CN105001112A - Water soluble chlorotetracycline succinic acid monoester salt, and preparation method thereof - Google Patents
Water soluble chlorotetracycline succinic acid monoester salt, and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of chemical synthesis, and more specifically relates to a water soluble chlorotetracycline succinic acid monoester salt, and a preparation method thereof. The preparation method is used for modifying chlorotetracycline. The chlorotetracycline succinic acid monoester salt possesses a structure represented by formula I, wherein M is used for representing Na, K, meglumine, arginine, or lysine. According to the preparation method, grafting modification of chlorotetracycline with succinic anhydride is carried out so as to obtain the chlorotetracycline succinic acid monoester salt with water solubility better than that of chlorotetracycline, and broad-spectrum antibacterial property of the water soluble chlorotetracycline succinic acid monoester salt is the same as that of chlorotetracycline in animal bodies.
Description
Technical field
The invention belongs to chemosynthesis technical field, be specifically related to water-soluble duomycin succinic monoester salt and preparation method thereof.
Background technology
Duomycin (Chlortetracycline, CTC) is tetracycline antibiotics, and chemical structure only instead of H with Cl with tsiklomitsin on C-7 position, so duomycin is also called 7-Uromycin, structural formula is as follows:
Isphamycin is golden yellow or yellow crystallization, odorless, bitter, and slightly soluble in water and ethanolic soln is almost insoluble in acetone, ether or trichloromethane, but can be dissolved in alkaline hydrated oxide and carbonate solution.The specific rotatory power of Isphamycin between-235 to-250, between pH value 2.3-3.3.The has a broad antifungal spectrum of duomycin, all can produce restraining effect to gram-positive microorganism, negative bacterium, Rickettsiae, spirochete, chlamydozoan, mycoplasma, some protozoon etc.
Duomycin belongs to tetracycline medication, the protein synthesis of main suppression sensitive microbial, the mechanism of action is combined with the 30S small subunit A position of microorganism, further interference aminoacyl tRNA is combined with 30S small subunit, make aminoacyl tRNA can not enter on mRNA by position, inhibit the prolongation of peptide chain during protein synthesis; Duomycin can also stop the release of synthetic protein peptide chain.Duomycin is more responsive to the ribosomal effect of 70S, can Selective depression sensitive microbial, thus has good safety performance.At present, the duomycin types of formulation used both at home and abroad has: feed grade duomycin (ChlortetracyclineFeed Grade), Isphamycin (Chlortetracycline Hydrochloride), chlorotetracycline eye ointment (Chlortetracycline EyeOintment or Chlortetracycline Hydrochloride Ophthalmic Ointment), chlorotetracycline ointment (Chlortetracycline Ointment), Isphamycin tablet (Chlortetracycline Hydrochloride Tablets), Isphamycin capsule (Capsulate Chlortetracycline Hydrochloride), hydrochloride for injection duomycin (Chlortetracycline Hydrochloride Pro Injection) etc.
No matter be that duomycin or Isphamycin solvability in water are limited.Easily decompose in water, poor chemical stability, solubility property be poor, have when bad smell or taste, use pungency or pain etc. are produced to body.Its preparation type and clinical application are subject to certain restrictions, and also have impact on duomycin medicine plays due effect simultaneously.Therefore, improve the water-soluble of duomycin and improve its stability, finding and create novel strong antibacterial ability duomycin derivative, becoming one of focus of current duomycin structure of modification and modified research.
Tetracyclines derivative has multiple ionizableization functional group, wherein C1-keto-acid, C3-enol form/keto-acid, C10-, C11-, C12-phenolic/keto-acid and C4-dimethylin etc., has corresponding soda acid ionization parameter, affects the lipid of duomycin; Tsiklomitsin has three acid dissociation constants (pKa=3.3,7.68 and 9.69) and can form positively charged ion; Can zwitter-ion and anionic form existence under acidity, slightly acidic and alkaline condition.The structural formula of tetracyclines derivative is as follows:
Therefore, these are structural modification and the transformation of tetracycline antibiotics, and the discovery of prodrug provides sufficient feasibility in theory foundation.The modifying for chemical structure of medicine is based on the original basic chemical structure of medicine, only chemically modified is carried out to wherein some functional group, original physico-chemical property may be changed by modifying, to overcome above-mentioned shortcoming, improve the activity of medicine and heighten the effect of a treatment, therefore, drug modification has extremely important effect in clinical application.Succsinic acid is as the Main Means of current drug modification both domestic and external, and it can react with multi-medicament.
Summary of the invention
The technical problem to be solved in the present invention modifies duomycin and transforms.
The invention provides duomycin succinic monoester salt, have such as formula the structure shown in I:
Wherein, M is Na, K, meglumine, arginine or Methionin.
Present invention also offers the preparation method of duomycin succinic monoester salt, comprise the following steps:
A. be dissolved in organic solution by Isphamycin, add sodium carbonate and stir, under 30 ~ 80 DEG C of conditions, stirred solution becomes homogeneous phase; Described organic solution is the mixing solutions of organic solvent I and water, and the mass ratio shared by organic solvent I is mixing solutions 40%-90%;
B. by succinyl oxide and catalyst mix, then join in the homogeneous phase that step a obtains, return stirring 0.5 ~ 5 hour, hcl acidifying is to pH=6, and cooling obtains duomycin monomester succinate solid;
C. in organic solvent II, duomycin monomester succinate is dissolved in backflow, and add corresponding alkali and stir, cooling, namely generates target product; Described corresponding alkali is that pharmaceutically acceptable becomes saline and alkaline, comprises sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, arginine, Methionin or meglumine.
Concrete, organic solvent I described in step a refers to any one in ethanol, acetone, ethylene glycol, acetonitrile, propylene glycol, glycerol, tetrahydrofuran (THF) or Isosorbide-5-Nitrae-dioxane.
Concrete, Isphamycin described in step a and sodium carbonate mol ratio are 1 ︰ 1 ~ 1.5.
Concrete, succinyl oxide described in step b and catalyst molar ratio are 1 ︰ 0.1 ~ 1.5.
Concrete, catalyzer described in step b is any one or more mixture in dicyclohexylcarbodiimide DCC, 4-dimethylamino pyridine DMAP, triethylamine, pyridine; Catalyzer mol ratio is between any two 0 ~ 1.0 ︰ 1.0 ~ 0, and the total amount of catalyzer is not 0.
Concrete, in step b, the molar weight of succinyl oxide is 1.2 ~ 5.0 times of Isphamycin molar weight.
Concrete, organic solvent II described in step c is the mixture of any one or two kinds of in ethanol, Virahol, acetonitrile, DMF, N,N-dimethylacetamide, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF), acetone; Volume ratio between solvent is 0 ~ 1.0 ︰ 1.0 ~ 0, but the cumulative volume of solvent is not 0.
Concrete, the monomester succinate of duomycin described in step c and corresponding alkali mol ratio 1 ︰ 1.0 ~ 2.0.
Present invention also offers described duomycin succinic monoester salt and prepare the purposes in animal-feed.
The preparation method that present invention also offers described duomycin succinic monoester salt is preparing the purposes in animal-feed.
Beneficial effect of the present invention: the present invention passes through duomycin and succinyl oxide grafting and modifying, synthesize a kind of water-soluble duomycin succinic monoester salt being better than duomycin, it has the broad spectrum antibacterial that Isphamycin has in animal body, bacteriostasis for part gram-positive microorganism, Gram-negative bacteria is better than Isphamycin, duomycin succinic monoester salt has enhancing body immunizing power, promotes growth of animal effect simultaneously, can be used for preparing immunostimulant and fodder additives, there is good application prospect.
Embodiment
The preparation of embodiment 1, duomycin succinic acid monoester sodium salt
Be dissolved in the aqueous ethanolic solution of 40% by Isphamycin (1.0mol), add sodium carbonate (1.2mol) solid and stir, under 80 DEG C of conditions, stirred solution becomes homogeneous phase; Add succinyl oxide (5.0mol) and dicyclohexylcarbodiimide (1.2mol), return stirring 3 hours, hcl acidifying is to pH=6, and cooling obtains duomycin monomester succinate solid in batches.
By obtained duomycin monomester succinate (1mol), be dissolved in ethanol, backflow, portion-wise addition sodium hydroxide (1.0mol), stir, cooling, namely generate target product duomycin succinic acid monoester sodium salt.Product is pale yellow powder, and productive rate is 77.8%.Measure through HPLC, product purity is 98.6%; Measure through FAB-MS (fast atom bombardment MS), molecular weight of product is 600.9, is 600.94 consistent with the molecular weight calculated value of target product.
The preparation of embodiment 2, duomycin succinic acid monoester sodium salt
Be dissolved in the aqueous acetone solution of 90% by Isphamycin (1.0mol), add sodium carbonate (1.5mol) solid and stir, under 60 DEG C of conditions, stirred solution becomes homogeneous phase; Add succinyl oxide (1.2mol) and 4-dimethylamino pyridine (1.8mol), return stirring 0.5 hour, hcl acidifying is to pH=6, and cooling obtains duomycin monomester succinate solid in batches.
By obtained duomycin monomester succinate (1mol), be dissolved in Virahol, backflow, portion-wise addition sodium hydroxide (2.0mol), stir, cooling, namely generate target product duomycin succinic acid monoester sodium salt.Product is pale yellow powder, and productive rate is 81.3%.Measure through HPLC, product purity is 98.58%; Measure through FAB-MS, molecular weight of product is 600.1, is 600.94 consistent with the molecular weight calculated value of target product.
The preparation of embodiment 3, duomycin monomester succinate sylvite
Be dissolved in the aqueous glycol solution of 70% by Isphamycin (1.0mol), add sodium carbonate (1.0mol) solid and stir, under 30 DEG C of conditions, stirred solution becomes homogeneous phase; Add succinyl oxide (3.0mol) and triethylamine (4.5mol), return stirring 5 hours, hcl acidifying is to pH=6, and cooling obtains duomycin monomester succinate solid in batches.
By obtained duomycin monomester succinate (1mol), be dissolved in DMF, backflow, portion-wise addition potassium hydroxide (1.5mol), stir, cooling, namely generate target product duomycin monomester succinate sylvite.Product is pale yellow powder, and productive rate is 85.9%.Measure through HPLC, product purity is 99.1%; Measure through FAB-MS, molecular weight of product is 617.2, is 617.05 consistent with the molecular weight calculated value of target product.
The preparation of embodiment 4, duomycin succinic acid monoester sodium salt
Be dissolved in the acetonitrile solution of 80% by Isphamycin (1.0mol), add sodium carbonate (1.5mol) solid and stir, under 80 DEG C of conditions, stirred solution becomes homogeneous phase; Add succinyl oxide (3.0mol) and pyridine (0.5mol), return stirring 2.5 hours, hcl acidifying is to pH=6, and cooling obtains duomycin monomester succinate solid in batches.
By obtained duomycin monomester succinate (1mol), be dissolved in Isosorbide-5-Nitrae-dioxane, backflow, portion-wise addition sodium carbonate (1.5mol), stir, cooling, namely generate target product duomycin succinic acid monoester sodium salt.Product is pale yellow powder, and productive rate is 76%.Measure through HPLC, product purity is 99.6%; Measure through FAB-MS, molecular weight of product is 600.2, is 600.94 consistent with the molecular weight calculated value of target product.
The preparation of embodiment 5, duomycin monomester succinate sylvite
Be dissolved in the aqueous solution of propylene glycol of 70% by Isphamycin (1.0mol), add sodium carbonate (1.0mol) solid and stir, under 60 DEG C of conditions, stirred solution becomes homogeneous phase; Add succinyl oxide (4.0mol) and triethylamine/pyridine (each 0.5mol of triethylamine, pyridine), return stirring 3.5 hours, hcl acidifying is to pH=6, and cooling obtains duomycin monomester succinate solid in batches.
By obtained duomycin monomester succinate (1mol), be dissolved in tetrahydrofuran (THF), backflow, portion-wise addition salt of wormwood (1.5mol), stir, cooling, namely generate target product duomycin monomester succinate sylvite.Product is pale yellow powder, and productive rate is 80.9%.Measure through HPLC, product purity is 99.0%; Measure through FAB-MS, molecular weight of product is 617.1, is 617.05 consistent with the molecular weight calculated value of target product.
The preparation of embodiment 6, duomycin mono succinate ester arginine salt
Be dissolved in the glycerin solution of 50% by Isphamycin (1.0mol), add sodium carbonate (1.2mol) solid and stir, under 50 DEG C of conditions, stirred solution becomes homogeneous phase; Add succinyl oxide (2.0mol) and DCC/DMAP mixture (wherein DCC0.2mol, DMAP 0.3mol), return stirring 4 hours, hcl acidifying is to pH=6, and cooling obtains duomycin monomester succinate solid in batches.
By obtained duomycin monomester succinate (1mol), be dissolved in ethanol/acetonitrile (volume ratio of ethanol and acetonitrile is 1.0 ︰ 1.0) mixed solvent, backflow, portion-wise addition arginine (1.5mol), stir, cooling, namely generates target product duomycin mono succinate ester arginine salt.Product is pale yellow powder, and productive rate is 82.2%.Measure through HPLC, product purity is 99.01%; Measure through FAB-MS, molecular weight of product is 753.09, is 753.15 consistent with the molecular weight calculated value of target product.
The preparation of embodiment 7, duomycin monomester succinate lysine salt
Be dissolved in the tetrahydrofuran aqueous solution of 70% by Isphamycin (1.0mol), add sodium carbonate (1.5mol) solid and stir, under 70 DEG C of conditions, stirred solution becomes homogeneous phase; Add succinyl oxide (3.5mol) and DCC/ triethylamine mixture (wherein DCC 0.3mol, triethylamine 0.2mol), return stirring 3.5 hours, hcl acidifying is to pH=6, and cooling obtains duomycin monomester succinate solid in batches.
By obtained duomycin monomester succinate (1mol), be dissolved in 1,4-dioxane/tetrahydrofuran (THF) (1, the volume ratio of 4-dioxane/tetrahydrofuran (THF) is 0.5 ︰ 1.0) in mixed solvent, backflow, portion-wise addition Methionin (1.5mol), stirs, cooling, namely generates target product duomycin monomester succinate lysine salt.Product is pale yellow powder, and productive rate is 86.1%.Measure through HPLC, product purity is 99.34%; Measure through FAB-MS, molecular weight of product is 725.11, is 725.15 consistent with the molecular weight calculated value of target product.
The preparation of embodiment 8, duomycin monomester succinate meglumine salt
Be dissolved in by Isphamycin (1.0mol) in the Isosorbide-5-Nitrae-dioxane aqueous solution of 90%, add sodium carbonate (1.0mol) solid and stir, under 50 DEG C of conditions, stirred solution becomes homogeneous phase; Add succinyl oxide (2.0mol) and DCC/DMAP/ pyridine mixtures (each 0.1mol), return stirring 5 hours, hcl acidifying is to pH=6, and cooling obtains duomycin monomester succinate solid in batches.
By obtained duomycin monomester succinate (1mol), be dissolved in acetonitrile/acetone (volume ratio of acetonitrile/acetone is 1.0 ︰ 0.5) mixed solvent, backflow, portion-wise addition meglumine (2.0mol), stir, cooling, namely generates target product duomycin monomester succinate meglumine salt.Product is pale yellow powder, and productive rate is 89.9%.Measure through HPLC, product purity is 99.7%; Measure through FAB-MS, molecular weight of product is 775.20, is 775.18 consistent with the molecular weight calculated value of target product.
The preparation of embodiment 9, duomycin mono succinate ester arginine salt
Be dissolved in the aqueous ethanolic solution of 70% by Isphamycin (1.0mol), add sodium carbonate (1.5mol) solid and stir, under 60 DEG C of conditions, stirred solution becomes homogeneous phase; Add succinyl oxide (4.0mol) and DMAP/ triethylamine/pyridine mixtures (wherein DMAP 0.6mol in batches, triethylamine 0.1mol, pyridine 0.9mol), return stirring 1 hour, hcl acidifying is to pH=6, and cooling obtains duomycin monomester succinate solid.
By obtained duomycin monomester succinate (1mol), be dissolved in N, dinethylformamide/N,N-dimethylacetamide (DMF/N, the volume ratio of N-N,N-DIMETHYLACETAMIDE is 1.0 ︰ 1.0) in mixed solvent, backflow, portion-wise addition arginine (1.2mol), stirs, cooling, namely generates target product duomycin mono succinate ester arginine salt.Product is pale yellow powder, and productive rate is 90.2%.Measure through HPLC, product purity is 99.0%; Measure through FAB-MS, molecular weight of product is 753.1, is 753.15 consistent with the molecular weight calculated value of target product.
The preparation of embodiment 10, duomycin monomester succinate meglumine salt
Be dissolved in the acetonitrile solution of 90% by Isphamycin (1.0mol), add sodium carbonate (1.5mol) solid and stir, under 80 DEG C of conditions, stirred solution becomes homogeneous phase; Add succinyl oxide (3.0mol) and DCC/DMAP/ pyridine mixtures (wherein DCC 0.1mol in batches, DMAP 0.2mol, pyridine 0.3mol), return stirring 2 hours, hcl acidifying is to pH=6, and cooling obtains duomycin monomester succinate solid.
By obtained duomycin monomester succinate (1mol), be dissolved in acetonitrile/1,4-dioxane (acetonitrile/1, the volume ratio of 4-dioxane is 1.0 ︰ 1.0) in mixed solvent, backflow, portion-wise addition meglumine (1.5mol), stirs, cooling, namely generates target product duomycin monomester succinate meglumine salt.Product is pale yellow powder, and productive rate is 87%.Measure through HPLC, product purity is 99.5%; Measure through FAB-MS, molecular weight of product is 775.07, is 775.18 consistent with the molecular weight calculated value of target product.
The preparation of embodiment 11, duomycin monomester succinate meglumine salt
Be dissolved in the tetrahydrofuran aqueous solution of 90% by Isphamycin (1.0mol), add sodium carbonate (1.5mol) solid and stir, under 80 DEG C of conditions, stirred solution becomes homogeneous phase; Add succinyl oxide (3.0mol) and DCC/DMAP/ triethylamine mixture (wherein DCC 0.3mol in batches, DMAP 0.2mol, triethylamine 0.1mol), return stirring 2 hours, hcl acidifying is to pH=6, and cooling obtains duomycin monomester succinate solid.
By obtained duomycin monomester succinate (1mol), be dissolved in tetrahydrofuran (THF)/1,4-dioxane (tetrahydrofuran (THF)/1, the volume ratio of 4-dioxane is 0.5 ︰ 1.0) in mixed solvent, backflow, portion-wise addition meglumine (1.5mol), stirs, cooling, namely generates target product duomycin monomester succinate meglumine salt.Product is pale yellow powder, and productive rate is 85.4%.Measure through HPLC, product purity is 99.01%; Measure through FAB-MS, molecular weight of product is 775.22, is 775.18 consistent with the molecular weight calculated value of target product.
Embodiment 12, different duomycin succinic monoester salt solvability compare
Duomycin succinic monoester salt target compound provided by the invention, significantly improving the water-soluble of traditional duomycin and Isphamycin, carrying out solubility test according to specifying under solubleness item in 2010 editions Chinese Pharmacopoeias to testing sample.Appropriate tester is fully ground to form fine powder, takes 0.1g powder respectively in the distilled water of a certain amount of 25 DEG C.In powerful jolting 30 second every 5 minutes, observe the dissolving situation in 30 minutes.When there is no visual visible particles of solute, be and dissolve completely.Record the volume dissolving distilled water corresponding to 0.1g powder.Compared with the explanation corresponding with solubleness vocabulary of terms in pharmacopeia by result, draw respective substance solubility test result.The results are shown in Table 1.As can be seen from Table 1, different duomycin succinic monoester salt is all soluble in water, and in water, solvability is greatly improved.
The dissolving situation of the different compound of table 1
| Determinand | Distilled water volume (ml) | Solvability |
| Duomycin | 185.00 | Atomic molten |
| Isphamycin | 9.60 | Slightly soluble |
| Duomycin succinic acid monoester sodium salt | 0.32 | Yi Rong |
| Duomycin monomester succinate sylvite | 0.28 | Yi Rong |
| Duomycin monomester succinate meglumine salt | 0.66 | Yi Rong |
| Duomycin mono succinate ester arginine salt | 0.72 | Yi Rong |
| Duomycin monomester succinate lysine salt | 0.83 | Yi Rong |
Embodiment 13, different duomycin succinic monoester salt bacteriostasis compare
Standard E. coli, pneumococcus, Salmonellas, influenzae, golden staphylococci, suis, mycoplasma and bordetella bacilli are inoculated in nutrient broth enrichment liquid, 37 DEG C of incubated overnight.Be heated to by sterilized nutrient agar and melt completely, be poured in culture dish, every ware 15ml (lower floor), treats that it solidifies.In addition, be cooled to by the PDA substratum of thawing about 50 DEG C to be mixed into the above-mentioned several bacterium liquid of test organisms, the substratum 5ml being mixed with bacterium be added to (upper strata) to be solidified on the substratum solidified.Directly vertically put Oxford cup with aseptic technique in media surface, pressurize gently, make it contact tight with substratum, in cup, add liquid 100 μ l to be checked.Put 37 DEG C to cultivate 36 hours, observations, inhibition zone size chi directly measures reading.
The results are shown in Table 2.Result shows the broad spectrum antibacterial that different duomycin succinic monoester salt has Isphamycin and has, and the bacteriostasis for part gram-positive microorganism, Gram-negative bacteria is better than Isphamycin.
Table 2 different duomycin monomester succinate salt pair bacterium inhibition zone size (mm), 36 hours
The impact of embodiment 14, duomycin monomester succinate salt pair immunity of organism
Select the healthy weanling pig 180 of 30 ages in days, male and female half and half, the principle close according to body weight, male and female ratio is identical, 6 treatment group are entered in random assignment, often process 5 repetitions, often repeat 6 piglets (3 male 3 is female).No significant difference between original body mass between each repeating groups, average out to 6.54 ± 0.21 kilograms.Feed not containing antibiotic feed, 3 days time, to get rid of the medicine that may vertically produce early stage to the impact of test pig.Start to add Experimental agents to feed, in feed, chemical feeding quantity is 75ppm later, free choice feeding, freely drinks water, 21 days trial periods.In test 8:00 in the 21st day morning, from often processing random selecting 5 pig aseptic venous collection blood sample 8ml, after slant setting to precipitation serum, through the centrifugal 10mins of 3000r/min, collect serum in-20 deepfreezes to analyzing.The content of serum immune globulin (IgG, IgM, IgA), all according to test kit specification sheets, adopts euzymelinked immunosorbent assay (ELISA) to measure, is undertaken by microplate reader; IFN-γ and IL-12 level all record by ELISA detection kit method.
Measurement result is in table 3.IgA, IgM, IgG are the common indexs of immunology detection.Immunoglobulin G (immunoglobulinG, IgG) for body content is maximum and topmost Ig, account for total immune globulin from 70% ~ 80%, belong to secondary immune response antibody, i.e. the important antibody of body subinfection again.It has antibody activity to virus, bacterium and parasite etc., is also uniquely by the Ig of placenta, can make new born animal adaptive immune antibody by natural passive immunity.Immunoglobulin A (immunoglobulinA, IgA) is divided into serotype IgA and secretory IgA (SIgA) two Z kind.The former accounts for 10% ~ 15% of serum total Ig, and the latter is mainly present in juice, as: saliva, tear, breast milk, nasal secretions, bronchial secretion liquid and gastro-intestinal secretion liquid.SIgA is synthesized by the lymphoid tissue of respiratory tract, digestive tube, urogenital tract, and local infection, the pathology such as inflammation or tumour at SIgA change in concentration and these positions are closely related.Immunoglobulin M (immunoglobulin M, IgM) is the Ig in primary immune response reaction, no matter be in ontogeny or after body is subject to antigenic stimulation, IgM is the antibody occurred the earliest.IgM is the maximum Ig of molecular mass, accounts for 5% ~ l0% of serum total Ig.IgM has the ability of strong aggegation antigen.IFN-γ: lymphocytic type Interferon, rabbit.IFN is a kind of broad-spectrum disease resistance toxic agent, not direct killing or suppression virus, and mainly make cell produce antiviral protein by cell surface receptor effect, thus suppress copying of hepatitis B virus, its type is divided three classes, α-(white corpuscle) type, β-(inoblast) type, γ-(lymphocyte) type; Interferon, rabbit has affects Growth of Cells, and the multiple biological activity such as differentiation, immunity moderation function.IL-12: interleukin 12.IL-2 can improve body Phagocytic Function, has the effect of enhancing body non-specific immune function.
As can be seen from Table 3, compared with Isphamycin group, duomycin succinic monoester salt group of the present invention (duomycin succinic acid monoester sodium salt, duomycin monomester succinate sylvite, duomycin monomester succinate lysine salt, duomycin mono succinate ester arginine salt and duomycin monomester succinate meglumine salt) all can improve to different levels IgA, IgM, IgG, IFN-γ and the IL-12 level in organism, enhancing body immunizing power is wherein good with the effect of duomycin monomester succinate lysine salt, duomycin mono succinate ester arginine salt again.
The impact of the general immune indexes of table 3 duomycin monomester succinate salt pair body
The impact of embodiment 15, duomycin monomester succinate salt pair animal piglet body growth index
Select the healthy weanling pig 120 of 30 ages in days, male and female half and half, the principle close according to body weight, male and female ratio is identical, 6 treatment group are entered in random assignment.No significant difference between original body mass between each repeating groups, average out to 6.38 ± 0.17 kilograms.Start to add Experimental agents to feed, in feed, chemical feeding quantity is 75ppm, free choice feeding, freely drinks water, 27 days trial periods.Test determination initial weight, day weight gain, daily ingestion amount, total feed consumption rate, final weight, calculate feedstuff-meat ratio.Record and the results are shown in Table 4.From feedstuff-meat ratio data presentation: the feedstuff-meat ratio of duomycin succinic monoester salt, all lower than Isphamycin group, illustrates that the duomycin succinic monoester salt of new synthesis all has the function improving efficiency of feed utilization; Wherein the efficiency of feed utilization of duomycin monomester succinate lysine salt, duomycin mono succinate ester arginine salt and duomycin monomester succinate meglumine salt improves more remarkable comparatively speaking.
The impact of table 4 duomycin monomester succinate salt pair animal piglet body growth index
What finally illustrate is, above embodiment is only in order to illustrate technical scheme of the present invention and unrestricted, although by referring to the preferred embodiments of the present invention, invention has been described, but those of ordinary skill in the art is to be understood that, various change can be made to it in the form and details, and not depart from the spirit and scope of the present invention that appended claims limits.
Claims (10)
1. duomycin succinic monoester salt, has such as formula the structure shown in I:
Wherein, M is Na, K, meglumine, arginine or Methionin.
2. the preparation method of duomycin succinic monoester salt, is characterized in that: comprise the following steps:
A. be dissolved in organic solution by Isphamycin, add sodium carbonate and stir, under 30 ~ 80 DEG C of conditions, stirred solution becomes homogeneous phase; Described organic solution is the mixing solutions of organic solvent I and water, and the mass ratio shared by organic solvent I is mixing solutions 40 ~ 90%;
B. by succinyl oxide and catalyst mix, then join in the homogeneous phase that step a obtains, return stirring 0.5 ~ 5 hour, hcl acidifying is to pH=6, and cooling obtains duomycin monomester succinate solid;
C. in organic solvent II, duomycin monomester succinate is dissolved in backflow, and add corresponding alkali and stir, cooling, namely generates target product; Described corresponding alkali is that pharmaceutically acceptable becomes saline and alkaline, comprises sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, arginine, Methionin or meglumine.
3. method as claimed in claim 2, is characterized in that: organic solvent I described in step a refers to any one in ethanol, acetone, ethylene glycol, acetonitrile, propylene glycol, glycerol, tetrahydrofuran (THF) or Isosorbide-5-Nitrae-dioxane.
4. method as claimed in claim 2 or claim 3, is characterized in that: Isphamycin described in step a and sodium carbonate mol ratio are 1 ︰ 1 ~ 1.5.
5. the method as described in any one of claim 2 ~ 4, is characterized in that: succinyl oxide described in step b and catalyst molar ratio are 1 ︰ 0.1 ~ 1.5.
6. the method as described in any one of claim 2 ~ 5, is characterized in that: catalyzer described in step b is any one or more mixture in dicyclohexylcarbodiimide DCC, 4-dimethylamino pyridine DMAP, triethylamine, pyridine; Catalyzer mol ratio is between any two 0 ~ 1.0 ︰ 1.0 ~ 0, but the total amount of catalyzer is not 0.
7. the method as described in any one of claim 2 ~ 6, is characterized in that: in step b, the molar weight of succinyl oxide is 1.2 ~ 5.0 times of Isphamycin molar weight.
8. the method as described in any one of claim 2 ~ 7, it is characterized in that: organic solvent II described in step c is ethanol, Virahol, acetonitrile, N, the mixture of any one or two kinds of in dinethylformamide, N,N-dimethylacetamide, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran (THF), acetone; Volume ratio between solvent is 0 ~ 1.0 ︰ 1.0 ~ 0, but the cumulative volume of solvent is not 0.
9. the method as described in any one of claim 2 ~ 8, is characterized in that: the monomester succinate of duomycin described in step c and corresponding alkali mol ratio 1 ︰ 1.0 ~ 2.0.
10. duomycin succinic monoester salt according to claim 1 or the method described in any one of claim 2 ~ 9 are preparing the purposes in animal-feed.
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| CN111233831A (en) * | 2020-03-18 | 2020-06-05 | 郑州市华农兽药研究院 | Dichroa febrifuga succinic acid monoester and preparation method and application thereof |
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