CN109942579A - Beta-lactamase inhibitor dicyclic compound containing urea and its preparation method and application - Google Patents
Beta-lactamase inhibitor dicyclic compound containing urea and its preparation method and application Download PDFInfo
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- lactamase inhibitor
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Abstract
The invention discloses beta-lactamase inhibitor dicyclic compounds containing urea and its preparation method and application, solve the problems, such as existing bacterial drug resistance.The present invention includes structural formula shown in formula I, R in the structural formula1And R2It is separately or concurrently H, NHR3, 4~6 circle heterocyclic rings, aromatic ring, the alkanoyl of l~5 C; the alkoxy acyl of l~5 C, fragrant sulfonyl, alkyl sulphonyl; aromatic rings acyl group is replaced containing heteroatomic heterocyclic acyl, or optionally by the alkyl of Cl~4, the alkoxy of l~4 C, halogen or the halogenated alkyl of l~4 C;X is Na or H in the structural formula.2 to 4 times of reduced effect is presented in the MIC of cefotaxime when the compounds of this invention and beta-Lactam antibiotic cefotaxime are used in combination.
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to beta-lactamase inhibitor dicyclic compound containing urea and its preparation
Methods and applications.
Background technique
Bacterium is all especially often to pass through beta-lactam in Gram-negative bacteria to the drug resistance of beta-lactam antibiotic
Enzyme mediates.Beta-lactamase is the enzyme for being catalyzed beta-lactam cyclizing hydrolysis, the antibacterial that it can be such that beta-lactam antibiotic activates
Drug inactivation, and make bacterial resistance occurred.Inhibit beta-lactamase that can slow down or prevent β-with the inhibitor of beta-lactamase
The degradation of lactam antibiotics, and restore beta-lactam antibiotic to the inhibiting effect of beta-lactamase.It is generated in tracking
Find many beta-lactamases not by the suppression of widely used beta-lactamase on the market at present in the bacterium of beta-lactamase
Preparation significantly inhibits, such as KPC.To which there is an urgent need to find that the inhibitor of new beta-lactamase combines use with associated antibiotic
It is infected caused by the bacterium as beta-lactam resistance in treating.
The mankind are faced with the challenge of bacterial drug resistance, and either gram-positive bacteria or Gram-negative bacteria and multiple medicine is resistance to
All there is drug resistance very serious in Mycobacterium tuberculosis of medicine etc..Bacterial resistance phenomenon is especially serious in China.To current
Until, the inhibitor of widely used beta-lactamase has clavulanic acid, Sulbactam and Tazobactam Sodium in the market.Due to more next
More bacteriums to the inhibitor of these beta-lactamases and antibiotic group at compound medicine produce the drug resistance got worse
Property, how to develop it is a kind of new to a variety of inhibitor that can generate beta-lactamase drug-fast bacteria be one extremely pay close attention to ask
Topic.
Summary of the invention
The purpose of the present invention is to provide a kind of beta-lactamase inhibitor dicyclic compound containing urea and preparation method thereof and
Using obtaining a kind of inhibitor of the drug resistance that can fight a variety of drug-fast bacterias for generating beta-lactamases of new construction.
The present invention is realized by following proposal:
Beta-lactamase inhibitor dicyclic compound containing urea, structural formula is shown in formula I,
R in the structural formula1And R2It is separately or concurrently H, NHR3, 4~6 circle heterocyclic rings, aromatic ring, the alkanoyl of l~5 C, C l
~5 alkoxy acyl, fragrant sulfonyl, alkyl sulphonyl, aromatic rings acyl group, containing heteroatomic heterocyclic acyl, or optionally
Ground is replaced by the alkyl of l~4 C, the alkoxy of l~4 C, halogen or the halogenated alkyl of l~4 C;
X is Na or H in the structural formula.
Further, the R3 is 4~6 circle heterocyclic rings, aromatic ring, the alkanoyl of l~5 C, the alkoxy acyl of l~5 C, fragrant sulphur
Acyl group, alkyl sulphonyl, aromatic rings acyl group, containing heteroatomic heterocyclic acyl, or optionally by the alkyl of l~4 C, C l
~4 alkoxy, halogen or the halogenated alkyl of l~4 C replaces.
Further, the hetero atom in the heterocyclic acyl is N, S or O.
" optionally by ... replace " in R group of the present invention refers to that the group of R can be replaced by these groups, can also not
Replaced by these groups, that is, be not limited in the case where being replaced by these cited groups, also includes not by cited this
The case where a little groups replace.This expression way with " R be the alkyl of substituted or non-substituted C1~6, C3~6 naphthenic base or
Heterocyclylalkyl, phenyl, naphthalene, wherein substituent group is the alkyl of C1~4, the alkoxy of C1~4, amino, hydroxyl, cyano or halogen
Element " expression way it is identical, but substituted or non-substituted restriction not only narrowly refers to a heatable brick bed base of C1~6, but is expanded to
All groups include the naphthenic base or Heterocyclylalkyl, substituted or non-substituted benzyl of substituted or non-substituted C3~6
Base, substituted or non-substituted menaphthyl etc., wherein substituent group is the alkyl of C1~4, the alkoxy of C1~4, amino, hydroxyl, cyanogen
Base or halogen.
Term " alkyl " for indicating that saturated hydrocarbyl, the alkyl of C1~6 refer to the saturated hydrocarbyl containing 1~6 carbon atom,
The alkyl of C1~4 refers to the saturated hydrocarbyl containing 1~4 carbon atom.
Term " naphthenic base " refers to non-aromatic carbocyclyl, the alkyl including cyclisation.Naphthenic base may include two rings or polycyclic system
System.The example of naphthenic base includes cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, and the naphthenic base of C3~6 refers to containing 1~6 carbon
The naphthenic base of atom.
Term " Heterocyclylalkyl " refers to non-aromatic miscellaneous carbocylic radical, and the alkyl including cyclisation, wherein one or more are at ring carbon
Atom is replaced by hetero atom such as 0, N or S atom.Heterocyclylalkyl preferably has 3,4,5 or 6 ring member nitrogen atoms.
Further, structural formula described in the Formulas I are as follows:
The preparation method of beta-lactamase inhibitor dicyclic compound containing urea, comprising:
Step 1: preparation (2S, 5R) -2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane -7-
Ketone;
Step 2: using (2S, 5R) -2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane-7-ketone
Compound shown in formula I is made after participating in substitution reaction as raw material.
Further, in step 1, using (2S, 5R) -6- (benzyl oxygroup) -7- oxo -1,6- diazabicylo [3.2.1]
Octane -2- formamide, which is dissolved in solvent, obtains mixed solution, then in mixed solution be added two (trifluoracetic acid) iodobenzenes into
Row reaction, adjusts pH to 7-8, is extracted after reduced pressure, then by washing, after dry, filtering and chromatography, obtain (2S,
5R) -2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane-7-ketone.
Further, the solvent in step 1 is acetonitrile and water, and the substance that adjusting pH is used in step 1 is sodium bicarbonate.
Further, extraction is used using methylene chloride, washing using saturated sodium-chloride water solution in step 1
Anhydrous sodium sulfate is dry.
Further, the reaction condition in step 1 are as follows: stir 4 days at room temperature.
It combines and is used for beta-Lactam antibiotic the invention also discloses beta-lactamase inhibitor dicyclic compound containing urea
Treat the application in bacterium infection drug.
Compared with prior art, the present invention having the following advantages and benefits:
1, the present invention have in the prior art inhibitor in structure have larger difference, be the interior acyl of the completely new β-of a class formation
The inhibitor of amine enzyme, and slow down or prevent effect with fabulous to the drug resistance for the drug-fast bacteria for generating a variety of beta-lactamases;
2, the MIC of cefotaxime is presented 2 to 4 when the compounds of this invention and beta-Lactam antibiotic cefotaxime are used in combination
Reduction effect again is very significant.
Specific embodiment
To make the objectives, technical solutions, and advantages of the present invention clearer, below with reference to embodiment, the present invention is made
Further to be described in detail, exemplary embodiment of the invention and its explanation for explaining only the invention, are not intended as to this
The restriction of invention.
Embodiment 1
(2S, 5R) -2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane-7-ketone is prepared, it is specific to make
Standby process is as follows:
By (2S, 5R) -6- (benzyl oxygroup) -7- oxo -1,6- diazabicylo [3.2.1] octane -2- formamide
(46.4g, 169mmol) is added in the mixed solution of acetonitrile (500ml) and water (500ml), and two (trifluoracetic acids) are then added
Iodobenzene (79.8g, 186mmol), is then stirred at room temperature 4 days, is neutralized to pH=7-8 with sodium bicarbonate solid, is concentrated under reduced pressure
Solvent is removed, is extracted with methylene chloride (500ml × 3), merges organic phase, is successively washed through saturated sodium-chloride water solution (250ml)
It washs, anhydrous sodium sulfate drying, filtering, silica gel column chromatography obtains (2S, 5R) -2- amino -6- (benzyl oxygroup) -1,6- diazabicylo
[3.2.1] octane-7-ketone (24.0g, 58%).
The reaction route of above-mentioned steps is as follows:
To (2S, 5R) -2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane-7-ketone prepared
Structure verified, verification result is as follows:
1H NMR(400MHz,CDCl3)δ7.45–7.26(m,5H),6.66(s,1H),6.04(s,1H),4.68(s,2H),
3.40-3.21 (m, 1H), 3.15 (dd, J=10.6,3.2Hz, 1H), 2.96 (ddd, J=10.1,9.1,3.8Hz, 1H), 2.45
(dd, J=11.8,9.6Hz, 1H), 2.07 (ddd, J=12.9,7.4,3.8Hz, 1H), 1.96-1.77 (m, 1H), 1.49
(ddd, J=16.3,13.0,3.7Hz, 1H), 1.34-1.10 (m, 1H)
13C NMR(101MHz,CDCl3)δ176.54,137.68,128.45,128.43,127.95,76.89,59.72,
56.99,49.22,28.22,27.77。
Embodiment 2
The preparation method of beta-lactamase inhibitor dicyclic compound containing urea further includes by (2S, the 5R)-in embodiment 1
2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane-7-ketone is reacted as raw material generates present invention inhibition
The method of agent.
The reaction route of the present embodiment is as follows:
The specific reaction process and structure verification result of the present embodiment are as follows:
Under nitrogen protection, by (2S, 5R) -2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane -7-
Ketone (1.20g, 4.86mmol) and the mixing of dry methylene chloride (50ml), are cooled at 0 DEG C, sequentially add triethylamine
(2.0ml, 14.58mmol), DMAP (20mg) and acetic anhydride (0.99g, 9.72mmol) then continue stirring 30 minutes at 0 DEG C
Methanol 1ml quenching reaction is added afterwards, dry rear silica gel column chromatography is concentrated under reduced pressure and obtains N- ((2S, 5R) -6- (benzyl oxygroup) -7- oxygroup -
1,6- diazabicylo [3.2.1] octane -2- base) acetamide (1.35g, 96%).
1H NMR(400MHz,CDCl3)δ7.45–7.27(m,5H),6.26(s,1H),6.26(s,1H),5.58(s,1H),
5.14 (dd, J=5.7,2.5Hz, 1H), 4.71 (m, 2H), 4.13-3.91 (m, 1H), 3.23 (m, 2H), 2.18 (m, 3H),
2.01(m,2H),1.73–1.57(m,1H),1.57–1.46(m,1H).
13C NMR(101MHz,CDCl3)δ172.95,172.26,137.46,128.52,128.37,128.06,76.20,
53.42,51.48,44.30,22.40,21.54,19.88。
By N- ((2S, 5R) -6- (benzyl oxygroup) -7- Oxy-1,6- diazabicylo [3.2.1] octane -2- base) acetyl
Amine (1.30g, 4.5mmol) and isopropanol/purified water (30ml/30ml) mixing, sequentially add 10% Pd/C (1.30g), three
Ethamine (0.091g, 0.9mmol) and sulfur trioxide trimethylamine complex compound (0.70g, 5.0mmol) vacuumize/hydrogen displacement three
Secondary, then hydrogenation is stayed overnight at room temperature, and diatomite filtering washs filter cake with water 15ml, and dry rear silica gel column layer is concentrated under reduced pressure
Analysis is washed with purified water 250ml with sodium ion exchange resin (100g) is passed through after the dissolution of 5ml purified water, filtrate decompression is concentrated
Do ({ [(2S, 5R) -2- acetylaminohydroxyphenylarsonic acid 7- oxo -1,6- diazabicylo [3.2.1] octyl- 6- yl] oxygroup } sulfonyl) sodium
Salt (0.30g).
1H NMR(400MHz,D2O) δ 4.97 (t, J=4.6Hz, 1H), 4.02 (d, J=14.4Hz, 1H), 3.51-3.42
(m, 1H), 3.31 (dd, J=14.4,2.7Hz, 1H), 2.14 (s, 3H), 2.00-1.89 (m, 1H), 1.89-1.70 (m, 2H),
1.66–1.54(m,1H)。
Embodiment 3
The preparation method of beta-lactamase inhibitor dicyclic compound containing urea further includes by (2S, the 5R)-in embodiment 1
2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane-7-ketone is reacted as raw material generates present invention inhibition
The method of agent.
The reaction route of the present embodiment is as follows:
The specific reaction process and structure verification result of the present embodiment are as follows:
Under nitrogen protection, by (2S, 5R) -2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane -7-
Ketone (247mg, 1mmol) and the mixing of dry methylene chloride (20ml), are cooled at 0 DEG C, sequentially add triethylamine (0.41ml,
3mmol) and methanesulfonic acid acid anhydride (261mg, 1.5mmol), it is water-soluble that sodium bicarbonate saturation is added after then continuing stirring 1 hour at 0 DEG C
Liquid 20ml quenching reaction, methylene chloride (20ml × 3) extraction, merges organic phase, successively through saturated sodium-chloride water solution (20ml)
Washing, anhydrous sodium sulfate is dry, filters, and silica gel column chromatography obtains N- ((2S, 5R) -6- (benzyl oxygroup) -7- Oxy-1,6- phenodiazine
Miscellaneous two ring [3.2.1] octane -2- base) Methanesulfomide (280mg, 86%).
1H NMR(400MHz,CDCl3) δ 7.54-7.29 (m, 5H), 4.77 (m, 2H), 4.39 (d, J=3.7Hz, 1H),
4.02 (dd, J=14.7,1.3Hz, 1H), 3.32-3.12 (m, 2H), 3.06 (s, 3H), 2.21-1.97 (m, 1H), 1.87-
1.71(m,3H).
13C NMR(101MHz,CDCl3)δ171.97,137.41,128.55,128.40,128.13,76.38,55.25,
52.78,43.78,39.00,22.18,19.74.
By N- ((2S, 5R) -6- (benzyl oxygroup) -7- Oxy-1,6- diazabicylo [3.2.1] octane -2- base) methylsulphur
Amide (940mg, 2.89mmol) and isopropanol/purified water (20ml/20ml) mixing, sequentially add 10% Pd/C (940mg),
Triethylamine (0.080ml) and sulfur trioxide trimethylamine complex compound (450mg, 3.24mmol), vacuumize/hydrogen displacement three times, so
Hydrogenation is stayed overnight at room temperature afterwards, and diatomite filtering washs filter cake with water 10ml, is concentrated under reduced pressure after doing and obtains crude product.
Methanol 20ml dissolution is added in crude product obtained in the previous step, Sodium Ethylhexanoate (959mg, 5.78mmol) then is added
Methanol (5ml) solution, be stirred overnight at room temperature, be concentrated under reduced pressure it is dry after be added after isopropanol 15ml is beaten 2 hours and filter, isopropanol
Washing obtains white solid ({ [(2R, 5R) -2- methylsulfonyl amido -7- oxo -1,6- diazabicylo [3.2.1] octyl- after drying
6- yl] oxygroup } sulfonyl) sodium salt 480mg.
1H NMR(400MHz,D2O) δ 4.47 (m, 1H), 3.85 (d, J=14.0Hz, 1H), 3.47-3.37 (m, 1H),
3.34 (dd, J=14.0,2.4Hz, 1H), 3.11 (s, 3H), 2.10-1.86 (m, 2H), 1.78-1.70 (m, 1H), 1.70-
1.55(m,1H)。
Embodiment 4
The preparation method of beta-lactamase inhibitor dicyclic compound containing urea further includes by (2S, the 5R)-in embodiment 1
2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane-7-ketone is reacted as raw material generates present invention inhibition
The method of agent.
The reaction route of the present embodiment is as follows:
The specific reaction process and structure verification result of the present embodiment are as follows:
Under nitrogen protection, by (2S, 5R) -2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane -7-
Ketone (988mg, 4mmol) and the mixing of dry methylene chloride (80ml), sequentially add niacin (548mg, 4.4mmol) and HATU
DIPEA (1.74ml, 10mmol) is added after ten minutes and then continues to be stirred overnight at room temperature for (1.673g, 4.4mmol), stirring,
It is concentrated under reduced pressure and does, silica gel column chromatography obtains N- ((2S, 5R) -6- (benzyl oxygroup) -7- oxo -1,6- diazabicylo [3.2.1]
Octyl- 2- yl) niacinamide (1.40g).
By N- ((2S, 5R) -6- (benzyl oxygroup) -7- oxo -1,6- diazabicylo [3.2.1] octyl- 2- yl) niacinamide
The mixing of (1.40g) and isopropanol/purified water (15ml/15ml), sequentially adds 10% Pd/C (1.40g), triethylamine
(0.11ml) and sulfur trioxide trimethylamine complex compound (623mg, 4.48mmol), vacuumize/hydrogen displacement three times, then in room temperature
Lower hydrogenation is stayed overnight, and diatomite filtering washs filter cake with water 10ml, is concentrated under reduced pressure after doing and obtains crude product 1.46g.
By crude product 1.46g obtained in the previous step be added dehydrated alcohol 5ml dissolution, then be added Sodium Ethylhexanoate (1.0g,
Dehydrated alcohol (5ml) solution 6mmol), is filtered, ethanol washing after being stirred at room temperature 2 hours, white solid is obtained after drying, then
It is filtered afterwards twice with dehydrated alcohol mashing, dries ({ [(2S, 5R) -2- (nicotinoyl amido) -7- oxo -1,6- diazabicylo
[3.2.1] octyl- 6- yl] oxygroup } sulfonyl) sodium salt 150mg.
1H NMR(400MHz,D2O) δ 8.67-8.38 (m, 2H), 7.93 (d, J=7.9Hz, 1H), 7.43 (dd, J=7.7,
5.3Hz, 1H), 5.07 (t, J=4.8Hz, 1H), 3.74 (d, J=13.3Hz, 1H), 3.46-3.22 (m, 2H), 2.03-1.97
(m,2H),1.89–1.69(m,1H),1.69–1.51(m,1H)。
Embodiment 5
The preparation method of beta-lactamase inhibitor dicyclic compound containing urea further includes by (2S, the 5R)-in embodiment 1
2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane-7-ketone is reacted as raw material generates present invention inhibition
The method of agent.
The reaction route of the present embodiment is as follows:
The specific reaction process and structure verification result of the present embodiment are as follows:
Under nitrogen protection, by (2S, 5R) -2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane -7-
Ketone (988mg, 4mmol) and the mixing of dry methylene chloride (80ml), sequentially add pyrazine -2- formic acid (546mg, 4.4mmol)
With HATU (1.673g, 4.4mmol), DIPEA (1.74ml, 10mmol) is added after ten minutes and then continues to stir at room temperature for stirring
Overnight, it is concentrated under reduced pressure and does, silica gel column chromatography obtains N- ((2S, 5R) -6- (benzyl oxygroup) -7- oxo -1,6- diazabicylo
[3.2.1] octyl- 2- yl) pyrazine -2- formamide (1.30g).
By N- ((2S, 5R) -6- (benzyl oxygroup) -7- oxo -1,6- diazabicylo [3.2.1] octyl- 2- yl) niacinamide
The mixing of (1.30g) and isopropanol/purified water (20ml/20ml), sequentially adds 10% Pd/C (1.30g), triethylamine
(0.10ml) and sulfur trioxide trimethylamine complex compound (573mg), vacuumize/hydrogen displacement three times, then hydrogenation is anti-at room temperature
It should stay overnight, diatomite filtering washs filter cake with water 10ml, is concentrated under reduced pressure after doing and obtains crude product 1.817g.
Crude product 1.817g obtained in the previous step dehydrated alcohol 10ml/ methanol 1ml is dissolved, Sodium Ethylhexanoate is then added
Dehydrated alcohol (5ml) solution of (1.222g, 7.36mmol), is filtered, ethanol washing after being stirred at room temperature 2 hours, then with anhydrous
Ethyl alcohol mashing is filtered afterwards twice, obtains ({ [(2S, 5R) -2- (pyrazine -2- formyl through further preparation chromatographic isolation after drying
Amido) -7- oxo -1,6- diazabicylo [3.2.1] octyl- 6- yl] oxygroup } sulfonyl) sodium salt 30mg.
1H NMR(400MHz,D2O) δ 8.80 (d, J=1.0Hz, 1H), 8.64-8.48 (m, 2H), 5.14 (t, J=
4.7Hz, 1H), 3.82 (d, J=14.7Hz, 1H), 3.44-3.24 (m, 2H), 2.01 (m, 2H), 1.91-1.71 (m, 1H),
1.71–1.50(m,1H)。
Embodiment 6
The preparation method of beta-lactamase inhibitor dicyclic compound containing urea further includes by (2S, the 5R)-in embodiment 1
2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane-7-ketone is reacted as raw material generates present invention inhibition
The method of agent.
The reaction route of the present embodiment is as follows:
The specific reaction process and structure verification result of the present embodiment are as follows:
Under nitrogen protection, by (2S, 5R) -2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane -7-
Ketone (1.235g, 5mmol) and the mixing of dry methylene chloride (50ml), sequentially add triethylamine (3.5ml, 25mmol) and front three
Base silicon substrate isocyanates (2.5ml, 18mmol) is concentrated under reduced pressure after then continuing at room temperature stirring 5 days and does, and silica gel column chromatography obtains 1-
((2S, 5R) -6- (benzyl oxygroup) -7- oxo -1,6- diazabicylo [3.2.1] octyl- 2- yl) urea (1.15g, 79.3%)
1H NMR(400MHz,CDCl3) δ 7.44-7.28 (m, 5H), 4.81 (d, J=2.9Hz, 1H), 4.72 (s, 2H),
3.84 (d, J=14.1Hz, 1H), 3.20 (s, 1H), 3.09 (dd, J=14.6,2.1Hz, 1H), 2.03-1.95 (m, 1H),
1.91(m,1H),1.72–1.54(m,1H),1.54–1.43(m,1H).
13C NMR(101MHz,CDCl3)δ174.06,160.42,137.28,128.55,128.49,128.15,76.23,
53.60,52.99,43.29,22.48,20.09.
By 1- ((2S, 5R) -6- (benzyl oxygroup) -7- oxo -1,6- diazabicylo [3.2.1] octyl- 2- yl) urea
The mixing of (1.00g, 2.8mmol) and isopropanol/purified water (10ml/10ml), sequentially adds 10% Pd/C (1.00g), three second
Amine (0.078ml) and sulfur trioxide trimethylamine complex compound (436mg, 3.14mmol), vacuumize/hydrogen displacement three times, then exist
Hydrogenation is stayed overnight at room temperature, and diatomite filtering washs filter cake with water 10ml, is concentrated under reduced pressure after doing and obtains crude product.
Methanol 5ml dissolution is added in crude product obtained in the previous step, Sodium Ethylhexanoate (0.93g, 5.60mmol) then is added
Methanol (3ml) solution, be stirred overnight at room temperature, be concentrated under reduced pressure it is dry after dehydrated alcohol mashing is added filters afterwards three times, dry
({ [(2S, 5R) -2- urea groups -7- oxo -1,6- diazabicylo [3.2.1] octyl- 6- yl] oxygroup } sulfonyl) sodium salt 132mg.
1H NMR(400MHz,D2O) δ 3.79 (m, 1H), 3.41 (m, 1H), 3.22 (s, 1H), 3.14 (dd, J=14.6,
2.4Hz,1H),1.94–1.73(m,2H),1.73–1.53(m,2H).
13C NMR(101MHz,D2O)δ176.45,161.57,53.96,47.52,45.87,25.37,20.52。
Embodiment 7
The preparation method of beta-lactamase inhibitor dicyclic compound containing urea further includes by (2S, the 5R)-in embodiment 1
2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane-7-ketone is reacted as raw material generates present invention inhibition
The method of agent.
The reaction route of the present embodiment is as follows:
The specific reaction process and structure verification result of the present embodiment are as follows:
Under nitrogen protection, by (2S, 5R) -2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane -7-
Ketone (988mg, 4mmol) and the mixing of dry methylene chloride (50ml), are cooled at 0 DEG C, sequentially add triethylamine (2.8ml,
20mmol) with dimethylamine acyl chlorides (0.92ml, 10mmol), sodium bicarbonate saturated water is added after then continuing stirring 5 days at room temperature
Solution 20ml quenching reaction, methylene chloride (20ml × 3) extraction, merges organic phase, successively through saturated sodium-chloride water solution
(20ml) washing, anhydrous sodium sulfate be dry, filtering, silica gel column chromatography obtain 3- ((2S, 5R)-6- (benzyl oxygroup) oxo-1-7-,
6- diazabicylo [3.2.1] octyl- 2- yl) -1,1- dimethyl urea (1.20g).
1H NMR (400MHz, DMSO-d6) δ 7.49-7.18 (m, 5H), 6.56 (d, J=5.4Hz, 1H), 4.57 (s,
2H), 3.82 (t, J=5.6Hz, 1H), 3.07-2.86 (m, 2H), 2.75 (s, 6H), 1.90-1.77 (m, 1H), 1.72-1.52
(m,2H),1.40–1.29(m,1H).
13C NMR(101MHz,DMSO-d6)δ173.91,164.58,138.11,128.16,128.10,127.51,
75.59,57.38,54.51,48.12,37.59,24.41,24.23.
By 3- ((2S, 5R) -6- (benzyl oxygroup) -7- oxo -1,6- diazabicylo [3.2.1] octyl- 2- yl) -1,1- two
Methylurea (1.10g, 3.40mmol) and isopropanol/purified water (20ml/20ml) mixing, sequentially add 10% Pd/C
(1.10g), triethylamine (0.094ml) and sulfur trioxide trimethylamine complex compound (527mg, 3.79mmol) vacuumize/hydrogen displacement
Three times, then hydrogenation is stayed overnight at room temperature, and diatomite filtering washs filter cake with water 10ml, is concentrated under reduced pressure after doing and obtains crude product.
Methanol 5ml dissolution is added in crude product obtained in the previous step, Sodium Ethylhexanoate (1.129g, 6.80mmol) then is added
Methanol (3ml) solution, be stirred overnight at room temperature, be concentrated under reduced pressure it is dry after be added after isopropanol 10ml is beaten 2 hours and filter, isopropanol
Washing obtains white solid after drying, then filtered with dehydrated alcohol mashing afterwards twice, dry ({ [(2R, 5R) -2- methylsulfonyl
Amido -7- oxo -1,6- diazabicylo [3.2.1] octyl- 6- yl] oxygroup } sulfonyl) sodium salt 172mg.
1H NMR(400MHz,D2O) δ 3.61 (m, 1H), 3.47 (dd, J=10.7,3.1Hz, 1H), 3.30-3.15 (m,
1H), 2.82 (s, 6H), 2.49 (dd, J=12.4,9.8Hz, 1H), 1.93 (m, 2H), 1.65-1.48 (m, 1H), 1.36-1.23
(m,1H)。
Embodiment 8
The preparation method of beta-lactamase inhibitor dicyclic compound containing urea further includes by (2S, the 5R)-in embodiment 1
2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane-7-ketone is reacted as raw material generates present invention inhibition
The method of agent.
The reaction route of the present embodiment is as follows:
The specific reaction process and structure verification result of the present embodiment are as follows:
Under nitrogen protection, by (2S, 5R) -2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane -7-
Ketone (988mg, 4mmol) and the mixing of dry methylene chloride (80ml), sequentially add pyrazine -2- formic acid (546mg, 4.4mmol)
With HATU (1.673g, 4.4mmol), DIPEA (1.74ml, 10mmol) is added after ten minutes and then continues to stir at room temperature for stirring
Overnight, it is concentrated under reduced pressure and does, silica gel column chromatography obtains tert-butyl 4- (((2S, 5R) -6- (benzyl oxygroup) -7- oxo -1,6- diaza
Two rings [3.2.1] octyl- 2- yl) carbamoyl) piperidines -1- carboxylate (1.80g).
1H NMR(400MHz,CDCl3)δ7.48–7.28(m,5H),6.36–5.89(m,1H),4.79–4.61(m,2H),
4.10 (ddd, J=18.7,13.3,6.3Hz, 3H), 3.33-3.06 (m, 2H), 2.89-2.43 (m, 3H), 2.12-1.99 (m,
2H),1.85–1.49(m,7H),1.46(s,9H).
13C NMR(101MHz,CDCl3)δ176.39,172.96,154.66,137.26,128.56,128.24,
128.17,79.67,76.16,53.32,51.60,43.33,38.28,28.44,28.08,22.30.
By tert-butyl 4- (((2S, 5R) -6- (benzyl oxygroup) -7- oxo -1,6- diazabicylo [3.2.1] octyl- 2- yl)
Carbamoyl) piperidines -1- carboxylate (1.80g, 4mmol) and isopropanol/purified water (20ml/20ml) mixing, sequentially add
10% Pd/C (1.80g), triethylamine (0.11ml) and sulfur trioxide trimethylamine complex compound (623mg, 4.48mmol) is taken out true
Three times, then hydrogenation is stayed overnight at room temperature for sky/hydrogen displacement, and diatomite filtering is washed filter cake with water 10ml, is concentrated under reduced pressure
Crude product is obtained after dry.
Crude product obtained in the previous step and methylene chloride (40ml) are mixed, are cooled to 0 DEG C of addition trifluoroacetic acid 16ml, then
It is warmed to room temperature stirring 1 hour after stirring 3 hours at 0 DEG C, is concentrated under reduced pressure after doing and obtains crude product 460mg, then use methylene chloride
The mixed solution of 0.5ml/ acetonitrile 5ml dissolves, and is filtered to remove insoluble matter, and it is molten that methanol 10ml and water 4ml is added after filtrate concentration is dry
Solution, { [(2S, 5R) -2- (piperidines -4- formamido) -7- oxo -1,6- diazabicylo is done to obtain in filtrate decompression concentration after filtering
[3.2.1] octyl- 6- yl] oxygroup } sulfonate 290mg.
1H NMR(400MHz,D2O) δ 4.89 (t, J=4.8Hz, 1H), 4.13 (d, J=14.3Hz, 1H), 3.53 (s,
1H), 3.46-3.28 (m, 3H), 3.16 (m, 1H), 3.00 (td, J=13.0,3.1Hz, 2H), 2.12 (m, 1H), 1.97 (m,
1H),1.93–1.65(m,5H),1.53(m,1H)。
Embodiment 9
The preparation method of beta-lactamase inhibitor dicyclic compound containing urea further includes by (2S, the 5R)-in embodiment 1
2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane-7-ketone is reacted as raw material generates present invention inhibition
The method of agent.
The reaction route of the present embodiment is as follows:
The specific reaction process and structure verification result of the present embodiment are as follows:
Under nitrogen protection, by (2S, 5R) -2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane -7-
Ketone (988mg, 4mmol) and the mixing of dry methylene chloride (80ml), sequentially add BOC-L- proline (946mg, 4.4mmol)
With HATU (1.673g, 4.4mmol), DIPEA (1.74ml, 10mmol) is added after ten minutes and then continues to stir at room temperature for stirring
Overnight, it is concentrated under reduced pressure and does, silica gel column chromatography obtains tert-butyl (2S) -2- (((2S, 5R) -6- (benzyl oxygroup) -7- oxo -1,6- bis-
Azabicyclic [3.2.1] octyl- 2- yl) carbamoyl) pyrrolin -1- carboxylate (1.08g).
By tert-butyl (2S) -2- (((2S, 5R) -6- (benzyl oxygroup) -7- oxo -1,6- diazabicylo [3.2.1] octyl-
2- yl) carbamoyl) pyrrolin -1- carboxylate (1.07g, 2.4mmol) and isopropanol/purified water (20ml/20ml) mixing,
Sequentially add 10% Pd/C (1.10g), triethylamine (0.067ml) and sulfur trioxide trimethylamine complex compound (374mg,
2.69mmol), vacuumize/hydrogen displacement three times, then at room temperature hydrogenation stay overnight, diatomite filtering, washed with water 10ml
Filter cake is washed, is concentrated under reduced pressure after doing and obtains crude product.
Crude product obtained in the previous step and methylene chloride (30ml) are mixed, are cooled to 0 DEG C of addition trifluoroacetic acid 10ml, then
It is warmed to room temperature stirring 1 hour after stirring 3 hours at 0 DEG C, dry rear acetonitrile 15ml mashing is concentrated under reduced pressure, uses methylene chloride after filtering
The mixed solution of 2.5ml/ acetonitrile 5ml is beaten, and { [(2S, 5R) -2- ((S)-pyrrolin -2- formamide) -7- is dried after filtering
Oxo -1,6- diazabicylo [3.2.1] octyl- 6- yl] oxygroup } sulfonate 170mg.
1H NMR(400MHz,D2O) δ 4.94 (t, J=5.0Hz, 1H), 4.82 (dd, J=8.9,6.3Hz, 1H), 3.95
(d, J=14.1Hz, 1H), 3.53 (m, 1H), 3.44-3.24 (m, 3H), 2.55-2.33 (m, 1H), 2.09-1.78 (m, 6H),
1.60(m,1H)。
Embodiment 10
The preparation method of beta-lactamase inhibitor dicyclic compound containing urea further includes by (2S, the 5R)-in embodiment 1
2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane-7-ketone is reacted as raw material generates present invention inhibition
The method of agent.
The reaction route of the present embodiment is as follows:
The specific reaction process and structure verification result of the present embodiment are as follows:
Under nitrogen protection, by (2S, 5R) -2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane -7-
Ketone (494mg, 2mmol) and the mixing of dry methylene chloride (40ml), sequentially add L-Glutimic acid (546mg, 2.2mmol) and
DIPEA (0.87ml, 5mmol) is added after ten minutes and then continues at room temperature stirred for HATU (836mg, 2.2mmol), stirring
Night is concentrated under reduced pressure and does, and silica gel column chromatography obtains (2S)-N- ((2S, 5R) -6- (benzyl oxygroup) -7- oxo -1,6- diazabicylo
[3.2.1] octyl- 2- yl) -5- oxo pyrrolin -2- formamide (651mg).
1H NMR(400MHz,CDCl3)δ7.39–7.26(m,5H),7.00(s,1H),6.24(s,1H),4.88(s,1H),
4.80–4.66(m,2H),4.58(m,1H),3.88(m,1H),3.38(m,1H),3.24(m,1H),2.48–2.01(m,4H),
1.86(m,3H),1.42(m,1H).
By (2S)-N- ((2S, 5R) -6- (benzyl oxygroup) -7- oxo -1,6- diazabicylo [3.2.1] octyl- 2- yl) -
5- oxo pyrrolin -2- formamide (651mg, 1.8mmol) and isopropanol/purified water (10ml/10ml) mixing, sequentially add
10% Pd/C (650mg), triethylamine (0.051ml) and sulfur trioxide trimethylamine complex compound (650mg), vacuumize/hydrogen sets
It changes three times, then hydrogenation is stayed overnight at room temperature, and diatomite filtering washs filter cake with water 10ml, is concentrated under reduced pressure after doing and is obtained slightly
Product.
Crude product obtained in the previous step methanol 5ml is dissolved, the nothing of Sodium Ethylhexanoate (598mg, 3.6mmol) is then added
Water-ethanol (4ml) solution is concentrated after being stirred at room temperature 3 hours and does, and is then filtered with dehydrated alcohol mashing, is obtained afterwards three times after drying
({ [(2S, 5R) -2- ((S) -5- oxo pyrrolin -2- formamido) -7- oxo -1,6- diazabicylo [3.2.1] octyl- 6-
Base] oxygroup } sulfonyl) sodium salt 130mg.
1H NMR(400MHz,D2O) δ 4.94-4.83 (m, 2H), 4.00 (d, J=14.2Hz, 1H), 3.52 (s, 1H),
3.37 (dd, J=14.4,2.7Hz, 1H), 2.60-2.41 (m, 1H), 2.37-2.27 (m, 2H), 2.08-1.80 (m, 4H),
1.59(m,1H)。
Embodiment 11
The preparation method of beta-lactamase inhibitor dicyclic compound containing urea further includes by (2S, the 5R)-in embodiment 1
2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane-7-ketone is reacted as raw material generates present invention inhibition
The method of agent.
The reaction route of the present embodiment is as follows:
The specific reaction process and structure verification result of the present embodiment are as follows:
Under nitrogen protection, by (2S, 5R) -2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane -7-
Ketone (988mg, 4mmol) and Isosorbide-5-Nitrae-dioxane (50ml) mixing, are added sulfonamide (2.304g, 24mmol), then heat up back
Night is flowed through, is concentrated under reduced pressure and does, silica gel column chromatography obtains N- ((2S, 5R) -6- (benzyl oxygroup) -7- Oxy-1,6- diazabicylo
[3.2.1] octane -2- base) sulfamide (1.24g).
1H NMR(400MHz,DMSO-d6)δ7.41–7.18(m,5H),6.84–6.51(m,3H),4.69(m,2H),
4.32-4.00 (m, 1H), 3.66 (d, J=13.3Hz, 1H), 3.25 (dd, J=13.5,2.8Hz, 1H), 3.08 (s, 1H),
1.97–1.73(m,2H),1.52-1.45(m,2H).
13C NMR(101MHz,DMSO-d6)δ172.92,138.02,128.16,128.13,127.53,75.30,
56.02,52.52,43.60,21.60,21.33.
By N- ((2S, 5R) -6- (benzyl oxygroup) -7- Oxy-1,6- diazabicylo [3.2.1] octane -2- base) amino
Sulfonamide (1.14g, 3.5mmol) and isopropanol/purified water (15ml/15ml) mixing, sequentially add 10% Pd/C
(1.14g), triethylamine (0.097ml) and sulfur trioxide trimethylamine complex compound (545mg), vacuumize/hydrogen displacement three times, then
Hydrogenation is stayed overnight at room temperature, and diatomite filtering washs filter cake with water 10ml, is concentrated under reduced pressure after doing and obtains crude product.
Crude product obtained in the previous step methanol 15ml is dissolved, the nothing of Sodium Ethylhexanoate (1.08g, 3.6mol) is then added
Water-ethanol (5ml) solution is concentrated after being stirred at room temperature 3 hours and does, and is then filtered with dehydrated alcohol mashing, is obtained afterwards three times after drying
({ [(2S, 5R) -2- (amino-sulfonyl) -7- oxo -1,6- diazabicylo [3.2.1] octyl- 6- yl] oxygroup } sulfonyl) sodium
Salt 340mg
1H NMR(400MHz,D2O) δ 4.35 (dd, J=5.3,3.8Hz, 1H), 3.67 (m, 1H), 3.47-3.26 (m,
2H),2.04(m,1H),1.91(m,1H),1.76–1.58(m,2H)。
Embodiment 12
The preparation method of beta-lactamase inhibitor dicyclic compound containing urea further includes by (2S, the 5R)-in embodiment 1
2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane-7-ketone is reacted as raw material generates present invention inhibition
The method of agent.
The reaction route of the present embodiment is as follows:
The specific reaction process and structure verification result of the present embodiment are as follows:
Under nitrogen protection, by (2S, 5R) -2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane -7-
Ketone (1.545g, 6.25mmol) and DMF (40ml) mixing, sequentially add N, bis--BOC-S- methyl isothiourea of N'- (2.72g,
9.38mmol) with mercury chloride (2.547g, 9.38mmol) and triethylamine (1.3ml, 9.38mmol), then it is stirred overnight at room temperature,
Silica gel column chromatography obtains 810mg white solid after post-processing.
Previous step product (800mg, 1.64mmol) and isopropanol/purified water (15ml/15ml) are mixed, sequentially added
10% Pd/C (800mg), triethylamine (0.046ml) and sulfur trioxide trimethylamine complex compound (255mg), vacuumize/hydrogen sets
It changes three times, then hydrogenation is stayed overnight at room temperature, and diatomite filtering washs filter cake with water 10ml, is concentrated under reduced pressure after doing and is obtained slightly
Product.
Crude product obtained in the previous step and methylene chloride (20ml) are mixed, are cooled to 0 DEG C of addition trifluoroacetic acid 8ml, then
It is warmed to room temperature stirring 1 hour after stirring 3 hours at 0 DEG C, dry rear acetonitrile 10ml mashing is concentrated under reduced pressure, is beaten after filtering with methanol 2ml
Slurry, dries { [(2S, 5R) -2- guanidine radicals -1,6- diazabicylo [3.2.1] octyl- 6- yl] oxygroup } sulfonate after filtering
141mg。
1H NMR(400MHz,D2O) δ 4.15 (m, 2H), 3.31-3.15 (m, 1H), 2.92 (dd, J=13.2,11.2Hz,
1H),2.28–2.05(m,2H),1.63(m,1H),1.53–1.35(m,1H).
13C NMR(101MHz,D2O)δ174.75,154.25,59.01,49.07,45.93,28.33,24.83。
The present invention carries out bacteriostatic activity MIC (mg/L) detection, testing result such as 1 institute of table to the inhibitor of above-described embodiment
Show.
Table 1
MIC is former according to the guidance of The Clinical and laboratoryStandard Institute (CLSI)
Micro-dilution method measurement then.
It cooperates with confrontation to generate a variety of beta-lactamases to be tested with antibiotic cefotaxime.These beta-lactamases
Belong to multiple classifications that Bush&Jacoby is divided, (Updated Functional Classification of β-
lactamases,Antimicrobial Agents and Chemotherapy,54:969-76(2010)).Synergistic effect table
The MIC of cefotaxime is presented 2 to 4 times when present the compound of the present invention and beta-Lactam antibiotic cefotaxime are used in combination
Reduce.
Above-described specific embodiment has carried out further the purpose of the present invention, technical scheme and beneficial effects
It is described in detail, it should be understood that being not intended to limit the present invention the foregoing is merely a specific embodiment of the invention
Protection scope, all within the spirits and principles of the present invention, any modification, equivalent substitution, improvement and etc. done should all include
Within protection scope of the present invention.
Claims (10)
1. beta-lactamase inhibitor dicyclic compound containing urea, which is characterized in that its structural formula is shown in formula I,
R in the structural formula1And R2It is separately or concurrently H, NHR3, 4~6 circle heterocyclic rings, aromatic ring, the alkanoyl of C1~5, the alkane of C1~5
Oxygen acyl group, fragrant sulfonyl, alkyl sulphonyl, aromatic rings acyl group, containing heteroatomic heterocyclic acyl, or optionally by C1~
4 alkyl, alkoxy, halogen or the halogenated alkyl of C1~4 of C1~4 replace;
X is Na or H in the structural formula.
2. beta-lactamase inhibitor dicyclic compound containing urea according to claim 1, which is characterized in that the R3 is 4
~6 circle heterocyclic rings, aromatic ring, the alkanoyl of C1~5, the alkoxy acyl of C1~5, fragrant sulfonyl, alkyl sulphonyl, aromatic rings acyl
Base, containing heteroatomic heterocyclic acyl, or optionally by the alkyl of C1~4, the alkoxy of C1~4, halogen or the halogen of C1~4
Substituted alkyl replaces.
3. beta-lactamase inhibitor dicyclic compound containing urea according to claim 1 or 2, which is characterized in that described miscellaneous
Hetero atom in ring acyl group is N, S or O.
4. beta-lactamase inhibitor dicyclic compound containing urea according to claim 3, which is characterized in that the Formulas I institute
The structural formula stated are as follows:
5. the preparation method of beta-lactamase inhibitor dicyclic compound containing urea characterized by comprising
Step 1: preparation (2S, 5R) -2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane-7-ketone;
Step 2: using (2S, 5R) -2- amino -6- (benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane-7-ketone conduct
Compound shown in formula I is made after participating in substitution reaction in raw material.
6. the preparation method of beta-lactamase inhibitor dicyclic compound containing urea according to claim 5, which is characterized in that
It is molten using (2S, 5R) -6- (benzyl oxygroup) -7- oxo -1,6- diazabicylo [3.2.1] octane -2- formamide in step 1
Solution obtains mixed solution in solvent, then in mixed solution be added two (trifluoracetic acid) iodobenzenes reacted, adjust pH to
7-8 is extracted after reduced pressure, then by washing, after dry, filtering and chromatography, obtains (2S, 5R) -2- amino -6-
(benzyl oxygroup) -1,6- diazabicylo [3.2.1] octane-7-ketone.
7. the preparation method of beta-lactamase inhibitor dicyclic compound containing urea according to claim 6, which is characterized in that
Solvent in step 1 is acetonitrile and water, and the substance that adjusting pH is used in step 1 is sodium bicarbonate.
8. the preparation method of beta-lactamase inhibitor dicyclic compound containing urea according to claim 6, which is characterized in that
Using methylene chloride, washing is dry using anhydrous sodium sulfate using saturated sodium-chloride water solution for extraction in step 1.
9. the preparation method of beta-lactamase inhibitor dicyclic compound containing urea according to claim 6, which is characterized in that
Reaction condition in step 1 are as follows: stir 4 days at room temperature.
10. beta-lactamase inhibitor dicyclic compound containing urea according to claim 1-4 and beta-lactam are anti-
Raw element combination is for treating the application in bacterium infection drug.
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CN1655781A (en) * | 2002-01-28 | 2005-08-17 | 安万特医药股份有限公司 | Novel heterocyclic compounds which are active as inhibitors of beta-lactamases |
WO2014141132A1 (en) * | 2013-03-14 | 2014-09-18 | Naeja Pharmaceutical Inc. | NEW HETEROCYCLIC COMPOUNDS AND THEIR USE AS ANTIBACTERIAL AGENTS AND β-LACTAMASE INHIBITORS |
CN105801579A (en) * | 2014-12-31 | 2016-07-27 | 卢来春 | Beta-lactamase inhibitor |
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CN1655781A (en) * | 2002-01-28 | 2005-08-17 | 安万特医药股份有限公司 | Novel heterocyclic compounds which are active as inhibitors of beta-lactamases |
WO2014141132A1 (en) * | 2013-03-14 | 2014-09-18 | Naeja Pharmaceutical Inc. | NEW HETEROCYCLIC COMPOUNDS AND THEIR USE AS ANTIBACTERIAL AGENTS AND β-LACTAMASE INHIBITORS |
CN105801579A (en) * | 2014-12-31 | 2016-07-27 | 卢来春 | Beta-lactamase inhibitor |
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