Derivatives of 8,8a-dihydroindeno[1,2-d]thiazole substituted at 8a position, method for their preparing and their applying as medicinal agents, for example, as anorectics

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to polycyclic dihydrothiazoles and their physiologically acceptable salts and physiologically functional derivatives. Invention describes compounds of the formula (I): wherein r1 and R1' mean independently of one another atoms H, F, Cl, Br and J; R2 means hydrogen atom (H); R3 means chlorine (Cl), bromine (Br) atom; R4 means phenyl, and a method for their preparing. Compounds can be used, for example, as anorectics for prophylaxis or obesity treatment.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

5 cl, 2 tbl, 1 ex

 

The invention relates to polycyclic to dihydrothiazolo, and their physiologically acceptable salts and physiologically functional derivatives.

In the prior art already described derivatives of thiazolidine with anorexically action (patent Austria No. 365181).

The task of the invention to provide other compounds that are therapeutically suitable anorexically action.

The invention relates, therefore, to compounds of formula (I):

where

R1, R1' denote, independently of one another, H, F, Cl, Br, J, CF3, NO2, CN, COOH, COO-(C1-C6)-alkyl, CONH2, CONH-(C1-C6)-alkyl, CON-[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, and alkyl residues one, several or all of the hydrogen atoms may be replaced by fluorine atoms, or one hydrogen atom may be replaced by HE, OC(O)CH3, OS(O)H, O-CH2-phenyl, NH2, NH-CO-CH3or N(SOON2-phenyl)2; SO2-NH2, SO2NH-(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2S-(C1-C6)-alkyl, S-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(C1-C6)-alkyl, SO2-(CH2)n -phenyl, and n may be 0-6 and the phenyl residue up to twice may be substituted with F, Cl, Br, HE, CF3, NO2CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2; NH2, NH-(C1-C6)-alkyl, N-[(C1-C6)-alkyl]2, NH-(C1-C7)-acyl, phenyl, biphenyl, O-(CH2)n-phenyl, and n may be 0-6; 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, 2 - or 3-furanyl or 2 - or 3-thienyl, and phenyl, biphenylyl, nattily, peredelnyj, farnily or thienyl cycles, respectively, can be up to three times substituted with F, Cl, Br, J, HE, CF3, NO2CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH-(C1-C6)-alkyl, N-[(C1-C6)-alkyl]2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2;

1,2,3-triazole-5-yl, and triazole ring in position 1, 2 or 3 may be replaced by stands or benzyl;

tetrazol-5-yl, and tetrazole the ring in position 1 or 2 can be replaced by stands or benzyl;

R2 denotes H, (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, (CH2)n-furyl, C(O)-(C1-C6)-alkyl, C(O)-(C3-C6-cycloalkyl, C(O)-(CH2) n-phenyl, C(O)-(CH2)n-thienyl, C(O)-(CH2)n-pyridyl, C(O)-(CH2)n-furyl, and n may be equal to 0-5 and where the phenyl, thienyl, pyridyl, furyl, respectively, up to twice may be substituted with Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl;

R3 denotes Cl, Br, CH2-COO-(C1-C6)-alkyl, CH2-COOH, CH2-CONH2;

R4 means (C1-C8)-alkyl, (C3-C7-cycloalkyl, (C2-C6)-alkenyl, (C2-C6)-quinil, (C4-C7)-cycloalkenyl, and in the alkyl residues one, several or all of the hydrogen atoms may be replaced by fluorine atoms or one hydrogen atom may be replaced by HE, OC(O)CH3, OS(O)H, O-CH2-phenyl or-(C1-C4)-alkyl; (CH2)n-pyrrolidin-1-yl, (CH2)n-piperidine-1-yl, (CH2)n-morpholine-4-yl, (CH2)n-piperazine-1-yl, (CH2)n-N-4-methylpiperazin-1-yl, (CH2)n-N-4-benzylpiperazine-1-yl, (CH2)n-phthalimide, and n can be 1-6;

(CH2)n-aryl, and n may be 0-6 and the aryl may mean phenyl, biphenyl, 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl, 2 - or 3-furyl, 2-, 4 - or 5-thiazolyl, 2-, 4 - or 5-oxazolyl, 1-pyrazolyl, 3 - or 5-isoxazolyl, 2 - or 3-pyrrolyl, 2 - or 3-pyrido inil, 2-, 4 - or 5-pyrimidinyl, 2-pyrazinyl, 2-(1,3,5-triazinyl), 2 - or 5-benzimidazolyl, 2-benzothiazolyl, 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, tetrazol-5-yl, indol-3-yl, indol-5-yl or N-Mei-2-, -4 - or-5-yl and aryl residue or heteroaryl residue up to twice may be substituted with F, Cl, Br, HE, CF3, NO2CN, OCF3, O-(C1-C6)-alkyl, S-(C1-C6)-alkyl, SO-(C1-C6)-alkyl, (CH2)n-SO2-(C1-C6)-alkyl, (CH2)n-SO2-NH2, (CH2)n-SO2-N=CH-N(CH3)2), where n may be 0-6; (C1-C6)-alkyl, (C3-C6)-cycloalkyl, COOH, COO-(C1-C6)-alkyl, COO-(C3-C6)-cycloalkyl, CONH2, CONH-(C1-C6)-alkyl, CON-[(C1-C6)-alkyl]2, CONH-(C3-C6)-cycloalkyl, NH2, NH-CO-(C1-C6)-alkyl, NH-CO-phenyl, NH-SO2(C1-C6)-alkyl, NH-SO2-phenyl, and the phenyl ring up to twice may be substituted with F, Cl, CN, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, COOH, COO-(C1-C6)-alkyl or CONH2; pyrrolidin-1-yl, morpholine-1-yl, piperidine-1-yl, piperazine-1-yl, 4-methylpiperazin-1-yl, (CH2)n-phenyl, O-(CH2)n-phenyl, S-(CH2)n-phenyl, SO2-(CH 2)n-phenyl, and n may be equal 0-3;

(CH2)n-A-R8, and n can be 1-6;

A represents O, NH, N-(C1-C6)-alkyl, NCHO, N-(CH3), S, SO, SO2;

R8 means (C1-C8)-alkyl, (C3-C8-cycloalkyl, and in the alkyl residues of one or more hydrogen atoms may be replaced by fluorine atoms or one hydrogen atom may be replaced by HE, OC(O)CH3, OS(O)H, O-CH2-phenyl or-(C1-C4)-alkyl;

(CH2)m-aryl, and m=0-6, and the aryl may mean phenyl, thienyl or pyridyl and aryl part up to twice may be substituted with F, Cl, Br, HE, CF3, NO2CN, OCF3, O-(C1-C6)-alkyl, S-(C1-C6)-alkyl, SO-(C1-C6)-alkyl, (CH2)n-SO2-(C1-C6)-alkyl, (CH2)n-SO2-NH2, (CH2)n-SO2-N=CH-N(CH3)2), (CH2)n-SO2-NH-[(C1-C6)-alkyl], (CH2)n-SO2-N-[(C1-C8)-alkyl]2, (CH2)n-SO2-NH-[(C3-C8)-cycloalkyl], (CH2)n-SO2-N-[(C3-C8-cycloalkyl]2and n may be 0-6; (C1-C6)-alkyl, (C3-C6)-cycloalkyl, COOH, COO-(C1-C6)-alkyl, COO-(C3-C8)-cycloalkyl, CONH2, CONH-(Csub> 1-C6)-alkyl, CON-[(C1-C6)-alkyl]2, CONH-(C3-C6)-cycloalkyl, NH2, NH-(C1-C6)-alkyl, N-[(C1-C6)-alkyl]2, NH-CO-(C1-C6)-alkyl, NH-CO-phenyl, NH-SO2-phenyl, and the phenyl ring up to twice may be substituted with F, Cl, CN, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, COOH, COO-(C1-C6)-alkyl or CONH2; NH-SO2-(C1-C6)-alkyl, N-[(C1-C6)-alkyl]-SO2-(C1-C6)-alkyl, pyrrolidin-1-yl, morpholine-1-yl, piperidine-1-yl, piperazine-1-yl, 4-methylpiperazin-1-yl, (CH2)p-phenyl, O-(CH2)p-phenyl, S-(CH2)pis phenyl or SO2-(CH2)p-phenyl, and p may be equal 0-3;

and their physiologically acceptable salts and physiologically functional derivatives.

Preferred compounds of formula (I), where

R1, R1' denote, independently of one another, H, F, Cl, Br, J, CF3, NO2, CN, COOH, COO-(C1-C6)-alkyl, CONH2, CONH-(C1-C6)-alkyl, CON-[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, and alkyl residues one, several or all of the hydrogen atoms may be replaced by fluorine atoms, or one at the m hydrogen may be replaced by HE, OS(O)CH3, OS(O)H, O-CH2-phenyl, NH2, NH-CO-CH3or N(SOON2-phenyl)2; SO2-NH2, SO2NH-(C1-C6)-alkyl, SO2N-[(C1-C6)-alkyl]2S-(C1-C6)-alkyl, S-(CH2)n-phenyl, SO-(C1-C6)-alkyl, SO-(CH2)n-phenyl, SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl, and n may be 0-6 and the phenyl residue up to twice may be substituted with F, Cl, Br, HE, CF3, NO2CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2; NH2, NH-(C1-C6)-alkyl, N-[(C1-C6)-alkyl]2, NH-(C1-C7)-acyl, phenyl, biphenyl, O-(CH2)n-phenyl, and n may be 0-6; 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, 2 - or 3-furanyl or 2 - or 3-thienyl, and phenyl, biphenylyl, nattily, peredelnyj, farnily or thienyl cycles, respectively, can be up to three times substituted with F, Cl, Br, J, HE, CF3, NO2CN, OCF3About-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH-(C1-C6)-alkyl, N-[(C1-C6)-alkyl]2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2; 1,2,3-triazole-5-yl, and triazole ring in position 1, 2 or 3 may be replaced by stands or benzyl;

t is terazol-5-yl, and tetrazole the ring in position 1 or 2 can be replaced by stands or benzyl;

R2 denotes H, (C1-C6)-alkyl, (C3-C6-cycloalkyl, (CH2)n-phenyl, (CH2)n-thienyl, (CH2)n-pyridyl, (CH2)n-furyl, C(O)-(C1-C6)-alkyl, C(O)-(C3-C6-cycloalkyl, C(O)-(CH2)n-phenyl, C(O)-(CH2)n-thienyl, C(O)-(CH2)n-pyridyl, C(O)-(CH2)n-furyl, and n may be equal to 0-5 and where the phenyl, thienyl, pyridyl, furyl, respectively, up to twice may be substituted with Cl, F, CN, CF3, (C1-C3)-alkyl, HE, O-(C1-C6)-alkyl;

R3 denotes Cl, Br, CH2-COO-(C1-C6)-alkyl, CH2-COOH, CH2-CONH2;

R4 means (C1-C8)-alkyl, (C3-C7-cycloalkyl, (C2-C6)-alkenyl, (C2-C6)-quinil, (C4-C7)-cycloalkenyl, and in the alkyl residues one, several or all of the hydrogen atoms may be replaced by fluorine atoms or one hydrogen atom may be replaced by HE, OC(O)CH3, OS(O)H, O-CH2-phenyl or-(C1-C4)-alkyl;

(CH2)n-pyrrolidin-1-yl, (CH2)n-piperidine-1-yl,

(CH2)n-morpholine-4-yl, (CH2)n-piperazine-1-yl,

(CH2)n-N-4-methylpiperazin-1-and is,

(CH2)n-N-4-benzylpiperazine-1-yl,

(CH2)n-phthalimide, and n can be 1-6;

(CH2)n-aryl, and n may be 0-6 and the aryl may mean phenyl, 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl and aryl residue or heteroaryl residue up to twice may be substituted with F, Cl, Br, HE, CF3, O-(C1-C6)-alkyl, (CH2)n-SO2-(C1-C6)-alkyl, (CH2)n-SO2-NH2, (CH2)n-SO2-N=CH-N(CH3)2), where n may be 0-6; NH-SO2-(C1-C6)-alkyl, NH-SO2-phenyl, and the phenyl ring up to twice may be substituted with F, Cl, CN, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, COOH, COO-(C1-C6)-alkyl or CONH2;

(C1-C6)-alkyl, COOH, COO-(C1-C6)-alkyl or CONH2;

(CH2)n-A-R8, and n can be 1-6;

A represents O, NH, (C1-C6)-alkyl, SO2;

R8 means (C1-C8)-alkyl, (C3-C8-cycloalkyl, and in the alkyl residues of one or more hydrogen atoms may be replaced by fluorine atoms or one hydrogen atom may be replaced by HE, OC(O)CH3, OS(O)H, O-CH2-phenyl or-(C1-C4)-alkyl;

(CH2)m -aryl, and m=0-6, and the aryl may mean phenyl, thienyl or pyridyl and aryl part up to twice may be substituted with F, Cl, Br, HE, CF3, O-(C1-C6)-alkyl, (CH2)n-SO2-(C1-C6)-alkyl, (CH2)n-SO2-NH2, (CH2)n-SO2-N=CH-N(CH3)2), where n may be 0-6; NH-SO2-(C1-C6)-alkyl, NH-SO2-phenyl, and the phenyl ring up to twice may be substituted with F, Cl, CN, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, COOH, COO(C1-C6)-alkyl, CONH2and n may be 0-6;

COOH, COO-(C1-C6)-alkyl or CONH2;

and their physiologically acceptable salts and physiologically functional derivatives.

Especially preferred compounds of formula (I), where

R1, R1' denote, independently of one another, H, F, Cl, Br, HE, O-(C1-C6)-alkyl, (C1-C6)-alkyl, and alkyl residues one hydrogen atom may be replaced by IT;

R2 denotes H, (C1-C6)-alkyl, C(O)-(C1-C6)-alkyl;

R3 denotes Cl, Br, CH2-COO-(C1-C6)-alkyl, CH2-COOH, CH2-CONH2;

R4 means (C1-C4)-alkyl or (C3-C6-cycloalkyl, and in the alkyl residues one hydrogen atom may be substitutes the n on IT;

(CH2)n-aryl, and n may be 0-6 and the aryl may mean phenyl, 1 - or 2-naphthyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl and aryl residue or heteroaryl residue up to twice may be substituted with F, Cl, Br, HE, CF3, O-(C1-C6)-alkyl, SO2-(C1-C6)-alkyl, (CH2)n-SO2-NH2and n may be 0-6; (C1-C6)-alkyl, COOH, COO-(C1-C6)-alkyl or CONH2;

(CH2)n-A-R8, and n can be 1-6;

And means ON, SO2;

R8 means (C1-C8)-alkyl, (C3-C8-cycloalkyl, and in the alkyl residues one hydrogen atom may be replaced by IT; (CH2)m-aryl, and m=0-6, and the aryl may mean phenyl or thienyl and aryl part up to twice may be substituted with F, Cl, Br, HE, CF3, O-(C1-C6)-alkyl, SO2(C1-C6)-alkyl, SO2-NH2, COOH, COO-(C1-C6)-alkyl or CONH2;

and their physiologically acceptable salts.

The invention relates to compounds of formula (I) in the form of their racemates, racemic mixtures and pure enantiomers, and to their diastereomers and their mixtures.

Alkyl, alkeline and alkyline residues in the substituents R1, R1', R2, R3, R4, R8 and can be both linear and branched.

The pharmacist is Cesky acceptable salts due to their higher water solubility compared to the original, or basic compounds are particularly suitable for applications in medicine. These salts must include pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable additive salts of acids proposed according to the invention compounds are salts of inorganic acids as hydrochloric acid, Hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, acid and sulfuric acid, and organic acids, such as acetic acid, benzosulfimide, benzoic acid, citric acid, econsultation, fumaric acid, gluconic acid, glycolic acid, setinova acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonate, succinic acid, p-toluensulfonate, tartaric acid and triperoxonane acid. For medical purposes especially preferably using salt and hydrochloric acid. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (like sodium and potassium salts), and salts of alkaline earth metals (as magnesium salt and calcium).

Salts with a pharmaceutically unacceptable anion is also included in the scope of the invention as useful intermediates for obtaining or purification of pharmaceutically acceptable salts and/or for whom the sing when non-therapeutic, for example in vitro, applications.

Used herein, the term "physiologically functional derivative" refers to any physiologically acceptable derivative proposed according to the invention the compounds of formula (I), for example, ester, which when administered to a mammal, such as man, is able (directly or indirectly) to form a compound of formula (I) or its active metabolite.

To physiologically functional derivatives are also proletarienne form proposed according to the invention compounds. Such proletarienne forms in vivo can be metabolised to offer according to the invention compounds. These proletarienne forms themselves may or may not be active.

Proposed according to the invention compounds may be present in various polymorphic forms, for example as amorphous and crystalline polymorphous forms. All polymorphic forms proposed according to the invention compounds are included in the scope of the invention are the subject matter of the invention.

Hereinafter, all references to "compound (compounds) according to the formula (I)" refers to the compound (compounds) of the formula (I)described (described) above, and their salts, solvate and physiologically functional derivatives as described above.

The number of compounds according to formula (I), as needed in order the achieve the desired biological effect, depends on a number of factors, for example, selected from specific connections, intended use, type of administration and the clinical condition of the patient. In General, the daily dose amount in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day per kilogram of body weight, for example, 3-10 mg/kg/day. An intravenous dose may amount to, for example, in the range from 0.3 mg/kg to 1.0 mg/kg, which prigodnye be introduced in the form of infusion of 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for these purposes may include, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter of the compounds according to formula (I). Single doses may contain, for example, from 1 mg to 10 g of biologically active substances. Thus, ampoules for injection may contain, for example, from 1 mg to 100 mg, and oral input of the dosage form in the form of single doses, as, for example, tablets or capsules, may contain, for example, from 1.0 mg to 1000 mg, typically from 10 mg to 600 mg of biologically active substances. In the case of pharmaceutically acceptable salts of the above mass data refer to mass produced from salt ion dihydrothiazolo. For the prevention or therapy of the abovementioned conditions, the compounds of formula (I) can be used by themselves in the form of compounds, however, preferably together with an acceptable carrier are in the ideal pharmaceutical composition. The media, of course, must be acceptable, in the sense that it is compatible with other components of the composition and is not harmful to the health of the patient. The carrier may be solid or liquid or both and is preferably used together with the compound to obtain a dosage form as a single dose, for example, in the form of a tablet, which may contain from 0.05 to 95 mass. % biologically active substances. There also may be other pharmaceutically active agents, including other compounds according to formula (I). Proposed according to the invention pharmaceutical compositions can be obtained by one of the known pharmaceutical methods, which essentially consist in the fact that the components are mixed with pharmacologically acceptable carriers and/or auxiliary substances.

Proposed according to the invention pharmaceutical compositions are those suitable for oral, rectal, local, peroral (for example sublingual), or parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable route of administration in each individual case depends on the type and severity of the treated condition and the kind used in each case, the compounds according to formula (I). In volume izopet the tion also includes the index of the dosage form and index prolonged dosage forms. Preferred are resistant to acid and gastric juice dosage forms. Suitable, resistant to gastric juice coating include acetated cellulose, polyvinylacetate, hydroxypropylmethylcellulose and anionic polymers of methacrylic acid and methyl methacrylate.

Suitable pharmaceutical compounds for oral administration may be in the form of separate units, such as capsules, membrane wafers, tablets for sucking or tablets, which contain, respectively, a certain number of compounds according to formula (I); as powders or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an emulsion oil-in-water or water-in-oil. These compositions, as already mentioned, can be prepared by any suitable pharmaceutical method which includes a step, in the case where the biologically active substance and the carrier (which may consist of one or more additional components) is introduced into the contact. In General, the compositions are obtained by uniform and homogeneous mixing of the biologically active substance with a liquid and/or finely dispersed solid carrier, after which the product, if necessary, is formed. For example, the tablet can get that powder or granules of the compound is pressed or moulded, in case the need is and together with one or more additional components. Molded tablets can be obtained by tabletting suitable connection device in a freely flowing form, such as in the form of a powder or granulate, if necessary, mixed with a binder, which imparts lubricity tablets substance, inert diluent and/or one (several) of surface-active/dispersing agent. Molded tablets can be obtained by molding in a suitable device, powder, moistened with an inert liquid diluent connection.

Pharmaceutical compositions suitable for peroral (sublingual) administration include tablets for sucking, which contain the compound according to formula (I) with a flavoring substance, usually sucrose and gum Arabic or Trianta, and lozenges, which comprise the compound in an inert basis as gelatin and glycerol or sucrose and gum Arabic.

Suitable pharmaceutical compositions for parenteral administration preferably include sterile aqueous compositions of the compounds according to formula (I), which preferably is isotonic with the blood provided the recipient. These compositions are preferably injected intravenously, although the introduction can be made subcutaneously, intramuscularly or II andstc the dermal in the form of injections. These compositions preferably you can obtain the fact that the compound is mixed with water and the resulting solution make sterile and isotonic with blood. Introduced by injection proposed according to the invention the compositions contain, in General, 0.1 to 5 wt.% active connection.

Suitable pharmaceutical compositions for rectal injection are preferably in the form of suppositories with disposable dose. You can get them to the fact that the compound according to formula (I) is mixed with one or more conventional solid carriers, such as cocoa butter, and an appropriate mixture of mold.

Suitable pharmaceutical compositions for local application on the skin are preferably in the form of ointment, cream, lotion, paste, spray, aerosol or oil. As a carrier, you can apply vaseline, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. Biologically active substance, in General, is in a concentration of 0.1-15 wt.%, for example, 0.5 to 2 wt.%, in the calculation of the composition.

It is also possible percutaneous introduction. Suitable pharmaceutical compositions for percutaneous applications can be in the form of individual patches that are suitable for long-term close contact with the epidermis of the patient. These patches are more suitable way contain biologically AK the active substance in water, if necessary, buffered solution, dissolved and/or dispergirovannom in adhesive means or dispergirovannom in the polymer. A suitable concentration of biologically active substances is about 1-35%, preferably about 3-15%. As a special ability, biologically active substance, such as, for example, described in Pharmaceutical Research, 2 (6), 318 (1986), released by electric or electrophoresis.

The object of the invention, then, is a method of obtaining compounds of General formula (I), characterized in that compounds of the formula (I) receive the following according to the following reaction scheme:

For this purpose, compounds of General formula (II):

where R1 and R1' have the specified value, using the compounds of formula Z-CH2-COOR, where Z means, for example, halogen atom and R denotes, for example, methyl, converted into the compound of the formula (III)where R3 denotes-CH2-COOR.

The compounds of formula (III), then, with the help of halogen, e.g. bromine, converted into the compounds of formula (IV), where R1 and R1' have the stated meaning and R3 denotes, for example, -CH2-COOR.

The compounds of formula (IV) then, using thioamides formula (VI):

where R4 has the specified value is converted into the compounds of formula (I). Link the formula (I), where R3 denotes a chlorine atom or bromine, can be obtained in such a way that the compounds of formula (V) enter into an interaction with a halogenation reagent, such as N-chlorosuccinimide or N-bromosuccinimide.

The compounds of formula (I) can also be in the form of salts with acids. As inorganic acids, for example, use: halogen acids as hydrochloric acid and Hydrobromic acid, and also sulfuric acid, phosphoric acid and amidosulfonic.

As organic acids should for example be mentioned: formic acid, acetic acid, benzoic acid, p-toluensulfonate, benzosulfimide, succinic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, citric acid, L-ascorbic acid, salicylic acid, izational acid, methanesulfonate, triftormetilfullerenov, 1,2-benzisothiazol-3(2H)-he, 6-methyl-1,2,3-oxathiazin-4(3H)-one-2,2-dioxide.

The above method is preferably carried out so that the compounds of the formula (IV) enter into interaction with thioamides of the formula (VI) in a molar ratio of from 1:1 to 1:1,5. The reaction is preferably carried out in an inert solvent, for example, in polar organic solvents, such as dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, dioxane, tetrahydrofuran, acetonitrile, nitrome is an or diethylethylenediamine ether. As a particularly preferred solvents, however, are methyl acetate and ethyl acetate, alcohols, short-chain as methanol, ethanol, propanol, isopropanol, and the lowest dealkylation, as, for example, acetone, butane-2-one or hexane-2-it. You can also use a mixture of these reaction media; as it is also possible to use mixtures of these solvents with solvents that are less suitable for individual use, as, for example, mixtures of methanol with benzene, ethanol with toluene, methanol, diethyl ether or tert-butylmethylamine ether, ethanol tetrachloride, acetone chlorform, dichloromethane or 1,2-dichloroethane, and, accordingly, the more polar the solvent is better to use in excess.

Components of the reaction can be suspended or dissolved in an appropriate reaction medium. In principle, the components of the reaction can also be entered into cooperation without solvent, in particular if the corresponding thioamide has low melting point. The reaction proceeds only weakly exothermically and it can be performed at a temperature of from -10°to 150°C, preferably from 30°to 100°C. as particularly favorable, as a rule, is the range of temperatures from 50°to 90°C.

About aiternate reaction largely depends on the reaction temperature and ranges from 2 minutes to 3 days at higher accordingly, the lower temperatures. In favorable temperatures, the duration of the reaction is, in General, from 5 minutes to 48 hours.

The compounds of formula (I) in the form of their additive salts with an acid are often deposited in the form of sparingly soluble salts in the reaction, it is sensible to add a suitable precipitant. As such, using, for example, hydrocarbons like benzene, toluene, cyclohexane or heptane, or carbon tetrachloride; especially as particularly suitable are alkalemia the acetic acid esters as ethyl acetate or n-butyl acetate, or a simple dialkyl ethers like diethyl ether, diisopropyl ether, di-n-butyl ether or tert-butyl methyl ether. If at the end of the reaction, the reaction mixture remains in solution, the salts of the compounds of formula (I), if necessary after concentration of the reaction solution, the precipitated using one of these precipitators. Next, a solution of the reaction mixture also preferably can be entered under stirring in a solution of one of these precipitators. Since the reaction of compounds of formula (IV) with thioamides of the formula (VI) proceeds almost quantitatively obtained crude products often are analytically pure. Processing of the reaction mixture can also be implemented in such a way that re is clonney the mixture is alkalinized with the addition of organic bases, such as, for example, triethylamine or diisobutylamine or ammonia or morpholine or piperidine, or 1,8-diazabicyclo[5,4,0]undec-7-ene and the reaction product after concentration purify by chromatography, for example, when using a column with silica gel. As a suitable eluting environments for this purpose are, for example, mixtures of ethyl acetate with methanol, mixtures of dichloromethane with methanol, mixtures of toluene with methanol or ethyl acetate or a mixture of ethyl acetate with hydrocarbons as heptane. If purification of the crude product is carried out using the following method, clean the base of the compounds of formula (I) additive product with the acid compounds of formula (I) can be obtained in such a way that the base is dissolved or suspended in an organic proton solvent as methanol, ethanol, propanol or isopropanol, or in an organic aprotic solvent like ethyl acetate, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, acetone, or butane-2-it, and this mixture is then mixed with at least equimolar amounts of an inorganic acid, such as the hydrogen chloride dissolved in an inert solvent, such as diethyl ether or ethanol, or another of the above inorganic or organic acids.

The compounds of formula (I) can be paracrystals the close co of a suitable inert solvent, as, for example, acetone, butane-2-it, acetonitrile, nitromethane. Especially preferred, however, is pereosazhdeniya of solvent, such as, for example, dimethylformamide, dimethylacetamide, nitromethane, acetonitrile, preferably methanol or ethanol.

The reaction of compounds of formula (IV) with thioamides of the formula (VI) can also be carried out in such a way that the reaction mixture are added in at least equimolar amount of base, such as, for example, triethylamine, and the thus obtained compounds of formula (I) then, if necessary, transferred to their additive products with acid.

Additive products with acid compounds of the formula (I) by treatment with bases can be converted into compounds of General formula (I) (free base). As the bases used, for example, solutions of inorganic hydroxides, as the hydroxide of lithium, sodium, potassium, calcium or barium; carbonates or bicarbonates like sodium carbonate or potassium bicarbonate, sodium or potassium, ammonia and amines as triethylamine, Diisopropylamine, dicyclohexylamine, piperidine, morpholine, methyldicyclohexylamine.

Thioamides of General formula (VI) are either commercially available or they can be obtained for example by reacting the corresponding carboxylic acid amide of the formula (V) with pentasulfide phosphorus in pyridine is (R.N.Hurd, G.Delameter, Chem. Rev., 61, 45 (1961)) or with Lawesson reagent in toluene, pyridine, triamide hexamethylphosphoric acid [Scheibye, Pedersen and Lawesson, Bull. Soc. Chim. Belges, 87, 229 (1978)], preferably in a mixture of tetrahydrofuran with 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone or 1,3-dimethyl-2-imidazolidinone. This is a hydroxyl group, an amino group or an additional carbonyl group would be protected by again tsepliaeva protective group, such as, for example, using benzyl, tert-butoxycarbonyl, benzyloxycarbonyl residue, respectively, by changing, if necessary, in a cyclic acetal. Ways to implement this is described, for example, the manual Th.W.Greene and P.G.M.Wuts "Protective Groups in Organic Synthesis", second edition, 1991, John Wiley and Sons, new York.

Thioamides of the formula (VI) also get the fact that the NITRILES of General formula (VII):

enter into interaction with hydrogen sulfide (Houben-Weil, IX, 762) or thioacetamide (..Taylor, J.A.Zoltewicz, J. Am. Chem. Soc., 82, 2656 (1960)) or O,O-Diethyldithiophosphoric acid. Interaction with hydrogen sulfide is preferably carried out in an organic solvent like methanol or ethanol; interaction with thioacetamide is carried out in a solvent as dimethylformamide, adding hydrochloric acid; interaction with O,O-Diethyldithiophosphoric acid is carried out in rest retele, as ethyl acetate, in an acid, for example HCl, conditions, at room temperature or when heated.

The following examples serve to illustrate the invention but do not limit the scope of protection. The measured melting temperature, respectively, the decomposition (TPL) are without amendment, and, in General, depend on the heating rate.

Examples

Table 1

ExampleR1; R1'R2R3R4SolTPL [°]
16-Cl; HHBrphenyl-148
26-Cl; HHClphenyl-88

The compounds of formula (I) are positive effects on fat metabolism, in particular they are suitable as anorexically funds. The compounds can be used individually or in combination with other anarxicheskij biologically active substances. Such other anorexicskin biologically active substances indicated, for example, in the "Roten Liste", Chapter 01, section "Tools for weight loss/Means for lowering the appetite." Compounds suitable for PR is the prevention, in particular, for the treatment of obesity. The compounds are suitable, furthermore, for prevention and particularly for the treatment of type II diabetes.

The effectiveness of the compounds was tested as follows:

Biological test model

Testing anoreksighennogo actions carried out on female NMRI mice. After being deprived of food for 24 hours through the gastric tube was administered the test drug. When an individual content and with free access to drinking water to the animals 30 minutes after the drug administration proposed condensed milk. The consumption of condensed milk was determined every half hour for 7 hours and observed the General health of animals. The measured consumption of milk was compared with that of untreated control animals.

Table 2

Anorexically the action defined as a reduction of the cumulated consumption of milk treated compared with untreated animals
Link/ Example

Oral dose [mg/kg]Number of animals/ the cumulated consumption of milk of treated animals

N/[ml]
Number of animals/ the cumulated consumption of raw milk control the animals N/[ml] The reduction of the cumulated consumption of milk in % relative to the control
Example 1505/0,645/3,5082

From the table it can be seen that the compounds of formula (I) show a very good anorexically action.

Below describes in detail the receipt of certain compounds, other compounds of formula (I) are obtained in a similar manner.

Example 1 (compound 1):

8A-Bromo-6-chloro-2-phenyl-8,8A-dihydroindeno[1,2-d]thiazol-3A-ol

a) 2-Bromo-5-Clorinda-1-he:

10 g (0.06 mol) of 5-Clorinda-1-it under stirring and at room temperature is dissolved in 120 ml of glacial acetic acid. Added dropwise 0.05 ml of 48%HBr solution in water and then 3,074 ml (0.06 mol) of bromine, dissolved in 25 ml of glacial acetic acid.

After stirring for 2 hours at room temperature the reaction ends (control by means of thin layer chromatography). A solution of crude product while mixing, slowly bring dropwise to 300 ml of a mixture of ice water. Precipitated precipitated crude product is filtered under vacuum and washed thoroughly with water. The wet residue is removed from the filter with ethyl acetate and the phases of the filtrate are separated. The organic phase the tub over sodium sulfate, filtered and concentrated in vacuo. The residue is dissolved in 120 ml of n-heptane by heating, the hot solution is filtered through a folded filter and then the solution is left to stand at a temperature of 0°for crystallization. The crystalline product is filtered under vacuum and dried in vacuum. TPL: 94-96°C.

b) 6-Chloro-2-phenyl-8,8A-dihydroindeno[1,2-d]thiazol-3A-ol:

1.0 g of 2-Bromo-5-Clorinda-1-it is at room temperature, dissolved in 20 ml of anhydrous acetone and mixed with 620 mg thiobenzamide. Stirred for 6 hours at room temperature, vegascasinoonline hydrobromide product is filtered off under vacuum, the residue is washed with acetone and dried in vacuum. Free base get that salt making in a mixture of 30 ml of ethyl acetate and 20 ml of saturated solution of sodium bicarbonate and stirred for 20 minutes. The organic phase is separated, washed with a saturated solution of sodium chloride and dried over magnesium sulfate. Filtered and the filtrate concentrated in vacuo. Get 6-chloro-2-phenyl-8,8A-dihydroindeno[1,2-d]thiazol-3A-ol with a melting point 164-165°C.

(C) 8A-Bromo-6-chloro-2-phenyl-8,8A-dihydroindeno[1,2-d]thiazol-3A-ol:

1.51 g of the Compound of example 1b and 0,89 g of N-bromosuccinimide dissolved in 20 ml of carbon tetrachloride is mixed with 50 mg of benzoyl peroxide and stirred for 3 h the owls while boiling under reflux. The cooled reaction solution is shaken twice with 20 ml water, the organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. After chromatographic purification using silica gel, using dichloromethane as the eluting means get 8A-bromo-6-chloro-2-phenyl-8,8A-dihydroindeno[1,2-d]thiazol-3A-ol with a melting point 148°C.

1. The compounds of formula (I):

where R1, R1' mean independently from each other H, F, Cl, Br, J;

R2 denotes H;

R3 denotes Cl, Br;

R4 denotes phenyl;

and their physiologically acceptable salts and physiologically functional derivatives.

2. Compounds according to claim 1 for use as a drug for the prophylaxis or treatment of obesity.

3. A drug for the prophylaxis or treatment of obesity containing one or more compounds according to claim 1.

4. The drug according to claim 3, characterized in that it additionally contains one or more other anorexically biologically active substances.

5. Method of preparing compounds according to claim 1, characterized in that, according to the following scheme:

either the compound of formula (IV), where R1 and R1' are indicated for formula (I) values and Hal means halogen atom is R means alkyl residue, using the compounds of formula (VI)wherein R4 is specified for formula (I) is, or the compound of formula (V), where R1, R1', R2 and R4 are specified for formula (I) value, using a halogenation reagent such as N-chlorosuccinimide or N-bromosuccinimide, converted into the compounds of formula (I).



 

Same patents:

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to polycyclic dihydrothiazoles of formula I , containing in substituted alkyl residues in 2-posiiton, as well as physiologically accepted salts thereos, having anorexia action. In formula Y is direct bond; X is CH2; R1 and R1' are independently H, Cl; R2 and R3 are H; R4 is (C8-C16-cycloalkyl, (CH2)n-A-R8, wherein n = 1-6, excepted group of formula -CH2-O-CH2-phenyl with unsubstituted phenyl; A is O, S; R8 is methyl or (CH2)m-aryl, where in m = 0-6; and aryl may represent phenyl, wherein aryl group may be optionally substituted with one or two substituents, selected from Cl, O-(C1-C6)-alkyl or (C1-C6)-alkyl. Also disclosed is method for production thereof.

EFFECT: new anorexia pharmaceuticals.

5 cl, 4 ex, 2 tbl

The invention relates to polycyclic, thiazolidin-2 - ildenafil amines and their physiologically acceptable salts and physiologically functional derivatives

The invention relates to novel polycyclic to dihydrothiazolo General formula (I), where Y is a simple bond; X is CH2; R1 is H, F, Cl, NO2, CN, COOH, (C1-C6)-alkyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, and alkyl residues one, several or all of the hydrogen atoms may be replaced by fluorine; (CH2)n-phenyl, SO2-(C1-C6)-alkyl, and n = 0 and the phenyl residue up to twice may be substituted by F, Cl, CF3, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; O-(CH2)n-phenyl, and n = 0 and phenyl cycle can be one - to twofold substituted by Cl, (C1-C6)-alkyl; 1 - or 2-naphthyl, 2 - or 3-thienyl; R1' is hydrogen; R2 is H, (C1-C6)-alkyl, R3 is hydrogen; R4 - (C1-C8)-alkyl, (C3-C7-cycloalkyl, (CH2)n-aryl, and n = 0-1, and aryl can be phenyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl, 2 - or 3-furyl, indol-3-yl, indol-5-yl, and aryl or heteroaryl residue up to twice may be substituted by F, Cl, HE, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, 2-, 3-, 4-pyridium, pyrrol-1-yl, with peregrinae ring may be substituted CF3; and their physio is

The invention relates to new derivatives of asola General formula I, where R1and R2the same or different, each represents hydrogen, cycloalkyl and so forth, or R1and R2forming (a) a condensed ring, (b) or (C), which may be optionally substituted substituted lower alkyl, amino group and the like; R3, R6, R7, R8the same or different, each represents a hydrogen atom, and so on; R4represents a cyano, tetrazolyl, -COOR9and so on; R5represents a hydrogen atom or lower alkyl; D represents optionally substituted lower alkylene; X and Z are the same or different, each represents oxygen or sulfur, Y is-N= or-CH=; A is-B is-O-, -S-B-, -B-S - or-In-; represents the lowest alkylene or lower albaniles; n = 2

-d - galactopyranosides -2) - 4,5-dihydrothiazolo-4 - carboxylic acid" target="_blank">

The invention relates to carbohydrates and heterocyclic compounds and in particular to a new method of obtaining-D-galactoside D-luciferin formula I

used as a substrate for the enzyme activity determination-galactosidase, which can find application in genetic engineering, enzyme analysis and DNA probes

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

FIELD: endocrinology.

SUBSTANCE: abnormally corpulent persons are treated by reduced-caloricity diet with limited content of carbohydrate-containing components and fats. In particular, caloricity of meal is reduced to 1200 kcal, including carbohydrate-containing components with glycemic index below 40. When initial weight is reduced by 5% and the weight is stabilized for 3 months, caloricity is increased to a specified value, calculated in terms of formula for daily caloricity recommended by World Health Organization taking into account sex, age, weight, and physical activity, glycemic index of carbohydrate-containing components ranging from 40 to 69 until the weight is lowered to desired level.

EFFECT: achieved stable and long-term reduction of weight owing to lowered insulin resistance of organism.

3 tbl

FIELD: cosmetics, pharmaceutical chemistry.

SUBSTANCE: invention relates to cosmetic composition used for loss weight comprising at least one compound that induces producing IL-6 by adipocytes in form of mixture with NPY antagonist and/or α2 antagonist and with an excipient for the cosmetic variant. Invention provides effectiveness of fatty acids efflux from adipocytes and inhibitory effect on fatty acids incorporation into cells that results to the loss weight effect. The composition shows good stability in storage being without reducing its activity. The composition has no adverse effects.

EFFECT: valuable properties of composition.

11 cl, 3 dwg, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of glucopyranosyloxybenzylbenzene represented by the formula (I): wherein R1 represents hydrogen atom or hydroxy(lower)alkyl; R2 represents lower alkyl group, lower alkoxy-group and lower alkylthio-group being each group is substituted optionally with hydroxy- or (lower)alkoxy-group, or to its pharmaceutically acceptable salts. Also, invention relates to pharmaceutical composition eliciting hypoglycemic activity and to a method for treatment and prophylaxis of hyperglycemia-associated diseases, such as diabetes mellitus, obesity and others, and to their intermediate compounds. Invention provides preparing new derivatives of glucopyranosyloxybenzylbenzene that elicit the excellent inhibitory activity with respect to human SGLT2.

EFFECT: valuable medicinal properties of compounds.

13 cl, 2 tbl, 2 ex

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to polycyclic dihydrothiazoles of formula I , containing in substituted alkyl residues in 2-posiiton, as well as physiologically accepted salts thereos, having anorexia action. In formula Y is direct bond; X is CH2; R1 and R1' are independently H, Cl; R2 and R3 are H; R4 is (C8-C16-cycloalkyl, (CH2)n-A-R8, wherein n = 1-6, excepted group of formula -CH2-O-CH2-phenyl with unsubstituted phenyl; A is O, S; R8 is methyl or (CH2)m-aryl, where in m = 0-6; and aryl may represent phenyl, wherein aryl group may be optionally substituted with one or two substituents, selected from Cl, O-(C1-C6)-alkyl or (C1-C6)-alkyl. Also disclosed is method for production thereof.

EFFECT: new anorexia pharmaceuticals.

5 cl, 4 ex, 2 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention represents ligands MC-4 and/or MC-3 of the formula (I): , wherein X means hydrogen atom, -OR1, -NR1R1' and -CHR1R1' wherein R1 and R1' are taken among the group: hydrogen atom, (C1-C6)-alkyl and acyl; (1) each R2 is taken independently among the group: hydrogen atom, (C1-C6)-alkyl; or (2) (a) R2 bound with carbon atom that is bound with X and Z1 and substitute R5 can be optionally bound to form carbocyclic or heterocyclic ring that is condensed with phenyl ring J; or (b) R2 bound with carbon atom that is bound with ring Ar can be bound with R7 to form ring condensed with ring Ar; each among Z1, Z2 and Z3 is taken independently from the following groups: -N(R3e)C(R3)(R3a)-, -C(R3)(R3a)N(R3e)-, -C(O)N(R3d)-, -N(R3d)C(O)-, -C(R3)(R3a)C(R3b)(R3c)-, -SO2N(R3d)- and -N(R3d)SO2- wherein each among R3, R3a, R3b and R3c, R3d, R3e when presents is taken independently among hydrogen atom and (C1-C6)-alkyl; p is a whole number from 0 to 5 wherein when p above 0 then R4 and R4' are taken among hydrogen atom, (C1-C6)-alkyl and aryl; R5 represents 5 substitutes in phenyl ring J wherein each R5 is taken among hydrogen atom, hydroxy-, halogen atom, thiol, -OR12, -N(R12)(R12'), (C1-C6)-alkyl, nitro-, aryl wherein R12 and R12' are taken among hydrogen atom and (C1-C6)-alkyl; or two substitutes R5 can be bound optionally to form carbocyclic or heterocyclic ring that is condensed with phenyl ring J; q = 0, 1, 2, 3, 4 or 5 wherein when q above 0 then R6 and R6' are taken among hydrogen atom and (C1-C6)-alkyl; Ar is taken among the group consisting of phenyl, thiophene, furan, oxazole, thiazole, pyrrole and pyridine; R7 are substitutes at ring Ar wherein each R7 is taken among hydrogen, halogen atom, -NR13R13', (C1-C6)-alkyl and nitro- wherein R13 and R13' are taken among hydrogen atom and (C1-C6)-alkyl; r is a whole number from 0 to 7 wherein when r is above 0 then R8 and R8' are taken among hydrogen atom and (C1-C6)-alkyl; B is taken among -N(R14)C(=NR15)NR16R17, -NR20R21, heteroaryl ring and heterocycloalkyl ring wherein R14-R17, R20 and R21 are taken independently among hydrogen atom and (C1-C6)-alkyl; s = 0, 1, 2, 3, 4 or 5 wherein when s is above 0 then R and R9' are taken among hydrogen atom and (C1-C6)-alkyl; R10 is taken among the group consisting of optionally substituted bicyclic aryl ring and optionally substituted bicyclic heteroaryl ring; D is taken among hydrogen atom, amino- and -C(O)R11 wherein R11 is taken among the following group: hydroxy-, alkoxy-, amino-, alkylamino-, -N(R19)CH2C(O)NH2 wherein R19 represents (C1-C6)-alkyl, -NHCH2CH2OH and -N(CH3)CH2CH2OH, or its isomers, salts, hydrates or biohydrolysable ester, amide or imide.

EFFECT: valuable medicinal properties of compounds.

18 cl, 107 ex

FIELD: improved method for oil production.

SUBSTANCE: target oil, enriched in HODE, or esters thereof is obtained by controlled oxidation of linoleic acid and/or linolenic acid or esters thereof in presence of oxidation catalyst. Oxidation is stopped when total HODE or ester content is more than 5 %, and/or content of isomeric 9-hydroxy-10,12-octadecadienic acid (9-HODE) or esters thereof is more than 1,5 %; and hydroperoxides formed in oxidation process are reduced with reducing agent in presence of antioxidant. Invention is also relates to oil enriched in 9-HODE or esters or salts thereof having an lipolytic action; to drug or food additive for obesity treatment; cosmetic for local treatment of cellulite. Compound for controlling of adipocyte lipolytic activity and hydrolysis of triglycerides accumulated in adipocytes is also disclosed.

EFFECT: novel pharmaceutical composition for obesity treatment.

11 cl, 1 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention describes a method for prophylaxis or treatment of states that involves inhibition of activity of enzyme that catalyzes hydrolysis of ester functional groups and wherein indicated state represents obesity or accompanying disorder, and wherein compound of the formula (1):

is prescribed, or its pharmaceutically acceptable salt, ester, amide or a precursor. Also, invention relates to a method for manufacturing the medicinal preparation used for prophylaxis or treatment of states wherein inhibition of activity of enzyme is required wherein indicated enzyme catalyzes hydrolysis of ester functional groups. In the formula (1) A means a 6-membered aromatic or heteroaromatic ring; R1 means a branched or unbranched alkyl (its carbon chain can be broken by one or more oxygen atoms), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, reduced arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, reduced aryl, reduced heteroaryl, reduced heteroarylalkyl or their substituted derivative wherein a substitute is taken independently among the following group: halogen atom, alkyl, alkyl substituted with halogen atom, aryl, arylalkyl, heteroaryl, reduced heteroaryl, reduced heteroarylalkyl, arylalkoxy-, cyano-, nitro-group, -C(O)R4, -CO2R4, -SOR4, -SO2R4, -NR6R7, -OR6, -SR6, -C(O)CX1X2NR6R7, -C(O)NR4R5, -C(O)N(OR5)R6, -NR6C(O)R4, -CR6(NH2)CO2R6, -NCX1X2CO2R6, -N(OH)C(O)NR6R7, -N(OH)C(O)R4, -NHC(O)NR6R7, -C(O)NHNR6R7, -C(O)N(OR5)R6 or lipid, or steroid (natural or synthetic) under condition that any substituting heteroatom in R1 or R2 must be separated from exocyclic nitrogen atom by at least two carbon atoms (preferably, saturated atoms), and wherein R4 represents hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl, OR6, NHCX1X2CO2R6 or NR6R7; R5 represents hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl; R6 and R7 are taken independently among hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, heteroarylalkyl, reduced heteroarylalkyl or -(CH2)n(OR5)m wherein n = from 1 to 12, preferably, from 2 to 10; m = from 1 to 3; R5 means preferably (C2-C10)-alkyl; X1 and X2 represent independently hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, heteroarylalkyl or reduced heteroarylalkyl. Also, invention describes compound of formulae (II), (IIa) and (IIb) given in the description and a method for preparing compound of formulae (II), (IIa) and (IIb), pharmaceutical composition used for prophylaxis or treatment of obesity and/or accompanying disorder, nutrition product, a method for prophylaxis or treatment of obesity or accompanying disorders, a method for inhibition of activity of enzymes, a method for reducing fat content in animals, a cosmetic method for maintaining this weight and a new intermediate compound of the formula (IV) indicated in the description. Invention discloses the possibility for prophylaxis or treatment of obesity or accompanying disorders.

EFFECT: valuable medicinal properties of compounds.

33 cl, 1 dwg, 2 tbl, 5 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention describes a method for prophylaxis or treatment of states wherein inhibition of enzyme activity is required wherein this enzyme catalyzes hydrolysis reaction of ester functional groups and wherein indicated disorder represents obesity or accompanying disease. Method involves prescribing compound of the formula (1):

or its pharmaceutically acceptable salt, ester, amide or precursor wherein in the formula (1) a means six-membered aromatic or heteroaromatic ring; R1 means a branched or unbranched alkyl (its carbon chain can be broken possibly by one or more oxygen atoms), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, reduced arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, reduced aryl, reduced heteroaryl, reduced heteroarylalkyl or their substituted derivative wherein a substitute represents one or more group taken independently among the following group: halogen atom, alkyl, halogen-substituted alkyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, reduced heteroarylalkyl, arylalkoxy-, cyano-, -C(O)R4, -CO2R4, -SOR4, -SO2R4, -NR6R7, -OR6, -SR6, -C(O)CX1X2NR6R7, -C(O)NR4R5, -C(O)N(OR5)R6, -NR6C(O)R4, -CR6(NH2)CO2R6, -NCX1X2CO2R6, -N(OH)C(O)NR6R7, -N(OH)C(O)R4, -NHC(O)NR6R7, -C(O)NHNR6R7, -C(O)N(OR5)R6, or lipid or steroid (natural or synthetic one) under condition that any substituting heteroatom in R1 or R2 must be segregated from nitrogen exocyclic atom by at least two carbon atoms (preferably, saturated ones); R2 means hydrogen atom or group, such as determined for R1 and wherein R4 represents hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl, OR6, NHCX1X2CO2R6 or NR6R7; R5 represents hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl; R6 and R7 are taken independently among hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, heteroarylakyl, reduced heteroarylalkyl or -(CH2)n(OR5)m wherein n = from 1 to 12 but preferably from 2 to 10; m = from 1 to 3; for R5 (C2-C10)-alkyl is preferable; X1 and X2 represent independently hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, heteroarylalkyl or reduced heteroarylalkyl. Also, invention describes compounds of formulas (II), (IIa), (IIb) given in the invention description, method for preparing compound of the formula (II), pharmaceutical composition used for prophylaxis or treatment of obesity or accompanying disorder, the nutrition foodstuff, method for prophylaxis or treatment of obesity or accompanying disorders, method for inhibition of enzymes activity, method for reducing the fat content in animals, cosmetic method for maintaining this weight of animals. Invention discloses the possibility for prophylaxis or treatment of obesity or accompanying disorders.

EFFECT: valuable medicinal properties of compounds.

30 cl, 1 dwg, 2 tbl, 5 ex

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to polycyclic dihydrothiazoles of formula I , containing in substituted alkyl residues in 2-posiiton, as well as physiologically accepted salts thereos, having anorexia action. In formula Y is direct bond; X is CH2; R1 and R1' are independently H, Cl; R2 and R3 are H; R4 is (C8-C16-cycloalkyl, (CH2)n-A-R8, wherein n = 1-6, excepted group of formula -CH2-O-CH2-phenyl with unsubstituted phenyl; A is O, S; R8 is methyl or (CH2)m-aryl, where in m = 0-6; and aryl may represent phenyl, wherein aryl group may be optionally substituted with one or two substituents, selected from Cl, O-(C1-C6)-alkyl or (C1-C6)-alkyl. Also disclosed is method for production thereof.

EFFECT: new anorexia pharmaceuticals.

5 cl, 4 ex, 2 tbl

FIELD: medicine, organic chemistry.

SUBSTANCE: the present innovation deals with new benzothiazole derivatives and medicinal preparation containing these derivatives for treating diseases mediated by adenosine receptor A2.A.. The present innovation provides efficient treatment of the above-mentioned diseases.

EFFECT: higher efficiency of therapy.

14 cl, 354 ex

The invention relates to polycyclic, thiazolidin-2 - ildenafil amines and their physiologically acceptable salts and physiologically functional derivatives
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