CN106955280A - A kind of medicine for preventing and treating Haemophilus parasuis and its application - Google Patents
A kind of medicine for preventing and treating Haemophilus parasuis and its application Download PDFInfo
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- CN106955280A CN106955280A CN201710133832.4A CN201710133832A CN106955280A CN 106955280 A CN106955280 A CN 106955280A CN 201710133832 A CN201710133832 A CN 201710133832A CN 106955280 A CN106955280 A CN 106955280A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
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- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
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- C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
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Abstract
A kind of medicine for preventing and treating Haemophilus parasuis, specially Rhein or derivatives thereof, Rhein or Rhein derivatives or its pharmaceutically acceptable salt and hydrate can be used as the medicine for preventing or treating the relevant disease as caused by haemophilus parasuis.The invention further relates to the Rhein or derivatives thereof in the purposes for preparing the medicine for prevention and/or Prevention or treatment related symptoms as caused by haemophilus parasuis or disease.By inventor to the new mechanism of the Rhein or derivatives thereof and the discovery of New function, Scientific Usage of Drugs can be accomplished, shot the arrow at the target, it is evident in efficacy, beneficial to the rehabilitation of sick pig.
Description
Technical field
The present invention relates to veterinary drug technical field, more particularly to a kind of medicine for preventing and treating Haemophilus parasuis, is specially big
Yellow acid or/and its derivative, the invention further relates to the purposes of the medicine.
Background technology
Haemophilus parasuis (Haemophilus parasuis, HPS) is prevalent in the upper respiratory tract of pig, Neng Gouyin
Rise pig Ge Lasaiershi disease (Disease) [1], clinical symptoms mainly have under 40 DEG C -42.5 DEG C of heating, appetite
Drop, apocleisis is slow in reacting, has difficulty in breathing, cough, abdominal respiration, arthroncus, walks lamely and even paralyse, ear skin, belly skin
Lower oedema, have sharp ears is blue, and cyanosis on the inside of ear four limbs, pale anaemia, surrounding eyelids subcutaneous dropsy, eye conjunctiva reddens, and dorsal body setae is thick
Disorderly, back pore has skin of abdomen between needle point sample bleeding, two back legs to have a large amount of bluish violet spots [2-5].Age of onset was from 2 weeks
Age to 4 monthly ages are generally more common in the piglet of 5-8 week old.The good and more healthy swinery of sanitary condition, stress be because once running into
Often it is more easy to break out this after element, such as reproductive and respiratory syndrome virus, circovirus type II, pseudorabies virus and influenza virus infection, very
Mix sense to infectious pleurisy Actinobacillus, Pasteurella, streptococcus etc., course of infection is often also even more serious, fall ill
Rate is up to 10%-15%, and sometimes up to 40%, case fatality rate is up to 50%-80% [6,7].In addition haemophilus parasuis may be used also
Cause septicemia, and sequelae, such as chronic limping of Sow abortion, boar [8] may be left after acute infection.The disease is at present
In worldwide distribution, oneself turns into the typical bacterial infectious disease of influence pig industry, has this disease in pig industry developed country
Popular and generation, and haemophilus disease has the situation for tending to be serious, and huge economic loss [9,10] is brought to pig industry.
At present, antibiotic medicine preventing and treating and vaccine immunity are mainly to the prevention and controls of Haemophilus parasuis both at home and abroad.
Many raisers and manufacturing enterprise take the mode of antibiotic spice to prevent whole swinery, and morbid pig mass selection is resisted with sensitive
The raw heavy dose of intramuscular injection of element is treated.But not only led due to unscientific, blindness abuse of antibiotics during preventing and treating
Cause the disease to generate drug resistance to many antibiotic, delay the state of an illness, also result in antibiotics toxic in animal body and remain, to food
Safety brings potential threat.And vaccine immunity due to the cross-protection between the numerous serotypes of haemophilus parasuis is low can not be right
The disease provides fully effective immunoprotection.In view of the seriousness that is endangered in pig industry of the disease, abuse of antibiotics bring it is negative
The application present situation that face rings and vaccine immunity often fails, it is necessary to which researching and developing a kind of can prevent and treat the sick safety well
Have no drug resistance generation novel chiral synthon and popularization and application.
Knowledge based on inventor, shows that Rhein and its derivative are prepared for preventing and/or controlling currently without report
The medicinal usage for the treatment of is not reported even more.
Bibliography：
1.Zhou X,Xu X,Zhao Y,Chen P,Zhang X,Chen H,Cai X.Distribution of
antimicrobial resistance among different serovars of Haemophilus parasuis
isolates.Veterinary microbiology,2010,141:168-173.
2. merchant love minister in ancient times, Li Chunling, the present Research herdings of Wang Gui equality haemophilus parasuis virulence factors and animal doctor,
2008,40:92-94.
3. all ages put down, Wang Jian, the haemophilus parasuis virulence factors such as Ge Feifei grind make internal disorder or usurp progress herdings and animal doctor,
2010,42:101-104.
4. Xue state is clever, that appoints great waves Haemophilus parasuis epidemiology and virulence factor grinds the Chinese herding beasts of progress that make internal disorder or usurp,
2009,36:168-171.
5.Oliveira S,Pijoan C.Haemophilus parasuis:new trends on diagnosis,
epidemiol-ogy and control.Vet Microbiol.2004,99:1-12.
6.Costa-Hurtado M,Ballester M,Galofré-MilàN,Darji A,Aragon V.VtaA8
and VtaA9 from Haemophilus parasuis delay phagocytosis by alveolar
macrophages.Vet Res.2012,27:43-57.
7.Narita M,Kawashima K,Matsuura S,Uchimura A,Miura Y.Pneumonia in
pigs infected with pseudorabies virus and Haemophilus parasuis serovar 4.J
Comp Pathol.1994,110:329-39.
8.Kim J,Chung HK,Jung T,Cho WS,Choi C,Chae C.Postweaning
multisystemic wasting syndrome of pigs in Korea:prevalence,microscopic
lesions and coexisting microorganisms.J Vet Med Sci.2002,64:57-62.
9. Cai Xu is prosperous, the harm of Chen Huanchun Haemophilus parasuis and its control strategy cultivation and feed, 2004,6:
34-37.
10.Straw BE,Allaire SD,Meigeling WL,Taylor DJ.Diseases of swine.8th
Edition.Ames,lowa,USA:Lowa state universitu press,1999,475-481.
The content of the invention
A kind of new preventing and treating haemophilus parasuis is provided it is an object of the invention to mend compound after screening
The medicine of disease, has no drug resistance safely；Prevent or treat by pair as preparing it is a further object to provide this kind of medicine
Application in relevant disease medicine caused by haemophilus suis.
To achieve these goals, a kind of medicine for preventing and treating Haemophilus parasuis that the present invention is provided is Rhein or big
Yellow acid derivative, it is defined by lower formula (I) or (II) respectively：
Including its single isomers, the racemic of isomers or non-racemic mixture, oxide or its pharmaceutically may be used
The salt and hydrate of receiving
Wherein, R1Selected from-COOH or-SO3H；R2~R6Selected from hydrogen, alkyl, halogen ,-CN ,-OH ,-N3、-NO2、-N(R)2、
- CH ═ NR ,-OR ,-COR ,-OCOR, wherein, R is methyl or ethyl.
It is alkyl, cycloalkyl, cycloalkenyl group, alkenyl, alkynyl or aryl the present invention relates to described substituent；Wherein, alkyl
The number of carbon be 1-10, the number of the carbon of cycloalkyl is 3-8, and the number of the carbon of cycloalkenyl group is 5-6, and the number of the carbon of alkenyl is
2-6, the number of the carbon of alkynyl is 2-6, and the number of the carbon of aryl is 6-10.
In another aspect of the present invention, the pharmaceutically acceptable salt provided is selected from sylvite or sodium salt.
It is being oral formulations, external preparation, suction it is still another aspect of the present invention to provide the optional formulation of the medicine
Preparation, through nasal preparation, per rectum preparation, percutaneous preparation or ejection preparation.Preferably oral formulations.
In the present invention in one aspect, to having suffered from or having suffered from or be in the wind with Haemophilus parasuis
The pig pig of danger applies the medicine containing Rhein and its derivative of prevention and/or therapeutically effective amount.
The effective dose includes apply about 0.1mg/kg daily to pig to about 10000mg/kg body weight.
In another aspect of the invention there is provided the pharmaceutical composition containing Rhein or/and its derivative, described
Pharmaceutical composition in, Rhein or/and its derivative proportion, by weight, account for whole preparation gross weight be 10%-
80%.
In the world, inventor uses the screening from natural Chinese medicinal herb to obtain a Rhein without any side effects
And its derivative, effectively prevent and/or treat first Haemophilus parasuis.Accomplish Scientific Usage of Drugs, shoot the arrow at the target.It is also first
The secondary this function of being found that Haemophilus parasuis, has filled up the country of Chinese herbal medicine modernization, international blank, beneficial to the health of pig
It is multiple, production and the raising of yield.
Embodiment
The substantive of the present invention is understood in order to provide, certain of the present invention is hereinafter described with different the level of details
A little aspect, pattern, embodiment, modification and features.
In implementing the present invention, it may, having used zoology, medicine organic chemistry, cell biology, immunology, micro- life
Many conventional arts such as thing.These technologies are well known.
Elaboration is further retouched in detail to present invention work with reference to embodiment：
A kind of medicine for preventing and treating Haemophilus parasuis is Rhein or Rhein derivatives or its pharmaceutical salts, and described is big
Yellow acid derivative is the compound with formula (1),
Wherein, R1Selected from-COOH or-SO3H；R2~R6Selected from hydrogen, alkyl, halogen ,-CN ,-OH ,-N3、-NO2、-N(R)2、
- CH ═ NR ,-OR ,-COR ,-OCOR, wherein, R is methyl or ethyl.
It is alkyl, cycloalkyl, cycloalkenyl group, alkenyl, alkynyl or aryl the present invention relates to described substituent；Wherein, alkyl
The number of carbon be 1-10, the number of the carbon of cycloalkyl is 3-8, and the number of the carbon of cycloalkenyl group is 5-6, and the number of the carbon of alkenyl is
2-6, the number of the carbon of alkynyl is 2-6, and the number of the carbon of aryl is 6-10.
The pharmaceutical salts that the present invention is provided are selected from sylvite, sodium salt.
The invention further relates to described Rhein or Rhein derivatives or its pharmaceutical salts as prepare prevent or treat by
Application in relevant disease medicine caused by haemophilus parasuis.
The medicine and preparation method of the present invention is described in more detail in the following example, but embodiment is not constituted to this hair
Bright limitation.
It will be understood by those skilled in the art that the Rhein and its derivative include its single isomers, isomers
Racemic or non-racemic mixture, oxide or its pharmaceutically acceptable salt and hydrate.
In the specific embodiment of the present invention, by rheum officinale acid compound carry out base group modification, such as amination,
The chemical modification such as carboxylated, aldehyde radical, Benzylation, can prepare activity and the different rheum officinale acid compound of physicochemical property derives
Thing.
In certain specific embodiments of the invention, the yellow acid derivative of the present invention is prepared for.Described Rhein spreads out
Biology includes but is not limited to：2,4,5,6,7- pentamethyls Rhein (HX-1), 7- ethyls Rhein derivatives (HX-2), 7- acetyl
Base Rhein derivatives (HX-3), 7- vinyl Rhein derivatives (HX-4), 7- bromos Rhein derivatives (HX-5) etc..
The definition of some terms used in this specification, unless otherwise indicated, all technologies used herein and section
Learn the meaning equivalent in meaning that term generally has and those skilled in the art are generally understood that.
The preventive use and therapeutical uses of Rhein and its derivative
In an embodiment of the invention, screening dynamics reality is carried out by using potential candidate compound
Test, those skilled in the art's screening is with the preventive and therapeutic action to haemophilus parasuis bacterial strain.Especially, candidate is passed through
The dynamics screening experiment of compound determines that Rhein and its derivative can prevent and treat haemophilus parasuis bacterial strain completely.
Term " treatment " used herein refers to measure treating treatment measures and prevent or preventing, wherein,
Prevent or slow down the pathological symptom suffered from or the imbalance of (decrease) subject.If receiving controlling according to method described herein
The Rhein and its derivative for the treatment of amount, then the symptom of subject succeed " treatment ", subject shows, it is observed that
And/or it is measured to one or more signs and symptom reduction and the disappearance of symptom.It is also understood that treatment described herein or anti-
Only the various patterns of medical conditions are intended to mean that " notable ", it include all treatment or prevention and less than all treatment or
Prevention, wherein having reached the result that certain biology is related or medical science is related.
In the specific embodiment of the present invention, prevention is applied to subject and/or therapeutically effective amount contains rheum officinale
The medicine of acid and its derivative.
Term " effective dose " used herein refers to being enough the treatment needed for obtaining and/or preventive effect, for example, drawn
Play prevention or mitigate the amount of the symptom with pathological symptom or disease.The amount of composition of subject is administered to by depending on disease
The property of type and seriousness and individual, such as health condition, age, sex, body weight and the tolerance to medicine usually.
The amount additionally depends on extent, seriousness and type.Those skilled in the art be possible to according to these factors and other because
Usually determine suitable dosage.The composition may also be combined with one or more other therapeutic compounds to be administered.Herein
In the method for description, compound of the invention can be administered to one or more signs with pathological symptom or pathological symptom
Subject.For example, " therapeutically effective amount " refers to the average level for minimally mitigating the physiological action of symptom.
Generally, the dosage is possible to prevent or mitigates seriousness or the extension of institute's treatment situation or indication.Correct agent
Amount will depend on environment, the situation for example treated, administration time table, the compound whether be administered alone or with it is another
Holistic health of the therapeutic agent with reference to administration, the plasma half-life of the compound and subject.
Can use includes oral, external application, and suction, intranasal, per rectum, percutaneous or injection method of application is used subject
Medicine.
In the specific embodiment of the present invention, it is prepared for containing for the compound disclosed herein, daily
Dosage scheme be about 0.1mg/kg to about 10000mg/kg body weight, be preferably from about 1mg/kg to about 1000mg/kg body weight, more
Preferably 1mg/kg to about 500mg/kg, most preferably 1mg/kg are to about 200mg/kg body weight.Daily can be using 1 to 6 time, preferably
It is daily to apply 2 or 3 times.Interval can also be irregular, skilled artisans recognize that compound or its is pharmaceutically acceptable
The optimised quantity of salt and the interval of single-dose by by the nature and extent of situation to be treated, form, approach and the site of administration
And the subject treated concrete condition and determine, and most preferably scheme can be determined with routine techniques.Art technology
Personnel should also be understood that the optimum process for the treatment of, i.e., the compound given daily in given number of days or its can pharmaceutically connect
The administration quantity for the salt received can be determined by those skilled in the art using conventional treatment method of testing.In treatment use
In, there is relatively high dosage to be sometimes needs in relatively short time interval, until the process of disease slows down or terminates as
Only, the disease or pathological symptom and preferably up to subject shows partial or are fully improved.Therefore, patient can be right
The administering mode of effecting prevention property of patient.It would be recognized by those skilled in the art that some factors can influence to effectively treat one
The order of severity of the dosage of subject and time, including but not limited to disease or imbalance, previous treatment, health condition and/
Or age and the Other diseases of presence of subject.Combined moreover, being compareed using the treatment of therapeutically effective amount described herein
Thing can include single therapy or a series of treatments to treat a subject.
The compound of the present invention can be applied together with other at least one Chinese herbal medicines.Chinese patent drug can select radix bupleuri, Radix Angelicae Sinensis,
The red sage root, cassia twig, the root of herbaceous peony, dried orange peel, prepared RHIZOMA PINELLIZE without adju-vant, lopseed, notopterygium root, radix rehmanniae recen, balloonflower root, Mugua Wan, dahuoluo pills, Xiao Huoluo Dan,
Rhizoma cyperi, semen brassicae, radix aconiti agrestis, RADIX ACONITI LATERALIS PREPARATA, caulis lonicerae, bark of ash, ramulus mori, Poria cocos.It will be appreciated by those skilled in the art that with the present invention
The above-claimed cpd applied together of compound can be made a choice according to described various disease or pathological symptom.
The compound or Chinese herbal medicine can either be combined as single preparation be administered simultaneously in unit dosage forms or
Sequentially apply.Under any circumstance, a variety of therapeutic agents can in any order or be even administered simultaneously.If simultaneously, described
A variety of therapeutic agents can be provided as single, unified form or in multiple forms (for example, being used as single tablet or each
Independent tablet or two kinds of capsule different preparations).A kind of therapeutic agent in the therapeutic agent may be provided with multiple dose type, or
Two kinds therein of person can provide as multiple dose type.If simultaneously, the time interval between multidose can be from
About half was arrived less than about 1 week, less than about 2 weeks, less than about 4 weeks, less than about 2 months, less than about 4 months or is even less than more than 0 week
Change in the scope in year.
Terms used herein " unit dosage forms " refer to be suitable as the unit dose for humans and animals subject
Physically separated unit, compound of each unit comprising single scheduled volume or with other agent combinations, its amount is computed
It is enough to produce desired effects with pharmaceutically acceptable diluent, carrier or media mix.
In the embodiment of the present invention, the pharmaceutical composition containing Rhein or derivatives thereof is prepared, it is used for
Treatment and/or the pathological symptom or disease of prevention haemophilus parasuis bacterial strain.It is right by modes such as oral, external application, inhalations
Snibject and play a role.Therefore the pharmaceutical composition of the present invention can be prepared into various formulations, for example, for for oral use
The composition of medicine can be capsule, tablet, pulvis, granule, lozenge, effervescent tablet, syrup, emulsion, the prepared product of controlled release, fast
Prepared product, oral liquid dosage forms of instant solution etc.；Composition for external application medication can be liniment type medicine, creme, outer
Deposited, ointment, lotion, the gentle spray of liquid spray etc..The composition being administered for inhalation can be solution, disperse
Liquid, dry powder etc.；Can also subordinate plant extract high-purity rheum officinale acid compound, prepare liposome nano rhubarb acid,
It is prepared into ejection preparation and extended drug form.In described pharmaceutical composition, Rhein or its derivative institute accounting
Example, accounts for the gross weight of whole preparation as 0.0%-99.0%, preferably 0.0%-90%, more preferably 10%- using weight
80%, most preferably 25-70%.
In pharmaceutical preparation of the present invention, by taking oral formulations as an example, pharmaceutically acceptable auxiliary material used includes but not limited to
In lubricant, such as carboxymethyl cellulose, cross-linked carboxymethyl cellulose, PVPP, magnesium stearate, stearic acid
Calcium, or zinc stearate, stearic acid, Compritol 888 ATO, sodium stearyl fumarate, talcum, silica gel；Disintegrant, such as starch, ring
Dextrin；Diluent or compression agent, such as D-sorbite, microcrystalline cellulose, lactose, sucrose, mannitol xylitol, erythritol；Adjust
Taste substance or other compositions, such as strawberry, orange, banana, peppermint, honey.
Carrier granular can be lactose or the crystal or spheroid of sucrose；Or composite sphere or particle, such as make by using starch
Sucrose is set to granulate the sugared spheroid to be formed for adhesive, the carbonic acid calcospherite formed by starch as adhesive or malt paste
Essence.Carrier granular can also be the particle of any other medical acceptable excipient, such as guar gum particle, xanthans
Particle/hydroxy propyl cellulose crude granule.Carrier can have diversified forms, and all these selections and the adjustment of amount are obviously in this area skill
In the limit of power of art personnel.
Recorded by following examples, more fully understand the present invention, but be not limited to the embodiment.
Embodiment
The bacteriostatic activity of the Rhein of embodiment 1
Medicine and reagent：
Soybean caseinAgarCulture medium (TSB), Rhein, ampicillin, DMSO, horse serum, nicotinamide adenine two
Nucleotides (NAD), ethanol, it is AR, PBS (phosphate buffer 0.0lmol/L, pH7.4, two water phosphorus
Sour disodium hydrogen 2.9g, potassium dihydrogen phosphate 0.2g, sodium chloride 8.0g, potassium chloride 0.2g, distilled water 1000mL).
Strain：
Haemophilus parasuis
Experimental method：
The preparation of culture medium
TSB culture medium 30g, are added in 1000mL distilled water, and dissolving is boiled in heating, packing, 121 DEG C of autoclavings 15 minutes
It is standby.5mL horse serums and 100 μ gNAD are added in the TSB culture mediums configured per 100mL.
The culture of test organisms
In desinfection chamber, haemophilus parasuis bacterial strain (1-25 bacterial strains are clinical strains) is inoculated with being used under alcolhol burner
Pin scrapes a small amount of inclined-plane lawn, bacteria suspension is made with a certain amount of sterilized water on test strain inclined-plane, then takes a certain amount of add
Melt to oneself and be cooled to again in 50 DEG C or so of TSB culture mediums, shake up, pour at once in sterile petri dish, after after abundant condensation
After being sealed with plug, 18-24h is cultivated in 37 DEG C standby.Bacterium solution ImL is drawn, 1 is pressed with TSB culture mediums：1000 dilutions, make bacterium solution
Concentration is about 105cfu/mL。
Antibacterial experiment：
Candidate drug is dissolved in the solution that 2560/ μm of L is configured in DMSO, then with doubling dilution by chemicals dilating
Into-determine concentration gradient (128/ μm of L, 64/ μm of L, 32/ μm of L, 16/ μm of L, 8/ μm of L, 4/ μm of L, 2/ μm of L, 1/ μm of L, 0.5/ μm of L,
0.25/ μm of L) with DMSO in.100u L culture medium is separately added into sterilizing microtiter plate first, Article 2 is the positive
Control, adds 100 μ L bacteria suspensions.90 μ L bacteria suspension and 10 μ L drug solution are added in remaining hole.Each drug solution
Concentration is parallel 3 times.The culture dish handled is cultivated into 24h, observation in 37 DEG C.
MIC measure
After each microtiter plate can intuitively determine its MIC value, 50 μ L are added in each hole of plate
PBS (phosphate buffer 0.0lmol/L, pH 7.4, phosphate dihydrate disodium hydrogen 2.9g, potassium dihydrogen phosphate 0.2g, chlorination
Sodium 18.0g, potassium chloride 0.2g, distilled water l000mL), wherein including 2mg MTT/mL.Continue to be incubated 4-5h at room temperature.By hole
In material isopropanol that 100 μ L contain 5%1M hydrochloric acid is removed and adds to extract dyestuff.Continuation is incubated 12h at room temperature, in
ELIASA determines each hole light absorbs (OD values), determines wavelength 550nm.Minimum of the medicine to bacterial growth is calculated according to each hole OD values
Inhibition concentration.
Experimental result
The MIC measured is shown in Table shown in l
Suppression MIC value (μ g/mL) of the Rhein of table 1 to bacterium
Experiment shows that Rhein has obvious inhibitory action to haemophilus parasuis.
Embodiment 2 prepares 2,4,5,6,7- pentamethyls Rhein (HX-1)
Rhein (1.42g, 0.005mol), DMF (50mL), the lower addition iodine of stirring are sequentially added in 250mL three-necked bottles
Methane (7.1g, 0.05mol) and p-methyl benzenesulfonic acid (0.17g), at room temperature, stir 24h, TLC detection display reactions are complete, add water
(10mL), at room temperature, stirs 24h, will be poured into reaction solution in 500mL frozen water, filter, and filter cake is vacuum dried, obtains yellow
Brown solid 1.6g, through silica gel post separation, collects product, is recovered under reduced pressure after solvent, obtains 2,4,5,6,7- pentamethyl Rheins
0.60g, yield is 33.9%.1H-NMR (CDCl3,300MHz) δ：13.7 (s, 1H) 11.9 (s, 2H), 2.4~2.5 (m,
15H)。
Embodiment 3 prepares 7- ethyls Rhein derivatives (HX-2)
Rhein (1.42g, 0.005mol), DMF (50mL), the lower addition bromine of stirring are sequentially added in 250mL three-necked bottles
Ethane (1.1g, 0.01mol) and p-methyl benzenesulfonic acid (0.17g), at 60 DEG C, stir 2h, TLC detection display reactions are complete, add water
(10mL), at room temperature, stirs 24h, will be poured into reaction solution in 500mL frozen water, filter, and filter cake is vacuum dried, obtains yellow
Brown solid 1.5g, through silica gel post separation, collects product, is recovered under reduced pressure after solvent, obtains 7- ethyl Rhein 0.31g, yield is
21.4%.1H-NMR (CDCl3,300MHz) δ：13.7 (s, 1H) 11.9 (s, 2H), 8.1 (s, 1H), 7.8 (d, 1H), 7.7 (m,
2H), 2.5 (m, 2H), 1.3 (t, 3H).
Embodiment 4 prepares 7- acetyl group Rhein derivatives (HX-3)
7- ethyls Rhein derivatives (HX-2) (1.56g, 0.005mol), acetic acid are sequentially added in 250mL three-necked bottles
(150mL), stirring is lower to be added at chromic anhydride (1.5g, 0.015mol), 50 DEG C, stirs 4h, and TLC detection display reactions are complete, in room
It under temperature, will pour into 500mL frozen water, filter in reaction solution, filter cake is vacuum dried, Tan solid 1.5g is obtained, through silica gel
Post separation, collects product, is recovered under reduced pressure after solvent, obtains 7- acetyl group Rhein 0.81g, yield is 49.7%.1H-NMR
(CDCl3,300MHz) δ：13.7 (s, 1H) 11.9 (s, 2H), 8.1 (s, 1H), 7.9 (d, 1H), 7.8 (d, 1H), 7.7 (s, 1H),
2.6(s,3H)。
Embodiment 5 prepares 7- vinyl Rhein derivatives (HX-4)
7- ethyls Rhein derivatives (HX-2) (1.56g, 0.005mol), DMF are sequentially added in 250mL three-necked bottles
(50mL), stirring is lower to be added at bromo-succinimide (1.0g, 0.006mol), 80 DEG C, stirs 7h, TLC detection display reactions
Completely, potassium tert-butoxide (0.6g, 0.005mol) is added, at 100 DEG C, 1h is stirred, will be poured into reaction solution in 500mL frozen water,
Filtering, filter cake is vacuum dried, Tan solid 1.1g is obtained, through silica gel post separation, product is collected, is recovered under reduced pressure after solvent,
7- vinyl Rhein 0.11g are obtained, yield is 7.01%.1H-NMR (CDCl3,300MHz) δ：13.7(s,1H)11.9(s,
2H), 8.1 (s, 1H), 7.8 (d, 1H), 7.7 (m, 2H), 6.9 (m, 1H), 5.4 (d, 2H).
Embodiment 6 prepares 7- bromos Rhein derivatives (HX-5)
Rhein (1.42g, 0.005mol) is sequentially added in 250mL three-necked bottles, DMF (50mL) is slow to drip under stirring
Plus bromine (0.8g, 0.005mol), at 0 DEG C, 1h is stirred, TLC detection display reactions are complete, 500mL ice will be poured into reaction solution
In water, filtering is vacuum dried by filter cake, obtains yellow solid 1.1g, through silica gel post separation, collects product, solvent is recovered under reduced pressure
Afterwards, 7- bromo Rhein 0.6g are obtained, yield is 31.75%.1H-NMR (CDCl3,300MHz) δ：13.7(s,1H)11.9(s,
2H), 8.1 (s, 1H), 7.8 (d, 1H), 7.7 (m, 2H).
Using haemophilus parasuis as strain subject, contrast Rhein and part Rhein derivatives (HX-1, HX-2, HX-3,
HX-4, HX-5) MIC (MIC), test result indicate that, Rhein derivatives HX-1 bacteriostatic activity and Rhein
Close, Rhein derivatives HX-2, HX-3, HX-4, HX-5 bacteriostatic activity are better than Rhein.
The present invention is not limited to particular implementation described in this application, as the single of single aspect of the invention
Explanation.It will be understood by those skilled in the art that carried out in the case of spirit and scope can not departed from it is various modification and
Change.As described above, in addition to enumerating herein, the functionally equivalent purposes in the scope of the present disclosure is for this
It is obvious for the those skilled in the art in field.Such change and modification are intended to fall in scope of the following claims
It is interior.The disclosure is limited only by appended claims and with the four corner that the scope of such claim is equal.Should
Work as understanding, the disclosure is not limited to specific method, reagent, composition and biosystem, certainly, methods described, reagent, combination
Thing and biosystem can change.It can also be appreciated that term used herein is only used for describing specific embodiment, it is not used to
It is restricted.
All patents referred herein or reference, patent application, earlier application and the publication full text by reference
It is incorporated herein so that they are not contradicted with the clearly teaching of this specification.Other implement is proposed within the scope of the claims
Mode.
Claims (9)
1. Rhein or/and its derivative are used for the purposes for preventing and/or treating the medicine of Haemophilus parasuis in preparation, its
It is characterised by：Described medicine is respectively lower formula (I) by Rhein or Rhein derivatives and (II) is defined including its is independent
Isomers, the racemic of isomers or non-racemic mixture, oxide or its pharmaceutically acceptable salt and hydrate,
Wherein, R1Selected from-COOH or-SO3H；R2~R6Selected from hydrogen, alkyl, halogen ,-CN ,-OH ,-N3、-NO2、-N(R)2、-CH═
NR ,-OR ,-CHO ,-COR ,-OCOR, wherein, R is methyl or ethyl.
2. the medicine of preventing and treating Haemophilus parasuis according to claim 1, it is characterised in that：Described substituent is alkane
Base, cycloalkyl, cycloalkenyl group, alkenyl, alkynyl or aryl；Wherein, the number of the carbon of alkyl is 1-10, and the number of the carbon of cycloalkyl is
3-8, the number of the carbon of cycloalkenyl group is 5-6, and the number of the carbon of alkenyl is 2-6, and the number of the carbon of alkynyl is 2-6, the carbon of aryl
Number is 6-10.
3. purposes according to claim 1, it is characterised in that：Described pharmaceutically acceptable salt is selected from sylvite or sodium
Salt.
4. purposes as claimed in claim 1 or 2, it is characterised in that：The medicine is oral formulations.
5. purposes as claimed in claim 4, it is characterised in that：The purposes, which also includes applying pig, prevents and/or treats to have
Effect amount 0.1mg/kg to about 10000mg/kg body weight the medicine containing Rhein and its derivative.
6. purposes as claimed in claim 7, it is characterised in that：Described pig is to have suffered from or suffered from or be in suffer from
The pig of the risk of Haemophilus parasuis.
7. a kind of preparation method of pentamethyl Rhein, it is characterised in that：Described method is concretely comprised the following steps：In 250mL tri-
Rhein (1.42g, 0.005mol), DMF (50mL), the lower addition iodomethane (7.1g, 0.05mol) of stirring are sequentially added in neck bottle
With p-methyl benzenesulfonic acid (0.17g), at room temperature, 24h is stirred, TLC detection display reactions are complete, and add water (10mL), at room temperature, stirs
24h is mixed, will be poured into reaction solution in 500mL frozen water, is filtered, filter cake is vacuum dried, Tan solid 1.6g is obtained, through silica gel
Post separation, collects product, is recovered under reduced pressure after solvent, obtains 2,4,5,6,7- pentamethyl Rhein 0.60g, yield is 33.9%.1H-
NMR (CDCl3,300MHz) δ：13.7 (s, 1H) 11.9 (s, 2H), 2.4~2.5 (m, 15H).
8. a kind of preparation method of ethyl Rhein, it is characterised in that：Described method is concretely comprised the following steps：In the necks of 250mL tri-
Sequentially add Rhein (1.42g, 0.005mol) in bottle, DMF (50mL), stirring is lower add bromoethane (1.1g, 0.01mol) and
P-methyl benzenesulfonic acid (0.17g), at 60 DEG C, stirs 2h, TLC detection display reactions are complete, and add water (10mL), at room temperature, stirring
24h, will be poured into 500mL frozen water in reaction solution, filtering, and filter cake is vacuum dried, Tan solid 1.5g be obtained, through silicagel column
Separation, collects product, is recovered under reduced pressure after solvent, obtains 7- ethyl Rhein 0.31g, yield is 21.4%.1H-NMR (CDCl3,
300MHz)δ：13.7 (s, 1H) 11.9 (s, 2H), 8.1 (s, 1H), 7.8 (d, 1H), 7.7 (m, 2H), 2.5 (m, 2H), 1.3 (t,
3H)。
9. purposes as claimed in claim 4, it is characterised in that：The medicine is also included containing the dilution with pharmaceutically being received
Agent or carrier mixing Rhein or/and its derivative pharmaceutical composition, in described pharmaceutical composition, Rhein or/
With its derivative proportion, by weight, the gross weight for accounting for whole preparation is 10%-80%.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL2033150B1 (en) * | 2022-09-27 | 2023-06-16 | Inst Animal Health Guangdong Academy Agricultural Sciences | Application of limonium wrightii naphthoquinone in preparing anti- haemophilus parasuis drug |
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| CN106344549A (en) * | 2016-11-02 | 2017-01-25 | 江苏康缘药业股份有限公司 | Application of rhein in preparation of drugs for preventing and/or treating hand-foot-and-mouth disease |
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2017
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| CN106344549A (en) * | 2016-11-02 | 2017-01-25 | 江苏康缘药业股份有限公司 | Application of rhein in preparation of drugs for preventing and/or treating hand-foot-and-mouth disease |
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| NL2033150B1 (en) * | 2022-09-27 | 2023-06-16 | Inst Animal Health Guangdong Academy Agricultural Sciences | Application of limonium wrightii naphthoquinone in preparing anti- haemophilus parasuis drug |
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