NO801402L - Cefalosporin-mellomprodukt for fremstilling av terapeutisk aktive cefalosporinderivater - Google Patents
Cefalosporin-mellomprodukt for fremstilling av terapeutisk aktive cefalosporinderivaterInfo
- Publication number
- NO801402L NO801402L NO80801402A NO801402A NO801402L NO 801402 L NO801402 L NO 801402L NO 80801402 A NO80801402 A NO 80801402A NO 801402 A NO801402 A NO 801402A NO 801402 L NO801402 L NO 801402L
- Authority
- NO
- Norway
- Prior art keywords
- acid
- alkyl
- ester
- cephalosporine
- group
- Prior art date
Links
- HOKIDJSKDBPKTQ-UHFFFAOYSA-N 3-(acetyloxymethyl)-7-[(5-amino-5-carboxypentanoyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C(NC(=O)CCCC(N)C(O)=O)C12 HOKIDJSKDBPKTQ-UHFFFAOYSA-N 0.000 title 2
- 239000013067 intermediate product Substances 0.000 title 1
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000003831 tetrazolyl group Chemical class 0.000 claims description 6
- 125000001113 thiadiazolyl group Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 150000001768 cations Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 229930186147 Cephalosporin Natural products 0.000 claims 2
- 229940124587 cephalosporin Drugs 0.000 claims 2
- 150000001780 cephalosporins Chemical class 0.000 claims 2
- -1 1-aminopropyl Chemical group 0.000 description 66
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000002253 acid Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- 239000007795 chemical reaction product Substances 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- YGBFLZPYDUKSPT-MRVPVSSYSA-N cephalosporanic acid Chemical class S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C[C@H]21 YGBFLZPYDUKSPT-MRVPVSSYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 150000003839 salts Chemical group 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 150000008065 acid anhydrides Chemical class 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
- 125000004103 aminoalkyl group Chemical class 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 238000010531 catalytic reduction reaction Methods 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920000388 Polyphosphate Polymers 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000001205 polyphosphate Substances 0.000 description 2
- 235000011176 polyphosphates Nutrition 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 125000005270 trialkylamine group Chemical group 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- QCRRYVOUDYRBOP-IOJJLOCKSA-N (6r)-7-amino-3-[[5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl]sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S([C@@H]1C(C(N1C=1C(O)=O)=O)N)CC=1CSC1=NN=C(CO)S1 QCRRYVOUDYRBOP-IOJJLOCKSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LLAPDLPYIYKTGQ-UHFFFAOYSA-N 1-aminoethyl Chemical group C[CH]N LLAPDLPYIYKTGQ-UHFFFAOYSA-N 0.000 description 1
- ORLCYMQZIPSODD-UHFFFAOYSA-N 1-chloro-2-[chloro(2,2,2-trichloroethoxy)phosphoryl]oxybenzene Chemical compound ClC1=CC=CC=C1OP(Cl)(=O)OCC(Cl)(Cl)Cl ORLCYMQZIPSODD-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- AMOYMEBHYUTMKJ-UHFFFAOYSA-N 2-(2-phenylethoxy)ethylbenzene Chemical compound C=1C=CC=CC=1CCOCCC1=CC=CC=C1 AMOYMEBHYUTMKJ-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- AVZBOAGCVKEESJ-UHFFFAOYSA-O 2-ethyl-1,2-benzoxazol-2-ium-7-ol Chemical class C1=CC(O)=C2O[N+](CC)=CC2=C1 AVZBOAGCVKEESJ-UHFFFAOYSA-O 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 1
- SDXAWLJRERMRKF-UHFFFAOYSA-N 3,5-dimethyl-1h-pyrazole Chemical compound CC=1C=C(C)NN=1 SDXAWLJRERMRKF-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- IGIJSFNBEUBMGB-UHFFFAOYSA-N 4-(cyclohexyliminomethylideneamino)-n,n-diethylcyclohexan-1-amine Chemical compound C1CC(N(CC)CC)CCC1N=C=NC1CCCCC1 IGIJSFNBEUBMGB-UHFFFAOYSA-N 0.000 description 1
- SXIFAEWFOJETOA-UHFFFAOYSA-N 4-hydroxy-butyl Chemical group [CH2]CCCO SXIFAEWFOJETOA-UHFFFAOYSA-N 0.000 description 1
- MLXPGVGNTLPQIY-UHFFFAOYSA-N 5-(hydroxymethyl)-3h-1,3,4-thiadiazole-2-thione Chemical compound OCC1=NN=C(S)S1 MLXPGVGNTLPQIY-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- HDFFVHSMHLDSLO-UHFFFAOYSA-N Dibenzyl phosphate Chemical compound C=1C=CC=CC=1COP(=O)(O)OCC1=CC=CC=C1 HDFFVHSMHLDSLO-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- ASMQGLCHMVWBQR-UHFFFAOYSA-N Diphenyl phosphate Chemical compound C=1C=CC=CC=1OP(=O)(O)OC1=CC=CC=C1 ASMQGLCHMVWBQR-UHFFFAOYSA-N 0.000 description 1
- 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 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 125000005118 N-alkylcarbamoyl group Chemical group 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000005076 adamantyloxycarbonyl group Chemical group C12(CC3CC(CC(C1)C3)C2)OC(=O)* 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 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
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- UHAAFJWANJYDIS-UHFFFAOYSA-N n,n'-diethylmethanediimine Chemical compound CCN=C=NCC UHAAFJWANJYDIS-UHFFFAOYSA-N 0.000 description 1
- VMESOKCXSYNAKD-UHFFFAOYSA-N n,n-dimethylhydroxylamine Chemical compound CN(C)O VMESOKCXSYNAKD-UHFFFAOYSA-N 0.000 description 1
- RZLQZPMXRKQEPL-UHFFFAOYSA-N n-[(2-sulfanylidene-3h-1,3,4-thiadiazol-5-yl)methyl]acetamide Chemical compound CC(=O)NCC1=NN=C(S)S1 RZLQZPMXRKQEPL-UHFFFAOYSA-N 0.000 description 1
- JVHPKYBRJQNPAT-UHFFFAOYSA-N n-cyclohexyl-2,2-diphenylethenimine Chemical compound C1CCCCC1N=C=C(C=1C=CC=CC=1)C1=CC=CC=C1 JVHPKYBRJQNPAT-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 125000001715 oxadiazolyl group Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- CMPQUABWPXYYSH-UHFFFAOYSA-N phenyl phosphate Chemical compound OP(O)(=O)OC1=CC=CC=C1 CMPQUABWPXYYSH-UHFFFAOYSA-N 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 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
- 159000000001 potassium salts Chemical class 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical class 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 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 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229920001567 vinyl ester resin Polymers 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Description
Foreliggende oppfinnelse angår hittil ukjente cefalosporan7syrederivater som kan anvendes som utgangsmateriale for fremstilling av nye antibakterielt aktive cefalosporansyredérivater med den generelle formel I
hvor
R er acyl,
R 2 er en amino-lavere-alkyl-, lavere alkanoylamino-lavere-alkyl-,
lavere alkoksykarbonylamino-lavere-alkyl-, lavere alkan-sulfonylamino-lavere-alkyl-, lavere alkoksykarbonylamino-lavere-alkanoylamino-lavere-alkyl-, lavere alkylureido-lavere-alkyl-, guanidino-karbonylamino-lavere-alkyl- eller hydroksy-lavere-alkyl-substituert tiadiazolyl- eller tetrazolylgruppe, og
M er et hydrogenatom eller et ugiftig, farmasøytisk godtagbart kation^.
Betegnelsen "acyl", som er angitt som betydningen av R , betyr særlig en lavere alkanoylgruppe som er substituert med en lavere alkyltiogruppe, en fenylgruppe eller en lavere alkyl-substituert oksadiazolyl-, tienyl- eller tetrazolylgruppe,
idet alkyldelen av den lavere alkanoylgruppe kan være ytterligere substituert med en hydroksygruppe, en aminogruppe eller en lavere alkoksykarbonylaminogruppe,
"Amino-lavere-alkyl", som er en substituent i tiadiazolyl-eller .tetrazolylgruppen, er f;eks. aminometyl, 1-aminoetyl, 2-aminoetyl, 1-aminopropyl, 2-aminopropyl, 3-aminopropy1, 1-aminobutyl, 2-aminobutyl, 3-aminobutyl, 4-aminobuty1, 5-amino-pentyl, 6-aminoheksyl, 2-aminoisopropyl og 3-aminoisobutyl.
Andre substituenter er f.eks. en alkoksykarbonyl-substituert aminoalkylgruppe, hvor alkoksykarbonylgruppen kan være metoksykarbonyl, etoksykarbonyl, propoksykarbonyl, isopropoksykarbonyl, butoksykarbonyl, isobutoksykarbonyl og tért.butoksykarbonyl, en alkansulfonylsubstituert aminoalkyl gruppe, hvor alkansulfonylgruppen kan være metansulfony1, etansulfonyl, propansulfony1, isopropansulfonyl, butansulfonyl, isobutansulfonyl, tert.butansulfonyl, pentansulfonyl og heksan-sulfonyl, en N-alkyl-karbamoylsubstituert aminoalkylgruppe, hvor N-alkylkarbamoylgruppen kan være N-metylkarbamoy1, N-etylkarbamoyl og N-propylkarbamoyl, og en 1-guanidino-karbonylsubstituert aminoalkylgruppe.
"Hydroksy-lavere-alkyl", som er en annen substituent i tiadiazol- eller tetrazolylgruppen, er f.eks. hydroksymetyl, 1-hydroksyetyl, 2-hydroksyetyl, 1-hydroksypropyl, 2-hydroksypropyl, 3-hydroksypropyl, 1-hydroksybutyl, 2-hydroksybutyl, 3-hydroksybutyl, 4-hydroksybutyl, 5-hydroksypentyl, 6-hydroksy-heksyl, 2-hydroksyisopropyl og 3-hydroksyisobutyl.
De nye forbindelser i henhold til oppfinnelsen har den generelle formel
hvor R 2 og M har den ovenfor angitte betydning.
De her omhandlede cefalosporansyredérivater med den generelle formel IV kan fremstilles ved at en 7-substituert cefalosporansyre med den generelle formel II
hvor R^ betegner en alkanoylgruppe og M har den ovenfor angitte betydning, omsettes med en tiolforbindelse med den generelle formel III
hvor R 2hår den ovenfor angitte betydning, eller et alkalimetallsalt derav.
Betegnelsen "alkanoyl", som er angitt i sammenheng med R 3 i formel II, angir f.eks. acetyl, propionyl, butyryl, pentanoyl! og heksanoyl.
Alkalimetallsalter av tiolforbindelsen med den generelle formel III kan f.eks. være natrium- eller kaliumsalter.
Omsetningen av en 7-substituert cefalosporansyre med den generelle formel II med en tiolforbindelse med den generelle formel III eller et alkalimetallsalt derav kan utføres i et opp-løsningsmiddel så som vann, aceton, kloroform, nitrobenzen, dimetylformamid, metanol, etanol, dimétylsulfoksyd eller et hvilket som helst organisk oppløsningsmiddel, som er inert overfor reaksjonen, fortrinnsvis i et sterkt polart oppløsningsmiddel. Det kan som oppløsningsmidler anvendes hydrofile oppløsnings-midler i blanding med vann. Omsetningen utføres fortrinnsvis i omtrentlig nøytralt medium. Når . forbindelsen med den generelle formel II eller tiolforbindelsen med den generelle formel III anvendes i fri form, utføres omsetningen fortrinnsvis i nærvær av en base så som et alkalimetallhydroksyd, alkalimetallkarbonåt, alkalimetallbikarbonat eller et trialkylamin. Reaksjonstemperaturen er ikke begrenset, og omsetningen utføres vanligvis ved romtemperatur eller under oppvarmning. Reaksjonsproduktet kan under anvendelse av konvensjonell fremgangsmåter isoleres fra reaksjonsblandingen.
Når omsetningen utføres under anvendelse av en forbindelse med den generelle formel III, hvor R 2er en amino-lavere-alkyl-substituert tiadiazolyl- eller tetrazolylgruppe, kan de frie aminogrupper beskyttes under anvendelse av konvensjonelle beskyttelsesgrupper. I dette tilfelle kan amino-beskyttelsesgruppen om nødvendig fjernes fra reaksjonsproduktet.
Fjernelsen av aminobeskyttelsesgruppen kan utføres under anvendelse av en konvensjonell fremgangsmåte så som spaltning med syre og katalytisk reduksjon, og fremgangsmåten velges avhengig av arten åv beskyttelsesgruppen på aminogruppen. Spaltningen med syre er. en av de mest egnede fremgangsmåter og kan anvendes til fjernelse av substituenter så som benzyloksykarbonyl, substituert benzyloksykarbonyl, alkoksykarbonyl, substituert alkoksykarbonyl, aralkoksykarbony1, adamantyloksy-karbonyl, trityl, substituert fenyltio, substituert aralkyliden, substituert alkyliden og substituert cykloalkyliden.. Den til den ovenfor angitte omsetning anvendte syre velges avhengig av arten av aminobeskyttelsesgruppen, og egnede syrer er f.eks.I maursyre og trifluoreddiksyre, som lett avdampes under redusert trykk. Når spaltningen med syre utføres i et oppløsningsmiddel, kan det som oppløsningsmiddel anvendes et hydrofilt organisk oppløsningsmiddel, vann eller en blanding derav. Den kata-lytiske reduksjon kan anvendes til fjernelse av amino-beskyttelsesgrupper så som benzyloksykarbonyl, substituert benzyloksykarbonyl og 2-pyridyImetoksykarbony 1. En egnet katalysator er palladium, men det kan også anvendes andre katalysatorer,.som konvensjonelt anvendes til katalytisk reduksjon.
Trifluoracetylgruppen kan fjernes ved behandling av reaksjonsproduktet med vann, og halogensubstituerte alkoksy-karbonylgrupper og 8-kinolyloksykarbonylgrupper kan fjernes ved behandling av reaksjonsproduktet med et tungmetall så som kobber og sink. Fjernelsen av aminobeskyttelsesgruppen kan utføres uten isolering og rensning av reaks jonsproduktet 'fra • reaksjonsmediet.
Forbindelsene med den generelle formel I kan fremstilles ved at en forbindelse med den generelle formel IV eller et derivat derav ved aminogruppen og/eller karboksylgruppen, omsettes med en organisk karboksylsyre med den generelle formel V
hvor R''" har den ovenfor angitte betydning, eller et reaktivt derivat derav ved karboksylgruppen.
Derivatet av forbindelsen med den generelle formel IV ved karboksylgruppen kan være et salt så som et magnesiumsalt, kalsium-salt eller trietylaminsalt, en ester så som en metylester, etyl-ester, propylester, butylester, pentylester, trimetylsilylester, 2-mesyletylester, 2-jodetylester, 2,2,2-trikloretylester, benzyl-ester, 4-metoksybenzylester, 4-nitrobenzylester, fenacylester, fenetylester, tritylester, difenylmetylester, bis (metoksyfenyl)-metylester, 3,4-dimetoksybenzylester, (1-cyklopropyl)etylester, etynylester eller 4-hydroksy-3,5-di-tert.butylbenzylester, et
aktivert amid, et syrcanhydrid el.':i.r ct syrchalocjenid.
Derivatet av forbindelsen med den generelle formel IV ved aminogruppen kan være reaksjonsproduktet av en forbindelse med den generelle formel IV og en silylforbindelse så som bis (trimetyl- 'i silyl)acetamido.
Det reaktive derivat av den organiske karboksylsyre med den generelle formel V ved karboksylgruppen kan være et syre-halogenid, et syrcanhydrid, et aktivert amid eller en aktivert ester. Som eksempler på egnede forbindelser kan angis ot syre-klorid, et syreazid, et blandet syreanhydrid med en syre så som en dialkylfosforsyre, fenylfosforsyre, difenylfosforsyre, dibenzyl-fosforsyre,. halogenert fosforsyre, dialkylfosforsyrling, svovel-syrling, tiosvovelsyre, svovelsyre, alkylkarbonsyre, alifatisk karboksylsyre (f.eks. pivalinsyre, pentansyre, isopentansyre, 2,-etylsmørsyre eller trikloreddiksyrc) eller aromatisk karboksylsyre (f;eks. benzocsyre), et symmetrisk syreanhydrid, et syreamid med imidazol, 4-substituert imidazol, dimetylpyrazol, triazol eller tetrazol eller en ester (f.eks. cyanometylester, metoksy-metylester, vinylester, propargylester, p-nitrofenylester, (2,4-di-nitrofenylester, triklorfenylester, pentaklorfenylester, metan-sulfonylfenylester, fenylazofenylester, fenyltioester, p-nitro-fenyltioester, p-kresyltioester, karboksymetyltioester, pyranyl-ester,. pyridylester, piperidylester, 8-kinoly ltioester eller en ester med N, N-dimety lhydroksylamin, 1-hyd rok sy- 2- (III) - pyr idon , N-hydroksysuccinimid eller N-hydroksyftalimid). Det egnede derivat kan eventuelt utvelges avhengig av arten av den anvendte organiske karboksylsyre med den generelle formel V.
Omsetningen utføres vanligvis i et oppløsningsmiddel så
som aceton, dioksan, acetonitril, kloroform, metylenklorid, etylen-klorid, tetrahydrof uran, etylacetat, dirnetylformamid, pyridin . eller et hvilket som helst annet organisk oppløsningsmiddel, som er inert overfor omsetningen. Blant disse oppløsningsmidler kan hydrofile oppløsningsmidler anvendes i blanding med vann.
Når den organiske karboksylsyre med den generelle formel V anvendes i form. av den frie syre eller et salt derav, utføres, omsetningen fortrinnsvis i nærvær av et kondensasjonsmiddel så' som N,N'-dicykloheksylkarbodiimid, N-cykloheksyl-N<1->morfolinoetyl-karbodiimid, N-cykloheksyl-N'-(4-dietylaminocykloheksyl)karbodiimid, N,N<1->dietyl-karbodiimid, N,N<1->diisopropylkarbodiimid, N-étyl-N'-(3-dimetylaminopropyl)karbodiimid,N,N'-karbonyldi-(2-metylimidazol) pentametylenketen-N-cykloheksylim.in, difenylketen-N-cyklo-heksylimin, alkoksyacetylen, 1-alkoksy-l-kloretylen, trialkyl- | fosfitt, etylpolyfosfat, isopropylpolyfosfat, fosforoksyklorid, fosfortriklorid, tionylklorid, oksalylklorid, trifen<y>lfos fin, 2-etyl-7-hydroksy-benzisoksazoliumsalt, 2-etyl-5-(m-sulfofeny1)-isoksazoliumhydroksy-intermolekylært salt og (klormetylen) - dimetylammoniumklorid. Saltet av den organiske karboksylsyre med den generelle formel V kan være et alkalimetallsalt, et jordalkalimetallsalt, et ammoniumsalt eller et salt med en organisk base så som trimetylamin eller dicykloheksylamin.
Omsetningen kan utføres i nærvær av en base så som et alkalimetallbikarbonat, et trialkylamin eller N,N-dialkyl-benzylamin eller pyridin. Når basen eller kondensasjonsmidlet er flytende, kan den også anvendes som oppløsningsmiddel. Reaksjonstemperaturen er.ikke begrenset, og omsetningen utføres vanligvis under avkjøling eller ved romtemperatur.
Forbindelsene med formel I oppviser en høy antibakteriell aktivitet og hemmer veksten av et antall mikroorganismer,' herunder grampositive og gramnegative bakterier.
Fremstilling av forbindelsene ifølge foreliggende oppfinnelse belyses nærmere ved de følgende eksempler:
Eksempel 1
1,36 g 7-aminocefalosporansyre, 1,04 g 5-acetamidometyl-1,3,4-tiadiazol-2-tiol og 885 mg natriumhydrogenkarbonat oppløses i 70 ml vann, og oppløsningen omrøres ved 60°C i 5 timer. Efter omsetningen innstilles reaksjonsblandingen på
ehpH-verdi på 5, og reaksjonsblandingen får derefter stå natten over i et kjøleskap. De utfelte krystaller oppsamles ved filtrering, hvorved fåes 1,03 g 7-amino-3-(5-acetamido'metyl-1,3,4-tiadiazol-2-yl)tiometyl-3-cefem-4-karboksylsyre med smeltepunkt 195-197°C (spaltning).
IR-spektrum: vJJJJjjg1:1795og1640cm"<1.>
NMR-spektrum: 6 (D20 + DC1) (ppm): 2,12 (3H, s), 3,83 (2H, s), 4,30 (1H, d, J = 14 Hz) , 4,64 (lH, d, J = 14 Hz) , 4,79 (2H, s) , 5,22 (1H, d, J = 5 Hz), 5,37 (1H, d, J 4,5 Hz).
Eksempel 2 i
I
1,24 g 5-tert.butoksykarbonylaminometyl-1,3,4-tiadiazol-2-tiol oppløses i 10 ml aceton. Oppløsningen settes til 40 ml av en vandig oppløsning inneholdende 0,84 g natriumhydrogenkarbonat. Den- blandede oppløsning oppvarmes på et vannbad ved 70-75°C. Til oppløsningen settes på en gang ved 55°C 1,35 g 7-aminocefalosporansyre. Blandingen omrøres ved 65-70°C i 2 timer og avkjøles derefter med is til 0-5°C. Reaksjonsblandingen innstilles på en pH-verdi på 5,0-5,2 med 10%ig saltsyre. Den utfelte lysegule bestanddel fraskilles ved filtrering, vaskes med vann og aceton og tørres derefter, hvorved fåes 1,28 g 7-an]ino-3-(5-tert .butoksykarbonylaminomety 1-1,3,4-tiadiazol-2-y1)tiometyl-3-cefem-4-karboksylsyre med smeltepunkt over 2 20°C.
IR-spektrum: vJJ^ks1' 1805'1700°91625 cm~ 1-
NMR-spektrum: 6 (D20 + NaHC03) (ppm): 1,41 (9H, s), 3,39
(1H, d, J = 17- Hz) , 3,79 (1H, d, J = 17 Hz) , 4,08 (1H, d.,
J
J = 14 Hz), 4,55 (lH, d, J = 14 Hz), 4,60 (2H, s), 5,08 (1H, d, J = 4,5 Hz), 5,50 (1H, d, J = 4,5 Hz).
Eksempel 3
0,84 g natriumhydrogenkarbonat og 0,74 g 5-hydroksymety1-1,3,4-tiadiazol-2-tiol oppløses■i 40 ml vann, og oppløsningen oppvarmes på et vannbad.
Til oppløsningen settes på én gang ved 45°C 1,36 g 7-aminocef alosporansyre. Blandingen omrøres ved 70-7.3°C i 1 time. Efter omsetningen avkjøles blandingen til 0-5°C, og innstilles på en pH-verdi- på 5,0 med 10%ig saltsyre. De utfelte krystaller oppsamles ved filtrering, hvorved fåes 1,20 g 7-amino-3-(5-hydroksymety1-1,3,4-tiadiazol-2-yl)tiometyl-3-cefem-4-karboksylsyre med smeltepunkt 194-199°C (spaltning).
IR-spektrum: v™^<1>: 3200, 1805'og 1625 cm"<1>
NMR-spektrum: 6 (D20 + DC1) (ppm): 3,85 (2H, s). , 4,38 (1H, d, J = 14 Hz), 4,70 (1H, d, J = 14 Hz), 5,12 (2H, s), 5,20 (1H, d, J = 5 Hz), 5,38 (1H, d, J = 5 Hz).
Claims (1)
- Cefalosporin-mellomprodukt for fremstilling av terapeutisk aktive cefalosporinderivater med formelenhvor R"*" er acyl, R 2 er en amino-lavere-alkyl-, lavere ålkanoylamino-lavere-alkyl-, lavere alkoksykarbonylamino-lavere-alkyl-, lavere alkan- sulfonylamino-lavere-alkyl-, lavere alkoksykarbonylamino-lavere-alkanoylamino-lavere-alkyl-, lavere alkylureido-lavere-alkyl-, guanidino-k.arbonylamino-lavere-alkyl- eiler hydroksy-lavere-alkyl-substituert tiadiazolyl- eller tetrazolylgruppe, og M er et hydrogenatom eller et ugiftig, farmasøytisk godtagbart kation, karakterisert ved at det har den generelle formel.hvor R 2 og M er som angitt ovenfor.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP48037205A JPS5939439B2 (ja) | 1973-03-30 | 1973-03-30 | ７−置換−３−ｎ，ｓ含有複素環チオメチル−３−セフエム−４−カルボン酸誘導体の製造法 |
| JP48073898A JPS5852997B2 (ja) | 1973-06-29 | 1973-06-29 | ７− チカン −３− ヒドロキシアルキルチカンフクソカンチオメチル −３− セフエム −４− カルボンサンルイノ セイゾウホウ |
| JP13936473A JPS5716118B2 (no) | 1973-12-12 | 1973-12-12 | |
| JP741096A JPS5734837B2 (no) | 1973-12-26 | 1973-12-26 | |
| JP1308374A JPS5732074B2 (no) | 1974-01-30 | 1974-01-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO801402L true NO801402L (no) | 1974-10-01 |
Family
ID=27518056
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO741137A NO741137L (no) | 1973-03-30 | 1974-03-29 | Fremgangsmåte for fremstilling av substituerte tiometyl-3-cefem-4-karboksylsyrederivater |
| NO80801402A NO801402L (no) | 1973-03-30 | 1980-05-12 | Cefalosporin-mellomprodukt for fremstilling av terapeutisk aktive cefalosporinderivater |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO741137A NO741137L (no) | 1973-03-30 | 1974-03-29 | Fremgangsmåte for fremstilling av substituerte tiometyl-3-cefem-4-karboksylsyrederivater |
Country Status (10)
| Country | Link |
|---|---|
| AR (1) | AR207752A1 (no) |
| BE (1) | BE812951A (no) |
| CH (3) | CH610903A5 (no) |
| DE (1) | DE2415402C2 (no) |
| FR (1) | FR2223002B1 (no) |
| GB (1) | GB1461948A (no) |
| NL (1) | NL180422C (no) |
| NO (2) | NO741137L (no) |
| NZ (1) | NZ173837A (no) |
| SE (1) | SE428297B (no) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4379924A (en) | 1973-12-25 | 1983-04-12 | Takeda Chemical Industries, Ltd. | Cephalosporin derivatives |
| US4093723A (en) | 1976-05-19 | 1978-06-06 | Smithkline Corporation | 7-Acyl-3-(sulfonic acid and sulfamoyl substituted tetrazolyl thiomethyl) cephalosporins |
| BE845338A (fr) * | 1975-09-02 | 1977-02-21 | Nouvelles cephalosporines, procede pour leur obtention et application pharmaceutique | |
| US4171368A (en) * | 1975-10-30 | 1979-10-16 | Smithkline Corporation | 7-Acylamino-3-(sulfaminoalkyl substituted tetrazolylthiomethyl)cephalosporins, antibacterial compositions containing them and methods of treating bacterial infections with them |
| US4171362A (en) * | 1975-10-30 | 1979-10-16 | Smithkline Corporation | 7-Acylamino-3-(sulfaminoalkyl substituted tetrazolylthiomethyl)cephalosporins antibacterial compositions containing them and methods of treating bacterial infections with them |
| US4118491A (en) * | 1976-03-11 | 1978-10-03 | Smithkline Corporation | 7-Acyl-3-(sulfaminoalkyl substituted tetrazolylthiomethyl)cephalosporins, antibacterial compositions containing them and methods of treating bacterial infections with them |
| IL50546A (en) * | 1975-10-30 | 1980-07-31 | Smithkline Corp | 7-acyl-3-(1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid derivatives and pharmaceutical compositions containing them |
| US4171433A (en) * | 1975-10-30 | 1979-10-16 | Smithkline Corporation | 7-Amino-3-(sulfaminoalkyl substituted tetrazolylthiomethyl)cephalosporin intermediates for preparing 7-acylamino cephalosporins |
| US4101656A (en) | 1976-07-12 | 1978-07-18 | Smithkline Corporation | 7β-Acylamino-3-(alkanesulfonamidoalkyl substituted tetrazolylthiomethyl) cephalosporins, antibacterial compositions containing them and methods of treating bacterial infections with them |
| US4066762A (en) * | 1976-07-12 | 1978-01-03 | Smithkline Corporation | Derivatives of 7-(2-substituted-2-hydroxyiminoacetamido)-3-(1-substituted tetrazol-5-ylthiomethyl-3-cephem-4-carboxylic acid |
| US4083975A (en) | 1976-09-24 | 1978-04-11 | Smithkline Corporation | 7-Acylamino-3-(3-sulfomethyl-1,2,4-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acids |
| US4064242A (en) * | 1976-11-04 | 1977-12-20 | Smithkline Corporation | 7-Acylamino-3-[1-(2,3-dihydroxypropyl)tetrazole-5-ylthiomethyl]-3-cephem-4-carboxylic acids |
| US4117123A (en) * | 1977-06-09 | 1978-09-26 | Smithkline Corporation | 7-Acylamino-3-[1-(2-sulfamidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acids |
| AU1733701A (en) | 1999-12-16 | 2001-06-25 | Sumitomo Pharmaceuticals Company, Limited | Substituted guanidine derivatives |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3641021A (en) * | 1969-04-18 | 1972-02-08 | Lilly Co Eli | 3 7-(ring-substituted) cephalosporin compounds |
| DE1953861C2 (de) * | 1969-10-25 | 1982-12-23 | Fujisawa Pharmaceutical Co., Ltd., Osaka | 7-Tetrazolylacetamido-3-thiomethyl-3-cephem-4- carbonsäuren |
| US3757014A (en) * | 1971-05-07 | 1973-09-04 | Bristol Myers Co | Ts 1,3,4 - oxadiazol-2-yl)thiomethyl)-3-cephem-4-carboxylic acid and sal7-(d-(alpha-amino-alpha-pheyle-acetamido)) - 3-(s-(5-hydroxymethyl - |
| CA999574A (en) | 1972-06-14 | 1976-11-09 | Smith Kline And French Canada Ltd. | 7-hydroxyhalophenylacetamido-3-h heterocyclicthiomethyl cephalosporins |
-
1974
- 1974-01-01 AR AR253054A patent/AR207752A1/es active
- 1974-03-28 BE BE142549A patent/BE812951A/xx not_active IP Right Cessation
- 1974-03-29 GB GB1414374A patent/GB1461948A/en not_active Expired
- 1974-03-29 CH CH963977A patent/CH610903A5/xx not_active IP Right Cessation
- 1974-03-29 SE SE7404306A patent/SE428297B/xx unknown
- 1974-03-29 NZ NZ173837A patent/NZ173837A/xx unknown
- 1974-03-29 FR FR7411408A patent/FR2223002B1/fr not_active Expired
- 1974-03-29 NL NLAANVRAGE7404330,A patent/NL180422C/xx not_active IP Right Cessation
- 1974-03-29 DE DE2415402A patent/DE2415402C2/de not_active Expired
- 1974-03-29 CH CH963877A patent/CH610902A5/xx not_active IP Right Cessation
- 1974-03-29 NO NO741137A patent/NO741137L/no unknown
- 1974-03-29 CH CH442874A patent/CH595388A5/xx not_active IP Right Cessation
-
1980
- 1980-05-12 NO NO80801402A patent/NO801402L/no unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU6735374A (en) | 1975-10-02 |
| CH610902A5 (en) | 1979-05-15 |
| FR2223002B1 (no) | 1977-11-04 |
| NL180422C (nl) | 1987-02-16 |
| NL180422B (nl) | 1986-09-16 |
| SE7404306L (no) | 1974-10-01 |
| DE2415402C2 (de) | 1985-12-19 |
| CH610903A5 (en) | 1979-05-15 |
| AR207752A1 (es) | 1976-10-29 |
| NL7404330A (no) | 1974-10-02 |
| FR2223002A1 (no) | 1974-10-25 |
| BE812951A (fr) | 1974-09-30 |
| SE428297B (sv) | 1983-06-20 |
| DE2415402A1 (de) | 1974-10-03 |
| NZ173837A (en) | 1978-07-28 |
| NO741137L (no) | 1974-10-01 |
| GB1461948A (en) | 1977-01-19 |
| CH595388A5 (no) | 1978-02-15 |
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