CN1419450A - 抗微生物药物的硝酸盐 - Google Patents
抗微生物药物的硝酸盐 Download PDFInfo
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- CN1419450A CN1419450A CN01807154A CN01807154A CN1419450A CN 1419450 A CN1419450 A CN 1419450A CN 01807154 A CN01807154 A CN 01807154A CN 01807154 A CN01807154 A CN 01807154A CN 1419450 A CN1419450 A CN 1419450A
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- 239000004599 antimicrobial Substances 0.000 title claims abstract description 15
- 150000002826 nitrites Chemical class 0.000 title 1
- 239000003814 drug Substances 0.000 claims abstract description 35
- 150000002823 nitrates Chemical class 0.000 claims abstract description 31
- 238000002360 preparation method Methods 0.000 claims abstract description 28
- 230000000845 anti-microbial effect Effects 0.000 claims abstract description 18
- 230000000843 anti-fungal effect Effects 0.000 claims abstract description 6
- 230000000840 anti-viral effect Effects 0.000 claims abstract description 6
- 229940121375 antifungal agent Drugs 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 551
- -1 4-fluorophenyl Chemical group 0.000 claims description 320
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 87
- 125000003277 amino group Chemical group 0.000 claims description 80
- 229910052757 nitrogen Inorganic materials 0.000 claims description 63
- 229910052727 yttrium Inorganic materials 0.000 claims description 56
- 229910002651 NO3 Inorganic materials 0.000 claims description 49
- 239000000203 mixture Substances 0.000 claims description 46
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 33
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical class O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 30
- 229910052799 carbon Inorganic materials 0.000 claims description 29
- 125000001424 substituent group Chemical group 0.000 claims description 29
- 229940079593 drug Drugs 0.000 claims description 28
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 claims description 23
- 150000003254 radicals Chemical class 0.000 claims description 21
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 16
- 229960003276 erythromycin Drugs 0.000 claims description 16
- 229960005404 sulfamethoxazole Drugs 0.000 claims description 15
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 claims description 15
- 229960000723 ampicillin Drugs 0.000 claims description 14
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 14
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical class CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 claims description 13
- 229960004150 aciclovir Drugs 0.000 claims description 12
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 claims description 12
- 125000001893 nitrooxy group Chemical class [O-][N+](=O)O* 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- 229960003405 ciprofloxacin Drugs 0.000 claims description 11
- 229960000282 metronidazole Drugs 0.000 claims description 11
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 229960001139 cefazolin Drugs 0.000 claims description 10
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 claims description 10
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 claims description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 125000000524 functional group Chemical group 0.000 claims description 9
- 229960005206 pyrazinamide Drugs 0.000 claims description 9
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical class NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 claims description 9
- 229960005322 streptomycin Drugs 0.000 claims description 9
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 claims description 9
- 229960001082 trimethoprim Drugs 0.000 claims description 9
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 8
- 229940106164 cephalexin Drugs 0.000 claims description 8
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 claims description 8
- 229960003350 isoniazid Drugs 0.000 claims description 8
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical class NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- 229960003022 amoxicillin Drugs 0.000 claims description 7
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 claims description 7
- HMFHBZSHGGEWLO-TXICZTDVSA-N beta-D-ribose Chemical group OC[C@H]1O[C@@H](O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-TXICZTDVSA-N 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 229960002626 clarithromycin Drugs 0.000 claims description 7
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 claims description 7
- 229960002227 clindamycin Drugs 0.000 claims description 7
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 claims description 7
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 claims description 7
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 claims description 6
- 239000004098 Tetracycline Substances 0.000 claims description 6
- 229960005361 cefaclor Drugs 0.000 claims description 6
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 claims description 6
- 229960003722 doxycycline Drugs 0.000 claims description 6
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims description 6
- 229960000268 spectinomycin Drugs 0.000 claims description 6
- UNFWWIHTNXNPBV-WXKVUWSESA-N spectinomycin Chemical compound O([C@@H]1[C@@H](NC)[C@@H](O)[C@H]([C@@H]([C@H]1O1)O)NC)[C@]2(O)[C@H]1O[C@H](C)CC2=O UNFWWIHTNXNPBV-WXKVUWSESA-N 0.000 claims description 6
- 229960002180 tetracycline Drugs 0.000 claims description 6
- 229930101283 tetracycline Natural products 0.000 claims description 6
- 235000019364 tetracycline Nutrition 0.000 claims description 6
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 6
- 239000003242 anti bacterial agent Substances 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 claims description 4
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000004475 Arginine Substances 0.000 claims description 4
- MQJKPEGWNLWLTK-UHFFFAOYSA-N Dapsone Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=C1 MQJKPEGWNLWLTK-UHFFFAOYSA-N 0.000 claims description 4
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 claims description 4
- 229930010555 Inosine Natural products 0.000 claims description 4
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 claims description 4
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 claims description 4
- 229930193140 Neomycin Natural products 0.000 claims description 4
- 239000004100 Oxytetracycline Substances 0.000 claims description 4
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 claims description 4
- HDOVUKNUBWVHOX-QMMMGPOBSA-N Valacyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCOC(=O)[C@@H](N)C(C)C)C=N2 HDOVUKNUBWVHOX-QMMMGPOBSA-N 0.000 claims description 4
- 229960003805 amantadine Drugs 0.000 claims description 4
- 229960004821 amikacin Drugs 0.000 claims description 4
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 claims description 4
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 229960004099 azithromycin Drugs 0.000 claims description 4
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 claims description 4
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 claims description 4
- 229960003644 aztreonam Drugs 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 229960003012 cefamandole Drugs 0.000 claims description 4
- OLVCFLKTBJRLHI-AXAPSJFSSA-N cefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](O)C=3C=CC=CC=3)[C@H]2SC1 OLVCFLKTBJRLHI-AXAPSJFSSA-N 0.000 claims description 4
- 229960002129 cefixime Drugs 0.000 claims description 4
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 claims description 4
- 229960001958 cefodizime Drugs 0.000 claims description 4
- XDZKBRJLTGRPSS-BGZQYGJUSA-N cefodizime Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(C)=C(CC(O)=O)S1 XDZKBRJLTGRPSS-BGZQYGJUSA-N 0.000 claims description 4
- LTINZAODLRIQIX-FBXRGJNPSA-N cefpodoxime proxetil Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(=O)OC(C)OC(=O)OC(C)C)C(=O)C(=N/OC)\C1=CSC(N)=N1 LTINZAODLRIQIX-FBXRGJNPSA-N 0.000 claims description 4
- 229960004797 cefpodoxime proxetil Drugs 0.000 claims description 4
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 229960000860 dapsone Drugs 0.000 claims description 4
- 229960002656 didanosine Drugs 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
- 229960000285 ethambutol Drugs 0.000 claims description 4
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 claims description 4
- 229960002001 ethionamide Drugs 0.000 claims description 4
- 229960004396 famciclovir Drugs 0.000 claims description 4
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 claims description 4
- 239000003574 free electron Substances 0.000 claims description 4
- 229960002182 imipenem Drugs 0.000 claims description 4
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 claims description 4
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- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 claims description 4
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- 239000002777 nucleoside Substances 0.000 claims description 4
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- IWVCMVBTMGNXQD-PXOLEDIWSA-N oxytetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-PXOLEDIWSA-N 0.000 claims description 4
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- 125000006678 phenoxycarbonyl group Chemical group 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 4
- 229960001225 rifampicin Drugs 0.000 claims description 4
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 claims description 4
- SKIVFJLNDNKQPD-UHFFFAOYSA-N sulfacetamide Chemical compound CC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 SKIVFJLNDNKQPD-UHFFFAOYSA-N 0.000 claims description 4
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- GPTONYMQFTZPKC-UHFFFAOYSA-N sulfamethoxydiazine Chemical compound N1=CC(OC)=CN=C1NS(=O)(=O)C1=CC=C(N)C=C1 GPTONYMQFTZPKC-UHFFFAOYSA-N 0.000 claims description 4
- 229960002229 sulfametoxydiazine Drugs 0.000 claims description 4
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 claims description 4
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
- C07C237/26—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton of a ring being part of a condensed ring system formed by at least four rings, e.g. tetracycline
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
- C07D215/32—Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/91—Nitro radicals
- C07D233/92—Nitro radicals attached in position 4 or 5
- C07D233/94—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to other ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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Abstract
抗微生物药物的硝酸盐用于制备抗微生物药物,具体为抗病毒、抗真菌和抗细菌药物。
Description
本发明涉及在抗微生物疗法中全身性使用和非全身性使用的化合物或它们的药用组合物。
已知在感染治疗中抗微生物药物的广泛使用已引起对这些药物,例如抗病毒药、抗真菌药和抗细菌药具有抗性的毒株的产生。
当微生物形成抗微生物疗法对其无效的生长和繁殖机制时,或者当微生物产生能够中和药物的酶时,通常出现这种抗性。然后,抗性微生物株能够繁殖,引起疾病延长和恶化,伴随感染可能在公众中扩散。这个事实,正如所知道的,在社会-经济和环境卫生水平下能够决定值得注意的后果。
解决该问题的一种方法是增加抗微生物药物的剂量。在这方面,存在增加的局部和全身性副作用发生率的缺陷。除此以外,由于病原与非病原微生物菌群之间失去平衡,衍生于抗微生物药物本身的微生物重复感染的事件经常发生。人们熟知抗微生物药物必须作用于引起疾病过程的病原体,而不改变对有机体有用的非病原微生物。
一种广泛用于解决微生物抗性和/或药物-抗性株扩散的问题的方法已经引入到用作抗微生物药物的治疗新分子中。迄今所得结果并不令人满意。
因此,需要不仅对微生物有活性而且预防和/或减少微生物抗性的药物,从而使之成为完全和有效抗微生物的疗法,所述药物在避免毒副作用的常规最小剂量下是有效的。所述毒副作用包括例如皮疹和对胃、肝和肾的副作用。
申请人令人惊奇和意外地发现:通过使用显示能够有效与微生物相互作用并能够预防或降低微生物抗性的化合物可以解决以上技术问题。
本发明的一个目的是抗微生物药物的硝酸盐或它们的药用组合物在制备用于治疗感染性疾病的药物中的用途。本发明优先涉及抗病毒、抗真菌和抗细菌药物的硝酸盐或它们的药用组合物的用途;用于制备本发明的硝酸盐的抗微生物药物必须满足以下试验:在造成单一病理变化的具体病原微生物的培养基中,在抗微生物药物有效且在哺乳动物细胞内不产生细胞毒性的浓度下接种抗微生物药物。
参见例如在抗菌药的实施例中报道的培养基中的体外稀释试验。
更具体地说,本发明涉及化合物的硝酸盐或它们的药用组合物在制备作为抗微生物药物用来治疗感染性疾病的药物中的用途,所述化合物优先选自以下类型:类型I)其中:R1=H、Cl或二甲基氨基,R2=H、OH或自由价,R3=H、CH3,当R2为具有C-R3键的电子对的自由价时,它形成双键且R3为亚甲基,R4=H、OH,R5=H、CH2OH或以下取代基中的一个:类型II)其中:X和Y彼此不同,为C或N,R6=环丙基、C2H5、4-氟代苯基、2,4-二氟代苯基、2-氟代乙基,R7=H、氨基、CH3,R8=H或F,当Y=N时,R8为自由价且其为在氮原子上的自由电子对,R9=H、CH3或以下取代基中的一个:其中M=H、CH3、C2H5、OH,其中T1为H、OH,R8和R9一起形成具有下式的二价基团:-O-CH2-O- (IIP),R10=H、Cl、F,当X=N时,R10为自由价且其为在氮原子上的自由电子对,R6和R10一起形成以下二价基团:当式(II)中的X=N时,R10为自由价且其与氮相邻的碳原子形成双键;类型IIIa):其中:Z=S、C,R11=H、式(IIIaF)的新戊酰氧基亚甲基,其中T2为叔丁基,R12=Cl、CH3、式(IIIaF)的乙酰氧基亚甲基,其中T2为CH3、2-丙烯基或以下取代基中的一个:R13=氨基、OH或取代基(IIIaD):R14为苯基、4-羟基苯基或基团(IIIaE);类型IIIb):其中:X=CH、N,Y=C、N,R15=COOH、COO-、(CH3)3CCOOCH2OCO-或(CH3)2CHOCOOCH(CH3)OCO-,R16=H、CH3、C2H5、-CH=CH2、NH2COOCH2-、CH3COOCH2-、或以下取代基中的一个: 当R15为羧酸根阴离子时,R16为选自以下的基团:(IIIbL)、(IIIbM)或(IIIbN)R17=OH、OCH3、C2H5、-OCH2COOH、-CH2COOH;类型IIIc):其中:R18为以下取代基中的一个: R19=H、CH3COOCH2-或以下基团中的一个:类型IVa):其中:R20为以下取代基中的一个: R21=H、具有T2=叔丁基的基团(IIIaF)、CH(CH3)OCOOC2H5或以下取代基中的一个:-CH2CH2N(CH2CH3)2.HI(IVaR),类型IVb)其中:R22=H、CH3,R23选自以下基团:
-CH2CH2NHCH=NH(IVbD),类型IVc)其中:R33、R34、R36,彼此相同或不同,为H、CH3;R35=H、-CH2OCONH2,类型V)其中R24=H、Br、OCH3、CH3OCH2CH2O-;类型VI)其中:R25为以下取代基中的一个:类型VII)其中R26=H、或以下取代基中的一个:苯甲酰基、乙酰基、3-甲基-2-丁烯酰基、氨基甲酰基、氨基硫代NH2C(S)-、2-吡啶基、吡嗪基、2-嘧啶基、2-噻唑基、水杨酰-4-基、6-氯-哒嗪-3-基、1-乙基-1,2-二氢-2-氧代-嘧啶-4-基、5,6-二甲氧基-嘧啶-4-基、2,6-二甲氧基-嘧啶-4-基、4-甲基-嘧啶-2-基、5-甲氧基-嘧啶-2-基、4,6-二甲基-嘧啶-2-基、6-甲氧基-2-甲基-嘧啶-4-基、5-甲基-嘧啶-2-基、2,6-二甲基-嘧啶-4-基、3-甲氧基-吡嗪-2-基、6-甲氧基-哒嗪-3-基、4,6-二乙基-1,3,5-三嗪-2-基、5-乙基-1,3,4-噻二唑-2-基、5-甲基-1,3,4-噻二唑-2-基、4-甲氧基-1,2,5-噻二唑-3-基、4-甲基-噻唑-2-基、3-甲基-异噻唑-5-基、4,5-二甲基-噁唑-2-基、3,4-二甲基-异噁唑-5-基、4,5-二甲基-2-噁唑基氨基亚氨基甲基、5-甲基-异噁唑-3-基、1-苯基-1H-吡唑-5-基、4-甲基氨基磺酰基苯基、4-氨基磺酰基苯基、3,4-二甲基苯甲酰基、4-异丙氧基苯甲酰基;类型VIII)其中:R27=H、4,6-二甲基-嘧啶-2-基;R28=2,4-二氨基-6-羧基苯基、2,4-二氨基苯基、3-羧基-4-羟基苯基;类型IX)其中:R29=H、OH,R30=COOH、苯氧基羰基、4-(氨基)苯基亚硫酰基、肼基羰基;类型X)其中:R31=氨基、NH2-CH2-、苄基氨基,R32=氨基、4-(羟基乙基氨基)苯基、-N=C(NH2)2、4-(氨基)苯基、4-(氨基甲基)苯基、4-(羧基甲基氨基)苯基、4-(羧基丙酰基氨基)苯基、2-氨基-噻唑-5-基;类型XI)其中:M=O、S,R52=H、C2H5、C3H7,R53=氨基、-NHNH2、或以下取代基中的一个:类型XII)其中:R37=Cl、OH;类型XIIIa)其中:R38=H、乙酰基、COC2H5(丙酰基),R39=H、丙酰基、COC3H7(丁酰基)、COCH2CH(CH3)2(异戊酰基),R40=H、丙酰基,R41=H,或:类型XIIIb)其中:R47=H、CH3,W=CO(羰基)、-N(CH3)CH2-,R48=H,或R48与W一起形成二价基团:类型XIVa)其中:R42=OH、氨基,R43=H、(R)-4-氨基-2-羟基丁酰基、(S)-4-氨基-2-羟基丁酰基,R44=H、OH,R45=H、OH,类型XIVb)其中:R46=-CH2OH;-CHO类型XIVc)其中:R49=CH3、C4H9;类型XIVd)其中:R50=H、C2H5,R51=3-氨基-6-(氨基甲基)-3,4-二氢-2H-吡喃-2-基:类型XIVe)其中:R60=OH、氨基,R61=H或以下取代基中的一个:类型XV)其中R54=CH3、环戊基;类型XVIa)其中:Xb=N、C,R55=H、氨基,R56=H、OH、氨基,R57为β-D-呋喃核糖基或4-乙酰氧基-3-(乙酰氧基甲基)1-丁基类型XVIb)其中:R58=H、氨基,R59=CH2OCH2CH2OH、CH2OCH(CH2OH)CH2OH、CH2OCH2CH2OCOCH(NH2)CH(CH3)2、β-D-(2,3-二脱氧)呋喃核糖基;类型XVII):以下化合物:O-2-氨基-2-脱氧-α-D-吡喃型葡萄糖基-(1→4)-O-[3-脱氧-3-(甲基氨基)-α-D-吡喃木糖基-(1→6)]-2-脱氧-D-链霉胺(庆大霉素A),1-(2-羟基乙基)-2-甲基-5-硝基咪唑(甲硝唑),(S)-2-氨基-5-[(氨基亚氨基甲基)氨基]戊酸(精氨酸),(+)-2,2’-(亚乙基二亚氨基)二-1-丁醇(乙胺丁醇),1-氨基金刚烷(金刚烷胺),2’,3’-二脱氧胞嘧啶核苷(扎西他滨),吡嗪酰胺、吗甲吡嗪酰胺、磺胺乙酰甲氧吡嗪、氯法齐明、环丝氨酸、链异烟肼、脱氧二氢链霉素、米卡霉素、罗沙米星、卡波霉素、阿来西定、安巴腙、氯羟喹、负霉素、硝羟喹啉、泊非霉素、牛黄罗定、替贝碘铵、安普霉素、替考拉宁、万古霉素、噻苯达唑、甲苯达唑、阿苯达唑、氯甲氧吖胺、茴香霉素、地美硝唑、二脒那秦、醋甘氨酸盐、依氟鸟氨酸、卤夫酮、胡米铵、羟茋巴脒、咪多卡、异丙硝唑、月桂胍、尼莫唑、氧芬胂、喷他脒、氧二苯脒、普罗帕脒、嘌罗霉素、乙胺嘧啶、米帕林、喹匹拉明、Quintine、塞克硝唑、司替巴脒(stilbamidine)、替硝唑。
在类型I中:
当R1=H,R2=OH,R3=CH3,R4=H,R5=(IA)时,化合物称作阿哌环素,
当R1=Cl,R2=OH,R3=CH3,R4=H,R5=H时,化合物称作金霉素,
当R1=Cl,R2=OH,R3=CH3,R4=H,R5=CH2OH时,化合物称作氯莫环素,
当R1=Cl,R2=OH,R3=H,R4=H,R5=H时,化合物称作地美环素,
当R1=H,R2=H,R3=CH3,R4=OH,R5=H时,化合物称作多西环素,
当R1=H,R2=OH,R3=CH3,R4=H,R5=(IB)时,化合物称作胍甲环素,
当R1=H,R2=OH,R3=CH3,R4=H,R5=(ID)时,化合物称作赖甲环素,
当R1=Cl,R2=自由价并具有形成双键的C-R3键的电子对,且R3为亚甲基,R4=OH,R5=H时,化合物称作甲氯环素,
当R1=H,R2=自由价并具有形成双键的C-R3键的电子对,且R3为亚甲基,R4=OH,R5=H时,化合物称作美他环素,
当R1=二甲基氨基,R2=H,R3=H,R4=H,R5=H时,化合物称作米诺环素,
当R1=H,R2=OH,R3=H,R4=OH,R5=H时,化合物称作土霉素,
当R1=H,R2=OH,R3=CH3,R4=H,R5=(IC)时,化合物称作匹哌环素,
当R1=H,R2=OH,R3=CH3,R4=H,R5=H时,化合物称作四环素,
当R1=H,R2=H,R3=H,R4=H,R5=H时,化合物称作山环素。
在类型II中:
当R6=环丙基,R7=H,R8=F,R9=(IIA),伴随M=H,R10=H,X=Y=C时,化合物称作环丙沙星,
当R6=环丙基,R7=H,R8=F,R9=(IIF),R10=Cl,X=Y=C时,化合物称作克林沙星,
当R6=4-氟苯基,R7=H,R8=F,R9=(IID),R10=H,X=Y=C时,化合物称作二氟沙星,
当R6=C2H5,R7=H,R8=F,R9=(IIA),伴随M=H,R10=自由价,X=N,Y=C时,化合物称作依诺沙星,
当R6=环丙基,R7=H,R8=F,R9=(IIA),伴随M=C2H5,R10=H,X=Y=C时,化合物称作恩氟沙星,
当R6=氟代乙基,R7=H,R8=F,R9=(IIA),伴随M=CH3,R10=F,X=Y=C时,化合物称作氟罗沙星,
当R6与R10形成二价基团(IIM),R7=H,R8=F,R9=H,X=Y=C时,化合物称作氟甲喹,
当R6=环丙基,R7=CH3,R8=F,R9=(IIB),R10=H,X=Y=C时,化合物称作格帕沙星,
当R6=乙基,R7=H,R8=F,R9=(IIB),R10=F,X=Y=C时,化合物称作洛美沙星,
当R6与R10形成二价基团(IIM),R7=H,R8=F,R9=(IIE),伴随T1=OH,X=Y=C时,化合物称作那氟沙星,
当R6=C2H5,R7=H,R8=H,R9=CH3,R10=自由价,X=N,Y=C时,化合物称作萘啶酸,
当R6=C2H5,R7=H,R8=F,R9=(IIA),伴随M=H,R10=H,X=Y=C时,化合物称作诺氟沙星,
当R6与R10形成二价基团(IIN),R7=H,R8=F,R9=(IIA),伴随M=CH3,X=Y=C时,化合物称作氧氟沙星,
当R6=C2H5,R7=H,R8与R9形成二价基团(IIP),R10=H,X=Y=C时,化合物称作奥索利酸,
当R6与R10形成二价基团(IIO),R7=H,R8=F,R9=(IIH),X=Y=C时,化合物称作Pazufloxacin,
当R6=乙基,R7=H,R8=F,R9=(IIA),伴随M=CH3,R10=H,X=Y=C时,化合物称作培氟沙星,
当R6=C2H5,R7=H,R8=自由价,R9=(IIA),伴随M=H,R10=自由价,X=Y=N时,化合物称作吡哌酸,
当R6=C2H5,R7=H,R8=自由价,R9=(IIE),伴随T1=H,R10=自由价,X=Y=N时,化合物称作吡咯米酸,
当R6与R10形成二价基团(IIQ),R7=H,R8=F,R9=(IIA),伴随M=CH3,X=Y=C时,化合物称作芦氟沙星,
当R6=环丙基,R7=氨基,R8=F,R9=(IIC),R10=F,X=Y=C时,化合物称作司氟沙星,
当R6=2,4-二氟苯基,R7=H,R8=F,R9=(IIF),R10=自由价,X=N,Y=C时,化合物称作托氟沙星,
当R6=2,4-二氟苯基,R7=H,R8=F,R9=(IIG),R10=自由价,X=N,Y=C时,化合物称作曲沃沙星(Trovafloxacin),
当R6=环丙基,R7=H,R8=F,R9=(IID),R10=H,X=Y=C时,化合物称作达氟沙星,
当R6=4-氟苯基,R7=H,R8=F,R9=(IIA),伴随M=H,R10=H,X=Y=C时,化合物称作沙氟沙星。
在类型IIIa中:
当R11=H,R12=Cl,R13=氨基,R14=苯基,Z=S时,化合物称作头孢克洛,
当R11=H,R12=CH3,R13=氨基,R14=4-羟基苯基,Z=S时,化合物称作Cefafroxil,
当R11=H,R12=(IIIaB),R13=氨基,R14=4-羟基苯基,Z=S时,化合物称作头孢曲秦,
当R11=H,R12=(IIIaC),R13=(IIIaD),R14=4-羟基苯基,Z=S时,化合物称作头孢匹胺,
当R11=H,R12=2-丙烯基,R13=氨基,R14=4-羟基苯基,Z=S时,化合物称作头孢丙烯,
当R11=H,R12=CH3,R13=氨基,R14=(IIIaE),Z=S时,化合物称作头孢沙定,
当R11=H,R12=CH3,R13=氨基,R14=苯基,Z=S时,化合物称作头孢氨苄,
当R11=H,R12=CH3,R13=(IIIaF),伴随T2=CH3,R14=苯基,Z=S时,化合物称作头孢来星,
当R11=H,R12=CH3,R13=氨基,R14=(IIIaE),Z=S时,化合物称作Cephadrine,
当R11=H,R12=Cl,R13=氨基,R14=苯基,Z=C时,化合物称作氯碳头孢,
当R11=(IIIaF),伴随T2=叔丁基,R12=CH3,R13=氨基,R14=苯基,Z=S时,化合物称作Pivcefalexin,
当R11=H,R12=(IIIaC),R13=OH,R14=苯基,Z=S时,化合物称作头孢孟多。
在类型IIIb中:
当R15=(CH3)3CCOOCH2OCO-,R16=NH2COOCH2-,R17=C2H5,X=CH,Y=C时,化合物称作头孢卡品pivoxil,
当R15=COO-,R16=(IIIbL),R17=甲氧基,X=Y=N时,化合物称作头孢克定,
当R15=COOH,R16=-CH=CH2,R17=OH,X=N,Y=C时,化合物称作头孢地尼,
当R15=COOH,R16=(IIIbA),R17=OCH3,X=N,Y=C时,化合物称作头孢托仑,
当R15=COO-,R16=(IIIbM),R17=OCH3,X=N,Y=C时,化合物称作头孢吡肟,
当R15=COOH,R16=CH3,R17=OCH3,X=N,Y=C时,化合物称作头孢他美,
当R15=COOH,R16=-CH=CH2,R17=-OCH2OCOOH,X=N,Y=C时,化合物称作头孢克肟,
当R15=COOH,R16=(IIIbC),R17=OCH3,X=N,Y=C时,化合物称作头孢甲肟,
当R15=COO-,R16=(IIIbN),R17=OCH3,X=Y=N时,化合物称作头孢唑兰,
当R15=(CH3)2CHOCOOCH(CH3)OCO-,R16=C2H5,R17=OCH3,X=N,Y=C时,化合物称作头孢泊肟丙酯,
当R15=COOH,R16=(IIIbD),R17=OCH3,X=N,Y=C时,化合物称作头孢特仑,
当R15=COOH,R16=H,R17=-CH2COOH,X=CH,Y=C时,化合物称作头孢布烯,
当R15=COOH,R16=(IIIbH),R17=OCH3,X=N,Y=C时,化合物称作头孢曲松,
当R15=COOH,R16=(IIIbE),R17=OCH3,X=N,Y=C时,化合物称作头孢唑南,
当R15=COOH,R16=(IIIbF),R17=OCH3,X=N,Y=C时,化合物称作头孢地秦,
当R15=COOH,R16=CH3COOCH2-,R17=OCH3,X=N,Y=C时,化合物称作头孢噻肟,
当R15=COOH,R16=(IIIbG),R17=OCH3,X=N,Y=C时,化合物称作头孢噻呋。
在类型IIIc中:
当R18=(IIIcD),R19=(IIIcH)时,化合物称作头孢替安,
当R18=(IIIcE),R19=H时,化合物称作头孢唑肟,
当R18=(IIIcF),R19=(IIIcN)时,化合物称作头孢唑林,
当R18=(IIIcG),R19=(IIIcM)时,化合物称作头孢雷特,
当R18=(IIIcA),R19=(IIIcL)时,化合物称作头孢米诺,
当R18=(IIIcB),R19=CH3COOCH2-时,化合物称作头孢菌素C。
在类型IVa中:
当R20=(IVaF)和R21=H时,化合物称作美西林,
当R20=(IVaF)和R21=(IIIaF),伴随T2=叔丁基时,化合物称作美西林pivoxil,
当R20=(IVaA)和R21=H时,化合物称作阿莫西林,
当R20=(IVaB)和R21=H时,化合物称作氨苄西林,
当R20=(IVaM)和R21=H时,化合物称作阿帕西林,
当R20=(IVaG)和R21=H时,化合物称作阿扑西林,
当R20=(IVaB)和R21=-CH(CH3)OCOOC2H5时,化合物称作巴氨西林,
当R20=(IVaE)和R21=H时,化合物称作氨环己青霉素,
当R20=(IVaC)和R21=H时,化合物称作依匹西林,
当R20=(IVaC)和R21=H时,化合物称作海他西林,
当R20=(IVaC)和R21=(IVaS)时,化合物称作仑氨西林,
当R20=(IVa)和R21=H时,化合物称作美洛西林,
当R20=(IVaD)和R21=(IVaR)时,化合物称作喷沙西林氢碘酸盐,
当R20=(IVaP)和R21=H时,化合物称作青霉素N,
当R20=(IVaB)和R21=(IIIaF),伴随T2=叔丁基时,化合物称作匹氨西林,
当R20=(IVaN)和R21=H时,化合物称作喹那西林,
当R20=(IVaB)和R21=(IVaU)时,化合物称作舒他西林,
当R20=(IVaB)和R21=(IVaT)时,化合物称作酞氨西林。
在类型IVb中:
当R22=CH3,R23=(IVbA)时,化合物称作美罗培南,
当R22=H,R23=(IVbC)时,化合物称作帕尼培南,
当R22=H,R23=(IVbD)时,化合物称作亚胺培南。
在类型IVc中:
当R33=CH3,R34=CH3,R35=H,R36=CH3时,化合物称作氨曲南,
当R33=H,R34=H,R35=-CH2OCONH2,R36=H时,化合物称作卡芦莫南。
在类型V中:
当R24=Br时,化合物称作溴莫普林,
当R24=OCH3时,化合物称作甲氧苄啶,
当R24=CH3OCH2CH2O-时,化合物称作四氧普林。
在类型VI中:
当R25=(VID)时,化合物称作呋喃他酮,
当R25=(VIC)时,化合物称作呋唑氯铵,
当R25=(VIE)时,化合物称作硝呋复林,
当R25=(VIA)时,化合物称作硝呋吡醇,
当R25=(VIB)时,化合物称作硝呋拉嗪。
在类型VII中:
当R26=H时,化合物称作磺胺,
当R26=苯甲酰基时,化合物称作磺胺苯酰,
当R26=乙酰基时,化合物称作磺胺醋酰,
当R26=3-甲基-2-丁烯酰基时,化合物称作磺胺戊烯,
当R26=氨基甲酰基时,化合物称作磺胺酰脲,
当R26=NH2C(S)-时,化合物称作磺胺硫脲,
当R26=2-吡啶基时,化合物称作磺胺吡啶,
当R26=吡嗪基时,化合物称作磺胺吡嗪,
当R26=2-嘧啶基时,化合物称作磺胺嘧啶,
当R26=2-噻唑基时,化合物称作磺胺噻唑,
当R26=水杨酰-4-基时,化合物称作磺胺水杨酸,
当R26=6-氯-哒嗪-3-基时,化合物称作磺胺氯达嗪,
当R26=1-乙基-1,2-二氢-2-氧代-嘧啶-4-基时,化合物称作磺胺西汀,
当R26=5,6-二甲氧基-嘧啶-4-基时,化合物称作磺胺多辛,
当R26=2,6-二甲氧基-嘧啶-4-基时,化合物称作磺胺地索辛,
当R26=4-甲基-嘧啶-2-基时,化合物称作磺胺甲嘧啶,
当R26=5-甲氧基-嘧啶-2-基时,化合物称作磺胺对甲氧嘧啶,
当R26=4,6-二甲基-嘧啶-2-基时,化合物称作磺胺二甲嘧啶,
当R26=6-甲氧基-2-甲基-嘧啶-4-基时,化合物称作磺胺甲氧甲嘧啶,
当R26=5-甲基-嘧啶-2-基时,化合物称作磺胺培林,
当R26=2,6-二甲基嘧啶-4-基时,化合物称作磺胺索嘧啶,
当R26=3-甲氧基-吡嗪-2-基时,化合物称作磺胺林,
当R26=6-甲氧基-哒嗪-3-基时,化合物称作磺胺甲氧嗪,
当R26=4,6-二乙基-1,3,5-三嗪-2-基时,化合物称作磺胺均三嗪,
当R26=5-乙基-1,3,4-噻二唑-2-基时,化合物称作磺胺乙二唑,
当R26=5-甲基-1,3,4-噻二唑-2-基时,化合物称作磺胺甲二唑,
当R26=4-甲氧基-1,2,5-噻二唑-3-基时,化合物称作磺胺美曲,
当R26=4-甲基-噻唑-2-基时,化合物称作磺胺甲噻唑,
当R26=3-甲基-异噻唑-5-基时,化合物称作磺胺异噻唑,
当R26=4,5-二甲基-噁唑-2-基时,化合物称作磺胺噁唑,
当R26=3,4-二甲基-异噁唑-5-基时,化合物称作磺胺异噁唑,
当R26=4,5-二甲基-2-噁唑基氨基亚氨基甲基时,化合物称作磺胺胍诺,
当R26=5-甲基-异噁唑-3-基时,化合物称作磺胺甲噁唑,
当R26=1-苯基-1H-吡唑-5-基时,化合物称作磺胺苯吡唑,
当R26=4-甲基氨基磺酰基苯基时,化合物称作4’-(甲基氨磺酰基)对氨基苯磺酰基苯胺,
当R26=4-氨基磺酰基苯基时,化合物称作N4磺胺酰磺胺,
当R26=3,4-二甲基苯甲酰基时,化合物称作N-对氨基苯磺酰基-3,4-二甲基苯甲酰胺,
当R26=4-异丙氧基苯甲酰基时,化合物称作磺胺普罗林。
在类型VIII中:
当R27=H,R28=2,4-二氨基-6-羧基苯基时,化合物称作磺胺柯定,
当R27=H,R28=2,4-二氨基苯基时,化合物称作磺胺米柯定,
当R27=4,6-二甲基-嘧啶-2-基,R28=3-羧基-4-羟基苯基时,化合物称作柳氮磺嘧啶,
在类型IX中:
当R29=OH,R30=COOH时,化合物称作对氨基水杨酸,
当R29=OH,R30=肼羰基时,化合物称作对氨基水杨酰肼,
当R29=OH,R30=苯氧基羰基时,化合物称作氨基水杨酸苯酯,
当R29=H,R30=4-(氨基)苯基亚硫酰基时,化合物称作4,4’-亚硫酰基二苯胺,
在类型X中:
当R31=氨基,R32=4-(羟基乙基氨基)苯基时,化合物称作2-对磺胺酰苯胺基乙醇,
当R31=氨基,R32=-N=C(NH2)2时,化合物称作磺胺脒,
当R31=NH2-CH2-,R32=氨基时,化合物称作磺胺米隆,
当R31=苄基氨基,R32=氨基时,化合物称作苄磺胺,
当R31=氨基,R32=4-(羧基甲基氨基)苯基时,化合物称作醋地砜,
当R31=氨基,R32=4-(氨基)苯基时,化合物称作氨苯砜,
当R31=氨基,R32=4-(羧基丙酰基氨基)苯基时,化合物称作琥珀氨苯砜,
当R31=氨基,R32=4-(氨基甲基)苯基时,化合物称作对-磺胺酰苄胺,
当R31=氨基,R32=2-氨基-噻唑-5-基时,化合物称作噻唑砜,
在类型XI中:
当R52=C2H5,R53=氨基,M=S时,化合物称作乙硫异烟胺,
当R52=H,R53=-NHNH2,M=O时,化合物称作异烟肼,
当R52=C3H7,R53=氨基,M=S时,化合物称作丙硫异烟胺,
当R52=H,R53=(XIA),M=O时,化合物称作苯磺烟肼,
当R52=H,R53=(XIB),M=O时,化合物称作维拉烟肼,
当R52=H,R53=(XIC),M=O时,化合物称作奥匹烟肼,
当R52=H,R53=(XID),M=O时,化合物称作水杨烟肼,
当R52=H,R53=(XIE),M=O时,化合物称作furonazide,
当R52=H,R53=(XIF),M=O时,化合物称作葡烟腙。
在类型XII中:
当R37=Cl时,化合物称作克林霉素,
当R37=OH时,化合物称作林可霉素。
在类型XIIIa中:
当R38=乙酰基,R39=异戊酰基,R40=H,R41=H时,化合物称作交沙霉素,
当R38=丙酰基,R39=丙酰基,R40=H,R41=H时,化合物称作麦迪霉素A1,
当R38=H,R39=丁酰基,R40=丙酰基,R41=H时,化合物称作罗他霉素,
当R38=H,R39=H,R40=H,R41=(XIIIaB)时,化合物称作螺旋霉素I,
当R38=乙酰基,R39=H,R40=H,R41=(XIIIaB)时,化合物称作螺旋霉素II,
当R38=丙酰基,R39=H,R40=H,R41=(XIIIaB)时,化合物称作螺旋霉素III,
当R38=H,R39=异戊酰基,R40=H,R41=H时,化合物称作柱晶白霉素。
在类型XIIIb中:
当R47=H,R48=H,W=-N(CH3)CH2-时,化合物称作阿奇霉素,
当R47=CH3,R48=H,W=羰基时,化合物称作克拉霉素,
当R47=H,R48=H,W=羰基时,化合物称作红霉素,
当R47=H,R48和W一起形成(XIIIbA)时,化合物称作地红霉素。
在类型XIVa中:
当R42=OH,R43=(S)-4-氨基-2-羟基丁酰基,R44=OH,R45=OH时,化合物称作阿米卡星,
当R42=氨基,R43=(R)-4-氨基-2-羟基丁酰基,R44=H,R45=H时,化合物称作阿贝卡星,
当R42=氨基,R43=H,R44=H,R45=H时,化合物称作地贝卡星,
当R42=氨基,R43=H,R44=OH,R45=H时,化合物称作妥布霉素。
在类型XIVb中:
当R46=-CH2OH时,化合物称作双氢链霉素,
当R46=-CHO时,化合物称作链霉素。
在类型XIVc中:
当R49=CH3时,化合物称作大观霉素,
当R49=C4H9时,化合物称作丙大观霉素。
在类型XIVd中:
当R50=H,R51=(XIVdA)时,化合物称作小诺米星,
当R50=C2H5,R51=3-氨基-6-(氨基甲基)-3,4-二氢-2H-吡喃-2-基时,化合物称作奈替米星,
当R50=H,R51=3-氨基-6-(氨基甲基)-3,4-二氢-2H-吡喃-2-基时,化合物称作西索米星。
在类型XIVe中:
当R60=氨基,R61=(XIVeA)时,化合物称作新霉素,
当R60=OH,R61=(XIVeB)时,化合物称作巴龙霉素,
当R60=氨基,R61=H时,化合物称作核糖霉素。
在类型XV中:
当R54=CH3时,化合物称作利福平,
当R54=环戊基时,化合物称作利福喷汀。
在类型XVIa中:
当Xb=N,R55=H,R56=OH,R57=β-D-呋喃核糖基时,化合物称作肌苷,
当Xb=N,R55=氨基,R56=H,R57=4-乙酰氧基-3-(乙酰氧基甲基)1-丁基时,化合物称作泛昔洛韦,
当Xb=C,R55=H,R56=氨基,R57=β-D-呋喃核糖基时,化合物称作杀结核菌素。
在类型XVIb中:
当R58=H,R59=β-D-(2,3-二脱氧)呋喃核糖基时,化合物称作去羟肌苷,
当R58=氨基,R59=CH2OCH2CH2OH时,化合物称作阿昔洛韦,
当R58=氨基,R59=CH2OCH2CH2OCOCH(NH2)CH(CH3)2时,化合物称作伐昔洛韦,
当R58=氨基,R59=CH2OCH(CH2OH)CH2OH时,化合物称作更昔洛韦。
以下化合物为优选:
在类型I中:
当R1=H,R2=H,R3=CH3,R4=OH,R5=H时,化合物称作多西环素,
当R1=H,R2=OH,R3=H,R4=OH,R5=H时,化合物称作土霉素,
当R1=H,R2=OH,R3=CH3,R4=H,R5=H时,化合物称作四环素。
在类型II中:
当R6=环丙基,R7=H,R8=F,R9=(IIA),伴随M=H,R10=H,X=Y=C时,化合物称作环丙沙星,
当R6=C2H5,R7=H,R8=H,R9=CH3,R10=自由价,X=N,Y=C时,化合物称作萘啶酸,
当R6=C2H5,R7=H,R8=F,R9=(IIA),伴随M=H,R10=H,X=Y=C时,化合物称作诺氟沙星,
当R6与R10形成二价基团(IIN),R7=H,R8=F,R9=(IIA),伴随M=CH3,X=Y=C时,化合物称作氧氟沙星。
在类型IIIa中:
当R11=H,R12=Cl,R13=氨基,R14=苯基,Z=S时,化合物称作头孢克洛,
当R11=H,R12=CH3,R13=氨基,R14=苯基,Z=S时,化合物称作头孢氨苄,
当R11=H,R12=(IIIaC),R13=OH,R14=苯基,Z=S时,化合物称作头孢孟多。
在类型IIIb中:
当R15=COOH,R16=乙烯基,R17=-OCH2OCOOH,X=N,Y=C时,化合物称作头孢克肟,
当R15=(CH3)2CHOCOOCH(CH3)OCO-,R16=C2H5,R17=OCH3,X=N,Y=C时,化合物称作头孢泊肟proxetil,
当R15=COOH,R16=(IIIbF),R17=OCH3,X=N,Y=C时,化合物称作头孢地秦。
在类型IIIc中:
当R18=(IIIcF),R19=(IIIcN)时,化合物称作头孢唑林。
在类型IVa中:
当R20=(IVaA)和R21=H时,化合物称作阿莫西林,
当R20=(IVaB)和R21=H时,化合物称作氨苄西林,
当R20=(IVaM)和R21=H时,化合物称作阿帕西林。
在类型IVb中:
当R22=H,R23=(IVbD)时,化合物称作亚胺培南。
在类型IVc中:
当R33=CH3,R34=CH3,R35=H,R36=CH3时,化合物称作氨曲南。
在类型V中:
当R24=OCH3时,化合物称作甲氧苄啶。
在类型VI中:
当R25=(VIE)时,化合物称作硝呋复林。
在类型VII中:
当R26=5-甲基-异噁唑-3-基时,化合物称作磺胺甲噁唑。
在类型X中:
当R31=氨基,R32=4-(氨基)苯基时,化合物称作氨苯砜。
在类型XI中:
当R52=C2H5,R53=氨基,M=S时,化合物称作乙硫异烟胺,
当R52=H,R53=-NHNH2,M=O时,化合物称作异烟肼。
在类型XIIIb中:
当R47=H,R48=H,W=-N(CH3)CH2-时,化合物称作阿奇霉素,
当R47=H,R48=H,W=羰基时,化合物称作红霉素,
当R47=CH3,R48=H,W=羰基时,化合物称作克拉霉素。
在类型XIVa中:
当R42=OH,R43=(S)-4-氨基-2-羟基丁酰基,R44=OH,R45=OH时,化合物称作阿米卡星,
当R42=氨基,R43=H,R44=OH,R45=H时,化合物称作妥布霉素。
在类型XIVb中:
当R46=-CHO时,化合物称作链霉素,
在类型XIVc中:
当R49=CH3时,化合物称作大观霉素。
在类型XIVd中:
当R50=C2H5,R51=3-氨基-6-(氨基甲基)-3,4-二氢-2H-吡喃-2-基时,化合物称作奈替米星。
在类型XIVe中:
当R60=氨基,R61=(XIVeA)时,化合物称作新霉素。
在类型XV中:
当R54=CH3时,化合物称作利福平。
在类型XVIa中:
当Xb=N,R55=H,R56=OH,R57=β-D-呋喃核糖基时,化合物称作肌苷。
当Xb=N,R55=氨基,R56=H,R57=4-乙酰氧基-3-(乙酰氧基甲基)1-丁基时,化合物称作泛昔洛韦。
在类型XVIb中:
当R58=H,R59=β-D-(2,3-二脱氧)呋喃核糖基时,化合物称作去羟肌苷,
当R58=氨基,R59=CH2OCH2CH2OH时,化合物称作阿昔洛韦,
当R58=氨基,R59=CH2OCH2CH2OCOCH(NH2)CH(CH3)2时,化合物称作伐昔洛韦,
当R58=氨基,R59=CH2OCH(CH2OH)CH2OH时,化合物称作更昔洛韦。
在类型XVII中:
O-2-氨基-2-脱氧-α-β-吡喃葡萄糖基-(1→4)-O-[3-脱氧-3-(甲基氨基)-α-D-吡喃木糖基-(1→6)]-2-脱氧-D-链霉胺(庆大霉素A),(S)-2-氨基-5-[(氨基亚氨基甲基)氨基]戊酸(精氨酸),(+)-2,2’-(亚乙基二亚氨基)二-1-丁醇(乙胺丁醇),1-氨基金刚烷(金刚烷胺),2’,3’-二脱氧胞嘧啶核苷(扎西他滨),吡嗪酰胺、吗甲吡嗪酰胺、替考拉宁、万古霉素、甲硝唑。
本发明的另一个目的也为用于制备不包括红霉素、异烟肼、吡嗪酰胺、甲硝唑、阿昔洛韦的硝酸盐在内的药物的抗微生物药,优选为抗病毒、抗真菌和抗细菌药物的硝酸盐化合物或它们的药用组合物。
在本发明中也可以使用以上列出的抗微生物药物的相应的硝基氧基(nitrooxy)衍生物的硝酸盐,所述硝基氧基衍生物的特征在于在它们的分子中存在一个或更多个,优选一个具有以下通式(I-N)的取代基,
-B-(W)p-ONO2
(I-N)其中:p为1或0;B=-TB-Y-TBI-,其中TB和TBI为相同或不同;TB为共价连接于药物分子的化学或活性官能团的化学官能团并且为(CO)或X,其中X=O、S、NH,条件是当药物的活性官能团为OH或NH2或SH时,X=(CO);当药物的活性官能团为羧基时,TB为X;TBI=(CO)tx或(X)txx,其中tx和txx为0或1;条件是当txx=0时,tx=1,当txx=1时,tx=0;X如上定义;Y为选自以下结构的二价连接桥:
其中:
nIX为0-3的整数,优选为1;
nIIX为0-3的整数,优选为1;
RTIX、RTIX’、RTIIX、RTIIX’彼此之间相同或不同,为H或线性或分支的C1-C4烷基,RTIX、RTIX’、RTIIX、RTIIX’优选为H。
Y3为包含至少一个能变成盐的氮原子的环;Y优选为包含一或两个氮原子的杂环,该环为饱和的、不饱和的或芳族的,优选具有5或6个原子。
-亚烷基R’,其中R’为线性或分支的C1-C20烷基,优选为C2-C6烷基,由一个或更多个以下的基团任选取代,包括:-NHCOR3Y,其中R3Y为线性或分支的C1-C5烷基,-NH2、-OH;
-C5-C7亚环烷基环,由R’任选取代,R’如上定义,其中亚环烷基的一个或更多个C原子能够由杂原子任选取代;
其中n3为0-3的整数且n3’为1-3的整数;
其中n3和n3’具有以上指明的含义;其中:R4Y为OH、H、烃氧基(alcoxy)R5YO-,其中R5Y为线性或分支或环状的C1-C10烷基,R5Y优选为甲基;R2Y为包含一个或更多个双键的线性或分支的C2-C10亚链烯基,R2Y优选为亚乙烯基(-CH=CH-);
其中R1f=H、CH3且nf为0-6的整数;优选0-4;式(I-N)的W为二价基团-Tc-YT-,其中:当tx=0时,Tc=(CO),当txx=0时,Tc=X;条件是在式(I-N)中,当p=1时,YT不同于Y并且处于二价基团B中:
-Y为以上定义的具有取代基NHCOR3Y的R’,R’优选为C2饱和的烷基且R3Y为CH3;TB=S;TB1为-CO-;Y优选为-CH2-CH(NHCOCH3)-且式(I-N)中的B优选具有以下结构:或
Y3优选为包含一个氮原子的6-元芳族环,所述环在以下位置:2,6;2,3;2,5中具有两个自由价。
Y3优选为在位置2和6上取代的Y12(pirydil)。Y1(吡唑)能够被3,5-二取代。
本发明的另一个目为用于制备药物的以上列出的优选具有抗病毒、抗真菌和抗细菌活性的抗微生物化合物的硝基氧基衍生物的硝酸盐或它们的药用组合物,当在式(I-N)中p=0时,所述硝酸盐不包括红霉素、异烟肼、吡嗪酰胺、甲硝唑、阿昔洛韦的硝基氧基衍生物的硝酸盐。
按照本领域熟知的方法,能够制备在它们的分子中具有一个或更多个式(I-N)的取代基的抗细菌药物的衍生物。
通常,按照本领域熟知的方法,如果在药物的分子中或在式(I-N)的二价基团B或W中存在一个以上的活性基团COOH和/或HX,其中X如上定义,则反应前必须保护所述活性基团;例如,如Th.W.Greene:“Protective groups in organic synthesis”,Harward UniversityPress,1980描述的那样。
按照先前技术中熟知的方法,例如在反应条件下,于惰性溶剂例如甲苯、氯仿、DMF等中,通过亚硫酰氯或草酰氯,pm或PV卤化物可制备酰卤。
1)当在式(I-N)中药物的活性化学官能团为羧基和p=0时,通过以下方法能够制备相应的硝基氧基衍生物:
1.a)在-5℃至50℃范围内的温度下,于溶剂例如DMF、THF、氯仿等中,在缩合催化剂例如4-二甲基氨基吡啶(DMAP)存在下,通过用脱水剂例如N,N’-羰基二咪唑(CDI)、N-羟基-苯并三唑和二环己基碳二亚胺(DCC)处理酸RCOOH(其中R为药物基团)和式HO-Y-Hal的卤代醇衍生物,其中Y如上定义且Hal为卤素原子,例如Cl、Br、I,可偶合产生式(1/C)的酯。
1.b)或者,酸RCOOH可首先转变为碱金属盐例如钠或钾盐并且与通式Y(Hal)2的二卤代衍生物反应,其中Y和Hal如上定义。
1.c)或者,所述酸可首先转变为式R-CO-Cl(其中R为药物基团)的酰氯,然后与式HO-Y-Hal的卤代醇或式HO-Y-OH的二醇反应,其中Y如上定义且Hal为卤素(Cl、Br、I):
1.d)按照以下流程,在反应条件下,于有机惰性溶剂中,酸RCOOH与式Hal-Y-Hal的二卤化物,其中Y和Hal如上定义,可偶合形成酯:
1.e)当在以上描述的反应中得到的化合物具有式R-COO-Y-Hal时,按照以下流程,在有机溶剂例如乙腈、四氢呋喃中,通过使化合物R-CO-O-Y-Hal与AgNO3反应,可得到相应的硝基氧基衍生物:
1.f)当在以上描述的反应中得到的化合物具有式R-COO-Y-OH时,首先将羟基卤化,例如通过PBr3、PCl5、SOCl2、PPh3+I2,然后在有机溶剂例如乙腈、四氢呋喃中,与AgNO3反应。
2)当在式(I-N)中p=0时,可用羟基饱和R的自由价,相应的硝基氧基衍生物的合成方法如下:
2.a)按照以下流程,式R-OH的药物与式Hal-Y-COOH的卤代酸或式HO-Y-COOH的羟基酸,其中Y和Hal如上定义,按照本领域熟知的反应可偶合产生式(2/A)或(2/B)的酯:
2.b)当在以上描述的反应中得到的化合物具有式R-OCO-Y-Hal或R-OCO-Y-OH时,如在1.f和1.e中分别描述的,可得到相应的硝基氧基衍生物。
3.当在式(I-N)中p=1和药物分子的活性基团为羧基时,得到相应的硝基氧基衍生物的合成方法为如下的方法:
3.a)式RCOH的药物可首先转变为式R-CO-Cl(其中R为药物基团)的酰氯,然后按照本领域已知的方法,与式HX-Y-COOH的化合物反应,得到式R-CO-X-Y-COOH的化合物,使它转变为相应的钠盐,然后与式Hal-YT-R8Y的化合物反应,其中Hal和YT如上定义且R8Y为Cl、Br、I、OH.
3.b)当YT为线性C4亚烷基时,在四氢呋喃中,在卤化剂例如CBr4或N-溴代琥珀酰亚胺存在下,式(3.A)的酸化合物与三苯基膦反应,直接得到其中R8Y=Br的式(3.A’)的化合物,然后将所述化合物转变为如在1.e下所述的相应的硝基氧基衍生物。
4)当在式(I-N)中p=1和抗菌药的活性基团为羟基时,得到相应的硝基氧基衍生物的合成方法为以下方法:
4.a)按照本领域已知的方法,式R-OH的药物与式HX-Y-COHal的酰卤,其中X、Y和Hal如上定义,可偶合产生式R-O-CO-Y-XH(4/A)的酯,然后其与式R8Y-YT-COHal的化合物反应,其中R8Y和YT如上定义。
4.b)或者,如在1.a描述的,在二环己基碳二亚胺存在下,药物R-OH与其中X和Y如上定义的式HX-Y-COOH的化合物反应,得到式R-O-CO-Y-XH的化合物,然后它与其中R8Y和YT如上定义的式R8Y-YT-COCl的化合物反应,得到以下化合物:R-O-CO-Y-X-CO-YT-R8Y(4/B)。当R8Y=OH时,如以上1.f)中描述的,将相应于式(4/B)或(4a’)的化合物卤化;当R8=Hal时,在有机溶剂例如乙腈、四氢呋喃中,式(4/B)的化合物与AgNO3反应。
按照在WO 95/30641中描述的合成方法(其通过引用结合到本文中),也能制备抗菌药的硝基氧基衍生物。
在本发明的盐或它们的组合物中,当可能时,也可以使用一种或更多种上述抗微生物的化合物的异构体,包括光学异构体。
本发明的硝酸盐包含至少一摩尔的硝酸根离子/一摩尔的化合物。硝酸根离子摩尔数/前体摩尔数的比例优选是一元的。当分子中存在更多的氨基(aminic group),碱性足以使之能够变成盐时可得到具有更高摩尔比的盐。
按照先有技术中熟知的技术,以相应的药用组合物,采用常见的赋形剂配制本发明的盐;参见例如“Remington’s PharmaceuticalSciences 15版”。
按照在Merck Index 14版中描述的方法(其通过引用结合到本文中),可制备属于以上提及类型的盐的前体。
通过以下方法制备抗菌化合物的硝酸盐。
当待成盐的化合物作为溶于优选不合有羟基的有机溶剂,例如乙腈、乙酸乙酯、四氢呋喃等中的游离碱得到的时候,在优选等于或高于10%w/v的浓度下,通过使化合物溶于该溶剂中,加入相应于存在于化合物中的可成盐的氨基的摩尔数的量的浓硝酸,可制备所述盐。优选在相同的溶剂中稀释硝酸。优选在加入期间和加入后于0℃-20℃范围内的温度下将它冷却。
通常经过滤和用溶剂洗涤回收产品。
当化合物难溶解时,或者在以上提及的溶剂中,以难溶盐的形式得到时,可以使用相应的含羟基化溶剂的混合物。这样的溶剂的实例为甲醇、乙醇和水。然后加入含非极性溶剂的硝酸后,通过稀释如此得到的混合物能够加速硝酸盐的沉淀。
当用盐酸使起始化合物成盐时,通过将硝酸银直接加入到化合物溶液中制备硝酸盐是可能的。过滤氯化银后,浓缩溶液,冷却以回收硝酸盐。
当起始化合物为盐时,通过用钠或钾的碳酸氢盐或碳酸盐的饱和溶液,或者用氢氧化钠或氢氧化钾的稀溶液处理,也能够释放相应的碱。然后,用合适的有机溶剂(例如卤化溶剂、酯、醚)提取碱,然后干燥。蒸发有机溶液,并且按照先前的制备方法,通过将碱溶于乙腈或其它的以上提及的溶剂中,进行加工。
本发明的化合物和组合物能够用于全身使用,例如采用先有技术中已知的制剂例如片剂或胶囊剂经口服给予它们,或者以灭菌的、无热原的生理溶液中的制剂,任选加入先有技术中已知的其它的赋形剂,经非肠道途径,例如经静脉或肌内给予它们。
在凝胶或软膏剂的形式下或通过气溶胶(经吸入),使用本发明的硝酸盐用于局部使用是可能的。
如上所述,本发明的化合物用于使用前体抗微生物药物治疗的相同病因的疗法。然而,由于本发明的产物显示改善的活性,它们甚至能够在更低的剂量下使用。这是有利的,因为这样避免了以上提及的前体的副作用。
给出以下实施例仅作为阐明本发明且它们对本发明不构成限制。实施例制备实施例实施例1头孢氨苄硝酸盐的制备
在避光下,用硝酸银(2.22g,13.06mmol)处理头孢氨苄盐酸盐(3g,13.02mmol)在乙腈(150ml)和四氢呋喃(150ml)的混合物中的溶液。在室温下将它搅拌30分钟,然后过滤氯化银并把溶液减压浓缩到最初体积的一半。加入乙醚(100ml)并在5℃下冷却后,过滤得到的固体。干燥后,得到4.3g为无定形固体的头孢氨苄硝酸盐。收率80%。
C16H18N4O7S的元素分析理论值%:C 46.83;H 4.42;N 13.65;S 7.81实测值%:C 46.81;H 4.44;N 13.63;S 7.80实施例2克林霉素硝酸盐的制备
通过加入硝酸银(1.12g,6.59mmol)并且按照在实施例1中报道的方法,从克林霉素盐酸盐(3g,6.5mmol)的乙醇(100ml)溶液起始,制备化合物。得到为无定形固体的克林霉素硝酸盐。收率70%。C18H34ClN3O8S的元素分析:理论值%:C 44.30;H 7.02;Cl 7.26;N 8.61;S 6.57实测值%:C 44.32;H 7.03;Cl 7.23;N 8.62;S 6.55实施例3阿莫西林硝酸盐的制备
通过加入硝酸银(0.850g,5.0mmol),然后按照在实施例1中报道的方法,从阿莫西林盐酸盐(2g,4.98mmol)在乙腈(80ml)/四氢呋喃(80ml)的混合物中的溶液起始,制备化合物。得到为无定形固体的阿莫西林硝酸盐。收率78%。C16H20N4O8S的元素分析:理论值%:C 44.86;H 4.71;N 13.08;S 7.48实测值%:C 44.89;H 4.74;N 13.11;S 7.45实施例4四环素硝酸盐的制备
通过加入硝酸银(0.71g,4.17mmol),然后按照在实施例1中报道的方法,从四环素盐酸盐(2g,4.16mmol)的甲醇(100ml)溶液起始,制备化合物。得到为无定形固体的四环素硝酸盐。收率60%。C22H25N3O11的元素分析:理论值%:C 52.07;H 4.97;N 8.28实测值%:C 52.05;H 4.99;N 8.30实施例5克拉霉素硝酸盐的制备
在0℃冷却下,向克拉霉素(2g,2.67mmol)在乙腈(50ml)和氯仿(80ml)的混合物中的溶液中加入在乙腈(5ml)中的65%HNO3溶液(0.2ml)。加入后,使混合物达到室温并于搅拌下维持2小时。减压蒸发溶剂。把残余物溶于氯仿(50ml)中并加入乙醚(50ml)。在5℃下冷却,过滤分离沉淀。干燥后,得到1.83g(2.26mmol)为无定形固体的克拉霉素硝酸盐。收率80%。C38H78N2O16的元素分析:理论值%:C 56.28;H 8.70;N 3.45实测值%:C 56.25;H 8.72;N 3.46实施例6环丙沙星硝酸盐的制备
将三乙胺(0.9ml,6.5mmol)加入到环丙沙星盐酸盐(2g,5.4mmol)在200ml二氯甲烷中的悬浮液中。在搅拌下,把溶液维持30分钟。用水(100ml)洗涤溶液,经硫酸钠干燥有机相,然后真空蒸发,得到相应的环丙沙星碱(1.03g)。将该物质溶于乙腈(60ml)/四氢呋喃(50ml)的混合物中。把溶液用冰冷却,并用在乙腈(5ml)中的(0.220ml)的65%硝酸溶液处理。在冷却搅拌30分钟后,用乙醚处理。过滤分离的固体,用乙醚洗涤,真空干燥。得到1.2g为无定形固体的环丙沙星硝酸盐。收率45%。C17H19N4O6F的元素分析:理论值%:C 51.78;H 4.86;N 14.21;F 4.82实测值%:C 51.75;H 4.84;N 14.25;F 4.80实施例7磺胺甲噁唑硝酸盐的制备
通过加入在乙腈(5ml)中的65%硝酸溶液(0.500ml),按照在实施例5中报道的方法,从在甲醇(100ml)中的磺胺甲噁唑(2g,7.9mmol)溶液起始,制备化合物。得到为无定形固体的磺胺甲噁唑硝酸盐。收率60%。C10H12N4O6S的元素分析:理论值%:C 37.97;H 3.82;N 17.71;S 10.15实测值%:C 37.99;H 3.83;N 17.73;S 10.13实施例8甲氧苄啶硝酸盐的制备
通过加入在乙腈(5ml)中的65%硝酸溶液(0.360ml),然后按照在实施例5中描述的方法,从甲氧苄啶(1.5g,5.17mmol)的氯仿(80ml)溶液起始,合成化合物。得到为无定形固体的甲氧苄啶硝酸盐。收率60%。C14H19N5O6的元素分析:理论值%:C 47.59;H 5.42;N 19.82实测值%:C 47.57;H 5.44;N 19.83实施例9吡嗪酰胺硝酸盐的制备
通过加入在乙腈(5ml)中的65%硝酸溶液(1.2ml),然后按照在实施例5中描述的方法,从在乙腈(30ml)/四氢呋喃(30ml)的混合物中的吡嗪酰胺(2g,16.24mmol)溶液起始,制备化合物。得到为无定形固体的吡嗪酰胺硝酸盐。收率74%。C5H6N4O4的元素分析:理论值%:C 32.27;H 3.25;N 30.10实测值%:C 32.29;H 3.24;N 30.13实施例10硝呋复林硝酸盐的制备
通过加入在乙腈(3ml)中的65%硝酸溶液(0.210ml),然后按照在实施例5中描述的方法,从在四氢呋喃(20ml)/乙腈(20ml)的混合物中的硝呋复林溶液(1g,2.96mmol)起始,制备化合物。得到为无定形固体的硝呋复林硝酸盐。收率55%。C13H16N6O9的元素分析:理论值%:C 39.01;H 4.03;N 20.99实测值%:C 39.03;H 4.05;N 21.01实施例11阿昔洛韦硝酸盐的制备
通过加入在乙腈(5ml)中的65%硝酸溶液(0.310ml),然后按照在实施例5中描述的方法,从在四氢呋喃(20ml)/乙腈(20ml)的混合物中的阿昔洛韦溶液(1g,4.44mmol)起始,制备化合物。得到为无定形固体的阿昔洛韦硝酸盐。收率60%。C8H12N6O6的元素分析:理论值%:C 33.34;H 4.20;N 29.17实测值%:C 33.31;H 4.22;N 29.19实施例12甲硝唑硝酸盐的制备
通过加入在乙腈(3ml)中的65%硝酸溶液(0.410ml),然后按照在实施例5中描述的方法,从在四氢呋喃(10ml)/乙腈(15ml)的混合物中的甲硝唑溶液(1g,5.84mmol)起始,制备化合物。得到为无定形固体的甲硝唑硝酸盐。收率70%。C6H10N4O6的元素分析:理论值%:C 30.77;H 4.30;N 24.03实测值%:C 30.74;H 4.28;N 24.01实施例13红霉素硝酸盐的制备
通过加入在乙腈(5ml)中的65%硝酸溶液(0.200ml),然后按照在实施例5中描述的方法,从溶解在氯仿(30ml)/乙腈(20ml)的混合物中的红霉素溶液(2g,2.72mmol)起始,制备化合物。得到为无定形固体的红霉素硝酸盐。收率83%。元素分析:理论值%:C 55.76;H 8.59;N 3.51实测值%:C 55.79;H 8.60;N 3.53实施例14头孢唑林硝酸盐的制备
通过将在乙腈(5ml)中的65%硝酸溶液(0.250ml)加入在甲醇(50ml)中的头孢唑林溶液(1.5g,3.3mmol)中,然后按照在实施例5中报道的方法,制备化合物。得到为无定形固体的头孢唑林硝酸盐。收率60%。C14H15N9O7S3的元素分析:理论值:C 32.49;H 2.92;N 24.36;S 18.59实测值:C 32.48;H 2.94;N 24.37;S 18.57实施例15氨苄西林硝酸盐的制备
通过加入在乙腈(5ml)中的65%硝酸溶液(0.450ml),并按照在实施例5中报道的方法,从在由乙腈(30ml)在四氢呋喃(20ml)形成的混合物中的氨苄西林溶液(2g,5.72mmol)起始,制备化合物。得到为无定形固体的氨苄西林硝酸盐。收率55%。C16H20N4O7S的元素分析:理论值%:C 46.60;H 4.89;N 13.58;S 7.77实测值%:C 46.56;H 5.91;N 13.59;S 7.76药理实施例
在抗菌药的培养基上的体外稀释试验
抗微生物化合物的硝酸盐拮抗微生物抗性产生的能力与相应的前体的能力的比较已被评价。
通过使用如Sahm等(S.D.Sahm,J.A.Washington“抗菌敏感性试验:稀释法”临床微生物手册,A.Balows,W.J.Hausler,Jr,K.L.Hermann,H.D.Isenberg,H.J.Shadomy编辑,1991,美国微生物学会)描述的培养基上的体外稀释方法,已确定这样的活性。按照这个方法,可测定具有能抑制一些细菌菌株生长的抗微生物活性物质的水溶液浓度。对于前体,选择在所采用实验条件下,仍然可观察微生物生长的该物质的最大浓度,并且相同的浓度用于相应的硝酸盐。按照标准的并且对本领域技术人员是熟知的方法(National Committeefor Clinical Laboratory Standards,1990“对于需氧生长细菌的稀释抗微生物敏感性试验的方法”。批准标准M7-A2。National Committee forClinical Laboratory Standards,Villanova,Pa),制备用于制备受试抗生素的菌株物质的溶剂和必需的稀释液。按照标准方法也可进行培养基的制备并且使用CAMH液体培养基(阳离子调节的Mueller-Hinton液体培养基)(National Committee for Clinical Laboratory Standards,1990“对于需氧生长细菌的稀释抗微生物敏感性试验的方法”。批准标准M7-A2。National Committee for Clinical Laboratory Standards,Villanova,Pa)。
按照标准方法进行接种过程并且接种物的最终浓度为5×105CFU(菌落形成单位)/ml。所使用的微生物为大肠杆菌(Escherichia Coli)(ATCC25922)和金黄色葡萄球菌(Staphylococcus Aureus)(ATCC29213)。
于35℃,将试管温育20小时,然后读数。以定量方法用裸眼确定微生物生长或微生物不存在,并且其分别表明对抗微生物药物的微生物抗性或敏感性。在表1和2中报道试验结果,这些结果显示硝酸盐具有高于前体的抗微生物活性。实施例161-乙基-6,8-二氟-1,4-二氢-7-(3-甲基-1-哌嗪基)-4-氧代-3-喹啉羧酸4-硝基氧基丁基酯硝酸盐的合成A)1-乙基-6,8-二氟-1,4-二氢-7-(3-甲基-N-叔丁氧基羰基-1-哌嗪基)-4-氧代-3-喹啉羧酸4-溴代丁基酯的合成
在0℃下,向搅拌着的1-乙基-6,8-二氟-1,4-二氢-7-(3-甲基-1-哌嗪基)-4-氧代-3-喹啉羧酸盐酸盐(504.14mg,1.3mmol)在1,4-二噁烷(2.6ml)和NaOH 2M(1.3ml)中的溶液中加入二碳酸二叔丁酯(306mg,1.4mmol)。搅拌2小时后,过滤悬浮液并用1,4-二噁烷洗涤沉淀,干燥,得到1-乙基-6,8-二氟-1,4-二氢-7-(3-甲基-N-叔丁氧基羰基-1-哌嗪基)-4-氧代-3-喹啉羧酸,其无须进一步纯化即可使用。
向1-乙基-6,8-二氟-1,4-二氢-7-(3-甲基-N-叔丁氧基羰基-1-哌嗪基)-4-氧代-3-喹啉羧酸和NaHCO3(11mg,1.3mmol)在DMF(10ml)中的悬浮液中加入1,4-二溴代丁烷(1.4g,6.5mmol)。
把混合物回流1小时并在冷却后依次加入水和乙酸乙酯。分离两相后,用水洗涤有机层,用硫酸钠干燥,减压蒸发。经硅胶层析法纯化残余物,用乙酸乙酯/正己烷(v/v 2/1)洗脱,得到为无定形固体的1-乙基-6,8-二氟-1,4-二氢-7-(3-甲基-N-叔丁氧基羰基-1-哌嗪基)-4-氧代-3-喹啉羧酸4-溴代丁基酯(380mg,0.65mmol)。收率50%。B)1-乙基-6,8-二氟-1,4-二氢-7-(3-甲基-1-哌嗪基)-4-氧代-3-喹啉羧酸4-硝基氧基丁基酯的合成
向1-乙基-6,8-二氟-1,4-二氢-7-(3-甲基-N-叔丁氧基羰基-1-哌嗪基)-4-氧代-3-喹啉羧酸4-硝基氧基丁基酯(300mg,0.51mmol)在无水乙腈(5ml)中的溶液中加入硝酸银(170mg,1mmol)。在暗处中把混合物回流4小时。
过滤悬浮液并用水(3×8ml)洗涤滤液,用硫酸钠干燥,然后真空蒸发。
在惰性气氛(N2)下,于室温下,通过用三氟乙酸(1ml)处理1小时使化合物脱除保护。经减压蒸发除去三氟乙酸,并经弱碱性离子交换树脂(Amberlyst_A-21)上的层析法纯化残余物,用乙酸乙酯洗脱,得到为无定形固体的1-乙基-6,8-二氟-1,4-二氢-7-(3-甲基-1-哌嗪基)-4-氧代-3-喹啉羧酸4-硝基氧基丁基酯(150mg,0.32mmol)。1H NMR(ppm):8.25(1H,s);7.85(1H,d);4.52(2H,t);4.5-4.2(4H,m);3.4-2.8(7H,m);1.94-1.83(4H,m);1.48(3H,m);1.06(3H,d)。C)1-乙基-6,8-二氟-1,4-二氢-7-(3-甲基-1-哌嗪基)-4-氧代-3-喹啉羧酸4-硝基氧基丁基酯硝酸盐的合成
向1-乙基-6,8-二氟-1,4-二氢-7-(3-甲基-1-哌嗪基)-4-氧代-3-喹啉羧酸4-硝基氧基丁基酯(150mg,0.32mmol)在CH2Cl2(2ml)中的溶液中加入HCl-AcOEt 1M(0.5ml)。在室温下搅拌1小时后,减压蒸发溶剂,并把残余物溶于THF(4ml)中且加入硝酸银(55mg,3.03mmol)。在室温下搅拌该混合物1小时,过滤悬浮液,并用THF洗涤沉淀,干燥,得到为无定形固体的1-乙基-6,8-二氟-1,4-二氢-7-(3-甲基-1-哌嗪基)-4-氧代-3-喹啉羧酸4-硝基氧基丁基酯硝酸盐(1 50mg)。收率88%。元素分析:
%C %H %N %F
理论值 47.46 5.12 13.18 7.15
实测值 47.50 5.10 13.10 7.20实施例171-乙基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)-3-喹啉羧酸4-硝基氧基丁基酯硝酸盐的合成A)1-乙基-6-氟-1,4-二氢-4-氧代-7-(N-叔丁氧基羰基-1-哌嗪基)-3-喹啉羧酸4-溴代丁基酯的合成
在-4℃下,向1-乙基-6-氟-1,4-二氢-7-(3-甲基-1-哌嗪基)-4-氧代-3-喹啉羧酸盐酸盐(2.5g,7.8mmol)和KOH 2M(11.7ml)在1,4-二噁烷(15ml)中的溶液中加入二碳酸二叔丁酯(1.75g,8mmol)。在0℃下把混合物搅拌1小时,之后除去冷却浴并搅拌直到温度升到室温(大约1小时)。加入水(15ml)并在冷却后过滤混合物,干燥沉淀,得到1-乙基-6-氟-1,4-二氢-4-氧代-7-(N-叔丁氧基羰基-1-哌嗪基-)-3-喹啉羧酸,其无须进一步纯化即可使用。
在惰性气氛(N2)下,向1-乙基-6-氟-1,4-二氢-4-氧代-7-(N-叔丁氧基羰基-1-哌嗪基-)-3-喹啉羧酸和18-冠醚-6(1,4,7,10,13-五氧杂环十五烷)在无水THF(20ml)中的悬浮液中加入1,4-二溴代丁烷(1.4g,6.5mmol)。
把混合物回流1小时并在冷却后依次加入水和乙酸乙酯。
分离两相后,用水洗涤有机层,用硫酸钠干燥,减压蒸发。
经硅胶层析法纯化残余物,用乙酸乙酯/正己烷(v/v 2/1)洗脱,得到为无定形固体的1-乙基-6-氟-1,4-二氢-7-(3-甲基-N-叔丁氧基羰基-1-哌嗪基)-4-氧代-3-喹啉羧酸4-溴代丁基酯(380mg,0.65mmol)。收率66%。B)1-乙基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)-3-喹啉羧酸4-硝基氧基丁基酯硝酸盐的合成
向1-乙基-6-氟-1,4-二氢-4-氧代-7-(N-叔丁氧基羰基-1-哌嗪基)-3-喹啉羧酸4-硝基氧基丁基酯(443.5mg,0.8mmol)在无水乙腈(7ml)中的溶液中加入硝酸银(406mg,0.8mmol)。在惰性气氛(N2)下,在暗处中把混合物回流5小时,过滤悬浮液,真空蒸发滤液。将残余物溶于CH2Cl2(10ml)中并用水(5×10ml)洗涤混合物,用硫酸钠脱水,然后减压蒸发溶剂。
在惰性气氛(N2)下,于室温下,用三氟乙酸(1.6ml)使化合物脱除保护1小时。减压蒸发三氟乙酸,并经弱碱性离子交换树脂(Amberlyst_A-21)上的层析法纯化残余物,用甲醇洗脱,得到为黄色无定形固体的1-乙基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)-3-喹啉羧酸4-硝基氧基丁基酯硝酸盐(306mg,0.7mmol)。1H NMR(DMSO)ppm:7.39(5H,d);7.03(8H,d);5.96(2H,s);4.58(2H,m);4.38(2H,m);4.18(2H,m);3.33(4H,m);3.16(4H,m);1.94-1.83(4H,m);1.8-1.86(4H,m);1.35(3H,t)。C)1-乙基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)-3-喹啉羧酸4-硝基氧基丁基酯硝酸盐的合成
向1-乙基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)-3-喹啉羧酸4-硝基氧基丁基酯(300mg,0.68mmol)在CH2Cl2(5ml)中的溶液中加入HCl-AcOEt 1M(0.8ml)。在室温下搅拌1小时后,减压蒸发溶剂。把残余物溶于THF(10ml)中并加入硝酸银(120mg,0.70mmol)。在室温下将混合物搅拌1小时,过滤悬浮液,并用THF洗涤沉淀,干燥,得到为无定形固体的1-乙基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)-3-喹啉羧酸4-硝基氧基丁基酯硝酸盐(300mg)。收率85%。
元素分析:
%C %H %N %F
理论值 48.10 5.25 14.02 3.80
实测值 48.05 5.30 14.11 3.75实施例183-[[4-[1-环丙基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)-3-喹啉羰基氧基]-3-甲氧基]苯基]-2-丙烯酸4-(硝基氧基丁基)丁基酯硝酸盐的合成A)1-环丙基-6-氟-1,4-二氢-4-氧代-7-(N-叔丁氧基羰基-1-哌嗪基-)-3-喹啉羧酸的合成
在室温下,向1-环丙基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基-)-3-喹啉羧酸(3.31g,10mmol)在CH2Cl2(120ml)中的悬浮液中加入TEA(4.21ml,30mmol)和二碳酸二叔丁酯(4.4g,30mmol)。在室温下,把混合物搅拌12小时。在-5℃下冷却后,过滤悬浮液,将收集的沉淀溶于CH2Cl2(200ml)中,并用AcOH水溶液0.3M(100ml)洗涤生成的溶液。
用硫酸钠干燥有机相,真空蒸发溶剂。把残余物从CH2Cl2(10ml)/正己烷(100ml)的混合物中结晶,得到1-环丙基-6-氟-1,4-二氢-4-氧代-7-(N-叔丁氧基羰基-1-哌嗪基-)-3-喹啉羧酸(3.93g)。收率91%。m.p.248-249℃(分解)。B)3-[[4-[1-环丙基-6-氟-1,4-二氢-4-氧代-7-(N-叔丁氧基羰基-1-哌嗪基)-3-喹啉羰基氧基]-3-甲氧基]苯基]-2-丙烯酸4-(硝基氧基丁基)丁基酯的合成
向1-环丙基-6-氟-1,4-二氢-4-氧代-7-(N-叔丁氧基羰基-1-哌嗪基-)-3-喹啉羧酸(5.36g,12.43mmol)和3-[(3-甲氧基-4-羟基)苯基]-2-丙烯酸4-硝基氧基丁基酯(3.78g,12.43mmol)在CH2Cl2(100ml)中的溶液中依次加入Ph3P(4.89g,18.64mmol)和DEAP(2.94ml,18.64mmol)。在室温下,把混合物搅拌2小时,然后减压蒸发溶剂。经硅胶层析法纯化残余物,用CH2Cl2/丙酮(v/v 30/1)洗脱,得到3-[4-[1-环丙基-6-氟-1,4-二氢-4-氧代-7-(N-叔丁氧基羰基-1-哌嗪基)-3-喹啉羰基氧基]-3-甲氧基]-2-丙烯酸4-(硝基氧基丁基)丁基酯(3.5g)。收率40%。C)3-[4-[1-环丙基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)-3-喹啉羰基氧基]-3-甲氧基]2-丙烯酸4-(硝基氧基丁基)丁基酯盐酸盐的合成
向3-[4-[1-环丙基-6-氟-1,4-二氢-4-氧代-7-(N-叔丁氧基羰基-1-哌嗪基)-3-喹啉羰基氧基]-3-甲氧基]-2-丙烯酸4-(硝基氧基丁基)丁基酯(3.5g)在CH2Cl2(50ml)中的溶液中加入HCl-AcOEt 20%(5ml)。在室温下搅拌2小时后,减压蒸发溶剂,并把残余物溶于丙酮(40ml)中。在0℃下冷却30分钟后,过滤悬浮液,并用乙醚洗涤收集的沉淀,得到为黄色固体的3-[4-[1-环丙基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)-3-喹啉羰基氧基]-3-甲氧基]2-丙烯酸4-(硝基氧基丁基)丁基酯盐酸盐(2g)。m.p.207-209℃。1H NMR(DMSO)ppm:9.26(1H,s),8.68(1H,s),7.85(1H,d),7.68(1H,d),7.53(2H,dd),7.35(1H,dd),7.20(1H,d),6.74(1H,d),4.6(2H,t),4.2(2H,t),3.83(3H,s),3.76(1H,m),5.52(4H,m),3.33(4H,s),1.78(4H,m),1.32-1.16(4H,m)。D)3-[[4-[1-环丙基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)-3-喹啉羰基氧基]-3-甲氧基]苯基]-2-丙烯酸4-(硝基氧基丁基)丁基酯硝酸盐的合成
向3-[[4-[1-环丙基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)-3-喹啉羰基氧基]-3-甲氧基]苯基]-2-丙烯酸4-(硝基氧基丁基)丁基酯盐酸盐(2g,3.03mmol)在THF(20ml)中的溶液中加入硝酸银(514mg,3.03mmol)。在室温下搅拌1小时后,过滤混合物,并用THF洗涤沉淀且干燥,得到为无定形固体的3-[4-[1-环丙基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)-3-喹啉羰基氧基]-3-甲氧基]2-丙烯酸4-(硝基氧基丁基)丁基酯硝酸盐(2g)。收率96%。元素分析:
%C %H %N %F
理论值 54.78 5.17 9.98 2.71
向甲硝唑(7.5g,43.82mmol)在CHCl3(75ml)和DMF(93ml)中的溶液中加入4-溴代丁酸(6.1g,36.51mmol)。在室温下把混合物搅拌24小时后,用水洗涤有机相,用硫酸钠干燥,减压蒸发。
经硅胶柱层析法纯化残余物,用二氯甲烷/丙酮(v/v 9/1)洗脱,得到4-溴代丁酸2-甲基-5-硝基咪唑-1-乙基酯(6.5g,20.3mmol)。收率55%。B)4-(硝基氧基)丁酸2-甲基-5-硝基咪唑-1-乙基酯的合成
向4-溴代丁酸2-甲基-5-硝基咪唑-1-乙基酯(6.4g,20.05mmol)在无水乙腈(170ml)中的溶液中加入硝酸银(5.11g,30.07mmol)。在40℃下,于暗处把混合物加热48小时。过滤混合物,并用水洗涤滤液,用硫酸钠干燥,真空蒸发。
经硅胶柱层析法纯化残余物,用二氯甲烷/丙酮(v/v 9/1)洗脱,得到为油的4-(硝基氧基)丁酸2-甲基-5-硝基咪唑-1-乙基酯(3.68g,12.17mmol)。收率60%。1H NMR(DMSO)ppm:8.08(1H,s);4.55(2H,t);4.53(2H,t);4.43(2H,t);2.51(2H,s);2.40(2H,t);1.91(2H,tt)。C)4-(硝基氧基)丁酸2-甲基-5-硝基咪唑-1-乙基酯硝酸盐的合成
向4-(硝基氧基)丁酸2-甲基-5-硝基咪唑-1-乙基酯(3.68g,12.17mmol)在CH2Cl2(80ml)中的溶液中加入HCl-AcOEt 1M(12.2ml)。在室温下搅拌1小时后,减压蒸发溶剂,并把残余物溶于THF(75ml)中。加入硝酸银(2g,12.17mmol)。在室温下搅拌该混合物1小时,过滤悬浮液,并用THF洗涤沉淀,干燥,得到4-(硝基氧基)丁酸2-甲基-5-硝基咪唑-1-乙基酯硝酸盐(4.2g)固体。收率90%。元素分析:
%C %H %N
理论值 31.50 3.96 18.37
实测值 31.45 3.90 18.29实施例204-(硝基氧基)丁酸5-硝基-8-羟基喹啉酯硝酸盐的合成A)4-溴代丁酸5-硝基-8-羟基喹啉酯的合成
在0℃下,向nitroxoline(4.32g,22.72mmol)和三乙胺(2.75g,27.26mmol)在CHCl3(100ml)和DMF(69ml)中的溶液中加入4-溴代丁酰氯(5.05g,27.26mmol)。在室温下搅拌24小时后,加入另一份三乙胺(0.46g,4.5mmol)和4-溴代丁酰氯(0.83g,4.5mmol)。在室温下把混合物搅拌48小时。加入水和二氯甲烷,分离这两相后,用水洗涤有机层,用硫酸钠干燥,减压蒸发。
经硅胶柱层析法纯化残余物,用乙酸乙酯/正己烷(v/v 2/8)洗脱,得到为油的4-溴代丁酸5-硝基-8-羟基喹啉酯(6.86g,20.22mmol)。收率90%。1H NMR(CDCl3)ppm:9.06(2H,m);8.44(1H,d);7.65(1H,m);7.5(1H,d);3.66(2H,m);3.03(2H,m);2.42(2H,m)。B)4-(硝基氧基)丁酸5-硝基-8-羟基喹啉酯的合成
向4-溴代丁酸5-硝基-8-羟基喹啉酯(6.86g,20.2mmol)在无水乙腈(100ml)中的溶液中加入硝酸银(13.65g,80.3mmol)。在40℃下,于暗处把混合物加热64小时。然后过滤混合物,用硫酸钠干燥滤液,减压蒸发。经硅胶柱层析法纯化残余物,用乙酸乙酯/正己烷(v/v 3/7)洗脱,得到为黄色无定形固体的4-(硝基氧基)丁酸5-硝基-8-羟基喹啉酯(2.05g,6.38mmol)。收率31%。(m.p.=68℃)。1H NMR(DMSO)ppm:9.02(1H,dd);8.97(1H,d);8.45(1H,dd);7.65(1H,m);7.54(1H,dd);4.74(2H,t);2.97(2H,t);2.03(2H,m)。C)4-(硝基氧基)丁酸5-硝基-8-羟基喹啉酯硝酸盐的合成
向4-(硝基氧基)丁酸5-硝基-8-羟基喹啉酯(2.05g,6.38mmol)在乙酸乙酯(40ml)中的溶液中加入HCl-AcOEt 1M(6.4ml)。在室温下搅拌1小时后,减压蒸发溶剂,并把残余物溶于THF(50ml)中且加入硝酸银(1.08g,6.38mmol)。在室温下将混合物搅拌1小时,过滤悬浮液,并用THF洗涤沉淀,干燥,得到4-(硝基氧基)丁酸2-甲基-5-硝基咪唑-1-乙基酯硝酸盐(2.2g)固体。收率89%。元素分析:
%C %H %N
理论值 39.01 3.22 13.99
实测值 38.94 3.14 13.91实施例216-(D-(-)-α-氨基苯基乙酰氨基)青霉烷酸4-(硝基氧基)丁基酯硝酸盐的合成A)6-(D-(-)-α-氨基苯基乙酰氨基)青霉烷酸钠盐的合成
向氨苄西林(5.09g,14.6mmol)在无水乙醇(120ml)中的溶液中加入乙醇钠(0.99g,14.6mmol)。在室温下将混合物搅拌1小时,然后在60℃下搅拌30分钟。减压蒸发混合物,得到为白色固体的6-(D-(-)-α-氨基苯基乙酰氨基)青霉烷酸钠盐(5.4g,14.5mmol)。收率99%。B)6-(D-(-)-α-叔丁氧基羰基氨基苯基乙酰氨基)青霉烷酸的合成
在0℃的温度下,向6-(D-(-)-α-氨基苯基乙酰氨基)青霉烷酸钠盐(5.4g,14.57mmol)在1,4-二噁烷(166ml)和水(121ml)中的溶液中加入二碳酸二叔丁酯(5.08g,23.31mmol)在1,4-二噁烷(45ml)中的溶液。当加入结束时,温度升至室温并继续搅拌48小时。然后减压蒸发混合物。把残余物溶于5%NaHCO3水溶液中,用乙醚洗涤;通过在0℃的温度下加入H3PO4 50%(11ml),将水相的pH值调至2。用乙酸乙酯提取水相后,干燥合并的有机相,减压蒸发,得到6-(D-(-)-α-叔丁氧基羰基氨基苯基乙酰氨基)青霉烷酸,其无须进一步纯化即可使用。1H NMR(CDCl3)ppm:7.34(5H,s);6.85(1H,bs);5.8(1H,bs);5.6(1H,dd);5.45(1H,d);5.22(1H,bs);4.38(1H,s);1.4(15H,m)。B)6-(D-(-)-α-氨基苯基乙酰氨基)青霉烷酸4-溴代丁基酯的合成
向6-(D-(-)-α-叔丁氧基羰基氨基苯基乙酰氨基)青霉烷酸(6.36g,14.15mmol)在DMF(60ml)中的溶液中加入三乙胺(2.76ml,19.81mmol)。搅拌30分钟后,加入1,4-二溴丁烷(6.11g,28.30mmol)并把混合物搅拌12小时。
然后,在悬浮液下加入乙醚,并滤除Et3N.HBr。用水洗涤有机相,用硫酸钠干燥,减压蒸发。
经硅胶柱层析法纯化残余物,用乙酸乙酯/正己烷(v/v 15/85)洗脱,得到为白色固体的6-(D-(-)-α-氨基苯基乙酰氨基)青霉烷酸4-溴代丁基酯(3.2g)。1H NMR(CDCl3)ppm:7.35(5H,m);6.6(1H,bs);5.6(1H,m);5.4(1H,d);5.2(1H,bs);4.39(1H,s);4.18(2H,m);3.42(2H,t);1.9(4H,m);1.4(15H,m)。C)6-(D-(-)-α-氨基苯基乙酰氨基)青霉烷酸4-硝基氧基丁基酯的合成
向6-(D-(-)-α-氨基苯基乙酰氨基)青霉烷酸4-溴代丁基酯(3.12g,5.34mmol)在乙腈(50ml)中的溶液中加入硝酸银(1.27g,7.48mmol)。在40℃下,于暗处中把混合物加热10小时。然后过滤混合物,减压蒸发。经硅胶柱层析法纯化残余物,用乙酸乙酯/正己烷(v/v 3/7)洗脱,得到为黄色无定形固体的6-(D-(-)-α-氨基苯基乙酰氨基)青霉烷酸4-硝基氧基丁基酯(0.9g)。1H NMR(CDCl3)ppm:7.35(5H,m);6.6(1H,bs);5.6(1H,m);5.4(1H,m);5.2(1H,bs);4.5(2H,m);4.4(1H,s);4.2(2H,m);1.8(4H,bs);1.4(15H,m)。D)6-(D-(-)-α-氨基苯基乙酰氨基)青霉烷酸4-硝基氧基丁基酯硝酸盐的合成
在0℃下,向6-(D-(-)-α-氨基苯基乙酰氨基)青霉烷酸4-硝基氧基丁基酯(0.9g,1.58mmol)在乙酸乙酯(10ml)中的溶液中加入在AcOEt中的HCl 1M溶液(1.5ml)。在0℃下将混合物搅拌20分钟并在室温下搅拌1小时。减压蒸发溶剂,把残余物溶于THF(5ml)中并加入硝酸银(268mg,1.58mmol)溶液。在室温下将混合物搅拌1小时,然后过滤,并用THF洗涤沉淀,干燥,得到6-(D-(-)-α-氨基苯基乙酰氨基)青霉烷酸4-硝基氧基丁基酯硝酸盐(736mg)固体。收率88%。元素分析:
%C %H %N %S
理论值 45.36 5.14 13.22 6.05
实测值 45.28 5.08 13.16 5.97
表1
菌株大肠杆菌(ATCC25922):头孢唑林和头孢唑林硝酸盐、氨苄西林和氨苄西林硝酸盐的抗微生物活性。 | ||
化合物 | 浓度(μ g/ml) | 响应 |
头孢唑林头孢唑林·HNO3 | 0.50.5 | 生长未生长 |
氨苄西林氨苄西林·HNO3 | 1.01.0 | 生长未生长 |
表2
菌株金黄色葡萄球菌(ATCC29213):克林霉素和克林霉素硝酸盐、环丙沙星和环丙沙星硝酸盐、磺胺甲噁唑和磺胺甲噁唑硝酸盐、甲氧苄啶和甲氧苄啶硝酸盐、红霉素和红霉素硝酸盐的抗微生物活性。 | ||
化合物 | 浓度(μg/ml) | 响应 |
克林霉素克林霉素·HNO3 | 0.030.03 | 生长未生长 |
环丙沙星环丙沙星 | 0.051.0 | 生长未生长 |
磺胺甲噁唑磺胺甲噁唑·HNO3 | 2020 | 生长未生长 |
甲氧苄啶甲氧苄啶·HNO3 | 0.50.5 | 生长未生长 |
红霉素红霉素·HNO3 | 0.060.06 | 生长未生长 |
Claims (13)
1.用作药物的抗微生物化合物的硝酸盐或它们的药用组合物,所述硝酸盐不包括红霉素、异烟肼、吡嗪酰胺、甲硝唑、阿昔洛韦的硝酸盐。
2.权利要求1的硝酸盐,其中所述抗微生物化合物选自以下类型:类型I)其中:R1=H、Cl或二甲基氨基,R2=H、OH或自由价,R3=H、CH3,当R2为具有C-R3键的电子对的自由价时,它形成双键且R3为亚甲基,R4=H、OH,R5=H、CH2OH或以下取代基中的一个:类型II)其中:X和Y彼此不同,为C或N,R6=环丙基、C2H5、4-氟代苯基、2,4-二氟代苯基、2-氟代乙基,R7=H、氨基、CH3,R8=H或F,当Y=N时,R8为自由价且其为在氮原子上的自由电子对,R9=H、CH3或以下取代基中的一个:其中M=H、CH3、C2H5、OH,其中T1为H、OH,R8和R9一起形成具有下式的二价基团:-O-CH2-O- (IIP),R10=H、Cl、F,当X=N时,R10为自由价且其为在氮原子上的自由电子对,R6和R10一起形成以下二价基团:当式(II)中的X=N时,R10为自由价且其与氮相邻的碳原子形成双键;类型IIIa):其中:Z=S、C,R11=H、式(IIIaF)的新戊酰氧基亚甲基,其中T2为叔丁基,R12=Cl、CH3、式(IIIaF)的乙酰氧基亚甲基,其中T2为CH3、2-丙烯基或以下取代基中的一个:R13=氨基、OH或取代基(IIIaD):R14为苯基、4-羟基苯基或基团(IIIaE);类型IIIb):其中:X=CH、N,Y=C、N,R15=COOH、COO-、(CH3)3CCOOCH2OCO-或(CH3)2CHOCOOCH(CH3)OCO-,R16=H、CH3、C2H5、-CH=CH2、NH2COOCH2-、CH3COOCH2-、或以下取代基中的一个: 当R15为羧酸根阴离子时,R16为选自以下的基团:(IIIbL)、(IIIbM)或(IIIbN)R17=OH、OCH3、C2H5、-OCH2COOH、-CH2COOH;类型IIIc):其中:R18为以下取代基中的一个:R19=H、CH3COOCH2-或以下基团中的一个:类型IVa:其中:R20为以下取代基中的一个: R21=H、具有T2=叔丁基的基团(IIIaF)、CH(CH3)OCOOC2H5或以下取代基中的一个:-CH2CH2N(CH2CH3)2.HI(IVaR),类型IVb)其中:R22=H、CH3,R23选自以下基团:
-CH2CH2NHCH=NH (IVbD),类型IVc)其中:R33、R34、R36,彼此相同或不同,为H、CH3;R35=H、-CH2OCONH2,类型V)其中R24=H、Br、OCH3、CH3OCH2CH2O-;类型VI)其中:R25为以下取代基中的一个:类型VII)其中R26=H、或以下取代基中的一个:苯甲酰基、乙酰基、3-甲基-2-丁烯酰基、氨基甲酰基、氨基硫代NH2C(S)-、2-吡啶基、吡嗪基、2-嘧啶基、2-噻唑基、水杨酰-4-基、6-氯-哒嗪-3-基、1-乙基-1,2-二氢-2-氧代-嘧啶-4-基、5,6-二甲氧基-嘧啶-4-基、2,6-二甲氧基-嘧啶-4-基、4-甲基-嘧啶-2-基、5-甲氧基-嘧啶-2-基、4,6-二甲基-嘧啶-2-基、6-甲氧基-2-甲基-嘧啶-4-基、5-甲基-嘧啶-2-基、2,6-二甲基-嘧啶-4-基、3-甲氧基-吡嗪-2-基、6-甲氧基-哒嗪-3-基、4,6-二乙基-1,3,5-三嗪-2-基、5-乙基-1,3,4-噻二唑-2-基、5-甲基-1,3,4-噻二唑-2-基、4-甲氧基-1,2,5-噻二唑-3-基、4-甲基-噻唑-2-基、3-甲基-异噻唑-5-基、4,5-二甲基-噁唑-2-基、3,4-二甲基-异噁唑-5-基、4,5-二甲基-2-噁唑基氨基亚氨基甲基、5-甲基-异噁唑-3-基、1-苯基-1H-吡唑-5-基、4-甲基氨基磺酰基苯基、4-氨基磺酰基苯基、3,4-二甲基苯甲酰基、4-异丙氧基苯甲酰基;类型VIII)其中:R27=H、4,6-二甲基-嘧啶-2-基;R28=2,4-二氨基-6-羧基苯基、2,4-二氨基苯基、3-羧基-4-羟基苯基;类型IX)其中:R29=H、OH,R30=COOH、苯氧基羰基、4-(氨基)苯基亚硫酰基、肼基羰基;类型X)其中:R31=氨基、NH2-CH2-、苄基氨基,R32=氨基、4-(羟基乙基氨基)苯基、-N=C(NH2)2、4-(氨基)苯基、4-(氨基甲基)苯基、4-(羧基甲基氨基)苯基、4-(羧基丙酰基氨基)苯基、2-氨基-噻唑-5-基;类型XI)其中:M=O、S,R52=H、C2H5、C3H7,R53=氨基、-NHNH2、或以下取代基中的一个:类型XII)其中:R37=Cl、OH;类型XIIIa)其中:R38=H、乙酰基、丙酰基,R39=H、丙酰基、丁酰基、异戊酰基,R40=H、丙酰基,R41=H,或:类型XIIIb)其中:R47=H、CH3,W=CO、-N(CH3)CH2-,R48=H,或R48与W一起形成二价基团:类型XIVa)其中:R42=OH、氨基,R43=H、(R)-4-氨基-2-羟基丁酰基、(S)-4-氨基-2-羟基丁酰基,R44=H、OH,R45=H、OH;类型XIVb)其中:R46=-CH2OH;-CHO类型XIVc)其中:R49=CH3、C4H9;类型XIVd)其中:R50=H、C2H5,R51=3-氨基-6-(氨基甲基)-3,4-二氢-2H-吡喃-2-基:类型XIVe)其中:R60=OH、氨基,R61=H或以下取代基中的一个:类型XV)其中R54=CH3、环戊基;类型XVIa)其中:Xb=N、C,R55=H、氨基,R56=H、OH、氨基,R57为β-D-呋喃核糖基或4-乙酰氧基-3-(乙酰氧基甲基)1-丁基;类型XVIb)其中:R58=H、氨基,R59=CH2OCH2CH2OH、CH2OCH(CH2OH)CH2OH、CH2OCH2CH2OCOCH(NH2)CH(CH3)2、β-D-(2,3-二脱氧)呋喃核糖基;类型XVII):以下化合物属于类型XVII:
O-2-氨基-2-脱氧-α-D-吡喃葡萄糖基-(1→4)-O-[3-脱氧-3-(甲基氨基)-α-D-吡喃木糖基-(1→6)]-2-脱氧-D-链霉胺(庆大霉素A)、1-(2-羟基乙基)-2-甲基-5-硝基咪唑(甲硝唑)、(S)-2-氨基-5-[(氨基亚氨基甲基)氨基]戊酸(精氨酸)、(+)-2,2’-(亚乙基二亚氨基)二-1-丁醇(乙胺丁醇)、1-氨基金刚烷(金刚烷胺)、2’,3’-二脱氧胞嘧啶核苷(扎西他滨)、吡嗪酰胺、吗甲吡嗪酰胺、磺胺乙酰甲氧吡嗪、氯法齐明、环丝氨酸、链异烟肼、脱氧二氢链霉素、米卡霉素、罗沙米星、卡波霉素、阿来西定、安巴腙、氯羟喹、负霉素、硝羟喹啉、泊非霉素、牛黄罗定、替贝碘铵、安普霉素、替考拉宁、万古霉素、噻苯达唑、甲苯达唑、阿苯达唑、氯甲氧吖胺、茴香霉素、地美硝唑、二脒那秦、醋甘氨酸盐、依氟鸟氨酸、卤夫酮、胡米铵、羟茋巴脒、咪多卡、异丙硝唑、月桂胍、尼莫唑、氧芬胂、喷他脒、氧二苯脒、普罗帕脒、嘌罗霉素、乙胺嘧啶、米帕林、喹匹拉明、Quintine、塞克硝唑、司替巴脒、替硝唑。
3.权利要求2的硝酸盐,该硝酸盐选自:
在类型I中:
当R1=H,R2=OH,R3=CH3,R4=H,R5=(IA)时,化合物称作阿哌环素,
当R1=Cl,R2=OH,R3=CH3,R4=H,R5=H时,化合物称作金霉素,
当R1=Cl,R2=OH,R3=CH3,R4=H,R5=CH2OH时,化合物称作氯莫环素,
当R1=Cl,R2=OH,R3=H,R4=H,R5=H时,化合物称作地美环素,
当R1=H,R2=H,R3=CH3,R4=OH,R5=H时,化合物称作多西环素,
当R1=H,R2=OH,R3=CH3,R4=H,R5=(IB)时,化合物称作胍甲环素,
当R1=H,R2=OH,R3=CH3,R4=H,R5=(ID)时,化合物称作赖甲环素,
当R1=Cl,R2=自由价并具有形成双键的C-R3键的电子对,且R3为亚甲基,R4=OH,R5=H时,化合物称作甲氯环素,
当R1=H,R2=自由价并具有形成双键的C-R3键的电子对,且R3为亚甲基,R4=OH,R5=H时,化合物称作美他环素,
当R1=二甲基氨基,R2=H,R3=H,R4=H,R5=H时,化合物称作米诺环素,
当R1=H,R2=OH,R3=H,R4=OH,R5=H时,化合物称作土霉素,
当R1=H,R2=OH,R3=CH3,R4=H,R5=(IC)时,化合物称作匹哌环素,
当R1=H,R2=OH,R3=CH3,R4=H,R5=H时,化合物称作四环素,
当R1=H,R2=H,R3=H,R4=H,R5=H时,化合物称作山环素,
在类型II中:
当R6=环丙基,R7=H,R8=F,R9=(IIA),伴随M=H,R10=H,X=Y=C时,化合物称作环丙沙星,
当R6=环丙基,R7=H,R8=F,R9=(IIF),R10=Cl,X=Y=C时,化合物称作克林沙星,
当R6=4-氟苯基,R7=H,R8=F,R9=(IID),R10=H,X=Y=C时,化合物称作二氟沙星,
当R6=C2H5,R7=H,R8=F,R9=(IIA),伴随M=H,R10=自由价,X=N,Y=C时,化合物称作依诺沙星,
当R6=环丙基,R7=H,R8=F,R9=(IIA),伴随M=C2H5,R10=H,X=Y=C时,化合物称作恩氟沙星,
当R6=氟代乙基,R7=H,R8=F,R9=(IIA),伴随M=CH3,R10=F,X=Y=C时,化合物称作氟罗沙星,
当R6与R10形成二价基团(IIM),R7=H,R8=F,R9=H,X=Y=C时,化合物称作氟甲喹,
当R6=环丙基,R7=CH3,R8=F,R9=(IIB),R10=H,X=Y=C时,化合物称作格帕沙星,
当R6=乙基,R7=H,R8=F,R9=(IIB),R10=F,X=Y=C时,化合物称作洛美沙星,
当R6与R10形成二价基团(IIM,R7=H,R8=F,R9=(IIE),伴随T1=OH,X=Y=C时,化合物称作那氟沙星,
当R6=C2H5,R7=H,R8=H,R9=CH3,R10=自由价,X=N,Y=C时,化合物称作萘啶酸,
当R6=C2H5,R7=H,R8=F,R9=(IIA),伴随M=H,R10=H,X=Y=C时,化合物称作诺氟沙星,
当R6与R10形成二价基团(IIN),R7=H,R8=F,R9=(IIA),伴随M=CH3,X=Y=C时,化合物称作氧氟沙星,
当R6=C2H5,R7=H,R8与R9形成二价基团(IIP),R10=H,X=Y=C时,化合物称作奥索利酸,
当R6与R10形成二价基团(IIO),R7=H,R8=F,R9=(IIH),X=Y=C时,化合物称作Pazufloxacin,
当R6=乙基,R7=H,R8=F,R9=(IIA),伴随M=CH3,R10=H,X=Y=C时,化合物称作培氟沙星,
当R6=C2H5,R7=H,R8=自由价,R9=(IIA),伴随M=H,R10=自由价,X=Y=N时,化合物称作吡哌酸,
当R6=C2H5,R7=H,R8=自由价,R9=(IIE),伴随T1=H,R10=自由价,X=Y=N时,化合物称作吡咯米酸,
当R6与R10形成二价基团(IIQ),R7=H,R8=F,R9=(IIA),伴随M=CH3,X=Y=C时,化合物称作芦氟沙星,
当R6=环丙基,R7=氨基,R8=F,R9=(IIC),R10=F,X=Y=C时,化合物称作司氟沙星,
当R6=2,4-二氟苯基,R7=H,R8=F,R9=(IIF),R10=自由价,X=N,Y=C时,化合物称作托氟沙星,
当R6=2,4-二氟苯基,R7=H,R8=F,R9=(IIG),R10=自由价,X=N,Y=C时,化合物称作曲沃沙星,
当R6=环丙基,R7=H,R8=F,R9=(IID),R10=H,X=Y=C时,化合物称作达氟沙星,
当R6=4-氟苯基,R7=H,R8=F,R9=(IIA),伴随M=H,R10=H,X=Y=C时,化合物称作沙氟沙星,
在类型IIIa中:
当R11=H,R12=Cl,R13=氨基,R14=苯基,Z=S时,化合物称作头孢克洛,
当R11=H,R12=CH3,R13=氨基,R14=4-羟基苯基,Z=S时,化合物称作Cefafroxil,
当R11=H,R12=(IIIaB),R13=氨基,R14=4-羟基苯基,Z=S时,化合物称作头孢曲秦,
当R11=H,R12=(IIIaC),R13=(IIIaD),R14=4-羟基苯基,Z=S时,化合物称作头孢匹胺,
当R11=H,R12=2-丙烯基,R13=氨基,R14=4-羟基苯基,Z=S时,化合物称作头孢丙烯,
当R11=H,R12=CH3,R13=氨基,R14=(IIIaE),Z=S时,化合物称作头孢沙定,
当R11=H,R12=CH3,R13=氨基,R14=苯基,Z=S时,化合物称作头孢氨苄,
当R11=H,R12=CH3,R13=(IIIaF),伴随T2=CH3,R14=苯基,Z=S时,化合物称作头孢来星,
当R11=H,R12=CH3,R13=氨基,R14=(IIIaE),Z=S时,化合物称作Cephadrine,
当R11=H,R12=Cl,R13=氨基,R14=苯基,Z=C时,化合物称作氯碳头孢,
当R11=(IIIaF),伴随T2=叔丁基,R12=CH3,R13=氨基,R14=苯基,Z=S时,化合物称作Pivcefalexin,
当R11=H,R12=(IIIaC),R13=OH,R14=苯基,Z=S时,化合物称作头孢孟多,
在类型IIIb中:
当R15=(CH3)3CCOOCH2OCO-,R16=NH2COOCH2-,R17=C2H5,X=CH,Y=C时,化合物称作头孢卡品pivoxil,
当R15=COO-,R16=(IIIbL),R17=甲氧基,X=Y=N时,化合物称作头孢克定,
当R15=COOH,R16=-CH=CH2,R17=OH,X=N,Y=C时,化合物称作头孢地尼,
当R15=COOH,R16=(IIIbA),R17=OCH3,X=N,Y=C时,化合物称作头孢托仑,
当R15=COO-,R16=(IIIbM),R17=OCH3,X=N,Y=C时,化合物称作头孢吡肟,
当R15=COOH,R16=CH3,R17=OCH3,X=N,Y=C时,化合物称作头孢他美,
当R15=COOH,R16=-CH=CH2,R17=-OCH2OCOOH,X=N,Y=C时,化合物称作头孢克肟,
当R15=COOH,R16=(IIIbC),R17=OCH3,X=N,Y=C时,化合物称作头孢甲肟,
当R15=COO-,R16=(IIIbN),R17=OCH3,X=Y=N时,化合物称作头孢唑兰,
当R15=(CH3)2CHOCOOCH(CH3)OCO-,R16=C2H5,R17=OCH3,X=N,Y=C时,化合物称作头孢泊肟丙酯,
当R15=COOH,R16=(IIIbD),R17=OCH3,X=N,Y=C时,化合物称作头孢特仑,
当R15=COOH,R16=H,R17=-CH2COOH,X=CH,Y=C时,化合物称作头孢布烯,
当R15=COOH,R16=(IIIbH),R17=OCH3,X=N,Y=C时,化合物称作头孢曲松,
当R15=COOH,R16=(IIIbE),R17=OCH3,X=N,Y=C时,化合物称作头孢唑南,
当R15=COOH,R16=(IIIbF),R17=OCH3,X=N,Y=C时,化合物称作头孢地秦,
当R15=COOH,R16=CH3COOCH2-,R17=OCH3,X=N,Y=C时,化合物称作头孢噻肟,
当R15=COOH,R16=(IIIbG),R17=OCH3,X=N,Y=C时,化合物称作头孢噻呋,
在类型IIIc中:
当R18=(IIIcD),R19=(IIIcH)时,化合物称作头孢替安,
当R18=(IIIcE),R19=H时,化合物称作头孢唑肟,
当R18=(IIIcF),R19=(IIIcN)时,化合物称作头孢唑林,
当R18=(IIIcG),R19=(IIIcM)时,化合物称作头孢雷特,
当R18=(IIIcA),R19=(IIIcL)时,化合物称作头孢米诺,
当R18=(IIIcB),R19=CH3COOCH2-时,化合物称作头孢菌素C,
在类型IVa中:
当R20=(IVaF)和R21=H时,化合物称作美西林,
当R20=(IVaF)和R21=(IIIaF),伴随T2=叔丁基时,化合物称作美西林pivoxil,
当R20=(IVaA)和R21=H时,化合物称作阿莫西林,
当R20=(IVaB)和R21=H时,化合物称作氨苄西林,
当R20=(IVaM)和R21=H时,化合物称作阿帕西林,
当R20=(IVaG)和R21=H时,化合物称作阿扑西林,
当R20=(IVaB)和R21=-CH(CH3)OCOOC2H5时,化合物称作巴氨西林,
当R20=(IVaE)和R21=H时,化合物称作氨环己青霉素,
当R20=(IVaC)和R21=H时,化合物称作依匹西林,
当R20=(IVaC)和R21=H时,化合物称作海他西林,
当R20=(IVaC)和R21=(IVaS)时,化合物称作仑氨西林,
当R20=(IVa)和R21=H时,化合物称作美洛西林,
当R20=(IVaD)和R21=(IVaR)时,化合物称作喷沙西林氢碘酸盐,
当R20=(IVaP)和R21=H时,化合物称作青霉素N,
当R20=(IVaB)和R21=(IIIaF),伴随T2=叔丁基时,化合物称作匹氨西林,
当R20=(IVaN)和R21=H时,化合物称作喹那西林,
当R20=(IVaB)和R21=(IVaU)时,化合物称作舒他西林,
当R20=(IVaB)和R21=(IVaT)时,化合物称作酞氨西林,
在类型IVb中:
当R22=CH3,R23=(IVbA)时,化合物称作美罗培南,
当R22=H,R23=(IVbC)时,化合物称作帕尼培南,
当R22=H,R23=(IVbD)时,化合物称作亚胺培南,
在类型IVc中:
当R33=CH3,R34=CH3,R35=H,R36=CH3时,化合物称作氨曲南,
当R33=H,R34=H,R35=-CH2OCONH2,R36=H时,化合物称作卡芦莫南,
在类型V中:
当R24=Br时,化合物称作溴莫普林,
当R24=OCH3时,化合物称作甲氧苄啶,
当R24=CH3OCH2CH2O-时,化合物称作四氧普林,
在类型VI中:
当R25=(VID)时,化合物称作呋喃他酮,
当R25=(VIC)时,化合物称作呋唑氯铵,
当R25=(VIE)时,化合物称作硝呋复林,
当R25=(VIA)时,化合物称作硝呋吡醇,
当R25=(VIB)时,化合物称作硝呋拉嗪,
在类型VII中:
当R26=H时,化合物称作磺胺,
当R26=苯甲酰基时,化合物称作磺胺苯酰,
当R26=乙酰基时,化合物称作磺胺醋酰,
当R26=3-甲基-2-丁烯酰基时,化合物称作磺胺戊烯,
当R26=氨基甲酰基时,化合物称作磺胺酰脲,
当R26=NH2C(S)-时,化合物称作磺胺硫脲,
当R26=2-吡啶基时,化合物称作磺胺吡啶,
当R26=吡嗪基时,化合物称作磺胺吡嗪,
当R26=2-嘧啶基时,化合物称作磺胺嘧啶,
当R26=2-噻唑基时,化合物称作磺胺噻唑,
当R26=水杨酰-4-基时,化合物称作磺胺水杨酸,
当R26=6-氯-哒嗪-3-基时,化合物称作磺胺氯达嗪,
当R26=1-乙基-1,2-二氢-2-氧代-嘧啶-4-基时,化合物称作磺胺西汀,
当R26=5,6-二甲氧基-嘧啶-4-基时,化合物称作磺胺多辛,
当R26=2,6-二甲氧基-嘧啶-4-基时,化合物称作磺胺地索辛,
当R26=4-甲基-嘧啶-2-基时,化合物称作磺胺甲嘧啶,
当R26=5-甲氧基-嘧啶-2-基时,化合物称作磺胺对甲氧嘧啶,
当R26=4,6-二甲基-嘧啶-2-基时,化合物称作磺胺二甲嘧啶,
当R26=6-甲氧基-2-甲基-嘧啶-4-基时,化合物称作磺胺甲氧甲嘧啶,
当R26=5-甲基-嘧啶-2-基时,化合物称作磺胺培林,
当R26=2,6-二甲基嘧啶-4-基时,化合物称作磺胺索嘧啶,
当R26=3-甲氧基-吡嗪-2-基时,化合物称作磺胺林,
当R26=6-甲氧基-哒嗪-3-基时,化合物称作磺胺甲氧嗪,
当R26=4,6-二乙基-1,3,5-三嗪-2-基时,化合物称作磺胺均三嗪,
当R26=5-乙基-1,3,4-噻二唑-2-基时,化合物称作磺胺乙二唑,
当R26=5-甲基-1,3,4-噻二唑-2-基时,化合物称作磺胺甲二唑,
当R26=4-甲氧基-1,2,5-噻二唑-3-基时,化合物称作磺胺美曲,
当R26=4-甲基-噻唑-2-基时,化合物称作磺胺甲噻唑,
当R26=3-甲基-异噻唑-5-基时,化合物称作磺胺异噻唑,
当R26=4,5-二甲基-噁唑-2-基时,化合物称作磺胺噁唑,
当R26=3,4-二甲基-异噁唑-5-基时,化合物称作磺胺异噁唑,
当R26=4,5-二甲基-2-噁唑基氨基亚氨基甲基时,化合物称作磺胺胍诺,
当R26=5-甲基-异噁唑-3-基时,化合物称作磺胺甲噁唑,
当R26=1-苯基-1H-吡唑-5-基时,化合物称作磺胺苯吡唑,
当R26=4-甲基氨基磺酰基苯基时,化合物称作4’-(甲基氨磺酰基)对氨基苯磺酰基苯胺,
当R26=4-氨基磺酰基苯基时,化合物称作N4磺胺酰磺胺,
当R26=3,4-二甲基苯甲酰基时,化合物称作N-对氨基苯磺酰基-3,4-二甲基苯甲酰胺,
当R26=4-异丙氧基苯甲酰基时,化合物称作磺胺普罗林,
在类型VIII中:
当R27=H,R28=2,4-二氨基-6-羧基苯基时,化合物称作磺胺柯定,
当R27=H,R28=2,4-二氨基苯基时,化合物称作磺胺米柯定,
当R27=4,6-二甲基-嘧啶-2-基,R28=3-羧基-4-羟基苯基时,化合物称作柳氮磺嘧啶,
在类型IX中:
当R29=OH,R30=COOH时,化合物称作对氨基水杨酸,
当R29=OH,R30=肼基羰基时,化合物称作对氨基水杨酰肼,
当R29=OH,R30=苯氧基羰基时,化合物称作氨基水杨酸苯酯,
当R29=H,R30=4-(氨基)苯基亚硫酰基时,化合物称作4,4’-亚硫酰基二苯胺,
在类型X中:
当R31=氨基,R32=4-(羟基乙基氨基)苯基时,化合物称作2-对磺胺酰苯胺基乙醇,
当R31=氨基,R32=-N=C(NH2)2时,化合物称作磺胺脒,
当R31=NH2-CH2-,R32=氨基时,化合物称作磺胺米隆,
当R31=苄基氨基,R32=氨基时,化合物称作苄磺胺,
当R31=氨基,R32=4-(羧基甲基氨基)苯基时,化合物称作醋地砜,
当R31=氨基,R32=4-(氨基)苯基时,化合物称作氨苯砜,
当R31=氨基,R32=4-(羧基丙酰基氨基)苯基时,化合物称作琥珀氨苯砜,
当R31=氨基,R32=4-(氨基甲基)苯基时,化合物称作对-磺胺酰苄胺,
当R31=氨基,R32=2-氨基-噻唑-5-基时,化合物称作噻唑砜,
在类型XI中:
当R52=C2H5,R53=氨基,M=S时,化合物称作乙硫异烟胺,
当R52=H,R53=-NHNH2,M=O时,化合物称作异烟肼,
当R52=C3H7,R53=氨基,M=S时,化合物称作丙硫异烟胺,
当R52=H,R53=(XIA),M=O时,化合物称作苯磺烟肼,
当R52=H,R53=(XIB),M=O时,化合物称作维拉烟肼,
当R52=H,R53=(XIC),M=O时,化合物称作奥匹烟肼,
当R52=H,R53=(XID),M=O时,化合物称作水杨烟肼,
当R52=H,R53=(XIE),M=O时,化合物称作furonazide,
当R52=H,R53=(XIF),M=O时,化合物称作葡烟腙,
在类型XII中:
当R37=Cl时,化合物称作克林霉素,
当R37=OH时,化合物称作林可霉素,
在类型XIIIa中:
当R38=乙酰基,R39=异戊酰基,R40=H,R41=H时,化合物称作交沙霉素,
当R38=丙酰基,R39=丙酰基,R40=H,R41=H时,化合物称作麦迪霉素A1,
当R38=H,R39=丁酰基,R40=丙酰基,R41=H时,化合物称作罗他霉素,
当R38=H,R39=H,R40=H,R41=(XIIIaB)时,化合物称作螺旋霉素I,
当R38=乙酰基,R39=H,R40=H,R41=(XIIIaB)时,化合物称作螺旋霉素II,
当R38=丙酰基,R39=H,R40=H,R41=(XIIIaB)时,化合物称作螺旋霉素III,
当R38=H,R39=异戊酰基,R40=H,R41=H时,化合物称作柱晶白霉素,
在类型XIIIb中:
当R47=H,R48=H,W=-N(CH3)CH2-时,化合物称作阿奇霉素,
当R47=CH3,R48=H,W=羰基时,化合物称作克拉霉素,
当R47=H,R48=H,W=羰基时,化合物称作红霉素,
当R47=H,R48和W一起形成(XIIIbA)时,化合物称作地红霉素,
在类型XIVa中:
当R42=OH,R43=(S)-4-氨基-2-羟基丁酰基,R44=OH,R45=OH时,化合物称作阿米卡星,
当R42=氨基,R43=(R)-4-氨基-2-羟基丁酰基,R44=H,R45=H时,化合物称作阿贝卡星,
当R42=氨基,R43=H,R44=H,R45=H时,化合物称作地贝卡星,
当R42=氨基,R43=H,R44=OH,R45=H时,化合物称作妥布霉素,
在类型XIVb中:
当R46=-CH2OH时,化合物称作双氢链霉素,
当R46=-CHO时,化合物称作链霉素,
在类型XIVc中:
当R49=CH3时,化合物称作大观霉素,
当R49=C4H9时,化合物称作丙大观霉素,
在类型XIVd中:
当R50=H,R51=(XIVdA)时,化合物称作小诺米星,
当R50=C2H5,R51=3-氨基-6-(氨基甲基)-3,4-二氢-2H-吡喃-2-基时,化合物称作奈替米星,
当R50=H,R51=3-氨基-6-(氨基甲基)-3,4-二氢-2H-吡喃-2-基时,化合物称作西索米星,
在类型XIVe中:
当R60=氨基,R61=(XIVeA)时,化合物称作新霉素,
当R60=OH,R61=(XIVeB)时,化合物称作巴龙霉素,
当R60=氨基,R61=H时,化合物称作核糖霉素,
在类型XV中:
当R54=CH3时,化合物称作利福平,
当R54=环戊基时,化合物称作利福喷汀,
在类型XVIa中:
当Xb=N,R55=H,R56=OH,R57=β-D-呋喃核糖基时,化合物称作肌苷,
当Xb=N,R55=氨基,R56=H,R57=4-乙酰氧基-3-(乙酰氧基甲基)1-丁基时,化合物称作泛昔洛韦,
当Xb=C,R55=H,R56=氨基,R57=β-D-呋喃核糖基时,化合物称作杀结核菌素,
在类型XVIb中:
当R58=H,R59=β-D-(2,3-二脱氧)呋喃核糖基时,化合物称作去羟肌苷,
当R58=氨基,R59=CH2OCH2CH2OH时,化合物称作阿昔洛韦,
当R58=氨基,R59=CH2OCH2CH2OCOCH(NH2)CH(CH3)2时,化合物称作伐昔洛韦,
当R58=氨基,R59=CH2OCH(CH2OH)CH2OH时,化合物称作更昔洛韦。
4.权利要求3的化合物,该化合物选自:
在类型I中:
当R1=H,R2=H,R3=CH3,R4=OH,R5=H时,化合物称作多西环素,
当R1=H,R2=OH,R3=H,R4=OH,R5=H时,化合物称作土霉素,
当R1=H,R2=OH,R3=CH3,R4=H,R5=H时,化合物称作四环素,
在类型II中:
当R6=环丙基,R7=H,R8=F,R9=(IIA),伴随M=H,R10=H,X=Y=C时,化合物称作环丙沙星,
当R6=C2H5,R7=H,R8=H,R9=CH3,R10=自由价,X=N,Y=C时,化合物称作萘啶酸,
当R6=C2H5,R7=H,R8=F,R9=(IIA),伴随M=H,R10=H,X=Y=C时,化合物称作诺氟沙星,
当R6与R10形成二价基团(IIN),R7=H,R8=F,R9=(IIA),伴随M=CH3,X=Y=C时,化合物称作氧氟沙星,
在类型IIIa中:
当R11=H,R12=Cl,R13=氨基,R14=苯基,Z=S时,化合物称作头孢克洛,
当R11=H,R12=CH3,R13=氨基,R14=苯基,Z=S时,化合物称作头孢氨苄,
当R11=H,R12=(IIIaC),R13=OH,R14=苯基,Z=S时,化合物称作头孢孟多,
在类型IIIb中:
当R15=COOH,R16=乙烯基,R17=-OCH2OCOOH,X=N,Y=C时,化合物称作头孢克肟,
当R15=(CH3)2CHOCOOCH(CH3)OCO-,R16=C2H5,R17=OCH3,X=N,Y=C时,化合物称作头孢泊肟丙酯,
当R15=COOH,R16=(IIIbF),R17=OCH3,X=N,Y=C时,化合物称作头孢地秦,
在类型IIIc中:
当R18=(IIIcF),R19=(IIIcN)时,化合物称作头孢唑林,
在类型IVa中:
当R20=(IVaA)和R21=H时,化合物称作阿莫西林,
当R20=(IVaB)和R21=H时,化合物称作氨苄西林,
当R20=(IVaM)和R21=H时,化合物称作阿帕西林,
在类型IVb中:
当R22=H,R23=(IVbD)时,化合物称作亚胺培南,
在类型IVc中:
当R33=CH3,R34=CH3,R35=H,R36=CH3时,化合物称作氨曲南,
在类型V中:
当R24=OCH3时,化合物称作甲氧苄啶,
在类型VI中:
当R25=(VIE)时,化合物称作硝呋复林,
在类型VII中:
当R26=5-甲基-异噁唑-3-基时,化合物称作磺胺甲噁唑,
在类型X中:
当R31=氨基,R32=4-(氨基)苯基时,化合物称作氨苯砜,
在类型XI中:
当R52=C2H5,R53=氨基,M=S时,化合物称作乙硫异烟胺,
当R52=H,R53=-NHNH2,M=O时,化合物称作异烟肼,
在类型XIIIb中:
当R47=H,R48=H,W=-N(CH3)CH2-时,化合物称作阿奇霉素,
当R47=CH3,R48=H,W=羰基时,化合物称作克拉霉素,
当R47=H,R48=H,W=羰基时,化合物称作红霉素,
在类型XIVa中:
当R42=OH,R43=(S)-4-氨基-2-羟基丁酰基,R44=OH,R45=OH时,化合物称作阿米卡星,
当R42=氨基,R43=H,R44=OH,R45=H时,化合物称作妥布霉素,
在类型XIVb中:
当R46=-CHO时,化合物称作链霉素,
在类型XIVc中:
当R49=CH3时,化合物称作大观霉素,
在类型XIVd中:
当R50=C2H5,R51=3-氨基-6-(氨基甲基)-3,4-二氢-2H-吡喃-2-基时,化合物称作奈替米星,
在类型XIVe中:
当R60=氨基,R61=(XIVeA)时,化合物称作新霉素,
在类型XV中:
当R54=CH3时,化合物称作利福平,
在类型XVIa中:
当Xb=N,R55=H,R56=OH,R57=β-D-呋喃核糖基时,化合物称作肌苷,
当Xb=N,R55=氨基,R56=H,R57=4-乙酰氧基-3-(乙酰氧基甲基)1-丁基时,化合物称作泛昔洛韦,
在类型XVIb中:
当R58=H,R59=β-D-(2,3-二脱氧)呋喃核糖基时,化合物称作去羟肌苷,
当R58=氨基,R59=CH2OCH2CH2OH时,化合物称作阿昔洛韦,
当R58=氨基,R59=CH2OCH2CH2OCOCH(NH2)CH(CH3)2时,化合物称作伐昔洛韦,
当R58=氨基,R59=CH2OCH(CH2OH)CH2OH时,化合物称作更昔洛韦,
在类型XVII中:
O-2-氨基-2-脱氧-α-D-吡喃葡萄糖基-(1→4)-O-[3-脱氧-3-(甲基氨基)-α-D-吡喃木糖基-(1→6)]-2-脱氧-D-链霉胺(庆大霉素A),(S)-2-氨基-5-[(氨基亚氨基甲基)氨基]戊酸(精氨酸),(+)-2,2’-(亚乙基二亚氨基)二-1-丁醇(乙胺丁醇),1-氨基金刚烷(金刚烷胺),2’,3’-二脱氧胞嘧啶核苷(扎西他滨),吡嗪酰胺、吗甲吡嗪酰胺、替考拉宁、万古霉素。
5.权利要求1-4的包含硝基氧基的抗微生物药物的硝酸盐,其特征在于在它们的分子中存在一个或更多个,优选一个具有以下通式(I-N)的取代基,-B-(W)p-ONO2(I-N)其中:p为1或0;B=-TB-Y-TBI-,其中TB和TBI为相同或不同;TB为共价连接于药物分子的化学或活性官能团的化学官能团并且为(CO)或X,其中X=O、S、NH,条件是当药物的活性官能团为OH或NH2或SH时,X=(CO);当药物的活性官能团为羧基时,TB为X;TBI=(CO)tx或(X)txx,其中tx和txx为0或1;条件是当txx=0时,tx=1,当txx=1时,tx=0;X如上定义;Y为选自以下结构的二价连接桥:
其中:
nIX为0-3的整数,优选为1;
nIIX为0-3的整数,优选为1;
RTIX、RTIX’、RTIIX、RTIIX’彼此之间相同或不同,为H或线性
或分支的C1-C4烷基,RTIX、RTIX’、RTIIX RTIIX’优选为H;
Y3为包含至少一个能变成盐的氮原子的环;Y优选为包含一
或两个氮原子的杂环,该环为饱和的、不饱和的或芳族的,
优选具有5或6个原子;亚烷基R’,其中R’为线性或分支的C1-C20烷基,优选为C2-C6烷基,由一个或更多个以下的基团任选取代,包括:-NHCOR3Y,其中R3Y为线性或分支的C1-C5烷基,-NH2、-OH;C5-C7亚环烷基环,由R’任选取代,R’如上定义,其中亚环烷基的一个或更多个C原子能够由杂原子任选取代;其中n3为0-3的整数且n3’为1-3的整数;其中n3和n3’具有以上指明的含义;其中:R4Y为OH、H、烃氧基R5YO-,其中R5Y为线性或分支或环状的C1-C10烷基,R5Y优选为甲基;R2Y为包含一个或更多个双键的线性或分支的C2-C10亚链烯基,R2Y优选为亚乙烯基(-CH=CH-);
其中R1f=H、CH3且nf为0-6的整数;优选0-4;式(I-N)的W为二价基团-Tc-YT-,其中:当tx=0时,Tc=(CO),当txx=0时,Tc=X;条件是在式(I-N)中,当p=1时,YT不同于Y并且处于二价基团B中:
-Y为以上定义的具有取代基NHCOR3Y的R’,R’优选为C2饱和的烷基且R3Y为CH3;TB=S;TB1为-CO-;Y优选为-CH2-CH(NHCOCH3)-且式(I-N)中的B优选具有以下结构:或
Y为式(V-Y)的二价基团,其中R4Y为OR5Y且R5Y优选为CH3,
7.权利要求6的硝酸盐,其中Y3为包含一个氮原子的6-元芳族环,所述环在以下位置:2,6;2,3;2,5中具有两个自由价。
8.权利要求7的硝酸盐,其中Y3为在位置2和6上取代的Y12(pirydil)。
9.权利要求1-8的硝酸盐,其中使用在权利要求1-4中描述的化合物的一种或更多种异构体,包括光学异构体。
10.权利要求1-9的硝酸盐,该硝酸盐包含一个摩尔的硝酸根离子/一个摩尔的化合物。
11.权利要求1-10的抗微生物药物的硝酸盐化合物,该硝酸盐化合物不包括红霉素、异烟肼、吡嗪酰胺、甲硝唑、阿昔洛韦的硝酸盐。
12.权利要求1-10的硝酸盐在制备作为抗微生物剂的药物中的用途。
13.权利要求12的硝酸盐的用途,用于制备抗病毒、抗真菌和抗细菌药物。
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IT2000MI000092A IT1317735B1 (it) | 2000-01-26 | 2000-01-26 | Sali di agenti antimicrobici. |
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EP (1) | EP1253924B1 (zh) |
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CA (1) | CA2397754A1 (zh) |
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IT (1) | IT1317735B1 (zh) |
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- 2001-01-16 DK DK01909631T patent/DK1253924T3/da active
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- 2001-01-16 WO PCT/EP2001/000430 patent/WO2001054691A1/en active IP Right Grant
- 2001-01-16 AU AU37308/01A patent/AU785330B2/en not_active Ceased
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CN111295372A (zh) * | 2018-09-29 | 2020-06-16 | 江苏亚虹医药科技有限公司 | 硝羟喹啉前药及其用途 |
CN111295372B (zh) * | 2018-09-29 | 2021-03-09 | 江苏亚虹医药科技股份有限公司 | 硝羟喹啉前药及其用途 |
CN115745806A (zh) * | 2022-11-08 | 2023-03-07 | 天津民祥药业有限公司 | 盐酸金刚烷胺尾气料的回收工艺 |
CN115745806B (zh) * | 2022-11-08 | 2024-05-07 | 天津民祥药业有限公司 | 盐酸金刚烷胺尾气料的回收工艺 |
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WO2001054691A1 (en) | 2001-08-02 |
PT1253924E (pt) | 2006-09-29 |
AU3730801A (en) | 2001-08-07 |
RU2288231C2 (ru) | 2006-11-27 |
DE60118885T2 (de) | 2006-11-30 |
BR0107824A (pt) | 2002-11-05 |
ES2262629T3 (es) | 2006-12-01 |
DK1253924T3 (da) | 2006-08-21 |
EP1253924A1 (en) | 2002-11-06 |
ITMI20000092A1 (it) | 2001-07-26 |
US6794372B2 (en) | 2004-09-21 |
CY1105419T1 (el) | 2010-04-28 |
CA2397754A1 (en) | 2001-08-02 |
JP2003520814A (ja) | 2003-07-08 |
AU785330B2 (en) | 2007-01-18 |
ATE323488T1 (de) | 2006-05-15 |
US20030105066A1 (en) | 2003-06-05 |
DE60118885D1 (de) | 2006-05-24 |
ITMI20000092A0 (it) | 2000-01-26 |
EP1253924B1 (en) | 2006-04-19 |
MXPA02007239A (es) | 2002-12-09 |
KR20030016220A (ko) | 2003-02-26 |
IT1317735B1 (it) | 2003-07-15 |
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