1. A fluoroquinolone derivative having a structure represented by general formula (I) or an isomer thereof or a pharmaceutically acceptable salt thereof or a mixture of the foregoing structures:

wherein: r₁Alkyl selected from C1-C4; or R₁Selected from spiro or bridged alkane chains sharing one or two carbon atoms with the pyrrolidinyl group to which they are attached, R₁Contains 1 to 6 carbon atoms;

selecting one O atom on benzene ring and R₂Or R₃Connecting: and R₂When they are linked, R₂Selected from substituted or unsubstituted C2-C4 alkylene, R₃Is absent; and R₃When they are linked, R₂Selected from the group consisting of C3-C6 cycloalkyl, R₃Is selected from alkyl of C1-C3.

2. The fluoroquinolone derivative according to claim 1, having a structure represented by general formula (I-a) or (I-2) or an isomer thereof or a pharmaceutically acceptable salt thereof or a mixture of the aforementioned structures:

n1 is a natural number of 1 to 3.

3. A fluoroquinolone derivative according to claim 1 or 2, wherein the salt is a hydrochloride salt.

4. A fluoroquinolone derivative according to claim 1 or 2, wherein R₁When they share two carbon atoms with the pyrrolidinyl group to which they are attached, the carbon atom is NH in formula (I)₂The C atom to which it is attached.

5. A fluoroquinolone derivative according to claim 1 or 2, having the structure shown in the following structural formula or isomers thereof or pharmaceutically acceptable salts thereof or mixtures of the above structures:

6. the fluoroquinolone derivative according to claim 1 or 2, wherein the fluoroquinolone derivative is obtained by subjecting a raw material represented by formula (3) and a raw material represented by formula (1) to substitution reaction and deprotection:

7. an antibacterial drug comprising one or more fluoroquinolone derivatives according to any one of claims 1 to 6.

8. The antibacterial agent according to claim 7, wherein the antibacterial agent is an antibacterial agent that inhibits one or more of Escherichia coli, Staphylococcus aureus, and Tetragenococcus.

Background

The increase in bacterial resistance has become a serious problem in the clinical practice of antimicrobial chemotherapy. Since the incidence of drug-resistant bacteria such as methicillin-resistant staphylococcus aureus (MRSA), vancomycin-resistant streptococcus (VRE), and penicillin-resistant streptococcus (PRSP) is on the rise, there is an urgent need to develop effective drugs for infection.

Quinolone antibacterial agents are mainly achieved by inhibiting DNA gyrase and topoisomerase iv in bacteria, thereby causing DNA double strand breaks and preventing their reconnection. The 1 st generation quinolone drugs were marketed in 1962 with only moderate activity against gram-negative bacteria and low oral absorption. Through structural modification, 2 nd, 3 rd and 4 th generation quinolone medicaments are developed and produced, and representative thereof are pipemidic acid, ciprofloxacin, moxifloxacin and the like.

The fluoroquinolone medicaments are chemically synthesized medicaments taking 4-oxo-1, 4-dihydroquinoline-3-carboxylic acid as a parent nucleus structure, have remarkable medicinal properties, such as broad-spectrum bactericidal property, small toxic and side effects after use, relatively simple and easy synthesis of a medicament molecular structure, moderate medicament price and broad-spectrum activity, and become antibacterial medicaments which are synthesized, developed and applied quickly at home and abroad (Chang, X.; Meyer, M.T.; Liu, X.; et al. Envrion. Polluti.2010, 53,1444; Andreu, V.; Blasco C.; Pic, Y.TrAC Trends in antibacterial chemistry.2007,26,534).

Disclosure of Invention

The invention provides a fluoroquinolone derivative with a good antibacterial effect.

The invention also provides an antibacterial drug which comprises one or more of the fluoroquinolone derivatives and has a good antibacterial effect on test bacteria.

A fluoroquinolone derivative having a structure represented by general formula (I) or an isomer thereof or a pharmaceutically acceptable salt thereof or a mixture of the foregoing structures:

wherein: r₁Alkyl selected from C1-C4; or R₁Selected from spiro or bridged alkane chains sharing one or two carbon atoms with the pyrrolidinyl group to which they are attached, R₁Contains 1 to 6 carbon atoms;

in the general formula (I), one O atom on the benzene ring is selected from R₂Or R₃Connecting: and R₂When they are linked, R₂Selected from substituted or unsubstituted C2-C4 alkylene, when R is₃Is absent; and R₃When they are linked, R₂Selected from the group consisting of C3-C6 cycloalkyl, R₃Is selected from alkyl of C1-C3.

Preferably, in the general formula (I), the O atom and R on the benzene ring₂When they are linked, R₂Selected from substituted or unsubstituted C2 to C3 alkylene; and R₃When they are linked, R₂Selected from the group consisting of C3-C4 cycloalkyl, R₃Is selected from alkyl of C1-C3.

As a further preference, the R group₃Selected from methyl and ethyl.

Preferably, the compound has a structure represented by the general formula (I-a) or (I-2) or an isomer thereof or a pharmaceutically acceptable salt thereof or a mixture of the above structures:

n1 is a natural number of 1-3; more preferably, n1 is 1 or 2.

Preferably, the salt is the hydrochloride salt.

Preferably, R₁When they share two carbon atoms with the pyrrolidinyl group to which they are attached, the carbon atom is NH in formula (I)₂The C atom to which it is attached.

Preferably, R₁Alkyl selected from C1-C3; or R₁Selected from spiro or bridged alkane chains sharing one or two carbon atoms with the pyrrolidinyl group to which they are attached, R₁Contains 2 to 6 carbon atoms. As further preferred, R₁In the structure of a bridged ring (sharing two C atoms), R₁Contains 1 to 4 carbon atoms; r₁Is a spiro ring(sharing a C atom) structure, R₁Contains 1 to 6 carbon atoms.

Preferably, C designated by 1 and 2 is S, R configuration, S, S configuration, R, S configuration, R, R configuration.

Preferably, the compound has a structure represented by the following structural formula or an isomer thereof or a pharmaceutically acceptable salt thereof or a mixture of the above structures:

preferably, the compound is obtained by subjecting a raw material represented by formula (3) and a raw material represented by formula (1) to substitution reaction and deprotection:

the raw material shown in the formula (3) can be prepared from(2) Under the action of palladium-carbon catalyst, removing protecting group of carbobenzoxy by normal pressure hydrogenolysis.

When the compound represented by the formula (3) and the compound represented by the formula (1) are reacted, the molar ratio of the compound represented by the formula (3) to the compound represented by the formula (1) is preferably 1.5 to 2.5: 1. More preferably, the molar ratio of the compound represented by the formula (3) to the compound represented by the formula (1) is 2: 1. The reaction temperature is 90-110 ℃. The reaction solvent is DMSO or DMF. After the reaction is finished, extracting with an extracting agent (such as dichloromethane, chloroform, toluene and the like), removing the solvent to obtain a crude product, and recrystallizing with an alcohol solvent (ethanol) to obtain the target product.

The method comprises the steps of removing a carbobenzoxy protecting group by normal pressure hydrogenolysis with a formula (2) as an initial raw material under the action of a palladium-carbon catalyst, obtaining a product (3) with a quantitative yield without purification, and heating the product and a compound shown in the formula (1) in an organic solvent (such as DMSO) to 90-110 ℃ for substitution reaction to obtain an intermediate with a Boc protecting group respectively, wherein in the step, the raw material shown in the formula (1) can be completely reacted, so that the subsequent purification is facilitated, the dosage of the compound shown in the formula (3) is 1 time excessive, the obtained crude product is deprotected under the action of concentrated hydrochloric acid to form a hydrochloride, the compound fluoroquinolone derivative with high purity can be obtained by ethanol crystallization, and the total yield reaches 55-65%.

An antibacterial drug comprising one or more of the fluoroquinolone derivatives described above.

Preferably, the antibacterial drug is an antibacterial drug inhibiting one or more of escherichia coli, staphylococcus aureus and tetracoccus.

The compound shown in the formula (2) is used as a starting material, and a plurality of fluoroquinolone derivatives are synthesized through hydrogenolysis, coupling (or substitution) and deprotection, wherein the total yield is 50-65%. The result of the antibacterial activity test shows that the content of the antibacterial agent is 6 mg.mL^-1Under the concentration, the target compound synthesized by the method has good inhibition effect on escherichia coli, staphylococcus aureus and tetralococcus, wherein A1 and A2 in the compound respectively have the best inhibition effect on staphylococcus aureus and escherichia coli, and are weaker than levofloxacin; the compound A5 (shown in the example) has better inhibiting diameter on tetragenococcus than levofloxacin, and the experimental result shows that the compound formed by introducing 3-aminopyrrolidine into C7 position of fluoroquinolone has good inhibiting effect on three test bacteria, which provides a certain reference for further design of the structure of the quinolone compound.

Detailed Description

2a and 2e reference (Bohdan, A.; Chalyk, M.V.; Butko, O.O.; Yanhyna, K.S.; Gavrilenko, T.D.; Pavel, K.M.Chem.Eur.J.2017,23,16782; Elvira, R.Z., Alexander, Y.S., Nadezhda, S.B., et al.chemistry of heterocylic Compounds,2019,55:676 678 and Stephen, T.W.WO 2012125893,2014.)2c and 2d reference (Hisashi, T., Satoshi, K., Takahihi, K., et al. US2014142096A1,2014) and 2b, 2f, 2g and 2h are available from Shanghai chemical Co., Ltd.

Example (b): synthesis of A1-A6 and B1-B4

Dissolving the pyrrolidine 2 a-2 h (1.15mmol) in 30mL of methanol, adding a palladium-carbon catalyst (20mg, 5% Pd/C), carrying out hydrogenation reaction for 1h under normal pressure under the condition of hydrogen, carrying out TCL (thermal transfer chromatography) tracing reaction, filtering to remove palladium-carbon catalyst solids after the reaction is finished, and removing the solvent under reduced pressure to obtain quantitative intermediates 3 a-3 h, wherein the next reaction is directly carried out without purification.

Dissolving the compound 1a or 1b (0.47mmol) in 3mL DMSO, adding the intermediate 3 a-3H (0.94mmol), heating to 100 ℃, reacting for 2H, and adding H₂The system was diluted with O and extracted with DCM (20 mL. times.3). And (3) drying the combined DCM, performing rotary evaporation to remove the solvent to obtain a yellow solid, putting the solid in an ice bath, adding concentrated hydrochloric acid (5mL), gradually heating to the normal temperature, reacting for 1h, performing plate tracking reaction, and crystallizing the solid by using ethanol after the solvent is removed by rotary evaporation to obtain compounds A1-A6 and compounds B1-B4.

Reaction correspondence table:

130mg of compound A1, light yellow solid, 67.6% m.p.229-230 ℃;¹H NMR(600MHz,DMSO)δ15.34(s,1H),8.93(s,1H),8.31(s,2H),7.58(dd,J＝13.9,1.7Hz,1H),4.94～4.85(m,1H),4.57～4.52(m,1H),4.29(t,J＝9.7Hz,2H),4.26～4.16(m,1H),3.87(dd,J＝24.9,11.9Hz,1H),3.39(s,1H),1.45(dd,J＝6.6,2.1Hz,3H),1.12(dd,J＝9.0,4.7Hz,1H),0.90～0.83(m,1H),0.80～0.69(m,2H)；13C NMR(151MHz,DMSO)δ176.1,166.3,153.0,146.0,137.4,130.4,124.9,117.3,106.6,103.6,68.2,67.9,57.2,54.8,50.7,31.7,31.7,24.8,18.0；HRMS(ESI)calcd for[(C₁₉H₂₁ClFN₃O₄－HCl)+H]⁺＝C₁₉H₂₀FN₃O₄(M+H)⁺374.1511,found 374.1480.

compounds A2 to A6 and B1 to B4 were synthesized in the same manner as described above.

90mg of compound A2, namely a light yellow solid, 59.6 percent, m.p.231-232 ℃;¹H NMR(600MHz,DMSO)δ15.37(s,1H),8.93(s,1H),8.43(s,2H),7.56(d,J＝13.2Hz,1H),4.93～4.86(m,1H),4.55(d,J＝10.8Hz,1H),4.34～4.22(m,1H),4.16～3.99(m,2H),3.81～3.69(m,3H),2.40～2.32(m,1H),2.17～2.07(m,1H),2.02～1.85(m,4H),1.46(t,J＝6.3Hz,3H)；¹³C NMR(151MHz,DMSO)δ176.2,166.3,146.3,130.3,125.2,125.0,116.5,106.3,104.0,103.8,68.2,67.9,55.6,55.0,45.9,31.5,24.1,18.3,17.9,15.3；HRMS(ESI)calcd for[(C₂₀H₂₃ClFN₃O₄－HCl)+H]⁺＝C₂₀H₂₂FN₃O₄(M+H)⁺388.1667,found 388.1640.

88mg of compound A3, light yellow solid, 60.2% m.p.232-233 ℃;¹H NMR(600MHz,DMSO)δ15.37(s,1H),8.92(s,1H),8.43(s,2H),7.56(d,J＝13.9Hz,1H),4.89(s,1H),4.55(d,J＝11.4Hz,1H),4.30(t,J＝12.4Hz,1H),4.18(ddd,J＝16.1,11.2,4.5Hz,1H),3.92(ddd,J＝12.7,10.2,2.9Hz,1H),3.79(t,J＝12.9Hz,1H),3.60～3.49(m,2H),1.85(d,J＝9.7Hz,1H),1.65(dd,J＝21.2,10.9Hz,6H),1.54(dd,J＝11.6,5.9Hz,1H),1.46(dd,J＝6.3,3.5Hz,3H)；¹³C NMR(151MHz,DMSO)δ176.4,166.7,146.5,130.7,125.5,125.3,116.8,106.6,104.2,104.1,68.5,68.2,56.4,55.4,51.6,36.5,30.4,24.8,24.4,18.6,18.2；HRMS(ESI)calcd for[(C₂₁H₂₅ClFN₃O₄－HCl)+H]⁺＝C₂₁H₂₄FN₃O₄(M+H)⁺402.1824,found 402.1792.

70mg of compound A4, light yellow solid, 49.8% m.p.233-234 ℃;¹H NMR(600MHz,DMSO)δ15.35(s,1H),8.94(s,1H),8.25(s,2H),7.58(d,J＝13.8Hz,1H),4.89(s,1H),4.55(d,J＝11.2Hz,1H),4.37～4.29(m,1H),4.20～4.10(m,1H),3.87～3.71(m,2H),3.63(dd,J＝20.5,9.9Hz,1H),3.52(s,1H),1.67～1.52(m,6H),1.46(d,J＝6.6Hz,3H),1.34～1.21(m,4H)；¹³C NMR(151MHz,DMSO)δ176.2,166.3,146.3,136.3,125.1,125.1,116.8,106.4,103.9,103.7,68.1,67.9,57.9,56.6,54.9,43.3,33.5,28.5,25.4,22.5,18.1,17.9；HRMS(ESI)calcd for[(C₂₂H₂₇ClFN₃O₄－HCl)+H]⁺＝C₂₂H₂₆FN₃O₄(M+H)⁺416.1980,found 416.1945.

66mg of compound A5, light yellow solid, 58.8% m.p.215-216 ℃;¹H NMR(600MHz,DMSO)δ15.25(s,1H),8.99(s,1H),8.62(s,2H),7.63(d,J＝12.8Hz,1H),4.94(d,J＝6.7Hz,1H),4.61(d,J＝11.3Hz,1H),4.40(d,J＝11.3Hz,1H),3.91(dd,J＝53.9,10.3Hz,1H),3.67(d,J＝10.2Hz,1H),3.58(s,1H),3.55～3.46(m,1H),2.98(d,J＝3.3Hz,1H),2.36(dd,J＝23.2,15.4Hz,1H),2.16(dd,J＝13.7,8.0Hz,2H),1.68(dd,J＝21.1,12.0Hz,1H),1.47(d,J＝6.5Hz,3H),1.23(s,2H)；¹³C NMR(151MHz,DMSO)δ176.5,166.7,146.6,130.6,130.6,125.6,125.3,116.8,106.7,104.3,68.5,68.2,55.3,46.2,31.8,24.4,18.6,18.2,15.6；HRMS(ESI)calcd for[(C₁₉H₂₁ClFN₃ O ₄－HCl)+H]⁺＝C₁₉H₂₀FN₃ O ₄(M+H)⁺374.1511,found 374.1485.

110mg of compound A6, light yellow solid, 65.6% m.p.228-229 ℃;¹H NMR(600MHz,DMSO)δ8.91(s,1H),7.53(d,J＝13.4Hz,1H),4.87(d,J＝6.5Hz,1H),4.54(d,J＝11.3Hz,1H),4.30(d,J＝11.3Hz,1H),3.82(dt,J＝17.5,8.2Hz,1H),3.67～3.44(m,3H),2.12(s,1H),1.96(td,J＝14.0,7.0Hz,1H),1.78～1.66(m,3H),1.64～1.58(m,1H),1.42(dd,J＝20.8,6.7Hz,4H)；¹³C NMR(151MHz,DMSO)δ176.6,166.7,146.4,139.3,129.8 125.2,119.1,106.9,103.9,103.7,68.5,59.5,56.5,56.3,55.6,55.4,41.1,28.5,19.1,18.2；HRMS(ESI)calcd for[(C₂₀H₂₃ClFN₃O₄－HCl)+H]⁺＝C₂₀H₂₂FN₃O₄(M+H)⁺388.1667,found 388.1635.

80mg of compound B1, a red-brown solid, 60.1%. m.p.215-216 ℃;¹H NMR(600MHz,DMSO)δ15.12(s,1H),8.66(s,1H),8.51(s,2H),7.69(d,J＝11.8Hz,1H),4.14(s,1H),3.88(dd,J＝132.3,23.9Hz,5H),3.54(s,3H),2.16(s,1H),1.92(s,5H),1.17(s,1H),1.06(d,J＝32.1Hz,2H),0.91(s,1H)；¹³C NMR(151MHz,DMSO)δ176.0,166.0,163.6,152.0,150.4,141.0,136.3,134.4,117.6,106.3,61.6,59.5,55.5,53.4,45.9,40.8,30.7,24.0,15.2,9.5,8.6；HRMS(ESI)calcd for[(C₂₁H₂₅ClFN₃O₄－HCl)+H)⁺＝C₂₁H₂₄FN₃O₄(M+H)⁺402.1824,found 402.1789.

60mg of compound B2, light yellow solid, 55.5% m.p.235-236 ℃;¹H NMR(600MHz,DMSO)δ15.12(s,1H),8.67(s,1H),7.70(d,J＝13.9Hz,1H),4.17～4.12(m,1H),4.02(dd,J＝12.3,7.0Hz,1H),3.84(dd,J＝10.6,4.2Hz,1H),3.68～3.59(m,3H),3.57(s,3H),1.65～1.45(m,8H),1.41～1.26(m,4H),1.13(dd,J＝12.6,5.7Hz,1H),1.08～1.00(m,2H),1.01～0.92(m,1H)；¹³C NMR(151MHz,DMSO)δ176.2,166.0,152.2,150.6,141.3,136.6,134.6,117.9,106.9,106.6,62.1,57.8,56.5,53.7,43.4,40.8,40.1,33.5,28.5,25.5,22.5,9.3,8.9；HRMS(ESI)calcd for[(C₂₃H₂₉ClFN₃O₄－HCl)+H]⁺＝C₂₃H₂₈FN₃O₄(M+H)⁺430.2064,found 430.2096.

55mg of compound B3, light yellow solid, 58.9%. m.p.212-213 ℃;¹H NMR(600MHz,DMSO)δ15.14(s,1H),8.66(s,1H),8.39(s,2H),7.68(d,J＝13.9Hz,1H),4.18～4.11(m,1H),4.04(dd,J＝11.7,4.8Hz,1H),3.90(s,1H),3.75(dd,J＝9.0,4.3Hz,2H),3.66(d,J＝11.9Hz,1H),3.56(s,3H),2.43～2.32(m,1H),1.59(dt,J＝13.8,6.9Hz,1H),1.51～1.42(m,1H),1.26～1.08(m,3H),1.01(d,J＝7.3Hz,1H),0.98(t,J＝7.3Hz,3H),0.88(dd,J＝10.6,6.0Hz,1H)；¹³C NMR(151MHz,DMSO)δ176.4,166.3,152.3,150.8,141.3,137.0,135.0,117.9,107.1,106.7,62.4,55.9,53.9,51.9,42.6,41.1,19.8,12.9,10.1,8.8；HRMS(ESI)calcd for[(C₂₀H₂₅ClFN₃O₄－HCl)+H]⁺＝C₂₀H₂₄FN₃O₄(M+H)⁺390.1824,found 390.1785.

102mg of compound B4, light yellow solid, 55.6% m.p.223-224 ℃;¹H NMR(600MHz,DMSO)δ8.73(s,2H),8.64(s,1H),7.62(d,J＝13.7Hz,1H),4.14(s,1H),3.89(t,J＝7.5Hz,1H),3.87～3.82(m,1H),3.75(dd,J＝10.3,6.0Hz,1H),3.59(s,3H),3.54(s,1H),3.49～3.45(m,1H),2.33(d,J＝4.8Hz,1H),1.79(dd,J＝12.6,6.1Hz,1H),1.42～1.33(m,1H),1.14(s,1H),1.08～1.00(m,2H),0.94(t,J＝7.3Hz,5H)；¹³C NMR(151MHz,DMSO)δ176.1,165.9,154.0,152.4,150.4,141.8,136.2,134.4,118.1,106.5,62.0,54.5,54.1,53.2,43.5,40.8,23.5,12.0,9.3,8.8；HRMS(ESI)calcd for[(C₂₀H₂₅ClFN₃O₄－HCl)+H]⁺＝C₂₀H₂₄FN₃O₄(M+H)⁺390.1824,found 390.1798.

antimicrobial Activity test

In order to evaluate the antibacterial activity of fluoroquinolone derivatives, the present invention uses a filter paper method, and uses levofloxacin and DMSO as a positive control and a negative control, and the inhibitory activity of synthesized 10 target compounds on Escherichia coli (Escherichia coli), Staphylococcus aureus (Staphylococcus aureus) and tetracoccus (Micrococcus tetragenus) is determined, and the test results are shown in table 1:

TABLE 1 antibacterial Activity of the target Compounds

The results showed that the concentration was 6 mg. multidot.mL^-1At the concentration, the 10 target compounds synthesized by the invention have good inhibitory activity on 3 test bacteria. The inhibiting diameter of the target compound to the escherichia coli is 16.1-25.9 mm, wherein the inhibiting activity of A2 to the escherichia coli is the highest, and the inhibiting radius reaches levofloxacin82.5% of; the inhibiting diameter of the target compound to staphylococcus aureus is 13.9-24.0 mm, wherein the inhibiting activity of A1 to staphylococcus aureus is the highest, and the inhibiting radius reaches 81.6% of that of levofloxacin; the inhibiting diameter of the target compound to the tetracoccus is 14.2-24.8 mm, wherein the inhibiting radius of A5 exceeds that of levofloxacin, and the inhibiting radius is 119.3% of that of levofloxacin. The substituent at the C7 position of the compound A2 and the substituent at the C1 are the same, and the inhibition effect on the three test bacteria is basically the same; the substituent of the C7 position of the compound A4 is the same as that of the C2, but the inhibitory activity of the A4 to staphylococcus aureus and tetralococcus is obviously higher than that of the B2, and the inhibitory activity to escherichia coli is not obviously different. In general, 10 compounds synthesized by the present invention have inhibitory activity against three test bacteria, and the antibacterial activity of six compounds synthesized using the raw material 1a as a precursor is slightly higher than that of four compounds synthesized using the raw material 1b as a precursor.