JP2016516813A - 抗菌性シデロフォア−アミノペニシリン複合体 - Google Patents
抗菌性シデロフォア−アミノペニシリン複合体 Download PDFInfo
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- JP2016516813A JP2016516813A JP2016508929A JP2016508929A JP2016516813A JP 2016516813 A JP2016516813 A JP 2016516813A JP 2016508929 A JP2016508929 A JP 2016508929A JP 2016508929 A JP2016508929 A JP 2016508929A JP 2016516813 A JP2016516813 A JP 2016516813A
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- Prior art keywords
- compound
- bacterial infection
- compound according
- siderophore
- alkyl
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- 230000000844 anti-bacterial effect Effects 0.000 title abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 41
- 230000003115 biocidal effect Effects 0.000 claims abstract description 26
- 241000894006 Bacteria Species 0.000 claims abstract description 22
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims abstract description 20
- 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 abstract description 19
- 229960003022 amoxicillin Drugs 0.000 claims abstract description 18
- 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 abstract description 18
- 229960000723 ampicillin Drugs 0.000 claims abstract description 18
- 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 abstract description 18
- 150000001875 compounds Chemical class 0.000 claims description 113
- -1 hydroxy, carboxy Chemical group 0.000 claims description 36
- 239000003242 anti bacterial agent Substances 0.000 claims description 35
- 239000000203 mixture Substances 0.000 claims description 33
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical group 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 14
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- 208000035143 Bacterial infection Diseases 0.000 claims description 13
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 13
- 230000002401 inhibitory effect Effects 0.000 claims description 10
- 239000012453 solvate Substances 0.000 claims description 10
- 241000588724 Escherichia coli Species 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 229960003276 erythromycin Drugs 0.000 claims description 7
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical group O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical group CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 claims description 6
- QJBZDBLBQWFTPZ-UHFFFAOYSA-N pyrrolnitrin Chemical compound [O-][N+](=O)C1=C(Cl)C=CC=C1C1=CNC=C1Cl QJBZDBLBQWFTPZ-UHFFFAOYSA-N 0.000 claims description 6
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 claims description 6
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Chemical group CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 claims description 5
- 229960005287 lincomycin Drugs 0.000 claims description 5
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical group CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 claims description 5
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical group C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 claims description 4
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical group C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 229960003722 doxycycline Drugs 0.000 claims description 4
- 229960000318 kanamycin Drugs 0.000 claims description 4
- 229930027917 kanamycin Chemical group 0.000 claims description 4
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical group O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 claims description 4
- 229930182823 kanamycin A Chemical group 0.000 claims description 4
- 229960005404 sulfamethoxazole Drugs 0.000 claims description 4
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 claims description 4
- XIYOPDCBBDCGOE-IWVLMIASSA-N (4s,4ar,5s,5ar,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methylidene-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical group C=C1C2=CC=CC(O)=C2C(O)=C2[C@@H]1[C@H](O)[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O XIYOPDCBBDCGOE-IWVLMIASSA-N 0.000 claims description 3
- GUXHBMASAHGULD-SEYHBJAFSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical group C1([C@H]2O)=C(Cl)C=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O GUXHBMASAHGULD-SEYHBJAFSA-N 0.000 claims description 3
- 229930183010 Amphotericin Chemical group 0.000 claims description 3
- QGGFZZLFKABGNL-UHFFFAOYSA-N Amphotericin A Chemical group OC1C(N)C(O)C(C)OC1OC1C=CC=CC=CC=CCCC=CC=CC(C)C(O)C(C)C(C)OC(=O)CC(O)CC(O)CCC(O)C(O)CC(O)CC(O)(CC(O)C2C(O)=O)OC2C1 QGGFZZLFKABGNL-UHFFFAOYSA-N 0.000 claims description 3
- 239000004099 Chlortetracycline Chemical group 0.000 claims description 3
- FMTDIUIBLCQGJB-UHFFFAOYSA-N Demethylchlortetracyclin Chemical group C1C2C(O)C3=C(Cl)C=CC(O)=C3C(=O)C2=C(O)C2(O)C1C(N(C)C)C(O)=C(C(N)=O)C2=O FMTDIUIBLCQGJB-UHFFFAOYSA-N 0.000 claims description 3
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical group O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 claims description 3
- 229930182566 Gentamicin Chemical group 0.000 claims description 3
- 241000589516 Pseudomonas Species 0.000 claims description 3
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 claims description 3
- NHUHCSRWZMLRLA-UHFFFAOYSA-N Sulfisoxazole Chemical compound CC1=NOC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1C NHUHCSRWZMLRLA-UHFFFAOYSA-N 0.000 claims description 3
- 239000004098 Tetracycline Substances 0.000 claims description 3
- UFUVLHLTWXBHGZ-MGZQPHGTSA-N [(2r,3r,4s,5r,6r)-6-[(1s,2s)-2-chloro-1-[[(2s,4r)-1-methyl-4-propylpyrrolidine-2-carbonyl]amino]propyl]-4,5-dihydroxy-2-methylsulfanyloxan-3-yl] dihydrogen phosphate Chemical group CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](OP(O)(O)=O)[C@@H](SC)O1 UFUVLHLTWXBHGZ-MGZQPHGTSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 229960004821 amikacin Drugs 0.000 claims description 3
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical group O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 claims description 3
- 229940009444 amphotericin Drugs 0.000 claims description 3
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical group O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 claims description 3
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical group 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 3
- 229960003644 aztreonam Drugs 0.000 claims description 3
- 229960000603 cefalotin Drugs 0.000 claims description 3
- 229960005091 chloramphenicol Drugs 0.000 claims description 3
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical group 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 3
- CYDMQBQPVICBEU-UHFFFAOYSA-N chlorotetracycline Chemical group C1=CC(Cl)=C2C(O)(C)C3CC4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-UHFFFAOYSA-N 0.000 claims description 3
- 229960004475 chlortetracycline Drugs 0.000 claims description 3
- CYDMQBQPVICBEU-XRNKAMNCSA-N chlortetracycline Chemical group C1=CC(Cl)=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-XRNKAMNCSA-N 0.000 claims description 3
- 235000019365 chlortetracycline Nutrition 0.000 claims description 3
- 229960002227 clindamycin Drugs 0.000 claims description 3
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical group CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 claims description 3
- 229960002291 clindamycin phosphate Drugs 0.000 claims description 3
- 229960002398 demeclocycline Drugs 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 229960004679 doxorubicin Drugs 0.000 claims description 3
- 229960000285 ethambutol Drugs 0.000 claims description 3
- 229960002518 gentamicin Drugs 0.000 claims description 3
- 208000027096 gram-negative bacterial infections Diseases 0.000 claims description 3
- 229960003350 isoniazid Drugs 0.000 claims description 3
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical group NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 claims description 3
- 230000002147 killing effect Effects 0.000 claims description 3
- 231100000518 lethal Toxicity 0.000 claims description 3
- 230000001665 lethal effect Effects 0.000 claims description 3
- 229960001977 loracarbef Drugs 0.000 claims description 3
- 229940042016 methacycline Drugs 0.000 claims description 3
- 229960002132 pyrrolnitrin Drugs 0.000 claims description 3
- 229960005322 streptomycin Drugs 0.000 claims description 3
- 229960002135 sulfadimidine Drugs 0.000 claims description 3
- 229960000654 sulfafurazole Drugs 0.000 claims description 3
- ASWVTGNCAZCNNR-UHFFFAOYSA-N sulfamethazine Chemical compound CC1=CC(C)=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 ASWVTGNCAZCNNR-UHFFFAOYSA-N 0.000 claims description 3
- 229960005158 sulfamethizole Drugs 0.000 claims description 3
- VACCAVUAMIDAGB-UHFFFAOYSA-N sulfamethizole Chemical compound S1C(C)=NN=C1NS(=O)(=O)C1=CC=C(N)C=C1 VACCAVUAMIDAGB-UHFFFAOYSA-N 0.000 claims description 3
- 229960002180 tetracycline Drugs 0.000 claims description 3
- 235000019364 tetracycline Nutrition 0.000 claims description 3
- 229930101283 tetracycline Natural products 0.000 claims description 3
- 150000003522 tetracyclines Chemical class 0.000 claims description 3
- 241000588626 Acinetobacter baumannii Species 0.000 claims description 2
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Chemical group 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 description 2
- DYDCUQKUCUHJBH-UWTATZPHSA-N D-Cycloserine Chemical group N[C@@H]1CONC1=O DYDCUQKUCUHJBH-UWTATZPHSA-N 0.000 claims description 2
- DYDCUQKUCUHJBH-UHFFFAOYSA-N D-Cycloserine Chemical group NC1CONC1=O DYDCUQKUCUHJBH-UHFFFAOYSA-N 0.000 claims description 2
- 108010013198 Daptomycin Chemical group 0.000 claims description 2
- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical group 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 description 2
- PJSFRIWCGOHTNF-UHFFFAOYSA-N Sulphormetoxin Chemical compound COC1=NC=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1OC PJSFRIWCGOHTNF-UHFFFAOYSA-N 0.000 claims description 2
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Chemical group C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 claims description 2
- 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 group 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 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 229960003169 biapenem Drugs 0.000 claims description 2
- MRMBZHPJVKCOMA-YJFSRANCSA-N biapenem Chemical group 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 description 2
- 229960005361 cefaclor Drugs 0.000 claims description 2
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical group 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 description 2
- 229960003405 ciprofloxacin Drugs 0.000 claims description 2
- 229960003077 cycloserine Drugs 0.000 claims description 2
- DOAKLVKFURWEDJ-QCMAZARJSA-N daptomycin Chemical group C([C@H]1C(=O)O[C@H](C)[C@@H](C(NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@H](C(=O)N1)[C@H](C)CC(O)=O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCCCCCCCC)C(=O)C1=CC=CC=C1N DOAKLVKFURWEDJ-QCMAZARJSA-N 0.000 claims description 2
- 229960005484 daptomycin Drugs 0.000 claims description 2
- 229960000895 doripenem Drugs 0.000 claims description 2
- AVAACINZEOAHHE-VFZPANTDSA-N doripenem Chemical group 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 description 2
- 229960002770 ertapenem Drugs 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
- 229960002182 imipenem Drugs 0.000 claims description 2
- 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 description 2
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- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical group 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 description 2
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229960001225 rifampicin Drugs 0.000 claims description 2
- 229960002673 sulfacetamide Drugs 0.000 claims description 2
- SKIVFJLNDNKQPD-UHFFFAOYSA-N sulfacetamide Chemical compound CC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 SKIVFJLNDNKQPD-UHFFFAOYSA-N 0.000 claims description 2
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 claims description 2
- 229960004306 sulfadiazine Drugs 0.000 claims description 2
- 229960004673 sulfadoxine Drugs 0.000 claims description 2
- QPPBRPIAZZHUNT-UHFFFAOYSA-N sulfamerazine Chemical compound CC1=CC=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 QPPBRPIAZZHUNT-UHFFFAOYSA-N 0.000 claims description 2
- 229960002597 sulfamerazine Drugs 0.000 claims description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims 2
- VUFGUVLLDPOSBC-XRZFDKQNSA-M cephalothin sodium Chemical group [Na+].N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C([O-])=O)C(=O)CC1=CC=CS1 VUFGUVLLDPOSBC-XRZFDKQNSA-M 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- JAPHQRWPEGVNBT-UTUOFQBUSA-N loracarbef Chemical group C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CC[C@@H]32)C([O-])=O)=O)[NH3+])=CC=CC=C1 JAPHQRWPEGVNBT-UTUOFQBUSA-N 0.000 claims 1
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 claims 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 abstract description 70
- 239000000589 Siderophore Substances 0.000 abstract description 33
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- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
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Abstract
Description
本出願は、米国特許出願第13/865,801号(2013年4月18日出願)(この記載内容は参照により本明細書中で援用される)に対する優先権を主張する。
本発明は、国立衛生研究所により授与された契約番号AI054193およびT32GM075762下での政府支援によりなされた。
(式中、Xは、エステルまたはアミド結合を介して、式(I)の例示構造と共有結合される抗生物質であり;
mは、0または1〜11であり;
R1は、各々独立して、H、−C(=O)アルキル、−C(=O)アリールまたは−C(=O)O−アルキルであり;
R2は、各々独立して、H、アルキル、アルコキシ、ヒドロキシ、カルボキシ、ハロ、ニトロ、アミノまたはシアノであり;ならびに
nは、各々独立して、1、2または3である)
の化合物、あるいはその製薬上許容可能な塩または溶媒和物を提供する。
本発明は、鉄輸送媒介性薬剤送達化合物および方法を提供する。化合物の合成および効力は評価され、選択的抗シュードモナス化合物が発見された。本発明は、相対的に簡単なシデロフォア模倣物および抗生物質の種々の合成複合体を提供し、この複合体は、選択的に強力な抗細菌活性を有するが、一方、親抗生物質それ自体は、低活性であるかまたは実質的に完全に不活性である。
スキーム1.トリス−カテコレートシデロフォアならびに複合体10および11の合成
試薬および条件:(a)1. BH3−THF、THF、還流;2. Boc2O、Et3N、MeOH、還流、2つのステップに関して83%;(b)NiCl2、NaBH4、MeOH、音波処理92%;(c)メチルスクシニルクロリド、Et3N、CH2Cl2、0℃〜室温、75%;(d)6N HCl、還流、100%;(e)2,3−ジアシルオキシベンゾイルクロリド8、水性NaHCO3/THF、0℃〜室温、57%;(f)1. イソブチルクロロホルメート、N−メチルモルホリン、THF、0℃;2. アンピシリンまたはアモキシシリン、Et3N、THF/H2O、0℃〜室温、55%(10に関して)、50%(11に関して)。
a化合物10を、0.1mMで試験した。
b各化合物を、三重反復実験で試験した。
本明細書中で用いる場合、列挙される用語は以下の意味を有する。本明細書中で用いられるその他の用語および語句はすべて、当業者が理解するようなそれらの普通の意味を有する。このような普通の意味は、分野別辞書、例えばHawley’s Condensed Chemical Dictionary 14th Edition,by R.J.Lewis,John Wiley&Sons,New York,N.Y.,2001を参照することにより獲得され得る。
本明細書中に記載される化合物の調製物は、以下の実施例における方法により調製され得るし、あるいは有機合成の技術分野における既知の技法により調製され得る。抗生物質を式(I)と共役させるための多数の結合基は市販されており、および/または当該技術分野で記載されるように調製され得る。本明細書中に記載される化合物を調製するために用いられ得る一般的合成方法に関する、特に結合基を用いることに関する情報は、Greg T.Hermanson,Bioconjugate Techniques,Academic Press,San Diego,CA(1996)に見出され得る。抗生物質を式(A)に連結するために用いられ得る有用なリンカーおよび共役技法は、さらに、Roosenberg et al.,Curr.Med.Chem.2000,7,159;Wittmann et al.,Bioorg.Med.Chem.2002,10,1659;およびHeinisch et al.,J.Med.Chem.2002,45,3032に記載されている。当業者に周知のさらに有用な反応は、March’s Advanced Organic Chemistry Reactions,Mechanisms,and Structure,5th Ed.by Michael B.Smith and Jerry March,John Wiley&Sons,Publishers;およびWuts et al.(1999),Protective Groups in Organic Synthesis,3rd Ed.,John Wiley&Sons,Publishersで言及されている。
の化合物と縮合することにより容易に調製され得るが、この場合、Yは、脱離基、例えばハロゲン(例えば、アミンまたはアルコールとカップリングするため)、例えばクロリドである。式(A)の部分−C(=O)Yは、さらにまた、活性化カルボニルまたは活性エステルであり得るし、残りの変数は、式(I)に関して記載された通りである。このような縮合は、適切な溶媒および塩基(例えば、トリエチルアミン等)の存在下で、しばしば、有益には、室温またはそれより低い温度で実行され得る。抗生物質が利用可能なアミン部分を有さないが、しかし式(A)との連結を形成するために利用可能なヒドロキシルを有する場合、抗生物質のヒドロキシル基は、エステルを生成するために直接結合され得るし、あるいはまず、末端(任意に保護される)アミノ基を有するアルカン酸、例えば2−アミノ酢酸または3−アミノプロピオン酸のような基でエステル化され、その後、上記の縮合反応を実施して、本発明の化合物を提供する。
本明細書中に記載される化合物は、例えば化合物を製薬上許容可能な希釈剤、賦形剤または担体と組み合わせることにより、治療用薬学的組成物を調製するために用いられ得る。化合物は、塩または溶媒和物の形態で、担体に添加され得る。例えば、安定な非毒性の酸または塩基塩を生成するのに十分に塩基性または酸性である場合、塩としての化合物の投与が適切であり得る。製薬上許容可能な塩の例は、生理学的に許容可能な陰イオンを生成する酸を用いて形成される有機酸付加塩、例えばトシル酸塩、メタンスルホン酸塩、酢酸塩、クエン酸塩、マロン酸塩、酒石酸塩、コハク酸塩、安息香酸塩、アスコルビン酸塩、α−ケトグルタル酸塩およびb−グリセロリン酸塩である。適切な無機塩、例えば塩酸塩、ハロゲン化物、硫酸塩、硝酸塩、重炭酸塩および炭酸塩も生成され得る。
一般的情報 反応はすべて、標準技法を用いてアルゴン下で実行した。溶媒および試薬はすべて、商業的供給元から入手し、別記しない限り、さらに精製せずに用いた。テトラヒドロフラン(THF)を、ナトリウムおよびベンゾフェノンから蒸留した。UV光、ヨウ素またはKMnO4染色下で、可視化される0.25mmシリカゲルプレート上での薄層クロマトグラフィー(TLC)により、反応をモニタリングした。ソルベント技法シリカゲル60(32〜63μm)を用いて、シリカゲルカラムクロマトグラフィーを実施した。逆相C18シリカゲルは、イーライリリー社から御厚意により寄贈頂いたものであり、NMRスペクトルを周囲温度でVarian 600MHz分光計で記録した。YMC Pro C18逆相カラム(3.0×50mm)を用いて、HPLC分析を実行した。用いた移動相は、HPLC等級水(A)およびHPLC等級アセトニトリル(B)中の10mM酢酸アンモニウムであった。0.7mL/分の流量で、5%−80%のBで10分、次いで80%−95%のBで2分、その後、95%−5%のBで3分から、勾配を形成した(総実行時間15分)。UV検出器(254nm)およびYMC−Pack Pro C18カラム(150×20mm、粒子サイズ5μm)を用いて、15mL/分の流量で、Waters分取バイナリポンプ系で、分取HPLC精製を実施した。15mL/分の流量で、10mM酢酸アンモニウム水溶液およびアセトニトリルから、溶媒勾配を形成した。
HRMS(ESI) C25H51N4O6(M+H)+に関する計算値:503.3803,実測値:503.3815.
0℃に冷却した1.5mLの無水THF中の酸9(38mg、0.039mmol)およびN−メチルモルホリン(4.5μL、0.041mmol)の溶液に、イソブチルクロロホルメート(5.2μL、0.040mmol)を添加し、混合物をその温度で1時間撹拌した。1mLのTHF/H2O(4:1)中のD−フェニルグリシンアミド(8.6mg、0.057mmol)およびEt3N(10μL)の溶液を添加し、混合物を、0℃で1時間、室温で1時間、撹拌した。真空下でのTHFの除去後、残渣をH2O(5mL)中に懸濁し、EtOAc(5mL×3)で抽出した。併合有機層をNa2SO4上で乾燥し、濾過した。溶媒を真空下で除去し、残渣を、シリカゲル上でのクロマトグラフィー(5〜8%MeOH;CH2Cl2中)で生成して、複合体S1(28mg、66%)を白色固体として得た: 1HNMR(600MHz,DMSO−d6) δ8.41(d,J=7.9Hz,1H),8.31(t,J=5.3Hz,3H),7.65(br.s.,1H),7.25−7.45(m,14H),7.13および7.12(2×s,2H),5.36(d,J=8.2Hz,1H),3.11−3.17(m,6H),2.35−2.48(m,2H),2.30−2.34(m,2H),2.28(s,9H),2.21(s,9H),1.58−1.67(m,6H),1.37−1.44(m,6H);HRMS(ESI) C55H63N6O18(M+H)+:に関する実測値:1095.4193, 理論値:1095.4203.
一般的材料および方法 全ての液体および培地を、使用前にオートクレーブ処理(121℃、15分)により滅菌した。水溶液および培地はすべて、蒸留水、脱イオン水および濾過水(Millipore Milli−Q Advantage A10水精製系)を用いて調製した。ルリアブロス(LB)を、VWRから購入した。ミューラー・ヒントンNo.2ブロス(MHIIブロス;陽イオン調整)を、Sigma−Aldrich(St.Louis,MO)から購入した。2,2’−ビピリジンの1mg/mL滅菌水溶液0.8mLを49.2mLのMHIIブロスに添加することにより、鉄欠乏(−Fe)MHIIブロスを調製した。FeCl3の1mg/mL滅菌水溶液0.8mLを49.2mLのMHIIブロスに添加することにより、鉄濃化(+Fe)MHIIブロスを調製した。ミューラー・ヒントンNo.2寒天(MHII寒天;HiMedia Laboratories)を、VWRから購入した。2,2’−ビピリジンの1mg/mL滅菌水溶液0.5mLを、静かに混合しながら34mLの融解MHII寒天に添加することにより、鉄欠乏(−Fe)MHII寒天を調製した。FeCl3の1mg/mL滅菌水溶液0.5mLを、静かに混合しながら34mLの融解MHII寒天に添加することにより、鉄濃化(+Fe)MHII寒天を調製した。関連技法に関しては、Wencewicz,T.A.Dissertation,University of Notre Dame,Notre Dame,IN,2011も参照されたい。
以下の製剤は、本明細書中に記載される式の化合物、本明細書中に具体的に開示される化合物、あるいはその製薬上許容可能な塩または溶媒和物(以後、「化合物X」として言及)の治療的または予防的投与のために用いられ得る代表的薬学的剤形を示す:
(i) 錠剤1 mg/錠剤
「化合物X」 100.0
ラクトース 77.5
ポビドン 15.0
クロスカルメロースナトリウム 12.0
微晶質セルロース 92.5
ステアリン酸マグネシウム 3.0
300.0
(ii) 錠剤2 mg/錠剤
「化合物X」 20.0
微晶質セルロース 410.0
デンプン 50.0
デンプングリコール酸ナトリウム 15.0
ステアリン酸マグネシウム 5.0
500.0
(iii) カプセル mg/カプセル
「化合物X」 10.0
コロイド二酸化ケイ素 1.5
ラクトース 465.5
アルファデンプン 120.0
ステアリン酸マグネシウム 3.0
600.0
(iv) 注射液1(1mg/mL) mg/mL
「化合物X」(遊離酸形態) 1.0
二塩基性リン酸ナトリウム 12.0
一塩基性リン酸ナトリウム 0.7
塩化ナトリウム 4.5
1.0N水酸化ナトリウム溶液 十分量
(pHを7.0〜7.5に調節)
注射液用水 全量を1mLとするのに十分な量
(v) 注射液2(10mg/mL) mg/mL
「化合物X」(遊離酸形態) 10.0
一塩基性リン酸ナトリウム 0.3
二塩基性リン酸ナトリウム 1.1
ポリエチレングリコール400 200.0
0.1N水酸化ナトリウム溶液 十分量
(pHを7.0〜7.5に調節)
注射液用水 全量を1mLとするのに十分な量
(vi) エアゾール mg/缶
「化合物X」 20
オレイン酸 10
トリクロロモノフルオロメタン 5,000
ジクロロジフルオロメタン 10,000
ジクロロテトラフルオロエタン 5,000
(vii) 局所ゲル1 重量%
「化合物X」 5%
カルボマー934 1.25%
トリエタノールアミン 十分量
(pHを5〜7に調節)
メチルパラベン 0.2%
精製水 全量を100gとするのに十分な量
(viii) 局所ゲル2 重量%
「化合物X」 5%
メチルセルロース 2%
メチルパラベン 0.2%
プロピルパラベン 0.02%
精製水 全量を100gとするのに十分な量
(ix) 局所軟膏 重量%
「化合物X」 5%
プロピレングリコール 1%
無水軟膏基剤 40%
ポリソルベート80 2%
メチルパラベン 0.2%
精製水 全量を100gとするのに十分な量
(x) 局所クリーム1 重量%
「化合物X」 5%
白色蜜蝋 10%
液体パラフィン 30%
ベンジルアルコール 5%
精製水 全量を100gとするのに十分な量
(xi) 局所クリーム2 重量%
「化合物X」 5%
ステアリン酸 10%
グリセリルモノステアレート 3%
ポリオキシエチレンステアリルエーテル 3%
ソルビトール 5%
イソプロピルパルミテート 2%
メチルパラベン 0.2%
精製水 全量を100gとするのに十分な量
Claims (19)
- R1が、アセチル、プロパノイルまたはベンゾイルである請求項1記載の化合物。
- R2が、H、アルキル、アルコキシまたはヒドロキシである請求項1記載の化合物。
- R2が各々Hである請求項1記載の化合物。
- nが各々1である請求項1記載の化合物。
- mが、0、1、2または3である請求項1記載の化合物。
- Xが、アミカシン、アモキシシリン、アンピシリン、アンフォテリシン、アズトレオナム、バシロマイシン、BAL30072、ビアペネム、カルモナム、セファクロール、セファロチン、クロラムフェニコール、クロルテトラサイクリン、シプロフロキサシン、クリンダマイシン、リン酸クリンダマイシン、シクロセリン、ダプトマイシン、デメクロサイクリン、ドリペネム、ドキソルビシン、ドキシサイクリン、エルタペネメ、エリスロマイシン、エタンブトール、エリスロマイシン、ゲンタマイシン、イミペネム、イソニアジド、カナマイシン、リンコマイシン、ロラカルベフ、メロペネム、メタサイクリン、ムピロシン、ネオマイシン、ニスタチン、オキシテトラサイクリン、パニペネム、ピロールニトリン、リファムピン、ロリテトラサイクリン、ストレプトマイシン、スルファセタミド、スルファベンズアミド、スルファジアジン、スルファドキシン、スルファメラジン、スルファメタジン、スルファメチゾール、スルファメトキサゾール、スルフイソキサゾール、テトラサイクリンまたはチギモナムである請求項1記載の化合物。
- Xがアンピシリンまたはアモキシシリンである請求項1記載の化合物。
- 請求項1記載の化合物および製薬上許容可能な希釈剤または担体を含む組成物。
- グラム陰性細菌感染症を処置する方法であって、それを必要とする被験体に治療的有効量の請求項1記載の化合物を投与し、それにより細菌感染症を処置することを包含する方法。
- 前記細菌感染症が抗生物質耐性細菌により引き起こされる請求項11記載の方法。
- 前記細菌感染症がシュードモナス系細菌により引き起こされる請求項11記載の方法。
- グラム陰性細菌感染症を処置する方法であって、それを必要とする被験体に治療的有効量の請求項10記載の組成物を投与し、それにより細菌感染症を処置することを包含する方法。
- グラム陰性細菌を死滅させるかまたはその増殖を抑制する方法であって、前記細菌を、有効量致死量または抑制量の請求項1記載の化合物と接触させることを包含する方法。
- 前記細菌感染症が抗生物質耐性細菌により引き起こされる請求項15記載の方法。
- 前記細菌感染症がシュードモナス系細菌により引き起こされる請求項15記載の方法。
- 前記細菌感染症が、緑膿菌、大腸菌、アシネトバクター・バウマニまたはネズミチフス菌により引き起こされる請求項15記載の方法。
- グラム陰性細菌を死滅させるかまたはその増殖を抑制する方法であって、前記細菌を、有効量致死量または抑制量の請求項10記載の組成物と接触させることを包含する方法。
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