JP2017507183A - 治療的投与のための水溶性o−カルボニルホスホルアミダートプロドラッグ - Google Patents
治療的投与のための水溶性o−カルボニルホスホルアミダートプロドラッグ Download PDFInfo
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- JP2017507183A JP2017507183A JP2016570920A JP2016570920A JP2017507183A JP 2017507183 A JP2017507183 A JP 2017507183A JP 2016570920 A JP2016570920 A JP 2016570920A JP 2016570920 A JP2016570920 A JP 2016570920A JP 2017507183 A JP2017507183 A JP 2017507183A
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- 229940002612 prodrug Drugs 0.000 title abstract description 49
- 239000000651 prodrug Substances 0.000 title abstract description 49
- REEXCWGNXFPKPJ-UHFFFAOYSA-N 2-amino-2-oxo-1,3,2$l^{5}-dioxaphosphetan-4-one Chemical compound NP1(=O)OC(=O)O1 REEXCWGNXFPKPJ-UHFFFAOYSA-N 0.000 title abstract description 12
- 230000001225 therapeutic effect Effects 0.000 title description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 229
- 238000000034 method Methods 0.000 claims abstract description 49
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- -1 [3- ( 2,3,5-trifluoro-4- (4-oxo-3,4-dihydropyridin-1 (2H) -yl) phenyl) oxazolidine-2-one-5-yl] methyl Chemical group 0.000 claims description 112
- 125000000217 alkyl group Chemical group 0.000 claims description 96
- 239000000203 mixture Substances 0.000 claims description 39
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 241000124008 Mammalia Species 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 23
- 208000015181 infectious disease Diseases 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 19
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 230000000813 microbial effect Effects 0.000 claims description 9
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 8
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 125000001118 alkylidene group Chemical group 0.000 claims description 4
- 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- 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 4
- 125000001475 halogen functional group Chemical group 0.000 claims 3
- 125000005841 biaryl group Chemical group 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 56
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 13
- 229940124597 therapeutic agent Drugs 0.000 abstract description 6
- 239000003242 anti bacterial agent Substances 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 description 47
- 239000000543 intermediate Substances 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 22
- SULYVXZZUMRQAX-NSHDSACASA-N (5s)-5-[(1,2-oxazol-3-ylamino)methyl]-3-[2,3,5-trifluoro-4-(4-oxo-2,3-dihydropyridin-1-yl)phenyl]-1,3-oxazolidin-2-one Chemical compound C([C@H]1CN(C(O1)=O)C=1C=C(C(=C(F)C=1F)N1C=CC(=O)CC1)F)NC=1C=CON=1 SULYVXZZUMRQAX-NSHDSACASA-N 0.000 description 21
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 21
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
- 239000011734 sodium Substances 0.000 description 16
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- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 15
- 229910052760 oxygen Inorganic materials 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 125000005843 halogen group Chemical group 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
- 239000002585 base Substances 0.000 description 13
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- 238000003756 stirring Methods 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 12
- 159000000000 sodium salts Chemical class 0.000 description 12
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 11
- 239000001257 hydrogen Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 238000004949 mass spectrometry Methods 0.000 description 9
- 238000001990 intravenous administration Methods 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000000546 pharmaceutical excipient Substances 0.000 description 8
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 239000004599 antimicrobial Substances 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Substances C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 239000004793 Polystyrene Substances 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 229960003907 linezolid Drugs 0.000 description 6
- 229920002223 polystyrene Polymers 0.000 description 6
- 239000003039 volatile agent Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 5
- 238000001802 infusion Methods 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 239000006187 pill Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- YFYKZQGGHFSEHB-UHFFFAOYSA-N 1,2-oxazol-3-yloxyphosphonamidic acid Chemical class C1=CON=C1OP(=O)(N)O YFYKZQGGHFSEHB-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 0 Cc1cc(NP(O*)(O*)=O)n[o]1 Chemical compound Cc1cc(NP(O*)(O*)=O)n[o]1 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 150000001340 alkali metals Chemical class 0.000 description 4
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- 230000008901 benefit Effects 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
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- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 229940125773 compound 10 Drugs 0.000 description 4
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
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- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
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- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 4
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- 208000002463 Sveinsson chorioretinal atrophy Diseases 0.000 description 3
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- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
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- 239000012267 brine Substances 0.000 description 3
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 3
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- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 2
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- RHFWLPWDOYJEAL-UHFFFAOYSA-N 1,2-oxazol-3-amine Chemical class NC=1C=CON=1 RHFWLPWDOYJEAL-UHFFFAOYSA-N 0.000 description 2
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- 206010061218 Inflammation Diseases 0.000 description 2
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- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical group CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004944 pyrazin-3-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 208000020029 respiratory tract infectious disease Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 208000015339 staphylococcus aureus infection Diseases 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 239000012058 sterile packaged powder Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 description 1
- 229960002722 terbinafine Drugs 0.000 description 1
- IMCGHZIGRANKHV-AJNGGQMLSA-N tert-butyl (3s,5s)-2-oxo-5-[(2s,4s)-5-oxo-4-propan-2-yloxolan-2-yl]-3-propan-2-ylpyrrolidine-1-carboxylate Chemical compound O1C(=O)[C@H](C(C)C)C[C@H]1[C@H]1N(C(=O)OC(C)(C)C)C(=O)[C@H](C(C)C)C1 IMCGHZIGRANKHV-AJNGGQMLSA-N 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- YGNGABUJMXJPIJ-UHFFFAOYSA-N thiatriazole Chemical compound C1=NN=NS1 YGNGABUJMXJPIJ-UHFFFAOYSA-N 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229940061740 zyvox Drugs 0.000 description 1
- 150000003952 β-lactams Chemical class 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/664—Amides of phosphorus acids
-
- 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
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- 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
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
- C07F9/653—Five-membered rings
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- C—CHEMISTRY; METALLURGY
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/6574—Esters of oxyacids of phosphorus
- C07F9/65742—Esters of oxyacids of phosphorus non-condensed with carbocyclic rings or heterocyclic rings or ring systems
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Abstract
Description
治療薬及び生物活性化合物の新規O-カルボニルホスホルアミダートプロドラッグ誘導体、それらの医薬組成物、それらの使用方法、並びにこれを調製するための試薬及び方法を提供する。これらの化合物は、特に液体剤形中での治療的投与に適している。
治療薬の難溶性は、かかる化合物のそれを必要とする哺乳類への有効投与を制限する重大な問題点として広く認識されている。この問題点に対処するひとつの一般的方策は、化合物を化学的に誘導体化し、プロドラッグ、すなわちその投与時に親活性実体を放出する薬物誘導体を形成することであり、これは例えば、論文J. Med. Chem., 2004年, 2393頁において、Ettmayerらにより論評されている。
刊行物PCT JP1998/005709、US 6,417,175、PCT JP2001/006904、及びUS 6,906,055は、ある特定のホスホルアミダートプロドラッグを説明している。これらの化合物はいずれも、本明細書記載のO-カルボニルホスホルアミダートプロドラッグ基を欠いている。
R1は、H、C1-20アルキル、C3-6シクロアルキル、C2-4アルケニル、C2-4アルキニル、C1-4ヘテロアルキル、アリール、ヘテロアリール、Het1、Het2、C(=O)C1-4アルキル、C(=O)OH、C(=O)OC1-4アルキル、(CH2)mC(=O)OH、(CH2)mC(=O)C1-4アルキル、(CH2)mC(=O)OC1-4アルキル、NH2、NHC1-4アルキル、N(C1-4アルキル)C1-4アルキル、N(C1-4アルキル)アリール、OC1-4アルキル、SC1-4アルキル、(CH2)mC3-6シクロアルキル、(CH2)mC(=O)-アリール、又は(CH2)mC(=O)-Het1であり、ここで、mは、0、1、又は2であり;並びに
R2及びR3は、H、C1-20アルキル、C3-6シクロアルキル、C2-4アルケニル、C2-4アルキニル、C1-20ヘテロアルキル、アリール、ヘテロアリール、[3-(2,3,5-トリフルオロ-4-(4-オキソ-3,4-ジヒドロピリジン-1(2H)-イル)フェニル)オキサゾリジン-2-オン-5-イル]メチル、[3-(3-フルオロ-4-モルホリノフェニル)オキサゾリジン-2-オン-5-イル]メチル、[3-(3-フルオロ-4-(6-(2-メチル-2H-テトラゾール-5-イル)ピリジン-3-イル)フェニル)-オキサゾリジン-2-オン-5-イル]メチル、[3-(3-フルオロ-4-(6-(1-メチル-1H-テトラゾール-5-イル)ピリジン-3-イル)フェニル)-オキサゾリジン-2-オン-5-イル]メチル、Het1、Het2、C(=O)C1-4アルキル、(CH2)mC(=O)C1-4アルキル、(CH2)mC3-6シクロアルキル、(CH2)mC(=O)-アリール、及び(CH2)mC(=O)-Het1から独立して選択される。)。
R2は、イソオキサゾール-3-イル(任意に1つのR9により置換された)、C(=O)C1-4アルキル、(CH2)mC(=O)C1-4アルキル、(CH2)mC3-6シクロアルキル、(CH2)mC(=O)-アリール、又は(CH2)mC(=O)-Het1であり、ここで、mは、0、1、又は2であり;
R4及びR5は、独立してH又はFであり;並びに
R6及びR8は、独立してH、F、Cl、又はCNであり;並びに
R7は、C3-6シクロアルキル、アリール、ビアリール、Het1、Het2、又は4〜7-員の複素環基であるか;或いは、R6とR7は一緒に、ベンゼン環上に縮合された4〜7-員の複素環基を形成し;並びに
R9は、H、C1-6アルキル、ハロ、又はCNである。)。
R4及びR5は、独立してH又はFであり;並びに
R6及びR8は、独立してH、F、Cl、又はCNであり;並びに
R7は、C3-6シクロアルキル、アリール、ビアリール、Het1、Het2、又は4〜7-員の複素環基であるか;或いは、R6とR7は一緒に、ベンゼン環上に縮合された4〜7-員の複素環基を形成し;並びに
R9は、H、C1-6アルキル、ハロ、又はCNである。)。
R9は、H、C1-6アルキル、ハロ、又はCNであり;並びに
R10及びR11は、C1-20アルキル及びC3-6シクロアルキルから独立して選択されるか、又はR10とR11は一緒に、C1-20アルキリデン基である。)。
別に言及しない限りは、本明細書及び請求項において使用される下記の用語は、以下に示された意味を有する:
本発明の最も広い定義において、式Iの化合物のある特定の化合物が好ましくあり得る。ラジカル、置換基、及び範囲に関して以下に列記された具体的な値及び好ましい値は、単に例証のためであり;これらは、ラジカル及び置換基に関して他の定義された値又は、定義された範囲内の他の値を排除するものではない。
本発明の化合物は、以下に考察されたスキームのひとつ以上に従い調製されることができる。一般的に本発明のホスホルアミダート及びO-カルボニルホスホルアミダート化合物の合成は、例えば、PCT公報WO 2000/021960、WO 2004/056816、WO 2006/043121、及びWO 2009/020616に記載されたような、(イソオキサゾール-3-イル)アミノ基又はNH-アミド基などの、NH-含有基を組み込んでいるある特定の非-ホスホルアミダート誘導体について説明されたいくつかの公知の合成技術の方法に従う。
a) POCl3;塩基:例えば、N-メチルモルホリン(NMM)、TEA、Py、又はDIEA;次に、水;b) (t-BuO)2PN(i-Pr)2、1H-テトラゾール、t-BuOOH;次に、TFA又はHCl;c) 塩基:例えば、Na2CO3、NaOAc、Na2HPO4、TEA、NMM、(ジメチルアミノ)メチル-ポリスチレンなど;[R1C(=O)]2O、アルキル-N=C=O、又はR1C(=O)X、ここでX=Cl、4-ニトロフェノキシ、ペンタフルオロフェノキシなど。
a)RSO2Cl又は(RSO2)2O;塩基:例えば、N-メチルモルホリン(NMM)、TEA、Py、又はDIEA;b)O,O-ジアルキル-又はO,O-ジシクロアルキル-イソオキサゾール-3-イルホスホルアミダート試薬;塩基:例えば、NaH、LiOBu-t、KOBu-t、テトラメチルグアニジンなど;c)脱保護剤:例えば、PG=i-Pr又はi-Buに関してTMSBr又はTMSI;PG=Bnに関してH2/Pd/C;PG=t-Bu、又はPG=p-メトキシベンジル、又はPG=ベンズヒドリルに関してTFA、MsOH、又はHCl;PG=TMSCH2CH2に関してKF、TBAF、又はHF;PG=NCCH2CH2に関してアンモニア又はLiOH;d)塩基:例えば、Na2CO3、NaOAc、Na2HPO4、TEA、NMM、(ジメチルアミノ)メチル-ポリスチレンなど;[R1C(=O)]2O、アルキル-N=C=O、又はR1C(=O)X、ここでX=Cl、4-ニトロフェノキシ、ペンタフルオロフェニルなど;e)ミツノブ試薬:例えば、Ph3P/i-PrO2CN=NCO2Pr-I(DIAD);Ph3P/H2NC(=O)N=NC(=O)NH2;Bu3P/DIAD;Ph2P-ポリスチレン/DIAD;など;f)アルカリ金属塩基又はアミン、例えば、NaOH、Na2CO3、NaHCO3、NaOAc、Na2HPO4、メグルミン、グリシン、リシンなど;g)アルカリ金属塩基又はアミン、NaOH、Na2CO3、NaHCO3、NaOAc、Na2HPO4、メグルミン、グリシン、リシンなど;プロトン性溶媒、例えば水-含有EtOH、MeCN、THFなど、又はアルコール、例えばEtOHなど。
a)(R10O)(R11O)P(=O)Cl2;塩基:Py、NMM、DIEAなど;b)最適な塩基:Py、NMM、DIEA、DMAPなどにより支援された保護基(PG)による保護;アシル化又はスルホニル化試薬:PG=ArSO2に関してArSO2Cl;PG=Bocに関してBoc2O;PG=Cbzに関してCbzCl又はCbzOSuなど;c) (R10O)(R11O)P(=O)Cl2;塩基:DBU、DMAP、Py、NMM、KOBu-t、LiOBu-tなど;d)脱保護試薬:PG=ArSO2に関してMsOH又はMsOH-TFA;PG=ノシラートに関してRSH、塩基(Na2CO3、DBU、NMMなど);PG=Bocに関してTFA;PG=Cbzに関してH2/Pd/C又はHCOONH4/Pd;など。
本発明の実施態様は下記実施例において説明され、これは本発明の範囲を例示することを意味し、限定することを意味するものではない。合成技術分野の当業者に周知の一般的略号が、全体を通じて使用される。400 MHz 1H NMRスペクトル(δ, ppm)は、別に指定しない限りは、DMSO-d6中で測定される。陽イオン化法に関する質量分析(MS)データ(m/z)が提供される。クロマトグラフィーは、別に指定しない限りは、シリカゲルクロマトグラフィーを意味する。TLCは、薄層クロマトグラフィーを意味する。HPLCは、高速液体クロマトグラフィーを意味する。DMSO(ジメチルスルホキシド)、DCM(ジクロロメタン)、THF(テトラヒドロフラン)、MTBE(メチルtert-ブチルエーテル)、DMF(N,N-ジメチルホルムアミド)などの一般的略語が、全体を通じて使用される。別に指定しない限りは、全ての試薬は、商業的供給業者から得るか、又は入手可能な文献において説明された通常の方法により製造されるかのいずれかであった。
任意に、この化合物を、約0.2M水性Na2CO3 (媒質のpHは約8.5に)中に溶解し、EtOAc洗浄し、かつ水層を凍結乾燥することにより、ナトリウム塩として単離した。中間体3のナトリウム塩(D2O中)の1H NMR:
本発明のオキサゾリジノン系化合物は、グラム陽性微生物を含む様々な微生物に対する強力なインビボ有効性を示す。従って本発明の化合物は、有用な抗菌活性を有する。結果的に、本発明の化合物は、有用な抗微生物薬であり、かつ例えば多剤耐性ブドウ球菌、腸球菌、及び連鎖球菌などの好気性グラム陽性菌に加え、例えばバクテロイデス属及びクロストリジウム属の菌種などの嫌気性微生物、並びに、例えば結核菌(Mycobacterium tuberculosis)及びトリ結核菌(Mycobacterium avium)などの抗酸菌を含む、数多くのヒト及び動物の病原体に対し有効であり得る。
概して、本発明の化合物は、同様の有用性で働く物質の許容されるいずれかの投与様式により、治療的有効量で投与されることができる。例として、本発明の化合物は、経口的に、非経口的に、経皮的に、局所的に、経直腸的に、又は鼻腔内的に投与されることができる。本発明の化合物の、すなわち活性成分の実際の量は、治療される疾患の、すなわち治療される感染症の重症度、対象の年齢及び相対的健康状態、使用される化合物の効能、投与の経路及び形式、並びに他の要因などの、数多くの要因により左右され、それらは全て担当医の権限内である。
Claims (16)
- 下記式Iの化合物、又はそれらの医薬として許容し得る塩もしくは溶媒和物:
R1は、H、C1-20アルキル、C3-6シクロアルキル、C2-4アルケニル、C2-4アルキニル、C1-4ヘテロアルキル、アリール、ヘテロアリール、Het1、Het2、C(=O)C1-4アルキル、C(=O)OH、C(=O)OC1-4アルキル、(CH2)mC(=O)OH、(CH2)mC(=O)C1-4アルキル、(CH2)mC(=O)OC1-4アルキル、NH2、NHC1-4アルキル、N(C1-4アルキル)C1-4アルキル、N(C1-4アルキル)アリール、OC1-4アルキル、SC1-4アルキル、(CH2)mC3-6シクロアルキル、(CH2)mC(=O)-アリール、又は(CH2)mC(=O)-Het1であり、ここで、mは、0、1、又は2であり;並びに
R2及びR3は、H、C1-20アルキル、C3-6シクロアルキル、C2-4アルケニル、C2-4アルキニル、C1-20ヘテロアルキル、アリール、ヘテロアリール、[3-(2,3,5-トリフルオロ-4-(4-オキソ-3,4-ジヒドロピリジン-1(2H)-イル)フェニル)オキサゾリジン-2-オン-5-イル]メチル、[3-(3-フルオロ-4-モルホリノフェニル)オキサゾリジン-2-オン-5-イル]メチル、[3-(3-フルオロ-4-(6-(2-メチル-2H-テトラゾール-5-イル)ピリジン-3-イル)フェニル)-オキサゾリジン-2-オン-5-イル]メチル、[3-(3-フルオロ-4-(6-(1-メチル-1H-テトラゾール-5-イル)ピリジン-3-イル)フェニル)-オキサゾリジン-2-オン-5-イル]メチル、Het1、Het2、C(=O)C1-4アルキル、(CH2)mC(=O)C1-4アルキル、(CH2)mC3-6シクロアルキル、(CH2)mC(=O)-アリール、及び(CH2)mC(=O)-Het1から独立して選択される。)。 - 請求項1記載の式IIの化合物、又はそれらの医薬として許容し得る塩:
R2は、イソオキサゾール-3-イル(任意に1つのR9により置換された)、C(=O)C1-4アルキル、(CH2)mC(=O)C1-4アルキル、(CH2)mC3-6シクロアルキル、(CH2)mC(=O)-アリール、又は(CH2)mC(=O)-Het1であり、ここで、mは、0、1、又は2であり;
R4及びR5は、独立してH又はFであり;並びに
R6及びR8は、独立してH、F、Cl、又はCNであり;並びに
R7は、C3-6シクロアルキル、アリール、ビアリール、Het1、Het2、又は4〜7-員の複素環基であるか;或いは、R6とR7は一緒に、ベンゼン環上に縮合された4〜7-員の複素環基を形成し;並びに
R9は、H、C1-6アルキル、ハロ、又はCNである。)。 - 前記R4、R5、R6、及びR8が、H又はFから独立して選択され、並びにR7が、モルホリノ、2,3-ジヒドロピリジン-4(1H)-オン-1-イル、4-シアノピリジル、2-(2-メチル-2H-テトラゾール-5-イル)ピリジン-5-イル、2-(1-メチル-1H-テトラゾール-5-イル)ピリジン-5-イル、4-[N-(1H-1,2,3-トリアゾール-5-イル)メチルアミノメチル]フェニル、1-メチル-1,4,5,6-テトラヒドロ-1,2,4-トリアジン-4-イル、又は5,6-ジヒドロ-1,2,4-オキサジアジン-4-イルである、請求項2記載の式IIの化合物。
- 前記各R1が、独立してC1-8アルキル、(CH2)mC(=O)OC1-4アルキル、OC1-4アルキル、NHC1-4アルキル、N(C1-4アルキル)C1-4アルキル、アリール、又はHet2である、請求項1〜4のいずれか記載の化合物。
- 前記R4及びR9が、両方共Hであり、かつR5、R6、及びR8が、全てFである、請求項8記載の式IVの化合物。
- 前記R9がHであり、並びにR10及びR11の両方が、C1-20アルキルである、請求項10記載の式Vの化合物。
- 請求項1〜9のいずれか記載の化合物の治療的有効量及び医薬として許容し得る担体を含有する、医薬組成物。
- 請求項1〜9のいずれか記載の化合物又は請求項12記載の組成物の治療的有効量を、それを必要とする哺乳類へ投与することを含む、哺乳類における微生物感染症を治療する方法。
- 前記化合物が、医薬組成物で、経口的に、非経口的に、経皮的に、局所的に、経直腸的に、又は鼻腔内的に、哺乳類へ投与される、請求項13記載の方法。
- 前記化合物が、その水系の溶液として、かつ約50mg/mL〜約400mg/mLの前記化合物濃度で投与される、請求項13記載の方法。
- 前記化合物が、約1〜約75mg/kgの一日量で投与される、請求項13記載の方法。
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US9382276B2 (en) | 2016-07-05 |
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