CN103435650B - Monobactams compound, preparation method and pharmaceutical applications thereof - Google Patents
Monobactams compound, preparation method and pharmaceutical applications thereof Download PDFInfo
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Abstract
The invention belongs to medicinal chemistry art, be specifically related to a kind of novel beta-lactam compound and preparation method thereof, this compounds has monocycle beta-lactam structure, in treatment or prevention bacteriological infection, have using value.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of novel beta-lactam compound, preparation method and pharmaceutical applications thereof.
Background technology
β-lactam antibitics, through the discovery of last 100 years and application, has developed into the large class microbiotic of penicillins, cephalosporins, cephamycin-type, carbacephems, oxacephems, carbapenems and monobactams seven.Life and health for the universe has made tremendous contribution, is a current clinical application the largest class microbiotic.
Monocycle beta-lactam antibiotics is different from other six kinds of β-lactam antibiticss, and parent nucleus is a quaternary beta-lactam nucleus, and mechanism of action is unique, generally invalid for gram-positive microorganism, extremely strong for Gram-negative bacteria drug effect.Multiple β-lactamase is stablized, especially metallo-β-lactamase and carbapenem enzyme is stablized, make it occupy critical role when clinical treatment negative microbial infections.
From last century the eighties aztreonam and carumonam listing after, monocycle beta-lactam antibiotics listing of less types, widely use along with along with microbiotic, bacterial resistance phenomenon is day by day serious, has also caused the attention of various countries scientist.The appearance first of MRSA, has caused the upsurge for the research and development of resistant organism microbiotic.But for MRSA, MRSE, the even VRSA of drug resistance of vancomycin, all has alternative medicine to use clinically.At present, drug research seems attention degree deficiency for the research and development of negative resistant organism medicine.Clinically for negative microbial infections, main employing aztreonam or carbapenem antibiotic, once these two kinds of microbiotic generation resistances, doctor will feel simply helpless.In fact, clinically negative bacterium resistant rate considerably beyond positive bacteria.
Patent WO9847895 discloses a kind of structure of monocycle beta-lactam antibiotics, and wherein on beta-lactam nucleus, the substituting group of nitrogen is sulfonic group.Patent CN200680043076 and CN200880009346 discloses the compound of above-mentioned Momocycle-β-lactam Antibiotics and beta-lactamase inhibitor and carbapenem antibiotic.But do not comprise the structure of the phosphoryl replacement that patent of the present invention relates in the structure required by above-mentioned patent, the preparation method of the structural series compound that the phosphoryl that this patent relates to replaces also never reported by existing document.
Phosphation is some drugs normal metabolic processes in vivo, usually medicine Phosphation can not be increased the untoward reaction of former medicine.In addition, it is water-soluble that Phosphation has increase medicine, improves the advantages such as the targeting in body.Be hydrolyzed under the pH that phosphoric acid ester can be suitable in vivo, the effect of alkaline phosphatase, discharge former medicine and play a role.The Clindamycin Phosphate widely applied in the market is exactly successful examples microbiotic being carried out to phosphorylation.
Summary of the invention
Phosphate is the acidic substituent of medium tenacity, can change the cloud density on beta-lactam nucleus, thus affect anti-microbial activity.Contriver has designed and synthesized the monobactams compound of a kind phosphate ester, and determines its anti-microbial activity.
The invention provides and there is formula
the monocycle beta-lactam antibiotics of structure and pharmacy acceptable salt, racemic modification, individual isomer, hydrate or solvate:
Formula
Wherein:
R
1represent PO (ORa) (ORb), O-PO (ORa) (ORb),
,
,
or
Ra is selected from H, containing the alkyl of 1 to 3 carbon atom,
Rb is selected from H, containing the alkyl of 1 to 3 carbon atom;
R
2represent H, containing the alkyl of 1 to 3 carbon atom;
R
3represent H, containing the alkyl of 1 to 3 carbon atom;
Further, described compound is selected from:
Further, provide a kind of method preparing above-claimed cpd, specific features is as follows:
Employing formula A and formula B compound are under the catalysis of condensing agent, obtained after condensation and Deprotection step:
Wherein, in formula B, Rb is protecting group, diphenyl-methyl;
Rc is protecting group, trityl.
Further, described preparation method, the condensing agent that condensation step adopts is: N, N '-dicyclohexylcarbodiimide, DMAP, carbonyl dimidazoles, I-hydroxybenzotriazole.
Present invention also offers above-claimed cpd and pharmacy acceptable salt or hydrate thereof for the preparation for the treatment of or the purposes of prophylaxis of microbial infection medicine.
Double broth dilution method in the Antimicrobial test method (NCCLS99) of recommending by the American National Clinical Laboratory Standard council, measures the variant minimum inhibitory concentration MIC value (μ g/ml) by test product.Dissolve by aqueous samples employing aseptic double-distilled water in test product, all the other samples adopt dimethyl sulfoxide (DMSO) (DMSO) to dissolve, and sterilized water dilutes, and it is as shown in table 1 that the rear DMSO concentration of dilution is less than 1%. measurement results.
Table 1: representative compound different strains minimum inhibitory concentration (MIC) measurement result
Embodiment
Embodiment 1
(S, Z)-(3-(2-(2-aminooimidazole-4-base)-2-(((1,5-dihydroxyl-4-oxo-1,4-dihydropyridine-2-base) methoxyl group) imido grpup) acetamido)-2,2-dimethyl-4-aza-oxo-cyclobutane-1-bases) phosphonic acids (
-1) synthesis
Compound
-1 prepares through following flow process 1.
Flow process 1
In above-mentioned flow process, the method described in reference CN87104590 of preparing of compd B is carried out.
The preparation of compd A 1: get (S)-(2, 2-dimethyl-4-aza-oxo-cyclobutane-3-base) t-butyl carbamate 2.2g, be dissolved in the tetrahydrofuran (THF) of 30ml drying, hexane solution (2.5M) 4ml of n-Butyl Lithium is added dropwise at-78 DEG C, stir 30min, add chlorine phosphatase 11 .3g,-78 DEG C are stirred 1h, methyl alcohol 5ml is added dropwise in reaction solution, concentrated steaming desolventizes, be dissolved in 20ml methylene dichloride, be added dropwise to trifluoroacetic acid dichloromethane solution (1:1) 10ml, stirring at room temperature 30min, remove solvent under reduced pressure, column chromatography for separation obtains compd A 12.4g, yield 75%.
The preparation of intermediate C1: take (Z)-2-(2-tritylamino thiazole-4-yl)-2-(1, 5-bis-benzyloxy-4-pyriconyl-2-methoxyimino) acetic acid 4.5g, hydroxybenzotriazole (HOBT) 0.8g, dicyclohexylcarbodiimide 1.5g is dissolved in 30mlN, dinethylformamide (DMF), stirred at ambient temperature 1h, add above-claimed cpd A11.2g, stirred at ambient temperature 10h, reaction solution is placed into 4 DEG C of refrigerator 12h, filter, remove a small amount of insolubles, filtrate is poured in 50ml water, 3 extractions are divided with 100ml methylene dichloride, merge organic phase, concentrated, column chromatography, obtain off-white color solid intermediate C13.4g.
(S, Z)-(3-(2-(2-aminooimidazole-4-base)-2-(((1,5-dihydroxyl-4-oxo-1,4-dihydropyridine-2-base) methoxyl group) imido grpup) acetamido)-2,2-dimethyl-4-aza-oxo-cyclobutane-1-bases) phosphonic acids (
-1) preparation: upper step gained intermediate C13.0g is dissolved in 20ml methylene dichloride, be cooled to-10 DEG C, be added dropwise to dichloromethane solution (1:1) 5ml of trifluoroacetic acid, stirred at ambient temperature 2.5h, with 5% sodium bicarbonate aqueous solution washing reaction liquid to about pH=7, organic phase concentrates, column chromatography, obtain title compound (S, Z)-(3-(2-(2-aminooimidazole-4-base)-2-(((1, 5-dihydroxyl-4-oxo-1, 4-dihydropyridine-2-base) methoxyl group) imido grpup) acetamido)-2, 2-dimethyl-4-aza-oxo-cyclobutane-1-base) phosphonic acids (
-1) 1.8g.
1HNMR（DMSO-d6）：δ：1.31（s，3H），1.47（s，3H），4.31（s，2H），4.65（s，1H）5.71（m，1H），6.77（m，2H），7.54（s，1H），7.82（s，1H），8.09（s，1H），11.87（m，2H）。
Embodiment 2
((S, Z)-(3-(2-(2-aminooimidazole-4-base)-2-(((1,5-dihydroxyl-4-oxo-1,4-dihydropyridine-2-base) methoxyl group) imido grpup) acetamido)-2,2-dimethyl-4-aza-oxo-cyclobutane-1-bases) methyl-phosphonate (
-2) synthesis
Compd A 2 ((S)-3-amino-2, 2-dimethyl-4-aza-oxo-cyclobutane-1-base) preparation of methyl-phosphonate: get (S)-(2, 2-dimethyl-4-aza-oxo-cyclobutane-3-base) t-butyl carbamate 1.0g, be dissolved in the tetrahydrofuran (THF) of 20ml drying, hexane solution (2.5M) 2ml of n-Butyl Lithium is added dropwise at-78 DEG C, stir 30min, add chlorine mono phosphoric acid ester methyl esters 0.8g,-78 DEG C are stirred 1h, methyl alcohol 3ml is added dropwise in reaction solution, concentrated steaming desolventizes, be dissolved in 10ml methylene dichloride, be added dropwise to trifluoroacetic acid dichloromethane solution (1:1) 3ml, stirring at room temperature 30min, with 5% sodium bicarbonate aqueous solution washing reaction liquid to about pH=8, remove solvent under reduced pressure, column chromatography for separation obtains compd A 10.6g.
Title compound ((S, Z)-(3-(2-(2-aminooimidazole-4-base)-2-(((1,5-dihydroxyl-4-oxo-1,4-dihydropyridine-2-base) methoxyl group) imido grpup) acetamido)-2,2-dimethyl-4-aza-oxo-cyclobutane-1-bases) methyl-phosphonate (
-2) synthesis is carried out with reference to the method operation of embodiment 1.
1HNMR（DMSO-d6）：δ：1.29（s，3H），1.45（s，3H），3.66（s，3H），4.33（s，2H），4.67（s，1H），5.,69（m，1H），6.74（m，2H），7.56（s，1H），7.88（s，1H），8.13（s，1H），11.69（m，1H）。
Embodiment 3
(S, Z)-2-(2-aminooimidazole-4-base)-2-(((1,5-dihydroxyl-4-oxo-1,4-dihydropyridine-2-base) methoxyl group) imido grpup)-N-(2,2-dimethyl-1-(2-oxygen-1,3,2-dioxy phosphorus heterocycle amyl group-2-base)-4-aza-oxo-cyclobutane-3-base) ethanamide (
-6) synthesis
The chloro-2-oxygen-1 of compd A 6:2-, 3, the preparation of 2-dioxaphospholane: take phosphorus trichloride 15.4g and be dissolved in 20ml methylene dichloride, 1 is added dropwise under room temperature, 2-ethylene glycol 4.6g, dropwises stirring at room temperature reaction 1h, after pressure reducing and steaming solvent, underpressure distillation, collects 50-53 DEG C/3.0kPa cut.By steaming colourless liquid is dissolved in 20ml toluene, passing into oxygen 10h under stirring at room temperature, underpressure distillation, collecting 81-85 DEG C/6.0kPa cut, obtained 2-chloro-2-oxygen-1,3,2-dioxaphospholane (A6) 9.7g.
Title compound (S, Z)-2-(2-aminooimidazole-4-base)-2-(((1,5-dihydroxyl-4-oxo-1,4-dihydropyridine-2-base) methoxyl group) imido grpup)-N-(2,2-dimethyl-1-(2-oxygen-1,3,2-dioxy phosphorus heterocycle amyl group-2-base)-4-aza-oxo-cyclobutane-3-base) ethanamide (
-6) synthesized reference embodiment 1 method operation.
1HNMR（DMSO-d6）：δ：1.49（s，3H），1.53（s，3H），4.21（s，2H），4.43（m，4H），5.24（m，1H），5.66（s，1H），6.99（m，2H），7.57（s，1H），7.83（s，1H），8.04（s，1H）。
Embodiment 4
(S, Z)-2-(2-aminooimidazole-4-base)-2-(((1,5-dihydroxyl-4-oxo-1,4-dihydropyridine-2-base) methoxyl group) imido grpup)-N-(2,2-dimethyl-1-(2-oxidation-1,3,2-dioxy phosphorus heterocycle cyclohexyl-2-base)-4-aza-oxo-cyclobutane-3-base) ethanamide (
-7) synthesis
The preparation of compd A 7:2-chloro-2-oxygen-1,3,2-dioxaphosphorinane: take phosphorus oxychloride 7.8g and be dissolved in 10ml toluene, be added dropwise to 1,3-PD 3.9g under room temperature, dropwise stirring at room temperature reaction 1h, after pressure reducing and steaming solvent, add anhydrous diethyl ether 10ml in resistates, 0 DEG C of refrigeration 12h, filters and separates out solid, anhydrous diethyl ether 5ml recrystallization, obtain white crystal 2-chloro-2-oxygen-1,3,2-dioxaphosphorinane (A7) 3.9g.
Title compound (S, Z)-2-(2-aminooimidazole-4-base)-2-(((1,5-dihydroxyl-4-oxo-1,4-dihydropyridine-2-base) methoxyl group) imido grpup)-N-(2,2-dimethyl-1-(2-oxidation-1,3,2-dioxy phosphorus heterocycle cyclohexyl-2-base)-4-aza-oxo-cyclobutane-3-base) ethanamide (
-7) synthesized reference embodiment 1 method operation.
1HNMR（DMSO-d6）：δ：1.51（s，3H），1.53（s，3H），2.04（m，2H），4.01（m，4H），4.23（s，2H），4.43（m，4H），5.19（m，1H），5.63（s，1H），6.94（m，2H），7.59（s，1H），7.86（s，1H），8.02（s，1H）。
Embodiment 5
((2S, 3S)-3-((Z)-2-(2-aminooimidazole-4-base)-2-(((1,5-dihydroxyl-4-oxo-Isosorbide-5-Nitrae-dihydropyridine-2-base) methoxyl group) imido grpup) acetamido)-2-methyl-4-aza-oxo-cyclobutane-1-base) phosphonic acids (
-1) synthesis
Compound A-45 ((2S, 3S)-3-amino-2-methyl-4-aza-oxo-cyclobutane-1-base) preparation of phosphonic acids: get ((2S, 3S)-(2-methyl-4-aza-oxo-cyclobutane-3-base) t-butyl carbamate 0.7g, be dissolved in the tetrahydrofuran (THF) of 10ml drying, hexane solution (2.5M) 1.2ml of n-Butyl Lithium is added dropwise at-78 DEG C, stir 30min, add chlorine phosphoric acid 0.5g,-78 DEG C are stirred 1h, methyl alcohol 2ml is added dropwise in reaction solution, concentrated steaming desolventizes, be dissolved in 10ml methylene dichloride, be added dropwise to trifluoroacetic acid dichloromethane solution (1:1) 3ml, stirring at room temperature 30min, with 5% sodium bicarbonate aqueous solution washing reaction liquid to about pH=8, remove solvent under reduced pressure, column chromatography for separation obtains compound A-45 0.4g.
Title compound ((2S, 3S)-3-((Z)-2-(2-aminooimidazole-4-base)-2-(((1,5-dihydroxyl-4-oxo-Isosorbide-5-Nitrae-dihydropyridine-2-base) methoxyl group) imido grpup) acetamido)-2-methyl-4-aza-oxo-cyclobutane-1-base) phosphonic acids (
-1) preparation is carried out with reference to embodiment 1 working method.
1HNMR（DMSO-d6）：δ：1.31（m，3H），4.22（m，3H），5.18（s，1H），5.71（m，1H），6.70（m，2H），7.58（s，1H），7.91（s，1H），8.09（m，1H），11.92（m，2H）。
Embodiment 6
(S, Z)-2-(2-aminooimidazole-4-base)-2-(((1,5-dihydroxyl-4-oxo-Isosorbide-5-Nitrae-dihydropyridine-2-base) methoxyl group) imido grpup) acetamido)-2-methyl-4-aza-oxo-cyclobutane-1-base dihydroxyl phosphoric acid (
-1) synthesis
Compound
-1 prepares through following flow process 2
Compound D 1:(S)-3-amino-2, the preparation of 2-dimethyl-4-aza-oxo-cyclobutane-1-base phosphoric acid ester: take (S)-(1-hydroxyl-2, 2-dimethyl-4-aza-oxo-cyclobutane-3-base) t-butyl carbamate 2.3g, be dissolved in the methylene dichloride of 30ml drying, add triethylamine 1ml, 0-5 DEG C drips chlorine phosphatase 11 .2g, 5 DEG C are stirred 2h, cross and filter insolubles, drip dichloromethane solution (1:1) 2ml of trifluoroacetic acid, stirring at room temperature 30min, cross and filter insolubles, filtrate concentrates, column chromatography for separation, obtain Compound D 1 1.8g altogether, can be used for the next step.
Title compound (S, Z)-2-(2-aminooimidazole-4-base)-2-(((1,5-dihydroxyl-4-oxo-Isosorbide-5-Nitrae-dihydropyridine-2-base) methoxyl group) imido grpup) acetamido)-2-methyl-4-aza-oxo-cyclobutane-1-base dihydroxyl phosphoric acid (
-1) preparation is carried out with reference to embodiment 1 operation.
1HNMR（DMSO-d6）：δ：1.41（s，3H），1.48（s，3H），4.30（s，2H），4.62（s，1H）5.70（m，1H），6.80（m，2H），7.56（s，1H），7.84（s，1H），8.10（s，1H），11.89（m，2H）。
Embodiment 7
(S, Z)-2-(2-aminooimidazole-4-base)-2-(((1,5-dihydroxyl-4-oxo-1,4-dihydropyridine-2-base) methoxyl group) imido grpup)-N-(2,2-dimethyl-(1-(2-oxidation-1,3,2-dioxy phosphorus heterocycle amyl group-2-base) oxygen)-4-aza-oxo-cyclobutane-3-base) ethanamide (
-2) synthesis
Compound D 2:(S) amino-4, the 4-dimethyl-1-of-3-((2-is oxidized-1,3,2-dioxy phosphorus heterocycle amyl group-2-base) oxygen) azetidine-2-ketone preparation reference example 6 in the preparation method of Compound D 1 carry out.
Title compound (S, Z)-2-(2-aminooimidazole-4-base)-2-(((1,5-dihydroxyl-4-oxo-1,4-dihydropyridine-2-base) methoxyl group) imido grpup)-N-(2,2-dimethyl-(1-(2-oxidation-1,3,2-dioxy phosphorus heterocycle amyl group-2-base) oxygen)-4-aza-oxo-cyclobutane-3-base) ethanamide (
-2) preparation is carried out with reference to embodiment 1 operation.
1HNMR（DMSO-d6）：δ：1.52（s，3H），1.58（s，3H），4.24（s，2H），4.45（m，4H），5.22（m，1H），5.68（s，1H），7.01（m，2H），7.59（s，1H），7.85（s，1H），8.02（s，1H）。
Embodiment 8
(2S, 3S)-3-((Z)-2-(2-aminooimidazole-4-base)-2-(((1,5-dihydroxyl-4-oxo-Isosorbide-5-Nitrae-dihydropyridine-2-base) methoxyl group) imido grpup) acetamido)-2-methyl-4-aza-oxo-cyclobutane-1-base dihydroxyl phosphoric acid (
-1) synthesis
Compound d3: in the preparation reference example 6 of ((2S, 3S)-3-amino-2-methyl-4-aza-oxo-cyclobutane-1-base) phosphoric acid ester, preparation method's operation of Compound D 1 is carried out.
Title compound (2S, 3S)-3-((Z)-2-(2-aminooimidazole-4-base)-2-(((1,5-dihydroxyl-4-oxo-Isosorbide-5-Nitrae-dihydropyridine-2-base) methoxyl group) imido grpup) acetamido)-2-methyl-4-aza-oxo-cyclobutane-1-base dihydroxyl phosphoric acid (
-1) preparation is carried out with reference to embodiment 1 operation.
1HNMR（DMSO-d6）：δ：1.34（m，3H），4.21（m，3H），5.19（s，1H），5.73（m，1H），6.71（m，2H），7.57（s，1H），7.94（s，1H），8.10（m，1H），11.93（m，2H）。
Embodiment 9
(S, Z)-(3-(2-(2-aminooimidazole-4-base)-2-(((1,5-dihydroxyl-4-oxo-1,4-dihydropyridine-2-base) methoxyl group) imido grpup) acetamido)-2,2-dimethyl-4-aza-oxo-cyclobutane-1-bases) synthesis of phosphonic acids disodium
Weigh Compound (S, Z)-(3-(2-(2-aminooimidazole-4-base)-2-(((1,5-dihydroxyl-4-oxo-Isosorbide-5-Nitrae-dihydropyridine-2-base) methoxyl group) imido grpup) acetamido)-2,2-dimethyl-4-aza-oxo-cyclobutane-1-base) phosphonic acids 0.5g, be dissolved in 10ml methyl alcohol, be added dropwise to 5% sodium bicarbonate aqueous solution 1ml, stir 10min, filter, drying, obtains white solid 0.3g, HPLC purity 99.1%.
It should be noted that; the foregoing is only section Example of the present invention; the scope be not intended to limit the present invention, all any amendments done within the spirit and principles in the present invention, equivalent replacement and improvement etc., all should be included within protection scope of the present invention.
Claims (3)
1. there is the compound of chemical structure shown in general formula I,
It is characterized in that, wherein R
1, R
2, R
3select corresponding group with the compound be constructed as follows:
2. compound described in claim 1 for the preparation for the treatment of or prophylaxis of microbial infection medicine in application.
3. prepare a method for compound as claimed in claim 1, it is characterized in that the method adopts formula A and formula B compound under the catalysis of condensing agent, obtained after condensation and Deprotection step:
Wherein, condensing agent is: N, N '-dicyclohexylcarbodiimide, DMAP, carbonyl dimidazoles, I-hydroxybenzotriazole.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4681937A (en) * | 1982-09-27 | 1987-07-21 | E. R. Squibb & Sons, Inc. | 3-acylamino-2-oxo-1-azetidinyl esters of phosphonic acids, phosphoric acid and phosphoric acid esters |
| EP0243924A2 (en) * | 1986-04-28 | 1987-11-04 | E.R. Squibb & Sons, Inc. | 2-Oxo-1-(substituted phosphorous)azetidines |
| CN101410111A (en) * | 2005-12-07 | 2009-04-15 | 巴斯利尔药物股份公司 | Useful combinations of monobactam antibiotics with beta-lactamase inhibitors |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5888998A (en) * | 1997-04-24 | 1999-03-30 | Synphar Laboratories, Inc. | 2-oxo-1-azetidine sulfonic acid derivatives as potent β-lactamase inhibitors |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4681937A (en) * | 1982-09-27 | 1987-07-21 | E. R. Squibb & Sons, Inc. | 3-acylamino-2-oxo-1-azetidinyl esters of phosphonic acids, phosphoric acid and phosphoric acid esters |
| EP0243924A2 (en) * | 1986-04-28 | 1987-11-04 | E.R. Squibb & Sons, Inc. | 2-Oxo-1-(substituted phosphorous)azetidines |
| CN101410111A (en) * | 2005-12-07 | 2009-04-15 | 巴斯利尔药物股份公司 | Useful combinations of monobactam antibiotics with beta-lactamase inhibitors |
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