CN102304108B - Five-membered heterocyclic dicarbonyl derivative and application thereof on multi-drug resistant bacteria - Google Patents
Five-membered heterocyclic dicarbonyl derivative and application thereof on multi-drug resistant bacteria Download PDFInfo
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Abstract
The invention relates to the field of pharmaceutical chemistry, in particular to a five-membered heterocyclic dicarbonyl derivative (I) and application thereof on multi-drug resistant bacteria. Pharmacology experiments prove that the multi-drug resistant bacteria can be well inhibited through combined use of the compound in the invention and antibiotic.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to a class five-membered ring dicarbonyl derivative and the purposes on anti-multidrug resistance bacterium thereof.
Background technology
Microbiotic is that present clinical application is wide, a class antibacterium microbial medicine of large usage quantity, from penicillin in 1940 be applied to clinical since, it is playing an important role aspect disease with treating controlling.The antibacterium microbial medicine kind of using clinically at present is numerous, but along with antibiotic a large amount of and be widely used, particularly clinically unreasonable application, and even abuse, finally cause a large amount of generations of resistant organism.The concern and the anxiety that cause the whole world of the NDM-1 superbacteria that occurs especially recently, " NDM-1 superbacteria " is a kind of novel super resistant organism, because it carries New Delhi metallo-β-lactamase-1 (NewDelhi-Metallo-1, NDM-1) and well-known, this gene produces special β-lactamase, its activity needs metal ion to participate in, and at first the nearly all β-lactam antibitics that can deactivation comprises carbapenem again because produce and gain the name in India New Delhi.
The World Health Organization calls upon States to strengthen monitoring, urges various countries to take measures to resist drug tolerant bacteria, actively reduces the chance that bacterial antibiotic produces anti-medicine.U.S. CDC worries that it can be at global spread; It is that the superbacteria Infection outbreak is ready that Canada requires; French will carry out the superbacteria resistance to all patients who once was in hospital abroad and detect; Japan has indicated local government to sound the alarm of prevention and control superbacteria; China is built vertical superbacteria monitor network also, and strengthens research and development and resist medicine.
Therefore, the resistance that how to overcome bacterium has become the important topic of antibacterium microbial medicine research both at home and abroad at present.The method that solves resistance is numerous, wherein the resistance mechanism of directed toward bacteria research and development new drug is that solution resistance problem is a kind of effective method, be the method for at present comparatively successful antagonism bacterial resistance clinically with the inhibitor drug combination of microbiotic and multidrug resistance Production by Bacteria unboiled water solution antibiotic enzyme, and obtained certain effect on the clinical treatment drug-fast bacteria infection.The clinical compound preparation that is formed by ampicillin/sulbactam, amoxycilline Trihydrate bp/Sulbactam, Sulbactam/Cefoperazone, amoxicillin/clavulanate potassium etc. commonly used.Even if but drug combination, these compound preparations neither be all effective to all resistant organisms, especially NDM-1 enzyme, there is no effective inhibitor report, therefore developing new inhibitor has become very active field in the related disciplines such as current microbiological pharmacy, Computer-Aided Drug Design, pharmaceutical chemistry.
Summary of the invention
The antibiotic enzyme of hydrolysis that the present invention is produced take the multidrug resistance bacterium is as target, and destroys antibiotic active centre for this enzymatic hydrolysis and designed and synthesized a series of its inhibitor.For combined with antibiotic treatment multidrug resistance bacterium provides new selection.
(I) is as follows for structural formula of compound of the present invention:
G wherein
1Or G
2Independently represent separately hydrogen, hydroxyl, C
1-C
5Alkyl, C
1-C
5The C that haloalkyl, hydroxyl replace
1-C
5Alkyl, C
1-C
5Alkoxyl group, itrile group, amino, hydroxylamino, phenoxy group, phenyl, benzyl, C
1-C
5Alkylamino, C
1-C
5Alkoxy amino or phenyl amino;
A or B independently represent hydrogen, hydroxyl, C separately
1-C
5Phosphonate group alkyl, amino, hydroxylamino, sulfonic group, sulfahydantoin, phenyl, C
1-C
5The phenyl that alkyl replaces, benzyl, benzyloxy, phenyl amino, benzylamino or
Wherein W represents five yuan or hexa-member heterocycle, and m is 0 to 5 integer;
Z represents methylene radical, nitrogen-atoms, sulphur atom or Sauerstoffatom.
Described five yuan or hexa-member heterocycle refer to contain 1-2 five yuan or six-ring that is selected from N, S, O.
G
1Or G
2Preferably independent representation hydroxy, amino or hydroxylamino separately.
A or B preferably separately independent representation hydroxy, sulfonic group, sulfahydantoin,
Wherein W represents five yuan or hexa-member heterocycle, and m is 0 to 5 integer.
The preferred represention oxygen atom of Z or sulphur atom.
Simultaneously, the present invention also comprises any suitable anti-and steric isomer of the compound (I) with said structure feature.
Compound of the present invention can prepare in the following method:
Wherein, G
1, G
2, A, B, Z definition the same.
The invention also discloses a kind of antibacterial combination, wherein contain compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of general formula (I).
The present invention also discloses a kind of antibacterial combination, and it contains compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of β-lactam antibitics, general formula (I).The growth that general formula of the present invention (I) compound and microbiotic share effective anti-bacteria.
General formula of the present invention (I) compound not only has antibacterial actions, and can infect by effectively anti-multidrug resistance bacterium with the microbiotic coupling.
Aforementioned pharmaceutical compositions can be made the multiple formulations such as injection, tablet, injectable sterile powder, pulvis, granule, capsule, oral liquid, paste, creme.Above-mentioned various formulation all can be according to the ordinary method preparation of pharmaceutical field.Can import by the method for injection, oral, collunarium, eye drip, physics or chemistry mediation as muscle, endothelium, subcutaneous, vein, mucosal tissue; Or mixed by other materials or wrap up after import body.
The In Vitro Bacteriostasis experimental result shows, the compounds of this invention and Antibiotic combination use, and the multidrug resistance bacterium is had better restraining effect.Experimental procedure used and experimental result are as follows:
One, drug susceptibility test
The compounds of this invention compound concentration is the solution of 10uM and unites use with imipenum (IPM) 10ug, result demonstration: can produce obvious inhibition zone for the multidrug resistance bacterium.And alone microbiotic imipenum (IPM) 10ug can bacteria growing inhibiting.
Concrete steps are:
Compound with preparation is configured to the solution that concentration is 10 μ M, and drug susceptibility test adopts disk diffusion method: get bacterium preservation liquid to be measured 50 μ L and add 5mLMH meat soup, be placed in 37 ℃, cultivated in the 200rpm shaking table approximately 12 hours
Then use stroke-physiological saline solution, contrast 0.5 Maxwell opacity tube is proofreaied and correct bacterial concentration.
The drug sensitive test operation:
1. dip bacterium liquid with sterile cotton examination, after inside pipe wall is with crowded the going of unnecessary bacterium liquid rotation, evenly smear 3 times in media surface, each 60 °, at last along smearing a week in flat board;
2. flat board is put dry 3-5min under room temperature, with aseptic nipper, drug paper disk carefully is close to media surface, and each scraps of paper centers can not be moved after the scraps of paper stick at a distance of＞24mm again.According to the method record this compound to inhibition zones such as the intestinal bacteria of multidrug resistance, streptococcus aureuses at 10-16mm, demonstrate obvious fungistatic effect.
The bacteriostatic experiment of part of compounds of the present invention the results are shown in Table 1
Table 1 part of compounds of the present invention (10 μ M) and microbiotic (10ugIPM) share the restraining effect to the multidrug resistance bacterium
As seen from the above table, the compounds of this invention and imipenum share and can suppress significantly Multidrug resistant bacteria.Particularly CPU-ZH008, CPU-ZH 016, CPU-ZH 037 share the Escherichia coli Growth that can obviously suppress multidrug resistance with imipenum, and CPU-ZH008, CPU-ZH 023, CPU-ZH 041 share the staphylococcus aureus growth that can obviously suppress multidrug resistance with imipenum.Most preferred Compound C PU-ZH 008, itself and imipenum share all has obvious restraining effect afterwards to above-mentioned two strain multidrug resistance bacteriums.
The structure that the listed compound code name of table 1 is corresponding is as follows:
Two, microbiotic minimal inhibitory concentration (MIC) experiment
Compound C PU-ZH 008 is further carried out the comparative study of microbiotic minimal inhibitory concentration (MIC) after alone imipenum and drug combination.Experimental result shows: after drug combination, antibiotic MIC value can be reduced to 8 μ g/ml by＞128 μ g/ml.
Concrete steps are:
CPU-ZH 008 adds the microbiotic imipenum, is ground into uniform powder in aseptic mortar.Above-mentioned powder is dissolved with stroke-physiological saline solution, constant volume, through 0.2 μ m filtering with microporous membrane degerming, the compound final concentration is 10 μ M, the final concentration of imipenum is 1mg/ml.Be added to respectively after doubling dilution in 96 hole polystyrene plates of sterilization, the 1st to the 11st hole adds liquid, every hole 20 μ l, and the 12nd not dosing of hole seals after frost drying as growth control, saves backup below-20 ℃.The gene engineering colibacillus of expressing NDM-1 is cultivated in MH meat soup, and be diluted to 0.5 Maxwell than the bacteria suspension of turbid standard with stroke-physiological saline solution, after the dilution in 1: 1000 of MH meat soup, add 100 μ l in every hole, in the rearmounted 35 ℃ of normal air incubators of sealing, hatch 16-20h.At this moment, the 1st hole to the 11 hole drug levels are respectively 128,64,32,16,8,4,2,1,0.5,0.25,0.125 μ g/ml.
The MIC that records medicine is 8 μ g/ml, and does not contain the control drug MIC that the compounds of this invention only contains imipenum＞128 μ g/ml.
Embodiment
Embodiment 1
4-methyl-2-ethanoyl-5-propionyl-3-hydroxyl furans (CPU-ZH 003)
Propionyl chloride 9ml (0.1mol), 1-hydroxy-2-butanone 8.8ml (0.1mol) and 14g salt of wormwood (0.1mol) are joined in the 100ml three-necked bottle, induction stirring, 80 ℃ of back flow reaction 6 hours, rising temperature of reaction to 110 ℃, Acetylformic acid 8.5ml (0.1mol) slowly is added drop-wise in reaction solution, adds rear continuation reaction 10 hours.Suction filtration, concentrating under reduced pressure reaction solution, remaining liq ethyl acetate extraction.Concentrated, dry solid 10.56g, the total recovery 53.86% of getting.
Molecular formula: C
10H
12O
4, molecular weight: 196.20
MS(EI)m/z?196。
1H-NMR(AV-500，δ，DMSO-d
6)：1.15(t，3H)；1.92(s，3H)；2.48(s，3H)；3.75(q，2H)；5.40(s，1H)
Embodiment 2
3-((1-H-1,2,4-triazol radical) methylene radical)-2-ethanoyl-3-hydroxyl-minaline (CPU-ZH 008)
Chloracetic acid sodium 11.6g (0.1mol), 1-amino-2-acetone 7.5ml (0.1mol) and 14g salt of wormwood (0.1mol) are joined in the 100ml three-necked bottle, induction stirring, 95 ℃ of back flow reaction 6 hours, rising temperature of reaction to 110 ℃, with 1-H-1,2,4-triazol radical-2 oxo propionic acid 15g (0.1mol) slowly is added drop-wise in reaction solution, reaction is spent the night, and adds concentrated hydrochloric acid to pH to be about 4.0.Suction filtration, concentrating under reduced pressure reaction solution, remaining liq ethyl acetate: the mixed organic solvent extraction of chloroform=3: 1.Concentrated, dry solid 18.14g, the total recovery 71.13% of getting.
Molecular formula: C
10H
10N
4O
4, molecular weight: 250.22
MS(EI)m/z?249(M-1)。
1H-NMR(AV-500，δ，DMSO-d
6)：2.08(t，3H)；5.02(s，1H)；5.31(s，3H)；5.33(s，1H)；5.39(s，2H)；8.03(s，1H)；8.31(s，1H)
Embodiment 3
3,4-benzyloxy-2,5-thiophene dioctyl phthalate dimethyl ester (CPU-ZH 016)
With Acetyl Chloride 98Min. 8ml (0.1mol), 1-sulfydryl-2-acetone 0.1mol, 200mlDMF and 14g salt of wormwood (0.1mol), join in the 250ml three-necked bottle, induction stirring, 40 ℃ were reacted 3 hours, rising temperature of reaction to 85 ℃, oxalic acid dibenzyl ester 27g (0.1mol) slowly is added in reaction solution, reacted 5 hours.Suction filtration, concentrating under reduced pressure reaction solution, remaining liq chloroform extraction.Concentrated, dry solid 20.14g, the total recovery 53.02% of getting.
Molecular formula: C
22H
20O
6S, molecular weight: 412.47
MS(EI)m/z?435.1(M+23)
1H-NMR(AV-500，δ，DMSO-d
6)：3.00(s，3H)；5.16(s，2H)；7.24-7.41(m，5H)；7.83(s，2H)
Embodiment 4
1-hydroxyacetyl-2-amino-3-benzyl-4-formyl radical pentamethylene (CPU-ZH 019)
With 6-hydroxyl-5-oxo hexanal 13ml (0.1mol), benzyl carbamyl ketone 16.3g (0.1mol), 150mlDMF, join in the 250ml three-necked bottle, induction stirring, 80 ℃ were reacted 4 hours.Suction filtration, concentrating under reduced pressure reaction solution, remaining liq chloroform extraction.Concentrated, dry solid 15.23g, the total recovery 59.26% of getting.
Molecular formula: C
15H
15NO
3, molecular weight: 257.29
MS(EI)m/z?257。
1H-NMR(AV-300，δ，DMSO-d
6)：2.85(s，2H)；3.52(s，2H)；3.66(s，1H)；5.16(s，2H)；7.22-7.40(m，5H)；8.51(s，2H)；9.81(s，1H)
Embodiment 5
1-formamyl-2-(4-piperazinyl methyl)-3-phenyl amino-5-itrile group formylfuran (CPU-ZH 023)
With hydroxymethyl formamide 0.1mol, chloromethyl formyl nitrile 0.1mol, 120mlDMF and 14g salt of wormwood (0.1mol); join in the 250ml three-necked bottle; induction stirring; normal-temperature reaction 2.5 hours; rising temperature of reaction to 70 ℃; 4-piperazinyl acetylbenzene amido ketone 0.1mol slowly is added in reaction solution, reacted 9 hours.Suction filtration, concentrating under reduced pressure reaction solution, remaining liq dichloromethane extraction.Concentrated, dry solid 28.22g, the total recovery 80.63% of getting.
Molecular formula: C
18H
19N
5O
3, molecular weight: 353.38
MS(EI)m/z?353。
1H-NMR(AV-500，δ，DMSO-d
6)：1.90(s，1H)；2.35(t，4H)；2.68(t，4H)；3.65(s，2H)；4.01(s，1H)；；7.34-7.42(m，5H)
Embodiment 6
1-anilino formyl radical-2-hydroxylamino-5-N-methylcarbamoyl thiophene (CPU-ZH 037)
With N-methyl formyl radical chloromethyl ketone 0.1mol, N-anilino formyl radical thiomethyl alcohol 0.1mol, 150mlDMF and 14g salt of wormwood (0.1mol); join in the 250ml three-necked bottle; induction stirring; 45 ℃ were reacted 5 hours; rising temperature of reaction to 80 ℃; methylol formyl radical formaldehyde 0.1mol slowly is added in reaction solution, reacted 7 hours.Suction filtration, concentrating under reduced pressure reaction solution, remaining liq dichloromethane extraction.Concentrated, dry solid 28.22g, the total recovery 53.02% of getting.
Molecular formula: C
14H
14N
2O
2S, molecular weight: 274.34
MS(EI)m/z?274。
1H-NMR(AV-500，δ，DMSO-d
6)：1.98(s，1H)；2.85(s，3H)；4.08(s，1H)；7.16(s，1H)；7.2-7.6(m，5H)；9.08(s，1H)
Embodiment 7
1-benzoyl-2-benzylamino-3-sulfonic group amino-4-benzyl formyl radical thiophene (CPU-ZH 041)
With benzyl chloride methyl ketone 0.1mol, benzoyl thiomethyl alcohol 0.1mol, 150mlDMF and 14g salt of wormwood (0.1mol); join in the 250ml three-necked bottle; induction stirring; 55 ℃ were reacted 6 hours; rising temperature of reaction to 85 ℃; sulfahydantoin formyl radical benzyl keto-amine 0.1mol slowly is added in reaction solution, reacted 10 hours.Suction filtration, concentrating under reduced pressure reaction solution, remaining liq acetone extract.Concentrated, dry solid 20.06g, the total recovery 40.94% of getting.
Molecular formula: C
26H
22N
2O
4S
2, molecular weight: 490.60
MS(EI)m/z?490。
1H-NMR(AV-500，δ，DMSO-d
6)：4.08(s，2H)；4.30(s，2H)；4.45(s，2H)；7.21-7.35(m，10H)；7.61-7.80(m，5H)
Embodiment 8
1-hydroxylamino formyl radical-2-phenyl-3-sulfonic group-4-phenoxy group formylfuran (CPU-ZH 049)
With oxygen benzyl formate 0.1mol, hydroxylamino methylol ketone 0.1mol, 150mlDMF and 14g salt of wormwood (0.1mol); join in the 250ml three-necked bottle; induction stirring; 60 ℃ were reacted 1.5 hours; rising temperature of reaction to 75 ℃; sulfonic group formyl radical phenyl ketone 0.1mol slowly is added in reaction solution, reacted 6 hours.Suction filtration, the concentrating under reduced pressure reaction solution, remaining liq extracts with Virahol.Concentrated, dry solid 19.68g, the total recovery 50.85% of getting.
Molecular formula: C
18H
13NO
7S, molecular weight: 387.37
MS(EI)m/z?387。
1H-NMR(AV-500，δ，DMSO-d
6)：2.1(s，1H)；7.25-7.54(m，10H)；8.03(s，1H)
Embodiment 9
3-phosphonate group methylene radical-2-chloroethyl formyl radical--5-benzyl formyl radical-4-hydroxy thiophene (CPU-ZH 053)
With benzyl chloride methyl ketone 0.1mol, 4-chloro-2-oxo butyl sulfhydryl 0.1mol, 150mlDMF and 14g salt of wormwood (0.1mol), join in the 250ml three-necked bottle, induction stirring, 80 ℃ were reacted 6.5 hours, rising temperature of reaction to 90 ℃, 3-phosphonate group-Acetylformic acid 0.1mol slowly is added in reaction solution, reacted 4 hours.Suction filtration, concentrating under reduced pressure reaction solution, remaining liq n-butanol extraction.Concentrated, dry solid 16.03g, the total recovery 39.86% of getting.
Molecular formula: C
16H
17O
6PS, molecular weight: 368.35
MS(EI)m/z?367(M-1)。
1H-NMR(AV-500，δ，DMSO-d
6)：3.15(t，2H)；3.72(t，2H)；4.01(s，2H)；4.49(s，2H)；5.32(s，1H)；7.21-7.35(m，5H)
Embodiment 10
3-is to methylphenoxy-4-benzylamino-5-(the N-methoxyl group is amino) formyl radical-2-benzoyl thiophene (CPU-ZH 059)
With phenyl-chloride methyl ketone 0.1mol, mercapto methyl methoxyl group keto-amine 0.1mol, 150mlDMF and 14g salt of wormwood (0.1mol), join in the 250ml three-necked bottle, induction stirring, 85 ℃ were reacted 3 hours, rising temperature of reaction to 95 ℃, 2-benzylamino-2-oxo-acetic acids slowly is added in reaction solution toluene ester 0.1mol, reacted 5 hours.Suction filtration, the concentrating under reduced pressure reaction solution, remaining liq extracts with propyl alcohol.Concentrated, dry solid 19.51g, the total recovery 41.33% of getting.
Molecular formula: C
27H
24N
2O
4S, molecular weight: 472.57
MS(EI)m/z?472。
1H-NMR(AV-500，δ，DMSO-d
6)：2.33(s，3H)；3.69(s，3H)；4.01(s，1H)；4.33(s，2H)；6.67-7.06(q，4H)；7.21-7.34(m，5H)；7.62-7.90(m，5H)
Embodiment 11
Get gained compound (CPU-ZH008) 0.2g in embodiment 2, starch 3g, dextrin 1.5g mixes, and is tackiness agent with appropriate 35% pharmaceutical grade polyvinylpyrrolidone (PVP), granulate, compressing tablet.
Embodiment 12
get gained compound (CPU-ZH008) 4g in embodiment 2, N.F,USP MANNITOL 8g, be placed in container, add appropriate phosphate buffered saline buffer (0.05mol/L pH8.0) dissolving, inject water to 100ml, shake up, add 1～5g needle-use activated carbon, stirring at room 30～60 minutes, coarse filtration, with 0.22 μ m membrane filtration degerming, packing, every bottle of 1ml, adopt the method for quick-frozen, 5～15 ℃ of per minute coolings, be cooled to-50 ℃, kept 2 hours, vacuumize, slowly heat up under vacuum state, per hour 0.2～12 ℃ of heat-up rate, temperature stops when rising to 30 ℃ heating up, after being down to room temperature, temperature takes out, seal.
Claims (7)
1. the compound of general formula (I) or its pharmacy acceptable salt:
2. antibacterial combination wherein contains compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of claim 1.
3. antibacterial combination wherein contains compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of β-lactam antibitics, claim 1.
4. the antibacterial combination of claim 3, wherein β-lactam antibitics is imipenum.
5. the compound of claim 1 or its pharmacy acceptable salt are for the preparation of the purposes of antibacterials.
6. the compound of claim 1 or its pharmacy acceptable salt are for the preparation of the purposes of the medicine that prevents or treat Multidrug resistant bacteria to catch.
7. the compound of claim 1 or its pharmacy acceptable salt and antibiotic drug combination prepare the purposes of antibacterials.
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Non-Patent Citations (5)
| Title |
|---|
| D. J. Chadwick,et al.Preparation of Thiophen Esters by the Hinsberg Reaction.《J.C.S. Perkin I》.1972,2079-2081. |
| Janda，Miroslav,et al.2-Formyl-5-propionylthiophene.《CAPLUS》.2001,1-3. * |
| Mixed Intramolecular Hydrogen Bonding in Dihydroxythiophene-based Units and Boron and Technetium Chelation;Sangwon Ko,et al;《Bull. Korean Chem. Soc.》;20061231;第27卷(第2期);243-250 * |
| Preparation of Thiophen Esters by the Hinsberg Reaction;D. J. Chadwick,et al;《J.C.S. Perkin I》;19721231;2079-2081 * |
| Sangwon Ko,et al.Mixed Intramolecular Hydrogen Bonding in Dihydroxythiophene-based Units and Boron and Technetium Chelation.《Bull. Korean Chem. Soc.》.2006,第27卷(第2期),243-250. |
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