Compound for treating metabolic disorders

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the chemical-pharmaceutical industry, and represents using a biologically active agent for preparing a drug for metabolic disorders specified in a group consisting of insulin resistance syndrome and diabetes mellitus, including type I diabetes mellitus and type II diabetes mellitus, and obesity, wherein the agent represents a compound of formula

,

wherein n=1 or 2; m=0, 1, 2, 4 or 5; q=0; t=0 or 1; R3 represents hydrogen; A is phenyl, unsubstituted or substituted by 1 or 2 alkyls having 1 or 2 carbon atoms; and R1 is hydrogen or alkyl having 1 or 2 carbon atoms; or when R1 represents hydrogen - a pharmaceutically acceptable salt of the compound.

EFFECT: preparing the drug for metabolic disorders.

18 cl, 6 ex, 22 tbl

 

Diabetes mellitus represents one of the major causes of morbidity and mortality. Chronically elevated levels of glucose in the blood leads to depriving disability complications: nephropathy, often requiring dialysis or a kidney transplant; peripheral nephropathy; retinopathy leading to blindness; ulceration of the lower limbs and feet, leading to amputation; fatty infiltration of the liver, sometimes progressing to cirrhosis; and vulnerability to coronary artery disease and myocardial infarction.

There are 2 primary types of diabetes. Diabetes mellitus type I, or insulin-dependent diabetes mellitus (IDDM), is caused by autoimmune destruction of producing insulin by beta cells in the pancreatic islets. This disease usually begins in childhood or adolescence. Treatment consists primarily of multiple daily insulin injections in combination with frequent testing of glucose levels in the blood to guide the selection of doses of insulin because excess insulin may cause hypoglycemia and subsequent brain damage and other functions.

Diabetes type II or non-insulin dependent diabetes mellitus (NIDDM)usually develops in adulthood. NIDDM is associated with resistance utilizing glucose tissues like adipose tissue, muscle and liver to action is Sulina. Initially, the beta cells of the pancreatic islets is compensated by the excessive secretion of insulin. The ultimate failure of the islets occurs as a result of decompensation and chronic hyperglycemia. On the contrary, moderate deficiency Islands may precede or coincide with peripheral insulin resistance. There are several classes of drugs that can be used for the treatment of NIDDM: 1) means, releasing insulin, which directly stimulate the release of insulin, causing hypoglycemia risk; 2) the means, releasing insulin when eating foods that increase insulin secretion induced by glucose and should be taken before each meal; 3) biguanides, including Metformin, which weaken hepatic gluconeogenesis (which paradoxically increases in diabetes); 4) insulin sensitizers, such as derivative thiazolidinedione rosiglitazone and pioglitazone, which improve peripheral responsiveness to insulin, but which have side effects such as weight gain, edema, and sometimes toxic effect on the liver; 5) insulin injections, which are often necessary in the later stages of NIDDM, when developing the failure of the islets in conditions of chronic overstimulation.

The insulin resistance m which can also occur without severe hyperglycemia, and in General, it is associated with atherosclerosis, obesity, hyperlipidemia and essential hypertension. This group of pathologies is "metabolic syndrome" or "syndrome of resistance to insulin". Resistance to insulin is also associated with fatty infiltration of the liver, which can progress to chronic inflammation (NASH; "non-alcoholic steatohepatitis), fibrosis and cirrhosis. Cumulative syndromes of resistance to insulin, including, but not limited to, diabetes, underlie many of the major causes of illness and death in people aged over 40 years.

Despite the existence of these drugs, diabetes remains a major and growing public health concern. Complications of late-stage diabetes consume most of the resources of the national health. There is a need for new active when administered therapeutic tools that effectively directed to primary defects of resistance to insulin and islet failure with fewer or milder side effects than existing drugs.

Currently there is no safe and effective treatments for diseases due to fatty infiltration of the liver. Therefore, this treatment should be valuable when Leche is the research Institute of the state.

WO 02/100341 (Wellstat Therapeutic Corp.) discloses 4-(3-2,6-dimethylsiloxy)phenyl)butyric acid. WO 02/100341 not disclose any compounds within the scope of the following formula I, in which m=0, 1, 2, 4, or 5.

The invention relates to biologically active agent, as described below. This invention relates to the use of biologically active agent as described below, in the manufacture of medicinal products for the treatment of the syndrome of resistance to insulin, diabetes, cachexia, hyperlipidemia, diseases due to fatty infiltration of the liver, obesity, atherosclerosis or arteriosclerosis. This invention relates to a method of treatment of a mammal with the syndrome of resistance to insulin, diabetes, cachexia, hyperlipidemia, disease due to fatty infiltration of the liver, obesity, atherosclerosis or arteriosclerosis, comprising an introduction to the individual an effective amount of a biologically active agent as described below. The present invention relates to pharmaceutical compositions comprising a biologically active agent, described below, and a pharmaceutically acceptable carrier.

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

The formula I

where n=1 or 2; m=0, 1, 2, 4, or 5; q=0 and and 1; t=0 or 1; R2represents alkyl having from 1 to 3 carbon atoms; R3represents hydrogen, halogen, alkyl having from 1 to 3 carbon atoms, or alkoxygroup having from 1 to 3 carbon atoms;

Rather it represents a phenyl, unsubstituted or substituted 1 or 2 groups selected from halogen, alkyl having 1 or 2 carbon atoms, performative, alkoxygroup having 1 or 2 carbon atoms, and performatce; or cycloalkyl having from 3 to 6 ring carbon atoms, where cycloalkyl is unsubstituted or one or two ring carbon is independently monogamist the stands or ethyl; or a 5 - or 6-membered heteroaromatic ring having 1 or 2 ring heteroatoms selected from N, S and O and the heteroaromatic ring is covalently linked to the rest part of the compounds of formula I, the carbon ring; and R1represents hydrogen or alkyl having 1 or 2 carbon atoms. Alternatively, when R1represents hydrogen, a biologically active agent may be a pharmaceutically acceptable salt of the compounds of formula I.

The biologically active agents described above have activity in one or more assays of biological activity described below, which represent accepted experimental model of diabetes mellitus in humans and sink the mA resistance to insulin. Therefore, such agents could be used in the treatment of diabetes mellitus and syndrome of resistance to insulin. All of the illustrated compounds that were tested showed activity in at least one of the assays of biological activity in which they were tested.

Definition

Used in the present description, the term "alkyl" means a linear or branched alkyl group. An alkyl group that is identified as having a certain number of carbon atoms refers to any alkyl group having a certain number of carbons. For example, alkyl having 3 carbon atoms, may represent propyl or isopropyl; and alkyl having 4 carbon atoms, may represent an n-butyl, 1-methylpropyl, 2-methylpropyl or tert-butyl.

Used in the present description, the term "halogen" means fluorine, chlorine, bromine and iodine.

Used in the present description, the term "PERFLUORO"as in performative or performatce, means that the group is fluorine atoms instead of hydrogen atoms.

Used in the present description, the term "AC" refers to a group of CH3C(O)-.

Certain chemical compounds specified in the present description are shown below with their chemical names or two-letter code. Connect the t to CF CM, included in the range of formula I shown above.

BI4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxomalonate acid
W4-[[4-(2,6-dimethylsiloxy)-3-methoxy]phenyl]-4-oxomalonate acid
BU4-[3-[[N-(4-trifloromethyl)aminocarbonyl]-4-methoxy]phenyl]-4-oxomalonate acid
BV4-[3-[[N-(2,6-dimethylbenzyl)aminocarbonyl]-4-methoxy]phenyl]-4-oxomalonate acid
CA(2,6-dimethylbenzylamine)benzene
CB3-(3-(2,6-dimethylsiloxy)phenyl)-3-oxopropionate bromide
SS3-(3-(2,6-dimethylsiloxy)phenyl)-4-oxobutyrate
CD5-(3-(2,6-dimethylsiloxy)phenyl)-5-oxopentanoic acid
CE5-(3-(2,6-dimethylsiloxy)phenyl)butyric acid
CF3-(2,6-dimethylbenzylamine)phenylacetic acid
CG3-(2,6-dimethylbenzylamine)benzoic acid
SN3-(2,6-dimethylbenzylamine)of ethyl benzoate
CI6-[3-(2,6-dimethylsiloxy)phenyl]hexanoic acid
CJ6-[3-(2,6-dimethylsiloxy)phenyl]hexanoate ethyl
SK5-[3-(2,6-dimethylsiloxy)phenyl]pentane acid
CL5-[3-(2,6-dimethylsiloxy)phenyl]pentanoate ethyl
CM3-[3-(2,6-dimethylsiloxy)phenyl]propionic acid
CN3-[3-(2,6-dimethylsiloxy)phenyl]propanoate ethyl

Used in the present description, the term "comprising" is unlimited. The claim that use of this term may contain elements in addition to items set forth in such claim.

Compounds of the invention

In one embodiment, the agent, use, method or pharmaceutical composition described above, n=1; q=0; t=0; R3represents hydrogen and a represents a phenyl, unsubstituted or substituted 1 Il the 2 groups, selected from halogen, alkyl having 1 or 2 carbon atoms, performative, alkoxygroup having 1 or 2 carbon atoms, and performatce. In a more specific embodiment, And represents a 2,6-dimetilfenil. Examples of such compounds include 3-(2,6-dimethylbenzylamine)phenylacetic acid; 3-(2,6-dimethylbenzylamine)benzoic acid; 3-(2,6-dimethylbenzylamine)benzoate ethyl; 6-[3-(2,6-dimethylsiloxy)phenyl]hexanoic acid; 6-[3-(2,6-dimethylsiloxy)phenyl]hexanoate ethyl; 5-[3-(2,6-dimethylsiloxy)phenyl]pentane acid; 5-[3-(2,6-dimethylsiloxy)phenyl]pentanoate ethyl; 3-[3-(2,6-dimethylsiloxy)phenyl]propionic acid and 3-[3-(2,6-dimethylsiloxy)phenyl]propanoate ethyl.

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

Schema reactions

The biologically active agent of the present invention can be obtained in accordance with the following schemes reactions.

The compound of formula I, where m=0-2, q=0, t=0 or 1 and n=1 or 2, R3represents hydrogen, halogen, alkoxygroup having from 1 to 3 carbon atoms, or alkyl having from 1 to 3 carbon atoms, and R1represents hydrogen or alkoxygroup having 1 to 2 carbon atoms, i.e. compounds of the formula

where a has the meaning given above, can be obtained by reaction scheme I.

In reaction scheme I, A, t, n, m and R3have the meanings given above. R4represents an alkyl group having 1 to 2 carbon atoms, and Y represents a leaving group.

The compound of formula II is converted to the compound of formula V by reaction stage (a) using a condensation Mitsunobu II and III using triphenylphosphine and azodicarboxylate of diethyl or azodicarboxylate diisopropyl. The reaction is carried out in a suitable solvent, e.g. tetrahydrofuran. For the reaction stage (a) you can use any of the conditions commonly used in reactions of Mitsunobu.

The compound of the formula V can also be obtained by etherification or alkylation of the compounds of formula II with compound of formula IV, in accordance with stage (a). In the compound of formula IV Y include, but are not limited to, mesilate, tosyloxy, chlorine, bromine, iodine and the like. For the reaction stage (a) can be used any conventional method of etherification of a hydroxyl group interaction with the leaving group.

The compound of formula V is a compound of formula I, in which R1represents an alkyl group having 1 to 2 carbon atoms. The compound of formula V can be converted into St. the free acid, i.e. the compound of formula I, where R1represent H, hydrolysis of ester. Any conventional method of hydrolysis of ester will give the compound of formula I, where R1represents N.

The reaction according to scheme 1

The compound of formula I, where m=3-5, q=0, t=0 or 1 and n=1 or 2, R3represents hydrogen, halogen, alkoxygroup having from 1 to 3 carbon atoms, or alkyl having from 1 to 3 carbon atoms, and R1represents hydrogen or alkyl having from 1

to 2 carbon atoms, i.e. compounds of the formula

where a has the meaning given above, can be obtained by reaction scheme 2.

In reaction scheme 2 A, t, n, m, R1and R2have the above specified values. R4represents alkyl having 1 to 2 carbon atoms, p=1-3 and Y is a leaving group.

The compound of formula VI is converted to the compound of formula VII by reaction stage (b) using a condensation Mitsunobu VI to III using triphenylphosphine and azodicarboxylate of diethyl or azodicarboxylate diisopropyl. The reaction is carried out in a suitable solvent, e.g. tetrahydrofuran. For the reaction stage (b) you can use any of the conditions commonly used in reactions of Mitsunobu.

Link the formula VII can also be obtained by etherification or alkylation of the compounds of formula VI, a compound of formula IV by reaction stage (C) using a suitable base, such as potassium carbonate, sodium hydride, triethylamine, pyridine and the like. In the compound of formula IV Y includes, but is not limited to, mesilate, tosyloxy, chlorine, bromine, iodine and the like. For the reaction stage (C) you can use any of the usual conditions for the alkylation of the hydroxyl group of a halide or leaving group. Reaction stage (C) is preferable to stage (b), if the compound of formula IV is easily accessible.

Compound of formula VII is converted to the compound of formula IX by reaction stage (d) alkylation of compounds of formula VII, a compound of formula VIII. This reaction is carried out in the presence of an approximately molar equivalent of a conventional Foundation that converts acetophenone in complex 3-ketoester (i.e. complex gamma ketoester). When carrying out this reaction in General it is preferable to use alkali metal salts of hexamethyldisilane, such as bis(trimethylsilyl)amide, lithium and the like, but the conditions of the reaction is not limited to this. In General, this reaction is carried out in inert solvents, such as tetrahydrofuran: 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. In General, the reaction is carried out at temperatures from -65°C to 25°C. For the reaction of stage (d) you can use any of the conditions normally used in such alkylation reactions.

The compound of formula X is converted to the free acid by hydrolysis of ester. Any conventional method of hydrolysis of ester will give the compound of formula IX, where R1represents N.

The compound of formula IX is converted to the compound of formula X by reaction stage (e) recovery ketogroup group SN2. The reaction is carried out by heating the compounds of formula IX with hydrazine hydrate and a base, such as KOH or NaOH in a suitable solvent, such as ethylene glycol. When carrying out this reaction in General it is preferable to use KOH as base, but the conditions of the reaction is not limited to this. For the reaction of stage (e) you can use any of the conditions normally used in the reaction wolf-Kishner. The compound of formula X is a compound of formula I, where R1represents N.

In the compound of formula X acid can be converted into ester, i.e. a compound of formula I, where R1represents alkyl having 1 to 2 carbon atoms by esterification of the acid using a catalyst, for example, H2SO4, TsOH and the like, or by using dehydrating agents, for example, dicyclohexylcarbodiimide and similar in ethanol or methanol. To obtain the compounds of formula I, where R1represents alkyl having 1 to 2 carbon atoms, you can use any normal in the conditions in such esterification reactions.

Reaction scheme 2

The compound of formula I, where q=1, R2represents an alkyl group having from 1 to 3 carbon atoms, m=3-5, t=0 or 1 and n=1 or 2, i.e. compounds of the formula

where a has the meaning given above, R1represents hydrogen or alkyl having 1 to 2 carbon atoms, R3represents hydrogen, halogen, alkoxygroup having from 1 to 3 carbon atoms, or alkyl having from 1 to 3 carbon atoms, can be obtained by reaction scheme 3.

In reaction scheme 3 t, n, A, R1, R3and R2have the meanings given above. R4represents an alkyl group having 1 to 2 carbon atoms. Y represents chlorine or bromine and p=1-3.

The compound of formula XI can be mailroute to obtain the compounds of formula XII by reaction stage (f). For stage (f) you can use any standard conditions for the reaction of metilirovaniya hydroxyl group. Then the compound of formula XII is heated with the compound of the formula XIII to obtain the compounds of formula XIV. For the reaction of stage (g) you can use any of the conditions normally used to obtain amerosport.

In the compound of formula XIV alcohol can be substituted by chlorine or bromine by processing the connection is of formula XIV chloride tonila, bromine and tribromide phosphorus and the like to obtain the compounds of formula XV. For the reaction of stage (h) you can use any normal way to replace alcohol with chlorine or bromine.

The compound of formula XV can interact with the compound of the formula VI by reaction stage (i) in the presence of a suitable base such as potassium carbonate, sodium hydride, triethylamine and the like. The reaction is carried out in conventional solvents such as dimethylformamide, tetrahydrofuran and the like, to obtain the corresponding compound of formula XVI. For the reaction of stage (i) can be used any conventional method of etherification of a hydroxyl group in the presence of a base (preferably the base is potassium carbonate) with chlorine or bromine.

The compound of formula XVI can be converted into a compound of formula XVII by reaction stage (j) alkylation of compounds of formula XVI, a compound of formula VIII. This reaction is carried out in the presence of an approximately molar equivalent of a suitable base, such as hexamethyldisilane lithium. This reaction is carried out in the same manner as described in connection with the reaction of stage (d) scheme 2.

The compound of formula XVII can be converted into the free acid by hydrolysis of ester. Any conventional method of hydrolysis of ester will give compounds is their formula XVII, where R1represents N.

The compound of formula XVII can be converted into a compound of formula XVIII by reaction stage (k) restoring geography group SN2. The reaction can be carried out by heating the compounds of formula XVII with hydrazine hydrate and a base, such as KOH or NaOH, in a suitable solvent, such as ethylene glycol. When carrying out this reaction in General it is preferable to use KOH as base, but the condition for carrying out the reaction is not limited to this. For the reaction of stage (k), you can use any of the conditions normally used in the reaction wolf-Kishner.

The compound of formula XVIII is a compound of formula I, where R1represents N.

In the compound of formula XVIII acid can be converted into ester, i.e. a compound of formula I, where R1represents alkyl having 1 to 2 carbon atoms by esterification of the acid with the use of catalysts, for example, H2SO4, TsOH and the like, or by using dehydrating substances, such as dicyclohexylcarbodiimide and others like him, in ethanol or methanol. To obtain the compounds of formula I, where R1represents alkyl having 1 to 2 carbon atoms, it is possible to use any conventional conditions for such reactions of esterification.

Reaction schemes is 3

The compound of formula I, where m=0-2, q=1, t=0 or 1 and n=1 or 2, R3represents hydrogen, halogen, alkoxy having from 1 to 3 carbon atoms, or alkyl having from 1 to 3 carbon atoms, and R1represents alkyl having 1 to 2 carbon atoms, i.e. compounds of the formula

where a has the meaning given above, can be obtained by the reaction shown in scheme 4.

In reaction scheme 4 t, n, A, R3and R2have the meanings given above. R4represents an alkyl group having 1 to 2 carbon atoms. Y represents chlorine or bromine.

The compound of formula XV (obtained in the same manner as described in reaction scheme 3) can interact with the compound of the formula II by reaction stage (l) in the presence of a suitable base such as potassium carbonate, sodium hydride, triethylamine and the like. The reaction can be carried out in conventional solvents, such as dimethylformamide, tetrahydrofuran, dichloromethane and the like, to obtain the corresponding compound of formula XIX. For the reaction of stage (l) you can use any normal conditions of esterification of the hydroxyl group in the presence of a base (preferably the base is carbon is potassium) with chlorine or bromine.

The compound of formula XIX is a compound of formula I, where R1represents an alkyl group having 1 to 2 carbon atoms. The compound of formula XIX can be converted to the free acid i.e. the compound of formula I, where R1represent H, hydrolysis of ester. Any conventional method of hydrolysis of ester will give the compound of formula I, where R1represents N.

Reaction scheme 4

The compound of formula III, where t=0 or 1, n=1 or 2, i.e. compounds of the formula

A(CH2)t+n-OH,

where a has the meaning given above, can be obtained by reaction scheme 5.

In the reaction according to scheme 5 A has the meaning given above and Y represents a leaving group.

The compound of formula XX can be restored to the compound of formula XXI by reaction stage (m). The reaction is carried out using conventional reducing substances, for example, alkali metal hydride, such as sociallyengaged. The reaction is carried out in a suitable solvent, such as tetrahydrofuran. For the reaction of stage (m) you can use any of the conditions conventional in such reactions recovery.

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

The compound of formula XX can be converted into a compound of formula XXII by substitution of the hydroxyl group by halogen, moreover, the preferred halogen is bromine or chlorine. The corresponding halide reagents include thionyl chloride, bromine, tribromide phosphorus, tetrabromide carbon and the like, but are not limited to. For the reaction of stage (n) you can use any of the conditions conventional in such halogenation reactions.

The compound of formula XXII is a compound of formula IV where t=0 and n=1.

The compound of formula XXII can be converted into a compound of formula XXIII interaction XXII with an alkali metal cyanide such as sodium cyanide or potassium. The reaction is carried out in a suitable solvent, such as dimethylsulfoxide. For the reaction stage (a) you can use any of the conditions usually used in the preparation of nitrile.

The compound of formula XXIII can be converted into a compound of formula XXIV by reaction stage (b) by hydrolysis of the acid or base. When carrying out this reaction in General it is preferable to use basic hydrolysis, such as aqueous sodium hydroxide. For the reaction stage (b) you can use any of the conditions usually used in the hydrolysis of the nitrile.

The compound of formula XXIV can be restored to obtain the compounds of formula XXV by reaction stage (q). This reaction can be conducted in the same manner as described above in reaction stage (m).

Connection fo the mules XXV is a compound of formula III, where t=1 and n=1.

The compound of formula XXV can be converted into a compound of formula XXVI via reaction stage (r) in the same manner as described above in reaction stage (n).

The compound of formula XXVI is a compound of formula IV where t=1 and n=1.

The compound of formula XXVI can interact with malonates of diethyl using a suitable base such as sodium hydride, to obtain the compounds of formula XXVII. The reaction is carried out in suitable solvents, such as dimethylformamide, tetrahydrofuran and the like compounds. For the reaction stage (s) you can use any of the conditions conventional in such alkylation reactions.

The compound of formula XXVII can be gidrolizirovanny acid or base to obtain the compounds of formula XXVIII via reaction stage (t).

The compound of formula XXVIII can be converted into a compound of formula XXIX via reaction stage (u) in the same way as described previously for the reaction of stage (m).

The compound of formula XXIX is a compound of formula III, where t=1 and n=2.

The compound of formula XXVIX can be converted into a compound of formula XXX by reaction stage (v) in the same manner as previously described in connection with the reaction of stage (n). The compound of formula XXX is a compound of formula IV where t=1 and n=2.

Reaction scheme 5

The compound of formula II, where m=0, R4represents an alkyl group having 1 to 2 carbon atoms, and R3represents halogen, alkoxygroup having from 1 to 3 carbon atoms, or alkyl having from 1 to 3 carbon atoms, i.e. compounds of the formula

can be obtained by reaction scheme 6.

In the reaction according to scheme 6 R1represents N. R3and R4have the above values.

In the compound of formula XXXI R1represents N. The compound of formula XXXI can be converted into a compound of formula II by reaction stage (w) esterification of the compounds of formula XXXI with methanol or ethanol. The reaction can be conducted or with the use of catalysts, for example, H2SO4, TsOHand the like, or by using dehydrating agents, for example, dicyclohexylcarbodiimide and the like. For the reaction stage (w) you can use any of the conditions conventional in such esterification reactions.

Reaction scheme 6

The compound of formula VI, where R3represents halogen, alkoxygroup having from 1 to 3 carbon atoms, or alkyl having from 1 to 3 carbon atoms, i.e. compounds of the formula

you can get through the eacli scheme 7.

In reaction scheme 7 m=0, and R1represents N, and R3represents halogen, alkoxygroup having from 1 to 3 carbon atoms, or alkyl having from 1 to 3 carbon atoms.

In reaction scheme 7 m=0. Reaction scheme 7 is similar to the way George M. Rubottom et al., J. Org. Chem. 1983, 48, 1550-1552.

Reaction scheme 7

The compound of formula II, where m=1-2, R4represents an alkyl group having 1 to 2 carbon atoms, and R3represents halogen, alkoxygroup having from 1 to 3 carbon atoms, or alkyl having from 1 to 3 carbon atoms, i.e. compounds of the formula

can be obtained by reaction scheme 8.

In reaction scheme 8 R1represents H, R3represents halogen, alkoxygroup having from 1 to 3 carbon atoms, or alkyl having from 1 to 3 carbon atoms, R4represents an alkyl group having 1 to 2 carbon atoms, and R5represents a group protecting the hydroxy-group.

The compound of formula II where m=0, can be transformed into a compound of formula XXXII by stage (y) of the first protection of the hydroxy-group by using appropriate protective groups, such as groups, described in the publication by T. Greene, Protecting Groups in Organic Synthesis, and then removing the protecting group of ester guy is rolison of ester. Any conventional method of hydrolysis of ester will give the compound of formula XXXII, where R1represents N.

The compound of formula XXXII can be restored to the compounds of formula XXXIII with a conventional reducing agent, which turns the acid into alcohol by the reaction of stage (z). When carrying out this reaction, in General, preferably using sociallyengaged, but the conditions of the reaction is not limited to this. The reaction is carried out in a suitable solvent, such as tetrahydrofuran and similar compounds. For the reaction stage (z) you can use any of the conditions conventional in such reactions recovery.

The compound of formula XXXIII can be converted into a compound of formula XXXIV by substitution of hydroxy-group halogen, preferably is bromine or chlorine. Appropriate halogenation reagents include, but are not limited to, chloride tonila, bromine, tribromide phosphorus, tetrabromide carbon and the like. For the reaction stage (a') you can use any of the conditions conventional in such halogenation reactions.

The compound of formula XXXIV can be converted into a compound of formula XXXV interaction XXXIV with an alkali metal cyanide such as sodium cyanide or potassium. The reaction is carried out in a suitable solvent, such as dimethylsulfoxide. Sprovedene reaction stage (b') can be used in any conditions usually used in the preparation of NITRILES.

The compound of formula XXXV can be converted into a compound of formula XXXVI by reaction stage (c') by hydrolysis of the acid or base. When carrying out this reaction in General it is preferable to use basic hydrolysis, such as aqueous sodium hydroxide. For the reaction stage (C') you can use any of the conditions conventional for hydrolysis of the nitrile.

The compound of formula XXXVI can be converted into a compound of formula XXXVII by the reaction of stage (d') removing the group protecting the hydroxy-group, using suitable removing the protecting reagents, such as reagents described in the publication by T. Greene, Protecting Groups in Organic Synthesis.

The compound of formula XXXVII can be converted into a compound of formula II, where m=1, and R4represents an alkyl group having from 1 to 2 carbon atoms by esterification of compounds of formula XXXVII with methanol or ethanol. This reaction can be performed or the use of catalysts, for example, H2SO4, TsOH and the like, or by using dehydrating means, such as dicyclohexylcarbodiimide, and the like. For the reaction, you can use any of the conditions conventional in such esterification reactions.

The compound of formula XXXIV can interact with diethylmalonate with suitable founded the I, for example sodium hydride, to obtain the compounds of formula XXXVIII. The reaction is carried out in suitable solvents, such as dimethylformamide, tetrahydrofuran and the like. For the reaction of stage (e'), you can use any of the conditions conventional in such alkylation reactions.

The compound of formula XXXVIII can be subjected to hydrolysis with an acid or a base and removing group protecting the hydroxy-group, using suitable removing the protecting reagents, such as reagents described in the publication by T. Greene, Protecting Groups in Organic Synthesis, to obtain the compounds of formula XXXIX by the reaction of stage (f').

The compound of formula XXXIX can be converted into a compound of formula II, where m=2, and R4represents an alkyl group having from 1 to 2 carbon atoms by esterification of compounds of formula XXXIX with methanol or ethanol. This reaction can be performed or the use of catalysts, for example, H2SO4, TsOH and the like, or by using dehydrating agents, such as dicyclohexylcarbodiimide, and the like. For the reaction, you can use any of the conditions conventional in such esterification reactions.

Reaction scheme 8

The compound of formula XXXI, where m=0, R1represents N, and R1represents a halogen, i.e. compounds fo the mules

represent or those that are commercially available or which can be obtained in accordance with methods described in the literature, and represent the following connections:

1. 3-Br, or F-2-OHC6H3CO2H

Canadian Journal of Chemistry (2001), 79(11) 1541-1545.

2. 4-Br-2-OHC6H3CO2H

WO 9916747 or JP 04154773.

3. 2-Br-6-OHC6H3CO2H

JP 47039101.

4. 2-Br, 3-OHC6H3CO2H

WO 9628423.

5. 4-Br-3-OHC6H3CO2H

WO 2001002388.

6. 3-Br-5-OHC6H3CO2H

Journal of labelled Compounds and Radiopharmaceuticals (1992), 31 (3), 175-82.

7. 2-Br-5-OHC6H3CO2H 3-Cl-4-OHC6H3CO2H

WO 9405153 and US 5519133.

8. 2-Br-4-OHC6H3CO2H and 3-Br-4-OHC6H3CO2H

WO 20022018323

9. 2-Cl-6-OHC6H3CO2H

JP 06293700

10. 2-Cl-3-OHC6H3CO2H

Proceedings of the Indiana Academy of Science (1983), Volume date 1982, 92, 145-51.

11. 3-Cl-5-OHC6H3CO2H

WO 2002000633 and WO 2002044145.

12. 2-Cl-5-OHC6H3CO2H

WO 9745400.

13. 5-I-2-OHC6H3CO2H and 3-I, 2-OHC6H3CO2H

Z. Chem. (1976), 16(8), 319-320.

14. 4-I-2-OHC6H3CO2H

Journal of Chemical Research, Synopses (1994), (11), 405.

15. 6-I-2-OHC6H3CO2H

US 4932999.

16. 2-I-3-OHC6H3CO2H and 4-I-3-OHC6H3CO2H

WO 9912928.

17. 5-I-3-OHC6H CO2H

J. Med. Chem. (1973), 16(6), 684-7.

18. 2-I-4-C6H3CO2N

Collection of Czechoslovak Chemical Communications (1991), 56(2), 459-77.

19. 3-I-4-C6H3CO2,

J.O.C. (1990), 55(18), 55287-91.

The compound of formula XXXI, where m=0, R1represents N, and R3is alkoxygroup having from 1 to 3 carbon atoms, and the phenyl ring is substituted, as shown below:

can be synthesized through reaction scheme 9.

The reaction according to scheme 9 R1and R3have the meanings indicated above, and R4represents an alkyl group having 1 to 2 carbon atoms.

The compound of formula XL can be converted into a compound of formula XLI recovery of the aldehyde to a primary alcohol. When carrying out this reaction, preferably using sodium borohydride as a reducing reagent, but the reaction conditions are not limited to this. For the reaction of stage (g'), you can use any of the conditions suitable in such reactions recovery.

The compound of formula XLI can be converted into a compound of formula XLII via the reaction of stage (h') protection 1-3 diols using 1,1,3,3-tetraisopropyldisiloxane. Suitable conditions for this protective group can be described in a publication by T. Greene, Protecting Groups in Organic Synthesis.

The connection f is rmula XLII can be converted into a compound of formula XLIII by the reaction of stage (i') the protection of the phenolic group using benzyl bromide. Suitable conditions for this protective group can be described in a publication by T. Greene, Protecting Groups in Organic Synthesis.

The compound of formula XLIII can be converted into a compound of formula XLIV with unprotect using tetrabutylammonium fluoride by the reaction of stage (j'). Suitable conditions for removing protection can be described in a publication by T. Greene, Protecting Groups in Organic Synthesis.

The compound of formula XLIV can be converted into a compound of formula XLV through the reaction stage (k') by oxidation. For the reaction of stage (k') can be used with any conventional oxidizing group, which converts primary alcohol to the acid, for example chromium oxide and the like.

The compound of formula XLV can be converted into a compound of formula XLVI esterification of the compounds of formula XLV with methanol or ethanol. This reaction can be performed or the use of catalysts, for example, H2SO4, TsOH and the like, or by using dehydrating agents, for example, dicyclohexylcarbodiimide and the like. For the reaction of stage (l') you can use any of the conditions conventional in such esterification reactions.

The compound of formula XLVI can be converted into a compound of formula XLVII esterification or alkylation of the compounds of formula XLVI with a methyl halide or halide ethyl or propyl halide suitable about the reasons, for example, potassium carbonate, sodium hydride and the like. The reaction is carried out in conventional solvents such as tetrahydrofuran, dimethylformamide. The reaction is in General carried out at temperatures from 0°C to 40°C. For the reaction of stage (m') you can use any of the conditions suitable in such alkylation reactions.

The compound of formula XLVII can be converted into a compound of formula XLVIII removing the protecting group of ester and benzyl groups. Suitable conditions to remove protection can be described in a publication by T. Greene, Protecting Groups in Organic Synthesis.

Reaction scheme 9

The compound of formula XXXI, where m=0, R1represents N, and R3is alkoxygroup having from 1 to 3 carbon atoms, i.e. compounds of the formula

and represent, or those that are commercially available or which can be obtained in accordance with methods described in the literature, and represent the following connections:

1. 2-OMe-4-C6H3CO2N

US 2001034343 or WO 9725992.

2. 5-OMe-3-OHC6H3CO2H

J.O.C (2001), 66(23), 7883-88.

3. 2-OMe-5-OHC6H3CO2H

US 6194406 (Page 96) and the Journal of the American Chemical Society (1985), 107(8), 2571-3.

4. 3-OEt-5-OHC6H3CO2H

Taiwan Kexue (1996), 49(1), 51-56.

5. 4-0Et-3-OHC6H3CO2H

WO 9626176

6. 2-OEt-4-OC 6H3CO2H

Takeda Kenkyusho Nempo (1965), 24, 221-8.

JP 07070025.

7. 3-OEt-4-OHC6H3CO2H

WO 9626176.

8. 3-Org-2-C6H3CO2N

JP 07206658, DE 2749518.

9. 4-OPr-2-OHC6H3CO2H

Farmacia (Bucharest) (1970), 18(8), 461-6.

JP 08119959.

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

To adapt the synthesis of U.S. patent 6194406 (pp.96) using propyl iodide and ethyl iodide.

11. 4-Org-3-C6H3CO2N

To adapt the synthesis of WO 9626176

12. 2-OPr-4-OHC6H3CO2H

To adapt the synthesis of Takeda Kenkyusho Nempo (1965), 24, 221-8 using propylchloride.

13. 4-OEt-3-OHC6H3CO2H

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

14. 3-Org-5-C6H3CO2H

To adapt the synthesis of Taiwan Kexue (1996), 49(1), 51-56 using propylchloride.

The compound of formula XXXI, where m=0, R1represents N, and R3represents alkyl having from 1 to 3 carbon atoms, i.e. compounds of the formula

represent or those that are commercially available or which can be obtained in accordance with methods described in the literature, and represent the following connections:

1. 5-Me-3-OHC6H3CO2H 2-Me-5-OHC6H3CO2H

WO 9619437.

J.O.C. 2001, 66,7883-88.

2. 2-Me-4-OHC6H3CO2

WO 8503701.

3. 3-E-2-C6H3CO2H and 5-Et-2-OHC6H3CO2H

J. Med. Chem. (1971), 14(3), 265.

4. 4-Et-2-OHC6H3CO2H

Yaoxue Xuebao (1998), 33(1), 67-71.

5. 2-Et-6-OHC6H3CO2H and 2-n-WG-6-C6H3CO2N

J. Chem. Soc., Perkin Trans 1 (1979), (8), 2069-78.

6. 2-Et-3-OHC6H3CO2H

JP 10087489 and WO 9628423.

7. 4-Et-3-OHC6H3CO2H

J.O.C. 2001, 66, 7883-88.

WO 9504046.

8. 2-Et-5-OHC6H3CO2H

J.A.C.S (1974), 96(7), 2121-9.

9. 2-Et-4-OHC6H3CO2H and 3-Et-4-OHC6H3CO2H

JP 04282345.

10. 3-n-Pr-2-OHC6H3CO2H

J.O.C (1991), 56(14), 4525-29.

11. 4-n-Pr-2-OHC6H3CO2H

EP 279630.

12. 5-n-Pr-2-OHC6H3CO2H

J. Med. Chem. (1981), 24(10), 1245-49.

13. 2-n-Pr-3-OHC6H3CO2H

WO 9509843 and WO 9628423.

14. 4-n-Pr-3-OHC6H3CO2H

WO 9504046.

15. 2-n-Pr-5-OHC6H3CO2H

The synthesis can be adapted from J.A.C.S (1974), 96(7), 2121-9 using alpha-formylacetate ethyl.

16. 3-n-Pr 4-OHC6H3CO2H

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

17. 2-n-Pr 4-OHC6H3CO2H

3-propylene you can metilirovanie 3-propellants, which was then formalizovan 4-methoxy-3-benzaldehyde. The aldehyde can be oxidized by the reagent John with obtaining the appropriate acid, and removing the protection of a methyl group BBr3will give specified in is the head of the connection.

18.1. 3-Et-5-OHC6H3CO2H and 3-Pr-n-5-OHC6H3CO2H

To adapt the synthesis of the J.O.C. 2001, 66, 7883-88 2-ethylacrolein and 2-propylalanine.

Use in methods of treatment

The present invention relates to a method of treatment of a mammal with a condition selected from the group consisting of a syndrome of resistance to insulin and diabetes (primary and essential diabetes, such as type I diabetes or type II diabetes, and secondary essenziale diabetes), including the introduction of individual quantities of biologically active agent, as described in the present description, effective for the treatment of this condition. In accordance with the method of the present invention can reduce the symptom of diabetes or the probability of developing symptoms of diabetes, such as atherosclerosis, obesity, hypertension, hyperlipidemia, fatty liver infiltration, nephropathy, neuropathy, retinopathy, foot lesions and cataracts, and each symptom associated with diabetes. This invention also relates to a method for treating hyperlipidemia comprising the administration to the individual of the amount of biologically active agent, as described in the present description, effective for the treatment of this condition. As shown in the examples, connect the deposits reduce the levels of triglycerides and free fatty acids in the serum of animals with hyperlipidemia. This invention also relates to a method for treatment of cachexia, including the introduction of individual quantities of biologically active agent, as described in the present description, it is effective for the treatment of cachexia. This invention also relates to a method of treating obesity, comprising administration to the individual of the amount of biologically active agent, as described in the present description, it is effective for the treatment of this condition. This invention also relates to a method of treating a condition selected from atherosclerosis or arteriosclerosis, comprising the administration to the individual of the amount of biologically active agent, as described in the present description, an effective treatment for this condition. The active agents of the present invention is effective for the treatment of hyperlipidemia, fatty infiltration of the liver, cachexia, obesity, atherosclerosis or arteriosclerosis, regardless of whether the individual has diabetes or syndrome of resistance to insulin. The agent can enter any normal by systemic injection. Preferably the agent is administered orally. Accordingly, it is preferable that the drug was prepared in a form suitable for oral administration. Other routes of administration that can be used in accordance with the present invention include rectal, parenteral, by which nycli (for example, intravenous, subcutaneous, intramuscular or intraperitoneal injection) or intranasal.

Further embodiments of each of the uses and methods of treatment of the present invention include the introduction of any of the embodiments of the biologically active agents described above. Each of the agent and agent group are not repeated, but they are included in the present description of the use and methods of treatment, as if they were repeated.

Many of the diseases or disorders which are the focus of the compounds of the invention fall into two broad categories: the syndromes of resistance to insulin and the effects of chronic hyperglycemia. Dysregulation of energy metabolism, particularly in insulin resistance, which may occur in the absence of diabetes (persistent hyperglycemia as such, is associated with a variety of symptoms, including hyperlipidemia, atherosclerosis, obesity, essential hypertension, fatty infiltration of the liver (NASH; non-alcoholic steatohepatitis) and particularly in the context of cancer or systemic inflammatory disease, cachexia. Cachexia can also occur in the context of diabetes mellitus type I or late stage of type II diabetes. In view of improving the energy metabolism of tissues active agents of the invention can be applied for PR the prevention or relief of diseases and symptoms, associated with insulin resistance, as shown by animals in the examples. Although the group of signs and symptoms associated with insulin resistance, may coexist in individual patients, in many cases can dominate only one symptom due to individual differences in vulnerability of many physiological systems affected by insulin resistance. However, since insulin resistance is a major factor in many pathological conditions, drugs, which are aimed at this cell and molecular defect, can be used to prevent or facilitate in essence any symptom in any organ system, which may be caused or obestin insulin resistance.

When insulin resistance and concomitant inadequate insulin production by the pancreatic islets quite heavy, there is chronic hyperglycemia, which determines the beginning of diabetes mellitus type II (NIDDM). In addition to metabolic disorders associated with the above insulin resistance, pathological symptoms caused by hyperglycemia, also occur in patients with NIDDM. They include nephropathy, peripheral neuropathy, retinopathy, a microvascular disease, ulceration of the extremities and the consequences of non-enzymatic glycosylation b is lcov, for example, a damaged collagen and other connective tissue. The attenuation of hyperglycemia reduces the frequency of the beginning and the severity of these consequences of diabetes. Due to the fact that, as shown in the examples, the active agents and compositions of the invention help to reduce hyperglycemia in diabetes, they can be used to prevent complications of chronic hyperglycemia.

People and individuals mammals besides humans, can be treated in accordance with the method of treatment of the present invention. An experienced Clinician may, in clinical settings to determine the optimal dose of a particular active agent of the invention for a particular individual. In the case of oral administration to man for the treatment of disorders associated with insulin resistance, diabetes, hyperlipidemia, fatty liver infiltration, cachexia or obesity agent is generally administered in a daily dose of from 1 mg to 400 mg, administered 1 or 2 times/day. In the case of oral administration mouse, the agent is generally administered in a daily dose of from 1 mg to 300 mg of agent per 1 kg of body weight. Active agents in accordance with the invention is used as monotherapy in case of diabetes or syndrome of resistance to insulin, or in combination with one or more other drugs used in these types of diabetes, for example by means of releasing insulin, medium, what you releasing insulin when eating, the biguanides, or by insulin. Such additional drugs are administered in accordance with standard clinical practice. In some cases, the agents of the invention enhance the efficacy of other classes of drugs, providing the possibility of introducing patients to a lower (and therefore less toxic) doses of such drugs with satisfactory results.

Established safe and effective dose ranges from people for representative compounds are for Metformin - 500 up to 2550 mg/day; for gliburida from 1.25 to 20 mg/day; for GLUCOVANCE (combined composition of 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; for lovastatin from 10 to 80 mg/day; for pravastatin 10 to 40 mg/day; and for simvastatin - 5-80 mg/day; for clofibrate - 2000 mg/day; for gemfibrozil from 1200 to 2400 mg/day; for rosiglitazone - 4 to 8 mg/day; for pioglitazone 15 to 45 mg/day; for acarbose - from 75 to 300 mg/day; for Repaglinide from 0.5 to 16 mg/day.

Diabetes mellitus type I: Patient with type I diabetes to cope with their disease in the first place independent introduction from one to several doses of insulin per day with frequent monitoring of blood glucose to ensure vozmozhnostzanimatsya selection of dose and timing of insulin administration. Chronic hyperglycemia leads to complications such as nephropathy, neuropathy, retinopathy, foot lesions and early mortality; hypoglycemia due to the introduction of excessive doses of insulin may cause cognitive dysfunction or loss of consciousness. Patients with type I diabetes treated with the active agent of this invention in a dose of from 1 to 400 mg/day in the form of tablets or capsules or in the form of one or fractional doses. The intended effect is to reduce the dose or frequency of insulin required to maintain blood glucose in the satisfactory range, and reduced the incidence and severity of hypoglycemic episodes. Clinical outcome control by measurement of blood glucose and glucolysed hemoglobin (an indicator of the adequacy of glycemic control, integrated over a period of several months), and reduced frequency and severity of typical complications of diabetes. The biologically active agent of this invention can be introduced in combination with transplantation of islets to help maintain the antidiabetic efficacy of graft islets.

Diabetes type II: the Typical patient with diabetes mellitus type II (NIDDM) is coping with his disease diet programs and physical exercise, and medications, such as Metformin, glebo the ID, Repaglinide, rosiglitazone or acarbose, all of which provide some improvement in glycemic control in some patients, but none of them is not without side effects or actual insolvency of treatment due to progression of the disease. Over time in patients with NIDDM occurs islet failure, requiring insulin injections in a large proportion of patients. It is assumed that daily treatment of active agent in accordance with the invention (with additional classes of antidiabetic drugs or without them) will improve glycemic control, reduce the frequency of islet failure and will reduce the incidence and severity of common symptoms of diabetes. Additionally, active agents in accordance with the invention reduce elevated triglyceride and fatty acids, reducing by this the risk of cardiovascular disease, a leading cause of death in patients with diabetes. As is the case for all other therapeutic agents used to treat diabetes, dose optimization performed in selected patients in accordance with necessity, clinical effect and susceptibility to side effects.

Hyperlipidemia: Increased levels of triglycerides and free fatty acids in the blood affect a significant portion n of the village and represent an important risk factor for atherosclerosis and myocardial infarction. The active agents according to the invention can be applied to reduce the level of circulating triglycerides and free fatty acids in patients with hyperlipidemia. In patients with hyperlipidemia often have elevated levels of cholesterol in the blood, which also increase the risk of cardiovascular disease. Drugs that lower cholesterol, such as inhibitors of HMG-CoA reductase inhibitors ("statins"), you can enter the patients with hyperlipidemia in addition to the means of the invention, it is not necessarily included in the same pharmaceutical composition.

Fatty infiltration of the liver: a Significant part of the population is affected with fatty infiltration of the liver, also known as nonalcoholic steatohepatitis (NASH; NASH often associated with obesity and diabetes. Steatosis of the liver, the presence of droplets of triglycerides in hepatocytes, predisposes the liver to chronic inflammation (detected in the biopsy specimens in the form of infiltration of inflammatory leukocytes), which can lead to fibrosis and cirrhosis. Fatty infiltration of the liver in General is detected by the observation of increased levels of serum specific for the liver enzymes such as transaminases ALT and AST, which serve as indicators of damage to the hepatocytes, as well as symptoms, which include fatigue and pain in the liver, although the final is EGNOS often requires a biopsy. The alleged beneficial effect is to reduce inflammation of the liver and fat, resulting in a weaker, stop or eliminate the progression of NASH in the direction of fibrosis and cirrhosis.

The pharmaceutical composition

The present invention relates to pharmaceutical compositions comprising a biologically active agent, as described in the present description, and pharmaceutically acceptable carrier. Further embodiments of the pharmaceutical compositions of this invention include any of the embodiments described above biologically active agents. Each of the agent and agent group are not repeated, but they are included in the present description of pharmaceutical compositions 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 oral composition comprises from 1 mg to 400 mg of this agent. Convenient for the individual 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 usual means of systemic administration, including rectally, for example in the form of suppositories, parenterale, for example in the form of solutions for injection or intranasal.

Biologically active compounds can be processed with pharmaceutically inert, inorganic or organic carriers for pharmaceutical compositions. Lactose, corn starch or its derivatives, talc, stearic acid or its salts and the like can be used, for example, 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, carriers are not usually required in the case of soft gelatin capsules, other than the soft gelatin. Suitable carriers for the manufacture of solutions and syrups are, for example, water, polyols, glycerine, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.

Farmatsevticheskii compositions can, moreover, contain preservatives, solubilizing tools, stabilizers, wetting means, emulsifying agents, sweetening agents, flavorings, salts to change the osmotic what about the pressure, buffers covering means or antioxidants. They may also contain other therapeutically valuable substances, in particular antidiabetic or lipid-lowering means, which act through mechanisms that differ from those that underlie the effects of compounds of the invention. Tools that can preferably be combined with the compounds of the invention in a single composition, include, but are not limited to, biguanides, such as Metformin, tools, releasing insulin, such as releasing insulin, a sulfonylurea gliburid and other releasing insulin, sulfonylureas, drugs that lower cholesterol, such as "satinowye" inhibitors of HMG-CoA reductase, such as atrovastatin, lovastatin, pravastatin and simvastatin, agonists of PPAR-alpha, such as clofibrate, and gemfibrozil, agonists of PPAR-gamma, such as preparations of thiazolidinediones (eg, rosiglitazone and pioglitazone), alpha-glucosidase inhibitors such as acarbose (which inhibits the digestion of starch) and means releasing insulin when eating, such as Repaglinide. The amount of additional funds, combined with compliance with the doses used in standard clinical practice. Set a safe and effective dose ranges for certain representative compounds p is estaline above.

The invention will be better understood by reference to the following examples, which illustrate but do not limit the invention described here.

EXAMPLES of CHEMICAL SYNTHESIS

Example 1

3-(2,6-Dimethylbenzylamine)phenylacetic acid

Stage a: 3-hydroxyphenylacetate ethyl

To a stirred solution of 3-hydroxyphenylacetic acid (10 g, and 65.7 mmol) and 1,3-dicyclohexylcarbodiimide (DCC, 16,27 g of 78.8 mmol) in DMF (30 ml) is added pyridine (2.5 ml) followed by the addition of absolute ethanol (15 ml, 255,5 mmol). The reaction mixture was stirred at room temperature for 16 h, filtered, concentrated and purified flash chromatography on a column of silica gel (hexane:ethyl acetate 2:1) to obtain specified in the connection header.

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: 3-(2,6-dimethylbenzylamine)of ethyl phenylacetate

A solution of 2,6-dimethylbenzyl alcohol (5,25 g, and 38.6 mmol) and azodicarboxylate diisopropyl (DIAD, 8,49 g, 42 mmol) in THF (30 ml) and DMF (13 ml) is added dropwise to a solution of 3-hydroxyphenylacetate ethyl (stage And, of 6.66 g, 37 mmol) and triphenylphosphine (11 g, 42 mmol) in THF (100 ml). The reaction mixture was stirred at room temperature for 4 h, diluted with simple ether and washed with water. The organic layer from the shat over Na 2SO4, filtered, concentrated and purified flash chromatography on a column of silica gel (hexane:ethyl acetate 1:1) to obtain specified in the connection header.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); 2,4 (C, 6N); 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: 3-(2,6-dimethylbenzylamine)phenylacetic acid

To a stirred solution of 3-(2,6-dimethylbenzylamine)of ethyl phenylacetate (stage b, 4 g of 13.6 mmol) in absolute ethanol (30 ml) is added 1N NaOH (20 ml) at room temperature. The reaction mixture was stirred for 3 h, acidified with 1N HCl and concentrated. The residue is transferred into chloroform and washed with 0,1N HCl, dried over Na2SO4, filtered, concentrated and purified flash chromatography on a column of silica gel (hexane:ethyl acetate 1:1) to obtain specified in the connection header.

1H NMR (270 MHz, CDCl3): 2,4 (C, 6N); the 3.65 (s, 2H); to 5.1 (s, 2H); to 6.9 (m, 2H); 7,15-to 7.35 (m, 5H).

Example 2

3-(2,6-Dimethylbenzylamine)benzoic acid

Stage a: 3-(2,6-dimethylbenzylamine)of ethyl benzoate

To a stirred solution of 3-hydroxybenzoate ethyl (12,21 g, 73,47 mmol) and triphenylphosphine (21,01 g, 80,13 mmol) in dry THF (100 ml) is added dropwise a solution of 2,6-dimethylbenzyl alcohol (10 g, of 73.5 mmol) of azodicarboxylate diisopropyl (16,19 g, 80,13 mmol) in dry THF (35 ml) and dry DM (15 ml) at ambient temperature. After 3 h stirring at room temperature the reaction mixture was diluted with diethyl ether and washed twice with water and saturated salt solution. The combined organic layers dried over Na2SO4, filtered, concentrated and purified flash chromatography using as eluent ethyl acetate:hexane (1:3).

1H NMR (270 MHz, CDCl3): 1,4 (t, 3H); 2,4 (C, 6N); 4,4 (square, 2H); to 5.1 (s, 2H); and 7.1 (m, 2H); to 7.2 (m, 2H); to 7.4 (t, 1H); to 7.9 (m, 2H).

Stage b: 3-(2,6-dimethylbenzylamine)benzoic acid

To a stirred solution of 3-(2,6-dimethylbenzylamine)ethyl benzoate (stage A, to 16.31 g, 57,4 mmol) in absolute alcohol (150 ml) is added 1N NaOH. After 3 hours stirring at room temperature the reaction mixture was acidified with 1M HCl and concentrated in vacuo. The organic residue is transferred into chloroform and washed with 0,1N HCl, dried over Na2SO4, filtered, concentrated and purified flash chromatography using chloroform:methanol (95:5, amplified acetic acid as eluent.

1H NMR (270 MHz, CDCl3): 2,4 (C, 6N); to 5.1 (s, 2H); 7,15-7,35 (m, 4H); to 7.4 (t, 1H); 7,8 (m, 2H).

Example 3:3-(2,6-Dimethylbenzylamine)benzoic acid

Stage a: Connection Mitsunobu - 3-(2,6-dimethylbenzylamine)of ethyl benzoate

Table 1
The ofComplex hydroxyetherRTRTHFBenzyl-
HE
DIADTHFProduct
Mole cular-Naya weight166,17262,29136,19202,21284,35
Weight15,025,812,3to 19.9
Volume4019,440
Mol0,0900,0980,0900,098
D of 1.027

theoretical yield of 25.7 g; actual output 19,85 g; fractional output 0,773.

Mass = g; volume = ml

A solution of 3-hydroxybenzoate ethyl and triphenylphosphine in anhydrous THF cooled in an ice bath to 5°C in nitrogen atmosphere. In a separate flask was prepared a solution of 2,6-dimethylbenzyl alcohol and DIAD in anhydrous THF and transferred via cannula into the first flask. The addition is very exothermic with the rise of temperature from 5°C to 18°C within the first 2 min add (a few ml). The addition is completed within 22 min at a maximum temperature of 24°C. After 30 min stirring, a precipitate, and the ice bath removed. Thin layer chromatography (Tlc) (hexane:simple ether 1:1, UV) after 2.5 h shows a trace remaining of the source material.

Diverse systems of solvents used for the best branch of the TRR from the product, they include: 10:3 hexane:simple ether; 4:1 hexane:EtOAc; CH2Cl2; 1:1 CH2Cl2; hexane; 10% CH2Cl2in hexano; and 5% simple air hexano. The latter solvent system gives the best separation, solvents CH2Cl2tend suirou the smash product and TRR together and quickly.

Table 2
Data tlc
ConnectionRf (H:E 1:1)Rf (5% E/H 1:1)
TPP0,860,61
Product0,750,27
Phenol0,490
BnOH0,410
TPP=O0,060
N = hexane, E = easy ethyl ester

After 7 h the reaction mixture was filtered to remove solids (14.3 g, tlc shows that the oxide TRR) and the filter cake washed with hexane:simple ether 1:1 (60 ml). The filtrate is concentrated to obtain a yellow mixture of oil and solids. It is collected in 100 ml simple ether and 100 ml of hexanol and allow to settle for about 1 hour, the Solids are collected by vacuum filtration (24,0 g, tlc shows only the oxide TRR, total number of remote TV is rdih substances is to 38.3 g) and the filtrate concentrated to obtain a solid cream color.

The solid is dissolved in 100 ml of CH2Cl2and put on a pad of silica gel (diameter 9.5 cm to a height of 6 cm, ~325 g). His elute CH2Cl2and collected in 2×500 ml and 2×250 ml flask. Product and TRR together elute in the first 2 bulb and the oxide RTR is held. Concentrate first 2 fractions to obtain a 23.6 g of white powder. LC/MS (liquid chromatography/mass spectrometry) (labeled M-01) shows the desired product with a purity of 78% 11% TRR as the main impurity.

The crude product is dissolved in about 100 ml of a simple ester by heating and allow to cool. Deposited a small amount of solids. Add 70 g of silica gel and concentrated. It is applied onto a bed of silica gel (260 g, more than the equivalent of Biotage 75S) and elute 1 l of 5% ether in hexano and collect approximately 200 ml fractions (4 fractions). The first fraction contains RTR, 4th faction is composed of almost pure product, the second and the third was a cross-faction. Silica gel elute 1 l of 30% ether in hexano and collected in 3 fractions. Fractions 5 and 6 have the product, and concentrated to obtain white solids, 19,85 g (yield 77%).

1H and13With NMR spectra consistent with the desired product.

LC/MS shows M+N=285,1 and purity of 97.7% UV at 250 nm.

1H NMR (270 MHz, CDCl3): 1,4(t, 3H); 2,4 (C, 6N); 4,4 (square, 2H); to 5.1 (s, 2H); and 7.1 (m, 2H); to 7.2 (m, 2H); to 7.4 (t, 1H), and 7.7 (m, 2H).

Stage: Saponificate

Table 3
ConnectionEsterEtOH40% NaOHWaterProduct
Molecular weight284,3510N256,30
Equivalent to2,13
Weight10,0
Volume2507,510
Mol0,0350,075
Theoretical output 8,01 g; actual yield 5.0 g; fractional yield of 0.55.

Ester (10 g) stage And collected in 50 ml of absolute EtOH. It is not very soluble, and portions of 50 ml EtOH add up until not achieved the volume of 250 ml In the solution still contains some amount of solid substances, and conduct heat to the formation of the solution (46°C). Add a solution of 7.5 ml of 10 N NaOH, diluted with 10 ml water, and the solution stirred for 1 h Tlc (hexane:simple ether, UV) shows that ester consumed, and intensive spot appears on the zero line.

Development

The reaction mixture was concentrated on a rotary evaporator at 50°C To produce a white solid. Solid emuleret in 250 ml of deionized water and the insoluble material collected by filtration. The filtrate is put aside for some time.

The filter cake was washed with 2×200 ml simple ether and explore LC/MS after each washing. Purity respectively 98.4% and 98.7 per cent. Solid is stirred in 200 ml of simple ether for 15 min and collected and filtered. LC/MS shows that its purity of 99.5%. Solids emuleret in 100 ml of deionized water and treated with 2.5 ml concentrated the Oh HCl. Control of pH with indicator paper indicates pH 1. The suspension is stirred for 22 min, and collected by vacuum filtration. The filter cake was washed with several portions of water (total volume ~100 ml). Dried in vacuum at 45°C With P2O5.

1H NMR spectrum consistent with the desired product, wide IT is centered at about 6 ppm

1H NMR (270 MHz, CDCl3): 2,4 (C, 6N); to 5.1 (s, 2H); and 7.1 (m, 2H); 7,15-to 7.3 (m, 2H); to 7.4 (t, 1H); 7,8 (m, 2H).

Example 4: 6-[3-(2,6-Dimethylsiloxy)phenyl]hexanoic acid

Stage A: Synthesis of bromide of triphenylmethylchloride of phosphonium

Table 4
ConnectionMolecular weightMothgramsmlDensity
Triphenylphosphine262,290,045011,80209,08
Ethyl-5-bromovalerate209,080,060012,54 9,46of 1.321
Benzene78,0225

Dissolve 11,80 g of triphenylphosphine in 25 ml of toluene in a nitrogen atmosphere in a 3-necked flask with a capacity of 100 ml round bottom, oborudovaniemi, thermocouple, and reflux condenser with an inlet for nitrogen. 12,54 g ethyl-5-bromovalerate added to a solution, heated under reflux (110°C.) and stirred for 2 h, the Reaction mixture was analyzed after 1 and 2 hours, the Reaction mixture was cooled to room temperature (<25°C) and toluene decanted from the oily solid. The remainder emuleret in 100 ml of hexanol three times, each time decanter hexane. The oily residue is heated in the apparatus Cuellar at 40°C, 0.1 Torr for 30 min to obtain 19,0 g (89,6%) of a white oily solid. NMR (32R) and NMR (13(C) show the desired product.

Stage: Obtaining complex ethyl ester of 6-[3-(2,6-dimethylsiloxy)phenyl]Gex-5-ene acid

Table 5
Connection Molecular weightMothGramsMI
Bromide of triphenylmethylchloride of phosphonium471,370,0282to 13.29
3-(2,6-dimethylbenzylamine)benzaldehyde240,300,02085,00
Sodium hydride24,000,03100,745
The sulfoxide78,1340/20

The mixture to 13.29 g of the bromide of triphenylmethylchloride of phosphonium and 0,745 g of sodium hydride in 40 ml of DMSO is stirred for 30 min in nitrogen atmosphere in a 3-necked flask with a capacity of 100 ml round bottom equipped with a stirrer, reflux condenser with the inlet to and the PTA and thermocouple. The mixture changes color from light yellow and heated to 40.2°C to 23.2°C. to 5.00 g of 3-(2,6-dimethylbenzylamine)benzaldehyde was dissolved in 20 ml of DMSO and added dropwise over a 4-minute period to the reaction mixture. The mixture is heated from 21.8°C to 26.8°C. the Reaction mixture is stirred and allow to cool to room temperature. The reaction mixture was analyzed by 1 h, and LC-MS shows that remains almost the entire original aldehyde and about 3% of the desired product. The reaction mixture is heated through 2 and 3 hours LC-MS shows the presence of about 20% remaining of the original aldehyde and 17% of the desired product. The reaction mixture is cooled to room temperature and placed in the refrigerator overnight.

The reaction mixture allow to warm to room temperature and stirred. The mixture to 5.56 g (118 mm) of bromide of triphenylmethylchloride of phosphonium and 0.312 g of sodium hydride in 15.0 ml DMSO was stirred for 30 min in nitrogen atmosphere. The mixture was added in the form of a bolus to the reaction mixture, heated to 50°C. and stirred for 6 hours

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); 1.8 m (m, 2H); 2,2-2,4 (m, 10H); 4,2 (square, 2H); to 5.1 (s, 2H); 5,6-6,2 (m, 1H); at 6.4 (t, 1H); the 6.9 and 7.3 (m, 7H).

Stage C: Obtain 6-[3-(2,6-dimethylsiloxy)phenyl]ethylhexanoate

Reference: Journal of Org. Chemistry, Vol. 34, No. 11, p. 3684-85. Nov. 1969.

Table 6
ConnectionMolecular weightthe mmolgramsml
Complex ethyl ester of 6-[3-(2,6-dimethylsiloxy)phenyl]-hexenoic acid352,477,702,71
Tris(triphenylphosphine)-
chloride (I)
925,230,0280,0259
Benzene78,1160,0
Absolute ethanol46,0760,0

2,71 g complex ethyl ester of 6-[3-(2,6-dimethylsiloxy)phenyl]Gex-5-ene acid are dissolved in 120 ml of degassed 1:1-mixture of benzene and absolute ethanol in 300 ml of a compression reactor Parr stainless steel. To the solution add 0,259 g of Tris(triphenylphosphine)chloride (I) (Wilkinson catalyst). The reaction mixture was bubbled for 5 times with hydrogen, heated to 0°C, at 80 psig with hydrogen and stirred overnight.

The reaction mixture is cooled to room temperature and remove the gases. Analysis of LC-MS does not show the original olefin. The reaction solution bubbled with nitrogen and filtered through a layer of celite. The filtrate was concentrated in vacuo to obtain 3,40 g of brown oil. The oil is dissolved in 12 ml of a mixture 1:1 of hexanol:chloroform. Silica gel elute with 100 ml of a mixture 1:1 of hexanol:chloroform and 200 ml of a mixture of 95:5 hexanol:ethyl acetate, collecting 50 ml fractions. Pure fractions are combined and concentrated in vacuo to obtain 2.70 g (99,0%) of a dark yellow oil. LC-MS shows the desired product ~72%. The product is used without further purification.

Stage D: Obtain 6-[3-(2,6-dimethylsiloxy)phenyl]hexanoic acid

Table 7
ConnectionMolecular weightthe mmolgramsml
6-[3-(2,6-dimethylsiloxy)phenyl]-ethylhexanoate354,480,00762,69
Ethanol35
of 1.0 N sodium hydroxide40,010

2,69 g of 6-[3-(2,6-dimethylsiloxy)phenyl]ethylhexanoate dissolved in 35 ml of absolute ethanol and 10 ml of 1N aqueous sodium hydroxide in a flask with a capacity of 100 ml round bottom equipped with a stirrer, thermocouple and reflux condenser. The yellow solution is heated under reflux and stirred for 2 h, the Reaction mixture was analyzed, and LC-MS showed the original complex ethyl ester. The reaction mixture is cooled to room temperature and concentrated in vacuo to a yellow oil, which mainly solidifies after standing. 50 ml of water is added to the residue and stirred for 10 minutes the Aqueous solution is extracted with three times 50 ml of ethyl acetate. The aqueous layer was acidified with 3 ml of 6N aqueous HCl and extracted with three times 50 ml of ethyl acetate. The combined organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to obtain ~2.2 g yellow resinous solid. The residue is stirred in 75 ml of water for 30 minutes, the Solids are collected by filtration and dried in a vacuum oven at 40°C for receipt of 1.62 g (90,5%) beige firmly what about the substance. LC-MS and NMR show the desired product is >98%.

1H NMR (270 MHz, CDCl3): 1,4 (m, 2H); to 1.7 (m, 4H); 2.3 to 2.4 (m, 8H); 2,6 (t, 2H); 5,0 (s, 2H); to 6.8 (m, 3H); 7,0-to 7.3 (m, 4H).

Example 5:5-[3-(2,6-dimethylsiloxy)phenyl]pentane acid

Stage A: Obtaining complex ethyl ester 5-[3-(2,6-dimethylsiloxy)phenyl]Penta-4-ene acid

Table 8
ConnectionMolecular weightmothgram
we
ml
The bromide triphenylethylene of phosphonium457,340,022010,06
3-(2,6-dimethylbenzylamine)-benzaldehyde240,300,01623,89
Sodium hydride24,000,02420,581
The sulfoxide78,13 30,0/15,0

The mixture 10,06 g of bromide triphenylethylene of phosphonium and 0,581 g of sodium hydride and 30.0 ml of DMSO is stirred for 30 min in nitrogen atmosphere in a 3-necked flask with a capacity of 100 ml round bottom equipped with a stirrer, a reflux condenser with an inlet for nitrogen and a thermocouple. The mixture changes color from yellow to orange and heated to 26.7°C to 19.8°C. to 3.89 g of 3-(2,6-dimethylbenzylamine)benzaldehyde was dissolved in 15.0 ml DMSO and added dropwise over 3 min to the reaction mixture. The mixture changes color from orange to yellow and heated to 34.0°C to 26.7°C. the Reaction mixture is stirred and allow to cool to room temperature for 3 hours, the Reaction mixture was analyzed after 1 and 3 hours LC shows the progress of the reaction with the remainder of the original aldehyde from ~15% to ~13%. The reaction mixture is heated to 50°C. and stirred for 2 h, the Reaction mixture was analyzed after 1 and 2 h, LC-MS shows little change compared with the previous samples at the remaining ~12% of the original aldehyde. The reaction mixture is cooled to room temperature and placed overnight in a refrigerator.

The reaction mixture allow to warm to room temperature and stirred. The mixture 3,20 g (70 mm) bromide triphenylethylene of phosphonium and 0,185 g of sodium hydride in 10.0 ml DMSO peremeci is up for 30 min in nitrogen atmosphere. The mixture was added in the form of a bolus to the reaction mixture at room temperature for 2 hours

The reaction mixture was analyzed after 1 and 2 hours LC shows the progress of the reaction with the remainder of the original aldehyde from ~13% to ~4%. The reaction mixture is heated to 50°C. and stirred for 2 h, the Reaction mixture was cooled to room temperature and poured over 50 g of ice with 50 ml of water. The aqueous mixture is extracted three times 125 ml ethyl acetate and the combined organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to obtain 12.9 g of brown oil. LC shows ~40% of the desired product.

The oil is dissolved in 30 ml of a mixture of 95:5 hexanol:ethyl acetate and chromatographic on a column of silica gel BIOTAGE 75S using 5 l of a mixture of 95:5 hexanol:ethyl acetate. The desired product eluted quickly, perhaps due to residual DMSO in the development. The fractions containing the desired product are combined and concentrated in vacuo to obtain 4.9 g of a yellow oil. The oil is dissolved in 10 ml of a mixture 1:1 of hexanol:chloroform. Silica gel elute with 200 ml of a mixture 1:1 of hexanol:chloroform and 200 ml of a mixture of 9:1 hexanol:ethyl acetate, collecting fractions of 50 ml. Pure fractions are combined and concentrated in vacuo to obtain 3,40 g (62,0%) pale yellow oil, which basically solidifies after standing. LC-MS and NMR show a desirable product >98% when the ratio between CIS - and TRANS-isomers of about 30:70 based on the Wittig reaction, giving predominantly the TRANS isomer.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); 2,4-2,7 (m, 10H); 4,1 (square, 2H); to 5.1 (s, 2H); 5,6-6,2 (m, 1H); 6.5 in (t, 1H); to 6.8 (m, 7H).

Stage: Obtain 5-[3-(2,6-dimethylsiloxy)phenyl]ethylpentane

Reference: Journal of Org. Chemistry, Vol. 34, No. 11, p. 3684-85. Nov. 1996.

Table 9
ConnectionMolecular weightthe mmolgramsml
Complex ethyl ester 5-[3-(2,6-dimethylsiloxy)phenyl]-Penta-4-ene acid338,4to 6.802,30
Tris(triphenylphosphine)
chloride (I)
925,230,240,222
Benzene78,1155,0
Absolute ethanol46,0755,0

2.50 g of complex ethyl ester 5-[3-(2,6-dimethylsiloxy)phenyl]Penta-4-ene acid are dissolved in 110 ml of degassed 1:1-mixture of benzene and absolute ethanol in 300 ml of a compression reactor Parr stainless steel. To the solution add 0,222 g of Tris(triphenylphosphine)chloride (I) (Wilkinson catalyst). The reaction mixture was bubbled for 5 times with hydrogen, heated to 60°C, at 80 psig with hydrogen and stirred overnight.

The reaction mixture is cooled to room temperature and ventilate. Analysis of LC-MS does not show the original olefin. The reaction solution bubbled with nitrogen and filtered through a layer of celite. The filtrate was concentrated in vacuo to obtain 3,20 g of brown oil. The oil is dissolved in 12 ml of a mixture 1:1 of hexanol:chloroform and placed on 30 g of silica gel, equilibrated with a mixture of 1:1 hexanol:chloroform. Silica gel elute with 100 ml of a mixture 1:1 of hexanol:chloroform and 200 ml of a mixture of 95:5 hexanol:ethyl acetate, collecting 50 ml fractions. Pure fractions are combined and concentrated in vacuo to obtain 2.30 g (99,0%) pale yellow oil. LC-MS shows the desired product ~93%. The product is used without further purification.

1H NMR (270 MHz, CDCl3): 1 (t, 3H); 1,4 (m, 4H); 2.0 (t, 2H); 2,1 (s, 6N)and 2.4 (m, 2H); 3,8 (square, 2H); 4.7 in (s, 2H); 6.5 in (m, 3H); 6,8-7,0 (m, 4H).

Stage C: Obtain 5-[3-(2,6-dimethylsiloxy)phenyl]pentanol acid

img src="https://img.russianpatents.com/1173/11733516-s.jpg" height="119" width="108" />

Table 10
ConnectionMolecular weightthe mmolgramsml
5-[3-(2,6-dimethylsiloxy)phenyl]-ethylpentane340,460,00802,72
Ethanol35
1,0N sodium hydroxide40,010

of 2.72 g of 5-[3-(2,6-dimethylsiloxy)phenyl]ethylpentane dissolved in 35 ml of absolute ethanol and 10 ml of 1N aqueous sodium hydroxide in a flask with a capacity of 100 ml round bottom equipped with a stirrer and reflux condenser. The solution obtained light yellow color, heated under reflux and stirred for 1 h, the Reaction mixture was analyzed, and LC-MS does not show the original ester. The reaction mixture is cooled to room temperature and concentrated in vacuo to a white solid prophetic is TBA. 50 ml of water is added to dissolve the solids. The aqueous solution is extracted with three times 50 ml of ethyl acetate. The aqueous layer was acidified with 3 ml of 6N HCl solution and extracted with three times 50 ml of ethyl acetate. The combined organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to obtain about 2.5 g of the white resin solids. The solid is stirred in 25 ml of hexanol for 30 min, collected by filtration and dried in a vacuum oven at 40°C. to obtain a 2.12 g (84,8%) of white solids. LC-MS and NMR show the desired product is >99%.

1H NMR (270 MHz, CDCl3): 1,7 (m, 4H); 2,4 (m, 8H); 2,6 (m, 2H); 5,0 (s, 2H); to 6.8 (m, 3H); 7,0-to 7.3 (m, 4H).

Example 6: 3-[3-(2,6-Dimethylsiloxy)phenyl]propionic acid

Stage A: Synthesis of ethyl-3-hydroxyphenylpropionic

Table 11
ConnectionMolecular weightthe mmolgramsml
3-(3-hydroxyphenyl)propionic acid166,180,03015,00
Ethanol46,075,0
Concentrated sulphuric acid96,030,5

to 5.00 g of 3-(3-hydroxyphenyl)propionic acid are dissolved in 50 ml of absolute ethanol in a 3-necked flask with a capacity of 100 ml round bottom equipped with a mechanical stirrer, reflux condenser and thermocouple. 0.5 ml of concentrated sulfuric acid added to the solution and heated under reflux (80°C.) and stirred for 2 h, the Reaction mixture was analyzed, and LC-MS shows the desired product free of starting material. The reaction mixture was cooled to <5°C in an ice bath and neutralized to a pH of about 7 to 10 ml of 10% aqueous solution of sodium carbonate. The neutralized solution was concentrated in vacuo to about 10 ml and diluted with 25 ml water. The solution is extracted with three times 25 ml of ethyl acetate. The combined organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to obtain of 5.06 g (86,5%) of a dark amber oil. LC-MS shows the desired product of >99.5%pure.

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: intes ethyl-3-(2,6-dimethylbenzylamine)phenylpropionate

Table 12
ConnectionMolecular weightthe mmolgramsml
Ethyl 3-hydroxyphenylpropionic194,230,0260of 5.05
2,6-Dimethylbenzylamine alcohol136,190,02713,69
Azodicarboxylate of isopropyl202,210,02965,99
Triphenylphosphine262,290,02967,76
Tetrahydrofuran72,1124/76

A solution of 3.69 g of 2,6-dimethylbenzyl alcohol and of 5.99 g of azodicarboxylate of isopropyl in 24 ml of THF was added drop is to the solution of 5.05 g of ethyl-3-hydroxyphenylpropionic and 7,76 g of triphenylphosphine in 76 ml of THF with such speed, to keep the temperature of the reaction mixture <25°C (Tmax=22,3°C). The reaction mixture was stirred at room temperature for 4 h in a 3-necked flask with a capacity of 250 ml round bottom equipped with a stirrer, funnel for adding and thermocouple. The reaction mixture was analyzed after 3 and 4 h at room temperature. LC-MS shows predominantly the desired product at ~4.5% of the source material. The reaction mixture was concentrated in vacuo to obtain a dark yellow oil. 200 ml of hexanol add to the oil, and the solution is stirred in an ice bath (<5°C) for 1 h, the Solids are collected by filtration and washed 3 times with 40 ml of hexanol. Solids analyze, and NMR shows that they are a mixture of triphenylphosphine oxide and restored DIAD. LC-MS shows that the hexane filtrate contains ~58% of the desired product. The filtrate was concentrated in vacuo to obtain 10.2 g of yellow oil. The oil is dissolved in 5 ml of absolute ethanol, add 75 ml of hexanol and the solution placed in the freezer over night. The solids are collected by filtration and dried. NMR shows that 4.3 g of white solids comprise ~80%. Solids combined with the filtrate hexanol/ethanol and concentrated in vacuo to obtain 9.3 g of light yellow oil, which its shades without further purification.

1H NMR (270 MHz, CDCl 3): 1,2 (t, 3H); 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: Synthesis of 3-(2,6-dimethylbenzylamine)phenylpropionic acid

Table 13
ConnectionMolecular weightthe mmolgramsml
3-(2,6-dimethylbenzylamine)-ethyl phenylpropionate312,409,3
Ethanol46,0775
7,5N sodium hydroxide40,04,0

9.3 g of oil containing about 60% of 3-(2,6-dimethylbenzylamine)ethyl phenylpropionate, dissolved in 75 ml of absolute ethanol in odnogolosy flask with a capacity of 250 ml round bottom equipped with a stirrer and reflux condenser. To the solution was added to 4.0 ml 7,5N sodium hydroxide. Light yellow solution is heated with reverse Kholodilin the kom (80 ° C) and stirred for 1 h The reaction mixture is analyzed, and LC-MS shows the desired product and the absence of the source of ester. The reaction mixture is cooled to room temperature and concentrated in vacuo to obtain a yellow oil. The oil is dissolved with 25 ml of water and extracted with three times 25 ml of a simple ester. The aqueous layer was cooled to <5 º C and acidified to pH 1 by slow addition of 15 ml of 6N aqueous HCl. The precipitated solid is collected by filtration, washed three times with 25 ml water and dried in air. Solids emuleret in 100 ml of hexanol and is collected by filtration, washed with three times 25 ml of hexanol and air-dried. LC-MS shows that the solids comprise ~80% of the desired product. Solids are heated to 70 º C in 44 ml of a mixture of 3:1 absolute ethanol:water. The solution is stirred and allow to cool to room temperature in a bath with tap water. The solids are collected by filtration, washed with 20 ml of a mixture of 3:1 absolute ethanol:water and air-dried. LC-MS shows that solids are ~98.5% of the desired product. Solids are heated to 70 º C in 36 ml of a mixture of 3:1 absolute ethanol:water. The solution is stirred and allow to cool to room temperature in a bath with tap water. The solids are collected by filtration, washed with 20 ml of a mixture of 3:1 absolute ethanol:water and su is at on the air. LC-MS and NMR show that solids are >99.5% of the desired product. White solid is dried in a vacuum oven at 40 º C for 2 h to obtain 3,91 g (52,9%).

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

EXAMPLES of BIOLOGICAL ACTIVITY

For all the following examples, the biological activity of the compound CF receive in accordance with example 1 chemical synthesis. For experiments activity in vivo connection get CG in accordance with example 3 synthesis. For experiments activity in vitro connection get CG in accordance with example 2 synthesis.

Example:Anti-diabetic effects in mice ob/ob

In obese mice (ob/ob)there is a defect in the protein leptin regulator of appetite and energy metabolism, leading to hyperphagia, obesity and diabetes.

Male fat (homozygous ob/ob) mice C57BL/6J age approximately 8 weeks to get in Jackson Labs (Bar Harbor, ME) and randomly include groups of 5 animals each, so that the groups had similar body weight (45-50 g) and glucose levels in serum (≥300 mg/DL in fed state). A minimum of 7 days provide animals for adaptation after receipt. All animals are kept under conditions of controlled temperature (23 º C), relative humidity (50±5%) and light (7:0-19:00) and give the possibility of free access to standard food (Formulab Diet 5020 Quality Lab Products, Elkridge, MD) and water.

Cohorts of treatment administered daily oral doses of vehicle (1% hypromellose), compounds BI, CF, CA, CB, CC, or CD within 2 weeks. At the end of the treatment period take 100 μl of venous blood in a heparinized capillary tube from posabilities sinus mice ob/ob for chemical analysis of serum.

After 2 weeks of daily oral administration the compound BI (100 mg/kg) and compound CF (60 mg/kg) caused a significant reduction in blood levels of glucose (table 14), triglycerides, and free fatty acids (table 15), as described below.

Table 14
The effects of compounds BI, CF, CA, CB, CC and CD on the model of type II diabetes in male mice ob/ob
GroupGlucose, mg/DLGlucose (% of control)
Media (control)to 423.6±55,0100,0±13,0
BI - 30 mg/kg301,4±29,071,0±7,0
BI - 60 m is/kg 248,8±20,059,0±5,0*
BI 100 mg/kg196,3±6,046,0±1,0*
CF - 60 mg/kg161,2±14,038,0±3,0*
CA - 60 mg/kg402,6±61,095±14,0
CB - 60 mg/kg494,4±72,3117,0±17,0
SS - 60 mg/kg444,4±89,5105±21,0
CD - 60 mg/kg505,6±63,5119,0±15,0
*p<0.05 is statistically significant compared to control media.
Table 15
The effects of compounds BI, CF, CA, CB, CC and CD
the levels of glucose, triglycerides and free fatty acids
in the monitored plasma in obese (ob/ob) mice
GroupGlucose ± standard error of mean (SEM)Triglycerides ± SEMFree fatty acids ± SEM
Mediato 423.6±55,0the level of 121.8±29,41612,4±169,7
BI - 30 mg/kg301,4±29,066,6±3,61272,8±32,5
BI - 60 mg/kg248,8±20,061,4±3,61168,6±56,7
BI 100 mg/kg196,3±6,055,0±3,41245,4±20,0
BI - 60 mg/kg161,2±14,053,8±1,51081,6±47,7
CA - 60 mg/kg402,6±61,0of 92.6±13,71572,2±118,0
CB - 60 mg/kg 494,4±72,3of 118.8±18,02076,2±169,0
SS - 60 mg/kg444,4±89,5to 91.6±13,42043,6±285,0
CD - 60 mg/kg505,6±63,5119,0±14,21961,8±194,2

The example In:Anti-diabetic effects in mice db/db

In mice db/db defective leptin signaling, leading to hyperphagia, obesity and diabetes. In addition, unlike mice, ob/ob on the background of C57BL/6J mice db/db background C57BL/KS are deficiency needs insulin cells of the pancreatic islets, resulting in progression from hyperinsulinemia (associated with peripheral insulin resistance) to hypoinsulinemic diabetes.

Male fat (homozygous db/db) mice C57BL/Ksola age approximately 8 weeks to get in Jackson Labs (Bar Harbor, ME) and randomly include in groups of 5-7 animals each so that the groups had similar body weight (50-55 g) and glucose levels in serum (≥300 mg/DL in fed state); males thin (heterozygous db/+) mice served as cohort controls. A minimum of 7 days provided the tons of animals to adapt after receipt. All animals are kept under conditions of controlled temperature (23 º C), relative humidity (50±5%) and light (7:00-19:00) and give the possibility of free access to standard food (Formulab Diet 5008, Quality Lab Products, Elkridge, MD) and water.

Cohorts of treatment administered daily oral doses of vehicle (1% hypromellose), compounds of BI, CE, BT, BU, BV or fenofibrate for 2 weeks. At the end of the treatment period take 100 μl of venous blood in a heparinized capillary tube from posabilities sinus mice db/db for chemical analysis of serum.

The effects of compounds of the invention on glucose levels in the blood in negrodem condition shown in table 16; the effects on the levels of triglycerides and free fatty acids in serum are shown in table 17.

Table 16
The effects of compounds BI, CE, BT, BU, BV or fenofibrate in mice db/db
GroupGlucose mg/DLGlucose (% of control)
Media (control)692,5±55,4100±8
BI 100 mg/kg347,0±43,1* 50±6*
CE - 93 mg/kg372,0±53,8*54±8*
BT - 107 mg/kg684,3±63,699±9
BU - 128 mg/kg533,3±46,777±7
BV - 115 mg/kg789,5±38,9114±6
Fenofibrat - 113 mg/kg563,2±49,081±7
*The levels of glucose in the blood thin without diabetes heterozygous db/+ mice, are 208,5±6.6 mg/DL.
Table 17
The effects of compounds BI, CE, BT, BU, BV or fenofibrate on the levels of triglycerides and free fatty acids in serum in mice db/db
GroupTriglycerides ± SEM (mg/DL)Free fatty acids ± SEM (µm)
Thin114,2±8,72315,8±238,3
Media232,8±20,73511,8±257,6
BI77,8±5,31997,2±196,4
CE132,0±15,22867,4±267,7
BTof 211.5±21,53897,7±291,3
BU172,5±9,93587,0±156, 3mm
BV153,2±14,23373,8±233,6
Fenofibrateto 109.3±9,13318,5±208,7

Example:Anti-diabetic effect in mice db/db

Mice C57BL/Ksola defective leptin signaling, leading to hyperphagia, obesity and diabetes. In addition, unlike mice, ob/ob on the background of C57BL/6J mice db/db background C57BL/KS are deficiency needs insulin cells of the pancreatic islets, resulting in progression from hyperinsulinemia (associated with peripheral insulin resistance) to hypoinsulinemic diabetes.

Male fat (gomasio the data db/db) mice C57BL/Ksola age approximately 8 weeks to get in Jackson Labs (Bar Harbor, ME) and sorted into groups of 7 animals each, so that the groups had similar body weight (40-45 g) and glucose levels in serum (≥300 mg/DL in fed state). A minimum of 7 days provide animals for adaptation after receipt. All animals are kept under conditions of controlled temperature (23 º C), relative humidity (50±5%) and light (7:00-19:00) and give the possibility of free access to standard food (Formulab Diet 5008, Quality Lab Products, Elkridge, MD) and water.

Cohorts of treatment administered daily oral doses of vehicle (1% hypromellose), compounds BI, CF, CG or phenylacetate in 17 days. At the end of the treatment period take blood samples to measure the levels of glucose and triglycerides in serum. A statistically significant decrease in glucose levels or triglycerides in the blood in comparison with animals treated with oral media, is considered a positive screening result for drug.

Table 18
The effects of compounds BI, CF, CG or phenylacetate
on the model of type I diabetes in mice db/db
GroupGlucose, mg/DL
(±SEM)
Triglycerides (mg/DL)
The media (to the Troll) 812±34352±27
BI 100 mg/kg472±54116±4
BI - 150 mg/kg348±6790±6
CF - 30 mg/kg586±31156±20
CF - 60 mg/kg604±36120±13
CF - 100 mg/kg391±6192±6
CG - 100 mg/kg753±24166±14
The phenylacetate - 300 mg/kg661±64171±33
*p<0.05 is statistically significant compared to control media.

Example D:The potential activation of transcription of the compounds on human and mouse PPARα and PPARγ

Materials and methods:

Cells were seeded in 24-hole tablets 1 day before transfection at a concentration of 5×104-2×105cells/well, depending on the cell type. Cells transferout using the reagent of lipofectamine 2000 from Invitrogen. 0.8 μg of Dncoco added to 50 μl of medium Optimem Reduced Serum (serum-free; Gibco). Lipofectamine 2000 add (2,5 μl/well) in another test tube containing 50 ál of Optimem medium. Plasmid DNA is added in the ratio of 4:3 (reporter:activator); when appropriate, DNA salmon sperm was replaced by a plasmid expressing the activator. Used reporter plasmid is a pFR-Luc, which has a gene for Firefly luciferase GAL4 UAS (STRATAGENE)containing the promoter. Expressing the activator plasmids containing the fusion domain that binds DNA yeast GAL4 (dbd) or domain, a ligand-binding human PPARα (LBD; A.A.. 167-468), or human PPARγ LBD (a.a.176-479). Also use DNA constructs containing the mouse PPARα and PPARγ LBD fused with the binding domain of the GAL4 DNA. These 2 solution incubated at room temperature for 5 min, and then combine. The combined solution is incubated at room temperature for about 30 minutes, the Cells washed once in PBS and each well was added 100 μl transfection mixture. Tablets incubated at 37º in an incubator with 5% CO2for 4.5 h, followed by aspiration transfection mixture at re-submission in tablets full environments EMEM (with the addition of 10% FBS (fetal calf serum), 1X glutamine). 24 h after transfection tablets process the corresponding compounds in full environments EMEM with subsequent single washing the PBS and add 100 ál of lisanova buffer of 1X reporter/well (Promega) at 24 h after treatment. The tablets were subjected to one cycle of freezing/thawing prior to analysis. About 10 μl of the lysate is added to 100 μl of the substrate of Firefly luciferase, mixed by pipetting and analyze on a luminometer for 10 using the integration features (relative luciferase units/RLU) or Microbeta Trilux (pulses luciferase in 1/LCPS). Each processing is performed in three repetitions in mnozhestvennykh experiments.

The results:

Table 19
A hybrid protein LBD murine PPARγ: potential activation of transcription in cells Hepa1.6 (cell line hepatoma mice).
Values are presented in relative luciferase units (RLU) ± standard deviation
ControlsBICF
No processing208±38Nana
3 μm of rosiglitazone1817±331 Nana
1 micronna210±51361±138
3 micronsna256±33602±144
5 µmna254±81710±87
7 PMna265±61786±418
kmna355±531140±111
30 µmna441±2031253±554
100 mmna820±353 1534±608
na = not applicable; nd = not done.
Tables 20A and 20b
Hybrid proteins LBD mouse PPARα and PPARγ:
the potential activation of transcription of the C3A cells (cell line human hepatoma). The values presented in pulses luciferase in 1 (LCPS) ± standard deviation
20A.Murine PPARα
Wy/
control
BICECFCG
Reporter8,73±1,85nananana
No processing20,27±2,61nananana
1 micron 406,73±80,1114,67±1,08for 9.47±2,1413,17±7,844,43±2,25
3 microns295,8±40,3115,2±2,78to 9.57±2,615,63±0,429,17±3,72
10 µm324,37±11,0615,1±3,781,17±2,49153,15±24,47,87±0,7
30 µm414±122,5210,43±1,817,4±0,23358,6±5,2311,63±5,01
100 mm325,3±91,83shed 15.37±6,216,23±0,17201,5±50,8411,8±8,95
200 micronsthe 115.2±21,5218,6±11,668±1,88106,77±32,5380,3±2
na = not applicable.
20b.Murine PPARγ
RosiglitazoneBICECFCG
Reporter8,73±1,85nananana
No processing8,03±1,82nananana
1 micron196,8±138,92,4±2.26 and 14,3±4,50,33±0,21of 8.47±5,01
3 microns60,1±29,142,6±1,4113,43±8,510,6±total of 8.7414,8±4,3
10 µm432,7±137,42,2±1,576,03±3,7517,2±2120,87±4,1
30 µm378±274,54,9±4,429,6±5,4688,2±33,255,4±30,6
100 mm308,6±110,12,63±1,9611,7±11,745,8±36,978,8±23,1
200 micronsNd65,77 the 10,55 10,5±9,293,6±29,7to 101.2±59,1

na = not applicable; nd = not done.
Note: the Concentrations listed in the previous table presents for the tested compounds. The concentration of rosiglitazone was 1/5 the concentration of test compounds; thus, 1 μm of test compounds were compared with 0.2 μm of rosiglitazone, etc.
Table 21
Hybrid proteins LBD mouse PPARα and PPARγ:
the potential activation of transcription in cells C3A.
The values presented in RLU ± standard deviation
21A.Murine PPARα
ControlsCFCG
Only reporter2259±300nana
No processing1217±161nana
100 μm Wy55972±5162nana
100 µm
fenoprofen
4440±213nana
100 µm BI4421±118nana
1 micronNa2694±159361±398
3 micronsNa4527±740706±399
5 µmNa7188±1753492±160
7 PMNa14325±1032652±190
10 µmNa16680±2432394±84
30 µmNa38105±3133651±643
100 mmNa41037±5401926±1362
Na - not applicable.
21b.Murine PPARγ
ControlsBICFCG
No processing302±119nanana
3 μm of rosiglitazone 17264±8260nanana
1 micronna746±362146±119634±195
3 micronsna174±153579±557nd
5 µmna996±855476±527nd
7 PMna220±137834±984nd
10 µmna479±353207±107405±318
30 µmna557±639818±1201 1562±354

100 mmna3330±1848237±2162555±1609
na = not applicable; nd = not done.
Table 22
Hybrid proteins LBD of the human PPARα and PPARγ:
the potential activation of transcription in cells C3A.
The values presented in LCPS ± standard deviation
22A.Human PPARα
WyBICFCECG
Reporter21,93±6,0nananana
No processing180,8±32,2n nanana
1 micron181,8±47,6of 127.7±7,137±11,514,7±14,610,9±11,6
3 microns153,1±2,8128±70,747±22,813,2±5,819,1±6,1
10 µm315,4±36,552,7±8,219,9±7,826,2±1,417,9±5,2
30 µm648,6±47,555,4±16,240,2±18,910,67±1,238,2±21,1
100 mm412,23±11420,9±13,119±14, 6,33±2,623,9±5,3
200 micronsnd31,1±29,412,9±8,312,8±3,7159,4±29,6
na = not applicable; nd = not done.
22b. Human PPARγ
RosiglitazoneBICECFCG
Reporterof 21.9±6,1nananana
No processing39,9±17,5nananana
1 micron124±33,8 43,3±11,660±11,66,2±0,647,9±7,2
3 microns134,8±47,826±4,573,3±30,949,4±7,873,6±39,1
10 µm626,6±22740,1±13,557,3±22,6141,5±25,972,5±28,2
30 µm887,2±338,222,9±10,328,5±16,4230,4±97,2205,6±37,1
100 mm1034,1±400,534,6±15,637,7±23,4225,2±57,5403,6±86,1
200 micronsNd227,3±25,8 12,3±4,8280,1±89,7598,1±190,4
na = not applicable; nd = not done.
Note: the Concentrations listed in the previous table presents for the tested compounds. The concentration of rosiglitazone was 1/5 the concentration of test compounds; thus, 1 μm of test compounds were compared with 0.2 μm of rosiglitazone, etc.

1. The use of biologically active agent to obtain drugs for the treatment of metabolic disorders selected from the group consisting of a syndrome of resistance to insulin and diabetes, including type I diabetes and type II diabetes, and obesity,
where the agent is a compound of the formula

where
n=1 or 2;
m=0, 1, 2, 4, or 5;
q=0;
t=0 or 1;
R3represents hydrogen;
A represents a phenyl, unsubstituted or substituted 1 or 2 alkilani having 1 or 2 carbon atoms; and
R1represents hydrogen or alkyl having 1 or 2 carbon atoms; or
when R1represents hydrogen, pharmaceutically acceptable salt of the compound.

2. The use according to claim 1, where n=1; q=0; t=0; R3represents hydrogen; and A is a Hairdryer is l, unsubstituted or substituted by 1 or 2 alkilani having 1 or 2 carbon atoms.

3. The use according to claim 2, where A represents a 2,6-dimetilfenil.

4. The use according to claim 3, where the biologically active agent is selected from the group consisting of
2-(3-(2,6-dimethylbenzylamine)phenylacetic acid;
3-(2,6-dimethylbenzylamine)benzoic acid;
ethyl 3-(2,6-dimethylbenzylamine)benzoate;
6-(3-(2,6-dimethylsiloxy)phenyl)hexanoic acid;
ethyl 6-[3-(2,6-dimethylsiloxy)phenyl]hexanoate;
5-[3-(2,6-dimethylsiloxy)phenyl]pentanol acid;
ethyl 5-(3-(2,6-dimethylsiloxy)phenyl)pentanoate;
3-(3-(2,6-dimethylsiloxy)phenyl)propionic acid;
ethyl 3-(3-(2,6-dimethylsiloxy)phenyl)propanoate.

5. The use according to any one of claims 1 to 4, where the drug is formulated for oral administration.

6. A method of treating a mammal with a metabolic disorder selected from the group consisting of a syndrome of resistance to insulin, diabetes mellitus, including type I diabetes and type II diabetes, and obesity, comprising administration to the individual of the amount of biologically active agent,
where the agent is a compound of the formula

where
n=1 or 2;
m=0, 1, 2, 4, or 5;
q=0;
t=0 or 1;
R3represents hydrogen;
A represents phenyl, substituted with 1 or 2 alkilani having 1 or 2 acomplete; and
R1represents hydrogen or alkyl having 1 or 2 carbon atoms, or
when R1is a hydrogen -
pharmaceutically acceptable salt of the compound.

7. The method according to claim 6, where n=1; q=0; t=0; R3represents hydrogen; and A is phenyl, unsubstituted or substituted 1 or 2 alkilani having 1 or 2 carbon atoms.

8. The method according to claim 7, where A represents a 2,6-dimetilfenil.

9. The method of claim 8, where the biologically active agent is selected from the group consisting of
2-(3-(2,6-dimethylbenzylamine)phenylacetic acid;
3-(2,6-dimethylbenzylamine)benzoic acid;
ethyl 3-(2,6-dimethylbenzylamine)benzoate;
6-[3-(2,6-dimethylsiloxy)phenyl)hexanoic acid;
ethyl 6-[3-(2,6-dimethylsiloxy)phenyl]hexanoate;
5-(3-(2,6-dimethylsiloxy)phenyl]pentanol acid;
ethyl 5-(3-(2,6-dimethylsiloxy)phenyl)pentanoate;
3-(3-(2,6-dimethylsiloxy)phenyl)propionic acid;
ethyl 3-(3-(2,6-dimethylsiloxy)phenyl)propanoate.

10. The method according to claim 6, where the individual is a human.

11. The method according to claim 10, where the agent is administered orally in an amount of from 1 mg to 400 mg/day.

12. The method according to any of PP-11, where the state represents a syndrome of resistance to insulin or diabetes type II.

13. The method according to claim 6, where the treatment reduces a symptom of diabetes or the probability times the ing symptom of diabetes.

14. Pharmaceutical composition for oral administration suitable for the treatment of metabolic disorders selected from the group consisting of a syndrome of resistance to insulin, diabetes mellitus, including type I diabetes and type II diabetes, and obesity, including pharmaceutically acceptable carrier and from 1 mg to 400 mg of bioactive agent,
where the agent is a compound of the formula

where
n=1 or 2;
m=0, 1, 2, 4, or 5;
q=0;
t=0 or 1;
R3represents hydrogen;
A represents a phenyl, unsubstituted or substituted 1 or 2 alkilani having 1 or 2 carbon atoms; and
R1represents hydrogen or alkyl having 1 or 2 carbon atoms, or
when R1is a hydrogen -
pharmaceutically acceptable salt of the compound.

15. The pharmaceutical composition according to 14, where n=1; q=0; t=0;
R3represents hydrogen; and
A represents a phenyl, unsubstituted or substituted 1 or 2 alkilani having 1 or 2 carbon atoms.

16. The pharmaceutical composition according to item 15, where A represents a 2,6-dimetilfenil.

17. The pharmaceutical composition according to clause 16, where the biologically active agent is selected from the group consisting of
2-(3-(2,6-dimethylbenzylamine)phenylacetic acid;
3-(2,6-dimethylbenzylamine)benzoic acid;
ethyl 3-(2,6-dimethyle is siloxy)benzoate;
6-(3-(2,6-dimethylsiloxy)phenyl)hexanoic acid;
ethyl 6-[3-(2,6-dimethylsiloxy)phenyl]hexanoate;
5-(3-(2,6-dimethylsiloxy)phenyl]pentanol acid;
ethyl 5-(3-(2,6-dimethylsiloxy)phenyl)pentanoate;
3-(3-(2,6-dimethylsiloxy)phenyl)propionic acid;
ethyl 3-(3-(2,6-dimethylsiloxy)phenyl)propanoate.

18. The pharmaceutical composition according to any one of p-17 in oral dosage form.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1 and R2 represent hydrogen atom; R3 represents benzyl, substituted -O(C1-4alkyl); R5 represents methyl; R6 represents C1-6alkyl; R11 and R12 together form 5-membered heterocyclyldiyl of structure R19 andR20 are independently selected from C1-6alkyl; R13 represents fragment ; R16 represents NO2, R14, R15, R17, and R18 represent hydrogen atom.

EFFECT: compounds of formula (VII) as intermediate products for obtaining macrolides.

6 cl, 18 dwg; 3 ex

FIELD: chemistry.

SUBSTANCE: disclosed are novel 4-biphenyl carboxylic acid derivatives of formula 1 as an organic mechanoluminescent material. Also disclosed is a mechanoluminescent composition which contains an effective amount of the mechanoluminescent substance of formula 1 and a luminescent substance.

EFFECT: novel efficient mechanoluminescent materials based on cheap and nontoxic organic substances.

3 cl, 2 dwg, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds - benzoquinone derivatives of formula (I): , where each of R1 and R2 is O-C(O)phenyl; where the phenyl is substituted with 1 substitute selected from halide, nitro, C1-C6 alkyl or C1-C6 alkoxy, and pharmaceutically acceptable salts thereof.

EFFECT: low activity of pancreatic lipase based on compounds of the said formula.

6 cl, 3 tbl, 23 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing dialkyl ether of naphthalene dicarboxylic acid used in production of different polymer materials such as polyesters or polyamides from a liquid-phase reaction mixture containing low-molecular alcohol, naphthalene dicarboxylic acid, and material which contains polyethylene naphthalate, in mass ratio of alcohol to acid between 1:1 and 10:1, at temperature between 260°C and 370°C and pressure between 5 and 250 absolute atmospheres.

EFFECT: method enables production of highly pure NDC.

6 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new substituted phenoxy-aceitic acids (I), in which: X is halogen, cyano, nitro or C1-4alkyl, which is substituted with one or more halogen atoms; Y is chosen from hydrogen, halogen or C1-C6alkyl, Z is phenyl, naphthyl or ring A, where A is a six-member heterocyclic aromatic ring containing one or two nitrogen atoms, or can be 6,6- or 6,5-condensed bicycle which contains one O, N or S atoms, or can be 6,5-condensed bicycle which contains two O atoms, where phenyl, naphthyl or ring A can all be substituted with one or more substitutes, independently chosen from halogen, CN, OH, nitro, COR9, CO2R6, SO2R9, OR9, SR9, SO2NR10R11, CONR10R11, NR10R11, NHSO2R9, NR9SO2R9, NR6CO2R6, NR9COR9, NR6CONR4R5, NR6SO2NR4R5, phenyl or C1-6alkyl, where the last group can possibly be substituted with one or more substitutes, independently chosen from halogen; R1 and R2 independently represent a hydrogen atom or C1-6alkyl group, R4 and R5 independently represent hydrogen, C3-C7cycloalkyl or C1-6alkyl, R6 is a hydrogen atom of C1-6alkyl; R8 is C1-4alkyl; R9 is C1-6alkyl, possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; R10 and R11 independently represent phenyl, 5-member aromatic ring which contains two heteroatoms, chosen from N or S, hydrogen, C3-C7cycloalkyl or C1-6alkyl, where the last two groups are possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; or R10 and R11 together with the nitrogen atom to which they are bonded, can form a 3- to 8-member saturated heterocyclic ring, which possibly contains one or more atoms chosen from O, S(O)n (where n= 0, 1 or 2), NR8.

EFFECT: invention relates to a method of modulating activity of CRTh2 receptors, involving administration of therapeutically effective amount of formula compound or its pharmaceutically acceptable salt to a patient.

9 cl, 170 ex

FIELD: chemistry.

SUBSTANCE: invention refers to synthesis of [18F]fluororganic compounds ensured by reaction of [18F]fluoride and relevant halogenide or sulphonate with alcoholic vehicle of formula 1 where R1, R2 and R3 represent hydrogen atom or C1-C18 alkyl.

EFFECT: possibility for mild process with low reaction time and high yield.

21 cl, 2 tbl, 27 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with formula , in which R represents H, (C1-C12)-alkyl or (C1-C4)-alkyl-(C6-C12)-aryl. In the alkyl, one or more CH2-groups can be substituted with -O-. The invention also relates to the method of obtaining these compounds. The method involves reacting dimethylbenzoic acid ester with formula where R assumes values given above, with a chlorinating agent in an inert solvent or without a solvent at temperature above 40°C, and then cleaning, if necessary. Formula (I) compounds are essential intermediate products during synthesis of PPAR agonists with formula , in which R represents H, (C1-C12)-alkyl or (C1-C4)-alkyl-(C6-C12)-aryl. In the alkyl, one or more CH2-groups can be substituted with -O-; Y represents -(CH2)3-, 1,3-phenylene, 1,3-cyclohexanediyl; R' represents H, F, Br, CF3, (C1-C6)-alkyl, O-(C1-C6)-alkyl, phenyl; CF3; obtained from reaction of compounds with formula with formula (I) compounds in toluene, N-methylpyrrolidone or other aprotic solvents, in the presence of a suitable base, at temperature lying in the -78°C - +50°C interval, with subsequent extractive processing and, if necessary, crystallisation of the end product.

EFFECT: obtaining new compounds.

8 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula I R1 represents phenyl, possibly substituted with phenyl or heterocyclic group, or heterocyclic group, possibly substituted with phenyl, where said heterocyclic group represents mono- or bicyclic ring, containing 4-12 atoms, of which at least one atom is selected from nitrogen, sulfur or oxygen, each phenyl or heterocyclic group possibly being substituted with one or more than one of the following groups: C1-6alkyl group; phenylC1-6alkyl, alkyl, phenyl or alkylphenyl group is possibly substituted with one or more than one from Rb; halogen; -ORa; -OSO2Rd; -SO2Rd; -SORd; -SO2ORa; where Ra represents H, C1-6alkyl group, phenyl or phenylC1-6alkyl group; where R represents halogeno, -OH, -OC1-4alkyl, Ophenyl, -OC1-4alkylphenyl, and Rd represents C1-4alkyl; group -(CH2)m-T-(CH2)n-U-(CH2)p- is bound either in third, or in fourth position in phenyl ring, as shown with figures in formula I, and represents group selected from one or more than one of the following: O(CH2)2, O(CH2)3, NC(O)NR4(CH2)2, CH2S(O2)NR5(CH2)2, CH2N(R6)C(O)CH2, (CH2)2N(R6)C(O)(CH2)2, C(O)NR7CH2, C(O)NR7(CH2)2 and CH2N(R6)C(O)CH2O; V represents O, NR8 or single bond; q represents 1, 2 or 3; W represents O, S or single bond; R2 represents halogeno or C1-4alkoxyl group; r represents 0, 1, 2 or 3; s represents 0; and R6 independently represent H or C1-10alkyl group; R4, R5, R7 and R8 represent hydrogen atom; and to their pharmaceutically acceptable salts.

EFFECT: increase of composition efficiency.

12 cl, 31 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing dimethyl-1,5-naphthalene dicarboxylate that is used in preparing polymers based on thereof and articles made of these polymers. The economic and effective method involves the following stages: (1) dehydrogenation of 1,5-dimethyltetraline to yield 1,5-dimethylnaphthalene; (2) oxidation of 1,5-dimethylnaphthalene prepared at dehydrogenation stage to yield 1,5-naphthalene dicarboxylic acid being without accompanying isomerization stage, and (3) esterification of 1,5-naphthalene dicarboxylic acid prepared at oxidation stage in the presence of methanol to yield the final dimethyl-1,5-naphthalene dicarboxylate.

EFFECT: improved preparing method.

9 cl, 3 dwg, 5 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing acylated 1,3-dicarbonylic compounds used as agrochemicals or intermediate products in manufacturing agrochemicals. Also, invention describes a method for preparing tautomeric forms of acylated 1,3-dicarbonylic compounds. Method involves the arrangement reaction of the corresponding enol ester and this rearrangement reaction is carried out in the presence of alkaline metal azide. Method provides eliminating the requirement in expensive isolating process of catalyst/reagent in systems for waste treatment.

EFFECT: improved preparing method.

7 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel omega-3 lipid compounds of general formula (I) or to their pharmaceutically acceptable salt, where in formula (I): R1 and R2 are similar or different and can be selected from group of substitutes, consisting of hydrogen atom, hydroxy group, C1-C7alkyl group, halogen atom, C1-C7alkoxy group, C1-C7alkylthio group, C1-C7alkoxycarbonyl group, carboxy group, aminogroup and C1-C7alkylamino group; X represents carboxylic acid or its carbonate, selected from ethylcarboxylate, methylcarboxylate, n-propylcarboxylate, isopropylcarboxylate, n-butylcarboxylate, sec-butylcarboxylate or n-hexylcarboxylate, carboxylic acid in form of triglyceride, diglyceride, 1-monoglyceride or 2-monoglyceride, or carboxamide, selected from primary carboxamide, N-methylcarboxamide, N,N-dimethylcarboxamide, N-ethylcarboxamide or N,N-diethylcarboxamide; and Y stands for C16-C22 alkene with two or more double bonds, which have E- and/or Z-configuration.

EFFECT: described are pharmaceutical and lipid compositions, which contain said compounds, for application as medications, in particular, for treatment and/or prevention of peripheral insulin resistance and/or condition of diabetes, for instance, type 2 diabetes, increased levels of triglycerides and/or levels of non-HDL cholesterol, LDL cholesterol and VLDL cholesterol, hyperlipidemic condition, for instance, hypertriglyceridemia (HTG), obesity or condition of excessive body weight, fatty liver disease, for instance, non-alcoholic fatty liver disease (NAFLD) or inflammatory disease or condition.

60 cl, 3 tbl, 65 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

in which m equals 1; n equals 1 or 2; t equals 0 or 1; and A is phenyl, substituted with 2 alkyl groups containing 1 or 2 carbon atoms.

EFFECT: compounds of the disclosed formula can be used as intermediate compounds for producing compounds used to treat various metabolic diseases, such as insulin resistance syndrome, diabetes, hyperlipidaemia, bacony liver, cachexia, obesity, atherosclerosis and arteriosclerosis.

17 tbl, 2 dwg, 53 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a method of producing a compound of formula (I), where N equals 0, and values of substitutes R, R1 are given in claim 1, which involves: (i) esterification of a compound of formula (V) with an alcohol of formula , where m and m' are independently equal to 0 or 1; under the condition that both are not equal to 0 at the same time and values of A are given in claim 1, to obtain a compound of formula (III); (ii) reaction of the compound of formula (III) and a compound of formula (IV) to obtain a compound of formula (II); and (iii) reaction of the compound of formula (II) with L-CH2-C≡CH, wherein L is a leaving group, to form a compound of formula (I); intermediate compounds of formula (II), formula (III) and formula (XII) are also disclosed.

EFFECT: improved method.

15 cl, 19 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula (I) where X is carboxylic acid, carboxylates, carboxylic anhydride, diglyceride, triglyceride, phospholipid, or carboxamides, or to any their pharmaceutically acceptable salt. The invention particularly refers to (4Z, 7Z, 10Z, 13Z, 16Z, 19Z)-ethyl 2-ethyldocosa-4,7,10,13,16,19-hexanoate. The invention also refers to a food lipid composition and to a composition for diabetes, for reducing insulin, blood glucose, plasma triglyceride, for dislipidemia, for reducing blood cholesterol, body weight and for peripheral insulin resistance, including such compounds. Besides, the invention refers to methods for treating and/or preventing diabetes, dislipidemia, peripheral insulin resistance, body weight reduction and/or weight gain prevention, insulin, blood cholesterol, blood glucose and/or plasma triglyceride reduction.

EFFECT: higher clinical effectiveness.

61 cl, 4 tbl, 16 dwg, 5 ex

FIELD: chemistry.

SUBSTANCE: method of regioselective obtainment of 1-R1-2-R2-3-acetyl-glycerol derivative of the Formula 1 involves the following stages: Obtainment of 1-R1-3-(protective group)-glycerol of Formula 3 by adding protective group to 3rd position in 1-R1-glycerol of Formula 2; obtainment of 1-R1-2-R2-3-(protective group)-glycerol of Formula 4 by adding R2 group to 2nd position of 1-R1-3-(protective group)-glycerol of Formula 3, where R2 group is added by reaction of R2-OH with 1-R1-3-(protective group)-glycerol in the presence of aprotic organic solvent, catalyst and dehydrating medium; aprotic organic solvent is selected out of group consisting of hexane, heptane, dichloromethane, ethyl acetate, tetrahydrofuran and mixes thereof; dimethylaminopyridine is catalyst; and dicyclohexylcarbodiimide is dehydration medium; simultaneous removal of protective group and acetylation of 1-R1-2-R2-3-(protective group)-glycerol of Formula 4, where protective group removal reaction and acetylation reaction are performed using Lewis acid and acetic anhydride or using acetylation agent; Lewis acid is selected out of group including zink chloride (ZnC2), tin chloride (SnCl2), boron trifluoride diethyl ether (BF3Et2O) and mixes thereof; acetylation agent is selected out of group including acetylchloride, acetylbromide and mixes thereof, where compounds of Formulae 1-4 are racemic or optically active; R1 is palmitic acid group, R2 is linoleic acid group; P is trityl or trialkylsilyl as protective group; alkyl in trialkylsilyl is an alkylic group containing 1-5 carbon atoms, so that if the protective group is trityl then 1-R1-3-(protective group)-glycerol is obtained in the presence of pyridine solvent at 40-60°C or in the presence of nonpolar aprotic organic solvent and organic base within 0°C to room temperature range; nonpolar aprotic organic solvent is selected out of group including pyridine, dichloromethane, tetrahydrofuran, ethyl acetate and mixes thereof; organic base is selected out of group including triethylamine, tributylamine, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU) and mixes thereof, and if the protective group is trialkylsilyl then 1-R1-3-(protective group)-glycerol is obtained in the presence of aprotic organic solvent and organic base within 0°C to room temperature range; aprotic organic solvent is selected out of group including dichloromethane, tetrahydrofuran, ethyl acetate, dimethylformamide and mixes thereof; and organic base is selected out of group including imidazole, triethylamine, and mixes thereof. [Formula 1] , [Formula 2] , [Formula 3] , [Formula 4] .

EFFECT: obtainment of glycerol derivative with high efficiency and output.

8 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel hexafluoroisopropanol-substituted ether derivatives of formula (I) to their pharmaceutically acceptable salts and to esters which are capable of bonding with LXR-alpha and/or LXR-beta, as well as to pharmaceutical compositions based on said compounds. In formula (I) R1 is hydrogen, lower alkyl or halogen, one of groups R2 and R3 is hydrogen, lower alkyl or halogen, and the second of groups R2 and R3 is -O-CHR4-(CH2)m-(CHR5)n-R6. Values of R4, R5, R6 m and n are given in the formula of invention.

EFFECT: novel compounds have useful biological properties.

22 cl, 4 dwg, 102 ex

FIELD: organic chemistry, medicine, pharmacy.

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

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 6 tbl, 6 sch, 251 ex

The invention relates to an improved process for the preparation of ethyl ester of 10-(2,3,4-trimetoksi-6-were) decanoas acid, which is an intermediate product, suitable for the synthesis of idebenone - drug nootropic action

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

in which m equals 1; n equals 1 or 2; t equals 0 or 1; and A is phenyl, substituted with 2 alkyl groups containing 1 or 2 carbon atoms.

EFFECT: compounds of the disclosed formula can be used as intermediate compounds for producing compounds used to treat various metabolic diseases, such as insulin resistance syndrome, diabetes, hyperlipidaemia, bacony liver, cachexia, obesity, atherosclerosis and arteriosclerosis.

17 tbl, 2 dwg, 53 ex

Up!