CN104876909A - Aminomethyltriazole substituted polyfluoroquinolone carboxylic acid derivative as well as preparation method and application of derivative - Google Patents

Abstract

The invention discloses an aminomethyltriazole substituted polyfluoroquinolone carboxylic acid derivative as well as a preparation method and an application of the derivative. The chemical structural general formula of the derivative is a formula I as shown in the description, wherein R represents dimethylamino, diethylamino, piperidyl, morpholinyl, piperazinyl, substituted piperazinyl or pyrrolidyl. According to the aminomethyltriazole substituted polyfluoroquinolone carboxylic acid derivative, the effective joining of an advantage pharmacophore, namely a polyfluoroquinolone carboxylic acid framework, an effective substituent 7-amino and a functional triazole heterocycle is realized, and therefore, the anti-drug resistance activity of a new compound can be improved; in short, the derivative can be used for developing anti-infection medicines of a brand new structure as a new antibacterial active substance.

Description

A polyfluoroquinolone carboxylic acid derivative substituted by aminomethyltriazole and its preparation method and application

technical field

The invention belongs to the field of innovative drug synthesis, and specifically relates to a polyfluoroquinolone carboxylic acid derivative substituted by aminomethyltriazole, and also relates to a preparation method of the polyfluoroquinolone carboxylic acid derivative substituted by aminomethyltriazole. and its application in anti-infective drugs.

Background technique

Fluoroquinolones have attracted much attention as broad-spectrum, high-efficiency, and low-toxic anti-infective drugs widely used in clinical practice. However, due to the increasing severity of bacterial drug resistance, how to overcome bacterial drug resistance has become an urgent social and public health security issue in the field of anti-infective drug therapy. Although there are many options for solving bacterial drug resistance strategies, an effective and economical approach is to optimize the structure based on the structural characteristics of existing drugs and continuously promote the production of new drugs. The structure-effect relationship study of fluoroquinolone antibacterial activity shows that: in addition to the C-3 carboxyl and C-4 carbonyl are active pharmacophore necessary for antibacterial activity, the C-7 substituent, especially the introduction of C-7 piperazine The base has a great influence on expanding its antibacterial spectrum, improving antibacterial activity and improving pharmacokinetics. For this reason, the C-7 position of the current clinical fluoroquinolone drug molecule mostly has a piperazine substituent. At the same time, in order to discover new antibacterial active fluoroquinolone compounds, many studies have focused on the changes of the N-substituent of piperazine, but there are few changes in the insertion of functional linking chains between the piperazine group and the quinoline ring skeleton.

Contents of the invention

For this reason, the purpose of the present invention is to provide a kind of aminomethyltriazole substituted polyfluoroquinolone carboxylic acid derivatives, which have antibacterial effect and efficacy, and simultaneously provide a kind of aminomethyltriazole substituted polyfluoroquinolone carboxylic acid derivatives Methods for the preparation of derivatives.

In order to achieve the above object, the technical solution adopted in the present invention is: a polyfluoroquinolone carboxylic acid derivative substituted by aminomethyltriazole, whose chemical structural formula is as shown in general formula (I):

Formula (I)

In formula (I), R is dimethylamino, diethylamino, piperidinyl, morpholinyl, piperazinyl, substituted piperazinyl or pyrrolidinyl. Such compounds are compounds of the following specific structures:

The preparation method of the polyfluoroquinolone carboxylic acid derivatives substituted by the aminomethyltriazole, the fleroxacin precursor carboxylic acid-1-(2-fluoroethyl)-6 shown in the formula (II) of commercial supply , 7,8-trifluoro-quinolinone carboxylic acid is prepared as a raw material,

Formula (II)

Concrete preparation steps are as follows:

1) Substitution reaction of 1-(2-fluoroethyl)-6,7,8-trifluoro-quinolinone carboxylic acid represented by formula (II) with sodium azide to prepare the compound represented by formula (III) 1-(2-fluoroethyl)-6,8-difluoro-7-azido-quinolin-4(1H)-one-3-carboxylic acid;

Formula (III)

2) The azide compound shown in formula (III) and propyne bromide are reacted by click chemistry (click chemistry) to obtain 1-(2-fluoroethyl)-6,8-difluoro -7-(4-Bromomethyl-[1,2,3]triazol-1-yl)-quinolin-4(1H)-one-3-carboxylic acid;

Formula (IV)

3) The nucleophilic substitution reaction of bromomethyltriazole compound shown in formula (IV) and amine donor RH occurs Br, and after the reaction is complete, the target compound is obtained as shown in formula (I),

Formula (I)

In formula I, R is dimethylamino, diethylamino, piperidinyl, morpholinyl, piperazinyl, substituted piperazinyl or pyrrolidinyl.

The molar ratio of 1-(2-fluoroethyl)-6,7,8-trifluoro-quinolin-4(1H)-one-3-carboxylic acid and sodium azide represented by the formula (II) It is 1:1.0～1.5.

The 1-(2-fluoroethyl)-6,8-difluoro-7-azido-quinolin-4(1H)-one-3-carboxylic acid represented by the formula (III) and bromopropyl The molar ratio of alkyne is 1:1.0～1.2.

1-(2-fluoroethyl)-6,8-difluoro-7-(4-bromomethyl-[1,3,4]triazol-1-yl)- The molar ratio of quinoline-4(1H)-one-3-carboxylic acid to amine donor RH is 1:1.0-3.0.

Application of the aminomethyltriazole-substituted polyfluoroquinolone carboxylic acid derivatives in the preparation of anti-infective drugs.

The anti-infection medicine is a medicine for treating infectious diseases caused by Escherichia coli, gram staphylococcus aureus, multidrug-resistant escherichia coli and methicillin-resistant staphylococcus aureus.

The aminomethyltriazole-substituted polyfluoroquinolone carboxylic acid derivatives of the present invention are based on the principle of pharmacophore combination, and the functional triazole is inserted between the dominant pharmacophore skeleton polyfluoroquinolone carboxylic acid and the effective substituent C-7 amino group Compared with the structure of the fluoroquinolone drug fleroxacin shown in formula (V) for clinical application, the heterocyclic linking chain overcomes the drug resistance of fluoroquinolone drugs through the change of the C-7 substituent structure, and can be used as a new structure Fluoroquinolone anti-infective drug development.

Formula (V) fleroxacin

Detailed ways

The technical solution of the present invention will be described in detail below through specific examples.

The preparation method of the polyfluoroquinolone carboxylic acid derivatives substituted by aminomethyltriazole of the present invention uses the fleroxacin precursor carboxylic acid—1-(2-fluoroethyl)- 6,7,8-trifluoro-quinolinone carboxylic acid is prepared as raw material,

Formula (II)

Concrete preparation steps are as follows:

1) Substitution reaction of 1-(2-fluoroethyl)-6,7,8-trifluoro-quinolinone carboxylic acid represented by formula (II) with sodium azide to prepare the compound represented by formula (III) 1-(2-fluoroethyl)-6,8-difluoro-7-azido-quinolin-4(1H)-one-3-carboxylic acid,

Formula (III)

The specific production steps are: compound (II) (10.0g, 35.0mmol) and sodium azide (2.8g, 43.0mmol) were dissolved in DMSO (50mL), stirred and reacted at 60°C for 24h; the reaction mixture was slowly poured into ice- The aqueous mixture (200 mL) was adjusted to pH 7.0 with concentrated hydrochloric acid; the resulting solid was collected by filtration, washed with water, and dried in vacuo. The crude product was recrystallized from a mixed solvent of ethanol-DMF (V/V=5:1) to obtain a yellow solid (III), with a yield of 86%, mp 232-234°C. ¹ H NMR (400MHz, DMSO-d ₆ ) δ: 15.53 (brs, 1H, COOH), 8.68 (s, 1H, 2-H), 8.04 (1H, d, J=13.2Hz, 5-H), 4.84 (d, J=6.8Hz, 2H, FCH ₂ ), 4.73 (d, J=6.8Hz, 2H, NCH ₂ ); MS (m/z): Calcd. for C ₁₂ H ₇ F ₃ N ₄ O ₃ : 312.21[M] ⁺ ; Found: 313[M+H] ⁺ ;

2) The azide compound shown in formula (III) and propyne bromide are reacted by click chemistry (click chemistry) to obtain 1-(2-fluoroethyl)-6,8-difluoro -7-(4-Bromomethyl-[1,2,3]triazol-1-yl)-quinolin-4(1H)-one-3-carboxylic acid,

Formula (IV)

The specific production steps are: add n-butanol (150mL) and water (50mL) into a 500mL three-necked reaction flask, and add compound (III) (10.0g, 32.0mmol) shown in formula (III) and pentahydrate in turn under stirring. After copper sulfate (2.0g, 8.0mmol) and vitamin C sodium salt (1.6g, 8.0mmol), slowly add a mixture of propyne bromide (4.5g, 39.0mmol) and dichloromethane (50mL) dropwise, and in The reaction was stirred at 50°C until complete (TLC detection, developer V(CHCl ₃ ):V(MeOH)=5:1). Cool to room temperature, add water (10 mL), stir, and let stand to separate layers. The aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from absolute ethanol to obtain a yellow solid (IV). The yield was 78%, and the mp was 227-229°C. ¹ H NMR (400MHz, DMSO-d ₆ ) δ: 15.56 (brs, 1H, COOH), 8.73 (s, 1H, 2-H), 8.06 (1H, d, J=13.2Hz, 5-H), 7.78 ( s, 1H, 5′-H), 4.86 (d, J=6.8Hz, 2H, FCH ₂ ), 4.75 (d, J=6.8Hz, 2H, NCH ₂ ); MS(m/z): Calcd.for C ₁₅ H ₁₀ BrF ₃ N ₄ O ₃ : 431.17 [M] ⁺ ; Found: 431 and 433 [M+H] ⁺ for ⁷⁹ Br and ⁸¹ Br.

3) The nucleophilic substitution reaction of bromomethyltriazole compound shown in formula (IV) and amine donor RH occurs Br, and after the reaction is complete, the target compound is obtained as shown in formula (I),

Formula (I)

In formula I, R is dimethylamino, diethylamino, piperidinyl, morpholinyl, piperazinyl, substituted piperazinyl or pyrrolidinyl.

The general synthetic preparation steps of the target compound (I) are: 1-(2-fluoroethyl)-6,8-difluoro-7-(4-bromomethyl-[1,2,3]triazole-1- base)-quinolin-4(1H)-one-3-carboxylic acid IV (1.0g, 2.5mmol) was suspended in N,N-diylformamide (10mL), the amine donor RH (5.0mmol) and Triethylamine (0.4 g, 4.0 mmol). The mixed reactant was stirred and reacted at 60°C for 10h. The solvent was distilled off under reduced pressure, the residue was dissolved with 2 mol/L dilute hydrochloric acid aqueous solution, and the insoluble matter was filtered off. The filtrate was basified to 7.0 with concentrated ammonia, extracted with chloroform (3×20 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from absolute ethanol to obtain the target compound (I) as a yellow solid.

Example 1

1-(2-fluoroethyl)-6,8-difluoro-7-(4-dimethylaminomethyl-[1,2,3]triazol-1-yl)-quinoline-4(1H) - Keto-3-carboxylic acid (I-1), its chemical structural formula is:

That is, R in formula I is dimethylamino.

The preparation method of the compound is as follows: using dimethylamine as the amine donor, according to the above-mentioned general preparation method of the target object (I), the light yellow crystal (I-1) is obtained, the yield is 83.0%, and the mp is 232-234°C. ¹ H NMR (400MHz, DMSO-d ₆ ): δ15.55 (1H, brs, COOH), 8.82 (1H, s, 2-H), 8.07 (d, J=13.2Hz, 1H, 5-H), 7.78(1H,s,5′-H),5.36(s,2H,NCH ₂ ),4.88(d,J=6.8Hz,2H,FCH ₂ ),4.76(d,J=6.8Hz,2H,NCH ₂ ),2.45(s,6H,2×CH ₃ ); MS(m/z): Calcd.for C ₁₇ H ₁₆ F ₃ N ₅ O ₃ :395.34[M] ⁺ ; Found: 396[M+H] ⁺ .

Example 2

1-(2-fluoroethyl)-6,8-difluoro-7-(4-diethylaminomethyl-[1,2,3]triazol-1-yl)-quinoline-4(1H) - Keto-3-carboxylic acid (I-2), its chemical structural formula is:

That is, R in formula I is diethylamino.

The preparation method of the compound is as follows: using diethylamine as the amine donor, according to the above-mentioned general preparation method of the target object (I), the light yellow crystal (I-2) is obtained, the yield is 76.0%, and the mp is 223-225°C. ¹ H NMR (400MHz, DMSO-d ₆ ): δ15.54 (1H, brs, COOH), 8.79 (1H, s, 2-H), 8.03 (d, J=13.2Hz, 1H, 5-H), 7.76 (1H, s, 5′-H), 5.33 (s, 2H, NCH ₂ ), 4.86 (d, J=6.8Hz, 2H, FCH ₂ ), 4.74 (d, J=6.8Hz, 2H, NCH ₂ ), 2.38(q, J=5.6Hz, 4H, 2×CH ₂ ), 1.36(t, J=5.6Hz, 6H, 2×CH ₃ ); MS(m/z): Calcd.for C ₁₉ H ₂₀ F ₃ N ₅ O ₃ : 423.40[M] ⁺ ; Found: 424[M+H] ⁺ .

Example 3

1-(2-fluoroethyl)-6,8-difluoro-7-(4-piperidine-1-methyl-[1,2,3]triazol-1-yl)-quinoline-4( 1H)-keto-3-carboxylic acid (I-3), its chemical structural formula is:

That is, R in formula I is piperidin-1-yl.

The preparation method of the compound is as follows: using piperidine as the amine donor, according to the above-mentioned general preparation method of the target object (I), the light yellow crystal (I-3) is obtained, the yield is 80%, and the mp is 235-237°C. ¹ H NMR (400MHz, DMSO-d ₆ ): δ15.55 (1H, brs, COOH), 8.81 (1H, s, 2-H), 8.05 (d, J=13.2Hz, 1H, 5-H), 7.78(1H,s,5′-H),5.35(s,2H,NCH ₂ ),4.88(d,J=6.8Hz,2H,FCH ₂ ),4.75(d,J=6.8Hz,2H,NCH ₂ ),3.07～2.26(m,4H,N(CH ₂ ) ₂ ),1.63～1.55(m,6H,3×CH ₂ ); MS(m/z): Calcd.for C ₂₀ H ₂₀ F ₃ N ₅ O ₃ : 435.41[M] ⁺ ; Found: 436[M+H] ⁺ .

Example 4

1-(2-fluoroethyl)-6,8-difluoro-7-(4-morpholine-4-methyl-[1,2,3]triazol-1-yl)-quinoline-4( 1H)-keto-3-carboxylic acid (I-4), its chemical structural formula is:

That is, R in formula I is morpholin-4-yl.

The preparation method of the compound is as follows: using morpholine as the amine donor, according to the above-mentioned general preparation method of the target object (I), the light yellow crystal (I-4) is obtained, the yield is 86.0%, and the mp is 241-243°C. ¹ H NMR (400MHz, DMSO-d ₆ ): δ15.58 (1H, brs, COOH), 8.86 (1H, s, 2-H), 8.07 (d, J=13.2Hz, 1H, 5-H), 7.83(1H,s,5′-H),5.37(s,2H,NCH ₂ ),4.92(d,J=6.8Hz,2H,FCH ₂ ),4.78(d,J=6.8Hz,2H,NCH ₂ ), 3.76(t, J=5.6Hz, 4H, O(CH ₂ ) ₂ ), 2.56(t, J=5.6Hz, 4H, N(CH ₂ ) ₂ ); MS(m/z): Calcd.for C ₁₉ H ₁₈ F ₃ N ₅ O ₄ : 437.38 [M] ⁺ ; Found: 438 [M+H] ⁺ .

Example 5

1-(2-fluoroethyl)-6,8-difluoro-7-(4-piperazine-1-methyl-[1,2,3]triazol-1-yl)-quinoline-4( 1H)-keto-3-carboxylic acid (I-5), its chemical structural formula is:

That is, R in formula I is piperazin-1-yl.

The preparation method of the compound is as follows: using piperazine as the amine donor, according to the above-mentioned general preparation method of the target object (I), the light yellow crystal (I-5) is obtained, the yield is 83%, and the mp is 244-246°C. ¹ H NMR (400MHz, DMSO-d ₆ ): δ15.56 (1H, brs, COOH), 8.84 (1H, s, 2-H), 8.03 (d, J=13.2Hz, 1H, 5-H), 7.80(1H,s,5′-H),5.34(s,2H,NCH ₂ ),4.88(d,J=6.8Hz,2H,FCH ₂ ),4.74(d,J=6.8Hz,2H,NCH ₂ ), 3.46(t, J=6.4Hz, 4H, piperazine-H), 2.67(t, J=6.4Hz, 4H, piperazine-H); MS(m/z): Calcd.for C ₁₉ H ₁₉ F ₃ N ₆ O ₃ : 436.40[M] ⁺ ; Found: 437[M+H] ⁺ .

Example 6

1-(2-fluoroethyl)-6,8-difluoro-7-[4-(4-methyl-piperazine-1-methyl)]-[1,2,3]triazole-1- Base)-quinoline-4(1H)-one-3-carboxylic acid (I-6), its chemical structural formula is:

That is, R in formula I is 4-methyl-piperazin-1-yl.

The preparation method of this compound is: using N-methylpiperazine as the amine donor, according to the general preparation method of the above-mentioned target object (I), the light yellow crystal (I-6) is obtained, the yield is 85%, and mp238～ 240°C. ¹ H NMR (400MHz, DMSO-d ₆ ): δ15.55 (1H, brs, COOH), 8.86 (1H, s, 2-H), 8.06 (d, J=13.2Hz, 1H, 5-H), 7.83 (1H, s, 5′-H), 5.37 (s, 2H, NCH ₂ ), 4.90 (d, J=6.8Hz, 2H, FCH ₂ ), 4.76 (d, J=6.8Hz, 2H, NCH ₂ ), 3.45(t, J=6.4Hz, 4H, piperazine-H), 2.84(t, J=6.4Hz, 4H, piperazine-H), 2.46(s, 3H, N-CH ₃ ); MS(m/ z): Calcd.for C ₂₀ H ₂₁ F ₃ N ₆ O ₃ : 450.42[M] ⁺ ; Found: 451[M+H] ⁺ .

Example 7

1-(2-fluoroethyl)-6,8-difluoro-7-[4-(4-ethyl-piperazine-1-methyl)]-[1,2,3]triazole-1- Base)-quinoline-4(1H)-one-3-carboxylic acid (I-7), its chemical structural formula is:

That is, R in formula I is 4-ethyl-piperazin-1-yl.

The preparation method of this compound is: using N-ethylpiperazine as the amine donor, according to the general preparation method of the above-mentioned target object (I), the light yellow crystal (I-7) is obtained, the yield is 77%, and mp234～ 236°C. ¹ H NMR (400MHz, DMSO-d ₆ ): δ15.53 (1H, brs, COOH), 8.82 (1H, s, 2-H), 8.01 (d, J=13.2Hz, 1H, 5-H), 7.78(1H,s,5′-H),5.34(s,2H,NCH ₂ ),4.87(d,J=6.8Hz,2H,FCH ₂ ),4.74(d,J=6.8Hz,2H,NCH ₂ ), 3.62(t, J=6.4Hz, 4H, piperazine-H), 3.24(t, J=6.4Hz, 4H, piperazine-H), 2.53(q, J=5.2Hz, 2H, N-CH ₂ ) ,1.36(t,J＝5.2Hz,3H,CH ₃ ); MS(m/z): Calcd.for C ₂₁ H ₂₃ F ₃ N ₆ O ₃ :464.45[M] ⁺ ;Found: 465[M+H ] ⁺ .

Example 8

1-(2-fluoroethyl)-6,8-difluoro-7-[4-(3-methyl-piperazine-1-methyl)]-[1,2,3]triazole-1- Base)-quinoline-4(1H)-one-3-carboxylic acid (I-8), its chemical structural formula is:

That is, R in formula I is 3-methyl-piperazin-1-yl.

The preparation method of this compound is: using 2-methylpiperazine as the amine donor, according to the general preparation method of the above-mentioned target object (I), the light yellow crystal (I-8) is obtained, the yield is 73%, and mp216～ 218°C. ¹ H NMR (400MHz, DMSO-d ₆ ): δ15.56 (1H, brs, COOH), 8.92 (1H, s, 2-H), 8.07 (d, J=13.2Hz, 1H, 5-H), 7.85(1H,s,5′-H),5.38(s,2H,NCH ₂ ),4.92(d,J=6.8Hz,2H,FCH ₂ ),4.78(d,J=6.8Hz,2H,NCH ₂ ), 3.53～3.12(m, 4H, piperazine-H), 2.83～2.66(m, 3H, piperazine-H), 1.32(d, J＝6.2Hz, 3H, CH ₃ ); MS(m/z): Calcd.for C ₂₀ H ₂₁ F ₃ N ₆ O ₃ : 450.42[M] ⁺ ; Found: 451[M+H] ⁺ .

Example 9

1-(2-fluoroethyl)-6,8-difluoro-7-(4-pyrrolidin-1-methyl)-[1,2,3]triazol-1-yl)-quinoline-4 (1H)-keto-3-carboxylic acid (I-9), its chemical structural formula is:

That is, R in formula I is pyrrolidin-1-yl.

The preparation method of the compound is as follows: using pyrrolidine as the amine donor, according to the above-mentioned general preparation method of the target object (I), the light yellow crystal (I-9) is obtained, the yield is 81%, and the mp is 224-226°C. ¹ H NMR (400MHz, DMSO-d ₆ ): δ15.53 (1H, brs, COOH), 8.86 (1H, s, 2-H), 8.03 (d, J=13.2Hz, 1H, 5-H), 7.82(1H,s,5′-H),5.35(s,2H,NCH ₂ ),4.87(d,J=6.8Hz,2H,FCH ₂ ),4.72(d,J=6.8Hz,2H,NCH ₂ ), 3.04～2.85(4H, m, pyrrolindine-H), 1.52～1.48(4H, m, pyrrolindine-H); MS(m/z): Calcd.for C ₁₉ H ₁₈ F ₃ N ₅ O ₃ :421.38 [M] ⁺ ; Found: 422[M+H] ⁺ .

Test case

One, the in vitro antimicrobial activity assay of the aminomethyltriazole substituted polyfluoroquinolone carboxylic acid derivatives provided by embodiment 1-9

According to the standard method of "Executive Standards for Antimicrobial Susceptibility Test: Supplement M100-S22 of the 22nd Edition", for Staphylococcus aureus, Escherichia coli, methicillin-resistant positive Staphylococcus aureus and multidrug-resistant colon The antibacterial activity of bacilli was determined by:

1. Test sample

The polyfluoroquinolone carboxylic acid derivatives substituted with the aminomethyltriazoles provided by Examples 1-9, and its structural analog fleroxacin (FL) are as test samples, totally 10 kinds, wherein FL is a control group, implement Example 1-9 samples are experimental groups;

The experimental microbial bacterial strains were standard Gram-positive Staphylococcus aureus S.aureus ATCC-29213 (SA), standard Escherichia-negative Escherichia coli E.coli ATCC-25922 (EC), methicillin-resistant positive Staphylococcus aureus MR S.aureus ATCC-25923 (MR-SA) and multidrug-resistant Escherichia coli MDR E.coli ATCC-35218 (MDR-EC) (provided by the Laboratory Department of Huaihe College of Clinical Pharmacy, Henan University), and inoculated in the broth In MH medium, cultivate at 37°C for 18 hours, and dilute to 1/200 with broth as the experimental bacterial solution for later use.

Take by weighing 1.28mg of test sample compound respectively, dissolve in 1.0mL DMSO, make 1.28mg/mL mother liquor, dilute to 64, 32, 16, 8, 4, 2, 1 by two times dilution method with broth , 0.5, 0.25, 0.125 μg/mL concentration gradient test sample solution for use.

2. Measurement method

The specific steps of the assay method are:

Add 90 μL of the above-mentioned 1/200 experimental bacterial solution to a clean and sterile 96-well culture plate, and then add 10 μL of test sample solution with different concentration gradients to make the final bacterial concentration of each well about 5×10 ⁵ CFU/mL, positive control 10 μL of different concentrations of ciprofloxacin. At the same time, a blank control and a solvent control (DMSO was added to the experimental bacterial solution to make the concentration 5 wt%) were set up, and each treatment was repeated three times. The 96-well plate was shaken (15 rpm) on a TS-8 transfer decolorization shaker at 37° C., and incubated in the dark for 18 h. Then observe the bacterial growth situation in each well with the naked eye, and the concentration in the well culture plate without bacterial growth is the minimum bacteriostatic growth agent concentration MIC value (minimum inhibitory concentration value); This evaluation of its antibacterial activity, the results are shown in Table 1.

Table 1 The antibacterial activity (MIC) of each test sample

As can be seen from Table 1, the compounds provided by Examples 1-9 show a certain broad-spectrum antibacterial activity to 4 kinds of experimental bacterial strains, especially the activity of the compound containing piperazinyl is equivalent to the activity of fleroxacin, especially The activity against the two drug-resistant bacterial strains is not only stronger than that of the control fleroxacin, but also there is no drug resistance phenomenon, which provides an important basis for the development of new anti-resistant fluoroquinolone drugs. Therefore, according to the general approach of drug development, conventional antibacterial in vitro screening is carried out first, and then targeted research is carried out, so the compound of the present invention has strong antibacterial drug resistance activity, which can be obtained by forming a salt with an acceptable acid for the human body or with Medicinal carriers are mixed to prepare anti-infective drugs.

Claims (8)

1. a polyfluoroquinolone carboxylic acid derivative that aminomethyltriazole replaces, is characterized in that, has the structural general formula of following formula (I): In formula (I), R is dimethylamino, diethylamino, piperidyl, morpholinyl, piperazine, substituted piperazinyl or pyrrolidinyl. 2. the aminomethyltriazole substituted polyfluoroquinolone carboxylic acid derivatives according to claim 1, is characterized in that, is specifically the compound of following structure: 3. a preparation method of polyfluoroquinolone carboxylic acid derivatives substituted by aminomethyltriazole described in claim 1 or 2, is characterized in that, concrete preparation steps comprise: (1) 1-(2-fluoroethyl)-6,7,8-trifluoro-quinolin-4(1H)-one-3-carboxylic acid represented by commercially available formula (II) as raw material, Carry out substitution reaction with sodium azide to obtain 1-(2-fluoroethyl)-6,8-difluoro-7-azido-quinoline-4(1H)-one-3-one shown in formula (III) carboxylic acid; (2) The compound shown in formula (III) is reacted with propyne bromide by click chemistry, and after the reaction is finished, 1-(2-fluoroethyl)-6 shown in formula (IV) can be obtained through post-processing, 8-Difluoro-7-(4-bromomethyl-[1,2,3]triazol-1-yl)-quinolin-4(1H)-one-3-carboxylic acid; Then formula (IV) and The nucleophilic substitution reaction of bromine occurs in the amine donor RH, and the polyfluoroquinolone carboxylic acid derivatives substituted by the aminomethyltriazole shown in the formula (I) can be obtained through aftertreatment; 4. the preparation method of the polyfluoroquinolone carboxylic acid derivatives that aminomethyltriazole replaces according to claim 3 is characterized in that, the 1-(2-fluoroethyl) shown in described formula (II) The molar ratio of -6,7,8-trifluoro-quinolin-4(1H)-one-3-carboxylic acid to sodium azide is 1:1.0-1.5. 5. the preparation method of the polyfluoroquinolone carboxylic acid derivatives that aminomethyltriazole replaces according to claim 3 is characterized in that, the 1-(2-fluoroethyl) shown in described formula (III) The molar ratio of -6,8-difluoro-7-azido-quinolin-4(1H)-one-3-carboxylic acid to propyne bromide is 1:1.0-1.2. 6. the preparation method of the polyfluoroquinolone carboxylic acid derivatives substituted by aminomethyltriazole according to claim 3 is characterized in that, the 1-(2-fluoroethyl) shown in the formula (IV) -6,8-Difluoro-7-(4-bromomethyl-[1,3,4]triazol-1-yl)-quinolin-4(1H)-one-3-carboxylic acid with amine donor The molar ratio of RH is 1:1.0-3.0. 7. The application of the aminomethyltriazole substituted polyfluoroquinolone carboxylic acid derivatives according to claim 1 or 2 in the preparation of anti-infective drugs. 8. the application of the polyfluoroquinolone carboxylic acid derivatives substituted by aminomethyltriazole according to claim 7 in the preparation of anti-infective drugs, characterized in that, the anti-infective drugs are for the treatment of Escherichia negative large intestine bacilli, Gram Staphylococcus aureus, multi-drug resistant Escherichia coli and methicillin resistant Staphylococcus aureus.