CN102731301A - 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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- CN102731301A CN102731301A CN2012102245945A CN201210224594A CN102731301A CN 102731301 A CN102731301 A CN 102731301A CN 2012102245945 A CN2012102245945 A CN 2012102245945A CN 201210224594 A CN201210224594 A CN 201210224594A CN 102731301 A CN102731301 A CN 102731301A
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- compound
- acceptable salt
- pharmacy acceptable
- salt
- thymol
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- MGSRCZKZVOBKFT-UHFFFAOYSA-N thymol Natural products CC(C)C1=CC=C(C)C=C1O MGSRCZKZVOBKFT-UHFFFAOYSA-N 0.000 title abstract description 47
- 239000005844 Thymol Substances 0.000 title abstract description 31
- 229960000790 thymol Drugs 0.000 title abstract description 31
- -1 Thymol ester Chemical class 0.000 title abstract description 19
- 238000002360 preparation method Methods 0.000 title abstract description 9
- 241000894006 Bacteria Species 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 18
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
- 241000233866 Fungi Species 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 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
- 150000003839 salts Chemical class 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 16
- 230000001580 bacterial effect Effects 0.000 claims description 12
- 241001465754 Metazoa Species 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
- 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
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 241000588769 Proteus <enterobacteria> Species 0.000 claims description 3
- 208000002474 Tinea Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 230000001256 tonic effect Effects 0.000 claims description 3
- 241000186046 Actinomyces Species 0.000 claims description 2
- BMFMQGXDDJALKQ-BYPYZUCNSA-N Argininic acid Chemical class NC(N)=NCCC[C@H](O)C(O)=O BMFMQGXDDJALKQ-BYPYZUCNSA-N 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- 206010012504 Dermatophytosis Diseases 0.000 claims description 2
- 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 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 241001460074 Microsporum distortum Species 0.000 claims description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 150000001413 amino acids Chemical class 0.000 claims description 2
- 159000000007 calcium salts Chemical class 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 159000000003 magnesium salts Chemical class 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
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- 150000007524 organic acids Chemical group 0.000 claims description 2
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- 239000001103 potassium chloride Substances 0.000 claims description 2
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 159000000000 sodium salts Chemical group 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
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- 235000020188 drinking water Nutrition 0.000 abstract 1
- 230000000116 mitigating effect Effects 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 8
- 230000003115 biocidal effect Effects 0.000 description 7
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- 239000000203 mixture Substances 0.000 description 7
- 235000013824 polyphenols Nutrition 0.000 description 7
- 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
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000006837 decompression Effects 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 5
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- 0 CC(C*)c(ccc(*)c1)c1OC(*)=C Chemical compound CC(C*)c(ccc(*)c1)c1OC(*)=C 0.000 description 4
- 235000007303 Thymus vulgaris Nutrition 0.000 description 4
- 230000000845 anti-microbial effect Effects 0.000 description 4
- 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
- 239000001585 thymus vulgaris Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 241000246358 Thymus Species 0.000 description 3
- 230000003385 bacteriostatic effect Effects 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
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
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- 108090000371 Esterases Proteins 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 125000003636 chemical group Chemical group 0.000 description 2
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- 238000013461 design Methods 0.000 description 2
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 150000002220 fluorenes Chemical class 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
- 241000272525 Anas platyrhynchos Species 0.000 description 1
- 108010001478 Bacitracin Proteins 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
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- HUPDHUPLXXOEHG-UUYOSTAYSA-N CC(/C=N\C(OCC1c(cccc2)c2-c2c1cccc2)=O)=C1CC1 Chemical compound CC(/C=N\C(OCC1c(cccc2)c2-c2c1cccc2)=O)=C1CC1 HUPDHUPLXXOEHG-UUYOSTAYSA-N 0.000 description 1
- 235000019750 Crude protein Nutrition 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 241000207923 Lamiaceae Species 0.000 description 1
- 208000005141 Otitis Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 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 1
- 241000228143 Penicillium Species 0.000 description 1
- 235000019779 Rapeseed Meal Nutrition 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 240000006001 Thymus serpyllum Species 0.000 description 1
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- 235000013905 glycine and its sodium salt Nutrition 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
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- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
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- 150000003053 piperidines Chemical class 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
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- 150000007660 quinolones Chemical class 0.000 description 1
- 150000004053 quinones Chemical class 0.000 description 1
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- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
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- 125000003639 thymyl group Chemical group C1(=CC(C)=CC=C1C(C)C)* 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
- 150000003952 β-lactams Chemical class 0.000 description 1
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
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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 the pharmaceutical chemistry field, be specifically related to one type of thymol ester compound, can be used for treatment or the prevention of bacterial disease or the fungi that cause 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 penicillium mould, and human multiple disease because of infectation of bacteria all can have through microbiotic in for some time treats fully.Since 20th century along with science and technology development; The research of antibacterials such as sulfamido, PCs, aminoglycoside, paraxin, tetracyclines, Macrolide obtains development at full speed; Particularly antimicrobial drugs such as semisynthetic penicillin, cynnematin, novel ss-lactam, quinolones come out; Make and treat various infectation of bacteria effectively and become possibility; For ensureing human health, prolongs life has been made outstanding contribution, and basic science such as biology, chemistry progress is also had important feedback influence.Yet because human more and more for antibiotic abuse drug tolerant bacteria, clinical picture shows: the antibacterials misapplication, and not only can cause huge waste, and can induce the generation of bacterial drug resistance and increase, and the generation of many medicine property illness.
Hydroquinone compound (Quinonoid) is the one type of novel cpd of in the active ingredient of Chinese herbs research process, finding at present that is different from present common antimicrobial agents mechanism of action.It shows many-sided physiologically active, as anti-oxidant, remove radical, inhibition or kill bacteria growth and effect such as antiviral, at aspects such as medicine, agricultural chemicals, cosmetic material and foodstuff additive purposes is widely arranged
[7,8,9]Therefore, the quinones composition also is much accounted of gradually.
Thymol (Thymol) be at first from Labiatae Chinese herbal medicine Thymus vulgaris (Thymus serpyllum L.) extraction separation to antibiotic effective ingredient, be a kind of representational hydroquinone compound.Modern pharmacology experiment proof
[, the thymol antibacterial effect is stronger, has a broad antifungal spectrum; Toxicity is low, streptococcus aureus, Corynebacterium diphtheriae, Pseudomonas aeruginosa, Bacillus proteus etc. is all had suppress or killing action, and its germicidal action is stronger than phenol; And toxicity is low; The oral cavity mucosa is had sterilization, fungicidal action, there is anticorrosion, local anesthetic action in the carious tooth chamber, the disinfection, tinea, actinomycosis and the otitis that are used for oral cavity, throat are also all effective in cure.External results of pharmacodynamic test also shows; Thymol all has in various degree sterilization and bacteriostatic action to the enteritis common bacteria; Wherein the bacteriostatic action to streptococcus aureus is the strongest, secondly is that Corynebacterium diphtheriae, various paratyphosum Bacterium and pathogenic colon bacillus, enterotoxigenic E and enteroinvasive E, Pseudomonas aeruginosa all have certain bacteriostatic action.In livestock industry, thymol is promoted the use of as the anti-microbial activity composition in the animal feedstuff additive at present; In the dietetic food health, thymol also can be used for sterilization, seasoning, control honeybee mite, kills mould spores.
But active ingredient of Chinese herbs thymol more or less certain defective of existence aspect pharmacodynamics and pharmacokinetics mainly contains that drug effect is not high, too greatly or in vivo accretion rate is too fast and cross and wait slowly for toxicity.Utilize medicinal design principle of pro-drug etc.; Imagination is carried out the acidylate protection with the phenolic hydroxyl group in the thymol basic chemical structure; Synthesizing series thymol acyl compounds, ether derivants, make it get in body after, through of the degraded of serum esterase with other enzymes systems; Slowly release parent drug thymol and other chemical groups or activeconstituents and bring into play anti-microbial effect; In expection reaches the ideal body in the antibiotic drug effect, go back degradable and discharge some other pharmacophoric group, bring into play the curative effect of medication effect of other groups.Experiment in vivo and vitro shows that the thymol ester derivative has good antibiotic, fungicidal activity, demonstrates the excellent development prospect.
Summary of the invention
Reactive group phenolic hydroxyl group in the thymol molecule is that it carries out the target spot of at first considering that chemical structure is modified transformation, and phenolic hydroxyl group can generate ester with carboxylic acid.Utilize medicinal design principle of pro-drug etc., the phenolic hydroxyl group in the thymol basic chemical structure is carried out acidylate protection, synthesizing series thymol acyl compounds; After making it get in the body; Through of the degraded of serum esterase, slowly release parent drug thymol and other chemical groups or activeconstituents and bring into play anti-microbial effect, in expection reaches the ideal body in the antibiotic drug effect with other enzymes system; 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 the thymol ester derivative has good antibiotic, fungicidal activity, demonstrates the excellent development prospect.
The compound of structural formula of the present invention (I) or its be acceptable salt pharmaceutically:
Wherein pharmacy acceptable salt is meant above-claimed cpd and metal, amino acid, contains the salt that amino basic cpd, carboxylic acidic cpd, mineral acid or organic acid form.
Wherein pharmacy acceptable salt is meant sodium salt, sylvite, calcium salt, magnesium salts, arginic acid salt, hydrochloride, vitriol, phosphoric acid salt, PHENRAMINE MALEATE, fumarate, citrate, mesylate, tosilate or the tartrate of above-claimed cpd.
The purposes of The compounds of this invention refers to that above-claimed cpd or its pharmacy acceptable salt are used to prepare disease or the fungi that treatment or prevention of bacterial cause and 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 used to prepare treatment, alleviate or prevent to cause because of dysentery bacterium, clostridium spp, bacillus aerogenes capsulatus the animal feedstuff additive or the tap water tonic of necrotic enteritis.
The invention also discloses a kind of pharmaceutical composition; Wherein contain the said structure formula compound and the pharmaceutically acceptable carrier of treating significant quantity, this pharmaceutical composition can also be pharmacy acceptable salt and the pharmaceutically acceptable carrier that contains the structural formula I compound of treating significant quantity.Said pharmaceutical composition can be a 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 was used to treat, the human dosage range was 0.5mg～2000mg/ days.Also can be according to the difference and the disease severity of formulation, using dosage exceeds this scope.
Structural formula I of the present invention or its pharmacy acceptable salt are used to prepare treatment, alleviate or prevent to cause because of dysentery bacterium, clostridium spp, bacillus aerogenes capsulatus the 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 excellent development and be worth.
Embodiment
Embodiment 1
The preparation of thymol succinyl-ester:
Take by weighing thymol (0.52 g, 3.4 mmol), Succinic anhydried (0.92 g; 8.37 mmol) adding is equipped with in the 100 mL there-necked flasks of whipping appts; Add pyridine (20 mL), 75 ℃ of reaction 6h, TLC detection reaction degree [V (ETHYLE ACETATE): V (sherwood oil)=4:1 is a developping agent]; Question response is cooled to room temperature after finishing basically.The decompression rotary evaporation is removed pyridine, adds 20 mL water, with ether 50 mL * 3 extractions; After combined ether layer water (10mL * 3) washing, use anhydrous sodium sulfate drying, must get yellow oily liquid behind the reclaim under reduced pressure ether; Add 50 mL ether and 20 mL l frozen water, place 30min, separatory is collected organic phase; Water merges organic phase with 20ml extracted with diethyl ether twice, adds anhydrous Na
2SO
4(5g) dried overnight.The reclaim under reduced pressure organic solvent gets yellow oily liquid, separates through silicagel column, and eluent is V (sherwood oil): V (ETHYLE ACETATE)=3:8, collects product, behind the decompression and solvent recovery, gets 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 magnetic tape trailer aspiration receiving apparatus, add fluorenes methoxy carbonyl acyl glycocoll (4.9 g, 16.4 mmol) and add methylene dichloride (30 mL), oxalyl chloride (15 mL).Reflux stirring reaction 3h, reduction vaporization is removed the residue oxalyl chloride, gets 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), room temperature drips and goes up step reaction generation F-moc-glycyl chloride and toluene (20mL) mixed solution under the agitation condition, after dropwising; Be heated to 55 ℃; Continue reaction 6 h, TLC monitoring reaction ［ developping agent: petroleum ether-ethyl acetate=6:1, V/V ］.After treating that the raw material primitive reaction fully, decompression steams toluene, and residue adds saturated NaHCO with ETHYLE ACETATE (100 mL) dissolving
3Solution 50 mL stir 20 min, tell ethyl acetate layer, and with frozen water (30 mL * 3) washing, ethyl acetate layer is with SODIUM SULPHATE ANHYDROUS 99PCT (5g) drying, and reclaim under reduced pressure ETHYLE ACETATE, residue is with the separation and purification of silica gel G chromatography column, sherwood oil: ETHYLE ACETATE (V:V
=6:1) be elutriant, collect product, get white solid (F-moc-glycyl thyme phenolic ester) 0.87g, yield 61.2%. behind the decompression and solvent recovery
1H-NMR (CDCl
3, 400MHz) 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 continued stirring reaction 0.5 hour, TLC monitoring reaction ［ developping agent: petroleum ether-ethyl acetate=20:1, V/V ］.After treating that the raw material primitive reaction fully; Decompression steams organic solvent, and residue washs with frozen water (30 mL * 3) with ETHYLE ACETATE (60 mL) dissolving; Ethyl acetate layer is with SODIUM SULPHATE ANHYDROUS 99PCT (5g) drying; Reclaim under reduced pressure ETHYLE ACETATE, residue is with the separation and purification of silica gel G chromatography column, sherwood oil: ETHYLE ACETATE (V:V
=20:1) be elutriant, collect product, get yellow solid (glycyl thyme phenolic ester) 0.16g, yield 65.1% behind the decompression and solvent recovery.
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 shows good antibacterial activity with embodiment 2 compounds in the in-vitro 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; PIN: HB1019, the rich biological ltd in sea, business garden, manufacturer Qingdao.
Supply the preparation of examination bacterium liquid: 5 kinds of bacterial strains are inoculated nutrient agar respectively.Cultivate 24 hours choice criteria bacterium colony culture transferrings in the liquid nutritional broth culture for 37 ℃, cultivate after 6 hours for 37 ℃, the Maxwell is 10 than turbid adjustment bacterial concentration
8Subsequent use behind the cFu/ml.Receive the dissolving of reagent thing: 2 solid chemical compound monomers dissolve respectively; Taking by weighing 1g medicine+1ml methyl alcohol (total concn g/ml) is mother liquor, gets the substratum that mother liquor is configured to 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 place on the test-tube stand, put into first pipe drawing medicine (stoste) 1ml respectively with aseptic technique, draw 1ml behind the mixing and put into the 2nd pipe; Draw 1ml behind the mixing and put into the 3rd pipe, so do by doubly measuring and be diluted to the 10th pipe, behind the mixing; Draw respectively in every different weaker concn medicine 1ml add in the no medicine plate after, pour into the 9ml nutrient agar drug level in the substratum be respectively: 100mg, 50mg; 12.5mg; 6.25mg it is subsequent use that 3.125mg, 1.56mg and 0.78mg/ml pour plate solidify the back; Other establish one not the normal control of pastille use substratum, background methyl alcohol contrast is carried out with above-mentioned method is parallel.Supply the examination bacterial classification inoculation: will adjust bacterial concentration is 10
8CFu/ml, dilute 1000 times after, get respectively with the standard inoculation ring and to supply examination bacterium liquid 1 standard ring (bacteria containing amount is about 10
4CFu/ml), be inoculated in the culture medium flat plate surface of different pharmaceutical concentration.It is the bacterial plaque of 5-8mm that multiple spot inoculation different bacterium forms diameter; After 37 ℃ of incubators were cultivated 24h, observations was on the flat board of front and back 2 different concns gradients medicine; The concentration that makes amount of bacteria reduce 80-90 ‰ suddenly is MIC; Do not have bacterial growth fully, and in liquid nutritional meat soup (NB), cultivate at every turn, confirm that the concentration of no bacterial growth is MBC.The result is following:
Embodiment 4: the animal feedstuff additive embodiment
Toxicity test.Material: receive the reagent article: thymol succinyl-ester, thymol glycyl ester, self-control, purity 98.5% is used preceding thin up.6 of animal health rabbit (nz's kind).Provide by the Medical University Of Anhui experimental center.
Experimental technique: get 6 of healthy rabbits, be divided into 3 groups at random, use the tap water that contains thymol succinyl-ester, thymol glycyl ester to feed respectively 30 days.
Result and discussion: The acute toxicity tests was fed after 30 days, and rabbit is not all taken place to poison or be dead.Cut open the equal no abnormality seen phenomenons of main organs such as the inspection visual inspection heart, liver,spleen,kidney.
The animal feeding embodiment
Measure mixture of the present invention and reduce appearance of dysentery bacterium, clostridium, particularly clostridium perfringens and the usefulness that increases the growth of animal rate.Poult is made an experiment, contains the commercially available food of following essentially consist to its nursing:
| The nursing program | Feed in advance | The growth feed | The 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 wheat, soyflour, pea, rapeseed meal, bone meal and oil to mix, prepare these food sufficient quantity.In the food of using to control group; Also the ratio with the 22mg/kg feed adds Zinc-bacitracin; It is a kind of traditional growth stimulant; And in the food of using to experimental group, add the mixture of 50mg/kg feed; 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 fed 49 days by two kinds of feed compsns.Obtain following result:
| ? | Experimental group 1 | Experimental group 2 | Control group |
| Number of animals | 1200 | 1275 | 1400 |
| Duck, beginning weight in average, g | 35.1 | 35.2 | 35.3 |
| The equal weight of 49 balances, g | 2060 | 2070 | 2055 |
| Every day increment, g | 51.76 | 51.77 | 51.78 |
| Feed conversion rate | 1.71 | 1.72 | 1.74 |
The result obviously explains the advantage that the present invention brings.
Claims (7)
1. the compound of following structural or its pharmacy acceptable salt:
2. the compound of claim 1 or its pharmacy acceptable salt, wherein pharmacy acceptable salt be claim 1 compound and metal, amino acid, contain the salt that amino basic cpd, carboxylic acidic cpd, mineral acid or organic acid form.
3. the compound of claim 2 or its pharmacy acceptable salt, wherein pharmacy acceptable salt is sodium salt, sylvite, calcium salt, magnesium salts, arginic acid salt, hydrochloride, vitriol, phosphoric acid salt, PHENRAMINE MALEATE, fumarate, citrate, mesylate, tosilate or the tartrate of the compound of claim 1.
4. pharmaceutical composition wherein contains compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of claim 1.
5. the compound of claim 1 or its pharmacy acceptable salt are used to prepare the purposes that disease that treatment or prevention of bacterial cause or fungi cause disease medicament.
6. the compounds for treating bacterium of claim 1, the disease of fungi infestation, wherein bacterium, fungi comprise: streptococcus aureus, Corynebacterium diphtheriae, Pseudomonas aeruginosa, Bacillus proteus, dermatophytosis, actinomyces, mould spores.
7. the compound of claim 1 or its pharmacy acceptable salt are used to prepare treatment, alleviate or prevent to cause because of dysentery bacterium, clostridium spp, bacillus aerogenes capsulatus the animal feedstuff additive or the tap water tonic of necrotic enteritis.
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Cited By (6)
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| CN109180600A (en) * | 2018-09-21 | 2019-01-11 | 五邑大学 | A kind of thymol analog and its application |
| CN110063908A (en) * | 2019-05-10 | 2019-07-30 | 武汉轻工大学 | Nano emulsion type mouthwash and its preparation method and application method |
| CN110475473A (en) * | 2016-08-23 | 2019-11-19 | 奇特利奇公司 | Containing monoterpene/Phenylpropanoid Glycosides compound and preparation method thereof and as the purposes of insecticide |
| CN112679355A (en) * | 2020-12-23 | 2021-04-20 | 华南农业大学 | Application of 7-aldehyde-9-isobutyryloxy-8-hydroxythymol in preparation of antibacterial agent or antibacterial drug |
| CN115124633A (en) * | 2022-06-24 | 2022-09-30 | 广东粤威制药有限公司 | Preparation method and application of thymol composition |
| US11696581B2 (en) * | 2016-08-23 | 2023-07-11 | Kittrich Corporation | Monoterpenoid/phenylpropanoid-containing compounds and methods of their making and use as seed treatments |
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| CN110475473A (en) * | 2016-08-23 | 2019-11-19 | 奇特利奇公司 | Containing monoterpene/Phenylpropanoid Glycosides compound and preparation method thereof and as the purposes of insecticide |
| US11696581B2 (en) * | 2016-08-23 | 2023-07-11 | Kittrich Corporation | Monoterpenoid/phenylpropanoid-containing compounds and methods of their making and use as seed treatments |
| CN109180600A (en) * | 2018-09-21 | 2019-01-11 | 五邑大学 | A kind of thymol analog and its application |
| CN110063908A (en) * | 2019-05-10 | 2019-07-30 | 武汉轻工大学 | Nano emulsion type mouthwash and its preparation method and application method |
| CN110063908B (en) * | 2019-05-10 | 2022-03-15 | 武汉轻工大学 | Nano emulsion type mouth wash and preparation method and application method thereof |
| CN112679355A (en) * | 2020-12-23 | 2021-04-20 | 华南农业大学 | Application of 7-aldehyde-9-isobutyryloxy-8-hydroxythymol in preparation of antibacterial agent or antibacterial drug |
| CN112679355B (en) * | 2020-12-23 | 2021-10-12 | 华南农业大学 | Application of 7-aldehyde-9-isobutyryloxy-8-hydroxythymol in preparation of antibacterial agent or antibacterial drug |
| CN115124633A (en) * | 2022-06-24 | 2022-09-30 | 广东粤威制药有限公司 | Preparation method and application of thymol composition |
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Effective date of registration: 20160808 Address after: 130114 No. 9685, Qingnian Road, Jilin, Changchun Patentee after: Jilin Yatai Mingxing Pharmaceutical Co., Ltd. Address before: 230001, room 15, building 648, 101 North Fuyang Road, Luyang District, Anhui, Hefei Patentee before: Hefei Jiquan Pharmaceutical Technology Co.,Ltd. |
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Address after: 130114 No. 9685 Youth Road, Changchun City, Jilin Province Patentee after: Jilin Yatai Yongantang Pharmaceutical Co., Ltd. Address before: 130114 No. 9685 Youth Road, Changchun City, Jilin Province Patentee before: Jilin Yatai Mingxing Pharmaceutical Co., Ltd. |
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Address after: 130102 No. 7988, beiyuanda street, North District, high tech Development Zone, Changchun City, Jilin Province Patentee after: Jilin Yatai Yongantang Pharmaceutical Co.,Ltd. Address before: 130114 No. 9685 Youth Road, Changchun City, Jilin Province Patentee before: Jilin Yatai Yongantang Pharmaceutical Co.,Ltd. |
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