CN102731301B - Thymol ester derivatives, its preparation method and application thereof - Google Patents
Thymol ester derivatives, its preparation method and application thereof Download PDFInfo
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- CN102731301B CN102731301B CN201210224594.5A CN201210224594A CN102731301B CN 102731301 B CN102731301 B CN 102731301B CN 201210224594 A CN201210224594 A CN 201210224594A CN 102731301 B CN102731301 B CN 102731301B
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- thymol
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- salt
- thymol ester
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- MGSRCZKZVOBKFT-UHFFFAOYSA-N thymol Natural products CC(C)C1=CC=C(C)C=C1O MGSRCZKZVOBKFT-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 239000005844 Thymol Substances 0.000 title claims abstract description 34
- 229960000790 thymol Drugs 0.000 title claims abstract description 34
- -1 Thymol ester Chemical class 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 241000894006 Bacteria Species 0.000 claims abstract description 22
- 239000003814 drug Substances 0.000 claims abstract description 19
- 201000010099 disease Diseases 0.000 claims abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- 241000193403 Clostridium Species 0.000 claims abstract description 5
- 208000004232 Enteritis Diseases 0.000 claims abstract description 5
- 230000001338 necrotic effect Effects 0.000 claims abstract description 4
- 241001465754 Metazoa Species 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 9
- 241000193830 Bacillus <bacterium> Species 0.000 claims description 7
- 239000000654 additive Substances 0.000 claims description 6
- 230000000996 additive effect Effects 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- 241000186227 Corynebacterium diphtheriae Species 0.000 claims description 5
- 241000191967 Staphylococcus aureus Species 0.000 claims description 5
- 208000001848 dysentery Diseases 0.000 claims description 5
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims description 4
- 239000008399 tap water Substances 0.000 claims description 4
- 235000020679 tap water Nutrition 0.000 claims description 4
- BMFMQGXDDJALKQ-BYPYZUCNSA-N Argininic acid Chemical class NC(N)=NCCC[C@H](O)C(O)=O BMFMQGXDDJALKQ-BYPYZUCNSA-N 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 3
- 241000588769 Proteus <enterobacteria> Species 0.000 claims description 3
- 159000000007 calcium salts Chemical class 0.000 claims description 3
- 159000000003 magnesium salts Chemical class 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
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- 235000019730 animal feed additive Nutrition 0.000 abstract 1
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- 230000000116 mitigating effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
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- 235000007303 Thymus vulgaris Nutrition 0.000 description 4
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 238000004659 sterilization and disinfection Methods 0.000 description 4
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
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- QIGBRXMKCJKVMJ-UHFFFAOYSA-N 1,4-Benzenediol Natural products OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 2
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- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- 0 CC(*)c1c(*)cc(C)cc1 Chemical compound CC(*)c1c(*)cc(C)cc1 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000371 Esterases Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
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- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 2
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- WCBVOPMSONYWEB-UHFFFAOYSA-N 2-aminoacetyl chloride Chemical compound NCC(Cl)=O WCBVOPMSONYWEB-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- IOAISUCAQCEHTA-UHFFFAOYSA-N 5-methyl-2-propan-2-ylphenol Chemical compound CC(C)C1=CC=C(C)C=C1O.CC(C)C1=CC=C(C)C=C1O IOAISUCAQCEHTA-UHFFFAOYSA-N 0.000 description 1
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- 150000007660 quinolones Chemical class 0.000 description 1
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- UCRLQOPRDMGYOA-DFTDUNEMSA-L zinc;(4r)-4-[[(2s)-2-[[(4r)-2-[(1s,2s)-1-amino-2-methylbutyl]-4,5-dihydro-1,3-thiazole-4-carbonyl]amino]-4-methylpentanoyl]amino]-5-[[(2s,3s)-1-[[(3s,6r,9s,12r,15s,18r,21s)-3-(2-amino-2-oxoethyl)-18-(3-aminopropyl)-12-benzyl-15-[(2s)-butan-2-yl]-6-(carbox Chemical compound [Zn+2].C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC([O-])=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2NC=NC=2)C(=O)N[C@H](CC([O-])=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 UCRLQOPRDMGYOA-DFTDUNEMSA-L 0.000 description 1
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention relates to the field of pharmaceutical chemistry, specifically to thymol ester compounds (I), its preparation method and an application thereof. It is proved through a pharmacology experiment that the thymol ester compounds (I) provided by the invention can be used to prepare medicines for treating or preventing diseases caused by bacteria or diseases caused by fungi and can be also used to prepare animal feed additives or drinking water tonifying formula for treating, mitigating or preventing necrotic enteritis caused by Shigella species, clostridium and Clostridium perfringens. The invention also discloses a preparation method of the derivatives and their pharmaceutical composition.
Description
Technical field
The present invention relates to pharmaceutical chemistry field, be specifically related to a class thymol ester compound, can be used for treatment treatment or prevent bacterial disease or fungi to cause disease, the invention also discloses its preparation method and also have their pharmaceutical composition.
Background technology
The antibiotic magical epoch have been started in the appearance of penicillin, and the multiple disease infecting because of bacterium of the mankind all can have by microbiotic and treat completely within for some time.Since 20th century along with scientific and technical development, the research of the antibacterials such as sulfamido, penicillins, aminoglycoside, paraxin, tetracyclines, Macrolide obtains development at full speed, particularly the antimicrobial drug such as semisynthetic penicillin, cynnematin, novel ss-lactam, quinolones comes out, make effectively to treat various bacteriums infection and become possibility, for ensureing human health, prolongs life has been made outstanding contribution, and the basic science such as biology, chemistry progress is also had to important feedback influence.But because the mankind are more and more for antibiotic abuse drug tolerant bacteria, clinical picture shows: antibacterials misapplication, not only can cause huge waste, and can induce the generation of bacterial drug resistance and increase, and the generation of many Drug illness.
Hydroquinone compound (Quinonoid) is a class novel cpd that is different from current common antimicrobial agents mechanism of action of finding in active ingredient of Chinese herbs research process at present.It shows many-sided physiologically active, as anti-oxidant, remove free radical, inhibition or kill bacteria growth and the effect such as antiviral, have purposes widely at aspects such as medicine, agricultural chemicals, cosmetic material and foodstuff additive
[7,8,9].Therefore, quinones composition is also taken seriously gradually.
Thymol (Thymol) is from Labiatae Chinese herbal medicine Thymus vulgaris (Thymus serpyllum L.), to extract the antibiotic effective ingredient being separated at first, is a kind of representational hydroquinone compound.Modern pharmacology experimental results show that
[thymol antibacterial effect is stronger, has a broad antifungal spectrum, toxicity is low, and streptococcus aureus, Corynebacterium diphtheriae, Pseudomonas aeruginosa, Bacillus proteus etc. are had and suppressed or killing action, and its germicidal action is stronger than phenol, and toxicity is low, oral cavity mucosa is had to sterilization, fungicidal action, there is to anticorrosion, local anesthetic action in carious tooth chamber, also all effective in cure for disinfection, tinea, actinomycosis and the otitis of oral cavity, throat.Pharmacodynamics in vitro test-results also shows, thymol all has sterilization and bacteriostasis effect in various degree to enteritis common bacteria, wherein the strongest to the bacteriostatic action of streptococcus aureus, be secondly that Corynebacterium diphtheriae, various paratyphosum Bacterium and pathogenic colon bacillus, enterotoxigenic E．Coli and enteroinvasive E．Coli, Pseudomonas aeruginosa all have certain bacteriostatic action.In livestock industry, thymol is promoted the use of at present as the Antibacterial Constituents in animal feedstuff additive; In dietetic food health, thymol also can be used for sterilization, seasoning, control honeybee mite, kills mould spores.
But active ingredient of Chinese herbs thymol certain defect of existence more or less aspect pharmacodynamics and pharmacokinetics, mainly contains that drug effect is not high, too greatly or in vivo accretion rate is too fast and excessively slow etc. for toxicity.Utilize medicinal design principle of pro-drug etc.; the phenolic hydroxyl group in thymol basic chemical structure is carried out acidylate protection by imagination; synthesizing series thymol acyl compounds, ether derivative; after making it enter in body; through the degraded of serum esterase and other enzymes system; slowly release parent drug thymol and other chemical groups or activeconstituents and bring into play anti-microbial effect; in expection reaches desirable body in antibacterial drug effect; also degradable discharges some other pharmacophoric group, brings into play the curative effect of medication effect of other groups.Experiment in vivo and vitro shows that thymol ester derivative has good antibacterial, fungicidal activity, demonstrates good DEVELOPMENT PROSPECT.
Summary of the invention
Active group phenolic hydroxyl group in thymol molecule is its target spot of first considering that carries out chemical structure modification transformation, and phenolic hydroxyl group can generate ester with carboxylic acid.Utilize medicinal design principle of pro-drug etc.; phenolic hydroxyl group in thymol basic chemical structure is carried out to acidylate protection; synthesizing series thymol acyl compounds; after making it enter in body; through the degraded of serum esterase and other enzymes system, slowly release parent drug thymol and other chemical groups or activeconstituents and bring into play anti-microbial effect, in expection reaches desirable body in antibacterial drug effect; also degradable discharges some other pharmacophoric group, brings into play the curative effect of medication effect of other groups.Experiment in vivo and vitro shows that thymol ester derivative has good antibacterial, fungicidal activity, demonstrates good DEVELOPMENT PROSPECT.
Pharmaceutically acceptable salt of the compound (I) of structural formula of the present invention or its:
Wherein pharmacy acceptable salt refers to the salt that above-claimed cpd and metal, amino acid, the basic cpd containing amino, carboxylic acidic cpd, mineral acid or organic acid form.
Wherein pharmacy acceptable salt refers to sodium salt, sylvite, calcium salt, magnesium salts, arginic acid salt, hydrochloride, vitriol, phosphoric acid salt, maleate, fumarate, citrate, mesylate, tosilate or the tartrate of above-claimed cpd.
The purposes of the compounds of this invention refers to above-claimed cpd or its pharmacy acceptable salt for the preparation for the treatment of or prevents bacterial disease or fungi to cause disease medicament.
Wherein bacterium, fungi comprise: streptococcus aureus, Corynebacterium diphtheriae, Pseudomonas aeruginosa, Bacillus proteus, dermatophytosis, actinomyces, mould spores.
Purposes refers to that above-claimed cpd or its pharmacy acceptable salt are for the preparation for the treatment of, alleviate or prevent to cause because of dysentery bacterium, clostridium, bacillus aerogenes capsulatus animal feedstuff additive or the tap water tonic of necrotic enteritis.
The invention also discloses a kind of pharmaceutical composition, wherein contain said structure formula compound and the pharmaceutically acceptable carrier for the treatment of significant quantity, this pharmaceutical composition can also be pharmacy acceptable salt and the pharmaceutically acceptable carrier that contains the structural formula I compound for the treatment of significant quantity.Described pharmaceutical composition can be dosage form conventional on the technology of pharmaceutics such as conventional tablet or capsule, slow releasing tablet or capsule, controlled release tablet or capsule, oral liquid, injection.
Usually, when structural formula I compound of the present invention is used for the treatment of, people is 0.5mg～2000mg/ days with dosage range.Also can be according to the difference of formulation and disease severity, using dosage exceeds this scope.
Structural formula I of the present invention or its pharmacy acceptable salt are for the preparation for the treatment of, alleviate or prevent to cause because of dysentery bacterium, clostridium, bacillus aerogenes capsulatus animal feedstuff additive or the tap water tonic of necrotic enteritis simultaneously.
Said structure formula I or its pharmacy acceptable salt have shown stronger physiologically active in actual pharmacodynamic experiment, have good exploitation and are worth.
Embodiment
Embodiment 1
The preparation of thymol succinyl-ester:
Take thymol (0.52 g, 3.4 mmol), Succinic anhydried (0.92 g, 8.37 mmol) add in the 100 mL there-necked flasks that whipping appts is housed, add pyridine (20 mL), 75 ℃ of reaction 6h, TLC detection reaction degree [V (ethyl acetate): V (sherwood oil)=4:1 is developping agent], question response is cooled to room temperature after substantially finishing.Decompression rotary evaporation is removed pyridine, add 20 mL water, with ether 50 mL × 3 extractions, after combined ether layer water (10mL × 3) washing, with anhydrous sodium sulfate drying, after reclaim under reduced pressure ether, must obtain yellow oily liquid, add 50 mL ether and 20 mL l frozen water, place 30min, separatory is collected organic phase, 20ml extracted with diethyl ether twice for water, merges organic phase, adds anhydrous Na
2sO
4(5g) dried overnight.Reclaim under reduced pressure organic solvent, obtains yellow oily liquid, separates through silicagel column, and eluent is V (sherwood oil): V (ethyl acetate)=3:8, collects product, after decompression and solvent recovery, obtains white solid 0.77g, yield 91.2%.
1H-NMR (CDCl
3, 400 MHz) δ: 7.22 (d,
J=4.6 Hz, 1H, Ar-
H), 7.05 (d,
J=12.0 Hz,1H, Ar-
H),6.82(s,1H,Ar-
H),2.99(m,1H,ArC
H(CH
3)
2),2.93(t,
J=8.0Hz,2H,C
H 2CH
2COOH),1.84(t,2H,H
2C
H 2COOH),2.33(s,3H,Ar-C
H 3),1.21(d,
J=2.8Hz,6H,ArCH(C
H 3)
2);IR(KBr)υ:2970,2924,1764,1704,1506,1440,1420,1403,1357,1281,1260,1137,1087,1057,900,830cm
-1. ESI-MS:
m/z(M + +H) 250.12(calcd:250.98).
Embodiment 2
The preparation of thymol glycyl ester
In 100 mL round-bottomed flasks of hot tail gas absorption unit, add fluorenes methoxy carbonyl acyl glycine (4.9 g, 16.4 mmol) and add methylene dichloride (30 mL), oxalyl chloride (15 mL).Reflux stirring reaction 3h, reduction vaporization is removed residue oxalyl chloride, obtains fluorenes methoxy carbonyl acyl glycyl chloride (F-moc-glycyl chloride) yellow solid.
In 150 mL three-necked flasks, add thymol (0.5 g, 3.3 mmol), pyridine (20.0 mL), DMAP (0.05g), under agitation condition, room temperature drips upper step reaction and generates F-moc-glycyl chloride and toluene (20mL) mixed solution, after dropwising, be heated to 55 ℃, continue reaction 6 h, TLC monitoring reaction ［ developping agent: petroleum ether-ethyl acetate=6:1, V/V ］.After raw material primitive reaction is complete, decompression steams toluene, and ethyl acetate for residue (100 mL) is dissolved, and adds saturated NaHCO
3solution 50 mL stir 20 min, separate ethyl acetate layer, with frozen water (30 mL × 3) washing, anhydrous sodium sulphate for ethyl acetate layer (5g) is dry, reclaim under reduced pressure ethyl acetate, silica gel G chromatography column separation and purification for residue, sherwood oil: ethyl acetate (V:V
=6:1) be elutriant, collect product, after decompression and solvent recovery, obtain white solid (F-moc-glycyl thyme phenolic ester) 0.87g, yield 61.2%.
1h-NMR (CDCl
3, 400MHz) and δ: 7.87 (d,
j=7.6Hz, 2H, Ar-
h), 7.64 (d,
j=7.6Hz, 2H, Ar-
h), 7.42 (t,
j=14.8Hz, 2H, Ar-
h), 7.33 (t, J=14.8Hz, 2H, Ar-
h), 7.23 (d,
j=7.6Hz, 1H, Ar-
h), 7.08 (d, J=7.6Hz, 1H, Ar-
h), 6.86 (s, 1H, Ar-
h), 5.37 (s, 1H, N-
h), 4.47 (d,
j=7.2Hz, 2H, Ar-C
h 2oCO), 4.32 (d,
j=7.6Hz, 2H, Ar-OCOC
h 2nH), 4.27 (d, J=7.8Hz, 1H, Ar-C
h-Ar), 2.97 (m, 1H, ArC
h(CH
3)
2), 2.34 (s, 3H, Ar-C
h 3), 1.21 (d,
j=6.8Hz, 6H, ArCH (C
h 3)
2); IR (KBr) υ: 3349.15,3037.79,2962.25,2867.74,1955.30,1909.68,1776.18,1700.93,1619.35,1541.42,1505.69,1450.49,1273.25,1167.32,1084.98,1052.66,988.94,947.47,905.99,758.40,735.47cm
-1. ESI-MS:
m/z (M + + H) 431.20 (calcd:430.20).
In 50 mL round-bottomed flasks, add F-moc-glycyl thyme phenolic ester (0.5g, 1.17 mmol), DMF (10 mL) and piperidines (2 mL).40 ℃ of conditions continue stirring reaction 0.5 hour, TLC monitoring reaction ［ developping agent: petroleum ether-ethyl acetate=20:1, V/V ］.After raw material primitive reaction is complete, decompression steams organic solvent, ethyl acetate for residue (60 mL) is dissolved, wash with frozen water (30 mL × 3), anhydrous sodium sulphate for ethyl acetate layer (5g) is dry, reclaim under reduced pressure ethyl acetate, silica gel G chromatography column separation and purification for residue, sherwood oil: ethyl acetate (V:V
=20:1) be elutriant, collect product, after decompression and solvent recovery, obtain yellow solid (glycyl thyme phenolic ester) 0.16g, yield 65.1%.
1H-NMR(CDCl
3,400MHz)δ:4.19（2H,N-
H 2 ）7.26-7.28(3H,Ar-
H),3.14(1H,ArC
H(CH
3)
2),1.91(3H,Ar-C
H 3),1.74(2H,C
H 2NH
2)1.66(6H,ArCH(C
H 3)
2);IR(KBr)υ:3442,3053,3001,2914,2889,2848,1716,1614,1470,1448,1286,1204,999,902,846,756,728 cm
-1. ESI-MS:
m/z 207.16.
Embodiment 3
Embodiment 1 and embodiment 2 compounds show good anti-microbial activity in vitro in antibacterial experiment:
bacterial classification:streptococcus aureus 1 strain (type strain ATCC6538), intestinal bacteria 1 strain (reference culture ATCC8099), Corynebacterium diphtheriae 1 strain, paratyphosum Bacterium 1 strain, the above 5 kinds of bacterial strains of dysentery bacterium 1 strain.
substratum:nutrient agar medium (NA) lot number: 20101216; Nutrient broth (NB) lot number: 20100806; Production code member: HB1019, the rich biological company limited in sea, business garden, manufacturer Qingdao.
for the preparation of examination bacterium liquid: 5 kinds of bacterial strains are inoculated respectively to nutrient agar.Cultivate 24 hours choice criteria bacterium colony culture transferrings in liquid nutritional broth culture for 37 ℃, cultivate after 6 hours for 37 ℃, Maxwell is 10 than turbid adjustment bacterial concentration
8for subsequent use after cFu/ml.The dissolving of tested medicine: 2 solid chemical compound monomers dissolve respectively, taking 1g medicine+1ml methyl alcohol (total concn g/ml) is mother liquor, gets mother liquor and be configured to the substratum of 0.78mg/ml, 1.56mg/ml, 3.125mg/ml, 6.25mg/ml, 12.5mg/ml, 25mg/ml, 50mg/ml, 100mg/ml drug level.The preparation of pastille substratum: get 10 of aseptic small test tubes and be placed on test-tube stand, put into the first pipe drawing respectively medicine (stoste) 1ml with aseptic technique, mix rear absorption 1ml and put into the 2nd pipe, mix rear absorption 1ml and put into the 3rd pipe, so do by doubly measuring and be diluted to the 10th pipe, after mixing, draw respectively in every different weaker concn medicine 1ml add without after in medicine plate, pouring into 9ml nutrient agar finally makes the drug level in substratum be respectively: 100mg, 50mg, 12.5mg, 6.25mg, 3.125mg, 1.56mg and 0.78mg/ml pour plate solidify rear for subsequent use, separately establish a not normal control substratum for pastille, the contrast of background methyl alcohol is carried out with aforesaid method is parallel.Inoculate for examination bacterial classification: will adjust bacterial concentration is 10
8cFu/ml, after diluting 1000 times, (bacteria containing amount is about 10 to get respectively confession examination bacterium liquid 1 standard ring with standard inoculation ring
4cFu/ml), be inoculated in the culture medium flat plate surface of different pharmaceutical concentration.Multiple spot inoculation different bacterium forms the bacterial plaque that diameter is 5-8mm, 37 ℃ of incubators are cultivated after 24h, observations, on the flat board of 2 the different concns gradient medicines in front and back, the concentration that makes amount of bacteria reduce suddenly 80-90 ‰ is MIC, completely without bacterial growth, and in liquid nutritional meat soup (NB), cultivate at every turn, confirm to be MBC without the concentration of bacterial growth.Result is as follows:
Embodiment 4: animal feedstuff additive embodiment
Toxicity test.Material: tested medicine: thymol succinyl-ester, thymol glycyl ester, self-control, purity 98.5%, uses front thin up.6 of animal health rabbit (New Zealand's kind).Provided by Medical University Of Anhui experimental center.
Experimental technique: get 6 of healthy rabbits, be divided at random 3 groups, use respectively containing the tap water of thymol succinyl-ester, thymol glycyl ester and feed 30 days.
Results and discussions: the acute toxicity tests was fed after 30 days, and rabbit does not all occur poisoning or dead.Cut open the main organs such as the inspection visual inspection heart, liver,spleen,kidney and be showed no unusual phenomenon.
Animal feeding embodiment
Measuring mixture of the present invention reduces the appearance of dysentery bacterium, clostridium, particularly clostridium perfringens and increases the usefulness of growth of animal rate.Poult is tested to the Commercial Food that contains following essentially consist to its nursing:
| Nursing program | Feed in advance | Growth feed | Later stage feed |
| Crude protein, % | 23.10 | 21.40 | 21.00 |
| Crude fat, % | 9.00 | 10.40 | 10.40 |
| Crude fiber, % | 3.00 | 3.20 | 3.40 |
| Crude ash content, % | 5.40 | 5.10 | 4.80 |
| Contrast, kg | 13.00 | 13.40 | 13.40 |
Provide the wheat of sufficient quantity, soyflour, pea, rapeseed meal, bone meal and oil are mixed, prepare these food.In the food of using to control group, also add Zinc-bacitracin with the ratio of 22mg/kg feed, it is a kind of traditional growth stimulant, and to the mixture that adds 50mg/kg feed in the food of using to experimental group, said mixture is made up of 3mg cresols, 38 mg thymol succinyl-esters (experimental group 1), 38 mg thymol glycyl esters (experimental group 2), 3.5 mg oxymethoxyallylbenzenes, 0.5mg capsicine and 10mg tannin, and the main ingredient in this mixture is thymol succinyl-ester, thymol glycyl ester.Fowl is divided into two groups, and feeds 49 days by two kinds of feed compositions.Obtain following result:
| Experimental group 1 | Experimental group 2 | Control group | |
| Number of animals | 1200 | 1275 | 1400 |
| Duck, starts weight in average, g | 35.1 | 35.2 | 35.3 |
| 49 days weight in averages, g | 2060 | 2070 | 2055 |
| Every day increment, g | 51.76 | 51.77 | 51.78 |
| Feed conversion rate | 1.71 | 1.72 | 1.74 |
Result obviously illustrates the advantage that the present invention brings.
Claims (3)
1. the purposes of thymol ester derivative: it is characterized in that: sodium salt, sylvite, calcium salt, magnesium salts, arginic acid salt, vitriol, phosphoric acid salt, maleate, fumarate, citrate, mesylate, tosilate or the tartrate of the compound of structural formula I and/or formula II causes the purposes of disease medicament for the preparation for the treatment of or pre-bacteriological protection
2. the purposes of thymol ester derivative according to claim 1, is characterized in that the bacterium that claim 1 is chatted is streptococcus aureus, Corynebacterium diphtheriae, Pseudomonas aeruginosa or Bacillus proteus.
3. the purposes of thymol ester derivative: it is characterized in that: the sodium salt of the compound of structural formula I and/or formula II, sylvite, calcium salt, magnesium salts, arginic acid salt, vitriol, phosphoric acid salt, maleate, fumarate, citrate, mesylate, tosilate or tartrate are for the preparation for the treatment of, alleviate or prevent because of dysentery bacterium, clostridium, bacillus aerogenes capsulatus causes the purposes of animal feedstuff additive or the tap water tonic of necrotic enteritis
.
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