Substituted derivatives of oxazol-benzoisothiazoldioxide, method for making and applying thereof

FIELD: pharmacology.

SUBSTANCE: invention refers to compounds of formula (I) as inhibitor of phosphotyrosinphosphotase 1B, and to application thereof for making a based medical product. In general formula (I) X represents C-R2; Y represents O, R1 represents phenyl, 5-merous heterocycle with one sulphur atom with phenyl residue, and heterocyclic residue being mono-, twice- or trisubstituted with halogen, CN, -OH, -CF3, -(C1-C6)alkyl, -COOH, -(CH2)-COOH, phenyl, -O-phenyl with phenyl ring being substituted with halogen; R2, R3, R4, R5, R6, R7 and R8 represent H.

EFFECT: compounds can find application in treating adipose and carbohydrate metabolic disorders, including for controlling blood glucose.

3 cl, 2 tbl, 8 ex

 

The invention relates to substituted derivatives of oxazole-benzothiazolylthio, and their physiologically acceptable salts.

State of the art already described derivatives benzothiadiazide similar structures, and their use for the treatment of diabetes (patent WO 02/11722).

The basis of the invention lies in the task of creating compounds that can prevent and treat diabetes diabetic connections must be therapeutically valuable downward (level) blood sugar effect. In particular, the connections should be superior action compared with the compounds of the patent WO 02/11722 or improved ADME profile (adsorption, distribution, metabolism and excretion).

The invention relates to compounds of formula I,

I

in which

X represents Oh,-R2;

Y represents O, C-R2,

and there is always one of the groups X and Y is O and the other represents C-R1;

R1, R2 independently of one another represent H, aryl, COOH, (C1-C6)alkylene-COOH, -COO(C1-C6)alkyl, (C1-C6)alkylen-soo(C1-C6)Akil, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkylen-aryl, heterocyclyl, (C1-C6)alkylen-heterocyclyl, CF3, OCF3CN, (CH 2)1-6-HE,-(C1-C6)alkyl, (C1-C6)alkyl, -C(O)O-alkyl, COOH, SOP(R9)(R10), and aryl residues and heterocyclic residues may be singly or multiply substituted by F, Cl, Br, (CH2)0-2OH, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)quinil, CF3, OCF3N(R9)(R10), piperidine, piperazine, piperazinone, N-(C1-C6-alkylen)piperazine, N-(C1-C6-alkylen)piperazinone, morpholine, thiomorpholine, NO2, CN, O-(C1-C6)alkyl, S(O)0-2-(C1-C6)alkyl, SO2-N(R9)(R10),-(C1-C6)alkyl, -COOH, (C1-C6)alkylene-COOH, COO(C1-C6)alkyl, (C1-C6)alkylen-soo(C1-C6)alkyl, (C3-C10)cycloalkyl, phenyl, and these piperidine, piperazine, piperazine, N-(C1-C6)alkylen-piperazine, N-(C1-C6)alkylen)piperazine, morpholine, thiomorpholine and phenyl cycles can be singly or multiply substituted by F, Cl, Br, (CH2)0-2HE, COOH, CN, NO2, -O-(C1-C6)alkyl, -NH-O-(C1-C6)alkyl, (CO)-NH-O-(C1-C6)alkylene-N(R9)(R10), -(CO)-(C1-C6)alkyl, -(C1-C6)alkyl, CF3, OCF3N(R9)(R10);

R3 represents H, (C1-C6)alkyl, (C -C6)alkylen-aryl, -C(O)aryl, (C1-C6)alkylen-heterocyclyl,-(C1-C6)alkyl, and aryl and heterocyclic residues may be singly or multiply substituted by F, Cl, Br, (C1-C6)alkyl, COOH, COO(C1-C6)alkyl, CF3or OCF3;

R4, R5 independently of one another represent H, F, Cl, Br, (C1-C6)alkyl, CF3, OCF3, NO2N(R9)(R10), CN, O-(C1-C6)alkyl,-(C1-C6)alkyl, COOH, (C1-C6)alkylene-COOH, CON(R9)(R10), (C1-C6)alkylen-SOP(R9)(R10), COO(C1-C6)alkyl, (C1-C6)alkylen-soo(C1-C6)alkyl, S(O)0-2-(C1-C6)alkyl, S(O)2N(R9)(R10), CH2OH, CH2OCH3;

R6, R7 independently of one another represent H, F, Cl, Br, (C1-C6)alkyl, cyclopropyl, tetraferriphlogopite, diversicolor; or

R6 and R7 together form the group=CH2;

R8 represents H, CH3, CF3CH2OH;

R9 represents H, (C1-C4)alkyl;

R10 represents H, (C1-C4)alkyl; or

R9 and R10 together with N-atom to which they are bound, form a 3-9-membered cyclic system,

and their physiologically acceptable salts.

Preferred compounds of formula I in which one or more residues have the following malignancies is implemented:

R1 represents aryl, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkylen-aryl, heterocyclyl, (C1-C6)alkylen-heterocyclyl, CF3, OCF3CN, (CH2)1-6-HE,-(C1-C6)alkyl,-(C1-C6)alkyl, C(O)O-alkyl, COOH, SOP(R9)(R10), and aryl residues and heterocyclic residues may be singly or multiply substituted by F, Cl, Br, (CH2)0-2OH, (C1-C6)alkyl, (C2-C6)alkenyl,

(C2-C6)quinil, CF3, OCF3N(R9)(R10), piperidine, piperazine, piperazinone, N-(C1-C6-alkylen)piperazine, N-(C1-C6-alkylen)piperazinone, morpholine, thiomorpholine, NO2, CN, O-(C1-C6)alkyl, S(O)0-2-(C1-C6)alkyl, SO2-N(R9)(R10),-(C1-C6)alkyl, -COOH, (C1-C6)alkylene-COOH, -COO(C1-C6)alkyl, (C0-C6)alkylen-soo(C1-C6)alkyl, (C3-C10)cycloalkyl, phenyl, and these piperidine, piperazine, piperazine, N-(C1-C6-alkylen)piperazine, N-(C1-C6-alkylen)piperazine, morpholine, thiomorpholine and phenyl cycles can be singly or multiply substituted by F, Cl, Br, (CH2)0-2HE, COOH, CN, NO2, -O-(C1-C6)alkyl, -NH-O-(C -C6)alkyl, -(CO)-NH-O-(C1-C6)alkylene-N(R9)(R10), -(CO)-(C1-C6)alkyl, -(C1-C6)alkyl, CF3, OCF3N(R9)(R10);

R2 represents H, aryl, COOH, (C1-C6)alkylene-COOH, -COO(C1-C6)alkyl, (C1-C6)alkylen-soo(C1-C6)alkyl, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkylen-aryl, heterocyclyl, (C1-C6)alkylen-heterocyclyl, CF3, OCF3CN, -(CH2)1-6-OH, O-(C1-C6)alkyl,-(C1-C6)alkyl, C(O)O-alkyl, COOH, SOP(R9)(R19), and aryl residues and heterocyclic residues may be singly or multiply substituted by F, Cl, Br, (CH2)0-2OH, (C1-C6)alkyl, (C2-C6)alkenyl,

(C2-C6)quinil, CF3, OCF3N(R9)(R10), piperidine, piperazine, piperazinone, N-(C1-C6-alkylen)piperazine, N-(C1-C6-alkylen)piperazinone, morpholine, thiomorpholine, NO2, CN, O-(C1-C6)alkyl, S(O)0-2-(C1-C6)alkyl, SO2-N(R9)(R10), CO-(C1-C6)alkyl, -COOH, (C1-C6)alkylene-COOH, -COO(C1-C6)alkyl, (C1-C6)alkylen-soo(C1-C6)alkyl, C3-C10-cycloalkyl, phenyl;

R3 represents H, (C1-C6 )alkyl, (C1-C6)alkylen-aryl, -C(O)aryl, (C1-C6)alkylen-heterocyclyl,-(C1-C6)alkyl;

R4, R5 independently of one another represent H, F, Cl, Br, (C1-C6)alkyl, CF3, OCF3, NO2N(R9)(R10), CN, O-(C1-C6)alkyl, CO-(C1-C6)alkyl, COOH, (C1-C6)alkylene-COOH, CON(R9)(R10), (C1-C6)alkylen-SOP(R9)(R10), COO(C1-C6)alkyl, (C1-C6)alkylen-soo(C1-C6)alkyl, S(O)0-2-(C1-C6)alkyl, S(O)2-N(R9)(R10), CH2OH, CH2OCH3;

R6, R7 independently of one another represent H, F, Cl, Br, (C1-C6)alkyl, cyclopropyl, tetraferriphlogopite, diversicolor; or

R6 and R7 together form the group=CH2;

R8 represents H, CH3, CF3CH2OH;

R9 represents H, (C1-C4)alkyl;

R10 represents H, (C1-C4)alkyl; or

R9 and R10 together with N-atom to which they are bound, form a 3-9-membered cyclic system,

and their physiologically acceptable salts.

Especially preferred compounds of formula I in which one or more residues have the following meaning:

R1 represents phenyl, naphthyl, Tinetti, pyridyl, and phenyl, naphthyl, Tinetti and pyridyl may be substituted one or more times F, Cl, r, (CH2)0-2OH, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)quinil, CF3, OCF3N(R9)(R10), piperidine, piperazine, piperazinone, N-(C1-C6-alkylen)piperazine, N-(C1-C6-alkylen)piperazinone, morpholine, thiomorpholine, NO2, CN, O-(C1-C6)alkyl, S(O)0-2-(C1-C6)alkyl, SO2-N(R9)(R10),-(C1-C6)alkyl, COOH, (C1-C6)alkylene-COOH, COO(C1-C6)alkyl, (C1-C6)alkylen-soo(C1-C6)alkyl, C3-C10-cycloalkyl, phenyl, and these piperidine, piperazine, piperazine, N-(C1-C6-alkylen)piperazine, N-(C1-C6-alkylen)piperazine, morpholine, thiomorpholine and phenyl cycles can be singly or multiply substituted by F, Cl, Br, (CH2)0-2HE, COOH, CN, NO2, -O-(C1-C6)alkyl, -NH-O-(C1-C6)-alkyl, (CO)-NH-O-(C1-C6)alkylene-N(R9)(R10), -(CO)-(C1-C6)-alkyl, -(C1-C6)alkyl, CF3, OCF3N(R9)(R10);

R2 represents H, (C1-C6)alkyl, COOH, (C1-C6)alkylene-COOH, -COO(C1-C6)alkyl, (C1-C6)alkylen-soo(C1-C6)alkyl;

R3 represents H, (C1-C6)alkyl, (C1-C6)alkylen-aryl, -C(O)Ari is, (C1-C6)alkylen-heterocyclyl,-(C1-C6)alkyl;

R4, R5 are H;

R6, R7 are H;

R8 represents H;

R9 represents H, (C1-C4)alkyl;

R10 represents H, (C1-C4)alkyl,

and their physiologically acceptable salts.

Very particularly preferred compounds of formula I in which one or more residues have the following meaning:

R1 represents phenyl, whereby phenyl, naphthyl, Tinetti and pyridyl may be substituted one or more times F, Cl, Br, (CH2)0-2OH, (C1-C6)alkyl,

(C2-C6)alkenyl, (C2-C6)quinil, CF3, OCF3N(R9)(R10), piperidine, piperazine, piperazinone, N-(C1-C6-alkylen)piperazine, N-(C1-C6-alkylen)piperazinone, morpholine, thiomorpholine, NO2, CN, O-(C1-C6)alkyl, S(O)0-2-(C1-C6)alkyl, SO2-N(R9)(R10),-(C1-C6)alkyl, COOH, (C1-C6)alkylene-COOH, COO(C1-C6)alkyl, (C1-C6)alkylen-soo(C1-C6)alkyl, C3-C10-cycloalkyl, phenyl, and these piperidine, piperazine, piperazine, N-(C1-C6-alkylen)piperazine, N-(C1-C6-alkylen)piperazine, morpholine, thiomorpholine openline cycles can be singly or multiply substituted by F, Cl, Br, (CH2)0-2HE, COOH, CN, NO2, -O-(C1-C6)alkyl, -NH-O-(C1-C6)alkyl, -(CO)-NH-O-(C1-C6)alkylene-N(R9)(R10), -(CO)-(C1-C6)alkyl, -(C1-C6)alkyl, CF3, OCF3N(R9)(R10);

R2 represents H, (C1-C6)alkyl, -C(O)O-(C1-C6)alkyl, -(C1-C6)alkylen-C(O)O-(C1-C6)alkyl, -COOH, (C1-C6)alkylene-COOH;

R3 represents H, (C1-C6)alkyl, (C1-C6)alkylen-aryl, -C(O)aryl, (C1-C6)alkylen-heterocyclyl,-(C1-C6)alkyl;

R4, R5 are H;

R6, R7 are H;

R8 represents H;

R9 represents H;

R10 represents H,

and their physiologically acceptable salts.

To clarify:

oxazolines balance

when values of the residues

X, equal to C-R2;

Y equal to About,

has the following structure:

and when values of the residues

X, equal to About;

Y is equal to C-R2,

has the structure

In further preferred compounds in which X represents C-R2, and Y represents O.

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

If residues or substituents in the compounds of formula I can occur repeatedly, they all independently of each other can have the values to be the same or different.

For use in medicine are especially suitable pharmaceutically acceptable salts due to their higher water solubility compared to the original or basic compounds. These salts must contain a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable additive salts with acids of the proposed compounds are salts of inorganic acids such as hydrochloric acid, Hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as, for example, acetic acid, benzolsulfonat, benzoic, citric, econsultancy, fumaric, gluconic, glycolic, setinova, lactic, lactobionic, maleic, malic, methansulfonate, amber, pair-toluensulfonate and tartaric acid. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), salts of alkaline earth metals (such as magnesium salts and calcium), (salt) of trometamol (2-amino-2-hydroxymethyl-1,3-propane diol), diethanolamine, lysine and Ethylenediamine.

Salts with a pharmaceutically aprielle the first anion, such as, for example, triptorelin, equally within the scope of invention as a necessary intermediate products to obtain or purification of pharmaceutically acceptable salts and/or for use in non-therapeutic (order), for example, in vitro.

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

To physiologically functional derivatives also include prodrugs of the proposed compounds, such as described in H. Okada and others, Chem. Pharm. Bull. 1994, 42, 57-61. These prodrugs can be metabolised in vivo to the proposed connection. These prodrugs may themselves be active or not.

The proposed compounds can also be present in various polymorphic forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the proposed compounds belong to the scope of the invention and are a further aspect of the invention.

Hereinafter all references to "compound(I) according to the formula I" refers to the compound(s) of formula I, as description is but higher and their salts, solvate and physiologically functional derivatives as described herein.

Under alkyl residue understand linear or branched hydrocarbon chain with one or more carbon atoms, such as, for example, methyl, ethyl, ISO-propyl, tert-butyl, hexyl.

Alkyl residues can be substituted one or more times by suitable groups such as, for example: F, Cl, Br, I, CF3, NO2N3, CN, COOH, COO-(C1-C6)alkyl, NH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2cycloalkyl, (C2-C6)alkenyl, (C2-C6)quinil, O-(C1-C6)alkyl O-CO-(C1-C6)alkyl, O-CO-(C1-C6)aryl, O-CO-(C1-C6)heterocyclyl; RHO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)alkyl, SO2N[(C1-C6)alkyl]2S-(C1-C6)alkyl, S-(CH2)n-aryl, S-(CH2)n-heterocyclyl, SO-(C1-C6)alkyl, SO-(CH2)n-aryl, SO-(CH2)n-heterocyclyl, SO2-(C1-C6)alkyl, SO2-(CH2)n-aryl, SO2-(CH2)n-heterocyclyl, SO2-NH(CH2)n-aryl, SO2-NH(CH2)n-heterocyclyl, SO2-N(C1-C6)alkyl)(CH2)n-aryl, SO2-N(C1-C6)alkyl)(CH2) n-heterocyclyl, SO2-N((CH2)n-aryl)2, SO2-N((CH2)n-(heterocyclyl)2and n may be=0-6 and the aryl residue or heterocyclic residue may be substituted up to two times F, Cl, Br, OH, CF3, NO2CN, OCF3About-(C1-C6)alkyl, (C1-C6)alkyl, NH2;

C(NH)(NH2), NH2, NH-(C1-C6)alkyl, N((C1-C6)alkyl)2, NH(C1-C7)acyl, NH-CO-(C1-C6)alkyl, NHCOO-(C1-C6)alkyl, NH-CO-aryl, NH-CO-heterocyclyl, NH-COO-aryl, NH-COO-heterocyclyl, NH-CO-NH-(C1-C6)alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocyclyl, N(C1-C6)alkyl-CO-(C1-C6)alkyl, N(C1-C6)alkyl-COO-(C1-C6)alkyl, N(C1-C6)alkyl-CO-aryl, N(C1-C6)alkyl-CO-heterocyclyl, N(C1-C6)alkyl-COO-aryl, N(C1-C6)alkyl-COO-heterocyclyl, N(C1-C6)alkyl-CO-NH-(C1-C6)alkyl), N(C1-C6)alkyl-CO-NH-aryl, N(C1-C6)alkyl-CO-NH-heterocyclyl, N((C1-C6)alkyl)-CO-N-(C1-C6)alkyl)2,

N((C1-C6)alkyl)-CO-N((C1-C6)alkyl)-CO-N((C1-C6)alkyl)aryl, - N((C1-C6)alkyl)-CO-N((C1-C6)alkyl)-CO-N((C1-C6)alkyl)heterocyclyl, N((C1-C5)alkyl)-CO-N-(aryl)2N((C1-C6)Alki is)-CO-N-(heterocyclyl) 2N(aryl)-CO-(C1-C6)alkyl, N(heterocyclyl)-CO-(C1-C6)alkyl, N(aryl)-COO-(C1-C6)alkyl, N(heterocyclyl)-COO-(C1-C6)alkyl, N(aryl)-CO-aryl, N(heterocycle)-CO-aryl, N(aryl), COO-aryl, N(heterocycle)-COO-aryl, N(aryl)-NH-(C1-C6)alkyl, N(heterocyclyl)-CO-NH-(C1-C6)alkyl), N(aryl)-CO-NH-aryl, N(heterocycle)-CO-NH-aryl, N(aryl)-CO-N-(C1-C6)alkyl)2N(heterocyclyl)-CO-N-(C1-C6)alkyl)2N(aryl)-SOP((C1-C6)alkyl)aryl, N(heterocycle)-CO-N((C1-C6)-alkyl)aryl, N(aryl)-CO-N-(aryl)2N(heterocyclyl)-CO-N-(aryl)2, aryl, O-(CH2)n-aryl, O-(CH2)n-heterocyclyl, and n may be=0-6 and the aryl residue or heterocyclic residue may be from one to 3 times substituted by F, Cl, Br, I, OH, 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.

Under alkenyl residue understand linear or branched hydrocarbon chain having two or more carbon atoms and one or more double bonds, such as, for example, vinyl, allyl, pentenyl.

Alkeneamine residues can be substituted one or more times suitable for the included groups, such as, for example: F, Cl, Br, I, CF3, NO2N3, CN, COOH, COO(C1-C6)alkyl, NH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2cycloalkyl,

(C1-C10)alkyl, (C2-C6)quinil, O-(C1-C6)alkyl-O-CO-(C1-C6)alkyl, O-CO-(C1-C6)aryl, O-CO-(C1-C6)heterocyclyl; RHO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)alkyl, SO2N[(C1-C6)alkyl]2S-(C1-C6)alkyl, S-(CH2)n-aryl, S-(CH2)n-heterocyclyl, SO-(C1-C6)alkyl, SO-(CH2)n-aryl, SO-(CH2)n-heterocyclyl, SO2-(C1-C6)alkyl,

SO2-(CH2)n-aryl, SO2-(CH2)n-heterocyclyl, SO2-NH(CH2)n-aryl, SO2-NH(CH2)n-heterocyclyl, SO2-N(C1-C6)alkyl)(CH2)n-aryl, SO2-N(C1-C6)alkyl)(CH2)n-heterocyclyl, SO2-N((CH2)n-aryl)2, SO2-N((CH2)n-(heterocyclyl)2and n may be=0-6 and the aryl residue or heterocyclic residue may be substituted up to two times F, Cl, Br, OH, CF3, NO2CN, OCF3About-(C1-C6)alkyl, (C1-C6)alkyl, NH2;

C(NH)(NH2), NH2, NH-(C1-C 6)alkyl, N((C1-C6)alkyl)2, NH(C1-C7)-acyl, NH-CO-(C1-C6)alkyl, NHCOO-(C1-C6)alkyl, NH-CO-aryl, NH-CO-heterocyclyl, NH-COO-aryl, NH-COO-heterocyclyl, NH-CO-NH-(C1-C6)-alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocyclyl, N(C1-C6)-alkyl-CO-(C1-C6)alkyl, N(C1-C6)alkyl-COO-(C1-C6)alkyl, N(C1-C6)alkyl-CO-aryl, N(C1-C6)alkyl-CO-heterocyclyl, N(C1-C6)alkyl-COO-aryl, N(C1-C6)alkyl-COO-heterocyclyl, N(C1-C6)alkyl-CO-NH-(C1-C6)alkyl), N(C1-C6)alkyl-CO-NH-aryl, N(C1-C6)alkyl-CO-NH-heterocyclyl, N((C1-C6)alkyl)-CO-N-(C1-C6)alkyl)2,

N((C1-C6)alkyl)-CO-N((C1-C6)alkyl)-CO-N((C1-C6)alkyl)aryl, - N((C1-C6)alkyl)-CO-N((C1-C6)alkyl)-CO-N((C1-C6)alkyl)heterocyclyl, N((C1-C6)alkyl)-CO-N-(aryl)2N((C1-C6)alkyl)-CO-N-(heterocyclyl)2N(aryl)-CO-(C1-C6)alkyl, N(heterocyclyl)-CO-(C1-C6)alkyl, N(aryl)-COO-(C1-C6)alkyl, N(heterocyclyl)-COO-(C1-C6)alkyl, N(aryl)-CO-aryl, N(heterocycle)-CO-aryl, N(aryl), COO-aryl, N(heterocycle)-COO-aryl, N(aryl)-NH-(C1-C6)alkyl, N(heterocyclyl)-CO-NH-(C1-C6)alkyl), N(aryl)-CO-NH-aryl, N(heterocycle)-CO-NH-aryl, N(aryl)-CO-N-(C1-C6)alkyl)2N(heterocyclyl)-CO-N-(C1-C6)alkyl)2N(aryl)-SOP((C1-C6)alkyl)aryl, N(heterocycle)-CO-N((C1-C6)alkyl)aryl, N(aryl)-CO-N-(aryl)2N(heterocyclyl)-CO-N-(aryl)2, aryl, O-(CH2)n-aryl, O-(CH2)n-heterocyclyl, and n may be=0-6 and the aryl residue or heterocyclic residue may be from one to 3 times substituted by F, Cl, Br, I, OH, 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.

Under alkynylaryl residue understand linear or branched hydrocarbon chain having two or more carbon atoms and one or more triple bonds, such as, for example, ethinyl, PROPYNYL, hexenyl.

Alkyline residues can be substituted one or more times by suitable groups such as, for example: F, Cl, Br, I, CF3, NO2N3, CN, COOH, COO(C1-C6)alkyl, NH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2cycloalkyl, (C2-C6)alkenyl, (C1-C10)alkyl,-(C1-C6)alkyl O-CO-(C1-C6)alkyl, O-CO-(C1-C6)aryl, O-CO-(C1-C6)gets recycler; RHO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)alkyl, SO2N[(C1-C6)alkyl]2S-(C1-C6)alkyl, S-(CH2)n-aryl, S-(CH2)n-heterocyclyl, SO-(C1-C6)alkyl, SO-(CH2)n-aryl, SO-(CH2)n-heterocyclyl, SO2-(C1-C6)alkyl, SO2-(CH2)n-aryl, SO2-(CH2)n-heterocyclyl, SO2-NH(CH2)n-aryl, SO2-NH(CH2)n-heterocyclyl, SO2-N(C1-C6)alkyl)(CH2)n-aryl, SO2-N(C1-C6)alkyl)(CH2)n-heterocyclyl, SO2-N((CH2)n-aryl)2, SO2-N((CH2)n-(heterocyclyl)2and n may be=0-6 and the aryl residue or heterocyclic residue may be substituted up to two times F, Cl, Br, OH, CF3, NO2CN, OCF3About-(C1-C6)alkyl, (C1-C6)alkyl, NH2;

C(NH)(NH2), NH2, NH-(C1-C6)alkyl, N((C1-C6)alkyl)2, NH(C1-C7)acyl, NH-CO-(C1-C6)alkyl, NHCOO-(C1-C6)alkyl, NH-CO-aryl, NH-CO-heterocyclyl, NH-COO-aryl, NH-COO-heterocyclyl, NH-CO-NH-(C1-C6)alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocyclyl, N(C1-C6)alkyl-CO-(C1-C6)alkyl, N(C1-C6)alkyl-COO-(C1-C6)alkyl, N(C1-C6 )alkyl-CO-aryl, N(C1-C6)alkyl-CO-heterocyclyl, N(C1-C6)alkyl-COO-aryl, N(C1-C6)alkyl-COO-heterocyclyl, N(C1-C6)alkyl-CO-NH-(C1-C6)alkyl), N(C1-C6)alkyl-CO-NH-aryl, N(C1-C6)alkyl-CO-NH-heterocyclyl, N((C1-C6)alkyl)-CO-N-(C1-C6)alkyl)2N((C1-C6)alkyl)-CO-N((C1-C6)alkyl)aryl, - N((C1-C6)alkyl)-CO-N((C1-C6)alkyl)-CO-N((C1-C6)alkyl)heterocyclyl, N((C1-C6)-alkyl)-CO-N-(aryl)2N((C1-C6)-alkyl)-CO-N-(heterocyclyl)2,

N(aryl)-CO-(C1-C6)alkyl, N(heterocyclyl)-CO-(C1-C6)alkyl, N(aryl)-COO-(C1-C6)alkyl, N(heterocyclyl)-COO-(C1-C6)alkyl, N(aryl)-CO-aryl, N(heterocycle)-CO-aryl, N(aryl), COO-aryl, N(heterocycle)-COO-aryl, N(aryl)-CO-NH-(C1-C6)alkyl, N(heterocyclyl)-CO-NH-(C1-C6)alkyl), N(aryl)-CO-NH-aryl, N(heterocycle)-CO-NH-aryl, N(aryl)-CO-N-(C1-C6)alkyl)2,

N(heterocyclyl)-CO-N-(C1-C6)alkyl)2N(aryl)-SOP((C1-C6)alkyl)aryl, N(heterocycle)-CO-N((C1-C6)alkyl)aryl, N(aryl)-CO-N-(aryl)2N(heterocyclyl)-CO-N-(aryl)2, aryl, O-(CH2)n-aryl, O-(CH2)n-heterocyclyl, and n may be=0-6 and the aryl residue or gets acyclically the remainder can be from one to 3 times replaced by F, Cl, Br, I, OH, 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.

Under the aryl residue understand the remains of phenyl, naphthyl, biphenyl, tetrahydronaphthyl, (remains of) alpha - or beta-tetralone, indanyl or indan-1-IMT.

Aryl residues can be substituted one or more times by suitable groups such as, for example: F, Cl, Br, I, CF3, NO2N3, CN, COOH, COO(C1-C6)alkyl, NH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2cycloalkyl,

(C1-C10)alkyl, (C2-C6)alkenyl, (C2-C6)quinil, O-(C1-C6)alkyl O-CO-(C1-C6)alkyl, O-CO-(C1-C6)aryl, O-CO-(C1-C6)heterocyclyl; RHO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)alkyl, SO2N[(C1-C6)alkyl]2S-(C1-C6)alkyl, S-(CH2)n-aryl, S-(CH2)n-heterocyclyl, SO-(C1-C6)alkyl, SO-(CH2)n-aryl, SO-(CH2)n-heterocyclyl, SO2-(C1-C6)alkyl, SO2-(CH2)n-aryl, SO2-(CH2)n-heterocyclyl, SO2-NH(CH2)n-aryl, SO2-NH(CH2 )n-heterocyclyl, SO2-N(C1-C6)alkyl)(CH2)n-aryl, SO2-N(C1-C6)alkyl)(CH2)n-heterocyclyl, SO2-N((CH2)n-aryl)2, SO2-N((CH2)n-(heterocyclyl)2and n may be=0-6 and the aryl residue or heterocyclic residue may be substituted up to two times F, Cl, Br, OH, CF3, NO2CN, OCF3About-(C1-C6)alkyl, (C1-C6)alkyl, NH2;

C(NH)(NH2), NH2, NH-(C1-C6)alkyl, N((C1-C6)alkyl)2, NH(C1-C7)-acyl, NH-CO-(C1-C6)alkyl, NHCOO-(C1-C6)alkyl, NH-CO-aryl, NH-CO-heterocyclyl, NH-COO-aryl, NH-COO-heterocyclyl, NH-CO-NH-(C1-C6)alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocyclyl, N(C1-C6)alkyl-CO-(C1-C6)alkyl, N(C1-C6)alkyl-COO-(C1-C6)alkyl, N(C1-C6)alkyl-CO-aryl, N(C1-C6)alkyl-CO-heterocyclyl, N(C1-C6)alkyl-COO-aryl, N(C1-C6)alkyl-COO-heterocyclyl, N(C1-C6)alkyl-CO-NH-(C1-C6)alkyl), N(C1-C6)alkyl-CO-NH-aryl, N(C1-C6)alkyl-CO-NH-heterocyclyl, N((C1-C6)alkyl)-CO-N-(C1-C6)alkyl)2N((C1-C6)alkyl)-CO-N((C1-C6)alkyl)aryl, - N((C1-C6)alkyl)-CO-N((C1-C6)alkyl)heterocycle is, N((C1-C6)alkyl)-CO-N-(aryl)2N((C1-C6)alkyl)-CO-N-(heterocyclyl)2N(aryl)-CO-(C1-C6)alkyl, N(heterocyclyl)-CO-(C1-C6)alkyl, N(aryl)-COO-(C1-C6)alkyl, N(heterocyclyl)-COO-(C1-C6)alkyl, N(aryl)-CO-aryl, N(heterocycle)-CO-aryl, N(aryl), COO-aryl, N(heterocycle)-COO-aryl, N(aryl)-CO-NH-(C1-C6)alkyl, N(heterocyclyl)-CO-NH-(C1-C6)alkyl), N(aryl)-CO-NH-aryl, N(heterocycle)-CO-NH-aryl, N(aryl)-CO-N-(C1-C6)alkyl)2,

N(heterocyclyl)-CO-N-(C1-C6)alkyl)2N(aryl)-SOP((C1-C6)alkyl)aryl, N(heterocycle)-CO-N((C1-C6)alkyl)aryl, N(aryl)-CO-N-(aryl)2N(heterocyclyl)-CO-N-(aryl)2, aryl, O-(CH2)n-aryl, O-(CH2)n-heterocyclyl, and n may be=0-6 and the aryl residue or heterocyclic residue may be from one to 3 times substituted by F, Cl, Br, I, OH, 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.

Under cycloalkenyl residue understand the cyclic system containing one or more cycles, which can be saturated or partially unsaturated (with one or two double bond is and), which is built only of carbon atoms, such as, for example, cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl or substituted.

Cycloalkyl residues can be substituted one or more times by suitable groups such as, for example: F, Cl, Br, I, CF3, NO2N3, CN, COOH, COO(C1-C6)alkyl, NH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2cycloalkyl,

(C1-C10)alkyl, (C2-C6)alkenyl, (C2-C6)quinil, O-(C1-C6)alkyl O-CO-(C1-C6)alkyl, O-CO-(C1-C6)aryl, O-CO-(C1-C6)heterocyclyl; RHO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)alkyl, SO2N[(C1-C6)alkyl]2S-(C1-C6)alkyl, S-(CH2)n-aryl, S-(CH2)n-heterocyclyl, SO-(C1-C6)alkyl, SO-(CH2)n-aryl, SO-(CH2)n-heterocyclyl, SO2-(C1-C6)alkyl, SO2-(CH2)n-aryl, SO2-(CH2)n-heterocyclyl, SO2-NH(CH2)n-aryl, SO2-NH(CH2)n-heterocyclyl, SO2-N(C1-C6)alkyl)(CH2)n-aryl, SO2-N(C1-C6)alkyl)(CH2)n-heterocyclyl, SO2-N((CH2)n-aryl)2, SO2-N((CH2)n-(heterocyclyl)2 and n may be=0-6 and the aryl residue or heterocyclic residue may be substituted up to two times F, Cl, Br, OH, CF3, NO2CN, OCF3About-(C1-C6)alkyl, (C1-C6)alkyl, NH2;

C(NH)(NH2), NH2, NH-(C1-C6)alkyl, N((C1-C6)alkyl)2, NH(C1-C7)acyl, NH-CO-(C1-C6)alkyl, NHCOO-(C1-C6)alkyl, NH-CO-aryl, NH-CO-heterocyclyl, NH-COO-aryl, NH-COO-heterocyclyl, NH-CO-NH-(C1-C6)alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocyclyl, N(C1-C6)alkyl-CO-(C1-C6)alkyl, N(C1-C6)alkyl-COO-(C1-C6)alkyl, N(C1-C6)alkyl-CO-aryl, N(C1-C6)alkyl-CO-heterocyclyl, N(C1-C6)alkyl-COO-aryl, N(C1-C6)alkyl-COO-heterocyclyl, N(C1-C6)alkyl-CO-NH-(C1-C6)alkyl), N(C1-C6)alkyl-CO-NH-aryl, N(C1-C6)alkyl-CO-NH-heterocyclyl, N((C1-C6)alkyl)-CO-N-(C1-C6)alkyl)2N((C1-C6)alkyl)-CO-N((C1-C6)alkyl)aryl, - N((C1-C6)alkyl)-CO-N((C1-C6)alkyl)heterocyclyl, N((C1-C6)alkyl)-CO-N-(aryl)2N((C1-C6)alkyl)-CO-N-(heterocyclyl)2N(aryl)-CO-(C1-C6)alkyl, N(heterocyclyl)-CO-(C1-C6)alkyl, N(aryl)-COO-(C1-C6)alkyl, N(heterocyclyl)-COO-(C1-the 6)alkyl, N(aryl)-CO-aryl, N(heterocycle)-CO-aryl, N(aryl), COO-aryl, N(heterocycle)-COO-aryl, N(aryl)-CO-NH-(C1-C6)alkyl), N(heterocyclyl)-CO-NH-(C1-C6)alkyl), N(aryl)-CO-NH-aryl, N(heterocycle)-CO-NH-aryl, N(aryl)-CO-N-(C1-C6)alkyl)2,

N(heterocyclyl)-CO-N-(C1-C6)alkyl)2N(aryl)-SOP((C1-C6)alkyl)aryl, N(heterocycle)-CO-N((C1-C6)alkyl)aryl, N(aryl)-CO-N-(aryl)2N(heterocyclyl)-CO-N-(aryl)2, aryl, O-(CH2)n-aryl, O-(CH2)n-heterocyclyl, and n may be=0-6 and the aryl residue or heterocyclic residue may be from one to 3 times substituted by F, Cl, Br, I, OH, 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.

Under heterocyclyl or heterocyclic residue understand the cycles and cyclic systems, which in addition to carbon atoms, contain heteroatoms, such as nitrogen, oxygen or sulfur. In addition to the above definition also include cyclic system in which heterocyclyl or heterocyclic residue is condensed with the benzene nuclei.

Suitable "heterocyclic rings" or "heterocyclics is their remnants are acridines, azocines, benzimidazolyl, benzofuran, benzothiazyl, benzothiophene, benzoxazole, benzthiazole, benzotriazolyl, asterisell, benzoxazolyl, benzisothiazole, benzimidazolinyl, carbazolyl, an-carbazolyl, carbolines, hintline, chinoline, 4H-indolizinyl, honokalani, hinokitiol, bromanil, bromanil, cinnoline, decahydroquinoline, 2N,6N-1,5,2-detainer, dihydrofuro[2,3-b]tetrahydrofuran, furyl, furutani, imidazolidinyl, imidazolyl, imidazolyl, 1H-indazole, indoline, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isopropanol, isoindolyl, isoindolines, isoindolyl, ethenolysis (benzimidazolyl), isothiazolin, isoxazolyl, morpholinyl, naphthyridine, octahydronaphthalene, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridines, phenanthrolines, phenazines, phenothiazines, phenoxathiin, phenoxazines, phthalazine, piperazinil, piperidinyl, pteridinyl, purinol, pyranyl, pyrazinyl, pyrazolidine, pyrazoline, pyrazolyl, pyridazinyl, pyridoxal, predominate, peridotite, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl 2N-pyrrolyl, pyrrolyl, tetrahydrofuranyl tetrahydroisoquinolines, tetrahydroquinoline, 6N-1,2,5-thiadiazine, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl 1,3,4-thiadiazolyl, thienyl, triazolyl, tetrazolyl and xantinol.

Pyridyl is 2-, 3-, and 4-pyridyl. Thienyl represents both 2-and 3-thienyl. Furyl represents both 2-and 3-furyl.

Additionally covered by the corresponding N-oxides of these compounds, as, for example, 1-hydroxy-2-, 3 - or 4-pyridyl.

Additionally covered one or more times Antonelliana derivatives of these heterocycles.

Heterocyclic ring or heterocyclic residues may be substituted one or more times by suitable groups such as, for example: F, Cl, Br, I, CF3, NO2N3, CN, COOH, COO(C1-C6)alkyl, NH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2cycloalkyl, (C1-C10)alkyl, (C2-C6)alkenyl, (C2-C6)quinil, O-(C1-C6)alkyl O-CO-(C1-C6)alkyl, O-CO-(C1-C6)aryl, O-CO-(C1-C6)heterocyclyl;

RHO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)alkyl, SO2N[(C1-C6)alkyl]2S-(C1-C6)alkyl, S-(CH2)n-aryl, S-(CH2)n-heterocyclyl, SO-(C1-C6)alkyl, SO-(CH2)n-aryl, SO-(CH2)n-heterocyclyl, SO2-(C1-C6)alkyl, SO2-(CH2)n-aryl, SO2-(CH2 )n-heterocyclyl, SO2-NH(CH2)n-aryl, SO2-NH(CH2)n-heterocyclyl, SO2-N(C1-C6)alkyl)(CH2)n-aryl, SO2-N(C1-C6)alkyl)(CH2)n-heterocyclyl, SO2-N((CH2)n-aryl)2, SO2-N((CH2)n-(heterocyclyl)2and n may be=0-6 and the aryl residue or heterocyclic residue may be substituted up to two times F, Cl, Br, OH, CF3, NO2CN, OCF3About-(C1-C6)alkyl, (C1-C6)alkyl, NH2;

C(NH)(NH2), NH2, NH-(C1-C6)alkyl, N((C1-C6)alkyl)2, NH(C1-C7)acyl, NH-CO-(C1-C6)alkyl, NHCOO-(C1-C6)alkyl, NH-CO-aryl, NH-CO-heterocyclyl, NH-COO-aryl, NH-COO-heterocyclyl, NH-CO-NH-(C1-C6)alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocyclyl, N(C1-C6)alkyl-CO-(C1-C6)alkyl, N(C1-C6)alkyl-COO-(C1-C6)alkyl, N(C1-C6)alkyl-CO-aryl, N(C1-C6)alkyl-CO-heterocyclyl, N(C1-C6)alkyl-COO-aryl, N(C1-C6)alkyl-COO-heterocyclyl, N(C1-C6)alkyl-CO-NH-(C1-C6)alkyl), N(C1-C6)alkyl-CO-NH-aryl, N(C1-C6)alkyl-CO-NH-heterocyclyl, N((C1-C6)alkyl)-CO-N-(C1-C6)alkyl)2N((C1-C6)alkyl)-CO-N((C1-C6)-and the keel)aryl, N((C1-C6)alkyl)-CO-N((C1-C6)alkyl)heterocyclyl, N((C1-C6)alkyl)-CO-N-(aryl)2N((C1-C6)alkyl)-CO-N-(heterocyclyl)2N(aryl)-CO-(C1-C6)alkyl, N(heterocyclyl)-CO-(C1-C6)alkyl, N(aryl)-COO-(C1-C6)alkyl, N(heterocyclyl)-COO-(C1-C6)alkyl, N(aryl)-CO-aryl, N(heterocycle)-CO-aryl, N(aryl), COO-aryl, N(heterocycle)-COO-aryl, N(aryl)-CO-NH-(C1-C6)alkyl, N(heterocyclyl)-CO-NH-(C1-C6)alkyl), N(aryl)-CO-NH-aryl, N(heterocycle)-CO-NH-aryl, N(aryl)-CO-N-(C1-C6)alkyl)2,

N(heterocyclyl)-CO-N-(C1-C6)alkyl)2N(aryl)-SOP((C1-C6)alkyl)aryl, N(heterocycle)-CO-N((C1-C6)alkyl)aryl, N(aryl)-CO-N-(aryl)2N(heterocyclyl)-CO-N-(aryl)2, aryl, O-(CH2)n-aryl, O-(CH2)n-heterocyclyl, and n may be=0-6 and the aryl residue or heterocyclic residue may be from one to 3 times substituted by F, Cl, Br, I, OH, 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.

The number of compounds according to formula I, which is required to achieve the desired biological effect depends on the t of a number of factors, for example, selected from specific connections, intended use, method of administration and the clinical condition of the patient. The usual daily dose is from 0.3 to 100 mg (typically from 3 mg to 50 mg) per kilogram body weight per day, for example, 3-10 mg/kg/day. An intravenous dose may, for example, range from 0.3 mg to 1.0 mg/kg, appropriately (she) may be introduced in the form of infusion of 10 ng to 100 ng per kilogram (body weight) per minute. Suitable infusion solutions for these purposes may include, for example, from 0.1 ng to 10 ng, typically from 1 ng to 10 ng per milliliter. Single doses may contain, for example, from 1 mg to 10 g of the active substance. Thus, ampoules for injection may contain, for example, from 1 mg to 100 mg, and oral input single dose composition, such as, for example, tablets or capsules may contain from 1.0 to 1000 mg, typically from 10 to 600 mg For the treatment of the above-mentioned States of the compounds according to formula I can be used in combination, but preferably they are administered with a suitable carrier in the form of pharmaceutical compositions. Of course, the media must be compatible in the sense that it is mixed with other components of the composition and harmless to the patient. The carrier may be a solid or a liquid or both and is preferably mixed with connected is eaten in the form of a single dose, for example, in the form of a tablet, which may contain from 0.05 to 95 wt.% the active substance. Similarly you can enter other pharmaceutically active substances, including additional compounds of formula I. the Proposed pharmaceutical composition can be obtained by known pharmaceutical methods, which mainly consist in the fact that the components are mixed with pharmacologically acceptable carriers and/or auxiliary substances.

The proposed pharmaceutical compositions are suitable for oral, rectal, local, peroral (for example sublingual) and parenteral (e.g. subcutaneous, intramuscular, transdermal or intravenous) administration, although suitable route of administration in each individual case depends on the type and severity treatable condition and the type of concrete used compounds according to formula I. In the scope of the invention also includes the index composition and index of the composition of prolonged action. Preferred compositions, resistant to acids and gastric juice. Suitable resistant to gastric juice coverings are acetated cellulose, polyvinylacetate, phthalate of hydroxypropylmethylcellulose and anionic polymers of methacrylic acid and methyl ester of metac the sludge acid.

Suitable pharmaceutical compounds for oral administration can be a separate unit, such as, for example, capsules, pills, tablets for sucking or tablets, which contain a certain number of compounds according to formula I which may be in the form of a powder or granules; in the form of a solution or suspension in an aqueous or nonaqueous liquid; or as emulsions (type) oil-in-water or water-in-oil. These compositions can, as already mentioned, can be prepared by any suitable pharmaceutical method which includes the stage at which contact the active substance and the carrier (which may consist of one or more additional components). Typically, the compositions have a uniform and homogeneous mixing of the active substance with a liquid and/or powdered solid carrier, after which the product if necessary formulate, for example, the tablet can be obtained by compressing and molding a powder or granules of the compound, if necessary with one or more additional components. Pressed tablets get pelletizing compounds in free flowing form such as powder or granules, if necessary mixed with a binder, means imparting lubricity, inert diluent and/or one (several) on Ernesto-active/dispersing means in a suitable machine. Molded tablets can be obtained by molding powder, moistened with an inert liquid diluent compounds in a suitable machine.

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

Suitable pharmaceutical compositions for parenteral administration are preferably sterile aqueous compositions of the compounds according to formula I, which preferably is isotonic with the blood of the intended recipient. These compositions are preferably administered intravenously, although it is possible to carry out the introduction of subcutaneous, intramuscular or transdermal injections. These compositions can preferably be obtained by mixing the compound with water, sterilizing the resulting solution and bringing it to isotonic with blood. The proposed compositions for injections usually contain from 0.1 to 5 wt.% active connection.

Suitable pharmaceutical compositions for rectal injection preferably represent a single candle. They can be the ü received, if the connection according to the formula I is mixed with one or more conventional solid carriers, for example cocoa butter, and the mixture obtained is formed.

Suitable pharmaceutical compositions for topical application to the skin preferably are ointments, creams, lotions, pastes, sprays, aerosols or oils. As carriers can be used vaseline, lanolin, polyethylene glycol, alcohols and combinations of two or more of these substances. The active ingredient is typically present in a concentration of from 0.1 to 15 wt.% compositions, for example, from 0.5 to 2%.

It is also possible transdermal administration. Suitable pharmaceutical compositions for transdermal application can be a separate patch, which is suitable for prolonged contact with the epidermis of the patient. These patches contain dissolved and/or dispersed in a proper way active substance in water, if necessary, the buffer solution in the auxiliary tool or dispersed in the polymer. A suitable concentration of the active substance is from about 1% to 35%, preferably from about 3% to 15%. As a special active substance can be released by electrotransport or iontophoresis, as described, for example, in Pharmaceutical Research, 2(6); 318 (1986).

The compound(I) of the formula (I) could the t to be implemented in combination with additional active substances.

As an additional active substances for combined preparations suitable all antidiabetics, which are named Roten Liste 2003, part 12. They can be combined with the proposed compounds of the formula I, in particular for a synergistic improvement actions. Introduction combinations of active substances may be either separate cottage of active substances to a patient, either in the form of a combined preparation in which the active substance is present in a single pharmaceutical composition. Most of the following active substances described in the USP Dictionary of USAN and international Drug Names, US Pharmacopeia, Rockville 2001.

Antidiabetic substances include insulin and derivatives of insulin, such as Lantus® (see www.lantus.com or HNR 1964, fast-acting insulin (see patent US 6221633), GLP-1 derivatives, such as, for example, described in patents WO 97/26265, WO 99/03861 and WO 01/04156, WO 00/34331, WO 00/34332, WO 91/11457 and US 6380357, as well as acting oral hypoglycemic agents.

Acting oral hypoglycemic substances include, preferably, sulfonylureas, biguanidines, meglitinides, oxadiazolidine, thiadiazolidine, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, breakers potassium channels, such as, for example, proposed in patents WO 97/26265 and WO 99/03861 of Novo Nordisk A/S, coustical the data to insulin (substance), inhibitors of liver enzymes involved in stimulating glycogenesis and/or glycogenolysis, modulators of the seizure of glucose, compounds that alter fat metabolism, such as antihyperlipidemic agents and antilipidemic substances, compounds that reduce the absorption of food, PPAR and PXR to define against agonists and biologically active substances that act on the beta-cell ATP-dependent potassium channels.

In one of the embodiments of the invention the compounds of formula I is administered in combination with an inhibitor of HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, tseriwastatina, rosuvastatin.

In one of the embodiments of the invention the compounds of formula I is administered in combination with inhibitors of resorption of cholesterol, such as, for example, ezetimibe, tiqueside, pemaquid.

In one of the embodiments of the invention the compounds of formula I is administered in combination with a PPAR-gamma agonist such as, for example, rosiglitazone, pioglitazone, JTT-501, Gl-262570.

In one of the embodiments of the invention the compounds of formula I is administered in combination with a PPAR-alpha agonist, such as, for example, GW 9578, GW 7647.

In one of the embodiments of the invention the compounds of formula I is administered in combination with a mixed PPAR alpha/gamma agonist such as, for example, GW-1536, AVE 8042, AE 8134, AVE 0847, or such as described in patent PCT/US 11833, PCT/US 11490, DE 10142734.4.

In one of the embodiments of the invention the compounds of formula I is administered in combination with vibrator, such as, for example, fenofibrate, clofibrate, bezafibrat.

In one of the embodiments of the invention the compounds of formula I is administered in combination with MTP-inhibitor, such as, for example, implitapide, BMS-201038, R-103757.

In one of the embodiments of the invention the compounds of formula I is administered in combination with inhibitors of resorption of bile acids (see, for example, US patents 6245744 or US 6221897), such as, for example, HMR 1741.

In one of the embodiments of the invention the compounds of formula I is administered in combination with a CETP-inhibitor, such as, for example JTT-705.

In one of the embodiments of the invention the compounds of formula I is administered in combination with a polymeric bile acid adsorbent such as, for example, cholestyramine, colesevelam.

In one of the embodiments of the invention the compounds of formula I is administered in combination with a stimulant LDL-receptor (see patent US 6342512), such as, for example, HMR1171, HMR1586.

In one of the embodiments of the invention the compounds of formula I is administered in combination with AST-inhibitor, such as, for example, avasimibe.

In one of the embodiments of the invention the compounds of formula I is administered in combination with anti what xidants, such as, for example, OPC-14117.

In one of the embodiments of the invention the compounds of formula I is administered in combination with an inhibitor of lipoprotein lipase activity, such as, for example, NO-1886.

In one of the embodiments of the invention the compounds of formula I is administered in combination with an inhibitor of ATP-citrate lyase, such as, for example, SB-204990.

In one of the embodiments of the invention the compounds of formula I is administered in combination with inhibitors stvalentines, such as, for example, BMS-188494.

In one of the embodiments of the invention the compounds of formula I is administered in combination with an agonist of lipoprotein(s), such as, for example, CI-1027 or nicotinic acid.

In one of the embodiments of the invention the compounds of formula I is administered in combination with a lipase inhibitor, such as orlistat.

In one of the embodiments of the invention the compounds of formula I is administered in combination with insulin.

In one of the embodiments of the compounds of formula I is administered in combination with a sulfonylurea such as, for example, tolbutamide, glibenclamide, glipizide or glimepiride.

In one of the embodiments of the compounds of formula I is administered in combination with biguanides, such as, for example, Metformin.

In one of the embodiments of the compounds of formula I is administered in combination with meglitinides, such as, for example the EP, Repaglinide.

In one of the embodiments of the compounds of formula I is administered in combination with thiazolidinones, such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds proposed in patent WO 97/41097 Dr. Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-girasolereale]phenyl]methyl]-2,4-thiazolidinedione.

In one of the embodiments of the compounds of formula I is administered in combination with inhibitors of α-glucosidase, such as, for example, miglitol or acarbose.

In one of the embodiments of the compounds of formula I is administered in combination with a biologically active substance that acts on the beta-cell ATP-dependent potassium channels, such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or Repaglinide.

In one of the embodiments of the compounds of formula I is administered in combination with more than one of vistasony compounds, e.g. in combination with a sulfonylurea and Metformin, a sulfonylurea and acarbose, Repaglinide and Metformin, insulin and a sulfonylurea, insulin and Metformin, insulin and troglitazone, insulin and lovastatin, etc.

In one additional embodiment, the compounds of formula I is administered in combination with CART-modulators (see “Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice” Asakawa, A, the other, M.: Hormone and Metabolic Research (2001), 33(9), 554-558), NPY antagonists, for example, hydrochloride {4-[4-aminoquinazolin-2-ylamino)methyl]cyclohexylmethyl}amide naphthalene-1-sulfonic acids (CGP A)), MS-agonists (e.g., [2-(3a-benzyl-2-methyl-3-oxo-2,3,3A,4,6,7 there is hexahydropyrazino[4,3-c]pyridine-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]amidon 1-amino-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid; (patent WO 01/91752)), antagonists of orexin (for example, the hydrochloride of 1-(2-methylbenzothiazol-6-yl)-3-[1,5]naphthiridine-4-rocephine (SB-334867-A)), H3 agonists (salt (3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-yl)propan-1-it with oxalic acid (patent WO 00/63208)); TNF agonists, CRF antagonists (e.g., [2-methyl-9-(2,4,6-trimetilfenil)-N-1,3,9-diazafluoren-4-yl]dipropylamine (patent WO 00/66585)), CRF BP antagonists (e.g. urocortin), agonists urocortin, β3 agonists (e.g., the hydrochloride of 1-(4-chloro-3-methysulfonylmethane)-2-[2-(2,3-dimethyl-1H-indole-6-yloxy)ethylamino]ethanol (patent WO 01/83451), agonists, MSH (melanocyte-stimulating hormone), CCK-A agonists (for example, the salt of {2-[4-(4-chloro-2,5-acid)-5-(2-cyclohexylethyl)thiazol-2-ylcarbonyl]-5,7-dimethylindole-1-yl}acetic acid with triperoxonane acid (patent WO 99/15525)); inhibitors of serotonin reuptake (e.g., dexfenfluramine), mixed serotonin and noradrenergic compounds (in the example, patent WO 00/71549), NT-agonists, for example, salt of 1-(3-ethylbenzophenone-7-yl)piperazine with oxalic acid (patent WO 01/0911), agonists bombezin, antagonists Galanina, growth hormone (e.g. human growth hormone), compounds which release growth hormone (tert-butyl ether 6-benzyloxy-1-(2-diisopropylaminoethanol)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (patent WO 01/85695), TR-agonists (see, for example, patent EP 0462884)severing protein 2 or 3 modulators, leptin agonists (see, for example, Lee, Daniel W.; Leinung, Matthew X; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26(9), 873-881), DA-agonists (bromocriptine, depression), inhibitors of lipase/amylase (for example, patent WO 00/40569), PPAR-modulators (e.g., patent WO 00/78312) RXR-modulators or TR-β-agonists.

In one of the embodiments of the invention additional biologically active agent is a leptin; see, for example, “Perspectives in therapeutic use of leptin”, Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-1622.

In one embodiment, the implementation of additional biologically active substance is dexamphetamine or amphetamine.

In one embodiment, the implementation of additional biologically active substance is a (substance), reducing blood pressure, that is passed as for example, ACE inhibitor.

In one embodiment, the implementation of additional biologically active substance is fenfluramine or dexfenfluramin.

In another variant implementation of additional biologically active substance is a sibutramine.

In one embodiment, the implementation of additional biologically active substance is a orlistat.

In one embodiment, the implementation of additional biologically active substance is mazindol or phentermine.

In one of the embodiments of the compounds of formula I is administered in combination with ballast substances, preferably insoluble dietary fiber (see, for example, Carob/Caromax®(Zunft H J and others, Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 September-October), 18(5), 230-6). Caromax is a Carob-containing product, (the company) Fa. Nutrinova, Nutrition Specialties &Food Ingredients GmbH, Industriepark Hoechst, 65926 Frankfurt am main). Combination with Caromax®can be done in a single composition or by separate villas of compounds of formula I and Caromax®. And Caromax®may also be entered in the form of a food product, such as, for example, baking or muesli.

It is clear that every suitable combination of the proposed compounds with one or more of the above compounds and the selection of the one or more additional pharmacologically active substances are considered as falling within the protection scope of the present invention.

The following examples serve to clarify the invention without limiting it.

Example No.XYR1R3R4R5R6R7R8Liquid chromatography/Mass spectrometry (M+H+)
1CHOHHHHHH353,1
2CHOHHHHHH405,9
3CHOHHHHHH396,0
4CHOHHHHHH456,0
5CHOHHHHHH438,1
6CHOHHHHHH 411,9
7CHOHHHHHH388,1
8CHOHNHHHH402,2

The activity of the compounds was tested as follows.

The enzymatic system tests to determine the inhibition of phosphatase

The compounds of formula I were tested in vitro at (object) inhibitory effect on phosphatase. The enzyme preparation and testing produced the following.

Receiving enzyme preparation

A) Cell culture:

The Sf9 cells (=type cells Spodoptera frugiperda, polecamy in vitro) were cultured in Spinner flasks and at 28°C in medium supplemented Grace's (Gibco-BRL) in 10%activated by heating fetal calf serum (Gibco-BRL) according to the Protocol Summers and Smith, A Manual for Methods for Baculoviuns Vectors and insect Culture Procedures [Bulletin No. 15555]. Texas A & M University, Texas Agricultural Experiment Station, College Station, TX, 1987).

Construction of recombinant transfer vectors based on Baculovirus: encoding cDNA for the regulatory and catalytic domains RTR IN person, but without the carboxy-terminal hydrophobic region (corresponding to AA 1-229) received polymerase chain reaction through primer with attached seats cloning and suitable matrices cDNA (obtained, for example, in vitro gene) and then cloned into expression vectors Baculovires (Amersham Pharmacia iotech.). Recombinant Baculoviren were obtained using gene-expression system Bac-to-Bac Baculivirus (obtained from Gibco=BRL). The gene was cloned into the donor plasmid pFASTBAC (Life Technologies). The obtained plasmid was transformed into the complementary cells DH10BAC Escherichia coli (available from Life Technologies). After transposition and selection of antibiotic recombinant DNA plasmids were isolated from the selected colonies of E. coli and then used for transfection of insect cells Sf9. The virus particles are amplified three times in air-conditioned environment to volume of viral biomass 500 ml.

C) Obtaining a recombinant protein

Infection with Baculovirus 500-ml culture of Sf9 cells usually carried out as described by Summers and Smith (see above). Sf9 cells at a density of 1-3 x 106cells/ml was besieged by centrifugation at 300·g min, the excess was removed and cells with a density of 1·107cells/ml, R is suspended in a suitable recombinant viral biomass (MOI 10). After careful shaking for 1.5 hours at room temperature was added a fresh environment to achieve the density of cells 1·106cells/ml the Cells were then cultured in suspension at 28°C for a suitable period after infection.

(C) Fractionation of cells and (getting) United cellular extracts of infected Sf9 cells

After infection for analysis of gene protein by the method of SDS-PAGE and Western blot analysis were selected aliquots. Fractionation cells were as described (Cromlish, W., and Kennedy, B. Biochem. Pharmacol. 52:1777-1785). Merged cell extract was obtained in 1-ml aliquot of infected Sf9 cells after infection of certain cells. Precipitated cells (300·g, 5 min), washed once with phosphate buffer (4°C), resuspendable in 50 μl of water and was completed by repeated freezing/thawing. Protein concentration was determined using the method Bradford'and and bovine serum albumin as the standard.

Testing

The specified test is based on the release of phosphate from the consensus substrate peptide, which was identified in the nanomolar concentration range method using malachite green, molybdate ammonium (Lanzetta, P.A., Alvarez, L.J., Reinach, P.S., Candia, O.A. Anal. Biohem. 100:95-97, 1979), adapted to the format of tablets for micrometrology. Dodecadepsipeptide, TRDIYETDYYRK (Botrend, Cologne) corresponds to the amino acid 1142-1153 of the catalytic domain of the insulin receptor and (auto)fosfauriliruetsa on tyrosinosis balances 1146, 1150 and 1151. Recombinant hPTP1B diluted buffer solution tests (40 mm Tris/HCl, pH 7.4, 1 mm EDTA, 20 mm DTT), the corresponding activity 1000-1500 nmol/min/mg protein and then (20 ml-portions) pre-incubated (15 min, 30°C) in the absence or in the presence of the test substance (5 μl) to the desired concentration (final concentration of DMSO up to 2%) in the total volume of 90 μl (buffer test). To start the reaction of dephosphorylation of the peptide substrate (10 μl of pre-heated to 30°C) was added to the pre-incubated enzyme preparation with or without test substance (final concentration of 0.2-200 μm) and incubation was performed for 1 hour. The reaction was completed by addition of 100 μl of malachite green hydrochloride (0,45%, 3 parts), tetrahydrate of ammonium molybdate (4.2% in 4n HCl) and 0.5% Tween 20 as a terminating solution. After incubation for 30 min at 22°C during the development of staining was determined by the absorbance at 650 nm using a reader with tablets for micrometrology (molecular devices). The results of the trial and blind experiments was measured three times. Activity RTR IN expected in nanomolar on the released phosphate per min and mg of the tree with potassium phosphate as standard. Inhibition of recombinant hPTP1B test substances was calculated as percentage of control values phosphatase. The value of the IC50shows a marked according to chetyrehmetrovoy nonlinear logistic regression curve.

C) Splitting of para-nitrophenylphosphate

The specified test is based on the change of absorption of the non-physiological substrate para-nitrophenylphosphate during the splitting up of NITROPHENOL in standard conditions (Tonks, N.K., Ditz, C.D., Fischer, E.H. J. Biol. Chem. 263: 6731-6737, 1988; Burke T.R., Ye, B., Yan, X.J., Wang, S.M., Jia, Z.C., Chen, L., Zhang, Z.Y., Barford, D. Biochemistry 35:15989-15996, 1996). Inhibitors in a suitable dilution was pietravalle to the reaction mixture, which contained 0.5-5 mm para-nitrophenylphosphate. Used the following buffer solutions (total volume 100 ál): (a) 100 mm sodium acetate (pH 5.5), 50 mm NaCl, 0.1% (weight/volume) bovine serum albumin, 5 mm glutathione, 5 mm DTT, 0.4 mm EGTA and 1 mm EDTA; (b) 50 mm Hepes/KOH (pH 7.4), 100 mm NaCl, 0.1% (weight/volume) bovine serum albumin, 5 mm glutathione, 5 mm DTT and 1 mm EDTA. The reaction was started by addition of enzyme and were carried out in the tablet to micrometrology at 25°C for 1 hour. The reaction was completed by addition of 100 μl of 0,2n. NaOH. The enzyme activity was determined by measuring the absorbance at 405 nm with a suitable adjustment of the absorption of the tested substances and para-nitrophenylphosphate. The results were expressed in percentage of the x control (blind experience) by comparing the number of formed para-NITROPHENOL in samples processed test substance (nmol/min/mg protein), with the number in the untreated samples. Calculated average value and the standard deviation, the value of IC50 was determined by regression analysis of the linear sections of the curve of inhibition.

Table 2
Biological activity
ExampleIC 50 (μm)
17,30
212,6
315,72
46,12
52,16
69,44
7162
8290

The table shows that the compounds of formula I inhibit the activity of phosphoribosyltransferase 1 (RTR) and, thus, are well suited for lowering blood sugar levels. They, in particular, applicable to the treatment of diabetes type I and II, insulin resistance, dyslipidemia, metabolic syndrome/syndrome X, morbid obesity, and reduce weight teamleiter.

Additionally, the compounds of formula I as a result of their inhibition RTR applicable for the treatment of hyperglycaemia, high blood pressure, atherosclerosis, abnormal functioning of the immune system, autoimmune diseases, allergic diseases such as asthma, arthritis, osteoarthritis, osteoporosis, proliferative disorders such as cancer and psoriasis, diseases with decreased or increased production of growth factors, hormones or cytokines that trigger the release of growth hormones.

Connection is also applicable to the treatment of diseases of the nervous system, such as, for example, Alzheimer's disease or multiple sclerosis.

Connection is also applicable to the treatment of disturbances of sensitivity and other psychic readings, such as, for example, depression, fear, neurosis, fear, schizophrenia, for treating disorders associated with circadian rhythm, and for the treatment of abuse of drugs. Additionally, they are applicable for the treatment of sleep disorders, syndrome temporary stopping of breathing during sleep, male and female sexual disorders, inflammations, acne, pigmentation of skin, disorders of steroid metabolism, skin diseases and fungal infections.

Hereinafter described in detail obtaining a sample 4 in table 1, the remaining compounds of formula I were obtained in the same way:

Exp the pilot part

To a solution of Na2SO3(27,36 g, 0,128 mol) in H2O (375 ml) was added a solution of (2-fluoro-5-nitrobenzylamine (30 g, 0,128 mol) in acetonitrile (250 ml) and the mixture was stirred for 24 h at room temperature. The solution was evaporated in vacuum, the residue is stirred with 100 ml of isopropanol, the solid was filtered and washed with a small amount of isopropanol or simple diethyl ether.

Output: 28,15,

The sodium salt of the sulphonic acids 1 (35,19 g, 0,1368 mol) were introduced in POCl3(430 ml) and then added PCl5(28,78 g, 0,137 mol). The mixture was heated for 5 hours at the boil under reflux. For processing was evaporated in vacuum and the residue poured into ice water. While the reaction product was separated as a pale yellow solid, which was filtered.

Output: 30,3,

The solution of the sulfonic acid chloride 1 (30,3 g, 0.12 mol) in CH2Cl2(125 ml) was added dropwise to concentrated ammonia (90 ml, 1.2 mol) at room temperature. The mixture was stirred for 20 h at room temperature and then acidified with HCl (1N) to pH 1. Then the organic phase was distilled under reduced pressure, and the reaction product was separated as a pale yellow solid. In conclusion, the product p of the shares was filtered.

Output: 25,01 g (89.4 per cent).

To a solution of compound 1 (25 g, 0,107 mol) in DMF (1 l) at room temperature was added databaseconnect (34,1 g, 33,42 ml, 0.22 mol) and the reaction mixture was stirred for 2 h at 130°C. the solvent is Then kept in vacuum, the residue was mixed with water (400 ml)was mixed with HCl (2n, 400 ml) and the product was repeatedly extracted with dichloromethane. The purified organic phase was dried (Na2SO4) and the solvent drove away under reduced pressure. The obtained residue was mixed with a small amount of cold isopropanol and then the reaction product was filtered.

Output: 20,8 g (91.3 percent).

535 mg of nitro compounds was dissolved in 100 ml of methanol/THF (1:1) and mixed with 5 mol.% Pd (10%on coal). Then was first made with hydrogen in the apparatus for hydrogenation at room temperature until cessation of hydrogen absorption (reaction time: 1 h). For processing the catalyst was filtered through a filter Celit®and the filtrate was evaporated under reduced pressure. The oily residue was stirred with a small amount of simple diethyl ether, filtered off, washed with n-pentane and dried in vacuum.

Output: 397 mg (86% of theory).

1.84 g (10 mmol) obtained above aniline suspended in 240 ml absolutno the dichloromethane and stirring at 20°C was mixed with 2.55 g (11 mmol) of 1,1'-thiocarbonyldi-2(1H)pyridone. The reaction mixture was stirred for 5 h at 20°C.

For processing the reaction mixture 3 times washed with 50 ml water, then the organic phase was dried over Na2SO4and the desiccant was filtered.

After removal of the solvent under reduced pressure was obtained a light yellow oil, which after addition of a small amount of simple diethyl ether crystallized.

Received 2,12 (9.4 mmol) of yellow crystals; yield 94% of theory.

Mass spectrum (ES+): 227,2

1H-NMR (500 MHz, d6-DMSO): (=of 4.57 (s, 2H), 6,85 (d, J=8,56 Hz, 1H), 7,33 (userd, J=8,56 Hz, 1H), 7,40 (users, 1H), 10,84 (users, 1H).

226 mg (1 mmol) obtained above isothiocyanate was dissolved in 10 ml obstetrician and with stirring, mixed with 339 mg (1.5 mmol) 2-azido-1-[3,5-di(tert-butyl)-4-hydroxyphenyl]Ethan-1-it is obtained from 2-bromo-1-[3,5-di(tert-butyl)-4-hydroxyphenyl]Ethan-1-it interaction with sodium azide in DMF as solvent, and 315 mg (1.2 mmol) of triphenylphosphine. The reaction mixture for 1 h was heated under reflux at boiling solvent. For processing the reaction mixture was evaporated under reduced pressure and the resulting oily residue was chromatographically on silica gel (40-63 μl, Fa. Merk) with a mixture of ethyl acetate/heptane (mixing ratio 1:1) as mobile phase.

Output: 288 mg (63% teorii)

Mass spectrum (ES+): 455,99

1H-NMR (500 MHz, d6-DMSO): (=to 1.42 (s, 18H), with 4.64 (s, 2H), PC 6.82 (d, J=8.6 Hz, 1H), 7,15 (s, 1H), 7,22 (s, 1H), 7,31 (s, 2H), of 7.48 (DD, J=8.6 and 2.1 Hz, 1H), of 7.70 (d, J=2.1 Hz, 1H), 10,11 (s, 1H), 10,15 (s, 1H).

1. The compounds of formula I

in which X represents C-R2;
Y represents O,
R1 represents a phenyl, 5-membered heterocycle with one atom of sulfur, and the remainder of the phenyl and heterocyclic residue may be once, twice or three times substituted by halogen, CN, -OH, -CF3-(C1-C6)alkyl, -COOH, -(CH2)-COOH, phenyl, -O-phenyl, where the phenyl ring may be substituted by galiena;
R2, R3, R4, R5, R6, R7 and R8 represent N.

2. The use of compounds according to claim 1 to obtain drugs for treatment of disorders of lipid and carbohydrate metabolism.

3. The use according to claim 2 for receiving drugs to reduce blood sugar levels.



 

Same patents:

FIELD: medicine.

SUBSTANCE: there are described derivatives of 1,3,4-oxadiazol-2-one of formula I and their pharmaceutically acceptable salts wherein ARYL represents phenyl which can have one substitute chosen from halogen; W represents chain or (CH2)m where m designates an integer 1 to 4; Z represents -O(CH2)n-, -(CH2)n-Y-(CH2)n- where Y designates O, n independently means an integer 1 to 5; X represents O or S; R1 represents C1-6 alkyl; R2 represents substituted phenyl where substitutes are chosen from the group including C1-6alkyl, C1-4perfluoralkyl. There are also described pharmaceutical composition, and method of treating a disease in mammal wherein said disease can be modulated by PPAR-delta receptor binding activity.

EFFECT: compounds possess agonist or antagonist activity with respect to PPAR-delta receptor.

9 cl, 2 tbl, 34 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), their R and S isomers; or a mixture of R and S isomers; or pharmaceutically acceptable salts. Disclosed compounds can be used as a medicinal agent with agonist properties towards PPAR. In formula (I) and L represents (II) or (III); R1, R2, R3, Ya, R4a, R", Yb, R4b are hydrogen; R and R' are independently hydrogen, C1-C4alkoxy; n equals 0, 1 or 2; m equals 0, 1 or 2; X1 is a -Z-(CH2)P-Q-W group; X2 is -CH2-, -C(CH3)2-, -O- or -S-.

EFFECT: invention relates to a pharmaceutical composition, which contains the disclosed compound, to use of the pharmaceutical composition as a medicinal agent, to use of the disclosed compound in making the pharmaceutical composition.

13 cl, 35 ex

FIELD: chemistry.

SUBSTANCE: object of present invention is the following compounds: thiazol-2-ylamide 2-(3,4-dichlorophenoxy) hexanoic acid, 2-(4-fluorophenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-methoxyphenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-methoxyphenoxy)-K-pyridin-2-ylhexaneamide, 2-(3,4-dichlorophenoxy)-4-methyl-N,3-thiazol-2-ylpentaneamide, 2-(1,1'-biphenyl-4-yloxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-isopropylphenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(3-methoxyphenoxy)-N-1,3-thiazol-2-ylhexaneamide, and others, named in the formula of invention. Present invention also relates to a pharmaceutical composition, which contains the invented compound as an active ingredient and use of compounds in preparing a medicinal agent which increases activity of glucose. The invention also pertains to a compound of formula (I) where G is -C(O)-; L1 is a direct bond, A is >N-, X is a direct bond, R1 is cyclohexyl, R3 is cyclohexyl, substituted with R34, R4 is hydrogen; R5 is thiazol-5-yl, substituted with R48.

EFFECT: obtaining compounds which can be used for preparing a medicinal agent which can be used for treating diseases caused by glucokinase deficiency, for preparing a medicinal agent for treating diseases where increased activity of glucokinase is favourable.

6 cl, 143 ex

FIELD: chemistry.

SUBSTANCE: invention relates to inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), their enatiomers, racemates and pharmaceutically acceptable salts, as well as a pharmaceutical composition based on said inhibitors and method of treating, preventing or suppressing inflammation and other conditions which are mediated by activity of leukotriene A4-hydrolase. In general formula (II) , X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is O; Z is chosen from a group which consists of O and a bond; W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to the nitrogen atom which is bonded to the said W; R4 is chosen from a group which consists of H, OCH3 and Cl; R6 is H or F; and R2' and R3' are each independently chosen from a group which consists of: A) H, C1-7alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-7alkyl, where each of substitutes (A) is independently substituted with 0 or 1 RQ, where each of said RQ is a carbon atom substitute, which is at least one carbon atom, separate from nitrogen atom; B) HetRa substitute; C) -C1-7alkyl-C(O)Rx; H) -C0-4alkyl-Ar5, where Ar5 is a 5-member heteroaryl, which has one heteroatom, chosen from a group >NRY, and 0 or 1 additional heteroatom -N=, and optionally contains two carbonyl groups, and optionally benzo-condensed; I) -C0-4alkyl-Ar5' , where Ar5' is a 5-member heteroaryl, which contains 3 or 4 nitrogen atoms; M) SO2C1-4alkyl; alternatively, R2' and R3', taken together with a nitrogen atom with which they are bonded, form a heterocyclic ring which contains at least one heteroatom, which is the said bonded nitrogen atom, where the said heterocyclic ring is chosen from a group which consists of i) 4-7-member heterocyclic ring HetRb, where the said 4-7-member heterocyclic ring HetRb has one heteroatom, which is the said bonded nitrogen atom, and is substituted with 0, 1 or 2 identical or different substitutes, where the said substitutes are chosen from a group which consists of -RY, -CN, -C(O)RY, -C0-4alkyl-CO2RY, -C0-4alkyl-C(O)CO2RY, -C0-4alkyl-ORY, -C0-4alkyl-C(O)NRYRZ-, -C0-4alkyl-NRYC(O)RZ-, -C(O)NRZORY, -C0-4alkyl-NRYCO2RY, -C0-4alkyl-NRYC(O)NRYRY, -C0-4alkyl-NRYC(S)NRYRZ, -NRYC(O)CO2RY, -C0-4alkyl-NRWSO2RY, 1,3-dihydrobenzoimidazol-2-on-1-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol- 5-yl, -C0-4alkyl-C(O)N(RY)(SO2RY), -C0-4alkyl-N(RY)(SO2)NRYRY, -C0-4alkyl-N(RY)(SO2)NRYCO2RY, halogen, , ,; ii) 5-7-member heterocyclic ring HetRC which has one additional heteroatom separated from the said bonded nitrogen atom by at least one carbon atom, where the said additional heteroatom is chosen from a group which consists of O, S(=O)2 and >NRM, where the said 5-7-member heterocyclic ring HetRC has 0 or 1 carbonyl group and is substituted with 0, 1 or 2 substitutes at identical or different substituted carbon atoms, where the said substitutes are chosen from a group which consists of -C(O)RY and RZ; iii) one of 1H-tetrazol-1-yl, where 1H-tetrazol-1-yl is substituted at the carbon atom by 0 or 1 substitute such as -C0-4alkyl-RZ, -C0-4alkyl-CO2RY; and iv) one of benzimidazol-1-yl, 2,8-diazospiro[4.5]decan-1-on-8-yl, 4-{[(2-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 4-{[(2-aminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 9-yl-tert-butyl ether 3,9-diazaspiro[5.5]undecane-3-carboxylic acid, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl, and where substitute HetRa is a 6-member heterocyclic ring, with a carbon atom at the bonding site and contains a >NRM group as a heteroatom, where the said heteroatom is separated from the said carbon atom at the bonding site with at least 1 additional carbon atom; Rk is chosen from a group which consists of H and -C1-4alkyl; RL is chosen from a group which consists of -CO2RS; RS is hydrogen; RM is chosen from a group which consists of RZ, -C(O)RY; RN is chosen from a group which consists of OCH3, CI, F, Br, I, OH, NH2, CN, CF3, CH3 and NO2; RQ is chosen from a group which consists of -CN, -C0-4alkyl-ORY, -C0-4alkyl-CO2RY, -C0-4alkyl-NRYRY, -C0-4alkyl-NRYCORY, -C0-4alkyl-NRYCONRYRZ, -C0-4alkyl-NRYSO2RY; RW is chosen from a group which consists of RY; RX is chosen from a group which consists of -ORY, -NRYRZ, -C1-4alkyl and -C1-4alkyl-RAr; RY is chosen from a group which consists of H, C1-4alkyl, -C0-4alkyl-RAr and -C0-4alkyl-RAr', each of which is substituted with 1 or 2 RN substitutes; RZ is chosen from a group which consists of RY, -C1-2alkyl-CO2RY ; RAr is a radical with a carbon atom at the bonding position, where the said radical is chosen from a group which consists of phenyl, pyridyl and pyrazinyl, where each carbon atom with permissible valence in each of the said groups is independently substituted with at least 0, 1 or 2 RN or 0 or 1 RL; RAr' is a 5-6-member ring which has 1 or 2 heteroatoms, chosen from a group which consists of O, S, N and >NRY, and has 0 or 2 unsaturated bonds and 0 or 1 carbonyl group, where each member with permissible valence in each of the said rings is independently substituted with 0 or 1 or 2 RK; Description is given of inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), a composition which contains these inhibitions, and their use for inhibiting activity of the LTA4H enzyme, as well as for treating, preventing or suppressing inflammation and/or conditions which are associated with such inflammation. In the said formula (I): X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is chosen from a group which consists of CH2 and O, W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to a nitrogen atom; R4 is chosen from a group which consist of H, OCH3, CI, F, Br, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 and R3 are each independently chosen from different groups.

EFFECT: new compounds have useful biological activity.

43 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds with formula I: , in which: R1 is R6C(O)-, HC(O)-, R6SO2-, R6OC(O)-, (R6)2NC(O)-, R6-, (R6)2NC(O)C(O)-; R2 is a hydrogen atom, -CF3 or R8; R3 is a hydrogen atom or (C1-C4)aliphatic group-; R4 is -COOH; R5 is -CH2F or -CH2O-2,3,5,6- tetrafluorophenyl; R6 is (C1-C12)aliphatic or (C3-C10)cycloaliphatic group, (C6-C10)aryl-, (C3-C10)heterocyclyl-; and where R6 is substituted with up to 6 substitutes, independently chosen from R; R is a halogen atom, OR7 and -R7; R7 is (C1-C6)aliphatic group-, (C3-C10)cycloaliphatic group; R8 is (C1-C12)aliphatic- or (C3-C10)cycloaliphatic group; to a pharmaceutical composition with caspase-inhibiting activity, based on compound with formula I, to methods of treatment as well as to methods of inhibiting caspase-mediated functions and to a method of reducing production of IGIF or IFN-β. The invention also relates to a method of preserving cells, as well as to a method of producing compound with formula I.

EFFECT: new compounds are obtained and described, which can be used for treating diseases in the development of which caspase activity takes part.

34 cl, 4 tbl, 43 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns indazol derivatives of general formulae (I) or (II) , where radicals and groups are defined as shown in cl. 1 of invention claim, and their pharmaceutically acceptable salts. Also invention claims medicine, method of medicine obtainment and application of claimed compounds in treatment and/or prevention of fatty acid metabolism derangement and glucose assimilation disorders.

EFFECT: inhibition of hormone-sensitive lipases.

13 cl, 1 tbl, 103 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention can be used for treating or preventing diseases and conditions, mediated by peroxisome proliferator activated gamma receptor (PPARγ). In formula (I) W represents a COOH group or -COOC-C1-C4alkyl; Y represents NH; Z represents S or O; X represents O; R1-R6 each independently represents a hydrogen atom or substitute, chosen from a group consisting of: C1-C4-alkyl, thienyl or phenyl, where phenyl is optionally substituted with one or more substitutes, independently chosen from a group consisting of C1-C4-alkyl, C1-C4-alkoxy, a halogen atom; -NO2 and -CN; A represents C1-C4-alkyl, -N(C1-C4-alkyl)-CO-C3-C7-cycloalkyl, aryl, chosen from a group consisting of phenyl, naphthyl, or heteroaryl, chosen from a group consisting of oxazolyl, isoxazolyl, thienyl, pyridyl, thiazolyl, thiadiazolyl, benzo[b]thienyl, imidazolyl, indolyl and carbazolyl, where aryl and heteroaryl are substituted or not substituted with one or more substitutes, independently chosen from a group consisting of C1-C4-alkyl, C1-C4-alkoxy, phenyl and a halogen atom; and n is an integer from 0 to 4. The invention also relates to a pharmaceutical composition, containing the invented compound as an active component, use of the compounds to make a medicinal agent, and method of treatment.

EFFECT: obtaining new biologically active compounds.

22 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invented compounds have inhibitory activity towards protein kinase. In formula 1a m lies between 0 and 1, R1 is chosen from a group which includes hydrogen, methyl, isopropyl, imidazolylpropyl, piperazinylpropyl, pyridinyl, diethylaminopropyl, hydroxyethyl, pyrimidinyl, morpholinopropyl, phenyl, cyclopropyl, morpholinoethyl, benzyl and morpholino, where any of pyridinyl, imidazolyl, piperazinyl or pyrimidinyl in R1 are optionally substituted with 1-3 radicals, independently chosen from a group, which includes methyl, methylamine, dimethylaminomethyl, cycloproylamine, hydroxyethylamine, diethylaminopropylamine, pyrrolydinylmethyl, morpholino, morpholinomethyl, piperazinylmethyl and piperazinyl, where any of morpholino and piperazinyl in R1 are optionally further substituted with a radical, chosen from a group which includes methyl, hydroxyethyl and ethyl, R2, R3 and R5 each represents hydrogen, R4 represents methyl, L is chosen from a group which includes -NR5C(O)- and -C(O)NR5-, R10 represents trifluoromethyl, and R11 is chosen from a group which includes halogen, morpholinomethyl, piperazinyl, optionally substituted with a methyl, ethyl or hydroxyethyl group; piperazinylmethyl, optionally substituted with a methyl or ethyl group, imidazolyl, optionally substituted with methyl, pyrrolidinylmethoxy and piperidinyl, optionally substituted with a hydroxy group.

EFFECT: more effective treatment.

4 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: in formula (1) compound, cysteinprotease is cathepsin K, cathepsin S, cathepsin L or cathepsin B. In formula (I) R is , AA1 is a bond, AA2 is a bond, R7 and R8 each independently represents hydrogen, C1-8 alkyl, CycA or C1-8 alkyl, substituted CycA, R9 is hydrogen, values of the rest of the radicals are given in the formula of invention. The invention also relates to a pharmaceutical composition, containing a formula (I) compound as an active ingredient, to a cysteinprotease inhibitor, method of inhibiting cysteinprotease, use of formula (I) compound in obtaining cysteinprotease inhibitor.

EFFECT: compound has inhibitory activity towards cysteinprotease.

10 cl, 16 tbl, 8 dwg, 224 ex

FIELD: chemistry.

SUBSTANCE: described are derivatives of 1,3,4-oxadiazol-2-on of formula (I) , where ARYL represents phenyl; Z represents -O(CH2)n- and n represents independent integer number from 1 to 5; X represents S; R1 represents C1-6alkyl; R2 represents phenyl, substituted with C1-6perfluoralkyl; or its pharmaceutically acceptable salt; based on it pharmaceutical composition; and method of disease treatment, where disease can be modulated by activity of PPAR-delta binding.

EFFECT: obtaining compounds which possess agonistic or antagonistic activity.

7 cl, 5 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to method of introduction of at least one active medicinal substance to patient, dependent on said active medicinal substance or active substances, method includes stages at which a) at least one, transdermal therapeutic system (TTS), which contains first active medicinal substance, for transdermal introduction of said active substance during given time period is applied and b) at the beginning or during transdermal introduction applied is at least one pastille, which contains the same active substance or second active substance, or additional active substances with the same indications for application as first active substance.

EFFECT: method of combined treatment and applied for it combinations of medications are described.

23 cl, 1 ex

FIELD: medicine.

SUBSTANCE: invention proposes compositions, which contain stabilised exendin-4(1-39) and allied compounds. Invention describes stabilised agonists of exendin-4, which contain at least one modified amino-acid remainder, in particular in position Asn28 of exendin-4(1-39) molecule.

EFFECT: increased efficiency of application in treatment of diseases.

15 cl, 9 dwg, 2 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of formula (I): , in which: Ra and Ra', identical or different, mean atom of hydrogen or alkyl, R1 means atom of hydrogen or alkyl, cycloalkyl, heterocycloalkyl or aryl, R2 means group of formula -(CH2)x-(CO)y-Y or -(CO)y-(CH2)x-Y, in which, x = 0, 1, 2, 3 or 4, y = 0 or 1, Y means atom of hydrogen or the following group: hydroxyl, alkyl, cycloalkyl, alkyloxyl, aryl, heteroaryl or -NR11R12, besides, Y is not an atom of hydrogen, when x=y=0, R11 and R12, identical or different, mean atom of hydrogen or the following group: alkyl, cycloalkyl, alkyloxyl or -NR13R14, or R11 and R12 together with atom of nitrogen, to which they are connected, create mono- or bicyclic structure, which contains 4-10 links and unnecessarily contain additionally 1-3 heteroatoms and/or 1-3 ethylene unsaturated links, besides this cycle is not necessarily substituted in any of positions with 1-3 groups, selected from atoms of halogen and hydroxyl, alkyl, cycloalkyl and alkyloxygroups; R13 and R14, identical or different, mean atom of hydrogen or alkyl, R3 means 1-3 groups, identical or different, available in any position of cyclic structure, to which they are connected, and selected from atoms of halogen; R5 means atom of hydrogen, R4 is selected from groups of formulae (a), (b), (c), which are not necessarily substituted with aryl group, described below: (a), (b), (c), in which p=0,1,2 or 3; m=0,1 or 2, and either a) X means link -N(R10)-, in which R10 is selected from: -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, - or R10 with atom of nitrogen, with which it is connected, and with atom of carbon, available in any position of cyclic structure of formula (a), but not with neighboring to mentioned atom of nitrogen, creates bridge, containing 3-5 links, or, b) X means link -C(R6)(R7)-, where R6 is selected from the following: atom of hydrogen, atom of halogen, group -(CH2)x-OR8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9 or -(CH2)x-NR8-COR9, in which x=0,1,2,3 or 4, alkyl, cycloalkyl, heterocycloalkyl, aryl, heterocycloalkyl, condensed with aryl, besides, alkyl, cycloalkyl or aryl groups are not necessarily substituted with 1 or several groups, selected from groups: R, R', -OR, -NRR', -COR; R7 is selected from atoms of hydrogen and halogen and the following groups: alkyls, -OR, -NRR', -NR-CO-R', -NR-COOR', -R8 and R9 are selected, independently from each other, from atom of hydrogen and the following groups: alkyls, cycloalkyls, aryls, -CO-alkyls, besides, alkyls and aryls are unnecessarily substituted with one or several groups, selected from groups: R, R', -OR, or R8 and R9 together create heterocycloalkyl,- R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, besides, mentioned hetero aryl groups represent aromatic groups, including from 5 to 10 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen and/or sulfur; besides mentioned heterocycloalkyl groups represent cycloalkyl groups, including from 5 to 6 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen or sulfur; in the form of base or acid-additive salt, and also in the form of hydrate or solvate. Invention is also related to medicinal agent, to pharmaceutical composition, to application, to method of production, and also to compounds of formulas (VI), (XVIII), (XIX).

EFFECT: new biologically active compounds have activity of agonists of melanocortin receptors.

27 cl, 16 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new compounds that comply with formula (I) , where: n is equal to 1, Ra, Ra', Rb, Rb', identical or different, mean atom of hydrogen or alkyl or cycloalkyl group, besides, Rb and Rb' may create carbon bridge having 4 links together with hydrogen atoms of cycle, to which they are connected, R1 means cyclohexyl group, R2 means 1,2,4-triazolyl group, R3 means 1-3 groups, selected from atoms of halogen, available in any position of cycle, to which they are connected, R5 means atom of hydrogen, R4 is selected from groups of formulas (a), (b) and (c), given below, mono- or polysubstituted with aryl group: (a), (b), (c), in which: p=0, 1, 2 or 3, m=0, 1 or 2, and either a) X means link -N(R10)-, where R10 is selected from: groups -CO-NR8R9, -COOR8, -(CH2)x-OR8, -(CH2)x-COOR8, -(CH2)x-COR8, in which x=1, 2, 3 or 4, heterocycloalkyl group, condensed with aryl group, cycloalkyl, aryl, heteroaryl, alkylaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, -CO-alkylaryl, -SO2-alkyl, -SO2-cycloalkyl, -SO2-aryl, besides, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are unnecessarly substituted with one or several groups selected from atoms of halogen and groups R, R', OR, NRR', -CN, -COOR, COR; or R10 together with atom of nitrogen, to which it is connected, and with atom of carbon, available in any position of cyclic structure of formula (a), but not in neighboring position to mentioned atom of nitrogen, creates a bridge that contains 3-5 links, R8 and R9 are selected, independently from each other, from atom of hydrogen and alkyl or cycloalkyl groups; R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, aryl groups; or b) X means link - C(R6)(R7)-, where R6 is selected from the following: atom of hydrogen, atom of halogen, groups -(CH2)x-OR8, -(CH2)x-COOR8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9 or -(CH2)x-NR8-COR9, in which x=0, 1, 2, 3 or 4, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl group, heterocycloalkyl group, condensed or non-condensed, available in spiro-position to cycle of formula (a), to which it is connected, heterocycloalkyl group, condensed with aryl group, besides, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are unnecessarily substituted with one or several groups selected from atoms of halogen and groups R, R', OR, NRR', -CO-NRR', -CN, -COOR, OCOR, COR, NRCOOR'; and heterocycloalkyl groups are unnecessarily condensed with aryl group; R7 is selected from atoms of hydrogen and halogen and alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl groups, -OR, -O-aryl, -O-alkylaryl, -O-alkylheteroaryl, groups -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NR-COOR', -NO2, -CN and -COOR, R8 and R9 are selected, independently from each other, from atom of hydrogen and alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl groups, -CO-alkyl, -CO-cycloalkyl, -CO-aryl, -(CH2)x-OR, where x=0, 1, 2, 3 or 4, besides, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are unnecessarily substituted with one or several groups selected from atoms of halogen and groups R, R', OR, NRR', -CO-NRR', -CN, -COOR, OCOR, COR, NRCOOR'; or R8 and R9 create together cycloalkyl or heterocycloalkyl; R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, heterocycloalkyl, aryl, or may together create cycloalkyl or heterocycloalkyl; besides heteroaryl group represents aromatic group that contains from 5 to 10 atoms and from 1 to 4 heteroatoms, selected from nitrogen, oxygen or sulfur; heterocycloalkyl group represents cycloalkyl group, which contains from 5 to 10 atoms and contains from 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur; in the form of base or acid-additive salt, and also in the form of hydrate or solvate. Invention is also related to medicinal agent, to pharmaceutical composition, to application, to method of production, and also to compounds of formulas (IV) , (V), (VI), (XXVIII), (XXIX), (II).

EFFECT: production of new biologically active compounds, having activity of agonists of melanocortin receptors.

36 cl, 22 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: there are described derivatives of 1,3,4-oxadiazol-2-one of formula I and their pharmaceutically acceptable salts wherein ARYL represents phenyl which can have one substitute chosen from halogen; W represents chain or (CH2)m where m designates an integer 1 to 4; Z represents -O(CH2)n-, -(CH2)n-Y-(CH2)n- where Y designates O, n independently means an integer 1 to 5; X represents O or S; R1 represents C1-6 alkyl; R2 represents substituted phenyl where substitutes are chosen from the group including C1-6alkyl, C1-4perfluoralkyl. There are also described pharmaceutical composition, and method of treating a disease in mammal wherein said disease can be modulated by PPAR-delta receptor binding activity.

EFFECT: compounds possess agonist or antagonist activity with respect to PPAR-delta receptor.

9 cl, 2 tbl, 34 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula: I where R1 represents hydrogen or C1-7-alkyl; R2 and R3 independently represent hydrogen; R4 and R5 independently represent hydrogen; R6, R7, R8 and R9 independently represent hydrogen, C1-7-alkyl; and one of R6, R7 and R8 represents where R10 represents hydrogen, C1-7-alkyl; R11 represents hydrogen, C1-7-alkyl; one of R12 or R13 represents hydrogen, C1-7-alkyl or fluorine-C1-7-alkyl; and the other represents undivided electron pair; R14 represents hydrogen, C1-7-alkyl, halogen; R15 represents aryl or aryl substituted with 1-3 groups chosen from C1-7-alkyl C1-7-alkoxy, halogen, fluorine-C1-7-alkyl and fluorine-C1-7-alkoxy; and n has a value 1, 2 or 3; and to all their enantiomers and to pharmaceutically acceptable salts and/or esters. The invention also concerns the pharmaceutical compositions.

EFFECT: production of new biologically active compounds with agonist activity with respect to PPARδ and PPARα.

20 cl, 25 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: compounds can be used for treatment and prevention of diseases associated with activity of specified enzyme, such as diabetes, obesity, diseases associated with food intake, dyslipidemia and hypertension. In general formula (I) , R1 represents methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, methoxymethyl, cyclopropyl methoxymethyl, 2-methyl thiazolyl, morpholinyl methyl or phenyl; R2 represents hydrogen, C1-4alkyl or phenyl; R3 represents hydrogen, C1-4alkyl or phenyl; R4 represents phenyl, naphthyl, thiophenyl, quinolyl or piperidyl where phenyl, naphthyl, thiophenyl, quinolyl and piperidyl are optionally substituted with one to three substitutes independently chosen of C1-4alkyl, halogen, C1-4alkoxy, cyano, trifluoromethyl, phenyl, phenyls C1-4alkyl, phenyloxy, oxasolyl and pyridinyl; R5 represents hydrogen, C1-4alkyl, phenyl-C1-4alkyl, C3-6dicloalkyl-C1-4alkyl or aminocarbonylC1-4alkyl.

EFFECT: higher clinical effectiveness.

17 cl, 2 dwg, 72 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), their R and S isomers; or a mixture of R and S isomers; or pharmaceutically acceptable salts. Disclosed compounds can be used as a medicinal agent with agonist properties towards PPAR. In formula (I) and L represents (II) or (III); R1, R2, R3, Ya, R4a, R", Yb, R4b are hydrogen; R and R' are independently hydrogen, C1-C4alkoxy; n equals 0, 1 or 2; m equals 0, 1 or 2; X1 is a -Z-(CH2)P-Q-W group; X2 is -CH2-, -C(CH3)2-, -O- or -S-.

EFFECT: invention relates to a pharmaceutical composition, which contains the disclosed compound, to use of the pharmaceutical composition as a medicinal agent, to use of the disclosed compound in making the pharmaceutical composition.

13 cl, 35 ex

FIELD: chemistry.

SUBSTANCE: object of present invention is the following compounds: thiazol-2-ylamide 2-(3,4-dichlorophenoxy) hexanoic acid, 2-(4-fluorophenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-methoxyphenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-methoxyphenoxy)-K-pyridin-2-ylhexaneamide, 2-(3,4-dichlorophenoxy)-4-methyl-N,3-thiazol-2-ylpentaneamide, 2-(1,1'-biphenyl-4-yloxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-isopropylphenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(3-methoxyphenoxy)-N-1,3-thiazol-2-ylhexaneamide, and others, named in the formula of invention. Present invention also relates to a pharmaceutical composition, which contains the invented compound as an active ingredient and use of compounds in preparing a medicinal agent which increases activity of glucose. The invention also pertains to a compound of formula (I) where G is -C(O)-; L1 is a direct bond, A is >N-, X is a direct bond, R1 is cyclohexyl, R3 is cyclohexyl, substituted with R34, R4 is hydrogen; R5 is thiazol-5-yl, substituted with R48.

EFFECT: obtaining compounds which can be used for preparing a medicinal agent which can be used for treating diseases caused by glucokinase deficiency, for preparing a medicinal agent for treating diseases where increased activity of glucokinase is favourable.

6 cl, 143 ex

FIELD: chemistry.

SUBSTANCE: in compounds of formula (I) , Q is: (IIa) or (IIb) , R1 is chosen from a group which consists of carboxylic aryl and carboxylic aryl which is substituted with substitute(s) independently chosen from a group which consists of halogen, cyano, nitro, C1-10alkyl, C1-10alkyl which is substituted with substitute(s) independently chosen from a group which consists of halogen, C1-9alkoxy, C1-9alkoxy which is substituted with substitute(s) independently chosen from a group which consists of halogen, mono-C1-5alkylamino, and heterocyclyl or heterocyclyl which is substituted with substitute(s) independently chosen from a group which consists of halogen, C1-5alkyl; R2 is C1-5alkyl, C1-5alkyl which is substituted with halogen, C1-5alkyl which is substituted with carboxylic aryl, C1-5alkoxy, -N(R2a)(R2b); where R2a and R2b are each independently hydrogen, C1-5alkyl or C1-5alkyl, substituted with substitute(s) independently chosen from a group which consists of hydroxyl, carboxylic aryl; L represents formula (IIIa); , where R3 and R4 are each hydrogen; A is a single bond, and B is a single bond or -CH2-; Z1, Z3, and Z4 are each independently hydrogen, halogen, C1-5alkyl, C1-5alkyl, substituted with carboxylic aryl, C1-5alkoxy, mono-C1-5alkylamino, di-C1-5alkylamino, carboxylic aryl, heterocyclyl or substituted heterocyclyl; Z2 is hydrogen, C1-5alkyl, C1-5alkyl which is substituted with carboxylic aryl, C1-5alkoxy, mono-C1-5alkylamino, di-C1-5alkylamino, carboxylic aryl, heterocyclyl or substituted heterocyclyl; Y is -C(O)NH-, -C(O)-, -C(S)NH-, -C(O)O- or -CH2-; where carboxylic aryl is phenyl; heterocyclyl is 1H-indolyl, 9H- xanthenyl, benzo[1,3]dioxolyl, furyl, imidazolyl, isoxazolyl, morpholinyl, piperazinyl, pyridyl, pyrrolidyl; halogen is fluorine, chlorine, bromine or iodine. The invention also relates to a pharmaceutical composition.

EFFECT: compounds can be used for treating central nervous system diseases, and for improving memory functioning, sleep, awakening, diabetes.

16 cl, 8 dwg, 4 tbl, 525 ex

FIELD: chemistry.

SUBSTANCE: invention relates to inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), their enatiomers, racemates and pharmaceutically acceptable salts, as well as a pharmaceutical composition based on said inhibitors and method of treating, preventing or suppressing inflammation and other conditions which are mediated by activity of leukotriene A4-hydrolase. In general formula (II) , X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is O; Z is chosen from a group which consists of O and a bond; W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to the nitrogen atom which is bonded to the said W; R4 is chosen from a group which consists of H, OCH3 and Cl; R6 is H or F; and R2' and R3' are each independently chosen from a group which consists of: A) H, C1-7alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-7alkyl, where each of substitutes (A) is independently substituted with 0 or 1 RQ, where each of said RQ is a carbon atom substitute, which is at least one carbon atom, separate from nitrogen atom; B) HetRa substitute; C) -C1-7alkyl-C(O)Rx; H) -C0-4alkyl-Ar5, where Ar5 is a 5-member heteroaryl, which has one heteroatom, chosen from a group >NRY, and 0 or 1 additional heteroatom -N=, and optionally contains two carbonyl groups, and optionally benzo-condensed; I) -C0-4alkyl-Ar5' , where Ar5' is a 5-member heteroaryl, which contains 3 or 4 nitrogen atoms; M) SO2C1-4alkyl; alternatively, R2' and R3', taken together with a nitrogen atom with which they are bonded, form a heterocyclic ring which contains at least one heteroatom, which is the said bonded nitrogen atom, where the said heterocyclic ring is chosen from a group which consists of i) 4-7-member heterocyclic ring HetRb, where the said 4-7-member heterocyclic ring HetRb has one heteroatom, which is the said bonded nitrogen atom, and is substituted with 0, 1 or 2 identical or different substitutes, where the said substitutes are chosen from a group which consists of -RY, -CN, -C(O)RY, -C0-4alkyl-CO2RY, -C0-4alkyl-C(O)CO2RY, -C0-4alkyl-ORY, -C0-4alkyl-C(O)NRYRZ-, -C0-4alkyl-NRYC(O)RZ-, -C(O)NRZORY, -C0-4alkyl-NRYCO2RY, -C0-4alkyl-NRYC(O)NRYRY, -C0-4alkyl-NRYC(S)NRYRZ, -NRYC(O)CO2RY, -C0-4alkyl-NRWSO2RY, 1,3-dihydrobenzoimidazol-2-on-1-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol- 5-yl, -C0-4alkyl-C(O)N(RY)(SO2RY), -C0-4alkyl-N(RY)(SO2)NRYRY, -C0-4alkyl-N(RY)(SO2)NRYCO2RY, halogen, , ,; ii) 5-7-member heterocyclic ring HetRC which has one additional heteroatom separated from the said bonded nitrogen atom by at least one carbon atom, where the said additional heteroatom is chosen from a group which consists of O, S(=O)2 and >NRM, where the said 5-7-member heterocyclic ring HetRC has 0 or 1 carbonyl group and is substituted with 0, 1 or 2 substitutes at identical or different substituted carbon atoms, where the said substitutes are chosen from a group which consists of -C(O)RY and RZ; iii) one of 1H-tetrazol-1-yl, where 1H-tetrazol-1-yl is substituted at the carbon atom by 0 or 1 substitute such as -C0-4alkyl-RZ, -C0-4alkyl-CO2RY; and iv) one of benzimidazol-1-yl, 2,8-diazospiro[4.5]decan-1-on-8-yl, 4-{[(2-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 4-{[(2-aminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 9-yl-tert-butyl ether 3,9-diazaspiro[5.5]undecane-3-carboxylic acid, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl, and where substitute HetRa is a 6-member heterocyclic ring, with a carbon atom at the bonding site and contains a >NRM group as a heteroatom, where the said heteroatom is separated from the said carbon atom at the bonding site with at least 1 additional carbon atom; Rk is chosen from a group which consists of H and -C1-4alkyl; RL is chosen from a group which consists of -CO2RS; RS is hydrogen; RM is chosen from a group which consists of RZ, -C(O)RY; RN is chosen from a group which consists of OCH3, CI, F, Br, I, OH, NH2, CN, CF3, CH3 and NO2; RQ is chosen from a group which consists of -CN, -C0-4alkyl-ORY, -C0-4alkyl-CO2RY, -C0-4alkyl-NRYRY, -C0-4alkyl-NRYCORY, -C0-4alkyl-NRYCONRYRZ, -C0-4alkyl-NRYSO2RY; RW is chosen from a group which consists of RY; RX is chosen from a group which consists of -ORY, -NRYRZ, -C1-4alkyl and -C1-4alkyl-RAr; RY is chosen from a group which consists of H, C1-4alkyl, -C0-4alkyl-RAr and -C0-4alkyl-RAr', each of which is substituted with 1 or 2 RN substitutes; RZ is chosen from a group which consists of RY, -C1-2alkyl-CO2RY ; RAr is a radical with a carbon atom at the bonding position, where the said radical is chosen from a group which consists of phenyl, pyridyl and pyrazinyl, where each carbon atom with permissible valence in each of the said groups is independently substituted with at least 0, 1 or 2 RN or 0 or 1 RL; RAr' is a 5-6-member ring which has 1 or 2 heteroatoms, chosen from a group which consists of O, S, N and >NRY, and has 0 or 2 unsaturated bonds and 0 or 1 carbonyl group, where each member with permissible valence in each of the said rings is independently substituted with 0 or 1 or 2 RK; Description is given of inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), a composition which contains these inhibitions, and their use for inhibiting activity of the LTA4H enzyme, as well as for treating, preventing or suppressing inflammation and/or conditions which are associated with such inflammation. In the said formula (I): X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is chosen from a group which consists of CH2 and O, W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to a nitrogen atom; R4 is chosen from a group which consist of H, OCH3, CI, F, Br, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 and R3 are each independently chosen from different groups.

EFFECT: new compounds have useful biological activity.

43 cl, 8 tbl, 12 dwg, 484 ex

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