JP2020536966A5 - - Google Patents

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Publication number

JP2020536966A5

JP2020536966A5 JP2020541834A JP2020541834A JP2020536966A5 JP 2020536966 A5 JP2020536966 A5 JP 2020536966A5 JP 2020541834 A JP2020541834 A JP 2020541834A JP 2020541834 A JP2020541834 A JP 2020541834A JP 2020536966 A5 JP2020536966 A5 JP 2020536966A5

Authority

JP

Japan

Prior art keywords

pharmaceutically acceptable

pharmaceutical composition

antibiotic

optionally substituted

zinc

Prior art date

2018-10-12

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Granted

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• HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 42
• 239000011701 zinc Substances 0.000 claims description 42
• 229910052725 zinc Inorganic materials 0.000 claims description 42
• 239000002555 ionophore Substances 0.000 claims description 41
• 230000000236 ionophoric effect Effects 0.000 claims description 41
• 230000003115 biocidal effect Effects 0.000 claims description 34
• 239000008194 pharmaceutical composition Substances 0.000 claims description 33
• 239000003242 anti bacterial agent Substances 0.000 claims description 27
• PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical class [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 claims description 22
• 239000012453 solvate Substances 0.000 claims description 19
• 125000000217 alkyl group Chemical group 0.000 claims description 18
• 244000052769 pathogen Species 0.000 claims description 17
• 239000002647 aminoglycoside antibiotic agent Substances 0.000 claims description 15
• 239000000203 mixture Substances 0.000 claims description 15
• 229940088710 antibiotic agent Drugs 0.000 claims description 14
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 12
• 125000000623 heterocyclic group Chemical group 0.000 claims description 12
• -1 zinc (II) coordination complex Chemical class 0.000 claims description 12
• 230000001717 pathogenic effect Effects 0.000 claims description 11
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 10
• 208000035143 Bacterial infection Diseases 0.000 claims description 8
• ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 8
• 229940126574 aminoglycoside antibiotic Drugs 0.000 claims description 8
• 125000003118 aryl group Chemical group 0.000 claims description 8
• 208000022362 bacterial infectious disease Diseases 0.000 claims description 8
• SOVUOXKZCCAWOJ-HJYUBDRYSA-N (4s,4as,5ar,12ar)-9-[[2-(tert-butylamino)acetyl]amino]-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=C(NC(=O)CNC(C)(C)C)C(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O SOVUOXKZCCAWOJ-HJYUBDRYSA-N 0.000 claims description 6
• 108010078777 Colistin Proteins 0.000 claims description 6
• JORAUNFTUVJTNG-BSTBCYLQSA-N n-[(2s)-4-amino-1-[[(2s,3r)-1-[[(2s)-4-amino-1-oxo-1-[[(3s,6s,9s,12s,15r,18s,21s)-6,9,18-tris(2-aminoethyl)-3-[(1r)-1-hydroxyethyl]-12,15-bis(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-h Chemical compound CC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O.CCC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O JORAUNFTUVJTNG-BSTBCYLQSA-N 0.000 claims description 6
• XDJYMJULXQKGMM-UHFFFAOYSA-N polymyxin E1 Natural products CCC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O XDJYMJULXQKGMM-UHFFFAOYSA-N 0.000 claims description 6
• 229960004089 tigecycline Drugs 0.000 claims description 6
• 108010093965 Polymyxin B Proteins 0.000 claims description 5
• 229960003346 colistin Drugs 0.000 claims description 5
• YZPOQCQXOSEMAZ-UHFFFAOYSA-N pbt2 Chemical compound ClC1=CC(Cl)=C(O)C2=NC(CN(C)C)=CC=C21 YZPOQCQXOSEMAZ-UHFFFAOYSA-N 0.000 claims description 5
• 229920000024 polymyxin B Polymers 0.000 claims description 5
• KNIWPHSUTGNZST-UHFFFAOYSA-N polymyxin E2 Natural products CC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O KNIWPHSUTGNZST-UHFFFAOYSA-N 0.000 claims description 5
• 229960005266 polymyxin b Drugs 0.000 claims description 5
• 241000894006 Bacteria Species 0.000 claims description 4
• 241000194033 Enterococcus Species 0.000 claims description 4
• 241000588724 Escherichia coli Species 0.000 claims description 4
• 229930182555 Penicillin Natural products 0.000 claims description 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 description 4
• 239000004098 Tetracycline Substances 0.000 claims description 4
• 239000003474 antibiotic adjuvant Substances 0.000 claims description 4
• 229960005091 chloramphenicol Drugs 0.000 claims description 4
• WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 claims description 4
• 150000001875 compounds Chemical class 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 239000003623 enhancer Substances 0.000 claims description 4
• 229960003276 erythromycin Drugs 0.000 claims description 4
• 229910052736 halogen Inorganic materials 0.000 claims description 4
• 150000002367 halogens Chemical class 0.000 claims description 4
• 229940049954 penicillin Drugs 0.000 claims description 4
• 229920001184 polypeptide Polymers 0.000 claims description 4
• 108090000765 processed proteins & peptides Proteins 0.000 claims description 4
• 102000004196 processed proteins & peptides Human genes 0.000 claims description 4
• 125000003107 substituted aryl group Chemical group 0.000 claims description 4
• 229960002180 tetracycline Drugs 0.000 claims description 4
• 229930101283 tetracycline Natural products 0.000 claims description 4
• 235000019364 tetracycline Nutrition 0.000 claims description 4
• 150000003522 tetracyclines Chemical class 0.000 claims description 4
• JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
• QCDFBFJGMNKBDO-UHFFFAOYSA-N Clioquinol Chemical compound C1=CN=C2C(O)=C(I)C=C(Cl)C2=C1 QCDFBFJGMNKBDO-UHFFFAOYSA-N 0.000 claims description 3
• 241000588748 Klebsiella Species 0.000 claims description 3
• 108010059993 Vancomycin Proteins 0.000 claims description 3
• 239000003814 drug Substances 0.000 claims description 3
• 229940079593 drug Drugs 0.000 claims description 3
• 229960003540 oxyquinoline Drugs 0.000 claims description 3
• 229960003165 vancomycin Drugs 0.000 claims description 3
• MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 claims description 3
• MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 claims description 3
• DQJCDTNMLBYVAY-ZXXIYAEKSA-N (2S,5R,10R,13R)-16-{[(2R,3S,4R,5R)-3-{[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-5-(ethylamino)-6-hydroxy-2-(hydroxymethyl)oxan-4-yl]oxy}-5-(4-aminobutyl)-10-carbamoyl-2,13-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazaheptadecan-1-oic acid Chemical compound NCCCC[C@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@@H](C)NC(=O)C(C)O[C@@H]1[C@@H](NCC)C(O)O[C@H](CO)[C@H]1O[C@H]1[C@H](NC(C)=O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DQJCDTNMLBYVAY-ZXXIYAEKSA-N 0.000 claims description 2
• MINDHVHHQZYEEK-UHFFFAOYSA-N (E)-(2S,3R,4R,5S)-5-[(2S,3S,4S,5S)-2,3-epoxy-5-hydroxy-4-methylhexyl]tetrahydro-3,4-dihydroxy-(beta)-methyl-2H-pyran-2-crotonic acid ester with 9-hydroxynonanoic acid Natural products CC(O)C(C)C1OC1CC1C(O)C(O)C(CC(C)=CC(=O)OCCCCCCCCC(O)=O)OC1 MINDHVHHQZYEEK-UHFFFAOYSA-N 0.000 claims description 2
• IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 2
• 150000004325 8-hydroxyquinolines Chemical class 0.000 claims description 2
• 229930186147 Cephalosporin Natural products 0.000 claims description 2
• IECPWNUMDGFDKC-UHFFFAOYSA-N Fusicsaeure Natural products C12C(O)CC3C(=C(CCC=C(C)C)C(O)=O)C(OC(C)=O)CC3(C)C1(C)CCC1C2(C)CCC(O)C1C IECPWNUMDGFDKC-UHFFFAOYSA-N 0.000 claims description 2
• 108010015899 Glycopeptides Proteins 0.000 claims description 2
• 102000002068 Glycopeptides Human genes 0.000 claims description 2
• 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 description 2
• 241000191967 Staphylococcus aureus Species 0.000 claims description 2
• 241000193998 Streptococcus pneumoniae Species 0.000 claims description 2
• 241001505901 Streptococcus sp. 'group A' Species 0.000 claims description 2
• ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 2
• 125000000304 alkynyl group Chemical group 0.000 claims description 2
• 229960000723 ampicillin Drugs 0.000 claims description 2
• 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 description 2
• 150000001450 anions Chemical class 0.000 claims description 2
• 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 description 2
• 229960003644 aztreonam Drugs 0.000 claims description 2
• YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 claims description 2
• 229940124587 cephalosporin Drugs 0.000 claims description 2
• 150000001780 cephalosporins Chemical class 0.000 claims description 2
• 229960005228 clioquinol Drugs 0.000 claims description 2
• YMDXZJFXQJVXBF-STHAYSLISA-N fosfomycin Chemical compound C[C@@H]1O[C@@H]1P(O)(O)=O YMDXZJFXQJVXBF-STHAYSLISA-N 0.000 claims description 2
• 229960004675 fusidic acid Drugs 0.000 claims description 2
• IECPWNUMDGFDKC-MZJAQBGESA-N fusidic acid Chemical compound O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C IECPWNUMDGFDKC-MZJAQBGESA-N 0.000 claims description 2
• 239000003120 macrolide antibiotic agent Substances 0.000 claims description 2
• 229960003085 meticillin Drugs 0.000 claims description 2
• 229960000282 metronidazole Drugs 0.000 claims description 2
• VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 claims description 2
• 229960003128 mupirocin Drugs 0.000 claims description 2
• 229930187697 mupirocin Natural products 0.000 claims description 2
• DDHVILIIHBIMQU-YJGQQKNPSA-L mupirocin calcium hydrate Chemical compound O.O.[Ca+2].C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC([O-])=O)OC1.C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC([O-])=O)OC1 DDHVILIIHBIMQU-YJGQQKNPSA-L 0.000 claims description 2
• IAIWVQXQOWNYOU-FPYGCLRLSA-N nitrofural Chemical compound NC(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 IAIWVQXQOWNYOU-FPYGCLRLSA-N 0.000 claims description 2
• 229960001907 nitrofurazone Drugs 0.000 claims description 2
• 229960001019 oxacillin Drugs 0.000 claims description 2
• 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 description 2
• LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 2
• 229940031000 streptococcus pneumoniae Drugs 0.000 claims description 2
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
• 229940124530 sulfonamide Drugs 0.000 claims description 2
• 150000003456 sulfonamides Chemical class 0.000 claims description 2
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
• IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 claims description 2
• 229960001082 trimethoprim Drugs 0.000 claims description 2
• 239000004246 zinc acetate Substances 0.000 claims description 2
• 239000011592 zinc chloride Substances 0.000 claims description 2
• 235000005074 zinc chloride Nutrition 0.000 claims description 2
• NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 claims description 2
• 229960001763 zinc sulfate Drugs 0.000 claims description 2
• 229910000368 zinc sulfate Inorganic materials 0.000 claims description 2
• 230000002401 inhibitory effect Effects 0.000 claims 2
• 244000052616 bacterial pathogen Species 0.000 claims 1
• 230000035945 sensitivity Effects 0.000 claims 1
• 239000000126 substance Substances 0.000 claims 1
• 238000000034 method Methods 0.000 description 21
• 239000005725 8-Hydroxyquinoline Substances 0.000 description 1
• 101150004219 MCR1 gene Proteins 0.000 description 1
• 206010034133 Pathogen resistance Diseases 0.000 description 1
• 101100206347 Schizosaccharomyces pombe (strain 972 / ATCC 24843) pmh1 gene Proteins 0.000 description 1
• 238000004519 manufacturing process Methods 0.000 description 1
• YKQOSKADJPQZHB-YNWHQGOSSA-N n-[(2s)-4-amino-1-[[(2s,3r)-1-[[(2s)-4-amino-1-oxo-1-[[(3s,6s,9s,12s,15r,18s,21s)-6,9,18-tris(2-aminoethyl)-3-[(1s)-1-hydroxyethyl]-12,15-bis(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-h Polymers CCC(C)CCCC(=O)N[C@@H](CCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O YKQOSKADJPQZHB-YNWHQGOSSA-N 0.000 description 1
• 231100000252 nontoxic Toxicity 0.000 description 1
• 230000003000 nontoxic effect Effects 0.000 description 1
• 239000003910 polypeptide antibiotic agent Substances 0.000 description 1
• 150000003839 salts Chemical class 0.000 description 1