Phenoxyacetate, pharmaceutical composition, method of prevention and treatment picornaviruses infection and method of combating picornaviruses

 

(57) Abstract:

Describes new phenoxyacetate General formula I, where Thi is thiadiazolyl or substituted thiadiazolyl containing as a substituent alkoxygroup, vermeil, deformity, trifluoromethyl, 1,1-dottorati, halogen, alkyl, cycloalkyl, hydroxyalkyl or alkoxyalkyl; Y - Allenby bridge containing 3 to 9 carbon atoms; R1and R2each independently selected from hydrogen, halogen, alkyl, hydroxyl, hydroxyalkyl, alkoxyalkyl, alkoxy, nitro, carboxy, alkoxycarbonyl, diformate or trifloromethyl; R3represents phenyl or a heterocyclic radical chosen from the group consisting of benzoxazolyl, benzothiazolyl, thiadiazolyl, oxazolyl, thiazolyl, oxadiazolyl - isoxazolyl, furyl, thienyl, pyridyl, or substituted phenyl, or substituted heterocycle containing, as a substituent alkyl, alkoxyalkyl, cycloalkyl, halogenated, hydroxyalkyl, alkoxy, hydroxy or foralkyl, or its pharmaceutically acceptable acid salt additive. The above compounds exhibit protivodetonatsionnuyu activity. Describes also a method of prevention and treatment, as well as the way ilicheskom replaced phenoxyacetate, methods for their preparation and use as protivodiareynogo tools.

Brief description of the invention

It was found that the compounds of formula 1 are effective protivogemorragicheskim means. Accordingly, this invention relates to compounds of the formula:

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where:

Thi - is thiadiazolyl or substituted thiadiazolyl containing as a substituent alkoxygroup, vermeil, deformity, trifluoromethyl, 1,1-dottorati, halogen, alkyl, cycloalkyl, hydroxyalkyl or alkoxyalkyl;

Y - Allenby bridge containing 3-9 carbon atoms;

R1and R2each independently selected from the group comprising hydrogen, halogen, alkyl, alkenyl, amino, alkylthio-, hydroxyl group, hydroxyalkyl, alkoxyalkyl, alkylthiomethyl, alkylsulfonates, alkylsulfonyl, alkoxy-, nitro-group, carboxy, alkoxycarbonyl, dialkylaminoalkyl, acylaminoalkyl, aminoalkyl, deformity, trifluoromethyl or cyano;

R3is alkoxycarbonyl, phenyl, alliteration or heterocyclic radical chosen from the group comprising benzoxazolyl, benzothiazolyl, thiadiazolyl, imidazolyl, dihydroimidazole, pyrimidinyl, pyrazinyl, pyridazinyl, or substituted phenyl or substituted heterocyclics radical containing as a substituent alkyl, alkoxyalkyl, cycloalkyl, halogenated, hydroxyalkyl, alkoxygroup, hydroxyl group, furyl, thienyl and foralkyl;

or their pharmaceutically acceptable acid additive salts.

The invention relates also to compositions for combating picornaviruses, including the compound of formula 1 in an amount to provide effective antipaternalism action, and a suitable carrier or excipient, and to methods of combating picornaviruses using these compositions, including systemic treatment picornavirus infections in the body-the host mammal.

A detailed description of the preferred embodiments

The compounds of formula 1 are useful for use as protivodiareynogo means and further described in detail.

The terms "alkyl" and "alkoxy" refers to aliphatic radicals, including branched, containing from one to five carbon atoms. Thus, the alkyl fragments of such radicals are, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl and so is a, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term "halogen" means bromine, chlorine, iodine or fluorine.

The term "heterocyclic radical" or Het refers to a heterocyclic radical containing 5 or 6 carbon atoms and from one to four nitrogen atoms and/or one oxygen atom or sulfur, provided that the heterocycle does not have two adjacent atoms of oxygen and/or sulfur. Examples of heterocyclic radicals are furyl, oxazolyl, isoxazolyl, Persil, imidazolyl, thiazolyl, tetrazolyl, thienyl, pyridyl, oxadiazolyl, thiadiazolyl, triazinyl, pyrimidinyl, etc., the Term "heterocycle" refers to the respective connections.

The term "heterocyclic radical" includes all known isomeric radicals described heterocycle, unless otherwise stated, for example, the term "thiadiazolyl" includes 1,3,4-thiadiazole-2-yl, 1,2,4-thiadiazole-5-yl and 1,2,4-thiadiazole-3-yl, the term "thiazolyl" includes 2-thiazolyl, 4-thiazolyl and 5-thiazolyl and other well-known variation known heterocyclic radicals. Therefore, imply any isomer specified heterocyclic radical. These heterocyclic radicals can join through any available nitrogen atom is available the nitrogen atom tetrazolium cycle, the term "furyl" include furyl, attached through any available carbon atom, etc. the Receipt of such isomers is described well enough known and qualified pharmacist or specialist in the field of organic chemistry.

Some of the compounds may exist as tautomers, and these compounds, although not listed, all and each tautomeric form, include all tautomeric forms. For example, pyridine and his tautomer hydroxypyridine are treated as one and the same fragment. Because of heterocyclic fragments of the compounds of this invention can contain, as substituents, a hydroxyl group, it should be borne in mind that under hydroxy-substituted heterocycles refers to all relevant tautomers.

When using the terms "hydroxyalkyl and alkoxyalkyl" note that hydroxyl and alkoxy groups may be in any possible position of the alkyl. Thus, the terms "hydroxyalkyl and alkoxyalkyl" include, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxyisopropyl, 2-, 3-, 4 - and 5-hydroxyphenyl etc., the term "alkoxygroup" refers to the respective groupplay group can be in any possible position alkoxygroup, except C-1 (genialne position). Thus, the term "hydroxyalkoxy" includes, for example, 2-hydroxyethoxy-, 2-hydroxypropoxy-, 2-hydroxyisopropyl-, 5-hydroxyphenoxy group, etc.

The term "alkylene" refers to a linear or branched divalent hydrocarbon radical containing from 1 to about 5 carbon atoms, such as methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentile, 1,4-(2-methyl) butylene, etc. Alkylen may also contain alkeneamine or alkyline connection.

The term "halogen" refers to the Halogens: fluorine, chlorine, bromine and iodine.

The term "halogenated" in this description refers to a halogen-substituted to the alkyl, such as foralkyl, chlorophenacyl, brachialis, bamporiki, bromacil, Italtel, chloroalkyl, and other similar fragments, in which halogenated contains one or more identical or different halogen atoms, which replaced hydrogen. For example, the term "halogenated" includes chlorodifluoromethyl, 1-chloroethyl, 2,2,2-trichloroethyl, 1,1-dichloroethyl, 2-chloro-1,1,1,2-tetraborates, bromacil etc.

The term "foralkyl" in this description means a preferred subclass of halogenation and belongs to fiorinolandfioricet, 1,1,2,3-tetracarbonyl etc.

The compounds of formula 1, where R3represents a nitrogen-containing heterocycle, have sufficient basicity to the formation of acid additive salts and are useful both in the free base form and in the form of an acid additive salts, and both forms constitute the scope of this invention. An acid additive salt in some cases are a form more convenient for use, and in practice the use of salt forms, respectively, equal to the application main form. Acids which can be used to obtain the acid additive salts preferably include such acids, which when connected with the free give basis pharmaceutically acceptable salts, i.e. salts, the anions of which are relatively innocuous to the animal organism in pharmaceutical doses, thus the beneficial properties inherent in the free base are not lost in the side effects attributed to the anions. Examples of suitable acid additive salts include the hydrochloride, hydrobromide, sulfate, acid sulfate, maleate, citrate, tartrate, methanesulfonate, p-toluensulfonate, dodecylsulfate, cyclohexanesulfamic, etc., However in the region of dannyh and organic acids. Acid additive salts of the basic compounds can be obtained by dissolving the free base in aqueous-alcohol solution containing the appropriate acid, with subsequent isolation of the salt by evaporation of the solution, or by the interaction of the free base and acid in an organic solvent, in this case salt is produced directly in the reaction or it precipitated the second organic solvent or emit in the concentration of the solution or by any other well-known methods. Although pharmaceutically acceptable salts of the basic compounds are preferred, the scope of the present invention includes all of the acid additive salt. All acid additive salts are useful as the starting material to obtain the free base, even if the particular salt is required only as an intermediate product, such as, for example, in the case when salt only get to clean or identification, or when it is used as an intermediate product when receiving a pharmaceutically acceptable salt by ion exchange.

The structure of the compounds of this invention were the ol of reactions, identification of products and assess their homogeneity was carried out by thin layer chromatography (TLC), gas chromatography (GC) or in other ways control the chemical interaction of organic substances.

As areagirls (inert) solvent in this invention can be used N-organic (NMP), methylene chloride (CH2Cl2), tetrahydrofuran (THF), benzene or any other solvent which does not participate in the reaction. In a preferred method, the reaction of producing compounds of the present invention is carried out in dry solvents under an inert atmosphere. Some reagents used in the example are indicated by the abbreviations: triphenylphosphine (TPP), triethylamine (TEA), diisopropylethylamine (D1PEA), and diethyl ester of azodicarboxylic acid (DEAD). Ether is a diethyl ether, unless a different value.

The compounds of formula 1 can be obtained in several different ways.

The compounds of formula 1 can be obtained by the reaction of a suitable hydroxy-Y-thiadiazole and the right R1-R2-R3-phenol, as described in U.S. patent 5242924 included in this application by reference.

The compounds of formula 1 can be obtained as a result of complex synthesis with the formation of thiadiazoles (Thi) fragment in the final stages of the synthesis.

To obtain compounds of formula 1, where Thi is a 1,2,4-thiadiazolyl, are compounds of the structure X-Y-O(R1-R2-4-R3-phenyl), where X is a functional group, the substituted 1,2,4-thiadiazole containing a suitable functional group. Compounds of structure X-Y,-O-(R1-R2-4-R3-phenyl) obtained from R1-R2-4-R3-phenols and compounds of the structure of the hydroxy-Y-X or halogen-Y-X the same methods which are used to obtain the compounds of formula 1 described above. Usually X is the position of the fragment (i.e., in the most remote from phenoxy slice position on Allenova the bridge). X can be introduced into the compound Y-O-(R1-R2-R3-phenol) before interaction with the thiadiazole containing functional group. For example, in the case when Y contains alkene or alkyne, the connection may communicate with a suitable tin-containing derivative forming compound, in which X represents naptime,4-thiadiazole, preferably iodine-1,2,4-thiadiazole with obtaining the compounds of formula 1.

In accordance with another way 1,2,4-thiadiazole can be formed from a functional group that is attached to Y, is normally in the position as described above. This method of obtaining 1,2,4-thiadiazole is well known: see, for example Katrisky and Rees, Comprehensive Heterocyclic. Chemistry (1985).

To obtain compounds of formula 1, where Thi is a 1,3,4-thiadiazole, preferably the formation of 1,3,4-thiadiazole at the final stage of the functional group at the Y. for Example, the connection patterns (alkoxycarbonyl)-Y, - O-(R1-R2-4-R3-phenyl) can react with obtaining carbazide, which then interacts with active sulfur compound, such as a reagent of Lawsone (Lawesson''s reagent) P4S10or a similar connection with the formation of 1,3,4-thiadiazole.

Obtaining compounds of structure X-Y,-O-(R1-R2-R3-phenyl), where X is a functional group described above.

In accordance with another method, the compound of formula 1, where T represents a 1,3,4-thiadiazole can be obtained by the interaction of the 1,3,4-thiadiazole containing a suitable functional group, with a compound X-Y is-O-(R1-R2-R formula 1, where R3is phenyl or heterocyclic radical, can be obtained by the interaction of the hydroxy-Y-thiadiazole or halogen-Y-thiadiazole with R1-R2-4-(functional group) phenol, followed by substitution of functional groups in the phenyl or heterocyclic group such as pyridyl, furyl, etc., on the final stage. For example, Thi-Y-O-(R1-R2-phenyl) borate, can interact with halogenopyrimidines with the formation of compound 1, where R3represents pyridyl. In accordance with another method, some heterocyclic R3easier to get as such by a heterocycle of the functional groups on the phenyl ring. This is the preferred method for heterocycles containing two or more heteroatoms, such as thiazolyl, oxadiazolyl, oxazolyl etc.

For example, in the case when R3represents a heterocycle, heterocyclic ring compounds of formula 1 can be obtained from the right R1-R2-(function group) phenoxy-Y-thiadiazole, (or ZO-R1-R24-(functional group) of phenol, where Z is a (Thi)-Y). In this method, a heterocycle, appears on the ring phenoxy-fragment on the final study is the first Deputy to the introduction of a 4-phenoxy position will depend on what a heterocycle must be contained in the final product, for example, in the case where Het is a 1,2,4-oxadiazolyl:

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connection 1 get any of the appropriate 4-Z-O-R1-R2-benzonitrile, where Z Is - Y-thiadiazole, by the reaction of, for example, with hydroxylamine hydrochloride, preferably in an inert solvent, preferably alkanol, for example, methanol, ethanol, n-butanol, etc., thus Obtained product interacts with the acid anhydride of formula (R CO)2O, where R' is alkyl, halogenated etc., or orthoformiate or complex ether formate, if R' is hydroxyl or alkoxygroup. R' appears at the P3the heterocycle of the final product. The reaction proceeds in the temperature range from room temperature up to the boiling temperature of the reaction mixture in the basic solvent such as pyridine. The product is a compound of formula 1, where R3=5-R'-1,2,4 - kidizoom, other connections get the same way.

R1-R2-R3the phenols used to obtain compounds of formula 1, are well known compounds. Usually they get the interaction accordingly protected phenol containing in position 4 functional group, such as, 939267, 4861971, 4857539, 5242924 or 4843087, which are introduced in the reference list of this invention, to obtain the corresponding appropriately protected geterotsiklicheskikh, the protective group is then removed by known methods. To obtain compounds of formula 1 can similarly be used, and other known phenols, for example, any 4-phenylphenol, 4-alkoxycarbonyl, substituted or unsubstituted, in accordance with the description above.

It is assumed that any R1-R2-R3the phenol may interact hydroxy-Y-thiadiazole or to give the compounds of formula 1.

R' may be the conversion of any way of turning the side groups of the heterocycle, for example by substitution of the hydroxyl group by chlorine, cleavage of the ether group with the formation of hydroxyl groups and in other ways.

Note that neither the time of the formation of heterocyclic substituents or pyridazine, nor the procedure for obtaining the intermediate products are not the determining factors for the successful synthesis of compounds of formula 1. Thus, with a reasonable selection of reagents can be obtained the compounds of formula 1.

In accordance with other referred removing the protective group is an R1-R2-R3-(heterocyclyl) phenol. This phenol interacts with cialisregalis.viagra or thiadiazolidine or connection patterns halogen-Y-X or hydroxy-Y-X, where the thiadiazole introduce a replacement or it is formed at the last stage of synthesis of the compounds of formula 1.

Hydroxy-Y-thiadiazole used in this invention are well known and commercially available or can be obtained by known methods. For example, commercially available halogen-1,2,4-thiadiazole can connect with-halogenoalkanes complex ether or halogenation complex ester using standard methods, such as interaction with tin iodide, preferably with subsequent restoration to alkanol by known methods.

In accordance with another way 1,3,4-cialisregalis.viagra, 1,3,4 - thiadiazolidine or R1-R2-R3-phenoxy-Y-1,3,4-thiadiazole can be obtained by the interaction of the appropriate phenoxy-Y-carbazide, for example, reagent Lassana under standard conditions as described above to obtain compounds of formula 1. Carbased can be obtained by the reaction of known phenoxyacetaldehyde acid or phenoxyalkanoic the th cycle).

Simple chemical transformations, common and well-known qualified specialist in this field of chemistry can be used for effective changes in the functional groups of the compounds of the present invention. For example, if you want, you can: acylation of hydroxy - or amino-substituted derivative to obtain the corresponding esters or amides, respectively, alkylation of phenyl or furfuryl deputies, splitting alilovic or benzyl ester to obtain the corresponding alcohols or phenols, hydrolysis of esters or amides of the corresponding acids, alcohols or amines, getting anhydrides, acid halides, aldehydes, simple aromatic alkylation, sulfonation of Karmazinov, education chlorine - or foralkyl from hydroxyalkyl or keto - compounds, substitution of the hydroxyl group of the halogen in the compounds, and the formation of other heterocycles, etc.

To obtain a complete picture of the reactions used in the chemistry of heterocyclic compound, see, for example, Katritzky and Ress Comprehensive Heterocyclic Chemistry or Castl Heteroclic Compouds, or any other research papers or academic publications in this field.

The source materials used to produce compounds of formula 1 are commercially available, known or can be obtained by known methods. A large number of ways of obtaining the source of the substances listed in the patents included in the reference list of this invention.

The experimental part of the description

In this description R1, R2, R3, R4X, Y and Het in the intermediate products adopt the same values as in the compounds of formula 1.

To introduce the names of the substituents in formula 1 atoms of the phenyl cycle of any of the compounds of formula 1. will be numbered as follows:

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Thus, when the compound of formula 1 contains a substituent in the phenyl cycle, he shall be called in accordance with this numbering system, not paying attention to how this connection is l, this means

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regardless of whether this fragment in connection 3,5-dimetilfenil or 2,6-dimetilfenil.

To introduce the names of the substituents in the compounds of formula 1 atoms 1,3,5 - thiadiazole cycle described in this invention will be enumerated as follows:

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regardless of the Deputy, who is in position 2 1,3,4-thiadiazolyl in order to prevent any confusion for the reader who may not be versed in the part of the nomenclature of chemical compounds. So:

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in the description named as 2-acetyl-1,2,4-thiadiazole-5-yl, and

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in the description named as 1,3,4-thiadiazole-5-yl, although in accordance with the rules of nomenclature these radicals may be named differently.

Example 1.

A. 4 ((4-Cyano-2,6-dimethyl)phenoxy) butyric acid

To a solution of 5 g (34 mmole) of 4-cyano-2,6-dimethylphenol in 120 ml of N-methylpyrrolidone add 5,86 g (42 mmole) of potassium carbonate, of 0.58 g (3 mmole) of potassium iodide and 4.8 ml (34 mmole) ethyl ester 4-pamakani acid, the mixture was incubated at a temperature of 60oC for 24 hours. The reaction mixture is cooled, diluted with water, filtered, the obtained solid white precipitate is washed with water, resulty ether is mixed at room temperature with 120 ml of a mixture of ethanol/water (4:1), containing 820 mg (34 mmole) Li HE, the ethanol is distilled off under vacuum, after which the aqueous layer was washed with water. The aqueous layer was acidified, and the resulting white solid is filtered off and dried, the result is 6,93 g(88%) 4- ((4-cyano-2,6-dimethyl)phenoxy) butyric acid.

B. tert-Butyl ether N-(4-((4-cyano-2,6-dimethyl) -phenoxy)butyryl) Karmazinov acid

To a solution of 4-((4-cyano-2,6-dimethyl)phenoxy) butyric acid (654 mg, of 2.81 mmole) in 15 ml of methylene chloride added 1.2 ml (16,86 mmole) of thionyl chloride, the mixture is refluxed for 3 hours. After that, the mixture is evaporated under vacuum, the residue in the form of oil is pale-yellow in 20 ml of THF is mixed with 409 mg (3,09 mmole) of tert-butyl methyl ether of kurbinovo acid and add a few drops of triethylamine, after which the mixture is refluxed for 1.5 hours. The reaction mixture is cooled, evaporated under vacuum, diluted with water and extracted with methylene chloride (x3). The combined organic fractions washed with brine, dried over sodium sulfate and evaporated under vacuum, the result 899 mg (92%) tert-butyl ether N-(4-((4-cyano-2,6-dimethyl)phenoxy)drilled) Karmazinov acid

C. N-(4-((4-Cyano-2,6-dimethyl)butyryl) Karmazinov acid and 25 ml triperoxonane acid in 100 ml of methylene chloride is stirred at a temperature of 0oC for 1 hour, then evaporated under vacuum to dryness. The residue is dissolved in water, washed with ether and the aqueous layer was alkalinized (to pH 9) with sodium hydroxide solution. The precipitated white solid allocate by filtration, washed with water and dried under vacuum, the result of 3.65 g (76,2%) of N-(4-((4-cyano-2,6-dimethyl)phenoxy)butyryl)- hydrazine.

D. N-Acetyl-N'-(4-((4-cyano-2,6-dimethyl)phenoxy)- butyryl)hydrazine

To a solution of 4-((4-cyano-2,6-dimethyl)phenoxy) butyric acid (3.9 g, 16,74 mmole) in 120 ml of methylene chloride add 6 ml of thionyl chloride, the mixture is refluxed for 3 hours, then cooled and evaporated under vacuum to obtain yellow oil. To the resulting oil is added 120 ml of THF, 1.22 g (16,74 mmole) acetylhydrazide and 5 drops of triethylamine, the mixture is refluxed for 3 hours. After that, the mixture is cooled, a white precipitate solids filtered off, washed with water and dried under vacuum, the result is 3.5 g (43%) of N-acetyl-N'(4-((4 - cyano-2,6-dimethyl)phenoxy)butyryl) of hydrazine.

E. 2-Methyl-5-(3-(4-cyano-2,6-dimethylphenoxy)propyl)- 1,3,4-thiadiazole

To a solution and 2.79 g (6.92 mmole) of reagent Lawson in 150 ml of THF type of 1.57 g (5,43 mmole) N-Asses, and then maintained at a temperature of 60oC during the night. After that, the reaction mixture is evaporated under vacuum, the residue is distilled using a rapid column chromatography on silica gel (60% ethyl acetate/hexane), the result is 700 mg of a yellow oil, after recrystallization which cleaning method of fast chromatography (hexane/ethyl acetate) to obtain 750 mg (48%) of 2-methyl-5-(3-(4-cyano - 2,6-dimethylphenoxy)propyl)-1,3,4-thiadiazole.

F. 2-Methyl-5-(3-(4-aminohydrocinnamic-2,6 - dimethylphenoxy)propyl)-1,3,4-thiadiazole

To a solution of 2-methyl-5-(3-(4-cyano-2,6-dimethylphenoxy)propyl)-1,3,4-thiadiazole (0,69 g, 2.4 mmole) in 75 ml of ethanol is added 1.5 g (12 mmole) of potassium carbonate and 0.34 g (12 mmole) of hydroxylamine hydrochloride, the mixture is stirred at a temperature of 50oC for 14 hours. The mixture is then filtered, the precipitate washed several times with warm ethanol, the filtrate is evaporated under vacuum, the result of 0.98 g of 2-methyl-5-(3-(4-aminohydrocinnamic-2,6-dimethylphenoxy) propyl)-1,3,4-thiadiazole, so pl. 79-80oC.

G. 2-methyl-5-(3-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy) propyl)-1,3,4-thiadiazole (Y = 1,3 - propylene, R1=R23,5-dimethyl, Thi = 2-methyl-1,3,4-thiadiazole-5-yl, R3= 5-methyl - 1,2, 4-exmg) in 10 ml of pyridine, add 0.3 ml (4.2 mmole) of acetylchloride, the resulting mixture was refluxed for 1 hour, then cooled and diluted with water. The mixture is extracted with ethyl acetate (x4), the organic fraction was washed with aqueous solution of hydrochloric acid and brine, then dried over sodium sulfate. The organic fraction is evaporated under vacuum and the residue as a yellow oil purified by liquid chromatography (MPLC)

(75% ethyl acetate in hexane), the result 342 mg (42%) 2-ethyl-5-(3-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2,6 - dimethylphenoxy)propyl)-1,3,4-thiadiazole in the form of a solid white crystalline substance, so pl. 83-84oC (from a mixture of ether/pentane).

Example 2

A. N-Propionyl-N'-(4-((4-cyano-2,6 - dimethyl)phenoxy)-butyryl) hydrazine

To a solution of N-(4-((4-cyano - 2,6-dimethyl)phenoxy)butyryl)hydrazine (2.3 g, 9,31 mmole, obtained in accordance with the method of example 1) in THF add 0,81 ml (9,31 mmole) of propanolamide and 1 ml of triethylamine and the resulting mixture was stirred at room temperature for 2 hours. After that, the mixture is evaporated under vacuum, the obtained white solid product is triturated with water, filtered, washed with ether and dried, the result 2,569 g (91%)

N-propionyl-N'-(4-((4-cyano - 2,6-dimethyl)phenoxy)butyryl) of hydrazine.

C. 2-Ethyl-5-(3-(4-aminohydrocinnamic-2,6 - dimethylphenoxy)propyl)-1,3,4-thiadiazole

To a solution of 2-ethyl-5- (3-(4-cyano-2,6-dimethylphenoxy)-propyl)-1,3,4-thiadiazole (1.6 g, 5,32 mmole) in ethanol add to 3.67 g (26,58 mmole) of potassium carbonate and 1.85 g (26,58 mmole) of hydroxylamine hydrochloride, the mixture was stirred at room temperature for 1.5 days. After that, the mixture is filtered, the filtrate evaporated under vacuum, the result of 1.12 g of 2-ethyl-5-(3-(4 - aminohydrocinnamic-2,6-dimethylphenoxy)propyl)-1,3,4 - thiadiazole, so pl. 158-160oC.

D. 2-Ethyl-5-(3-(4-(5-deformity-1,2,4 - oxadiazol-3-yl)-2,6-dimethylphenoxy)propyl)-1,3,4-thiadiazole (Y = 1,3-propylene, R1= R2= 3,5-dimethyl, Thi = 2-ethyl-1,3,4-thiadiazole, R3= 5-deformity-1,2,4-oxadiazol-3-yl)

To a solution of 2-Ethyl-5-(3-(4-aminohydrocinnamic-2,6 - dimethylphenoxy)propyl)-1,3,4-thiadiazole (800 mg, 2.4 mmole) in N-organic (3 ml) add the 1.44 ml (of 14.46 mmole) Adilov is within 4 hours, then cooled and diluted with water. The mixture is extracted with ethyl acetate (x4), the organic fraction was washed with water, brine and dried over sodium sulfate. The organic fraction is evaporated under vacuum and the residue purified by MPLC method (25-40% ethyl acetate in hexane), the result is 500 mg (55%) of 2-Ethyl-5-(3-(4-(5- deformity-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy) propyl)-1,3,4-thiadiazole in the form of a solid white crystalline substance, so pl. 83-84oC (from methylene chloride and hexane).

Example 3

A. To a solution of ethylsuccinate (25 g) in 300 ml of CH2Cl2cooled to 0oC, are added dropwise to 13.2 g propionitrile in a mixture of 100 ml of CH2Cl2and 27.4 ml aminobutiramida-ethylamine. The mixture is stirred at room temperature for 2 hours, then quenched with water, extracted with ethylenchloride, the organic layer dried and evaporated under vacuum. The solid residue is recrystallized from a mixture of ethyl acetate/hexane (5:1), the result is N-propionyl-N'-(ethyl) succinyl-hydrazide.

B. of 28.1 g of the product of example 3A was dissolved in 2 l of THF, add 89,8 g P4S10and the mixture is refluxed for 2 hours. After cooling, add 800 ml of 5% sodium carbonate solution and 1 l of ether at over magnesium sulfate and evaporated under vacuum, the result is an increase of 22.7 g (53%) of ethyl ester of 3-(5-ethyl-1,3,4-thiadiazole-2-yl) propionic acid.

C. 112 ml of 1 μm LAH (on air) to - 20oC under nitrogen atmosphere. Dropwise in the form of a suspension (in ether) is added an equimolar amount of (24 g) ester propionic acid obtained by the method 3B and the resulting mixture is stirred for 15 minutes. The reaction is quenched with water and the ground. The result is 3-(5-ethyl-1,3,4 - thiadiazole-2-yl) propanol (13,46 g) with a yield of 78%, prior to use in the next stage the product is distilled under vacuum (0.1 mm Hg), collecting the fraction with a boiling point of 130 - 140oC.

D. 9.7 g of 2,6-dimethyl-4-(5-deformity-1,2,4-oxadiazol-3 - yl) phenol (as described in the Application U.S. 07/869287 included in the reference list of this invention) 15.7 g of triphenylphosphine and 6.9 g of propanol was placed in 80 ml of THF. The mixture is cooled to < 5oC, and then added dropwise 10.4 g DEAD in 80 ml of THF under nitrogen atmosphere and the resulting mixture is stirred for 1 hour. The solution was poured into hexane and stirred until the formation of resin-solid mixture. The mixture is filtered to remove solids. The solution is evaporated under vacuum to obtain a solid residue, a pale yellow color. Technical product purified by column method, chromalox)propyl)-1,3,4-thiadiazole (Y = 1,3-propylene, R1= R2= 3,5-dimethyl, Thi = 2-ethyl-1,3,4-thiadiazole-5-yl, R3= 5 - deformity-1,2,4-oxadiazol-3-yl), so pl. 84oC.

Example 4

A. Methyl ester N-(4-((4-cyano-2-6 - dimethyl)phenoxy)-buterol) Karmazinov acid

To a solution of 4-((4 - cyano-2,6-dimethyl)phenoxy) butyric acid (247 ml of 1.06 mmole) in 15 ml of methylene chloride add 0.4 ml (5,48 mmole) of thionyl chloride, the mixture is refluxed for 3 hours. The mixture is evaporated under vacuum, the residue in the form of oil in 20 ml of THF is mixed with 104 ml (1.16 mmole) of methylcarbonate and add 3 drops of triethylamine, the mixture is then refluxed for 2 hours. The reaction mixture is cooled, evaporated under vacuum, diluted with water, and filtered the resulting precipitate white solid, the result is 275 mg of methyl ester of N-(4- ((4-cyano-2,6-dimethyl)phenoxy)butteroil) Karmazinov acid, so pl. 154-155oC.

B. 2-Oxo-5-(3-(4-cyano-2,6-dimethylphenoxy)propyl)-2,3-dihydro-1,3,4-thiadiazole

To a solution 1,72 g (5,65 mmole) of methyl ester of N-(4-((4-cyano-2,6-dimethyl)phenoxy)butteroil) Karmazinov acid in 100 ml of THF added 2,22 g (5,50 mmole) of reagent Lawson and the mixture is refluxed over night. Posleen/ethyl acetate, 1:1), the result 0,406 g (24,5%) 2-Oxo-5-(3-(4-cyano-2,6-dimethylphenoxy)propyl)-1,3, 4-thiadiazole-3H-2-it.

C. 2-Oxo-5-(3-4-aminohydrocinnamic-2,6-dimethylphenoxy)propyl)-1,3,4-thiadiazole-3H-2-he

To a solution of 2-oxo-5- (3-(4-cyano-2,6-dimethylphenoxy)-propyl)-2, Z-dihydro-1,3,4-thiadiazole (801 mg, 2,77 mmole) in 75 ml ethanol add 963 mg (13,86 mmole) of hydroxylamine hydrochloride and 191,3 mg (13,86 mmole) of potassium carbonate, the resulting mixture was stirred at room temperature overnight. The mixture is filtered and the filtrate evaporated under vacuum, the result is 826 mg (93%) of 2-oxo-5-(3-(4 - aminohydrocinnamic-2,6-dimethylphenoxy)propyl)-1,2 - dihydro-1,3,4-thiadiazole.

D. 2-Oxo-5-(3-(4-(5-deformity-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy)propyl)-1,2-dihydro-1,3,4-thiadiazole (Thi = 2-hydroxy-1,3,4-thiadiazole-5-yl, R1= R2= 3,5-dimethyl, Y = 1,3-propylene, R3= 5-deformity-1,2,4-oxadiazol-3-yl)

To a solution of 2-oxo-5-(3-(4 - aminohydrocinnamic-2,6-dimethylphenoxy)propyl)-1,2 - dihydro-1,3,4-thiadiazole (700 mg, 2,17 mmole) in N - methylpyrrolidinone (3 ml) is added 1.3 ml (13,02 mmole) ethyl ester DIPEROXY acid, the resulting mixture was heated to 90oC and kept at this temperature during the night. After that, the mixture obladayuthem sodium. The organic fraction is evaporated under vacuum and the residue in the form of a brown oil purified by MPLC method (25-35% ethyl acetate in hexane), the result 637 mg (67%) of 2-oxo- 5-(3-(4-(5-deformity-1,2,4-oxadiazol-3-yl)-2,6 - dimethylphenoxy)propyl)-1,2-dihydro-1,3,4-thiadiazole, so pl. 110-111oC (recrystallization: dichloromethane; methylene chloride/hexane).

Example 5

The following connections receive in accordance with the above-described methods:

< / BR>
Formula 1a

where Y is 1,3-propylene, R1= R2= 3,5-dimethyl, R3= 5-R5-1,2,4-oxadiazol-3-yl, Thi = 2-R4-1,3,4 - thiadiazolyl) (see tab. 1).

Get the following compounds of General formula 1b:

< / BR>
Formula 1b (see tab. 2).

Example 6

A. 3-Methyl-5-tributylamine-1, 2, 4-thiadiazole

To a cooled (-95oC, under fluid. N2and hexane) to a solution of 3-methyl-5-bromo-1,2,4-thiadiazole (9.4 g, 52,5 mmole) in 200 ml THF is added dropwise to 61.8 ml (105 mmole) of 1.7 N-utility at a temperature of - 90oC. the resulting solution was pink additionally stirred for 15 minutes and then added dropwise with 17.8 g (55 mmole) of the presence of TBT chloride at a temperature of -90oC . The solution is allowed to warm to 0oC, then the reaction quenched with a solution of ammonium chloride. the mind the result is 3-methyl-5-tributyl-1,2, 4-thiadiazole.

B. Ethyl ester -(3-methyl-1,2,4-thiadiazole-5-yl)- acrylic acid

To a solution of 3-methyl-5-tributylamine-1,2,3 - thiadiazole (49 mmole) in 160 ml of xylene added 11 g (49 mmole) ethyl ester (iodine)acrylic acid, and then Pd(PPh3)42.2 g, of 2.45 mmole). The mixture is heated to 120oC and kept at this temperature for 18 hours, then cooled and added a saturated aqueous solution of KF. The mixture is filtered (filter paper), the precipitate washed with ethyl acetate, the aqueous fraction is extracted with ethyl acetate (x3). The combined organic fraction dried over sodium sulfate and evaporated under vacuum. The residue is purified by chromatography (column 10 cm, silica gel, methylene chloride/acetone from 15/1 to 1/0) and re-chromatographic (column 10 cm, silica gel, ethyl acetate/hexane 1/5), the result is 2 g (21%) ethyl ester -(3-methyl-1,2,4-thiadiazole-5-yl) acrylic acid in the form of a white solid (recrystallization from a mixture of ethyl acetate/hexane). Then the acrylic ester reduced to the alcohol with

AH and using palladium on carbon and hydrogen get saturated alkyl.

C. 3-Methyl-5-(3-(4-(5-deformity-1,2,4-oxadiazol-3-the Teal, R3= 5-deformity-1,2,4-oxadiazol-3-yl).

A mixture of 5-(3-hydroxypropyl)-3-methyl-1,2,4-thiadiazole (242 mg, 1,53 mmole), 4-(5-deformity-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenol (as described in the application U.S. 07/869287 entered in the reference list of this invention) (400 mg, 1,67 mmole) and DEAD (290 mg, 1,67 mmole) is dissolved in 16 ml of THF. In the specified solution was added triphenylphosphine (438 mg, 1,67 mmole) at a temperature of 0oC and the mixture is left overnight at 20oC. the Solvent is evaporated under vacuum, add an aqueous solution of sodium bicarbonate, the mixture is extracted with methylene chloride (x7). The organic fraction is dried over sodium sulfate and evaporated under vacuum. The residue is purified by the method of column chromatography (silica gel, column 10 cm, ethyl acetate/hexane from 1/6 to 1/4), the result is 471 mg (81%) of 3-Methyl-5-(3-(4-(5-deformity - 1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy)propyl)-1,2,4 - thiadiazole in the form of a solid white crystalline substance, so pl. 62-64oC.

D. 3-Methyl-5-(3-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy) propyl)-1,2,4-thiadiazole (1, Thi = 3-methyl - 1,2,4-thiadiazol-5-yl, Y = 1,3-propylene, R1= R2= methyl, R3= 5-methyl-1,2,4-oxadiazol-3-yl).

A mixture of 5-(3-hydroxypropyl)-3-methyl-1,2,4-thiadiazole (66 mg, at 0.42 mmole), 4-(5-methyl-born to 0oC, add triphenylphosphine (120 mg, and 0.46 mmole) and the mixture allowed to warm to 20oC. the Solvent is distilled under vacuum, add aqueous sodium bicarbonate solution and extracted with methylene chloride (x3). The organic fraction is dried over sodium sulfate and evaporated under vacuum. The residue is purified by the method of column chromatography (silica gel, column 20 cm, ethyl acetate/hexane, from 1/6 to 1/4) followed by recrystallization from a mixture of ethyl acetate/hexane, the result is 88 mg (61%) of 3-methyl-5- (3-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy) propyl)-1,2,4-thiadiazole in the form of a solid white crystalline substance, so pl. 67-71oC.

Example 7

As additional examples, the phenols described only in General form, can further react with any known thiadiazolidine, cialisregalis.viagra or with any of these connections when using the above described methods for producing compounds of formula 1. It is assumed that from any of the phenol, as described in the application 07/869287 listed as references, as a result of complex transformations in accordance with the above described methods form a thiadiazole of formula 1. For the convenience of readers use the same nomenclature for compounds fo is R 8

Assume that 4-hydroxy-3,5-dimethylbenzonitrile can react with hydroxylamine hydrochloride in the conditions of example 2C and the resulting product may then interact with ethyl ether of Harborview acid and acetone. The result is a compound where Y = 1,3-propylene, giving a phenol, in which R1and R23,5-dimethyl, R3= 5-hydroxy-1,2,4-oxadiazol-3-yl. This phenol can react with any of previously received thiadiazolidine with the formation of compounds of formula 1.

B. the Connection described above, can interact with oxychlorination phosphorus (through the acceptor base) by boiling under reflux for about 4 hours, the result is 5-chloro-1,2,4-oxazol-3-yl of the formula 1.

Biological tests

Biological tests of the presented compounds of the formula 1 show that they have protivopedikuleznoy activity. They are useful in the inhibition picornaviruses reproduction in vitro and mainly active against picornaviruses, including enteroviruses, echo virus, kokako-virus and especially rhinoviruses. Testing in vitro of the compounds of this invention showed that the replication of the virus inhibited="ptx2">

The MIC determined by an automated estimate of the dose protecting 50% of infected tissue culture. Cell types in HeLa monolayers in 96-cell boards infect divorced picornaviruses, which in the absence of drugs demonstrate empirically getting 80-100 phagocytic effect (FCE). Test compounds are serially diluted 10 2-multiple cycles and added to the infected cells. After three days of incubation at 33oC and 2.5% content of carbon dioxide cells fixed with 5% solution of glutaric aldehyde acid, followed by staining with 0.25% solution of a purple dye in the water. After this card is washed, dried and measurement of optical density to determine the amount of dye remaining in the cell (a measure of intact cells). Define MICK, representing the concentration at which there is protection of 50% of the cells from the picornavirus-induced PCA compared with untreated control.

In accordance with the above described method presents the compounds of formula 1 have against 10 H - rhinoviral (HRV) serotypes, namely: HRV -3, -4, -5, -9, -16, -18, -38, -66, -75 and -67 (marked in the table as a group B) and for each Environnementale value MICK50and MICK80that represent the minimum concentration of the compound required for 50% and 80% inhibition of the tested serotypes, respectively. The test compounds, as installed, show protivodetonatsionnuyu activity against one or more of these serotypes.

In table 4, below, shows the results of tests of the presented compounds of the present invention. A group of picornaviruses that are used in the experiment are listed before values MICK50and MICK80and the number of serotypes against which it was tested compound (N) is indicated after values MICK50and MICK80.

The compound of example 3(d) have against 101-H-rhinoviruses: 1A, 1B, and 3-100 (except HRV 74) according to the method described above. MICK50and MICK80for example, the 3d form of 0.04 to 0.19 μm and μm, respectively.

Preliminary tests show that the compound of example 3(a) provides in vitro and in vivo excellent protection from korsakovia B3. In accordance with the methodology described above, MICK50in vitro for compounds of example 3(d) is 0.001 μg/ml.

Preliminary tests indicate that the value of PD50(protective dose of style to prevent korsakovian infection, and in infected mammals to prevent death due to infection.

Preliminary tests for the study of the bioavailability obtained on dogs, confirm that the compound of example 3 (d) has a very good bioavailability. Its solubility in artificial gastric juice is 1.1 mg/ml, and in artificial tissue fluid to 0.63 mg/ml

Recipe

The compounds of formula 1 can be administered in a composition (formulation) of any well known form, including songs extended release in combination with one or more non-toxic physiologically acceptable carriers, adjuvants or excipients, which together define as carriers. Compositions made with the use of a convenient and well-known qualified fragment of methods and technologies of preparation of formulations for the treatment of infections and for prophylactic use: for oral or nasal administration, in solid or liquid form, for rectal or topical application, etc.

The composition can be administered to man and animals orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), intracisternal the de nasal or transbukkalno spray.

Compositions for parenteral injection may include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for the preparation of sterile solutions or dispersions for injection. Examples of suitable aqueous and nonaqueous carriers, fillers, solvents or diluents are water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, polyalkylene glycols, etc.,), suitable mixtures, vegetable oils (such as olive oil), organic esters, suitable for injection, such as the ethyl ester of oleic acid. Proper fluidity can be maintained by applying a coating, such as lecithin, maintain the required particle size in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives, wetting, emulsifying and dispersing agents. Protection from exposure to microorganisms can be achieved by various antibacterial and antifungal substances, for example, parabens, chlorobutanol, phenol, sorbic acid, etc. May require the inclusion in the composition of the injection can be achieved chemicals, which prolong the absorption of the pharmaceutical form, for example, aluminum monostearate and gelatin.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, pellets and granules, which can slowly dissolve in the mouth to rinse the oral cavity and to go further in combination with a solution of the active ingredient. In such solid dosage forms the active substance is mixed with at least one conventional inert excipients (or carrier) such as sodium citrate and secondary acidic calcium phosphate or (a) a filler or diluent, for example, starch, lactose, sucrose, glucose, mannitol and siliciano acid, (b) binding agents, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and the Arabian gum, (c) humectants, for example glycerol, (d) dezinfeciruyuhimi agents, for example agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex compounds of silicon and sodium carbonate, (e) the dissolution retarders, for example paraffin, (f) absorption accelerators, for example Quaternary is, (h) absorbents such as kaolin and bentonite and (i) lubricating substances, for example talc, calcium stearate, magnesium stearate, solid polyethylene glycols, nutritionrelated or mixtures thereof. In the case of capsules, tablets and pills dosage forms can also include buffering agents.

Some of the solid dosage forms can be administered by inhalation powder "manually" or by using devices such as Spin - Haler, which is used for introduction of disodium chromoglycate (disodium cromoglycate) (Intal). When using this device, the powder may be encapsulated. In that case, when using the liquid composition, the drug may be injected through the nozzle of the device for aerosol or by any means, which can deliver the composition in individual portions, for example, using medical pipette or aerosol inhaler.

Solid compositions of a similar type may also be entered for use in soft or hard gelatin capsules using such excipients as lactose or milk sugar and high molecular weight glycols, etc.

Solid dosage forms such as solubilize coverage and other well-known cover. They may contain a contrast substance, and may constitute such a composition in which the release of the active substance or substances is slow on a certain area of the intestinal tract.

The active compounds can also be, if it is acceptable, in micro-encapsulated form, comprising one or more of the above fillers.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. Solid formulations can be prepared as a basis for liquid formulations. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used for these purposes, such as water or other solvents, solubilizing agents and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl ester acetic acid, benzyl alcohol, benzyl ester benzoic acid, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular oil, cotton seed oil, peanut oil, maize seeds), olive oil, castor oil and sesame oil, glycerol, tetrahydrobenzo inert fillers, the composition can also include adjuvants such as wetting agents, emulsifiers and suspendresume agents, sweetening, flavouring substances and flavouring agents.

In addition to the active substance suspension may contain suspendresume substances, for example ethoxylated isostearyl alcohols, polyoxyethylenesorbitan, polyethylene glycols of various molecular weights, sorbitan-esters, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant or mixtures of these substances, etc.

Compositions for rectal or vaginal injection preferably are suppositories which can be prepared by mixing the compounds of this invention with suitable not having irritating fillers or carriers, such as coconut oil, polyethylene or wax for suppositories, which at ordinary temperatures is a solid, but when the body temperature becomes liquid and therefore melt in the rectal or vaginal cavity and release the active component.

Compositions for administration in the form of aerosols produced by dissolving the compounds of formula 1 in water or a suitable Rast is ntom (propellant) and the subsequent introduction into the container, under pressure and comprising a metering valve for isolation of the substance in the form of droplets of the desired size.

Propellant used in the liquid (condensed) state, usually in the singular, and at atmospheric pressure has a boiling point below room temperature. For use in compositions intended for obtaining aerosol for medical purposes, the liquefied propellant must be non-toxic. Suitable for use in a liquefied state by propellants are the lower alkanes containing up to five carbon atoms, such as butane and pentane, or alkylchloride, such as methyl-, ethyl-, or propylchloride. Suitable liquefied propellants are fluorinated and ferroresonance alkanes produced under the trade name "Freon" (Freon) and Genetron" (Genetron).

Can also be used mixtures of these propellants.

The preferred liquefied propellants are propellant, not containing chlorine, for example, 134a (Tetrafluoroethane) and 227c (Heptafluoropropane) that can be used as described above. Usually in such aerosol formulations using the second solvent, such as ether, alcohol or glycol.

Acteristic active ingredient, and specific actions which must be achieved, and (b) restrictions, which take into account when obtaining compositions of active substances for humans and animals, as described in detail in this invention, and this application of the compositions is a characteristic feature of the present invention. Examples of suitable forms containing a single dose in accordance with this invention, the capsules are intended for oral administration or aerosols with metered "shot" and other forms presented in this description.

The compounds of this invention useful for the prevention and treatment of infections caused picornaviruses etiology, such as aseptic meningitis, upper respiratory infection, enteroviral infection, korsakovia (coxsackeivirus), enteroviruses, etc., used To treat effective but nontoxic quantity of the compound. The dose of a compound used for treatment depends on the route of administration (intranasal, intrabronchial, and the activity of the specific compound).

Dosage forms for local administration include ointments, powders, sprays and pharmaceutical forms for inhalation. The active ingredient is mixed under sterile conditions Bhodemon. These include formulations for the treatment of eye diseases, eye ointments, powders and solutions.

Note that the starting point for determining the dose for prophylaxis and treatment picornaviruses infection is based on determination of compounds in plasma at approximately established in laboratory conditions, the levels of minimum inhibitory concentration. For example, the MIC of 1 μg/ml, should lead to the desired initial level of plasma - 0.1 mg/ml and the dose for a mammal with an average weight of 70 kg is about 5 mg. Presumably, doses may range from 0.01 to 1000 mg.

The magnitude of the current dose of the active ingredient in the compositions can be varied to obtain the amount of the active ingredient, which gives an effective therapeutic result of this composition with this method of introduction. Therefore, we choose the magnitude of the dose depends on the desired therapeutic effect, the route of administration, the desired duration of treatment, and other factors and can easily be determined by a qualified pharmacist.

The process of developing a pharmaceutical dosage form includes a selection of podhodyashchee optimal bioavailability and the longest half-life in plasma, etc., it is well known qualified specialists, which in the development of pharmaceutical compositions for therapeutic use is usually defined in viv relationship "dose-effect".

In addition, it should be considered that the appropriate dose to achieve optimal results therapeutic action is the main subject of study for the specialist, which usually examines the relationship "dose-effect" when developing regulations for therapeutic applications. For example, the expert can consider the minimum inhibiting concentration in vitro as a primary factor to determine effective levels of drug in the plasma. However, this and other methods are the practical techniques used by experts in drug development.

Note that the value of the specific dose for any particular patient will depend on various factors, including weight, General health, sex, diet, time and route of administration, rate of absorption and expansion, combination with other drugs and the severity of the disease, and it can easily be determined by a qualified physician.

With the introduction from approximately 0 to 48 hours before infection of an animal host by pathogenic picornaviruses. When therapeutic introduction for inhibition of infection preferably introduction within one to two days after infection with pathogenic virus.

The magnitude of the input dose will depend on the type of picornavirus that you must to extract inhibit or prevent, the type of animal to which it is put, its age, health, weight, degree of infection, type of other treatment, if it were carried out, treatment frequency and nature of the desired effect.

The compounds of this invention are also used to prevent the spread picornaviruses infection. Connections may be used in aerosol sprayers for applying on the infected surface available for infection products, such as fabrics, etc. used by infected patients. In addition, the compounds can be used to handle household goods (fabrics, of other things available for mops, etc.,) to prevent the spread of infection through the inaktivirovanie picornaviruses.

Due to the fact that the compounds of this invention have the ability to suppress the growth of picornaviruses adding them to the environment where the development of a picornavirus, a feast, in aqueous solution with a surface-active substance, for disinfecting surfaces, which are attended by polio, kokako-, rhinovirus and/or other picornaviruses, such surfaces include, but the list is not limited to, glassware in hospitals, tables in restaurants, the surfaces intended for food, sinks in the bathrooms and other places where they can develop picornaviruses.

The contact with the nasal mucus may be the most important by passing picornavirus. Sterilization of the hands of people who are in contact with patients infected with rhinoviruses, prevents further spread of the disease. It is assumed that the connection of the present invention when hand washing or use for hand protection and products, inhibits reproduction of rhinovirus and reduces the chance of spreading disease.

1. Phenoxyacetate General formula I

< / BR>
where Thi - is thiadiazolyl or substituted thiadiazolyl containing as a substituent alkoxygroup, vermeil, deformity, trifluoromethyl, 1,1-dottorati, halogen, alkyl, cycloalkyl, hydroxyalkyl or alkoxyalkyl;

Y - Allenby bridge, the soda is hydroxyl, hydroxyalkyl, alkoxyalkyl, alkoxy, nitro, carboxy, alkoxycarbonyl, diformate or trifloromethyl;

R3represents phenyl or a heterocyclic radical chosen from the group consisting of benzoxazolyl, benzothiazolyl, thiadiazolyl, oxazolyl, thiazolyl, oxadiazolyl, isoxazolyl, furyl, thienyl, pyridyl or substituted phenyl, or substituted heterocyclic radical, where the Deputy is chosen from the group comprising alkyl, alkoxyalkyl, cycloalkyl, halogenated, hydroxyalkyl, alkoxy, hydroxy or foralkyl, or its pharmaceutically acceptable salt.

2. Connection on p. 1, in which Y represents a linear hydrocarbon chain containing from 3 to about 5 carbon atoms.

3. Connection on p. 2, in which R3represents a substituted or unsubstituted oxadiazolyl.

4. Connection on p. 3 in which R3selected from the group consisting of 5-deformity-1,2,4-oxadiazolyl, 5-vermeil-1,2,4-oxadiazolyl, 5-trifluoromethyl-1,2,4-oxadiazolyl.

5. Connection on p. 4, in which R1and R2are in positions 3 and 5 and R1and R2each independently selected from the group comprising hydrogen, methyl, chlorine and fluorine.

8. Connection on p. 7, which is 2-ethyl-5-[3-4-(5-deformity-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl]1,3,4-thiadiazole.

9. Pharmaceutical composition having antipaternalism effect, characterized in that it contains as active ingredient a compound according to any one of paragraphs.1, 3, 5, 7, or 8 in an amount to provide effective antipaternalism action.

10. The pharmaceutical composition according to p. 9, characterized in that as the active ingredient contains a connection on p. 3 in an amount to provide effective antipaternalism action.

11. The pharmaceutical composition according to p. 9, characterized in that as the active ingredient contains a connection on p. 5 in an amount to provide effective antipaternalism action.

12. The pharmaceutical composition according to p. 9, characterized in that as the active ingredient contains the connection song on p. 9, characterized in that as the active ingredient contains a connection on p. 8 in an amount to provide effective antipaternalism action.

14. The method of prevention or treatment picornaviruses infection in the body is the carrier of a mammal, characterized in that it enter the compound according to any one of paragraphs.1, 3, 5, 7, or 8 in an amount to provide effective antipaternalism action.

15. The method according to p. 14, wherein introduce a connection on p. 3 in an amount to provide effective antipaternalism action.

16. The method according to p. 14, wherein introduce a connection on p. 5 in an amount to provide effective antipaternalism action.

17. The method according to p. 14, wherein introduce a connection on p. 7 in an amount to provide effective antipaternalism action.

18. The method according to p. 14, wherein the administered compound under item 8 in an amount to provide effective antipaternalism action.

19. Method of combating picornaviruses, characterized in that the area is infected with these viruses, is treated with a compound according to any one of paragraphs.1, 3, 5, 7, or 8.

20. The way to deal with picor the p. 3.

21. Method of combating picornaviruses under item 19, characterized in that the area is infected with these viruses, process connection on p. 5.

22. Method of combating picornaviruses under item 19, characterized in that the area is infected with these viruses, process connection on p. 7.

23. Method of combating picornaviruses under item 19, characterized in that the area is infected with these viruses, process connection on p. 8.

 

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(I) where Z is oxygen or sulfur;

R is hydrogen or C1-3-alkyl; when Z stands for oxygen, R1is a halogen, amino group, acetylamino or-O-R2where R2is4-6-alkyl or C6-quinil; Z, meaning sulfur, R1is halogen, C1-8-alkyl, C6-alkenyl straight chain, cyclopropylmethyl, benzyloxypropionic, morpholino-, 4-methylpiperidino - or 4-hexylamino or a group-O-R2where R2linear or branched C3-6alkenyl,3-6-quinil, cyclopropylmethyl, -R3-O-R4or-R3-O-R4-O-R5where each of R3, R4and R5means1-4-alkyl, or R1represents a group S-R2where R2linear C2-8-alkyl, or their pharmaceutically acceptable salts
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