Compounds for treatment of metabolic disorders

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is application of biologically active substance for production of medication for treatment of syndrome of resistance to insulin, diabetes, including type I diabetes and type II diabetes, syndrome of ovary polycystosis, treatment or reduction of probability of atheroslerosis development, arterioslerosis, obesity, hypertension, hyperlipidemia, fatty infiltration of liver, nephropathy, neuropathy or retinopathy, feet ulceration or cataracts associated with diabetes, where medication represents compound of formula , as well as corresponding treatment method, pharmaceutical composition and biologically active substance of the same purpose.

EFFECT: increase of compound activity: 75% reduction of glucose level with loading in contrast to 10% reduction for analogues known before, as well as reduction of level of triglycerides in blood serum.

17 cl, 1 dwg, 2 tbl, 3 ex

 

CROSS-REFERENCE TO RELATED APPLICATIONS

The present invention claims the priority of U.S. Provisional Patent Application No. 60/734,803, filed November 9, 2005, the contents of which are incorporated into this description by reference.

The LEVEL of TECHNOLOGY

Diabetes mellitus is a major cause of morbidity and mortality. Chronically elevated levels of glucose in the blood leads to debilitating complications: nephropathy, usually causing the need for dialysis or a kidney transplant; peripheral neuropathy; retinopathy leading to blindness; ulceration of the legs and feet, leading to amputation; fatty infiltration of the liver, sometimes developing into cirrhosis; and susceptibility to coronary artery disease and myocardial infarction.

There are two main types of diabetes. Type I, or insulin-dependent diabetes mellitus (IDDM)occurs due to autoimmune destruction of insulin-producing beta cells in the pancreatic islets. This disease usually appears in childhood or adolescence. Treatment mainly consists of multiple daily injections of insulin, together with frequent measurements of blood glucose levels in the blood to regulate insulin doses, because excess insulin may cause hypoglycemia and subsequent failure of the brain and other functions.

Type II or non-insulin dependent diabetes mellitus (NIDDM), the usual develops in adulthood. NIDDM is associated with tissue resistance, using glucose, such as adipose tissue, muscle, and liver, to the action of insulin. First of pancreatic islet beta cells compensate by allocating excess insulin. The subsequent failure of the islets leads to decompensation and chronic hyperglycemia. On the other hand, reasonable islet failure may precede or coincide with peripheral insulin resistance. There are several classes of drugs that are suitable for the treatment of NIDDM: 1) relizer insulin, which directly stimulate insulin secretion, making the risk of hypoglycemia; 2) prandialno relizer insulin, which make it possible glucoseinduced insulin secretion, and which must be taken before each meal; 3) biguanides, including Metformin, which reduces hepatic gluconeogenesis (which is paradoxically elevated in diabetes); 4) insulin-were given insulin sensitizers, for example, thiazolidinedione derivative of rosiglitazone and pioglitazone, which improve peripheral sensitivity to insulin, but which cause side effects such as weight gain, edema and sometimes liver toxicity; 5) insulin injections, which are often necessary in the later stages of NIDDM, when the islets are denied in chronic overstimulation.

The resist is ntest to insulin may also occur without overt hyperglycemia and is usually associated with atherosclerosis, obesity, hyperlipidemia and hypertension. This group of disorders is “metabolic syndrome” or “syndrome of insulin resistance”. Insulin resistance is also associated with fatty infiltration of the liver, which may develop into chronic inflammation (NASH; “non-alcoholic steatohepatitis), fibrosis and cirrhosis. In aggregate, the syndromes of insulin resistance, including diabetes, but not limited only to them, underlie many of the major causes of morbidity and death in people aged 40 years and older.

Despite the existence of these drugs, diabetes remains a major and growing public health problem. Complications in the later stages of diabetes, consume a lot of resources of the national health. There is a need for new orally active therapeutic tools that effectively affect major violations of insulin resistance and failure of Islands with fewer or milder side effects than existing drugs.

Currently there is no safe and effective treatments for fatty infiltration of the liver. Therefore, such treatment would be valuable for the treatment of this condition.

WO 02/100341 (Wellstat Therapeutics Corp.) and WO 04/073611 (Wellstat Therapeutics Corp.) describe some of the connections, replaced the two is ogorode in the end position of the acid, for example, 4-(3-(2,6-dimethylsiloxy)phenyl)butane acid and 3-(2,6-dimethylbenzylamine)phenylacetic acid. WO 04/091486 (Wellstat Therapeutics Corp.) describes some compounds substituted by a hydroxy-group in the end position of the acid, for example 4-(3-(2,6-dimethylsiloxy)phenyl)-4-hydroxybutanoic acid. The above-mentioned publication does not describe any connections to the following formula I, in which end position acids substituted by alkyl.

The INVENTION

The present invention is a biologically active agent, as described below. This invention describes the use described below biologically active products in the production of drugs for the treatment of the syndrome of insulin resistance, diabetes, cachexia, hyperlipidemia, fatty infiltration of the liver, obesity, atherosclerosis or arteriosclerosis. This invention describes methods of treating a mammal with the syndrome of insulin resistance, diabetes, cachexia, hyperlipidemia, fatty infiltration of the liver, obesity, atherosclerosis or arteriosclerosis, comprising the administration to a mammal an effective amount described below biologically active products. This invention describes a pharmaceutical composition comprising as described below biologically active agent and pharmaceutically reception is emy media.

The biologically active agent in accordance with the present invention is a compound of the formula I:

in which n is 1 or 2; one of m and x is 0, and the other equal to 0, 1, 2, 3 or 4; q is 0 or 1; t is 0 or 1; R2is an alkyl with a number of carbon atoms from 1 to 3; R3represents hydrogen, halogen, alkyl with the number of carbon atoms from 1 to 3, or alkoxy with the number of carbon atoms from 1 to 3; one of R4and R5is an alkyl with a number of carbon atoms from 1 to 3, and the other represents hydrogen or alkyl with the number of carbon atoms from 1 to 3; A represents a phenyl, unsubstituted or substituted 1 or 2 groups selected from halogen, alkyl with the number of carbon atoms from 1 to 2, performative, alkoxy with the number of carbon atoms from 1 to 2 and performatce; or cycloalkyl with the number of carbon atoms in the cycle from 3 to 6, where cycloalkyl not substituted, or one or two carbon atoms in the cycle independently monogamist the stands or ethyl; or 5 - or 6-membered heteroaromatic cycle with 1 or 2 heteroatoms in the cycle selected from N, S and O and the heteroaromatic cycle covalently linked to the remainder of the compounds of formula I through a carbon atom of a given cycle; and R1represents hydrogen or alkyl with 1 or 2 carbon atoms. Alternatively, when R1 represents hydrogen, a biologically active agent may be a pharmaceutically suitable salt of the compounds of formula I.

The above-described biologically active funds are active in one or more tests on the biological activity described below, which are recognized experimental model of diabetes and syndrome of insulin resistance man on the animal. Thus, such funds may be suitable in the treatment of diabetes and syndrome of insulin resistance. All tested illustrative compounds showed activity in at least one of the tests for biological activity.

The drawing shows the dose-effect connection for the CW test with the PPARα transactivation in humans.

DETAILED description of the INVENTION

DEFINITION

When used in this description, the term “alkyl” means an alkyl group with a linear or branched chain. An alkyl group that is identified as containing a certain number of carbon atoms refers to any alkyl group with the specified number of carbon atoms. For example, alkyl with up to three carbon atoms may represent propyl or isopropyl; and alkyl with up to four carbon atoms may represent an n-butyl, 1-methylpropyl, 2-methylp the filing or tert-butyl.

When used in this specification, the term “halogen” refers to one or more fluorine, chlorine, bromine and iodine.

When used in this description, the term “PERFLUORO”as in performative or performatce, means that the group contains fluorine atoms instead of hydrogen atoms.

When used in this specification, “Ac” refers to the group of CH3C(O)-.

Some chemical compounds are referred to in this description of their chemical name or two-letter code indicated below. Join CW, CX and DP are included within formula I above.

CW 2-(3-(2,6-Dimethylsiloxy)phenyl)-2-(R,S)metalicana acid

CX 2-(3-(2,6-Dimethylsiloxy)phenyl)-2-(R,S)atelectasia acid

DP 3-(3-(2,6-Dimethylsiloxy)phenyl)-2-(R,S)methylpropanoate acid.

When used in this description and intermediate term “containing” is unlimited. The claim that use this term may include elements in addition to those described in this claim element.

COMPOUNDS of the PRESENT INVENTION

The asterisk in the above formula I denotes a chiral center. This invention describes the racemate, the (R)-enantiomer and (S)-enantiomer of compounds of formula I, each of which is active. Mixtures of these enantiomers can be R sdeleni using HPLC, for example, as described in Chirality 11: 420-425 (1999).

In the embodiment, tools, use, method or pharmaceutical composition described in the invention, x is 0 and m is 0, 1, 2, 3 or 4. In a more specific embodiment, m is 0, 2 or 4. In another embodiment, m is 0 and x is 0, 1, 2, 3 or 4. In a more specific embodiment, x is 0, 2 or 4.

In the embodiment, tools, use, method or pharmaceutical composition described in the invention, n is 1; q is 0; t is 0; R3represents hydrogen; and A is phenyl, unsubstituted or substituted 1 or 2 groups selected from halogen, alkyl with 1 or 2 carbon atoms, performative, alkoxy with 1 or 2 carbon atoms, performatce. In a more specific embodiment, A is 2,6-dimetilfenil. Examples of such compounds include compounds CW, CX and DP.

In a preferred embodiment, the biologically active funds in this invention, the tool is essentially pure (at least 98%).

The REACTION SCHEME

Biologically active products of the present invention can be obtained in accordance with the following reaction schema.

The compound of formula I where m is 0, x is 0 or 1, q is 0 and is 1, t is 0 or 1 and n is 1 or 2, R2is an alkyl with a number of carbon atoms from 1 to 3, R3represents hydrogen, halogen, alkoxy with the number of carbon atoms from 1 to 3 or an alkyl with a number of carbon atoms from 1 to 3, one of R4and R5is an alkyl with a number of carbon atoms from 1 to 3, and the other represents hydrogen or alkyl with the number of carbon atoms from 1 to 3. R1represents hydrogen or alkyl with the number of carbon atoms from 1 to 2, i.e. compounds of formula:

where A is the same as described above, can be obtained by the reaction scheme depicted in figure 1.

In the reaction scheme shown in scheme 1, A, t, n, m, q, x, R2, R3, R4and R5are the same as described above. R1represents an alkyl group with the number of carbon atoms from 1 to 2. R7represents an alkyl group with carbon atoms of 1 to 3 and Y1is a halide.

The compound of formula II alkylate compound of formula III from the reaction stage (a) obtaining the compounds of formula IV. The reaction is carried out in a suitable solvent, such as tetrahydrofuran, tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H)-pyrimidinone, tetrahydrofuran/hexamethylphosphoramide, etc. In General, the reaction is carried out in the presence of from 2 to 3 molar equivalents of the warping of obtaining the compounds of formula IV, where R4is an alkyl with a number of carbon atoms from 1 to 3 and R5represents hydrogen, or from 4 to 6 molar equivalents of base to obtain the compounds of formula IV, where R4and R5is an alkyl with a number of carbon atoms from 1 to 3. The traditional basis for this purpose can be sodium hydride, potassium hydride, bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide lithium, diisopropylamide lithium, etc. When carrying out this reaction usually prefer to use the alkali metal salts of hexamethyldisilane. The reaction is carried out at temperatures from -78°C to 25°C. Typically, the reaction takes from 6 to 72 hours. To clean the product, you can use traditional methods such as extraction, evaporation, chromatography and recrystallization.

The compound of formula IV is a compound of formula I, where R1represents an alkyl group with the number of carbon atoms from 1 to 2. The compound of formula IV can be converted to the free acid i.e. the compound of formula I, where R1represents H, by hydrolysis of ester. Any conventional method of hydrolysis of ester will give the compound of formula I, where R1represents H.

If A is a phenyl, substituted by 1 or 2 hydroxyl groups, usually prefer to protect hydroximino group of compounds of formula II. Suitable protective group can be described in Protective Groups in Organic Synthesis by T. Greene.

The protective group can be removed using suitable reagents for removing the protective group, such as described in Protective Groups in Organic Synthesis by T. Greene.

The compound of formula I, where m equals the number from 1 to 4, x is 0, q is 0 or 1, t is 0 or 1 and n is 1 or 2, R2is an alkyl with a number of carbon atoms from 1 to 3, R3represents hydrogen, halogen, alkoxy with the number of carbon atoms from 1 to 3 or an alkyl with a number of carbon atoms from 1 to 3, one of R4and R5represent alkyl with the number of carbon atoms from 1 to 3, and the other represents hydrogen or alkyl with the number of carbon atoms from 1 to 3. R1represents hydrogen or alkyl with the number of carbon atoms from 1 to 2, i.e. compounds of formula:

where A is the same as described above, can be obtained by the reaction scheme depicted in scheme 2.

In the reaction scheme depicted in scheme 2, A, t, n, m, q, x, R2, R3, R4and R5are the same as described above. R1represents an alkyl group with the number of carbon atoms from 1 to 2. Y1is a halide.

The compound of formula IV can be restored to the compounds of formula V by reaction stage (b). The reaction is carried out with the traditional label reductant, for example, alkali metal hydride, such as alumalite lithium. The reaction is carried out in a suitable solvent, such as tetrahydrofuran. For the reaction stage (b) you can use any of the conditions conventional for this reaction recovery.

The compound of formula V can be converted into a compound of formula VI by replacing a hydroxyl group, halogen group, and the halogen is preferably bromine or chlorine. Suitable halogenation reagents include, but are not limited to, oxalyl chloride, thionyl chloride, bromine, tribromide phosphorus, tetrabromide carbon, etc. For the reaction stage (c) you can use any of the conditions conventional for these halogenation reactions.

The compound of formula VI can be converted into a compound of formula VII by reaction of compound VI with an alkali metal cyanide, for example, copper cyanide, sodium or potassium. The reaction is carried out in a suitable solvent such as N,N-dimethylformamide, ethanol, dimethylsulfoxide, etc. For the reaction of stage (d), you can use any of the conditions traditionally used to obtain the nitrile.

Compound of formula VII can be converted into a compound of formula VIII by reaction stage (e) using acid or alkaline hydrolysis. When carrying out this reaction usually prefer to use the SQL basic hydrolysis, for example, aqueous sodium hydroxide. For the reaction of stage (e), you can use any of the conditions conventionally used in hydrolysis of the nitrile. To clean the product, you can use traditional methods such as extraction, evaporation, chromatography and recrystallization.

The compound of formula VIII is a compound of formula I where m is 1 and R1represents H.

The compound of formula VIII can be converted into a compound of formula I, where R1is an alkyl with a number of carbon atoms from 1 to 2 by esterification of compounds of formula VIII with methanol or ethanol. The reaction can be conducted or with the use of catalysts, for example, H2SO4, TsOH and the like, or by using dehydrating agents, e.g. dicyclohexylcarbodiimide and the like. For carrying out this reaction, you can use any of the conditions traditionally used in these reactions of esterification.

The compound of formula VI, you can enter into reaction with diethylmalonate when using a suitable base, such as sodium hydride, to obtain the compounds of formula IX. The reaction is carried out in a suitable solvent, such as dimethylformamide, tetrahydrofuran, etc. For the reaction of stage (f), you can use any of the conditions conventionally used in Acireale alkylation.

The compound of formula IX can hydrolyze and decarboxylate when using sodium hydroxide in a suitable solvent, such as ethanol-water, to obtain the compounds of formula X. For the reaction stage (g) you can use any of the conditions traditionally used in such reactions. To clean the product, you can use traditional methods such as extraction, evaporation, chromatography and recrystallization.

The compound of formula X is a compound of formula I where m is 2 and R1represents H.

The compound of formula X can be converted into a compound of formula I, where R1is an alkyl with a number of carbon atoms from 1 to 2 by esterification of compounds of formula X with methanol or ethanol. The reaction can be conducted or with the use of catalysts, for example, H2SO4, TsOH and the like, or by using dehydrating agents, e.g. dicyclohexylcarbodiimide and the like. For carrying out this reaction, you can use any of the conditions traditionally used in these reactions of esterification.

The compound of formula X can be restored to the compounds of formula XI by reaction stage (h). This reaction can be conducted in the same manner as described in this description previously for the reaction of stage (b).

The compound of formula XI can is about to turn into a compound of formula XII by reaction stage (i) in the same way, as described herein previously in the description of the reaction stage (c).

The compound of formula XII can be converted into a compound of formula XIII by reaction stage (j) in the same way as described in this description previously when describing the reaction of stage (d).

The compound of formula XIII can be converted into a compound of formula XIV by reaction stage (k) in the same way as described in this description previously when describing the reaction of stage (e). To clean the product, you can use traditional methods such as extraction, evaporation, chromatography and recrystallization.

The compound of formula XIV is the compound of formula I where m is 3 and R1represents H.

The compound of formula XIV can be converted into a compound of formula I, where R1is an alkyl with a number of carbon atoms from 1 to 2 by esterification of compounds of formula XIV methanol or ethanol. The reaction can be conducted or with the use of catalysts, for example, H2SO4, TsOH and the like, or by using dehydrating agents, e.g. dicyclohexylcarbodiimide and the like. For carrying out this reaction, you can use any of the conditions traditionally used in these reactions of esterification.

The compound of formula XII can be converted into a compound of formula XV by reaction stage (l) in the same way as is isano in this description previously when describing the reaction of stage (f).

The compound of formula XV can be converted into a compound of formula XVI by reaction stage (m) in the same way as described in this description previously when describing the reaction of stage (g). To clean the product, you can use traditional methods such as extraction, evaporation, chromatography and recrystallization.

The compound of formula XVI is a compound of formula I, where m is equal to 4 and R1represents H.

The compound of formula XVI can be converted into a compound of formula I, where R1is an alkyl with a number of carbon atoms from 1 to 2 by esterification of compounds of formula XVI methanol or ethanol. The reaction can be conducted or with the use of catalysts, for example, H2SO4, TsOH and the like, or by using dehydrating agents, e.g. dicyclohexylcarbodiimide and the like. For carrying out this reaction, you can use any of the conditions traditionally used in these reactions of esterification.

If A is a phenyl, substituted by 1 or 2 hydroxyl groups, usually preferred to protect the hydroxyl group of compounds of formula IV. Suitable protective group can be described in Protective Groups in Organic Synthesis by T. Greene.

The protective group can be removed using suitable reagents for removing the protective group, such as described in Proective Groups in Organic Synthesis by T. Greene.

The compound of formula I, where x is the number from 2 to 4, m is 0, q is 0 or 1, t is 0 or 1, and n is 1 or 2, R2is an alkyl with a number of carbon atoms from 1 to 3, R3represents hydrogen, halogen, alkoxy with the number of carbon atoms from 1 to 3 or an alkyl with a number of carbon atoms from 1 to 3, one of R4and R5is an alkyl with a number of carbon atoms from 1 to 3, and the other represents hydrogen or alkyl with the number of carbon atoms from 1 to 3. R1represents hydrogen or alkyl with the number of carbon atoms from 1 to 2, i.e. compounds of formula:

where A is the same as described above, can be obtained by the reaction scheme depicted in scheme 3.

In the reaction scheme depicted in scheme 3, A, t, n, m, q, x, R2, R3, R4and R5are the same as described above. Y is a halide or leaving group, p is a number from 2 to 4, s is equal to the number from 1 to 3, u is equal to the number from 1 to 3 and Y1is a halide. R1represents an alkyl group with the number of carbon atoms from 1 to 2.

The compound of formula XVII is converted into a compound of formula XIX by reaction stage (n) condensation on Mitsunobu XVII XVIII using triphenylphosphine and diethylazodicarboxylate or diisopropylcarbodiimide. Re is the Ktsia carried out in a suitable solvent, for example, tetrahydrofuran. For the reaction of stage (n) you can use any of the conditions traditionally used in the reactions of Mitsunobu.

The compound of formula XIX can also be obtained by etherification or alkylation of compounds of formula XVII compound of formula XX or a compound of formula XXI by reaction stage (o) using a suitable base such as potassium carbonate, sodium hydride, triethylamine, pyridine, etc. In the compound of formula XXI, Y include, but are not limited to, mesilate, tosyloxy, chlorine, bromine, iodine, etc. For the reaction stage (o), you can use any of the traditional conditions for the alkylation of the hydroxyl group of a halide or leaving group. Reaction stage (o) is preferred compared with the stage (n), if the compound of formula XXI readily available.

The compound of formula XIX is converted into a compound of formula XXIII by reaction stage (p) using a Wittig reaction by treating the compounds of formula XIX compound of formula XXII. For the reaction stage (p) you can use any traditional mode of interaction of the aldehyde with triarylphosphine hydrohalogenation. For the reaction stage (p), you can use any of the conditions traditionally used for the Wittig reaction. The product can be extracted and cleaned through methods such as extraction, evaporation, chromatog afia and recrystallization.

The compound of formula XXIII is converted into a compound of formula XXIV by reaction stage (q) by hydrogenation. The reaction is carried out using chlorotris(triphenylphosphine)rhodium (Wilkinson catalyst). The reaction is carried out in a suitable solvent, for example, absolute ethanol, and the like. For the reaction stage (q) can use any of the conditions conventional for these reactions. The product can be extracted and cleaned through methods such as extraction, evaporation, chromatography and recrystallization.

The compound of formula XXIV alkylate compound of formula III by reaction stage (r) to obtain the compounds of formula XXV. The reaction is carried out in a suitable solvent, such as tetrahydrofuran, tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H)-pyrimidinone, tetrahydrofuran/hexamethylphosphoramide, etc. In General, the reaction is carried out in the presence of from 2 to 3 molar equivalents of base to obtain the compounds of formula XXV, where R4is an alkyl with a number of carbon atoms from 1 to 3 and R5represents hydrogen, or from 4 to 6 molar equivalents of base to obtain the compounds of formula XXV, where R4and R5is an alkyl with a number of carbon atoms from 1 to 3. The traditional basis for this purpose may be a sodium hydride, potassium hydride, bis(trimethylsilyl)amide, potassium, bestemmelser)lithium amide, diisopropylamide lithium, etc. When carrying out this reaction, it is generally preferable to the use of alkali metal salts of hexamethyldisilane. The reaction is carried out at temperatures from -78°C to 25°C. Typically, the reaction takes from 6 to 72 hours. To clean the product, you can use traditional methods such as extraction, evaporation, chromatography and recrystallization.

The compound of formula XXV is a compound of formula I, where R1represents an alkyl group with the number of carbon atoms from 1 to 2. The compound of formula XXV can be converted to the free acid i.e. the compound of formula I, where R1represents H, by hydrolysis of ester. Any conventional method of hydrolysis of ester will give the compound of formula I, where R1represents H.

If A is a phenyl, substituted by 1 or 2 hydroxyl groups, usually preferred to protect the hydroxyl group of compounds of formula XVIII, a compound of formula XX and the compounds of formula XXI. Suitable protective group can be described in Protective Groups in Organic Synthesis by T. Greene.

The protective group can be removed using suitable reagents for removing the protective group, such as described in Protective Groups in Organic Synthesis by T. Greene.

The compound of formula II where m is 0, x is 0, q is 0, t is 0 is 1 if and n is 1 or 2, R3represents hydrogen, halogen, alkoxy with the number of carbon atoms from 1 to 3 or an alkyl with a number of carbon atoms from 1 to 3, and R1is an alkyl with a number of carbon atoms from 1 to 2, i.e. compounds of formula:

where A is the same as described above, can be obtained by the reaction scheme depicted in figure 4.

In the reaction scheme depicted in scheme 4, A, t, n, m, q, x, R1and R3are the same as described above. Y is a halide or leaving group.

The compound of formula XXVI is converted into a compound of formula II according to reaction stage (s) through the condensation on Mitsunobu XVIII XXVI using triphenylphosphine and diethylazodicarboxylate or diisopropylcarbodiimide. The reaction is carried out in a suitable solvent, e.g. tetrahydrofuran. For the reaction stage (s) you can use any of the conditions traditionally used in the reactions of Mitsunobu.

The compound of the formula II can also be obtained by esterification or alkylation of compounds of formula XXVI compound of formula XXI by reaction stage (s). In the compound of formula XXI Y include, but are not limited to, mesilate, tosyloxy, chlorine, bromine, iodine, etc. For the reaction stage (s) can be used any conventional method of etherification of a hydroxyl group with vzaimode istia with a halide or leaving group.

The compound of formula II where m is 0, x is 0, q is 1, t is 0 or 1 and n is 1 or 2, R2is an alkyl with a number of carbon atoms from 1 to 3, R3represents hydrogen, salt, alkoxy with the number of carbon atoms from 1 to 3 or an alkyl with a number of carbon atoms from 1 to 3, and R1is an alkyl with a number of carbon atoms from 1 to 2, i.e. compounds of formula:

where A is the same as described above, can be obtained by the reaction scheme depicted in scheme 5.

In the reaction scheme depicted in scheme 5, A, t, m, n, q, x, R1, R2and R3are the same as described above. Y1is a halide.

The compound of formula XXVII can be promutirovat with obtaining the compounds of formula XXVIII by the reaction of stage (t). For the reaction stage (t), you can use any of the conditions traditionally used in reactions metilirovaniya hydroxyl group. The compound of formula XXVIII is then heated with the compound of the formula XXIX obtaining the compounds of formula XXX. For the reaction stage (u) you can use any of the conditions traditionally used in obtaining aminoalcohols.

In the compound of formula XXX alcohol can be substituted by chlorine or bromine by reaction of compounds of formula XXX with oxalyl chloride, thionyl x is oredom, bromine, tribromide phosphorus, and the like to obtain the compounds of formula XX. For the reaction of stage (v) you can use any traditional method of substitution of alcohol with chlorine or bromine.

The compound of formula XX can enter into reaction with the compound of the formula XXVI by the reaction of stage (w) in the presence of a suitable base such as potassium carbonate, sodium hydride, triethylamine, pyridine and the like, the Reaction is carried out in a conventional solvent such as N,N-dimethylformamide, tetrahydrofuran, dichloromethane and the like, to obtain the corresponding compounds of formula II. For the reaction stage (w) can be used any conventional method of etherification of a hydroxyl group by chlorine or bromine in the presence of a base (this is the preferred base is a potassium carbonate).

If A is a phenyl, substituted by 1 or 2 hydroxyl groups, usually preferred to protect the hydroxyl group. Suitable protective group can be described in Protective Groups in Organic Synthesis by T. Greene.

The protective group can be removed using suitable reagents for removing the protective group, such as described in Protective Groups in Organic Synthesis by T. Greene.

The compound of formula XXVI, where m is 0, x is 0, R3represents hydrogen, halogen, alkoxy with the number of atoms of plastics technology : turning & the Yes from 1 to 3 or an alkyl with a number of carbon atoms from 1 to 3, and R1is an alkyl with a number of carbon atoms from 1 to 2, i.e. compounds of formula:

can be obtained by the reaction scheme depicted in scheme 6.

In the reaction scheme depicted in scheme 6, R1and R3are the same as described above. Y1is a halide.

The compound of formula XXXI can be restored to compounds of formula XXXII by reaction stage (x). The reaction is carried out using conventional reducing agent for example alkali metal hydride such as alumalite lithium. The reaction is carried out in a suitable solvent, such as tetrahydrofuran, etc. For the reaction stage (x) you can use any of the conditions conventional for these reactions recovery.

The compound of formula XXXII can be converted into a compound of formula XXXIII by substitution of hydroxyl group, halogen group, and the halogen is preferably bromine or chlorine. Suitable halogenation reagents include, but are not limited to, oxalyl chloride, thionyl chloride, bromine, tribromide phosphorus, tetrabromomethane etc. For the reaction stage (y) you can use any of the conditions conventional for these halogenation reactions.

The compound of formula XXXIII can be converted into a compound of formula XXXIV reaction XXXIII cyanide metal, n is the sample, the copper cyanide, sodium or potassium. The reaction is carried out in a suitable solvent such as N,N-dimethylformamide, ethanol, dimethylsulfoxide, etc. Any of the conditions traditionally used to obtain the nitrile can be used for the reaction stage (z).

The compound of formula XXXIV can be converted into a compound of formula XXXV by the reaction of stage (a') using acid or alkaline hydrolysis. When carrying out this reaction it is generally preferable to use alkaline hydrolysis, for example, aqueous sodium hydroxide. Any of the conditions traditionally used for the hydrolysis of NITRILES, can be used for the reaction stage (a').

The compound of formula XXXV can be converted into a compound of formula XXVI by the esterification of the compounds of formula XXXV with methanol or ethanol. The reaction may be carried out with the use of catalysts, for example, H2SO4, TsOH and the like, or with the use of dehydrating agents, e.g. dicyclohexylcarbodiimide and the like. For the reaction stage (b') you can use any of the conditions conventional for such reactions of esterification.

The compound of formula XVIII, where t is 0 or 1, n is 1 or 2, i.e. compounds of formula:

A-(CH2)t+n-OH

and the compound of formula XXI, where t is 0 or 1, n is 1 or 2, i.e. compounds fo the mules:

A-(CH2)t+n-Y

can be obtained by the reaction scheme depicted in scheme 7.

In the reaction scheme depicted in scheme 7, A is the same as described above. Y represents a leaving group.

The compound of formula XXXVI can be restored to the compounds of formula XXXVII by the reaction of stage (c'). The reaction is carried out using conventional reducing agent for example alkali metal hydride such as alumalite lithium. The reaction is carried out in a suitable solvent, such as tetrahydrofuran. Any of the conditions conventional for such reactions recovery, can be used for the reaction stage (c').

The compound of formula XXXVII is a compound of formula XVIII, where t is 0 and n is 1.

The compound of formula XXXVII can be converted into a compound of formula XXXVIII by replacement of the hydroxyl group, halogen group, and the halogen preferably represents bromine or chlorine. Suitable halogenation reagents include, but are not limited to, oxalyl chloride, thionyl chloride, bromine, tribromide phosphorus, tetrabromomethane etc. Any conditions conventional for these halogenation reactions, can be used for the reaction of stage (d').

The compound of formula XXXVIII is a compound of formula XXI, where t is 0 and n is 1.

The compound of formula XXXVIII, monoprinting in the compound of formula XXXIX by interaction XXXVIII with a metal cyanide, for example, copper cyanide, sodium or potassium. The reaction is carried out in a suitable solvent, such as ethanol, dimethyl sulfoxide and N,N-dimethylformamide, etc. Any of the conditions conventionally used in obtaining NITRILES, can be used for the reaction of stage (e').

The compound of formula XXXIX can be converted into a compound of formula XL by the reaction of stage (f') using acid or alkaline hydrolysis. In carrying out this reaction it is generally preferable to use alkaline hydrolysis, for example, aqueous sodium hydroxide. Any of the conditions conventionally used in the hydrolysis of NITRILES, can be used for the reaction of stage (f').

The compound of formula XL can be restored to the compounds of formula XLI in reaction stage (g'). This reaction can be performed in the same way as described earlier in this description for the reaction stage (c').

The compound of formula XLI is a compound of formula XVIII, where t is 1 and n is 1.

The compound of formula XLI can be converted into a compound of formula XIII by reaction stage (h') in the same way as described earlier in this description, when describing the reaction of stage (d').

The compound of formula XLII is a compound of formula XXI, where t is 1 and n is 1.

The compound of formula XXXVIII can be introduced into the reaction diethylmalonate using suitably is about Foundation, for example, sodium hydride, to obtain the compounds of formula XLIII. The reaction is carried out in suitable solvents, such as N,N-dimethylformamide, tetrahydrofuran, etc. Any of the conditions conventional for such alkylation reactions can be used for the reaction of stage (i').

The compound of formula XLIII can hydrolyze and decarboxylate using sodium hydroxide in a suitable solvent, such as ethanol-water to obtain the compounds of formula XLIV. Any of the conditions conventional for these reactions can be used for the reaction of stage (j').

The compound of formula XLIV can be converted into a compound of formula XLV by the reaction of stage (k') in the same way as described earlier in this description, when describing the reaction of stage (c').

The compound of formula XLV is a compound of formula XVIII, where t is 1 and n is 2.

The compound of formula XLV can be converted into a compound of formula XLVI by the reaction of stage (l') in the same way as described earlier in this description, when describing the reaction of stage (d').

The compound of formula XLVI is a compound of formula XXI, where t is 1 and n is 2.

If A is a phenyl, substituted by 1 or 2 hydroxyl groups, usually preferred to protect the hydroxyl group of formula XXXVI. Suitable protective group can be described in Protective Groups in Organic Snthesis by T. Greene.

The protective group can be removed using suitable reagents for removing the protective group, such as described in Protective Groups in Organic Synthesis by T. Greene.

Reaction scheme 7

The compound of formula XXXI, where R3represents a halogen, i.e. compounds of formula:

or commercially available, or can be obtained according to the methods described in the following sources:

The compound of formula XXXI, where R3represents alkoxy with the number of carbon atoms from 1 to 3, i.e. compounds of formula:

can be obtained by the reaction scheme depicted in scheme 8.

In the reaction scheme depicted in scheme 8, R1and R3are the same as described above. R6represents an alkyl group with the number of carbon atoms from 1 to 2. R8is an alkyl with a number of carbon atoms from 1 to 3. Y1is a halide.

The compound of formula XLVII can be converted into a compound of formula XLVIII recovery of the aldehyde to a primary alcohol. In carrying out this reaction it is preferable to use sodium borohydride as a reducing agent, but it is possible reductants are not limited only to them. Any of the conditions qualifying the data for reactions of recovery can be used for the reaction stage (m').

The compound of formula XLVIII can be converted into a compound of formula XLIX by the reaction of stage (n') by protecting 1-3 diols using 1,1,3,3-tetraisopropyldisiloxane. Suitable conditions for this protective group can be described in Protecting Groups in Organic Synthesis by T. Greene.

The compound of formula XLIX can be converted into a compound of formula L by the reaction of stage (o') by protecting the phenolic group of the benzyl bromide. Suitable conditions for this protective group can be described in Protecting Groups in Organic Synthesis by T. Greene.

The compound of formula L can be converted into a compound of formula LI by removing protection using tetrabutylammonium fluoride by the reaction of stage (p'). Suitable conditions for removing protection can be described in Protecting Groups in Organic Synthesis by T. Greene.

The compound of formula LI can be converted into a compound of formula LII by the reaction of stage (q') by oxidation. For the reaction stage (q') can be used any conventional oxidizing group, which converts primary alcohol to the acid, for example, chromium oxide, etc.

The compound of formula LII can be converted into a compound of formula LIII by the esterification of the compounds of formula LII methanol or ethanol. The reaction may be carried out with the use of catalysts, for example, H2SO4, TsOH and the like, or using dehydra arousih funds for example, dicyclohexylcarbodiimide and the like. For the reaction stage (r'), you can use any of the conditions conventional for such reactions of esterification.

The compound of formula LIII can be converted into a compound of formula LVI reaction stage (s') through the condensation on Mitsunobu LIII with LIV using triphenylphosphine and diethylazodicarboxylate or diisopropylcarbodiimide. The reaction can be carried out in a suitable solvent, e.g. tetrahydrofuran. For the reaction stage (s') you can use any of the conditions traditionally used in the reactions of Mitsunobu.

The compound of formula LIII can also be converted into the compound of formula LVI by esterification or alkylation of compounds of formula LIII compound of formula LV, as in the reaction stage (s'). The reaction is carried out using a suitable base such as potassium carbonate, sodium hydride, triethylamine, pyridine and the like, the Reaction is carried out in a conventional solvent such as N,N-dimethylformamide, tetrahydrofuran, dichloromethane and the like To the reaction stage (s') can be used any conventional method of etherification of a hydroxyl group by chlorine or bromine in the presence of a base (the base is preferably a potassium carbonate).

The compound of formula LVI can be converted into a compound of formulas is XXXI by removing protection from the ether and benzyl groups by the reaction of stage (t'). Suitable reagents for removing protection can be described in Protecting Groups in Organic Synthesis by T. Greene.

The compound of formula XXXI, where R3represents alkoxy with the number of carbon atoms from 1 to 3, i.e. compounds of formula:

or commercially available, or can be obtained in accordance with methods described in the following sources:

10. 2-OPr-5-OHC6H3CO2H and 2-OEt-5-OHC6H3CO2H

To adapt the synthesis described in US 6194406 (page 96)using propyliodide and ethyliodide.

11. 4-OPr-3-OHC6H3CO2H

To adapt the synthesis described in WO 9626176.

12. 2-OPr-4-OHC6H3CO2H

To adapt the synthesis described in Takeda Kenkyusho Nempo (1965), 24, 221-8, using propylgallate.

13. 4-OEt-3-OHC6H3CO2H

Biomedical Mass Spectrometry (1985), 12(4), 163-9.

14. 3-OPr-5-OHC6H3CO2H

To adapt the synthesis described in Taiwan Kexue (1996), 49(1), 51-56, using propylgallate.

The compound of formula XXXI, where R3is an alkyl with a number of carbon atoms from 1 to 3, i.e. compounds of formula:

or commercially available, or can be obtained in accordance with methods described in the following sources:

15. 2-n-Pr-5-OHC6H3CO2H

You can adapt the synthesis described in J.A.C.S (1974), 96(7), 2121-9 using ethyl alpha-formiller.

16. 3-n-Pr 4-OHC6H3CO2H

Polymer (1991), 32(11) 2096-105.

17. 2-n-Pr 4-OHC6H3CO2H

3-propylene you can promotionat 3-propellants, which was then formulirovalis to 4-methoxy-3-benzaldehyde. The aldehyde can oxidize the reagent Jones, getting the corresponding acid, and removing the protective methyl group using BBr3will give the target compound.

18. 1. 3-Et-5-OHC6H3CO2H and 3-Pr-n-5-OHC6H3CO2H

To adapt the synthesis described in J.O.C. 2001, 66, 7883-88 using 2-ethylacrolein and 2-profilekaley.

The compound of formula XVII, where R3represents hydrogen, halogen, alkoxy with the number of carbon atoms from 1 to 3 or an alkyl with a number of carbon atoms from 1 to 3, i.e. compounds of formula:

can be obtained by the reaction scheme depicted in scheme 9.

In the reaction scheme depicted in scheme 9, R3the same as described above. R6represents an alkyl group with the number of carbon atoms from 1 to 2, and P is a protective group.

The compound of formula LVII can be converted into a compound of formula LVIII by the reaction of stage (u') by protecting the hydroxy-group using appropriate protective the th group, such as described in Protecting Groups in Organic Synthesis by T. Greene.

The compound of formula LVIII can be converted into a compound of formula LIX by the reaction of stage (v') by restoring the acid to alcohol. The reaction can be conducted using conventional reducing agent for example alkali metal hydride such as alumalite lithium. The reaction can be carried out in a suitable solvent, such as tetrahydrofuran. Any of the conditions conventional for data recovery reactions, can be used for the reaction stage (v').

The compound of formula LIX can be converted into a compound of formula LX reaction stage (w') by oxidation of alcohol to aldehyde. The reaction can be performed using a suitable oxidant, for example, pyridinium chlorproma, dimethylsulfoxide, activated 2,4,6-trichloro[1,3,5]triazine (cyanuric chloride, TCT) under oxidizing conditions at Svernu (J.O.C. 2001, 66, 7907-7909), etc. Any of the conditions conventional for these oxidation reactions can be used for the reaction stage (w').

In the compound of formula LX, protection of the hydroxy-group can be removed from the reaction stage (x') using suitable reagents for removing protection, such as described in Protecting Groups in Organic Synthesis by T. Greene, obtaining the compounds of formula XVII.

The compound of formula XXII, where R1is sobieskiego group with the number of carbon atoms from 1 to 2 and p is equal to the number from 2 to 4, i.e. compounds of formula:

Ph3P+-(CH2)PCO2R1}Br-

can be obtained by the reaction scheme depicted in scheme 10.

In the reaction scheme depicted in scheme 10, R1and p are the same as described above.

The compound of formula LXI interacts with the compound of the formula LXII reaction stage (y') to obtain the compounds of formula XXII. Any of the conditions conventionally used in the interaction of triphenylphosphine with hydrohalogenation, can be used for the reaction stage (y').

The compound of formula LVII, where R6represents an alkyl group with the number of carbon atoms from 1 to 2 and R3represents halogen, alkoxy with the number of carbon atoms from 1 to 3 or an alkyl with a number of carbon atoms from 1 to 3, i.e. compounds of formula:

can be obtained by the reaction scheme depicted in scheme 11.

In the reaction scheme shown in scheme 11, R3and R6are the same as described above.

The compound of formula XXXI can be converted into a compound of formula LVII in reaction stage (z') by the esterification of the compounds of formula XXXI with methanol or ethanol. The reaction may be carried out with the use of catalysts, for example, H2SO4, TsOH and the like, or by using dehydrating means, e.g. the measures dicyclohexylcarbodiimide and the like. For the reaction stage (z') you can use any of the conditions conventional for such reactions of esterification.

USE IN METHODS of TREATMENT

This invention describes a method of treating a mammal with a condition selected from the group consisting of a syndrome of insulin resistance, diabetes (both primary main types of diabetes, such as type I diabetes or type II diabetes, secondary diabetes and polycystic ovary syndrome, comprising the administration to a mammal a number of biologically active products, as described herein, is effective for the treatment of this disease. In accordance with the method of the present invention can reduce a symptom of diabetes or the possibility of developing symptoms of diabetes, such as atherosclerosis, obesity, hypertension, hyperlipidemia, fatty liver infiltration, nephropathy, neuropathy, retinopathy, foot lesions and cataracts, every symptom relating to diabetes. The present invention also describes a method of treating hyperlipidemia, comprising the administration to a mammal a number of biologically active products, as described herein, is effective for the treatment of this disease. As shown in the examples, the data connection is of lower levels of triglycerides and free fatty acids in the serum of animals, patients with hyperlipidemia. The present invention also describes a method of treating cachexia comprising the administration to a mammal a number of biologically active products, as described herein, is effective for the treatment of cachexia. The present invention also describes a method of treating obesity comprising the administration to a mammal a number of biologically active products, as described herein, is effective for the treatment of this disease. The present invention also describes a method of treatment of a disease selected from atherosclerosis or arteriosclerosis, comprising the administration to a mammal a number of biologically active products, as described herein, is effective for the treatment of this disease. Active tool of the present invention is effective in the treatment of hyperlipidemia, fatty infiltration of the liver, cachexia, obesity, atherosclerosis or arteriosclerosis, regardless of, the subject suffers from diabetes or syndrome of insulin resistance. Means you can enter any traditional method of system administration. Preferably the agent is administered orally. Accordingly, it is preferable to produce the drug in a form suitable for oral administration. Other routes of administration, and the use of the present invention, include rectal, parenteral injection (e.g. intravenous, subcutaneous, intramuscular or intraperitoneal injection) or nasal.

Additional embodiments of each of the applications and methods of treatment of the present invention include the introduction of any of the embodiments described above biologically active agents. To avoid unnecessary redundancy, each such tool or group of tools is not repeated, but they are included in this description of the uses and methods of treatment, as if they were repeated.

Many of the diseases or disorders for which treatment is intended compounds of the present invention fall into two broad categories: the syndromes of insulin resistance and consequences of chronic hyperglycemia. The dysregulation of metabolism of energy-rich compounds, especially insulin resistance, which can occur in the absence of diabetes (chronic hyperglycemia) as such, is associated with many symptoms, including hyperlipidemia, atherosclerosis, obesity, hypertension, fatty infiltration of the liver (NASH; non-alcoholic steatohepatitis) and, especially in the context of cancer or systemic inflammatory disease, cachexia. Cachexia can also occur in conditions of type I diabetes or late stages of type II diabetes. For accounts which improve tissue metabolism of energy-rich compounds, active tool of the present invention is suitable for the prevention or mitigation of disease and symptoms associated with insulin resistance, as shown for animals in the examples. Despite the fact that one patient can be a group associated with insulin resistance signs and symptoms, in many cases can dominate only one symptom, due to individual differences in susceptibility of many physiological systems affected by insulin resistance. However, as insulin resistance makes the main contribution to many painful conditions, medicines for the treatment of cellular and molecular defects, suitable for the prevention or mitigation of virtually any symptom in any organ system, which can be a cause of insulin resistance or increases it.

When insulin resistance and the accompanying lack of insulin production by pancreatic islets expressed strongly, there is chronic hyperglycemia, which determines the beginning of diabetes mellitus type II (NIDDM). In addition to metabolic disturbances associated with the above insulin resistance in patients with NIDDM there are also secondary symptoms hyperglycemia. They include nephropathy, peripheral neuropa the Oia, retinopathy, capillary disease, ulceration of the extremities and the consequences of non-enzymatic glycolythiourea proteins, for example, damage to collagen and other connective tissue. The attenuation of hyperglycemia reduces the rate of occurrence and the severity of the consequences of diabetes. Since, as shown in the examples, the active means and compositions of the present invention help to reduce the hyperglycemia in diabetes, they are suitable for the prevention and mitigation of complications of chronic hyperglycemia.

In accordance with the method of treatment according to the present invention it is possible to treat both humans and other mammals. The optimal dose of a particular active means of this invention for a particular patient can be determined by a qualified physician in a clinical setting. In the case of oral administration to man for the treatment associated with insulin resistance disorders, diabetes, hyperlipidemia, fatty infiltration of the liver, cachexia or obesity, the tool is usually administered at a daily dosage of from 1 mg to 400 mg, with taking one or two times a day. In the case of oral administration mouse, this tool is usually administered at a daily dosage of from 1 to 300 mg money per kilogram of body weight. Active means according to this invention are used as monotherapy for diabetes or syndrome resistantanti the insulin, or in combination with one or more other medicines that are applied in these types of diseases, for example, releasename insulin, provalnymi releasename insulin, biguanides, or by insulin. Such additional drugs administered in accordance with standard clinical practice. In some cases, funds for this invention improves the effectiveness of other classes of drugs, making possible the introduction of a patients lower (and thus less toxic) doses of such funds with a satisfactory therapeutic results. The limits of safe and effective dose of the representative compounds for people are: Metformin - 500 up to 2550 mg/day; gliburid from 1.25 to 20 mg/day; GLUCOVANCE (combined drug Metformin and gliburida) from 1.25 to 20 mg/day gliburida and from 250 to 2000 mg/day of Metformin; atorvastatin 10 to 80 mg/day lovastatin from 10 to 80 mg/day; pravastatin 10 to 40 mg/day and simvastatin - 5-80 mg/day; clofibrate - 2000 mg/day; gemfibrozil from 1200 to 2400 mg/day rosiglitazone - 4 to 8 mg/day; pioglitazone 15 to 45 mg/day; acarbose - 75-300 mg/day; Repaglinide from 0.5 to 16 mg/day.

Diabetes mellitus type I: Patient with type I diabetes cope with the disease mainly through self-introduction from one to several doses of insulin per day, with frequent measurement level is glucose in the blood to ensure proper regulation of the dose and timing of insulin administration. Chronic hyperglycemia leads to complications, such as nephropathy, neuropathy, retinopathy, foot lesions and early mortality; hypoglycemia due to excessive doses of insulin may cause cognitive dysfunction or loss of consciousness. Patients with type I diabetes treated with from 1 to 400 mg/day active tool of the present invention, in the form of tablets or capsules in a single dose or in divided doses. The expected effect is a decrease in the dose or frequency of insulin required to maintain a satisfactory level of glucose in the blood, and reducing the frequency and severity of attacks of hypoglycemia. The outcome of the disease is monitored by measuring the level of blood glucose and glycosylated hemoglobin (match index glycemic control, are summarized for several months), and reducing the frequency of occurrence and severity of typical complications of diabetes. Biologically active substance according to the present invention can be entered in conjunction with transplantation of islets to contribute to the achievement of antidiabetic effect of transplanted islets.

Diabetes type II: the Typical patient with type II diabetes (NIDDM) copes with the disease using diet programs and exercises, as well as using a medication, such the AK Metformin, gliburid, Repaglinide, rosiglitazone or acarbose, each of which provides some improvement in glycemic control in some patients, but each of which has side effects or the risk of failure of treatment due to disease progression. Sometimes in patients with NIDDM observed failure of the islets, determining the need for insulin injections for a large percentage of patients. It is expected that daily treatment with the active agent of the present invention (together or separately from additional classes of antidiabetic drugs) will improve glycemic control, reduce the degree of rejection of islets and reduce the frequency of occurrence and severity of common symptoms of diabetes. In addition, active funds in this invention reduce elevated triglycerides and fatty acids in the serum, thereby reducing the risk of cardiovascular disease, the leading cause of death in patients with diabetes. As with all other therapies against diabetes, dose optimization is carried out for patients individually in accordance with the necessity, clinical effect and susceptibility to side effects.

Hyperlipidemia: Elevated levels of triglycerides and free fatty acids in the blood affect a significant percentage of the population, and Zn is a major risk factor for atherosclerosis and myocardial infarction. Active means according to this invention is suitable to reduce circulating triglycerides and free fatty acids in patients with hyperlipidemia. In patients with hyperlipidemia often there is also an increased level of cholesterol in the blood, which increases the risk of cardiovascular disease. Cholesterol drugs such as inhibitors of HMG-CoA reductase inhibitors (“statins”), you can enter the patients with hyperlipidemia in addition to the means for this invention, it is not necessarily included in the same pharmaceutical composition.

Fatty infiltration of the liver: a Significant number of the population affected with fatty infiltration of the liver, also known as nonalcoholic steatohepatitis (NASH; NASH often associated with obesity and diabetes. Hepatic steatosis, the presence of droplets of triglycerides with hepatocytes, predisposes the liver to chronic inflammation (identified in biopsy samples as infiltration of inflammatory leukocytes), which can lead to fibrosis and cirrhosis. Fatty infiltration of the liver is usually revealed by the observation of elevated blood levels of liver-specific enzymes such as transaminases ALT and AST, which are indicators of damage to the hepatocytes, and the presence of symptoms that include fatigue and pain in the liver, although the exact diagnosis is often required is : a biopsy. The expected benefit is a reduction of inflammation and liver fat content, leading to attenuation, termination or reversal of the progression of NASH in fibrosis or cirrhosis.

The PHARMACEUTICAL COMPOSITION

The present invention describes a pharmaceutical composition comprising a biologically active agent, as described herein, and a pharmaceutically acceptable carrier. Additional embodiments of the pharmaceutical compositions of the present invention contain one of the embodiments described above biologically active agents. To avoid unnecessary redundancy, each such tool or group of tools is not repeated, but they are included in this description of the uses and methods of treatment, as if they were repeated.

Preferably the composition is adapted for oral administration, for example, in the form of tablets, coated tablets, pills, hard or soft gelatine capsules, solutions, emulsions or suspensions. In General, the composition for oral administration contain 1 mg to 400 mg of such funds. For the patient it is convenient to swallow one or two tablets, coated tablets, pills or capsules a day. However, the composition can also be adapted for administration by any other conventional method of system introduction, including actally, for example, in the form of suppositories, parenterally, e.g. in the form of injection solutions or nasal.

Biologically active compounds can be treated pharmaceutically inert, inorganic or organic carriers for pharmaceutical compositions. For example, lactose, corn starch or its derivatives, talc, stearic acid or its salts etc can be used as such carriers for tablets, coated tablets, dragées and hard gelatin capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like, However, depending on the nature of the active ingredient, in the case of soft gelatin capsules usually do not need any other media, in addition to the soft gelatin. Suitable carrier materials for obtaining of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils, etc. are Suitable carriers for suppositories are, for example, natural or hydrogenated oils, waxes, fats, semi-liquid or liquid polyols and the like

Pharmaceutical compositions may also contain preservatives, soljubilizatory, stabilizers, moisturizers, emulsifiers, sweeteners, colorants, odorants, salts to change the osmotic Yes the population, buffer solutions, coatings, or antioxidants. They may also contain other therapeutically valuable substances, especially antidiabetic or lipid-lowering means, which act by mechanisms that are different from the mechanisms underlying the action of the compounds according to the present invention. Tools that can be usefully combined with the compounds according to this invention in one drug include, but are not limited to, biguanides, such as Metformin, relizer insulin, such as the sulfonylurea relizer insulin gliburid and other sulfonylurea relizer insulin, medications that lower cholesterol, such as “statin” inhibitors of HMG-CoA reductase inhibitor such as atorvastatin, lovastatin, pravastatin and simvastatin, PPAR-alpha agonists such as clofibrate, and gemfibrozil, PPAR-gamma agonists, such as preparations of thiazolidinediones (eg, rosiglitazone and pioglitazone), the alpha-glucosidase inhibitors such as acarbose (which inhibits the digestion of starch) and prandialno relizer insulin, such as Repaglinide. The amount of additional funds, combined with the compounds according to this invention in a single preparations correspond to the doses used in standard clinical practice. The limits of safe and effective dose for a specific REP the representative compounds listed above.

The invention will be better understood from the description of the following examples, which illustrate but do not limit the invention described in this specification.

EXAMPLES of CHEMICAL SYNTHESIS

Example 1

2-(3-(2,6-Dimethylsiloxy)phenyl)-2-metalicana acid

Stage A: Obtain ethyl 3-hydroxyphenylacetate:

A solution of 3-hydroxyphenylacetic acid (25 g, 164,31 mmol) and para-toluenesulfonic acid monohydrate (3,49 g, and 18.3 mmol) in absolute ethanol (260 ml) was boiled under reflux 4 hours or until until you react all of the original substance. The reaction mixture was concentrated, diluted with ethyl acetate and washed with water. The organic layer was dried over Na2SO4was filtered , concentrated and purified flash chromatography on a column of silica gel (hexane:ethyl acetate 2:1), obtaining specified in the header of the substance.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); 3,5 (s, 2H); 4,1 (square, 2H); of 6.6 to 7.2 (m, 4H).

Stage B: Obtain ethyl 3-(2,6-dimethylbenzylamine)phenylacetate:

A solution of 2,6-dimethylbenzyl alcohol (5,25 g, and 38.6 mmol) and diisopropylcarbodiimide (DIAD, 8,49 g, 42 mmol) in THF (30 ml) and DMF (13 ml) was added dropwise to a solution of ethyl 3-hydroxyphenylacetate (stage A, of 6.66 g, 37 mmol) and triphenylphosphine (11 g, 42 mmol) in THF (100 ml). The reaction mixture was stirred at room tempera is ur 4 hours, was diluted with ether and washed with water. The organic layer was dried over Na2SO4was filtered , concentrated and purified flash chromatography on a column of silica gel (hexane:ethyl acetate 4:1), obtaining specified in the header of the substance.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); 2,4 (s, 6H); 3,5 (s, 2H); 4,1 (square, 2H); to 5.1 (s, 2H); to 6.9 (m, 2H); 7,15-to 7.35 (m, 5H).

Stage C: Obtain ethyl 2-(3-(2,6-dimethylsiloxy)phenyl)-2-methyl acetate:

To a stirred solution of ethyl 3-(2,6-dimethylbenzylamine)phenylacetate (stage B, 4 g of 13.6 mmol) in dry THF (30 ml) at -68°C in an atmosphere of dry argon was added dropwise LiHMDS (1 M solution in THF, 17,45 ml of 17.4 mmol)and the resulting orange solution was stirred at low temperature for 30 min before it was added CH3I (5,71 g, 40,26 mmol). The reaction mixture was slowly heated to room temperature and stirred 15 hours. The reaction was suppressed by the ice and the product was extracted with EtOAc (2X), the organic phase is washed with saturated salt solution, dried over Na2SO4was filtered , concentrated and purified flash chromatography on a column of silica gel (hexane:ethyl acetate 5:1), obtaining specified in the header of the substance.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H), and 1.5 (t, 3H); 2,4 (s, 6H); 3,7 (m, 1H); 4,1 (square, 2H); 5,0 (s, 2H); to 6.9 (m, 2H); 7,15-to 7.35 (m, 5H).

Stage D: Obtain 2-(3-(2,6-dimethylsiloxy)phenyl)-2-metrokane acid:

To the mix is Astaro ethyl 2-(3-(2,6-dimethylsiloxy)phenyl)-2-methyl acetate (stage C, 3 g, 9.6 mmol) in absolute ethanol (60 ml) was added 1N NaOH (20 ml) at room temperature. The reaction mixture was stirred 3 hours, acidified to pH 3.5 to 4.0 with 1N HCl and concentrated. The residue was dissolved in chloroform and washed with 0,1N HCl, saturated salt solution, dried over Na2SO4was filtered , concentrated and purified flash chromatography on a column of silica gel (chloroform:methanol 95:5 with a drop of acetic acid), receiving specified in the header of the substance.

1H NMR (270 MHz, CDCl3receive: 1.5 (t, 3H); 2,4 (s, 6H); 3,7 (m, 1H); 5,0 (s, 2H); to 6.9 (m, 2H); 7,15-to 7.35 (m, 5H).

Example 2

2-(3-(2,6-Dimethylsiloxy)phenyl)-2-atelectasia acid

Stage A: Obtain ethyl 3-hydroxyphenylacetate

Specified in the title substance was obtained using the method described in example 1, step A.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); 3,5 (s, 2H); 4,1 (square, 2H); of 6.6 to 7.2 (m, 4H).

Stage B: Obtain ethyl 3-(2,6-dimethylbenzylamine)phenylacetate

Specified in the title substance was obtained using the method described in example 1, step C.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); 2,4 (s, 6H); 3,5 (s, 2H); 4,1 (square, 2H); to 5.1 (s, 2H); to 6.9 (m, 2H); 7,15-to 7.35 (m, 5H).

Stage C: Obtain ethyl 2-(3-(2,6-dimethylsiloxy)phenyl)-2-acetic acid ethyl ester

To a stirred solution of ethyl 3-(2,6-dimethylbenzylamine)phenylacetate (stage B, 4,84 g, 16,2 m is ol) in dry THF (60 ml) and HMPA (15 ml) at -78°C under argon atmosphere was added dropwise LDA (2 M solution in THF, 25 ml, 48,72 mmol) and the resulting orange solution was stirred at low temperature for 30 min before it was added CH3CH2I (10,13 g, 64,96 mmol). The reaction mixture was slowly heated to room temperature and stirred 15 hours. The reaction extinguished aqueous solution of citric acid and the product was extracted with EtOAc (2×), the organic phase is washed with saturated salt solution, dried over Na2SO4was filtered , concentrated and purified flash chromatography on a column of silica gel (hexane:ethyl acetate 4:1), obtaining specified in the header of the substance.

1H NMR (270 MHz, CDCl3): of 0.9 (t, 3H); 1,2 (t, 3H); 1.8 m (m, 1H); 2,1 (m, 1H)and 2.4 (s, 6H); 3,4 (t, 1H); 4,1 (square, 2H); 5,0 (s, 2H); to 6.9 (m, 2H); 7,15-7,30 (m, 5H).

Stage D: Obtain 2-(3-(2,6-dimethylsiloxy)phenyl)-2-ethyloctanoic acid

To a stirred solution of ethyl 2-(3-(2,6-dimethylsiloxy)phenyl)-2-acetic acid ethyl ester (stage C, 3,26 g, 10.0 mmol) in absolute ethanol (60 ml) was added 1N NaOH (20 ml) at room temperature. The reaction mixture was stirred 3 h, acidified with 1N HCl and concentrated. The residue was dissolved in chloroform and washed with 0,1N HCl, saturated salt solution, dried over Na2SO4was filtered , concentrated and purified flash chromatography on a column of silica gel (chloroform:methanol 95:5 with a drop of acetic acid), receiving specified in the header of the substance.

1H NMR (mg, CDCl3): of 0.9 (t, 3H); 1.8 m (m, 1H); 2,1 (m, 1H)and 2.4 (s, 6H); 3,4 (t, 1H); 5,0 (s, 2H); to 6.9 (m, 2H); 7,15-7,30 (m, 5H).

Example 3

3-(3-(2,6-Dimethylsiloxy)phenyl)-2-methylpropanoate acid

Stage A: Obtain ethyl 3-(3-hydroxyphenyl)propanoate

A solution of 3-hydroxyphenylpropionic acid (25 g, 150,60 mmol) and para-toluenesulfonic acid monohydrate (3.80 g, 20 mmol) in absolute ethanol (250 ml) was boiled under reflux 4 hours or until until you react all of the original substance. The reaction mixture was concentrated, diluted with ethyl acetate and washed with water. The organic layer was dried over Na2SO4was filtered , concentrated and purified flash chromatography on a column of silica gel (hexane:ethyl acetate 2:1), obtaining specified in the header of the substance.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); 2,6 (t, 2H); and 2.8 (t, 2H); 4,2 (square, 2H); 6,7-6,8 (m, 3H); to 7.2 (m, 1H).

Stage B: Obtain ethyl 3-(2,6-dimethylbenzylamine)phenylpropanoate

A solution of 2,6-dimethylbenzyl alcohol (7,71 g of 56.7 mmol) and diisopropylcarbodiimide (DIAD, 11,36 g, 56,18 mmol) in THF (30 ml) and DMF (13 ml) was added dropwise to a solution of ethyl 3-(3-hydroxyphenyl)propanoate (stage A, 10.0 g, 51,5 mmol) and triphenylphosphine (14,73 g, 56,18 mmol) in THF (100 ml) at 0°C. the Reaction mixture was stirred at room temperature for 4 h, diluted with ether and washed with water. The organic layer sushi and above Na 2SO4was filtered , concentrated and purified flash chromatography on a column of silica gel (hexane:ethyl acetate 4:1), obtaining specified in the header of the substance.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); 2,4 (s, 6H); 2,6 (t, 2H); 3,0 (t, 2H); 4,2 (square, 2H); to 5.1 (s, 2H); to 6.8 (m, 3H); 7,2-7,4 (m, 4H).

Stage C: Obtain ethyl 3-(3-(2,6-dimethylsiloxy)phenyl)-2-methylpropanoate

To a stirred solution of ethyl 3-(2,6-dimethylbenzylamine)phenylacetate (stage B, a 4.53 g, 14.5 mmol) in dry THF (30 ml) at -68°C in argon atmosphere was added dropwise LiHMDS (1 M solution in THF, to 21.77 ml, to 21.77 mmol)and the resulting orange solution was stirred at low temperature for 30 min before it was added CH3I (20,60 g, RUR 145.2 mmol). The reaction mixture was slowly heated to room temperature and stirred 15 hours. The reaction was suppressed by the ice and the product was extracted with EtOAc (2×), the organic phase is washed with saturated salt solution, dried over Na2SO4was filtered , concentrated and purified flash chromatography on a column of silica gel (hexane:ethyl acetate 5:1), obtaining specified in the header of the substance.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H), and 1.5 (t, 3H); 2,4 (s, 6H); of 2.51-of 2.58 (m, 1H); 2.71 to (DD, 1H); is 2.88 (DD, 1H); 4,2 (square, 2H); to 5.1 (s, 2H); to 6.9 (m, 3H); 7,2-7,4 (m, 4H).

Stage D: 3-(3-(2,6-dimethylsiloxy)phenyl)-2-methylpropanoic acid

To a stirred solution of ethyl 3-(3-(2,6-dimethylbenzylamine)FeNi is)-2-methylpropanoate (stage C, of 1.61 g, 4.9 mmol) in absolute ethanol (25 ml) was added 1N NaOH (10 ml) at room temperature. The reaction mixture was stirred 3 hours, acidified to pH 3.5 to 4.0 with 1N HCl and concentrated. The residue was dissolved in chloroform and washed with 0,1N HCl, saturated salt solution, dried over Na2SO4was filtered , concentrated and purified flash chromatography on a column of silica gel (chloroform:methanol 95:5 with a drop of acetic acid), receiving specified in the header of the substance.

1H NMR (270 MHz, CDCl3receive: 1.5 (t, 3H); 2,4 (s, 6H); of 2.51-of 2.58 (m, 1H); 2.71 to (DD, 1H); is 2.88 (DD, 1H); from 5.1 (s, 2H); to 6.9 (m, 3H); 7,2-7,4 (m, 4H).

In all examples, the biological activity of the following compounds CW received in accordance with the method of chemical synthesis of example 1.

EXAMPLES of BIOLOGICAL ACTIVITY

Example: Antidiabetic effect of compounds on CW db/db mice

Mouse db/db have a disturbance in the signal transmission leptin, leading to hyperphagia, obesity and diabetes. Moreover, unlike the ob/ob C57BL/6J and db/db mouse line C57BLKS feel the insufficiency of his insulinsensitive cells of pancreatic islets, resulting in progression of hyperinsulinemia (associated with peripheral insulin resistance) in hypoinsulinemic diabetes.

Obese males (db/db homozygous) C57BL/Ksola mice approximately 8 weeks of age b is obtained from Jackson Labs (Bar Harbor, ME) and randomly distributed into groups of 5-7 animals so that body mass (40-45 g) and glucose levels in serum (≥300 mg/DL after feeding) were approximately the same from group to group; not obese mouse male (db/+ heterozygous) acted as a control group. Adaptation period after allocation to groups was at least 7 days. All animals were kept under conditions of controlled temperature (23°C), relative humidity (50±5%) and light (7:00-19:00) and had unlimited access to standard food (Formulab Diet 5008, Quality Lab Products, Elkridge, MD) and water.

Mice were treated orally with daily doses of filler or connection CW for 2 weeks. At the end of the treatment period was selected 100 μl of venous blood in a heparinized capillary tube from the peri-orbital sinus for chemical analysis of serum. During sampling the blood of the mouse was in a state of feeding.

After 2 weeks of daily oral administration of the compound CW caused a significant decrease in the level of glucose in the blood (table 1). Similarly, the connection CW has reduced the level of triglycerides in blood serum (table 2).

Table 1
The act of bonding CW glucose in the blood and on the model db/db mice with type II diabetes
GroupGlucose mg/DL
Filler (control)735±66
Connection CW - 100 mg/kg171±66*
* p<0.05 is significantly different compared with the control group.

Table 2
The act of bonding CW on triglycerides
in the blood serum of db/db mice in the blood
GroupTriglycerides ± SEM (mg/DL)
Filler221±62
connection CW109±13

Example: the Effect of compounds on CW PPARα person

To study the effect of the compound on CW PPARα person was used the analysis of TRANS-activation. Analyses development using the modular domain structure of nuclear receptors. Got a hybrid protein of human or mouse binding domain of PPAR ligand (PPAR-LBD) and Gal4 DNA binding domain of yeast ("plasmid activator"). Construction of reporter gene consisted of Gal4 is NC connecting element in CIS-position to the luciferase reporter. When the agonist binds to Gal4/PPAR-LBD, a hybrid protein binds to Gal4 DNA binding element on the reporter gene, which leads to the transcription of the luciferase gene of the Firefly. Luciferase oxidizes the substrate luciferin in an ATP-dependent reaction; the amount of emitted light is a direct measure of the level of the enzyme and, consequently, the activity of ligand binding to PPAR-LBD.

Activator-expressing plasmids contained the Gal4 DNA-binding domain of yeast associated with binding and hinge domains (AA. 167-468) PPARα ligand person. Used reporter plasmid was a pFRLuc, which has a gene for Firefly luciferase under the control of the GAL4 UAS-containing promoter (Stratagene (La Jolla, CA).

One day before transfection cells were sown in 24-cell tablet with a density of 5×104-2×105cells/cell, depending on the cell type. The cells were transfectional using reagent Lipofectamine 2000 (Invitrogen (Calsbad, CA). Lipofectamine 2000 was added to 2.5 μl/cell) in a test tube containing 50 ál of Optimem medium. In the second test tube was added plasmid DNA at a ratio of 4:3 (reporter:activator); where necessary, DNA salmon sperm was replaced on the activator expressing plasmid with obtaining overall 0.8 µg DNA/cell. The obtained DNA was added to 50 μl of Optimem medium with onigen the m levels of serum without added serum).

Two of the resulting solution incubated at room temperature for 5 minutes, then combined. The combined solutions were incubated at room temperature for an additional 30 min for the formation of liposomal complex.

Cells were washed once with PBS and each well was added 100 μl transfectional mixture. The plates were incubated at 37°C in 5% CO2incubator for approximately 4 hours, with subsequent removal transfectional mixture and replace the medium on the medium with fresh (EMEM minimum essential medium Needle (Cambrex (East Rutherford, NJ)), to which was added 10% PBS and glutamine “EMEM complete”). 24 hours after transfection cells were treated with appropriate connections in full EMEM. After 24 hours after treatment cells were washed once with PBS and added reporter lyse buffer (Promega (Madison, WI)in the amount of 100 μl/cell. Cells were subjected to one cycle of freezing/thawing prior to analysis. About 10 μl of lysate was added to 100 μl of the substrate of Firefly luciferase.

The results show that PN2069 is a partial agonist of PPARα person (in the same experiment positive control Wy-14643 reached maximum activity ~40000 RLU). Cm. a drawing.

1. The use of biologically active products for the manufacture of a medicinal product for the treatment of a condition selected from the group consisting of Sindh the Ohm's resistance to insulin, diabetes, including type I diabetes and type II diabetes, and polycystic ovary syndrome; or to treat or reduce the likelihood of developing atherosclerosis, arteriosclerosis, obesity, hypertension, hyperlipidemia, fatty infiltration of the liver, nephropathy, neuropathy, retinopathy, ulceration of the feet or cataracts associated with diabetes; or for treating a condition selected from the group consisting of hyperlipidemia, cachexia, and obesity;
where the agent is a compound of the formula:

in which n is 1;
one of m and x is equal to 0, and the other is 0, 2 or 4;
q is 0;
t is 0;
R3represents hydrogen, halogen, alkyl with the number of carbon atoms from 1 to 3 or alkoxy with the number of carbon atoms from 1 to 3;
one of R4and R5represents methyl and the other represents hydrogen;
Rather it represents a 2,6-dimetilfenil; and
R1represents hydrogen or alkyl with 1 or 2 carbon atoms;
or, when R1represents hydrogen, a pharmaceutically acceptable salt of this compound.

2. The use according to claim 1, in which R3represents hydrogen.

3. The use according to claim 2, in which the biologically active agent is a 2-(3-(2,6-dimethylsiloxy)phenyl)-2-methyloxan acid.

4. The use according to any one of claims 1,2 or 3, in which Lech is the only means is in a form for oral administration.

5. A method of treating a mammal with a condition selected from the group consisting of a syndrome of insulin resistance, diabetes, polycystic ovary syndrome, hyperlipidemia, fatty infiltration of the liver, cachexia, obesity, atherosclerosis and arteriosclerosis comprising oral administration to a mammal a biologically active funds in the amount of from 1 to 400 mg / day, which represents a compound of the formula:

in which n is 1;
one of m and x is equal to 0, and the other is 0, 2 or 4;
q is 0;
t is 0;
R3represents hydrogen, halogen, alkyl with the number of carbon atoms from 1 to 3 or alkoxy with the number of carbon atoms from 1 to 3;
one of R4and R5represents methyl and the other represents hydrogen;
Rather it represents a 2,6-dimetilfenil; and
R1represents hydrogen or alkyl with 1 or 2 carbon atoms;
or, when R1represents hydrogen, a pharmaceutically acceptable salt of this compound.

6. The method according to claim 5, in which R3represents hydrogen.

7. The method according to claim 6, in which the biologically active agent is a 2-(3-(2,6-dimethylsiloxy)phenyl)-2-methyloxan acid.

8. The method according to any of PP-15, in which the subject is the man.

9. The method according to claim 5, in which sostenibilitat a syndrome of insulin resistance or type II diabetes.

10. The method according to claim 5, in which the treatment reduces a symptom of diabetes or the likelihood of developing symptoms of diabetes, where the symptom is selected from the group consisting of atherosclerosis, obesity, hypertension, hyperlipidemia, fatty infiltration of the liver, nephropathy, neuropathy, retinopathy, ulceration of the feet and cataracts associated with diabetes.

11. Pharmaceutical composition for use in treating a condition selected from the group consisting of a syndrome of insulin resistance, diabetes, polycystic ovary syndrome, hyperlipidemia, fatty infiltration of the liver, cachexia, obesity, atherosclerosis, arteriosclerosis, and adapted for oral administration containing a pharmaceutically acceptable carrier and from one milligram to four hundred milligrams of a biologically active products,
in which the tool is a compound of the formula:

in which n is 1;
one of m and x is equal to 0, and the other is 0, 2 or 4;
q is 0;
t is 0;
R3represents hydrogen, halogen, alkyl with the number of carbon atoms from 1 to 3 or alkoxy with the number of carbon atoms from 1 to 3;
one of R4and R5represents methyl and the other represents hydrogen;
Rather it represents a 2,6-dimetilfenil; and
R1represents hydrogen or alkyl with 1 or 2 carbon atoms;
and the and when R1represents hydrogen, a pharmaceutically acceptable salt of this compound.

12. The pharmaceutical composition according to claim 11, in which R3represents hydrogen.

13. The pharmaceutical composition according to item 12, in which the biologically active agent is a 2-(3-(2,6-dimethylsiloxy)phenyl)-2-methyloxan acid.

14. The pharmaceutical composition according to any one of § § 11-13 dosage form for oral administration.

15. Biologically active agent, where the agent is a compound of the formula:

in which n is 1;
one of m and x is equal to 0, and the other is 0, 2 or 4;
q is 0;
t is 0;
R3represents hydrogen, halogen, alkyl with the number of carbon atoms from 1 to 3 or alkoxy with the number of carbon atoms from 1 to 3;
one of R4and R5represents methyl and the other represents hydrogen;
Rather it represents a 2,6-dimetilfenil; and
R1represents hydrogen or alkyl with 1 or 2 carbon atoms;
or, when R1represents hydrogen, a pharmaceutically acceptable salt of this compound.

16. Biologically active substance according to item 15, in which R3represents hydrogen.

17. Biologically active substance according to item 15, which represents a 2-(3-(2,6-dimethylsiloxy)phenyl)-2-m is TELEXPO acid.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to cardiology, endocrinology, and can be used for normalising the blood microvesicle level in impaired glucose tolerance. That is ensured by graduated physical activity, and administration of metformin 500 mg twice a day. The therapeutic course is at least 5 weeks.

EFFECT: offered combination of therapeutic modalities enables normalising the blood microvesicle level in a relatively short time that promotes prevention of thrombotic complications in the case patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to gerontology, endocrinology, and can be used for pathologically raised biological age reduction in the patients with abdominal obesity. That is ensured by prescription of efficient graduated static and dynamic physical activity, daily swimming in a pool for not less than 30 minutes a day, and also administration of metformin in dosage 850 mg twice a day. The therapeutic course is 7 weeks.

EFFECT: offered combination of the modalities enables to adjust the biological and chronological ages that improves quality of life in the case patients.

2 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology, and can be used for normalisation of adenosine diphosphate and adenosine triphosphate thrombocyte secretion activity in the patients with arterial hypertension and impaired glucose tolerance. That is ensured by graduated physical activities, daily swimming in a pool for at least 20 minutes a day, and also prescribed metformin 500 mg twice a day and lisinopril 10 mg once a day in the morning.

EFFECT: combination of therapeutic modalities enables rapid normalisation of adenosine diphosphate and adenosine triphosphate thrombocyte secretion activity that promotes prevention of thrombotic complications in the case patients.

9 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to cardiology, endocrinology, and can be used for normalising the blood α2 antiplasmin concentration in arterial hypertension and impaired glucose tolerance. That is ensured by graduated physical activities, daily swimming in a pool for at least 20 minutes a day, and also prescribed metformin 500 mg twice a day and lisinopril 10 mg once a day at regular hours in the morning. The therapeutic course is 1 months.

EFFECT: offered combination of therapeutic modalities enables normalising the blood α2 antiplasmin level in a relatively short time that promotes prevention of thrombotic complications in the case patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to cardiology, endocrinology, and can be used for normalising the blood plasminogen activator inhibitor concentration in arterial hypertension and impaired glucose tolerance. That is ensured by graduated physical activities, daily swimming in a pool for at least 20 minutes a day, and also prescribed metformin 500 mg twice a day and lisinopril 10 mg once a day in the morning. The therapeutic course is 1 months.

EFFECT: offered combination of therapeutic modalities enables normalising the blood plasminogen activator inhibitor in a relatively short time that promotes prevention thrombotic complications in the case patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely, to endocrinology, and deals with treatment of diabetes mellitus. For this purpose into abdomen hypodermic cellular tissue of recipient introduced is injection composition, including bio-degradable gel-containing matrix and cell suspension of primary culture of patient's pancreatic islet tissue.

EFFECT: method ensures normalisation of glucose level in blood for a long time period due to recovery of function of patient's pancreatic islet tissue.

5 cl, 2 tbl

FIELD: medicine.

SUBSTANCE: invention belongs to medicine, notably, to gerontology, cardiology and can be used for pathologically raised biologic age in patients with arterial hypertension. To achieve this, rationally dosed static and dynamic physical exercises are administered, daily swimming in swimming pool at least 30 minutes daily and 10 mg of lisinopril daily in the morning. Course of treatment is 7 weeks.

EFFECT: combination of treatment methods ensures equalisation of biologic and chronologic ages, thus improving quality of life in this group of patients.

2 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to hematology, cardiology, endocrinology, and can be used for optimisation of functional reactivity of cardiovascular system (CVS) in patients with arterial hypertension with metabolic syndrome and heart failure of I-IIA stage. For this purpose, first, state of CVS functional reactivity at physicoemotional load is estimated. Systolic, diastolic, average dynamic (APavdyn.), heart rate (HR) are registered. On the basis of obtained parametres index of functional reactivity (IFR) before and after load is determined by formula IFR=(APavdyn.x HR)/100 (SU). Treatment is administered if IFR value increment is more than 20 SU. Treatment combines individually selected hypocaloric diet, daily swimming in swimming pool for not less than 15 minutes per day, morning hygienic gymnastics, therapeutic and preventive gymnastics and doing subdivided physical exercise during the day, and intake of valsartan 80 mg in the morning one time per day and pioglitazone 30 mg in the morning one time. Treatment duration is not less than 3 months.

EFFECT: method allows to diagnose failure of functional CVS reactivity, and combination of claimed methods of treatment allows to correct it efficiently, which favours prevention of complications of arterial hypertension with metabolic syndrome and heart failure of I-IIa stage.

2 ex

FIELD: medicine.

SUBSTANCE: invention can be used for optimising functional responsiveness of the cardiovascular system (CVS) in the elderly and senile patients suffering abdominal obesity and impaired glucose tolerance. That is ensured by estimating the state of functional responsiveness of the CVS in psychoemotional load. And systolic, diastolic, average dynamic pressure (BPav.dyn) and heart rate (HR) are recorded. These data are used to evaluate a functional responsiveness index (FRI) before and after load by formula: FRI=(BPav.dyn. × HR)/100 (standard units). The incrementing FRI more than by 20 standard units requires a therapy to be prescribed. The therapy combines individually prescribed low-calorie diet, daily swimming in a pool for at least 15 minutes a day, morning hygienic gymnastics, therapeutic gymnastics and graduated physical exercises throughout a day, and also administration of telmisartan 40 mg in the morning. The length of treatment is at least 3 weeks.

EFFECT: method allows for well-timed diagnosis of the impaired functional responsiveness of the CVS, and combination of the presented modalities ensures the effective correction to prevent complications of arterial hypertension with abdominal obesity and impaired glucose tolerance in the case patients.

2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology, cardiology and endocrinology, and concerns short-term optimisation of hyperfibrinogenemia in arterial hypertension and impaired glucose tolerance. That is ensured by the integrated treatment including graduated physical activity, daily swimming in a pool for at least 20 minutes, and introduction of metformin in dosage 500 mg 2 times a day and lisinopril in dosage 10 mg once a day at the same time in the morning for 1 month.

EFFECT: such complex drug-induced and drug-free therapy combined with empirically prescribed treatment length provides short-term normalisation of fibrinogen level and thereby reduced risk of thrombotic complications in the given group of the patients due to potentiation of therapeutic effect of separate components of an individual care.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein Q together with carbon and nitrogen atoms whereto attached forms a 5-6-members monocyclic heteroaromatic ring; or Q together with carbon and nitrogen atoms whereto attached forms a 9-10-members bicyclic heterocycle; R1 and R2 independently mean hydrogen, halogen, alkyl, alkyl substituted by one or more halogen, alkoxygroup, alkoxygroup substituted by alkoxygroup, alkylthiogroup, sulphonyl, free or etherified carboxygroup, carbamoyl, sulohamoyl, morpholinyl or pyridinyl; or R2 is absent; R3 means (C3-C6)cycloalkyl; R4 means hydrogen, halogen, lower alkyl or lowest alkyl substituted by one or more halogen; R5 means (C3-C6cycloalkyl, (C6-C10) aryl, (C3-C10)heterocyclyl or (C1-C6)alkyl optionally substituted by (C1-C6)alkoxygroup, (C3-C7)cycloalkyl, (C6-C10)aryl or (C3-C10)heterocyclyl; R6 means free or etherified carboxygroup; and n is an integer equal to 1-6; or to its enanthiomer, or a mixture of its enanthiomers, or its pharmaceutically acceptable salt. Besides, the invention refers to a method of glucokinase activation in mammals, to a method of treating pathological conditions associated with glucokinase activation in mammals and impaired glucose tolerance, as well as to a pharmaceutical composition based on these compounds and to application of said compositions for preparing a drug.

EFFECT: there are produced and described new compounds which are activators and can be used as therapeutic agents for treating the glucokinase mediated pathological conditions.

31 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound having structure

, radicals are as described in the formula of invention, as well as pharmaceutically-acceptable salt, prodrug, tautomer and stereoisomer thereof. The invention also relates to a composition, a set for modulating PPAR based on said compound, a method of treating a patient suffering from a disease or condition or at risk of a disease or condition, for which PPAR modulation is therapeutically useful.

EFFECT: novel compounds which are active towards PPAR are obtained and described.

41 cl, 622 ex, 8 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula

where X represents OR1, SR1 or NR1R2 where R1 and R2 independently represent C1-C5 lower alkyl, and R1 and R2 in NR1R2 can form a 5-7-members ring including an O heteroatom; or to its stereoisomer, to a pharmaceutically acceptable salt, hydrate or solvate. Besides, the invention refers to a method for making thereof and to a based pharmaceutical composition exhibiting DPP-IV inhibitor activity.

EFFECT: new compounds which can find application in medicine for prevention or treatment of the DPP-IV associated diseases, such as diabetes or obesity are produced.

12 cl, 1 tbl, 2 dwg, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention aims at a pharmaceutical composition in the form of a clear solution or a water mixture, a suspension or a semisolid composition containing at least one peptide compound of water solubility more than 1 mg/ml at room temperature and pH value within 4.0 to 6.0 selected from the group consisting of hGLP-1 (7-36)-NH2, as well as its analogues and derivatives, hGLP-1 (7-37)-OH, as well as its analogues and derivatives and/or exendin-4, as well as its analogues and derivatives, zinc and a solvent where less than 95 % of said peptide compound are dissolved by the solvent.

EFFECT: invention provides a long-term effect of the preparation with lower initial plasma concentrations.

20 cl, 1 dwg

FIELD: medicine.

SUBSTANCE: invention relates to field of pharmacology, medicine and food industry and deals with medicine for reduction of visceral fatty tissue accumulation, which contains compounds of formula or extract of plant Liliaceae, which includes these compounds, application of said compounds or extracts for inhibition of visceral fatty tissue accumulation as well as product on their basis.

EFFECT: invention insures efficient reduction of visceral fatty tissue accumulation.

19 cl, 2 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmacology and is intended for extension of nomenclature of herbal medications for treatment of diabetes mellitus. Medication, representing bog bilberry shoots, demonstrates activation of glucose absorption by ischemic brain in treatment of type II diabetes mellitus. Studies were Indices of glucose-tolerant test at initial level, 30, 60, 120 minutes after glucose loading, as well as level of glucosuric activity. At the background of experimental DM utilisation of glucose by ischemic brain was determined by arterial-venous difference.

EFFECT: obtained results substantiate possibility of bog bilberry shoots application in clinic.

1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmacology and is intended for extension of nomenclature of herbal medications for treatment of diabetes mellitus (DM). Studied are properties of Vaccinium axillare Nakai shoots, Far East plant, which had not been studied before. Glucose-tolerant test, made on male rats of Wistar line with weight 200-220 g, showed reliable hypoglycemic and glucosuric action of Vaccinium axillare Nakai shoots. Hypoglycemic effect of Vaccinium axillare Nakai is also confirmed in experiment on alloxan diabetes model. It has been established that newly studied plant activates glucose utilisation by brain, aggravated by angiopathy, at the background of alloxan diabetes.

EFFECT: obtained results indicate that Vaccinium axillare Nakai shoots have hypoglycemic and glucosuric effect and that new object has advantage in comparison with Vaccinium myrtillus due to more expressed hypoglycemic action and ability to activate glucose utilisation by brain in case of DM.

1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): where: A is a monocyclic or polycyclic aryl or heteroaryl group, where the heteroaryl radical denotes a 5-10-member cyclic system containing at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N; optionally substituted with one or more substitutes independently selected from a group comprising halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, C1-4alkoxy and a hydroxyl group; B is a monocyclic nitrogen-containing heteroaryl group, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from S and N; optionally substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, aryl and C1-8alkylthio; either a) R1 is a group of formula: -L-(CR'R")n-G, where L is a binding group selected from a group consisting of a direct bond, -(CO)-, -(CO)NR'- and -SO2-; R' and R" is independently selected from hydrogen atoms; n assumes values from 0 to 1; and G is selected from a group consisting of a hydrogen atom and C1-4alkyl, aryl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O, S and N; C3-8cycloalkyl and saturated heterocyclic groups, where heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one or two carbon atoms are substituted with a N heteroatom; where alkyl, C3-8cycloalkyl, aryl or heteroaryl groups are unsubstituted or substituted with one or more substitutes selected from halogen atoms; and R2 is a group selected from hydrogen atoms, halogen atoms and C1-4alkyl, C2-5alkynyl, C1-4alkoxy, -NH2 and cyano groups, where alkyl and alkynyl groups may be unsubstituted or substituted with one aryl group; or b) R2, R1 and -NH- group to which R1 is bonded form a group selected from groups of formulae and , where: Ra is selected from a hydrogen atom or groups selected from C1-4alkyl, C3-8cycloalkyl, aryl, aryl-C1-4alkyl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O and N; saturated heterocyclic rings, where the heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one carbon atom is substituted with a heteroatom selected from O and N; and C1-4alkylthio; where the aryl or heteroaryl groups are unsubstituted or substituted with one or more groups selected from halogen atoms, cyano group, trifluoromethoxy and carbamoyl; Rb denotes hydrogen; and pharmaceutically acceptable salts thereof and N-oxides; provided that the compound is not selected from N-[6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, and N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]formamide. The invention also relates to a pharmaceutical composition, use of compounds in any of claims 1-20, a method of treating a subject, as well as a composite product.

EFFECT: obtaining novel biologically active compounds having adenosine A2B receptor antagonist activity.

27 cl, 160 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: described are compounds of formula I , where R1 and R2, together with carbon atoms Ca and Cb to which they are bonded, form or R3, R5, R6 and R7 independently denote hydrogen, C1-C6alkyl or C3-C8cycloalkyl; and R4 denotes 2,2-dimethylpropyl, 3-methylbutyl, isopropyl, tert-butyl, cyclopropylmethyl, cyclopentylmethyl, 3,3-dimethylbutyl or 1-cyclopropyl-1-methylethyl. The invention also relates to pharmaceutically acceptable salts of such compounds and pharmaceutical compositions containing such compounds of salts thereof. The disclosed compounds and compositions are capable of inhibiting activity of the 11-β-hydroxysteroid dehydrogenase 1 (11-β-HSD1) enzyme.

EFFECT: possibility of using derivatives for treating and preventing diabetes, obesity, eating disorders, dyslipidaemia and hypertension.

22 cl, 1 tbl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof where R1 and R2 together denote a group selected form groups of formula (III-1): , where R9 denotes 1) a lower alkyl group, optionally substituted with a halogen atom or lower alkoxy group, 2) an aryl group, 3) an aralkyl group, 4) a heteroarylalkyl group, 5) a heteroaryl group, where the aryl, aralkyl, heteroarylalkyl and heteroaryl groups can be substituted with a halogen atom, lower alkyl group, optionally substituted with a lower alkoxy group or 1-3 halogen atoms, lower alkoxy group, optionally substituted with 1-3 halogen atoms, cyano group, hydroxy group, alkylsulphonyl group, cycloalkylsulphonyl group, aryl group, heteroaryl group, alkylaminocarbonyl group, alkanoyl amino group, alkyl amino group or dialkylamino group; R10 denotes a lower alkyl group, optionally substituted with 1-3 halogen atoms, or a lower alkylsulphonyl group; X9-X12 denotes a carbon atom or a nitrogen atom, where the carbon atom can be independently substituted with a lower alkyl group, optionally substituted with a halogen atom or a lower alkoxy group, lower alkoxy group, optionally substituted with a halogen atom, or a cyano group or a halogen atom; R3 denotes a) a group of formula (II-1): (ii-U where R4 and R5, taken together with a nitrogen atom, form a 5- or 6-member monocyclic ring, where the monocyclic ring may contain a substitute in form of a lower alkyl group, m1 equals 3; or b) a group of formula (II-2): , where R6 denotes a lower alkyl group or cycloalkyl group; m2 equals 1 or 2; X1-X4 all denote carbon atoms, or one of X1-X4 denotes a nitrogen atom and the rest denote carbon atoms; and where "heteroaryl" in each case relates to a 5- or 6-member aromatic ring containing 1-3 heteroatoms selected from a nitrogen atom, oxygen atom and a sulphur atom. The invention also relates to a histamine H3 receptor antagonist or inverse agonist, as well as a preventive or medicinal agent.

EFFECT: obtaining novel biologically active compounds, having histamine H3 receptor antagonist or inverse agonist activity.

11 cl, 8 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to bioadhesive carrier for mucous membranes with delayed release of active component. Carrier contains primary granules, which include active component, 1-75 wt % of diluting agent 1-10 wt % of alkyl sulfate of alkaline metal and 0.5-5 wt % of binding substance, as well as 5-80 wt % of bioadhesive polymer, selected from group including natural polymers, said natural polymers represent polysaccharides, natural proteins of animal or vegetable origin, or synthetic polymers and 5-80 wt % of polymer, ensuring delayed release of active component, carrier does not contain lactose and corn starch. Said carrier ensures delivery of active component during long period, constituting more than 20 hours.

EFFECT: invention relates to method of obtaining bioadhesive carrier and to its application for treatment of mucous membrane diseases.

33 cl, 7 dwg, 2 tbl, 13 ex

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