Substituted thiazolbenzoisothiazol dioxide derivatives, method of production and application

FIELD: chemistry; pharmacology.

SUBSTANCE: compounds of formula (I) as inhibitors of phosphotyrosine phosphotase 1B and their pharmaceutically acceptable salts, their application, based pharmaceutical composition and method of production. In general formula (I) , R1 indicates phenyl, naphthyl, thionaphthyl, pyridyl. Phenyl, naphthyl, thionaphthyl and pyridyl can be single- or multiple-substituted with F, Cl, Br, (CH2)0-2OH, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkinyl, CF3, OCF3, N(R9)(R10), piperidinone, piperazine, piperazinone, N-(C1-C6-alkylene)-piperazine, N-(C1-C6-alkylene)-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)-alkyleny-COO(C1-C6)-alkyl, (C3-C10)-cycloalkyl, phenyl. These piperidinone, piperazine, piperazinone, N-(C1-C6-alkylene)-piperazine, N-(C1-C6-alkylene)-piperazinone, morpholine, thiomorpholine, and phenyl rings can be single- or multiple-substituted with F, Cl, Br, (CH2)0-2OH, 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, OCF3, N(R9)(R10); R2 indicates H, (C1-C6)-alkyl, COOH, (C1-C6)-alkylene-COOH, COO(C1-C6)-alkyl, (C1-C6)-alkylene-COO(C1-C6)-alkyl; R3 indicates H, (C1-C6)-alkyl, (C1-C6)-alkylenphenyl, -C(O)-phenyl, (C1-C6)-alkylenheterocycle, where heterocycle represents 5-6-merous heterocyclic ring containing 1-2 heteroatoms, chosen of nitrogen and oxygen, CO-(C1-C6)alkyl; R4, R5 indicate H; R6 indicates H, R9 indicates H, (C1-C4)-alkyl; R10 indicates H, (C1-C4)-alkyl.

EFFECT: applications for treating diseases mediated with phosphotyrosine phosphotase 1B activity, such as diabetes type II, lipidosis and carbohydrate metabolic imbalance, insulin resistivity, reduced sugar content in blood.

9 cl, 2 tbl, 1 ex

 

This invention relates to substituted derivatives dioxide thiazoleethanol, and their physiologically tolerated salts and physiologically functional derivatives.

In the prior art already described structurally similar derivatives dioxide benzisothiazole, as well as their use for the treatment of diabetes (WO 02/11722).

The objective of this invention to provide compounds, which can prevent and treat diabetes. For this connection should be therapeutically useful effect of lowering the blood sugar level. In particular, these compounds must be detected, in comparison with the compounds of WO 02/11722, performance is improved or improved ADME profile (absorption, distribution, metabolism and excretion).

Thus, this invention relates to compounds of formula I,

where R1, R2 represent independently 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-alkylaryl, heterocycle, (C1-C6-alkalimetric, CF3, OCF3CN, (CH2)1-6-OH, O-(C1-C6)-alkyl, CO-(C1-C6)-alkyl, -C(O)O-alkyl, COOH, CON(R9)(R10), and the remains of the aryl, the AK, as heterocyclic residues, can be single - or multi-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, and these piperidine, piperazine, piperazine, N-(C1-C6-alkylen)-piperazine, N-(C1-C6-alkylen)-piperazine, morpholine, thiomorpholine and the phenyl ring may be single - or multi-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 denotes H, (C1-C6)-alkyl, (C1-C6-alkylaryl, -C(O)-aryl, (C1-C6-alkalimetric,-(C1-C6)alkyl, and aryl, heterocy the symbolic residues can be substituted once or several times F, Cl, Br, (C1-C6)-alkyl, COOH, COO(C1-6)-alkyl, CF3or OCF3;

R4, R5 denote independently from each other 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-alkylene-CON(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), CH2HE, CH2Och3;

R6, R7 represent, independently from each other H, F, Cl, Br, (C1-C6)-alkyl, cyclopropyl, tetraferriphlogopite, diversicolor; or

R6 and R7 together form the group =CH2;

R8 denotes H, CH3, CF3CH2IT;

R9 denotes H, (C1-C4)-alkyl;

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

R9 and R10 form together with the N atom to which they are attached, 3-9-membered cyclic system;

and their physiologically tolerated salts.

Preferred are the compounds of formula I in which one or more residues have the following meaning:

R1 denotes aryl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C1-C6-alkylaryl, heterocycle, (C1-C6-alkalimetric, CF3, OCF3CN, (CH2)1-6/sub> OH, O-(C1-C6)-alkyl, CO-(C1-C6)-alkyl, C(O)O-alkyl, COOH, CON(R9)(R10), and aryl residues and heterocyclic residues may be single - or multi-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, (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 the phenyl ring may be single - or multi-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, aryl, COOH, (C1-C6-alkylene-COOH, -COO(C1/sub> -C6)-alkyl, (C1-C6-alkylen-soo(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C1-C6-alkylaryl, heterocycle, (C1-C6-alkalimetric, CF3, OCF3CN, -(CH2)1-6-HE,-(C1-C6)-alkyl, CO-(C1-C6)-alkyl, C(O)O-alkyl, COOH, CON(R9)(R10), and aryl residues and heterocyclic residues may be single - or multi-substituted by F, Cl, Br, (CH2)0-2IT, (C1-C6)-alkyl, (C2-C6-alkenyl, (C2-C6-quinil, CF3OCF3N(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 denotes H, (C1-C6)-alkyl, (C1-C6-alkylaryl, -C(O)-aryl, (C1-C6-alkalimetric,-(C1-C6)alkyl;

R4, R5 denote independently from each other H, F, Cl, Br, (C1-C6)alkyl, CF3, OCF3, NO2N(9)(R10), CN, O-(C1-C6)-alkyl, CO-(C1-C6)-alkyl, COOH, (C1-C6-alkylene-COOH, -CON(R9)(R10), (C1-C6-alkylene-CON(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), CH2HE, CH2Och3;

R6, R7 represent, independently from each other H, F, Cl, Br, (C1-C6)-alkyl, cyclopropyl, tetraferriphlogopite, diversicolor; or

R6 and R7 together denote the group =CH2;

R8 denotes H, CH3, CF3CH2IT;

R9 denotes H, (C1-C4)-alkyl;

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

R9 and R10 form together with the N atom to which they are attached, 3-9-membered cyclic system;

and their physiologically tolerated salts.

Especially preferred are the compounds of formula I where one or more residues have the following meaning:

R1 denotes phenyl, naphthyl, Tinetti, pyridyl, and phenyl, naphthyl, Tinetti and pyridyl can be single - or multi-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-C6the alkyl is)-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, and these piperidine, piperazine, piperazine, N-(C1-C6-alkylen)-piperazine, N-(C1-C6-alkylen)-piperazine, morpholine, thiomorpholine and the phenyl ring may be single - or multi-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 denotes H, (C1-C6)-alkyl, COOH, (C1-C6-alkylene-COOH, -COO(C1-C6)-alkyl, (C1-C6-alkylen-soo(C1-C6)-alkyl;

R3 denotes H, (C1-C6)-alkyl, (C1-C6-alkylaryl, -C(O)-aryl, (C1-C6-alkalimetric,-(C1-C6)-alkyl;

R4, R5 denote H;

R6, R7 denotes H;

R8 denotes H;

R9 denotes H, (C1-C4)-alkyl;

R10 denotes H, (C1-C4)-alkyl;

and their pharmaceutically acceptable salts.

Especially preferred are the compounds of formula I where one or more residues have the following values:

R1 represents phenyl, whereby phenyl may be once or several times 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, and these piperidine, piperazine, piperazine, N-(C1-C6-alkylen)-piperazine, N-(C1-C6-alkylen)-piperazine, morpholine, thiomorpholine and the phenyl ring may be single - or multi-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 denotes H, (C1-C6)-alkyl, -C(O)O-(C1 -C6)-alkyl, -(C1-C6-alkylene-(C(O)O-(C1-C6)-alkyl, -COOH, -(C1-C6-alkylene-COOH;

R3 denotes H, (C1-C6)-alkyl, (C1-C6-alkylaryl, -C(O)-aryl, (C1-C6-alkalimetric,-(C1-C6)-alkyl;

R4, R5 denote H;

R6, R7 denotes H;

R8 denotes H;

R9 denotes H;

R10 denotes H;

and their physiologically acceptable salts.

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

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

Pharmaceutically acceptable salts on the basis of their higher water solubility compared to the original or basic compounds are particularly suitable for medical applications. These salts must be pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid additive salts of the compounds of this invention are salts of inorganic acids such as hydrochloric acid, Hydrobromic acid, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic KIS is on, such as, for example, acetic acid, benzolsulfonat, benzoic, citric, econsultancy, fumaric, gluconic, glycolic, setinova, lactic, lactobionic, maleic, malic, methansulfonate, succinic, p-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), salts of trometamol (2-amino-2-hydroxymethyl-1,3-propane diol), diethanolamine, lysine or Ethylenediamine.

Salts with a pharmaceutically unacceptable anion, such as, for example, triptorelin, are also included in the scope of this invention as useful intermediates for obtaining or purification of pharmaceutically acceptable salts and/or for use in non-therapeutic applications, for example, applications in vitro.

Used herein, the term "physiologically functional derivative" refers to any physiologically acceptable derivative compounds of formula I of this invention, 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 include p is Lekarstva compounds of the present invention, such as, for example, described in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolised in vivo to the compound of the present invention. These prodrugs may themselves be or may not be effective.

Compounds in accordance with this invention can exist in different polymorphic forms, for example, in the form of amorphous or crystalline polymorphic forms. All polymorphous forms of the compounds of the present invention is included in the scope of this invention and are as aspect of the present invention.

Further, all references to "compound (compound in accordance with formula I"refers to the compound (compounds) of formula I, described above, and their salts, solvate and physiologically functional derivatives.

The alkyl residue denotes unbranched or branched hydrocarbon chain with one or more carbon atoms, such as, for example, methyl, ethyl, isopropyl, tert-butyl, hexyl.

The alkyl residue may be single - or multi-substituted with suitable groups such as, for example:

F, Cl, Br, I, CF3, NO2N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, 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)-heterocycle;

RHO3H2, SO3H, SO2-NH2, SO2NH((C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2S-(C1-C6)-alkyl, S-(CH2)n-aryl, S-(CH2)n-heterocycle, SO-(C1-C6)-alkyl, SO-(CH2)n-aryl, SO-(CH2)n-heterocycle, SO2-(C1-C6)-alkyl, SO2-(CH2)n-aryl, SO2-(CH2)n-heterocycle, SO2-NH(CH2)n-aryl, SO2-NH(CH2)n-heterocycle, SO2-N(C1-C6)alkyl)(CH2)n-aryl, SO2-N(C1-C6)alkyl)(CH2)n-heterocycle, SO2-N((CH2)n-aryl)2, SO2-N((CH2)n-(heterocycle)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, OCF3, O-(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, NH-COO-(C1-C6)-alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle, NH-CO-NH-(C1-C6)-alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, 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-heterocycle, N(C1-C6)-alkyl, COO-aryl, N(C1-C6)-alkyl-COO-heterocycle, N(C1-C6)alkyl-CO-NH-(C1-C6)-alkyl), N(C1-C6)-alkyl-CO-NH-aryl, N(C1-C6)-alkyl-CO-NH-heterocycle, 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, N((C1-C6)-alkyl)-CO-N-(aryl)2N((C1-C6)-alkyl)-CO-N-(heterocycle)2N(aryl)-CO-(C1-C6)-alkyl, N(heterocycle)-CO-(C1-C6)-alkyl, N(aryl)-COO-(C1-C6)-alkyl, N(heterocycle)-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(heterocycle)-CO-NH-(C1-C6)-alkyl), N(aryl)-CO-NH-aryl, N(heterocycle)-CO-NH-aryl, N(aryl)-CO-N-((C1-C6)-alkyl)2, N(heterocycle)-CO-N((C1-C6)-alkyl)2N(aryl)-CO-N((C1-C6)-alkyl)-aryl, N(heterocycle)-CO-N((C1-C6)-alkyl)-aryl, N(aryl)-CO-N-(aryl)2, N(heterocycle)-CO-N-(aryl)2, aryl, O-(CH2)nis aryl, a is-(CH 2)n-heterocycle, and n may be 0-6, and the aryl residue or heterocyclic residue may be substituted 1-3 times by F, Cl, Br, I, HE, CF3, NO2CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2.

Alkanniny the remainder denotes unbranched 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 single - or multi-substituted with suitable groups such as, for example:

F, Cl, Br, I, CF3, NO2N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, 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)-heterocycle;

RHO3H2, SO3H, SO2-NH2, SO2NH((C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2S-(C1-C6)-alkyl, S-(CH2)n-aryl, S-(CH2)n-heterocycle, SO-(C1-C6)-alkyl, SO-(WITH the 2)n-aryl, SO-(CH2)n-heterocycle, SO2-(C1-C6)-alkyl, SO2-(CH2)n-aryl, SO2-(CH2)n-heterocycle, SO2-NH(CH2)n-aryl, SO2-NH(CH2)n-heterocycle, SO2-N(C1-C6)alkyl)(CH2)n-aryl, SO2-N(C1-C6)alkyl((CH2)n-heterocycle, SO2-N((CH2)n-aryl)2, SO2-N((CH2)n-(heterocycle)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, OCF3, O-(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, NH-COO-(C1-C6)-alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle, NH-CO-NH-(C1-C6)-alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, 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-heterocycle, N(C1-C6)-alkyl, COO-aryl, N(C1-C6)-alkyl-COO-heterocycle, N(C1-C6)alkyl-CO-NH-(C1-C6)-alkyl), N(C1-C6)-al the Il-CO-NH-aryl, N(C1-C6)-alkyl-CO-NH-heterocycle, 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, N((C1-C6)-alkyl)-CO-N-(aryl)2N((C1-C6)-alkyl)-CO-N-(heterocycle)2N(aryl)-CO-(C1-C6)-alkyl, N(heterocycle)-CO-(C1-C6)-alkyl, N(aryl)-COO-(C1-C6)-alkyl, N(heterocycle)-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(heterocycle)-CO-NH-(C1-C6)-alkyl), N(aryl)-CO-NH-aryl, N(heterocycle)-CO-NH-aryl, N(aryl)-CO-N-((C1-C6)-alkyl)2, N(heterocycle)-CO-N-((C1-C6)-alkyl)2N(aryl)-CO-N((C1-C6)-alkyl)-aryl, N(heterocycle)-CO-N((C1-C6)-alkyl)-aryl, N(aryl)-CO-N-(aryl)2, N(heterocycle)-CO-N-(aryl)2, aryl, O-(CH2)n-aryl, O-(CH2)n-heterocycle, and n may be 0-6, and the aryl residue or heterocyclic residue may be substituted 1-3 times by F, Cl, Br, I, HE, CF3, NO2CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH, the OO-(C 1-C6)-alkyl, CONH2.

Alkynylaryl the remainder denotes unbranched 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 single - or multi-substituted with suitable groups such as, for example:

F, Cl, Br, I, CF3, NO2N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2cycloalkyl, (C2-C6)-alkenyl, (C1-C10)-alkyl, O-(C1-C6)-alkyl, O-CO-(C1-C6)-alkyl, O-CO-(C1-C6)-aryl, O-CO-(C1-C6)-heterocycle;

RHO3H2, SO3H, SO2-NH2, SO2NH((C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2S-(C1-C6)-alkyl, S-(CH2)n-aryl, S-(CH2)n-heterocycle, SO-(C1-C6)-alkyl, SO-(CH2)n-aryl, SO-(CH2)n-heterocycle, SO2-(C1-C6)-alkyl, SO2-(CH2)n-aryl, SO2-(CH2)n-heterocycle, SO2-NH(CH2)n-aryl, SO2-NH(CH2)n-heterocycle, SO2-N(C1-C6)alkyl)(CH2)n-aryl, SO2-N(C1-C6)alkyl((CH2/sub> )n-heterocycle, SO2-N((CH2)n-aryl)2, SO2-N((CH2)n-(heterocycle)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, OCF3, O-(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, NH-COO-(C1-C6)-alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle, NH-CO-NH-(C1-C6)-alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, 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-heterocycle, N(C1-C6)-alkyl, COO-aryl, N(C1-C6)-alkyl-COO-heterocycle, N(C1-C6)alkyl-CO-NH-(C1-C6)-alkyl), N(C1-C6)-alkyl-CO-NH-aryl, N(C1-C6)-alkyl-CO-NH-heterocycle, 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, N((C1-C6)-alkyl)-CO-N-(aryl)2N((C1-C6)-alkyl)-CO-N-(heterocycle) 2N(aryl)-CO-(C1-C6)-alkyl, N(heterocycle)-CO-(C1-C6)-alkyl, N(aryl)-COO-(C1-C6)-alkyl, N(heterocycle)-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(heterocycle)-CO-NH-(C1-C6)-alkyl), N(aryl)-CO-NH-aryl, N(heterocycle)-CO-NH-aryl, N(aryl)-CO-N-((C1-C6)-alkyl)2, N(heterocycle)-CO-N-((C1-C6)-alkyl)2N(aryl)-CO-N((C1-C6)-alkyl)-aryl, N(heterocycle)-CO-N((C1-C6)-alkyl)-aryl, N(aryl)-CO-N-(aryl)2, N(heterocycle)-CO-N-(aryl)2, aryl, O-(CH2)n-aryl, O-(CH2)n-heterocycle, and n may be 0-6, and the aryl residue or heterocyclic residue may be substituted 1-3 times by F, Cl, Br, I, HE, CF3, NO2CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2.

Aryl residue denotes phenyl, nattily, biphenylyl, tetrahydronaphthalene, alpha - or beta-tetralone, indanyl or indan-1-onliny the rest.

Aryl residues can be single - or multi-substituted with suitable groups such as, for example:

F, Cl, Br, I, CF3NO 2N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, 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)-heterocycle;

RHO3H2, SO3H, SO2-NH2, SO2NH((C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2S-(C1-C6)-alkyl, S-(CH2)n-aryl, S-(CH2)n-heterocycle, SO-(C1-C6)-alkyl, SO-(CH2)n-aryl, SO-(CH2)n-heterocycle, SO2-(C1-C6)-alkyl, SO2-(CH2)n-aryl, SO2-(CH2)n-heterocycle, SO2-NH(CH2)n-aryl, SO2-NH(CH2)n-heterocycle, SO2-N(C1-C6)alkyl)(CH2)n-aryl, SO2-N(C1-C6)alkyl((CH2)n-heterocycle, SO2-N((CH2)n-aryl)2, SO2-N((CH2)n-(heterocycle)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, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2;

C(NH)(NH2), NH2, NH-(C1-the 6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, NH-CO-(C1-C6)-alkyl, NH-COO-(C1-C6)-alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle, NH-CO-NH-(C1-C6)-alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, 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-heterocycle, N(C1-C6)-alkyl, COO-aryl, N(C1-C6)-alkyl-COO-heterocycle, N(C1-C6)alkyl-CO-NH-(C1-C6)-alkyl), N(C1-C6)-alkyl-CO-NH-aryl, N(C1-C6)-alkyl-CO-NH-heterocycle, 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, N((C1-C6)-alkyl)-CO-N-(aryl)2N((C1-C6)-alkyl)-CO-N-(heterocycle)2N(aryl)-CO-(C1-C6)-alkyl, N(heterocycle)-CO-(C1-C6)-alkyl, N(aryl)-COO-(C1-C6)-alkyl, N(heterocycle)-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(heterocycle)-CO-NH-(C1-C6)-alkyl), N(aryl)-CO-NH-aryl, N(heterocycle)-CO-NH-aryl, N(aryl)-CO-N-( 1-C6)-alkyl)2, N(heterocycle)-CO-N-(C1-C6)-alkyl)2N(aryl)-CO-N((C1-C6)-alkyl)-aryl, N(heterocycle)-CO-N((C1-C6)-alkyl)-aryl, N(aryl)-CO-N-(aryl)2, N(heterocycle)-CO-N-(aryl)2, aryl, O-(CH2)n-aryl, O-(CH2)n-heterocycle, and n may be 0-6, and the aryl residue or heterocyclic residue may be substituted 1-3 times by F, Cl, Br, I, HE, CF3, NO2CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2.

Cycloalkenyl residue denotes a cyclic system containing one or more rings, which is saturated or partially unsaturated (with one or two double bonds), which consists exclusively of carbon atoms, such as, for example, cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl or substituted.

Cycloalkyl residues can be single - or multi-substituted with suitable groups such as, for example:

F, Cl, Br, I, CF3, NO2N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2cycloalkyl, (C1-C10)-alkyl, (C2-C6)-alkenyl, (the 2-C6-quinil), O-(C1-C6)-alkyl, O-CO-(C1-C6)-alkyl, O-CO-(C1-C6)-aryl, O-CO-(C1-C6)-heterocycle;

RHO3H2, SO3H, SO2-NH2, SO2NH((C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2S-(C1-C6)-alkyl, S-(CH2)n-aryl, S-(CH2)n-heterocycle, SO-(C1-C6)-alkyl, SO-(CH2)n-aryl, SO-(CH2)n-heterocycle, SO2-(C1-C6)-alkyl, SO2-(CH2)n-aryl, SO2-(CH2)n-heterocycle, SO2-NH(CH2)n-aryl, SO2-NH(CH2)n-heterocycle, SO2-N(C1-C6)alkyl)(CH2)n-aryl, SO2-N(C1-C6)alkyl((CH2)n-heterocycle, SO2-N((CH2)n-aryl)2, SO2-N((CH2)n-(heterocycle)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, OCF3, O-(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, NH-COO-(C1-C6)-alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle, NH-the O-NH-(C 1-C6)-alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, 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-heterocycle, N(C1-C6)-alkyl, COO-aryl, N(C1-C6)-alkyl-COO-heterocycle, N(C1-C6)alkyl-CO-NH-(C1-C6)-alkyl), N(C1-C6)-alkyl-CO-NH-aryl, N(C1-C6)-alkyl-CO-NH-heterocycle, 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, N((C1-C6)-alkyl)-CO-N-(aryl)2N((C1-C6)-alkyl)-CO-N-(heterocycle)2N(aryl)-CO-(C1-C6)-alkyl, N(heterocycle)-CO-(C1-C6)-alkyl, N(aryl)-COO-(C1-C6)-alkyl, N(heterocycle)-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(heterocycle)-CO-NH-(C1-C6)-alkyl), N(aryl)-CO-NH-aryl, N(heterocycle)-CO-NH-aryl, N(aryl)-CO-N-(C1-C6)-alkyl)2, N(heterocycle)-CO-N-(C1-C6)-alkyl)2N(aryl)-CO-N((C1-C6)-alkyl)-aryl, N(heterocycle)-CO-N((C1-C6)-alkyl)-aryl, N(aryl)-CO-N-(aryl)2N(GE is erotic)-CO-N-(aryl) 2, aryl, O-(CH2)n-aryl, O-(CH2)n-heterocycle, and n may be 0-6, and the aryl residue or heterocyclic residue may be substituted 1-3 times by F, Cl, Br, I, HE, CF3, NO2CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2.

Under the heterocycle or heterocyclic residue understand rings and cyclic systems, which, in addition to carbon, also contain heteroatoms, such as nitrogen, oxygen or sulfur. This definition includes cyclic systems in which the heterocycle or heterocyclic residue is condensed with a benzene nucleus.

Suitable "heterocyclic ring" or "heterocyclic residues are acridines, azocines, benzimidazole, benzofuran, benzothiazyl, benzothiophene, benzoxazole, benzthiazole, benzotriazolyl, asterisell, benzisoxazole, benzisothiazole, benzimidazolinyl, carbazolyl, an-carbazolyl, carbolines, hintline, chinoline, 4H-hemolysins, 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, tetrahydroisoquinoline, 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 refers to as a 2-, 3-, and 4-pyridyl. Thienyl refers to as 2-and 3-thienyl. Furyl refers to as 2-and 3-furyl.

In addition, this invention also includes the corresponding N-oxides of these compounds, for example, 1-hydroxy-2-, 3 - or 4-pyridyl.

In addition, in this invention includes one or multiple times benzeneamine derivatives of these heterocycles.

Heterocycle the definition of a ring or heterocyclic residues may be single - or multi-substituted with suitable groups, such as, for example:

F, Cl, Br, I, CF3, NO2N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, 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)-heterocycle;

RHO3H2, SO3H, SO2-NH2, SO2NH((C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2S-(C1-C6)-alkyl, S-(CH2)n-aryl, S-(CH2)n-heterocycle, SO-(C1-C6)-alkyl, SO-(CH2)n-aryl, SO-(CH2)n-heterocycle, SO2-(C1-C6)-alkyl, SO2-(CH2)n-aryl, SO2-(CH2)n-heterocycle, SO2-NH(CH2)n-aryl, SO2-NH(CH2)n-heterocycle, SO2-N(C1-C6)alkyl)(CH2)n-aryl, SO2-N(C1-C6)alkyl((CH2)n-heterocycle, SO2-N((CH2)n-aryl)2, SO2-N((CH2)n-(heterocycle)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, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH 2;

C(NH)(NH2), NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, NH-CO-(C1-C6)-alkyl, NH-COO-(C1-C6)-alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle, NH-CO-NH-(C1-C6)-alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, 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-heterocycle, N(C1-C6)-alkyl, COO-aryl, N(C1-C6)-alkyl-COO-heterocycle, N(C1-C6)alkyl-CO-NH-(C1-C6)-alkyl), N(C1-C6)-alkyl-CO-NH-aryl, N(C1-C6)-alkyl-CO-NH-heterocycle, 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, N((C1-C6)-alkyl)-CO-N-(aryl)2N((C1-C6)-alkyl)-CO-N-(heterocycle)2N(aryl)-CO-(C1-C6)-alkyl, N(heterocycle)-CO-(C1-C6)-alkyl, N(aryl)-COO-(C1-C6)-alkyl, N(heterocycle)-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(heterocycle)-CO-NH-(C1-C6)-alkyl), N(Ari is)-CO-NH-aryl, N(heterocycle)-CO-NH-aryl, N(aryl)-CO-N-(C1-C6)-alkyl)2, N(heterocycle)-CO-N-(C1-C6)-alkyl)2N(aryl)-CO-N((C1-C6)-alkyl)-aryl, N(heterocycle)-CO-N((C1-C6)-alkyl)-aryl, N(aryl)-CO-N-(aryl)2, N(heterocycle)-CO-N-(aryl)2, aryl, O-(CH2)n-aryl, O-(CH2)n-heterocycle, and n may be 0-6, and the aryl residue or heterocyclic residue may be substituted 1-3 times by F, Cl, Br, I, HE, CF3, NO2CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2.

The number of compounds in accordance with formula I, which is required to achieve the desired biological effect depends on a number of factors, for example, selected compounds, intended use, method of administration and the clinical condition of the patient. The usual daily dose is in the range from 0.3 mg to 100 mg (typically 3 mg to 50 mg) per kilogram body weight per day, for example, 3-10 mg/kg/day. An intravenous dose may, for example, be in the range of 0.3 mg to 1.0 mg/kg, which may be in the form of infusion of 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for this purpose may include, for example, 0,1ng - 10 mg, typically 1 ng to 10 mg per milliliter. Individual doses, for example, contain from 1 mg to 10 g of the active substance. Thus, ampoules for injection include, for example, 1 mg to 100 mg, orally administered drugs the individual doses, such as, for example, tablets or capsules may, for example, contain from 1.0 to 1000 mg, typically 10-600 mg For the treatment of the above conditions the compounds of formula I can be used themselves as a connection, but preferably they are from a portable storage media in the form of pharmaceutical compositions. This media must be, of course, be portable in the sense that it is compatible with other components of the composition and is not harmful to the health of the patient. This carrier can be solid or liquid or both, and preferably it is formed with a connection in the form of a single dose, for example, in the form of a tablet, which may contain 0,05 wt.% - 95 wt.% the active substance. Can also present additional pharmaceutically active substances, including additional compounds of formula I. the Pharmaceutical compositions of this invention can be prepared according to one of the known pharmaceutical methods, which essentially consist in that the components are mixed with a pharmacologically tolerable carriers and/or auxiliary substances is Tami.

The pharmaceutical compositions of this invention are those compositions which are suitable for oral, rectal, local, peroral (for example sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration, although the route of administration in each individual case depends on the type and severity of the subject to treatment status and the type of the used compounds in accordance with formula I. the scope of the present invention are also index form and index form extended release. Preferred are resistant to acid and gastric juice form. Suitable resistant to gastric juice coating include acetate-cellulose phthalate, polyvinyl acetate-phthalate, phthalate of hydroxypropylmethylcellulose and anionic polymers of methacrylic acid and methyl ester of methacrylic acid.

Suitable pharmaceutical compounds for oral administration can be in a separate single-dose, such as, for example, capsules, capsules with wafers, sucking tablets or pills, which in each case contain a certain amount of the compounds of formula I; in the form of a powder or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an emulsion of the type oil-in-water or in the Yes-in-oil. These compositions can be prepared, as mentioned above, in accordance with any suitable pharmaceutical method which includes a step in which the active substance and the carrier (which may consist of one or more additional components) is brought into contact. Typically, these compositions are prepared on a uniform and homogeneous mixing of the active substance with a liquid and/or powdered solid carriers, and then, if desirable, this product is formed. So, may be, for example, prepared tablet by compressing or molding a powder or granules of the compound, if necessary with one or more additional components. Molded tablets can be produced by tableting the compound in free-flowing form such as powder or granulate, if necessary mixed with a binding agent, lubricating agent, an inert diluent and/or one (several) of surface-active/dispersing means, in a suitable machine. Molded tablets may be prepared by molding a powder, moistened with an inert liquid diluent compounds in a suitable machine.

Pharmaceutical compositions suitable for peroral (sublingual) administration include sucking pill, which which may contain the compound of formula I with flavoring substance, usually sucrose and the Arabian gum or tragakant, and tablets that include this compound in an inert basis such as gelatin and glycerin or sucrose and Arabian gum.

Suitable pharmaceutical compositions for parenteral administration preferably include sterile aqueous compositions of the compounds of formula I, which are preferably isotonic with the blood of the intended recipient. These compositions are preferably injected intravenously, although administration can also be performed subcutaneously, intramuscularly or intradermally in the form of injections. These compositions can be preferably prepared by mixing the compound with water and sterilizing the resulting solution and bringing it to isotonicity with blood. Injectable compositions of this invention usually contain 0.1 to 5 wt.% active connection.

Suitable for rectal injection of the pharmaceutical compositions are preferably in the form containing a single dose suppositories. They can be prepared by mixing the compounds of formula I with one or more conventional solid carriers, for example cocoa butter, and introducing the mixture into the form.

Suitable pharmaceutical compositions for local application on the skin are preferably in the form of ointment, cream, lotion, paste, JV is her, aerosol or oil. As carriers can be used vaseline, lanoline, polyethylene glycols, alcohols and combinations of two or more of these substances. The active ingredient is typically present in a concentration of 0.1-15 wt.% compositions, for example, 0.5 to 2 wt.%.

It is also possible transdermal administration. Suitable pharmaceutical compositions for transdermal applications can be in the form of individual patches that are suitable for long term contact with the epidermis of the patient. These patches contain the active substance, if necessary dissolved in buffered aqueous solution and/or dispersed in the adhesive agent or dispersed in the polymer. A suitable concentration of the active substance is approximately 1%-35%, preferably about 3%-15%. As a special active substance, such as, for example, described in Pharmaceutical Research, 2(6): 318 (1986), may be released by electrotransport or iontophoresis.

Connection (connection) of the formula (I) can also be administered in combination with an additional active substances.

As an additional active substances for these combined drugs fit:

All antidiabetic, which are mentioned in the Roten Liste 2003, Kapitel 12. They can be combined with compounds of formula I of this invention, the particular for a synergistic improvement actions. The introduction of this combination of active substances may be either separate provision of active substances to patients, either in the form of combination products, where several active substances present in a single pharmaceutical composition. Most of the following active substances published in the USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001.

Antidiabetic include insulin and derivatives of insulin, such as Lantus® (see www.lantus.com) or HMR 1964, fast-acting insulins (see US 6221633), derivatives of GLP-1, such as, for example, those described in WO 97/26265, WO 99/03861 and WO 01/04156, WO 00/34331, WO 00/34332, WO 91/11457 and US 6380357, and orally effective hypoglycemic active substances.

Orally effective hypoglycemic active substances preferably include sulfonylureas, biguanidines, meglitinides, oxadiazolidine preparations, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, potassium channels openers, such as, for example, those described in WO 97/26265 and WO 99/03861 of Novo Nordisk A/S, insulin sensitizer, inhibitors of liver enzymes involved in stimulating gluconeogenesis and/or glycogenolysis, modulators of absorption of glucose altering fat metabolism of compounds such as antihyperlipidemic active compounds and antilipidemic active substances, compounds which reduce food intake, PPAR agonists and PXR to define against and active substances, which acts on the ATP-dependent potassium channel of the beta cells.

In one embodiment of the present 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 another embodiment of this 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 embodiment of the present invention the compounds of formula I is administered in combination with an agonist of PPAR-γsuch as rosiglitazone, pioglitazone, JTT-501, G1 262570.

In one embodiment of the present invention the compounds of formula I is administered in combination with an agonist of PPAR-αsuch as, for example, GW 9578, GW 7647.

In one embodiment of the present invention the compounds of formula I is administered in combination with a mixed PPAR agonists-α/γsuch as, for example, GW-1536, AVE 8042, AVE 8134, AVE 0847, or such as described in PCT/US00/11833, PCT/US 11490, DE10142734.4.

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

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

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

In one embodiment of the present invention the compounds of formula I is administered in combination with SER-inhibitor, such as, for example JTT-705.

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

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

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

In one embodiment of the present invention the compounds of formula I is administered in combination with antioxidants such as, for example, OPC-14117.

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

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

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

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

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

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

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

In another embodiment of this invention the compounds of formula I is administered in combination with meglitinides, such as, for example, Repaglinide.

In one embodiment of the present invention the compounds of formula I is administered in combination with thiazolidinediones, such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or described and in WO 97/41097 Dr. Reddy's Research Foundation connections, in particular 5-[[4-[3,4-dihydro-3-methyl-4-oxo-2-girasolereale]phenyl]methyl]-2,4-thiazolidinedione.

In one embodiment of the present invention the compounds of formula I is administered in combination with an inhibitor α-glucosidase, such as, for example, miglitol or acarbose.

In one embodiment of the present invention the compounds of formula I is administered in combination with an active substance that acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or Repaglinide.

In one embodiment of the present invention the compounds of formula I is administered in combination with more than one of the aforementioned 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 the next one embodiment of the present invention 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, et al., M.: Hormone and Metabolic Research (2001), 33(9), 554-558), NPY antagonists, such as, for example, {4-[(4-aminoquinazolin-2-ylamino)methyl]cyclohexylmethyl}amide naphthalene-1-sulfonic acid; GI is rochloride (CGP 71683A)), agonists MS (for example, [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]amide 1-amino-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid; (WO 01/91752)), antagonists of orexin (for example, 1-(2-methylbenzothiazol-6-ml)-3-[1,5]naphthiridine-4-rocephine; hydrochloride (SB-334867-A)), H3-antagonists (salt of oxalic acid (3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-yl)propan-1-she (WO 00/63208)); TNF agonists, CRF antagonists (e.g., [2-methyl-9-(2,4,6-trimetilfenil)-N-1,3,9-diazafluoren-4-yl]dipropylamine (WO 00/66585)), CRF BP antagonists (e.g.urocortin), agonists of urocortin, β3 agonists (e.g., 1-(4-chloro-3-methysulfonylmethane)-2-[2-(2,3-dimethyl-1H-indole-6-yloxy)ethylamino]ethanol; hydrochloride (WO 01/83451)), MSH agonists melanocytestimulating hormone agonists, CCK-a (e.g., salt triperoxonane acid {2-[4-(4-chloro-2,5-acid)-5-(2-cyclohexylethyl)thiazole-2-ylcarbonyl)-5,7-dimethylindole-1-yl}acetic acid (WO 99/15525)); inhibitors of the uptake of serotonin (e.g., dexfenfluramin), mixed serotonin and noradrenergic compounds (e.g., WO 00/71549), NT agonists, for example, a salt of oxalic acid 1-(3-ethylbenzophenone-7-yl)piperazine (WO 01/09111), agonists of bombezin antagonists Galanina, growth hormone (e.g. human growth hormone), compounds which release growth hormone (tert-butyl ether (6-b is siloxy-1-(2-diisopropylaminoethanol)-3.4-dihydro-1H-isoquinoline-2-carboxylic acid (WO 01/85695)), TRH agonists (see, for example, EP 0462884)separating protein 2, or a protein 3 modulators, leptin agonists (see, for example, Lee, Daniel W.; Leinung, Matthew C.; 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 (parlodel, depressin), inhibitors of lipase/amylase (for example, WO 00/40569), PPAR modulators (for example, WO 00/78312), RXR modulators or TR-βagonists.

In one embodiment of the present invention the compounds of formula I using an additional active substance leptin; see, for example, "Perspectives in therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacology (2001), 2(10), 1615-1622.

In one embodiment of the present invention the compounds of formula I using an additional active substance dexamfetamine or amphetamine.

In one embodiment of the present invention the compounds of formula I using an additional active substance that lowers blood pressure, such as, for example, ACE-inhibitor.

In one embodiment of the present invention the compounds of formula I using an additional active substance fenfluramine or dexfenfluramin.

In another embodiment, use of additional active ingredient sibutramine.

In one embodiment of the present invention the compounds of formula I using an additional active substances the creation orlistat.

In one embodiment of the present invention the compounds of formula I using an additional active substance is mazindol or phentermine.

In one embodiment, the compounds of formula I is administered in combination with ballast substances, preferably insoluble dietary fiber (see, for example, Carob/Caromax® (Zunft h j; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18(5), 230-6). Caromax® is a product that contains substances carob, firms Nutrinova, Nutrition Specialities &Food Ingredients GmbH, Industriepark Höchst, 65926 Frankfurt/Main). Combination with Caromax® may be in the composition or be entered by separate introduction of compounds of formula I and Caromax®. Caromax® can be entered also in the form of food, for example, in bakery products or muesli bars.

It is clear that every suitable combination of the compounds of this invention with one or more of the above compounds and the selected one or more additional pharmacologically effective substances considered as falling under the scope of the claims of this invention.

The following examples serve to explain the present invention, but not limit.

I

14 H H
ExampleR1R2R3R4R5R6R7R8Fp.
1HHHHHHH
2HHHHHHH
3HHHHHHH
4HHHHHHH
5CH3HHHHHH
6HHHHHH H
7HHHHHHH
8HHHHHHH
9HHHHHHH
10HHHHHHH
11HHHHHHH
12HHHHHHH
13COOHHHHHHHH
HHHHHHH
15HHHHHHH
16HHHHHHH
17HHHHHHH
18HHHHHHH
19HHHHHHH
20HHHHHHH
21 HHHHHHH
22HHHHHHH
23HHHHHHH
24HHHHHHH
25HHHHHHH
26HHHHHH
27HHHHHHH28HHHHHHH
29HHHHHHH
30HHHHHHH
31HHHHHHH
32HHHHHHH
33HHHHHH
34HHHHHH
35HHHHHHH
36HHHHHHH
37HHHHHH
38CH3HHHHHH
39HHHHHH
40CH3HHHHHH
41 CH3HHHHHH
42CH3HHHHHH
43HHHHHHH
44HHHHHHH
45HHHHHHH
46HHHHHHH
47HHHHHHH
48 HHHHHHH
49HHHHHHH
50HHHHHHH
51HHHHHHH
52HHHHHHH
53HHHHHHH
54HHHHHHH
55 HHHHHHH
56HHHHHHH
57HHHHHHH
58HHHHHH
64HHHHHH
65HHHHHH
66HHHHH
67HHHHHHH
68HHHHHHH
69HHHHHHH
72HHHHHHHH
73HHHHHHHH
74HHHHHHH
75HHHHH
76HHHHHHH
77HHHHHHH
78HHHHHHH
79HHHHHHH
80HHHHHHH
81HHHHHHH
82HHHH HHH
83HHHHHHH
84HHHHHHH
85HHHHHHH
86HHHHHHH
87HHHHHHH
88HHHHHHH
89HHHHHH
90HHHHHHH
91HHHHHHH
92HHHHHHH
93HHHHHHH
94HHHHHHH
95HHHHHHH
96HHHHH HH
106HHHHHHH
107HHHHHH
108HHHHH
109HHHHH
110CH3HHHHH
111 HHHHH
114HHHHHH
115HHHHHH
116HHHHHH
117HHHHHH
118HHHHHH
119H HHHHH
120HHHHHHH
121HHHHHH
122HHHHHH
123HHHHHH
124HHHHHH
125HHH HHH
126HHHHHH
127HHHHHH
128HHHHHH
129HHHHHH
130HHHHHH
131HHHH HH
132HHHHHHH
133HHHHHH
134HHHHHH
135HHHHHHH
138HHHHHHH
139HHHHHH

The effectiveness of the compounds tested follow the way.

Enzymatic test kits for detection of inhibition of phosphatase

The compounds of formula I were tested in in vitro assays for their inhibitory phosphatase action. Receiving enzyme and conducting this analysis was performed as follows.

Getting preparation of the enzyme:

A) cell Culture:

The Sf9 cells (type cells Spodoptera frugiperda obtained from Invitrogen) were cultured in rotating flasks at 28°in supplemented Grace's medium (Gibco BRL) with 10% V / V heat inactivated fetal calf serum (Gibco BRL) in accordance with the Protocol Summers and Smith (A Manual for Methods for Baculovirus Vectors and Insect Culture Procedures [Bulletin No. 15555]. Texas A & M University, Texas Agricultural Experiment Station, College Station, TX, 1987).

Construction of recombinant baculovirus vectors transfection: cDNA encoding a regulatory and catalytic domain of PTP1B man, but without carboxykinase hydrophobic domains (respectively, of amino acids 1-299) received polymerase chain reaction using primers with added sites cloning and appropriate cDNA-matrices (obtained, for example, from Invitrogen) and then cloned in baculovirus expressing vectors (Amersham Pharmacia Biotech). These recombinant baculoviruses were obtained using the expression of baculovirus Bac-to-Bac (obtained from Gibco BRL). This gene was cloned into the donor plasmid pFASTBAC (obtained from Life Technologies) Obtained plasmid was transformed into competent cells of Escherichia coli DH10BAC (obtained from Life Technologies). After transposition and selection using antibiotics this recombinant plasmid DNA of selected colonies of Escherichia coli were isolated and then used for transfection of cells Sf9 insect. Viral particle in the medium supernatant was replicated three times until I got a virus the initial volume of 500 ml.

C) preparation of recombinant protein:

Infection with baculovirus rotating culture 500 ml of Sf9 cells was performed essentially as described by Summers and Smith (see above). The Sf9 cells at a density of 1-3×106cells/ml was besieged by centrifugation at 300 g for 5 minutes, supernatant was removed and cells resuspendable with density 1×107cells/ml in a suitable initial solution of recombinant virus (MOI (multiplicity of infection) of 10). After careful shaking for 1.5 hours at room temperature was added a fresh environment to obtain a cell density of 1×106cells/ml and Then these cells were cultured in suspension at 28°during appropriate periods after postinfection.

(C) Cell fractionation and total cell extracts of infected Sf9 cells:

After postinfective aliquots of the same analysis of the expression of proteins were subjected to electrophoresis in LTO-SDS page and Western blot analysis. Fractionation of cells was performed as described (Cromlish, W. and Kennedy, B. Biochem. Pharmacol. 52: 1777-1785, 1996). bsie extracts cells were obtained from aliquots of 1 ml of infected Sf9 cells after certain periods of postinfective. Precipitated cells (300×g, 5 minutes), washed once in phosphate buffered saline (4°C)resuspendable in 50 μl of water and was destroyed by repeated freezing/thawing. The protein concentration was determined using Bradford method and bovine serum albumin as the standard.

Analysis:

A) Dephosphorylation of phosphopeptides:

This analysis is based on the release of phosphate from the consensus substrate peptide, which is found in the field of nanomolar concentrations, using a method with malachite green dye-molybdate of ammonium (Lanzetta, P.A., Alvarez, L.J., Reinbach, P.S., Candia, O.A. Anal Biochem. 100: 95-97, 1979)adapted to microplate format. This dodecadepsipeptide TRDIYETDYYRK (Biotrend, Köln) corresponds to amino acids 1142-1153 of the catalytic domains of the insulin receptor and (auto)fosfauriliruetsa at tyrosine residues 1146, 1150 and 1151. This recombinant hPTP1B was diluted with buffer for analysis (40 mm Tris/HCl, pH 7.4, 1 mm EDTA, 20 mm DTT), respectively activity 1000-1500 nmol/min/mg protein and then (one portion 20 μl) was preincubator (15 minutes, 30° (C) in the absence or in the presence of the test substance (5 μl) to the desired concentration (final concentration of DMSO 2% is the maximum) in a total volume of 90 μl of buffer (buffer for analysis). To start the reaction of dephosphorylation of the peptide substr the t (10 μl, heated beforehand to 30° (C) was added to predisturbance the preparation of the enzyme with the test substance or without test substance (final concentration of 0.2-200 μm) and incubation was continued 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 4 n HCl, 1 part) and 0.5% Tween-20 as a stop solution. After 30 minutes incubation at 22°for the development of staining was determined by absorption at 650 nm using a device for microtiter tablets (Molecular Devices). Sample and blank controls were measured in three replicates. The PTP1B activity was calculated as nanomoles released phosphate per minute and per mg of protein with potassium phosphate as standard. Inhibition of recombinant hPTP1B test substances was calculated as the percentage of phosphatases control. Figures IC50showed a significant fit with a nonlinear logistic regression curves with four parameters.

C) Cleavage of p-nitrophenylphosphate:

This analysis is based on the change of absorption of the non-physiological substrate p-nitrophenylphosphate while splitting up NITROPHENOL under standard conditions (Tonks, N.K., Diltz, 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 will pipeinput in a suitable ' intelligence the Institute in the reaction mixture, which contain 0.5 to 5 mm p-nitrophenylphosphate. Used the following buffers (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 of 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 microtiter tablets at 25°C for 1 hour. The reaction was completed by adding 100 μl of 0.2 N. NaOH. Activity of the enzyme was determined by measuring the absorption at 405 nm with appropriate allowances for the absorption of the test substance and p-nitrophenylphosphate. The results were expressed as percentage of control, comparing the number of generated p-NITROPHENOL in the treated test substance samples (nmol/min/mg protein) with the number in the untreated samples. Expected average and standard deviation figures IC50was determined by regression analysis of the linear part of the curves of inhibition.

Table 2

Biological activity
ExampleIC 50 (μm)
1>80
227,8
38,8
46,2
515,9
648,0
77,9
85,9
96,3
105,3
116,2
12>80
13>80
142,77

From this table we can see that the compounds of formula I inhibit the activity of phosphoriboisomerase 1B (PTP1B) and therefore suitable for lowering blood sugar levels. Thus, they are suitable in particular for the treatment of diabetes type I and II, insulin resistance, dyslipidemia, metabolic syndrome/syndrome X, painful fullness and weight reduction in mammals. In addition, the compounds of formula I, due to their inhibition of PTP1B, suitable for the treatment of hyperglyceridemia, high blood pressure, atherosclerosis, disorders of the immune system, autoimmune diseases, allergic diseases such as asthma, arthritis, osteoarthritis, osteoporosis, disorders of cell proliferation, such as cancer and psoriasis, diseases with decreased or increased production of growth factors, hormones or cytokines that trigger the release of growth hormones.

These compounds are suitable for treating diseases of the nervous force the topics such as, for example, Alzheimer's disease or multiple sclerosis.

These compounds suitable for treating disorders of perception and other psychiatric indications, such as, for example, depression, fear, nervousness, associated with fear, schizophrenia, for treating disorders associated with circadian rhythm and for the treatment of abuse of drugs.

In addition, these compounds are also suitable for the treatment of sleep disorders, insomnia, male and female sexual disorders, inflammations, acne, pigmentation of skin, disorders of steroid metabolism, skin diseases and fungal infections.

Next will be described a few examples, other compounds of formula I were obtained in a similar manner:

Experimental part:

To a solution of Na2SO3(27,36 g, 0,128 mol) in N2(375 ml) add a solution of 2-fluoro-5-nitrobenzylamine (30 g, 0,128 mol) in acetonitrile (250 ml) and the mixture stirred for 24 hours at room temperature. The solvent is removed in vacuum, the residue is stirred with 100 ml of isopropanol, the solid is filtered off and washed with a small amount of isopropanol or diethyl ether.

Output: 28,15 g

Sodium salt of sulfonic acid 1 (35,19 g, 0,1368 mol) placed the Ute in POCl 3(430 ml) and then add PCl5(28,78 g, 0,137 mol). The mixture is heated under reflux for 5 hours at reflux distilled. For processing evaporated in vacuum and the residue was poured into a mixture of ice water. The reaction product precipitates in the form of a light yellow solid, which is filtered off.

Output: 30,3 g

A solution of the acid chloride sulfonic acid 1 (30,3 g, 0.12 mol) in CH2Cl2(125 ml) is added dropwise to concentrated ammonia (90 ml, 1.2 mol) at room temperature. The mixture is stirred for 20 hours at room temperature and then acidified with HCl (1 BC) to pH 1. Then the organic phase is distilled off under reduced pressure, and the reaction product precipitates as a light yellow solid. Then the reaction product is filtered off.

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

To a solution of compound 1 (25 g, 0,107 mol) in DMF (1 l) is added at room temperature databaseconnect (34,1 g, 33,42 ml, 0.22 mol) and the reaction mixture is stirred for 2 hours at 130°C. then the solvent is distilled off in vacuum, the residue is mixed with water (400 ml), mixed with HCl (2 N., 400 ml) and the product repeatedly extracted with dichloromethane. The combined organic phases are dried (Na2SO4) and the solvent is distilled off under reduced pressure. The composition is different, the residue is stirred with a small amount of cold isopropanol and then the reaction product is filtered off.

Output: 20,8 g (91.3 percent).

535 mg of nitro compounds, dissolved in 100 ml of methanol/THF (1:1) and mixed with 5 mole % of Pd (10% on charcoal). After that hydronaut hydrogen in the apparatus for hydrogenation at room temperature until the absorption of hydrogen (reaction time: 1 hour).

For processing, the catalyst is filtered off through filter substance celite® and the filtrate is evaporated under reduced pressure. The oily residue is mixed with a small amount of diethyl ether, filtered off, washed with n-pentane and dried in vacuum.

Output: 397 mg (86% of theoretical)

368 mg (2 mmol) obtained as described above, the amine is dissolved in 30 ml of absolute THF and mixed with stirring at room temperature with 250 ál ethoxycarbonylmethylene. Then stirred for 4 hours at room temperature.

To process the solvent is removed under reduced pressure, the oily residue is stirred with diethyl ether and the reaction product is filtered off.

Yield 613 mg (97% of theoretical)of beige crystals.

504 mg (1.6 mmol) of the carbamate suspended in 10 ml of a mixture of THF/N2About (1:1) and stirring at room temperature is mixed with 3.2 ml (3.2 mmol) of 1 M aqueous NaOH. P is a promotional mixture is stirred for 5 hours at room temperature.

For processing under reduced pressure to about 1/3 the original volume evaporated and the reaction mixture is brought to pH 6 by addition of 2 n HCl solution, and the resulting thiourea slowly precipitates in the form of light beige crystals. The reaction product is filtered off and washed with water.

Yield 300 mg (77% of theoretical)

Example 1:

73 mg (0.3 mmol) of thiourea are dissolved in 5 ml of absolute ethanol and mixed with 85 mg (0.3 mmol) 4-(triptoreline)pencilvania. The reaction mixture is heated under reflux for 5 hours at reflux distilled solvent.

To process the solvent is removed under reduced pressure and the residue purified by chromatography on silica gel (15-25 microns; company: Merck) with a mixture of ethyl acetate/n-heptane, mixing ratio 1:1, as mobile phase.

Yield 79 mg (61% of theoretical).

1. The compounds of formula I,

where R1 denotes phenyl, naphthyl, Tinetti, pyridyl, and phenyl, naphthyl, Tinetti and pyridyl can be single - or multi-substituted by F, Cl, Br, (CH2)0-2IT, (C1-C6)-alkyl, (C2-C6-alkenyl, (C2-C6-quinil, CF3, OCF3N(R9)(R10), piperidine, piperazine, piperazinone, N-(C1-C6-alkylen)-piperazine, N-(C -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 the phenyl ring may be single - or multi-substituted by F, Cl, Br, (CH2)0-2OH, 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 denotes H, (C1-C6)-alkyl, COOH, (C1-C6-alkylene-COOH, COO(C1-C6)-alkyl, (C1-C6-alkylen-soo(C1-C6)-alkyl;

R3 denotes H, (C1-C6)-alkyl, (C1-C6-alkylether, -C(O)-phenyl, (C1-C6-alkalimetric, where the heterocycle is a 5-6-membered heterocyclic ring containing 1-2 heteroatom selected from nitrogen and oxygen, WITH-(C1-C6)alkyl;

R4, R5 denote H;

R6 denotes H,

R9 denotes H, (C1-C4)-alkyl;

R10denotes H, (C1-C4)-alkyl;

and their physiologically acceptable salts.

2. The compounds of formula I according to claim 1, characterized in that in them

R1 represents phenyl, whereby phenyl may be single - or multi-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 the phenyl ring may be single - or multi-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)-Ala is scrap, -(C1-C6)-alkyl, CF3, OCF3N(R9)(R10);

R2 denotes 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 denotes H, (C1-C6)-alkyl, (C1-C6-alkylether, -C(O)-phenyl, (C1-C6-alkalimetric, where the heterocycle is a 5-6-membered heterocyclic ring containing 1-2 heteroatom selected from nitrogen and oxygen, WITH-(C1-C6)alkyl;

R4, R5 denote H;

R6 denotes H,

R9 denotes H, (C1-C4)-alkyl;

R10 denotes H, (C1-C4)-alkyl;

and their physiologically acceptable salts.

3. The use of compounds according to one or more of claims 1 or 2 for the preparation of pharmaceutical compositions, inhibitory activity phosphoribosyltransferase 1B.

4. The pharmaceutical composition inhibiting activity phosphoribosyltransferase 1B, containing one or more compounds according to claim 1 or 2 effective to achieve a specified biological effect to the number.

5. The use according to claim 3 for the preparation of pharmaceutical compositions for lowering blood sugar.

6. The use according to claim 3 for the preparation of pharmaceutical compositions for the treatment of diabetestype II.

7. The use according to claim 3 for the preparation of pharmaceutical compositions for treating disorders of lipid and carbohydrate metabolism.

8. The use according to claim 3 for the preparation of pharmaceutical compositions for the treatment of insulin resistance.

9. Method of preparation of pharmaceutical compositions containing as active substance one or more of the compounds according to claim 1 or 2, characterized in that the active substance is mixed with a pharmaceutically acceptable carrier and the mixture result in suitable for introduction form.



 

Same patents:

FIELD: chemistry; pharmacology.

SUBSTANCE: new compounds of formula (I) and its pharmaceutically acceptable salts. Offered compounds possess properties of bacterial gyrase and Topo-IV activity inhibitor. In general formula (I) , W is chosen from CH or CF; X represents CH; Z represents O or NH; R1 represents phenyl or 5-6-merous heteroaryl ring containing 1-3 nitrogen atoms where R1 is substituted with 0-3 groups independently chosen from -(T)y-Ar, R', oxo, C(O)R', OR', N(R')2, SR', CN or C(O)N(R')2; R2 is chosen from C1-3alkyl and C3-7-cycloalkyl; and ring A represents 5-6-merous heteroaryl ring containing 1-3 heteroatoms, independently chosen of nitrogen, oxygen or sulphur provided the specified ring has hydrogen bond acceptor in position adjacent to that of joining to B ring where ring A is substituted with 0-3 groups independently chosen from R', oxo, CO2R', OR', N(R')2, halogen, CN, C(O)N(R')2, NR'C(O)R', or NR'SO2R', and where two substitutes in adjacent positions of ring A, together can form 6-merous saturated heterocyclic or heteroaryl ring containing 1-2 nitrogen atoms.

EFFECT: pharmaceutical compositions with properties of bacterial gyrase and Topo-IV activity inhibitor containing disclosed compound as active component, method of gyrase and/or Toro IV-activity inhibition, method of bacteria number reduction.

25 cl, 3 tbl, 4 dwg, 29 ex

FIELD: medicine.

SUBSTANCE: formula bond

or it pharmaceutically comprehensible salt where value of radicals are specified in the invention formula is described. The bonds are effective as inhibitors of protein kinases FLT-3 or KIT. A way of inhibition of activity kinases FLT-3 or KIT in the biological sample in vitro and application of bonds for manufacture of a medical product, suitable for treatment or simplification of gravity of disease or a condition, the chosen acute myelogenetic leukosis, acute progranulocytic leukemia or acute lymphocytic leukosis or cancer of ovaries are described also.

EFFECT: rising of efficiency of a composition and the method of treatment.

11 cl, 86 ex

FIELD: medicine.

SUBSTANCE: invention offers analogues of quinazoline of the formula I

where A is bound at least with one of atoms of carbon in position 6 or 7 of the dicyclic ring; X represents N. A represents the group Q or Z including tautomeric group Z form where Q and Z, have the formulas resulted more low in which symbols and radicals, have the value specified in item 1 of the formula of the invention. R1 represents phenyl, substituted -(G)nOAr or -O(G)nAr and where phenyl is unessentially replaced by halogen or C1-C10alkyl; where G represents C1-C4alkylene, n is peer 0 or 1. And Ar represents phenyl either pyridyl or thiazolyl where Ar is unessentially substituted by 1-2 substituents chosen from halogen or C1-C10alkyl; R2 and R3 represent N. The bonds of the formula I are inhibitors of the receptor tyrosine kinases of type 1. The invention includes also a way of treatment of hyperproliferative diseases, such as a cancer, application of bonds of the formula 1 in manufacture of medical products and pharmaceutical composition on the basis of these bonds.

EFFECT: rising of efficiency of a composition and the method of treatment.

14 cl, 6 dwg, 63 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts. Claimed compounds have antibacterial effect. In formula (I) , X is ; R1 is i) hydrogen, ii) (CH2)nNR5R6, iv) NRCO2R, v) (C1-6alkyl)CN, CN, (CH2)pOH; Y is NR*, O or S(O)p; is phenyl or 5-6-member heteroaryl with N or S as heteroatoms; R3 is NR(C=X2)R12, NR*R12, or -(O)n-5-6-member heteroaryl with 1-3 heteroatoms selected out of N, O, which can be linked over either carbon atom or heteroatom; the indicated 5-6-member heteroaryl can be optionally substituted by 1-3 groups of R7; R4, R4a, R4b and R4c are independently i) hydrogen, ii) halogen; other radicals are defined in the claim.

EFFECT: pharmaceutical composition containing effective volume of the claimed compound.

13 cl, 1 dwg, 194 ex

FIELD: chemistry.

SUBSTANCE: invention concerns benzothiazole derivatives of general formula (1) and their pharmaceutically acceptable acid-additive salts as adenosine receptor ligands with high affinity to A2A adenosine receptor, and based medicine. Compounds can be applied in treatment and prevention of diseases mediated by A2A adenosine receptors, such as Alzheimer's disease, some depressive states, toxicomania, Parkinson's disease. In general formula (I) , R is C5-C6-cycloalkyl non-substituted or substituted by hydroxy group, or is ethyl or isobutyl, or is tetrahydropyrane-4-yl or -(CH2)n-tetrahydrofurane-2 or 3-yl or is 5-hydroxybicyclo[2,2,1]hept-2-yl; X is CH or N; n is 0 or 1.

EFFECT: enhanced efficiency of composition and treatment method.

12 cl, 2 dwg, 14 ex

FIELD: chemistry.

SUBSTANCE: invention concerns method of treatment, alleviation and/or prevention of neurological state, particularly neurodegenerative disorders, involving administration of effective quantity of compound with formula I: . Also invention concerns application of compound of the formula I as neurotherapeutical, neuroprotective or antimyloid agent, pharmaceutical or veterinary composition for treatment, alleviation and/or prevention of neurological states, and compounds of the formula I on the following additional terms: (b) if R3, R and R' are H, and R2 is (CH2)2NR9R10, then both R9 and R10 are not ethyl or methyl; (c) if R3, R and R' are H, and R2 is (CH2)2NR9R10, then both R9 and R10 are not hydrogen or ethyl; (d) if R3, R and R' are H, and R2 is NR11R12, then both R11 and R12 are not hydrogen; (e) if R3, R and R' are H, and R2 is COR6, then R6 is not H, OH or CH2Cl; (f) if R3, R and R' are H, and R2 is not CH3 or CH2Cl; (g) if R3, R and R' are H, and R2 is HCNN R9R10, then both R9 and R10 are not H.

EFFECT: efficient treatment, alleviation and prevention of neurological state.

24 cl, 14 tbl, 21 ex, 14 dwg

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the formula I , where R0 is 1) monocyclic 6-14-member aryl, where aryl is independently mono-, di- or trisubstituted by R8, 2) heterocyclyl out of group of benzothiazolyl, indazolyl, pyridyl, where the said heterocyclyl is independently non-substituted or mono-, di- or trisubstituted by R8, and other radicals referred to in point 1 of the claim; R8 is halogen; on condition that R8 is at least one halogen atom if R0 is monocyclic 6-14-member aryl; substructure in the formula I is 4-8-member saturated, partly non-saturated or aromatic cyclic group including 0, 1 heteroatom selected out of nitrogen or sulfur, and is non-substituted or substituted 1, 2, 3 times by R3; Q is -(C0-C2)alkylene-C(O)NR10-, methylene; R1 is hydrogen atom, -(C1-C4)alkyl, where alkyl is non-substituted or substituted one to three times by R13; R2 is a direct link; R1-N-R2-V can form 4-8-member cyclic group selected out of piperazine or piperidine group; R14 is halogen, =O, -(C1-C8)alkyl, -CN; V is 1) 6-14-member aryl, where aryl is independently non-substituted or mono-, di- or trisubstituted by R14, and other radicals referred to in point 1 of the claim; G is direct link, -(CH2)m-NR10, where m is 0 and R10 is hydrogen, -(CH2)m-C(O)-(CH2)n-, where m is 0 or 1, and n is 0, -(CH2)m-C(O)-NR10-(CH2)n-, where m is 0 or 1, and n is 0, 1 or 2, -(CH2)m-, where m is 1; M is 1) hydrogen atom, 2) 6-14-member aryl, and other radicals referred to in point 1 of the claim; R3 is 1) hydrogen atom, 2) halogen atom, 3) -(C1-C4)alkyl, where alkyl is non-substituted, and other radicals referred to in point 1 of the claim; R11 and R12 are independently the same or different and are 1) hyfrogen atom, 2) -(C1-C6)alkyl, where alkyl is non-substituted or monosubstituted by R13, and other radicals referred to in point 1 of the claim; or R11 and R12 can form 4-8-member monocyclic heterocyclic ring together with nitrogen atoms to which they are linked, and beside the nitrogen atom the ring can include one or two similar or different ring heteroatoms selected out of oxygen, sulfur and nitrogen; where the said heterocyclic ring is independently non-substituted or mono-, disubstituted by R13; R13 is halogen, =O, -OH, -CF3, -(C3-C8)cycloalkyl, -(C0-C3)alkylene-O-R10; R10 is hydrogen, -(C1-C6)alkyl; R15 and R16 are independently hydrogen, -(C1-C6)alkyl; R17 is -(C1-C6)alkyl, -(C3-C8)cycloalkyl; in all stereoisomer forms and their mixes at any ratio, and physiologically tolerable salts. Compounds of the formula I are reversible inhibitors of enzyme factor Xa (FXa) and/or factor VIIa (FVIIa) of blood clotting, and can be generally applied in states accompanied by undesirable factor Xa and/or factor VIla activity, or supposing factor Xa and/or factor VIla inhibition for treatment or prevention. In addition, invention concerns methods of obtaining compounds of the formula I, their application as agents in pharmaceutical compositions.

EFFECT: obtaining compounds applicable as agents in pharmaceutical compositions.

19 cl, 1 tbl, 169 ex

FIELD: chemistry.

SUBSTANCE: description is given of a piperidine derivative with general formula (I) , where L represents CH or N; M represents CH or N; under the condition that, L and M both do not represent CH; R1 represents phenyl (possibly substituted with a halogen or C1-4alkyl), S(O)2(C1-4alkyl), S(O)2(C1-4fluroalkyl), S(O)2phenyl (possibly substituted with CF3 or OCF3), benzyl, benzoyl (possibly substituted with a halogen) or C(O)NHphenyl (possibly substituted with a halogen); R2 represents phenyl, possibly substituted with a halogen; R3 represents hydrogen or C1-4alkyl; R4 represents methyl or ethyl; R5 represents phenyl-NH, phenyl (C1-2alkyl), phenyl(C1-C2)alkyl-NH or pyridyl(C1-2alkyl). The phenyl can be substituted with a halogen, cyano, C1-4alkyl, C1-4alkoxy, S(O)k(C1-4alkyl) or S(O)2NR8R9; k is equal to 2; R8 and R9 represent hydrogen or its pharmaceutical salts. The compound is a modulator of the activity of the CCR5 receptor. Description is given of the method of obtaining the compound, where L represents N, and the pharmaceutical composition based on a compound with formula (I).

EFFECT: design of a method of obtaining a compound, where L represents N, and a pharmaceutical composition based a compound with formula (I).

7 cl, 7 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to derivatives of 4-[1-arylimidazol-4-yl ethynyl]-2-alkylpyridine and 4-[1-heteroarylimidazol-4-yl ethynyl]-2-alkylpyridine of general formula I having general formula I in which R1 stands for C1-C6alkyl; R2 stands for C1-C6alkyl or C3-C12cycloalkyl; R3 stands for aryl or heteroaryl, where aryl or heteroaryl are unsubstituted or contain substituents, selected from group, including halogen, C1-C6alkyl, S-C1-C6alkyl, C1-C6alkylhlogen, C1-C6alkoxygroup, halogen- C1-C6lkoxygroup, C3-C12cycloalkyl, C2-C11heterocycloakyl, C1-C6alkylminogroup,di- C1-C6alkylaminogroup, C1-C6alkoxyaminogroup, (C1-C6 alkoxy) C1-C6alkylaminogroup, C3-C12cycloalkylaminogroup, benzylaminogroup and cyanogroup, where said "aryl" represents phenyl, and said " heteroaryl" represents aromatic 5- or 6- member ring or one or more condensed rings, containing one or more heteroatoms, selected from group, which includes nitrogen, oxygen and sulfur; and R4 stands for hydrogen, C(O)H or CH2R5 , where R stands for hydrogen or its pharmaceutically acceptable salt. Invention also relates to method of obtaining compounds of general formula I, their application as anxiolytic, to based on them pharmaceutical composition and method of treatment or prevention of disorders, fully or partly mediated by metabotropic glutamate receptor of subtype 5.

EFFECT: obtaining novel heterocyclic compounds possessing useful biological properties.

15 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: there is disclosed compounds of formula II , where each R2 independently stands for H, halogen, cyano, NO2, OR5, NR6R7, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, substituted heterocyclo, arylalkyl, substituted arylalkyl, heterocycloalkyl or substituted heterocycloalkyl; B represents O, S, SO or SO2; each W and X independently represents C or N; n is within 0 to 4 if both W and X represent C, 0 to 3, if either X or W represent N, and 0 to 2 if both X and W represent N; R3, R5, R6, R7 are independently chosen from H, alkyl, substituted alkyl, alkenyl, alkinyl, substituted alkinyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, substituted heterocyclo; R4 represents optionally substituted 5-6-merous heteroaryl containing nitrogen atom provided (a) if R4 stands for pyridyl, R4 is not substituted with both hydroxy and methoxy groups; and (b) R4 stands for pyrimidinyl, it is n-substituted =O; A is chosen from following compounds of formula: , where D stands for S or O; m is within 0 to 6; R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26 and R27 are independently chosen from H, halogen, NR30R31, OR32, CO2R33, SO2R36, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkinyl, substituted alkinyl, -CN, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl; R28 and R29 are independently chosen from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl or together they form carbocyclic or heterocyclic ring consisting of 3 to 8 atoms; and R30, R31, R32, R33 and R36 are independently chosen from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkinyl, substituted alkinyl, cycloalkyl, substituted cycloalkyl, alkoxycarbonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, substituted heterocyclo, heterocycloalkyl or substituted heterocycloalkyl as pharmaceutical composition for cancer treatment containing compound of formula II.

EFFECT: production of new compounds and based pharmaceutical composition applied for cancer treatment.

18 cl, 147 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to the method of producing compounds with formula I and to their pharmaceutical salts. In formulae I, II, IV, V: R1 or R2 represent H, -(CH2)t(5-member heterocyclic compound), where t equals 4 and where the heterocyclic compound contains one nitrogen atom as the heteroatom, R3 is -(CH2)t(C6-C10aryl), where t equals 1. The given R3 groups are optionally substituted with 3 R4 groups. Each R4 is independently chosen from halogen. R8 is C1-C10alkyl, R9 is C1-C10alkyl, and n equals 2.

EFFECT: treatment of hyper-proliferative diseases using new intermediate compounds with formulae II, IV, V.

15 cl, 2 dwg, 11 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: chemistry.

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

EFFECT: enhanced efficiency of composition and treatment method.

5 cl, 1 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention concerns method of treatment, alleviation and/or prevention of neurological state, particularly neurodegenerative disorders, involving administration of effective quantity of compound with formula I: . Also invention concerns application of compound of the formula I as neurotherapeutical, neuroprotective or antimyloid agent, pharmaceutical or veterinary composition for treatment, alleviation and/or prevention of neurological states, and compounds of the formula I on the following additional terms: (b) if R3, R and R' are H, and R2 is (CH2)2NR9R10, then both R9 and R10 are not ethyl or methyl; (c) if R3, R and R' are H, and R2 is (CH2)2NR9R10, then both R9 and R10 are not hydrogen or ethyl; (d) if R3, R and R' are H, and R2 is NR11R12, then both R11 and R12 are not hydrogen; (e) if R3, R and R' are H, and R2 is COR6, then R6 is not H, OH or CH2Cl; (f) if R3, R and R' are H, and R2 is not CH3 or CH2Cl; (g) if R3, R and R' are H, and R2 is HCNN R9R10, then both R9 and R10 are not H.

EFFECT: efficient treatment, alleviation and prevention of neurological state.

24 cl, 14 tbl, 21 ex, 14 dwg

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) , where R1 is phenyl optionally substituted by halogen, cyano, C1-4alkyl or C1-4haloalkyl; R2 is hydrogen, C1-6alkyl or C3-6cycloalkyl; and R3 is a group with NH or OH and calculated or measured pKa from 1.0 to 8.0, selected out of: 2-oxo-thiazol-5-yl with C1-4fluoroalkyl, optionally substituted phenyl group, optionally substituted heterocyclyl group or CH2S(O)2(C1-4alkyl) group in position 4; 2-oxo-oxazol-5-yl with C1-4fluoroalkyl or CH2S(O)2(C1-4alkyl) in position 4; 1H-1,2,3-triazol-4-yl with C1-4alkyl, C3-6cycloalkyl, C1-4fluoroalkyl, S-R4 (where R4 is C1-4alkyl, C1-4fluoroalkyl or C3-6cycloalkyl), NHS(O)2(C1-4alkyl), N(C1-4alkyl)S(O)2(C1-4alkyl), phenyl group, heterocyclyl group or CH2S(O)2C1-4alkyl) group in position 5; 4-oxo-1H-1,4-dihydropyridine-3-yl with C1-4fluoroalkyl in position 2; 2,6-dioxo-1H-1,2,3,6-tetrahydropyrimidine-4-yl with C1-4alkyl, C3-6cycloalkyl or CH2(C1-3fluoroalkyl) in position 3 and optionally substituted in one or more other ring positions; 6-oxo-1H-1,6-dihydropyridine-3-yl with C1-4fluoroalkyl, cyano or phenyl in position 2 and/or in position 5 and optionally substituted in one or more other ring positions; 6-oxo-1H-1,6-dihydropyridine-3-yl with CH2CO2H at ring nitrogen atom and optionally substituted in one or more other ring positions; 2H-tetrazol-5-yl; CO2H, CH2CO2H or OCH2CO2H group at optionally substituted phenyl, optionally substituted CH2O phenyl or optionally substituted naphtyl ring or optionally substituted acylated dihydroisoquinolinyl ring; or group NHS(O)2(C1-4alkyl) at optionally substituted aromatic heterocyclic ring; or their tautomer where possible; in indicated positions where heterocyclyl ring in R3 can be optionally substituted, it can be optionally substituted by fluoro, chloro, bromo, C1-4alkyl, C3-6cycloalkyl, C1-4fluoroalkyl, S-R4 (where R4 is C1-4alkyl, C1-4fluoroalkyl or C3-6cycloalkyl), cyano, S(O)2(C1-4alkyl); in indicated positions where phenyl or naphtyl ring in R3 can be optionally substituted, it can be optionally substituted by halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4fluoroalkyl, OCF3, SCF3, nitro, S(C1-4alkyl), S(O)(C1-4alkyl), S(O)2(C1-4alkyl), S(O)2NH(C1-4alkyl), S(O)2N(C1-4alkyl)2, NHC(O)(C1-4alkyl) or NHS(O)2(C1-4alkyl); or its pharmaceutically acceptable salts. Also invention concerns compounds of formula (I), method of obtaining compounds of any of claims 1-12, as well as pharmaceutical composition.

EFFECT: obtaining novel bioactive compounds with chemokine receptor activity modulation effect.

16 cl, 51 ex

FIELD: chemistry.

SUBSTANCE: invention claims derivatives of pyridazin-3(2H)-one of formula (I), where R1, R2 and R4 are organic radicals described in the claim 1, R3 is cyclic group described in the claim, and R5 is phenyl or heteroaryl group described in the claim. Compounds of formula (I) inhibit phosphodiesterase 4 (PDE-4) and can be applied in treatment of various diseases or pathological states alleviated by PDE-4 inhibition, and in medicine production for treatment of aforesaid diseases. Also invention claims method of obtaining these compounds and intermediate compounds for their obtainment.

EFFECT: obtaining compounds which can be used in treatment of various diseases or pathological states and in medicine production for treatment of aforesaid diseases.

25 cl, 28 tbl, 243 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with formula I: , where L represents radical , in which R1 represents H, C1-4alkyl; n represents 0 or 1; or L represents radical , in which R1 represents H, C1-4alkyl; m equals 1; R represents H, halogen, C1-C4alkyl or C1-C4-alkoxy; Z represents a bond, -C(O)NH-, O or S; p is an integer from 1 to 5; Q represents a bond with the condition that, Z is not a bond, when p equals 1; or represents O, S or -C(O)NR6-, where R6 represents H, C1-4alkyl or C3-6cycloalkyl; or W and R6 together with a nitrogen atom, to which they are bonded, form or or Q represents -NR6-, or in the condition that, p is not equal to 1; W represents , , , , ,

, , ,

, , ,

, , , ,

, , , ,

, , , ,

, , , , ,

, , , , , and

.

EFFECT: obtaining compounds with agonistic activity towards PPAR receptors, which enables them to be used in pharmaceutical compositions and methods of treating conditions, mediated by these receptors.

12 cl, 7 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula 1 and their pharmaceutically acceptable salts as inhibitors of post-proline aminopepdidases, as well as to pharmaceutical composition based on them and application for manufacturing such composition, and to method of inhibition with their application. Compounds can be applied for treatment of diseases mediated by activity of post-proline aminopeptidases, such as type II diabetes and disturbed tolerance to glucose. In general formula 1 ,

either G1 represents -CH2-X2-(CH2)a-G3, and G2 represents H, or G2 represents -CH2-(CH2)a-G3, and G1 represents H; G3 is selected from group according to general formula 2 ,

group according to general formula 3

and group according to general formula 4 ;

a is 0, 1 or 2; b is 1 or 2; X1 is selected from CH2, S, CF2, CHF and O; X2 is selected from CH2; X3, X4 and X5 are selected from N; X6 is selected from NH; X7 is selected from NH; R1 is selected from H and CN; R2 represents H; R3 is selected from H, Cl, OH, NH2, NH-C1-C10alkyl and N(C1-C10alkyl)2; R4, R5, R6, R7 and R8 are independently selected from H, Br, Cl, F, OH, NO2; R9 represents H; R10, R11, R12, R13 and R14 are independently selected from H, Cl and CF3; R15 and R16 are independently selected from H, C1-C10alkyl, C1-C10alkenyl, C3-C10cycloalkyl, C3-C10cycloalkenyl, quinoline, naphtyl and -CH2-L-R17; R17 is selected from C1-C10alkyl, phenyl, naphtyl, quinolinyl and indolyl; L is selected from covalent bond, CH=CH and -C6H4-; on condition that when R15 and R16 both represent H, and b is 1, then X1 does not represent S or CH2.

EFFECT: obtaining compounds that can be applied for treatment of diseases mediated by activity of post-proline aminopeptidases, such as type II diabetes and disturbed tolerance to glucose.

58 cl, 10 tbl, 1705 ex

FIELD: chemistry.

SUBSTANCE: this invention refers to compounds of formula where one of R6, R7 or R8 means , and X, Y, substitutes of R1-R13 and n are as it is defined in item 1 of formula of invention, and to all their enantiomers, to pharmaceutically acceptable salts and/or esters.

EFFECT: production of compounds for treatment and/or prevention of diseases modulated by PPARδ and/or PPARα agonists.

26 cl, 1 tbl, 35 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, in particular to endocrinology, and relate to treatment of 2nd type diabetes complicated by a polyneuropathy. For this purpose against basic complex therapy of diabetes in addition tylorone is entered on 250 mg/days into 1st and 2nd days of treatment. Further tylorone is administered on 125 mg in two days on the third. On course of treatment the preparation dose makes not less than 2500 mg.

EFFECT: for the first time the developed regimen of the chosen immunomodulator administration for the given contingent of patients allows to raise efficiency of treatment.

2 ex

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