CN114539213A - Fluoroquinolone compound and preparation method and application thereof - Google Patents
Fluoroquinolone compound and preparation method and application thereof Download PDFInfo
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- CN114539213A CN114539213A CN202210177192.8A CN202210177192A CN114539213A CN 114539213 A CN114539213 A CN 114539213A CN 202210177192 A CN202210177192 A CN 202210177192A CN 114539213 A CN114539213 A CN 114539213A
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- Prior art keywords
- compound
- fluoro
- chloro
- dihydro
- oxo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 64
- 229940124307 fluoroquinolone Drugs 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims description 43
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 15
- -1 hydroxy, mercapto Chemical class 0.000 claims description 136
- 150000003839 salts Chemical class 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 claims description 5
- 229940126086 compound 21 Drugs 0.000 claims description 5
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 claims description 4
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 4
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims description 4
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 4
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 claims description 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 4
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 claims description 4
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 claims description 4
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 4
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 claims description 4
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 claims description 4
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 claims description 4
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 claims description 4
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 claims description 4
- 229940126657 Compound 17 Drugs 0.000 claims description 4
- 229940126639 Compound 33 Drugs 0.000 claims description 4
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 claims description 4
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims description 4
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- ICSNLGPSRYBMBD-UHFFFAOYSA-N alpha-aminopyridine Natural products NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 229940125773 compound 10 Drugs 0.000 claims description 4
- 229940125797 compound 12 Drugs 0.000 claims description 4
- 229940126543 compound 14 Drugs 0.000 claims description 4
- 229940125758 compound 15 Drugs 0.000 claims description 4
- 229940126142 compound 16 Drugs 0.000 claims description 4
- 229940126208 compound 22 Drugs 0.000 claims description 4
- 229940125833 compound 23 Drugs 0.000 claims description 4
- 229940125961 compound 24 Drugs 0.000 claims description 4
- 229940125846 compound 25 Drugs 0.000 claims description 4
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- 229940125898 compound 5 Drugs 0.000 claims description 4
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 claims description 4
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- IEDMMCZBIKXEJP-UHFFFAOYSA-N 3-chloro-2,4,5-trifluorobenzoyl chloride Chemical compound FC1=CC(C(Cl)=O)=C(F)C(Cl)=C1F IEDMMCZBIKXEJP-UHFFFAOYSA-N 0.000 claims description 3
- 235000011054 acetic acid Nutrition 0.000 claims description 3
- 229940125904 compound 1 Drugs 0.000 claims description 3
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- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 claims description 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- DPBJAVGHACCNRL-UHFFFAOYSA-N 2-(dimethylamino)ethyl prop-2-enoate Chemical compound CN(C)CCOC(=O)C=C DPBJAVGHACCNRL-UHFFFAOYSA-N 0.000 claims description 2
- 150000003930 2-aminopyridines Chemical class 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 235000011007 phosphoric acid Nutrition 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 150000003335 secondary amines Chemical class 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims 1
- 230000008025 crystallization Effects 0.000 claims 1
- 238000001228 spectrum Methods 0.000 abstract description 5
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 38
- 239000007858 starting material Substances 0.000 description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- DYDCPNMLZGFQTM-UHFFFAOYSA-N delafloxacin Chemical compound C1=C(F)C(N)=NC(N2C3=C(Cl)C(N4CC(O)C4)=C(F)C=C3C(=O)C(C(O)=O)=C2)=C1F DYDCPNMLZGFQTM-UHFFFAOYSA-N 0.000 description 8
- 229950006412 delafloxacin Drugs 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000003242 anti bacterial agent Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 150000007660 quinolones Chemical class 0.000 description 5
- 229940088710 antibiotic agent Drugs 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 229940124350 antibacterial drug Drugs 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- 241000192125 Firmicutes Species 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- VEBLEROFGPOMPB-UHFFFAOYSA-N n-methylcyclopropanamine Chemical compound CNC1CC1 VEBLEROFGPOMPB-UHFFFAOYSA-N 0.000 description 2
- 229960000210 nalidixic acid Drugs 0.000 description 2
- 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 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 2
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- PMZDQRJGMBOQBF-UHFFFAOYSA-N 1H-quinolin-4-one Natural products C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 241000304886 Bacilli Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 238000002814 agar dilution Methods 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- JODDVGWNUWGSMG-UHFFFAOYSA-N ethyl 2-(dimethylamino)prop-2-enoate Chemical compound CCOC(=O)C(=C)N(C)C JODDVGWNUWGSMG-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The fluoroquinolone compound disclosed by the invention is wide in antibacterial spectrum and has very good inhibitory or bactericidal activity, so that the fluoroquinolone compound has a good application prospect.
Description
Technical Field
The invention relates to a fluoroquinolone compound and a preparation method and application thereof.
Background
Quinolones are compounds with aromatic ring structure skeletons such as pyridone acid biphenyl or pyridine. Quinolone antibiotics, which contain a 4-quinolone bicyclic core structure, are generally considered nalidixic acid, a by-product unexpectedly found in the synthesis of chloroquine, an antimalarial compound. In 1962, Lescher found that nalidixic acid had moderate activity against various gram-negative bacilli. In the last 70-80 years, the discovery of fluoroquinolones promoted the rapid development of quinolones and made them exhibit a broader spectrum of activity and better pharmacokinetics than the first generation of quinolones. Fluoroquinolones, such as ciprofloxacin and ofloxacin, not only have effects on gram-negative bacteria and gram-positive bacteria, but also can inhibit mycobacterium tuberculosis. After more than 50 years of development, fluoroquinolone antibiotics become the first-line anti-infective chemotherapeutic medicine with broad spectrum, high efficiency and low toxicity which is clinically most widely used at present after cephalosporin. However, with the widespread use and even abuse of such drugs, bacterial resistance has increased year by year and has become a troublesome problem worldwide. Even the problem of limited use (resistance limitation) of antibiotics arises. Therefore, the development of more characteristic excellent fluoroquinolone antibacterial agents is imperative.
Delafloxacin (Delafloxacin) is the latest generation of broad-spectrum fluoroquinolone antibacterial Drugs developed by Wakunaga pharmaceutical company in japan and Melinta bio usa, and was approved by the FDA for the treatment of acute bacterial skin and skin structure infections in 2017 (Expert Opinion on Investigational Drugs 2015,24, 433-488; Infection and Drug Resistance 2018,11, 479-488). The chemical name of delafloxacin is 1- (6-amino-3, 5-difluoro-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-hydroxy-1-azetidinyl) -4-oxo-3-quinolinecarboxylic acid, and the chemical structure of delafloxacin is different from that of most other fluoroquinolone medicaments, and is mainly represented by the following 3 points: 1) the compound lacks strong basic groups at the C-7 position, so that the compound is weakly acidic, and the antibacterial activity in a weakly acidic environment can be enhanced; 2) c-8 chlorine (consistent with C-6 fluorine) can generate strong electron-withdrawing effect on aromatic rings, which is helpful for improving the stability of the molecules; 3) the presence of a 6-amino-3, 5-difluoro-2-pyridinyl substitution at the N-1 position allows the formation of a larger molecular surface than other fluoroquinolones (Annals of Clinical Microbiology and antibiotics, 2016,15, 34.). Clinical research shows that compared with other quinolone drugs, delafloxacin has a wider antibacterial spectrum and a better antibacterial effect, and particularly has an increased antibacterial property on gram-positive bacteria, so that delafloxacin has strong competitiveness in the future antibacterial drug market and can be used for treating various diseases.
Disclosure of Invention
The invention provides a series of unreported quinolone compounds with wide antibacterial spectrum, strong antibacterial activity and low toxic and side effects, a preparation method and application thereof by modifying the structure of the fluoroquinolone drug delafloxacin on the background, and the quinolone compounds show good results in antibacterial activity tests.
In order to realize the purpose, the technical scheme is as follows: a fluoroquinolone compound represented by formula (I), or a salt or hydrate thereof:
wherein R is1、R2、R3、R4Respectively is one of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C5-C6 cycloalkyl, C1-C6 alkyloxy, C1-C6 hydroxyalkylene, C1-C6 alkylmercapto, C1-C6 mercaptoalkylene, C1-C6 alkylamino, halogen, hydroxy, mercapto, cyano, nitro, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoromethyl and fluoromethoxy; r5Is C1-C4 alkoxy, halogenated C1-C4 alkoxy, NRbRcOr a multiple heterocyclic group.
Preferably, said R is1、R2、R3、R4Respectively is one of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, sulfydryl, cyano-group, nitryl, trifluoromethyl, trifluoromethoxy, difluoromethyl and difluoromethoxy; the R is5Is NRbRcOr a multiple heterocyclic group.
Preferably, said R is1、R2、R3、R4Respectively is one of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, sulfydryl, cyano-group, nitryl, trifluoromethyl, trifluoromethoxy, difluoromethyl and difluoromethoxy; the R is5Is NH (CH)3)、NH(CH2CH2CH3)、NH(CH2CH2CH2CH3)、N(CH2CH2CH3)2、N(CH3)(CH2CH3)、N(CH3)(CH2CH2CH3)、N(CH3)(CH2CH2CH2CH3)、N(CH2CH3)(CH2CH2CH3)、N(CH2CH3)(CH2CH2CH2CH3)、
Or a multiple heterocyclic group.
Preferably, said R is1、R2、R3、R4Respectively one of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, sulfydryl, cyano-group, nitro-group, trifluoromethyl, trifluoromethoxy, difluoromethyl and difluoromethoxy; the R is5Is composed of
Preferably, the fluoroquinolone compound is selected from:
compound 1
1- (2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (cyclopropyl (methyl) amino) -4-oxo-3-quinolinecarboxylic acid,
compound 2
1- (2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (cyclobutyl (methyl) amino) -4-oxo-3-quinolinecarboxylic acid,
compound 3
1- (2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-pyrrolidinyl-4-oxo-3-quinolinecarboxylic acid,
compound 4
1- (2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 5
1- (6-methyl-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-cyclobutylamino-4-oxo-3-quinolinecarboxylic acid,
compound 6
1- (6-methyl-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 7
1- (5-ethyl-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (cyclopentyl (methyl) amino) -4-oxo-3-quinolinecarboxylic acid,
compound 8
1- (5-ethyl-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-cyclopentylamino-4-oxo-3-quinolinecarboxylic acid,
compound 9
1- (4-methoxy-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (cyclohexyl (methyl) amino) -4-oxo-3-quinolinecarboxylic acid,
compound 10
1- (4-methoxy-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 11
1- (3, 5-dimethyl-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 12
1- (3-bromo-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (4-methylpiperazinyl) -4-oxo-3-quinolinecarboxylic acid,
compound 13
1- (3-bromo-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 14
1- (4-fluoro-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 15
1- (4-fluoro-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-methylpiperazin-1-yl) -4-oxo-3-quinolinecarboxylic acid,
compound 16
1- (5-chloro-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3, 5-dimethylpiperazin-1-yl) -4-oxo-3-quinolinecarboxylic acid,
compound 17
1- (5-chloro-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7-morpholine-4-oxo-3-quinolinecarboxylic acid,
compound 18
1- (6-hydroxy-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 19
1- (6-hydroxy-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-thiomorpholine-4-oxo-3-quinolinecarboxylic acid,
compound 20
1- (6-mercapto-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 21
1- (6-mercapto-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperidinyl-4-oxo-3-quinolinecarboxylic acid,
compound 22
1- (3-cyano-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 23
1- (3-cyano-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-pyrrolidinyl-4-oxo-3-quinolinecarboxylic acid,
compound 24
1- (4-nitro-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 25
1- (4-nitro-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid,
compound 26
1- (4-trifluoromethyl-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 27
1- (4-trifluoromethyl-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-aminopyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid,
compound 28
1- (5-trifluoromethoxy-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-hydroxyazetidinyl) -4-oxo-3-quinolinecarboxylic acid,
compound 29
1- (5-trifluoromethoxy-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-aminoazetidinyl) -4-oxo-3-quinolinecarboxylic acid,
compound 30
1- (6-difluoromethyl-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 31
1- (4-difluoromethoxy-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 32
1- (3-iodo-5-bromo-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 33
1- (3-nitro-6-fluoro-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 34
1- (2-quinolinyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid.
Preferably, the salt is formed by the fluoroquinolone compound and acid, and the acid is hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid or malic acid.
Preferably, the number of crystal water of the hydrate is any real number from 0 to 16.
The invention provides a preparation method of the fluoroquinolone compound, which comprises the following steps:
performing addition coupling reaction on 3-chloro-2, 4, 5-trifluorobenzoyl chloride and N, N-dimethylamino ethyl acrylate, performing substitution reaction on the obtained product with substituted 2-aminopyridine, performing cyclization through intramolecular nucleophilic substitution, hydrolyzing to obtain a compound V, and performing aromatic nucleophilic substitution reaction on the compound V and secondary amine to obtain the fluoroquinolone compound; the reaction formula of the preparation method is as follows:
the invention provides a pharmaceutical composition, which comprises the fluoroquinolone compound or the salt or hydrate thereof and a pharmaceutically acceptable carrier.
The invention provides an application of the fluoroquinolone compound or the salt or hydrate thereof or the pharmaceutical composition in preparing antibacterial drugs.
Has the advantages that:
the fluoroquinolone compound disclosed by the invention is wide in antibacterial spectrum and has very good inhibitory or bactericidal activity, so that the fluoroquinolone compound has a good application prospect.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.
Example 1: preparation of 1- (2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (cyclopropyl (methyl) amino) -4-oxo-3-quinolinecarboxylic acid (compound 1):
a) ethyl N, N-dimethylaminoacrylate (3.1g,24.0mmol), triethylamine (2.6g,26.2mmol) and toluene (40mL) were mixed, a mixed solution of 3-chloro-2, 4, 5-trifluorobenzoyl chloride (5g,21.8mmol) and toluene (20mL) was added dropwise, heated to 50 ℃ and concentrated after TLC monitoring for about 1 hour to complete the reaction, yielding 7.3g of compound II in 99% yield. LC/MS [ M + H ]]+＝336.05、[M+Na]+＝358.08、[M+K]+＝374.04。
b) Mixing the compound II (7g,20.8mmol), ethanol (70mL) and glacial acetic acid (3mL), dropwise adding an ethanol solution of 2-aminopyridine (2.1g,22.8mmol) at room temperature, heating to 40 ℃ after dropwise adding, cooling after TLC monitoring reaction, slowly adding a proper amount of water into the reaction liquid, stirring and filtering, and drying to obtain 7.6g of the compound III with the yield of 95%. LC/MS [ M + H ]]+＝385.05、[M+Na]+＝407.06、[M+K]+＝423.05。
c) Compound III (7.6g,19.7mmol), anhydrous potassium carbonate (4.1g,29.6mmol), and N, N-dimethylformamide (50mL) were mixed, heated to 90 ℃ and stirred for 2 hours, after completion of the TLC monitoring reaction, cooled, and the reaction mixture was slowly added with an appropriate amount of water, stirred, filtered, and dried to give compound IV 6.9g, with a yield of 96%. LC/MS [ M + H ]]+＝365.04、[M+Na]+＝387.06、[M+K]+＝403.04。
d) Compound IV (6.9g,18.9mmol), acetic acid (20mL), 6M HCl (4mL) were mixed, heated to 90-95 ℃ for reflux reaction for 4 hours, TLC monitored the completion of the reaction, cooled, added a suitable amount of water slowly to the reaction solution, stirred and filtered, the filter cake was washed with water to neutrality, and dried to give compound V6.0 g, yield 94%. LC/MS [ M + H ]]+＝337.01、[M+Na]+＝359.03、[M+K]+＝375.04。
e) Compound V (1.7g, 5.0mmol) is added to a suspension of N-methylcyclopropylamine (0.5g, 7.5mmol), triethylamine (1.0g, 10.0mmol) and acetonitrile (20mL), and the mixture is then refluxed until the absence of starting material is detected by TLC (typically 5-8 hours). The solution was cooled to room temperature and filtered, and the filter cake was washed with water and ether to give the crude product. Followed by recrystallizationAfter purification (DMF/EtOH), the desired product, 1.1g, 56% yield, 1- (2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (cyclopropyl (methyl) amino) -4-oxo-3-quinolinecarboxylic acid, was obtained. LC/MS [ M + H ]]+＝388.08、[M+Na]+＝410.05、[M+K]+＝426.01。
Example 2: preparation of 1- (2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (cyclobutyl (methyl) amino) -4-oxo-3-quinolinecarboxylic acid (compound 2):
compound V (1.7g, 5.0mmol) is added to a suspension of N-methylcyclopropylamine (0.6g, 7.5mmol), triethylamine (1.0g, 10.0mmol) and acetonitrile (20mL), and the mixture is then refluxed until the absence of starting material is detected by TLC (typically 5-8 hours). The solution was cooled to room temperature and filtered, and the filter cake was washed with water and ether to give the crude product. Subsequent purification by recrystallization (DMF/EtOH) gave the desired product 1- (2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (cyclobutyl (methyl) amino) -4-oxo-3-quinolinecarboxylic acid in 1.2g, 60% yield. LC/MS [ M + H ]]+＝402.08、[M+Na]+＝424.09、[M+K]+＝440.06。
Example 3: preparation of 1- (2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-pyrrolidinyl-4-oxo-3-quinolinecarboxylic acid (compound 3):
compound V (1.7g, 5.0mmol) was added to a suspension of tetrahydropyrrole (0.5g, 7.5mmol), triethylamine (1.0g, 10.0mmol) and acetonitrile (20mL), and the mixture was refluxed until no starting material was present as detected by TLC (typically 5-8 hours). The solution was cooled to room temperature and filtered, and the filter cake was washed with water and ether to give the crude product. Subsequent purification by recrystallization (DMF/EtOH) gave the desired product 1- (2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (cyclobutyl (methyl) amino) -4-oxo-3-quinolinecarboxylic acid in 1.0g, 53% yield. LC/MS [ M + H ]]+＝388.08、[M+Na]+＝410.05、[M+K]+＝426.08。
Example 4: preparation of 1- (2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid (Compound 4):
compound V (1.7g, 5.0mmol) was added to a suspension of anhydrous piperazine (0.6g, 7.5mmol), triethylamine (1.0g, 10.0mmol) and acetonitrile (20mL)The mixture is then refluxed until the absence of starting material is detected by TLC (typically 5-8 hours). The solution was cooled to room temperature and filtered, and the filter cake was washed with water and ether to give the crude product. Subsequent purification by recrystallization (DMF/EtOH) gave the desired product 1- (2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (cyclobutyl (methyl) amino) -4-oxo-3-quinolinecarboxylic acid in 1.3g, 65% yield. LC/MS [ M + H ]]+＝403.09、[M+Na]+＝425.08、[M+K]+＝441.09。
Example 5: preparation of 1- (6-methyl-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-cyclobutylamino-4-oxo-3-quinolinecarboxylic acid (Compound 5):
compound 5 was prepared in 62% yield in the same manner as in example 1, except that the corresponding starting material was used. LC/MS [ M + H ]]+＝403.09、[M+Na]+＝425.08、[M+K]+＝441.09。
Example 6: preparation of 1- (6-methyl-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid (Compound 6):
compound 6 was prepared in 58% yield in the same manner as in example 1, except that the corresponding starting material was used. LC/MS [ M + H ]]+＝417.11、[M+Na]+＝439.10、[M+K]+＝455.11。
Example 7: preparation of 1- (5-ethyl-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (cyclopentyl (methyl) amino) -4-oxo-3-quinolinecarboxylic acid (compound 7):
compound 7 was prepared in 49% yield in the same manner as in example 1, except that the corresponding starting material was used. LC/MS [ M + H ]]+＝444.14、[M+Na]+＝466.13、[M+K]+＝482.11。
Example 8: preparation of 1- (5-ethyl-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-cyclopentylamino-4-oxo-3-quinolinecarboxylic acid (compound 8):
compound 8 was prepared in 53% yield in the same manner as in example 1, except that the corresponding starting material was used. LC/MS [ M + H ]]+＝430.13、[M+Na]+＝452.15、[M+K]+＝468.13。
Example 9: preparation of 1- (4-methoxy-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (cyclohexyl (methyl) amino) -4-oxo-3-quinolinecarboxylic acid (Compound 9):
compound 9 was prepared in the same manner as in example 1 with the exception of using the corresponding starting material in 56% yield. LC/MS [ M + H ]]+＝460.14、[M+Na]+＝482.14、[M+K]+＝498.14。
Example 10: preparation of 1- (4-methoxy-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid (Compound 10):
compound 10 was prepared in the same manner as in example 1, except that the corresponding starting material was used, in a yield of 63%. LC/MS [ M + H ]]+＝433.09、[M+Na]+＝435.10、[M+K]+＝471.10。
Example 11: preparation of 1- (3, 5-dimethyl-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid (Compound 11):
compound 11 was prepared in 60% yield in the same manner as in example 1, except that the corresponding starting material was used. LC/MS [ M + H ]]+＝431.11、[M+Na]+＝453.12、[M+K]+＝469.12。
Example 12: preparation of 1- (3-bromo-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (4-methylpiperazinyl) -4-oxo-3-quinolinecarboxylic acid (compound 12):
compound 12 was prepared in 58% yield in the same manner as in example 1, except that the corresponding starting material was used. LC/MS [ M + H ]]+＝495.02、[M+Na]+＝517.02、[M+K]+＝533.02。
Example 13: preparation of 1- (3-bromo-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid (compound 13):
compound 13 was prepared in 55% yield in the same manner as in example 1, except that the corresponding starting material was used. LC/MS [ M + H ]]+＝481.00、[M+Na]+＝503.00、[M+K]+＝519.01。
Example 14: preparation of 1- (4-fluoro-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid (compound 14):
compound 14 was prepared in the same manner as in example 1 with the exception of using the corresponding starting material in a yield of 63%. LC/MS [ M + H ]]+＝421.08、[M+Na]+＝443.08、[M+K]+＝459.09。
Example 15: preparation of 1- (4-fluoro-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-methylpiperazin-1-yl) -4-oxo-3-quinolinecarboxylic acid (compound 15):
compound 15 was prepared in 55% yield in the same manner as in example 1, except that the corresponding starting material was used. LC/MS [ M + H ]]+＝435.10、[M+Na]+＝457.09、[M+K]+＝473.10。
Example 16: preparation of 1- (5-chloro-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3, 5-dimethylpiperazin-1-yl) -4-oxo-3-quinolinecarboxylic acid (compound 16):
compound 16 was prepared in 48% yield in the same manner as in example 1, except that the corresponding starting materials were used. LC/MS [ M + H ]]+＝465.09、[M+Na]+＝487.08、[M+K]+＝503.08。
Example 17: preparation of 1- (5-chloro-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7-morpholine-4-oxo-3-quinolinecarboxylic acid (compound 17):
compound 17 was prepared in the same manner as in example 1, except that the corresponding starting material was used, in a yield of 57%. LC/MS [ M + H ]]+＝438.03、[M+Na]+＝460.03、[M+K]+＝476.03。
Example 18: preparation of 1- (6-hydroxy-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid (compound 18):
compound 18 was prepared in 44% yield in the same manner as in example 1, except that the corresponding starting material was used. LC/MS [ M + H ]]+＝419.08、[M+Na]+＝441.09、[M+K]+＝457.08。
Example 19: preparation of 1- (6-hydroxy-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7-thiomorpholine-4-oxo-3-quinolinecarboxylic acid (Compound 19):
compound 19 was prepared in 46% yield in the same manner as in example 1, except that the corresponding starting material was used. LC/MS [ M + H ]]+＝436.05、[M+Na]+＝458.05、[M+K]+＝474.04。
Example 20: preparation of 1- (6-mercapto-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid (compound 20):
compound 21 was prepared in 43% yield in the same manner as in example 1, except that the corresponding starting material was used. LC/MS [ M + H ]]+＝435.06、[M+Na]+＝457.06、[M+K]+＝473.06。
Example 21: preparation of 1- (6-mercapto-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperidinyl-4-oxo-3-quinolinecarboxylic acid (compound 21):
compound 21 was prepared in the same manner as in example 1, with a yield of 48%, except that the corresponding starting material was used. LC/MS [ M + H ]]+＝434.07、[M+Na]+＝456.08、[M+K]+＝472.07。
Example 22: preparation of 1- (3-cyano-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid (compound 22):
compound 22 was prepared in the same manner as in example 1 with a yield of 56% except that the corresponding starting material was used. LC/MS [ M + H ]]+＝429.08、[M+Na]+＝450.08、[M+K]+＝466.08。
Example 23: preparation of 1- (3-cyano-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7-pyrrolidinyl-4-oxo-3-quinolinecarboxylic acid (compound 23):
compound 23 was prepared in the same manner as in example 1, except that the corresponding starting material was used, in a yield of 59%. LC/MS [ M + H ]]+＝413.07、[M+Na]+＝435.08、[M+K]+＝451.07。
Example 24: preparation of 1- (4-nitro-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid (compound 24):
compound 24 was prepared in the same manner as in example 1, except that the corresponding starting material was used, in a yield of 64%. LC/MS [ M + H ]]+＝448.09、[M+Na]+＝470.07、[M+K]+＝486.07。
Example 25: preparation of 1- (4-nitro-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid (compound 25):
compound 25 was prepared in 53% yield in the same manner as in example 1, except that the corresponding starting material was used. LC/MS [ M + H ]]+＝449.06、[M+Na]+＝471.06、[M+K]+＝487.05。
Example 26: preparation of 1- (4-trifluoromethyl-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid (compound 26):
compound 26 was prepared in the same manner as in example 1, except that the corresponding starting material was used, in a yield of 60%. LC/MS [ M + H ]]+＝471.09、[M+Na]+＝493.08、[M+K]+＝509.08。
Example 27: preparation of 1- (4-trifluoromethyl-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-aminopyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid (compound 27):
compound 27 was prepared in the same manner as in example 1, except that the corresponding starting material was used, in 44% yield. LC/MS [ M + H ]]+＝471.08、[M+Na]+＝493.09、[M+K]+＝509.08。
Example 28: preparation of 1- (5-trifluoromethoxy-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-hydroxyazetidinyl) -4-oxo-3-quinolinecarboxylic acid (compound 28):
compound 28 was prepared in the same manner as in example 1, except that the corresponding starting material was used, in a yield of 41%. LC/MS [ M + H ]]+＝474.05、[M+Na]+＝496.04、[M+K]+＝512.05。
Example 29: preparation of 1- (5-trifluoromethoxy-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-aminoazetidinyl) -4-oxo-3-quinolinecarboxylic acid (compound 29):
compound 29 was prepared in the same manner as in example 1, except that the corresponding starting material was used, in a yield of 40%. LC/MS [ M + H ]]+＝473.06、[M+Na]+＝495.06、[M+K]+＝511.06。
Example 30: preparation of 1- (6-difluoromethyl-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid (compound 30):
compound 30 was prepared in the same manner as in example 1, except that the corresponding starting material was used, in a yield of 63%. LC/MS [ M + H ]]+＝453.09、[M+Na]+＝475.06、[M+K]+＝491.09。
Example 31: preparation of 1- (4-difluoromethoxy-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid (compound 31):
compound 31 was prepared in 54% yield in the same manner as in example 1, except that the corresponding starting material was used. LC/MS [ M + H ]]+＝469.09、[M+Na]+＝491.08、[M+K]+＝507.10。
Example 32: preparation of 1- (3-iodo-5-bromo-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid (compound 32):
compound 32 was prepared in 58% yield in the same manner as in example 1, except that the corresponding starting material was used. LC/MS [ M + H ]]+＝606.89、[M+Na]+＝628.90、[M+K]+＝644.90。
Example 33: preparation of 1- (3-nitro-6-fluoro-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid (compound 33):
compound 33 was prepared in 66% yield in the same manner as in example 1, except that the corresponding starting material was used. LC/MS [ M + H ]]+＝466.07、[M+Na]+＝488.07、[M+K]+＝504.05。
Example 34: preparation of 1- (2-quinolyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid (Compound 34):
compound 34 was prepared in the same manner as in example 1, except that the corresponding starting material was used, in 51% yield. LC/MS [ M + H ]]+＝453.09、[M+Na]+＝475.11、[M+K]+＝491.12。
Example 35: antibacterial Activity test of Compounds of the present invention
To clarify the utility of the synthesized compounds, the minimum inhibitory concentrations (MIcs) of some target compounds were determined by the agar dilution method according to the CLSI standard. The experimental medium is Mueller. Hinton agar, and the culture plate is cultured for 18-24 h at 35 ℃. Specific results of the specific antimicrobial activity test are shown in table 1:
TABLE 1 in vitro antibacterial Activity of Compounds of the invention
Experimental results show that the compounds contained in the chemical structural general formula I generally have strong antibacterial activity.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. A fluoroquinolone compound represented by formula (I), or a salt or hydrate thereof:
wherein R is1、R2、R3、R4Respectively is one of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C5-C6 cycloalkyl, C1-C6 alkyloxy, C1-C6 hydroxyalkylene, C1-C6 alkylmercapto, C1-C6 mercaptoalkylene, C1-C6 alkylamino, halogen, hydroxy, mercapto, cyano, nitro, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoromethyl and fluoromethoxy; r5Is C1-C4 alkoxy, halogenated C1-C4 alkoxy, NRbRcOr a multiple heterocyclic group.
2. The fluoroquinolone compound or the salt or hydrate thereof according to claim 1, wherein R is1、R2、R3、R4Respectively is one of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, sulfydryl, cyano-group, nitryl, trifluoromethyl, trifluoromethoxy, difluoromethyl and difluoromethoxy; the R is5Is NRbRcOr a multiple heterocyclic group.
3. The fluoroquinolone compound or the salt or hydrate thereof according to claim 1 or 2, wherein R is1、R2、R3、R4Respectively is one of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, sulfydryl, cyano-group, nitryl, trifluoromethyl, trifluoromethoxy, difluoromethyl and difluoromethoxy; the R is5Is NH (CH)3)、NH(CH2CH2CH3)、NH(CH2CH2CH2CH3)、N(CH2CH2CH3)2、N(CH3)(CH2CH3)、N(CH3)(CH2CH2CH3)、N(CH3)(CH2CH2CH2CH3)、N(CH2CH3)(CH2CH2CH3)、N(CH2CH3)(CH2CH2CH2CH3)、
Or a multiple heterocyclic group.
4. A fluoroquinolone compound or a salt or hydrate thereof according to any one of claims 1 to 3, wherein R is1、R2、R3、R4Respectively are hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, sulfydryl, cyano,One of nitro, trifluoromethyl, trifluoromethoxy, difluoromethyl and difluoromethoxy; the R is5Is composed of
5. A fluoroquinolone compound, or a salt or hydrate thereof, according to any one of claims 1 to 3, wherein said fluoroquinolone compound is selected from the group consisting of:
compound 1
1- (2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (cyclopropyl (methyl) amino) -4-oxo-3-quinolinecarboxylic acid,
compound 2
1- (2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (cyclobutyl (methyl) amino) -4-oxo-3-quinolinecarboxylic acid,
compound 3
1- (2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-pyrrolidinyl-4-oxo-3-quinolinecarboxylic acid,
compound 4
1- (2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 5
1- (6-methyl-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-cyclobutylamino-4-oxo-3-quinolinecarboxylic acid,
compound 6
1- (6-methyl-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 7
1- (5-ethyl-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (cyclopentyl (methyl) amino) -4-oxo-3-quinolinecarboxylic acid,
compound 8
1- (5-ethyl-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-cyclopentylamino-4-oxo-3-quinolinecarboxylic acid,
compound 9
1- (4-methoxy-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (cyclohexyl (methyl) amino) -4-oxo-3-quinolinecarboxylic acid,
compound 10
1- (4-methoxy-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 11
1- (3, 5-dimethyl-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 12
1- (3-bromo-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (4-methylpiperazinyl) -4-oxo-3-quinolinecarboxylic acid,
compound 13
1- (3-bromo-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 14
1- (4-fluoro-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 15
1- (4-fluoro-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-methylpiperazin-1-yl) -4-oxo-3-quinolinecarboxylic acid,
compound 16
1- (5-chloro-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3, 5-dimethylpiperazin-1-yl) -4-oxo-3-quinolinecarboxylic acid,
compound 17
1- (5-chloro-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7-morpholine-4-oxo-3-quinolinecarboxylic acid,
compound 18
1- (6-hydroxy-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 19
1- (6-hydroxy-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7-thiomorpholin-4-oxo-3-quinolinecarboxylic acid,
compound 20
1- (6-mercapto-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 21
1- (6-mercapto-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperidinyl-4-oxo-3-quinolinecarboxylic acid,
compound 22
1- (3-cyano-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 23
1- (3-cyano-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-pyrrolidinyl-4-oxo-3-quinolinecarboxylic acid,
compound 24
1- (4-nitro-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 25
1- (4-nitro-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid,
compound 26
1- (4-trifluoromethyl-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 27
1- (4-trifluoromethyl-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-aminopyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid,
compound 28
1- (5-trifluoromethoxy-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-hydroxyazetidinyl) -4-oxo-3-quinolinecarboxylic acid,
compound 29
1- (5-trifluoromethoxy-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-aminoazetidinyl) -4-oxo-3-quinolinecarboxylic acid,
compound 30
1- (6-difluoromethyl-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 31
1- (4-difluoromethoxy-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 32
1- (3-iodo-5-bromo-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 33
1- (3-nitro-6-fluoro-2-pyridyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid,
compound 34
1- (2-quinolinyl) -8-chloro-6-fluoro-1, 4-dihydro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid.
6. A fluoroquinolone compound or a salt or hydrate thereof according to any one of claims 1 to 5, wherein the salt is a salt of the fluoroquinolone compound with an acid selected from the group consisting of hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid and malic acid.
7. The fluoroquinolone compound or the salt or hydrate thereof according to any one of claims 1 to 5, wherein the hydrate has a real number of water of crystallization from 0 to 16.
8. A process for the preparation of a fluoroquinolone compound according to any one of claims 1 to 7, comprising the steps of:
performing addition coupling reaction on 3-chloro-2, 4, 5-trifluorobenzoyl chloride and N, N-dimethylamino ethyl acrylate, performing substitution reaction on the obtained product with substituted 2-aminopyridine, performing cyclization through intramolecular nucleophilic substitution, hydrolyzing to obtain a compound V, and performing aromatic nucleophilic substitution reaction on the compound V and secondary amine to obtain the fluoroquinolone compound; the reaction equation of the preparation method is as follows:
9. a pharmaceutical composition comprising a fluoroquinolone compound or salt or hydrate thereof according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier.
10. Use of a fluoroquinolone compound or a salt or hydrate thereof according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 9 for the preparation of an antibacterial medicament.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1201459A (en) * | 1995-09-22 | 1998-12-09 | 涌永制药株式会社 | Novel pyridonecarboxylic acid derivatives or their salts and antibacterial agent comprising same as active ingredient |
| US6136823A (en) * | 1996-11-28 | 2000-10-24 | Wakunaga Pharmaceutical Co., Ltd. | Pyridonecarboxylic acid derivatives or salts thereof and drugs containing the same as the active ingredient |
| CN101061109A (en) * | 2004-11-17 | 2007-10-24 | 湧永制药株式会社 | Novel pyridonecarboxylic acid derivatives or salts thereof |
| CN101792443A (en) * | 2010-03-09 | 2010-08-04 | 北京欧凯纳斯科技有限公司 | Fluoro-carbostyril derivative as well as preparation method and application thereof |
| CN103524487A (en) * | 2013-09-29 | 2014-01-22 | 南京优科生物医药研究有限公司 | Sitafloxacin preparation method |
-
2022
- 2022-02-24 CN CN202210177192.8A patent/CN114539213A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1201459A (en) * | 1995-09-22 | 1998-12-09 | 涌永制药株式会社 | Novel pyridonecarboxylic acid derivatives or their salts and antibacterial agent comprising same as active ingredient |
| US6136823A (en) * | 1996-11-28 | 2000-10-24 | Wakunaga Pharmaceutical Co., Ltd. | Pyridonecarboxylic acid derivatives or salts thereof and drugs containing the same as the active ingredient |
| CN101061109A (en) * | 2004-11-17 | 2007-10-24 | 湧永制药株式会社 | Novel pyridonecarboxylic acid derivatives or salts thereof |
| CN101792443A (en) * | 2010-03-09 | 2010-08-04 | 北京欧凯纳斯科技有限公司 | Fluoro-carbostyril derivative as well as preparation method and application thereof |
| CN103524487A (en) * | 2013-09-29 | 2014-01-22 | 南京优科生物医药研究有限公司 | Sitafloxacin preparation method |
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