Anti-inflammatory and antineoplastic anticoagulant

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is offered the administration of heparin conjugated with 2-aminoethanesulfonic acid (taurine) of formula (1), synthesised with a condensing reagent - water-soluble 1-ethyl-3[3 (dimethylamino)propyl]carbodiimide as an anti-inflammatory and antineoplastic anticoagulant.

EFFECT: compound surpasses heparin in anticoagulating ability, has high anti-inflammatory activity, while antineoplastic activity is comparable with the effect of antineoplastic preparations (doxorubicin, cyclophosphan, vincristine).

5 tbl, 4 ex

 

The invention is intended for use in medicine and relates to tools having anticoagulant, anti-inflammatory and anticancer properties.

The inventive tool is a conjugate of (I) heparin and 2-aminoethanesulfonic acid (taurine) (Peredelkino YOU, Odinokov V.N., Lukin Y.S. the sibagatullin N.G., Suverov IVAN, Serik E.M., Dzhemilev sea level Way to obtain conjugates of heparin. // Pat. No. 2298406), belongs to the class of glycosaminoglycans (GAGS), which are known for their high biological activity.

In the body of the GAGS are a component of the extracellular matrix and perform regulatory functions, interacting with extracellular macromolecules, plasma proteins, components of the cell membrane, intracellular structures [Sugahara K., Kitagawa H. Recent advances in the study of the biosynthesis and functions of sulfated glycosaminoglycans // Curr. Opin. Struct. Biol., 2000. - V.10 (5). - P.518-527; Vieira T.C., Costa-Filho, A., Salgado N.C., Allodi, S., Valente A.P., Nasciutti LE, Silva L.C. Acharan sulfate, the new glycosaminoglycan from Achatina fulica Bowdich 1822. Structural heterogeneity, metabolic labeling and localization in the body, mucus and the organic shell matrix // Eur. J. Biochem., 2004. - V.271. - P.845-854]. In particular, heparin (II) is a cofactor of anti-thrombin III, and with it inhibits the activity of thrombin, factors IXa, XA, XIa and XIIa of the blood coagulation system, kallikrein [Murray R., Granner D., Maes P. etc. Biochemistry man: 3 so Vol.2. TRANS. and the main - M.: Mir, 1993].

Heparin is involved in cell proliferation, stimulates the migration of endothelial cells in capillaries, form electrostatic complexes with proteins-regulators of inflammation, participates in the control of receptor interactions, there is evidence of the presence of heparin immunomoduliruushimi activity [Immunology: 3 so V.3. TRANS. from English. Ed. Upolu. - M.: Mir, 1987-1989. - S-231]. Know about the ability of heparin to influence the complement cascade, which takes an active part in the development of inflammatory reactions [Galebskaya L.V., I.L. Solovtsov, Rumin E.V. modification of the proteolytic cascade of complement under the action of exogenous heparin // Matters. medicinal chemistry. 2001. - T. No. 1. - S-97].

It is known that the biological activity of heparin depends on the degree of sulfotyrosine molecules. The presence of a large number of sulfate groups attached significant negative charge of the molecules of heparin, which facilitates selective binding with the active centers of receptor proteins [Essentials of Glycobiology / Edit. by Varki, A., Cummings, R., Esko, J., Freeze, H. et al. - La Jolla, California: CSHL Press, 1991. - 653 p.; Ishida K, Wierzba M.K., T. Teruya, Simizu, S., Osada H. Novel heparin sulfate mimetic compounds as antitumor agents. // Chem. Biol. 2004. - V.11. - P.367-377]. Additional opportunities for enhancing the biological activity of heparin open in the put the I in its molecule different pharmacophoric groups, that not only provides the integrated effect of the conjugate, but also increases the bioavailability of pharmacophores. The high potential of this approach was shown in the conjugates of non-steroidal anti-inflammatory drugs (NSAIDs) with amino acids - ibuprofen-lysine, indomethacin-phenylalanine, indomethacin-glycine, etc. it Was determined that some conjugates of natural amino acids with NSAIDs is not inferior to the activity of the parent anti-inflammatory drugs, tens of times less toxic and have no gastrotoxicity [Anikin L.V. Biological activity of amides indometacin, naproxen, ibuprofen and natural amino acids. Thesis. on saisc. academic Art. Ph.D. dissertation, Tomsk, 2002]. The use of amino acids for modification of natural GAG through the formation of amide bond through the carboxyl group of the uronic acid residue provides the formation of stable and at the same time highly active conjugates GAG with new biological properties.

In this regard, a promising pharmacophore for modification of heparin is structuresa 2-aminoetansulfonovaya acid - taurine (III), which is a product of the metabolism of cysteine and methionine.

Taurine is a modulator of a large number of physiological processes in the body, is involved in the synthesis of other amino acids, sharing soda is I, potassium, calcium and magnesium. He also acts as a neurotransmitter, has a direct cardiotonic action and vasodilator effect by influencing the synthesis of prostacyclins, reduces platelet aggregation, inhibits hyperglycemic apoptosis of endothelial cells. Taurine is also included in the composition of the main component of bile, where it operates the conjugation of bile acids, preventing cholestasis. From literature data also aware of membrane stabilizing and antioxidant action of taurine [R. Lourenco, M.E. Camilo Taurine: a conditionally essential amino acid in humans? An overview in health and disease. Nutr. Hosp., 2002. - V.17 (6). - P.262-270].

The invention aims to expand the range of therapeutic action of potential drugs. It is solved by the conjugate (I) heparin with 2-aminoethanesulfonic acid (taurine) as anticoagulant tools with anti-inflammatory and antitumor activity.

Conjugate (I) and the method of its production are known. Heparin is extracted from pharmacopoeial preparation by precipitation in ethanol (sulfur - 13.9-14.6%, the ratio sharidny links with NHSO3H and NHAc-groups - 70-80/20-30). Conjugate (I) synthesize the work method, which consists in the reaction of heparin (II) with taurine III in an aqueous medium in the presence of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (CBI) as congenerous what about the reagent, pH 4.7-4.8, T 20-25°C, 1 h, ratio of reagents (II):(III):CBI=1:1.5:5 (U.S. Pat. Of the Russian Federation No. 2298406). Residues of taurine in the conjugate (I) ~50 mol%. per disaccharide glycosides link.

Analogous to the claimed connection anticoagulant action is pharmacopoeial heparin [Mashkovsky PPM Medicines. - M.: New wave, 2006. S-477].

The biological activity of the compound (I) was studied by determining the anticoagulant, anti-inflammatory and antitumor activity. As the comparison drug with the anticoagulant action was taken by the pharmaceutical heparin (5000 IU in 1 ml of JSC "Synthesis"). The reference drug with anti-inflammatory effect was ibuprofen (coated tablet 0.2 g, JSC ğtatkhimpharmpreparatyğ). As a reference antitumor activity used the standard scheme of chemotherapy HAZOR (cyclophosphamide, doxorubicin, vincristine and prednisone) [Gershanovich M., Filov VA, M.A. Governors, Governors A.A. Introduction to pharmacotherapy of malignant tumors - SPb.: Sothis, 1999. S]. Statistical processing of data was performed by the methods of parametric statistics using the software package "Statistika 6.0". Results were considered significant at p<0.05 student test.

Anticoagulant activity of compound (I) was determined after 20 min after intraperitoneal administration (dose 50 mgkg) by determining the prothrombin time by a standard method using a set of reagents "Techplast-test" ("Technology standard") and coagulometer "clot 1A" ("Hospitex"). The product comparison - heparin was injected in a similar way in doses of 5 and 50 mg/kg Control animals were injected with an equivalent volume of saline. It is established, that connection I exceeds pharmacopoeial heparin anticoagulation activity (table 1).

To determine anti-inflammatory activity used a standard model of inflammation caused by carrageenan and histamine [Manual on experimental (preclinical) study of new pharmacological substances. M: Remedium, 2000. S]. The compound (I) was administered intraperitoneally at a dose of 50 mg/kg comparison Drug ibuprofen (coated tablet 0.2 g, JSC ğtatkhimpharmpreparatyğ) was administered in the same way in doses of 15 and 50 mg/kg of the anti-Inflammatory effect was evaluated by the decrease, compared with the control, swelling index, which was calculated in percent as the ratio of the difference between healthy and inflamed paws to a healthy weight. The results obtained with both models indicate a high anti-inflammatory activity of compound I that is comparable to the activity of ibuprofen (tables 2, 3).

The study of antitumor activity were performed on mice with transplantable Lewis lung carcinoma. Compound I was administered once intraperitoneally at a dose of 50 mg/kg in a solution of 0.9% sodium chloride with the emulsifier Tween 80. The comparison group was administered the once parenteral complex anticancer drugs (doxorubicin, cyclophosphamide, vincristine, prednisolone), control mice - solution of 0.9% sodium chloride with the emulsifier Tween 80. The antitumor effect was determined by the dynamics of changes in volume of the primary nodes, as well as on the index of inhibition of tumor growth, which was defined as the ratio of the difference between a tumor mass in the control and experimental groups, the tumor weight in control. Found that compound I has significant antitumor activity comparable to the effect of anticancer drugs used in the scheme HAZOR (tables 4, 5).

Thus, the new compound - conjugate of heparin with taurine formula (I) can be considered as a promising anticoagulant agent that possesses anti-inflammatory and anticancer properties.

This invention is illustrated in the examples.

Example 1. The study of anticoagulant activity of a compound I.

The experiment was carried out on outbred mice weighing 25-30 g (6 animals per group). Compound I was administered intraperitoneally in a solution of 0.9% sodium chloride with the emulsifier Tween 80 at a dose of 50 mg/kg (molar fraction of heparin in conjunction with I - 39,4). The reference drug was pharmacopoeial heparin (heparin solution with an activity of 5000 IU in 1 ml of JSC "Synthesis"), which was injected similarly, two groups of mice at doses of 5 and 50 mg/kg (1 mg = 130 UNITS). Both doses are in the range featured tera is efticiency doses for humans (3340 and 33400 UNITS, respectively) [PPM Mashkovsky Medicinal product. M: New wave, 2006. S-477]. The heparin solution was prepared by diluting the standard drug with saline to the desired concentration and injected intraperitoneally in 0.2 ml/10 g weight. Control animals were injected with an equivalent volume of physiological solution with an emulsifier Tween 80. After 20 min after administration of the agents of the animals were killed by instant decapitate. The collected blood stabilized with sodium citrate (9:1), centrifuged for 7 min at 1000 rpm, the resulting plasma re-centrifuged 15 min at 3000 rpm and was determined by prothrombin time using a set of reagents "Techplast-test" ("Technology standard") and coagulometer "clot 1A" ("Hospitex") by a standard method.

Table 1 presents the values of prothrombin time, reflecting the anticoagulant properties of agents.

Table 1
The effect of compound I on the coagulation time in mice
GroupProthrombin time
The connection Ito 20.88**
Heparin 5 mg/kg10,94*
Heparin 50 mg/kg16,20**
Control8,04
** p<0.001; * p<0.01 compared to the control

Comparison of the data shows that the anticoagulant activity of compound I than the effect of the reference drug in doses of 5 and 50 mg/kg, respectively in 2 and 1.2 times. Thus, compound I is superior to pharmacopoeial heparin anticoagulation activity.

Example 2. Study of the anti-inflammatory effect of compound I on carragenine models of inflammation.

In the experience used 72 outbred mice males weighing 22-28, Animals were divided into 4 groups. Compound I was administered intraperitoneally at a dose of 50 mg/kg sodium chloride 0.9% from the emulsifier Tween 80 (over three steps). As a reference drug used anti-inflammatory drug ibuprofen (coated tablet 0.2 g, JSC ğtatkhimpharmpreparatyğ) at doses of 15 and 50 mg/kg with the same mode of administration. The dose of 50 mg/kg is the effective dose of ibuprofen in mice [Call WE, syropjatov BJ Doses of drugs and chemicals for laboratory animals. M.: Medicine, 1998. P.52]. Control animals were injected with an equivalent volume of saline.

Within 1 hour after the first injection agents (1/3 part d is PS) all mice subplanar a pillow hind paws were injected with 1% aqueous solution carragenin (logogen) in a volume of 0.05 ml Introduction agents were repeated twice at intervals of 1 hour. 3 hours after the last injection the animals were killed by cranio-cervical dislocation, cut off the hind legs below the ankle joint and determined the mass of each. Based on these data, calculate the index of edema, which was determined in percentage as the ratio of the mass difference between healthy and inflamed paws to a healthy weight. Anti-inflammatory effect was evaluated by the difference between the indexes of edema in the control and experimental groups. The results are presented in table 2.

As can be seen from the table, the introduction of compound I has caused a significant decrease carragenine of paw edema in mice. Marked antifogging effect (35%) was higher than in the Pharmacopoeia of ibuprofen at a dose of 15 mg/kg (18%) and closer to the effect of the reference drug in the dose of 50 mg/kg (43%), which indicates a pronounced anti-inflammatory action of the compounds I.

Example 3. Study of the anti-inflammatory effect of compound I on histamine-induced model of inflammation.

Histamine-induced model of inflammation were reproduced similarly described above, carragenine model [Manual on experimental (preclinical) study of new pharmacological substances. M: Remedium. 2000. S]. As logogen used a 0.1% aqueous solution of histamine in the volume of 0.05 m is.

In table 3 the data of anti-inflammatory effect of agents obtained on histamine-induced model.

Comparison of the data shows that inflammation induced by histamine, compound I exhibits anti-inflammatory activity comparable to that effect reference drug in the current dose of 50 mg/kg (58% vs. 55%).

Example 4. The study of antitumor activity of compound I on transplantable carcinoma of the lung Lewis.

The mice SW 1/6 (30 pieces) made the intramuscular perepevku suspension of 5×106tumor cells solid carcinoma, Lewis lung in a volume of 0.1 ml (Leno material from the collection of tumor strains of the Institute of Cytology and genetics SB RAS). Compound I was administered once intraperitoneally at a dose of 50 mg/kg in a solution of 0.9% sodium chloride with the emulsifier Tween 80. The comparison group was injected once parenteral complex anticancer drugs according to the standard scheme HAZOR: doxorubicin (4 mg/kg), cyclophosphamide (50 mg/kg), vincristine (0.1 mg/kg), prednisolone (5 mg/kg). Control mice - a solution of 0.9% sodium chloride with the emulsifier Tween 80.

On the 2nd, 3rd, 5th, 7th and 8 th day after injection was determined by the volume of tumors by measuring the sizes of the primary node in three mutually perpendicular directions. On the 9th day, the mice were killed by dislocation of sinohotel spine and calculated the index of inhibition of tumor growth, which was defined as the ratio of the difference between a tumor mass in the control and experimental groups, the tumor weight in control.

Change the volume of transplants lung carcinoma Lewis under the effect of the introduced agents shown in table 4.

It is established, that connection I was significantly delayed the tumor growth within 8 days after injection. The value of indexes of inhibition of tumor growth for both groups, reflecting the antitumor activity shown in the table. 5.

Table 5
Index values for the inhibition of tumor growth in experimental and reference groups
GroupThe inhibition of tumor growth, %
2 days3 days5 days7 days8 days
The connection I4236212326
HAZOR39343534

The data of table 5 show that compound I in a single parenteral dose of 50 mg/kg exhibits a noticeable anti-tumor effect is comparable to the action of antineoplastic drugs used according to the scheme of HAZOR. Thus, it is shown that the connection I have antitumor activity.

The conjugate of heparin with 2-aminoethanesulfonic acid formula

as anticoagulant tools with anti-inflammatory and antitumor activity.



 

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