CA2036190A1 - 1-carba (dethia) cephalosporin antibiotics - Google Patents
1-carba (dethia) cephalosporin antibioticsInfo
- Publication number
- CA2036190A1 CA2036190A1 CA 2036190 CA2036190A CA2036190A1 CA 2036190 A1 CA2036190 A1 CA 2036190A1 CA 2036190 CA2036190 CA 2036190 CA 2036190 A CA2036190 A CA 2036190A CA 2036190 A1 CA2036190 A1 CA 2036190A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- amino
- substituted
- formula
- phenyl
- 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.)
- Abandoned
Links
- 239000003242 anti bacterial agent Substances 0.000 title claims abstract description 10
- 229940088710 antibiotic agent Drugs 0.000 title claims description 6
- 229930186147 Cephalosporin Natural products 0.000 title description 5
- 229940124587 cephalosporin Drugs 0.000 title description 5
- 150000001780 cephalosporins Chemical class 0.000 title description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- -1 nitro, hydroxy Chemical group 0.000 claims description 160
- 150000001875 compounds Chemical class 0.000 claims description 55
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 48
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 37
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 20
- 150000002431 hydrogen Chemical class 0.000 claims description 19
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 16
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 16
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical group 0.000 claims description 14
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 13
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000004423 acyloxy group Chemical group 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 125000004760 (C1-C4) alkylsulfonylamino group Chemical group 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 125000004414 alkyl thio group Chemical group 0.000 claims description 7
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- 239000011593 sulfur Substances 0.000 claims description 7
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 5
- 125000002971 oxazolyl group Chemical group 0.000 claims description 5
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000001041 indolyl group Chemical group 0.000 claims description 4
- 125000000468 ketone group Chemical group 0.000 claims description 4
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000001425 triazolyl group Chemical group 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims 3
- 229910052760 oxygen Inorganic materials 0.000 claims 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 15
- 241001465754 Metazoa Species 0.000 abstract description 4
- 150000001782 cephems Chemical class 0.000 abstract 2
- 208000035143 Bacterial infection Diseases 0.000 abstract 1
- 208000022362 bacterial infectious disease Diseases 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 41
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 238000005481 NMR spectroscopy Methods 0.000 description 36
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 32
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 26
- 238000004458 analytical method Methods 0.000 description 24
- 239000000243 solution Substances 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 18
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 238000002360 preparation method Methods 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 13
- 229940093499 ethyl acetate Drugs 0.000 description 13
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- 229960004132 diethyl ether Drugs 0.000 description 12
- 230000003115 biocidal effect Effects 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- 229910001868 water Inorganic materials 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 239000006260 foam Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- UBOXGVDOUJQMTN-UHFFFAOYSA-N 1,1,2-trichloroethane Chemical compound ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical group [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 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
- 238000003756 stirring Methods 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 235000009518 sodium iodide Nutrition 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 101150041968 CDC13 gene Proteins 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 125000002843 carboxylic acid group Chemical group 0.000 description 2
- 125000006244 carboxylic acid protecting group Chemical group 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 238000007257 deesterification reaction Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 229910000080 stannane Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- XHKXXONQVDGOJE-UHFFFAOYSA-N (3,4-dihydroxyphenyl)carbamothioic S-acid Chemical compound OC1=CC=C(NC(S)=O)C=C1O XHKXXONQVDGOJE-UHFFFAOYSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- RLRBAMDAFZZWMM-UHFFFAOYSA-N 1-ethoxyethenyl(trimethyl)stannane Chemical compound CCOC(=C)[Sn](C)(C)C RLRBAMDAFZZWMM-UHFFFAOYSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- YTQQIHUQLOZOJI-UHFFFAOYSA-N 2,3-dihydro-1,2-thiazole Chemical group C1NSC=C1 YTQQIHUQLOZOJI-UHFFFAOYSA-N 0.000 description 1
- KLIDCXVFHGNTTM-UHFFFAOYSA-N 2,6-dimethoxyphenol Chemical group COC1=CC=CC(OC)=C1O KLIDCXVFHGNTTM-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
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 1
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 1
- 125000002103 4,4'-dimethoxytriphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)(C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H])C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 1
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- VQIOVQDAIOJJHF-UHFFFAOYSA-N O-phenyl N-pyridin-2-ylcarbamothioate Chemical compound C1(=CC=CC=C1)OC(NC1=NC=CC=C1)=S VQIOVQDAIOJJHF-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 238000010669 acid-base reaction Methods 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000005998 bromoethyl group Chemical group 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 150000001767 cationic compounds Chemical class 0.000 description 1
- UOCJDOLVGGIYIQ-PBFPGSCMSA-N cefatrizine Chemical group S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)[C@H](N)C=2C=CC(O)=CC=2)CC=1CSC=1C=NNN=1 UOCJDOLVGGIYIQ-PBFPGSCMSA-N 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004802 cyanophenyl group Chemical group 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000005828 desilylation reaction Methods 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical group CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 125000005816 fluoropropyl group Chemical group [H]C([H])(F)C([H])([H])C([H])([H])* 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910001411 inorganic cation Inorganic materials 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- BRMYZIKAHFEUFJ-UHFFFAOYSA-L mercury diacetate Chemical compound CC(=O)O[Hg]OC(C)=O BRMYZIKAHFEUFJ-UHFFFAOYSA-L 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- SNVLJLYUUXKWOJ-UHFFFAOYSA-N methylidenecarbene Chemical compound C=[C] SNVLJLYUUXKWOJ-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- VJZNUICECYWOFV-UHFFFAOYSA-N o-phenyl carbamothioate Chemical compound NC(=S)OC1=CC=CC=C1 VJZNUICECYWOFV-UHFFFAOYSA-N 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002892 organic cations Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- WXHIJDCHNDBCNY-UHFFFAOYSA-N palladium dihydride Chemical compound [PdH2] WXHIJDCHNDBCNY-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- ASUOLLHGALPRFK-UHFFFAOYSA-N phenylphosphonoylbenzene Chemical group C=1C=CC=CC=1P(=O)C1=CC=CC=C1 ASUOLLHGALPRFK-UHFFFAOYSA-N 0.000 description 1
- 125000005544 phthalimido group Chemical group 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- WSWCOQWTEOXDQX-MQQKCMAXSA-N sorbic acid group Chemical group C(\C=C\C=C\C)(=O)O WSWCOQWTEOXDQX-MQQKCMAXSA-N 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- IWXDXDCALKLIKB-UHFFFAOYSA-N tert-butylperoxycarbonyl (2-methylpropan-2-yl)oxy carbonate Chemical compound CC(C)(C)OOC(=O)OC(=O)OOC(C)(C)C IWXDXDCALKLIKB-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
Abstract 1-Carba(1-dethia)cephem antibacterial agents possessing a 3-(substituted or unsubstituted)thiazolo group are provided. Further provided is a method for treating bacterial infections in man and other animals and a pharmaceutical formulation utilizing said 1-carba(1-dethia)cephems.
Description
'2~3~
1-CARBA(DETHIA)CEPHALOSPORIN ANTIBIOTICS
In the field of antibacterial therapy, the need for new chemotherapeutic agents is one that will never extinguish. Mutant strains resistant to existing antibacterial agents are encountered frequently. To meet this need, considerable research effort continues to focus on such new agents.
The present invention provides various 3-(substituted or unsubstituted)thiazolo-l-carba(l-dethia)-cephems (i.e., l-carba(1-dethia)cephalosporins) useful as antibacterial agents against both gram-negative and gram-positive bacteria. The present invention provides 7~-(acylamino-1-carba(1-dethia) 3-substituted-3-cephem-4-carboxylic acids wherein the group at the 3-position is a 4-thiazole ring optionally substituted in the 2-position by nitro, cyano, phenyl, amino, halo, C1-C6 alkyl, C1-C6 substituted alkyl, an optionally-substi-tuted heterocyclic ring, substituted phenyl, or an acyl group. Also provided are novel 7-amino intermediates useful in the preparation of the compounds of the present invention. Also provided is a pharmaceutical 2 ~ 9 ~
formulation utilizing the compounds of the present invention and a method for treating antibacterial infections in man an other animals.
The present invention provides compounds of Formula (1):
Rl-N
,~ X (1) wherein X i9 a group selected from amino, halo, cyano, lS hydrogen, nitro, C1-C6 alkyl, C1-C6 substituted alkyl, a C3 to C6 heterocyclic ring containing 1, 2, or 3 nitrogen atoms and 0 or 1 sulfur or oxygen atoms, said ring optionally substituted by one or more groups selected from halo, nitro, hydroxy, C1-C6 alkyl, or Cl-C6 substituted alkyl;
phenyl, substituted phenyl or an acyl group of the formula O
Il R"C-, wherein R" is C1-C6 alkyl, C1-C6 substituted alkyl, phenyl, or substituted phenyl;
R3 is hydrogen, C1-C4 alkoxy, or a group of the formula -NHCH0; and R1 is an acyl group of the formula R2-C-, wherein R2 is hydrogen; Cl-C6 alkyl, C1-C6 alkyl substituted by cyano, carboxy, halogen, amino, C1-C4 alkoxy, Cl-C4 alkylthio, or trifluoromethylthio; a phenyl or substituted phenyl group represented by the formula a a''' ~
wherein a and a' independently are hydrogen, halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkanoyloxy, C1-C4 alkyl, C1-C4 alkylthio, amino, mono- or di(C1-C4 alkyl)amino, C1-C4 alkanoylamino, C1-C4 alkylsulfonylamino, carboxy, carbamoyl, hydroxymethyl, amino-methyl, or carboxymethyl;
a group represented by the formula <,~(Z)m- CH2--wherein a and a' have the same meanings as defined above, Z is 0 or S, and m is 0 or 1;
. .
a heteroarylmethyl group represented by the formula R~-CH2-wherein R1 is thienyl, furyl, benæothienyl, benzofuryl, indolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, and such heteroaryl groups substituted by 2~5~
amino, hydroxy, halogen, C1-C4 alkyl, Cl-C4 alkoxy, C1-C4 alkylsulfonylamino;
a substituted methyl group represented by the formula Q
wherein R2 is cyclohex-1,4-dienyl, or a phenyl group or substituted phenyl group represented by the formula a a~
wherein a and a' have the above defined meanings, or R2 is Rl as defined above, and Q is hydroxy, Cl-C4 alkanoyloxy, carboxy sulfo, or amino;
or R2 is a keto group or an oximino-substituted group represented by the formulae O N
wherein R3 is R1 or R2 as defined above and R4 is hydrogen, C1-C4 alkyl, or a group repre-sented by the formula :
-C-(CH2 ~nCOR5 b' wherein b and b' independently are hydrogen, or C1-C3 alkyl, and b and b' when taken together with the carbon to which they are bonded form a 3- to 6-membered carbocyclic ring, R5 is hydroxy, C1-C4 alkoxy, amino, C1-C4 alkyl-amino, or di(C1-C4 alkyl)amino, and n is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.
In the above Formula (1), one preferred R2 group is a keto group or an oximino-substituted group represented by the formulae O N
wherein R3 is Rl or R2 as defined above and R4 is hydrogen, Cl-C4 alkyl, or a group repre-sented by the formula b -C- ( CH2 ~nCORs wherein b and b' independently are hydrogen, : or Cl-C3 alkyl, and b and b' when taken together with the carbon to which they are bonded form 2~3~9~
a 3- to 6-membered carbocyclic ring, R5 y, C1 C4 alkoxy, amino, C1-C alkyl amino, or di(C1-C4 alkyl)amino, and n is 0, 1, 2, or 3.
A preferred Rl group is (2-aminothiazol-4-yl)methoximinoacetyl.
A further preferred R2 group is a substituted methyl group represented by the formula Rp-CH-Q
wherein R2 is cyclohex-1,4-dienyl, or a phenyl group or substituted phenyl group represented by the formula a ~ ~
<~ \~
a' ~
wherein a and a' have the above defined meanings, or R2 is R1 as defined above, and Q is hydroxy, C1-C4 alkanoyloxy, carboxy, sulfo, or amino.
A preferred R1 group is D-phenyl-glycyl.
As a further aspect of the present invention, there are provided intermediates of Formula (2) 2~3~
R1 b~
O ~ ~ X (2) wherein: Rl' is hydrogen or an amino protecting group;
R4 is hydrogen or a carboxy protecting group;
R3' is hydrogen, Cl-C4 alkoxy, or a group of the formula -NHCHO; and X is a group selected from amino, halo, cyano, hydrogen, nitro, Cl-C6 alkyl, Cl-C6 substituted alkyl, a C3 to C6 heterocyclic ring containing 1, 2, or 3 nitrogens and 0, or 1 sulfur or oxygen atoms, said ring optionally substituted by one or more groups selected from halo, nitro, hydroxy, Cl-C6 alkyl, or Cl-C6 substituted alkyl;
phenyl, substituted phenyl, or an acyl group of the formula o : R' " C-, wherein R " ' is Cl-C6 alkyl, Cl-C6 substituted ` alkyl, phenyl, or substituted phenyl. The compounds of formula (2) are useful as intermediates to the anti-bacterial agents of formula (1) In the above Formula (1), the term "Cl to C6 alkyl" denotes such radicals as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, tert-amyl, hexyl and the like. The preferred "Cl to C6alkyl" group is methyl.
The term "C1 to C6 substituted alkyl" denotes the above Cl to C6 alkyl groups that are substituted by one or two halogen, hydroxy, protected hydroxy, amino, protected amino, Cl to C7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carbamoyloxy, cyano, methylsulfonylamino, C1 to C4 alkoxy, phenyl, sub-stituted phenyl, or a C3 to C6 heterocyclic ring containing l, 2, or 3 nitrogen atoms and O or 1 sulfur or oxygen atoms, said ring optionally substituted by one or more groups selected from halo, nitro, hydroxy, or C1-C6 alkyl. The substituted alkyl groups may be substituted once or twice with the same or with different substituents.
Examples of the above substituted alkyl groups include cyanomethyl, nitromethyl, hydroxymethyl, trityl-oxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl, allyloxycarbonylmethyl, allyloxycarbonylaminomethyl, carbamoyloxymethyl, methoxymethyl, ethoxymethyl, t-butoxy methyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, 6-hydroxyhexyl, 2,4-dichloro(n-butyl), 2-amino(iso-propyl), 2-carbamoyloxyethyl chloroethyl, bromoethyl, fluoroethyl, iodoethyl, chloropropyl, bromopropyl, fluoropropyl, iodopropyl, phenylmethyl, phenylethyl, phenyl (3-pyridyl)methyl, phenyl(3-pyridyl)ethyl, and the like.
The term "C1 to Cg alkoxy" as used hereindenotes groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups.
The term "substituted phenyl" as used herein denotes a phenyl group substituted with one or two moieties chosen from the group consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, C1 to C6 alkyl, C1 to C~ alkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, aminomethyl, protected aminomethyl, trifluoromethyl or N-(methylsulfonylamino).
Examples of the term "substituted phenyl"
include a mono- or di(halo)phenyl group such as 4-chloro-phenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromo-phenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl and the like; a mono- or di(hydroxy)phenyl group such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as 3-or 4-nitrophenyl; a cyanophenyl group, for example, 4-cyanophenyl; a mono- or di(lower alkyl)phenyl group such as 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl, 4-(iso-propyl)phenyl, 4-ethylphenyl, 3-~n-propyl)phenyl and the like; a mono- or di(alkoxy)phenyl group, for example, 2,6-dimethoxyphenyl, 4-methoxyphenyl, 3-ethoxy-phenyl, 4-(iso-propoxy)phenyl, 4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl and the like; 3- or 4- tri-fluoromethylphenyl; a mono- or dicarboxyphenyl or (protected carboxy)phenyl group such as 4-carboxyphenyl or 2,4-di(protected carboxy)phenyl; a mono- or di-(hydroxymethyl)phenyl or (protected hydroxymethyl)-phenyl such as 3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)-phenyl or (protected aminomethyl)phenyl such as 2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)-phenyl; or a mono- or di(N-(methylsulfonylaminol)phenyl such as 3-(N-(methylsulfonylamino))phenyl. Also, the 9 ~
term "substituted phenyl" represents disubstituted phenyl groups wherein the substituents are different, for example, 3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy-4-chlorophenyl and the like. Preferred substituted phenyl groups include the 2- and 3-trifluoromethylphenyl, the 4-hydroxyphenyl, the 2-aminomethylphenyl and the 3-(N-(methylsulfonylamino))phenyl groups.
The terms "halo" and "halogen" refer to the fluoro, chloro, bromo or iodo groups.
The term "pharmaceutically-acceptable salt"
encompasses those salts that form with the carboxylate anions and includes salts formed with the organic and inorganic cations discussed above. Furthermore, the term includes salts that form by standard acid-base reactions with basic groups (such as amino groups) and organic or inorganic acids. Such acids include hydro-chloric, sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D-glutamic, d-camphoric, glutaric, phthalic, tartaric, lauric, stearic, salicyclic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic, and like acids.
The term "carboxy-protecting group" as used herein refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound.
Examples of such carboxylic acid protecting groups 2 ~
include 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxy-benzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylene-dioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4 "-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, ~-(trimethylsilyl)ethyl, ~-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)prop-1-en-3-yl, and like moieties. The species of carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the condition of subsequent reaction(s) on other positions of the molecule and can be removed at the appropriate point without disrupting the remainder of the molecule. In particular, it is important not to subject the carboxy-protected molecule to stxong nucleophilic bases or reductive conditions employing highly activated metal catalysts such as Raney nickel. (Such harsh removal conditions are also to be avoided when removing amino-protecting groups discussed below.) A preferred carboxylic acid protecting group is the allyl group. Similar carboxy-protecting groups used in the cephalosporin, penicillin and peptide arts can also be used to protect a carboxy group substituents~
Further examples of these groups are found in E. Haslam, "Protective Groups in Organic Chemistry", J.G.W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, and T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y., 1981, Chapter 5.
~ $ ~
X-79~7A - 12 -A related term is "protected carboxy", which refers to a carboxy group substituted with one of the above carboxy-protecting groups.
The term "amino-protecting group" as used herein refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups on the compound. Examples of such amino-protecting groups include the formyl group, the trityl group, the t-butoxycarbonyl group, the phthalimido group, the trichloroacetyl group, the chloroacetyl, bromoacetyl and iodoacetyl groups, urethane-type blocking groups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, 2-(4-xenyl)iso-propoxycar-bonyl, l,l-diphenyleth-1-yloxycarbonyl, 1,1-diphenyl-prop-l-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-~p-toluyI)prop-2-yloxycarbonyl, cyclopentanyloxy-carbonyl, 1-methylcyclopentanyloxycarbonyl, cyclo-hexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)-ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, 9-fluorenyl-methoxycarbonyl ("FMOC"), 2-(trimethylsilyl)ethoxy-carbonyl, allyloxycarbonyl, l-(trimethylsilylmethyl)-prop-l-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxy-carbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropyl-2 ~
methoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl, iso-bornyloxycarbonyl, 1-piperidyloxycarbonyl and the like;
the benzoylmethylsulfonyl group, the 2-(nitro)phenyl-sulfenyl group, the diphenylphosphine oxide group and like amino-protecting groups. The species of amino-protecting group employed is not critical so long as the derivatized amino group is stable to the condition of subsequent reaction(s) on other positions of the mole-cule and can be removed at the appropriate point without disrupting the remainder of the molecule. Preferred amino-protecting groups are the allyloxycarbonyl, the t-butoxycarbonyl, and the trityl groups. Similar amino-protecting groups used in the cephalosporin, penicillin and peptide art are also embraced by the above terms. Further examples of groups referred to by the above terms are described by J.W. Barton, "Pro-tective Groups In Organic Chemistry", J.G.W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 2, and T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y., 1981, Chapter 7.
The related term "protected amino" defines an amino group substituted with an amino-protecting group dis-cussed above.
In Formulae (1) and (2) above, when X is a C3-C6 heterocyclic ring containing 1, 2, or 3 nitrogen atoms and 0 or 1 sulfur or oxygen atoms, (i.e., a heterocyclic ring containing from 3 to 6 carbon atoms, 1, 2, or 3 nitrogen atoms and 0 or 1 sulfur or oxygen atoms) said ring optionally substituted by one or more halo, nitro, hydroxy, C1-Cff alkyl, or Cl-C6 substituted alkyl groups, examples of such rings include pyrrolyl, furanyl, 4-nitrothiazol-2-yl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, morpholinyl, oxazolyl, thiazolyl, 203~3~
thiadiazolyl, oxadiazolyl, l-methyl-3-pyridyl, 2-methyl-3-pyridyl, 3-methyl-4-nitro-imidazol-2-yl, and the like.
One intermediate (VI) can be prepared according to the following Scheme (A) OCH2CNH~
~L Cf~
CO2CH2 ~NO2 I~i, ~ OCH2CN
H~ ~
l CH2 o _N~ 11 OCH2CH, co2CH2 ~N2 l ~U) OCH2CNH~
~N ~ tOCH2CH3 2 5 C02CH2 ~N2 o l~lU~
3 0 ~ OCH*
N~,_~
OCH2CH~
~OCH*H3 ~ [V) CO2CH2 ~3No7 ' :
~3~
X-7967A - lS -o OCH2CN~ ~
FIN~ j~CH~ (V) CO2CH2 ~NO~
I~v~
+ ~CH2CNH~
~N~CI12Elr ~Vl) C0*H2 aNO2 I ~vi~
According to Scheme A, p-NO2 benzyl-7~-phenoxy-acetylamino-l-carba(l-dethia)-3-trifluoromethanesulfonyl-oxy-3-cephem-4-carboxylate (which can be prepared according to the method of Evans et al., U.S. Patent No. 4,673,737, incorporated herein by reference) is reacted with a compound of the formula CH2=C(OCH2CH3)-(Sn(X)3), wherein X is methyl or n-butyl, LiCl, and . - (CH3CN~2PdCl2 in a polar organic solvent, preferably N,N'-dimethylformamide to provide (II~. Further details of this type of transformation can be found in Cook et al. U.S. Patent No. 4,855,418, incorporated herein by reference. Compound (II~ can then be converted to the 3-(2-bromo-1,1-diethoxyethyl~ compound (III) with Br2/CCl4 in ethanol/CH2Cl2 using a base such as 2,6-lutidine.
Reactions (iii) and (iv) depict a methodwhereby the 7-phenoxyacetyl group may be replaced by the t-butoxycarbonyl group. First, compound (III) is ~.
~3~
acylated with di-tert-butoxydicarbonate in the presence of a base such as dimethylaminopyridine.
Secondly, the phenoxyacetyl group is displaced with a base such as LioH in a polar solvent such as tetrahydrofuran. Further description of this exchange can be found in Blaszczak et al., European Patent Appli-cation No. 88306996.5.
Finally, the 3-bromomethylcarbonyl compound (VI) can then be prepared from compound V by an acid catalyzed hydrolysis reaction with, for example, acetic acid in acetonitrile/water.
Compounds of Formula (1) can then be made from intermediate (VI) above by the following Scheme (B):
ol + OCH2CNH~r~
--N~ CH2Bt ( Vl ) COqCU2 aNO2 'I (vi) ~ OCH2CNH ~
p ~ ~ ~v~) COqCH2 ~NO2 (V~i) + OCH2CNH~
O
I
2 ~3 ~
X-7967A - 17 - ~
R1-NH ~
~ N ~ ~ X
In the above step (vi), the 3-(2-substituted) thiazolo compounds may be synthesized by reaction of intermediate (VI) with a compound of the formula S
Il H2N-C-X, wherein X is as defined in Formula 1, above. Thus, with the desired 3-(2-substituted thiazol-4-yl) sub-stituent in place, and with the de-esterification of the 4-p-nitrobenzyl ester occasionally occurring under the previously defined reaction conditions, the 4-carboxy position may be re-esterified to the 4-allyl ester using allyl bromide, NaI, (CH3CH2CH2CH2)4NHS04, and NaHCO3 in N,N'-dimethylformamide. If deesterifi-cation does not occur under these conditions, the p-nitrobenzyl protecting group may be removed by zinc reduction in a solvent mixture of N,N'-dimethyl-formamide/tetrahydrofuran/acetic acid or N,N'-dimethyl-formamide/tetrahydrofuran in HCl and reesterified as described above to the 4-allyl ester. The resulting amino protected, carboxy protected "nucleus" (i.e., formula (2)) can then be treated with p-toluenesulfonic acid H2O or trifluoroacetic acid to remove the 7-t-butoxycarbonyl group to provide the 7-amino 4-carboxy 2~3~
protected intermediate. Further, the 7-amino group can then be acylated with an activated form of the desired R1 substituent using standard procedures well-known in the ~-lactam art. Finally, all remaining amino and~or carboxy protecting groups can then be removed using conventional methodology.
The 7~-acylamino-7~-substituted-l-carbacephalo-sporins represented by Formula (1) wherein R3 is C1-C~
alkoxy can be prepared according to the method described by Koppel, U.S. Patent No. 3,994,885, incorporated herein by reference.
T~e 7~-formamido substituted compounds wherein R3 is -NHCHO can be obtained by the method described by Millner, U.S. Patent No. 4,539,159 incorporated herein by reference. According to this method, a 7~-acylamino-or 7~-protected amino-7~-methylthio-substituted 1-carbacephalosporin is reacted with anhydrous ammonia or an ammonium salt in the presence of mercuric acetate to form the corresponding 7~-amino derivative. The latter is formylated to the 7a-formamido derivative.
One skilled in the art will appreciate that although the above manipulations utilized phenoxyacetyl and t-butyloxycarbonyl as amino protecting groups and the p-nitrobenzyl group as carboxy-protecting group, there are many which would be equally efficacious.
The 1-carbacephalosporins provided by the invention form salts with suitable bases, in partic-ular, the pharmaceutically-acceptable, non-toxic salts.
The C-4 carboxy group of the 1-carbacephalosporin can form salts with the alkali and alkaline earth metal hydroxides, carbonates and bicarbonates. Examples of such pharmaceutically-acceptable salts are the sodium, 2~6~ ~
potassium, calcium and magnesium salts. Salts also may be formed with amines such as dibenzylamine, cyclohexyl-amine, triethylamine, ethanolamine, di-ethanolamine and like amines. Likewise, when the 1-carbacephalosporin is substituted by two or more carboxy groups, di- and tri-salts are obtained by conventional salt-forming methods.
The pharmaceutically-acceptable, non-toxic salts can be useful forms of the antibiotics for pre-paring antibiotic formulations.
This invention also provides a method for - treating infectious diseases in man and other animals caused by bacteria and pharmaceutical formulations suitable for administration in the treatment method.
The therapeutic method of this invention comprises administering to man or other animals an antibiotically effective non-toxic dose of a compound represented by Formula (1) or a pharmaceutically acceptable salt thereof.
An antibiotically effective amount is an amount between about 25 mg and about 2 grams. The compound or salt may be administered in a single . dose or in multiple doses throughout the day. Treat-ment may continue for a week to ten days or longer depending upon the duration of the infection. The particular dose and regimen can depend on such factors as the weight and age of the patient, the particular causative organism, the severity of the infection, the general health of the patient, and the tolerance of the individual to the antibiotic.
9 ~
The l-carbacephalosporins may be administered parenterally, orally, subcutaneously or rectally. AS
with other ~-lactam antibiotics, the method of this invention may be used prophylactically to prevent infections after exposure or before possible exposure, e.g., preoperatively. The antibiotic 1-carbaceph-alosporins may be administered by conventional methods, e.g., in capsules, tablets, by syringe, or by intra-venous drip.
The pharmaceutical formulations of the inven-tion comprise an antibiotically effective non-toxic amount of a l-carbacephalosporin represented by Formula (1) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Formulations for oral administration include capsules, tablets, lozenges and liquid suspensions.
The antibiotic or a salt thereof in the form of a dry powder can be encapsulated in gelatin capsules for oral use. The antibiotic may also be blended with an excipient, e.g., a stabilizer, prior to filling.
Capsules may contain between about 100 mg and about 500 mg to provide unit dosage formulations.
Tablets containing between about 100 mg and 500 mg of the antibiotic or a pharmaceutically accept-able salt thereof can be formulated by conventionalmeanæ and may contain in addition a binding agent, disintegrating agent, stabilizing agent, antioxidant, etc.
Liquid preparations of the antibiotic may be prepared for infant and geriatric use. Pediatric sus-pensions can be formulated with the antibiotic oral 2 ~ 3 ~
excipients such as suspending agents, flavoring agents, stabilizers and the like. Solutions of the antibiotics likewise may be formulated with solubilizing agents, flavoring agents, sugar, water, etc.
Parenteral formulations of the antibiotics for injection are formulated with Water-for-Injection, Ringer's solution, physiological saline or glucose solution. The antibiotic also may be administered in an intravenous fluid by the drip method.
For parenteral use, the antibiotic or a phar-maceutically acceptable salt thereof, can be made up preferably in dry crystalline powder form or as a lyophilized powder and filled into vials. Such vials may contain between about 100 mg and about 2 grams of antibiotic per vial.
The following Experimental Section provides further examples of the various aspects of the present invention but is not to be construed as limiting the scope therefor.
Experimental Section . Preparation 1 p-Nitrobenzyl 7~-phenoxyacetylamido-1-carba(l-dethia)-3-trifluoromethanesulfonyloxy-3-cephem-4-carboxylate The title compound can be prepared according to the method of Evans and Sjogren, U.S. Patent No.
4,673,737, incorporated herein by reference.
~3~
PreParation 2 Trimethyl(l-ethoxy-e~hen-l-yl)stannane (Ref: Organometallics, Vol. 1, No. 6, 1982, J.
Soderquist) A 19.18 ml (14.48 g, 200.36 mmol) sample of ethoxyethylene was dissolved in 100 ml of tetrahydrofuran, cooled to -78C, and treated with a solution of t-butyl-lithium (94.1 ml, 150.56 mmol, 1.6M) over 20 min. under argon. The reaction mixture was then allowed to warm to 0C over 35 min. and added via cannula to a -78C
solution of 20.0 g (100.4 mmol) of chlorotrimethyi-stannane in 40 ml of tetrahydrofuran and allowed to warm to room temperature gradually. After an additional 50 min., the mixture was guenched with saturated NH4Cl solution (400 ml) and extracted with diethyl ether (500 ml). The ether solution was then dried over anhydrous Na2SO4, filtered and concentrated to provide the crude product as a yellowish liquid (23.8 g; 100%). The crude product was then distilled at 40-41C and about 4 mm Hg to provide 12.05 g of the title compound.
lH NMR (300 MHz, CDCl3) ~4.65 (s, lH), 4.10 (s, lH), 3.70 (g, 2H), 1.25 (t, 3H~, and 0.18 (s, 9H).
2 ~
Preparation 3 p-Nitrobenzyl 7~-phenoxyacetylamino-1-carba(l-dethia)-3-(l-ethoxy-ethen-1-yl)-3-cephem-4-carboxylate.
A 1.0 g (1.77 mmol) sample of the title compound of Preparation 1, a 0.142 g (3.34 mmol) sample of lithium chloride, and a 0.043 g (0.167 mmol) sample of dichloropalladium (II) diacetonitrilate were dissolved in 3 ml of dimethylformamide and treated with 0.435 g (1.84 mmol) of trimethyl (l-ethoxy-ethen-l-yl)stannane.
The reaction was then gently warmed with a hot air gun for about 10 seconds, and allowed to stir at room temperature for about one hour. The reaction mixture was poured into 100 ml 1:1 mixture of ethyl acetate/
diethyl ether and 100 ml 10:1 mixture Brine/satd.
NaHCO3 solution. Organics were separated and dried over Na2SO4, filtered, and concentrated ln vacuo. Resultant crude dark oil was then diluted with 2 ml CH2Cl2 and 5 ml diethyl ether and 20 ml of hexane. A dark oil again resulted. Supernatant was decanted and to it was added an additional 40 ml hexane. Desired precipitated as a solid which was filtered and washed with hexane and dried to give 87 mg of the desired compound. The dark oil was chromatographed on 50 g of silica gel using 15-25% ethyl acetate/CH2Cl2 as eluent. The resulting product fractions were concentrated ln vacuo and treated with ~0 ml Et2O to provide 550 mg of the title compound (total yield 637 mg, 74%).
~3~L~
lH NMR: (300 MHz, CDC13) ~8.20 (d, J= 9Hz, 2H), 7.60 (d, J= 9Hz, 2H), 7.35 (t, J= 8Hz, 2H), 7.10 (m, 2H~, 6.90 (d, J= 8Ez, 2H), 5.45 (dd, J= 5,7Hz, lH), 5.37 (AB, 2H), 4.58 (S, 2H), 4.21 (d, J= 3 Hz, lH), 4.18 (d, J= 3Hz, lH), 3.95 (m, lH), 3.75 (m, 2H), 2~70 (dd, J= 4, 18Hz, lH), 2.30 (m, lH), 2.05 (m, lH), 1.50 (m, lH) and 1.25 (t, J= 7Hz, 3H) IR: (CHCl3) 3028, 1772, 1734, 1691, 1524, 1496, 1389, 1299, 1277, and 1207 cm 1 MS: m/e 521 (M ) Analysis Calculated for C27H27N3O8:
Calc.: C, 62.18i H, 5.22; N, 8.06;
Found: C, 62.43; H, 5.36; N, 8.30.
Preparation 4 p-Nitrobenzyl 7~-phenoxyacetylamino-1-carba(l-dethia)-3-(2-bromo-1,1-diethoxyethyl)-3-cephem-4-carboxylate A 570 mg sample of the material from Prepara-tion 4 was dissolved in 4.5 ml of ethanol/2 ml of CH2Cl2 and cooled to 0C. The solution was then treated with 0.153 ml (1.312 mmol) of 2,6-lutidine and 1.1 ml (1.1 mmol) of a 1.0 M Br2/CCl4 solution. The resulting mixture was then poured into a mixture of saturated sodium bicarbonate solution and 1:1 ethyl acetate/diethyl ether. The organic layer was separated, dried over 2 ~ 3 i~
anhydrous Na2S0~, filtered, and concentrated to provide a yellow foam which was used directly in the next step.
A 25 mg sample of the above product was purified over a silica gel (2.5 g) column using 7%
ethyl acetate/CH2Cl2 as eluent to provide 20 mg of the title compound.
lH NMR (300 NHz, CDCl3) ~8.23 (d, J= 9Hz, 2H), 7.60 (d, J= 9Hz, 2H) 7.35 (t, J= 8Hz, 2H), 7.10 (m, 2H), 6.95 (d, J= 8Hz, 2H), 5.35 (AB, 2H) 5.32 (dd, J= 5, 7Hz, lH), 4.58 (s, 2H), 3.95 (m, lH) 3.3-3.6 (2m, 4H), 2.48 (dd, J= 2, 16Hz, lH), 2.20 (m, lH) 2.05 (m, lH) 1.45 (m, lH) 1.16 (t, J= 4Hz, 3H) and 1.10 (t, J= 4Hz, 3H) IR: (CHCl3) 3019, 1772, 1751, 1749, 1695, 1349, 1290, }206 and 1073 cm 1 MS: m/e 646 (M + 1) Analysis Calculated for CpgH32N309Br:
Calc.: C, 53.88; H, 4.99; N, 6.50;
Found: C, 53.59; H, 4.75; N, 6.77.
., Preparation 5 p-Nitrobenzyl 7~-phenoxyacetyl-t-butyloxycarbonylamino-l-carba(l-dethia)-3-(2-bromo-1,1-diethoxy)-3-cephem-4-carboxylate A 700 mg sample of the product of preparation 4 ~as dissolved in 10 ml of CH2C12 at room temperature 2 ~ 3 ~
and treated with 0.256 ml (1.126 mmol) of di-tert-butyl dicarbonate, followed by 132 mg (1.08 mmol) of 4-dimethylaminopyridine and stirring for 30 min. An additional 50 ~1 of di-tert-butyl dicarbonate was added and the reaction stirred for about 30 min. The reaction mixture was chromatographed directly over a silica gel column (40 g) using 20-30% ethyl acetate/CH2Cl2 as eluent to provide 730 mg (90.5%) of the title compound.
lH NMR: (300 MHz, CDCl3) ~8.23 (d, J= 9Hz, 2H), 7.62 (d, J= 9Hz, 2H), 7.30 (t, J= 8Hz, 2H), 7.0 (m, 2H), 6.95 (d, J= 8Hz, 2H~, 5.70 (d, J= 4Hz, lH~, 5.35 (AB, 2H), 5.18 (d, J= 3Hz, 2H), 3.86 (m, lH), 3.35-3.7 (m, 4H), 2.5 (dd, J= 2, 18Hz, lH), 2.18 (m, lH), 1.85 (m, lH) 1.55 (s, 9H) 1.50 (m, lH) 1.16 (t, J= 4Hz, 3H) and 1.10 (t, J= 4Hz, 3H) IR: (CHCl3) 3019, 1791, 1747, 1349, 1226, 1205, and 1145 cm~l MS: m/e 672 (M -OC4Hg) Analysis Calculated for C34H40N3O11Br:
Calc.: C, 54.70; H, 5.40; N, 5.63;
Found: C, 53.55; H, 4.48, N, 6.42.
2~3~9~
Preparation 6 p-Nitrobenzyl 7~-t-butyloxycarbonylamino-1-carba (l-dethia)-3-(2-bromo-1,1-diethoxyethyl-3-cephem-4-carboxylate A 750 mg (O.957 mmol) sample of the product of Preparation 5 was dissolved in 8 ml of tetrahydro-furan, treated with 0.85 ml (0.85 mmol) of 1.0 M
lithium hydroxide soln. and sonicated. A further 0.155 ml portion of lithium hydroxide was added and sonication continued for 30 min. The reaction mixture was then poured into 50 ml of saturated sodium bicarbonate/75 ml ethyl acetate solution. The organic phase was separated and dried over anhydrous Na2 S04, filtered, and concen-trated to provide 410 mg of the product as a foam after column chromatography over silica gel (8% ethyl acetate/
CH2Cl2 ) -The above chromatography provided 176 mg of starting material which was re-submitted to the above conditions to obtain 102 mg of the title compound.
Total yield = 512 mg (86.6%).
1~ NMR: (300 MHz, CDCl3) ~8.23 (d, J= 9Hz, 2H), 7.61 (d, J= 9Hz, 2H), 5.35 (AB, 2H), 5.01 (m, lH), 5.09 (m, lH), 3.85 (m, lH), 3.3-3.6 (m, 4H), 2.47 (dd, J= 2, 16Hz, lH), 2.20 (m, lH), 2.10 (m, lH), 1.43 (s, 9H), 1.12 (t, J= 4Hz, 3H), and 1.08 (t, J= 4Hz, 3H) IR: (CHCl3) 1769, 1741, 1716, 1524, 1349, 1224, 1207, and 1160 cm 1 ~ ~ 3 ~
MS: 611 (M ) Analysis Calculated for C2 6H3~N3OgBr:
Calc.: C, 50.99; H, 5.60; N, 6.86;
Found: C, 51.99; H, 5.16; N, 7.67.
Preparation 7 p-Nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(2-bromomethylcarbonyl)-3-cephem-4-carboxylate A 125 mg (0.204 mmol) sample of the product of Preparation 6 was dissolved in 1.2 ml of acetonitrile/
0.25 ml of acetic acid/0.05 ml H2O and stirred for about 2 hours. The reaction mixture was then poured into ~50 ml) saturated sodium bicarbonate solution/(100 ml) 1:1 ethyl acetate/diethyl ether solution. The organic phase was separated, dried over anhydrous Na2SO4, filtered, and concentrated to provide 111 mg (about 100%) of the title compound as a white solid.
1H NMR: (300 MHz, CDCl3) ~8.20 (d, J= 9Hz, 2H), 7.62 (d, J= 9Hz, 2H), 5.33 (AB, 2H), 5.28 (dd, J= 4,7Hz, lH), 5.25 (d, J= 4Hz, lH), 4.03 (AB, 2H), 3.87 (m, lH), 2.80 (dd, J= 4,18Hz, lH), 2.45 (m, lH), 2.13 (m, lH) 1.57 (m, lH), and 1.4 (s, 9H) IR: (CHCl3) 3019, 1782, 1718, 1525, 1369, 1291, and 1159 cm 1 MS: m/e 480 (M+-C4Hg) Analysis Calculated for C22H24N3O8Br:
Calc.: C, 49.08; H, 4.49; N, 7.81;
Found: C, 49.29; H, 4.64; N, 7.62.
ExamPle 1 7~-t-butoxycarbonylamino-1-carba(1-dethia)-3-(2-phenyl-thiazolo)-3-cephem-4-carboxylic acid A 75 mg (0.140 mmol) sample of p-nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(1-dethia)-3-bromo-methylcarbonyl)-3-cephem-4-carboxylate (Preparation 7) was dissolved in 1.5 ml of isopropanol and 1 ml of 1,1,2-trichloroethane, followed by the addition of 20 mg (0.146 mmol) of phenylthiocarbamate. The reaction mixture was then heated to about 65C for 1.5 hours.
The reaction mixture was concentrated ln vacuo and treated with 3 ml of diethyl ether/4 ml hexane. The resulting solid (85% yield) was dried to provide the title compound.
Example 2 7,B-t-butoxycarbonylamino-l-carba(l-dethia)-3-(2-(4-NO2-- 3-methylimidazol-2-yl)-thiazol-4-yl-3-cephem-4-carboxylic acid A 127 mg sample of p-nitrobenzyl 7~-t-butoxy-carbonylamino-1-carba(1-dethia)-3-bromomethylcarbonyl-4-carboxylic acid was reacted with 4-NO2-3-methyl imidazolo thiocarbamate in a manner analogous to that of Example 1. Column chromatography ethylacetate/CH2Cl2 with a trace of acetic acid provided 85 mg of the title compound.
Example 3 p-Nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(2-(phenyl)(2-pyridyl)methylthiazol-4-yl)-3-cephem-4-carboxylate The title compound was prepared in a manner analogous to that of Example 1 (without deesterification) utilizing phenyl-2-pyridylthiocarbamate 710 mg (97.3%) lH NMR: (300 MHz, CDC13) ~8.60 (dd, J= 4, 9Hz, lH), 8.05 (d, J= 9Hz, 2H), 7.60 (m, 9H), 5.83 (d, J= 4Hz, lH), 5.15 (m, 3H), 4.70 (m, lH), 3.90 (m, lH), 2.92 (dd, J= 4, 18Hz, lH), 2.50 (m, lH), 2.20 (m, lH) 1.70 (m, lH) and 1.~8 (s~ 9H) Example 4 7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(2-phenylthiazol-4-yl)-3-cephem-4-carboxylic acid A 430 mg (0.746 mmol) sample of p-nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(2-phenyl-thiazol-4-yl)-3-cephem-4-carboxylate was dissolved in 5 ml dimethylformamide/6 ml tetrahydrofuran/4 ml acetic acid along with 200 mg (2.98 mmol) of Zn. Upon comple-tion, the reaction mixture was diluted with CH2Cl2 and filtered through filter (celite) aid. The organic phase was then washed sequentially with H2O, lN HCl, and NaHCO3 solution. The NaHCO3 solution was layered with CH2Cl2, acidified to a pH of 2. The CH2Cl2 layer was separated and the aqueous portion extracted with CH2C12.
2 ~ a The combined CH2Cl2 portions were dried over anhydrous Na2SO4, filtered, and concentrated. Crystallization over diethyl ether/hexane provided 270 mg (82.3%) of the title compound.
Example 5 p-Nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(2-aminothiazol-4-yl)-3-cephem-4-carboxylate A 600 mg (1.115 mmol) sample of p-nitrobenzyl-7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(bromo-methylcarbonyl)-3-cephem-4-carboxylate was dissolved in 15 ml of isopropanol/10 ml 1,1,2-trichloroethane along with 0.146 ~1.25 mmol) of 2,6-lutidine followed by 88.4 15 mg (1.16 mmol) of thiourea. -Workup analogous to that described above provided 220 mg of the title compound.
lH NMR: (300 MHz, CDCl3) 88.22 (m, 2H), 6.90 (m, lH), 6.58 (m, lH) 6.10 (s, 2H) 5.35 (m, 3H), 3.85 (m, lH), 2.85 (m, lH), 2.58 ~m, lH), 2.40 (m, lH), 1.80 (m, lH), and 1.45 (s, 9H) ExamPle 6 p-Nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(2-(2,3-dihydroxyphenyl)thiazol-4-yl)-3-cephem-4-carboxylate In a manner analogous to preceding examples, 3,4-dihydroxyphenylthiocarbamate was utilized to provide the title compound (380 mg).
2~3~
lH NMR: (300 ~Hz, CDCl3) ~7.90 (m, 2H), 7.40 (m, lH), 7.12 (m, 3H), 6.98 (s, lH), 6.84 (m, lH), 5.20 (m, 4H), 4.05 (m, lH), 2.84 (dd, J= 4, 18Hz, 1~) 2.35 (m, lH), 2.15 (m, lH), 1.75 (m, lH), and 1.45 (s, 9H) Example 7 p-Nitrobenzyl 7~-t-butoxycarbonyl-l-carba(l-dethia)-3-(2-(2,3-di-(t-butyldimethylsilyloxy)phenyl)thiazol-4-yl~-3-cephem-4-carboxylate A 370 mg sample of the compound produced in Example 6 above was dissolved in 4 ml of dimethyl-formamide and treated with 184 mg of t-butyldimethyl-silylchloride and 85 mg of imidazole and stirred for about 24 hours. An additional 180 mg of t-butyl-dimethylsilyl chloride and 90 mg of imidazole were added and the solution stirred an additional 24 hours.
The reaction mixture was then diluted with 100 ml of ethyl acetate and 100 ml of H2O. The organic phase was separated and washed with lO0 ml of saturated NaHCO3 solution. The organic phase was then dried over anhydrous Na2SO4 and purified over (50 g) silica gel using ethyl acetate as eluent. Further chromatography over silica gel (25% ethyl acetate/hexane) provided 320 mg of p-nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(1-dethia)-3-(3,4-di(t-butyldimethylsilyloxy)-phenylthiazol-4-yl-3-cephem-4-carboxylate.
H NMR: (300 MHz, CDCl3) ~8.0 (d, J= 9Hz, 2H), 7.32 (m, 2H), 7.22 (d, J= 9Hz, 2H), 7.05 (s, lH), 6.80 (m, lH), 5.28 (AB, 2H), 5.22 (m, lH), 5.05 (m, lH~, 3.95 tm, lH), 2.95 (dd J= 4, 18Hz, lH), 2.55 (m, lH), 2.20 (m, lH), 1.70 (m, lH), 1.42 (s, 9H) 1.0 (s, 9H), 0.97 (s, 9H), 0.23 (s, 6H), and 0.20 (s, 6H) Example 8 Allyl 7~-t-butoxycarbonylamino-1-carba(1-dethia)-3-(2-(2,3-di-(t-butyldimethylsilyloxy)phenyl)-3-cephem-4-carboxylate A. Removal of p-nitrobenzyl ester A 320 mg (0.382 mmol) sample of the title compound from Example 7 was dissolved in 2.5 ml of dimethylformamide/3 ml of tetrahydrofuran and 2.5 ml of acetic acid, treated with 100 mg (1.53 mmol) of Zn dust and stirred for 20 min. The reaction mixture was then treated with an additional 1 ml of acetic acid and 100 mg of Zn. After lh, the reaction mixture was filtered, diluted with ethyl acetate and washed with water. The organic phase was then dried and concentrated in vacuo azeotroping any remaining dimethylformamide away with toluene (5 times) to provide the title compound as a foam (220 mg, 82%) (some desilylation occurred)~
B. Formation of allyl ester A 215 mg (0.306 mmol) sample of the product from part A above is reacted with allyl bromide in 2 ~
dimethylformamide in the presence of tetra-n-butyl-ammonium hydrogen sulfate, sodium bicarbonate and sodium iodide to provide the title compound.
Example 9 Allyl 7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(2-phenylthiazol-4-yl)-3-cephem-4-carboxylate A 103 mg 0.234 mmol) sample of 7~-t-butoxy-carbonylamino-1-carba(l-dethia)-3-(2-phenylthiazol-4-yl)-3-cephem-4-carboxylic acid, prepared according to the foregoing examples, was dissolved in a small amount of N,N-dimethylformamide, treated with 60 mg (0.70 mmol) of NaHC03 and stirred for 10 min. The reaction mixture 15 was then treated with 83 mg (0.246 mmol) of tetra-n-butylammonium hydrogen sulfate, allowed to stir for 10 min., followed by treatment with 26 ~1 (0.294 mmol) of allyl bromide (followed by a additional 10~1) and 109 mg (0.725 mmol) of NaI. After stirring at room temperature overnight, the reaction mixture was poured into 30 ml of saturated NaHC03 solution and 50 ml of ethyl acetate. The organic phase was separated and washed (2x30 ml) with 0.5 N HCl solution, dried over anhydrous Na2 S04, filtered and concentrated ln vacuo to 25 provide the title compound. (100 mg, 89.3%, isolated as a solid from diethyl ether/hexane.) lH NMR: (300 MHz, CDCl3) ~7.90 (m, 2H), 7.40 (m, 3H), 7.15 (s, lH), 5.78 (m, lH), 5.10 (m, 4H), 4.65 (ABX, 2H), 30 3.90 (m, lH), 2.95 (dd, J= 4, 18Hz, lH), 2.50 (m, lH), 2.20 (m, lH), 1.70 (m, lH) and 1.45 (s, 9H).
.
.
~ 3 IR: (CHCl3) 1769, 1718, 1506, 1369, 1248, and 1161 cm 1 MS: m/e 482 (M + 1) AnalysiS Calculated for C2sH27N3sS:
Calc.: C, 62.35; H, 5.65; N, 8.73;
Found: C, 64.23; H, 5.81; N, 8.93.
Examples 10-18 According to the general methodolo~y of Example 9 and the preceding Examples, the followin~
compounds were prepared.
10. Allyl 7~-t-butoxycarbonylamino-l-carba-(1-dethia)-3-[2-(5-nitrothiazol-2-yl)thiazol-4-yl]-3-cephem-4-carboxylate lH NNR: (300 MHz, CDCl3) ~8.55 (s, lH), 7.43 (s, lH), 5.85 (m, lH), 5.25 (m, 3H), 5.10 (m, lH), 4.75 (ABX, 2H), 4.95 (m, lH), 2.98 (dd, J= 4, 18Hz, lH), 2.55 (m, lH), 2.23 (m, lH), 1.70 (m, lH) and 1.45 (s, 9H) IR: (CHCl3) 2976, 1772, 1719, 1390, 1351, 1251, and 1159 cm 1 MS: m/e 534 (M + 1) Analysis Calculated for C22H23NsO7S2:
Calc.: C, 49.52; H, 4.35; N, 13.13;
Found: C, 50.90; H, 4.33; N, 13.23.
11. Allyl 7~-t-butoxycarbonylamino-1-carba-(l-dethia)-3-[2-(4-fluorophenyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, C~C13) ~7.90 (m, 2H), 7.19 (s, lH), 7.12 (m, 2H), 5.8 (m, lH), 5.15 (m, 4H), 4.70 (ABX, 2H), 3.90 (m, lH), 2.95 (dd J= 4, 18Hz, lH), 2.50 (m, lH), 2.20 (m, lH), 1.70 (m, lH), and 1.45 (s, 9H) IR: (KBr) 3019, 2977, 1770, 1719, 1393, 1336, and 1157 cm MS: m/e 499 (M ) Analysis Calculated for C25H26N3O5SF:
Calc.: C, 60.10; H, 5.25; N, 8.41;
Found: C, 62.52; H, 5.57; N, 8.42.
12. Allyl 7~-t-butoxycarbonylamino-1-carba-(l-dethia)-3-[2-(4-pyridyl)thiazol-4-yl]-3-cephem-4-carboxylate ; 1H NMR: (300 MHz, CDCl3) ~8.72 ((d, J= 9Hz, 2H), 7.75 (d, J= 9Hz, 2H), 7.30 (s, lH), 5.80 (m, lH), 5.20 (m, 4H), 4.70 (ABX, 2H), 3.95 (m, lH), 3.0 (dd J= 4, 18Hz, lH), 2.58 (m, lH), 2.25 (m, lH), 2.25 (m, lH), 1.75 (m, lH), and 1.50 (s, 9H) IR: (CHCl3) 3020, 1771, 1718, 1505, 1393, 1348, 1248, and 1161 cm 1 ~3~
MS: m~e 482 (M ) A~alysis Calculated for C2~H2GN~O5S --Calc.: C, 59.74; H, 5.43; N, 11.61;
Found: C, 58.47; H, 5.23; N, 11.25.
13. Allyl 7~-t-butoxycarbonylamino-1-carba-(l-dethia)-3-[2-(3-methyl-4-nitroimidazol-2-yl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl3) ~8.10 (s, lH), 7.40 (s, lH), 5.62 (m, lH), 5.25 (m, 3H), 5.08 (d, J= 8Hz, lH), 4.70 (d, J= 6Hz, 2H), 4.48 (s, 3H), 3.95 (m, lH), 3.0 (dd J= 4, 18Hz, lH), 2.58 (m, lH), 2.25 (m, lH), 1.75 (m, lH), and 1.48 ~s, 9H) IR: (CHCl3) 3018, 1772, 1719, 1530, 1472, 1365, 1270, and 1161 cm 1 MS: m/e 530 (M ) 14. Allyl 7~-t-butoxycarbonylamino-1-carba-(l-dethia)-3-[2-(1,1-(2-pyridyl)(phenyl)methyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl3) ~8.60 (d, J= 4Hz, lH) 7.63 (t, J- 9Hz, lH), 7.30 (m, 5H), 7.18 (m, 2H), 7.13 (s, lH), 7.11 (6, lH), 5.86 (s, lH), 5.85 (s, lH), 5.65 (m, lH), 5.10 (m, 4H), 4.53 (d, J= 6Hz, lH), 4.47 (d J= 6Hz, lH), 4.28 (dd, J= 5, 15Hz, lH), 4.20 (dd, J= 5, 15Hz, lH), 3.88 (m, lH), 2.90 ~m, lH), 2.45 (m, lH), and 1.45 (s, 9H) 2 ~
IR: (CHCl3) 3019, 1769, 1718, 1496, 1393, 1369, 1247,and 1160 cm 1 MS: m/e 572 (M+) Analysis Calculated for C3lH32N40sS:
Calc.: C, 65.02; H, 5.63; N, 9.78;
Found: C, 65.01; H, 5.60; N, 9.52.
15. Allyl 7~-t-butoxycarbonylamino-1-carba-(l-dethia)-3-[2-(p-nitrophenyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl3) ~8.30 (d, J= 9Hz, 2H) 8.05 (d, 15 J= 9H~, 2H) 7.30 (s, lHl, 5.80 (m, lH), 5.20 (m, 4H), 4.68 (ABX, 2H), 3.g5 (m, lH), 3.0 (dd J= 4, 18Hz, lH), 2.55 (m, lH), 2.25 (m, lH), 1.70 (m, lH), and 1.45 (s, 9H) 20 IR: (CHCl3) 3020, 1771, 1719, 1525, 1348, 1248, and 1161 cm MS: m/e 527 (M + 1) Analysis Calculated for C25H26N407S;
Calc.: C, 57.03; H, 4.98; N, 10.64;
Fou~d: C, 57.48; H, 4.82; N, 11.33.
16. ~llyl 7~-t-butoxycarbonylamino-1-carba-30 (1-dethia)-3-[2-(3,4-(t-butyldimethylsilyloxy)phenyl)-thiazol-4-yl]-3-cephem-4-carboxylate 2 ~ L `3 ~
lH NMR: (300 MHz, CDCl3~ ~7.35 (m, 2H), 7.05 (s, lH), 6.85 (d, J= 9Hz, lH), 5.75 (m, lH), 5.15 (m, 4H), 4.65 (ABX, 2H), 3.90 (m, lH), 2.95 (dd J= 4, 18Hz, lH~, 2.48 (m, lH), 2.18 (m, lH), 1.70 (m, lH), 1.45 (s, 9H), 1.02 (s, 9H), 1.0 (s, 9H), 0.24 (s, 6H), and 0.21 (s, 6H) IR: (CHCl3) 2931, 1768, 1718, 1520, 1472, 1392, 1297, 1254 and 1161 cm 1 10 MS: m/e 742 (M + 1) Analysis Calculated for C37H55N307SSi2:
Calc.: C, 59.89; H, 7.47; N, 5.66;
Found: C, 62.22; H, 7.57; N, 5.65.
17. Allyl 7~-t-butoxycarbonylamino-1-carba-(l-dethia)-3-[2-(2-furenyl)thiazol-4-yl]-3-cephem-4-carboxylate 20 lH NMR: (300 MHz, CDCl3) ~7.48 (d, J= 2Hz, lH), 7.10 (s, lH), 6.95 (m, lH), 6.5 ~m, lH), 5.80 (m, lH), 5.15 (m, 4H), 4.68 (ABX, 2H), 3.90 (m, lH), 2.95 (dd J= 4, 18Hz, lH), 2.S0 (m, lH), 2.20 (m, lH), 1.70 (m, lH), and 1.45 (s, 9H) IR: (CHCl3) 3019, 1770, 1718, 1502, 1393, 1249, and 1160 cm MS: m/e 472 (M+ + 1) Analysis Calculated for C2 3H25N3O6S:
Calc.: C, 58.59; H, 5.34; N, 8.91;
Found: C, 59.83; H, 5.27; N, 8.41.
2 ~
18. Allyl 7~-t-butoxycarbonylamino-1-carba-(l-dethia)-3-[2-(3-pyridyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl3) ~9.1 (d, J= 2Hz, lH), 8.65 (d, J= 4Hz lH), 8.18 (m, lH), 7.38 (m, lH), 7.22 (s, lH), 5.80 (m, lH), 5.2 (m, 4H), 4.70 (ABX, 2H), 3.95 (m, lH), 3.0 (dd J= 4, 18Hz, lH), 2.52 (m, lH), 2.20 (m, lH), 1.70 (m, lH), and 1.48 (s, 9H) IR: (CHCl3) 3025, 1771, 1717, 1602, 1246, and 1162 cm 1 MS: m/e 482 (M ) Analysis Calculated for C24H26N4O5S:
Calc.: C, 59.74; H, 5.43; N, 11.61, Found: C, 59.90; H, 5.62; N, 11.63.
19. Allyl 7~-t-butoxycarbonylamino-1-carba-20 (1-dethia)-3-[2-(allyloxycarbonylamino)thiazol-4-yl]-3-cephem-4-carboxylate In a procedure analogous to Example 9 above, the title compound was prepared in 38% yield.
25 lH NNR: (300 MHz, CDCl3) ~8.70 (s, lH), 5.90 (m, 2H), 5.30 (m, 6H), 4.72 (d, J= 6Hz, 2H), 4.65 (d, J= 6Hz, 2H) 4.90 (m, lH), 3.85 (dd J= 4, 18Hz, lH), 2.38 (m, lH), 2.10 (m, lH), and 1.45 (æ, 9H) 30 IR: (CHCl3) 3018, 1769, 1722, 1549, 1237, and 1207 cm 1 MS: m/e 504 (M ) 2 ~
Analysis Calculated for C23H28N4O7S:
Calc.: C, 54.75; H, 5.59; N, ll.10;
Found: C, 54.93; H, 5.31; N, 11.94.
Coproduced in this reaction was allyl 7~-t-butoxy-carbonylamino-l-carba(l-dethia)-3-[2-[(allyloxy-carbonyl)(allyl)]amino]-thiazol-4-yl-3-cephem-4-carboxylate (45%).
lH NMR: (300 MHz, CDCl3) ~6.80 (s, lH), 5.90 (m, 2H), 5.25 (m, 5H), 5.05 (d, J= 8Hz, lH), 4.78 (d, J= 6Hz, 2H), 4.65 (d, J= 6Hz, 2H), 3.87 (m, lH), 2.88 (dd J= 4, 18Hz, lH), 2.40 (m, lH), 2.15 (m, lH), 1.65 (m, lH), and 1.45 (s, 9H) IR: (CHCl3) 3020, 1768, 1712, 1504, 1393, 1242, and 1157 cm~l MS: m/e 544 (M ) Analysis Calculated for C26H32N4O7S:
Calc.: C, 57.34; H, 5.92; N, 10.29;
- Found: C, 57.08; H, 5.86; N, 10.09.
It was subsequently discovered that the use of NaH in l-molar eguivalency as base resulted in the desired mono-allylated product.
~ ~ 3 ~
Example 20 Allyl 7~-[(2-allyloxycarbonylaminothiazol-4-yl)-Z-methoximinoacetylamino]-1-carba(l-dethia)-3-[2-(4-fluorophenyl)thiazol-4-yl]-3-cephem-4-carboxylate A. Deprotection An 80 mg (O.16 mmol) sample of allyl 7~-t-butoxycarbonylamino-l-carba(l-dethia)-3-[2-(4-fluoro-phenyl)thiazol-4-yl]-3-cephem-4-carboxylate was dis-solved in 1 ml of CH2C12 and 1 ml of trifluoroacetic acid. The solution was concentrated ln vacuo to provide a foam which was again treated with trifluroracetic acid and concentrated out of acetonitrile. From the resulting foam (CH2Cl2/diethyl ether/hexane) was obtained a tan solid.
B. Acylation In another container, a 46 mg (0.16 mmol) sample of (2-allyloxycarbonylaminothiazol-4-yl)-Z-methoximino acetic acid was dissovled in a small amount of CH2Cl2 and treated with 28 mg (0.16 mmol) of 2-chloro-4,6-dimethoxytria2ene and cooled to 0C. The reaction mixture was then diluted with an additional 1 ml of CH2Cl2 and treated with 19 ~1 (0.168 mmol) of N-methylmorpholine and stirred for about 40 min.
An additional 19 ~1 g N-methylmorpholine was added, followed by addition of the product from Part A, above, using about 2 ml of CH2Cl2 as wash. After 2 hours, the reaction mixture was concentrated ln vacuo and purified by column chromatography (silica gel, 30-40% ethyl acetate/CH2Cl2) to provide 42 mg of the title compound.
2~3~
lH NMR: (300 MHz, CDCl3) ~9.38 (s, lH), 7.90 (m, 2H), 7.20 (s, lH), 7.12 (m, 2H), 5.85 (m, 3H), 5.25 (m, 4H), 4.70 (m, 4H), 4.10 (m, lH), 4.05 (s, 3H), 3.05 (dd, J= 4, 18Hz, lH), 2.60 (m, lH), 2.30 (m, lH), and 1.95 (m, lH) Examples 21-30 ~The following compounds were prepared in a manner analogous to that used in Example 20.
21. Allyl 7~-[(2-allyloxycarbonylamino-thiazol-4-yl)-Z-methoximinoacetylamino]-l-carba(l-dethia)-3-[(2-phenyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl3) ~9.40 (s, lH), 7.90 (m, 3H), 7.40 (m, 2H), 7.20 (s, lH), 7.10 (s, lH), 5.95 (m, lH), 5.80 (m, lH), 5.60 (m, lH), 5.20 (m, 4H), 4.70 (m, 4H), 4.10 (m, lH), 4.05 (s, 3H), 3.0 (dd J= 4, 18Hz, lH), 20 2.60 (m, lH), 2.30 (m, lH), and 1.95 (m, lH) 22. Allyl 7~-[2-(allyloxycarbonylamino-thiazol-4-yl)-Z-methoximinoacetylamino]-l-carba(l-dethia)-3-[(pyridyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl3) ~9.55 (s, lH), 9.10 (s, lH), 8.65 (d, J= 6Hz, lH) 8.20 (d, J= 9Hz, lH), 8.05 (s, lH), 7.38 (m, lH), 7.30 (s, lH), 7.10 (s, lH), 5.95 ~m, lH), 5.80 (m, lH), 5.75 (m, lH), 5.25 (m, 4H), 4.70 ~m, 4H), 30 4.10 (m, lH), 4.05 (s, 3H), 3.0 (dd J= 4, 18Hz, lH), 2.60 (m, lH), 2.30 (m, lH), and 1.95 (m, lH) 2~3~
23. Allyl 7~-[2-(allyloxycarbonylamino-thiazol-4-yl]-Z-methoximinoacetylamino]-l-carba(l-dethia)-3-[(1-methyl-2-pyridyl)thiazol-4-yl]-3-cephem-4-carboxylate iodide A 58 mg sample of the title compound of Example 22 was dissolved in 0.9 ml of N,N-dimethyl-formamide and treated with 17~1 (0.278 mmol) of methyl-iodide. Crystallization by addition of diethyl ether/
hexane to the reaction mixture provided 56 mg (95%
yield) of the title compound.
lH NMR: (300 MHz, CDCl3) ~9.15 (s, lH), 8.80 (d, J= 9Hz, lH), 8.70 (d, J= 6Hz, lH), 8.10 (m, lH), 7.70 (s, lH), 7.60 (d, J= 9Hz, lH), 7.25, (s, lH), 5.95 (m, lH), 5.75 (m, lH), 5.55 (m, lH), 5.25 (m, 4H), 4.65 (m, 4H), 4.35 (s, 3H), 4.05 (m, lH), 3.95 (s, lH), 3.05 (dd J= 4, 18Hz, lH), 2.55 (m, lH), 2.10 (m, lH), and 1.85 (m, lH) 24. Allyl 7~-[2-(allyloxycarbonylamino-thiazol-4-yl]-Z-methoximinoacetylamino]-l-carba(l-dethia)-3-[2-[5-nitrothiazol-4-yl]thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl~) ~9.30 (s, lH), 8.55 (s, lH), 7.80 (s, lH), 7.45 (s, lH), 7.15 (s, lH), 5.90 ~m, 2H), 5.70 (m, lH), 5.30 (m, 4H), 4.70 (m, 4H), 4.10 (m, lH), 4.05 (s, 3H), 3.0 (dd J= 4, 18Hz, lH), 2.60 (m, lH), and 1.90 (m, lH) (using p-toluenesulfonic acid H2O in place of trifluoroacetic acid) 2~6~ ~
25. Allyl 7~-[(2-triphenylmethylaminothiazol-4-yl)-Z-triphenylmethoximinoacetylamino]-l-carba(1-dethia~-3-[2-[4-nitro-3-methylimidazol-2-yl]thiazol-4-yl-3-cephem-4-carboxylate (using p-toluenesulfonic acid H2O in place of trifluor~acetic acid) lH NMR: (300 MHz, CDCl3) ~8.05 (s, lH), 7.25 (m, 30H), 6.62 (s, H), 6.58 (d, J= 6Hz, lH), 6.43 (s, lH), 5.85 (m, lH), 5.45 (m, lH), 5.20 (m, 2H), 4.70 (m, 2H), 4.40 (s, 3H), 4.0 (m, lH), 2.58 (dd, J= 4, 18Hz, lH), 2.35, (m, lH), 2.10 (m, lH), and 1.45 (m, lH) 26. Allyl 7~-[(2-allyloxycarbonylamino-thiazol-4-yl]-Z-methoximinoacetylamino]-1-carba(1-dethia)-3-[2-[(phenyl)(2-pyridyl)methyl]thiazol-4-yl]-3-cephem-4-carboxylate ~H NMR: (300 MHz, CDCl3) ~9.60 (s, lH), 8.60 (d, J=
4Hz, lH), 8.05 (s, lH), 7.60 (m, lH), 7.25 (m, 5H), 7.20 (m, lH), 7.12 (s, lH), 7.0, (s, lH), 5.80 (m, 3H), 5.20 (m, 4H), 4.50 (m, 4H), 4.10 (m, lH), 4.0 (s, 3H), 2.90 (m, lH), 2.50 (m, lH), 2.20 (m, lH), and 1.90 (m, lH) 2~3~
27. Allyl 7~-[(2-allyloxycarbonylamino-thiazol-4-yl-Z-methoximinoacetylamino]-l-carba(l-dethia)-3-[2-(4-nitrophenyl)thiazol-4-yl]-3-cephem-4-carboxylate (using p-toluenesulfonic acid-H2O instead of trifluoroacetic acid) lH NMR: (300 MHz, CDCl3) ~9.60 (s, lH), 8.25 (d, J= 8Hz, 2H), 8.18 (s, lH), 8.05 (d, J= 8Hz, 2H), 7.35 (s, lH), 7.05, (s, lH), 5.90 (m, 3H), 5.25 (m, 4H), 4.70 (m, 4H), 4.15 (m, lH), 4.05 (s, 3H), 3.0 (dd, J= 4, 18Hz, lH), 2.60 (m, lH), 2.30 (m, lH), and 1.95 (m, lH) 28. Allyl 7~-[(2-allyloxycarbonylamino-thiazol-4-yl]-Z-methoximinoacetylamino]-l-carba(1-dethia)-3-[2-allyloxycarbonylaminothiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl3) ~9.60 (s, lH), 8.52 (s, lH), 8.10 (s, lH), 7.02 (s, lH), 6.80 (s, lH), 5.90 (m, 3H), 5.70 (m, lH), 5.25 (m, 6H), 4.70 (m, 6H), 4.05 (m, lH), 4.0 (s, 3H), 2.88 (dd, J= 4, 18Hz, lH), 2.43 (m, lH), 2.20 (m, lH), and 1.90 (m, lH) 29. Allyl 7~-[(2-allyloxycarbonylamino-thiazol-4-yl]-Z-methoximinoacetylamino]-l-carba(l-dethia)-3-[2-(3,4-(t-butyldimethylsilyl)oxy)phenyl-thiazol-4-yl]-3-cephem-4-carboxylate 2 ~ 3 ~
lH NMR: (300 MHz, CDCl3) ~9.45 (s, lH), 7.95 (s, lH), 7.35 (m, 2H), 7.12 (s, lH), 6.84 (m, lH), 5.95 (m, lH), 5.75 (m, 2H), 5.25 (m, 4H), 4.65 (m, 4H), 4.10 (m, lH), 4.02 (s, 3H), 3.0 (dd, J= 4, 18Hz, lH), 2.55 (m, lH), 2.25 (m, lH), 1.90 (m, lH), 1.0 (s, 9H), 0.97 (s, 9H), 0.23 (s, 6H), and 0.18 (s, 6H) 30. Allyl 7~-~(2-allyloxycarbonylamino-thiazol-4-yl)-Z-methoximinoacetylamino]-l-carba(l-10 dethia)-3-[2-(2-furyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl3) ~9.55 (s, lH), 8.05 (s, lH), 7.48 (s, lH), 7.15 (s, lH), 7.05 (s, lH), 6.95 (m, lH), 15 6.52 (m, lH), 5.85 (m, 3H), 5.25 (m, 4H), 4.70 (m, 4H), 4.10 (m, lH), 4.02 (s, 3H), 3.0 (dd, J= 4, 18Hz, lH), 2.55 (m, lH), 2.25 (m, lH) and 1.95 (m, lH) Example 31 Sodium 7~-[(2-aminothiazol-4-yl)-Z-methox-iminoacetylamino]-l-carba(l-dethia)-3-[2-(2-phenyl)-thiazol-4-yl]-3-cephem-4-carboxylate A 27 mg (0.0417 mmol) sample of allyl 7~-t(2-allyloxycarbonylaminothiazol-4-yl)-Z-methoximino-acetylamino]-1-carba(l-dethia)-3-[2-(phenyl)thiazol-4-yl]-3-cephem-4-carboxylate was dissolved in 1.5 ml of CH2Cl2, treated with 0.878 mg (0.0013 mmol) of bis triphenylphosphine Pd(II) dichloride and 6 ~1 (0.0917 mmol) of tri-n-butyltinhydride and stirred for 10 min.
~ ~ 3 ~
The reaction mixture was then treated with an additional 5.0 ~l of tri-n-butyltinhydride. After 10 min., the reaction mixture was quenched with a solution of 10 ~l concentrated HCl in 0.5 ml of CH3CN. The resulting mixture was treated with 10 ml of diethyl ether and 10 ml hexane and centrifuged (2X). The resulting solid was dried under vacuum to provide 16.0 mg of the free acid of the title compound (93% pure by HPLC) in 73.7%
yield.
A 130 mg (0.248 mmol) of the above was suspended in about 7 ml H20 and 2 ml CH3CN. A solution of 25 mg (0.297 mmol) of NaHC03 in 1.5 ml of H20 was prepared and added. The resulting solution was sonicated and passed through an HP20SS column eluting with 8% CH3CN-18%
CH3CN/H20. The desired fractions were concentrated and the resulting title compound washed with diethylether/
hexane to provide 125 mg (99.8% pure).
1H NMR: (300 MHz, d6-DMSO) ~9.2 (d, J= 9Hz, 2H), 7.85 (m, 2H), 7.65 (s, lH), 7.40 (m, 3~), 7.15 (s, 2H), 6.70 (s, lH), 5.25 (m, lH), 3.80 (s, 3H), 3.75 (m, lH), 2.95 (dd, J= 4, 18Hz, lH), 2.35 (m, lH), 1.90 (m, lH), and 1.70 (m, lH).
IR (KBr): 3500-3100, 1733, 1648, 1591, 1557, 1539, 1405 and 1376 cm MS: m/e 547 (M + 1) Analysis calculated for c23Hl9N6oss2Na:
Calc.: C, 50.54; H, 3.50; N, 15.38;
Found: C, 50.33; H, 3.76; N, 15.17.
2~3 r~ 1 ~ 3~
Examples 32-38 Examples 32-38 were prepared by methodology analogous to that of Example 31.
32. Sodium 7~-~(2-aminothiazol-4-yl)-Z-methoximinoacetylamino]-l-carba(l-dethia)-3-[2-(2-furyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, d6-DMSO) ~9.25 (d, J= 9Hz, lH), 7.80 (s, lH), 7.65 (s, lH), 7.20 (s, 2H), 6.95 (m, lH), 6.70 (s, lH), 6.60 (m, lH), 5.25 (m, lH),3.80 (s, 3H), 3.75 (m, lH), 3.85, (dd, J= 4, 18Hz, lH), 2.32 (m, lE), 1.85 (m, lH) and 1.65 (m, lH) IR (KBr): 3500-3200, 1744, 1647, 1595, 1538, 1404, 1383 and 1035 cm MS: m/e 537 (M + 1) Analysis calculated for C2lHl7N6O6S2Na:
Calc.: C, 47.01; H, 3.19; N, 15.66;
Found: C, 41.14; H, 2.95; N, 11.02.
.-- Residue: 12.74%
33. 7~-[(2-Aminothiazol-4-yl)-Z-hydroxy-iminoacetylamino]-l-carba(l-dethia)-3-[2-(4-nitro-3-methylimidazol-2-yl)thiazol-4-yl]-3-cephem-4-carboxylic acid 2~3~
H NMR: (300 MHz, d6-DMSO) ~9.15 (d, J= 9Hz, lH), 8.15 (s, lH), 7.88 (s, lH), 7.08 (s, 2H), 6.65 (s,lH), 5.40 (m, lH), 4.30 (s, 3H), 3.80 (m, lH), 3.90 (dd, J= 4, 18Hz, lH), 2.38 (m, lH), 1.95 (m, lH) and 1.7~ (m, lH) IR (KBr): 3500-3100, 1754, 1617, 1528, 1397, 1365, 1339, 1268 and 1209 cm 1 MS: m/e 560 (M + 1) Analysis calculated for C2 oH17Ns7 S2 Calc.: C, 42.93; H, 3.06; N, 22.53;
Found: C, 42.47; H, 3.38; N, 20.77.
34. 7~-[(2-aminothiazol-4-yl)-Z-methox-iminoacetylamino]-l-carba(1-dethia)-3-[2-(1-methyl-3-pyridyl)thiazol-4-yl]-3-cephem-4-carboxylic acid 1H NMR: (300 MHz, D2O) ~9.30 ~s, lH), 8.90 (d, J= 8Hz, lH), 8.78, (d, J= 6Hz, lH), 8.10 (m, lH), 7.65 ~s, lH), 6.95 (s, lH), 5.50, (d, J= 6Hz, lH), 4.45 (s, 3H), 4.10 (m, lH), 4.0 (s, 3H), 3.95, (m, lH), 2.58 (m, lH), 2.20 (m, lH), and 1.80 (m, lH) IR (KBr): 3200, 1758, 1674, 1532, 1384, 1203, and 1168 cm~1 MS: m/e 540 (M + 1) 35. Sodium 7~-[(2-aminothiazol-4-yl)-Z-methoximinoacetylamino~-1-carba(1-dethia)-3-[2-(4-nitro-phenyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, d6-DMSO) ~9.25 (d, J= 9Hz, lH), 8.25 (d, J= 9Hz, 2H), 8.15 (d, J= 9Hz, 2H), 7.85 (s, lH), 7.15 (s, 2H), 6.72 (s, lH), 5.25 (m, lH), 3.80 (s, 3H), 3.75 (m, lH), 2.95 (dd, J= 4, 18Hz, lH), 2.40 (m, lH), 1.90 (m, lH), and 1.70 (m, lH) IR (KBr): 3400-3200, 1733, 1649, 1594, 1523, 1402, 1345, 1050 and 851 cm 1 MS: m/e 592 (M + 1) Analysis calculated for C23H18N7O7S2Na:
Calc.: C, 46.70; H, 3.07; H, 16.57;
Found: C, 46.06; H, 3.05; N, 15.75.
Residue: 5.84%
36. 7~-[(2-aminothiazol-4-yl)-4-methox-iminoacetylamino]-l-carba(l-dethia)-3-[2-(5-nitro-thiazol-2-yl)thiazol-4-yl]-3-cephem-4-carboxylic acid 25 lH NMR: (300 MHz, d6-DMSO) ~9.35 (d, J= 9Hz, lH), 8.90 (s, lH), 8.02 (s, lH), 7.40 (s, 2H), 6.78 (s, lH), 5.45 (m, lH), 3.90 (m, lH), 3.80 (s, 3H), 2.95 (dd, J= 4, 18Hz, lH), 2.40 (m, lH), 2.0 (m, lH), and 1.70 (m, lH) 30 IR (KBr): 3419, 1764, 1629, 1524, and 1350 cm 1 MS: m/e 532 (M - C2 ) ~ ~ ,C~
Analysis calculated for C20Hl6N8O7S3:
Calc.: C, 41.66; H, 2.80; N, 19.43;
Found: C, 41.38; H, 2.90; N, 17.16.
S 37. 7~-[(2-aminothiazol-4-yl)-Z-methoximino-acetylamino]-l-carba(l-dethia)-3-[2-(4-fluorophenyl)-thiazol-4-yl]-3-cephem-4-carboxylic acid lH NMR: (300 MHz, d6-DNSO~ ~9.45 (d, J~ 9Hz, lH), 7.95 (m, 2H), 7.65 (s, lH), 7.35 (m, 2H), 6.83 (s, lH), 5.50 (m, lH), 3.95 (m, lH), 3.90 (s, 3H), 2.95 (m, lH), 2.40 (m, lH), 2.0 (m, lH), and 1.75 (m, lH) IR (KBr): 3400-3000, 1762, 1673, 1631, 1517, 1389, 1234, and 1046 cm 1 MS: m/e 543 (M + 1) Analysis calculated for C23H1gN6O5S2F:
Calc.: C, 50.92; H, 3.53; N, 15.49;
Found: C, 48.53; H, 3.66; N, 13.87.
38. 7~-[(2-aminothiazol-4-yl)-Z-methox-iminoacetylamino]-l-carba(1-dethia)-3-[2-(phenyl)(2-pyridyl)methyl)thiazol-4-yl]-3-cephem-4-carboxylic acid H NMR: (300 MHz, d6-DMSO) ~9.28 (d, J= 9Hz, lH), 8.50 (d, J= 4Hæ, lH), 7.70 (m, lH), 7.50 (s, lH), 7.45 (m, lH), 7.25 (m, 8H), 6.72 (s, lH), 5.90 (s, lH), 5.40 (m, lH), 3.80 (s, 3~), 2.85 (dd, J= 4, 18Hz, lH), 2.30 (m, lH), 1.90 (m, lH), and 1.65 (m, lH) `' ,c~ q~
IR (KBr): 3400-3000, 1758, 1671, 1619, 1589, 1532, and 1379 cm 1 MS: m/e 616 (M + 1) Analysis calculated for C29H25N705S2:
Calc.: C, 56.57; H, 4.09; H, 15.93;
Found: C, 55.11; H, 4.09; N, 15.30.
Example 39 Sodium 7~-[(2-aminothiazol-4-yl)-Z-methox-iminoacetylamino]-l-carba(l-dethia)-3-(2-aminothiazol-4-yl)-3-cephem-4-carboxylate 1H NMR: (300 MHz, d6-DMS0) 89.20 (d, J= 9Hz, lH), 7.15 (s, 2H~, 6.70 (s, lH), 6.60 (s, 2H), 6.55 (s, lH), 5.20 (m, lH), 3.78 (s, 3H), 3.62 (s, lH), 2.64 (dd J= 4, 18Hz, lH), 2.15 (m, lH), 1.75 (m, lH) and 1.60 (m, lH) IR (KBr): 3500-3100, 1744, 1661, 1607, 1591, 1527, 1382, 1350, and 1034 cm 1 . MS: m/e 485 (M ) Analysis calculated for C17H~6N705S2Na:
Calc.: C, 42.06; H, 3.32; N, 20.20;
Found: C, 42.38; H, 3.33; N, 18.59.
- 2~3~
Exam~le 40 Sodium 7~-~(2-aminothiazol-4-yl)-Z-methox-iminoacetylamino]-l-carba(l-dethia)-3-[2-(3,4-dihydroxy-phenyl)thiazol-4-yl]-3-cephem-4-carboxylate 1H NMR: (300 MHz, d6-DMSO) ~9.50 (s, lH), 9.25 (d, J= 9Hz, lH), 7.48 (m, lH), 7.28 (m, lH), 7.15 (m, 3H), 6.75 (d, J= 8Hz, lH), 6.70 (s, lH), 5.25 (m, lH), 3.80 (s, 3H), 3.72 (m, lH), 2.90, (dd, J= 4, 18 Hz, lH), 2.35 (m, lH), 1.88 (m, lH), and 1.65 (m, lH) IR (KBr): 3341, 3226, 2223, 1648, 1628, 1600, 1587, 1365, 1253, and 1159 cm 1 +
15 MS: m/e 579 (M + 1) Analysis calculated for C23H1gN6O7S2Na:
Calc.: C, 47.75; H, 3.31; N, 14.55;
Found: C, 42.41; H, 3.24; N, 12.35.
Residue: 7.69%
Exam~le 41 7~-(D-phenylglycylamino)-l-carba(l-dethia)-25 3-(2-aminothiazol-4-yl)-3-cephem-4-carboxylic acid H NMR: (300 MHz, D20) 87.60 (m, 5H), 6.60 (s, lH), 5.50 ~(d, J= 4Hz, lH), 5.22 (s, lH), 4.0 (m, lH), 2.70 (dd, J= 4, 18Hz, lH), 2.35 (m, lH), 1.78 (m, lH) and 1.35 (m, lH) q ~ Q`
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1-CARBA(DETHIA)CEPHALOSPORIN ANTIBIOTICS
In the field of antibacterial therapy, the need for new chemotherapeutic agents is one that will never extinguish. Mutant strains resistant to existing antibacterial agents are encountered frequently. To meet this need, considerable research effort continues to focus on such new agents.
The present invention provides various 3-(substituted or unsubstituted)thiazolo-l-carba(l-dethia)-cephems (i.e., l-carba(1-dethia)cephalosporins) useful as antibacterial agents against both gram-negative and gram-positive bacteria. The present invention provides 7~-(acylamino-1-carba(1-dethia) 3-substituted-3-cephem-4-carboxylic acids wherein the group at the 3-position is a 4-thiazole ring optionally substituted in the 2-position by nitro, cyano, phenyl, amino, halo, C1-C6 alkyl, C1-C6 substituted alkyl, an optionally-substi-tuted heterocyclic ring, substituted phenyl, or an acyl group. Also provided are novel 7-amino intermediates useful in the preparation of the compounds of the present invention. Also provided is a pharmaceutical 2 ~ 9 ~
formulation utilizing the compounds of the present invention and a method for treating antibacterial infections in man an other animals.
The present invention provides compounds of Formula (1):
Rl-N
,~ X (1) wherein X i9 a group selected from amino, halo, cyano, lS hydrogen, nitro, C1-C6 alkyl, C1-C6 substituted alkyl, a C3 to C6 heterocyclic ring containing 1, 2, or 3 nitrogen atoms and 0 or 1 sulfur or oxygen atoms, said ring optionally substituted by one or more groups selected from halo, nitro, hydroxy, C1-C6 alkyl, or Cl-C6 substituted alkyl;
phenyl, substituted phenyl or an acyl group of the formula O
Il R"C-, wherein R" is C1-C6 alkyl, C1-C6 substituted alkyl, phenyl, or substituted phenyl;
R3 is hydrogen, C1-C4 alkoxy, or a group of the formula -NHCH0; and R1 is an acyl group of the formula R2-C-, wherein R2 is hydrogen; Cl-C6 alkyl, C1-C6 alkyl substituted by cyano, carboxy, halogen, amino, C1-C4 alkoxy, Cl-C4 alkylthio, or trifluoromethylthio; a phenyl or substituted phenyl group represented by the formula a a''' ~
wherein a and a' independently are hydrogen, halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkanoyloxy, C1-C4 alkyl, C1-C4 alkylthio, amino, mono- or di(C1-C4 alkyl)amino, C1-C4 alkanoylamino, C1-C4 alkylsulfonylamino, carboxy, carbamoyl, hydroxymethyl, amino-methyl, or carboxymethyl;
a group represented by the formula <,~(Z)m- CH2--wherein a and a' have the same meanings as defined above, Z is 0 or S, and m is 0 or 1;
. .
a heteroarylmethyl group represented by the formula R~-CH2-wherein R1 is thienyl, furyl, benæothienyl, benzofuryl, indolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, and such heteroaryl groups substituted by 2~5~
amino, hydroxy, halogen, C1-C4 alkyl, Cl-C4 alkoxy, C1-C4 alkylsulfonylamino;
a substituted methyl group represented by the formula Q
wherein R2 is cyclohex-1,4-dienyl, or a phenyl group or substituted phenyl group represented by the formula a a~
wherein a and a' have the above defined meanings, or R2 is Rl as defined above, and Q is hydroxy, Cl-C4 alkanoyloxy, carboxy sulfo, or amino;
or R2 is a keto group or an oximino-substituted group represented by the formulae O N
wherein R3 is R1 or R2 as defined above and R4 is hydrogen, C1-C4 alkyl, or a group repre-sented by the formula :
-C-(CH2 ~nCOR5 b' wherein b and b' independently are hydrogen, or C1-C3 alkyl, and b and b' when taken together with the carbon to which they are bonded form a 3- to 6-membered carbocyclic ring, R5 is hydroxy, C1-C4 alkoxy, amino, C1-C4 alkyl-amino, or di(C1-C4 alkyl)amino, and n is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.
In the above Formula (1), one preferred R2 group is a keto group or an oximino-substituted group represented by the formulae O N
wherein R3 is Rl or R2 as defined above and R4 is hydrogen, Cl-C4 alkyl, or a group repre-sented by the formula b -C- ( CH2 ~nCORs wherein b and b' independently are hydrogen, : or Cl-C3 alkyl, and b and b' when taken together with the carbon to which they are bonded form 2~3~9~
a 3- to 6-membered carbocyclic ring, R5 y, C1 C4 alkoxy, amino, C1-C alkyl amino, or di(C1-C4 alkyl)amino, and n is 0, 1, 2, or 3.
A preferred Rl group is (2-aminothiazol-4-yl)methoximinoacetyl.
A further preferred R2 group is a substituted methyl group represented by the formula Rp-CH-Q
wherein R2 is cyclohex-1,4-dienyl, or a phenyl group or substituted phenyl group represented by the formula a ~ ~
<~ \~
a' ~
wherein a and a' have the above defined meanings, or R2 is R1 as defined above, and Q is hydroxy, C1-C4 alkanoyloxy, carboxy, sulfo, or amino.
A preferred R1 group is D-phenyl-glycyl.
As a further aspect of the present invention, there are provided intermediates of Formula (2) 2~3~
R1 b~
O ~ ~ X (2) wherein: Rl' is hydrogen or an amino protecting group;
R4 is hydrogen or a carboxy protecting group;
R3' is hydrogen, Cl-C4 alkoxy, or a group of the formula -NHCHO; and X is a group selected from amino, halo, cyano, hydrogen, nitro, Cl-C6 alkyl, Cl-C6 substituted alkyl, a C3 to C6 heterocyclic ring containing 1, 2, or 3 nitrogens and 0, or 1 sulfur or oxygen atoms, said ring optionally substituted by one or more groups selected from halo, nitro, hydroxy, Cl-C6 alkyl, or Cl-C6 substituted alkyl;
phenyl, substituted phenyl, or an acyl group of the formula o : R' " C-, wherein R " ' is Cl-C6 alkyl, Cl-C6 substituted ` alkyl, phenyl, or substituted phenyl. The compounds of formula (2) are useful as intermediates to the anti-bacterial agents of formula (1) In the above Formula (1), the term "Cl to C6 alkyl" denotes such radicals as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, tert-amyl, hexyl and the like. The preferred "Cl to C6alkyl" group is methyl.
The term "C1 to C6 substituted alkyl" denotes the above Cl to C6 alkyl groups that are substituted by one or two halogen, hydroxy, protected hydroxy, amino, protected amino, Cl to C7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carbamoyloxy, cyano, methylsulfonylamino, C1 to C4 alkoxy, phenyl, sub-stituted phenyl, or a C3 to C6 heterocyclic ring containing l, 2, or 3 nitrogen atoms and O or 1 sulfur or oxygen atoms, said ring optionally substituted by one or more groups selected from halo, nitro, hydroxy, or C1-C6 alkyl. The substituted alkyl groups may be substituted once or twice with the same or with different substituents.
Examples of the above substituted alkyl groups include cyanomethyl, nitromethyl, hydroxymethyl, trityl-oxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl, allyloxycarbonylmethyl, allyloxycarbonylaminomethyl, carbamoyloxymethyl, methoxymethyl, ethoxymethyl, t-butoxy methyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, 6-hydroxyhexyl, 2,4-dichloro(n-butyl), 2-amino(iso-propyl), 2-carbamoyloxyethyl chloroethyl, bromoethyl, fluoroethyl, iodoethyl, chloropropyl, bromopropyl, fluoropropyl, iodopropyl, phenylmethyl, phenylethyl, phenyl (3-pyridyl)methyl, phenyl(3-pyridyl)ethyl, and the like.
The term "C1 to Cg alkoxy" as used hereindenotes groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups.
The term "substituted phenyl" as used herein denotes a phenyl group substituted with one or two moieties chosen from the group consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, C1 to C6 alkyl, C1 to C~ alkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, aminomethyl, protected aminomethyl, trifluoromethyl or N-(methylsulfonylamino).
Examples of the term "substituted phenyl"
include a mono- or di(halo)phenyl group such as 4-chloro-phenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromo-phenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl and the like; a mono- or di(hydroxy)phenyl group such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as 3-or 4-nitrophenyl; a cyanophenyl group, for example, 4-cyanophenyl; a mono- or di(lower alkyl)phenyl group such as 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl, 4-(iso-propyl)phenyl, 4-ethylphenyl, 3-~n-propyl)phenyl and the like; a mono- or di(alkoxy)phenyl group, for example, 2,6-dimethoxyphenyl, 4-methoxyphenyl, 3-ethoxy-phenyl, 4-(iso-propoxy)phenyl, 4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl and the like; 3- or 4- tri-fluoromethylphenyl; a mono- or dicarboxyphenyl or (protected carboxy)phenyl group such as 4-carboxyphenyl or 2,4-di(protected carboxy)phenyl; a mono- or di-(hydroxymethyl)phenyl or (protected hydroxymethyl)-phenyl such as 3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)-phenyl or (protected aminomethyl)phenyl such as 2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)-phenyl; or a mono- or di(N-(methylsulfonylaminol)phenyl such as 3-(N-(methylsulfonylamino))phenyl. Also, the 9 ~
term "substituted phenyl" represents disubstituted phenyl groups wherein the substituents are different, for example, 3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy-4-chlorophenyl and the like. Preferred substituted phenyl groups include the 2- and 3-trifluoromethylphenyl, the 4-hydroxyphenyl, the 2-aminomethylphenyl and the 3-(N-(methylsulfonylamino))phenyl groups.
The terms "halo" and "halogen" refer to the fluoro, chloro, bromo or iodo groups.
The term "pharmaceutically-acceptable salt"
encompasses those salts that form with the carboxylate anions and includes salts formed with the organic and inorganic cations discussed above. Furthermore, the term includes salts that form by standard acid-base reactions with basic groups (such as amino groups) and organic or inorganic acids. Such acids include hydro-chloric, sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D-glutamic, d-camphoric, glutaric, phthalic, tartaric, lauric, stearic, salicyclic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic, and like acids.
The term "carboxy-protecting group" as used herein refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound.
Examples of such carboxylic acid protecting groups 2 ~
include 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxy-benzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylene-dioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4 "-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, ~-(trimethylsilyl)ethyl, ~-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)prop-1-en-3-yl, and like moieties. The species of carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the condition of subsequent reaction(s) on other positions of the molecule and can be removed at the appropriate point without disrupting the remainder of the molecule. In particular, it is important not to subject the carboxy-protected molecule to stxong nucleophilic bases or reductive conditions employing highly activated metal catalysts such as Raney nickel. (Such harsh removal conditions are also to be avoided when removing amino-protecting groups discussed below.) A preferred carboxylic acid protecting group is the allyl group. Similar carboxy-protecting groups used in the cephalosporin, penicillin and peptide arts can also be used to protect a carboxy group substituents~
Further examples of these groups are found in E. Haslam, "Protective Groups in Organic Chemistry", J.G.W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, and T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y., 1981, Chapter 5.
~ $ ~
X-79~7A - 12 -A related term is "protected carboxy", which refers to a carboxy group substituted with one of the above carboxy-protecting groups.
The term "amino-protecting group" as used herein refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups on the compound. Examples of such amino-protecting groups include the formyl group, the trityl group, the t-butoxycarbonyl group, the phthalimido group, the trichloroacetyl group, the chloroacetyl, bromoacetyl and iodoacetyl groups, urethane-type blocking groups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, 2-(4-xenyl)iso-propoxycar-bonyl, l,l-diphenyleth-1-yloxycarbonyl, 1,1-diphenyl-prop-l-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-~p-toluyI)prop-2-yloxycarbonyl, cyclopentanyloxy-carbonyl, 1-methylcyclopentanyloxycarbonyl, cyclo-hexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)-ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, 9-fluorenyl-methoxycarbonyl ("FMOC"), 2-(trimethylsilyl)ethoxy-carbonyl, allyloxycarbonyl, l-(trimethylsilylmethyl)-prop-l-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxy-carbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropyl-2 ~
methoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl, iso-bornyloxycarbonyl, 1-piperidyloxycarbonyl and the like;
the benzoylmethylsulfonyl group, the 2-(nitro)phenyl-sulfenyl group, the diphenylphosphine oxide group and like amino-protecting groups. The species of amino-protecting group employed is not critical so long as the derivatized amino group is stable to the condition of subsequent reaction(s) on other positions of the mole-cule and can be removed at the appropriate point without disrupting the remainder of the molecule. Preferred amino-protecting groups are the allyloxycarbonyl, the t-butoxycarbonyl, and the trityl groups. Similar amino-protecting groups used in the cephalosporin, penicillin and peptide art are also embraced by the above terms. Further examples of groups referred to by the above terms are described by J.W. Barton, "Pro-tective Groups In Organic Chemistry", J.G.W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 2, and T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, N.Y., 1981, Chapter 7.
The related term "protected amino" defines an amino group substituted with an amino-protecting group dis-cussed above.
In Formulae (1) and (2) above, when X is a C3-C6 heterocyclic ring containing 1, 2, or 3 nitrogen atoms and 0 or 1 sulfur or oxygen atoms, (i.e., a heterocyclic ring containing from 3 to 6 carbon atoms, 1, 2, or 3 nitrogen atoms and 0 or 1 sulfur or oxygen atoms) said ring optionally substituted by one or more halo, nitro, hydroxy, C1-Cff alkyl, or Cl-C6 substituted alkyl groups, examples of such rings include pyrrolyl, furanyl, 4-nitrothiazol-2-yl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, morpholinyl, oxazolyl, thiazolyl, 203~3~
thiadiazolyl, oxadiazolyl, l-methyl-3-pyridyl, 2-methyl-3-pyridyl, 3-methyl-4-nitro-imidazol-2-yl, and the like.
One intermediate (VI) can be prepared according to the following Scheme (A) OCH2CNH~
~L Cf~
CO2CH2 ~NO2 I~i, ~ OCH2CN
H~ ~
l CH2 o _N~ 11 OCH2CH, co2CH2 ~N2 l ~U) OCH2CNH~
~N ~ tOCH2CH3 2 5 C02CH2 ~N2 o l~lU~
3 0 ~ OCH*
N~,_~
OCH2CH~
~OCH*H3 ~ [V) CO2CH2 ~3No7 ' :
~3~
X-7967A - lS -o OCH2CN~ ~
FIN~ j~CH~ (V) CO2CH2 ~NO~
I~v~
+ ~CH2CNH~
~N~CI12Elr ~Vl) C0*H2 aNO2 I ~vi~
According to Scheme A, p-NO2 benzyl-7~-phenoxy-acetylamino-l-carba(l-dethia)-3-trifluoromethanesulfonyl-oxy-3-cephem-4-carboxylate (which can be prepared according to the method of Evans et al., U.S. Patent No. 4,673,737, incorporated herein by reference) is reacted with a compound of the formula CH2=C(OCH2CH3)-(Sn(X)3), wherein X is methyl or n-butyl, LiCl, and . - (CH3CN~2PdCl2 in a polar organic solvent, preferably N,N'-dimethylformamide to provide (II~. Further details of this type of transformation can be found in Cook et al. U.S. Patent No. 4,855,418, incorporated herein by reference. Compound (II~ can then be converted to the 3-(2-bromo-1,1-diethoxyethyl~ compound (III) with Br2/CCl4 in ethanol/CH2Cl2 using a base such as 2,6-lutidine.
Reactions (iii) and (iv) depict a methodwhereby the 7-phenoxyacetyl group may be replaced by the t-butoxycarbonyl group. First, compound (III) is ~.
~3~
acylated with di-tert-butoxydicarbonate in the presence of a base such as dimethylaminopyridine.
Secondly, the phenoxyacetyl group is displaced with a base such as LioH in a polar solvent such as tetrahydrofuran. Further description of this exchange can be found in Blaszczak et al., European Patent Appli-cation No. 88306996.5.
Finally, the 3-bromomethylcarbonyl compound (VI) can then be prepared from compound V by an acid catalyzed hydrolysis reaction with, for example, acetic acid in acetonitrile/water.
Compounds of Formula (1) can then be made from intermediate (VI) above by the following Scheme (B):
ol + OCH2CNH~r~
--N~ CH2Bt ( Vl ) COqCU2 aNO2 'I (vi) ~ OCH2CNH ~
p ~ ~ ~v~) COqCH2 ~NO2 (V~i) + OCH2CNH~
O
I
2 ~3 ~
X-7967A - 17 - ~
R1-NH ~
~ N ~ ~ X
In the above step (vi), the 3-(2-substituted) thiazolo compounds may be synthesized by reaction of intermediate (VI) with a compound of the formula S
Il H2N-C-X, wherein X is as defined in Formula 1, above. Thus, with the desired 3-(2-substituted thiazol-4-yl) sub-stituent in place, and with the de-esterification of the 4-p-nitrobenzyl ester occasionally occurring under the previously defined reaction conditions, the 4-carboxy position may be re-esterified to the 4-allyl ester using allyl bromide, NaI, (CH3CH2CH2CH2)4NHS04, and NaHCO3 in N,N'-dimethylformamide. If deesterifi-cation does not occur under these conditions, the p-nitrobenzyl protecting group may be removed by zinc reduction in a solvent mixture of N,N'-dimethyl-formamide/tetrahydrofuran/acetic acid or N,N'-dimethyl-formamide/tetrahydrofuran in HCl and reesterified as described above to the 4-allyl ester. The resulting amino protected, carboxy protected "nucleus" (i.e., formula (2)) can then be treated with p-toluenesulfonic acid H2O or trifluoroacetic acid to remove the 7-t-butoxycarbonyl group to provide the 7-amino 4-carboxy 2~3~
protected intermediate. Further, the 7-amino group can then be acylated with an activated form of the desired R1 substituent using standard procedures well-known in the ~-lactam art. Finally, all remaining amino and~or carboxy protecting groups can then be removed using conventional methodology.
The 7~-acylamino-7~-substituted-l-carbacephalo-sporins represented by Formula (1) wherein R3 is C1-C~
alkoxy can be prepared according to the method described by Koppel, U.S. Patent No. 3,994,885, incorporated herein by reference.
T~e 7~-formamido substituted compounds wherein R3 is -NHCHO can be obtained by the method described by Millner, U.S. Patent No. 4,539,159 incorporated herein by reference. According to this method, a 7~-acylamino-or 7~-protected amino-7~-methylthio-substituted 1-carbacephalosporin is reacted with anhydrous ammonia or an ammonium salt in the presence of mercuric acetate to form the corresponding 7~-amino derivative. The latter is formylated to the 7a-formamido derivative.
One skilled in the art will appreciate that although the above manipulations utilized phenoxyacetyl and t-butyloxycarbonyl as amino protecting groups and the p-nitrobenzyl group as carboxy-protecting group, there are many which would be equally efficacious.
The 1-carbacephalosporins provided by the invention form salts with suitable bases, in partic-ular, the pharmaceutically-acceptable, non-toxic salts.
The C-4 carboxy group of the 1-carbacephalosporin can form salts with the alkali and alkaline earth metal hydroxides, carbonates and bicarbonates. Examples of such pharmaceutically-acceptable salts are the sodium, 2~6~ ~
potassium, calcium and magnesium salts. Salts also may be formed with amines such as dibenzylamine, cyclohexyl-amine, triethylamine, ethanolamine, di-ethanolamine and like amines. Likewise, when the 1-carbacephalosporin is substituted by two or more carboxy groups, di- and tri-salts are obtained by conventional salt-forming methods.
The pharmaceutically-acceptable, non-toxic salts can be useful forms of the antibiotics for pre-paring antibiotic formulations.
This invention also provides a method for - treating infectious diseases in man and other animals caused by bacteria and pharmaceutical formulations suitable for administration in the treatment method.
The therapeutic method of this invention comprises administering to man or other animals an antibiotically effective non-toxic dose of a compound represented by Formula (1) or a pharmaceutically acceptable salt thereof.
An antibiotically effective amount is an amount between about 25 mg and about 2 grams. The compound or salt may be administered in a single . dose or in multiple doses throughout the day. Treat-ment may continue for a week to ten days or longer depending upon the duration of the infection. The particular dose and regimen can depend on such factors as the weight and age of the patient, the particular causative organism, the severity of the infection, the general health of the patient, and the tolerance of the individual to the antibiotic.
9 ~
The l-carbacephalosporins may be administered parenterally, orally, subcutaneously or rectally. AS
with other ~-lactam antibiotics, the method of this invention may be used prophylactically to prevent infections after exposure or before possible exposure, e.g., preoperatively. The antibiotic 1-carbaceph-alosporins may be administered by conventional methods, e.g., in capsules, tablets, by syringe, or by intra-venous drip.
The pharmaceutical formulations of the inven-tion comprise an antibiotically effective non-toxic amount of a l-carbacephalosporin represented by Formula (1) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Formulations for oral administration include capsules, tablets, lozenges and liquid suspensions.
The antibiotic or a salt thereof in the form of a dry powder can be encapsulated in gelatin capsules for oral use. The antibiotic may also be blended with an excipient, e.g., a stabilizer, prior to filling.
Capsules may contain between about 100 mg and about 500 mg to provide unit dosage formulations.
Tablets containing between about 100 mg and 500 mg of the antibiotic or a pharmaceutically accept-able salt thereof can be formulated by conventionalmeanæ and may contain in addition a binding agent, disintegrating agent, stabilizing agent, antioxidant, etc.
Liquid preparations of the antibiotic may be prepared for infant and geriatric use. Pediatric sus-pensions can be formulated with the antibiotic oral 2 ~ 3 ~
excipients such as suspending agents, flavoring agents, stabilizers and the like. Solutions of the antibiotics likewise may be formulated with solubilizing agents, flavoring agents, sugar, water, etc.
Parenteral formulations of the antibiotics for injection are formulated with Water-for-Injection, Ringer's solution, physiological saline or glucose solution. The antibiotic also may be administered in an intravenous fluid by the drip method.
For parenteral use, the antibiotic or a phar-maceutically acceptable salt thereof, can be made up preferably in dry crystalline powder form or as a lyophilized powder and filled into vials. Such vials may contain between about 100 mg and about 2 grams of antibiotic per vial.
The following Experimental Section provides further examples of the various aspects of the present invention but is not to be construed as limiting the scope therefor.
Experimental Section . Preparation 1 p-Nitrobenzyl 7~-phenoxyacetylamido-1-carba(l-dethia)-3-trifluoromethanesulfonyloxy-3-cephem-4-carboxylate The title compound can be prepared according to the method of Evans and Sjogren, U.S. Patent No.
4,673,737, incorporated herein by reference.
~3~
PreParation 2 Trimethyl(l-ethoxy-e~hen-l-yl)stannane (Ref: Organometallics, Vol. 1, No. 6, 1982, J.
Soderquist) A 19.18 ml (14.48 g, 200.36 mmol) sample of ethoxyethylene was dissolved in 100 ml of tetrahydrofuran, cooled to -78C, and treated with a solution of t-butyl-lithium (94.1 ml, 150.56 mmol, 1.6M) over 20 min. under argon. The reaction mixture was then allowed to warm to 0C over 35 min. and added via cannula to a -78C
solution of 20.0 g (100.4 mmol) of chlorotrimethyi-stannane in 40 ml of tetrahydrofuran and allowed to warm to room temperature gradually. After an additional 50 min., the mixture was guenched with saturated NH4Cl solution (400 ml) and extracted with diethyl ether (500 ml). The ether solution was then dried over anhydrous Na2SO4, filtered and concentrated to provide the crude product as a yellowish liquid (23.8 g; 100%). The crude product was then distilled at 40-41C and about 4 mm Hg to provide 12.05 g of the title compound.
lH NMR (300 MHz, CDCl3) ~4.65 (s, lH), 4.10 (s, lH), 3.70 (g, 2H), 1.25 (t, 3H~, and 0.18 (s, 9H).
2 ~
Preparation 3 p-Nitrobenzyl 7~-phenoxyacetylamino-1-carba(l-dethia)-3-(l-ethoxy-ethen-1-yl)-3-cephem-4-carboxylate.
A 1.0 g (1.77 mmol) sample of the title compound of Preparation 1, a 0.142 g (3.34 mmol) sample of lithium chloride, and a 0.043 g (0.167 mmol) sample of dichloropalladium (II) diacetonitrilate were dissolved in 3 ml of dimethylformamide and treated with 0.435 g (1.84 mmol) of trimethyl (l-ethoxy-ethen-l-yl)stannane.
The reaction was then gently warmed with a hot air gun for about 10 seconds, and allowed to stir at room temperature for about one hour. The reaction mixture was poured into 100 ml 1:1 mixture of ethyl acetate/
diethyl ether and 100 ml 10:1 mixture Brine/satd.
NaHCO3 solution. Organics were separated and dried over Na2SO4, filtered, and concentrated ln vacuo. Resultant crude dark oil was then diluted with 2 ml CH2Cl2 and 5 ml diethyl ether and 20 ml of hexane. A dark oil again resulted. Supernatant was decanted and to it was added an additional 40 ml hexane. Desired precipitated as a solid which was filtered and washed with hexane and dried to give 87 mg of the desired compound. The dark oil was chromatographed on 50 g of silica gel using 15-25% ethyl acetate/CH2Cl2 as eluent. The resulting product fractions were concentrated ln vacuo and treated with ~0 ml Et2O to provide 550 mg of the title compound (total yield 637 mg, 74%).
~3~L~
lH NMR: (300 MHz, CDC13) ~8.20 (d, J= 9Hz, 2H), 7.60 (d, J= 9Hz, 2H), 7.35 (t, J= 8Hz, 2H), 7.10 (m, 2H~, 6.90 (d, J= 8Ez, 2H), 5.45 (dd, J= 5,7Hz, lH), 5.37 (AB, 2H), 4.58 (S, 2H), 4.21 (d, J= 3 Hz, lH), 4.18 (d, J= 3Hz, lH), 3.95 (m, lH), 3.75 (m, 2H), 2~70 (dd, J= 4, 18Hz, lH), 2.30 (m, lH), 2.05 (m, lH), 1.50 (m, lH) and 1.25 (t, J= 7Hz, 3H) IR: (CHCl3) 3028, 1772, 1734, 1691, 1524, 1496, 1389, 1299, 1277, and 1207 cm 1 MS: m/e 521 (M ) Analysis Calculated for C27H27N3O8:
Calc.: C, 62.18i H, 5.22; N, 8.06;
Found: C, 62.43; H, 5.36; N, 8.30.
Preparation 4 p-Nitrobenzyl 7~-phenoxyacetylamino-1-carba(l-dethia)-3-(2-bromo-1,1-diethoxyethyl)-3-cephem-4-carboxylate A 570 mg sample of the material from Prepara-tion 4 was dissolved in 4.5 ml of ethanol/2 ml of CH2Cl2 and cooled to 0C. The solution was then treated with 0.153 ml (1.312 mmol) of 2,6-lutidine and 1.1 ml (1.1 mmol) of a 1.0 M Br2/CCl4 solution. The resulting mixture was then poured into a mixture of saturated sodium bicarbonate solution and 1:1 ethyl acetate/diethyl ether. The organic layer was separated, dried over 2 ~ 3 i~
anhydrous Na2S0~, filtered, and concentrated to provide a yellow foam which was used directly in the next step.
A 25 mg sample of the above product was purified over a silica gel (2.5 g) column using 7%
ethyl acetate/CH2Cl2 as eluent to provide 20 mg of the title compound.
lH NMR (300 NHz, CDCl3) ~8.23 (d, J= 9Hz, 2H), 7.60 (d, J= 9Hz, 2H) 7.35 (t, J= 8Hz, 2H), 7.10 (m, 2H), 6.95 (d, J= 8Hz, 2H), 5.35 (AB, 2H) 5.32 (dd, J= 5, 7Hz, lH), 4.58 (s, 2H), 3.95 (m, lH) 3.3-3.6 (2m, 4H), 2.48 (dd, J= 2, 16Hz, lH), 2.20 (m, lH) 2.05 (m, lH) 1.45 (m, lH) 1.16 (t, J= 4Hz, 3H) and 1.10 (t, J= 4Hz, 3H) IR: (CHCl3) 3019, 1772, 1751, 1749, 1695, 1349, 1290, }206 and 1073 cm 1 MS: m/e 646 (M + 1) Analysis Calculated for CpgH32N309Br:
Calc.: C, 53.88; H, 4.99; N, 6.50;
Found: C, 53.59; H, 4.75; N, 6.77.
., Preparation 5 p-Nitrobenzyl 7~-phenoxyacetyl-t-butyloxycarbonylamino-l-carba(l-dethia)-3-(2-bromo-1,1-diethoxy)-3-cephem-4-carboxylate A 700 mg sample of the product of preparation 4 ~as dissolved in 10 ml of CH2C12 at room temperature 2 ~ 3 ~
and treated with 0.256 ml (1.126 mmol) of di-tert-butyl dicarbonate, followed by 132 mg (1.08 mmol) of 4-dimethylaminopyridine and stirring for 30 min. An additional 50 ~1 of di-tert-butyl dicarbonate was added and the reaction stirred for about 30 min. The reaction mixture was chromatographed directly over a silica gel column (40 g) using 20-30% ethyl acetate/CH2Cl2 as eluent to provide 730 mg (90.5%) of the title compound.
lH NMR: (300 MHz, CDCl3) ~8.23 (d, J= 9Hz, 2H), 7.62 (d, J= 9Hz, 2H), 7.30 (t, J= 8Hz, 2H), 7.0 (m, 2H), 6.95 (d, J= 8Hz, 2H~, 5.70 (d, J= 4Hz, lH~, 5.35 (AB, 2H), 5.18 (d, J= 3Hz, 2H), 3.86 (m, lH), 3.35-3.7 (m, 4H), 2.5 (dd, J= 2, 18Hz, lH), 2.18 (m, lH), 1.85 (m, lH) 1.55 (s, 9H) 1.50 (m, lH) 1.16 (t, J= 4Hz, 3H) and 1.10 (t, J= 4Hz, 3H) IR: (CHCl3) 3019, 1791, 1747, 1349, 1226, 1205, and 1145 cm~l MS: m/e 672 (M -OC4Hg) Analysis Calculated for C34H40N3O11Br:
Calc.: C, 54.70; H, 5.40; N, 5.63;
Found: C, 53.55; H, 4.48, N, 6.42.
2~3~9~
Preparation 6 p-Nitrobenzyl 7~-t-butyloxycarbonylamino-1-carba (l-dethia)-3-(2-bromo-1,1-diethoxyethyl-3-cephem-4-carboxylate A 750 mg (O.957 mmol) sample of the product of Preparation 5 was dissolved in 8 ml of tetrahydro-furan, treated with 0.85 ml (0.85 mmol) of 1.0 M
lithium hydroxide soln. and sonicated. A further 0.155 ml portion of lithium hydroxide was added and sonication continued for 30 min. The reaction mixture was then poured into 50 ml of saturated sodium bicarbonate/75 ml ethyl acetate solution. The organic phase was separated and dried over anhydrous Na2 S04, filtered, and concen-trated to provide 410 mg of the product as a foam after column chromatography over silica gel (8% ethyl acetate/
CH2Cl2 ) -The above chromatography provided 176 mg of starting material which was re-submitted to the above conditions to obtain 102 mg of the title compound.
Total yield = 512 mg (86.6%).
1~ NMR: (300 MHz, CDCl3) ~8.23 (d, J= 9Hz, 2H), 7.61 (d, J= 9Hz, 2H), 5.35 (AB, 2H), 5.01 (m, lH), 5.09 (m, lH), 3.85 (m, lH), 3.3-3.6 (m, 4H), 2.47 (dd, J= 2, 16Hz, lH), 2.20 (m, lH), 2.10 (m, lH), 1.43 (s, 9H), 1.12 (t, J= 4Hz, 3H), and 1.08 (t, J= 4Hz, 3H) IR: (CHCl3) 1769, 1741, 1716, 1524, 1349, 1224, 1207, and 1160 cm 1 ~ ~ 3 ~
MS: 611 (M ) Analysis Calculated for C2 6H3~N3OgBr:
Calc.: C, 50.99; H, 5.60; N, 6.86;
Found: C, 51.99; H, 5.16; N, 7.67.
Preparation 7 p-Nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(2-bromomethylcarbonyl)-3-cephem-4-carboxylate A 125 mg (0.204 mmol) sample of the product of Preparation 6 was dissolved in 1.2 ml of acetonitrile/
0.25 ml of acetic acid/0.05 ml H2O and stirred for about 2 hours. The reaction mixture was then poured into ~50 ml) saturated sodium bicarbonate solution/(100 ml) 1:1 ethyl acetate/diethyl ether solution. The organic phase was separated, dried over anhydrous Na2SO4, filtered, and concentrated to provide 111 mg (about 100%) of the title compound as a white solid.
1H NMR: (300 MHz, CDCl3) ~8.20 (d, J= 9Hz, 2H), 7.62 (d, J= 9Hz, 2H), 5.33 (AB, 2H), 5.28 (dd, J= 4,7Hz, lH), 5.25 (d, J= 4Hz, lH), 4.03 (AB, 2H), 3.87 (m, lH), 2.80 (dd, J= 4,18Hz, lH), 2.45 (m, lH), 2.13 (m, lH) 1.57 (m, lH), and 1.4 (s, 9H) IR: (CHCl3) 3019, 1782, 1718, 1525, 1369, 1291, and 1159 cm 1 MS: m/e 480 (M+-C4Hg) Analysis Calculated for C22H24N3O8Br:
Calc.: C, 49.08; H, 4.49; N, 7.81;
Found: C, 49.29; H, 4.64; N, 7.62.
ExamPle 1 7~-t-butoxycarbonylamino-1-carba(1-dethia)-3-(2-phenyl-thiazolo)-3-cephem-4-carboxylic acid A 75 mg (0.140 mmol) sample of p-nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(1-dethia)-3-bromo-methylcarbonyl)-3-cephem-4-carboxylate (Preparation 7) was dissolved in 1.5 ml of isopropanol and 1 ml of 1,1,2-trichloroethane, followed by the addition of 20 mg (0.146 mmol) of phenylthiocarbamate. The reaction mixture was then heated to about 65C for 1.5 hours.
The reaction mixture was concentrated ln vacuo and treated with 3 ml of diethyl ether/4 ml hexane. The resulting solid (85% yield) was dried to provide the title compound.
Example 2 7,B-t-butoxycarbonylamino-l-carba(l-dethia)-3-(2-(4-NO2-- 3-methylimidazol-2-yl)-thiazol-4-yl-3-cephem-4-carboxylic acid A 127 mg sample of p-nitrobenzyl 7~-t-butoxy-carbonylamino-1-carba(1-dethia)-3-bromomethylcarbonyl-4-carboxylic acid was reacted with 4-NO2-3-methyl imidazolo thiocarbamate in a manner analogous to that of Example 1. Column chromatography ethylacetate/CH2Cl2 with a trace of acetic acid provided 85 mg of the title compound.
Example 3 p-Nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(2-(phenyl)(2-pyridyl)methylthiazol-4-yl)-3-cephem-4-carboxylate The title compound was prepared in a manner analogous to that of Example 1 (without deesterification) utilizing phenyl-2-pyridylthiocarbamate 710 mg (97.3%) lH NMR: (300 MHz, CDC13) ~8.60 (dd, J= 4, 9Hz, lH), 8.05 (d, J= 9Hz, 2H), 7.60 (m, 9H), 5.83 (d, J= 4Hz, lH), 5.15 (m, 3H), 4.70 (m, lH), 3.90 (m, lH), 2.92 (dd, J= 4, 18Hz, lH), 2.50 (m, lH), 2.20 (m, lH) 1.70 (m, lH) and 1.~8 (s~ 9H) Example 4 7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(2-phenylthiazol-4-yl)-3-cephem-4-carboxylic acid A 430 mg (0.746 mmol) sample of p-nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(2-phenyl-thiazol-4-yl)-3-cephem-4-carboxylate was dissolved in 5 ml dimethylformamide/6 ml tetrahydrofuran/4 ml acetic acid along with 200 mg (2.98 mmol) of Zn. Upon comple-tion, the reaction mixture was diluted with CH2Cl2 and filtered through filter (celite) aid. The organic phase was then washed sequentially with H2O, lN HCl, and NaHCO3 solution. The NaHCO3 solution was layered with CH2Cl2, acidified to a pH of 2. The CH2Cl2 layer was separated and the aqueous portion extracted with CH2C12.
2 ~ a The combined CH2Cl2 portions were dried over anhydrous Na2SO4, filtered, and concentrated. Crystallization over diethyl ether/hexane provided 270 mg (82.3%) of the title compound.
Example 5 p-Nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(2-aminothiazol-4-yl)-3-cephem-4-carboxylate A 600 mg (1.115 mmol) sample of p-nitrobenzyl-7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(bromo-methylcarbonyl)-3-cephem-4-carboxylate was dissolved in 15 ml of isopropanol/10 ml 1,1,2-trichloroethane along with 0.146 ~1.25 mmol) of 2,6-lutidine followed by 88.4 15 mg (1.16 mmol) of thiourea. -Workup analogous to that described above provided 220 mg of the title compound.
lH NMR: (300 MHz, CDCl3) 88.22 (m, 2H), 6.90 (m, lH), 6.58 (m, lH) 6.10 (s, 2H) 5.35 (m, 3H), 3.85 (m, lH), 2.85 (m, lH), 2.58 ~m, lH), 2.40 (m, lH), 1.80 (m, lH), and 1.45 (s, 9H) ExamPle 6 p-Nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(2-(2,3-dihydroxyphenyl)thiazol-4-yl)-3-cephem-4-carboxylate In a manner analogous to preceding examples, 3,4-dihydroxyphenylthiocarbamate was utilized to provide the title compound (380 mg).
2~3~
lH NMR: (300 ~Hz, CDCl3) ~7.90 (m, 2H), 7.40 (m, lH), 7.12 (m, 3H), 6.98 (s, lH), 6.84 (m, lH), 5.20 (m, 4H), 4.05 (m, lH), 2.84 (dd, J= 4, 18Hz, 1~) 2.35 (m, lH), 2.15 (m, lH), 1.75 (m, lH), and 1.45 (s, 9H) Example 7 p-Nitrobenzyl 7~-t-butoxycarbonyl-l-carba(l-dethia)-3-(2-(2,3-di-(t-butyldimethylsilyloxy)phenyl)thiazol-4-yl~-3-cephem-4-carboxylate A 370 mg sample of the compound produced in Example 6 above was dissolved in 4 ml of dimethyl-formamide and treated with 184 mg of t-butyldimethyl-silylchloride and 85 mg of imidazole and stirred for about 24 hours. An additional 180 mg of t-butyl-dimethylsilyl chloride and 90 mg of imidazole were added and the solution stirred an additional 24 hours.
The reaction mixture was then diluted with 100 ml of ethyl acetate and 100 ml of H2O. The organic phase was separated and washed with lO0 ml of saturated NaHCO3 solution. The organic phase was then dried over anhydrous Na2SO4 and purified over (50 g) silica gel using ethyl acetate as eluent. Further chromatography over silica gel (25% ethyl acetate/hexane) provided 320 mg of p-nitrobenzyl 7~-t-butoxycarbonylamino-1-carba(1-dethia)-3-(3,4-di(t-butyldimethylsilyloxy)-phenylthiazol-4-yl-3-cephem-4-carboxylate.
H NMR: (300 MHz, CDCl3) ~8.0 (d, J= 9Hz, 2H), 7.32 (m, 2H), 7.22 (d, J= 9Hz, 2H), 7.05 (s, lH), 6.80 (m, lH), 5.28 (AB, 2H), 5.22 (m, lH), 5.05 (m, lH~, 3.95 tm, lH), 2.95 (dd J= 4, 18Hz, lH), 2.55 (m, lH), 2.20 (m, lH), 1.70 (m, lH), 1.42 (s, 9H) 1.0 (s, 9H), 0.97 (s, 9H), 0.23 (s, 6H), and 0.20 (s, 6H) Example 8 Allyl 7~-t-butoxycarbonylamino-1-carba(1-dethia)-3-(2-(2,3-di-(t-butyldimethylsilyloxy)phenyl)-3-cephem-4-carboxylate A. Removal of p-nitrobenzyl ester A 320 mg (0.382 mmol) sample of the title compound from Example 7 was dissolved in 2.5 ml of dimethylformamide/3 ml of tetrahydrofuran and 2.5 ml of acetic acid, treated with 100 mg (1.53 mmol) of Zn dust and stirred for 20 min. The reaction mixture was then treated with an additional 1 ml of acetic acid and 100 mg of Zn. After lh, the reaction mixture was filtered, diluted with ethyl acetate and washed with water. The organic phase was then dried and concentrated in vacuo azeotroping any remaining dimethylformamide away with toluene (5 times) to provide the title compound as a foam (220 mg, 82%) (some desilylation occurred)~
B. Formation of allyl ester A 215 mg (0.306 mmol) sample of the product from part A above is reacted with allyl bromide in 2 ~
dimethylformamide in the presence of tetra-n-butyl-ammonium hydrogen sulfate, sodium bicarbonate and sodium iodide to provide the title compound.
Example 9 Allyl 7~-t-butoxycarbonylamino-1-carba(l-dethia)-3-(2-phenylthiazol-4-yl)-3-cephem-4-carboxylate A 103 mg 0.234 mmol) sample of 7~-t-butoxy-carbonylamino-1-carba(l-dethia)-3-(2-phenylthiazol-4-yl)-3-cephem-4-carboxylic acid, prepared according to the foregoing examples, was dissolved in a small amount of N,N-dimethylformamide, treated with 60 mg (0.70 mmol) of NaHC03 and stirred for 10 min. The reaction mixture 15 was then treated with 83 mg (0.246 mmol) of tetra-n-butylammonium hydrogen sulfate, allowed to stir for 10 min., followed by treatment with 26 ~1 (0.294 mmol) of allyl bromide (followed by a additional 10~1) and 109 mg (0.725 mmol) of NaI. After stirring at room temperature overnight, the reaction mixture was poured into 30 ml of saturated NaHC03 solution and 50 ml of ethyl acetate. The organic phase was separated and washed (2x30 ml) with 0.5 N HCl solution, dried over anhydrous Na2 S04, filtered and concentrated ln vacuo to 25 provide the title compound. (100 mg, 89.3%, isolated as a solid from diethyl ether/hexane.) lH NMR: (300 MHz, CDCl3) ~7.90 (m, 2H), 7.40 (m, 3H), 7.15 (s, lH), 5.78 (m, lH), 5.10 (m, 4H), 4.65 (ABX, 2H), 30 3.90 (m, lH), 2.95 (dd, J= 4, 18Hz, lH), 2.50 (m, lH), 2.20 (m, lH), 1.70 (m, lH) and 1.45 (s, 9H).
.
.
~ 3 IR: (CHCl3) 1769, 1718, 1506, 1369, 1248, and 1161 cm 1 MS: m/e 482 (M + 1) AnalysiS Calculated for C2sH27N3sS:
Calc.: C, 62.35; H, 5.65; N, 8.73;
Found: C, 64.23; H, 5.81; N, 8.93.
Examples 10-18 According to the general methodolo~y of Example 9 and the preceding Examples, the followin~
compounds were prepared.
10. Allyl 7~-t-butoxycarbonylamino-l-carba-(1-dethia)-3-[2-(5-nitrothiazol-2-yl)thiazol-4-yl]-3-cephem-4-carboxylate lH NNR: (300 MHz, CDCl3) ~8.55 (s, lH), 7.43 (s, lH), 5.85 (m, lH), 5.25 (m, 3H), 5.10 (m, lH), 4.75 (ABX, 2H), 4.95 (m, lH), 2.98 (dd, J= 4, 18Hz, lH), 2.55 (m, lH), 2.23 (m, lH), 1.70 (m, lH) and 1.45 (s, 9H) IR: (CHCl3) 2976, 1772, 1719, 1390, 1351, 1251, and 1159 cm 1 MS: m/e 534 (M + 1) Analysis Calculated for C22H23NsO7S2:
Calc.: C, 49.52; H, 4.35; N, 13.13;
Found: C, 50.90; H, 4.33; N, 13.23.
11. Allyl 7~-t-butoxycarbonylamino-1-carba-(l-dethia)-3-[2-(4-fluorophenyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, C~C13) ~7.90 (m, 2H), 7.19 (s, lH), 7.12 (m, 2H), 5.8 (m, lH), 5.15 (m, 4H), 4.70 (ABX, 2H), 3.90 (m, lH), 2.95 (dd J= 4, 18Hz, lH), 2.50 (m, lH), 2.20 (m, lH), 1.70 (m, lH), and 1.45 (s, 9H) IR: (KBr) 3019, 2977, 1770, 1719, 1393, 1336, and 1157 cm MS: m/e 499 (M ) Analysis Calculated for C25H26N3O5SF:
Calc.: C, 60.10; H, 5.25; N, 8.41;
Found: C, 62.52; H, 5.57; N, 8.42.
12. Allyl 7~-t-butoxycarbonylamino-1-carba-(l-dethia)-3-[2-(4-pyridyl)thiazol-4-yl]-3-cephem-4-carboxylate ; 1H NMR: (300 MHz, CDCl3) ~8.72 ((d, J= 9Hz, 2H), 7.75 (d, J= 9Hz, 2H), 7.30 (s, lH), 5.80 (m, lH), 5.20 (m, 4H), 4.70 (ABX, 2H), 3.95 (m, lH), 3.0 (dd J= 4, 18Hz, lH), 2.58 (m, lH), 2.25 (m, lH), 2.25 (m, lH), 1.75 (m, lH), and 1.50 (s, 9H) IR: (CHCl3) 3020, 1771, 1718, 1505, 1393, 1348, 1248, and 1161 cm 1 ~3~
MS: m~e 482 (M ) A~alysis Calculated for C2~H2GN~O5S --Calc.: C, 59.74; H, 5.43; N, 11.61;
Found: C, 58.47; H, 5.23; N, 11.25.
13. Allyl 7~-t-butoxycarbonylamino-1-carba-(l-dethia)-3-[2-(3-methyl-4-nitroimidazol-2-yl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl3) ~8.10 (s, lH), 7.40 (s, lH), 5.62 (m, lH), 5.25 (m, 3H), 5.08 (d, J= 8Hz, lH), 4.70 (d, J= 6Hz, 2H), 4.48 (s, 3H), 3.95 (m, lH), 3.0 (dd J= 4, 18Hz, lH), 2.58 (m, lH), 2.25 (m, lH), 1.75 (m, lH), and 1.48 ~s, 9H) IR: (CHCl3) 3018, 1772, 1719, 1530, 1472, 1365, 1270, and 1161 cm 1 MS: m/e 530 (M ) 14. Allyl 7~-t-butoxycarbonylamino-1-carba-(l-dethia)-3-[2-(1,1-(2-pyridyl)(phenyl)methyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl3) ~8.60 (d, J= 4Hz, lH) 7.63 (t, J- 9Hz, lH), 7.30 (m, 5H), 7.18 (m, 2H), 7.13 (s, lH), 7.11 (6, lH), 5.86 (s, lH), 5.85 (s, lH), 5.65 (m, lH), 5.10 (m, 4H), 4.53 (d, J= 6Hz, lH), 4.47 (d J= 6Hz, lH), 4.28 (dd, J= 5, 15Hz, lH), 4.20 (dd, J= 5, 15Hz, lH), 3.88 (m, lH), 2.90 ~m, lH), 2.45 (m, lH), and 1.45 (s, 9H) 2 ~
IR: (CHCl3) 3019, 1769, 1718, 1496, 1393, 1369, 1247,and 1160 cm 1 MS: m/e 572 (M+) Analysis Calculated for C3lH32N40sS:
Calc.: C, 65.02; H, 5.63; N, 9.78;
Found: C, 65.01; H, 5.60; N, 9.52.
15. Allyl 7~-t-butoxycarbonylamino-1-carba-(l-dethia)-3-[2-(p-nitrophenyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl3) ~8.30 (d, J= 9Hz, 2H) 8.05 (d, 15 J= 9H~, 2H) 7.30 (s, lHl, 5.80 (m, lH), 5.20 (m, 4H), 4.68 (ABX, 2H), 3.g5 (m, lH), 3.0 (dd J= 4, 18Hz, lH), 2.55 (m, lH), 2.25 (m, lH), 1.70 (m, lH), and 1.45 (s, 9H) 20 IR: (CHCl3) 3020, 1771, 1719, 1525, 1348, 1248, and 1161 cm MS: m/e 527 (M + 1) Analysis Calculated for C25H26N407S;
Calc.: C, 57.03; H, 4.98; N, 10.64;
Fou~d: C, 57.48; H, 4.82; N, 11.33.
16. ~llyl 7~-t-butoxycarbonylamino-1-carba-30 (1-dethia)-3-[2-(3,4-(t-butyldimethylsilyloxy)phenyl)-thiazol-4-yl]-3-cephem-4-carboxylate 2 ~ L `3 ~
lH NMR: (300 MHz, CDCl3~ ~7.35 (m, 2H), 7.05 (s, lH), 6.85 (d, J= 9Hz, lH), 5.75 (m, lH), 5.15 (m, 4H), 4.65 (ABX, 2H), 3.90 (m, lH), 2.95 (dd J= 4, 18Hz, lH~, 2.48 (m, lH), 2.18 (m, lH), 1.70 (m, lH), 1.45 (s, 9H), 1.02 (s, 9H), 1.0 (s, 9H), 0.24 (s, 6H), and 0.21 (s, 6H) IR: (CHCl3) 2931, 1768, 1718, 1520, 1472, 1392, 1297, 1254 and 1161 cm 1 10 MS: m/e 742 (M + 1) Analysis Calculated for C37H55N307SSi2:
Calc.: C, 59.89; H, 7.47; N, 5.66;
Found: C, 62.22; H, 7.57; N, 5.65.
17. Allyl 7~-t-butoxycarbonylamino-1-carba-(l-dethia)-3-[2-(2-furenyl)thiazol-4-yl]-3-cephem-4-carboxylate 20 lH NMR: (300 MHz, CDCl3) ~7.48 (d, J= 2Hz, lH), 7.10 (s, lH), 6.95 (m, lH), 6.5 ~m, lH), 5.80 (m, lH), 5.15 (m, 4H), 4.68 (ABX, 2H), 3.90 (m, lH), 2.95 (dd J= 4, 18Hz, lH), 2.S0 (m, lH), 2.20 (m, lH), 1.70 (m, lH), and 1.45 (s, 9H) IR: (CHCl3) 3019, 1770, 1718, 1502, 1393, 1249, and 1160 cm MS: m/e 472 (M+ + 1) Analysis Calculated for C2 3H25N3O6S:
Calc.: C, 58.59; H, 5.34; N, 8.91;
Found: C, 59.83; H, 5.27; N, 8.41.
2 ~
18. Allyl 7~-t-butoxycarbonylamino-1-carba-(l-dethia)-3-[2-(3-pyridyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl3) ~9.1 (d, J= 2Hz, lH), 8.65 (d, J= 4Hz lH), 8.18 (m, lH), 7.38 (m, lH), 7.22 (s, lH), 5.80 (m, lH), 5.2 (m, 4H), 4.70 (ABX, 2H), 3.95 (m, lH), 3.0 (dd J= 4, 18Hz, lH), 2.52 (m, lH), 2.20 (m, lH), 1.70 (m, lH), and 1.48 (s, 9H) IR: (CHCl3) 3025, 1771, 1717, 1602, 1246, and 1162 cm 1 MS: m/e 482 (M ) Analysis Calculated for C24H26N4O5S:
Calc.: C, 59.74; H, 5.43; N, 11.61, Found: C, 59.90; H, 5.62; N, 11.63.
19. Allyl 7~-t-butoxycarbonylamino-1-carba-20 (1-dethia)-3-[2-(allyloxycarbonylamino)thiazol-4-yl]-3-cephem-4-carboxylate In a procedure analogous to Example 9 above, the title compound was prepared in 38% yield.
25 lH NNR: (300 MHz, CDCl3) ~8.70 (s, lH), 5.90 (m, 2H), 5.30 (m, 6H), 4.72 (d, J= 6Hz, 2H), 4.65 (d, J= 6Hz, 2H) 4.90 (m, lH), 3.85 (dd J= 4, 18Hz, lH), 2.38 (m, lH), 2.10 (m, lH), and 1.45 (æ, 9H) 30 IR: (CHCl3) 3018, 1769, 1722, 1549, 1237, and 1207 cm 1 MS: m/e 504 (M ) 2 ~
Analysis Calculated for C23H28N4O7S:
Calc.: C, 54.75; H, 5.59; N, ll.10;
Found: C, 54.93; H, 5.31; N, 11.94.
Coproduced in this reaction was allyl 7~-t-butoxy-carbonylamino-l-carba(l-dethia)-3-[2-[(allyloxy-carbonyl)(allyl)]amino]-thiazol-4-yl-3-cephem-4-carboxylate (45%).
lH NMR: (300 MHz, CDCl3) ~6.80 (s, lH), 5.90 (m, 2H), 5.25 (m, 5H), 5.05 (d, J= 8Hz, lH), 4.78 (d, J= 6Hz, 2H), 4.65 (d, J= 6Hz, 2H), 3.87 (m, lH), 2.88 (dd J= 4, 18Hz, lH), 2.40 (m, lH), 2.15 (m, lH), 1.65 (m, lH), and 1.45 (s, 9H) IR: (CHCl3) 3020, 1768, 1712, 1504, 1393, 1242, and 1157 cm~l MS: m/e 544 (M ) Analysis Calculated for C26H32N4O7S:
Calc.: C, 57.34; H, 5.92; N, 10.29;
- Found: C, 57.08; H, 5.86; N, 10.09.
It was subsequently discovered that the use of NaH in l-molar eguivalency as base resulted in the desired mono-allylated product.
~ ~ 3 ~
Example 20 Allyl 7~-[(2-allyloxycarbonylaminothiazol-4-yl)-Z-methoximinoacetylamino]-1-carba(l-dethia)-3-[2-(4-fluorophenyl)thiazol-4-yl]-3-cephem-4-carboxylate A. Deprotection An 80 mg (O.16 mmol) sample of allyl 7~-t-butoxycarbonylamino-l-carba(l-dethia)-3-[2-(4-fluoro-phenyl)thiazol-4-yl]-3-cephem-4-carboxylate was dis-solved in 1 ml of CH2C12 and 1 ml of trifluoroacetic acid. The solution was concentrated ln vacuo to provide a foam which was again treated with trifluroracetic acid and concentrated out of acetonitrile. From the resulting foam (CH2Cl2/diethyl ether/hexane) was obtained a tan solid.
B. Acylation In another container, a 46 mg (0.16 mmol) sample of (2-allyloxycarbonylaminothiazol-4-yl)-Z-methoximino acetic acid was dissovled in a small amount of CH2Cl2 and treated with 28 mg (0.16 mmol) of 2-chloro-4,6-dimethoxytria2ene and cooled to 0C. The reaction mixture was then diluted with an additional 1 ml of CH2Cl2 and treated with 19 ~1 (0.168 mmol) of N-methylmorpholine and stirred for about 40 min.
An additional 19 ~1 g N-methylmorpholine was added, followed by addition of the product from Part A, above, using about 2 ml of CH2Cl2 as wash. After 2 hours, the reaction mixture was concentrated ln vacuo and purified by column chromatography (silica gel, 30-40% ethyl acetate/CH2Cl2) to provide 42 mg of the title compound.
2~3~
lH NMR: (300 MHz, CDCl3) ~9.38 (s, lH), 7.90 (m, 2H), 7.20 (s, lH), 7.12 (m, 2H), 5.85 (m, 3H), 5.25 (m, 4H), 4.70 (m, 4H), 4.10 (m, lH), 4.05 (s, 3H), 3.05 (dd, J= 4, 18Hz, lH), 2.60 (m, lH), 2.30 (m, lH), and 1.95 (m, lH) Examples 21-30 ~The following compounds were prepared in a manner analogous to that used in Example 20.
21. Allyl 7~-[(2-allyloxycarbonylamino-thiazol-4-yl)-Z-methoximinoacetylamino]-l-carba(l-dethia)-3-[(2-phenyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl3) ~9.40 (s, lH), 7.90 (m, 3H), 7.40 (m, 2H), 7.20 (s, lH), 7.10 (s, lH), 5.95 (m, lH), 5.80 (m, lH), 5.60 (m, lH), 5.20 (m, 4H), 4.70 (m, 4H), 4.10 (m, lH), 4.05 (s, 3H), 3.0 (dd J= 4, 18Hz, lH), 20 2.60 (m, lH), 2.30 (m, lH), and 1.95 (m, lH) 22. Allyl 7~-[2-(allyloxycarbonylamino-thiazol-4-yl)-Z-methoximinoacetylamino]-l-carba(l-dethia)-3-[(pyridyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl3) ~9.55 (s, lH), 9.10 (s, lH), 8.65 (d, J= 6Hz, lH) 8.20 (d, J= 9Hz, lH), 8.05 (s, lH), 7.38 (m, lH), 7.30 (s, lH), 7.10 (s, lH), 5.95 ~m, lH), 5.80 (m, lH), 5.75 (m, lH), 5.25 (m, 4H), 4.70 ~m, 4H), 30 4.10 (m, lH), 4.05 (s, 3H), 3.0 (dd J= 4, 18Hz, lH), 2.60 (m, lH), 2.30 (m, lH), and 1.95 (m, lH) 2~3~
23. Allyl 7~-[2-(allyloxycarbonylamino-thiazol-4-yl]-Z-methoximinoacetylamino]-l-carba(l-dethia)-3-[(1-methyl-2-pyridyl)thiazol-4-yl]-3-cephem-4-carboxylate iodide A 58 mg sample of the title compound of Example 22 was dissolved in 0.9 ml of N,N-dimethyl-formamide and treated with 17~1 (0.278 mmol) of methyl-iodide. Crystallization by addition of diethyl ether/
hexane to the reaction mixture provided 56 mg (95%
yield) of the title compound.
lH NMR: (300 MHz, CDCl3) ~9.15 (s, lH), 8.80 (d, J= 9Hz, lH), 8.70 (d, J= 6Hz, lH), 8.10 (m, lH), 7.70 (s, lH), 7.60 (d, J= 9Hz, lH), 7.25, (s, lH), 5.95 (m, lH), 5.75 (m, lH), 5.55 (m, lH), 5.25 (m, 4H), 4.65 (m, 4H), 4.35 (s, 3H), 4.05 (m, lH), 3.95 (s, lH), 3.05 (dd J= 4, 18Hz, lH), 2.55 (m, lH), 2.10 (m, lH), and 1.85 (m, lH) 24. Allyl 7~-[2-(allyloxycarbonylamino-thiazol-4-yl]-Z-methoximinoacetylamino]-l-carba(l-dethia)-3-[2-[5-nitrothiazol-4-yl]thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl~) ~9.30 (s, lH), 8.55 (s, lH), 7.80 (s, lH), 7.45 (s, lH), 7.15 (s, lH), 5.90 ~m, 2H), 5.70 (m, lH), 5.30 (m, 4H), 4.70 (m, 4H), 4.10 (m, lH), 4.05 (s, 3H), 3.0 (dd J= 4, 18Hz, lH), 2.60 (m, lH), and 1.90 (m, lH) (using p-toluenesulfonic acid H2O in place of trifluoroacetic acid) 2~6~ ~
25. Allyl 7~-[(2-triphenylmethylaminothiazol-4-yl)-Z-triphenylmethoximinoacetylamino]-l-carba(1-dethia~-3-[2-[4-nitro-3-methylimidazol-2-yl]thiazol-4-yl-3-cephem-4-carboxylate (using p-toluenesulfonic acid H2O in place of trifluor~acetic acid) lH NMR: (300 MHz, CDCl3) ~8.05 (s, lH), 7.25 (m, 30H), 6.62 (s, H), 6.58 (d, J= 6Hz, lH), 6.43 (s, lH), 5.85 (m, lH), 5.45 (m, lH), 5.20 (m, 2H), 4.70 (m, 2H), 4.40 (s, 3H), 4.0 (m, lH), 2.58 (dd, J= 4, 18Hz, lH), 2.35, (m, lH), 2.10 (m, lH), and 1.45 (m, lH) 26. Allyl 7~-[(2-allyloxycarbonylamino-thiazol-4-yl]-Z-methoximinoacetylamino]-1-carba(1-dethia)-3-[2-[(phenyl)(2-pyridyl)methyl]thiazol-4-yl]-3-cephem-4-carboxylate ~H NMR: (300 MHz, CDCl3) ~9.60 (s, lH), 8.60 (d, J=
4Hz, lH), 8.05 (s, lH), 7.60 (m, lH), 7.25 (m, 5H), 7.20 (m, lH), 7.12 (s, lH), 7.0, (s, lH), 5.80 (m, 3H), 5.20 (m, 4H), 4.50 (m, 4H), 4.10 (m, lH), 4.0 (s, 3H), 2.90 (m, lH), 2.50 (m, lH), 2.20 (m, lH), and 1.90 (m, lH) 2~3~
27. Allyl 7~-[(2-allyloxycarbonylamino-thiazol-4-yl-Z-methoximinoacetylamino]-l-carba(l-dethia)-3-[2-(4-nitrophenyl)thiazol-4-yl]-3-cephem-4-carboxylate (using p-toluenesulfonic acid-H2O instead of trifluoroacetic acid) lH NMR: (300 MHz, CDCl3) ~9.60 (s, lH), 8.25 (d, J= 8Hz, 2H), 8.18 (s, lH), 8.05 (d, J= 8Hz, 2H), 7.35 (s, lH), 7.05, (s, lH), 5.90 (m, 3H), 5.25 (m, 4H), 4.70 (m, 4H), 4.15 (m, lH), 4.05 (s, 3H), 3.0 (dd, J= 4, 18Hz, lH), 2.60 (m, lH), 2.30 (m, lH), and 1.95 (m, lH) 28. Allyl 7~-[(2-allyloxycarbonylamino-thiazol-4-yl]-Z-methoximinoacetylamino]-l-carba(1-dethia)-3-[2-allyloxycarbonylaminothiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl3) ~9.60 (s, lH), 8.52 (s, lH), 8.10 (s, lH), 7.02 (s, lH), 6.80 (s, lH), 5.90 (m, 3H), 5.70 (m, lH), 5.25 (m, 6H), 4.70 (m, 6H), 4.05 (m, lH), 4.0 (s, 3H), 2.88 (dd, J= 4, 18Hz, lH), 2.43 (m, lH), 2.20 (m, lH), and 1.90 (m, lH) 29. Allyl 7~-[(2-allyloxycarbonylamino-thiazol-4-yl]-Z-methoximinoacetylamino]-l-carba(l-dethia)-3-[2-(3,4-(t-butyldimethylsilyl)oxy)phenyl-thiazol-4-yl]-3-cephem-4-carboxylate 2 ~ 3 ~
lH NMR: (300 MHz, CDCl3) ~9.45 (s, lH), 7.95 (s, lH), 7.35 (m, 2H), 7.12 (s, lH), 6.84 (m, lH), 5.95 (m, lH), 5.75 (m, 2H), 5.25 (m, 4H), 4.65 (m, 4H), 4.10 (m, lH), 4.02 (s, 3H), 3.0 (dd, J= 4, 18Hz, lH), 2.55 (m, lH), 2.25 (m, lH), 1.90 (m, lH), 1.0 (s, 9H), 0.97 (s, 9H), 0.23 (s, 6H), and 0.18 (s, 6H) 30. Allyl 7~-~(2-allyloxycarbonylamino-thiazol-4-yl)-Z-methoximinoacetylamino]-l-carba(l-10 dethia)-3-[2-(2-furyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, CDCl3) ~9.55 (s, lH), 8.05 (s, lH), 7.48 (s, lH), 7.15 (s, lH), 7.05 (s, lH), 6.95 (m, lH), 15 6.52 (m, lH), 5.85 (m, 3H), 5.25 (m, 4H), 4.70 (m, 4H), 4.10 (m, lH), 4.02 (s, 3H), 3.0 (dd, J= 4, 18Hz, lH), 2.55 (m, lH), 2.25 (m, lH) and 1.95 (m, lH) Example 31 Sodium 7~-[(2-aminothiazol-4-yl)-Z-methox-iminoacetylamino]-l-carba(l-dethia)-3-[2-(2-phenyl)-thiazol-4-yl]-3-cephem-4-carboxylate A 27 mg (0.0417 mmol) sample of allyl 7~-t(2-allyloxycarbonylaminothiazol-4-yl)-Z-methoximino-acetylamino]-1-carba(l-dethia)-3-[2-(phenyl)thiazol-4-yl]-3-cephem-4-carboxylate was dissolved in 1.5 ml of CH2Cl2, treated with 0.878 mg (0.0013 mmol) of bis triphenylphosphine Pd(II) dichloride and 6 ~1 (0.0917 mmol) of tri-n-butyltinhydride and stirred for 10 min.
~ ~ 3 ~
The reaction mixture was then treated with an additional 5.0 ~l of tri-n-butyltinhydride. After 10 min., the reaction mixture was quenched with a solution of 10 ~l concentrated HCl in 0.5 ml of CH3CN. The resulting mixture was treated with 10 ml of diethyl ether and 10 ml hexane and centrifuged (2X). The resulting solid was dried under vacuum to provide 16.0 mg of the free acid of the title compound (93% pure by HPLC) in 73.7%
yield.
A 130 mg (0.248 mmol) of the above was suspended in about 7 ml H20 and 2 ml CH3CN. A solution of 25 mg (0.297 mmol) of NaHC03 in 1.5 ml of H20 was prepared and added. The resulting solution was sonicated and passed through an HP20SS column eluting with 8% CH3CN-18%
CH3CN/H20. The desired fractions were concentrated and the resulting title compound washed with diethylether/
hexane to provide 125 mg (99.8% pure).
1H NMR: (300 MHz, d6-DMSO) ~9.2 (d, J= 9Hz, 2H), 7.85 (m, 2H), 7.65 (s, lH), 7.40 (m, 3~), 7.15 (s, 2H), 6.70 (s, lH), 5.25 (m, lH), 3.80 (s, 3H), 3.75 (m, lH), 2.95 (dd, J= 4, 18Hz, lH), 2.35 (m, lH), 1.90 (m, lH), and 1.70 (m, lH).
IR (KBr): 3500-3100, 1733, 1648, 1591, 1557, 1539, 1405 and 1376 cm MS: m/e 547 (M + 1) Analysis calculated for c23Hl9N6oss2Na:
Calc.: C, 50.54; H, 3.50; N, 15.38;
Found: C, 50.33; H, 3.76; N, 15.17.
2~3 r~ 1 ~ 3~
Examples 32-38 Examples 32-38 were prepared by methodology analogous to that of Example 31.
32. Sodium 7~-~(2-aminothiazol-4-yl)-Z-methoximinoacetylamino]-l-carba(l-dethia)-3-[2-(2-furyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, d6-DMSO) ~9.25 (d, J= 9Hz, lH), 7.80 (s, lH), 7.65 (s, lH), 7.20 (s, 2H), 6.95 (m, lH), 6.70 (s, lH), 6.60 (m, lH), 5.25 (m, lH),3.80 (s, 3H), 3.75 (m, lH), 3.85, (dd, J= 4, 18Hz, lH), 2.32 (m, lE), 1.85 (m, lH) and 1.65 (m, lH) IR (KBr): 3500-3200, 1744, 1647, 1595, 1538, 1404, 1383 and 1035 cm MS: m/e 537 (M + 1) Analysis calculated for C2lHl7N6O6S2Na:
Calc.: C, 47.01; H, 3.19; N, 15.66;
Found: C, 41.14; H, 2.95; N, 11.02.
.-- Residue: 12.74%
33. 7~-[(2-Aminothiazol-4-yl)-Z-hydroxy-iminoacetylamino]-l-carba(l-dethia)-3-[2-(4-nitro-3-methylimidazol-2-yl)thiazol-4-yl]-3-cephem-4-carboxylic acid 2~3~
H NMR: (300 MHz, d6-DMSO) ~9.15 (d, J= 9Hz, lH), 8.15 (s, lH), 7.88 (s, lH), 7.08 (s, 2H), 6.65 (s,lH), 5.40 (m, lH), 4.30 (s, 3H), 3.80 (m, lH), 3.90 (dd, J= 4, 18Hz, lH), 2.38 (m, lH), 1.95 (m, lH) and 1.7~ (m, lH) IR (KBr): 3500-3100, 1754, 1617, 1528, 1397, 1365, 1339, 1268 and 1209 cm 1 MS: m/e 560 (M + 1) Analysis calculated for C2 oH17Ns7 S2 Calc.: C, 42.93; H, 3.06; N, 22.53;
Found: C, 42.47; H, 3.38; N, 20.77.
34. 7~-[(2-aminothiazol-4-yl)-Z-methox-iminoacetylamino]-l-carba(1-dethia)-3-[2-(1-methyl-3-pyridyl)thiazol-4-yl]-3-cephem-4-carboxylic acid 1H NMR: (300 MHz, D2O) ~9.30 ~s, lH), 8.90 (d, J= 8Hz, lH), 8.78, (d, J= 6Hz, lH), 8.10 (m, lH), 7.65 ~s, lH), 6.95 (s, lH), 5.50, (d, J= 6Hz, lH), 4.45 (s, 3H), 4.10 (m, lH), 4.0 (s, 3H), 3.95, (m, lH), 2.58 (m, lH), 2.20 (m, lH), and 1.80 (m, lH) IR (KBr): 3200, 1758, 1674, 1532, 1384, 1203, and 1168 cm~1 MS: m/e 540 (M + 1) 35. Sodium 7~-[(2-aminothiazol-4-yl)-Z-methoximinoacetylamino~-1-carba(1-dethia)-3-[2-(4-nitro-phenyl)thiazol-4-yl]-3-cephem-4-carboxylate lH NMR: (300 MHz, d6-DMSO) ~9.25 (d, J= 9Hz, lH), 8.25 (d, J= 9Hz, 2H), 8.15 (d, J= 9Hz, 2H), 7.85 (s, lH), 7.15 (s, 2H), 6.72 (s, lH), 5.25 (m, lH), 3.80 (s, 3H), 3.75 (m, lH), 2.95 (dd, J= 4, 18Hz, lH), 2.40 (m, lH), 1.90 (m, lH), and 1.70 (m, lH) IR (KBr): 3400-3200, 1733, 1649, 1594, 1523, 1402, 1345, 1050 and 851 cm 1 MS: m/e 592 (M + 1) Analysis calculated for C23H18N7O7S2Na:
Calc.: C, 46.70; H, 3.07; H, 16.57;
Found: C, 46.06; H, 3.05; N, 15.75.
Residue: 5.84%
36. 7~-[(2-aminothiazol-4-yl)-4-methox-iminoacetylamino]-l-carba(l-dethia)-3-[2-(5-nitro-thiazol-2-yl)thiazol-4-yl]-3-cephem-4-carboxylic acid 25 lH NMR: (300 MHz, d6-DMSO) ~9.35 (d, J= 9Hz, lH), 8.90 (s, lH), 8.02 (s, lH), 7.40 (s, 2H), 6.78 (s, lH), 5.45 (m, lH), 3.90 (m, lH), 3.80 (s, 3H), 2.95 (dd, J= 4, 18Hz, lH), 2.40 (m, lH), 2.0 (m, lH), and 1.70 (m, lH) 30 IR (KBr): 3419, 1764, 1629, 1524, and 1350 cm 1 MS: m/e 532 (M - C2 ) ~ ~ ,C~
Analysis calculated for C20Hl6N8O7S3:
Calc.: C, 41.66; H, 2.80; N, 19.43;
Found: C, 41.38; H, 2.90; N, 17.16.
S 37. 7~-[(2-aminothiazol-4-yl)-Z-methoximino-acetylamino]-l-carba(l-dethia)-3-[2-(4-fluorophenyl)-thiazol-4-yl]-3-cephem-4-carboxylic acid lH NMR: (300 MHz, d6-DNSO~ ~9.45 (d, J~ 9Hz, lH), 7.95 (m, 2H), 7.65 (s, lH), 7.35 (m, 2H), 6.83 (s, lH), 5.50 (m, lH), 3.95 (m, lH), 3.90 (s, 3H), 2.95 (m, lH), 2.40 (m, lH), 2.0 (m, lH), and 1.75 (m, lH) IR (KBr): 3400-3000, 1762, 1673, 1631, 1517, 1389, 1234, and 1046 cm 1 MS: m/e 543 (M + 1) Analysis calculated for C23H1gN6O5S2F:
Calc.: C, 50.92; H, 3.53; N, 15.49;
Found: C, 48.53; H, 3.66; N, 13.87.
38. 7~-[(2-aminothiazol-4-yl)-Z-methox-iminoacetylamino]-l-carba(1-dethia)-3-[2-(phenyl)(2-pyridyl)methyl)thiazol-4-yl]-3-cephem-4-carboxylic acid H NMR: (300 MHz, d6-DMSO) ~9.28 (d, J= 9Hz, lH), 8.50 (d, J= 4Hæ, lH), 7.70 (m, lH), 7.50 (s, lH), 7.45 (m, lH), 7.25 (m, 8H), 6.72 (s, lH), 5.90 (s, lH), 5.40 (m, lH), 3.80 (s, 3~), 2.85 (dd, J= 4, 18Hz, lH), 2.30 (m, lH), 1.90 (m, lH), and 1.65 (m, lH) `' ,c~ q~
IR (KBr): 3400-3000, 1758, 1671, 1619, 1589, 1532, and 1379 cm 1 MS: m/e 616 (M + 1) Analysis calculated for C29H25N705S2:
Calc.: C, 56.57; H, 4.09; H, 15.93;
Found: C, 55.11; H, 4.09; N, 15.30.
Example 39 Sodium 7~-[(2-aminothiazol-4-yl)-Z-methox-iminoacetylamino]-l-carba(l-dethia)-3-(2-aminothiazol-4-yl)-3-cephem-4-carboxylate 1H NMR: (300 MHz, d6-DMS0) 89.20 (d, J= 9Hz, lH), 7.15 (s, 2H~, 6.70 (s, lH), 6.60 (s, 2H), 6.55 (s, lH), 5.20 (m, lH), 3.78 (s, 3H), 3.62 (s, lH), 2.64 (dd J= 4, 18Hz, lH), 2.15 (m, lH), 1.75 (m, lH) and 1.60 (m, lH) IR (KBr): 3500-3100, 1744, 1661, 1607, 1591, 1527, 1382, 1350, and 1034 cm 1 . MS: m/e 485 (M ) Analysis calculated for C17H~6N705S2Na:
Calc.: C, 42.06; H, 3.32; N, 20.20;
Found: C, 42.38; H, 3.33; N, 18.59.
- 2~3~
Exam~le 40 Sodium 7~-~(2-aminothiazol-4-yl)-Z-methox-iminoacetylamino]-l-carba(l-dethia)-3-[2-(3,4-dihydroxy-phenyl)thiazol-4-yl]-3-cephem-4-carboxylate 1H NMR: (300 MHz, d6-DMSO) ~9.50 (s, lH), 9.25 (d, J= 9Hz, lH), 7.48 (m, lH), 7.28 (m, lH), 7.15 (m, 3H), 6.75 (d, J= 8Hz, lH), 6.70 (s, lH), 5.25 (m, lH), 3.80 (s, 3H), 3.72 (m, lH), 2.90, (dd, J= 4, 18 Hz, lH), 2.35 (m, lH), 1.88 (m, lH), and 1.65 (m, lH) IR (KBr): 3341, 3226, 2223, 1648, 1628, 1600, 1587, 1365, 1253, and 1159 cm 1 +
15 MS: m/e 579 (M + 1) Analysis calculated for C23H1gN6O7S2Na:
Calc.: C, 47.75; H, 3.31; N, 14.55;
Found: C, 42.41; H, 3.24; N, 12.35.
Residue: 7.69%
Exam~le 41 7~-(D-phenylglycylamino)-l-carba(l-dethia)-25 3-(2-aminothiazol-4-yl)-3-cephem-4-carboxylic acid H NMR: (300 MHz, D20) 87.60 (m, 5H), 6.60 (s, lH), 5.50 ~(d, J= 4Hz, lH), 5.22 (s, lH), 4.0 (m, lH), 2.70 (dd, J= 4, 18Hz, lH), 2.35 (m, lH), 1.78 (m, lH) and 1.35 (m, lH) q ~ Q`
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Claims (9)
1. A compound of Formula (1):
(1) wherein X is a group selected from amino, halo, cyano, hydrogen, nitro, C1-C6 alkyl, C1-C6 substituted alkyl, a C3 to C6 heterocyclic ring containing 1, 2, or 3 nitrogen atoms and O or 1 sulfur or oxygen atoms, said ring optionally substituted by one or more groups selected from halo, nitro, hydroxy, C1-C6 alkyl or C1-C6 substituted alkyl;
phenyl, substituted phenyl, or an acyl group of the formula , wherein R" is C1-C6 alkyl, C1-C6 substituted alkyl, phenyl, or substituted phenyl;
R3 is hydrogen, C1-C4 alkoxy, or a group of the formula -NHCHO; and R1 is an acyl group of the formula , wherein R" is hydrogen; C1-C6 alkyl, C1-C6 alkyl substituted by cyano, carboxy, halogen, amino, C1-C4 alkoxy, C1-C4 alkylthio, or trifluoromethylthio; a X-7967A (EPO) - 58 -phenyl or substituted phenyl group represented by the formula wherein a and a' independently are hydrogen, halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkanoyloxy, C1-C4 alkyl, C1-C4 alkylthio, amino, mono- or di(C1-C4 alkyl)amino, C1-C4 alkanoylamino, C1-C4 alkylsulfonylamino, carboxy, carbamoyl, hydroxymethyl, amino-methyl, or carboxymethyl;
a group represented by the formula wherein a and a' have the same meanings as defined above, Z is O or S, and m is O or 1;
a heteroarylmethyl group represented by the formula wherein R1 is thienyl, furyl, benzothienyl, benzofuryl, indolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, and such heteroaryl groups substituted by amino, hydroxy, halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 alkylsulfonylamino;
X-7967A (EPO) - 59 -a substituted methyl group represented by the formula wherein R2 is cyclohex-1,4-dienyl, or a phenyl group or substituted phenyl group represented by the formula wherein a and a' have the above defined meanings, or R2 is R1 as defined above, and Q is hydroxy, C1-C4 alkanoyloxy, carboxy, sulfo, or amino;
or R2 is a keto group or an oximino-substituted group represented by the formulae wherein R3 is R1 or R2 as defined above and R4 is hydrogen, C1-C4 alkyl, or a group repre-sented by the formula X-7967A (EPO) - 60 - wherein b and b' independently are hydrogen, or C1-C3 alkyl, and b and b' when taken together with the carbon to which they are bonded form a 3- to 6-membered carbocyclic ring, R5 is hydroxy, C1-C4 alkoxy, amino, C1-C4 alkylamino, or di(C1-C4 alkyl)amino; and n is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.
(1) wherein X is a group selected from amino, halo, cyano, hydrogen, nitro, C1-C6 alkyl, C1-C6 substituted alkyl, a C3 to C6 heterocyclic ring containing 1, 2, or 3 nitrogen atoms and O or 1 sulfur or oxygen atoms, said ring optionally substituted by one or more groups selected from halo, nitro, hydroxy, C1-C6 alkyl or C1-C6 substituted alkyl;
phenyl, substituted phenyl, or an acyl group of the formula , wherein R" is C1-C6 alkyl, C1-C6 substituted alkyl, phenyl, or substituted phenyl;
R3 is hydrogen, C1-C4 alkoxy, or a group of the formula -NHCHO; and R1 is an acyl group of the formula , wherein R" is hydrogen; C1-C6 alkyl, C1-C6 alkyl substituted by cyano, carboxy, halogen, amino, C1-C4 alkoxy, C1-C4 alkylthio, or trifluoromethylthio; a X-7967A (EPO) - 58 -phenyl or substituted phenyl group represented by the formula wherein a and a' independently are hydrogen, halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkanoyloxy, C1-C4 alkyl, C1-C4 alkylthio, amino, mono- or di(C1-C4 alkyl)amino, C1-C4 alkanoylamino, C1-C4 alkylsulfonylamino, carboxy, carbamoyl, hydroxymethyl, amino-methyl, or carboxymethyl;
a group represented by the formula wherein a and a' have the same meanings as defined above, Z is O or S, and m is O or 1;
a heteroarylmethyl group represented by the formula wherein R1 is thienyl, furyl, benzothienyl, benzofuryl, indolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, and such heteroaryl groups substituted by amino, hydroxy, halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 alkylsulfonylamino;
X-7967A (EPO) - 59 -a substituted methyl group represented by the formula wherein R2 is cyclohex-1,4-dienyl, or a phenyl group or substituted phenyl group represented by the formula wherein a and a' have the above defined meanings, or R2 is R1 as defined above, and Q is hydroxy, C1-C4 alkanoyloxy, carboxy, sulfo, or amino;
or R2 is a keto group or an oximino-substituted group represented by the formulae wherein R3 is R1 or R2 as defined above and R4 is hydrogen, C1-C4 alkyl, or a group repre-sented by the formula X-7967A (EPO) - 60 - wherein b and b' independently are hydrogen, or C1-C3 alkyl, and b and b' when taken together with the carbon to which they are bonded form a 3- to 6-membered carbocyclic ring, R5 is hydroxy, C1-C4 alkoxy, amino, C1-C4 alkylamino, or di(C1-C4 alkyl)amino; and n is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.
2. A compound of Claim 1 wherein R2 is a substituted methyl group represented by the formula wherein R2 is cyclohex-1,4-dienyl, or a phenyl group or substituted phenyl group represented by the formula wherein a and a' independently are hydrogen, halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkan-oyloxy, C1-C4 alkyl, C1-C4 alkylthio, amino, X-7967A (EPO) - 61 -mono- or di(C1-C4 alkyl) amino, C1-C4 alkanoyl-amino, C1-C4 alkylsulfonyl amino, carboxy, carbamoyl, hydroxymethyl, aminomethyl, or carboxymethyl; or R2 is thienyl, furyl, benzothienyl, benzofuryl, indolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, and such heteroaryl groups substituted by amino, hydroxy, halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 alkyl-sulfonylamino; and Q is hydroxy, C1-C4 alkanoyloxy, carboxy, sulfo, or amino.
3. A compound of Claim 2 wherein R2 is phenyl and Q is amino.
4. A compound of Claim 1 wherein R2 is a keto group or an oximino-substituted group represented by the formulae wherein R3 is hydrogen; C1-C6 alkyl, C1-C6 alkyl substituted by cyano, carboxy, halogen, amino, C1-C4 alkoxy, C1-C4 alkylthio, or trifluoromethylthio; cyclohex-1,4-dienyl, or a phenyl or substituted phenyl group represented by the formula X-7967A (EPO) - 62 -wherein a and a' independently are hydrogen, halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkanoyloxy, C1-C4 alkyl, C1-C4 alkylthio, amino, mono- or di(C1-C4 alkyl)amino, C1-C4 alkanoylamino, C1-C4 alkylsulfonylamino, carboxy, carbamoyl, hydroxymethyl, amino-methyl, or carboxymethyl;
a group represented by the formula wherein a and a' have the same meanings as defined above, Z is O or S, and m is O or 1;
or R3 is thienyl, furyl, benzothienyl, benzofuryl, indolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadia-zolyl, and such heteroaryl groups substituted by amino, hydroxy, halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 alkylsulfonylamino; and R4 is hydrogen, C1-C4 alkyl, or a group repre-sented by the formula wherein b and b' independently are hydrogen, or C1-C3 alkyl, and b and b' when taken together with the carbon to which they are bonded form a 3- to 6-membered carbocyclic ring, and R5 is hydroxy, C1-C4 alkoxy, amino, X-7967A (EPO) - 63 -C1-C4 alkylamino, or di(C1-C4 alkyl)amino and n is 0, 1, 2, or 3.
a group represented by the formula wherein a and a' have the same meanings as defined above, Z is O or S, and m is O or 1;
or R3 is thienyl, furyl, benzothienyl, benzofuryl, indolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadia-zolyl, and such heteroaryl groups substituted by amino, hydroxy, halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 alkylsulfonylamino; and R4 is hydrogen, C1-C4 alkyl, or a group repre-sented by the formula wherein b and b' independently are hydrogen, or C1-C3 alkyl, and b and b' when taken together with the carbon to which they are bonded form a 3- to 6-membered carbocyclic ring, and R5 is hydroxy, C1-C4 alkoxy, amino, X-7967A (EPO) - 63 -C1-C4 alkylamino, or di(C1-C4 alkyl)amino and n is 0, 1, 2, or 3.
5. A compound of Claim 4, wherein R3 is 2-aminothiazol-4-yl.
6. A compound of Claim 5 wherein R4 is methyl.
7. A compound of Formula (2):
(2) wherein R1 is hydrogen or an amino protecting group;
R4 is hydrogen or a carboxy protecting group; X is selected from the group consisting of amino, halo, cyano, hydrogen, nitro, C1-C6 alkyl, C1-C6 substituted alkyl, a C3 to C6 heterocyclic ring containing 1, 2, or 3 nitrogen atoms and O or 1 sulfur or oxygen atoms, said ring optionally substituted by one or more groups selected from halo, nitro, hydroxy, C1-C6 alkyl, or C1-C6 substituted alkyl; phenyl, substituted phenyl, or an acyl group of the formula , wherein R''' is C1-C6 alkyl, C1-C6 substituted alkyl, phenyl, or substituted phenyl; and R3 is hydrogen, C1-C4 alkoxy, or a group of the formula -NHCHO.
X-7967A (EPO) - 64 -
(2) wherein R1 is hydrogen or an amino protecting group;
R4 is hydrogen or a carboxy protecting group; X is selected from the group consisting of amino, halo, cyano, hydrogen, nitro, C1-C6 alkyl, C1-C6 substituted alkyl, a C3 to C6 heterocyclic ring containing 1, 2, or 3 nitrogen atoms and O or 1 sulfur or oxygen atoms, said ring optionally substituted by one or more groups selected from halo, nitro, hydroxy, C1-C6 alkyl, or C1-C6 substituted alkyl; phenyl, substituted phenyl, or an acyl group of the formula , wherein R''' is C1-C6 alkyl, C1-C6 substituted alkyl, phenyl, or substituted phenyl; and R3 is hydrogen, C1-C4 alkoxy, or a group of the formula -NHCHO.
X-7967A (EPO) - 64 -
8. A pharmaceutical formulation comprising as an active ingredient a compound as claimed in any one of Claims 1 to 6 or a pharmaceutically acceptable salt thereof, associated with one or more pharmaceuti-cally acceptable carriers, excipients, or diluents therefor.
9. A compound as claimed in any of Claims 1 to 6 or a pharmaceutically acceptable salt thereof for use as an antibiotic agent.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US47831090A | 1990-02-12 | 1990-02-12 | |
US478,310 | 1990-02-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2036190A1 true CA2036190A1 (en) | 1991-08-13 |
Family
ID=23899400
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA 2036190 Abandoned CA2036190A1 (en) | 1990-02-12 | 1991-02-12 | 1-carba (dethia) cephalosporin antibiotics |
Country Status (1)
Country | Link |
---|---|
CA (1) | CA2036190A1 (en) |
-
1991
- 1991-02-12 CA CA 2036190 patent/CA2036190A1/en not_active Abandoned
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