JP2019518771A - 抗感染症複素環式化合物およびその使用 - Google Patents
抗感染症複素環式化合物およびその使用 Download PDFInfo
- Publication number
- JP2019518771A JP2019518771A JP2018567199A JP2018567199A JP2019518771A JP 2019518771 A JP2019518771 A JP 2019518771A JP 2018567199 A JP2018567199 A JP 2018567199A JP 2018567199 A JP2018567199 A JP 2018567199A JP 2019518771 A JP2019518771 A JP 2019518771A
- Authority
- JP
- Japan
- Prior art keywords
- mmol
- tert
- alkyl
- amino
- trifluoromethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 150000002391 heterocyclic compounds Chemical class 0.000 title abstract description 3
- 230000002924 anti-infective effect Effects 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 386
- 238000000034 method Methods 0.000 claims abstract description 51
- 208000015181 infectious disease Diseases 0.000 claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- -1 indolyl compound Chemical class 0.000 claims description 210
- 125000000217 alkyl group Chemical group 0.000 claims description 54
- 150000003839 salts Chemical class 0.000 claims description 35
- 125000000623 heterocyclic group Chemical group 0.000 claims description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
- 230000001580 bacterial effect Effects 0.000 claims description 18
- 208000035143 Bacterial infection Diseases 0.000 claims description 16
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 241000894006 Bacteria Species 0.000 claims description 11
- 102000004167 Ribonuclease P Human genes 0.000 claims description 11
- 108090000621 Ribonuclease P Proteins 0.000 claims description 11
- 238000011282 treatment Methods 0.000 claims description 11
- 241000588724 Escherichia coli Species 0.000 claims description 10
- 241000194033 Enterococcus Species 0.000 claims description 8
- 241000588748 Klebsiella Species 0.000 claims description 8
- 241000589248 Legionella Species 0.000 claims description 8
- 208000007764 Legionnaires' Disease Diseases 0.000 claims description 8
- 241000589516 Pseudomonas Species 0.000 claims description 8
- 241000191940 Staphylococcus Species 0.000 claims description 8
- 241000194017 Streptococcus Species 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 230000005764 inhibitory process Effects 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000004193 piperazinyl group Chemical group 0.000 claims description 6
- 241000894007 species Species 0.000 claims description 6
- 208000035473 Communicable disease Diseases 0.000 claims description 5
- 241000194032 Enterococcus faecalis Species 0.000 claims description 5
- 206010017533 Fungal infection Diseases 0.000 claims description 5
- 241000606768 Haemophilus influenzae Species 0.000 claims description 5
- 241000588747 Klebsiella pneumoniae Species 0.000 claims description 5
- 208000031888 Mycoses Diseases 0.000 claims description 5
- 208000030852 Parasitic disease Diseases 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- 230000002538 fungal effect Effects 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- 241000588626 Acinetobacter baumannii Species 0.000 claims description 4
- 241000194031 Enterococcus faecium Species 0.000 claims description 4
- 241000588722 Escherichia Species 0.000 claims description 4
- 241000606790 Haemophilus Species 0.000 claims description 4
- 241000186781 Listeria Species 0.000 claims description 4
- 241000186359 Mycobacterium Species 0.000 claims description 4
- 241000588653 Neisseria Species 0.000 claims description 4
- 241000588652 Neisseria gonorrhoeae Species 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000001475 halogen functional group Chemical group 0.000 claims description 4
- 206010022000 influenza Diseases 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 241001465754 Metazoa Species 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 2
- 125000003725 azepanyl group Chemical group 0.000 claims description 2
- 125000002393 azetidinyl group Chemical group 0.000 claims description 2
- 125000005605 benzo group Chemical group 0.000 claims description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 2
- 230000003641 microbiacidal effect Effects 0.000 claims description 2
- 229940124561 microbicide Drugs 0.000 claims description 2
- 239000002855 microbicide agent Substances 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- 229960005475 antiinfective agent Drugs 0.000 abstract description 3
- 239000004599 antimicrobial Substances 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 351
- 239000011541 reaction mixture Substances 0.000 description 292
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 278
- 239000000243 solution Substances 0.000 description 234
- 239000007787 solid Substances 0.000 description 159
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 154
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 150
- 235000019439 ethyl acetate Nutrition 0.000 description 133
- 238000005481 NMR spectroscopy Methods 0.000 description 121
- 238000006243 chemical reaction Methods 0.000 description 112
- 238000003786 synthesis reaction Methods 0.000 description 104
- 230000015572 biosynthetic process Effects 0.000 description 102
- 230000002829 reductive effect Effects 0.000 description 95
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 86
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 82
- 239000012044 organic layer Substances 0.000 description 78
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 77
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 73
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 62
- 238000004809 thin layer chromatography Methods 0.000 description 61
- 238000003756 stirring Methods 0.000 description 59
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 57
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 57
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 56
- 238000004440 column chromatography Methods 0.000 description 51
- 239000003480 eluent Substances 0.000 description 50
- 239000012043 crude product Substances 0.000 description 43
- 239000000741 silica gel Substances 0.000 description 42
- 229910002027 silica gel Inorganic materials 0.000 description 42
- 229910052938 sodium sulfate Inorganic materials 0.000 description 42
- 235000011152 sodium sulphate Nutrition 0.000 description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 38
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 38
- 239000000203 mixture Substances 0.000 description 38
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 37
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 35
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 35
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 34
- 150000002990 phenothiazines Chemical class 0.000 description 33
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 31
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 30
- 238000010511 deprotection reaction Methods 0.000 description 28
- 239000000706 filtrate Substances 0.000 description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 27
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
- 239000011734 sodium Substances 0.000 description 25
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 23
- 238000000746 purification Methods 0.000 description 22
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- 238000004128 high performance liquid chromatography Methods 0.000 description 20
- 239000002253 acid Substances 0.000 description 19
- 150000001412 amines Chemical class 0.000 description 19
- 230000009467 reduction Effects 0.000 description 19
- 238000006722 reduction reaction Methods 0.000 description 19
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 235000019441 ethanol Nutrition 0.000 description 18
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 18
- VRVRGVPWCUEOGV-UHFFFAOYSA-N 2-aminothiophenol Chemical class NC1=CC=CC=C1S VRVRGVPWCUEOGV-UHFFFAOYSA-N 0.000 description 16
- 239000012267 brine Substances 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 16
- 229920006395 saturated elastomer Polymers 0.000 description 16
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 15
- 239000007788 liquid Substances 0.000 description 15
- 230000008707 rearrangement Effects 0.000 description 15
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 238000011065 in-situ storage Methods 0.000 description 13
- 238000006268 reductive amination reaction Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- HFHAVERNVFNSHL-UHFFFAOYSA-N 2-chloro-1,3-dinitro-5-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(C(F)(F)F)=CC([N+]([O-])=O)=C1Cl HFHAVERNVFNSHL-UHFFFAOYSA-N 0.000 description 11
- 150000001408 amides Chemical class 0.000 description 11
- 238000012746 preparative thin layer chromatography Methods 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- 229910052786 argon Inorganic materials 0.000 description 10
- 150000001502 aryl halides Chemical class 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- 239000011701 zinc Substances 0.000 description 10
- 108091032973 (ribonucleotides)n+m Proteins 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
- 229910000104 sodium hydride Inorganic materials 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- LDGHLZFFKMEAOE-UHFFFAOYSA-N 2-amino-5-bromobenzenethiol Chemical compound NC1=CC=C(Br)C=C1S LDGHLZFFKMEAOE-UHFFFAOYSA-N 0.000 description 8
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 8
- 230000008878 coupling Effects 0.000 description 8
- 238000010168 coupling process Methods 0.000 description 8
- 238000005859 coupling reaction Methods 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- 229940098779 methanesulfonic acid Drugs 0.000 description 8
- 229910052763 palladium Inorganic materials 0.000 description 8
- 229950000688 phenothiazine Drugs 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 7
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 7
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 7
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 7
- MVIYLBGOSHSIRW-UHFFFAOYSA-N 3-(trifluoromethyl)-10H-phenothiazin-1-amine Chemical compound FC(C=1C=C(C=2NC3=CC=CC=C3SC=2C=1)N)(F)F MVIYLBGOSHSIRW-UHFFFAOYSA-N 0.000 description 7
- JSGHMGKJNZTKGF-UHFFFAOYSA-N 3-[(2-methylpropan-2-yl)oxycarbonylamino]cyclohexane-1-carboxylic acid Chemical compound CC(C)(C)OC(=O)NC1CCCC(C(O)=O)C1 JSGHMGKJNZTKGF-UHFFFAOYSA-N 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- 150000001299 aldehydes Chemical class 0.000 description 7
- 238000003776 cleavage reaction Methods 0.000 description 7
- 150000002991 phenoxazines Chemical class 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 6
- SUMIWKAXIPIFDO-UHFFFAOYSA-N 7-bromo-3-(trifluoromethyl)-10H-phenothiazin-1-amine Chemical compound BrC=1C=C2SC=3C=C(C=C(C=3NC2=CC=1)N)C(F)(F)F SUMIWKAXIPIFDO-UHFFFAOYSA-N 0.000 description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 238000006069 Suzuki reaction reaction Methods 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 238000007872 degassing Methods 0.000 description 6
- 239000012280 lithium aluminium hydride Substances 0.000 description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- GSLVCSKQTRZYSF-UHFFFAOYSA-N 1-nitro-3-(trifluoromethyl)-10H-phenothiazine Chemical compound [O-][N+](=O)C1=C2NC3=C(SC2=CC(=C1)C(F)(F)F)C=CC=C3 GSLVCSKQTRZYSF-UHFFFAOYSA-N 0.000 description 5
- JEWIAYIESCUSKQ-UHFFFAOYSA-N 3-bromo-10h-phenothiazine Chemical compound C1=CC=C2SC3=CC(Br)=CC=C3NC2=C1 JEWIAYIESCUSKQ-UHFFFAOYSA-N 0.000 description 5
- FDGYZKRWYDJICZ-UHFFFAOYSA-N 7-bromo-1-nitro-3-(trifluoromethyl)-10h-phenothiazine Chemical compound S1C2=CC(Br)=CC=C2NC2=C1C=C(C(F)(F)F)C=C2[N+](=O)[O-] FDGYZKRWYDJICZ-UHFFFAOYSA-N 0.000 description 5
- 230000029936 alkylation Effects 0.000 description 5
- 238000005804 alkylation reaction Methods 0.000 description 5
- 239000012131 assay buffer Substances 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 230000007017 scission Effects 0.000 description 5
- NRZYYKACXDZFRF-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O.CC(C)(C)OC(N)=O NRZYYKACXDZFRF-UHFFFAOYSA-N 0.000 description 5
- RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 description 5
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 4
- IQLUXOIWMWKFLF-UHFFFAOYSA-N 2-(4-bromo-2-nitrophenyl)sulfanylaniline Chemical compound NC1=CC=CC=C1SC1=CC=C(Br)C=C1[N+]([O-])=O IQLUXOIWMWKFLF-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- 206010057190 Respiratory tract infections Diseases 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- SVIBPSNFXYUOFT-UHFFFAOYSA-N [1-[(2-methylpropan-2-yl)oxycarbonyl]indol-2-yl]boronic acid Chemical compound C1=CC=C2N(C(=O)OC(C)(C)C)C(B(O)O)=CC2=C1 SVIBPSNFXYUOFT-UHFFFAOYSA-N 0.000 description 4
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000002808 molecular sieve Substances 0.000 description 4
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 4
- 238000002953 preparative HPLC Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000012047 saturated solution Substances 0.000 description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- AOCSUUGBCMTKJH-UHFFFAOYSA-N tert-butyl n-(2-aminoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCN AOCSUUGBCMTKJH-UHFFFAOYSA-N 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- PPGBIIDGXRHRTD-UHFFFAOYSA-N 10h-phenothiazine-3-carbaldehyde Chemical compound C1=CC=C2SC3=CC(C=O)=CC=C3NC2=C1 PPGBIIDGXRHRTD-UHFFFAOYSA-N 0.000 description 3
- WKEYPPZTEITNHZ-UHFFFAOYSA-N 2-amino-4-bromobenzenethiol Chemical compound NC1=CC(Br)=CC=C1S WKEYPPZTEITNHZ-UHFFFAOYSA-N 0.000 description 3
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 3
- UUOLETYDNTVQDY-UHFFFAOYSA-N 2-chloro-3-nitropyridine Chemical compound [O-][N+](=O)C1=CC=CN=C1Cl UUOLETYDNTVQDY-UHFFFAOYSA-N 0.000 description 3
- SDERSMZNRRJTRI-UHFFFAOYSA-N 3-[7-(1H-indol-2-yl)pyrido[3,2-b][1,4]benzothiazin-10-yl]-N,N-dimethylpropan-1-amine Chemical compound N1C(=CC2=CC=CC=C12)C=1C=CC2=C(SC3=C(N2CCCN(C)C)N=CC=C3)C=1 SDERSMZNRRJTRI-UHFFFAOYSA-N 0.000 description 3
- FFCNEHRZRMLVIA-UHFFFAOYSA-N 3-bromo-10-(3-chloropropyl)phenothiazine Chemical compound BrC=1C=CC=2N(C3=CC=CC=C3SC=2C=1)CCCCl FFCNEHRZRMLVIA-UHFFFAOYSA-N 0.000 description 3
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 3
- VZEBSJIOUMDNLY-UHFFFAOYSA-N 6-bromo-1,3-benzothiazol-2-amine Chemical compound C1=C(Br)C=C2SC(N)=NC2=C1 VZEBSJIOUMDNLY-UHFFFAOYSA-N 0.000 description 3
- 0 N*(ccc(Br)c1)c1Sc(nccc1)c1[N+]([O-])=O Chemical compound N*(ccc(Br)c1)c1Sc(nccc1)c1[N+]([O-])=O 0.000 description 3
- XKYBZOYNEJZSHP-UHFFFAOYSA-N N-[1-(2-aminoethyl)piperidin-4-yl]-3-(trifluoromethyl)-10H-phenothiazin-1-amine Chemical compound NCCN1CCC(CC1)NC1=CC(=CC=2SC3=CC=CC=C3NC1=2)C(F)(F)F XKYBZOYNEJZSHP-UHFFFAOYSA-N 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 238000007351 Smiles rearrangement reaction Methods 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 150000001350 alkyl halides Chemical class 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- WJKJXKRHMUXQSL-UHFFFAOYSA-N benzyl glycinate 4-methylbenzenesulfonate salt Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.NCC(=O)OCC1=CC=CC=C1 WJKJXKRHMUXQSL-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- YIVNBFSMKOXEFB-UHFFFAOYSA-N ethyl 1-[[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]amino]-10H-phenothiazine-3-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)NC1=CC(=CC=2SC3=CC=CC=C3NC1=2)C(=O)OCC YIVNBFSMKOXEFB-UHFFFAOYSA-N 0.000 description 3
- SHKPDTMVAGOARV-UHFFFAOYSA-N ethyl 1-amino-10H-phenothiazine-3-carboxylate Chemical compound NC1=CC(=CC=2SC3=CC=CC=C3NC1=2)C(=O)OCC SHKPDTMVAGOARV-UHFFFAOYSA-N 0.000 description 3
- CBZCBFSVOAODOT-UHFFFAOYSA-N ethyl 1-nitro-10H-phenothiazine-3-carboxylate Chemical compound [N+](=O)([O-])C1=CC(=CC=2SC3=CC=CC=C3NC1=2)C(=O)OCC CBZCBFSVOAODOT-UHFFFAOYSA-N 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 3
- 238000006170 formylation reaction Methods 0.000 description 3
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000002054 inoculum Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- 230000000269 nucleophilic effect Effects 0.000 description 3
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 3
- 229910003446 platinum oxide Inorganic materials 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 3
- XVROWZPERFUOCE-UHFFFAOYSA-N tert-butyl n-(2-hydroxycyclohexyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CCCCC1O XVROWZPERFUOCE-UHFFFAOYSA-N 0.000 description 3
- ZJCHCPTZZNZOLM-UHFFFAOYSA-N tert-butyl phenothiazine-10-carboxylate Chemical compound C1=CC=C2N(C(=O)OC(C)(C)C)C3=CC=CC=C3SC2=C1 ZJCHCPTZZNZOLM-UHFFFAOYSA-N 0.000 description 3
- 150000003568 thioethers Chemical class 0.000 description 3
- 150000003573 thiols Chemical class 0.000 description 3
- 201000008827 tuberculosis Diseases 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- WRGKKASJBOREMB-UHFFFAOYSA-N 1,4-dibromo-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(Br)=CC=C1Br WRGKKASJBOREMB-UHFFFAOYSA-N 0.000 description 2
- JJEOVUUVOPJBRZ-UHFFFAOYSA-N 1-[8-fluoro-1-nitro-3-(trifluoromethyl)phenothiazin-10-yl]ethanone Chemical compound CC(=O)N1C2=C(SC3=CC(=CC(=C13)[N+]([O-])=O)C(F)(F)F)C=CC(F)=C2 JJEOVUUVOPJBRZ-UHFFFAOYSA-N 0.000 description 2
- DAVVEVVYMKOFJP-UHFFFAOYSA-N 1-bromo-2-nitro-10H-phenothiazine Chemical compound [N+](=O)([O-])C1=C(C=2NC3=CC=CC=C3SC=2C=C1)Br DAVVEVVYMKOFJP-UHFFFAOYSA-N 0.000 description 2
- BFCFYVKQTRLZHA-UHFFFAOYSA-N 1-chloro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1Cl BFCFYVKQTRLZHA-UHFFFAOYSA-N 0.000 description 2
- NNFKSNXHQAFTMO-UHFFFAOYSA-N 10-(3-azidopropyl)-3-bromophenothiazine Chemical compound N(=[N+]=[N-])CCCN1C2=CC=CC=C2SC=2C=C(C=CC1=2)Br NNFKSNXHQAFTMO-UHFFFAOYSA-N 0.000 description 2
- NOHRRIZJPUBQBB-UHFFFAOYSA-N 10-(3-chloropropyl)phenothiazine-3-carbaldehyde Chemical compound ClCCCN1C2=CC=CC=C2SC=2C=C(C=CC1=2)C=O NOHRRIZJPUBQBB-UHFFFAOYSA-N 0.000 description 2
- YVJCHMOUBZDWTD-UHFFFAOYSA-N 10h-phenothiazine Chemical compound C1=CC=C2NC3=C=CC=C[C]3SC2=C1 YVJCHMOUBZDWTD-UHFFFAOYSA-N 0.000 description 2
- QHOTUGFFUIJGCS-UHFFFAOYSA-N 15-piperidin-4-yl-11-(trifluoromethyl)-8-thia-1,14-diazatetracyclo[7.6.1.02,7.013,16]hexadeca-2,4,6,9,11,13(16),14-heptaene Chemical compound N1CCC(CC1)C1=NC=2C=C(C=C3SC=4C=CC=CC=4N1C=23)C(F)(F)F QHOTUGFFUIJGCS-UHFFFAOYSA-N 0.000 description 2
- JYWKEVKEKOTYEX-UHFFFAOYSA-N 2,6-dibromo-4-chloroiminocyclohexa-2,5-dien-1-one Chemical compound ClN=C1C=C(Br)C(=O)C(Br)=C1 JYWKEVKEKOTYEX-UHFFFAOYSA-N 0.000 description 2
- KKGJRFDKNIMILW-UHFFFAOYSA-N 2-[4-[11-(trifluoromethyl)-8-thia-1,14-diazatetracyclo[7.6.1.02,7.013,16]hexadeca-2,4,6,9,11,13(16),14-heptaen-15-yl]piperidin-1-yl]ethanamine Chemical compound FC(C=1C=C2SC=3C=CC=CC=3N3C2=C(C=1)N=C3C1CCN(CC1)CCN)(F)F KKGJRFDKNIMILW-UHFFFAOYSA-N 0.000 description 2
- FWTXFEKVHSFTDQ-UHFFFAOYSA-N 2-bromo-5-fluoroaniline Chemical compound NC1=CC(F)=CC=C1Br FWTXFEKVHSFTDQ-UHFFFAOYSA-N 0.000 description 2
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 2
- SUODCTNNAKSRHB-UHFFFAOYSA-N 2-ethylhexyl 3-sulfanylpropanoate Chemical compound CCCCC(CC)COC(=O)CCS SUODCTNNAKSRHB-UHFFFAOYSA-N 0.000 description 2
- NJTSRUPAGJPBFQ-UHFFFAOYSA-N 3-(3-bromophenothiazin-10-yl)-N,N-dimethylpropan-1-amine Chemical compound BrC=1C=CC=2N(C3=CC=CC=C3SC=2C=1)CCCN(C)C NJTSRUPAGJPBFQ-UHFFFAOYSA-N 0.000 description 2
- NXPOTQIVGBTBNG-UHFFFAOYSA-N 3-(trifluoromethyl)-6,7,8,9,9a,10-hexahydro-5aH-phenothiazin-1-amine Chemical compound FC(C=1C=C2SC3CCCCC3NC2=C(C=1)N)(F)F NXPOTQIVGBTBNG-UHFFFAOYSA-N 0.000 description 2
- YAFLSJODKUOVQC-UHFFFAOYSA-N 3-[3-(1H-indol-2-yl)-7-piperazin-1-ylphenothiazin-10-yl]propan-1-amine Chemical compound N1C(=CC2=CC=CC=C12)C=1C=CC=2N(C3=CC=C(C=C3SC=2C=1)N1CCNCC1)CCCN YAFLSJODKUOVQC-UHFFFAOYSA-N 0.000 description 2
- GLRTWTMWVAHZJC-UHFFFAOYSA-N 3-[3-(1H-indol-2-yl)phenothiazin-10-yl]propan-1-amine Chemical compound N1C(=CC2=CC=CC=C12)C=1C=CC=2N(C3=CC=CC=C3SC=2C=1)CCCN GLRTWTMWVAHZJC-UHFFFAOYSA-N 0.000 description 2
- UAUUZRBWSQILOU-UHFFFAOYSA-N 3-amino-N-[7-(1H-indol-2-yl)-3-(trifluoromethyl)-10H-phenothiazin-1-yl]cyclohexane-1-carboxamide Chemical compound NC1CCCC(C1)C(=O)Nc1cc(cc2Sc3cc(ccc3Nc12)-c1cc2ccccc2[nH]1)C(F)(F)F UAUUZRBWSQILOU-UHFFFAOYSA-N 0.000 description 2
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- BRQLQKMETRERNI-UHFFFAOYSA-N 7-(1H-indol-2-yl)-1-nitro-3-(trifluoromethyl)-10H-phenothiazine Chemical compound N1C(=CC2=CC=CC=C12)C=1C=C2SC=3C=C(C=C(C=3NC2=CC=1)[N+](=O)[O-])C(F)(F)F BRQLQKMETRERNI-UHFFFAOYSA-N 0.000 description 2
- POZNMGFZDMBMBC-UHFFFAOYSA-N 7-(1H-indol-2-yl)-3-(trifluoromethyl)-10H-phenothiazin-1-amine Chemical compound N1C(=CC2=CC=CC=C12)C=1C=C2SC=3C=C(C=C(C=3NC2=CC=1)N)C(F)(F)F POZNMGFZDMBMBC-UHFFFAOYSA-N 0.000 description 2
- BGNHKWDHUHHNEO-UHFFFAOYSA-N 7-(1H-indol-2-yl)-N-piperidin-4-yl-3-(trifluoromethyl)-10H-phenothiazin-1-amine 2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.FC(F)(F)c1cc(NC2CCNCC2)c2Nc3ccc(cc3Sc2c1)-c1cc2ccccc2[nH]1 BGNHKWDHUHHNEO-UHFFFAOYSA-N 0.000 description 2
- YHKASBDRJLTLHH-UHFFFAOYSA-N 7-bromo-1,3-benzothiazol-2-amine Chemical compound C1=CC(Br)=C2SC(N)=NC2=C1 YHKASBDRJLTLHH-UHFFFAOYSA-N 0.000 description 2
- VJSMJPVKLITADH-UHFFFAOYSA-N 7-chloro-1-nitro-3-(trifluoromethyl)-10h-phenothiazine Chemical compound S1C2=CC(Cl)=CC=C2NC2=C1C=C(C(F)(F)F)C=C2[N+](=O)[O-] VJSMJPVKLITADH-UHFFFAOYSA-N 0.000 description 2
- UMFGJKCSFKNMOJ-UHFFFAOYSA-N 8-(trifluoromethyl)-5H-pyrido[3,4-b][1,4]benzothiazin-6-amine Chemical compound Nc1cc(cc2Sc3cnccc3Nc12)C(F)(F)F UMFGJKCSFKNMOJ-UHFFFAOYSA-N 0.000 description 2
- VNSAUECFJOWILN-UHFFFAOYSA-N 9-nitro-7-(trifluoromethyl)-10H-phenothiazine-3-carbonitrile Chemical compound [N+](=O)([O-])C=1C=C(C=C2SC=3C=C(C=CC=3NC=12)C#N)C(F)(F)F VNSAUECFJOWILN-UHFFFAOYSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 206010018612 Gonorrhoea Diseases 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- 241000186365 Mycobacterium fortuitum Species 0.000 description 2
- 241000187481 Mycobacterium phlei Species 0.000 description 2
- NINIHFWEKXDSSD-UHFFFAOYSA-N N'-(2-aminoethyl)-N'-[2-[4-[[7-pyrrolidin-1-yl-3-(trifluoromethyl)-10H-phenothiazin-1-yl]amino]piperidin-1-yl]ethyl]ethane-1,2-diamine hydrochloride Chemical compound Cl.NCCN(CCN)CCN1CCC(CC1)Nc1cc(cc2Sc3cc(ccc3Nc12)N1CCCC1)C(F)(F)F NINIHFWEKXDSSD-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- GELVJDXLQSSJJY-UHFFFAOYSA-N N-(2-aminoethyl)-N'-[7-bromo-3-(trifluoromethyl)-10H-phenothiazin-1-yl]propane-1,3-diamine Chemical compound NCCNCCCNC1=CC(=CC=2SC3=CC(=CC=C3NC1=2)Br)C(F)(F)F GELVJDXLQSSJJY-UHFFFAOYSA-N 0.000 description 2
- GHDZEQVZAQRLIM-UHFFFAOYSA-N N-[(3-aminocyclohexyl)methyl]-3-(trifluoromethyl)-10H-phenothiazin-1-amine Chemical compound NC1CC(CCC1)CNC1=CC(=CC=2SC3=CC=CC=C3NC1=2)C(F)(F)F GHDZEQVZAQRLIM-UHFFFAOYSA-N 0.000 description 2
- GBRPKPGKXMJNGE-UHFFFAOYSA-N N-[(3-aminocyclohexyl)methyl]-7-bromo-3-(trifluoromethyl)-10H-phenothiazin-1-amine hydrochloride Chemical compound Cl.NC1CCCC(CNc2cc(cc3Sc4cc(Br)ccc4Nc23)C(F)(F)F)C1 GBRPKPGKXMJNGE-UHFFFAOYSA-N 0.000 description 2
- IDLRXZWCJYZXIW-UHFFFAOYSA-N N-[(3-aminocyclohexyl)methyl]-7-pyrrolidin-1-yl-3-(trifluoromethyl)-10H-phenothiazin-1-amine Chemical compound NC1CC(CCC1)CNC1=CC(=CC=2SC3=CC(=CC=C3NC1=2)N1CCCC1)C(F)(F)F IDLRXZWCJYZXIW-UHFFFAOYSA-N 0.000 description 2
- TVJLDLVWWXZPSH-UHFFFAOYSA-N N-[1-(2-aminoethyl)piperidin-4-yl]-7-(4-aminopiperidin-1-yl)-3-(trifluoromethyl)-10H-phenothiazin-1-amine Chemical compound NCCN1CCC(CC1)NC1=CC(=CC=2SC3=CC(=CC=C3NC1=2)N1CCC(CC1)N)C(F)(F)F TVJLDLVWWXZPSH-UHFFFAOYSA-N 0.000 description 2
- DDNLEIGRWRKXLT-UHFFFAOYSA-N N-[1-(2-aminoethyl)piperidin-4-yl]-7-(cyclopenten-1-yl)-3-(trifluoromethyl)-10H-phenothiazin-1-amine hydrochloride Chemical compound Cl.NCCN1CCC(CC1)Nc1cc(cc2Sc3cc(ccc3Nc12)C1=CCCC1)C(F)(F)F DDNLEIGRWRKXLT-UHFFFAOYSA-N 0.000 description 2
- KDKLBWADWVKDRA-UHFFFAOYSA-N N-[1-(2-aminoethyl)piperidin-4-yl]-7-chloro-3-(trifluoromethyl)-10H-phenothiazin-1-amine Chemical compound NCCN1CCC(CC1)NC1=CC(=CC=2SC3=CC(=CC=C3NC1=2)Cl)C(F)(F)F KDKLBWADWVKDRA-UHFFFAOYSA-N 0.000 description 2
- DHJGPMJOSCWPMA-UHFFFAOYSA-N N-[1-(2-aminoethyl)piperidin-4-yl]-7-cyclopentyl-3-(trifluoromethyl)-10H-phenothiazin-1-amine hydrochloride Chemical compound Cl.NCCN1CCC(CC1)Nc1cc(cc2Sc3cc(ccc3Nc12)C1CCCC1)C(F)(F)F DHJGPMJOSCWPMA-UHFFFAOYSA-N 0.000 description 2
- OBWORGPNLFWQQR-UHFFFAOYSA-N N-[3-(2-aminoethoxy)propyl]-7-bromo-3-(trifluoromethyl)-10H-phenothiazin-1-amine hydrochloride Chemical compound Cl.NCCOCCCNc1cc(cc2Sc3cc(Br)ccc3Nc12)C(F)(F)F OBWORGPNLFWQQR-UHFFFAOYSA-N 0.000 description 2
- 230000006181 N-acylation Effects 0.000 description 2
- 238000007126 N-alkylation reaction Methods 0.000 description 2
- YKUIHOHZFOLPOY-UHFFFAOYSA-N N-piperidin-4-yl-3-(trifluoromethyl)-6,7,8,9,9a,10-hexahydro-5aH-phenothiazin-1-amine Chemical compound N1CCC(CC1)NC=1C=C(C=C2SC3CCCCC3NC=12)C(F)(F)F YKUIHOHZFOLPOY-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- PLXBWHJQWKZRKG-UHFFFAOYSA-N Resazurin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3[N+]([O-])=C21 PLXBWHJQWKZRKG-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- IDOVRYXFKZVUHN-UHFFFAOYSA-N [1-[[1-(2-aminoethyl)piperidin-4-yl]amino]-10H-phenothiazin-3-yl]-pyrrolidin-1-ylmethanone Chemical compound NCCN1CCC(CC1)NC1=CC(=CC=2SC3=CC=CC=C3NC1=2)C(=O)N1CCCC1 IDOVRYXFKZVUHN-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 150000001347 alkyl bromides Chemical class 0.000 description 2
- 238000010640 amide synthesis reaction Methods 0.000 description 2
- 125000005365 aminothiol group Chemical class 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 150000001543 aryl boronic acids Chemical class 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical class C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 150000001728 carbonyl compounds Chemical class 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- SACNIGZYDTUHKB-UHFFFAOYSA-N ditert-butyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C(C)(C)C)C(C)(C)C SACNIGZYDTUHKB-UHFFFAOYSA-N 0.000 description 2
- ICFRQRXOJMOMEG-UHFFFAOYSA-N ethyl 1-(piperidin-4-ylamino)-10H-phenothiazine-3-carboxylate Chemical compound CCOC(=O)c1cc(NC2CCNCC2)c2Nc3ccccc3Sc2c1 ICFRQRXOJMOMEG-UHFFFAOYSA-N 0.000 description 2
- XSPNDVOBIXSGGA-UHFFFAOYSA-N ethyl 1-[[1-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]piperidin-4-yl]amino]-10H-phenothiazine-3-carboxylate Chemical compound C(C)(C)(C)OC(=O)NCCN1CCC(CC1)NC1=CC(=CC=2SC3=CC=CC=C3NC1=2)C(=O)OCC XSPNDVOBIXSGGA-UHFFFAOYSA-N 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 208000001786 gonorrhea Diseases 0.000 description 2
- 235000010299 hexamethylene tetramine Nutrition 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 238000003328 mesylation reaction Methods 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- RRUIYSOJPLHBMA-UHFFFAOYSA-N methyl 9-[[1-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]piperidin-4-yl]amino]-7-(trifluoromethyl)-10H-phenothiazine-3-carboxylate Chemical compound C(C)(C)(C)OC(=O)NCCN1CCC(CC1)NC=1C=C(C=C2SC=3C=C(C=CC=3NC=12)C(=O)OC)C(F)(F)F RRUIYSOJPLHBMA-UHFFFAOYSA-N 0.000 description 2
- OGLWIUMAGNYTHY-UHFFFAOYSA-N methyl 9-amino-7-(trifluoromethyl)-10H-phenothiazine-3-carboxylate Chemical compound NC=1C=C(C=C2SC=3C=C(C=CC=3NC=12)C(=O)OC)C(F)(F)F OGLWIUMAGNYTHY-UHFFFAOYSA-N 0.000 description 2
- IXVVQJABYRHDOJ-UHFFFAOYSA-N methyl 9-nitro-7-(trifluoromethyl)-10H-phenothiazine-3-carboxylate Chemical compound [N+](=O)([O-])C=1C=C(C=C2SC=3C=C(C=CC=3NC=12)C(=O)OC)C(F)(F)F IXVVQJABYRHDOJ-UHFFFAOYSA-N 0.000 description 2
- LLVBYEXIVJEZSD-UHFFFAOYSA-N n-(3-bromopyridin-4-yl)acetamide Chemical compound CC(=O)NC1=CC=NC=C1Br LLVBYEXIVJEZSD-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 2
- 229920002401 polyacrylamide Polymers 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- MFMLMKLBWODGNA-UHFFFAOYSA-N propane-1,3-diamine;hydrochloride Chemical compound Cl.NCCCN MFMLMKLBWODGNA-UHFFFAOYSA-N 0.000 description 2
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- UERGZBNUXKFLDF-UHFFFAOYSA-M sodium 4-acetamidopyridine-3-thiolate Chemical compound C(C)(=O)NC1=C(C=NC=C1)[S-].[Na+] UERGZBNUXKFLDF-UHFFFAOYSA-M 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 2
- ATHGHQPFGPMSJY-UHFFFAOYSA-N spermidine Chemical compound NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 2
- TZRQZPMQUXEZMC-UHFFFAOYSA-N tert-butyl n-(2-bromoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCBr TZRQZPMQUXEZMC-UHFFFAOYSA-N 0.000 description 2
- HFZOJUONOHDPHP-UHFFFAOYSA-N tert-butyl n-(3-formylcyclohexyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CCCC(C=O)C1 HFZOJUONOHDPHP-UHFFFAOYSA-N 0.000 description 2
- CKXZPVPIDOJLLM-UHFFFAOYSA-N tert-butyl n-piperidin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNCC1 CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 description 2
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 2
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 1
- LKKCSUHCVGCGFA-UHFFFAOYSA-N (2-hydroxycyclohexyl)azanium;chloride Chemical compound Cl.NC1CCCCC1O LKKCSUHCVGCGFA-UHFFFAOYSA-N 0.000 description 1
- RPAJSBKBKSSMLJ-DFWYDOINSA-N (2s)-2-aminopentanedioic acid;hydrochloride Chemical class Cl.OC(=O)[C@@H](N)CCC(O)=O RPAJSBKBKSSMLJ-DFWYDOINSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- KFUSEUYYWQURPO-UHFFFAOYSA-N 1,2-dichloroethene Chemical compound ClC=CCl KFUSEUYYWQURPO-UHFFFAOYSA-N 0.000 description 1
- AAAXMNYUNVCMCJ-UHFFFAOYSA-N 1,3-diiodopropane Chemical compound ICCCI AAAXMNYUNVCMCJ-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical group C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- AGRIQBHIKABLPJ-UHFFFAOYSA-N 1-Pyrrolidinecarboxaldehyde Chemical compound O=CN1CCCC1 AGRIQBHIKABLPJ-UHFFFAOYSA-N 0.000 description 1
- PXXYZXNGOXRJEE-UHFFFAOYSA-N 10-[(2-methylpropan-2-yl)oxycarbonyl]-1-[[1-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]piperidin-4-yl]amino]phenothiazine-3-carboxylic acid Chemical compound C(C)(C)(C)OC(=O)N1C2=CC=CC=C2SC=2C=C(C=C(C1=2)NC1CCN(CC1)CCNC(=O)OC(C)(C)C)C(=O)O PXXYZXNGOXRJEE-UHFFFAOYSA-N 0.000 description 1
- XUKJDTCEYYOATE-UHFFFAOYSA-N 10h-phenothiazin-1-amine Chemical compound S1C2=CC=CC=C2NC2=C1C=CC=C2N XUKJDTCEYYOATE-UHFFFAOYSA-N 0.000 description 1
- JMDJHHPCLNGILP-UHFFFAOYSA-N 10h-phenoxazin-1-amine Chemical compound O1C2=CC=CC=C2NC2=C1C=CC=C2N JMDJHHPCLNGILP-UHFFFAOYSA-N 0.000 description 1
- USASUEYARBQNBM-UHFFFAOYSA-N 1h-indol-2-ylboronic acid Chemical compound C1=CC=C2NC(B(O)O)=CC2=C1 USASUEYARBQNBM-UHFFFAOYSA-N 0.000 description 1
- QEBYEVQKHRUYPE-UHFFFAOYSA-N 2-(2-chlorophenyl)-5-[(1-methylpyrazol-3-yl)methyl]-4-[[methyl(pyridin-3-ylmethyl)amino]methyl]-1h-pyrazolo[4,3-c]pyridine-3,6-dione Chemical compound C1=CN(C)N=C1CN1C(=O)C=C2NN(C=3C(=CC=CC=3)Cl)C(=O)C2=C1CN(C)CC1=CC=CN=C1 QEBYEVQKHRUYPE-UHFFFAOYSA-N 0.000 description 1
- JOAGDVSCYWJMMJ-UHFFFAOYSA-N 2-(trifluoromethyl)-10H-phenothiazin-1-amine hydrochloride Chemical compound C1=CC=C2C(=C1)NC3=C(S2)C=CC(=C3N)C(F)(F)F.Cl JOAGDVSCYWJMMJ-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- DRQWUAAWZFIVTF-UHFFFAOYSA-N 2-amino-5-bromophenol Chemical compound NC1=CC=C(Br)C=C1O DRQWUAAWZFIVTF-UHFFFAOYSA-N 0.000 description 1
- TYRZAGMAVZESQX-UHFFFAOYSA-N 2-amino-5-chlorobenzenethiol Chemical compound NC1=CC=C(Cl)C=C1S TYRZAGMAVZESQX-UHFFFAOYSA-N 0.000 description 1
- PQMCFTMVQORYJC-UHFFFAOYSA-N 2-aminocyclohexan-1-ol Chemical compound NC1CCCCC1O PQMCFTMVQORYJC-UHFFFAOYSA-N 0.000 description 1
- PZFDERGEFPLQDC-UHFFFAOYSA-N 2-bromo-1h-pyridin-2-amine Chemical compound NC1(Br)NC=CC=C1 PZFDERGEFPLQDC-UHFFFAOYSA-N 0.000 description 1
- DYNANBWWSGPRGV-UHFFFAOYSA-N 2-chloro-3-nitro-5-(trifluoromethyl)aniline Chemical compound NC1=CC(C(F)(F)F)=CC([N+]([O-])=O)=C1Cl DYNANBWWSGPRGV-UHFFFAOYSA-N 0.000 description 1
- ZAISDHPZTZIFQF-UHFFFAOYSA-N 2h-1,4-thiazine Chemical compound C1SC=CN=C1 ZAISDHPZTZIFQF-UHFFFAOYSA-N 0.000 description 1
- IDWRJRPUIXRFRX-UHFFFAOYSA-N 3,5-dimethylpiperidine Chemical compound CC1CNCC(C)C1 IDWRJRPUIXRFRX-UHFFFAOYSA-N 0.000 description 1
- PCTFIHOVQYYAMH-UHFFFAOYSA-N 3,5-dinitro-4-chlorobenzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=C(Cl)C([N+]([O-])=O)=C1 PCTFIHOVQYYAMH-UHFFFAOYSA-N 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- NVORBAXCWWFMSA-UHFFFAOYSA-N 3,7-dibromo-10h-phenothiazine Chemical compound C1=C(Br)C=C2SC3=CC(Br)=CC=C3NC2=C1 NVORBAXCWWFMSA-UHFFFAOYSA-N 0.000 description 1
- ONHPLTTUFWVRET-UHFFFAOYSA-N 3-(3-bromophenothiazin-10-yl)propan-1-amine Chemical compound BrC=1C=CC=2N(C3=CC=CC=C3SC=2C=1)CCCN ONHPLTTUFWVRET-UHFFFAOYSA-N 0.000 description 1
- XVRYLICBZGYABT-UHFFFAOYSA-N 3-[3-(1,3-benzothiazol-2-yl)phenothiazin-10-yl]-N,N-dimethylpropan-1-amine Chemical compound S1C(=NC2=C1C=CC=C2)C=1C=CC=2N(C3=CC=CC=C3SC=2C=1)CCCN(C)C XVRYLICBZGYABT-UHFFFAOYSA-N 0.000 description 1
- JNQGHXVZMISBFA-UHFFFAOYSA-N 3-[3-(1H-indol-2-yl)phenothiazin-10-yl]-N,N-dimethylpropan-1-amine Chemical compound N1C(=CC2=CC=CC=C12)C=1C=CC=2N(C3=CC=CC=C3SC=2C=1)CCCN(C)C JNQGHXVZMISBFA-UHFFFAOYSA-N 0.000 description 1
- CKTUXQBZPWBFDX-UHFFFAOYSA-N 3-azaniumylcyclohexane-1-carboxylate Chemical compound NC1CCCC(C(O)=O)C1 CKTUXQBZPWBFDX-UHFFFAOYSA-N 0.000 description 1
- DDQYSZWFFXOXER-UHFFFAOYSA-N 3-bromopyridin-4-amine Chemical compound NC1=CC=NC=C1Br DDQYSZWFFXOXER-UHFFFAOYSA-N 0.000 description 1
- LJQNMDZRCXJETK-UHFFFAOYSA-N 3-chloro-n,n-dimethylpropan-1-amine;hydron;chloride Chemical compound Cl.CN(C)CCCCl LJQNMDZRCXJETK-UHFFFAOYSA-N 0.000 description 1
- JLAKCHGEEBPDQI-UHFFFAOYSA-N 4-(4-fluorobenzyl)piperidine Chemical compound C1=CC(F)=CC=C1CC1CCNCC1 JLAKCHGEEBPDQI-UHFFFAOYSA-N 0.000 description 1
- MHIJDDIBBUUVMD-UHFFFAOYSA-N 4-amino-3-sulfanylbenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1S MHIJDDIBBUUVMD-UHFFFAOYSA-N 0.000 description 1
- LOPWTHRQPGTEKR-UHFFFAOYSA-N 4-bromo-2-(3-nitropyridin-2-yl)sulfanylaniline Chemical compound BrC1=CC(=C(N)C=C1)SC1=NC=CC=C1[N+](=O)[O-] LOPWTHRQPGTEKR-UHFFFAOYSA-N 0.000 description 1
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 description 1
- IJRKLHTZAIFUTB-UHFFFAOYSA-N 5-nitro-2-(2-phenylethylamino)benzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1NCCC1=CC=CC=C1 IJRKLHTZAIFUTB-UHFFFAOYSA-N 0.000 description 1
- YQPRMJWKJAUFDN-UHFFFAOYSA-N 7-bromo-10H-pyrido[3,2-b][1,4]benzothiazine Chemical compound Brc1ccc2Nc3ncccc3Sc2c1 YQPRMJWKJAUFDN-UHFFFAOYSA-N 0.000 description 1
- KGAHZRUSCGKPPP-UHFFFAOYSA-N 7-bromo-N-piperidin-4-yl-3-(trifluoromethyl)-10H-phenothiazin-1-amine Chemical compound BrC=1C=C2SC=3C=C(C=C(C=3NC2=CC=1)NC1CCNCC1)C(F)(F)F KGAHZRUSCGKPPP-UHFFFAOYSA-N 0.000 description 1
- LNDYZQFOPWOTSY-UHFFFAOYSA-N 7-chloro-3-(trifluoromethyl)-10H-phenothiazin-1-amine Chemical compound ClC=1C=C2SC=3C=C(C=C(C=3NC2=CC=1)N)C(F)(F)F LNDYZQFOPWOTSY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- RHVGAYVMFPIAME-UHFFFAOYSA-N 8-fluoro-1-nitro-3-(trifluoromethyl)-10H-phenothiazine Chemical compound FC1=CC=C2SC=3C=C(C=C(C=3NC2=C1)[N+](=O)[O-])C(F)(F)F RHVGAYVMFPIAME-UHFFFAOYSA-N 0.000 description 1
- VTSUXWDPMLDQNT-UHFFFAOYSA-N 8-fluoro-3-(trifluoromethyl)-10H-phenothiazin-1-amine Chemical compound FC1=CC=C2SC=3C=C(C=C(C=3NC2=C1)N)C(F)(F)F VTSUXWDPMLDQNT-UHFFFAOYSA-N 0.000 description 1
- HEAQNKNNYQENIR-UHFFFAOYSA-N 9-[[1-(2-aminoethyl)piperidin-4-yl]amino]-7-(trifluoromethyl)-10H-phenothiazine-3-carbonitrile Chemical compound NCCN1CCC(CC1)NC=1C=C(C=C2SC=3C=C(C=CC=3NC=12)C#N)C(F)(F)F HEAQNKNNYQENIR-UHFFFAOYSA-N 0.000 description 1
- SSLJDHINCIBLRR-UHFFFAOYSA-N 9-amino-7-(trifluoromethyl)-10H-phenothiazine-3-carbonitrile Chemical compound NC=1C=C(C=C2SC=3C=C(C=CC=3NC=12)C#N)C(F)(F)F SSLJDHINCIBLRR-UHFFFAOYSA-N 0.000 description 1
- MGFLJHICHMLYBH-UHFFFAOYSA-N 9-nitro-7-(trifluoromethyl)-10H-phenothiazine-3-carboxylic acid Chemical compound [N+](=O)([O-])C=1C=C(C=C2SC=3C=C(C=CC=3NC=12)C(=O)O)C(F)(F)F MGFLJHICHMLYBH-UHFFFAOYSA-N 0.000 description 1
- ZHGNHOOVYPHPNJ-UHFFFAOYSA-N Amigdalin Chemical compound FC(F)(F)C(=O)OCC1OC(OCC2OC(OC(C#N)C3=CC=CC=C3)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C2OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C1OC(=O)C(F)(F)F ZHGNHOOVYPHPNJ-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- AHLPXQWRTRKQDW-UHFFFAOYSA-N CC(C)(C)OC(NCCN(CC1)CCC1[N]1(C(OC(C)(C)C)=O)N2c(cccc3)c3Sc3c2c1cc(C(N1CCCC1)=O)c3)=O Chemical compound CC(C)(C)OC(NCCN(CC1)CCC1[N]1(C(OC(C)(C)C)=O)N2c(cccc3)c3Sc3c2c1cc(C(N1CCCC1)=O)c3)=O AHLPXQWRTRKQDW-UHFFFAOYSA-N 0.000 description 1
- KGZAALNJBACRIW-UHFFFAOYSA-N CC(C1)C(C#N)=CC(C)=C1Nc(c(NC1CCN(CCN)CC1)cc(C(F)(F)F)c1)c1S Chemical compound CC(C1)C(C#N)=CC(C)=C1Nc(c(NC1CCN(CCN)CC1)cc(C(F)(F)F)c1)c1S KGZAALNJBACRIW-UHFFFAOYSA-N 0.000 description 1
- FAJHWKFUQLTQGS-UHFFFAOYSA-N CN(C)CCCN1c(ccc(C=O)c2)c2Sc2ccccc12 Chemical compound CN(C)CCCN1c(ccc(C=O)c2)c2Sc2ccccc12 FAJHWKFUQLTQGS-UHFFFAOYSA-N 0.000 description 1
- 241001640117 Callaeum Species 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 206010011409 Cross infection Diseases 0.000 description 1
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 208000002476 Falciparum Malaria Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 241001249678 Klebsiella pneumoniae subsp. pneumoniae Species 0.000 description 1
- 241000589242 Legionella pneumophila Species 0.000 description 1
- 241000308139 Legionella pneumophila subsp. pneumophila Species 0.000 description 1
- 241000186779 Listeria monocytogenes Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241001467552 Mycobacterium bovis BCG Species 0.000 description 1
- GZBUASUAPNBLLY-UHFFFAOYSA-N N-(2-aminoethyl)-N'-[7-(3,5-dimethylpiperidin-1-yl)-3-(trifluoromethyl)-10H-phenothiazin-1-yl]propane-1,3-diamine hydrochloride Chemical compound Cl.CC1CC(C)CN(C1)c1ccc2Nc3c(NCCCNCCN)cc(cc3Sc2c1)C(F)(F)F GZBUASUAPNBLLY-UHFFFAOYSA-N 0.000 description 1
- RUQWJGCZNQNHNF-UHFFFAOYSA-N N-(2-aminoethyl)-N'-[7-(cyclopenten-1-yl)-3-(trifluoromethyl)-10H-phenothiazin-1-yl]propane-1,3-diamine hydrochloride Chemical compound Cl.NCCNCCCNc1cc(cc2Sc3cc(ccc3Nc12)C1=CCCC1)C(F)(F)F RUQWJGCZNQNHNF-UHFFFAOYSA-N 0.000 description 1
- IBRSMQDLCLITIC-UHFFFAOYSA-N N-[1-(2-aminoethyl)piperidin-4-yl]-7-(aminomethyl)-3-(trifluoromethyl)-10H-phenothiazin-1-amine Chemical compound NCCN1CCC(CC1)NC1=CC(=CC=2SC3=CC(=CC=C3NC1=2)CN)C(F)(F)F IBRSMQDLCLITIC-UHFFFAOYSA-N 0.000 description 1
- LKHVRWZXNFNNOH-UHFFFAOYSA-N N-[1-(2-aminoethyl)piperidin-4-yl]-7-(aminomethyl)-3-(trifluoromethyl)-10H-phenothiazin-1-amine 2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.NCCN1CCC(CC1)Nc1cc(cc2Sc3cc(CN)ccc3Nc12)C(F)(F)F LKHVRWZXNFNNOH-UHFFFAOYSA-N 0.000 description 1
- QQYZFVPPGCMRHM-UHFFFAOYSA-N N-[7-bromo-3-(trifluoromethyl)-10H-phenothiazin-1-yl]-3-chloropropanamide Chemical compound BrC=1C=C2SC=3C=C(C=C(C=3NC2=CC=1)NC(CCCl)=O)C(F)(F)F QQYZFVPPGCMRHM-UHFFFAOYSA-N 0.000 description 1
- WVVOBOZHTQJXPB-UHFFFAOYSA-N N-anilino-N-nitronitramide Chemical compound [N+](=O)([O-])N(NC1=CC=CC=C1)[N+](=O)[O-] WVVOBOZHTQJXPB-UHFFFAOYSA-N 0.000 description 1
- OFJULKSNVSCFFT-UHFFFAOYSA-N N-piperidin-4-yl-3-(trifluoromethyl)-10H-phenothiazin-1-amine Chemical compound N1CCC(CC1)NC1=CC(=CC=2SC3=CC=CC=C3NC1=2)C(F)(F)F OFJULKSNVSCFFT-UHFFFAOYSA-N 0.000 description 1
- BHUXGEUTAPRVNK-UHFFFAOYSA-N NCCN(CC1)CCC1Nc1cc(C(F)(F)F)cc(Sc2c3)c1Nc2ccc3C1=CCCC1 Chemical compound NCCN(CC1)CCC1Nc1cc(C(F)(F)F)cc(Sc2c3)c1Nc2ccc3C1=CCCC1 BHUXGEUTAPRVNK-UHFFFAOYSA-N 0.000 description 1
- 241000588650 Neisseria meningitidis Species 0.000 description 1
- 206010029803 Nosocomial infection Diseases 0.000 description 1
- JZFYZCJSCVGSPN-UHFFFAOYSA-N OC(O)=O.CC(C)(C)[K] Chemical compound OC(O)=O.CC(C)(C)[K] JZFYZCJSCVGSPN-UHFFFAOYSA-N 0.000 description 1
- 239000008118 PEG 6000 Substances 0.000 description 1
- 201000011336 Plasmodium falciparum malaria Diseases 0.000 description 1
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 102000004389 Ribonucleoproteins Human genes 0.000 description 1
- 108010081734 Ribonucleoproteins Proteins 0.000 description 1
- 101710154250 Small basic protein Proteins 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000201788 Staphylococcus aureus subsp. aureus Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- DRBWRJPFNOBNIO-KOLCDFICSA-N [(2r)-1-[(2r)-2-(pyridine-4-carbonylamino)propanoyl]pyrrolidin-2-yl]boronic acid Chemical compound N([C@H](C)C(=O)N1[C@@H](CCC1)B(O)O)C(=O)C1=CC=NC=C1 DRBWRJPFNOBNIO-KOLCDFICSA-N 0.000 description 1
- USEIVAXWNKSGLX-UHFFFAOYSA-N [10-[3-(dimethylamino)propyl]-3-(trifluoromethyl)phenothiazin-1-yl]thiourea Chemical compound CN(C)CCCN1C2=C(SC3=CC(=CC(NC(N)=S)=C13)C(F)(F)F)C=CC=C2 USEIVAXWNKSGLX-UHFFFAOYSA-N 0.000 description 1
- ZKHQWZAMYRWXGA-KNYAHOBESA-N [[(2r,3s,4r,5r)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] dihydroxyphosphoryl hydrogen phosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)O[32P](O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KNYAHOBESA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 150000001348 alkyl chlorides Chemical class 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- CZLFQMXZQQPSIO-UHFFFAOYSA-N amino cyclohexanecarboxylate Chemical compound NOC(=O)C1CCCCC1 CZLFQMXZQQPSIO-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 238000009635 antibiotic susceptibility testing Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 description 1
- 229960004191 artemisinin Drugs 0.000 description 1
- 229930101531 artemisinin Natural products 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- UDSAIICHUKSCKT-UHFFFAOYSA-N bromophenol blue Chemical compound C1=C(Br)C(O)=C(Br)C=C1C1(C=2C=C(Br)C(O)=C(Br)C=2)C2=CC=CC=C2S(=O)(=O)O1 UDSAIICHUKSCKT-UHFFFAOYSA-N 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 150000003997 cyclic ketones Chemical class 0.000 description 1
- PNZXMIKHJXIPEK-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1CCCCC1 PNZXMIKHJXIPEK-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- UZBHNSVUMGIKLU-UHFFFAOYSA-N cyclopenten-1-ylboronic acid Chemical compound OB(O)C1=CCCC1 UZBHNSVUMGIKLU-UHFFFAOYSA-N 0.000 description 1
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 229940032049 enterococcus faecalis Drugs 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- HCFPRFJJTHMING-UHFFFAOYSA-N ethane-1,2-diamine;hydron;chloride Chemical compound [Cl-].NCC[NH3+] HCFPRFJJTHMING-UHFFFAOYSA-N 0.000 description 1
- DLLJVQNYBYOKGS-UHFFFAOYSA-N ethoxyethane;pentane Chemical compound CCCCC.CCOCC DLLJVQNYBYOKGS-UHFFFAOYSA-N 0.000 description 1
- ZCLGVXACCAZJOX-UHFFFAOYSA-N ethyl 3-chloropropanoate Chemical compound CCOC(=O)CCCl ZCLGVXACCAZJOX-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 239000004312 hexamethylene tetramine Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229940115932 legionella pneumophila Drugs 0.000 description 1
- 238000002514 liquid chromatography mass spectrum Methods 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 1
- GLARUGUGPKWING-UHFFFAOYSA-N methyl 2-oxo-3,4-dihydro-1h-naphthalene-1-carboxylate Chemical compound C1=CC=C2C(C(=O)OC)C(=O)CCC2=C1 GLARUGUGPKWING-UHFFFAOYSA-N 0.000 description 1
- CAVJWIQCXLYELB-UHFFFAOYSA-N methyl 9-[[1-(2-aminoethyl)piperidin-4-yl]amino]-7-(trifluoromethyl)-10H-phenothiazine-3-carboxylate Chemical compound NCCN1CCC(CC1)NC=1C=C(C=C2SC=3C=C(C=CC=3NC=12)C(=O)OC)C(F)(F)F CAVJWIQCXLYELB-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 201000009671 multidrug-resistant tuberculosis Diseases 0.000 description 1
- KRKPYFLIYNGWTE-UHFFFAOYSA-N n,o-dimethylhydroxylamine Chemical compound CNOC KRKPYFLIYNGWTE-UHFFFAOYSA-N 0.000 description 1
- ZONOJQNMZGORON-UHFFFAOYSA-N n-(2-bromo-5-fluorophenyl)acetamide Chemical compound CC(=O)NC1=CC(F)=CC=C1Br ZONOJQNMZGORON-UHFFFAOYSA-N 0.000 description 1
- NTBNRLSFZRKXTH-UHFFFAOYSA-N n-[4-bromo-2-(3-nitropyridin-2-yl)sulfanylphenyl]acetamide Chemical compound CC(=O)NC1=CC=C(Br)C=C1SC1=NC=CC=C1[N+]([O-])=O NTBNRLSFZRKXTH-UHFFFAOYSA-N 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 150000002832 nitroso derivatives Chemical class 0.000 description 1
- 108091027963 non-coding RNA Proteins 0.000 description 1
- 102000042567 non-coding RNA Human genes 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 229940078552 o-xylene Drugs 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000008261 resistance mechanism Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229940063673 spermidine Drugs 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- HYAIMXAKHMNGKP-UHFFFAOYSA-N tert-butyl 1-(3-chloropropanoylamino)-7-pyrrolidin-1-yl-3-(trifluoromethyl)phenothiazine-10-carboxylate Chemical compound ClCCC(=O)NC1=CC(=CC=2SC3=CC(=CC=C3N(C1=2)C(=O)OC(C)(C)C)N1CCCC1)C(F)(F)F HYAIMXAKHMNGKP-UHFFFAOYSA-N 0.000 description 1
- YUXJEIFKSLUXAU-UHFFFAOYSA-N tert-butyl 1-amino-7-pyrrolidin-1-yl-3-(trifluoromethyl)phenothiazine-10-carboxylate Chemical compound NC1=CC(=CC=2SC3=CC(=CC=C3N(C1=2)C(=O)OC(C)(C)C)N1CCCC1)C(F)(F)F YUXJEIFKSLUXAU-UHFFFAOYSA-N 0.000 description 1
- RNBUMUMUOLDRQY-UHFFFAOYSA-N tert-butyl 1-nitro-7-pyrrolidin-1-yl-3-(trifluoromethyl)phenothiazine-10-carboxylate Chemical compound CC(C)(C)OC(=O)N1c2ccc(cc2Sc2cc(cc(c12)[N+]([O-])=O)C(F)(F)F)N1CCCC1 RNBUMUMUOLDRQY-UHFFFAOYSA-N 0.000 description 1
- PGJABCQORNHEMI-UHFFFAOYSA-N tert-butyl 2-(7-bromo-10H-phenothiazin-3-yl)indole-1-carboxylate Chemical compound BrC=1C=C2SC=3C=C(C=CC=3NC2=CC=1)C=1N(C2=CC=CC=C2C=1)C(=O)OC(C)(C)C PGJABCQORNHEMI-UHFFFAOYSA-N 0.000 description 1
- ZGPSAYFWHOSRLA-UHFFFAOYSA-N tert-butyl 2-[10-[3-(dimethylamino)propyl]phenothiazin-3-yl]indole-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1C(=CC2=CC=CC=C12)C=1C=CC=2N(C3=CC=CC=C3SC=2C=1)CCCN(C)C ZGPSAYFWHOSRLA-UHFFFAOYSA-N 0.000 description 1
- HMPSTDOCUJQAPT-UHFFFAOYSA-N tert-butyl 2-[7-bromo-10-(3-chloropropyl)phenothiazin-3-yl]indole-1-carboxylate Chemical compound BrC=1C=C2SC=3C=C(C=CC=3N(C2=CC=1)CCCCl)C=1N(C2=CC=CC=C2C=1)C(=O)OC(C)(C)C HMPSTDOCUJQAPT-UHFFFAOYSA-N 0.000 description 1
- BFQJIZKPNRKRTD-UHFFFAOYSA-N tert-butyl 9-amino-7-(trifluoromethyl)-1,2,3,4,4a,10a-hexahydrophenothiazine-10-carboxylate Chemical compound NC=1C=C(C=C2SC3CCCCC3N(C=12)C(=O)OC(C)(C)C)C(F)(F)F BFQJIZKPNRKRTD-UHFFFAOYSA-N 0.000 description 1
- VACLTXTYDFLHJW-UHFFFAOYSA-N tert-butyl n-(2-chloroethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCl VACLTXTYDFLHJW-UHFFFAOYSA-N 0.000 description 1
- MLDSDVASYUUDLT-UHFFFAOYSA-N tert-butyl n-(3-oxopropyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCC=O MLDSDVASYUUDLT-UHFFFAOYSA-N 0.000 description 1
- MUDQGIOQWIBILS-UHFFFAOYSA-N tert-butyl n-[2-(4-oxopiperidin-1-yl)ethyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCN1CCC(=O)CC1 MUDQGIOQWIBILS-UHFFFAOYSA-N 0.000 description 1
- DNSTUAQHBFISRZ-UHFFFAOYSA-N tert-butyl n-cyclohexylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCCCC1 DNSTUAQHBFISRZ-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- RSPCKAHMRANGJZ-UHFFFAOYSA-N thiohydroxylamine Chemical compound SN RSPCKAHMRANGJZ-UHFFFAOYSA-N 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000001195 ultra high performance liquid chromatography Methods 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- NLIVDORGVGAOOJ-MAHBNPEESA-M xylene cyanol Chemical compound [Na+].C1=C(C)C(NCC)=CC=C1C(\C=1C(=CC(OS([O-])=O)=CC=1)OS([O-])=O)=C\1C=C(C)\C(=[NH+]/CC)\C=C/1 NLIVDORGVGAOOJ-MAHBNPEESA-M 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
- C07D279/24—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom
- C07D279/28—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom with other substituents attached to the ring system
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/46—Phenazines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
- C07D265/38—[b, e]-condensed with two six-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/20—[b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/06—Peri-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
Description
Aは、SおよびOから選択され;
X1、X2、X3、X4およびX5の各々は、独立して、CおよびNから選択され;
R1は、
−H、
−C1〜6アルキル、
−C1〜6アルキル−アミノであって、アミノ基は、任意選択により1または2つのC1〜6アシルまたはC1〜6アルキル基で置換される、−C1〜6アルキル−アミノ、および
−C1〜6アルキル−ヘテロシクリルであって、ヘテロシクリル基は、5員または6員の脂肪族ヘテロシクリルまたは任意選択によりベンゾ縮合された芳香族ヘテロシクリルであり、かつ任意選択により1つ以上のR6基で置換される、−C1〜6アルキル−ヘテロシクリル
からなる群から選択され;
R2は、−H、−CF3、−NO2、−N(R5)2、−NHR5、−N(R5)C(O)R5および−N(R5)C(S)N(R5)2からなる群から選択され;または
R1およびR2は、それらが結合されている原子と合わせて、1つ以上のR5基で置換された5員または6員の縮合複素環を形成し;
R3は、−CF3、−CN、−Cl、−C1〜6アルキル、−C3〜6シクロアルキル、−C(O)NH2、−C(O)NH−C1〜6アルキル、−NH−ヘテロシクリル、−フェニルおよび−ヘテロシクリルから選択され、ここで、ヘテロシクリル基は、5員または6員の脂肪族複素環または任意選択によりベンゾ縮合された芳香族複素環であり、かつR3は、任意選択により1つ以上のR6基で置換され;
R4およびR8の各々は、H、−CN、−ハロ、−CF3、−C1〜6アルコキシ、−CO2−C1〜6アルキル、−NO2、−C1〜6アルキル−NH2、−ヘテロシクリルおよび−CONHm[(CH2)nNH2]2〜mから選択され、ここで、ヘテロシクリル基は、5員または6員の脂肪族複素環または任意選択によりベンゾ縮合された芳香族複素環であり;
R5の各例は、独立して、
−H、
任意選択により1つ以上のR6基で置換された−C1〜6アルキル、
任意選択により1つ以上のR6基で置換された−C2〜6アルケニル、
任意選択により1つ以上のR6基で置換された−C0〜3アルキル−C3〜6シクロアルキル−C0〜3アルキル、
任意選択により1つ以上のR6基で置換された−フェニル、
任意選択により1つ以上のR6基で置換された−C=C−Ph、および
任意選択により1つ以上のR6基で置換された−C0〜3アルキル−ヘテロシクリル−C0〜3アルキルであって、ヘテロシクリル基は、5員、6員または7員の脂肪族複素環または任意選択によりベンゾ縮合された芳香族複素環である、−C0〜3アルキル−ヘテロシクリル−C0〜3アルキル
からなる群から選択され;
R6の各例は、独立して、−ハロ、−CN、−C1〜6アルキル、−OH、−C1〜6アルコキシ、−C1〜6アルキル−NH2、−NHm[(CH2)nNH2]2〜m、−NH2、−NH−C1〜6アルキルおよび−N−C1〜6ジアルキルからなる群から選択され;
nおよびmは、整数であり、ここで、nの各例は、独立して、2または3から選択され、かつmの各例は、独立して、0または1から選択され;
ただし、R2が−Hである場合、R1は、−Hまたは−C1〜6アルキルでないことを条件とする)
またはその薬学的に許容される塩を有する。
Aは、SおよびOから選択され;
X1は、CおよびNから選択され;
R1は、
−H、
−C1〜3アルキル、
−C1〜3アルキル−アミノであって、アミノ基は、任意選択により1または2つのアセチルまたはC1〜3アルキル基で置換される、−C1〜3アルキル−アミノ、および
−C1〜3アルキル−ヘテロシクリルであって、ヘテロシクリル基は、イミダゾリル、ピペラジニルおよびチオモルホリニルから選択され、かつ任意選択により1つ以上のR6基で置換される、−C1〜3アルキル−ヘテロシクリル
からなる群から選択され;
R2は、−H、−CF3、−NO2、−N(R5)2、−NHR5、−N(R5)C(O)R5および−N(R5)C(S)N(R5)2からなる群から選択され;または
R1およびR2は、それらが結合されている原子と合わせて、1つ以上のR5基で置換された5員または6員の縮合複素環を形成し;
R3は、−CF3、−CN、−Cl、−C1〜3アルキル、−C3〜6シクロアルキル、−C(O)NH2、−C(O)NH−C1〜3アルキル、−NH−ピペラジニル、−フェニル、−ピリジニル、−インドリル、−ベンゾイミダゾリル、−ベンゾチアゾリルおよび−ベンゾピラゾリルから選択され、ここで、R3は、任意選択により1つ以上のR6基で置換され;
R4およびR8の各々は、H、−CN、−Cl、−F、−CF3、−C1〜3アルコキシ、−CO2Me、−NO2、−C1〜3アルキル−NH2、−ピペラジニル、−インドリルおよびCONHm[(CH2)nNH2]2〜mから選択され;
R5の各例は、独立して、
−H、
任意選択により1つ以上のR6基で置換された−C1〜3アルキル、
任意選択により1つ以上のR6基で置換された−C2〜3アルケニル、
任意選択により1つ以上のR6基で置換された−C0〜3アルキル−C3〜6シクロアルキル−C0〜3アルキル、
任意選択により1つ以上のR6基で置換された−フェニル、
任意選択により1つ以上のR6基で置換された−C=C−Ph、および
任意選択により1つ以上のR6基で置換された−C0〜3アルキル−ヘテロシクリル−C0〜3アルキルであって、ヘテロシクリル基は、アゼチジニル、ピロリジニル、ピペリジニル、ピペラジニル、モルホリニル、アゼパニルおよびインドリルから選択される、−C0〜3アルキル−ヘテロシクリル−C0〜3アルキル
からなる群から選択され;
R6の各例は、独立して、−F、−Cl、−CN、−C1〜3アルキル、−OH、−C1〜3アルコキシ、−C1〜3アルキル−NH2、−NHm[(CH2)nNH2]2〜m、−NH2、−NHMeおよび−NMe2からなる群から選択され;
nおよびmは、整数であり、ここで、nの各例は、独立して、2または3から選択され、かつmの各例は、独立して、0または1から選択され;
ただし、R2が−Hである場合、R1は、−Hまたは−C1〜3アルキルでないことを条件とする、構造を有し得る。
ただし、R2が−Hである場合、R1は、−Hまたは−C1〜3アルキルでなく、かつR8は、Hでないことを条件とする、構造を有し得る。
他に明記しない限り、全ての反応を乾燥窒素およびまたはアルゴン雰囲気下で実施した。他に明記しない限り、全ての未処理の出発物質、溶媒および試薬を民間の供給元(例えば、AVRA Chemicals、Apollo Scientific Limited、Bepharma Ltd.、Combi−Blocks Inc.、Sigma Aldrich Chemicals Pvt.Ltd.、Ultra Labs、Toronto Research Chemicals Inc.、Chemical House、RFCL Limited、Spectro Chem Pvt.Ltd.、Leonid Chemicals、Loba Chemie、Changzhou Yangyuan、NeoSynth.、Rankemなど)から購入し、さらに精製することなくそのまま使用した。代わりに、試薬は、文献において知られている手順によって合成され得る。
図1は、選択された3,N−10−二置換フェノチアゼンの合成のための一般的な合成スキームIを示す。2−アミノチオフェノール(Ia)のハロゲン化アリール(Ib)との求核置換により、対応するチオエーテル(Ic)を得た。チオエーテル(Ic)のN−ホルミル化に続くスマイルス転位により、3−置換フェノチアゼン(Ie)を得た。塩基としてNaHを用いる異なるアルキルハロゲン化物によるIeのN−アルキル化により、対応するN−10−アルキル化フェノチアゼン(IfおよびIh)を得た。モノハロアルキル化フェノチアゼン(If)を求核剤(アミンおよびアルコール)と反応させ、その後、HClを用いて塩を調製して、対応する塩(Ih)を得た。Ihのエステル類似体の場合、エステル加水分解に続いてアミドを形成して標題の化合物(Ii)を得た。
図4は、選択された3,N−10−二置換フェノチアゼンの合成のための一般的な合成スキームIVを示す。2−アミノ−5−ブロモベンゼンチオール(IVa)の1−クロロ−2−ニトロベンゼン(IVb)との求核置換により、化合物IVcを得た。化合物IVcのN−ホルミル化に続くスマイルス転位により、3−ブロモフェノチアゼン(IVe)を得た。NaHを用いる臭化アルキルによる化合物IVeのN−アルキル化により、N−10−アルキル化フェノチアゼン(IVf)を得た。化合物IVfの求核置換に続く還元および得られたアミンの保護により、化合物IVgを得た。並行して、化合物IVfのアミンとの反応により、化合物IVhを得た。化合物IVgおよびIVhのアリールボラン化合物との鈴木カップリングにより、対応する3−アリールフェノチアゼン(IVjおよびIVi)を得た。化合物IVjおよびIViの脱保護により、標題の化合物IVlおよびIVkを得る。最後に、IVkと塩化アシルまたはハロゲン化アルキルの反応により、対応する標題の化合物IVlを得た。
1H NMR(400MHz,DMSO−d6)δ1.93−1.99(m,4H),2.11(d,J=10.7Hz,4H),2.91(s,2H),3.11−3.19(m,2H),3.31−3.39(m,8H),3.61−3.68(m,5H),6.61(d,J=22.4Hz,2H),7.09(s,1H),7.20−7.43(m,2H),8.32(d,J=17.5Hz,6H),8.61(s,1H),10.89(s,1H).LC−MS m/z(M+H):507.1
1H NMR(400MHz,DMSO−d6)δ1.32(s,9H),1.94−1.96(m,4H),3.22−3.30(m,4H),6.59−6.61(m,2H),7.33−7.37(m,1H),7.45−7.46(m,1H),7.70−7.80(m,1H),8.27(brs,1H),8.32(s,1H).LC−MS m/z(M+H):482.1
1H NMR(400MHz,DMSO−d6)δ1.79(s,4H),1.92(d,J=11.4Hz,2H),2.12(d,J=12.4Hz,2H),3.13(d,J=10.1Hz,2H),3.30−3.39(m,9H),3.61(d,J=10.2Hz,4H),6.40−6.47(m,1H),6.58(s,1H),6.78(t,J=6.6Hz,1H),6.91−7.02(m,3H),8.11(s,1H),8.31(s,3H),8.59(s,1H),10.94(brs,1H)LC−MS m/z(M+H):438.2
1H NMR(400MHz,DMSO−d6)δ3.62(s,3H),6.43(brs,2H),6.77(d,J=8.16Hz,1H),7.33(d,J=2.05Hz,1H),7.65(dd,J=8.5Hz,1H)
LC−MS m/z(M+H):215.0
1H NMR(400MHz,CDCl3)δ0.87−0.95(m,6H),1.25−1.40(m,9H),1.55−1.65(m,1H),2.35(s,3H),2.57(t,J=7.02Hz,2H),2.95(t,J=7.06Hz,2H),4.07−4.09(m,2H),8.43(d,J=5.5Hz,1H),8.47(t,J=5.7Hz,1H),8.68(s,1H),8.98(brs,1H).LC−MS m/z(M+H):353.48
LC−MS m/z(M+H):409.1
LC−MS m/z(M+H):749.2
下の表13は、合成された化合物のLC−MSデータを提供し、化合物を得るためにいずれの一般的な合成方法(スキーム番号)が使用されたかを示す。
本出願により開示される化合物は、抗感染症活性を有する。
− エシェリキア・コリ(Escherichia coli)(ATCC25922)
− スタフィロコッカス・アウレウス(Staphylococcus aureus)(ATCC25923)
これらの試験の結果を表15に示す。
エンテロコッカス・フェカーリス(Enterococcus faecalis)(ATCC29212)
シュードモナス・エルギノーサ(Pseudomonas aeruginosa)(ATCC27853)
スタフィロコッカス・アウレウス亜種アウレウス(Staphylococcus aureus subsp.aureus)(ATCC29213)
クレブシエラ・ニューモニエ亜種ニューモニエ(Klebsiella pneumoniae subsp.pneumoniae)(ATCC13883)
ストレプトコッカス・ニューモニエ(Streptococcus pneumoniae)(ATCC33400)
ヘモフィルス・インフルエンザエ(Haemophilus influenzae)(ATCC49766)
ナイセリア・メニンギティディス(Neisseria meningitidis)(ATCC13077)
リステリア・モノサイトゲネス(Listeria monocytogenes)(ATCC15313)
レジオネラ・ニューモフィラ亜種ニューモフィラ(Legionella pneumophila subsp.pneumophila)(ATCC33152)
マイコバクテリウム・ボビスBCG(Mycobacterium bovis BCG)(ATCC19210)
これらの試験の結果を表16に示す。
MIC値を、臨床・検査標準協会(Clinical and Laboratory Standards Institute)(CLSI)によるガイドラインに基づく標準的な微量液体希釈法を用いて決定した。簡潔に述べると、化合物をDMSOに溶解させて10mMとした。それらを陽イオン調整ミュラーヒントン培地(CAMHB)中において、試験した最高濃度の4倍に希釈した。CAMHBにおける段階2倍希釈を微量希釈プレート中で行った。試験される細菌株の接種菌液を、CAMHB中で18〜24時間経たプレート由来のコロニーの懸濁液を作製することにより調製した。接種菌液を希釈し、それにより、播種後の各ウェルは、約5×105CFU/mLを含有した。CAMHB中の50μlの量の化合物に等量の接種菌液を添加した。トレーをプラスチックバッグに密封し、35℃で16〜20時間インキュベートした。増殖の検出を促進するために、レサズリン色素を最終濃度0.001%となるように添加し、室温で1時間インキュベートした。レサズリンの還元、結果として細菌の増殖が青色から桃色への変化として見られる。MICは、微生物の増殖を完全に阻害する化合物の最小濃度である。
本アッセイは、E.コリ(E.coli)リボヌクレアーゼP RNA、M1 RNAによる基質pATSerUGの切断が化合物によりどの程度阻害されるかに基づく。
化合物に関して阻害が検出され得るかどうかを試験するためにリボヌクレアーゼP活性の初期阻害を測定した。最大量の化合物、すなわち、10μlの切断反応液中におけるアッセイ用緩衝液中に新たに溶解した化合物から8μlの上清を使用した。阻害の程度を、正規化された切断(化合物を有する切断を化合物なしの切断で割った比)から判断した。この比が0.5未満であった場合、IC50値が決定される。
8つの異なる濃度、概して化合物の最高濃度から8000倍希釈の範囲について切断を試験した。IC50値およびヒル勾配をGraphPad Prismソフトウェアを用いて計算した。決定されたIC50値を表15に列挙する。
Claims (24)
- 式I:
Aは、SおよびOから選択され;
X1、X2、X3、X4およびX5の各々は、独立して、CおよびNから選択され;
R1は、
−H、
−C1〜6アルキル、
−C1〜6アルキル−アミノであって、アミノ基は、任意選択により1または2つのC1〜6アシルまたはC1〜6アルキル基で置換される、−C1〜6アルキル−アミノ、および
−C1〜6アルキル−ヘテロシクリルであって、ヘテロシクリル基は、5員または6員の脂肪族ヘテロシクリルまたは任意選択によりベンゾ縮合された芳香族ヘテロシクリルであり、かつ任意選択により1つ以上のR6基で置換される、−C1〜6アルキル−ヘテロシクリル
からなる群から選択され;
R2は、−H、−CF3、−NO2、−N(R5)2、−NHR5、−N(R5)C(O)R5および−N(R5)C(S)N(R5)2からなる群から選択され;または
R1およびR2は、それらが結合されている原子と合わせて、1つ以上のR5基で置換された5員または6員の縮合複素環を形成し;
R3は、−CF3、−CN、−Cl、−C1〜6アルキル、−C3〜6シクロアルキル、−C(O)NH2、−C(O)NH−C1〜6アルキル、−NH−ヘテロシクリル、−フェニルおよび−ヘテロシクリルから選択され、ここで、ヘテロシクリル基は、5員または6員の脂肪族複素環または任意選択によりベンゾ縮合された芳香族複素環であり、かつR3は、任意選択により1つ以上のR6基で置換され;
R4およびR8の各々は、H、−CN、−ハロ、−CF3、−C1〜6アルコキシ、−CO2−C1〜6アルキル、−NO2、−C1〜6アルキル−NH2、−ヘテロシクリルおよび−CONHm[(CH2)nNH2]2〜mから選択され、ここで、ヘテロシクリル基は、5員または6員の脂肪族複素環または任意選択によりベンゾ縮合された芳香族複素環であり;
R5の各例は、独立して、
−H、
任意選択により1つ以上のR6基で置換された−C1〜6アルキル、
任意選択により1つ以上のR6基で置換された−C2〜6アルケニル、
任意選択により1つ以上のR6基で置換された−C0〜3アルキル−C3〜6シクロアルキル−C0〜3アルキル、
任意選択により1つ以上のR6基で置換された−フェニル、
任意選択により1つ以上のR6基で置換された−C=C−Ph、および
任意選択により1つ以上のR6基で置換された−C0〜3アルキル−ヘテロシクリル−C0〜3アルキルであって、ヘテロシクリル基は、5員、6員または7員の脂肪族複素環または任意選択によりベンゾ縮合された芳香族複素環である、−C0〜3アルキル−ヘテロシクリル−C0〜3アルキル
からなる群から選択され;
R6の各例は、独立して、−ハロ、−CN、−C1〜6アルキル、−OH、−C1〜6アルコキシ、−C1〜6アルキル−NH2、−NHm[(CH2)nNH2]2〜m、−NH2、−NH−C1〜6アルキルおよび−N−C1〜6ジアルキルからなる群から選択され;
nおよびmは、整数であり、ここで、nの各例は、独立して、2または3から選択され、かつmの各例は、独立して、0または1から選択され;
ただし、R2が−Hである場合、R1は、−Hまたは−C1〜6アルキルでないことを条件とする)
の化合物またはその薬学的に許容される塩。 - 式II:
Aは、SおよびOから選択され;
X1は、CおよびNから選択され;
R1は、
−H、
−C1〜3アルキル、
−C1〜3アルキル−アミノであって、アミノ基は、任意選択により1または2つのアセチルまたはC1〜3アルキル基で置換される、−C1〜3アルキル−アミノ、および
−C1〜3アルキル−ヘテロシクリルであって、ヘテロシクリル基は、イミダゾリル、ピペラジニルおよびチオモルホリニルから選択され、かつ任意選択により1つ以上のR6基で置換される、−C1〜3アルキル−ヘテロシクリル
からなる群から選択され;
R2は、−H、−CF3、−NO2、−N(R5)2、−NHR5、−N(R5)C(O)R5および−N(R5)C(S)N(R5)2からなる群から選択され;または
R1およびR2は、それらが結合されている原子と合わせて、1つ以上のR5基で置換された5員または6員の縮合複素環を形成し;
R3は、−CF3、−CN、−Cl、−C1〜3アルキル、−C3〜6シクロアルキル、−C(O)NH2、−C(O)NH−C1〜3アルキル、−NH−ピペラジニル、−フェニル、−ピリジニル、−インドリル、−ベンゾイミダゾリル、−ベンゾチアゾリルおよび−ベンゾピラゾリルから選択され、ここで、R3は、任意選択により1つ以上のR6基で置換され;
R4およびR8の各々は、H、−CN、−Cl、−F、−CF3、−C1〜3アルコキシ、−CO2Me、−NO2、−C1〜3アルキル−NH2、−ピペラジニル、−インドリルおよびCONHm[(CH2)nNH2]2〜mから選択され;
R5の各例は、独立して、
−H、
任意選択により1つ以上のR6基で置換された−C1〜3アルキル、
任意選択により1つ以上のR6基で置換された−C2〜3アルケニル、
任意選択により1つ以上のR6基で置換された−C0〜3アルキル−C3〜6シクロアルキル−C0〜3アルキル、
任意選択により1つ以上のR6基で置換された−フェニル、
任意選択により1つ以上のR6基で置換された−C=C−Ph、および
任意選択により1つ以上のR6基で置換された−C0〜3アルキル−ヘテロシクリル−C0〜3アルキルであって、ヘテロシクリル基は、アゼチジニル、ピロリジニル、ピペリジニル、ピペラジニル、モルホリニル、アゼパニルおよびインドリルから選択される、−C0〜3アルキル−ヘテロシクリル−C0〜3アルキル
からなる群から選択され;
R6の各例は、独立して、−F、−Cl、−CN、−C1〜3アルキル、−OH、−C1〜3アルコキシ、−C1〜3アルキル−NH2、−NHm[(CH2)nNH2]2〜m、−NH2、−NHMeおよび−NMeからなる群から選択され;
nおよびmは、整数であり、ここで、nの各例は、独立して、2または3から選択され、かつmの各例は、独立して、0または1から選択され;
ただし、R2が−Hである場合、R1は、−Hまたは−C1〜3アルキルでないことを条件とする)
を有する、請求項1に記載の化合物またはその薬学的に許容される塩。 - R2は、−H、−CF3、−N(R5)2、−NHR5、−N(R5)C(O)R5および−N(R5)C(S)N(R5)2からなる群から選択され;
ただし、R2が−Hである場合、R1は、−Hまたは−C1〜3アルキルでなく、かつR8は、Hでないことを条件とする、請求項1または2に記載の化合物。 - R8は、Hではない、請求項1〜3のいずれか一項に記載の化合物。
- X1、X2、X3、X4およびX5は、Cである、請求項1〜4のいずれか一項に記載の化合物。
- R1は、Hである、請求項1〜5のいずれか一項に記載の化合物。
- R2は、−NH2および−NHR5からなる群から選択される、請求項1〜6のいずれか一項に記載の化合物。
- R2は、−NHC(O)R5である、請求項1〜6のいずれか一項に記載の化合物。
- R2は、Hである、請求項1〜5のいずれか一項に記載の化合物。
- R4は、Hである、請求項1〜9のいずれか一項に記載の化合物。
- Aは、Sである、請求項1〜10のいずれか一項に記載の化合物。
- R3は、−CF3および−インドリルからなる群から選択される、請求項1〜11のいずれか一項に記載の化合物。
- 療法によるヒトまたは動物の身体の治療方法に使用するための、請求項1〜12のいずれか一項に記載の化合物またはその薬学的に許容される塩。
- 前記療法は、感染症の治療または予防である、請求項11に記載の使用のための、請求項1〜12のいずれか一項に記載の化合物またはその薬学的に許容される塩。
- 前記感染症は、細菌、真菌または寄生虫感染症である、請求項12に記載の使用のための、請求項1〜12のいずれか一項に記載の化合物またはその薬学的に許容される塩。
- 前記感染症は、スタフィロコッカス(Staphylococcus)、エンテロコッカス(Enterococcus)、ストレプトコッカス(Streptococcus)、シュードモナス(Pseudomonas)、レジオネラ(Legionella)、クレブシエラ(Klebsiella)、ヘモフィルス(Haemophilus)、ナイセリア(Neisseria)、リステリア(Listeria)、エシェリキア(Escherichia)およびマイコバクテリウム(Mycobacterium)から選択される属の細菌によって引き起こされるかまたは併発される細菌感染症である、請求項11に記載の使用のための、請求項1〜12のいずれか一項に記載の化合物またはその薬学的に許容される塩。
- 前記細菌感染症は、S.アウレウス(S.aureus)、E.フェカーリス(E.faecalis)、E.フェシウム(E.faecium)、S.ニューモニエ(S.pneumoniae)、E.コリ(E.coli)、K.ニューモニエ(K.pneumoniae)、H.インフルエンザ(H.influenza)、A.バウマニ(A.baumannii)、P.エルギノーサ(P.aeruginosa)、P.エルギノーサ(P.aeruginosa)、N.ゴノレエ(N.gonorrhoeae)から選択される細菌種によって引き起こされるかまたは併発される、請求項14に記載の使用のための、請求項1〜12のいずれか一項に記載の化合物またはその薬学的に許容される塩。
- 感染症を治療する方法であって、それを必要とする患者に治療有効量の請求項1〜12のいずれか一項に記載の化合物を投与することを含む方法。
- 前記感染症は、細菌、真菌または寄生虫感染症である、請求項18に記載の方法。
- 前記感染症は、スタフィロコッカス(Staphylococcus)、エンテロコッカス(Enterococcus)、ストレプトコッカス(Streptococcus)、シュードモナス(Pseudomonas)、レジオネラ(Legionella)、クレブシエラ(Klebsiella)、ヘモフィルス(Haemophilus)、ナイセリア(Neisseria)、リステリア(Listeria)、エシェリキア(Escherichia)およびマイコバクテリウム(Mycobacterium)から選択される属の細菌によって引き起こされるかまたは併発される細菌感染症である、請求項19に記載の方法。
- 前記細菌感染症は、S.アウレウス(S.aureus)、E.フェカーリス(E.faecalis)、E.フェシウム(E.faecium)、S.ニューモニエ(S.pneumoniae)、E.コリ(E.coli)、K.ニューモニエ(K.pneumoniae)、H.インフルエンザ(H.influenza)、A.バウマニ(A.baumannii)、P.エルギノーサ(P.aeruginosa)、P.エルギノーサ(P.aeruginosa)、N.ゴノレエ(N.gonorrhoeae)から選択される細菌種によって引き起こされるかまたは併発される、請求項19に記載の方法。
- 細菌のリボヌクレアーゼP活性の阻害における、請求項1〜12のいずれか一項に記載の化合物またはその塩の使用。
- 殺菌薬としての、請求項1〜12のいずれか一項に記載の化合物またはその塩の使用。
- 薬学的に許容される賦形剤、アジュバント、希釈剤および/または担体と合わせて、請求項1〜12のいずれか一項に記載の化合物またはその薬学的に許容される塩を含む医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE1650906 | 2016-06-23 | ||
SE1650906-9 | 2016-06-23 | ||
PCT/SE2017/050697 WO2017222466A1 (en) | 2016-06-23 | 2017-06-22 | Anti-infective heterocyclic compounds and uses thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2019518771A true JP2019518771A (ja) | 2019-07-04 |
Family
ID=59285299
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018567199A Ceased JP2019518771A (ja) | 2016-06-23 | 2017-06-22 | 抗感染症複素環式化合物およびその使用 |
Country Status (13)
Country | Link |
---|---|
US (1) | US11130741B2 (ja) |
EP (1) | EP3475277B1 (ja) |
JP (1) | JP2019518771A (ja) |
KR (1) | KR20190025920A (ja) |
CN (1) | CN109641889A (ja) |
AU (1) | AU2017279905B2 (ja) |
BR (1) | BR112018076734A2 (ja) |
CA (1) | CA3028347A1 (ja) |
IL (1) | IL263651A (ja) |
MX (1) | MX2018016339A (ja) |
RU (1) | RU2019101646A (ja) |
SG (1) | SG11201811183WA (ja) |
WO (1) | WO2017222466A1 (ja) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020169682A1 (en) * | 2019-02-19 | 2020-08-27 | Yncrea Hauts De France | Hydrazide derivatives and their specific use as antibacterial agents by controlling acinetobacter baumannii bacterium |
WO2024062043A1 (en) * | 2022-09-21 | 2024-03-28 | Universiteit Antwerpen | Substituted phenothiazines as ferroptosis inhibitors |
CN115947671B (zh) * | 2022-11-21 | 2023-09-26 | 荣灿生物医药技术(上海)有限公司 | 一种含氨基甲酸酯键的脂质化合物及其应用 |
CN115806503A (zh) * | 2022-12-02 | 2023-03-17 | 中国海洋大学 | 一种选择性组蛋白去乙酰化酶抑制剂及其制备方法和应用 |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB812109A (en) * | 1956-08-23 | 1959-04-15 | Basf Ag | Improvements in the dyeing of structures of linear aromatic polyesters |
GB857546A (en) * | 1955-12-23 | 1960-12-29 | Olin Mathieson | Trifluoromethyl-phenothiazine derivatives |
US3040043A (en) * | 1959-03-18 | 1962-06-19 | Degussa | 3-trifluoromethyl-10-[3'-(4"-(2"'-hydroxy ethyl)-homopiperazino)-propyl]-phenothiazine and 3-trifluoromethyl-10-[3'-(4"-(2"'-acetoxyethyl)-homopiperazino)-propyl]-phenothiazine |
US3082210A (en) * | 1959-10-29 | 1963-03-19 | Rhone Poulenc Sa | New 10-(azetidinyl-alkyl)phenthiazines |
DE2214699A1 (de) * | 1972-03-25 | 1973-09-27 | Hoechst Ag | Wasserunloesliche farbstoffe, verfahren zu ihrer herstellung und deren verwendung zum faerben von halb- und vollsynthetischen fasermaterialien |
JP2013525437A (ja) * | 2010-04-30 | 2013-06-20 | プロステッタ アンチバイラル インコーポレイテッド | 抗ウイルス化合物 |
JP2014521678A (ja) * | 2011-08-02 | 2014-08-28 | ヘルムホルツ ツェントラム ミュンヘン ドイチェス フォーシュングスツェントラム フュール ゲズントハイト ウント ウンヴェルト ゲーエムベーハー | フェノチアジン誘導体によるmalt1プロテアーゼの選択的阻害 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2810318B1 (fr) * | 2000-06-15 | 2005-09-23 | Laurent Galey | Derives de diamano-phenothiazine |
WO2003062388A2 (en) | 2002-01-16 | 2003-07-31 | The Regents Of The University Of California | Inhibition of rna function |
AU2005237208B2 (en) | 2004-04-30 | 2009-12-03 | Bkg Pharma Aps | Treatment of infectious diseases |
WO2008080398A1 (en) * | 2007-01-05 | 2008-07-10 | Bkg Pharma Aps | Anti - infective agents such as phenothiazine and thioxanthene derivates to treat infectious diseases |
EP2246349A1 (en) * | 2009-04-20 | 2010-11-03 | BKG Pharma ApS | Treatment of infectious diseases |
US8809317B2 (en) * | 2011-03-29 | 2014-08-19 | Prosetta Antiviral Inc. | Antiviral compounds |
WO2012122716A1 (en) * | 2011-03-17 | 2012-09-20 | Merck Sharp & Dohme Corp. | Tetracyclic xanthene derivatives and methods of use thereof for treatment of viral diseases |
CN104812394B (zh) * | 2012-11-26 | 2018-10-19 | 开普敦大学 | 吩噻嗪衍生物及其治疗肺结核的用途 |
CN103709122B (zh) * | 2013-11-29 | 2016-05-25 | 四川大学 | 用于治疗的抗肿瘤和抗真菌化合物 |
-
2017
- 2017-06-22 MX MX2018016339A patent/MX2018016339A/es unknown
- 2017-06-22 JP JP2018567199A patent/JP2019518771A/ja not_active Ceased
- 2017-06-22 EP EP17735653.2A patent/EP3475277B1/en active Active
- 2017-06-22 AU AU2017279905A patent/AU2017279905B2/en not_active Expired - Fee Related
- 2017-06-22 RU RU2019101646A patent/RU2019101646A/ru not_active Application Discontinuation
- 2017-06-22 WO PCT/SE2017/050697 patent/WO2017222466A1/en unknown
- 2017-06-22 SG SG11201811183WA patent/SG11201811183WA/en unknown
- 2017-06-22 US US16/312,627 patent/US11130741B2/en active Active
- 2017-06-22 CA CA3028347A patent/CA3028347A1/en not_active Abandoned
- 2017-06-22 CN CN201780051840.2A patent/CN109641889A/zh active Pending
- 2017-06-22 BR BR112018076734-4A patent/BR112018076734A2/pt not_active IP Right Cessation
- 2017-06-22 KR KR1020197001706A patent/KR20190025920A/ko not_active Application Discontinuation
-
2018
- 2018-12-11 IL IL263651A patent/IL263651A/en unknown
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB857546A (en) * | 1955-12-23 | 1960-12-29 | Olin Mathieson | Trifluoromethyl-phenothiazine derivatives |
GB812109A (en) * | 1956-08-23 | 1959-04-15 | Basf Ag | Improvements in the dyeing of structures of linear aromatic polyesters |
US3040043A (en) * | 1959-03-18 | 1962-06-19 | Degussa | 3-trifluoromethyl-10-[3'-(4"-(2"'-hydroxy ethyl)-homopiperazino)-propyl]-phenothiazine and 3-trifluoromethyl-10-[3'-(4"-(2"'-acetoxyethyl)-homopiperazino)-propyl]-phenothiazine |
US3082210A (en) * | 1959-10-29 | 1963-03-19 | Rhone Poulenc Sa | New 10-(azetidinyl-alkyl)phenthiazines |
DE2214699A1 (de) * | 1972-03-25 | 1973-09-27 | Hoechst Ag | Wasserunloesliche farbstoffe, verfahren zu ihrer herstellung und deren verwendung zum faerben von halb- und vollsynthetischen fasermaterialien |
JP2013525437A (ja) * | 2010-04-30 | 2013-06-20 | プロステッタ アンチバイラル インコーポレイテッド | 抗ウイルス化合物 |
JP2014521678A (ja) * | 2011-08-02 | 2014-08-28 | ヘルムホルツ ツェントラム ミュンヘン ドイチェス フォーシュングスツェントラム フュール ゲズントハイト ウント ウンヴェルト ゲーエムベーハー | フェノチアジン誘導体によるmalt1プロテアーゼの選択的阻害 |
Non-Patent Citations (18)
Title |
---|
HETEROCYCLIC COMMUNICATIONS, vol. 6, no. 4, JPN5019005574, 2000, DE, pages 369 - 374, ISSN: 0004633666 * |
HETEROCYCLIC COMMUNICATIONS, vol. 8, no. 2, JPN5019005569, 2002, DE, pages 195 - 198, ISSN: 0004457833 * |
HETEROCYCLIC COMMUNICATIONS, vol. 8, no. 3, JPN5019005572, 2002, pages 293 - 298, ISSN: 0004633668 * |
HETEROCYCLIC COMMUNICATIONS, vol. 8, no. 3, JPN5019005573, 2002, DE, pages 265 - 270, ISSN: 0004457836 * |
HETEROCYCLIC COMMUNICATIONS, vol. 8, no. 5, JPN5019005571, 2002, DE, pages 447 - 450, ISSN: 0004457835 * |
HETEROCYCLIC COMMUNICATIONS, vol. 8, no. 6, JPN6021007199, 2002, pages 549 - 552, ISSN: 0004457837 * |
J.CHEM.SCI., vol. 126, no. 1, JPN6021007203, 2014, pages 197 - 204, ISSN: 0004633670 * |
JOURNAL OF CHEMICAL SCIENCES, vol. 126, no. 1, JPN5019005565, 2014, IN, pages 197 - 204, ISSN: 0004633667 * |
JOURNAL OF FLUORINE CHEMISTRY, vol. 132, no. 6, JPN5019005566, 2011, NL, pages 420 - 426, ISSN: 0004457830 * |
JOURNAL OF MEDICINAL AND PHARMACEUTICAL CHEMISTRY, vol. 6, JPN6021007202, 1960, pages 659 - 668, ISSN: 0004633669 * |
JOURNAL OF ORGANIC CHEMISTRY, vol. 80, no. 21, JPN5019005568, 2015, pages 11108 - 11114, ISSN: 0004457832 * |
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 79, no. 16, JPN5019005570, 1957, US, pages 4375 - 4379, ISSN: 0004457834 * |
NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, vol. 29, no. 3, JPN6021007206, 2010, pages 178 - 189, ISSN: 0004633673 * |
NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, vol. 31, no. 7, JPN6021007205, 2012, pages 680 - 691, ISSN: 0004633672 * |
ORIENTAL JOURNAL OF CHEMISTRY, vol. 28, no. 4, JPN6021007204, 2012, pages 1769 - 1775, ISSN: 0004633671 * |
PHOSPHORUS, SULFUR AND SILICON AND THE RELATED ELEMENTS, vol. 178, no. 12, JPN5019005567, 2003, US, pages 2671 - 2678, ISSN: 0004457831 * |
REGISTRY(STN)[ON LINE], JPN6021007200, 19 September 2008 (2008-09-19), ISSN: 0004457838 * |
REGISTRY(STN)[ON LINE], JPN6021007201, 29 August 2004 (2004-08-29), ISSN: 0004457839 * |
Also Published As
Publication number | Publication date |
---|---|
EP3475277A1 (en) | 2019-05-01 |
CN109641889A (zh) | 2019-04-16 |
KR20190025920A (ko) | 2019-03-12 |
CA3028347A1 (en) | 2017-12-28 |
MX2018016339A (es) | 2019-09-04 |
RU2019101646A3 (ja) | 2020-07-23 |
WO2017222466A1 (en) | 2017-12-28 |
US20190233384A1 (en) | 2019-08-01 |
IL263651A (en) | 2019-01-31 |
EP3475277B1 (en) | 2021-10-20 |
AU2017279905A1 (en) | 2019-01-31 |
BR112018076734A2 (pt) | 2019-03-26 |
AU2017279905B2 (en) | 2021-10-14 |
SG11201811183WA (en) | 2019-01-30 |
US11130741B2 (en) | 2021-09-28 |
RU2019101646A (ru) | 2020-07-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101346357B (zh) | 氨基二氢噻嗪衍生物 | |
AU688120B2 (en) | New piperidine compounds, process for their preparation and the pharmaceutical compositions which contain them | |
AU2004247559B2 (en) | Benzamide derivative or salt thereof | |
JP2019518771A (ja) | 抗感染症複素環式化合物およびその使用 | |
JP6117430B2 (ja) | 選択的ヒストン脱アセチル化酵素抑制剤としての新規化合物およびこれを含む薬剤学的組成物 | |
JP7175888B2 (ja) | 選択的hdac1、2阻害剤としてのピペラジン誘導体 | |
JP5927174B2 (ja) | 二環式部分を持つtrpv1バニロイド受容体拮抗薬 | |
TWI313266B (en) | Thiazoline derivatives and pharmaceutical composition containing the same | |
JP3638874B2 (ja) | 新規なピペラジンおよびピペリジン化合物 | |
BRPI0920966A2 (pt) | derivado de piridina-3-carboxiamida | |
AU2003212305A1 (en) | Cyclic amides | |
JP2009508929A (ja) | Ccr3受容体リガンドとしてのアミノ−アルキル−アミド誘導体 | |
AU2005313312A1 (en) | Phenylpiperazine derivatives with a combination of partial dopamine-D2 receptor agonism and serotonin reuptake inhibition | |
CA2612969A1 (en) | Oxazolidinone derivatives and use thereof as antibiotics | |
TR201809769T4 (tr) | İkameli̇ ti̇yazol veya oksazol p2x7 reseptör antagoni̇stleri̇. | |
CA3083061A1 (en) | 1,2,4-oxadiazole derivatives as histone deacetylase 6 inhibitors | |
CZ20023721A3 (cs) | Piperazinové a piperidinové sloučeniny, způsob jejich přípravy a farmaceutické prostředky, které je obsahují | |
CA2436699A1 (en) | Piperidine derivatives as subtype selective n-methyl-d-aspartate antagonists | |
BRPI0707802A2 (pt) | compostos de prolinamidas substituÍdas, sais fisiologicamente compatÍveis e uso dos mesmos, medicamento e processo de produÇço do mesmo | |
US20040067960A1 (en) | Heterocyclic substituted piperazines for the treatment of schizophrenia | |
KR20070091646A (ko) | 도파민-d2 수용체 및 세로토닌 재흡수 위치에 대한친화도를 함께 갖는 페닐피페라진 | |
KR20010042471A (ko) | Mrp1의 억제 방법 | |
AU7083098A (en) | Benzimidazole derivative | |
CA3199333A1 (en) | C-myc mrna translation modulators and uses thereof in the treatment of cancer | |
JP2017535562A (ja) | 抗がん剤としての新規な1,3,5−トリアジン系pi3k阻害剤及びその製造方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20200415 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20210304 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20210308 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20210527 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210906 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20211108 |
|
A045 | Written measure of dismissal of application [lapsed due to lack of payment] |
Free format text: JAPANESE INTERMEDIATE CODE: A045 Effective date: 20220328 |