10^ celler/ml), dyrket i Mueller Hinton-buljong, ble inokulert på Mueller Hinton agarplater som inneholdt forsøksforbindelser ved forskjellige konsentrasjoner. Etter dyrking ved 37°C i 20 timer ble minimal inhiberende konsentrasjon (MIC ug/ml) bestemt. A platinum loop, each containing test bacteria (10 3 cells/ml), grown in Mueller Hinton broth, was inoculated onto Mueller Hinton agar plates containing test compounds at various concentrations. After cultivation at 37°C for 20 hours, minimal inhibitory concentration (MIC µg/ml) was determined.
Som vist i tabellene l-a og 1-b, var forbindelse 1 omtrent like virksom som referanseforbindelsen mot bakteriestammene, bortsett fra Pseudomonas aeruginosa, mot hvilken forbindelse 1 var mer en 10 ganger så virksom som referanseforbindelsen og Ceftazidim. As shown in Tables 1-a and 1-b, compound 1 was approximately as active as the reference compound against the bacterial strains, except for Pseudomonas aeruginosa, against which compound 1 was more than 10 times as effective as the reference compound and Ceftazidime.
Eksperimentelt eksempel 2Experimental example 2
Beskytteljesegenskap mot systemisk infeksjon ble bestemt som følger. En vandig suspensjon av forsøksbakterier ble inji-sert intraperitonealt i ti 4-ukers gamle ICR-mus. En time etter infeksjonen ble forsøksforbindelsene tilført intra-venøst. Antallet overlevende mus ble talt opp 1 uke etter injeksjonen for å bestemme dosen, hvor 50 % av forsøksdyrene var levende (ED50: m<g>/k<g>). Protective properties against systemic infection were determined as follows. An aqueous suspension of experimental bacteria was injected intraperitoneally into ten 4-week-old ICR mice. One hour after the infection, the test compounds were administered intravenously. The number of surviving mice was counted 1 week after the injection to determine the dose, where 50% of the test animals were alive (ED50: m<g>/k<g>).
Som vist i tabellene 2-a og 2-b, var forbindelse 1 tydelig mer virksom enn referanseforbindelsen til å beskytte dyrene fra eksperimentell infeksjon og var spesielt mer en 10 ganger så virksom som referanseforbindelsen mot infeksjoner med Klebsiella pneumoniae og Pseudomonas aeruginosa. As shown in Tables 2-a and 2-b, compound 1 was clearly more effective than the reference compound in protecting the animals from experimental infection and in particular was more than 10 times as effective as the reference compound against infections with Klebsiella pneumoniae and Pseudomonas aeruginosa.
Nedenfor er LD50til representative eksempler av forbindelsene ifølge foreliggende oppfinnelse vist i tabell 3, hvor LD50ble bestemt i henhold til probitmetoden. Below, the LD50 for representative examples of the compounds according to the present invention are shown in table 3, where the LD50 was determined according to the probit method.
Forbindelsene ifølge foreliggende oppfinnelse er aktive mot mikroorganismer, så som grampositive aerobiske bakterier, så som Staphylococcus aureus, streptococci osv., gramnegative aerobiske bakterier, så som Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus morganii, Serratia marcescens, Pseudomonas aeruginosa, Citrobacter, Entero-bacter, Flavobacter osv., og er anvendelige for behandling av infeksjonssykdommer forårsaket av disse mikroorganismer. Forbindelsene ifølge foreliggende oppfinnelse viser en terapeutisk virkning mot Pseudomonas aeruginosa-infeksjoner som er mer virksom enn dem til tidligere kjente (3-laktam-antibiotika, og disse forbindelser er antatt å være meget trygge. Følgelig er det ventet at forbindelsene ifølge foreliggende oppfinnelse er ekstremt anvendelige mot Pseudomonas-infeksj oner. The compounds according to the present invention are active against microorganisms, such as gram-positive aerobic bacteria, such as Staphylococcus aureus, streptococci, etc., gram-negative aerobic bacteria, such as Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus morganii, Serratia marcescens, Pseudomonas aeruginosa, Citrobacter, Enterobacter, Flavobacter, etc., and are applicable for the treatment of infectious diseases caused by these microorganisms. The compounds of the present invention show a therapeutic effect against Pseudomonas aeruginosa infections that is more effective than that of previously known (3-lactam antibiotics, and these compounds are believed to be very safe. Accordingly, it is expected that the compounds of the present invention are extremely applicable against Pseudomonas infections.
Cefalosporinderivatene fremskaffet ved foreliggende oppfinnelse, kan anvendes som farmasøytiske forbindelser, f.eks. i form av farmasøytiske blandinger inneholdende cefalosporinderivater sammen med passende farmasøytisk akseptable bærermidler. Den farmasøytiske blanding kan ha fast form, så som tabletter, kapsler osv. eller en flytende form, så som injeksjoner osv. Blandingene kan steriliseres og kan inneholde hjelpestoffer, generelt anvendt i farma-søytisk teknikk, så som natriumhydrogenkarbonat, sitronsyre, propylenglykol, Tween 80 osv. The cephalosporin derivatives obtained by the present invention can be used as pharmaceutical compounds, e.g. in the form of pharmaceutical compositions containing cephalosporin derivatives together with suitable pharmaceutically acceptable carriers. The pharmaceutical mixture can be in solid form, such as tablets, capsules, etc. or a liquid form, such as injections, etc. The mixtures can be sterilized and can contain excipients, generally used in pharmaceutical technology, such as sodium bicarbonate, citric acid, propylene glycol, Tween 80 etc.
Videre er det også foretrukket å bruke forbindelsene ifølge foreliggende oppfinnelse etter at de er blitt dannet til frysetørkede produkter eller pulvere, fulgt av oppløsning av disse i et vanlig oppløsningsmiddel, f.eks. vann eller fysiologisk saltvann før bruk. Forbindelsene kan bli brukt oralt eller parenteralt. Mens doser varierer, avhengig av alder og tilstand til pasienten, tilstanden og typen sykdom osv., kan fra ca. 0,01 til ca. 10 g, fortrinnsvis fra ca. 0,1 til ca. 5 g, bli brukt som en daglig dose for en voksen. Parenteral tilførsel av forbindelsene fremskaffet ifølge foreliggende oppfinnelse, er spesielt foretrukket. Furthermore, it is also preferred to use the compounds according to the present invention after they have been formed into freeze-dried products or powders, followed by their dissolution in a common solvent, e.g. water or physiological saline before use. The compounds may be used orally or parenterally. While doses vary, depending on the age and condition of the patient, the condition and type of illness, etc., from approx. 0.01 to approx. 10 g, preferably from approx. 0.1 to approx. 5 g, be used as a daily dose for an adult. Parenteral administration of the compounds obtained according to the present invention is particularly preferred.
Nedenfor vil foreliggende oppfinnelse bli beskrevet under referanse til eksemplene nedenfor, men er ikke betraktet å være begrenset til disse. Below, the present invention will be described with reference to the examples below, but is not considered to be limited to these.
Eksempel 1Example 1
Fremstilling av (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy-4,5-dihydroksyfenyl)metyl]oksyimino]acetamido]-3-[(2-karboksy-5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tio-metyl] -8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre ( forbindelse 1) Preparation of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-[ (2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio-methyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct- 2-ene-2-carboxylic acid (compound 1)
Trinn 1Step 1
Fremstilling av 5- bromo- 2, 2, 6- trimetylbenzodioksolPreparation of 5-bromo-2,2,6-trimethylbenzodioxole
Til en oppløsning av 2,2,5-benzodioksol (21 g) i diklormetan (160 ml) ble det tilsatt pyridin (12,1 ml), fulgt av dråpevis tilsetning av en oppløsning av brom (7,5 ml) under is-avkjøling, og oppløsningen ble omrørt ved romtemperatur i 1 time. Etter fjerning av oppløsningsmidlet under redusert trykk ble residuet ekstrahert med eter (200 ml). Oppløs-ningen ble vasket tre ganger med vann (100 ml hver gang), to ganger med en vandig oppløsning av sitronsyre (1 N, 100 ml hver gang), én gang med en mettet, vandig oppløsning av natriumhydrogenkarbonat (100 ml) og én gang med saltlake (100 ml). Den vaskede oppløsning ble tørket over vanfritt natriumsulfat. Den tørkede oppløsning ble konsentrert under redusert trykk, og residuet ble opprenset ved silikagel kolonnekromatografi for å gi 28,4 g av den ønskede forbindelse . To a solution of 2,2,5-benzodioxole (21 g) in dichloromethane (160 mL) was added pyridine (12.1 mL), followed by dropwise addition of a solution of bromine (7.5 mL) under ice- cooling, and the solution was stirred at room temperature for 1 hour. After removal of the solvent under reduced pressure, the residue was extracted with ether (200 mL). The solution was washed three times with water (100 ml each time), twice with an aqueous solution of citric acid (1 N, 100 ml each time), once with a saturated aqueous solution of sodium bicarbonate (100 ml) and once once with brine (100 ml). The washed solution was dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 28.4 g of the desired compound.
IR (KBr, cm-<1>): 1493, 1379, 1251, 1241, 1216, 856. IR (KBr, cm-<1>): 1493, 1379, 1251, 1241, 1216, 856.
NMR (CDC13, ppm): 6,9 (1H, s), 6,6 (1H, s), 2,3 (3H, s), NMR (CDCl 3 , ppm): 6.9 (1H, s), 6.6 (1H, s), 2.3 (3H, s),
1,7 (6 H, s). 1.7 (6 H, p).
Trinn 2Step 2
Fremstilling av 2, 2, 6- trimetylbenzodioksol- 5- karboksylsyre Til en suspensjon av magnesiumpulver (9,64 g) i tørr eter (17 ml) ble det sakte tilsatt en oppløsning av produktet fra trinn 1 (28 g) og etylbromid (24,8 g) i tørr eter (114 ml). Tilsetning av ca. 4 ml av oppløsningen var tilstrekkelig for å forårsake spontan tilbakeløpskoking, og den gjenværende del ble tilsatt dråpevis over en periode på 1,5 time for å opprettholde den spontane tilbakeløpskoking. Etter avslut- ning av den dråpevise tilsetning ble reaksjonsblandingen kokt under tilbakeløp i ytterligere 30 min. og derpå avkjølt til romtemperatur og helt over knuste stykker av tørris. Omrøring ble fortsatt inntil alle stykker av tørris var borte. Den resulterende oppløsning ble surgjort med vandig saltsyre (20 %, 92 ml) under isavkjøling og ekstrahert to ganger med eter (100 ml hver gang). Eteroppløsningen ble vasket fire ganger med vann (50 ml hver gang) og derpå ekstrahert fem ganger med isavkjølt, vandig natriumhydroksyd-oppløsning (konsentrasjon 10 %, 50 ml hver gang). Ekstraktet ble surgjort med 20 % saltsyre under isavkjøling og omrøring til pH 2, og de utfelte krystaller ble separert ved filtrering. Krystallene således erholdt, ble vasket, tørket og rekrystallisert med eter-heksan (1:4) for å gi 10,8 g av den ønskede forbindelse. Preparation of 2,2,6-trimethylbenzodioxole-5-carboxylic acid To a suspension of magnesium powder (9.64 g) in dry ether (17 ml) was slowly added a solution of the product from step 1 (28 g) and ethyl bromide (24 .8 g) in dry ether (114 ml). Addition of approx. 4 ml of the solution was sufficient to cause spontaneous reflux and the remaining portion was added dropwise over a period of 1.5 hours to maintain the spontaneous reflux. After completion of the dropwise addition, the reaction mixture was boiled under reflux for a further 30 min. and then cooled to room temperature and poured over crushed pieces of dry ice. Stirring was continued until all pieces of dry ice were gone. The resulting solution was acidified with aqueous hydrochloric acid (20%, 92 mL) under ice-cooling and extracted twice with ether (100 mL each time). The ether solution was washed four times with water (50 ml each time) and then extracted five times with ice-cold aqueous sodium hydroxide solution (concentration 10%, 50 ml each time). The extract was acidified with 20% hydrochloric acid under ice-cooling and stirring to pH 2, and the precipitated crystals were separated by filtration. The crystals thus obtained were washed, dried and recrystallized with ether-hexane (1:4) to give 10.8 g of the desired compound.
IR (KBr, cm"<1>): 3000, 1682, 1498, 1259, 1210, 982. IR (KBr, cm"<1>): 3000, 1682, 1498, 1259, 1210, 982.
NMR (CDC13, ppm): 7,5 (1H, s), 6,6 (1H, s), 2,6 (3H, s), NMR (CDCl 3 , ppm): 7.5 (1H, s), 6.6 (1H, s), 2.6 (3H, s),
1,7 (6 H, s). 1.7 (6 H, p).
Trinn 3Step 3
Fremstilling av t- butyl- 2, 2, 6- trimetylbenzodioksol- 5-karboksylat Preparation of t-butyl-2,2,6-trimethylbenzodioxole-5-carboxylate
Til en suspensjon av produktet erholdt i trinn 2 (10,6 g) i benzen (50 ml) ble det tilsatt tionylklorid (15,5 ml) og N,N-dimetylformamid (2 dråper), og blandingen ble oppvarmet til 60°C i 30 min. Oppløsningsmidlet ble fjernet under redusert trykk, og residuet ble oppløst i metylenklorid (50 ml). Oppløsningen ble så tilsatt dråpevis til en is-avkjølt blanding av t-butanol (37,6 g) og pyridin (24,6 ml), og blandingen ble omrørt ved romtemperatur i 7 timer. Etter fjerning av oppløsnigsmidlet under redusert trykk ble eter (200 ml) tilsatt residuet. Eteroppløsningen ble vasket to ganger med vann (80 ml hver gang), to ganger med vandig saltsyre (IN, 80 ml hver gang), én gang med en mettet, vandig oppløsning av natriumhydrogenkarbonat (80 ml) og én gang med saltlake, og den vaskede oppløsning ble tørket over vannfritt natriumsulfat. Den tørkede oppløsning ble konsen trert under redusert trykk, og residuet ble renset ved silikagel kolonnekromatografi for å gi 11,2 g av den ønskede forbindelse. To a suspension of the product obtained in step 2 (10.6 g) in benzene (50 ml) was added thionyl chloride (15.5 ml) and N,N-dimethylformamide (2 drops) and the mixture was heated to 60°C for 30 min. The solvent was removed under reduced pressure and the residue was dissolved in methylene chloride (50 mL). The solution was then added dropwise to an ice-cooled mixture of t-butanol (37.6 g) and pyridine (24.6 mL), and the mixture was stirred at room temperature for 7 hours. After removal of the solvent under reduced pressure, ether (200 mL) was added to the residue. The ether solution was washed twice with water (80 mL each), twice with aqueous hydrochloric acid (IN, 80 mL each), once with a saturated aqueous solution of sodium bicarbonate (80 mL), and once with brine, and the washed solution was dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 11.2 g of the desired compound.
IR (KBr, cm-<1>): 2979, 1713, 1498, 1375, 1253, 1165. IR (KBr, cm-<1>): 2979, 1713, 1498, 1375, 1253, 1165.
NMR (CDC13, ppm): 7,3 (1H, s), 6,6 (1H, s), 2,5 (3H, s), NMR (CDCl 3 , ppm): 7.3 (1H, s), 6.6 (1H, s), 2.5 (3H, s),
1,7 (6 H, s), 1,6 (9 H, s). 1.7 (6H, s), 1.6 (9H, s).
Trinn 4Step 4
Fremstilling av t- butyl- 6- bromometyl- 2, 2- dimetylbenzo-dioksol- 5- karboksylat Preparation of t-butyl-6-bromomethyl-2,2-dimethylbenzo-dioxole-5-carboxylate
Til en oppløsning av produktet erholdt i trinn 3 (11,2 g) i karbontetraklorid (60 ml) ble det tilsatt N-bromosuccinimid (7,6 g) og benzoylperoksyd (30 mg), og blandingen ble kokt under tilbakeløp i 40 min. Reaksjonsblandingen ble så avkjølt til romtemperatur, og uoppløselig materiale ble fjernet ved filtrering. Filtratet ble konsentrert under redusert trykk, og residuet ble opprenset ved silikagel kolonnekromatografi for å gi 11,5 g av denønskede forbindelse . To a solution of the product obtained in step 3 (11.2 g) in carbon tetrachloride (60 ml) was added N-bromosuccinimide (7.6 g) and benzoyl peroxide (30 mg), and the mixture was refluxed for 40 min. The reaction mixture was then cooled to room temperature, and insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 11.5 g of the desired compound.
IR (KBr, cm-<1>): 2980, 1689, 1510, 1287, 1157. IR (KBr, cm-<1>): 2980, 1689, 1510, 1287, 1157.
NMR (CDCI3, ppm): 7,3 (1H, s), 6,8 (1H, s), 4,9 (2H, s), NMR (CDCl 3 , ppm): 7.3 (1H, s), 6.8 (1H, s), 4.9 (2H, s),
1,7 (6 H, s), 1,6 (9 H, s). 1.7 (6H, s), 1.6 (9H, s).
Trinn 5Step 5
Fremstilling av t- butyl- 2, 2- dimetyl- 6-( N- ftaloyloksymetyl)-benzodioksol- 5- karboksylat Preparation of t-butyl-2,2-dimethyl-6-(N-phthaloyloxymethyl)-benzodioxole-5-carboxylate
Til en oppløsning av produktet erholdt i trinn 4 (11,5 g) i acetonitril (108 ml) ble det tilsatt dråpevis en oppløsning av N-hydroksyftalimid (5,5 g) og trietylamin (4,7 ml) i acetonitril (32 ml) ved romtemperatur, og blandingen ble om-rørt i 4 timer. Reaksjonsblandingen ble helt opp i isvann og ekstrahert to ganger med etylacetat (400 ml hver gang). Det organiske lag ble vasket to ganger med en vandig opp-løsning av sitronsyre (1 N, 200 ml hver gang), fire ganger med en mettet, vandig oppløsning av natriumhydrogenkarbonat (200 ml hver gang) og to ganger med saltlake (200 ml). Den vaskede oppløsning ble tørket over vannfritt natriumsulfat. Den tørkede oppløsning ble konsentrert under redusert trykk, og residuet ble renset ved silikagel kolonnekromatografi for å gi 11,2 g av denønskede forbindelse. To a solution of the product obtained in step 4 (11.5 g) in acetonitrile (108 ml) was added dropwise a solution of N-hydroxyphthalimide (5.5 g) and triethylamine (4.7 ml) in acetonitrile (32 ml ) at room temperature, and the mixture was stirred for 4 hours. The reaction mixture was poured into ice water and extracted twice with ethyl acetate (400 ml each time). The organic layer was washed twice with an aqueous solution of citric acid (1 N, 200 ml each time), four times with a saturated aqueous solution of sodium bicarbonate (200 ml each time) and twice with brine (200 ml) . The washed solution was dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 11.2 g of the desired compound.
IR (KBr, cm-<1>): 2990, 1735, 1499, 1264, 1162, 981, 701. NMR (CDC13, ppm): 7,8 (4H, m), 7,3 (1H, s), 7,2 (1H, s), IR (KBr, cm-<1>): 2990, 1735, 1499, 1264, 1162, 981, 701. NMR (CDCl 3 , ppm): 7.8 (4H, m), 7.3 (1H, s), 7.2 (1H, s),
5,6 (2 H, s), 1,7 (6H, s), 1,5 (9 H, s). 5.6 (2H, s), 1.7 (6H, s), 1.5 (9H, s).
Trinn 6Step 6
Fremstilling av t- butyl- 6- aminooksymetyl- 2, 2- dimetylbenzo-dioksol- 5- karboksylat Preparation of t-butyl-6-aminooxymethyl-2,2-dimethylbenzo-dioxole-5-carboxylate
Til en oppløsning av produktet erholdt i trinn 5 (11,1 g) i metylenklorid (180 ml), og oppløsningen ble avkjølt til -5-30°C. Til den kalde oppløsning ble det tilsatt en oppløs-ning av metylhydrazin (1,4 ml) i metylenklorid (20 ml), og blandingen ble omrørt i 1 time med isavkjøling. Metylhydrazin (0,3 ml) ble igjen tilsatt til blandingen, og omrøring ble fortsatt i 30 min. Uoppløselig materiale ble filtrert av, og filtratet ble konsentrert under redusert trykk. Residuet ble renset ved silikagel kolonnekromatografi for å gi 7,6 g av denønskede forbindelse. To a solution of the product obtained in step 5 (11.1 g) in methylene chloride (180 ml), the solution was cooled to -5-30°C. To the cold solution was added a solution of methylhydrazine (1.4 ml) in methylene chloride (20 ml) and the mixture was stirred for 1 hour with ice cooling. Methylhydrazine (0.3 mL) was again added to the mixture and stirring was continued for 30 min. Insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7.6 g of the desired compound.
IR (KBr, cm-<1>): 3530, 2990, 1703, 1498, 1252, 1160. NMR (CDCI3, ppm): 7,3 (1 H, s), 6,9 (1 H, s), 5,7-4,8 (2 H, IR (KBr, cm-<1>): 3530, 2990, 1703, 1498, 1252, 1160. NMR (CDCl 3 , ppm): 7.3 (1 H, s), 6.9 (1 H, s), 5.7-4.8 (2H,
bs), 5,3 (2 H, s), 1,7 (6H, s), 1,6 (9 H, s) . bs), 5.3 (2H, s), 1.7 (6H, s), 1.6 (9H, s).
Trinn 7Step 7
Fremstilling av 2-(2-amino-4-tiazolyl)-2-[Z-[(5-t-butoksykarbonyl-2,2-dimetylbenzodioksol-6-yl)metyl]oksyimino]-eddiksyre Preparation of 2-(2-amino-4-thiazolyl)-2-[Z-[(5-t-butoxycarbonyl-2,2-dimethylbenzodioxol-6-yl)methyl]oxyimino]-acetic acid
Til en oppløsning av produktet erholdt i trinn 6 (7,6 g) i N,N-dimetylformamid (35 ml) ble det tilsatt (2-aminotiazol-4-yl)glyoksylsyre (4,4 g), og blandingen ble omrørt ved romtemperatur i 30 min. Reaksjonsblandingen ble konsentrert under redusert trykk, og residuet ble oppløst i etylacetat (200 ml). Oppløsningen ble vasket fire ganger med vann To a solution of the product obtained in step 6 (7.6 g) in N,N-dimethylformamide (35 ml) was added (2-aminothiazol-4-yl)glyoxylic acid (4.4 g) and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (200 mL). The solution was washed four times with water
(80 ml hver gang) og én gang med saltlake (80 ml) og tørket over vannfritt natriumsulfat. Den tørkede oppløsning ble konsentrert under redusert trykk, og residuet ble rekrystallisert med eter-heksan, (1:1) for å gi 10,2 g av den ønskede forbindelse som krystaller. (80 ml each time) and once with brine (80 ml) and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure, and the residue was recrystallized with ether-hexane, (1:1) to give 10.2 g of the desired compound as crystals.
IR (KBr, cm"<1>): 2290, 1702, 1617, 1498, 1261. IR (KBr, cm"<1>): 2290, 1702, 1617, 1498, 1261.
NMR (DMSO-d6, ppm): 7,24 (1 H, s), 7,2 (2 H, bs), 6,94 (1 H, NMR (DMSO-d6, ppm): 7.24 (1H, s), 7.2 (2H, bs), 6.94 (1H,
s), 6,86 (1 H, s), 5,4 (2 H, s), 1,7 (6H, s), 1,5 (9 H, s). s), 6.86 (1H, s), 5.4 (2H, s), 1.7 (6H, s), 1.5 (9H, s).
Trinn 8Step 8
Fremstilling av (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(5-t-butoksykarbonyl-2,2-dimetylbenzodioksol-6-yl)metyl]oksy-imino]acetamido]-3-[(2-difenylmetyloksykarbonyl-5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tiometyl]-8-okso-5-tia-l-azabicyklo[ 4, 2, 0] okt- 2- en- 2- karboksylsyre- difenylmetylester Til en oppløsning av produktet erholdt i trinn 7 (3,0 g) og (6R,7R)-7-amino-3-[(2-difenylmetyloksykarbonyl-5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tiometyl]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre-difenylmetylester (5,0 g) i metylenklorid (120 ml) ble det tilsatt N,N-di-cykloheksylkarbodiimid (1,7 g), og blandingen ble omrørt i 12 timer ved romtemperatur. Reaksjonsblandingen ble så konsentrert under redusert trykk, og residuet ble oppløst i aceton (50 ml), og uløselig materiale ble filtrert av. Filtratet ble renset ved silikagel kolonnekromatografi for å gi 5,4 g av denønskede forbindelse. Preparation of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(5-t-butoxycarbonyl-2,2-dimethylbenzodioxol-6-yl)methyl]oxy- imino]acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[ 4, 2.0] oct- 2- ene- 2- carboxylic acid- diphenyl methyl ester To a solution of the product obtained in step 7 (3.0 g) and (6R,7R)-7-amino-3-[(2-diphenylmethyloxycarbonyl-5 -methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid- diphenyl methyl ester (5.0 g) in methylene chloride (120 ml) was added N,N-dicyclohexylcarbodiimide (1.7 g) and the mixture was stirred for 12 hours at room temperature. The reaction mixture was then concentrated under reduced pressure, and the residue was dissolved in acetone (50 mL), and insoluble material was filtered off. The filtrate was purified by silica gel column chromatography to give 5.4 g of the desired compound.
IR (KBr, cm"<1>): 1791, 1700, 1498, 1377, 1223. IR (KBr, cm"<1>): 1791, 1700, 1498, 1377, 1223.
NMR (DMSO-d6, ppm): 9,8 (1 H, d, J = 8 Hz), 7,6-7,1 (25 H, NMR (DMSO-d6, ppm): 9.8 (1 H, d, J = 8 Hz), 7.6-7.1 (25 H,
m), 7,0 (1 H, s), 6,96 (1 H, s), 6,8 m), 7.0 (1 H, s), 6.96 (1 H, s), 6.8
(1 H, s), 5,9 (1 H, dd, J = 8,5 Hz), 5,4 (2 H, s), 5,3 (1 H, d, J = 5 Hz), 4,3 (1 H, s), 5.9 (1 H, dd, J = 8.5 Hz), 5.4 (2 H, s), 5.3 (1 H, d, J = 5 Hz), 4 ,3
(2 H, s), 3,7 (2 H, ABq), 2,6 (3 H, s), 1,6 (6H, s), 1,5 (9 H, s). (2H, s), 3.7 (2H, ABq), 2.6 (3H, s), 1.6 (6H, s), 1.5 (9H, s).
Trinn 9Step 9
Fremstilling av (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[ ( 2-karboksy-4,5-dihydroksyfenyl)metyl]oksyimino]acetamido] - 3-[(2-karboksy-5-metyl-s-triazolo[l,5-a]pyrimidin-7-yl)tio-metyl] -8-okso-5-tia-l-azabicyklo[ 4 ,2,0]okt-2-en-2-karboksylsyre Preparation of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-[ (2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio-methyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct- 2-ene-2-carboxylic acid
Til en suspensjon av produktet fra trinn 8 (5,4 g) i diklor-etan (3,5 ml) ble det tilsatt anisol (3,5 g). Til blandingen ble det tilsatt trifluoreddiksyre (14 ml) under isavkjøling, og den resulterende blanding ble omrørt ved romtemperatur i 6 timer. Reaksjonsblandingen ble så helt opp i eter (300 ml). De utfelte krystaller ble suspendert i vann (45 ml), og pH til suspensjonen ble justert til 8,2 med natriumhydrogenkarbonat. Den resulterende oppløsning ble påført en Diaion HP-20-kolonne og eluert med vann. Frak-sjoner som inneholdt den ønskede forbindelse, ble samlet opp og konsentrert under redusert trykk. Residuet ble rekrystallisert ved å helle dette opp i etanol (70 ml) for å gi 1,6 g av de rensede krystaller. To a suspension of the product from step 8 (5.4 g) in dichloroethane (3.5 ml) was added anisole (3.5 g). To the mixture was added trifluoroacetic acid (14 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was then poured into ether (300 mL). The precipitated crystals were suspended in water (45 ml), and the pH of the suspension was adjusted to 8.2 with sodium bicarbonate. The resulting solution was applied to a Diaion HP-20 column and eluted with water. Fractions containing the desired compound were collected and concentrated under reduced pressure. The residue was recrystallized by pouring it into ethanol (70 mL) to give 1.6 g of the purified crystals.
IR (KBr, cm"<1>): 1762, 1598, 1515, 1376, 1314. IR (KBr, cm"<1>): 1762, 1598, 1515, 1376, 1314.
NMR (D20, ppm): 7,2 (1 H, s), 7,1 (1 H, s), 7,0 (2 H, s), NMR (D 2 O, ppm): 7.2 (1 H, s), 7.1 (1 H, s), 7.0 (2 H, s),
5,7 (1 H, d, J = 5 Hz), 5,4 (2 H, s), 5,1 (1 H, d, J = 5 Hz), 4,3 (2 H, ABq), 3,5 5.7 (1 H, d, J = 5 Hz), 5.4 (2 H, s), 5.1 (1 H, d, J = 5 Hz), 4.3 (2 H, ABq), 3.5
(2 H, ABq), 2,6 (3H, s).(2H, ABq), 2.6 (3H, s).
Eksempel 2Example 2
Fremstilling av (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy-4,5-dihydroksyfeny1)metyl]oksyimino]acetamido]-3-[(2-karboksy-5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tio-metyl] -8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre Preparation of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-[ (2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio-methyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct- 2-ene-2-carboxylic acid
Trinn 1Step 1
Fremstilling av etyl-2-(2-amino-4-tiazolyl)-2-[Z-[(5-t-butoksykarbonyl-2,2-dimetylbenzodioksol-6-yl)metyl]oksy-imino] acetat Preparation of ethyl 2-(2-amino-4-thiazolyl)-2-[Z-[(5-t-butoxycarbonyl-2,2-dimethylbenzodioxol-6-yl)methyl]oxy-imino] acetate
Til en oppløsning av etyl-2-(2-amino-4-tiazolyl)-2-(Z-hyd- roksyimino)acetat (lg) i tørr dimetylformamid (10 ml) ble det tilsatt 60 % vandig oppløsning av natriumhydrid (200 mg) under isavkjøling, og blandingen ble omrørt i 15 min. Til A 60% aqueous solution of sodium hydride (200 mg ) under ice-cooling, and the mixture was stirred for 15 min. To
blandingen ble det tilsatt dråpevis en oppløsning av produktet erholdt i eksempel 1, trinn 4 (1,9 g) i dimetylformamid (10 ml). Blandingen ble omrørt under isavkjøling i 1,5 time. Reaksjonsblandingen ble så helt opp i en isavkjølt blanding av konsentrert saltsyre og etylacetat (200 ml hver gang) og omrørt grundig. Det organiske lag ble separert og vasket én gang med mettet, vandig oppløsning av natriumhydrogenkarbonat (100 ml) og to ganger med saltlake (100 ml). Den vaskede oppløsning ble tørket over vannfritt natriumsulfat. Den tørkede oppløsning ble konsentrert under redusert trykk, og residuet ble rekrystallisert med heksan (50 ml) for å gi 1,85 g av den ønskede forbindelse. to the mixture was added dropwise a solution of the product obtained in Example 1, step 4 (1.9 g) in dimethylformamide (10 ml). The mixture was stirred under ice cooling for 1.5 hours. The reaction mixture was then poured into an ice-cooled mixture of concentrated hydrochloric acid and ethyl acetate (200 ml each time) and stirred thoroughly. The organic layer was separated and washed once with saturated aqueous sodium bicarbonate solution (100 mL) and twice with brine (100 mL). The washed solution was dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure and the residue was recrystallized with hexane (50 mL) to give 1.85 g of the desired compound.
NMR (CDC13, ppm): 7,3 (1H, s), 6,9 (1H, s), 6,7 (1H, s), NMR (CDCl 3 , ppm): 7.3 (1H, s), 6.9 (1H, s), 6.7 (1H, s),
5,7 (2 H, bs), 5,6 (2 H, s), 4,4 (2 H, q, J = 7 Hz), 1,7 (6 H, s), 1,6 (9 H, s), 1,4 (3 H, t, J = 7 Hz). 5.7 (2 H, bs), 5.6 (2 H, s), 4.4 (2 H, q, J = 7 Hz), 1.7 (6 H, s), 1.6 (9 H, s), 1.4 (3 H, t, J = 7 Hz).
Trinn 2Step 2
Fremstilling av 2-(2-amino-4-tiazolyl)-2-[Z-[(5-t-butoksykarbonyl-2,2-dimetylbenzodioksol-6-yl)metyl]oksyimino]eddiksyre Preparation of 2-(2-amino-4-thiazolyl)-2-[Z-[(5-t-butoxycarbonyl-2,2-dimethylbenzodioxol-6-yl)methyl]oxyimino]acetic acid
Til en suspensjon av produktet fra trinn 1 (lg) i etanol ble det tilsatt en vandig oppløsning av natriumhydroksyd (konsentrasjon 2 N, 2,1 ml), og blandingen ble omrørt i 2 timer ved romtemperatur og så i 1 time ved 63°C. Reaksjonsblandingen konsentrert under redusert trykk, og vann (20 ml) ble tilsatt til residuet. Blandingen ble surgjort med vandig saltsyre (1 N) til pH 3 og ekstrahert med etylacetat (50 ml). Ekstraktet ble vasket to ganger med saltlake (30 ml hver gang) og tørket over vannfritt natrium-sulf at. Den tørkede oppløsning ble konsentrert under redusert trykk, og residuet ble rekrystallisert med eter-heksan (1:1, 30 ml) for å gi 870 mg av denønskede forbindelse som krystaller. To a suspension of the product from step 1 (1g) in ethanol was added an aqueous solution of sodium hydroxide (concentration 2 N, 2.1 ml) and the mixture was stirred for 2 hours at room temperature and then for 1 hour at 63°C . The reaction mixture was concentrated under reduced pressure, and water (20 mL) was added to the residue. The mixture was acidified with aqueous hydrochloric acid (1 N) to pH 3 and extracted with ethyl acetate (50 mL). The extract was washed twice with brine (30 ml each time) and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure and the residue was recrystallized with ether-hexane (1:1, 30 mL) to give 870 mg of the desired compound as crystals.
IR (KBr, cm-<1>): 2290, 1617, 1498, 1261. IR (KBr, cm-<1>): 2290, 1617, 1498, 1261.
NMR (DMSO-d6, ppm): 7,24 (1 H, s), 7,2 (2 H, bs), 6,94 (1 H, NMR (DMSO-d6, ppm): 7.24 (1H, s), 7.2 (2H, bs), 6.94 (1H,
s), 6,86, 5,4 (2 H, s), 1,7 (6 H, s), 1,5 (9 H, s). s), 6.86, 5.4 (2H, s), 1.7 (6H, s), 1.5 (9H, s).
Disse data er i fullstendig overensstemmelse med dem i trinn 7 i eksempel 1. These data are in complete agreement with those in step 7 of Example 1.
Trinn 3Step 3
Fremstilling av (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy-4,5-dihydroksyf enyl)metyl]oksyimino]acetamido]-3-[(2-karboksy-5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tio-metyl] -8-okso-5-tia-l-azabicyklo[ 4 ,2,0]okt-2-en-2-karboksylsyre Preparation of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxyimino]acetamido]-3- [(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio-methyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct -2-ene-2-carboxylic acid
Tittelforbindelsen angitt ovenfor ble fremstilt fra produktet i trinn 2, ifølge fremgangsmåtene i trinnene 8 og 9 i eksempel 1. The title compound indicated above was prepared from the product of Step 2, according to the procedures of Steps 8 and 9 of Example 1.
IR (KBr, cm-<1>): 1762, 1598, 1515, 1376, 1314. IR (KBr, cm-<1>): 1762, 1598, 1515, 1376, 1314.
NMR (D20, ppm): 7,2 (1 H, s), 7,1 (1 H, s), 7,0 (2 H, s), NMR (D 2 O, ppm): 7.2 (1 H, s), 7.1 (1 H, s), 7.0 (2 H, s),
5,7 (1 H, d, J = 5 Hz), 5,4 (2 H, s), 5,1 (1 H, d, J = 5 Hz), 4,3 (2 H, ABq), 3,5 (2 H, ABq), 2,6 (3H, s). 5.7 (1 H, d, J = 5 Hz), 5.4 (2 H, s), 5.1 (1 H, d, J = 5 Hz), 4.3 (2 H, ABq), 3.5 (2H, ABq), 2.6 (3H, s).
Disse data er i fullstendig overensstemmelse med dem i trinn 9 i eksempel 1. These data are in complete agreement with those in step 9 of Example 1.
Ifølge fremgangsmåten beskrevet i eksempel 1, ble forbindelser av eksempler 3 og 4, beskrevet nedenfor, fremstilt. Ifølge fremgangsmåten beskrevet i eksempel 2, ble forbindelser av eksempler 5 og 6 fremstilt. According to the method described in Example 1, compounds of Examples 3 and 4, described below, were prepared. According to the procedure described in Example 2, compounds of Examples 5 and 6 were prepared.
Eksempel 3 Example 3
(6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy-4,5-dihydroksyfenyl)metyl]oksyimino]acetamido]-3-[(5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tiometyl]-8-okso-5-tia-l-azabicyklo[ 4, 2, 0] okt- 2- en- 2- karboksylsyre (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-[(5 -methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid
IR (KBr, cm"<1>): 1762, 1595, 1514, 1380. IR (KBr, cm"<1>): 1762, 1595, 1514, 1380.
NMR (D20, ppm): 8,5 (1 H, s), 7,2 (1 H, s), 7,1 (1 H, s), NMR (D2O, ppm): 8.5 (1H, s), 7.2 (1H, s), 7.1 (1H, s),
7,0 (2 H, s), 5,7 (1 H, d, J = 5 Hz), 5,4 (2 H, s), 5,1 (1 H, d, J = 5 Hz), 4,3 (2 H, ABq), 3,5 (2 H, ABq), 2,6 (3H, s). 7.0 (2 H, s), 5.7 (1 H, d, J = 5 Hz), 5.4 (2 H, s), 5.1 (1 H, d, J = 5 Hz), 4.3 (2H, ABq), 3.5 (2H, ABq), 2.6 (3H, s).
Eksempel 4 Example 4
(6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy-4,5-dihydroksyfenyl)metyl]oksyimino]acetamido]-3-[(5-karboksy-s-triazolo[1,5-a]pyrimidin-7-yl)tiometyl]-8-okso-5-tia-l-azabicyklo[ 4, 2, 0] okt- 2- en- 2- karboksylsyre (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-[(5 -carboxy-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid
IR (KBr, cm"<1>): 1762, 1595, 1534, 1396. IR (KBr, cm"<1>): 1762, 1595, 1534, 1396.
NMR (D20, ppm): 8,5 (1 H, s), 7,3 (1 H, s), 7,1 (1 H, s), NMR (D2O, ppm): 8.5 (1H, s), 7.3 (1H, s), 7.1 (1H, s),
7,0 (2 H, s), 5,7 (1 H, d, J = 5 Hz), 5,4 (2 H, s), 5,1 (1 H, d, J = 5 Hz), 4,3 (2 H, ABq), 3,5 (2 H, ABq). 7.0 (2 H, s), 5.7 (1 H, d, J = 5 Hz), 5.4 (2 H, s), 5.1 (1 H, d, J = 5 Hz), 4.3 (2H, ABq), 3.5 (2H, ABq).
Eksempel 5 Example 5
(6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy-4,5-dihydroksyfenyl)metyl]oksyimino]acetamido]-3-[(5-karboksy-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tiometyl]-8-okso-5-tia- l- azabicyklo[ 4, 2, 0] okt- 2- en- 2- karboksylsyre IR (KBr, cm"<1>): 1762, 1595, 1515, 1390. (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-[(5 -carboxy-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia- l- azabicyclo[ 4, 2, 0] oct- 2- en- 2- carboxylic acid IR (KBr, cm"<1>): 1762, 1595, 1515, 1390.
NMR (D20, ppm): 8,5 (1 H, s), 7,2 (1 H, s), 7,1 (1 H, s), NMR (D2O, ppm): 8.5 (1H, s), 7.2 (1H, s), 7.1 (1H, s),
7,0 (2 H, s), 5,7 (1 H, d, J = 5 Hz), 5,4 (2 H, s), 5,1 (1 H, d, J = 5 Hz), 4,3 (2 H, ABq), 3,5 (2 H, ABq), 2,6 (2 H, s). 7.0 (2 H, s), 5.7 (1 H, d, J = 5 Hz), 5.4 (2 H, s), 5.1 (1 H, d, J = 5 Hz), 4.3 (2H, ABq), 3.5 (2H, ABq), 2.6 (2H, s).
Eksempel 6 Example 6
(6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy-4,5-dihydroksyfenyl)metyl]oksyimino]acetamido]-3-[(2-hydroksy-sulfonyl-5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tiometyl]-8- okso- 5- tia- l- azabicyklo[ 4, 2, 0] okt- 2- en- 2- karboksylsyre IR (KBr, cm"<1>): 1763, 1596, 1510, 1395, 1368. (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-[(2 -hydroxy-sulfonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8- oxo- 5- thia- l- azabicyclo[ 4, 2, 0] oct- 2- ene-2-carboxylic acid IR (KBr, cm"<1>): 1763, 1596, 1510, 1395, 1368.
NMR (D20, ppm): 7,2 (1 H, s), 7,1 (1 H, s), 7,0 (2 H, s), NMR (D 2 O, ppm): 7.2 (1 H, s), 7.1 (1 H, s), 7.0 (2 H, s),
5,7 (1 H, d, J = 5 Hz), 5,4 (2 H, s), 5,1 (1 H, d, J = 5 Hz), 4,3 (2 H, ABq), 3,5 (2 H, ABq), 2,6 (3 H, s). 5.7 (1 H, d, J = 5 Hz), 5.4 (2 H, s), 5.1 (1 H, d, J = 5 Hz), 4.3 (2 H, ABq), 3.5 (2 H, ABq), 2.6 (3 H, s).
Eksempel 7Example 7
Fremstilling av maursyresolvatet av (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy-4,5-dihydroksyfenyl)metyl]oksy-imino ]acetamido]-3-[(2-karboksy-5-metyl-s-triazolo[1,5-a]-pyrimidin-7-yl)tiometyl]-8-okso-5-tia-l-azabicyklo[4,2,0]-okt- 2- en- 2- karboksylsyre Preparation of the formic acid solvate of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxy-imino ]acetamido] -3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]-pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4,2,0 ]-oct- 2- en- 2- carboxylic acid
Trifluoreddiksyresalt av (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy-4,5-dihydroksyfenyl)metyl]oksyimino]acetamido] -3-[(2-karboksy-5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tiometyl]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre (3,0 g) ble oppløst i maursyre (15 ml) ved romtemperatur. Til blandingen ble det tilsatt vann (15 ml), og blandingen ble tillatt å stå 1 time ved romtemperatur. Ytterligere 5 ml vann ble tilsatt, og blandingen ble omrørt i 30 min. ved romtemperatur. Til blandingen ble det tilsatt kjernekrystaller, og omrøring ble fortsatt i 1 time. Utfelte krystaller ble separert ved filtrering, vasket med vann (20 ml) og lufttørket for å gi 1,95 g av den ønskede forbindelse. Trifluoroacetic acid salt of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxyimino]acetamido] -3-[ (2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2- ene-2-carboxylic acid (3.0 g) was dissolved in formic acid (15 mL) at room temperature. To the mixture was added water (15 ml) and the mixture was allowed to stand for 1 hour at room temperature. A further 5 ml of water was added and the mixture was stirred for 30 min. at room temperature. To the mixture was added core crystals, and stirring was continued for 1 hour. Precipitated crystals were separated by filtration, washed with water (20 mL) and air dried to give 1.95 g of the desired compound.
IR (Nujol, cm-<1>): 3600-2200, 3269, 1770, 1654, 1596, 1517, IR (Nujol, cm-<1>): 3600-2200, 3269, 1770, 1654, 1596, 1517,
1509, 1303, 1188, 1159, 1101, 1061, 1509, 1303, 1188, 1159, 1101, 1061,
1025, 962, 904, 853, 794, 770. 1025, 962, 904, 853, 794, 770.
NMR (DMSO-d6, ppm): 9,61 (1 H, d, J = 8 Hz), 9,44 (1 H, bs), NMR (DMSO-d 6 , ppm): 9.61 (1 H, d, J = 8 Hz), 9.44 (1 H, bs),
9,18 (1 H, bs), 8,12 (s, HCOOH), 7,40 (1 H, s), 7,35 (1 H, s), 7,17 (2 H, s), 6,89 (1 H, s), 6,75 (1 H, s), 5,88 (1 H, dd, J = 8, 4 Hz), 5,39 (2 H, s), 5,20 (1 H, d, J = 4 Hz), 4,43 (2 H, s), 3,70 (2 9.18 (1H, bs), 8.12 (s, HCOOH), 7.40 (1H, s), 7.35 (1H, s), 7.17 (2H, s), 6 .89 (1 H, s), 6.75 (1 H, s), 5.88 (1 H, dd, J = 8, 4 Hz), 5.39 (2 H, s), 5.20 ( 1 H, d, J = 4 Hz), 4.43 (2 H, s), 3.70 (2
H, ABq), 2,62 (3 H, s). H, ABq), 2.62 (3 H, s).
Røntgenstrålediffraksjonsmønster (gitt som d-avstander i Ångstrøm-enheter og prosentvise intensiteter): X-ray diffraction pattern (given as d-spacings in Angstrom units and percentage intensities):
Eksempel 8 Example 8
Fremstilling av maursyresolvatet av (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy-4,5-dihydroksyfenyl)metyl]oksy-imino ] acetamido] -3- [ (2-karboksy-5-metyl-s-triazolo[1,5-a]-pyrimidin-7-yl)tiometyl]-8-okso-5-tia-l-azabicyklo[4,2,0]-okt- 2- en- 2- karboksylsyre Preparation of the formic acid solvate of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxy-imino]acetamido] -3- [ (2-carboxy-5-methyl-s-triazolo[1,5-a]-pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4,2,0 ]-oct- 2- en- 2- carboxylic acid
Trinatriumsalt av (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-t(2-karboksy-4,5-dihydroksyfenyl)metyl]oksyimino]acetamido]-3-[(2-karboksy-5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tio-metyl] -8-okso-5-tia-l-azabicyklo[ 4 ,2,0]okt-2-en-2-karboksylsyre (1,1 g) ble oppløst i vann (3 ml), og maursyre (1,5 ml) og vann (2 ml) ble tilsatt til oppløsningen. Blandingen ble omrørt i 5 min. ved romtemperatur. Ytterligere 5 ml vann ble tilsatt, og blandingen ble omrørt i 30 min. ved 0°C. Utfelte krystaller ble separert ved filtrering, vasket med vann (5 ml) og lufttørket for å gi 0,98 g av den ønskede forbindelse. Trisodium salt of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-t(2-carboxy-4,5-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-[(2 -carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio-methyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2- ene-2-carboxylic acid (1.1 g) was dissolved in water (3 ml), and formic acid (1.5 ml) and water (2 ml) were added to the solution. The mixture was stirred for 5 min. at room temperature. A further 5 ml of water was added and the mixture was stirred for 30 min. at 0°C. Precipitated crystals were separated by filtration, washed with water (5 ml) and air dried to give 0.98 g of the desired compound.
IR (Nujol, cm-<1>): 3600-2200, 3255, 1764, 1701, 1653, 1597, IR (Nujol, cm-<1>): 3600-2200, 3255, 1764, 1701, 1653, 1597,
1542, 1517, 1305, 1268, 1220, 1203, 1186, 2272, 1157, 1103, 1065, 1020, 962, 1542, 1517, 1305, 1268, 1220, 1203, 1186, 2272, 1157, 1103, 1065, 1020, 962,
907, 852, 795, 771. 907, 852, 795, 771.
NMR (DMS0-d6, ppm): 9,61 (1 H, d, J = 8 Hz), 9,44 (1 H, bs), NMR (DMS0-d6, ppm): 9.61 (1 H, d, J = 8 Hz), 9.44 (1 H, bs),
9,18 (1 H, bs), 8,12 (s, HCOOH), 7,40 (1 H, s), 7,35 (1 H, s), 7,17 (2 H, s), 6,89 (1 H, s), 6,75 (1 H, s), 5,88 (1 H, dd, J = 8, 4 Hz), 5,39 (2 H, s), 5,20 (1 H, d, J = 4 Hz), 4,43 (2 H, s), 3,70 (2 9.18 (1H, bs), 8.12 (s, HCOOH), 7.40 (1H, s), 7.35 (1H, s), 7.17 (2H, s), 6 .89 (1 H, s), 6.75 (1 H, s), 5.88 (1 H, dd, J = 8, 4 Hz), 5.39 (2 H, s), 5.20 ( 1 H, d, J = 4 Hz), 4.43 (2 H, s), 3.70 (2
H, ABq), 2,62 (3 H, s). H, ABq), 2.62 (3 H, s).
Røntgenstrålediffraksjonsmønster (gitt som d-avstander i Ångstrøm-enheter og prosentvise intensiteter): X-ray diffraction pattern (given as d-spacings in Angstrom units and percentage intensities):
Eksempel 9 Example 9
Fremstilling av hydrat av (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy-4,5-dihydroksyfenyl)metyl]oksyimino]acetamido] -3- [ (2-karboksy-5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tiometyl]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre Preparation of hydrate of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxyimino]acetamido]-3 - [ (2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct- 2-ene-2-carboxylic acid
Trifluoreddiksyresalt av (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy-4,5-dihydroksyfenyl)metyl]oksyimino]acetamido] -3- [ (2-karboksy-5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tiometyl]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre (3,0 g) ble oppløst i maursyre (15 ml) ved rom temperatur. Til blandingen ble det tilsatt vann (15 ml), og blandingen ble omrørt i 1 time ved romtemperatur. Ytterligere 5 ml vann ble tilsatt, og blandingen ble omrørt i 30 min. ved romtemperatur. Til blandingen ble det tilsatt kjernekrystaller og vann (10 ml), og omrøring ble fortsatt i 1 time. Utfelte krystaller ble separert ved filtrering, vasket én gang med vann (20 ml) og én gang ved omrøring i 30 ml vann og lufttørket for å gi 1,85 g av den ønskede forbindelse. Trifluoroacetic acid salt of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxyimino]acetamido] -3- [ (2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2- ene-2-carboxylic acid (3.0 g) was dissolved in formic acid (15 ml) at room temperature. To the mixture was added water (15 ml) and the mixture was stirred for 1 hour at room temperature. A further 5 ml of water was added and the mixture was stirred for 30 min. at room temperature. To the mixture was added core crystals and water (10 ml) and stirring was continued for 1 hour. Precipitated crystals were separated by filtration, washed once with water (20 ml) and once by stirring in 30 ml of water and air dried to give 1.85 g of the desired compound.
IR (Nujol, cm-<1>): 3600-2200, 3261, 1768, 1653, 1595, 1517, IR (Nujol, cm-<1>): 3600-2200, 3261, 1768, 1653, 1595, 1517,
1509, 1305, 1269, 1188, 1158, 1103, 1509, 1305, 1269, 1188, 1158, 1103,
1063, 1024, 962, 903, 853, 795, 770. NMR (DMSO-d6, ppm): 9,54 (1 H, d, J = 8 Hz), 7,41 (1 H, s), 1063, 1024, 962, 903, 853, 795, 770. NMR (DMSO-d 6 , ppm): 9.54 (1 H, d, J = 8 Hz), 7.41 (1 H, s),
7,36 (1 H, s), 7,4-6,9 (2 H, bs), 6,76 (1 H, s), 5,81 (1 H, dd, J = 8, 5 Hz), 5,39 (2 H, s), 5,21 (1 H, d, J = 5 Hz), 4,43 (2 H, bs), 4,1 (2 H, bs), 2,6 (3 H, s) . 7.36 (1 H, s), 7.4-6.9 (2 H, bs), 6.76 (1 H, s), 5.81 (1 H, dd, J = 8, 5 Hz) , 5.39 (2 H, s), 5.21 (1 H, d, J = 5 Hz), 4.43 (2 H, bs), 4.1 (2 H, bs), 2.6 ( 3H, s) .
Røntgenstrålediffraksjonsmønster (gitt som d-avstander i Ångstrøm-enheter og prosentvise intensiteter): X-ray diffraction pattern (given as d-spacings in Angstrom units and percentage intensities):
Eksempel 10 Example 10
Fremstilling av hydrat av (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2- [Z-[(2-karboksy-4,5-dihydroksyfenyl)metyl]oksyimino]acetamido] -3- [ (2-karboksy-5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tiometyl]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre Preparation of hydrate of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxyimino]acetamido]-3 - [ (2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct- 2-ene-2-carboxylic acid
Trinatriumsalt av (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy-4,5-dihydroksyfenyl)metyl]oksyimino]acetamido]-3- [(2-karboksy-5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tio-metyl] -8-okso-5-tia-l-azabicyklo[ 4 ,2,0]okt-2-en-2-karboksylsyre (1,1 g) ble oppløst i vann (3 ml), og maursyre (1,5 ml) ble tilsatt til oppløsningen. Blandingen ble omrørt i 5 min. ved romtemperatur. Ytterligere 5 ml vann ble tilsatt, og blandingen ble omrørt i 30 min. ved 0°C. Utfelte krystaller ble separert ved filtrering og vasket med vann (en gang hver med 2 og 1 ml). Til oppløsningen ble det tilsatt vann (15 ml), og blandingen ble omrørt i 1 time ved romtemperatur. Utfelte krystaller ble separert ved filtrering, vasket én gang med vann (20 ml) og én gang ved omrøring i 30 ml vann og lufttørket for å gi 0,89 g av den ønskede forbindelse . Trisodium salt of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxyimino]acetamido]-3- [ (2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio-methyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct- 2-ene-2-carboxylic acid (1.1 g) was dissolved in water (3 mL), and formic acid (1.5 mL) was added to the solution. The mixture was stirred for 5 min. at room temperature. A further 5 ml of water was added and the mixture was stirred for 30 min. at 0°C. Precipitated crystals were separated by filtration and washed with water (once each with 2 and 1 ml). To the solution was added water (15 ml) and the mixture was stirred for 1 hour at room temperature. Precipitated crystals were separated by filtration, washed once with water (20 ml) and once by stirring in 30 ml of water and air dried to give 0.89 g of the desired compound.
IR (Nujol, cm-<1>): 3600-2200, 3275, 1769, 1652, 1596, 1542, IR (Nujol, cm-<1>): 3600-2200, 3275, 1769, 1652, 1596, 1542,
1521, 1519, 1307, 1272, 1190, 1160, 1103, 1064, 1026, 964, 901, 854, 795, 1521, 1519, 1307, 1272, 1190, 1160, 1103, 1064, 1026, 964, 901, 854, 795,
770. 770.
NMR (DMSO-d6, ppm): 9,54 (1 H, d, J = 8 Hz), 7,41 (1 H, s), NMR (DMSO-d 6 , ppm): 9.54 (1 H, d, J = 8 Hz), 7.41 (1 H, s),
7,36 (1 H, s), 6,89 (1 H, s), 7,4-6,9 (2 H, bs), 6,76 (1 H, s), 5,81 (1 H, dd, J = 8, 5 Hz), 5,39 (2 H, s), 5,21 (1 H, d, J = 5 Hz), 4,43 (2 H, bs), 4,1 (2 H, bs), 2,6 (3 H, s). 7.36 (1 H, s), 6.89 (1 H, s), 7.4-6.9 (2 H, bs), 6.76 (1 H, s), 5.81 (1 H , dd, J = 8, 5 Hz), 5.39 (2 H, s), 5.21 (1 H, d, J = 5 Hz), 4.43 (2 H, bs), 4.1 ( 2 H, bs), 2.6 (3 H, s).
Røntgenstrålediffraksjonsmønster (gitt som d-avstander i Ångstrøm-enheter og prosentvise intensiteter): X-ray diffraction pattern (given as d-spacings in Angstrom units and percentage intensities):
Eksempel 11 Example 11
Fremstilling av hydrat av (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2- [Z-[(2-karboksy-4,5-dihydroksyfenyl)metyl]oksyimino]acetamido] -3- [ (2-karboksy-5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tiometyl]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre Preparation of hydrate of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxyimino]acetamido]-3 - [ (2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct- 2-ene-2-carboxylic acid
Maursyresolvat av (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy-4,5-dihydroksyfenyl)metyl]oksyimino]acetamido]-3- [(2-karboksy-5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tio-metyl] -8-okso-5-tia-l-azabicyklo[ 4, 2 ,0]okt-2-en-2-karboksylsyre (1,85 g), erholdt i enten eksempel 7 eller 8, ble opp-løst i maursyre (10 ml). Til oppløsningen ble det tilsatt vann (12 ml), og blandingen ble omrørt i 30 min. ved romtemperatur. Ytterligere 10 ml vann ble tilsatt, og blandingen ble omrørt i 1 time ved romtemperatur. Utfelte krystaller ble separert ved filtrering, vasket med vann (30 ml) og lufttørket for å gi 0,89 g av den ønskede forbindelse. Formic acid solvate of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxyimino]acetamido]-3- [ (2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio-methyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct- 2-ene-2-carboxylic acid (1.85 g), obtained in either Example 7 or 8, was dissolved in formic acid (10 ml). To the solution was added water (12 ml) and the mixture was stirred for 30 min. at room temperature. Another 10 ml of water was added and the mixture was stirred for 1 hour at room temperature. Precipitated crystals were separated by filtration, washed with water (30 mL) and air dried to give 0.89 g of the desired compound.
IR (Nujol, cm-<1>): 3600-2200, 3275, 1769, 1652, 1596, 1542, IR (Nujol, cm-<1>): 3600-2200, 3275, 1769, 1652, 1596, 1542,
1521, 1519, 1307, 1272, 1190, 1160, 1521, 1519, 1307, 1272, 1190, 1160,
1103, 1064, 1026, 964, 901, 854, 795, 1103, 1064, 1026, 964, 901, 854, 795,
770. 770.
NMR (DMSO-d6, ppm): 9,54 (1 H, d, J = 8 Hz), 7,41 (1 H, s), NMR (DMSO-d 6 , ppm): 9.54 (1 H, d, J = 8 Hz), 7.41 (1 H, s),
7,36 (1 H, s), 6,89 (1 H, s), 7,4-6,9 (2 H, bs), 6,76 (1 H, s), 5,81 (1 H, dd, J = 8, 5 Hz), 5,39 (2 H, s), 5,21 (1 H, d, J = 5 Hz), 4,43 (2 H, bs), 4,1 (2 H, bs), 2,6 (3 H, s). 7.36 (1 H, s), 6.89 (1 H, s), 7.4-6.9 (2 H, bs), 6.76 (1 H, s), 5.81 (1 H , dd, J = 8, 5 Hz), 5.39 (2 H, s), 5.21 (1 H, d, J = 5 Hz), 4.43 (2 H, bs), 4.1 ( 2 H, bs), 2.6 (3 H, s).
Røntgenstrålediffraksjonsmønster (gitt som d-avstander i Ångstrøm-enheter og prosentvise intensiteter): X-ray diffraction pattern (given as d-spacings in Angstrom units and percentage intensities):
De følgende eksempler beskriver utførlig typiske farma-søytiske preparater inneholdende cefalosporinderivatene ifølge foreliggende oppfinnelse. Disse eksempler er ikke ment å begrense typer av forbindelser som anvendes, men fremgangsmåtene er anvendelige for alle forbindelsene ifølge foreliggende oppfinnelse. The following examples describe in detail typical pharmaceutical preparations containing the cephalosporin derivatives according to the present invention. These examples are not intended to limit the types of compounds used, but the methods are applicable to all the compounds according to the present invention.
Eksempel A (Fremgangsmåte for fremstilling av parenterale injeksjoner) Example A (Procedure for the preparation of parenteral injections)
(6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy-4,5-dihydroksyfenyl)metyl]oksyimino]acetamido]-3-[(2-karboksy-5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tiometyl]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre (500 g) og 3 ekvivalente mengder av natriumhydrogenkarbonat ble blandet homogent og fordelt i 15 ml's lufttette beholdere, som hver veide 500 mg, ved vanlige fremgangsmåter. (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-[(2 -carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene- 2-Carboxylic acid (500 g) and 3 equivalent amounts of sodium bicarbonate were mixed homogeneously and dispensed into 15 ml airtight containers, each weighing 500 mg, by standard methods.
Eksempel B (Fremgangsmåte for fremstilling av frysetørkede parenterale injeksjoner) Example B (Procedure for the manufacture of freeze-dried parenteral injections)
(6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy-4,5-dihydroksyfenyl)metyl]oksyimino]acetamido]-3-[(2-karboksy-5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tiometyl]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre-trinatriumsalt (550 g) ble oppløst i 2,2 1 sterilt vann, og 2 ml hver av denne oppløsning ble helt opp i 10 ml's ampuller, fryse-tørket og forseglet ved vanlige fremgangsmåter for å frem-bringe et frysetørket preparat for parenterale injeksjoner. (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-[(2 -carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene- 2-Carboxylic acid trisodium salt (550 g) was dissolved in 2.2 L of sterile water, and 2 ml each of this solution was poured into 10 ml ampoules, lyophilized and sealed by conventional methods to produce a lyophilized preparation for parenteral injections.
Eksempel C (Fremgangsmåte for fremstilling av frysetørkede parenterale injeksjoner) Example C (Procedure for the manufacture of freeze-dried parenteral injections)
(6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy-4,5-dihydroksyfenyl)metyl]oksyimino]acetamido]-3-[(5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tiometyl]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre-trinatriumsalt (500 g) ble oppløst i 1,0 1 sterilt vann, og 2 ml hver av denne oppløsning ble helt opp i 10 ml's ampuller, fryse-tørket og forseglet ved vanlige fremgangsmåter for å frem-bringe et frysetørket preparat for parenterale injeksjoner. (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-[(5 -methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid- trisodium salt (500 g) was dissolved in 1.0 L of sterile water, and 2 ml each of this solution was poured into 10 ml ampoules, lyophilized and sealed by conventional methods to produce a lyophilized preparation for parenteral injections.
Eksempel D (Fremgangsmåte for fremstilling av tabletter for oral administrering) Example D (Procedure for the preparation of tablets for oral administration)
Granuler ble fremstilt ved vanlige fremgangsmåter ved å anvende 100 g (6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy-4,5-dihydroksyfeny1)metyl]oksyimino]acetamido]-3-[(5-karboksymetyl-s-triazolo[1,5-a]pyrimidin-7-yl)tiometyl]- 8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre, 100 g laktose, 30 g stiveles og 10 g polyvinylpyrrolidon. Stivelse (30 g) og magnesiumstearat (5 g) ble ytterligere tilsatt til granulene, og den resulterende blanding ble presset til tabletter som hver veide 275 mg. Granules were prepared by conventional methods using 100 g of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl ]oxyimino]acetamido]-3-[(5-carboxymethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]- 8-oxo-5-thia-1-azabicyclo[4,2,0 ]oct-2-ene-2-carboxylic acid, 100 g of lactose, 30 g of starch and 10 g of polyvinylpyrrolidone. Starch (30 g) and magnesium stearate (5 g) were further added to the granules and the resulting mixture was compressed into tablets weighing 275 mg each.
Eksempel E (Fremgangsmåte for fremstilling av gelatinkapsler for oral administrering) Example E (Procedure for the preparation of gelatin capsules for oral administration)
(6R,7R)-7-[2-(2-amino-4-tiazolyl)-2-[Z-[(2-karboksy-4,5-dihydroksyfenyl)metyl]oksyimino]acetamido]-3-[(2-karboksy-5-metyl-s-triazolo[1,5-a]pyrimidin-7-yl)tiometyl]-8-okso-5-tia-l-azabicyklo[4,2,0]okt-2-en-2-karboksylsyre (100 g), vannoppløselig polyvinylpyrrolidon (15 g), mannitol (15 g), talkum (15 g) og magnesiumstearat (5 g) ble blandet homogent og fylt opp i gelatinkapsler som hver veide 150 mg. (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-[(2-carboxy-4,5-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-[(2 -carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene- 2-carboxylic acid (100 g), water-soluble polyvinylpyrrolidone (15 g), mannitol (15 g), talc (15 g) and magnesium stearate (5 g) were mixed homogeneously and filled into gelatin capsules each weighing 150 mg.
Claims (23)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61280019A JPS63132893A (en) | 1986-11-25 | 1986-11-25 | Novel cephalosporin derivative, production thereof and antibacterial agent containing said derivative as active ingredient |
| PCT/JP1987/000902 WO1988003924A1 (en) | 1986-11-25 | 1987-11-20 | Novel cephalosporin derivatives and their crystalline derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO883287L true NO883287L (en) | 1988-07-22 |
| NO883287D0 NO883287D0 (en) | 1988-07-22 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO883287A NO883287D0 (en) | 1986-11-25 | 1988-07-22 | Cephalosporins. |
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| Country | Link |
|---|---|
| NO (1) | NO883287D0 (en) |
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| NO883287D0 (en) | 1988-07-22 |
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