4-hydroxybenzamide drug derivatives

FIELD: medicine.

SUBSTANCE: there are presented drug derivatives wherein said derivatives contain a H₂S-releasing fragment of 4-hydroxythiobenzamide which is either covalently bond with the drug, or forms a pharmaceutically acceptable salt with the antilipidemic drug.

EFFECT: compounds show higher activity, or reduced side effects.

5 cl, 26 ex, 22 dwg

This application is published as a partial continuation of application PCT/CA2006/000484, published on 31 March 2006, for which priority has been claimed, on the basis of an application PCT/CA2005/000819, published on 27 may 2005. Further, this application is a partial continuation of patent application U.S. 11/759154, which is a partial continuation of application PCT/CA2006/000484 and for which priority has been claimed, on the basis of the provisional application for U.S. patent No. 60/804067 published on 6 June 2006. Further, this application is claimed priority from provisional applications U.S. patent No. 60/807639, published July 18, 2006, and 60/887188, published on 30 January 2007.

The technical FIELD

The present invention relates to releasing the hydrogen sulfide (H₂S) derived medicinal substances having improved activity and/or reduced side effects. In particular, the present invention relates to derivatives of drugs, including H₂S-releasing fragment 4-hydroxytyramine or covalently associated with the drug, or forming a salt with the drug.

The LEVEL of TECHNOLOGY

Nitric oxide (NO) and carbon monoxide (CO), synthesized from L-arginine under the action of NO-synthetase and heme under the action of oxygenase heme, represent, meet the but a well-known neurotransmitter and is also involved in the regulation of vascular tone. Recent studies assume that the hydrogen sulfide (H₂S) is a third gaseous mediator mammals. H₂S is synthesized from L-cysteine or under the action of cystathionine beta-synthetase (CBS) or cystathionine gamma-LiAZ (CSE), both enzymes use pyridoxal 5'-phosphate (vitamin B₆) as cofactor.

It is assumed that H₂S stimulates ATP-sensitive potassium channels (K_ATPIn smooth muscle cells of blood vessels, neurons, cardiomyocytes and pancreatic beta-cells. In addition, H₂S can react with reactive oxygen and/or nitrogen molecules, limiting their toxic effects and alleviating their physiological functions, acting similarly to nitric oxide.

Recent studies have shown that H₂S involved in the regulation of vascular tone, myocardial contractions, neurotransmission and secretion of insulin. The lack of H₂S is observed in various animal models of arterial and pulmonary hypertension, Alzheimer's disease, damage to the mucosa of the stomach and liver cirrhosis. It is assumed that exogenous H₂S improves when myocardial dysfunction associated with ischemia/reperfusion injury, and reduces the damage of the discussion of the gastric mucosa, due to anti-inflammatory drug.

More specifically, the recently observed that H₂S activates anti-inflammatory and analgesic activity. H₂S is an endogenous compound produced in many tissues and affect many features (Wang, Two's company, three''s a crowd: can H₂S be the third endogenous gaseous transmitter? FASEB J. 2002; 16: 1792-1798). Also, as has been shown, it is a vasodilator and can suppress the adhesion of leukocytes to the vascular endothelium (Wang, 2002; Fiorucci et al., Inhibition of hydrogen sulfide generation contributes to gastric injury caused by anti-inflammatory nonsteroidal drugs. Gastroenterology. 2005; 129: 1210-1224).Next, Fiorucci et al. (2005) demonstrated that pre-treatment of donor H₂S can reduce the severity due to NSAID gastric damage in rats.

It is assumed that the production of endogenous H₂'s changed in many diseases. In addition, the levels of H₂S may depend on the currently used drugs. For example, acetylsalicylic acid and nonsteroidal anti-inflammatory drug substance (NSAID)have been shown to have a suppressive effect on CSE-H₂S path in the mucosa of the gastrointestinal tract (Fiorucci, S. et al.). This effect may contribute to the damage of the gastric mucosa, is stipulated by the tion of these medicinal substances. Thus, pharmacological modulation of the levels of H₂S may have significant therapeutic potential.

It is also assumed that H₂S may play a role in cardiovascular disease and, as such, its level should be investigated in patients with various risk factors for atherosclerosis, such as hypertension, hyperlipidemia, diabetes, etc. Shows that H₂S extinguished reactive particles of oxygen (ROS) (Whiteman, M. et al., The novel neuromodulator hydrogen sulfide: an endogenous peroxynitrate 'scavenger'?, J Neurochem. 2004; 90: 765-768), and discusses the important role of oxidative stress in numerous diseases, such as atherosclerosis, hypertension, Alzheimer's disease and so on, it is assumed that excessive production of ROS can cause deficiency of H₂S.

Beta-blockers, which are used for the treatment of angina, hypertension and cardiac arrhythmia, detect respiratory side effects such as shortness of breath, bronchostenosis etc. and, therefore, can cause problems in patients affected by asthma, bronchitis and the like. Therefore, beta-blockers additionally worsen the condition for respiratory diseases such as asthma. However, in asthmatic patients should apply a reduced dose of the mentioned drugs in order not to expose additional is Noah danger of respiratory function. Thus, the efficacy of beta-blockers is reduced.

Antithrombotic agents, such as dipyridamole, aspirin, etc. used to prevent thrombotic events have a number of side effects such as stomach pain, nausea and other complications in relation to the gastrointestinal tract. In patients with pathologies associated with oxidative stress, therapeutic effects or tolerability of these drugs, as in the case of aspirin significantly reduced.

Bronchodilators, such as salbutamol, etc. that are used in the treatment of asthma and bronchitis and medicinal substances active against cholinergic system, applied in pathological conditions, such as incontinence. Their introduction can cause side effects that damage the cardiovascular system of the patient, causing problems like cardiovascular and hypertensive patients.

Expectorants and mucolytic agents used in the treatment of inflammatory conditions of the respiratory organs, can lead to an increase in heartburn and irritation of the stomach, especially in elderly patients.

Inhibitors of bone resorption, such as diphosphonates (e.g., alendronate, etc.) is a medicinal substance having a high gastrointestinal toxicity.

Inhib the Torah phosphodiesterase, such as, for example, sildenafil, zaprinast used in the treatment of cardiovascular and respiratory diseases, are characterized by similar problems, such as tolerability and/or efficacy, particularly in pathological conditions under oxidative stress.

Antiallergic drugs such as cetirizine, montelukast, etc. have such problems in the above-mentioned pathological conditions, particularly in relation to their effectiveness.

Antiangiogenesis tools such as ACE-inhibitors, such as enalapril, captopril, and so on, and inhibitors of the receptor, such as losartan, etc. that are used in the treatment of cardiovascular diseases. These medicinal substances can cause respiratory side effects (ie, cough etc), particularly in pathological conditions under oxidative stress.

Antidiabetic drugs as insulin-sensitizing and cause hypoglycemia, such as, for example, sulfonylureas, tolbutamide, glipizide, gliclazide, gliburid, nicotinamide, etc., ineffective in the prevention of complications in diabetes. Their introduction may give side effects such as, for example, damage to the stomach. These phenomena become more intense under pathological conditions of oxidative stress.

Antibiotics,such as ampicillin, clarithromycin and so on, and antiviral agents such as acyclovir, etc., find problems in relation to their portability, for example, they cause irritation of the gastrointestinal tract.

Anticancer drugs such as doxorubicin, daunorubicin, cisplatin, etc. have high toxicity, in some organs, including the stomach and intestines. Mentioned toxicity in worsening the condition of the above-mentioned pathologies induced oxidative stress.

Medicinal substances against dementia, such as nicotine and cholinomimetic drugs, are characterized by poor tolerability, especially under pathological conditions under oxidative stress.

Thus, there is a need for the development of affordable drugs with improved therapeutic characteristics, that is, having low toxicity and/or higher efficiency, so that they could be administered to patients with painful conditions with oxidative stress and/or endothelial dysfunctions, avoiding serious shortcomings of medicinal substances of the prior art.

Unexpectedly, the authors of the present invention for the first time found that 4-hydroxycobalamin (also referred to here as a 4-HTB or TBZ) is effective in releasing H₂'s what fragmentum in the tissues, when it is either covalently linked to the drug, or forms a salt with the drug, and the obtained derivative drugs have reduced side effects. For example, derivatives of medicinal substances of the present invention create significantly less gastrointestinal and/or cardiovascular side effects.

The INVENTION

In one aspect of the present invention provided derivatives of drugs where the above-mentioned derivatives include H₂S-releasing fragment 4-hydroxytyramine (also referred to here as a 4-HTB or TBZ), which is either covalently linked to the drug, or forms a salt with the drug. Compounds of the present invention exhibit unexpectedly high activity compared with the drug, taken separately, 4-gidroksicarbamidom, taken separately, and the combination of drug and 4-hydroxytyramine entered separately but sequentially detect reduced side effects, or both.

Compounds of the present invention create a mild, transient increase in the concentration of H₂S in the plasma. Without having to be bound to any theory short-term increase in concentration of H₂S in the plasma to the th remains within the physiological range, may contribute to the increased activity of medicinal substances, reduced damage to the gastrointestinal tract and/or reduced cardiovascular toxicity.

Further, the compounds of the present invention unexpectedly cause a much smaller increase in systolic blood pressure with the introduction of hypertensive rats that were observed during the introduction of the drug itself. Reduced tendency to raise blood pressure can reduce cardiovascular side effects often seen with prolonged use of some drugs.

According to the present invention is provided compounds having the following General formula:

where A represents the balance of the medicinal substance, Y is selected from the group consisting of-C(O)O-, -C(O)NH-, -C(O)OC(O)-, -C(O)NHCH₂C(O)-, O, S, N,or group is absent, and X is aor,and pharmaceutically acceptable salts of compounds in which if Y is absent, then the derived medicinal substance may be a salt of A and X. In the preferred embodiment, A and X are linked is through the ether bridge, anhydrite bridge, thioester bridge, amide bridge or azo-bridge. In one embodiment, a salt formed with the remainder of drugs, using thiocarbamoylation instead of 4-hydroxytyramine.

The medicinal substance can be selected from a variety of known classes of drugs including, for example, proteins, peptides, nucleotides, drugs against obesity, food products with enhanced nutritional value, corticosteroids, elastase inhibitors, analgesics, antifungals, anticancer tools, anti-emetics, analgesics, cardiovascular drugs, anti-inflammatory medications, deworming drugs, antiarrhythmic agent, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, ANTIEPILEPTICS tools, antihistamines, antihypertensive agents, antimuskarinovoe act occurs means antimycobacterial agents, antineoplastic agents, immunosuppressants, tools, directed to the thyroid gland, antiviral agents, anxiolytic sedatives (hypnotics means and neuroleptics), astringents, beta-adrenoblokatory, cardiac ionotropic agents, corticosteroids, antitussives (expectorant and mucolytic agents), d is eretici, dopaminergic funds (medicinal substance against Parkinson's disease), gematologicheskie tools, immunological tools, medicines regulating lipid metabolism, muscle relaxants, parasympathomimetics tools, thyrocalcitonin and bisphosphonates and parathyroid glands, prostaglandins, sex hormones, anti-allergic agents, stimulants, anorexicskin tools, sympathomimetic funds, funds that are active against the thyroid gland, vasodilators and xantina.

These medicinal substances are especially applicable in the present invention:

non-steroidal anti-inflammatory drug substance (NSAID): acetylsalicylic acid (ASA), diclofenac, naproxen, indomethacin, flurbiprofen, sulindac, ibuprofen, aceclofenac, acemetacin, benoxaprofen, benzophenon, bromfenac, Burlakova acid, butibufen, carprofen, celecoxib, cicloprofen, cinmetacin, clidanac, clairac, diflunisal, etodolac, etoricoxib, fenbufen, fenclofenac, venglarik, fenoprofen, fentiazac, flunoxaprofen, paraprotein, furubotn, furofenac, ibufenac, indoprofen, isoxepac, Ketoprofen, Ketorolac, loxoprofen, lonazolac, lumiracoxib, medicinova and mefenamovaya acid, meclofenamic acid, meloxicam, nabumetone, pyramidula acid, salsalate, miroprofen, oxaprozin, the oaks is inak, parecoxib, phenylbutazone, pirprofen, piroxicam, pyrazoles, proteinemia acid, rofecoksib, sodium salicylate, suprofen, tiaprofenic acid, tolmetin, valdecoxib, zomepirac, and the like;

analgesic medicinal ingredients: acetaminophen, acetaminoohen, aminofluorescein, acetylsalicylic 2-amino-4-picolina acid, atsetilsalitsilovaja acid, Anileridine, benoxaprofen of benzylmorphine, acetate 5-bromosalicylic acid, Buletin, buprenorphine, butorphanol, capsaicin, cinchophen, ciramadol, cloretazine, clonixin, codeine, desomorphine, dezocine, Dihydrocodeine, dihydromorphine, dimepheptanol, dipyridyl, eptazocine, Eloxatin, Ethylmorphine, eugenol, floctafenine, posposil, glutenin, hydrocodone, hydromorphone, hydroxypethidine, ibufenac, para-lactofree, Levorphanol, meptazinol, metazocine, metopon, morphine, nalbuphine, Nicomorphine, norlevorphanol, normorphine, oxycodone, Oxymorphone, pentazocine, phenazocine, fenocor, Phenoperidine, phenylbutazone, fenilsalitsilat, phenyramidol, salicin, salicylamide, thiorphan, tramadol, diacerein, actarit, and the like;

medicinal agents against inflammation of the colon: 4 - or 5-aminosalicylic acid, trimebutine, and the like;

respiratory and urogenital funds (bronchodilatory and medicinal substances active against cholinergic system expectorants/mucolytics, anti-asthma/allergic antigistaminny medicinal substance): bronchodilatory and medicinal substances active against cholinergic system: acetylen, albuterol, bambuterol, bamifylline, methyl sulfate of Bionime, bitolterol, carbuterol, clenbuterol, clorprenaline, dioxygen, Tefillin, ephedrine, epinephrine, Apraksina, atarelin, Ethylmorphine, etofillin, fenoterol, bromide plutonium, geksoprenalin, bromide ipratropium, isoetharine, isoproterenol, mabuterol, metaproterenol, oxybutinin, bromide oxitropium, pirbuterol, procaterol, protocell, proxyphylline, reproterol, rimiterol, salmeterol, soterenol, terbutaline, 1-teoretyczny acid, bromide Tiotropium, triethanol, tulobuterol, zaprinast, cyclotron, NS-21, 2-hydroxy-2,2-diphenyl-N-(1,2,3,6-tetrahydropyridine-4-ylmethyl)ndimethylacetamide and the like;

expectorants/mucolytics: Ambroxol, Bromhexine, domodal, erdosteine, guaiacol, guaifenesin, audirovannyj glycerin, latesteijn, mesna, sobrero, stepronin, Turpin, tiopronin, and the like;

anti-asthma/allergic antihistamine drug substances: acrivastine, allocated, amlexanox, cetirizine, clonezepam, chromoglycate, chromalin, epinastine, Fexofenadine, formoterol, histamine, hydroxyzine, levocabastine, lodoxamide, mabuterol, montelukast, the upper part is of oil, reprint, seratrodast, suplatast, toilet, terfenadine, tiaramide, urushiol, Bromhexine, and the like;

ACE-inhibitors: alacepril, benazepril, captopril, ceronapril, cilazapril; delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, losartan, multiperil, naftopidil, perindopril, inapril, ramipril, spirapril, temocapril, trandolapril, urapidil, and the like;

beta-blockers: acebutolol, alprenolol, amosulalol, arotinolol, atenolol, betaxolol, bevantolol, bukamal, buretrol, bufuralol, bunitrolol, bupranolol, butalbital, carazolol, carteolol, carvedilol, celiprolol, atemolol, dilevalol, epanolol, esmolol, indenolol, labetalol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, ngoxolo, nebivolol, neftaly, nipradilol, oxprenolol, penbutolol, pindolol, practolol, pronethalol, propranolol, sotalol, sulfinol, talinolol, tertatolol, tilisolol, timolol, celiprolol, sibenaler, and the like;

antithrombotic agents and vasodilators: acetorphine, acetylsalicylic acid, argatroban, Bamyan, hemisuccinate bedfordia, benziodarone, betahistine, brombenzene, bufend, citicoline, lobengula, clopidogrel, cyclandelate, dalteparin, dipyridamole, droprenilamine, enoxaparin, fendilin, ifenprodil, iloprost, indobufen, isbogrel, isoxsuprine, heparin, lamifiban, metrodin, NADR the Parin, nicotinoyl alcohol, nylidrin, ozagrel, perhexiline, phenylpropanolamine, prenilamin, piperalin, sodium salt reviparin, ridogrel, suloctidil, tieferen, Tinzaparin, triflusal, nitinat ksantinola, and the like;

antidiabetic agents: acarbose, carbutamide, glibornuride globaliza, miglitol, Repaglinide, troglitazone, 1-butyl-3-methanol-urea, tolrestat, nicotinamide, and the like;

antitumour substances: ancitabine, astromicin, azacytidine, azaserine, 6-azauridine, bikalutamid, karubitsin, casinopolis, chlorambucil, chlorozotocin, cytarabine, daunorubicin, defoamed, demecolcine, deeperin, 6-diazo-5-oxo-1-norleucine, docetaxel, doxifluridine, doxorubicin, droloxifene, edatrexate, eflornithine, enocitabine, epirubicin, epitiostanol, etanidazole, etoposide, phenetidine, fludarabine, fluorouracil, gemcitabine, hexestrol, idarubitsin, lonidamine, mannomustine, melphalan, menogaril, 6-mercaptopurine, methotrexate, mitobronitol, mitolactol, mitomycin, mitoxantrone, mopidamol, mycofenolate acid, nineteen, nogalamycin, paclitaxel, pentostatin, pirarubicin, piritrexim, plicamycin, Pogorelova acid, porfimer sodium, porfiromycin, propagermanium, puromycin, ranimustine, retinoic acid, roquinimex, streptonigrin, streptozocin, teniposide, tinoisamoa acid, timipre, t is guanin, tomudex, topotecan, trimetrexate, tubercidin, ubenimex, vinblastine, vincristine, vindesine, vinorelbine, zorubicin, and the like;

antiulcer drug substances: ε-acetamidomalonate acid, arbaprostil, cetraxate, cimetidine, ecabet, enprostil, espasol, irsogladine, misoprostol, omeprazole, ornoprostil, pantoprazole, plaunotol, rioprostil, reciprocal, retraxit, sofalcone, chromoprotein, and the like;

protivoepidemicheskie medicinal substance (statins: atorvastatin, cilastatin, termostatic, fluvastatin, lovastatin, mevastatin, nystatin, pentostatin, pepstatin, pravastatin sodium, simvastatin, and the like;

antibiotics: amdinocillin, amoxicillin, ampicillin, apalcillin, apicillin, aspoxicillin, azidophenyl, azidocillin, azlotillin, aztreonam, benzoles, benzyl penicillin acid, biapenem, bicozamycin, capreomycin, carbenicillin, carindacillin, carumonam, cefaclor, cephalo-Smoking, cefamandole, cetirizine, cefazedone, Cefazolin, cefbuperazone, aplidin, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefmenoxime, cefmetazole, cefminox, apodizing, cefonicid, cefoperazone, ceforanide, Cefotaxime, cefotetan, cefotiam, cefoxitin, cefozopran, cefpimizole, cefpiramide, cefpirome, cefprozil, cefroxadine, cefsulodin, ceftazidime, cefteram, ceftezole, ceftibuten, ceftiofur, artisansin, Ceftriaxone, cefuroxime, carusona, cefacetrile sodium, cephalexin, cephaloglycin, tsefaloridin, cephalosporin C, cephalothin, cephapirin-sodium, cefradine, chloramphenicol, chlortetracycline, cinoxacin, clavulanic acid, climatically, cloxacillin, ciclacillin, cycloserine, demeclocycline, dicloxacillin, ampicillin, penecillin, flomoxef, floxacillin, hetacillin, imipenem, inanition, loracarbef, lymecycline, mafenide, meclocycline, Meropenem, metampicillin, metatsiklina, methicillin sodium, mezlocillin, minocycline, moxalactam, mupirocin, mixin, negamycin, novobiocin, oxacillin, panipenem, potassium salt of penicillin G, penicillin N, penicillin O, penicillin V potassium salt of phenethicillin, epicillin, piperacillin, pirlimycin, porfiromycin, propicillin, hinzelin, riipinen, rolitetracycline, sancycline, medicalizing, spectinomycin, sulbactam, sulbenicillin, temocillin, tetracycline, tikarcillin, Tiemann, tubercidin, azithromycin, clarithromycin, distamycin, antimycin, erythromycin, josamycin, midecamycin, mikamycin, oleandomitsin, rifabutin, rifamide, viomycin, rifaximin, rokitamycin, spiramycin, troleandomycin, viomycin, virginiamycin; amikacin, apramycin, arbekacin, dibekacin, dihydrostreptomycin, fortymile, gentamicin micronomicin, neomycin, netilmicin, paromomycin, ribostamycin, sesame is in, spectinomycin, streptomycin, tobramycin, trospectomycin; bacampicillin, cefcapene-pivoxil, cefpodoxim-proxetil, panipenem, pivampicillin, pureflex, sultamicillin, talampicillin; carbomycin, clindamycin, lincomycin, mikamycin, rosaramicin, ciprofloxacin, clinafloxacin, difloxacin, enoxacin, enrofloxacin, fleroxacin, flumequine, grepafloxacin, lomefloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin, pazufloxacin, pefloxacin, pipemedia acid, pyramidula acid, rufloxacin, sparfloxacin, cosultation, trovafloxacin, clomocycline, grimalkin, oxytetracycline, nifurpirinol, nitocris; para-aminosalicylic acid, hydrazide pair-aminosalicylic acid, clofazimine, deoxycylindrospermopsin, etambutol, gluconate, isoniazid, opiniated, phenyliminomethyl, rifampin, rifapentine, salinated, 4-4'-selfinitiation, acetazolam, dapson, successive, para-sulfonylbisbenzenamine, thiazolane, acetyl sulfamethoxypyrazine, mafenide, 4'-(methylsulfonyl)sulfanilamide, salazosulfapyridine, sulfabenzamide, sulfacetamide, sulfachlorpyridazine, sulfurization, sulfation, sulfadiazine, sulfacetamide sulfadimetoksin, sulfadoxine, sulfatides, sulfaguanidine, alfaguara, sulfalen, sulfamerazine, sulfamate, sulfamethazine, Sul is amitiza, sulfamethazine, sulfamethoxazole, sulfamethoxypyridazine, sulfamethizole, sulfometuron, sulfamethizole, sulfamoxole, sulfanilamide, 2-pair-sulfenylchlorination, N,4-sulfonilmorpholid, sulfanilimide, N-sulfanilyl-3,4-xiemed, solfataric, sulfaphenazole, sulfuration, sulfapyrazine, sulfapiridin, sulfanomides, sulfasalazin, sulfathiazole, sulfadimidine, sulfisomidine, sulfisoxazole, 4-sulfanilamide salicylic acid; negamycin, carumonam, Klochikhin, nitroxoline, arginine, metronidazole, and the like;

antiviral medicinal ingredients: acyclovir, amantadine, cidofovir, cytarabine, didanosine, dideoxyadenosine, edoxudine, famciclovir, floxuridine, ganciclovir, idoxuridine, indinavir, ketocal, lamivudine, MADU, penciclovir, podophyllotoxin, ribavirin, rimantadine, shinaver, sorivudine, stavudine, trifluridine, valacyclovir, vidarabine, xanetia acid, zalcitabine, zidovudine; and the like;

inhibitors of bone resorption (bisphosphonates): alendronat acid, Butakova acid, heteronomy acid, Occitania acid, pamidronate acid, risedronate acid, and the like;

medicinal substances against dementia: amiridin, lazabemide, mofegiline, sabeluzole, oksiratsetam, ipidacrine, nebracetam, taken, velnacrine, and the like.

Above the e predecessors of medicinal substances are prepared according to the methods known in the prior art. See, for example,TheMerck Index, 13^thEdition (2001), Merck & Co., Whitehouse Station, N.J.included in this description by reference. If available, can be applied to such isomers, including optical isomers.

Pharmaceutically acceptable salts of the compounds of the present invention, such as, for example, salts with alkaline metals and alkaline earth metals, non-toxic amines and amino acids are also part of the present invention. Preferred salts of the compounds of the present invention are salts with arginine and agmatine. Also included are pharmaceutically acceptable salts accession acid.

Derivatives according to the invention can be applied according to therapeutic indications for medications the predecessor, making it possible to achieve the advantages which are given below for these drugs.

Derivative NSAID according to the present invention are very well-tolerated and effective, even when the body is weakened and is in a state of oxidative stress. Derivative NSAID can be used in those pathological conditions in which inflammation plays a significant pathogenic role, as, for example, without limitation, in the case of cancer, asthma, myocardial infarction.

More to the particular, derivative NSAID according to the present invention can be applied to, without limitation, the treatment of inflammation in an individual, and for treatment of other disorders associated with inflammation, such as analgetika in the treatment of pain and headaches, or as an antipyretic for the treatment of fever. For example, the compounds according to the invention can be applied to treat arthritis, including, without limitation, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis. Such compounds according to the invention can be applied for the treatment of asthma, bronchitis, menstrual cramps, tendonitis, bursitis, painful skin conditions such as psoriasis, eczema, burns and dermatitis, and postoperative inflammation, including eye surgery, such as cataract surgery and surgery related to refraction. Compounds according to the invention can also be applied to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, spastic colitis and ulcerative colitis and for the prevention or treatment of cancer, such as colorectal cancer. Compounds according to the invention can be applied for treating inflammation in such diseases as vascular diseases, headaches and migraines, Uzes is the same nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, diseases of the neuromuscular connections, including myasthenia gravisgravis, a disease of the white matter of the brain, including multiple sclerosis, sarcoidosis, neurotic syndrome, behceta, polymyositis, gingivitis, nephritis, hypersensitivity, swelling occurring after injury, myocardial ischemia, and the like. The connection can also be used in the treatment of ophthalmic diseases such as retinitis, retinopathy, uveitis, photophobia, and of acute damage to the eye tissues. The connection can also be used in the treatment of inflammation of the respiratory organs, such as inflammation associated with viral infections and cystic degeneration. The connection can also be used for the treatment of certain disorders of the Central nervous system, such as cortical dementias including Alzheimer's disease. Compounds according to the invention can be applied as anti-inflammatory agents, for example in the treatment of arthritis, with the additional advantage of significantly less harmful side effects. These compounds can also be applied in the treatment of allergic rhinitis, respiratory distress syndrome, endotoxic shock, atherosclerosis, and damages the Oia Central nervous system, received in stroke, ischemia and trauma. The connection can also be used in the treatment of pain, without limitation, postoperative pain, dental pain, muscular pain, and pain that occur in cancer. Besides being able to be applied for treatment of humans, these compounds can also be used to treat mammals, including horses, dogs, cats, rats, mice, sheep, pigs, etc.

Derivatives protivotarannogo medicinal substances of the present invention, for example derivatives of 4 - or 5-aminosalicylic acid, derivatives of trimebutine, and the like, can be applied for the prevention or treatment of various diseases, particularly inflammatory conditions of the gastrointestinal tract, including, without limitation, inflammatory condition of the mouth, such as inflammation of the mucous membrane, infectious diseases (e.g. viral, bacterial and fungal diseases), and Crohn's disease; inflammatory condition of the esophagus, such as esophagitis, state, obtained by chemical damage (e.g., swallowed lye), gastroesophageal reflux, biliary reflux, esophagitis Barrett, Crohn's disease and benign esophageal stricture; inflammatory conditions such as gastritis (e.g., Helicobacter pylori, impaired gastric acidity and atrophic gastritis), glutino what I disease, stomach ulcer and duodenal ulcer, precancerous damage to the stomach, non-ulcer dyspepsia and Crohn's disease; inflammatory condition of the stomach, such as Crohn's disease, excessive development of microflora, peptic ulcer and crack ulcer; inflammatory condition of the colon, such as Crohn's disease, ulcerative colitis, spastic colitis, infectious colitis (e.g., pseudomembranous colitis, such as colitis, caused by the bacteriumClostridium difficile, salmonelosis enteritis, shigellosis infections, yersiniosis, cryptosporidiosis, microsporidial infection, and viral infection)with radiation-induced colitis, colitis in patients with reduced immune response (for example, Tiflis), precancerous conditions of the colon (e.g., dysplasia, inflammatory condition of the intestine and colon polyps), proctitis, inflammation associated with hemmoroid, spastic proctalgia and rectal fissures; hepatic related to the gall bladder and/or bile ducts, such as cholangitis, primary sclerosing cholangitis, primary biliary cirrhosis and cholecystitis; and purulent inflammation of the bowel.

Statins are used for prophylaxis and treatment of atherosclerosis, which causes chest pain, heart attacks, strokes and alternating lameness in individuals who are or may be in the group of risk for atherosclerosis. Risk factors for atherosclerosis include abnormally elevated levels of cholesterol, heredity for heart attacks (especially in youth), old age and diabetes. The majority of patients prescribed statins because of high levels of cholesterol. Despite the fact that reduction of cholesterol levels is important, heart disease is complex and can play the role of other factors, such as inflammation. It is known, however, that statins have shown adverse effects, such as liver disease, may have carcinogenic potential, create muscle side effects and myopathy.

Derivative of a statin according to the present invention can reduce the side effects associated with statins, and/or have improved pharmacological activity. Suddenly, a derivative of simvastatin, a complex 4-thiocarbamoylation ether-2-{2-[8-(2,2-dimethylbutyryl)-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]ethyl}-6-oxitetraciclina-4-silt ester of succinic acid, reduces platelet aggregation at concentrations of 3, 10 and 30 μm compared with the corresponding statin entered separately. Next, the derived simvastatin according to the present invention causes a significant increase in platelet cAMP compared with the same concentrations of simvastatin entered separately.

Derivatives of antithrombotic drugs of the present invention, for example derivatives of aspirin, patentiert antithrombotic activity with improved gastrointestinal tolerability. The main purpose of antithrombotic drugs is in the prevention and treatment of venous thromboembolism (VTE), prevention of stroke in patients with atrial fibrillation and the prevention and treatment of acute coronary syndrome (ACS).

Derivatives bronchodilators and derivative drugs, active against cholinergic system, can be used to relieve symptoms of asthma by relaxing the tension of the muscles that constrict the lumen of the airway. In kratkodeystvuyuschim forms derived bronchodilators alleviate or stop asthma symptoms and are very useful during an attack of asthma. In long-acting forms of derivatives bronchodilators help to control the symptom of the asthma and prevent asthma attacks. Derivative of the present invention reduce the side effects by influencing the cardiovascular system, such as tachycardia, hypertension, etc.

Derivative salt and mucolytic means of the present invention can be applied to loosen and remove mucus and phlegm from the respiratory tract. Gastrointestinal tolerability salt and mucolytic funds may be improved through the modified 4-gidroksicarbamidom derivatives, as first described in the present invention.

Derivatives of bisphosphonates of the present invention can be applied in the treatment or prevention of disorders of calcium metabolism or diseases, such as osteoporosis, ankylosing spondylitis, bone metastases, kidney stones, heterotrophic the bones, rheumatoid arthritis, osteoarthritis or degenerative arthritis. Toxicity to the gastrointestinal tract from derivatives of the present invention may be reduced.

Therapeutic efficacy derived inhibitors of phosphodiesterase (PDE) (bronchodilators) of the present invention is an improved and side effects reduced. PDE inhibitors have proven potential as anti-inflammatory drugs, especially respiratory diseases. They suppress you shall order his inflammatory signals, for example, cytokines, and inhibit the production of reactive oxygen molecules. PDE-inhibitors have a high therapeutic and commercial potential as non-steroidal anti-inflammatory agents for inflammatory respiratory diseases such as asthma, COPD and rhinitis.

Higher efficiency and/or lower side effects can also be observed for the derivatives of antileukotriene drugs, ACE inhibitors, antidiabetic drugs, antibiotic, antiviral and anticancer drugs.

Compounds of the present invention can be obtained according to the following schema:

Scheme 1 below uses the example of synthesis of a derivative NSAID, 4-thiocarbamoylation ether [2-(2,6-dichlorophenylamino)phenyl]acetic acid. In this scheme, the reagent Lawesson applies for the introduction of sulfur in releasing the hydrogen sulfide fragment after the group covalently bound to the remainder of the NSAID.

Scheme 1

Diclofenac (1), which has a free carboxyl group, is first dissolved in dimethylformamide and was added hydroxybenzotriazole (HOBt) and 1,3-dicyclohexylcarbodiimide (DCC). To this mixture was added 4-hydroxybenzamide under conditions suitable for the formation of intermediate compounds is of the present invention (for example, 4-carbamoylmethyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate (2)); in the specified intermediate connection no sulfur. Suitable connection, which may introduce sulfur, such as reagent Lawesson, was added to obtain the compounds of the present invention (for example, 4-thiocarbamoylation ether [2-(2,6-dichlorophenylamino)phenyl]acetic acid (3).

Depending on the specific condition or conditions that can be cured, individuals can be compounds of the present invention in any acceptable therapeutically effective and safe dosage, which can be easily determined by the person skilled in the art. These compounds, most preferably, may be administered in dosages ranging from about 1 to about 2000 mg per day, in single or divided doses, although there will inevitably be variation depending on the weight and condition of the individual, which can be cured, and the selected route of administration. It is clear that the dosage will depend on the applicable specific medicinal substance, forming compounds of the present invention. However, the level of dosage, which is in the range from about 0.1 to about 100 mg/kg, preferably between about 5 and 90 mg/kg, and more preferably between approximately 5 and 50 mg/kg, it is the most desirable. Variations may nevertheless occur depending upon the weight and condition of patients who are cured and their individual reactions to the above mentioned medication, as well as the type of the selected pharmaceutical compositions of the period and the time interval during which this introduction is carried out. In some instances, dosage levels below the lower limit of the above range may be more than adequate, while in other cases, higher doses can be used without causing any undesirable side effects, provided that such larger doses are first divided into several small doses for administration throughout the day.

Compounds of the present invention can be introduced in any pharmaceutical form, the nature of which will depend on the route of administration. These pharmaceutical compositions can be prepared by conventional methods using a compatible, pharmaceutically acceptable excipients or carriers. Examples of such compositions include capsules, tablets, transdermal patches, diamonds, lozenges, sprays, syrups, powders, granules, gels, elixirs, suppositories, and the like, drugs used for the preparation of solutions for immediate admission, injectable preparations, rectal, nasal, ocular, vaginal, etc. drugs. Preferred put the m administration are oral and rectal route.

Tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be used for oral administration in accordance with various loosening agents such as starch (preferably corn, potato starch or starch from tapioca), aginova acid and certain complex silicates, together with granulating binder such as polyvinylpyrrolidone, sucrose, gelatin and gum Arabic. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulphate and talc, can be used for tabletting purposes. Solid compositions of a similar type can also be used as fillers in gelatin capsules; preferred materials for this purpose also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration the active ingredient, they can be combined with a sweetener or flavoring agents, coloring agent and, if necessary, emulsification and/or suspendresume agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations.

Dosage form can be prepared the La immediate release a controlled release, extended release, delayed release or directional delayed release. The definitions of these terms are known to specialists in this field. In addition, the profile release dosage forms can be managed mixed polymer composition, the composition to the coated matrix composition in the form of separate particles, the composition is in the form of coated particles, composition, based on ion-exchange resin based on osmosis composition, or biodegradable polymer composition. Without having to be bound to any theory, it is assumed that the release can be controlled through favorable diffusion, dissolution, erosion coating, ion exchange, reverse osmosis or their combinations.

For parenteral administration can be applied to the solution of active compound in either sesame or peanut oil or in aqueous propylene glycol. Aqueous solutions should be suitably buffered {preferably to a pH greater than 8)if necessary and the liquid diluent first is to isotone. Aqueous solutions suitable for intravenous injection. Preparation of all these solutions under sterile conditions is easily achieved by standard pharmaceutical techniques, good is known to specialists in this field.

The following examples further describe and make it possible for a person skilled in the art to make and use the invention. However, it will be understood that these embodiments of provided to illustrate the invention and should not be discussed as limiting the scope of invention, which is defined in the claims.

BRIEF DESCRIPTION of FIGURES

The figure 1 presents the index of disease activity in mice with TNBS-induced colitis after treatment with 5-amino-2-(4-thiocarbonyldiimidazole)benzoic acid (compoundXXVII),mesalamine separately, 4-gidroksicarbamidom (4-HTB) separately and mix mesalamine and 4-HTB.

The figure 2 shows the activity of myeloperoxidase (MPO) mice having TNBS-induced colitis after treatment with 5-amino-2-(4-thiocarbonyldiimidazole)benzoic acid (compoundXXVII),mesalamine separately, 4-HTB separately and mix mesalamine and 4-hydroxytyramine (4-HTB).

The figure 3 shows the magnitude of the perception of pain for mesalamine and 5-amino-2-(4-thiocarbonyldiimidazole)benzoic acid (compoundXXVII) in the presence or in the absence of glibenclamide.

The figure 4 presents the index of perception of pain for 5-amino-2-(4-thiocarbonyldiimidazole)benzoic acid (compoundXXVII),mesalamine and 4-hydroxide the benzamide (4-HBT).

The figure 5 presents a diagram of leukocyte adhesion on the length of time 60-65 minutes for 5-amino-2-(4-thiocarbonyldiimidazole)benzoic acid (compoundXXVIIin the presence of aspirin or aspirin together with glibenclamide.

The figure 6 presents a diagram showing the generation of H₂S from cysteine, 5-amino-2-(4-thiocarbonyldiimidazole)benzoic acid (compoundXXVII4-hydroxytyramine (4-HBT).

Figure 7a shows an index of abdominal reflex otdergivanija values (AWR) in the model rats perception of visceral pain with the use of media, maleate of trimebutine and thiocarbamoylation of trimebutine (connectionIII).

Figure 7b shows an index of abdominal reflex otdergivanija values (AWR) in the model of perception of visceral pain in rats with the use of media and thiocarbamoylation separately.

The figure 8 shows the index of gastric damage, measured in rats treated with media, diclofenac, 4-gidroksicarbamidom (TBZ) and 4-thiocarbamoylation ether [2-(2,6-dichlorophenylamino)phenyl]acetic acid (compoundXVII).

The figure 9 presents the content of prostaglandin E₂(PGE₂in the stomach, obtained in rats treated with media, diclofenac, 4-gidroksicarbamidom (TBZ) and 4-thiocarbamoylation ether [2-(2,6-di is hlorfeniramina)phenyl]acetic acid (compound XVII).

The figure 10 presents the index of gastric damage, measured in rats treated with media, naproxen, and 4-dicarbonitrile ether 2-(6-methoxynaphthalene-2-yl)propionic acid (compoundXX).

The figure 11 presents the level of synthesis of thromboxane B₂in the blood of rats figure 10.

The figure 12 shows the number exstirpanda PGE₂received in the subcutaneous pocket of the rat using studies of air pockets on rats, handling media, diclofenac and 4-thiocarbamoylation ether [2-(2,6-dichlorophenylamino)phenyl]acetic acid (compoundXVII).

The figure 13 shows the contents of all of thromboxane B₂(TXB₂in the blood of rats on the figure 12.

The figure 14 shows the inhibition of increase in paw of the rats treated with media, diclofenac and 4-thiocarbamoylation ether [2-(2,6-dichlorophenylamino)phenyl]acetic acid (compoundXVII).

The figure 15 shows the number exstirpanda PGE₂received in the subcutaneous pocket of the rat with the use of pockets research on rats with the introduction of media, naproxen, and 4-dicarbonitrile ether 2-(6-methoxynaphthalene-2-yl)propionic acid (compound XX).

In the figure 16 presents the synthesis of thromboxane (ng/ml) in human blood (in vitro) as a function of concentration of indometacin, and 4-CTI is remoistenable ether [1-(4-chlorbenzoyl)-5-methoxy-2-methyl-1-H-indol-3-yl]acetic acid (compound XIX).

Figure 17 presents the surface area, in mm²gastric ulcers in rats after daily treatment for one week by the media, diclofenac, 4-dicarbonitrile ether 2-(6-methoxynaphthalene-2-yl)propionic acid (compoundXVII),naproxen and 4-dicarbonitrile ether 2-(6-methoxynaphthalene-2-yl)propionic acid (compoundXX).

The figure 18 shows the increase in systolic blood pressure (mm Hg) rats treated with media, naproxen and 4-dicarbonitrile ether 2-(6-methoxynaphthalene-2-yl)propionic acid (compoundXX).

The figure 19 shows the amount of hydrogen sulfide formed from 4-hydroxytyramine (TBZ) and 4-thiocarbamoylation ether [2-(2,6-dichlorophenylamino)phenyl]acetic acid (compoundXVII)when the incubation buffer and the homogenate of the liver.

The figure 20 shows the effect of simvastatin and mixed 4-thiocarbamoylation ester 2-{2-[8-(2,2-dimethylbutyryl)-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]ethyl}-6-oxitetraciclina-4-silt ester of succinic acid (compoundI) on ADP-induced aggregation of human platelets.

The figure 21 shows the effect of simvastatin and 4-thiocarbamoylation ester 2-{2-[8-(2,2-dimethylbutyryl)-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]ethyl}-6-oxitetraciclina-4-silt ether Yang is ary acid (compound I) at the concentration cAMP of human platelets.

A DETAILED DESCRIPTION of the PREFERRED embodiments

Getting connections

Thin-layer chromatography was performed on silikagelevye plates Macherey-Nagel 50 with fluorescent indicator and the plates were examined under UV light (254 nm). For column chromatography was used Kieselgel 60. All synthetic reagents were purchased from Aldrich chemical company Sigma and was used without purification. Solvents were of analytical grade purity or higher purity and were used as they were delivered. Rotary evaporator Buchi R-114 was used to remove the solvents under vacuum. Structures were established by spectroscopic methods¹H-NMR protons and¹³C-NMR. Spectra were measured on the instrument Varian Mercury Plus 400. Chemical shifts were measured relative to Me₄Si as internal standard. Mass spectra of the synthesized products have been mass-spektrometrometria Applied BioSystem API 2000. The melting point was measured on the device Buchi B-540. The purity of the target compounds were identified by means of RP-HPLC. The column was attached to the injector Rheodyne model 7725, the system for Waters HPLC 600, tunable detector optical density Waters 486 set at a wavelength of 215 or 235 nm, and the recording device is a Waters 746. Synthesized joint is had satisfactory elemental analyses; analyses were performed only on the key elements, the results were within ±0.4% of theoretical values.

EXAMPLE 1. Synthesis of 4-thiocarbamoylation ether [2-(2,6-dichlorophenylamino)phenyl]acetic acid (also referred to as Compound (XVII)

Synthesis of 4-carbamoylmethyl 2-[2-(2,6-dichlorophenylamino)phenyl]acetate (5)

To a solution of1(diclofenac, 890 mg, 3.0 mmol) in 50 ml of N,N-dimethylformamide, was added hydroxybenzotriazole (445 mg, 3.3 mmol) and DCC (680 mg, 3.3 mmol) under stirring at 0°C for 1 hour. To the reaction mixture were added 4-hydroxybenzamide (4, 616 mg, 4.5 mmol) and was stirred for 1 hour at 0°C and 3 hours at room temperature. After filtration the filtrate was evaporated under reduced pressure, the oily residue thus obtained was dissolved in chloroform; the organic layer was washed with saturated saline, dried over anhydrous MgSO₄was filtered and the solvent was evaporated. The crude product5uploaded on an open column with silica gel and was suirable a mixture of CH₂Cl₂/MeOH (9/1), from which the received 4-carbamoylmethyl-2-(2-(2,6-dichlorophenylamino)phenyl)acetate (5) (212 mg, 17% yield).

Synthesis of 4-thiocarbamoylation ether [2-(2,6-dichlorophenylamino)phenyl]acetic acid (6)

4-Carbamoylmethyl 2-(2-(2,6-dichlorophenylamino)the dryer is l)acetate ( 5, 480 mg, to 1.14 mmol) and reagent Lawesson (460 mg, to 1.14 mmol) was dissolved in 20 ml of anhydrous benzene. The reaction mixture was warmed to 50°C and was stirred for 6 hours. The solvent was removed under reduced pressure; the crude residue was purified on a column of silica gel (dichloromethane/methyl alcohol 9,5/0,5) to obtain pure compound 6 (446 mg, 91% yield).

¹H-NMR (CDCl₃): δ 4,07 (s, 2H), 6,59 (d, 1H), to 6.67 (s, 1H), 6,98 (t, 1H), 7,14 (t, 1H), 7,19 (d, 1H), 7,28 (m, 1H), 7,33 (d, 2H), 7,63 (s, 1H), of 7.97 (d, 2H);

¹³C-NMR (DMSO-d₆): δ 38,8, 118,8, 121,8, 122,6, 123,7, 124,4, 128,7, 129,1, 129,6, 131,2, 137,2, 137,8, 142,9, 153,5, 170,5, 193,2, 201,7.

MS (EI), m/e 431 (M⁺);

TPL 170-172°C.

EXAMPLE 2. Synthesis of 4-thiocarbamoyl-2-(2-(2-chloro-6-forgenerating)-5-were)acetate (also referred to as Compound (XVIII)

Synthesis of 4-carbamoylmethyl 2-(2-(2-chloro-6-forgenerating)-5-were)acetate (5)

To a solution of 1 (lumiracoxib, 223 mg, 0.75 mmol) in 15 ml of dimethylformamide, was added hydroxybenzotriazole (111 mg, 0,825 mmol) and DCC (170 mg, 0,825 mmol) under stirring at 0°C for 1 hour. To the reaction mixture were added 4-hydroxybenzamide (4, 154 mg, 1,125 mmol) and was stirred for 1 hour at 0°C and 3 hours at room temperature. After filtration the filtrate was evaporated under reduced pressure to remove solvent. The oily residue thus obtained, Rast is oral in chloroform; the organic layer was washed with saturated saline, dried over anhydrous MgSO₄was filtered and the solvent was evaporated. The crude product5uploaded on an open column with silica gel and was suirable a mixture of CH₂Cl₂/MeOH (9/1), after the column was obtained 4-carbamoylmethyl-2-(2-(2-chloro-6-forgenerating)-5-were) acetate (5) (111 mg, 35% yield).

Synthesis of 4-thiocarbamoyl 2-(2-(2-chloro-6-forgenerating)-5-were)acetate (6)

4-Carbamoylmethyl-2-(2-(2-chloro-6-forgenerating)-5-were)acetate, 5 (110 mg, 0.27 mmol) and reagent Lawesson (109 mg, 0.27 mmol) was dissolved in 15 ml of anhydrous benzene. The reaction mixture was warmed to 60°C and was stirred for 3 hours. The solvent was removed under reduced pressure; the crude residue was purified on a column of silica gel (dichloromethane/methyl alcohol to 9.5:0.5) is to obtain pure compounds6(59 mg, 51%yield).

¹H-NMR (CDCl₃): δ 2,32 (s, 3H), 4,01 (s, 2H), 6,46 (s, 1H), 6,70 (d, 1H), 6,92 (t, 1H), 7,01 (d, 2H), 7,11 (d, 2H), 7,19 (d, 1H), 7.62mm (s, NH), to 7.84 (d, 2H);

¹³C-NMR (DMSO-d₆): δ 20,8, 30,7, 115,1, 119,2, 122,0, 122,3, 124,1, 124,9, 126,1, 128,2, 129,2, 132,3, 134,8, 138,6, 140,9, 153,7, 154,6, 156,2, 170,4, 201,7

MS (EI), m/e 429 (M⁺); TPL: 120-122°C.

EXAMPLE 3. Synthesis of 4-thiocarbamoylation ether 2-acetoxybenzoic acid (also referred to as Compound (XVI)

Synthesis of 4-carbamoylmethyl 2-acetic is benzoate (5)

To a solution of1(acetylsalicylic acid 500 mg, 2.77 mmol) in 15 ml of dimethylformamide, was added hydroxybenzotriazole (412 mg, of 3.05 mmol) and DCC (628 mg, of 3.05 mmol) under stirring at 0°C for 1 hour. To the reaction mixture were added 4-hydroxybenzamide (4, 418 mg of 3.05 mmol) and was stirred for 1 hour at 0°C and 3 hours at room temperature. After filtration the filtrate was evaporated under reduced pressure to remove solvent. The oily residue thus obtained was dissolved in chloroform; the organic layer was washed with saturated saline, dried over anhydrous MgSO₄was filtered and the solvent was evaporated. The crude product5uploaded on an open column with silica gel and was suirable a mixture of CH₂Cl₂/MeOH (9/1), with a column received 4-carbamoylmethyl 2-acetoxybenzoic (5) (410 mg, 47% yield).

Synthesis of 4-thiocarbamoyl 2-(2-(2-chloro-6-forgenerating)-5-were)acetate (6)

4-Carbamoylmethyl 2-acetoxybenzoic,5(410 mg, 1.37 mmol) and reagent Lawesson (554 mg, 1.37 mmol) was dissolved in 35 ml of anhydrous benzene. The reaction mixture was warmed to 60°C and was stirred for 3 hours. The solvent was removed under reduced pressure; the crude residue was purified on a column of silica gel (dichloromethane/methyl alcohol to 9.5:0.5) is to obtain 470 mg of the crude compound6. Receiving the Noah compound was purified by the method of preparative HPLC, held in systems of two solvents: A: 100% acetonitrile with 0.1% TFA, B: 100% H₂O with 0.1% TFA linear gradient from 10% A to 60% b over 35 min, UV detection at 254 nm, flow rate 30 ml/min)that gave the pure compound6(324 mg, 71%yield).

¹H-NMR (CDCl₃): δ is 2.30 (s, 3H), 7,17 (d, 1H), 7,21 (d, 2H), 7,40 (t, 1H), 7,66 (t, 1H), 7,94 (d, 2H), and 8.2 (d, 1H).

¹³C-NMR (DMSO-d₆): δ 21,2, 121,9, 122,4, 124,3, 126,4, 128,7, 132,4, 135,1, 137,3, 151,5, 153,7, 162,7, 169,8, 201,8.

MS (EI), m/e 316(M⁺); TPL: 154-156°C.

EXAMPLE 4. Synthesis of 4-thiocarbamoylation ether [1-(4-chlorbenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid (also referred to as Compound (XIX)

Synthesis of 4-carbamoylmethyl 2-[1-(4-chlorbenzoyl)-5-methoxy-2-methylindol-3-yl]acetate (5)

To a solution of1(indomethacin, 3 g, scored 8.38 mmol) in 60 ml of dimethylformamide was added hydroxybenzotriazole (1.25 g, which 9.22 mmol) and DCC (1.9 grams, which 9.22 mmol) under stirring at 0°C for 1 hour. To the reaction mixture 4-hydroxybenzamide (4, 1,72 g, 12.6 mmol) was added and was stirred for 1 hour at 0°C and 2 hours at room temperature. After filtration the filtrate was evaporated under reduced pressure to remove solvent. The oily residue thus obtained was dissolved in ethyl acetate; the organic layer was washed with saturated saline solution, a 5% solution of NaHCO₃, 10% citric acid is then dried over anhydrous MgSO ₄was filtered and the solvent was evaporated. The crude product5uploaded on an open column with silica gel and was suirable a mixture of CH₂Cl₂/MeOH (9,5/0,5), with a column received 4-carbamoylmethyl-2-[1-(4-chlorbenzoyl)-5-methoxy-2-methylindol-3-yl]acetate (5) (479 mg, 12% yield).

Synthesis of 4-thiocarbamoyl-2-[1-(4-chlorbenzoyl)-5-methoxy-2-methylindol-3-yl]acetate (6)

Dissolved 4-carbamoylmethyl-2-[1-(4-chlorbenzoyl)-5-methoxy-2-methylindol-3-yl]acetate5(340 mg, 0.71 mmol) and reagent Lawesson (287 mg, 0.71 mmol) in 15 ml of anhydrous benzene. The reaction mixture was warmed to 60°C and was stirred for 4 hours. The solvent was removed under reduced pressure; the crude residue was purified on a column of silica gel (dichloromethane/methyl alcohol to 9.5:0.5) is to obtain 178 mg of the crude compound6. The compound obtained was purified by the method of preparative HPLC carried out in systems with two solvents: A: 100% acetonitrile with 0.1% TFA, B: 100% H₂O with 0.1% TFA linear gradient from 10% A to 80% A in 30 min, UV detection at 254 nm, flow rate 30 ml/min)that gave the pure compound6(56 mg, 16% yield).

¹H-NMR (CDCl₃): δ of 2.45 (s, 3H), 3,83 (s, 3H, OCH₃), 3,91 (s, 2H), 6,70 (d, 1H), to 6.88 (d, 1H),? 7.04 baby mortality (s, 1H), 7,11 (d, 2H), 7,47 (d, 2H), to 7.67 (d, 2H), 7,88 (d, 2H).

¹³C-NMR (DMSO-d₆): δ 13,6, 30,8, 56,0, 101,5, 111,9, 112,0, 115,3, 121,7, 128,6, 129,4, 130,8, 131,2, 131,4, 134,0, 136,8, 137,1, 139,7, 156,2, 157,9, 167,6, 169,8, 201,8.</>

MS (EI), m/e 493 (M⁺); TPL: 224-226°C.

EXAMPLE 5. Synthesis of 4-dicarbonitrile ether 2-(6-methoxynaphthalene-2-yl)propionic acid (also referred to as Compound XX)

Synthesis of 4-carbamoylmethyl 2-(2-methoxynaphthalene-6-yl)propanoate (5).

To a solution of1(naproxen, 4 g of 17.4 mmol) in 80 ml of dimethylformamide was added hydroxybenzotriazole (2,59 g, 19.14 per mmol) and DCC (2,59 g, 19.14 per mmol) under stirring at 0°C for 1 hour. To the reaction mixture were added 4-hydroxybenzamide (4, 3.58 g, and 26.1 mmol) and was stirred for 1 hour at 0°C and 2 hours at room temperature. After filtration the filtrate was evaporated under reduced pressure to remove solvent. The oily residue thus obtained was dissolved in ethyl acetate; the organic layer was washed with saturated saline solution, a 5% solution of NaHCO₃, 10% citric acid and then dried over anhydrous MgSO₄was filtered and the solvent was evaporated. The crude product5uploaded on an open column with silica gel and was suirable a mixture of CH₂Cl₂/MeOH (9,5/0,5), with a column received 4-carbamoylmethyl-2-(2-methoxynaphthalene-6-yl)propanoate (5) (1,91 g, 32% yield).

Synthesis of 4-thiocarbamoyl 2-(2-methoxynaphthalene-6-yl)propanoate (6)

4-Carbamoylmethyl 2-(2-methoxynaphthalene-6-yl)propanoate5(1.80 g, 4,34 mmol) and Reagan is Lawesson (1.75 g, 4,34 mmol) was dissolved in 130 ml of anhydrous benzene. The reaction mixture was warmed to 60°C and was stirred for 4 hours. The solvent was removed under reduced pressure; the crude residue was purified on a column of silica gel (dichloromethane/methyl alcohol of 9.75:0.25 in) to obtain 2.9 g of the crude compound6. The compound obtained was purified by open column with silica gel and was suirable a mixture of CH₂Cl₂/MeOH (9,5/0,5)), which gave the pure compound 6 (970 mg, yield 61%).

¹H-NMR (DMSO-d₆): δ equal to 1.59 (d, 3H), 3,86 (s, 3H, OCH₃), are 4.24 (DD, 1H), 7,06 (d, 2H), 7,18 (d, 1H), 7,31 (s, 1H), 7,50 (d, 1H), to 7.84 (s, 1H) a 7.85 (d, 1H), 7,86 (s, 1H), 7,89 (d, 2H), for 9.47 and 9,84 (s, 2H, NH₂).

¹³C-NMR (DMSO-d₆): δ 19,1, 45,2, 55,9, 106,5, 119,6, 121,6, 126,6, 126,9, 128,0, 129,4, 129,9, 134,2, 135,6, 137,8, 153,4, 158,1, 173,3, 199,7. MS (EI), m/e 366 (M⁺);

TPL: 196-198°C.

EXAMPLE 6. Synthesis of 4-thiocarbamoyl 2-(4-isobutylphenyl)propanoate

To a solution of1(ibuprofen, a 3.87 g of 18.8 mmol) in 80 ml of dimethylformamide, was added hydroxybenzotriazole (2.8 g, of 20.7 mmol) and DCC (4,27 g of 20.7 mmol) under stirring at 0°C for 1 hour. To the reaction mixture were added 4-hydroxybenzamide (2, a 3.9 g, 28 mmol) and was stirred for 1 hour at 0°C and 2 hours at room temperature. After filtration the filtrate was evaporated under reduced pressure to remove solvent. The oily residue thus obtained about what atom, was dissolved in ethyl acetate; the organic layer was washed with saturated saline solution, a 5% solution of NaHCO₃, 10% citric acid and then dried over anhydrous MgSO₄was filtered and the solvent was evaporated. The crude product3uploaded on an open column with silica gel and was suirable a mixture of CH₂Cl₂/MeOH (9,5/0,5), with a column received 4-carbamoylmethyl 2-(4-isobutylphenyl)propanoate (3) (2,48 g, yield 40%).

Synthesis of 4-thiocarbamoyl 2-{4-isobutylphenyl)propanoate (4)

4-carbamoylmethyl 2-{4-isobutylphenyl)propanoate,3(2,48 g, 7.62 mmol) and reagent Lawesson (3.1 g, 7.62 mmol) was dissolved in 130 ml of anhydrous benzene. The reaction mixture was warmed to 60°C and was stirred for 4 hours. The solvent was removed under reduced pressure. The compound obtained was purified by open column with silica gel and was suirable a mixture of CH₂Cl₂/MeOH (9,5/0,5), which gave a net connection4(1.45 g, 55% yield).

¹H-NMR (DMSO-d₆): δ 0,84 (d, 6H), to 1.48 (d, 3H), 1,79-to 1.82 (m, 1H), 2,42 (d, 2H), of 4.05 (DD, 1H), 7,05 (d, 2H), 7,15 (d, 2H), 7,28 (d, 2H) 7,88 (d, 2H), 9,49 and 9,87(s, 2H, NH₂).

¹³C-NMR (DMSO-d₆): δ 19,2, 22,9, 30,3, 44,9, 121,6, 127,9, 129,5, 130,0, 137,8, 138,0, 140,8, 153,3, 173,3, 199,6.

MS (EI), m/e 341 (M⁺); TPL: 121-123°C.

EXAMPLE 7. Synthesis of 4-thiocarbamoyl-2-(4-oxoferin)phenylpropanoate

Synthesis of 4-carbamoylmethyl-2-(4-oxoferin)fenil is openout(3)

To a solution of1(Ketoprofen, 3 g of 11.8 mmol) in 80 ml of dimethylformamide was added hydroxybenzotriazole (1,76 g, 13 mmol) and DCC (2,68 g, 13 mmol) under stirring at 0°C for 1 hour. To the reaction mixture were added 4-hydroxybenzamide (2, 2,43 g of 17.7 mmol) and was stirred for 1 hour at 0°C and 2 hours at room temperature. After filtration the filtrate was evaporated under reduced pressure to remove solvent. The oily residue thus obtained was dissolved in ethyl acetate; the organic layer was washed with saturated saline solution, a 5% solution of NaHCO₃, 10% citric acid and then dried over anhydrous MgSO₄was filtered and the solvent was evaporated. The crude product3uploaded on an open column with silica gel and was suirable a mixture of CH₂Cl₂/MeOH (9,5/0,5), which received 4-carbamoylmethyl-2-(4-oxoferin)phenylpropanoate (3) (1.84 g, 42% yield).

Synthesis of 4-thiocarbamoyl-2-(4-oxoferin)phenylpropanoate (4)

4-carbamoylmethyl-2-(4-oxoferin)phenylpropanoate (3) (1.84 g, is 4.93 mmol) and reagent Lawesson (2 g, is 4.93 mmol) was dissolved in 100 ml of anhydrous benzene. The reaction mixture was warmed to 60°C and was stirred for 4 hours. The solvent was removed under reduced pressure. The compound obtained was purified by open column with silica gel and was suirable a mixture of CH₂Cl₂/MeOH (a 9.5/0.5), and h is o gave pure compound 4(0.45 g, yield 23%).

¹H-NMR (DMSO-d₆): δ of 1.53 (d, 3H), 4,25 (DD, 1H), was 7.08 (d, 2H), 7,54-7,73 (m, 9H), of 7.90 (d,2H), 9.51 and 9,88 (s, 2H, NH₂).

¹³C-NMR (DMSO-d₆): δ 19,2, 44,9, 121,6, 129,3, 129,5, 129,8, 130,3, 132,6, 133,5, 137,6, 137,9, 138,1, 141,2, 153,3, 154,5, 156,1, 163,8, 172,9, 199,6.

MS (EI), m/e 390 (M⁺); TPL: 114-116°C.

EXAMPLE 8. Synthesis of 4-thiocarbamoyl-2-(3-fluoro-4-phenyl)phenylpropanoate

Synthesis of 4-carbamoylmethyl-2-(3-fluoro-4-phenyl)phenylpropanoate (3)

To a solution of1(flurbiprofen, 2 g, 8.2 mmol) in 80 ml of dimethylformamide was added hydroxybenzotriazole (1.22 g, of 9.02 mmol) and DCC (1.86 g, of 9.02 mmol) under stirring at 0°C for 1 hour. To the reaction mixture were added 4-hydroxybenzamide (2, 1.7 g, 12.2 mmol) and was stirred for 1 hour at 0°C and 2 hours at room temperature. After filtration the filtrate was evaporated under reduced pressure to remove solvent. The oily residue thus obtained was dissolved in ethyl acetate; the organic layer was washed with saturated saline solution, a 5% solution of NaHCO₃, 10% citric acid and then dried over anhydrous MgSO₄was filtered and the solvent was evaporated. The crude product3uploaded on an open column with silica gel and was suirable a mixture of CH₂Cl₂/MeOH (9,5/0,5), from which 4-carbamoylmethyl-2-(3-fluoro-4-phenyl)phenylpropanoate (3) received (1,09 g, 37% in the course).

Synthesis of 4-thiocarbamoyl-2-(3-fluoro-4-phenyl)phenylpropanoate (4)

4-carbamoylmethyl-2-(3-fluoro-4-phenyl)phenylpropanoate3(1,09 g, 3 mmol) and reagent Lawesson (1,21 g, 3 mmol) was dissolved in 70 ml of anhydrous benzene. The reaction mixture was warmed to 60°C and was stirred for 4 hours. The solvent was removed under reduced pressure. The compound obtained was purified by open column with silica gel and was suirable a mixture of CH₂Cl₂/MeOH (9,5/0,5), which gave a net connection4(0.35 g, 31% yield).

¹H-NMR (DMSO-d₆): δ of 1.55 (d, 3H), 4,21 (DD, 1H), 7,32-of 7.55 (m, 8H), of 7.90 (d, 2H), 9.51 and 9,88 (s, 2H, NH₂).

¹³C-NMR (DMSO-d₆): δ 19,1, 44,7, 115,9, 116,2, 121,7, 124,8, 128,6, 129,3, 129,4, 129,5, 131,7, 135,8, 137,7, 142,6, 153,7, 158,3, 163,5, 173,1, 199,6.

MS (EI), m/e 380 (M⁺); TPL: 142-144°C.

EXAMPLE 9. The General scheme of synthesis for 4-thiocarbamoylation esters of 4 - or 5-amino-2-hydroxybenzoic acid (8) (also referred to as Compound XXVII)

Synthesis of 4 - or 5-tert-butoxycarbonylamino-2-hydroxybenzoic acid (1)

To a solution of 4 - or 5-aminosalicylic acid (10.0 mmol) in 25 ml of dioxane and 12.5 ml of water, was added triethylamine (15.0 mmol) and di-tert-BUTYLCARBAMATE (15.0 mmol) under stirring at 0°C for 1/2 hour. The reaction mixture was stirred mechanically for 24 hours at room temperature. After evaporation of the solvent to which the STATCOM was added dropwise 3M HCl (15 ml). The precipitate was filtered, washed with water and dried. The residue was loaded on an open column with silica gel and was suirable a mixture of CH₂Cl₂/MeOH (9/1), with a column received a 4 - or 5-tert-butoxycarbonylamino-2-hydroxybenzoic acid (1) (yield 80%).

Synthesis of 4 - or 5-tert-butoxycarbonylamino-2-tert-butoxybenzoic acid (2)

A mixture of compound (1) (12,0 mmol), concentrated H₂SO₄(6.0 mmol) and DCM (100 ml) was stirred in an atmosphere isobutilene gas (5 psi) for 6 hours at room temperature. The solution was washed with cold 10% NaHCO₃(2×100 ml), saturated brine (100 ml), dried (Na₂SO₄) and was evaporated. The residue was dissolved in a mixture of 1:1 MeOH/CCl₄(400 ml), washed with water (300 ml), then was extracted with a mixture of 1:1 MeOH/water (2×200 ml). The extract was dried (Na₂SO₄) and evaporated to yield a white solid (2), which was recrystallized from a mixture of DCM/hexane (yield 83%).

Synthesis of 4-thiocarbamoylation ether 4 - or 5-amino-2-hydroxybenzoic acid (8)

To a solution of 4 - or 5-tert-butoxycarbonylamino-2-hydroxybenzoic acid (2) (3.0 mmol) in 50 ml of dimethylformamide, was added hydroxybenzotriazole (3.3 mmol) and DCC (3.3 mmol) under stirring at 0°C for 1 hour. To the reaction mixture were added 4-hydroxycobalamin (3.0 mmol) was mechanically stirred during 3 hours at 0°C and 72 hours at room temperature. After filtration the filtrate was evaporated under reduced pressure to remove solvent. The oily residue thus obtained was dissolved in ethyl acetate; the organic layer was washed with saturated saline, dried over anhydrous MgSO₄was filtered and the solvent was evaporated. The crude intermediate compound (7) was treated with 40% TFA solution in CH₂Cl₂. After 2 hours the solvent was removed, which led to the compound (8) in the form of the crude residue. The residue was loaded on an open column with silica gel and was suirable a mixture of CH₂Cl₂/MeOH (8/2), with a column received 4-thiocarbamoylation ether 4 - or 5-amino-2-hydroxybenzoic acid (8), the compound of formula XXVII (yield 48%).

EXAMPLE 10. Synthesis of tributyltinchloride

Getting 4-thiocarbamoylation 2-(dimethylamino)-2-phenylbutyramide ester 3,4,5-trimetoxybenzoic acid (tributyltinchloride)

To a mixture of 4-(thiocarbamoyl)benzoic acid (0.1 mol) and trimebutine (0.1 mol) was added to a mixture of water (200 ml) and ethanol (20 ml) and the resulting suspension was stirred at room temperature until, until it became transparent. Then the solution was frozen and liofilizirovanny to obtain the desired salt (yield quantitative).

¹H-NMR (400 MHz, DMSO-d 6): δ 0,60 (t, 3H), of 1.45 and 1.75 (m, 4H), 1,80-1,90 (m, 2H), 2,28 (s, 6H), 2,90 is 3.40 (m, 2H), 3,69 (s, 9H), 3,95 (m, 1H), 4,73 (DD, 2H), 7,01 (s, 2H), 7,22 (m, 1H), 7,35 (m, 2H), 7,46 (d, 2H) to 7.93 (DD, 4H), 9,65 (users, 1H, NH), of 10.05 (users, 1H, NH).

¹³C-NMR (400 MHz, DMSO-d₆): δ 9,07, 28,9, 56,5, 60,8, 64,5, 65,7, 107,1, 125,3, 127,4, 128,1, 128,6, 129,5, 129,7, 132,3, 141,8, 142,5, 148,5, 153,4, 154,8, 165,9, 169,4, 172,5, 188,6.

TPL 66-68°C (decomp).

Synthesis of 4-(thiocarbamoyl)benzoic acid

The compound was synthesized according to the methods previously described in the literature (Fairfull, E.S., Lowe J.L, Peak D.A. J. Chem. Soc. 1952, 742,), which is incorporated in this description by reference.

4-{Thiocarbamoyl)benzoic acid (2)

3 g of 4-cyanobenzoic acid1(to 20.4 mmol) was dissolved in 40 ml of pyridine was added to 2.1 ml of triethylamine (of 20.4 mmol). Dry hydrogen was passed through the solution constant flow for 4 hours. Then the mixture was poured into water and the solid is collected by filtration, recrystallization from petroleum ether resulted of 2.51 g of pure compound2(yield 68%).

MS (ESI)m/e of 182.2 (M⁺).

¹H-NMR (DMSO-d₆): δ a 7.92 (DD, 4H), 9,68 (s, 1H, NH), 10,12 (s, 1H, NH), 13,25 (s, 1H, OH).

¹³C-NMR (DMSO-d₆): δ 127,3, 129,6, 132,0, 148,5, 169,4, 188,6. So pl. 296-298°C (decomp.)

EXAMPLE 11. Synthesis of 4 mixed-thiocarbamoylation ether - 2-{2-[8-(2,2-dimethylbutyryl)-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]ethyl}-6-oxitetraciclina-4-ilen e the Ira succinic acid (3) (also referred to as Compound (I)

Synthesis of 4 mixed-carbamoylphenoxy ether - 2-{2-[8-(2,2-dimethylbutyryl)-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]ethyl}-6-oxitetraciclina-4-silt ester of succinic acid (2)

A solution of 420 mg (0.001 mol) of simvastatin (1) in 3 ml of dichloromethane was treated with 110 mg of succinic anhydride and 10 mg of DMAP. After 36 hours under stirring was added 210 mg (0.001 mol) and EDCI 170 mg (0,0012 mol) 4-hydroxybenzamide.

After 1 hour the solvent was removed under reduced pressure and the crude residue was purified on a column of silica gel with elution with a mixture of dichloromethane/methyl alcohol (9,5/0,5) to obtain compound 2 as a white solid (350 mg, yield 55%).

MS (EI), m/e 638 (M⁺);

¹H-NMR (DMSO-d₆) δ 0,831 (m, 6H, 2-Me), 1,075 (m, 9H, 3-Me), of 1.53 (m, 6H), of 1.97 (m, 2H), and 2.27 (m, 5H), 2,52 (d, 2H), 2,62 (d, 2H), 3,68 (m, 1H), 4,07 (m, 1H), 5,52 (m, 1H), 5,50 (ushort, 1H), 5,77 (DD, 1H), 5,96 (d, 1H); was 7.08 (d, 2H), 7,87 (d, 2H), 7,94 (users, 2H).

Synthesis of 4 mixed-thiocarbamoylation ether - 2-{2-[8-(2,2-dimethylbutyryl)-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]ethyl}-6-oxitetraciclina-4-silt ester of succinic acid (3)

Mixed 4-carbamoylphenoxy ether - 2-{2-[8-(2,2-dimethylbutyryl)-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]ethyl}-6-oxitetraciclina-4-silt ester of succinic acid is you ( 2) (0.35 g, 0,000548 mol) and the reagent Lawesson (0,221 g, 0,000548 mol) was dissolved in 30 ml of anhydrous benzene. The reaction mixture was warmed to 50°C and was stirred for 6 hours. The solvent was removed under reduced pressure; the crude residue was purified on a column of silica gel (dichloromethane/methyl alcohol to 9.5:0.5 to) to obtain 35 mg of pure compound3(yield 10%).

MS (EI), m/e 654 (M⁺);

¹H-NMR (DMSO) δ 0,831 (m, 6H, 2-Me), 1,075 (m, 9H, 3-Me), of 1.53 (m, 6H), of 1.97 (m, 2H), and 2.27 (m, 5H), 2,52 (d, 2H), 2,62 (d, 2H), 3,68 (m, 1H), 4,07 (m, 1H), 5,52 (m, 1H), 5,50 (ushort, 1H), 5,77 (DD, 1H), 5,96 (d, 1H); 7,11 (d, 2H), 7,9 (d, 2H), 9,48 (s, 1H), 9,86 (s, 1H).

TESTING CONNECTION

EXAMPLE 12. Comparison of indices of disease activity and myeloperoxidase (MPO)activity 5-amino-2-(4-thiocarbonyldiimidazole)benzoic acid

Standard experimental animal model of colitis induced in the colon of the mouse 2,4,6-trinitrobenzenesulfonic acid (TNBS) is used in the following example. A detailed description of this model was published (Santucci et al. (2003) Gastroenterology 124:1381-94), the work included in this description as a reference material. Briefly, Balb/c mice 6-8 weeks of age received TNBS the introduction of the colon at the dose of 1.5 mg in 0.1 ml of 30% ethanol. Mice were randomizable for different treatment groups (n=6 per group). Starting one hour later and continuing every 12 hours during 5 days mice were treated orally with vehicle (1% carboxymethylcellulose (CMC)), separately 5-ASA (mesalamine) (100 mg/kg), 4-gidroksicarbamidom (denoted in the figures as a 4-HTB) (100 mg/kg), 5-amino-2-(4-thiocarbonyldiimidazole)benzoic acid (100 mg/kg) (hereinafter referred to as the ConnectionXXVII)and equimolar doses of mesalamine (50 mg/kg) and (4-HTB) (50 mg/kg). *p<0.05 is shown in relation to the group treated with the carrier. Each group consisted of at least 5 animals.

Mice examined (blind) at the end of the experiment in the presence of diarrhea were tested for occult blood and measured their weight and condition Factor of the disease was calculated based on these data (on a scale from 0 to 4, as described in the work cited above). After killing cut out a sample of the colon for measuring the activity of myeloperoxidase (MPO) as a marker of infiltration of granulocytes. All results cited in comparison with the results obtained in healthy mice in the same way.

The figure 1 shows that the connectionXXVIIis almost three times more effective than or mesalamine separately, 4-HTB separately or a mixture of mesalamine and 4-HTB in relation to the symptoms. Next, Figure 2 shows that the connectionXXVIIreduces inflammation, which is shown slimming the m infiltration of granulocytes (reduced MPO activity).

EXAMPLE 13. Comparison of 5-amino-2-(4-thiocarbonyldiimidazole)benzoic acid and mesalamine in the model of perception of visceral pain in rats

The following example was used to model the perception of visceral pain in rats preclinical model of spastic colitis. Rats (male, Wistar, 200-250 g, obtained from Charles River, Monza, Italy), were kept in plastic cages in a controlled environment with 12-hour cycle of day and night, with lights on at 7:00 in the morning. Tap water and standard laboratory diet were unlimitedly available. Before the experiments the rats were individually trained from 2-3 hours a day in a cage made of plexiglass within 2-3 days. This allowed them to adapt to the environment movement-limiting. Food was unavailable for 12 hours prior to the registration of colorectal stretching (CRD). The experiments were conducted with awake rats and conducted blind, in which the observer was not informed about the nature of the medicinal substance, administered to each animal.

On the day of testing, rats were euthanized ether inhalation and 2-cm rubber balloon was inserted rectally into 2 cm from the edge of the anus and recorded at the base of the tail. The balloon was connected via a two-channel catheter with a pressure sensor for continuous monitoring of rectal pressure to what newterm ( PowerLab PC, A.D. Instruments, Milford, MA, USAand with a syringe for inflating/lowering air cylinder. Then the rats were placed in small cages (20×8×8 cm) on the raised platform Plexiglas™, they were allowed to Wake up and adapt for 1 hour. After recovery from sleep with the animals spent the CRD technique and tested for their behavioral responses. The night before experiments tanks pumped and left during the night, so that the latex stretched and cylinders became pliable.

20-second CRD held every 5 minutes, was applied in increments of 0.4 ml from the original 0.4 ml to 1.6 ml of water. To achieve an accurate measurement of the characteristics of the colon and perception stretching was repeated twice for each intensity data for each animal were averaged for analysis. Each animal underwent a double set of CRD. Twenty minutes after the first sequence CRD (0.4 ml - 1.6 ml water), drugs were injected intraperitoneally (I.P. Pavlova.) and perform the second sequence of the CRD. Behavioral responses during the first and second sequence CRD were recorded and compared.

Behavioral response to CRD was evaluated by measuring abdominal reflex otdergivanija (AWR) using semi-quantitative measurement (1). AWR is an uncontrolled motor reflex, similar viscera otonomy reflex, but it has the great advantage that, in contrast to the latter, does not require abdominal surgery for the implantation of the writing electrodes and the presence of wires in the wall of the abdominal muscles, which can cause an incremental increase in sensitivity (Ness, T.J. and Gebhart, G.F. (1990) Pain41:167-234included in this description by reference).

Measurement AWR, consisting in the visual observation of the response of the animal CRD different levels of observer-blind method and the correlation value AWR according to behavioral scale that previously described inAl-Chaer, E.D. et al. (2000) Gastroenterology19:1276-85the work included in this description by reference, where the value 0 corresponds to the absence of a behavioral response to CRD, the value 1 corresponds to a short movement of the head at the onset of the stimulus, then there is stillness, the value of 2 corresponds to a mild contraction of abdominal muscles, although rats do not raise the stomach from the platform, the value 3 corresponds to a strong contraction of the abdominal muscles with the rise of the abdomen from the platform and the value 4 corresponds to the hard contraction of the abdominal muscles, which is confirmed by the bending of the body arc and the rise of the abdomen, pelvic structures, and the scrotum.

The model of perception of visceral pain in rats, as described above, PR is changed to compare the values of the reaction of 5-amino-2-(4-thiocarbonyldiimidazole)benzoic acid (compound XXVII)or with, or in the absence of glibenclamide, an inhibitor of ATP-sensitive K⁺(K_ATPchannels.

Figure 3 shows the units of perception of pain as a response to 0.8 ml of colorectal tension in the groups of rats (at least 5 per group)treated with media, mesalamine (100 mg/kg), and the connectionXXVII(100 mg/kg). ConnectionXXVIIsignificantly reduces pain perception (*p<0.05 with respect to the group treated with carrier), while mesalamine has no significant effect. Reducing the perception of pain by the connectionXXVIIasked by pretreatment with glibenclamide (10 mg/kg I.P. Pavlova. 30 minutes before), while pretreatment with glibenclamide does not affect the perception of pain in the group treated with the carrier or mesalamine, on the assumption that the antinociceptive activity of compoundsXXVIImay be mediated by ATP-sensitive K⁺(K_ATP) channels. Figure 4 shows that 4-hydroxycobalamin (4-HTB) separately (100 mg/kg) has no significant effect on the perception of pain.

EXAMPLE 14. The influence of 5-amino-2-(4-thiocarbonyldiimidazole)benzoic acid on adhesion of leukocytes to vascular endothelium in vivo.

Adhesion of leukocytes examined using intravital microscopy, as described in detail previously (Wallace et al., (1993) Am. J. Physiol. 265: 993-998included in the data is e description by reference). Rats were anestesiologi action pentobarbital sodium (60 mg/kg I.P. Pavlova.) and made the cautery dissection along the abdominal region. A tracheotomy was performed to facilitate breathing. Rats were placed in position on the back, and the segment of mesentery temporarily brought to the surface through an abdominal incision. The mesentery was carefully placed over the optically transparent basis for inspection, which allowed the probing of the 2-cm²the tissue segment. All unprotected fabric covered with gauze soaked in saline solution to minimize dehydration. The substrate temperature was kept at 37°C and mesentery poured warmed saline solution, buffered with bicarbonate (pH of 7.4). Intravital microscope (Nikon L25/0,35) and the eyepiece ×10 used to monitor mesenteric capillary circulation. For the study were selected postcapillary venules with diameters ranging from 20 to 40 μm. A video camera mounted on the microscope (Panasonic™, digital 5000), passed the image on the monitor, and images were recorded for analysis during playback using the cassette recorder. Image mesenteric capillary blood flow was recorded for 5 minutes prior to administration of aspirin (background level)at the time of the introduction of aspirin (time 0-5) and every 15 minutes for 60 minutes. Adhesion of leukocytes from Eraly quantitatively blind from video vessels, made within a 5-minute periods, as the number of leukocytes that remain stationary along the walls of the vessel within 30 s or more (expressed per 100 μm length venules). Groups of rats (at least 5 in each group) was pre-treated with 5-amino-2-(4-thiocarbonyldiimidazole)benzoic acid (compoundXXVII)(100 mg/kg), mesalamine (50 mg/kg) or media for 60 min before administration of aspirin (or media). These medicinal substance was administered intragastrically. In some experiments, rats were treated with glibenclamide (10 mg/kg I.P. Pavlova.) or medium for 30 min before the introduction of these compounds.

Figure 5 shows the adhesion of leukocytes to the end time of the experiment (minutes 60-65). This figure illustrates the ability of the connectionXXVIIto suppress due to aspirin adhesion of cells and the ability of pre-treatment with glibenclamide pay this effect of inhibition of leukocyte adhesion.

EXAMPLE 15. Generation H₂S of 5-amino-2-(4-thiocarbonyldiimidazole)benzoic acid

5-Amino-2-(4-thiocarbonyldiimidazole)benzoic acid (compoundXXVII)tested on the generation of H₂S in three different conditions. Measured concentrations of H₂S, which were generated within 1 hour at 1 nm concentrations of L-cysteine, 4-HBT (4-hydroxy who obenzene) and 5-amino-2-(4-thiocarbonyldiimidazole)benzoic acid. The release of H₂S were tested in three conditions: (i) when the connection was in the buffer, (ii) when the connection was in the homogenate of the liver, and (iii) when the connection was in the homogenate of the liver together with the inhibitor of cystathionine γ-LiAZ (PAG = DL-propargylglycine; 2 nm). The results are presented in Figure 6. *p<0.05 compared to the release in the group treated with the carrier. *p>0.05 with respect to the appropriate group 'homogenates of liver'. The enzymatic capacity of production of H₂S was determined using the same reactor described previously (Khan et al. (1980) Microchem J. 25, 388-395included in this description by reference). 2-ml reaction mixture for the research was introduced into the reactor. The mixture contained 1 nm of L-cysteine (or connection), 2 nm pyridoxal 5'-phosphate and 100 nm buffer potassium phosphate (pH=7,4). A steady stream of nitrogen was passed through the mixture through a gas-feeding capillary. The reaction was initiated by transferring tubes from the ice bath in a bath of water at 37°C. a Stream of nitrogen endured sulphurous acid in the second reactor, containing 4 ml of non-oxidizing the sulfide buffer (SAOB), consisting of 2 M KOH, 1 M salicylic acid and 0.22 M ascorbic acid at a pH of 12.8[5]. After incubation at 37°C

within 90 minutes was added 1 ml of 10% solution of trichloroacetic acid to the mixture in order austan the IC reaction. The remainder of the H₂S in the mixture were transferred to a flow of nitrogen for a further 60 minutes incubation at 37°C. the Concentration of sulfide in SAOB-the solution was measured by sulfidecontaining electrode (Model 9616 S^2-/Ag⁺electrode, Orion Research, Beverly, MA, USA). For studies in which the test compounds were incubated in the homogenate of the liver, 100-150 mg selected rat liver homogenized in 1 ml extractor protein T-PER, cooled by ice. The homogenates were added to the reaction mixture at a concentration of 10% (wt./vol.). 2 nm DL-propargylglycine incubated with liver homogenate for 5 min at 37°C prior to enzymatic reaction.Khan, S.U. Morris, G.F. and Hidiroglou, M. (1980).Rapid assessment of the concentration of sulfide in the rumen and blood selfinspections ion electrode described inMicrochem. J. 25:388-395,which is incorporated in this description by reference.

The results presented in figure 6, assume that the connectionXXVIIhas the following distinctive features:

1. ConnectionXXVIIreleases H₂S spontaneously (in the buffer)that it is desirable for local effect in the digestive tract. 4-HTB and L-cysteine does not release significant quantities of H₂S, if you are incubated only in the buffer;

2. The release of H₂'s more in the presence of tissue;

3. The release of H₂S from the connectionXXVIIhappens regardless actively the t of the two main enzymes for endogenous synthesis of H ₂S (cystathionine β-synthase and cystathionine-γ-lease). This was demonstrated by the lack of effect of inhibitors of these enzymes (PAG; DL-propargylglycine), on the generation of H₂S from the connectionXXVII. In contrast, the release of H₂S of L-cysteine significantly inhibited PAG;

4. The concentration of H₂S received from the connectionXXVIIis in the range of 10-20 μm, if you are using 1 nm connection. Concentrations of up to 5 nm mesalamine can be measured in the lumen of the colon after the patients took regular doses of this drug substance (Dig. Dis. Sci. 1989; 34: 573-578). Endogenous concentrations of H₂S can be quite large, of the order of 160 μm (Antioxid. Redox Signal. 2003; 5, 493-501). ConnectionXXVIIreleases H₂S concentrations in the physiological range, thus minimizing the possibility of toxicity due to H₂S.

EXAMPLE 16. Comparison of the actions of thiocarbamoylation of trimebutine with trimebutina separately and with thiocarbamoylation separately on the model of perception of visceral pain in rats

The experiments were conducted as described in Example 13, except that each group of 5 rats received carrier, the maleate of trimebutine (10 mg/kg)or equimolar doses of thiocarbamoylation of trimebutine (compound III), or ondeletecommand.

Figures 7(a) and 7(b) show that thiocarbamoylation of trimebutine is more effective than or maleate of trimebutine, or thiocarbamoylation, in reducing visceral pain as a response to colorectal distension.

Thus, thiocarbamoylation of trimebutine can be applied for the treatment of abdominal pain associated with various inflammatory conditions of the digestive tract, as well as functional gastrointestinal disorders such as spastic colitis, dyspepsia, etc. which are characterized by increased visceral nociception (with or without accompanying inflammation).

EXAMPLE 17. Gastrointestinal safety of NSAID compounds of the present invention

A derivative of diclofenac of the present invention, 4-thiocarbamoylation ether [2-(2,6-dichlorophenylamino)phenyl]acetic acid, also referred to here as the connectionXVII,researched on his gastrointestinal safety in rats. In particular, we measured gastric damage, gastric synthesis of PGE₂, ulceration of the small intestine and hematocrit.

Male Wistar rats with weighing 175-200 g were not given food for 18 hours before by oral administration of 1% carboxymethylcellulose (medium; 0.2 ml) separately, or one of the following fluids in the vehicle: diclofenac (20 mg/is d), 4-thiocarbamoylation ether [2-(2,6-dichlorophenylamino)phenyl]acetic acid (compoundXVII)(27.3 mg/kg), 4-hydroxycobalamin (TBZ) (7,3 mg/kg) or diclofenac together with TBZ. The dose of a compoundXVIIwas equimolar dose of diclofenac 20 mg/kg Analogice, the dose of TBZ was equimolarly the dose of a compoundXVII.

Each group contained 5 rats. Three hours after injection of the test compounds, the rats were euthanized and the amount of gastric hemorrhagic damage was measured blind (in mm). "The coefficient of gastric damage was obtained by summing the lengths of all injuries in the stomach. As can be seen from Figure 8, there was no damage to the stomach in the group "media" or "connectionXVII". ConnectionXVIIcauses significantly less damage to the stomach than diclofenac. In addition, the effect of no damage of the stomach is not observed if the fragment NSAID (diclofenac) and TBZ is entered separately, but at the same time.

These observations were confirmed by histological examination are blind. Samples (100-200) gastric tissue was cut to measure the synthesis of prostaglandin E₂(PGE_aas described in detail previously (Wallace et al., Cyclooxygenase 1 contributes to inflammatory responses in rats and mice: implications for gastrointestinal toxicity. Gastroenterology 1998;115;101-109,which is incorporated in this description by reference). Briefly, samples TKA and bashed with scissors for 30 min, then placed in 1 ml buffer phosphate (pH of 7.4) and placed in an agitated water bath (37°C) for 20 minutes and Then the samples were immediately centrifuged for 1 min at 9000g and the supernatant was immediately frozen to -80°C for subsequent measurement of the concentration of PGE₂using specific ELISA test (Wallace et al., 1998).

As can be seen from Figure 9, diclofenac (with or without concomitant introduction of TBZ) and the connectionXVIIsignificantly reduce the amount of synthesis of PGE₂in the stomach, indicating that the inhibition of COX-1 and/or COX-2. TBZ is not separately reduces the synthesis of PGE₂in the stomach compared with the carrier. Thus, the absence of gastric damage in rats treated with compoundXVII,as shown in figure 1, does not apply to changes in the ability of these drugs to inhibit prostaglandin synthesis in the stomach. Suppression of the synthesis of PGE₂in the stomach is almost equal in the case of these drugs, and in the case of equimolar doses of diclofenac.

Figure 10 shows that the derivative of naproxen the present invention, 4-dicarbonitrile ester 2-(6-methoxynaphthalene-2-yl)propionic acid (compoundXX),causes significantly less damage than naproxen separately. This experiment was conducted in exactly the same way as those presented at the Phi is ur 8. Naproxen and connectionXX,everyone is administered orally at a dose of 60 µmol/kg, and 3 hours later damage to the stomach researched blind. Damage to the stomach did not respond to discovery in any of the rats treated with compoundXX.Each group consisted of 5 rats. These observations were confirmed by histological examination are blind.

Inhibition of COX-1 was also measured using the same rats. Immediately after collecting exudates from his pocket, 1 ml of blood was collected from the lower genital vein of each rat was placed in a glass test tube and allowed to clot for 45 min as described previously (Wallace et al., Gastroenterology 1998). The samples are then centrifuged for 3 min at 9000g and the supernatant was frozen at -80°C for subsequent measurement of concentrations of thromboxane B₂using specific ELISA test. As shown in figure 11, naproxen and compound XX, each significantly (*p<0,05) inhibit the activity of COX-1 compared with group treated with the carrier.

EXAMPLE 18. Inhibition of cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) step 4-thiocarbamoylation ether [2-(2,6-dichlorophenylamino)phenyl]acetic acid.

Inhibition of COX-2 in vivo was measured using a modified version of a previously published model (Wallace et al., Limited anti-inflammatory efficcy of cyclo-oxygenase-2 inhibition in carrageenan-airpouch inflammation. Br. J. Pharmacol. 1999; 126:1200-1204,which is incorporated in this description by reference). Briefly, subcutaneous pocket was created by repeated injection of air for several days. Once started, the inflammation in your pocket can be caused by injection of 1 ml of 1% zymosan. This causes a large increase in prostaglandin E₂(PGE₂within the pocket, which, as shown, is achieved almost exclusively by the action of COX-2. Each group of 5 rats orally treated for 30 min before the injection of carrageenan, vehicle (1% carboxymethylcellulose), diclofenac (3 mg/kg) or 4-thiocarbamoylation ether [2-(2,6-dichlorophenylamino)phenyl]acetic acid, a compoundXVII(4,1 mg/kg). Another group of 5 rats received media, but also the injection of 0.9% sterile saline in a pocket, in a quantity which comes with simhasanam.

As can be seen from Figure 12, the pre-treatment or diclofenac, or connectionXVIIsignificantly reduced concentrations of PGE₂within the pocket, which arose as a response to the injection zymosan. *p<0.05 with respect to the group treated with carrier + zymosan. These results indicate that both compounds significantly inhibited COX-2. In contrast, TBZ one does not influence significantly on the activity of COX-2.

Inhibition of COX-1 was also measured with the use of the group of the same rats, using the same method as described for Figure 11. As shown in figure 13, diclofenac and connectionXVII,each inhibit total synthesis of thromboxane in the blood, which takes place under the action of COX-1 more than 80%. In contrast, TBZ not impact significantly on the activity of COX-1.

EXAMPLE 19. Impact of derivative NSAID damage to the stomach, the activity of COX-1 and COX-2 in vivo

Anti-inflammatory effects (inhibition of COX-2 and COX-1) and gastric safety of a number of compounds were compared with the use of the research described above. The results are summarized in table 1. All original NSAID cause significant gastric damage. However, derivatives TBZ according to the present invention show improved gastrointestinal safety compared to the original drug. You can also see from table 1 that the derivative TBZ or retain, or, ironically, increase their ability to inhibit COX-1 and/or COX-2 compared to the original drug substance.

EXAMPLE 20. Impact of derivative NSAID inflammation

Anti-inflammatory effects of 4-thiocarbamoylation ether [2-(2,6-dichlorophenylamino)phenyl]acetic acid (compoundXVIIwith the same diclofenac was investigated using model carraginanous edema of the hind legs, as previously described inWallace et al., Gatroenterology 1998 . Male rats of Wistar with weighing 175-200 g were given the test compounds orally 30 min prior to pomodorini injection of 100 ál of 1% lambda-carrageenan. The volume of paw was measured using gidravlicheskaya Ugo Basile before injection of carrageenan and then in 1-hour intervals for 5 hours. Each group consisted of 5 rats were treated with diclofenac sodium at doses of 1, 3 or 10 mg/kg or with compound XVII dose equimolar to diclofenac 3 mg/kg

As shown in figure 14, diclofenac dependent on dose was reduced swelling of the legs due to pomodorini injection of carrageenan. ConnectionXVIIintroduced at a dose equimolar to diclofenac 3 mg/kg, reduced swelling of the legs to a greater extent. Indeed, the effect of the connectionXVIIon the swelling of the paws was comparable with the effect of diclofenac at a dose of 10 mg/kg

Because the connectionXVIIinhibits prostaglandin synthesis to the same extent as diclofenac, increased activity of the new compounds according to the invention in a model of paw edema most likely refers to another property of the connection. Previously it was demonstrated that the donors of hydrogen sulfide can significantly reduce due to carrageenan swelling of the paws of rats (Zanardo et al., Hydrogen sulphide is an endogenous modulator of leukocyte-mediated inflammation. FASEB J 2006;20:2118-2120included in this description by reference), that is they way without having to be bound to any theory, it is assumed that the release of H₂S from the connectionXVIIis fuelling anti-inflammatory characteristics in comparison with diclofenac.

Without having to be bound to any theory, it is also assumed that some additional activity of the compounds according to this invention, in models of inflammation can be attributed to the enhanced inhibition activity of COX-2. The effects of media, naproxen and 4-dicarbonitrile ether 2-(6-methoxynaphthalene-2-yl)propionic acid (compoundXX) were compared with model air pocket in rats (as described for Figure 12). Each group consisted of 5 rats. Naproxen and connectionXX,each was administered at the dose of 60 µmol/kg As shown in figure 15 as naproxen and connectionXXsignificantly inhibit the activity of COX-2 compared with the group treated with media (*p<0,05. **p<0,01).

Also, without having to be bound to any theory, it is possible that some additional activity NSAID derivatives according to this invention, in models of inflammation can be attributed to the enhanced inhibition activity of COX-1. The effects of media, indometacin and 4-thiocarbamoylation ether [1-(4-chlorbenzoyl)-5-methoxy-2-methyl-1-H-indol-3-yl]acetic acid (compoundXIX) were compared with their effects on the total number of thromboxane In ₂in human blood in vitro. Aliquots (0.5 ml) of blood from healthy volunteers was added to glass tubes containing 10 μl of methanol separately, or one of the tested drugs, prepared so that the final concentration should be 0.1, 0.3, and 1 or 3 μm. The tubes were placed in a water bath (37°C) with gentle shaking for 45 min, after which they were centrifuged (1000g) for 10 minutes. The concentration of thromboxane B₂each sample is then determined using a specific ELISA test, as in the studies presented in figure 11. As shown in figure 16, as indometacin and connectionXIXcreated dependent on the concentration of inhibiting the activity of COX-1 compared with group treated with the carrier. However, at concentrations of 1 and 3 μm, the connectionXIXcreated significantly greater (*p<0.05) inhibition of the activity of COX-1 than what received the action of indomethacin.

EXAMPLE 21. Adhesion of leukocytes to vascular endothelium; NSAID derivatives of the present invention

Adhesion of leukocytes to the vascular endothelium represents the first event in the inflammatory reactions and contributes to the formation of blood clots. Donors of hydrogen sulfide has been shown to reduce the adhesion of leukocytes caused by aspirin or Pro-inflammatory Tripeptide, fMLP (Zanardo et al., FASEB J. 2006; 20: 211-2120 ). The effects of multiple NSAID derivatives of the present invention on the adhesion of leukocytes were studied by means of intravital microscopy in rats, as described in detailZanardo et al. FASEB J 2006; 20: 2118-2120.

Briefly, mesenteric postcapillary venules shot in rats was investigated under an optical microscope. After recording the background level on the interval 5 min one of the test compounds listed in table 2 below, was administered intragastrically at a dose of 30 μmol/kg, with the exception of naproxen and 4-dicarbonitrile ether 2-(6-methoxynaphthalene-2-yl)propionic acid (compoundXX),which was administered at the dose of 60 µmol/kg All the test compounds prepared in an environment of 1% carboxymethylcellulose. Changes of leukocyte adhesion within venules were recorded on a video camera attached to the microscope, and quantitative determination of the number of attached leukocytes was performed in blinded fashion by evaluating the recorded video images. Each group consisted of 5 male Wistar rats weighing 150-175 g Leukocyte was considered to be "adhered", if he remained motionless for 30 seconds or more (the results below are expressed as value ± SEM). At the end of the experiment, the stomach was opened and examined for the presence of gastric damage under a dissecting microscope.

From table 2 we can see that TBZ is a derivative of aspirin according to the present invention, the connectionXVIsignificantly reduces the number of attached cells at 100 μm length of the vessel compared with aspirin separately. In addition, the connectionXVIsignificantly reduces the percentage of gastric damage, compared with aspirin separately. Similarly, the following table 2 shows that TBZ is a derivative of diclofenac of the present invention, the connectionXVII,significantly reduces the number of attached lacazio per 100 μm length of the vessel and reduces the percentage of gastric damage in comparison with diclofenac separately. Similarly, next, table 2 shows that TBZ is a derivative of naproxen according to the present invention, the connectionXXsignificantly reduces the number of attached cells at 100 μm length of the vessel and reduces the percentage of gastric damage compared to naproxen separately.

Interestingly, TBZ-derived lumiracoxib, COX-2 selective inhibitor that has been reduced is significant gastrointestinal side effect, connectionXVIII,still does not show cases of gastric damage, but the number of attached cells at 100 μm length of the vessel is significantly reduced compared to lumiracoxib separately. Thus, covalent binding of TBZ with selective against COX-2 NSAID can reduce the cardiovascular side effects of these COX-2 inhibitors.

Thus, NSAID derivatives of the present invention can reduce the cardiovascular side effects of NSAID by reducing leukocyte adhesion.

EXAMPLE 22. The effect of NSAID derivatives of the present invention to cure stomach ulcers

NSAID, including those that are selective against COX-2, often inhibit the recovery of previously incurred gastric ulcers (Stadler et al., Diclofenac delays healing of gastroduodenal mucosal lesions. Double-blind, placebo-controlled endoscopic study in healthy volunteers. Digestive Diseases and Sciences 1991; 36: 594-600). To determine the effects of two compounds according to the present invention on the healing of ulcers (connectionXVIIand the connectionXX), compared to diclofenac and naproxen, respectively, in rats treated these medicinal substances after the ulcers were created in their stomachs. Gastric ulcers created by serosal application of acetic acid, as describedElliott et al., A nitric oxide-releasing nonsteroidal anti-inflammatory drug accelerates gastric ulcer healing in rats. Gastroenterology 199; 109: 524-530. Three days after the start, groups of 5 rats each group were treated twice a day, oral, media, diclofenac, (30 µmol/kg), compoundXVII(30 µmol/kg), naproxen (60 µmol/kg) or compoundXX(60 µmol/kg). After 4 days of this treatment, rats were euthanized and the stomach was excised and photographed. Ulcer size (in mm²) was determined by planimetric individual processing blind, used for rats. In the subgroup of 5 rats euthanized 3 days after the creation of gastric ulcers (that is, before drug treatment), the average surface area of the ulcers was 24±2 mm². As shown in figure 17, rats treated with media, diclofenac, or naproxen, show a similar degree of recovery. However, rats treated with compoundXVIIor connectionXX,exhibit a significantly greater recovery (*p<0.05 compared with diclofenac and naproxen, respectively). Processing TBZ alone will not impact significantly on the healing of gastric ulcers compared with a group treated with the carrier.

EXAMPLE 23. The influence of NSAID derivatives of the present invention on blood pressure

NSAID, including those that exhibit selectivity for COX-2, can exacerbate hypertension, pre-existing, and to interfere with the effectiveness of some of the Academy of Sciences of hipertenzivnih tools ( Whelton, A. Nephrotoxicity of nonsteroidal antiinflammatory drugs: physiologic foundations and clinical implications. Am. J. Med. 1999;106 (5B):13S-24S). Rats received the drug substance intraperitoneally after creating hypertension, to determine the effects of derivative of naproxen in the present invention the connectionXXcompared to the blood pressure with naproxen, taken separately. Rats were given drinking water containing methyl ether Nω-nitro-L-arginine (400 mg/l) for 7 days before the experiment, as described previouslyRibeiro et al. (Chronic inhibition of nitric oxide synthesis: A new model or arterial hypertension. Hypertension 1992;20:298-303). Rats (5 to 8 per group) were anestesiologi the halothane gas and the carotid artery was inserted a catheter for measuring blood pressure, which was writing continuously on a chart recorder. After measurement of blood pressure, is stable for at least 15 minutes, or naproxen, or connectionXXwas injected intraperitoneally in the form of a bolus injection with a concentration of 60 mmol/kg Changes in blood pressure were recorded within 60 minutes after injection. Average blood pressure was 150±6 mm Hg. Figure 18 shows that naproxen causes a significant increase in systolic blood pressure. In contrast, the connectionXXno increases in systolic blood pressure compared with the group treated with the carrier, and the change in blood pressure which is substantially less than the pressure that is caused by diclofenac and naproxen, respectively.

EXAMPLE 24. Measurement generation H₂S 4-thiocarbamoylation ether [2-(2,6-dichlorophenylamino)phenyl]acetic acid

For comparison, the release of H₂S in vitro, due to a 4-thiocarbamoylation ether [2-(2,6-dichlorophenylamino)phenyl]acetic acid, the connectionXVIIand TBZ, 100-150 mg selected samples of liver homogenized in 1 ml of cooled ice protein extractor T-PER. 2-ml reaction mixture for the study was introduced in the mixture cooled with ice 250 μl of 0,1N NaOH in a sealed 3-necked reactor. A mixture containing 1 mm connectionXVIIor 1 mm TBZ, was dissolved in PEG and 100 mm buffer with potassium phosphate (pH=7,4). Incubation was performed in the presence of, or without 10% (wt./about.) homogenate of liver and 2 mm pyridoxal 5'-phosphate. A steady stream of nitrogen was passed through the mixture through the inlet gas capillary. The reactor was kept at 37°C and extraction of the H₂S began the introduction of 1 ml of 10% solution of trichloroacetic acid. The flow of nitrogen translated sulphurous acid in another reactor through the cooled connector and propulsiveness in 2 ml of non-oxidizing sulfide buffer (SAOB), consisting of 2 M KOH, 1 M salicylic acid and 0.22 M ascorbic acid at a pH of 12.8. After 30 minutes SAOB solution was removed and the concentration of sulfide was measured through sulfidecontaining electrode (Model 9616 S ^2-/Ag*electrode, Orion Research, Beverly, MA, USA) and were expressed as the concentration of H₂S (Ubuka, 2002; Khan et al., 1980). Reactions were initiated by transferring the tubes from the ice bath in a water bath at 37°C. a Stream of nitrogen translated sulphurous acid in the second reactor, containing 2 ml of SAOB described earlier. After incubation at 37°C for 90 minutes, 1 ml of 50% solution of trichloroacetic acid was added to the mixture to stop the reaction. Remaining in a mixture of H₂S translated with a stream of nitrogen for a further 30 minutes incubation at 37°C. the Concentration of sulfide in SAOB-solution was measured sulfidecontaining electrode, as described above (Ubuka, 2002; Khan et al., 1980).

As shown in figure 19, the incubation connectionXVIIin the buffer results in a significantly greater release of H₂S than in the case of an equivalent amount of TBZ. Similarly, there is a greater release of H₂S from the connectionXVIIthan TBZ at incubation with liver homogenate.

EXAMPLE 25

Action mixed 4-thiocarbamoylation 2-{2-[8-(2,2-dimethylbutyryl)-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]ethyl}-6-oxitetraciclina-4-silt ester of succinic acid (compound I) and simvastatin on the aggregation of human platelets in vitro.

Platelet-rich plasma (PRP) was obtained, as described in detail previously (Ma L, Elliott SN, Cirino G, Buret A, Ignarro LJ, Wallace JL. Platelet modulate gastric ulcer healing through the release of endostatin and VEGF. Proc Natl Acad Sci USA98:6470-6475,which is incorporated in this description by reference). The concentration of platelets in PRP was led to 1×108 per ml by dilution buffer Tired (Tyrode) (pH of 7.4). Aliquots (400 µl) platelets were placed in a glass cuvette and placed in aggregometer platelets ChronoLog. Aggregation in response to addition to the cell adenosine diphosphate (ADP) was controlled within a period of 5 minutes First built the curve of the concentration-response to ADP,

then the concentration of ADP, generating 70-80% of maximal aggregation was used for all subsequent studies. Suspension PRP pre-incubated for 10 min at 37°C

with different concentrations (3-30 μm) of simvastatin or of the compounds I, or with vehicle (methanol). Then evaluated the aggregation response to ADP. The experiments were repeated 4-6 times for each concentration of each drug.

The figure 20 shows the effects of simvastatin and compound I on ADP-induced aggregation of human platelets. Only simvastatin reduces platelet aggregation at a concentration of 30 PM, while the connection I significantly reduces platelet aggregation at concentrations of 3, 10 and 30 μm (asterisks indicate a significant decrease in platelet aggregation compared with the corresponding group treated with the carrier; p<0,05).

EXAMPLE 26. The act of bonding and simvastatin on the cAMP of human platelets in vitro

Platelet-rich plasma (PRP) was obtained as described above. Aliquots of 400 μl of PRP was placed in a glass test tube that contained IBMX (isobutyl-1-methylxanthines; 0.5 mm), non-selective phosphodiesterase inhibitor. After two minutes in a test tube was added to the medium (methanol) or various concentrations (3-100 μm) of simvastatin or compounds I. as a positive control, some aliquots of platelets were treated with Forskolin (10 μm), a known activator of adenylate cyclase. After ten minutes, the samples of PRP was centrifuged at 9000g for 2 min and supernatant was discarded. The pellets re-suspended in buffer were irradiated with ultrasound for 2 min, then the concentration of cAMP was determined using specific antispyzone ELISA studies (Cayman Chemical Co., Ann Arbor, MI, USA). The experiments were repeated 4-6 times for each concentration of each drug.

The figure 21 shows the effects of simvastatin and compound I in the concentration cAMP of human platelets. The dotted line shows the levels of cAMP in platelets treated with Forskolin (10 μm). Only simvastatin significantly increases cAMP platelets at the higher concentration (100 μm), while compound I induces a significant increase in cAMP in platelets at concentrations of 10, 30 and 100 μm). (Asterisks indicate significant is the reduction of platelet aggregation compared with the corresponding group, the processed media; p<0,05).

1. The compound or its pharmaceutically acceptable salt of the General formula:

where a represents protivogipertonicheskoe medicinal substance, Y is selected from the group consisting ofor absent, and X is selected from the group consisting oformoreover, if Y is absent, the compound can be a salt and X.

2. The compound according to claim 1, where Y represents the groupand X
represents

3. The compound according to claim 1 or 2, in which antihyperlipidemic drug is a statin.

4. The compound according to claim 3, in which the statin is selected from the group consisting of atorvastatin, tsilastatina, dermistatin, fluvastatin, lovastatin, mevastatin, pravastatin sodium and simvastatin.

5. The compound according to claim 4, in which the compound is a mixed 4-thiocarbamoylation ether - 2-{2-[8-(2,2-dimethylbutyryl)-2,6-dimethyl-1,2,6,7,8,8A-hexahydronaphthalen-1-yl]ethyl}-6-oxitetraciclina-4-silt ester of succinic acid.