GB1573786A - L-isomers of 3-heterothiomethyl ureido cephalosporins - Google Patents
L-isomers of 3-heterothiomethyl ureido cephalosporins Download PDFInfo
- Publication number
- GB1573786A GB1573786A GB9511/77A GB951177A GB1573786A GB 1573786 A GB1573786 A GB 1573786A GB 9511/77 A GB9511/77 A GB 9511/77A GB 951177 A GB951177 A GB 951177A GB 1573786 A GB1573786 A GB 1573786A
- Authority
- GB
- United Kingdom
- Prior art keywords
- compound
- amino
- methyl
- phenyl
- lower alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- -1 ureido cephalosporins Chemical class 0.000 title claims description 38
- 229930186147 Cephalosporin Natural products 0.000 title description 4
- 229940124587 cephalosporin Drugs 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 58
- 125000000217 alkyl group Chemical group 0.000 claims description 47
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 43
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 34
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 9
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 8
- 159000000000 sodium salts Chemical class 0.000 claims description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 5
- 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 claims description 5
- 150000002500 ions Chemical class 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- 239000011591 potassium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical class S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 4
- 125000003638 stannyl group Chemical group [H][Sn]([H])([H])* 0.000 claims description 4
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 5
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 150000001342 alkaline earth metals Chemical class 0.000 claims 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 5
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 5
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- NQBRFIXRZDTIRQ-UHFFFAOYSA-N (4-methoxyphenyl)methyl n-diazocarbamate Chemical compound COC1=CC=C(COC(=O)N=[N+]=[N-])C=C1 NQBRFIXRZDTIRQ-UHFFFAOYSA-N 0.000 description 4
- 241000534944 Thia Species 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 3
- 239000004471 Glycine Substances 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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 150000002148 esters Chemical group 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 description 3
- 229910000028 potassium bicarbonate Chemical class 0.000 description 3
- 239000011736 potassium bicarbonate Chemical class 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- YGBFLZPYDUKSPT-MRVPVSSYSA-N cephalosporanic acid Chemical group S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C[C@H]21 YGBFLZPYDUKSPT-MRVPVSSYSA-N 0.000 description 2
- HOKIDJSKDBPKTQ-GLXFQSAKSA-N cephalosporin C Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CCC[C@@H](N)C(O)=O)[C@@H]12 HOKIDJSKDBPKTQ-GLXFQSAKSA-N 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000000395 magnesium oxide Substances 0.000 description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 2
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000001665 trituration Methods 0.000 description 2
- XLMSKXASROPJNG-YFKPBYRVSA-N (2r)-2-amino-2-thiophen-2-ylacetic acid Chemical compound OC(=O)[C@@H](N)C1=CC=CS1 XLMSKXASROPJNG-YFKPBYRVSA-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
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 1
- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000588777 Providencia rettgeri Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000607720 Serratia Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- YSVZGWAJIHWNQK-UHFFFAOYSA-N [3-(hydroxymethyl)-2-bicyclo[2.2.1]heptanyl]methanol Chemical compound C1CC2C(CO)C(CO)C1C2 YSVZGWAJIHWNQK-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 125000005042 acyloxymethyl group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- ZGUNAGUHMKGQNY-UHFFFAOYSA-N alpha-phenylglycine Chemical compound OC(=O)C(N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- NVYVHAPFRUEAJN-UHFFFAOYSA-N anisole;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.COC1=CC=CC=C1 NVYVHAPFRUEAJN-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229960000603 cefalotin Drugs 0.000 description 1
- VUFGUVLLDPOSBC-XRZFDKQNSA-M cephalothin sodium Chemical compound [Na+].N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C([O-])=O)C(=O)CC1=CC=CS1 VUFGUVLLDPOSBC-XRZFDKQNSA-M 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 1
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 102220079670 rs759826252 Human genes 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Description
(54) L-ISOMERS OF 3-HETEROTHIOMETHYL UREIDO
CEPHALOSPORINS
(71) We, E. R. SQUIBB & SONS INC., a corporation organised and existing under the laws of the State of Delaware, United States of America, of Lawrenceville-Princeton Road, Princeton, New Jersey, United States of America, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed to be particularly described in and by the following statement: This invention provides the optically active L-isomer form of the cephalosporins of the formula
wherein R1 is phenyl, thienyl, or furyl; R4 represents certain heterocyclic groups; and
Rs represents hydrogen, lower alkyl, phenyl-lower alkyl, diphenyl-lower alkyl, substituted phenyl-lower alkyl, tri(lower alkyl)stannyl, tri(lower alkyl)silyl, a salt forming ion, or the group
wherein R is lower alkyl, phenyl, phenyl-lower alkyl, or substituted phenyl or phenyllower alkyl.
The invention also extends to pharmaceutical compositions comprising such compounds and a pharmaceutical carrier.
The various groups represented by the symbols have the meaning defined below and these definitions are retained throughout this specification.
The lower alkyl groups referred to throughout this specification are straight or branched chain hydrocarbon groups containing 1 to 8 carbon atoms, preferably 1 to 4 carbons. Examples of the type of groups contemplated are methyl, ethyl, propyl, iso propyl, butyl and t-butyl. The lower alkoxy groups are such lower alkyl groups attached to an oxygen, e.g., methoxy, ethoxy and propoxy. The phenyl-lower alkyl and diphenyllower alkyl groups are such lower alkyl groups attached to phenyl, e.g., benzyl, phenethyl and diphenylmethyl.
The substituted phenyl and substituted phenyl-lower alkyl groups have one or two (preferably only one) simple substituents selected from halogen (preferably chlorine or bromine), lower alkyl and lower alkoxy, e.g. 2-, 3- or 4-chiorophenyl, 2-, 3-, or 4bromophenyl, 3,4-dichlorophenyl, 2-methylphenyl, 4-ethoxyphenyl, 2-, 3-, or 4-chlorobenzyl and 2-, 3-, or 4-ethylphenethyl.
The salt forming ions represented by R, are metal ions, e.g., aluminum, alkali metal ions such as sodium or potassium, alkaline earth metal ions such as calcium or magnesium, or amine salt ions, of which a number are known for this purpose, for example those derived from phenyl-lower alkylamines such as dibenzylamine, N,Ndibenzylethylenediamine, lower alkylamines such as methylamine, triethylamine, and N-lower alkylpiperidines such as N-ethylpiperidine.
The heterocyclic groups represented by R, are
wherein R5 is hydrogen or alkyl of 1 to 4 carbons.
The preferred embodiments of this invention are the compounds of formula I wherein:
R3 is hydrogen, sodium or potassium.
R" is
especially 5-methyl-1,3,4-thiadiazol-2-yl and 1-methyl-lH-tetrazol-5-yl.
The L-isomer compounds of formula I are preferably prepared by reacting an a-amino compound of the formula
preferably in the form of its trifluoroacetic acid salt with an alkali or alkaline earth cyanate such as potassium cyanate in solution at a pH of from 7 to 8.
The compounds of formula II can be prepared by acylating a 3-heterothiomethyl7-aminocephalosporin of the formula
wherein R3 is preferably diphenylmethyl or t-butyl or other ester protecting groups with an acid chloride of the formula
or an a-(substituted)amino acid of the formula
wherein Y is a protecting group such as
The protecting group is removed, for example, by treatment with trifluoroacetic acid and anisole to yield the trifluoroacetate salt of the compound of formula II.
The L-isomer compounds of formula I can also be prepared by reacting an a-ureido compound of the formula
with the compound of formula III.
This reaction is carried out by converting the ti-ureido compound of formula VI to a mixed carbonic or other anhydride by treating a solution of the tz-ureido compound in an organic solvent containing a tri(lower alkyl)amine with an anhydride forming agent, i.e. a lower alkyl chloroformate, an aryl chloroformate, or an acyl halide, at reduced temperature of from 0 C to - 20"C.
Alternatively, the a-ureido compound of formula VI can be converted to an activated ester by reacting with a carboxyl group activating agent such as dicyclohexyl carbodiimide or bisimidazole carbonyl. In some cases the carboxyl group may be activated by conversion to an acid halide, e.g., the chloride, or to an azide.
The L-isomers of formula I can also be prepared by reacting the compound of formula VI with 7-ACA (with the carboxyl group modified as necessary) preferably in the presence of dicyclohexylcarbodiimide to yield the compound of formula VII (as disclosed in Pat. No. 3,833,568)
followed by treatment with the compound of the formula
(VIII) R4-S-H in solution at a pH of from 7.8 to 8.0.
Similarly, the L-isomers of formula I where R3 is an ester-forming group can be prepared by reacting the compounds of formula IV or V with an ester of 7-ACA preferably in the presence of dicydohexsTlcarbodiimide followed by treatment with an acid (HX), preferably trifluoroacetic acid in the presence of anisole, to yield the salt of formula
The salt of formula IX is then treated with an alkali metal or alkaline earth metal cyanate followed by treatment with the compound of formula VIII to yield the desired compounds.
The compounds of formula I wherein R, is lower alkyl, phenyl-lower alkyl, substituted phenyl-lower alkyl, diphenyl-lower alkyl, or the acyloxymethyl group
may be obtained by reacting the compound of formula III where R, is H or the .7ACA either before or after the acylation of the 7-amino substituent with one or two moles of a compound of the formula
(X) halo-R3 or (XI) R3=N+=N- wherein halo is preferably chlorine or bromine in an inert solvent such as dimethylformamide, acetone, dioxane or benzene, at about or below ambient temperature.
Similarly, the compounds of formula I wherein R3 is tri(lower alkyl)stannyl or tri(lower alkyl)silyl are obtained by introducing such groups onto the 3-heterothiomethyl cephalosporanic acid moiety either before or after the acylation reaction.
The carboxylate salts of the compounds of formula I are formed by reacting the carboxyl group of the cephalosporanic acid moiety, i.e. R3 is hydrogen, with any of the salt forming ions described above
The L-isomer copounds of formula I have a broad spectrum of antibacterial activity against both gram positive and gram negative organisms such as Staphylococcus aureus, Salmonella schottmuelleri, Kiebsiella pneumoniae, Proteus rettgeri,
Escherichia coli, etc. In particular, it has been found that these L-isomers are considerably more active than the corresponding D-isomer or D,L-isomeric mixture against beta-lactamase producing organisms such as Enterobacter, indole-positive Proteus, resistant Escherichia coli, and Serratia.
The compounds of formula I can be used as antibacterial agents to combat infections due to organisms such as those named above, and in general may be utilized in a manner similar to cephalothin and other cephalosporins. For example, a compound of formula I or a physiologicaly acceptable salt thereof may be used in various animal species in an amount of 1 to 100 mg./kg., e.g. 5.0 mg./kg. in mice, daily, orally or parenterally, in single or two to four divided doses to treat infections of bacterial origin.
Up to about 600 mg. of a compound of formula I or a physiologically acceptable salt thereof may be incorporated in an oral dosage form such as tablets, capsules or elixirs or in an injectable form in a sterile aqueous vehicle prepared according to conventional pharmaceutical practice.
Illustrative process details are provided in the examples for the various reactions.
All temperatures are on the centigrade scale and 'ether' is diethyl ether.
Example 1.
7ss - [[[(Aminocarbonyl)amino] (L - 2 - thienyl)acetyl]amino] - 3 - [[(1 - methyl
1H - tetrazol - 5 - yl)thio]methyl - 8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct
2 - ene - 2 - carboxylic acid a) L - a - [[[(4 - Methoxyphenyl)methoxy] carbonyl] amino] - 2- thiophenacetic
acid
14.2 g. of L-(2-thienyl)glycine(prepiied by~tSie rnethod oHsEmura et al..
Nippon Kagaku Zasshi, Vol. 82, p. 1688-91 (1961); Chem. Abst., Vol. 58, p.
11464f) are suspended in 142 ml. of water and brought into solution by the addition of 37.9 ml. of triethylamine. A solution of 20.6 g. of (p-methoxyphenyl)methoxycarbonylazide in 152 ml. of dioxane is added with stirring. The mixture which is turbid at first becomes clear after 30 minutes. This is stirred for an additional hour at room temperature. The dioxane is then evaporated in vacuum. Flakes form in the aqueous phase which are extracted by shaking with ether. The aqueous phase is cooled to 00, layered over with ethyl acetate and acidified with 2N hydrochloric acid to pH 2.5. The aqueous phase is extracted twice more with ethyl acetate, the combined ethyl acetate extracts are dried with magnesium sulfate and concentrated in vacuum to 23.5 g. of
L - a - [[[(4 - methoxyphenyl)methoxy] carbonyl] amino] - 2 - thiopheneacetic acid; m.p. 100-102 ; [α]D20=+68.3 (c= 1, tetrahydrofuran).
b) 7ss - [[[[[(4 - Methoxyphenyl)methoxy]tarbonyl]amino] (L - 2 - thienyl) acetyl]amino]- 3 - [[(1 - methyl - 1H- tetrazol - 5 - yl)thio]methyl]- 8
oxo - 5 - thia - 1 - azabicyclo[4.2.0] oct - 2 - ene - 2 - carboxylic acid, diphenyl
methyl ester
14.9 g. of 3 - [(1 - methyl - 1H - tetrazol - 5 - yl)thio] - 7 - aminocephalosporanic acid, diphenylmethyl ester are dissolved in 300 ml. of methylene chloride and 300 ml. of anhydrous tetrahydrofuran are added. Then 11.62 g. of L - ur - [[[(4 methoxyphenyl)methoxy] carbonyl] amino] - 2 - thiopheneacetic acid from part (a) are added, the mixture is cooled to 00, and a solution of 6.79 g. of dicyclohexylcarbodiimide in 100 ml. of anhydrous tetrahydrofuran is added dropwise with stirring over 30 minutes. The reaction mixture is stirred for 90 minutes at 05 and 90 minutes at room temperature. The precipitated dicyclohexylurea is then filtered off and the filtrate is concentrated in vacuum. The residue is taken up with ethyl acetate, filtered, washed with sodium bicarbonate solution and with water. The ethyl acetate solution is dried with magnesium sulfate, treated with activated charcoal, filtered and concentrated in vacuum to a small volume. On stirring in excess petroleum ether, 24 g. of 7a - [[[[[(4 - methoxyphenyl)methoxy]carbonyl]amino] - (L - 2 - thienyl)acetyl]- amino] - 3 - [[(1 - methyl - 1H - tetrazol - 3 - yl)thio]methyl] - S - oxo - 3 - thia- 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid, diphenylmethyl ester; m.p.
110 ; are obtained as a precipitate.
c) 7ss - [[( - Amino - L - 2 - thienyl)acetyl]amino] - 3 - [[(1 - methyl - 1H
tetrazol - 5-yl)thio]methyl]- 8 - oxo - 3 - thia -1 - azabicyclo[4.2.0]oct - 2
ene - 2 - carboxylic acid, trifluoroacetic acid salt
24 g. of the diphenylmethyl ester product from part (b) are stirred in 100 ml. of anisole and 300 ml. of trifluoroacetic acid are added dropwise at 00. After 10 minutes, this mixture is evaporated under vacuum. The residue is treated with ether and filtered to yield 17.8 g. of 7,3 - [[(a - amino - L - 2 - thienyl)acetyl]amino] - 3 - [[(1methyl - 1H - tetrazol - 3- - yl)thio]methyl] - 8 - oxo - 3 - thia - 1 - azabicyclo [4.2.0] oct - 2 - ene - 2 - carboxylic acid, trifluoroacetic acid salt.
d) 7,3 - [[[(Aminocarbonyl)amino] (L - 2 - thienyl)acetyl]amino] - 3 - [[(1
methyl - 1H - tetrazol - 5 - yl)thio]methyll - 8 - oxo - 3 - thia - 1 - azabicyclo
[4.2.0] oct - 2 - ene - 2 - carboxylic acid
12 g. of the trifluoroacetic acid salt product from part (c) are added to a solution of 3.4 g. of potassium cyanate in 85 ml. of water and stirred for 3 hours at room temperature. This mixture is filtered and the filtrate is acidified to pH 1.5 with 2N hydrochloric acid while cooling. The precipitate is isolated and yields 6.8 g. of 7ss [[[(aminocarbonyl]amino] (L - 2 - thienyl)acetyl]amino] - 3 - [[(1 - methyl - 1H- tetrazol - 5-yl)thio]methyl]- 8 - oxo - 3 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene2 - carboxylic acid; m.p. 149--1530 (dec.).
An aqueous equimolar solution of this acid and sodium bicarbonate is lyophilized to yield 7,3 - [[[(aminocarbonyl)amino] - (L - 2 - thienyl)acetyl]amino] - 3 - [[(1methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 3 - thia - 1 - azabicyclo
[4.2.0]oct - 2 - ene - 2 - carboxylic acid, sodium salt; m.p. 187188 (dec.). In a similar manner, one can obtain the potassium salt.
Example 2.
7,3 - [[[(Aminocarbonyl]amino] (L - 3 - thienyl) acetyl]amino] - 3 - [[(1 - methyl 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct
2 - ene - 2 - carboxylic acid a) L - a - [[[(4 - Methoxyphenyl)methoxyj carbonyl] amino] - 3 - thiopheneacetic
acid
18 g. of L-(3-thienyl)glycine (prepared by the method of Nishimura et al., supra) are suspended in 300 ml. of water with 10 g. of magnesium oxide. 32 g. of (p-methoxyphenyl)methoxycarbonylazide in 250 ml. of dioxane are added dropwise. The mixture is stirred for 24 hours at room temperature, then the dioxane is distilled off. The residue is filtered and the filtrate is extracted by shaking with ether. The aqueous phase is layered with ethyl acetate and acidified to pH 2.5 with 2N hydrochloric acid with cooling. The ethyl acetate is washed with water, dried over sodium sulfate and evaporated. The residual oil is dissolved in toluene, cyclohexane is added, and the mixture is refrigerated. Crystallization begins and 20.8 g. of white crystalline L - a - [[[(4 methoxyphen0yl)methoxy] carbonyl] amino] - 3 - thiopheneacetic acid are obtained; m.p. 95-97 : [a]n,,2'=t+76.80 (0.1% in methanol).
b) 7fi - [[[[[(4 - Methoxyphenyl)methoxy]carbonyl]amino] (L - 3 - thienyl)
acetyl]amino] - 3 - [[(1 - methyl - 1H- tetrazol - 5 - yl)thio]methyl] - 8
oxo - 5 - thia - 1 - azabicyclo [4.2.0]oct - 2 - ene - 2 - carboxylic acid, diphenyl
methyl ester
10 g. of the L - a 1 [[[(4 - methoxyphenyl)methoxy]carbonyl]amino] - 3 - thiopheneacetic acid from part (a) are dissolved in 150 ml. of tetrahydrofuran and stirred for 15 minutes at 0 with 6.5 g. of dicyclohexylcarbodiimide. Then 14 g. of 3 - [(1methyl - 1H - tetrazol - 5 - yl)thio] - 7 - aminocephalosporanic acid, diphenylmethyl ester dissolved in 100 ml. of tetrahydrofuran are added. After 12 hours, the reaction mixture is filtered, the filtrate is treated with charcoal and evaporated in vacuum. The residual brown oil is dissolved in 20 ml. of methylene chloride and added dropwise to a mixture of ether and petroleum ether. 20 g. of light yellow 7P - [[[[[(4 - methoxy- phenyl)methoxy] carbonyl] amino] (L - 3 - thienyl) - acetyl]amino] - 3 - [[(1methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid, diphenylmethyl ester are obtained; m.p. 95".
c) 7ss - [[(e - Amino - L - 3 - thienyl)acetyl]amino] - 3 - [[(1 - methyl - 1H
tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct - 2
ene - 2 - carboxylic acid, trifluoroacetic acid salt
13 g. of the diphenylmethyl ester product from part (b) are dissolved in 200 ml.
of anisole-trifluoroacetic acid (1:4) at 5". After 10 minutes stirring, the mixture is evaporated under vacuum. The residue is treated with a mixture of ether and petroleum ether and filtered to yield 8.4 g. of solid yellow 7p - [[(a - amino - L - 3 - thienyl)acetyl]amino] - 3 - [[(1 - methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5thia - 1 - azabicyclo[4.2.0] oct - 2 - ene - 2 - carboxylic acid, trifluoroacetic acid salt; m.p. 1250 (dec.).
d) 7,3 - [[[(Aminocarbonyl)amino] (L - 3 - thienyl)acetyl]amino] - 3 - [[(1
methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo [4.2.0] oct - 2 - ene - 2 - carboxylic acid
7.9 g. of the trifluoroacetic acid salt product from part (c) are dissolved in 50 ml.
of water and the pH is adjusted to 7.2 with 2N sodium hydroxide. After the addition of 1.5 g. of potassium cyanate, the mixture is stirred for 3 hours at constant pH. The reaction mixture is cooled, adjusted to pH 1.5 with 2N hydrochloric acid, the precipitate is filtered off and dissolved in methanol ,then treated with charcoal. Concentrating the methanolic solution crystallizes 4.2 g. of 7,3 - [[[(aminocarbonyl)amino] (L - 3thienyl)acetyl]amino] - 3 - [[(1 - methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8
oxo - 5 - thia - 1 - azabicyclo[4.2.01oct - 2 - ene - 2 - carboxylic acid; m.p. 157 (dec.).
An equimolar solution of this acid and potassium bicarbonate is lyophilized to obtain as a yellow powder 7,3 - [[[(aminocarbonyl)amino] (L - 3 - thienyl)acetyl]- amino] - 3 - [[(1 - methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia- 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid, potassium salt; m.p. 1740 (dec.). In a similar manner, by employing sodium bicarbonate, one obtains the sodium salt.
Example 3.
7,3 - [[[(Aminocarbonyl)amino] (L - phenyl)acetyl]amino] - 3 - [[(1 - methyl
1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - S - thia - 1 - azabicyclo [4.2.0] oct- 2 - ene - 2 - carboxylic acid a) L - a - [[[(4 - Methoxyphenyl)methoxy]carbonyl]amino]phenylacetic acid
L-Phenylglycine (obtained from D,L-phenylglycine by the method of Nishimura et al., supra) and magnesium oxide are suspended in water and reacted with a solution of (p-methoxyphenyl)methoxycarbonylazide in dioxane according to the procedure of example 1 (a) to yield L - a - [[[(4 - methoxyphenyl)methoxy] carbonyl] amino] phenylacetic acid.
b) 7,3 - [[[[[(4 - Methoxyphenyl)methoxy] carbonyl] amino] (L - phenyl)acetyl] - amino] - 3 - [[(1 - methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5- thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid, diphenylmethyl ester
7 - Amino - 3 - [[(1 - methyl - 1N - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5- thia - 1 - azabicyclo[4.2.0] oct - 2 - ene - 2 - carboxylic acid, diphenylmethyl ester and
L - a - [[[(4 - methoxyphenyl)methoxy] carbonyl] amino] phenylacetic acid from part (a) are reacted in the presence of dicyclohexylcarbodiimide according to the procedure of example 1(b) to yield 7,3 - [[[[[(4 - metboxyphenyl)methoxy]carbonyl]amino] (L - phenyl)acetyl]amino] - 3 - [[(1 - methyl - 1H - tetrazol - 5 - yl)thio]methyl]8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid, diphenylmethyl ester; m.p. 1170 (dec.).
c) 7,3 - [[(e - Amino - L - phenyl)acetyl]amino] - 3 - [[(1 - methyl - IH - tetra
zol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo acid, trifluoroacetic
acid salt
The diphenylmethyl ester product from part (b) is treated with trifluoroacetic acid and anisole according to the procedure of example l(c) to yield 7,3 - [[(ex- amino - L - phenyl)acetyl]amino] - 3 - [[(1 - methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo [4.2.0] oct - 2 - ene - 2 - carboxylic acid, trifluoroacetic acid salt.
d) 7,3 - [[[.(Aminocarbonyl)amino] (L - phenyl)acetyl]amino] -3- [[(1-methyl- 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct- 2 - ene - 2 - carboxylic acid
The trifluoroacetic acid salt product from part (c) is reacted with potassium cyanate according to the procedure of example 1 (d) to yield 7,3 - [[[(aminocarbonyl)- amino] (L - phenyl)acetyl]amino] - 3 - [[(1 - methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic avid; m.p. 156 (dec.).
An aqueous equimolar solution of this acid and potassium bicarbonate is freezedried to yield 7,3 - [[[(aminocarbonyl)amino] (L - phenyl)acetyl]amino] - 3 - [[(1methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo
[4.2.0]oct - 2 - ene - 2 - carboxylic acid, potassium salt; m.p. 1740 (dec.).
Similarly, by substituting sodium bicarbonate for the potassium bicarbonate one obtains the corresponding sodium salt.
Example 4.
7,3 - [[[(Aminocarbonyl)amino] (L - 2 - furyl)acetyl]amino] - 3 - [[(1 - methyl 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct- 2 - ene - 2 - carboxylic acid a) L - a - [[[(4 - Methoxyphenyl)methoxy] carbonyl] amino] - 2 - furanacetic acid
40 g. of L-(2-furyl)glycine (obtained from D,L-(2-furyl)glycine by the method of Nishimura et al., supra) are stirred into 455 ml. of water and brought into solution by the addition of 122 ml. of triethylamine. A solution of 66 g. of (p-methoxyphenyl)methoxycarbonylazide in 455 ml. of dioxane is added with stirring. The turbid mixture becomes clear after 30 minutes reaction time and the dioxane is evaporated in vacua The aqueous phase is washed with ether, cooled to 0 , layered over with ethyl acetate and acidified to pH 2.5 with 2N hydrochloric acid. This mixture is extracted twice with ethyl acetate, the combined ethyl acetate extracts are dried with magnesium sulfate and concentrated in vacuo. The oily residue solidifies upon trituration with petroleum to yield 74 g. of L - a - [[[(4 - methoxyphenyl)methoxy]carbonyl]amino] - 2 - furanacetic acid; m.p. 9195 (dec.).
b) 7,3 - [[[[[(4 - Methoxyphenyl)methoxy]carbonyl]amino] (L - 2 - furyl)acetyl]
amino] - 3 - [[(1 - methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5- thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid, diphenylmethyl ester
36.4 g. (0.074 moles) of 3 - [(1 - methyl - 1H - tetrazol - 5 - yl)thio] - 7aminocephalosporanic acid, diphenylmethyl ester are dissolved in 370 ml. of methylene chloride. Then a solution of 27 g. (0.038 moles) of L - a - [[[(4 - methoxyphenyl) methoxyjcarbonylj amino] - 2 - furanacetic acid, from part (a), in 450 ml. of tetrahydrofuran is added, the mixture is cooled to 0 , and a solution of 16.73 g. (0.081 moles) of dicyclohexylcarbodiimide in 150 ml. of tetrahydrofuran is added dropwise.
The mixture is stirred for 90 minutes at 0 and 90 minutes at room temperature. The precipitated dicyclohexylurea is filtered off under suction and the filtrate is concentrated. The residue is taken up in ethyl acetate, washed three times with sodium bicarbonate solution and three times with water, dried and concentrated. The concentrated residue solidifies upon trituration with ether. This material is filtered under suction and stirred in 250 ml. of ethyl acetate. The mixture is stirred for 2 hours at 0 and filtered under suction to yield 30.4 g. of 7,3 - [[[[[(4 - methoxyphenyl)methoxy] carbonyl] - amino] (L - 2 - furyl)acetyl]amino] - 3 - [[(1 - methyl - 1H - tetrazol - 5 - yl)thio]methyl - 8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid, diphenylmethyl ester, m.p. 149--152".
c) 7 - [[(α - Amino - L - 2 - furyl)acetyl]amino]- 3 - [[(1-methyl-1H-tetra- zol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene
2 - carboxylic acid, trifluoroacetic acid salt
30 g. of the diphenylmethyl ester product from part (b) are treated with 120 ml.
of anisole and 390 ml. of trifluoroacetic acid according to the procedure of example 1(c) to yield 21.9 g. of 7,3 - [[(a - amino - L - 2 - furyl)acetyl]amino] - 3 - [[(1methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo [4.2.0]oct - 2 - ene - 2 - carboxylic acid, trifluoroacetic acid salt; m.p. 133135 (dec.).
d) 7,3 - [[[(Aminocarbonyl)amino] (L - 2 - furyl)acetyl]amino] - 3 - [[(1
methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo
[4.2.0]oct - 2 - ene - 2 - carboxylic acid
28.2 g. of the trifluoroacetic acid salt product from part (c) are suspended in 290 ml. of water at room temperature. 8.15 g. of potassium cyanate are added and the mixture is stirred for three hours at room temperature. The almost clear solution is cooled to 0-SO and acidified to pH 3.5. A flocculant precipitate is filtered off. The clear filtrate is acidified to pH 1.5 and allowed to stand in the refrigerator at about 0-So to yield 19.8 g. of 7,3 - [[[(aminocarbonyl)amino] (L - 2 - furyl)acetyl]- amino] - 3 - [[(1 - methyl - 1H - tetrazol - 5 - yl)thio]methyl] - S - oxo - S - thia-</
Similarly, by employing the 7-aminocephalosporanic acid derivative of Col. A within the procedures of examples 2 to 5, other compounds within the scope of the invention are obtained.
WHAT WE CLAIM IS:
1. An L-isomer compound of the formula:
wherein Rl is phenyl, thienyl, or furyl; R, is hydrogen, lower alkyl, phenyl-lower alkyl, diphenyl-lower alkyl, tri(lower alkyl)silyl, tri(lower alkyl)stannyl, a salt forming ion, substituted phenyl-lower alkyl or the group
wherein R is lower alkyl, phenyl, phenyl-lower alkyl or substituted phenyl or phenyllower alkyl and wherein said phenyl substituent is halogen, lower alkyl or lower alkoxy; and R, is
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (41)
1. An L-isomer compound of the formula:
wherein Rl is phenyl, thienyl, or furyl; R, is hydrogen, lower alkyl, phenyl-lower alkyl, diphenyl-lower alkyl, tri(lower alkyl)silyl, tri(lower alkyl)stannyl, a salt forming ion, substituted phenyl-lower alkyl or the group
wherein R is lower alkyl, phenyl, phenyl-lower alkyl or substituted phenyl or phenyllower alkyl and wherein said phenyl substituent is halogen, lower alkyl or lower alkoxy; and R, is
wherein Rs is hydrogen or alkyl of 1 to 4 carbons.
2. The compound of claim 1 wherein R, is hydrogen, alkyl of 1 to 4 carbons, benzyl, phenethyl, diphenylmethyl, trimethylsilyl, trimethylstannyl, aluminum, an alkaline earth metal, an alkali metal, or the group
wherein R is alkyl of 1 to 4 carbons, phenyl, benzyl, or phenethyl.
3. The compound of claim 2 wherein R1 is 2-thienyl or 3-thienyl and R, is hydrogen, sodium or potassium.
4. The compound of claim 3 wherein R5 is methyl.
5. The compound of claim 4 wherein R4 is
6. The compound of claim 5 wherein R. is
7. The compound of claim 5 wherein R4 is
8. The compound of claim 7 wherein Rl is 2-thienyl.
9. 7,3 - [[[(Aminocarbonyl)amino] (L - 2 - thienyl)acetylaamino] - 3 - [[(1methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo [4.2.0] oct - 2 - ene - 2 - carboxylic acid.
10. The sodium salt of the compound of claim 9.
11. The potassium salt of the compound of claim 9.
12. The compound of claim 7 wherein R1 is 3-thienyl.
13. 7,3 - [[[(Aminocarbonyl)amino] (L - 3 - thienyl)acetyl]amino] - 3 - [[(1methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo [4.2.0] oct - 2 - ene - 2 - carboxylic acid.
14. The sodium salt of the compound of claim 13.
1S. The potassium salt of the compound of claim 13.
16. The compound of claim 3 wherein R4 is
17. The compound of claim 2 wherein Rl is 2-furyl or 3-furyl and R3 is hydrogen, sodium or potassium.
18. The compound of claim 17 wherein R, is methyl.
19. The compound of claim 17 wherein R4 is
20. The compound of claim 19 wherein R is
21. The compound of claim 19 wherein R4 is
22. The compound of claim 21 wherein Rl is 2-furyl.
23. 7,3 - [[[(Aminocarbonyl)amino] (L - 2 - furyl)acetyl]amino] - 3 - [[(1methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo [4.2.0] oct - 2 - ene - 2 - carboxylic acid.
24. The sodium salt of the compound of claim 23.
25. The potassium salt of the compound of claim 23.
26. The compound of claim 21 wherein R1 is 3-furyl.
27. 7,3 - [[[(Aminocarbonyl)amino] (L - 3 - furyl)acetyl]amino] - 3 - [[(1methyl - 1H - tetrazol - 5 - yl)thio]methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo [4.2.0] oct - 2 - ene - 2 - carboxylic acid.
28. The sodium salt of the compound of claim 27.
29. The potassium salt of the compound of claim 27.
30. The compound of claim 17 wherein R is
31. The compound of claim 2 wherein R1 is phenyl and Ra is hydrogen, sodium or potassium.
32. The compound of claim 31 wherein Ra is methyl.
33. The compound of claim 32 wherein R, is
34. The compound of claim 33 wherein R, is
35. The compound of claim 33 wherein Rd is
36. 7,3 - [[[(Aminocarbonyl)amino] (L - phenyl)acetyl]amino] - 3 - [[(1methyl - 1H - tetrazol - S - yl)thio] methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo
[4.2.0] oct - 2 - ene - 2 - carboxylic acid.
37. The sodium salt of the compound of claim 36.
38. The potassium salt of the compound of claim 36.
39. The compound of claim 1 as named in any of the Examples.
40. A pharmaceutical composition comprising a compound according to any preceding claim and a pharmaceutical carrier.
41. A composition according to claim 40 in the form of a tablet, capsule, elixir or sterile aqueous injectable preparation.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/664,796 US4088816A (en) | 1974-09-20 | 1976-03-08 | 3-Heterothio substituted 7-(ureido-heteroacetyl) cephalosporins |
| US05/664,795 US4088815A (en) | 1974-09-20 | 1976-03-08 | 3-Heterothio-7-ureido cephalosporins |
| US05/764,134 US4127716A (en) | 1976-03-08 | 1977-02-02 | 3-heterothiomethyl ureido cephalosporins |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1573786A true GB1573786A (en) | 1980-08-28 |
Family
ID=27418117
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9511/77A Expired GB1573786A (en) | 1976-03-08 | 1977-03-07 | L-isomers of 3-heterothiomethyl ureido cephalosporins |
Country Status (16)
| Country | Link |
|---|---|
| JP (1) | JPS52108996A (en) |
| AT (1) | AT352876B (en) |
| AU (1) | AU2236777A (en) |
| CA (1) | CA1088517A (en) |
| CS (1) | CS191190B2 (en) |
| DD (1) | DD129793A5 (en) |
| DE (1) | DE2707812A1 (en) |
| DK (1) | DK97077A (en) |
| ES (1) | ES456591A1 (en) |
| FR (1) | FR2343745A2 (en) |
| GB (1) | GB1573786A (en) |
| NL (1) | NL7702405A (en) |
| NZ (1) | NZ183332A (en) |
| PL (1) | PL196501A1 (en) |
| PT (1) | PT66272B (en) |
| SE (1) | SE7702558L (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2927534A1 (en) * | 1979-07-07 | 1981-01-08 | Bayer Ag | OPTICALLY PURE HETEROCYCLIC AMINO ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE |
-
1977
- 1977-02-14 NZ NZ183332A patent/NZ183332A/en unknown
- 1977-02-15 CA CA271,818A patent/CA1088517A/en not_active Expired
- 1977-02-17 AU AU22367/77A patent/AU2236777A/en not_active Expired
- 1977-02-23 DE DE19772707812 patent/DE2707812A1/en not_active Ceased
- 1977-03-04 CS CS771474A patent/CS191190B2/en unknown
- 1977-03-04 DK DK97077A patent/DK97077A/en not_active Application Discontinuation
- 1977-03-07 GB GB9511/77A patent/GB1573786A/en not_active Expired
- 1977-03-07 SE SE7702558A patent/SE7702558L/en not_active Application Discontinuation
- 1977-03-07 NL NL7702405A patent/NL7702405A/en not_active Application Discontinuation
- 1977-03-07 PT PT66272A patent/PT66272B/en unknown
- 1977-03-07 ES ES456591A patent/ES456591A1/en not_active Expired
- 1977-03-08 PL PL19650177A patent/PL196501A1/en unknown
- 1977-03-08 AT AT155177A patent/AT352876B/en not_active IP Right Cessation
- 1977-03-08 DD DD7700197733A patent/DD129793A5/en unknown
- 1977-03-08 FR FR7706808A patent/FR2343745A2/en active Pending
- 1977-03-08 JP JP2583677A patent/JPS52108996A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| SE7702558L (en) | 1977-09-09 |
| ATA155177A (en) | 1979-03-15 |
| AT352876B (en) | 1979-10-10 |
| FR2343745A2 (en) | 1977-10-07 |
| NZ183332A (en) | 1979-10-25 |
| DE2707812A1 (en) | 1977-09-15 |
| CS191190B2 (en) | 1979-06-29 |
| CA1088517A (en) | 1980-10-28 |
| ES456591A1 (en) | 1978-02-16 |
| PL196501A1 (en) | 1978-02-13 |
| DK97077A (en) | 1977-09-09 |
| JPS52108996A (en) | 1977-09-12 |
| NL7702405A (en) | 1977-09-12 |
| PT66272B (en) | 1978-08-08 |
| AU2236777A (en) | 1978-08-24 |
| DD129793A5 (en) | 1978-02-08 |
| PT66272A (en) | 1977-03-31 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed [section 19, patents act 1949] |