Derivatives (r)-(-)-methylphenylacetonitrile and method of production thereof

 

(57) Abstract:

The invention relates to new derivatives of (R)-(-)-methylphenylacetonitrile formula I, where R is a hydrocarbon residue with the number of C-atoms to 5, with ZNS activity and inhibiting TNF-product, and the way they are received, namely, that the racemate derived methylphenylacetonitrile together with optically active auxiliary substance is transferred into the mixture of diastereomers and then separating the optically active auxiliary substance. Technical result: the compounds of formula I suitable for pharmaceutical drug used for the treatment and prevention of diseases, which are solved by stimulating TNF. 2 S. and 3 C.p. f-crystals, 3 PL.

The invention relates to derivatives of (R)-(-)-methylphenylacetonitrile, to a method for their production and to their use as pharmaceuticals.

From U.S. patent 4186129 it is known that derivatives of phenyloxazolidine have inhibiting phosphodiesterase properties and, additionally, there is a depression on the Central nervous system, cause antidopaminergics, antinociceptive and anticonvulsant action. Further, in EP-0198919 apicillin drugs is got with a good efficiency phenyloxazolidine.

In these publications only mention that the separation of the racemate to the antipodes can be accomplished by conventional methods, without enantiomers and not exploring their pharmacological activity or not setting of the purity of the obtained compounds. To reduce drug side effects, it is desirable to assign a uniform active substance that can be used in large dosages.

Now found that having the R-configuration derivative of methylphenylacetonitrile particularly effective and better suited for use as a drug than the racemate.

The invention relates to (R)-(-)-methylphenylcarbinol formula I

< / BR>
where R denotes a hydrocarbon residue with the number of C-atoms to 5.

As the remainder of the hydrocarbon should be called, for example, ethyl, propyl, isobutyl, Isobutanol, butyl, cyclobutyl and cyclopentyl.

The compounds of formula I also inhibit TNF-product and is therefore suitable for the treatment of diseases which are due to the activation of TNF.

Under the diseases that are transmitted through TNF, should be understood as diseases caused by the formation of TNF and diseases in the cat the mother as TNF-, and TNF-, which are both antagonizers compounds of formula I. Preferably inhibited TNF-.

The compounds of formula I are suitable, therefore, to obtain a pharmaceutical preparation, which is used for the treatment and prevention of disease in the living organism, which are solved by stimulating TNF. Diseases that are influenced by excessive or unregulated stimulation of TNF, are, for example, allergic and inflammatory diseases, autoimmune disease, pneumonic diseases and diseases of bone resorption, infectious diseases such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gout, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, ARDS (acute syndrome suffocation), pulmonary sarcoidosis, asthma, silicosis, cachexia, ulcerative colitis, Crohn's disease, osteoporosis, damage to the body after reperfusion, inflammatory diseases of the Central nervous system, as malaria with brain damage, multiple sclerosis, panencephalitis, infectious diseases like AIDS, rabies cattle, inflammatory skin diseases, as nettle fever, psoriasis, atopic dermatology Parkinson, dementia, for example, after multiple heart attacks and stroke.

The effectiveness of compounds of the formula I in the above indications may be detected by appropriate conventional pharmacological tests.

New (R)-(-)-methylphenylacetonitrile can be obtained from the racemate by chromatography on chiral columns or through the diastereomers with an optically active auxiliary substances. As the optically active auxiliary substances are used, for example, (R)-1-(1-naphthyl)-utilitzant, which allows to obtain optically active compound in a simple way with good yields and with high purity. The interaction is carried out in inert solvents, such as toluene, benzene, etc. or their mixtures, in the presence of organic bases, for example tertiary amine like triethylamine, at elevated temperature or the boiling point of the reaction mixture. The resulting mixture of diastereomeric allophanate separated by chromatography on silica gel quantitatively components. Then separated diastereomers allophanate processing bases break down, for example, with an alkaline alcoholate, in a polar solvent with optically active methylphenylacetonitrile. As the polar of p is the sludge ether. It is advisable to interact in an atmosphere of inert gas.

The invention also includes a method of producing compounds of the formula I, characterized by the fact that their racemate with an optically active auxiliary substance is transferred into the mixture of diastereomers and then separating the optically active auxiliary substance, or a racemate chromatographic on chiral columns. Obtaining compounds of formula 1 can be made by the Department (R, S)-5-(3-benzyloxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone, for example by chromatography and subsequent cleavage of the benzyl group and esterification. Cleavage of the benzyl group is carried out, for example, by hydrogenation in the presence of a catalyst, such as palladium on a suitable carrier in inert solvents, such as ethyl acetate. Subsequent esterification of hydroxy occurs in the presence of bases with a reactive derivative as a halide, tosylate or mesilate, in polar solvents, such as dimethylformamide or alcohols at temperatures up to the boiling point of the solvent. As suitable bases, for example, brush connection, as hydroxides, carbonates, alcoholate or sodium hydride or potassium.

If the substituent R is derived. For example, recovery can be performed by catalytic method with a catalyst of palladium/charcoal in an inert solvent at room temperature or at elevated temperature.

The methods according to the invention allow to obtain the compounds of formula I with a purity of 99%.

For example, 5-(3-cyclopentyloxy-4-methoxyphenyl)-5-methyl - 2-oxazolidinone (compound I) it can be shown that optically active (R)-(-)-connection is unexpectedly effective connection.

Improved efficiency of new chiral derivatives of methylphenylacetonitrile in comparison with the racemate can be shown on rats using typical of phosphodiesterase type IV (GE IV) inhibitors Head twitch and Grooming-reaction. The racemate and the corresponding enantiomers gave Wistar - rats male intraperitoneally (i.p.) and was determined by monitoring the appearance of Head twitches and Grooming reaction within 15-75 min after injection. As can be seen from the table. 1, (S)-(+)-enantiomer in contrast to the racemate 4 times (Head twitches) or 6 times (Grooming) is weaker in terms of efficiency, while (R)-(-)- enantiomer was 4 times more effective (Head twitches) or as effective (Grooming) in comparison with the racemate.

The effect of the enantiomers on the Central nervous system brain in vitro (European Journal of Pharmacology, volume 127, 105-115 (1986)). IC50- values (the concentration at which occurs the inhibitory effect of 50%), were converted to constant braking Kiwhich are calculated according to the following formula:

Ki= IC50[I + (L/KD)],

where L denotes the concentration of radioactive indicator and KDdenotes the dissociation constant3H-binding rolipram which is defined separately (table. 2).

Macrophages and microglial cells that perform the functions of macrophages in the brain, stimulate the release of TNF - during experimental allergic encephalomyelitis (EAE). If macrophages, for example, stimulate liposaccharide (LPS), then there is a selection of TNF - in vitro and in vivo for several hours.

Murine macrophage cell line RAW264) pre-incubated for 30 min in the presence and absence of various concentrations of PDE-IV inhibitors and then stimulated with LPS (10 ng/ml). After 18 h after stimulation remove culture medium and measured TNF-release by using specific ELISA test.

The sample was received from different companies, among others from the company "British Biotechnology, Gensym", and perform the test as described production is the ranking with the racemate shown in example 5-(3-propoxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone (compound 2) table. 3.

From table. 3 shows that (-)-enantiomer in two times more effective than the racemate, and 10 times more effective than (+)-enantiomer.

Since the new compounds of the formula I differ not only increased efficiency, but also small side effects and low toxicity, the use of optically active (R)-(-) - methylphenylacetonitrile for the manufacture of medicines is particularly advantageous.

Medicines manufactured by conventional means, and the active substance with suitable carriers, excipients and/or additives lead in the form of a pharmaceutical preparation which is suitable for enteral or parenteral application. Obtained in this way the dosage form can be used as medicinal products in human medicine or veterinary medicine. The application can be oral or sublingual, as a solid in the form of capsules or tablets or as a liquid in the form of solutions, suspensions, Alexiou, aerosols or emulsions, or rectally in the form of suppositories, or in the form used in case of need also subcutaneously, intramuscularly or intravenously injectable solutions or toniceski or intrathecal. As Artie organic and inorganic substances-media as, for example, water, gelatin, gum Arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. in Addition, if necessary, may contain preservatives, stabilizers, substances with a high surface activity, emulsifiers or salts to change the osmotic pressure or buffer solutions.

The pharmaceutical preparations may be in solid form such as tablets, pills, suppositories, capsules, or liquid form such as solutions, suspensions or emulsions.

As systems-carriers can be used as surface-active excipients such as salts, herbal acids or animal or vegetable phospholipids and their mixtures, as well as liposomes or their components.

For oral administration suitable in particular tablets, coated tablets or capsules with talc and/or carriers or binders based on hydrocarbon, as, for example, lactose, corn or potato starch. The application can also be in liquid form, such as juice, to which is added if necessary saccharin.

The compounds of formula I are used in doses sufficient to reduce TNF-product from the assignment method, depending on the age and weight of the patient, the type and severity of the disease, which is treated and similar factors. The daily dose is 0.1 to 25 mg, preferably 0.5 to 5 mg, and the dose can be given as prescribed single dose or divided into two or more daily doses.

Since the starting compounds is not described, they are known from these publications or can be obtained analogously to known compounds or ways described here.

The following examples should clarify the method according to the invention.

Source connection:

(R,S)-2-(3-cyclopentyloxy-4 - methoxyphenyl)-2-hydroxy-1-Propylamine

of 16.9 g of 3-cyclopentyloxy-4-methoxyacetophenone dissolve when heated in 12.5 ml of trimethylsilylacetamide. After addition of 700 mg of iodide of zinc comes in a strong thermal effect; then cooled to 20oC and stirred for 30 min in nitrogen atmosphere. The reaction mixture is mixed with 100 ml of tetrahydrofuran and added dropwise over 20 min a solution of 4.4 g of lithium aluminum hydride in 100 ml of tetrahydrofuran. After 30 minutes, carefully add 100 ml of a saturated solution of tartrate of potassium-sodium. Formed mushy mass, from which you can decant phase of tetrahydrofuran. Casio is trageriemen is evaporated in vacuum. The residue is dissolved in 300 ml ethyl acetate and extracted 3 times, each in 50 ml of 2 N. hydrochloric acid. The combined acidic extracts using 4 N. sodium liquor adjust to pH 13 and extracted 6 times, each time with 100 ml of a simple diethyl ether. The ether extracts are dried over sodium sulfate and evaporated in vacuum. Get the remainder of 16.4 g (R,S)-2-(3 - cyclopentyloxy-4-methoxyphenyl)-2-hydroxy-1-Propylamine with a melting point of 82oC.

(R,S)-5-(3-cyclopentyloxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone

A solution of 16.4 g (R,S)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-hydroxy - 1-Propylamine in 150 ml of tetrahydrofuran is mixed with 10.2 g of N,N'-carbonyldiimidazole and stirred for 3 h at room temperature. The reaction mixture is evaporated in vacuo, the residue is dissolved in 500 ml ethyl acetate and the solution washed 2 times, each time with 50 ml of 2 N. hydrochloric acid and then water, dried and evaporated in vacuum. As the remainder of the gain of 17.7 g (R,S)-5-(3-cyclopentyloxy - 4-methoxyphenyl)-5-methyl-2-oxazolidinone. The melting point 83,5oC.

(R,S)-2-(4-methoxy-3-propoxyphenyl)-2-hydroxy-1-Propylamine

A mixture of 30 g of 4-methoxy-3-propoxyethanol and 25 ml of trimethylsilylacetamide mixed with 1.4 g of the iodide CIN is mixed with a suspension of 8.0 g of lithium aluminum hydride in 200 ml of tetrahydrofuran and heated one hour before boiling. After cooling to 4oC is diluted with 750 ml simple diethyl ether, and the mixture is gently mixed and then for 45 min with saturated sodium bicarbonate solution until the precipitation of the solid aluminium hydroxide. The organic phase is separated, and the remaining inorganic substance is washed with 1000 ml of a simple diethyl ether. The combined organic phases are evaporated in vacuo, the residue is absorbed in dichloromethane and extracted 4 times, each time in 80 ml of aqueous 2 N. hydrochloric acid. The combined acidic aqueous phases using aqueous 5 n sodium hydroxide solution is brought to pH 10, and after saturation with sodium chloride is extracted repeatedly with ethyl acetate. The United extracts dried over sodium sulfate and evaporated in vacuum. As the remainder of the gain of 25.0 g (R,S)-2-(4-methoxy-3 - propoxyphenyl) -2-hydroxy-1-Propylamine with a melting point of 90oC.

(R,S)-5-(4-methoxy-3-propoxyphenyl)-5-methyl-2-oxazolidinone

A solution of 24.0 g (R,S)-2-(4-methoxy-3-propoxyphenyl)-2-hydroxy - 1-Propylamine in 260 ml of tetrahydrofuran is mixed under ice cooling from 19.4 g of N, N'-carbonyldiimidazole and then stirred for 16 h at room temperature. The solvent is evaporated in vacuum, the residue is dissolved in 300 ml of the washed organic phase with sodium bicarbonate solution and sodium chloride solution, dried over sodium sulfate and evaporated in vacuum. Oily residue 28 g purified by chromatography on a column of silica gel with a mixture of hexane-ethyl acetate as solvent. Obtain 24.5 g (R,S)-5-(4-methoxy-3-propoxyphenyl)-5-methyl-2-oxazolidinone. The melting point 71oC.

(R,S)-2-(3-ethoxy-4-methoxyphenyl)-2-hydroxy-1-Propylamine

A mixture of 28 g of 3-ethoxy-4-methoxyacetophenone and 25 ml of trimethylsilylacetamide mixed with 1.4 g of zinc iodide and heated for 4 h to 100oC. After cooling, the reaction mixture is diluted with 200 ml of tetrahydrofuran, mixed dropwise with a suspension of 8.0 g of lithium aluminum hydride in 200 ml of tetrahydrofuran and heated 1 h to a boil. After cooling to 4oC is diluted with 750 ml simple diethyl ether, and the mixture is then gently mixed for 45 min with saturated sodium bicarbonate solution until the precipitation of aluminium hydroxide. The organic phase is separated, and the remaining inorganic substance is washed using 1000 ml simple diethyl ether. The combined organic phases are evaporated in vacuo, the residue is absorbed in dichloromethane and extracted 4 times, each time in 80 ml of aqueous 2 n hydrochloric acid. The combined acidic aqueous phases using water RAO with ethyl acetate. The United extracts dried over sodium sulfate and evaporated in vacuum. As the remainder of the gain of 26.1 g (R,S)-2-(3-ethoxy-4 - methoxyphenyl)-2-hydroxy-1-Propylamine with a melting point of 88oC.

(R,S)-5-(3-ethoxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone

A solution of 11.2 g (R,S)-2-(3-ethoxy-4-methoxyphenyl)-2-hydroxy-1 - Propylamine in 130 ml of tetrahydrofuran while cooling with ice mixed with 9.7 g of N,N'-carbonyldiimidazole and then stirred for 16 h at room temperature. The solvent is evaporated in vacuum, the residue is dissolved in 200 ml of ethyl acetate, and the solution is washed 2 times, each time with 50 ml aqueous solution of 1 N. hydrochloric acid. After that, the organic phase is washed with sodium bicarbonate solution and sodium chloride, dried over sodium sulfate and evaporated in vacuum. Oily residue 12 g purified by chromatography on a column of silica gel with a mixture of hexane-ethyl acetate as solvent. Obtain 9.6 g (R, S)-5-(3-ethoxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone. The melting point 102oC.

Example 1.

Receiving and separation of diastereomeric allophanate.

of 17.7 g (R,S)-5-(3-cyclopentyloxy-4-methoxyphenyl)-5-oxazolidinone dissolved in 240 ml of toluene. After adding 9 ml Treaty who eat evaporated in vacuum. The remainder of 31.1 g chromatographic on a column of silica gel (Kromasil, 10 μm) with a mixture of hexane-simple diethyl ether (6:4). Elute 11.5g amide N-[(R)-1- (1-naphthyl)ethyl]-(R)-5-(3-cyclopentyloxy-4-methoxyphenyl)-5 - methyl-2-oxazolidinone-3-carboxylic acid, melting point 124oC []D= -o8 (CHCl3) and 13.5 g of amide N-[(R)-1-(1-naphthyl)ethyl]-(S)-5-(3-cyclopentyloxy-4-methoxyphenyl)-5 - methyl-2-oxazolidinone-3-carboxylic acid, oily, []D= 41o(CHCl3).

(R)-(-)-5-(3-cyclopentyloxy-4-methoxyphenyl)-5-methyl-2 - oxazolidinone

A solution of 11.0 g of amide N-[(R)-1-(1-naphthyl)ethyl]-(R)-5-(3-cyclopentyloxy - 4-methoxyphenyl)-5-methyl-2-oxazolidinone-3-carboxylic acid in 230 ml of tetrahydrofuran is mixed under ice cooling and under nitrogen atmosphere with 2.3 g of ateleta potassium and stirred for 30 min at room temperature. After adding 700 ml of ethyl acetate, washed 2 times, each time with 50 ml of 2 N. hydrochloric acid and then with water, dried and evaporated in vacuum. The crude product is 12.3 g chromatographic on a column of silica gel (Kromasil, 10 μm) with a mixture of ethyl acetate-hexane (3:7). Elute 6.8 g and recrystallized from hexane-dichloromethane. Output: 6,23 g (R)-(-)-5-(3-cyclopentyloxy-4 - methoxyphenyl)-5-methyl-2-oxazolidinyl)-5-methyl-2 - oxazolidinone

A solution of 490 mg of amide N-[(R)-1-(1-naphthyl)ethyl]-(S)-5-(3-cyclopentyloxy - 4-methoxyphenyl)-5-methyl-2-oxazolidinone-3-carboxylic acid in 10 ml of tetrahydrofuran is mixed under nitrogen atmosphere with 90 mg of ateleta potassium and stirred for 1 h at room temperature. After adding 50 ml of ethyl acetate, washed 2 times, each time 10 ml of 2 N. hydrochloric acid and then water, dried and evaporated in vacuum. The crude product is 470 mg chromatographic on a column of silica gel (Kromasil, 10 μm) with a mixture of ethyl acetate-hexane (3:7). Elute 260 mg of crystalline (S)-(+)-5-(3-cyclopentyloxy-4 - methoxyphenyl)-5-methyl-2-oxazolidinone. The melting point of 80oC []D= +38o(CHCl3).

Example 2.

Receiving and separation of diastereomeric allophanate.

14.6 g (R,S)-5-(4-methoxy-3-propoxyphenyl)-5-methyl-2-oxazolidinone dissolved in 200 ml of toluene. After addition of 7.7 ml of triethylamine and 10.0 g (R)-1-(1-naphthyl)-utilizationof the reaction solution is heated for 16 h under nitrogen atmosphere to a boil. After cooling to room temperature, evaporated in vacuo, the residue is dissolved in ethyl acetate, the solid composite part is filtered off and the solution concentrated in vacuo. The remainder chromatographic on a column of silica gel (which to obtain 7.0 g of amide N- [(R)-1-(1-naphthyl)ethyl]-(R)-5-(4-methoxy-3-propoxyphenyl)-5-methyl - 2-oxazolidinone-3-carboxylic acid. The melting point 106oC []D= -9o(CHCl3). Then elute 12.4 g of amide N- (R)-1-(1-naphthyl)ethyl-(S)-5-(4-methoxy-3-propoxyphenyl)-5-methyl - 2-oxazolidinone-3-carboxylic acid as an oil, []D= -43o(CHCl3).

(R)-(-)-5-(4-methoxy-3-propoxyphenyl)-5-methyl-2-oxazolidinone

Under ice cooling a solution of 10.0 g of amide N-[(R)-1-(1-naphthyl)ethyl]- (R)-5-(4-methoxy-3-propoxyphenyl)-5-methyl-2-oxazolidinone-3-carboxylic acid in 200 ml of tetrahydrofuran is stirred with 2.3 g of ateleta potassium and then stirred at room temperature for 1.5 hours After addition of 400 ml of ethyl acetate, washed 2 times, each time with 50 ml of 2 N. hydrochloric acid and then water, dried and evaporated in vacuum. The crude product was 8.3 g chromatographic using a mixture of ethyl acetate and hexane as solvent on a column of silica gel. Get 5.3g (R)-(-)-5-(4-methoxy-3-propoxyphenyl)- 5-methyl-2-oxazolidinone, which is recrystallized from a mixture of ethyl acetate-hexane. Output: 4,5, melting Point: 93oC []D= -48o(CHCl3).

(S)-(+)-5-(4-methoxy-3-propoxyphenyl)-5-methyl-2-oxazolidinone

Under ice cooling a solution of 13.8 g of amide N-[(R)-1-(1-naphthyl)ethyl]- (S)-5-(4-methoxy-3-propoxyphenyl)-5-methyl-2-oxazolidinone-3-carboxylic what round 16 PM After addition of 400 ml of ethyl acetate, washed 2 times, each time with 50 ml of 2 N. hydrochloric acid and then with water, and evaporated in vacuum. The crude product is 16.5 g chromatographic using a mixture of ethyl acetate and hexane as solvent on a column of silica gel. Gain of 8.3 g (S)-(+)-5-(4-methoxy-3-propoxyphenyl)-5-methyl-2-oxazolidinone. After crystallization from hexane-ethyl acetate remain 6,4, melting Point 94oC []D= +45o(CHCl3).

Example 3.

Receiving and separation of diastereomeric allophanate.

5.9 g (R,S)-5-(3-ethoxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone dissolved in 90 ml of toluene. After the addition of 3.3 ml of triethylamine and 4.8 g (R)-1-(1-naphthyl)-utilizationof the reaction solution is heated for 25 hours in a nitrogen atmosphere to a boil. After cooling to room temperature, evaporated in vacuo, the residue is dissolved in ethyl acetate, the solid integral part of the filter and concentrate the solution under vacuum. The remainder chromatographic on a column of silica gel (Kromasil, 10 μm) with a mixture of ethyl acetate-hexane (3: 7). Elute 4,55 g of amide N-[(R)-1-(1-naphthyl)ethyl] - (R)-5-(3-ethoxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone-3 - carboxylic acid. The melting point 112oC []D= -12oD= -39o(CHCl3).

(R)-(-)-5-(3-ethoxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone

Under ice cooling a solution of 7.3 g of amide N-[(R)-1(1-naphthyl-ethyl]- (R)-5-(3-ethoxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone-3-carboxylic acid in 100 ml of tetrahydrofuran is mixed with 1.8 g of ateleta potassium and then stirred at room temperature for 30 minutes After adding 300 ml of ethyl acetate, washed 2 times, each time with 50 ml of 2 N. hydrochloric acid and then water, dried and evaporated in vacuum. The crude product chromatographic with a mixture of ethyl acetate and hexane as solvent on a column of silica gel. Obtain 3.8 g (R)-(-)-5-(3-ethoxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone. After recrystallization from hexane-ethyl acetate remains 3,1, melting Point 87oC []D= -51o(CHCl3).

(S)-(+)-5-(3-ethoxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone

Under ice cooling a solution of 10.1 g of amide N-[(R)-1(1-naphthyl)ethyl]- (S)-5-(3-ethoxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone-3-carboxylic acid in 200 ml of tetrahydrofuran is mixed with 3.6 g of ateleta potassium and then stirred for 16 h at room temperature. After adding 400 ml of ethyl acetate, washed 2 times each time with 50 ml of 2 N. hydrochloric acid and datacastle solvent on a column of silica gel. Obtain 5.5 g (S)-(+)-5-(3-ethoxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone. After recrystallization from hexane-ethyl acetate remains 4,1, melting Point 85oC []D= +49o(CHCl3).

Example 4.

Separation of diastereomers (R,S)-5-(3-benzyloxy-4-methoxyphenyl)- 5-methyl-2-oxazolidinone.

3 g (R,S)-5-(3-benzyloxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone is obtained similarly to (R,S)-5-(3-cyclopentyloxy-4-methoxyphenyl)-5 - methyl-2-oxazolidinone - chromatographic on Chirapher-column (25 μm) Program installation with a mixture of hexane-dioxane. Elute 1.2 g (S)-(+)-5-(3-benzyloxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone, melting point 115, 8mmoC []D= +38,9o(CHCl3), and 1.1 g (R)-(-)-5-(3-benzyloxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone, the melting point of 116.7oC []D= +38,4o(CHCl3).

(R)-(-)-5-(3-hydroxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone

1.1 g (R)-(-)-5-(3-benzyloxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone dissolved in 40 ml ethyl acetate and mixed with 100 mg of 10% palladium/charcoal. Hydronaut until the absorption of hydrogen. After filtration on silica gel and evaporation in vacuo receive 750 mg (R)-(-)-5-(3-hydroxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone, point PLA is 2-oxazolidinone

A solution of 80 mg (R)-(-)-5-(3-hydroxy-4-methoxyphenyl)-5-methyl-2 - oxazolidinone in 1 ml of dimethylformamide is mixed with 25 mg of sodium hydride (55-65%) and stirred for 15 min at 60oC. After cooling buried 0,04 ml bromocyclobutane and stirred for 2 h at 110oC. the Reaction mixture was concentrated in oil vacuum in the round tube dry. The residue is purified by chromatography on a column of silica gel with a mixture of hexane - ethyl acetate as solvent. Get up to 52 mg (R)-(-)-5-(3- CYCLOBUTANE-4-methoxyphenyl)-5-methyl-2-oxazolidinone, melting point 132,5oC []D= -38,6o(CHCl3).

Example 5.

(R)-(-)-5-(3-isobutyryloxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone

A solution of 710 mg (R)-(-)-5-(3-hydroxy-4-methoxyphenyl)-5-methyl-2 - oxazolidinone in 30 ml of ethanol is mixed in turn with 658 mg of potassium carbonate and of 0.48 ml chloride Metallica. After 15 h stirring at 70oC was filtered and the solution is evaporated in vacuum. The oily residue is purified by chromatography on a column of silica gel with a mixture of hexane-ethyl acetate as solvent. Obtain 620 mg (R)-(-)-5-(3-isobutyryloxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone, oily, []D= -24,3oC.

Example 6.

(R)-(-)-5-(3-isobut is ledenon dissolved in 10 ml ethyl acetate and stirred with 50 mg of palladium/charcoal (10%). Hydronaut until the absorption of hydrogen. After filtration on diatomaceous earth and evaporation in vacuo get oily residue. The crude product is purified by chromatography on a column of silicagel, with a mixture of hexane-acetone as solvent. Obtain 186 mg (R)-(-)-5-(3-isobutoxy-4-methoxyphenyl)- 5-methyl-2-oxazolidinone, melting point 93,7oC []D= -24,7o.

1. Derivatives (R)-(-)-methylphenylacetonitrile formula I

< / BR>
where R is a hydrocarbon residue with the number of C-atoms up to 5.

2. Derivatives (R)-(-)-methylphenylacetonitrile under item 1, representing:

(R)-(-)-5-(3-cyclopentyloxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone,

(R)-(-)-5-(3-ethoxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone,

(R)-(-)-5-(4-methoxyphenyl-3-propoxy)-5-methyl-2-oxazolidinone,

(R)-(-)-5-(3-CYCLOBUTANE-4-methoxyphenyl)-5-methyl-2-oxazolidinone,

(R)-(-)-5-(3-isobutyryloxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone.

(R)-(-)-5-(3-isobutoxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone.

3. Derivatives (R)-(-)-methylphenylacetonitrile formula I according to one of paragraphs.1 or 2, with ZNS activity.

4. Derivatives (R)-(-)-methylphenylacetonitrile formula I according to one of paragraphs.1 and vizvolnogo of methylphenylacetonitrile together with optically active auxiliary substance is transferred into the mixture of diastereomers and then separating the optically active auxiliary substance.

 

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n2 = 0 or 1,

n3 = 0, 1, 3 or 3, provided that

n1 + n2 + n3 < 4;

R0represents hydrogen or A;

R1represents hydrogen, A, OA, phenoxy, Ph, OH, F, Cl, Br, CN, CF3, COOH, COOA, acyloxy with 1-4 carbon atoms, carboxamido, -CHNH2, -CH2NHA, -CH2NA2,

-CH2NHAc, -CH2NHSO2CH3,

or

R0and R1together represent alkylenes chain with 1 to 3 carbon atoms or alkenylamine chain with 2 to 3 carbon atoms;

R2represents hydrogen, A, Ac, or-CH2-R4;

R3represents-CH2-R4or-CHA-R4;

R4is a Ph, 2-, 3 - or 4-pyridyl (unsubstituted or monosubstituted R5) or thiophene (unsubstituted, mono - or disubstituted by A, OA, OH, F, Cl, Br, CN and/or CF3or the other what it is, di-, tri-, Tetra-, or pentamidine F, CF3partially or fully fluorinated A, A and/or OA;

R6, R7, R8and R9each independently represents H, A, OA, phenoxy, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NHA, NA2, Ac, Ph, cycloalkyl c 3-7 carbon atoms, -CH2NH2, -CH2NHA, -CH2NA2, -CH2N HAC or-CH2NHSO2CH3or two coming together constitute the remainder alkylenes chain with 3-4 carbon atoms, and/or R1and R6together predstavljaet a chain with 3 or 4 carbon atoms;

A represents alkyl with 1-6 carbon atoms;

Ac is alkanoyl with 1-10 carbon atoms or aroyl with 7 to 11 carbon atoms;

Ph represents phenyl (unsubstituted or substituted R5, 2-, 3 - or 4-pyridium or phenoxyl group);

and physiologically acceptable salts, their derivatives

The invention relates to methods of producing new derivatives of 1,4-dihydropyridines-3,5-dicarboxylic acid in the form of the R-isomers of General formula I, where R1and R3the same or different and mean C1-C8-alkyl which may be substituted C1-C6-alkoxyl or hydroxyl, R2is phenyl which may be substituted with halogen or cyano

The invention relates to new derivatives of 1,4-dihydropyridines F.-ly (I), where R1and R3denote C1-C8-alkyl, unsubstituted or substituted C1-C6-alkoxyl or hydroxyl, or C3-C7-cycloalkyl, R2denotes a substituted phenyl, and the Deputy is chosen from the group comprising halogen, cyano, ethinyl, triptoreline, methyl, methylthio, trifluoromethyl, or C1-C4-alkoxyl
The invention relates to the field of treatment of acute CNS, and in particular to methods of treatment OSPS in children, and can be used in clinical practice

The invention relates to medicine, in particular, neurology, and is the application selegilina (L-N-(1-phenylisopropyl)-N-methyl-N-Propylamine) or its pharmaceutically acceptable salts for the treatment of epileptic disorders
The invention relates to medicine and can be used for the treatment of neuroses and neurosis-like disorders

The invention relates to medicine, pharmacology, and relates to means for reducing the consumption of ethyl alcohol and the severity of the pathological craving for ethanol

The invention relates to new derivatives of oxazolidinones General formula (I) listed in the description, as well as their salt

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new derivatives of carbamic acid esters of the general formula (I):

and their pharmaceutically acceptable salts eliciting activity with respect to metabotropic glutamate receptors mGlu of group I that can be used for treatment of acute and/or chronic neurological disorders. In the general formula (I) R1 means hydrogen atom or (C1-C7)-alkyl; R2 and R2' mean independently of one another hydrogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom or trifluoromethyl; X means oxygen (O), sulfur (S) atom or two hydrogen atoms not forming a bridge; A1/A2 mean independently of one another phenyl or 6-membered heterocycle comprising 1 or 2 nitrogen atom; B represents group of the formula:

wherein R3 means (C1-C7)-alkyl and others; Y means -O-, -S- or a bond; Z means -O- or -S-; or B means 5-membered heterocyclic group of formulae: (a) , (b) , (c) or (d) . Also, invention relates to methods for preparing compounds and to a medicinal agent based on thereof.

EFFECT: improved preparing methods, valuable medicinal properties of compounds.

22 cl, 1 tbl, 2 sch, 78 ex

FIELD: medicine, gastroenterology.

SUBSTANCE: traditional eradication therapy should be supplemented with licopid at the dosage of 10 mg per os once daily before breakfast for 10 d. The present innovation prevents transfer of microorganisms into inactive form, accelerates restoration of mucosal epithelial layer in gastroduodenal area, provides complete eradication of microorganisms, that in its turn, favors to prevent disease exacerbation and restoration of gastroduodenal functions.

EFFECT: higher efficiency of therapy.

3 dwg, 2 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to pharmaceutical composition for intranasal administration contains zolmitriptan that is agonist of 5-HT1-receptor and pharmaceutically acceptable carrier. The composition has pH value less 6.0. The composition can be used for treatment of migraine and related disorders. The composition shows the improved stability in storage and provides effective relief for patients suffering with migraine.

EFFECT: improved and valuable medicinal properties of composition.

11 cl, 1 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

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