CN101597283A - Triazolyl oxazolidinone compounds and antibacterial application thereof - Google Patents
Triazolyl oxazolidinone compounds and antibacterial application thereof Download PDFInfo
- Publication number
- CN101597283A CN101597283A CNA2009100410382A CN200910041038A CN101597283A CN 101597283 A CN101597283 A CN 101597283A CN A2009100410382 A CNA2009100410382 A CN A2009100410382A CN 200910041038 A CN200910041038 A CN 200910041038A CN 101597283 A CN101597283 A CN 101597283A
- Authority
- CN
- China
- Prior art keywords
- acid
- oxazolidine
- compound
- morpholinyl
- phenyl
- 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.)
- Pending
Links
- -1 Triazolyl oxazolidinone compounds Chemical class 0.000 title claims abstract description 101
- 230000000844 anti-bacterial effect Effects 0.000 title abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 241000894006 Bacteria Species 0.000 claims abstract description 13
- 125000003118 aryl group Chemical group 0.000 claims abstract description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 7
- 125000001924 fatty-acyl group Chemical group 0.000 claims abstract description 6
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims abstract description 5
- 125000003435 aroyl group Chemical group 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 56
- 150000001875 compounds Chemical class 0.000 claims description 31
- 229940125904 compound 1 Drugs 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- SYOANZBNGDEJFH-UHFFFAOYSA-N 2,5-dihydro-1h-triazole Chemical compound C1NNN=C1 SYOANZBNGDEJFH-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229940126142 compound 16 Drugs 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 125000002971 oxazolyl group Chemical group 0.000 claims description 4
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 125000001425 triazolyl group Chemical group 0.000 claims description 4
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 3
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- KVSASDOGYIBWTA-UHFFFAOYSA-N chloro benzoate Chemical compound ClOC(=O)C1=CC=CC=C1 KVSASDOGYIBWTA-UHFFFAOYSA-N 0.000 claims description 3
- 229940125773 compound 10 Drugs 0.000 claims description 3
- 229940125797 compound 12 Drugs 0.000 claims description 3
- 229940126543 compound 14 Drugs 0.000 claims description 3
- 229940125758 compound 15 Drugs 0.000 claims description 3
- 229940126214 compound 3 Drugs 0.000 claims description 3
- 229940125898 compound 5 Drugs 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 3
- 150000003053 piperidines Chemical group 0.000 claims description 3
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 claims description 2
- 235000003704 aspartic acid Nutrition 0.000 claims description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 2
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 229960002989 glutamic acid Drugs 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- JVJQPDTXIALXOG-UHFFFAOYSA-N nitryl fluoride Chemical compound [O-][N+](F)=O JVJQPDTXIALXOG-UHFFFAOYSA-N 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 125000005561 phenanthryl group Chemical group 0.000 claims description 2
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 5
- 230000036457 multidrug resistance Effects 0.000 abstract description 5
- 230000005764 inhibitory process Effects 0.000 abstract description 2
- 239000007787 solid Substances 0.000 description 21
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- 238000001819 mass spectrum Methods 0.000 description 16
- 238000010189 synthetic method Methods 0.000 description 15
- 239000011734 sodium Substances 0.000 description 14
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 241000191967 Staphylococcus aureus Species 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 5
- 229960003085 meticillin Drugs 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 208000035143 Bacterial infection Diseases 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 241000191963 Staphylococcus epidermidis Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000000845 anti-microbial effect Effects 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 208000022362 bacterial infectious disease Diseases 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 230000000452 restraining effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 241000194032 Enterococcus faecalis Species 0.000 description 2
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 229940032049 enterococcus faecalis Drugs 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229960003907 linezolid Drugs 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- RUBQQRMAWLSCCJ-UHFFFAOYSA-N 1,2-difluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C(F)=C1 RUBQQRMAWLSCCJ-UHFFFAOYSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241001360526 Escherichia coli ATCC 25922 Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 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 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000004500 asepsis Methods 0.000 description 1
- MYPYJXKWCTUITO-KIIOPKALSA-N chembl3301825 Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)C(O)[C@H](C)O1 MYPYJXKWCTUITO-KIIOPKALSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- VKFAUCPBMAGVRG-UHFFFAOYSA-N dipivefrin hydrochloride Chemical compound [Cl-].C[NH2+]CC(O)C1=CC=C(OC(=O)C(C)(C)C)C(OC(=O)C(C)(C)C)=C1 VKFAUCPBMAGVRG-UHFFFAOYSA-N 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- YLNSNVGRSIOCEU-UHFFFAOYSA-N oxiran-2-ylmethyl butanoate Chemical compound CCCC(=O)OCC1CO1 YLNSNVGRSIOCEU-UHFFFAOYSA-N 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229940037645 staphylococcus epidermidis Drugs 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses triazolyl oxazolidinone compounds and antibacterial application thereof.Triazolyl oxazolidinone compounds, its structural formula be suc as formula shown in (I), and R is aromatic base, replace aminomethyl, the methylol that replaces of heterocyclic substituted methyl, methylol, methylol that fatty acyl group replaces, methylol that aroyl replaces or 4-hetaroylpyrazol.Triazolyl oxazolidinone compounds provided by the invention and at pharmacy acceptable salt has good antibacterial activity, particularly the multidrug resistance bacterium is had good inhibition activity, has a extensive future.
Description
Technical field
The present invention relates to the pharmaceutical chemistry technical field, specifically, relate to the purposes of triazolyl oxazolidinone compounds and conduct treatment infectation of bacteria medicine thereof.
Background technology
Microbiotic and synthesising bacteria anti-reflecting medicine are the choice drugs of present human treatment's bacterial infection disease, but because life-time service and unreasonable abuse cause increasing bacterium that resistance is appearred in existing antibacterials, even multidrug resistance.More common have methicillin resistant staphylococcus aureus (MRSA) and staphylococcus epidermidis (MRSE), a drug-fast streptococcus pneumoniae etc., bring serious problems for the treatment of bacterial infection disease, cause the significant prolongation of patient time and the mortality ratio that increases.
Oxazolidine ketone antibacterials are bacterial-infection resisting medicines that a class is novel, complete synthesis, have unique effect mechanism, and the one oxazolidine ketone antibacterials-Linezolid successfully went on the market in 2000, had significant curative effect for multiple drug-fast bacteria infection disease.At present oxazolidine ketone antibacterials are being carried out deep structural modification and optimization, with the development novel drugs that anti-microbial activity is higher, antimicrobial spectrum is wider.
Summary of the invention
The purpose of this invention is to provide a class and have anti-microbial activity, particularly to the effective triazolyl oxazolidinone compounds of multidrug resistance bacterium.
1. the invention provides suc as formula shown in (I) and contain 1,2 of replacement, 3-triazole Jie Gou De oxazolidone compounds:
In the formula (I), R is aromatic base, replace aminomethyl, the methylol that replaces of heterocyclic substituted methyl, methylol, methylol that fatty acyl group replaces, methylol that aroyl replaces or 4-hetaroylpyrazol.
Aromatic base is phenyl, naphthyl, xenyl, anthryl or phenanthryl, is good with phenyl wherein.
" replacement aminomethyl " expression one replaced and dibasic aminomethyl etc. by alkyl and aryl replace, N wherein, and the N-dimethylaminomethyl is the best.
" heterocycle " expression contains 1-4 and is selected from N, O, S heteroatomic five yuan or hexa-member heterocycle aromatic base and non-aromatic base, comprising piperidines, Pyrrolidine, phthalimide-based, morpholinyl, oxazolidine ketone group, furyl, thienyl, pyridyl, imidazolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazyl, pyrimidyl, pyridazinyl etc., is good with piperidines, phthalimide-based, morpholinyl, oxazolidine ketone group wherein.
" alkyl " represents the saturated or undersaturated of 1-6 carbon, the alkane chain of straight or branched comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, allyl group, amyl group, isopentyl, neo-pentyl, tert-pentyl, hexyl, isohexyl etc.
" fatty acyl group " represents the saturated or undersaturated of 1-6 carbon; straight or branched; and contain the fatty acyl group of halogenic substituent; comprising ethanoyl, propionyl, different propionyl, butyryl radicals, isobutyryl, secondary butyryl radicals, uncle's butyryl radicals, allyl acyl group, pentanoyl, isovaleryl, valeryl, pivaloyl, caproyl, dissident's acyl group and contain corresponding acyl group that halogen (comprising fluorine, chlorine, bromine, iodine) replaces etc., is the best with ethanoyl and dichloro-acetyl wherein.
" aroyl " expression contains the aryl formyl radical of replacement, and substituting group comprises alkyl, aryl, hydroxyl, nitro, fluorine, chlorine, bromine, iodine, amino etc., is the best with methyl, fluorine, chlorine, nitro, the tertiary butyl wherein.
" 4-hetaroylpyrazol " expression contains the aromaticity heterocyclic radical formyl radical of replacement; comprising furyl, thienyl, pyridyl, imidazolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazyl, pyrimidyl, pyridazinyl etc., is the best with furyl, thienyl, pyridyl wherein.
" can be substituted " be meant above-mentioned " aryl ", " aromaticity heterocycle ", " alkyl ", can by optional halogen atom, alkyl, alkoxyl group ,-OH ,-NH
2,-NO
2Replace Deng group.
Above-mentioned formula (title of I) Suo Shi oxazolidone compounds 1-16 is as follows respectively:
Compound 1:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-phenyl-1-H-1,2, the 3-triazole)-1-base] Jia Ji oxazolidine-2-ketone;
Compound 2:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-methylol-1-H-1,2, the 3-triazole)-1-base] Jia Ji oxazolidine-2-ketone;
Compound 3:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-aminomethyl-1-H-1,2, the 3-triazole)-1-base] Jia Ji oxazolidine-2-ketone;
Compound 4:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-{[4-(N, N-dimethyl) aminomethyl-1-H-1,2, the 3-triazole]-1-base } Jia Ji oxazolidine-2-ketone;
Compound 5:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-morpholinyl methyl-1-H-1,2, the 3-triazole)-the 1-yl] first base oxazolidine-2-ketone;
Compound 6:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-{[4-(2-Yang Dai oxazolidine-3-yl) methyl isophthalic acid-H-1,2, the 3-triazole]-1-base } Jia Ji oxazolidine-2-ketone;
Compound 7:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-acetoxy-methyl-1-H-1,2, the 3-triazole)-1-base] Jia Ji oxazolidine-2-ketone;
Compound 8:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-dichloro-acetoxy methyl isophthalic acid-H-1,2, the 3-triazole)-1-base] Jia Ji oxazolidine-2-ketone;
Compound 9:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-furans-2-methanoyl methyl isophthalic acid-H-1,2, the 3-triazole)-1-base] Jia Ji oxazolidine-2-ketone;
Compound 10:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-thiophene-2-methanoyl methyl isophthalic acid-H-1,2, the 3-triazole)-1-base] Jia Ji oxazolidine-2-ketone;
Compound 11:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-pyridine-2-methanoyl methyl isophthalic acid-H-1,2, the 3-triazole)-1-base] Jia Ji oxazolidine-2-ketone;
Compound 12:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-is to toluyl oxygen ylmethyl-1-H-1,2,3-triazole)-1-base] Jia Ji oxazolidine-2-ketone;
Compound 13:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-is to fluorobenzoyl oxygen ylmethyl-1-H-1,2,3-triazole)-1-base] Jia Ji oxazolidine-2-ketone;
Compound 14:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-is to chlorobenzoyl oxygen ylmethyl-1-H-1,2,3-triazole)-1-base] Jia Ji oxazolidine-2-ketone;
Compound 15:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-p-nitrophenyl methanoyl methyl isophthalic acid-H-1,2, the 3-triazole)-1-base] Jia Ji oxazolidine-2-ketone;
Compound 16:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-is to tert.-butylbenzene methanoyl methyl isophthalic acid-H-1,2,3-triazole)-1-base] Jia Ji oxazolidine-2-ketone;
Formula (chemical structural formula of I) Suo Shi oxazolidone compounds 1-16 sees Table 1:
The structural formula of table 1. target compound
2. the present invention also provides the synthetic method of above-mentioned (I) formula Suo Shi oxazolidone compounds, and its synthesis flow is as follows:
With 3,4-difluoro nitrobenzene, morphine quinoline and (R)-the butanic acid glycidyl ester is a raw material, press literature method (Brickner, S.J.et al J.Med.Chem.1996,39,673-679) synthesized intermediate (R)-3-[(3-fluoro-4-morpholinyl) phenyl]-2-oxo-5-oxazolidine triazo-methane compound.Shown oxazolidone compounds 1-16 under-10-80 ℃ condition, replacing synthetic (I) formula of propine generation ring-closure reaction by solvent with organic solvent and water mixed liquid in the presence of the catalyzer again with 3-.The catalyzer here is Cu
+Salt is such as CuI and pass through CuSO
4Cu with ascorbic sodium salt reaction generation
+Salt; The organic solvent here comprises tetrahydrofuran (THF), dimethyl formamide, dimethyl sulfoxide (DMSO), acetone, methyl alcohol, ethanol equal solvent.The volume ratio of organic solvent and water is 1: 1-5.
3. the present invention also provides the above-mentioned formula (pharmacy acceptable salt of I) Suo Shi oxazolidone compounds." pharmacy acceptable salt " is meant the salt that forms with mineral acids such as hydrochloric acid, sulfuric acid, hydrofluoric acid, Hydrogen bromide, phosphoric acid, nitric acid, with the salt of organic acids formation such as formic acid, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, with the salt of acidic amino acids formation such as aspartic acid, L-glutamic acid.De oxazolidone compounds of the present invention and salt thereof can be made into various pharmaceutically acceptable various carrier formulations or are used for the preparation of different dosing form, and its effective weight content is 0.1%-99.9%.
4. the present invention also provides above-mentioned formula (I) Suo Shi oxazolidone compounds and in the purposes of pharmacy acceptable salt as the medicine of the infectious diseases that causes of treatment infectious diseases, particularly multidrug resistance bacterium.
Compared with prior art, the present invention has following advantage:
Triazol radical De oxazolidone compounds provided by the invention and at pharmacy acceptable salt has good antibacterial activity, and the multidrug resistance bacterium is also had good inhibition activity, has a extensive future.
Embodiment
Embodiment 1:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-phenyl-1-H-1,2,3-triazole)-1-base] Jia Ji oxazolidine-2-ketone (compound 1) synthetic
(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-2-oxo-5-oxazolidine triazo-methane compound 321mg (1mmol) is dissolved in the mixed solvent of 5ml tetrahydrofuran (THF) and 4ml water, the cupric sulfate pentahydrate that adds ascorbic sodium salt 0.5mmol and 0.01mmol, stirring is cooled to about 0 ℃, drip phenylacetylene 127.5mg (1.25mmol), finish, continuation is stirred about 0 ℃, adopts thin layer to follow the tracks of, and treats till the whole disappearances of raw material.Reaction finishes, and adds 20ml water and stirs, and has light yellow solid to produce, and filters, collect solid, wash filter cake with water, vacuum-drying gets the yellow solid crude product, with purification by silica gel column chromatography (methylene dichloride and ethyl acetate gradient elution), get light yellow solid 360mg, yield 85.1%.Fusing point: 195.8-197.0 ℃.
1HNMR (400MHz, DMSO-d
6) δ: 8.63 (s, 1H), 7.86 (d, J=7.2Hz, 1H), 7.46 (d, J=7.2Hz, 2H), 7.33-7.40 (m, 3H), 7.16 (d, J=8.8Hz, 1H), 7.04 (t, J=8.8Hz, 1H), 5.18-5.19 (m, 1H), 4.87 (d, J=4.4Hz, 2H), 4.25 (t, J=8.8Hz, 1H), 3.93 (t, J=8.8Hz, 1H), 3.73 (s, 4H), 2.95 (s, 4H);
13CNMR (100MHz, DMSO-d
6) δ: 47.68,51.12,52.61,66.60,71.24,107.20 (d, J=25.9Hz), 114.82,119.63 (d, J=3.6Hz), 122.84,125.68,128.43,129.39,130.98,133.41 (d, J=10.3Hz), 136.16 (d, J=8.9Hz), 146.89,153.76 (d, J=23.7Hz), 156.18; High resolution mass spectrum (C
22H
22FN
5O
3+ Na
+): theoretical value 446.1604, measured value 446.1619.
Embodiment 2:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-methylol-1-H-1,2,3-triazole)-1-base] Jia Ji oxazolidine-2-ketone (compound 2) synthetic
Synthetic method and compound 1 synthetic similar, light yellow solid 354mg, yield 93.9%.Fusing point: 218.6-219.8 ℃.
1HNMR (400MHz, DMSO-d
6) δ: 8.03 (s, 1H), 7.47 (dd, J=2.4Hz, J '=15.2Hz, 1H), 7.17 (dd, J=1.6Hz, J '=8.8Hz, 1H), 7.06 (t, J=9.6Hz, 1H), 5.08-5.15 (m, 1H), 4.80 (d, J=5.2Hz, 2H), 4.51 (s, 2H), 4.21 (t, J=9.2Hz, 1H), 3.88 (dd, J=6.0Hz, J '=9.2Hz, 1H), 3.73 (t, J=4.4Hz, 4H), 2.96 (t, J=4.4Hz, 4H);
13CNMR (100MHz, DMSO-d
6) δ: 47.64,51.12,52.24,55.40,66.60,71.39,107.18 (d, J=25.9Hz), 114.83,119.71 (d, J=3.7Hz), 124.12,133.46 (d, J=10.5Hz), 136.13 (d, J=9.7Hz), 148.64,153.76 (d, J=23.8Hz), 156.18; High resolution mass spectrum (C
17H
20FN
5O
4+ Na
+): theoretical value 400.1397, measured value 400.1398.
Embodiment 3:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-aminomethyl-1-H-1,2,3-triazole)-1-base] Jia Ji oxazolidine-2-ketone (compound 3) synthetic
Synthetic method and compound 1 synthetic similar, light yellow solid 321mg, yield 85.3%.Fusing point: 177.9-180.0 ℃.
1HNMR (400MHz, CDCl
3+ Methanol-d
4) δ: 7.99 (s, 1H), 7.38 (dd, J=2.4Hz, J '=14.0Hz, 1H), 7.07 (dd, J=1.6Hz, J '=8.4Hz, 1H), 6.95 (t, J=8.8Hz, 1H), and 5.11-5.14 (m, 1H), 4.75-4.90 (m, 2H), 4.38 (s, 2H), 4.21 (t, J=8.8Hz, 1H), 3.97 (dd, J=6.0Hz, J '=9.6Hz, 1H), 3.88 (t, J=4.4Hz, 4H), 3.06 (t, J=4.4Hz, 4H);
13CNMR (100MHz, CDCl
3+ Methanol-d
4) δ: 30.94,47.92,51.19,52.59,67.16,71.14,107.95 (d, J=26.0Hz), 114.79 (d.J=2.8Hz), 119.23 (d, J=3.7Hz), 124.47,132.78 (d, J=10.5Hz), 136.94 (d, J=8.7Hz), 145.94,154.46,156.90; High resolution mass spectrum (C
17H
21FN
6O
3+ Na
+): theoretical value 399.1557, measured value 399.1561.
Embodiment 4:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-{[4-(N, N-dimethyl) aminomethyl-1-H-1,2,3-triazole]-1-base } Jia Ji oxazolidine-2-ketone (compound 4) synthetic
Synthetic method and compound 1 synthetic similar, light yellow solid 312mg, yield 77.2%.Fusing point: 166.8-168.3 ℃.
1HNMR (400MHz, DMSO-d
6) δ: 8.00 (s, 1H), 7.42 (d, J=14.8Hz, 1H), 7.12 (d, J=8.0Hz, 1H), 7.04 (t, J=8.8Hz, 1H), 5.12 (s, 1H), 4.78 (s, 2H), 4.20 (t, J=8.8Hz, 1H), 3.85 (s, 1H), 3.73 (s, 4H), 3.47 (s, 2H), 2.95 (s, 4H), 2.09 (s, 6H);
13CNMR (100MHz, DMSO-d
6) δ: 44.92,47.48,51.12,52.31,53.93,66.60,71.16,107.07 (d, J=26.0Hz), 114.68,119.66 (d, J=3.5Hz), 125.08,133.39 (d, J=10.5Hz), 136.10 (d, J=8.6Hz), 144.35,153.75 (d, J=18.2Hz), 156.18; High resolution mass spectrum (C
19H
25FN
6O
3+ H
+): theoretical value 405.2050, measured value 405.2055.
Embodiment 5:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-morpholinyl methyl-1-H-1,2,3-triazole)-the 1-yl] first base oxazolidine-2-ketone (compound 5) synthetic
Synthetic method and compound 1 synthetic similar, light yellow solid 332mg, yield 77.4%.Fusing point: 169.5-171.3 ℃.
1HNMR (400MHz, DMSO-d
6) δ: 8.05 (s, 1H), 7.41 (d, J=14.8Hz, 1H), 7.11 (d, J=8.8Hz, 1H), 7.03 (t, J=9.6Hz, 1H), 5.13 (d, J=4.0Hz, 1H), 4.79 (s, 2H), 4.20 (t, J=9.2Hz, 1H), 3.87 (dd, J=5.2Hz, J '=8.8Hz, 1H), 3.73 (s, 4H), 3.58 (s, 2H), 3.52 (s, 4H), 2.95 (s, 4H), 2.37 (s, 4H);
13CNMR (100MHz, DMSO-d
6) δ: 47.42,51.13,52.39,52.98,66.35,66.60,71.08,107.00 (d, J=26.1Hz), 114.63,119.63 (d, J=3.7Hz), 125.58,133.34 (d, J=10.5Hz), 136.09 (d, J=8.7Hz), 143.38,153.74 (d, J=17.8Hz), 156.17; High resolution mass spectrum (C
21H
27FN
6O
4+ Na
+): theoretical value 469.1976, measured value 469.1980.
Embodiment 6:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-{[4-(2-Yang Dai oxazolidine-3-yl) methyl isophthalic acid-H-1,2,3-triazole]-1-base } Jia Ji oxazolidine-2-ketone (compound 6) synthetic
Synthetic method and compound 1 synthetic similar, light yellow solid 340mg, yield 76.2%.Fusing point: 170.4-173.0 ℃.
1HNMR (400MHz, DMSO-d
6) δ: 8.01 (s, 1H), 7.43 (dd, J=2.4Hz, J '=15.2Hz, 1H), 7.14 (dd, J=2.0Hz, J '=8.8Hz, 1H), 7.04 (t, J=8.8Hz, 1H), 5.10-5.16 (m, 1H), 4.81 (d, J=4.8Hz, 2H), 4.41 (s, 2H), 4.18-4.23 (m, 3H), 3.88 (dd, J=5.6Hz, J '=9.6Hz, 1H), 3.73 (t, J=4.4Hz, 4H), 3.39-3.44 (m, 2H), 2.96 (t, J=4.4Hz, 4H);
13CNMR (100MHz, DMSO-d
6) δ: 44.24,47.54,51.13,52.49,62.15,66.60,71.17,75.88,78.55,107.06 (d, J=26.1Hz), 114.72,119.64 (d, J=3.9Hz), 124.92,133.37 (d, J=10.5Hz), 136.13 (d, J=8.6Hz), 142.69,153.75 (d, J=18.5Hz), 156.18,158.15; High resolution mass spectrum (C
20H
23FN
6O
5+ H
+): theoretical value 447.1792, measured value 447.1790.
Embodiment 7:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-acetoxy-methyl-1-H-1,2,3-triazole)-1-base] Jia Ji oxazolidine-2-ketone (compound 7) synthetic
(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-methylol-1-H-1,2, the 3-triazole)-1-base] Jia Ji oxazolidine-2-ketone (compound 2) 188.5mg (0.5mmol) is dissolved in the 5ml methylene dichloride, add 75.75mg (0.75mmol) triethylamine, stir and be cooled to about 0 ℃ dripping acetyl chloride 43.2mg (0.55mmol), finish, continue under 0 ℃ of left and right sides condition to stir 2 hours, slowly rise to room temperature, continue to stir 3 hours, in reaction solution, add 20ml water, stir, separatory is used dichloromethane extraction water layer three times, each 10ml methylene dichloride of using, merge organic layer, behind anhydrous sodium sulfate drying, filter, get the thick product of yellow solid after removing solvent, with purification by silica gel column chromatography (methylene dichloride and ethyl acetate gradient elution), get light yellow solid 174mg, yield 83.0%.Fusing point: 108.5-110.2 ℃.
1HNMR (400MHz, CDCl
3) δ: 7.83 (s, 1H), 7.34 (dd, J=2.4Hz, J '=14.4Hz, 1H), 7.00 (dd, J=2.8Hz, J '=8.8Hz, 1H), 6.90 (t, J=8.8Hz, 1H), 5.20 (s, 2H), 5.08-5.02 (m, 1H), and 4.77-4.73 (m, 2H), 4.18-4.13 (m, 1H), 3.92-3.89 (m, 1H), 3.86 (t, J=4.8Hz, 4H), 3.04 (t, J=4.8Hz, 4H), 2.07 (s, 3H);
13CNMR (100MHz, CDCl
3) δ: 35.77,47.42,50.89 (d, J=2.7Hz), 52.23 (d, J=9.1), 57.36,66.91,70.30,107.69 (d, J=26.1Hz), 114.28 (d, J=3.5Hz), 118.80 (d, J=3.9Hz), 124.28,132.10 (d, J=10.2Hz), 136.91 (d, J=8.8Hz), 145.43,153.33,154.15 (d, J=245.5Hz), 170.77; High resolution mass spectrum (C
19H
22FN
5O
5+ Na
+): theoretical value 442.1503, measured value 442.1498.
Embodiment 8:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-dichloro-acetoxy methyl isophthalic acid-H-1,2,3-triazole)-1-base] Jia Ji oxazolidine-2-ketone (compound 8) synthetic
Synthetic method and compound 7 synthetic similar, light yellow solid 203mg, yield 83.2%.Fusing point: 80.4-82.5 ℃.
1HNMR (400MHz, CDCl
3) δ: 7.93 (s, 1H), 7.33 (dd, J=2.4Hz, J '=14.4Hz, 1H), 7.00 (dd, J=1.6Hz, J '=8.8Hz, 1H), 6.91 (t, J=8.8Hz, 1H), 5.95 (s, 1H), 5.39 (s, 2H), and 5.05-5.08 (m, 1H), 4.72-4.83 (m, 2H), 4.11-4.18 (m, 1H), 3.90-3.92 (m, 1H), 3.86 (t, J=4.4Hz, 4H), 3.04 (t, J=4.4Hz, 4H);
13CNMR (100MHz, CDCl
3) δ: 47.41,50.90 (d, J=2.7Hz), 52.34,60.00,63.96,66.89,70.26,107.64 (d, J=26.0Hz), 114.25 (d, J=3.0Hz), 118.86 (d, J=3.8Hz), 125.79,132.16 (d, J=10.3Hz), 136.81 (d, J=8.8Hz), 141.90,153.31 (d, J=245.4Hz), 164.37; High resolution mass spectrum (C
19H
20Cl
2FN
5O
5+ Na
+): theoretical value 510.0723, measured value 510.0734.
Embodiment 9:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-furans-2-methanoyl methyl isophthalic acid-H-1,2,3-triazole)-1-base] Jia Ji oxazolidine-2-ketone (compound 9) synthetic
Synthetic method and compound 7 synthetic similar, light yellow solid 196mg, yield 83.2%.Fusing point: 153.6-154.4 ℃.
1HNMR (400MHz, CDCl
3) δ: 7.99 (s, 1H), 7.58 (s, 1H), 7.34 (dd, J=1.6Hz, J '=14.4Hz, 1H), 7.19 (d, 3.2Hz, 1H), 6.99 (d, J=7.6Hz, 1H), 6.92 (t, J=8.8Hz, 1H), 6.50 (dd, J=1.6Hz, J '=3.2Hz, 1H), 5.43 (s, 2H), 5.07 (s, 1H), 4.77 (t, J=16.0Hz, 2H), 4.16 (t, J=8.8Hz, 1H), 3.92 (t, J=8.8Hz, 1H), 3.86 (t, J=4.4Hz, 4H), 3.04 (t, J=4.4Hz, 4H);
13CNMR (100MHz, CDCl
3) δ: 47.56,50.94 (d, J=2.7Hz), 52.38,57.67,66.88,70.35,107.63 (d, J=26.0Hz), 111.99,112.70,114.23 (d, J=3.0Hz), 118.72,118.90 (d, J=3.7Hz), 121.79,132.36 (d, J=10.3Hz), 136.62 (d, J=8.5Hz), 144.04,146.72,148.61,153.38 (d, J=177.5Hz), 158.36; High resolution mass spectrum (C
22H
22FN
5O
6+ Na
+): theoretical value 494.1452, measured value 494.1455.
Embodiment 10:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-thiophene-2-methanoyl methyl isophthalic acid-H-1,2,3-triazole)-1-base] Jia Ji oxazolidine-2-ketone (compound 10) synthetic
Synthetic method and compound 7 synthetic similar, light yellow solid 186mg, yield 76.4%.Fusing point: 83.4-83.5 ℃.
1HNMR (400MHz, CDCl
3) δ: 7.93 (s, 1H), 7.80 (d, J=3.2Hz, 1H), 7.57 (d, J=4.8Hz 1H), 7.33 (dd, J=2.4Hz, J '=14.4Hz, 1H), 7.09 (t, J=4.8Hz, 1H), 6.99 (dd, J=1.6Hz, J '=8.8Hz, 1H), 6.87 (t, J=8.8Hz, 1H), 5.43 (s, 2H), 5.06 (d, J=3.2Hz, 1H), 4.70-4.80 (m, 2H), 4.15 (t, J=8.8Hz, 1H), 3.92 (t, J=8.8Hz, 1H), 3.86 (t, J=4.4Hz, 4H), 3.03 (t, J=4.4Hz, 4H);
13CNMR (100MHz, CDCl
3) δ: 47.51,50.93,52.31,57.93,66.93,70.26,107.63 (d, J=26.1Hz), 114.26,118.80,127.85,128.48,132.20 (d, J=10.3Hz), 132.93 (d, J=7.5Hz), 134.01,135.35,136.06,136.84 (d, J=9.1Hz), 153.31,154.17 (d, J=245.4Hz), 161.95; High resolution mass spectrum (C
22H
22FN
5O
5S+Na
+): theoretical value 510.1223, measured value 510.1223.
Embodiment 11:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-pyridine-2-methanoyl methyl isophthalic acid-H-1,2,3-triazole)-1-base] Jia Ji oxazolidine-2-ketone (compound 11) synthetic
Synthetic method and compound 7 synthetic similar, light yellow solid 187mg, yield 77.6%.Fusing point: 78.2-80.5 ℃.
1HNMR (400MHz, CDCl
3) δ: 8.75 (d, J=3.6Hz, 1H), 8.13 (d, J=7.6Hz, 1H), 7.98 (s, 1H), 7.84 (d, J=7.6Hz, 1H), 7.49 (d, J=4.8Hz 1H), 7.33 (dd, J=2.0Hz, J '=14.0Hz, 1H), 6.98 (d, J=7.2Hz, 1H), 6.87 (t, J=8.8Hz, 1H), 5.55 (s, 2H), and 5.04-5.06 (m, 1H), 4.69-4.79 (m, 2H), and 4.12-4.16 (m, 1H), 3.90-3.94 (m, 1H), 3.86 (t, J=4.4Hz, 4H), 3.03 (t, J=4.4Hz, 4H);
13CNMR (100MHz, CDCl
3) δ: 47.57,50.93,52.26,58.65,66.97,70.29,107.62 (d, J=26.1Hz), 114.24,118.80 (d, J=3.8Hz), 125.46,125.84,127.18,132.22 (d, J=10.4Hz), 136.81 (d, J=8.7Hz), 137.10,143.20,147.49,149.99,153.33,154.16 (d, J=245.2Hz), 164.93; High resolution mass spectrum (C
23H
23FN
6O
5+ Na
+): theoretical value 505.1612, measured value 505.1610.
Embodiment 12:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-is to toluyl oxygen ylmethyl-1-H-1,2,3-triazole)-1-base] Jia Ji oxazolidine-2-ketone (compound 12) synthetic
Synthetic method and compound 7 synthetic similar, light yellow solid 175mg, yield 70.7%.Fusing point: 167.5-169.3 ℃.
1HNMR (400MHz, CDCl
3) δ: 7.92 (s, 1H), 7.91 (d, J=8.0Hz, 2H), 7.32 (d, J=2.4Hz, 1H), 7.22 (d, J=8.0Hz, 2H), 6.98 (dd, J=2.0Hz, J '=8.8Hz, 1H), 6.84 (t, J=8.8Hz, 1H), 5.43 (s, 2H), 5.02-5.08 (m, 1H), 4.69-4.79 (m, 2H), 4.13 (t, J=8.8Hz, 1H), 3.90 (t, J=8.8Hz, 1H), 3.85 (t, J=4.4Hz, 4H), 3.01 (t, J=4.4Hz, 4H), 2.93 (s, 3H);
13CNMR (100MHz, CDCl
3) δ: 21.69,47.51,50.89,52.26,58.68,66.92,70.33,107.59 (d, J=26.0Hz), 114.24,118.78 (d, J=3.8Hz), 125.43,126.84,129.13,129.78,132.22 (d, J=10.3Hz), 136.79 (d, J=8.7Hz), 143.80,143.99,153.37,154.13 (d, J=245.6Hz), 166.38; High resolution mass spectrum (C
25H
26FN
5O
5+ Na
+): theoretical value 518.1816, measured value 518.1817.
Embodiment 13:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-is to fluorobenzoyl oxygen ylmethyl-1-H-1,2,3-triazole)-1-base] Jia Ji oxazolidine-2-ketone (compound 13) synthetic
Synthetic method and compound 7 synthetic similar, light yellow solid 165mg, yield 66.1%.Fusing point: 117.8-118.4 ℃.
1HNMR (400MHz, CDCl
3) δ: 8.05 (dd, J=5.6Hz, J '=8.8Hz, 2H), 7.93 (s, 1H), 7.31 (d, J=2.4Hz, 1H), 7.09 (t, J=8.8Hz, 2H), 6.97 (dd, J=2.0Hz, J '=8.8Hz, 1H), 6.86 (t, J=8.8Hz, 1H), 5.44 (s, 2H), and 5.03-5.08 (m, 1H), 4.71-4.81 (m, 2H), 4.14 (t, J=8.8Hz, 1H), 3.93 (dd, J=6.0Hz, J '=9.2Hz, 1H), 3.86 (t, J=4.8Hz, 4H), 3.03 (t, J=4.8Hz, 4H);
13CNMR (100MHz, CDCl
3) δ: 47.44,50.89 (d, J=2.8Hz), 52.31,57.88,66.90,70.24,107.68 (d, J=26.0Hz), 114.27 (d, J=3.1Hz), 115.47 (d, J=21.9Hz), 118.81 (d, J=3.9Hz), 125.50,125.83 (d, J=2.9Hz), 132.32 (d, J=9.4Hz), 136.82 (d, J=8.4Hz), 143.60,153.29,154.15 (d, J=245.2Hz), 164.65,165.34,167.17; High resolution mass spectrum (C
24H
23F
2N
5O
5+ Na
+): theoretical value 522.1565, measured value 522.1562.
Embodiment 14:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-is to chlorobenzoyl oxygen ylmethyl-1-H-1,2,3-triazole)-1-base] Jia Ji oxazolidine-2-ketone (compound 14) synthetic
Synthetic method and compound 7 synthetic similar, light yellow solid 162mg, yield 62.8%.Fusing point: 163.5-164.0 ℃.
1HNMR (400MHz, CDCl
3) δ: 7.96 (s, 1H), 7.93 (d, J=2.8Hz, 2H), 7.40 (d, J=8.4Hz, 2H), 7.30 (dd, J=2.4Hz, J '=14.0Hz, 1H), 6.96 (dd, J=2.0Hz, J '=8.8Hz, 1H), 6.84 (t, J=8.8Hz, 1H), 5.44 (s, 2H), and 5.03-5.09 (m, 1H), 4.71-4.80 (m, 2H), 4.14 (t, J=8.8Hz, 1H), 3.92 (dd, J=6.0Hz, J '=9.2Hz, 1H), 3.86 (t, J=4.4Hz, 4H), 3.02 (t, J=4.4Hz, 4H);
13CNMR (100MHz, CDCl
3) δ: 47.41,50.88 (d, J=2.8Hz), 52.31,57.96,66.92,70.21,107.68 (d, J=26.0Hz), 114.29 (d, J=3.0Hz), 118.76 (d, J=4.0Hz), 125.51,128.05,128.76,131.16,132.08 (d, J=10.2Hz), 136.88 (d, J=8.8Hz), 139.70,143.49,153.27,154.13 (d, J=245.5Hz), 165.44; High resolution mass spectrum (C
24H
23ClFN
5O
5+ Na
+): theoretical value 538.1269, measured value 538.1278.
Embodiment 15:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-p-nitrophenyl methanoyl methyl isophthalic acid-H-1,2,3-triazole)-1-base] Jia Ji oxazolidine-2-ketone (compound 15) synthetic
Synthetic method and compound 7 synthetic similar, light yellow solid 157mg, yield 59.7%.Fusing point: 64.0-65.1 ℃.
1HNMR (400MHz, CDCl
3) δ: 8.23-8.25 (m, 2H), 8.15-8.17 (m, 2H), 8.0 (s, 1H), 7.27 (d, J=14.0Hz, 1H), 6.94 (d, J=8.4Hz, 1H), 6.84 (t, J=8.8Hz, 1H), 5.49 (s, 2H), and 5.06-5.12 (m, 1H), 4.75-4.85 (m, 2H), 4.16 (t, J=9.2Hz, 1H), 3.92 (t, J=8.0Hz, 1H), 3.84 (s, 4H), 3.01 (s, 4H);
13CNMR (100MHz, CDCl
3) δ: 47.37,50.84 (d, J=2.6Hz), 52.40,58.49,66.87,70.32,107.66 (d, J=25.9Hz), 114.33,118.70 (d, J=4.1Hz), 123.52,125.80,130.89,132.04 (d, J=10.1Hz), 134.98,136.84 (d, J=8.7Hz), 142.89,150.59,153.37,154.02 (d, J=245.4Hz), 164.41; High resolution mass spectrum (C
24H
23FN
6O
7+ Na
+): theoretical value 549.1510, measured value 549.1514.
Embodiment 16:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-is to tert.-butylbenzene methanoyl methyl isophthalic acid-H-1,2,3-triazole)-1-base] Jia Ji oxazolidine-2-ketone (compound 16) synthetic
Synthetic method and compound 7 synthetic similar, light yellow solid 162mg, yield 60.3%.Fusing point: 147.5-148.5 ℃.
1HNMR (400MHz, CDCl
3) δ: 7.96 (d, J=8.4Hz, 2H), 7.92 (s, 1H), 7.44 (d, J=8.4Hz, 2H), 7.33 (dd, J=2.4Hz, J '=14.4Hz, 1H), 6.99 (dd, J=2.0Hz, J '=8.8Hz, 1H), 6.88 (t, J=8.8Hz, 1H), 5.44 (s, 2H), and 5.02-5.08 (m, 1H), 4.69-4.79 (m, 2H), 4.16 (t, J=8.8Hz, 1H), 3.93 (dd, J=6.0Hz, J '=9.2Hz, 1H), 3.85 (t, J=4.8Hz, 4H), 3.02 (t, J=4.8Hz, 4H), 1.32 (s, 9H);
13CNMR (100MHz, CDCl
3) δ: 31.09,35.11,47.53,50.90 (d, J=2.7Hz), 52.24,57.69,66.91,70.30,107.62 (d, J=26.0Hz), 114.24 (d, J=3.0Hz), 118.80 (d, J=4.1Hz), 125.40,126.79,129.64,132.23 (d, J=10.2Hz), 136.81 (d, J=8.8Hz), 143.88,153.34,154.16 (d, J=245.3Hz), 156.97,166.34; High resolution mass spectrum (C
28H
32FN
5O
5+ Na
+): theoretical value 560.2285, measured value 560.2286.
Embodiment 17:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-methylol-1-H-1,2,3-triazole)-hydrochloride of 1-base] Jia Ji oxazolidine-2-ketone is synthetic
With (R)-3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-methylol-1-H-1,2,3-triazole)-1-base] Jia Ji oxazolidine-2-ketone (compound 2) 500mg is dissolved in the 10ml methyl alcohol, stirring cools to 0-5 ℃, drips 23.3% hydrogen chloride methanol solution, regulates pH=2-3, continue to stir 60 minutes, filter, get light yellow solid, vacuum-drying, get its hydrochloride 523mg, yield 95.4%, m.p.＞230 ℃, and decompose gradually.
Dui Shang Shu oxazolidone compounds and carry out antibacterial activity in vitro at pharmacy acceptable salt and measure, measuring method is as follows:
1) after test-compound dissolved with DMSO, it was standby to be configured to 800 μ g/ml mother liquors.
2) test method: adopt MB to cultivate and measure the minimum inhibitory concentration (MIC) of compound to strain subject with doubling dilution based on 96 orifice plates.Gradient dilution makes parallel each hole concentration be: 128,64,32,16,8,4,2,1,0.5,0.25,0.125,0.0625 (μ g/ml); Place 37 ℃ of incubators to cultivate 24 hours, with 96 orifice plates after (MULTISKAN EX) microplate reader scan test, in uv-absorbing showed the hole of asepsis growth, getting wherein, the drug level the lowest was to be subjected to the minimum inhibitory concentration (MIC) of reagent product to being tried bacterium.
3) positive controls is Linezolid, Ciprofloxacin, penicillin and vancomycin.
4) experimental strain: E.coli is escherichia coli ATCC25922; SA is streptococcus aureus (staphylococcusaureus) ATCC25923; MRSA
1Be the clinical separation subspecies of methicillin-resistant Staphylococcus aureus (methicillin-resistantstaphylococcus aureus); MRSA
2Be the clinical separation subspecies of methicillin-resistant Staphylococcus aureus (methicillin-resistant staphylococcus aureus); SE is staphylococcus epidermidis (staphylococcusepidermidis) ATCC12228; EF is enterococcus faecalis (enterococcus faecalis) ATCC29212
Above-mentioned formula (I) Suo Shi oxazolidone compounds and see Table 2 in minimum inhibitory concentration (MIC) value of pharmacy acceptable salt.
The minimum inhibitory concentration of table 2. target compound (MIC) (unit is μ g/ml)
Can draw all compounds by table 2 data intestinal bacteria are not suppressed effect, compounds all except compound 16 are all to there being restraining effect in various degree for the positive bacteria that tries, wherein compound 2 and compound 7-15 are to stronger for the positive bacteria restraining effect of examination, and especially the restraining effect to methicillin-resistant Staphylococcus aureus is stronger.
Claims (10)
1. triazolyl oxazolidinone compounds, its structural formula is suc as formula shown in (I):
In the formula (I), R is aromatic base, replace aminomethyl, the methylol that replaces of heterocyclic substituted methyl, methylol, methylol that fatty acyl group replaces, methylol that aroyl replaces or 4-hetaroylpyrazol.
2. triazolyl oxazolidinone compounds as claimed in claim 1 is characterized in that described aromatic base is phenyl, naphthyl, xenyl, anthryl or phenanthryl.
3. triazolyl oxazolidinone compounds as claimed in claim 1 is characterized in that described heterocycle is piperidines, Pyrrolidine, phthalimide-based, morpholinyl, oxazolidine ketone group, furyl, thienyl, pyridyl, imidazolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazyl, pyrimidyl or pyridazinyl.
4. triazolyl oxazolidinone compounds as claimed in claim 1 is characterized in that described fatty acyl group is ethanoyl, propionyl, different propionyl, butyryl radicals, isobutyryl, secondary butyryl radicals, uncle's butyryl radicals, allyl acyl group, pentanoyl, isovaleryl, valeryl, pivaloyl, caproyl, dissident's acyl group or contains the corresponding acyl group that halogen replaces.
5. triazolyl oxazolidinone compounds as claimed in claim 1 is characterized in that described aroyl is to contain by alkyl, aryl, hydroxyl, nitro, fluorine, chlorine, bromine, iodine or the amino aryl formyl radical that replaces.
6. triazolyl oxazolidinone compounds as claimed in claim 1 is characterized in that described 4-hetaroylpyrazol is furyl, thienyl, pyridyl, imidazolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazyl, pyrimidyl or pyridazinyl.
7. triazolyl oxazolidinone compounds as claimed in claim 1 is characterized in that comprising following compound:
Compound 1:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-phenyl-1-H-1,2, the 3-triazole)-1-base] Jia Ji oxazolidine-2-ketone, R=-Ph;
Compound 2:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-methylol-1-H-1,2, the 3-triazole)-1-base] Jia Ji oxazolidine-2-ketone, R=-CH
2OH;
Compound 3:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-aminomethyl-1-H-1,2, the 3-triazole)-1-base] Jia Ji oxazolidine-2-ketone, R=-CH
2NH
2
Compound 4:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-{[4-(N, N-dimethyl) aminomethyl-1-H-1,2, the 3-triazole]-1-base } Jia Ji oxazolidine-2-ketone, R=-CH
2NMe
2
Compound 5:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-morpholinyl methyl-1-H-1,2, the 3-triazole)-the 1-yl] first base oxazolidine-2-ketone,
Compound 6:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-{[4-(2-Yang Dai oxazolidine-3-yl) methyl isophthalic acid-H-1,2, the 3-triazole]-1-base } Jia Ji oxazolidine-2-ketone,
Compound 7:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-acetoxy-methyl-1-H-1,2, the 3-triazole)-1-base] Jia Ji oxazolidine-2-ketone,
Compound 8:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-dichloro-acetoxy methyl isophthalic acid-H-1,2, the 3-triazole)-1-base] Jia Ji oxazolidine-2-ketone,
Compound 9:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-furans-2-methanoyl methyl isophthalic acid-H-1,2, the 3-triazole)-1-base] Jia Ji oxazolidine-2-ketone,
Compound 10:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-thiophene-2-methanoyl methyl isophthalic acid-H-1,2, the 3-triazole)-1-base] Jia Ji oxazolidine-2-ketone,
Compound 11:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-pyridine-2-methanoyl methyl isophthalic acid-H-1,2, the 3-triazole)-1-base] Jia Ji oxazolidine-2-ketone,
Compound 12:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-is to toluyl oxygen ylmethyl-1-H-1,2,3-triazole)-1-base] Jia Ji oxazolidine-2-ketone,
Compound 13:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-is to fluorobenzoyl oxygen ylmethyl-1-H-1,2,3-triazole)-1-base] Jia Ji oxazolidine-2-ketone,
Compound 14:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-is to chlorobenzoyl oxygen ylmethyl-1-H-1,2,3-triazole)-1-base] Jia Ji oxazolidine-2-ketone,
Compound 15:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-p-nitrophenyl methanoyl methyl isophthalic acid-H-1,2, the 3-triazole)-1-base] Jia Ji oxazolidine-2-ketone,
Compound 16:(R)-and 3-[(3-fluoro-4-morpholinyl) phenyl]-5-[(4-is to tert.-butylbenzene methanoyl methyl isophthalic acid-H-1,2,3-triazole)-1-base] Jia Ji oxazolidine-2-ketone,
8. the salt that forms of described triazolyl oxazolidinone compounds of claim 1 and mineral acid or organic acid.
9. salt as claimed in claim 8 is characterized in that described mineral acid is hydrochloric acid, sulfuric acid, hydrofluoric acid, Hydrogen bromide, phosphoric acid or nitric acid; Described organic acid is formic acid, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, aspartic acid or L-glutamic acid.
10. the application of the salt of the described triazolyl oxazolidinone compounds of claim 1 or its formation on treatment infectation of bacteria medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2009100410382A CN101597283A (en) | 2009-07-10 | 2009-07-10 | Triazolyl oxazolidinone compounds and antibacterial application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2009100410382A CN101597283A (en) | 2009-07-10 | 2009-07-10 | Triazolyl oxazolidinone compounds and antibacterial application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101597283A true CN101597283A (en) | 2009-12-09 |
Family
ID=41418902
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2009100410382A Pending CN101597283A (en) | 2009-07-10 | 2009-07-10 | Triazolyl oxazolidinone compounds and antibacterial application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101597283A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103601724A (en) * | 2013-11-14 | 2014-02-26 | 暨南大学 | Novel oxazolidinone compound, as well as preparation method and application thereof |
| CN110845486A (en) * | 2019-12-02 | 2020-02-28 | 中国人民解放军第二军医大学 | Triazole alcohol derivative and preparation method and application thereof |
| CN112321580A (en) * | 2020-05-13 | 2021-02-05 | 河南科技大学第一附属医院 | Oxazole linked triazole medicine molecule for sterilization and disinfection and preparation method and application thereof |
-
2009
- 2009-07-10 CN CNA2009100410382A patent/CN101597283A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103601724A (en) * | 2013-11-14 | 2014-02-26 | 暨南大学 | Novel oxazolidinone compound, as well as preparation method and application thereof |
| CN103601724B (en) * | 2013-11-14 | 2016-05-25 | 暨南大学 | A kind of novel oxazolidinone compounds and its preparation method and application |
| CN110845486A (en) * | 2019-12-02 | 2020-02-28 | 中国人民解放军第二军医大学 | Triazole alcohol derivative and preparation method and application thereof |
| CN110845486B (en) * | 2019-12-02 | 2023-03-21 | 中国人民解放军第二军医大学 | Triazole alcohol derivative and preparation method and application thereof |
| CN112321580A (en) * | 2020-05-13 | 2021-02-05 | 河南科技大学第一附属医院 | Oxazole linked triazole medicine molecule for sterilization and disinfection and preparation method and application thereof |
| CN112321580B (en) * | 2020-05-13 | 2021-05-14 | 河南科技大学第一附属医院 | Oxazole linked triazole medicine molecule for sterilization and disinfection and preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2917010B2 (en) | Optically active pyridonecarboxylic acid derivative | |
| EP0324298B1 (en) | 7-(1-azetidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic-acid derivatives, their preparation and their use as medicaments | |
| Cooper et al. | Preparation and in vitro and in vivo evaluation of quinolones with selective activity against Gram-positive organisms | |
| JPH08504205A (en) | Tropon-Substituted Phenyloxazolidinone Antibacterial Agent | |
| CN102827155A (en) | Oxazolidinone compounds and application of oxazolidinone compound in preparation of antibiotic medicine | |
| CN103755722B (en) | The synthetic method of a kind of Levofloxacin and Ofloxacine USP 23 | |
| US5696132A (en) | Pyridonecarboxylic acid derivatives | |
| CN101597283A (en) | Triazolyl oxazolidinone compounds and antibacterial application thereof | |
| JP3745433B2 (en) | Heterocyclic compounds | |
| CN101434584A (en) | Chiral oxazolidinone compound with antibacterial activity | |
| CN102153533B (en) | 3-nitro-2H-chromene compounds with antibacterial activity and preparation method and application thereof | |
| CA2926443A1 (en) | Heteroaryl linked quinolinyl modulators of ror.gamma.t | |
| WO2023160672A1 (en) | Compounds and compositions for treating conditions associated with lpa receptor activity | |
| CN113072481B (en) | Indolo-cyclobutane skeleton compound, synthesis method and application | |
| JP2023544653A (en) | Heterocyclic-substituted fused γ-carboline derivatives, production methods, intermediates and uses thereof | |
| JP6402120B2 (en) | Novel 1,2,4-oxadiazole compounds active against gram-positive pathogens | |
| CN100545150C (en) | Contain pyridine ring De oxazolidone compounds, Preparation method and use | |
| CN108117534B (en) | Benzo-oxygenated aliphatic cyclomethylamines | |
| JPH0696572B2 (en) | Pyridonecarboxylic acid derivatives, their esters and their salts | |
| WO2016123146A1 (en) | Bridged compounds for the treatment of bacterial infections | |
| CN104610159B (en) | A kind of imidazoles hydrazides 01 derivatives and its preparation method and application | |
| CN112457309A (en) | Phenyl-substituted pyrido-pyrimidinamine compound and application thereof as antibacterial drug | |
| KR100530016B1 (en) | Oxazolidinone derivatives, methods for producing the same and antibacterial composition containing the said compounds | |
| CA3235475A1 (en) | Process | |
| CN114097804A (en) | Application of diaminopyrimidine compound in preventing and treating agricultural pathogenic bacteria |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20091209 |