CN101724019A - Thymopeptide-5 active esters, medicinal composition containing same and application thereof - Google Patents
Thymopeptide-5 active esters, medicinal composition containing same and application thereof Download PDFInfo
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- CN101724019A CN101724019A CN200810167833A CN200810167833A CN101724019A CN 101724019 A CN101724019 A CN 101724019A CN 200810167833 A CN200810167833 A CN 200810167833A CN 200810167833 A CN200810167833 A CN 200810167833A CN 101724019 A CN101724019 A CN 101724019A
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Abstract
The invention relates to thymopeptide-5 active esters, medicinal composition containing the same and application thereof. The thymopeptide-5 active esters are esters generated by combining thymopeptide-5 C-end carboxyl and/or aspartic acid lateral chain carboxyl with alcoholic hydroxyl. Experimental results show that the thymopeptide-5 active esters have the functions of significant immune potentiation and oxidation resistance, enhanced stability and prolonged half-life.
Description
Technical field
The present invention relates to the esterified derivative of thymopeptide-5 and contain their wherein one or more pharmaceutical composition and purposes.
Background technology
Thymopoietin (thymopoietin) is by a kind of polypeptide hormone that contains 49 amino-acid residues of thymic epithelial cells's excretory, thymopeptide-5 (Thymopentin, TP-5) be the 32-36 amino acids fragment of thymopoietin, its aminoacid sequence is: Arg-Lys-Asp-Val-Tyr.TP-5 is the reactive site of thymopoietin, its function is identical with thymopoietin, it is a kind of at the lymphocytic immunostimulant of T, can promote the ripe and differentiation of T cell, impel the multiple lymphokine of sophisticated T emiocytosis (as interleukin-22 and gamma-interferon etc.), can also promote the generation of interleukin-2 acceptor, improve the activity of SOD in the peripheral blood.In the impaired animal model of immunologic balance, no matter be that immune response is too high or too low, TP-5 all can realize balance adjustment, these characteristics make it to show potentiality in the relevant human disease treatment of immunologic balance imbalance.
Thymopeptide-5 can be induced prothymocyte and the peripheral T cell of activation, has significant clinical related immune and regulates active.Clinical study shows that thymopeptide-5 all shows curative effect preferably in treatment tumour, some disease of viral infection, autoimmune function disorder disease (as rheumatoid arthritis, lupus erythematosus, genital herpes, chronic nephritis, allergic dermatitis, diabetes etc. and immune deficiency, immunologic hypofunction diseases associated).It can reduce serious recurrent herpes simplex virus infection patient's recurrence rate and postpone recurrence time; It to antitumorly put, chemotherapy and prevention major operation postoperative infection have tangible clinical effectiveness; Can prevent long-term diabetic subject's complication and promote its rehabilitation; Chronic hepatitis B, hepatitis C and viral hepatitis are merged biliary tract infection, peritonitis, enteritis, septicemia and therapy for hepatic encephalopathy positive effect, has tangible the moon to transfer to usefulness to experimental index: HBV-DNA (+), HBeAg (+), HCV-RNA (+), whose anti-HCV (+) etc.To the patient of early stage acquired immunodeficiency syndrome, the benefit of thymopeptide-5 maximum is the immunological competence that can increase patient.Its security is fine, a large amount of studies confirm that no obvious toxic and side effects.
TP-5 is a peptide medicament, is easily degraded by hydrochloric acid in gastric juice, must parenteral admin, be degraded to amino acid very soon in human plasma by proteolytic enzyme and aminopeptidase, and the transformation period is about 30 seconds, needs long-term frequent medication.Therefore, TP-5 is modified, strengthen its action intensity, prolonging its action time in vivo has application promise in clinical practice.Actively produce exploitation thymosin class high-end product, in time eliminating old product has been extremely urgent, and no matter this is that society or factory commercial city are had very significant meaning.
Up to the present, existingly much thymopeptide-5 is carried out the exploration of structure of modification.CN1626549A discloses the derivative of thymopeptide-5 Pegylation, and it is by amino or linking group of carboxyl terminal at thymopeptide-5, polyoxyethylene glycol is connected on the molecule of thymopeptide-5.There are multinomial patent (U.S. Patent No. 4,361,673 and 4 in the U.S., 420,424) disclose the wire analogue of thymopeptide-5, their adopt retro-inverso technology that used amino acid is replaced, and the C-end carboxyl after structure replaced has carried out the methyl esters modification.
Though thymopeptide-5 research is more extensive, Shang Weijian directly is modified into the report of ester to thymopeptide-5.The present invention adopts into the ester method thymopeptide-5 is carried out structural modification, improve the body internal stability to reach, prolong half-life strengthens the purpose of its action effect, have poor stability at polypeptide drug, problems such as the interior transformation period weak point of body provide new research thinking and approach.
Summary of the invention
An object of the present invention is to provide the active ester of thymopeptide-5.
Another object of the present invention provides the composition that comprises thymopeptide-5 active esters.
Also purpose of the present invention provides the purposes of thymopeptide-5 active esters.
According to an aspect of the present invention, provide thymopeptide-5 active esters, its C-end carboxyl and/or aspartic acid side chain carboxyl group for thymopeptide-5 combines the ester that is produced with alcoholic extract hydroxyl group.Thymopeptide-5 active esters of the present invention comprises the carboxyl in any site among the TP-5 and the ester that the alcoholic extract hydroxyl group covalent attachment forms.
In one embodiment, thymopeptide-5 active esters of the present invention has structure shown in the formula (I):
Wherein, R and R ' are alkyl independently of one another, for example are saturated long chain aliphatic alcohol alkyl, are preferably C
nH
2n+1, wherein n is the integer between 1 and 20, is preferably the integer between 2 and 12, more preferably the integer between 2 and 8 most preferably is 2,6 or 12.
In another embodiment, thymopeptide-5 active esters of the present invention has structure shown in the formula (II):
Wherein, R is an alkyl, for example is saturated long chain aliphatic alcohol alkyl, is preferably C
nH
2n+1, wherein n is the integer between 1 and 20, is preferably the integer between 2 and 12, more preferably the integer between 2 and 8 most preferably is 2,6 or 12.
In going back an embodiment, thymopeptide-5 active esters of the present invention has structure shown in the formula (III):
Wherein, R is an alkyl, for example is saturated long chain aliphatic alcohol alkyl, is preferably C
nH
2n+1, wherein n is the integer between 1 and 20, is preferably the integer between 2 and 12, more preferably the integer between 2 and 8 most preferably is 2,6 or 12.
According to a further aspect in the invention, provide a kind of pharmaceutical composition, it contains the thymopeptide-5 active esters of the present invention and the pharmaceutical excipient of significant quantity.
Alleged herein " significant quantity of thymopeptide-5 active esters " is meant when being given the patient who needs this gland pentapeptide active ester of use, can produce the amount of this thymopeptide-5 active esters of desired clinical efficacy.
Thymopeptide-5 active esters among the present invention can obtain by the whole bag of tricks as known in the art, or buys from the market by commercial sources.
Those of ordinary skill in the art can pass through the whole bag of tricks as known in the art, pharmaceutical composition of the present invention is mixed with various pharmaceutical dosage forms, for example solid, semisolid and liquid preparation.
Pharmaceutical composition of the present invention can be via various route of administration, whole body or topical as known in the art.
In accordance with a further aspect of the present invention, provide thymopeptide-5 active esters preparation be used for the treatment of or the medicine of prophylaxis of tumours, disease of viral infection, autoimmune disorder in purposes.
According to purposes of the present invention, wherein said autoimmune disorder is rheumatoid arthritis, lupus erythematosus, genital herpes, chronic nephritis, allergic dermatitis or diabetes.
Thymopeptide-5 active esters biologically active height among the present invention, characteristics such as the interior transformation period prolongation of organism have good application prospects.
Description of drawings
Fig. 1 is the enhancing rate result of different modifying thing.
Fig. 2 is measurement result plasma half-life.
Embodiment
We provide following examples further to set forth the present invention, but these embodiment do not limit the present invention in any way.
Dehydrated alcohol 20ml puts in the reaction flask, adds thionyl chloride 2ml under the condition of ice bath, adds thymopeptide-5 200mg, is stirred to react completely.Excess ethanol and thionyl chloride are removed in decompression rotary evaporation down, obtain white product.Behind the dissolve with methanol, HPLC-MS measures, m/z 736.4,368.8 (base peak).
Anhydrous hexanol 20ml puts in the reaction flask, adds thionyl chloride 2ml under the condition of ice bath, adds thymopeptide-5 200mg, and reaction is to reaching balance under the agitation condition.Adopt the rotary evaporation decompression to remove hexanol, separate and purifying, obtain white product.HPLC-MS measures, and m/z 848.6,424.9.
Lauryl alcohol (lauryl alcohol) 50ml, 50ml mixes with tetrahydrofuran (THF), adds thionyl chloride 2ml under the condition of ice bath, adds thymopeptide-5 500mg, continues reaction to reaching balance.Reaction finishes, and adopts the rotary evaporation decompression to remove thionyl chloride and tetrahydrofuran (THF).In residual reaction solution, add acetum, treat layering after, the water layer freeze-drying, separation and purification, product is analyzed through HPLC-MS, m/z is 508.7,1016.4.
Embodiment 4.MTT method detects the proliferative response of carboxylate to mouse spleen lymphocyte
The preparation of splenocyte suspension: aseptic condition takes out down mouse spleen, spleen is cut into small pieces and grinds, and crosses 200 mesh sieves and makes splenocyte suspension.After the splitting erythrocyte, wash three times counting.With the RPMI RPMI-1640 that contains 10%FBS (foetal calf serum) splenocyte concentration is adjusted to 1 * 10
7Cell/ml.
In 96 orifice plates, add 100 microlitre splenocyte suspensions, the sample of 50 microlitres, 10 microlitre ConA, 40 microlitre substratum, contrast adds the nutrient solution that 50 microlitres contain 10% serum, and cumulative volume is 200 microlitres.Cell is in 5%CO
237 ℃ of incubators in cultivate, cultivate to finish preceding 6 hours, every hole adds MTT solution (5mg/ml) 20 microlitres, continues to hatch to experiment and finishes.96 orifice plates are centrifugal, and careful the suction abandoned supernatant liquor, adds 200 microlitre methyl-sulphoxides, 100 rev/mins of joltings of 37 ℃ of horizontal shaking tables 15 minutes.570nm wavelength place reads absorbance on microplate reader, the results are shown in Table 1.
The calculation formula of enhancing rate is as follows: enhancing rate %=(measuring OD value-contrast OD value)/contrast OD value
*100%
Table 1.MTT method detects the propagation of thymopeptide-5 carboxylate to mouse spleen lymphocyte
60 of SD rats, male, about body weight 180 ± 20g, be divided into 6 groups at random, that is: normal group, model group, esterification object height (2.5mg/kg), in (0.5mg/kg), low dose group (0.1mg/kg), the positive drug group (TP-5,0.5mg/ml).The drug powder physiological saline solution is made into 0.5mg/ml, 0.1mg/ml, 0.02mg/ml solution, is respectively applied for high, medium and low dosage group, every rat 2ml.Except that the normal control group, equal subcutaneous injection every day of all the other rats hydrocortisone injection 10mg/, 7d causes the immunosuppression model continuously, and the total SOD level of rat plasma this moment descends.Rat after the modeling is afraid of cold, aversion to cold and preference for warmth, roll up hogback, health is become thin.From beginning subcutaneous injection administration in the 8th day, normal control group and model group gave isopyknic physiological saline, successive administration 14d.6h blood sampling after the last administration, separated plasma is measured SOD content in the serum.The results are shown in Table 2.
Table 2. thymopeptide-5 ethyl ester is to the active influence of immunosuppression rat SOD due to the hydrocortisone
Embodiment measures for 6. plasma half-lives
Because the plasma half-life of medicine is shorter, therefore, blood plasma is diluted with physiological saline at 1: 1 with reference to relevant document, be determined as follows with the blood plasma after the dilution.
HLPC condition: Waters HPLC chromatographic instrument, 2487 UV-detector, Venusil MP C
18Post (150
*4.6mm), methyl alcohol-phosphate buffered saline buffer (pH3.0 includes 0.2% triethylamine) is made moving phase, and sampling volume 20 μ l detect wavelength: 220nm, 275nm.Flow velocity: 1.0min.
Go out drug level C by calculated by peak area, with the logarithm (logC) of drug level the time (t) is carried out linear regression, getting the transformation period by regression equation calculation is TP-5:1.3min; TP-5 diethyl ester: 2.0min, promptly carboxylate prolonged to some extent than the transformation period of former medicine.The results are shown in Figure 2.
Claims (9)
1. thymopeptide-5 active esters, its C-end carboxyl and/or aspartic acid side chain carboxyl group for thymopeptide-5 combines the ester that is produced with alcoholic extract hydroxyl group.
2. according to the thymopeptide-5 active esters of claim 1, it is characterized in that its have formula (I), (II) or (III) shown in structure:
Wherein, R and R ' are saturated long chain aliphatic alcohol alkyl independently of one another.
3. according to the thymopeptide-5 active esters of claim 2, wherein R and R ' are C independently of one another
nH
2n+1, and n is the integer between 1 and 20.
4. according to the thymopeptide-5 active esters of claim 3, wherein n is the integer between 2 and 12.
5. according to the thymopeptide-5 active esters of claim 3, wherein n is the integer between 2 and 8.
6. according to the thymopeptide-5 active esters of claim 3, wherein n is 2,6 or 12.
7. pharmaceutical composition, it contains any one thymopeptide-5 active esters and the pharmaceutical excipient of claim 1 to 6 of significant quantity.
Any one thymopeptide-5 active esters of claim 1 to 6 preparation be used for the treatment of or the medicine of prophylaxis of tumours, disease of viral infection, autoimmune disorder in purposes.
9. purposes according to Claim 8, wherein said autoimmune disorder is rheumatoid arthritis, lupus erythematosus, genital herpes, chronic nephritis, allergic dermatitis or diabetes.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558301A (en) * | 2011-12-13 | 2012-07-11 | 烟台海安多肽药物研发技术有限公司 | Functional precision structure drug modifier-thymopetidum acetyl methyl ester conjugate (FPSDM-TP5) and preparation method thereof |
| CN109942452A (en) * | 2019-03-01 | 2019-06-28 | 浙江工业大学 | A kind of Olefination derivative of tyrosine and its preparation and application |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1202131C (en) * | 2003-03-24 | 2005-05-18 | 吉林大学 | Technology of one kettle method for liquid phase synthesizing thymopentapeptide |
| CN1626549A (en) * | 2003-12-11 | 2005-06-15 | 中国人民解放军军事医学科学院基础医学研究所 | Carbowax alcoholized ramification of TimopEntin, combination of medication and application |
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2008
- 2008-10-13 CN CN 200810167833 patent/CN101724019B/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558301A (en) * | 2011-12-13 | 2012-07-11 | 烟台海安多肽药物研发技术有限公司 | Functional precision structure drug modifier-thymopetidum acetyl methyl ester conjugate (FPSDM-TP5) and preparation method thereof |
| CN109942452A (en) * | 2019-03-01 | 2019-06-28 | 浙江工业大学 | A kind of Olefination derivative of tyrosine and its preparation and application |
| CN109942452B (en) * | 2019-03-01 | 2021-10-29 | 浙江工业大学 | Leucine alkene derivative and preparation and application thereof |
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