WO2009064414A1 - Beta-lactamase inhibitors - Google Patents
Beta-lactamase inhibitors Download PDFInfo
- Publication number
- WO2009064414A1 WO2009064414A1 PCT/US2008/012706 US2008012706W WO2009064414A1 WO 2009064414 A1 WO2009064414 A1 WO 2009064414A1 US 2008012706 W US2008012706 W US 2008012706W WO 2009064414 A1 WO2009064414 A1 WO 2009064414A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- hydroxyl
- cycloalkyl
- aryl
- heteroaryl
- Prior art date
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- 239000003781 beta lactamase inhibitor Substances 0.000 title claims description 12
- 229940126813 beta-lactamase inhibitor Drugs 0.000 title claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 11
- -1 amino, carbonyl Chemical group 0.000 claims description 659
- 125000000623 heterocyclic group Chemical group 0.000 claims description 338
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 328
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 326
- 125000003118 aryl group Chemical group 0.000 claims description 318
- 125000001072 heteroaryl group Chemical group 0.000 claims description 315
- 229910052736 halogen Inorganic materials 0.000 claims description 287
- 150000002367 halogens Chemical group 0.000 claims description 287
- 125000001424 substituent group Chemical group 0.000 claims description 273
- 125000000217 alkyl group Chemical group 0.000 claims description 258
- 125000003545 alkoxy group Chemical group 0.000 claims description 255
- 125000003342 alkenyl group Chemical group 0.000 claims description 251
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 251
- 125000000304 alkynyl group Chemical group 0.000 claims description 251
- 125000004104 aryloxy group Chemical group 0.000 claims description 251
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 251
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 251
- 125000003375 sulfoxide group Chemical group 0.000 claims description 245
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 239
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 239
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 239
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical group OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 238
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical group [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 238
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 238
- 150000003573 thiols Chemical group 0.000 claims description 238
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 226
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 226
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 226
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 226
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims description 226
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 225
- 125000004089 sulfido group Chemical group [S-]* 0.000 claims description 140
- 229910052760 oxygen Inorganic materials 0.000 claims description 85
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 76
- 229910052799 carbon Inorganic materials 0.000 claims description 76
- 125000004432 carbon atom Chemical group C* 0.000 claims description 75
- 125000005842 heteroatom Chemical group 0.000 claims description 75
- 229910052757 nitrogen Inorganic materials 0.000 claims description 74
- 239000001257 hydrogen Substances 0.000 claims description 60
- 229910052739 hydrogen Inorganic materials 0.000 claims description 60
- 125000004122 cyclic group Chemical group 0.000 claims description 50
- 150000002431 hydrogen Chemical class 0.000 claims description 45
- 229910052796 boron Inorganic materials 0.000 claims description 37
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 32
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 28
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 18
- 239000003782 beta lactam antibiotic agent Substances 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 17
- 239000002132 β-lactam antibiotic Substances 0.000 claims description 17
- 229940124586 β-lactam antibiotics Drugs 0.000 claims description 17
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 14
- 125000003277 amino group Chemical group 0.000 claims description 13
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 12
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 229930186147 Cephalosporin Natural products 0.000 claims description 9
- 241000124008 Mammalia Species 0.000 claims description 9
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 9
- 229940124587 cephalosporin Drugs 0.000 claims description 9
- 150000001780 cephalosporins Chemical class 0.000 claims description 9
- 208000035143 Bacterial infection Diseases 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 230000001580 bacterial effect Effects 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 claims description 4
- 206010034133 Pathogen resistance Diseases 0.000 claims description 3
- 229930182555 Penicillin Natural products 0.000 claims description 3
- 238000011282 treatment Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 150000003462 sulfoxides Chemical class 0.000 claims 6
- BSIMZHVOQZIAOY-SCSAIBSYSA-N 1-carbapenem-3-carboxylic acid Chemical compound OC(=O)C1=CC[C@@H]2CC(=O)N12 BSIMZHVOQZIAOY-SCSAIBSYSA-N 0.000 claims 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 4
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims 4
- 206010041925 Staphylococcal infections Diseases 0.000 claims 4
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 claims 4
- 229960003644 aztreonam Drugs 0.000 claims 4
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 claims 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 3
- 229960001991 ceftizoxime Drugs 0.000 claims 2
- NNULBSISHYWZJU-LLKWHZGFSA-N ceftizoxime Chemical compound N([C@@H]1C(N2C(=CCS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 NNULBSISHYWZJU-LLKWHZGFSA-N 0.000 claims 2
- 229940049954 penicillin Drugs 0.000 claims 2
- 235000019371 penicillin G benzathine Nutrition 0.000 claims 2
- JETQIUPBHQNHNZ-NJBDSQKTSA-N (2s,5r,6r)-3,3-dimethyl-7-oxo-6-[[(2r)-2-phenyl-2-sulfoacetyl]amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound C1([C@H](C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)S(O)(=O)=O)=CC=CC=C1 JETQIUPBHQNHNZ-NJBDSQKTSA-N 0.000 claims 1
- LZKPUSJSJVEXAW-WDXSGGTDSA-N (4s,5r,6s)-3-[7-[1-(2-amino-2-oxoethyl)pyridin-1-ium-3-carbonyl]imidazo[5,1-b][1,3]thiazol-2-yl]-6-[(1r)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C([O-])=O)=O)[C@H](O)C)C(SC1=2)=CN1C=NC=2C(=O)C1=CC=C[N+](CC(N)=O)=C1 LZKPUSJSJVEXAW-WDXSGGTDSA-N 0.000 claims 1
- WVPAABNYMHNFJG-QDVBXLKVSA-N 2,2-dimethylpropanoyloxymethyl (6r,7r)-7-[[(z)-2-(2-amino-1,3-thiazol-4-yl)pent-2-enoyl]amino]-3-(carbamoyloxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(=O)OCOC(=O)C(C)(C)C)=O)C(=O)\C(=C/CC)C1=CSC(N)=N1 WVPAABNYMHNFJG-QDVBXLKVSA-N 0.000 claims 1
- KZDCMKVLEYCGQX-UDPGNSCCSA-N 2-(diethylamino)ethyl 4-aminobenzoate;(2s,5r,6r)-3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;hydrate Chemical compound O.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 KZDCMKVLEYCGQX-UDPGNSCCSA-N 0.000 claims 1
- HGGAKXAHAYOLDJ-FHZUQPTBSA-N 6alpha-[(R)-1-hydroxyethyl]-2-[(R)-tetrahydrofuran-2-yl]pen-2-em-3-carboxylic acid Chemical compound S([C@@H]1[C@H](C(N1C=1C(O)=O)=O)[C@H](O)C)C=1[C@H]1CCCO1 HGGAKXAHAYOLDJ-FHZUQPTBSA-N 0.000 claims 1
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 claims 1
- BHELIUBJHYAEDK-OAIUPTLZSA-N Aspoxicillin Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3[C@H](C(C)(C)S[C@@H]32)C(O)=O)=O)NC(=O)[C@H](N)CC(=O)NC)=CC=C(O)C=C1 BHELIUBJHYAEDK-OAIUPTLZSA-N 0.000 claims 1
- QYQDKDWGWDOFFU-IUODEOHRSA-N Cefotiam Chemical compound CN(C)CCN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC=3N=C(N)SC=3)[C@H]2SC1 QYQDKDWGWDOFFU-IUODEOHRSA-N 0.000 claims 1
- KEJCWVGMRLCZQQ-YJBYXUATSA-N Cefuroxime axetil Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(=O)OC(C)OC(C)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 KEJCWVGMRLCZQQ-YJBYXUATSA-N 0.000 claims 1
- JWCSIUVGFCSJCK-CAVRMKNVSA-N Disodium Moxalactam Chemical compound N([C@]1(OC)C(N2C(=C(CSC=3N(N=NN=3)C)CO[C@@H]21)C(O)=O)=O)C(=O)C(C(O)=O)C1=CC=C(O)C=C1 JWCSIUVGFCSJCK-CAVRMKNVSA-N 0.000 claims 1
- UIOFUWFRIANQPC-JKIFEVAISA-N Floxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl UIOFUWFRIANQPC-JKIFEVAISA-N 0.000 claims 1
- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical compound O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)NC1=CC=CC(C(O)=O)=C1 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 claims 1
- 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 claims 1
- TYMABNNERDVXID-DLYFRVTGSA-N Panipenem Chemical compound C([C@@H]1[C@H](C(N1C=1C(O)=O)=O)[C@H](O)C)C=1S[C@H]1CCN(C(C)=N)C1 TYMABNNERDVXID-DLYFRVTGSA-N 0.000 claims 1
- 229930195708 Penicillin V Natural products 0.000 claims 1
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 claims 1
- KLFSEZJCLYBFKQ-WXYNYTDUSA-N [(3s)-3-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-[(1,5-dihydroxy-4-oxopyridin-2-yl)methoxyimino]acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] hydrogen sulfate Chemical compound O=C1N(OS(O)(=O)=O)C(C)(C)[C@@H]1NC(=O)C(\C=1N=C(N)SC=1)=N/OCC1=CC(=O)C(O)=CN1O KLFSEZJCLYBFKQ-WXYNYTDUSA-N 0.000 claims 1
- 229960003022 amoxicillin Drugs 0.000 claims 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 claims 1
- 229960000723 ampicillin Drugs 0.000 claims 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims 1
- XMQVYNAURODYCQ-SLFBBCNNSA-N apalcillin Chemical compound C1([C@@H](NC(=O)C=2C(=C3N=CC=CC3=NC=2)O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 XMQVYNAURODYCQ-SLFBBCNNSA-N 0.000 claims 1
- 229950001979 apalcillin Drugs 0.000 claims 1
- 229960000202 aspoxicillin Drugs 0.000 claims 1
- 229950003588 axetil Drugs 0.000 claims 1
- 229960003623 azlocillin Drugs 0.000 claims 1
- JTWOMNBEOCYFNV-NFFDBFGFSA-N azlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCNC1=O JTWOMNBEOCYFNV-NFFDBFGFSA-N 0.000 claims 1
- 229960002699 bacampicillin Drugs 0.000 claims 1
- PFOLLRNADZZWEX-FFGRCDKISA-N bacampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)[C@H](C(S3)(C)C)C(=O)OC(C)OC(=O)OCC)=CC=CC=C1 PFOLLRNADZZWEX-FFGRCDKISA-N 0.000 claims 1
- MRMBZHPJVKCOMA-YJFSRANCSA-N biapenem Chemical compound C1N2C=NC=[N+]2CC1SC([C@@H]1C)=C(C([O-])=O)N2[C@H]1[C@@H]([C@H](O)C)C2=O MRMBZHPJVKCOMA-YJFSRANCSA-N 0.000 claims 1
- 229960003169 biapenem Drugs 0.000 claims 1
- 229960003669 carbenicillin Drugs 0.000 claims 1
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 claims 1
- 125000002843 carboxylic acid group Chemical group 0.000 claims 1
- UIMOJFJSJSIGLV-JNHMLNOCSA-N carumonam Chemical compound O=C1N(S(O)(=O)=O)[C@H](COC(=O)N)[C@@H]1NC(=O)C(=N/OCC(O)=O)\C1=CSC(N)=N1 UIMOJFJSJSIGLV-JNHMLNOCSA-N 0.000 claims 1
- 229960000662 carumonam Drugs 0.000 claims 1
- RRYMAQUWDLIUPV-BXKDBHETSA-N cefacetrile Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC#N)[C@@H]12 RRYMAQUWDLIUPV-BXKDBHETSA-N 0.000 claims 1
- 229960003972 cefacetrile Drugs 0.000 claims 1
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 claims 1
- 229960005361 cefaclor Drugs 0.000 claims 1
- 229960004841 cefadroxil Drugs 0.000 claims 1
- NBFNMSULHIODTC-CYJZLJNKSA-N cefadroxil monohydrate Chemical compound O.C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=C(O)C=C1 NBFNMSULHIODTC-CYJZLJNKSA-N 0.000 claims 1
- FUBBGQLTSCSAON-PBFPGSCMSA-N cefaloglycin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)COC(=O)C)C(O)=O)=CC=CC=C1 FUBBGQLTSCSAON-PBFPGSCMSA-N 0.000 claims 1
- 229950004030 cefaloglycin Drugs 0.000 claims 1
- CZTQZXZIADLWOZ-CRAIPNDOSA-N cefaloridine Chemical compound O=C([C@@H](NC(=O)CC=1SC=CC=1)[C@H]1SC2)N1C(C(=O)[O-])=C2C[N+]1=CC=CC=C1 CZTQZXZIADLWOZ-CRAIPNDOSA-N 0.000 claims 1
- XIURVHNZVLADCM-IUODEOHRSA-N cefalotin Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C(O)=O)C(=O)CC1=CC=CS1 XIURVHNZVLADCM-IUODEOHRSA-N 0.000 claims 1
- 229960000603 cefalotin Drugs 0.000 claims 1
- OLVCFLKTBJRLHI-AXAPSJFSSA-N cefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](O)C=3C=CC=CC=3)[C@H]2SC1 OLVCFLKTBJRLHI-AXAPSJFSSA-N 0.000 claims 1
- 229960003012 cefamandole Drugs 0.000 claims 1
- 229960001139 cefazolin Drugs 0.000 claims 1
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 claims 1
- SMSRCGPDNDCXFR-CYWZMYCQSA-N cefbuperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H]([C@H](C)O)C(=O)N[C@]1(OC)C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 SMSRCGPDNDCXFR-CYWZMYCQSA-N 0.000 claims 1
- 229960001817 cefbuperazone Drugs 0.000 claims 1
- 229950004627 cefcapene pivoxil Drugs 0.000 claims 1
- JUVHVMCKLDZLGN-TVNFHGJBSA-N cefclidin Chemical compound N([C@@H]1C(N2C(=C(C[N+]34CCC(CC3)(CC4)C(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=NSC(N)=N1 JUVHVMCKLDZLGN-TVNFHGJBSA-N 0.000 claims 1
- 229950011467 cefclidin Drugs 0.000 claims 1
- 229960003719 cefdinir Drugs 0.000 claims 1
- RTXOFQZKPXMALH-GHXIOONMSA-N cefdinir Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 RTXOFQZKPXMALH-GHXIOONMSA-N 0.000 claims 1
- 229960002142 cefditoren pivoxil Drugs 0.000 claims 1
- AFZFFLVORLEPPO-UVYJNCLZSA-N cefditoren pivoxil Chemical compound S([C@@H]1[C@@H](C(N1C=1C(=O)OCOC(=O)C(C)(C)C)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1\C=C/C=1SC=NC=1C AFZFFLVORLEPPO-UVYJNCLZSA-N 0.000 claims 1
- DASYMCLQENWCJG-XUKDPADISA-N cefetamet pivoxil Chemical compound N([C@@H]1C(N2C(=C(C)CS[C@@H]21)C(=O)OCOC(=O)C(C)(C)C)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 DASYMCLQENWCJG-XUKDPADISA-N 0.000 claims 1
- 229950000726 cefetamet pivoxil Drugs 0.000 claims 1
- 229960002129 cefixime Drugs 0.000 claims 1
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 claims 1
- XAKKNLNAJBNLPC-MAYKBZFQSA-N cefluprenam Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)/C=C/C[N+](C)(CC)CC(N)=O)C([O-])=O)C(=O)C(=N/OCF)\C1=NSC(N)=N1 XAKKNLNAJBNLPC-MAYKBZFQSA-N 0.000 claims 1
- 229950001334 cefluprenam Drugs 0.000 claims 1
- 229960001958 cefodizime Drugs 0.000 claims 1
- XDZKBRJLTGRPSS-BGZQYGJUSA-N cefodizime 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=1CSC1=NC(C)=C(CC(O)=O)S1 XDZKBRJLTGRPSS-BGZQYGJUSA-N 0.000 claims 1
- DYAIAHUQIPBDIP-AXAPSJFSSA-N cefonicid Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)[C@H](O)C=2C=CC=CC=2)CC=1CSC1=NN=NN1CS(O)(=O)=O DYAIAHUQIPBDIP-AXAPSJFSSA-N 0.000 claims 1
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- 229960004682 cefoperazone Drugs 0.000 claims 1
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 claims 1
- ZINFAXPQMLDEEJ-GFVOIPPFSA-N cefoselis 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=1CN1C=CC(=N)N1CCO ZINFAXPQMLDEEJ-GFVOIPPFSA-N 0.000 claims 1
- 229950001580 cefoselis Drugs 0.000 claims 1
- 229960004261 cefotaxime Drugs 0.000 claims 1
- GPRBEKHLDVQUJE-VINNURBNSA-N cefotaxime Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1 GPRBEKHLDVQUJE-VINNURBNSA-N 0.000 claims 1
- 229960001242 cefotiam Drugs 0.000 claims 1
- WZOZEZRFJCJXNZ-ZBFHGGJFSA-N cefoxitin Chemical compound N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)CC1=CC=CS1 WZOZEZRFJCJXNZ-ZBFHGGJFSA-N 0.000 claims 1
- 229960002682 cefoxitin Drugs 0.000 claims 1
- 229960002642 cefozopran Drugs 0.000 claims 1
- QDUIJCOKQCCXQY-WHJQOFBOSA-N cefozopran Chemical compound N([C@@H]1C(N2C(=C(CN3C4=CC=CN=[N+]4C=C3)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=NSC(N)=N1 QDUIJCOKQCCXQY-WHJQOFBOSA-N 0.000 claims 1
- LNZMRLHZGOBKAN-KAWPREARSA-N cefpimizole Chemical compound N1=CNC(C(=O)N[C@@H](C(=O)N[C@@H]2C(N3C(=C(C[N+]=4C=CC(CCS(O)(=O)=O)=CC=4)CS[C@@H]32)C([O-])=O)=O)C=2C=CC=CC=2)=C1C(=O)O LNZMRLHZGOBKAN-KAWPREARSA-N 0.000 claims 1
- 229950004036 cefpimizole Drugs 0.000 claims 1
- 229960005446 cefpiramide Drugs 0.000 claims 1
- PWAUCHMQEXVFJR-PMAPCBKXSA-N cefpiramide Chemical compound C1=NC(C)=CC(O)=C1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 PWAUCHMQEXVFJR-PMAPCBKXSA-N 0.000 claims 1
- 229960000466 cefpirome Drugs 0.000 claims 1
- 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 claims 1
- 229960005090 cefpodoxime Drugs 0.000 claims 1
- WYUSVOMTXWRGEK-HBWVYFAYSA-N cefpodoxime Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)C(=O)C(=N/OC)\C1=CSC(N)=N1 WYUSVOMTXWRGEK-HBWVYFAYSA-N 0.000 claims 1
- 229960004797 cefpodoxime proxetil Drugs 0.000 claims 1
- LTINZAODLRIQIX-FBXRGJNPSA-N cefpodoxime proxetil Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(=O)OC(C)OC(=O)OC(C)C)C(=O)C(=N/OC)\C1=CSC(N)=N1 LTINZAODLRIQIX-FBXRGJNPSA-N 0.000 claims 1
- 229960002588 cefradine Drugs 0.000 claims 1
- 229960003202 cefsulodin Drugs 0.000 claims 1
- SYLKGLMBLAAGSC-QLVMHMETSA-N cefsulodin Chemical compound C1=CC(C(=O)N)=CC=[N+]1CC1=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)[C@@H](C=3C=CC=CC=3)S(O)(=O)=O)[C@H]2SC1 SYLKGLMBLAAGSC-QLVMHMETSA-N 0.000 claims 1
- 229940036735 ceftaroline Drugs 0.000 claims 1
- 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 claims 1
- 229960000484 ceftazidime Drugs 0.000 claims 1
- 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 claims 1
- XSPUSVIQHBDITA-RKYNPMAHSA-N cefteram 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=1CN1N=NC(C)=N1 XSPUSVIQHBDITA-RKYNPMAHSA-N 0.000 claims 1
- 229950002506 cefteram pivoxil Drugs 0.000 claims 1
- 229960004086 ceftibuten Drugs 0.000 claims 1
- UNJFKXSSGBWRBZ-BJCIPQKHSA-N ceftibuten Chemical compound S1C(N)=NC(C(=C\CC(O)=O)\C(=O)N[C@@H]2C(N3C(=CCS[C@@H]32)C(O)=O)=O)=C1 UNJFKXSSGBWRBZ-BJCIPQKHSA-N 0.000 claims 1
- VOAZJEPQLGBXGO-SDAWRPRTSA-N ceftobiprole Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(\C=C/4C(N([C@H]5CNCC5)CC\4)=O)CS[C@@H]32)C(O)=O)=O)=N1 VOAZJEPQLGBXGO-SDAWRPRTSA-N 0.000 claims 1
- 229950004259 ceftobiprole Drugs 0.000 claims 1
- 229960004755 ceftriaxone Drugs 0.000 claims 1
- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone 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=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 claims 1
- 229960001668 cefuroxime Drugs 0.000 claims 1
- JFPVXVDWJQMJEE-IZRZKJBUSA-N cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 JFPVXVDWJQMJEE-IZRZKJBUSA-N 0.000 claims 1
- 229960002620 cefuroxime axetil Drugs 0.000 claims 1
- CXHKZHZLDMQGFF-ZSDSSEDPSA-N cefuzonam 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=1CSC1=CN=NS1 CXHKZHZLDMQGFF-ZSDSSEDPSA-N 0.000 claims 1
- 229950000807 cefuzonam Drugs 0.000 claims 1
- 229940106164 cephalexin Drugs 0.000 claims 1
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 claims 1
- RDLPVSKMFDYCOR-UEKVPHQBSA-N cephradine Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CCC=CC1 RDLPVSKMFDYCOR-UEKVPHQBSA-N 0.000 claims 1
- 229960003326 cloxacillin Drugs 0.000 claims 1
- LQOLIRLGBULYKD-JKIFEVAISA-N cloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl LQOLIRLGBULYKD-JKIFEVAISA-N 0.000 claims 1
- HGBLNBBNRORJKI-WCABBAIRSA-N cyclacillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C1(N)CCCCC1 HGBLNBBNRORJKI-WCABBAIRSA-N 0.000 claims 1
- 229960004244 cyclacillin Drugs 0.000 claims 1
- YFAGHNZHGGCZAX-JKIFEVAISA-N dicloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(Cl)C=CC=C1Cl YFAGHNZHGGCZAX-JKIFEVAISA-N 0.000 claims 1
- 229960001585 dicloxacillin Drugs 0.000 claims 1
- AVAACINZEOAHHE-VFZPANTDSA-N doripenem 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](CNS(N)(=O)=O)C1 AVAACINZEOAHHE-VFZPANTDSA-N 0.000 claims 1
- 229960000895 doripenem Drugs 0.000 claims 1
- 229960002770 ertapenem Drugs 0.000 claims 1
- 229960000379 faropenem Drugs 0.000 claims 1
- 229960004273 floxacillin Drugs 0.000 claims 1
- 229960003884 hetacillin Drugs 0.000 claims 1
- DXVUYOAEDJXBPY-NFFDBFGFSA-N hetacillin Chemical compound C1([C@@H]2C(=O)N(C(N2)(C)C)[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 DXVUYOAEDJXBPY-NFFDBFGFSA-N 0.000 claims 1
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical group C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 claims 1
- 229960002182 imipenem Drugs 0.000 claims 1
- 238000000338 in vitro Methods 0.000 claims 1
- 238000001727 in vivo Methods 0.000 claims 1
- 229960000433 latamoxef Drugs 0.000 claims 1
- 229960002260 meropenem Drugs 0.000 claims 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 claims 1
- 229960003085 meticillin Drugs 0.000 claims 1
- 229960000198 mezlocillin Drugs 0.000 claims 1
- YPBATNHYBCGSSN-VWPFQQQWSA-N mezlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCN(S(C)(=O)=O)C1=O YPBATNHYBCGSSN-VWPFQQQWSA-N 0.000 claims 1
- WIDKTXGNSOORHA-CJHXQPGBSA-N n,n'-dibenzylethane-1,2-diamine;(2s,5r,6r)-3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;tetrahydrate Chemical compound O.O.O.O.C=1C=CC=CC=1CNCCNCC1=CC=CC=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 WIDKTXGNSOORHA-CJHXQPGBSA-N 0.000 claims 1
- GPXLMGHLHQJAGZ-JTDSTZFVSA-N nafcillin Chemical compound C1=CC=CC2=C(C(=O)N[C@@H]3C(N4[C@H](C(C)(C)S[C@@H]43)C(O)=O)=O)C(OCC)=CC=C21 GPXLMGHLHQJAGZ-JTDSTZFVSA-N 0.000 claims 1
- 229960000515 nafcillin Drugs 0.000 claims 1
- UWYHMGVUTGAWSP-JKIFEVAISA-N oxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1 UWYHMGVUTGAWSP-JKIFEVAISA-N 0.000 claims 1
- 229960001019 oxacillin Drugs 0.000 claims 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 claims 1
- 229950011346 panipenem Drugs 0.000 claims 1
- 229940056360 penicillin g Drugs 0.000 claims 1
- 229940056367 penicillin v Drugs 0.000 claims 1
- BPLBGHOLXOTWMN-MBNYWOFBSA-N phenoxymethylpenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1 BPLBGHOLXOTWMN-MBNYWOFBSA-N 0.000 claims 1
- 229960002292 piperacillin Drugs 0.000 claims 1
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 claims 1
- 229960003342 pivampicillin Drugs 0.000 claims 1
- ZEMIJUDPLILVNQ-ZXFNITATSA-N pivampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)[C@H](C(S3)(C)C)C(=O)OCOC(=O)C(C)(C)C)=CC=CC=C1 ZEMIJUDPLILVNQ-ZXFNITATSA-N 0.000 claims 1
- DWHGNUUWCJZQHO-ZVDZYBSKSA-M potassium;(2s,5r,6r)-6-[[(2r)-2-amino-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;(2r,3z,5r)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound [K+].[O-]C(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21.C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 DWHGNUUWCJZQHO-ZVDZYBSKSA-M 0.000 claims 1
- XFGOMLIRJYURLQ-GOKYHWASSA-N razupenem Chemical group C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)SC(SC=1)=NC=1C1=C[C@H](C)NC1 XFGOMLIRJYURLQ-GOKYHWASSA-N 0.000 claims 1
- 229960004932 sulbenicillin Drugs 0.000 claims 1
- 229960001114 temocillin Drugs 0.000 claims 1
- BVCKFLJARNKCSS-DWPRYXJFSA-N temocillin Chemical compound N([C@]1(OC)C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C(C(O)=O)C=1C=CSC=1 BVCKFLJARNKCSS-DWPRYXJFSA-N 0.000 claims 1
- 229960004659 ticarcillin Drugs 0.000 claims 1
- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 claims 1
- 102000006635 beta-lactamase Human genes 0.000 abstract description 17
- 108020004256 Beta-lactamase Proteins 0.000 abstract description 12
- 150000007513 acids Chemical class 0.000 abstract description 5
- 239000002253 acid Substances 0.000 abstract description 4
- 239000003112 inhibitor Substances 0.000 abstract description 4
- 108090000204 Dipeptidase 1 Proteins 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 229940041011 carbapenems Drugs 0.000 description 4
- 150000003952 β-lactams Chemical class 0.000 description 4
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 108010068385 carbapenemase Proteins 0.000 description 3
- 230000002759 chromosomal effect Effects 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 108010071437 oxacillinase Proteins 0.000 description 3
- 239000013612 plasmid Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 150000001413 amino acids Chemical group 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002960 penicillins Chemical class 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- DBVFWZMQJQMJCB-UHFFFAOYSA-N 3-boronobenzoic acid Chemical class OB(O)C1=CC=CC(C(O)=O)=C1 DBVFWZMQJQMJCB-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 101100026178 Caenorhabditis elegans egl-3 gene Proteins 0.000 description 1
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 1
- 101000740462 Escherichia coli Beta-lactamase TEM Proteins 0.000 description 1
- 108010087702 Penicillinase Proteins 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 1
- 229960003324 clavulanic acid Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical compound O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 description 1
- 229960005256 sulbactam Drugs 0.000 description 1
- LPQZKKCYTLCDGQ-WEDXCCLWSA-N tazobactam Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1 LPQZKKCYTLCDGQ-WEDXCCLWSA-N 0.000 description 1
- 229960003865 tazobactam Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- beta-lactamase inhibitors While maintaining good inhibitory activity against ESBLs, the legacy beta-lactamase inhibitors are largely ineffective against the new Class A carbapenemases, against the chromosomal and plasmid-mediated Class C cephalosporinases and against many of the Class D oxacillinases. To address this growing therapeutic vulnerability, a new generation of beta-lactamase inhibitors must be developed with broad spectrum functionality. The novel boronic acid based inhibitors described herein address this medical need.
- C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
- An additional aspect is for a method of treating a bacterial infection in a mammal comprising administering to a mammal in need thereof:
- R 4 is selected from the group consisting of:
- Y 1 and Y 2 are independently hydrogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminosulfonyl, aminocarbonyl, carbonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, halogen, heteroaryl, heteroaryloxy, heterocyclyl, sulfido, sulfonyl, or sulfoxido, or taken together Y 1 and Y 2 form a cyclic structure containing from 3-12 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S;
- R 4 is selected from the group consisting of:
- substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
- Xi and X 2 are independently hydroxyl, halogen, NR 4 R 5 , C1-C6 alkoxy, or when taken together Xi and X 2 form a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together X 1 and X 2 form a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S 1 or when taken together Xi and X 2 form a cyclic boron amide-ester where said chain contains from 2-20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or X 1 and Ri together form a cyclic ring where said ring contains 2 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O 1 N, or S 1 and X 2
- antibiotic is used herein to describe a compound or composition which decreases the viability of a microorganism, or which inhibits the growth or reproduction of a microorganism. "Inhibits the growth or reproduction” means increasing the generation cycle time by at least 2-fold, preferably at least 10-fold, more preferably at least 100-fold, and most preferably indefinitely, as in total cell death.
- an antibiotic is further intended to include an antimicrobial, bacteriostatic, or bactericidal agent.
- bacteria of the genus Staphylococcus such as Staphylococcus aureus and Staphylococcus epidermidis
- Streptococcus such as Streptococcus agalactine, Streptococcus pneumoniae and Streptococcus faecalis
- Micrococcus such as Micrococcus luteus
- Bacillus such as Bacillus subtilis
- Listerella such as Listerella monocytogenes
- Escherichia such as Escherichia coli
- Klebsiella such as Klebsiella pneumoniae
- Proteus such as Proteus mirabilis and Proteus vulgaris
- Salmonella such as Salmonella typhosa
- Shigella such as Shigella sonnei
- Enterobacter such as Enterobacter aerogenes and Enterobacter cloacae
- Serratia such as Serratia marcescens
- Pseudomonas such as Pseudomonas aeruginosa
- Acinetobacter such as Acinetobacter anitratus
- Nocardia such as Nocardia autotrophica
- Mycobacterium such as Mycobacterium fortuitum.
- beta-lactamase means an enzyme produced by a bacteria that has the ability to hydrolyze the beta-lactam ring of beta-lactam antibiotics. Such enzymes are often classified into 4 major classes (Classes A, B, C, and D) according to the so-called Ambler classification scheme, based principally on protein homology.
- alkynyl includes both straight chain and branched alkynyl moieties containing 2-6 carbon atoms containing at least one triple bond, preferably the alkynyl moiety has one or two triple bonds.
- cycloalkyl refers to an alicyclic hydrocarbon group having 3-7 carbon atoms.
- halogen is defined as Cl, Br, F, and I.
- Aryl is defined as an aromatic hydrocarbon moiety selected from the group: phenyl, ⁇ -naphthyl, ⁇ -naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, acenaphthenyl, groups.
- Arylalkyl is defined as aryl-C1-C6alkyl ⁇ .
- Arylalkyl moieties include benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like.
- Alkylaryl is defined as C1-C6alkyl-aryl-
- Heteroarylalkyl is defined as heteroaryl-C1-C6alkyl-.
- Alkylheteroaryl is defined as C1-C6alkyl-heteroaryl ⁇ .
- Heterocyclyloxy is defined as CS-Cyheterocyclyl-O-.
- Sulfonic acid is defined as -SO 3 H.
- Hydroxyl is defined as -OH
- Thiol is defined as -SH
- Aminosulfonyl is defined as -S(O) 2 -N- where the sulfur is optionally substituted and the nitrogen is attached to the rest of the molecule.
- Guanidino is defined as -N1(H)-C(NH)-N2(H) ⁇ where N1 is optionally substituted and N2 is attached to the rest of the molecule.
- Sulfido is defined as -S- where sulfur is bound to an optional substituent and also to the rest of the molecule.
- Sulfoxido is defined as -S(O)- where sulfur is bound to an optional substituent and also to the rest of the molecule.
- Optional substituents may be attached to the group or atom which they substitute in a variety of ways, either directly or through a connecting group of which the following are examples: alkyl, amine, amide, ester, ether, thioether, sulfonamide, sulfamide, sulfoxide, urea.
- an optional substituent may itself be further substituted by another substituent, the latter being connected directly to the former or through a connecting group such as those exemplified above.
- R 1 Js -C(O)R 4 ; -C(O)NR 4 R 5 ; -C(O)OR 4 ; -S(O) 2 R 4 , -C( NR 4 R 5 )R 4 , - C ⁇ NR 4 R 5 )NR 4 R 5 , hydrogen, or is selected from the group consisting of:
- substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino (wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group), sulfido, and sulfoxido,
- X 1 and X2 are independently hydroxyl, halogen, NR4R 5 , C1-C6 alkoxy, or when taken together X 1 and X 2 form a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together X 1 and X 2 form a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together X 1 and X 2 form a cyclic boron amide-ester where said chain contains from 2-20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, Or X 1 and R 1 together form a cyclic ring where said ring contains 2 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X
- C1-C10 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino (wherein any of the C1-C10 carbons comprise part of said oxyimino group), sulfido, and sulfoxido,
- Beta-lactamase inhibitors can be administered to subjects in a biologically compatible form suitable for pharmaceutical administration in vivo to, e.g., increase antibacterial activity of beta-lactam antibiotics.
- Administration of a beta- lactamase inhibitor as described herein can be in any pharmacological form including a therapeutically active amount of a beta-lactamase inhibitor alone or in combination with a pharmaceutically acceptable carrier.
- a therapeutically active amount of a beta-lactamase inhibitor may vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the beta-lactamase inhibitor to elicit a desired response in the subject. Dosage regimes may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
- a beta-lactamase inhibitor can also be linked or conjugated with agents that provide desirable pharmaceutical or pharmacodynamic properties.
- a beta-lactamase inhibitor can be coupled to any substance known in the art to promote penetration or transport across the blood-brain barrier such as an antibody to the transferrin receptor, and administered by intravenous injection (see, e.g., Friden PM et al., Science 259:373-77 (1993)).
- a beta- lactamase inhibitor can be stably linked to a polymer such as polyethylene glycol to obtain desirable properties of solubility, stability, half-life, and other pharmaceutically advantageous properties (see, e.g., Davis et al., Enzyme Eng. 4:169-73 (1978); Burnham NL, Am. J. Hosp. Pharm. 51 :210-18 (1994)).
- a beta-lactamase inhibitor can be in a composition which aids in delivery into the cytosol of a cell.
- the beta-lactamase inhibitor may be conjugated with a carrier moiety such as a liposome that is capable of delivering the beta-lactamase inhibitor into the cytosol of a cell.
- a carrier moiety such as a liposome that is capable of delivering the beta-lactamase inhibitor into the cytosol of a cell.
- a beta-lactamase inhibitor can be modified to include specific transit peptides or fused to such transit peptides which are capable of delivering their beta-lactamase inhibitor into a cell.
- the pharmaceutical compositions further comprise an effective amount of a beta-lactam antibiotic.
- exemplary ⁇ -lactam antibiotics include penicillins, cephalosporins, carbapenems, monobactams, bridged monobactams, or a combination thereof.
- Pencillins include, but are not limited to, benzathine penicillin, benzylpenicillin, phenoxymethylpenicillin, procaine penicillin, oxacillin, methicillin, dicloxacillin, flucloxacillin, temocillin, amoxicillin, ampicillin, co-amoxiclav, azlocillin, carbenicillin, ticarcillin, mezlocillin, piperacillin, apalcillin, hetacillin, bacampicillin, sulbenicillin, mecicilam, pevmecillinam, ciclacillin, talapicillin, aspoxicillin, cloxacillin, nafcillin, pivampicillin, or a combination thereof.
- the formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents.
- the compositions may be formulated so as to provide rapid, sustained, or delayed release of the active ingredients after administration to the patient by employing procedures well known in the art.
- the formulations can also contain substances that diminish proteolytic degradation and/or substances which promote absorption such as, for example, surface active agents.
- Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- the specification for the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
- the specific dose can be readily calculated by one of ordinary skill in the art, e.g., according to the approximate body weight or body surface area of the patient or the volume of body space to be occupied.
- resistant and “highly resistant” are well-understood by those of ordinary skill in the art (see, e.g., Payne et al., Antimicrobial Agents and Chemotherapy 38:767-772 (1994); Hanaki et al., Antimicrobial Agents and Chemotherapy 30:1120-1126 (1995)).
- highly resistant bacterial strains are those against which the MIC of methicillin is >100 ⁇ g/mL.
- slightly resistant bacterial strains are those against which the MIC of methicillin is >25 ⁇ g/mL.
- Contacting means that the beta-lactamase and the inhibitor are brought together so that the inhibitor can bind to the beta-lactamase. Amounts of a compound effective to inhibit a beta-lactamase may be determined empirically, and making such determinations is within the skill in the art. Inhibition includes both reduction and elimination of beta-lactamase activity.
- Step 3 Synthesis of (1R)-1-(4-Oxo-4-thiophen-2-yl-butyrylamino)-2-(2- hydroxy-3-carboxyphenyl)ethyl-1-boronic acid.
- Step 2 Synthesis of (1R)-1-(2-acetylamino)-2-(2-hydroxy-3- carboxyphenyl)ethyl-1-boronic acid.
- Step 2 Synthesis of (1f?)-1-[3-(carboxymethoxy)-phenyl]acetylamino- (3-carboxy -2-hydroxy) benzyl-methylboronic acid.
- Step 2 Synthesis of (4-Bromo-thiophen-2-yl)-acetic acid.
- Step 3 Synthesis of (4-Bromo-thiophen-2-yl)-acetic acid.
- Step 4 Synthesis of (1R)-1-(2-(4-bromothiophen-2-yl)acetylamino)-2- (2-hydroxy-3-carboxyphenyl)ethyl-1 -boronic acid.
- This was prepared as described in Example 6 from 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02,6]dec-4-ylmethyl)-benzoic acid te/f-butyl ester and 2 eq of 4- Bromo-thiophen-2-yl)-acetyl chloride.
- the final product was further purified by preparative HPLC. ESI-MS m/z 410 (MH-H 2 O) + .
- Example 10 (1 R)-1 -(2-phenylacetylamino)-2-(2-hvdroxy-3-carboxyphenyl)ethyl-1 -boronic acid
- Step 1 Synthesis of (1R)-2-Methoxy-3-[2-[2-(2,5- dimethoxyphenyl)acetylamino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1. 0 2>6 ]dec-4-yl)-ethyl]-benzoic acid te/t butyl ester.
- Step 1 Synthesis of 3-[2-(Cyclopropanecarbonyl-amino)-2-(2,9,9- trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0 2>6 ]dec-4-yl)-ethyl]-2-methoxy- benzoic acid tert-butyl ester. Prepared from 2-Methoxy-3-(2,9,9-trimethyl-3,5- dioxa-4-bora-tricyclo[6.1.1.0 2 ' 6 ]dec-4-ylmethyl)-benzoic acid tert-butyl ester and cyclopropylcarbonyl chloride following the procedure described in Step 7 of Example 3.
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Abstract
Disclosed herein are alpha-aminoboronic acids and their derivatives which act as inhibitors of beta-lactamases. Also disclosed herein are pharmaceutical compositions comprising alpha-aminoboronic acids and methods of use thereof.
Description
TITLE BETA-LACTAMASE INHIBITORS
CROSS-REFERENCE TO RELATED APPLICATION This application claims the benefit of U.S. Provisional Application No.
61/002,797, filed November 13, 2007, which is incorporated by reference in its entirety.
FIELD OF THE INVENTION The present disclosure relates to α-aminoboronic acids and their derivatives which act as inhibitors of beta-lactamase enzymes.
BACKGROUND OF THE INVENTION Antibiotics are the most effective drugs for curing bacteria-infectious diseases clinically. They have a wide market for their advantages of good antibacterial effect, and limited side effect. Among them, beta-lactam antibiotics (for example, penicillins, cephalosporins, and carbapenems) are widely used because they have a very strong bactericidal effect (by blocking cell division) and very low toxicity. To counter the efficacy of the various beta-lactams, bacteria have evolved to produce variants of beta-lactam deactivating enzymes called beta-lactamases, and in the ability to share this tool inter- and intra-species. The rapid spread of this mechanism of bacterial resistance can severely limit beta-lactam treatment options in the hospital and in the community. Beta-lactamases are typically grouped into 4 classes: Ambler classes A, B, C, and D, based on their amino acid sequences. Enzymes in classes A, C, and D are active-site serine beta- lactamases, while class B enzymes, which are encountered less frequently, are Zn-dependent. Newer generation cephalosporins and carbapenems were developed partly based on their ability to evade the deactivating effect of the early sehne-based beta-lactamase variants. However, a recent surge in new versions of serine-based beta-lactamases — for example Class A Extended- Spectrum Beta-Lactamase (ESBL) enzymes, Class A carbapenemases (e.g. KPC-2), chromosomal and plasmid mediated Class C cephalosporinases (AmpC, CMY, etc.), and Class D oxacillinases — has begun to diminish the utility of the
beta-lactam antibiotic family, including the more recent generation beta-lactam drugs, leading to a serious medical problem. Indeed the number of catalogued serine-based beta-lactamases has exploded from less than ten in the 1970s to over 300 variants (see, e.g., Jacoby & Bush, "Amino Acid Sequences for TEM, SHV and OXA Extended-Spectrum and Inhibitor Resistant β-Lactamases", on the Lahey Clinic website).
The commercially available beta-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam) were developed to address the beta-lactamases that were clinically relevant in the 1970s and 1980s (e.g. penicillinases). These enzyme inhibitors are available only as fixed combinations with penicillin derivatives. No combinations with cephalosporins (or carbapenems) have been developed or are clinically available. This fact, combined with the increased use of newer generation cephalosporins and carbapenems, is driving the selection and spread of the new beta-lactamase variants (ESBLs, carbapenemases, chromosomal and plasmid-mediated class C, class D oxacillinases, etc.). While maintaining good inhibitory activity against ESBLs, the legacy beta-lactamase inhibitors are largely ineffective against the new Class A carbapenemases, against the chromosomal and plasmid-mediated Class C cephalosporinases and against many of the Class D oxacillinases. To address this growing therapeutic vulnerability, a new generation of beta-lactamase inhibitors must be developed with broad spectrum functionality. The novel boronic acid based inhibitors described herein address this medical need.
Use of a boronic acid compound to inhibit a beta-lactamase enzyme has been limited. For example, U.S. Patent No. 7,271 ,186 discloses beta-lactamase inhibitors that target AmpC (from class C). Ness et al. (Biochemistry (2000)
39:5312-21) discloses beta-lactamase inhibitors that target TEM-1 (a non-ESBL TEM variant from class A; one of approximately 140 known TEM-type beta- lactamase variants). Because there are three major molecular classes of serine- based beta-lactamases, and each of these classes contain significant numbers of beta-lactamase variants, inhibition of one or a small number of beta-lactamases is unlikely to be of therapeutic value. Therefore, there is an imperative need to develop novel beta-lactamase inhibitors with broad spectrum functionality.
SUMMARY OF THE INVENTION One aspect is for a compound of the formula:
(a) aryl group substituted with from O to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(b) heteroaryl group substituted with from O to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(c) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido;
R2 is hydrogen, or is selected from the group consisting of:
(a) C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C6 carbons comprise part of said oxyimino group, sulfido, and sulfoxido, (b) C3-C7 cycloalkyl any carbon of which can be substituted with from
0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl,
aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and (e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
R3 is an aryl or heteroaryl group substituted with from 1 to 4 substituents wherein one of the substituents is a hydroxyl or amino group located at the 2 position relative to the group containing Y1 and Y2, and wherein the remaining substituents are selected from the group consisting of hydroxyl, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminocarbonyl, carbonyl, aminosulfonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, guanidino, halogen, heteroaryl, heterocyclyl , sulfido, sulfonyl, sulfoxido, sulfonic acid, sulfate, and thiol;
R4 is selected from the group consisting of:
(a) C1-C10 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C10 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally
substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and (e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
ydrogen or is selected from the group consisting of:
(a) C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, (d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy,
heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
Xi and X2 are independently hydroxyl, halogen, NR4R5, C1-C6 alkoxy, or when taken together X1 and X2 form a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together X1 and X2 form a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together X1 and X2 form a cyclic boron amide-ester where said chain contains from 2-20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, Or X1 and R1 together form a cyclic ring where said ring contains 2 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, halogen, NR4R5, C1-C6 alkoxy, or X1 and R3 together form a cyclic ring where said ring contains 3 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, halogen, NR4R5, or C1-C6 alkoxy;
Y1 and Y2 are independently hydrogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminosulfonyl, aminocarbonyl, carbonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, halogen, heteroaryl, heteroaryloxy, heterocyclyl, sulfido, sulfonyl, or sulfoxido, or taken together Y1 and Y2 form a cyclic structure containing from 3-12 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S;
or a salt thereof;
provided that, when Ri is -C(O)R4, R2 is hydrogen, R3 is a phenyl group having two substituents consisting of a hydroxyl at the 2-position and a carboxylic acid at the 3-position relative to the group containing Y1 and Y2, Xi and X2 are hydroxyl or X1 is hydroxyl and X2 is replaced by the ortho-hydroxyl oxygen of R3 such that a 6-membered ring is formed, and Y1 and Y2 are hydrogen, R4 is not unsubstituted C1 alkyl.
Another aspect is for a pharmaceutical composition comprising: (a) one or more compounds discussed above; (b) one or more β-lactam antibiotics; and (c) one or more pharmaceutically acceptable carriers.
A further aspect is for a pharmaceutical composition comprising: (a) one or more compounds discussed above; and (b) one or more pharmaceutically acceptable carriers.
An additional aspect is for a method of treating a bacterial infection in a mammal comprising administering to a mammal in need thereof:
(i) an effective amount of a compound having the formula:
C(=NR4R5)R4, -C(=N R4R5)N R4R5, hydrogen, or is selected from the group consisting of:
(a) aryl group substituted with from O to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(b) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(c) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido;
R2 is hydrogen, or is selected from the group consisting of:
(a) C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C6 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy,
heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, (d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and (e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
R3 is an aryl or heteroaryl group substituted with from 1 to 4 substituents wherein one of the substituents is a hydroxyl or amino group located at the 2 position relative to the group containing Yi and Y2, and wherein the remaining substituents are selected from the group consisting of hydroxyl, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminocarbonyl, carbonyl, aminosulfonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, guanidino, halogen, heteroaryl, heterocyclyl , sulfido, sulfonyl, sulfoxido, sulfonic acid, sulfate, and thiol;
R4 is selected from the group consisting of:
(a) C1-C10 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C10 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
R5 is hydrogen or is selected from the group consisting of: (a) C1-C6 alkyl any carbon of which can be substituted with from
0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl,
alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
Xi and X2 are independently hydroxyl, halogen, NR4R5, C1-C6 alkoxy, or when taken together Xi and X2 form a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together Xi and X2 form a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together Xi and X2 form a cyclic boron amide-ester where said chain contains from 2-20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or X1 and R1 together form a cyclic ring where said ring contains 2 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, halogen, NR4R5, C1- C6 alkoxy, or X1 and R3 together form a cyclic ring where said ring contains 3 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, halogen, NR4R5, or C1- C6 alkoxy;
Y1 and Y2 are independently hydrogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminosulfonyl, aminocarbonyl, carbonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, halogen, heteroaryl, heteroaryloxy, heterocyclyl, sulfido, sulfonyl, or sulfoxido, or taken together Y1 and Y2 form a cyclic structure containing from 3-12
carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S;
or a salt thereof; and
(ii) an effective amount of a β-lactam antibiotic.
Another aspect is for a method of treating a bacterial infection in a mammal comprising administering to a mammal in need thereof an effective amount of a compound having the formula:
(a) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, (b) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(c) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl,
alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido; drogen, or is selected from the group consisting of:
(a) C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C6 carbons comprise part of said oxyimino group, sulfido, and sulfoxido, (b) C3-C7 cycloalkyl any carbon of which can be substituted with from
0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
R3 is an aryl or heteroaryl group substituted with from 1 to 4 substituents wherein one of the substituents is a hydroxyl or amino group located at the 2 position relative to the group containing Yi and Y2, and wherein the remaining substituents are selected from the group consisting of hydroxyl, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminocarbonyl, carbonyl, aminosulfonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, guanidino, halogen, heteroaryl, heterocyclyl , sulfido, sulfonyl, sulfoxido, sulfonic acid, sulfate, and thiol;
R4 is selected from the group consisting of:
(a) C1-C10 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy,
heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido, (b) C3-C10 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl,
cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido; drogen or is selected from the group consisting of: (a) C1-C6 alkyl any carbon of which can be substituted with from O to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido, (b) C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido, (c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy,
aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
X1 and X2 are independently hydroxyl, halogen, NR4R5, C1-C6 alkoxy, or when taken together Xi and X2 form a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together Xi and X2 form a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together Xi and X2 form a cyclic boron amide-ester where said chain contains from 2-20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, Or X1 and R1 together form a cyclic ring where said ring contains 2 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, halogen, NR4R5, C1-C6 alkoxy, or X-i and R3 together form a cyclic ring where said ring contains 3 to 10
carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, halogen, NR4R5, or C1-C6 alkoxy;
Yi and Y2 are independently hydrogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminosulfonyl, aminocarbonyl, carbonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, halogen, heteroaryl, heteroaryloxy, heterocyclyl, sulfido, sulfonyl, or sulfoxido, or taken together Yi and Y2 form a cyclic structure containing from 3-12 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S;
or a salt thereof.
A further aspect is for a method of reducing bacterial resistance to a β- lactam antibiotic comprising contacting a bacterial cell having resistance to a β- lactam antibiotic with an effective amount of a beta-lactamase inhibitor with broad-spectrum functionality having the formula:
(a) aryl group substituted with from O to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(b) heteroaryl group substituted with from O to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl,
aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and (c) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido; drogen, or is selected from the group consisting of:
(a) C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C6 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol,
sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and (e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
R3 is an aryl or heteroaryl group substituted with from 1 to 4 substituents wherein one of the substituents is a hydroxyl or amino group located at the 2 position relative to the group containing Yi and Y2, and wherein the remaining substituents are selected from the group consisting of hydroxyl, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminocarbonyl, carbonyl, aminosulfonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, guanidino, halogen, heteroaryl, heterocyclyl , sulfido, sulfonyl, sulfoxido, sulfonic acid, sulfate, and thiol;
R4 is selected from the group consisting of:
(a) C1-C10 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido, (b) C3-C10 cycloalkyl any carbon of which can be substituted with from
0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl,
aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and (e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido; ydrogen or is selected from the group consisting of: (a) C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido, (b) C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
X1 and X2 are independently hydroxyl, halogen, NR4R5, C1-C6 alkoxy, or when taken together X1 and X2 form a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together X1 and X2 form a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together X1 and X2 form a cyclic boron amide-ester where said chain contains from 2-20 carbon atoms and,
optionally, 1-3 heteroatoms which can be O, N, or S, or Xi and Ri together form a cyclic ring where said ring contains 2 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, halogen, NR4R5, C1-C6 alkoxy, or X1 and R3 together form a cyclic ring where said ring contains 3 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, halogen, NR4R5, or C1-C6 alkoxy;
Yi and Y2 are independently hydrogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminosulfonyl, aminocarbonyl, carbonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, halogen, heteroaryl, heteroaryloxy, heterocyclyl, sulfido, sulfonyl, or sulfoxido, or taken together Yi and Y2 form a cyclic structure containing from 3-12 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S;
or a salt thereof. An additional aspect is for use of a beta-lactamase inhibitor with broad- spectrum functionality having the formula:
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
R3 is an aryl or heteroaryl group substituted with from 1 to 4 substituents wherein one of the substituents is a hydroxyl or amino group located at the 2 position relative to the group containing Yi and Y2, and wherein the remaining substituents are selected from the group consisting of hydroxyl, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminocarbonyl, carbonyl, aminosulfonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, guanidino, halogen, heteroaryl, heterocyclyl , sulfido, sulfonyl, sulfoxido, sulfonic acid, sulfate, and thiol;
lected from the group consisting of:
(a) C1-C10 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C10 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl,
alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and (e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido; drogen or is selected from the group consisting of:
(a) C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the
molecule comprise part of said oxyϊmino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
Xi and X2 are independently hydroxyl, halogen, NR4R5, C1-C6 alkoxy, or when taken together Xi and X2 form a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together X1 and X2 form a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3
heteroatoms which can be O, N, or S1 or when taken together Xi and X2 form a cyclic boron amide-ester where said chain contains from 2-20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or X1 and Ri together form a cyclic ring where said ring contains 2 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O1 N, or S1 and X2 is hydroxyl, halogen, NR4R5, C1-C6 alkoxy, or Xi and R3 together form a cyclic ring where said ring contains 3 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, halogen, NR4R5, or C1-C6 alkoxy;
Yi and Y2 are independently hydrogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminosulfonyl, aminocarbonyl, carbonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, halogen, heteroaryl, heteroaryloxy, heterocyclyl, sulfido, sulfonyl, or sulfoxido, or taken together Yi and Y2 form a cyclic structure containing from 3-12 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S;
or a salt thereof;
provided that, when Ri is -C(O)R4, R2 is hydrogen, R3 is a phenyl group having two substituents consisting of a hydroxyl at the 2-position and a carboxylic acid at the 3-position relative to the group containing Yi and Y2, X1 and X2 are hydroxyl or X1 is hydroxyl and X2 is replaced by the ortho-hydroxyl oxygen of R3 such that a 6-membered ring is formed, and Y1 and Y2 are hydrogen, R4 is not unsubstituted C1 alkyl;
in combination with a β-lactam antibiotic in the manufacture of a medicament for the treatment of a bacterial infection.
Another aspect is for a composition for use in combination with a β-lactam antibiotic in reducing a bacterial infection comprising:
(b) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(c) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido; drogen, or is selected from the group consisting of:
(a) C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl,
sulfonyl, guanidino, oxyimino wherein any of the C1-C6 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and (e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy,
heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
R3 is an aryl or heteroaryl group substituted with from 1 to 4 substituents wherein one of the substituents is a hydroxyl or amino group located at the 2 position relative to the group containing Yi and Y2, and wherein the remaining substituents are selected from the group consisting of hydroxyl, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminocarbonyl, carbonyl, aminosulfonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, guanidino, halogen, heteroaryl, heterocyclyl , sulfido, sulfonyl, sulfoxido, sulfonic acid, sulfate, and thiol;
R4 is selected from the group consisting of:
(a) C1-C10 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido, (b) C3-C10 cycloalkyl any carbon of which can be substituted with from
0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the
molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido; drogen or is selected from the group consisting of:
(a) C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl,
heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, (d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano,
thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
Xi and X2 are independently hydroxyl, halogen, NR4R5, C1-C6 alkoxy, or when taken together Xi and X2 form a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together Xi and X2 form a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together Xi and X2 form a cyclic boron amide-ester where said chain contains from 2-20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or X1 and Ri together form a cyclic ring where said ring contains 2 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, halogen, NR4R5, C1-C6 alkoxy, or X1 and R3 together form a cyclic ring where said ring contains 3 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, halogen, NR4R5, or C1-C6 alkoxy;
Y1 and Y2 are independently hydrogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminosulfonyl, aminocarbonyl, carbonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, halogen, heteroaryl, heteroaryloxy, heterocyclyl, sulfido, sulfonyl, or sulfoxido, or taken together Y1 and Y2 form a cyclic structure containing from 3-12 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S;
or a salt thereof;
provided that, when R1 is -C(O)R4, R2 is hydrogen, R3 is a phenyl group having two substituents consisting of a hydroxyl at the 2-position and a carboxylic acid at the 3-position relative to the group containing Y1 and Y2, X1 and X2 are hydroxyl
or X1 is hydroxyl and X2 is replaced by the ortho-hydroxyl oxygen of R3 such that a 6-membered ring is formed, and Yi and Y2 are hydrogen, R4 is not unsubstituted C1 alkyl.
Other objects and advantages will become apparent to those skilled in the art upon reference to the detailed description that hereinafter follows.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1. General synthetic scheme (scheme 1) for the synthesis of α- amidoboronic acids using an isopropyl ester derived from 3-boronobenzoic acid compounds.
Figure 2. General synthetic scheme (scheme 2) for the synthesis of α- amidoboronic acids using a tert-butyl ester derived from 3-boronobenzoic acid compounds.
Figure 3. Equilibrium between the boronic acid open chain form and the boronic ester cyclic form of compounds possessing an ortho-phenol group.
Figure 4. Structure of three beta-lactam antibiotics, PZ-601 , ME1036, and BAL30072.
DETAILED DESCRIPTION OF THE INVENTION Applicants specifically incorporate the entire contents of all cited references in this disclosure. Further, when an amount, concentration, or other value or parameter is given as either a range, preferred range, or a list of upper preferable values and lower preferable values, this is to be understood as specifically disclosing all ranges formed from any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether ranges are separately disclosed. Where a range of numerical values is recited herein, unless otherwise stated, the range is intended to include the endpoints thereof, and all integers and fractions within the range. It is not intended that the scope of the invention be limited to the specific values recited when defining a range.
The present invention relates generally to novel α-aminoboronic acids and their derivatives which act as broad-spectrum inhibitors of beta-lactamase enzymes. Beta-lactamases hydrolyze beta-lactam antibiotics, and are therefore an important cause of β-lactam antibiotic resistance. The compounds of the recent invention, particularly when administered in combination with a β-lactam antibiotic, overcome this resistance mechanism and render beta-lactamase producing bacteria susceptible to the β-lactam antibiotic. The present invention also relates to pharmaceutical compositions comprising a compound of the present invention, or salt thereof, an optional beta-lactam antibiotic, and a pharmaceutically acceptable excipient. The present invention also relates to a method for treating a bacterial infection in a mammal by administration of a therapeutically acceptable amount of the aforementioned pharmaceutical compositions. The present invention also relates to a method for increasing the effectiveness of a beta-lactam antibiotic in mammals by administering an effective amount of a compound of the present invention in combination with an effective amount of such beta-lactam antibiotic.
Definitions
In the context of this disclosure, a number of terms shall be utilized. As used herein, the term "about" or "approximately" means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.
The term "antibiotic" is used herein to describe a compound or composition which decreases the viability of a microorganism, or which inhibits the growth or reproduction of a microorganism. "Inhibits the growth or reproduction" means increasing the generation cycle time by at least 2-fold, preferably at least 10-fold, more preferably at least 100-fold, and most preferably indefinitely, as in total cell death. As used in this disclosure, an antibiotic is further intended to include an antimicrobial, bacteriostatic, or bactericidal agent. Non-limiting examples of antibiotics useful according to this aspect of the invention include penicillins, cephalosporins, aminoglycosides, sulfonamides, macrolides, tetracycline, lincosides, quinolones, chloramphenicol, vancomycin, metronidazole, rifampin, isoniazid, spectinomycin, trimethoprim, sulfamethoxazole, and others.
The term "beta-lactam antibiotic" is used to designate compounds with antibiotic properties containing a beta-lactam functionality. Non-limiting examples of beta-lactam antibiotics useful according to this aspect of the invention include penicillins, cephalosporins, penems, carbapenems, and monobactams. Beta- lactam antibiotics are effective (in the absence of resistance) against a wide range of bacterial infections. These include those caused by both gram-positive and gram-negative bacteria, for example, bacteria of the genus Staphylococcus (such as Staphylococcus aureus and Staphylococcus epidermidis), Streptococcus (such as Streptococcus agalactine, Streptococcus pneumoniae and Streptococcus faecalis), Micrococcus (such as Micrococcus luteus), Bacillus (such as Bacillus subtilis), Listerella (such as Listerella monocytogenes), Escherichia (such as Escherichia coli), Klebsiella (such as Klebsiella pneumoniae), Proteus (such as Proteus mirabilis and Proteus vulgaris), Salmonella (such as Salmonella typhosa), Shigella (such as Shigella sonnei), Enterobacter (such as Enterobacter aerogenes and Enterobacter cloacae),
Serratia (such as Serratia marcescens), Pseudomonas (such as Pseudomonas aeruginosa), Acinetobacter (such as Acinetobacter anitratus), Nocardia (such as Nocardia autotrophica), and Mycobacterium (such as Mycobacterium fortuitum). The term "beta-lactamase" means an enzyme produced by a bacteria that has the ability to hydrolyze the beta-lactam ring of beta-lactam antibiotics. Such enzymes are often classified into 4 major classes (Classes A, B, C, and D) according to the so-called Ambler classification scheme, based principally on protein homology.
The term "beta-lactamase inhibitors with broad-spectrum functionality" as used herein refers to the ability of an inhibitor to inhibit a broad range of beta- lactamase enzymes, spanning multiple subtypes from multiple classes (for example numerous enzyme subtypes from both Ambler Class A and Ambler Class C). In some embodiments, beta-lactamase enzyme(s) from at least two classes of beta-lactamase enzymes are inhibited by a compound disclosed herein, with preferred embodiments being those where beta-lactamase enzyme(s) from more than two classes of beta-lactamase enzymes are inhibited by a compound disclosed herein.
The term "comprising" is intended to include embodiments encompassed by the terms "consisting essentially of and "consisting of. Similarly, the term
"consisting essentially of is intended to include embodiments encompassed by the term "consisting of.
The terms "effective amount", "therapeutically effective amount", and "therapeutically effective period of time" are used to denote known treatments at dosages and for periods of time effective to show a meaningful patient benefit, i.e., healing of conditions associated with bacterial infection, and/or bacterial drug resistance. Preferably, such administration should be parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. When administered systemically, the therapeutic composition is preferably administered at a sufficient dosage to attain a blood level of inhibitor of at least about 100 μg/mL, more preferably about 1 mg/mL, and still more preferably about 10 mg/mL. For localized administration, much lower concentrations than this may be effective, and much higher concentrations may be tolerated.
The term "mammal" refers to a human, a non-human primate, canine, feline, bovine, ovine, porcine, murine, or other veterinary or laboratory mammal. Those skilled in the art recognize that a therapy which reduces the severity of a pathology in one species of mammal is predictive of the effect of the therapy on another species of mammal.
Chemical Definitions
The term alkyl means both straight and branched chain alkyl moieties of 1- 12 carbons, preferably of 1-8 carbon atoms.
The term alkenyl means both straight and branched alkenyl moieties of 2- 8 carbon atoms containing at least one double bond, and no triple bond, preferably the alkenyl moiety has one or two double bonds. Such alkenyl moieties may exist in the E or Z conformations; the compounds of this invention include both conformations.
The term alkynyl includes both straight chain and branched alkynyl moieties containing 2-6 carbon atoms containing at least one triple bond, preferably the alkynyl moiety has one or two triple bonds.
The term cycloalkyl refers to an alicyclic hydrocarbon group having 3-7 carbon atoms.
The term halogen is defined as Cl, Br, F, and I.
Aryl is defined as an aromatic hydrocarbon moiety selected from the group: phenyl, α-naphthyl, β-naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, acenaphthenyl, groups.
Heteroaryl is defined as an aromatic heterocyclic ring system (monocyclic or bicyclic) where the heteroaryl moieties are selected from, but not limited to,: (1) furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N- methylpyrrole, pyrazole, N-methylpyrazole, 1 ,3,4-oxadiazole, 1 ,2,4-triazole, 1- methyl-1 ,2,4-triazole, 1 H-tetrazole, 1-methyltetrazole, 1 ,2,4-thiadiazole, 1 ,3,4- thiadiazole, 1 ,2,3-thiadiazole, 1 ,2,3-triazole, 1-methyl-1 ,2,3-triazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N- methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline; (2) a bicyclic aromatic heterocycle where a phenyl, pyridine, pyrimidine or pyridizine ring is: (a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5 or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S.
Arylalkyl is defined as aryl-C1-C6alkyl~. Arylalkyl moieties include benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like. Alkylaryl is defined as C1-C6alkyl-aryl- Heteroarylalkyl is defined as heteroaryl-C1-C6alkyl-. Alkylheteroaryl is defined as C1-C6alkyl-heteroaryl~.
Heterocyclyl is defined as a saturated or partially saturated heterocyclic moiety selected from, but not limited to; aziridinyl, azetidinyl, 1 ,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl,
dihydroazetidinyl, dihydro-1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl.
Alkoxy is defined as C1-C6alkyl-O~.
Cycloalkoxy is defined as CS-CTcycloalkyl-O-. Aryloxy is defined as aryl-O-.
Heteroaryloxy is defined as heteroaryl-O-.
Heterocyclyloxy is defined as CS-Cyheterocyclyl-O-.
Sulfonic acid is defined as -SO3H.
Sulfate is defined as -OSO3H. Amino is defined as -NH2.
Cyano is defined as -CN
Hydroxyl is defined as -OH
Thiol is defined as -SH
Carboxyl is defined as -CO2H. Trialkylammonium is defined as (A1)(A2)(A3)N+- where A1 , A2 and A3 are independently alkyl, cycloalkyl, heterocyclyl and the nitrogen is positively charged.
Carbonyl is defined as -C(O)- where the carbon is optionally substituted and also attached to the rest of the molecule. Aminocarbonyl is defined as -C(O)-N-, where the carbon is optionally substituted and the nitrogen is attached to the rest of the molecule.
Oxycarbonyl is defined as -C(O)-O-, where the carbon is optionally substituted and the oxygen is attached to the rest of the molecule.
Aminosulfonyl is defined as -S(O)2-N- where the sulfur is optionally substituted and the nitrogen is attached to the rest of the molecule.
Sulfonyl is defined as -S(O)2-- where the sulfur is bonded to an optional substituent and also to the rest of the molecule.
Guanidino is defined as -N1(H)-C(NH)-N2(H)~ where N1 is optionally substituted and N2 is attached to the rest of the molecule. Oxyimino is defined as (=N-O-A) where the nitrogen is double bonded to a carbon which is attached to the rest of the molecule and A can be hydrogen, optionally substituted: alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl.
Sulfido is defined as -S- where sulfur is bound to an optional substituent and also to the rest of the molecule.
Sulfoxido is defined as -S(O)- where sulfur is bound to an optional substituent and also to the rest of the molecule.
Where a group or atom is described as "optionally substituted" one or more of the following substituents may be present on that group or atom: hydroxyl, halogen, carboxyl, cyano, thiol, amino, sulfonic acid, sulfate, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, arylakyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, trialkylammonium. Optional substituents may be attached to the group or atom which they substitute in a variety of ways, either directly or through a connecting group of which the following are examples: alkyl, amine, amide, ester, ether, thioether, sulfonamide, sulfamide, sulfoxide, urea. As appropriate an optional substituent may itself be further substituted by another substituent, the latter being connected directly to the former or through a connecting group such as those exemplified above.
Beta-Lactamase Inhibitors
The present disclosure relates to compounds of formula I:
(a) aryl group substituted with from O to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(b) heteroaryl group substituted with from O to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl,
alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(c) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido; drogen, or is selected from the group consisting of: (a) C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino (wherein any of the C1-C6 carbons comprise part of said oxyimino group), sulfido, and sulfoxido, . (b) C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino (wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group), sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino (wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group), sulfido, and sulfoxido;
R3 is an aryl or heteroaryl group substituted with from 1 to 4 substituents wherein one of the substituents is a hydroxyl or amino group located at the 2 position relative to the group containing Yi and Y2, and wherein the remaining substituents are selected from the group consisting of hydroxyl, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminocarbonyl, carbonyl, aminosulfonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, guanidino, halogen, heteroaryl, heterocyclyl , sulfido, sulfonyl, sulfoxido, sulfonic acid, sulfate, and thiol; R4 is selected from the group consisting of:
(a) C1-C10 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino (wherein any of the C1-C10 carbons comprise part of said oxyimino group), sulfido, and sulfoxido, (b) C3-C10 cycloalkyl any carbon of which can be substituted with from
0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino (wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group), sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl,
aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and (e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino (wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group), sulfido, and sulfoxido; ydrogen or is selected from the group consisting of:
(a) C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino (wherein any of the C1-C10 carbons comprise part of said oxyimino group), sulfido, and sulfoxido,
(b) C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino (wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group), sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino (wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group), sulfido, and sulfoxido;
X1 and X2 are independently hydroxyl, halogen, NR4R5, C1-C6 alkoxy, or when taken together X1 and X2 form a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together X1 and X2 form a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together X1 and X2 form a cyclic boron amide-ester where said chain contains from 2-20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, Or X1 and R1 together form a
cyclic ring where said ring contains 2 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, halogen, NR4R5, C1-C6 alkoxy, or Xi and R3 together form a cyclic ring where said ring contains 3 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S1 and X2 is hydroxyl, halogen, NR4R5, or C1-C6 alkoxy;
Yi and Y2 are independently hydrogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminosulfonyl, aminocarbonyl, carbonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, halogen, heteroaryl, heteroaryloxy, heterocyclyl, sulfido, sulfonyl, or sulfoxido, or taken together Yi and Y2 form a cyclic structure containing from 3-12 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S.
Preferred embodiments are those compounds of Formula (I) wherein Ri is -C(O)R4; R2 is hydrogen; R3 is an aryl or heteroaryl group substituted with from 2 to 4 substituents wherein one of the substituents is a hydroxyl or amino group located at the 2- position relative to the group containing Yi and Y2, and a second substituent is a carboxylic acid group and wherein the remaining substituents are selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido; R4 is selected from the group consisting of:
(a) C1-C10 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino (wherein any of the C1-C10 carbons comprise part of said oxyimino group), sulfido, and sulfoxido,
(b) C3-C10 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally
substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino (wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group), sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and (e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino (wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group), sulfido, and sulfoxido;
Xi and X2 are hydroxyl, or when taken together Xi and X2 form a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or Xi and Ri together form a cyclic ring where said ring contains 2 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, or Xi and R3 together form a cyclic ring where said ring contains 3 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S and X2 is hydroxyl; Yi and Y2 are independently hydrogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminosulfonyl, aminocarbonyl, carbonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, halogen, heteroaryl, heteroaryloxy, heterocyclyl, sulfido, sulfonyl, or sulfoxide
Other preferred embodiments are those compounds of Formula (I) wherein Ri is -C(O)R4; R2 is hydrogen; R3 is an aryl group having a hydroxyl at the 2- position and a carboxylic acid at the 3-position relative to the group containing Y1 and Y2; R4 is C 1 -C 10 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino (wherein any of the C1-C10 carbons comprise part of said oxyimino group), sulfido, and sulfoxido; Xi and X2 are hydroxyl, or X1 is hydroxyl and X2 is replaced by the ortho-hydroxyl oxygen of R3 such that a 6-membered ring is formed; and Y1 and Y2 are hydrogen. Other preferred embodiments are those compounds of Formula (I) wherein
R1 is -C(O)R4; R2 is hydrogen; R3 is an aryl group having a hydroxyl at the 2- position and a carboxylic acid at the 3-position relative to the group containing Y1 and Y2; R4 is C3-C10 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino (wherein any of the carbons of the cycloalkyl group
other than the one attached to the rest of the molecule comprise part of said oxyimino group), sulfido, and sulfoxido; Xi and X2 are hydroxyl, or Xi is hydroxyl and X2 is replaced by the ortho-hydroxyl oxygen of R3 such that a 6-membered ring is formed; and Yi and Y2 are hydrogen. Other preferred embodiments are those compounds of Formula (I) wherein
Ri is -C(O)R4; R2 is hydrogen; R3 is an aryl group having a hydroxyl at the 2- position and a carboxylic acid at the 3-position relative to the group containing Yi and Y2; R4 is aryl or heteroaryl substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido; Xi and X2 are hydroxyl, or Xi is hydroxyl and X2 is replaced by the ortho-hydroxyl oxygen of R3 such that a 6-membered ring is formed; and Yi and Y2 are hydrogen.
Other preferred embodiments are those compounds of Formula (I) wherein R1 is -C(O)R4; R2 is hydrogen; R3 is an aryl group having a hydroxyl at the 2- position and a carboxylic acid at the 3-position relative to the group containing Y1 and Y2; R4 is a heterocycle substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino
(wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group), sulfido, and sulfoxido; X1 and X2 are hydroxyl, or X1 is hydroxyl and X2 is replaced by the ortho-hydroxyl oxygen of R3 such that a 6-membered ring is formed; and Y1 and Y2 are hydrogen.
Beta-Lactamase Inhibitor Synthesis
The compounds of the current invention can be synthesized using the general routes depicted in Figures 1 and 2. In Figure 1 , the boronic acid is first
converted to the chiral boronic ester by reaction with (+)-pinanediol, and the carboxylic acid group is subsequently protected as the isopropyl ester using 2- iodopropane and potassium carbonate in N,N-dimethylformamide (DMF). In Figure 2, the carboxylic acid group is first protected as the tert-butyl ester using 2-methylpropene in the presence of catalytic sulfuric acid, and the boronic acid is then subsequently converted to the chiral boronic ester with (+)-pinanediol. In both routes, homologation using (chloromethyl)lithium as described by Sadhu and Matteson, Organometallics, 1985, 4, 1687-1689 affords the benzylboronic esters. Conversion to the bis(trimethylsilyl)amine intermediates can be achieved using the conditions described by Schoichet et al., J. Am. Chem. Soc. 2003, 725, 685-695. These intermediates could then be converted to the desired amide by reaction with an acid chloride or other active ester such as that derived from the reaction of a carboxylic acid with isobutyl chloroformate or from the reaction of a carboxylic acid with a tetramethyluronium agent such as O-(7-Azabenzotriazol-1- yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU). Removal of the pinanediol groups and deprotection of the carboxylic acids and phenol groups can be accomplished in one step under acidic conditions such as aqueous HCI in dioxane or BCl3 θr BBr3 in dichloromethane. Based on literature precedent, it is assumed that Applicants obtain predominantly the 1-(R) enantiomer, although one skilled in the art will recognize that minor amounts of the 1-(S) isomer may be present in the reaction products. Also, there is a possibility that those compounds possessing an ortho-hydroxy group on the aryl ring of R3 can exist either as the free boronic acid or as the cyclic boronate ester, or as a mixture of the cyclic form and the open chain form as depicted in Figure 3 (Strynadka et al. Biochemistry, 2000, 39(18), 5312-5321).
Administration of Beta-Lactamase Inhibitors
Beta-lactamase inhibitors can be administered to subjects in a biologically compatible form suitable for pharmaceutical administration in vivo to, e.g., increase antibacterial activity of beta-lactam antibiotics. Administration of a beta- lactamase inhibitor as described herein can be in any pharmacological form including a therapeutically active amount of a beta-lactamase inhibitor alone or in combination with a pharmaceutically acceptable carrier.
A therapeutically active amount of a beta-lactamase inhibitor may vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the beta-lactamase inhibitor to elicit a desired response in the subject. Dosage regimes may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
The therapeutic or pharmaceutical compositions can be administered by any suitable route known in the art including, for example, intravenous, subcutaneous, intramuscular, transdermal, intrathecal, or intracerebral or administration to cells in ex vivo treatment protocols. Administration can be either rapid as by injection or over a period of time as by slow infusion or administration of slow release formulation.
A beta-lactamase inhibitor can also be linked or conjugated with agents that provide desirable pharmaceutical or pharmacodynamic properties. For example, a beta-lactamase inhibitor can be coupled to any substance known in the art to promote penetration or transport across the blood-brain barrier such as an antibody to the transferrin receptor, and administered by intravenous injection (see, e.g., Friden PM et al., Science 259:373-77 (1993)). Furthermore, a beta- lactamase inhibitor can be stably linked to a polymer such as polyethylene glycol to obtain desirable properties of solubility, stability, half-life, and other pharmaceutically advantageous properties (see, e.g., Davis et al., Enzyme Eng. 4:169-73 (1978); Burnham NL, Am. J. Hosp. Pharm. 51 :210-18 (1994)).
Furthermore, a beta-lactamase inhibitor can be in a composition which aids in delivery into the cytosol of a cell. For example, the beta-lactamase inhibitor may be conjugated with a carrier moiety such as a liposome that is capable of delivering the beta-lactamase inhibitor into the cytosol of a cell. Such methods are well known in the art (see, e.g., Amselem S et al., Chem. Phys. Lipids 64:219-37 (1993)). Alternatively, a beta-lactamase inhibitor can be modified to include specific transit peptides or fused to such transit peptides which are capable of delivering their beta-lactamase inhibitor into a cell. In addition, the beta-lactamase inhibitor can be delivered directly into a cell by microinjection.
The compositions are usually employed in the form of pharmaceutical preparations. Such preparations are made in a manner well known in the pharmaceutical art. One preferred preparation utilizes a vehicle of physiological saline solution, but it is contemplated that other pharmaceutically acceptable carriers such as physiological concentrations of other non-toxic salts, five percent aqueous glucose solution, sterile water, or the like may also be used. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any standard media or agent is incompatible with the active compound, use thereof in the therapeutic compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions. It may also be desirable that a suitable buffer be present in the composition. Such solutions can, if desired, be lyophilized and stored in a sterile ampoule ready for reconstitution by the addition of sterile water for ready injection. The primary solvent can be aqueous or alternatively non-aqueous. A beta-lactamase inhibitor can also be incorporated into a solid or semi-solid biologically compatible matrix which can be implanted into tissues. The carrier can contain other pharmaceutically-acceptable excipients for modifying or maintaining the pH, osmolarity, viscosity, clarity, color, sterility, stability, rate of dissolution, or odor of the formulation. Such excipients are those substances usually and customarily employed to formulate dosages for parenteral administration in either unit dosage or multi-dose form or for direct infusion by continuous or periodic infusion.
In some embodiments, the pharmaceutical compositions further comprise an effective amount of a beta-lactam antibiotic. Exemplary β-lactam antibiotics include penicillins, cephalosporins, carbapenems, monobactams, bridged monobactams, or a combination thereof. Pencillins include, but are not limited to, benzathine penicillin, benzylpenicillin, phenoxymethylpenicillin, procaine penicillin, oxacillin, methicillin, dicloxacillin, flucloxacillin, temocillin, amoxicillin, ampicillin, co-amoxiclav, azlocillin, carbenicillin, ticarcillin, mezlocillin, piperacillin, apalcillin, hetacillin, bacampicillin, sulbenicillin, mecicilam, pevmecillinam, ciclacillin, talapicillin, aspoxicillin, cloxacillin, nafcillin, pivampicillin, or a
combination thereof. Cephalosporins include, but are not limited to, cephalothin, cephaloridin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin, cephacetril, cefotiam, cefotaxime, cefsulodin, cefoperazone, ceftizoxime, cefinenoxime, cefinetazole, cephaloglycin, cefonicid, cefodizime, cefpirome, ceftazidime, ceftriaxone, cefpiramide, cefbuperazone, cefozopran, cefepim, cefoselis, cefluprenam, cefuzonam, cefpimizole, cefclidin, cefixime, ceftibuten, cefdinir, cefpodoxime axetil, cefpodoxime proxetil, cefteram pivoxil, cefetamet pivoxil, cefcapene pivoxil, cefditoren pivoxil, cefuroxime, cefuroxime axetil, loracarbacef, latamoxef, anti-methicillin-resistant Staphylococcus aureus (MRSA) cephalosporins (e.g., ceftobiprole or ceftaroline), or a combination thereof. Carbapenems include, but are not limited to, imipenem, meropenem, ertapenem, faropenem, doripenem, biapenem, panipenem, anti-MRSA carbapenems (e.g., PZ-601 or ME1036, see Expert Rev. Anti-lnfect. Ther. (2008) 6:39-49), or a combination thereof. Monobactams include, but are not limited to, aztreonam, carumonam, BAL30072 (Basilea
Poster F1-1173, Ann. lnterscience Conf. Antimicrob. Agents Chemother. (2008)), or a combination thereof. See Figure 4 for structures of PZ-601 , ME1036, and BAL30072.
The beta-lactamase inhibitors or their pharmaceutically acceptable salts may be administered at the same time as the dose of beta-lactam antibiotics or separately. This may be carried out in the form of a mixture of the two active ingredients or in the form of a pharmaceutical combination of the two separate active ingredients.
The dosage of the beta-lactamase inhibitors and of their pharmaceutically acceptable salts may vary within wide limits and should naturally be adjusted, in each particular case, to the individual conditions and to the pathogenic agent to be controlled. In general, for a use in the treatment of bacterial infections, the daily dose may be between 0.250 g and 10 g per day, by the oral route in humans, or else between 0.25 g and 10 g per day by the intramuscular or intravenous route. Moreover, the ratio of the beta-lactamase inhibitor or of the pharmaceutically acceptable salt thereof to the beta-lactam antibiotic may also vary within wide limits and should be adjusted, in each particular case, to the individual conditions. In general, a ratio ranging from about 1 :20 to about 1 :1 is recommended.
Dose administration can be repeated depending upon the pharmacokinetic parameters of the dosage formulation and the route of administration used.
It is also provided that certain formulations containing a beta-lactamase inhibitor are to be administered orally. Such formulations are preferably encapsulated and formulated with suitable carriers in solid dosage forms. Some examples of suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, gelatin, syrup, methyl cellulose, methyl- and propylhydroxybenzoates, talc, magnesium, stearate, water, mineral oil, and the like. The formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents. The compositions may be formulated so as to provide rapid, sustained, or delayed release of the active ingredients after administration to the patient by employing procedures well known in the art. The formulations can also contain substances that diminish proteolytic degradation and/or substances which promote absorption such as, for example, surface active agents.
It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals. The specific dose can be readily calculated by one of ordinary skill in the art, e.g., according to the approximate body weight or body surface area of the patient or the volume of body space to be occupied. The dose will also be calculated dependent upon the particular route of administration selected. Further refinement of the calculations necessary to determine the appropriate dosage for treatment is routinely made by those of ordinary skill in the art. Such
calculations can be made without undue experimentation by one skilled in the art in light of the activity disclosed herein in assay preparations of target cells. Exact dosages are determined in conjunction with standard dose-response studies. It will be understood that the amount of the composition actually administered will be determined by a practitioner, in the light of the relevant circumstances including the condition or conditions to be treated; the choice of composition to be administered; the age, weight, and response of the individual patient; the severity of the patient's symptoms; and the chosen route of administration.
Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Compounds which exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the methods disclosed herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.
Inhibition of Bacterial Growth
The present disclosure also provides methods for inhibiting bacterial growth, by e.g. reducing bacterial resistance to a β-lactam antibiotic, such methods comprising contacting a bacterial cell culture, or a bacterially infected cell culture, tissue, or organism, with a beta-lactamase inhibitor described herein. Preferably, the bacteria to be inhibited by administration of a beta-lactamase inhibitor of the invention are bacteria that are resistant to beta-lactam antibiotics. More preferably, the bacteria to be inhibited are beta-lactamase positive strains that are highly resistant to beta-lactam antibiotics. The terms "resistant" and "highly resistant" are well-understood by those of ordinary skill in the art (see, e.g., Payne et al., Antimicrobial Agents and Chemotherapy 38:767-772 (1994); Hanaki et al., Antimicrobial Agents and Chemotherapy 30:1120-1126 (1995)). Preferably, highly resistant bacterial strains are those against which the MIC of methicillin is >100 μg/mL. Preferably, slightly resistant bacterial strains are those against which the MIC of methicillin is >25 μg/mL.
These methods are useful for inhibiting bacterial growth in a variety of contexts. In certain preferred embodiments, the compound of the invention is administered to an experimental cell culture in vitro to prevent the growth of beta- lactam resistant bacteria. In certain other preferred embodiments the compound of the invention is administered to a mammal, including a human, to prevent the growth of beta-lactam resistant bacteria in vivo. The method according to this embodiment of the invention comprises administering a therapeutically effective amount of a beta-lactamase inhibitor for a therapeutically effective period of time to a mammal, including a human. Preferably, the beta-lactamase inhibitor is administered in the form of a pharmaceutical composition as described supra. In some embodiments, a beta-lactam antibiotic is co-administered with the beta- lactamase inhibitor as described supra.
Assays for the inhibition of beta-lactamase activity are well known in the art. For instance, the ability of a compound to inhibit beta-lactamase activity in a standard enzyme inhibition assay may be used (see, e.g., Page, Biochem J. 295:295-304 (1993)). Beta-lactamases for use in such assays may be purified from bacterial sources or, preferably, are produced by recombinant DNA techniques, since genes and cDNA clones coding for many beta-lactamases are known (see, e.g., Cartwright & Waley, Biochem J. 221 :505-12 (1984)).
Alternatively, the sensitivity of bacteria known, or engineered, to produce a beta- lactamase to an inhibitor may be determined. Other bacterial inhibition assays include agar disk diffusion and agar dilution (see, e.g., Traub & Leonhard, Chemotherapy 43:159-67 (1997)). Thus, a beta-lactamase can be inhibited by contacting the beta-lactamase enzyme with an effective amount of an inventive compound or by contacting bacteria that produce the beta-lactamase enzymes with an effective amount of such a compound so that the beta-lactamase in the bacteria is contacted with the inhibitor. The contacting may take place in vitro or in vivo. "Contacting" means that the beta-lactamase and the inhibitor are brought together so that the inhibitor can bind to the beta-lactamase. Amounts of a compound effective to inhibit a beta-lactamase may be determined empirically, and making such determinations is within the skill in the art. Inhibition includes both reduction and elimination of beta-lactamase activity.
Examples
The disclosure herein is further defined in the following Examples. It should be understood that these Examples, while indicating preferred embodiments, are given by way of illustration only. From the above discussion and these Examples, one skilled in the art can ascertain the preferred features, and without departing from the spirit and scope thereof, can make various changes and modifications to adapt it to various uses and conditions.
Example 1
(1 R)-1 -(2-thiophene-2-yl-acetylamino)-2-(2-hvdroxy-3-carboxyphenyl)ethyl-1 - boronic acid
Step 1. Synthesis of 2-Methoxy-3-(2,9,9-Trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02>6]dec-4-yl)-benzoic acid. A solution of (+)-pinanediol (17.4 g, 102.0 mmole) and 3-borono-2-methoxybenzoic acid (20.0 g, 102.4 mmole) in tetrahydrofuran (THF, 140 ml_) was stirred for 15 h at ambient temperature. The solution was concentrated in vacuo, and the residue was washed with hexanes to afford 29.6 g (88%) of the product as a slowly crystallizing white solid. ESI-MS m/z 331 (MH) +.
Step 2. Synthesis of 2-Methoxy-3-(2,9,9-Trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02>6]dec-4-yl)-benzoic acid isopropyl ester. A solution of 2-
methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.026]dec-4-yl)-benzoic acid (22.3g, 67.6 mmole), 2-iodopropane (13.5 ml_, 13.5 mmole) and potassium carbonate (18.7 g, 13.5 mmole) in N,N-dimethylformamide (DMF, 337 ml_) was stirred at ambient temperature for 18 h. The reaction was quenched with water and extracted twice with ethyl acetate (EtOAc). The combined organic layers were washed with water, brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on SiO2 using a gradient of 40% dichloromethane (DCM)/hexane to 90% DCM/hexane to afford 20.3 g (81%) of product as a white solid. Electrospray ionization-mass spectrum (ESI-MS) m/z 373 (MH)+. Step 3. Synthesis of 2-Methoxy-3-(2,9,9-Trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02>6]dec-4-ylmethyl)-benzoic acid isopropyl ester. To a solution of 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.026]dec-4-yl)- benzoic acid isopropyl ester (10.6 g, 28.49 mmole) and chloroiodomethane (2.6 ml_, 35.61 mmole) in THF (84 ml_) at -1000C was added n-butyllithium (n-BuLi, 2.5 M in hexanes, 14.2 ml_, 35.50 mmole) over 6 minutes. The solution was stirred at -1000C for 45 min. The reaction was allowed to warm up gradually while stirring overnight. The reaction was quenched with water and extracted twice with ethyl acetate. The combined organic layers were washed with water, brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on SiO2 using a gradient of 40% DCM/hexane to 70%
DCM/hexane to afford 15.1 g (71%) of product as a colorless oil. ESI-MS m/z 387 (MH)+.
Step 4. Synthesis of (1R)-2-Methoxy-3-[2-(2-Thiophen-2-yl- acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02>6]dec-4-yl)- ethyl]-benzoic acid isopropyl ester. To a solution of anhydrous dichloromethane (2.2 ml_, 34.5 mmole) in THF (77 ml_) at -100°C was added n- BuLi (2.5M in hexanes, 10.4 mL, 25.8 mmole) over 15 min. The solution was stirred for 30 min at -1000C at which point the microcrystalline LiCHCI2 precipitate was visible. A solution of 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02i6]dec-4-ylmethyl)-benzoic acid isopropyl ester (8.31 g, 21.5 mmole) in THF (16 mL) was added over 5 min by syringe. The mixture was stirred at -1000C for 15 min, then warmed to 00C and held for 2 h. The solution was then cooled to -78°C and a solution of lithium bis(trimethylsilyl)amide (LHMDS, 1.0 M in THF, 25.8 mL, 25.8 mmole) was added over 5 min. The
reaction was allowed to warm gradually while stirring overnight. The mixture was then cooled to -100C and anhydrous methanol (1.04 mL, 25.8 mmole) was added. This stirred for 45 min, then the bath was removed and the solution stirred at ambient temperature for 1.25 h. After cooling to -78°C, 2- thiopheneacetyl chloride (3.45 mL, 27.9 mmole) was added and the solution stirred at -78°C for 1.5 h. Then, the cooling bath was removed and the solution stirred at ambient temperature for 1.5 h. The reaction was quenched with water and extracted twice with EtOAc. The organic layers were combined, washed with water, brine, dried (MgSO4) and concentrated in vacuo to afford a pale yellow solid as crude product. The residue was chromatographed on SiO2 using a gradient of 15% EtOAc/hexanes to 35% EtOAc/hexanes to afford 2.17 g (20%) of product as a white solid. ESI-MS m/z 540 (MH)+.
Step 5. Synthesis of (1R)-1-(2-thiophene-2-yl-acetylamino)-2-(2- hydroxy-3-carboxyphenyl)ethyl-1-boronic acid. To a solution of (1 R)-2- Methoxy-3-[2-(2-Thiophen-2-yl-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo- [6.1.1.026]dec-4-yl)-ethyl]-benzoic acid isopropyl ester, (1.16 g, 21.48 mmole) in 1 ,4-dioxane (22 mL) was added 22 mL of 3N HCI. The mixture was heated to 1100C and held for 90 min. The solution was cooled and diluted with 20 mL H2O and extracted twice with diethyl ether (Et2O). The aqueous layer was concentrated to afford a sticky residue as crude product. The residue was triturated with 5 mL H2O to induce crystallization. The solids were washed twice with water and once with diethyl ether and dried in vacuo to afford 250 mg (33%) of the product as white powder. ESI-MS m/z 332 (MH-H2O)+.
Example 2
(1 R)-1-(2-thiophene-2-yl-acetylamino)-2-(2-hvdroxy-4-carboxyphenyl)ethyl-1- boronic acid
Step 1, Synthesis of 4-Methoxy-3-(2,9,9-Trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1. 02>6]dec-4-yl)-benzoic acid. A solution of (+)-pinanediol (8.7, 51.0 mmole) and 3-borono-4-methoxybenzoic acid (10.0 g, 51.2 mmole) in THF (70 mL) was stirred for 30 min at room temperature. The solution was concentrated in vacuo, and the residue was washed with hexanes to afford 15.1 g (89%) of the product as a slowly crystallizing white solid. ESI-MS m/z 331 (MH)+.
Step 2, Synthesis of 4-Methoxy-3-(2,9,9-Trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1. 02>6]dec-4-yl)-benzoic acid isopropyl ester. A solution of 4- methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02'6]dec-4-yl)-benzoic acid (15.Og, 45.4 mmole), 2-iodopropane (9.1 ml_, d=1.7, 90.7 mmole) and potassium carbonate (12.6 g, 90.7 mmole) in DMF (220 ml_) was stirred at ambient temperature for 18 h. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with water, brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on Siθ2 using a gradient of 40% DCM/hexane to 90% DCM/hexane to afford 13.5 g (80%) of product as a white solid. ESI-MS m/z 373
Step 3. Synthesis of 4-Methoxy-3-(2,9,9-Trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1. 02 β]dec-4-ylmethyl)-benzoic acid isopropyl ester. To a solution of 4-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02 f3]dec-4- yl)-benzoic acid isopropyl ester (10.6, 28.49 mmole) and chloroiodomethane (2.6 ml_, 35.61 mmole) in THF (84 ml_) at -1000C was added n-BuLi (2.5M in hexanes, 14.2 ml_, 35.61 mmole) over 6 minutes. The solution was stirred at -1000C for 45 min, then the bath was removed and the solution stirred at ambient temperature for 15 h. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on SiO2 using a gradient of 40% DCM/hexane to 70% DCM/hexane to afford 14.2 g (66%) of product as a colorless oil which contained 50% of the starting 4-methoxy-3- (2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02i6]dec-4-yl)-benzoic acid isopropyl ester. ESI-MS m/z 387 (MH)+.
Step 4. Synthesis of (1R)-4-Methoxy-3-[2-(2-Thiophen-2-yl- acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1. 02l6]dec-4-yl)- ethyl]-benzoic acid isopropyl ester. To a solution of anhydrous dichloromethane (2.2 mL, 34.5 mmole) in THF (77 ml_) at -1000C was added n- BuLi (2.5M in hexanes, 10.4 mL, 25.8 mmole) over 15 min. The solution was stirred for 30 in at -1000C at which point the microcrystalline LiCHCI2 precipitate was visible. A solution of 4-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02 6]dec-4-ylmethyl)-benzoic acid isopropyl ester (8.31 g, 21.5 mmole) in THF (16 mL) was added over 5 min by syringe. The mixture was
stirred at -1000C for 15 min, then warmed to 00C and held for 1 h. The solution was then cooled to -78°C and a solution of LHMDS (1.0 M in THF, 25.8 ml_, 25.8 mmole) was added over 5 min. The reaction was allowed to warm gradually while stirring overnight. The mixture was then cooled to -100C and anhydrous methanol (1.04 ml_, 25.7 mmole) was added. This stirred for 45 min, then the bath was removed and the solution stirred at ambient temperature for 1.25 h. After cooling to -78°C, 2-thiopheneacetyl chloride (3.45 ml_, 27.9 mmole) was added and the solution stirred at -78°C for 15 min. The cooling bath was removed and the solution stirred at ambient temperature until complete. The reaction was quenched with water and extracted twice with EtOAc. The organic layers were combined, washed with water, brine, dried (MgSO4) and concentrated in vacuo to afford a yellow solid as crude product. The residue was chromatographed on SiO2 using a gradient of 15% EtOAc/hexane to 35% EtOAc/hexane to afford 570 mg (5%) of product as a pale yellow solid. ESI-MS m/z 540 (MH)+.
Step 5. Synthesis of (1R)-1-(2-thiophene-2-yl-acetylamino)-2-(6- hydroxy-3-carboxyphenyl)ethyl-1-boronic acid. To a solution of (1 R)-4- Methoxy-3-[2-(2-Thiophen-2-yl-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02'6]dec-4-yl)-ethyl]-benzoic acid isopropyl ester (150 mg, 0.28 mmole) in DCM (2.5 ml_) was added 2.2 ml_ of 1 M BBr3 at -780C. The reaction was allowed to warm gradually while stirring for 18 h. The reaction was quenched with 10 ml_ of H2O. The solution was extracted twice with Et2O. The aqueous layer was concentrated to afford a sticky residue as crude product. It was further purified by preparative HPLC to afford 8 mg (8 %) of the product as an off-white powder. ESI-MS m/z 332 (MH-H2O)+.
Example 3 (1 f?)-1 -(3-hvdroxy-phenyl)acetylamino-1 -(3-carboxy-2-hvdroxy)benzyl-methyl boronic acid Step 1. Synthesis of 3-Borono-2-methoxybenzoic acid tert-butyl ester. To a solution of 3-borono-2-methoxybenzoic acid (Combi-blocks, 5.0 g, 25.5 mmole) in 1 ,4-dioxane (30 mL) in a sealed tube was added cone. H2SO4 (1.5 mL). The solution was cooled to 00C and an equal volume of 2- methylpropene was bubbled in. The tube was sealed and allowed to stir at
ambient temperature for 18 h. The solution was cooled in an ice bath, the seal was opened and the solution stirred at ambient temperature for 30 min. The solution was basified with saturated aq. NaHCO3 and extracted twice with EtOAc. The combined organic layers were washed with water (5x), brine, dried (Na2SO4) and concentrated in vacuo to afford 4.0 g (62%) of the product as a white solid. ESI-MS m/z 275 (M+Na)+.
Step 2. Synthesis of 2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02l6]dec-4-yl)-benzoic acid tert-butyl ester. A solution of 3- Borono-2-methoxybenzoic acid tert-butyl ester (4.0 g, 15.9 mmole), THF (21 mL), and (+)-pinanediol (2.70 g, 15.9 mmole) was stirred at room temperature for 1 h. The solution was concentrated in vacuo, and the residue chromatographed on SiO2 with 6% EtOAc/hexane to afford 5.0 g (86%) of the product as a slowly crystallizing solid. ESI-MS m/z 409 (M+Na)+.
Step 3. Synthesis of 2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo [6.1.1.02>6]dec-4-ylmethyl)-benzoic acid tert-butyl ester. A solution of 2-Methoxy-3-(2,9,9-trimethyl-3)5-dioxa-4-bora-tricyclo[6.1.1.026]dec-4-yl)-benzoic acid tert-butyl ester (8.5 g, 22 mmol) and chloroiodomethane (4.6 g, 26.4 mmol) in THF (65 mL) under argon was cooled to -100°C [MeOH, liq. N2 slush bath], n- BuLi (10.56 mL, 2.5M in hexane, 26.4 mmol) was added dropwise over a period of 10 minutes and the mixture stirred overnight. The reaction was quenched with H2O (100 mL) and the aqueous phase was extracted with EtOAc (3 x 75 mL), the combined organic layers were dried over MgSO4, and concentrated in vacuo. Purification by flash column chromatography on silica gel [Rf = 0.21 , (DCM/Hexane, 70:30, v/v)] afforded 8 g of the resultant compound as a colorless oil in 91% yield. ESI-MS m/z 401 (MH)+.
Step 4. Synthesis of (3-Benzyloxy-phenyl)-acetic acid benzyl ester. A mixture of 3-hydroxyphenylacetic acid (14.65 g, 96 mmole), benzyl bromide (27.4 mL, 231 mmole), potassium carbonate (39.9 g, 289 mmole) and dimethylformamide (DMF, 240 mL) was stirred at ambient temperature for 3 days. The reaction mixture was diluted with 1 N NaOH and extracted twice with 50% EtOAC/hexanes. The combined organic layers were washed twice with 1 N NaOH, water, brine, dried (Na2SO4) and concentrated in vacuo to afford 28.2 g (92%) of the product as a colorless oil which was used without further purification. ESI-MS m/z 319 (MH)+.
Step 5. Synthesis of 3-Benzyloxyphenylacetic acid. A solution of (3- benzyloxy-phenyl)-acetic acid benzyl ester (9.0 g, 27.1 mmole), 1 N NaOH (84 ml_, 84 mmole) and methanol (84 mL) was heated to 500C and stirred overnight. Water was added and the mixture extracted twice with Et2O. The aqueous layer was acidified to pH 1 with concentrated HCI. The precipitated solids were collected by filtration, washed with water and dried to afford 5.34 g (79%) of the product as a white solid. ESI-MS m/z 243 (MH)+.
Step 6. Synthesis of 3-Benzyloxyphenylacetyl chloride. A solution of 3-benzyloxyphenylacetic acid (2.75 g, 11.4 mmole) in thionyl chloride (8.5 mL) was refluxed for 45 minutes, and the excess thionyl chloride was removed by distillation at atmospheric pressure and then the residual thionyl chloride was removed by adding chloroform three times and concentrating in vacuo each time.
Step 7. Synthesis of 3-[2-[2-(3-Benzyloxy-phenyl)-acetylamino]-2- (2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02>6]dec-4-yl)-ethyl]-2- methoxy-benzoic acid tert -butyl ester. To anhydrous CH2CI2 (1.25 mL, 19.49 mmol) in anhydrous THF (55 mL) under argon at -1000C [MeOH, Nq. N2 slush bath], n-BuLi (7.2 mL, 2.5M in hexane, 17.99 mmol) was added dropwise and the mixture was stirred for 30 minutes. A THF (10 mL) solution of 2-Methoxy-3- (2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02'6]dec-4-ylmethyl)-benzoic acid tert-butyl ester (6.0 g, 14.99 mmol) was added over a period of 20 minutes. After 40 minutes the cooling bath was removed and the mixture warmed slowly to 00C. After 2 hours the reaction flask was cooled to -78°C, LHMDS (16.5 mL, 1 M in THF, 16.5 mmol) was added slowly and the resultant solution was warmed to room temperature gradually while stirring overnight. Anhydrous MeOH (0.66 mL, 16.49 mmol) was added at -100C, the reaction stirred for 1 h at the same temperature and then for 1 h at room temperature. 3-Benzyloxyphenylacetyl chloride (6.4 g, 24 mmol) was added at -78°C and the mixture stirred for 40 minutes and allowed to reach room temperature. After 2.5 h the reaction was quenched with H2O (75 mL) and the aqueous phase was extracted with EtOAc (3 x 75 mL), the combined organic layers were dried over MgSO4, and concentrated in vacuo. Purification by flash column chromatography on silica gel [Rf = 0.45, (EtOAc/Hexane, 40:60, v/v)] afforded 3.3 g of the resultant compound as pale yellow solid in 33% yield. ESI-MS m/z 654 (MH)+.
Step 8. Synthesis of (1R)-1-(3-hydroxy-phenyl)acetylamino-1-(3- carboxy-2-hydroxy) benzyl-methyl boronic acid. To a solution of 3-[2-[2-(3- Benzyloxy-phenyl)-acetylamino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02 6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester (250 mg, 0.38 mmol) in dioxane (4 ml_), 6N HCI (4 ml_) was added dropwise at 110°C. Reaction progress was monitored by LC/MS for the disappearance of starting material. After 6 h H2O (25 ml_) was added and the mixture extracted with Et2O (3 x 20 ml_). The aqueous solution was concentrated in vacuo and purified by preparative HPLC to give 80 mg of resultant compound as a white solid in 58% yield. ESI-MS m/z 342 (MH-H2O)+.
Example 4
(1f?)-1-[3-(2-amino)-ethoxy-phenyllacetylamino- 1-(3-carboxy -2-hvdroxy) benzyl- methylboronic acid hydrochloride Step 1. Synthesis of 3-[2-[2-(3-Hydroxy-phenyl)-acetylamino]-2-(2,9,9- trimethyl-S.δ-dioxa^-bora-tricyclotβ.i.i.O^dec^-ylJ-ethyll^-methoxy- benzoic acid tert-butyl ester. To a solution of 3-[2-[2-(3-Benzyloxy-phenyl)- acetylamino]-2-(2)9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02 6]dec-4-yl)-ethyl]- 2-methoxy-benzoic acid tert-butyl ester (1.24 g, 1.9 mmol) in MeOH (17 ml_), Pd(OH)2 (380 mg) was added and the mixture stirred under H2 (45 psi) atmosphere for 5 h. The reaction mixture was filtered through CELITE® (diatomaceous earth) and concentrated in vacuo. Purification by flash column chromatography on silica gel [Rf = 0.35, (EtOAc/Hexane, 40:60, v/v)] afforded 0.6 g of the resultant phenol as a colorless oil in 57% yield. ESI-MS m/z 564 (MH)+. Step 2. Synthesis of 3-[2-{2-[3-(2-tert-Butoxycarbonylamino-ethoxy)- phenyl]-acetyl amino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02>6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester. To a solution of 3-[2-[2-(3-Hydroxy-phenyl)-acetylamino]-2-(2,9,9-trimethyl-3,5- dioxa-4-bora-tricyclo[6.1.1.02 6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester (280 mg, 0.5 mmol) in methylene chloride (5 ml_) under argon was added triphenylphosphine (328 mg, 1.25 mmol) and N-boc-ethanolamine (0.19 ml_, 1.25 mmol) and the mixture cooled to 0°C. Diisopropylazodicarbozylate (DIAD, 253 mg, 1.25 mmol) was added dropwise and the mixture stirred for 1 h. The ice bath was removed and the reaction stirred for another 4 h at room temperature. The
reaction was quenched with H2O (10 ml_) and the aqueous phase was extracted with EtOAc (3 x 25 ml_), the combined organic layers were dried over MgSO4, and concentrated in vacuo. Purification by flash column chromatography on silica gel [Rf = 0.25, (EtOAc/Hexane, 40:60, v/v)] afforded 180 mg of the resultant compound as colorless oil in 51% yield. ESI-MS m/z 708 (MH)+.
Step 3. Synthesis of (1/?)-1-[3-(2-amino)-ethoxy-phenyl]acetylamino- 1-(3-carboxy -2-hydroxy) benzyl-methylboronic acid hydrochloride. To a solution of 3-[2-{2-[3-(2-tert-Butoxycarbonylamino-ethoxy)-phenyl]-acetyl amino}- 2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.026]dec-4-yl)-ethyl]-2-methoxy- benzoic acid tert-butyl ester (180 mg, 0.25 mmol) in dioxane (3 ml_), 3N HCI (3 ml_) was added dropwise at 1100C. Reaction progress was monitored by LC/MS for the disappearance of starting material. After 1 h, H2O (20 ml_) was added and the mixture extracted with Et2O (3 x 20 ml_). The aqueous solution was concentrated in vacuo and purified by preparative HPLC to give 15 mg of resultant compound as a white solid in 15% yield. ESI-MS m/z 385 (MH-H2O)+.
Example 5
(1R)-1-(4-Oxo-4-thiophen-2-yl-butyrylamino)-2-(2-hvdroxy-3-carboxyphenyl)ethyl-
1-boronic acid Step 1. Preparation of carbonic acid isobutyl ester 4-Oxo-4-thiophen-
2-yl-butyryl ester. To a solution of 4-oxo-4-(thiophen-2-yl)butanoic acid (2.57 g, 13.95 mmole) and 4-methylmorpholine (NMM, 1.7 ml_, 15.4 mmole) in 14 ml_ of DCM at O0C was added isobutylchloroformate (1.8 ml_, 13.95 mmole). The mixture was stirred for 45 min at 00C to complete the preparation of the mixed anhydride.
Step 2. Synthesis of (1R)-2-Methoxy-3-[2-(4-Oxo-4-thiophen-2-yl- butyrylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1. 02>6]dec-4- yl)-ethyl]-benzoic acid tert-butyl ester. To a solution of anhydrous dichloromethane (0.70 ml_, 10.9 mmole) in THF (17 ml_) at -1000C was added n- BuLi (2.5M in hexanes, 3.4 mL, 8.4 mmole) over 15 min. The solution was stirred for 30 min at -1000C at which point the microcrystalline LiCHCI2 precipitate was visible. A solution of 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02'6]dec-4-ylmethyl)-benzoic acid tert-butyl ester (2.8 g, 7.0 mmole) in THF (6 mL) was added over 5 min by syringe. The mixture was stirred at -
100°C for 15 min, then warmed to 00C and held for 2 h. The solution was then cooled to -78°C and a solution of LHMDS (1.0 M in THF, 8.4 mL, 8.4 mmole) was added over 5 min. The reaction was allowed to warm gradually while stirring overnight. The mixture was then cooled to -100C and anhydrous methanol (0.33 mL, 8.4 mmole) was added. This stirred for 45 min, then the bath was removed and the solution stirred at ambient temperature for 1.25 h. After cooling to -78°C, the 0.5M carbonic acid isobutyl ester 4-Oxo-4-thiophen-2-yl-butyryl solution from Step 1 was added and the solution stirred at -78°C for 15 min. The cooling bath was removed and the solution stirred at ambient temperature until completion. The reaction was quenched with water and extracted twice with EtOAc. The organic layers were combined, washed with water, brine, dried (MgSO4) and concentrated in vacuo to afford a yellow solid as crude product. The residue was chromatographed on Siθ2 using a gradient of 25% EtOAc/hexanes to 40% EtOAc/hexanes to afford 514 mg (12%) of product as white solid. ESI-MS m/z 596 (MH)+.
Step 3. Synthesis of (1R)-1-(4-Oxo-4-thiophen-2-yl-butyrylamino)-2-(2- hydroxy-3-carboxyphenyl)ethyl-1-boronic acid. To a solution of (1 R)-2- Methoxy-3-[2-(4-Oxo-4-thiophen-2-yl-butyrylamino)-2-(2,9,9-trimethyl-3,5-dioxa- 4-bora-tricyclo[6.1.1.02i6]dec-4-yl)-ethyl]-benzoic acid tert-butyl ester, (510 mg, 0.85 mmole) in 1 ,4-dioxane (9 mL) was added 9 mL of 3N HCI. The mixture was heated to 1100C and held for 90 min. The solution was cooled and diluted with 15 mL of H2O, and extracted twice with Et2O. The aqueous layer was concentrated to afford a sticky residue as crude product. The residue was triturated with 5 mL H2O to induce crystallization. The solids were washed twice with water and once with Et2O and then dried in vacuo to afford 120 mg (35%) of the product as a white powder. ESI-MS m/z 374 (MH-H2O)+.
Example 6
(1 R)-1 -(2-acetylamino)-2-(2-hvdroxy-3-carboxyphenyl)ethyl-1 -boronic acid Step 1. Synthesis of (1 R)-2-Methoxy-3-[2-(2-acetylamino)-2-(2,9,9- trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1. 02>6]dec-4-yl)-ethyl]-benzoic acid tert butyl ester. To a solution of anhydrous dichloromethane (0.64 mL, 8.6 mmole) in THF (19 mL) at -100°C was added n-BuLi (2.5M in hexanes, 2.7 mL, 6.3 mmole) over 15 min. The solution was stirred for 30 min at -1000C at which
point the microcrystalline LiCHCI2 precipitate was visible. A solution of 2- methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.O2 e3]dec-4-ylmethyl)- benzoic acid tert-butyl ester (2.1 g, 5.25 mmole) in THF (4 ml_) was added over 5 min by syringe. The mixture was stirred at -1000C for 15 min, then warmed to 00C and held for 2 h. The solution was then cooled to -78°C and a solution of LHMDS (1.0 M in THF, 5.3 mL, 5.3 mmole) was added over 5 min. The reaction was allowed to warm gradually while stirring overnight. The mixture was then cooled to -100C and anhydrous methanol (0.26 mL, 5.3 mmole) was added. This stirred for 45 min, then the bath was removed and the solution stirred at ambient temperature for 1.25 h. After cooling to -78°C, acetyl chloride (0.78 mL, 9.6 mmole) was added and the solution stirred at -78°C for 1.5 h. Then, the cooling bath was removed and the solution stirred at ambient temperature for 1.5 h. The reaction was quenched with water and extracted twice with EtOAc. The organic layers were combined, washed with water, brine, dried (MgSO4) and concentrated in vacuo to afford a pale yellow solid as crude product. The residue was chromatographed on SiO2 using a gradient of 40% EtOAc/hexanes to 60% EtOAc/hexanes to afford 562 mg (23%) of product as a white solid. ESI-MS m/z 472 (MH)+.
Step 2. Synthesis of (1R)-1-(2-acetylamino)-2-(2-hydroxy-3- carboxyphenyl)ethyl-1-boronic acid. To a solution of (1 R)-2-Methoxy-3-[2-(2- hydrogenacetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-thcyclo[6.1.1.02|6]dec- 4-yl)-ethyl]-benzoic acid tert butyl ester, (370 mg, 0.78 mmole) in 1 ,4-dioxane (8 mL) was added 8 mL of 3N HCI. The mixture was heated to 110°C and held for 90 min. The solution was cooled and diluted by 8 mL H2O and extracted twice with Et2O. The aqueous layer was concentrated to afford a sticky residue as crude product. The residue was further purified by preparative HPLC to afford 105 mg (50 %) of the product as white powder. ESI-MS m/z 250 (MH-H2O)+.
Example 7 (1 f?)-1-r3-(carboxymethoxy)-phenvnacetylamino- (3-carboxy -2-hvdroxy) benzyl- methylboronic acid
Step 1. Synthesis of 3-[2-[2-(3-Carbamoylmethoxy-phenyl)- acetylamino]-2-(2,9,9-trimethyl-3J5-dioxa-4-bora-tricyclo[6.1.1.02'6]dec-4-yl)- ethyl]-2-methoxy-benzoic acid tert-butyl ester. To a solution of 3-[2-[2-(3-
Hydroxy-phenyl)-acetylamino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.026]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester (610 mg, 1.08 mmol), prepared as described in Example 4, in DMF (5 ml_) under argon was added K2CO3 (300 mg, 2.16 mmol). After stirring for 10 minutes, bromoacetamide (300 mg, 2.16 mmol) was added and the mixture stirred for 7 h at room temperature. The reaction was quenched with H2O (20 ml_) the aqueous phase was extracted with EtOAc (3 x 35 ml_), the combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by flash column chromatography on silica gel [Rf = 0.15, (EtOAc/Hexane, 80:20, v/v)] afforded 309 mg of the resultant compound as a colorless oil in 46% yield. ESI-MS m/z 621 (MH)+.
Step 2 Synthesis of (1f?)-1-[3-(carboxymethoxy)-phenyl]acetylamino- (3-carboxy -2-hydroxy) benzyl-methylboronic acid. To a solution of 3-[2-[2-(3- Carbamoylmethoxy-phenyl)-acetylamino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.026]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester (70 mg, 0.11 mmol) in dioxane (3 ml_), 3N HCI (3 ml_) was added dropwise at 110°C. Reaction progress was monitored by LC/MS for the disappearance of starting material. After 1 h H2O (20 ml_) was added and the mixture extracted with Et2O (3 x 20 ml_). The aqueous solution was concentrated in vacuo and purified by preparative HPLC to give 14 mg of resultant compound as a white solid in 29% yield. ESI-MS m/z 400 (MH-H2O)+.
Example 8
(1 R)- 1 -[(3-carbamoylmethoxy)-phenvn-acetylamino- (3-carboxy -2-hvdroxy) benzyl-methylboronic acid
To a solution of 3-[2-[2-(3-Carbamoylmethoxy-phenyl)-acetylamino]-2- (2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo [6.1.1.026]dec-4-yl)-ethyl]-2-methoxy- benzoic acid tert-butyl ester (500 mg, 0.8 mmol) in DCM (9 mL), prepared as described in Example 7, BCI3 (4.8 mL, 1 M solution in DCM) was added dropwise at -78°C. The mixture was stirred for 1.5 h at the same temperature then warmed to room temperature. After 4 h the reaction was quenched with water (70 mL) and the mixture extracted with Et2O (3 x 40 mL). The aqueous solution was concentrated in vacuo and purified by preparative HPLC to give 120 mg of resultant compound as a white solid in 37% yield. ESI-MS m/z 399 (MH-H2O)+.
Example 9 (1 R)-1-(2-(4-bromo-thiophen-2-nyl)acetylamino)-2-(2-hvdroxy-3- carboxyphenyl)ethyl-1 -boronic acid Step 1. Synthesis of [2-(4-Bromo-thiophen-2-yl)-1-dimethylamino- vinyl]-methoxymethyl-phosphinic acid ethyl ester. To a suspension of sodium hydride (852 mg, 60% mineral oil dispersion, 22.2 mmol) in 34 ml_ of THF was added slowly a solution of tetraethyl dimethylaminomethylene diphosphonate (6.92 g, 20.93 mmol) in 34 ml_ of THF. After stirring 1 h, a solution of 4-bromo-2- thiophene carboxaldehyde (4 g, 20.94 mmol) in 34 ml_ of THF was added. The resulting mixture was heated at reflux for 1 h, then cooled to ambient temperature. The reaction mixture was partitioned between diethyl ether and water. The organic layer was washed sequentially with 1 N HCI, water and brine, dried (MgSO4) and concentrated. The crude product was further purified by flash column chromatography on SiO2, eluting with a gradient of 15% EtOAc/hexanes to 25% EtOAc/hexanes to afford the titled compound of 2.4 g (31 %) as a pale yellow solid. ESI-MS m/z 368 (MH)+.
Step 2. Synthesis of (4-Bromo-thiophen-2-yl)-acetic acid. A mixture of [2-(4-Bromo-thiophen-2-yl)-1-dimethylamino-vinyl]-methoxymethyl-phosphinic acid ethyl ester (2.4 g, 6.51 mmol) and 42 ml_ of 6N HCI was heated at reflux for 2 h. After cooling to ambient temperature, ice water was added and the mixture was partitioned between diethyl ether and water. The organic layer was washed with water twice, brine, dried (MgSO4) and concentrated in vacuo to afford 1.30 g (91%) of the title compound. Step 3. Synthesis of (4-Bromo-thiophen-2-yl)-acetyl chloride. A solution of 4-Bromo-thiophen-2-yl)-acetic acid (1.302 g, 5.9 mmole) in thionyl chloride (6 ml_) was refluxed for 1 h. The solution was cooled and concentrated in vacuo to afford the acid chloride as a very sticky hard dark green oil.
Step 4. Synthesis of (1R)-1-(2-(4-bromothiophen-2-yl)acetylamino)-2- (2-hydroxy-3-carboxyphenyl)ethyl-1 -boronic acid. This was prepared as described in Example 6 from 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02,6]dec-4-ylmethyl)-benzoic acid te/f-butyl ester and 2 eq of 4- Bromo-thiophen-2-yl)-acetyl chloride. The final product was further purified by preparative HPLC. ESI-MS m/z 410 (MH-H2O)+.
Example 10 (1 R)-1 -(2-phenylacetylamino)-2-(2-hvdroxy-3-carboxyphenyl)ethyl-1 -boronic acid
Prepared from 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02'6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 1.3 eq of phenylacetyl chloride following the procedure described in Example 6. The final product was purified by preparative HPLC. ESI-MS m/z 326 (MH-H2O)+.
Example 11 (1 R)-1 -(thiophene^-carbonyl-amino^-^-hvdroxy-S-carboxyphenvOethyl-i - boronic acid
Prepared from 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02'6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 1.3 eq of 2- thiophenecarbonyl chloride following the procedure described in Example 6. The final product was purified by preparative HPLC. ESI-MS m/z 318 (MH-H2O)+.
Example 12 (1 R, 2'S)-1 -(2-amino-2-phenylacetylamino)-2-(2-hvdroxy-3-carboxyphenyl)ethyl-
1 -boronic acid formate salt Step 1. Synthesis of (S)-tert-Butoxycarbonylamino-phenyl-acetic acid
[1 ,2,3]triazolo[4,5-b]pyridin-3-yl ester. To a solution of L-Boc-α-phenylglycine (2.51 g, 10 mmole) in 16 mL of DCM at 00C was added N-methylmorpholine (NMM, 1.65 mL, 15 mmole) followed by O-(7-Azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU, 3.81 g, 10 mmole). The solution was stirred for 30 min at 00C and then 30 min at ambient temperature. The solution was used as is for the acylation step.
Step 2. Synthesis of 3-[2-(2-tert-Butoxycarbonylamino-2-phenyl- acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02'6]dec-4-yl)- ethyl]-2-methoxy-benzoic acid tert-butyl ester. To a solution of anhydrous DCM (0.48 mL, 7.5 mmole) in THF (9 mL) at -1000C was added n-BuLi (2.5 M in THF, 2.4 mL, 6.0 mmole) over 15 min. After stirring for 30 min at -1000C, a solution of 3-[2-(2-tert-Butoxycarbonylamino-2-phenyl-acetylamino)-2-(2,9,9- trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.026]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester (2.0 g, 5.0 mmole) in THF (4 mL) was added over 4 min, and
the transfer made quantitative with 2 mL THF. The solution was stirred for 5 min at -1000C and then 30 min at O0C. After cooling to -780C1 LHMDS (1.0 M in THF, 6.0 mL, 6.0 mmole) was added and the solution allowed to warm to room temperature slowly with stirring overnight. After cooling to -10°C, MeOH (0.245 mL, 6.0 mmole) was added and the solution stirred at -100C for 1 h then warmed to room temperature and held for an additional hour. The solution was then cooled to -100C and the solution of (S)-tert-Butoxycarbonylamino-phenyl-acetic acid [1 ,2,3]triazolo[4,5-b]pyridin-3-yl ester from Step 1 was added in one portion. The cooling bath was removed and the solution allowed to stir overnight. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with 1 N HCI, water, brine, dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica gel to afford 470 mg (14%) of product as a yellow foam. ESI-MS m/z 663 (MH)+.
Step 3. Synthesis of (1R, 2'S)-1-(2-amino-2-phenylacetylamino)-2-(2- hydroxy-3-carboxyphenyl)ethyl-1-boronic acid formate salt. To a solution of 3-[2-(2-tert-Butoxycarbonylamino-2-phenyl-acetylamino)-2-(2,9,9-trimethyl-3,5- dioxa-4-bora-tricyclo[6.1.1.02 6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester (220 mg, 0.33 mmole) in DCM (1.0 mL) at -78°C was added BCI3 (1 M in DCM, 3.0 mL, 3.0 mmole). The cooling bath was removed and the solution stirred at ambient temperature for 3 h. The reaction, was quenched with water and extracted three times with ether. The aqueous layer was concentrated in vacuo, and the residue purified by preparative HPLC using solvents buffered with 0.1 % formic acid to afford 19.4 mg (16%) of the product as a white solid. ESI- MS m/z 341 (MH-H2O)+.
Example 13 (1f?)-1-Benzoylamino- 1-(3-carboxy-2-hvdroxy)benzyl-methylboronic acid
Step 1 Synthesis of (1A?)-1-benzoylamino-1-(3-ferf-butoxycarbonyl-2- methoxy) benzyl-methylboronate. Prepared from 2-Methoxy-3-(2,9,9-trimethyl- 3,5-dioxa-4-bora-tricyclo[6.1.1.02f6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and benzoyl chloride following the procedure described in Step 7 of Example 3. The crude product was purified by flash column chromatography [Rf = 0.2, silica gel (EtOAc/Hexane, 30:70, v/v)] to give a 30% yield of product. ESI-MS m/z 534 (MH)+.
Step 2. Synthesis of (1R)-1-Benzoylamino- 1-(3-carboxy-2- hydroxy)benzyl-methylboronic acid. To a solution of 3-[2-Benzoylamino-2- (2,9, 9-trimethyl-3 , 5-d ioxa-4-bora-tricyclo[6.1.1.02i6]dec-4-yl)-ethyl]-2-methoxy- benzoic acid tert-butyl ester (330 mg, 0.62 mmol) in dioxane (6 ml_), 3N HCI (6 ml_) was added dropwise at 110°C. After 1 h H2O (40 ml_) was added and the mixture extracted with Et2O (3 x 30 ml_). The aqueous solution was concentrated in vacuo and purified by preparative HPLC to give 20 mg of resultant compound as a white solid in 10% yield. ESI-MS m/z 312 (MH-H2O)+.
Example 14
(1f?)-1-lsobutyrylamino-1-(3-carboxy-2-hydroxy)benzyl-methylboronic acid
Step 1 Synthesis of 3-[2-lsobutyrylamino-2-(2,9,9-trimethyl-3,5-dioxa- 4-bora-tricyclo [6.1.1.02l6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester. Prepared from 2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02'6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and isobutyryl chloride following the procedure described in Step 7 of Example 3. The crude product was purified by flash column chromatography [Rf = 0.25, silica gel (EtOAc/Hexane, 40:60, v/v)] to afford a 21 % yield of product. ESI-MS m/z 500 (MH)+. Step 2. Synthesis of (1ft)-1-lsobutyrylamino- 1-(3-carboxy -2- hydroxy)benzyl-methylboronic acid. To a solution of 3-[2-lsobutyrylamino-2- (2,9,9-trimethyl-3,5-dioxa-4-bora-thcyclo [6.1.1.02 6]dec-4-yl)-ethyl]-2-methoxy- benzoic acid tert-butyl ester (225 mg, 0.45 mmol) in dioxane (5 ml_), 3N HCI (5 ml_) was added dropwise at 110°C. After 1 h H2O (40 ml_) was added and the mixture extracted with Et2O (3 x 30 ml_). The aqueous solution was concentrated in vacuo and purified by preparative HPLC to give 60 mg of resultant compound as a white solid in 48% yield. ESI-MS m/z 278 (MH-H2O)+.
Example 15 (1 R)-1-Cvclopentanecarbonylamino-(3-carboxy-2-hvdroxy)benzyl-methylboronic acid
Step 1. Synthesis of 3-[2-(Cyclopentanecarbonyl-amino)-2-(2,9,9- trimethyl-S.δ-dioxa^-bora-tricycloβ.i.i.O^dec^-ylJ-ethyll^-methoxy- benzoic acid tert-butyl ester. Prepared from 2-Methoxy-3-(2,9,9-trimethyl-3,5-
dioxa-4-bora-tricyclo[6.1.1.02 6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and cyclopentanecarbonyl chloride following the procedure described in Step 7 of Example 3. The crude product was purified by flash column chromatography [Rf = 0.15, silica gel (EtOAc/Hexane, 30:70, v/v)] to afford the product in 25% yield. ESI-MS m/z 526 (MH)+.
Step 2. Synthesis of (1R)-1-Cyclopentanecarbonylamino-(3-carboxy- 2-hydroxy)benzyl-methylboronic acid. To a solution of 3-[2- (Cyclopentanecarbonyl-amino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02'6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester (260 mg, 0.49 mmol) in dioxane (5 mL), 3N HCI (5 ml_) was added dropwise at 1100C. After 1 h H2O (40 mL) was added and the mixture extracted with Et2O (3 x 30 mL). The aqueous solution was concentrated in vacuo and purified by preparative HPLC to give 40 mg of resultant compound as a white solid in 28% yield. ESI-MS m/z 304 (MH-H2O)+.
Example 16 (1 R)-1-(propionylamino)-2-(2-hydroxy-3-carboxyphenyl)ethyl-1-boronic acid
Prepared from 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02'6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 1.3 eq of propionyl bromide following the procedure described in Example 6. The final product was purified by preparative. ESI-MS m/z 264 (MH-H2O)+.
Example 17
(1 R)-1 -(2-(2.5-dimethoxyphenyl)-acetylamino)-2-(2-hvdroxy-3- carboxyphenvQethyl-i-boronic acid
Prepared from 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02'6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 1.3 eq of 2,5- Dimethoxyphenylacetyl chloride following the procedure described in Example 6. ESI-MS m/z 386 (MH-H2O)+.
Example 18 (1 R)-1-(2-(2.5-dihvdroxyphenyl)acetylamino)-2-(2-hvdroxy-3-carboxyphenyl)ethyl-
1-boronic acid
Step 1. Synthesis of (1R)-2-Methoxy-3-[2-[2-(2,5- dimethoxyphenyl)acetylamino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1. 02>6]dec-4-yl)-ethyl]-benzoic acid te/t butyl ester. Prepared from 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02 6]dec-4- ylmethyl)-benzoic acid tert-butyl ester and 1.3 eq of 2,5-Dimethoxyphenylacetyl chloride following the procedure described in Example 6. ESI-MS m/z 608 (MH)+. Step 2. Synthesis of (1R)-1-(2-(2,5-dihydroxyphenyl)acetylamino)-2-
(2-hydroxy-3-carboxyphenyl)ethyl-1-boronic acid. To a solution of (1 R)-2- Methoxy-3-[2-[2-(2,5-dimethoxyphenyl)acetylamino]-2-(2,9,9-trimethyl-3,5-dioxa- 4-bora-tricyclo[6.1.1. 02i6]dec-4-yl)-ethyl]-benzoic acid te/ϊ-butyl ester (249 mg, 0.4 mmol) in DCM (4 ml_), BBr3 (4.2 mL, 1 M solution in DCM) was added dropwise at -78 0C. The mixture was stirred while the temperature was slowly warmed up to ambient temperature. After 4.5 h, the reaction was quenched with water (10 mL) and the mixture extracted with Et2O (3 x 10 mL). The aqueous solution was concentrated in vacuo and purified by preparative HPLC to afford 40 mg (26%) of the product as a white solid. ESI-MS m/z 358 (MH-H2O)+.
Example 19
(1 f?)-1-Hvdroxyacetylamino-1-(3-carboxy-2-hvdroxy)benzyl-methyl boronic acid Step 1. Synthesis of 3-[2-(2-Acetoxy-acetylamino)-2-(2,9,9-trimethyl- 3,5-dioxa-4-bora-tricyclo[6.1.1.02>6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester. Prepared from 2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02 6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and acetoxyacetyl chloride following the procedure described in Step 7 of Example 3. The crude product was purified by flash column chromatography [Rf = 0.2, silica gel (EtOAc/Hexane, 40:60, v/v)] to afford the product in 10% yield. ESI-MS m/z 530 (MH)+.
Step 2. Synthesis of (1R)-1-Hydroxyacetylamino-1-(3-carboxy-2- hydroxy)benzyl-methylboronic acid. To a solution of 3-[2-(2-Acetoxy- acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.026]dec-4-yl)- ethyl]-2-methoxy-benzoic acid tert-butyl ester (80 mg, 0.15 mmol) in dioxane (2
ml), 3N HCI (2 ml) was added dropwise at 1100C. After 1 h H2O (20 ml) was added and the mixture extracted with Et2O (3x30 ml). The aqueous solution was concentrated in vacuo and purified by preparative HPLC to give 9 mg of resultant compound as a white solid in 22% yield. ESI-MS m/z 266 (MH-H2O)+.
Example 20 (1f?)-1-Cvclopropanecarbonyl-amino-1-(3-carboxy-2-hvdroxy)benzyl- methylboronic acid
Step 1. Synthesis of 3-[2-(Cyclopropanecarbonyl-amino)-2-(2,9,9- trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02>6]dec-4-yl)-ethyl]-2-methoxy- benzoic acid tert-butyl ester. Prepared from 2-Methoxy-3-(2,9,9-trimethyl-3,5- dioxa-4-bora-tricyclo[6.1.1.02'6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and cyclopropylcarbonyl chloride following the procedure described in Step 7 of Example 3. The crude product was purified by flash column chromatography [Rf = 0.16, silica gel (EtOAc/Hexane, 40:60, v/v)] to afford the product in 22% yield. ESI-MS m/z 498 (MH)+.
Step 2. Synthesis of (1/?)-1-Cyclopropanecarbonylamino-1-(3- carboxy-2-hydroxy)benzyl-methylboronic acid. To a solution of 3-[2- (Cyclopropanecarbonyl-amino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02 6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester (177 mg, 0.35 mmol) in dioxane (4 ml), 3N HCI (4 ml) was added dropwise at 1100C. After 1 h H2O (25 ml) was added and the mixture extracted with Et2O (3x30 ml). The aqueous solution was concentrated in vacuo and purified by preparative HPLC to give 20 mg of resultant compound as a white solid in 20% yield. ESI-MS m/z 276 (MH-H2O)+.
Example 21
(1 fi)-1 -Hexanoylamino-(3-carboxy-2-hydroxy)benzyl-methylboronic acid Step 1. Synthesis of 3-[2-(Hexanoylamino)-2-(2,9,9-trimethyl-3,5- dioxa-4-bora-tricyclo[6.1.1.02>6]dec-4-yl)-ethyl]-2-nnethoxy-benzoic acid tert- butyl ester. Prepared from 2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02 6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and hexanoyl chloride following the procedure described in Step 7 of Example 3. The crude product was purified by flash column chromatography [Rf = 0.18, silica gel
(EtOAc/Hexane, 40:60, v/v)] to afford the product in 22% yield. ESI-MS m/z 528 (MH)+.
Step 2. Synthesis of (1R)-1-Hexanoylamino-(3-carboxy-2- hydroxy)benzyl-methylboronic acid. To a solution of 3-[2-Hexanoylamino-2- (2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02i6]dec-4-yl)-ethyl]-2-methoxy- benzoic acid tert-butyl ester (175 mg, 0.33 mmol) in dioxane (4 ml), 3N HCI (4 ml) was added dropwise at 110°C. After 1 h H2O (25 ml) was added and the mixture extracted with Et2O (3x30 ml). The aqueous solution was concentrated in vacuo and purified by preparative HPLC to give 14 mg of resultant compound as a white solid in 14% yield. ESI-MS m/z 306 (MH-H2O)+.
Example 22 (1 R)-1 -(2-benzyloxyacetylamino)-2-(2-hvdroxy-3-carboxyphenyl)ethyl-1 -boronic acid Prepared from 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02 6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 1.3 eq of benzyloxyacetyl chloride following the procedure described in Example 6. The final product was purified by preparative HPLC. ESI-MS m/z 356 (MH-H2O)+.
Example 23
(1R)-1-(pentanoylamino)-2-(2-hvdroxy-3-carboxyphenyl)ethyl-1 -boronic acid
Prepared from 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.026]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 1.3 eq of valeryl chloride following the procedure described in Example 6. The final product was purified by preparative HPLC. ESI-MS m/z 292 (MH-H2O)+.
Example 24 (1 R)-1 -(heptanoylamino)-2-(2-hvdroxy-3-carboxyphenyl)ethyl-1 -boronic acid
Prepared from 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02'6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 1.3 eq of heptanoyl chloride following the procedure described in Example 6. The final product was purified by preparative HPLC. ESI-MS m/z 320 (MH-H2O)+.
Example 25 (1 ffl-1 -(3.3-Dimethyl-butyryl amino)-(3-carboxy-2-hvdroxy)benzyl-methylboronic acid
Prepared from 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02i6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 3,3- dimethylbutyryl chloride following the procedure described in Steps 7 and 8 of Example 3. The final product was purified by preparative HPLC. ESI-MS m/z 306 (MH-H2O)+.
Example 26
(1 R)-1 -(4-Fluorobenzoylamino)-(3-carboxy-2-hvdroxy)benzyl-methylboronic acid
Prepared from 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02'6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 4-fluorobenzoyl chloride following the procedure described in Steps 7 and 8 of Example 3. The final product was purified by preparative HPLC. ESI-MS m/z 330 (MH-H2O)+.
Example 27 (1 R)-1-(1-naphthoyl amino)-2-(2-hvdroxy-3-carboxyphenyl)ethyl-1-boronic acid
Prepared from 2-methoxy-3-(2,9,9-thmethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02'6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 1.3 eq of 1- naphthoyl chloride following the procedure described in Example 6. The final product was purified by preparative HPLC. ESI-MS m/z 362 (MH-H2O)+.
Example 28 (1 R)-1 -(3-hvdroxybenzoyl amino)-2-(2-hvdroxy-3-carboxyphenyl)ethyl-1 -boronic acid
Prepared from 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02 6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 1.3 eq of 3- methoxybenzoyl chloride following the procedure described in Example 18. The final product was purified by preparative HPLC. ESI-MS m/z 328 (MH-H2O)+.
Example 29 (1 R)-1 -(3-methoxybenzoyl amino)-2-(2-hvdroxy-3-carboxyphenyl)ethyl-1 -boronic acid
Prepared from 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.026]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 1.3 eq of 3- methoxybenzoyl chloride following the procedure described in Example 6. The final product was purified by preparative HPLC. ESI-MS m/z 342 (MH-H2O)+.
Example 30 (1 R)-1-(2-methylbenzoyl amino)-2-(2-hvdroxy-3-carboxyphenyl)ethyl-1 -boronic acid
Prepared from 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02'6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 1.3 eq of 2- methylbenzoyl chloride following the procedure described in Example 6. The final product was purified by preparative HPLC. ESI-MS m/z 326 (MH-H2O)+.
Example 31 (1 R)-I -(e-Chloro-pyridine-S-carbonvD-amino-i -(3-carboxy-2-hvdroxy)benzyl- methylboronic acid Step 1 Synthesis of 3-[2-[(6-Chloro-pyridine-3-carbonyl)-amino]-2-
(Σ.Θ.Θ-trimethyl-a.δ-dioxa^-bora-tricyclotβ.i.i.O^dec^-yO-ethyll-Z- methoxy-benzoic acid tert-butyl ester. Prepared from 2-Methoxy-3-(2,9,9- trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02 6]dec-4-ylmethyl)-benzoic acid tert- butyl ester and 6-chloro-nicotinoyl chloride following the procedure described in Step 7 of Example 3. The crude product was purified by flash column chromatography [Rf = 0.18, silica gel (EtOAc/Hexane, 30:70, v/v)] to give a 24% yield of product. ESI-MS m/z 569 (MH)+.
Step 2. Synthesis of (1fi)-1-(6-Chloro-pyridine-3-carbonyl)-amino-1-(3- carboxy-2-hydroxy)benzyl-methylboronic acid. To a solution of 3-[2-[(6- Chloro-pyridine-3-carbonyl)-amino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02'6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester (400 mg, 0.7 mmol) in dioxane (9 mL), 3N HCI (9 mL) was added dropwise at 11O0C. After 1 h H2O (40 mL) was added and the mixture extracted with Et2O (3 x 40 mL). The aqueous solution was concentrated in vacuo and purified by preparative
HPLC to give 9 mg of resultant compound as a white solid in 4% yield. ESI-MS m/z 347 (MH-H2O)+.
Example 32 (1f?)-1-(4-Chloro-benzoyl)-amino-1-(3-carboxy-2-hvdroxy)benzyl-methylboronic acid
Step 1 Synthesis of 3-[2-(4-Chloro-benzoylamino)-2-(2,9,9-trimethyl- 3,5-dioxa-4-bora-tricyclo[6.1.1.02>6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester. Prepared from 2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02|6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 4-chloro- benzoyl chloride following the procedure described in Step 7 of Example 3. The crude product was purified by flash column chromatography [Rf = 0.33, silica gel (EtOAc/Hexane, 30:70, v/v)] to give a 28% yield of product. ESI-MS m/z 568 (MH)+. Step 2. (1 /?)-1 -(4-Chloro-benzoyl)-amino-1 -(3-carboxy-2- hydroxy)benzyl-methyl boronic acid. To a solution of 3-[2-(4-Chloro- benzoylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.026]dec-4-yl)- ethyl]-2-methoxy-benzoic acid tert-butyl ester (640 mg, 1.12 mmol) in dioxane (11 ml), 3N HCI (11 ml) was added dropwise at 110°C. After 1 hr H2O (25 ml) was added and the mixture extracted with Et2O (3x400 ml). The aqueous solution was concentrated in vacuo and purified by analytical HPLC to give 13 mg of resultant compound as a white solid in 3% yield. ESI-MS m/z 346 (MH-H2O)+.
Example 33 (1 f?)-1 -(4-Methoxybenzoyl)-amino-1 -(3-carboxy-2-hvdroxy)benzyl-methylboronic acid
Step 1. Synthesis of 2-Methoxy-3-[2-(4-methoxybenzoylamino)-2- (2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02>6]dec-4-yl)-ethyl]-benzoic acid tert-butyl ester. Prepared from 2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4- bora-tricyclo[6.1.1.02'6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 4- methoxybenzoyl chloride following the procedure described in Step 7 of Example 3. The crude product was purified by flash column chromatography [Rf = 0.22, silica gel (EtOAc/Hexane, 40:60, v/v)] to give a 26% yield of product. ESI-MS m/z 564 (MH)+.
Step 2. (1f?)-1-(4-Methoxybenzoyl)-amino-1-(3-carboxy-2- hydroxy)benzyl-methyl boronic acid. To a solution of 2-Methoxy-3-[2-(4- methoxybenzoylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02 6]dec- 4-yl)-ethyl]-benzoic acid tert-butyl ester (225 mg, 0.4 mmol) in dioxane (4 ml), 3N HCI (4 ml) was added dropwise at 1100C. After 1 hr H2O (25 ml) was added and the mixture extracted with Et2O (3x30 ml). The aqueous solution was concentrated in vacuo and purified by analytical HPLC to give 16 mg of resultant compound as a white solid in 11 % yield. ESI-MS m/z 342 (MH-H2O)+.
Example 34
(1 R)-1-(2-methoxybenzoyl amino)-2-(2-hvdroxy-3-carboxyphenyl)ethyl-1 -boronic acid
Prepared from 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.026]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 1.3 eq of 2- methoxybenzoyl chloride following the procedure described in Example 6. The final product was purified by preparative HPLC. ESI-MS m/z 342 (MH-H2O)+.
Example 35
(1 R)-1-(2-hvdroxybenzoyl amino)-2-(2-hvdroxy-3-carboxyphenyl)ethyl-1 -boronic acid
Prepared from 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02'6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 1.3 eq of 2- methoxybenzoyl chloride following the procedure described in Example 18. The final product was purified by preparative HPLC. ESI-MS m/z 328 (MH-H2O)+.
Example 36 (1 f?)-1 -(4-Hvdroxybenzoyl)-amino-1 -(3-carboxy-2-hvdroxy)benzyl-methylboronic acid
To a solution of 2-Methoxy-3-[2-(4-methoxybenzoylamino)-2-(2,9,9- trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02 6]dec-4-yl)-ethyl]-benzoic acid tert-butyl ester (225 mg, 0.4 mmol), prepared as described in Example 33, in DCM (9 mL), BBr3 (2.4 mL, 1 M solution in DCM) was added dropwise at -78°C. The mixture was stirred for 2 h at the same temperature then warmed to room temperature. After 4 h the reaction was quenched with water (50 mL) and the mixture extracted
with Et2O (3 x 40 mL). The aqueous solution was concentrated in vacuo and purified by preparative HPLC to give 15 mg of resultant compound as a white solid in 11% yield. ESI-MS m/z 328 (MH-H2O)+.
Example 37
(1 R)-1-(2-acetamidoacetylamino)-2-(2-hvdroxy-3-carboxyphenyl)ethyl-1-boronic acid
Prepared from 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02'6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 2 eq of N- acetylglycine following the procedure described in Steps 1 , 2 and 3 of Example 12 while the reaction temperature was kept at -78°C for 2 h in Step 3. The final product was purified by preparative HPLC. ESI-MS m/z 307 (MH-H2O)+.
Example 38 (1 R)-1 -(3-aminopropanoylamino)-2-(2-hvdroxy-3-carboxyphenyl)ethyl-1 -boronic acid formate salt
Prepared from 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02'6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 2 eq of Boc- beta-alanine following the procedure described in Steps 1 , 2 and 3 of Example 12 except that the reaction temperature for Step 3 was allowed to gradually warm from -78°C to -300C over 2 hours before quenching. The final product was obtained after purification by preparative HPLC using solvents buffered with 0.1 % formic acid. ESI-MS m/z 279 (MH-H2O)+.
Example 39
(1 R)-1 -(2-Amino-thiazol-4-yl)-acetylamino-1 -(3-carboxy-2-hvdroxy)benzyl- methylboronic acid formate salt
Step 1. Synthesis of [2-(Trityl-amino)-thiazol-4-yl]-acetic acid methyl ester. A solution of methyl-2-amino-4-thiazoleacetic acid (3.Og, 17.4 mmole), diisopropylethylamine (3.0 mL, 17.2 mmole), and trityl chloride (5.3 g, 19.0 mmole) in 70 mL of DCM was stirred for 4 days. Water was added, the layers separated and the aqueous layer extracted once with DCM. The organic layers were combined, washed twice with water, brine, dried (Na2SO4) and concentrated in vacuo. The crude product was chromatographed on SiO2 using a gradient of
10% EtOAc/hexane to 40% EtOAc/hexane to afford 6.45 g (89%) of the title product as a white solid.
Step 2. Synthesis of [2-(Trityl-amino)-thiazol-4-yl]-acetic acid. A solution of [2-(Trityl-amino)-thiazol-4-yl]-acetic acid methyl ester (3.0 g, 7.25 mmole), methanol (50 ml_) and 1 N aqueous NaOH (20 ml_) was stirred at ambient temperature for 23 h. During this time the solution went from a slurry to homogeneous. Water was added and the solution extracted twice with Et2O. The aqueous layer was acidified to pH 1 with 3N HCI resulting in a white precipitate. The solids were collected by filtration, washed with water and dried in vacuo to afford 2.32 g (80%) of the title product as a white solid.
Step 3. Synthesis of 3-[2-[2-(2-Amino-thiazol-4-yl)-acetylamino]-2- (2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02 6]dec-4-yl)-ethyl]-2- methoxy-benzoic acid tert-butyl ester. To anhydrous CH2CI2 (1.4 ml_, 21.8 mmol) in anhydrous THF (53 ml_) under argon at -100°C [MeOH, Hq. N2 slush bath], n-BuLi (8.1 ml_, 2.5M in hexane, 22.2 mmol) was added dropwise and the mixture was stirred for 30 minutes. A THF (12 ml_) solution of 2-Methoxy-3- (2,9,9-thmethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02'6]dec-4-ylmethyl)-benzoic acid tert-butyl ester (6.73 g, 16.81 mmol) was added over a period of 20 minutes. After 40 minutes the cooling bath was removed and the mixture warmed slowly to 0°C. After 2 hours the reaction flask was cooled to -78°C, LHMDS (18.5 ml_, 1 M in THF, 18.5 mmol) was added slowly and the resultant solution was warmed to room temperature gradually while stirring overnight. Anhydrous MeOH (0.75 ml_, 16.49 mmol) was added at -100C, the reaction stirred for 1 h at the same temperature and then for 1 h at room temperature. At this stage LCMS indicated the formation of 2-Methoxy-3-[2-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02,6]dec-4-yl)-2-(trimethylsilanyl-amino)-ethyl]-benzoic acid tert- butyl ester intermediate.
In a separate dry round bottom flask under argon containing [2-(Trityl- amino)-thiazol-4-yl]-acetic acid, dry DCM (50 ml) was added. The content in the flask were cooled to 00C. NMM (1.6 mL, 15.12 mmol) was added followed by HATU (4.1 g, 10.8 mmol) and the mixture stirred for 30 min at 00C and then 1 hr at room temperature. To this reaction mixture was added 30 mL of the solution from Step 1 dropwise at -200C. The cooling bath was removed and the reaction stirred at room temperature. After 2 h the reaction was quenched with H2O (75
mL) and the aqueous phase was extracted with EtOAc (3 x 75 ml_), the combined organic layers were dried over MgSO4, and concentrated in vacuo. Purification by flash column chromatography on silica gel [Rf = 0.5, (EtOAc/Hexane, 60:40, v/v)] afforded 0.88 g of the resultant compound as pale yellow solid in 19% yield. ESI-MS m/z 812 (MH)+.
Step 4. Synthesis of (1/?)-1-(2-Amino-thiazol-4-yl)-acetylamino-1-(3- carboxy-2-hydroxy)benzyl-methylboronic acid formate salt. Prepared from 2-Methoxy-3-(2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02'6]dec-4-yl)-2-{2- [2-(trityl-amino)-thiazol-4-yl]-acetylamino}-ethyl)-benzoic acid tert-butyl ester and BCI3, following the procedure described in Example 8. The crude product was purified by preparative HPLC using solvents buffered with formic acid to give 10 mg of resultant compound as a white solid in 5% yield. ESI-MS m/z 348 (MH- H2O)+.
Example 40
(1 R)-1-(Pyrazol-1-yl-acetyl amino)-2-(2-hvdroxy-3-carboxyphenyl)ethyl-1-boronic acid
Prepared from 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02'6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 2 eq of 2-(1 H- pyrazol-1-yl)acetic acid following the procedure described in Steps 1 , 2 and 3 of Example 12 while the reaction temperature was kept at -78 0C for 2 h in Step 3. The final product was obtained after purification by preparative HPLC. ESI-MS m/z 316 (MH-H2O)+.
Example 41
(1 R)-1 -(2-aminoacetylamino)-2-(2-hvdroxy-3-carboxyphenyl)ethyl-1 -boronic acid formate salt
Prepared from 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02'6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 2 eq of Boc- glycine following the procedure described in Example 12 except that the reaction temperature for Step 3 was allowed to gradually warm from -78°C to -300C over 2 hours before quenching. The final product was obtained after purification by preparative HPLC using solvents buffered with 0.1% formic acid. ESI-MS m/z 265 (MH-H2O)+.
Example 42 (1 f?)-1 -(3-aminomethyl)-benzoylamino-1 -(3-carboxy-2-hvdroxy)benzyl-methyl boronic acid formate Step 1 Synthesis of 3-[2-[3-(tert-Butoxycarbonylamino-methyl)- benzoylamino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo6.1.1.02|6]dec-4-yl)- ethyl]-2-methoxy-benzoic acid tert-butyl ester. Prepared from 2-Methoxy-3- (2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02'6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 3-(tert-Butoxycarbonylaminomethyl)-benzoic acid following the procedure described in Step 3 of Example 39. The crude product was purified by flash column chromatography [Rf = 0.26, silica gel (EtOAc/Hexane, 30:70, Wv)] to give a 22% yield of product. ESI-MS m/z 663 (MH)+.
Step 2. Synthesis of (1R)-1-(3-aminomethyl)-benzoylamino-1-(3- carboxy-2-hydroxy)benzyl-methyl boronic acid formate. Prepared from 3-[2- [3-(tert-Butoxycarbonylamino-methyl)-benzoylamino]-2-(2,9,9-trimethyl-3,5-dioxa- 4-bora-tricyclo[6.1.1.02'6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester and BCI3, following the procedure described in Example 8. The crude product was purified by preparative HPLC using solvents buffered with 0.1% formic acid to give 10 mg of resultant compound as a white solid in 4% yield. ESI-MS m/z 341 (MH-H2O)+.
Example 43 (1 R)-1 -(2,6-Dichlorobenzoyl)-amino-1 -(3-carboxy-2-hvdroxy)benzyl- methylboronic acid Step 1 Synthesis of 3-[2-(2,6-Dichlorobenzoylamino)-2-(2,9,9- trimethyl-S.δ-dioxa^-bora-tricycloIβ.i .i .O^dec-A-ylJ-ethyll^-methoxy- benzoic acid tert-butyl ester. Prepared from 2-Methoxy-3-(2,9,9-trimethyl-3,5- dioxa-4-bora-tricyclo[6.1.1.02 6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 2,6-dichlorobenzoyl chloride following the procedure described in Step 7 of Example 3. The crude product was purified by flash column chromatography [Rf = 0.33, silica gel (EtOAc/Hexane, 30:70, v/v)] to give a 17% yield of product. ESI- MS m/z 603 (MH)+.
Step 2. Synthesis of (1/?)-1-(2,6-Dichloro-benzoyl)-amino-1-(3- carboxy-2-hydroxy)benzyl-methyl boronic acid. To a solution of 3-[2-(2,6-
Dichlorobenzoylamino^^.θ.θ-trimethyl-S.δ-dioxa^-bora-tricycloie.1.1.02 6]dec- 4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester (350 mg, 0.58 mmol) in DCM (9 ml_), BCI3 (3.5 mL, 1 M solution in DCM) was added dropwise at -78°C. The mixture was stirred for 2 h at the same temperature then warmed to room temperature. After 4 h the reaction was quenched with water (50 mL) and the mixture extracted with Et2O (3 x 40 mL). The aqueous solution was concentrated in vacuo and purified by preparative HPLC to give 6 mg of resultant compound as a white solid in 4% yield. ESI-MS m/z 381 (MH-H2O)+.
Example 44
(1 R)-1-(1-methyl-3-phenyl-1 H-pyrazole-5-carbonyl -amino)-2-(2-hvdroxy-3- carboxyphenyl)ethyl-1 -boronic acid
Prepared from 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.026]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 1.3 eq of 1- methyl-3-phenyl-1 H-pyrazole-5-carbonyl chloride following the procedure described in Example 18 except that BCI3 was used in place of BBr3 and the reaction temperature for the final step was allowed to gradually warm from -78°C to -300C over 2 hours before quenching. The final product was further purified by preparative HPLC. ESI-MS m/z 392 (MH-H2O)+.
Example 45 (1 R)-1-(2-(1 ,3-dioxoisoindolin-2-yl)acetyl amino)-2-(2-hvdroxy-3- carboxyphenyl)ethyl-1 -boronic acid
Prepared from 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.026]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 2 eq of N- phthaloylglycine following the procedure described in Example 12 while the reaction temperature was kept at -78 0C for 2 h in Step 3. The final product was further purified by preparative HPLC. ESI-MS m/z 395 (MH-H2O)+.
Example 46
(1 R)-1-(isoxazole-5-carbonyl -amino)-2-(2-hvdroxy-3-carboxyphenyl)ethyl-1- boronic acid
Prepared from 2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02 6]dec-4-ylmethyl)-benzoic acid tert-butyl ester and 1.3 eq of
isoxazole 5-carbonyl chloride following the procedure described in Example 18 except that BCI3 was used in place of BBr3 and reaction temperature was kept at -78 0C for 2 h for the final step. The final product was purified by preparative HPLC. ESI-MS m/z 303 (MH-H2O)+.
Example 47 (1 ft)-1 -r3-(5-methyl-f 1.2.41oxadiazol-3-yl)-benzovπ-amino-1 -(3-carboxy-2- hvdroxy)benzyl-methylboronic acid
Step 1. Synthesis of 2-Methoxy-3-[2-[3-(5-methyl-[1,2,4]oxadiazol-3- yl)-benzoyl amino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02'6]dec- 4-yl)-ethyl]-benzoic acid tert-butyl ester. Prepared from 2-Methoxy-3-(2,9,9- trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02 6]dec-4-ylmethyl)-benzoic acid tert- butyl ester and 3-(5-Methyl-[1 ,2,4]oxadiazol-3-yl)-benzoic acid following the procedure described in Step 1 of Example 39. The crude product was purified by flash column chromatography [Rf = 0.23, silica gel (EtOAc/Hexane, 40:60, v/v)] to give a 15% yield of product. ESI-MS m/z 616 (MH)+.
Step 2. (1 R)-1 -[3-(5-methyl-[1 ,2,4]oxadiazol-3-yl)-benzoylamino]-1 -(3- carboxy-2-hydroxy)benzyl-methylboronic acid. Prepared from 2-Methoxy-3- [2-[3-(5-methyl-[1 ,2,4]oxadiazol-3-yl)-benzoylamino]-2-(2,9,9-trimethyl-3,5-dioxa- 4-bora-tricyclo[6.1.1.02 6ldec-4-yl)-ethyl]-benzoic acid tert-butyl ester and BCI3, following the procedure described in Example 8. The crude product was purified by preparative HPLC to give 8 mg of resultant compound as a white solid in 3% yield. ESI-MS m/z 394 (MH-H2O)+.
Example 48
(1 f?)-1 -(6-morpholin-4-yl-pyridine-3-carbonyl)-amino-1 -(3-carboxy-2- hvdroxy)benzyl-methylboronic acid
Step 1. Synthesis of 2-Methoxy-3-[2-[(6-morpholin-4-yl-pyridine-3- carbonyl)-amino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02>6]dec-4- yl)-ethyl]-benzoic acid tert-butyl ester. Prepared from 2-Methoxy-3-(2,9,9- trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.026]dec-4-ylmethyl)-benzoic acid tert- butyl ester and 6-Morpholin-4-yl-nicotinoyl chloride following the procedure described in Step 7 of Example 3. The crude product was purified by flash
column chromatography [Rf = 0.21 , silica gel (EtOAc/Hexane, 70:30, v/v)] to giver a 27% yield of product. ESI-MS m/z 620 (MH)+.
Step 2. (1 /?)-1 -(6-morpholin-4-yl-pyridine-3-carbonyl)-amino-1 -(3- carboxy-2-hydroxy)benzyl-methylboronic acid. Prepared from 2-Methoxy-3- [2-[(6-morpholin-4-yl-pyridine-3-carbonyl)-amino]-2-(2,9,9-trimethyl-3,5-dioxa-4- bora-tricyclo[6.1.1.02'6]dec-4-yl)-ethyl]-benzoic acid tert-butyl ester and BCI3, following the procedure described in Example 8. The crude product was purified by preparative HPLC to give 80 mg of resultant compound as a white solid in 30% yield. ESI-MS m/z 398 (MH-H2O)+.
Example 49 (1f?)-1-(1-Acetyl-piperidine-4-carbonyl)-amino-1-(3-carboxy-2-hvdroxy)benzyl- methylboronic acid
Step 1. Synthesis of 3-[2-[(1-Acetyl-piperidine-4-carbonyl)-amino]-2- (2,9,9-trimethyl-3>5-dioxa-4-bora-tricyclo[6.1.1.02>6]dec-4-yl)-ethyl]-2- methoxy-benzoic acid tert-butyl ester. Prepared from 2-Methoxy-3-(2,9,9- thmethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02'6]dec-4-ylmethyl)-benzoic acid tert- butyl ester and 1-Acetyl-piperidine-4-carboxylic acid following the procedure described in Step 7 of Example 3. The crude product was purified by flash column chromatography [Rf = 0.12, silica gel (MeOH/CH2CI2, 2:98, v/v)] to give a 18% yield of product. ESI-MS m/z 583(MH)+.
Step 2. (1 /?)-1 -(1 -Acetyl-piperidine-4-carbonyl)-amino-1 -(3-carboxy-2- hydroxy)benzyl-methylboronic acid. Prepared from 3-[2-[(1-Acetyl-piperidine- 4-carbonyl)-amino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02 f5]dec-4-yl)- ethyl]-2-methoxy-benzoic acid tert-butyl ester and BCI3, following the procedure described in Example 8. The crude product was purified by preparative HPLC to give 58 mg of resultant compound as a white solid in 25% yield. ESI-MS m/z 361 (MH-H2O)+.
Exemplary compounds of the present invention are shown in Table 1 along with respective molecular weights (MW) and low-resolution electrospray ionization mass spectral analytical results (ESI Mass Spec).
Table 1. Examples of compounds of the present invention.
Example 50
Experimental Method for β-Lactamase Enzyme Assays Isolation of β-lactamases. Crude β-lactamase extracts were prepared from 20 ml overnight cultures with shaking. Escherichia coli cells containing SHV-5 or CTXM-15, Enterobacter cloacae cells containing P99, and Klebsiella pneumoniae cells containing KPC-2 were further diluted 10-fold and grown to mid-log phase (OD at 600 nm, .5-.8) in Mueller-Hinton Il (MH-II) broth at 37°C. The cells were pelleted at 500Og, washed and resuspended in 2 ml_ PBS pH 7.0. The β-lactamases were extracted by four cycles of freezing and thawing followed by centrifugation. β-lactamase activity in the extracts was measured with the chromogenic cephalosporin nitrocefin. The amount of protein in each β- lactamase preparation was determined by the bicinchoninic acid (BCA) assay. β-lactamase Inhibition. To determine the level of inhibition of β- lactamase enzymes, compounds were diluted in PBS at pH 7.0 to yield concentrations between 100 and 0.005 μM in microtiter plates. An equal volume of diluted enzyme stock was added, and the plates were incubated at 37°C for 10
min. Nitrocefin solution was then dispensed as substrate into each well at a final concentration of 100 μM, and the plates were immediately read with the kinetic program at 486 nm for 10 min on the SPECTRAMAX® Plus384 (high-throughput microplate spectrophotometer; Molecular Devices Corp., Sunnyvale, CA). Maximum rates of metabolism were then compared to those in control wells (without inhibitors), and percentages of enzyme inhibition were calculated for each concentration of inhibitor. The concentration of inhibitor needed to reduce the initial rate of hydrolysis of substrate by 50% (IC5o) was calculated as the residual activity of β-lactamase at 486 nm using the SoftMax Pro 5.0 software (Molecular Devices Corp.).
Using the methodology described above, examples of the current invention were evaluated for their ability to inhibit β-lactamase enzymes. The results of these assays are summarized in Table 2 for representative enzymes across different subtypes (note SHV-5 and CTXM-15 exemplify different subclasses of Ambler Class A Extended Spectrum Beta Lactamases, KPC-2 exemplifies Class A carbapenemases, and P99 represents chromosomal Class C AmpC), where A represents an IC5O of > 1 μM, B represents an IC5O of 0.1 to 1 μM, C represents an IC50 of 0.01 to 0.1 μM, and D represents an IC5O of < 0.01 μM. NT = Not tested.
Table 2. Inhibition of diverse β-lactamases by example compounds of the present invention.
Example 51
In vitro Antibacterial Assays of 3-Lactamase Inhibition To determine the ability of test compounds to potentiate the inhibition of the growth of bacterial strains producing beta-lactamase enzymes, classic cell based screening assays were employed. Four bacteria strains producing beta- lactamase enzymes were used: K. pneumoniae expressing the Class A Extended Spectrum Beta-Lactamase (ESBL) CTX-M-15, E. coli expressing the Class A ESBL SHV-5, E. cloacae expressing the Class C P99+, and K. pneumoniae expressing the Class A carbapenemase KPC-2. In order to evaluate the ability of test compounds to inhibit beta-lactamase activity,
Applicants used a modification of the broth microdilution assay. The assay was conducted in Cation Adjusted Mueller Hinton Broth (CAMHB, BD # 212322, BD Diagnostic Systems, Sparks, MD). Bacteria strains were grown for 3-5 hours in CAMBH broth. All four strains were grown in presence of 50 μg/mL ampicillin to ensure resistance is maintained. In the meantime, test compounds were diluted in DMSO to a 0.1 mg/mL stock. The compounds were added to a microtiter plate and were diluted in 2-fold serial dilutions in CAMHB in a final concentration range of 8 μg/mL to 0.015 μg/ml. An overlay of CAMHB containing a cephalosporin was added to the compounds at a final static concentration of 8 μg/ml. Ceftazidime (CAZ, Sigma# C3809-1G, Sigma-Aldrich, St. Louis, MO) was used as the partner antibiotic for K. pneumoniae expressing Ambler Class A ESBL CTX-M-15 (MIC alone = 128 μg/ml), E. coli expressing Class A ESBL SHV-5 (MIC alone >1024 μg/mL), K. pneumoniae expressing Ambler Class A carbapenemase KPC-2 (MIC alone = 32 μg/mL), and E. cloacae expressing Class C P99+ AmpC (MIC alone = 128 μg/mL). Titration of test compounds with MIC readout indicates the concentration of test article needed to sufficiently inhibit beta lactamase enzyme activity and protect the intrinsic antibacterial activity of the cephalosporin. Each of these compound plates are made in quadruplicate, one for each bacteria strain. In addition to the titration of test compounds the MICs of a panel of cephalosporins is also tested to ensure the strains are behaving consistently from test to test. Once the test compound and cephalosporin are added the plates can be inoculated, lnocula are conducted according to CLSI broth microdilution method. After inoculation the plates are incubated for 16-20 hours at 37°C then the Minimal Inhibitory Concentration (MIC) of the test compound is determined visually.
Using the methodology described above, examples of the current invention were evaluated for their ability to inhibit the growth of β-lactamase producing bacteria in the presence of a β-lactam antibiotic. Representative results are shown in Table 3 where A represents an MIC > 8 μg/mL, B represents an MIC between 1 and 8 μg /mL, and C represents an MIC of < 1 μg /mL. NT = Not Tested.
Table 3. Broad spectrum inhibition of bacterial growth. MIC of example compounds of the invention in the presence of a fixed amount (8 μg/mL) of Ceftazidime β-lactam antibiotic.
Claims
1. A compound of the formula:
(a) aryl group substituted with from O to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(b) heteroaryl group substituted with from O to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(c) heterocyclic group substituted with from O to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido; drogen, or is selected from the group consisting of:
(a) C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C6 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxide), and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
R3 is an aryl or heteroaryl group substituted with from 1 to 4 substituents wherein one of the substituents is a hydroxyl or amino group located at the 2 position relative to the group containing Y1 and Y2, and wherein the remaining substituents are selected from the group consisting of hydroxyl, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminocarbonyl, carbonyl, aminosulfonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, guanidino, halogen, heteroaryl, heterocyclyl , sulfido, sulfonyl, sulfoxido, sulfonic acid, sulfate, and thiol;
R4 is selected from the group consisting of:
(a) C1-C10 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C10 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido; ydrogen or is selected from the group consisting of:
(a) C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
Xi and X2 are independently hydroxyl, halogen, NR4R5, C1-C6 alkoxy, or when taken together Xi and X2 form a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together X1 and X2 form a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together X1 and X2 form a cyclic boron amide-ester where said chain contains from 2-20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, Or X1 and R1 together form a cyclic ring where said ring contains 2 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, halogen, NR4R5, C1-C6 alkoxy, or X1 and R3 together form a cyclic ring where said ring contains 3 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, halogen, NR4R5, or C1-C6 alkoxy;
Y1 and Y2 are independently hydrogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminosulfonyl, aminocarbonyl, carbonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, halogen, heteroaryl, heteroaryloxy, heterocyclyl, sulfido, sulfonyl, or sulfoxido, or taken together Yi and Y2 form a cyclic structure containing from 3-12 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S;
or a salt thereof;
provided that, when R1 is -C(O)R4, R2 is hydrogen, R3 is a phenyl group having two substituents consisting of a hydroxyl at the 2-position and a carboxylic acid at the 3-position relative to the group containing Y1 and Y2, Xi and X2 are hydroxyl or X1 is hydroxyl and X2 is replaced by the ortho-hydroxyl oxygen of R3 such that a 6-membered ring is formed, and Y1 and Y2 are hydrogen, R4 is not unsubstituted C1 alkyl.
2. The compound of claim 1 , wherein R-i is -C(O)R4; R2 is hydrogen; R3 is an aryl or heteroaryl group substituted with from 2 to 4 substituents wherein one of the substituents is a hydroxyl or amino group located at the 2- position relative to the group containing Y1 and Y2, and a second substituent is a carboxylic acid group and wherein the remaining substituents are selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido;
R4 is selected from the group consisting of:
(a) C1-C10 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido, (b) C3-C10 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
Xi and X2 are hydroxyl, or when taken together Xi and X2 form a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or Xi and Ri together form a cyclic ring where said ring contains 2 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, or X1 and R3 together form a cyclic ring where said ring contains 3 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S and X2 is hydroxyl;
Yi and Y2 are independently hydrogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminosulfonyl, aminocarbonyl, carbonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, halogen, heteroaryl, heteroaryloxy, heterocyclyl, sulfido, sulfonyl, or sulfoxido;
or a salt thereof;
provided that, when R3 is a phenyl group having two substituents consisting of a hydroxyl at the 2-position and a carboxylic acid at the 3-position relative to the group containing Y1 and Y2, X1 and X2 are hydroxyl or X1 is hydroxyl and X2 is replaced by the ortho-hydroxyl oxygen of R3 such that a 6-membered ring is formed, and Y1 and Y2 are hydrogen, R4 is not unsubstituted C1 alkyl.
3. The compound of claim 2, wherein R1 is -C(O)R4; R2 is hydrogen; R3 is an aryl group having a hydroxyl at the 2-position and a carboxylic acid at the 3- position relative to the group containing Y1 and Y2; R4 is C1-C10 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1- C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido; Xi and X2 are hydroxyl, or X1 is hydroxyl and X2 is replaced by the ortho-hydroxyl oxygen of R3 such that a 6-membered ring is formed; and Yi and Y2 are hydrogen;
or a salt thereof;
provided that, when R3 is a phenyl group having two substituents consisting of a hydroxyl at the 2-position and a carboxylic acid at the 3-position relative to the group containing Yi and Y2, and Xi and X2 are hydroxyl or X1 is hydroxyl and X2 is replaced by the ortho-hydroxyl oxygen of R3 such that a 6-membered ring is formed, R4 is not unsubstituted C1 alkyl.
4. The compound of claim 2, wherein R1 is -C(O)R4; R2 is hydrogen; R3 is an aryl group having a hydroxyl at the 2-position and a carboxylic acid at the 3- position relative to the group containing Y1 and Y2; R4 is C3-C10 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido; X1 and X2 are hydroxyl, or X1 is hydroxyl and X2 is replaced by the ortho-hydroxyl oxygen of R3 such that a 6-membered ring is formed; and Y1 and Y2 are hydrogen; or a salt thereof.
5. The compound of claim 2, wherein R1 is -C(O)R4; R2 is hydrogen; R3 is an aryl group having a hydroxyl at the 2-position and a carboxylic acid at the 3- position relative to the group containing Y1 and Y2; R4 is aryl or heteroaryl substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido; Xi and X2 are hydroxyl, or X1 is hydroxyl and X2 is replaced by the ortho-hydroxyl oxygen of R3 such that a 6-membered ring is formed; and Yi and Y2 are hydrogen; or a salt thereof.
6. The compound of claim 2, wherein Ri is -C(O)R4; R2 is hydrogen; R3 is an aryl group having a hydroxyl at the 2-position and a carboxylic acid at the 3- position relative to the group containing Y1 and Y2; R4 is a heterocycle substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido; X1 and X2 are hydroxyl, or X1 is hydroxyl and X2 is replaced by the ortho-hydroxyl oxygen of R3 such that a 6-membered ring is formed; and Y1 and Y2 are hydrogen; or a salt thereof.
7. The compound of claim 2, wherein the compound is
8. A pharmaceutical composition comprising:
(a) one or more compounds of claim 1 ;
(b) one or more β-lactam antibiotics; and
(c) one or more pharmaceutically acceptable carriers.
9. The pharmaceutical composition of claim 8, wherein the β-lactam antibiotic is a penicillin, cephalosporin, carbapenem, monobactam, bridged monobactam, or combination thereof.
10. The pharmaceutical composition of claim 9, wherein the penicillin is benzathine penicillin, benzylpenicillin, phenoxymethylpenicillin, procaine penicillin, oxacillin, methicillin, dicloxacillin, flucloxacillin, temocillin, amoxicillin, ampicillin, co-amoxiclav, azlocillin, carbenicillin, ticarcillin, mezlocillin, piperacillin, apalcillin, hetacillin, bacampicillin, sulbenicillin, mecicilam, pevmecillinam, ciclacillin, talapicillin, aspoxicillin, cloxacillin, nafcillin, pivampicillin, or a combination thereof.
11. The pharmaceutical composition of claim 9, wherein the cephalosporin is cephalothin, cephaloridin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin, cephacetril, cefotiam, cefotaxime, cefsulodin, cefoperazone, ceftizoxime, cefinenoxime, cefinetazole, cephaloglycin, cefonicid, cefodizime, cefpirome, ceftazidime, ceftriaxone, cefpiramide, cefbuperazone, cefozopran, cefepim, cefoselis, cefluprenam, cefuzonam, cefpimizole, cefclidin, cefixime, ceftibuten, cefdinir, cefpodoxime axetil, cefpodoxime proxetil, cefteram pivoxil, cefetamet pivoxil, cefcapene pivoxil, cefditoren pivoxil, cefuroxime, cefuroxime axetil, loracarbacef, latamoxef, or a combination thereof.
12. The pharmaceutical composition of claim 9, wherein the cephalosporin is an anti-MRSA cephalosporin.
13. The pharmaceutical composition of claim 12, wherein the anti-MRSA cephalosporin is ceftobiprole, ceftaroline, or a combination thereof.
14. The pharmaceutical composition of claim 9, wherein the carbapenem is imipenem, meropenem, ertapenem, faropenem, doripenem, biapenem, panipenem, or a combination thereof.
15. The pharmaceutical composition of claim 9, wherein the carbapenem is an anti-MRSA carbapenem.
16. The pharmaceutical composition of claim 15, wherein the anti-MRSA carbapenem is PZ-601 or ME1036.
17. The pharmaceutical composition of claim 9, wherein the monobactam is aztreonam, carumonam, BAL30072, or a combination thereof.
18. A pharmaceutical composition comprising:
(a) one or more compounds of claim 1 ; and
(b) one or more pharmaceutically acceptable carriers.
19. The pharmaceutical composition of claim 8 or 18, comprising more than one beta-lactam antibiotic.
20. A method of treating a bacterial infection in a mammal comprising administering to a mammal in need thereof:
(i) an effective amount of a compound having the formula:
(a) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(b) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(c) heterocyclic group substituted with from O to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido; R2 is hydrogen, or is selected from the group consisting of:
(a) C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C6 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and (e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
R3 is an aryl or heteroaryl group substituted with from 1 to 4 substituents wherein one of the substituents is a hydroxyl or amino group located at the 2 position relative to the group containing Y1 and Y2, and wherein the remaining substituents are selected from the group consisting of hydroxyl, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminocarbonyl, carbonyl, aminosulfonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, guanidino, halogen, heteroaryl, heterocyclyl , sulfido, sulfonyl, sulfoxido, sulfonic acid, sulfate, and thiol;
R4 is selected from the group consisting of:
(a) C1-C10 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxide
(b) C3-C10 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, a Iky I heteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
R5 is hydrogen or is selected from the group consisting of:
(a) C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido, (c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
Xi and X2 are independently hydroxyl, halogen, NR4R5, C1-C6 alkoxy, or when taken together Xi and X2 form a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together Xi and X2 form a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together X1 and X2 form a cyclic boron amide-ester where said chain contains from 2-20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or X1 and R1 together form a cyclic ring where said ring contains 2 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S1 and X2 is hydroxyl, halogen, NR4R5, C1- C6 alkoxy, or X1 and R3 together form a cyclic ring where said ring contains 3 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, halogen, NR4R5, or C1- C6 alkoxy;
Y1 and Y2 are independently hydrogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminosulfonyl, aminocarbonyl, carbonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, halogen, heteroaryl, heteroaryloxy, heterocyclyl, sulfido, sulfonyl, or sulfoxido, or taken together Y1 and Y2 form a cyclic structure containing from 3-12 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S;
or a salt thereof; and (ii) an effective amount of a β-lactam antibiotic.
21. The method of claim 20, wherein the mammal is a human.
22. A method of treating a bacterial infection in a mammal comprising administering to a mammal in need thereof an effective amount of a compound having the formula:
(b) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(c) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido;
R2 is hydrogen, or is selected from the group consisting of:
(a) C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C6 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
R3 is an aryl or heteroaryl group substituted with from 1 to 4 substituents wherein one of the substituents is a hydroxyl or amino group located at the 2 position relative to the group containing Y1 and Y2, and wherein the remaining substituents are selected from the group consisting of hydroxyl, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminocarbonyl, carbonyl, aminosulfonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, guanidino, halogen, heteroaryl, heterocyclyl , sulfido, sulfonyl, sulfoxido, sulfonic acid, sulfate, and thiol;
R4 is selected from the group consisting of:
(a) C1-C10 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C10 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
R5 is hydrogen or is selected from the group consisting of:
(a) C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
Xi and X2 are independently hydroxyl, halogen, NR4R5, C1-C6 alkoxy, or when taken together Xi and X2 form a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together Xi and X2 form a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S1 or when taken together Xi and X2 form a cyclic boron amide-ester where said chain contains from 2-20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, Or X1 and Ri together form a cyclic ring where said ring contains 2 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, halogen, NR4R5, C1-C6 alkoxy, or Xi and R3 together form a cyclic ring where said ring contains 3 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, halogen, NR4R5, or C1-C6 alkoxy;
Y1 and Y2 are independently hydrogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminosulfonyl, aminocarbonyl, carbonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, halogen, heteroaryl, heteroaryloxy, heterocyclyl, sulfido, sulfonyl, or sulfoxido, or taken together Y1 and Y2 form a cyclic structure containing from 3-12 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S;
or a salt thereof.
23. A method of reducing bacterial resistance to a β-lactam antibiotic comprising contacting a bacterial cell having resistance to a β-lactam antibiotic with an effective amount of a beta-lactamase inhibitor with broad-spectrum functionality having the formula:
(a) aryl group substituted with from O to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(b) heteroaryl group substituted with from O to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(c) heterocyclic group substituted with from O to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido;
R2 is hydrogen, or is selected from the group consisting of: (a) C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C6 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
R3 is an aryl or heteroaryl group substituted with from 1 to 4 substituents wherein one of the substituents is a hydroxyl or amino group located at the 2 position relative to the group containing Yi and Y2, and wherein the remaining substituents are selected from the group consisting of hydroxyl, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminocarbonyl, carbonyl, aminosulfonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, guanidino, halogen, heteroaryl, heterocyclyl , sulfido, sulfonyl, sulfoxido, sulfonic acid, sulfate, and thiol;
R4 is selected from the group consisting of:
(a) C1-C10 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C10 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido; R5 is hydrogen or is selected from the group consisting of:
(a) C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sύlfoxido,
(b) C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxide and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
Xi and X2 are independently hydroxyl, halogen, NR4R5, C1-C6 alkoxy, or when taken together Xi and X2 form a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O1 N, or S, or when taken together Xi and X2 form a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together Xi and X2 form a cyclic boron amide-ester where said chain contains from 2-20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or Xi and R1 together form a cyclic ring where said ring contains 2 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, halogen, NR4R5, C1-C6 alkoxy, or X1 and R3 together form a cyclic ring where said ring contains 3 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, halogen, NR4R5, or C1-C6 alkoxy;
Y1 and Y2 are independently hydrogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminosulfonyl, aminocarbonyl, carbonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, halogen, heteroaryl, heteroaryloxy, heterocyclyl, sulfido, sulfonyl, or sulfoxido, or taken together Y1 and Y2 form a cyclic structure containing from 3-12 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S; or a salt thereof.
24. The method of claim 23, further comprising contacting the bacterial cell with an effective amount of a β-lactam antibiotic.
25. The method of claim 23, wherein the contacting of the bacterial cell takes place in vivo.
26. The method of claim 23, wherein the contacting of the bacterial cell takes place in vitro.
27. Use of a beta-lactamase inhibitor with broad-spectrum functionality having the formula:
(a) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(b) heteroaryl group substituted with from O to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(c) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido;
R2 is hydrogen, or is selected from the group consisting of:
(a) C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C6 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxide
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
R3 is an aryl or heteroaryl group substituted with from 1 to 4 substituents wherein one of the substituents is a hydroxyl or amino group located at the 2 position relative to the group containing Y1 and Y2, and wherein the remaining substituents are selected from the group consisting of hydroxyl, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminocarbonyl, carbonyl, aminosulfonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, guanidino, halogen, heteroaryl, heterocyclyl , sulfido, sulfonyl, sulfoxido, sulfonic acid, sulfate, and thiol;
R4 is selected from the group consisting of: (a) C1-C10 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C10 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guamdino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alky!, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
R5 is hydrogen or is selected from the group consisting of:
(a) C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido, (c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
X1 and X2 are independently hydroxyl, halogen, NR4R5, C1-C6 alkoxy, or when taken together Xi and X2 form a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together X1 and X2 form a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together X1 and X2 form a cyclic boron amide-ester where said chain contains from 2-20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, Or X1 and Ri together form a cyclic ring where said ring contains 2 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, halogen, NR4R5, C1-C6 alkoxy, or X1 and R3 together form a cyclic ring where said ring contains 3 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, halogen, NR4R5, or C1-C6 alkoxy;
Y-i and Y2 are independently hydrogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminosulfonyl, aminocarbonyl, carbonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, halogen, heteroaryl, heteroaryloxy, heterocyclyl, sulfido, sulfonyl, or sulfoxido, or taken together Y1 and Y2 form a cyclic structure containing from 3-12 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S;
or a salt thereof;
provided that, when R1 is -C(O)R4, R2 is hydrogen, R3 is a phenyl group having two substituents consisting of a hydroxyl at the 2-position and a carboxylic acid at the 3-position relative to the group containing Y1 and Y2, X1 and X2 are hydroxyl or X1 is hydroxyl and X2 is replaced by the ortho-hydroxyl oxygen of R3 such that a 6-membered ring is formed, and Y1 and Y2 are hydrogen, R4 is not unsubstituted C1 alkyl;
in combination with a β-lactam antibiotic in the manufacture of a medicament for the treatment of a bacterial infection.
28. A composition for use in combination with a β-lactam antibiotic in reducing a bacterial infection comprising:
(b) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(c) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido;
R2 is hydrogen, or is selected from the group consisting of:
(a) C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C6 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
R3 is an aryl or heteroaryl group substituted with from 1 to 4 substituents wherein one of the substituents is a hydroxyl or amino group located at the 2 position relative to the group containing Y1 and Y2, and wherein the remaining substituents are selected from the group consisting of hydroxyl, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminocarbonyl, carbonyl, aminosulfonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, guanidino, halogen, heteroaryl, heterocyclyl , sulfido, sulfonyl, sulfoxido, sulfonic acid, sulfate, and thiol;
R4 is selected from the group consisting of:
(a) C1-C10 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C10 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyϊmino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
R5 is hydrogen or is selected from the group consisting of:
(a) C1-C6 alkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the C1-C10 carbons comprise part of said oxyimino group, sulfido, and sulfoxido,
(b) C3-C7 cycloalkyl any carbon of which can be substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the cycloalkyl group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido,
(c) aryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido,
(d) heteroaryl group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido, and
(e) heterocyclic group substituted with from 0 to 3 substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cyano, thiol, sulfonic acid, sulfate, optionally substituted: alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, oxyimino wherein any of the carbons of the heterocyclic group other than the one attached to the rest of the molecule comprise part of said oxyimino group, sulfido, and sulfoxido;
Xi and X2 are independently hydroxyl, halogen, NR4R5, C1-C6 alkoxy, or when taken together Xi and X2 form a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together X1 and X2 form a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, or when taken together Xi and X2 form a cyclic boron amide-ester where said chain contains from 2-20 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, Or X1 and Ri together form a cyclic ring where said ring contains 2 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, halogen, NR4R5, C1-C6 alkoxy, or Xi and R3 together form a cyclic ring where said ring contains 3 to 10 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S, and X2 is hydroxyl, halogen, NR4R5, or C1-C6 alkoxy;
Y1 and Y2 are independently hydrogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, aminosulfonyl, aminocarbonyl, carbonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, halogen, heteroaryl, heteroaryloxy, heterocyclyl, sulfido, sulfonyl, or sulfoxido, or taken together Yi and Y2 form a cyclic structure containing from 3-12 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N, or S;
or a salt thereof;
provided that, when R1 is -C(O)R4, R2 is hydrogen, R3 is a phenyl group having two substituents consisting of a hydroxyl at the 2-position and a carboxylic acid at the 3-position relative to the group containing Y1 and Y2, X1 and X2 are hydroxyl or Xi is hydroxyl and X2 is replaced by the ortho-hydroxyl oxygen of R3 such that a 6-membered ring is formed and Yi and Y2 are hydrogen, R4 is not unsubstituted C1 alkyl.
Priority Applications (15)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2008321444A AU2008321444A1 (en) | 2007-11-13 | 2008-11-13 | Beta-lactamase inhibitors |
| BRPI0820532-9A BRPI0820532A2 (en) | 2007-11-13 | 2008-11-13 | beta-lactamase inhibitors |
| MX2010005250A MX2010005250A (en) | 2007-11-13 | 2008-11-13 | Beta-lactamase inhibitors. |
| CN200880112051A CN101861324A (en) | 2007-11-13 | 2008-11-13 | Beta-lactamase inhibitors |
| CA2705393A CA2705393A1 (en) | 2007-11-13 | 2008-11-13 | Beta-lactamase inhibitors |
| EA201000775A EA201000775A1 (en) | 2007-11-13 | 2008-11-13 | BETA LACTAMASE INHIBITORS |
| US12/742,526 US20100286092A1 (en) | 2007-11-13 | 2008-11-13 | Beta-lactamase inhibitors |
| EP08848689A EP2220097A1 (en) | 2007-11-13 | 2008-11-13 | Beta-lactamase inhibitors |
| JP2010534032A JP2011503181A (en) | 2007-11-13 | 2008-11-13 | Beta-lactamase inhibitor |
| US12/464,609 US20100120715A1 (en) | 2007-11-13 | 2009-05-12 | Beta-lactamase inhibitors |
| PCT/US2009/064165 WO2010056827A1 (en) | 2008-11-13 | 2009-11-12 | Beta-lactamase inhibitors |
| ZA2010/02467A ZA201002467B (en) | 2007-11-13 | 2010-04-08 | Beta-lactamase inhibitors |
| IL205205A IL205205A0 (en) | 2007-11-13 | 2010-04-19 | Beta - lactamase inhibitors |
| TN2010000203A TN2010000203A1 (en) | 2007-11-13 | 2010-05-07 | Beta-lactamase inhibitors |
| MA32883A MA31874B1 (en) | 2007-11-13 | 2010-05-31 | BETA-LACTAMASES INHIBITORS |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US279707P | 2007-11-13 | 2007-11-13 | |
| US61/002,797 | 2007-11-13 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US12/464,609 Continuation-In-Part US20100120715A1 (en) | 2007-11-13 | 2009-05-12 | Beta-lactamase inhibitors |
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| WO2009064414A1 true WO2009064414A1 (en) | 2009-05-22 |
Family
ID=40344560
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
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| PCT/US2008/012705 WO2009064413A1 (en) | 2007-11-13 | 2008-11-13 | Beta-lactamase inhibitors |
| PCT/US2008/012706 WO2009064414A1 (en) | 2007-11-13 | 2008-11-13 | Beta-lactamase inhibitors |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
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| PCT/US2008/012705 WO2009064413A1 (en) | 2007-11-13 | 2008-11-13 | Beta-lactamase inhibitors |
Country Status (21)
| Country | Link |
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| US (2) | US20100317621A1 (en) |
| EP (2) | EP2220097A1 (en) |
| JP (2) | JP2011503181A (en) |
| KR (2) | KR20100109901A (en) |
| CN (2) | CN101861324A (en) |
| AR (2) | AR069463A1 (en) |
| AU (2) | AU2008321444A1 (en) |
| BR (2) | BRPI0820531A2 (en) |
| CA (2) | CA2705393A1 (en) |
| CO (1) | CO6331427A2 (en) |
| CR (1) | CR11372A (en) |
| EA (2) | EA201000775A1 (en) |
| EC (1) | ECSP10010246A (en) |
| GT (1) | GT201000143A (en) |
| IL (1) | IL205205A0 (en) |
| MA (1) | MA31874B1 (en) |
| MX (2) | MX2010005252A (en) |
| TN (1) | TN2010000203A1 (en) |
| TW (2) | TW200936143A (en) |
| WO (2) | WO2009064413A1 (en) |
| ZA (1) | ZA201002467B (en) |
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