CN104817558B - A kind of 1-cyclopropyl-7-aminomethyl triazole-fluorine naphthycidonecarboxyacid acid analog derivative and its preparation method and application - Google Patents
A kind of 1-cyclopropyl-7-aminomethyl triazole-fluorine naphthycidonecarboxyacid acid analog derivative and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of 1 cyclopropyl 7 aminomethyl triazole fluorine naphthycidonecarboxyacid acid analog derivative and its preparation method and application, use such as following formula I chemical structure of general formula:
Description
Technical field
The invention belongs to original new drug synthesis field, be specifically related to a kind of 1-cyclopropyl-7-aminomethyl triazole-fluorine naphthyridones
Carboxylic acid derivative, also relates to the preparation method of 1-cyclopropyl-7-aminomethyl triazole-fluorine naphthycidonecarboxyacid acid analog derivative,
And its application in anti-infectives.
Background technology
Fluoroquinolone receives much concern as clinical widely used wide spectrum, efficient, low toxicity anti-infectives.But, by
How day by day serious in current bacterial resistance, overcome bacterial drug resistance to become anti-infectives treatment field urgently to be resolved hurrily
Society's publilc health safety problem.Although the strategy solving bacterial resistance has multiple choices, but effectively and the approach of economy is base
Architectural feature in existing medicine carries out structure optimization, constantly promotes the generation of new drug.The structure of fluoroquinolone antibacterial activity-effect is closed
It is that research shows: in addition to C-3 position carboxyl and C-4 carbonyl are activity pharmacophore necessary to antibacterial activity, C-7 bit substituent, especially
It is introduced into C-7 piperazinyl to expanding its antimicrobial spectrum, improving antibacterial activity and improve pharmacokinetics etc. and all have considerable influence.For
This, the C-7 position of the most clinical flouroquinolone drugs molecule has piperazine substituted more.Meanwhile, for finding new antibacterial activity fluorine quinoline
Promise ketonic compound, many researchs focus mostly in the change of piperazine N-substituent group, and insertion connects between piperazinyl and quinoline ring skeleton
The change of chain link is the fewest.
Summary of the invention
It is an object of the invention to provide a kind of 1-cyclopropyl-7-aminomethyl triazole-fluorine naphthycidonecarboxyacid acid analog derivative, simultaneously
The preparation method and application of 1-cyclopropyl-7-aminomethyl triazole-fluorine naphthycidonecarboxyacid acid analog derivative are provided.
In order to realize object above, the technical solution adopted in the present invention is: a kind of 1-cyclopropyl-7-aminomethyl triazole-
Fluorine naphthycidonecarboxyacid acid analog derivative, its chemical structural formula is as shown in logical formula (I):
Formula (I)
In formula (I), R is dimethylamino, lignocaine, piperidyl, morpholinyl, pyrrolidinyl, piperazinyl or substituted-piperazinyl
Base.This compounds is specially the compound of following structure:
The preparation method of the 1-cyclopropyl-7-aminomethyl triazole-fluorine naphthycidonecarboxyacid acid analog derivative of the present invention, supplies with business
The fluorine chlorine naphthycidonecarboxyacid acid shown in precursor carboxylic acid formula (II) answering Gemifloxacin is that raw material is prepared from,
Formula (II)
Concrete preparation process is as follows:
1) the fluorine chlorine naphthycidonecarboxyacid acid shown in formula (II) and Hydrazoic acid,sodium salt generation substitution reaction are prepared 1-shown in formula (III)
Cyclopropyl-6-fluoro-7-azido-[1,8] naphthyridines-4 (1H)-one-3-carboxylic acid；
Formula (III)
2) compound shown in formula (III) and bromo propine are reacted to obtain the 1-ring third shown in formula (IV) by click chemistry
The fluoro-7-of base-6-(4-bromomethyl-[1,2,3] triazol-1-yl)-[1,8] naphthyridines-4 (1H)-one-3-carboxylic acid；
Formula (IV)
3) by the nucleophilic substitution of bromomethyl triazole compounds shown in formula (IV) with amine donor RH generation Br, question response is complete
After Quan through post processing must as shown in formula (I) target compound.
Formula (I)
The 1-fluoro-7-of cyclopropyl-6-chloro-[1,8] naphthyridines-4 (1H)-one-3-carboxylic acid shown in described formula (II) and Azide
The mol ratio of sodium is 1:1.0～1.5.
1-cyclopropyl-6-fluoro-7-azido-[1,8] naphthyridines-4 (1H)-one-3-carboxylic acid shown in described formula (III) and bromine
Mol ratio for propine is 1:1.0～1.2.
The 1-fluoro-7-of cyclopropyl-6-(4-bromomethyl-[1,3,4] triazol-1-yl)-[1,8] naphthalene shown in described formula (IV)
Pyridine-4 (1H)-one-3-carboxylic acid is 1:1.0～3.0 with the mol ratio of amine donor RH.
Described 1-cyclopropyl-7-aminomethyl triazole-fluorine naphthycidonecarboxyacid acid analog derivative is in preparing anti-infectives
Application.
Described anti-infectives is big by an angstrom Xi Shi negative bacterium, gram staphylococcus aureus, multidrug resistance for treatment
Catching caused by enterobacteria and Methicillin resistant Staph. aureus.
1-cyclopropyl-7-aminomethyl triazole-fluorine naphthycidonecarboxyacid acid analog derivative the split based on pharmacophore of the present invention is former
Reason, will insert function triazole heterocycle between advantage pharmacophore skeleton fluorine naphthycidonecarboxyacid acid and effective substituent group C-7 amino, should with clinic
The structure of testing afloqualone medicament ciprofloxacin (V) compare, by the change of C-7 substituent structure, overcome fluorine quinoline promise
The drug resistance of ketone medicine, can develop as the fluoroquinolone anti-infectives of brand new.
Formula (V) ciprofloxacin
Detailed description of the invention
Below by specific embodiment, technical scheme is described in detail.
The preparation method of the 1-cyclopropyl-7-aminomethyl triazole-fluorine naphthycidonecarboxyacid acid analog derivative of the present invention, supplies with business
The fluorine chlorine naphthycidonecarboxyacid acid shown in precursor carboxylic acid formula (II) answering Gemifloxacin is that raw material is prepared from,
Formula (II)
Concrete preparation process is as follows:
1) the fluorine chlorine naphthycidonecarboxyacid acid shown in formula (II) and Hydrazoic acid,sodium salt generation substitution reaction are prepared 1-shown in formula (III)
Cyclopropyl-6-fluoro-7-azido-[1,8] naphthyridines-4 (1H)-one-3-carboxylic acid；
Formula (III)
Specific make step is: compound (II) (10.0g, 35.0mmol) and Hydrazoic acid,sodium salt (2.8g, 43.0mmol) are molten
Solution is in DMSO (50mL), and stirring at normal temperature reacts 24h.Reactant mixture is slowly poured in ice-water mixture (200mL), with dense
Hydrochloric acid adjusts pH to 7.0.The solid that filter collection produces, washes with water, vacuum drying.Crude product ethanol-DMF (V/V=5:1) mixes molten
Agent recrystallization, obtains yellow solid (III), yield 86%, mp 216-218 DEG C (dec.).1H NMR(400MHz,DMSO-d6)δ:
15.56 (brs, 1H, COOH), 8.87 (s, 1H, 2-H), 8.13 (d, J=13.2Hz, 1H, 5-H), 3.66～3.57 (m, 1H,
1 '-H), 1.34～1.26 (m, 4H, 2 '-and 3 '-H)；MS(m/z):Calcd.for C12H8FN5O3:289.23[M]+；Found:
290[M+H]+。
2) compound shown in formula (III) is reacted by click chemistry (click chemistry) with bromo propine
The 1-fluoro-7-of cyclopropyl-6-(4-bromomethyl-[1,2,3] triazol-1-yl)-[1,8] naphthyridines-4 (1H)-one-3-shown in formula (IV)
Carboxylic acid.
Formula (IV)
Specific make step is: add n-butyl alcohol (150mL) and water (50mL), stirring in three mouthfuls of reaction bulbs of 500mL
Under to be sequentially added into the compound (10.0g, 34.6mmol) shown in formula (III), copper sulphate pentahydrate (2.0g, 8.0mmol) and dimension raw
After element C sodium salt (1.6g, 8.0mmol), slowly dropping bromo propine (4.2g, 35.0mmol) and the mixing of dichloromethane (50mL)
Thing, and 50 DEG C of stirring reactions to (TLC detects, developing solvent V (CHCl completely3): V (MeOH)=5:1).Cooling room temperature, adds water
(10mL), stirring, stratification.Aqueous phase dichloromethane extracts, and merges organic facies, is dried with anhydrous sodium sulfate.Remove under reduced pressure
Solvent, residue dehydrated alcohol recrystallization, obtain yellow solid (IV), yield 76%, mp 237-239 DEG C.1H NMR
(400MHz,DMSO-d6): δ 15.54 (brs, 1H, COOH), 8.86 (s, 1H, 2-H), 8.07 (d, J=13.2Hz, 1H, 5-H),
7.86(s,1H,5″-H),4.84(s,2H,BrCH2), 3.68～3.61 (m, 1H, 1 '-H), 1.31～1.24 (m, 4H, 2 '-with
3′-H)；MS(m/z):Calcd.for C15H11BrFN5O3:408.19[M]+；Found:408 and 410 [M+H]+for 79Br and81Br；Anal.Calcd for C15H11BrFN5O3:C 44.14,H 2.72,N 17.16；Found C 44.37,H 2.62,N
17.41.
3) by the nucleophilic substitution of bromomethyl triazole compounds shown in formula (IV) with amine donor RH generation Br, question response is complete
Quan Houjing process shown in target compound such as formula (I).
Formula (I)
In Formulas I, R is dimethylamino, lignocaine, piperidyl, morpholinyl, pyrrolidinyl, piperazinyl or substituted piperazinyl.
General synthetically prepared step is: the fluoro-7-of 1-cyclopropyl-6-(4-bromomethyl-[1,2,3] triazol-1-yl)-[1,
8], during naphthyridines-4 (1H)-one-3-carboxylic acid IV (1.0g, 2.5mmol) is suspended in acetonitrile (15mL), amine donor RH is added
(5.0mmol) with triethylamine (0.4g, 4.0mmol).Mixed reactant is stirred at reflux 12h, removes solvent under reduced pressure, and residue is used
2mol/L diluted hydrochloric acid aqueous solution dissolves, and filters insoluble matter.Filtrate with strong aqua ammonia alkalization to pH=7.0, with chloroform extraction (3 ×
20mL), merging organic facies, anhydrous sodium sulfate is dried.Remove solvent under reduced pressure, residue dehydrated alcohol recrystallization, obtain yellow solid
Body object (I).
Embodiment 1
The fluoro-7-of 1-cyclopropyl-6-(4-dimethyl aminomethyl-[1,2,3] triazol-1-yl)-[1,8] naphthyridines-4 (1H)-one-3-
Carboxylic acid (I-1), its chemical structural formula is:
I.e. R in Formulas I is dimethylamino.
The preparation method of this compound is: with dimethylamine for amine donor, according to the general preparation side of above-mentioned object (I)
Method, obtains pale yellow crystals thing (I-1), productivity 82.0%, m.p.231-233 DEG C.1H NMR(400MHz,DMSO-d6):δ15.46
(brs, 1H, COOH), 8.89 (s, 1H, 2-H), 8.17 (d, J=13.2Hz, 1H, 5-H), 7.88 (s, 1H, 5 "-H), 5.23 (s,
2H,NCH2),3.67-3.56(m,1H,1′-H),2.44(s,6H,2×CH3), 1.35～1.26 (m, 4H, 2 '-and 3 '-H)；MS
(m/z):Calcd.for C17H17FN6O3:372.36[M]+；Found:373[M+H]+。
Embodiment 2
The fluoro-7-of 1-cyclopropyl-6-(4-diethylamino methyl-[1,2,3] triazol-1-yl)-[1,8] naphthyridines-4 (1H)-one-3-
Carboxylic acid (I-2), its chemical structural formula is:
I.e. R in Formulas I is lignocaine.
The preparation method of this compound is: with diethylamine for amine donor, according to the general preparation side of above-mentioned object (I)
Method, obtains pale yellow crystals thing (I-2), productivity 71.0%, m.p.225-227 DEG C.1H NMR(400MHz,DMSO-d6):δ15.45
(brs, 1H, COOH), 8.86 (s, 1H, 2-H), 8.16 (d, J=13.2Hz, 1H, 5-H), 7.86 (s, 1H, 5 "-H), 5.21 (s,
2H,NCH2),3.71-3.64(m,1H,1′-H),2.46-2.38(m,4H,2×CH2),1.32-1.15(m,10H,2′-,3′-H
With 2 × CH3)；MS(m/z):Calcd.for C19H21FN6O3:400.42[M]+；Found:401[M+H]+。
Embodiment 3
The fluoro-7-of 1-cyclopropyl-6-(4-piperidines-1-methyl-[1,2,3] triazol-1-yl)-[1,8] naphthyridines-4 (1H)-one-
3-carboxylic acid (I-3), its chemical structural formula is:
I.e. R in Formulas I is piperidin-1-yl.
The preparation method of this compound is: with piperidines for amine donor, according to the general preparation side of above-mentioned object (I)
Method, obtains pale yellow crystals thing (I-3), productivity 76.0%, m.p.234-236 DEG C.1H NMR(400MHz,DMSO-d6):δ15.45
(brs, 1H, COOH), 8.87 (s, 1H, 2-H), 8.14 (d, J=13.2Hz, 1H, 5-H), 7.88 (s, 1H, 5 "-H), 5.26 (s,
2H,NCH2),3.67-3.64(m,1H,1′-H),3.06-2.27(m,4H,N(CH2)2),1.63-1.04(m,10H,2′-,3′-H
With 3 × CH2)；MS(m/z):Calcd.for C20H21FN6O3:412.43[M]+；Found:413[M+H]+。
Embodiment 4
The fluoro-7-of 1-cyclopropyl-6-(4-morpholine-4-methyl-[1,2,3] triazol-1-yl)-[1,8] naphthyridines-4 (1H)-one-
3-carboxylic acid (I-4), its chemical structural formula is:
I.e. R in Formulas I is morpholine-4-base.
The preparation method of this compound is: with morpholine for amine donor, according to the general preparation side of above-mentioned object (I)
Method, obtains pale yellow crystals thing (I-4), productivity 87.0%, m.p.241-243 DEG C.1H NMR(400MHz,DMSO-d6):δ15.53
(brs, 1H, COOH), 8.94 (s, 1H, 2-H), 8.17 (d, J=13.2Hz, 1H, 5-H), 7.93 (s, 1H, 5 "-H), 5.26 (s,
2H,NCH2), 3.68-3.57 (m, 5H, 1 '-H and O (CH2)2), 3.23 (t, J=5.4Hz, 4H, N (CH2)2),1.34-1.23(m,
4H, 2 '-and 3 '-H)；MS(m/z):Calcd.for C19H19FN6O4:414.40[M]+；Found 415[M+H]+。
Embodiment 5
The fluoro-7-of 1-cyclopropyl-6-(4-piperazine-1-methyl-[1,2,3] triazol-1-yl)-[1,8] naphthyridines-4 (1H)-one-
3-carboxylic acid (I-5), its chemical structural formula is:
I.e. R in Formulas I is piperazine-1-base.
The preparation method of this compound is: with piperazine for amine donor, according to the general preparation side of above-mentioned object (I)
Method, obtains pale yellow crystals thing (I-5), productivity 85%, m.p.245-247 DEG C.1H NMR(400MHz,DMSO-d6):δ15.56
(brs, 1H, COOH), 8.95 (s, 1H, 2-H), 8.21 (d, J=13.2Hz, 1H, 5-H), 8.03 (s, 1H, 5 "-H), 5.28 (s,
2H,NCH2), 3.67-3.35 (m, 5H, 1 '-H and piperazine-H), 2.63-2.68 (m, 4H, piperazine-H),
1.36-1.27(m,4H,2′-and 3′-H)；MS(m/z):Calcd.for C19H20FN7O3:413.41[M]+；Found 414
[M+H]+。
Embodiment 6
The fluoro-7-of 1-cyclopropyl-6-[4-(4-thyl-piperazin-1-methyl)]-[1,2,3] triazol-1-yl)-[1,8] naphthyridines-
4 (1H)-one-3-carboxylic acid (I-6), its chemical structural formula is:
I.e. R in Formulas I is 4-thyl-piperazin-1-base.
The preparation method of this compound is: with N methyl piperazine for amine donor, according to the general system of above-mentioned object (I)
Preparation Method, obtains pale yellow crystals thing (I-6), productivity 84%, m.p.243-245 DEG C.1H NMR(400MHz,DMSO-d6):δ
15.54 (brs, 1H, COOH), 8.92 (s, 1H, 2-H), 8.14 (d, J=13.2Hz, 1H, 5-H), 7.96 (s, 1H, 5 "-H),
5.33(s,2H,NCH2), 3.68-3.27 (m, 5H, 1 '-H and piperazine-H), 2.76-2.63 (m, 4H, piperazine-
H),2.34(s,3H,N-CH3), 1.36-1.24 (m, 4H, 2 '-and 3 '-H)；MS(m/z):Calcd.for C20H22FN7O3:
427.44[M]+；Found 428[M+H]+。
Embodiment 7
The fluoro-7-of 1-cyclopropyl-6-[4-(4-ethyl-piperazin-1-methyl)]-[1,2,3] triazol-1-yl)-[1,8] naphthyridines-
4 (1H)-one-3-carboxylic acid (I-7), its chemical structural formula is:
I.e. R in Formulas I is 4-ethyl-piperazin-1-base.
The preparation method of this compound is: with NEP for amine donor, according to the general system of above-mentioned object (I)
Preparation Method, obtains pale yellow crystals thing (I-7), productivity 78%, m.p.236-238 DEG C.1H NMR(400MHz,DMSO-d6):δ
15.53 (brs, 1H, COOH), 8.97 (s, 1H, 2-H), 8.15 (d, J=13.2Hz, 1H, 5-H), 7.95 (s, 1H, 5 "-H),
5.33(s,2H,NCH2), 3.64-3.31 (m, 5H, 1 '-H and piperazine-H), 2.76-2.68 (m, 4H, piperazine-
H), 2.26 (q, J=5.6Hz, 2H, NCH 2CH3),1.36-1.18(m,7H,CH3, 2 '-and 3 '-H)；MS(m/z):Calcd.for
C21H24FN7O3:441.47[M]+；Found 442[M+H]+。
Embodiment 8
The fluoro-7-of 1-cyclopropyl-6-[4-(3-thyl-piperazin-1-methyl)]-[1,2,3] triazol-1-yl)-[1,8] naphthyridines-
4 (1H)-one-3-carboxylic acid (I-8), its chemical structural formula is:
I.e. R in Formulas I is 3-thyl-piperazin-1-base.
The preparation method of this compound is: with 2-methyl piperazine for amine donor, according to the general system of above-mentioned object (I)
Preparation Method, obtains pale yellow crystals thing (I-8), productivity 68%, m.p.215-217 DEG C.1H NMR(400MHz,DMSO-d6):δ
15.48 (brs, 1H, COOH), 9.03 (s, 1H, 2-H), 8.17 (d, J=13.2Hz, 1H, 5-H), 7.98 (s, 1H, 5 "-H),
5.36(s,2H,NCH2), 3.73-3.37 (m, 5H, 1 '-H and piperazine-H), 2.68-2.57 (m, 3H, piperazine-
H),1.35-1.23(m,7H,CH3, 2 '-and 3 '-H)；MS(m/z):Calcd.for C20H22FN7O3:427.44[M]+；Found:
428[M+H]+。
Embodiment 9
The fluoro-7-of 1-cyclopropyl-6-(4-pyrrolidine-1-methyl)-[1,2,3] triazol-1-yl)-[1,8] naphthyridines-4 (1H)-
Ketone-3-carboxylic acid (I-9), its chemical structural formula is:
I.e. R in Formulas I is pyrrolidin-1-yl.
The preparation method of this compound is: with pyrrolidine for amine donor, according to the general preparation side of above-mentioned object (I)
Method, obtains pale yellow crystals thing (I-9), productivity 83%, m.p.246-248 DEG C.1H NMR(400MHz,DMSO-d6):δ15.45
(brs, 1H, COOH), 8.97 (s, 1H, 2-H), 8.15 (d, J=13.2Hz, 1H, 5-H), 8.04 (s, 1H, 5 "-H), 5.28 (s,
2H,NCH2),3.65-3.57(m,1H,1′-H),3.13-2.85(m,4H,pyrrolindine-H),1.64-1.13(m,8H,
Pyrrolindine-, 2 '-and 3 '-H)；MS(m/z):Calcd.for C19H19FN6O3:398.40[M]+；Found:399[M+
H]+。
Test example
One, the In Vitro Anti of 1-cyclopropyl-7-aminomethyl triazole-fluorine naphthycidonecarboxyacid acid analog derivative that embodiment 1-9 provides
Bacterium determination of activity is according to the standard side of " sensitivity testing to antibacterials execution standard: the 22nd edition data supplementary issue M100-S22 "
Method, to staphylococcus aureus, angstrom Xi Shi escherichia coli, methicillin-resistant positive staphylococcus aureus and the colibacillary antibacterial work of multidrug resistance
Property is measured:
1, test sample
1-cyclopropyl-7-aminomethyl triazole-fluorine naphthycidonecarboxyacid acid the analog derivative provided with embodiment 1-9, and comparison ring
Third husky star (CF) is test sample, and totally 10 kinds, wherein CF is matched 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 angstrom Xi Shi negative bacterium E.coli ATCC-25922 (EC), methicillin-resistant positive staphylococcus aureus MR S.aureus
ATCC-25923 (MR-SA) and multidrug resistance escherichia coli MDR E.coli ATCC-35218 (MDR-EC) are (by He'nan University Huaihe River
River clinical laboratory of clinical pharmacy institute provides), and be inoculated in meat soup MH culture medium, cultivate 18h, and become with broth dilution for 37 DEG C
1/200 is standby as experiment bacterium solution.
Weigh the test sample compound of 1.28mg respectively, be dissolved in 1.0mL DMSO, be made into the mother solution of 1.28mg/mL,
It is diluted to the test of 64,32,16,8,4,2,1,0.5,0.25,0.125 μ g/mL Concentraton gradient by doubling dilution method with meat soup
Sample liquid is standby.
2, assay method
Concretely comprising the following steps of assay method:
In 96 well culture plates of cleaning sterile, add above-mentioned 1/200 experiment bacterium solution 90 μ L, be subsequently adding variable concentrations ladder
The test sample liquid 10 μ L of degree, makes the final bacterial concentration in every hole be about 5 × 105CFU/mL, positive control is the ring of respective concentration
Third husky star 10 μ L.Set blank and solvent control (adding DMSO in experiment bacterium solution, the concentration making DMSO is simultaneously
5wt%), each process 3 repetition.96 orifice plates are vibrated (15rpm) at 37 DEG C on TS-8 transfer decolorization swinging table, dark bar
18h is cultivated under part.Then detect by an unaided eye every hole bacterial growth situation, is without the concentration in the well culture plate of bacterial growth
Little antibacterial growth drug concentration MIC value (minimum inhibitory concentration value)；Each data are parallel
Measure three times, seek its meansigma methods, evaluate its antibacterial activity with this, the results are shown in Table shown in 1.
The antibacterial activity (MIC) of each test sample of table 1
As it can be seen from table 1 to 4 kinds of experiment bacterial strains, the compound that embodiment 1-9 provides demonstrates that certain wide spectrum resists
Bacterium activity, especially contain piperazinyl compound activity quite or be better than comparison ciprofloxacin activity, particularly to 2
The activity of drug-resistant bacteria strain is better than the activity of comparison, and this is that the overriding resistance flouroquinolone drugs developing new construction provides important depending on
According to.Therefore, it is the antibacterial in-vitro screening first carrying out routine according to the general way of drug development, grinds the most targetedly
Study carefully, so the compound of the present invention has strong antibacterium drug resistance activity, salt or and medicine can be become by acid acceptable with human body
It is mixed with anti-infection drug with carrier.
Claims (7)
1. 1-cyclopropyl-7-aminomethyl triazole-fluorine naphthycidonecarboxyacid acid analog derivative, it is characterised in that be specially following knot
The compound of structure:
Or
Or
Or
Or
Or
Or
Or
Or
。
2. the preparation side of the 1-cyclopropyl-7-aminomethyl triazole-fluorine naphthycidonecarboxyacid acid analog derivative described in a claim 1
Method, it is characterised in that concrete preparation process includes:
(1) with the 1-fluoro-7-of cyclopropyl-6-chloro-[1,8] naphthyridines-4 (1H)-one-3-carboxylic acid shown in formula (II) for raw material, with folded
Sodium nitride carries out substitution reaction and obtains 1-cyclopropyl-6-fluoro-7-azido-[1,8] naphthyridines-4 (1H)-one-3-shown in formula (III)
Carboxylic acid；
Formula (II) formula (III)
(2) compound shown in formula (III) is reacted by click chemistry with bromo propine, reaction terminate after, post-treated can
The 1-fluoro-7-of cyclopropyl-6-(4-bromomethyl-[1,2,3] triazol-1-yl)-[1,8] naphthyridines-4 (1H)-one shown in formula (IV)-
3-carboxylic acid；Then there is substitution reaction, the post-treated 1-ring third obtained shown in formula (I) with amine donor RH in formula (IV) compound
Base-7-aminomethyl triazole-fluorine naphthycidonecarboxyacid acid analog derivative；
Formula (IV) formula (I)
R is、、、、、、、Or。
The preparation side of 1-cyclopropyl-7-aminomethyl triazole-fluorine naphthycidonecarboxyacid acid analog derivative the most according to claim 2
Method, it is characterised in that the 1-fluoro-7-of cyclopropyl-6-chloro-[1,8] naphthyridines-4 (1H)-one-3-carboxylic acid shown in described formula (II) with
The mol ratio of Hydrazoic acid,sodium salt is 1:1.0 ~ 1.5.
The preparation side of 1-cyclopropyl-7-aminomethyl triazole-fluorine naphthycidonecarboxyacid acid analog derivative the most according to claim 2
Method, it is characterised in that the 1-cyclopropyl-6-fluoro-7-azido shown in described formula (III)-[1,8] naphthyridines-4 (1H)-one-3-carboxylic
Acid is 1:1.0 ~ 1.2 with the mol ratio of bromo propine.
The preparation side of 1-cyclopropyl-7-aminomethyl triazole-fluorine naphthycidonecarboxyacid acid analog derivative the most according to claim 2
Method, it is characterised in that the 1-fluoro-7-of cyclopropyl-6-(4-bromomethyl-[1,3,4] triazol-1-yl) shown in described formula (IV)-[1,
8] naphthyridines-4 (1H)-one-3-carboxylic acid is 1:1.0 ~ 3.0 with the mol ratio of amine donor RH.
6. the 1-cyclopropyl-7-aminomethyl triazole-fluorine naphthycidonecarboxyacid acid analog derivative described in claim 1 is preparing anti-infective
Application in thing.
1-cyclopropyl-7-aminomethyl triazole-fluorine naphthycidonecarboxyacid acid analog derivative the most according to claim 6 is preparing anti-sense
Application in dye medicine, it is characterised in that described anti-infectives is for treating by an angstrom Xi Shi negative bacterium, gram gold Portugal
Coccus, multidrug resistance escherichia coli and the medicine caught caused by Methicillin resistant Staph. aureus.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0203488A2 (en) * | 1985-05-30 | 1986-12-03 | Bayer Ag | 7-Azolyl-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinoline carboxylic acids and 1,8-naphthyridine carboxylic acids, process for their preparation and bactericidal agents containing them |
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- 2015-04-24 CN CN201510203507.1A patent/CN104817558B/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0203488A2 (en) * | 1985-05-30 | 1986-12-03 | Bayer Ag | 7-Azolyl-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinoline carboxylic acids and 1,8-naphthyridine carboxylic acids, process for their preparation and bactericidal agents containing them |
Non-Patent Citations (1)
| Title |
|---|
| Structure aided design of chimeric antibiotics;Tomislav Karoli, et al.;《Bioorganic & Medicinal Chemistry Letters》;20120222;第22卷;第2428-2433页 * |
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