CN88102467A - 新型头孢菌素化合物和抗菌素的制备方法 - Google Patents
新型头孢菌素化合物和抗菌素的制备方法 Download PDFInfo
- Publication number
- CN88102467A CN88102467A CN88102467.8A CN88102467A CN88102467A CN 88102467 A CN88102467 A CN 88102467A CN 88102467 A CN88102467 A CN 88102467A CN 88102467 A CN88102467 A CN 88102467A
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- Prior art keywords
- thiomethyl
- methyl
- formula
- compound
- pyridone
- Prior art date
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- -1 cephalosporin compounds Chemical class 0.000 title claims abstract description 201
- 229930186147 Cephalosporin Natural products 0.000 title claims abstract description 11
- 229940124587 cephalosporin Drugs 0.000 title claims abstract description 11
- 238000000034 method Methods 0.000 title claims description 35
- 238000002360 preparation method Methods 0.000 title claims description 5
- 239000003242 anti bacterial agent Substances 0.000 title 1
- 229940088710 antibiotic agent Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 88
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 230000000269 nucleophilic effect Effects 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract 8
- 239000001257 hydrogen Substances 0.000 claims abstract 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract 6
- 150000002431 hydrogen Chemical class 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 58
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 39
- 125000006239 protecting group Chemical group 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 5
- 244000005700 microbiome Species 0.000 abstract description 3
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 108
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 66
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 29
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 28
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 28
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 28
- 239000007864 aqueous solution Substances 0.000 description 26
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 239000000460 chlorine Substances 0.000 description 20
- 238000001035 drying Methods 0.000 description 20
- 238000001556 precipitation Methods 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 16
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 159000000000 sodium salts Chemical class 0.000 description 12
- 238000005406 washing Methods 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 10
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- 230000000845 anti-microbial effect Effects 0.000 description 8
- 125000004429 atom Chemical group 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 description 6
- 239000005864 Sulphur Substances 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 125000004414 alkyl thio group Chemical group 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 229940124530 sulfonamide Drugs 0.000 description 5
- KSHKXMCFEPVEFT-UHFFFAOYSA-N 2-(carboxymethylamino)-2-methoxyacetic acid Chemical compound COC(C(=O)O)NCC(=O)O KSHKXMCFEPVEFT-UHFFFAOYSA-N 0.000 description 4
- AIDPUKZQMIOJNU-UHFFFAOYSA-N COC=1C(C(C(=NC1)CO)OCC1=CC=CC=C1)=O Chemical compound COC=1C(C(C(=NC1)CO)OCC1=CC=CC=C1)=O AIDPUKZQMIOJNU-UHFFFAOYSA-N 0.000 description 4
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 150000003222 pyridines Chemical class 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 125000003396 thiol group Chemical group [H]S* 0.000 description 4
- BWUNCUQUIFRBTA-UHFFFAOYSA-N 1-hydroxy-2-(hydroxymethyl)-5-methoxy-3-phenylmethoxypyridin-4-one Chemical compound O=C1C(OC)=CN(O)C(CO)=C1OCC1=CC=CC=C1 BWUNCUQUIFRBTA-UHFFFAOYSA-N 0.000 description 3
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 3
- 0 CC(C(*)NC1C(C(C(O)=O)N(C)OC)C(C)C1)S Chemical compound CC(C(*)NC1C(C(C(O)=O)N(C)OC)C(C)C1)S 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000001780 cephalosporins Chemical class 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- BEJNERDRQOWKJM-UHFFFAOYSA-N kojic acid Chemical compound OCC1=CC(=O)C(O)=CO1 BEJNERDRQOWKJM-UHFFFAOYSA-N 0.000 description 3
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 3
- 229950004288 tosilate Drugs 0.000 description 3
- YXIWHUQXZSMYRE-UHFFFAOYSA-N 1,3-benzothiazole-2-thiol Chemical compound C1=CC=C2SC(S)=NC2=C1 YXIWHUQXZSMYRE-UHFFFAOYSA-N 0.000 description 2
- VQKFNUFAXTZWDK-UHFFFAOYSA-N 2-Methylfuran Chemical compound CC1=CC=CO1 VQKFNUFAXTZWDK-UHFFFAOYSA-N 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- JVQIKJMSUIMUDI-UHFFFAOYSA-N 3-pyrroline Chemical compound C1NCC=C1 JVQIKJMSUIMUDI-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- LKEIMALRYRYZOB-UHFFFAOYSA-N CN1C(C=C(C=C1)S(=O)(=O)O)=O Chemical compound CN1C(C=C(C=C1)S(=O)(=O)O)=O LKEIMALRYRYZOB-UHFFFAOYSA-N 0.000 description 2
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
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- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
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- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
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- BBOPZLFBGQCZHF-UHFFFAOYSA-N [Br].C[Mg] Chemical compound [Br].C[Mg] BBOPZLFBGQCZHF-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 150000003863 ammonium salts Chemical class 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
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- 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 2
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- CSNXUYRHPXGSJD-UHFFFAOYSA-N isoquinolin-5-ol Chemical compound N1=CC=C2C(O)=CC=CC2=C1 CSNXUYRHPXGSJD-UHFFFAOYSA-N 0.000 description 2
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- WZNJWVWKTVETCG-UHFFFAOYSA-N kojic acid Natural products OC(=O)C(N)CN1C=CC(=O)C(O)=C1 WZNJWVWKTVETCG-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
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- 229910052700 potassium Inorganic materials 0.000 description 2
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- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
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- 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 2
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- OBETXYAYXDNJHR-SSDOTTSWSA-M (2r)-2-ethylhexanoate Chemical compound CCCC[C@@H](CC)C([O-])=O OBETXYAYXDNJHR-SSDOTTSWSA-M 0.000 description 1
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- SNUSZUYTMHKCPM-UHFFFAOYSA-N 1-hydroxypyridin-2-one Chemical compound ON1C=CC=CC1=O SNUSZUYTMHKCPM-UHFFFAOYSA-N 0.000 description 1
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- 229920001429 chelating resin Polymers 0.000 description 1
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- 125000001309 chloro group Chemical group Cl* 0.000 description 1
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- 239000000470 constituent Substances 0.000 description 1
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- 229940079593 drug Drugs 0.000 description 1
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- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
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- 159000000003 magnesium salts Chemical class 0.000 description 1
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- 235000019359 magnesium stearate Nutrition 0.000 description 1
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- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
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- 231100000252 nontoxic Toxicity 0.000 description 1
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- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
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- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 235000007715 potassium iodide Nutrition 0.000 description 1
- 229960004839 potassium iodide Drugs 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
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- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- GCLGEJMYGQKIIW-UHFFFAOYSA-H sodium hexametaphosphate Chemical compound [Na]OP1(=O)OP(=O)(O[Na])OP(=O)(O[Na])OP(=O)(O[Na])OP(=O)(O[Na])OP(=O)(O[Na])O1 GCLGEJMYGQKIIW-UHFFFAOYSA-H 0.000 description 1
- 235000019982 sodium hexametaphosphate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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- 238000012546 transfer Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
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Abstract
一种新型的头孢菌素化合物(式I)或其药理学上可接受的盐。通式(I)中的R1和R2可以相同也可以不同,它们分别为氢,C1-5的低级烷基,苯基或取代了的苯基,A为氢或一个亲核化合物的残基。上述化合物和其盐对革兰氏阳性或革兰氏阴性微生物具有良好的抗菌活性。
Description
本发明是关于一种新型具有广谱抗菌活性(包括对绿脓假单胞菌的抗菌活性)的头孢菌素化合物及其制备方法。本发明特别涉及一种新型头孢菌素衍生物,其中7-位上带有(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)烷氧基亚氨基乙酰胺基,该衍生物对于由病原体导致的人类和各种动物的疾病有良好的治疗作用,因此可用做医药和兽药。
头孢菌素抗菌素广泛用于治疗由病原菌导致的疾病,但是在抗菌能力、抗菌谱、临床药理效果等方面都很难令人满意。
本发明者以前发现:在7-位上带有2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-甲酰胺基)乙酰胺基的新型头孢菌素衍生物对于多种病原体有很强的抗菌作用。该发现描述在日本专利申请60-140989、61-77893和61-77894中。这些衍生物特别是对绿脓假单孢菌有很强的抗菌能力。据认为,该抗菌活性来自在7-位上的1,5-二羟基-4-吡啶酮-2-甲酰胺基取代基。通过进一步研究该衍生物上的1,5-二羟基-4-吡啶酮结构,并特别侧重在7-位上支链的研究,终于发现了对革兰氏阴性菌(包括绿脓假单胞菌)具有广谱抗菌作用的新型头孢菌素化合物(式Ⅰ),该化合物对制造β-内酰胺酶的各种细菌有特别强的抗菌活性,由此完成了本发明。
本发明是关于可用做抗菌剂的具有通式(Ⅰ)的头孢菌素化合物及其药理上可接受的盐,和含这些化合物或盐作为活性组份的抗菌剂,
其中R1和R2是氢原子、1至5个碳原子的低级烷基、苯基或被取代的苯基,它们可以相同或不同,A是氢原子或亲核化合物残基。
通式(Ⅰ)化合物是顺式异构体,而在7-位取代基上有一个不对称碳原子时,D-构型和L-构型也可以存在。但是本发明既不包括D和L构型,也不包括DL构型。另外,作为7-位取代基的1,5-二羟基-4-吡啶-2-烷氧亚氨基部分可以下面所示的互变异构体形式存在。尽管本发明包括上述两种异构体,但还是用“吡啶酮式”这一术语表述该结构。
本发明式(Ⅰ)化合物的药理上可接受盐的例子包括医用盐,特别是常用的无毒性盐,例如碱金属盐(如钠盐、钾盐等)、碱土金属盐(如钙盐、镁盐等)、铵盐、与有机碱形成的有机盐(例如有机铵盐,如三乙胺盐、吡啶盐、乙醇胺盐、三乙醇胺盐、二环己胺盐)、碱性氨基酸盐(例如与赖氨酸或精氨酸等形成的盐)。
通式(Ⅰ)化合物中用A表示的亲核化合物残基的例子包括羟基、巯基、氨基甲酰基、氨基甲酰氧基、叠氮基、2至5个碳原子的烷酰氧基,或季铵基,如下式的吡啶鎓或取代的吡啶鎓基:
其中n是零或整数3至5,R3和R4可以相同或不同并且是氢原子、囟原子、1至5个碳原子的直链或支链烷基、羟基、氨基、氨基甲酰基、磺酸基、亚磺酰氨基、磺烷基、1至5个碳原子的直链或支链烷硫基、囟代烷硫基、环烷硫基、环烷甲硫基、羧烷硫基、烷氧烷硫基或被烷基取代的氨基烷硫基,以及可被任意取代的喹啉鎓、异喹啉鎓、噻唑啉鎓、N-烷基吡咯烷鎓等,或者由硫相连的杂环,即杂环硫基,或苯基,与硫基相连的被取代的苯基。
这里所说的杂环是指含有1至4个选自O、S和N的杂原子的5元或6元环,如吡啶基、N-氧吡啶基、嘧啶基、哒嗪基、N-氧哒嗪基、吡唑基、二唑基、噻唑基、噻二唑基、噁二唑基、三唑基、四唑基、三嗪基等,或双环杂环,例如环烯并吡啶基、苯并噻唑基、苯并咪唑基、苯并恶唑基、三氮杂茚基等。上述杂环可以带有取代基,如1至3个碳原子的低级烷基、囟代烷基、烷氧基、囟原子、羟基、巯基、氨基、羧基、氨基甲酰基、低级烷基氨基-低级烷基(含1至3个碳原子)、羧甲基、羟烷基、磺烷基、烷巯基、烷氧羰基等。
A表示下式的吡啶鎓硫基或被取代的吡啶鎓硫基:
式中n是零或3至5的整数,R5和R6可以相同或不同,它们是氢原子、囟原子或可以含囟原子的1至5个碳原子的低级烷基,R7表示1至5个碳原子的直链或支链烷基、囟代烷基、环丙基、环丙甲基、链烯基、氧原子或-(CH2)m B(其中m是0至3的整数,B是羟基)、烷氧基、氨基、被烷基取代的氨基、羧基、氨基甲酰基、磺酸基、磺酰氨基、异羟肟酸基、氰基、硫羟基、烷硫基、甲磺酰氨基羰基或乙酰氨基磺酰基。
本发明式(Ⅰ)化合物的3-位取代基的具体例子如下述,应注意的是下述例子不是仅有的。
吡啶翁甲基,4-甲基吡啶鎓甲基,
2,3-二甲基吡啶鎓甲基,
2,3-环戊烯并吡啶鎓甲基,
2,3-环己烯并吡啶鎓甲基,
4-氨基甲酰基吡啶鎓甲基,
3-氨基甲酰基吡啶鎓甲基,
4-甲硫基吡啶鎓甲基,
3-甲硫基吡啶鎓甲基,
2-甲硫基吡啶鎓甲基,
4-乙硫基吡啶鎓甲基,
4-烯丙硫基吡啶鎓甲基,
2-烯丙硫基吡啶鎓甲基,
4-环丙甲硫基吡啶鎓甲基,
3-环丙甲硫基吡啶鎓甲基,
4-环丙硫基吡啶鎓甲基,
4-环戊硫基吡啶鎓甲基,
4-(2,2,2-三氟乙基)硫基吡啶鎓甲基,
4-(2-羟乙基)硫基吡啶鎓甲基,
3-(2-羟乙基)硫基吡啶鎓甲基,
2-(2-羟乙基)硫基吡啶鎓甲基,
2-环丙硫基吡啶鎓甲基,
4-三甲基硅基吡啶鎓甲基,
3-三甲基硅基吡啶鎓甲基,
4-三氟甲硫基吡啶鎓甲基,
4-(2-氟乙基)硫基吡啶鎓甲基,
4-羧甲硫基吡啶鎓甲基,
4-氨基甲酰甲硫基吡啶鎓甲基,
4-(N,N-二甲氨基乙基)硫基吡啶鎓甲基,
2,3-环戊烯并-4-甲硫基吡啶鎓甲基,
2,3-环戊烯并-4-乙硫基吡啶鎓甲基,
2,3-环戊烯并-4-烯丙硫基吡啶鎓甲基,
2,3-环戊烯并-4-环丙甲硫基吡啶鎓甲基,
2,3-环戊烯并-4-环丙硫基吡啶鎓甲基,
2,3-环戊烯并-4-戊硫基吡啶鎓甲基,
2,3-环戊烯并-4-(2,2,2-三氟乙基)硫基吡啶鎓甲基,
2,3-环戊烯并-4-(2-羟乙基)硫基吡啶鎓甲基,
2,3-环戊烯并-4-(2-氟乙基)硫基吡啶鎓甲基,
2,3-环戊烯并-4-羧甲硫基吡啶鎓甲基,
2,3-环戊烯并-4-氨基甲酰甲硫基吡啶鎓甲基,
2,3-环戊烯并-4-(N,N-二甲基氨基乙基)硫基吡啶鎓甲基,
2,3-环己烯并-4-甲硫基吡啶鎓甲基,
2,3-环己烯并-4-环丙甲硫基吡啶鎓甲基,
2,3-环己烯并-4-环丙硫基吡啶鎓甲基,
2,3-环己烯并-4-(2-羟乙基)硫基吡啶鎓甲基,
2,3-环己烯并-4-(2,2,2-三氟乙基)硫基吡啶鎓甲基,
2,3-环己烯并-4-羧甲硫基吡啶鎓甲基,
2,3-环己烯并-4-氨基甲酰甲硫基吡啶鎓甲基,
5,6-环戊烯并-2-甲硫基吡啶鎓甲基,
5,6-环戊烯并-2-烯丙硫基吡啶鎓甲基,
5,6-环戊烯并-2-环丙硫基吡啶鎓甲基,
5,6-环戊烯并-2-(2-羟乙基)硫基吡啶鎓甲基,
5,6-环戊烯并-2-(2-氟乙基)硫基吡啶鎓甲基,
5,6-环戊烯并-2-羧甲硫基吡啶鎓甲基,
5,6-环戊烯并-2-氨基甲酰甲硫基吡啶鎓甲基,
(喹啉鎓-1-基)甲基,
(3-氨基喹啉鎓-1-基)甲基,
(5-氨基喹啉鎓-1-基)甲基,
(5-羟基喹啉鎓-1-基)甲基,
(6-羟基喹啉鎓-1-基)甲基,
(7-羟基喹啉鎓-1-基)甲基,
(4-氨基甲酰基喹啉鎓-1-基)甲基,
(5-三氟甲基喹啉鎓-1-基)甲基,
(异喹啉鎓-2-基)甲基,
(5-羟基异喹啉鎓-2-基)甲基,
(4-羟基异喹啉鎓-2-基)甲基,
(5-氨基异喹啉鎓-2-基)甲基,
(4-氨基异喹啉鎓-2-基)甲基,
(3-甲基异喹啉鎓-2-基)甲基,
(5-羟基异喹啉鎓-2-基)甲基,
(8-羟基异喹啉鎓-2-基)甲基,
(4-氨基甲酰基异喹啉鎓-2-基)甲基,
(5-三氟甲基异喹啉鎓-2-基)甲基,
(噻吩并[3,2-c]吡啶鎓-5-基)甲基,
(噻吩并[2,3-b]吡啶鎓-7-基)甲基,
(噻吩并[3,2-b]吡啶鎓-4-基)甲基,
(噻吩并[2,3-c]吡啶鎓-6-基)甲基,
(噻吩并[3,4-b]吡啶鎓-4-基)甲基,
(噻吩并[3,4-c]吡啶鎓-5-基)甲基,
(4-甲基噻吩并[2,3-b]吡啶鎓-7-基)甲基,
(呋喃并[2,3-c]吡啶鎓-6-基)甲基,
(呋喃并[3,2-c]吡啶鎓-5-基)甲基,
(呋喃并[2,3-b]吡啶鎓-7-基)甲基,
(呋喃并[3,2-b]吡啶鎓-4-基)甲基,
(2-甲基呋喃并[3,2-b]吡啶鎓-4-基)甲基,
(2,4-二甲基呋喃并[2,3-b]吡啶鎓-4-基)甲基,
(噻唑并[4,5-c]吡啶鎓-5-基)甲基,
(2-氨基噻唑并[4,5-c]吡啶鎓-5-基)甲基,
(2-甲基噻唑并[4,5-c]吡啶鎓-5-基)甲基,
(1,3-二氢呋喃并[3,4-b]吡啶鎓-4-基)甲基,
(1,3-二氢吡咯并[3,4-b]吡啶鎓-4-基)甲基,
(2-甲基-1,3-二氢吡咯并[3,4-b]吡啶鎓-4-基)甲基,
(2,2-二甲基-1,3-二氢吡咯并[3,4-b]吡啶鎓-4-基)甲基,
(1,3-二氢噻吩并[3,4-b]吡啶鎓-4-基)甲基,
(2-氧代-1,3-二氢噻吩并[3,4-b]吡啶鎓-4-基)甲基,
(吡喃鎓-1-基)甲基,
(3-甲基吡喃鎓-1-基)甲基,
(3,5-二甲基吡喃鎓-1-基)甲基,
[3-(2-羟乙基)氨基吡喃鎓-1-基]甲基,
(3-氨基吡喃鎓-1-基)甲基,
(3-二甲氨基吡喃鎓-1-基)甲基,
(噻唑啉鎓-3-基)甲基,
(4-甲基噻唑啉鎓-3-基)甲基,
(1-甲基吡咯烷鎓-1-基)甲基,
三甲铵甲基,
N,N-二甲基-N-(2-羟乙基)铵甲基,
N,N-二甲基-N-烯丙基铵甲基,
N,N-二乙基-N-甲基铵甲基,
苯硫甲基,(4-羟苯基)硫甲基,
(4-氟苯基)硫甲基,
(1H-四唑-5-基)硫甲基,
(1-甲基-1H-四唑-5-基)硫甲基,
(1-氨基-1H-四唑-5-基)硫甲基,
[1-(二甲基氨基乙基)-1H-四唑-5-基]硫甲基,
[1-(2-羟乙基)-1H-四唑-5-基]硫甲基,
[1-(2-羧乙基)-1H-四唑-5-基]硫甲基,
(1-羧甲基-1H-四唑-5-基)硫甲基,
(1-氨基甲酰甲基-1H-四唑-5-基)硫甲基,
(1-磺甲基-1H-四唑-5-基)硫甲基,
[1-(2-磺乙基)-1H-四唑-5-基]硫甲基,
(1-氨磺酰甲基-1H-四唑-5-基)硫甲基,
(1,3,4-噻二唑-5-基)硫甲基,
(2-甲基-1,3,4-噻二唑-5-基)硫甲基,
(2-乙硫基-1,3,4-噻二唑-5-基)硫甲基,
(2-氨基甲酰基-1,3,4-噻二唑-5-基)硫甲基,
(2-乙氧羰基-1,3,4-噻二唑-5-基)硫甲基,
(2-乙氧基-1,3,4-噻二唑-5-基)硫甲基,
(2-三氟甲基-1,3,4-噻二唑-5-基)硫甲基,
(2-羧基-1,3,4-噻二唑-5-基)硫甲基,
(2-甲氨基-1,3,4-噻二唑-5-基)硫甲基,
(2-氨基-1,3,4-噻二唑-5-基)硫甲基,
(2-巯基-1,3,4-噻二唑-5-基)硫甲基,
(2-氨基甲酰甲基-1,3,4-噻二唑-5-基)硫甲基,
(1,2,3-噻二唑-5-基)硫甲基,
(4-甲基-1,2,3-噻二唑-5-基)硫甲基,
(4-氨基甲酰基-1,2,3-噻二唑-5-基)硫甲基,
(4-乙氧羰基-1,2,3-噻二唑-5-基)硫甲基,
(1,2,4-噻二唑-5-基)硫甲基,
(3-甲基-1,2,4-噻二唑-5-基)硫甲基,
(3-苯基-1,2,4-噻二唑-5-基)硫甲基,
(噻唑-2-基)硫甲基,
(4-甲基噻唑-2-基)硫甲基,
(4-苯基噻唑-2-基)硫甲基,
(4-三氟甲基噻唑-2-基)硫甲基,
(4-羧甲基噻唑-2-基)硫甲基,
(5-甲基噻唑-2-基)硫甲基,
(5-苯基噻唑-2-基)硫甲基,
(噻唑-5-基)硫甲基,
(4-氨基甲酰基噻唑-5-基)硫甲基,
(4-乙氧羰基-5-基)硫甲基,
(4-羧基-3-羟基异噻唑-5-基)硫甲基,
(4-氰基-3-羟基异噻唑-5-基)硫甲基,
(1,3,4-噁二唑-5-基)硫甲基,
(2-甲基-1,3,4-噁二唑-5-基)硫甲基,
(2-苯基-1,3,4-噁二唑-5-基)硫甲基,
(2-羧甲基-1,3,4-噁二唑-5-基)硫甲基,
(1,2,4-噁二唑-5-基)硫甲基,
(3-甲基-1,2,4-噁二唑-5-基)硫甲基,
(3-苯基-1,2,4-噁二唑-5-基)硫甲基,
(噁唑-2-基)硫甲基,
(4-甲基噁唑-2-基)硫甲基,
(吡唑-5-基)硫甲基,
(1-甲基咪唑-2-基)硫甲基,
(1H-1,2,3-三唑-5-基)硫甲基,
(1-甲基-1H-1,2,3-三唑-5-基)硫甲基,
(1H-1,2,4-三唑-5-基)硫甲基,
(1-甲基-1H-1,2,4-三唑-5-基)硫甲基,
(4-甲基-3-三氟甲基-4H-1,2,4-三唑-5-基)硫甲基,
(1H-1,3,4-三唑-5-基)硫甲基,
(1-甲基-1H-1,3,4-三唑-5-基)硫甲基,
(1-羧甲基-1H-1,3,4-三唑-5-基)硫甲基,
(1-氨基甲酰甲基-1H-1,3,4-三唑-5-基)硫甲基,
(2-甲基-1H-1,3,4-三唑-5-基)硫甲基,
(2-羧甲基-1H-1,3,4-三唑-5-基)硫甲基,
(2-苯基-1H-1,3,4-三唑-5-基)硫甲基,
(2,5-二氢-2-甲基-5-氧代-6-羟基-1,2,4-三嗪-3-基)硫甲基,
(4,5-二氢-4-甲基-5-氧代-6-羟基-1,2,4-三嗪-3-基)硫甲基,
(2,3-二氢-3-甲基-2-氧代-6-羟基-1,3,5-三嗪-4-基)硫甲基,
(3,4-二氢-4-甲基-1,1,3-三氧代-2H-1,2,4,6-噻三嗪-5-基)硫甲基,
(5-甲基均三唑并[1,5-a]咪啶-7-基)硫甲基,
(2-羧基-5-甲基均唑并[1,5-a]咪啶-7-基)硫甲基,
(哒嗪-3-基)硫甲基,
(2-羟基哒嗪-3-基)硫甲基,
(咪啶-2-基)硫甲基,
(苯并噻唑-2-基)硫甲基,
(苯并咪唑-2-基)硫甲基,
(苯并噁唑-2-基)硫甲基,
(3H-4-喹唑啉-2-基)硫甲基,
(吡啶-4-基)硫甲基,
(吡啶-3-基)硫甲基,
(吡啶-2-基)硫甲基,
(3-甲基吡啶-4-基)硫甲基,
(2,3-二甲基吡啶-4-基)硫甲基,
(2-羧基吡啶-4-基)硫甲基,
(2-氨基甲酰基吡啶-4-基)硫甲基,
(2,3-环戊烯并吡啶-4-基)硫甲基,
(吡啶-N-氧-4-基)硫甲基,
(5,6-环戊烯并吡啶-2-基)硫甲基,
(2,3-环己烯并吡啶-4-基)硫甲基,
(5,6-环己烯并吡啶-2-基)硫甲基,
(1-甲基吡啶鎓-4-基)硫甲基,
(1-甲基吡啶鎓-2-基)硫甲基,
(1-甲基吡啶鎓-3-基)硫甲基,
(1-乙基吡啶鎓-4-基)硫甲基,
(1-烯丙基吡啶鎓-4-基)硫甲基,
[1-(2,2,2-三氟乙基)吡啶鎓-4-基]硫甲基,
(1-羟甲基吡啶鎓-4-基)硫甲基,
(1-氨基甲酰甲基吡啶鎓-4-基)硫甲基,
[1-(1-羧乙基)吡啶鎓-4-基]硫甲基,
(1-(2-羟乙基)吡啶鎓-4-基]硫甲基,
(1-二甲氨基乙基吡啶鎓-4-基)硫甲基,
(1-环丙基吡啶鎓-4-基)硫甲基,
(1-环丙甲基吡啶鎓-4-基)硫甲基,
(1-甲硫甲基吡啶鎓-4-基)硫甲基,
(1-氰基甲基吡啶鎓-4-基)硫甲基,
[1-(2-氟乙基)吡啶鎓-4-基]硫甲基,
(1-羟氨羰甲基吡啶鎓-4-基)硫甲基,
[1-(2-磺乙基)吡啶鎓-4-基]硫甲基,
(1-磺甲基吡啶鎓-4-基)硫甲基,
(1-氨磺酰甲基吡啶鎓-4-基)硫甲基,
(1-N,N-二甲基氨磺酰甲基吡啶鎓-4-基)硫甲基,
(2,6-二甲基-1-羧甲基吡啶鎓-4-基)硫甲基,
(3,5-二甲基-1-羧甲基吡啶鎓-4-基)硫甲基,
(2-羧基-1-甲基吡啶鎓-4-基)硫甲基,
(1-乙基吡啶鎓-3-基)硫甲基,
(1-烯丙基吡啶鎓-3-基)硫甲基,
(1-环丙基吡啶鎓-3-基)硫甲基,
[1-(2-羟乙基吡啶鎓-3-基]硫甲基,
(1-羧甲基吡啶鎓-3-基)硫甲基,
(1-氨基甲酰基甲基吡啶鎓-3-基)硫甲基,
[1-(2-氟乙基)吡啶鎓-3-基]硫甲基,
[1-(2,2,2-三氟乙基)吡啶鎓-3-基]硫甲基,
(1-磺甲基吡啶鎓-3-基)硫甲基,
(1-氨磺酰甲基吡啶鎓-3-基)硫甲基,
[1-(2-磺乙基)吡啶鎓-3-基]硫甲基,
(1-乙基吡啶鎓-2-基)硫甲基,
(1-烯丙基吡啶鎓-2-基)硫甲基,
(1-环丙基吡啶鎓-2-基)硫甲基,
[1-(2-羟乙基)吡啶鎓-2-基]硫甲基,
(1-羧甲基吡啶鎓-2-基)硫甲基,
(1-氨基甲酰基甲基吡啶鎓-2-基)硫甲基,
[1-(1-羧乙基)吡啶鎓-2-基]硫甲基,
[1-(2-氟乙基)吡啶鎓-2-基]硫甲基,
[1-(2,2,2-三氟乙基)吡啶鎓-2-基]硫甲基,
(1-磺甲基吡啶鎓-2-基)硫甲基,
(1-氨磺酰甲基吡啶鎓-2-基)硫甲基,
[1-(2-磺乙基)吡啶鎓-2-基]硫甲基,
(2,3-环戊烯并-1-甲基吡啶鎓-4-基)硫甲基,
(2,3-环戊烯并-1-乙基吡啶鎓-4-基)硫甲基,
(2,3-环戊烯并-1-烯丙基吡啶鎓-4-基)硫甲基,
[2,3-环戊烯并-1-(2,2,2-三氟乙基)吡啶鎓-4-基]硫甲基,
(2,3-环戊烯并-1-羧甲基吡啶鎓-4-基)硫甲基,
(2,3-环戊烯并-1-氨基甲酰甲基吡啶鎓-4-基)硫甲基,
[2,3-环戊烯并-1-(2-羟乙基)吡啶鎓-4-基]硫甲基,
(2,3-环戊烯并-1-二甲氨基乙基吡啶鎓-4-基)硫甲基,
(2,3-环戊烯并-1-环丙基吡啶鎓-基)硫甲基,
(2,3-环戊烯并-1-环丙甲基吡啶鎓-4-基)硫甲基,
(2,3-环戊烯并-1-氰甲基吡啶鎓-4-基)硫甲基,
(2,3-环戊烯并-1-磺甲基吡啶鎓-4-基)硫甲基,
[2,3-环戊烯并-1-(2-氟乙基)吡啶鎓-4-基]硫甲基,
[2,3-环戊烯并-1-(2-磺乙基)吡啶鎓-4-基]硫甲基,
[2,3-环戊烯并-1-(2-氨磺酰乙基)吡啶鎓-4-基]硫甲基,
(5,6-环戊烯并-1-甲基吡啶鎓-2-基)硫甲基,
(5,6-环戊烯并-1-乙基吡啶鎓-2-基)硫甲基,
(5,6-环戊烯并-1-烯丙基吡啶鎓-2-基)硫甲基,
[5,6-环戊烯并-1-(2-氟乙基)吡啶鎓-2-基]硫甲基,
[5,6-环戊烯并-1-(2-羟乙基)吡啶鎓-2-基]硫甲基,
(5,6-环戊烯并-1-羧甲基吡啶鎓-2-基)硫甲基,
(2,3-环己烯并-1-甲基吡啶鎓-4-基)硫甲基,
(2,3-环己烯并-1-羧甲基吡啶鎓-4-基)硫甲基,
(2,3-环己烯并-1-氨基甲酰甲基吡啶鎓-4-基)硫甲基,
[2,3-环己烯并-1-(2-羟乙基)吡啶鎓-4-基]硫甲基,
[2,3-环己烯并-1-(二甲氨基乙基)吡啶鎓-4-基]硫甲基,
(2,3-二氢-1H-吲哚鎓-5-基)硫甲基。
本发明者根据日本专利申请60-140989公开的方法合成了保护形式的2-羟甲基-1,5-二羟基-4-吡啶酮,该化合物是7-位取代基的构成体之一。即可以通过使被保护的曲酸(Ⅱ)与盐酸羟胺或R9ONH2(或其盐)在吡啶等存在下进行反应而得到该化合物,
式中R8和R9是可脱除的保护基,如苄基、对硝基苄基、邻硝基苄基、对甲氧苄基、二苯甲基等。
此外,式(Ⅲ)化合物与R9X(其中X是囟原子或重氮基)反应,在不同的R9X,反应溶剂及反应条件(如温度)下,可以得到产物(Ⅳa)或(Ⅳb),或其混合物。
本发明的头孢菌素化合物(通式Ⅰ)可以通过下述方法A)或B)得到。
A)使通式(Ⅴa)化合物或(Ⅴb)化合物或此种羧酸的易反应衍生物与通式(Ⅵ)化合物或其盐,或其甲硅烷基化产物反应,然后脱去保护基。
式(Ⅴa)和(Ⅴb)中,R10是氢原子或氨基的保护基,R1、R2、R8和R9的定义同上;或(Ⅵ)中,R11是氢原子或羧基保护基,A的定义同上。
B)使通式(Ⅶa)或(Ⅶb)化合物与一种亲核化合物反应,然后如果需要则除去保护基,得到通式(Ⅰ)化合物。
式中Y是乙酰氧基或囟原子;R8′是氢原子或R8;R9′是氢原子或R9;R1、R2、R8、R9、R10和R11的定义同上。这里的亲核化合物是与通式(Ⅰ)中A相应的化合物。
对于上述通式中氨基和羧基的保护基,宜采用在β-内酰胺和肽合成领域使用的有关保护基。
氨基保护基的例子有甲酰、邻苯二甲酰、一氯乙酰、二氯乙酰、三氯乙酰、甲氧羰基、乙氧羰基、叔丁氧羰基、三氯乙氧羰基、苄氧羰基、对硝基苄氧羰基、二苯甲氧羰基、甲氧甲氧羰基、三苯甲基、三甲基硅基等。羧基保护基例子有叔丁基、叔戊基、烯丙基、苄基、对硝苄基、对甲氧苄基、二苯甲基、苯基、对硝苯基、甲氧甲基、乙氧甲基、苄氧甲基、乙酰氧甲基、甲硫甲基、三苯甲基、三氯乙基、三甲基硅基、二甲基甲硅烷基等。
在方法A中通式(Ⅴa)或(Ⅴb)与(Ⅵ)化合物的缩合反应可采用通常用于青霉素和头孢菌素酰化的方法进行。
上述易反应衍生物的例子包括酰囟、酸酐、活性酰胺、活性酯等。较好的例子有酰氯、酰溴,下述酸的混合酸酐,如:乙酸、新戊酸、异戊酸、三氯乙酸等,与吡唑、咪唑、二甲基吡唑、苯并三唑等形成的活泼酰胺,对硝基苯酯、2,4-二硝基苯酯、三氯苯酯等活泼酯,以及与1-羟基-1H-吡啶酮、N-羟基丁二酰亚胺、N-羟基苯并三唑、N-羟基邻苯二甲酰亚胺等形成的活泼酯。
另外,在此反应中,如果使用游离酸形式的式(Ⅴa)或式(Ⅴb)化合物,则最好在缩合剂存在下进行反应,也就是说,此反应可在一种缩合剂存在下进行,此缩合剂例如是碳化二亚胺[例如N,N-二环己基碳化二亚胺、N-环己基-N′-吗啉代乙基碳化二亚胺、N-环己基-N′-(4-二乙基氨基环己基)碳化二亚胺等)或酰胺(如N-甲基甲酰胺,N,N-二甲基甲酰胺等]与囟化物(如亚硫酰氯、磷酰氯、碳酰氯等)反应而生成的试剂[所谓的维斯米尔(Vilsmeiev)试剂]。
上述反应如果使用上述易反应衍生物中的酰囟或酸酐,则需要在酸结合剂存在下进行。酸结合剂的例子有包括有机碱,如三乙胺、三甲胺、乙基异丙胺、N,N-二甲胺、N-甲基吗啉、吡啶等;如钠、钾、钙等的氢氧化物;碱金属盐,如碱金属碳酸盐及酸式碳酸盐等;还有环氧化合物,如环氧乙烷、环氧丙烷等。
该反应通常在对反应无不良影响的溶剂中进行。溶剂的例子有水、丙酮、乙腈、二噁烷、四氢呋喃、乙酸乙酯、二氯甲烷、氯仿、二氯乙烷、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜或它们的混合物。
对反应温度没有特别的限制,但反应一般在-30℃~40℃进行;至于反应时间,此反应一般进行30分钟到10小时便可完成。
将所得酰化产物的保护基脱除时,根据不同的保护基,可选择酸法、碱法、肼法等,按照β-内酰胺和肽合成领域中常用的方法进行。
使通式(Ⅷ)化合物或其盐与(Ⅸa)化合物或(Ⅸb)化合物反应,然后根据需要脱除羧基保护基,可得到式(Ⅴa)或(Ⅴb)化合物。
式(Ⅷ)中R10和R11的定义同上;
式(Ⅸa)和(Ⅸb)中,Z是囟原子或磺酸根,如甲磺酰氧基、甲苯磺酰氧基、三氟甲磺酰氧基等。
该缩合反应可在-50℃~70℃下及溶剂中进行,如果需要亦可在碱存在下进行。其中碱和溶剂可选用方法A的酰化反应所用的碱和溶剂。方法B中通式(Ⅶa)和(Ⅶb)化合物与亲核化合物的反应可按头孢菌素化学中常用方法进行。也就是说,如果通式(Ⅶa)或(Ⅶb)中的Y是乙酰氧基,则反应一般是最好在极性溶剂中进行,该溶剂的例子包括水、磷酸盐缓冲液、丙酮、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、二甲亚砜、二噁烷、甲醇、乙醇等或上述溶剂与水的混合物。
反应最好在接近中性条件下进行。尽管反应温度并不很苛刻,但合适的温度是室温至约80℃。
反应时间取决于反应条件,一般为1~10小时。
另外,碱金属囟化物(如碘化物、碘化钾等)的存在可以促进反应进行。
如果由Y为囟原子的式(Ⅶa)或(Ⅶb)化合物制备所需产物,则反应最好在无水条件下和下述溶剂中进行:丙酮、二噁烷、四氢呋喃、乙酸乙酯、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜等。反应温度最好为0~50℃;反应完成需时为1~5小时。
按上述方法得到的式(Ⅰ)化合物可用常规方法使之从反应混合物中分离出来。例如,可以适当地结合使用采用吸收树脂的提纯,沉淀,结晶等方法进行分离,其中树脂的例子有Amberlite XAD-2(由Rohm和Haas公司生产),Diaion HP-20(由三菱化学公司生产)。
含有通式(Ⅰ)化合物或其盐作为主要成分的抗菌剂可以各种药物剂型使用,例如有注射液(如静脉注射液、肌内注射液等)、口服剂(如胶囊、片剂、粉剂等)以及肠内用药、含油栓剂、水溶性栓剂等等。按照常规方法,采用常规赋形剂、填充剂、粘合剂、湿润剂、崩解剂、表面活性剂、润滑剂、分散剂、缓冲剂、保存剂、助溶剂、防腐剂、甜味剂、止痛剂等制备这些剂型。生产方法的具体例子在以下实施例有更详细的描述。
适宜的用药量应根据各个病人的病症严重程度、年龄、性别等来确定,但举例来说,成人的日用剂量一般为250~3000mg,每天分1~4次用药。
通过以下实施例更详细地叙述本发明,但应指出,这些实施例只是一些例子而已,在本发明范围内还可以作出各种改变及改进。
在这些实施例中,核磁共振谱(NMR)数据(δ值)在是用400兆赫核磁共振仅测得的。在使用重水溶剂时,δ值是以水的峰值(取为4.82)作标准;在使用其它氘化溶剂时,δ值是以TMS(四甲基甲硅烷)作为标准。
参考例1
5-对甲氧苄氧基-1-羟-2-羟甲基-4-吡啶酮
(a)将42.6g曲酸溶于350ml N,N-二甲基甲酰胺,再加82.8g无水碳酸钾及55g对甲氧苄基氯,在70~75℃反应1.5小时。反应之后,将反应混合物浓缩至约一半体积,再滴加到冰冷却下的700ml水中。滤出形成的沉淀物,用水及乙酸乙酯洗,干燥,得59.9g 5-对甲氧苄氧基-2-羟甲基-4-吡啶酮。
NMR(CDCl3)δ;
3,80(3H,s),4.43(2H,s),4.96(2H,s),6.50(1H,s),6.88(2H,d),7.30(2H,d),7.51(1H,s)
(b)把39.3g 5-对甲氧苄氧基-2-羟甲基-4-吡啶酮溶于600ml吡啶中,再加52.2g盐酸羟胶,在70~75℃反应2.5小时。反应后,把反应混合物浓缩至100ml,并在加100ml水后加到冰冷却下的75ml盐酸与225ml水的混合液中。把pH调至2~2.5,在同样温度下搅拌30分钟。滤出形成的晶体,用水洗,干燥,得16.6g标题化合物。
NMR(DMSO-d6)δ;
3.76(3H,s),4.46(2H,s),5.03(2H,s),6.86(1H,s),6.93(2H,d),7.37(2H,d),7.97(1H,s)
参考例2
4-二苯甲氧基-5-对甲氧苄氧基-2-羟甲基吡啶-N-氧化物
把44.3g 5-对甲氧苄氧基-1-羟-2-羟甲基-4-吡啶酮悬浮在320ml甲基溶纤剂(2-甲氧乙醇)中,再加入33.4ml三乙胺使之溶解。此后再加入150ml含46.6g二苯基重氮甲烷的甲基溶纤素溶液,在60℃反应5小时。
反应后将反应混合物浓缩至约100ml,加入乙酸乙酯与异丙醚的1∶1混合液200ml。滤出形成的粗晶体,用乙酸乙酯与异丙醚的1∶1混合液及异丙醚洗,干燥。所得晶体悬浮在500ml二氯甲烷中,滤出不溶物。把二氯甲烷溶液浓缩至小体积,加入乙酸乙酯,滤出形成的晶体,干燥,得42g所要的标题化合物。
NMR(CDCl3)δ;
3.82(3H,s),4.57(2H,s),5.06(2H,s),6.28(1H,s),6.69(1H,s),6.89(2H,d),7.2-7.5(12H,m),7.91(1H,s)
参考例3
1,5-二-对甲氧苄氧基-2-羟甲基-4-吡啶酮
把27.7g 5-对甲氧苄氧基-1-羟-2-羟甲基-4-吡啶酮悬浮在300ml N,N-二甲基甲酰胺中,再加入27.7g无水碳酸钾及17.3g对甲氧苄基氯,在室温反应4小时。反应混合物浓缩至小体积,加入600ml CHCl3,然后水洗,再用无水MgSO4干燥,进一步浓缩至约200ml。加入200ml异丙醚,滤出形成的晶体,干燥,得38.9g所要的标题化合物。
NMR(CDCl3)δ;
3.75(3H,2),3.80(3H,s),4.49(2H,s),4.90(2H,s),5.01(2H,s),6.47(1H,s),6.82(2H,d),6.87(2H,d),6.98(1H,s),7.20(2H,d),7.23(2H,d)
参考例4
1-二苯甲氧基-5-对甲氧苄氧基-2-羟甲基-4-吡啶酮
把5.54g 5-对甲氧苄氧基-1-羟-2-羟甲基-4-吡啶酮悬浮于40mlN,N-二甲基甲酰胺中,再在冰冷却下加入2.24g叔丁醇钾使之溶解。加入4.94g二苯甲基溴,室温反应2.5小时。
反应后,反应混合物浓缩至约20ml,再滴加到乙酸乙酯(200ml)与水(100ml)的混合液中。滤出形成的沉淀,用水及乙酸乙酯洗,再干燥,得7.29g所要的标题化合物。
NMR(CDCl3)δ;
3.78(3H,s),4.51(2H,s),4.59(2H,s),6.18(1H,s),6.58(1H,s),6.63(1H,s),6.82(2H,d),7.16(2H,d),7.3-7.5(10H,m)
实施例1
(6R,7R)-7-[(Z)-2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧亚氨基乙酰胺基]-3-(1-甲基-吡啶鎓-4-基)硫基甲基-头孢-3-烯-4-羧酸盐
(a)把2.2g 4-二苯甲氧基-5-对甲氧苄氧基-2-羟甲基吡啶-N-氧化物悬浮在50ml CH2Cl2中,在冰冷却下加入1ml亚硫酰氯和1滴N,N-二甲基甲酰胺,在同样温度下反应3小时。加入40ml饱和Na HCO3水溶液和50ml CH2Cl2。CH2Cl2层用水洗,用无水MgSO4干燥,减压浓缩至干。残余物溶于40ml N,N-二甲基甲酰胺中,加入2.1g(Z)-2-(2-三苯甲氨基噻唑-4-基)-2-羟亚氨基乙酸烯丙酯及1.24g(无水)K2CO3,室温下反应过夜。反应混合物中加入200ml CHCl3。依次用水、稀盐酸和水洗,用无水MgSO4干燥,减压浓缩至干。
用硅胶柱层析法提纯残余物,得2.18g(Z)-2-(2-三苯甲氨基噻唑-4-基)-2-(4-二苯甲氧基-5-对甲氧苄氧基吡啶-N-氧-2-基)甲氧亚氨基乙酸烯丙酯。
NMR(CDCl3)δ;
3.83(3H,s),4.89(2H,d),5.04(2H,s),5.37(2H,dd),5.38(2H,s),6.0(1H,m),6.40(1H,s),6.57(1H,s),6.90(2H,d),6.93(1H,s),6.96(1H,s),7.1-7.5(27H,m),7.87(1H,s)
(b)把1.74g(a)中制得的烯丙酯溶于15ml CH2Cl2和15ml乙酸乙酯中,加入450mg 2-乙基己酸钾和60mg四(三苯膦)合钯(palladium tetrakistriphenylphosphine),室温下反应1小时。反应混合物中加入150ml CHCl3。加50ml水,再加6N盐酸调水层pH至2,再用水洗涤。水洗后,用无水MgSO4干燥,浓缩至小体积。加乙醚,滤出形成的晶体,用乙醚-CH2Cl2(4∶1)混合液洗,干燥,得1.36g(Z)-2-(2-三苯甲氨基噻唑-4-基)-2-(4-二苯甲氧基-5-对甲氧苄氧基吡啶-N-氧-2-基)甲氧亚氨基乙酸。
NMR(DMSO-d6)δ;
3.76(3H,s),5.01(2H,s),5.16(2H,s),6.80(1H,s),6.96(2H,d),7.1-7.5(29H,m),8.06(1H,s)
(c)把1.15g上述产物溶于30ml CH2Cl2中,在-5℃加入730mg(6R,7R)-7-氨基-3-氯甲基-头孢-3-烯-4-羧酸对甲氧苄酯的对甲苯磺酸盐及0.54ml吡啶,并搅拌10分钟。再于-10~-15℃,加入0.14ml磷酰氯,反应1小时。反应后,加100ml乙酸乙酯,再用15% NaCl水溶液洗两次,每次用50ml。用无水MgSO4干燥,浓缩至干,得1.6g(6R,7R)-7-[(Z)-2-(2-三苯甲氨基噻唑-4-基)-2-(4-二苯甲氧基-5-对甲氧苄氧基吡啶-N-氧-2-基)甲氧亚氨基乙酰胺基]-3-氯甲基-头孢-3-烯-4-羧酸对甲氧苄酯。
NMR(CDCl3)δ;
3.36(2H,ABq),3.80(3H,s),3.83(3H,s),4.45(2H,ABq),4.97(1H,d),5.02(2H,ABq),5.21(2H,ABq),5.82(1H,dd),6.90(4H,m),7.1-7.5(31H,m),7.87(1H,s)
(d)把2.65mg按(c)制得的3-氯甲基化合物溶于0.55ml二甲亚砜中,加入30mg 1-甲基-4-硫代吡啶酮,室温下反应1.5小时。反应混合物中加入30ml CH2Cl2,用15%食盐水洗两次,每次10ml。用无水MgSO4干燥,浓缩至约3ml,滴加到8ml乙酸乙酯中。滤出形成的沉淀,干燥,得190g(6R,7R)-7-[(Z)-2-(2-三苯甲氨基噻唑-4-基)-2-(4-二苯甲氧基-5-对甲氧苄氧基吡啶-N-氧-2-基)硫基甲基-头孢-3-烯-4-羧酸对甲氧苄酯。将其悬浮在14ml苯甲醚中,加0.43ml三氟乙酸,室温反应30分钟。把反应混合物滴加到6ml异丙醚中,滤出形成的沉淀,用异丙醚洗,干燥。把135mg所得沉淀溶于3ml水中,在冰冷却下加入1ml饱和NaHCO3水溶液,然后搅拌10分钟。用HP-20柱层析纯化(以5%丙酮水溶液洗脱),得35mg所要的标题化合物的钠盐。
NMR(DMSO-d6)δ;
3.44(2H,ABq),4.20(3H,s),4.29(2H,ABq),5.11(1H,d),5.29(2H,ABq),5.75(1H,d),6.72(1H,s),7.04(1H,s),7.62(1H,s),7.82(2H,d),8.39(2H,d)
除分别用试剂[A]代替[d]中的1-甲基-4-硫代吡啶酮外,按照同实施例1所述相似的方法,制得实施例2-13的化合物。
实施例2
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟-4-吡啶酮-2-基)甲氧亚氨乙酰胺基]-3-(1-乙基-吡啶-4-基)硫基甲基-头孢-3-烯-4-羧酸盐
[A]1-乙基-4-硫代吡啶酮
NMR(D2O)δ;
1.57(3H,t),3.44(2H,ABq),4.29(2H,ABq),4.45(2H,q),5.11(1H,d),5.28(2H,ABq),5.74(1H,d),6.71(1H,s),7.01(1H,s),7.61(1H,s),7.82(2H,d),8.45(2H,d)
实施例3
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟-4-吡啶酮-2-基)甲氧亚氨乙酰胺基]-3-[1-(2-羟乙基)吡啶鎓-4-基]硫基甲基-头孢-3-烯-4-羧酸盐
[A]1-(2-羟乙基)-4-硫代吡啶酮
NMR(D2O)δ;
3.44(2H,ABq),4.01(2H,m),4.30(2H,ABq),4.52(2H,m),5.11(1H,d),5.27(2H,ABq),5.74(1H,d),6.70(1H,s),7.02(1H,s),7.59(1H,s),7.85(2H,d),8.43(2H,d)
实施例4
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟-4-吡啶酮-2-基)甲氧亚氨乙酰胺基]-3-[(2,3-环戊烯并-1-甲基吡啶鎓-4-基)硫基甲基-头孢-3-烯-4-羧酸盐
[A]1-甲基-环戊烷并[b]4-硫代吡啶酮
NMR(D2O)δ;
2.21(2H,m),2.97(2H,m),3.16(2H,m),3.54(2H,ABq),4.03(3H,s),4.31(2H,s),5.17(1H,d),5.28(2H,bs),5.71(1H,d),6.70(1H,s),6.92(1H,s),7.59(1H,s),7.75(1H,d),8.16(1H,d)
实施例5
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟-4-吡啶酮-2-基)甲氧亚氨乙酰胺基]-3-(1-甲基-1H-四唑-5-基)硫基甲基-头孢-3-烯-4-羧酸
[A]5-巯基-1-甲基-1H-四唑
NMR(D2O)δ;
3.43(2H,ABq),4.05(3H,s),4.29(2H,ABq),5.13(1H,d),5.30(2H,ABq),5.74(1H,d),6.70(1H,s),7.02(1H,s),7.61(1H,s)
实施例6
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟-4-吡啶酮-2-基)甲氧亚氨乙酰胺基]-3-(1,2,3-噻二唑-5-基)硫基甲基-头孢-3-烯-4-羧酸
[A]5-巯基-1,2,3-噻二唑
NMR(D2O)δ;
3.47(2H,ABq),4.16(2H,ABq),5.13(1H,d),5.32(2H,ABq),5.76(1H,d),6.81(1H,s),7.09(1H,s),7.68(1H,s),8.74(1H,s)
实施例7
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟-4-吡啶酮-2-基)甲氧亚氨乙酰胺基]-3-[1-(2-二甲氨乙基)-1H-四唑-5-基]硫基甲基-头孢-3-烯-4-羧酸
[A]5-巯基-1-(2-二甲氨乙基)-1H-四唑
NMR(D2O)δ;
2.64(6H,s),3.38(2H,t),3.51(2H,ABq),4.23(2H,ABq),4.72(2H,m),5.14(1H,d),5.31(2H,ABq),5.76(1H,d),6.73(1H,s),7.08(1H,s),7.64(1H,s)
实施例8
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟-4-吡啶酮-2-基)甲氧亚氨乙酰胺基]-3-[1-(2-羟乙基)-1H-四唑-5-基]硫基甲基-头孢-3-烯-4-羧酸
[A]5-巯基-1-(2-羟乙基)-1H-四唑
NMR(D2O)δ;
3.26(1H,d),3.72(1H,d),4.05(2H,m),4.09(1H,d),4.40(1H,d),4.57(2H,m),5.14(1H,d),5.30(1H,d),5.38(1H,d),5.79(1H,d),6.89(1H,s),7.09(1H,s),7.78(1H,s)
实施例9
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟-4-吡啶酮-2-基)甲氧亚氨乙酰胺基]-3-(4,5-二氢-4-甲基-5-氧代-6-羟-1,2,4-三嗪-3-基)硫基甲基-头孢-3-烯-4-羧酸A]3-巯基-4,5-二氢-4-甲基-5-氧代-6-羟-1,2,4-三嗪
NMR(D2O)δ;
3.23(1H,d),3.49(3H,s),3.73(1H,d),3.82(1H,d),4.54(1H,d),5.10(1H,d),5.25(1H,d),5.37(1H,d),5.77(1H,d),6.75(1H,s),7.08(1H,s),7.66(1H,s)
实施例10
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟-4-吡啶酮-2-基)甲氧亚氨乙酰胺基]-3-(2,5-二氢-4-甲基-5-氧代-6-羟-1,2,4-三嗪-3-基)硫基甲基-头孢-3-烯-4-羧酸
[A]3-巯基-2,5-二氢-2-甲基-5-氧代-6-羟-1,2,4-三嗪
NMR(D2O)δ;
3.43(2H,ABq),3.69(3H,s),4.22(2H,ABq),5.16(1H,d),5.33(2H,ABq),5.82(1H,d),6.86(1H,s),7.11(1H,s),7.74(1H,s)
实施例11
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟-4-吡啶酮-2-基)甲氧亚氨乙酰胺基]-3-(吡啶-4-基)硫基甲基-头孢-3-烯-4-羧酸
[A]4-巯吡啶
NMR(D2O)δ;
3.24(1H,d),3.65(1H,d),3.84(1H,d),4.49(1H,d),5.04(1H,d),5.24(1H,d),5.35(1H,d),5.74(1H,d),6.69(1H,s),7.08(1H,s),7.37(2H,d),7.59(1H,s),8.35(2H,d)
实施例12
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟-4-吡啶酮-2-基)甲氧亚氨乙酰胺基]-3-(1-环丙基吡啶鎓-4-基)硫基甲基-头孢-3-烯-4-羧酸
[A]1-环丙基-4-硫代吡啶
NMR(D2O)δ;
1.32(4H,m),3.46(2H,ABq),4.12(1H,m),4.30(2H,ABq),5.13(1H,d),5.30(2H,ABq),5.75(1H,d),6.74(1H,s),7.02(1H,s),7.63(1H,s),7.81(2H,d),8.54(2H,d)
实施例13
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟-4-吡啶酮-2-基)甲氧亚氨乙酰胺基]-3-(2,3-二氢-3-甲基-2-氧代-6-羟-1,3,5-三嗪-4-基)硫基甲基-头孢-3-烯-4-羧酸
[A]4-巯-2,3-二氢-3-甲基-2-氧代-6-羟-1,3,5-三嗪
NMR(D2O)δ;
3.45(3H,s),3.53(2H,ABq),4.27(2H,ABq),5.22(3H,m),5.82(1H,d),6.69(1H,s),7.10(1H,s),7.65(1H,s)
实施例14
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟-4-吡啶酮-2-基)甲氧亚氨乙酰胺基]-3-吡啶鎓甲基-头孢-3-烯-4-羧酸盐
(a)把4.41g(Z)-2-(2-三苯甲氨基噻唑-4-基)-2-(4-二苯甲氧基-5-对甲氧苄氧基吡啶-N-氧-2-基)甲氧亚氨乙酸乙酯(此化合物按照和实施例1(a)相似的方法制得,只是将(Z)-2-(2-三苯甲氨基噻唑-4-基)-2-羟亚氨乙酸烯丙酯用相应的乙酯化合物代替)溶于30ml乙醇及10ml四氢呋喃(THF)中。加入10ml 2N NaOH水溶液和5ml水,室温下反应4小时。
滤出形成的晶体,以THF-乙醇-水(1∶3∶5)混合液洗,再悬浮在30ml水中。在冰冷却下,加5ml 1N HCl,搅拌半小时。沉淀滤出,水洗,干燥,得2.55g(Z)-2-(2-三苯甲氨基噻唑-4-基)-2-(4-二苯甲氧基-5-对甲氧苄氧基吡啶-N-氧-2-基)甲氧亚氨乙酸。此化合物的光谱数据和实施例1(b)的化合物一致。
(b)在冰冷却下,把0.87mlN,N-二甲基甲酰胺及1.03ml磷酰氯加到8.1ml CH2Cl2中,搅拌1小时。把855mg(a)中制得(Z)-2-(2-三苯甲氨基噻唑-4-基)-2-(4-二苯甲氧基-5-对甲氧苄氧基吡啶-N-氧-2-基)甲氧亚氨乙酸溶于8.5ml CH2Cl2中,在-15℃向其中加入1ml上面制得的二氯甲烷溶液,在相同温度下反应1小时。此后,在-3℃将此反应混合物滴加到事先悬浮720mg(6R,7R)-7-氨基-3-吡啶翁甲基-头孢-3-烯-4-羧酸二盐酸盐于12ml乙腈并加入1.44ml双三甲硅基三氟乙酰胺使其溶解而得到的溶液中,再于冰冷却下反应1小时。反应后,反应混合物中加入100ml CH2Cl2,用15%食盐水洗2次,每次50ml。
用无水MgSO4干燥,浓缩,然后滤出加50ml乙醚后析出的沉淀,水洗,干燥,得1.15g(6R,7R)-7-[(Z)-2-(2-三苯氨基噻唑-4-基)-2-(4-二苯甲氧基-5-对甲氧苄氧基吡啶-N-氧-2-基)甲氧亚氨乙酰胺基]-3-吡啶鎓甲基-头孢-3-烯-4-羧酸盐酸盐。
(c)把600mg(b)中制得的3-吡啶鎓甲基化合物悬浮在1ml苯甲醚中,在冰冷却下加入2.25ml三氯乙酸,反应半小时。把反应混合物倾入40ml异丙醚中,滤出形成的沉淀,用异丙醚洗,再干燥。悬浮470mg所得沉淀,再在冰冷却下用饱和NaHCO3水溶液中和使之溶解。纯化是在Diaion HP-20上进行柱层析(用水和5%丙酮水溶液洗脱),再在Sephadex LH-20上进行柱层析(用50%甲醇水溶液洗脱),得84mg标题化合物的钠盐。
NMR(D2O)δ;
3.27(2H,ABq),5.21(1H,d),5.29(2H,ABq),5.48(2H,ABq),5.86(1H,d),6.73(1H,s),7.06(1H,s),7.54(1H,s),8.16(2H,m),8.64(1H,m),8.99(2H,d)
实施例15
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟-4-吡啶酮-2-基)甲氧亚氨乙酰胺基]-3-乙酰氧甲基-头孢-3-烯-4-羧酸
(a)把4.04g按照实施例1-(b)制得的羧酸和1.55g(6R,7R)-7-氨基-3-乙酰氧甲基-头孢-3-烯-4-羧酸叔丁酯溶于80ml CH2Cl2中,并冷却至-15℃。
加入1.53ml吡啶和0.49ml磷酰氯,在-15℃~-10℃搅拌半小时。反应混合物中加120ml食盐水,再用乙酸乙酯提取。用饱和NaCl水溶液洗两次,用NaHCO3水溶液洗一次,再用NaCl水溶液洗一次。用MgSO4脱水,浓缩,残余物进行硅胶柱层析法(250g)纯化(CHCl3∶CH3OH=30∶1),得3.56g(6R,7R)-7-[(Z)-2-(2-三苯甲氨基噻唑-4-基)-2-(4-二苯甲氧基-5-对甲氧苄氧基吡啶-N-氧-2-基)甲氧亚氨乙酰胺基]-3-乙酰氧甲基-头孢-3-烯-4-羧酸叔丁酯。
(b)把3.56g按(a)制得的化合物悬浮在3ml苯甲醚中,再于冰冷却下加入10ml三氟乙酸,室温反应2.5小时。把反应混合物滴加到80ml异丙醚中,滤出形成的沉淀,用异丙醚洗,再干燥。把2.21g所得沉淀悬浮在20ml水中,用饱和NaHCO3水溶液调节pH使之溶解。此溶液用HP-20(220ml)纯化。收集含所需化合物的流分(水~5%丙酮水溶液洗脱液),浓缩,冻干,得1.06g标题化合物的钠盐。
NMR(D2O)δ;
2.15(3H,s),3.22(1H,d),3.63(1H,d),4.74(1H,d),4.94(1H,d),5.19(1H,d),5.32(1H,d),5.40(1H,d),5.84(1H,d),6.94(1H,s),7.11(1H,s),7.82(1H,s)
实施例16
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟-4-吡啶酮-2-基)甲氧亚氨乙酰胺基]-3-(4-甲硫基吡啶鎓)甲基-头孢-3-烯-4-羧酸盐
(a)把120mg实施例1-(c)所得3-氯甲基化合物溶于1ml丙酮,再加入0.5ml含18mg碘化钠的丙酮溶液,室温反应45分钟。蒸去丙酮,再加1ml CH2Cl2,滤去不溶物以除去盐。蒸去CH2Cl2,残余物中加1ml乙腈和38mg 4-甲硫基吡啶,在搅拌下室温反应1.5小时。反应混合物中加0.05ml乙酸及10ml甲苯,蒸溶剂至干。残余物中加8ml乙酸乙酯及2ml异丙醚,搅拌,滤去不溶物,得100mg(6R,7R)-7-[(Z)-2-(2-三苯甲氨基噻唑-4-基)-2-(4-二苯甲氧基-5-对甲氧苄氧基吡啶-N-氧-2-基)甲氧亚氨乙酰胺基]-3-(4-甲硫吡啶鎓)甲基-头孢-3-烯-4-羧酸对甲氧苄酯。
(b)把100mg(a)中得到的3-取代化合物悬浮在0.07ml苯甲醚和1ml三氟乙酸中,加0.5ml甲酸,室温搅拌1小时。滤去不溶物,把滤液滴加到30ml异丙醚中,滤出形成的沉淀。此后把沉淀溶于1ml水中,在冰冷却下加饱和NaHCO3水溶液中和,再用HP-20进行柱层析提纯(以10%丙酮水溶液洗脱),得16g标题化合物的钠盐。
NMR(D2O)δ;
3.24(2H,AB,q),5.13(1H,d),5.21(1H,d),5.22(1H,d),5.36(1H,d),5.38(1H,d),5.83(1H,d),6.71(1H,s),7.01(1H,s),7.54(1H,s),7.81(2H,d),8.56(2H,d)
除分别用试剂[A]代替实施例16-(a)中的4-甲硫基吡啶外,按与该例相似的方法处理,制得以下实施例17-18的化合物。
实施例17
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟-4-吡啶酮-2-基)甲氧亚氨乙酰胺基]-3-(4-氨甲酰吡啶鎓)甲基-头孢-3-烯-4-羧酸盐
[A]异烟酰胺
NMR(D2O)δ;
2.94(1H,d),3.58(1H,d),5.17(1H,d),5.34(2H,ABq),5.40(1H,d),5.66(1H,d),5.83(1H,d),6.76(1H,s),7.02(1H,s),7.49(1H,s),8.43(2H,d),9.14(2H,d)
实施例18
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟-4-吡啶酮-2-基)甲氧亚氨乙酰胺基]-3-(异喹啉鎓-2-基)甲基-头孢-3-烯-4-羧酸盐
[A]异喹啉
NMR(D2O)δ;
2.94(1H,d),3.55(1H,d),5.15(2H,m),5.32(1H,d),5.48(1H,d),5.67(1H,d),5.83(1H,d),6.64(1H,s),7.03(1H,s),7.37(1H,s),8.07(1H,m),8.25(2H,m),8.45(3H,m),8.62(1H,d)
实施例19
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟-4-吡啶酮-2-基)甲氧亚氨乙酰胺基]-3-(4-环丙硫基吡啶鎓)甲基-头孢-3-烯-4-羧酸盐
把200mg(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟-4-吡啶酮-2-基)甲氧亚氨乙酰胺基]-3-乙酰氧甲基-头孢-3-烯-4-羧酸的钠盐溶于1ml乙腈及1ml水中,加入525mg碘化钠及160mg 4-环丙硫基吡啶,用10%磷酸水溶液调pH至6.5~7.0后,在65℃反应3小时。反应之后,加10ml丙酮,滤出形成的沉淀。此产物用HP-20柱(用5%丙酮水溶液洗脱)和Sephadex LH-20柱(以50%甲醇水溶液洗脱)进行层析,得15mg所要标题化合物的钠盐。
NMR(D2O)δ;
0.84(2H,bs),1.35(2H,m),2.42(1H,m),3.31(1H,ABq),5.1-5.5(5H,m),5.84(1H,d),6.71(1H,s),7.02(1H,s),7.55(1H,s),7.99(2H,d),8.56(2H,d)
实施例20
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟-4-吡啶酮-2-基)甲氧亚氨乙酰胺基]-3-(4-环丙甲硫基吡啶)甲基-头孢-3-烯-4-羧酸盐
除用4-环丙甲硫基吡啶代替4-环丙硫基吡啶外,重复同实施例17相似的方法,得到所要的标题化合物钠盐。
NMR(D2O)δ;
0.42(2H,m),0.72(2H,m),1.24(1H,m),3.03(2H,d),3.31(2H,ABq),5.1-5.4(5H,m),5.84(1H,d),6.72(1H,s),7.04(1H,s),7.60(1H,s),7.84(2H,d),8.56(2H,d)
实施例21
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟-4-吡啶酮-2-基)甲氧亚氨乙酰胺基]-3-(2,3-环戊烯并-1-甲基吡啶鎓-4-基)硫基甲基-头孢-3-烯-4-羧酸盐
(a)把4g 1,5-二对甲氧苄氧基-2-羟甲基-4-吡啶酮溶于100ml CH2Cl2,在-10℃向其中滴加2.2ml亚硫酰氯,在相同温度下反应1小时,在冰冷却下进一步反应2小时。
加入150ml饱和NaHCO3水溶液和50ml CH2Cl2。CH2Cl2层用无水MgSO4去水,浓缩。所得晶体用CH2Cl2洗,得3.05g 1,5-二对甲氧苄氧基-2-氯甲基-4-吡啶酮。把2.5g此产物溶于50ml N,N-二甲基甲酰胺,加入2.35g(Z)-2-(2-三苯甲氨基噻唑-4-基)-2-羟亚氨基乙酸烯丙酯和1.66g无水K2CO3,室温反应过夜。反应之后,反应混合物中加入150ml乙酸乙酯,再用水及15%食盐水洗,用无水MgSO4干燥,浓缩至约20ml。加20ml乙醚,滤出所得沉淀,得3.62g(Z)-2-(2-三苯甲氨基噻唑-4-基)-2-(1,5-二对甲氧苄氧基-4-吡啶酮-2-基)甲氧亚氨乙酸烯丙酯。
NMR(CDCl3)δ;
3.79(3H,s),3.81(3H,s),4.72(2H,d),4.96(2H,s),4.99(2H,s),5.09(2H,s),5.22(1H,d),5.33(1H,d),5.86(1H,m),6.47(1H,s),6.54(1H,s),6.8-7.0(5H,m),7.3(17H,m),7.19(2H,d)
(b)用3.39g该烯丙酯,按类似于实施例1-(b)的步骤操作,得2.65g(Z)-2-(2-三苯甲氨基噻唑-4-基)-2-(1,5-二对甲氧苄氧基-4-吡啶酮-2-基)甲氧亚氨乙酸。
将1.62g此产物悬浮在40ml CH2Cl2中,然后加入1.08g(6R,7R)-7-氨基-3-氯甲基-头孢-3-烯-4-羧酸对甲氧苄酯的对甲苯磺酸盐,再于-10℃加入0.8ml吡啶和0.2ml磷酰氯,反应1小时。反应后,加入80ml CH2Cl2和40ml15%盐水,有机层用15%盐水洗,用无水MgSO4干燥,浓缩至干。残余物用硅胶柱层析法提纯(CHCl3∶CH3OH=50∶1洗脱),得890mg(6R,7R)-7-[(Z)-2-(2-三苯甲氨基噻唑-4-基)-2-(1,5-二对甲氧苄氧基-4-吡啶酮-2-基)甲氧亚氨乙酰胺基]-3-氯甲基头孢-3-烯-4-羧酸对甲氧苄酯。
NMR(CDCl3)δ;
3.46(2H,ABq),3.77(3H,s),3.78(3H,s),3.79(3H,s),4.47(2H,ABq),4.9-5.1(7H,m),5.20(2H,ABq),5.79(1H,dd),6.43(1H,s),6.78(1H,s),6.88(6H,m),6.99(1H,s),7.17(2H,d),7.30(20H,m)
(c)将200mg(b)中得到的3-氯甲基化合物溶于0.5ml二甲亚砜中,加入36mg 1-甲基环戊烷并[b]4-硫代吡啶酮,反应1.5小时。加入10ml乙酸乙酯,滤出形成的沉淀。把沉淀悬浮在0.14ml苯甲醚中,加入0.43ml三氟乙酸,室温反应半小时。反应之后,把反应混合物滴加到8ml异丙醚中,滤出沉淀。将其干燥,然后悬浮在3ml水中,加1.1ml饱和NaHCO3水溶液使之溶解,溶液用HP-20柱层析进行纯化(以5%丙酮水溶液洗脱),得56mg所要的标题化合物钠盐。
此化合物的光谱数据同实施例4的化合物一致。
实施例22
注射制剂
把实施例1的化合物在无菌条件下分装入管形瓶中,使每瓶有1000mg[浓度]。
实施例23
胶囊
实施例1化合物 250份(浓度)
乳糖 60份(浓度)
硬脂酸镁 5份(浓度)
将以上成分均匀混合并装入胶囊,使每个胶囊含250mg(浓度)。
实施例24
直肠给药用的软胶囊
在由下列成份组成的基质中:
橄榄油 160份
聚氧乙烯月桂基醚 10份
六偏磷酸钠 5份
加入25份(浓度)实施例1化合物,均匀混合后,装入直肠给药用的软胶囊中,使每个胶囊中含250mg(浓度)。
实施例25
(6R,7R)-7-[Z]-2-(2-氨基噻唑-4-基)-2-(1,5-二羟-4-吡啶酮-2-基)甲氧亚氨乙酰胺基]-3-(1,2,3-噻二唑-5-基)硫基甲基-头孢-3-烯-4-羧酸
(a)使用13.29g在参考例4中制得的1-二苯甲氧基-5-对甲氧苄氧基-2-羟甲基-4-吡啶酮,按照和实施例21-(a)相似的步骤,制得19.05g(Z)-2-(2-三苯甲氨基噻唑-4-基)-2-(1-二苯甲氧基-5-对甲氧苄氧基-4-吡啶酮-2-基)甲氧亚氨乙酸。
NMR(CDCl3)δ;
3.75(3H,s),4.51(2H,s),5.08(2H,s),6.33(1H,s),6.56(1H,s),6.67(1H,s),6.79(2H,d),7.00(1H,s),7.09(2H,d),7.2-7.4(26H,m)
(b)把854mg(a)中得到的化合物溶解在20ml CH2Cl2中,再于冰冷却下加入540mg(6R,7R)-7-氨基-3-氯甲基-头孢-3-烯-4-羧酸对甲氧苄酯的对甲苯磺酸盐和0.4ml吡啶。
然后,于-10℃--15℃下滴加0.1ml三氯氧化磷,并于同样温度下反应30分钟。
反应后,加入20ml饱和NaCl和40ml乙酸乙酯,用饱和盐水洗有机层两次。用硫酸镁干燥,并减压浓缩至干,得到1.58g(6R,7R)-7-[(Z)-2-(2-三苯甲氨基噻唑-4-基)-2-(1-二苯甲氧基-5-对-甲氧苄氧基-4-吡啶酮-2-基)-甲氧基亚氨基乙酰氨基]-3-氯甲基头孢-3-烯-4-羧酸对-甲氧基苄酯粗粉末。
(c)将所得氯甲基化合物溶解于2ml二甲基亚砜中,加175mg 5-巯基-1,2,3-噻二唑的钠盐,并于室温下反应1小时。然后,按实施例1-(d)的类似方法进行,得到203mg标题化合物的钠盐。
所得化合物的NMR数据与实施例6化合物一致。
下面实施例26-46的化合物经类似于实施例23的方法处理,但实施例25(c)中的5-巯基-1,2,3-噻二唑分利用试剂[A]代替。
实施例26
(6R,7R)-7-[Z]-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧基亚氨基乙酰氨基]-3-(4-甲基噁唑-2-基)硫甲基-头孢-3-烯-4-羧酸
[A]2-巯基-4-甲基噁唑
NMR(D2O)δ;
2.13(3H,s),3.47(2H,ABq),4.18(2H,ABq),5.08(1H,d),5.30(2H,ABq),5.74(1H,d),6.72(1H,s),7.07(1H,s),7.64(1H,s)
实施例27
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧基亚氨基乙酰氨基]-3-(苯并噻唑-2-基)硫甲基-头孢-3-烯-4-羧酸
[A]2-巯基苯并噻唑
NMR(D2O)δ;
3.37(2H,ABq),4.32(2H,ABq),4.94(1H,d),5.25(2H,ABq),5.72(1H,d),6.67(1H,s),7.04(1H,s),7.42(1H,t),7.54(1H,t),7.57(1H,s),7.86(1H,d),7.91(1H,d)
实施例28
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧基亚氨基乙酰氨基]-3-(1,3,4-噻二唑-2-基)硫甲基-头孢-3-烯-4-羧酸
[A]2-巯基-1,3,4-噻二唑
NMR(D2O)δ;
3.49(2H,ABq),4.28(2H,ABq),5.10(1H,d),5.29(2H,ABa),5.75(1H,d),6.72(1H,s),7.07(1H,s),7.65(1H,s),9.43(1H,s)
实施例29
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧基亚氨基乙酰氨基]-3-(4-甲基-1,2,3-噻二唑-5-基)-硫甲基-头孢-3-烯-4-羧酸
[A]5-巯基-4-甲基-1,2,3-噻二唑
NMR(D2O)δ;
2.67(3H,s),3.23(1H,d),3.72(1H,d),3.79(1H,d),4.34(1H,d),5.12(1H,d),5.24(1H,d),5.36(1H,d),5.74(1H,d),6.72(1H,s),7.08(1H,s),7.62(1H,s)
实施例30
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧基亚氨基乙酰氨基]-3-(4-羟苯基)硫甲基-头孢-3-烯-4-羧酸
[A]4-羟基苯硫酚
NMR(D2O)δ;
3.14(1H,d),3.44(1H,d),3.66(1H,d),4.37(1H,d),4.98(1H,d),5.26(1H,d),5.33(1H,d),5.67(1H,d),6.69(1H,s),6.84(2H,d),7.07(1H,s),7.37(2H,d),7.60(1H,s)
实施例31
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧基亚氨基乙酰氨基]-3-(4-氟苯基)硫甲基-头孢-3-烯-4-羧酸
[A]4-氟苯硫酚
NMR(D2O)δ;
3.15(1H,d),3.52(1H,d),3.70(1H,d),4.44(1H,d),4.97(1H,d),5.23(1H,d),5.34(1H,d),5.65(1H,d),6.71(1H,s),7.10(3H,m),7.45(2H,m),7.63(1H,s)
实施例32
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧基亚氨基乙酰氨基]-3-(4-氨基甲酰基噻唑-5-基)硫甲基-头孢-3-烯-4-羧酸
[A]5-巯基-4-氨基甲酰基噻唑
NMR(D2O)δ;
3.20(1H,d),3.73(1H,d),3.74(1H,d),4.45(1H,d),5.06(1H,d),5.29(2H,ABq),5.74(1H,d),6.71(1H,s),7.07(1H,s),7.62(1H,s),8.92(1H,s)
实施例33
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧基亚氨基乙酰氨基]-3-(噻唑-5-基)硫甲基-头孢-3-烯-4-羧酸A]5-巯基噻唑
NMR(D2O)δ;
3.20(1H,d),3.52(1H,d),3.80(1H,d),4.33(1H,d),5.13(1H,d),5.31(2H,ABq),5.70(1H,d),6.73(1H,s),7.08(1H,s),7.62(1H,s),7.86(1H,s)9.02(1H,s)
实施例34
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧基亚氨基乙酰氨基]-3-(2-甲基-1,3,4-噻二唑-5-基)硫甲基-头孢-3-烯-4-羧酸
[A]5-巯基-2-甲基-1,3,4-噻二唑
NMR(D2O)δ;
2.75(3H,s),3.23(1H,d),3.74(1H,d),3.94(1H,d),4.50(1H,d),5.10(1H,d),5.31(2H,ABq),5.76(1H,d),6.72(1H,s),7.08(1H,s),7.63(1H,s)
实施例35
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧基亚氨基乙酰氨基]-3-(4-乙氧羰基-1,2,3-噻二唑-5-基)硫甲基-头孢-3-烯-4-羧酸
[A]5-巯基-4-乙氧羰基-1,3,4-噻二唑
NMR(D2O)δ;
1.43(3H,t),3.23(1H,d),3.58(1H,d),4.11(1H,d),4.41(1H,d),4.48(2H,q),5.11(1H,d),5.27(2H,ABq),5.80(1H,d),6.71(1H,s),7.01(1H,s),7.59(1H,s)
实施例36
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧基亚氨基乙酰氨基]-3-(4-氨基甲酰基-1,2,3-噻二唑-5-基)硫甲基-头孢-3-烯-4-羧酸
[A]5-巯基-4-氨基甲酰基-1,2,3-噻二唑
NMR(D2O)δ;
3.21(1H,d),3.60(1H,d),4.07(1H,d),4.38(1H,d),5.10(1H,d),5.26(2H,ABq),5.78(1H,d),6.70(1H,s),7.02(1H,a),7.58(1H,s)
实施例37
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧基亚氨基乙酰氨基]-3-(2-乙氧基-1,3,4-噻二唑-5-基)硫甲基-头孢-3-烯-4-羧酸
[A]5-巯基-2-乙氧基-1,3,4-噻二唑
NMR(D2O)δ;
1.46(3H,t),3.22(1H,d),3.76(1H,d),3.83(1H,d),4.44(1H,d),4.54(2H,q),5.12(1H,d),5.29(2H,ABq),5.74(1H,d),6.71(1H,s),7.07(1H,s),7.63(1H,s)
实施例38
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧基亚氨基乙酰氨基]-3-(2-乙氧基-1,3,4-噻二唑-5-基)硫甲基-头孢-3-烯-4-羧酸
[A]5-巯基-2-乙硫基-1,3,4-噻二唑
NMR(D2O)δ;
1.41(3H,t),3.22(1H,d),3.26(2H,q),3.72(1H,d),3.95(1H,d),4.50(1H,d),5.10(1H,d),5.28(2H,ABq),5.74(1H,d),6.71(1H,s),7.07(1H,a),7.62(1H,s)
实施例39
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧基亚氨基乙酰氨基]-3-(2-乙氧羰基-1,3,4-噻二唑-5-基)硫甲基-头孢-3-烯-4-羧酸
[A]5-巯基-2-乙氧羰基-1,3,4-噻二唑
NMR(D2O)δ;
1.41(3H,t),3.47(2H,ABq),4.35(2H,ABq),4.50(2H,q),5.12(1H,d),5.28(1H,ABq),5.77(1H,d),6.72(1H,s),7.04(1H,s),7.63(1H,s)
实施例40
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧基亚氨基乙酰氨基]-3-(2-氨基甲酰基-1,3,4-噻二唑-5-基)硫甲基-头孢-3-烯-4-羧酸A]5-巯基-2-氨基甲酰基-1,3,4-噻二唑
NMR(D2O)δ;
3.48(2H,ABq),4.33(2H,ABq),5.11(1H,d),5.28(2H,ABq),5.76(1H,d),6.70(1H,s),7.06(1H,s),7.60(1H,s)
实施例41
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧基亚氨基乙酰氨基]-3-(4-乙氧羰基噻唑-5-基)硫甲基-头孢-3-烯-4-羧酸
[A]5-巯基-4-乙氧羰基噻唑
NMR(D2O)δ;
1.45(3H,t),3.28(1H,d),3.72(1H,d),3.90(1H,d),4.47(2H,q),4.57(1H,d),5.10(1H,d),5.32(2H,ABq),5.78(1H,d),6.72(1H,s),7.10(1H,s),7.63(1H,s),8.93(1H,s)
实施例42
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧基亚氨基乙酰氨基]-3-(1,2,4-噻二唑-5-基)硫甲基-头孢-3-烯-4-羧酸
[A]5-巯基-1,2,4-噻二唑
NMR(D2O)δ;
3.31(1H,d),3.77(1H,d),4.20(1H,d),4.67(1H,d),5.16(1H,d),5.34(2H,ABq),5.83(1H,d),6.75(1H,s),7.13(1H,s),7.65(1H,s),8.66(1H,s)
实施例43
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧基亚氨基乙酰氨基]-3-(3-甲基-1,2,4-噻二唑-5-基)硫甲基-头孢-3-烯-4-羧酸
[A]5-巯基-3-甲基-1,2,4-噻二唑
NMR(D2O)δ;
2.63(3H,s),3.29(1H,d),3.72(1H,d),4.14(1H,d),4.61(1H,d),5.16(1H,d),5.34(2H,ABq),5.82(1H,d),6.77(1H,s),7.11(1H,s),7.67(1H,s)
实施例44
(6R,7R)-7-[(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧基亚氨基乙酰氨基]-3-(4-苯基噻唑-2-基)硫甲基-头孢-3-烯-4-羧酸
[A]2-巯基-4-苯基噻唑
NMR(D2O)δ;
3.43(2H,ABq),4.22(2H,ABq),5.00(1H,d),5.28(2H,ABq),5.72(1H,d),6.69(1H,s),7.06(1H,s),7.47-7.54(3H,m),7.62(1H,s),7.78(1H,s),7.86(2H,d)
实施例45
(6R,7R)-7-〔(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧亚氨基乙酰氨基〕-3-(噻唑-2-基)硫甲基-头孢-3-烯-4-羧酸
〔A〕2-巯基噻唑
NMR(D2O)δ;
3.50(2H,ABq),4.19(2H,ABq),5.09(1H,d),5.31(2H,ABq),5.74(1H,d),6.73(1H,s),7.09(1H,s),7.34(1H,s),7.64(1H,s),7.81(1H,s)
实施例46
(6R,7R)-7-〔(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧亚氨基乙酰氨基〕-3-(3,4-二氢-4-甲基-1,1,3-三氧代-2H-1,2,4,6-噻三嗪-5-基)硫甲基-头孢-3-烯-4-羧酸
〔A〕3,4,5,6-四氢-4-甲基-1,1,3-三氧代-2H-1,2,4,6-噻三嗪-5-硫酮
NMR(D2O)δ;
3.41(3H,s),3.51(2H,ABq),4.12(2H,ABq),5.17(1H,d),5.31(2H,ABq),5.81(1H,d),6.75(1H,s),7.09(1H,s),7.68(1H,s)
实施例47
(6R,7R)-7-〔(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧亚氨基乙酰氨基〕-3-甲基-头孢-3-烯-4-羧酸
(a)将(Z)-2-(2-三苯甲氨基噻唑-4-基)-2-(1-二苯甲氧基-5-对-甲氧基苄氧基-4-吡啶酮-2-基)甲氧亚氨基乙酸(427mg)和(6R,7R)-7-氨基-3-甲基-头孢-3-烯-4-羧酸叔丁酯(135mg)溶解于二氯甲烷(10ml)中,并冷却至10℃。然后,加吡啶(0.17ml),再加三氯氧化磷(52μl)于此溶液中,于-10℃--5℃下搅拌45分钟。加饱和NaCl水溶液于反应混合物中,然后,用乙酸乙酯提取。相继用饱和Nacl水溶液,饱和碳酸氢钠水溶液,饱和Nacl水溶液洗涤乙酸乙酯层,用硫酸镁干燥,并减压蒸出乙酸乙酯。残留物经硅胶(50g)柱色谱纯化,洗脱剂为CHCl3∶MeOH(30∶1,得到276mg(6R,7R)-7-〔(Z)-2-(2-三苯甲氨基噻唑-4-基)-2-(1-二苯甲氧基-5-对甲氧基苄氧基-4-吡啶酮-2-基)甲氧亚氨基乙酰氨基〕-3-甲基-头孢-3-烯-4-羧酸叔丁酯。
(b)将276mg(a)步所得化合物悬浮于苯甲醚(0.25ml)中,并在冰浴冷却下加三氟乙酸(1ml),然后,在室温下搅拌2.5小时。将反应混合物加到二异丙醚(30ml)中,并滤出沉淀。干燥后,将其悬浮于水(10ml)中,并用饱和碳酸氢钠水溶液调节至pH8.2使其溶解。此溶液用HP-20(100ml,水洗脱)和LH-20(50ml)纯化,含该化合物的馏份经冷冻干燥后,得41mg标题化合物的钠盐。
NMR(D2O)δ;
1.93(3H,s),3.05(1H,d),3.53(1H,d),5.12(1H,d),5.27(1H,d),5.36(1H,d),5.74(1H,d),6.78(1H,s),7.09(1H,s),7.69(1H,s)
实施例48
(6R,7R)-7-〔(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧亚氨基乙酰氨基〕-3-羟甲基-头孢-3-烯-4-羧酸
将(6R,7R)-7-〔(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧亚氨基乙酰氨基〕-3-乙酰氧甲基-头孢-3-烯-4-羧酸钠(100mg)溶解于50%甲醇水溶液(2ml)中,并冷却至-20℃。加1N NaOH(0.2ml)并在-20℃--25℃下搅拌30分钟。再次加1N NaOH(0.2ml)并于同样温度下再搅拌1小时。用1N Hcl调节至PH6并减压蒸出甲醇。用饱和碳酸氢钠水溶液调节至PH8,并用HP-20(70ml,水洗脱)和LH-20(50%甲醇水溶液)纯化此溶液,得到54mg标题化合物的钠盐。
NMR(D2O)δ;
3.27(1H,d),3.59(1H,d),4.27(1H,d),4.31(1H,d),5.15(1H,d),5.25(1H,d),5.35(1H,s),5.78(1H,d),6.73(1H,s),7.08(1H,s),7.64(1H,s)
用类似于实施例53的方法处理,但实施例53-(d)中的5-巯基-1,2,3-噻唑分别用试剂〔A〕代替,得到下面实施例49-50的化合物。
实施例49
(6R,7R)-7-〔(Z)-2-(2-氨基噻唑-4-基)-2-〔(RS)-1-(1,5-二羟基-4-吡啶酮-2-基)乙氧亚氨基〕乙酰氨基〕-3-〔1-(2-二甲氨基乙基)-1H-四唑-5-基〕硫甲基-头孢-3-烯-4-羧酸
〔A〕5-巯基-1-(2-二甲氨基乙基)-1H-四唑
NMR(D2O)δ;
1.61(3H,t),2.40(3H,s),2.41(3H,s),3.10(2H,m),3.33(1/2H,d),3.52(1/2H,d),3.77(1/2H,d),3.83(1/2H,d),4.13(1/2H,d),4.15(1/2H,d),4.38(1/2H,d),4.41(1/2H,d),4.60(2H,m),5.15(1/2H,d),5.26(1/2H,d),5.80(2H,m),6.63(1/2H,s),6.73(1/2H,s),7.04(1H,s),7.59(1H,s)
实施例50
(6R,7R)-7-{(Z)-2-(2-氨基噻唑-4-基)-2-〔(RS)-1-(1,5-二羟基-4-吡啶酮-2-基)乙氧亚氨基〕乙酰氨基}-3-(1,2,4-噻二唑-5-基)硫甲基-头孢-3-烯-4-羧酸
〔A〕5-巯基-1,2,4-噻二唑
NMR(D2O)δ;
1.61(3H,t),3.28(1/2H,d),3.49(1/2H,d),3.70(1/2H,d),3.80(1/2H,d),4.13(1/2H,d),4.17(1/2H,d),4.63(1/2H,d),4.67(1/2H,d),5.12(1/2H,d),5.23(1/2H,d),5.8-5.9(2H,m),6.64(1/2H,s),6.76(1/2H,s),7.03(1H,s),7.62(1/2H,s),7.63(1/2H,s),8.60(1H,s)
实施例51
(6R,7R)-7-〔(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧亚氨基乙酰氨基〕-3-乙烯基-头孢-3-烯-4-羧酸
(a)重复类似于实施例47-(a)的过程,但用198mg(6R,7R)-7-氨基-3-乙烯基-头孢-3-烯-4-羧酸二苯甲酯代替(6R,7R)-7-氨基-3-甲基-头孢-3-烯-4-羧酸叔丁酯,得到400mg(6R,7R)-7-〔(Z)-2-(2-三苯甲氨基噻唑-4-基)-2-(4-二苯甲氧基-5-对-甲氧基苄氧基吡啶-N-氧-2-基)-甲氧亚氨基乙酰氨基〕-3-乙烯基-头孢-3-烯-4-羧酸二苯甲酯。
(b)将380mg(a)步所得化合物溶解于0.41ml苯甲醚中,并在冰浴冷却下加1.22ml三氟乙酸,然后,在同样温度下反应1小时。将反应混合物滴加到30ml二异丙醚中,滤出生成的沉淀,用二异丙醚洗涤,干燥。将170mg所得沉淀物悬浮于3ml水中,加饱和碳酸氢钠水溶液至PH7.9,使其溶解,然后,往Diaion HP-20柱色谱(用水-5%丙酮水溶液洗脱)和Sephadex LH-20柱色谱(用50%MeOH水溶液洗脱)纯化,得到80mg标题化合物。
NMR(D2O)δ;
3.54(2H,s),5.18(1H,d),5.29(1H,d),5.30(2H,ABq),5.47(1H,d),5.79(1H,d),6.71(1H,s),6.75(1H,dd),7.09(1H,s),7.62(1H,s)
实施例52
(6R,7R)-7-〔(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧亚氨基乙酰氨基〕-3-叠氮甲基-头孢-3-烯-4-羧酸
将58mg(6R,7R)-〔(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)甲氧亚氨基乙酰氨基〕-3-乙酰氧甲基-头孢-3-烯-4-羧酸钠溶解于1ml水中,加20mg叠氮化钠,并在以饱和碳酸氢钠水溶液调节至PH6.5-6.8后,于60-65℃下反应4.5小时。反应混合物直接用HP-20柱色谱(水洗脱)和LH-20柱色谱(50%甲醇水溶液洗脱)纯化,得到标题化合物的钠盐。
NMR(D2O)δ;
3.42(2H,ABq),4.11(2H,ABq),5.17(1H,d),5.30(2H,ABq),5.80(1H,d),6.70(1H,s),7.08(1H,s),7.61(1H,s)
实施例53
(6R,7R)-7-{(Z)-2-(2-氨基噻唑-4-基)-2-〔(RS)-1-(1,5-二羟基-4-吡啶酮-2-基)乙氧亚氨基〕乙酰氨基}-3-(1,2,3-噻二唑-5-基)-硫甲基-头孢-3-烯-4-羧酸
(a)将2g1,5-二-对-甲氧基苄氧基-2-羟甲基-4-吡啶酮溶解于50ml乙腈中,加10g活性二氧化锰,并于50℃下反应3.5小时。
反应完成后滤出二氧化锰,然后,用乙腈洗涤并减压浓缩滤液。将残余物溶于100ml二氯甲烷,水洗,无水硫酸镁干燥,减压浓缩,然后,用硅胶柱色谱(洗脱剂为氯仿∶甲醇=50∶1)纯化,得到1.15g2-甲酰基-1,5-二-对-甲氧基苄氧基-4-吡啶酮。
NMR(CDCl3)δ;
3.81(3H,s),3.82(3H,s),5.00(2H,s),5.08(2H,s),6.72(1H,s),6.84(2H,d),6.89(2H,d),7.05(2H,d),7.10(1H,s),7.31(2H,d),9.60(1H,s)
(b)将1.09g此甲酰基化合物悬浮于20mlTHF中,在冰浴冷却下加7.5ml1M甲基溴化镁的四氢呋喃溶液,并在同样温度下反应1小时。将30ml稀氯化铵水溶液加到此反应混合物中,然后,用120ml乙酸乙酯提取。用水洗提取液,无水硫酸镁干燥并减压浓缩。残余物经硅胶柱色谱(氯份∶甲醇=50∶1洗脱)纯化,得到530mg1,5-二-对-甲氧基苄氧基-2-〔(RS)-1-羟乙基〕-4-吡啶酮。
NMR(CDCl3)δ;
1.44(3H,d),3.79(3H,s),3.80(3H,s),4.87(2H,ABq),4.95(1H,q),5.04(2H,ABq),6.54(1H,s),6.80(2H,d),6.90(2H,d),6.99(1H,s),7.21(2H,d),7.25(2H,d)
(c)按照类似于实施例19(a)和(b)的步骤,使用495mg上面(b)步所得醇化合物,得到320mg(6R,7R)-7-{(Z)-2-(2-三苯甲氨基噻唑-4-基)-2-〔(RS)-1-(1,5-二-对-甲氧基苄氧基-4-吡啶酮-2-基)乙氧亚氨基〕乙酰氨基}-3-氯甲基-头孢-3-烯-4-羧酸对-甲氧基苄酯。
(d)将150mg上面所得氯甲基化合物溶解于0.4ml二甲基亚砜中,加30mg5-巯基-1,2,3-噻二唑,并在室温下反应1小时。接着,按照类似实施例1-(d)的步骤进行,得到51mg标题化合物的钠盐。
NMR(D2O)δ;
1.57(3/2H,d),1.62(3/2H,d),3.48(1H,ABq),3.60(1H,ABq),4.11(1H,ABq),4.16(1H,ABq),5.12(1/2H,d),5.21(1/2H,d),5.75(1/2H,d),5.78(1/2H,d),5.81(1H,q),6.61(1/2H,s),6.71(1/2H,s),7/02(1/2H,s),7/04(1/2H,s),7.54(1/2H,s),7.56(1/2H,s),8.72(1H,s)
实施例54
(6R,7R)-7-{(Z)-2-(2-氨基噻唑-4-基)-2-〔(RS)-1-(1,5-二羟基-4-吡啶酮-2-基)丙氧亚氨基〕乙酰氨基}-3-(1,2,3-噻二唑-5-基)-硫甲基-头孢-3-烯-4-羧酸
按照类似实施例53的方法,但用乙基溴化镁代替实施例53-(b)中的甲基镁化溴,得到标题化合物。
NMR(D2O)δ;
1.03(3H,t),2.00(2H,m),3.40(1/2H,d),3.51(1/2H,d),3.77(1/2H,d),3.83(1/2H,d),3.97(1/2H,d),4.01(1/2H,d),4.43(1/2H,d),4.46(1/2H,d) 5.20(1/2H,d),5.27(1/2H,d),5.68(1H,m),5.83(1H,d),6.61(1/2H,s),6.72(1/2H,s),7.08(1H,s),7.62(1H,s),8.77(1H,s)
实施例55
(6R,7R)-7-{(Z)-2-(2-氨基噻唑-4-基)-2-〔(RS)-1-苯基-1-(1,5-二羟基-4-吡啶酮-2-基)甲氧亚氨基〕乙酰氨基}-3-(1,2,3-噻二唑-5-基)-硫甲基-头孢-3-烯-4-羧酸
按照类似实施例53的方法,但用苯基镁化溴代替实施例53-(b)中的甲基镁化溴,得到标题化合物。
NMR(D2O)δ;
3.10(1/2H,d),3.15(1/2H,d),3.51(1/2H,d),3.64(1/2H,d),3.97(1/2H,d),4.02(1/2H,d),4.25(1/2H,d),4.31(1/2H,d),5.07(1/2H,d),5.12(1/2H,d),5.68(1/2H,d),5.73(1/2H,d),6.68(1/2H,s),6.76(1/2H,s),6.82(1/2H,s),6.95(1/2H,s),7.11(1/2H,s),7.12(1/2H,s),7.40(5H,s),7.77(1/2H,s),7.82(1/2H,s),8.74(1/2H,s),8.75(1/2H,s)
试验实施例
本发明的通式(Ⅰ)化合物或其盐是一类新化合物,这类化合物具有良好的抗菌活性,它能在包括草兰氏阳性和草兰氏阴性微生物在内的很宽的范围内抑制病原微生物的生长。为了演示本发明通式(Ⅰ)化合物的效用,表1给出代表性的通式(Ⅰ)化合物的抗菌活性值。
在7-位上有(Z)-2-(2-氨基噻唑-4-基)-2-(1,5-二羟基-4-吡啶酮-2-基)烷氧亚氨基基团的化合物与1-位(N-位)上无羟基的5-羟基-5-吡啶酮-2-烷氧亚氨基化合物或4,5-二羟基苄氧亚氨基化合物相比,呈现抗菌活性,特别是对草兰氏阴性微生物(包括绿脓假单孢菌)具有极优良的抗菌活性,并且在水中的溶解性很好,而这一点对于注射应用是很重要的。
用小鼠测定了本发明化合物的急性毒性,其LD50为2g/kg或更高,这表明毒性很低。
Claims (11)
3、按照权利要求1或2的方法,其中通式Ⅰ中的R1为氢和R2为氢。
4、按照权利要求1的方法,其中通式Ⅰ中的R1为氢和R2为甲基。
5、按照权利要求1的方法,其中通式Ⅰ中的R1为氢和R2为乙基。
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EP (1) | EP0289002B1 (zh) |
KR (1) | KR960015033B1 (zh) |
CN (1) | CN1022629C (zh) |
AT (1) | ATE113286T1 (zh) |
CA (1) | CA1339417C (zh) |
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CN110655526A (zh) * | 2018-06-28 | 2020-01-07 | 中国科学院上海药物研究所 | 头孢菌素-铁载体轭合物及其制备方法和用途 |
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JPH0633281B2 (ja) * | 1987-11-11 | 1994-05-02 | 明治製菓株式会社 | 新規セファロスポリン化合物及び抗菌剤 |
JPH0248580A (ja) * | 1988-08-10 | 1990-02-19 | Meiji Seika Kaisha Ltd | 新規セファロスポリン系化合物及び抗菌剤 |
DE3923541A1 (de) * | 1989-07-15 | 1991-01-24 | Hoechst Ag | Cephalosporinderivate und verfahren zu ihrer herstellung |
EP0544958A1 (en) * | 1990-08-09 | 1993-06-09 | Tanabe Seiyaku Co., Ltd. | Cephalosporin compounds and processes for preparing the same |
EP0579221A1 (en) * | 1992-07-17 | 1994-01-19 | Takeda Chemical Industries, Ltd. | Cephem compounds, their production and use |
CA2952968A1 (en) | 2014-07-01 | 2016-01-07 | Rempex Pharmaceuticals, Inc. | Boronic acid derivatives and therapeutic uses thereof |
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JPS60140989A (ja) | 1983-12-27 | 1985-07-25 | Sony Corp | 走査線変換方法 |
JPS6177894A (ja) | 1984-09-25 | 1986-04-21 | 株式会社東芝 | デ−タ表示装置 |
AU586229B2 (en) * | 1985-04-01 | 1989-07-06 | Mochida Pharmaceutical Co., Ltd. | Cephalosporin derivatives |
US4758557A (en) * | 1985-06-26 | 1988-07-19 | Meiji Seika Kaisha, Ltd. | Cephalosporin derivatives and bactericides containing the same |
CA1283404C (en) * | 1986-07-01 | 1991-04-23 | Shigeru Sanai | Cephalosporin compounds, processes for their preparation and antibacterial agents |
JPH0633281B2 (ja) * | 1987-11-11 | 1994-05-02 | 明治製菓株式会社 | 新規セファロスポリン化合物及び抗菌剤 |
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1988
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- 1988-04-27 EP EP88106760A patent/EP0289002B1/en not_active Expired - Lifetime
- 1988-04-27 AT AT88106760T patent/ATE113286T1/de active
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CN110655526A (zh) * | 2018-06-28 | 2020-01-07 | 中国科学院上海药物研究所 | 头孢菌素-铁载体轭合物及其制备方法和用途 |
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DE3851906D1 (de) | 1994-12-01 |
IE881280L (en) | 1988-10-30 |
KR880012608A (ko) | 1988-11-28 |
CA1339417C (en) | 1997-09-02 |
ATE113286T1 (de) | 1994-11-15 |
EP0289002A3 (en) | 1990-11-22 |
CN1022629C (zh) | 1993-11-03 |
US5028601A (en) | 1991-07-02 |
DE3851906T2 (de) | 1995-04-27 |
EP0289002A2 (en) | 1988-11-02 |
IE66264B1 (en) | 1995-12-27 |
ES2067453T3 (es) | 1995-04-01 |
EP0289002B1 (en) | 1994-10-26 |
KR960015033B1 (ko) | 1996-10-24 |
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