Monoaminooxidase (mao-b) inhibitors

FIELD: chemistry.

SUBSTANCE: invention refers to novel compounds of the general formula (I) , where R1, R2 are independently H or C1-C6-alkyl; R3, R4 are independently H or C1-C6-alkyl; R5 is halogen, CN; n, m or o are 0, 1 or 2; and to pharmaceutically acceptable salts thereof.

EFFECT: compounds with monoaminooxidase B inhibition properties applicable in obtainment of pharmaceutical drugs with relevant effect.

14 cl, 3 dwg, 31 ex

 

This invention relates to benzyloxypropionic General formula

where

R1and R2independently of one another are N or C1-C6-alkyl;

R3and R4independently of one another are N or C1-C6-alkyl;

R5represents halogen, CN, (C1-C6)-alkyl or (C1-C6)-alkoxy;

n, m and o are 0, 1 or 2;

and their pharmaceutically acceptable salts.

This invention includes both the individual isomers of the compounds of formula I and their racemic and nerezisca mixture.

The compounds of formula I and their pharmaceutically acceptable salts, individual isomers of compounds of formula I and their racemic and nerezisca mixture (hereinafter: the Pharmaceutical Compound) have pharmacological activity and are suitable for use as pharmaceuticals. In particular, Pharmaceutical Compounds inhibit the activity of monoamine oxidase Century

Monoamine oxidase (MAO) is a flavin-containing enzyme responsible for the oxidative deamination of endogenous monoamine neurotransmitters, such as dopamine, serotonin, epinephrine, or norepinephrine, and trace amines, such as phenethylamine, as well as the number of amine Xen is biotikos. This enzyme exists in two forms, MAO-a and MOA-encoded by different genes (A.W.Bach et al., Proc. Natl. Acad. Sci. USA 1988, 85, 4934-4938) and different tissue distribution, structure and substrate specificity. MAO-A has a higher affinity for serotonin, octopamine, adrenaline and noradrenaline, whereas phenylethylamine and tyramine are the natural substrates for MAO-Century, it Is believed that dopamine is oxidized by both isoforms. MAO-b is widely distributed in certain organs, including the brain (A.M.Cesura and A.Pletscher, Prog. Drug Research 1992, 38, 171-297). I believe that with age, MAO-b activity in the brain increases. This increase was explained by gliosis associated with aging (C.J.Fowler et al., J.Neural.Transm.1980, 49, 1-20). Furthermore, the activity of MAO-b is significantly higher in the brain of patients with Alzheimer's disease (P.Dostert et al., Biochem. Pharmacol. 1989, 38, 555-561) and was found highly expressed in astrocytes around senile plaques (Saura et.al., Neoroscience 1994, 70, 755-774). In this regard, since the oxidative deamination of primary monoamines under the action of MAO leads to NH3, aldehydes and H2O2, substances with an established or potential toxicity, it is assumed that there is a reasonable explanation for the use of selective MAO-b inhibitors for the treatment of dementia and Parkinson's disease. Inhibition of MAO-b causes a decrease in the enzymatic inactivation of diam is on and thus, prolonging the health of neurotransmitter in dopaminergic neurons. Also degenerative processes associated with aging and diseases Alzheimer's and Parkinson's, can be explained by oxidative stress due to increased activity of MAO and, as a consequence, the increased formation of H2O2under the action of MAO-Century Therefore, MAO-b inhibitors can affect both reduce the formation of oxygen radicals, and increase levels of monoamines in the brain.

Given the above-mentioned effect of MAO-b IN neurological disorders, there is considerable interest to obtain an effective and selective inhibitors that would control this enzymatic activity. For example, the pharmacology of some well-known MAO-b is discussed D.Bentue-Ferrer et.al. in CNS Drugs 1996, 6, 217-236. The main limitation of activity and irreversible selective MAO-a inhibitor is compliance with dietary restrictions because of the risk of occurrence of hypertensive crisis if used tiramina with food, as well as the possibility of interactions with other medicines (D.M.Gardner et al., J.Clin. Psychiatry 1996, 57, 99-104), and to the reversible and selective MAO-inhibitors, particularly for MAO-B, these adverse facts are to a lesser extent. Thus, there is a need for MAO-b inhibitors with high is some selectivity and without adverse side effects, the usual irreversible MAO-inhibitors with low selectivity to the enzyme.

Pharmaceutical Compounds, respectively, are useful as selective inhibitors of monoamine oxidase In, for example, in the treatment or prevention of diseases and conditions in which plays a role or is included activity monoamine oxidase Century features of this condition include acute and/or chronic neurological disorders.

Acute and/or chronic neurological disorders include psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory disorders like mild cognitive impairment, age-related cognitive decline, multi-infarct dementia, Parkinson's disease, memory impairment associated with depression or anxiety, down syndrome, stroke, traumatic brain injury and attention deficit disorder. Other conditions that can be treated are limited brain function caused by bypass operations or transplants, poor cerebral perfusion, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycemia. Also conditions that can be treated are acute and chronic pain, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by HIV, eye injuries, re is ineptia, idiopathic parkinsonism or medicated Parkinson's disease, and conditions which lead to glutamate-insufficient functions, such as muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychotic attacks, opiate addiction, anxiety, vomiting, dyskinesia and depression.

In one embodiment of acute and/or chronic neurological disturbance is Alzheimer's disease. In another embodiment of acute and/or chronic neurological disturbance is a mild cognitive disorder or senile dementia.

Thus, the present invention is to create connections that need to have the above useful properties. It has been found that the compounds of formula I of this invention and their pharmaceutically acceptable salts show the potential to be highly selective MAO-b inhibitors. In addition, objects of the present invention are also drugs, based on the compound of formula I in accordance with this invention, the production method of the compounds of formula I and their pharmaceutically acceptable salts, and also the use of compounds of formula I for the treatment or prevention of diseases mediated by inhibitors monoamine oxidase, and accordingly the use of manufacturer for the appropriate medication.

The following definitions of common terms used in this application, apply regardless of whether these terms separately or in combination. It should be noted that in the description and appended claims, the singular number include the plural, except in those cases where the context clearly should be the opposite.

The term "C1-C6-alkyl" ("lower alkyl")as used in this application, denotes unbranched or branched saturated hydrocarbon residues with 1 to 6 carbon atoms, preferably 1-4 carbon atoms, such as methyl, ethyl, n-propyl, ISO-propyl, n-butyl, sec-butyl, tert-butyl, etc.

The term "halogen" denotes fluorine, chlorine, bromine and iodine.

"Alkoxy" or "(C1-C6)-alkoxy" means a residue-O-R, where R represents the residue of a lower alkyl as defined here. Examples of alkoxyalkyl include, but are not limited to, methoxy, ethoxy, isopropoxy etc.

The term "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable, they are generally safe, non-toxic and are not junk neither biologically nor otherwise not appropriate and which possess the desired pharmacological activity ishodnoj the connection. These salts derived from inorganic or organic acids or bases.

Such salts include:

(1) acid additive salts formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids, for example acetic acid, benzosulfimide acid, benzoic acid, camphorsulfonic acid, citric acid, econsultancy acid, fumaric acid, glucoheptonate acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, almond acid, methanesulfonic acid, Mukanova acid, 2-naphtalenesulfonic acid, propionic acid, salicylic acid, succinic acid, Dibenzoyl-L-tartaric acid, tartaric acid, p-toluensulfonate acid, trimethylhexanoic acid, 2,2,2-triperoxonane acid and the like; or

(2) salts formed when either the replacement of the acidic proton in the initial connection of a metal ion such as alkali metal ion, alkali earth metal ion or an aluminum ion; or in coordination with an organic or inorganic base. Acceptable institutions the institutions of the Foundation include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

It should be understood that all references to pharmaceutically acceptable salts include forms include solvent (solvate) or crystal forms (polymorphs) of the same acid additive salt.

"Pharmaceutically acceptable," such as pharmaceutically acceptable carrier, excipient etc., means pharmacologically acceptable and substantially non-toxic to the subject, which introduces a particular connection.

"Therapeutically effective amount" means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the life of the object undergoing a course of treatment.

In addition, as used here, the term "mammal that is in need in the treatment of acute and/or chronic neurological disorders" means a mammal, such as a person that suffers from or is at risk to suffer from acute and/or chronic neurological disorder.

Used the terms "treat", "treating", "treatment", etc. applicable to acute and/or chronic neurological disturbance, are treated as methods that slow down, improve weaken or eliminate such violation or any of the symptoms associated with the violation, disturbing subject, and to methods which prevent the violation or any symptoms of its manifestation.

Among the compounds of the present invention preferred are the compounds of formula I or their pharmaceutically acceptable salts.

Preferred compounds of formula I are those in which o represents 1, a m is 0, for example, the following connections:

2-(4-benzyloxy-phenoxy)-N-methyl-acetamide", she

2-[4-(4-cyano-benzyloxy)-phenoxy]-N-methyl-acetamide", she

2-[4-(4-chloro-benzyloxy)-phenoxy]-N-methyl-acetamide", she

2-[4-(2-fluoro-benzyloxy)-phenoxy]-N-methyl-acetamide", she

2-[4-(3-fluoro-benzyloxy)-phenoxy]-N-methyl-acetamide", she

2-[4-(4-fluoro-benzyloxy)-phenoxy]-N-methyl-acetamide", she

(RS)-2-[4-(3-fluoro-benzyloxy)-phenoxy]-N-methyl-propionamide,

(RS)-2-[4-(3-chloro-benzyloxy)-phenoxy]-N-methyl-propionamide,

(S or R)-2-[4-(3-chloro-benzyloxy)-phenoxy]-N-methyl-propionamide,

(RS)-2-[4-(4-cyano-benzyloxy)-phenoxy]-N-methyl-propionamide,

(RS)-2-[4-(3-fluoro-benzyloxy)-phenoxy]-N-methyl-butyramide,

(RS)-2-[4-(3-chloro-benzyloxy)-phenoxy]-N-methyl-butyramide or

(RS)-2-[4-(4-cyano-benzyloxy)-phenoxy]-N-methyl-butyramide.

Also preferred are the compounds of formula I, in which o is 2 and m is 0, for example 3-[4-(3-fluoro-benzyloxy)-phenoxy]-propiona the doctor

Another preferred group of compounds of formula I are those where o represents 0, m represents 2, for example 2-[4-(3-fluoro-benzyloxy)-phenyl]-ethyl ether of carbamino acid.

Also preferred are the compounds of formula I, where o represents 0 and m is 1, for example 4-(3-fluoro-benzyloxy)-benzyl ester methylcarbamyl acid.

In addition, a preferred group of compounds of formula I are those where o represents 1 and m represents 1, for example 2-[4-(3-fluoro-benzyloxy)-benzyloxy]-ndimethylacetamide.

These compounds of General formula I and their pharmaceutically acceptable salts can be obtained is known from the prior art methods, for example, the methods described below, in which

a) compound of the formula

subjected to interaction with the compound of the formula

where Y is a leaving group, to obtain compounds of formula

where the substituents such as described above, or

b) the compound of the formula

where R6represents a C1-C6-alkyl, are subjected to interaction with the amine of the formula

obtaining the compounds of formula

where the substituents are as described above, or

C) the compound of the formula

subjected to interaction with KOCN or R3-N=C=O (VII) to give compounds of the formula

where the substituents are as described above, or

g) the compound of the formula

subjected to interaction with the compound of the formula HNR3R4(V) obtaining the compounds of formula

where the substituents are as described above, and

if desired, transfer the compounds obtained into pharmaceutically acceptable acid additive salt.

According to the present invention in schemes 1-3 shows the possibility of obtaining compounds of General formula I.

Scheme 1

Deputies, n, m and o have the above meanings and Y is a leaving group.

Compounds of General formula I can be obtained by synthesis of ethers by the Williamson, starting from the corresponding para-substituted phenols of the formula II by reaction with benzyl halides, tozilaty, mesylates or triflate formula III. As grounds, for example, you can use the alcoholate or carbonates (sodium carbonate, potassium or cesium). Preferred solvents are lower alcohols, acetonitrile and the and lower ketones at a temperature from 20°C to the temperature of reflux distilled. Another way represents the interaction of the benzyl alcohols of the formula III with the corresponding phenols of formula II by reaction of combinations of Mitsunobu. Usually the reaction is carried out in inert solvents, such as diethyl ether or tetrahydrofuran, using dialkyldithiocarbamate, in the presence of phosphines (for example, tributyl or triphenylphosphine). In the case when R7represents NR3R4in the above-mentioned reactions alkylation directly get the desired compounds of formula I.

The ester of formula IV can be converted into the desired end product of the General formula I using standard procedures: aminolysis with HNR3R4in solvents like methanol, tetrahydrofuran and the like, or by saponification to the corresponding acid (e.g., LiOH or KOH in methanol), the activation of the acid via the acid chloride (thionyl chloride or oxalylamino) or activated with N,N'-dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) and the like, and interaction with the amine HNR3R4.

Compounds of General formula II and IX can be obtained by using the compound of formula IV or I, optionally substituted benzyl residue, which can function as a transitional group and chipped off during hydrogenolysis. Received in financial p is Tata phenols of the formula II and IX can then be re-alkilirovanii other benzyl group under the above conditions. As is known to a qualified specialist in this field, this process is possible only in the case when other substituents and functional groups are stable under the above reaction conditions hydrogenolysis and alkylation.

Figure 2 shows the method of obtaining intermediates for compounds of formula I. Similarly to the procedures described previously, mono-alkylation of phenol X with benzyl halides, tozilaty, mesylates or triflate formula III by reaction synthesis of ethers Williamson leads to hydroxyl derivative of formula XI. Another way represents the interaction of the benzyl alcohols of the formula III with the corresponding phenols of formula X by reaction of combinations of Mitsunobu. Usually the reaction is carried out in inert solvents, such as diethyl ether or tetrahydrofuran, using dialkyldithiocarbamate, in the presence of phosphines (such as tributyl or triphenylphosphine). The compounds of formula XI can be further alkilirovanii under the action of the ester derivatives of formula XII with obtaining compounds of formula IV. This alkylation reaction can also be carried out in the previously described conditions, primarily well known to a qualified specialist in this field.

The compounds of formula XIV can be obtained by joining Michael hydroxyl derivatives, with therefore, its salts, formulas XI to the acrylates of formula XIII in a solvent that is inert under these reaction conditions, preferably in concentrated acrylate at a temperature of from room temperature to the temperature of reflux distilled. Grounds for obtaining the alcoholate can be, for example, sodium or sodium hydride. In order to obtain the compounds of formula I, the above intermediate compounds of formula IV and XIV is treated with amines of the formula V according to the above procedures.

Scheme 2

Deputies, n and m have the above meanings. Figure 3 illustrates the formation of compounds of formula Ia and Ib, where n=0. The reaction of the hydroxyl derivative of formula VI with potassium cyanate or alkylsulfonate in sealed vessels using solvents such dichloromethane or toluene at temperatures from room temperature up to 100°C leads to the formation of carbamates of formula Ia.

The carbonates of the formula VIII are formed during the reaction of hydroxyl derivatives of formula VI with phenyl-chloroformate, preferably substituted phenyl-chloroformate, for example 4-nitrophenyl chloroformiate. The compounds of formula Ib obtained when the interaction of these carbonates with amines of General formula V, preferably in sealed test tubes and the solvent, inert under the reaction conditions, for example tetrahydrofuran or dixonary a temperature of 0 to 60°C.

Scheme 3

Deputies, n and m have the above meanings. Also compounds of General formula I may exist in optically pure form. According to the known methods, the separation of the antipodes can be done either at an early stage of the synthesis, starting with compounds of formula XII, during the salt formation with optically active amines, such as, for example, (+)- or (-)-1-phenylethylamine or (+)- or (-)-1-naphthylethylene, and separation of the diastereomeric salts by fractional crystallization or by derivatization with chiral auxiliary substance, such as, for example, (+)- or (-)-2-butanol, (+)- or (-)-1-phenylethanol, (+)- or (-)-menthol and separation of the diastereomeric products khromatograficheskii and/or crystallization and subsequent disconnection with chiral auxiliary substance; or at the latest stage in the separation of enantiomers of formula I, chromatography on chiral phase. Moreover, the compounds of formula I can also be obtained from enantioface intermediate compounds obtained by biotransformation, such as hydrolysis of esters of formula IV, IX, XII or XIV under the action of enzymes, such as hydrolases or lipase. To determine the absolute configuration of the obtained derivatives net diastereomeric salts or derivatives can be analyzed traditional spectroscopic the ski techniques the most appropriate of which is x-ray spectroscopy on single crystals.

Pharmaceutically acceptable salts of compounds of formula I can be easily obtained according to known methods, taking into account the nature of the turn in the Sol connection. For the formation of pharmaceutically acceptable salts of basic compounds of formula I suitable inorganic or organic acids are, for example, as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate acid, p-toluensulfonate acid and other Compounds containing alkaline or alkaline earth metals such as sodium, potassium, calcium, magnesium and the like, basic amines or basic amino acids suitable for the formation of pharmaceutically acceptable salts of acidic compounds.

As already mentioned, the compounds of formula 1 and their pharmaceutically acceptable salts are inhibitors monoamine oxidase In and can be used for the treatment or prevention of diseases which can be useful MAO-b inhibitors. These diseases include acute and chronic neurological disorders, cognitive disorders and memory impairment. Treatable neurological disorders are, for example, traumatic and chronic degenerative processes of the nervous system such as Alzheimer's disease, other dementia, minimal cognitive impairment or Parkinson's disease. Other indications include psychiatric disorders, such as depression, anxiety, panic attack, social phobia, schizophrenia, eating disorders and metabolic disorders such as obesity, and the prevention and treatment of withdrawal symptoms caused by alcohol, nicotine, and other drugs that cause addiction. Other treatable indications can be deficiency syndrome significance (G.M.Sullivan, international application number WO 01/34172 A2), peripheral neuropathy caused by cancer chemotherapy (G.Bobotas, international application number WO 97/33572 A1), or the treatment of multiple sclerosis (R.Y.Harris, international application number WO 96/40095 A1) and other neirolepticalkie disease.

Using the following method, examined the pharmacological activity of the compounds.

The pharmacological activity of the Pharmaceutical Compounds can be shown, for example, as follows:

cDNA coding MAO-a and MAO-b person was temporarily transfusional into EBNA cells using the described Schlaeger and Christensen procedure [Cytotechnology 15:1-13 (1998)]. After transfection cells homogeny Aravali in the homogenizer transmitter station in 20 mm Tris HCl buffer, pH 8.0, containing 0.5 mm EGTA and 0.5 mm phenylmethanesulfonyl. Cell membranes were obtained by centrifugation at 45000 × g and after twice washing with 20 mm Tris HCl buffer, pH 8.0, containing 0.5 mm EGTA, membrane resuspendable in the above buffer and aliquots were stored at -80°C until use.

The enzymatic activity of MAO-a and MAO-b were tested on 96-well tablet using suitable spectrophotometric analysis, tailored according to the method described by Zhou and Panchuk-Voloshina [Analitical Biochemistry 253:169-174 (1997)]. Briefly, aliquots of membranes were incubated in 0.1 M potassium phosphate buffer at pH 7.4 for 30 minutes at 37°C without or with various concentrations of compounds. Then began the enzymatic reaction by adding MAO substrate tyramine together with 1 U/ml horseradish peroxidase (Roche Biochemical) and 80 μm N-acetyl-3,7-dihydroxyquinoxaline (Amplex Red, Molecular Probes). Then the samples were incubated for 30 minutes at 37°C in a final volume of 200 μl and was determined by optical density at a wavelength of 570 nm using a card reader for tablets SpectraMax (Molecular Devices). Background (non-specific) optical density for the MAO-a was determined in the presence of 10 μm clorgyline, and MAO-b in the presence of 10 μm L-deprenyl.

Values IR50was determined by inhibition curves obtained using the nine duplicated concentrations and is hibitor, the selection of data by four-parameter logistic equation using a computer program.

Compounds of the present invention represent a specific MAO-b inhibitors. Values IR50compounds of the formula I, measured during the previously described analysis are within 1 μm or less, and ideally 0.1 ám or less. The table below shows typical values IR50compounds of formula I in one of their enantiomeric forms:

ExampleMAO-b [IR50(μm)]MAO-AND [IR50(μm)]
20,052>10
30,0282,86
40,0122,44
5of 0.081>9
60,021>10
70,009of 5.40
110,031>1
120,015>10
130,009>10
140,031>10
170,056>10
180,028>10
190,074>10
230,044>10
240,068>10
260,089>10
270,051>10

Pharmaceutical Compounds can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, can be effective in d is the detailed introduction, for example in the form of suppositories, or parenterally, for example in the form of solutions for injection.

Pharmaceutical Compounds can be processed with pharmaceutically inert, inorganic or organic carriers for pharmaceutical drugs. Lactose, corn starch or its derivatives, talc, stearic acid or its salts etc 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 substance for soft gelatin capsules carriers usually are not required. Suitable carriers for the receiving of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and other Adjuvants such as alcohols, polyols, glycerol, vegetable oils, etc. can be used for aqueous injection solutions of water-soluble salts of compounds of the formula I, but, as a rule, they are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like

Moreover, the pharmaceutical preparations can containing the ü preservatives, soljubilizatory, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for regulating the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically valuable substances.

The dosage may vary within wide limits and, of course, must be chosen according to individual requirements in each particular case. In General, an effective dosage for oral or parenteral administration is in the range of 0.01-20 mg/kg/day, for all the above indications dosage of 0.1-10 mg/kg/day is preferred. The daily dosage for an adult weighing 70 kg, respectively, is in the range of 0.7 to 1400 mg per day, preferably in the range 7-700 mg per day.

The following examples illustrate the invention. They do not limit the scope of the invention, but only to explain it.

Example 1

2-[4-(4-Fluoro-benzyloxy)-phenoxy]-ndimethylacetamide

a) 4-(4-Fluoro-benzyloxy)-phenol

To a solution of 10 g of hydroquinone in 90 ml of acetonitrile was added 8,58 g of 4-ftorangidridy and 15.7 g of potassium carbonate. The mixture was heated to 90°C and was stirred for 18 hours. To complete the reaction mixture was cooled to room temperature and added cold water. The resulting solid was filtered, washed twice with cold water and dried. For the purification and separation from diafora the crude product was chromatographically on silica gel, using as eluent a mixture of heptane and ethyl acetate in the ratio of 4:1. 4-(4-Fluoro-benzyloxy)-phenol was obtained as white solids weight of 4.05 g (27% of theory); MS: m/e=218 (M)+.

b) Ethyl ester of [4-(4-fluoro-benzyloxy)-phenoxy]-acetic acid

To a solution of 3 g of 4-(4-fluoro-benzyloxy)-phenol in 40 ml of 2-butanone was added 2.5 g of potassium carbonate and 1.6 ml of ethyl-bromoacetate. The mixture was stirred for 3 hours at 80°C., then the reaction is completed within 24 hours was gradually added in four portions 1.7 g of potassium carbonate and 1.9 ml of ethyl-bromoacetate. To complete the reaction mixture was cooled to room temperature, added water and was extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. Ethyl ester [4-(4-fluoro-benzyloxy)-phenoxy]-acetic acid was obtained in the form of brownish crystals 2,95 g (71% of theoretical), which was pure enough to use them in the next stage without further purification; MS: m/e=304 (M)+.

a) 2-[4-(4-Fluoro-benzyloxy)-phenoxy]-ndimethylacetamide

To a solution of 500 mg of ethyl ester [4-(4-fluoro-benzyloxy)-phenoxy]-acetic acid in 10 ml of tetrahydrofuran dobavlyali,3 ml of sodium hydroxide solution (1 BC). The mixture was heated to 50°C for 2 hours, then cooled to room temperature and was added 3.3 ml of hydrochloric acid (1 BC). While the tetrahydrofuran was evaporated under reduced pressure, the acid precipitated, after which it was collected on a funnel for filtering. After washing with water and drying under reduced pressure received 376 mg of [4-(4-fluoro-benzyloxy)-phenoxy]-acetic acid, which is immediately used for further transformation.

The crude acid was dissolved in 5 ml of N,N-dimethylformamide, were added to 293 mg of 1,1'-carbonyl-diimidazole and the resulting solution was heated to 50°C for 1 hour. Then the mixture was cooled to room temperature, was added 0.16 ml of ammonium hydroxide solution (25%) and continued to stir at room temperature for 18 hours. To complete the process to the reaction mixture was added water to precipitate the product, which was collected on a funnel for filtration and washed with water. 2-[4-(4-Fluoro-benzyloxy)-phenoxy]-ndimethylacetamide weight of 337 mg (74% of theoretical) was obtained in the form of a solid white color after crystallization from water; MS: m/e=276 (M+N)+.

Example 2

2-(4-Benzyloxy-phenoxy)-N-methyl-ndimethylacetamide

a) 4-Benzyloxy-phenol

Similarly to the procedure described in example 1(a)was subjected to the alkylation of hydroquinone with benzylbromide to obtain 4-benzyloxy-phenol as a colorless solid.

b) Methyl ester of (4-benzyloxy-phenoxy)-acetic acid

Similarly to the procedure described in example 1(b)was subjected to the alkylation of 4-benzyloxy-phenol with methyl-bromoacetate, using as the Foundation of cesium carbonate, to obtain the methyl ester (4-benzyloxy-phenoxy)-acetic acid as white crystals; MS: m/e=272 (M)+.

a) 2-(4-Benzyloxy-Phenoxy)-N-methyl-ndimethylacetamide

Similarly to the procedure described in example 1(C), carried out the reaction of (4-benzyloxy-phenoxy)-acetic acid with methylamine using as a condensing reagent 1,1'-carbonyl-diimidazole. 2-(4-Benzyloxy-phenoxy)-N-methyl-ndimethylacetamide was obtained as white crystals; MS: m/e=272 (M+N)+.

Example 3

2-[4-(4-Cyano-benzyloxy)-phenoxy]-N-methyl-ndimethylacetamide

a) 2-(4-Hydroxy-phenoxy)-N-methyl-ndimethylacetamide

A solution of 4.7 g of 2-(4-benzyloxy-phenoxy)-N-methyl-ndimethylacetamide [example 2(C)] in 150 ml of tetrahydrofuran was first made at atmospheric pressure and room temperature, using as catalyst 470 mg of 10% Pd/C. To complete the reaction mixture was filtered through Dicalite filter and the resulting solution evaporated under reduced pressure. The residue in ether was ground into a powder and a solid substance was collected on a funnel for filtering. After drying, got 2,95 g (93% of theoretical) of 2-(4-hydroxy-phenoxy)-N-methyl-acetone is in the form of white crystals; MS: m/e=181 (M)+.

b) 2-[4-(4-Cyano-benzyloxy)-phenoxy]-N-methyl-ndimethylacetamide

To a solution of 500 mg of 2-(4-hydroxy-phenoxy)-N-methyl-ndimethylacetamide in 25 ml of 2-butanone added 762 mg of potassium carbonate and 595 mg of 4-methyl bromide-benzonitrile. The reaction mixture was stirred at room temperature for 60 hours. To complete the process to the reaction mixture were added water and then extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate, the combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure. The residue is triturated in ether and the resulting crystals were collected on a funnel for filtering. After drying, received 744 mg (95% of theoretical) of 2-[4-(4-cyano-benzyloxy)-phenoxy]-N-methyl-ndimethylacetamide in the form of white crystals; MS: m/e=297 (M+N)+.

Example 4

2-[4-(4-Chloro-benzyloxy)-phenoxy]-N-methyl-ndimethylacetamide

Similarly to the procedure described in example 3(6)was subjected to the alkylation of 2-(4-hydroxy-phenoxy)-N-methyl-ndimethylacetamide [example 3(a)] 1-methyl bromide-4-chlorobenzene 2-butanone, using as the base, potassium carbonate, to obtain 2-[4-(4-chloro-benzyloxy)-phenoxy]-N-methyl-ndimethylacetamide in the form of white crystals; MS: m/e=306 (M+N)+.

Example 5

2-[4-(2-Fluoro-benzyloxy)-phenoxy]-N-methyl-ndimethylacetamide

Similarly to the procedure described in example 3(b)was subjected to the alkylation of 2-(4-hydroxy-pheno is si)-N-methyl-ndimethylacetamide [example 3(a)] 1-methyl bromide-2-florasulam 2-butanone, using as the base, potassium carbonate, to obtain 2-[4-(2-fluoro-benzyloxy)-phenoxy]-N-methyl-ndimethylacetamide in the form of white crystals; MS: m/e=290 (M+N)+.

Example 6

2-[4-(3-Fluoro-benzyloxy)-phenoxy]-N-methyl-ndimethylacetamide

Similarly to the procedure described in example 3(b)was subjected to the alkylation of 2-(4-hydroxy-phenoxy)-N-methyl-ndimethylacetamide [example 3(a)] 1-methyl bromide-3-florasulam 2-butanone, using as the base, potassium carbonate, to obtain 2-[4-(3-fluoro-benzyloxy)-phenoxy]-N-methyl-ndimethylacetamide in the form of white crystals; MS: m/e=290 (M+N)+.

Example 7

2-[4-(4-Fluoro-benzyloxy)-phenoxy]-N-methyl-ndimethylacetamide

A mixture of 500 mg of ethyl ester [4-(4-fluoro-benzyloxy)-phenoxy]-acetic acid [example 1(b)] and 2 ml of methylamine (approximately 8 M in ethanol) was stirred for 18 hours at 80°C. To complete the solution was cooled to room temperature and added water. Pure product was besieged and was collected on a funnel for filtering. After drying, received 398 mg (86% of theoretical) of 2-[4-(4-fluoro-benzyloxy)-phenoxy]-N-methyl-ndimethylacetamide in the form of white crystals; MS: m/e=290 (M+N)+.

Example 8

2-[4-(4-Fluoro-benzyloxy)-phenoxy]-N,N-dimethyl-ndimethylacetamide

Similarly to the procedure described in example 7, were aminals ethyl ester [4-(4-fluoro-benzyloxy)-phenoxy]-acetic acid with dimethylamine to obtain 2-[4-(4-FPO is-benzyloxy)-phenoxy]-N,N-dimethyl-ndimethylacetamide in the form of white crystals; MS: m/e=304 (M+N)+.

Example 9

(RS)-2-(4-Benzyloxy-phenoxy)-N-methyl-propionamide

a) Methyl ester of (RS)-2-(4-Benzyloxy-phenoxy)-propionic acid

Similarly to the procedure described in example 1(b)was subjected to the alkylation of 4-benzyloxy-phenol [example 2(a)] methyl-(RS)-2-bromopropionate in acetone, using as the Foundation of cesium carbonate, to obtain the methyl ester of (RS)-2-(4-benzyloxy-phenoxy)-propionic acid as light yellow oil; MS: m/e=304 (M+NH4)+.

b) (RS)-2-(4-Benzyloxy-Phenoxy)-N-methyl-propionamide

Similarly to the procedure described in example 7, were aminals methyl ester (RS)-2-(4-benzyloxy-phenoxy)-propionic acid with methylamine to obtain (RS)-2-(4-benzyloxy-phenoxy)-N-methyl-propionamide in the form of a solid white; MS: m/e=286 (M+N)+.

Example 10

(RS-2-[4-(2-Fluoro-benzyloxy)-phenoxy]-N-methyl-propionamide

a) (RS)-2-(4-Hydroxy-Phenoxy)-N-methyl-propionamide

Similarly to the procedure described in example 3(a)was subjected to hydrogenolysis (RS)-2-(4-benzyloxy-phenoxy)-N-methyl-propionamide to obtain (RS)-2-(4-hydroxy-phenoxy)-N-methyl-propionamide in the form of white crystals; MS: m/e=194 (M-N)-.

b) (RS)-2-[4-(2-Fluoro-benzyloxy)-phenoxy]-N-methyl-propionamide

Similarly to the procedure described in example 3(b)was subjected to the alkylation of (RS)-2-(4-hydroxy-phenoxy)-N-methyl-propionamide 2-farbensymposium 2-butanone, using as the base, potassium carbonate, to obtain (RS)-2-[4-(2-fluoro-benzyloxy)-phenoxy]-N-methyl-propionamide in the form of white crystals; MS: m/e=304 (M+N)+.

Example 11

(RS)-2-[4-(3-Fluoro-benzyloxy)-phenoxy]-N-methyl-propionamide

Similarly to the procedure described in example 3(b)was subjected to the alkylation of (RS)-2-(4-hydroxy-phenoxy)-N-methyl-propionamide with 3-farbensymposium 2-butanone, using as the base, potassium carbonate, to obtain (RS)-2-[4-(3-fluoro-benzyloxy)-phenoxy]-N-methyl-propionamide in the form of a solid white; MS: m/e=304 (M+N)+.

Example 12

(RS)-2-[4-(3-Chloro-benzyloxy)-phenoxy]-N-methyl-propionamide

Similarly to the procedure described in example 3(b)was subjected to the alkylation of (RS)-2-(4-hydroxy-phenoxy)-N-methyl-propionamide with 3-chlorobenzylamino 2-butanone, using as the base, potassium carbonate, to obtain (RS)-2-[4-(3-chloro-benzyloxy)-phenoxy]-N-methyl-propionamide in the form of a solid white; MS: m/e=320 (M+N)+.

Example 13

(R or S)-2-[4-(3-Chloro-benzyloxy)-phenoxy]-N-methyl-propionamide and (S or R)-2-[4-(3-chloro-benzyloxy)-phenoxy]-N-methyl-propionamide

Division 300 mg two isomers of (RS)-2-[4-(3-chloro-benzyloxy)-phenoxy]-N-methyl-propionamide (example 12) was carried out on a preparative chiral HPLC column (CHIRALPAK® AD, pressure: 20 bar, flow rate: 35 ml/min), using it is as eluent a mixture of n-heptane and ethanol in the ratio of 85:15. The first was suirable 122 mg (41% of theoretical) of (R or S)-2-[4-(3-chloro-benzyloxy)-phenoxy]-N-methyl-propionamide, then 860 mg (39% of theoretical) of (S or R)-2-[4-(3-chloro-benzyloxy)-phenoxy]-N-methyl-propionamide, both isomers in the form of a solid white color.

Example 14

(RS)-2-[4-(4-Cyano-benzyloxy)-phenoxy]-N-methyl-propionamide

Similarly to the procedure described in example 3(b)was subjected to the alkylation of (RS)-2-(4-hydroxy-phenoxy)-N-methyl-propionamide 4-methyl bromide-benzonitrile 2-butanone, using as the base, potassium carbonate, to obtain (RS)-2-[4-(4-cyano-benzyloxy)-phenoxy]-N-methyl-propionamide in the form of a solid white; MS: m/e=311 (M+N)+.

Example 15

(RS)-2-(4-Benzyloxy-phenoxy)-N-methyl-butyramide

a) Ethyl ester of (RS)-2-(4-benzyloxy-phenoxy)-butyric acid

Similarly to the procedure described in example 1(b)was subjected to the alkylation of 4-benzyloxy-phenol [example 2(a)] ethyl-(RS)-2-bromobutyrate in acetone, using as the Foundation of cesium carbonate, to obtain the ethyl ester of (RS)-2-(4-benzyloxy-phenoxy)-butyric acid as a brown oil; MS: m/e=314 (M)+.

b) (RS)-2-(4-Benzyloxy-phenoxy)-N-methyl-butyramide

Similarly to the procedure described in example 7, were aminals ethyl ester of (RS)-2-(4-benzyloxy-phenoxy)-butyric acid with methylamine to obtain (RS)-2-(4-benzyloxy-phenoxy)N-methyl-butyramide in the form of a solid white; MS: m/e=300 (M+N)+.

Example 16

(RS)-2-[4-(2-Fluoro-benzyloxy)-phenoxy]-N-methyl-butyramide

a) (RS)-2-(4-Hydroxy-phenoxy)-N-methyl-butyramide

Similarly to the procedure described in example 3(a)was subjected to hydrogenolysis (RS)-2-(4-benzyloxy-phenoxy)-N-methyl-butyramide to obtain (RS)-2-(4-hydroxy-phenoxy)-N-methyl-butyramide in the form of white crystals; MS: m/e=210 (M+N)+.

b) (RS)-2-[4-(2-Fluoro-benzyloxy)-phenoxy]-N-methyl-butyramide

Similarly to the procedure described in example 3(b)was subjected to the alkylation of (RS)-2-(4-hydroxy-phenoxy)-N-methyl-butyramide with 2 farbensymposium 2-butanone, using as the base, potassium carbonate, to obtain (RS)-2-[4-(2-fluoro-benzyloxy)-phenoxy]-N-methyl-butyramide in the form of a solid white; MS: m/e=318 (M+N)+.

Example 17

(RS)-2-[4-(3-Fluoro-benzyloxy)-phenoxy]-N-methyl-butyramide

Similarly to the procedure described in example 3(b)was subjected to the alkylation of (RS)-2-(4-hydroxy-phenoxy)-N-methyl-butyramide with 3-farbensymposium 2-butanone, using as the base, potassium carbonate, to obtain (RS)-2-[4-(3-fluoro-benzyloxy)-phenoxy]-N-methyl-butyramide in the form of a solid white; MS: m/e=318 (M+N)+.

Example 18

(RS)-2-[4-(3-Chloro-benzyloxy)-phenoxy]-N-methyl-butyramide

Similarly to the procedure described in example 3(b)was subjected to the alkylation of (RS)-2-(4-hydroxy-phenoxy)-N-methyl-butyr the MFA 3-chlorobenzylamino 2-butanone, using as the base, potassium carbonate, to obtain (RS)-2-[4-(3-chloro-benzyloxy)-phenoxy]-N-methyl-butyramide in the form of a solid white; MS: m/e=334 (M+N)+.

Example 19

(RS)-2-[4-(4-Cyano-benzyloxy)-phenoxy]-N-methyl-butyramide

Similarly to the procedure described in example 3(b)was subjected to the alkylation of (RS)-2-(4-hydroxy-phenoxy)-N-methyl-butyramide 4-methyl bromide-benzonitrile 2-butanone, using as the base, potassium carbonate, to obtain (RS)-2-[4-(4-cyano-benzyloxy)-phenoxy]-N-methyl-butyramide in the form of a solid white; MS: m/e=325 (M+N)+.

Example 20

2-(4-Benzyloxy-phenoxy)-2,N-dimethyl-propionamide

Similarly to the procedure described in example 7, were aminals ethyl ester 2-(4-benzyloxy-phenoxy)-2-methyl-propionic acid with methylamine to obtain 2-(4-benzyloxy-phenoxy)-2,N-dimethyl-propionamide in the form of a solid white; MS: m/e=300 (M+N)+.

Example 21

2-[4-(3-Fluoro-benzyloxy)-phenoxy]-2,N-dimethyl-propionamide

a) 2-(4-Hydroxy-phenoxy)-2,N-dimethyl-propionamide

Similarly to the procedure described in example 3(a)was subjected to hydrogenolysis of 2-(4-benzyloxy-phenoxy)-2,N-dimethyl-propionamide [example 20] to obtain 2-(4-hydroxy-phenoxy)-2,N-dimethyl-propionamide in the form of a solid white; MS: m/e=209 (M)+.

b) 2-[4-(3-Fluoro-benzyloxy)-Phenoxy-2,N-dimethy the-propionamide

Similarly to the procedure described in example 3(b)was subjected to the alkylation of 2-(4-hydroxy-phenoxy)-2,N-dimethyl-propionamide with 3-farbensymposium 2-butanone, using as the base, potassium carbonate, to obtain 2-[4-(3-fluoro-benzyloxy)-phenoxy]-2,N-dimethyl-propionamide in the form of a brown oil; MS: m/e=318 (M+N)+.

Example 22

2-[4-(3-Chloro-benzyloxy)-phenoxy]-2,N-dimethyl-propionamide

Similarly to the procedure described in example 3(b)was subjected to the alkylation of 2-(4-hydroxy-phenoxy)-2,N-dimethyl-propionamide with 3-chlorobenzylamino 2-butanone, using as the base, potassium carbonate, to obtain 2-[4-(3-chloro-benzyloxy)-phenoxy]-2,N-dimethyl-propionamide in the form of a brown oil; MS: m/e=334 (M+N)+.

Example 23

3-[4-(3-Fluoro-benzyloxy)-phenoxy]-propionamide

a) Methyl ester of 3-[4-(3-fluoro-benzyloxy)-phenoxy]-propionic acid

To a solution of 1.5 g of 4-(3-fluoro-benzyloxy)-phenol (obtained by the procedure similar to that described in example 1(a) 4-(4-fluoro-benzyloxy)-phenol) and 1.4 mg of hydroquinone in 5 ml of methyl acrylate was added sodium and heated under reflux for 7.5 hours. Then the mixture was cooled to room temperature and neutralized with acetic acid. After evaporation under reduced pressure the residue was dissolved in ether and ethyl acetate and the resulting solution was extracted three times the ode. The organic layer was dried over magnesium sulfate and then evaporated under reduced pressure. The crude product is recrystallized in a small volume of methanol. Methyl ester of 3-[4-(3-fluoro-benzyloxy)-phenoxy]-propionic acid was obtained as white crystals weighing 1.1 g (54% of theoretical); MS: m/e=304 (M+N)+.

b) 3-[4-(3-Fluoro-benzyloxy)-phenoxy]-propionic acid

A solution of 500 mg of methyl ester of 3-[4-(3-fluoro-benzyloxy)-phenoxy]-propionic acid by weight in a mixture of 5 ml of tetrahydrofuran and 25 ml of 19% hydrochloric acid was heated for 7 hours at 70°C. To complete the process tetrahydrofuran evaporated under reduced pressure and the aqueous layer was extracted three times with 40 ml of ethyl acetate. The combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure. The crude product is triturated in ether and the solid product was collected on a funnel for filtering. After drying was obtained 3-[4-(3-fluoro-benzyloxy)-phenoxy]-propionic acid by weight of 114 mg (30% of theoretical) in the form of white crystals.

C) 3-[4-(3-Fluoro-benzyloxy)-phenoxy]-propionamide

A solution of 70 mg of 3-[4-(3-fluoro-benzyloxy)-phenoxy]-propionic acid in 4 ml dichloromethane (plus 1 drop of N,N-dimethylformamide) was cooled to 0°C and added to 0.03 ml of oxalicacid. Within 1.5 hours was carried out by stirring, after which the ball is Shui part of the dichloromethane evaporated. Preparing a solution of 0.5 ml of aqueous ammonium hydroxide (25%) in 1 ml of tetrahydrofuran and cooled to 0°C. a Solution of acid chloride was added to the above solution and the mixture was left to warm to room temperature with continued stirring over the weekend. To complete the process, the reaction mixture was evaporated under reduced pressure and the residue triturated in ether to obtain 3-[4-(3-fluoro-benzyloxy)-phenoxy]-propionamide mass of 42 mg (60% of theoretical) as a white solid; MS: m/e=307 (M+NH4)+.

Example 24

2-[4-(3-Fluoro-benzyloxy)-phenyl]-ethyl ether of carbamino acid

a) 2-[4-(3-Fluoro-benzyloxy)-phenyl]-ethanol

To a mixture of 5.0 g of 2-(4-hydroxyphenyl)-ethanol and 5.0 g of potassium carbonate in 100 ml of acetonitrile was added dropwise in an argon atmosphere at 0°C to 4.5 ml of 3-ftorangidridy. After complete addition, the mixture was continued to stir for 15 minutes at 0°C., then the reaction mixture was left to warm to room temperature and was stirred for 18 hours. To complete the process the solvent is evaporated under reduced pressure, then the residue was dissolved in ethyl acetate and the solution washed with water. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. For purification the crude product (10.2 g of yellow oil) of chromatographia is whether on silica gel, using as eluent a mixture of dichloromethane and methanol in the ratio 95:5. After recrystallization from a mixture of ether and cyclohexane were obtained 4.1 g (46% of theoretical) of 2-[4-(3-fluoro-benzyloxy)-phenyl]-ethanol in the form of a solid white; MS: m/e=247 (M+N)+.

b) 2-[4-(3-Fluoro-benzyloxy)-phenyl]-ethyl ether of carbamino acid

To a suspension of 1.0 g of 2-[4-(3-fluoro-benzyloxy)-phenyl]-ethanol and 0.66 g of potassium isocyanate in 2 ml of benzene is added dropwise with stirring in an argon atmosphere at room temperature was added to 0.62 ml triperoxonane acid. After stirring at room temperature for 18 hours the reaction mixture was diluted with water, then was extracted three times with dichloromethane. The combined organic layers were dried over potassium carbonate and evaporated. Received 2-[4-(3-fluoro-benzyloxy)-phenyl]-ethyl ether of carbamino acid by mass of 0.52 g (44% of theoretical) as a solid white; MS: m/e=290 (M+N)+.

Example 25

4-(3-Fluoro-benzyloxy)-benzyl ether of carbamino acid

a) 4-(3-Fluoro-benzyloxy)-benzaldehyde

To a mixture of 4-hydroxy-benzaldehyde weight of 6.0 g of potassium carbonate by weight of 13.58 g in 60 ml of N,N-dimethylformamide is added dropwise at room temperature was added a solution of 3-ftorangidridy mass 11,14 g in 30 ml of N,N-dimethylformamide. After 3 hours the reaction mixture resbala and water and was extracted with ether. The organic layer was washed with water, dried over magnesium sulfate and evaporated to obtain an oil (9,85 g), which was led; MS: m/e=230 (M)+. The crude product was used in the next stage without additional purification.

b) [4-(3-Fluoro-benzyloxy)-phenyl]-methanol

The solution with 3.79 g of 4-(3-fluoro-benzyloxy)-benzaldehyde in 10 ml of tetrahydrofuran is added dropwise at room temperature was added to a suspension of lithium aluminum hydride by weight of 1.25 g in 40 ml of tetrahydrofuran. The mixture was left for 2 hours at room temperature, and then cooling was added dropwise 1.25 ml of water, then 3,75 ml of sodium hydroxide solution (1 BC) and again, 1.25 ml of water. The mixture was filtered through a filter Dicalit and the tetrahydrofuran was removed from the solution under reduced pressure. The residual phase was extracted with ethyl acetate, the combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure. The residue was led from a mixture of ether and n-hexane, obtaining of 2.26 g (59% of theoretical) of [4-(3-fluoro-benzyloxy)-phenyl]-methanol in the form of a solid white; MS: m/e=232 (M)+.

b) 4-(3-Fluoro-benzyloxy)-benzyl ether of carbamino acid

Similarly to the procedure described in example 24(b)was subjected to reaction [4-(3-fluoro-benzyloxy)-phenyl]-methanol with potassium isocyanate and triperoxonane acid in benzene with the floor is the group of 4-(3-fluoro-benzyloxy)-benzyl ether of carbamino acid in the form of a solid white; MS: m/e=293 (M+NH4)+.

Example 26

4-(3-Fluoro-benzyloxy)-benzyl ester methylcarbamyl acid

A solution of 1.0 g of [4-(3-fluoro-benzyloxy)-phenyl]-methanol [example 25B)], of 0.03 ml of triethylamine and 0,245 g of methyl isocyanate in 40 ml of dichloromethane was heated for 3 days at 40°C in tightly closed glass tube. In this case, as shown by NMR, the degree of conversion reached 50%. To complete the reaction mixture was cooled and evaporated. The residue was dissolved in 2 ml of pyridine and 1 ml of acetic anhydride, the solution was stirred at room temperature for 3 hours. The mixture is then evaporated under reduced pressure. For purification the crude product was chromatographically on silica gel, using as eluent a mixture of heptane and ethyl acetate in the ratio of 2:1. 4-(3-Fluoro-benzyloxy)-benzyl ester methylcarbamyl acid was obtained by mass of 580 mg (47% of theoretical) in the form of a solid white; MS: m/e=289 (M)+.

Example 27

2-[4-(3-Fluoro-benzyloxy)-benzyloxy]-ndimethylacetamide

To a solution of 500 mg of [4-(3-fluoro-benzyloxy)-phenyl]-methanol [example 25(b)] in 10 ml of tetrahydrofuran at room temperature was added 57 mg of sodium hydride (55% dispersion in oil) and stirred for 1 hour. Then he added 183 mg of chloracetamide and the mixture was heated under reflux for 48 hours. For the head is Rhenia process to the chilled mixture was added water and was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. For purification the crude product was chromatographically on silica gel, using as eluent a gradient of dichloromethane - a mixture of dichloromethane and methanol in the ratio of 4:1. After crystallization from ether there was obtained 2-[4-(3-fluoro-benzyloxy)-benzyloxy]-ndimethylacetamide mass of 29 mg (5% of theoretical) in the form of a solid white; MS: m/e=307 (M+NH4)+.

Example

Tablets of the following composition is prepared in the traditional way:

mg tablet
The active ingredient100
Powdered lactose95
White corn starch35
Polyvinylpyrrolidone8
Na carboximetilkrahmal10
Magnesium stearate2
Weight pills250

Example B

Tablets of the following composition is prepared in the traditional way

mg tablet
The active ingredient200
Powdered lactose100
White corn starch64
Polyvinylpyrrolidone12
Na carboximetilkrahmal20
Magnesium stearate4
Weight pills400

The example In

Prepare capsules of the following composition:

mg/capsule
The active ingredient50
Crystalline lactose60
Microcrystalline cellulose34
Talc5
Magnesium stearate1
The weight of the contents of the capsules150

The active ingredient with a suitable particle size, crystalline lactose and microcrystalline cellulose are mixed with each other until a homogeneous mixture, sieved and then mixed with talc and magnesium stearate. The final mixture to fill hard gelatin capsules of suitable size.

Example D

Solution for injection may be of the following composition and prepared in the traditional way:

The active ingredient1.0 mg
1 N. HClof 20.0 µl
Acetic acid0.5 mg
NaCl8.0 mg
Phenol10.0 mg
1 N. Paonto pH 5
H2Oto 1 ml

1. Compounds of General formula

where R1, R2independently of one another are N or C1-C6-alkyl;
R3, R4independently of one another are N or C1-C6 -alkyl;
R5represents halogen, CN;
n, m and o are 0,1 or 2;
and their pharmaceutically acceptable salts,
with the exception of
4-(benzyloxy)-phenyl-N-BUTYLCARBAMATE,
2-[4-(phenylmethoxy)phenoxy]ndimethylacetamide,
4-(phenylmethoxy)phenyl ether dimethylcarbinol acid,
2-[4-(3-chlorobenzoic)bisoxy]ndimethylacetamide,
4-benzyloxy-benzyl ester dimethylcarbinol acid,
4-benzyloxy-phenyl ester methylcarbamyl acid,
2-[4-[(4-chlorophenyl)methoxy]phenoxy]-2-methyl-propionamide and
2-[4-[(4-chlorophenyl)methoxy]phenoxy]-2-methyl-]-N-(1-methylethyl)-propionamide,
and also provided that the excluded compounds of General formula (I)where one of R1or R2represents a C1-C6-alkyl and the other represents H;
R3and R4represent H;
n, m are 0; and
o represents 1.

2. The compounds of formula I according to claim 1, where o represents 1 and m represents 0, except
2-[4-(phenylmethoxy)phenoxy]ndimethylacetamide,
2-[4-[(4-chlorophenyl)methoxy]phenoxy]-2-methyl-propionamide and
2-[4-[(4-chlorophenyl)methoxy]phenoxy]-2-methyl-N-(1-methylethyl)propionamide,
and also provided that the excluded compounds of General formula (I)where one of R1or R2represents a C1-C6-alkyl and the other represents H;
R3R 4represent H;
n, m are 0; and
o represents 1.

3. The compounds of formula I according to claim 2, which represent
2-(4-benzyloxy-phenoxy)-N-methyl-acetamide", she
2-[4-(4-cyano-benzyloxy)-phenoxy]-N-methyl-acetamide", she
2-[4-(4-chloro-benzyloxy)-phenoxy]-N-methyl-acetamide", she
2-[4-(2-fluoro-benzyloxy)-phenoxy]-N-methyl-acetamide", she
2-[4-(3-fluoro-benzyloxy)-phenoxy]-N-methyl-acetamide", she
2-[4-(4-fluoro-benzyloxy)-phenoxy]-N-methyl-acetamide", she
(RS)-2-[4-(3-fluoro-benzyloxy)-phenoxy]-N-methyl-propionamide,
(RS)-2-[4-(3-chloro-benzyloxy)-phenoxy]-N-methyl-propionamide,
(S or R)-2-[4-(3-chloro-benzyloxy)-phenoxy]-N-methyl-propionamide,
(RS)-2-[4-(4-cyano-benzyloxy)-phenoxy]-N-methyl-propionamide,
(RS)-2-[4-(3-fluoro-benzyloxy)-phenoxy]-N-methyl-butyramide,
(RS)-2-[4-(3-chloro-benzyloxy)-phenoxy]-N-methyl-butyramide, or
(RS)-2-[4-(4-cyano-benzyloxy)-phenoxy]-N-methyl-butyramide.

4. The compounds of formula I according to claim 1, where o is 2 and m is 0.

5. The compounds of formula I according to claim 4, one of which is a 3-[4-(3-fluoro-benzyloxy)-phenoxy]-propionamide.

6. The compounds of formula I according to claim 1, where o represents 0 and m is 2.

7. The compounds of formula I according to claim 6, one of which is a 2-[4-(3-fluoro-benzyloxy)-phenyl]-ethyl ether of carbamino acid.

8. The compounds of formula I according to claim 1, where o represents 0, and m represents the t of a 1, with the exception of 4-benzyloxy-benzyl ester dimethylcarbinol acid.

9. The compounds of formula I of claim 8, one of which is a 4-(3-fluoro-benzyloxy)-benzyl ester methylcarbamyl acid.

10. The compounds of formula I according to claim 1, where o represents 1 and m represents 1.

11. The compounds of formula I of claim 10, one of which is a 2-[4-(3-fluoro-benzyloxy)-benzyloxy]-ndimethylacetamide.

12. The pharmaceutical preparation having the property inhibitor of monoamine oxidase B, containing a therapeutically effective amount of one or more compounds of General formula I

where R1, R2independently of one another are N or C1-C6-alkyl;
R3, R4independently of one another are N or C1-C6-alkyl;
R5represents halogen, CN;
n, m and o are 0, 1 or 2;
or their pharmaceutically acceptable salts,
and pharmaceutically acceptable excipients, except for the following compounds:
4-(benzyloxy)-phenyl-N-BUTYLCARBAMATE,
2-[4-(phenylmethoxy)phenoxy]ndimethylacetamide,
4-(phenylmethoxy)phenyl ether dimethylcarbinol acid,
2-[4-(3-chlorobenzoic)bisoxy]ndimethylacetamide,
4-benzyloxy-benzyl ester dimethylcarbinol acid,
4-benzyloxy-phenyl ester metalk raminosoa acid,
2-[4-[(4-chlorophenyl)methoxy]phenoxy]-2-methyl-propionamide and
2-[4-[(4-chlorophenyl)methoxy]phenoxy]-2-methyl-N-(1-methylethyl)-propionamide,
and also provided that the excluded compounds of General formula (I)where one of R1or R2represents a C1-C6-alkyl and the other represents H;
R3and R4represent H;
n, m are 0; and
o represents 1.

13. The compound according to any one of claims 1 to 11, as well as its pharmaceutically acceptable salts, having the property inhibitor of monoamine oxidase Century

14. The use of compounds of General formula I

where R1, R2independently of one another are N or C1-C6-alkyl;
R3, R4independently of one another are N or C1-C6-alkyl;
R5represents halogen, CN;
n, m and o are 0, 1 or 2;
with the exception of
4-(benzyloxy)-phenyl-N-BUTYLCARBAMATE,
2-[4-(phenylmethoxy)phenoxy]ndimethylacetamide,
4-(phenylmethoxy)phenyl ether dimethylcarbinol acid,
2-[4-(3-chlorobenzoic)bisoxy]ndimethylacetamide,
4-benzyloxy-benzyl ester dimethylcarbinol acid,
4-benzyloxy-phenyl ester methylcarbamyl acid,
2-[4-[(4-chlorophenyl)methoxy]phenoxy]-2-methyl-propionamide and
2-[4-[(4-chlorophenyl)methoxy]phenoxy]-2-N-(1-methylethyl)-propionamide,
and also provided that the excluded compounds of General formula (I)where one of R1or R2represents a C1-C6-alkyl and the other represents H;
R3and R4represent H;
n, m are 0; and
o represents 1;
and its pharmaceutically acceptable salts for the manufacture of a pharmaceutical preparation having the property inhibitor of monoamine oxidase Century



 

Same patents:

FIELD: chemistry.

SUBSTANCE: method of producing cyclopropyl-condensed inhibitors of dipeptidyl peptidase IV involves using BOC-protected amine with structural formula (3) , obtained through reductive amination of acid with formula (1) by treating the said acid with ammonium formate, nicotinamide adenine dinucleotide, dithiothreitol and partially purified concentrate of phenyl alanine dehydrogenase and formate dehydrogenase (PDH/FDH) enzymes and without separation - by treating the obtained amine of formula (2) with ditertbutyl dicarbonate, obtaining BOC-protected amine.

EFFECT: cutting on costs.

13 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , in which A is selected from one or several X and/or Y groups; X represents methylene group; Y represents C2-alkinylene group; n represent integer number from 1 to 5; R1 represents group R2, optionally substituted with one or several R3 and/or R4 groups; R2 represents group selected from pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphtyl, chinolinyl, isochinolinyl, dihydroisochinolinyl, 2-oxo-3,4-dihydrochinolinyl, indolyl, benzimidazolyl, pyrrolopyridinyl; R3 represents group selected from halogen atoms, groups C1-6-alkyl, C3-7-Cycloalkyl, C1-6-alkoxy, NR5R6 and phenyl; R4 represents group selected from groups: phenyl, naphtyl, pyridinyl; R4 group or groups can be substituted with one or several R3 groups, similar or different from each other; R5 and R6 independently on each other represent C1-6-alkyl group; R7 represents hydrogen atom or C1-6-alkyl group; R8 represents hydrogen atom or group C1-6-alkyl, C3-7-cycloalkyl, C3-7-Cycloalkyl- C1-3-alkylene; in form of base, acid-additive salt, hydrate or solvate. Invention also relates to methods of obtaining formula (I) compound by any of ii. 1-3, to compounds, determined by general formula (IV), (VII), to pharmaceutical composition, as well as to application of formula (I) compounds by any of ii. 1-3.

EFFECT: obtaining novel biologically active compounds possessing activity of enzyme FAAH inhibitors.

10 cl, 5 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention is related to method for preparation of N-alkyl-O-alkyl urethanes of general formula I: , II, where R, R1 stand for alkyl groups of normal or branched structure with number of carbon atoms from 1 to 8, arylalkyl or alcoalkyl, and also heterylalkyl groups, which consists in the fact that alcohol R1OH interacts with symmetrical disubstituted urea II, where R, R1 have the same meaning that in formula I, at increased temperature, which is characterised by the fact that process is carried out in continuous or periodical mode and additionally tin-organic catalyst is introduced in amount from 0.01 to 1 mole % at the ratio of reagents urea: aliphatic alcohol 1:(1÷60) mole and temperature from 140 to 220°C.

EFFECT: application of this method makes it possible to increase yield of N-alkyl-O-alkyl urethanes of general formula I, process performance at optimal conditions and with reduced time of reaction mass soaking in column.

1 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula I in form of free base or acid-additive salt, method of their obtaining, pharmaceutical composition based on them and their application s antagonists of metabotropic glutamate receptors (mGluR5). The invention can be applied in the treatment of the illnesses connected with the disorder of glutamatic signal transfer and the disorder of nervous system partially or completety mediate mGluR5. In general formula T represents 0 or 1, A represents hydroxy, X represents hydrogen, Y represents hydrogen or A forms simple bond with X or Y; ring methylene group directly bound with CH(X)-, can be dimethylated; R0 represents hydrogen, C1-C4alkyl, C1-C4alkoxy, halogen, cyano, and R represents -COR3, -COOR3 or -SO2R6,where R3 represents C1-C4alkyl, C3-C7cycloakyl, and R6 represents C1-C4alkyl, C3-C7cycloakyl, or R represents -C(O)R3, where R3 represents furanyl, trifluoromethyl, pyridinyl, morpholinyl or methylpiperasinyl; or -C(O)OR3, where R3 represents tetrahydrofuranyl, R' represents hydrogen, C1-C4alkyl or 4-methoxybenzyl, and R" represents hydrogen or C1-C4alkyl, or R' and R" together form group -CH2-(CH2)p-, where p represents 0, 1 or 2, one of symbols n and p does not represent 0, on condition that R0 does not represent hydrogen, trifluoromethyl and methoxy, when m represents 1, n represents 0, A represents hydroxy, X and Y both represent hydrogen, R represents COOEt and R' and R" together form group -(CH2)2-.

EFFECT: efficient application of compounds for treatment of diseases caused by disturbance of transduction of glutamatergic signal and diseases of nervous system.

8 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of structural formula I and their pharmaceutically acceptable salts. In structural formula I , X is oxygen; Y is oxygen; Y1 Y2, R7 and R4 represent H; X1 and X2 are independently selected from a group consisting of hydrogen, an alkyl group containing 1 to 5 carbon atoms, in which one or more hydrogen atoms of the alkyl group can be substituted with a halogen, aryl group containing 6 to 10 carbon atoms or a cycloalkyl group containing 3 to 9 carbon atoms, or a 5-9-member heterocyclic group with 2 heteroatoms selected from N and O, or a cycloalkyl group containing 5 to 9 carbon atoms; values of the rest of the radicals are given in the formula of invention. The invention also pertains to a pharmaceutical composition having properties of selective inhibitors of type IV phosphodiesterase, containing a therapeutically effective amount of the invented compound.

EFFECT: increased effectiveness of the compounds.

6 cl, 23 ex

The invention relates to new compounds of formula (1) or their pharmaceutically acceptable salts, where R1a, R2a, R3aand R4arepresent, each independently, hydrogen, hydroxyl, C1-C6alkyl, C1-C6alkoxy, benzyloxy, acetoxy, trifluoromethyl or halogen, and R5aand R6arepresent, each independently, tert-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzenesulfonyl or p-bromobenzyloxycarbonyl, which is an intermediate compound for the synthesis of benzimidazole derivatives and their pharmaceutically acceptable salts exhibiting excellent hypoglycemic effect

The invention relates to methods for producing polyvinylpolypyrrolidone, which are intermediates for the production of polyvinylpolypyrrolidone and the corresponding polyurethane polymers

FIELD: chemistry.

SUBSTANCE: method of producing cyclopropyl-condensed inhibitors of dipeptidyl peptidase IV involves using BOC-protected amine with structural formula (3) , obtained through reductive amination of acid with formula (1) by treating the said acid with ammonium formate, nicotinamide adenine dinucleotide, dithiothreitol and partially purified concentrate of phenyl alanine dehydrogenase and formate dehydrogenase (PDH/FDH) enzymes and without separation - by treating the obtained amine of formula (2) with ditertbutyl dicarbonate, obtaining BOC-protected amine.

EFFECT: cutting on costs.

13 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel improved method of obtaining benzylamine derivative of general formula (3)

and method of obtaining from the latter of carbamate derivative of general formula (6) where X1 represents halogen atom and R1 represents acyl group selected from C1-C7-linear or branched aliphatic acyl group, C3-C6-cycloalkylcarbonyl group, and aromatic acyl group, R3 represents alkyl group. Methods include interaction of benzyl derivative of general formula (1)

with halogen compound of general formula (2): where X2 represents halogen atom, and R2 represents acyl group selected from C1-C7-linear or branched aliphatic acyl group, C3-C6-cycloalkylcarbonyl group, and aromatic acyl group, in presence of Lewis acid. From obtained compound of general formula (3) carbamate derivative of general formula (6) is obtained. For this purpose compound of general formula (3) is subjected to hydrolysis obtaining aminoderivative of general formula (4)

which is further subjected to interaction with ester of halogen-formic acid of general formula (5) where X1 and R2 are determined above, X3 represents halogen atom, and R3 represents alkyl group, in presence of base. Invention also relates to novel acylbenzylamine derivatives of general formula (7):

where X1 represents halogen atom, each of R2 and R4 independently represents C1-C7-linear or branched aliphatic acyl group, C3-C6-cycloalkylcarbonyl group, and R can additionally represent hydrogen atom. Benzylamine derivatives of formula (3) and formula (7) can be used as intermediate products for obtaining agricultural or garden bactericide based on formula (6) carbamate.

EFFECT: elaboration of improved method of obtaining benzylamine derivative.

5 cl, 1 tbl, 3 ex

FIELD: catalyst preparation methods.

SUBSTANCE: invention relates to alumina-supported catalyst preparation method and employment thereof in reactions of nucleophilic substitution of aromatic halides containing electron-accepting group. In particular, alumina support impregnated with alkali selected from alkali metal hydroxides is prepared by treating alkali metal hydroxide aqueous solution with aluminum oxide in organic solvent followed by drying thus obtained catalyst mixture at temperature not lower than 150°C. Catalyst is, in particular, used to introduce electron-accepting protective groups into organic compounds comprising at least one of -OH, -SH, and -NH, as well as in reaction of substituting amino, thio, or ether group for halogen in a haloarene and in preparation of 2-puperidinobenzonitrile.

EFFECT: simplified preparation of catalyst and regeneration of spent catalyst, and avoided involvement of dangerous reactants.

11 cl, 20 ex

FIELD: chemistry.

SUBSTANCE: described is a compound of formula

or its pharmaceutically acceptable salt, where m, p, q, Ar, R1 and R2 are as given in the description, as well as a pharmaceutical composition with selective affinity to 5-HT receptors which contains a formula (I) compound.

EFFECT: obtained compounds have selective affinity to 5-HT receptors and can be used, as expected, in treating certain central nervous system disorders.

21 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to improved method of preparing solid particles used as phenolic antioxidants and including in, in fact, crystal form compound of formula: in which one of R1 and R2 independently on each other represent hydrogen atom or C1-C4alkyl, and the other one represents C3-C4alkyl; x represents zero (direct bond) or number from one to three; and Y represents C8-C22alkoxy or groups of incomplete formulas

or in which one of R1' and R2' independently on each other represent hydrogen atom or C1-C4alkyl, and the other one represents C3-C4alkyl; x represents zero (direct bond) or number from one to three; y represents number from two to ten; and z represents number from two to six, in which homogeneous water dispersion is prepared, which includes compound (I) or mixture of such compounds, where R1, R2, R1' R2', Y, x, y and z have values given above, by addition of incomplete ether of fatty acid polyoxyethylene sorbitan and inoculating crystals, and obtained crystals are separated from dispersion and process is carried out until solid particles are obtained. Invention also relates to novel crystal forms pentaerythrite tetrakis-[3-(3,5-ditret-butyl-4-hydroxyphenyl)propionate], (µ-form) of pentaerythrite tetrakis 3-(3,5-ditret-butyl-4-hydroxyphenyl)propionate], crystal form of N,N'-hexane-1,6-diyl-bis-[3-(3,5-ditret-butyl-4-hydroxyphenyl propionamide)], crystal form of N,N'-hexane-1,6-diyl-bis-[3-(3,5-ditret-butyl-4-hydroxyphenyl propionamide)] and crystal modification (β-form) of N,N'-hexane-4,6-diylbis-[3-(3,5-ditret-butyl-4- hydroxyphenyl propionamide)].

EFFECT: elaboration of improved method of preparing solid particles used as phenolic antioxidants.

10 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), including its pharmaceutically acceptable salts, solvates, ethers and amides, possessing ability to bind ERα- and ERβ-estrogen receptors, to pharmaceutical composition based on them, to versions of applying claimed compounds in medication preparation and to method of binding ERα- and ERβ-estrogen receptors. (I), where R1 represents H, OH or C1-12alkoxy, or halogen; R2 represents H, OH or halogen; R3 represents C1-12alkyl, halogeno-C1-12alkyl, C3-10cycloalkyl, C1-12alkoxy or C1-12alkoxyC1-12alkyl; R4 represents H or C1-12alkoxy; R5 represents H, halogen or halogeno-C1-12alkyl; R6 represents -(Y)z-R7; R8 represents phenyl or 5- or 6-member heteroaryl, containing N, O or S as heteroatom, where said phenyl and heteroaryl are possibly substituted with OH, halogeno, halogenoC1-12alkyl or C1-12alkoxy. Values R7, Y and z are presented in invention formula.

EFFECT: novel compounds possess useful biological properties.

19 cl, 7 dwg, 1 tbl, 70 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new cycloalkylidene compounds with formula (I), to their pharmaceutical salts, esters and amide, capable of selective bonding ERα- and ERβ-estrogen receptors, as well as to pharmaceutical compositions based on them, their use in making medicinal preparations and the method of selective bonding ERα- and ERβ-estrogen receptors. . Denotations of R1-R7, X, p, q, as well as specific representatives of new cycloalkylidene compounds are given in the formula of invention.

EFFECT: obtaining new cylcoalkylidene compounds.

31 cl, 6 dwg, 108 ex

FIELD: chemistry.

SUBSTANCE: novel compounds of formulas , , , , , , (designation of all groups are given in invention formula) are used for treatment of different metabolic diseases, such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver, cachexia, obesity, atherosclerosis and arteriosclerosis.

EFFECT: using compounds as biologically active agent and creating pharmaceutical compositions based on said compounds.

124 cl, 52 ex, 17 tbl, 2 dwg

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, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I): wherein R1 represents (C1-C3)-alkyl, halogen atom, halogen-(C1-C6)-alkyl, cyano-, (C1-C6)-alkoxy- or halogen-(C1-C6)-alkoxy-group; each among radicals R21, R22, R23 and R24 is chosen independently from group consisting of hydrogen atom and fluorine atom; R3 represents hydrogen atom or (C1-C3)-alkyl; A means bivalent group of the formulae (a): , (b): or (c): R4 represents hydrogen atom or (C1-C3)-alkyl; each radical among R5, R6 and R7 represents independently hydrogen atom or (C1-C6)-alkyl; n = 1, 2 or 3 under condition that 3-[4-(3-chlorobenzoxy)phenyl]-N-ethylpropioneamide and 3-[4-(4-bromobenzyloxy)phenyl]propioneamide are excluded. Also, invention relates to a medicinal agent possessing inhibitory effect with respect to activity of monoaminooxidase B that comprises one or more compounds of the formula (I) and pharmaceutically acceptable excipients. Invention proposes derivatives of cinnamic acid possessing inhibitory effect with respect to activity of monoaminooxidase B.

EFFECT: valuable medicinal and biochemical properties of compounds.

9 cl, 22 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to (R)-enantiomers of 2-arylpropionamides of the formula (Ia): and their pharmaceutically acceptable salts wherein Aryl represents phenyl group substituted with a group chosen from isopropyl, acetyl, (2'',6''-dichlorophenyl)amino-group, α-hydroxyisopropyl, (R,S)-α-hydroxybenzyl and its individual R-isomers, (R,S)-(α-methylbenzyl) and its individual R-isomer and (R,S)-α-hydroxy-α-methylbenzyl and its individual R-isomer; R represents hydrogen atom (H) or (C1-C4)-alkyl; R' represents the following groups: -amino acid residue consisting of linear or branched (C1-C6)-alkyl substituted with carboxy-group -CO2H; -residue of the formula: -CH2-CH2X-(CH2-CH2O)nR wherein R has abovementioned values; n means a whole number from 0 to 1 while X represents oxygen atom; -heteroaryl chosen from the group consisting of 2-pyrimidinyl or 4-pyrimidinyl. Also, invention proposes a pharmaceutical composition inhibiting of interleukin-8-induced chemotaxis of neutrophiles and comprising as an active components (R)-enantiomers of 2-arylpropionamides of the formula (I) and their pharmaceutically acceptable salts in mixture with a suitable carrier. Also, invention proposes a method for preparing compounds of the formula (Ia). Also, invention proposes (R)-enantiomers of 2-arylpropionic acids of the formula (Va) given in the invention description and their pharmaceutically acceptable salts. Proposed (R)-2-arylpropionamides are useful in prophylaxis and treatment of tissue damage caused by enhanced accumulation of polymorphonuclear neutrophiles in the inflammation sites.

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

13 cl, 6 tbl, 24 ex

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