CN100343223C - Ester compound of thymol and/or carvacrol, preparing method and its medicinal active composition - Google Patents
Ester compound of thymol and/or carvacrol, preparing method and its medicinal active composition Download PDFInfo
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- CN100343223C CN100343223C CNB2005100515920A CN200510051592A CN100343223C CN 100343223 C CN100343223 C CN 100343223C CN B2005100515920 A CNB2005100515920 A CN B2005100515920A CN 200510051592 A CN200510051592 A CN 200510051592A CN 100343223 C CN100343223 C CN 100343223C
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Abstract
The present invention relates to an ester compound of thymol and/or carvacrol in a general formula (I). In the general formula (I), R<1> is methyl, R<2> is isopropyl, and R<1> is in a contraposition relation with R<2>. -O-(X)-O-is in an adjacent position with R<1> or R<2>. X=-CO-CS-, -CO-(CH 2)n-CO-, wherein n=0, 1, 2. The composition with the medicine activity of the ester compound is used for treating the infection induced by parasites, bacteria or anti-medicine bacteria of fowl, and is a new generation of medicine for fowl.
Description
Technical field
The present invention relates to ester compound and medical compounds thereof, particularly relate to ester compound, preparation method and the pharmaceutical activity composition thereof of thymol and/or isothymol.
Background technology
In recent years because the mankind and livestock and poultry are widely-used or abuse of antibiotics, Resistant strain increases day by day, the speed that Resistant strain occurs surpasses the research new drug and is applied to clinical speed, the mankind are caused serious threat, WHO gives a warning: " mankind some day, common infectation of bacteria and yield to no remedy control ".This objective fact occurs, and cause countries in the world the world of medicine extensive concern, thereby people studies new medicine approach and turn to natural drug again.In European and American countries, carried out broad research, the volatile oil of finding plant has restraining effect to 25 kinds of common bacterial strains, wherein volatile oil " wild marjoram oil Origano oil " effective ingredient thymol and the isothymol to plant wild marjoram (Origanum VulgareL) receives publicity especially, studies show that some bacterium is had anti-microbial activity.
Wild marjoram oil also receives animal doctor's circle concern simultaneously, the pathogenic bacteria of animal and human's body and parasite, and extremely similar or similar fully, it is also effective to bacterium and the parasite of animal.Someone claims that wild marjoram oil is a bouvardin, and is effective equally with modern microbiotic penicillin, Streptomycin sulphate and vancomycin.
Yet the problem that exists in natural wild marjoram oil (effective ingredient isothymol/thymol) use: (a). because natural wild marjoram oil, thymol and isothymol all belong to volatile oil, livestock and poultry are used and all make pre-mixture, may lose because of volatilization, cause underdosage, affect the treatment.(b). natural wild marjoram oil, thymol and isothymol all are phenolic compounds, and easy oxidation discoloration generates invalid quinones, can influence drug quality and curative effect.(c). when isothymol/thymol is oral gi tract there is the calcination pain sensation.(d). natural wild marjoram oil effective constituent isothymol/thymol all is a phenolic compound, absorbs slowly, drains soon, influences intravital pharmacokinetics process.
Summary of the invention
The objective of the invention is to overcome the problem that above-mentioned prior art exists, be engaged in drug development and clinical trial for a long time through the contriver, the treatment of diseases that the special concern Resistant strain is brought out, the exploitation provide have breakthrough progressive drug effect height, cost is low, the new thymol that purposes is wide and/or the ester compound of isothymol.
Another object of the present invention provides the preparation method of the ester compound of such thymol and/or isothymol.
The pharmaceutical activity composition that also has another purpose that this ester compound is provided of the present invention.
The ester compound of thymol provided by the invention and/or isothymol has following general formula
R wherein
1Be methyl, R
2Be sec.-propyl, R
1And R
2
Contraposition each other;-O-(X)-O-can with R
1
Be ortho position or and R
2Be the ortho position, X=-CO-,
-CS-,-CO-(CH
2) n-CO-, n=0 wherein, 1,2.
The ester compound of thymol provided by the invention and/or isothymol is
Two-hundred li esters of carbonic acid
Carbonic acid two-Sheep's-parsley ester
Two-hundred li esters of thiocarbonic acid SOH
Thiocarbonic acid SOH two-Sheep's-parsley ester
Two-hundred li esters of oxalic acid
Oxalic acid two-Sheep's-parsley ester
Carbonic acid Thymus vulgaris celery ester, thiocarbonic acid SOH Thymus vulgaris celery ester, oxalic acid Thymus vulgaris celery ester, two-hundred li esters of propanedioic acid, propanedioic acid two-Sheep's-parsley ester, two-hundred li esters of Succinic Acid, Succinic Acid two-Sheep's-parsley ester etc.
The present invention directly sets about from the structure of wild marjoram oil effective constituent-thymol and isothymol; at first consider synthetic precursor compound protection hydroxyl; this class precursor compound is a prodrug, and under the catalysis of enzyme, metabolism produces compounds effective competence exertion drug effect in vivo.Esterase is the most ubiquitous a kind of enzyme in the humans and animals body.So the ester compound of design and synthetic thymol and isothymol, it is as general formula (I) compound, and it is a class higher-boiling compound or a solid chemical compound, and is not volatile; Phenolic hydroxyl group is protected, and to daylight, air-stable, is difficult for deterioration by oxidation; Improve precursor compound pharmaco-kinetic processes in vivo, thereby can improve drug effect.In clinical body, studies confirm that, particularly Resistant strain is had better curative effect for better antimicrobial compounds, and the effect of anticoccidial is better than diclazuril, suitable with toltrazuril, become the antibiotic and antiparasitic new veterinary drug of a new generation, have the advantages that a medicine is used more.
The manufacture method of the ester compound of thymol provided by the invention and/or isothymol comprises the manufacture method of (sulfo-) carbonic ether or diester.
(sulfo-) carbonic ether manufacture method:
1. thymol and/or isothymol are dissolved in the organic solvent A, after the dissolving under agitation, lead to or add phosgene or triphosgene, or thio phosgene, 2. at 0～-10 ℃, splash into dehydrogenation hydracid agent mixed solution (agent of dehydrogenation hydracid is dissolved in the organic solvent A), after adding, again in stirring at room 2～4 o'clock, with thin-layer chromatography wherein thymol and/or isothymol: phosgene or thio phosgene: the mol ratio of dehydrogenation hydracid agent is 2.1: 1: 3, or thymol and/or isothymol: triphosgene: the mol ratio of dehydrogenation hydracid agent is 6.3: 1: 7.3. reaction is finished, and the elimination solids is washed solids with a small amount of organic solvent, merges organic layer, with the saturated common salt washing repeatedly, uses anhydrous sodium sulfate drying again, and behind the recovery organic solvent, if residue is a liquid, available underpressure distillation or fractionation make pure product.If solid can be used the organic solvent B recrystallization, get pure product.
Or diester manufacture method:
1. thymol and/or isothymol are dissolved in the organic solvent A, after the dissolving, under agitation add dicarboxylic acid chloride, under 0～-10 ℃, 2. splash into the dehydrogenation hydracid agent mixed solution that is dissolved in organic solvent A, after adding, again in stirring at room 2～4 o'clock, wherein thymol and/or isothymol: dicarboxylic acid chloride: the mol ratio of dehydrogenation hydracid agent is 2.1: 1: 3, and 3. the elimination solids is finished in reaction, wash solids with a small amount of organic solvent, merge organic layer, with the saturated common salt washing repeatedly, use anhydrous sodium sulfate drying again, after reclaiming organic solvent, residue is a liquid, and available underpressure distillation or fractionation make pure product.If solid can be used the organic solvent B recrystallization, get pure product.
In the manufacture method according to (sulfo-) carbonic ether of thymol provided by the invention and/or isothymol or diester, described ester comprises two-hundred li esters of above-mentioned carbonic acid, carbonic acid two-Sheep's-parsley ester, carbonic acid Thymus vulgaris celery ester, two-hundred li esters of thiocarbonic acid SOH, thiocarbonic acid SOH two-Sheep's-parsley ester, thiocarbonic acid SOH Thymus vulgaris celery ester, two-hundred li esters of oxalic acid, oxalic acid two-Sheep's-parsley ester, oxalic acid Thymus vulgaris celery ester, 200 li esters of propanedioic acid, propanedioic acid two-Sheep's-parsley ester, propanedioic acid Thymus vulgaris celery ester, two-hundred li esters of Succinic Acid, Succinic Acid two-Sheep's-parsley ester, Succinic Acid Thymus vulgaris celery ester.
Described organic solvent A is an ether, sherwood oil, and hexanaphthene, normal hexane, trichloromethane, methylene dichloride etc. are any.
The agent of described dehydrogenation hydracid is: organic bases such as pyridine, triethylamine, TEBA+NaOH etc.; Mineral alkali such as sodium hydroxide, potassium hydroxide, sodium hydroxide+sodium sulphite mixed solution, salt of wormwood etc. any.
Described recrystallization organic solvent B is that ethyl acetate, acetone, methyl alcohol add 95% ethanol.
Described triphosgene is 21 trichloromethyls-carbonic ether, is a kind of nontoxic solid, and thermal degradation generates three molecule phosgene, has another name called solid phosgene.
Pharmaceutical activity composition provided by the invention comprises ester compound and the vehicle or the additive of following general formula (I).
R wherein
1Be methyl, R
2Be sec.-propyl, R
1And R
2
Contraposition each other;-O-(X)-O-can with R
1
For the ortho position or with R2 be the ortho position, X=-CO-,
-CS-,-CO-(CH
2) n-CO-, n=0 wherein, 1,2.
Concrete pharmaceutical active compounds is two-hundred li esters of carbonic acid, carbonic acid two-Sheep's-parsley ester, two-hundred li esters of thiocarbonic acid SOH, thiocarbonic acid SOH two-Sheep's-parsley ester, two-hundred li esters of oxalic acid, oxalic acid two-Sheep's-parsley ester, carbonic acid Thymus vulgaris celery ester, thiocarbonic acid SOH Thymus vulgaris celery ester, oxalic acid Thymus vulgaris celery ester etc., can be active ingredient separately or form the pharmaceutical activity composition, be preferably two-hundred li esters of carbonic acid of 3: 7: two-hundred li esters of carbonic acid two-Sheep's-parsley ester or thiocarbonic acid SOH: two-hundred li esters of thiocarbonic acid SOH two-Sheep's-parsley ester or oxalic acid: oxalic acid two-Sheep's-parsley ester with any ratio.Described vehicle or additive are known in the art, for example ethanol, W-Gum, tween, beta-cyclodextrin, ethyl acetate, PVP etc.This pharmaceutical activity composition can be for example pre-mixture preparation, solution, inclusion agent, microcapsule formulation etc., or above-mentioned form preparation directly is mixed into mixed feeding or bird tap water with feed or drinking-water.Select for use can different vehicle etc. along with these medicament differences.In order to improve antibiotic and the parasiticide effect, it is similar or similar fully in view of the pathogenic bacteria and parasite of humans and animals, directly set about synthetic precursor compound from the structure of wild marjoram oil effective constituent-thymol and isothymol, be the above-mentioned ester compound of thymol and/or isothymol, this ester compound pharmaceutically is being called precursor compound, external invalid, metabolism generates in vivo active compound.Under the catalysis of enzyme, metabolism produces compounds effective competence exertion drug effect to this prodrug in vivo.Esterase is the most ubiquitous a kind of enzyme in the humans and animals body.So the ester compound of design and synthetic thymol and isothymol, it is as general formula (I) compound, and it is a class higher-boiling compound or a solid chemical compound, and is not volatile; Phenolic hydroxyl group is protected, and is to daylight, air-stable, not perishable; Improve precursor compound pharmaco-kinetic processes in vivo, thereby can improve drug effect.In body, studies confirm that, obtained better anti-microbial effect, particularly Resistant strain is had better curative effect, and the effect of anticoccidial is better than diclazuril, suitable with toltrazuril, have breakthrough progress, be expected to become the antibiotic and anti-parasite medicine of the treatment people of a new generation, fowl, poultry.Have the advantages that a medicine is used more.
The ester compound of thymol provided by the invention and/or isothymol and pharmaceutical activity composition
Compare with natural wild marjoram oil, wild marjoram oil effective constituent thymol, isothymol, precursor compounds such as two-hundred li esters of thiocarbonic acid SOH, thiocarbonic acid SOH two-Sheep's-parsley ester, two-hundred li esters of carbonic acid, carbonic acid two-Sheep's-parsley ester, two-hundred li esters of oxalic acid, oxalic acid two-Sheep's-parsley ester have following characteristics:
1). pharmaceutically be called precursor compound and be diprotic acid such as thymol and isothymol and carbonic acid, thiocarbonic acid SOH, oxalic acid and form the phenolic ester compounds.The free phenolic hydroxyl group does not exist, the characteristic reaction that does not show phenolic hydroxyl group as: do not show acid, for neutral compound, to the gi tract nonirritant; Be not subjected to the influence of the deterioration by oxidation of daylight and air.
2). precursor compound itself is a kind of nonactive ester compound, and people, animal and poultry must make to discharge activeconstituents in vivo through the conversion of enzyme, just produce drug effect and toxic reaction, so the toxicity of precursor compound are very little, even actual nontoxic.
3). because precursor compound is ester compound, so fat-soluble increase, the absorption in enteron aisle, intravital distribution and metabolism greatly improve, and be better than thymol, isothymol, improved bioavailability, strengthens antibiotic and effect and effect anticoccidial.
4). studies show that in the clinical body: wild marjoram oil effective constituent thymol, isothymol monomer or mixture, use separately, can only suppress the coccidia effect; And have synergy as the mixture of two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7), can be used alone as anticoccidial drug.The anticoccidial effect is compared with toltrazuril with two kinds of present clinical application best anticoccidial drug-diclazurils, and it is better than diclazuril, can be equal to mutually with toltrazuril.And have anti-microbial effect concurrently, can treat simultaneously because of coccidiosis and cause concurrent inflammation; Also having somatotrophic effect, is that other anticoccidial drug is incomparable.
5). anti-microbial activity can be proposed comment mutually with modern microbiotic, to reference culture and Resistant strain such as Salmonellas and all very sensitive property of intestinal bacteria,
Two-hundred li esters of oral administration thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) 2 * 10
-6Two-hundred li esters of carbonic acid and carbonic acid two-Sheep's-parsley ester (3: 7) 2 * 10
-6Premixing feedstuff treat the inflammation that Salmonellas (reference culture and Resistant strain) is brought out whole body, treated five days, both mortality ratio are 0%, sick chicken curative ratio is 100%.Showing to have significant curative effect to the reference culture and the disease due to the Resistant strain of whole body.And thymol and isothymol (3: 7)) 2 * 10
-6Premixing feedstuff, also through five days treatment, sick chicken death rate is 15%, curative ratio is 84.3%; Be starkly lower than the former.
With two-hundred li esters of thiocarbonic acid SOH and the administration of thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) 100-200mg/kg mixed feeding, can significantly reduce the mortality ratio that the drug-fast coli-infection chick of multiple antimicrobial drug is caused, significantly improve the clinical infection symptom of chicken, reduce and cure chicken intestinal bacteria separation rate, intramuscular injection artificial challenge chick colibacillosis is had significant curative effect, significantly be better than Norxin, the administration of Vibravenos 150mg/kg mixed feeding.
6). wherein the precursor compound of two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) is antibiotic the strongest with effect anticoccidial, and a medicine is used more.
Embodiment
The present invention further specifies the present invention with the following example, but protection scope of the present invention is not limited to the following example.
Embodiment 1
Synthesizing of thymol
The 400g aluminum trichloride (anhydrous) is suspended in 900g 1, in the 2-ethylene dichloride, be cooled to-9～-10 ℃, with 216g meta-cresol-1, the mixed solution of 2-ethylene dichloride 200g splashes in the aluminum trichloride (anhydrous) suspension, and temperature keeps-10 ℃, splash into 174g 2 cbloropropane isopropyl chloride temperature and remain on-5～-10 ℃ of reactions 8～10 hours, with thin layer chromatography (tlc) detection reaction terminal point.After clarifying reaction liquid poured in the trash ice into ice and separate, ice is separated in the liquid impouring separating funnel again, told lower floor, water layer is with 1, the 2-ethylene dichloride extracts three each 50ml, merges organic layer, and organic layer washes with water to neutrality, washing lotion is with a small amount of 1, the 2-ethylene dichloride extracts once, merges organic layer, washs with saturated nacl aqueous solution, use anhydrous sodium sulfate drying again, get anhydrous orange liquid.
Liquid concentration is reclaimed 1, behind the 2-ethylene dichloride, vacuum fractionation, receipts are adopted 84～86 ℃/10mmHg fraction and are got the pure product 500g of thymol.After the placement crystallization MP:49～51.5 ℃, D
25 ℃0.9699, n
201.5227.
H
1MNR δ ppm:1.28501～1.28501 (6HCH
3-C-CH
3), 3.30216 (CH
3) 3.16918～3.22430 (CH-), 4.65913 (ArH) 6.59585～6.59764 (ArH) 6.75714～6.77464 (1H, ARH) 7.10609～7.12162 (ArH AB peaks).
Embodiment 2
Synthesizing of isothymol
1. limonene nitrosyl chloride preparation
40.8g limonene (L-limonene) is dissolved in the 40ml Virahol, this solution is chilled to below 10 ℃.The 120ml concentrated hydrochloric acid is dissolved in the 80ml Virahol, with 20.7g Sodium Nitrite saturated aqueous solution, adding limonene-aqueous isopropanol medium velocity simultaneously by dropping funnel is controlled to be temperature of reaction and is lower than 10 ℃, stirred 15 minutes, be incubated filtration in a hour, wash solid, must measure and be 50g with suddenly alcohol, use chloroform-methanol (1: 3) recrystallization again, fusing point: 103 ℃.
2. carvoxime preparation
The nitrosyl chloride of 40g limonene (crude product), 20ml dimethyl formamide (DMF) and 125ml Virahol are put in the four-necked bottle and were refluxed 30 minutes, to react and pour into night in the 500ml frozen water, vigorous stirring, changed after-filtration at ice, solid is given a baby a bath on the third day after its birth inferior with the 50ml frozen water, wash once with the 15ml cold isopropanol, dry 27g, 66～69 ℃ of the fusing points of getting.
3. Karvon preparation
Getting 10gL-carvoxime and 15% oxalic acid aqueous solution 100ml puts in the four neck flasks, stirring and refluxing 2 hours, follow wet distillation, the distillate ether extraction, the ether extracted liquid anhydrous sodium sulfate drying behind the recovery ether, carries out vacuum fractionation, collect BP88～90 ℃/4mmHg cut, 7g L-Karvon.
4. isothymol preparation
Get 15g L-Karvon and 40% dilute sulphuric acid 47ml puts in the four-necked bottle, reflux, stirred 3 hours, divide and remove dilute sulphuric acid, organic layer washes with water, flush away sulfuric acid, water layer merges, and uses ether extraction, ether layer and oil reservoir merge, wash neutrality again with water, the ether layer anhydrous sodium sulfate drying is behind the recovery ether, decompression divides gold-plating to collect BP:118～122 ℃/18mmHg, the pure isothymol of 11g.d
200.976，bp
760237℃。Long-term low temperature is placed and is solidified, mp:0～3 ℃.
H
1MNR δ ppm:1.18470～1.25054 (6H, CH
3-C-CH
3), 3.30216 (3H-CH
3), 3.16918-3.22430 (CH-), 4.65913 (1H, ArH) 6.59585-6.59764 (ArH) 6.59585-6.59764 (ArH) 6.75714-6.77464 ﹠amp; (7.10609-7.12162 ArH AB peak).
Embodiment 3
Two-hundred li ester preparations of thiocarbonic acid SOH
Thymol 31.54g and chloroform 300ml put in the four-necked bottle, stir down, and temperature is controlled at-6～-8 ℃ and drips thiophosgene, dropping sodium 6g closes the solution of moisture sodium sulphite 1.2g and 81ml water again, and temperature is controlled at below-5～-7 ℃, drips to finish, rise to room temperature, continue to stir 2～4 hours, control reaction end with thin-layer chromatography, tell organic layer, water layer chloroform extraction twice, branch vibration layer, chloroform layer merges, use anhydrous sodium sulfate drying, reclaim chloroform, debris is carried out the post layer and is separated.With 1: 10 silica gel, be developping agent with the sherwood oil, collect petroleum ether solution, concentrating under reduced pressure gets the red-brown crude product, the cut of BP122～124 ℃/5mmHg is collected in reduced pressure distillation again, elaboration 30g, yield is 50～51%.
Du1.1285～1.1289，
UVmax (methyl alcohol) 202,203,204,248,
H
1NMR: δ PPM 1.24493～1.28009 (12H, 2CH
3-C-CH
3), 2.37001 (6H, 2AR-CH3), 2.99897～3.05415 (2H, 2-CH-), 6.88962 (2H, 2ARH), 6.89135～7.29762 (4H 2ARH AB peaks)
Embodiment 4
The preparation of thiocarbonic acid SOH two-Sheep's-parsley ester
Isothymol 31.54g and chloroform 300ml put in the four-necked bottle, stir down, and temperature is controlled at 0 ℃ and drips the thio phosgene 10.3g solution of dropping sodium 6g and moisture sodium sulphite 1.2g and 81ml water again, temperature is controlled at below-6～-8 ℃, drips to finish, and rises to room temperature, continue to stir 2～4 hours, control reaction end, tell organic layer with thin-layer chromatography, twice of chloroform extraction of water layer, branch vibration layer, chloroform layer merge uses anhydrous sodium sulfate drying, reclaims chloroform, debris is carried out the post layer and is separated.With 1: 10 silica gel, be expansion with the sherwood oil, collect petroleum ether solution, concentrating under reduced pressure gets the deep yellow crude product, the cut of BP:120～124 ℃/5mmHg is collected in reduced pressure distillation, elaboration 32.4g, yield is 52～53%.
D
201.1229～1.1240，
Uvmax (methyl alcohol) 201,204,203,
H
1NMR: δ PPM 1.23384～1.27862 (12H, 2CH
3-C-CH
3), 2.21434 (6H, 2AR-CH
3), 2.89449～2.94976 (2H, 2-CH-), 6.92979～6.93315 (2H, 2AR-H), 7.0964～7.21989 (4H, 2AR-H AB peaks).
Embodiment 5
Two-hundred li ester preparations of carbonic acid
Thymol 31.54g and chloroform 300ml put in the four-necked bottle, stir down, and temperature is controlled at 0 ℃ and adds triphosgene 10.3g, the solution of dropping sodium 7.29g and moisture sodium sulphite 1.2g and 81ml water again, temperature is controlled at below-6～-9 ℃, drips to finish, rise to room temperature, continue to stir 2～4 hours, control reaction end with thin-layer chromatography, tell organic layer, water layer chloroform extraction twice, branch vibration layer, chloroform layer merge uses anhydrous sodium sulfate drying, reclaim chloroform, debris is carried out the post layer and is separated.With 1: 10 silica gel, be expansion with the sherwood oil, collect petroleum ether solution, reclaim sherwood oil, underpressure distillation boils off the low boilers of BP:80～90 ℃/5mmHg, finished product 27～30g.Place for some time, spontaneous curing becomes white crystalline form solid, and mp:52～54 ℃ yield is 44.3～54%.
Uvmax (methyl alcohol) 201,204,212,
H
1NMR: δ PPM 1.22384～1.26174 (12H, 2.CH
3-C-CH
3), 2.32473 (6H, 2AR-CH3), 3.14311～3.23493 (2H, 2 ,-CH-), 6.99892～7.02431 (2H, 2, AR-H), 7.02757～7.21822 (4H, 2AR-H, AB peaks)
Embodiment 6
The preparation of carbonic acid two-Sheep's-parsley ester
Isothymol 31.45g and chloroform 300ml put in the four-necked bottle, stir down, and temperature is controlled at 0 ℃ and adds triphosgene, the solution of dropping sodium 8.1g and moisture sodium sulphite 1.4g and 81ml water again, temperature is controlled at below-5～-7 ℃, drips to finish, rise to room temperature, continue to stir 6～8 hours, control reaction end with thin-layer chromatography, tell organic layer, water layer chloroform extraction twice, branch vibration layer, chloroform layer merge uses anhydrous sodium sulfate drying, reclaim chloroform, debris is carried out the post layer and is separated.With 1: 50 silica gel, be expansion with the sherwood oil, collect petroleum ether solution, reclaim sherwood oil, underpressure distillation boils off the lower boiling of bp:80～90 ℃/5mmHg, finished product 27～30g, yield is 44.3～54%.
Uvmax (methyl alcohol) 202,204,205,
H
1NMR: δ PPM:1.22036～1.25046 (12H, 2.CH
3-C-CH
3), 2.27784 (6H, 2AR-CH3),, 2.8117～2.9410 (2H, 2-CH-), 7.01915 (2H, 2AR-H), 7.02505～7.22167 (4H, AR-H, AB peaks).
Embodiment 7
Two-hundred li ester preparations of oxalic acid
Thymol 15.2g and oxalyl chloride 6.15g are added in the anhydrous 100ml sherwood oil, be cooled to 0 ℃, under agitation, slowly splash into pyridine 7.7g and sherwood oil 20ml mixed solution, temperature is controlled at-4～-6 ℃, drips off the back stirring at room 4 hours, controls terminal point with thin-layer chromatography.Remove by filter pyridine hydrochloride, use a small amount of sherwood oil desalinization of soil by flooding or leaching acid pyridine again, merge organic layer, wash, be washed to neutrality with saturated sodium carbonate, the petroleum ether layer anhydrous sodium sulfate drying, steaming petroleum ether, debris cooling, crystallization, filtration drying get crude product.Doubly measure 95% ethyl alcohol recrystallization through 5-10, get elaboration 16g.Mp:54.5～57.5 ℃, yield 18.28%.
VUmax (methyl alcohol): 202,204, (nm)
H
1NMR: δ PPM:1.23523～1.24907 (12H, 2.CH
3-C-CH
3), 2.3574 (6H, 2AR-CH3), 306152.～3.11675 (2H, 2-CH-), 6.99723～6.999 (2H, 2ARH), 7.09430～7.26561 (4H, AR-H, AB peaks).
Embodiment 8
The preparation of oxalic acid two-Sheep's-parsley ester
Isothymol 15.2g and oxalyl chloride 6.15g are added in the anhydrous 100ml sherwood oil, be cooled to 0 ℃, under agitation, slowly splash into pyridine 7.7g and sherwood oil 20ml mixed solution, temperature is controlled at below-5～-7 ℃, drips off the back stirring at room 2～4 hours, controls terminal point with thin-layer chromatography.Remove by filter pyridine hydrochloride, use a small amount of sherwood oil desalinization of soil by flooding or leaching acid pyridine again, merge organic layer, wash, be washed to neutrality with saturated sodium carbonate, the petroleum ether layer anhydrous sodium sulfate drying, steaming petroleum ether, debris cooling, crystallization, filtration drying get crude product.Doubly measure 95% ethyl alcohol recrystallization through 5-10, get elaboration 16g.
Mp：59.0～61.5.℃。Yield 18.28%.
VUmax (methyl alcohol): 202,204, (nm)
H
1NMR: δ PPM 1.2486～1.2625 (12H, 2.CH
3-C-CH
3), 2.2400 (6H, 2AR-CH3), 2.8736.～2.9423 (2H, 2-CH-), 7.0359～7.0388 (2H, 2AR-H), 7.0850～7.22467 (4H, AR-H, AB peaks).
Embodiment 9
5% pre-mixture preparation:
Medicine 5kg
95% ethanol 20L
W-Gum 95kg
100 ℃ of oven dry W-Gums are put in the mixing machine, started mixing machine, medicine 5kg is dissolved in 5 L95% ethanolic solns again, slowly adds in the mixing machine, mixes 30 minutes, after uniformity coefficient to be determined is qualified, puts in the baking oven, and content is measured in 60 ℃ of oven dry, qualified back packing.Described medicine is meant two-hundred li ester monothiocarbonic acids of thiocarbonic acid SOH, two-Sheep's-parsley ester (3: 7), and following examples are identical.
Embodiment 10
5% solution:
Medicine 5kg
95% ethanol 20L
10% tween 1kg
Distilled water adds to 100kg
The 5kg medicine is dissolved in 95% ethanol of 20L, stirs adding 10% tween 1kg down, after stirring, adding distil water after stirring evenly, filters settled solution packing, every bottle of one-tenth/100ml to 100kg again.
Embodiment 11
5% inclusion compound:
Medicine 5kg
Beta-cyclodextrin (medicinal) 20kg
Distilled water 40kg
Ethyl acetate 5kg
W-Gum 75kg
Beta-cyclodextrin (medicinal) 20kg and distilled water 40kg are mixed and heated to 80 ℃, get transparent solution, under agitation, add the medicine ethyl acetate solution, after fully stirring, be cooled to room temperature, logical icy salt solution is static spends the night, and filters, the water flush away is the beta-cyclodextrin of inclusion not, wash with ethyl acetate, dry inclusion compound is mixed into 5% mixture again with starch again.
Embodiment 12
5% microcapsule formulation:
Medicine 5kg
PVP (medicinal) 95kg
5kg medicine and 95kg PVP are put in the micro-capsule machine, added certain amount of solvent, mix, measure uniformity coefficient, qualified after drying removes and desolvates, and measures content, qualified back packing.Usage and consumption:
Embodiment 13
Coccidiosis medicine mixed feeding:
Pre-mixture 2Kg and 1 ton of feed of 5% of embodiment 9 are mixed, and the mixed fodder that becomes to contain 100ppm is used for mixed feeding.
Embodiment 14
The antimicrobial drug mixed feeding:
Pre-mixture 4Kg and 1 ton of feed of 5% of embodiment 9 are mixed, and the mixed fodder that becomes to contain 200ppm is used for mixed feeding.
Embodiment 15
Coccidiosis medicine drinking-water:
Solution 2kg and 1 ton of water of 5% of embodiment 10 are mixed, be made into the drinking-water that contains 100ppm, use for bird drinking-water.
Embodiment 16
The antimicrobial drug tap water
Solution 4kg and 1 ton of water of 5% of embodiment 10 are mixed, be made into the drinking-water that contains 200ppm, use for bird drinking-water.
Pharmaceutical activity composition toxicity and pharmacological property according to the ester compound of thymol provided by the invention and/or isothymol
One, acute toxicity test
Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) are to the dead the results list 1 of its mouse oral acute toxicity
Table 1
| Group | Dosage (g/kg) | Number of animals | Dead sum | Mortality ratio |
| 1 | 3.180 | 10 | 10 | 100％ |
| 2 | 2.129 | 10 | 7 | 70％ |
| 3 | 1.418 | 10 | 3 | 30％ |
| 4 | 0.949 | 10 | 1 | 10％ |
| 5 | 0.647 | 10 | 0 | 0 |
Can calculate two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) per os LD according to result in the table to mouse
50Be 1.660g/kg, the 95% credible 1.387～1.986g/kg that is limited to.
The result shows by table 1 acute toxicity test in mice, to the per os LD of mouse
50Be 1.660g/kg, judge by international acute toxicity grading criteria, two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) are low toxicity to the toxicity rank of mouse, show that two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) toxicity are lower, safety range is big, so can use safely in veterinary clinic.
Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) are to the dead the results list 2 of fryer per os acute toxicity
Table 2
| Group | Dosage (g/kg) | Number of animals | Death toll | Mortality ratio |
| 1 | 12.128 | 10 | 10 | 100％ |
| 2 | 8.085 | 10 | 6 | 60％ |
| 3 | 5.390 | 10 | 5 | 50％ |
| 4 | 3.557 | 10 | 2 | 20％ |
| 5 | 2.372 | 10 | 1 | 10％ |
| 6 | 1.595 | 10 | 1 | 10％ |
| 7 | 1.067 | 10 | 0 | 0 |
Can calculate two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) per os LD according to result in the table to fryer
50Be 5.395g/kg, the 95% credible 4.285～6.792g/kg that is limited to.
Show that by table 2 fryer The acute toxicity tests two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) are to the per os LD of fryer
50Be 5.395g/kg, by international acute toxicity grading criteria (the oral LD of rat
50Data) judge, two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) are actual nontoxic to the toxicity rank of fryer, show that two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) are extremely low to the toxicity of chicken, safety range is big, so can use safely in veterinary clinic.
Two, antibiotic and coccidiostat activity clinical study
1. " to the chick infected chicken dysentery characterized by white mucous stool Salmonellas reference culture test of pesticide effectiveness "
Test method:
7 Japanese instar chicklings are used in this research, each treatment group and every pigeon breast portion of infection control group intramuscular inoculation white dysentery Salmonellas bacterium liquid (10
9CFU/ml), dosage only is defined as 0.4-0.5ml/ according to pre-test result.Normal healthy controls winding kind is measured stroke-physiological saline solution equally.
Each treatment group chicken behind the intramuscular injection inoculated bacteria 3 hours gives mixed feeding pharmacological agent by table 3, continuous use 5 days.Normal healthy controls, infect and respectively to organize chicken after contrast and administration finish and give blank and do not contain the medicine complete feed, drinking-water is not limit.
The compound of treatment usefulness: two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7); Two-hundred li esters of carbonic acid and carbonic acid two-Sheep's-parsley ester (3: 7), thymol+isothymol (3: 7).Six groups of medication groups, dosage such as table 3;
Clinical observation:
Observe after 10 days continuously after the drug withdrawal and cut open inspection.Before and after the inoculation white dysentery Salmonellas, conscientiously observe the response situation of chicken, and write down its clinical symptom, mainly comprise diet desire, mental status and ight soil etc., record feed intake and death condition.Dead chicken is cutd open inspection, and get liver and carry out the bacterium separation and Culture, microscopy is identified behind the gramstaining.
The therapeutic evaluation index:
Mortality ratio: all at duration of test, the classical symptom and the death of white dysentery Salmonella infection appear, and typical pathology appears in ptomatopsia, isolates the white dysentery Salmonellas by liver, is judged to be to infect death.Calculate the mortality ratio of each group according to dead chicken number.
Curative ratio: all at duration of test, mental status and appetite recover normal after the drinking-water administration, and it is just rare white not occur, and ight soil does not have Salmonellas to detect through separation and Culture, is judged to healing, and according to curing chicken, the ratio that accounts for the total group test chicken is calculated curative ratio.
Weightening finish: according to test just and respectively organize the body weight of chicken during off-test, calculate every chicken and increase weight, calculate every group of test chicken in view of the above, average weight gain and standard deviation.
The result:
The chicken of intramuscular injection infected chicken dysentery characterized by white mucous stool Salmonellas, the general initial apocleisis that shows as, drowsiness, attitude is unusual, draws white loose stool, and adularescent ight soil is stuck with paste at the cloaca place.Respectively organizing the chicken death time behind the intramuscular injection infected chicken dysentery characterized by white mucous stool Salmonellas sees Table 4.Get the duration of test chicken liver of dying of illness and be inoculated in the S.S nutrient agar, cultivate after 24 hours for 37 ℃ and on S.S agar, grow up to colourless translucent, circular dewdrop sample, the big small colonies of needle point.Microscopy is the tyrothricin of Gram-negative, the blunt circle in two ends.The inspection result that cuts open of the dead chicken of duration of test shows that the liver enlargement appears in most chickens, and the surface is dispersed in or gather canescence tip-like or the downright bad point of grains of sand shape, and the pulmonary congestion that has, kidney are swollen slightly, and a small amount of urate is arranged in the ureter.
After the off-test, each group survival chicken weighs, all cuts open and kills, and checks pathology situation, bacterial isolate bacterium.Remove the infection indivedual chickens of control group (3/9) and still have obviously white dysentery Salmonella infection symptom, as the slight enlargement of liver, matter is crisp, the surface is dispersed in a small amount of canescence tip-like or the downright bad point of grains of sand shape, pericardial thickening, outside the duodenum slight bleeding, other each treatment group chickens are not all found macroscopic white dysentery Salmonella infection symptom.Infecting control group gets 9,10 chickens of other groups and gets liver inoculation S.S nutrient agar, carry out the bacterium separation and Culture, cultivate after 24 hours for 37 ℃, remove infection control group (7/9) and isothymol+thymol low dose group (2/10) part chicken and be separated to pathogenic bacteria, and microscopy is accredited as outside the white dysentery Salmonellas behind gramstaining, and other each treatment groups all are not separated to the white dysentery Salmonellas.
Mortality ratio, curative ratio, weightening finish that statistics is respectively organized chicken the results are shown in Table 5.
Table 3 is respectively organized test chicken and is handled and body weight
| Grouping | Quantity (only) | Body weight (X ± SDg) | Handle |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) high dose group | 19 | 70.55±10.247 | Infection, 200mg/kg mixed feeding |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) low dose group | 19 | 68.46±10.220 | Infection, 100mg/kg mixed feeding |
| Two-hundred li esters of carbonic acid and carbonic acid two-Sheep's-parsley ester (3: 7) high dose group | 19 | 68.75±9.724 | Infection, 200mg/kg mixed feeding |
| Two-hundred li esters of carbonic acid and carbonic acid two-Sheep's-parsley ester (3: 7) low dose group | 19 | 69.39±11.542 | Infection, 100mg/kg mixed feeding |
| Thymol+isothymol (3: 7) high dose group | 19 | 69.39±12.104 | Infection, 200mg/kg mixed feeding |
| Thymol+isothymol (3: 7) low dose group | 19 | 69.32±12.135 | Infection, 100mg/kg mixed feeding |
| Infect control group | 19 | 68.27±10.688 | Infection, not administration |
| The normal healthy controls group | 19 | 70.00±12.065 | Do not infect, not administration |
Respectively organize the chicken death condition behind the table 4 intramuscular injection infected chicken dysentery characterized by white mucous stool Salmonellas
| Group | Sum | ＜24h | 24-48 h | 48-72 h | 72-96 h | 96-12 0h | 120-1 44h | 144-1 68h | ＞168h |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) high dose group | 19 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) low dose group | 19 | 1 | 2 | 1 | 0 | 0 | 0 | 0 | 0 |
| Two-hundred li esters of carbonic acid and carbonic acid two-Sheep's-parsley ester (3: 7) high dose group | 19 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Two-hundred li esters of carbonic acid: carbonic acid two-Sheep's-parsley ester (3: 7) low dose group | 19 | 1 | 3 | 0 | 0 | 0 | 0 | 0 | 0 |
| Thymol+isothymol (3: 7) high dose group | 19 | 2 | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Thymol+isothymol (3: 7) low dose group | 19 | 2 | 2 | 0 | 0 | 1 | 0 | 0 | 0 |
| Infect control group | 19 | 2 | 1 | 3 | 0 | 0 | 1 | 1 | 2 |
| The normal healthy controls group | 19 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Table 5 medicine is to white dysentery Salmonella infection curative effect
| Group | Death toll | Mortality ratio (%) | Curative ratio (%) | Weightening finish (XISDg) in 15 days |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) high dose group | 0 | 0 | 100 | 190.63±32.12 |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) low dose group | 4 | 21.1 | 78.9 | 183.04±41.06 |
| Two-hundred li esters of carbonic acid and carbonic acid two-Sheep's-parsley ester (3: 7) high dose group | 0 | 0 | 100 | 185.44±40.86 |
| Two-hundred li esters of carbonic acid and carbonic acid and carbonic acid two Sheep's-parsley ester (3: 7) low dose group | 4 | 21.1 | 78.9 | 171.43±47.13 |
| Thymol+isothymol (3: 7) high dose group | 3 | 15.8 | 84.2 | 159.17±37.60 |
| Thymol+isothymol (3: 7) low dose group | 5 | 26.3 | 73.7 | 150.32±39.6 |
| Infect control group | 10 | 52.6 | - | 137.39±54.90 |
| The normal healthy controls group | 0 | 0.0 | - | 196.60±37.76 |
According to table 4,5 as seen, each medicine 100,200mg/kg mixed feeding all can significantly be improved the clinical infection symptom of curing chicken.
Each medicine 100,200mg/kg mixed feeding all can significantly be improved the clinical infection symptom of curing chicken.
Two-hundred li esters of 200mg/kg thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7), two-hundred li esters of carbonic acid: the administration of carbonic acid Sheep's-parsley ester (3: 7) high dosage mixed feeding all can in time stop the chick death of being brought out by intramuscular injection white dysentery Salmonellas reference culture, significantly reduce white dysentery Salmonellas type strain and infect mortality ratio, has significant curative effect, significantly be better than 100mg/kg mixed feeding administration group, but the pathological change of cuing open inspection after clinical symptom of each administration group chicken and the off-test all significantly alleviates than infecting control group, significantly reduces and cures chicken white dysentery Salmonellas reference culture separation rate (P＜0.05).
Simultaneously, two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH Sheep's-parsley ester (3: 7) and the weightening finish of high and low dose group all are significantly higher than infects control group (P＜0.05), be lower than the normal healthy controls group, but weightening finish does not relatively have significant difference (P＞0.05) with the normal healthy controls group.Each the administration group weightening finish of two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7), two-hundred li esters of carbonic acid and carbonic acid two-Sheep's-parsley ester (3: 7) and isothymol+thymol is suitable, the difference on the not statistically significant (P＞0.05).
Two-hundred li esters of 200mg/kg thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7), two-hundred li esters of carbonic acid and the administration of carbonic acid two-Sheep's-parsley ester (3: 7) group mixed feeding all can significantly reduce the mortality ratio that chick infected chicken dysentery characterized by white mucous stool Salmonellas reference culture causes, significantly improve the clinical infection symptom of chicken, reduce and cure chicken white dysentery Salmonellas reference culture separation rate, intramuscular injection Salmonellas reference culture is brought out the white scour of chicken have significant curative effect, be better than 100mg/kg mixed feeding administration group and isothymol+thymol 100, the administration of 200mg/kg mixed feeding.
2. " chick is infected the resistance white dysentery Salmonellas test of pesticide effectiveness "
The therapeutic test method
With 56 1 age in days yellow-feathered broilers, female, hero has concurrently, is provided by Chinese poultry institute.Feed to 7 ages in days with the complete feed that does not contain any antibacterials.It is negative that sampling observation before the test of this group chicken, serology detect fowl white dysentery Salmonellas.Single plumage is weighed before the test, and random packet is divided into 4 groups, 20 of normal healthy controls groups, and other organize 18 every group.The test chicken grouping sees Table 6.
Table 6 is respectively organized test chicken and is handled and body weight
| Grouping | Quantity (only) | Body weight (X ± SDg) | Handle |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) high dose group 200mg/kg | 18 | 63.12 ± 14.99 | Infect.The 200mg/kg mixed feeding |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) low dose group 150mg/kg | 18 | 62.94 ± 6.65 | Infect.The 150mg/kg mixed feeding |
| Infect control group | 18 | 61.97 ± 11.70 | Infect.Not administration |
| The normal healthy controls group | 20 | 74.63 ± 8.04 | Do not infect.Not administration |
White dysentery Salmonellas clinical separation strain S
997, provide by veterinary college Preventive Veterinary Medicine teaching and research room of Yangzhou University.The white dysentery Salmonellas that the inclined-plane is preserved is inoculated on the S.S agar plate, and the single colony inoculation of picking is in the LB substratum behind 37 ℃ of cultivation 16h, and 37 ℃ of concussions are cultivated.Carry out bacterial count before the use, bacterial concentration is 6.4 * 10
9CFU/ml.
Each treatment group and every pigeon breast portion of infection control group intramuscular inoculation white dysentery Salmonellas bacterium liquid (6.4 * 10 during 7 ages in days
9CFU/ml), dosage is 0.5ml/.Normal healthy controls winding kind stroke-physiological saline solution.
Each treatment group chicken behind the intramuscular injection inoculated bacteria 2 hours gives pharmacological agent by table 6 mixed feeding, continuous use 5 days.Infection contrast, normal healthy controls chicken are all given blank and are not contained the medicine complete feed, and drinking-water is not all limit.
Clinical observation
Observe after 7 days continuously after the drug withdrawal and cut open inspection.Dead chicken is cutd open inspection, and get liver and carry out the bacterium separation and Culture, microscopy is identified behind the gramstaining.
Therapeutic evaluation index: with above-mentioned.
The medicine of fowl salmonellosis is to S
997Sensitivity test
Measure 14 kinds with paper disk method and clinically be usually used in controlling the medicine of fowl salmonellosis S
997Susceptibility.The result shows, white dysentery Salmonellas clinical separation strain S
997Various medicines have all been shown susceptibility in various degree.The results are shown in Table 7.
Table 7 white dysentery Salmonellas clinical separation strain S
997Drug sensitive test result (antibacterial circle diameter: mm) to 14 kinds of antimicrobial drugs
| Medicine | White dysentery Salmonellas clinical separation strain S 997 |
| Gentamicin | 21.50 |
| Kantlex | 20.08 |
| Amikacin | 19.00 |
| Xin Meisu | 18.21 |
| Ofloxacine USP 23 | 0 |
| Ciprofloxacin | 0 |
| Norfloxicin | 0 |
| Vibravenos | 11.05 |
| Tsiklomitsin | 8.44 |
| Paraxin | 7.23 |
| The amoxycilline Trihydrate bp | 14.52 |
| The Ampicillin Trihydrate | 14.28 |
| Trichofuron | 19.27 |
| Sulfamethoxazole | 0 |
Intramuscular injection infected chicken dysentery characterized by white mucous stool Salmonellas S
997Chicken, the general initial apocleisis that shows as, drowsiness, attitude is unusual, draws white loose stool, adularescent ight soil is stuck with paste at the cloaca place.Get the duration of test chicken liver of dying of illness and be inoculated in the S.S nutrient agar, cultivate after 24 hours for 37 ℃ and on S.S agar, grow up to colourless translucent, circular dewdrop sample, the big small colonies of needle point.Microscopy is the tyrothricin of Gram-negative, the blunt circle in two ends.The inspection result that cuts open of the dead chicken of duration of test shows that loosing in most chicken livers surface has the downright bad point of canescence tip-like, and a small amount of urate is arranged in the ureter.
After the off-test, each group survival chicken weighs, all cuts open and kills, and checks pathology situation, bacterial isolate bacterium (table 8).Infect the indivedual chickens of control group (5/12) and still have obviously white dysentery Salmonella infection symptom, other each treatment group chickens are not all found macroscopic white dysentery Salmonella infection symptom.Get 10 chickens for every group and get liver inoculation S.S nutrient agar, carry out the bacterium separation and Culture, cultivate after 24 hours for 37 ℃, remove infection control group (5/12) part chicken and be separated to pathogenic bacteria, and microscopy is accredited as outside the white dysentery Salmonellas behind gramstaining, and the other treatment group all is not separated to the white dysentery Salmonellas.
Each group survival chicken pathology and bacterial isolate bacterium situation after table 8 off-test
| Group | Cut open the inspection number | Hepatic disease | Duodenal hemorrhage | Bacterium separates positive |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) high dose group 200mg/kg | 18 | 0 | 0 | 0/10 |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) low dose group 150mg/kg | 18 | 0 | 0 | 0/10 |
| Infect control group | 12 | 2 | 3 | 5/10 |
| The normal healthy controls group | 20 | 0 | 0 | 0/10 |
Table 9 pair resistance Salmonellas is brought out the curative effect of white dysentery
| Group | Death toll | Mortality ratio (%) | Curative ratio (%) | Weightening finish in 12 days (X ± SDg) |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) high dose group 200 mg/kg | 0 | 0.0 | 100 | 130.49±23.97 |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) low dose group 150 mg/kg | 0 | 0.0 | 100 | 129.17±16.65 |
| Infect control group | 6 | 33.3 | - | 101.45±26.12 |
| The normal healthy controls group | 0 | 0.0 | - | 137.68±16.98 |
150, the administration of 200mg/kg mixed feeding all can significantly reduce the mortality ratio (table 9) that chick infection resistance white dysentery Salmonellas causes, significantly improve the clinical infection symptom of chicken, reduce and cure chicken white dysentery Salmonellas separation rate, the intramuscular injection artificial challenge white scour of chicken is had significant curative effect.
3. " to resistance intestinal bacteria O
78Infect the test of pesticide effectiveness of chick "
Yangzhou University's veterinary college is to the test of pesticide effectiveness of resistance coli-infection chick, and with 140 1 age in days three yellow fryer, female, hero has concurrently.Provide by Chinese poultry institute.Feed to 7 ages in days with the complete feed that does not contain any antibacterials.Single plumage is weighed 20 every group of random packet before the test.Avian escherichia coli O
78, all after corresponding biochemical identification, be defined as causing the pathogenic bacterial strains (seeing Table 10) of chicken colibacillosis.The intestinal bacteria that the inclined-plane is preserved are inoculated on the maconkey agar flat board, and the single colony inoculation of picking is in broth medium behind 37 ℃ of cultivation 24h, and 37 ℃ of concussions are cultivated.Carry out bacterial count with the maconkey agar flat board before using, bacterial concentration is 10
9CFU]/Ml. is through the colibacillary chicken of infectable infection, the general initial apocleisis that shows as, and the feather pine is disorderly, dipteron is sagging, spirit is depressed, and is drowsiness, and chilly is had difficulty in breathing, and attitude is unusual, draws white loose stool.Beginning in 6 hours is dead behind the intramuscular injection ehec infection, and each is organized the chicken death time and sees Table 11.Get the chicken liver of dying of illness and be inoculated in the maconkey agar substratum, 37 ℃ cultivate on maconkey agar, grow up to neat in edge after 16 hours, projection, smooth surface are moistening slightly, the pink bacterium colony of diameter 1.5-2 millimeter.Get bacterium smear, gramstaining, microscopy and see the blunt circle in two ends, short and thick negative bacterium.
The inspection result that cuts open of the dead chicken of duration of test shows that escherichia coli acute sepsis symptom appears in most chickens: liver is green, chest muscle hyperemia, and the blunt circle of liver edge also has each organ to be septicemia individually and changes; The airbag wall muddiness, thicken, the content yellow-green colour, have be mixed with cheesy thing.Indivedual hearts, liver have fibrinous exudate, pericardium muddiness, the formation fiber disposition coating that has, also pathology such as visible peritonitis.Be diagnosed as chicken colibacillosis in sum.
After the off-test, each group survival chicken weighs, all cuts open and kills, and checks pathology situation, bacterial isolate bacterium (table 12).Still have the obvious coli-infection symptom except that infecting the indivedual chickens of control group (5/11), other each treatment group chickens are not all found macroscopic coli-infection symptom.Get 10 aseptic liver inoculation maconkey agar substratum of getting of chicken for every group, carry out the bacterium separation and Culture, cultivate after 24 hours for 37 ℃, remove infection control group (5/11) part chicken and be separated to pathogenic bacteria, and microscopy is accredited as outside the intestinal bacteria behind gramstaining, and other each treatment groups (two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7)) all are not separated to intestinal bacteria.
Table 10 three strain intestinal bacteria are to the drug sensitive test result (antibacterial circle diameter: mm) of 12 kinds of antimicrobial drugs
| Medicine | Avian escherichia coli O 78 | Intestinal bacteria-1 | Intestinal bacteria-2 |
| Gentamicin | 24.04 | 0 | 0 |
| Streptomycin sulphate | 23.90 | 9.08 | 14.78 |
| Kantlex | 23.24 | 0 | 0 |
| Amikacin | 24.12 | 0 | 0 |
| Spectinomycin | 21.38 | 17.26 | 16.00 |
| Ciprofloxacin | 25.06 | 0 | 13.52 |
| Norfloxicin | 23.36 | 0 | 12.00 |
| Vibravenos | 18.67 | 0 | 7.64 |
| Paraxin | 25.54 | 0 | 19.92 |
| The amoxycilline Trihydrate bp | 19.22 | 0 | 0 |
| Trichofuron | 17.18 | 11.36 | 16.08 |
| Trimethoprim-sulfamethoxazole | 18.50 | 0 | 0 |
Mortality ratio, curative ratio, weightening finish that statistics is respectively organized chicken the results are shown in Table 13.
Respectively organize the chicken death condition behind the table 11 intramuscular injection ehec infection
| Group | Sum | ＜24h | 24-48 h | 48-72 h | 72-96 h | 96-12 0h | 120-14 4h | 144-16 8h | ＞168h |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) high dosage (200 mg/kg) | 20 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Dosage group (150 mg/kg) in two-hundred li esters of thiocarbonic acid SOH and the thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) | 20 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) low dose group (100 mg/kg) | 20 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Norfloxicin 150 mg/kg | 20 | 1 | 3 | 1 | 1 | 0 | 0 | 0 | 0 |
| Vibravenos control group 150mg/kg | 20 | 2 | 1 | 0 | 1 | 1 | 0 | 0 | 0 |
| Infect control group | 20 | 4 | 3 | 1 | 0 | 1 | 0 | 0 | 0 |
| The normal healthy controls group | 20 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Each group survival chicken pathology and bacterial isolate bacterium situation after table 12 off-test
| Group | Cut open the inspection number | Hepatic disease | Pericardial thickening | Airsacculitis | Bacterium separates positive |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) high dose group (200mg/kg) | 20 | 0 | 0 | 0 | 0/20 |
| Dosage group (150mg/kg) in two-hundred li esters of thiocarbonic acid SOH and the thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) | 20 | 0 | 0 | 1 | 0/20 |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) low dose group (100mg/kg) | 19 | 0 | 0 | 1 | 0/19 |
| Norfloxicin control group (150mg/kg) | 14 | 0 | 0 | 4 | 2/14 |
| Vibravenos control group (150mg/kg) | 15 | 0 | 0 | 4 | 2/15 |
| Infect control group | 11 | 5 | 5 | 10 | 5/11 |
| The normal healthy controls group | 20 | 0 | 0 | 0 | 0/20 |
Mortality ratio, curative ratio, weightening finish that statistics is respectively organized chicken the results are shown in Table 13.
The resistance intestinal bacteria result of treatment of table 13 pair chicken
| Group | Death toll | Mortality ratio (%) | Curative ratio (%) | Weightening finish in 12 days (X ± SDg) |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) high dose group (200mg/kg) | 0 | 0.0 | 100.0 | 133.51±22.24 |
| Dosage group (150mg/kg) in two-hundred li esters of thiocarbonic acid SOH and the thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) | 0 | 0.0 | 100.0 | 131.12±27.39 |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) low dose group (100mg/kg) | 1 | 5.0 | 95.0 | 124.12±33.43 |
| Control group norfloxicin (150mg/kg) | 6 | 30.0 | 70.0 | 119.53±25.86 |
| Vibravenos control group (150mg/kg) | 5 | 25.0 | 75.0 | 119.45±25.51 |
| Infect control group | 9 | 45.0 | - | 95.66±22.03 |
| The normal healthy controls group | 0 | 0.0 | - | 137.68±16.98 |
According to table two-hundred li esters of the visible thiocarbonic acid SOH of 11-13 with thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) is clinical all can significantly improve the clinical infection symptom of chicken with the administration of 100-200mg/kg mixed feeding, can also significantly reduce simultaneously and cure chicken intestinal bacteria separation rates (P＜0.05).All can in time stop the chick acute death that causes by the pathogenic resistance intestinal bacteria of intramuscular injection, significantly reduce the coli-infection mortality ratio, and the remarkable various clinical symptom that cause by coli-infection of improving, the infection that pathogenic resistance intestinal bacteria are caused has significant curative effect, significantly is better than norfloxicin and Vibravenos 150mg/kg mixed feeding administration group.
The pathological change of cuing open inspection after the off-test all significantly alleviates (P＜0.05) than infecting control group.Weightening finish all is significantly higher than infects control group and norfloxicin 150mg/kg, Vibravenos 150mg/kg mixed feeding administration group (P＜0.05), and does not relatively have significant difference (P＞0.05) with the normal healthy controls group.And high, middle dosage group weightening finish quite, the difference on the not statistically significant (P＞0.05).
This shows with two-hundred li esters of thiocarbonic acid SOH and the administration of thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) 100-200mg/kg mixed feeding, can significantly reduce chick and infect the mortality ratio that multiple antimicrobial drug resistance intestinal bacteria are caused, significantly improve the clinical infection symptom of chicken, reduce and cure chicken intestinal bacteria separation rate, intramuscular injection artificial challenge chick colibacillosis had significant curative effect, significantly be better than bacterium and infect the various clinical symptom that cause, the infection that pathogenic resistance intestinal bacteria are caused has significant curative effect, significantly is better than norfloxicin, the administration of Vibravenos 150mg/kg mixed feeding.
4. " anti-chicken coccidia activity research "
Infect 17 age in days chickens with Eimeria tenella (Eimeria tenella), 20 every group, except that not infecting not administration group, every chicken is through crop inoculating spores egg capsule 11 * 10 in other each groups
4Individual, behind the inoculation 12h, the beginning administration, administration seven fates are analysed observation experiment table 14 as a result.
The anticoccidial index of each group of table 14
| Group | Dosage * 10 -6 | The relative weight gain rate (%) | Survival rate (%) | Pathology value 0-40 | Egg capsule value 0-40 | ACI |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) | 50 | 81.86 | 80 | 28 | 1 | 132.86 |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) | 100 | 94.78 | 95 | 28.4 | 1 | 160.38 |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) | 150 | 92.93 | 90 | 26.7 | 1 | 155.23 |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (1: 9) | 50 | 90.35 | 65 | 35.7 | 1 | 118.65 |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (1: 9) | 100 | 77.72 | 70 | 36.7 | 0 | 111.02 |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (1: 9) | 150 | 98.75 | 80 | 20.0 | 1 | 157.75 |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley acid esters (1: 1) | 50 | 89.90 | 55 | 39.2 | 20 | 85.70 |
| Thiocarbonic acid SOH two-thymotic acid ester and thiocarbonic acid SOH two-Sheep's-parsley ester (1: 1) | 100 | 76.10 | 60 | 32.3 | 20 | 83.80 |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (1: 1) | 150 | 94.16 | 80 | 23.8 | 10 | 140.36 |
| Toltrazuril | 25 | 97.16 | 95 | 22.5 | 0 | 169.66 |
| Diclazuril | 1 | 86.68 | 70 | 34.4 | 1 | 121.28 |
| Negative control | - | 100.00 | 100 | 0.00 | 0 | 200.00 |
| Infect contrast | - | 50.66 | 55 | 40.0 | 40 | 25.66 |
The result shows: in each dosage group, and two-hundred li esters of thiocarbonic acid SOH: thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) 100 * 10
-6Group ACI is 160.38; Be higher than other two dosage groups; In two-hundred li esters of thiocarbonic acid SOH and each dosage group of thiocarbonic acid SOH two-Sheep's-parsley ester (1: 9), 150 * 10
-6Group ACI is 157.75, all is better than other two dosage groups; In two-hundred li esters of thiocarbonic acid SOH and each dosage group of thiocarbonic acid SOH two-Sheep's-parsley ester (1: 1), 150 * 10
-6ACI is 140.36, is better than other two dosage groups; From the precursor compound of thymol and isothymol, two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) 100 * 10
-6Group 100 * 10
-6Organize best.Toltrazuril 25 * 10
-6ACI is 169.66, and is the highest in this test; Diclazuril 1 * 10
-6Group ACI 121.28 is lower than two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) 100 * 10
-6Group 100 * 10
-6Group.
Infect the back and killed remaining chicken on the 20th day, rate of body weight gain, the relative weight gain rate, caecum lesion is kept the score as table 15:
Table 15
| Group | Dosage * 10 -6 | Rate of body weight gain (%) | The relative weight gain rate (%) | Caecum lesion keep the score (0～4) |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH Sheep's-parsley ester (3: 7) | 50 | 257 | 85.10 | 1.33 |
| Two-hundred li ester-thiocarbonic acid SOH two-Sheep's-parsleys of thiocarbonic acid SOH ester (3: 7) | 100 | 266 | 88.08 | 0.67 |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) | 150 | 225 | 74.50 | 0.50 |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (1: 9) | 50 | 239 | 79.15 | 1.33 |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (1: 9) | 100 | 244 | 80.79 | 0.67 |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (1: 9) | 150 | 265 | 87.75 | 0.50 |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (1: 1) | 50 | 161 | 55.00 | 1.67 |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (1: 1) | 100 | 196 | 65.00 | 1.00 |
| Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (1: 1) | 150 | 224 | 74.17 | 0.67 |
| Toltrazuril | 25 | 230 | 76.16 | 0.00 |
| Diclazuril | 1 | 228 | 75.50 | 0.80 |
| Negative control | - | 302 | 100 | 0.00 |
| Infect contrast | - | 151 | 50 | 2.00 |
The result shows: in two-hundred li esters of thiocarbonic acid SOH and each dosage group of thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7), and 100 * 10
-6The group rate of body weight gain is up to 266%; A little more than other two dosage groups, from the recovery 150 * 10 of caecum
-6Group better; At two-hundred li esters of thiocarbonic acid SOH and each dosage group the relative weight gain rate of thiocarbonic acid SOH two-Sheep's-parsley ester (1: 9) is 244%, is better than other two dosage groups, from the recovery 150 * 10 of caecum
-6Group better; In two-hundred li esters of thiocarbonic acid SOH and each dosage group of thiocarbonic acid SOH two-Sheep's-parsley ester (1: 1), 150 * 10
-6The group rate of body weight gain is 224%, is better than other two dosage groups, from the recovery 150 * 10 of caecum
-6Group better; Toltrazuril 25 * 10
-6The group rate of body weight gain is 230%, is lower than thiocarbonic acid SOH two-thymyl ester and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) 150 * 10
-6Group, two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) 100 * 10
-6Group is higher than two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (1: 1) 150 * 10
-6Group, the recovery of its caecum is best; Diclazuril 1 * 10
-6Group rate of body weight gain 228% is lower than two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (1: 1), is higher than thiocarbonic acid SOH two-thymyl ester and thiocarbonic acid SOH two-Sheep's-parsley ester (1: 9) 150 * 10
-6Group and 100 * 10
-6Group does not have the good of 200 li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) from the recovery of caecum.
In sum, the coccidian oocyst number of experimental infection is every chicken 11 * 10
4Individual, because the virulence of coccidia is stronger, the mortality ratio that infects contrast reaches 45%, infect more seriously, and the chicken group the dead time occurs for infecting the back the 5th day, as a whole, though every group ACI value is not high, with respect to the severity that infects, result of treatment still clearly.Compare in the precursor compound of thymol and isothymol, two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) are better; Mortality ratio and toltrazuril 1 * 10
-6Mortality ratio identical, simultaneously both ACI are respectively 160.38,169.66, differ not to be very big, because that the administration of toltrazuril drinking-water absorbs is good than spice; Two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester (3: 7) 100 * 10
-6The mortality ratio of group is lower than the diclazuril group, rate of body weight gain is apparently higher than the diclazuril group, that two-hundred li esters of possible thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester are that the precursor compound of wild marjoram oil has is antibiotic, growth promoting function is relevant, and ACI significantly is higher than the diclazuril group.
So, the ester compound of thymol and/or Sheep's-parsley, being preferably two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester is a kind of natural wild marjoram oil effective ingredient: the precursor compound of thymol and isothymol, its curative effect is better than natural wild marjoram oil, toxicity is also minimum, even can say nontoxic.It is the new veterinary drug of a new generation's antibiotic (especially to Resistant strain) and anticoccidial, can replace or partly replace microbiotic and existing anticoccidial drug.
Claims (10)
1, the thymol of a kind of general formula (1) or the ester compound of isothymol
R wherein
1Be methyl, R
2Be sec.-propyl, R
1And R
2
Contraposition each other;-O-(X)-O-and R
1
Be ortho position or and R
2Be the ortho position, X=-CO-,-CS-,
-CO-(CH
2) n-CO-, n=0 wherein, 1,2; Do not comprise X=-CO-and R
2Be the ortho position ester compound.
2,, it is characterized in that described ester compound is carbonic acid two-Sheep's-parsley ester, two-hundred li esters of thiocarbonic acid SOH, thiocarbonic acid SOH two-Sheep's-parsley ester, two-hundred li esters of oxalic acid, oxalic acid two-Sheep's-parsley ester, two-hundred li esters of propanedioic acid, propanedioic acid two-Sheep's-parsley ester, two-hundred li esters of Succinic Acid or Succinic Acid two-Sheep's-parsley ester according to the ester compound of claim 1.
3, the preparation method of a kind of claim 1 or 2 ester compound comprises the thiocarbonic ester or the carbonic ether preparation of thymol or isothymol:
1. thymol or isothymol are dissolved in the organic solvent A, after the dissolving, under agitation logical adding phosgene or triphosgene, or thio phosgene; 2. splash in 0～-10 ℃ and be dissolved in dehydrogenation hydracid agent mixed solution in the organic solvent A, after adding again in stirring at room 2～4 o'clock; 3. back elimination solids is finished in reaction, washes solids with a small amount of organic solvent, merges organic layer, with the saturated common salt washing repeatedly, use anhydrous sodium sulfate drying again, behind the recovery organic solvent, residue is a liquid, with underpressure distillation or fractionation, residue is a solid organic solvent B recrystallization, gets pure product;
Or diester preparation:
1. thymol or isothymol are dissolved in the organic solvent A, under agitation add dicarboxylic acid chloride after the dissolving; 2. under 0～-10 ℃, splash into the mixed solution that is dissolved in dehydrogenation hydracid agent in the organic solvent A, after adding, in stirring at room 2～4 o'clock; 3. back elimination solids is finished in reaction, washes solids with a small amount of organic solvent, merges organic layer, with the saturated common salt washing repeatedly, use anhydrous sodium sulfate drying again, behind the recovery organic solvent, residue is a liquid, with underpressure distillation or fractionation, residue is a solid organic solvent B recrystallization, gets pure product.
4, according to the preparation method of the ester compound of claim 3, it is characterized in that described thymol or isothymol: phosgene or thio phosgene: the mol ratio of dehydrogenation hydracid agent is 2.1: 1: 3 or thymol or isothymol: triphosgene: the mol ratio of dehydrogenation hydracid agent is 6.3: 1: 7.
5, according to the preparation method of the ester compound of claim 3, it is characterized in that described organic solvent A is ether, sherwood oil, hexanaphthene, normal hexane, trichloromethane or methylene dichloride; The agent of described dehydrogenation hydracid is organic bases or mineral alkali; Described recrystallization organic solvent B is ethyl acetate, acetone or methyl alcohol and 95% ethanol.
6, according to the preparation method of the ester compound of claim 5, it is characterized in that described organic bases is pyridine or triethylamine; Described mineral alkali is sodium hydroxide, potassium hydroxide, sodium hydroxide-sodium sulphite mixed solution or salt of wormwood.
7, a kind of pharmaceutical activity composition comprises ester compound and the vehicle or the additive of following general formula (1),
R wherein
1Be methyl, R
2Be sec.-propyl, R
1And R
2
Contraposition each other;-O-(X)-O-and R
1For
Ortho position or and R
2Be the ortho position; X=-CO-,-CS-,-CO-(CH
2) n-CO-,
N=0 wherein, 1,2.
8, according to the pharmaceutical activity composition of claim 7, the ester compound that it is characterized in that described general formula (1) is two-hundred li esters of carbonic acid, carbonic acid two-Sheep's-parsley ester, two-hundred li esters of thiocarbonic acid SOH, thiocarbonic acid SOH two-Sheep's-parsley ester, two-hundred li esters of oxalic acid, oxalic acid two-Sheep's-parsley ester, two-hundred li esters of propanedioic acid, propanedioic acid two-Sheep's-parsley ester, two-hundred li esters of Succinic Acid, Succinic Acid two-Sheep's-parsley ester, can be active ingredient separately or form the pharmaceutical activity composition with any ratio.
9,, it is characterized in that two-hundred li esters of thiocarbonic acid SOH and thiocarbonic acid SOH two-Sheep's-parsley ester ratio are 3: 7 according to the pharmaceutical activity composition of claim 7 or 8; The ratio of two-hundred li esters of carbonic acid and carbonic acid two-Sheep's-parsley ester is 3: 7; Two-hundred li esters of oxalic acid and oxalic acid two-Sheep's-parsley ester ratio are 3: 7.
10,, it is characterized in that described pharmaceutical activity composition comprises pre-mixture preparation, solution, inclusion agent or microcapsule formulation, coccidiosis medicine or antimicrobial drug mixed feeding, coccidiosis medicine or antimicrobial drug tap water according to the pharmaceutical activity composition of claim 7.
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| JPS63255259A (en) * | 1987-04-14 | 1988-10-21 | Sanko Kaihatsu Kagaku Kenkyusho:Kk | Production of asymmetric sulfone |
| JPH044222A (en) * | 1990-04-20 | 1992-01-08 | Idemitsu Kosan Co Ltd | Raw material for optical equipment |
| CN1523005A (en) * | 2003-09-04 | 2004-08-25 | 中国科学院成都有机化学有限公司 | Reaction rectification process for interesterification synthesis of carbonic acid diaryl ester |
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| JPS63255259A (en) * | 1987-04-14 | 1988-10-21 | Sanko Kaihatsu Kagaku Kenkyusho:Kk | Production of asymmetric sulfone |
| JPH044222A (en) * | 1990-04-20 | 1992-01-08 | Idemitsu Kosan Co Ltd | Raw material for optical equipment |
| CN1523005A (en) * | 2003-09-04 | 2004-08-25 | 中国科学院成都有机化学有限公司 | Reaction rectification process for interesterification synthesis of carbonic acid diaryl ester |
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| Synthesis of carbonates of polysubstituted phenols Svishchuk,A. A.,Makhnovskii,N. K.,Sukharenko,N. V.,Basalkevich,E,Ukrainskii Khimicheskii Zhurnal (Russian Edition),Vol.41 No.5 1975 * |
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