MXPA97010004A - Vinyl-pirrolydinone cephalosporins with substitute basi - Google Patents
Vinyl-pirrolydinone cephalosporins with substitute basiInfo
- Publication number
- MXPA97010004A MXPA97010004A MXPA/A/1997/010004A MX9710004A MXPA97010004A MX PA97010004 A MXPA97010004 A MX PA97010004A MX 9710004 A MX9710004 A MX 9710004A MX PA97010004 A MXPA97010004 A MX PA97010004A
- Authority
- MX
- Mexico
- Prior art keywords
- oxo
- hydrogen
- formula
- amino
- compounds
- Prior art date
Links
- 150000001780 cephalosporins Chemical class 0.000 title claims abstract description 4
- -1 pyrrolidin-2-ylmethyl Chemical group 0.000 claims abstract description 188
- 150000001875 compounds Chemical class 0.000 claims abstract description 92
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 65
- 239000001257 hydrogen Substances 0.000 claims abstract description 64
- 150000002148 esters Chemical class 0.000 claims abstract description 42
- 239000011780 sodium chloride Substances 0.000 claims abstract description 38
- 150000003839 salts Chemical class 0.000 claims abstract description 36
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 33
- 125000006239 protecting group Chemical group 0.000 claims abstract description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 201000009910 diseases by infectious agent Diseases 0.000 claims abstract description 14
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 claims abstract description 12
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 230000000069 prophylaxis Effects 0.000 claims abstract description 10
- 150000004677 hydrates Chemical class 0.000 claims abstract description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims abstract description 8
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 8
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 6
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims abstract description 4
- 150000002500 ions Chemical class 0.000 claims abstract 2
- 239000002253 acid Substances 0.000 claims description 112
- SCNWTQPZTZMXBG-UHFFFAOYSA-N 2-methyloct-2-enoic acid Chemical compound CCCCCC=C(C)C(O)=O SCNWTQPZTZMXBG-UHFFFAOYSA-N 0.000 claims description 69
- 238000000034 method Methods 0.000 claims description 17
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 125000003277 amino group Chemical group 0.000 claims description 8
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 8
- 229910001413 alkali metal ion Inorganic materials 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 6
- 125000005117 dialkylcarbamoyl group Chemical group 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 239000003518 caustics Substances 0.000 claims description 2
- 230000000875 corresponding Effects 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims 1
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 1
- 229910052783 alkali metal Inorganic materials 0.000 abstract description 2
- 150000001340 alkali metals Chemical class 0.000 abstract description 2
- 210000003702 immature single positive T cell Anatomy 0.000 description 102
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Inorganic materials [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 91
- 239000000203 mixture Substances 0.000 description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 40
- 235000002639 sodium chloride Nutrition 0.000 description 26
- 239000000243 solution Substances 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 238000001914 filtration Methods 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 10
- 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 10
- 108060009526 FEN1 Proteins 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- GUBYYDHSFIQMDU-UHFFFAOYSA-N 2-methyloct-3-enoic acid Chemical compound CCCCC=CC(C)C(O)=O GUBYYDHSFIQMDU-UHFFFAOYSA-N 0.000 description 7
- 101700074018 CPT1A Proteins 0.000 description 7
- 101700031500 TECR Proteins 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 230000001681 protective Effects 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 5
- HPBPNWPROCLLAA-UHFFFAOYSA-N 2-bromoethanone Chemical group BrC[C]=O HPBPNWPROCLLAA-UHFFFAOYSA-N 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N Anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000005903 acid hydrolysis reaction Methods 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 3
- UMGDCJDMYOKAJW-UHFFFAOYSA-N Thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 230000002378 acidificating Effects 0.000 description 3
- 125000006242 amine protecting group Chemical group 0.000 description 3
- 125000000751 azo group Chemical group [*]N=N[*] 0.000 description 3
- 125000001797 benzyl group Chemical class [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 238000005227 gel permeation chromatography Methods 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 229960003085 meticillin Drugs 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 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 3
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 3
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 101700003360 ARF1 Proteins 0.000 description 2
- LEKJTGQWLAUGQA-UHFFFAOYSA-N Acetyl iodide Chemical compound CC(I)=O LEKJTGQWLAUGQA-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 101700008436 PCSK1 Proteins 0.000 description 2
- 229940055023 Pseudomonas aeruginosa Drugs 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L Sodium thiosulphate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 241000295644 Staphylococcaceae Species 0.000 description 2
- FIQMHBFVRAXMOP-UHFFFAOYSA-N Triphenylphosphine oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 238000002814 agar dilution Methods 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 125000001589 carboacyl group Chemical group 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
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- 238000004440 column chromatography Methods 0.000 description 2
- 125000000853 cresyl group Chemical class C1(=CC=C(C=C1)C)* 0.000 description 2
- 229910052906 cristobalite Inorganic materials 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 229940113088 dimethylacetamide Drugs 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 238000006698 hydrazinolysis reaction Methods 0.000 description 2
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- 239000002054 inoculum Substances 0.000 description 2
- 150000003893 lactate salts Chemical class 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 125000005544 phthalimido group Chemical group 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
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- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
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- 229910052682 stishovite Inorganic materials 0.000 description 2
- 150000003467 sulfuric acid derivatives Chemical class 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
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- RYYWUUFWQRZTIU-UHFFFAOYSA-N thiophosphoric acid Chemical compound OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 description 2
- 229910052905 tridymite Inorganic materials 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- MCTKPDMQZKONOO-WXIWBVQFSA-M (2E)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetate;1-methyl-1-prop-2-enylpyrrolidin-1-ium Chemical compound C=CC[N+]1(C)CCCC1.S1C(N)=NC(C(=N/OC2CCCC2)\C([O-])=O)=N1 MCTKPDMQZKONOO-WXIWBVQFSA-M 0.000 description 1
- XEZIFGWTSLOMMT-MEFGMAGPSA-N (2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-trityloxyiminoacetic acid Chemical compound S1C(N)=NC(C(=N\OC(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)\C(O)=O)=C1 XEZIFGWTSLOMMT-MEFGMAGPSA-N 0.000 description 1
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- MKSTXMDSWOHKOR-SCSAIBSYSA-N (3R)-3-aminopyrrolidine-1-carboxylic acid Chemical compound N[C@@H]1CCN(C(O)=O)C1 MKSTXMDSWOHKOR-SCSAIBSYSA-N 0.000 description 1
- NCSXOMQDXHCTOY-UHFFFAOYSA-N 1,1,2,3-tetramethylguanidine Chemical compound CNC(=NC)N(C)C NCSXOMQDXHCTOY-UHFFFAOYSA-N 0.000 description 1
- JDDXNENZFOOLTP-UHFFFAOYSA-N 1,2,4-triazol-1-ium-1-ylidenemethanediamine;chloride Chemical compound Cl.NC(=N)N1C=NC=N1 JDDXNENZFOOLTP-UHFFFAOYSA-N 0.000 description 1
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- CCDRSXNKUWPFAB-UHFFFAOYSA-N 4-[(3-bromo-2-oxopyrrolidin-1-yl)methyl]piperidine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCC1CN1C(=O)C(Br)CC1 CCDRSXNKUWPFAB-UHFFFAOYSA-N 0.000 description 1
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- YNHIGQDRGKUECZ-UHFFFAOYSA-L Bis(triphenylphosphine)palladium(II) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
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- 239000004472 Lysine Substances 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N Meta-Chloroperoxybenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- OKVSEPXFKOQRQV-UHFFFAOYSA-N N-ethylformamide;hydrochloride Chemical compound Cl.CCNC=O OKVSEPXFKOQRQV-UHFFFAOYSA-N 0.000 description 1
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- UQYZFNUUOSSNKT-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 UQYZFNUUOSSNKT-UHFFFAOYSA-N 0.000 description 1
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- YFOJTKPOMRZOGM-UHFFFAOYSA-N dichloromethane;triphenylphosphane Chemical compound ClCCl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YFOJTKPOMRZOGM-UHFFFAOYSA-N 0.000 description 1
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- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 125000006351 ethylthiomethyl group Chemical group [H]C([H])([H])C([H])([H])SC([H])([H])* 0.000 description 1
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- 238000006703 hydration reaction Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
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- 230000002401 inhibitory effect Effects 0.000 description 1
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
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- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
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- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate Chemical class CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
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- 108090000765 processed proteins & peptides Proteins 0.000 description 1
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- RWRDLPDLKQPQOW-UHFFFAOYSA-N pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 150000004040 pyrrolidinones Chemical class 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- 238000010555 transalkylation reaction Methods 0.000 description 1
- 125000005208 trialkylammonium group Chemical group 0.000 description 1
- PIILXFBHQILWPS-UHFFFAOYSA-N tributyltin Chemical compound CCCC[Sn](CCCC)CCCC PIILXFBHQILWPS-UHFFFAOYSA-N 0.000 description 1
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical group CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 description 1
- SIOVKLKJSOKLIF-CMDGGOBGSA-N trimethylsilyl (1E)-N-trimethylsilylethanimidate Chemical compound C[Si](C)(C)OC(/C)=N/[Si](C)(C)C SIOVKLKJSOKLIF-CMDGGOBGSA-N 0.000 description 1
Abstract
The present invention relates to cephalosporin derivatives of the general formula (see formula) (I) wherein X is CH or N, Rûes hydrogen or cyclopentyl, Rýes a group of the formula (see formulas) Rües hydrogen, an ion of alkali metal or a tertiary ammonium group: R 4 is hydrogen, an amino protecting group, pyrrolidin-2-ylmethyl, azetidin-3-ylmethyl, iminomethyl, 1-carbamimidoyl, R 5 is hydrogen, diakylcarbamoyl, w-hydroxyalkyl, w-aminoalkyl, pyridinium-1-ylmethyl, 1-hydroxy-3-aminomethyl-propyl or (hydroxy) - (pyrrolidin-2-yl) -methyl, R6 is hydrogen, trifluoromethyl or hydroxyl, and R7 is alkyl, w-hydroxy-alkyl, cycloalkyl , 3-pyrrolidinyl, 3-azetidinyl, iminomethyl or 1-carbamimidoyl, as well as their easily hydrolysable esters, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula I and their esters and salts; the invention also relates to the preparation of compounds of formula I, to its use as pharmaceutical substances eutiacally active, particularly for the treatment and prophylaxis of infectious diseases and pharmaceutical preparations containing a compound of formula I for the treatment and prophylaxis of infectious diseases
Description
BASIC DESCRIPTION OF THE INVENTION
The present invention relates to cephalosporin derivatives of the general formula
where X is CH or N; R- is hydrogen or cyclopentyl; R- is a group of the formula
REF: 26419
R3 is hydrogen, an alkali metal ion or a tertiary ammonium group; R 4 is hydrogen, an amino protecting group, pyrrolidin-2-ylmethyl, azetidin-3-ylmethyl, iminomethyl, 1-carbamimidoyl; R5 is hydrogen, dialkylcarbamoyl,? -hydroxyalkyl,? -am noa qu, p r? n o- - me or, - rox - - - aminomethyl - propyl or (hydroxy) - (pyrrolidin - 2 - yl) - methyl; R6 is hydrogen, trifluoromethyl or hydroxyl; and R ^ is alkyl,? -hydroxy-alkyl, cycloalkyl, 3-pyrrolidinyl, 3-azetidinyl, iminomethyl or 1-carbamimidoyl; as well as their easily hydrolysable esters, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula I and their esters and salts. In addition, the invention relates to the preparation of compounds of formula I; to their use as pharmaceutically active substances, particularly for the treatment and prophylaxis of infectious diseases, and to pharmaceutical preparations containing a compound of the formula I for the treatment and prophylaxis of infectious diseases, especially infectious diseases caused by methicillin-resistant Staphy-lococcus aureus (MRSA). Preferred compounds of formula I are compounds wherein X is CH or N; R3- is hydrogen; R2 is a group of the formula
R6
R3 is hydrogen, an alkali metal ion or a tertiary ammonium group; R 4 is hydrogen, an amine, iminomethyl or 1-carbamimidoyl protecting group; R5 is hydrogen, hydroxymethyl; R6 is hydrogen or hydroxyl; and R7 methyl or 2-hydroxyethyl; as well as their easily hydrolysable esters, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula I and their esters and salts. The compounds of the present formula I are useful in the treatment of infectious diseases caused by bacterial pathogens, in particular Staphylococci aureus (MRSA) and Pseudomonas aeruginosa resistant to methicillin. In the above compounds of the formula I the substituted pyrrolidinone R2 may be present
in the form E or in the form Z. Compounds of the formula la are generally preferred, ie compounds wherein the pyrrolidinone takes the form E. The term "protected amino group" refers to groups such as those used in chemistry of the peptides, such as an alkoxycarbonyl group such as tert-butoxycarbonyl, allyloxy carbonyl and the like; a substituted alkoxycarbonyl group such as trichloroethoxycarbonyl, etc .; an optionally substituted aralkoxycarbonyl group, for example, p-nitrobenzyloxycarbonyl or benzyloxycarbonyl; an aralkyl group such as trityl or benzhihydryl; an alkanoyl group such as formyl or acetyl; a halogen-alkanoyl group such as chloroacetyl, bromoacetyl, iodoacetyl or trifluoroacetyl; or a silyl protecting group such as the trimethylsilyl group. Preferred amine protecting groups are tert-butoxycarbonyl (t-BOC), allyloxycarbonyl (ALLOC) and trityl. As the term "alkyl" is used herein, it refers to straight and branched chain hydrocarbon groups with 1 to 8 carbon atoms and preferably 1 to 4, for example methyl, ethyl, n-propyl, isopropyl, tertiary butyl and the like. As the term "? -hydroxy-alkyl" is used herein, it refers to straight and branched chain saturated hydrocarbon groups as defined above with a hydroxyl group in the terminal position, for example hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and Similar. As the term "α-amino-alkyl" is used herein, it refers to straight and branched chain saturated hydrocarbon groups as defined above which include an amino group in the terminal position, for example aminomethyl, 2-aminoethyl, 3-aminopropyl and similar. As used herein pharmaceutically acceptable salts useful in this invention include salts derived from metals, salts of amino acids and salts of mineral or organic acids.Examples of preferred metal salts are those derived from the alkali metals, for example lithium (Li +), sodium (Na +) and potassium (K "1"), of alkaline earth metals, for example magnesium (Mg ++). Salts derived from amino acids such as, for example, salts with arginine or lysine. Examples of salts of mineral acids are, for example, chlorides, sulfates or phosphates, and examples of salts of organic acids mesylates, napsylates, besylates, alloys, silicilates, tartrates, lactates, citrates, benzoates, succinates, acetates and the like.
Chlorides, sulfates, phosphates, lactates or mesylates are especially preferred. As easily hydrolysable esters of the compounds of formula I, compounds of the formula I are to be understood, wherein the carboxyl group in the 2-position is present in the form of an easily hydrolysable ester group. Examples of these esters, which may be of conventional type, are the alkanoyloxy-lower alkyl esters (for example the acetoxymethyl ester, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl), the lower alkoxycarbonyloxyalkyl esters (for example the ethoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethyl), lactonyl esters (for example phthalidyl and thiophthalidyl ester), lower alkoxymethyl esters (for example ethoxymethyl ester) and lower alkanoylaminomethyl esters (for example the ester of acetamidomethyl). Other esters can also be used (for example the benzyl and cyano ethyl esters). Other examples of these esters are the following: (2, 2-dimethyl-1-oxo-propoxy) methyl ester; 2- [(2-methylpropoxy) carbonyl] -2-pentenyl ester; 1- [[(1-Methylethoxy) carbonyl] oxy] ethyl ester; 1- (acetyloxy) ethyl ester; (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl ester; 1- [[(cyclohexyloxy) carbonyl] oxy] ethyl ester; and 3,3-dimethyl-2-oxobutyl ester. It will be appreciated by those skilled in the art that easily hydrolysable esters of the compounds of the present invention can be formed in a free carboxyl group of the compound. Examples of salts of the compounds of formula I are defined under "pharmaceutically acceptable salts" above. A preferred embodiment of the invention are compounds of the formula I wherein X is CH or N and R2 represents a group of the formula
wherein R 4 is hydrogen, iminomethyl or 1-carbamimidoyl; R5 is hydrogen or hydroxymethyl; and R6 is hydrogen or hydroxyl. In another preferred embodiment of the compounds of formula I X is CH or N and R2 represents a group of the formula
where R4, R and R have the meaning indicated above. Especially preferred are compounds of formula I wherein R5 and R6 are hydrogen. An especially preferred embodiment of the invention are compounds of formula I, wherein X is CH and R2 is a group of the formula
where R4 is as defined above. An especially preferred additional group of compounds is constituted by compounds of the formula I wherein X is N and R2 is a group of the formula
where R4 is as defined above. A further preferred embodiment are compounds of the formula I, wherein X is CH or N R1 is hydrogen or cyclopentyl R2 is a group of the formula
R3 is hydrogen, an alkali metal ion or a tertiary ammonium group, R4 is hydrogen, a protective amino group; R5 is hydrogen, dialkylcarbamoyl, and R6 is hydrogen or trifluoromethyl, as well as their easily hydrolysable esters, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula I and their esters and salts. These especially preferred compounds are, for example A: (6R, 7R) -7 - [(Z) -2- (5-amino- [1,2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino acid ] -8-oxo-3- [(E) - (R) -2-oxo [l, 3"] bipyridin-lidinyl-3-ylidenemethyl] -5-thia-l-aza-bicyclo [4, 2, 0 ] oct-2-en-2-carboxylic acid
N-OH
C02H ° B: acid (6R, 7R) -7- [(Z) -2- (5-amino- [1,2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -d-oxo- 3- [(E) - (S) -2-oxo [1,3 '] bipyridin-lidinyl-3-ylidemethyl] -5-thia-l-aza-bicyclo [4, 2, 0] oct-2-en -2-carboxylic
C: (6R, 7R) -7- [(Z) -2- (5-amino- [1,2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E)] acid - (R) -l'-iminomethyl-2-oxo [1,3 '] -bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] -oct-2- en-2-carboxylic
D: (6R, 7R) -7 - [(Z) -2- (5-amino- [1,2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E)] - (R) -1 '-carbamimidoyl-2-oxo- [1,3'] -bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bici-clo [4.2.0] -oct -2-en-2-carboxylic
E: (6R, 7R) -7- [(Z) -2- (5-amino- [1,2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) acid] -l-azetidin-3-ylmethyl-2-oxy-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] -oct-2-en-2-carboxylic acid
F: (6R, 7R) -7 - [(Z) -2- (5-amino- [1,2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) acid] -5'-hydroxymethyl-2-oxo- [1,3 '] -bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-1-aza-bicyclo [4.2.0] -oct-2-en-2 -carboxylic
The compounds of formula I, as well as their easily hydrolysable salts and esters, can be hydrated. The hydration may be carried out in the course of the preparation process or may occur gradually as a result of hygroscopic properties of an initially anhydrous product. The compounds of the present invention are useful as antibiotics having potent and broad antibacterial activity; especially against Staphylococci (MRSA) and Pseudomonas aeruginosa resistant to methicillin. The products according to the invention can be used as medicaments, for example in the form of pharmaceutical preparations for parenteral administration, and for this purpose they are preferably carried out in the form of preparations such as lyophilisates or dry powders for dilution with customary agents, such as water or isotonic common salt or carbohydrate solution (eg glucose). Depending on the nature of the pharmacologically active compound, the pharmaceutical preparations may contain the compound for the prevention and treatment of infectious diseases in mammals, humans and non-humans. A daily dose of from about 10 mg to about 4000 mg, especially from about 50 mg to about 3000 mg, is usual, those skilled in the art appreciating that the dosage will depend on age, condition of the mammals, and type. of diseases that are prevented or treated. The daily dose can be administered in a single dose or can be divided into several doses. An average single dose of about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg and 2000 mg can be contemplated. Representative compounds (A and B, above) of the present invention were tested. In vitro activity was determined by minimal inhibitory concentration with the agar dilution method on Mueller Hinton agar, inoculum = 104 CFU / spot.
* Agar dilution method on Mueller-Hinton agar, inoculum: 10 ^ CFQ / spot The efficacy in vivo was determined with an abscess model in mice, infected with S. aureus 270 A (MRSA). The dose (ip) was 10 mg / kg. The mean log of colony foraging units (CFU) was determined. A reduction of more than one hundred times was obtained in the number of CFUs with compound A compared to the untreated control. Compound A was more active than vancomycin, the current drug for clinical infections due to MRSA.
Efficacy in vivo
The compounds of the formula I according to the invention, as well as their pharmaceutically acceptable salts, hydrates, or easily hydrolysable esters can be prepared according to the invention for example (a) by treating a compound of the formula II
wherein R2 is as defined above, or a respective ester or salt, the amino group and the carboxylic groups present in the compound of formula II can be unprotected or protected, with a carboxylic acid of the general formula III
wherein Rf is hydrogen or an amine protecting group, R1 'is hydrogen, cyclopentyl or a hydroxyl protecting group and X is as defined above, or with a respective reactive functional derivative, or (b) dissociating the amino protecting group, hydroxyl and / or carboxyl in a compound having the formula IV
wherein R2 is as defined above, R ^ is hydrogen or an amino protecting group; R ^ - "is hydrogen or a hydroxyl protecting group, R ^ 1 is hydrogen or a carboxyl protecting group, with the proviso that at least one of R ^, R1" and Rn is a corresponding protecting group, or a respective salt . The reaction of compounds of formula II and III or a reactive derivative of formula III according to embodiment (a) can be carried out in a manner known per se. The carboxyl group in compounds of formula II can be protected, for example, by esterification to form an easily dissociable ester such as silyl ester (for example trimethylsilyl ester), a tert-butyl ester, allyl, p-ethoxybenzyl or a benzhydryl. The amino group present in the acylating agent of the formula III can be protected. Possible protecting groups Rf are, for example, protective groups which are cleavable by acid hydrolysis (for example terbutoxycarbonyl or trityl groups), by basic hydrolysis (for example the trifluoroacetyl group), by hydrazinolysis (for example the phthalimido group) or by dissociation catalytic in the presence of Pd (the allyloxycarbonyl group). Preferred protecting groups are the allyloxycarbonyl groups, tert-butyloxycarbonyl, chloroacetyl, bromoacetyl and acetyl iodine, especially the chloroacetyl group. The latter-mentioned protective groups can be dissociated by treatment with thiourea. The 7-amino group in compounds II can be protected, for example, by a silyl protecting group such as the trimethylsilyl group. In the reaction of a 7-amino compound of formula II with a carboxylic acid of formula III or a respective reactive functional derivative, for example, a free carboxylic acid can be reacted with a ester mentioned above of a compound of formula II in The presence of a carbodiimide such as dicyclohexylcarbodiimide in an inert solvent such as ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide, and then the ester group can be dissociated. According to another embodiment, a salt of an acid of the formula II (for example a trialkylammonium salt such as the triethylammonium salt) is reacted with a reactive functional derivative of a carboxylic acid of the formula III in an inert solvent (for example dimethylformamide). or dimethyl acetamide). According to another embodiment, the preferred acylation, wherein the amino group present in the acylating agent of the formula III does not need to be protected, involves the use of a reactive functional derivative of the acylating agent of the formula III, for example, a mixed anhydride of thiophosphoric acid of the carboxylic acid, a 1-hydroxybenzotriazole ester or a 2-benzothiazolyl thioester. For example, a mixed thiophosphoric acid anhydride can be reacted with the compound of formula II, preferably in a polar solvent such as dimethyl formamide (DMF), dichloromethane, or a mixture of EMF / i-propanol / water in the presence of a base as, for example, triethylamine. The 1-hydroxybenzotriazole ester, as well as the 2-benztriazolyl thioester can be reacted with the compound II in an inert organic solvent such as a chlorinated hydrocarbon, for example methylene chloride, or in dimethylformamide, dimethylacetamide, acetone, ethyl acetate or in a mixture of these solvents with water.
A reactive 2-benzthiazolyl thioester of this type is, for example
This compound is new and forms part of the present invention. The reaction of a 7-amino compound of formula II with the crboxylic acid of formula III or a respective reactive derivative can be carried out, conveniently at a temperature between about -40 ° C and + 60 ° C, for example at temperature ambient. The mode (b) of the process of the present invention involves deprotection (separation) of a protected amino group in azo or azo a and a to the protected pyrrolidine ring (R4 as the protective group), and / or protected hydroxyl or carboxylic groups present in a compound of the formula IV and can be carried out as follows: Separation of aminic protective groups As indicated above, the amine protecting groups can be dissociated by acid hydrolysis (for example the group ter -butoxycarbonyl or trityl), for example aqueous formic acid, trifluoroacetic acid or by basic hydrolysis (for example the trifluoroacetyl group). Other protecting groups can be dissociated by hydra-zinolysis (for example the phthalimido group). The allyloxycarbonyl group can be dissociated by Pd-catalyzed transfer to nucleophiles. The chloroacetyl, bromoacetyl and iodoacetyl groups are dissociated by treatment with thiourea. The amino-protecting groups which are cleavable by acid hydrolysis are preferably separated with the aid of a lower alkancarboxylic acid which may be halogenated. In particular, formic acid or trifluoroacetic acid is used. The reaction is carried out in the acid or in the presence of a co-solvent such as a halogenated lower alkane, for example methylene chloride. The acid hydrolysis is generally carried out at room temperature, although it can be carried out at a slightly higher or slightly lower temperature (for example a temperature in the range of about -30 ° C to + 40 ° C). The protecting groups which are dissociable under basic conditions are generally hydrolysed with aqueous caustic alkali diluted between 0 ° C and 30 ° C. The protecting groups of chloroacetyl, bromoacetyl and acetyl iodine can be dissociated using thiourea in acidic, neutral or alkaline medium between about 0 ° C-30 ° C. Separation of hydroxyl protecting groups The term "hydroxyl protecting group" refers to protecting groups as conventionally used in the art such as trityl (triphenylmethyl), trimethylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl, triphenylmethyl, lower alkanoyl, acetyl, tetrahydropyranyl. , benzyl, p-nitrobenzyl and the like. Preferred hydroxyl protecting groups are such as are commonly known in the art, for example for protection of hydroxyimino groups (R - * - = hydrogen in compounds of formula I), usually trityl, lower alkanoyl, especially acetyl, tetrahydropyranyl. These protective groups are separated, for example, as follows: -trityl in acidic solvent such as 90% formic acid between about 0 and 50 ° C or triethylsilane in trifluoroacetic acid between about -20 to 25 ° C; in organic solutions of hydrochloric acid between -50 and 25 ° C; -acetyl with weak inorganic bases such as sodium bicarbonate in methanol or ethanol / water between about 0 and 50 ° C; -tetrahydropyranyl with weak organic acids such as p-toluenesulfonic acid in an alcohol, for example ethanol, between about 0 ° C and the boiling point of the mixture. Separation of protective groups in the carboxyl function The term "carboxylic acid protecting group" refers to protecting groups conventionally used to replace the acidic proton of a carboxylic acid. As carboxyl protecting groups an ester form can be used which can easily be converted to a free carboxyl group under mild conditions, for example methoxymethyl, ethylthio-methyl, 2,2,2-trichloroethyl, 2-haloethyl, 2- (trimethylsilyl) -ethyl, tert-butyl, allyl, benzyl, triphenylmethyl (trityl), diphenylmethyl, p-nitrobenzyl, p-methoxybenzyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, i-propyl-dimethylsilyl. Benzhydryl, tert-butyl, p-nitrobenzyl, p-methoxybenzyl and allyl are preferred. These protecting groups can be separated as follows: benzhydryl trifluoroacetic acid with anisole, phenol, cresol or triethylsilane between about -40 ° C and room temperature; hydrogen with Pd / C in an alcohol such as ethanol or in tetrahydrofuran; BF3 ~ acetic acid etherate between about 0 and 50 ° C; tert-butyl formic acid or trifluoroacetic acid with or without anisole, phenol, cresol or triethylsilane and a solvent such as dichloromethane between about -10 ° C and room temperature;
sodium p-nitrobenzyl sulfide in acetone / water between about 0 and room temperature; or hydrogen with Pd / C in an alcohol such as ethanol or in tetrahydrofuran; p-methoxybenzyl formic acid between about 0 and 50 ° C; or trifluoroacetic acid and anisole, phenol or triethylsilane between about -40 ° C and room temperature; allyl transalkylation reaction catalysed by palladium (O) in the presence of tri-n-butyltin hydride and acetic acid, see, for example F. Guibé et al. in J. Org. Chem. (1987) 52, 4984-4993 Other methods for the preparation of the compounds according to the invention are known in the art. The compounds of formula I can be prepared, for example, analogously to the methods described in US Pat. No. 5,523,400 and according to the examples given below. Examples EXAMPLE 1 Preparation of the acylating agent S-benzothiazole-2-yl ester of (Z) - (5-amino- [1,2,] thiadiazol-3-yl) -trityloxyimino-thioacetic acid
To a salt suspension of 1-allyl-1-methyl-prirolidinium (Z) - (5-amino- [1, 2, 4] thiadiazol-3-yl) -trityloxyimino-acetate (1.89 g, 3.4 mmol) in 25 ml of acetonitrile was added at 0 ° C 2,2'-dithio-bisbenzothiazole (1.36 g, 4.1 mmol). Within 40 minutes a solution of triethylphosphite (0.7 ml, 5.8 mmol) in 7 ml of acetonitrile was added and the mixture was stirred at room temperature for 27 hours. The precipitate was collected by filtration and washed with acetonitrile and n-hexane. Yield: 1.615 g (82%) beige IR crystals. { KBr) 1704, 1619, 1003 cm-1 MS (ISP) 580.2 (M + H) +. EXAMPLE 2 2.1. Preparation of an allyl ester mixture of the acid (IR, 3 'R) - and (ÍS, 3' R) -3-bromo-2-oxo [1,3 '] bipyrrolidinyl-1' -carbo-xylic
A solution of (R) -3-amino-pyrrolidine-l-carboxylic acid (1: 3.2) allyl ester trifluoroacetate (47.84 g, 0.089 mol) in 180 ml of dichloromethane was treated with sodium hydroxide solution aqueous 50% (72 ml, 0.894 mol). To the vigorously stirred mixture was added, within 18 minutes at 0 ° C, a solution of 2-bromo-4-chloro-butanoyl chloride (21.62 g, 0.098 mol) in 90 ml of dichloromethane. The reaction mixture was stirred at 0 ° C for 1 hour. The phases were separated, the aqueous phase was extracted twice with 100 ml of dichloromethane and several times with ml of water were added. It was dried over magnesium sulfate and the solvent was removed by evaporation. The residual yellow oil (32 g) was redissolved in 380 ml of dichloromethane and 190 ml of a 50% aqueous sodium hydroxide solution and 3.23 g of a solution were added with vigorous stirring and at room temperature.
Dowex 2 x 10. After 6 hours the phases were separated, the aqueous phase was extracted twice with 150 ml of dichloromethane.
The combined organic phases were washed once with 100 ml of water, once with brine, dried over magnesium sulfate and concentrated. Yield: 28.7 g (quant.) Of a yellow oil IR (net) 1697 cm "1 MS (ISP) 317.2 (M) + In accordance with the procedure set forth in the preceding example, the following additional compounds were prepared: 2.2 Mixture of allyl ester of acid (IR, 3'S) and (lS, 3'S) -3-bromo-2-oxo- [1,3 '] ipirrolidinyl-1' -carboxylic IR (net) 1697 an-1 MS (ISP ) 317.2 (M) + 2.3 Allyl ester mixture of (3R, S, 3'RS) - and (3RS, 3 'SR) -3-bromo-2-oxo- [1,3'] bipyrrolidinyl -1 '-carboxylic
IR (net) 1695 arT1 MS (EI) 259 (M-OC3H5). 2.4. Allyl ester of (RS) -3- (3-bromo-2-oxo-pyrrolidin-1-yl) -azetidine-1-carboxylic acid (net) 1700 cpT1 EM (ISP, (M) 2.5. (RS) -4- (3-Bromo-2-oxo-pyrrolidin-1-ylmethyl) -piperidine-1-carboxylic acid (net) 1699 cm-1 MS (ISP) 345.2 (M) + 2.6 Diallysis ester of (RS) -4- (3-bromo-2-oxo-pyrrolidin-1-yl) -pyrazolidin-1,2-dicarboxylic acid (KBr) 1704 arT1 MS (ISP) 404 (M + H) + 2.7. 1: 1 mixture of allyl ester of (3S, 4R) -3- [(R) - and
[(S) -3-brop »-2-oxo-pyrrolidin-1-ylmethyl] -4-trifluoromethyl-pyrrolidin-1-carboxylane IR (KBr) 1702_m-l MS (ISP) 401.3 (MH) +. 2.8. Allyl ester mixture of acid (3R, 3'S, 5'S) - and
(3S, 3 'S, 5' S) -3-bromo-5 '-dimethylcarba? Poil-2-oxo- [1,3'] bipyridin-lidinyl-1 '-caxboxyloid IR (KBr) 1699, 1649 cm- 1 MS (EI) 388 (M + H) + 2.9. Mixture 1: 1 of acid (3R, 3'S, 5'S) - and OS ^ 'S ^' SJ-S-brano- 5 '- «_ ü_t? Ethyl < _arbamoyl-2-oxo- [1,3 '] bipyrrolidinyl-1' -carboxylic acid
IR (KBr) 1698, 1654 cm-1 MS (ISP) 388.1 (MH) + 2.10 Allyous ester of (RS) -3- (3-bromo-2-oxo-pyrrolidin-1-ylmethyl) -azetidin- acid 1-carboxylic IR (KBr) 1698 cp? -1 EM (ISP) 319.2 (MH) + EXAMPLE 3 3.1. Bromide mixture of (IR, 3'R) and (ÍS, 3'R) - (1-allyloxycarbonyl-2-oxo- [1,3'-3-bipyrrolidinyl-3-yl) -triphenyl-phosphonium
It was dissolved in 80 ml of dichloromethane triphenylphosphine (23.62 g, 0.090 mol) and a mixture of the allyl ester of the acid (IR, 3'R) - and (lS ^ 'RAS-bromo ^ -oxo-U ^ Mbipirrolidinil-l Carboxylic acid (28.56 g, 0.090 mol) in 80 ml of dichloromethane The solvent was removed in vacuo and the residual oil was heated for 2 hours at 100 [deg.] C. The resulting solid was dissolved in 130 ml of dichloromethane and It was added with stirring to 1500 ml of n-hexane resulting in the separation of the product The solvent was decanted and the residue was triturated with 1500 ml of diethyl ether The solid thus formed was collected by filtration, washed with n-hexane and ether diethyl ether and dried in vacuo to give 45.1 g (78%) of the product as colorless crystals IR (KBr) 1682 cm-1 MS (ISP) 499.3 (M) +. in the preceding example the following additional compounds were prepared: 3.2 Mix of (3R, 3'S) and (3S, 3'S) bromide - (1-allyloxycarbonyl-2-oxo [1, 3 '] bipir rolidinyl-3-yl) -triphenyl-phosphonium IR (KBr) 1684 cm-1 MS (ISP) 499.2 (M) +.
3. 3. Bromide mixture of (3S, 3'S) and (3S, 3'S) - (1'-allyloxycarbonyl-2-oxo [1, 3 '] bipyrrolidinyl-3-yl) -triphenyl-phosphonium IR (KBr) 1684 cm-1 MS (ISP) 499.4 (M + H) +. 3.4. Bromide of (RS) - [1- (l-allyloxycarbonyl-azetidin-3-yl) -2-oxo-pyrrolidin-3-yl] -triphenylphosphonium IR (KBr) 1687 cm-1 MS (ISP) 485.4 (M + H) +. 3.5. Bromide of (RS) - [1- (l-allyloxycarbonyl-piperidin-4-ylmethyl-2-oxo-pyrrolidin-3-yl] -triphenylphosphonium IR (KBr) 1688 cm-1 MS (ISP) 527.3 (M + H) +., 3.6 Brcmide of (RS- [l- (1, 2-bis-allyloxy-rbonyl-pyrazolidin-4-yl) -2-oxo-pyrrolidin-3-yl] -trif enyl-phosphonium IR (KBr ) 1688 ero-1 MS (ISP) 585.5 (H) + .3.1. Mixing 1: 1 bromide of [(R) - and [(S) -l- [(S) -l-allyloxycarbonyl-pyrrolidin- 2-ylmethyl] -2-oxo-pyrrolidin-3-yl] -trifenyl-phosphonium IR (KBr) 1682 arT1 EM (ISP) 513.4 (M) + .3,8 Mixing 1: 1 brcmuro of (3S , 4R) - [(R) - and [(s) -l- (i-allyloxycarbonyl-4-trifluorocnethyl-pirtolidin-3-i_j »tyl) -2-oxo-pyrrolidin-3-yl] -trif enylphosphonium IR (KBr) 1690 ctrT1 EM (ISP) 581.2 (MH) +. 3.9 Mixing 1: 1 brcmide of (3R, 3'S, 5'S) - and (3S, 3'S, 5'S) - (1'- -alloyloxy) carbonyl-5'-dimethylcarbamoyl-2-oxo [1,3 '] ipyrrolidinyl-3-yl) -tri phenyl-phosphonium IR (KBr) 1687 arf1 MS (ISP) 570.3 (M) + 3.10 Mixture 1: 1 brcmuro of (3R, 3 'S, 5' R) - and (3S, 3 'S, 5 * S) - -3 (1'-allyloxycarbonyl-5'-dimethyl) arba? rl-2-oxo [1,3'-Jbipyrroli-dinyl-3-yl) -triphenyl-phosphonium IR (KBr) 1686 cm-1 MS (ISP) 570.3 (M) +. 3.11. Bromide of (RS) -tl- (l-allyloxycarbonyl-azetidin-3-ylmethyl) -2-oxo-pyrrolidin-3-yl] -triphenyl-phosphonium (1: 1) IR (KBr) 1679 an-1 EM (ISP ) 499.2 (M) +. EXAMPLE 4 4.1. Benzhydryl ester of (E) - (2R, 6R, 7R) -3- [(R) -l'-Allyloxycarbonyl-2-oxo- [1, 3 '] bipyrrolidinyl-3-ylidenemethyl] -7-tert-butoxycarbonylamino -8-oxo-5-thia-l-azabicyclo [4.2.0] oct-3-en-2-carboxylic acid
A suspension of the bromide mixture of (IR, 3'R) and (1S, 3'R) - (1 * allyloxycarbonyl-2-oxo- [1, 3 *] was refluxed for 1 hour and a half. bipyrrolidinyl-3-yl) -triphenyl-phosphonium (43.5 g, 0.075 mol) and benzhydryl ester of (2R, 6R, 7R) -ter-butoxycarbonylamino-3-formyl-8-oxo-5-thia-l- azabicyclo [4.2.0] oct-3-en-2-carboxylic acid (33.74 g, 0.068 mol) in 950 ml of butylene oxide. The solvent was removed in vacuo and the residue was purified by column chromatography (300 g of SiO2, ethyl acetate: n-hexane = 2: 1, 3: 1) to give 67, 8 g of a 1: 1 mixture (molar ratio) containing the product and triphenylphosphine oxide in the form of a yellow foam. No further purification was necessary to proceed to the next stage. IR (KBr) 1781, 1744 cm-1 MS (ISP) 732.5 (M + NH 4) +. In accordance with the procedure set forth in the preceding example, the following additional compounds were prepared: 4.2. Benzhydryl ester of (E) - (2R, 6R, 7R) -3- [(S) -l'-allyloxycarbonyl-2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -7-tert-butoxycarbonylamino -8-oxo-5-thia-l-azábicyclo [.2.0] oct-3-en-2-carboxylic IR (KBr) 1782, 1744, 1705 arT1 MS (ISP) 732.4 (M + NH) +. 4.3. Mixture of benzhydryl ester of (E) - (2R, 6R, 7R) -3- [(R) - and [(allyloxycarbonyl ^ -oxo-U ^ 'jbipyrrolidinyl-S-ylidenemethyl] -ter-butoxycarbonylamino- d-oxo-S-thia-l-azabicyclo [4.2.0] oct-3-en-2-carboxylic IR (KBr) 1780, 1744, 1704 aiT1 MS (ISP) 715.4 (M + H) + 4.4 Benzhydryl ester of (E) - (2R, 6R, 7R) -3- [1- (1-Allyloxycarbonyl-azetidin-3-yl) -2-oxo-pyrrolidin-3-ylidenemethyl] -7-ter -butoxycarbonylamino-8-oxo-5-thia-l-azabicyclo [4.2.0] oct-3-en-2-carboxylic IR (KBr) 1782, 1743, 1713 aiT1 EM (ISP) 718.4 (M + NH4) A 4.5 Benzhydryl ester of (E) - (2R, 6R, 7R) -3- [l- (1-allyloxycarbonyl-piperidin-4-ylmethyl) -2-oxo-pyrrolidin-3-ylidene-methyl] -7 -ter-butoxycarbonylamino-8-oxo-5-thia-l-azabicyclo- [4.2.0] oct-3-en-2-carboxylic IR (KBr) 1779, 1743, 1692 n-1 EM (ISP) 760.5 (M + NH) + 4.6 Ester benzhydrilic acid (E) - (2R, 6R, 7R) -3- [l - [(3S, 4R) -l-allyloxycarbonyl-4-trifluoromethyl-pyrrolidin-3-ylmethyl. ] -2-oxo-pyrrolidin-3-ylidenemethyl] -7-tert-butoxycarbonylamino-8 -oxo-5-thia-l-aza-bicyclo [4.2.0] ost-3-en-2-sa? tooxiliso IR (KBr) 1782, 1711 crn-1 MS (ISP) 797.0 (MH) +. EXAMPLE 5 5.1. Mixture of benzhydryl ester of (E) - (5R, 6R, 7R) - and
- (5S, 6R, 7R) -3- [(R) -l'-allyloxycarbonyl-2-oxo- [l, 3I] bipyrrolidi-nil-3-ylidenemethyl] -7-tert-butoxycarbonylamino-5, 8-dioxo -5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
A solution of the above-described mixture of benzhydryl ester of (E) - (2R, 6R, 7R) -3- [(R) -1'-allyloxycarbonyl-2-oxo- [1], was cooled to -10 ° C. 3 '] bipyrrolidinyl-3-ylidenemethyl] -7-tert-butoxy-rbonylamino-8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-3-en-2-carboxylic acid and triphenylphosphine oxide (67, 8 g, 0.068 mol) in 400 ml of dichloromethane. To this was added dropwise a solution of m-chloroperbenzoic acid (70%, 16.82 g, 0.068 mol) in 250 ml of dichloromethane. The resulting solution was stirred for 2 and a half hours between -5 and 0 ° C, 150 ml of aqueous sodium thiosulfate solution (5%) were added and the mixture was stirred for 15 minutes. The phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane. The combined organic phases were washed with each of 150 ml of aqueous solutions of sodium thiosulfate (5%), sodium bicarbonate (5%) and finally brine. The solution was dried over magnesium sulfate, concentrated after filtration and purified by column chromatography (1000 g of SiO2, ethyl acetate: n-hexane = 3: 1.1: 0 and ethyl acetate: methanol = 9).
: 1) . Yield: 36.3 (73%) IR (KBr) 1797, 1711 an_1 EM (ISP) 748.5 (M + NH4) +. In accordance with the procedure set forth in the preceding example, the following additional compounds were prepared: 5.2. Benzhydryl ester mixture of (E) - (5R, 6R, 7R) - and - (5S, 6R, 7R) -3 - [(S) -l'-allyloxycarbonyl-2-oxo- [1, 3 '] bipyrrolidinyl-3-ylidenemethyl] -7-tert-butoxycarbonylamino-5, 8-dioxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic IR (KBr) 1796, 1710 crn -1 MS (ISP) 748.5 (M + NH 4) +. 5.3. Benzhydryl ester mixture of (E) - (5R, 6R, 7R) - and - (5S, 6R, 7R) -3- (1'-allyloxycarbonyl-2-oxo- [1,3 '] bipyrrolidinyl-3-) ilidemethyl] -7-tert-butoxycarbonylamino-5, 8-dioxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid (conf. to C3 'in bipyrrolidine-fraction R and S) IR (KBr) 1796, 1716 c "1 MS (ISP) 748.5 (M + NH 4) + 5.4 Mixture of benzhydryl ester of (E) - (5R, 6R, 7R) - and - (5S, 6R, 7R) -3- [1- (1- (1-Allyloxycarbonyl-azetidin-3-yl) -2-oxo-pyrrolidin-3-ylidenemethyl] -7-tert-butoxycarbonylamino-5, 8-dioxo -5-thia-1-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic IR (KBr) 1797, 1718 crn-1 MS (ISP) 734.5 (M + NH4) +. Benzhydryl ester mixture of (E) - (5R, 6R, 7R) - and - (5S, 6R, 7R) -3- [1- (1- (l-allyloxycarbonyl-piperidin-4-ylmethyl-2-oxo) -pyrrolidin-3-ylidenemethyl] -7-tert-butoxycarbonylamino-5, 8-dioxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic IR (KBr) 1795, 1721 1692 cm "1 MS (ISP) 776.5 (M + NH 4) + 5.6 Benzhydrilic acid ester mixture (E) - ( 5R, 6R, 7R) - and - (5S, 6R, 7R) -3- [1- [(3S, 4R) -1-allyloxycarbonyl-4-trifluoromethyl-pyrrolidin-3-ylmethyl] -2-oxo-pyrrolidin- 3-ylidene-methyl] -7-tert-butoxycarbonylamino-5,8-dioxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxyliso IR (KBr) 1797, 1718 cpT1 EM ( ISP) 734.5 (M + NH4) +. EXAMPLE 6 6.1. Benzhydryl ester of (E) - (6R, 7R) -3- [(R) -l'-allyloxycarbonyl-2-oxo [1,3'] bipyrrolidinyl-3-ylidenemethyl] -7-tert-butoxycarbonylamino-8- oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
To a solution of a 1: 1 mixture of benzhydryl ester of (E) - (6R, 7R) - and - (5S, 6R, 7R) -3- [(R) -l'-allyloxycarbonyl-2-oxo) 1, 3 '] bipyrrolidinyl-3-ylidenemethyl] -7-tert-butoxycarbonyl-amino-5, 8-dioxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid ( 36.3 g, 0.050 mol) in 370 ml of dichloromethane, 30 ml of EMF and 44 ml of N-methylacetamide was added within 20 minutes at -30 ° C a solution of phosphorus tribromide (19.1 ml, 0.203 mol ) in 56 ml of dichloromethane. After stirring for 1 1/2 hours at -30 ° C, the mixture was allowed to warm to -5 ° C and cooled with 800 ml of cold water. The phases were separated, the aqueous phase was extracted twice with 300 ml of dichloromethane. The combined organic phases were washed with 500 ml of water and brine and dried over magnesium sulfate. After removal of the solvent in vacuo, the residue was treated with a 1: 1 mixture of ethyl acetate and n-hexane (700 ml). The precipitated product was collected by filtration. Performance: 32, 9 g (91%) of orange crystals. IR (KBr) 1785, 1715 an "1 MS (ISP) 732.5 (M + NH4) + In accordance with the procedure set forth in the preceding paragraph, the following additional compounds were prepared: 6.2 Benzhydryl ester of (E) acid - (6R, 7R) -3- [(S) -1'-Allyloxycarbonyl-2-oxo [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -7-tert-butoxycarbonylamino-8-oxo-5-thia-1 -aza-bicyclo [4.2.0] oct-2-en-2-carboxylic IR (KBr) 1786, 1712 crn-1 EM (ISP) 732.5 (M + NH) + 6.3 Ester benzhydrylic acid (E) ) - (6R, 7R) - and - [(S) -l'-allyloxycarbonyl-2-oxo [1, 3 '] bipyrrolidinyl-3-ylidenemethyl] -7-tert-butoxycarbonylamino-8-oxo-5-thiamine l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic IR (KBr) 1785, 1712 cpf1 EM (ISP) 732.6 (M + NH4) + 6.4 Benzhydryl ester of the acid (E) - (6R, 7R) -3- [1- (1-Allyloxycarbonyl-azetidin-3-yl) -2-oxo-pyrrolidin-3-ylidenemethyl] -7-tert-butoxycarbonylamino-8-oxo-5-thia-1- aza-bicyclo [4.2.0] oct-2-en-2-carboxylic IR (KBr) 1786, 1717 atT1 EM (ISP) 718, 6 (M + NH) + .6.5 Benzhydryl ester of (E) - ( 6R, 7R) -3- [1- (1-Allyloxycarbonyl-piperidin-4-ylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl] -7-tert-butoxycarbonylamino-8-oxo-5-thia-1-aza-bicyclo [ 4.2.0] oct-2-en-2-carboxylic IR (KBr) 1784, 1688 cm-1 MS (ISP) 760, 6 (M + NH) +. 6.6. Diallyl ester of the acid (E) - (6R, 7R) -4- [3- (2-benzhicyryloxy-_bonyl-7-tert-butoxy-2-bonylaraine-8-oxo-5-thia-1-aza-bicyclo [ 4.2.0] oct-2-en-3-ylmethylene) -2 -oxo-pyrrolidin-1-yl] pyrazolidin-1,2-dicarboxylane IR (KBr) 1785 crn "MS (ISP) 800.6 (MH) + 6.7 Ester benzhydryl of (E) - (6R, 7R) -3- [l- [(S) -l-alyloxy-coryloyl-pyrrolidin-1-ylmethyl] -2-oxo-pyrrolidin-3-ylidene-methyl ester ] -7-ter-butoxica_ ± »nila? T_Lno-8-oxo-5-thia-l-azabicyclo- [4.2.0] oat-2-en-2-aarboxiliao IR (KBr) 1784 can-1 EM (ISP 729.3 (M + -H) + 6.8 Benzhydryl ester of (E) - (6R, 7R) -3- [l - [(3S, 4R) -l-allyloxycarbonyl-4-trifluoromethyl-pyrrolidin- 3-yl-ethyl] -2-oxo-pyrrolidin-3-ylidenemethyl] -7-t »r-butoxycarbonylamino-8-oxo-5-thia-1-aza-biaialo [4.2.0] ost-2-en-2 carboxylase IR (KBr) 1790, 1713 cm-1 MS (ISP) 797.4 (MH) +. 6.9 Ester benzhydrylis of (E) - (6R, 7R) -3- [(3S, 5 »S) - 1'-allyloxycarbonyl-5'-butylcarbamoyl-2-oxo [1,3 *] bipyrrolidin-3-ylidenemethyl] -7-tert-butoxyarbonyl no-8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carbaxiliao IR (KBr) 1787, 1713 crn-1 EM (ISP) 786.4 (MH) + . 6.10. Ester benzhydryl of allyloxycarbonyl-5 • -dimethylsate? Barnoyl-2-oxo [1,3-?]] Bipyrrolidinyl-3-ylidenemethyl] -7-tßr-butoxysia ± nylamino-8-oxo-5-thia-l-aza- bis-cyclo [4.2.0] oct-2-en-2-carboxylic acid IR (KBr) 1786, 1712 cm "1 MS (ISP) 786.5 (MH) +.
6. 11. Benzhydrylis ester of (E) - (6R, 7R) -3- [l- (l-allyloxy? ±) onyl-azetidin-3-ylmethyl) -2-oxo-pyrrolidin-3-ylidene-methyl] - 7-tert-butoxy < 3a__bonilap non-8-o_co-5-thia-l-azabisyclo- [4.2.0] oct-2-en-2-carboxyliao IR (KBr) 1780, 1700 can-1 EM (ISP) 715.3 (M + H ) + EXAMPLE 7 7.1. (E) - (6R, 7R) -3- [(R) -l'-Allyloxycarbonyl-2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl) -7-amino-8- (tr) acid trifluoroacetate oxo-5-thia-l-aza-bio [4.2.0] oct-2-en-2-carboxylic acid
To a solution of benzhydryl ester of (E) - (6R, 7R) -3- [(R) -1'-allyloxy-carbonyl-2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl) -7 -ter-butoxycarbonylamino-8-oxo-5-thia-l-aza-bio [4.2.0] oct-2-en-2-carboxylic acid (32.9 g, 0.046 mol) in 320 ml of dichloromethane was added to 0 ° C 32 ml of anisole and 180 ml of trifluoroacetic acid. The mixture was stirred for 2 and a half hours with stirring at room temperature, concentrated to a volume of 50 ml and poured into 1000 ml of ice-cold diethyl ether. The precipitated solid was collected by filtration and dried. Yield: 24.9 g (98%) beige beige IR (KBr) 1782, 1680 crn-1 MS (ISP) 466.4 (M + NH) +.
The following additional compounds were prepared according to the process or exposure in the preceding example: 7.2. (E) - (6R, 7R) -3- [(S) -l'-allyloxycarbonyl-2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl) -7-amino-8- acid trifluoroacetate oxo-5-thia-l-aza-bio [4.2.0] oct-2-en-2-carboxylic IR (KBr) 1782, 1679 an "1 MS (ISP) 466.3 (M + NH4) +. (E) - (6R, 7R) -3- [R) - and - [(S) -l'-allyloxycarbonyl-2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl) -7-trifluoroacetate -amino-8-oxo-5-thia-l-aza-bio [4.2.0] oct-2-en-2-carboxylic IR (KBr) 1783, 1681 cm "1 MS (ISP) 449.5 (M + NH) +. 7.4. (E) - (6R, 7R) -3- [l- (1-allyloxycarbonyl-azeitidin-3-yl) -2-oxo-pyrrolidin-3-ylidenemethyl] -7-amino-8-oxo-5-trifluoroacetate -thia-l-aza-bio [4.2.0] oct-2-en-2-carboxylic IR (KBr) 1783, 1681 cm "1 MS (ISP) 435.5 (M + NH) + .7,5. trifluoroacetate (E) - (6R, 7R) -3- [l- (1- Allyloxycarbonyl-piperidin-4-ylmethyl) -2-oxo-pyrrolidin-3-ylidenemethyl] -7-amino-8-oxo-5-tia acid -l-aza-bio [4.2.0] oct-2-en-2-carboxylic IR (KBr) 1784, 1681 c "1 MS (ISP) 492.3 (M-H + NH3) ~. 7.6. Acid (E) - (6R, 7R) -7-amino-3- [l- (1, 2-bis-allyloxycarbonyl-pyrazolidin-4-yl) -2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo -5-thia-l-aza-bio [4.2.0] oct-2-en-2-carboxyliso melting point 148-149 ° C 7.7. (E) - (6R, 7R) -3- [l- [(S) -l-allyloxysarbonyl-pyrrolidin-2-ylp < / RTI > ethyl] -2-oxo-pyrrolidin-3-ylidenemethyl] -7-amino-8-oxo-5-thia-l-aza-bio [4.2.0] oct-2-en-2-carboxyliao (1: 0, 2) IR (KBr) 1780, 1690 crn-1 MS (ISP) 463.3 (MH) +. 7.8. Acid (E) - (6R, 7R) -3- [l - [(3S, 4R) -l-Allyloxycarbonyl-4-trifluoromethyl-pyrrolidin-3-ylmethyl] -2-oxo-pyrrolidin-3-ylidene] - 7-amino-8-oxo-5-thia-l-azabisyclo [4.2.0] oct-2-en-2-carboxylic IR (KBr) 1779, 1686 cpT1 MS (ISP) 531.3 (MH) +. 7.9. Methyl (E) Trifluoroacetate - (6R, 7R) -3- [(3'S, 5'S) -11-allyloxycarbonyl-5 * -di? Netylcarbarooyl-2-oxo [1,3 '] bipyrrolidinyl-3-ylidenemethyl) -7 -amino-8-oxo-5-thia-l-azabio [4.2.0] oct-2-en-2-carboxyliso (1: 0.4) IR (KBr) 1779, 1681 arf1 EM (ISP) 520.2 (MH) +. 7.10. Trifluoroacetate of the acid (E) - (6R, 7R) -3- [O 'S' 'RJ-1-allyloxycarbonyl-5'-dimethylcarbamoyl-2-oxo [1,3'] bipyrrolidinyl-3-ylidenemethyl] -7-amino -8-oxo-5-thia-l-azabisyclo [4.2.0] ost-2-en-2-setrboxyliso (1: 0.5) IR (KBr) 1779, 1681 arT1 EM (ISP) 520.3 (MH ) + EXAMPLE 8 8.1. Acid (dR ^ RAS-pEAIRAl'-allyloxycarbonyl ^ -oxo- ^ bi-pyrrolidinyl-3-ylidenemethyl] -7- [(Z) -2- (5-amino- [1, 2, 4] thiadiazol- -il) -2-trityloximino-acetylamino] -8-oxo-5-thia-l-aza-bio- [4.2.0] oct-2-en-2-carboxylic
A solution of acid trifluoroacetate (6R, 7R) -3- [(E) - (R) -1'-allyloxycarbonyl-2-oxo- [1,3 '] bi-pyrrolidinyl-3-ylidenemethyl] -7-amino -8-oxo-5-thia-l-aza-bio- [4.2.0] oct-2-en-2-carboxylic acid (3.90 g, 7.06 mmol)) in 75 ml of EMF was treated with ester (Z) - (5-amino- [1,2,4] thia-diazol-3-yl-trityloxyimino-thioacetic acid S-benzothiazole-2-yl (4.5 g)7.76 mmol) for 48 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue was distributed between 550 ml of ethyl acetate and 375 ml of water. The solid was discarded, the phases were separated and the aqueous phase was extracted with 150 ml of ethyl acetate. The combined organic phases were concentrated after which the product was separated. It was collected by filtration, washed with ethyl acetate and dried. Yield: 4.42 g (68%) of beige crystals IR (KBR) 1785, 1681 crn-1 EM (ISP) 878.6 (M + NH4) +. In accordance with the procedure set forth in the preceding example, the following additional compounds were prepared: 8.2. Acid (6R, 7R) -3 - [(E) - (S) -l * -alloxycarbonyl-2-oxo- [1,3'] bipyrrolidinyl-3-ylidenemethyl] -7- [(Z) -2- ( 5-amino- [1,2,4] -thiadiazol-3-yl) -2-trityloxyimino-acetylamino] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en- 2-carboxylic IR (KBR) 1784, 1680 cm "1 MS (ISP) 878.6 (M + NH4) +. 8.3 Acid (6R, 7R) -3 - [(E) - (R) - and - ( S) -l'-allyloxycarbonyl-2-oxo- [1, 3 '] bipyrrolidinyl-3-ylidenemethyl] -7- [(Z) -2- (5-amino- [1, 2, 4] -thiadiazol-3 -yl) -2-trityloxyimino-acetylamino] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic IR (KBR) 1783, 1681 an "1 ME ( ISP) 861.5 (M + NH) +. 8.4. Acid (6R, 7R) -3- [(E) -l- (1-allyloxycarbonyl-acetidin-3-yl-2-oxo-pyrrolidin-3-ylidenethyl] -7- [(Z) -2- (5- amino- [1,2,4] -thiadiazol-3-yl) -2-trityloxyimino-acetylamino] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2 carboxylic IR (KBR) 1784, 1683 crn "1 MS (ISP) 864.3 (M + NH) +., 8.5 Acid (6R, 7R) -7 - [(Z) -2- (5-amino- [l , 2,4] diadiazol-3-yl) -2-trithyloxyimino-asethylamino] -3- [(E) -1- (1,2-bis-allyloxysarbonyl-pyrazolidin-4-yl) -3-oxo-pyrrolidin- 3-ylidenemethyl] -8-oxo-5-thia-l-o-aza-bicyclo [4.2.0] oct-2-en-2-sarboxylic melting point 184-185ßC EM (ISP) 946.1 (M + -H) + 8.6 - Acid (6R, 7R) -3 - [(E) -l - [(S) -l-allyloxysarbonyl-pyrrolidin-2-ylmethyl] -2-oxo-pyrrolidin-3-ylidene-ethyl] -7 - [(Z) -2- (5-amino- [1,2,4] thiadiazol-3-yl) -2-trityloxy-amino-aoethylamino] -8-oxo-5-thia-1-aza-biscyclo [4.2. 0] ost-2-en-2-sarboxiliso IR (KBr) 1790, 1681 arT1 EM (ISP) 875.4 (MfH) +.
8. 7. (6R, 7R) -3 - [(E) -l - [(3S, 4R) -l-allyloxycarbonyl-4-trifluoromethyl-pyrrolidin-3-ylmethyl] -2-oxo-pyrrolidin-3-ylidene acid methyl] -7- [(Z) -2- (5-amino- [1,2,4] thiadiazol-3-yl) -2-trityloxy-imino-ao-β-pentaptin] -8-oxo-5-thia-l- aza-bicyclo [4.2.0] ost-2-en-2-sarboxiliso IR (KBr) 1790, 1687 cpT1 EM (ISP) 943.7 (MH) +. EXAMPLE 9 9.1. Acid mixture (6R, 7R) -3- [(E) - (R) - and - (S) -l'-allyloxycarbonyl-2-oxo- [1,3'] bipyrrolidinyl-3-ylidenemethyl] -7- [(Z) -2- (2-amino-thiazol-4-yl) -2-trityloxyimino-acetylamino] -8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-en- 2-carboxylic
A solution of (E) - (6R, 7R) -3- [(R) - and [(S) -l * -alloxycarbonyl-2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -trifluoroacetate] -7-amino-8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid (721 mg, 1.3 mmol) in 25 ml of EMF was treated with ester 1-Benzothiazolylic acid (Z) - (2-aminothiazol-4-yl) -trityloxyiminoacetic acid (782 mg, 1.43 mmol) at room temperature for 36 hours. The reaction mixture was concentrated in vacuo and the residue was distributed between 100 ml of ethyl acetate and 50 ml of water. The insoluble material was separated by filtration, the phases were separated and the organic phase was concentrated after which the product precipitated. The solid was collected by filtration, washed with ethyl acetate and dried. Yield: 725 mg (60%) IR (KBr) 1783, 1681 cm "1 MS (ISP) 860.6 (M + H) + In accordance with the procedure set forth in the preceding example, the following additional compounds were prepared: 9.2 Acid (6R, 7R) -3 - [(E) - (R) -l'-allyloxycarbonyl-2-oxo [1,3 '] - bipyrrolidinyl-3-ylidenemethyl] -7- [(Z) -2- (2-amino-thiazol-4-yl) -2-trityloxyimino-acetylamino] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic IR (KBr) 1783, 1679 cm "1 MS (ISP) 860.5 (M + H) +. 9.3. Acid (6R, 7R) -3- [(E) -1- (1-allyloxycarbonyl-azetidin-3-yl) -2-oxo-pyrrolidin-3-ylidenemethyl] -7- [(Z) -2- (2 -amino-thiazol-4-yl) -2-trityloxyimino-acetylamino] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic IR (KBr) 1785, 1680 arT1 MS (ISP) 846.6 (M + H) +. 9.4. Acid (6R, 7R) -3- [(E) -1- (allyloxycarbonyl-piperidin-4-ylmethyl) -2-oxo-pyrrolidin-3-ylidenemethyl] -7- [(Z) -2- (2-amino - thiazol-4-yl) -2-trityloxyimino-acetylamino] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic IR (KBr) 1782, 1673 cm -1 MS (ISP) 888.5 (M + H) +. 9.5 Acid (6R, 7R) -3 - [(E) -l- (1, 2-bis-allyloxyaarbonyl-pyrazolidin-4-yl) -2-oxo-pyrrolidin-3-ylid-bismyl] -7- [(Z) - 2- (2-ano-thiazol-4-yl) -2-trityloxyimino-acetylamino] -8-oxo-5-thia-l-aza-biaiclo [4.2.0] oct-2-en-2-sarboxiliso IR (KBr) 1756 an-1 MS (ISP) 536.3 (MH) +. 9.6. Acid (6R, 7R) -3 - [(E) -l - [(3S, 4R) -l-allyloxycarbonyl-4-trifluoromethyl-pyrrolidin-3-ylmethyl] -2-oxo-pyrrolidin-3-ylidenemethyl] -7 - [(Z) -2- (2-amino-thiazol-4-yl) -2-trityloxyimino-asethylamino] -8-oxo-5-thia-l-aza-bisislo [4.2.0] ost-2-en -2-carboxylism IR (KBr) 1790, 1686 atT1 MS (ISP) 942.4 (M + -H) +. 9.7. Acid (6R, 7R) -3 - [(E) -l - [(S) -l-aluyloxycarbonyl-pyrrolidin-2-ylmethyl] -2-oxo-pyrrolidin-3-ylidenemethyl] -7- [(Z) - 2- (2-amino-thiazol-4-yl) -2-trityloxyimino-aoethylamino] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] ost-2-en-2-sarboxyloid IR ( KBr) 1783, 1685 cpT1 MS (ISP) 874.5 (M + H) +. EXAMPLE 10 10.1. (6R, 7R) -7- [(Z) -2- (5-amino- [1, 2, 4] thiadiazol-3-yl) -2-trityloxyimino-acetylamino] -8-oxo-3-hydrochloride [(E) - (R) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
To a suspension of (6R, 7R) -3- [(E) - (R) -1'-allyloxycarbonyl-2-oxo [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -7- [(Z) - acid] - -am no-,, a azo - - - - r ox mn -ace amno -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid (4, 12 g, 4.79 mmol) in 280 ml of dichloromethane was added 1.87 ml (7.66 mmol) of N, O-bis (trimethylsilyl) acetamide whereupon an orange solution was formed which was then treated with 84 g. mg (0.12 mmol) of bis- (triphenyl-phosphine) -palladium dichloride (II), 5.48 ml (95.8 mmol) of acetic acid and 11.7 ml (44.1 mmol) of hydride tributyltin and stirred at room temperature for 40 minutes. After adding a few drops of water, the suspension was poured into 1500 ml of diethyl ether containing 12 ml of a 6M hydrogen chloride solution in diethyl ether. The suspension was stirred for 2 hours and the product was collected by filtration. Performance: 4, 04 g (99%) beige beige IR (KBr) 1781, 1659 cm "1 MS (ISP) 777.4 (M + H) + In accordance with the procedure set forth in the preceding example, the following additional compounds were prepared: 10.2 (6R, 7R) -7 - [(Z) -2- (5-amino- [1,2,4] thiadiazol-3-yl) -2-trityloxyimino-acetylamino] -8-0x0- acid dihydrochloride 3- [(E) - (S) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2 carboxylic IR (MIR) 1779, 1660 crn "1 MS (ISP) 777.4 (M + H) +. 10.3. Mixture of (6R, 7R) -7- [(Z) -2- (5-amino- [1,2,4] thiadiazol-3-yl) -2-trityloxyimino-acetylamino] -8-oxo- acid dihydrochloride - - - and - -o -, rro - - enme -5-tia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic IR (MIR) 1780, 1660 cm "1 EM (ISP ) 777.3 (M + H) + .10.4 (6R, 7R) -7- [(Z) -2- (5-amino- [1, 2, 4] thiadiazol-3-yl) - dihydrochloride 2-trityloxyimino-acetylamino] -3- [(E) -1- azetidin-3-yl-2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0 ] oct-2-en-2-carboxylic IR (KBr) 1780, 1667 <; ____! MS (ISP) 763.3 (M + H) +. 10.5. Mixture of (6R, 7R) -7- [(Z) -2- (2-amino-thiazol-4-yl) -2-trityloxyimino-acetylamino] -8-oxo-3- [(E) - acid dihydrochloride] (R) - and (S) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic IR (MIR) 1780, 1659 sn "1 MS (ISP) 776.4 (M + H) + .10.6 (6R, 7R) -7- [(Z) -2- (2-amino-thiazole-) dihydrochloride. 4-yl) -2-trityloxyimino-acetylamino] -3- [(E) -l-azetidin-3-yl-2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza- bicyclo [4.2.0] oct-2-en-2-carboxylic IR (KBr) 1780, 1661 cm-! MS (ISP) 762.5 (M + H) +. 10.7 (6R, 7R) - Hydrochloride 7- [(Z) -2- (2-amino-thiazol-4-yl) -2-trityloxyimino-acetylamino] -8-oxo-3- [(E) -2-oxo-l-piperidin-4-ylmethyl] -pyrrolidin-3-ylidenemethyl] -5-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic IR (KBr) 1778, 1661, 1631 crn "1 MS (ISP) 804.7 (M + H) +.
. 8. (6R, 7R) -7- [(Z) -2- (5-amino- [1, 2,4] thiadiazol-3-yl) -2-trityloxyimino-acetylamino] -8-oxo- (6R, 7R) acid hydrochloride 3- [(E) -2-oxo-l-pyrazolidin-4-yl-pyrrolidin-3-ylidenemethyl] -5-thia-l-aza-bisislo [4.2.0] oct-2-en-2-sarboxyl isolate of fusion 163-164 ° C IR (KBr) 1785 cpT1 MS (ISP) 778.4 (MfH) +. 10.9. Acid Hydrochloride (6R, 7R) -7- [(Z) -2- (5-amino- [1, 2,4] thiadiazol-3-yl) -2-triyloxy-p-p-a-ethylamino] -8-oxo-3 - [(E) -l-oxo-2- [(3R, 4R) -4-trifluorocarbonyl-pyrrolidin-3-yltrnenyl] -pyrrolidin-3-ylidne-methyl] -5-thia-l-aza-bisislo [4.2 .0] ost-2-en-2-saxboxylous IR (KBr) 1790, 1633 crn "1 MS (ISP) 859.4 (M + H) + EXAMPLE 11 11.1 Acid (6R, 7R) -7- [ (Z) -2- (5-a? R_ino- [l, 2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -8-oxo-3- [(E) - (R) -2 -oxo- [1, 3 '] bipi-rrolidinyl-3-ylidenemethyl] -5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
To a solution of acid dihydrochloride (6R, 7R) -7 - [(Z) -2- (5-amino- [1,2,4] thiadiazol-3-yl) -2-trityloxyimino-acetylamino] - -8 -OXO-3- [(E) - (R) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -5- thia-l-aza-bicyclo [4.2.0] oct-2-en -2-carboxylic acid (4.04 g, 4.76 mmol) in 26 ml of trifluoroacetic acid was added at 0-5 ° C 1.69 ml of triethylsilane and the mixture was stirred for 30 minutes. The reaction mixture was poured with stirring over 780 ml of ice-cold diethyl ether after which the product was separated as a beige solid. After stirring for 1 hour the solid was collected by filtration and dried. The product was purified by gel chromatography (MCI Gel 75-150 μ, using a gradient of water with increasing concentrations of acetonitrile). Yield: 1.24 g (49%) IR (MIR) 1764, 1658 crn "1 MS (ISP) 535.1 (M + H) +. 1 H-NMR (DMS0, 250 MHz): inter alia d 1.92 -2.16 (m, 2H), 3.60 (d, J = 17 Hz, 1H), 3.79 (d, J = 17 Hz, 1H), 4.66, (m, 1H), 5, 07 (d, J = 8 Hz, 1H), 5.75 (dd, J - 5 Hz, J = 8 Hz 1H), 7.30 (s, 1H), 8.05 (s, 2H), 9, 46 (d, J = 8 Hz, 1H), 10.3 (broad s, 1H), 12.0 (s broad, 1H) ppm In accordance with the procedure set forth in the preceding example, the following additional compounds were prepared: 11.2 Acid (6R, 7R) -7- [(Z) -2- (5-amino- [1,2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -8-oxo-3- [(E) - (S) -2-oxo- [1, 3 '] bipi-rrolidinyl-3-ylidenemethyl] -5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2 carboxylic IR (KBr) 1766, 1687 crn-1 MS (ISP) 535.2 (M + H). 1 H-NMR (DMS0, 250 MHz): inter alia d 1.92-2.16 (m, 2H); 4.58 (m, 1H), 5.08 (d, J = 8 Hz, 1H), 5.75 (dd, J = 5 Hz, J = 8 Hz 1H);
7.30 (s, 1H); , s, H); ,, J = Hz, 1H); 1 (broad s, 1H) ppm. 11.3. Acid mixture (6R, 7R) -7- [(Z) -2- (5-amino- [1,2,4] thia-diazol-3-yl) -2-hydroxyimino-acetylamino] -8-oxo- 3- [(E) - (R) - and - (S) -2-oxo- [1, 3 *] bipi-rrolidinyl-3-ylidenemethyl] -5-thia-l-aza-bicyclo [4.2.0] Oct-2-en-2-carboxylic IR (KBr) 1765, 1659 cm "1 MS (ISP) 535.3 (M + H) +., 11.4 Acid (6R, 7R) -7 - [(Z) -2 - (5-amino- [1,2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) -l-azetidin-3-yl-2-oxo-pi-rrolidin- 3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic IR (KBr) 1762, 1689, 1668 cm-1 MS (ISP) 521, 2 (M + H) + .11.5 (6R, 7R) -7- [(Z) -2- (2-amino-thiazol-4-yl) -2-hydroxy-imino-acetylamino] -8-oxo acid -3- [(E) - (R) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -5-thia-l-azabicyclo [.2.0] oct-2-en-2-carboxylic acid
IR (KBr) 1766, 1670 cm "1 MS (ISP) 534.2 (M + H) + .11.6 Mixture of acid dihydrochloride (6R, 7R) -7- [(Z) -2- (2-amino -thiazol-4-yl) -2-hydroxy-imino-acetylamino] -8-oxo-3- [(E) - (R) - and - (S) -2-oxo- [1,3 '] bipyrrolidinyl- 3-ylidenemethyl] -5-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic IR (KBr) 1775, 1667 an "1 MS (ISP) 534.3 (M + H) +. 11.7. Acid dihydrochloride (6R, 7R) -7- [(Z) -2- (2-amino-thiadiazol-4-yl) -2-hydroxyimino-acetylamino] -3- [(E) -l-azetidin-3- il-2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo- [4.2.0] oct-2-en-2-carboxylic IR (KBr) 1776, 1669, 1668 crn "1 MS (ISP) 520.2 (M + H) +. 11.8 (6R, 7R) -7- [(Z) -2- (2-amino-thiazol-4-yl) -2-acid trifluoroacetate -hydroxyimino-acetylamino] -8-oxo-3- [(E) -2-oxo-l-piperidin-4-ylmethyl-pyrrolidin-3-ylidenemethyl] -5-thia-l-aza-bicyclo [4.2.0] Oct-2-en-2-carboxylic IR (KBr) 17741664 cm "1 MS (ISP) 562.4 (M + H) +. 11.9 7 - [(Z) -2- (5-amino- [1,2,4] thiadiazol-3-yl) - 2-hydroxy-pyro-aoethylamino] -8-oxo-3- [(E) -2-oxo-l-pyrazolidin-4-yl-pyrrolidin-3-ylidenemethyl] -5-thia-l-azabisislo [4.2.0] ost -2-en-2-sarboxiliao IR (KBr) 1756 cpT1 EM (ISP) 536.3 (MH) +. 11.10 Acid (6R, 7R) -7 - [(Z) -2- (2-aptino-thiazole -4-yl) -2-hydroxyimino-aoethylamino] -8-oxo-3- [(E) -2-oxo-l-piperidin-4-yl-pyrrolidin-3-ylidenemethyl] -5-thia-l-aza -bisislo [4.2.0] ost-2-en-2-carboxylic melting point 239-240 ° C IR (KBr) 1764 can-1 MS (ISP) 535.3 (MH) +. 11.11. 7R) -7- [(Z) -2- (5-amino- [1,2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -8-oxo-3- [(E) -2 -oxo-l-pyrazolidin-2-ylmethyl-pyrrolidin-3-ylidene-γ-lyl] -5-thia-l-azabicyclo [4.2.0] ost-2-en-2-sarboxyliane IR (KBr) 1785, 1624 cm " 1 MS (ISP) 549.1 (M + H) +. 11.12. Acid (6R, 7R) -7 - [(Z) -2- (2-amino-thiazol-4-yl) -2-hyd-X »xii-nino-asethylarino] -8-oxo-3- [(E ) - (S) -2-oxo-l-pyrrolidin-2-ylmethyl-pyrrolidin-3-ylidenethyl] -5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-cazbaxiliao IR ( KBr) 1767 crn "1 MS (ISP) 548.2 (M + H) + .11.13 Acid (6R, 7R) -7 - [(Z) -2- (2-amino-thiazol-4-yl) - 2-hydroxyimino-aethylamino] -8-oxo-3- [(E) - (S) -2-oxo-l- [(3R, 4R) -4-trif luorx »-thyl-pyrrolidin-3-i_Ji» ethyl- pitxolidin-3-ylidenemethyl] -5-thia-1-aza-biscyclo [4.2.0] oct-2-en-2-sarboxylyl IR (KBr) 1770, 1665 an-1 MS (ISP) 616.3 (M + H) +. 11.14 Acid (6R, 7R) -7- [(Z) -2- (2-amino- [1,2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -8- oxo-3- [(E) -2-oxo-l- [(3R, 4R) -trif luorotryptyl-pyrrolidin-3-i-J-t-ethyl-pyrrolidin-3-ylidene-phenyl] -5-thia-1-aza-bicyclo [4.2 .0] oct-2-en-2-carboxyloyl IR (KBr) 1768, 1625 crn "1 11.15. Acid (6R, 7R) -7 - [(Z) -2- (2-amino- [1,2,4] thiadiazol-3-yl) -2-hydroxyimino-asethylamino] -3- [(E) - ( 3 'S, 5' R) -5 '-dimethylsar-bamoyl-2-oxo- [1, 3 »] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-za-bisislo [4.2. 0] oct-2-en-2-aarboxiliane IR (KBr) 1768, 1656 cm "1 MS (ISP) 606.1 (M + H) + .11.16 Assay format (6R, 7R) -7- [( Z) -2- (5-amino- [1,2,4] -thiadiazol-3-yl) -2-hydroxyimino-asethylamino] -3- [(E) - (3 'S, 5' S) -5 '-dimethyl-sarbamoyl-2-oxo- [1, 3'] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicialo [4.2.0] oct-2-en-2-sarboxyloride IR (KBr) 1768 crn-MS (ISP) 606.1 (MH) +. 11.17 Acid (6R, 7R) -7 - [(Z) -2- (2-amino- [1,2,4] thiadiazole -4-yl) -2-hydroxyimino-asethylamino] -3- [(E) - (3 'S, 5' R) -5 '-dimethylsar-bamoyl-2-oxo- [1,3'] bipyrrolidinyl-3 -ylidanmethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-ßn-2-sarboxylyl IR (KBr) 1766, 1656 cm-1 MS (ISP) 605.3 (M + H) + .11.18 Asido (6R, 7R) -7- [(Z) -2- (2-a_nino- [l, 2,4] thiadiazol-4-yl) -2-hid_x >ximin-aa-ethylamino] -3- [(E) - (3 'S, 5' S) -5'-dimethylsarba-moyl-2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -8-oxo -5-tia-l-aza-bisislo [4.2.0] ost-2-en-2-sarboxiliso IR (KBr) 1767, 1657 cm_1 MS (ISP) 605.1 (MH) +. EXAMPLE 12 12.1. Mixture of (6R, 7R) -7- [(Z) -2- (5-amino- [1,2,4] thiadiazol-3-yl) -2-cyclopentyloxyiminoacetylamino] -8-oxo-3- [ (E) - (R) - and - (S) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -5-thia-l-aza-bicyclo [4.2.0] oct-2-en -2-carboxylic
To a suspension of 454 mg (1.19 mmol salt (Z) - (5-amino- [1, 2, 4] thiadiazol-3-yl) -cyclopentyloxyimino-acetate 1-allyl-1-methyl-pyrrolidinium in 9 , 5 ml of dimethylformamide was added 451 mg (1.19 mmol) of 0-benzotriazol-1-yl-N, N, N ', N'-tetra-ethyluronium hexafluorophosphate (HBTU) and the mixture was stirred for 1 hour. To the resulting orange solution was added a mixture of (E) - (6R, 7R) -3- [(R) - and - [(S) -l'-allyloxycarbonyl-2-oxo- [1, 3] trifluoroacetate]. '] bipyrrolidinyl-3-ylidene-butyl) -7-amino-8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid (600 mg, 1, 08 mmol) and the mixture was stirred for 40 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue was distributed between 100 ml of ethyl acetate and 70 ml of water. The phases were separated and the organic phase was concentrated, after which the product precipitated. The solid was collected by filtration, washed with ethyl acetate and dried, yielding 291 mg (39%) of a beige amorphous powder. The separation of the allyloxycarbonyl protecting group was carried out according to example 9. The product was purified by gel chromatography (MCI Gel 75-150 μ, using a gradient of water with increasing concentrations of acetonitrile). Yield: 40 mg (16%) beige beige IR (KBr) 1771, 1672 aa "1 MS (ISP) 603.3 (M + H) + .12.2 Acid (6R, 7R) -7 - [(Z) -2- (5-amino- [1,2,4] thiadiazol-3-yl) -2-cyclopentyloxyiminoacetylamino] -8-oxo-3- [(E) - (R) -2-oxo- [1,3 *] bipyrrolidinyl-3-ylidenemethyl] -5-thia-l-aza-bicyclo- [4.2.0] oct-2-en-2-carboxylic IR (KBr) 1777, 1670 aiT1 EM (ISP) 603.2 (M + H) + EXAMPLE 13 13.1 Acid mixture (6R, 7R) -3- [(E) - (R) - and - (S) -l'-allyloxycarbonyl-2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -7- [(Z) -2- (2-amino-thiazol-4-l) - -cic opentyloxy-mino-acetylamino] 8-oxo-5-thia-l-aza-bicyclo [4.2 .0] oct-2-en-2-carboxylic acid
A suspension of (E) - (6R, 7R) -3- [(R) - and [(S) -ll-allyloxycarbonyl-2-oxo- [1,3'] acid bipyridinyl-3- trifluoroacetate. ylidenmethyl] -7-amino-8-oxo-5-thia-l-aza-bicyclo- [4.2.0] oct-2-en-2-carboxylic acid (555 mg, 1.0 mmol) in 20 ml of DMF was treated for 12 hours at room temperature with (Z) - (2-aminothiazol-4-yl) -cyclo-pentyloxyimino-thioacetic acid S-benzothiazole-2-yl ester (445 mg, 1.1 mmol). The reaction mixture was concentrated in vacuo and the residue was triturated in a mixture of 70 ml of ethyl acetate and 50 ml of water. The solid was collected by filtration, washed with water, ethyl acetate and dried. Yield: 484 mg (71%). IR (KBr) 1778, 1677, 1629 aiT1 MS (ISP) 686.4 (M + H) +. In accordance with the procedure set forth in the preceding example, the following additional compounds were prepared: 13.2. Acid (6R, 7R) -3- [(E) -1- (1-allyloxycarbonyl-azetidin-3-yl) -2-oxo-pyrrolidin-3-ylidenemethyl] -7- [(Z) -2- (2 -amino-thiazol-4-yl) -2- cyclopentyloxy__i_Lno-acetylairu.no] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic IR (KBr) 1774, 1673 crn "MS (ISP) 672.4 (M + H) + .13.3 Acid (6R, 7R) -3- [(E) -1- (allyloxycarbonyl-piperidin-4-ylmethyl) -2-oxo -pyrrolidin-3-ylidenemethyl] -7- [(Z) -2- (2-amino-thiazol-4-yl) -2-cyclopentyloxyimino-acetylamino] -8-oxo-5-thia-l-aza-bicyclo [ 4.2.0] oct-2-en-2-carboxylic IR (KBr) 1779, 1676, 1630 cm "1 MS (ISP) 714.5 (M + H) +.
EXAMPLE 14 14.1. Acid mixture (6R, 7R) -7- [(Z) -2- (2-amino-thiazol-4-yl) -2-cyclopentyloxyiminoacetylamino] -8-oxo-3- [(E) - (R ) - and (S) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -5-thia-l-aza-bicyclo [4.2.0] -oct-2-en-2-carboxylic acid.
The separation of the allyloxycarbonyl protecting group in the mixture of (6R, 7R) -3- [(E) - (R) - and - (S) -l'-allyloxycarbonyl-2-oxo [1,3] acids ] bipyrrolidinyl-3-ylidenemethyl] -7- [(Z) -2- (2-amino-thiazol-4-yl) -2-cyclopentyloxyiminoacetylamino] -8-oxo-5-thia-1-aza-bicyclo [ 4.2.0] oct-2-en-2-carboxylic acids was carried out using the procedure described in Example 9. The crude product (328 mg) was purified by gel chromatography (MCI Gel 75-150 μ, using a gradient of water with increasing concentrations of acetonitrile). The crude product was crystallized from the chromatographic fractions and collected by filtration. Yield: 102 mg (28%) of yellow crystals IR (KBr) 1770, 1666, 1625 an-1 MS (ISP) 602.4 (M + H) +. In accordance with the procedure set forth in the preceding example, the following additional compounds were prepared: 14.2. (6R, 7R) -7- [(Z) -2- (2-Amino-thiazol-4-yl) -2-cyclopentyloxyimino-acetylamino] -3- (E) -1- azetidin-3-yl-hydrochloride - 2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo- [4.2.0] oct-2-en-2-carboxylic IR (KBr) 1780, 1661 cm "1 MS (ISP) 588.3 (M + H) + .14.3 (6R, 7R) -7- [(Z) -2- (2-amino-thiazol-4-yl) -2-cyclopentyloxyimino- (6R, 7R) acid hydrochloride. acetylamino] -8-oxo-3- [(E) -2-oxo-l-piperidin-4-ylmethyl-pyrrolidin-3-ylidenemethyl] -5-thia-l-aza-bicyclo [4.2.0] oct-2 -in-2-carboxylic IR (KBr) 1771, 1665, 1627 cm "1 MS (ISP) 630.6 (M + H) +. EXAMPLE 15 Asido (6R, 7R) -7- [(Z) -2- (5-amino- [1, 2, 4] thiadiazol-3-yl) -2-hi-droxyimino-asethylamino] -3- [( E) - (R) -1'-iminomethyl-2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bisislo [4.2.0] ost-2 -in-2-sarboxiliso
To a suspension of 66 mg of sodium hydride (65% in mineral oil) in 2 ml of DMSO were added 200 mg of ethylformamide hydrochloride and 100 mg (0.2 mmol) of aceid (6R, 7R) -7- [( Z) -2- (5-amino- [1, 2,4] thiadiazol-3-yl) -2-hydroxyimino-aaethylamino] -β-oxo-3- [(E) - (R) -2-oxo- [1, 3 '] bipirtolidinyl-3-ylidenemethyl] -5-thia-l-aza-bisislo [4.2.0] ost-2-en-2ss_z_boxiliso.
The reassonal mixture was shaken for 30 minutes at room temperature before being hydrolyzed with some drops of water. Purification by reverse phase chromatography on MCI gel by elution with water: acetonitrile = 9: 1. Yield: 30 mg IR (KBr) 1767 an-1 MS (ISP) 562.2 (M + H) +. EXAMPLE 16 Acid (6R, 7R) -7- [(Z) -2- (5-amino- [1, 2, 4] thiadiazol-3-yl) -2-hi-droxyimino-aoethylamino] -3- [( E) - (R) -1 '-sarbamimidoyl-2-oxo- [1,3'] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-1-aza-bicyclo [4.2.0] ost-2 -in-2-sarboxilioo
To a solution of [1,2,4] triazole-1-carboxamidine hydrochloride in 1 ml of DMSO was added 13 μl of tetramethylguanidine and 53 mg of aceid (6R, 7R) -7- [(Z) -2 - (5-amino- [1, 2, 4] thiadiazol-3-yl) -2-hidzx > ximin-acetylamino] -8-oxo-3- [(E) - (R) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -5-thia-l-aza-bicyclo [4.2.0 ] oct-2-en-2-carboxylyl. After 1 hour of stirring at room temperature, the reaction mixture was purified by reverse phase chromatography on MCI gel by elution with water: acetonitrile = 9: 1. Yield: 30 mg IR (KBr) 1769 aiT1 MS (ISP) 577.0 (M + H) +. EXAMPLE 17 Following the procedures set forth in the previous examples, the following compounds can be prepared: 17.1. Acid (6R-7R) -7 - [(Z) -2- (5-a_nino- [1, 2,4] thiazol-3-yl) -2-hi__roxii_t? Ino-acetylamino] -3- [(E) -5'-hydroxymethyl-2-oxo [1,3 '] -bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-1-aza-bicyclo [4.2.0] -oct-2-en-2 carboxylic
17. 2. Acid (6R, 7R) -3- [(E) -5] -aminomethyl-2-oxo [1,3 '] -bipyrrolidinyl-3-ylidenemethyl] -7- [(Z) -2- (5- amino- [1, 2, 4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] -oct-2- en-2-carboxylic 17.3. (6R, 7R) -7- [(Z) -2- (5-amino- [1, 2, 4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -8-oxo-3- [(E ) -2-oxo-5 '-pyridin-l-io-1-ylmethyl [1,3'] bipyrrolidinyl-3-ylidenemethyl] -5-thia-l-aza-bicyclo [4.2.0] oct-2-en -2-carboxylate
17. 4. Acid (6R, 7R) -7 - [(Z) -2- (5-amino- [1,2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) -5! - (1-hydroxy-3-methylamino-propyl) -2-oxo [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic
17. 5. Acid (6R, 7R) -7 - [(Z) -2- (5-amino- [1, 2,4] thiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) -4 '-hydroxy-2-oxo- [1,3'] - bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] -oct-2-en-2 -carboxylic OH
O ^ OH 17.6. Acid (6R, 7R) -7- [(Z) -2- (5-amino- [1, 2,4] thiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) -5 '- (hydroxy-pyrrolidin-2-yl-methyl) -2-oxo [1,3'] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct- 2-en-2-carboxylic acid
17. 7. Acid (6R, 7R) -7 - [(Z) -2- (5-amino- [1,2,4] thidiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) -2-oxo-l-pyrrolidin-3-ylmethyl-pyrrolidin-3-ylidenemethyl] -5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
17. 8. Acid (6R, 7R) -7 - [(Z) -2- (5-amino- [1,2,4] thidiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) -l-azeitidin-3-ylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
.OH
O QH ° 17.9. (6R, 7R) -7- [(Z) -2- (5-amino- [1,2,4] thidiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) -1] acid '-azeitidin-3-ylmethyl-2-oxo- [1,3'] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2 -carboxylic
17. 10. Acid (6R, 7R) -7 - [(Z) -2- (5-amino- [1, 2,4] thiazol-3-yl) -2-hydroxyimino-acetylamino] -8-oxo-3- [(E) -2-oxo-l '-pyrrolidin-2-ylmethyl- [1,3'] bipyrrolidinyl-3-ylidenemethyl] -5-thia-l-aza-bicyclo [4.2.0] oct-2-en -2-carboxylic
17. 11. Acid (6R, 7R) -7 - [(Z) -2- (5-amino- [1, 2,4] thiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) -1- [2- (2-hydroxy-ethylamino) -ethyl] -2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2- en-2-carboxylic
17. 12. Acid (6R, 7R) -7- [(Z) -2- (5-amino- [1, 2, 4] thiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) -1- (2-methylamino-ethyl) -2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
17. 13. Acid (6R, 7R) -7- [(Z) -2- (5-amino- [1, 2, 4] thiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) -1- (-2-cyclopropylamino-ethyl) -2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo- [4.2.0] oct-2-en-2 carboxylic
17. 14. Acid (6R, 7R) -7- [(Z) -2- (5-amino- [1, 2, 4] thiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) -1- [2- (i -omethylamino) -ethyl] -2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo- [4.2.0] oct-2-en- 2-carboxylic
17. 15. Acid (6R, 7R) -7- [(Z) -2- (5-amino- [1,2,4] thidiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) -1- (2-guanidino-ethyl) -2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
17. 16. Acid (6R, 7R) -7- [(Z) -2- (5-a.ru.no- [1,2,4] thiazol-3-yl) -2-hydroxyimino-acetylamino] -8-oxo- 3- [(E) -2-oxo-l- (2-piperazin-1-yl-ethyl) -pyrrolidin-3-ylidenemethyl] -5-thia-1-aza-bicyclo [4.2.0] -oct-2 -in-2-carboxylic
17. 17. Acid (6R, 7R) -7- [(Z) -2- (5-amino- [1,2,4] thiazol-3-yl) -2-hydroxyimino-acetylamino] -8-oxo-3- [(E) -2-oxo-l- [2- (pyrrolidin-3-ylamino) -ethyl] -pyrrolidin-3-ylidenemethyl] -5-thia-l-aza-bicyclo [4.2.0] oct-2- en-2-carboxylic
17. 18. Acid (6R, 7R) -7- [(Z) -2- (5-amino- [1, 2,4] thiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) -1- [2- (azeitidin-3-ylamino) -ethyl] -2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2- en-2-carboxylic
17. 19. Acid (6R, 7R) -7- [(Z) -2- (5-eu¬no- [1,2,4] thiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [ (E) -l-carbamimidoylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
17. 20. Acid (6R, 7R) -7- [(Z) -2- (5-amino- [1,2,4] thiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) -1- (2-iminomethyl-azeitidin-3-yl) -2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-en- 2-carboxylic
17. 21. Acid (6R, 7R) -7- [(Z) -2- (5-amino- [1, 2,4] thiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) -1- (1-carbamimidoyl-azetidin-3-yl) -2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo- [4.2.0] oct-2-en -2-carboxylic
17. 22. Acid (6R, 7R) -7- [(Z) -2- (5-amino- [1,2,4] thidiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) -l- (1-iminomethyl-azetidin-3-ylmethyl) -2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en- 2-carboxylic
17. 23. Acid (6R, 7R) -7 - [(Z) -2- (5-amino- [1,2,4] thidiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) -l- (l-carbamimidoyl-azetidin-3-ylmethyl) -2-oxo-pyrorlidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en- 2-carboxylic
17. 24. (6R, 7R) -7- [(Z) -2- (2-Amino-thiazol-4-yl-2-hydroxy-imino-acetylamino] -3- [(E) -5'-hydroxymethyl) acid 2-oxo- [1,3 '] -bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo- [4.2.0] oct-2-en-2-carboxylic acid
17. 25. Acid (6R, 7R) -3- [(E) -5'-aminomethyl-2-oxo [1, 3 *] bipyridin-lyrinyl-3-ylidenemethyl] -7- [(Z) -2- (2 -amino-thiazol-4-yl) -2-hydroxyimino-acetylamino] -8-oxo-5-thia-l-aza-bicyclo [4.2.0. | oct-2-en-2-carboxylic acid
17. 26. (6R, 7R) -7 - [(Z) -2- (2-amino-thiazol-4-yl) -2-hydroxyimino-acetylamino] -8-oxo-3- [(E) -2-oxo -5'-pyridin-l-io-l-ylmethyl- [1,3 *] bipyrrolidinyl-3-ylidenemethyl] -5-thia-l-aza-bicyclo [4.2.0] -oct-2-en-2- carboxylate
17. 27. Acid (6R, 7R) -7- [(Z) -2- (2-amino-thiazol-4-yl) -2-hydroxy-imino-acetylamino] -3- [(E) -5 '~ ( l-hydroxy-3-methylamino-propyl) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2- en-2-carboxylic
17. 28. (6R, 7R) -7 - [(Z) -2- (2-Amino-thiazol-4-yl) -2-hydroxy-imino-acetylamino] -3- [(E) -4'-hydroxy acid -2-oxo [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid
17. 29. (6R, 7R) -7- [(Z) -2- (2-amino-thiazol-4-yl) -2-hydroxy-imino-acetylamino] -3- [(E) -5'- ( hydroxy-pyrrolidin-2-yl-methyl) -2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2- en-2-carboxylic
17. 30. (6R, 7R) -7- [(Z) -2- (2-Amino-thiazol-4-yl) -2-hydroxy-imino-acetylamino] -8-oxo-3- [(E) - acid] 2-oxo-l-pyrrolidin-3-ylmethyl-pyrrolidin-3-ylidenemethyl] -5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
17. 31. Acid (6R, 7R) -7- [(Z) -2- (2-amino-thiazol-4-yl) -2-hydroxy-imino-acetylamino] -3- [(E) -l-azetidin- 3-ylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
17. 32. (6R, 7R) -7- [(Z) -2- (2-Amino-thiazol-4-yl) -2-hydroxy-imino-acetylamino] -3- [(E) -l'-azetidin -3-ylmethyl-2-oxo [1,3 '] -bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo- [4.2.0] oct-2-en-2-carboxylic acid
17. 33. (6R, 7R) -7- [(Z) -2- (2-amino-thiazol-4-yl) -2-hydroxy-imino-acetylamino] -8-oxo-3- [(E) - acid. 2-oxo-l '-pyrrolidin-2-ylmethyl- [1,3'] bipyrrolidinyl-3-ylidenemethyl] -5-thia-l-aza-bicyclo [4.2.0] -oct-2-en-2-carboxylic acid
17. 34. Acid (6R, 7R) -7- [(Z) -2- (2-amino-thiazol-4-yl) -2-hydroxy-imino-acetylamino] -3- [(E) -1- [2 - (2-hydroxy-ethylamino) -ethyl] 2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
17. 35. (6R, 7R) -7 - [(Z) -2- (2-amino-thiazol-4-yl) -2-hydroxy-imino-acetylamino] -3- [(E) -1- (2) acid -methylamino-ethyl) -2-oxo-pyrro-lidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
17. 36. (6R, 7R) -7- [(Z) -2- (2-amino-thiazol-4-yl) -2-hydroxy-imino-acetylamino] -3- [(E) -1- (2) acid -cyclopropylamino-ethyl) -2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
17. 37. Acid (6R, 7R) -7- [(Z) -2- (2-amino-thiazol-4-yl) -2-hydroxy-imino-acetylamino] -3- [(E) -1- [2 - (iminomethylamino) -ethyl] -2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
17. 38. Acid (6R, 7R) -7- [(Z) -2- (2-amino-thiazol-4-yl) -2-hydroxy-imino-acetylamino] -3- [(E) -1- (2 -guanidino-ethyl) -2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
17. 39. (6R, 7R) -7- [(Z) -2- (2-Amino-thiazol-4-yl) -2-hydroxy-imino-acetylamino] -8-oxo-3- [(E) - acid] 2-oxo-l- (2-piperazin-l-yl-ethyl) -pyrrolidin-3-ylidenemethyl] -5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
17. 40. (6R, 7R) -7- [(Z) -2- (2-amino-thiazol-4-yl) -2-hydroxy-imino-acetylamino] -8-oxo-3- [(E) - acid. 2-oxo-l- [2- (pyrrolidin-3-yl) yl) -ethyl] pyrrolidin-3-ylidenemethyl] -5-thia-l-aza-bicyclo- [4.2.0] oct-2-en-2 carboxylic
17. 41. (6R, 7R) -7 - [(Z) -2- (2-amino-thiazol-4-yl) -2-hydroxy-imino-acetylamino] -3- [(E) -1- [2 - (azetidin-3-ylamino) -ethyl] -2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] -oct-2-en-2 carboxylic
17. 42. (6R, 7R) -7 - [(Z) -2- (2-Amino-thiazol-4-yl) -2-hydroxy-i-o-acetylamino] -3- [(E) -l-carbamimidoylmethyl] acid -2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
17. 43. (6R, 7R) -7- [(Z) -2- (2-amino-thiazol-4-yl) -2-hydroxy-imino-acetylamino] -3- [(E) -l- (l -aminomethyl-azetidin-3-yl) -2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
17. 44. (6R, 7R) -7 - [(Z) -2- (2-amino-thiazol-4-yl) -2-hydroxy-imino-acetylamino] -3- [(E) -1- (l -carbamimidoyl-azetidin-3-yl) -2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] -oct-2-en-2-carboxylic acid
.OH
O ^ OH 17.45. Acid (6R, 7R) -7- [(Z) -2- (2-Amino-thiazol-4-yl) -2-hydroxy-imino-acetylamino] -3- [(E) -l- (l-iminomethyl) -azetidin-3-ylmethyl) -2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo- [4.2.0] oct-2-en-2-carboxylic acid
17. 46. (6R, 7R) -7- [(Z) -2- (2-amino-thiazol-4-yl) -2-hydroxy-imino-acetylamino] -3- [(E) -1- (l -carbamimidoyl-azetidin-3-ylmethyl) -2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:
Claims (3)
1 . - Compounds of formula I, in accordance with the 2 claim 22a, because R is CH and R is a group of formula wherein R4 is as defined in claim
2. 8. Compounds of formula I, according to claim 2, characterized by the fact that X is N and R 'is a group of formula wherein R4 is as defined in claim 2. 9. Compounds of formula I, according to claim 1, characterized in that X is CH or N; R1 is hydrogen or cyclopentyl; R ^ is a group of formula * R is hydrogen, a non-caustic metal ion or a tertiary ammonium group; R 4 is hydrogen, an amino protecting group; R5 is hydrogen, dialkylcarbamoyl; and R ^ is hydrogen or trifluoromethyl; as well as their easily hydrolysable esters, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula I and their esters and salts. 10.- The compounds Acid (6R, 7R) -7 - [(Z) -2- (5-amino- [1,2,4] thiadiazol-3-yl) -2-hi-droxyimino-acetylamino] -8 -oxo-3- [(E) - (R) -2-oxo- [1,3 '] bipyridinyl-3-ylidenemethyl] -5-thia-l-aza-bicyclo [4.2.0] oct-2 -en-2-carboxylic acid, (6R, 7R) -7- [(Z) -2- (5-amino- [1,2,4] thiadiazol-3-yl) -2-hi-droxyimino-acetylamino] -8-oxo-3- [(E) - (S) -2-oxo- [1,3'-bipyridin-lidinyl-3-ylidenemethyl] -5-thia-1-aza-bicyclo [4.2.0] oct- 2-en-2-carboxylic acid, (6R, 7R) -7- [(Z) -2- (5-amino- [1, 2, 4] thiadiazol-3-yl) -2-hi-droxii ino- acetylamino] -3- [(E) - (R) -1'-iminomethyl-2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza-bicyclo [ 4.2.0] oct-2-en-2-carboxylic acid, (6R, 7R) -7- [(Z) -2- (5-amino- [1, 2, 4] thiadiazol-3-yl) -2 -hydroxyimino-acetylamino] -3- [(E) - ((R) -1 '-carbamimidoyl-2-oxo- [1, 3 '] bipyrrolidinyl-3-ylidenemethyl)] -8-oxo-5-thia-l-aza-bicyclo- [4.2.0] oct-2-en-2-carboxylic acid, (6R, 7R) -7- [(Z) -2- (5-amino- [1, 2,4] thiadiazol-3-yl) -2-hydroxyimino-acetylamino] -3- [(E) -l-azetidin-3-ylmethyl- 2-oxo-p r - - - - - - - - -. . - -en-2-carboxylic acid, Acid (6R, 7R) -7- [(Z) -2- (5-amino- [1, 2,4] thiadiazol-3-yl) -2-hi-droxyimino-acetylamino ] -3- [(E) -5'-hydroxymethyl-2-oxo- [1,3 '] bi-pyrrolidinyl-3-ylidenemethyl] -8-oxo-45-thia-1-aza-bicyclo- [4.2. 0] oct-2-en-2-carboxylic acid. 11. Compounds according to any of claims 1 to 10 for use as pharmaceutically active substances, particularly for the treatment and prophylaxis of infectious diseases. 12. Process for the preparation of compounds of formula I, whose process is characterized in that it comprises treating a compound having the formula II wherein R2 is as defined in claim 1, or a respective ester or salt, the amino group and the carboxylic groups present in the compound of formula II may be unprotected or protected, with a carboxylic acid of the general formula III wherein R ^ is hydrogen or an amino protecting group, R1 is hydrogen, cyclopentyl or a hydroxyl protecting group and X is as defined above, or a respective reactive functional derivative, or (b) dissociates the amino, hydroxyl and / or carboxyl in a compound having the formula IV is hydrogen or an amino protecting group, R1 is hydrogen or a hydroxyl protecting group, R * 1 is hydrogen or a carboxyl protecting group, with the proviso that at least one of Rf, R1"and Rh is a corresponding protecting group, or a respective salt 1
3. The compound of formula Illa the S-benzothiazol-2-yl ester of (Z) - (5-amino- [1,2,4] thiadiazol-3-yl) -trityloxyimino- thioacetic agent 14.- A pharmaceutical preparation characterized in that it contains a compound according to any of claims 1 to 10 and a therapeutically inert carrier, particularly for the treatment and prophylaxis of infectious diseases 15.- The use of the compounds in accordance with any of claims 1 to 10 in the treatment and prophylaxis of infectious diseases or for the preparation of medicaments for the treatment and prophylaxis of infectious diseases. SUMMARY OF THE INVENTION The present invention relates to cephalosporin derivatives of the general formula where X is CH or N; R1 is hydrogen or cyclopentyl; R2 is a group of the formula R3 is hydrogen, an alkali metal ion or a tertiary ammonium group; R 4 is hydrogen, an amino protecting group, pyrrolidin-2-ylmethyl, azetidin-3-ylmethyl, iminomethyl, 1-carbamimidoyl; R5 is hydrogen, dialkylcarbamoyl,? -hydroxyalkyl, -aminomethyl-propyl or (hydroxy) - (pyrrolidin-2-yl) -methyl; R ^ is hydrogen, trifluoromethyl or hydroxyl; and R7 is alkyl, -hydroxy-alkyl, cycloalkyl, 3-pyrrolidinyl, 3-azetidinyl, iminomethyl or 1-carbamimidoyl; as well as their easily hydrolysable esters, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula I and their esters and salts; the invention also relates to the preparation of compounds of formula I; to their use as pharmaceutically active substances, particularly for the treatment and prophylaxis of infectious diseases and to pharmaceutical preparations containing a compound of formula I for the treatment and prophylaxis of infectious diseases.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP96120472 | 1996-12-19 | ||
| EP96120472.4 | 1996-12-19 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MX9710004A MX9710004A (en) | 1998-09-30 |
| MXPA97010004A true MXPA97010004A (en) | 1998-11-16 |
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