5- {(3,5-bis)1,1-dimethylethyl(-4-hydroxyphenyl)-methyl} -4 - thiazolidinone, which has anti-inflammatory and anti-arthritis properties


(57) Abstract:

Usage: in medicine, in particular as anti-inflammatory and anti-arthritis activity. The inventive product - 5 - {[3,5 - bis(1,1 - dimethylethyl) - 4 oksifenil] - methyl} - 4 - thiazolidinone; BF C18H27NO2S ; so pl. 149 - 152°C. Reagent 1: 5 - {[3,5 - bis(1,1 - dimethylethyl) - 4 oksifenil] - methylene} - 2 - thioxo - 4 - thiazolidinone. Reaction conditions: hydrogenation reagent 1 in the presence of palladium on coal in the solvent environment. 7 table.

The invention relates to a new di-tert-butylaniline derivative used for the treatment of inflammatory processes, as well as caused by ischemia damaged cells.

As you know, mammals, both for man and animals can suffer from various diseases accompanied by inflammation, which is accompanied by swelling, tenderness, decreased mobility, pain, and fever. There are many anti-inflammatory drugs, is effective in the symptomatic treatment of inflammatory diseases such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, joint diseases, etc. are, however, many such funds oblad age and pathogenesis of rheumatic and arthritic diseases remain unclear. At the same time, a growing demand for safer, better balanced drugs that would slow down the development of inflammatory diseases and facilitate its flow. For example, in rheumatoid arthritis any means, relieving inflammation, plays an important role to reduce or slow the development of vechnosti.

The present invention relates to a specific di-tert-butylaniline derivative, used as anti-inflammatory agents, which are also applicable to slow down the progression of arthritic diseases. One of the compounds used in the method and composition of the present invention, namely 5- { [3,5-bis(1,1-dimethylethyl)-4-hydroxyben-yl] methylene} -2-thioxo-4-thiazolidinone described by Teuber et al., Liebigs Ann. Chem., 757 (1978) as an intermediate connection when receiving certain compounds, which in turn is used for spin-labeling of peptides. No biological use for this intermediate compounds has not been described. Certain 3,5-di-tert-butyl-4-hydroxybenzylidene azole derivatives as anti-inflammatory drugs are indicated in the work Isomura et al., Chem. Pharm. Bull., 32(1), 152 (1984).

On the anti-inflammatory active the ptx2">

In U.S. patent N 4464382 stated that certain derivatives of rhodanine are inhibitors aldesleukin. However, in all the claimed compounds must be present as a substituent at the nitrogen atom in the ring of rhodanine acetic acid.

In accordance with the invention, it was found that di-tert-butylaniline derived formulas

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(I) applicable for treatment of inflammatory diseases such as arthritis.

The compound of formula I is a new connection.

The compound of the formula I can be obtained by catalytic hydrogenation of 5- { [3,5-bis(1,1-dimethylethyl)-4-hydroxide-Neil] methylene }-2-thioxo-4-thiazolidinone (compound of formula (II).

The results also compound Ia:5- { (3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl] methylene }-4-thiazolidinone.

The relative content of each depends on temperature, pressure and duration of the hydrogenation, the solvent and the specific type of the used catalyst. For example, when processing the compounds of formula II with 5% palladium on coal in ethanol at 100about18 h approximate ratio Ia/I is 60: 40. Or the specified transformation can be accomplished by heating the compounds IIa in Sol is ensiling communication can be carried out by heating thione with a reducing agent, such as the hydride triamcinolone, in particular tri-n-butilbiguanid in an inert solvent, such as toluene, and preferably in the presence of an initiator of free radicals, such as azobisisobutyronitrile. The reaction is usually conducted in the temperature range of 50-120about, Restore the connection of the formula I, where R1and R2represent the relationship.

The following examples illustrate the method of obtaining the compounds of the present invention.

P R I m e R 1. 5-{ [3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl] methylene} - 2-thioxo-4-thiazolidinone (compound II).

In nitrogen atmosphere in 2500 ml of glacial acetic acid is heated to boiling 117,2 g of 3,5-di-tert-butyl-4-hydroxybenzaldehyde, 66.6 g of rhodanine and 143.5 grams of fused sodium acetate. After heating for 23 h, the reaction mixture is cooled and transferred to a mixture of 1 l of ethanol and 1 l of ice water and stirred. Add 500 ml of water after stirring for 30 min and the resulting precipitate was separated by filtration. The solid is weighed into 500 ml of ethyl acetate and filtered. The precipitate was dissolved in 3 l of ethanol, boil and add water until the turbidity of the solution (about 450 ml). After cooling the mixture to room temperature LASS="ptx2">

Calculated, % : C 61,86; N 6,63; N 4,01; Found, %: C 62,13; N 6,55; N 4,15.

P R I m e R s 2-3. 5- {[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene} -4-thiazolidinone (compound Ia) and 5- {[3,5-bis (1,1-dimethylethyl)-4-hydroxyphenyl]methyl} -4-thiazolidinone (compound I).

The solution to 69.9 g of 5- {[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] methylene} -2-thioxo-4-thiazolidinone in 4 l of ethanol hydronaut under pressure 500 psi (35 bar) during the day when 100aboutIn the presence of 200 g of a 5% palladium on coal. The reaction mixture is filtered and evaporated to dryness. Portions of the product is dissolved in 1 volume of hot ethyl acetate, diluted with 2 volumes of hexane, filtered and loaded into a chromatographic column filled with silica gel. Leaching with a solution of 35% ethyl acetate in hexane get different fractions which are combined in accordance with the purity of each compound. In total, chromatographytandem obtained 4.6 g of compound Ia. Fractions with predominant content of the compound Ia is crystallized from a mixture of ethyl acetate with hexane to obtain a total of 13,79 g of compound Ia. Re-chromatography of the fractions containing the contaminated compound I, on the silicon oxide using to flush 25% ethyl acetate in hexane, poluchilos; so pl. 209-213aboutC.


Calculated, %: C 67,67; N 7,89; N Of 4.38.

Found, %: C 67,44; N 8,11; N 4,65.

3) 5- {[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl] methyl} -4-thiazolidinone; so pl. 149-152aboutC.


Calculated, %: C 67,25; H Of 8.47; N 4,36.

Found, %: C 67,43; N 8,44; N 4,21.

It was found that the connection is discussed in example 3, shows a remarkably high activity in the treatment of inflammatory bowel bypass, i.e., that it is useful in the treatment of inflammatory bowel disease.

As proof of the identified activity, are presented below the experimental data.

As far as we know, does not currently have connections, which cured this disease, and that definitely applies to the compound disclosed in J. A. C. S., 1932, 54, 1668.

And finally, the compound of example 3 allatoxin.

Rats Spraque-Dawley obtained from Charles River Laboratories, Portaqe M1 (of any gender, weight 250 g) was administered orally twice a day the test compound or vehicle (control) for 3 days. On the third day, rats made enema inside the bypass of the intestine containing 2% acetic acid, ferestrele has caused a dramatic inflammatory response to bypass the gut, which was characterized by bleeding in the rectum, diarrhea, erosion of the epithelium and destruction of the gaps of the cells and glands. After 24 h the test and control animals were euthanized, they had removed a segment of bowel bypass length of 10 cm and disclosed in the longitudinal direction. Tissue damage, available in the remote, open the bypass section of the intestine was observed by three independent, "blind" observer, giving assessment on a scale from 0 to 4 (zero-normal, four is the strongest inflammation). In each subjected to the test group was 5-7 rats. The results of the tests are given below.

Suppression of colitis induced by acetic acid Compound of the Observed example of damage Control 3,40,3 Example 3 0,40,1

Rats Spraque-Dawley obtained from Charles River Laboratories, Portage, M1 (male, weight 300 g) were starved for 24 hours at 24 h, the test animals were injected orally at the rate of 3 ml/kg rat, medium (control) or the test compound, dissolved in a carrier. After 30 min, each animal was given 100% ethanol. After 60 min after alcohol administration, all animals were killed and their stomachs removed and washed. Tissue damage inside the remote open the stomach was observed in three independent Nalepa consisted of 6 rats. The test results obtained from animals that were administered the test substance dissolved in the medium, compared with the results obtained from animals that were injected only media, with the aim of determining the percent suppression of damages that can be attributed to the effect of the test compounds. The test results are given in table. 1.

It has been found that the compounds of formula I inhibit in vitro 5-lipovenos. In addition, it was shown that the compounds are inhibitors of phospholipase A2. Moreover, the compounds showed activity in vivo in various test systems designed to detect anti-inflammatory and anti-arrhythmic drugs. This pharmacodynamic effect is shown in the following test systems.

Experiments with carragenine.

The compounds were tested for anti-inflammatory activity in test methods described by C. A. Winter, Proc. Soc. Exp. Biol. Med., III., 544 (1962). In this test, the inflammation cause by injection carrageenin in hind paws of rats. Before the injection is administered test compounds to determine the percentage of inhibition compared with the control animals. The results are shown in table. 2.

J. Pharmac., 69, 467 (1980) Guinea pigs of both sexes race Hartley weighing 250-300 g make-sensitive ovalbumin injection each animal with a single dose of 1 μg of ovalbumin mixed with 50 mg of aluminum hydroxide. These animals rely on 21-26 day for injection into the pads of ovalbumin, covalently linked to agarose.

Granulomatose cause inflammation by injection of 0.1 ml of Affi-gel Ovalbumin (Laboratories Bio-Rad, Richmond, PCs California) pads sensitive Guinea pigs. 3 days after injection to measure the amount of injectionand and reinjection pads of the paws. The amount of pads (pads of the feet) change by displacing the water by using a Statham pressure transducer' and a digital voltmeter. The difference in the amount of feet between inyecciones and reinjection tabs shows the degree of inflammation. Histological examination of inflamed paws shows infiltration of neutrophils between the first and third day and macrophages to the third day. To 11 days observed focal extensive granulomatose inflammation. A marked infiltration of inflammatory cells, mainly consisting of macrophages, reducing the number of multinuclear giant cells, eosinophils, plasma cells and lymphocytes of Ovalbumin in the ball of the foot for 3 days before, give the test compound, clinical Antirheumatic drugs, such as penicillamine or a placebo, which is 8 days mix in the diet or administered orally through the nose using a gastric probe for 4 days. Replace the volume of the paws and the difference in volume injectionand and reinjection feet with a difference on the third day and the first day of treatment with medications. The percentage of inhibition granulomatoses inflammation calculated by the following equation:

% inhibition = 1 - 100 , where Time.about.-3 is the difference in the amount of feet between inyecciones and reinjection feet on the third day and Time.about.-11 is the difference in volumes injectionand and reinjection feet on the eleventh day. The results of the tests are summarized in table. 3.

Experiments with induced collagen arthritis

According to the method Strawich and Nimni Biochemistry, 10, 3905 (1971)/from bovine articular cartilage secrete collagen type II. Collagen is dissolved in acetic acid and stored at -20aboutC. Collagen type II was diluted to a concentration of 2 mg/ml and carefully emuleret in an equal volume of incomplete auxiliary substance Freund' a (NFW). The emulsion containing about 0.5 mg of collagen is injected into the injection Gia injected intradermally on day 0. Three times a week during the test, measure and record the volumes of the rear legs to identify the inflammatory response. Since day 1, the test group of animals receives the test compounds in the form of a suspension in carboxymethyl cellulose (medium) orally via a stomach tube, 5 days per week (Monday - Friday). Control animals receive the medium without the test compound. At the end of the test (day 28 or 30) in animals with cardiac puncture away the blood, in which the use of techniques with passive agglutination of red blood cells determine the level of antibodies to collagen anti-type II in serum, using treated with glutaraldehyde red blood cells sheep, to which collagen type II paired [Avrameas et al., Immunochemistry 6, 67 (1969); Andrio-poulos and other Arth. Rheum., 19, 613 613 (1976)]. Cellular signal or the delayed hypersensitivity type response to collagen type II is measured by radiometric ear indicator [Kostiala, Immunoloqy, 33, 561 (1967)]. In some cases, radiographs of the hind paws of two or three animals from each group determine bone damage caused by immunization with collagen type II and action of drugs. Injection NPV without collagen II is used to nematolosa (media).

The test results of the compounds of formula I in the system caused by collagen arthritis summarized in table. 4. % inhibition calculated by the following formula:

% inhibition = 1 - 100, where Vtis the volume of the hind legs of the animal treated with the compound (test group);

Vcis the volume of the hind legs of the animal not receiving connection (media-carbomethoxyamino, control group);

Vvis the volume of the hind legs of the animal treated with the carrier (carbomethoxyamino) and NFW without collagen II (negative control group).

The development of tests called auxiliary substance arthritis in rats.

The compounds were tested for the ability to change the swelling of the hind paws and bone damage that occurs in the result caused by the auxiliary substance edema in rats. With the aim to quantify the inhibition of swelling of hind paws in the result caused by the auxiliary substance arthritis made it defines two phases of inflammation: (1) primary and secondary in inyecciones the back foot and (2) secondary reinjections the back foot, which begins to develop after about 11 days after inducyruetsa activity. Cm. Chang, Arth. Rheum.,20, 1135-1141 (1977).

Called auxiliary substance induce arthritis in male rats race Lewis-Wistar (200-210 g) only peressini injection in the right hind paw with 0.1 ml of 0.5% suspension of killed heating liofilizovannyh Mycobacterium tuberculosis (Calbiochem-Perrigen-C) in mineral oil (modification of methods described in the paper by Winter et al., Arth. Rheum., 9, 394-397 (1966). One group of 10 rats ("TB-control) were subjected only to such processing. Another group of 5 rats was not processed (normal control). Each test compound suspended in carboxymethylcellulose (1% ) and administered orally to rats (groups of 5 rats) daily doses of 50 mg/kg, starting from the first day and 28 day after the injection of auxiliary substances (29 doses). Measure the feet by using a Statham pressure transducer' and a digital voltmeter with displacement of mercury. Volumes as injectionand and reinjection hind legs is measured in day 16, 18, 21, 23, 25, 28 and 30. On the 30th day off radiograph after sacrifice of the animals. Volume measurements injectionand feet, held from 16 days and 30, postpone using the computer for TV control, normal control and for animals, taking drugs is social control)/measure. The results obtained are summarized in table. 5.

It was also shown that the compounds of formula I prevent caused by ischemia cell damage, in particular damage to neuronal cells by the impact, as shown by the following test system.

Modeling of shock in rats

Kick in rats cause a blockage of the four arteries, which in the brain is blood, according to the following method. Male rats of Wistar race anaesthetize with metofane and placed in stereotoxic tool. On the dorsal surface of the neck make a longitudinal incision. Neck muscles are away, providing access to the dorsal surface of the spine. The two vertebral arteries reveal where they pass through the first cervical vertebra. Both arteries tightly sealed by the application of Elektroprivreda. After coagulation of the vertebral arteries of the rat is removed from stereotaxic instrument and the surgical wound is sutured. Then on the ventral surface of the neck make two longitudinal cuts. Reveal two common carotid artery and remove the surrounding nerves and connective tissue. Each carotid artery impose aromaticheski clip, made mainly from silicon trubecki clamp is designed that may be compressed with blocked carotid artery, if you pull a small thread of Celestica that comes out of the wound. Circulation to the brain via the carotid artery can be restored when the tension on the thread from elastica. After the surgery waiting 24 hours until the rats will Wake up.

On the day of the test compounds suspended in 2% Arabian gum and administered orally at different times before the induction stroke. The strokes (cerebral ischemia) causes compression around the carotid artery clamping for 30 minutes. During this time the rats, whose shot was successfully invoked lose reflex straightening and become insensitive to the stimulants. After 30 minutes of ischemia burden on the clamps removed with restoration of blood flow to the brain. Rats again allow connections on the morning after impact. On the third day after hitting animals given high dose barbiturate anesthetic and their brains poured in situ 10% neutral buffer formalin. After washing with aqueous formaldehyde in a quantity sufficient for fixation of the brain, the brain removed and stored in 10% formalin until the preparation of histological sections.

One of the areas of the brain most sensitive to induced ischemia on the, which remain insensitive within 30 min of ischemia, CA1pyramidal cell layer completely destroyed. This layer is examined under a microscope in histological sections prepared from hippocam. Brain damage graduate according to the following scale: - no damage, fully intact cell layer; 1 - slight damage to one-third of CA1layer destroyed; 2 - moderate damage, destroyed two-thirds of CA1layer; 3 - severe damage to the complete destruction of CA1layer.

With the aim of obtaining an accurate picture of the damage investigated corruption in 10-12 slices from each brain. Average damage count for each group. Indicators for animals treated with compounds compared statistically with the figures for the control group who received only the vehicle (2% Arabian gum), which was used for the suspension of the compounds. The level of significance determined using t-criterion of student. The results obtained are summarized in table. 6.

The compounds of formula I are anti-inflammatory and anti-arthritis means; and the invention provides methods of their use. Methods are vvedennya, intramuscularly, or through the nose, and is usually used in the form of pharmaceutical compositions. A characteristic feature of these compounds is that they are effective when administered orally. Such compositions are prepared by methods well known in pharmacology, and they contain at least one active connection.

In the manufacture of the compositions of the present invention are usually mixed with a carrier, or diluted by a carrier, or include in the media, which may be in the form of a capsule, sachet, paper or other container. If the media is used as a diluent, it may be solid, semi-solid or liquid material, which plays the role of the carrier, excipient or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lepestok, bags, wafers, Alexiou, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10 wt.% active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and powders in sterile bags.

Some examples of applicable carriers, excipients and diluents include lactose, dextrose, sucrose, Sora is kristallicheskuyu cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl - and propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The formulations can additionally include: lubricating, wetting means, emulsifiers, suspender the following tools, preservatives, sweetening tools and fragrances. Compositions of the invention can be designed to provide quick, sustained or delayed allocation of the active ingredient after administration to the patient by using well-known procedures.

The composition is preferably produced in a unit dosage forms, each dosage contains from about 5-500 mg, more than about 25-300 mg of the active component. The term "unit dosage form" refers to physically discrete unit, applicable as a unit dosage for administration to humans and other mammals, each unit contains a specified quantity of active ingredient calculated to create the desired therapeutic effect, in a mixture with a suitable pharmaceutical carrier.

The active compounds are effective in a wide range of dosages. For example, dosages per day, usually fall in the range of about 0.5-200 mg/kg of body weight. Predue to understand the number of compounds used in practice will be determined by the physician from the point of view of the particular circumstances, including the disease, selection of the introduced compound, chosen route of administration, age, weight and response of the individual patient, the severity of symptoms of the patient, resulting in the above intervals dosages in no way intended to limit the scope of the invention.

The following examples of compositions can be used as an active ingredient any one of the compounds of formula I. Examples are illustrative and are not intended to limit the scope of the invention.

P R I m e R 4. Hard gelatin capsules is obtained by using the following components:



5-{ [3,5-Bis(1,1-



methyl}-2-thioxo-4 - thiazolidinone 250

The dried starch 200 magnesium Stearate 10

The above components are mixed and the mixture fill hard gelatin capsules in the amount of 460 mg.

P R I m e R 5. Tablets obtained by using the following components:



5- {[3,5-Bis(1,1-



new keys lot of 5

The components are mixed and pressed to form tablets, each weighing 665 mg

P R I m e R 6. Get a spray solution containing the following components, wt%:

Number, %

5- {[3,5-Bis(1,1-



methyl} -4-thiazole - Denon 0.25 Ethanol 29,75 Propellant 22 (chloripromene) 70,00

The active compound is mixed with ethanol and the resulting mixture is mixed with part propellant 22, cooled to -30aboutWith, and transferred to a filling device. Then the required number served in a stainless steel container and diluted with the remaining amount propellant. Finally, the supply container valve device.

P R I m e R 7. Tablets, each containing 60 mg of active ingredient, are prepared as follows (mg):

5- {[3,5-Bis(1,1-



methylene }-2-CTI - with-4-thiazolidinone 60 Starch 45

Microcrystal - ical cellulose 35


Lydon (as 10% solution in water) 4

Natrocarbonatite - telcanal 4.5 magnesium Stearate 0.5 Talc 1

Total: 150

The active ingredient, starch and cellulose sieved on 45 mesh (U.S. standard) and thoroughly mix. Received the e granules dried at 50-60aboutWith and sieved on 18 mesh (U.S. standard). Natrocarbonatite-starch, magnesium stearate and talc, previously sifted through a sieve of 60 mesh (U.S. standard), added to the granules which, after mixing pressed on teletrauma machine to obtain tablets each weighing 150 mg

P R I m e R 8. Candles containing each 225 mg of the active component, was prepared as follows:

5- {[3,5-Bis(1,1-




2 thioxo-4-thiazo - ledenon, 225 mg

Glycerides of Nazi-

freed fatty acids, mg 2000

The active ingredient is sifted through a sieve of 60 mesh (U.S. standard) and suspended in the glycerides of saturated fatty acids, pre-melted at the lowest possible temperature. The resulting mixture is then poured into molds for candles on 2 g and cool.

P R I m e R 9. Capsules, each containing 150 mg of the drug, was obtained as follows:

5- {[3,5-Bis(1,1-



methylene} -2-thiazo - ledenon, 150 mg Starch, 164 mg


health Zell - vine, 164 mg Stearate magnesium, mg 22

Just 500

The active ingredient, cellulose, starch and magnesium stearate smey in the amount of 500 mg.

5- { (3,5-bis)1,1-Dimethylethyl(-4-hydroxyphenyl)-methyl } -4-thiazolidinone formula

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it has anti-inflammatory and anti-arthritis properties.


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12 cl, 2 dwg, 32 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compounds of the general formula (1): wherein X is chosen from sulfur atom and methylene group; X1 is chosen from sulfur atom and methylene group; X2 is chosen from oxygen (O), sulfur (S) atoms and methylene group; X3 means -NR5 or carbonyl group; R1 means hydrogen atom or nitrile group; R and R3 are chosen independently from hydrogen atom (H) and (C1-C6)-alkyl; R4 means R4A when X3 means -NR5 and R4B when X3 means carbonyl group; R4A is chosen from -R6R7NC(=O), -R6R7NC(=S), -R8(CH2)qC(=O), -R8(CH2)qC(=S), -R8(CH2)qSO2 and -R8(CH2)qOC(=O); R4B means -R6R7N; R5 means hydrogen atom (H); R6 and R7 are chosen independently from -R8(CH2)q, or they form in common -(CH2)2-Z1-(CH2)2- or -CHR9-X2-CH2-CHR10-; R8 is chosen from hydrogen atom (H), (C1-C4)-alkyl, cycloalkyl group condensed with benzene ring, acyl, dialkylcarbamoyl, dialkylamino-group, N-alkylpiperidyl, optionally substituted aryl, optionally substituted α-alkylbenzyl, optionally substituted aroyl, optionally substituted arylsulfonyl and optionally substituted heteroaryl representing monocyclic 5- and 6-membered ring aromatic group with one or two heteroatoms chosen from nitrogen, oxygen and sulfur atoms, and derivatives of abovementioned rings condensed with benzene; R9 and R10 are chosen independently from hydrogen atom (H), hydroxymethyl and cyanomethyl groups; Z1 is chosen from -(CH2)r-, -O-, and -N((CH2)q)R8)-; Z2 means optionally the substituted ortho-phenylene group; m = 1-3; n = 0-4; p = 2-5; q = 0-3, and r = 1 or 3. Proposed compounds are inhibitors of dipeptidyl-peptidase IV and can be used in preparing pharmaceutical compositions designated for treatment of different diseases, among them, diabetes mellitus of type 2.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

22 cl, 8 tbl, 453 ex

FIELD: medicine.

SUBSTANCE: method involves using dipeptidyl peptidase IV (DP IV or CD 26) or DP IV-like enzyme for producing drug for treating stress or anxiety cases. Inhibitors are usable in combination with neuropeptides Y. The inhibitors are transported in physiologically compatible carriers. The inhibitors are also produced as prodrugs.

EFFECT: enhanced effectiveness of treatment.

6 cl, 11 dwg, 2 tbl

FIELD: organic chemistry.

SUBSTANCE: invention relates to new polymorphous crystalline forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)-amino]-ethoxy]-benzyl]-thiazolidine-2,4-dione maleate of formula and stereomers thereof.

EFFECT: polymorphous crystalline forms of high stability.

12 cl, 1 tbl, 13 dwg, 5 ex

FIELD: organic chemistry, medicine, cosmetics, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means radical of the following formulae: (a) or (b) wherein R2 and R3 are similar or different and mean hydrogen atom, alkyl with 10-12 carbon atoms, aryl, radical -OR7; X means a binding fragment of the following formula: -(CH2)m-(Z)n-(CO)p-(W)q- wherein a binding fragment can be read from the left to the right or inversely; R4 means alkyl with 1-12 carbon atoms, aryl, aralkyl, heteroaryl or 9-fluorenylmethyl; Y means radical -CH2 or sulfur atom; R5 means hydroxyl, alkoxyl with 1-6 carbon atoms, radical -NH-OH or radical -N(R8)(R9); R6 means alkyl with 1-12 carbon atoms, radical -OR10 or radical -(CH2)r-COR11; R7 means hydrogen tom or aralkyl; Z means oxygen atom or radical -NR12; W means oxygen atom, radical -NR13 or radical -CH2; m, n, p and q are similar or different and can mean 0 or 1 under condition that the sum (m + n + p + q) = 2 or above, and when p = 0 then n or q = 0; R8 means hydrogen atom; R9 means hydrogen atom or aryl; r means 0 or 1; R10 means alkyl with 1-12 carbon atoms; R11 means hydroxyl or radical -OR14; R12 means hydrogen atom or alkyl with 1-12 carbon atoms; R13 means hydrogen atom or alkyl with 1-12 carbon atoms; R14 means alkyl with 1-12 carbon atoms; and optical and geometric isomers of abovementioned compounds of the formula (I), and their salts also. These compounds are useful as activating agents of receptors of type PPAR-γ in pharmaceutical compositions designated for using in medicine, in particular, in dermatology, in treatment of cardiovascular diseases and related to immunity of diseases and/or diseases associated with lipid metabolism, and in cosmetic compositions also.

EFFECT: valuable properties of compounds and compositions.

19 cl, 1 tbl, 2 dwg, 37 ex