CN104817537A - 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolones carboxylic acid derivative, method for preparing same and application of 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolones carboxylic acid derivative - Google Patents

1-cyclopropyl-7-aminomethyl triazole-fluoroquinolones carboxylic acid derivative, method for preparing same and application of 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolones carboxylic acid derivative Download PDF

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CN104817537A
CN104817537A CN201510198052.9A CN201510198052A CN104817537A CN 104817537 A CN104817537 A CN 104817537A CN 201510198052 A CN201510198052 A CN 201510198052A CN 104817537 A CN104817537 A CN 104817537A
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cyclopropyl
carboxylic acid
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triazole
fluoroquinolones
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胡国强
胡海廷
杨彤
闫强
吴书敏
倪礼礼
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Henan University
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    • 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
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    • 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
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Abstract

The invention discloses a 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolones carboxylic acid derivative, a method for preparing the same and application of the 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolones carboxylic acid derivative. The 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolones carboxylic acid derivative is shown as a chemical structural general formula I, and R in the formula I can represent dimethylamino or lignocaine or piperidinyl or morpholino or piperazinyl or substituted piperazinyl or pyrrolidyl. The 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolones carboxylic acid derivative, the method and the application have the advantages that framework-cyclopropyl fluoroquinolones carboxylic acid which is dominant pharmacophore, 7-amine which is an effective substituent and functional triazole heterocycle are effectively combined with one another, accordingly, the anti-drug-resistance activity of the 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolones carboxylic acid derivative which is a novel chemical compound can be improved, and the 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolones carboxylic acid derivative can be used as novel anti-infection medicine with novel antibacterial active substance development structures.

Description

A kind of 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolone carboxylic analog derivative and its preparation method and application
Technical field
The invention belongs to original new drug synthesis field, be specifically related to a kind of 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolone carboxylic analog derivative, also relate to the preparation method of 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolone carboxylic analog derivative simultaneously, and its application in anti-infectives.
Background technology
Fluoroquinolone is as clinical widely used wide spectrum, efficient, low toxicity anti-infectives and receiving much concern.But day by day serious due to current bacterial resistance, how overcoming bacterial drug resistance has become anti-infectives treatment field social publilc health safety problem urgently to be resolved hurrily.Although solve the strategy of bacterial resistance have multiple choices, effectively and the approach of economy carries out composition optimizes based on the constitutional features of existing medicine, the generation of new drug is constantly promoted.Structure-effect relationship the research of fluoroquinolone anti-microbial activity shows: except C-3 position carboxyl and C-4 carbonyl are the necessary active pharmacophore of anti-microbial activity, C-7 bit substituent, especially introduce C-7 piperazinyl to its antimicrobial spectrum of expansion, improve anti-microbial activity and improve pharmacokinetics etc. and all have considerable influence.For this reason, the C-7 position of current clinical flouroquinolone drugs molecule has piperazine substituted more.Meanwhile, for finding new anti-microbial activity fluoroquinolone compound, much research focuses mostly in the substituent change of piperazine N-, and the change of inserting function connection chain between piperazinyl and quinoline ring skeleton is very few.
Summary of the invention
The object of this invention is to provide a kind of 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolone carboxylic analog derivative, the preparation method and application of 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolone carboxylic analog derivative are provided simultaneously.
In order to realize above object, the technical solution adopted in the present invention is: a kind of 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolone carboxylic analog derivative, and its chemical structural formula is as shown in general formula (I):
In formula (I), R is dimethylamino, diethylin, piperidyl, morpholinyl, piperazinyl, substituted piperazinyl or pyrrolidyl.This compounds is specially the compound of following structure:
The preparation method of described 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolone carboxylic analog derivative is that raw material is prepared from the Ciprofloxacin precursor carboxylic acid shown in the formula of commercial offers (II)-fluorine chloroquinoline keto-earboxylic acid,
Concrete preparation process is as follows:
1) the fluorine chlorine naphthyridon carboxylic acid shown in formula (II) and sodiumazide generation substitution reaction are obtained 1-cyclopropyl-6-fluoro-7-nitrine yl-quinoline-4 (1H)-one-3-carboxylic acid shown in formula (III);
2) triazo-compound shown in formula (III) and bromo propine are passed through click chemistry (click chemistry) and react to obtain the fluoro-7-of 1-cyclopropyl-6-(4-brooethyl-[1 shown in formula (IV), 2,3] triazol-1-yl)-quinoline-4 (1H)-one-3-carboxylic acid;
3) brooethyl triazole compounds formula (IV) Suo Shi and amine donor RH be there is the nucleophilic substitution reaction of Br, question response completely after through process target compound such as formula shown in (I),
In formula I, amino R is dimethylamino, diethylin, piperidyl, morpholinyl, piperazinyl, substituted piperazinyl or pyrrolidyl.
The mol ratio of 1-cyclopropyl-6-fluoro-7-chlorine-quinoline-4 (1H)-one-3-carboxylic acid shown in described formula (II) and sodiumazide is 1:1.0 ~ 1.5.
The mol ratio of 1-cyclopropyl-6-fluoro-7-nitrine yl-quinoline-4 (1H)-one-3-carboxylic acid shown in described formula (III) and bromo propine is 1:1.0 ~ 1.2.
The mol ratio of the fluoro-7-of 1-cyclopropyl-6-(4-brooethyl-[1,3,4] triazol-1-yl)-quinoline-4 (1H)-one-3-carboxylic acid shown in described formula (IV) and amine donor RH is 1:1.0 ~ 3.0.
Described 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolone carboxylic analog derivative is preparing the application in anti-infectives.
Further, described anti-infectives is the medicine that catch for the treatment of caused by dust Xi Shi negative bacterium, gram staphylococcus aureus, multidrug resistance intestinal bacteria and Methicillin resistant Staph. aureus.
1-cyclopropyl-7-aminomethyl triazole-fluoroquinolone carboxylic analog derivative of the present invention is based on the principle of hybridization of pharmacophore, function triazole heterocycle connection chain is inserted by between advantage pharmacophore skeleton fluoroquinolone carboxylic and effective substituting group C-7 amino, compared with the structure of the fluoroquinolones Ciprofloxacin (V) of clinical application, by the change of C-7 substituent structure, overcome the resistance of flouroquinolone drugs, can be used as the fluoroquinolone anti-infectives exploitation of brand new.
Formula (V) Ciprofloxacin
Embodiment
Below by specific embodiment, technical scheme of the present invention is described in detail.
The preparation method of 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolone carboxylic analog derivative of the present invention is that raw material is prepared from the Ciprofloxacin precursor carboxylic acid shown in the formula of commercial offers (II)-fluorine chloroquinoline keto-earboxylic acid,
Concrete preparation process is as follows:
1) the fluorine chlorine naphthyridon carboxylic acid shown in formula (II) and sodiumazide generation substitution reaction are obtained 1-cyclopropyl-6-fluoro-7-nitrine yl-quinoline-4 (1H)-one-3-carboxylic acid shown in formula (III),
Concrete making step is: compound (II) (10.0g, 35.0mmol) and sodiumazide (2.8g, 43.0mmol) are dissolved in DMSO (50mL), 60 DEG C of stirring reaction 24h; Reaction mixture is slowly poured in ice-water mixture (200mL), adjusts pH to 7.0 with concentrated hydrochloric acid; The solid that filter collection produces, washes with water, vacuum-drying.Crude product ethanol-DMF (V/V=5 ︰ 1) mixed solvent recrystallization, obtains yellow solid (III), yield 53%, mp 224 ~ 226 DEG C. 1h NMR (400MHz, DMSO-d 6) δ: 15.48 (brs, 1H, COOH), 8.77 (s, 1H, 2-H), 7.76 (1H, d, J=13.2Hz, 5-H), 7.53 (1H, d, J=7.2Hz, 8-H), 3.72 ~ 3.63 (m, 1H, 1 '-H), 1.37 ~ 1.24 (4H, m, 2 '-and 3 '-H); MS (m/z): Calcd.forC 13h 9fN 4o 3: 288.24 [M] +; Found:289 [M+H] +.
2) triazo-compound shown in formula (III) and bromo propine are passed through click chemistry (click chemistry) and react to obtain the fluoro-7-of 1-cyclopropyl-6-(4-brooethyl-[1 shown in formula (IV), 2,3] triazol-1-yl)-quinoline-4 (1H)-one-3-carboxylic acid
Concrete making step is: in three mouthfuls of reaction flasks of 500mL, add propyl carbinol (150mL) and water (50mL), triazo-compound (the 10.0g shown in formula (III) is added successively under stirring, 34.6mmol), cupric sulfate pentahydrate (2.0g, 8.0mmol) with vitamin C sodium salt (1.6g, 8.0mmol), slowly drip bromo propine (4.2g, 35.0mmol) with the mixture of methylene dichloride (50mL), and at 50 DEG C of stirring reactions to (TLC detects, developping agent V (CHCl completely 3): V (MeOH)=5:1).Cooling room temperature, add water (10mL), stirring, stratification.Aqueous phase dichloromethane extraction, merges organic phase, uses anhydrous sodium sulfate drying.Remove solvent under reduced pressure, resistates dehydrated alcohol recrystallization, obtain yellow solid (IV), yield 68%, mp 242-244 DEG C. 1h NMR (400MHz, DMSO-d 6): δ 15.47 (1H, brs, COOH), 8.87 (1H, s, 2-H), 7.87 (1H, d, J=13.2Hz, 5-H), 7.75 (s, 1H, 5 "-H), 7.61 (1H; d, J=7.2Hz, 8-H), 4.86 (s, 2H, BrCH 2), 3.75 ~ 3.63 (m, 1H, 1 '-H), 1.33 ~ 1.26 (m, 4H, 2 '-and 3 '-H); MS (m/z): Calcd.forC 16h 12brFN 4o 3: 407.20 [M] +; Found:407and 409 [M+H] +for 79br and 81br.
3) brooethyl triazole compounds formula (IV) Suo Shi and amine donor RH be there is the nucleophilic substitution reaction of Br, question response completely after through process target compound such as formula shown in (I),
In formula I, R is dimethylamino, diethylin, piperidyl, morpholinyl, piperazinyl, substituted piperazinyl or pyrrolidyl.
The general synthesis preparation process of target compound (I) is: the fluoro-7-of 1-cyclopropyl-6-(4-brooethyl-[1,2,3] triazol-1-yl)-quinoline-4 (1H)-one-3-carboxylic acid IV (1.0g, 2.5mmol) be suspended in N, in N-bis-base methane amide (10mL), add amine donor RH (5.0mmol) and triethylamine (0.4g, 4.0mmol).Mixed reactant is at 60 DEG C of stirring reaction 10h.Remove solvent under reduced pressure, resistates 2mol/L diluted hydrochloric acid aqueous solution dissolves, filtering insolubles.Filtrate to pH=7.0, with chloroform extraction (3 × 20mL), merges organic phase, anhydrous sodium sulfate drying with strong aqua alkalization.Remove solvent under reduced pressure, resistates dehydrated alcohol recrystallization, obtain yellow solid target compound (I).
Embodiment 1
The fluoro-7-of 1-cyclopropyl-6-(4-dimethyl aminomethyl-[1,2,3] triazol-1-yl)-quinoline-4 (1H)-one-3-carboxylic acid (I-1), its chemical structural formula is:
Namely the R in formula I is dimethylamino.
The preparation method of this compound is: take dimethylamine as amine donor, according to the general preparative methods of above-mentioned target compound (I), obtains pale yellow crystals thing (I-1), productive rate 75.0%, m.p.226 ~ 228 DEG C. 1h NMR (400MHz, DMSO-d 6): δ 15.46 (1H, brs, COOH), 8.88 (1H, s, 2-H), 8.05 (d, J=13.2Hz, 1H, 5-H), 7.86 ~ 7.82 (2H, m, 5-H and 5 "-H), 7.64 (1H; d, J=7.2Hz, 8-H), 5.35 (s, 2H, NCH 2), 3.68 ~ 3.54 (m, 1H, 1 '-H), 2.43 (s, 6H, 2 × CH 3), 1.27 ~ 1.18 (m, 4H, 2 '-and 3 '-H); MS (m/z): Calcd.for C 18h 18fN 5o 3: 371.37 [M] +; Found:372 [M+H] +.
Embodiment 2
The fluoro-7-of 1-cyclopropyl-6-(4-diethylamino methyl-[1,2,3] triazol-1-yl)-quinoline-4 (1H)-one-3-carboxylic acid (I-2), its chemical structural formula is:
Namely the R in formula I is diethylin.
The preparation method of this compound is: take diethylamine as amine donor, according to the general preparative methods of above-mentioned target compound (I), obtains pale yellow crystals thing (I-2), productive rate 64.0%, m.p.218 ~ 220 DEG C. 1h NMR (400MHz, DMSO-d 6): δ 15.47 (brs, 1H, COOH), 8.85 (s, 1H, 2-H), 8.03 (d, J=13.2Hz, 1H, 5-H), 7.86 ~ 7.76 (2H, m, 5-H and 5 "-H), 7.62 (1H; d, J=7.2Hz, 8-H), 5.33 (2H, s, NCH 2), 3.68 ~ 3.57 (1H, m, 1 '-H), 2.44 ~ 2.36 (m, 4H, 2 × CH 2), 1.34 ~ 1.17 (m, 10H, 2 '-, 3 '-H and 2 × CH 3); MS (m/z): Calcd.for C 20h 22fN 5o 3: 399.43 [M] +; Found:400 [M+H] +.
Embodiment 3
The fluoro-7-of 1-cyclopropyl-6-(4-piperidines-1-methyl-[1,2,3] triazol-1-yl)-quinoline-4 (1H)-one-3-carboxylic acid (I-3), its chemical structural formula is:
Namely the R in formula I is piperidin-1-yl.
The preparation method of this compound is: take piperidines as amine donor, according to the general preparative methods of above-mentioned target compound (I), obtains pale yellow crystals thing (I-3), productive rate 63.0%, m.p.225 ~ 227 DEG C. 1h NMR (400MHz, DMSO-d 6): δ 15.43 (brs, 1H, COOH), 8.86 (s, 1H, 2-H), 8.07 (d, J=13.2Hz, 1H, 5-H), 7.87 ~ 7.82 (2H, m, 5-H and 5 "-H), 7.65 (1H; d, J=7.2Hz, 8-H), 5.31 (s, 2H, NCH 2), 3.66 ~ 3.58 (m, 1H, 1 '-H), 3.05 ~ 2.28 (m, 4H, N (CH 2) 2), 1.63 ~ 1.08 (m, 10H, 2 '-, 3 '-H and 3 × CH 2); MS (m/z): Calcd.forC 21h 22fN 5o 3: 411.44 [M] +; Found:412 [M+H] +.
Embodiment 4
The fluoro-7-of 1-cyclopropyl-6-(4-morpholine-4-methyl-[1,2,3] triazol-1-yl)-quinoline-4 (1H)-one-3-carboxylic acid (I-4), its chemical structural formula is:
Namely the R in formula I is morpholine-4-base.
The preparation method of this compound is: take morpholine as amine donor, according to the general preparative methods of above-mentioned target compound (I), obtains pale yellow crystals thing (I-4), productive rate 77.0%, m.p.236 ~ 238 DEG C. 1h NMR (400MHz, DMSO-d 6): δ 15.56 (brs, 1H, COOH), 9.07 (s, 1H, 2-H), 8.23 (d, J=13.2Hz, 1H, 5-H), 7.93 ~ 7.86 (2H, m, 5-H and 5 "-H), 7.71 (1H; d, J=7.2Hz, 8-H), 5.33 (s, 2H, NCH 2), 3.72 ~ 3.62 (m, 5H, 1 '-H and O (CH 2) 2), 3.26 (t, J=5.4Hz, 4H, N (CH 2) 2), 1.31 ~ 1.20 (m, 4H, 2 '-and 3 '-H); MS (m/z): Calcd.forC 20h 20fN 5o 4: 413.41 [M] +; Found 414 [M+H] +.
Embodiment 5
The fluoro-7-of 1-cyclopropyl-6-(4-piperazine-1-methyl-[1,2,3] triazol-1-yl)-quinoline-4 (1H)-one-3-carboxylic acid (I-5), its chemical structural formula is:
Namely the R in formula I is piperazine-1-base.
The preparation method of this compound is: take piperazine as amine donor, according to the general preparative methods of above-mentioned target compound (I), obtains pale yellow crystals thing (I-5), productive rate 72%, m.p.241 ~ 243 DEG C. 1h NMR (400MHz, DMSO-d 6): δ 15.58 (brs, 1H, COOH), 9.05 (s, 1H, 2-H), 8.20 (d, J=13.2Hz, 1H, 5-H), 7.97 ~ 7.85 (2H, m, 5-H and 5 ' '-H), 7.68 (1H, d, J=7.2Hz, 8-H), 5.31 (s, 2H, NCH 2), 3.68 ~ 3.36 (m, 5H, 1 '-H and piperazine-H), 2.87 ~ 2.65 (m, 4H, piperazine-H), 1.32-1.18 (m, 4H, 2 '-and 3 '-H); MS (m/z): Calcd.forC 20h 21fN 6o 3: 412.43 [M] +; Found 413 [M+H] +.
Embodiment 6
The fluoro-7-of 1-cyclopropyl-6-[4-(4-thyl-piperazin-1-methyl)]-[1,2,3] triazol-1-yl)-quinoline-4 (1H)-one-3-carboxylic acid (I-6), its chemical structural formula is:
Namely the R in formula I is 4-thyl-piperazin-1-base.
The preparation method of this compound is: take N methyl piperazine as amine donor, according to the general preparative methods of above-mentioned target compound (I), obtains pale yellow crystals thing (I-6), productive rate 81%, m.p.237 ~ 239 DEG C. 1h NMR (400MHz, DMSO-d 6): δ 15.52 (brs, 1H, COOH), 9.05 (s, 1H, 2-H), 8.17 (d, J=13.2Hz, 1H, 5-H), 7.86 ~ 7.83 (2H, m, 5-H and 5 "-H), 7.65 (1H; d, J=7.2Hz, 8-H), 5.28 (s, 2H, NCH 2), 3.66 ~ 3.35 (m, 5H, 1 '-H and piperazine-H), 2.86 ~ 2.67 (m, 4H, piperazine-H), 2.31 (s, 3H, N-CH 3), 1.33 ~ 1.22 (m, 4H, 2 '-and 3 '-H); MS (m/z): Calcd.for C 21h 23fN 6o 3: 426.45 [M] +; Found 427 [M+H] +.
Embodiment 7
The fluoro-7-of 1-cyclopropyl-6-[4-(4-ethyl-piperazin-1-methyl)]-[1,2,3] triazol-1-yl)-quinoline-4 (1H)-one-3-carboxylic acid (I-7), its chemical structural formula is:
Namely the R in formula I is 4-ethyl-piperazin-1-base.
The preparation method of this compound is: take NEP as amine donor, according to the general preparative methods of above-mentioned target compound (I), obtains pale yellow crystals thing (I-7), productive rate 64%, m.p.231 ~ 233 DEG C. 1h NMR (400MHz, DMSO-d 6): δ 15.48 (brs, 1H, COOH), 8.96 (s, 1H, 2-H), 8.16 (d, J=13.2Hz, 1H, 5-H), 7.86 ~ 7.79 (2H, m, 5-H and 5 ' '-H), 7.63 (1H, d, J=7.2Hz, 8-H), 5.26 (s, 2H, NCH 2), 3.63 ~ 3.28 (m, 5H, 1 '-H and piperazine-H), 2.75 ~ 2.66 (m, 4H, piperazine-H), 2.24 (q, J=5.6Hz, 2H, NCH 2cH 3), 1.35 ~ 1.16 (m, 7H, CH 3, 2 '-and 3 '-H); MS (m/z): Calcd.for C 22h 25fN 6o 3: 440.48 [M] +; Found 441 [M+H] +.
Embodiment 8
The fluoro-7-of 1-cyclopropyl-6-[4-(3-thyl-piperazin-1-methyl)]-[1,2,3] triazol-1-yl)-quinoline-4 (1H)-one-3-carboxylic acid (I-8), its chemical structural formula is:
Namely the R in formula I is 3-thyl-piperazin-1-base.
The preparation method of this compound is: with 2-methylpiperazine for amine donor, according to the general preparative methods of above-mentioned target compound (I), obtains pale yellow crystals thing (I-8), productive rate 53%, m.p.211 ~ 213 DEG C. 1h NMR (400MHz, DMSO-d 6): δ 15.45 (brs, 1H, COOH), 9.05 (s, 1H, 2-H), 8.22 (d, J=13.2Hz, 1H, 5-H), 7.96 ~ 7.88 (2H, m, 5-H and 5 "-H), 7.71 (1H; d, J=7.2Hz, 8-H), 5.32 (s, 2H, NCH 2), 3.74 ~ 3.36 (5H, m, 1 '-H and piperazine-H), 2.75 ~ 2.63 (3H, m, piperazine-H), 1.37 ~ 1.22 (7H, m, CH 3, 2 '-and 3 '-H); MS (m/z): Calcd.for C 21h 23fN 6o 3: 426.45 [M] +; Found:427 [M+H] +.
Embodiment 9
The fluoro-7-of 1-cyclopropyl-6-(4-tetramethyleneimine-1-methyl)-[1,2,3] triazol-1-yl)-quinoline-4 (1H)-one-3-carboxylic acid (I-9), its chemical structural formula is:
Namely the R in formula I is pyrrolidin-1-yl.
The preparation method of this compound is: take tetramethyleneimine as amine donor, according to the general preparative methods of above-mentioned target compound (I), obtains pale yellow crystals thing (I-9), productive rate 75%, m.p.235 ~ 237 DEG C. 1h NMR (400MHz, DMSO-d 6): δ 15.46 (1H, brs, COOH), 9.18 (1H, s, 2-H), 8.13 (1H, d, J=13.2Hz, 5-H), 8.02 ~ 7.87 (2H, m, 5-H and 5 "-H), 7.68 (1H; d, J=7.2Hz, 8-H), 5.26 (2H, s, NCH 2), 3.64 ~ 3.55 (1H, m, 1 '-H), 3.02 ~ 2.87 (4H, m, pyrrolindine-H), 1.65 ~ 1.16 (8H, m, pyrrolindine-, 2 '-and 3 '-H); MS (m/z): Calcd.forC 20h 20fN 5o 3: 397.41 [M] +; Found:398 [M+H] +.
Test example
One, the antibacterial activity in vitro of 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolone carboxylic analog derivative that embodiment 1-9 provides measures standard method according to " sensitivity testing to antibacterials operative norm: the 22 edition data supplementary issue M100-S22 ", measures staphylococcus aureus, dust Xi Shi intestinal bacteria, the positive staphylococcus aureus of methicillin-resistant and the colibacillary anti-microbial activity of multidrug resistance:
1, test sample
1-cyclopropyl-7-aminomethyl triazole-fluoroquinolone carboxylic the analog derivative provided with embodiment 1-9, and contrast Ciprofloxacin (CF) is test sample, totally 10 kinds, wherein CF is control group, and embodiment 1-9 sample is experimental group;
Experimental microbial bacterial strain is respectively standard Gram-positive staphylococcus aureus S.aureus ATCC-29213 (SA), standard dust Xi Shi negative bacterium E.coli ATCC-25922 (EC), positive staphylococcus aureus MR S.aureus ATCC-25923 (MR-SA) of methicillin-resistant and multidrug resistance intestinal bacteria MDR E.coli ATCC-35218 (MDR-EC) (being provided by clinical laboratory of Huaihe River clinical pharmacy institute of He'nan University), and be inoculated in meat soup MH substratum, cultivate 18h for 37 DEG C, and become 1/200 for subsequent use as experimental bacteria liquid with broth dilution.
Take the test sample compound of 1.28mg respectively, be dissolved in 1.0mL DMSO, be made into the mother liquor of 1.28mg/mL, the test sample liquid being diluted to 64,32,16,8,4,2,1,0.5,0.25,0.125 μ g/mL concentration gradient by doubling dilution method with meat soup is for subsequent use.
2, measuring method
The concrete steps of measuring method are:
In 96 well culture plates of cleaning sterile, add above-mentioned 1/200 experimental bacteria liquid 90 μ L, then add the test sample liquid 10 μ L of different concns gradient, make the whole bacterial concentration of every Kongzui be about 5 × 10 5cFU/mL, positive control is the Ciprofloxacin 10 μ L of different concns.Establish blank and solvent control (add DMSO in experimental bacteria liquid, make its concentration be 5wt%), each process 3 repetition simultaneously.96 orifice plates are shifted vibration (15rpm) on decolorization swinging table at TS-8 at 37 DEG C, under dark condition, cultivates 18h.Then detect by an unaided eye every hole bacterial growth situation, is minimum antibacterial growth drug concentration MIC value (minimum inhibitory concentration value) without the concentration in the well culture plate of bacterial growth; Each data replicate(determination) three times, asks its mean value, evaluates its anti-microbial activity, the results are shown in Table shown in 1 with this.
The anti-microbial activity (MIC) of each test sample of table 1
As can be seen from Table 1, the compound that embodiment 1-9 provides demonstrates certain inhibit activities to 4 kinds of experiment bacterial strains, the activity of the compound especially containing piperazinyl is suitable with the activity contrasting Ciprofloxacin, particularly the activity of 2 drug-resistant bacteria strains is better than to the activity of contrast Ciprofloxacin, without the generation of resistance phenomenon, this is that the overriding resistance flouroquinolone drugs developing new texture provides important evidence.Therefore, it is the antibacterial in-vitro screening first carrying out routine according to the general way of drug development, then study targetedly, thus compound of the present invention to have strong antibacterium resistance active, by with the acceptable sour salify of human body or be mixed with anti-infection drug with pharmaceutical carrier.

Claims (8)

1. 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolone carboxylic analog derivative, is characterized in that, has the general structure as shown in the formula (I):
In formula (I), R is dimethylamino, diethylin, piperidyl, morpholinyl, piperazine, substituted piperazinyl or pyrrolidyl.
2. 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolone carboxylic analog derivative according to claim 1, is characterized in that, be specially the compound of following structure:
3. a preparation method for 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolone carboxylic analog derivative described in claim 1 or 2, it is characterized in that, concrete preparation process comprises:
(1) with 1-cyclopropyl-6-fluoro-7-chlorine-quinoline-4 (1H)-one-3-carboxylic acid shown in the formula of commercial offers (II) for raw material, carry out substitution reaction with sodiumazide and obtain 1-cyclopropyl-6-fluoro-7-nitrine yl-quinoline-4 (1H)-one-3-carboxylic acid shown in formula (III);
(2) compound shown in formula (III) and bromo propine are reacted by click chemistry, after reaction terminates, the fluoro-7-of 1-cyclopropyl-6-(4-brooethyl-[1 shown in formula (IV) can be obtained through aftertreatment, 2,3] triazol-1-yl)-quinoline-4 (1H)-one-3-carboxylic acid; Then there is the nucleophilic substitution reaction of Br in formula (IV) and amine donor RH, can obtain the 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolone carboxylic analog derivative shown in formula (I) through aftertreatment;
4. the preparation method of 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolone carboxylic analog derivative according to claim 3, it is characterized in that, the mol ratio of 1-cyclopropyl-6-fluoro-7-chlorine-quinoline-4 (1H)-one-3-carboxylic acid shown in described formula (II) and sodiumazide is 1:1.0 ~ 1.5.
5. the preparation method of 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolone carboxylic analog derivative according to claim 3, it is characterized in that, the mol ratio of 1-cyclopropyl-6-fluoro-7-nitrine yl-quinoline-4 (1H)-one-3-carboxylic acid shown in described formula (III) and bromo propine is 1:1.0 ~ 1.2.
6. the preparation method of 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolone carboxylic analog derivative according to claim 3, it is characterized in that, the fluoro-7-of 1-cyclopropyl-6-(4-brooethyl-[1 shown in described formula (IV), 3,4] triazol-1-yl) mol ratio of-quinoline-4 (1H)-one-3-carboxylic acid and amine donor RH is 1:1.0 ~ 3.0.
7. the 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolone carboxylic analog derivative described in claim 1 or 2 is preparing the application in anti-infectives.
8. 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolone carboxylic analog derivative is preparing the application in anti-infectives according to claim 7, it is characterized in that, described anti-infectives is the medicine that catch for the treatment of caused by dust Xi Shi negative bacterium, gram staphylococcus aureus, multidrug resistance intestinal bacteria and Methicillin resistant Staph. aureus.
CN201510198052.9A 2015-04-24 2015-04-24 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolones carboxylic acid derivative, method for preparing same and application of 1-cyclopropyl-7-aminomethyl triazole-fluoroquinolones carboxylic acid derivative Pending CN104817537A (en)

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* Cited by examiner, † Cited by third party
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CN112480099A (en) * 2020-12-22 2021-03-12 广东省微生物研究所（广东省微生物分析检测中心） 1,3, 4-oxadiazole-ciprofloxacin heterozygote and preparation method and application thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112480099A (en) * 2020-12-22 2021-03-12 广东省微生物研究所（广东省微生物分析检测中心） 1,3, 4-oxadiazole-ciprofloxacin heterozygote and preparation method and application thereof

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