NZ618882B2 - Compounds, pharmaceutical compositions and a method for the prophylaxis and treatment of the adhesion process - Google Patents

Abstract

Disclosed are inhibitory compounds of a p38 MAP kinase with a structure of type (I), which can be used for the treatment or prophylaxis of adhesion, wherein R1 represents the water soluble polymers chitosan, polyvinyltetrazole, carboxymethyl cellulose salts, polyvinylimidazole, polyethylenimine, polyvinylpyridines, polyvinyltriazole, polyacrylic acid salts, and polymethacrylic acid salts. The water soluble polymers form conjugates with the p38 MAP kinase inhibitor compound SB203580 (4-[4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-1H-imidazol-5-yl]pyridine). Also disclosed are methods for the prophylaxis and/or treatment of a disease or a condition in which there is the possibility of the formation and/or growth of adhesions in the serous cavity which makes it possible to dispense with the additional administration of a preparation in the post-operative period. lyvinylpyridines, polyvinyltriazole, polyacrylic acid salts, and polymethacrylic acid salts. The water soluble polymers form conjugates with the p38 MAP kinase inhibitor compound SB203580 (4-[4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-1H-imidazol-5-yl]pyridine). Also disclosed are methods for the prophylaxis and/or treatment of a disease or a condition in which there is the possibility of the formation and/or growth of adhesions in the serous cavity which makes it possible to dispense with the additional administration of a preparation in the post-operative period.

Description

Compounds, pharmaceutical compositions and a method for the prophylaxis and treatment of the adhesion process FIELD OF INVENTION The present invention relates to the fields of pharmacy, clinical and experimental medicine and nary e. In ul ar, it relates to new compounds for the treatment and tion of adhesions, pharmaceutical compositions containing these compounds, and to a method for the treatment and prevention of adhesion formation. Compounds described in this invention show ting effects on р38 МАР-kinase.

BACKGROUND OF THE INVENTION on formation is a topical problem of clinical medicine. Since adhesion especially often inhibits normal movement of tissues, including organs, it is considered as a serious complication after surgery. The incidence of intraperitoneal adhesions ranges from 67 to 93% after general surgical nal operations and up to 97% after open gynaecological pelvic procedures.

It has been estimated that in the United States, there are 117 hospitalisations for adhesion-related problems per 0 people, and the total cost for hospital and surgical expenditure is about $1.3 billion [Abdominal adhesiolysis: inpatient care and expenditures in the United States in 1994/ N.F. Ray, W.G. Denton, M.

Thamer et al.// J. Am. Coll. Surg.- 1998.- Vol. 186.- P. 1–9].

The main ches in preventing adhesions include ing surgical techniques, limiting trauma to intra-abdominal structures, and applying adjuvants to decrease adhesion formation [Risberg B.O. Adhesions: Preventive strategies/ B.O. Risberg// Eur. J. Surg. Suppl.- 1997.- Vol. 577.- P. 32-39]. r, the use of some medicinal preparations for the prevention of adhesions is limited by the following factors: 1) Ischemic zones are at risk of adhesion formation, but they are distant from blood flow and thus from pharmacological effects of medications stered by common routes (per os, intravenously, intramuscularly, etc.); 2) An ely rapid tion mechanism which is typical for the peritoneal membrane affects the elimination half-life and efficacy of many medicinal agents administered intraperitoneally; 3) Any anti-adhesion agent should show its specific activity against the adhesion formation but not the normal wound repair which is necessary for adequate surgical treatment.

Intra-peritoneal thrombokinase, fibrinolysin, streptokinase, urokinase, hyaluronidase, rypsin, trypsin, papain, and pepsin act directly by breakdown of the fibrinous mass and indirectly by stimulating nogen activator activity. The use of these agents is still awaiting appropriate human clinical trials [Alpay Z. Postoperative adhesions: from formation to prevention/ Z.

Alpay, G.M. Saed, M.P. Diamond// Semin. Reprod. Med.- 2008.- Vol. 26, N 4.- P. 313-321].

The use of non-steroidal anti-inflammatory agents, glucocorticosteroids and antihistamines, progesterone/estrogen, anticoagulants, fibrinolytics, and otics has not been found very ive in reducing adhesions and has been associated with an inadequate safety profile and a high incidence of various side effects [Pathogenesis, consequences, and control of peritoneal adhesions in ologic surgery/ Practice committee of the American society for uctive ne, The society of reproductive surgeons// Fertil. Steril.- 2008.- Vol. 90, Suppl. 5.- S. 144-149].

A pathologically justified approach to the prevention of adhesions is the use of methods and agents preventing approximation and adhesion of injured nal surfaces [Davey A.K. Surgical adhesions: A timely update, a great challenge for the future/ A.K. Davey, P.J. Maher// J. of lly Invasive Gynecology.- 2007.- Vol. 14.- P. 15–22].

An ideal barrier showing a high safety and efficacy profile should be noninflammatory, nonimmunogenic, and persist during the critical remesothelisation phase, staying in place t sutures or staples, and furthermore remain active in the presence of blood and be completely degradable.

In addition, it should neither interfere with healing, promote infection and oncological process, nor itself cause adhesions [Yeo Y. rs in the prevention of peritoneal adhesions/ Y. Yeo, D.S. // European. J. of Pharmaceutics and Biopharmaceutics.- 2008.- Vol. 68.- P. 57–66].

Nowadays, polymer solutions [Falabella C.A. Cross-linked hyaluronic acid films to reduce intra-abdominal postsurgical adhesions in an experimental model/ C.A. lla, W. Chen// Dig. Surg.-. 2009.- Vol. 26, N 6.- P. 476-481], solid membranes [Hyaluronan derivatives in postsurgical adhesion prevention/ D.

Pressato, E. Bigon, M. Dona et al. // in: Hyaluronan: Proceedings of an International Meeting, September 2000, North East Wales Institute, UK, Woodhead Publishing, Cambridge, England, 2002. - P. 491–499], precasted [A novel hyaluronan-based gel in laparoscopic adhesion prevention: preclinical evaluation in an animal model/ P.A.D. Laco, M. Stefanetti, D. Pressato et al.// Fertil. Steril.- 1998.- Vol. 69.- P. 318–323] or in situ els [Next-generation hydrogel films as tissue ts and adhesion rs/ S.L. Bennett, D.A.

Melanson, D.F. ana et al.// J. Card. Surg.- 2003.- Vol. 18.- P. 494–499] are used as these barriers preventing adhesion ion.

The use of crystalloid solutions for long-term separation of abdominal layers has been found inappropriate due to the rapid absorption of water and electrolytes from peritoneal cavity, with up to 500 ml of iso-osmolar sodium chloride absorbed in less than 24 hours in humans [Kinetics of peritoneal fluid absorption in adult man/ L. Shear, C. Swartz, J. Shinaberger et al.// N. Engl. J. Med.- 1965.- Vol. 272.- P. 123-127]. Because it takes 5 to 8 days for peritoneal surfaces to remesothelialise, a crystalloid solution should be absorbed well before the process of fibrin deposition and adhesion formation are complete. Clinical studies showed an adhesion re-formation rate of approximately 80% in patients who received lloid solutions [De Cherney A.H. Clinical problem of intraperitoneal rgical adhesion formation following general surgery and the use of adhesion tion barriers/ A.H. De Cherney, G.S di Zerega// Surg. Clin. North. Am.- 1997.- Vol. 77.- P. 671-688].

Attempts have been made to use different polymer materials, in ular polymers of glucose (Dextran 70, isodextrin), carboxymethyl cellulose, and hyaluronic acid. n 70 (32% dextran 70 n, Pharmacia, Sweden)) is a frequently used solution for adhesion prevention. Its main teristics are as follows: dextran is slowly absorbed and draws fluid into the abdominal cavity. It also ses clot formation [Gutmann J.N. Principles of laparoscopic microsurgery and adhesion prevention/ J.N. Gutmann, M.P. Diamond// in: Practical Manual of Operative Laparoscopy and Hysteroscopy: Ed. Azziz R., Murphy A.A.- New York: Springer, 1992.- P. 55-64]. Follow-up studies of the initial observation did not show a reduction in adhesions. Moreover, significant side s, such as ascites, weight gain, pleural effusion, labial edema, liver function abnormalities, and, albeit rare, disseminated intravascular coagulation and laxis, were noted, and dextran solution is used very rarely now. [di Zerega G.S. Contemporary adhesion prevention/ G.S. di Zerega// Fertil. Steril. - 1994.- Vol. 61.- P. 219-235].

The results have been inconsistent [Tulandi T. Intraperitoneal instillates/ T. i// Infertil. Reprod. Med. Clin. North. Am.- 1994.- Vol. 5.- P. 479-483] Difficulties have been found in using porous trafluoroethylene membranes as local barriers due to the ion of pseudocapsules [The Surgical Membrane Study Group: Prophylaxis of pelvic sidewall adhesions with Gore-Tex surgical ne: A multicentre clinical investigation// Fertil. Steril.- 1992.- Vol. 57.- P. 921-923]. Moreover, it has been technically difficult to use this material in laparoscopic surgery [Tulandi T. on prevention in scopic surgery/ T.

Tulandi// Int. J. Fertil. Menopausal. Stud.- 1996.- Vol. 41.- P. 452-457]. It requires a physical fixation and is not degradable. Therefore, it should be left or surgically removed later. Removal procedures may cause surgical traumas and lead to adhesion formation. These technical difficulties and ity problems have made the medication unpopular, and it is used very rarely now.

Oxidised regenerated cellulose (Interceed) is the only adjuvant approved for the specific purposes of postsurgical adhesion prevention. ORC appears to decrease adhesion formation-reformation beyond that achieved with meticulous al technique. ORC reduces both raw surface area and the occurrence of adhesion formation-reformation by a margin of 20% [Interceed (TC7) Adhesions Barrier Study Group: Prevention of postsurgical adhesions by Interceed (TC7), an absorbable adhesion barrier: A prospective, randomized multicenter clinical /Fertil. Steril.- 1989.- Vol.51.- P. 933-938]. When applied to a raw peritoneal surface, it becomes gel within 8 hours gistic effects of Interceed (TC7) and n in reducing adhesion formation in the rabbit uterine horn model/M.P.

Diamond, C.B. Linsky, T. Cunningham et al.//Fertil. Steril.- 1991.- Vol.55.- P. 389-394]. ORC can be applied easily by laparoscopy, and does not need suturing.

However, clinical observation indicates that small s of bleeding at the time that ORC is applied results in blood permeating the weave of the material.

Fibroblasts grow along the strands of d blood with uent collagen deposition and vascular proliferation [Frankfurter D. Pelvic adhesive disease/D.

Frankfurter, A.H. De Cherney//Postgrade Obstet. Gynecol.- 1996.- Vol.16.- P. 1- ]. This means that the presence of intraperitoneal blood s any beneficial effect t of blood on the efficacy of barrier adhesion reduction in the rabbit uterine horn model/C.B. Linsky, M.P Diamond., G.S. di Zerega et nfertility.- 1988.- Vol.11.- P. 0].

Summing up the current approaches to the prevention of postoperative adhesions in the peritoneal cavity, Burlev V.A. et al. (2009) [Burlev V.А.

Peritoneal adhesions: pathogenesis and prophylaxis. V.А. Burlev, Е.D.

Dubinskaya, А.S. Gasparov//Reproductive ers.- 2009.- No.3.- P. 36 -44] regret to state that all current methods for adhesion prevention are insufficiently ive (and quite expensive as well) and further studies are required to improve the efficacy of anti-adhesion es.

The most similar to the present invention in technical terms is a method for the tion of adhesions consisting in the injection of a combination of sterile Lintex-Mesogel gel and derinate into the serous sac [Method for the prevention of postoperative adhesions: Patent 2363476 of the Russian Federation: МКП51: A61K31/711, A61K31/717, A61P41/00 / Gomon М.S., Lipatov V.А., Konoplya А.I., Bezhin А.I., Loktionov А.L., Kasyanova М.А., Sukovatykh B.S., Godova А.Yu.; patent applicant/holder Gomon М.S., Lipatov V.А.- No. 2007147670/14; submitted on December 20, 2007; published on August 10, 2009, tter No. 22.- 6 pages].

This method for the prevention of adhesions consists in the following.

During abdominal operation, for example, laparotomy or laparoscopy, and/or before the covering of the serous sac at the final stage of the surgical intervention, the areas with high probability of primary or recurrent adhesion development (for example, deseronised areas, motic areas, areas with acute or possible mation, trauma zones after adhesion dissection, areas of abdominal drying, etc.) are d with sterile Lintex-Mesogel gel and depot derinate. The volume of derinate is 1% to 25% of total mixture volume. The combination of the derinate and polymer gel is achieved when a mixture is prepared extemporaneously immediately before use, with the correct tions of components. The ratio of gel-to-derinate solution volumes (based on 1.5 mg of derinate in 1 kg) should be such as the injected solution does not exceed 25% of the total volume, because more fluid may reduce the viscosity of the gel and its anti-adhesion activity. For adhesion prevention purposes, a portion of gel is applied to the serous surface using a syringe or squeezed into the palm of the surgeon’s hand from the container where the e has been prepared, and applied by smooth movements on the raw abdominal surface, deseronised areas and areas where adhesions may occur (areas with signs of inflammation or ischemia: edema, hyperemia, d vessels, oration, peristalsis, decreased pulsation of abdominal vessels, etc.). When diffusion processes occur (for e, after nal on in patients with generalised peritonitis), the combination of gel and derinate is applied at a dose calculated according to the table mentioned by G. ga (1999 г.), that is 2.4 ml/kg for humans, and 10.7 ml/kg for animals (rats). When laparoscopic procedures are performed, specific injectors are used to apply gel with depot derinate.

Disadvantages of this method include the necessity to prepare the sterile solution during the operation, which can make the surgical process more complicated. Other disadvantages e difficulties in achieving homogeneity, ulties in derinate dosing (need to be weighed), the need to use specific injectors/manipulators in laparoscopic procedures, and an absence of components inhibiting the activity of fibroblasts – cells which synthetic ty stimulates adhesion formation.

The р38 МАР-kinase inhibitor SB203580 is known to be an inhibitor of lammatory cytokine production [Badger A.M., Bradbeer J.N., Votta B. et al.

Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function// J. Pharmacol. Exp. Ther.- 1996.- Vol. 279.- P. 1453 - 1461]. r, no data were obtained by the inventors and no literature references were found ning the use of р38 МАР-kinase tor as an agent exhibiting dhesion activity.

DETAILED DESCRIPTION OF THE INVENTION The purpose of the present ion is to develop compounds for the prevention and ent of adhesions, and to develop pharmaceutical compositions containing a sufficient amount of one and/or several of the compounds described above and a pharmaceutically acceptable carrier, diluent or ent.

Another purpose of the invention is to develop a method for adhesion prevention allowing to avoid additional administration of medications in the erative period.

The inventors of the present invention found out that р38 МАР-kinase inhibitors may be used for the treatment and tion of adhesion formation. In particular, a compound [4-(4-fluorophenyl)(4-methylsulfonyl-phenyl)(4- pyridyl)-1Н-imidazole], also known as SB203580 (chemical a is shown in A.Cuenda et. al, FEBS Letters 364(1995) 229-233), and other new compounds of type (I)-(VII) (described below), prepared according to the present invention at the concentration of 0.1 to 100 µg/ml (on the basis of active substance inhibiting р 38 МАР-kinase activity ) and in the amount of 0.1 to 500 ml (depending on serous sac surface), sufficient to moisten the serous sac surface, provide a barrier to adhesion formation in the injured serous sac (Fig.1).

The present invention is characterised by the development of new compounds for the prevention and treatment of adhesions showing an inhibiting activity targeted at excessive proliferation response when involved in pathological processes of serous surfaces, and by the development of pharmaceutical compositions ning a ient amount of one and/or several compounds for adhesion prevention, together with a method for the prevention and treatment of adhesions using these compounds.

The group of the compounds described above may be characterised by the following structural formulas.

Type (I): R1 R1 O F S N Me - x y or type (II): R1 R1 F An S Me x y or type (III): - - An An + + R1 R1 R1 • • O F N S N Me F S Me x y z or type (IV): R1 R1 S N Me I - x y or type (V): R1 R1 S Me x y or type (VI): - - An An + + R1 R1 R1 • • O N S I Me I S Me x y z or type (VII): R1 R1 F An S Me x y where R1 is a base unit of water soluble polymers of natural or synthetic origin; x , y and z — integral values, where x, y and z ≠ 0. X, Y and Z values depend on the number of monomer units in a polymer molecule. In fact, each le has n of monomers. Some of these monomers bind to the p38 МАР- kinase inhibitor, the rest of the molecule remains unbound. Thus, (X+Y) = n (or in some cases X+Y+Z = n and n<6000), where n may be any integral number. In one embodiment of the present invention, x+y+z > 10.

The present invention relates to the use of SB203580 for new indications, namely as a nd exhibiting anti-adhesion activity.

Moreover, the present invention relates to pharmaceutical compositions that are characterised by a sufficient amount of any of the bed compounds of type (I)-(VII), or their combinations, or compound SB203580, or its ations with any of the compounds of type (I)-(VII), and a pharmaceutically acceptable carrier, t or excipient.

The amount of the active ingredient in the pharmaceutical composition, namely the amount of the compound of type (I)-(VII) or compound SB203580 or their combinations, sufficient to achieve therapeutic effects, may vary depending both on the compound used or the route of its stration, and on the area of serous sac surface in a treated patient.

The acceptable dose of the nd of type (I)-(VII) or compound SB203580 used for the treatment of serous sac surface is about 0.01 µg to 50 mg on the basis of a compound inhibiting p38 MAP-kinase activity.

Although the active ingredient may be administered separately as a raw chemical substance, it is preferable to include it into the pharmaceutical composition. The amount of the active ingredient is also preferable to be 0.00001% to 99.99999% of the total pharmaceutical composition volume.

Therefore, drug formulations may be presented in the form of standard dosage units or single doses and may be prepared using any of the known pharmaceutical methods. s described in А.I. Tikhonov, Т.G. Yarnykh ation Technology”, published by NPU 2002, pages 228, 229, 242, may be used as one of the alternatives to prepare the ceutical ition. All methods include the phase of interaction the active ingredient to the carrier, which consists of one or more excipients. Pharmaceutical compositions are usually ed by the steady and close contact (of the active ingredient with the liquid carrier.

The pharmaceutical composition according to the t invention can be prepared and administered in liquid form for perfusion systems, in the form of spray, spraying and vaporisation solution, foamy aerosol, gel or suspension, or in any other liquid form.

As regards to the route of administration, it is appropriate to apply the on over the serous sac surface, including wounds and organs, or to spray the solution for the prevention of adhesions using a l sprayer immediately after its ation.

Once prepared, the adhesion prevention solution can be sprayed over the necessary areas, and the solution used for adhesion prevention in the wound areas also can be sprayed evenly over the necessary areas. The areas of potential adhesion formation can also be ghly sprayed.

For spraying the solution, a r with two pressure pulverisers can be used, in which drops of the solution are transferred by air or carbon dioxide, or a sprayer with one pressure pulveriser, in which the solution turns into small particles.

The technical result of the ion lies in the fact that the compounds of type (I)-(VII) are generated by conjugation of the base polymer and a protonated derivate of pyridine-imidazole or pyridine-pyrrole, and that the pharmaceutical composition containing a sufficient amount of the compound of type (I)-(VII) and/or compound SB203580, and a pharmaceutically acceptable carrier, diluent or excipient has been ed.

Any appropriate base polymer can be used to generate compounds of type (I)-(VII). It is preferable to use as base polymers polyethylenimine and its copolymers, polyvinylpyridines and their mers, polyvinylimidazole and its copolymers, nyltriazole and its copolymers, chitosan and its derivates, carboxymethyl cellulose salts, polyacrylic acid and its copolymers, polymethacrylic acid and its copolymers, or polymethylmethacrylic acid and its copolymers .

The invention also es that the pharmaceutical composition is administered intraperitoneally during surgical, minimally invasive or diagnostic procedures for the tion or treatment of any disease or medical condition associated with adhesion ion and/or development.

The method for prevention of adhesions consists in the following: An appropriate р38 МАР-kinase inhibitor is injected into the serous sac immediately after operative and/or diagnostic procedures.

As one of the variant for adhesion prevention, р38 МАР-kinase inhibitors, in ular SB203580 or one of the compounds of type (I)-(VII) or their combinations are injected in the sterile solution form at the concentration of 0 .1 to 100 µg/ml (on the basis of active substance inhibiting р38 МАР-kinase activity ) and in the sufficient amount to moisten the serous sac surface. The solution is administered once at a dose that may inhibit not less than 50% of р38 МАР-kinase ty in injured areas.

A specific feature of the method is that with a disease or medical ion associated with serous sac disorders the pharmaceutical composition containing SB203580 or one of the compounds of type (I)-(VII) or their combination is administered by the surgical subject.

The method can be used for the treatment of diseases or medical conditions accompanied by exudation or bleeding in the serous sac, or by damage to the serous membrane.

Compounds intended for adhesion prevention, pharmaceutical compositions containing these compounds and the method for the prevention and treatment of adhesions described in the present invention may be used in the fields of experimental and clinical ne, and/or nary practice. Its functionality has been confirmed by the distinctive characteristics and features described above.

Thus, the ors have trated convincing ce that р38 МАР- kinase inhibitors may be used as medications with anti-adhesion activity.

Moreover, the inventors have achieved the aim of generating compounds that are effective in the treatment and/or prevention of adhesions, and developed pharmaceutical compositions using these compounds with a ient amount of one of the nds and/or their combination and a pharmaceutically acceptable carrier, diluent or excipient. Moreover, the inventors have developed an effective method for adhesion tion allowing to avoid additional administration of medications in the postoperative period.

BRIEF DESCRIPTION OF DRAWINGS Drawing 1 (therapeutic efficacy of compound SB203580, a р38 МАР- kinase inhibitor) Drawing 1 shows a histological n of the intestinal wall in the area of adhesion formation. No signs of adhesions are shown in the animal from the experimental group, even at the abdominal trauma zone and in the area of the postoperative suture (position C), van Gieson's staining.

Drawing 2 (therapeutic cy of compound SB203580, a р38 МАР- kinase inhibitor) g 2 shows a histological section of the intestinal wall in the area of on formation in an animal from the control group (van Gieson's staining).

The observed adhesions are characterized by a greater length, density of connective tissue (position A), and signs of vascularisation (position B).

Drawing 3 (therapeutic efficacy of р38 МАР-kinase inhibitor — compound of type (I), where R1 is a base unit of nylimidazole) Drawing 3 shows a histological section of the intestinal wall in the area of adhesion formation ion A) in an animal from the control group 30 days after modelling (van Gieson's ng). Intestinal wall adhesions (position A) and wellvascularised adhesions (position B) are shown.

Drawing 4 (therapeutic efficacy of р38 МАР-kinase tor — compound of type (I), where R1 is a base unit of polyvinylimidazole) g 4 shows a histological section of the intestinal wall in the area of adhesion formation. No signs of adhesions in the animal from the experimental group are evident, even at the abdominal trauma zone and in the area of the postoperative suture (position C), 30 days after modelling (van Gieson's staining).

Drawing 5 (therapeutic efficacy of р38 МАР-kinase inhibitor — compound of type (I), where R1 is a base unit of polyvinylimidazole) Drawing 5 shows the severity of adhesion formation on Day 7, 14 and 28 in the control group compared to that in the experimental group.

Drawing 6 UV-VIS spectrum of protonated salt aqueous solution of compound of type (I), where R1 is a base unit of polyvinylimidazole. Line 1 - water, Line 2 - aqueous solution of nylimidazole, Line 3 - compound (I), Line 4 - nd (I)+polymer polyvinylimidazole.

UV-VIS spectrum of protonated salt aqueous solution of compound of type (I), where R1 is a base unit of carboxymethyl cellulose. Line 1 - water, Line 2 - aqueous solution of polyvinylimidazole, Line 3 - compound (I), Line 4 - compound (I)+polymer carboxymethyl cellulose.

Drawing 8 UV-VIS um of protonated salt aqueous solution of compound of type (I), where R1 is a base unit of polyvinyltriazole. Line 1 - water, Line 2 - aqueous solution of polyvinylimidazole, Line 3 - compound (I), Line 4 - compound (I)+polymer polyvinyltriazole.

DETAILED DESCRIPTION OF PREFERRED IMPLEMENTATION VARIANTS OF THE INVENTION The following examples are used as illustration, but not to limit the scope of the present invention.

Example 1 Preparation of the compounds of type (I)-(VII) with anti-adhesion activity nds of type (I)-(VII) are prepared during the three-phase process according to schemes 1-3 given below.

During the first phase, an aqueous-based polymer solution, for e, polyvinylimidazole, is prepared according to scheme 1 for the synthesis of the compounds of type (I)-(VII) with anti-adhesion activity.

During the second phase, aqueous protonated solutions of the compounds of type (I)-(VII) are prepared by dissolving them in the aqueous solution of any nonorganic or c acid (HAn) according to scheme 2. Record UV-VIS spectra of s solutions of the compounds of type (I)-(VII).

During the third phase, mix the obtained aqueous polymer solution with the s solution of the compounds of type II), leave for 1 hour at room temperature until complete degradation of protonated salts dation of salts exposed to the high-alkaline medium of aqueous polymer solutions) forming the compound of type (I)-(VII) as a conjugate of the base polymer and active ingredient e 3).

Record UV-VIS spectra again and according to their transformation (compared to protonated salts), state a formation of the compound of type (I)-(VII) with polymers.

These compounds of type (I)-(VII), as opposed to parent nds without polymers, may be used for the treatment and tion of adhesion formation.

Scheme 1.

Preparation of aqueous polymer solution Polymer + n H2O Polymer(H)n(OH)n Preparation of aqueous polyvinylimidazole on n H2O N N N + n OH N N N m n m-n Preparation of aqueous carboxymethyl cellulose solution O O OM OH C C O n H2O O + n M + n OH O O O O RO RO OR OR n n R=H,CH2C(O)OM; M=Na+, K+, NH4+ etc.

Preparation of s chitosan solution OH OH n H2O O O O O HO HO + n OH NH2 NH3 n n Scheme 2 Preparation of water-soluble protonated compounds of type (I)-(VII) F F HAn H N N An O N O S N N S N H H Me Me Scheme 3 Preparation of the compounds of type II) N N N x + n OH + y An N N O N H S N n m-n Водный раствор Водный раствор соли поливинилимидазола соединения № 2 Example 2 According to schemes 1-3 given in example 1 (see above), a compound of type (I) was generated on the basis of chitosan, a polymer of natural origin: , where x and y — integral values, x, y ≠ 0.

Example 3 According to schemes 1-3 given in example 1 (see above), a nd of type (I) was generated on the basis of polyvinylimidazole, a polymer of synthetic origin: , where x and y — integral values, x, y ≠ 0.

Example 4 According to schemes 1-3 given in example 1 (see above), a compound of type (I) was generated on the basis of carboxymethyl cellulose, a polymer of synthetic origin: , where x and y — integral values, x, y ≠ 0.

Example 5 Adhesions in the peritoneal cavity were generated in tory animals (Wistar rats, 9 months of age, weight of 220-250 g) by ng the surface of caecum and abdominal wall scarification in the injured area. The study was conducted in compliance with the principles of the European Convention for the Protection of Vertebrate Animals used for Experimental and other ific Purposes (Strasbourg, , 1986), as well as with regulations for humane treatment specified in Guidance for Proper Conduct of Animal Experiments (Attachment to Order No. 755 of the Ministry of Health of the USSR, dated August 12, 1977).

Ten laboratory animals were used in this study. They were divided into 2 groups: the experimental group and the control group.

Before rhaphy, 3 ml of sterile solution SB203580, р38 МАР-kinase inhibitor, at the concentration 10 µg/ml was injected once into the experimental animals. The calculation was based on the minimum volume of solution required to moisten the peritoneal surface (diZerega G.S. Peritoneum, peritoneal healing and adhesion formation/ G.S. diZerega// in: Perotoneal surgery: Ed. G.S. diZerega.- Berlin-Heidelberg-New York: Springer, 2006.- P. 3 -38), and the concentration was calculated on the basis of IC50 in the boundary layer of cells.

The control animals received a corresponding amount of normal saline solution.

On Day 28 after the nal cavity being injured, all animals were ied for the examination of abdominal cavity organs and the assessment of the severity and nce of adhesions, deformation of abdominal cavity organs and distribution structures of different types of adhesions. The severity of adhesions was scored according to micro- and macroscopic adhesion scales [Micronized ed oid fraction may prevent formation of intraperitoneal adhesions in rats// H.G. Yilmaz, I.H. Tacyildiz, C. Keles et al.// Fertil. Steril.- 2005.- Vol. 84, Suppl. 2.- P 1083-1087].

The visceral peritoneum and abdominal organs involved in adhesion formation were examined histologically after on in FineFIX solution (Milestone), paraffin g, ng with hematoxylin-eosin and van Gieson's staining.

Adhesions in the peritoneal cavity were observed in 100% of control animals, and intestinal wall adhesions were detected in 100% of cases. Thus, Fig. 2 shows a ogical section of the intestinal wall in the area of adhesion formation (position A) in the animal from the control group (van Gieson's staining). The observed adhesions were characterized by a greater length and density of tive tissue, and signs of vascularisation (position В).

No cases of intestinal wall adhesions were observed in the experimental animals. Fig. 1 (Attachment to Application) shows no signs of ons in the animal from the experimental group, even at the abdominal trauma zone and in the area of the erative suture (position C), van Gieson's staining.

The severity of adhesion formation was scored as 7 in the control group, and as 2 in the experimental group (р<0.01).

Results of the study suggest that the described method may be used for the prevention of adhesions in the serous sac after surgical interventions.

Thus, the described method is considered to be efficient in preventing adhesion formation when the specified medication is ed once immediately after the operative procedures, and results in l injuries and simplifies the prevention of adhesions, while it decreases the risk of organ injuries and the risk of infections in the serous sac.

Example 6 Adhesions in the peritoneal cavity were generated in laboratory animals (Wistar rats, 9 months of age, weight of 220-250 g) by injuring the surface of caecum and abdominal wall scarification in the injured area. The study was conducted in compliance with the principles of the European Convention for the Protection of rate s used for Experimental and other Scientific Purposes (Strasbourg, France, 1986), as well as with regulations for humane treatment specified in Guidance for Proper Conduct of Animal Experiments hment to Order No. 755 of the Ministry of Health of the USSR, dated August 12, 1977).

Thirty laboratory animals were used in this study. They were divided into 2 : the experimental group and the control group.

Before celiorrhaphy, a pharmaceutical composition (3 ml) ning the compound according to example 2, at the concentration 2? 10-3 mol/l was injected once in experimental animals. The calculation was based on the minimum volume of solution required to moisten the peritoneal surface [diZerega G.S. Peritoneum, peritoneal g and adhesion formation/ G.S. diZerega// in: Perotoneal surgery: Ed. G.S. diZerega.- Berlin-Heidelberg-New York: er, 2006.- P. 3-38]). The control s were injected with a corresponding amount of saline solution.

On Day 7, 14 and 28 after the nal cavity being injured, all animals were autopsied for the ation of abdominal cavity organs and the assessment of the severity and incidence of adhesions, deformation of abdominal cavity organs and distribution structures of different types of adhesions. The visceral peritoneum and abdominal organs involved in adhesion formation were examined histologically after fixation in FineFIX solution (Milestone), paraffin filling, ng with hematoxylin-eosin and van Gieson's staining.

Adhesions in the peritoneal cavity were ed in 100% of the control animals, and intestinal wall adhesions were ed in 100% of cases. The observed adhesions were terised by a greater length and density of connective tissue, and signs of vascularisation (Attachment to Application, Fig. 3).

Also, Fig. 3 shows a histological section of the intestinal wall in the area of adhesion formation (position A) in the animal from the control group 30 days after modelling (van Gieson's staining). Intestinal wall adhesions (position A) and wellvascularised adhesions (position B) were shown.

No cases of intestinal wall adhesions were observed in experimental animals. Fig. 4 shows no signs of adhesions in the animal from the experimental group, even at the abdominal trauma zone and in the area of the postoperative suture (position C), 30 days after modelling (van 's staining).

On Day 7, 14 and 28, the severity of adhesion formation was significantly higher in the control group than in the experimental group (Figure 5).

Example 7 Adhesions in the peritoneal cavity were generated in laboratory animals divided into 8 experimental groups, each composed of 25 individuals (Wistar male rats, 9 months of age, weight of 180-200 g) to te the effects of the compounds of type II) on the basis of chitosan, carboxymethyl cellulose, nyltetrazole, polyethylenimine, polyvinyltriazole, and polyacrylic acid on the prevention and course of adhesions. The study was conducted according to the methods described in example 5 and 6 of the present ion.

Compounds of type (I)-(VII) on the basis of an, carboxymethyl cellulose, polyvinyltetrazole, hylenimine, polyvinyltriazole, and polyacrylic acid (at a dose of 10 mg/kg based on the compound inhibiting р38 МАР-kinase activity) were injected in the sterile solution form in animals of all experimental groups (once, after the surgical intervention) after the modelling of adhesion formation.

The control animals were injected with a corresponding amount of saline solution.

On Day 7, 14 and 28 after the abdominal cavity being injured, all animals were autopsied for the examination of abdominal cavity organs and the ment of the severity and incidence of adhesions, deformation of abdominal cavity organs and distribution structures of different types of adhesions. The al peritoneum and abdominal organs involved in adhesion formation were examined histologically after fixation in FineFIX solution (Milestone), paraffin filling, ng with hematoxylin-eosin and van Gieson's staining.

Adhesions in the peritoneal cavity were observed in 100% of the control animals, and intestinal wall adhesions were detected in 100% of cases.

No cases of intestinal wall adhesions were observed in any of 6 experimental groups.

On Day 7, 14 and 30, the severity of on formation was significantly higher in the control group than in the experimental group.

Claims (29)

Claims 1.

1. Use of p38 MAP kinase inhibitors in the manufacture of a medicament for preventing the formation and/or growth of adhesions of serous cavity.

2. Use according to claim 1, wherein p38 MAP kinase inhibitor is a compound 4- 5 (4-fluorinephenyl)(4-methylsulphinylphenyl)(4-pyridyl)-1H-imidazole.

3. Use according to claim 1, wherein the compound of p38 MAP kinase tor is a compound of type (I): R1 R1 O F S N Me - x y or (II): R1 R1 F An S Me x y or (III): - - An An + + R1 R1 R1 • • O F N S N Me F S Me x y z or (IV): R1 R1 S N Me I - x y or (V): R1 R1 S Me x y or (VI): - - An An + + R1 R1 R1 • • O N S I Me I S Me x y z or (VII): R1 R1 F An S Me x y where R1 – structural unit of water-solvable polymers of basic character of natural or 5 synthetic origin comprising salts of polyacrylic acid, polymethacrylic acid, polymethylmethacrylic acid or their copolymers and derivatives, polyethylenimine and its mers, polyvinylpyridines and their copolymers, polyvinylimidazole and its copolymers, polyvinyltriazole and its copolymers, polyvinyltetrazole and its copolymers, chitosan and its tes, carboxymethyl cellulose; x, y and z are whole numbers, besides if x≥1, y≥1, z=0, than x+y=n, if x≥1, y≥1, z≥1, than x+y+z=n, wherein n – the number of monomer units in a polymer molecule, wherein n is 5 integral number and n<6000.

4. Use ing to claim 3, wherein R1 is ural units of an.

5. Use according to claim 3, wherein R1 is structural units of nyltetrazole.

6. Use according to claim 3, wherein R1 is structural units of carboxymethylcellulose salts. 10

7. Use ing to claim 3, wherein R1 is structural units of polyvinyl imidazole.

8. Use according to claim 3, wherein R1 is structural units of polyethylenimine.

9. Use according to claim 3, wherein R1 is structural units of polyvinylpyridines.

10. Use according to claim 3, wherein R1 is structural units of polyvinyltriazoles.

11. Use according to claim 3, wherein R1 is structural units of polyacrylic acid. 15

12. Use according to claim 3, wherein R1 is structural units of polymethacrylic acid.

13. Use according to one of claims 3-12, wherein p38 MAP kinase inhibitor is any of type (I)-(VII) nds or its combination with each other or with compound 4-(4-fluorinephenyl)(4-methylsulphinylphenyl)(4-pyridyl)-1H- 20 imidazole.

14. Use according to claim 1, wherein adhesions associated with any surgeries and procedures with invasion into serous cavity, including minimally invasive ones such as laparoscopy, oscopy, and arthroscopy but there are not a full list.

15. Use according to claim 1, wherein adhesions associated with exudation in 25 serous sac.

16. Use according to claim 1, wherein adhesions associated with bleeding in the serous sac.

17. Use according to claim 1, wherein adhesions associated with damage of serous membrane.

18. Use according to claim 1, wherein adhesions associated with surgical and/or 5 diagnostic procedure and medicament is in the form of a sterile solution in the volume enough for moistening the entire e of serous sac.

19. Compound p38 of MAP kinase inhibitor of type (I) R1 R1 O F S N Me - x y or (II) R1 R1 F An S Me x y or (III) - - An An + + R1 R1 R1 • • O F N S N Me F S Me x y z or (IV) R1 R1 S N Me I - x y or (V) R1 R1 S Me x y or (VI) - - An An + + R1 R1 R1 • • O N S I Me I S Me x y z or (VII) R1 R1 F An S Me x y where R1 is a base unit of water soluble polymers of natural or synthetic origin 5 comprising salts of polyacrylic acid, thacrylic acid, polymethylmethacrylic acid or their copolymers and derivatives, polyethylenimine and its copolymers, polyvinylpyridines and their copolymers, polyvinylimidazole and its copolymers, polyvinyltriazole and its copolymers, nyltetrazole and its copolymers, chitosan and its derivates, carboxymethyl cellulose; x, y and z are integral values, besides if x≥1, y≥1, z=0, than x+y=n, if x≥1, y≥1, z≥1, than x+y+z=n, wherein n – the number of monomer units in a polymer molecule, wherein n is integral 5 number and n<6000.

20. A compound according to claim 19, where R1 is a base unit of chitosan.

21. A compound according to claim 19, where R1 is a base unit of polyvinyltetrazole.

22. A compound according to claim 19, where R1 is a base unit of carboxymethyl 10 cellulose salts.

23. A compound according to claim 19, where R1 is a base unit of polyvinylimidazole.

24. A compound according to claim 19, where R1 is a base unit of polyethylenimine. 15

25. A nd according to claim 19, where R1 is a base unit of polyvinylpyridines.

26. A compound according to claim 19, where R1 is a base unit of polyvinyltriazole.

27. A compound according to claim 19, where R1 is a base unit of polyacrylic 20 acid salts.

28. A compound according to claim 19, where R1 is a base unit of polymethacrylic acid salts.

29. A ceutical composition containing a sufficient amount of any of compounds according to claims 19-28 or its combinations, and a ceutically 25 acceptable carrier, t or excipient.