Cyclic 5-nitropyridin-2-yl-thioalkenyl-4-dithiocarbamate derivatives having antifungal activity and use thereof

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclic 5-nitropyridin-2-yl-thioalkenyl-4-dithiocarbamate derivatives of general formula (I) or pharmaceutically acceptable acid- or base addition salts thereof. The compounds have antifungal activity even in case of deep, subcutaneous and surface mycoses in humans, caused by strains (including those resistant to existing drugs) of mycosis causative agents. In general formula , R denotes nitro, cyano, halide-substituted C1-C6 alkyl group, n=1, 2 or 3. The invention also relates to use of compounds of formula (I), a method of producing said compounds, a pharmaceutical composition and a method for treatment using said compounds.

EFFECT: improved method.

12 cl, 2 tbl, 6 ex

 

The invention relates to new derivatives of cyclic 5-nitropyridine-2-yl-thioalkyl-4-dithiocarbamato General formula (I), their pharmaceutically acceptable salt and/or solvate, active against strains of yeasts and pathogenic fungi, the way they are received, farmkompanijam and medicines containing these compounds, and their use as antifungal, in particular antimycotic drugs.

The problem of the search for new antifungal agents due to the considerable spread of fungal infections (mycoses) in humans and animals. This is due to the lowering of immune protection in human population and development of resistance in pathogens of fungal infections to commercially available drugs. The problem of rapid development of resistance due to the fact that many antifungal drugs are derivatives of the same class of compounds (primarily the polyene and azole), and their lack of efficacy and toxicity. The difficulty in the treatment of fungal infections is largely due to the fact that fungi are eukaryotic microorganisms. This fact greatly limits the potential selection of targets, the impact of which can effectively inhibit the growth of pathogens of fungal infections without objnamespace on humans and animals. Most of the available medicine antifungal drugs - polyene, azole and allylamine affecting the main component of the membrane of fungi is ergosterol, do not provide adequate selectivity and effectiveness. They are very toxic, in addition, many strains of pathogens of fungal infections acquired resistance to drugs of azoles.

There are various derivatives of dithiocarbamates, which can be used mainly in agriculture as fungicides, herbicides (see patent JP 5606580, SU 579844).

Antimicrobial activity of some dithiocarbamates also described in the articles:

- V.Makarov, O.Riabova, A.Yuschenko, N.Urlyapova, A.Daudova, P.F.Zipfel, U.Mollmann, Synthesis and Antileprosy Activity of Some Dialkyldithiocarbamates, J. Antimicrobial Chemother., Apr 2006, 57, 1134-1138;

- Mohamed GG, Ibrahim NA, Attia HA. Synthesis and antifungicidal activity of some transition metal complexes with benzimidazole dithiocarbamate ligand. Spectrochim Acta A Mol Biomol Spectrosc. 2009 Apr; 72(3): 610-5;

- Nogueira LJ, de Resende MA, Oliveira SR, de Araujo MH, Magalhaes TF, de Oliveira MB, Martins CV, Lopes MT, Araujo e Silva AC, Donnici CL. In vitro susceptibility of Aspergillus spp. to dithiocarbamate organoruthenium compounds. Mycoses. 2011 Sep; 54(5): e323-9.

There are various fungicidal mixtures, for example mixtures of amides and derivatives of pyridines with known dithiocarbamate (see patent US 6407126). Also known compounds containing derivatives of thiazoline and pyridine fragments. So, for example, patent EP 2107058 A1 describes compounds containing thiazolinones and originaly fragments as a tool for pest control, such as aphid myzus persicae. In the patent US 2009/0270630 describes the derivatization of rosiglitazone-compounds containing thiazolidinone and pyridine fragments, which is used in the treatment of hypoglycemic disorders.

The present invention consists in the search for new pharmacologically active compounds (derivatives of heterocyclic compounds) against fungal infections (mycoses), including strains resistant to existing drugs (N.Berila, J.Subík., Epidemiol Mikrobiol Imunol. 2010, 59(2), 67-79; R. Di Santo, Nat. Prod. Rep., 2010, 27(7), 1084-98; R. Musiol, M.Serda, S.Hensel-Bielowka, J.Polanski. Curr. Med. Chem. 2010, 17(18), 1960-73), have low toxicity and do not cause side effects in relation to warm-blooded organisms.

This problem was solved by the synthesis of new derivatives of cyclic 5-nitropyridine-2-yl-thioalkyl-4-dithiocarbamate, which are composed of dithiocarboxylic fragment, where the nitrogen atom of the urethane group is part of a heterocyclic ring. This fragment in the compounds of the present invention is -1,3-thiazolidinedione, -1,4-dimorpholinyldiethyl or-perhydro-1,5-tiosemikarbazida.

Derivatives of cyclic 5-nitropyridine-2-yl thioalkyl-4-dithiocarbamates of the present invention correspond to the General formula (I)

where R is nitro, cyano, alojamiento1-C6alkyl group, preferably triptorelin group, n=1, 2, or 3.

The invention also relates to pharmaceutically acceptable acid or basic additive salts of these compounds. The compound can be obtained and used in crystalline form.

The synthesized compounds of General formula (I) and their pharmaceutically acceptable acid or basic additive salts investigated in relation to strains causing various fungal infections (mycoses), and can be used to produce drugs based on them.

The term "pharmaceutically acceptable salts of the compounds of formula (I)" means any salt of inorganic or organic acids or bases, which have the necessary pharmacological activity of the parent compound. These salts can be obtained in situ during the synthesis, isolation or purification of the compounds of formula (I) or specially prepared.

The proposed connection can be in the form of stereochemical isomeric forms, tautomers or crystalline modifications.

Pharmaceutically additive salts with acids are characterized by the fact that contain therapeutically active non-toxic salt additive form with acids, which are able to form compounds form the s (I). These additive salts with acids can be obtained by treating compound in the form of bases represented by the General formula (I)with appropriate acids, including inorganic acids, for example: halogen acid, hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric or phosphoric acid; organic acids such as: acetic acid, hydroxyoctanoic acid, propionic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, maleic or fumaric acid, malic, tartaric, citric acid or other acids.

Used in the context of this invention, the term "additive salt" also includes various solvate, which is able to form compounds of General formula (I)and physiologically acceptable salts and solvate or a mixture of these compounds.

The invention also relates to a method of obtaining compounds of General formula (I). The method consists in the interaction of the corresponding 5-nitro-2-halogenpoeten formula II, where Hal means fluorine, chlorine, bromine or iodine salt of the corresponding dithiocarbamate General formula III in a suitable solvent according to the following scheme (1):

where R and n have the above in formula (I) values, with the allocation of the resulting p is oduct in free form or in pharmaceutically acceptable acid or basic additive salt.

The method is as follows.

The intermediate compound of formula II (where Hal is fluorine, chlorine, bromine or iodine) by the reaction of nucleophilic substitution, where as the nucleophile is ion dithiocarbamates acid, which can be introduced into the reaction in the form of its sodium or potassium salt (scheme (1)). The reaction takes place in a suitable solvent, such as lower alcohols, acetone, ethylmethylketone, dimethylformamide. All radicals have the meanings specified above. The reaction can be conducted at a temperature in the range from +10 to +100°C. the Stirring can increase the reaction rate.

The source and intermediate compounds of formula II and III are known compounds and can be obtained by commonly known methods.

The results of the synthesis, testing pharmacological activity of the compounds of formula (I)below in examples illustrate but do not limit the scope of the present invention.

Example 1.

3,5-dinitropyridine-2-yl, thiomorpholine-4-carbolicious (compound No. 1).

Synthesis of sodium salt tomorrowinstrumental acid.

To a solution 5,04 g thiomorpholine in 50 ml of ethanol was added with vigorous stirring a solution of 1.95 g of sodium hydroxide in 15 ml of water. The reaction mass is then cooled to 10°C and to it was slowly added dropwise 2,95 ml of carbon disulfide. Received restoredarray at room temperature for 2 hours and evaporated under vacuum. The obtained white solid crystalline residue is recrystallized from ethyl alcohol and get a 8.9 g of sodium salt tomorrowinstrumental acid dihydrate.

To a suspension of 0.2 g of 3,5-dinitro-2-chloropyridine in 10 ml of ethanol under vigorous stirring sprinkled 0.28 g of sodium salt tomorrowinstrumental acid dihydrate. The reaction mass becomes orange tint and after 20 minutes, it was diluted with 70 ml of cold water. The formed yellow precipitate is filtered off, air-dried during the day and recrystallized from ethyl acetate. Obtain 0.17 g of 3,5-dinitropyridine-2-yl, thiomorpholine-4-carbodiimide.

Yield: 50%.

T square: 132-135°C (ethyl acetate)

MS (m/z): 346 (M+)

1H NMR (DMSO-d6): 9.56 (1H, s, H), 9.28 (1H, s, H), 3.46(4H, m, N(CH2)2), 2.65 (4H, m, S(CH2)2) ppm

Elemental analysis of C10H10N4O4S3:

Calc.: C, 34.67; H, 2.91; N, 16.17

Found: C, 34.63; H, 2.90; N, 16.22

Example 2.

3,5-dinitropyridine-2-yl 1,3-thiazolidin-3-carbolicious (compound No. 2)

Connection # 2 was synthesized similarly to compound No. 1, but using as a nucleophilic agent the sodium salt of 1,3-thiazolidinedione acid obtained by the method described in example 1.

Yield: 58%.

T square: 126-129°C (EtOH)

MS (m/z): 332 (M+)

1H NMR (DMSO-d6): 9.51 (1H, s, H),9.29 (1H, s, H), 4.66(4H, m, N(CH2)2), 2.28 (2H, m, SCH2) ppm

Elemental analysis of C9H8N4O4S3:

Calc.: C, 32.52; H, 2.43; N, at 16.86

Found: C, at 32.43; H, 2.47; N, 16.92

Example 3.

5-nitro-3-cyanopyridine-2-yl, thiomorpholine-4-carbolicious (compound No. 3)

Compound No. 3 was synthesized according to the method described for the compound No. 1, but using as the starting 5-nitro-3-cyano-2-chloropyridine synthesized by the method of M. Winn, M. Zydowsky, Altenbach R.J. 2-(Alkylamino)nicotinic acid and analogs. Potent angiotensin II antagonists // J. Med. Chem. - 1993. - Vol.36. - P.2676-2688.

Yield: 81%.

T square: 136-137°C (ethyl acetate)

MS (m/z): 326 (M+)

1H NMR (DMSO-d6): 9.69 (1H, s, H), 8.61 (1H, s, H), 3.42(4H, m b, N(CH2)2), 2.54 (4H, m, S(CH2)2) ppm

Elemental analysis of C11H10N4O2S3:

Calc.: C, 40.47; H, 3.09; N, 17.16

Found: C, 40.43; H, 3.18; N, 17.11

Example 4.

5-nitro-3-cyanopyridine-2-yl 1,3-thiazolidin-4-carbolicious (compound No. 4)

Compound No. 4 was synthesized according to the method described for the compound No. 2, but using as the starting 5-nitro-3-cyano-2-chloropyridine synthesized by the method of M. Winn, M. Zydowsky, Altenbach R.J. 2-(Alkylamino)nicotinic acid and analogs. Potent angiotensin II antagonists // J. Med. Chem. - 1993. - Vol.36. - P.2676-2688.

Yield: 52%.

T square: 107-109oC (ethyl Acetate)

MS (m/z): 312 (M+)

1H NMR (DMSO-d6): 9.77 (1H, s, H), 8.74 (1H, s, H), 4.60 (4H, m, N(CH2)2), 2.23 (2H, m,SCH 2) ppm

Elemental analysis of C10H8N4O2S3:

Calc.: C, 38.45; H, 2.58; N, at 17.93

Found: C, 38.38; H, 2.64; N, 17.91

Example 5.

5-nitro-3-triptorelin-2-yl-thiomorpholine-4-carbolicious (compound No. 5)

Compound No. 5 was synthesized according to the method described for the compound No. 1, but using as the starting 5-nitro-3-trifluoromethyl-2-chloropyridine synthesized according to the method described in patents US 20100298321 and EP 1632477.

Yield: 36%.

T square: 150-151°C (ethanol)

MS (m/z): 293 (M+)

1H NMR (DMSO-d6): 9.50 (1H, s, H), 8.83 (1H, s, H), 3.41(4H, m, N(CH2)2), 2.72 (4H, m, S(CH2)2) ppm

Elemental analysis of C11H10F3N3O2S3:

Calc.: C, 35.76; H, 2.73; N, 11.37

Found: C, 35.71; H, 2.66; N, 11.49

Example 6.

5-nitro-3-triptorelin-2-yl 1,3-thiazolidin-4-carbolicious (compound No. 6)

Compound 6 was synthesized according to the method described for the compound No. 2, but using as the starting 5-nitro-3-trifluoromethyl-2-chloropyridine synthesized according to the method described in patents US 20100298321 and EP 1632477.

Yield: 18%.

T square: 123-125°C (methanol)

MS (m/z): 355 (M+)

1H NMR (DMSO-d6): 9.51 (1H, s, H), 8.79 (1H, s, H), 4.57 (4H, m, N(CH2)2), 2.32 (2H, m, SCH2) ppm

Elemental analysis of C10H8F3N3O2S3:

Calc.: C, 33.80; H, 2.27; N, 11.82

Found: C, 3.84; H, 2.22; N, at 11.93

The object of the invention is also a pharmaceutical composition having fungicidal properties comprising the compound or its pharmaceutically acceptable acidic or basic additive salts, or mixtures thereof in a pharmacologically effective amount of, as well as pharmaceutically acceptable carrier and adjuvants. Preferably, the active ingredient was part of the pharmaceutical compositions of the present invention in the form of single doses.

The term "unit dose" means any effective amount of the active ingredient in combination with pharmaceutically acceptable excipients contained in the dosage form of the pharmaceutical composition used for one-time use by the patient.

The term "effective amount" means an amount of active ingredient, which when administered to patients provides prevention, reduction or elimination of symptoms of the diseases to be prevented or treated.

The pharmaceutical composition according to the present invention in the form of tablets, capsules, injections, ointments, candles, and other ready-made forms (see below), as are compounds or their pharmaceutically acceptable salts can be used for the treatment and prevention of diseases or disorders in humans and W is the animals caused by strains of pathogens fungal infections (mycoses), including those resistant to current drugs.

The compounds of formula (I), pharmaceutically acceptable salt, solvate, pharmaceutical composition or drug based on them can be used for the treatment of humans or animals by conventional methods, including:

- enteric form of introduction, for example, in the form of tablets, pellets, pills, beads, powders, capsules, suspensions, syrups, emulsions, rectal suppositories, including Transbaikalia and sublingual forms of introduction, and others;

- parenteral form of administration, in the form of an injectable form of the introduction of, for example, in the form of solutions, emulsions, suspensions, powders and tablets for obtaining solutions, and implantation, lyophilised drugs, enter in the body parenterally (subcutaneously, intramuscularly, intravenously, intraarterially, cavities), and others; in the form of non-injection forms of administration, for example in the form of suppositories for vaginal injection, aerosol, spray, creams, ointments, gels, suspensions, emulsions, liniments, solutions, drops, patches, powders, powders, powders, lotions and other

The invention also relates to the use of compounds of General formula (I) and their pharmaceutically acceptable acid or basic additive salts may in cu is stallion.com or pharmaceutical compositions based on them for the preparation of drugs for the treatment and prevention of fungal infections in humans and animals. Moreover, the compounds exhibit anti-fungal activity in the case of deep subcutaneous or superficial mycoses in humans and animals caused by strains (including those resistant to available drugs) agents of fungal diseases.

As pharmaceutically acceptable excipients in the form of pharmaceutical compositions according to the invention can be any pharmaceutically acceptable components that are compatible with the active ingredient and do not harm patients, traditionally used for the preparation of dosage forms, such as fillers, binders, granulating agents, solubilizing agents, means for sliding, stabilizers, diluents, adjuvants, preservatives, buffer components systems, solvents, dispersing agents, preservatives, lubricating agents, flavorings, thickeners, dyes, emulsifiers, regulators prolonged delivery and other

Pharmaceutically acceptable excipients are, for example, lactose, Inositol, glucose, mannitol, dextran, cyclodextrin, sorbitol, starch and its modifications, sucrose, magnesium aluminosilicate, synthetic aluminum silicate, crystalline cellulose, carboxymethylcellulose sodium, hydroxypropyltrimonium starch, carboxymethylcellulose calcium is Oia, ion-exchange resins, methylcellulose, gelatin, gum Arabic, hydroxypropylcellulose,hypromellose, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate, anhydrous silicic acid, magnesium stearate, talc, carboxyvinyl polymer, titanium oxide, ester of fatty acids and of sorbitol, sodium lauryl sulphate, glycerin, glycerin fatty acid ester, lanolin, glycoregulation, Polysorbate, macrogol, vegetable oil, wax, paraffin, propylene glycol, polyethylene glycol, water, ethanol, polyalcohol, polyoxyethylenesorbitan castor oil, sodium chloride, sodium hydroxide, hydrochloric acid, dibasic sodium phosphate, monotony sodium phosphate, citric acid, glutamic acid, benzyl alcohol, methyl p-oxybenzoic, ethyl p-oxybenzoic and other

Pharmaceutically acceptable excipients in obtaining pharmaceutical compositions in the form of ointments, creams and suppositories are, for example, natural or hardened oils, for example cocoa butter, waxes, fats, ester of glycerol and a saturated fatty acid, glycoregulation, macrogol, semi-solid or liquid polyols, triglycerides and other Basis for ointments, creams, suppositories may also include a surfactant or stabilizer.

The composition according to the invention may also contain taxicompany, which will provide a quick prolonged or delayed release of the active ingredient after use by patients. Prolonged action of the composition can be achieved with agents that slow the absorption of the active principle, for example, aluminum monostearate and gelatin.

As stated above, it is preferable that the active ingredient was part of the pharmaceutical compositions of the present invention in the form of single doses.

The pharmaceutical composition of the present invention in a single unit dose can contain the active ingredient in a quantity in the range from 2 to 0.5 g in 100 g of the composition, in a daily therapeutic dose of from 1.8 to 7.2 mg of active ingredient per 1 kg of weight. An effective amount of the active ingredient in some compositions may exceed the above limits.

The pharmaceutical compositions can be prepared by any known method in this field, for example by mixing the components using one or more pharmaceutically acceptable auxiliary substances.

The object of the invention is also a method of treating or preventing disease in humans or animals caused by strains, fungal infections, including those resistant to existing drugs, with compounds of General Faure the uly (I), and their pharmaceutically acceptable acid or basic additive salts, or mixtures thereof, or pharmaceutical compositions based on them in an effective amount.

Description antifungal activity of the compounds according to the invention.

The pharmacological activity of the compounds of the present invention was investigated in accordance with the methodological guidelines for the study of pharmacological substances (Manual on experimental (preclinical) study of new pharmacological substances. Edited by Prof. Rugarama. - 2-ed.. Rev. and ext., M.: JSC "Publishing house "Medicine", 2005).

1. The activity of compounds of General formula I against laboratory and clinical strains of fungi.

The compounds of General formula I showed a high activity against laboratory and clinical strains, including those resistant to antifungal drugs.

Determination of antifungal activity against reference strains: Candida albicans ATCC 14053, Candida albicans ATCC 24433, Candida parapsilosis ATCC 22019, Cryptococcus humiculus ATCC 9949 and Aspergilla niger ATCC 16404 and clinical strains of fungi was performed by the method of twofold serial dilutions in liquid nutrient medium RPMI 1640 with micromethods.

For preparation of inoculum used a suspension of yeast cells and a suspension of spores in sterile saline (0.85 per cent Nal). The density of the suspensions was monitored spectrophotometrically.

To obtain the inoculum source suspensions of yeast and fungal spores were diluted standard medium (RPMI 1640). The final concentration of cells was 1-5×103cells/ml for yeast and 0.4-5×104cells/ml for fungi.

The number of cells in the inoculum was verified by plating on agar Saburo and counting of grown colonies. All solutions of test compounds were prepared immediately prior to use.

Sample test compound in the amount of 4.8 mg was dissolved in 3 ml DMSO, receiving the initial concentration of 1.6 mg/ml (1600 mcg/ml). Next, in the same solvent was preparing a series of twofold dilutions from 1600 to of 3.13 μg/ml For the production experiment the obtained solutions were diluted 50 times in the standard used to experience medium RPMI 1640.

Experiments were performed in sterile 96-well flat-bottom plates in RPMI medium 1640, in the wells containing 200 μl of medium. The final concentration of compounds in the experience after making inoculum ranged from 16 to 0.03 μg/ml when the concentration of the solvent (DMSO) 1%.

Each drug in the experiment was attended not less than three times. In the panel of the experiment as a control were included wells that do not contain the tested preparations.

The plates were incubated at 35°C without in the trachymene. Minimal inhibitory concentration (MIC) of the tested compounds were read at 24 hours of cultivation for Candida albicans and 48 hours of cultivation for Aspergillus niger. MBC was defined as the lowest concentration that completely prevents visible growth of the test organism.

The results of the determination of antifungal activity are presented in table 1.

Table 1
Antifungal activity specified in the examples, the compounds according to the invention of General formula (I) with respect to laboratory strains of fungi. The minimum inhibitory concentration in μg/ml
The number of the sample (Number of connections)Candida albicans ATCC 14053Aspergilus niger ATCC 16404
182
241
30,50,5
411
5322
6321

Connection # 3 were selected for further studies as the most active on the results of the conducted experiments.

We studied the activity in vitro of the compounds No. 3 against laboratory and clinical strains of fungi listed in table 2

Table 2
Spectrum of antifungal activity of compound No. 3 in vitro
MicroorganismsActivity mcg/ml
Candida albicans ATCC 140530,5
Candida albicans ATCC 244330,5
Candida albicans 608M0,5
Candida albicans 2-041,0
Candida glabrata 75-051,0
Candida glabrata 3-051,0
Candida tropicalis 100M4,0
Candida tropicalis 56-052,0
Candida tropicalis 42-052,0
Candida parapslosis ATCC 22019 1,0
Candida parapsilosis 7-044,0
Candida parapsilosis 37-050,5
Candida kruzei 432M1,0
Candida kruzei 80-051,0
Cryptococcus humiculus ATCC 99490,5
Aspergillus niger ATCC 164040,5
Fusarium oxysporum VKM F-1401,0
Candida kruzei 432M1,0
Candida kruzei 80-051,0
Microsporum canis wedge.4,0
Trychophyton rubrum wedge.2,0
Trychophyton mentagrophytes wedge.2,0

Estimation of acute toxicity after a single intragastric administration of compound No. 3 mice of BALB. Figure LD50amounted to more than 5000 mg/kg, which corresponds to group 4, moderately toxic compounds according to the classification of Hodge and Sterner.

The following are examples of pharmaceutical compositions in the form of various forms, suitable for the conference is mainly defined as a medicinal product.

Example A. Preparation of tablets containing 50-500 mg of the active ingredient. The active ingredient is mixed with 1600 mg of starch, 1600 mg of powdered lactose, 400 mg of talc and pressed together in the bar. The resulting block is crushed into granules and sieved through a sieve, collecting the granules with a size 14-16 mesh. The obtained granules tabletirujut in a suitable form tablets weighing 560 mg each.

Example B. Capsules containing 50-500 mg of active ingredient, according to the invention receive thorough mixing the active compounds with lactose powder in a 2:1 ratio. Received poroshkoobraznuju mix pack 300 mg in gelatin capsules of suitable size.

Example C. Injectable compositions for intramuscular, intraperitoneal or subcutaneous injection can be prepared by mixing 50-500 mg of active compound with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injectable water. The resulting solution is filtered and placed in 1 ml ampoules which are sealed and sterilized in an autoclave.

Example d Ointment, cream or suppositories can be manufactured as follows: the active substance is melted in a small amount of ointment, cream or candlestick bases. The resulting melt is thoroughly mixed with the required quantity of base, preheated (35-80)°C. the resulting mixture was homogenized. Ready mix restofline the state poured into tubes or used for the manufacture of candles.

1. Derivatives of cyclic 5-nitropyridine-2-yl-thioalkyl-4-dithiocarbamato General formula (I)

where R is nitro, cyano, alojamiento C1-C6alkyl group, n=1, 2, or 3,
or their pharmaceutically acceptable acidic or basic additive salt, possibly in crystalline form.

2. Compounds according to claim 1, where R is nitro, cyano, triptorelin group.

3. Compounds according to claim 1, selected from the group:
- 3,5-dinitropyridine-2-yl, thiomorpholine-4-carbolicious (compound No. 1);
- 3,5-dinitropyridine-2-yl 1,3-thiazolidin-3-carbolicious (compound No. 2);
- 5-nitro-3-cyanopyridine-2-yl, thiomorpholine-4-carbolicious (compound No. 3);
- 5-nitro-3-cyanopyridine-2-yl 1,3-thiazolidin-4-carbolicious (compound No. 4).

4. Pharmaceutical composition having activity against strains of fungi, pathogens of fungal infections comprising as an active ingredient the compound or its pharmaceutically acceptable acidic or basic additive salt according to claim 1 or 2, a pharmacologically effective amount.

5. The pharmaceutical composition according to claim 4, comprising the compound according to claim 1, selected from the group:
- 3,5-dinitropyridine-2-yl, thiomorpholine-4-carbolicious (compound No. 1);
- 3,5-dinitropyridine-2-yl 1,3-thiazolidin-3-carbolicious (compound No. 2);
- 5-nitro-3-cyanopyridine-2-yl, timoho the Ino-4-carbolicious (compound No. 3);
- 5-nitro-3-cyanopyridine-2-yl 1,3-thiazolidin-4-carbolicious (compound No. 4).

6. The pharmaceutical composition according to claim 4 or 5 in a form suitable for enteral, parenteral, rectal administration, including Transbaikalia and sublingual forms of introduction, for vaginal insertion, in a form suitable for injection.

7. The pharmaceutical composition according to claim 4 or 5 in a form suitable for use as a single dose.

8. The pharmaceutical composition according to claim 6 in the form of tablets, capsules, ointments, suppositories, injections, placed in the package.

9. The use of compounds with the General formula (I) or their pharmaceutically acceptable acidic or basic additive salts is possible in crystalline form according to claims 1, 2 or 3, or a pharmaceutical composition according to any one of claims 4 or 5 for the preparation of drugs for the treatment and prevention of fungal infections.

10. A method of treating or preventing a fungal infection involving the introduction or application of the subject compound or its pharmaceutically acceptable acidic or basic additive salt according to claim 1 or 2, or a pharmaceutical composition according to any one of claims 4 or 5 in an effective amount.

11. The method according to claim 10, characterized in that is used as a compound selected from the group
- 3,5-dinitropyridine-2-yl, thiomorpholine-4-carbolicious (compound No. 1);
- 3,5-dinitropyridine-2-yl 1,3-t is solidin-3-carbolicious (compound No. 2);
- 5-nitro-3-cyanopyridine-2-yl, thiomorpholine-4-carbolicious (compound No. 3);
- 5-nitro-3-cyanopyridine-2-yl 1,3-thiazolidin-4-carbolicious (compound No. 4) or their pharmaceutically acceptable acidic or basic additive salt or pharmaceutical composition based on them.

12. The method of obtaining compounds of General formula (I) according to claim 1 interaction of the corresponding 5-nitro-2-halogenpoeten formula (II), where Hal means fluorine, chlorine, bromine or iodine, salt of the corresponding dithiocarbamate General formula (III) in a suitable solvent according to the following scheme

where R and n have the listed according to claim 1, with the selection of the obtained product in free form or in pharmaceutically acceptable acid or basic additive salt.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), stereoisomers, trans- and cis-isomers, racemates or pharmaceutically acceptable salts thereof, having modulating activity on histamine H3-receptors. In formula (I) m equals 0; one of R1 and R2 is selected from a group which includes hydrogen, C1-10alkoxycarbonyl, amido-, carboxy-, C3-8cycloalkyl, halogen, -NRARB, (NRARB)carbonyl, or a group of formula -L2-R6; the other of R1 and R2 is selected from a group which includes hydrogen, halogen; each of R3a and R3b is independently selected from a group which includes hydrogen; each of R4 and R5 is independently selected from a group which includes C1-10alkyl and C1-10hydroxyalkyl; or R4 and R5, taken together with a nitrogen atom to which each is bonded, form a heteroaromatic ring of the type (a) or (b), where Q1 is O or C; Q2 is -N(R20)-; R20 is selected from a group which includes hydrogen and C1-10alkoxycarbonyl; each of p1 and p2 is independently equal to 1, 2 or 3; each of q1, q2, q3, q4 and q5 are independently equal to 0, 1 or 2; and wherein each carbon atom in the ring is substituted with hydrogen or 0, 1 or 2 substitutes, independently selected from a group which includes hydrogen, hydroxy group, fluorine, C1-10alkyl, C1-10hydroxyalkyl and C1-10fluoroalkyl; R6 is a phenyl, heterocycle or heterocycloC1-4alkyl, wherein the heterocycle is a 4-6-member aromatic or non-aromatic ring which contains 1 or 2 heteroatoms independently selected from N, O and S, optionally condensed with a benzene ring, wherein the phenyl or heterocycle can be unsubstituted or optionally substituted with one or more substitutes independently selected from a group which includes C1-4alkoxy, C1-4alkyl, cyano, halogen and oxo-; L is a bond or C1-4alkylene; L2 is a bond, C1-4alkylene, -C(=O)-, -SO2N(R14a)-, -N(R14a)SO2-, -C(O)N(R14a)-, -N(Rl4a)C(O)- or -N(R15)-; R10 is selected from a group which includes hydrogen; R14a is selected from a group which includes hydrogen; R15 is selected from a group which includes hydrogen; and RA and RB are independently selected from a group which includes hydrogen, C1-10alkyl, C1-10acyl, C1-4halogenalkyl, C1-10alkoxycarbonyl, C3-8cycloalkyl and C3-8cycloalkylcarbonyl. The invention also relates to a pharmaceutical composition which contains compounds of formula (I), a method for selective modulation of effects of histamine H3-receptors, use of said compounds in producing a medicament for treating a condition or disorder modulated by histamine H3-receptors, as well as specific compounds of formula (I).

EFFECT: improved properties of compounds.

18 cl, 2 tbl, 154 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a compound having chemical formula or a salt thereof, where: Ar is an optionally substituted heteroaryl; R1 in each case is independently selected from a group which includes halogen, lower alkyl, optionally substituted with one or more substitutes selected from fluorine, lower alkoxy, fluorine-substituted lower alkoxy, monoalkylamino, dialkylamino, -O-R5, -N(R5)-R6 and -N(R5)-C(X)-R7; m equals 0 or 1; n equals 0, 1 or 2; R2 is hydrogen or a halogen; L2 is -S(O)2-; R3 is a lower alkyl, optionally substituted with fluorine, C3-6 cycloalkyl, optionally substituted with a lower alkyl, a 5- or 6-member nitrogen-containing heterocycloalkyl, optionally substituted with one or more substitutes selected from fluorine, lower alkyl, fluorine-substituted lower alkyl, lower alkoxy, fluorine-substituted lower alkoxy, lower alkylthio or fluorine-substituted lower alkylthio, aryl, optionally substituted with a halogen, lower alkyl, optionally substituted with a halogen or lower alkoxy, optionally substituted with a halogen, or a heteroaryl, optionally substituted with a halogen or a lower alkyl; L1 is selected from a group which includes -O-, -C(R12R13)-X-, -X-C(R12R13)-, -C(R12R13)-N(R11)-, -(R11)-C(R12R13)-, -C(X)-N(R11)-, -N(R11)-C(X)-; X is O; R11 is hydrogen; R4 is hydrogen or a lower alkyl; R5 and R6 in each case are independently selected from a group which includes hydrogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, where each is optionally substituted with one or more substitutes selected from fluorine, lower alkoxy, fluorine-substituted lower alkoxy, lower alkylthio, fluorine-substituted lower alkylthio, monoalkylamino, dialkylamino; R7 in each case is independently selected from a group which includes lower alkyl; where the terms "lower alkyl", "lower alkoxy", "lower alkylthio", "monoalkylamino", "dialkylamino", "cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", are as described in the claim. The invention also discloses a pharmaceutical composition for treating Raf kinase mediated diseases which is based on a compound of formula I; use of the compound of formula I to produce a medicinal agent is also disclosed.

EFFECT: novel compound which can be useful in treating diseases and conditions associated with aberrant activity of protein kinases is obtained and described.

9 cl, 13 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: application describes prodrugs being 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxyethoxy)-phenyl]pyridine-3,5-dicarbonitryl derivatives, and a method for preparing them.

EFFECT: invention can find application in treating and/or preventing cardiovascular diseases.

8 cl, 4 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula III which possess the properties of JAK pathway inhibitors and JAK-kinase inhibitors. In formula III: X is specified in a group consisting of C1-C10alkyl, amino, halogen, carboxyl, carboxylic acid ester, C2alkynyl, substituted tri-C1-C6alkylsilyl; R represents hydrogen; the cycle A is specified in a group consisting of C6aryl, bicycloheptene, five-and sis-member mono- or 10-member bicyclic heteroaryl including 1 to 3 heteroatoms specified in a group of heteroatoms, including N, O or S, and five- or six-member mono- or 10-member bicyclic heterocycle, including 1 to 2 heteroatoms specified in a group of heteroatoms, including N or O; p means 0, 1, 2 or 3; each of R2 is independently specified in a group consisting of C1-C6alkyl, C1-C4alkyl substituted by 1 to 3 substitutes. The other substitute and radical values are specified in the patent claim.

EFFECT: compounds may be used in preparing a therapeutic agent for T-cell mediated autoimmune disease, for treating or preventing allograft rejection in a recipient, for treating or preventing a type IV hypersensitivity reactions, which includes administering the above agent containing the compound according to cl 1-11, in an amount effective to treat the autoimmune disease or the allograft rejection or the type IV hypersensitivity.

23 cl, 7 dwg, 12 tbl, 43 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely to new 1,2-dihydroquinoline derivatives of general formula , or to a pharmaceutically acceptable salt thereof, wherein R1 represents a lower alkyl group; R2 represents a hydrogen atom; each of R3 and R4 represents a lower alkyl group; R5 represents a lower alkyl group; R6 represents a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group; X represents -CO-, -C(O)NR8 - or -S(O)2-; each of R7 and/or R8 may be identical or different, and represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower cycloalkyl group, a phenyl or naphthyl group, a saturated or unsaturated monocyclic 5- or 6-member heterocyclyl with one or two heteroatoms specified in nitrogen, oxygen and sulphur atoms, and 3-5 carbon atoms in a cycle, a lower alkoxy group, a phenoxy group; provided R7 and/or R8 represent a lower alkyl group, a lower alkoxy group, the mentioned lower alkyl group and lower alkoxy group may contain one or three groups specified in a halogen atom, a phenyl group, an unsubstituted monocyclic 6-member heterocyclyl with one heteroatom specified in a nitrogen atom, and 5 carbon atoms in a cycle, a lower alkoxy group, and -NRaRb as a substitute (substitutes); provided R7 and/or R8 represent a phenyl group, a saturated or unsaturated monocyclic 5- or 6-member heterocyclyl with one or two heteroatoms specified in nitrogen, oxygen and sulphur atoms, and 3-5 carbon atoms in a cycle, a phenoxy group, the mentioned phenyl group, saturated or unsaturated monocyclic 5- or 6-member heterocyclyl with one or two heteroatoms specified in nitrogen, oxygen and sulphur atoms, and 3-5 carbon atoms in a cycle, phenoxy group may contain one or two groups specified in a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, a phenyl group, a hydroxyl group, a lower alkoxy group, a halogen-substituted lower alkoxy group, a lower alkylthio group, a lower alkylcarbonyl group, a lower alkoxycarbonyl group, a lower alkylcarbonyloxy group, -NRaRb, a nitro group and a cyano group as a substitute (substitutes); Ra and Rb may be identical or different, and each of them represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group; Y represents a lower alkylene group; Z represents an oxygen atom; p is equal to 2, provided p is equal to 2, R6 may be identical or different. The invention also relates to a pharmaceutical composition and a glucocorticoid receptor modulator of the compound of formula (1).

EFFECT: there are produced new 1,2-dihydroquinoline derivatives possessing glucocorticoid receptor binding activity.

7 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyrrol derivatives of formula (1): or a pharmaceutically acceptable salt thereof wherein the values A, R1-R3, n are specified in clause 1 of the patent claim.

EFFECT: compounds (1) inhibit activity against the interleukin IL-6 production that allows using them both in pharmaceutical compositions, and in a prophylactic drug for ocular inflammatory disease.

23 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing substituted pyrimidin-5-yl carboxylic acids of formula I and can be used in organic chemistry. The method is realised by reacting N-substituted guanidines and hetarylamidines with ethoxymethylene derivatives of 1,3-ketoesters according to a scheme given below (where the substitutes are as defined in the claim).

EFFECT: improved method of producing substituted pyrimidin-5-yl carboxylic acids of formula I.

2 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to a method of producing M-(1,5,3-dithiazepan-3-yl)amides of general formula (1) where R = p-C5H4N (a), (CH3)3CO (b), o-CH3OC6H4 (c), which involves reaction of N1,N1,N6,N6-tetramethyl-2,5-dithiahexane-1,6-diamine with a hydrazide of general formula RC(O)NHNH2 [R is as described above] in the presence of a samarium nitrate crystalline hydrate Sm(NO3)3·6H2O catalyst with molar ratio N1,N1,N6,N6-tetramethyl-2,5-dithiahexane-1,6-diamine:RC(O)NHNH2:Sm(NO3)3·6H2O=10:10:(0.3-0.7) at temperature of 65-75°C and atmospheric pressure in the mixture of solvents - ethyl alcohol and chloroform for 20-28 hours.

EFFECT: method of producing N-(1,5,3-dithiazepan-3-yl)amides with high selectivity and output, which can be used as biologically active compounds, selective sorbents and extractants of noble and precious metals.

1 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds for treating cell-proliferative disorders having formula (II): wherein the values R1,R2, X, A, B, R6, R7, R9 are specified in cl. 1 of the patent claim with the exception of the compound of formula: .

EFFECT: there are presented compounds possessing anticancer activity.

95 cl, 27 dwg, 11 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to a method of producing N-(1,5,3-dithiazepinan-3-yl)amides of general formula (1): where R = p-C5H4N (a), (CH3)3CO (b), o-CH3OC6H4 (c) which involves reaction of t-butyl-1,5,3-dithiazepinane with a hydrazide of general formula RC(O)NHNH2 [R is as described above] in the presence of an iron chloride crystalline hydrate catalyst FeCl3-6H2O in molar ratio t-butyl-1,5,3-dithiazepinane:RC(O)NHNH2:FeCl3-6H2O=10:10:(0.3-0.7) at temperature of 65-75°C and atmospheric pressure of a mixture of solvents - ethyl alcohol-chloroform for 40-48 hours.

EFFECT: novel method of producing N-(1,5,3-dithiazepinan-3-yl)amides with high selectivity and output, which can be used as biologically active compounds, selective sorbents and extractants of noble and precious metals.

1 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, and concerns an agent for treating or disinfecting of alkyl, aryl-(3,5-di-tert-butyl-4-hydroxybenzyl)phosphonium bromides and nitrates of general formula , having simultaneous bactericidal, fungicidal and antioxidant activity at low concentrations, high thermal stability and low toxicity, which can find application in medicine and veterinary science.

EFFECT: what is presented is a new therapeutic agent.

7 dwg, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a formulation for delivery of amphotericin B and other drugs, wherein the formulation contains an active ingredient, one or more esters of glycerol and fatty acids and one or more esters of fatty acids containing polyoxyethylene oxide, wherein the ratio of esters of glycerol and fatty acids and esters of fatty acids containing polyoxyethylene oxide makes from approximately 20:80 to approximately 80:20 vol/vol.

EFFECT: formulation is applicable for preparing the drug with improved bioavailability for infectious diseases.

13 cl, 21 dwg, 8 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely to a composition for local administration. The pharmaceutical composition for local administration characterised by the fact that it contains ketoconazole, or fluconazole, or terbinafine, as well as liposomes, an emulsifier, a preserving agent, demineralised water taken in certain proportions (versions).

EFFECT: composition provides fast cutaneous penetration of the active substances.

3 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to 2-amino-1-((phosphonoxy)methyl)-3-(3-((4-((2-pyridinyloxy)methyl)phenyl)methyl)-5-isoxazolyl)pyridinium of formula: and salts thereof effective as an antimycotic agent, and to pharmaceutical compositions and therapeutic agents based on it and the use thereof in treating mycotic diseases.

EFFECT: what is presented is the new effective antimycotic agent with improved water solubility and safety.

6 cl, 16 dwg, 3 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention relates to fish-breeding and veterinary. Application of fluoxastrobin as preparation for fighting mycoses in fish and invertebrates, as well as in all stages of their development, caused by fungi of genus Saprolegnia, Achlya, Aphanomyces.

EFFECT: invention ensures stop of development or cessation of vital activity of pathogenic fungi in breeding and maintenance of fish for prevention and treatment of fish diseases in aqua-culture, water bodies for breeding, reservoirs for breeding, aquariums, natural water bodies for sport fishing, ponds and sea reservoirs for fish.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound and a pharmaceutically acceptable salt thereof to be used as an antifungal agent, particularly, a therapeutic agent for deep fungal disease. The fungus Acremonium persicinum is collected, and a cyclic compound is recovered from its cultural fluid.

EFFECT: what is presented is the compound applicable as an antifungal agent.

10 cl, 16 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine. A dosage form for treating mycotic infections contains nanosomes of cholesterol-containing amphotericin B of the diameter within the range of 20-200 nm in physiologic saline, the ratio of lipid to amphotericin B ranges from 45:1 to 45:15. Amphotericin B is exposed to ultrasound to destruct at the final stage to transform the particles into smaller and less lamellar nanosomes.

EFFECT: invention provides lower nephrotoxicity and effective antimycotic activity.

3 cl, 11 tbl, 3 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds: 4-(1-cyclohepta-2,4,6-trienyl)aniline of formula I and chloride thereof of formula II . The compounds have antimicrobial activity towards a range of opportunistic pathogens: Staphylococcus aureus, Staphylococcus epidermis. Staphylococcus saprophytics, Escherichia coli and Candida albicans, as well as yeast-like fungi Candida albicans.

EFFECT: compounds have activity which is considerably higher than that of existing analogues in terms of antimicrobial action, as well as activity of the existing analogue which is closest in terms of structure with respect to yeast-like fungi Candida albicans.

1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to compounds of hyperbranched polymer Boltorn H complexes which may be used as substances, bases, ingredients and other biologically active substances in preparing chemopreparations for treating and preventing human fungoid diseases, particularly Candida mycosis, as well as to a method for preparing said compounds. The compounds of hyperbranched polymer Boltorn H complexes contains 10 to 14 groups of propionic or acrylic acids and 10 to 14 metal ions. The given compounds possess anti-candida activity on Candida albicans, Candida krusei, Candida tropicalis, Candida parapsilosis and provides action on the Candida proteinase system and the cell wall components. The method for preparing said compounds consists in synthesis of the compounds containing 10 to 14 groups of propionic or acrylic acids and 10 to 14 metal ions with the use of consecutive reactions of etherification, substitution and addition.

EFFECT: higher preventive and clinical effectiveness in the disease.

2 cl, 3 tbl, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula (I) X=N or C-R3; R1 stands for proton, saturated or unsaturated linear alkoxy radical, which has 2-5 carbon atoms; cycloalkyloxy radical, which has to 6 carbon atoms, saturated linear alkylmercapto radical, which has 1-3 carbon atoms; amino radical, having 1-10 carbon atoms, selected from saturated or unsaturated linear mono- or dialkylamino radical, or cycloalkylamino radical, cyclic amino radical, and each of cyclic groups can be substituted with 1-2 metal groups, or benzylaminogroup; R2 represents proton, saturated or unsaturated, linear alkyl radical, which has 1-5 carbon atoms, or cyclic aliphatic radical, which has to 6 carbon atoms, trifluoromethyl, stiryl or methylmercaptogroup; R3 stands for trifluoromethyl, formyl, acetyl, nitro, benzoyl, cyanogroup or alkoxycarbonyl sunstituent, which has 1-3 carbon atoms in alkoxygroup.

EFFECT: obtaining novel 2-nitroheterylthiocyanates of general formula (I), or their pharmaceutically acceptable additive salts with acids or bases, probably in crystalline form, possessing activity with respect to strains of fungi, causative agents of fungal infections, their application for treatment of fungal infections, as well as obtaining based on them pharmaceutical composition.

8 cl, 3 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new carboxamide compounds of formula I-A' or I-A" , as well as to tautomers thereof and pharmaceutically acceptable salts thereof, wherein R1 means hydrogen, C1-C10-alkyl, C3-C7-cycloalkyl-C1-C4alkyl, aryl-C1-C6-alkyl or hetaryl-C1-C4-alkyl, wherein aryl and hetaryl in the two last mentioned radicals may be substituted or have 1 radical R1c; wherein R1a represents C1-C6-alkoxy, R1c is independently specified in halogen, CN, CF3, O-CF3, O-CHF2, C1-C6-alkyl, C1-C6-alkoxy, hetaryl, O-CH2-aryl, - (CH2)p-NRc6Rc7 with p = 0 or 1; wherein Rc6 represents C1-C6-alkyl or SO2-C1-C6-alkyl, and Rc7 represents C1-C6-alkyl, or the two radicals Rc6 and Rc7 together with an N atom form 5- or 6-member, optionally substituted C1-C4-alkyl nitrogen-containing heterocyclyl which can optionally have 1 heteroatom from the group O and N as ring members, R2 means C1-C10-alkyl, C3-C7-cycloalkyl, aryl, hetaryl, wherein aryl and hetaryl in the two last mentioned radicals may be unsubstituted or carry 1, 2 or 3 identical or different R2c radicals; wherein R2c have one of the values specified for R1c; R3a and R3b together with a carbon atom whereto attached, are C=O; X means hydrogen or a radical of formulas C(=O)-O-Rx1 or C(=O)-NRx2Rx3, wherein Rx1 means C1-C6-alkyl, Rx2 means H or C1-C6-alkyl, and Rx2 means H, one of the variables Y1, Y2, Y3 and Y4 forms a nitrogen atom, and the rest variables Y1, Y2, Y3 and Y4 mean CH, n is equal to 0 or 1, Ry is independently specified in halogen, CN, aryl, -NH-SO2-Ry4, -(CH2)p-NRy6Ry7 with p = 0; wherein Ry4 means C1-C6-alkyl, Ry6 has one of the values specified for Rc6, and Ry7 has one of the values specified for Rc7; m means 0 or 1 for formulas I-A', and Rw is specified in halogen, C1-C6-alkyl, C1-C6-alkoxy, wherein C1-C6-alkyl can have 1 substitute Rwa, aryl, -(CH2)p-NRw6Rw7 with p = 0 or 1, Rwa has one of the values specified for R1a, or represents NRa2SO2Ra4, Ra2 represents H, Ra4 represents C1-C6-alkyl, Rw6 has one of the values specified for Rc6, Rw7 has one of the values specified for Rc7, m is equal to 0, 1 or 2 for formula I-A", and Rw6* has one of the values specified for Rw, E has one of the values specified for: -CHRE2-CHRE3-, -CH2-O-, -O-CH2-, -S-CH2-, -CH2-S-, -CH2-SO2-, -SO2-CH2-, wherein Re2, Re3 represent hydrogen; wherein aryls defined above, represent mono- or bicyclic aromatic hydrocarbon radicals such as phenyl or naphthyl, and hetaryls defined above, represent 5 - or 6-member aromatic heterocyclic radicals containing 1 or 2 heteroatoms specified in nitrogen, oxygen and sulphur and can additionally contain a condensed benzene ring. Also, the invention refers to specific compounds, pharmaceutical compositions containing them and use thereof.

EFFECT: there are prepared new derivatives of carboxamide compounds effective in the treating the disorders caused by higher activity of calpain.

15 cl, 1 tbl, 195 ex

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