Benzyloxy-derivatives as monoamine oxidase b inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzyloxy-derivatives of general formula (I) , where R1 is a halogen; R2 is a 5-member heteroaryl group containing 2 or 3 heteroatoms selected from a group consisting of N, O or S, which can be substituted with R3, where R3 is a lower alkyl or -C(O)R; R is -NR'R" or lower alkoxy; R'/R" independently represent H; as well as to their pharmaceutically acceptable salts. Formula I compounds inhibit monoamine oxidase B.

EFFECT: compounds can be used for preparing a medicinal agent.

5 cl, 15 ex

 

This invention relates to a benzyloxy derivative of General formula

where R1is a halogen;

R2represents-C(O)NH2, -C(NH2)=N-OH, -C(O)CH2Br,

-C(O)N(CH3)Och3or-C(O) - lower alkyl, or represents a 5-membered heteroaryl group containing 2 or 3 heteroatoms selected from the group consisting of N, O or S, which may be substituted by lower alkyl, -NR'r R ' or-C(O)R;

R represents a-NR'r R", lower alkyl or lower alkoxy;

R'/R" independently of one another represent hydrogen or lower alkyl; 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 is aretransmitted, such as dopamine, serotonin, epinephrine, or norepinephrine, and trace amines, such as phenethylamine, and amine number of xenobiotics. 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 seems appropriate use of selective MAO-b inhib the tori for the treatment of dementia and Parkinson's disease. Inhibition of MAO-b causes a decrease in the enzymatic inactivation of dopamine 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 inhibitors is discussed D.Bentue-Ferrer et. al. in CNS Drugs 1996, 6, 217-236. The main limitation of activity irreversible and non-selective MAO 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 factors the s are to a lesser extent. Thus, there is a need for MAO-b inhibitors with high selectivity and without adverse side effects common to 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 turns on the activity of 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, amlawdaily and chronic pain, chorea Huntington's, amyotrophic lateral sclerosis (ALS), dementia caused by HIV, eye injuries, retinopathy, 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 1 of the present invention and their pharmaceutically acceptable salts show the potential to be highly selective MAO-b inhibitors. In addition, objects of the present invention are drugs, based on the compound of formula 1 according to this invention, a method of making compounds of formula 1 and their pharmaceutically acceptable salts, and also the use of compounds of formula 1 for the treatment or prevention of diseases of oreopanax monoamine oxidase inhibitors, and, accordingly, the application for the manufacture of corresponding medicaments.

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 "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.

"Lower alkoxy" means a residue-O-R, where R represents the residue of a lower alkyl as defined here. Examples of alkoxy radicals include, but are not limited to, methoxy, ethoxy, isopropoxy etc.

The term "5-membered heteroaryl containing 2 or 3 heteroatoms selected from the group consisting of N, O or S" means the system heteroaromatic ring selected from the group consisting of [1.2.4]oxadiazolyl, 1,3-thiazolyl, imidazolyl, pyrazolyl or isoxazolyl. The preferred groups are[1.2.4]oxadiazolyl, 1,3-thiazolyl or imidazolyl.

"Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable, they are generally safe, non-toxic and are not biologically undesirable, or otherwise inappropriate, and which possess the desired pharmacological activity of the parent compound. 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 such as acetic acid, benzolsulfonat 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, mandelic acid, methanesulfonate acid, Mukanova acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, Dibenzoyl-L-tartaric acid, tartaric acid, p-toluensulfonate acid, trimethylation the traveler 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 organic bases 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 which 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 neurologist who ical violation" means a mammal, for example the person that is suffering or is at risk to suffer from acute and/or chronic neurological disorder.

As used here, the terms "treat", "treating", "treatment", etc. applicable to acute and/or chronic neurological disturbance, are treated as methods that slow down, improve, reduce or eliminate such violation or any symptoms associated with this disorder disturbing subject at the present time, and to methods that prevent such breach or any symptoms of its manifestation.

Among the compounds of the present invention preferred are the compounds of formula 1 or its pharmaceutically acceptable salt.

Also preferred are the compounds of formula I in which R2represents a 5-membered heteroaryl group containing 2 or 3 heteroatoms selected from the group consisting of N, O or S, which may be substituted, R3representing a lower alkyl, -NR'r R ' or-C(O)R. the Following structure includes such compounds.

Compounds of formula IA are, for example, the following:

(R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-4-(5-methyl-[1.2.4]oxadiazol-3-yl)-pyrrolidin-2-it,

ethyl ester of 3-{(R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-[1.2.4]oxadiazol-5-carboxylic acid is you,

amide 3-{(R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-[1.2.4]oxadiazol-5-carboxylic acid,

(R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-4-(2-methyl-thiazol-4-yl)-pyrrolidin-2-he /

(R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-4-(1H-imidazol-4-yl)-pyrrolidin-2-it.

In addition, compounds of formula I are those in which R2represents-C(O)NH2, -C(NH2)=N-OH, -C(O)CH2Br, -C(O)N(CH3)Och3or-C(O) - lower alkyl, for example

amide (R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-carboxylic acid,

(R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-N-hydroxy-5-oxo-pyrrolidin-3-carboxamidine,

methoxy-methyl-amide (R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-carboxylic acid, or

(R)-4-acetyl-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-it.

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

a) compound of the formula

subjected to interaction with ammonium acetate in the presence of a condensing reagent such, for example, CDI (1,1'-carbonyldiimidazole), with compounds of the formula

where R1is such as described above, or

b) the compound of the formula

/p>

subjected to interaction with thionyl chloride to obtain the compounds of formula

where R1is such as described above, or

C) the compound of the formula

subjected to interaction with hydroxylamine to obtain the compounds of formula

where R1is such as described above, or

g)the compound of the formula

subjected to interaction with acetylchloride in the presence of a base to obtain the compounds of formula

where R1is such as described above, or

d)the compound of the formula

subjected to interaction with heterocalixarenes with obtaining the compounds of formula

where R1is such as described above, or

e) a compound of the formula

subjected to interaction with NH4OH obtaining the compounds of formula

where R1is such as described above, or

g)the compound of the formula

subjected to interaction with thionyl chloride in the presence of N,N'-dimethylformamide, trimethylsilyldiazomethane and HBr with obtaining the compounds of formula

where R1is such as described above, or

C) the compound of the formula

subjected to interaction with formamide to obtain the compounds of formula

where R1is such as described above, or

and the connection formula

subjected to interaction with thioacetamide in THF to obtain the compounds of formula

where R1is such as described above, or

K) the compound of the formula

subjected to interaction with N,O-dimethylhydroxylamine hydrochloride and CDI with obtaining the compounds of formula

where R1is such as described above, or

l) a compound of the formula

subjected to interaction with MeMgBr in THF to obtain the compounds of formula

where R1is such as described above, and

if desired, transfer the obtained compound of formula I in a pharmaceutically active acid additive salt.

According to the present invention in schemes 1 and 2 show the possibility of obtaining compounds of General formula I.

Compounds of General formula I can be obtained by reaction of compounds of formula II with 1,1'-carbonylcyanide what SOLOM (CDI) in N,N'-dimethylformamide (DMF) and adding ammonium acetate (scheme 1), to obtain the corresponding amide of formula I-1. A nitrile compound can be obtained from the amide dehydration reagent such as thionyl chloride, preferably at 90°C. the Reaction of the compound of formula III with hydroxylamine hydrochloride in the presence of a base like N,N-diisopropylethylamine (DIPEA) leads to the desired N-hydroxy-carboxamidine formula I-2, which reacts with acetylchloride in the presence of a base such as pyridine, to obtain the compounds of formula I-4 or heterocalixarenes obtaining compounds of formula I-3. The corresponding amide of formula I-5 can be obtained from the ester by heating with ammonia in a solvent such as methanol.

Scheme 1

The definition of R1is the same as described above.

Other compounds of General formula I can be obtained by the reaction of compounds of formula II with thionyl chloride in the presence of catalytic N,N'-dimethylformamide with the formation of the intermediate acid chloride, which reacts with trimethylsilyldiazomethane and 33% Hydrobromic acid in acetic acid to obtain 2-bromo-acetyl compound I-6. The compounds of formula I, where R2means imidazole (I-8), can be obtained by heating under reflux of the compounds of formula I-6 with formamide and water. The compounds of formula I, where R2means tiaso the (I-7), you can get the reflux of the compounds of formula I-6 with thioacetamide in a solvent such as tetrahydrofuran.

Other compounds of formula I, where R2means amide, such methoxyethylamine (I-9), can be obtained from the corresponding acids of formula II and 1,1'-carbonyldiimidazole (CDI) in N,N'-dimethylformamide (DMF) with the formation of the activated intermediate which is reacted with an appropriate amine, such methoxyethylamine. Methoxyethylamine I-9 reacts with nucleophiles, such allylanisole, such as methylmagnesium, to obtain the corresponding ketone of formula 1-10.

Scheme 2

Deputy R1has the meaning as described above.

Pharmaceutically acceptable salts of the compounds of formula 1 can be easily obtained according to known methods, taking into account the nature of the turn in the Sol connection. Inorganic or organic acids, such 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 the like, are suitable for the formation of pharmaceutically acceptable the salts of basic compounds of formula I. Compounds containing alkaline or alkaline earth metals, for example 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 I and their pharmaceutically acceptable salts are inhibitors of monoamine oxidase In and can be used for the treatment or prevention of diseases in which MAO-b inhibitors may be useful. 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, the international who owned the patent application # 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 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 are homogenized by 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 45,000 × 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 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 califorina buffer, pH 7.4, for 30 min at 37°C without or with various concentrations of compounds. After this is started enzymatic reaction, 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 was determined for MAO-A 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 of inhibitor, the selection of the data to a 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:

0,016
ExampleMAO-b [IR50(μm)]
30,018
4
50,043
60,429
80,387
90,187
100,392
110,011

Pharmaceutical compounds can be used as medicaments, for example 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 rectal administration, 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 gelatin what's 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 contain 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 described what's testimony 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 explain the invention. They do not limit the scope of the invention, and only submit it.

Example 1

Amide (R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-carboxylic acid

(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-carboxylic acid (1.5 g, of 0.005 mol) was dissolved in anhydrous N,N'-dimethylformamide in an argon atmosphere and cooled to 0°C. 1,1'-Carbonyldiimidazole (1.4 g 0,009 mol) was added to the mixture and the reaction mixture was stirred for one hour while the temperature was raised from 0°C to room temperature. Was added ammonium acetate (5.6 g, 0,073 mol) and the reaction mixture was stirred for one hour at room temperature. Water to the mixture was added dropwise, and the precipitated sludge. The solid was filtered, washed with water and dried in vacuum, obtaining of 1.36 g (0,0041 mol, 91% of theoretical) specified in the title compounds as white solids. MS (m/e)=329,3 (M+N)+.

Example 2

(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-carbonitril

A mixture of the amide (R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-carboxylic acid (0.400 g, 0.001 mol) and thionyl chloride (2.3 ml, to 0.032 mol) was heated with reverse holodilniki is in the atmosphere of argon for 3 hours. The mixture was cooled to room temperature, diluted with 5 ml of tetrahydrofuran, was concentrated in vacuum and purified by column chromatography on silica gel, using as eluent a mixture of ethyl acetate and hexane in the ratio 2:3. Fraction of the product was concentrated to dryness, obtaining (0,106 g, 28% of theoretical) of a light brown oil. MS (m/e)=311,1 (M+N)+.

Example 3

(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-N-hydroxy-5-oxo-pyrrolidin-3-carboxamide

(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-carbonitrile (0,211 g, 0.001 mol) and hydroxylamine hydrochloride (0,047 g, 0.001 mol) was dissolved in ethanol (4 ml) was added N,N-diisopropylethylamine (0,120 ml, 0.001 mol). The reaction mixture was stirred at reflux for three hours. The reaction mixture was cooled to room temperature, the solvent evaporated, the residue was extracted with dichloromethane and was purified by column chromatography on silica gel, using as eluent a mixture of dichloromethane and methanol in a ratio of 19:1, and was obtained (0,220 g, 94% of theoretical) of yellow oil. MS (m/e)=344,3 (M+N)+.

Example 4

(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-4-(5-methyl-[1.2.4]oxadiazol-3-yl)-pyrrolidin-2-he

(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-N-hydroxy-5-oxo-pyrrolidin-3-carboxamidine (0,020 g of 0.58 mmol) was dissolved in 0.4 ml of pyridine and slowly we use the and acetylchloride (0.01 ml, 0,116 mmol) at 0°C. Then the mixture was stirred at 70°C overnight. Added ice water and stirred the mixture for one hour. Extraction with a saturated solution of ammonium chloride and dichloromethane gave the crude product, which was purified by column chromatography on silica gel, using as eluent a mixture of dichloromethane and methanol in a ratio of 19:1, and got mentioned in the title compound as a pale yellow solid (0,0197 g, 92% of theoretical). MS (m/e)=368,4 (M+N)+.

Example 5

Ethyl ester of 3-{(R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-[1.2.4]oxadiazol-5-carboxylic acid

(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-N-hydroxy-5-oxo-pyrrolidin-3-carboxamidine (0,020 g of 0.58 mmol) was dissolved in 0.4 ml of pyridine and slowly added ETHYLACETYLENE (0.01 ml, 0,116 mmol) at 0°C. Then the mixture was stirred at 70°C for half an hour. Added ice water and stirred the mixture for one hour. Extraction with a saturated solution of ammonium chloride and dichloromethane gave the crude product, which was purified by column chromatography on silica gel, using as eluent a mixture of ethyl acetate and hexane in a ratio of 2:1, and got mentioned in the title compound as a pale yellow solid (0,019 g, 77% of theoretical). MS (m/e)=426,3 (M+N)+.

Example 6

Amide 3-{(R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-[1.2.4]oxadiazol-5-carboxylic acid

Ethyl ester of 3-{(R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-[1.2.4]oxadiazol-5-carboxylic acid (0,110 g, 0.25 mmol) was dissolved in 3.5 ml of ammonia (2 M solution in methanol). The resulting mixture was stirred at 50°for half an hour. The mixture was cooled to 0°C and precipitated solid. The reaction mixture was filtered, and the solid is washed with hexane and dried in vacuum. The residue is suspended in ethyl acetate and heated under reflux. Added diethyl ether, the suspension was cooled to 0°C and filtered, obtaining mentioned in the title compound as light brown solid (0,045 g, 44% of theoretical). MS (m/e)=397,4 (M+H)+.

Example 7

(R)-4-(2-Bromo-acetyl)-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-he

(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-carboxylic acid (0,204 g of 0.62 mmol) was dissolved in a mixture of dichloromethane (4 ml), thionyl chloride (0.15 ml, 2.1 mmol) and catalytic amount of N,N'-dimethylformamide. The reaction mixture was stirred for half an hour at room temperature before the formation of the intermediate acylchlorides. Then the solvent was removed under reduced pressure, and the residue suspended in toluene, concentrated in vacuum and dried. The resulting oil was dissolved in acetonitrile (2 ml) and added trimethylsilyldiazomethane (2 M in hexane) (1,55 ml, 3.1 mmol in argon atmosphere. The resulting yellow solution was stirred at room temperature for half an hour, while there was diazoketone. After cooling the reaction mixture to 0°C was added dropwise Hydrobromic acid (33% in acetic acid) (0,71 ml, 4 mmol). The resulting dark solution was stirred for half an hour at room temperature. Was added sodium bicarbonate (5 ml) and the mixture was extracted with dichloromethane. The organic layers were dried over magnesium sulfate, filtered and evaporated to dryness, obtaining a residue that was purified by column chromatography on silica gel, using as eluent a mixture of ethyl acetate and hexane in a ratio of 1:1, and got mentioned in the title compound as a pale yellow oil (0,067 g, yield of 67.5% of theoretical). MS (m/e)=407,3 (M+N)+.

Example 8

(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-4-(2-methyl-thiazol-4-yl)-pyrrolidin-2-he

(R)-4-(2-Bromo-acetyl)-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-he (0,040 g, 0,098 mmol) was dissolved in tetrahydrofuran (1 ml)was added thioacetamide (0,007 g, 0,098 mmol) and the mixture was stirred at 40°C for 24 hours. The tetrahydrofuran is evaporated, and the residue was purified by column chromatography on silica gel, using as eluent a mixture of ethyl acetate and hexane, first in the ratio of 1:1, then 4:1, and has been specified in the header of the connection light is on-yellow solid (0,030 g, 80% of theoretical). MS (m/e)=383,3 (M+N)+.

Example 9

(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-4-(1H-imidazol-4-yl)-pyrrolidin-2-he

(R)-4-(2-Bromo-acetyl)-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-he (0,050 g, 0,123 mmol) was dissolved in water (0.1 ml), was added formamide (0.6 ml) and the mixture was stirred at reflux for 6 hours. Added 2 M HCl and the mixture was extracted with ethyl acetate. The aqueous layer was neutralized with an aqueous solution (10%) sodium hydroxide (pH 7-8) and again extracted with ethyl acetate to obtain the crude material which was subjected to chromatography on silica gel, using as eluent a mixture of dichloromethane and methanol in a ratio of 19:1. Got to 0.011 g (25% of theoretical) specified in the title compound as a colourless solid. MS (m/e)=352,4 (M+N)+.

Example 10

Methoxy-methyl-amide (R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-carboxylic acid

(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-carboxylic acid (0,200 g, 0.001 mol) was dissolved in anhydrous N,N'-dimethylformamide (1 ml) in an argon atmosphere and cooled the solution to 0°C. 1,1'-Carbonyldiimidazole (to 0.108 g, 0.001 mol) was added to the mixture and the reaction mixture was stirred for one hour while the temperature was raised from 0°C to room temperature. After adding N,O-dimethylhydroxylamine hydrochloride (0,g, 0.001 mol) and pyridine (0,053 ml, 0.001 mmol) the reaction mixture was stirred for two hours at room temperature. Was added water (10 ml) and hydrochloric acid (0.1 g) and the mixture was extracted with ethyl acetate. The organic phase is washed with sodium carbonate solution (1 M) and was extracted again with ethyl acetate, getting 0,225 g (99% of theoretical). The crude product obtained in this way was used in the next stage without additional purification. MS (m/e)=373,4 (M+N)+.

Example 11

(R)-4-Acetyl-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-he

Methoxy-methyl-amide (R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-carboxylic acid (0,050 g, 0,143 mmol) was dissolved in argon atmosphere in tetrahydrofuran (1 ml) was added methylmagnesium (0,188 mmol, 0,063 ml) at 0°C. the resulting solution was stirred at 0°C for two hours. Added water at 0°C and the mixture was stirred for one hour. Extraction with ethyl acetate gave a residue, which was subjected to chromatography on silica gel, using as eluent a mixture of ethyl acetate and cyclohexane in the ratio of 9:1, and received 0,040 g (91% of theoretical) specified in the title compounds as white solids. MS (m/e)=328,4 (M+N)+.

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 stearate 4
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 made in the traditional way:

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

1. Compounds of General formula

where R1is a halogen;
R2represents a 5-membered heteroaryl group containing 2 or 3 heteroatoms selected from the group consisting of N, O or S, which may be substituted, R3where R3represents lower alkyl or-C(O)R;
R represents a-NR'r R" or lower alkoxy;
R'/R" independently of one another represent hydrogen;
and their pharmaceutically acceptable salts.

2. The compounds of formula I according to claim 1, which represent
(R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-4-(5-methyl-[1.2.4]oxadiazol-3-yl)-pyrrolidin-2-it,
ethyl ester of 3-{(R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-[1.2.4]oxadiazol-5-carboxylic acid,
amide 3-{(R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-[1.2.4]oxadiazol-5-carboxylic acid,
(R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-4-(2-methyl-thiazol-4-yl)-pyrrolidin-2-only
(R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-4-(1H-imidazol-4-yl)-pyrrolidin-2-it.

3. The compound of formula I according to claim 1 or 2, its pharmaceutically acceptable salt, inhibiting the monoamine oxidase Century

4. Medicine, inhibiting the monoamine oxidase B, containing one or more compounds according to claim 1 or 2, and pharmaceutically acceptable excipients.

5. The use of the compounds of formula I according to claim 1 or 2, its pharmaceutically acceptable salts for the manufacture of drugs that inhibits monoamine oxidase Century



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of aryl and heteroarylpiperidinecarboxylates, of formula (I): , where: type means integer numbers from 1 to 3, such that m+n is integer number from 2 to 5; p means integer number from 1 to 7; A means simple connection or is selected from one or several groups X, Y; X means -CH2-; Y means C2-alkynilene group; R1 means group R5, substituted with one or several groups R6 and/or R7; R2 means H, F, OH; R3 means H; R4 means H, C1-6-alkyl; R5 means group selected from phenyl, pyridinyl, pyrimidinyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphthyl, chinolynyl, tetrahydrochinolinyl, isochinolinyl, tetrahydroisochinolinyl, indolyl, indolinyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzizoxazolyl, benzothiazolyl, benzithiazolyl, benzotriazolyl, benzoxadiazolyl, pyrrolopyridinyl; R6 means halogen, CN, C1-6-alkyl, C3-7-cycloalkyl, C1-6-alkoxy, OH, C1-6-fluoroalkyl, C1-6-fluoroalkoxy, or cycle selected from pyrrolidine and piperidine cycle, besides this cycle is unnecessarily substituted with C1-6-alkyl group; R7 means phenyl group, besides group or groups R7 may be substituted with one or several groups R6, identical or differing from each other, selected from halogen, C1-6-alkyl and C1-6-fluoroalkyl, C1-6-alkoxy, in the form of pharmaceutically acceptable base or acid-additive salt.

EFFECT: compounds are applicable as inhibitors of FAAH ferment.

10 cl, 1 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives (indole-3-yl)heterocyclic compounds of formula 1: , where: A represents 5-member aromatic heterocyclic ring, where X1, X2 and X3 are independently selected from N, O, S, CR; R means H, (C1-4)alkyl; or R, when it is available in X2 or X3, may form 5-8-member ring together with R3; R1 means 5-8-member saturated carbocyclic ring, which unnecessarily contains heteroatom O; R2 means H; or R2 is connected to R7 with creation of 6-member ring, which unnecessarily contains heteroatom O, or where mentioned heteroatom is connected to position 7 of indole ring; R3 and R4 independently mean H, (C1-6)alkyl, which is unnecessarily substituted with OH, (C1-4)alkyloxy; or R3 together with R4 and N, with which they are connected, creates 4-8-member ring, which unnecessarily contains additional heteroatom, selected from O and S, and unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy or (C1-4)alkyloxy-(C1-4)alkyl; or R3 together with R5 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; or R3 together with R, when present in X2 or X3, creates 5-8-member ring; R5 means H; or R5 together with R3 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; R5' means H; R6 means one substituent selected from H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; R7 means H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; or R7 is connected to R2 with creation of 6-member ring, which unnecessarily contains additional heteroatom O, and where heteroatom is connected to position 7 of indole ring; or its pharmaceutically acceptable salt. Compounds of formula I display activity of agonists to cannabinoid receptor CB1.

EFFECT: possibility to use them for treatment of pains of various nature.

10 cl, 1 tbl, 42 ex

FIELD: medicine.

SUBSTANCE: invention is related to new heterocyclic compounds of common formula (I), and also their pharmaceutically acceptable salts, hydrates and/or solvates, possessing properties of human neutrophil elastase. In common formula (I) , A means phenyl or pyridyl cycle, R1 and R3 each means atom of hydrogen, R2 means atom of fluorine, chlorine, bromine, nitro group or cyano group, R4 means cyano group, alkyl carbonyl group with number of carbon atoms in alkyl residue from one to four, or alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, besides alkoxycarbonyk group with number of carbon items in alkoxyl residue from one to four, may be substituted with substituent, which is selected from the group that includes hydroxyl group, alkoxygroup with number of carbon atoms from one to four, alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, mono- or dialkylaminogroup, with number of carbon atoms in each of alkyl residues from one to four, 5-6-member heteroaryl group, which contains from 1 to 4 heteroatoms in heteroaryl ring, selected from nitrogen, oxygen or sulfur, possibly susbstituted with alkyl group, which contains from 1 to 4 atoms of carbon and possibly condensed with benzene ring, and 5-8 member heterocyclyl group, which contains from 1 to 3 heteroatoms from group of nitrogen, oxygen or sulfur, or SO, SO2 possibly substituted with ketogroup, R5 means methyl group, R6 means atom of hydrogen, alkyl group with number of carbon atoms from one to four, mono- or dialkylaminocarbonyl group with number of carbon atoms in each of alkyl residues from one to four, etc., Y1, Y2, Y3, Y4 and Y5 each means CH-group. Invention is also related to pharmaceutical composition.

EFFECT: possibility of application for treatment of chronic obstructive lung diseases, acute coronary syndrome, acute myocardial infarction and progressing cardiac decompensation.

8 cl, 1 dwg, 111 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of benzoindazole of formula I , where radicals A1, A2, A3, R1, R2, R3, R4 and n have values mentioned in formula of invention, and their pharmaceutically acceptable salts, and also to application of these compounds for production of medicinal agent intended for modulation of α2-subsort of GABA receptor, and pharmaceutical composition that contains it.

EFFECT: application of compounds for preparation of medicinal agent intended for treatment of depression, disorder in the form of anxiety, psychic disorder, disturbed ability to learning and cognition, sleep disturbance, disorder in the form of cramps or fits or pain.

16 cl, 5 tbl, 40 ex

FIELD: medicine.

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

EFFECT: higher clinical effectiveness.

17 cl, 2 dwg, 72 ex

FIELD: chemistry.

SUBSTANCE: 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 relates to a method of producing 2-heteroaryl derivatives of benzothiazole and benzoxazole of formula by boiling amine with general formula with acid chloride of general formula , where R=2-furyl or 2-thienyl, X = S or O, in 1-methyl-2-pyrrolidone.

EFFECT: method increases output of product to 78 to 90% and environmental friendliness of the process.

1 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I-a), where R1 and R2, each independently, represent -COORA (where RA is hydrogen or C1-8 alkyl), -CONRBSO2RC (where RB is hydrogen or C1-8 alkyl, RC is C1-8 hydrocarbon), -D-R1 is -CO-(CH2)2-R1, -CO-(CH2)3-R1, -CO-(CH2)4-R1 or C1-4alkylene-R1; E is a bond or C1-4alkylene; ring formula represents a 3,4-dihydro-2H-1,4-benzoxazine or 1H-indole ring; V is , where R110 is hydrogen or C1-8 alkyl, and the arrow shows that it is bonded to ring A; the group with formula is a phenyl group, which can contain a group with formula , where ring 2 is a C5-10 mono- or bicyclic aromatic carbocyclic ring, which can be partially or completely saturated, spirobicyclic carbocyclic ring, or a carbocyclic ring bonded by a bridge bond; where W is -O-CH2-, -O-(CH2)2, -O-(CH2)3, -O-(CH2)4, -O-(CH2)5, -CH2-O, -(CH2)2-O-, -(CH2)3-O-, -(CH2)4-O-, -(CH2)5-O-, -O-(CH2)3-O-, -O-(CH2)4-O-, -O-(CH2)5-O-, C1-6 alkylene, its N-oxide, its salt or its solvate. The invention also relates to a pharmaceutical composition based on formula I-a compound and its use.

EFFECT: obtaining new derivatives of benzoxazine and indole, with antagonistic effect on cysLT2 and which are useful for preventing and/or curing respiratory diseases, such as bronchial asthma, chronic obstructive lung diseases.

8 cl, 57 tbl, 261 ex

FIELD: medicine.

SUBSTANCE: invention covers thaizole derivatives of formula (I) and to their pharmaceutically acceptable salts. In formula I: X1 and X2 differ from each other and represent sulphur atom or carbon atom; R1 represents phenyl group; phenyl group substituted by 1-2 members chosen from the group including halogen atoms, alkoxygroup with 1-6 carbon atoms, hydroxygroup, phenylalkoxygroup with 7-12 carbon atoms; phenyl group fused with 5-7-membered heteroaromatic or nonaromatic ring with at least one heteroatom consisting of N, O and S; pyridyl group; R2 represents hydrogen atom, halogen atom, alkyl group with 1-6 carbon atoms, alkyl group with 1-6 carbon atoms substituted by 1-5 halogen atoms, alkoxygroup with 1-6 carbon atoms, or hydroxyalkyl group with 1-5 carbon atoms; A represents group which is presented by formula or . Also, the invention concerns ALK5 inhibitor containing compound of the invention as an active component, stimulators of hair follicles proliferation and hair growth, and also to thiazole derivative of formula where A1 represents .

EFFECT: higher efficiency.

12 cl, 2 tbl, 50 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: new 5-sulphanyl-4H-1,2,4-triazole derivatives of general formula I (meaning of radicals R1-R3 are indicated in the description of the invention), methods of their preparation by liquid-phase parallel synthesis and pharmaceutical composition are claimed.

EFFECT: claimed compounds display high affinity to some subtypes of somostatin receptors of the SST2 and SST5 subtypes and possibility of their usage for treatment of pathological states or diseases involving one or more of the given somostatin receptors

9 cl, 708 ex

FIELD: pharmacology.

SUBSTANCE: described are enantiomer-free compounds with a general formula of (1) wherein the R1, R2, R3, R4 and X- residue may have as specified in the invention formula, intermediary compounds, a pharmaceutical composition as well as their application in the capacity of medications intended for respiratory tract diseases treatment.

EFFECT: new enantiomer-free b-agonists, their preparation method and application in the capacity of medications.

11 cl, 5 dwg, 3 tbl, 37 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of aryl and heteroarylpiperidinecarboxylates, of formula (I): , where: type means integer numbers from 1 to 3, such that m+n is integer number from 2 to 5; p means integer number from 1 to 7; A means simple connection or is selected from one or several groups X, Y; X means -CH2-; Y means C2-alkynilene group; R1 means group R5, substituted with one or several groups R6 and/or R7; R2 means H, F, OH; R3 means H; R4 means H, C1-6-alkyl; R5 means group selected from phenyl, pyridinyl, pyrimidinyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphthyl, chinolynyl, tetrahydrochinolinyl, isochinolinyl, tetrahydroisochinolinyl, indolyl, indolinyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzizoxazolyl, benzothiazolyl, benzithiazolyl, benzotriazolyl, benzoxadiazolyl, pyrrolopyridinyl; R6 means halogen, CN, C1-6-alkyl, C3-7-cycloalkyl, C1-6-alkoxy, OH, C1-6-fluoroalkyl, C1-6-fluoroalkoxy, or cycle selected from pyrrolidine and piperidine cycle, besides this cycle is unnecessarily substituted with C1-6-alkyl group; R7 means phenyl group, besides group or groups R7 may be substituted with one or several groups R6, identical or differing from each other, selected from halogen, C1-6-alkyl and C1-6-fluoroalkyl, C1-6-alkoxy, in the form of pharmaceutically acceptable base or acid-additive salt.

EFFECT: compounds are applicable as inhibitors of FAAH ferment.

10 cl, 1 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention is related to new heterocyclic compounds of common formula (I), and also their pharmaceutically acceptable salts, hydrates and/or solvates, possessing properties of human neutrophil elastase. In common formula (I) , A means phenyl or pyridyl cycle, R1 and R3 each means atom of hydrogen, R2 means atom of fluorine, chlorine, bromine, nitro group or cyano group, R4 means cyano group, alkyl carbonyl group with number of carbon atoms in alkyl residue from one to four, or alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, besides alkoxycarbonyk group with number of carbon items in alkoxyl residue from one to four, may be substituted with substituent, which is selected from the group that includes hydroxyl group, alkoxygroup with number of carbon atoms from one to four, alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, mono- or dialkylaminogroup, with number of carbon atoms in each of alkyl residues from one to four, 5-6-member heteroaryl group, which contains from 1 to 4 heteroatoms in heteroaryl ring, selected from nitrogen, oxygen or sulfur, possibly susbstituted with alkyl group, which contains from 1 to 4 atoms of carbon and possibly condensed with benzene ring, and 5-8 member heterocyclyl group, which contains from 1 to 3 heteroatoms from group of nitrogen, oxygen or sulfur, or SO, SO2 possibly substituted with ketogroup, R5 means methyl group, R6 means atom of hydrogen, alkyl group with number of carbon atoms from one to four, mono- or dialkylaminocarbonyl group with number of carbon atoms in each of alkyl residues from one to four, etc., Y1, Y2, Y3, Y4 and Y5 each means CH-group. Invention is also related to pharmaceutical composition.

EFFECT: possibility of application for treatment of chronic obstructive lung diseases, acute coronary syndrome, acute myocardial infarction and progressing cardiac decompensation.

8 cl, 1 dwg, 111 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2-heteroaryl derivatives of benzothiazole and benzoxazole of formula by boiling amine with general formula with acid chloride of general formula , where R=2-furyl or 2-thienyl, X = S or O, in 1-methyl-2-pyrrolidone.

EFFECT: method increases output of product to 78 to 90% and environmental friendliness of the process.

1 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I-a), where R1 and R2, each independently, represent -COORA (where RA is hydrogen or C1-8 alkyl), -CONRBSO2RC (where RB is hydrogen or C1-8 alkyl, RC is C1-8 hydrocarbon), -D-R1 is -CO-(CH2)2-R1, -CO-(CH2)3-R1, -CO-(CH2)4-R1 or C1-4alkylene-R1; E is a bond or C1-4alkylene; ring formula represents a 3,4-dihydro-2H-1,4-benzoxazine or 1H-indole ring; V is , where R110 is hydrogen or C1-8 alkyl, and the arrow shows that it is bonded to ring A; the group with formula is a phenyl group, which can contain a group with formula , where ring 2 is a C5-10 mono- or bicyclic aromatic carbocyclic ring, which can be partially or completely saturated, spirobicyclic carbocyclic ring, or a carbocyclic ring bonded by a bridge bond; where W is -O-CH2-, -O-(CH2)2, -O-(CH2)3, -O-(CH2)4, -O-(CH2)5, -CH2-O, -(CH2)2-O-, -(CH2)3-O-, -(CH2)4-O-, -(CH2)5-O-, -O-(CH2)3-O-, -O-(CH2)4-O-, -O-(CH2)5-O-, C1-6 alkylene, its N-oxide, its salt or its solvate. The invention also relates to a pharmaceutical composition based on formula I-a compound and its use.

EFFECT: obtaining new derivatives of benzoxazine and indole, with antagonistic effect on cysLT2 and which are useful for preventing and/or curing respiratory diseases, such as bronchial asthma, chronic obstructive lung diseases.

8 cl, 57 tbl, 261 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new benzimidazole derivatives with general formula (I), where A represents -CH2-, -C(O), -C(O)-C(Ra)(Rb)-, X represents a -CH- radical; Ra and Rb independently represent a hydrogen atom or (C1-C6)alkyl radical; R1 represents a hydrogen atom or (C1-C8)alkyl radical; R2 represents a (C1-C8)alkyl radical; R3 represents -(CH2)P-Z3, -C(O)-Z'3 or -C(O)-NH-Z"3; Z3 represents (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkyl-N(RN)carbonyl, (C3-C7)cycloalkyl, aryl, arylthio or heteroaryl radical, Z3 is bonded to the -(CH2)P- through a carbon atom, heteroaryl radical, which is a 5-10- member heteroaryl, which contains 1-2 identical or different heteroatoms, chosen from sulphur, nitrogen or oxygen, and optionally substituted with one or more identical or different substitutes, chosen from halogen, nitro group or -(CH2)P'-V30-Y3; aryl radical, chosen from phenyl or naphthyl, optionally substituted with one or more identical or different substitutes, chosen from halogen, nitro group, cyano group, (C2-C6)alkenyl, pyrrolidinyl, phenyl, phenyloxy, phenylalkyloxy, 5-7- member heteroaryl, containing 1-3 nitrogen atoms and -(CH2)p'-V31-Y3; V30 represents -O-, -C(O)-, -C(O)-O- or a covalent bond; V31 represents -O-, -S-, -SO2-, -C(O)-, -C(O)-O-, -N(RN)-, -NH-C(O)- or a covalent bond; Y3 represents a hydrogen atom or (C1-C6)alkyl radical, optionally substituted with one or more identical or different halogen radicals; RN represents a hydrogen atom or (C1-C6)alkyl radical; Z3 represents a radical with a given formula (see below); Z'3 represents a phenyl radical, optionally substituted with one ore more identical or different substitutes, chosen from -(CH2)P"-V'3-Y'3; V'3 represents -O-; Y'3 represents a hydrogen atom or (C1-C6)alkyl radical; Z"3 represents a hydrogen atom or -(CH2)q-A"3 radical; A"3 represents (C1-C6)alkyl, phenyl or thienyl radical; alkyl or phenyl radical can be optionally substituted with one or more identical or different substitutes, chosen from halogen and -V"3-Y"3; V"3 represents -O-, -C(O)-, -C(O)-O- or a covalent bond; Y"3 represents a hydrogen atom or (C1-C6)alkyl radical; p is an integer from 0 to 6; p' and p" independently represent an integer from 0 to 1; q is an integer from 0 to 2; R4 represents a radical with formula -(CH2)S-R'4; R'4 represents a 5-7- member heterocycloalkyl, containing at least one nitrogen atom and optionally substituted with (C1-C6)alkyl; or a radical with formula -NW4W'4; W4 represents a hydrogen atom; W'4 represents a hydrogen atom; s is an integer from 0 to 6; in racemic or enantiomeric form or any combination of the said forms, or its pharmaceutically acceptable salt. The invention also relates to a method of obtaining a compound in paragraph 1, a pharmaceutical composition based on the said compound and its use in making a medicinal agent.

EFFECT: new benzimidazole derivatives have good affinity to certain subtypes of melanocortin receptors.

26 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new pyrimidine derivatives with general formula (I), their tautomeric or stereoisomeric form, in free form, in form of pharmaceutically acceptable salt or C1-6alkyl ester which are effective antagonists of CRTH2 (G-protein-associated chemoattractant receptor, ex prone on Th2 cells) and can be used for preventing and treating diseases related to CRTH2 activity, particularly in treatment of allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, diseases related to eosinophil. In formula (I) R1 is hydrogen, or in which n is an integer from 0 to 6; -Q1- is -NH-, -N(C1-6alkyl)- or -O; Y is hydrogen, C1-6alkyl, C3-6cycloalkyl, optionally substituted with C1-6alkyl, C3-6cycloalkyl, condensed with a benzene ring, phenyl, naphthyl or 5-6-member heteroaryl, possibly condensed with a benzene ring, and containing at least one heteroatom, chosen from a group consisting of oxygen and nitrogen, where the said phenyl, naphthyl or heteroaryl are optionally substituted on the displaceable position with one or several substitutes, chosen from a group consisting of cyano, halogen, nitro, guanidine, pyrroyl, sulfamoyl, phenyloxy, phenyl, di(C1-6)alkylamino, C1-6alkanoylamino, C1-6alkyl, optionally mono-, di- or tri-substituted with halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen and C1-6alkylthio, optionally mono-, di- or tri-substituted with halogen; or phenyl, condensed with 1,3-dioxolane; R2 is hydrogen or C1-6alkyl; R3 is a halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen, or , R3a and R3b are independently C3-8cycloalkyl or C1-6alkyl, this C1-6alkyl is optionally substituted with hydroxyl, carboxy, C3-6cycloalkylcarbamoyl, C5-6heterocyclocarbonyl containing a heteroatom in form of nitrogen, or C1-6alkoxy, q is an integer from 1 to 3; R3c is hydrogen, hydroxyl or carboxy; Xa is -O-; R4 is hydrogen, halogen, di(C1-6alkyl) amino or C1-6alkyl, optionally substituted C1-6alkoxy or mono- , di- or tri-substituted with halogen; R5 is hydrogen or C1-6alkyl; and R6 is carboxy, carboxamide, nitrile or tetrazolyl.

EFFECT: wider field of use of compounds.

32 cl, 9 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: in new compounds with general formula (I): , R1 stands for a naphthyl group, which can be substituted with a halogen atom, W represents a bond, a equals 0, 1 or 2, X1 represents C1-4alkylene, which can be substituted with a hydroxy group, Y1 represents -C(O)-,A represents a piperazine ring or piperidine ring, X2 represents a bond, Y2 represents -C(O)-, -S(O)2- or -C(=NR7)- (where R7 represents a hydrogen atom), X3 represents C1-4alkylene, which can be substituted with a hydroxyl group, oxo group or C1-6alkyl group; or C2-4alkylene, which can be substituted with a C1-6alkyl group, where two alkyl groups can be bonded to each other forming, together with carbon atoms to which they are bonded, an aryl ring when X3 represents C2-4alkylene, substituted with two alkyl groups, Z3 represents -N(R4)- or a bond (where R4 represents a hydrogen atom, C1-6alkyl group, which can be substituted with a hydroxy group or methoxy group, or acyl group), represents a single or double bond, where if represents a single bond, then Z1 represents -C(R2)(R2')-, -N(R2)- or -O- and Z2 represents C(R3)(R3')-, -N(R3)-, -O- or a bond (under the condition that, when Z2 represents -O-, then Z is different from -O-), and when represents a double bond, then Z1 represents -C(R3)= or a nitrogen atom and Z2 represents =C(R3)- or a nitrogen atom, each of R2, R2', R3 and R3' represents a hydrogen atom or C1-6alkylene. The invention also relates to salts of the given new compounds. The invention also relates to compounds, chosen from the group, to pharmaceutical compositions, to use of compounds in sub-paragraph 1 or 2, to prevention or treatment methods, as well as to the method of obtaining compounds in paragraph 1.

EFFECT: obtaining new biologically active compounds, which inhibit activated factor X of blood clotting and have anticoagulation activity and antithrombotic activity.

33 cl, 46 ex, 1 tbl

FIELD: chemistry; medicine.

SUBSTANCE: in novel triazole derivatives of general formula I or their pharmaceutically acceptable salts R4 is hydrogen; X is selected from group, consisting of single bond, NH- and groups: , values of R1-R3 radicals are given in description, pharmaceutical composition containing them, and application of novel compounds for obtaining medication for treating hyperglycemia, insulin-resistance, type 2 diabetes, fat exchange derangements, obesity, atheroslerosis and metabolic syndrome.

EFFECT: medications possess higher efficiency.

26 cl, 8 ex, 2 tbl

FIELD: chemistry; medicine.

SUBSTANCE: compounds of claimed invention possess properties of positive allosteric modulator mGluR5. In general formula I , W represents 6-member heterocycloalkyl ring with 1-2 heteroatoms, selected from N, O; R1 and R2 independently represent hydrogen, C1-C6-alkyl; P and Q each independently is selected from: , R3, R4, R5, R6 and R7 independently represent hydrogen; halogen; -CN; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; halogen-C1-C6-alkyl; 5-6-member heteroaryl with 1-2 atoms N as heteroatoms; 6-member heterocycle with 2 heteroatoms representing N, O; phenyl, optionally substituted with halogen; naphtyl; -OR8; where optionally two substituents together with located between them atoms form 9-10-member bicyclic aryl or heteroaryl ring with 1-2 heteroatoms, selected from N, S; R8 represents hydrogen, C1-C6-alkyl; D, E, F, G and H independently represent -C(R3)=, -O-, -N=, -N(R3)- or -S-; A represents ethinyl, -C(=O)NR8- or group of formula . B represents -C(=O)-C0-C2-alkyl-, -C(=O)-C2-C6-alkenyl-. Invention also relates to pharmaceutical composition based on invention compounds.

EFFECT: novel compounds possess useful biological proprties.

20 cl, 3 dwg, 75 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of indole of the general formula (I): wherein R1 means -S(O)0-2-A wherein A means phenyl optionally substituted with one or some groups or some groups chosen from (lower)-alkyl, (lower)-alkoxy-group, halogen atom, (lower)-halogenalkyl, (lower)-alkylsulfonyl or (lower)-halogenalkylsulfonyl, naphthyl, pyridinyl or benzothiazolyl; R2 means hydrogen atom, (C1-C6)-alkyl; R3 means hydrogen atom, (C1-C6)-alkyl; R4 means hydrogen atom, or one radical among R5, R6 or R7 means group of the general formula (B) wherein W means group -CH- or nitrogen atom, and others mean independently hydrogen atom; R8 means hydrogen atom, (C1-C10)-alkyl; R9 and R10 mean independently hydrogen atom, or their pharmaceutically acceptable salts. Compounds of the formula (I) possess affinity to 5-HT6 receptors that allows their using in pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 14 ex

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