US20150025053A1 - Cephalosporin compound - Google Patents
Cephalosporin compound Download PDFInfo
- Publication number
- US20150025053A1 US20150025053A1 US14/333,966 US201414333966A US2015025053A1 US 20150025053 A1 US20150025053 A1 US 20150025053A1 US 201414333966 A US201414333966 A US 201414333966A US 2015025053 A1 US2015025053 A1 US 2015025053A1
- Authority
- US
- United States
- Prior art keywords
- compound
- formula
- bacteria
- pseudomonas aeruginosa
- gram
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 229930186147 Cephalosporin Natural products 0.000 title abstract description 18
- 229940124587 cephalosporin Drugs 0.000 title abstract description 18
- -1 Cephalosporin compound Chemical class 0.000 title abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 97
- 238000000034 method Methods 0.000 claims abstract description 36
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 34
- 241000894006 Bacteria Species 0.000 claims abstract description 29
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims abstract description 29
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 208000015181 infectious disease Diseases 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 13
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 208000008745 Healthcare-Associated Pneumonia Diseases 0.000 claims description 5
- 208000035473 Communicable disease Diseases 0.000 claims description 4
- 206010035664 Pneumonia Diseases 0.000 claims description 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims 1
- 229940125797 compound 12 Drugs 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 239000012453 solvate Substances 0.000 claims 1
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 36
- 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 abstract description 10
- 229960003085 meticillin Drugs 0.000 abstract description 10
- 241000191967 Staphylococcus aureus Species 0.000 abstract description 9
- 230000003115 biocidal effect Effects 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 4
- ORFOPKXBNMVMKC-DWVKKRMSSA-N ceftazidime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 ORFOPKXBNMVMKC-DWVKKRMSSA-N 0.000 description 26
- 229960000484 ceftazidime Drugs 0.000 description 26
- 241000699670 Mus sp. Species 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 19
- 230000001580 bacterial effect Effects 0.000 description 16
- 208000035143 Bacterial infection Diseases 0.000 description 15
- 208000022362 bacterial infectious disease Diseases 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 13
- 208000032376 Lung infection Diseases 0.000 description 13
- 238000001727 in vivo Methods 0.000 description 12
- 210000000689 upper leg Anatomy 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 10
- 108010059993 Vancomycin Proteins 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 150000001780 cephalosporins Chemical class 0.000 description 9
- 238000007920 subcutaneous administration Methods 0.000 description 9
- 229960003165 vancomycin Drugs 0.000 description 9
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 241000589516 Pseudomonas Species 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 8
- 230000003389 potentiating effect Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 description 8
- 241000192125 Firmicutes Species 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- 206010040047 Sepsis Diseases 0.000 description 7
- 239000003242 anti bacterial agent Substances 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 229940036735 ceftaroline Drugs 0.000 description 7
- ZCCUWMICIWSJIX-NQJJCJBVSA-N ceftaroline fosamil Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OCC)C=2N=C(NP(O)(O)=O)SN=2)CC=1SC(SC=1)=NC=1C1=CC=[N+](C)C=C1 ZCCUWMICIWSJIX-NQJJCJBVSA-N 0.000 description 7
- DHSUYTOATWAVLW-WFVMDLQDSA-N cilastatin Chemical compound CC1(C)C[C@@H]1C(=O)N\C(=C/CCCCSC[C@H](N)C(O)=O)C(O)=O DHSUYTOATWAVLW-WFVMDLQDSA-N 0.000 description 7
- 238000012809 post-inoculation Methods 0.000 description 7
- 229940027836 primaxin Drugs 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 208000013223 septicemia Diseases 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 241000588747 Klebsiella pneumoniae Species 0.000 description 5
- 241000191940 Staphylococcus Species 0.000 description 5
- 229940088710 antibiotic agent Drugs 0.000 description 5
- 239000002054 inoculum Substances 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- 230000009885 systemic effect Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 238000002815 broth microdilution Methods 0.000 description 4
- HVFLCNVBZFFHBT-ZKDACBOMSA-N cefepime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 HVFLCNVBZFFHBT-ZKDACBOMSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000011081 inoculation Methods 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 4
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- HPNOLZPGSCCGPI-QTYBPQHISA-N CO/N=C(\C(=O)C[C@@H]1C(=O)N2C(C(=O)OCC3=CC=C(OC)C=C3)=C(CCl)CS[C@H]12)C1=C(Cl)SC(N)=N1 Chemical compound CO/N=C(\C(=O)C[C@@H]1C(=O)N2C(C(=O)OCC3=CC=C(OC)C=C3)=C(CCl)CS[C@H]12)C1=C(Cl)SC(N)=N1 HPNOLZPGSCCGPI-QTYBPQHISA-N 0.000 description 3
- PVRYJCLNCDSDLK-WIYUQANSSA-M CO/N=C(\C(=O)C[C@@H]1C(=O)N2C(C(=O)[O-])=C(CN3=CC(NC(=O)NC4=CC=C(CCCC(=N)N)C=C4)=C(N)C=C3)CS[C@H]12)C1=C(Cl)SC(N)=N1 Chemical compound CO/N=C(\C(=O)C[C@@H]1C(=O)N2C(C(=O)[O-])=C(CN3=CC(NC(=O)NC4=CC=C(CCCC(=N)N)C=C4)=C(N)C=C3)CS[C@H]12)C1=C(Cl)SC(N)=N1 PVRYJCLNCDSDLK-WIYUQANSSA-M 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 206010041925 Staphylococcal infections Diseases 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 239000004202 carbamide Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 229960002100 cefepime Drugs 0.000 description 3
- DKOQGJHPHLTOJR-WHRDSVKCSA-N cefpirome Chemical compound N([C@@H]1C(N2C(=C(C[N+]=3C=4CCCC=4C=CC=3)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 DKOQGJHPHLTOJR-WHRDSVKCSA-N 0.000 description 3
- 229960000466 cefpirome Drugs 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- KREURDNASOOIGJ-KMKOMSMNSA-N (2z)-2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-methoxyiminoacetic acid Chemical compound CO\N=C(/C(O)=O)C=1N=C(N)SC=1Cl KREURDNASOOIGJ-KMKOMSMNSA-N 0.000 description 2
- PBKFYMCZYNFVIA-IUODEOHRSA-N (4-methoxyphenyl)methyl (6r,7r)-7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1=CC(OC)=CC=C1COC(=O)C1=C(CCl)CS[C@H]2N1C(=O)[C@H]2N PBKFYMCZYNFVIA-IUODEOHRSA-N 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- AJJTWCADNHRFRY-ZGSKRRFDSA-M CO/N=C(\C(=O)C[C@@H]1C(=O)N2C(C(=O)[O-])=C(CN3=CC(NC(=O)NC4=CC=C(CCCC(C)=N)C=C4)=C(N)C=C3)CS[C@H]12)C1=C(Cl)SC(N)=N1 Chemical compound CO/N=C(\C(=O)C[C@@H]1C(=O)N2C(C(=O)[O-])=C(CN3=CC(NC(=O)NC4=CC=C(CCCC(C)=N)C=C4)=C(N)C=C3)CS[C@H]12)C1=C(Cl)SC(N)=N1 AJJTWCADNHRFRY-ZGSKRRFDSA-M 0.000 description 2
- 102000009338 Gastric Mucins Human genes 0.000 description 2
- 108010009066 Gastric Mucins Proteins 0.000 description 2
- PQMWYJDJHJQZDE-UHFFFAOYSA-M Methantheline bromide Chemical compound [Br-].C1=CC=C2C(C(=O)OCC[N+](C)(CC)CC)C3=CC=CC=C3OC2=C1 PQMWYJDJHJQZDE-UHFFFAOYSA-M 0.000 description 2
- 238000005273 aeration Methods 0.000 description 2
- 244000052616 bacterial pathogen Species 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000001332 colony forming effect Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 208000027096 gram-negative bacterial infections Diseases 0.000 description 2
- 208000027136 gram-positive bacterial infections Diseases 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 231100000518 lethal Toxicity 0.000 description 2
- 230000001665 lethal effect Effects 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- HIKSJHJBLCWIJW-UHFFFAOYSA-N tert-butyl n-amino-n-pyridin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)N(N)C1=CC=NC=C1 HIKSJHJBLCWIJW-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- NLARCUDOUOQRPB-WTKPLQERSA-N (2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetic acid Chemical compound CO\N=C(/C(O)=O)C1=CSC(N)=N1 NLARCUDOUOQRPB-WTKPLQERSA-N 0.000 description 1
- KFCMZNUGNLCSJQ-NFBKMPQASA-N (4-methoxyphenyl)methyl (6r,7r)-3-(chloromethyl)-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1=CC(OC)=CC=C1COC(=O)C1=C(CCl)CS[C@H]2N1C(=O)[C@H]2NC(=O)CC1=CC=CC=C1 KFCMZNUGNLCSJQ-NFBKMPQASA-N 0.000 description 1
- FJJSPXDEYHEEHF-XBARRRKZSA-N (4-methoxyphenyl)methyl (6r,7r)-7-[[(2z)-2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound S([C@@H]1[C@@H](C(N11)=O)NC(=O)\C(=N/OC)C2=C(SC(N)=N2)Cl)CC(CCl)=C1C(=O)OCC1=CC=C(OC)C=C1 FJJSPXDEYHEEHF-XBARRRKZSA-N 0.000 description 1
- NCCJWSXETVVUHK-ZYSAIPPVSA-N (z)-7-[(2r)-2-amino-2-carboxyethyl]sulfanyl-2-[[(1s)-2,2-dimethylcyclopropanecarbonyl]amino]hept-2-enoic acid;(5r,6s)-3-[2-(aminomethylideneamino)ethylsulfanyl]-6-[(1r)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound C1C(SCC\N=C/N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21.CC1(C)C[C@@H]1C(=O)N\C(=C/CCCCSC[C@H](N)C(O)=O)C(O)=O NCCJWSXETVVUHK-ZYSAIPPVSA-N 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N 1,3,5-Me3C6H3 Natural products CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical group NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- PSQZJKGXDGNDFP-UHFFFAOYSA-N 2,2,3,3,3-pentafluoropropan-1-ol Chemical compound OCC(F)(F)C(F)(F)F PSQZJKGXDGNDFP-UHFFFAOYSA-N 0.000 description 1
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- MPZMVUQGXAOJIK-UHFFFAOYSA-N 4-bromopyridine;hydron;chloride Chemical compound Cl.BrC1=CC=NC=C1 MPZMVUQGXAOJIK-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 0 C*1(CC(CS[C@@]2[C@]3NC(C(c4c[s]c(N)n4)=NOC)=O)=C(C([O-])=O)N2C3=O)CCCC1 Chemical compound C*1(CC(CS[C@@]2[C@]3NC(C(c4c[s]c(N)n4)=NOC)=O)=C(C([O-])=O)N2C3=O)CCCC1 0.000 description 1
- AGOZAMUOKOPJDL-DIHLKZBKSA-N C.C.CO/N=C(\C(=O)O)C1=C(Cl)SC(N)=N1.CO/N=C(\C(=O)O)C1=C(Cl)SC(N)=N1.O=C1CCC(=O)N1Cl.[2H]CF Chemical compound C.C.CO/N=C(\C(=O)O)C1=C(Cl)SC(N)=N1.CO/N=C(\C(=O)O)C1=C(Cl)SC(N)=N1.O=C1CCC(=O)N1Cl.[2H]CF AGOZAMUOKOPJDL-DIHLKZBKSA-N 0.000 description 1
- MQXNOMRCRGCDFM-VKYJLJAZSA-N C.CO/N=C(\C(=O)C[C@@H]1C(=O)N2C(C(=O)OCC3=CC=C(OC)C=C3)=C(CCl)CS[C@H]12)C1=C(Cl)SC(N)=N1.CO/N=C(\C(=O)O)C1=C(Cl)SC(N)=N1.COC1=CC=C(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](N)C(=O)N23)C=C1 Chemical compound C.CO/N=C(\C(=O)C[C@@H]1C(=O)N2C(C(=O)OCC3=CC=C(OC)C=C3)=C(CCl)CS[C@H]12)C1=C(Cl)SC(N)=N1.CO/N=C(\C(=O)O)C1=C(Cl)SC(N)=N1.COC1=CC=C(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](N)C(=O)N23)C=C1 MQXNOMRCRGCDFM-VKYJLJAZSA-N 0.000 description 1
- IGQAHCTUTBXRKT-HMNWJAKSSA-N C.COC1=CC=C(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](CC(=O)CC4=CC=CC=C4)C(=O)N23)C=C1.COC1=CC=C(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](N)C(=O)N23)C=C1.ClCCl Chemical compound C.COC1=CC=C(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](CC(=O)CC4=CC=CC=C4)C(=O)N23)C=C1.COC1=CC=C(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](N)C(=O)N23)C=C1.ClCCl IGQAHCTUTBXRKT-HMNWJAKSSA-N 0.000 description 1
- DVJLXRZFIRMBGL-VEUDKXNTSA-N CC(C)(O/N=C(\C(=O)C[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3=CC=CC=C3)CS[C@H]12)C1=CSC(N)=N1)C(=O)O Chemical compound CC(C)(O/N=C(\C(=O)C[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3=CC=CC=C3)CS[C@H]12)C1=CSC(N)=N1)C(=O)O DVJLXRZFIRMBGL-VEUDKXNTSA-N 0.000 description 1
- LRKHKETXQNDOKF-IODBXWCGSA-N CC(C)(O\N=C(\C(=O)N[C@H]1[C@H]2SC=C(C[n+]3ccccc3)C(N2C1=O)C([O-])=O)c1csc(N)n1)C(O)=O Chemical compound CC(C)(O\N=C(\C(=O)N[C@H]1[C@H]2SC=C(C[n+]3ccccc3)C(N2C1=O)C([O-])=O)c1csc(N)n1)C(O)=O LRKHKETXQNDOKF-IODBXWCGSA-N 0.000 description 1
- GJTZOHDXBBWODJ-UHFFFAOYSA-N CC1=CN=CC=C1CNC(=O)C1=CC=C(CCN/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C=C1 Chemical compound CC1=CN=CC=C1CNC(=O)C1=CC=C(CCN/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C=C1 GJTZOHDXBBWODJ-UHFFFAOYSA-N 0.000 description 1
- WYMWNPZUESCZRC-CFLLIGIISA-N CCCC1=CC=C(C(=O)NCC2=CC=[N+](CC3=C(C(=O)[O-])N4C(=O)[C@@H](CC(=O)/C(=N\OC)C5=C(Cl)SC(N)=N5)[C@H]4SC3)C=C2)C=C1 Chemical compound CCCC1=CC=C(C(=O)NCC2=CC=[N+](CC3=C(C(=O)[O-])N4C(=O)[C@@H](CC(=O)/C(=N\OC)C5=C(Cl)SC(N)=N5)[C@H]4SC3)C=C2)C=C1 WYMWNPZUESCZRC-CFLLIGIISA-N 0.000 description 1
- XPUWGVJYWBKMFV-MPVNUPCCSA-N CO/N=C(\C(=O)C[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3=C4CCCC4=CC=C3)CS[C@H]12)C1=CSC(N)=N1 Chemical compound CO/N=C(\C(=O)C[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3=C4CCCC4=CC=C3)CS[C@H]12)C1=CSC(N)=N1 XPUWGVJYWBKMFV-MPVNUPCCSA-N 0.000 description 1
- LPLHEYQHDDRNLX-KLNSIKNBSA-N CO/N=C(\C(=O)C[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3=CC=C(CN)C=C3)CS[C@H]12)C1=CSC(N)=N1 Chemical compound CO/N=C(\C(=O)C[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3=CC=C(CN)C=C3)CS[C@H]12)C1=CSC(N)=N1 LPLHEYQHDDRNLX-KLNSIKNBSA-N 0.000 description 1
- YQMAWODKFGCXRQ-NIHWBIBOSA-N CO/N=C(\C(=O)C[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3=CC=C(CNC(=O)C4=CC(CCCC(=O)C(F)(F)F)=CC=C4)C=C3)CS[C@H]12)C1=C(Cl)SC(N)=N1 Chemical compound CO/N=C(\C(=O)C[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3=CC=C(CNC(=O)C4=CC(CCCC(=O)C(F)(F)F)=CC=C4)C=C3)CS[C@H]12)C1=C(Cl)SC(N)=N1 YQMAWODKFGCXRQ-NIHWBIBOSA-N 0.000 description 1
- ASOAIKYGSBFFOW-KUNKYQTRSA-N CO/N=C(\C(=O)C[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3=CC=C(CNC(=O)C4=CC=CC=C4)C=C3)CS[C@H]12)C1=C(Cl)SC(N)=N1 Chemical compound CO/N=C(\C(=O)C[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3=CC=C(CNC(=O)C4=CC=CC=C4)C=C3)CS[C@H]12)C1=C(Cl)SC(N)=N1 ASOAIKYGSBFFOW-KUNKYQTRSA-N 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 201000008225 Klebsiella pneumonia Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000037942 Methicillin-resistant Staphylococcus aureus infection Diseases 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 206010031252 Osteomyelitis Diseases 0.000 description 1
- 241001635237 Paonias Species 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 206010035717 Pneumonia klebsiella Diseases 0.000 description 1
- 208000032536 Pseudomonas Infections Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 208000009470 Ventilator-Associated Pneumonia Diseases 0.000 description 1
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 1
- WXIONIWNXBAHRU-UHFFFAOYSA-N [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium Chemical compound C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 WXIONIWNXBAHRU-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000003927 aminopyridines Chemical class 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- 238000009635 antibiotic susceptibility testing Methods 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 208000037815 bloodstream infection Diseases 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 206010014665 endocarditis Diseases 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 1
- 229960002260 meropenem Drugs 0.000 description 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- DPEOHPOIEZBHPY-UHFFFAOYSA-N n-chloro-1,3-thiazol-2-amine Chemical class ClNC1=NC=CS1 DPEOHPOIEZBHPY-UHFFFAOYSA-N 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000723 toxicological property Toxicity 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 239000006150 trypticase soy agar Substances 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 229960001572 vancomycin hydrochloride Drugs 0.000 description 1
- LCTORFDMHNKUSG-XTTLPDOESA-N vancomycin monohydrochloride Chemical compound Cl.O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 LCTORFDMHNKUSG-XTTLPDOESA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 150000003952 β-lactams Chemical group 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/48—Methylene radicals, substituted by hetero rings
- C07D501/56—Methylene radicals, substituted by hetero rings with the 7-amino radical acylated by carboxylic acids containing hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/60—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 3 and 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
Definitions
- This disclosure is directed to a cephalosporin compound which is useful as an antibiotic, as well as pharmaceutical compositions comprising the compound, methods of using the compound as an antibacterial agent, and processes and intermediates for preparing the compound.
- cephalosporin derivative compounds with various substitutions on a beta-lactam core have antibacterial activity.
- Cephalosporin compounds with a quaternary ammonium group at the 3-position of the cephalosporin beta lactam core structure and an aminothiazole/oxime structure at the 7-position can provide antibacterial activity against multiple types of bacteria, including Gram-negative bacteria Pseudomonas aeruginosa (Pa).
- ceftazidime and cefpirome which include the cephalosporin core with an aminothiazolyl group at the 7-position and a quaternary salt substituent at the 3-position, have antibacterial activity against a wide spectrum of bacteria from Gram-positive bacteria in addition to Pseudomonas aeruginosa.
- compounds such as ceftazidime and cefpirome may not be satisfactory in the antibacterial activity against both Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA).
- MRSA methicillin-resistant Staphylococcus aureus
- infectious diseases caused by methicillin-resistant Staphylococcus aureus (MRSA) continue to present significant clinical challenges.
- MRSA methicillin-resistant Staphylococcus aureus
- a cephalosporin compound with antibacterial activity against Gram-negative and Gram-positive bacteria including Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA)
- MRSA methicillin-resistant Staphylococcus aureus
- this disclosure provides a cephalosporin compound of formula (I) having antibacterial activity against both Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA), for example as measured according to Minimum Inhibitory Concentrations (MICs) as measured by the method of Examples 3-5.
- MICs Minimum Inhibitory Concentrations
- cephalosporin compound having the structure:
- the cephalosporin compound of formula (I) has antibacterial activity against both Gram-negative bacteria and Gram-positive bacteria and is useful in treating a bacterial infection in a host, such as a human or other mammal.
- pharmaceutical compositions comprising formula (I), or a pharmacologically acceptable salts thereof can be independently effective against both Gram-negative bacteria such as Pseudomonas aeruginosa and Gram-positive bacteria such as Staphylococcus aureus —including MRSA—with a MIC of not more than about 4 micrograms/mL (as measured according to the method of Example 3).
- Methods of treating bacterial infections can include administering to an infected host a pharmaceutical composition comprising an antibacterially effective amount of the compound of formula (I), or a pharmacologically acceptable salt thereof.
- the compound of formula (I) can be prepared by a variety of synthetic routes, including synthetic schemes described herein. These synthetic routes can be applied to large scale synthesis with appropriate adjustment of reaction sequence, reaction conditions, isolation/purification methods and choice of solvents which are environmentally friendly and cost-effective.
- terapéuticaally effective amount refers to a total administered amount of an antibacterial compound that is effective to perform the function being sought by the researcher or clinician without unduly harming the tissues of the subject to which the agent is administered.
- subject refers to an animal, a plant, or a cell culture.
- a subject is a human or other animal patient in need of antibacterial treatment.
- CDI 1,1′-Carbonyldiimidazole
- DIPEA diisopropylethylamine
- EDCl 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide
- HAP Hospital-Acquired Pneumonia
- HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
- MRSA Methicillin-resistant Staphylococcus aureus
- NCS N-Chlorosuccinimide
- Pa Pseudomonas aeruginosa
- Pd 2 (dba) 3 Tris(dibenzylideneacetone)dipalladium(0).
- PdCl 2 (dppf) Pd[1,1-bis (diphenylphosphino) ferrocene]dichloropalladium(II)
- VAP Ventilator-Associated Pneumonia
- FIG. 1 depicts the efficacy of the compound of formula (I) against MRSA #712 thigh infection compared with vancomycin in neutropenic mice.
- FIG. 2 depicts the efficacy of the compound of formula (I) against ceftazidime-susceptible pseudomonas aeruginosa # 44 (ATCC#27853) lung infection compared with ceftazidime and primaxin in neutropenic mice.
- FIG. 3 depicts the efficacy of the compound of formula (I) against ceftazidime-susceptible pseudomonas aeruginosa # 2245 lung infection compared with ceftazidime and primaxin in neutropenic mice.
- FIG. 4 depicts the efficacy of the compound of formula (I) against ceftazidime-resistant pseudomonas aeruginosa # 2545 lung infection compared with ceftazidime and primaxin in neutropenic mice.
- FIG. 5 depicts the synthesis of the compound of formula (I).
- FIG. 6 depicts the distribution of MICs of the compound of formula (I) against MRSA and Pa strains with comparators.
- a compound of formula (I), or a pharmaceutically acceptable salt thereof which is useful for treating bacterial infections.
- pharmaceutical compositions comprising the cephalosporin compound of formula (I) have a surprisingly broad spectrum of antibacterial activity and are useful to inhibit or kill various bacteria.
- the antibacterial compound disclosed herein can be used in the manufacture of antibacterial medicaments and in methods for the treatment of bacterial infections, including treatment of both certain Gram-positive and Gram-negative bacterial infections.
- the cephalosporin compound of formula (I), or a pharmacologically acceptable salt thereof has the following structure:
- the compound of formula (I) has a MIC (measured by the method of Example 3) against Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) of less than or equal to about 1-2 micrograms/mL.
- formula (I) Also included in formula (I) are zwitterionic forms containing an anionic carboxylic moiety and the cationic nitrogen in the pyridinium moiety.
- the imino group in the C-7 side chain position of the cephalosporin fused ring structure of formula (I) are shown in the “syn” (Z) configuration.
- the compound of formula (I) are preferably prepared as the syn-isomer (Z-isomer), or in mixtures comprising an amount of the syn-isomer (e.g., at least 90%) to provide a desired level of antibacterial activity, including compound of formula (I) that are syn isomers which are essentially free of the corresponding anti imino isomers.
- the compound of formula (I) can be prepared from cephalosporin intermediate compound 4a as described in the Examples, or following literature procedures.
- literature procedures see, e.g., (a) Lattrell, R.; Blumbach, J.; Duerckheimer, W.; Friedhaber, H. W.; Fleischmann, K.; Kirrstetter, R.; Mencke, B.; Scheunemann, K. H.; Schrinner, E.; et al. J. of Antibiotics 1988, 41, 1374.
- the antibiotic activity of the compound of formula (I) was measured against a variety of pathogenic microorganisms including Gram-positive and Gram-negative bacteria, including against Staphylococcus and Pseudomonas bacteria.
- Minimum inhibitory concentrations (MICs) for the compound of formula (I) against certain Staphylococcus, Pseudomonas and pneumoniae strains are listed in micrograms/mL in Table 2.
- the MICs were determined as described in Example 4. Accordingly, the compound of formula (I) can be included in pharmaceutical antibacterial compositions and are useful both in the manufacture of medicaments for treating bacteria or bacterial infections, and in methods of treating conditions caused by bacteria such as infections.
- Pharmaceutical antibacterial compositions can be formed by combining the compound of formula (I) or a pharmacologically acceptable salt thereof with a pharmacologically acceptable carrier suitable for delivery to a recipient subject (e.g., a human) in accordance with known methods of drug delivery.
- a pharmacologically acceptable carrier suitable for delivery to a recipient subject (e.g., a human) in accordance with known methods of drug delivery.
- Antibacterial pharmaceutical compositions suitable for administration of one or more compound of formula (I) can be formulated.
- the compound of formula (I), and/or pharmacologically acceptable salts of formula (I) can be included in a pharmaceutical antibacterial composition along with one or more carriers.
- compositions can be formed by combining the compound of formula (I) or a pharmacologically acceptable salt thereof with a pharmacologically acceptable carrier suitable for delivery to a recipient subject (e.g., a human) in accordance with known methods of drug delivery.
- Antibacterial pharmaceutical compositions suitable for administration of one or more compound of formula (I) can be formulated.
- the compound of formula (I), and/or pharmacologically acceptable salts of formula (I) can be included in a pharmaceutical antibacterial composition along with one or more carriers.
- Pharmaceutical preparations can be prepared in accordance with standard procedures and are administered at dosages that are selected to treat infection (see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. and Goodman and Gilman's “The Pharmaceutical Basis of Therapeutics,” Pergamon Press, New York, N.Y., the contents of which are incorporated herein by reference, for a general description of the methods for administering various antimicrobial agents for human therapy).
- the compound of formula (I) can be formulated as a variety of salts to improve stability or toxicological properties of the compound, increase or decrease solubility, improve pharmacokinetic performance of the compound (e.g., C max or AUC measurements) or improve storage properties (e.g., to reduce hygroscopicity) of a pharmaceutical composition.
- pharmaceutically-acceptable salt refers to pharmaceutical salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and are commensurate with a reasonable benefit/risk ratio.
- Pharmaceutically-acceptable salts are well known in the art. For example, S. M. Berge, et al.
- a pharmaceutical composition can include a pharmaceutically-acceptable carrier and the compound of formula (I) and/or salts of formula (I).
- pharmaceutically-acceptable carrier refers generally to solvents, dispersion media, excipients, coatings, matrices, stabilizers, buffers, absorption enhancers, adjuvents, controlled release media, and the like, that are compatible with an intended use, such as pharmaceutical administration.
- the use of such carriers for pharmaceutically active substances is well known in the art.
- compositions can be formulated for parenteral delivery, including intravenous, intramuscular, intraperetoneal, subcutaneous, intraocular, intrathecal, intra-articular, intra-synovial, cisternal, intrahepatic, intralesional and intracranial injection, infusion, and/or inhaled routes of administration for the therapeutic treatment of medical conditions, such as bacterial infections.
- compositions for parenteral injection can comprise pharmaceutically-acceptable aqueous or nonaqueous solutions of antibacterial compound of formula (I) in addition to one or more of the following: pH buffered solutions, adjuvants (e.g. preservatives, wetting agents, emulsifying agents, and dispersing agents), liposomal formulations, nanoparticles, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
- adjuvants e.g. preservatives, wetting agents, emulsifying agents, and dispersing agents
- liposomal formulations nanoparticles, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
- the pharmaceutical composition can include any of the commonly used intravenous fluids and administered by infusion, such as physiological saline or Ringer's solution.
- the antibacterial compound of formula (I) disclosed herein, and pharmacologically acceptable salts thereof, including pharmaceutical compositions comprising these compounds, is useful in the manufacture of antibacterial pharmaceutical compositions, and treatment of bacteria.
- the antibacterial compounds are useful in treating and eliminating a broad spectrum of bacterial pathogens, including both gram negative and gram positive bacterial infections.
- the antibacterial compound of formula (I) can be used in vivo, for example, to treat bacterial infections in a subject, as well as in vitro, for example to treat cells (e.g., bacteria) in culture to eliminate or reduce the level of bacterial contamination of a cell culture.
- the compound of formula (I), or a pharmaceutical composition thereof is administered to a cell culture, such as by administering in a nutrient medium.
- Methods of treating bacterial infections in subjects can include the administration of a therapeutically effective amount of the compound of formula (I) or a pharmacologically acceptable salt thereof.
- Methods of treatment of such infections include administering to a subject in need thereof a therapeutically effective amount of the compound of formula (I).
- the compound can be parenterally administered to a subject having or suspected to have a bacterial infection, such as a gram negative infection.
- the antibacterial compound of formula (I) is preferably used in vivo to treat an infection in a subject by administering a therapeutically effective amount of the compound of formula (I) in a pharmaceutical composition.
- the method can comprise parenterally administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective dose of at least one compound of formula (I).
- Pharmaceutical compositions include compositions comprising compound(s) of formula (I) in a dose sufficient to achieve the intended purpose, i.e., the treatment or prevent of infectious diseases.
- the amount and concentration of antibacterial compound of formula (I) in the pharmaceutical composition, as well as the quantity of the pharmaceutical composition administered to a subject, can be selected based on clinically relevant factors, such as medically relevant characteristics of the subject (e.g., age, weight, gender, other medical conditions, and the like), the solubility of the antibacterial compound in the pharmaceutical composition, the potency and activity of the antibacterial compound, any toxicity associated with the pharmaceutical composition dose and method of administration, and the manner of administration of the pharmaceutical composition.
- medically relevant characteristics of the subject e.g., age, weight, gender, other medical conditions, and the like
- the solubility of the antibacterial compound in the pharmaceutical composition e.g., the solubility of the antibacterial compound in the pharmaceutical composition
- the potency and activity of the antibacterial compound e.g., any toxicity associated with the pharmaceutical composition dose and method of administration, and the manner of administration of the pharmaceutical composition.
- a pharmaceutical composition comprising a therapeutically effective dose of the compound of formula (I) can be administered intravenously to a patient for treatment of gram negative infections in a clinically safe and effective manner, including one or more separate administrations of the composition.
- the total daily dose of the compound of formula (I) can be about 2.0 mg/kg/day to about 50 mg/kg/day of all compound of formula (I) administered intravenously to a subject one to three times a day (e.g., QD, BID or TID).
- the amount per administered dose or the total amount administered will depend on such factors as the nature and severity of the infection, the age and general health of the patient, the tolerance of the patient to the compound and the microorganism or microorganisms involved in the infection.
- the total amount of the pharmaceutical composition administered can be selected to be therapeutically effective.
- the pharmaceutical compositions comprising the compound of formula (I) can be used to treat a subject having a bacterial infection in which the infection is caused or exacerbated by a gram-negative bacteria.
- a method of treating a bacterial infection in a host can include administering to an infected host a pharmaceutical composition comprising a therapeutically effective dose (e.g., an antibacterially effective amount) of the compound of formula (I), or a pharmacologically acceptable salt thereof.
- the pharmaceutical composition and/or compound(s) of formula (I) can be administered to treat a bacterial infection or population in vitro (e.g., a bacterial colony on a surface outside the body) or in vivo (e.g., within an infected host).
- the bacterial infection or population can include Gram-negative and/or Gram-positive bacteria.
- the Gram-negative bacteria can comprise Pseudomonas aeruginosa and the Gram-positive bacteria can include Staphylococcus aureus.
- the bacteria can form an infection present in vitro (e.g., a bacterial colony or sample), or in vivo (e.g., an infected host subject).
- the bacterial infection can be identified as a methicillin-resistant Staphylococcal infection.
- the antibacterially effective dose and therapeutically effective amount of the compound(s) of Formula (I) can be effective in killing both a Pseudomonas aeruginosa bacteria and a MRSA bacteria with a MIC that is less than the comparable value for a compound in Table 1, and/or independent MIC values measured according to Example 3 that is not more than about 4 micrograms/mL (e.g., including values of about 3.5, 3.0, 2.5, 2.0, 1.5, 1.0, 0.5 micrograms/mL or lower) independently measured against each of Pseudomonas aeruginosa bacteria and methicillin-resistant Staphylococcal bacteria.
- a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I) can be administered to a patient presenting symptoms of an infection.
- the compounds of this invention can be used to treat infections of cSSSI and HAP/VAP in adults or children.
- methicillin resistant Staphylococcus aureus infections and/or Pseudomonas infections may be treated with the compound of formula (I).
- Other representative types of infections or bacteria-related medical conditions which can be treated or prevented with pharmaceutical compositions comprising antibacterial compound of formula (I) include, but are not limited to, skin and skin structure infections, urinary tract infections, pneumonia, endocarditis, catheter-related blood stream infections, osteomyelitis, and the like.
- the patient may treated with the pharmaceutical compositions comprising the compound of formula (I) upon presenting symptoms consistent with a bacterial infection.
- the pharmaceutical compositions may be administered prior to or after identifying the types of bacteria present in the patient.
- the nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts ( ⁇ ) expressed in parts per million (ppm) versus tetramethylsilane (TMS) as reference standard.
- the relative area reported for the various shifts in the proton NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule.
- the nature of the shifts as to multiplicity is reported as broad singlet (br s), broad doublet (br d), singlet (s), multiplet (m), doublet (d), quartet (q), doublet of doublet (dd), doublet of triplet (dt), and doublet of quartet (dq).
- the solvents employed for taking NMR spectra are DMSO-d6 (perdeuterodimethysulfoxide), D 2 O (deuterated water), CDCl 3 (deuterochloroform) and other conventional deuterated solvents.
- the prep-HPLC conditions are: Waters SunFire® C18 (30 ⁇ 100 mm, 5 ⁇ m) column; flow rate: 50 mL/min, UV or Mass-triggered fraction collection; sample loading: each injection loading varied from 30-80 mg depending for different crude samples depending on their solubility and purity profiles; solvent system: solvent A: water with 0.5% formic acid, solvent B: acetonitrile with 0.5% formic acid.
- Step 1 Preparation of (6R,7R)-4-methoxybenzyl 7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
- Step 3 Synthesis of Compound 4a via EDCI Coupling
- cephalosporin core intermediate 6 was synthesized by amide coupling of 7-aminocephalosporin derivative 3 and chloroaminothiazole derivative 5.
- Urea tail 12 was prepared by CDI mediated urea formation of aniline derivative 8 and aminopyridine derivative 11. Coupling of intermediate 6 and urea tail 12, followed by global deprotection using TFA/anisol provided the final product (I), which was purified by reverse phase HPLC using 0.1% formic acid buffer in water/acetonitrile.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
- The present application is a continuation application of U.S. application Ser. No. 14/020,230, filed Sep. 6, 2013, which claims priority to U.S. Provisional Application No. 61/698,241, filed on Sep. 7, 2012. The entire contents of these applications are incorporated herein by reference in their entirety.
- This disclosure is directed to a cephalosporin compound which is useful as an antibiotic, as well as pharmaceutical compositions comprising the compound, methods of using the compound as an antibacterial agent, and processes and intermediates for preparing the compound.
- A variety of cephalosporin derivative compounds with various substitutions on a beta-lactam core have antibacterial activity. Cephalosporin compounds with a quaternary ammonium group at the 3-position of the cephalosporin beta lactam core structure and an aminothiazole/oxime structure at the 7-position can provide antibacterial activity against multiple types of bacteria, including Gram-negative bacteria Pseudomonas aeruginosa (Pa). For example, ceftazidime and cefpirome, which include the cephalosporin core with an aminothiazolyl group at the 7-position and a quaternary salt substituent at the 3-position, have antibacterial activity against a wide spectrum of bacteria from Gram-positive bacteria in addition to Pseudomonas aeruginosa. However, even compounds such as ceftazidime and cefpirome may not be satisfactory in the antibacterial activity against both Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA). In addition, infectious diseases caused by methicillin-resistant Staphylococcus aureus (MRSA) continue to present significant clinical challenges. There remains a need for novel cephalosporin antibiotics which have improved antibacterial activity also against these and other bacteria.
- A cephalosporin compound with antibacterial activity against Gram-negative and Gram-positive bacteria, including Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA), is disclosed. In particular, this disclosure provides a cephalosporin compound of formula (I) having antibacterial activity against both Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA), for example as measured according to Minimum Inhibitory Concentrations (MICs) as measured by the method of Examples 3-5.
- Provided herein is a cephalosporin compound having the structure:
- The cephalosporin compound of formula (I) has antibacterial activity against both Gram-negative bacteria and Gram-positive bacteria and is useful in treating a bacterial infection in a host, such as a human or other mammal. For example, pharmaceutical compositions comprising formula (I), or a pharmacologically acceptable salts thereof, can be independently effective against both Gram-negative bacteria such as Pseudomonas aeruginosa and Gram-positive bacteria such as Staphylococcus aureus—including MRSA—with a MIC of not more than about 4 micrograms/mL (as measured according to the method of Example 3). Methods of treating bacterial infections can include administering to an infected host a pharmaceutical composition comprising an antibacterially effective amount of the compound of formula (I), or a pharmacologically acceptable salt thereof.
- The compound of formula (I) can be prepared by a variety of synthetic routes, including synthetic schemes described herein. These synthetic routes can be applied to large scale synthesis with appropriate adjustment of reaction sequence, reaction conditions, isolation/purification methods and choice of solvents which are environmentally friendly and cost-effective.
- The term “therapeutically effective amount,” as used herein refers to a total administered amount of an antibacterial compound that is effective to perform the function being sought by the researcher or clinician without unduly harming the tissues of the subject to which the agent is administered.
- The term “subject,” as used herein, refers to an animal, a plant, or a cell culture. In one embodiment, a subject is a human or other animal patient in need of antibacterial treatment.
- The following abbreviations have the following meanings unless otherwise indicated. Abbreviations not defined below have their generally accepted meaning.
- Boc=tert-butoxycarbonyl
- Boc2O=di-tert-butyldicarbonate
- CDI=1,1′-Carbonyldiimidazole
- CFU=colony-forming units
- CLSI=Clinical Laboratory Standards Institute
- cSSSI=complicated skin and skin structure infections
- DCC=N,N′-Dicyclohexylcarbodiimide
- DCM=dichloromethane
- DIPEA=diisopropylethylamine
- DMF=N,N-dimethylformamide
- DMSO=dimethyl sulfoxide
- DPPA=diphenylphosphoryl azide
- EDCl=1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide
- HCl=hydrochloride
- EtOAc=ethyl acetate
- ESI-MS=Electrospray ionization mass spectrometry
- HAP=Hospital-Acquired Pneumonia
- HATU=2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
- HCl=hydrochloride
- HOBT=1-hydroxybenzotrizole
- hrs=hours
- HPLC=High performance liquid chromatography
- Hunig's base=N,N-Diisopropylethylamine
- mCPBA=meta-Chloroperoxybenzoic acid
- MIC=Minimum inhibitory concentration
- mL=milliliter
- MS=Mass spectrometry
- MRSA=Methicillin-resistant Staphylococcus aureus
- NCS=N-Chlorosuccinimide
- NMR=nuclear magnetic resonance
- Pa=Pseudomonas aeruginosa
- Pd2(dba)3=Tris(dibenzylideneacetone)dipalladium(0).
- PdCl2(dppf)=Pd[1,1-bis (diphenylphosphino) ferrocene]dichloropalladium(II)
- PFPOH=pentafluorophenol
- PMB=para-methoxybenzyl
- Prep=Preparative
- ppm=parts per million
- rt=room temperature
- THF=tetrahydrofuran
- TFA=trifluoroacetic acid
- TMS=tetramethylsilane
- TLC=thin layer chromatography
- VAP=Ventilator-Associated Pneumonia
- Xantphos=4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
-
FIG. 1 depicts the efficacy of the compound of formula (I) againstMRSA # 712 thigh infection compared with vancomycin in neutropenic mice. -
FIG. 2 depicts the efficacy of the compound of formula (I) against ceftazidime-susceptible pseudomonas aeruginosa #44 (ATCC#27853) lung infection compared with ceftazidime and primaxin in neutropenic mice. -
FIG. 3 depicts the efficacy of the compound of formula (I) against ceftazidime-susceptiblepseudomonas aeruginosa # 2245 lung infection compared with ceftazidime and primaxin in neutropenic mice. -
FIG. 4 depicts the efficacy of the compound of formula (I) against ceftazidime-resistantpseudomonas aeruginosa # 2545 lung infection compared with ceftazidime and primaxin in neutropenic mice. -
FIG. 5 depicts the synthesis of the compound of formula (I). -
FIG. 6 depicts the distribution of MICs of the compound of formula (I) against MRSA and Pa strains with comparators. - Provided herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, which is useful for treating bacterial infections. In particular, pharmaceutical compositions comprising the cephalosporin compound of formula (I) have a surprisingly broad spectrum of antibacterial activity and are useful to inhibit or kill various bacteria. For example, the antibacterial compound disclosed herein can be used in the manufacture of antibacterial medicaments and in methods for the treatment of bacterial infections, including treatment of both certain Gram-positive and Gram-negative bacterial infections. The cephalosporin compound of formula (I), or a pharmacologically acceptable salt thereof has the following structure:
- The compound of formula (I) has a MIC (measured by the method of Example 3) against Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) of less than or equal to about 1-2 micrograms/mL.
- Also included in formula (I) are zwitterionic forms containing an anionic carboxylic moiety and the cationic nitrogen in the pyridinium moiety. The imino group in the C-7 side chain position of the cephalosporin fused ring structure of formula (I) are shown in the “syn” (Z) configuration. The compound of formula (I) are preferably prepared as the syn-isomer (Z-isomer), or in mixtures comprising an amount of the syn-isomer (e.g., at least 90%) to provide a desired level of antibacterial activity, including compound of formula (I) that are syn isomers which are essentially free of the corresponding anti imino isomers.
- The antibacterial properties of this compound based on minimum inhibitory concentrations (MICs) against certain Staphylococcus and Pseudomonas strains is listed in micrograms/mL which can be compared to comparable MICs measured for the compounds of Table 1.
- The compound of formula (I) can be prepared from cephalosporin intermediate compound 4a as described in the Examples, or following literature procedures. For similar literature procedures, see, e.g., (a) Lattrell, R.; Blumbach, J.; Duerckheimer, W.; Fehlhaber, H. W.; Fleischmann, K.; Kirrstetter, R.; Mencke, B.; Scheunemann, K. H.; Schrinner, E.; et al. J. of Antibiotics 1988, 41, 1374. (b) Lattrell, R.; Blumbach, J.; Duerckheimer, W.; Fleischmann, K.; Kirrstetter, R.; Klesel, N.; Mencke, B.; Scheunemann, K. H.; Schwab, W.; et al. J. of Antibiotics 1988, 41, 1395. (c) Hanaki, H.; Yamazaki, H.; Harada, H.; Kubo, R.; Kobayashi, T.; Atsuda, K.; Sunakawa, K. J. of Antibiotics 2005, 58, 69-73; (d) Long, D. D.; Aggen, J. B.; Chinn, J.; Choi, S.-K.; Christensen, B. G.; Fatheree, P. R.; Green, D.; Hegde, S. S.; Judice, J. K.; Kaniga, K.; Krause, K. M.; Leadbetter, M.; Linsell, M. S.; Marquess, D. G.; Moran, E. J.; Nodwell, M. B.; Pace, J. L.; Trapp, S. G.; Turner, S. D. J. of Antibiotics 2008, 61, 603-614, all of which are incorporated by reference in their entireties.
- The antibiotic activity of the compound of formula (I) was measured against a variety of pathogenic microorganisms including Gram-positive and Gram-negative bacteria, including against Staphylococcus and Pseudomonas bacteria. Minimum inhibitory concentrations (MICs) for the compound of formula (I) against certain Staphylococcus, Pseudomonas and pneumoniae strains are listed in micrograms/mL in Table 2. The MICs were determined as described in Example 4. Accordingly, the compound of formula (I) can be included in pharmaceutical antibacterial compositions and are useful both in the manufacture of medicaments for treating bacteria or bacterial infections, and in methods of treating conditions caused by bacteria such as infections.
- Pharmaceutical antibacterial compositions can be formed by combining the compound of formula (I) or a pharmacologically acceptable salt thereof with a pharmacologically acceptable carrier suitable for delivery to a recipient subject (e.g., a human) in accordance with known methods of drug delivery. Antibacterial pharmaceutical compositions suitable for administration of one or more compound of formula (I) can be formulated. The compound of formula (I), and/or pharmacologically acceptable salts of formula (I) can be included in a pharmaceutical antibacterial composition along with one or more carriers.
- Pharmaceutical compositions can be formed by combining the compound of formula (I) or a pharmacologically acceptable salt thereof with a pharmacologically acceptable carrier suitable for delivery to a recipient subject (e.g., a human) in accordance with known methods of drug delivery. Antibacterial pharmaceutical compositions suitable for administration of one or more compound of formula (I) can be formulated. The compound of formula (I), and/or pharmacologically acceptable salts of formula (I) can be included in a pharmaceutical antibacterial composition along with one or more carriers. Pharmaceutical preparations can be prepared in accordance with standard procedures and are administered at dosages that are selected to treat infection (see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. and Goodman and Gilman's “The Pharmaceutical Basis of Therapeutics,” Pergamon Press, New York, N.Y., the contents of which are incorporated herein by reference, for a general description of the methods for administering various antimicrobial agents for human therapy).
- The compound of formula (I) can be formulated as a variety of salts to improve stability or toxicological properties of the compound, increase or decrease solubility, improve pharmacokinetic performance of the compound (e.g., Cmax or AUC measurements) or improve storage properties (e.g., to reduce hygroscopicity) of a pharmaceutical composition. As used herein, the term “pharmaceutically-acceptable salt” refers to pharmaceutical salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically-acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66:1-19. Pharmaceutically-acceptable salts of compound of formula (I) may be prepared by conventional means from the corresponding compound of the invention by treating, for example, the compound with the appropriate acid or base. Examples of publications describing the selection and formation of pharmacologically acceptable salts of medicinal compounds include Haynes, Delia A., et al., “Occurrence of Pharmacologically acceptable Anions and Cations in the Cambridge Structural Database,” Journal of Pharmaceutical Sciences, v. 94, no. 10, 2111-2120 (October 2005), and Stahl, P H, et al., Eds., “Handbook of Pharmaceutical Salts: Properties, Selection and Use,” Weinheim/Zurich, Wiley-VCH/VHCA.
- A pharmaceutical composition can include a pharmaceutically-acceptable carrier and the compound of formula (I) and/or salts of formula (I). As used herein, the phrase “pharmaceutically-acceptable carrier” refers generally to solvents, dispersion media, excipients, coatings, matrices, stabilizers, buffers, absorption enhancers, adjuvents, controlled release media, and the like, that are compatible with an intended use, such as pharmaceutical administration. The use of such carriers for pharmaceutically active substances is well known in the art. The pharmaceutical compositions can be formulated for parenteral delivery, including intravenous, intramuscular, intraperetoneal, subcutaneous, intraocular, intrathecal, intra-articular, intra-synovial, cisternal, intrahepatic, intralesional and intracranial injection, infusion, and/or inhaled routes of administration for the therapeutic treatment of medical conditions, such as bacterial infections.
- Pharmaceutical compositions for parenteral injection can comprise pharmaceutically-acceptable aqueous or nonaqueous solutions of antibacterial compound of formula (I) in addition to one or more of the following: pH buffered solutions, adjuvants (e.g. preservatives, wetting agents, emulsifying agents, and dispersing agents), liposomal formulations, nanoparticles, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. For intravenous (IV) use, the pharmaceutical composition can include any of the commonly used intravenous fluids and administered by infusion, such as physiological saline or Ringer's solution.
- The antibacterial compound of formula (I) disclosed herein, and pharmacologically acceptable salts thereof, including pharmaceutical compositions comprising these compounds, is useful in the manufacture of antibacterial pharmaceutical compositions, and treatment of bacteria. Significantly, the antibacterial compounds are useful in treating and eliminating a broad spectrum of bacterial pathogens, including both gram negative and gram positive bacterial infections. The antibacterial compound of formula (I) can be used in vivo, for example, to treat bacterial infections in a subject, as well as in vitro, for example to treat cells (e.g., bacteria) in culture to eliminate or reduce the level of bacterial contamination of a cell culture. In one embodiment, the compound of formula (I), or a pharmaceutical composition thereof, is administered to a cell culture, such as by administering in a nutrient medium. Methods of treating bacterial infections in subjects (e.g., humans and animals) can include the administration of a therapeutically effective amount of the compound of formula (I) or a pharmacologically acceptable salt thereof.
- Methods of treatment of such infections include administering to a subject in need thereof a therapeutically effective amount of the compound of formula (I). The compound can be parenterally administered to a subject having or suspected to have a bacterial infection, such as a gram negative infection.
- The antibacterial compound of formula (I) is preferably used in vivo to treat an infection in a subject by administering a therapeutically effective amount of the compound of formula (I) in a pharmaceutical composition. The method can comprise parenterally administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective dose of at least one compound of formula (I). Pharmaceutical compositions include compositions comprising compound(s) of formula (I) in a dose sufficient to achieve the intended purpose, i.e., the treatment or prevent of infectious diseases. The amount and concentration of antibacterial compound of formula (I) in the pharmaceutical composition, as well as the quantity of the pharmaceutical composition administered to a subject, can be selected based on clinically relevant factors, such as medically relevant characteristics of the subject (e.g., age, weight, gender, other medical conditions, and the like), the solubility of the antibacterial compound in the pharmaceutical composition, the potency and activity of the antibacterial compound, any toxicity associated with the pharmaceutical composition dose and method of administration, and the manner of administration of the pharmaceutical composition.
- A pharmaceutical composition comprising a therapeutically effective dose of the compound of formula (I) can be administered intravenously to a patient for treatment of gram negative infections in a clinically safe and effective manner, including one or more separate administrations of the composition. The total daily dose of the compound of formula (I) can be about 2.0 mg/kg/day to about 50 mg/kg/day of all compound of formula (I) administered intravenously to a subject one to three times a day (e.g., QD, BID or TID). The amount per administered dose or the total amount administered will depend on such factors as the nature and severity of the infection, the age and general health of the patient, the tolerance of the patient to the compound and the microorganism or microorganisms involved in the infection. The total amount of the pharmaceutical composition administered can be selected to be therapeutically effective.
- In particular, the pharmaceutical compositions comprising the compound of formula (I) can be used to treat a subject having a bacterial infection in which the infection is caused or exacerbated by a gram-negative bacteria. A method of treating a bacterial infection in a host can include administering to an infected host a pharmaceutical composition comprising a therapeutically effective dose (e.g., an antibacterially effective amount) of the compound of formula (I), or a pharmacologically acceptable salt thereof.
- The pharmaceutical composition and/or compound(s) of formula (I) can be administered to treat a bacterial infection or population in vitro (e.g., a bacterial colony on a surface outside the body) or in vivo (e.g., within an infected host). The bacterial infection or population can include Gram-negative and/or Gram-positive bacteria. For example, the Gram-negative bacteria can comprise Pseudomonas aeruginosa and the Gram-positive bacteria can include Staphylococcus aureus. The bacteria can form an infection present in vitro (e.g., a bacterial colony or sample), or in vivo (e.g., an infected host subject). For instance, the bacterial infection can be identified as a methicillin-resistant Staphylococcal infection. Preferably, the antibacterially effective dose and therapeutically effective amount of the compound(s) of Formula (I) can be effective in killing both a Pseudomonas aeruginosa bacteria and a MRSA bacteria with a MIC that is less than the comparable value for a compound in Table 1, and/or independent MIC values measured according to Example 3 that is not more than about 4 micrograms/mL (e.g., including values of about 3.5, 3.0, 2.5, 2.0, 1.5, 1.0, 0.5 micrograms/mL or lower) independently measured against each of Pseudomonas aeruginosa bacteria and methicillin-resistant Staphylococcal bacteria.
- A pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I) can be administered to a patient presenting symptoms of an infection. The compounds of this invention can be used to treat infections of cSSSI and HAP/VAP in adults or children. In particular methicillin resistant Staphylococcus aureus infections and/or Pseudomonas infections may be treated with the compound of formula (I). Other representative types of infections or bacteria-related medical conditions which can be treated or prevented with pharmaceutical compositions comprising antibacterial compound of formula (I) include, but are not limited to, skin and skin structure infections, urinary tract infections, pneumonia, endocarditis, catheter-related blood stream infections, osteomyelitis, and the like. In treating such conditions, the patient may treated with the pharmaceutical compositions comprising the compound of formula (I) upon presenting symptoms consistent with a bacterial infection. The pharmaceutical compositions may be administered prior to or after identifying the types of bacteria present in the patient.
- The specific examples which follow illustrate the synthesis of certain compounds used in the preparation of the compound of formula (I). Further, the disclosure includes variations of the methods described herein to produce the compound of formula (I) that would be understood by one skilled in the art based on the instant disclosure.
- All temperatures are understood to be in Centigrade (C) when not specified. The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (γ) expressed in parts per million (ppm) versus tetramethylsilane (TMS) as reference standard. The relative area reported for the various shifts in the proton NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the shifts as to multiplicity is reported as broad singlet (br s), broad doublet (br d), singlet (s), multiplet (m), doublet (d), quartet (q), doublet of doublet (dd), doublet of triplet (dt), and doublet of quartet (dq). The solvents employed for taking NMR spectra are DMSO-d6 (perdeuterodimethysulfoxide), D2O (deuterated water), CDCl3 (deuterochloroform) and other conventional deuterated solvents. The prep-HPLC conditions are: Waters SunFire® C18 (30×100 mm, 5 μm) column; flow rate: 50 mL/min, UV or Mass-triggered fraction collection; sample loading: each injection loading varied from 30-80 mg depending for different crude samples depending on their solubility and purity profiles; solvent system: solvent A: water with 0.5% formic acid, solvent B: acetonitrile with 0.5% formic acid.
-
-
- To a suspension of PCl5 (3.21 g) in dry DCM (50 mL) at 0° C. was added anhydrous pyridine (1.24 mL) and the resulting white suspension was stirred for 0.5 h. 7-Phenylacetamido-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxy benzyl ester (5.0 g) was added. After stirring at 0° C. for additional 2 h, the reaction mixture was cooled to −40° C. and methanol (15 mL) was added dropwise. The stirring was continued at −30° C. for additional 0.5 h, and the reaction mixture was then concentrated. To the residue were added water (5 mL), EtOAc (20 mL) and diethyl ether (200 mL), and the mixture was stirred at 0° C. until precipitation formed. The yellow precipitate was collected by filtration, rinsed with diethyl ether and then 20% DCM in diethyl ether, and dried under high vacuum. The resulting light yellow solid was used directly in
step 3. ESI-MS (EI+, m/z): 369.05. -
- To a solution of (Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetic acid (15.0 g) in anhydrous DMF (150 mL) was added NCS (11.95 g) and the mixture was stirred at rt for 2-3 hrs. The reaction mixture was concentrated to remove most of the DMF. The resulting oil was added dropwise to DCM (˜600 mL) at 0° C. with stirring. Solid precipitation was collected by filtration, rinsed with DCM and dried under high vacuum to provide a brownish solid (11.8 g, 67%). ESI-MS (EL, m/z): 236.0. 1H NMR (300 MHz, DMSO-d6) δ 7.60 (br s, 2H), 3.88 (s, 3H).
-
- To a solution of (6R,7R)-4-methoxybenzyl 7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (6.8 g) in dry DMF (60 mL) was added (Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(methoxyimino)acetic acid (4.17 g). The mixture was cooled to 0° C., then 2,4,6-collidine (2.3 g) and EDCI (3.4 g) were added sequentially. After 2 hrs, the solution was poured into cold water and filtered. The solid was rinsed with water, dried under high vacuum and purified by silica gel chromatography (DCM:EtOAc=3:1) to afford 4a (5.0 g, 57%). ESI-MS (EL, m/z): 586.04; 1H NMR (400 MHz, D2O) δ 9.60 (d, J=8.8 Hz, 1H), 7.39 (br s, 2H), 7.36 (d, J=8.4 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 5.83 (dd, J=8.8, 5.2 Hz, 1H), 5.24 (d, J=12.0 Hz, 1H), 5.19 (d, J=5.2 Hz, 1H), 5.18 (d, J=12.0 Hz, 1H), 4.54 (d, J=11.4 Hz, 1H), 4.46 (d, J=11.4 Hz, 1H), 3.86 (s, 3H), 3.76 (s, 3H), 3.70 (d, J=18.0 Hz, 1H), 3.54 (d, J=18.0 Hz, 1H).
-
- A mixture of 4-bromo-pyridine hydrochloride salt (8.0 g), tert-butyl hydrazinecarboxylate (10.87 g), CuI (784 mg), L-4-hydroxyproline (1.08 g) and Cs2CO3 (33.50 g) in dry DMSO (41 mL) under N2 was heated at 80° C. with efficient stirring for 5-6 hrs. After cooled to rt, the reaction mixture was diluted with EtOAc (150 mL) and saturated NH4Cl (150 mL). The organic layer was separated and the aqueous was extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography (DCM to 10% MeOH/DCM gradient) to provide the title compound (3.4 g, 40%). ESI-MS (EL, m/z): 210.0 [M+H]+. 1H NMR (300 MHz, DMSO) δ 8.38 (d, J=4.9 Hz, 2H), 7.64 (d, J=6.4 Hz, 2H), 5.12 (s, 2H), 3.34 (s, 1H), 1.51 (s, 9H).
- As shown in Table 1, the antibacterial activity of the comparator compounds was demonstrated by the minimum inhibitory concentrations (MIC) of the compounds against various bacteria measured by using the broth microdilution method performed according to Clinical and Laboratory Standards Institute (CLSI) guidelines with modifications as described below (CLSI guidelines can be derived from the CLSI document M7-A8 published in January 2009: “Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Eighth Edition”).
- To prepare for MIC testing, individual colonies were isolated by streaking frozen glycerol material containing Staphylococcus or Pseudomonas spp. onto rich, non-selective, tryptic soy agar containing 5% sheep's blood (TSAB), and incubated at 37° C. for 18-24 hrs.
- On the day of testing, primary cultures were started by scraping off 5-10 colonies from the TSAB plates. The material was suspended in ˜5 mL of cation adjusted Mueller Hinton Broth (CAMHB) in 14 mL culture tubes and incubated at 37° C. with aeration (200 rpm) for ˜2 hrs until the OD600 was ≧0.1.
- Inoculum cultures were prepared by standardizing the primary cultures to OD600=0.1 and then adding 20 μL of the adjusted primary culture per 1 mL CAMHB for Pseudomonas and CAMHB plus 4% NaCl for MRSA so that the final inoculum density was ˜105 colony forming units per milliliter. Diluted inoculum cultures were used to inoculate 50 μL per well in 96 well broth microdilution assay plates. 50 μL of CAMHB that contained compound concentrations ranging from 64-0.06 μg/mL in two-fold dilutions was also added to the broth microdilution assay plates for a
final volume 100 μL per well, therefore final culture OD600 was approximately 0.001 and the final NaCl concentration for the MRSA strain was 2%. - Plates were incubated for 18-20 hours at 37° C. with aeration (200 rpm). Following incubation, growth was confirmed visually placing plates over a viewing apparatus (stand with a mirror underneath) and then OD600 was measured using a SpectraMax 340PC384 plate reader (Molecular Devices, Sunnyvale, Calif.). Growth was defined as turbidity that could be detected with the naked eye or achieving minimum OD600 of 0.1. MIC values were defined as the lowest concentration producing no visible turbidity.
- As shown in Table 2, the efficacy of the compound of formula (I) was evaluated in mouse septicemia, thigh and lung infection models against multiple strains of MRSA, ceftazidime-susceptible and -resistant Pseudomonas aeruginosa and ceftazidime-resistant Klebsiella pneumoniae and compared with standard antibiotic treatment.
- I. Summary
-
- The compound of formula (I) is a novel broad spectrum cephalosporin with potent in vitro activities against G(+) and G(−) bacteria including MRSA and Pseudomonas aeruginosa (Pa). In vivo efficacy of (I) was evaluated against strains of MRSA, and ceftazidime-resistant Pa and Klebsiella pneumonia (Kpn) in mouse septicemia, thigh and lung infections. Septicemia: CD-1 mice received lethal bacterial inocula IP, followed by 2 doses of antibiotics SC at 1 and 6 hrs post-inoculation. Dose calculated to protect 50% of the mice (PD50) was derived based on probit analysis of percentage survival. Thigh and lung infections: Thighs or lungs of neutropenic mice were inoculated with MRSA or Pa. Two treatment doses were given SC at 1 and 6 hrs post-inoculation. Tissues were harvested at ˜24 hrs post-inoculation and bacterial burdens quantified. Efficacious dose resulting in a 2-log bacterial CFU reduction (ED−2log) compared with vehicle-treated mice was calculated. (I) demonstrated potent in vivo activity against several drug-resistant strains. Its in vivo potency against a clinical isolate of MRSA was comparable to vancomycin and ceftaroline. (I) also had good activities against ceftazidime-resistant Pa and Kpn. (I) exhibits excellent in vivo efficacy against infections caused by MRSA, and ceftazidime-resistant Pa and Kpn in mice.
- II. Methods
-
- A. Animals: Six week-old, specific pathogen free, female CD-1 mice purchased from Charles River Laboratories (Wilmington, Mass.) were used for all studies after acclimation in Cubist animal facility. All animal procedures were approved by the Cubist Institutional Animal Care and Use Committee.
- B. Bacteria and In Vitro Susceptibility Testing:
MRSA # 712,Pseudomonas aeruginosa # 2245 and #2545, and Klebsiella pneumoniae #573 are clinical isolates;Pseudomonas aeruginosa # 44 is an ATCC strain (ATCC#27853). MIC was determined in MHB by standard CLSI microdilution. MICs of individual strains are shown in Table 2 andFIGS. 1-4 . - C. Comparator Antibiotics Used in Animal Studies: Vancomycin hydrochloride USP was purchased from Hospira (Lake Forest, Ill.); ceftazidime hydrate from Sigma; Primaxin (imipenem and cilastatin) from Merck; ceftaroline was synthesized at a CRO.
- D. Mouse Septicemia: Mice received lethal inocula of bacteria in 6% hog gastric mucin intraperitoneally (IP), followed by two treatment doses of antibiotics via subcutaneous (SC) administration at 1 and 6 hrs post-inoculation. The survival of animals was recorded daily for 7 days. The antibiotic dose calculated to protect 50% of the mice (PD50) was derived based on probit analysis of percentage survival.
- E. Mouse Thigh and Lung Infections: Mice were rendered neutropenic by two IP injections of
cyclophosphamide 4 days (150 mg/kg) and 1 day (100 mg/kg) before bacterial inoculation. Thigh or lung infection was induced by an intramuscular injection of 0.2 mL or intranasal inoculation of 0.1 mL inoculum preparation from an overnight bacterial culture into left thigh or nares. Tissues from one group of mice receiving no treatment (No Rx) were harvested at 1 hr for determination of baseline of bacterial burden. The remaining mice received two treatment doses of vehicles or antibiotics given SC at 1 and 6 hrs post-inoculation. Tissues from the treated mice were harvested at ˜24 hrs post-inoculation. Tissue bacterial burdens were quantified by serial dilution and spiral plating of homogenates. Doses of (I) were confirmed analytically. The efficacious dose resulting in a 2-log or a 3-log bacterial CFU reduction (ED—log or ED−3log) as compared with vehicle-treated mice at 24 h was derived by linear regression analysis.
- III. Results
-
- A. (I) displayed potent efficacy in all systemic infection models. Its PD50 value of 2.0±0.3 mg/kg against
MRSA # 712 septicemia was comparable to vancomycin and ceftaroline. (I) was significantly more potent in vivo than ceftazidime against the CLSI reference strain of Pseudomonas aeruginosa #44 (PD50: 5.3±0.7 vs. 33.9±7.4 mg/kg, respectively. (I) demonstrated good in vivo potency against ceftazidime-resistantPseudomonas aeruginosa # 2545 and Klebsiella pneumoniae #573 systemic infections (Table 1). - B. (I) led to a dose-dependent reduction of
MRSA # 712 burden in the thigh vs. vehicle controls with an ED−2log of 68.9 mg/kg (FIG. 1 ). In contrast, vancomycin at 110 mg/kg SC resulted in a smaller reduction in bacterial CFU (˜1.5 log). The vancomycin dose was chosen based on PK studies showing that the plasma exposure at this dose level in mice (data on file) was approximately equivalent to that in humans. - C. (I) showed marked efficacy against ceftazidime-susceptible
Pseudomonas aeruginosa # 44 and #2245 lung infections with ED−3log values of 4.1 and 5.2 mg/kg, respectively. Ceftazidime had higher ED−3log values of 50.4 and 27.2 mg/kg, respectively (FIGS. 2 and 3 ). Bacterial burden in the lung at the highest doses of (I) in these two studies approached the lower limit of detection of the assay. - D. (I) was efficacious against a ceftazidime-resistant
Pseudomonas aeruginosa # 2545 lung infection (FIG. 4 ). Its ED−3log value was 11.4 mg/kg. In contrast, ceftazidime up to144.5 mg/kg had minimal impact on the bacterial burden in the lung.
- A. (I) displayed potent efficacy in all systemic infection models. Its PD50 value of 2.0±0.3 mg/kg against
- IV. Conclusions
-
- A. (I) exhibited excellent efficacy against systemic and tissue infections caused by MRSA and ceftazidime-resistant Pseudomonas aeruginosa and Klebsiella pneumoniae in mice.
- B. In vivo efficacy of (I) against a clinical isolate of MRSA was comparable to both vancomycin and ceftaroline in the thigh infection model in neutropenic mice.
- C. (I) appeared more efficacious than ceftazidime in lung infections caused by ceftazidime-susceptible Pseudomonas strains in neutropenic mice.
- D. (I) maintained potent activity vs. a mouse lung infection induced by a ceftazidime-resistant Pseudomonas isolate.
- I. Summary
-
- The 3rd and 4th generation cephalosporins bearing pyridinium or quaternary ammonium groups at the C-3′ position, such as ceftazidime (CAZ) and cefepime, have potent activity against Gram-negative bacteria including Pseudomonas aeruginosa (Pa). However, their activity against Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) is weak, limiting their clinical usefulness for empiric treatment. Thus, a broad spectrum cephalosporin with improved activity against both Pa and MRSA would be of particular interest. The compound of formula (I) demonstrated potent in vitro activity and broad spectrum coverage against both Gram-positive and Gram-negative bacteria, including MRSA and Pa. The MIC90 of the compound of formula (I) is equivalent to that of CAZ against Pa, and comparable to those of ceftaroline and vancomycin against MRSA. The compound of formula (I) has potent antibacterial activity against serious bacterial pathogens such as Pa and MRSA.
- II. Biological Activity Assay
-
- A. The antibacterial activity of the compounds in Table 3 were demonstrated by the minimum inhibitory concentrations (MIC) using the broth microdilution method performed according to Clinical and Laboratory Standards Institute (CLSI) guidelines with minor modifications.
- B. MIC values were defined as the lowest concentration producing no visible turbidity. MIC90 values were defined as the concentration required to inhibit growth of 90% of the strains tested.
- C. SAR was performed using the following isolates: Sa399 (ATCC43300, MRSA), Sa1721 (NARSA NRS384, MRSA USA 300), Pa44 (ATCC27853), and 4 clinical isolates (Pa2241, Pa2086 (mucoid strain), Pa2694 and Pa2698).
- D. The in vitro antibacterial activity of the compound of formula (I) was further evaluated in an expanded MRSA and Pa MIC panel (see Table 4 and
FIG. 6 ).
- III. Efficacy Study
-
- A. A mouse systemic infection model was used to determine in vivo efficacy. An overnight culture of S. aureus 712 (MRSA, clinical isolate) or Pa44 (ATCC 27853) suspended in 6% hog gastric mucin to prepare the inoculum. Mice were challenged via intraperitoneal (IP) inoculation of the bacteria with a lethal dose of 2×107 CFU/mouse.
- B. Mice were given subcutaneous (SC) doses of test compound or saline at 1 and 6 hours after bacterial inoculation. The dose that protected 50% of the mice (PD50) was calculated by probit analysis based on percentage of mice surviving for 7 days post-inoculation.
- C. Compounds were formulated in a dosing solution of saline or D5W.
- As shown in
FIG. 5 , cephalosporin core intermediate 6 was synthesized by amide coupling of 7-aminocephalosporin derivative 3 andchloroaminothiazole derivative 5.Urea tail 12 was prepared by CDI mediated urea formation ofaniline derivative 8 andaminopyridine derivative 11. Coupling of intermediate 6 andurea tail 12, followed by global deprotection using TFA/anisol provided the final product (I), which was purified by reverse phase HPLC using 0.1% formic acid buffer in water/acetonitrile. - The examples and illustrative embodiments described herein are provided by way of illustration, and do not constitute additional limitations on the scope of the claims. While some embodiments have been shown and described in the instant specification, the specification as ready by one of ordinary skill in the relevant arts also discloses various modifications and substitutions of embodiments explicitly disclosed herein. The exemplary embodiments from the specification are not provided to read additional limitations into the claims.
-
TABLE 2 PD50 and ED-2log of (I) in Mouse Systemic, Thigh and Lung Infections Septicemia PD50 Thigh (T) and Bacterial (I) or (±SE, Lung (L) MIC Strain Comparator mg/kg) ED2log (mg/kg) (μg/ml) MRSA #712 (I) 2.0 ± 0.3 68.9 (T) 2 Ceftaroline 1.0 ± 0.1 ND 1 Vancomycin 2.0 ± 1.3 >110 (T) 1 Pa #44 (I) 5.3 ± 0.7 1.8 (L) 1 (ATCC27853) Ceftazidime 33.9 ± 7.4 25.6 (L) 1 Primaxin <2 <8 (L) 1 Pa #2545 (I) <10.4 6.7 (L) 2 Ceftazidime >140.5 >144.5 (L) 32-64 Primaxin >4 <8 (L) ND Kpn #573 (I) <1.3 ND 1 Ceftazidime 50.3 ± 8.4 ND 256 Primaxin 1.0 ± 0.6 ND 0.12 -
TABLE 3 In vitro activities of the compound of formula (I) and comparators Com- MIC (μg/ml) pound MRSA Pseudomonas (I) Sa399 Sa1721 Pa44 Pa2241 Pa2086 Pa2694 Pa2698 Ceftaro- 0.5 2 8 16 16 >64 >64 line Ceftazi- 64 >64 2 2 2 8 8 dime (I) 2 8 2 1 8 8 8 -
TABLE 4 MIC90 of the compound of formula (I) against MRSA and Pa with comparators MIC90 (μg/mL) MRSA Pseudomonas aeruginosa Compound (n = 21) (n = 100) Ceftazidime — 8 Meropenem — 4 Ceftaroline 1 — Vancomycin 1 — (I) 2 8
Claims (14)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/333,966 US20150025053A1 (en) | 2012-09-07 | 2014-07-17 | Cephalosporin compound |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261698241P | 2012-09-07 | 2012-09-07 | |
US14/020,230 US8809314B1 (en) | 2012-09-07 | 2013-09-06 | Cephalosporin compound |
US14/333,966 US20150025053A1 (en) | 2012-09-07 | 2014-07-17 | Cephalosporin compound |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/020,230 Continuation US8809314B1 (en) | 2012-09-07 | 2013-09-06 | Cephalosporin compound |
Publications (1)
Publication Number | Publication Date |
---|---|
US20150025053A1 true US20150025053A1 (en) | 2015-01-22 |
Family
ID=51301639
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/020,230 Active US8809314B1 (en) | 2012-09-07 | 2013-09-06 | Cephalosporin compound |
US14/333,966 Abandoned US20150025053A1 (en) | 2012-09-07 | 2014-07-17 | Cephalosporin compound |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/020,230 Active US8809314B1 (en) | 2012-09-07 | 2013-09-06 | Cephalosporin compound |
Country Status (1)
Country | Link |
---|---|
US (2) | US8809314B1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10376496B2 (en) | 2013-09-09 | 2019-08-13 | Merck, Sharp & Dohme Corp. | Treating infections with ceftolozane/tazobactam in subjects having impaired renal function |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2463181B (en) | 2007-05-14 | 2013-03-27 | Univ New York State Res Found | Induction of a physiological dispersion response in bacterial cells in a biofilm |
US8809314B1 (en) * | 2012-09-07 | 2014-08-19 | Cubist Pharmacueticals, Inc. | Cephalosporin compound |
US9872906B2 (en) | 2013-03-15 | 2018-01-23 | Merck Sharp & Dohme Corp. | Ceftolozane antibiotic compositions |
US20140274991A1 (en) | 2013-03-15 | 2014-09-18 | Cubist Pharmaceuticals, Inc. | Ceftolozane pharmaceutical compositions |
US20160176897A1 (en) * | 2014-12-23 | 2016-06-23 | Merck Sharp & Dohme Corp. | 7-aminocephem derivative compounds |
BR112018009725A8 (en) | 2015-12-10 | 2019-02-26 | Naeja Rgm Pharmaceuticals Ulc | cefém compounds, their production and use |
US11541105B2 (en) | 2018-06-01 | 2023-01-03 | The Research Foundation For The State University Of New York | Compositions and methods for disrupting biofilm formation and maintenance |
CN110407744A (en) * | 2019-08-13 | 2019-11-05 | 上海毕得医药科技有限公司 | A kind of synthetic method of 1- (4-aminopyridine -2- base) ethyl ketone |
EP4129276A4 (en) | 2020-03-31 | 2023-10-18 | Mitsubishi Tanabe Pharma Corporation | Pharmaceutical composition |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8809314B1 (en) * | 2012-09-07 | 2014-08-19 | Cubist Pharmacueticals, Inc. | Cephalosporin compound |
Family Cites Families (179)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL37879A (en) | 1970-10-27 | 1974-12-31 | Ciba Geigy Ag | 3-unsubstituted cephalosporin derivatives,process for their manufacture and compositions containing them |
US4299829A (en) | 1976-03-12 | 1981-11-10 | Fujisawa Pharmaceutical Co., Ltd. | 2-Lower alkyl-7-substituted-2 or 3-cephem 4-carboxylic acid compounds |
PH17188A (en) | 1977-03-14 | 1984-06-14 | Fujisawa Pharmaceutical Co | New cephem and cepham compounds and their pharmaceutical compositions and method of use |
US4496562A (en) | 1977-03-14 | 1985-01-29 | Fujisawa Pharmaceutical Co., Ltd. | 7-Substituted-3-cephem-4-carboxylic acid esters |
US4464369A (en) | 1977-03-14 | 1984-08-07 | Fujisawa Pharmaceutical Co., Ltd. | 7-Acylamino-3-cephem-4-carboxylic acid derivatives and pharmaceutical compositions |
US4409217A (en) | 1977-03-14 | 1983-10-11 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
JPS543087A (en) | 1977-06-03 | 1979-01-11 | Fujisawa Pharmaceut Co Ltd | Preparation of cephalosporin compound |
GB1604738A (en) | 1977-07-28 | 1981-12-16 | Yamanouchi Pharma Co Ltd | 1,3-dithietane-2-carboxylic acid derivatives and the preparation thereof |
JPS609719B2 (en) | 1977-08-06 | 1985-03-12 | 武田薬品工業株式会社 | Cephalosporin derivatives and their production method |
US4370326A (en) | 1977-09-13 | 1983-01-25 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds and composition |
IT1192287B (en) | 1977-11-14 | 1988-03-31 | Fujisawa Pharmaceutical Co | PHARMACEUTICAL ACTION DERIVATIVES OF CEPHALOSPORANIC ACID AND RELATED PREPARATION PROCEDURE |
US4363807A (en) | 1978-04-06 | 1982-12-14 | Fujisawa Pharmaceutical Company, Limited | Cepham compounds |
SE7804231L (en) | 1978-04-14 | 1979-10-15 | Haessle Ab | Gastric acid secretion |
AR228726A1 (en) | 1978-05-26 | 1983-04-15 | Glaxo Group Ltd | PROCEDURE FOR THE PREPARATION OF ANTIBIOTIC (6R, 7R) -7 - ((Z) -2- (2-AMINOTIAZOL-4-IL) -2- (2-CARBOXIPROP-2-OXIIMINO) ACETAMIDO) -3- (1- PIRIDINIOMETIL) CEF-3-EM-4-CARBOXILATO |
US4264597A (en) | 1978-06-06 | 1981-04-28 | Masashi Hashimoto | Cephalosporin analogues and processes for the preparation thereof |
US4268509A (en) | 1978-07-10 | 1981-05-19 | Fujisawa Pharmaceutical Co., Ltd. | New cephem compounds and processes for preparation thereof |
US4284631A (en) | 1978-07-31 | 1981-08-18 | Fujisawa Pharmaceutical Co., Ltd. | 7-Substituted cephem compounds and pharmaceutical antibacterial compositions containing them |
US4305937A (en) | 1978-08-17 | 1981-12-15 | Fujisawa Pharmaceutical Co., Ltd. | 2-Lower alkyl-7-substituted-2 or 3-cephem-4-carboxylic acid compounds and antibacterial pharmaceutical compositions containing them |
US4703046A (en) | 1978-09-08 | 1987-10-27 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds and processes for preparation thereof |
EP0009671B1 (en) | 1978-09-12 | 1984-06-13 | Fujisawa Pharmaceutical Co., Ltd. | Starting compounds for preparing cephem compounds and processes for their preparation |
US4327093A (en) | 1978-10-24 | 1982-04-27 | Fujisawa Pharmaceutical Co., Ltd. | 3,7-Disubstituted-2 or 3-cephem-4-carboxylic acid compounds |
DE2945248A1 (en) | 1978-11-13 | 1980-05-22 | Fujisawa Pharmaceutical Co | CEPHEM COMPOUNDS, METHOD FOR THEIR PRODUCTION AND ANTIBACTERIAL PHARMACEUTICAL AGENTS CONTAINING THE SAME |
US4390534A (en) | 1978-12-29 | 1983-06-28 | Fujisawa Pharmaceutical Co., Ltd. | Cephem and cepham compounds |
US4332798A (en) | 1978-12-29 | 1982-06-01 | Fujisawa Pharmaceutical Co., Ltd. | 7-Amino-thia-diazole oxyimino derivatives of cephem and cephem compounds |
AU536842B2 (en) | 1978-12-29 | 1984-05-24 | Fujisawa Pharmaceutical Co., Ltd. | Cephalosporin antibiotics |
US4291031A (en) | 1979-02-19 | 1981-09-22 | Fujisawa Pharmaceutical Co., Ltd. | 3-Phosphonocephalosporanic acid derivatives, and pharmaceutical composition comprising the same |
US4339449A (en) | 1979-03-27 | 1982-07-13 | Fujisawa Pharmaceutical Company, Limited | Analogous compounds of cephalosporins, and pharmaceutical composition comprising the same |
FR2462439A1 (en) | 1979-07-26 | 1981-02-13 | Roussel Uclaf | NOVEL PROCESS FOR THE PREPARATION OF PRODUCTS DERIVED FROM 7 - / (2-ARYL) 2-HYDROXYIMINO ACETAMIDO / CEPHALOSPORANIC ACID |
DE3069560D1 (en) | 1979-09-03 | 1984-12-06 | Fujisawa Pharmaceutical Co | Cephem compounds, processes for their preparation and pharmaceutical compositions containing them |
US4338313A (en) | 1979-10-12 | 1982-07-06 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
US4332800A (en) | 1979-10-12 | 1982-06-01 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
US4381299A (en) | 1980-03-07 | 1983-04-26 | Fujisawa Pharmaceutical Co., Ltd. | 7-Amino-thiadiazole oxyimino derivatives of cephem and cepham compounds |
US4409214A (en) | 1979-11-19 | 1983-10-11 | Fujisawa Pharmaceutical, Co., Ltd. | 7-Acylamino-3-vinylcephalosporanic acid derivatives and processes for the preparation thereof |
US4409215A (en) | 1979-11-19 | 1983-10-11 | Fujisawa Pharmaceutical Co., Ltd. | 7-Acylamino-3-substituted cephalosporanic acid derivatives and processes for the preparation thereof |
US4420477A (en) | 1979-11-30 | 1983-12-13 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
US4443443A (en) | 1979-12-17 | 1984-04-17 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
US4405617A (en) | 1980-02-11 | 1983-09-20 | Fujisawa Pharmaceutical Co., Ltd. | 3-(Propynyltetrazol)thiomethyl-3-cephems |
JPS56125392A (en) | 1980-03-06 | 1981-10-01 | Fujisawa Pharmaceut Co Ltd | Cepham and cephem compound and preparation thereof |
US4470980A (en) | 1980-03-07 | 1984-09-11 | Interx Research Corp. | Method of increasing oral absorption of β-lactam antibiotics |
DE3173613D1 (en) | 1980-07-04 | 1986-03-13 | Fujisawa Pharmaceutical Co | 7-oxo-cephalosporins and 6-oxo-penicillins, their analogues and process for their preparation |
US4443444A (en) | 1980-08-11 | 1984-04-17 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
DE3175156D1 (en) | 1980-08-29 | 1986-09-25 | Fujisawa Pharmaceutical Co | New cephem compounds and processes for preparation thereof |
US4416879A (en) | 1980-09-08 | 1983-11-22 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
GR78245B (en) | 1980-09-12 | 1984-09-26 | Ciba Geigy Ag | |
US4367228A (en) | 1980-10-29 | 1983-01-04 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compound and composition |
US4431642A (en) | 1980-12-01 | 1984-02-14 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
ES507942A0 (en) | 1980-12-15 | 1983-02-01 | Fujisawa Pharmaceutical Co | A PROCEDURE FOR PREPARING DERIVATIVES OF 7-ACYLAMINOCEFHALOSPORANIC ACID. |
EP0055465B1 (en) | 1980-12-31 | 1989-08-23 | Fujisawa Pharmaceutical Co., Ltd. | 7-acylaminocephalosporanic acid derivatives and processes for the preparation thereof |
US4427677A (en) | 1980-12-31 | 1984-01-24 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
GR76342B (en) | 1981-02-02 | 1984-08-06 | Fujisawa Pharmaceutical Co | |
US4336253A (en) | 1981-03-11 | 1982-06-22 | Eli Lilly And Company | Cephalosporin antibiotics |
JPS6011917B2 (en) | 1981-04-09 | 1985-03-28 | 山之内製薬株式会社 | Novel cephalosporin compounds |
DE3118732A1 (en) | 1981-05-12 | 1982-12-02 | Hoechst Ag, 6000 Frankfurt | CEPHALOSPORINE DERIVATIVES AND METHOD FOR THEIR PRODUCTION |
JPS57193489A (en) | 1981-05-21 | 1982-11-27 | Fujisawa Pharmaceut Co Ltd | Syn-isomer of 7-substituted-3-cephem-4-carboxylic acid ester and its preparation |
GR75487B (en) | 1981-06-22 | 1984-07-23 | Fujisawa Pharmaceutical Co | |
IE53429B1 (en) | 1981-08-03 | 1988-11-09 | Fujisawa Pharmaceutical Co | New cephem compounds and processes for preparation thereof |
US4430499A (en) | 1981-09-08 | 1984-02-07 | Eli Lilly And Company | 7-[2-(2-Aminooxazol-4-yl)-2-(oximino)acetamido]cephalosporin antibiotics |
US4577014A (en) | 1981-09-08 | 1986-03-18 | Eli Lilly And Company | Thieno and furopyridinium-substituted cephalosporins |
US4436912A (en) | 1981-09-08 | 1984-03-13 | Eli Lilly And Company | 7-[2-(2-Aminooxazol-4-yl)-2-(oximino)acetamido cephalosporin antibiotics and intermediates therefor |
JPS5859991A (en) | 1981-09-14 | 1983-04-09 | Fujisawa Pharmaceut Co Ltd | Novel cephem compound and its preparation |
US4521413A (en) | 1981-09-14 | 1985-06-04 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
US4450270A (en) | 1981-10-02 | 1984-05-22 | Eli Lilly And Company | Dioximino cephalosporin antibiotics |
US4402955A (en) | 1981-10-02 | 1983-09-06 | Eli Lilly And Company | Dioximino cephalosporin antibiotics |
US4501739A (en) | 1982-01-19 | 1985-02-26 | Eli Lilly And Company | Thieno and furopyridinium-substituted cephalosporins |
DE3207840A1 (en) | 1982-03-04 | 1983-09-15 | Hoechst Ag, 6230 Frankfurt | "CEPHALOSPORINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF" |
US4640915A (en) | 1982-03-29 | 1987-02-03 | Fujisawa Pharmaceutical Co., Ltd. | 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid derivatives |
US4563449A (en) | 1982-07-19 | 1986-01-07 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
US4546101A (en) | 1982-09-10 | 1985-10-08 | Fujisawa Pharmaceutical Co., Ltd. | New cephem compounds useful for treating infectious diseases in human being and animals and processes for preparation thereof |
GB8323034D0 (en) | 1983-08-26 | 1983-09-28 | Fujisawo Pharmaceutical Co Ltd | 7-substituted-3-vinyl-3-cephem compounds |
US4609730A (en) | 1982-11-22 | 1986-09-02 | Fujisawa Pharmaceutical Co., Ltd. | 7-[substituted imino-2-(2-aminothiazol-4-yl)-acetamido]-3(2,2-dihalovinyl or ethynyl)-3-cephem-4-carboxylic acid (syn isomers), having antimicrobial activities |
GR79043B (en) | 1982-12-06 | 1984-10-02 | Fujisawa Pharmaceutical Co | |
US4608373A (en) | 1982-12-13 | 1986-08-26 | Yamanouchi Pharmaceutical Co., Ltd. | Cephem compounds |
US4487768A (en) | 1982-12-22 | 1984-12-11 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
US4463003A (en) | 1982-12-22 | 1984-07-31 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
DE3247613A1 (en) | 1982-12-23 | 1984-07-05 | Hoechst Ag, 6230 Frankfurt | CEPHALOSPORINE DERIVATIVES AND METHOD FOR THEIR PRODUCTION |
US4499088A (en) | 1983-01-04 | 1985-02-12 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
DE3316798A1 (en) | 1983-05-07 | 1984-11-08 | Hoechst Ag, 6230 Frankfurt | METHOD FOR PRODUCING CEPHEM COMPOUNDS |
FR2550200B1 (en) | 1983-08-01 | 1988-04-08 | Fujisawa Pharmaceutical Co | PROCESS FOR THE PREPARATION OF CEPHEM COMPOUNDS WITH ANTIMICROBIAL ACTIVITY AND NOVEL PRODUCTS THUS OBTAINED |
EP0137442A3 (en) | 1983-10-08 | 1986-01-15 | Hoechst Aktiengesellschaft | Cephalosporin derivatives and process for their preparation |
US4690921A (en) | 1983-10-11 | 1987-09-01 | Yamanouchi Pharmaceutical Co., Ltd. | Cephalosporin compounds and salts thereof |
US4748172A (en) | 1983-10-17 | 1988-05-31 | Eli Lilly And Company | 3-bicyclicpyridinium-methyl cephalosporins |
US4692443A (en) | 1983-10-17 | 1987-09-08 | Eli Lilly And Company | 3-bicyclicpyridinium-methyl cephalosporins |
GB8329030D0 (en) | 1983-10-31 | 1983-11-30 | Fujisawa Pharmaceutical Co | Cephem compounds |
GB8401093D0 (en) | 1984-01-16 | 1984-02-15 | Fujisawa Pharmaceutical Co | Cephem compounds |
JPS60169486A (en) | 1984-02-10 | 1985-09-02 | Yamanouchi Pharmaceut Co Ltd | Preparation of 7-amino-3-substituted methyl-3-cephem-4- carboxylic acid and lower alkylsilyl derivative thereof |
GB8406231D0 (en) | 1984-03-09 | 1984-04-11 | Fujisawa Pharmaceutical Co | Cephem compounds |
JPS60214792A (en) | 1984-04-06 | 1985-10-28 | Taiho Yakuhin Kogyo Kk | Penamylacid ester derivative |
US4705851A (en) | 1984-09-28 | 1987-11-10 | Fujisawa Pharmaceutical Co., Ltd. | Process for the preparation of 3-phosphoniummethyl-3-cephem compounds |
US4761410A (en) | 1985-01-14 | 1988-08-02 | Fujisawa Pharmaceutical Co., Ltd. | Cephem Compounds |
DE3687279T2 (en) | 1985-01-21 | 1993-05-13 | Nippon Pharma Dev Inst | BETA LACTAM ANTIBIOTICS. |
GB8504072D0 (en) | 1985-02-18 | 1985-03-20 | Fujisawa Pharmaceutical Co | Cephem compounds |
JPS6230789A (en) | 1985-08-01 | 1987-02-09 | Yamanouchi Pharmaceut Co Ltd | 7-formylaminocephalosporin compound and production thereof |
CN86107947A (en) | 1985-11-22 | 1987-05-27 | 藤沢药品工业株式会社 | New cephem compounds and preparation method thereof |
EP0237735B1 (en) | 1986-03-17 | 1994-03-30 | Fujisawa Pharmaceutical Co., Ltd. | 3,7-Disubstituted-3-cephem compounds and process for production of the same |
US4833134A (en) | 1986-08-19 | 1989-05-23 | Takeda Chemical Industries, Ltd. | Cephem compounds |
US5162520A (en) | 1986-09-22 | 1992-11-10 | Fujisawa Pharmaceutical Co., Ltd. | Intermediates for cephem compounds |
CA1293719C (en) | 1986-09-22 | 1991-12-31 | Takao Takaya | Cephem compounds and processes for preparation thereof |
US4882434A (en) | 1986-10-29 | 1989-11-21 | Takeda Chemical Industries, Ltd. | Gamma-lactonecarboxylic acid derivatives and their use as antibacterial agents or intermediates |
ES2053508T3 (en) | 1986-11-24 | 1994-08-01 | Fujisawa Pharmaceutical Co | COMPOUNDS OF 3-PIRROLIDINYL-THIO-1-AZABICICLO (3.2.0) HEPT-2-ENO-2-CARBOXILICOS. |
KR880006244A (en) | 1986-11-24 | 1988-07-22 | 후지사와 도모 기찌 로 | 3-Pyrrolidinylthio-1-azabibischloro [3.2.0] hapt2-ene-2-carboxylic acid compound and preparation method thereof |
AU1630988A (en) | 1987-05-30 | 1988-12-01 | Kyoto Pharmaceutical Industries, Ltd. | Cephalosporin compound and pharmaceutical composition thereof |
IE61679B1 (en) | 1987-08-10 | 1994-11-16 | Fujisawa Pharmaceutical Co | Water-soluble antibiotic composition and water-soluble salts of new cephem compounds |
US5073550A (en) | 1987-08-14 | 1991-12-17 | Hoffmann-La Roche Inc. | Cephalosphorins with sulfur-containing oxyimino side chain |
US5138066A (en) | 1987-08-14 | 1992-08-11 | Hoffmann-La Roche, Inc. | Intermediates for cephalosporins with sulfur-containing oxyimino side chain |
EP0303172A3 (en) | 1987-08-14 | 1991-05-15 | F. Hoffmann-La Roche Ag | Oxyimino-cephalosporins |
ZA885709B (en) | 1987-08-19 | 1989-04-26 | Fujisawa Pharmaceutical Co | Novel crystalline 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido)-3-vinyl-3-cephem-4-carboxylic acid(syn isomer) |
US5663163A (en) | 1987-09-07 | 1997-09-02 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds and processes for preparation thereof |
US5210080A (en) | 1987-09-07 | 1993-05-11 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
IE63094B1 (en) | 1987-09-14 | 1995-03-22 | Fujisawa Pharmaceutical Co | Cephem compound and a process for preparation thereof |
DK637888A (en) | 1987-11-24 | 1989-05-25 | Hoffmann La Roche | carboxylic esters |
GB8804058D0 (en) | 1988-02-22 | 1988-03-23 | Fujisawa Pharmaceutical Co | 3-alkenyl-1-azabicyclo(3 2 0)hept-2-ene-2-carboxylic acid compounds |
US5173485A (en) | 1988-03-09 | 1992-12-22 | Fujisawa Pharmaceutical Company, Ltd. | Cephem compounds |
CS273349B2 (en) | 1988-03-31 | 1991-03-12 | Hoffmann La Roche | Method of cephalosporin's new derivatives production |
US5336768A (en) | 1988-05-24 | 1994-08-09 | Hoffmann-La Roche Inc. | Antibacterial cephalosporin compounds |
KR900006811B1 (en) | 1988-05-11 | 1990-09-21 | 주식회사 럭 키 | Cephalosphorin derivatives and its process |
US4963544A (en) | 1988-05-23 | 1990-10-16 | Fujisawa Pharmaceutical Company, Ltd. | 3-pyrrolidinylthio-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylic acid compounds |
US5244890A (en) | 1988-06-06 | 1993-09-14 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
EP0366189A3 (en) | 1988-10-24 | 1992-01-02 | Norwich Eaton Pharmaceuticals, Inc. | Novel antimicrobial lactam-quinolones |
JP2785195B2 (en) | 1989-01-11 | 1998-08-13 | ソニー株式会社 | Optical encoder for disk drive |
GB8905301D0 (en) | 1989-03-08 | 1989-04-19 | Fujisawa Pharmaceutical Co | New cephem compound and a process for preparation thereof |
JPH0347187A (en) | 1989-04-12 | 1991-02-28 | Yamanouchi Pharmaceut Co Ltd | New cephalosporin derivative |
US5102877A (en) | 1989-04-28 | 1992-04-07 | Fujisawa Pharmaceutical Co., Ltd. | 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds |
NO903360L (en) | 1989-08-11 | 1991-02-12 | Ici Pharma | ANTIBIOTIC COMPOUNDS. |
GB8923844D0 (en) | 1989-10-23 | 1989-12-13 | Fujisawa Pharmaceutical Co | Carbapenem compounds |
US5215982A (en) | 1989-11-10 | 1993-06-01 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
US4982596A (en) | 1990-01-26 | 1991-01-08 | Buell Industries, Inc. | Die for manufacturing a fastener blank |
KR910015587A (en) | 1990-02-27 | 1991-09-30 | 후지사와 토모키치로 | Cefem compound |
US5234920A (en) | 1990-08-23 | 1993-08-10 | Bristol-Myers Squibb Company | Antibiotic C-7 catechol-substituted cephalosporin compounds, compositions, and method of use thereof |
US5095012A (en) | 1990-08-23 | 1992-03-10 | Bristol-Myers Squibb Company | Antibiotic c-7 catechol-substituted cephalosporin compounds, compositions, and method of use thereof |
US5286721A (en) | 1990-10-15 | 1994-02-15 | Fujisawa Pharmaceutical Co., Ltd. | 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid compounds |
US5281589A (en) | 1991-06-15 | 1994-01-25 | Cheil Foods & Chemicals, Inc. | 3-fused pyridiniummethyl cephalosporins |
JPH05155890A (en) | 1991-12-11 | 1993-06-22 | Toyama Chem Co Ltd | New cephalosporin derivative and its salt |
JP3145483B2 (en) | 1992-05-28 | 2001-03-12 | 富山化学工業株式会社 | Novel cephalosporin derivatives and their salts |
US5523400A (en) | 1993-04-16 | 1996-06-04 | Hoffmann-La Roche Inc. | Cephalosporin antibiotics |
KR100194994B1 (en) | 1993-06-05 | 1999-06-15 | 손경식 | New cefem compound |
EP0678095A1 (en) | 1993-11-06 | 1995-10-25 | Taiho Pharmaceutical Co., Ltd. | Crystalline penicillin derivative, and its production and use |
EP0664117A1 (en) | 1994-01-25 | 1995-07-26 | F. Hoffmann-La Roche Ag | Liposome solutions |
TW293010B (en) | 1994-04-20 | 1996-12-11 | Hui-Po Wang | Method for preparing cephalosporin derivatives |
AU2577495A (en) | 1994-05-23 | 1995-12-18 | Korea Institute Of Science And Technology | Cephalosporin compounds and processes for the preparation thereof |
KR100248851B1 (en) | 1994-08-16 | 2000-04-01 | 이치로 키타사토 | A novel cephem derivative |
DE4440141A1 (en) | 1994-11-10 | 1996-05-15 | Hoechst Ag | Novel crystalline cephem acid addition salts and process for their preparation |
DE69736775T2 (en) | 1996-04-04 | 2007-08-23 | Shionogi & Co., Ltd. | CEPHEM COMPOUNDS AND MEDICAMENTS CONTAINING THESE COMPOUNDS |
AU5006499A (en) | 1998-07-23 | 2000-02-14 | Intrabiotics Pharmaceuticals, Inc. | Compositions and methods for the treatment or prevention of pulmonary infections |
TW526202B (en) | 1998-11-27 | 2003-04-01 | Shionogi & Amp Co | Broad spectrum cephem having benzo[4,5-b]pyridium methyl group of antibiotic activity |
US6207661B1 (en) | 1999-02-22 | 2001-03-27 | Baxter International Inc. | Premixed formulation of piperacillin sodium and tazobactam sodium injection |
US6696412B1 (en) | 2000-01-20 | 2004-02-24 | Cubist Pharmaceuticals, Inc. | High purity lipopeptides, Lipopeptide micelles and processes for preparing same |
US6599893B2 (en) | 2000-08-29 | 2003-07-29 | Essential Therapeutics, Inc. | Cephalosporin antibiotics and prodrugs thereof |
ES2254671T3 (en) | 2001-05-01 | 2006-06-16 | Astellas Pharma Inc. | CEFEM COMPOUNDS. |
TWI335332B (en) | 2001-10-12 | 2011-01-01 | Theravance Inc | Cross-linked vancomycin-cephalosporin antibiotics |
TW200305422A (en) | 2002-03-18 | 2003-11-01 | Shionogi & Co | Broad spectrum cefem compounds |
TWI325323B (en) | 2002-05-24 | 2010-06-01 | Theravance Inc | Cross-linked glycopeptide-cephalosporin antibiotics |
BR0215776A (en) | 2002-06-07 | 2005-03-01 | Orchid Chemicals & Pharm Ltd | Process for the preparation of pename derivatives from cefame derivatives |
BRPI0315188B8 (en) | 2002-10-30 | 2021-05-25 | Astellas Pharma Inc | compound and pharmaceutical composition |
AU2002952355A0 (en) | 2002-10-30 | 2002-11-14 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
DE10304403A1 (en) | 2003-01-28 | 2004-08-05 | Röhm GmbH & Co. KG | Process for the preparation of an oral dosage form with immediate disintegration and drug release |
WO2004113350A1 (en) | 2003-05-23 | 2004-12-29 | Theravance, Inc. | Cross-linked glycopeptide - cephalosporin antibiotics |
ES2302034T3 (en) | 2003-07-11 | 2008-07-01 | Theravance, Inc. | CEPHALOSPORINE-GLICOPEPTIDE ANTIBIOTICS RETICULATED. |
US7589233B2 (en) | 2003-07-29 | 2009-09-15 | Signature R&D Holdings, Llc | L-Threonine derivatives of high therapeutic index |
US8173840B2 (en) | 2003-07-29 | 2012-05-08 | Signature R&D Holdings, Llc | Compounds with high therapeutic index |
ATE463248T1 (en) | 2003-09-18 | 2010-04-15 | Astellas Pharma Inc | CEPHEM COMPOUNDS |
JP4535366B2 (en) | 2003-12-03 | 2010-09-01 | 塩野義製薬株式会社 | Method for producing cephem agent |
CA2553038A1 (en) | 2004-01-30 | 2005-08-18 | Wyeth | Compositions substantially free of galactomannan containing piperacillin and tazobactam |
WO2005078848A2 (en) | 2004-02-11 | 2005-08-25 | University Of Tennessee Research Foundation | Inhibition of tumor growth and invasion by anti-matrix metalloproteinase dnazymes |
US20070219191A1 (en) | 2004-03-05 | 2007-09-20 | Yasuhiro Nishitani | 3-Pyridinium Methyl Cephem Compound |
US7417143B2 (en) | 2004-04-07 | 2008-08-26 | Orchid Chemicals & Pharmaceuticals Limited | Process for the preparation of Tazobactam in pure form |
RU2007111484A (en) | 2004-10-14 | 2008-11-20 | Вайет (Us) | COMPOSITIONS CONTAINING PIPERACILLINE, TASOBACTAM AND AMINOCARBOXYLIC ACID IN SODIUM LACTATE SOLVENT |
EP1919449A2 (en) | 2005-06-07 | 2008-05-14 | Foamix Ltd. | Antibiotic kit and composition and uses thereof |
US20090275552A1 (en) | 2006-04-28 | 2009-11-05 | Mahesh Vithalbhai Patel | Therapy for Treating Resistant Bacterial Infections |
WO2008030469A2 (en) | 2006-09-07 | 2008-03-13 | Merial Limited | Soft chewable, tablet, and long-acting injectable veterinary antibiotic formulations |
FI119678B (en) | 2006-11-28 | 2009-02-13 | Ipsat Therapies Oy | Use of beta-lactamase |
DE102007009242A1 (en) | 2007-02-22 | 2008-09-18 | Evonik Röhm Gmbh | Pellets with enteric-coated matix |
AU2008229604B2 (en) | 2007-03-20 | 2013-05-30 | Scf Pharma Inc. | Compositions comprising polyunsaturated fatty acid monoglycerides or derivatives thereof and uses thereof |
JP3141040U (en) | 2007-08-02 | 2008-04-24 | 劉 政憲 | Auxiliary equipment |
JP3141041U (en) | 2007-08-13 | 2008-04-24 | 法子 寺澤 | Art flower made from the bottom of a plastic bottle |
US20090098088A1 (en) | 2007-10-10 | 2009-04-16 | The Procter & Gamble Company | Methods And Kits For The Treatment Of Diverticular Conditions |
WO2009134948A1 (en) | 2008-05-01 | 2009-11-05 | The Procter & Gamble Company | Methods and kits for the treatment of inflammatory bowel disorder conditions |
RU2016115906A (en) | 2009-06-10 | 2018-11-28 | Текфилдз Байокем Ко., Лтд. | COMPOSITIONS OR MEDICATIONS OF ANTIMO-MICROBIAL AND RELATIVE ANTIMO-MICROBIAL COMPOUNDS Possessing a High Penetrating Ability |
JP2013500974A (en) | 2009-07-28 | 2013-01-10 | アナコール ファーマシューティカルズ,インコーポレイテッド | Trisubstituted boron-containing molecules |
WO2013036783A2 (en) | 2011-09-09 | 2013-03-14 | Cubist Pharmaceuticals, Inc. | Methods for treating intrapulmonary infections |
-
2013
- 2013-09-06 US US14/020,230 patent/US8809314B1/en active Active
-
2014
- 2014-07-17 US US14/333,966 patent/US20150025053A1/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8809314B1 (en) * | 2012-09-07 | 2014-08-19 | Cubist Pharmacueticals, Inc. | Cephalosporin compound |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10376496B2 (en) | 2013-09-09 | 2019-08-13 | Merck, Sharp & Dohme Corp. | Treating infections with ceftolozane/tazobactam in subjects having impaired renal function |
US10933053B2 (en) | 2013-09-09 | 2021-03-02 | Merck Sharp & Dohme Corp. | Treating infections with ceftolozane/tazobactam in subjects having impaired renal function |
Also Published As
Publication number | Publication date |
---|---|
US8809314B1 (en) | 2014-08-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8809314B1 (en) | Cephalosporin compound | |
US6916803B2 (en) | 3-(Heteroaryl acetamido)-2-oxo-azetidine-1-sulfonic acids derivatives as antibacterial agents | |
US8314217B2 (en) | Cross-linked glycopeptide-cephalosporin antibiotics | |
US7601690B2 (en) | Cross-linked glycopeptide-cephalosporin antibiotics | |
US9630977B2 (en) | Cephalosporin derivatives and pharmaceutical compositions thereof | |
US20090137460A1 (en) | Cross-linked glycopeptide-cephalosporin antibiotics | |
ES2302034T3 (en) | CEPHALOSPORINE-GLICOPEPTIDE ANTIBIOTICS RETICULATED. | |
JP2018502845A5 (en) | ||
Greenlee et al. | Dicationic 2-fluorenonylcarbapenems: Potent anti-MRS agents with improved solubility and pharmacokinetic properties | |
KR100455544B1 (en) | Cephalosporin Antibiotics | |
US10265408B2 (en) | Cleavable conjugates of antibiotics and an antibacterial cell-penetrating peptide | |
EP1618106B1 (en) | Carbacephem beta-lactam antibiotics | |
Yoshizawa et al. | S-3578, a new broad spectrum parenteral cephalosporin exhibiting potent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa synthesis and structure-activity relationships | |
Kamachi et al. | Synthesis and biological activity of a new cephalosporin, BMY-28232 and its prodrug-type esters for oral use | |
WO2008094203A2 (en) | Polar ester prodrugs of heterocyclic hybrid antibacterial compounds and salts thereof | |
US11746111B2 (en) | Siderophore conjugated pyrazolidinones, and analogues thereof | |
US10717757B2 (en) | Ketolides having antibacterial activity | |
Maruyama et al. | CP5484, a novel quaternary carbapenem with potent anti-MRSA activity and reduced toxicity | |
US11912650B2 (en) | Bakuchiol derivatives, pharmaceutically acceptable salts thereof, and preparation method and use of the same | |
EP4342484A1 (en) | Pharmaceutical composition comprising macrocosine compound and method for preparing macrocosine compound | |
EP4025577A1 (en) | Siderophore cephalosporin conjugates and uses thereof | |
JP2017105714A (en) | Multiple drug discharge pump inhibitor | |
KR20050037553A (en) | Cephalosporins | |
WO2001057041A1 (en) | 1-methylcarbapenem compounds |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: CUBIST PHARMACEUTICALS, INC., MASSACHUSETTS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HE, YONG;GU, YU GUI;YE, NING;REEL/FRAME:033360/0766 Effective date: 20131010 |
|
AS | Assignment |
Owner name: CUBIST PHARMACEUTICALS LLC, NEW JERSEY Free format text: CHANGE OF NAME;ASSIGNOR:CUBIST PHARMACEUTICALS, INC.;REEL/FRAME:036283/0189 Effective date: 20150629 |
|
AS | Assignment |
Owner name: MERCK SHARP & DOHME CORP., NEW JERSEY Free format text: NUNC PRO TUNC ASSIGNMENT;ASSIGNOR:CUBIST PHARMACEUTICALS LLC;REEL/FRAME:036268/0626 Effective date: 20150805 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |