Employment of (r)-arylpropionic acids to prepare drugs for treatment of humans and animals liable to be therapeutically affected via nf-κb activation inhibition

FIELD: pharmaceutical industry.

SUBSTANCE: employment of title compounds is based on their ability of inhibiting NF-κB activation cascade. Invention provides compositions with these acids to treat patients suffering from diseases caused by formation of NF-κB.

EFFECT: expanded therapeutical possibilities.

6 cl, 6 dwg


The object of this invention is the use of (R)-arylpropionic acids to obtain drugs for the treatment of diseases of humans and animals, which can have a therapeutic effect by inhibiting the activation of NF-κ (nuclear factor Kappa b).

Arylpropionic acids and their derivatives have been used for long as nonsteroidal anti-inflammatory and analgesic drugs. Well-known representatives of this group of biologically active substances are ibuprofen, flurbiprofen, Ketoprofen, naproxen, tiaprofenic acid and fenoprofen [propionic acid Derivatives; Goodman & Gilman's, the Pharmacological basis of therapeutics, Chapter 27, str (ninth edition, 1996)].

On the basis of molecular structure with one asymmetric carbon atom arylpropionic acids and their derivatives are chiral, existing in the form of (R)- and (S)-enantiomeric forms. Usually during the chemical synthesis of these biologically active substances get in the form of a racemate. These biologically active substances up to (S)-naproxen [Williams: the Enantiomers with arthritic disorders; Pharmac. Ther., volume 46, str-295 (1990); Evans: Enantioselective pharmacodynamics and pharmacokinetics of chiral non-steroidal anti-inflammatory drugs. Eur J Clin Pharmacol 42: 237-256 (1992)] and the last de is ibuprofen [Symposium: the Latest information about (S) - (+)-ibuprofen; Going/Kitzbuhl February 2-4, 1996] and dexketoprofen [certificate No. 1831 dated June 22, 1993, p.7; certificate No. 2144 dated July 9, 1996, p.16] are used in medicines still in the form of racemates.

Therapeutically desired inhibiting inflammation and analgesic effect arylpropionic acids and their derivatives is described, mainly with the inhibition of prostaglandin biosynthesis [Vane and Botting: Review the mechanism of action of anti-inflammatory drugs. In the collection: Improved non-steroidal anti-inflammatory drugs are inhibitors of the enzyme SOH-2, p.1-27, ed. Lancester: Kluwer Academic Publishers (1996)]. This is due to the inhibition involved in the formation of prostaglandins, enzymes cyclooxygenase 1 and 2 (MOR-1 and MOR-2 or PGHS-1 and PGHS-2). Due to the reduced formation of prostaglandins are attenuated depending on these inflammatory mediators of the inflammatory symptoms, such as pain, swelling, erythema, edema formation, warm and constraint functions. Inhibition of prostaglandin synthesis is considered the common distinguishing feature of the mechanism of anti-inflammatory and analgesic actions. Therapeutically desirable inhibition of production of prostaglandins in exposed disease target tissue results in other organosilane that have certain concentration protag is Andonov, unwanted effects of drugs. Especially affected as a result of undesirable effects gastrointestinal tract, kidneys, lungs, and platelets.

It is known that in relation to inhibition of prostaglandin synthesis are significant differences between enantiomeric forms arylpropionic acids [Williams (see above); Evans (see above); Brooks and Day: New non-steroidal anti-inflammatory drugs, published by Birkhauser, Basel, str-126 (1985)]. While all of (S)-enantiomers of these compounds reveal a clear-cut inhibition of prostaglandin synthesis, this action does not determine in the case of (R)-enantiomers in therapeutically important area of concentration. Thus, (R)-arylpropionic acids and their derivatives is not credited in therapeutic concentrations neither desirable nor undesirable drug effects that have any connection with the inhibition of production of prostaglandins. Regardless of the absence of such unwanted effects with a specific mechanism of action of (R)-enantiomers of this class of biologically active substances can detect unwanted specific for the substance of the action.

Due to the long-known therapeutic and economic values used in the form of a racemate arylpropionic acids attempts to justify the thought of applying racemic biologically active substances. In the case of ibuprofen, the use of the racemate is justified mainly by the fact that in the human or animal is more or less clear inversion of (R)-ibuprofen (S)-ibuprofen [Caldwell and others: the Metabolic chiral inversion and available enantioselectivity 2-arylpropionic acids and their biological consequences; Biochemical Pharmacology, vol 37, No. 1, p.105-114(1988)], which is also part of the (R)-form after inversion in (S)-form can be effective as an inhibitor of prostaglandin synthesis. In addition, for (R)-ibuprofen describes the inhibition of polymorphonuclear leukocytes in vitro, which in inflammatory diseases could be useful [Villanueva and others: Equipotent inhibition of R(-)-and S(+)- and racemic ibuprofen function of human polymorphonuclear cells in vitro; Br. J. clin. Pharmac., 35, 235-242 (1993)]. therapeutic importance of this mechanism in the application of racemic ibuprofen could not, however, be shown. In the case of (R)-flurbiprofen inversion neglected.

The fact that therapeutic action arylpropionic acids, essentially, is attributed to inhibition of prostaglandin synthesis, has led to the conclusion that the use of pure (S)-enantiomers, if necessary, racemic compounds, but not pure (R)-enantiomers, is rational. Initially unexpected discovery, the (R)-flurbiprofen has antinociceptive action which is not related to inhibition of peripheral biosynthesis of prostaglandins, caused the development of drugs based on (R)-flurbiprofen [patent Germany 4028906 C2; European patent EP 0607128 B1; U.S. patent 5206029 and 5200198] as analgesics without inhibiting inflammation of the effective components. It was later also described an analgesic effect for (R)-Ketoprofen [patent Germany 4319438 C1; international patent application WO 93/176671.

More recent publications confirm the antinociceptive effect of (R)-flurbiprofen [Geisslinger, Schaible: New perspectives on the place of application and antinociceptive actions of the enantiomers of flurbiprofen, J. Clin Pharmacol, 36, 513-520 (1996); Buritova, Besson: Peripheral and/or Central effects of racemic, S(+)- and R(-)-flurbiprofen inflammatory nociceptive processes: a study of the protein c-Fos in the spinal cord of the rat, British J. Pharmacology, 125, 87-101 (1998)]. In clinical studies patients were able to confirm the analgesic effect of (R)-flurbiprofen [1] and (R)-Ketoprofen [Cooper and others: Analgesic efficacy and safety of (R)-Ketoprofen in postoperative dental pain; J. Clin Pharmacol, 38, 11S-18S (1998)].

Figure 1: placebo Controlled double-blind study of 180 women with acute pain after episiotomy (curves averages)

Hospitalized patients were randomly divided into three groups, according belnyj each, which was prescribed medication, and the group receiving placebo (30 patients). Each patient received within 48 hours, otherwise, normally proceeding childbirth single dose under investigation prescribed medications (25 mg (R) - (-)-flurbiprofen or 100 mg of (R) - (-)-flurbiprofen, or 1000 mg paracetamol) or orally was given a placebo. Shortly before oral administration of the study drugs or placebo at the exact time points of the study(15, 30, 45, 60, 120, 180, 240, 300 and 360 minutes) of patients were questioned about their pain. The effectiveness of the drugs was assessed using the scale of perception of pain (0 = no perception of pain, 1 = weak, 2 = moderate, 3 = strong). The results of the process over time are summarized in the figure 1 curves of mean values for individual groups of patients.

Experimental animal studies indicate that the effect of (R)-flurbiprofen can be explained by the inhibiting inflammatory and antinociceptive effect on the Central nervous system [Birutova (see above); Neugebauer and others: Antinociceptive effects of R(-)- and S(+)-flurbiprofen on neurons of the spinal dorsal horn of bone of rats trapped hypervolume in acute inflammation of the knee joint; J. Pharmacol Exp Ther, 275, 618-628 (1995)]. Known peripheral inhibitory inflammation of the antinociceptive action of flurbiprofen could be detected, on the contrary, solely in the case of (S)-enantiomers [Birutova (see above) and Neugebauer (see above)]. According to the modern level of knowledge, from this derive significant conclusions as to the optimal treatment of peripheral inflammatory diseases would be used as the selected tool (S)-arylpropionate acid. To reduce closely associated with the inhibition of prostaglandin synthesis undesirable effects on the gastrointestinal tract, etc. should not, for example, take (S)-flurbiprofen oral and should be applied topically to inflamed or painful areas. (R)-Flurbiprofen however, due to a Central action to apply systematically [Birutova (see above)], for example, orally, intramuscularly or intravenously.

Despite these latest findings almost exclusively on the Central action of (R)-flurbiprofen was unexpectedly found that (R)-flurbiprofen in certain concentrations is a potent and specific inhibitor of activation of nuclear transcription factor NF-κB. NF-κb is a ubiquitous transcription factor that plays a Central role in cells during immune and inflammatory responses, as well as with the expression of cytokines, chemokines, cell adhesion molecules, growth factors, immunoreceptor, acute phase proteins, various EN zymes is s and other transcription factors [Lee, Burckart: Nuclear factor Kappa b: an Important transcription factor and therapeutic target, J. Clin. Pharm., 38, 981-993 (1998)].

Activation of NF-κcan be ingibirovany at various stages of the cascade of activation using a variety of biologically active substances. Thus, glucocorticoids inhibit NF-κthrough direct Association or by amplifying expression. Cyclosporine and tacrolimus prevent the activation of NF-κby inhibiting phosphatase, affecting the level of calcium in the urine, which indirectly induces the splitting of the I-κB. Desoxypeganine inhibits NF-κby blocking the displacement of its engine. Aspirin and salicylate inhibit the previously mentioned phenomena, which induce the phosphorylation of I-κC. Tepoxalin and antioxidants inhibit the activation of NF-κby changing the redox state of the cell. Further research is needed to develop specific inhibitors for the treatment of diseases that are affected by NF-κ [Lee, Burckart: Nuclear factor Kappa b: an important transcription factor and therapeutic target, J. Clin. Pharm., 38, 981-993 (1998)].

It is known that (R)-ibuprofen and (S)-ibuprofen inhibit activation of the transcription factor NF-κthrough a complex phorbol ester (TPA), which leads to regulation of activated esters of phorbol protein kinase C and caused, blagoj the OC this, phosphorylation and inactivation of I-κnot, however, able to affect the activation of NF-κthrough 11a-15(S)-dihydroxy-9-oxo-5-CIS, 13-TRANS-prostatitious acid (PGE2) or lipopolysaccharide (LPS). The applicability of ibuprofen so limited. [N.Scheuren and other "Modulation of transcription factors, non-steroidal anti-inflammatory drugs", Naunyn-Schmiedeberg''s Arch. Pharmacol., volume 354, number 4, Supplement 1, 1996; N. Scheuren and others, "Enantiomers non-steroidal anti-inflammatory drug ibuprofen are strong and specific inhibitors of transcription factor NF-Kappa beta", Naunyn-Schmiedeberg''s Arch. Pharmacol., volume 357, No. 4, Annex, 1998; N. Scheuren and other "Modulation of transcription factor NF-Kappa, beta enantiomers non-steroidal medications ibuprofen", VG. J. Pharmacol., volume 123, No. 4, 1998; N. Scheuren and others, "Weak inhibitors of cyclooxygenase may strengthen their antinociceptive effects of modulation of transcription factors", Adv. Exp. Med. Biol., volume 433, 1997].

The invention has set the task to find other biologically active substances which inhibit the activation of NF-κC.

Suddenly it was just discovered that others are not racemethionine (R)-arylpropionate acid can interfere with the disease by specific inhibition of the steps inside the cascade activation of NF-κCentury Due to the widespread functions of the transcription factor NF-κwhen the military regulation of medicines with (R)-arylpropionate acids or their derivatives are suitable not only known for easing pain through antinociceptive effect on the Central nervous system [patent Germany 4028906 C2], but under proper use and dose are also used in all diseases in which it may be therapeutically useful in the inhibition of activation of NF-κB. According to the invention, these medicines can be used not only for pain and rheumatic diseases, but also in tumors, autoimmune diseases, asthma, shock, inflammatory bowel disease (Crohn's disease, ulcerative colitis), radiation injuries, arteriosclerosis, Alzheimer's disease, in the treatment of rejection reactions after transplantation of tissues and organs, etc. in appropriately selected dose and finished pharmaceutical form.

We report here the observation is related to the inhibition of the formation of NF-κsuddenly, as according to the prior art pharmacological effects arylpropionic acids was attributed to other mechanisms. This led earlier to the use of the racemate or the (S)-enantiomers for pain or inflammation in smaller doses.

In the international patent application WO 98/09603 the following describes the applicability of (R)-enantiomers of nonsteroidal anti-inflammatory drugs in tumor diseases, in particular cancer of the colon and breast, cystic fibrosis and Alzheimer's disease.

Unexpectedly, it was found that (R)-flurbiprofen and others are not metabolized in SOA is a complex thioethers and who eat the most ramispina (R)-arylpropionate acid inhibit the activation of NF-κ In about 100 times stronger than the corresponding (S)-enantiomers. To achieve a satisfactory actions they must, however, be used in higher doses than usually known therapeutic use of racemic arylpropionic acids. Due to good endurance because almost no effect of these doses of (R)-arylpropionic acids on peripheral biosynthesis of prostaglandins and no racemization occurring in (S)-enantiomers is possible, however, when using (R)-enantiomers set such high doses that can be achieved desired inhibitory effect on the activation of NF-κwithout need to fear derived from (S)-form of unwanted effects. Biologically active substances are used preferably in most cases free of (S)-enantiomers, i.e. have an optical purity higher than 90%, in particular more than 99%, if it is not desirable as a "side effect" is also known to reduce pain and inflammation action (S)-enantiomers. In contrast, (R)-ibuprofen should not expect relevant adverse effects due to missing inversion R⇒S if not metabolized in SOA is a complex tiefer (R)-arylpropionic acids. Medicinal product according to the invention allows the t to expect, thus, improved range of therapeutic action, as compared with the use of racemic arylpropionic acid or (S)-enantiomers. Conducted human studies prove good gastrointestinal tolerability (R)-flurbiprofen and other (R)-arylpropionic acids [Jerussi and others: Clinical endoscopic evaluation of gastroduodenal tolerance of Ketoprofen, flurbiprofen, the racemic Ketoprofen and paracetamol: a randomized disposable-blind, placebo controlled study; J. Clin. Pharmacol, 38, 19S-24S (1998)], which has been observed in earlier experiments on animals [patent Germany 4028906 C2].

Since the discovery of nuclear transcription factor NF-κwithin ten years, carried out extensive research using endogenous and exogenous substances on the study of biological function and influence on the formation of NF-κCentury Of the known pharmacological substances previously described, inter alia, the glucocorticoids, such as dexamethasone and prednisone, immunosuppressants, such as cyclosporine, tacrolimus and desoxypeganine, at therapeutic concentrations, as in effect on the activation of NF-κC. formed by biochemical inversion of (R)-ibuprofen in (S)-ibuprofen intermediate metabolites of (R)-ibuprofen - coenzyme a complex tiefer also is found inhibition of activation of NF-κ In, and therefore a speculative assumption that (R)-ibuprofen through the known metabolic activation in human body (R)-ibuprofen-COA-complex tiefer would the action, which itself is (R)-ibuprofen is not. [Brune and others: Medicines containing ibuprofen is a complex tiefer, as inhibitors dependent Nf-κIn the formation of mediators of inflammation and pain, patent application Germany 19716713 A1, international patent application WO 98/47502].

Unexpectedly, it was found that other therapeutically useful derivatives arylpropionic acids, such as flurbiprofen, Ketoprofen, naproxen, tiaprofenic acid and fenoprofen, which do not detect appreciable formation of SOA is a complex thioesters in humans and therefore not racemized, cause a marked inhibition of activation of NF-κand, therefore, have the potential to be related to the influence of this mechanism of therapeutic effects. This group further indicated "not ramispina (abbreviated NR) (R)-arylpropionate acid".

Medicinal product according to the invention on the basis of NR (R)-arylpropionic acids and their derivatives as inhibitors of the activation of NF-κfor the treatment of diseases that are affected by modifying the activation of NF-κbased on the following experiment is lnyh research:

Figure 2: Depending on the concentration of the influence of (R)- and (S)-flurbiprofen ((R)-flu and (S)-flu) on the activation of transcription factor NF-κin RAW cells. Analysis of geldersekade (analysis of the shift of the spot during electrophoresis; a kit for determining the shift in the gel, firm Boehringer Mannheim) shows that the lipopolysaccharide (LPS) (1 μg/ml) leads to activation of NF-κ (complex of P50/P65 NF-κ) (traces 2 and 10). Micromolar concentrations of (R)-flurbiprofen (traces№№ 3, 4, 5, 6, 7 against track No. 2 as a control) were able to inhibit this LPS-induced activation of NF-κB. Densitometric determination showed that (S)-flurbiprofen in respect of these properties was approximately 100 times less active (tracks No. 11, 12, 13, 14 against the track No. 10 as a control).

Tracks 1 and 8 represent, respectively, estimulando control cells.

As the nuclear transcription factor NF-κis, among other things, responsible for the formation of a number of enzymes with Pro-inflammatory and ucoopanoki properties, determined the influence of (R)-flurbiprofen on induced simhasanam swelling of the paws of rats (methods described: Meller ST, and Gebhart GF: Vnutriplitnyi zymosan as reliable, able to be quantified model of thermal and mechanical hyperalgesia in rats; European Journal of Pain, 1, 43-52 (1997). Figa-combine the obtained results of the s.

Figa-in: time-Dependent increase in paw of the rat as measured using plethysmography) after vnutripochvennogo introduction zymosan. After applying zymosan [Meller and Gebhart (see above)] in hind paw of the rat manifests itself as a symptom of inflammation increase paws (the group using the placebo, the use of filler = phosphate buffer (FB)). Based on the inhibitory effect of (R)-flurbiprofen on the activation of NF-κat dosages between 1 and 27 mg/kg body weight (the use of intraperitoneal) becomes apparent sudden decrease legs. This effect was particularly pronounced between 2 and 6 hours after application of zymosan. Dexamethasone (CODE) (0.5 mg/kg body weight), a known inhibitor of the activation of NF-κused as a positive control. (S)-Flurbiprofen is also demonstrated in accordance with the expectation of reducing the amount of paws, and this effect is, however, not due to inhibition of activation of NF-κand the inhibition of the synthesis of proinflammatory prostaglandins. (S)-Flurbiprofen is a known inhibitor of cyclooxygenase.

Figure 4: summary of the impact of 9 mg/kg (R)-flurbiprofen ((R)-flu), 9 mg/kg (S)-flurbiprofen ((S)-flu) and 0.5 mg/kg dexamethasone (INDEX) versus placebo (P) in 24 hours. Effects of 9 mg/kg (R)-flurbiprofen was comparable with 0.5 mg/to the dexamethasone.

Known to produce and chiral separation arylpropionic acids and their derivatives. For example, reference should be made to international patent application WO 93-17677 and the literature mentioned there.

Derivatives arylpropionic acids mean derivatives according to the invention, fissile in the gastrointestinal tract (oral application) or in the blood in arylpropionate acid, as, for example, a complex alkalemia esters with 1 to 6 carbon atoms in the alkyl residue, which under certain conditions may contain amino groups or hydroxyl groups, amides or alkylamide with 1-6 carbon atoms in the alkyl residue, and pharmaceutically tolerated salts, in particular the salt of the amino acids with alkali, alkaline earth metal, ammonium salt, amino acids, preferably lisinac, meglumine, tromethamine, Argent, or salt with aluminum. Such compounds are also known.

The magnitude of prophylactic or therapeutic dose NR (R)-arylpropionic acid in the treatment in the acute and chronic treatment of diseases varies according to the power complaints treated. Dose and frequency of dosages differ in accordance with age, weight and response of the individual patient. Usually, the daily dose NR (R)-arylpropionic acid described complaints should the ü between about 50 mg and 2000 mg, taken in one or several stages. Preferably the daily dose is between about 100 mg and 500 mg, taken in one or several stages. When caring for patients treatment should begin with low dosages, possible from 20 mg to 200 mg, and the dosage is increased to about 1000 mg, or higher, in each case depending on the overall response of the patient. It is further recommended that infants, children, patients over 65 years of age and patients with impaired renal function or liver initially receive low doses, based on individual response and determining the level in blood. In some cases it may be necessary to use dosages outside this area, which is obvious to the expert. Further note that your family doctor or medical specialist in the clinic depending on the overall response of the patient knows how and when to interrupt treatment, to modify or discontinue. The expression "number, which is sufficient for inhibition of NF-κbut not enough to cause a negative reaction (inhibition of prostaglandin synthesis)" covered by the above measured quantities and instructions for dosing. Can be applied to any kind of introduction to provide the patient an effective dosage of NR (R)-arylpropionic acid. For example, can be used orally, rectal the Naya, percutaneous, parenteral (subcutaneous, intramuscular, intravenous), vnutriobolochechnoe, EPI - or epidurals and similar forms of introduction. Possible forms for application are, for example, tablets, dispersions, suspensions, solutions, capsules, patches and similar forms.

Pharmaceutical finished dosage forms is presented of the invention encompass NR (R)-arylpropionic acid as a biologically active substance or its pharmaceutically tolerated derivative and a pharmaceutically tolerable carrier, and to choose other medicinal supplements.

The expression "pharmaceutically tolerated derivatives or their pharmaceutically tolerated derivative" refers to derivatives, derived from pharmaceutically portable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Because the components in this invention are acidic, can be obtained derivatives with pharmaceutically tolerated, non-toxic bases, including inorganic and organic bases. Suitable pharmaceutically tolerated main added derivatives as components of the presents invention comprise salts with metals, obtained from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or organization is practical salt, derived from lysine, N,N’-dibenziletilendiaminom, choline, diethanolamine, Ethylenediamine, meglumine (N-methylglucamine), tromethamine, arginine and alkylamines followed with 1-6 carbon atoms in the alkyl residue.

Finished dosage forms of this invention include dosage forms as suspensions, solutions, elixirs and aerosols. If used solid forms for oral administration can be applied to devices such as starch, sugar, microcrystalline cellulose, diluents, auxiliary means for granulating, substances imparting lubricity, binders, solvents and similar compounds. Solid forms for oral administration (as, for example, powders, capsules and tablets) are preferred over liquid forms for oral administration. Preferred solid forms for oral administration are tablets. The tablets may optionally be coated with standardized aqueous or anhydrous means to cover.

In addition to the usual above forms of application components according to the invention can be introduced by known means in the form of a delayed release and/or in the form of a quick release. For example, giving a hydrophobic additive to oral forms of application are Zam is daysim way helping raspadaemosti, and surfactants contribute to the solubility and thereby act of accelerating, and, as you know, both forms can be mixed and presented in the form of granules, so that part of the biologically active substance is released quickly, and the residue is slowing down.

Pharmaceutical finished dosage forms of the present invention, which are suitable for oral administration, can in the form of separate units, such as capsules, pills or tablets, or aerosol cleaners, which may contain in each case, the specified number of biologically active substances in the form of powder or granules, or in the form of a solution or suspension in an aqueous liquid, non-aqueous liquid, emulsion oil in water or a liquid emulsion of water in oil. Such finished dosage forms may be obtained by any pharmaceutical method, but all methods include mixing a bioactive substance with a carrier, which consists of one or more necessary components. Usually finished dosage forms are produced by uniform and thorough mixing of the biologically active substances with liquid carriers or finely divided solid carriers or both and then, if necessary, by forming the product into the desired form of application.

For example, the tablet can the be obtained by extrusion or molding, with one or more additional components. Molded tablets can be obtained by pressing the corresponding device when the biologically active substance is introduced in granular form, as, for example, powdered or in the form of granules, mix to choose from, with a binder, which imparts lubricity agent, with an inert diluent, dispersant or surface-active agent. Molded tablets may also be obtained by molding in a suitable device, crushed to a powder component, moistened with an inert liquid diluent, and subsequent drying. Preferably, each tablet contains between 50 mg and 1000 mg of biologically active substances and pills every or each capsule contains between about 50 mg and 600 mg of biologically active substances. Particularly preferably tablets, pills or capsule contains one of four dosages, namely, 50 mg, 100 mg, 200 mg or 500 mg of biologically active substances.

1. Pharmaceutical composition for the inhibition of the cascade activation of nuclear factor Kappa b, containing a biologically active substance (R)-flurbiprofen, R-Ketoprofen, (R)-naproxen or (R)-tiaprofenic acid or derivatives thereof and an acceptable carrier, while biologists is if the active substance is taken in an effective amount.

2. The pharmaceutical composition according to claim 1, characterized in that it contains a biologically active substance in an amount of from 50 to 1000 mg/dose.

3. The pharmaceutical composition according to claim 2, characterized in that it contains a biologically active substance in an amount of from 200 to 500 mg/dose.

4. The pharmaceutical composition according to claim 1, characterized in that the biologically active substance contains less than 1% of (S)-isomer.

5. The pharmaceutical composition according to claim 1, characterized in that, as specified derived biologically active substances it contains its salt of alkali metal, alkaline earth metal, ammonium or aluminum salt or the salt of the amino acids, preferably lisinac, meglumine, tromethamine, Argent.

6. The pharmaceutical composition according to claim 1, characterized in that it presents in the form of tablets, pills or powder.


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7 cl, 16 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to novel pyrasolbenzodiazepines of formula I 1 (in formula R1 is hydrogen, -NO2, -CN, halogen, -OR5, -COOR7, -CONR8R9, -NR10R11, NHCOR12, NHSO2R13; each R2 and R4 independently of one another are hydrogen, halogen, -NO2, -CF3; R3 is hydpegen, C3-C8-cycloalkyl, aryl, in particular C6-C10-aromatic group having 1 or 2 rings, 5-10-membered heteroaryl, having 1 or 2 rings and1-3 heteroatoms, selected from N, O, and S, -COOR7, CN, C2-C6-alkenyl, -CONR8R9 or C1-C6-alkyl optionally substituted with OR9-group, F or aryl as mentioned above; R5 is C1-C6-alkyl; R7 is hydrogen or C1-C6-alkyl; each independently of one another are hydrogen or C1-C6-alkyl optionally substituted with hydroxyl or NH2, or alternatively R8 and R9 together form morpholino group; each R10,R11 and R12 independently of one another are hydrogen or C1-C6-alkyl; R13 is C1-C6-alkyl optionally substituted with halogen or -NR14R15; each R14 and R15 independently of one another are hydrogen or C1-C6-alkyl optionally substituted with halogen; or alternatively -NR14R15 is morpholino group) or pharmaceutically acceptable salts thereof, as well as to certain pyrasolbenzodiazepine derivatives, thiolactam intermediates for production of compound (I) and pharmaceutical compositions containing the same. Compound and pharmaceutical composition of present invention are cycline-dependent kinase (CDK2) inhibitors and antiproliferation agents used in treatment or controlling disorders associated with cell proliferation, in particular breast, colon, lung and/or prostate tumors.

EFFECT: new antiproliferation agents.

20 cl, 12 tbl, 8 ex

FIELD: organic chemistry and pharmaceutical compositions.

SUBSTANCE: invention relates to new 3-(5)-heteroaryl-substituted pyrazoles of formula I , tautomers or pharmaceutically acceptable salt of compounds and tautomers. In formula R1 is hydride, piperidinyl substituted with methyl, lower alkyl optionally substituted with halogen, hydroxyl, lower alkylanimo or morpholino; R2 is hydride, lower alkyl, amino, aminocarbonylamino, lower alkylaminocarbonylamino, lower alkylsulfonylamino, aminosulfonylamino, lower alkylaminosulfonylamino; Ar1 is phenyl optionally substituted with one or more independently selected halogen; HetAr2 is pyridinyl with the proviso that R2 is not amino or n-propyl when HetAr2 is pyridinyl; and HetAr2 is not 2-pyriridinyl when R2 is hydrogen or lower alkyl. Compounds of formula I have kinase p38 inhibitor activity and are useful in pharmaceutical compositions for treatment of various diseases.

EFFECT: new effective kinase p38 inhibitors.

23 cl, 6 dwg, 1 tbl, 1 ex

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: 5-aryl-1H-1,2,4-triazole derivatives of general formula I

, pharmaceutically acceptable salts thereof or pharmaceutical composition containing the same are described. In formula R1 is C1-C6-alkyl, C1-C6-haloalkyl or phenyl; R2 is C3-C8-cycloalkyl; phenyl optionally substituted with one or more substituents selected from C1-C4-alkyl; halogen, hydroxyl, C1-C4-alkoxy, nitro, di-(C1-C4)-alkylamino, C1-C4-alkylsulphonyl, C1-C4- alkylsulphonylamino, and methylenedioxy; phenyl-(C1-C4)-alkyl, wherein phenyl is substituted with C1-C4-alkoxy; or pyridil. New compounds are effective and selective cyclooxygenase-2 (COX-2) inhibitors and useful in treatment of inflammations.

EFFECT: new compounds for inflammation treatment.

10 cl, 36 ex, 1 tbl

FIELD: biochemistry.

SUBSTANCE: the present innovation deals with an anti-sense oligonucleotide or one of its derivatives which can inhibit expression of human eg5 protein being relative to kinesin of motor proteins. The oligonucleotide has got a sequence being correspondent to that of nucleic acid coding certain part of human eg5. This innovation deals with the way to obtain the above-mentioned oligonucleotides, pharmaceutical composition for inhibiting human eg5 and its application. Advantage of the innovation deals with developing e new preparation to be applied for inhibiting cell proliferation.

EFFECT: higher efficiency of inhibition.

11 cl, 1 dwg, 2 ex, 3 tbl

FIELD: veterinary science.

SUBSTANCE: on should apply 1-(ethoxy)sylatrane as a stimulating agent for reproductive capacity in female furred animals and viability of their offspring. The innovation enables to improve reproductive function in females and viability of whelps.

EFFECT: higher efficiency.

3 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: method involves carrying out hernia removal in intralaminar way. Posterior longitudinal ligament defect is covered with Tacho-Comb plate after having done disk cavity curettage. Subcutaneous fat fragment on feeding pedicle is brought to dorsal surface of radix and dural sac.

EFFECT: enhanced effectiveness of treatment; reduced risk of traumatic complications.

1 dwg