CN103030635A - 联芳基杂环取代的噁唑烷酮抗菌药 - Google Patents
联芳基杂环取代的噁唑烷酮抗菌药 Download PDFInfo
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- CN103030635A CN103030635A CN2012103949955A CN201210394995A CN103030635A CN 103030635 A CN103030635 A CN 103030635A CN 2012103949955 A CN2012103949955 A CN 2012103949955A CN 201210394995 A CN201210394995 A CN 201210394995A CN 103030635 A CN103030635 A CN 103030635A
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- Prior art keywords
- alkyl
- amino
- methyl
- unit
- compound
- Prior art date
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- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 title abstract description 7
- 229940124350 antibacterial drug Drugs 0.000 title abstract 2
- 125000005841 biaryl group Chemical group 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 87
- 238000002360 preparation method Methods 0.000 claims abstract description 65
- 150000003839 salts Chemical class 0.000 claims abstract description 37
- 229940002612 prodrug Drugs 0.000 claims abstract description 31
- 239000000651 prodrug Substances 0.000 claims abstract description 31
- 239000003814 drug Substances 0.000 claims abstract description 18
- 239000000203 mixture Substances 0.000 claims abstract description 11
- 208000035473 Communicable disease Diseases 0.000 claims abstract description 10
- -1 C 1-6Alkyl-carbonyl oxygen Chemical compound 0.000 claims description 146
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 54
- 239000001257 hydrogen Substances 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- 229910052760 oxygen Inorganic materials 0.000 claims description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
- 125000001072 heteroaryl group Chemical group 0.000 claims description 27
- 125000004432 carbon atom Chemical group C* 0.000 claims description 25
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 125000005843 halogen group Chemical group 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 6
- 125000004434 sulfur atom Chemical group 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 5
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 4
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 claims description 4
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 claims description 4
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims description 4
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims description 4
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 claims description 4
- 125000003830 C1- C4 alkylcarbonylamino group Chemical group 0.000 claims description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 125000002541 furyl group Chemical group 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
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000004076 pyridyl 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
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 3
- 125000004750 (C1-C6) alkylaminosulfonyl group Chemical group 0.000 claims description 3
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 3
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 3
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 claims description 3
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 229910052721 tungsten Inorganic materials 0.000 claims description 2
- 229910052727 yttrium Inorganic materials 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000002585 base Substances 0.000 description 83
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 72
- 235000002639 sodium chloride Nutrition 0.000 description 32
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 16
- 150000003851 azoles Chemical class 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- 238000001819 mass spectrum Methods 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- GNEGRVGUGXZPAN-UHFFFAOYSA-N 5-bromo-n-(2-methyltetrazol-5-yl)pyridin-2-amine Chemical compound CN1N=NC(NC=2N=CC(Br)=CC=2)=N1 GNEGRVGUGXZPAN-UHFFFAOYSA-N 0.000 description 11
- CAAULPUQFIIOTL-UHFFFAOYSA-N methyl dihydrogen phosphate Chemical compound COP(O)(O)=O CAAULPUQFIIOTL-UHFFFAOYSA-N 0.000 description 11
- VSBORNFIVNCMCN-UHFFFAOYSA-L [Na+].[Na+].P(OC)([O-])(=S)[S-] Chemical compound [Na+].[Na+].P(OC)([O-])(=S)[S-] VSBORNFIVNCMCN-UHFFFAOYSA-L 0.000 description 10
- 125000000217 alkyl group Chemical group 0.000 description 10
- 125000004429 atom Chemical group 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 10
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 230000000845 anti-microbial effect Effects 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 244000005700 microbiome Species 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 229960001866 silicon dioxide Drugs 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 6
- 229960003907 linezolid Drugs 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 5
- 0 C1Cc2ccccc2*C1 Chemical compound C1Cc2ccccc2*C1 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000003810 ethyl acetate extraction Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 210000002381 plasma Anatomy 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000003826 tablet Substances 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
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 4
- AZUKLCJYWVMPML-UHFFFAOYSA-N 2-methyltetrazol-5-amine Chemical compound CN1N=NC(N)=N1 AZUKLCJYWVMPML-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 239000004599 antimicrobial Substances 0.000 description 4
- 125000005605 benzo group Chemical group 0.000 description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 229940023488 pill Drugs 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 229940032147 starch Drugs 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- SYOANZBNGDEJFH-UHFFFAOYSA-N 2,5-dihydro-1h-triazole Chemical compound C1NNN=C1 SYOANZBNGDEJFH-UHFFFAOYSA-N 0.000 description 3
- DJQYMSCLJMVQAE-UHFFFAOYSA-N 5-bromo-n-[1-(methoxymethyl)triazol-4-yl]pyridin-2-amine Chemical compound N1=NN(COC)C=C1NC1=CC=C(Br)C=N1 DJQYMSCLJMVQAE-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 3
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 241000191967 Staphylococcus aureus Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000003125 aqueous solvent Substances 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 3
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- XFALPSLJIHVRKE-GFCCVEGCSA-N tedizolid Chemical compound CN1N=NC(C=2N=CC(=CC=2)C=2C(=CC(=CC=2)N2C(O[C@@H](CO)C2)=O)F)=N1 XFALPSLJIHVRKE-GFCCVEGCSA-N 0.000 description 3
- 235000019587 texture Nutrition 0.000 description 3
- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 description 2
- BLSQLHNBWJLIBQ-OZXSUGGESA-N (2R,4S)-terconazole Chemical compound C1CN(C(C)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2N=CN=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 BLSQLHNBWJLIBQ-OZXSUGGESA-N 0.000 description 2
- QEGNUYASOUJEHD-UHFFFAOYSA-N 1,1-dimethylcyclohexane Chemical compound CC1(C)CCCCC1 QEGNUYASOUJEHD-UHFFFAOYSA-N 0.000 description 2
- GQHPEGRGFVYWKA-UHFFFAOYSA-N 1-(methoxymethyl)triazol-4-amine Chemical compound COCN1C=C(N)N=N1 GQHPEGRGFVYWKA-UHFFFAOYSA-N 0.000 description 2
- ZHXUWDPHUQHFOV-UHFFFAOYSA-N 2,5-dibromopyridine Chemical compound BrC1=CC=C(Br)N=C1 ZHXUWDPHUQHFOV-UHFFFAOYSA-N 0.000 description 2
- XNMQEEKYCVKGBD-UHFFFAOYSA-N 2-butyne Chemical compound CC#CC XNMQEEKYCVKGBD-UHFFFAOYSA-N 0.000 description 2
- WWUVJRULCWHUSA-UHFFFAOYSA-N 2MP Natural products CCCC(C)=C WWUVJRULCWHUSA-UHFFFAOYSA-N 0.000 description 2
- WSSSPWUEQFSQQG-UHFFFAOYSA-N 4-methyl-1-pentene Chemical compound CC(C)CC=C WSSSPWUEQFSQQG-UHFFFAOYSA-N 0.000 description 2
- PEAOEIWYQVXZMB-UHFFFAOYSA-N 5-bromo-2-chloropyridine Chemical compound ClC1=CC=C(Br)C=N1 PEAOEIWYQVXZMB-UHFFFAOYSA-N 0.000 description 2
- OMKZNDRXXSKPMF-UHFFFAOYSA-N 5-bromo-n-(2-methyltetrazol-5-yl)-1,3-thiazol-2-amine Chemical compound CN1N=NC(NC=2SC(Br)=CN=2)=N1 OMKZNDRXXSKPMF-UHFFFAOYSA-N 0.000 description 2
- NWKXZSJNKSBISD-UHFFFAOYSA-N 5-bromo-n-(2-methyltriazol-4-yl)pyridin-2-amine Chemical compound CN1N=CC(NC=2N=CC(Br)=CC=2)=N1 NWKXZSJNKSBISD-UHFFFAOYSA-N 0.000 description 2
- WPJHMUDROIGILP-UHFFFAOYSA-N 5-bromo-n-methyl-n-(2-methyltetrazol-5-yl)pyridin-2-amine Chemical compound C=1C=C(Br)C=NC=1N(C)C=1N=NN(C)N=1 WPJHMUDROIGILP-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- LYCITGUZCIFODE-LLVKDONJSA-N CC1(C)OB(c(c(F)c2)ccc2N(C[C@H](CO)O2)C2=O)OC1(C)C Chemical compound CC1(C)OB(c(c(F)c2)ccc2N(C[C@H](CO)O2)C2=O)OC1(C)C LYCITGUZCIFODE-LLVKDONJSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 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 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
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- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical class CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
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- 229950009965 radezolid Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 239000012266 salt solution Substances 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
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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Abstract
本发明涉及通式(I)所示的联芳基杂环取代的噁唑烷酮抗菌药化合物、其药学上可接受的盐、异构体或其前药,其中R1、R2、R3、R4、R5、A和B的定义同说明书中所述定义;本发明还涉及这些化合物的制备方法,含有这些化合物的药物组合物和药物制剂,以及这些化合物在制备治疗和/或预防感染性疾病的药物和治疗和/或预防感染性疾病方面的应用。
Description
1、技术领域
本发明属于医药技术领域,具体涉及联芳基杂环取代的噁唑烷酮抗菌药、其药学上可接受的盐、其异构体以及其前药,这些化合物的制备方法,含有这些化合物的药物组合物和药物制剂,以及这些化合物在制备治疗和/或预防感染性疾病的药物和治疗和/或预防感染性疾病方面的应用。
2、背景技术 噁唑烷酮类抗菌药是继磺胺类和氟喹诺酮类后开发的一类新型化学全合成抗菌药,具有抑制多重耐药革兰氏阳性菌的作用。利奈唑胺是第一个上市的噁唑烷酮类抗菌素,
它对革兰氏阳性菌具有较强的抑制作用,与其他抗菌药无交叉耐药性。其作用机制独特,能抑制细菌蛋白质合成的早期阶段。利奈唑胺主要用于治疗由耐药革兰氏阳性菌引起的感染性疾病,也可用于外科感染性疾病的治疗。
CN201010508824.1公开了Trius Therapeutics生物制药公司的临床III期药物TR-701,在体内代谢为其有效成分TR-700,用于由革兰氏阳性菌引起的感染性疾病,
然而,临床上革兰氏阳性菌的耐药情况越来越严重,而噁唑烷酮类抗菌素的临床用药品种单一,目前仅利奈唑胺一个药物上市,远远不能满足临床需求,且利奈唑胺的耐药情况越来越严重,因此,急需扩大噁唑烷酮类抗生素的临床应用品种,开发出对耐药性革兰氏阳性菌高度有效的抗菌药物。
3、发明内容
为满足临床需求,本发明提供了一类具有较好抗菌活性的抗感染化合物,具体技术方案如下:
通式(I)所示的化合物、其药学上可接受的盐、其异构体或其前药:
其中,
R1选自(1)-OR6,(2)-NR6R6’,(3)-COR6,(4)-COOR6,(5)-OCOR6,(6)-CONR6R6’,(7)-NR6COR6’,(8)-OCONR6R6’,(9)-NR6COOR6’,(10)-NR6CONR6’R6,(11)-CSR6,(12)-CSOR6,(13)-OCSR6,(14)-CSNR6R6’,(15)-NR6CSR6’,(16)-OCSNR6R6’,(17)-NR6CSOR6’,(18)-NR6CSNR6’R6,(19)-NR6C(NR6)NR6’R6,(20)-S(O)pR6,(21)-SO2NR6R6’,或(22)R6,
p为0,1或2,
R6、R6’选自:(1)氢,(2)C1-6烷基,(3)C2-6烯基,(4)C2-6炔基,(5)3-14元的环烷基,(6)6-14元芳基,(7)3-14元的杂环基,包含一个或多个选自N、S、O和/或SO2的杂原子,(8)-COC1-6烷基,(9)-COC2-6烯基,或(10)-COC2-6炔基;
R2、R3独立地选自氢,卤素或C1-6烷基;
R4选自:(1)氢,(2)C1-6烷基,(3)C2-6烯基,(4)C2-6炔基,(5)3-14元环烷基,(6)6-14元芳基,(7)3-14元杂环基,包含一个或多个选自N、S、O和/或SO2的杂原子,(8)-COC1-6烷基,(9)-COC2-6烯基,或(10)-COC2-6炔基;
R5选自未被取代的或被1-3个R7取代的以下基团:
(1)3-14元环烷基,
(2)6-14元芳基,
(3)3-14元杂环基,或
(4)5-14元杂芳基,
R7选自卤素、羧基、羟基、氨基、氰基、硝基、C1-6烷基、羧基C1-6烷基、羟基C1-6烷基、氨基C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氧基C1-6烷基、C1-6烷基氨基、二(C1-6烷基)氨基、二(C1-6烷基)氨基C1-6烷基、C1-6烷基羰基、C1-6烷基羰基氧基、 C1-6烷氧基羰基、氨基甲酰基、氨基甲酰基C1-6烷基、C1-6烷基氨基甲酰基、二(C1-6烷基)氨基甲酰基、氨基磺酰基、氨基磺酰基C1-6烷基、C1-6烷基氨基磺酰基、二(C1-6烷基)氨基磺酰基、C1-6烷基磺酰氨基、C1-6烷基磺酰基、C1-6烷基羰基氨基或胍基。
优选地,式(I)具有下述通式(II)所示的结构:
其中,R1、R2、R3、R4、R5、X和Y如通式(I)中所定义。
通式(II)所示的化合物、其药学上可接受的盐、其异构体或其前药,优选为:
其中,
R2、R3独立的选自氢或卤素;
X、Y分别独立地为C原子或N原子;
R4选自:(1)氢,(2)C1-4烷基,(3)C2-4烯基,(4)C2-4炔基,(5)-C(O)C1-4烷基,(6)-C(O)C2-4烯基,或(7)-C(O)C2-4炔基;
R5选自未被取代的或被1-3个R7取代的5-14元杂芳基,该5-14元杂芳基包含一个或多个选自N、S、O和/或SO2的杂原子,
R7选自卤素、羧基、羟基、氨基、氰基、硝基、C1-4烷基、羧基C1-4烷基、羟基C1-4烷基、氨基C1-4烷基、卤代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基、C1-4烷氧基C1-4烷基、C1-4烷基氨基、二(C1-4烷基)氨基、二(C1-4烷基)氨基C1-4烷基、C1-4烷基羰基、C1-4烷基羰基氧基、C1-4烷氧基羰基、氨基甲酰基、氨基甲酰基C1-4烷基、C1-4烷基氨基甲酰基、二(C1-4烷基)氨基甲酰基、氨基磺酰基、氨基磺酰基C1-4烷基、C1-4烷基氨基磺酰基、二(C1-4烷基)氨基磺酰基、C1-4烷基磺酰氨基、C1-4烷基磺酰基、C1-4烷基羰基氨基或胍基。
通式(II)所示的化合物、其药学上可接受的盐、其异构体或其前药,优选为:
其中,
R1选自-NHCOCH3或-OH;
R2、R3独立地选自氢或卤素;
R4选自氢或C1-4烷基;
X、Y分别独立地为C原子或N原子;
R 5选自未被取代的或被1-3个R7取代的5-8元单杂芳基,该5-8元单杂芳基包含一个或多个选自N、S、O和/或SO2的杂原子,
R7选自C1-4烷基或卤代C1-4烷基。
通式(II)所示的化合物、其药学上可接受的盐、其异构体或其前药,优选为:
其中,
R1选自-NHCOCH3或-OH;
R2为氢;
R3为氟;
R4为氢;
X为C原子;
Y为N原子;
R5选自未被取代的或被1-2个R7取代的5-6元单杂芳基,该5-6元单杂芳基包含一个或多个选自N、S或O的杂原子,
R7选自C1-4烷基或卤代C1-4烷基。
通式(I)所示的化合物、其药学上可接受的盐、其异构体或其前药,优选为:
其中,
R1选自-NHCOCH3或-OH;
R2为氢;
R3为氟;
R4为氢;
X为C原子;
Y为N原子;
R5选自未被取代的或被1-2个R7取代的吡咯基、呋喃基、咪唑基、1,2,4-三唑基、1,2,3-三唑基、吡唑基、噁唑基、异噁唑基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、吡啶基、嘧啶基、噻唑基、异噻唑基、1,2,3,4-四唑基、吡喃基或吡嗪基,
R7为C1-4烷基。
优选地,式(I)具有下述通式(III)所示的结构:
其中,R1、R2、R3、R4、R5、Q、W和Z如通式(I)中所定义。
通式(III)所示的化合物、其药学上可接受的盐、其异构体或其前药,优选为:
其中,
R2、R3独立的选自氢或卤素;
W、Z分别独立地为C原子或N原子,Q独立地为CH2、NH、O或S原子;
R4选自:(1)氢,(2)C1-4烷基,(3)C2-4烯基,(4)C2-4炔基,(5)-C(O)C1-4烷基,(6)-C(O)C2-4烯基,或(7)-C(O)C2-4炔基;
R5选自未被取代的或被1-3个R7取代的5-14元杂芳基,该5-14元杂芳基包含一个或多个选自N、S、O和/或SO2的杂原子,
R7选自卤素、羧基、羟基、氨基、氰基、硝基、C 1-4烷基、羧基C1-4烷基、羟基C1-4烷基、氨基C1-4烷基、卤代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基、C1-4烷氧基C1-4烷基、C1-4烷基氨基、二(C1-4烷基)氨基、二(C1-4烷基)氨基C1-4烷基、C1-4烷基羰基、C1-4烷基羰基氧基、C1-4烷氧基羰基、氨基甲酰基、氨基甲酰基C1-4烷基、C1-4烷基氨基甲酰基、二(C1-4烷基)氨基甲酰基、氨基磺酰基、氨基磺酰基C1-4烷基、C1-4烷基氨基磺酰基、二(C1-4烷基)氨基磺酰基、C1-4烷基磺酰氨基、C1-4烷基磺酰基、C1-4烷基羰基氨基或胍基。
通式(III)所示的化合物、其药学上可接受的盐、其异构体或其前药,优选为:
其中,
R1选自-NHCOCH3或-OH;
R2、R3独立地选自氢或卤素;
R4选自氢或C1-4烷基;
W、Z分别独立地为C原子或N原子,Q独立地为NH、O或S原子;
R5选自未被取代的或被1-3个R7取代的5-8元单杂芳基,该5-8元单杂芳基包含一个或多个选自N、S、O和/或SO2的杂原子,
R7选自C1-4烷基或卤代C1-4烷基。
进一步优选为:
其中,
R1选自-NHCOCH3或-OH;
R2为氢;
R3为氟;
R4为氢;
W、Z分别独立地为C原子或N原子,Q独立地为O或S原子;
R5选自未被取代的或被1-2个R7取代的5-6元单杂芳基,该5-6元单杂芳基包含一个或多个选自N、S或O的杂原子,
R7选自C1-4烷基或卤代C1-4烷基。
进一步优选为:
其中,
R1选自-NHCOCH3或-OH;
R2为氢;
R3为氟;
R4为氢;
W为N原子,Z为C原子,Q为S原子;
R5选自未被取代的或被1-2个R7取代的吡咯基、呋喃基、咪唑基、1,2,4-三唑基、1,2,3-三唑基、吡唑基、噁唑基、异噁唑基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、吡啶基、嘧啶基、噻唑基、异噻唑基、1,2,3,4-四唑基、吡喃基或吡嗪基,
R7为C1-4烷基。
发明详述
本发明所述的“卤素”是指氟原子、氯原子、溴原子、碘原子等。优选氟原子和氯原子。
本发明所述的“C1-6烷基”表示直链或支链的含有1-6个碳原子的烷基,如甲基、乙基、正丙基、异丙基、正丁基、2-甲基丙基、1-甲基丙基、1,1-二甲基乙基、正戊基、3-甲基丁基、2-甲基丁基、1-甲基丁基、1-乙基丙基、正己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。优选C1-4烷基。本发明所述“C1-4烷 基”指含有1-4个碳原子上述实施例。
本发明所述的“C2-6烯基”是指含有双键的碳原子数为2-6的直链或支链或环状的烯基,如乙烯基、1-丙烯基、2-丙烯基、1-甲基乙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-甲基-1-丙烯基、2-甲基-1-丙烯基、1-甲基-2-丙烯基、2-甲基-2-丙烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、3-甲基-1-丁烯基、1-甲基-2-丁烯基、2-甲基-2-丁烯基、3-甲基-2-丁烯基、1-甲基-3-丁烯基、2-甲基-3-丁烯基、3-甲基-3-丁烯基、1,1-二甲基-2-丙烯基、1,2-二甲基-1-丙烯基、1,2-二甲基-2-丙烯基、1-乙基-1-丙烯基、1-乙基-2-丙烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、3-甲基-1-戊烯基、4-甲基-1-戊烯基、1-甲基-2-戊烯基、2-甲基-2-戊烯基、3-甲基-2-戊烯基、4-甲基-2-戊烯基、1-甲基-3-戊烯基、2-甲基-3-戊烯基、3-甲基-3-戊烯基、4-甲基-3-戊烯基、1-甲基-4-戊烯基、2-甲基-4-戊烯基、3-甲基-4-戊烯基、4-甲基-4-戊烯基、1,1-二甲基-2-丁烯基、1,1-二甲基-3-丁烯基、1,2-二甲基-1-丁烯基、1,2-二甲基-2-丁烯基、1,2-二甲基-3-丁烯基、1,3-二甲基-1-丁烯基、1,3-二甲基-2-丁烯基、1,3-二甲基-2-丁烯基、2,2-二甲基-3-丁烯基、2,3-二甲基-1-丁烯基、2,3-二甲基-2-丁烯基、2,3-二甲基-3-丁烯基、3,3-二甲基-1-丁烯基、3,3-二甲基-2-丁烯基、1-乙基-1-丁烯基、1-乙基-2-丁烯基、1-乙基-3-丁烯基、2-乙基-1-丁烯基、2-乙基-2-丁烯基、2-乙基-3-丁烯基、1,1,2-三甲基-2-丙烯基、1-乙基-1-甲基-2-丙烯基、1-乙基-2-甲基-1-丙烯基、1-乙基-2-甲基-2-丙烯基、1,3-丁二烯基、1,3-戊二烯基、1,4-戊二烯基、2,4-戊二烯基、1,4-己二烯基、2,4-己二烯基、环戊烯基、1,3-环戊二烯基、环己烯基和1,4-环己二烯基等。双键可任选地为顺式和反式。
本发明所述的“C2-6炔基”是指含有三键的碳原子数为2-6的直链或支链的炔基,如乙炔基、1-丙炔基、2-丙炔基、2-丁炔基、3-丁炔基、1-甲基-2-丙炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-甲基-2-丁炔基、1-甲基-3-丁炔基、2-甲基-3-丁炔基、1,1-二甲基-2-丙炔基、1-乙基-2-丙炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基、1-甲基-2-戊炔基、4-甲基-2-戊炔基、1-甲基-3-戊炔基、2-甲基-3-戊炔基、1-甲基-4-戊炔基、2-甲基-4-戊炔基、3-甲基-4-戊炔基、1,1-二甲基-2-丁炔基、1,1-二甲基-3-丁炔基、1,2-二甲基-3-丁炔基、2,2-二甲基-3-丁炔基、1-乙基-2-丁炔基、1-乙基-3-丁炔基、2-乙基-3-丁炔基和1-乙基-1-甲基-2-丙炔基等。
本发明所述的“C1-6烷氧基”、“C1-6烷基氨基”、“二(C1-6烷基)氨基”、“C1-6烷基羰基氧基”、“C1-6烷氧基羰基”、“C1-6烷基羰基”、“C1-6烷基磺酰基”、“C1-6烷基磺酰氨基”、“C1-6烷基羰基氨基”、“C1-6烷基氨基甲酰基”、“二(C1-6烷基)氨基甲酰基”、“C1-6烷基氨基磺酰基”、“二(C1-6烷基)氨基磺酰基”分别是指“C1-6烷基-O-”基团、“C1-6烷基-NH-”基团、“(C1-6烷基)2N-”基团、 “C1-6烷基-C(O)-O-”基团、“C1-6烷基-O-C(O)-”基团、“C1-6烷基-C(O)-”基团、“C1-6烷基-SO2-”基团、“C1-6烷基-SO2-NH-”基团、“C1-6烷基-C(O)NH-”基团、“C1-6烷基-NH-C(O)-”基团、“(C1-6烷基)2N-C(O)-”基团、“C1-6烷基-NH-SO2-”基团、“(C1-6烷基)2N-SO2-”基团,其中“C1-6烷基”如前文所定义。
本发明所述的“C1-4烷氧基”、“C1-4烷基氨基”、“二(C1-4烷基)氨基”、“C1-4烷基羰基氧基”、“C1-4烷氧基羰基”、“C1-4烷基羰基”、“C1-4烷基磺酰基”、“C1-4烷基磺酰氨基”、“C1-4烷基羰基氨基”、“C1-4烷基氨基甲酰基”、“二(C1-4烷基)氨基甲酰基”、“C1-4烷基氨基磺酰基”、“二(C1-4烷基)氨基磺酰基”分别是指“C1-4烷基-O-”基团、“C1-4烷基NH-”基团、“(C1-4烷基)2N-”基团、“C1-4烷基-C(O)-O-”基团、“C1-4烷基-O-C(O)-”基团、“C1-4烷基-C(O)-”基团、“C1-4烷基-SO2-”基团、“C1-4烷基-SO2-NH-”基团、“C1-4烷基-C(O)-NH-”基团、“C1-4烷基-NH-C(O)-”基团、“(C1-4烷基)2N-C(O)-”基团、“C1-4烷基-NH-SO2-”基团、“(C1-4烷基)2N-SO2-”基团,其中“C1-4烷基”如前文所定义。
本发明所述的“羟基C1-6烷基”、“羧基C1-6烷基”、“氨基C1-6烷基”、“氨基磺酰基C1-6烷基”、“二(C1-6烷基)氨基C1-6烷基”、“C1-6烷氧基C1-6烷基”、“氨基甲酰基C1-6烷基”分别是指一个以上羟基、羧基、氨基、氨基磺酰基、二(C1-6烷基)氨基、C1-6烷氧基、氨基甲酰基取代C1-6烷基所形成的基团,其中“C1-6烷基”如前文所定义。
本发明所述的“羟基C1-4烷基”、“羧基C1-4烷基”、“氨基C1-4烷基”、“氨基磺酰基C1-4烷基”、“二(C1-4烷基)氨基C1-4烷基”、“C1-4烷氧基C1-4烷基”、“氨基甲酰基C1-4烷基”分别是指一个以上羟基、羧基、氨基、氨基磺酰基、二(C1-4烷基)氨基、C1-4烷氧基、氨基甲酰基取代C1-4烷基所形成的基团,其中“C1-4烷基”如前文所定义。
本发明所述的“卤代C1-6烷基”指一个以上“卤素”原子取代“C1-6烷基”所形成的基团,所述的“卤代C1-4烷基”指一个以上“卤素”原子取代“C1-4烷基”所形成的基团,所述“卤素”和“C1-6烷基”、“C1-4烷基”如前文所定义。
本发明所述的“卤代C1-6烷氧基”指一个以上“卤素”原子取代“C1-6烷氧基”所形成的基团,所述的“卤代C1-4烷氧基”指一个以上“卤素”原子取代“C1-4烷氧基”所形成的基团,所述“卤素”、“C1-6烷氧基”、“C1-4烷氧基”如前文所定义。
本发明所述的“3-14元环烷基”是指3-14个碳原子的环状烷烃部分去除一个氢原子衍生的基团,包括3-8元单环烷基、6-14元并环烷基,优选3-8元单环烷基、3-6元单环烷基和5-6元单环烷基。“3-8元单环烷基”、“3-6元单环烷基”、“5-6元环环烷基”分别为下述实例中含有3-8个、3-6个、5-6个碳原子的具体实例。
3-8元单环烷基,其实例包括但不限于:环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基、环辛烷基、甲基环丙烷基、二甲基环丙烷基、甲基环丁烷基、二甲基环丁烷基、甲基环戊烷基、二甲基环戊烷基、甲基环己烷基、二甲基环己烷基等。
6-14元并环烷基,是指由两个或两个以上环状结构彼此共用两个相邻的碳原子所形成的6-14元环状基团,优选6-12元并环烷基,6-10元并环烷基。其实例包括但不限于:二环[3.1.0]己烷基、二环[4.1.0]庚烷基、二环[2.2.0]己烷基、二环[3.2.0]庚烷基、二环[4.2.0]辛烷基、八氢并环戊二烯基、八氢-1H-茚基、十氢化萘基、十四氢菲基等。
7-12元桥环基,是指任意两个环共用两不相邻的原子形成的含有7-12个碳原子或/和杂原子的结构,所述的杂原子选自N、S、O、CO、SO和/或SO2等。其中包括例如“7-10元桥环基”、“7-9元桥环基”、“7-8元桥环基”等。其实例包括但不限于例如: 等。
7-12元螺环基,是指至少有两个环共享一个原子形成的含有7-12个碳原子或/和杂原子的结构,所述的杂原子选自N、S、O、CO、SO和/或SO2等。其中包括例如“7-10元螺环基”、“7-9元螺环基”、“7-8元螺环基”等。其实例包括但不仅限于例如: 等。
本发明所述的“6-14元芳基”是指环原子为6-14元碳原子的环状芳香基团,包括6-8元单环芳基和8-14元稠环芳基。6-8元单环芳基包括苯基、环辛四烯基等。8-14元稠环芳基是指由两个或两个以上环状结构彼此共用两个相邻的碳原子所形成的环状基团,包括萘基、蒽基和菲基等,还包括8-14元部分饱和稠环芳基,例如苯并3-8元单环环烷基、,具体实例如2,3-二氢-1H-茚基、1H-茚基、1,2,3,4-四氢萘基、1,4-二氢萘基等。优选6-10元芳基,进一步优选苯或苯并3-8元单环环烷基。
所述的“5-14元杂芳基”,其环原子除了碳原子外,还包括一个或多个杂原子,所述“杂原子”选自N、S、O、CO、SO和/或SO2等。杂芳基可通过碳或杂环原子键合。包括5-8元单杂芳基和8-14元稠杂芳基。
5-8元单杂芳基,优选5-6元单杂芳基,包括但不限于吡咯基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁唑基、1,2,3-三嗪基、1,2,4-三嗪基、四唑基、噁三唑基、2H-1,2-噁嗪基、4H-1,2-噁嗪基、6H-1,2-噁嗪基、2H-1,3-噁嗪基、4H-1,3-噁嗪基、6H-1,3-噁嗪基、2H-1,4-噁嗪基、4H-1,4-噁嗪基、异噁嗪基、哒嗪基、嘧啶基和吡嗪基等;
8-14元稠杂芳基包括但不限于苯并呋喃基、异苯并呋喃基、苯并噻吩基、吲哚基、异吲哚基、喹啉基、异喹啉基、吲嗪基、吲唑基、酞嗪基、喹喔啉基、喹唑啉基、苯并二嗪基、苯并异噁唑基、苯并噁嗪基、苯并咪唑基、吡啶并吡啶基、吡唑并[3,4-b]吡啶基、嘌呤基、吖啶基和呫吨基等。
本发明所述“3-14元杂环基”是指含有一至多个杂原子的3-14元环状基团,所述“杂原子”选自N、S、O、CO、SO和/或SO2等。包括3-8元单杂环基和6-14元稠杂环基。
3-8元单杂环基,是指含有3-8个环原子(其中至少含有一个杂原子)的单环杂环基,优选5-7元单杂环基,具体实例包括但不仅限于2,5-二氢噻吩基、4,5-二氢吡唑基、3,4-二氢-2H-吡喃基、5,6-二氢-4H-1,3-噁嗪基、氮杂环丙烷基、氮杂环丁烷基、硫杂环丁烷基、四氢呋喃基、四氢吡咯基、咪唑烷基、吡唑烷基、四氢呋喃基、1,4-二氧杂环己烷基、1,3-二氧杂环己烷基、1,3-二硫杂环己烷基、吗啉基、哌嗪基等。
6-14元稠杂环基是指含有6-14个环原子(其中至少含有一个杂原子)由两个或两个以上环状结构彼此共用两个相邻的原子连接起来形成的并环结构,优选6-10元稠杂环基,如苯并 3-8元单杂环基形成的结构,3-8元单杂环基并3-8元单杂环基形成的结构。具体实例包括但不限于:1,3-二氢苯并呋喃基、苯并[d][1.3]二氧杂环戊烯基、异吲哚啉基、色满基、1,2,3,4-四氢吡咯并[3,4-c]吡咯、 等。
本发明所述的“1-3个”是指1个、2个或3个。
本发明所述的“3-8元”是指3元、4元、5元、6元、7元或8元,优选5-8元,进一步优选5-7元,更进一步优选5-6元。
表1本发明的化合物
本发明还提供了上述化合物的制备方法,但不仅限于以下方法:
反应方程式:
原料1 原料2 中间体1
中间体1 原料3 本发明化合物(II)
X=Br,I,OTf
反应步骤:
步骤1中间体1的制备
将原料1,原料2,无机碱(如叔丁醇钾、碳酸铯、碳酸钾等)和钯催化剂(如Pd(dppf)Cl2, Pd2(dba)3,Pd(PPh3)4,Pd(PPh3)2Cl2等)、BINAP溶于甲苯中,加热回流反应过夜。加水,用乙酸乙酯萃取,有机相干燥,浓缩,固体经硅胶柱分离得中间体1。
步骤2本发明化合物(II)的制备
将中间体1,原料3,无机碱(如碳酸铯、碳酸钾等)和钯催化剂(如Pd(dppf)Cl2,Pd(PPh3)4,Pd(PPh3)2Cl2等)溶于二氧六环和水中,加热回流反应至原料消失。将溶剂蒸干,固体经硅胶柱分离纯化得本发明化合物(II)。
以上反应方程式中的R1、R2、R3、R4、R5、R6、X或Y如前文所定义。
本发明式(III)化合物可参照式(II)化合物的方法制备。
本发明化合物的“药学上可接受的盐”是指本发明化合物与药学上可接受的、非毒性碱或酸形成的碱加成盐或酸加成盐,包括有机酸盐、无机酸盐、有机碱盐、无机碱盐。有机酸盐包括甲酸盐、乙酸盐、丙酸盐、苯磺酸盐、苯甲酸盐、对甲苯磺酸盐、2,3-二羟基丁二酸盐、樟脑磺酸盐、柠檬酸盐、甲磺酸盐、乙磺酸盐、丙磺酸盐、富马酸盐、葡糖酸盐、谷氨酸盐、羟乙磺酸盐、乳酸盐、马来酸盐、苹果酸盐、扁桃酸盐、粘酸盐、双羟萘酸盐、泛酸盐、琥珀酸盐、酒石酸盐等,特别优选苯甲酸盐、苯磺酸盐、对甲苯磺酸盐、甲磺酸盐、柠檬酸盐、马来酸盐、富马酸盐、酒石酸盐。无机酸盐包括氢氯酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、硝酸盐等,特别优选氢氯酸盐、氢溴酸盐、硫酸盐、磷酸盐。有机碱盐包括胺盐,包括与伯、仲和叔胺、环胺和碱离子交换树脂形成的盐,可以选自与下列有机碱形成的盐:例如精氨酸、甜菜碱、咖啡因、胆碱、N,N’-二苄基乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基-吗啉、N-乙基哌啶、葡甲胺、氨基葡萄糖、组氨酸、海巴明、异丙基胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺和氨丁三醇等。无机碱盐包括与氨、碱金属、碱土金属形成的盐,例如铵盐以及锂盐、钠盐、钾盐、钙盐、镁盐、锌盐、钡盐、铝盐、铁盐、铜盐、亚铁盐、锰盐、二价锰盐,特别优选铵盐以及钠盐、钾盐、钙盐、镁盐。本发明式(I)化合物与磷酸形成磷酸酯,并进一步与金属盐形成式(I)化合物磷酸酯金属盐,例如磷酸酯二钠盐。
本发明化合物的“前药”,指在生理条件下或通过溶剂分解可以转化为任何式(I)化合物或转化为式(I)化合物的药物可接受的盐的化合物(称为原药)。当对患者给药时,前体药物可以是无活性的,但其在体内转化为活性化合物。当本发明式(I)化合物存在羟基时,可以与氨基酸、磷酸等形成酯型前药,前药在水或者酸溶液中稳定,在血液中的酯酶或者磷酸酶的作用下解离形成游离化合物。本发明式(I)化合物的前药比原药具有更优异的溶解性,更容易被动物体或者人体吸收,在血液中更好的转化为原药化合物,发挥抗菌活性。
本发明化合物的“异构体”是指化学式相同而结构不同的化合物,包括构像异构体(结构异构体)和立体异构体(构型异构体)等。“立体异构体”,指当本发明化合物含有一个或多个不对称中心,因而可作为外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体。本发明化合物有不对称中心,这类不对称中心各自会独立地产生两个光学异构体,本发明的范围包括所有可能的光学异构体和非对映异构体混合物和纯的或部分纯的化合物。本发明所述的化合物若含有烯烃双键,除非特别说明,本发明包括顺式异构体和反式异构体。
本发明所述的化合物还可以以互变异构体形式存在,其通过一个或多个双键位移而具有不同的氢的连接点。各互变异构体及其混合物都包括在本发明的化合物中。
例如本发明式(I)所示化合物及其在制备过程中的中间体,R5代表的时,会发生互变,在制备了其中之一时,相当于制备了其互变异构体。所有涉及上述情况的本发明化合物及其制备中间体,视为等同,均包含在本发明范围中。
本发明还提供药物组合物,它含有上面所述的本发明通式(I)化合物或其药学上可接受的盐、它们的异构体或其前药和一种或多种药用载体和/或稀释剂。所述组合物可以制成临床上或药学上可接受的任一剂型,优选为口服制剂和注射剂。
本发明化合物或其药学上可接受的盐或它们的异构体可以经口服、肠胃外(静脉内、肌肉内、皮下或直肠)、局部等给药等方式施用于哺乳动物,例如人。本发明化合物的用量范围为大约0.1-100mg/kg体重/天,例如为3-50mg/kg体重/天。
用于肠胃外给药时,可将本发明化合物或其药学上可接受的盐或它们的异构体配制成注射剂,包括用于肌内注射、静脉注射、静脉滴注、皮下注射等的无菌溶液型、乳液型、分散液型或混悬液型制剂,以及供临用前配制或稀释成溶液、分散液或混悬液的注射用无菌粉末或浓溶液。
所述注射剂可采用现有制药领域中的常规方法生产,可选用水性溶剂或非水性溶剂。最常用的水性溶剂为注射用水,也可用0.9%氯化钠溶液或其他适宜的水溶液;常用的非水性溶剂为植物油,例如供注射用大豆油,其他还有乙醇、丙二醇、聚乙二醇等的水溶液等。配制注射剂时,可以不加入添加剂,也可根据药物的性质加入适宜的添加剂,如渗透压调节剂、 pH值调节剂、增溶剂、填充剂、抗氧剂、抑菌剂、乳化剂、助悬剂等。常用的渗透压调节剂包括氯化钠、葡萄糖、氯化钾、氯化镁、氯化钙、山梨醇等,优选氯化钠或葡萄糖;常用的pH值调节剂包括醋酸-醋酸钠、乳酸、枸橼酸-枸橼酸钠、碳酸氢钠-碳酸钠等;常用的增溶剂包括聚山梨酯80、丙二醇、卵磷脂、聚氧乙烯蓖麻油等;常用的填充剂包括乳糖、甘露醇、山梨醇、右旋糖酐等;常用的抗氧剂有亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠等;常用抑菌剂为苯酚、甲酚、三氯叔丁醇等。
所述药物组合物也可以采用常规方法配制为经直肠或局部给药的剂型,包括栓剂、软膏剂、乳膏剂、贴剂、散剂、喷雾剂、吸入剂等。
用于口服给药时,可将本发明化合物或其药学上可接受的盐或它们的异构体采用常规方法配制成常规的固体制剂,如片剂、胶囊剂、丸剂、颗粒剂等;也可制成口服液体制剂,如口服溶液剂、口服混悬剂、糖浆剂等。片剂以口服普通片为主,另有含片、舌下片、口腔贴片、咀嚼片、分散片、可溶片、泡腾片、缓释片、控释片与肠溶片等。胶囊剂依据其溶解与释放特性,可分为硬胶囊、软胶囊、缓释胶囊、控释胶囊和肠溶胶囊等。丸剂包括滴丸、糖丸、小丸等。颗粒剂可分为可溶颗粒、混悬颗粒、泡腾颗粒、肠溶颗粒、缓释颗粒和控释颗粒等。
在制备口服制剂时,可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。常用填充剂包括淀粉、糖粉、磷酸钙、硫酸钙二水物、糊精、微晶纤维素、乳糖、预胶化淀粉、甘露醇等;常用粘合剂包括羧甲基纤维素钠、PVP-K30、羟丙基纤维素、淀粉浆、甲基纤维素、乙基纤维素、羟丙甲纤维素、胶化淀粉等;常用崩解剂包括干淀粉、交联聚维酮、交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素等;常用润滑剂包括硬脂酸镁、滑石粉、十二烷基硫酸钠、微粉硅胶等。
另一方面,本发明还提供本发明通式(I)化合物或其药学上可接受的盐或它们的异构体在制备治疗和/或预防感染性疾病的药物方面的应用。
再一方面,本发明还提供治疗和/或预防感染性疾病的方法,包括将本发明通式(I)化合物或其药学上可接受的盐或它们的异构体给予需要此治疗或预防的哺乳动物,例如人。
实验证明,本发明化合物具有良好的抗菌活性,可用于治疗和/或预防各种感染性疾病。
本发明的噁唑烷酮抗菌素对革兰氏阳性菌具有良好的抗菌活性,对革兰氏阳性耐药菌也具有良好的抗菌活性,可用于治疗和/或预防由革兰氏阳性菌引起的各种疾病。
以下通过抗菌活性实验进一步阐述本发明化合物有益效果,但不应将此理解为本发明化合物仅具有下列有益效果。
实验例1本发明化合物的体外抗菌活性
供试菌种:耐甲氧西林金黄色葡萄球菌(MRSA)、甲氧西林敏感的金黄色葡萄球菌 (MSSA)、耐甲氧西林的表皮葡萄球菌(MRSE)、甲氧西林敏感的金黄色葡萄球菌(MSSE)、屎肠球菌、粪肠球菌、肺炎链球菌。来源:千佛山医院、云南省第一人民医院、上海仁济医院、吉林省人民医院、西南医院。
测试物:本发明化合物1、3、4、6、8、11,参照各实施例方法制得。
对照药:利奈唑胺。
实验方法:标准琼脂稀释法,参考National Committee for Clinical LaboratoryStandards.2006.Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria ThatGrow Aerobically,Approved Standard-Seventh Edition M7-A7。
实验结果和结论:
表1本发明化合物的抗菌活性
实验结果表明,本发明化合物与利奈唑胺相比,对供试菌株都有较好的抗菌活性,差异明显,说明本发明化合物具有较好的临床应用潜力。
实验例2本发明化合物的大鼠体内药代动力学实验
测试物化合物2,3,5,7,9,按照实施例方式自制,用生理盐水溶解。
受试动物
实验方法
给药按照下表方式给药,给药前禁食不禁水16小时,给药后4小时给食。
I.V代表静脉推注给药
P.O代表灌胃给药
采血I.V:按照下表时间点进行采血,每个时间点采取100μl左右全血加入到肝素钠抗凝管中,4℃条件下在低温高速离心机中8000转/分钟离心6分钟,分离血浆,血浆于-80℃冰箱冻存。
血浆样品分析
化合物5,7,9:分别取20μl血浆,加入100μl浓度为50ng/ml的Torezolid(TR-700)甲醇溶液,涡旋混匀5分钟,12000转/分钟离心5分钟,取上清液100μl加入到100μl中,涡旋混匀2分钟,使用LC-MS/MS分析。
化合物2:取20μl血浆,加入100μl浓度为50ng/ml的雷得唑来(Radezolid)的甲醇溶液,涡旋混匀3分钟,12000转/分钟离心5分钟,取上清液100μl加入到100μl中,涡旋混匀2分钟,使用LC-MS/MS分析。
化合物3:取20μl血浆,加入800μl浓度为10ng/ml的KBP-3957甲基叔丁基醚溶液,涡旋混匀10分钟,12000转/分钟离心5分钟,取上清液400μl加入到96孔板中,氮气吹干,加入200μl甲醇∶水(7∶3)溶液,涡旋混匀10分钟,使用LC-MS/MS分析。
追踪检测化合物2是化合物1的前药,化合物5是化合物4的前药,化合物7是化合物6的前药,化合物9是化合物8的前药,所以给药后分别检测原药化合物1、4、6、8的PK结果。
计算公式绝对生物利用度F%=[AUC]INF(Po)*Dose(IV)/[AUC]INF(IV)*Dose(PO)
实验结果见表3、4。
表3本发明化合物的大鼠PK评价结果(I.V)
表4本发明化合物的大鼠PK评价结果(P.O)
AUCinf代表药时曲线下面积0→∞
CL代表清除率
Vss代表表观分布容积
T1/2代表半衰期
Tmax代表血药达峰时间
Cmax代表血药峰浓度
F%代表绝对生物利用度
实验结论
由表3、4可以看出,本发明化合物具有良好的药代动力学性质,成药性好。
4、具体实施方式
以下通过实施例形式的具体实施方式,对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
实施例1(R)-3-(3-氟-4-(6-((2-甲基-2H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷-2-酮(化合物1)的制备
(1)5-溴-N-(2-甲基-2H-四氮唑-5-基)吡啶-2-胺的制备
将2-甲基-2H-四氮唑-5-胺(7.7g,78mmol),2-氯-5-溴吡啶(10g,52mmol),和叔丁醇钾(11.6g,104mmol)溶于100mL THF中,加热回流反应12h。加水,用乙酸乙酯萃取,有机相干燥,浓缩,固体经硅胶柱分离(二氯甲烷∶甲醇=100∶1)得5-溴-N-(2-甲基-2H-四氮唑-5-基)吡啶-2-胺200mg,产率1.5%。
将5-溴-N-(2-甲基-2H-四氮唑-5-基)吡啶-2-胺(200mg,0.78mmol),(R)-3-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)苯基)-5-(羟甲基)噁唑烷-2-酮(317mg,0.94mmol),碳酸铯(508mg,1.56mmol)和Pd(dppf)Cl2(90mg,0.16mmol)溶于16mL二氧六环和4mL水中,加热至100度反应6h。将溶剂蒸干,固体经硅胶柱分离(二氯甲烷∶甲醇=40∶1)得(R)-3-(3-氟-4-(6-((2-甲基-2H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷-2-酮90mg,产率30%。
分子式:C17H16FN7O3 质谱(m/e):386.2(M+1)
1H NMR:(400MHz,DMSO-d6)δ10.48(s,1H),8.42(s,1H),7.93(d,1H),7.65(d,1H),7.60(m,2H),7.44(d,1H),5.24(m,1H),4.73(m,1H),4.29(s,3H),4.12(t,1H),3.87(m,1H),3.67(m,1H),3.58(m,1H).
实施例2(S)-N-((3-(3-氟-4-(6-((2-甲基-2H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-2-氧代噁唑烷-5-基)甲基)乙酰胺(化合物3)的制备
(1)(S)-N-((3-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)苯基)-2-氧代-噁唑烷-5-基)甲基)乙酰胺的制备
于干燥的反应瓶中加入30mL 1,4-二氧环己烷,3.31g(10mmol)(S)-N-((3-(3-氟-4-溴苯基)-2-氧代噁唑烷-5-基)甲基)乙酰胺,2.54g(10mmol)双戊酰二硼烷,和0.98g(10mmol)醋酸钾,并向其中通入氩气,然后加入0.3g Pd(PPh3)2Cl2,继续向反应液中通入氩气,于90℃搅拌反应过夜。将得到的反应混合物冷却至室温,并用硅藻土过滤,乙酸乙酯和盐水萃取,有机层用无水硫酸钠干燥、浓缩,析出灰色固体,过滤得3.22g产物,收率85.2%。
(2)(S)-N-((3-(3-氟-4-(6-(2-甲基-2H-四氮唑-5-基氨基)吡啶-3-基)苯基)-2-氧代噁唑烷-5-基)甲基)乙酰胺的制备
操作同实施例1(2)。但以(S)-N-((3-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)苯基)-2-氧代噁唑烷-5-基)甲基)乙酰胺替代(R)-3-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)苯基)-5-(羟甲基)噁唑烷-2-酮,产率15%。
分子式:C19H19FN8O3 质谱(m/e):427.2(M+1)
1H NMR:(400MHz,DMSO-d6)δ10.48(s,1H),8.42(s,1H),8.25(t,1H),7.93(d,1H),7.75(d,1H),7.62(m,2H),7.40(d,1H),4.77(m,1H),4.29(s,3H),4.16(t,1H),3.78(m,1H),3.37(t,2H),1.81(s,3H).
实施例3(R)-3-(3-氟-4-(6-((1-甲基-1H-四氮唑-5-基)氨基)吡啶-3 - 基)苯基)-5-(羟甲基)噁唑烷-2-酮(化合物4)的制备
(1)5-溴N-(1-甲基-1H-四氮唑-5-基)吡啶-2-胺的制备
(2)(R)-3-(3-氟-4-(6-((1-甲基-1H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷-2-酮的制备
操作同实施例1(2),但以5-溴-N-(1-甲基-1H-四氮唑-5-基)吡啶-2-胺替代5-溴-N-(2-甲基-2H-四氮唑-5-基)吡啶-2-胺,产率11%。
分子式:C17H16FN7O3 质谱(m/e):386.2(M+1)
1H-NMR(400MHz,DMSO,):δ3.32-3.56(m,1H),3.58-3.71(m,1H),3.85-3.87(m,1H),3.95(S,3H),4.10-4.15(t,1H),4.72-4.74(t,1H),5.23-5.25(t,1H),7.44-7.46(t,1H),7.60-7.66(m,2H),7.81-7.84(d,1H),7.98-8.01(d,1H),8.46(s,1H),10.38(s,1H)
实施例4(R)-(3-(3-氟-4-(6-((1-甲基-1H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-2-氧代噁唑烷-5-基)甲基磷酸酯二钠盐(化合物5)的制备
(1)(R)-(3-(3-氟-4-(6-((1-甲基-1H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-2-氧代噁唑烷-5-基)甲基二氢磷酸酯的制备
将(R)-3-(3-氟-4-(6-((1-甲基-1H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷-2-酮(200mg,0.52mmol)溶于30mL THF中,冰水浴下加入三乙胺(262mg,2.6mmol),半小时后加入三氯氧磷(397mg,2.6mmol),室温下反应12h,滴加水(180mg,10mmol),过滤得产物140mg,产率57%。
(2)(R)-(3-(3-氟-4-(6-((1-甲基-1H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-2-氧代噁唑烷-5-基)甲基磷酸酯二钠盐的制备
将(R)-(3-(3-氟-4-(6-((1-甲基-1H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-2-氧代噁唑烷-5-基)甲基二氢磷酸酯(140mg,0.3mmol)溶于15mL甲醇中,加入甲醇钠(48mg,0.9mmol),室温下反应12h,过滤得产物110mg,产率71.6%。
分子式:C17H15FN7Na2O6P 质谱(m/e):466.0(M+1)
1H-NMR(400MHz,DMSO):δ3.88-3.90(m,1H),3.95(S,3H),4.02-4.09(m,2H),4.19(t,1H),4.93(s,1H),7.43-7.45(d,1H),7.62-7.68(m,2H),7.96-7.98(d,1H),8.13(3,1H),8.23-8.26(d,1H),8.53(d,1H)
实施例5(R)-3-(3-氟-4-(6-(甲基(1-甲基-1H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷-2-酮(化合物6)的制备
(1)5-溴-N-甲基-N-(1-甲基-1H-四氮唑-5-基)吡啶-2-胺的制备
将5-溴-N-(1-甲基-1H-四氮唑-5-基)吡啶-2-胺(1g,3.9mmol)溶于50mL THF中,慢慢加入叔丁醇钾(0.88g,7.8mmol)和碘甲烷(1.1g,7.8mmol),加热到70度反应12h。过滤,浓缩后经硅胶柱(二氯甲烷∶甲醇=100∶1)分离得产物330mg,产率31%。
(2)(R)-3-(3-氟-4-(6-(甲基(1-甲基-1H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷-2-酮的制备
操作同实施例1(2),但以5-溴-N-甲基-N-(1-甲基-1H-四氮唑-5-基)吡啶-2-胺替代5-溴 -N-(2-甲基-2H-四氮唑-5-基)吡啶-2-胺,产率24%。
分子式:C18H18FN7O3 质谱(m/e):400.2(M+1)
1H-NMR(400MHz,DMSO):δ3.45(s,3H),3.57(m,1H),3.66(m,1H),3.76(S,3H),3.84-3.88(t,1H),4.09-4.11(t,1H),4.72-4.73(t,1H),5.22-5.25(t,1H),7.15-7.17(d,1H),7.42-7.45(d,1H),7.56-7.65(m,2H),7.96-7.99(d,1H),8.36(s,1H)
(1)(R)-(3-(3-氟-4-(6-(甲基(1-甲基-1H-四氮唑-5-基)氨基)吡啶-3-基)苯基)噁唑烷-2-酮-5-基)甲基二氢磷酸酯的制备
操作同实施例4(1),但以(R)-3-(3-氟-4-(6-(甲基(1-甲基-1H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷-2-酮替换(R)-3-(3-氟-4-(6-((1-甲基-1H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷-2-酮,产率74%。
(2)(R)-(3-(3-氟-4-(6-(甲基(1-甲基-1H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-2-氧代噁唑烷-5-基)甲基磷酸酯二钠盐的制备
操作同实施例4(2),但以(R)-(3-(3-氟-4-(6-(甲基(1-甲基-1H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-2-氧代噁唑烷-5-基)甲基二氢磷酸酯替换(R)-(3-(3-氟-4-(6-((1-甲基-1H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-2-氧代噁唑烷-5-基)甲基二氢磷酸酯产率61%。
分子式:C18H17FN7Na2O6P 质谱(m/e):480.0(M+1)
1H-NMR(400MHz,DMSO):δ3.47(s,3H),3.75(S,3H),3.85-3.89(t,1H),4.01-4.08(m,2H),4.15-4.20(s,1H),7.15-7.17(d,1H),7.40-7.43(d,1H),7.57-7.63(m,2H),7.96-7.99(d,1H),8.31(s, 1H),8.34(s,1H)
实施例7(R)-3-(3-氟-4-(6-(甲基(2-甲基-2H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷-2-酮(化合物8)的制备
(1)5-溴-N-甲基-N-(2-甲基-2H-四氮唑-5-基)吡啶-2-胺的制备
操作同实施例5(1),但以5-溴-N-(2-甲基-2H-四氮唑-5-基)吡啶-2-胺替代5-溴-N-(1-甲基-1H-四氮唑-5-基)吡啶-2-胺,产率31%。
(2)(R)-3-(3-氟-4-(6-(甲基(2-甲基-2H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷-2-酮的制备
操作同实施例1(2),但以5-溴-N-甲基-N-(2-甲基-2H-四氮唑-5-基)吡啶-2-胺替代5-溴-N-(2-甲基-2H-四氮唑-5-基)吡啶-2-胺,产率27%。
分子式:C18H18FN7O3 质谱(m/e):400.2(M+1)
1H-NMR(400MHz,DMSO):δ3.58(d,1H),3.65(m,4H),3.85-3.88(m,1H),4.1-4.14(t,1H),4.32(s,3H),4.73-4.74(t,1H),5.24(s,1H),7.44-7.46(d,1H),7.59-7.65(m,2H),7.93-8.01(d,2H),8.52(s,1H)
实施例8(R)-(3-(3-氟-4-(6-(甲基(2-甲基-2H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-2-氧代噁唑烷 - 5 - 基)甲基磷酸酯二钠盐(化合物9)的制备
(1)(R)-(3-(3-氟-4-(6-(甲基(2-甲基-2H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-2-氧代噁唑烷-5-基)甲基二氢磷酸酯的制备
操作同实施例4(1),但以(R)-3-(3-氟-4-(6-(甲基(2-甲基-2H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷-2-酮替换(R)-3-(3-氟-4-(6-((1-甲基-1H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷-2-酮,产率67%。
(2)(R)-(3-(3-氟-4-(6-(甲基(2-甲基-2H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-2-氧代噁唑烷-5-基)甲基磷酸酯二钠盐的制备
操作同实施例4(2),但以(R)-(3-(3-氟-4-(6-(甲基(2-甲基-2H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-2-氧代噁唑烷-5-基)甲基二氢磷酸酯替换(R)-(3-(3-氟-4-(6-((1-甲基-1H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-2-氧代噁唑烷-5-基)甲基二氢磷酸酯,产率94%。
分子式:C18H17FN7Na2O6P 质谱(m/e):480.0(M+1)
1H-NMR(400MHz,DMSO):δ3.196(s,3H),3.84-4.02(m,4H),4.19(s,3H),4.84(s,1H),7.08(s,1H),7.21-7.24(d,2H),7.41-7.43(d,1H),7.85-7.861(d,1H),8.13(s,1H)
实施例9(R)-3-(3-氟-4-(6-((1-甲基-1H-吡唑-3-基)氨基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷 - 2 - 酮(化合物10)的制备
(1)5-溴-N-(1-甲基-1H-吡唑-3-基)吡啶-2-胺的制备
操作同实施例1(1),但以1-甲基-1H-吡唑-3-胺替代2-甲基-2H-四氮唑-5-胺,产率9%。
(2)(R)-3-(3-氟-4-(6-(1-甲基-1H-吡唑-3-基)氨基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷-2-酮的制备
操作同实施例1(2),但以5-溴-N-(1-甲基-1H-吡唑-3-基)吡啶-2-胺替代5-溴-N-(2-甲基-2H-四氮唑-5-基)吡啶-2-胺,产率16%。
分子式:C19H18FN5O3 质谱(m/e):384.2(M+1)
1H-NMR(400MHz,DMSO):δ3.573-3.574(m,1H),3.774(m,1H),3.737(s,3H),3.85-3.87(t,1H),4.089-4.11(t,1H),4.72-4.73(m,1H),5.22-5.25(t,1H),6.29-6.30(s,1H),7.31-7.33(d,1H),7.31-7.33(d,1H),7.39-7.72(m,3H),7.72-7.75(d,1H),8.28(s,1H),9.39(s,1H)
实施例10(R)-3-(3-氟-4-(6-((1-甲基-1H-1,2,3-三氮唑-5-基)氨基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷-2-酮(化合物11a)的制备
操作同实施例1(2),但以5-溴-N-(1-甲基-1H-1,2,3-三氮唑-5-基)吡啶-2-胺替代5-溴-N-(2-甲基-2H-四氮唑-5-基)吡啶-2-胺,产率11%。
分子式:C18H17FN6O3 质谱(m/e):385.2(M+1)
1H NMR(DMSO-d6):δ9.86(s,1H),8.36(s,1H),7.91(m,1H),7.78(d,1H),7.57(m,2H),7.42(d,1H),7.10(d,1H),5.24(s,1H),4.73(m,1H),4.21(s,1H),4.08(s,3H),3.86(m,1H),3.67(m,1H),3.57(m,1H)
参照化合物11a的制备方法,还可以制得化合物11。
实施例11(R)-3-(3-氟-4-(6-(( 2 -甲基-2H-1,2,3-三氮唑-4-基)氨基)吡啶3-基)苯基)-5-(羟甲基)噁唑烷-2-酮(化合物12)的制备
(1)5-溴-N-(2-甲基-2H-1,2,3-三氮唑-4-基)吡啶-2-胺的制备
操作同实施例1(1),但以2-甲基-2H-1,2,3-三氮唑-4-胺替代2-甲基-2H-四氮唑-5-胺,产率50%。
操作同实施例1(2),但以5-溴-N-(2-甲基-2H-1,2,3-三氮唑-4-基)吡啶-2-胺替代5-溴-N-(2-甲基-2H-四氮唑-5-基)吡啶-2-胺,产率11%。
分子式:C18H17FN6O3 质谱(m/e):385.2(M+1)
1H NMR(DMSO-d6):δ9.92(s,1H),8.33(s,1H),8.19(m,1H),7.75(d,1H),7.58(m,2H),7.43(t,1H),6.99(d,1H),5.25(s,1H),4.73(m,1H),4.12(s,1H),4.01(s,3H),3.86(m,1H),3.68(m,1H),3.56(m,1H)
实施例123-((3-氟-4-(6-((1H-1,2,3-三氮唑-4-基)氨基)吡啶3-基)-3-氟苯基)-5-(羟甲基)噁唑烷-2-酮(化合物13a)的制备
1)1-(甲氧甲基)-4-硝基-1H-1,2,3-三氮唑的制备
将4-硝基-1H-1,2,3-三氮唑(6.468g,56.707mmol)和碳酸钾(15.683g,113.472mmol)加入150mL丙酮中,冰浴下将氯甲基甲醚(4.74mL,62.407mmol)滴加到上述混合物中,完毕后向反应液中加入水与乙酸乙酯,分液,水相用乙酸乙酯萃取,合并有机相,饱和氯化钠洗,无水硫酸钠干燥,过滤,浓缩,硅胶柱层析(乙酸乙酯∶石油醚=1∶5)得1-(甲氧甲基)-4-硝基-1H-1,2,3-三氮唑,为淡黄色液体5.517g,收率61.5%。
2)1-(甲氧甲基)-4-氨基-1H-1,2,3-三氮唑的制备
将1-(甲氧甲基)-4-硝基-1H-1,2,3-三氮唑(5.517g,34.891mmol)、锌粉(22.697g,349.185mmol)和氯化铵(18.678g,349.187mmol)依次加入到甲醇(100mL)和四氢呋喃(100mL)混合溶剂中,搅拌18小时,抽滤除去不溶物,浓缩得1-(甲氧甲基)-4-氨基-1H-1,2,3-三氮唑,为棕黄色油状物3.56g,收率79.6%。
3)5-溴-N-(1-(甲氧甲基)-1H-1,2,3-三氮唑-4-基)吡啶-2-胺的制备
将1-(甲氧甲基)-4-氨基-1H-1,2,3-三氮唑(3.56g,27.784mmol)、2,5-二溴吡啶(19.608g,82.773mmol)和叔丁醇钾(9.345g,83.252mmol)加入DMF(100mL)中,升温至70℃,搅拌72小时,将反应液倾入水中,然后用乙酸乙酯提取,合并的有机相用饱和氯化钠溶液洗,无水硫酸钠干燥,浓缩,硅胶柱层析(乙酸乙酯∶石油醚=1∶30)分离得5-溴-N-(1-(甲氧甲基)-1H-1,2,3-三氮唑-4-基)吡啶-2-胺为黄色固体0.318g,收率4%。
4)3-(3-氟-4-(6-((1-(甲氧甲基)-1H-1,2,3-三氮唑-4-基)氨基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷啉-2-酮
将5-溴-N-(1-(甲氧甲基)-1H-1,2,3-三氮唑-4-基)吡啶-2-胺(0.318g,1.119mmol)、3-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)-5-(羟甲基)噁唑烷-2-酮(0.852g,2.527mmol)、碳酸钠(0.357g,3.368mmol)、PdCl2(dppf)2(0.064g)加入20mL二氧六环和2滴水中,在氮气保护下回流反应18h,冷却到室温,过滤,浓缩,硅胶柱层析(CH3OH∶CH2Cl2=1∶25),得到3-(3-氟-4-(6-((1-(甲氧甲基)-1H-1,2,3-三氮唑-4-基)氨基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷啉-2-酮粗品0.709g。
5)3-((3-氟-4-(6-((1H-1,2,3-三氮唑-4-基)氨基)吡啶-3-基)-3-氟苯基)-5-(羟甲基)噁唑烷-2-酮的制备
将上步得到的3-(3-氟-4-(6-((1-(甲氧甲基)-1H-1,2,3-三氮唑-4-基)氨基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷-2-酮粗品溶于20mL四氢呋喃中,向溶液中加入6N盐酸20mL和浓盐酸4mL,反应回流18h。浓缩,硅胶柱层析(CH3OH∶CH2Cl2=1∶50),得到淡黄色固体,甲醇重结晶得3-(3-氟-4-(6-((1H-1,2,3-三氮唑-4-基)氨基)吡啶-3-基)-3-氟苯基)-5-(羟甲基)噁唑烷-2-酮70mg,两步收率16.9%。
1H NMR(DMSO-d6)δ:10.10(br.s.,1H),8.36(s,1H),7.96-8.07(m,1H),7.86(m,1H),7.53-7.67(m,1H),7.44(m,1H),7.04-7.18(m,1H),4.73(m,1H),4.12(m,1H),3.87(m,2H),3.68(m,2H)
参照上述化合物13a的制备方法,可以制备化合物13。
实施例13(R)-3-(3-氟-4-(2-((2-甲基-2H-四氮唑-5-基)氨基)噻唑-5-基)苯基)-5-(羟甲基)噁唑烷-2-酮(化合物14)的制备
(1)5-溴-N-(2-甲基-2H-四氮唑-5-基)噻唑-2-胺的制备
操作同实施例1(1),但以2,5-二溴噻唑替代2-氯-5-溴吡啶,产率27%。
(2)5-溴噻唑-2-基(2-甲基-2H-四氮唑-5-基)碳酸叔丁酯的制备
将5-溴-N-(2-甲基-2H-四氮唑-5-基)噻唑-2-胺(0.7g,2.68mmol)和三乙胺(0.8mL,5.72mmol)溶于50mL二氯甲烷中,滴加Boc2O(0.7g,3.2mmol),室温下搅拌12h,加水用乙酸乙酯萃取,无水硫酸钠干燥,浓缩后得产物0.84g,产率97%。
(3)(R)-5-(2-氟-4-(5-(羟甲基)-2-氧代噁唑烷-3-基)苯基)噻唑-2-基(2-甲基-2H-四氮唑-5-基) 碳酸叔丁酯的制备
操作同实施例1(2),但以5-溴噻唑-2-基(2-甲基-2H-四氮唑-5-基)碳酸叔丁酯替代5-溴-N-(2-甲基-2H-四氮唑-5-基)吡啶-2-胺,产率16%。
(4)(R)-3-(3-氟-4-(2-((2-甲基-2H-四氮唑-5-基)氨基)噻唑-5-基)苯基)-5-(羟甲基)噁唑烷-2-酮的制备
将(R)-5-(2-氟-4-(5-(羟甲基)-2-氧代噁唑烷-3-基)苯基)噻唑-2-基(2-甲基-2H-四氮唑-5-基)碳酸叔丁酯(180mg,0.37mmol)溶于30mL二氯甲烷中,加入TFA(0.4mL,5mmol),室温下反应过夜。浓缩后粗产物经硅胶柱纯化(二氯甲烷∶甲醇=20∶1)得(R)-3-(3-氟-4-(2-((2-甲基-2H-四氮唑-5-基)氨基)噻唑-5-基)苯基)-5-(羟甲基)噁唑烷-2-酮50mg。
分子式:C15H14FN7O3S 质谱(m/e):392.2(M+1)
1H NMR(DMSO-d6):δ12.07(s,1H),7.72(m,2H),7.63(m,1H),7.40(d,1H),5.23(s,1H),4.73(m,1H),4.31(s,3H),4.10(t,1H),3.85(t,1H),3.68(m,1H),3.56(m,1H)
实施例14(R)-(3-(3-氟-4-(6-((2-甲基-2H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-2-氧代噁唑烷-5-基)甲基磷酸酯二钠盐(化合物2)的制备
(1)(R)-(3-(3-氟-4-(6-((2-甲基-2H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-2-氧代噁唑烷-5-基)甲基二氢磷酸酯的制备
操作同实施例4(1),但以(R)-3-(3-氟-4-(6-((2-甲基-2H-四氮唑-5-基)氨基)吡啶-3-基)苯 基)-5-(羟甲基)噁唑烷-2-酮替换(R)-3-(3-氟-4-(6-((1-甲基-1H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-5-(羟甲基)噁唑烷-2-酮。
(2)(R)-(3-(3-氟-4-(6-(甲基(2-甲基-2H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-2-氧代噁唑烷-5-基)甲基磷酸酯二钠盐的制备
操作同实施例4(2),但以(R)-(3-(3-氟-4-(6-((2-甲基-2H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-2-氧代噁唑烷-5-基)甲基二氢磷酸酯替换(R)-(3-(3-氟-4-(6-((1-甲基-1H-四氮唑-5-基)氨基)吡啶-3-基)苯基)-2-氧代噁唑烷-5-基)甲基二氢磷酸酯。
分子式:C17H15FN7Na2O6P 质谱(m/e):465.1(M+1)
1H-NMR(400MHz,DMSO):δ7.98(s,1H),7.51(d,1H),7.06-7.17(m,2H),6.96-7.00(m,2H),4.75-4.82(m,1H),4.12(s,3H),3.81-3.96(m,4H)。
Claims (12)
1.通式(I)所示的化合物、其药学上可接受的盐、其异构体或其前药,
其中,
R1选自(1)-OR6,(2)-NR6R6’,(3)-COR6,(4)--COOR6,(5)-OCOR6,(6)-CONR6R6’,(7)-NR6COR6’,(8)-OCONR6R6’,(9)-NR6COOR6’,(10)-NR6CONR6’R6,(11)-CSR6,(12)-CSOR6,(13)-OCSR6,(14)-CSNR6R6’,(15)-NR6CSR6’,(16)-OCSNR6R6’,(17)-NR6CSOR6’,(18)-NR6CSNR6’R6,(19)-NR6C(NR6)NR6’R6,(20)-S(O)pR6,(21)-SO2NR6R6’,或(22)R6,
p为0,1或2,
R6、R6’选自:(1)氢,(2)C1-6烷基,(3)C2-6烯基,(4)C2-6炔基,(5)3-14元的环烷基,(6)6-14元的芳基,(7)3-14元的杂环基,包含一个或多个选自N、S、O和/或SO2的杂原子,(8)-COC1-6烷基,(9)-COC2-6烯基,或(10)-COC2-6炔基;
R2、R3独立地选自氢,卤素或C1-6烷基;
R4选自:(1)氢,(2)C1-6烷基,(3)C2-6烯基,(4)C2-6炔基,(5)3-14元环烷基,(6)6-14元芳基,(7)3-14元杂环基,包含一个或多个选自N、S、O和/或SO2的杂原子,(8)-COC1-6烷基,(9)-COC2-6烯基,或(10)-COC2-6炔基;
R5选自未被取代的或被1-3个R7取代的以下基团:
(1)3-14元环烷基,
(2)6-14元芳基,
(3)3-14元杂环基,或
(4)5-14元杂芳基,
R7选自卤素、羧基、羟基、氨基、氰基、硝基、C1-6烷基、羧基C1-6烷基、羟基C1-6烷 基、氨基C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氧基C1-6烷基、C1-6烷基氨基、二(C1-6烷基)氨基、二(C1-6烷基)氨基C1-6烷基、C1-6烷基羰基、C1-6烷基羰基氧基、C1-6烷氧基羰基、氨基甲酰基、氨基甲酰基C1-6烷基、C1-6烷基氨基甲酰基、二(C1-6烷基)氨基甲酰基、氨基磺酰基、氨基磺酰基C1-6烷基、C1-6烷基氨基磺酰基、二(C1-6烷基)氨基磺酰基、C1-6烷基磺酰氨基、C1-6烷基磺酰基、C1-6烷基羰基氨基或胍基。
3.如权利要求1或2任一项所述的化合物、其药学上可接受的盐、其异构体或其前药,
其中,
R2、R3独立的选自氢或卤素;
X、Y分别独立地为C原子或N原子;
R4选自:(1)氢,(2)C1-4烷基,(3)C2-4烯基,(4)C2-4炔基,(5)-C(O)C1-4烷基,(6)-C(O)C2-4烯基,或(7)-C(O)C2-4炔基;
R5选自未被取代的或被1-3个R7取代的5-14元杂芳基,该5-14元杂芳基包含一个或多个选自N、S、O和/或SO2的杂原子,
R7选自卤素、羧基、羟基、氨基、氰基、硝基、C1-4烷基、羧基C1-4烷基、羟基C1-4烷基、氨基C1-4烷基、卤代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基、C1-4烷氧基C1-4烷基、C1-4烷基氨基、二(C1-4烷基)氨基、二(C1-4烷基)氨基C1-4烷基、C1-4烷基羰基、C1-4烷基羰基氧基、C1-4烷氧基羰基、氨基甲酰基、氨基甲酰基C1-4烷基、C1-4烷基氨基甲酰基、二(C1-4烷基)氨基甲酰基、氨基磺酰基、氨基磺酰基C1-4烷基、C1-4烷基氨基磺酰基、二(C1-4烷基)氨基磺酰基、C1-4烷基磺酰氨基、C1-4烷基磺酰基、C1-4烷基羰基氨基或胍基。
4.如权利要求3所述的化合物、其药学上可接受的盐、其异构体或其前药,
其中,
R1选自-NHCOCH3或-OH;
R2、R3独立地选自氢或卤素;
X、Y分别独立地为C原子或N原子;
R4选自氢或C1-4烷基;
R5选自未被取代的或被1-3个R7取代的5-8元单杂芳基,该5-8元单杂芳基包含一个或多个选自N、S、O和/或SO2的杂原子,
R7选自C1-4烷基或卤代C1-4烷基。
5.如权利要求4所述的化合物、其药学上可接受的盐、其异构体或其前药,
其中,
R1选自-NHCOCH3或-OH;
R2为氢;
R3为氟;
R4为氢;
X为C原子;
Y为N原子;
R5选自未被取代的或被1-2个R7取代的5-6元单杂芳基,该5-6元单杂芳基包含一个或多个选自N、S或O的杂原子,
R7选自C1-4烷基或卤代C1-4烷基。
6.如权利要求5所述的化合物、其药学上可接受的盐、其异构体或其前药,
其中,
R5选自未被取代的或被1-2个R7取代的吡咯基、呋喃基、咪唑基、1,2,4-三唑基、1,2,3-三唑基、吡唑基、噁唑基、异噁唑基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、吡啶基、嘧啶基、噻唑基、异噻唑基、1,2,3,4-四唑基、吡喃基或吡嗪基,
R7为C1-4烷基。
10.一种药物组合物,包含权利要求1-9任一权利要求所述的化合物、其药学上可接受的盐、其异构体或其前药和一种或多种药用载体和/或稀释剂。
11.一种药物制剂,包含权利要求1-9任一项所述的化合物、其药学上可接受的盐、其异构体或其前药和一种或多种药用载体和/或稀释剂,可以制成临床上或药学上可接受的任一剂型。
12.如权利要求1-9任一权利要求所述的化合物、其药学上可接受的盐、其异构体或其前药在制备治疗和/或预防感染性疾病的药物方面的应用。
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CN104496979A (zh) * | 2014-09-17 | 2015-04-08 | 博瑞生物医药技术(苏州)有限公司 | 一种噁唑烷酮类化合物及其中间体的制备方法 |
CN105524008B (zh) * | 2014-10-21 | 2018-09-07 | 山东轩竹医药科技有限公司 | 噁唑烷酮抗菌药中间体的制备方法 |
US20230219941A1 (en) | 2020-06-18 | 2023-07-13 | Akagera Medicines, Inc. | Oxazolidinone compounds, liposome compositions comprising oxazolidinone compounds and methods of use thereof |
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Effective date of registration: 20190702 Address after: 101113 Room 301, Building 3, East of Qishanzhuang Village, Zhangjiawan Town, Tongzhou District, Beijing (in Beijing Sihuan Pharmaceutical Co., Ltd.) Patentee after: Beijing Aohe Pharmaceutical Research Institute Co., Ltd. Address before: 250101 No. 2518 Tianchen Street, Jinan High-tech Development Zone, Shandong Province Patentee before: Shandong Xuanzhu Medical Technology Co., Ltd. |