Derivatives of pyridazinones, as well as their salt or a stereochemical isomeric form, antiviral composition and heterocyclic derivatives

 

(57) Abstract:

Usage: in medicine as compounds with antiviral activity. The essence of the invention: derivatives of f-crystals (I) in which one or two carbon atoms of methylene groups in the residue can be substituted by alkyl (C1-C4) alkoxygroup (C1-C4or two carbon methylene group of the above-mentioned residue can be connected by bridge with alkane (C2-C4) deliamam radical, X is CH or N; each of m and n, independently of one another, denote 1, 2 and 3, and the sum m+n is equal to 3, 4, or 5, R1hydrogen, halogen, alkyl (C1-C4each of R2and R3independently represent hydrogen or (C1-C4) alkyl, Alk-alkane (C1-C4) diyl, each of R4-R5independently denotes hydrogen or halogen, (C1-C4) alkyl, and Het group; oxadiazol, oxazole, thiazole, thiadiazole. Reagent A: Amin. Reagent B: derivatives of pyridazine, W-tsepliaeva group. The process is conducted in a reaction-inert solvent in the presence of a base. Heterocyclic derivatives - amines, f-crystals A. Antiviral composition comprises an inert diluent and, as active principle carried the us derivatives which have the General formula:

(1) where one or two carbon atoms of methylene groups in the residue-NX - may be substituted by alkyl WITH1-C4, alkoxygroup1-C4or two carbon atom of the methylene groups of the above-mentioned residue can be connected by bridge with alkane(C2-C4)delovym radical; X represents CH or a nitrogen atom; each of m and n, independently of one another, denotes 1, 2, 3, and the sum m+n is 3, 4 or 5; R1denotes a hydrogen atom, alkyl WITH1-C4the halogen atom; each of R2and R3independently denotes a hydrogen atom or alkyl WITH1-C4; l denotes alkane(C1-C4)diyl, each of R4and R5independently denotes hydrogen atom or halogen atom, or WITH1-C4-alkyl, and t denotes the group of one of formulae

where R6denotes a hydrogen atom, alkyl (C1-C6), oxyalkyl(C1-C6), cycloalkyl(C3-C6), phenyl or amino; each of R7independently denotes a hydrogen atom, alkyl (C1-C6), cycloalkyl(C3-C6), phenyl or trifluoromethyl, and their salts or a stereochemical isomeric salt. They are obtained by processing the basic form of the compounds of formula I corresponding acids, in particular mineral, for example kaleidotrope acid, such as hydrochloric, Hydrobromic and the like acids, sulfuric acid, nitric acid, phosphoric acid and the like, or organic acids, for example acetic, exucuse, propane, 2-oxopropanoic, ethicality, perpendicularly, butanedioate, (Z)-2-botanically, (E)-2-botanically, 2-oxobutanoate, 2,3-dioxabicyclo, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, econsultancy, benzosulfimide, 4-methylbenzenesulfonate, cyclohexanesulfamic, 2-oksibenzoynoy, 4-amino-2-oksibenzoynoy and the like acids.

The compounds of formula (I) can contain in the molecule asymmetric carbon atoms. The absolute configuration of these centers may be indicated stereochemical descriptors R and S. the relative configuration of the two asymmetric centers may be specified CIS - and TRANS-stereochemical descriptors. In all cases, the chemical designation of compounds comprises a mixture of all possible stereochemical isomeric forms, and the compounds moderatable a subject matter.

The compounds of formula [I] in their molecules may contain ketoenamine tautomeric system and, therefore, such compounds can be present in their ketoform, as well as their enol forms.

Known derivatives of pyridinylamino possessing antiviral activity (EPO N A-0156433 and EPO N A-0320032).

Closest to the compounds of the invention are derivatives of pyridazinones, which also possess antiviral activity, are described in U.S. patent N 4992433.

In particular, the compound of the formula

matters d1= 625 ng/ml and d2= 115 ng/ml in the test for determining the minimum inhibitory concentration picornavirus.

The aim of the invention is new derivatives of pyridazinones with improved antiviral properties.

This goal is achieved derivatives pyridazinone General formula

in which one or two carbon atoms of methylene groups in the residue-NX - may be substituted by alkyl WITH1-C4, alkoxygroup1-C4or two carbon atom of the methylene groups of the above-mentioned residue can be connected by bridge with alkane(C2-C4)delovym radical; X appears the SUB>1denotes a hydrogen atom, alkyl(C1-C4), a halogen atom; each of R2and R3independently denotes a hydrogen atom or alkyl(C1-C4); l denotes alkane(C1-C4)diyl; each of R4and R5independently denotes hydrogen atom or halogen atom, (C1-C4)alkyl, and t denotes the group of one of formulae

where R6denotes a hydrogen atom, alkyl(C1-C6), oxyalkyl(C1-C6), cycloalkyl3-C6, phenyl or amino, each of R7independently denotes a hydrogen atom, alkyl WITH1-C6cycloalkyl3-C6, phenyl or trifluoromethyl, and their salts or a stereochemical isomeric form.

The compounds of formula I is produced by reaction of the amine of formula II with pyridazine formula III.

(I)W denotes the corresponding tsepliaeva group, for example halogen atom, in particular fluorine atom, chlorine, bromine or iodine, and in some instances W may also be sulfonyloxy, for example 4-methyl-benzosulfimide, benzosulfimide-, 2-naphthalenesulfonate, methanesulfonate, triftormetilfullerenov and another from londonites solvent, for example, water, an aromatic solvent, such as benzene, methylbenzene, xylene, chlorobenzene, methoxybenzene and the like; alkanol (C1-C6), for example in methanol, ethanol, 1-butanol and the like; a ketone, e.g. 2-propanone, 4-methyl-2-pentanone and the like; complex ester, e.g. ethyl acetate, γ-butyrolactone and the like; in a simple ether, e.g. 1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxane and the like; dipolar aprotic solvent, such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, pyridine, 1,3-dimethyl-3,4,5,6-tetrahydro-2/1H/-pyrimidinone, 1,3-dimethyl-2-imidazolidinone, 1,1,3,3-tetramethylrhodamine, 1-methyl-2-pyrrolidinone, nitrobenzene, acetonitrile and the like, or in mixtures of such solvents. To bind the acid which is formed during the course of this reaction, if desired, you can add the appropriate base, for example, carbonate, bicarbonate, hydroxide, oxide, carboxylate, alkoxide, hydride or amide of alkaline or alkaline-earth metal, for example sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, calcium oxide, sodium acetate, sodium methoxide, hydride of nataliceline, N-ethyl-N-/1-methyl-ethyl/-2-propanamine, 4-ethylmorpholine, 1,4-diazabicyclo/2,2,2/octane, pyridine and the like. In some cases, it may be acceptable adding iodide salt, preferably the alkali metal iodide, or a crown ether, such as 1,4,7,10,13,16-hexaoxacyclooctadecane, and the like. The reaction rate can be increased by stirring and a slight increase of temperature, and more specifically, the reaction can be carried out at the boiling temperature of the reaction mixture under reflux. In addition, it may be advantageous to carry out the above reaction of N-alkylation in an inert atmosphere, in particular not containing oxygen argon or gaseous nitrogen.

Another option specified reaction of N-alkylation can be carried out in known in the art conditions using a catalyst of the reaction phase transition. In addition, the target products can also be obtained by alkylation of the corresponding phenol and pyridinoline; or phenol and an alcohol in the presence of a mixture of diethylazodicarboxylate with triphenylphosphine, or any other known from the prior art methods.

The present invention relates to new compounds of General formula II

HNXAlkOHet, cat-alkyl, alkoxygroup1-4or two carbon atom of the methylene groups of the above-mentioned residue can be connected by bridge with alkane(C2-C4)dialnum radical; X represents CH or a nitrogen atom; each of m and n, independently of one another, denotes 1, 2, 3, and the sum m+n is 3, 4 or 5.

Al is an alkane (C1-C4)diyl, R4and R5independently denotes a hydrogen atom or a halogen atom, a C1-C4-alkyl;

Het denotes a group of formula

< / BR>
where R6denotes a hydrogen atom, alkyl WITH1-C6oxyalkyl1-C6cycloalkyl(C3-C6), phenyl or amino; each of R7independently represents hydrogen, alkyl (C1-C6), cycloalkyl(C3-C6)phenyl or trifluoromethyl, or their acid additive salt or a stereochemical isomers, which are intermediate compounds to obtain the desired products of formula I.

These intermediate products are obtained by the O-alkylation of phenol V

the reagent of formula XXV; reaction of phenol (V) with an alcohol of the formula (XXXI) or, alternatively, O-alkylation of the alcohol of formula (XXVI) with the appropriate reagent forms the ASS="ptx2">

< / BR>
Intermediates of formula (II) can be obtained by any other known methods.

Pure stereochemical isomeric forms of the compounds of the present invention can be obtained according to known in the art procedures. Diastereoisomer can be separated by physical separation, in particular by selective crystallization and chromatographic processing, for example, counter current distribution, liquid chromatography processing and the like by, and the enantiomers can be separated from each other so known in the art separation methods, such as selective crystallization of their diastereomeric salts with chiral acids.

Pure stereochemical isomers can also be derived from the corresponding pure stereochemical isomeric forms of the appropriate starting materials, provided that the reaction proceeds by stereospecific principle. The preferred option when you wish to obtain a specific stereoisomer of the specified connection should be synthesized according stereoselective methods of obtaining. The implementation of such methods is advantageous to use enantiomerically pure starting materials.

Connection f is given low toxicity to cells in combination with a satisfactory antiviral effect. Antiviral activity of compounds of the formula I is demonstrated in the test for "minimum inhibitory the picornaviruses concentration (MIC), the results of which illustrate useful antiviral activity of the compounds of the present invention.

Thus, the compounds of the invention are useful agents in the inhibition of viral replication. The compounds of formula (I), pharmaceutically acceptable salts and their stereochemical isomeric form exhibit activity against picornaviruses a wide range, including enteroviruses, such as poliovirus, Coxsackievirus, echoviruses, enteroviruses, in particular enterovirus 70, and especially against rhinoviruses numerous strains, for example against serotypes of human viruses HRV-2, -3, -4, -5, -6, -9, -14, -15, -29, -39, -51, -59, -63, -70, -85, -86 and things like that. A series of compounds also shows activity against serotype RV-45, especially tenacious strain of rhinovirus.

The new compounds of formula (I) can be introduced into the composition of various farmaceutyczny compositions for systemic or local application. To prepare the pharmaceutical compositions of the present invention, an effective amount of a particular compound (0.05 to 15 wt.), possibly acceptable carrier, which covers materials in a broad range of forms, depending on the desired form of the preparation for introduction into the body. Such pharmaceutical compositions are desirable in the form of a unit dose, acceptable, in particular, for introduction into the body orally, rectally, subcutaneously, intranasally, parenterally or for instillation in the eye. For example, in the preparation of compositions in dosage form for oral administration may be used any of the usual pharmaceutical media, such as water, glycols, oils and the like, in the case of oral liquid preparations, in particular suspensions, syrups, elixirs and solutions, or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrator agents and the like, in the case of powders, pills, capsules and tablets. Because of the ease of introduction into the organism of tablets and capsules represent the most advantageous oral compositions in unit dosage form, in which, obviously, use solid pharmaceutical carriers. For the preparation of parenteral compositions, the carrier typically includes sterilized water at least as the main component, although may sadvary for injection, in which the carrier is a saline solution, glucose solution or a mixture of saline solution and glucose. You can cook suspension for injection, which may include appropriate liquid carriers, suspendresume agents and the like. Can be prepared solid preparations which are intended for the preparation of them shortly before the application of liquids. In the compositions acceptable for subcutaneous injection into the body, the carrier may include an agent that promotes rapid penetration, and/or acceptable wetting agent, possibly in combination with appropriate additives of any nature in minor quantities, such additives should not have a significant harmful impact on the skin. These supplements can facilitate the introduction into the body under the skin and/or may have a supporting effect in the preparation of the desired compositions. Such compositions can be prepared in the form of creams, lotions, aerosol products and/or emulsions and maintained in a transdermal vehicle type matrix or reservoir, which is usually used in the technique for this purpose.

Part of the preparation acceptable for local injection into the body, accti in the form of a thickened composition, for example, ointments, creams, jellies, lapping and the like of the drug, which can be applied with a swab. Pharmaceutical composition that is acceptable for local injection into the body, can also be used in the form of drops, lotions or preparation for spraying. To an acceptable aerosol preparations include solutions and solids composition in powder form, which can be combined with a pharmaceutically acceptable carrier, in particular an inert compressed gas.

Thus the present invention relates to pharmaceutical compositions that include the compounds of formula (I), their pharmaceutically acceptable salts or derivatives in stereochemical isomeric form and the cyclodextrin or its derivative. When processing the designated infection such based on the cyclodextrin compositions for continuous and variable selection in high enough concentrations of antiviral compounds of formula (I), continued for a long period of time.

Such compositions are particularly useful for treatment of local viral infections, in particular in cases of mucous membranes or eyes.

Cyclodextrin, which PR is nesennye and replaced by the known cyclodextrins, or their pharmaceutically acceptable derivatives.

In cyclodextrine derivatives for use in the compositions according to the invention a preferred value Sz (degree of substitution) is in the range from 0.125 to 3, in particular from 0.3 to 2, more particularly from 0.3 to 1, and the value of the MOH (the average degree of molar substitution) is in the range from 0.125 to 10, in particular from 0.3 to 3, more particularly from 0.3 to 1.5.

To prepare these specific pharmaceutical compositions based on cyclodextrin selected antiviral compound (or compounds) of formula (I), its pharmaceutically acceptable salt or a stereochemical isomeric variant enter into cyclodextrins molecules, and such a method in the technique known for other active components. In the final compositions, the molar ratio between cyclodextrin and antiviral compound is from about 1:1 to 5:1, in particular from about 1: 1 to 2:1. Thus, typically, this song should be prepared by dissolving the cyclodextrin in water and adding to this solution antiviral compounds, preferably with vigorous stirring and at a temperature in the interval is CLASS="ptx2">

In the final compositions, the amount of cyclodextrin should be from about 2.5 to 40 wt. in particular from about 2.5 to 25 wt. more specifically from 5 to 25 wt. or from 5 to 20 wt. for example, 10 wt. and the number activitiesthese component should be from about 0.001 to 0.1 wt. in particular about 0.005 to 0.075 wt. more specifically from 0.01 to 0.05 wt. for example, approximately of 0.025 wt. while the rest should fall to the share of water, preservative and all bases for the preparation of medicines.

Thus, in particular, the pharmaceutical compositions may consist only of water, cyclodextrin and anti-virus agents without the necessity of using such co-solvents as ethanol and surface-active agents.

Composition based on cyclodextrin according to the invention can be applied in aerosol form, for example, using such propellant as nitrogen, carbon dioxide, freon, or without propellant, in particular, using a mechanical sprayer in the form of drops or semi-solid mass, in particular thickened compositions plants that are by the swab. In special cases of application can be used semi-solid compositions, in particular the other songs on cyclodextrines basis, you can add any of the usual pharmaceutical environment in particular glycols, oils, alcohols and the like, but in concentrations that are below concentrations causing irritation. To stabilize the compositions of the pH value can increase or decrease, or stabilize the addition of the corresponding acids, bases or buffer systems, such as citrate, phosphate buffers. Sodium chloride, mannitol, glucose and the like give the compositions of isotonicity. Additionally it is recommended to add the preservative composition, in particular a mercury salt or a complex salt, such as phenyl acetate, nitrate or borate mercury, phenethyl alcohol, ethanol, propylene glycol and the like. Acceptable thickeners for the preparation of the above gelled compositions comprise polyvinyl alcohols, oksipropilmetiltselljulozy, acetylcellulose, methylcellulose, polyvinylpyrrolidone, polymers of acrylic acid and the like.

Depending on the type of virus, which is necessary to struggle, these compositions on cyclodextrines basis can cause the vagina, nose, mouth, eyes, lungs or cheeks thus, to control viruses that do not fall into the circulatory system of the patient, such as viruses that live on when those infected places, where a natural protective mechanism prevents the receipt of antiviral agents for extended periods of time due to efficient removal of activitiesthese connection with the infected area. Such removal can be achieved by cleaning due to the motion of age or discharge, or by absorption.

The pharmaceutical composition may include the same or a different anti-virus agent on another carrier, which allows the composition to show the effect of another profile, for example an extensive period of time during which the composition exhibits an action, or additional maintenance of a low level at a specific point in the selection mode cyclodextrin.

It is convenient to prepare pharmaceutical compositions in disposable dosage form for ease of introduction into the body and uniformity of dosage. The term "disposable dosage form" is used to refer to in the text of the description and the claims physically discrete portions that are acceptable for use as a single dose, and in each portion contains a specified number activitiesthese component, designed to achieve the desired therapeutic effect himself tablets (which are provided with notches or coating tablets), capsules, pills, powders, wafers, injectable solutions or suspensions, drops, full teaspoons, tablespoons, and the like, as well as spacearound disposable packaging.

An effective amount of the active ingredient (compound [1]) is from 0.001 to 50 mg/kg body weight, preferably from 0.01 to 10 mg/kg of live weight.

The essence of the invention is illustrated in the following examples, which are not limited in any of the aspects of its framework.

Experimental part

A. Obtaining intermediates

P R I m e R 1. a) a Mixture of 224 hours piperazine, 97 h ethyl-4-(3-chloropropoxy)-benzoate and 1044 hours of methylbenzol stirred over night at the boiling point under reflux. After cooling, the reaction mixture was washed with water (3 times), dried, filtered and evaporated, getting 115,2 hours (yield 98.5 per cent ) of ethyl-4-[3-(1-piperazinil)-propoxy] -benzo - ATA (intermediate 1). In a similar way to enjoy ethyl-4-[2-(1-piperazinil)-ethoxy]-benzoate (intermediate 2).

b) In a mixture of 1.6 hours dispersion of sodium hydride in mineral oil (50%) from 71.2 hours of tetrahydrofuran are added dropwise a solution of 2.64 h N-oxopropanenitrile 22.3 h tetrahydrofurane 40,0 PM tetrahydrofuran (THF). Stirring is continued over night at the boiling point under reflux. After cooling, the reaction mixture was poured into a mixture of ice water. The product is extracted with dichloromethane and the extract was dried, filtered and evaporated, getting to 5.0 hours (exit 79,0% ) 1-{ 3-[4-(3-ethyl-1,2,4-oxadiazol-5-yl)-phenoxy]-propyl}-piperazine (intermediate 3).

Similarly also receive: 2,6-dichloro-4-(3-ethyl-1,2,4-oxadiazol-5-yl)-phenol with a melting point 173,3about(Intermediate 4) and 2-chloro-4-(3-ethyl-1,2,4-oxadiazol-5-yl)-phenol with a melting point 90,7about(Intermediate 5).

P R I m m e R 2. In a mixture of 29.9 hours-ethyl-4-oxybenzoates with 316 including ethanol individual portions add 35,6 including ethoxide sodium. After stirring for 1/2 h at room temperature is added dropwise a solution of 31.7 hours N-oxopropanenitrile 79 including ethanol. Stirring is continued for 1/2 h at room temperature and overnight at the boiling point under reflux. The reaction mixture is evaporated and the residue is dissolved in water. After neutralization with acetic acid, the residue is filtered off and dried. The product is distilled processing through column chromatography [liquid rootnodename 99:1] Eluent with the desired fraction is evaporated and the residue is stirred in petroleum ether. The precipitate then filtered and dried, obtaining 7,56 hours (exit 22,1%) of 4-(3-ethyl-1,2,4-oxadiazol-5-yl)-phenol with a melting point 137,7about(Intermediate 6).

P R I m e R 3. A mixture of 4.0 h N-oxopropanenitrile, 2.9 hours, sodium methoxide, 94,8 including ethanol and 25.3 including molecular sieves was stirred for 15 min at room temperature. Then the mixture was added to 7.5 hours-ethyl-4-[2-(4-piperidinyl)-ethoxy] benzoylmethylecgonine and stirring is continued for 12 h at boiling temperature under reflux. The cooled reaction mixture is filtered and the filtrate is evaporated. The remainder is shared between the salt water and dichloromethane. The organic layer is separated, dried, filtered and evaporated, getting 6.5 h (output 89,9%) 4-{[2-4-(3-ethyl-1,2,4-oxadiazol-5-yl)-phenoxy]-ethyl}-PI-peridine (intermediate 7).

P R I m e R 4. A mixture of 19 hours of hydrazide 4-oksibenzoynoy acid with 89,8 including 1,1,1-triethoxypropane refluxed over night. After cooling, the precipitate is filtered off, washed with petroleum ether and dried, receiving 23 PM (output 96,7%) of 4-(5-ethyl-1,3,4-oxadiazol-2-yl)-phenol (product 8).

Similarly also receive 4-(5-ethyl-1,3,4-thiadiazole-2-yl)-phenol (intermediate 9).

P is mperature boiling under reflux. Then the reaction mixture was poured into water and the product extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue is purified by chromatographic processing column [silica gel; a mixture of chloroform with methanol in the ratio] Eluent with the desired fraction is evaporated, receiving 1.5 h (output 23, 1%) 4-/1,2,4-oxadiazol-3-yl)-phenol (intermediate 10).

P R I m e R 6. A mixture of 14.1 hours 3,5-dichloro-N,4-dioxoanthracene with 6.5 hours of propanolol and 98 hours of pyridine is stirred for 4 hours at the boiling temperature under reflux. Then the reaction mixture was concentrated and the residue is divided between water and dichloromethane. The organic layer is separated and successively washed twice with water and dilute sodium chloride solution. The combined aqueous layers washed with dichloromethane and then filtered through diatomaceous earth. After acidification with acetic acid, the precipitate is filtered and dissolved in dichloromethane. This solution is dried, filtered and evaporated. The residue is crystallized from ethanol-water. The product is filtered and dried in a vacuum at a temperature of 50aboutWith the receiving of 4.25 hours (exit 25,6%) of 2,6-dichloro-4-(5-ethyl-1,2,4-oxadiazol-3-yl)-phenol with temperature is TA, 2,7 hours of ammonium acetate and 52,5 h of acetic acid is stirred for 6 h at boiling temperature under reflux. Add additional 2,7 hours of ammonium acetate and stirring is continued for 5 hours at the boiling temperature under reflux and overnight at room temperature. The reaction mixture was poured into water and the precipitate is filtered off, receiving the first product fraction. The aqueous layer was subjected to extraction treatment with methylbenzol. The extract was dried, filtered and evaporated, getting to 3.8 hours (exit 66,9%) of 4-(2-ethyl-4-oxazolyl)-phenol (intermediate 12).

Similarly receive a 4-(2-propyl-4-oxazolyl)-phenol (intermediate 13).

P R I m e R 8. A mixture of 4.6 hours 4-oxybenzoyl from 4.5 hours 1-bromo-2-butanone and 79 hours of ethanol is stirred for 5 hours at the boiling temperature under reflux. After cooling, the precipitate is filtered off and dried in a vacuum at a temperature of 50aboutWith the receiving of 5.6 hours (yield of 65.2) 4-(4-ethyl-2-thiazolyl)-fragilaria (intermediate 14).

Similarly receive a 4-(5-ethyl-2-thiazolyl)-phenol (intermediate 15) and 4-(4,5-dimethyl-2-thiazolyl)-finalgear - RAID with a melting point 257,5about(Intermediate 16).

P R I m e R ature boiling under reflux, the Reaction mixture was then concentrated to 1/4 of its original volume and to the residue add 2,2'-oxybisethane. The precipitate is filtered and dissolved in water. After alkalizing liquid ammonia product is extracted with dichloromethane. The extract was dried, filtered and evaporated, getting to 3.3 hours (exit 40,2% ) of 4-(2-ethyl-4-thiazole)-phenol (intermediate 17).

P R I m e R 10. a) stir the mixture 175,4 including ethyl-4-piperidineacetate with 116,6 including sodium carbonate and 2250 hours of trichlormethane added dropwise 119,4 including ethylchloride. After stirring for 4 h at room temperature the reaction mixture is diluted with 400 hours of water. The organic layer is separated, dried, filtered and evaporated, getting 277 hours (100% output) ethyl-1-(etoxycarbonyl)-4-piperidineacetate (intermediate 18).

b) a Mixture of 168 g potassium hydroxide with 1000 hours of water is stirred at a temperature of 10aboutC. After warming to room temperature, it was added 249,4 including intermediate 18 and 400 hours of ethanol. Stirring is continued over night. The solvent is evaporated and the cooled residue was diluted with water, and then acidified with hydrochloric acid, keeping the temperature below 20aboutC. the Product is extracted twice by 520 hours of dichloromethane and the combined extracts washed with water, dried, filtered and evaporated. The remainder suspendiruetsa and dried, getting 170,7 h 1-(etoxycarbonyl)-4-piperidineacetic acid (intermediate 19).

C) To 960 hours of chloride tiomila add 155,15 including intermediate 19 at a temperature of 10aboutC. After stirring overnight at room temperature, the reaction mixture is evaporated. The residue is distilled, getting 157 hours (yield of 93.3% ) ethyl-4-(2-chloro-2-oxoethyl)-1-piperidinyl - barcelata with a boiling point of 140-145aboutWith at a residual pressure of 133 PA (intermediate 20).

g) a Mixture of 157 hours of intermediate 20 with 75 hours 2,6-dimethylpyridine and 1890 hours of tetrahydrofuran hydronaut at normal pressure and room temperature using 15 PM 10% palladium catalyst on charcoal. After absorption of the calculated amount of hydrogen the catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in dichloromethane. This solution was washed with two portions of dilute hydrochloric acid and water, dried, filtered and evaporated. The residue is distilled, receiving the 122.7 hours (yield of 91.6%) ethyl-4-(2-oxoethyl)-1-piperidinecarboxylate with a boiling point of 125 to 130aboutWith at a residual pressure of 133 PA (intermediate 21).

d) a Mixture of 13.9 hours of intermediate 21 from 39.5 hours of methanol and 5 g potassium acetate is subjected to hydrogenation under normal D. the VA of hydrogen the catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in water and the product extracted with methylbenzol. The extract is dried, filtered and evaporated, getting to 8.3 hours (yield of 58.9%) ethyl-4-(2-oxyethyl)-1-piperidinecarboxylate (intermediate 22).

e) a Mixture of 8.3 hours of intermediate 22 176 hours 35% hydrochloric acid is stirred for 1 h at boiling temperature under reflux. The reaction mixture is evaporated, getting to 6.1 hours (exit 89,8%) 4-piperidinecarboxylate (intermediate 23).

P R I m e R 11. a) a Mixture of 6.1 hours 3,6-dichloropyridazine from 6.8 hours of intermediate 23, 21 including sodium carbonate and 188 including N,N-dimethylformamide is stirred overnight at a temperature of 60aboutC. the Reaction mixture is evaporated and the residue is divided between water layers and trichlormethane. The organic layer is dried, filtered and evaporated, and the residue is purified by treatment in a chromatographic column [silica gel:a mixture of chloroform with methanol in the ratio of 97:3] Eluent with the desired fraction is evaporated, getting to 5.2 hours (exit 52,5%) 1-(6-chloro-3-pyridazinyl)-4-piperidinemethanol (intermediate 24).

Similarly also receive 1-(6-chloro-3-pyridazinyl)-4-piperidino - panel (intermediate 25); 1-(6-chloro-3-pyridazinyl)-4-piperidinemethanol (intermediate 26); ethyl-4-{ 2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]originator (intermediate 28); TRANS-1-(6-chloro-3-pyridazinyl)-3-methyl-4-piperidine - ethanol (intermediate 29); 1-(6-chloro-3-pyridazinyl)-hexahydro-1H-azepin-4-ethanol (intermediate 30). In accordance with a slightly modified method of obtaining were also obtained 1-(6-methyl-3-pyridazinyl)-4-piperidinemethanol with a melting point of 84.8about(Intermediate 31) (the mixture is stirred for 5 hours at a temperature of 150aboutC); 1-(6-methyl-3-pyridazinyl)-4-piperidinemethanol with a boiling point of 99-100aboutWith under a residual pressure of 8 PA (intermediate 32) (the mixture is stirred for 5 hours at a temperature of 150aboutC); 1-(6-methyl-3-pyridazinyl)-4-piperidinemethanol with a melting point 120,1about(Intermediate 33) (the mixture is stirred for 5 hours at a temperature of 150aboutWith N,N-dimethylacetamide); ethyl-4-{ 2-[4-(6-chloro-3-pyridazinyl)-1-piperazinil]-benzoate melting temperature 132,9about(Intermediate 34) (the mixture is stirred for 7 hours at a temperature of 140aboutC).

b) 5.1 ch. chloride tiomila added dropwise a solution of 5.2 hours of intermediate 24 133 including dichloromethane. After stirring over night at room temperature the reaction mixture is evaporated. The residue is divided between water layers and trichlormethane. The organic layer is dried, filtered and Similarly also receive 3-chloro-6-[4-(3-chlorpropyl)-1-piperidinyl] -pyrazin (intermediate 36); 3-[4-(2-chloroethyl)-1-piperidinyl]-6-ethylpyridine (intermediate 37); 4-(2-chloroethyl)-1-(6-chloro-3-pyridazinyl)-hexahydro-1H-azepin (intermediate 38); 3-chloro-6-[2-chloroethyl)-3-methyl-1-piperidinyl]-pyridazine (intermediate 39).

P R I m e R 12. a) a Mixture of 7.5 G. of ethyl-3-(2-oxyethyl)-8-azabicyclo-(3.2.1)octane-8-CT - barcelata (obtained by the described in the application for the European patent N 0320032) from 127 hours hydrochloric acid is refluxed for 1/2 h and then evaporated. The residue is dissolved in water and the whole mass is alkalinized by addition of sodium hydroxide. The product is extracted with trichloromethane, and the extract is washed, dried, filtered and evaporated, getting to 5.1 hours (exit 99,6%) 8-azabicyclo(3.2.1)Octan-3-ethanol (intermediate 40).

b) a Mixture of 5 hours 3,6-dichloropyridazine with 5.1 CH intermediate 40, 3,5 including sodium carbonate and 188 including N,N-dimethylformamide is stirred from Friday evening until Monday morning at a temperature of 60aboutC. After cooling, the reaction mixture was poured into water. The product is subjected to extraction treatment with methylbenzol, and the extract is washed with water, dried, filtered and evaporated. The residue is purified by chromatographic processing in column [silica gel; chloroform mixed with methanol in a ratio of 97:3] Buena (intermediate 41).

Similarly also receive 8-(6-methyl-3-pyridazinyl)-8-azabicyclo (3.2.1)Octan-3-ethanol (intermediate 42).

in a chilled (ice bath) mixture of 4.8 hours of chloride tiomila with 66 hours of dichloromethane are added dropwise a solution of 5.1 hours of intermediate 41 200 hours of dichloromethane. After stirring over night at room temperature the reaction mixture is washed with dilute ammonia, dried, filtered and evaporated, having a 4.3 hours (exit 79,1%) of 3-(2-chloroethyl)-8-(6-chloro-3-pyridazinyl)-8-sadicic - lo(3.2.1)octane (intermediate 43).

Similarly also receive 3-(2-chloroethyl)-8-(6-methyl-3-pyridazinyl)- 8-azabicyclo(3.2.1)octane (intermediate 43).

Similarly also receive 3-(2-chloroethyl)-8-(6-methyl-3-pyridazinyl)-8-azabicyclo(3.2.1)octane (intermediate 44).

P R I m e p 13. a) a Mixture of 25.9 hours CIS-3-methoxy-1-(phenylmethyl)-4-piperidinemethanol (obtained by the described in the application for the European patent N 0320032) with 198 hours of methanol hydronaut at normal pressure and a temperature of 50aboutWith together with 3 hours 10% palladium on charcoal as catalyst. After absorption of the calculated amount of hydrogen the catalyst is filtered off and the filtrate is evaporated, getting to 16.5 ins from 8.5 hours intermediate 45 and 6.4 g sodium carbonate is mixed with an overnight at a temperature of 140aboutC. the Reaction mixture was separated between water and dichloromethane. The organic layer is separated, dried, filtered and evaporated. The residue is purified by treatment through column chromatography [silica gel; a mixture of chloroform with methanol in the ratio of 97: 3] Eluent with the target fraction is evaporated, getting to 8.5 hours (exit 63,8% ) of CIS-3-methoxy-1-(6-methyl-3-pyridazinyl)-4-piperidine - ethanol (intermediate 46).

Similarly also receive 1-(6-methyl-3-pyridazinyl)-3-pyrrolidine-Nol (intermediate 47) and 1-(6-methyl-3-pyridazinyl)-3-piperidinol (intermediate 48).

in mixed and cooled (ice bath) mixture of 8 o'clock chloride tiomila with 66 hours of dichloromethane are added dropwise a solution of 8.5 hours of intermediate 46 133 including dichloromethane. The mass is stirred over night. The reaction mixture is evaporated and the residue separated between layers of diluted ammonia and dichloromethane. The organic layer is separated, dried, filtered and evaporated, getting to 8.1 hours (yield of 88.3%) of 3-[4-2-chloroethyl)-3-methoxy-1-piperidinyl]-6-methyl - pyridazine (intermediate 49).

P R I m e R 14. a) stir In a mixture of 67 hours 4-piperidinemethanol with reflect for 2 h at boiling temperature under reflux. After cooling, the reaction mixture is washed with water, dried, filtered and evaporated, semi-tea 75 hours (70% yield) of ethyl-4-(oxymethyl)-1-piperidinecarboxylate (intermediate 50).

b) In the mixed and cooled (ice bath) solution of 46 hours of intermediate 50 450 hours of trichlormethane added dropwise 60 hours of chloride tiomila. After stirring overnight at a temperature of 20aboutWith the reaction mixture is evaporated. The residue is evaporated together with methylbenzol, receiving 48 hours (yield of 93.3%) ethyl-4-(chloro-methyl)-1-piperidinyloxy - LVL (intermediate 51).

C) a Mixture of 10.3 hours of intermediate 51 to 190.5 with hours of hydrochloric acid is stirred for 45 minutes at boiling temperature under reflux. After cooling, the reaction mixture is evaporated, getting to 8.6 hours (100% yield) of a mixture of 3-(2-chloroethyl)-pyrrolidinecarboxamido with 4-(chloromethyl)-piperidinemethanol in the ratio 2:1 (intermediate 52).

g) a Mixture of 8.9 hours 3,6-dichloropyridazine from 8.6 hours of intermediate 52, 21,2 including sodium carbonate and 235 including N,N-dimethylformamide is stirred overnight at a temperature of 65aboutC. the Reaction mixture is then poured into a mixture of ice water and the product is subjected to extraction treatment with dichloromethane. The extract was dried, filtroil-1-piperidinyl)-pyridine in the ratio 2:1 (intermediate 53).

P R I m e R 15. In stirred and cooled (ice bath) mixture of 7.1 hours of chloride tiomila with 66 hours of dichloromethane are added dropwise a solution of 6.2 hours of intermediate 33 200 h, dichloromethane. Stirring is continued overnight at room temperature. Then the reaction mixture is evaporated and the residue separated between layers of liquid ammonia with dichloromethane. The organic layer is separated, dried, filtered and evaporated, getting 5,2 h (yield of 76.8% ) of a mixture of 3-[3-(2-chloroethyl)-1-pyrrolidinyl]-6-methylpyridazine with 3-(4-chloromethyl-1-piperidinyl)-6-methylpyridazin - in the ratio of 1: 1 (intermediate 54).

P R I m e R 16. In mixed and cooled (at a temperature of 0about(C) a mixture of 25.2 hours of ethanthiol with 39,9 including dichloromethane add 12 o'clock aluminum trichloride. The solution is allowed to warm to room temperature, and then add it to 6.1 hours 4-ethyl-5-(4-methoxyphenyl)-isoxazol. Stirring at room temperature continued throughout the night. Then the reaction mixture was poured into a mixture of ice water and hydrochloric acid. The precipitate is filtered and the organic layer of the filtrate is separated, dried, filtered and evaporated receiving the first product fraction. The precipitate is dissolved in a dilute solution of potassium hydroxide. Fri. The total yield is 5.6 hours (exit to 98.6%) of 4-(4-ethyl-5-isoxazolyl)-phenol (intermediate 55).

P R I m e R 17. In a chilled (ice bath) mixture of 9.8 hours of monohydrochloride hydroxylamine 30 PM water with 119 hours of ethanol are added dropwise to 25.6 hours of sodium methoxide in 30% methanol and after stirring for 15 min a solution of 12 o'clock 3-oxobutanamide 79 including ethanol. The whole mass is stirred for 1 h and refluxed over night. After cooling, the reaction mixture is filtered and the filtrate is evaporated. The residue is dissolved with trichloromethane and the resulting solution was dried, filtered and evaporated, getting 11 hours (exit 66,5%) N,3-dioxopyrimidine (intermediate 56).

C. obtain the final compounds

P R I m e R 18. A mixture of 2.4 hours 3-chloro-6-methylpyridazine with 5.7 hours of intermediate 7 and 2.1 g sodium carbonate is stirred for 3 hours at a temperature of 140aboutC. After cooling, the reaction mixture was separated between layers dichloromethane and water. The organic layer is separated, dried, filtered and evaporated. The residue is purified by chromatographic processing column [silica gel; chloroform mixed with methanol in a ratio of 98:2] Eluent with the target fraction is evaporated and the residue crystallized from two portions of the Teal-1,2,4-oxadiazol-5-yl)-Fe - Naxi/-ethyl]-1-piperidinyl} 6-methylpyridazine with a melting point 122,0about(Connection 5).

P R I m e R 19. A mixture of 3.12 PM 3-[4-(2-chloroethyl)-1-piperidinyl]-6-methylpyridazine with 2,47 h 4-(5-ethyl-1,2,4-oxadiazol-3-yl)phenol, 1,38 including sodium carbonate and 94 including N,N-dimethylacetamide is stirred overnight at a temperature of 110aboutC. After cooling, the reaction mixture was poured into water. The precipitate is filtered off, washed with water and dissolved in trichloromethane. This solution is dried, filtered and evaporated. The residue is purified chromatography [silica gel; a mixture of chloroform with methanol in the ratio of 97:3] Eluent with the target fraction is evaporated and the residue is crystallized from 2-propanone. The product is filtered and dried, obtaining a 1.7 hours (exit 33,2%) 3-{4-[2-/4-(5-ethyl-1,2,4-oxadiazol-3-yl)-phenoxy/-ethyl]-1-piperidinyl}-6 - methylpyridazine with a melting point 125,3about(Connection 6).

P R I m e R 20. A mixture of 5.6 hours of intermediate 14 from 4.8 hours intermediate 37,5 including sodium carbonate and 141 including N,N-dimethylformamide is stirred for 5 hours at a temperature of 110aboutC. the Reaction mixture was poured into water. The precipitate is filtered and dissolved in dichloromethane. This solution is dried, filtered and evaporated. The residue is purified chromatography [silica gel; dichloromethane is mixed with methanol in a ratio of 8:2] Eluent with C and sodium, dried, filtered and evaporated. The residue is crystallized from 2-propanol. The product is filtered and dried in a vacuum at a temperature of 50aboutWith receiving 1.0 hours 3-{4-{2-/4-ethyl-2-thiazolyl)-phenoxy/-ethyl]-1-piperidinyl} -6-Meile - ridazin with a melting point 112,6about(Compound 22).

P R I m e R 21. In (chilled to a temperature of 10about(C) a mixture of 4,4 including intermediate 32 3.8 hours of intermediate 12, and 7.5 hours of triphenylphosphine and 66,8 hours of tetrahydrofuran are added dropwise a solution of 5 hours of diethylazodicarboxylate in a small amount of tetrahydrofuran. After stirring over night at room temperature the reaction mixture is evaporated. The residue is purified by chromatographic processing column [silica gel, mixture of dichloromethane with methanol in the ratio of 99:1] Eluent with the target fraction is evaporated and the residue is crystallized from 2-propanol. The product is filtered and dried in a vacuum at a temperature of 50aboutWith getting to 1.4 hours (exit 17,8%) 3-{4-[2-/4-(2-ethyl-4-oxazolyl)-phenoxy/-ethyl] -1-piperidinyl} -6-metylene - DESINA with a melting point 123,6about(Compound 21).

P R I m e R 22. In a suspension of 0.85 h of a 50% dispersion of sodium hydride and 44.5 hours of tetrahydrofuran are added dropwise 1,95 including N-oxygensensitive. Stirring is then continued throughout the night with boiling under reflux. The reaction mixture is evaporated and the residue is stirred in water for 1/2 o'clock, the Residue is filtered off, washed with water and dissolved in dichloromethane. This solution is dried, filtered and evaporated, and the residue is crystallized from 2,2'-oxybisethane. The product is filtered and dried in a vacuum at a temperature of 50aboutWith getting to 2.7 hours (exit 41,3%) 3-methyl-6-{4-[2-/4-(3-pentyl-1,2,4-oxadiazol-5-yl)-phenoxy/ethyl] -1-PI is the period idols melting temperature 111,1aboutWith (compound 12).

P R I m e R 23. A mixture of 3.1 h N-hydroxy-2-methylpropanamide with 2.0 h ethoxide sodium and 79 hours of ethanol is stirred for 15 minutes Then add to 5.1 hours of intermediate 27 and stirring is continued over night at the boiling point under reflux. The reaction mixture is evaporated and the residue is divided between water and dichloromethane. The organic layer is separated, dried, filtered and evaporated, and the residue is crystallized from 2-propanol. The product is filtered, washed with 2-propanol and 2,2'-oxybisethane and dried at a temperature of 60aboutWith getting to 1.7 hours (yield of 27.8%) 3-methyl-6-{ 4-[2-[4-/3-(1-methylethyl)-1,2,4-oxadiazol-5-yl/-phenoxy] -ethyl] -1-piperid is also 3-{4-[2-/4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-phenoxy/ethyl]-1-piperidinyl-6-methylpyridazine using sodium methoxide instead of ethoxide sodium; melting point 143,8about(Compound 7).

All the compounds and their physico-chemical characteristics are given in table. 1-4.

C. Biological examples

Strong antiviral effect of the compounds of the formula /1/ shown in the following examples.

P R I m e R 24. The test to determine the minimum concentration inhibiting the picornaviruses.

The minimum inhibitory concentration for the compounds of the present invention in the fight against human rhinovirus strains RV/ -2, -9, -14, -15, -29, -39, -41, -42, -45, -51, -59, -63, -70, -72, -85, -86 and -89 determined during the standard experiment with the reduction of the cytopathic effect, subject to the following. In each of the 96 wells plate with 96 holes for tissue culture microtitre add 60 ál medium for content of cells Ohio Hel (primary environment the Needle, which was added 5% serum in the womb of a calf, DAY). In two wells add 60 ál of the compounds of formula I in the form of a solution of the corresponding initial dilution. After that add 120 ál of infectious virus solution in the main environment, Needle and 2% buffer Hipes, 2% a DAY and 30 mmol of magnesium chloride in each of all wells, except those used in co-infected with the virus solution is approximately 100.

Value JCT50represents the dose of virus that triggers a cytopathic effect in 50% of infected cells. 150 μl of the thus prepared mixtures of the virus with the compound is transferred to microtitre plate with cells of Ohio Hela, grown in 100 μl of growth medium. During each test are provided with appropriate control experiments for viruses, cells and connections. Plates are incubated for 3-5 bottoms at a temperature of 33aboutC in an atmosphere with 5% carbon dioxide. Their daily checked with an optical microscope without staining and reading, when in control experiments with viruses achieved 100% cytopathic effect (the centre e), and the virus back titration confirms that the test used the value JCT 50from 32 to 256. The magnitude IR50during each test series, the virus connection accept such concentration in ng/ml, which protects 50% of the cells from the cytopathic effect in comparison with the control experiments (without processing). In the implementation of the standard test procedures of the proposed connection used against rhinoviruses two groups; the first group consists of serotypes Dogo serotype determine the amount of IR50the performance of each connection is determined in terms Med1and Med2that represent the average values IR50all serotypes respectively from the first and second groups.

The results of the tests with the use of the compounds of the present invention are summarized in the following table. 1.

D. Examples of compounds

Typical pharmaceutical compositions in disposable dosage form for systemic or topical application in the treatment of warm-blooded animals in accordance with the invention is illustrated using the following medications.

The term "its active component" (A. K.), used in all these examples, is used to denote the compounds of formula I, its pharmaceutically acceptable acid adduct or its stereochemical isomeric variants.

P R I m e R 25. Drops for oral intake. 500 g A. K. dissolved in 0.5 l of 2-oxopropanoic acid and 1.5 l of the polyethylene glycol at a temperature of 60-80aboutC. After cooling to a temperature of 30-40aboutTo add in a solution of 35 l of polyethylene glycol and the mixture was thoroughly stirred. Then add a solution of 1750 Matricaria 2.5 l of purified water is important, needed to bring the volume to 50 l, prepare a solution for oral administration in the form of droplets, which contains 10 mg/ml A. K. on the drop. The prepared solution is poured into appropriate containers.

P R I m e R 26. Solutions for oral consumption. 9 g of methyl-4-oxybenzoates and 1 g of propyl-4-oxybenzoates dissolved in 4 l of boiling purified water. In 3 l of this solution are dissolved first 10 g of 2,3-dioxabicyclo, and then 20 g A. K. the Latter solution is combined with the rest of the first solution and add a mixture of 12 l 1,2,3-propanetriol and 3 l of 70% aqueous solution of sorbitol. 0.5 l of water dissolve 40 g Matricaria and added to a solution of 2 ml essences of raspberry and 2 ml essences gooseberry. The latter solution is combined with the first and add water in an amount necessary to achieve a volume of 20 l, prepare a solution for oral consumption, containing 5 mg A. K. full teaspoon (5 ml). The prepared solution is poured into appropriate containers.

P R I m e R 27. The capsule. 20 Mr. A. K. 6 g of lauryl sodium, 56 g of starch, 56 g of lactose, 0,8 colloidal silicon dioxide, and 1.2 g of magnesium stearate are intensively mixed together. After that, the mixture is Packed in 1000 acceptable for this purpose, the capsule is coated. Manufacturing core tablet.

A mixture of 100 g A. K. 570 g lactose and 200 g starch is thoroughly mixed, then moistened with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone (product llidon To 90 R") about 200 ml of water. Wet powder mixture is classified, dried and re-classified. Then add 100 g microcrystalline cellulose (product vicel ") and 15 g hydrogenating vegetable oil (product "Sterotex "). The whole mass is thoroughly mixed and molded out of it by pressing tablets, receiving 10,000 tablets each containing 10 mg activitiesthese component.

Floor.

In a solution of 10 g methyl cellulose (product thocel 60HG ") in 75 ml of denatured alcohol add a solution of 5 g of ethyl cellulose (product thocel 22 cps") in 150 ml of dichloromethane. Then add 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. The last solution is added first, and then the total mass is added 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated colour suspension (product spray K-1-2109") and the whole mixture homogenized. In the apparatus for coating using prigotovili. 1.8 g of methyl-4-oxybenzoates and 0.2 g of propyl-4-oxybenzoates dissolved in approximately 0.5 l of boiling water for injection. After cooling to a temperature of about 50aboutTo the solution was added with stirring 4 g lactic acid, 0.05 grams propylene glycol and 4 g A. K. the Solution is further cooled to room temperature and added to water for injection in an amount necessary to bring the volume to 1 l, having a solution of 4 mg A. K. per milliliter. This solution is sterilized by filtration U. S. P. XVII p. 811) and poured into sterile containers.

P R I m e R 30. Suppositories. 3 Mr. A. K. dissolved in a solution of 3 g of 2,3-dioxabicyclo in 25 ml of polyethylene glycol 400. Mix between a 12 g surfactant (product "SPAN"), and triglycerides (product Witepsol 555 ") in an amount necessary to bring the mass up to 300, the Latest the mixture is thoroughly mixed with the first solution. Thus prepared mixture was poured into moulds at a temperature of 37-38aboutWith receiving 100 suppositories each containing 30 mg A. K.

P R I m e R 31. Aerosol preparations. a) In a solution of 0.1 g oksipropil-beta-cyclodextrin (MOH= 0,43) in 0.7 ml of distilled water add 730 µg in 0.1 n hydrochloric acid solution and what atom solution by adding 0.1 N. the sodium hydroxide solution was adjusted to 5.5. Then add 4 mg of sodium chloride and 0.15 mg of phenylacetate mercury and the whole mass is stirred until complete dissolution. Next, add distilled water to a volume of 1 ml. of This solution is injected into a glass vial, closed with a device with a mechanical pulverizer, feed during application of 0.1 ml for each cycle.

b) In a solution of 0.1 g of dimethyl-beta-cyclodextrin in 0.7 ml of distilled water add 600 mcg of 0.1 n hydrochloric acid solution and 2 mg A. K. After stirring for 10 min at room temperature in the mixture is dissolved 10 mg of polyvinyl alcohol and the pH value thus prepared solution by addition of 0.1 n sodium hydroxide solution was adjusted to 5.5. Then add 4 mg of sodium chloride and 2 mg of phenethyl alcohol and the whole mass is stirred until the formation of the solution. To bring volume to 1.0 ml add distilled water and the mixture is then poured into a glass vial, closed with a device with a mechanical sprayer that during application of the medication delivers 0.1 ml of fluid for each cycle.

1. Derivatives of pyridinylamino General formula

< / BR>
where one or two carbon tamakoshi, or two carbon atoms of the methylene groups of the above-mentioned residue can be connected by bridge with alkane-C2- C4-deylam;

X is CH or nitrogen;

m and n are 1, 2, 3, independently from each other, and m + n is 3, 4 or 5;

R1hydrogen, C1WITH4-alkyl, halogen;

R2and R3hydrogen or C1WITH4-alkyl;

Alk alkane-C1WITH4-diyl;

R4and R5hydrogen, halogen or1WITH4-alkyl;

Het group is one of the General formulas

< / BR>
< / BR>
< / BR>
where R6hydrogen, C1WITH6-alkyl, C1- C6-oxyalkyl,3WITH6-cycloalkyl, phenyl or amino;

R7hydrogen, C1WITH6-alkyl, C3- C6-cycloalkyl, phenyl or trifluoromethyl,

as well as their salt or a stereochemical isomeric form.

2. Antiviral composition comprising an active ingredient and an inert carrier, characterized in that the active substance it contains derivatives of pyridinylamino General formula

< / BR>
where one or two carbon atoms of methylene groups in the balance

< / BR>
can be overridden WITH the1WITH4-alkyl, C1- C4-alkoxygroup or two carbon atom of the methylene group is>m and n are 1, 2, 3 independently from each other, and m + n is 3, 4 or 5;

R1hydrogen, C1WITH4-alkyl, halogen;

R2and R3hydrogen or C1WITH4-alkyl;

Alk alkane-C1WITH4-diyl;

R4and R5hydrogen, or halogen, or C1- C4-alkyl;

Het group is one of the General formulas

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where R6hydrogen, C1WITH6-alkyl, C1- C6-oxyalkyl,3WITH6-cycloalkyl, phenyl or amino;

R7hydrogen, C1WITH6-alkyl, C3WITH6-cycloalkyl, phenyl or trifluoromethyl,

as well as their salt or a stereochemical isomeric form in the amount of 0.05 - 15 wt.

3. Heterocyclic derivatives of General formula

< / BR>
where one or two carbon atoms of methylene groups in the balance

< / BR>
can be overridden WITH the1WITH4-alkyl, C1- C4-alkoxygroup or two carbon atom of the methylene groups of the specified residue can be connected by bridge with alkane-C2WITH4-deylam;

X is CH or nitrogen;

m and n are 1, 2, 3, and m + n is 3, 4 or 5;

Alk alkane-C1WITH4-diyl;

R4and R5hydrogen, or halogen, or C1- C4-alkyl;

Het is l, WITH1- C6-oxyalkyl,3WITH6-cycloalkyl, phenyl or amine;

R7hydrogen, C1WITH6-alkyl, C3- C6-cycloalkyl, phenyl or trifluoromethyl,

or their acid additive salt or a stereochemical isomers.

Priority signs:

26.12.89 when Het group is one of the General formulas

< / BR>
< / BR>
where R6H1WITH6-alkyl, C3- C6-cycloalkyl, R7hydrogen, C1WITH6-alkyl, C3- C6-cycloalkyl and salt or a stereochemical isomeric form;

18.04.90 when Het group is one of the General formulas

< / BR>
< / BR>
< / BR>
R6WITH1WITH6-oxyalkyl, phenyl, amino, R7phenyl.

 

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FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an intermediate compound, i. e. tert.-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-yl}-(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl]acetate that can be used in synthesis of compound of the formula (IV)

eliciting inhibitory effect on activity of HMG-CoA-reductase and, therefore, can be used for preparing pharmaceutical agents for treatment, for example, hypercholesterolemia, hyperproteinemia and atherosclerosis. Also, invention relates to a method for preparing indicated intermediate compound by reaction of the new parent compound - diphenyl-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-ylmethyl]phosphine oxide with tert.-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate in the presence of a strong base in simple ether or aromatic solvents or their mixtures at temperature in the range from -200C to -900C. Also, invention relates to a method for preparing of compound of the formula (IV) wherein R1 means hydrogen atom or pharmaceutically acceptable cation and to a method for preparing intermediate compounds of the formula (VI):

wherein each P1 and P2 represents independently (C1-C4)-alkyl or group:

and wherein P3 represents (C1-C8)-alkyl. Applying new intermediate compounds and proposed methods provide enhancing quality and yield of compounds.

EFFECT: improved preparing methods.

9 cl, 1 tbl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

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