[1,2,4]-dithiazoli(di)ne derivatives, glutathione-s-transferase and nadph: quinone-oxidoreductase for prevention and treatment of unfavourable states associated with cytotoxicity in whole and apoptosis particularly

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I): wherein dashed lines present single or double bonds, and the values of radicals R1, R2, R3, R4 are described in cl. 1 of the patent claim. Besides the invention refers to application and a based pharmaceutical composition for prevention and treatment of neurodegenerative diseases and other diseases wherein cell dystrophy and/or cell loss (apoptosis) caused by free radicals act the main part.

EFFECT: production of new compounds and the based pharmaceutical composition which can find application in medicine for prevention and treatment of neurodegenerative diseases.

6 cl, 3 ex

 

The present invention relates to derivatives of 5-imino-5H-[1,2,4]-dithiazole-3-yl-amine and [1,2,4]-dithiazole-3,5-diligen-diamine as inducers of glutathione-S-transferase (GST) and NADPH:quinone oxidoreductase (NQO), to methods of producing these compounds and to novel intermediate compounds useful in the synthesis of the aforementioned derivatives of [1,2,4]-dithiazole(di). The invention also relates to the use of compounds disclosed in this application, to obtain (production) of the medicinal product, giving favorable (positive) effect. The positive effect disclosed in this application or obvious to the person skilled in the art from the description and known knowledge in this area. The invention also relates to the use of compounds of the invention for receiving (production) drugs for treating or preventing the disease or condition. More specifically, the invention relates to a new use for the treatment of a disease or condition, opened in this application or obvious to the person skilled in the art from the description and known knowledge in this area. In embodiments of the invention specific compounds with a specific mechanism of action disclosed in this application, is used to obtain the medicines useful for the prevention and treatment of adverse conditions associated with what ototoksicnosti in General and apoptosis in particular.

Apoptosis is strongly associated with morphogenesis and histogenesis in the development process, and are involved in maintaining homeostasis and in the bio-protection (defensive), and represents the death of cells that have an important role in maintaining the lifespan of an individual. When the process of destruction of regulated genes, impaired innate or after birth, apoptosis is excessively induced or inhibited, which causes functional disorders in various organs and, respectively, of the disease. Drugs showing inhibitory activity against apoptosis, can be used as a means of prevention and treatment of diseases that are believed to be due to activation of apoptosis.

The aim of the present invention was to develop anti-apoptotic compounds with mechanisms of action different from any of the mechanisms known in this field.

Unexpectedly, it was found that derivatives of [1,2,4]-dithiazole(di)are inducers of glutathione-S-transferase (GST), NADPH:quinone oxidoreductase (NQO), and other enzymes in the control (regulation) "antioxidant responsive element (ARE). Full regulation of the activity of these enzymes can have positive effects in the treatment of neurodegenerative diseases and other diseases, which play a decisive role on the agreed free radicals dystrophy cells and/or death of cells. The invention relates to compounds of General formula (I):

in which

the dotted line between carbon atom 5 and the adjacent nitrogen atoms represent a single or double bond, provided that one of these two relations is a single bond and the other is a double bond, provided that when the double bond is between carbon atom 5 and the nitrogen atom n 4, R4 is absent, and when the double bond is between carbon atom 5 and a nitrogen atom in the Exo-position, R2 is absent,

R1, R2, R3 and R4 independently represent a branched or unbranched alkyl (C1-4)group, optionally containing sulfur atoms or sulfoxide, amide, ketone, thioketone or sulfonic groups and optionally substituted with halogen, cyano, mono - or dialkyl(C1-4)amino, trifluoromethyl, (C1-4)alkoxygroup or hydroxyl, or

R1 and R2 together with the nitrogen atom to which they are attached, form a 4-8-membered ring system, which may be present other (substituted) heteroatoms selected from N, O and S, and where this ring system may be optionally substituted branched or non-branched alkyl(C1-4), halogen, cyano, mono - or dialkyl(C1-4)amino group, by trifluoromethyl, (C1-4)alkoxygroup or hydroxyl, or where this ring system contains amide, ketone, thioketone, sulfonic or sulfoxide functional groups,

R3 represents hydrogen, a branched or unbranched alkyl(C1-4) group, optionally containing sulfur atoms or sulfoxide, amide, ketone, thioketone or sulfonic groups and optionally substituted with halogen, cyano, mono - or dialkyl(C1-4)amino, trifluoromethyl, (C1-4)alkoxygroup, S-alkyl(C1-4), SH or hydroxyl, or

R3 represents an aryl group, optionally substituted branched or non-branched alkyl(C1-4), aryl, alkyl(C1-4)aryl group, SH, S-alkyl(C1-4), halogen, cyano, mono - or dialkyl(C1-4)amino group, a group of CF3group OCF3, SCF group3, a nitro-group, a hydroxy-group or (C1-4)alkoxygroup, and their tautomers, stereoisomers and N-oxides, and pharmaceutically acceptable salts, hydrate and solvate mentioned compounds of formula I and their tautomers, stereoisomers and N-oxide.

Such compounds are new and are inducers of glutathione-S-transferase (GST), NADPH:quinone oxidoreductase (NQO).

The invention relates to racemates, mixtures of di is Stereolab, as well as the individual stereoisomers of the compounds having formula (I). In the description of the substituents reduction 'is alkyl(C1-4)' means 'methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl or 2-methyl-n-propyl'. 'Aryl' means furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolin, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, phenyl, indazoles, indolyl, indolizinyl, isoindolyl, gasoline[b]furanyl, benzo[b]thiophenyl, benzimidazolyl, benzothiazolyl, purinol, chinoline, ethanolic, hinely, phthalazine, hintline, honokalani, 1,8-naphthyridine, pteridine, naphthyl or azulene, preferably phenyl, pyridyl or naphthyl. 'Optionally substituted' means that the group may or may not be further substituted by one or more groups specified.

Prodrugs of the compounds mentioned above are included in the scope of the present invention. Prodrugs are therapeutic agents that are inactive by themselves, but which are transformed into one or more active metabolites. Prodrugs are bio-reversible derivatives of drug molecules that are commonly used to overcome some of the barriers to expression (extraction) use the parent drug molecule. Such barriers include RA is torimoto, permeability, stability, presystemic metabolism and constraints in achieving the targets, but are not limited to (Medicinal Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed.: F.D. King, p.215; J. Stella, "Prodrugs as therapeutics", Expert Opin. Ther. Patents, 14(3), 277-280, 2004; P. Ettmayer et al., "Lessons learned from marketed and investigational prodrugs", J. Med. Chem., 47, 2393-2404, 2004). Prodrugs, i.e. compounds that when administered to humans by any known included in the exchange, into compounds having the formula (I)are part of the invention. This applies in particular to compounds with primary or secondary amino or hydroxy groups. Such compounds can be subjected to reaction interaction with organic acids, which gives the compounds having formula (I), in which there is an additional group that is easily removed after the introduction, for example amidin, enamine, the basis of manniche, hydroxymethylene derived, O-(acyloxymethyl-carbamate)-derivative, carbamate, ester, amide or enamine, but are not limited to this.

N-oxides of the compounds mentioned above are included in the scope of the present invention. Tertiary amines can lead or not to lead to N-oxide metabolites. The degree to which N-oxidation varies from trace amounts to almost quantitative conversion. N-oxides can be more active than them with the corresponding tertiary amines, or less active. Then as N-oxides are easily reduced to their corresponding tertiary amines by chemical means, in humans this occurs in varying degrees. Some N-oxides are almost quantitative recovery transformation into the corresponding tertiary amines, in other cases the transformation is barely detectable reaction or even completely absent. (M.H.Bickel: "The pharmacology and Biochemistry of N-oxides"That Pharmaco-logical Reviews, 21(4), 325-355, 1969).

The invention especially relates to compounds of General formula (Ia):

in which

R1 and R2 independently represent a branched or unbranched alkyl(C1-4) group, optionally containing sulfur atoms or sulfoxide, amide, ketone, thioketone or sulfonic groups and optionally substituted with halogen, cyano, mono - or dialkyl(C1-4)amino, trifluoromethyl, (C1-4)alkoxygroup or hydroxyl, or

R1 and R2 together with the nitrogen atom to which they are attached, form a 4-8-membered ring system, which may be present other (substituted) heteroatoms selected from N, O and S, and where this ring system may be optionally substituted branched or non-branched alkyl(C1-4), halogen, qi is nography, mono - or dialkyl(C1-4)amino, trifluoromethyl, (C1-4)alkoxygroup or hydroxyl, or where this ring system contains amide, ketone, thioketone, sulfonic or sulfoxide functional groups,

R3 represents hydrogen, a branched or unbranched alkyl(C1-4) group, optionally containing sulfur atoms or sulfoxide, amide, ketone, thioketone or sulfonic groups and optionally substituted with halogen, cyano, mono - or dialkyl(C1-4)amino, trifluoromethyl, (C1-4)alkoxygroup, S-alkyl(C1-4), SH or hydroxyl, or

R3 represents an aryl group, optionally substituted branched or non-branched alkyl(C1-4), aryl, alkyl(C1-4)aryl group, SH, S-alkyl(C1-4), halogen, cyano, mono - or dialkyl(C1-4)amino group, a group of CF3group OCF3, SCF group3, a nitro-group, a hydroxy-group or (C1-4)alkoxygroup.

To a greater extent, the invention relates to compounds of General formula (Ia), in which:

R1 and R2 independently represent a branched or unbranched alkyl(C1-4) group, or R1 and R2 together with the nitrogen atom to which they are attached, form a 5-6-membered ring system in which to logoutresultevent oxygen atoms, and, where this ring system may be optionally substituted branched or non-branched alkyl(C1-4),

R3 represents an aryl group, optionally substituted branched or non-branched alkyl(C1-4), aryl, alkyl(C1-4)aryl group, SH, S-alkyl(C1-4), halogen, cyano, mono - or dialkyl(C1-4)amino group, a group of CF3group OCF3, SCF group3, a nitro-group, a hydroxy-group or (C1-4)alkoxygroup.

Still more, the invention relates to compounds of General formula (Ia), in which:

R1 and R2 independently represent a methyl group, or R1 and R2 together with the nitrogen atom to which they are attached, form a 5-6-membered ring system which may contain one oxygen atom, and where this ring system may be optionally substituted methyl group,

R3 represents phenyl or pyridyloxy group, optionally substituted branched or non-branched alkyl(C1-4), a benzyl group, SH, SCH group3, halogen, cyano, a group of CF3group OCF3, SCF group3, a nitro-group, a hydroxy-group or a methoxy group.

In particular, the invention relates to compounds of General formula (Ib)

in which

R1, R3 and R4 independently represent a branched or unbranched alkyl(C1-4) group, optionally containing sulfur atoms or sulfoxide, amide, ketone, thioketone or sulfonic groups and optionally substituted with halogen, cyano, mono - or dialkyl(C1-4)amino, trifluoromethyl, (C1-4)alkoxygroup or hydroxyl, or

aryl group, optionally substituted branched or non-branched alkyl(C1-4), aryl, alkyl(C1-4)aryl group, SH, S-alkyl(C1-4), halogen, cyano, mono - or dialkyl(C1-4)amino group, a group of CF3group OCF3, SCF group3, a nitro-group, a hydroxy-group or (C1-4)alkoxygroup.

And to a greater extent, the invention relates to compounds of General formula (Ib), in which:

R1, R3 and R4 independently represent a branched or unbranched alkyl(C1-4) group or aryl group, optionally substituted branched or non-branched alkyl(C1-4), aryl, alkyl(C1-4)aryl, halogen, a group of CF3group OCF3, SCF group3, a nitro-group, a hydroxy-group or a methoxy group.

Still more, the invention relates to compounds of General formula (Ib), in which:

R1, R3 and R4 is independently researched the Simo represent a methyl group or phenyl group, optionally substituted branched or non-branched alkyl(C1-4), halogen, a group of CF3group OCF3, hydroxy-group or a methoxy group.

COMMON FEATURES of SYNTHESIS

Compounds with the General formula (Iaor (Ibcan be obtained in accordance with the three methods (scheme A.1, B.1 and C.1):

The choice of specific methods of synthesis depends on factors known to specialists in this field, such as the compatibility of functional groups with the reagents, the use of protective groups, catalysts, activating reagents and reagents for the reaction combinations, and structural features, the ultimate connection that I receive.

Pharmaceutically acceptable salts may be obtained using standard methods, well known in this field, for example, by mixing the compounds of the present invention with a suitable acid, for example with inorganic acid, such as hydrochloric acid or organic acid.

Compounds of the invention of General formula (I)and their salts are inducible glutathione-S-transferase (GST), NADPH:quinone oxidoreductase (NQO), and other enzymes in the regulation of the antioxidant choose what to say the active element (ARE). Full control (regulation) of the activity of these enzymes can have positive effects in the treatment of neurodegenerative diseases and other diseases, in which a crucial role is played by free radicals dystrophy cells and/or death of cells (apoptosis). Compounds of the invention are active at doses in the range 0.1-100 mg/kg after oral administration and are useful for the prevention and treatment of adverse conditions associated with apoptosis. The above condition represents, for example, neurodegenerative disorders, such as, for example, ischemic stroke, traumatic brain injury, acute disseminated encephalomyelitis, amyotrophic lateral sclerosis (ALS), pigmentary retinal degeneration, mild cognitive impairment, Alzheimer's disease, pseudoceros liver Peak, senile dementia, a syndrome of progressive supranuclear palsy, subcortical dementia, disease, Wilson-Konovalov), multiple heart attacks, arteriosclerotic dementia, AIDS-related dementia, spinal cerebellar degeneration, spinocerebellar syndromes retinal degeneration, ataxia, ataxia-telangiectasia, brain damage associated with epilepsy, spinal cord injury, tired leg syndrome, Huntington's disease and disease P is arkinson, degeneration of the striatum (the striatum nigrum), cerebral vasculitis, mitochondrial, encephalo-myo, neuronally ceroid-lipofuscinosis, spinal muscular atrophy (illness werdnig of Hoffmann), lysosomal storage disorders involving the Central nervous system, leukodystrophy, violations of the cycle of the formation of urea, hepatic encephalopathy, renal encephalopathy, metabolic encephalopathy, porphyria, bacterial and viral meningitis and encephalitis, prion diseases, poisoning/intoxication neurotoxic compounds syndrome Gillain Barre, chronic inflammatory neuropathy, polymyositis, dermatomyositis, brain damage caused by radiation exposure; irritable bowel syndrome and inflammatory bowel disease, granulomatous enteritis and ulcerative colitis, a disease of the abdomen, perigastric (gastritis pylorus of the stomach) Helicobacter and other infectiousgastritis, necrotizing enterocolitis, pseudomembranous enterocolitis enterocolitis caused by radiation exposure, lymphocytic gastritis, graft versus host disease, acute and chronic pancreatitis; liver disease, such as alcoholic hepatitis, viral hepatitis, metabolic hepatitis, autoimmune hepatitis, hepatitis caused by radiation is radiation, cirrhosis, hemolytic uremic syndrome, glomerulonephritis, Leposavic, viral diseases such as fulminant hepatitis; diseases of the joints, such as injury and osteoarthritis; immunosuppression or immunodeficiency, particularly autoimmune diseases such as idiopathic inflammatory myopathy, chronic neutropenia, thrombocytopenic thromboembolitic purpura, rheumatoid arthritis, idiopathic thrombocytopenic purpura, autoimmune hemolytic syndromes, antiphospholipid syndrome, myocarditis, multiple sclerosis and its diagnostic sub-classification: for remitting multiple sclerosis, secondary progressive multiple sclerosis, primary progressive multiple sclerosis, progressive relapsing multiple sclerosis, acute disseminated sclerosis, benign relapsing multiple sclerosis or asymptomatic multiple sclerosis, neuroptimal (syndrome)), lymphocytic hipofisis, diffuse goiter thyroid, Addison's disease, hypoparathyroidism, type 1 diabetes, systemic lupus erythematous, vulgar pemphigus, bullous pemphigoid, psoriatic arthritis, endometriosis, autoimmune orchitis, autoimmune erectile dysfunction, sarcoidosis, Wegener's granulomatosis, autoimmune deafness syndrome SEG the s-Larsson, autoimmune uveoretinitis, interstitial cystitis syndrome? and fibromyalgia; myelodysplasia, such as aplastic anemia; dermatological diseases, including pemphigus vulgaris, dermatomyositis, atopic dermatitis, purple Seleina's disease, acne, systemic sclerosis, seborrheic keratosis, cutaneous mastocytosis, chronic proliferative dermatitis, diskeratoz, scleroderma, interstitial granulomatous dermatitis, psoriasis, bacterial skin infections, fungal skin diseases, leprosy, cutaneous leishmaniasis, vitiligo, toxic epidermal necrolysis syndrome Steven Johnson, adenoma sebaceous glands, alopecia, photodamage skin white spot disease, deep skin wounds, incontinence of pigment, thermal damage to the skin, exanthematous pustules, lichenoid dermatosis, skin allergic vasculitis, cytotoxic dermatitis, diseases of the inner ear, such as, for example, caused by ecotravel cell death auditory hair and hearing loss caused by aminoglycoside cell death auditory hair and hearing loss, hearing loss caused by ototoxic medication, perilymphatic fistula, cholesteatoma, cochlear or vestibular ischemia, Meniere's disease, hearing loss caused by radiation exposure, hearing loss, caused by bacterial or viral infections, and ID is opatijska hearing loss; after transplantation: graft-versus host disease, acute and chronic rejection of transplanted organs: heart, lung, kidney, skin, cornea, bone marrow or liver disease; wound healing and the rejection reaction of a transplanted tissue.

PHARMACEUTICAL

Compounds of the invention can be converted into a form suitable for administration by conventional methods using auxiliary substances such as liquid or solid carrier material. The pharmaceutical compositions of the invention can be introduced inside (enterline), orally, parenterally (intramuscularly or intravenously), rectally or locally (topically). They can be introduced in the form of solutions, powders, tablets, capsules (including microcapsules), ointments (creams or gels or suppositories. Suitable excipients for such compositions are pharmaceutically commonly used solid or liquid fillers and diluents, solvents, emulsifiers, lubricants, flavouring agents, colouring agents and/or substances for the buffer solution. Commonly used excipients that can be specified are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars or sugar alcohols (alidity), talc, milk protein (lactoprotein), gelatin, starch, C is llulose and its derivatives, animal and vegetable oils, such as olive oil fish liver oil, sunflower oil, peanut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and one - or polyhydric alcohols, such as glycerin.

Compounds of the present invention, usually administered in the form of pharmaceutical compositions, which constitute an important and new ways of carrying out the invention due to the presence of compounds, in particular compounds with a specific mechanism of action disclosed in this application. Types of pharmaceutical compositions that may be used include tablets, chewable tablets, capsules, solutions, solutions for parenteral administration, suppositories, suspensions and other types disclosed in this application or obvious to the person skilled in the art from the description or from the known knowledge in this area, but are not limited to this. In embodiments of the invention provide a pharmaceutical pack or kit comprising one or more containers filled with one or more ingredients of the pharmaceutical compositions of the invention. Complete with so(s) container(s) can be various paper information, such as instructions for use, or note in the form adopted by the government established the eat, which regulates the manufacture, use or sale of pharmaceutical products, where the notice reflects approval by the institution to manufacture, use or sale for the introduction of a human or animal.

PHARMACOLOGICAL METHODS

Spectrophotometric determination of induction of EC 2.5.1.18 (GST)

Cells of rat PC-12 and incubated for 24 hours with the test compound. The GST activity was measured using 1-chloro-2,4-dinitrobenzene (CDNB) and glutatione (GSH) as substrates (substrates). The enzyme catalyzes the reaction converting these substrates in the S-(2,4-dinitrophenyl)glutathione - product, which is determined spectrophotometrically at 340 nm. The effect of test compounds is expressed as RES50: the negative logarithm of the molar concentration of compound that causes 50% induction of enzyme activity. Also determine the maximum percentage of enzyme induction (seeDrukarchet al. "Anethole dithiolethione prevents oxidative damage in gluthathione-depleted astrocytes", Eur. J. Pharmacol., 329, 259-262, 1997).

Spectrophotometric determination of induction of EC 1.6.99.2 (NQO)

Cells of rat PC-12 and incubated for 24 hours with the test compound. The activity of NAD(P)H oxidoreductase (NQO, EC 1.6.99.2) is measured with the use of menadione (vitamin K3) as substrate and MTT as an indicator of the connection. Education is their formazane of MTT determined spectrophotometrically at 540 nm. The percentage stimulation (PS) is calculated relative to the maximum action reference compound D3T. Record the maximum percentage (level) stimulation with a concentration that caused this maximum percentage and is Rea50(the negative logarithm of the molar concentration of the compound that caused half-maximal induction of enzyme activity equal to the reference connection D3T) (seeMurphyet al., "Enhanced NAD(P)H: Quinone reductase activity defenses in neuronal cells prevents free radical-mediated damage", J. Neurochem., 71, 69-77, 1998 and Prochaskaet al., Analytical Biochemistry, 169, 328-336, 1988).

DOSE

The effectiveness of compounds of the invention as inducers of glutathione-S-transferase (GST), NADPH:quinone oxidoreductase (NQO) is determined as described above. From the measured efficiency for the compounds of formula (I) can be estimated theoretical, the lowest effective dose. When the concentration of the compound that is twice as large, the measured value of the enzymatic activity of the EU50will probably be doubled. The translation of this concentration in mg compound per kg of patient's weight gives the lowest theoretical effective dose, assuming a perfect (complete) bioavailability (of bioavailability). Pharmacokinetic, pharmacodynamic and consider other factors may change the dose, specifically introduced in the direction Bolshoye smaller values. It is advisable entered the dosage is 0.001-1000 mg/kg, preferably 0.1 to 100 mg/kg body weight of the patient.

TREATMENT

The term "treatment"as used in this application, refers to any kind of treatment of a condition or disease of a mammal, preferably a human, and includes: (1) preventing the disease or condition in a subject which may be predisposed to the disease but has not yet been diagnosed in his presence, (2) inhibiting the disease or condition, i.e. stop/delay its development, (3) relieving the disease or condition, i.e. the achievement of regression (return) status, or (4) removal of conditions caused by disease, or termination manifestations of symptoms.

EXAMPLES

EXAMPLE 1: materials AND METHODS

All reactions involving compounds that are sensitive to moisture, carried out in dry nitrogen atmosphere. All other commercially available chemicals used without additional purification. The reaction is controlled by using thin-layer chromatography (TLC) on plastic plates coated with silica gel (Merck silica gel 60 F254)with the indicated eluent. Connection visualize by UV light (254 nm) or by I2. Flash chromatography refers to the cleaning of the specified ale the NTA and Acros silica gel (0,030-0.075 mm). The spectra of nuclear magnetic resonance (1H NMR) determined in the indicated solvent. Constant interaction J are given in Hz. The shape of the peaks in the NMR spectra indicate the character 'q' (Quartet), 'dq' (double Quartet), 'bs' (broad singlet) and m (multiplet).

EXAMPLE 2: Synthesis of specific compounds with a specific mechanism of action

The WAY of SYNTHESIS:

Used thiocarbanilide are either available commercially or by methods described in the publication Gordeleret al.,Chem.Ber., 103(1970)3393 and von Braunet al.,Berichte Deutsche Chem. Ges., 36(1903)2274.

The connection A2:

Procedure a (figure A.1) stage i+ii:

of 12.3 grams (99 mmol) of N,N-dimethylthiocarbamate dissolved in 60 ml of acetonitrile. Under stirring, the reaction mixture was added a solution of 9.9 g (99 mmol) of isothiocyanate potassium (KSCN) in 180 ml of acetonitrile. The mixture is then heated to the boiling point, after which boiling under reflux continued for three minutes. Then the reaction mixture was added to a stirred solution of 13.5 grams (90 mmol) of 4-n-butyl-aniline in 100 ml of acetonitrile. The last mixture is stirred for a short time, after which the solvent is removedinthe vacuum. Add water, in the presence of residual oil becomes solid. The mixture of the solid/water turn in WM is enzio, after which it is filtered. The residue is washed with water, then a small amount of isopropanol, and then leave it to dry. Crude yield 24.4 g (92%). Recrystallization from isopropanol (approximately 200 ml) gives of 16.7 grams (63%) of the corresponding dithiobiuret, melting point (t..) to 89.5-91°C.1H NMR (90 MHz, d6-DMSO) δ (ppm (ppm)): 0,93 (t, 3H), 1,15-2,05 (m, 4H), 2,61 (t, 3H), 3,35 (C, 6N), 7,18 (d, 2H), 7,55 (d, 2H), 9,79 (s, 2H).

The method of A1 (figure A.1) stage iii+iv:

of 11.8 grams (40 mmol) of pre-cooked dithiobiuret dissolved in 300 ml of alcohol. With stirring a solution containing of 13.5 grams of iodine (53.2 mmol) and 16.7 of potassium iodide (100 mmol) in 20 ml of water, until, while not disappear staining with iodine. The solution is allowed to stand, the formation of crystals. The mixture is filtered, the residue is washed with alcohol, isopropanol and petroleum ether, giving a 13.4 grams (80%) salt itestosterone acid.Stage ivto 10.5 grams of the latter substances suspended in water (250 ml) and with stirring, add 14 ml of 2n. the solution of KOH. After 1.5 hours, the suspension is filtered, the residue is washed with water, a small amount of isopropanol and petroleum ether, giving a 6.5 grams. The last number is recrystallized from 100 ml of naphtha, which gives 3.3 g (45%) of pure product A2 in the form freedoms is wow grounds. The melting temperature (t..) 81-82,5°C.1H NMR (90 MHz, CDCl3) δ (ppm): 0,93 (t, 3H), 1,1-1,9 (m, 4H), 2,60 (t, 2H), 3,35 (C, 6N), 6,94 and 7,16 (DD, 4H).

Connection A19:

Procedure a (figure A.1) stage i-iv:

2 g (16.3 mmol) of dimethylthiocarbamate and 1.58 grams KNCS (16.3 mmol) suspended in acetonitrile and heated to the boiling temperature under reflux for 2 minutes using a jet air dryer (hair dryer). To the resulting hot mixture of 1.97 g (16.3 mmol) of (2,6-dimethylaniline in 10 ml of acetonitrile. After 1 hour the mixture is filtered and the filtrate concentrated. The resulting oil containing dithiobiuret, dissolved in 40 ml of ethanol and add a solution of 6.7 grams of iodine and 8.4 grams of potassium iodide in 20 ml of water as long as the solution does not change its color. Stirring is continued for 1 hour, after which the reaction mixture is filtered, the residue is washed with water, 2M KOH solution and again with water. Then the residue was washed with diethyl ether and allowed to dry, giving 2.2 g (49%) of free base A19 in the form of a yellowish solid. The melting temperature (t..) 236,3-239,2°C (DSC - differential scanning calorimetry).1H NMR (200 MHz, d6-DMSO) δ (ppm): 2.26 and (C, 6N), to 2.57 (s, 6N), 7,16 was 7.45 (m, 4H). Mass spectrometry (Cl): (M++1):266.

In accordance with the synthesis, preveden the m above get connection A1-A22 (table a), General formula (1and):

ConnectionR1R2R3Melting point, °C
A1MeMePh216 (Razlog.)
A2MeMe4-(n-But)-Ph81-82,5
A3MeMe4-MeO-Phof 129.5-131, 5mm
A4MeMe3-Cl-Ph113-114,5
A5MeMe2,6-(di-Cl)-Ph191,5-of 193.5
A6Me Me3-NO2-Ph134,5 to 136.5
A7-(CH2)4-Ph149-151,5
A8-(CH2)2O(CH2)2-Ph175,5-176,6
A9MeMe2-Me-Phon 138.5-140
A10MeMe4-NO2-Ph170-171,5
A11MeMe4-F-Ph137-138,5
A12MeMe2-(i-Pr)-Phto 194.6-197,5
A13MeMe2-F-Phto 126.8-128,2
A14MeMe 2-MeS-Ph119,4 to 120.3
A15MeMe3-Me-Ph201-204
A16MeMe2-Et-Phof 177.8-184
A17MeMe2-MeO-Ph148,5-152
A18MeMe2-CF3-Ph129,1-130, 8mm
A19MeMe2,6-(di-Me)-Ph236,3-239,2
A20MeMe2-pyridyl166-173
A21MeMe2-benzyl-Ph176-182
A22MeMe3-pyridyl83-90

(in all cases, the connections get in the form of free bases, except for A1, which is obtained as a salt itestosterone acid (mono-hydroiodide). Abbreviations stand for:IU= methyl;Ph= phenyl;Et= ethyl;But= butyl;i-Pr= ISO-propyl;)

The WAY of SYNTHESIS:

Compound B4:

Procedure b (figure B.1) stage i+ii:

10 g (56 mmol) of thiocarbonyldiimidazole dissolved in tetrahydrofuran (THF) (400 ml). Add 4,78 grams (56 mmol) of piperidine and stirred at 50°C for 3 hours. The mixture was partially concentrated and then mixed with 500 ml of 7n. solution of NH3in methanol, after which it is placed in a sealed vessel overnight at 45°C. At room temperature the reaction mixture was partially concentrated, then its cool. The precipitate, containing a derivative of thiourea, collected and dried, giving 1.3 g (16%) as a gray solid.

Procedure b (figure B.1) stage iii+iv:

1 gram (6,85 mmol) derived urea previous stage is dissolved in 40 ml of acetonitrile, and then add 500 mg of powdered KOH and the mixture is stirred for 30 minutes at room temperature. Then add 1.02 grams (6,85 mmol) 2-methylphenylethylamine and the reaction mixture is stirred for 2 hours. The mixture is filtered and the filtrate concentrated. Get the Eesa resulting oil is dissolved in ethanol (40 ml) and add a solution of 6.7 grams of iodine and 8.4 grams of potassium iodide in 20 ml of water until while the solution does not change its color. Stirring is continued for 1 hour, then the reaction mixture is filtered, the residue is washed with water, 2M KOH solution and again with water. Then the residue was washed with diethyl ether and allowed to dry, giving 781 mg (39%) of free baseB4as not quite white solid. The melting temperature (t..) 104,3-to 112.2°C (DSC - differential scanning calorimetry).1H NMR (200 MHz, d6-DMSO) δ (ppm): 1.77 in (C, 6N), 2,31 (s, 3H), of 3.78 (broad, 4H), 6,95-7,40 (m, 4H). Mass spectrometry (Cl): (M++1):292.

In accordance with the synthesis described above, receive connections B1-B16 (table V), the General formula (1A):

Connection.R1 and R2R3Melting point, °C
B1-(CH2)2O(CH2)2-2-Me-Ph139-142
B2-(CH2)4-2-Me-Phto 126.8-128
B3-(CH2)2NMe(CH2)2-2-Me-Ph134142
B4-(CH2)5-2-Me-Phthe 104.3-to 112.2
B5-(CH2)2O(CH2)2-3-Me-Ph217-226
B6-(CH2)2O(CH2)2-2-MeO-Ph160-164
V7-(CH2)2O(CH2)2-2-F-Ph144-149
B8-(CH2)2O(CH2)2-2-CF3-Ph138-140,5
B9-(CH2)2O(CH2)2-2-MeS-Ph160-168
10-(CH2)2O(CH2)2-2-Et-Ph195,6
B11-(CH2)2S(CH2)2-2-Et-Ph145, 2mm
B12-(CH2)2S(CH2)2-2-F-Ph178,7
B13-CH2-CH(CH3)OCH(CH3)-CH2-2-Et-Phof 182.2-188,1
B14-CH2-CH(CH3)OCH(CH3)-CH2-2-F-Ph199,4-the amount of 203.9
B15-CH2-CH(CH3)OCH(CH3)-CH2-2-MeO-Ph193,4-196,5
B16-(CH2)2O(CH2)2-179,5-183

(in all cases, the connections get in the form of free bases)

The WAY of SYNTHESIS:

Compound C10:

The methodology (figure C.1) stage i:

With stirring, 3.4 grams (a 32.6 mmol) was dissolved in 100 ml of acetonitrile, and then add 1.3 g (a 32.6 mmol) of powdered NaOH. Stirring is continued for 3 hours. Then add 5 grams (a 32.6 mmol) 4-perteneciente, after this mixture is allowed to react throughout the night. Add water and tert-butyl IU the silt ether (TBME), and 5 ml of concentrated hydrochloric acid. After stirring/shaking two-phase mixture, the organic layer is separated and concentratedin the vacuum. The rest move in toluene and filtered. Allocated oily substance and it is removed from the filtrate. The filtrate was concentrated in vacuo, the residue is move in TBME and 1M NaOH solution. The aqueous layer was washed through TBME three times. Then the aqueous layer was acidified with concentrated hydrochloric acid, then extracted through TBME (3×).

The combined organic fraction was concentrated in vacuo, giving 2.5 g (30%) derived dithiobiuret in the form of a yellow solid.

The method of C1 (figure C.1) stage ii:

2.5 g (9.7 mmol) of dithiobiuret prepared at stage i, is dissolved in 80 ml of dichloromethane, and to this is added dropwise a solution of 0.5 ml (9.8 mmol, density = cash consideration of USD 3,119 g/ml) of bromine in 20 ml of dichloromethane. The reaction mixture is stirred for 30 minutes and the precipitate formed is filtered off. The residue was washed with dichloromethane and TBME and then leave to dryin the vacuumthat gives a 1.8 grams of an orange solid. The latter is suspended in dichloromethane and treated by 4,21 ml (30 mmol, 3 EQ., density = 0,72 g/ml) of triethylamine, all is stirred for 30 minutes. The reaction mixture is washed with water, the (3×), after that, the organic layer concentratedin the vacuum. The residue is recrystallized twice from ethanol, giving 275 mg (11%) of yellow product C10. The melting temperature (t..) 81,2-84,4°C (DSC - differential scanning calorimetry).1H NMR (200 MHz, CDCl3) δ (ppm): 3,26 (s, 3H), of 3.57 (s, 3H), 6,95-7,20 (m, 4H).

In accordance with the synthesis described above, receive connections C1-C11, the General formula (1b) (table a):

ConnectionR1R4R3Melting point, °C
C1MeMeMe100-102
C2MeMePh80-82
C3MeMe4-Me-Ph100-101,4
C4Me Me4-Me-Phof 113.2-114,5
C5MeMe2-(I-Pr)-Ph80,5-82 and 293-296
C6MeMe2-MeO-Ph85,7-88,6 and 291-296
C7MeMe4-MeO-Ph54,6-56,2 and 286-295
C8MeMe2-Cl-Ph92,5-to 95.3
C9MeMe2,6-(di-Cl)-Ph82,8-83,8
C10MeMe4-F-Ph81,2-84,4
C11MeMe3-F-Pha 76.5 77.6 in

(in all cases, the connections get in the form of free bases)

Specific connections with specific mechanics is the PTO's actions, the synthesis of which is described above, is designed to further illustrate the invention, and, therefore, believe that they do not limit the scope of the invention in any way. Other embodiments of the invention will be obvious to experts in this area from consideration of the description and practical use of the invention disclosed in this application. Thus understood that the description and examples should be considered only as illustrations, and the true scope and essence of the invention defined by the claims.

EXAMPLE 3: the COMPOSITION of the a10 CONNECTION

For oral(p.o.)introduction: the desired quantity (0.5 to 5 mg) solid connections a10 in a glass flask and add a few glass beads and the solid is crushed by shaking/stirring for 2 minutes. After adding 1 ml of 1% solution of methylcellulose in water, and 2 (about./about.) poloxamer 188 (Lutrol F68) connection is suspended by shaking/stirring for 10 minutes. the pH is brought to 7 with a few drops of an aqueous solution of NaOH (0,1N.). The remaining particles in suspension additionally suspended when using ultrasonic baths.

For intraperitoneal(I.P. Pavlova.)introduction:the desired amount (0.5 to 15 mg) solid connections a10 in glass number is e add a few glass beads and the solid is crushed by shaking/stirring for 2 minutes. After adding 1 ml of 1% methylcellulose and 5% mannitol in water connection is suspended by shaking/stirring for 10 minutes. At the end of the pH adjusted to 7.

EXAMPLE 4: the RESULTS of PHARMACOLOGICAL TESTS

Some data on enzyme induction, obtained in accordance with the protocols described above, are shown in the table below.

ENZYMATIC INDUCTION
GSTNQO
ConnectionRES50REA50
A25,25,2
A10of 5.45,8
B55,3the 5.7
C2 5,86,2
C35,8the 5.7
C115,65,3

1. Compounds of General formula (I)

in which the dashed lines provide a single or double bond, selected from the group consisting of compounds having the following substituents:

CH3
R1R2R3R4
CH3CH32-pyridyl-
CH3CH33-pyridyl-
CH3CH32-F-phenyl-
CH3CH32-CH3-phenyl-
CH32-CF3-phenyl-
CH3CH32-CH3CH2-phenyl-
CH3CH32-(i-Pr)-phenyl-
CH3CH32-CH3O-phenyl-
CH3CH32-CH3S-phenyl-
CH3CH32-benzyl-phenyl-
CH3CH32,6-Cl2-phenyl-
CH3CH32,6-(CH3)2-phenyl-
CH3CH33-Cl-phenyl/td> -
CH3CH33-CH3-phenyl-
CH3CH33-NO2-phenyl-
CH3CH34-F-phenyl-
CH3CH34-CH3O-phenyl-
CH3CH34-(n-Bu)-phenyl-
-(CH2)4-Phenyl-
-(CH2)4-2-CH3-phenyl-
-(CH3)5-2-CH3-phenyl-
-(CH2)2O(CH2)2-Phenyl-
-(CH2)2O(CH2)2-2-F-phenyl-
-(CH2)2O(CH2)2-2-CH3-phenyl-
-(CH2)2O(CH2)2-2-CF3-phenyl-
-(CH2)2O(CH2)2-2-CH3CH2-phenyl-
-(CH2)2O(CH2)2-2-CH3O-phenyl-
-(CH2)2O(CH2)2-2-CH3S-phenyl-
-(CH2)2O(CH2)2-3-CH3-phenyl-
-(CH2)2O(CH2)2-
-CH2-CH(CH3)Och(CH3)-CH2-2-F-phenyl-
-CH2-CH(CH3)Och(CH3)-CH2-2-CH3O-phenyl-
-CH2-CH(CH3)Och(CH3)-CH2-2-CH3CH2-phenyl-
-(CH2)2S(CH2)2-2-F-phenyl-
-(CH2)2S(CH2)2-2-CH3CH2-phenyl-
-(CH2)2N(CH3)(CH2)2-2-CH3-phenyl-
CH3-ClCH3
CH3-CH3CH3
CH3-2-(i-Pr)-phenylCH3
CH3-2-CH3O-phenylCH3
CH3-2,6-Cl2-phenylCH3
CH3-3-F-phenylCH3
CH3-4-F-phenylCH3

their pharmacologically acceptable salts of the mentioned compounds of the formula (I).

2. The use of compounds of General formula (I)

in which the dotted line between carbon atom 5 and the adjacent nitrogen atoms represent a single or double bond, provided that one of these two relations is a single bond and the other is a double bond, provided that when a double bond finds the Xia between carbon atom 5 and the nitrogen atom n 4, R4 is absent and when the double bond is between carbon atom 5 and the nitrogen atom in anthopology, R2 is absent
R1, R2, R3 and R4 independently represent a branched or unbranched alkyl(C1-4)or
R1 and R2 together with the nitrogen atom to which they are attached, form a 4-8-membered ring system, which may be present other (substituted) heteroatoms selected from N, O and S, and where this ring system may be optionally substituted branched or non-branched alkyl(C1-4), or
R3 represents hydrogen, a branched or unbranched alkyl(C1-4)or
R3 represents an aryl group, optionally substituted branched or non-branched alkyl(C1-4), aryl, alkyl(C1-4)aryl group, SH, S-alkyl(C1-4), halogen, a group of CF3group OCF3, SCF group3, a nitro-group, a hydroxy-group or (C1-4)alkoxygroup, as well as pharmaceutically acceptable salts of the mentioned compounds of the formula (I) to obtain a pharmaceutical composition for the prevention and treatment of neurodegenerative diseases and other diseases, in which a crucial role is played by free radicals dystrophy cells and/or death of cells (apoptosis).

3. The pharmaceutical composition is I for the prevention and treatment of neurodegenerative diseases and other diseases, in which the decisive role is played by free radicals dystrophy cells and/or death of cells (apoptosis), containing, in addition to a pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable auxiliary substance, a pharmacologically active amount of at least one compound claimed in claim 1, or its salt, as an active ingredient.

4. The compound according to claim 1, or its salt for use as a drug for the prevention and treatment of neurodegenerative diseases and other diseases, in which a crucial role is played by free radicals dystrophy cells and/or death of cells (apoptosis).

5. The use of compounds according to claim 1 to obtain a pharmaceutical composition for the prevention and treatment of neurodegenerative diseases and other diseases, in which a crucial role is played by free radicals dystrophy cells and/or death of cells (apoptosis).

6. The use according to claim 2 or 5 where the above-mentioned neurodegenerative diseases are ischemic stroke, traumatic brain injury, amyotrophic lateral sclerosis (ALS), mild cognitive disturbance, Alzheimer's disease, senile dementia, spinal cord injury, tired leg syndrome, Huntington's disease and the disease is of arkinson, the irritable bowel syndrome and inflammatory bowel disease, granulomatous enteritis (Crohn's disease and ulcerative colitis, cirrhosis, rheumatoid arthritis, multiple sclerosis, type 1 diabetes, graft versus host disease, acute and chronic rejection of transplanted organs: heart, lung, kidney, skin, cornea, bone marrow or liver; and the reaction of rejection of the tissue.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula I and to their pharmaceutically acceptable acid addition salts. The compounds of the present invention exhibit the properties of glycine carrier 1 (GlyT-1) inhibitors. In formula I , R1 represents -OR1', -SR1' or morpholinyl; R1' represents lower alkyl, halogen-substituted lower alkyl, or represents -(CH2)n-lower cycloalkyl; R2 represents -S(O)2-lower alkyl, -S(O)2NH-lower alkyl, NO2 or CN; X1 represents CR3 or N; X2 represents CR3' or N; R3/R3' independently represent hydrogen, halogen, lower alkyl, CN, NO2, -S(O)2-phenyl, -S(O)2-lower alkyl, -S(O)2-pyridine-2, 3 or 4-yl, phenyl optionally substituted with one or two substitutes specified from the group consisting of NO2 or halogen, or represent halogen-substituted lower alkyl, or represent -C(O)-lower alkyl; n has a value of 0, 1 or 2. The invention also concerns a drug containing one or more compounds of the invention and pharmaceutically appropriate excipients.

EFFECT: preparation of the compounds exhibiting the properties of glycine carrier inhibitors.

20 cl, 1 tbl, 133 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) , where R1 is selected from group, including: phenyl, unsubstituted or mono-, di- or tri-substituted independently with lower alkyl, lower alkoxy group, halogen or lower halogenalkyl; naphtyl; tetrahydronaphtyl; C3-7cycloalkyl; -(CHR3)m-phenyl, where m stands for 1, 2, or 3; and phenyl is unsubstituted or mono-, di- or tri-substituted with lower alkoxy group, and where R3 is independently selected from hydrogen and lower alkyl; -(CH2)n-heteroaryl, where n stands for 1, 2 or 3; term "heteroaryl" relates to aromatic 5- or 6- member ring or bicyclic 9-member aromatic groups, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur; -(CH2)n-heteroaryl, where n stands for 1, 2 or 3; term "heteroaryl" relates to aromatic 5- or 6- member ring or bicyclic 9-member aromatic groups, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur, and heteroaryl is mono-, di- or tri-substituted independently with lower alkoxy group; and R2 is selected from group including: n-butyl; phenyl, unsubstituted or mono-, di- or tri-substituted independently with lower alkyl, halogen or lower alkoxy group; heteroaryl, where term "heteroaryl" relates to aromatic 5-member ring, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur; unsubstituted or mono-, di- or tri-substituted independently with lower alkoxy group; -C(O)-NR4R5; where R4 and R5 stand for lower alkyl or together with nitrogen atom, to which they are bound, form 5-member heterocycle, which can additionally contain heteroatom, selected from N or S, and to their pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds, able to inhibit DPP-IV.

13 cl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, pharmaceutical compositions based on the said compounds, as well as methods of using said compounds in preparing medicinal agents.

EFFECT: obtaining compounds and a composition which can inhibit phosphatase cdc25, particularly phosphatase cdc25-C and can be particularly used for treating cancer.

12 cl, 56 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I and their pharmaceutically acceptable salts. The disclosed compounds have inhibitory effect on CDK1 kinase. In formula I , R1 is hydrogen or R2-(X)n-; X is a lower alkylene or cyclic lower alkylene; R2 denotes ; where denotes phenyl; cycloalkyl containing 3-6 carbon atoms; 4-6-member heterocycloalkyl ring having 3-5 carbon atoms and 1-2 oxygen atoms; R5, R6 and R7 are independently selected from a group containing hydrogen or halide; R4 is hydrogen or -(O)k(CH2CH2O)y-R10; R19 is hydrogen; R20 is hydrogen or -C(O)-R11; R10 and R11 is a lower alkyl; n and k are equal to 0 or 1; y is an integer from 0 to 3.

EFFECT: obtaining a pharmaceutical composition with inhibitory effect on CDK1 kinase, containing one or more of the disclosed compounds.

15 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzene derivatives of general formula (I) or salts thereof: [Chem. 12]

(Symbols in the given formula have the following values X1:-NR12-C(=O)- or -C(=O)-NR12-, X2 : -NR13 -C(=O)-, Ring A is a 6-member ring, if necessary having 1 or 2 double bonds and if necessary having 1-3 heteroatoms selected from N, O, Ring B is a benzene ring or a 6-member heteroaryl ring having 1-3 heteroatoms selected from N, R is a hydrogen atom or a residue of β-D- glucopyranoside uronic acid; R1-R8 are identical or different and each denotes a hydrogen atom, a halogen atom, -O-(lower alkyl), R9-R11 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-(lower alkyl), -(CH2)n-N(lower alkyl)2, -(CH2)n-NH(lower alkyl), -(CH2)n-N(lower alkyl) (if necessary substituted with -C=O; a 6-member heterocycle having 1-3 heteroatoms selected from N, S, O) -(CH2)n-(C=O)-N(lower alkyl)2, -(CH2)n-(C-O)-N(lower alkyl) (if necessary substituted with -C=O, alkyl, a 6-member heterocycle having 1-3 heteroatoms selected from N) -(CH2)n- if necessary substituted with alkyl, -COCH3, -SO2CH3, -COOCH3, -C=O, CF3, -OCH3, OH, halogen; 5-7-member heterocycle having 1-3 heteroatoms selected from N, S, O), -(CH2)n-O- (if necessary substituted with alkyl; 6-member heterocycle having 1-3 heteroatoms selected from N), n is an integer from 0 to 3, R12 and R13 denote a hydrogen atom, provided that in R1-R11, when two lower alkyls are bonded to a nitrogen atom, they can together form a 3-8-member nitrogen-containing heterocycle.) The invention also relates to benzene derivatives of general formula (II), to a pharmaceutical composition, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds which are active as inhibitors of activated blood-coagulation factor X.

16 cl, 365 ex, 42 tbl

FIELD: chemistry.

SUBSTANCE: formula (I) compounds, radicals of which are defined in the formula of invention, are described. A pharmaceutical composition containing formula (I) compounds is also described.

EFFECT: obtaining compounds which have inhibitory activity on protein kinase MEK1/2 and are meant for use as a therapeutically active substance which is useful for treating MEK1/2 mediated diseases.

13 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: benzamide derivatives are presented by the formula [1] or its salt, where Z is -O-, -NR5-, -S-, -SO-; 1 is 0 or 1; m is 0 or 1; R1 is hydrogen atom, C1-6-alkyl group, R2 is hydrogen atom, hydroxylic group, C1-6- alkyl group, carboxyl group, C1-6-alkoxycarbonyl group or -CONR10R11, or R2 and R1 together form =O; R3 is hydrogen atom or C1-6-alkyl group; R4 is hydrogen atom or halogen atom; V is direct bond or -(CR21R22)n-; P1 and P2 rings are the same or different, and each is aromatic or saturated carbocyclic group, or 5-10-member saturated or unsaturated heterocyclic group containing 1-3 heteroatoms selected out of N, O, S.

EFFECT: obtainment of compound with excellent inhibition effect on vanilloid receptor type 1 activity, efficiency in treatment of diseases involving vanilloid receptor type 1 activity.

17 cl, 56 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , where R1 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl and lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl, which can be substituted with a halogen; R2 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl or lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl which can be substituted with a halogen; or R1 and R2 together with the nitrogen atom to which they are bonded form a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring which optionally contains the same heteroatom selected from oxygen or sulphur, where the said saturated or partially heterocyclic ring is unsubstituted or substituted with one or two groups independently selected from a group consisting of lower alkyl, halogen, halogenalkyl, cyano group, hydroxy group, lower hydroxyalkyl, lower alkoxy group, oxo group; A is selected from , and , where m equals 0 or 1; R3 is a lower alkyl; n equals 0; R4 is a lower alkyl; p equals 1; q equals 0, 1 or 2; R5 is hydrogen; and their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on formula I compounds.

EFFECT: new quinoline derivatives are obtained, which have antagonistic effect on histamine 3 receptors (H3 receptors).

18 cl, 4 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, pharmaceutical compositions based on the said compounds, as well as methods of using said compounds in preparing medicinal agents.

EFFECT: obtaining compounds and a composition which can inhibit phosphatase cdc25, particularly phosphatase cdc25-C and can be particularly used for treating cancer.

12 cl, 56 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula I and their pharmaceutically acceptable salts and esters. The disclosed compounds have inhibitory effect on cyclin-dependant kinase. In formula I R1 denotes , R3 is selected from a group consisting of H, CO2R6, C(O)R6, SO2R6 and SO2NR5R6, R5 and R6 are each independently selected from a group which includes H and (lower)alkyl, R2 is phenyl which contains one, two or three substitutes independently selected from a group which includes halogen or -O-(lower)alkyl.

EFFECT: preparation of a pharmaceutical composition which contains an effective amount of a formula I compound as an active ingredient.

6 cl, 1 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention describes a phenothiazine derivative, specifically 2-(1-(2-(2-chloro-10H-phenothiazin-10-yl)-2-oxoethyl)-5-methyl-1H-1,2,4-triazol-3-yl)phenol of formula I: .

EFFECT: obtaining compounds with hypotensive and antiarrhythmic activity during intraperitoneal administration.

3 tbl

FIELD: medicine.

SUBSTANCE: invention refers to methods for producing 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzotiazin-3-carboxamides-1,1-dioxide (meloxicam) of formula of a high degree purity. In one of the ways potassium salt monohydrate of meloxicam of formula is dissolved, which is produced by interaction of meloxicam formula (II) with potassium hydroxide or potassium carbonate dissolved in water or in a mixture of water and organic solvent and, if desired, crystallisation of this monohydrate potassium salt of meloxicam of formula (I) in water or in a mixture of water and organic solvent, insoluble impurities are removed and the resulting solution is processed with organic or inorganic acid and crystallise meloxicam. The invention also refers to potassium salt monohydrate of meloxicam of formula (I) and method of its production, as well as to anti-inflammatory pharmaceutical composition based on it.

EFFECT: improvement of composition efficacy.

18 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: formula (I) compounds, radicals of which are defined in the formula of invention, are described. A pharmaceutical composition containing formula (I) compounds is also described.

EFFECT: obtaining compounds which have inhibitory activity on protein kinase MEK1/2 and are meant for use as a therapeutically active substance which is useful for treating MEK1/2 mediated diseases.

13 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: in the formula (I) , R1 is metoxymethyl; R2 is selected out of -C(O)NR4R5, -SO2NR4R5, -S(O)PR4 and HET-2; R3 is selected out of halogeno, fluoromethyl, metoxy and cyano; HET-1 is 5- or 6-member heteroaryl ring linked by C atom and containing nitrogen atom in 2 position and possibly 1 or 2 additional ring heteroatoms selected independently out of O, N and S, which is possible substituted at available carbon atom or at ring nitrogen atom by 1 substitute selected independently out of R6, provided that it would not cause ring quaternisation. The other radicals are indicated in the invention claim. Also invention refers to pharmaceutical composition containing claimed compound as active component, and methods of obtaining compound of the formula (I).

EFFECT: compounds with glucokinase inhibition effect.

19 cl, 2 tbl, 61 ex

FIELD: chemistry.

SUBSTANCE: claimed compounds show effect on receptor activated by peroxysome proliferate δ (PPARδ). In formula I: [Formula I] , [Formula VII] , [Formula VI] , A is R1 is C1-4alkyl group; R3 groups are different and denote halogen atom or C1-4alkyl group substituted or unsubstituted by halogen; R4 is R5 is hydrogen atom or hydroxyl group; the other radicals are as defined in the invention claim. Also invention refers to methods of compound I obtainment, to intermediary compounds VI, VII and methods of their obtainment, to medicines of diabetes, obesity, atherosclerosis, hyperlipidemia treatment and prevention, containing thiazole derivative of the formula I as active component.

EFFECT: enhanced activity of derivatives.

21 cl, 10 tbl, 102 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of the formula (I): , where R1 is C1-C8alkyl optionally substituted with one to three substitutes selected out of substitute group A; R2 is C1-C6alkyl or C1-C6alkoxyC1-C6alkyl; R3 is C1-C6alkyl or C1-C6alkoxy; or R2 and R3 together with adjoining carbon atoms form optionally substituted non-aromatic 5-10-member carbon ring; R4 is hydrogen; G is group represented by the formula: or the rest as provided in the invention claim; and to pharmaceutical composition, application of claimed compounds, and method of atopic dermatitis prevention or treatment.

EFFECT: novel compounds useful as atopic dermatitis treatment medication and antipruritic medicines.

24 cl, 75 ex, 290 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to cyclic derivatives of aminobenzoic acid and to their pharmaceutically acceptable salts of general formula , in which ring Ar is a phenyl group, a 5-member aromatic heterocyclic group containing 1-2 heteroatoms selected from nitrogen, sulphur and oxygen, or a benzothiazolyl group; where the said groups can have 1-2 substitutes selected from a group comprising lower alkyl; a phenyl group; a phenyl group substituted with 1-2 halogens; a phenyl group substituted with a lower alkoxy group; a phenyl group substituted with a halogen-substituted lower alkyl group; a phenoxy group substituted with a halogen; a halogen; Z is an oxygen atom or -(CH2)-n (where n equals 0, 1 or 2); Y is C1-C4 alkylene, C2-C4 alkenylene or general formula (2) -T-A-U- (2) in which T is a single bond, C1-C4 alkylene or C2-C4 alkenylene; U is single bond, C1-C4 alkylene; values of the rest of radicals are given in the formula of invention.

EFFECT: obtaining a PPARα, agonist which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid, and an agent which reduces the level of lipids which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid.

12 cl, 16 tbl, 184 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel α-(N-sulfonamido)acetamides of the formula (I) or their optical isomers wherein values R1, R, R2 and R3 are given in the invention claim. Proposed compounds are inhibitors of production of β-amyloid peptide and can be used for inhibition of production of β-amyloid peptide. Also, invention relates to pharmaceutical composition based on these compounds and to a method for inhibition of production of β-amyloid peptide.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

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