The way to obtain 2-substituted 4-(3-tert-butyl-4 - hydroxyphenyl)-thiazolo

 

(57) Abstract:

Usage: medicine for the treatment of inflammatory diseases. The inventive product 2-substituted 4-(3-tert,butyl-4-hydroxyphenyl)-thiazolin f-ly I, where R1- alkyl, R2is hydrogen, alkyl, A-chain of the formula: - (CH2)n-J-CR3R4; - -CH=CR3-(CH2)mor CH=N-O-(CH2)n-; Y is a simple bond, oxygen, sulfur, a carbonyl group, R3and R4- H, alkyl, n=0 to 3, m=1 - 4, z-tetrazol, CN-group, or a group of f-crystals-C(=O)X, where X is hydroxy, the residue of f-crystals R5or NR6R7where R5alkyl which may be substituted by hydroxyl, C1-C3-alkoxygroup or C1-C3-alkylamino; R6and R7is hydrogen alkyl. Reagent 1: amide thiocarbonates acid f-crystals: H2N-C(=S)AZ . Reagent 2: halogen-1-phenylalanin f-crystals 2, where L is halogen. 7 tab., f-crystals 1 and 2: , .

The invention relates to organic synthesis and concerns a method for obtaining new 2-substituted 4-(3-tert.butyl-4-hydroxyphenyl)-thiazolo.

These new compounds possess high therapeutic activity for the treatment of inflammation, in particular rheumatic diseases.

Found that the need to arpegiate deep and prolonged intervention in the inflammatory process, satisfied by gaining new thiazole derivatives, for which the characteristic is 5-alkyl-3-tert.butyl-4-hydroxyphenylethyl Deputy, and another Deputy with a carboxyl or a derivative of her group. By combining these two substituents on the thiazole ring in enhanced degree suppressed immunopathological processes underlying the chronic phase of inflammation and, therefore, is achieved favorable Antirheumatic mechanism of action.

Thanks to its properties, inhibiting cyclo - and lipoxygenase, its ability to deactivate through its antioxidant potential of oxygen radicals, as well as your property favorable to intervene in impaired immune system, new thiazole derivatives suitable for use in medicinal products, especially those that are shown in inflammatory rheumatic diseases. Thus, the object of the invention is a method of obtaining a new 2-substituted 4-(3-tert.butyl-4-hydroxyphenyl)-thiazolo General formula

< / BR>
(I) where R1is saturated or unsaturated WITH1-C5is an alkyl group with straight chain or branched,

R2>n-Y-CR3R4-; -CH=CR3-/CH2/m- or-CH=N-0-/CH2/n- moreover - it is a simple bond, oxygen atom or sulfur, or carbonyl group,

R3and R4- same or different and represent a hydrogen atom or an alkyl residue with 2 C-atoms,

n is a number from 1 to 4, and

m is a number from 0 to 3, and

Z - tetrazol or CN group or a residue of the formula

-C-, where X is a hydroxy - group or a residue of the General formula R5Or

R6R7N-, and R5is1-C4-alkyl residue, a straight chain or branched, which may be substituted by hydroxyl,1-C3-alkoxygroup or1-C3-alkylaminocarbonyl, R6and R7- same or different, represent a hydrogen atom, a C1-C6-alkyl residue, a straight chain or branched, or when R6means a hydrogen atom or a C1-C4is an alkyl residue.

R7is hydroxyl, WITH1-C3-alkoxy - or tetrazol-5-yl group, or X with structural elements And/C=0/ - together represents a residue of the General formula II

CHR8< / BR>
(II) when R8means a hydrogen atom, a C1-C3- is ormula I, in which X is hydroxy or hydroxylamino.

The connection according to the invention receive what amide thiocarbonates acid of General formula III

H2N--A-Z

(III) is subjected to interaction with the 2-halogen-1-phenyl-alkanoate formula IV

where A, Z, R1, R2have the above values, and L is halogen, preferably chlorine or bromine, for transformations usually take equimolar amounts of reactants are used primarily polar solvents such as alcohols (methanol, ethanol, various propanol or butanol), but also lower aliphatic carboxylic acids, such as formic acid and acetic acid, and esters of acetic acid, acetone, butane-2-it, dimethylformamide or acetonitrile, or mixtures of the mentioned solvents.

This reaction is carried out usually at temperatures from about 20aboutC to the boiling temperature of the reaction medium, particularly from about 50 to 80aboutC, and the time the reaction is within less than one hour and about 3 o'clock

Thiocarbamide General formula III required for the method (a) can be obtained according to the method known to the expert, for example, as a result of merger with doctitle Foundation, used in catalytic to equimolar quantities is amines, such as triethylamine, pyridine, but also the alcoholate and hydrosulfide alkali metals. This reaction is carried out in an organic solvent, in particular alcohol, like methanol, ethanol or propanol, or pyridine; particularly suitable is a mixture of pyridine and triethylamine. The reaction temperature is in the range between about 0aboutC and the boiling point of the employed solvent, preferably this reaction is carried out at room temperature (about 20-30aboutC).

Another form of the method is to use dithiophosphoric acid-0,0-dialkylamino, in particular methyl or ethyl ether complex as a source of hydrogen sulfide (S. W. Walter, and K. D. Bode, Angew. Chem., 1966, 78, S. 517-532), in which the primary cleavage product deposition in the reaction mixture podaetsya hydrogen chloride at temperatures of about -10 to 20aboutWith, preferably about -10 to 0aboutC.

Used as educt 2-halogen-1-phenylalanine formula IV are known from the literature, or they can be easily obtained from 1-(3-alkyl-5-tert. butyl-4-hydroxy-phenyl)-alkanones the result of turning the>As suitable compound IV should be called, for example, 2-bromo-1-(3,5-di-tert. -butyl-4-hydroxyphenyl)-alanon and 2-bromo-1-(3-methyl-5-tert.butyl-4-hydroxyphenyl)-Etalon, which can be obtained by the halogenation correspondingly substituted 1-phenylalaninol in elementary bromine or copper-II bromide according to the method of L. C. King and Y. K. Ostrum, J. Org.Chem., 1964, 29, S. 3459-3461.

To obtain those compounds of the formula IV, in which Z denotes a chlorine atom, are suitable in particular sulfurylchloride introduced into the reaction preferentially at temperatures between about 10 and 30aboutIn the presence of inert solvents, such as methylene chloride or chloroform, with the corresponding 1-phenylalanine. Another way to get is the Friedel-Craft-acylation of 2-alkyl -, tert-butylphenol using mainly chloroacetanilide in the presence of Lewis acids such as aluminum chloride or mortified. The proposed compounds of General formula I can, if they contain a carboxyl group, form salts with inorganic or organic bases. Therefore, these salts are also subject of the present invention.

Preferred are salts with inorganic bases, especially the physical is its 2-substituted 4-(3-alkyl-5-tert-butyl-4-hydroxyphenyl)-thiazole formula I and their corresponding salts because of their valuable pharmacological properties in a special way suitable for use as biologically active substances in medicinal products, in particular for such medicines, which are used for the treatment of inflammatory rheumatic diseases. They could be released separately, for example in the form of microcapsules, in mixtures with one another or in combination with appropriate auxiliary substances and/or substances-carriers.

The subject of securities of the invention to provide medicaments which comprise at least one of the compounds of formula I and/or at least one connection of their respective salts, or contain one of these biologically active substances together with a pharmaceutically suitable and physiologically tolerated substances-carriers, solvents and/or other auxiliary substances.

The proposed medicinal product can be applied orally, toxic, rectal or in this case also dropped, while preferably oral administration.

Appropriate solid or liquid Galenika form preparations include, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and drugs with protagorean the issuance of the biologically inosital, explosive materials, a binder, a substance for coating, means swelling, sliding or lubricants, flavorings, means for sweetening or agents of dissolution. As the most frequently used excipients should be called, for example, magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and derivatives thereof, animal and vegetable oils, polietilenglikoli and solvents, such as sterile water or monovalent or polyvalent alcohols, such as glycerin.

Mainly receive and let go of pharmaceuticals in certain dosage units, with each unit contains as an active component part of a certain dose of at least one of the compounds of formula I and/or the corresponding salts. When the solid dosage units such as tablets, capsules, coated tablets or suppositories, this dose can be up to about 800 mg, but preferably approximately from 100 to 500 mg.

For the treatment of adult patients suffering from populationgenetics diseases, depending on the effectiveness of the compounds according to the formula I and/is TBA, mostly about 300-1100 mg, oral vacations. In some circumstances, however, may be acceptable as well higher or lower daily doses. Vacation daily doses can be performed as in the single issue in a single unit dosage, and multiple vacations divided doses at regular intervals.

Can be used the compounds of formula I and the corresponding salts upon receipt of the above galenically forms of cooking together with other suitable biologically active substances, for example, antimikotika, thrombozytenanstieg inhibitory substances, painkillers and other steroid and not steroid anti-inflammatory drugs.

The structure of all the below-described compounds was confirmed by elemental analysis and infrared andIH-NMR-spectra. The compounds of formula I obtained according to the following examples and similarly presented in table.1.

P R I m e R 1. Ethyl ester of 3-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)- thiazol-2-yl]propionic acid

and1) 2-bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-alanon

20.6 g agravat to a boil for 15 minutes dropwise dilute bromine in the amount of 14.4 g (90 mmol). After this in the next 2 hours and heated under reflux, the mixture is cooled, diluted with 50 ml of water, separate the organic phase and dried over sodium sulfate. After removal of the solvent under reduced pressure, the solid residue precrystallization of methylene chloride.

Yield: 20.5 g (72% Teoret. values)

Melting point: 105-108aboutWITH

WITH16H23VG2ABOUT2(mol. weight = 327,3)

and2) Amide 3-(etoxycarbonyl)-thiopropionic acid

In a solution of 31.8 g (0.25 mol) of ethyl ether complex 3-cyanopropionic acid and 34.6 ml (0.25 mol) of triethylamine in 75 ml of pyridine was added with stirring at room temperature for 9 h, the hydrogen sulfide. After settling overnight, the reaction mixture upon cooling, acidified 2N, hydrochloric acid and was extracted repeatedly with ethyl ether complex of acetic acid. Connected and dried over sodium sulfate the organic phase is concentrated in a gentle manner under reduced pressure. The remaining oily residue (35,0 g = 87% of theoretical value) consists, according to gas chromatographic analysis of approximately 87% of amide 3-(etoxycarbonyl)-thiopropionic acid and 13% Adilov fenil)-thiazol-2-yl] -propio new acid

36,0 g (of 0.11 moles) of 2-bromo-1(3,5-di-tert-butyl-hydroxyphenyl)ethanone from the stage and1) and 17.7 g (of 0.11 mol.) amide 3-(etoxycarbonyl)-thiopropionic acid (reactive component mixture of substances obtained from the stage and2) was heated in 100 ml of ethyl ether acetic acid for 1.5 h in a reverse flow. After cooling and processing through NaHCO3solution the organic phase was separated, dried and concentrated under reduced pressure. Mixing the remaining oily sludge using petroleum ether (40-60about(C) allowed to obtain a crystalline residue.

Output: the 33.4 g (78% of theoretical values)

Melting point: 55-56aboutWITH

WITH22H31NO3S (mol.m. = 389,6)

Analysis: calculated: 67,83%; N 8,02%; N 3,60%; S 8,23%

found: 67,81%; N 8,05%; N 3,57%; S 8,44%

Similarly obtain compounds of General formula I in which the substituents have the values listed in the table.1.

Pharmacological testing and results

The proposed test compounds of formula I, anti-inflammatory action, influence on immunopathological processes, properties, decontamination oxygen radicals and the effects on arachidonic acid metabolism OS which I inspirowane anti-inflammatory activity (table.2)

Research carried out by the method of Pearson (Arthrit. Rheum. 1959, 2, 44). As experimental animals were the males of Wistar rats-Levis - strain weighing between 130 and 200, Exposed to the test compounds were applied in doses of 50 mg per 1 kg of body weight once a day from the 1st to the 5th day of the experiment orally (p. O.). Animals one control group received only indifferent basis of the medicinal product. Each drug group and the control group consisted of 8 animals. As the impact criterion was the percentage reduction, you can multiply the volume of the paw compared with the increase in paw untreated control group. ED50- values were determined graphically from the curve describing the effect of the doses.

As a comparative drug were used 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthiazole - i.e., the compound of General formula

according to the aforementioned U.S. patent US-a-4 535 165.

2. Suppression of immunopathological processes.

It is widely recognised that a progressive course of inflammatory rheumatic diseases caused mostly impaired adaptation of the immune system and, therefore, more causal therapy can only go through the er - option)

In the experimental system described in paragraph (a), animals were subjected to treatment with only 1-th to 12-th experimental day. After the interval within 9 days, free from manipulation, is the volume of the paw - left and right hind paws (compare PL.3). In this test, classically, nesteroidnyi anti-inflammatory drugs are ineffective because they are not able to suppress the immunopathological processes underlying the chronic phase of inflammation. Further, the results clearly show the superiority of the proposed compounds of formula I compared to the reference drug from US-a-4 535 165, which in PERPER - modification complementary arthritis shows only the indicated action.

C) Backup passive ARTHUS reaction

As experimental animals used male Sprague-Dawley - rats weighing between 100 and 200 g were divided into groups respectively for 8 animals. These animals were given 1 h after oral vacation test substance 0.5 mg of antibody in 0.1 ml of sodium chloride solution subphotosphere in the left hind paw as an injection. After 4 h was measured ARTHUS reaction, and as the measurement parameter for the action served is designed only indifferent basis of the medicinal product.

According to the table.4, for example, the following has been changed they differ only as strong suppressive substance for the ARTHUS reaction.

3. Action as a trap radicals and as inhibitors of arachidonic acid metabolism

a) Properties as traps radicals.

Test in this test, which allows to make a conclusion on the anti-inflammatory potential of the substances was carried out according to Smith (Smith) and others, Biochem. Pharmacol., 1987, 36, 1456. Thus traced reaction proposed connections with the stable radical 1,1-diphenyl-2-picryl-hydrosil (D) optically at 20aboutC. the rate Constant and order of reaction n in the table.5 was determined in the usual way graphically.

C) arachidonic acid Metabolism.

The inhibitory effect of the proposed connection on the decomposition of arachidonic acid catalyzed by cyclooxygenase and lipooxygenase, in vitro (laboratory conditions), was measured using the tests described in Weithmann und Alpermann, Arznelm. - Forsoh., 1985, 35, 947.

In microsomal cyclooxygenase system (fraction from sheep seminal vesicles, Fa. Paesel, Frankfurt, Germany) synthesis, catalyzed by cyclooxygenase - the synthesis of prostaglandins is altemating at 492 nm. In lipoxygenase system in the laboratory incubated CIS-9, CIS-12 linoleic acid by lipoxygenase (L 72127 Fa.Sigma, Deisenhofen, Germany), and the formation of conjugated double connections made by the reaction of oxygenlive, was observed optically at 234 nm.

Effects of inhibitors and/or concentration of inhibitor required for 50% inhibition of the activity of enzymes (IC50values) were determined for the following suggested examples:

Lipoxygenase (enzyme)

Example 8: IC50= 50 M

Example 12: 50 m: 73% inhibition

Example 15: at 100 M: 78% inhibition

Cyclooxygenase (microsome assay)

Example 7: at 100 M: 65% inhibition

Example 8: at 100 M: 75% inhibition

Example 16: IC50= 34 M

In addition, the proposed substance was characterized as inhibitors metabolite of arachidonic acid in cell leucocytes in vitro systems. For proof of metabolites lipoxygenase by ionophore And calcium 23 187 (70 mmol./l) were incubated stimulated Human-neutrophils14C-arachidonic acid (81 mmol./l), and the main metabolites formed after 15 min at 37aboutWith as 5-hydroxy-eicosatetraenoic acid, (ISI after separation by HPLC using regiomontana in proportions (table.6). Accordingly determined the impact on proinflammatory metabolites of arachidonic acid - thromboxane and LTB4in cultures obtained from fat cells of rats (table.7).

The way to obtain 2-substituted 4-(3-tert-butyl-4-hydroxyphenyl)-thiazolo formula I

< / BR>
(I) in which R1is saturated or unsaturated WITH1-C5is an alkyl group with straight chain or branched;

R2is a hydrogen atom or an alkyl residue with 1 to 3 C-atoms;

And an intermediate chain of the formula

-(CH2)n-Y-CR3R4-; -CH= CR3-(CH2)m- or-CH=N-0-(CH2)nand Y is a simple bond, oxygen atom or sulfur or a carbonyl group,

R3and R4- same or different, and represent a hydrogen atom or an alkyl residue with the number of C-atoms to 2, and m is a number 0-3, and

n is a number from 1 to 4, and

Z - represents tetrazolyl, CN group or a residue of the formula

X - means a hydroxy-group or a residue of the General formula R5O-, or R6R7N-, and R5is1-C4-alkyl residue, a straight chain or branched, which may be substituted by hydroxyl,1-C5-Ala the haunted and represent a hydrogen atom,

WITH1-C6- alkyl residue, a straight chain or branched, or when R6means a hydrogen atom or a C1-C4is an alkyl residue, R7represents hydroxy, C1-C3-alkoxy - or tetrazol-5-yl group, or X together with the structural elements-And-(C = =0) - represents the balance of the General formula II

CHR8(II) when R8means a hydrogen atom, a C1-C3is an alkyl residue or1-C3- alkoxylates, as well as physiologically compatible salts of such compounds of General formula I, in which X represents a hydroxy - or hydroxyamino, and optionally their physiologically-tolerated salts, characterized in that

(a) amide thiocarbonates acid of General formula III

(III) is subjected to interaction with the 2-halogen-1-phenyl-alkanoate General formula IV

where A, Z, R1and R2have the above values, and L is halogen, preferably chlorine or bromine, to obtain the target product.

The WAY to OBTAIN 2-SUBSTITUTED 4-(3-TERT-BUTYL-4-HYDROXYPHENYL)-THIAZOLO General formula I

< / BR>
where R1- saturated or unsaturated C1-C5is an alkyl group with straight chain or branched:
- J - CR3R4- ; - CH=CR3-(CH2)m- or-CH= N-O-(CH2)n-, and J is a simple bond, oxygen, or sulfur, or carbonyl group, R3and R4the same or different, is hydrogen or alkyl residue with the number of carbon atoms up to 2; m=0 to 3; n=1 to 4;

Z - terazosina or CN group, or a residue of General formula

--X ,

where X is a hydroxy-group or a residue of the General formula R5O or R6R7N -, and R5- C1-C4is an alkyl residue with a straight chain or branched, which may be substituted by hydroxyl, C1-C3-alkoxygroup or C1-C3-alkylaminocarbonyl, R6and R7the same or different, is hydrogen, C1-C6is an alkyl residue with a straight chain or branched, or, when R6is hydrogen or C1-C4is an alkyl residue, R7- hydroxy-, C1-C3-alkoxy or tetrazol-5-idgruppo, or X together with the structural elements-And-(C=O) - remainder General formula II

CR8< / BR>
where R8is hydrogen, C1-C3is an alkyl residue or a C1-C3-alkoxylates, as well as physiologically compatible salts of such compounds of General formula 1, where X is hydroxy or hydroxyamino the howl of the acid of General formula III

H2N--A-Z

subjected to interaction with the 2-halogen-1-phenylalanine General formula IY

< / BR>
where A, Z, R1and R2have the specified values;

L is halogen, preferably chlorine or bromine,

obtaining the target product.

 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the following formulae:

and , and to a pharmaceutical composition possessing the PPAR-ligand binding activity and comprising the indicated compound, and a pharmaceutically acceptable vehicle. Also, invention relates to a method for treatment of patient suffering with physiological disorder that can be modulated with the compound possessing the PPAR-ligand binding activity. Method involves administration to the patient the pharmaceutically effective dose of indicated compound or its pharmaceutically acceptable salt.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 1 tbl, 104 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula: or wherein x means 1, 2, 3 or 4; m means 1 or 2; n means 1 or 2; Q represents carbon atom (C) or nitrogen atom (N); A represents oxygen atom (O) or sulfur atom (S); R1 represents lower alkyl; X represents -CH; R2 represents hydrogen (H) or halogen atom; R2a, R2b and R2c can be similar or different and they are chosen from hydrogen atom (H), alkyl, alkoxy-group or halogen atom; R3 represents aryloxycarbonyl or alkoxyaryloxycarbonyl; Y represents -CO2R4 wherein R4 represents hydrogen atom (H) or alkyl, and including all their stereoisomers, their prodrugs as esters and their pharmaceutically acceptable salts. These compounds are useful antidiabetic and hypolipidemic agents and agents used against obesity also.

EFFECT: valuable medicinal properties of compounds.

29 cl, 12 tbl, 587 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: Disclosed are compound of formula I wherein Het represents group of formula 2 (m = 0 or 1; X is hydrogen or C1-C12-alkyl or C1-C4-haloalkyl; Y is group of formula 3 and 4 wherein substitutes have meanings described in specification); A represents hydrogen, unsubstituted C1-C12-alkyl; C3-C8-cycloalkyl, or aryl; B represents hydrogen or C1-C6-alkyl; or A and B with carbon atom to which they are attached form saturated C3-C10-alkyl; A and Q1 together represent unsubstituted C3-C6-alkanediyl, wherein two non-adjacent carbon atoms optionally form further unsubstituted cycle; meanings of the rest substitutes are as described in specification.

EFFECT: new agents for controlling of agriculture pests.

4 cl, 28 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their pharmaceutically acceptable salts and esters. In the general formula (I) X means oxygen (O) or sulfur (S) atom; R means hydrogen atom (H) or (C1-C6)-alkyl; R1 means H, -COOR, (C3-C8)-cycloalkyl or (C1-C6)-alkyl, (C2-C6)-alkenyl or (C1-C6)-alkoxyl and each of them can be unsubstituted or comprises substitutes; values of radicals R2, R3, R4, R5 and R6 are given in the invention claim. Also, invention relates to a pharmaceutical composition based on compounds of the general formula (I) and to intermediate compounds of the general formula (II) and the general formula (III) that are used for synthesis of derivatives of indane acetic acid. Proposed compounds effect on the blood glucose level and serum triglycerides level and can be used in treatment of such diseases as diabetes mellitus, obesity, hyperlipidemia and atherosclerosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 6 tbl, 6 sch, 251 ex

FIELD: chemistry; oxa-and thiazole derivatives.

SUBSTANCE: oxa- and thiazole derivatives have general formula . Their stereoisomers and pharmaceutical salts have PPARα and PPARγ activity. The compounds can be used for treating diseases, eg. diabetes and anomaly of lipoproteins through PPARα and PPARγ activity. In the general formula, x has value of 1, 2, 3 or 4; m has value of 1 or 2; n has value of 1 or 2; Q represents C or N; A represents O or S; Z represents O or a bond; R1 represents H or C1-8alkyl; X represents CH; R2 represents H; R2a, R2b and R2c can be the same or different and they are chosen from H, alkoxy, halogen; R3 represents aryloxycarbonyl, alkyloxycarbonyl, alkyl(halogen)aryloxycarbonyl, cycloalkylaryloxycarbonyl, cycloalkyloxyaryloxycarbonyl, arylcarbonylamino, alkylsulphonyl, cycloheteroalkyloxycarbonyl, heteroarylalkenyl, alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl, halogenalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl, aryloxyarylalkyloxycarbonyl, arylalkenylsulphonyl, heteroarylsulphonyl, arylsulphonyl, arylalkenylarylalkyl, arylalkoxycarbonyl-heteroarylalkyl, heteroaryloxyarylalkyl, where alkyl is in form of C1-8alkyl; Y represents CO2R4, where R4 represents H or C1-8alkyl; including all their stereoisomers and pharmaceutical salts, under the condition that, if A is O, then R3 is not aryloxycarbonyl or alkoxyaryloxycarbonyl.

EFFECT: the compounds can be used in curing such diseases as diabetes and lipoprotein anomalies.

10 cl, 30 dwg, 12 tbl, 584 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and pharmaceutically acceptable salts. Claimed compounds have modulation effect on CB cannabinoid receptor. In the general formula (I) , R and R1 are the same or different and are phenyl optionally substituted by 1-3 substitutes Y, where Y is substitute selected out of group including chlorine, iodine, bromine, fluorine, on condition that X is not a sub-group (ii); or one of R and R1 radicals is phenyl group, while the other radical is formed or linear C2-8-alkyl group or benzyl group; X is one of the sub-groups (i) or (ii). Also invention concerns application of the compounds in obtaining pharmaceutical composition, pharmaceutical composition with modulation effect on CB cannabinoid receptor, and compound of the general formula (IV) with radical values as indicated in the claim.

EFFECT: enhanced efficiency of composition and treatment method.

5 cl, 1 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with formula (I): where R1 and R2 each independently represents a hydrogen atom, C1-8 alkyl or a halogen atom; R3 represents C1-8 alkyl, which can be substituted with 1-3 halogen atom(s) or phenyl; R4 represents a hydrogen atom or C1-8 alkyl; R5 and R6 each independently represents a hydrogen atom; X represents a sulphur atom or oxygen atom; ring A is 4-(trifluoromethyl)piperidin-1-yl, 2,2-difluoro-1,3- benzodioxol-5-yl or 3,4-dihydro-1H-isoquinolin-2-yl. The invention also relates to salts or solvates of this derivative, as well as medicinal preparation, pharmaceutical composition, method of preventing and/or treating diseases, caused by PPAR, and use of this derivative.

EFFECT: obtaining new biologically active compounds, which can be used for preventing and/or treating diseases caused by PPARδ.

8 cl, 39 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention pertains to dimetansulphonate N-hydroxy-4-{5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy}benzamidine, method of producing thereof, pharmaceutical compositions based on the said compound and a peroral pharmaceutical composition.

EFFECT: wider field of use of the compounds.

9 cl, 5 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention covers thaizole derivatives of formula (I) and to their pharmaceutically acceptable salts. In formula I: X1 and X2 differ from each other and represent sulphur atom or carbon atom; R1 represents phenyl group; phenyl group substituted by 1-2 members chosen from the group including halogen atoms, alkoxygroup with 1-6 carbon atoms, hydroxygroup, phenylalkoxygroup with 7-12 carbon atoms; phenyl group fused with 5-7-membered heteroaromatic or nonaromatic ring with at least one heteroatom consisting of N, O and S; pyridyl group; R2 represents hydrogen atom, halogen atom, alkyl group with 1-6 carbon atoms, alkyl group with 1-6 carbon atoms substituted by 1-5 halogen atoms, alkoxygroup with 1-6 carbon atoms, or hydroxyalkyl group with 1-5 carbon atoms; A represents group which is presented by formula or . Also, the invention concerns ALK5 inhibitor containing compound of the invention as an active component, stimulators of hair follicles proliferation and hair growth, and also to thiazole derivative of formula where A1 represents .

EFFECT: higher efficiency.

12 cl, 2 tbl, 50 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: in formula (1), R1 is di-C1-6alkoxyphenyl group; A is one of the following groups (i)-(vi); (i) -CO-B-, where B is C1-6alkylene group; (ii) -CO-Ba-, where Ba is C2-6alkenylene group; (iii) -CH(OH)-B-; (iv) -COCH((C)OOR3)-Bb-, where R3 is C1-6alkyl group and Bb is C1-6alkylene group. Values of the other radicals are specified in the patent claim. Invention also concerns the pharmaceutical composition exhibiting properties of a phosphodiesterase PDE4 inhibitor containing the compound under the invention; the phosphodiesterase 4 inhibitor containing as an active component the compound of the invention; preventive or therapeutic preparation for atopic dermatitis containing as an active component the compound of the invention.

EFFECT: higher effectiveness of application of the compound.

8 cl, 24 tbl, 262 ex

Up!