CN109942579B - Beta-lactamase inhibitor urea-containing bicyclic compound and preparation method and application thereof - Google Patents
Beta-lactamase inhibitor urea-containing bicyclic compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a beta-lactamase inhibitor urea-containing bicyclic compound, a preparation method and application thereof, which solve the problem of drug resistance of the existing bacteria. The invention comprises a structural formula shown as a formula I, wherein R in the structural formula1And R2Each or both of H and NHR34-6 membered heterocycle, aromatic ring, alkanoyl of C l-5, alkoxyacyl of C l-5, aromatic sulfonyl, alkylsulfonyl, aromatic alkanoyl, heterocyclic acyl containing hetero atom, or optionally substituted with alkyl of Cl-4, alkoxy of C l-4, halogen or haloalkyl of C l-4; in the structural formula, X is Na or H. The MIC of ceftazidime exhibited a 2 to 4-fold reduction in the compounds of the invention when used in combination with the beta-lactam antibiotic ceftazidime.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a beta-lactamase inhibitor urea-containing bicyclic compound and a preparation method and application thereof.
Background
The resistance of bacteria to beta-lactam antibiotics, particularly in gram-negative bacteria, is often mediated by beta-lactamases. Beta-lactamases are enzymes that catalyze the hydrolysis of the beta-lactam ring, which inactivates the antibiotic active by the beta-lactam antibiotic and causes bacterial resistance. Inhibition of beta-lactamases with inhibitors of beta-lactamases may slow or prevent the degradation of beta-lactam antibiotics and restore the inhibitory effect of beta-lactam antibiotics on beta-lactamases. Many beta-lactamases were found in the pursuit of beta-lactamase-producing bacteria not significantly inhibited by inhibitors of beta-lactamases currently widely used in the market, such as KPC. There is thus an urgent need to find new inhibitors of beta-lactamases in combination with related antibiotics for the treatment of infections caused by beta-lactam resistant bacteria.
People are confronted with the challenge of bacterial drug resistance, and the drug resistance of gram-positive bacteria or gram-negative bacteria, multi-drug resistant mycobacterium tuberculosis and the like is very serious. The phenomenon of bacterial resistance is particularly severe in China. To date, the widely used inhibitors of beta-lactamases on the market are clavulanic acid, sulbactam and tazobactam. Because more and more bacteria generate increasingly serious drug resistance to the compound drug consisting of the inhibitor of the beta-lactamase and antibiotics, how to develop a new inhibitor for a plurality of bacteria capable of generating the beta-lactamase drug resistance is a great concern.
Disclosure of Invention
The invention aims to provide a beta-lactamase inhibitor urea-containing bicyclic compound, a preparation method and application thereof, and the inhibitor with a new structure and capable of resisting the drug resistance of various drug-resistant bacteria generating beta-lactamase is obtained.
The invention is realized by the following scheme:
the structural formula of the beta-lactamase inhibitor containing urea bicyclic compound is shown as a formula I,
in the formula, R1And R2Each or both of H and NHR34-6 membered heterocycle, aromatic ring, alkanoyl of C l-5, alkoxyacyl of C l-5, aromatic sulfonyl, alkylsulfonyl, aromatic aroyl, heterocyclic acyl containing hetero atom, or optionally substituted with alkyl of C l-4, alkoxy of C l-4, halogen or haloalkyl of C l-4;
in the structural formula, X is Na or H.
Further, R3 is a 4-6 membered heterocycle, an aromatic ring, an alkanoyl group of C l-5, an alkoxyacyl group of C l-5, an aromatic sulfonyl group, an alkylsulfonyl group, an aromatic alkanoyl group, a heterocyclic acyl group containing a hetero atom, or optionally substituted with an alkyl group of C l-4, an alkoxy group of C l-4, a halogen or a haloalkyl group of C l-4.
Further, the heteroatom in the heterocyclic acyl group is N, S or O.
The expression "optionally … substituted" in the R groups of the invention means that the R groups may or may not be substituted by these groups, i.e. not only by the groups listed, but also by none of the groups listed. This expression is similar to the expression "R is substituted or unsubstituted C1-6 alkyl, C3-6 cycloalkyl or heterocycloalkyl, phenyl, naphthyl, wherein the substituents are C1-4 alkyl, C1-4 alkoxy, amino, hydroxyl, cyano or halogen", but the definition of substituted or unsubstituted is not limited to C1-6 alkyl in a narrow sense, but is extended to all the groups mentioned, including substituted or unsubstituted C3-6 cycloalkyl or heterocycloalkyl, substituted or unsubstituted benzyl, substituted or unsubstituted naphthylmethyl, wherein the substituents are C1-4 alkyl, C1-4 alkoxy, amino, hydroxyl, cyano or halogen.
The term "alkyl" is used to denote a saturated hydrocarbon group, C1-6 alkyl refers to a saturated hydrocarbon group containing 1-6 carbon atoms, and C1-4 alkyl refers to a saturated hydrocarbon group containing 1-4 carbon atoms.
The term "cycloalkyl" refers to a non-aromatic carbocyclic group, including cyclized alkyl groups. Cycloalkyl groups may include bicyclic or polycyclic ring systems. Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and C3-6 cycloalkyl groups refer to cycloalkyl groups having 1-6 carbon atoms.
The term "heterocycloalkyl" refers to a non-aromatic heterocarbocyclyl group, including cyclized alkyl groups, wherein one or more ring-forming carbon atoms are replaced with a heteroatom such as a 0, N, or S atom. The heterocycloalkyl group preferably has 3, 4, 5, or 6 ring-forming atoms.
Further, the structural formula of the formula I is as follows:
a process for preparing a urea-containing bicyclic compound as a beta-lactamase inhibitor comprising:
step one, preparing (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octane-7-ketone;
and step two, adopting (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octane-7-ketone as a raw material to participate in a substitution reaction to prepare the compound shown in the formula I.
Further, in the first step, (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide is dissolved in a solvent to obtain a mixed solution, then iodobenzene bis (trifluoroacetate) is added into the mixed solution to perform reaction, the pH is adjusted to 7-8, extraction is performed after decompression concentration, and after washing, drying, filtering and chromatography, the (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octane-7-one is obtained.
Further, the solvent in the step one is acetonitrile and water, and the substance for adjusting the pH in the step one is sodium bicarbonate.
Further, in the first step, dichloromethane was used for extraction, and a saturated aqueous solution of sodium chloride was used for washing, and dried over anhydrous sodium sulfate.
Further, the reaction conditions in the step one are as follows: stir at room temperature for 4 days.
The invention also discloses application of the beta-lactamase inhibitor containing urea bicyclic compound and beta-lactam antibiotic in medicaments for treating bacterial infection.
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. the inhibitor has larger difference in structure in the prior art, is an inhibitor of beta-lactamase with a brand-new structure, and has excellent effect of slowing down or preventing the drug resistance of drug-resistant bacteria generating various beta-lactamase;
2. when the compound is used together with beta-lactam antibiotic ceftazidime, the MIC of the ceftazidime is reduced by 2 to 4 times, and the effect is very obvious.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail below with reference to examples, and the exemplary embodiments and descriptions thereof are only used for explaining the present invention and are not used as limitations of the present invention.
Example 1
The preparation of (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octan-7-one is carried out as follows:
(2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (46.4g, 169mmol) was added to a mixed solution of acetonitrile (500ml) and water (500ml), iodobenzene bis (trifluoroacetate) (79.8g, 186mmol) was then added, followed by stirring at room temperature for 4 days, neutralization with a sodium bicarbonate solid to a pH of 7-8, concentration under reduced pressure to remove the solvent, extraction with dichloromethane (500 ml. times.3), combination of the organic phases, washing with a saturated aqueous sodium chloride solution (250ml), drying over anhydrous sodium sulfate, filtration, silica gel column chromatography to give (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octane-7-one (24.0g, 58%).
The reaction route of the steps is as follows:
the structure of the prepared (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octane-7-one is verified, and the 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。
example 2
A process for the preparation of a β -lactamase inhibitor, a urea-containing bicyclic compound, further comprising reacting (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octan-7-one of example 1 as a starting material to form an inhibitor of the invention.
The reaction scheme of this example is as follows:
the specific reaction process and structure verification result of this example are as follows:
under the protection of nitrogen, (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octan-7-one (1.20g, 4.86mmol) and dried dichloromethane (50ml) were mixed, the temperature was reduced to 0 ℃, triethylamine (2.0ml, 14.58mmol), DMAP (20mg) and acetic anhydride (0.99g, 9.72mmol) were sequentially added, then stirring was continued at 0 ℃ for 30 minutes, 1ml of methanol was added to quench the reaction, and the reaction mixture was concentrated under reduced pressure and dried, and then subjected to silica gel column chromatography to obtain N- ((2S,5R) -6- (benzyloxy) -7-oxy-1, 6-diazabicyclo [3.2.1] octan-2-yl) 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。
Mixing N- ((2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octan-2-yl) acetamide (1.30g, 4.5mmol) and isopropanol/purified water (30ml/30ml), adding 10% Pd/C (1.30g), triethylamine (0.091g, 0.9mmol) and a trimethylamine trioxide complex (0.70g, 5.0mmol) in this order, evacuating/replacing with hydrogen three times, then hydrogenating at room temperature overnight, filtering with diatomaceous earth, washing the filter cake with 15ml of water, concentrating under reduced pressure to dryness, subjecting to silica gel column chromatography, dissolving with 5ml of purified water, passing through a sodium ion exchange resin (100g), washing with 250ml of purified water, concentrating the filtrate under reduced pressure to dryness to give ({ [ (2S,5R) -2-acetylamino-7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonyl) sodium salt (0.30 g).
1H NMR(400MHz,D2O)δ4.97(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)。
Example 3
A process for the preparation of a β -lactamase inhibitor, a urea-containing bicyclic compound, further comprising reacting (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octan-7-one of example 1 as a starting material to form an inhibitor of the invention.
The reaction scheme of this example is as follows:
the specific reaction process and structure verification result of this example are as follows:
under the protection of nitrogen, (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octane-7-one (247mg, 1mmol) and dried dichloromethane (20ml) were mixed, the temperature was reduced to 0 ℃, triethylamine (0.41ml, 3mmol) and methanesulfonic anhydride (261mg, 1.5mmol) were sequentially added, stirring was continued at 0 ℃ for 1 hour, then 20ml of a saturated aqueous solution of sodium bicarbonate was added to quench the reaction, dichloromethane (20 ml. times.3) was extracted, the organic phases were combined, washed with a saturated aqueous solution of sodium chloride (20ml), dried over anhydrous sodium sulfate, filtered, and subjected to silica gel column chromatography to give N- ((2S,5R) -6- (benzyloxy) -7-oxy-1, 6-diazabicyclo [3.2.1] octane-2-yl) methanesulfonamide (280mg, 86%).
1H NMR(400MHz,CDCl3)δ7.54–7.29(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.
Mixing N- ((2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-yl) methanesulfonamide (940mg, 2.89mmol) and isopropanol/purified water (20ml/20ml), sequentially adding 10% Pd/C (940mg), triethylamine (0.080ml) and a sulfur trioxide trimethylamine complex (450mg, 3.24mmol), vacuumizing/hydrogen replacing three times, then hydrogenating at room temperature overnight, filtering with diatomite, washing a filter cake with 10ml of water, and concentrating under reduced pressure to obtain a crude product.
The crude product obtained in the previous step was dissolved in 20ml of methanol, followed by addition of a solution of sodium ethylhexanoate (959mg, 5.78mmol) in methanol (5ml), stirring overnight at room temperature, drying by concentration under reduced pressure, addition of 15ml of isopropanol, beating for 2 hours, filtration, washing with isopropanol, and drying to obtain 480mg of sodium ({ [ (2R,5R) -2-methanesulfonamido-7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonyl) salt as a white solid.
1H NMR(400MHz,D2O)δ4.47(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)。
Example 4
A process for the preparation of a β -lactamase inhibitor, a urea-containing bicyclic compound, further comprising reacting (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octan-7-one of example 1 as a starting material to form an inhibitor of the invention.
The reaction scheme of this example is as follows:
the specific reaction process and structure verification result of this example are as follows:
(2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octan-7-one (988mg, 4mmol) and dried dichloromethane (80ml) were mixed under nitrogen, nicotinic acid (548mg, 4.4mmol) and HATU (1.673g, 4.4mmol) were added in this order, and after stirring for 10 minutes, DIPEA (1.74ml, 10mmol) was added and stirring was continued overnight at room temperature, and the mixture was concentrated under reduced pressure to dryness and subjected to silica gel column chromatography to give N- ((2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] oct-2-yl) nicotinamide (1.40 g).
N- ((2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] oct-2-yl) nicotinamide (1.40g) and isopropanol/purified water (15ml/15ml) were mixed, 10% Pd/C (1.40g), triethylamine (0.11ml) and a trimethylamine trioxide complex (623mg, 4.48mmol) were added in this order, vacuum/hydrogen substitution was performed three times, then hydrogenation reaction was performed overnight at room temperature, filtration was performed with celite, the filter cake was washed with 10ml of water, and crude 1.46g was obtained after drying by concentration under reduced pressure.
Dissolving 1.46g of the crude product obtained in the previous step in 5ml of absolute ethanol, adding a solution of sodium ethylhexanoate (1.0g, 6mmol) in 5ml of absolute ethanol, stirring at room temperature for 2 hours, filtering, washing with ethanol, drying to obtain a white solid, pulping twice with absolute ethanol, filtering, and drying to obtain 150mg of ({ [ (2S,5R) -2- (nicotinamide) -7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonyl) sodium salt.
1H NMR(400MHz,D2O)δ8.67–8.38(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)。
Example 5
A process for the preparation of a β -lactamase inhibitor, a urea-containing bicyclic compound, further comprising reacting (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octan-7-one of example 1 as a starting material to form an inhibitor of the invention.
The reaction scheme of this example is as follows:
the specific reaction process and structure verification result of this example are as follows:
under the protection of nitrogen, (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octane-7-one (988mg, 4mmol) and dried dichloromethane (80ml) were mixed, pyrazine-2-carboxylic acid (546mg, 4.4mmol) and HATU (1.673g, 4.4mmol) were added in this order, and after stirring for 10 minutes, DIPEA (1.74ml, 10mmol) was added and then stirring was continued overnight at room temperature, and then concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel to give N- ((2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] oct-2-yl) pyrazine-2-carboxamide (1.30 g).
N- ((2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] oct-2-yl) nicotinamide (1.30g) and isopropanol/purified water (20ml/20ml) were mixed, 10% Pd/C (1.30g), triethylamine (0.10ml) and a trimethylamine trioxide complex (573mg) were sequentially added, vacuum/hydrogen substitution was performed three times, then hydrogenation reaction was performed overnight at room temperature, celite filtration was performed, the filter cake was washed with 10ml of water, and crude 1.817g was obtained after drying by concentration under reduced pressure.
1.817g of the crude product obtained in the previous step was dissolved in 10ml of absolute ethanol/1 ml of methanol, followed by addition of a solution of sodium ethylhexanoate (1.222g, 7.36mmol) in absolute ethanol (5ml), stirring at room temperature for 2 hours, filtration, washing with ethanol, beating twice with absolute ethanol, filtration, drying and further preparative chromatography to give 30mg of ({ [ (2S,5R) -2- (pyrazine-2-carboxamido) -7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonyl) sodium salt.
1H NMR(400MHz,D2O)δ8.80(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)。
Example 6
A process for the preparation of a β -lactamase inhibitor, a urea-containing bicyclic compound, further comprising reacting (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octan-7-one of example 1 as a starting material to form an inhibitor of the invention.
The reaction scheme of this example is as follows:
the specific reaction process and structure verification result of this example are as follows:
(2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octan-7-one (1.235g, 5mmol) and dried dichloromethane (50ml) were mixed under nitrogen, triethylamine (3.5ml, 25mmol) and trimethylsilyl isocyanate (2.5ml, 18mmol) were added in this order, and then stirring was continued at room temperature for 5 days, followed by concentration under reduced pressure to dryness, and silica gel column chromatography gave 1- ((2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] oct-2-yl) urea (1.15g, 79.3%)
1H NMR(400MHz,CDCl3)δ7.44–7.28(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.
1- ((2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] oct-2-yl) urea (1.00g, 2.8mmol) and isopropanol/purified water (10ml/10ml) were mixed, 10% Pd/C (1.00g), triethylamine (0.078ml) and a trimethylamine trioxide complex (436mg, 3.14mmol) were sequentially added, vacuum/hydrogen substitution was performed three times, hydrogenation was then performed at room temperature overnight, filtration was performed with celite, the filter cake was washed with 10ml of water, and the crude product was obtained after concentration under reduced pressure.
The crude product obtained in the previous step was dissolved in 5ml of methanol, and then a solution of sodium ethylhexanoate (0.93g, 5.60mmol) in 3ml of methanol was added, stirred at room temperature overnight, concentrated to dryness under reduced pressure, then slurried with anhydrous ethanol three times, filtered and dried to obtain 132mg of ({ [ (2S,5R) -2-ureido-7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonyl) sodium salt.
1H NMR(400MHz,D2O)δ3.79(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。
Example 7
A process for the preparation of a β -lactamase inhibitor, a urea-containing bicyclic compound, further comprising reacting (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octan-7-one of example 1 as a starting material to form an inhibitor of the invention.
The reaction scheme of this example is as follows:
the specific reaction process and structure verification result of this example are as follows:
under the protection of nitrogen, (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octane-7-one (988mg, 4mmol) and dried dichloromethane (50ml) are mixed, the temperature is reduced to 0 ℃, triethylamine (2.8ml, 20mmol) and dimethylamine acyl chloride (0.92ml, 10mmol) are sequentially added, then stirring is continued for 5 days at room temperature, 20ml of saturated aqueous solution of sodium bicarbonate is added for quenching reaction, dichloromethane (20ml multiplied by 3) is extracted, organic phases are combined, the organic phases are sequentially washed by saturated aqueous solution of sodium chloride (20ml), dried by anhydrous sodium sulfate, filtered, and subjected to silica gel column chromatography to obtain 3- ((2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] oct-2-yl) -1, 1-dimethylurea (1.20 g).
1H NMR(400MHz,DMSO-d6)δ7.49–7.18(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.
3- ((2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] oct-2-yl) -1, 1-dimethylurea (1.10g, 3.40mmol) and isopropanol/purified water (20ml/20ml) were mixed, 10% Pd/C (1.10g), triethylamine (0.094ml) and a trimethylamine complex (527mg, 3.79mmol) were added in this order, vacuum/hydrogen substitution was performed three times, hydrogenation was performed at room temperature overnight, diatomaceous earth was filtered, the filter cake was washed with 10ml of water, and the crude product was obtained after drying by concentration under reduced pressure.
The crude product obtained in the previous step was dissolved in 5ml of methanol, and then a solution of sodium ethylhexanoate (1.129g, 6.80mmol) in 3ml of methanol was added, stirred overnight at room temperature, concentrated to dryness under reduced pressure, then 10ml of isopropanol was added, slurried for 2 hours, filtered, washed with isopropanol, dried to give a white solid, then slurried twice with absolute ethanol, filtered and dried to give 172mg of ({ [ (2R,5R) -2-methanesulfonamido-7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonyl) sodium salt.
1H NMR(400MHz,D2O)δ3.61(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)。
Example 8
A process for the preparation of a β -lactamase inhibitor, a urea-containing bicyclic compound, further comprising reacting (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octan-7-one of example 1 as a starting material to form an inhibitor of the invention.
The reaction scheme of this example is as follows:
the specific reaction process and structure verification result of this example are as follows:
(2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octan-7-one (988mg, 4mmol) and dried dichloromethane (80ml) were mixed under nitrogen, pyrazine-2-carboxylic acid (546mg, 4.4mmol) and HATU (1.673g, 4.4mmol) were added in this order, and after stirring for 10 minutes, DIPEA (1.74ml, 10mmol) was added and stirring was continued overnight at room temperature, and the mixture was concentrated to dryness under reduced pressure and chromatographed to give tert-butyl 4- (((2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] oct-2-yl) carbamoyl) piperidine-1-carboxylate (1.80 g).
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.
Tert-butyl 4- (((2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] oct-2-yl) carbamoyl) piperidine-1-carboxylate (1.80g, 4mmol) and isopropanol/purified water (20ml/20ml) were mixed, 10% Pd/C (1.80g), triethylamine (0.11ml) and trimethylamine trioxide complex (623mg, 4.48mmol) were added in this order, vacuum/hydrogen substitution was carried out three times, hydrogenation was carried out overnight at room temperature, celite was filtered, the filter cake was washed with 10ml of water, and the crude product was obtained after drying by concentration under reduced pressure.
Mixing the crude product obtained in the last step with dichloromethane (40ml), cooling to 0 ℃, adding 16ml of trifluoroacetic acid, stirring at 0 ℃ for 3 hours, raising to room temperature, stirring for 1 hour, concentrating under reduced pressure to dryness to obtain 460mg of crude product, dissolving with a mixed solution of dichloromethane 0.5 ml/acetonitrile 5ml, filtering to remove insoluble substances, concentrating the filtrate to dryness, adding 10ml of methanol and 4ml of water to dissolve, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain 290mg of { [ (2S,5R) -2- (piperidine-4-carboxamido) -7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonate.
1H NMR(400MHz,D2O)δ4.89(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)。
Example 9
A process for the preparation of a β -lactamase inhibitor, a urea-containing bicyclic compound, further comprising reacting (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octan-7-one of example 1 as a starting material to form an inhibitor of the invention.
The reaction scheme of this example is as follows:
the specific reaction process and structure verification result of this example are as follows:
under the protection of nitrogen, (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octane-7-one (988mg, 4mmol) and dried dichloromethane (80ml) were mixed, then BOC-L-proline (946mg, 4.4mmol) and HATU (1.673g, 4.4mmol) were added in this order, after stirring for 10 minutes, DIPEA (1.74ml, 10mmol) was added, then stirring was continued overnight at room temperature, and the mixture was concentrated to dryness under reduced pressure and chromatographed to give tert-butyl (2S) -2- (((2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] oct-2-yl) carbamoyl) pyrroline-1-carboxylate (1.08 g).
Tert-butyl (2S) -2- (((2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] oct-2-yl) carbamoyl) pyrroline-1-carboxylate (1.07g, 2.4mmol) and isopropanol/purified water (20ml/20ml) were mixed, 10% Pd/C (1.10g), triethylamine (0.067ml) and a trimethylamine trioxide complex (374mg, 2.69mmol) were sequentially added, vacuum/hydrogen substitution was performed three times, then hydrogenation reaction was performed overnight at room temperature, celite filtration was performed, the filter cake was washed with 10ml of water, and the crude product was obtained after drying under reduced pressure.
Mixing the crude product obtained in the last step with dichloromethane (30ml), cooling to 0 ℃, adding 10ml of trifluoroacetic acid, stirring at 0 ℃ for 3 hours, raising to room temperature, stirring for 1 hour, concentrating under reduced pressure to dryness, pulping with 15ml of acetonitrile, filtering, pulping with a mixed solution of dichloromethane 2.5 ml/acetonitrile 5ml, filtering, and drying to obtain 170mg of { [ (2S,5R) -2- ((S) -pyrroline-2-carboxamide) -7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonate.
1H NMR(400MHz,D2O)δ4.94(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)。
Example 10
A process for the preparation of a β -lactamase inhibitor, a urea-containing bicyclic compound, further comprising reacting (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octan-7-one of example 1 as a starting material to form an inhibitor of the invention.
The reaction scheme of this example is as follows:
the specific reaction process and structure verification result of this example are as follows:
under the protection of nitrogen, (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octane-7-one (494mg, 2mmol) and dried dichloromethane (40ml) were mixed, L-pyroglutamic acid (546mg, 2.2mmol) and HATU (836mg, 2.2mmol) were added in this order, and after stirring for 10 minutes, DIPEA (0.87ml, 5mmol) was added, followed by further stirring overnight at room temperature, concentration under reduced pressure to dryness, and silica gel column chromatography to obtain (2S) -N- ((2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] oct-2-yl) -5-oxopyrroline-2-carboxamide (651 mg).
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).
(2S) -N- ((2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] oct-2-yl) -5-oxopyrroline-2-carboxamide (651mg,1.8mmol) and isopropanol/purified water (10ml/10ml) were mixed, 10% Pd/C (650mg), triethylamine (0.051ml) and the trimethylamine trioxide complex (650mg) were added in this order, vacuum/hydrogen substitution was carried out three times, hydrogenation was then carried out overnight at room temperature, celite was filtered, the filter cake was washed with 10ml of water, and the crude product was obtained after drying under reduced pressure.
The crude product obtained in the previous step was dissolved in 5ml of methanol, and then a solution of sodium ethylhexanoate (598mg, 3.6mmol) in anhydrous ethanol (4ml) was added, stirred at room temperature for 3 hours and concentrated to dryness, followed by three times beating with anhydrous ethanol, filtration and drying to obtain 130mg of ({ [ (2S,5R) -2- ((S) -5-oxopyrroline-2-carboxamido) -7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonyl) sodium salt.
1H NMR(400MHz,D2O)δ4.94–4.83(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)。
Example 11
A process for the preparation of a β -lactamase inhibitor, a urea-containing bicyclic compound, further comprising reacting (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octan-7-one of example 1 as a starting material to form an inhibitor of the invention.
The reaction scheme of this example is as follows:
the specific reaction process and structure verification result of this example are as follows:
under the protection of nitrogen, (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octane-7-one (988mg, 4mmol) and 1, 4-dioxane (50ml) were mixed, sulfonamide (2.304g, 24mmol) was added, and then N- ((2S,5R) -6- (benzyloxy) -7-oxy-1, 6-diazabicyclo [3.2.1] octane-2-yl) sulfamide (1.24g) was obtained by heating to reflux overnight, concentrating under reduced pressure to dryness and performing silica gel column chromatography.
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.
Mixing N- ((2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-yl) sulfamide (1.14g, 3.5mmol) and isopropanol/purified water (15ml/15ml), sequentially adding 10% Pd/C (1.14g), triethylamine (0.097ml) and a trimethylamine trioxide complex (545mg), vacuumizing/replacing with hydrogen for three times, then hydrogenating at room temperature overnight, filtering with diatomite, washing a filter cake with 10ml of water, and concentrating under reduced pressure to obtain a crude product.
The crude product obtained in the previous step was dissolved in 15ml of methanol, followed by addition of a solution of sodium ethylhexanoate (1.08g, 3.6mol) in anhydrous ethanol (5ml), stirring at room temperature for 3 hours, concentration to dryness, beating with anhydrous ethanol three times, filtration and drying to obtain 340mg of ({ [ (2S,5R) -2- (aminosulfonyl) -7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonyl) sodium salt
1H NMR(400MHz,D2O)δ4.35(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)。
Example 12
A process for the preparation of a β -lactamase inhibitor, a urea-containing bicyclic compound, further comprising reacting (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octan-7-one of example 1 as a starting material to form an inhibitor of the invention.
The reaction scheme of this example is as follows:
the specific reaction process and structure verification result of this example are as follows:
under nitrogen protection, (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octan-7-one (1.545g, 6.25mmol) and DMF (40ml) were mixed, followed by addition of N, N' -di-BOC-S-methylisothiourea (2.72g, 9.38mmol), mercuric chloride (2.547g, 9.38mmol) and triethylamine (1.3ml, 9.38mmol), stirring overnight at room temperature, and post-treatment was performed on a silica gel column to give 810mg of a white solid.
Mixing the product of the last step (800mg, 1.64mmol) with isopropanol/purified water (15ml/15ml), sequentially adding 10% Pd/C (800mg), triethylamine (0.046ml) and sulfur trioxide trimethylamine complex (255mg), vacuumizing/replacing with hydrogen for three times, then carrying out hydrogenation reaction at room temperature overnight, filtering with diatomite, washing a filter cake with 10ml of water, and concentrating under reduced pressure to obtain a crude product.
Mixing the crude product obtained in the last step with dichloromethane (20ml), cooling to 0 ℃, adding 8ml of trifluoroacetic acid, stirring at 0 ℃ for 3 hours, raising to room temperature, stirring for 1 hour, concentrating under reduced pressure, pulping with 10ml of acetonitrile, filtering, pulping with 2ml of methanol, filtering, and drying to obtain 141mg of { [ (2S,5R) -2-guanidino-1, 6-diazabicyclo [3.2.1] oct-6-yl ] oxy } sulfonate.
1H NMR(400MHz,D2O)δ4.15(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 inhibitor of the above embodiment is tested for inhibitory activity MIC (mg/L) in the invention, and the test results are shown in Table 1.
TABLE 1
MIC is measured by microdilution according to The guidelines of The Clinical and Laboratory Standard Institute (CLSI).
Synergistic antagonism with the antibiotic ceftazidime was tested for the production of various beta-lactamases. These beta-lactamases belong to a number of classes classified by Bush & Jacoby, (Updated Functional Classification of beta-lactamases, antibacterial Agents and Chemotherapy,54:969-76 (2010)). The synergistic effect is shown by the 2 to 4 fold reduction in MIC of ceftazidime when the compounds of the invention are used in combination with the beta-lactam antibiotic ceftazidime.
The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are merely exemplary embodiments of the present invention, and are not intended to limit the scope of the present invention, and any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (8)
1. The beta-lactamase inhibitor contains a urea bicyclic compound, which is characterized in that the structural formula is shown as a formula I,
in the formula, R1And R2H, C1-5 alkanoyl, C1-5 alkylsulfonyl, aromatic acyl, heterocyclic acyl containing hetero atom, or R1And R2Each or both of which is optionally substituted with C1-4 alkyl;
in the structural formula, X is Na or H.
2. The beta-lactamase inhibitor urea-containing bicyclic compound of claim 1, wherein the heteroatom in the heterocyclic acyl group is N, S or O.
3. The beta-lactamase inhibitor urea-containing bicyclic compound of claim 2, wherein the formula I has the structural formula:
4. a process for the preparation of a β -lactamase inhibitor urea-containing bicyclic compound according to any one of claims 1-3, comprising:
step one, preparing (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octane-7-one:
dissolving (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide in a solvent to obtain a mixed solution, adding iodobenzene bis (trifluoroacetic acid) into the mixed solution to perform reaction, adjusting the pH to 7-8, performing extraction after reduced pressure concentration, and obtaining (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octane-7-one after washing, drying, filtering and chromatography;
step two, adopting (2S,5R) -2-amino-6- (benzyloxy) -1, 6-diazabicyclo [3.2.1] octane-7-ketone as a raw material to participate in a substitution reaction to prepare a compound shown as a formula I,
5. the method of claim 4, wherein the solvents used in step one are acetonitrile and water, and the substance used to adjust the pH in step one is sodium bicarbonate.
6. The method of claim 4, wherein the extraction in step one is performed using methylene chloride, the washing is performed using a saturated aqueous solution of sodium chloride, and the drying is performed using anhydrous sodium sulfate.
7. The method of preparing a beta-lactamase inhibitor urea-containing bicyclic compound of claim 4, wherein the reaction conditions in step one are: stir at room temperature for 4 days.
8. Use of a beta-lactamase inhibitor urea-containing bicyclic compound according to any one of claims 1-3 in the manufacture of a medicament for the treatment of a bacterial infection.
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| 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 |
| CN107531708A (en) * | 2015-03-31 | 2018-01-02 | 拜欧蒂姆公司 | Novel heterocyclic compounds and they prevent or treat bacterium infection in application |
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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 |
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