CN104262433A - 噁二唑-腺苷型化合物作为TyrRS抑制剂及其制法和用途 - Google Patents
噁二唑-腺苷型化合物作为TyrRS抑制剂及其制法和用途 Download PDFInfo
- Publication number
- CN104262433A CN104262433A CN201410534494.1A CN201410534494A CN104262433A CN 104262433 A CN104262433 A CN 104262433A CN 201410534494 A CN201410534494 A CN 201410534494A CN 104262433 A CN104262433 A CN 104262433A
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- CN
- China
- Prior art keywords
- base
- oxadiazole
- purine
- methylamino
- amino
- 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.)
- Granted
Links
- DKWPRQOPQLKWHS-MCDZGGTQSA-N [C@@H]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C=NC=2C(N)=NC=NC12.O1N=NC=C1 Chemical class [C@@H]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C=NC=2C(N)=NC=NC12.O1N=NC=C1 DKWPRQOPQLKWHS-MCDZGGTQSA-N 0.000 title claims abstract description 15
- 101710146427 Probable tyrosine-tRNA ligase, cytoplasmic Proteins 0.000 title claims 3
- 102100025336 Tyrosine-tRNA ligase, mitochondrial Human genes 0.000 title claims 3
- 101710107268 Tyrosine-tRNA ligase, mitochondrial Proteins 0.000 title claims 3
- 238000002360 preparation method Methods 0.000 title abstract description 4
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- 150000001875 compounds Chemical class 0.000 claims abstract description 25
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- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 180
- -1 methylamino- Chemical class 0.000 claims description 110
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 46
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 20
- 230000000845 anti-microbial effect Effects 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 235000019441 ethanol Nutrition 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000003480 eluent Substances 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 10
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- 229940040526 anhydrous sodium acetate Drugs 0.000 claims description 10
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 claims description 8
- 238000010898 silica gel chromatography Methods 0.000 claims description 8
- ZXLNOQLIBVACTD-UHFFFAOYSA-N (methylideneamino)urea Chemical compound NC(=O)NN=C ZXLNOQLIBVACTD-UHFFFAOYSA-N 0.000 claims description 7
- UJTTUOLQLCQZEA-UHFFFAOYSA-N 9h-fluoren-9-ylmethyl n-(4-hydroxybutyl)carbamate Chemical compound C1=CC=C2C(COC(=O)NCCCCO)C3=CC=CC=C3C2=C1 UJTTUOLQLCQZEA-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
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- 238000000034 method Methods 0.000 claims description 7
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- 238000001035 drying Methods 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- WVKIFIROCHIWAY-UHFFFAOYSA-N hydron;2-(methylamino)acetic acid;chloride Chemical compound Cl.CNCC(O)=O WVKIFIROCHIWAY-UHFFFAOYSA-N 0.000 claims description 6
- 238000006386 neutralization reaction Methods 0.000 claims description 6
- 238000000967 suction filtration Methods 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 239000012317 TBTU Substances 0.000 claims description 5
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 claims description 5
- 229960000583 acetic acid Drugs 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 claims description 5
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
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- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 abstract description 10
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- 230000002223 anti-pathogen Effects 0.000 abstract 1
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- 229960004125 ketoconazole Drugs 0.000 abstract 1
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- 229960004756 ethanol Drugs 0.000 description 10
- VUUFPZIGOAEYHC-UHFFFAOYSA-N 2-bromo-7h-purine Chemical compound BrC1=NC=C2NC=NC2=N1 VUUFPZIGOAEYHC-UHFFFAOYSA-N 0.000 description 8
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- 241000894006 Bacteria Species 0.000 description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 8
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- 238000011160 research Methods 0.000 description 4
- MINDHVHHQZYEEK-UHFFFAOYSA-N (E)-(2S,3R,4R,5S)-5-[(2S,3S,4S,5S)-2,3-epoxy-5-hydroxy-4-methylhexyl]tetrahydro-3,4-dihydroxy-(beta)-methyl-2H-pyran-2-crotonic acid ester with 9-hydroxynonanoic acid Natural products CC(O)C(C)C1OC1CC1C(O)C(O)C(CC(C)=CC(=O)OCCCCCCCCC(O)=O)OC1 MINDHVHHQZYEEK-UHFFFAOYSA-N 0.000 description 3
- 101710176147 Isoleucine-tRNA ligase, cytoplasmic Proteins 0.000 description 3
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- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/167—Purine radicals with ribosyl as the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Citations (4)
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US20040266666A1 (en) * | 2003-05-23 | 2004-12-30 | Fatheree Paul R. | Cross-linked glycopeptide-cephalosporin antibiotics |
CN1777577A (zh) * | 2003-01-08 | 2006-05-24 | 希龙公司 | 抗菌剂 |
CN101765585A (zh) * | 2007-06-12 | 2010-06-30 | 尔察祯有限公司 | 抗菌剂 |
WO2014012014A1 (en) * | 2012-07-13 | 2014-01-16 | Massachusetts Institute Of Technology | Methods and products related to protozoan disease |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1777577A (zh) * | 2003-01-08 | 2006-05-24 | 希龙公司 | 抗菌剂 |
US20040266666A1 (en) * | 2003-05-23 | 2004-12-30 | Fatheree Paul R. | Cross-linked glycopeptide-cephalosporin antibiotics |
CN101765585A (zh) * | 2007-06-12 | 2010-06-30 | 尔察祯有限公司 | 抗菌剂 |
WO2014012014A1 (en) * | 2012-07-13 | 2014-01-16 | Massachusetts Institute Of Technology | Methods and products related to protozoan disease |
Non-Patent Citations (4)
Title |
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JEEWOO LEE,等: "Ester and Hydroxamate Analogues of Methionyl and Isoleucyl Adenylates as Inhibitors of Methionyl-tRNA and Isoleucyl-tRNA Synthetases", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
P.-C. LV,等: "Aminoacyl-tRNA Synthetase Inhibitors As Potent Antibacterials", 《CURRENT MEDICINAL CHEMISTRY》 * |
PAMELA BROWN,等: "Molecular Recognition of Tyrosinyl Adenylate Analogues by Prokaryotic Tyrosyl tRNA Synthetases", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
王庆,等: "氨酰tRNA合成酶抑制剂作为新型抗感染药物的研究进展", 《现代生物医学进展》 * |
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