GB2061276A - Imidazole and tetrazole derivatives of 7-[(2-amino-4-thiazolyl)- oximino] cephalosporins - Google Patents
Imidazole and tetrazole derivatives of 7-[(2-amino-4-thiazolyl)- oximino] cephalosporins Download PDFInfo
- Publication number
- GB2061276A GB2061276A GB8034000A GB8034000A GB2061276A GB 2061276 A GB2061276 A GB 2061276A GB 8034000 A GB8034000 A GB 8034000A GB 8034000 A GB8034000 A GB 8034000A GB 2061276 A GB2061276 A GB 2061276A
- Authority
- GB
- United Kingdom
- Prior art keywords
- formula
- compound
- hydrogen
- methyl
- amino
- 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.)
- Granted
Links
- 229930186147 Cephalosporin Natural products 0.000 title claims description 9
- 229940124587 cephalosporin Drugs 0.000 title claims description 9
- 150000003536 tetrazoles Chemical class 0.000 title claims description 7
- 150000001780 cephalosporins Chemical class 0.000 title description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 title 3
- -1 p-methoxy benzyl Chemical group 0.000 claims abstract description 216
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 190
- 150000001875 compounds Chemical class 0.000 claims abstract description 143
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 129
- 239000001257 hydrogen Substances 0.000 claims abstract description 125
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 97
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 50
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 38
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 36
- 239000011734 sodium Substances 0.000 claims abstract description 36
- 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 abstract description 35
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 32
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 32
- 239000011591 potassium Substances 0.000 claims abstract description 32
- 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 abstract description 15
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 11
- 125000006000 trichloroethyl group Chemical group 0.000 claims abstract description 7
- 150000001340 alkali metals Chemical group 0.000 claims abstract description 6
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 129
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 88
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 77
- 238000000034 method Methods 0.000 claims description 74
- 239000002253 acid Substances 0.000 claims description 64
- 150000002431 hydrogen Chemical group 0.000 claims description 49
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 46
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 36
- 239000000203 mixture Substances 0.000 claims description 35
- 159000000000 sodium salts Chemical class 0.000 claims description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 26
- 150000002148 esters Chemical class 0.000 claims description 21
- 239000007858 starting material Substances 0.000 claims description 21
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 20
- 125000006239 protecting group Chemical group 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 150000003462 sulfoxides Chemical class 0.000 claims description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
- 239000002262 Schiff base Substances 0.000 claims description 10
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 10
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 10
- 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 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 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 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 150000003457 sulfones Chemical class 0.000 claims description 5
- 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 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- SCKXCAADGDQQCS-UHFFFAOYSA-N Performic acid Chemical compound OOC=O SCKXCAADGDQQCS-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000007822 coupling agent Substances 0.000 claims description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 claims description 4
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical class C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 claims description 3
- 150000004753 Schiff bases Chemical group 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 3
- KQZJGGQRUUTKGP-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione;sodium Chemical compound [Na].C1=CC=C2C(=O)N(O)C(=O)C2=C1 KQZJGGQRUUTKGP-UHFFFAOYSA-N 0.000 claims description 2
- 229910007161 Si(CH3)3 Inorganic materials 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 230000000844 anti-bacterial effect Effects 0.000 claims 3
- 239000003937 drug carrier Substances 0.000 claims 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims 2
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 claims 1
- 125000001174 sulfone group Chemical group 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 63
- 239000000047 product Substances 0.000 description 54
- 239000000243 solution Substances 0.000 description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 40
- AZFKQCNGMSSWDS-UHFFFAOYSA-N MCPA-thioethyl Chemical compound CCSC(=O)COC1=CC=C(Cl)C=C1C AZFKQCNGMSSWDS-UHFFFAOYSA-N 0.000 description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
- 238000002844 melting Methods 0.000 description 24
- 230000008018 melting Effects 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 238000003756 stirring Methods 0.000 description 21
- SCNWTQPZTZMXBG-UHFFFAOYSA-N 2-methyloct-2-enoic acid Chemical compound CCCCCC=C(C)C(O)=O SCNWTQPZTZMXBG-UHFFFAOYSA-N 0.000 description 17
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 16
- 229940093499 ethyl acetate Drugs 0.000 description 15
- 235000019439 ethyl acetate Nutrition 0.000 description 15
- 239000002002 slurry Substances 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- LKHYFCSSVZVVNF-UHFFFAOYSA-N ethyl hexanoate;sodium Chemical compound [Na].CCCCCC(=O)OCC LKHYFCSSVZVVNF-UHFFFAOYSA-N 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 11
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 9
- 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 9
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- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 8
- QIJIUJYANDSEKG-UHFFFAOYSA-N 2,4,4-trimethylpentan-2-amine Chemical compound CC(C)(C)CC(C)(C)N QIJIUJYANDSEKG-UHFFFAOYSA-N 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- 241001024304 Mino Species 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 6
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- 238000007254 oxidation reaction Methods 0.000 description 6
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 6
- 229920001429 chelating resin Polymers 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- OOLDPDOCYQTXMR-UHFFFAOYSA-N 2-(2h-tetrazol-5-ylmethoxy)isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1OCC1=NN=NN1 OOLDPDOCYQTXMR-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
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- 238000004587 chromatography analysis Methods 0.000 description 4
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 4
- 239000007800 oxidant agent Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical group C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 4
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- 208000015181 infectious disease Diseases 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 239000004570 mortar (masonry) Substances 0.000 description 2
- SNHHXBSBDDJWHP-UHFFFAOYSA-N o-(1h-imidazol-2-ylmethyl)hydroxylamine;hydrochloride Chemical compound Cl.NOCC1=NC=CN1 SNHHXBSBDDJWHP-UHFFFAOYSA-N 0.000 description 2
- MMCZUHVQISUEKD-UHFFFAOYSA-N o-(2h-tetrazol-5-ylmethyl)hydroxylamine Chemical compound NOCC1=NN=NN1 MMCZUHVQISUEKD-UHFFFAOYSA-N 0.000 description 2
- HKMHQPIWKXUOPK-UHFFFAOYSA-N o-[(1-methyltetrazol-5-yl)methyl]hydroxylamine Chemical compound CN1N=NN=C1CON HKMHQPIWKXUOPK-UHFFFAOYSA-N 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 229910052682 stishovite Inorganic materials 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- 229910052905 tridymite Inorganic materials 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- VMASTYPGLHRVNL-UHFFFAOYSA-N 2-(2-amino-1,3-thiazol-4-yl)-2-oxoacetic acid Chemical compound NC1=NC(C(=O)C(O)=O)=CS1 VMASTYPGLHRVNL-UHFFFAOYSA-N 0.000 description 1
- JPJMIBGVCGNFQD-UHFFFAOYSA-N 2-(2-formamido-1,3-thiazol-4-yl)-2-oxoacetic acid Chemical compound OC(=O)C(=O)C1=CSC(NC=O)=N1 JPJMIBGVCGNFQD-UHFFFAOYSA-N 0.000 description 1
- OYBZNZWJLAXIJL-UHFFFAOYSA-N 2-(chloromethyl)-1h-imidazole;hydrochloride Chemical compound Cl.ClCC1=NC=CN1 OYBZNZWJLAXIJL-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- XDSDCTDECRVDTB-UHFFFAOYSA-N 2-bromo-2-methylpropanenitrile Chemical compound CC(C)(Br)C#N XDSDCTDECRVDTB-UHFFFAOYSA-N 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- CTSLUCNDVMMDHG-UHFFFAOYSA-N 5-bromo-3-(butan-2-yl)-6-methylpyrimidine-2,4(1H,3H)-dione Chemical compound CCC(C)N1C(=O)NC(C)=C(Br)C1=O CTSLUCNDVMMDHG-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000588919 Citrobacter freundii Species 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 241000147019 Enterobacter sp. Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 235000015429 Mirabilis expansa Nutrition 0.000 description 1
- 244000294411 Mirabilis expansa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000334216 Proteus sp. Species 0.000 description 1
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 description 1
- 241000607714 Serratia sp. Species 0.000 description 1
- GUKJSRAWYVHJFX-UHFFFAOYSA-N [5-(chloromethyl)tetrazol-1-yl]-phenylmethanone Chemical compound C(C1=CC=CC=C1)(=O)N1N=NN=C1CCl GUKJSRAWYVHJFX-UHFFFAOYSA-N 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000000872 buffer Substances 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
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- YGBFLZPYDUKSPT-MRVPVSSYSA-N cephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C[C@H]21 YGBFLZPYDUKSPT-MRVPVSSYSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 239000005457 ice water Substances 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
- 238000005342 ion exchange Methods 0.000 description 1
- VFQXVTODMYMSMJ-UHFFFAOYSA-N isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 235000013536 miso Nutrition 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- PSBKYMODPYHLAW-UHFFFAOYSA-N octan-4-amine Chemical compound CCCCC(N)CCC PSBKYMODPYHLAW-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
- 229940116357 potassium thiocyanate Drugs 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- VGTPCRGMBIAPIM-UHFFFAOYSA-M sodium thiocyanate Chemical compound [Na+].[S-]C#N VGTPCRGMBIAPIM-UHFFFAOYSA-M 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 125000000101 thioether group Chemical group 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
Abstract
A compound of the formula <IMAGE> wherein R is hydrogen, alkali metal, <IMAGE> p-methoxy benzyl, diphenylmethyl, benzyl, trichloroethyl, lower alkyl or <IMAGE> R1 is hydrogen or methyl; R2 is hydrogen or methyl; R3 is hydrogen or methyl; R4 is hydrogen, -OCONH2, <IMAGE> R5 is hydrogen or methyl; R6 is hydrogen, methyl, benzyl or acetyl; R7 is hydrogen or lower alkyl; R8 is hydrogen or -CONH2; R9 is hydrogen, lower alkyl, <IMAGE> or -(CH2)p-N-(lower alkyl)2; <IMAGE> R18 is hydrogen or lower alkyl; R19 is hydrogen, lower alkyl, -(CH2)p-COOR20, -(CH2)p-SO3R20 or -(CH2)p-N-(lower alkyl)2; R20 is hydrogen, sodium or potassium, and p is an integer from 1 to 4.
Description
SPECIFICATION I midazole and tetrazole derivatives of 7-[(2-amino-4-thiazolyl)oximino] cephalosporins
This invention is directed to cephalosporins of the formula
wherein R is hydrogen, alkali metal,
Si(CH3)3, p-methoxybenzyl, diphenylmethyl, benzyl, trichloroethyl,
or lower alkyl;
R, and R2' R3 and R5 are independently selected from hydrogen and methyl;
Ra is hydrogen, -OCONH2,
R6 is hydrogen, methyl, benzyl or acetyl;
R, is hydrogen or lower alkyl;
R8 is hydrogen or-CONH2;
R9 is hydrogen, lower alkyl,
or -(CH2)-N-(Iower alkyl)2; R10 is hydrogen or lower alkyl;
R1l is hydrogen, sodium or potassium; n is 1,2,3 or 4; misO,1 or2;
pis 1,2,3or4;;
When R4 is pyridinium or carbamoyl substituted pyridinium, the compounds can be structurally represented as having the formula:
wherein R8 is hydrogen or carbamoyl, and to cephalosporins of the formula
R12 represents hydrogen, sodium, potassium, benzyl, p-methoxybenzyl, diphenylmethyl, t-butyl, trichloroethyl. -CH2-O-lower alkyl.
R13 and R14 are independently selected from hydrogen, methyl, ethyl, n-propyl, i-propyl and carboxyl.
R,5 is hydrogen, methyl or alkali metal such as sodium or potassium.
R16 is in the -configuration and is hydrogen or methoxy.
X is hydrogen,
R17 is hydrogen or lower alkyl.
R18 is hydrogen or lower alkyl.
R19 is hydrogen, lower alkyl, -(CH2)p-COOR20-(CH2)p-SO3R20 or-(CH2)p-N(lower alkyl)2.
n is zero or an lnteger from 1 to 4.
m is zero, one or two
p is an integer from 1 to 4.
R20 is hydrogen, sodium, or potassium.
When X is pyridinium or carbamoyl substituted pyridinium, the compounds can be structurally represented as having the formula
wherein Z is hydrogen or carbamoyl.
The lower alkyl groups referred to throughout this specification include straight or branched chain hydrocarbon groups containing 1 to 4 carbon atoms, e.g., methyl, ethyl, i-propyl, butyl, etc.
The compounds of formula I, la, II and lib and their intermediates that have the 2-amino 4thiazolyl group as part of their structure are tautomeric and can contain a 2-imino group. Thus, the compounds of formula I can be represented as:
and the compounds of formula II can be represented as
The intermediates and final products are structurally represented and named throughout this ;pecification as 2-amino-4-thiazoles though both forms are within the scope of the invention.
The compounds of formula I and II and the intermediates described below having the oximino substituent
can be obtained as the syn or anti isomer or as a mixture of isomers. All of these isomeric forms are within the scope of this invention. However, in general, it is preferred to obtain the final products in the syn form since that isomeric form has the greatest activity.
The symbol
is being used to represent sulfide alone or bonded to either one or two oxygens. When the sulfide is bonded to only one oxygen the sulfoxides of formulas I and 11 and in the various intermediates described below can be in either the a- or p-configuration, When the sulfoxide is only in the ss-configuration it will be represented as
and when it is only in the a-configuration it will be represented as
The cephalosporins of formula I can be prepared by various methods.For example, the compounds of formula I wherein R4 is -OCONH2,
wherein R4, and m are as defined above and R1 is an ester protecting group such as benzyl, diphenylmethyl, t-butyl, p-methoxybenzyl or trichloroethyl, with a compound of the formula
wherein R1, R2, R3, R5, R6 and n are as defined above, to yield an intermediate of the formula
The acylation reaction is carried out in the presence of a coupling agent such as dicyclohexylcarbodiimide.
The intermediate of formula Vll is then treated to remove the ester protecting group and yield the compounds of formula I in the acid form. Preferably, in the above reactions, R is diphenylmethyl and the intermediate of formula VII is treated with trifluoroacetic acid to remove the diphenylmethyl group.
The compounds of formula VI are obtained by reacting 2-amino-4-thiazole glyoxylic acid of the formula
with a compound of the formula
The compound of formula IX can be prepared by treating N-hydroxyphthalimide sodium salt with a compound of the formula
to yield the compound of the formula
Treatment of Xl with hydrochloric acid yields the reactant of formula IX.
The 7-amino cephalosporanic acid ester a- and p-sulfoxides of formula V (m is one) are prepared by converting the 7-amino cephalosporanic acid starting material (m is zero) to the Schiff base ester of the formula
which is then oxidized with a percarboxylic acid such as m-chloroperbenzoic acid to yield a mixture of - and p-sulfoxide Schiff base cephalosporin esters. The Schiff base sidechain is cleaved by treatment with toluenesulfonic acid and the a- and ,B-sulfoxide 7-amino cephalosporanic acid esters are separated chromatographically. Further oxidation of the a-sulfoxide yields the corresponding sulfone (m is two) of formula V.
The compounds of formula la can be prepared by reacting a compound of formula I wherein R is hydrogen and R4 is
with pyridine or carbamoylsubstituted pyridine in a polar solvent such as water and in the presence of a catalyst such as an alkali metal thiocyanate according to the procedures taught in U.S. Patent 3,792,047 and German Offeniegungsschrift2,234,280.
Also, the compounds of formula I wherein R4 is heterothio (i.e.
can be prepared by reacting the compound of formula I wherein R is hydrogen and R4 is
with a mercaptan of the formula hetero-S-H or an alkali metal (preferably sodium) mercaptan salt of the formula
hetero-S-alkali metal.
Such methods of introducing a heterothio group in the 3-position are disclosed in various U.S. Patents including 3,955,213,4,066,762.
The ,3-sulfoxide compounds of formula I (m is one) can also be prepared by the direct oxidation of the corresponding sulfide compound (m is zero). Suitable oxidizing agents are percarboxylic acids such as m-chloroperbenzoic acid, peracetic acid, etc. and this reaction can be performed at from about OOC to about 250C.
Also, the sulfone compounds of formula I (m is two) can be prepared by the direct oxidation of the corresponding cr-sulfoxide compound (m is one). Again percarboxylic acids such as m-chloroperbenzoic acid and peracetic acid are the preferred oxidizing agents.
The compounds of formula I wherein R is sodium or potassium are prepared by reacting the corresponding compound of formula I wherein R is hydrogen with the appropriate salt forming ion.
The compounds of formula I wherein R is
can be obtained by treating the corresponding free acid of formula I with a compound of the formula
wherein halo is chlorine or bromine in an inert solvent such as dimethylformamide at or below ambient temperature.
Similarly, the compounds of formula I wherein R is
are prepared by treating free acid, compound of formula I with a compound of the formula
wherein L is hydroxy or Br as taught in U.S. Patents 3,860,579, 3,951,954, and 4,072,677.
Preferred compounds of formula I are
wherein the oximino group is in the syn configuration;
n is one or two
m is zero or one provided that when m is one the sulfoxide is in the ,B-configuration; R is hydrogen, sodium or potassium; Rr, R2, R3 and R5 are independently selected from hydrogen and methyl;
R4 is
R6 is hydrogen, methyl, benzyl or acetyl;
R, is hydrogen;
R8 is hydrogen or
R9 is hydrogen, methyl,
or-(CH2)-N(CH3)2; R1, is hydrogen, sodium or potassium and p is 1 or 2.
Most preferred are the above compounds wherein R4 is
The cephalosporins of formula li can be prepared by various methods. For example, the compound wherein X is hydrogen,
or heterothio (i.e.
can be obtained by acylating an ester of the formula
wherein X, R16, and m are as defined above and R21 is an ester protecting group such as benzyl, diphenylmethyl, t-butyl, p-methoxybenzyl or trichloroethyl, with a compound of the formula
wherein R13, R14, and n are as defined above and R15 is hydrogen or methyl; to yield the intermediate of the formula:
The acylation reaction is carried out in the presence of a coupling agent such as dicyclohexylcarbodiimide. The acid of formula XIII is treated with monosilyltrifluoroacetamide prior to the acylation reaction.
The intermediate of formula XIV is then treated to remove the R21 ester protecting group and yield the compounds of formula II in the acid form. Preferably, in the above reactions, R21 is diphenylmethyl and the intermediate of formula XIV is treated with trifluoroacetic acid and anisole to remove the diphenylmethyl group.
The compounds of formula XIII in the syn configuration are obtained by reacting an optionally protected 2-amino-4-thiazole glyoxylic acid of the formula
wherein R22 is hydrogen or a conventional amino protecting group such as formyl, trityl or tbutoxycarbonyl, with a tetrazole of the formula
wherein R14 is hydrogen or methyl. The R22 protecting group if present can be removed by conventional procedures after the above reaction to yield the syn configuration intermediates of formula XI II.
The tetrazole of formula XVI can be prepared by treating N-hydroxyphthalimide with a nitrile of the formula
to yield the compound of the formula
which is then treated with sodium azide to give the compound of the formula
Treatment of the compound of formula X with methyl iodide yields
Treatment of either XIX or XIXA with hydrochloric acid at reflux temperature yields the reactant of formula XVI.
The syn form of the compound of formula XIII also be obtained by reacting a 2- protected amino a:-(oximino)-4-thiazole acetic acid of the formula
wherein R22 is as defined above and alkyl is preferably ethyl, with a tetrazole of the formula
wherein halo is preferably chlorine and R23 is hydrogen, a protecting group such as benzoyl, or methyl.
The R22 and R23 protecting groups if present are removed after the reaction by conventional procedures.
The anti form of the compound of formula XIII can be obtained by reacting a 2- protected amino 4-thiazolyl-glyoxylic acid ester of the formula
wherein R22 is as defined above and alkyl is preferably ethyl, with the tetrazole of formula XXI. The R22 and R23 protecting groups, if present, are removed after the reaction by conventional procedures.
The 7-amino cephalosporanic acid ester a- and p-sulfoxides of formula XII (m is one) are prepared by converting the 7-amino cephalosporanic acid starting material (m is zero) to the Schiff base ester of the formula
which is then oxidized with a percarboxylic acid such as m-chloroperbenzoic acid to yield a mixture of a- and ,B-sulfoxide Schiff base cephalosporin esters. The Schiff base sidechain is cleaved by treatment with toluenesulfonic acid and the a- and p-sulfoxide 7-amino cephalosporanic acid esters are separated chromatographically. Further oxidation of the a-sulfoxide yields the corresponding sulfone (m is two) of formula XII.
The compounds of formula llb can be prepared by reacting a compound of formula II wherein R12 is hydrogen and X is
with pyridine or carbamoyl substituted pyridine in a polar solvent such as water and in the presence of a
catalyst such as an alkali metal thiocyanate according to the procedures taught in U.S. Patent 3,792,047 and German Offenlegungsschrift 2,234,280.
Also, the compounds of formula II wherein X is heterothio (i.e.
can be prepared by reacting the compound of formula II wherein R12 is hydrogen and X is
with a mercaptan of the formula
(XXIV) hetero-S-H or an alkali metal (preferably sodium) mercaptan salt of the formula
(XXV) hetero-S-alkali metal
Such methods of introducing a heterothio group in the 3-position are disclosed in various U.S. Patents including 3,955,213, 4,066,762.
The ss-sulfoxide compounds of formula II (m is one) can also be prepared by the direct oxidation of the corresponding sulfide compound (m is zero). Suitable oxidizing agents are percarboxylic acids such as m-chloroperbenzoic acid, peracetic acid, etc., and this reaction can be performed at from about OOC to about 250.
Also, the sulfone compounds of formula II (m is two) can be prepared by the direct oxidation of the corresponding a-sulfoxide compound (m is one). Again, percarboxylic acids such as m-chloroperbenzoic acid and peracetic acid are the preferred oxidizing agents.
The compounds of formula il wherein R12, R15 and R20 are sodium or potassium are prepared by reacting the corresponding compound of formula II wherein R12, R15 and R20 are hydrogen with a base having the appropriate cation.
The compounds of formula II wherein R12 is
can be obtained by treating the corresponding free acid of formula II with one or two moles of the compound of the formula
wherein halo is chlorine or bromine in an inert solvent such as dimethylformamide at or below ambient temperature.
Similarly, the compounds of formula II wherein R12 is
are prepared by treating free acid compound of formula II with a compound of the formula (XXVII)
wherein L is hydroxy or Br as taught in U.S. Patents 3,860,579, 3,951,954, and 4,072,677.
Preferred compounds of formula II are wherein R12 is hydrogen, sodium or potassium; R13 and R14 are both hydrogen; n is one; R15 is hydrogen, methyl, sodium or potassium; R16 is hydrogen; X is hydrogen,
R19 is hydrogen, methyl, -CH2-C00R20,
or -(CH2)2-N(CH3)2; and R20 is hydrogen, sodium or potassium.
Most preferred are the above compounds wherein the oximino group
is in the syn configuration; R15 is hydrogen, sodium or potassium; and X is
In particular, those most preferred compounds of formula II as defined above in addition to their broad spectrum of antimicrobial activity, also exhibit exceptional activity against a range of gramnegative microorganisms, e.g., Serratia sp., indole positive Proteus sp., Enterobacter sp., and strains of Klebsiella pneumoniae. These compounds show a high degree of stability to ,B-lactamases from both gram-positive and gram-negative bacteria.
The compounds of formula I and II are useful antibacterial agents possessing activity against various gram negative organisms including Klebsiella, Proteus, and Enterobacter species. These compounds are also active against strains of Escherichia coli, Citrobacter freundii, Salmonella typhimurium, etc. They may 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 other gram-negative antibacterial agents. For example, a compound of formula I and II or a physiologically acceptable salt thereof may be used in various animal species in an amount of about 1 to 100 mg/kg., daily in parenteral form, in single or two to four divided doses to treat infections of bacterial origin, e.g., 5.0 mg./kg. in mice.
Up to about 600 mg. of an acid compound of formula I and II or a physiologically acceptable salt or ester thereof may be incorporated in an injectable form prepared according to conventional pharmaceutical practice.
Illustrative process details are in the examples for the various reactions. All temperatures are on the centrigrade scale.
EXAMPLE 1 [6R-[6α,7ss(Z)]]-3-[(Acetyloxy)methyl]-[[(2-amino-4-thlazolyl)[(1H-imidazol-2-yl- methoxy)imino]acetyl]amino]-8-oxo-5-thia- 1 -azabicyclo[4.2.O]oct-2-ene-2-carboxyllc acid, sodium salt
a) 2-( 1 H-lmidazol-1 -yl-methoxy)-1 H-isoindole-1 ,3(2H) dione
5.1 g sodium salt of N-Hydroxyphthalimide and 1.9 g 2-chloromethyl imidazole hydrochloride
(Journal of Chem. Soc. 1965, 4577) are stirred at room temperature in dry methanol for 2 hours. The solvent is distilled off in vacuo and the residue treated with aqueous sodium bicarbonate and extracted 3 to 4 times with chloroform.The combined organic layers are dried over sodium sulfate, filtered and evaporated to dryness 1.7 g of 2-(1 H-lmidazol-1 -yl-methoxy)-1 H-isoindole-1 ,3(2H)dione remains as crystalline solid with a melting point of 158-160 C.
b) 2-[(Aminoxy)methyl]-1 H-imidazole hydrochloride (1:2)
1.5 g of 2-( 1 H-imidazol-l -yl-methoxy)-l H-isoindole-1,3(2H) dione is refluxed with stirring for 4 hours in 20 ml of 17.5% HCI aqueous. The mixture is cooled to room temperature and the precipitated phthalic acid is filtered off. The mother liquor is evaporated to dryness. 0.8 g of 2-[(aminoxy)methyl]-1 Himidazole hydrochloride (1 :2) remains with a melting point of 182-183 C.
c) 2-Amino-a-[(1 H-imidazol-2-yl-methoxy)imino]-4-thiazole acetic acid, hydrochloride (1:2) (Z)
2 g of 2-[(aminoxy)methyl]-1 H-imidazolehydrochloride (1 :2) from example 1 (b) and 2.24 9 2amino-thiazol-4-glyoxylic acid are suspended with stirringin 50 ml H20. The pH is adjusted with potassium carbonate to 6 and stirring is continued for 12 hours. The pH is then adjusted to 6.4 with hydrochloric acid. After 2 hours 0.8 g of crystalline 2-amino-a-[( 1 H-imidazol-2-yl-methoxy)imino]-4- thiazole acetic acid hydrochloride (1:2) is filtered off with a melting point of 1 58-1 600C (dec.).
d) [6R-[6α,7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[2-a mino-4-thiazolyl)[(1 H-imidazol-2-yl-methoxy)imino]acetyl]-a mino-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-ca rboxylic acid, diphenylmethyl ester.
1.2 g 2-Amino-a-[(1 H-imidazol-2-yl-methoxy)imino]-4-thiazole acetic acid hydrochloride (1:2) of example 1(c), 1,84 g 7ACA-benzhydryl ester and 0.54 g Hydroxybenzotriazole are dissolved in 50 ml dimethylformamide (DMF). At 0 C 1.1 g of Dicyclohexylcarbodiimide in 20 ml of acetonitrile is added to the DMF solution and stirred for 24 hours at OOC. After this time the solvent is removed in vacuo and the residue dissolved in acetone and filtered. The mother liquor is evaporated to dryness and the oily residue poured into 0 C aqueous sodium bicarbonate.The crystalline precipitate is filtered off, and purified by column chromatography using SiO2 and ethyl acetate as eluant to yield 1.5 g [6R [6bx,7,B(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl) [(1 H-imidazol-2-yl-methoxy)-imino]acetyl]amino]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester with a melting point of 11 50C (dec.).
e) [6R-[6et,7p(z)]]-3-[(Acetyloxy(methyl]-7-[[(2-amino-4-thiazolyl)] (1 H-imidazol-2-yl- methoxy)lmino]acetyl]-amino]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetate salt
920 mg of [6R-[6a,7p(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(1 H-imidazol-2-yl- methoxy)-lmino]acetyl]amino]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester is suspended in 2.5 ml anisole with stirring at 0%C. 5 ml trifluoroacetic acid are added and the mixture is stirred for an additional hour at OOC. After this time the solution is poured into 100 ml of a 1::1 mixture of ether/petrol ether The precitated acid is filtered off, washed with ether and dried to yield 850 mg of [6R-[6a,7,B(Z)]]-3-[(Acetyloxy(methyl]-7-[[(2-amino-4-thiazolyl)[(1 H-imidazol2-yl-methoxy)imino]acetyl]-amino]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid trifluoroacetate salt.
f) [6R-[6a!,7fi(Z)]]-3-[(Acetyloxy(methyl]-7-[[(2-amino-4-thiazolyl) [(1 H-imidazol-2-yl- methoxy)iminolacetyl]-amino]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt.
850 mg of [6R-[6α,7ss(Z)]]-3-[(Acetyloxy(methyl]-7-[[(2-amino-4-thiazoly)[(1 H-imidazol-2-ylmethoxy)iminolacetyl]-amino]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid, trifluoroacetate salt is dissolved in 1 5 ml of dry acetone/methanol (1:1) and treated at O C with 765 mg of sodium ethylhexanoate in 5 ml butanol. After 10 minutes stirring the mixture is poured into 100 ml of ether and 630 mg of precipitated [6R-[6a,7(Z)jj-3-[(acetyIoxy(methylj-7-[[(2-a mino-4-thiazolyl) [(1 Himidazol-2-yl-methoxy)iminolacetyl]-amino]-8-oxo-5-thla-1-azabicyclo[4,5,0]oct-2-ene-2-carboxylic acid, sodium salt is filtered off having a melting point of 1 63-1 650C.
EXAMPLE 2 [5S[5α,6ss,7α(Z)]]-3[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(1H-imidazol-2-yl methoxy)imino]acetyl]-amino]-8-oxo-5-thia-1-azablcyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide sodium salt
a) [5S[5α,6ss,7α(Z)]]-3[(Acetyloxy)methyl]-7-[[(2-a mino-4-thiazolyl) [(1 H-imidazol-2-ylmethoxy)imino]acetyl]-amino]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide benzhydryl ester
2 g of 2-amino-a-[(1 H-imidazol-2-yl-methoxy)imino]-4-thiazole acetic acid hydrochloride (1:2) of example 1c, 2.95 g of 7ACA-benzhydrylester-P-sulfoxide and 1.2 g hydroxybenzotriazole are dissolved in 80 ml dimethylformamide cooled to 0 C and 1.8 g dicyclohexylcarbodiimide is added.The solution is stirred at 0 C over night. The solvent is removed in vacuo and the oily residue stirred at 0 C with
aqueous sodium bicarbonate solution. The precipitated compound is filtered off, and purified by column chromatography using SiO2 and acetone as eluent to yield 2.2 g of [5S[5α,6ss,7α(Z)]]- 3[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(1H-imidazol-2-yl-methoxy)imino]acetyl]-amino]-8-oxo 5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide benzhydryl ester.
b) [5S[5α,6ss,7α(Z)]]-3[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl[(1H-imidazol-2-yl- methoxy)imino]acetyl]-amino]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid, 5-oxide trifluoroacetate.
A slurry of 2 g of [5S[5α,6ss,7α(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(1 H-imidazol2-yl-methoxy)imino] acetyl]-a mino]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-ca rboxylic acid, 5oxide benzhyryl ester and 6 g anisole are stirred at OOC, while 8 ml of trifluoroacetic acid is added.
Stirring is continued for 45 minutes and the solution is now poured into 200 ml of ether. The precipitate is filtered and washed with ether to yield 1.8 g of [5S(5α,6ss,7α(Z)]]-3-[(acetyloxy)methyl]-[[(2- amino-4-thiazolyl) [(1 H-imidazoi-2-yl-methoxy)iminolacetyl]-a mino]-8-oxo-5-thia- 1 azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide trifluoroacetate.
c) [5S[5(x,6,B,7a(Z)]]-3-[(Acetyloxy)methyl] -7-[[(2-amino-4-thiazolyl) [(1 H-imidazol-2-yl- methoxy)imino]acetyl]-amino]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide sodium salt.
1.9 g of [S[5(x,6A,7(x(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(1 H-imidazol-2-yl methoxy)imino]acetyl]-a mino]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate of Example 2(b) are treated in 5 ml dimethylformamide/methanol (1:1) for 5 minutes
with stirring. 200 ml of ether are added and the precipitated sodium salt is filtered off, yielding 1.1 g of [5S[[5α,6ss,7α(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-a mino-4-thiazolyl) [(1 H-imidazol-2-yl
methoxy)imino]acetyl]-amino]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-ca rboxylic acid, 5-oxide sodium salt having a melting point of 1 40-1 450C (dec.).
EXAMPLE 3 J6R-[6a, 7(Z)iT 7-[[(2-A mino-4-thiazolyl)[( 1 H4midazol-2-yl-m ethoxy)imino]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, sodium salt.
When 2-Amino-(x-[(1 H-imidazol-2-yl-methoxy)imino]-4-thiazole acetic acid hydrochloride (1:2) of example 1 (c) is reacted with 3-(1-methyl-1 H-tetrazolyl)-7ACA-benzhydryl ester according to the procedure given in Example 1(d), [6R-[6a,7(Z)]j-7-[[(Amino-4-thiazolyI)[(1 H-imidazol-2-yl methoxy)iminojacetylj-aminoj-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 is obtained. This compound is then processed as described in Example 1 (e) and 1(f), i.e. cleavage of the benzhydryl moiety by treatment with trifluoroacetic acid and subsequent formation of the sodium salt.By this method [6R-[6α,7ss(Z)]]-7- [[(2-amino-4-thiazolyl)-[( 1 H-imidazol-2-yl-methoxy)imino]acetyl]-amino]-3-[[(1 -methyl-1 H-tetrazolyl 5-yl)thio] methyl]-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt is obtained: having a melting point of 1 98-2000C (dec.).
EXAMPLE 4 [5S-[5α,6ss,7α(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazoly)[(1H-imidazol-2-yl- methoxy)imino]acetyll-amino]-8-oxo-5-thia- 1 -azabicyclo[4.2. O]oct-2-ene-2-carboxyllc acid, 5,5 dioxide sodium salt
a) [5S-[5α,6ss,7α]]-3-[(Acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid, 5-oxide, diphenylmethyl ester (i.e., p-sulfoxide) and [5R-[5α,6α;,7ss]]-3- [(Acetyloxy)methyl]-7-amino-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-ca rboxylic acid, 5-oxide, diphenylmethyl ester (i.e., a-sulfoxide) A slurry of 50 g of 7-aminocephalosporanic acid (7-ACA) in 1 liter of water is stirred magnetically while t-octyl amine is added dropwise, thereby maintaining the pH between 7 and 8. After one hour the undissolved solid is filtered (Celite) (registered Trade Mark) and the filtrate is treated with a solution prepared by adjusting a mixture of 10 ml of 5-octylamine and 20 ml of water to pH 8.0 with 6N hydrochloric acid. The resulting solution is then treated with 10 ml of salicylaldehyde. After 2 minutes a solid forms and after 5 minutes an additional 10 ml of salicylaldehyde is added. The slurry is stirred for an additional 10 minutes, cooled to 0 C for 4.5 hours and filtered. The filter cake is slurried twice with 300 ml of cold water and filtered. The wet cake is dried at 60 in vacuo over large amounts of P205 to give 66 g of tan solid 7-salicylaldiminocephalosporanic acid, t-octyl amine salt.
A slurry of 25.25 g (0.05 mole) of the above t-octyl amine salt (powdered with a mortar and pestle) in 250 ml of dry acetonitrile is treated with 9.5 g (0.05 mole) of p-toluenesulfonic acid monohydrate. After 10 minutes, a solution of 9.7 g (0.05 mole) of diphenyldiazomethane in 50 ml of acetonitrile is added over the course of 1 5 minutes. After one hour, the slurry is filtered, the solid is washed with acetonitrile and the combined fj!tratg and washings ,irn evanorated in vacuo. The resulting oil is chromatographed on a 300 g silica gel column eluted with methylene chloride.Fractions (500 ml) 2-3 contain 7.5 g of the desired diphenylmethyl ester product plus some higher Rf impurity (monitored by silica gel TLC with 3:1 chloroform-ethyl acetate development):fractions 4-1 1 | contain 12.3 g of pure 7-salicyclaldiminocephalosporanic acid, diphenylmethyl ester; NMR (CDCl3) # 1.97 (s, 3H, CH3CO); 3.23 and 3.60 (AB q, J = 19 Hz, 2H, c-2); 4.67 and 5.01 (AB q, J = 14 Hz, 2H, C-3'); 4.99 (d, J = 5 Hz, 1 H, c-6); 5.20 (broadened d, J = 5 Hz, 1 H, C-7); 6.62-7.60 (m, about 1 5H); 9.07 (broad s, 1 H, -CH=N-).
A solution of 12.3 g (0.023 mole) of the above diphenylmethyl ester product in 125 ml of methylene chloride is cooled to 0 and a solution of 4.6 g (0.023 mole) of 85% m-chloroperbenzoic acid in 70 ml of methylene chloride is added over the course of 1 5 minutes. After one hour, the slurry is washed with a mixture of 100 ml of 5% sodium bicarbonate and 50 ml of 6% sodium sulfite solution.
The organic layer is dried and evaporated in vacuo. The resulting oil crystallizes from 70 ml of ethyl acetate giving 8.7 9 of a mixture of a- and ss-sulfoxides. A second crop of 1.5 g of a mixture of a- and ,B- sulfoxides is also obtained. The major (a-) isomer has a lower field acetate methyl (2.02 ppm) and C-2 quartet (3.57 and 4.10 ppm) when compared to those of the minor (ss) isomer (1.97,3.26 and 3.94 ppm, respectively).
A slurry of 10 9 (0.018 mole) of the above 7-salicyladiminocephalosporanic acid, diphenylmethyl ester a- and ss-sulfoxide mixture in 100 ml of ethyl acetate is treated with 3.42 g (0.018 mole) of ptoluenesulfonic acid monohydrate. After 5.5 hours, 300 ml of ether is added and the gummy solid is triturated, filtered, and washed twice with ether. The moist solid is dissolved in 200 ml of ethyl acetate and the solution is washed with 100 ml of 5% sodium bicarbonate solution, dried, and evaporated to give 8.0 9 of residue.Chromatography on a 300 g silica gel column eluted with 3:1 chloroform-ethyi acetate gives (500 ml fractions):fraction 3, 1.0 g of recovered 7-salicylaldimino-cephalosporanic acid, diphenylmethyl ester; fractions 6-1 6, 4.5 g of [5R-[5α,6α,7ss]]-3-[(acetyloxy)methyl]-7-amino-8-oxo- 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester (i.e., α-sulfoxide isomer):NMR (CDCl3) # 2.00 (CH3COO); 3.43 and 4.06 ppm (AB q, C-2); fractions 22-30 (eluant is changed to ethyl acetate after fraction 16) 1.5 g of [5S-[5a,6,7a]]-3-[(aceWloxy)methyI-7-amino-8- oxo-5-thia-l -azabicycio[4.2.0]oct-2-ene-2-carboxyiic acid, 5-oxide, diphenylmethyl ester (i.e., p- sulfoxide isomer):NMR (CDCl3) # 2.10 (CH3COO-); 2.97 and 3.54 ppm (AB q, C-2).
b) [6R-[6α,7ss]-3-[(Acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5-dioxide, diphenylmethyl ester [5R-[5α,6α,7ss]]-3-[(Acetyloxy)methyl]-7-amino-8-oxo-5-thia-1 -azabicyclo[4.2 .0]oct-2 -ene-2carboxylic acid, 5-oxide, diphenylmethyl ester from Example 4(a) is added to methylene chloride and cooled to OOC. An equimolar amount of m-chloroperbenzoic acid in methylene chloride is added. After the reaction is completed, the slurry is treated with 5% sodium bicarbonate and 5% sodium sulfite. The organic layer is dried and evaporated in vacuo.Preparative thin layer chromatography of the residue yields [6R-[6a,7jj-3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid, 5,5-dioxide, diphenylmethyl ester.
c) [5S-[5a,6p,7 α(Z)]]-3-[Acetyloxy)methyl]-7-[[(2-a mino-4-thiazolyl)[( 1 H-imidazol-2-yl- methoxy)imino]acetyl]-amino]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5dioxide, diphenylmethyl ester
Following the procedure of Example 1 (d) but substituting [5S- [5a,6,ss,7]]-3-[(acetyloxy)methyl]-7- amino-8-oxo-5-thia-l -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5-dioxide, diphenylmethyl ester for 7 ACA-diphenylmethyl ester then [5S-[5α,6ss,7α;(Z)]]-3-[(acetyloxy)-methyl]-7-[[(2-amino-4- thiazolyl[( 1 H-imidazol-2-yl-methoxy)imino]acetyl]- amino]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene- 2-carboxylic acid 5,5 dioxide, diphenylmethyl ester is formed.
d) [5S-(5a,6,7a)]-3-[(Acetyloxy)methyIj-7-[[(2-amino4-thiazolyl) [(1 H-imidazol-2-yl methoxy)imino]acetyl]a mino]-8-oxo-5-thia- 1 -azabicyclo[4.2 .0]oct-2-ene-2-carboxylic acid 5,5 dioxide trifluoroacetate salt
Following the procedure of Example 1 (e) but substituting [5S-[5α,6ss,7α(Z)]]-3- [(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl[(1H-imidazol-2-yl-methoxy)imino]acetyl]amino]-8-oxo-5thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 5,5-dioxide diphenylmethyl ester for [6R [6α ;7ss(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[1H-imidazol-2yl-methoxy)imino]acetyl]- amino]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester then [5S (5a,6,7a)]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyI[( 1 H-i midazol-2-yl-methoxy)imino]acetyl]- amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 5,5 dioxide trifluoroacetate salt is formed.
e) [55-[5a,613,7a(Z)j]-3-[(Acetyloxy)methylj-7-[[(2-amino-4-thiazolyl)[(1 H-imidazol-2-yl
methoxy)imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5 dioxide, sodium salt
Following the procedure of Example 1 (f) but substituting [5S-(5α,6ss,7α)]-3-[(acetyloxy)methyl]-7- [[(2-amino-4-thiazolyl)[1H-imidazol-2-yl-methoxy)imino]acetyl]-amino]-8-oxo-5-thia-1
azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 5,5 dioxide trifluoroacetate salt for [6R-[6α,7ss(Z)]]-3- [(acetyloxy) methyl]-7-[[(2-a mino-4-thiazolyl) [(1 H-imidazol-2-yl-methoxy)imino]acetyl]amino]-8-oXo-5- thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetate salt to form [5S-[5α;,6ss,7ss(Z)]]-3- [(acetyloxy)methyl]-7-[[(2-amino-4-thiazoly)[(1H-imidazol-2-yl-methoxy)imino]acetyl]amino]-8-oxo 5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5 dioxide, sodium salt.
EXAMPLE 5 [5R-[5a, 6a, 7ss]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[( l H-imidazol-2-yl methoxy)imino]acetyl]amino]-8-oxo-5-thia- 1 -azabicyclo[4.2.O]oct-2-ene-2-carboxyllc acid, 5-oxide,
sodium salt (i.e. a-sulfoxide) a) [5R-[5α,6α7ss]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(1H-imidazol-2-yl methoxy)imino]acetyl]amino]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 5-oxide,
diphenylmethyl ester
Following the procedure of Example 1 (d) but substituting [5R-[5α,6α7ss]]-3-[(acetyloxy)methyl]-7- amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester (i.e.
a-sulfoxide) (made as in Example 4(a) for 7 ACA-diphenylmethyl ester, then [5R-[5α,6α7ss]]-3- [(acetyloxy)methyl-7-[[2-amino-4-thiazoly[(1H-imidazol-2-yl-methoxy)imino]acetyl]amino]-8-oxo-5 thia-l -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 5-oxide, diphenylmethyl ester is formed.
b) [5R-[5α,6α,7ss]-3-[(Acetyloxy)methyl]-7-[[(2-a mino-4-thiazolyl) [(1 H-imidazol-2-yl methoxy)imino]acetyl]amino]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide,
trifluoroacetate
Following the procedure of Example 1 (e) but substituting [5R-[5α, 6α,7ss]]-3-[(Acetyloxy)methyl]- 7-[[(2-amino-4-thiazoly][(1H-imidazol-2-yl-methoxy)imino]acetyl]-amino]-8-oxo-5-thia-1 azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 5-oxide, diphenylmethyl ester in place of [6R-[6α;,7ss(Z)]]- 3-[(acetyloxy) methyl]-7-[[(2-amino-4-thiazolyl) [(1 H-imidazol-2-yl-methoxy)imino] acetyl] amino]-8 oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester then [5R-[5α,6α,7ss]]- 3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(1H-imidazol-2-yl-methoxy)imino]acetyl]amino]-8 oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, trifluoroacetate is formed.
c) [5R-[5α,6α,7ss]]-3-[[Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl) [(1 H-imidazol-2-yl
methoxy)imino]acetyl]amino]-8-oxo-5-thia 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxvlic acid, 5-oxide,
sodium salt (i.e. a-sulfoxide)
Following the procedure of Example 1 (f) but substituting [5R-[5α,6α,7ss]]-3-[(acetyloxy)methyl]-7- [[(2-a mino-4-thiazolyl)[( 1 H-imidazol-2-yl-methoxy)imino]acetyl] amino]-8-oxo-5-thia-1
azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, trifluoroacetate in place of [6R-[6α;,7ss(Z)]]-3- [(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(1H-imidazol-2-yl-methoxy)imino]acetyl]amino]-8-oxo 5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetate salt then [5R-[5α,6α,7ss]]-3- [(acetyloxy)methyl]-7-[[2-amino-4-thiazolyl) [(1 H-imidazol-2-yl-methoxy)imino]acetyl] aminojr8-oxo- 5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, sodium salt (i.e. a-sulfoxide) is formed.
EXAMPLES 6-31 Following the'prncedure of Examples 1 to 5 but employing the ester shown in Col. I and the acid
shown in Col. II one obtains the ester shown in Col. III. Removal of the ester protecting group yields the
acid product shown in Col.IV.
Example R4 R R1 R2 R3 R5 R6 m n 6 # # -H -H -H -H -CH3 one two 7 # -C(CH3)3 -H -H -CH3 -H -CH3 zero one 8 # # -CH3 -CH3 -CH3 -H -CH3 zero one 9 # # -H -H -CH3 -H -CH3 zero one 10 # # -H -H -CH3 -H -H two one 11 # # -CH3 -CH3 -CH3 -H -H zero one 12 # # -H -H -CH3 -H -CH3 zero one 13 # # -H -H -CH3 -H -CH3 zero one 14 # # -CH3 -H -CH3 -H -H zero one
Example R4 R R1 R2 R3 R5 R6 m n 15 # # -H -H -CH3 zero zero 16 # # -H -H -CH3 one one 17 # # -H -H -H -H -CH3 one one 18 # # -H -H -H -H -CH3 two one 19 # # -CH3 -CH3 -H -H -CH3 zero one 20 # # -H -H -H -H -CH3 zero one 21 # # -CH3 -H -H -H -H zero one 22 # # -H -H -H -H -H zero one 23 # # -H -H -H -H -H one one
Example R4 R R1 R2 R3 R5 R6 m n 24 # # -H -H -H -H -CH3 zero one 25 # # -H -H -H -H -CH3 one one 26 # # -CH3 -CH3 -H -H -CH3 one one 27 # # -CH3 -CH3 -H -H -CH3 zero one 28 # # -H -H -H -H -CH3 zero one
Example R4 R R1 R2 R3 R5 R6 m n 29 # # -H -H -H -H -CH3 zero one 30 # # -H -H -H -H -CH3 one one 31 # # -H -H -H -H -CH3 zero one
The acid products of Examples 6 to 31 can be converted to the sodium or potassium according to known procedures.
The products of Examples 6 to 31 are obtained as the syn or anti isomer depending upon the
configuration of the acid shown in Col. II. Also, when R1 and R2 are not the same, the products are
obtained in the D-, L- or D,L-form depending upon the optical activity of the acid shown in Col. II.
EXAMPLE 32 [6R-[6α,7ss(Z)]]-3-[[4-(Aminocarbonyl)pyridino]methyl]-7-[[(2-amino-4-thiazolyl)[(1H-imidazol-2-yl- methoxy)imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. (syn
isomer)
A mixture of 0.005 mole of the sodium salt product of Example 1, 0.0075 mole of 4
pyridinecarboximide, 12 9 of potassium thiocyanate, and 7.5 ml of water are heated at 50O for 24
hours. The resulting solution is passed through a chromatography column filled with the ion exchange
Amberlite XAD-2 ("Amberlite" is a Registered Trade Mark). The column is washed with water and the
titled compound is eluted with a mixture of water:methanol (8:2). The methanol is evaporated from the
eluate and the aqueous solution is lyophilized.The amorphous residue is triturated with ether and
filtered under suction to yield [6R-[6α-[6α,7ss](Z)]]-3-[[4-(aminocarbonyl)pyridino]methyl]-7-[[(2-amino-4- thiazolyl)[(1H-imidazol-2-yl-methoxy)imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene
2-carboxylic acid.
EXAMPLES 33-40
Following the procedure of Example 32 but employing the cephalosporanic acid sodium salt
shown in Col. I and the pyridine compound shown in Col. II, one obtains the product shown in Col. III.
Example R1 R2 R3 R5 R5 m n R9 0 33 -H - CH3 one zero -CNH2 (4) 0 34 -H - CH3 two zero -CNH2 (3) 35 -H -H -H -H -CH3 zero one -H 36 -H -H -H zero zero -H 0 37 -H -H -H one zero -CNH2 (4) 0 38 -CH3 -CH3 -H -H -H zero one -CNH2 (2) 39 -H -H -H zero zero -H 0 II 40 -H -H - CH3 -H zero one -CNH2 (4)
The products of Examples 33 to 40 are obtained in the syn or anti configuration depending upon the configuration of the 3-acetoxymethyl starting material shown in Col. I. Similarly, when m is one the compounds are obtained as the a- or p-sulfoxide depending upon the orientation of the 3acetoxymethyl sulfoxide starting material. Also, when R1 and R2 are not the same, the products are obtained in the D-, L- or D,L-isomeric form depending upon the optical activity of the starting material shown in Col. I.
EXAMPLE 41 [6R-[6α,7ss(Z)]]-7-[[(2-Amino-4-thiazolyl)[(1H-imidazol-2-yl-methoxy)imino]acetylamino]-3-[[(5- methyl-1,3,4-thiadiazolyl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt
0.002 mole of the sodium salt product of Example 1 is brought into solution in 100 ml of a phosphate buffer at a pH of 6.4. Then 0.0024 mole of 5-methyl-1,3,4-thiadiozolyl-2-thio] is added. The solution is heated at 600 for six hours. After cooling, the pH is adjusted to 7.0 and the solution is chromatographed on the ion exchange resin Amberlite XAD-2.The fraction containing the desired product is freeze dried to yield [6R-[6a7(Z)j]-7-[[(2-a mino-4-thiazolyl) [(1 H-imidazol-2-ylmethoxy)imino]acetyl]amino]-3-[[(5-methyl-1,3,4-thiadiazolyl)thio]methyl-8-oxo-5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt.
EXAMPLES 42-47 Following the procedure of Example 41 but employing the cephalosporanic acid sodium salt shown in Col. I and the thiol shown in Col. II, one obtains the product shown in Col. III.
Col. II
HS-hetero
Col. #
Example R1 R2 R3 R5 R6 m n hetero 42 -H -H -CH3 zero zero # 43 -CH3 -CH3 -CH3 -H -CH3 two one # 44 -CH3 -H -CH3 one zero # 45 -H -H -H -H -H zero one # 46 -H -H -H one zero # 47 -H -H -H -CH3 two one # The products of Examples 42 to 47 are obtained in the syn or anti configuration depending upon the configuration of the 3-acetoxymethyl starting material shown in Col. I.Similarly, when m is one the compounds are obtained as the a- or ss- sulfoxide depending upon the orientation of the 3acetoxymethyl sulfoxide starting material. Also, when R, and R2 are not the same, the products are obtained in the D-, L- or D,L-isomeric form depending upon the optical activity of the starting material shown in Col. I.
EXAMPLE 48 [5S[5α,6ss,7α(Z)]]-3-[(Acetyloxy)methyl]-7-[[2-amino-4-thiazolyl[1H-imidazol-2-yl- methoxy)imino[acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide sodium salt (ss-sulfoxide, syn isomer)
The product of Example 2 can also be prepared by the following procedure.
1.69 g of [6R-[6a!,7,B(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(1 H-imidazol-2-ylmethoxy)imino]acetyl]-amino]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is obtained as in Example 1 (e) is dissolved in 35 ml of methylene chloride and cooled to OOC. 17 ml trifluoroacetic acid is added while stirring. 0.459 g of m-chloroperbenzoic acid is added and stirring is continued for 2.5 hours. The solvent is removed in vacuo and about 400 ml of ether is added. The precipitate is filtered off and washed with ether to yield 1.5 9 of [5S]5α,6ss,7α(Z)]]-3-[(acetyloxy)methyl]-7-[[(2- amino-4-thlazolyl[(1H-imidazol-2-yl-methoxy)imino]acetyl]-amino]-8-oxo-5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, trifluoroacetate salt having a melting point of 160 to 1650C.
This acid can be converted to its sodium salt by the procedure in Example 1(f).
EXAMPLES 49-57 Following the procedure of Example 48 the sulfides shown in Col. I can be oxidized to the p- sulfoxide shown in Col. II.
Col. I
Example R1 R2 n R3 R5 R5 R4 0 49 -H -H one -H -H -CH3 50 -H -H one -CH3 -H -CH3 H3 N 51 zero -H -H -H OH 3 52 -CH3 -CH3 one -H -H -CH3 -0- -OH3 53 -H -H one -H -H 0 --H-CH, -O- -CH3 54 --H --H one --H --H --CH, -S H3 o II 55 -H -H one -H -H -CH3 --OO--C-NH, 0 II 56 -H -CH3 one -H -H -CH3 --OO--C-NH, 0 II 57 -CH3 -CH3 one -H -H -CH3 --OO--C-NH, The products of Examples 49 to 57 are obtained in the syn or anti configuration depending upon the configuration of the sulfide starting material shown in Col. I. Also, when R1 and R2 are not the same, the products are obtained in the D-, L- or D,L-isorneric form depending upon the optical activity of the starting material shown in Col. I.
The acid products of Examples 1 to 57 can also be converted to various ester forms (i.e., R is
etc.) according to known procedures.
EXAMPLE 58 [6R-[6α,7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(1H-tetrazo]-5-yl- methoxy)imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, disodium
salt (i.e. syn isomer)
a) 2-Cyanomethoxy-1 H-isoindole-1 ,3(2H)dione A 400 ml. dimethylformamide solution of 50 g N-hydroxyphthalimide (0.31 mol.), 25.4 g chloroacetonitrile (0.34 mol.) and 37.2 9 (0.37 mol.) triethylamine is stirred until colorless. The solution
is added to 2 litres of water. The precipitated compound is then filtered off, washed with water and
dried to yield 65.8 9 of 2-cyanomethoxy-1 H-isoindole-1 ,3(2H)dione with a melting point of 1500 to
1520C.
b) 2-(1 H-Tetrazol-5-yl-methoxy)-1 H-isoindole-1 ,3(2H)-dione 56.8 g 2-Cyanomethoxy-1 H-isoindole-1 ,3(2H)dione (0.28 mol.) is dissolved in 500 ml. dry tetrahydrofuran. 55.5g of sodium azide (0.85 mol.) is added to the stirred mixture. A solution of 40.1 9 aluminum chloride in 250 ml. of dry tetrahydrofuran is added with cooling. The solution is maintained at reflux temperature for 32 hours. After cooling to 0 C about 250 ml. of 2N HCl is added dropwise, then an amount of water sufficient to form a clear solution is added. Thef organic layer is separated, the aqueous phase is then saturated with NaCI and extracted twice with 200 ml. portions of tetrahydrofuran. The combined organic layers are dried with sodium sulfate and evaporated to dryness.
The oily residue is treated with alcohol and the precipitated tetrazole compound is filtered off to yield 2 (1 H-tetrazol-5-yl-methoxy)-1 H-isoindole-1 ,3(2H)dione with a melting point of 227 to 2280C.
c) 5-[(Aminoxy)methyl]-1 H-tetrazole, hydrochloride
70.8 9 of 2-(1 H-tetrazol-5-yl-methoxy)-1 H-isondole-1 ,3(2H)dione (0.29 mol.) in 700 ml. of 20% aqueous HCL is refluxed with stirring. The solution is cooled and filtered. The filtrate is evaporated to dryness. 1 50 ml. of water are added and filtered. Evaporation of the solvent yields 43 g of crude 5 [(aminoxy)methyl]-1 H-tetrazole, hydrochloride with a melting point of 1 630C (alcohol-ether).
d) 2-Amino-a-[( 1 H-tetrazol-5-yl-methoxy)imino]-4-thiazole acetic acid (syn isomer)
1.0 g 5-[(Aminoxy)methyl]-1 H-tetrazole, hydrochloride and 1.3 9 2-formylamino-4-thiazole glyoxylic acid are stirred for 24 hours at 500C. The solution is then cooled to room temperature and the precipitated compound filtered off to yield 1.9 g of 2-amino-a-[(1 H-tetrazol-5-yl-methoxy)imino]-4thiazole acetic acid (syn isomer) with a melting point of 1920 to 1 930C (H20).
e) [6R-[6α,7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-a mino-4-thiazolyl) [(1 H-tetrazole-5-ylmethoxy)imino]acetyl]a minoj-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester (syn isomer)
4 g 2-Amino-a-[( 1 H-tetrazol-5-yl-methoxy)imino]-4-thiazole acetic acid in 50 ml. of dry dimethylformamide are treated with 6.1 ml. of monosilyltrifluoroacetamide at 60 C for 15 minutes with stirring. To the cooled solution 7.5 g 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1azabicyclo[4.2.0.]oct-2-ene-2-carboxylic acid, diphenylmethyl ester in 100 ml. of dry acetonitrile is added. The solution is cooled to 1 50C and 4.4 g dicylohexylcarbodiimide in 100 ml. acetonitrile is slowly added dropwise and the temperature is maintained for 12 hours.The urea formed is filtered off and the solvent distilled off in vacuo. The residue is treated with 500 ml. saturated aqueous sodium chloride solution and extracted three times with 200 ml. portions of ethyl acetate. The organic layers are extracted 10 times with 30 ml. portions of saturated aqueous sodium bicarbonate solution. The sodium bicarbonate extracts are combined, 300 ml. ethylacetate are added and the mixture is acidified with 2N phosphoric acid. The aqueous layer is once more extracted with 100 ml. ethyl acetate. The organic extracts are dried with sodium sulfate and the solvent removed in vacuo. The residue is dissolved in 50 ml. acetone and poured in a 2:1 mixture of ether/petroleum ether with stirring.The precipitated diphenylmethyl ester is filtered off to yield 5 g of [6R-[6α-[7ss(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino- 4-thiazolyl)[(1H-tetrazole-5-yl-methoxy)imino]acetyl] amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2ene-2-carboxylic acid, diphenylmethyl ester with a melting point of 138 to 143 C (dec.).
f) [6R-[6a,7(Z)]]-3-[(Aceloxy)methyIj-7-[[(2-amino-4-thiazolyl) [(1 H-tetrazole-5-yl methoxy)imino]acetyl]amino]-8-oxo-5-thia -azabicyclo[4.2,0]oct-2-ene-2-carboxylic acid, trifluoroacetate (syn isomer)
5 g of the diphenylmethyl ester of example 1 e is suspended in 14 ml. of anisole. The stirred solution is cooled to 0 C. At this temperature 28 g of trifluoroacetic acid is added dropwise and the temperature is maintained at 0 C for 30 minutes; 100 ml. of methanol is added and the mixture poured into 1 liter of ethyl ether with vigorous stirring. The compound is filtered off and dried in vacuo to yield 3.5 9 of [6R-[6α,7ss(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-a mino-4-thiazolyl) [(1 H-tetrazole-5-ylmethoxy)imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetate having a melting point of 130 to 135 C (dec.).
9) [6R-[6α,7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl) [(1 H-tetrazole-5-vl- methoxy)imino]acetyl]amino]-8-oxo-5-thia-1-azablicyclo[4.2.0]oct-2-ene-2-carboxylic acid, disodium
salt (syn isomer)
5 9 of the product of Example 1f are dissolved in 20 ml. of a 1:1 mixture of methanol/acetonitrile.
20 ml. of a 1 N sodium ethyl hexanoate solution in butyl alcohol is added and the mixture is poured into
500 ml. diethyl ether. The precipitated crude disodium salt is filtered off. The compound is about 60%
pure to yield 3.6 9 [6R-[6et,7p(2)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(1 H-tetrazole-5-yl- methoxy)imino]acetyl]amino]-8-oxo-5-thia- 1 -azabicyclol4.2.0]oct-2-ene-2-carboxylic acid, disodium salt with a melting point greater than 3000 C. Further purification is accomplished by high performance
liquid chromatography using a LiChrosorb RP 18 (10 4m) Hibor III Column Solvent with CH3OH:0.01M HP042 buffer (52:48).
EXAMPLE 59 [6R-[6α,7ss(E)]]3-[(Acetyloxy)methyl]-7-[[2-amino-4-thiazolyl)[(1H-tetrazole-5-yl- methoxy)imino]acetyl]amino]-8-oxo-5-thia- 1 -azahicyclo[4.2.O]o ct-2-ene-2-carboxyllc acid. disodium salt (anti isomer)
a) 2-(Formylamino)-a-[( 1 H-tetrazol-5-yl-methoxy)imino]-4-thiazole acetic acid, ethyl ester (anti isomer)
3 9 2-Formylamino-4-thiazolyl-glyoxylic acid, ethyl ester and 2 9 of 5-[(aminoxy)methyl]-1 Htetrazole hydrochloride of Example 58C are stirred in anhydrous pyridine overnight at 600 C. The
insoluble precipitate is filtered off and the filtrate evaporated to dryness.The residue is
chromatographed over Silica gel with ethyl acetate as eluant. 2.9 9 of 2-(formyl)-amino)-α-[(1 Htetrazol-5-yl-methoxy)imino]-4-thiazole acetic acid, ethyl ester is obtained with a melting point of 880 to 960C (CH3 OH/H20).
b) 2-Amino-a-[(1 H-tetrazol-5-yl-methoxy)imino]-4-thiazole acetic acid (anti isomer)
0.5 9 of the product of Example 59a are stirred for 40 hours in 6.6 ml. conc. HCI and 3.3 ml. water
at 300 C. The compund crystallizes on cooling to yield 0.25 g, of 2-amino-a-[(1 H-tetrazol-5-yl
methoxy)imino]-4-thiazole acetic acid (anti isomer) with a melting point of 174 C.
c) [6R-[6α,7ss(E)]]-3-[(Acetyloxy)methyl]-7-[[(2-a mino-4-thiazolyl) [(1 H-tetrazole-5-yl
methoxy)imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,
diphenylmethyl ester (anti isomer)
When 2-Amino-a[(1 H-tetrazol-5-yl-methoxy)imino]-4-thiazole acetic acid (anti isomer) is treated
with-3-[[acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid
diphenylmethyl ester according to the procedure given in Example 58e, [6R-[6α,7ss(E)]- [(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(1H-tetrazol-5-yl-methoxy)imino]acetyl]amino]-8-oxo-5 thia-l -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester (Anti isomer) is obtained with
a melting point of 1180 to 1 200C (dec.).
d) [6R-[6cr,7,5(E)]]-3-[(acetyloxy)methyl]-7-[[(2-a mino-4-thiazolyl)] (1 H-tetrazol-5-yl- methoxy)imino]acefyl]amino]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, disodium
salt (anti isomer)
Treatment of the diphenylmethyl ester of Example 59c with trifluoroacetic acid according to the
procedure of Example 58f results in formation of the corresponding cephalosporanic acid, but in the anti
form (melting point 142 to 1 500C (dec.).When this acid is treated with sodium ethyl hexanoate
according to Example 58 9 6R-(6α,7ss(E)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)-[(1 Htetrazol-5-yl-methoxy)imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid, disodium salt (anti isomer) is obtained with a melting point greater than 2800C.
EXAMPLE 60 [6R-[6α,7ss(Z)]]-7-[[(2-amino-4-thiazolyl)[(1H-tetrazol-5-yl-methoxy)imino]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, disodium
salt (i.e. syn isomer)
a) 2-(Tritylamino)-α-[(1-benzoyl-1H-tetrazol-5-yl-methoxy)imino]-4-thiazole acetic acid, ethyl ester
(syn)
1.2 9 2-(Tritylamino)-α-(oximino)-4-thiazole acetic acid, ethyl ester, 0.6 9 1-benzoyl-5- chloromethyl-1 H-tetrazole and 0.5 9 potassium carbonate are stirred together in 20 ml dry
dimethylformamide at room temperature overnight. 20 ml. acetone are added and the insoluble
potassium chloride is filtered off.The mother liquor is evaporated to dryness and chromatographed over a Silica gel column using ethyl acetate/CHCl3/ether 3:2:1 mixture as eluent to yield 1.4 9 of 2 (tritylamino)-α-[(1-benzoyl-1 H-tetrazol-5-yl-methoxy)-imino]-4-thiazole acetic acid, ethyl ester (syn
isomer) with a melting point of 1320 to 1 340C.
b) 2-(Amino)-a-[(1 H-tetrazol-5-yl-methoxy) imino]-4-thiazole acetic acid (syn isomer)
1.4 9 of the product of Example 60a is stirred in 20 ml. 5% HCI at room temperature overnight.
The precipitate is filtered off and washed with ether to yield 0.5 9 of 2-(amino)-a-[(1 H-tetrazol-5-yl- methoxy)-imino]-4-thiazole acetic acid (syn isomer).
c) [6R-[6α,7ss(Z)]]-7-[[(2-amino-4-thiazolyl)[1H-tetrazol-5-yl-methoxy)imino]acetyl]amino]-3-[[(1- methyl H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1 -azabicyclo[4.2.0] oct-2-ene-2-carboxylic acid, disodium salt (syn isomer)
When the carboxylic acid of Example 60b is reacted as described in Example 58e using 7-amino3-[[(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 instead of 3-[(acetyloxy)methoxy]-7-amino-8-oxo-5-thia-1- azabicycio[4.2.0loct-2-ene-2-carboxylic acid, diphenylmethyl ester, followed by cleavage of the protecting ester moiety as described in Example 58f and subsequent formation of the disodium salt as described in Example 589 [6R-[6a,7/3(2)]]-7-[[(2-amino-4-thiazolyl)-[(1 H-tetrazol-5-ylmethoxy)imino]acetyl]amino]-3-[[(1 -methyl-1 H-tetrazol-5-yl )thio] methyll-8-oxo-5-thia- 1 azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, disodium salt, is formed with a melting point of 2400 to 2450C (dec.).
EXAMPLE 61 [6R-[6α,7ss(E)]]-7-[[(2-amino-4-thiazolyl)[(1H-tetrazol-5-yl-methoxy)imino]acetyl]amino]-3-[[(1-methyl- 1H-tetrazol-5-yl]thio]methyl]-8-oxo-5-thia- 1 -azabicyclo[4.2. O]oct-2-ene-2-carboxylic acid disodium salt (i.e. anti isomer)
The corresponding anti-isomer is obtained when 2-amino-a-[(1 H-tetrazol-5-yl-methoxy)imino]-4- thiazole-acetic acid (anti isomer) of Example 59b is processed as described in Examples 60c.
EXAMPLE 62 [6R-[6α,7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[2-amino-4-thiazolyl)[1H-tetrazol-5-yl- dimethylmethoxy)imino]-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, disodium salt (i.e. syn isomer)
When 5-[l-(aminoxy)-l -methylethyl]-l H-tetrazole, hydrochloride (which is obtained when chloroacetonitrile in Example 58a is replaced by bromo-isobutyronitrile and the compound formed subsequently treated like in Examples 58b and 58c is processed as described in Examples 58d, 58e 58f and 58g, [6R-[6a,7 (z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(1 H-tetrazol-5-yl- dimethylmethoxy) imino]acetyl]amino]-8-oxo-5-thia-1 -azabicyclo[4.2 .0]oct-2-ene-2-carboxylic acid, disodium salt is obtained.
EXAMPLE 63 [6R-[6α,7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(1-methyl-1H-tetrazol-5-yl- methoxy)imino]-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt (syn isomer) a) 2-(1-Methyl-1 H-tetrazol-5-yl-methoxy)-1 H-isoindole-1,3 (2H) dione
5 9 2-(1 H-tetrazol-5-yl-methoxy)-1 H-isoindole-1, 3(2H)dione of Example 58b is stirred at room temperature in 50 ml. dimethylformamide with 5 9 methyliodide in the presence of 5 9 potassium carbonate-for 24 hours.The insoluble inorganic precipitates are filtered off, the mother liquor evaporated to dryness and the residue crystallized with alcohol to yield 4.8 9 of 2-(1 -methyl-1 Htetrazol-5-yl-methoxy)-1 H-isoindole-1,3(2H) dione with a melting point of 1280 to 130 C.
b) 5-[(Aminoxy)methyl)-1 -methyl-1 H-tetrazole hydrochloride
Using the procedure of Example 58c wherein 2-(1 H-tetrazol-5-yl-methoxy)-1 H-isoindole-1,3(2H) dione is replaced by 2-(1-methyl-1 H-tetrazol-5-yl-methoxy)-1 H-isoindole-1 ,3(2H)dione, 5- [(aminoxy)methyl]-1 -methyl-1 H-tetrazole, hydrochloride is obtained.
c) [6R-[6a,7(Z)]]-3-[(Acewloxy)methyIj-7-[[2-amino-4-thiazolyI) [(1 -methyl-1 H-tetrazole-5-ylmethoxy)imino]-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt (syn isomer)
When 5-[(aminoxy)methyl]-1-methyl-1 H-tetrazole, hydrochloride of Example 63b is treated with 2-formyl-amino-4-thiazolyl-giyoxylic acid as described in Example 58d the corresponding syn-isomer of 2-amino-α-[(1-methyl-1H-tetrazol-5-yl-methoxy) imino]-4-thiazole acetic acid is obtained which is processed as described in Example 58e, 58f, 58g. By this route, [6R-[6α;, 7ss(Z)]]-3-[(acetyloxy)methyl]- 7-[(2-amino-4-thiazolyl)[(1-methyl-1H-tetrazol)-5-yl-methoxy)imino]acetyl]amino]-8-oxo-5-thia-1 azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt (syn isomer) is obtained.
EXAMPLE 64 [5S-[5α,6ss,7α(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)-[(1H-tetrazol-5-yl- methoxy)imino]acetyl]-amino]-8-oxo-5-thia- 1 -azabicyclo[4. 2. O]oct-2 -ene-2 -carboxylic acid, 5-oxide, disodium salt (p-sulfoxide, syn isomer).
10 m Mol of [6R-[6α,7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazoly)[(1 H-tetrazol-5-ylmethoxy)imino]acetyl]amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid of Example 58f is suspended in 20 ml of dry methylene chloride and cooled to 00. At this temperature, 10 ml of trifluoroacetic acid is added and stirring is continued until the solution is completed. Then 10 mmol. of m-chloroperbenzoic acid is added and the solution is stirred at 0 for 3 hours. The solvent is removed in vacuo and the residue stirred with ethyl acetate and filtered. The precipitate is then dissolved in a 1:1 mixture of methanol/acetone and an equivalent amount of sodium ethyl hexanoate in butyl alcohol (1 Nsolution) is added and the solution is stirred.After 10 min. the mixture is poured into 200 ml. of diethyl ether and the precipitated compound is filtered off to yield [5S-[5a,6,7a(Z)j]-3-[(aceWloxy)methyl]-7- [[(1-amino-4-thiazolyl)-[(1H-tetrazol-5-yl-methoxy)imino]acetyl]amino]-8-oxo-5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, disodium salt (p-sulfoxide, syn isomer) with a melting point of 250O to 2560C.
EXAMPLE 65 [5S-[5α,6ss,7α(Z)]]-3-[(Acetyloxy)methyl-7-[[(2-amino-4-thiazolyl)(1H-tetrazol-5-yl- methoxy)imino]acetyll-amino]-8-oxo-5-thia- 1 -azabicyclo[4.2. O]oct-2-ene-2-carboxyllc acid, 5-oxide, disodium salt (suffoxide, syn isomer) a) [5S-[5α,6ss,7α]-3-[(Acetyloxy)methyl]]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid, 5-oxide, diphenylmethyl ester (i.e., F,-sulfoxide) and [5R-[5α,6α;,7ss]]-3-[(Acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid, 5-oxide, diphenylmethyl ester (i.e., a-sulfoxide)
A slurry of 50 g. of 7-aminocephalosporanic acid (7-ACA) in 1 liter of water is stirred magnetically while t-octyl amine is added dropwise, thereby maintaining the pH between 7 and 8. After one hour the undissolved solid is filtered (Celite) and the filtrate is treated with a solution prepared by adjusting a mixture of 10 ml. of t-octylamine and 20 ml. of water to pH 8.0 with 6N hydrochloric acid. The resulting solution is then -treated with 10 ml. of salicylaldehyde. After 2 minutes a solid forms and after 5 minutes an additional 10 ml. of salicyclaldehyde is added. The slurry is stirred for an additional 10 minutes, cooled to 0 for 4.5 hours and filtered. The filter cake is slurried twice with 300 ml.of cold water and filtered. The wet cake is dried at 60 in vacuo over large amounts of P2Q5 to give 66 g. of tan solid 7salicylaldimino-cephalosporanic acid, t-octyl amine salt.
A slurry of 25.25 g. (0.05 mole) of the above t-octyl amine salt (powdered with a mortar and pestle) in 250 ml. of dry acetonitrile is treated with 9.5 g. (0.05 mole) of p-toluenesulfonic acid monohydrate. After 10 minutes, a solution of 9.7 g. (0.05 mole) of diphenyldiazomethane in 50 ml. of acetonitrile is added over the course of 1 5 minutes. After one hour, the slurry is filtered, the solid is washed with acetonitrile, and the combined filtrate and washings are evaporated in vacuo. The resulting oil is chromatographed on a 300 g. silica gel column eluted with methylene chloride.Fractions (500 ml.) 2-3 contain 7.5 g. of the desired diphenylmethyl ester product plus some higher Rf impurity (monitored by silica gel TLC with 3:1 chloroform-ethyl acetate development): fractions 4-11 1 contain 12.3 g. of pure 7-salicylaldimino-cephalosporanic acid, diphenylmethyl ester, NMR (CDCI3) a 1.97 (s, 3H, CH3CO); 3.23 and 3.60 (AB q, J = 19 Hz, 2H, C-2); 4.67 and 5.01 (AB q, J = 14 Hz, 2H, C-3'); 4.99 (d, J = 5 Hz, 1 H, C-6); 5.20 (broadened d, J = 5 Hz, 1 H, C-7); 6.62-7.60 (m, about 15H); 9.07 (broad s, 1H, -CH=N-).
A solution of 12.3 g. (0.023 mole) of the above diphenylmethyl ester product in 125 ml. of
methylene chloride is cooled to 0 and a solution of 4.6 g. (0.023 mole) of 85% m-chlorobenzoic acid in 70 ml. of methylene chloride is added over the course of 15 minutes. After one hour, the slurry is washed with a mixture of 100 ml. of 5% sodium bicarbonate and 50 ml. of 6% sodium sulfite solution.
The organic layer is dried and evaporated in vacuo. The resulting oil crystallizes from 70 ml. of ethyl acetate giving 8.7 g. of a mixture of a- and p-sulfoxides. A second crop of 1.5 g. of a mixture of a- and p-sulfoxides is also obtained. The major (a-) isomer has a lower field acetate methyl (2.02 ppm) and C-2 quartet (3.57 and 4.10 ppm) when compared to those of the minor (ss) isomer (1.97,3.26 and 3.94 ppm, respectively).
A slurry of 10 g. (0.018 mole) of the above 7-salicyladiminocephalosporanic acid, diphenylmethyl ester, a- and p-sulfoxide mixture in 100 ml. of ethyl acetate is treated with 3.42 g. (0.018 mole) of ptoluenesulfonic acid monohydrate. After 5.5 hours, 300 ml. of ether is added and the gummy solid is triturated, filtered, and washed twice with ether. The moist solid is dissolved in 200 ml. of ethyl acetate and the solution is washed with 100 ml. of 5% sodium bicarbonate solution, dried, and evaporated to give 8.0 g. of residue.Chromatography on a 300 g. silica gel column eluted with 3:1 chloroform-ethyl acetate gives (500 ml. fractions):fraction 3, 1.0 g. of recovered 7-salicylaldimino-cephalosporanic acid, diphenylmethyl ester; fractions 6-16, 4.5 g. of [5R-[5α,6α,7ss]]-3-[(acetyloxy)methyl]-7-amino-8-oxo- 5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenyimethyl ester (i.e., a-sulfoxide isomer):NMR (CDCl3) # 2.00 (CH3COO-); 3.43 and 4.06 ppm (AB q, C-2); fractions 22-30 (eluant is changed to ethyl acetate after fraction 16) 1.5 g. of [55-[5a,6/3,7a]j-3-[(acewloxy)methyl]-7-amino-8- oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenyl-methyl ester (i.e., p > - sulfoxide isomer):NMR (CDCl3) # 2.10 (CH3C00-); 2.97 and 3.54 ppm (AB q, C-2).
b) [5S-[5a,6/3,7a(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)( 1 H-tetrazol-5-ylmethoxy)imino]-acetyl]amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester.
2-amino-a-[(1 H-tetrazol-5-yl-methoxy) imino]-4-thiazoleacetic acid from Example 58d the ss- sulfoxide diphenylmethyl ester from part (a), and N-hydroxybenzotriazole are dissolved in 50 ml. of dimethyl sulfoxide. After the addition of 25 ml. of acetonitrile, the solution is cooled to 0 with stirring.
Dicyclohexylcarbodiimide is then added and stirring at 0 is continued for 1 5 hours. After this time, the insoluble urea is filtered off. The mother liquor is poured onto ice and the resulting precipitate is filtered off and washed with water. The crude product is suspended in 20 ml. of cold aqueous sodium bicarbonate solution and extracted three times with methyl ethyl ketone. The aqueous phase is filtered, acidified with phosphoric acid in the cold, and extracted three more times with methyl ethyl ketone. The organic layers are combined, dried, and the solvent is distilled off. The residue is dissolved in a few mls.
of methanol and poured into diethyl ether to yield as a precipitate [5S-[5α,6ss,7α(Z)]]-3- [(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)(1H-tetrazol-5-yl-methoxy)-imino]-acetyl]amino]-8-oxo-5thia- 1 -azabicyclo[4.2.0]-oct-2-ene-2-ca rboxylic acid, 5-oxide, diphenylmethyl ester.
c) [5S-[5α,6ss,7α(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)(1H-tetrazol-5-yl- methoxy)imino]acetyl]-amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, disodium salt (p-sulfoxide, syn isomer)
The diphenylmethyl ester product from part (b) is suspended in 3 ml. of anisole at 0 and 6 ml. of trifluoroacetic acid are slowly added dropwise with stirring.After the addition is completed, the mixture is stirred for an additional hour at 0 . The solution is then poured into 200 ml. of diethyl ether with stirring to yield as a precipitate [5S-[5cE,6A,7cE(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyí)(1 H tetrazol-5-yl-methoxy)imino]acetyl]-amino]-8-oXo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
This acid is dissolved in 20 ml. of methanol and an equivalent amount of 1N sodium ethyl hexanoate in butanol is added at 0 with stirring. After 30 minutes, 200 ml. of ether are added precipitating [5S-[5α,6ss,7α(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)(1H-tetrazol-5-yl- methoxy)imino]-acetyl]amino]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-ca rboxylic acid, 5-oxide, disodium salt, m.p. 250 -256 C dec.
EXAMPLE 66 [5R-[5α,6α,7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(1H-tetrazol-5-yl- methoxy)imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, disodium salt (α-sulfoxide, syn isomer) a) [5R-[5α,6α;,7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(1H-tetrazol-5-yl- methoxy)imino]-acetyl]-amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester 2-Amino-a-[(i H-tetrazol-5-yl-methoxy) imino]-4-thiazole-acetic acid and the a-sulfoxide diphenylmethyl ester from Example 65(a) are reacted in the presence of N-hydroxybenzotriazole and dicyclohexylcarbodiimide according to the procedure of Example 65(b) to yield [5R-[5α,6α,7ss(Z)]]-3- [(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[1H-tetrazol-5-yl-methoxy)imino]acetyl]amino]-8-oxo-5thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester.
b) [5R-[5a,6a,7/3(Z)j]-3-[(AceWloxy)methylj-7-[[(2-amino-4-thiazolyl)[( 1 H-tetrazol-5-yl methoxy)imino]-acetyI]amino]-8-oxo-5-thi -azabicyclo[4.2 .0]oct-2-ene-2-carboxylic acid, 5-oxide, disodium salt (a-sulfoxide, syn isomer)
The diphenylmethyl ester from part (a) is treated with anisole and trifluoroacetic acid at 0 according to the procedure of Example 65(c) to yield [5R-[5α,6α,7ss(Z)]]-3-[(acetyloxy)methyl]-7-[[(2- a mino-4-thiazolyl) [(1 H-tetrazol-5-yl-methoxy)imino)-acetyl]-a mino]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide.
This acid product is treated with sodium ethyl hexanoate to yield [5R-[5α,6α,7ss(Z)]]-3- [(acetyloxy)-methyl]-7-[[(2-amino-4-thiazolyl)1H-tetrazol-5-yl-methoxy)imino]acetyl]amino]-8-oxo-5 thia-l -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, disodium salt.
EXAMPLE 67 [5S-[5α,6ss,7α(Z)]]-7-[[(2-Amino-4-thiazolyl)(1H-tetrazol-5-yl-methoxy)imino]acetyl]amino]-3-[[1- methyl- iH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5oxide, disodium salt {/3-sulfoxide, syn isomer) a) [55-[5a,6/3,7aj]-7-Amino-3-[[( 1-methyl-1 H-tetrazol-5-yl)thio] methyl]-8-oxo-5-thia- 1 - atabicyclo[4.2 .0]oct-2-ene-2-ca rboxylic acid, 5-oxide, diphenylmethyl ester (i.e., p-sulfoxide) and [5R- [5α,6α,7α;ss]]-7-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, 5-oxide, diphenylmethyl ester (i.e., a-sulfoxide).
Following the procedure of Example 65(a) but substituting 7-amino-3-[[(1 -methyl-l H-tetrazol-5- yl)-thio]methyl]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxyiic acid for the 7-ACA one obtains a mixture of the desired sulfoxide products which are then separated chromatographically to yield the individual a- and /3-sulfoxides.
b) [5S-[5α,6ss,7α(Z)]]-7-[[(2-Amino-4-thiazolyl)-(1H-tetrazol-5-yl-methoxy)imino]acetyl]amino]-3- [[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclp[4.2.0]oct-2-ene-2-carboxylic acid,
5-oxide, diphenylmethyl ester.
1 g. of 2-Amino-a-[(i H-tetrazol-5-yl-methoxy)-imino]-4-thiazoleacetic acid, from Example 58(d), 1.82 g. of [5S-[5,6/3,7 a]j-7-a mino-3-[[( 1-methyl-1 H-tetrazol-5-yl)thio] methyl]-8-oxo-5-thia- 1 - azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester (i.e., p-sulfoxide) from part (a), and 0.52 g. of N-hydroxybenzotriazole are dissolved in 100 ml. of dimethyl sulfoxide and 50 ml. of acetonitrile. The solution is cooled to 0 and 1.04 g. of dicyclohexylcarbodiimide in 20 ml. of acetronitrile are added dropwise with stirring. The temperature is maintained at 0 for 12 hours. After this time, the insoluble urea is filtered off.The mother liquor is poured into 500 ml. of ice water and the precipitated product is filtered off, washed with water and dried to yield [5S-[5a,6/3,7a(Z)]]-7-{[(2- amino-4-thiazolyl)-(1H-tetrazol-5-yl-methoxy)imino)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, 5-oxide, diphenylmethyl ester.
c) [5S-[α,6ss,7α(Z)]]-7-[[(2-Amino-4-thiazolyl)(1H-tetrazol-5-yl-methoxy)imino]acetyl]amino]-3- [[(1-methyl- 1 -H-tetrazol-5-yl)thioj methyl]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, disodium salt (p-sulfoxide, syn isomer)
The diphenylmethyl ester product from part (b) is suspended at 0 in 3 ml. of anisole. While stirring vigorously, 6 ml. of trifluoroacetic acid are added and the stirring is continued for an additional hour.The resulting solution is poured into 500 ml. of diethyl ether and the crystalline product is filtered off to yield [5S-[5a,6,B,7a(Z)1]-7-[[(2-a mino-4-thiazolyl)( 1 H-tetrazol-5-yl-methoxy)imino]-acety]amino- 3-[[( methyl 1 H-tetrazol-5-yl)thio]-methyl]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide.
This acid is converted to its disodium salt by suspending the acid in 10 ml. of methanol and adding 6.3 ml. of a 1N solution of sodium ethyl hexanoate in butanol. The mixture is stirred for 30 minutes and then diluted with 200 ml. of ether to crystallize out [55-[5a, 6/3,7a(Z)]j-7-[[(2-amino-4-thiazolyl)-(1 Htetrazol-5-yl-methoxy)imino]-acetyl]amino]-3-[[1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia 1 -azabicyclo[4.2.0]oct-2-ene-2-ca rboxylic acid, 5-oxide, disodi um salt.
EXAMPLE 68 [5R-[5α,6α,7ss(Z)]]-7-[[(2-Amino-4-thiazolyl)[(1H-tetrazol-5-yl-methoxy)imino]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, 5oxide, disodium salt { sulfoxide, syn isomer)
a) [5R-] 5,6cr,7,B(Z)]]-7-[[(2-Amino-4-thiazolyl) [(1 H-tetrazol-5-yl-methoxy)imino]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.
5-oxide, diphenylmethyl ester
Following the procedure of Example 67(b) but substituting [5R-[5a,6a,7/3)]-7-amino-3-[[(1 -methyl1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester from Example 67(a) for the /3-sulfoxide, one obtains [5R-[5a,6a,7/3(Z)]j-7-[[(2- amino-4-thiazolyl)(1H-tetrazol-5-yl-methoxy)imino]acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5yl)thio] methyl]-8-oxo-5-thia- 1 -azabicyclo[4.2.0] oct-2-ene-2-carboxylic acid, 5-oxide, diphenyl methyl ester.
b) [5R-[5α,6α,7ss(Z)]]-7-[[(2-Amino-4-thiazolyl)[(1 H-tetrazol-5-yl-methoxy)imino]acetyl] amino]-3 [[(-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, disodium salt (a-sulfoxide, syn isomer)
The diphenylmethyl ester product from part (a) is treated with anisole and trifluoroacetic acid at O' according to the procedure of Example 10(c) to yield [5R-[5α,6α,7ss(Z)]]-7-[[(2-amino-4-thiazolyl)[(1 Htetrazol-5-yl-methoxy)imino]acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide.
This acid is converted to its disodium salt by treatment with sodium ethyl hexanoate to yield (5R- [5a,6a,7/3(Z)]]-7-[[(2-a mino-4-thiazolyl) [(1 H-tetrazol-5-yl-methoxy)imino]acetyl]amino]-3-[[( methyl 1 H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1 -azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, disodium salt.
EXAMPLE 69 [6R-[60r, 7/3(z)]]-3-[(A ce tyloxy)meth yl]- 7-[[(2 -amino-4-thiazolyl)[( 1 H-te trazol-5-yl-m ethoxy)imino]- acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5-dioxide, disodium salt (syn isomer) a) [6R-[6α,7ss]]-3-[(Acetyloxy)methyl]-7-a mino-8-oxo-5-thia- 1 -azabicyclo[4.2 .0]oct-2-ene-2- carboxylic acid, 5,5-dioxide, diphenylmethyl ester [5R-[5α,6α,7ss]]-3-[(Acetyloxy)methyl-7]-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid, 5-oxide, diphenylmethyl ester from Example 65(a) is added to methylene chloride and cooled to 00. An equimolar amount of m-chloroperbenzoic acid in methylene chloride is added. After the reaction is completed, the slurry is treated with 5% sodium bicarbonate and 5% sodium sulfite. The organic layer is dried and evaporated in vacuo. Preparative thin layer chromatography of the residue yields [6R-[6a,7/3]j-3-[(acetyloxy)methyl]-7-a mino-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2carboxylic acid, 5,5-dioxide, diphenylmethyl ester.
b) [6R-[6α,7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-a mino-4-thiazolyl) [(1 H-tetrazol-5-yl methoxy)imino]acetyl]-amino]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5dioxide, diphenylmethyl ester 2-Amino-a-[(1 H-tetrazol-5-yl-methoxy) imino]-4-thiazoleacetic acid from Example 1 (d) and the [6R-[6α;,7ss]]-3-[[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5-dioxide, diphenylmethyl ester from part (a) are reacted in the presence of Nhydroxybenzotriazole and dicyclohexylcarbodiimide according to the procedure of Example 65 (b) to yield j6R-[6a,7/3(Z)j]-3-[(acetyloxy)methyl]-7-[[(2-a mino-4-thiazolyl) [(1 H-tetrazol-5-yl- methoxy)imino]acefyl]amino]-8-oxo-5-thia -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5-dioxide, diphenylmethyl ester.
c) [6R-[6α,7ss(Z)]]-3-[(Acetyloxy)methyl-7-[[(2-a mino-4-thiazolyl)](1 H-tetrazol-5-yl- methoxy)imino]acetyl]-a mino]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-ca rboxylic acid, 5,5dioxide, disodium salt (syn isomer)
The diphenylmethyl ester product from part (b) is treated with anisole and trifluoroacetic acid at 00 according to the procedure of Example 65(c) to yield [6R-[6α,7ss(Z)]]-3-[(acetyloxy)methyl-7-[[(2- a mino-4-thiazolyl) [1 H-tetrazol-5-yl-methoxy)imino]-acetyl] amino-8]-oxo-5-thia- 1 -azabicyclo[4.2.0]oct2-ene-2-carboxylic acid, 5,5-dioxide.
This acid is converted to its disodium salt by treatment with sodium ethyl hexanoate to yield [6R [6er,7jB(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-a mino-4-thiazolyl)j( 1 H-tetrazol-5-ylmethoxy)imino]acetyl]amino]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-ca rboxylic acid, 5,5-dioxide, disodium salt.
EXAMPLES 70-95 Following the procedure of Examples 58 to 63 and 65 to 69 but employing the ester shown in Col
I and the acid shown in Col. II one obtains the ester shown in Col. III. Removal of the ester protecting group yields the acid product shown in Col. IV.
Col. I
Col. II
Col. Ill
Col. IV
Example X R21 R16 R13 R14 R15 m n 70 # # -H -H -H -H one two 71 # -C(CH3)3 -H -H -COOH -H zero one 72 # # -H -CH3 -CH3 -H zero one 73 # # -OCH3 -H -H -H zero one 74 # # -H -H -H -H two one 75 # # -H -C2H5 -C2H5 -H zero one 76 # # -H -H -H -H zero one 77 H # -H -H -H -H zero one 78 H # -H -CH3 -H -H zero one
Example X R21 R16 R13 R14 R15 m n 79 # # -H -H -H -H zero one 80 # # -H -H -H -H zero two 81 # # -H -H -H -H one one 82 # # -H -H -H -H two one 83 # # -H -CH3 -CH3 -H zero one 84 # # -OCH3 -H -H -H zero one 85 # # -H -CH3 -H -H zero one 86 # # -H -H -H -H zero one 87 # # -H -H -COOH -H one one
Example X R21 R16 R13 R14 R15 m n 88 # # -H -H -H -H zero one 89 # # -OCH3 -H -COOH -H zero one 90 # # -H -CH3 -C2H5 -H zero one 91 # # -H -CH3 -CH3 -H zero one 92 # # -H -H -H -H zero one
Example X R21 R16 R13 R14 R15 m n 93 # # -H -H -H -H zero one 94 # #
-H -H -H -H one one 95 # # -H -H -H -H zero one The acid products of Examples 70 to 95 can be converted to the sodium or potassium according to known procedures.
The products of Examples 70 to 95 are obtained as the syn or anti isomer depending upon the configuration of the acid shown in Col. II. Also, when R,3 and R,4 are not the same, the products are obtained in the D-, L- or D,L-form depending upon the optical activity of the acid shown in Col. II.
EXAMPLE 96 [6R-[6α,7ss(Z)]]-3-[[4-(Aminocarbonyl)pyridino]methyl]-7-[[(2-amino-4-thiazoly)[1H-tetrazol-5-yl- methoxyimino]acetyl]amino]-8-oxo-5-thia I -azabicyclo[4.2.0]oct-2-ene-2-caroxylic acid, (syn isomer)
A mixture of 0.005 mole of the disodium salt product of Example 58, 0.0075 mole of 4pyridinecarboxamide, 12 g. of sodium thiocyanate, and 7.5 ml. of water are heated at 50O for 24 hours.
The resulting solution is passed through a chromatography column filled with Amberlite XAD-2. The column is washed with water and the titled compound is eluted with a mixture of water:methanol (8:2).
The methanol is evaporated from the eluate and the aqueous solution is lyophilized. The amorphous residue is triturated with ether and filtered under suction to yield [6R-[6α,7ss(Z)]]-3-[[4- (aminocarbonyl)pyridino]-methyl]-7-[[(2-a mino-4-thiazolyl) [(1 H-tetrazol-5-yl methoxy)imino]acetyl]amino]-8-oxo-5-thia 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
EXAMPLES 97-164 Following the procedure of Example 96 but employing the cephalosporanic acid sodium salt shown in Col. I and the pyridine compound shown in Col. II, one obtains the product shown in Col. Ill.
Col. I
Col. Ii
Col. III
The products of Examples 97 to 104 are obtained in the syn or anti configuration depending upon the configuration of the 3-acetoxymethyl starting material shown in Col. I. Similarly, when m is one the compounds are obtained as the a- or /3-sulfoxide depending upon the orientation of the 3acetoxymethyl sulfoxide starting material. Also, when R, and R2 are not the same, the products are obtained in the D-, L- or D,L-isomeric form depending upon the optical activity of the starting material shown in Col. I.
EXAMPLE 105 [6R-[6α,7ss(Z)]]-7-[[(2-Amino-4-thiazolyl)[(1H-tetrazol-5yl-methoxy)imino]acetyl]amino]-3-[[(5-methyl- 1,3,4,-thiadiazolyl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid, disodium salt
0.002 mole of the disodium salt product of Example 58 is brought into solution in 100 ml. of a phosphate buffer at a pH of 6.4. Then 0.0024 mole of 5-methyl-1,3,4-thiadiazolyl-2-thio]is added. The solution is heated at 600 for six hours. After cooling, the pH is adjusted to 7.0 and the solution is chromatographed on the ion exchange resin Amberlite XAD-2.The fraction containing the desired product is freeze dried to yield [6R-]6α,7ss(Z)]]-7-[[(2-amino-4-thiazolyl)[(1 H-tetrazol-5y1- methoxy)imino]acetyl]-amino]-3-[[(5-methyl-1,3,4-thiadiazolyl)thio]methyl]-8-oxo-5-thia-1 azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, disodium salt.
EXAMPLES 106-111 Following the procedure of Example 105 but employing the cephalosporanic acid sodium salt shown in Col. I and the thiol shown in Col. II, one obtains the product shown in Col. III.
Col. I
Col. II
HS-hetero
Col. III
Example R16 R13 R14 R15 m hetero 106 -H -H -H -H zero # 107 -H -CH3 -CH3 -H two # 108 -OCH3 -CH3 -H -H one # 109 -H -H -H -H zero # 110 -H -H -H -H one # 111 -H -H -H -CH3 two # The products of Examples 106 to 111 are obtained in the syn or anti configuration depending upon the configuration of the 3-acetoxymethyl starting material shown in Col. I.Similarly, when m is one the compounds are obtained as the a- or p- sulfoxide depending upon the orientation of the 3acetoxymethyl sulfoxide starting material. Also, when R1 and R2 are not the same, the products are obtained in the D-, L- or D,L-isomeric form depending upon the optical activity of the starting material shown in Col.
EXAMPLE 112 [5S-[5α,6ss,7α(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(1H-tetrazol-5-yl- methoxy)imino]acetyl]amino]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, disodium salt (/3-suffoxide, syn isomer)
The product of Example 8 can also be prepared by the following procedure.
1 g. of [6R-[5cr,7p(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-a mino-4-thiazolyl) [(1 H-tetrazol-5-ylmethoxy)-imino]acetyl]amino]-8-oxo-5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid from
Example 58 is dissolved in 10 ml. of trifluoroacetic acid at 00, 0.39 g. of m-chloroperbenzoic acid are added, and the solution is stirred at 0 for 1.5 hours. Then 500 ml. of diethyl ether are added and the precipitated product is filtered off to yield [55-[5a,6/3,7a(Z)jj-3-[(acetyloxy)-methyl]-7-[[(2-amino-4- thiazolyl) [(1 H-tetrazol-5-yl-methoxy)imino]acetyl]amino]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2carboxylic acid.
This acid can be converted to its disodium salt by treatment with sodium ethyl hexanoate as set forth in Example 65.
EXAMPLES 113-121 Following the procedure of Examples 112 the sulfides shown in Col. I can be oxidized to the p- sulfoxide shown in Col. II.
Col. I
Col. II
Example Rl6 R13 R14 R15 X 113 -H -H -H -H -CH3 3 N N 114 -H -H -H -CH3 S 21 Ii 5 N N 115 -H -H -H 4 Nj CH3 116 --OCH, -CH3 -CH -H -O--OH3 0 117 -H -H -H -O-0-CH3 118 -H C2H -H -H -St,gi H3 0 II 119 -H -H -H -H --OO--C-NH, 0 120 -H -H -CH3 -H --OO--C-NH, 0 II 121 -H H3 -CH3 -H -O-C-CH3 The products of Examples 113 to 121 are obtained in the syn or anti configuration depending upon the configuration of the sulfide starting material shown in Col. I. Also, when R 1 and R2 are not the same, the products are obtained in the D-, L- or D,L-isomeric form depending upon the optical activity of the starting material shown in Col. I.
EXAMPLE 122 [6R[6α,7ss(Z)]]-7-[[2-Amino-4-thiazolyl)[(1H-tetrazol-5-yl-methoxy)imino]acetyl]amino]-3-[[(1-methyl- 1 H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5-dioxide, disodium salt [5R-[5α,6α;,7ss(Z)]]-7-[[(2-Amino-4-thiazolyl)[(1H-tetrazol-5-yl-methoxy)imino]acetyl]amino]-3- [[(1-methyl-1 H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid from Example 58 is dissolved in trifluoroacetic acid and reacted with m-chlorperbenzoic acid according to the procedure of Example 112 to yield [6R-[6a,7/3(Z)]j-7-[[(2-amino-4-thiazolyl)[( 1 H-tetrazol-5-yl- methoxy)imino]acetyl]amino]-3-]](1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5-dioxide.
This acid can be converted to its disodium salt by treatment with sodium ethyl hexanoate as set forth in the previous Examples.
EXAMPLES 123-129 Following the procedure of Example 122 the a-sulfoxides shown in Col. I can be oxidized to the sulfones shown in Col. II.
Col. I
Col. II
Example R16 R13 R14 R15 X n 123 -H -H -H -H # one 124 -H -H -H -H # two 125 -H -CH3 -H -H # one 126 -OCH3 -H -H -CH3 # one 127 -H -C2H5 -H -H # one 128 -H -C3H7 -H -H # one 129 -H -H -H -H # one The products of Examples 123 to 129 are obtained in the syn of anti configuration depending upon the configuration of the a-sulfoxide starting material shown in Col. I. Also when R1 and R2 are not the same, the products are obtained in the D-, L- or D,L-isomeric form depending upon the optical activity of the starting material shown in Col.
The acid products of Examples 58 to 129 can also be converted to various ester forms (i.e., R is
, etc.) according to known procedures.
Claims (1)
1. A compound of the formula I:
wherein
R is hydrogen, alkali metal,
lower alkyl, Si(CH3)3,
p-methoxybenzyl, diphenylmethyl, benzyl, trichloroethyl or lower alkyl
R1 is hydrogen or methyl;
R2 is hydrogen or methyl;
R3 is hydrogen or methyl; R4 is hydrogen, -OC0NH2,
lower alkyl; R5 is hydrogen or methyl; R6 is hydrogen, methyl, benzyl or acetyl;
R7 is hydrogen or lower alkyl; R5 is hydrogen or-CONH2;
R9 is hydrogen, lower alkyl,
or-(CH2)p-N-(lower alkyl)2; R10 is hydrogen or lower alkyl;R11 is hydrogen, sodium or potassium; n is 1, 2, 3 or 4; m is 0, 1 or 2; p is 1,2,3 or 4; or a compound of the formula ll:
including its imino tautomeric form wherein the
group is in the syn or anti configuration; R,2 is hydrogen, sodium, potassium, benzyl, p-methoxybenzyl, trichloroethyl, diphenylmethyl, t-butyl, -CH2-O-lower alkyl,
R13 and Ra4 are independently selected from hydrogen, methyl, ethyl, i-propyl, n-propyl, and carboxyl;
R,5 is hydrogen, methyl,
sodium or potassium; R,6 is in the a-configuration and is hydrogen or methoxy; m is zero, one or two; n is zero or an integer from 1 to 4; R17@@@ is hydrogen or lower alkyl;X is hydrogen
R18 is hydrogen or lower alkyl; R19 is hydrogen, lower r alkyl, -(CH2)p -COOR20-, -(CH2)p -SO3R20, or (CH2)p N-(lower alkyl)2; R20 is hydrogen, sodium or potassium, and p is an integer from 1 to 4.
2. A compound according to claim 1 having the formula I defined in Claim 1.
3. The compound of Claim 2 wherein the
is in the syn configuration;
n is one or two
m is zero or one provided that when m is one the sulfoxide is in the p-configuration; R is hydrogen, sodium, potassium,
or -CH2O-CO-lower alkyl;
R1,R2,R3,R5,R6'R8 and R11 is each as defined in Claim 1;
R4 is
R9 is hydrogen, methyl-(CH2)p
or (CH2)p-N(CH3)2; and p is l or 2.
4. The compound of Claim 3 wherein R4 is
5.[5S-[5α,6ss,7α(Z)]]-3-[acetyloxy)methyl[-7-[[(2-amino-4-thiazolyl)[(1H-imidazol-2-yl- methoxy)imino]acetyl]amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, sodium salt.
6. [6R-[6a,7p(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-a mino-4-thiazolyl) [(1 H-imidazol-2-yl- methoxy)imino]acetyl]amino]-8-oxo-5-thia -azabicyclo[4.2.0]oct-2-ene-2-carboxyiic acid, sodium salt.
7. The compound of Claim 3 wherein R4 is
and R19 @@ is hydrogen or methyl;
8. [6R-[6α,7ss(Z)]]-7-[[(2-amino-4-thiazolyl)[(1H-imidazol-2-yl-methoxy)imino]-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 sodium salt.
9. An antibacterial pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more antibacterially active compounds of the formula I defined in any one of Claims 1 to 8.
10. A compound according to Claim 1 having the formula II defined in Claim 1 including its imino tautomeric form wherein the
group is in its syn or anti configuration.
11. A compound according to Claim 10, wherein R12 is 2,2,2-trichloroethyl.
12. The compound of Claim 10 wherein R12 is hydrogen, sodium or potassium; R16 is hydrogen;
R,3 and R,4 are both hydrogen; m is zero or one provided that when m is one the sulfoxide is in the o5- configuration; X is hydrogen,
R19 is hydrogen, methyl, -CH2-COOR20,-CH2-SO3R20 or-(CH2)2N(CH3)2; and R20 is hydrogen, sodium or potassium, and wherein the
group is in the syn configuration.
13. The compound of Claim 12 wherein X is hydrogen.
14. The compound of Claim 12 having the formula
wherein Z is hydrogen or
1 5. The compound of Claim 12 wherein X is
16. The compound of Claim 12 wherein X is
and R,g is hydrogen, methyl, -CH2-COOR20'-CH2-SO3R20 or -(CH2)2N(CH3)2; and R20 is hydrogen, sodium or potassium.
17. The compound of Claim 16 wherein X is
18. The compound of Claim 17 wherein m is zero.
1 9. [6R-[6α,7ss(Z)]]-7-[[(2-ar mino-4-thiazolyl)[( 1 H-tetrazoí-5-yl-methoxy)imino]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, disodium salt.
20. The compound of Claim 1 7 wherein m is one.
21. [5S-[5α,6ss,7α(Z)]]-7-[[(2-amino-4-thiazolyl)[(1-H-tetrazol-5-yl-methoxy)imino]acetyl]amino]- 3-[[(1-methyl-1H-tetrazol-5-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxvlic acid, 5-oxide, disodium salt.
22. The compound of Claim 12 wherein X is
23. The compound of Claim 22 wherein m is zero.
24. [6R-[6a,7/3(Z)j]-3-[(acetyloxy)methylj-7-[[(2-a mino-4-thiazolyl) [1 H-tetrazol-5-ylmethoxy-imino]acetyl]amino]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acrid, disodium salt.
25. [6R-[6a,7/3(Z)jI-3-[(acetyloxy)methyl]-7-[[(2-a mino-4-thiazolyl)-[(1 methyl 1 H-tetrazol)-5-yl- methoxy)imino]acetyl]amino]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, disodium salt.
26. The compound of Claim 22 wherein m is one.
27. [5S-[5a,6/3,7 a(Z)-]j-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)( 1 H-tetrazol-5-yl- methoxy)imino]acetyl]amino]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, disodium salt.
28. An antibacterial pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more antibacterially active compounds of the formula ll defined in any one of Claims 10 to 27, including an imino tautomeric form thereof wherein the
group is in the syn or anti configuration.
29. An antibacterial pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more antibacterially active compounds of the formula II defined in Claim 1, wherein R is hydrogen, sodium, potassium, -CH2-0-lower alkyl,
R13 and R4 are independently selected from the group consisting of hydrogen, methyl, ethyl, i-propyl, npropyl and carboxyl; R,ss is hydrogen, methyl, sodium or potassium; R16 is in the a-configuration and is hydrogen or methoxy; m is zero, one or two; R" is hydrogen or lower alkyl; X is hydrogen,
R18 is hydrogen, lower alkyl, - (CH2)p-COOR20 -(CH2)p-SO3R20 or-(CH2)p-N-(lower alkyl)2;R20 is hydrogen, sodium or potassium; n is zero or an integer from 1 to 4; and p is an integer from 1 to 4.
30. The composition of Claim 29 wherein R,2 is hydrogen, sodium or potassium; R,3 and R,4 are both hydrogen; R,5 is hydrogen, methyl, sodium or potassium; R,6 is hydrogen; m is zero or one provided that when m is one the sulfoxide is in the pi-configuration; X is hydrogen,
R19 is hydrogen, methyl, - CH2COOR20,-CH2SO3R20, or-(CH2)2N(CH3)2; R20 is hydrogen, sodium or potassium; and n is zero or an integer from 1 to 4.
31. [6R-[6a,7pi(E)]]-3-[(Acetyíoxy)methyl]-7-[[(2-amino-4-thiazoíyl)[(1 H-tetrazol-5-ylmethoxy)imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, disodium salt.
32. An enantiomer of a compound of the general formula I or II defined in Claim 1.
33. A separate stereoisomer of a compound of the general formula I or II defined in Claim 1.
34. A method of preparing a compound of the general formula I defined in Claim 1, wherein R4 is other than hydrogen or
which comprises acylating in the presence of a coupling agent. an ester of the formula
wherein Rp is a protecting group, with a compound of formula
to yield a compound of the formula VII:
and optionally removing the ester protective group to obtain a compound of the formula I wherein R is hydrogen.
35. A method according to Claim 34, wherein Rp 5 diphenylmethyl and is removed by treatment with trifluoroacetic acid.
36. A method according to Claim 34 or 35 wherein the compound of the formula VI is obtained by reacting a compound of the formula VIII:
with a compound of the formula IX:
37. A method according to Claim 36, wherein the compound of formula IX is prepared by treating
N-hydroxy-phthalimide sodium salt with a compound of the formula X:
to yield a compound of the formula Xl:
which is then treated with hydrochloric acid.
38. A method according to any one of Claims 34 to 37, wherein the compound of formula VI is prepared by converting a 7-amino cephalosporanic acid to a Schiff base ester of the formula:
oxidising this with a percarboxylic acid to yield a mixture of a- and /3-sulfoxide Schiff base cephalosporanic esters, cleaving the Schiff base side chain, separating the a- and B- sulfoxide 7-amino cephalosporanic acid esters and further oxidising the a- sulfoxide to a sulfone (m=2) or formula (V).
39. A method of preparing a compound of the formula la:
wherein R1, R2, R3, R5, R6,m, and n are as defined in Claim 1 and R8 is hydrogen or carbamoyl, which comprises reacting a compound of the formula I defined in Claim 1 wherein R is hydrogen and R4 is
with pyridine or carbamoyl substituted pyridine in a polar solvent and in the presence of a catalyst.
40. A method of preparing a compound of the formula I defined in Claim 1 wherein R4 is heterothio, which comprises reacting a compound of formula I wherein R is hydrogen and R4 is
with a mercaptan of the formula: hetero-S-H or with an alkali metal salt thereof.
41. A method of preparing a p-sulfoxide (m=1) compound of the formula I defined in Claim 1, which comprises oxidising a corresponding sulphide (m=O).
42. A method of preparing a sulfone (m=2) of a compound of the formula I defined in claim 1 which comprises oxidising a corresponding a-sulfoxide (m=1).
42. A method of preparing a compound of the formula I defined in Claim 1 wherein R is sodium or potassium which comprises reacting a corresponding compound of formula I wherein R is hydrogen with an appropriate salt forming ion.
44. A method of preparing a compound of the formula I defined in Claim 1 wherein R is
which comprises treating a corresponding free acid of the formula I respectively with a compound of the formula
or with a compound of the formula
wherein L is hydroxy or bromine.
45. A method of preparing a compound of the general formula I defined in Claim 1, substantially as herein before described with reference to any one of the foregoing individual examples 1 to 57.
46. A syn or anti compound of the general formu!a I defined in Claim 1, when prepared by a method as claimed in Claim 45, or a sodium or potassium salt thereof, in D-, L- or D,L-form, or an imino tautomer thereof.
47. A method of preparing a compound of the general formula II defined in Claim 1, wherein X is other than
which comprises acylating in the presence of a coupling agent an ester of the formula XII:
wherein R2, is an ester protecting group, with a compound of the formula XIII
wherein R15 is hydrogen or methyl, to yield an intermediate of the formula XIV:
and removing the R2, ester protecting group to yield a compound of formula li in the acid form.
48. A method according to Claim 47, wherein R2, is diphenylmethyl and the intermediate of formula XIV is treated with trifluoroacetic acid and anisole to remove the protective group.
49. A method according to Claim 47 or 48, wherein the compound of formula XIII is in the syn configuration and is obtained by reacting an optionally protected compound of the formula XV;
wherein R22 is hydrogen or an amino protecting group, with a tetrazole of the formula XVI:
wherein R,4 is hydrogen or methyl, and removing the R22 protecting group if present.
50. A method according to Claim 49, wherein the compound of formula XVI is prepared by treating N-hydroxyphthalimide with a compound of the formula XVI I:
to yield a compound of the formula XVIII:
treating this compound with sodium azide to qive a comDound of the formula XIX:
and treating this compound with hydrochloric acid.
51. A method according to Claim 49, wherein the compound of formula XVI is prepared by treating a compound of the formula X:
with methyl iodide to give a compound of the formula XIXA:
and treating this compound with hydrochloric acid.
52. A method according to Claim 47 or 48 wherein the compound of formula XIII is in the syn form and is obtained by reacting a compound of the formula XX:
wherein R22 is hydrogen or an amino protecting group with a compound of the formula XXI:
wherein R23 is hydrogen, a protecting group such as benzoyl, or methyl, and removing the R22 and R23 protecting groups if present.
53. A method according to Claim 47 or 48, wherein the compound of formula XIII is in the anti form and is obtained by reacting a compound of the formula XXII:
wherein R22 is hydrogen or an amino protecting group with a compound of formula XXI:
wherein R23 is hydrogen, a protecting group such as benzoyl, or methyl, and removing the R22 and R23 protecting groups if present.
54. A method according to any one of Claims 47 to 53, wherein there is employed a 7-amino cephalosporanic acid ester - or p-sulphoxide (m=l ) of the formula XII which is prepared by converting a 7-amino acid starting material (m=O) to Schiff base ester of the formula XXIII:
oxidising this compound with a percarboxylic acid to yield a mixture of a- and p-sulfoxide Schiff base cephalosporin esters, cleaving the sidechain with toiuenesulphonic acid and separating the cr- and - sulfoxide 7-amino cephalosporanic acid esters.
55. A method according to Claim 54 wherein there is employed a sulphone (m=2) of formula XII obtained by oxidising an a-sulfoxide (m=l) of formula XII.
56. A method of preparing a compound of the formula lIb;
Wherein Z is hydrogen or carbamoyl which comprises reacting a compound of the formula II defined in
Claim 1 wherein R,2 is hydrogen and X is
with pyridine or carbamoyl substituted pyridine in a polar solvent and in the presence of a catalyst.
57. A method of preparing a compound of the general formula II defined in Claim 1, wherein X is heterothio, which comprises reacting a compound of formula II wherein R,2 is hydrogen and Xis
with a mercaptan of the formula: hetero-S--H I or with an alkali metal salt thereof.
58. A method of preparing a ,e-sulfoxide (m=l) compound of the formula II defined in Claim 1, which comprises oxidising a corresponding sulphide (m=O).
59. A method of preparing an a-sulphone (m=2) of the formula II defined in Claim 1, which comprises oxidising a corresponding a-sulfoxide (m=1).
60. A method of preparing a compound of the formula II defined in Claim 1, wherein R,2, R,5 and
R20 are sodium or potassium by treating a corresponding compound of formula II wherein R,2, R,5 and
R20 are hydrogen with an appropriate base.
61. A method of preparing a compound of the formula II defined in Claim 1, wherein R,2 is
by treating a corresponding free acid respectively with
alkyl or with
wherein L is hydroxy or bromine.
62. A method of preparing a compound of the general formula II defined in Claim 1, substantially as hereinbefore described with reference to any one of the foregoing individual Examples 58 to 164.
63. A syn or anti compound of the general formula II defined in Claim 1, when prepared by a method as claimed in Claim 62, or a sodium or potassium salt thereof in D-, L- or D,L-form, or an imino tautomer thereof.
64. The features hereinbefore disclosed, or their equivalents, in any novel selection.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8827679A | 1979-10-25 | 1979-10-25 | |
| US06/125,801 US4271157A (en) | 1980-02-28 | 1980-02-28 | Imidazole derivatives of 7-[(2-amino-4-thiazolyl)-oximino] cephalosporins |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2061276A true GB2061276A (en) | 1981-05-13 |
| GB2061276B GB2061276B (en) | 1983-05-25 |
Family
ID=26778500
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8034000A Expired GB2061276B (en) | 1979-10-25 | 1980-10-22 | Imidazole and tetrazole derivatives of 7-((2-amino-4-thiazolyl)-oximino)cephalosporins |
Country Status (5)
| Country | Link |
|---|---|
| CA (1) | CA1161430A (en) |
| DE (1) | DE3040257A1 (en) |
| FR (1) | FR2467854A1 (en) |
| GB (1) | GB2061276B (en) |
| IT (1) | IT8050000A0 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0091130A2 (en) * | 1982-04-06 | 1983-10-12 | Daiichi Seiyaku Co., Ltd. | Cephalosporin derivatives, process for preparing and pharmaceutical compositions containing said compounds |
| US4598075A (en) * | 1982-08-07 | 1986-07-01 | Tanabe Seiyaku Co., Ltd. | Cephalosporin compounds |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT381944B (en) * | 1984-04-10 | 1986-12-10 | Biochemie Gmbh | METHOD FOR PRODUCING CEPHALOSPORINANTIBIOTICS |
-
1980
- 1980-10-22 GB GB8034000A patent/GB2061276B/en not_active Expired
- 1980-10-24 IT IT8050000A patent/IT8050000A0/en unknown
- 1980-10-24 FR FR8022870A patent/FR2467854A1/en active Granted
- 1980-10-24 CA CA000363265A patent/CA1161430A/en not_active Expired
- 1980-10-24 DE DE19803040257 patent/DE3040257A1/en not_active Withdrawn
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0091130A2 (en) * | 1982-04-06 | 1983-10-12 | Daiichi Seiyaku Co., Ltd. | Cephalosporin derivatives, process for preparing and pharmaceutical compositions containing said compounds |
| EP0091130A3 (en) * | 1982-04-06 | 1984-07-25 | Daiichi Seiyaku Co. Ltd. | Cephalosporin derivatives, process for preparing and pharmaceutical compositions containing said compounds |
| US4598075A (en) * | 1982-08-07 | 1986-07-01 | Tanabe Seiyaku Co., Ltd. | Cephalosporin compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2467854B1 (en) | 1983-12-16 |
| GB2061276B (en) | 1983-05-25 |
| DE3040257A1 (en) | 1981-05-07 |
| FR2467854A1 (en) | 1981-04-30 |
| IT8050000A0 (en) | 1980-10-24 |
| CA1161430A (en) | 1984-01-31 |
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| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19951022 |