The pharmaceutical composition inhibiting 5-lipoxygenase, 4-(4-phenyl-1-piperazinil) phenylpropane and method thereof

 

(57) Abstract:

The pharmaceutical composition inhibiting 5-lipoxygenase, 4-(phenyl-1-piperazinil)phenylpropane and how to obtain it. The essence of the invention: 1. Pharmaceutical compositions that inhibit 5-lipoxygenase, containing as the active ingredient 4-(4-phenyl-1-piperazinil) phenols of General formula I given in the description, where R1and R3each independently H, C1-6alkyl or halogen: R3- H, halogen, NO2; R4- H or CF3, J - H, NO2C1-6alkylamino,1-6alkylcarboxylic, C1-6alkyl, C1-6alkylsulphonyl, hydroxy, halogen or heterocyclic radical, possibly substituted, provided that at least one R1and R2represents alkyl or halogen, R3- halogen or NO2or R4- trifluoromethyl. 4-(4-phenyl-1-piperazinil)phenylpropane General formula I and a method thereof, which consists in the fact that alkoxybenzenes General formula II given in the description, are dialkylamino in an acidic medium or by means of a strong nucleophile. 3 S. p. f-crystals, 12 tab.

The present invention otnositelnoi form and method of its production and pharmaceutical composition inhibiting 5-lipoxygenase.

Known derivatives of 4-(4-phenyl-1-piperazinil)phenyl as intermediates for producing compounds having fungicidal and bactericidal properties (U.S. Patent N 4267179 and 4619931; EP N 0228125).

Also known N, N'-bis(4 oksifenil)piperazine as an intermediate product for producing compounds with pharmacological properties that are used in the treatment of allergic and autoimmune diseases.

The present invention is the creation of a new derivative of 4-(4-phenyl-1-piperazinil)phenyl, possessing the ability to inhibit 5-lipoxygenase, and method of producing such compounds and new pharmaceutical compositions inhibiting 5-lipoxygenase, containing as active principle 4-(4-phenyl-1-piperazinil)phenylpropane.

This object is achieved by the new derivatives of 4-(4-phenyl-1-piperazinil)phenyl General formula:

< / BR>
or its pharmaceutically acceptable salt accession acid or its stereoisomeric form, where

R1and R2each independently represents hydrogen, C1-6alkyl or Galil; Y represents hydrogen, nitro, C1-6alkylamino, C1-6alkylcarboxylic, C1-6alkyl, C1-6alkylsulphonyl, hydroxy, halogen or a heterocyclic radical of the formula

< / BR>
R represents a C1-6alkyl;

A - C/R14//R15/ B-CH2- or-CH2-CH2or A and B taken together form a bivalent radical of formula-CH=CH-(j) or-CH=N(k), where the C atom of the specified last radical (k) is connected with S; R14and R15each independently represents hydrogen or C1-6alkyl; and each of the divalent radicals B, -CH=CH(j) and-CH=N(k) one or where possible two hydrogen atoms can be replaced by C1-6alkyl or phenyl; and divalent radical B two pairs of hydrogen atom may be substituted C4-6alkanediols;

R5is hydrogen or C1-6alkyl;

R6is hydrogen, C1-6alkyl, C3-7was cycloalkenyl C1-6alkyl, (phenyl) C1-6alkyl; and C1-6alkyl, C3-7cycloalkyl and (phenyl) C1-6the alkyl can be substituted by an oxo - or hydroxy - on any carbon atom C1-6alkyl or C3-7cycloalkyl part, provided that the C atom is not attached to the nitrogen atom, having specified the radical R6;

D2- =N-, =CH - Il>-6alkyl, possibly substituted oxo - on any carbon atom, provided that the carbon atom is not adjacent to the nitrogen atom, having specified the radical R8;

each R9is hydrogen or C1-6alkyl;

X is O or S;

R10is hydrogen or C1-6alkyl;

R11is hydrogen or C1-6alkyl;

R12- C1-6alkyl, does not necessarily substituted oxo - on any carbon atom, provided that the carbon atom not adjacent to the nitrogen atom, having specified the radical R12; or R11and R12taken together form a radical (C3-5alkanethiol;

R13- C1-6alkyl or (phenyl) C1-6alkyl, and specified (phenyl) C1-6the alkyl may be substituted by oxo or oxine any of the carbon atoms of C1-6alkyl part, provided that the carbon atom not adjacent to the nitrogen atom, having specified the radical R13;

simultaneously phenyl may be substituted by one or two substituents selected from halogen, C1-6of alkyl, C1-6alkyloxy, hydroxy - or trifloromethyl,

provided that

a) at least one of R1or R2represents C1-6the alkyl or halogen, or

b) R3represent lcil, C1-6alkylamino, C1-6alkylsulphonyl, halogen or heterocyclic radical of formula (b); radical (c), where R6- C3-7cycloalkyl,

was trihalo C1-6alkyl or C7cycloalkyl, substituted oxo-; radical (d) or (e); radical (h), where R11and R12taken together form a C3-5alkanethiol radical; or a radical of the formula (i), where R13- (phenyl) C1-6alkyl, substituted oxo - or hydroxy - on any carbon atom C1-6alkyl part, provided that the carbon atom is not attached to the nitrogen atom, having specified the radical R13;

phenyl possibly substituted by one or two radicals selected from halogen, C1-6of alkyl, C1-6alkyloxy, hydroxy - or trifloromethyl, in an effective amount.

In the above definitions C1-6alkyl means saturated hydrocarbon radicals with a straight or branched chain containing 1-6 carbon atoms, for example methyl, ethyl, propyl, 1-methylethyl, four isomers of butyl, isomers pentile and hexyl; C3-6alkenyl is a hydrocarbon radicals, straight and branched chain, containing one double bond and from 3 to 6 carbon atoms, for example 2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenoate radicals with straight and branched chain, containing one triple bond and from 3 to 6 carbon atoms, such as 2-PROPYNYL, 2-butynyl, 3-butynyl, 2-pentenyl, 3-pentenyl or 4-pentenyl and isomers of hexenyl; and if it is said that C3-6alkenyl or C3-6quinil substituted on the nitrogen atom, the carbon atom of the specified C3-6alkenyl or C3-7the quinil associated with the specified heteroatom preferably is saturated; C3-5cycloalkyl denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C4-6alcander and C1-6alcander indicate dwuhvalentny saturated hydrocarbon radicals containing from 3 to 5 or, respectively, from 4 to 6 carbon atoms, for example 1,3-propandiol, 1,4-butandiol, 1,5-pentanediol and 1,6-hexandiol; halogen refers to fluorine, chlorine, bromine or iodine; the term "mono-, di - and trihalogen C1-6alkyl", used above, refers to C1the alkyl radicals in which one, two or three hydrogen atoms replaced by halogen atoms. As examples of such radicals can lead to vermeil, deformity, trifluoromethyl, trichloromethyl, 2-chloroethyl, 2,2,2-triptorelin etc.

Depending on the nature of the various substituents of the compounds of formula (I) may contain an asymmetric carbon atom. PR is their isomeric forms, moreover, these mixes contain all diastereoisomers and enantiomers basic molecular structure. The absolute configuration of each chiral center may be indicated stereochemical designations R and S, with this notation, R and S corresponds to the rules described in Pure Appl. Chem.", 1976, 45, 11-30.

In some connections, the stereochemical configuration is not determined experimentally. In these cases, resolved to conditionally designate stereochemical isomer obtained first, as A, as a stereoisomer, received the second as "B", without further reference to the actual stereochemical configuration.

Pure isomeric forms of the compounds of formula (I) can be isolated from the mixture by conventional methods of separation. Preferably, if you want to get particular stereoisomer, the specified connection synthesize stereoselective methods of getting them. For these methods successfully used enantiomerically pure source materials.

The compounds of formula (I) possess the properties of bases and, therefore, can be converted into a therapeutically active non-toxic cyclododecene salt by treatment with appropriate acids such as inorganic acids, chlorestol is similar; or organic acids such as acetic, propanoic, exucuse, 2-oxopropanoic, 2-oxopropanoic, attentionwas, papandonatos, buttonboy, (Z)-2 - butandione, (E)-2-butandione, 2-oxibutinina, 2,3-dioxaborinane, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, econsultancy, benzosulfimide, 4 - methylbenzenesulfonate, cyclohexanesulfamic, 2-oksibenzoynoy, 4-amino-2-oksibenzoynoy and similar acids.

Conversely, the salt can be converted into a free base by treatment with alkali.

Used above the term "cyclododecene salt" also includes a solvate, which can form compounds of formula (I), and these solvate is also included in the scope of the present invention. Examples of the solvate include, for example, hydrates, alcoholate, etc.,

The most interesting new compounds are:

2,4-dihydro-4-/4-4-(4-hydroxy-3, 5dimethylphenyl)-1-piperazinil/phenyl/-5-methyl-2-(1-methylpropyl)-3H-1,2,4-triazole-3-one,

2-/2-(4-bromophenyl)-1-methyl-2-oxoethyl)-2,4-dihydro-4- /4-/4-hydroxy-3, 5dimethylphenyl)-1-piperazinil/phenyl/-5-methyl-3H-1,2,4 - triazole-3-one and

2-/2-(4-bromophenyl)-2-hydroxy-1-methylethyl/-2,4-dihydro-4-/4-/4-(hydroxy-3, 5dimethylphenyl)-1-piperazinil/underwater General formula II

< / BR>
where

R1, R2, R3, R4and Y are specified in paragraph 1 values, and R16-C1-6alkyl, in an acidic medium or by means of a strong nucleophile, and if necessary, the transformation of the target product, where R6or R13is (phenyl) C1-6alkyl, substituted oxo - C1-6alkyl part, by restoring using tetraborate sodium in C1-4alkanol, the target product of the formula (I), where R6or R13is (phenyl) C1-6alkyl, substituted hydroxy - C1-6alkyl part.

The compounds of formula (I) can be transformed one into another by known methods functional rearrangements. Below are some examples.

The compounds of formula (I) containing nitrosomethyl, can be converted into the corresponding amines by stirring and, if desired, heat source nitro compounds in a hydrogen-containing atmosphere in the presence of a suitable amount of an appropriate catalyst, such as platinum on charcoal, palladium on charcoal, Raney Nickel and other similar catalysts. Suitable solvents are, for example, alcohols, for example methanol, ethanol, etc.

The atoms of halogen - same mixing and if desired, heating the starting compounds in a suitable solvent in a hydrogen atmosphere in the presence of an appropriate catalyst, for example palladium on coal or similar catalyst.

The compounds of formula (I) in which Y denotes an amine, can also be converted into other compounds covered by formula (I); for example compounds in which Y denotes a (C4alkyl)carbylamine can be obtained by using the reaction of selective N-acylation with acid chloride or carboxylic acid anhydride in a suitable solvent, for example an aromatic hydrocarbon, for example benzene, methylbenzene etc., dipolar aprotic solvent, for example N, N-dimethylformamide, dimethyl sulfoxide, etc., or mixtures of such solvents, in the presence of an appropriate base, for example N,N-diethylethanamine, pyridine and the like bases.

Many intermediate and source materials used in the above reactions are known compounds which can be obtained in accordance with known techniques to obtain these or similar compounds, and some intermediate compounds are new. Some methods for such soy(I) can be obtained using known techniques. Diastereoisomer can be separated by physical separation methods such as selective crystallization and chromatography, for example, countercurrent distribution, column chromatography or liquid chromatography high resolution, and enantiomers may be separated by known separation methods, for example methods of selective crystallization of the diastereomeric salts obtained from optically active acids. Pure stereoisomers can also be derived from the corresponding pure stereochemical isomeric forms of the appropriate starting compounds with the aid of stereospecific reactions.

The compounds of formula (I) are strong and selective inhibitors of the enzyme 5-lipoxygenase both in vitro and in vivo. Inhibition of the enzyme 5-lipoxygenase effectively blocks the metabolic pathways leading from arahidonovoy acid to leukotriene - substances, which are known to have a number of strong physiological activities and are believed to be involved in various allergic, anaphylactic and inflammatory reactions (Science, 220, 568-575, 1983).

Leukotrienes C4D4and E4(LTC4, LTD4and LTE4intensively cause the reduction of the TB vessels, resulting in the leakage of intravascular fluid and proteins in the tissue and the formation of Eden. Leukotriene B2strong hemodynamically and chemotactic agent with respect to leukocytes, it is proposed to apply as an important mediator in the reactions of the immediate and subacute hypersensitivity and inflammatory processes in The New England Journal of Medicine, 303, 822-825, 1980; "The Leukotrienes: Chemistry and Biology", ed. L. W. Chackin, D. M. Bailey, Academic Press, Orlando, 195-214, 1984). All of the above leukotrienes are derived from a common intermediate compound 5-hydroperoxidation acid (5-HPETE), which is formed from arachidonic acid under the action of 5-lipoxygenase. Other lipoxygenase, such as 12 - and 15-lipoxygenase, convert arachidonic acid to other mono - and dioxaphospholane with opposing or synergistic biological activity. In addition, aware of the increased recovery of the products of the enzymatic activity of 5-lipoxygenase and 12-lipoxygenase from affected skin of patients with psoriasis and atopic dermatitis (Prostaglandins, 29, 611-619, 1985; J. Invest. Dermatol. 83, 70-73, 1983; Lancet; 222-223, 1984).

Therefore, inhibitors due to the action lipoxygenase metabolic pathways arachidonate drugs to suppress the above-mentioned harmful effects of leukotrienes. Related diseases and/or disorders include, e.g., asthma, allergies, anaphylaxis, psoriasis and inflammatory reactions, such as arthritis and dermatitis. The value of the present invention is that the compounds of formula (I), recommended for use in accordance with the present method, are strong and selective inhibitors against the enzyme 5-lipoxygenase. Most of the other inhibitors, which are messages that do not have the selectivity and simultaneously suppress other lipoxygenase and/or cyclooxygenase, an enzyme involved in the metabolism of arachidonic acid to prostaglandins. The compounds of formula (I) slightly inhibit soybean 15-lipoxygenase, 12-lipoxygenase in human platelet, collagenase platelet person and thromboxane Aothe synthetase. In addition, the compounds of formula (I) are, as a rule, only mild nonspecific anti-oxidant properties.

The compounds of formula (I)is orally active, as shown by the test Suppression induced by dextran formation of oedema in the ears of mice" (example 19).

Specialists in this field of medicine can easily determine the effective amount of inhibitor of 5-lipoxygenase from 0.1 mg/kg to 10 mg/kg of live weight.

Given their overwhelming 5-lipoxygenase activity of the compounds according to the present invention can be prepared for introduction into various pharmaceutical forms. To prepare the pharmaceutical compositions according to the present invention an effective amount of a specific compound or its cyclododecanol salt, is taken as the active ingredient is thoroughly mixed with a pharmaceutically acceptable carrier, and this carrier can be of different types depending on the type of drug that is intended for injection. Such pharmaceutical compositions are preferably in manufacturing the dosage at one time, preferably suitable for administration orally, rectally, subcutaneously or parenterally. For example, for the preparation of compositions in the form of an oral dose can be applied to any of the usual pharmaceutical carriers, such as water, glycols, oils, alcohols, etc., in the case of cooking liquid oral compositions, such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents, etc., for the preparation of powders, pills, capsules and tablets. Best oral tonnes of solid pharmaceutical carriers. Carrier for parenteral compositions typically include sterilized water, at least in the most part, but may also contain other ingredients, for example, to increase the solubility of the active ingredient. For example, can be prepared solutions for injection, in which the carrier comprises saline solution, glucose solution or a mixture of saline solution and glucose. Can also be prepared suspension for injection, and in this case can be applied to the corresponding liquid media, suspendresume agents, etc., In compositions for subcutaneous injection, the carrier does not necessarily contain the agent, accelerating penetration, and/or a suitable wetting agent, not necessarily in combination with minimum amounts of additives of any nature, which does not have significant adverse effects on the skin. These supplements can facilitate the introduction into the skin and/or may be useful in obtaining the desired compositions. These compositions can be introduced in various ways, such as by transdermal in the form of ointment. Cyclododecene salts of compounds of formula (I) is more suitable for the preparation of aqueous compositions due to their better solubility in water compared to sootwetstwu at one time to facilitate the admission and uniformity of dosage. The term "dosage at one time", is used here in the description and in the claims refers to physically discrete units suitable for use as a single dose, and each unit contains a defined quantity of active ingredient calculated to provide the desired therapeutic effect in combination with the required pharmaceutical carrier. As examples of such doses at one time can lead tablets (including tablets incision or coating), capsules, pills, powders, sachets, pills, solutions or suspensions for injection, etc. and their dedicated short number.

The following examples illustrate, but in no way limit the present invention in all its features. Provided otherwise indicated, all parts are given by weight.

A. the production of intermediate compounds

Example 1.

a) To a stirred solution of 20 hours of 1-(4-isothiocyanates) -4-(4-methoxyphenyl)piperazine in 325 including dichloromethane add 40 hours of methanol, saturated with ammonia. The reaction mixture is stirred for 5 days at room temperature. Precipitated precipitated product is filtered off, washed with dichloromethane and dried, poluchaut CLASS="ptx2">

b) a Mixture of 5 h N-/4-/4-(4-methoxyphenyl)-1-piperazinil/phenyl/urea, 3 hours 2-chloro-1-phenylethanone, 1,7 including sodium acetate and 100 hours of acetic acid is stirred for 4 hours at a temperature of 80oC. After cooling, the reaction mixture is evaporated the residue is stirred in 130 hours of dichloromethane. All this neutralist solution of sodium bicarbonate. Precipitated precipitated product is filtered off, washed with water and dichloromethane and crystallized from 1,4-dioxane. The product is filtered and dried, get to 4.5 hours (69,6 %) N-/4-/4-methoxyphenyl)1-piperazinil/phenyl/-4-phenyl-2-thiazoline; so pl. 269,7oC (intermediate compound 2).

c) a Mixture of 4.6 h N-/4-/4-(4-methoxyphenyl)-1-piperazinil/- phenyl/-4-phenyl-2-thiazoline, 2 hours of brometane, 1 tsp sodium hydroxide and 94 including N,N-dimethylformamide is stirred for 16 h at room temperature. Add another portion of 2 hours of brometane and 1 tsp of sodium hydroxide and continue stirring for 4 hours at a temperature of 50oC. the Reaction mixture is diluted with water. Precipitated precipitated product is filtered off and purified by the method of column chromatography over silica gel using as eluent trichlormethane. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanon the Il-2-thiazoline; so pl. 223,6oC (intermediate compound 3).

Example 2.

a) a Mixture of 5.7 hours 4-/4-(4-methoxyphenyl)-1-piperazinil/benzenamine, 3 hours 2-isothiocyanato-1,1-methoxyethane and 100 hours of 1,4-dioxane is stirred at boiling for 1 h, the Reaction mixture is evaporated. The residue is purified by the method of column chromatography over silica gel using as eluent a mixture of trichloromethane and methanol (98:2 by volume). Pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone get to 3.1 hours (36%) of N-(2,2 - dimethoxymethyl)-N'-4-(4-methoxyphenyl)-1-piperazinil/phenyl/- thiourea (intermediate compound 4).

b) a Mixture of 17,6 including N-(2,2-dimethoxymethyl)-N'-4/-4/(4-methoxyphenyl)-1-piperazinil/phenyl/ thiourea and 120 hours of formic acid is stirred for 1 h at room temperature. The reaction mixture is evaporated in vacuum and the residue is dissolved in 133 hours of dichloromethane. The mixture is neutralized with sodium bicarbonate solution. Precipitated precipitated product is filtered off, washed with water and dichloromethane and crystallized from 4-methyl-2-pentanone. The product is filtered and dried, get to 8.5 hours (52,0 %) 4,5-dihydro-5-methoxy-N/4-/4-(4-methoxyphenyl)-1 - piperazinil/phenyl/-2-thiazoline; so pl. 177,5oC (intermediate compounds is of brometane, 3 hours of sodium hydroxide in pellets and 207 including N,N-dimethylformamide is stirred for 16 h at room temperature. The reaction mixture is diluted with water. Precipitated precipitated product is filtered off and purified by the method of column chromatography over silica gel using as eluent a mixture of trichloromethane, ethyl acetate, hexane and methanol (49:30:20:1 by volume). The second fraction is collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered and dried, get to 7.3 h (44,4%) hemihydrate N-ethyl-4,5-dihydro-5-methoxy-N-/4-/4-(4-methoxyphenyl)-1-Pipa - retinyl/phenyl/-2-thiazoline; so pl. 131, 5mmoC (intermediate compound 6).

Example 3.

a) a Mixture of 10 am, 1-(4-isothiocyanates)-4-(4-methoxyphenyl)- piperazine, 3 hours 2-amino-2-methyl-1-propanol and 260 hours of dichloromethane is stirred overnight at room temperature. Precipitated precipitated product is filtered off, washed with dichloromethane and 2-propanone and dried, get 11.7 hours (91,9%) of N-(2-hydroxy-1,1-dimethylethyl)-N'-4/4-(4-methoxyphenyl)-1-Pipa - retinyl/phenyl/thiourea; so pl. 221,6oC (intermediate compound 7).

b) a Mixture of 74 including N-(2-hydroxy-1,1-dimethylethyl)-N'-4/-4/-(4 - methoxyphenyl)-1-piperazinil/phenyl/thiourea and 360 hours of formic acid is dichloromethane. All this is neutralized with sodium bicarbonate solution. Precipitated precipitated product is filtered off, washed with water and dichloromethane and purified by the method of column chromatography over silica gel using as eluent a mixture of trichloromethane and saturated ammonia methanol (99: 1 by volume). Collect the pure fractions and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered and dried, get 44,1 hours (62,4%) 4,5-dihydro-N-/4-/4-(4-methoxyphenyl)-1-piperazinil/phenyl/-4,4 - dimethyl-2-thiazoline; so pl. 232,0oC (intermediate compound 8).

c) a Mixture of 37 hours 4,5-dihydro-N-/4-/4-(4-methoxyphenyl)- 1-piperazinil/phenyl/-4,4-dimethyl-2-thiazoline, 5 hours of a 50% dispersion of sodium hydride and 376 including N, N-dimethylformamide is stirred for 2 hours at a temperature of 70oC. After cooling to room temperature, to the reaction mixture is added slowly to 14.1 hours of iodomethane. All this is stirred for one hour at room temperature. The reaction mixture is diluted with water. Precipitated precipitated product is filtered off, washed with water and 2-propanol and purified by the method of column chromatography such as liquid chromatography high resolution) over silica gel using as eluent a mixture of di the house column chromatography over silica gel using as eluent a mixture of dichloromethane and methanol (98 : 2 by volume). Pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone, receive a 4-/4-(4-methoxyphenyl)-1-piperazinil/-N-(3,4,4-trimethyl-2 - thiazolidinone)benzolamide (intermediate compound 9).

The second fraction is collected and boiled in 2-propanol. After cooling the product is filtered and dried, get a 19.5 hours (51,0%) 4,5-dihydro-N-/4-/4-(4-methoxyphenyl)-1-piperazinil/phenyl/-N, 4,4 - trimethyl-2-thiazoline; so pl. 166,6oC (intermediate compound 10).

Example 4.

a) a Mixture of 47.8 hours 1-(4-isothiocyanatobenzene)-4-(4-methoxyphenyl) piperazine, 100 g of hydrazine hydrate and 400 hours of 1,4-dioxane is stirred at boiling for one hour. The reaction mixture is cooled and poured into water. Precipitated precipitated product is filtered off, washed with water and methanol and dried, get 46 PM (89%) N-/4-/4-(4-methoxyphenyl)-1-piperazinil/phenyl/ hydrazinecarbothioamide (intermediate compound 11).

b) a Mixture of 3.6 h N-/4-/4-(4-methoxyphenyl)-1-piperazinil/- phenyl/hydrazinecarbothioamide, 1 h acetic anhydride and 150 hours of trichlormethane stirred for one hour with reflux. After cooling, the precipitated precipitated product is filtered off and dried, get to 3.6 hours (90,1%) acetic acid 2-///4-/4-(4-methoxyphenyl)-MES 2,6 PM acetic acid 2-///4-/4-(4-methoxyphenyl)-1 - piperazinil/-phenyl/amino/thiocolchicoside and 74 hours of methansulfonate stirred for 2 h at room temperature. The reaction mixture was poured with stirring into a mixture of ammonium hydroxide with crushed ice. Precipitated precipitated product is filtered off, washed with water and crystallized from N,N-dimethyformamide. The product is filtered and dried, get h 2,1 (84,7%) N-/4-/4-(4-methoxyphenyl)-1-piperazinil/phenyl/-5 - methyl-1,3,4-thiadiazole-2-amine; so pl. 276,7oC (intermediate compound 13).

d) a Mixture of 10.6 hours N/4-/4-(4-methoxyphenyl)-1-piperazinil/-phenyl-5 - methyl-1,3,4-thiadiazole-2-amine, 0.5 hours of brometane, 4 tsp granulated sodium hydroxide and 188 including N,N-dimethylformamide is stirred for 4 hours at a temperature of 40 - 50oC. After addition of water crystallized product is filtered off and purified by the method of column chromatography over silica gel using as eluent a mixture of trichloromethane, methanol, ethyl acetate and hexane (48 : 2 : 30 : 20 by volume). Collect the first fraction and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered and dried, receive 2.9 hours (25.3%) of N-(3-ethyl-5-methyl-1,3,4-thiadiazole-2(3H(ilidene)-4-/4-(4-methoxyphenyl) -1-Pieper is t is distilled off. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered, dried, and get about 6.5 hours (56,7%) N-ethyl-N-/4-/4-(4-methoxyphenyl)-1-piperazinil/phenyl/-5 - methyl-1,3,4-thiadiazole-2-amine; so pl. 186,8oC (intermediate compound 15).

Example 5.

To a stirred mixture of 17.2 hours phenyl-/4-/4-(4-methoxy-3, 5dimethylphenyl)-1-piperazinil/phenyl/carbamate, 225 including N,N-dimethylformamide and 9.1 h N,N-diethylethanamine add to 9.6 hours of chlorotrimethylsilane. All this stirred first for 2 h at room temperature, then for 2 hours at a temperature of 80oC. After cooling, add a 10.1 hours Hydrobromic 2-brometalia and continue stirring for one hour. The resulting solution was added to stir the mixture of 9.2 hours of a 50% dispersion of sodium hydride and 45 o'clock N,N-dimethylformamide. After stirring for 2 h at room temperature is added dropwise 6,15 PM 1-bromopropane. After adding continue stirring over night at room temperature. The reaction mixture was poured into water. Precipitated precipitated product is filtered off and crystallized from 2-propanol, receive 5,6 PM(33,1%) 1-/4-/4-(4-methoxy-3, 5dimethylphenyl)-1-piperazinil/-phenyl/-3-propyl-2-imidazolidinone (intermediate compounds. the Teal-2-piperidinecarboxylate, 4 o'clock N,N-dimethyl-4-pyridylamine and 300 hours of 1,4-dioxane is stirred for 5 hours at boiling point. After saturation with water, the reaction mixture was heated for 30 minutes After cooling, the precipitated precipitated product is filtered off, washed with 2-propanol and purified by the method of column chromatography over silica gel using as eluent a mixture of trichloromethane and methanol (99 : 1 by volume). Pure fractions are collected and the eluent is evaporated. The residue is crystallized from 1-butanol. The product is filtered and dried, get 24,8 hours (47,5%) of 5,6,7,8-tetrahydro-2-/4-/4-(methoxyphenyl)-1 - piperazinil/-phenyl/imidazo/1,5-a/pyridine-1,3(2H, 8H)-dione; so pl. 223,4oC (intermediate compound 17).

Example 7.

a) To a stirred and cooled in an ice bath, a mixture of 15 hours 1-(4-nitrophenyl)hydrazine and 160 hours of absolute ethanol added to 13.5 hours of hydrochloric utilitymodule. After stirring for 3 h while cooling the reaction mixture is poured into water. Precipitated precipitated product is filtered off, washed with water and dried, get 19 hours (85%) of 1-(1-amoxicilian)-2-(4 - nitrophenyl)hydrazine; so pl. 101,8oC; (intermediate compound 18).

b) a Mixture of 10 am, 1-(1-amoxicilian)-2-(4-nitrophen is th the mixture is cooled. Precipitated precipitated product is filtered off, washed with methylbenzol and dried, get 8 hours(67%) 1-/1-(4-morpholinyl)ethylidene/-2-(4-nitrophenyl)hydrazine; so pl. 175,9oC (intermediate compound 19).

c) a Mixture of 13 hours 1-/1-(4-morpholinyl)ethylidene/-2-(4-nitrophenyl) hydrazine, 8,5 hours 1-isocyanatopropyl, 1 h N,N-dimethyl-4-pyridylamine and 39 hours of dichloromethane is stirred at boiling point for 2 hours All of this is evaporated and to the residue add 90 hours of xylene. Continue stirring at the boiling temperature for 3 hours, the Reaction mixture was cooled and filtered through diatomaceous earth. The filtrate is saturated with petroleum ether. Precipitated precipitated product is filtered off and crystallized from 2-propanol, get to 8.5 hours (65%) of 2,4-dihydro-5-methyl-2-(4-nitrophenyl)-4-propyl-3H-1,2,4-triazole-3-one; so pl. 125,4oC (intermediate compound 20).

d) a Mixture of 57 am 2,4-dihydro-5-methyl-2-(4-nitrophenyl)-4-propyl - 3H-1,2,4-triazole-3-one and 400 hours of methanol hydronaut under normal pressure at room temperature in the presence of 5 hours the catalyst of 20% palladium on coal. After absorption of the calculated amount of hydrogen the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybisethane. 3-it; so pl. 138,8oC (intermediate compound 21).

e) a Mixture of 25 o'clock N,N-bis(2-chloroethyl)-4-methoxybenzylamine, 23,2 including 2-(4-AMINOPHENYL)-2,4-AMINOPHENYL)-2,4-dihydro-5-methyl-4-propyl - 3H-1,2,4-triazole-3-one, 2 hours of potassium iodide and 200 hours of cyclohexanone is stirred at boiling point for 5 hours using the water separator. The reaction mixture is cooled and neutralized with sodium bicarbonate solution. The product is filtered off and dissolved in trichloromethane. The solution is filtered through silica gel and the solvent is evaporated. The residue is crystallized from 1-butanol and receive 18 hours (44%) of 2,4-dihydro-2-/4-/4-(4-methoxyphenyl)-1-piperazinil/phenyl/-5 - methyl-4-propyl-3H-1,2,4-triazole-3-one; so pl. 202,2oC (intermediate compound 22).

Example 8.

a) To a stirred solution of 42.8 hours of a 50% dispersion of sodium hydride in 200 hours of dimethyl sulfoxide is added slowly dropwise a solution of 50 hours 2,4(1H, 3H)-pyrimidinedione 800 hours of dimethyl sulfoxide, maintaining a constant temperature (20oC) by cooling in a water-ice bath. Add 62,9 h 1-fluoro-4-nitrobenzene, and the reaction mixture is stirred overnight at a temperature of 50oC. After cooling, the reaction mixture is then poured into 2500 hours of water. Washed with dichloromethane. the pH of the aqueous phase bringing the 2,4(1H,3H)-pyrimidinedione; so pl.o300oC (intermediate compound 23).

b) a Mixture of 3 hours 1-(4-nitrophenyl)-2,4(1H,3H)-pyrimidinedione, 1,4 including potassium hydroxide and 67.5 including N,N-dimethylacetamide is stirred for one hour at room temperature in a nitrogen atmosphere. Type of 1.52 hours of brometane and continue stirring over night at room temperature. The reaction mixture is poured into 100 hours of ice water. The product is filtered off and stirred in methanol. The product is filtered and dried in vacuum at a temperature of 60oC, get the 2.4 hours (65,6%) 3-ethyl-1-(4-nitrophenyl)-2,4-(1H, 3H)-pyrimidinedione; so pl. 182,5oC (intermediate compound 24).

c) a Mixture of 28.4 hours 3-ethyl-1-(4-nitrophenyl)-2,4(1H,3H)-pyrimidinedione, 5 hours of 4% aqueous solution of thiophene in methanol and 500 hours 2-methoxyethanol hydronaut at normal pressure and a temperature of 50oC in the presence of 3 hours the catalyst 5% PT on coal. After absorption of the calculated amount of hydrogen the catalyst is filtered off and the filtrate concentrated to a volume of approximately 150 hours After cooling the product is filtered off (the filtrate is put aside) and dried in vacuum at a temperature of 60oC get the first fraction of 16.5 hours of 1-(4-AMINOPHENYL)-3-ethyl-2,4(1H, 3H)-pyrimidinedione (connected intermediate byvaut and dried in a vacuum at a temperature of 60oC, get a second fraction of 5.7 hours intermediate compound 20. Total yield: 22,2 hours (88,3%) of intermediate compound 25; so pl. 190,8oC.

d) a Mixture of 17,47 including N,N-bis(2-chloroethyl)-4-methoxybenzylamine of 16.3 hours 1-(4-AMINOPHENYL)-3-ethyl-2,4(1H,3H)-pyrimidinedione, 11,83 including sodium bicarbonate and 240 hours of 1-butanol is stirred for 24 h at boiling temperature. After cooling, add 150 hours of water. The product is filtered and crystallized from methylbenzene. The product is filtered and dried in vacuum at a temperature of 60oC, get to 10.6 hours (37,0%) 3-ethyl-1/4-/4-(4-methoxyphenyl)-1-piperazinil/phenyl/-2,4(1H, 3H)- pyrimidinedione; so pl. 210,2oC (intermediate compound 26).

Example 9.

a) a Mixture of 40 hours of 2-(4-nitrophenyl)-1,2,4-triazine-3,5(2H,4H)- dione, 25,7 h 1-bromobutane, 26,25 including potassium carbonate and 720 h N,N-dimethylformamide is stirred overnight at a temperature of 45oC. the Reaction mixture is poured into 2000 hours of ice water. Precipitated precipitated product is filtered off, washed with water and 2,2'-oxybisethanol and stirred in methanol. The product is filtered and dried in a vacuum at a temperature of 70oC, get to 33.9 hours (68,6%) 4-butyl-2-(4-nitrophenyl)-1,2,4-triazine - 3,5(2H, 4H)-dione (intermediate compound 27).

b) the Mixture to 33.9 hours 4-butyl-2-(the ri normal pressure and room temperature in the presence of 3 hours catalyst 10% palladium on coal. After absorption of the calculated amount of hydrogen the catalyst is filtered off, the filtrate is evaporated and get 29 PM (92,8%) of 2-(4-AMINOPHENYL)-4-butyl-1,2,4-triazine - 3,5(2H, 4H)-dione as a residue (intermediate compound 28).

c) a mixture 27,1 including N,N-bis(2-chloroethyl)-4-methoxybenzamide, 29 hours 2-(4-AMINOPHENYL)-4-butyl-1,2,4-triazine-3,5(2H, 4H)-dione, 18,4 including sodium bicarbonate and 350 hours of 2-methyl-2-propanol is stirred over night at boiling point. After cooling, add 200 hours of water. Precipitated precipitated product is filtered off and crystallized from 4-methyl-2-pentanone. The product is filtered and dried in vacuum at a temperature of 75oC, get to 19.8 hours (41,3%) 4-butyl-2-/4-/4-(4-methoxyphenyl)-1-piperazinil/phenyl/-1,2,4 - triazine-3,5(2H,4H)-dione; so pl. 181,3oC; (intermediate compound 29).

Example 10.

a) To 990 hours cooled in an ice bath of tetrahydrofuran is added at the parts 156 including aluminium chloride and all this vigorously stirred until complete dissolution of the solids. The resulting solution was rapidly added to a stirred suspension of 208 hours of sodium azide in 225 hours of tetrahydrofuran and continue stirring for 1 h at reflux temperature. After cooling to room temperature the Reaction mixture is heated slowly to boiling point and continue stirring overnight at reflux temperature. The reaction mixture is acidified while cooling 800 hours 6 N. hydrochloric acid and the mixture is evaporated. The residue is stirred in a solution of sodium bicarbonate and washed with trichloromethane. The aqueous layer was acidified with concentrated hydrochloric acid and the mixture is evaporated. The residue is stirred in 2-propanol. The precipitation is filtered off and the filtrate is evaporated, receive 32 hours of 1,4-dihydro-1-propyl-5H-tetrazol-5-she as a residue (intermediate compound 30).

b) a mixture of 38 hours 1-fluoro-4-nitrobenzene, 32 including 1,4-dihydro-1-propyl-5H-tetrazol-5-it, 14 hours of sodium carbonate and 200 hours of dimethyl sulfoxide is stirred heated for 4 hours at a temperature of 120oC. the Reaction mixture is cooled and poured into water. Precipitated precipitated product is filtered off and crystallized from 2-propanol, get 46 PM (74%) of 1,4-dihydro-1-(4-nitrophenyl)-4-propyl-5H-tetrazol-5-it; so pl. to 91.1oC (intermediate compound 31).

c) a Mixture of 43 hours of 1,4-dihydro-1-(4-NITROPHENOL)-4-propyl-5H - tetrazol-5-she and 400 hours of methanol hydronaut at normal pressure and room temperature in the presence of 4 hours the catalyst is 10% palladium on coal. After absorption of the calculated amount of hydrogen the catalyst is filtered off and the filtrate is evaporated. The remainder of preida 1-(4-AMINOPHENYL)-1,4-dihydro-4-propyl-5H-tetrazol-5-it; so pl. 203,6oC (intermediate compound 32).

d) a Mixture of 25 o'clock N,N-bis(2-chloroethyl)-4-methoxybenzylamine, 25,5 hours of monohydrochloride 1-(4-AMINOPHENYL)-1,4-dihydro-4-propyl-5H - tetrazol-5-it, 2 hours of potassium iodide and 200 hours of cyclohexanol stirred at the boiling temperature for 5 h using the water separator. The reaction mixture is cooled and neutralized with sodium bicarbonate solution. The product is filtered and crystallized from 1-butanol, get to 15.5 hours (39%) of 1,4-dihydro-1-/4-/4-(4-methoxyphenyl)-1-piperazinil/-phenyl/-4 - propyl-5H-tetrazol-5-it; so pl. 189,7oC (intermediate compound 33).

Example 11.

a) To a stirred mixture of 54.3 including 3-bromo-4-/4-(4-methoxyphenyl)- 1-piperazinil/benzolamide and 189 including 1,1-dioxide tetrahydrothiophene add parts at a temperature of 160oC for 30 min 28,6 including ethyl-/(dimethylamino)methylene/hydrazinecarboxamide. After the addition was finished, continue mixing at a temperature of 170oC to complete the distillation of ethanol. After cooling to room temperature, add 120 hours 4-methyl-2-pentanone for dissolving the adhesive residue. The reaction mixture is heated until complete dissolution. After cooling, the emergent phase is decanted and the residue stirred in 2,2'-oxybisethane. About the 2,4-triazole-3-one (intermediate compound 34).

b) To stir the mixture 45 PM 4-/3-bromo-4-/4-(4-methoxyphenyl) -1-piperazinil/phenyl/-2,4-dihydro-3H-1,2,4-triazole-3-one and 90 hours of dimethyl sulfoxide is added 15 hours of powdered potassium hydroxide. Then add to 6.2 hours 2-bromobutane and the reaction mixture stirred for 20 h at room temperature. The reaction mixture was poured into water. The product is extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue is purified by the method of column chromatography over silica gel using as eluent a mixture of trichloromethane and methanol (99 : 1 by volume). Pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of methylbenzene and hexane (1 : 2 by volume). Precipitated precipitated product is filtered off and recrystallized from 80 hours of methanol. The product is filtered and dried in vacuum at a temperature of 60oC get the first fraction 14,7 (29,8%) 4-/3-bromo-4-(4-methoxyphenyl)-1-piperazinil/phenyl/-2,4-dihydro-2- (1-methylpropyl)-3H-1,2,4-triazole-3-one; so pl. 144,6oC. Collect less pure fractions and the eluent is evaporated. The residue is additionally cleaned by the method of column chromatography such as liquid chromatography high resolution) over silica gel using mixtures of ethyl acetate and methanol (97:3 by volume of the second fraction 4-/3-bromo-4-/4-(4-methoxyphenyl)-1-piperazinil/phenyl/-2,4-dihydro-2- (1-methylpropyl)-3H-1,2,4-triazole-3-one; so pl. 144,7oC (intermediate compound 35).

Example 12.

a) To a stirred solution of 25.0 hours 2,2,2-triptoreline 175 including N, N-diethylethanamine add on parts 62,2 including 2-naphthalenesulfonate. After adding added dropwise within 20 min the mixture for 1.5 hours N,N-dimethyl-4-pyridylamine and 25 hours of ethyl acetate. After adding continue stirring over night at room temperature. The reaction mixture is filtered and the filtrate is evaporated in a vacuum.

The residue is stirred in water and the solidified product is filtered off under reduced pressure. Precipitated precipitated product is dissolved in dichloromethane. The organic layer is dried, filtered and evaporated in vacuum. The residue is treated with petroleum ether. After filtration of precipitated precipitated product is crystallized from 2-propanol. The product is filtered, dried and receive 65,3 hours (89%) of 2,2,2-triptorelin-2-naphthalenesulfonate; so pl. 72,7oC (intermediate compound 36).

b) a Mixture of 17.5 hours 2,4-dihydro-4-/4-/4-(4-methoxyphenyl)-1 - piperazinil/phenyl/-3H-1,2,4-triazole-3-one, obtained as described in example XVII of U.S. patent N 4267179, 19,5 hours 2,2,2-triptorelin-2-naphthalenesulfonate, 10,0 including potassium carbonate and 135 including N,N-dimethylformamide 145oC. Posrat in dichloromethane. The organic layer is dried, filtered and evaporated in vacuum. The residue is purified by the method of column chromatography over silica gel using trichloromethane as eluent. Collect the pure fractions and the eluent is evaporated. The residue is crystallized from 2-butanone. The product is filtered and dried, get to 9.2 hours (42.4%) of 2,4-dihydro-4-/4-/4-(4-methoxyphenyl)-1 - piperazinil/phenyl/-2-(2,2,2-triptorelin)-3H-1,2,4-triazole-3-one; so pl. 208,0oC (intermediate compound 37).

B. obtain the final compounds

Example 13.

A mixture of 16 hours 4,5-dihydro-2-/4-/4-(4-methoxyphenyl)-1 - piperazinil/phenyl/-5-methyl-4-propyl-3H-1,2,4-triazole-3-one and 375 hours of a 48% solution of Hydrobromic acid in water is stirred at boiling point for 4 hours After cooling, the precipitated precipitated product is filtered off and dissolved in a mixture of methanol and water. All this is neutralized with sodium bicarbonate solution. Precipitated precipitated product is filtered off and crystallized from 1,4-dioxane, get 13 hours (85%) of 4,5-dihydro-2-/4-/4-(4-oxyphenyl)-1-piperazinil/phenyl/-5-methyl-4 - propyl-3H-1,2,4-triazole-3-one; so pl. 252,9oC (connection 8.10).

Example 14.

A mixture of 2.2 hours 1-ethyl 1-3-/4-/4-methoxyphenyl/-1-piperazinil/phenyl/- 5,5-dimethyl-2-thioxo-4-imidazolidinone, 75 ivali for 4 h at the temperature of reflux distilled. After cooling, was added to 100 hours of water. The precipitated product was filtered and dissolved in a mixture of methanol and water. Then the solution was neutralized using sodium carbonate. The product was extracted with trichloromethane. The extract is evaporated and the residue crystallized from 1-butanol. The product is filtered, dried, get 1.4 hours (66,0%) 1-/ethyl-3-/4-4 oksifenil/-1-piperazinil/phenyl/-5,5-dimethyl - 2-thioxo-4-imidazolidinone; so pl. 230,2oC.

Example 15.

A mixture of 6.3 hours hemihydrate N-ethyl-4,5-dihydro-5-methoxy-N-/4-/4-(4- methoxyphenyl)-1-piperazinil/phenyl/-2-thiazoline, 1 tsp of sodium sulfite and 150 hours of 48% aqueous Hydrobromic acid is stirred for 12 hours at a temperature of reflex. The reaction mixture is evaporated in vacuum and the residue dissolved in a mixture of trichloromethane and water. The solution is neutralized with sodium bicarbonate solution and the product extracted with 1500 hours of trichlormethane. The extract was dried, filtered and evaporated in vacuum. The residue is crystallized from 2-propanol. The product is filtered and dried, get to 4.5 hours(81,5%) 4-/4-/4-/ethyl-(2-thiazolyl)-amino/phenyl/-1-piperazinil/phenol; so pl. 214,6oC (connection 3.08).

Example 16.

To a stirred mixture of 300 hours 48% aqueous solution of Hydrobromic the butyl-2-/4-/4-(4-methoxyphenyl)-1-piperazinil/-phenyl/-1,2,4 - triazine-3,5(2H,4H)-don. Stirring is continued for 5 hours at boiling point. After cooling, the precipitated precipitated product is filtered off and dissolved in a mixture of water and methanol. The mixture is neutralized with saturated sodium bicarbonate solution. Precipitated precipitated product is filtered off and crystallized twice: first from 4-methyl-2-pentanol and then from 1-propanol. The product is filtered and dried in vacuum at a temperature of 75oC, get to 9.1 hours (50, 2%) of 4-butyl-2-/4-/4- (4-oxyphenyl)-1-piperazinil/phenyl/-1,2,4-triazine-3,5(2H, 4H)-dione; so pl. 202,3oC (connection 10.05).

Example 17.

A mixture of 6 o'clock 2-/1-(4-chlorobenzoyl)propyl/-2,4-dihydro-4-/4-/4-/(4- oxyphenyl)-1-piperazinil/phenyl/-3H-1,2,4-triazole-3-one, 103 hours of 1,4-dioxane and 40 hours of methanol is stirred at room temperature, slowly adding dropwise a solution of 1.5 hours of tetrahydroborate of sodium in 25 hours of water. After adding continue stirring for 1 h at room temperature. The reaction mixture is poured into 1500 hours water, to which is added a small amount of acetic acid. After stirring for 30 min precipitated precipitated product is filtered off, washed with water and methanol and dried, get the 5.7 hours(95,3%) 2-/1-/4-chlorophenyl)-oxymethyl/propyl/-2,4 - dihydro-4-/4-/4-(4-oxa in table. 1-11, obtained by the method described in the example, the number of which is specified in the column "Sample N".

C. Pharmacological examples

The value of inhibiting lipoxygenase properties of the compounds of formula (I) clearly proved by the following tests.

Example 18.

Suppression arachidonate 5-lipoxygenase in the pop-up layer basophilic leukemia cells of rats

Rat basophilic leukemia (LWL) cells grown as described (Adv. Prostaglandin Thromb. Leuk. Res., 11, 141-145). They are washed and suspended at a concentration of 5710ocells/ml in a 50 Molina buffer solution of sodium phosphate (pH 7,4) containing 1 mmol ethylenediaminetetraacetic acid (adtc) and 0.1% gelatin. Cells are homogenized by means of ultrasound, resulting homogenate was centrifuged at 1000 x g for 60 minutes Emergent layer made aliquot and stored at a temperature of 70oC, used as a source of 5-lipoxygenase activity.

The activity of the enzyme was tested at a temperature of 37-5C in the reaction mixture (total volume 0.4 ml) containing 50 mmol buffer phosphate (pH of 7.4), 2 mmol adenosine triphosphate (ATP), 2 mmol of calcium chloride, 2 mm glutathione, the test compound (10-8-104C-arachidonic acid and closing in 15 min by adding 0.3 ml of ice-cold mixture of ethyl ether:methanol:0.2 M citric acid (30: 4: 1). After shaking and centrifugation (300 x g, 5 min), the organic layer (N 150 ml), separated, dried over anhydrous sodium sulfate and extracted with 1 ml ethyl acetate. Then the extract is evaporated in vacuo, the residue is dissolved in 20 ml of ethanol. Aliquot of sample (20 - 30 000 counts per minute) is applied to the coating layer 0.25 mm silicon dioxide film (Merck) for thin-layer chromatography and elute with a mixture of chloroform: methanol:water:acetic acid(90: 9: 0,05: 1). Radioactive sample is applied by the method of autoradiography, cut out and radioactivity counted using a liquid scintillator. The results of calculations obtained for the samples corresponding to the products of arachidonic acid and lipoxygenase, 5-HPETE and LTB50summed and calculated the percentage of formation of lipoxygenase products. To study the suppression of the obtained response curves of concentration and values PC4by determining the percent suppression of the formation of lipoxygenase products in the presence of the test compound compared to eingeborenen control sample. In the first column of the table. 12% is the mol of compound of formula (I).

Example 19.

Suppression induced by dextran formation of oedema in the ears of mice

Intravenous injection to mice dextran T500(Pharmacia) and sky-blue dye of pontamine leads to the holding of vascular permeability and the formation of oedema, which is characterized by intense blue ears. It is assumed that the determination of the amount released from the vessels of the dye allows to quantify inhibitory 5-lipoxygenase activity of the tested compounds (Drug. Dev. Res., 8, 213-218, 1986). For experiments applied weakened male Swiss mice weighing 24-26, Experiments conducted between 13.00 and 17.00 hours in the afternoon when the ambient temperature is 21+1oC. Mice were treated orally tested compound of the formula (I), dissolved in 150 ml of either polyethylene glycol (PEG 200), or oxypropylation in doses that changed from 1.25 to 40 mg/kg body weight. In control experiments mice received the same amount of solvent. One hour after treatment, mice were injected with isotonic saline solution containing 60 mg/ml dextrin T 500and 13 mg/ml blue dye pentamin in an amount of 0.1 ml per 10 g body weight. After 1 h 45 min animals killed JFK is according to the description (Drug Dev. Res., 8, 213-218, 1986). The calculated percentage suppression of much of the ear due to the introduction of the compounds of formula (I) in the dose of 10 mg/kg of body weight are presented in the second column of the table. 12.

Column a: inhibition of 5-lipoxygenase in the pop-up layer of the rat basophilic leukemia acids, % suppression at a dose of 2.5 mmol.

Column B: suppression induced by dextran blue in the face ears in mice % suppression at the dose of 10 mg/kg body weight - means "not tested".

D. Examples of compositions.

The following compositions are examples of typical pharmaceutical compositions in dosage at one time, suitable for system introduction to animals and the person in accordance with the present invention.

The term "active ingredient" (and. I.) used in these examples relates to a compound of formula (I) or its pharmaceutically acceptable cyclododecanol salt.

Example 20.

Drops for oral administration

Dissolve 500 PM.and. in 0.5 l of 2-oxopropanoic acid and 1.5 l of the polyethylene glycol at a temperature of 60-80oC. After cooling to a temperature of 30-40oC added 35 l of polyethylene glycol and the mixture was thoroughly stirred. Then there was added a solution of 1750 hours the sodium characreristic up to a volume of 50 l, the result is a solution for drip oral administration containing 10 mg/ml.and. The resulting solution was poured into appropriate containers.

Example 21.

Solution for oral administration

Dissolve 9 o'clock methyl-4-oxybenzoates and 1 o'clock propyl-4-oxybenzoates in 4 l of boiling purified water. In 3 l of this solution are dissolved first 10 hours of 2,3-dioxaborinane acid, then 20 PM.and. The latter solution is combined with the remaining part of the first solution and add 12 l 1,2,3-propanetriol and 3 l of 70% aqueous solution of sorbitol. Dissolve 40 including sodium saccharin in 0.5 l of water and add 2 ml of raspberry and 2 ml Krajowej essences. The latter solution is combined with the first, add the required amount of water to volume of 20 l and receive a solution for oral administration containing 5 mg of active ingredient in a teaspoon (5 ml). The resulting solution fill a suitable container.

Example 22.

Capsules

Vigorously mix 20 PM.and., 6 hours lauryl sodium, 56 g starch, 56 including lactose, 0,8 including colloidal silicon dioxide, and 1.2 g magnesium stearate. Then the mixture fill 1000 suitable solid capsules, each of which contains 20 mg of the active ingredient.

Example 23.

Floor

To a solution of 10 hours of methyl cellulose (Methocel 60 HG ) in 75 ml of denatured ethanol is added a solution of 5 hours of ethyl cellulose (Ethocel 22 SDR ) in 150 ml of dichloromethane. Then add 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. Melt 10 hours of polyethylene glycol and dissolved in 75 ml of dichloromethane. The last solution is added to the first and then add back to 2.5 hours of octadecanoate magnesium, 5 hours of polyvinylpyrrolidone and 30 ml of concentrated suspensions of the dye (Opa-spray K-1-2109 ) and the mixture is homogenized. The core tablet cover thus obtained mixture in the apparatus for coating pills.

Example 24.

Injection

Dissolve 1,8 including 4-of oxybenzoates and 0.2 hours propyl-4-oxybenzoates will bring is shivani 4 hours lactic acid is 0.05 g propylene glycol and 4 PM.and. The solution is cooled to room temperature and add water for injection to a volume of 1 l, get a solution containing 4 mg/ml.A. The solution is sterilized by filtration (USP, HOOP, S. 811) and fill them sterile containers.

Example 25.

Candles

Dissolve 3 PM.and. in solution 3 o'clock 2,3-dioxaborinane acid in 25 ml of polyethylene glycol 400. Alloy 12 o'clock surfactants (Span ) and triglycerides in an amount necessary to bring up to 300 hours the mixture is thoroughly mixed with the first solution. Thus obtained mixture was poured into moulds at a temperature of 37-38C to obtain 100 candles, each of which contains 30 mg/ml.and.

Comparative data

Properties of inhibiting 5-lipoxygenase connection 2,6-di-tration.-butyl-4-/2'-thienoyl/phenol, known under pressure prifile and proposed in U.S. patent N 4172082 analyzed in accordance with the test procedures described in examples 18 and 19.

The percentage of inhibition of formation of products of 5-lipoxygenase in the cells of rat Basophilic Leukemia (LWL) at 2.5 m was 50%. The percentage of inhibition stiff ears as a result of edema, and%.

The comparison of these results to connect the prototype with biological data for the target compounds clearly show that the connection is the prototype are less active in vitro and in vivo.

1. The pharmaceutical composition inhibiting 5-lipoxygenase, containing the active principle and a pharmaceutically acceptable carrier, characterized in that it contains as active principle 4-(4-phenyl-1-piperazinil) phenylpropane General formula I

< / BR>
or its pharmaceutically acceptable salt accession acid or its stereoisomeric form,

where R1and R2each independently represents hydrogen, C1- C6alkyl or halogen;

R3represents hydrogen, halogen or nitro;

R4represents hydrogen or trifluoromethyl;

Y represents hydrogen, nitro, C1- C6alkylamino, C1- C6-alkylcarboxylic, C1- C6alkyl, C1- C6alkylsulphonyl, hydroxy, halogen or a heterocyclic radical of the formula

< / BR>
< / BR>
R represents a C1- C6alkyl;

A - C/R14//R15/ B - -CH2or CH2- CH2or a and b taken together form a bivalent radical of formula is SUP> each independently represents hydrogen or C1- C6alkyl; and each of the divalent radicals (B - CH = CH - (j) and-CH = N - (K) one or where possible two hydrogen atoms can be replaced by C1- C6alkyl or phenyl; and divalent radical B two pairs of hydrogen atom may be substituted C4- C6alkanediols;

R5is hydrogen or C1- c6alkyl;

R6is hydrogen, C1- C6alkyl, C3- C7cycloalkyl, trihalo1- C6alkyl, (phenyl)1- C6alkyl; WITH1- C6alkyl, C3- C7cycloalkyl and (phenyl)1- C6the alkyl can be substituted by oxo or hydroxy on any carbon atom WITH1- C6alkyl or C3- C7cycloalkyl part, provided that the indicated atom is not attached to the nitrogen atom, having specified the radical R6;

D2- N-CH - or =CH(CH3)-;

D1Is-N= or-CH=;

each R7is hydrogen or C1- C6alkyl;

R8- C1- C6alkyl, possibly substituted by oxo on any carbon atom, provided that the specified carbon atom is not adjacent to the nitrogen atom, having specified the radical R8;
R11is hydrogen or C1-6alkyl;

R12- C1-6alkyl, does not necessarily substituted oxo on any carbon atom, provided that the carbon atom not adjacent to the nitrogen atom, having specified the radical R12; or R11and R12taken together form a radical (C3- C5alkanethiol;

R13- C1- C6alkyl or (phenyl)1- C6alkyl, and specified (phenyl)1- C6the alkyl may be substituted by oxo or hydroxy on any of the carbon atoms WITH1- C6alkyl part, provided that the carbon atom not adjacent to the nitrogen atom, having specified the radical R13;

simultaneously, the phenyl radical may be substituted by one or two substituents selected from halogen, C1- C6of alkyl, C1- C6alkyloxy, hydroxy or trifloromethyl,

provided that

a) at least one of R1or R2is1- C6alkyl or halogen, or

b) R3represents halogen or nitro; or

c) R4represents trifluoromethyl; or

d) Y represents C1- C6alkyl, C1- C6alkylamino,1- C7 cycloalkyl, trihalo1- C6alkyl or C7-cycloalkyl, substituted oxo-; radical (d) or (e); radical (h), where R11and R13taken together, form WITH the3- C5alkanethiol radical; or a radical of the formula (i), where R13- (phenyl)1- C6alkyl, substituted oxo - or hydroxy - on any carbon atom WITH1- C6alkyl part, provided that the carbon atom is not attached to the nitrogen atom, having specified the radical R13;

phenyl possibly substituted by one or two radicals selected from halogen, C1- C6of alkyl, C1- C6alkyloxy, hydroxy or trifloromethyl, in an effective amount.

2. 4-(4-phenyl-1-piperazinil) phenylpropane General formula:

< / BR>
or its pharmaceutically acceptable salt accession acid or its stereoisomeric form, where R1, R2, R3, R4and Y are specified in paragraph 1.

3. The method of obtaining 4-(4-phenyl-1-piperazinil) phenylpropanol General formula I or its pharmaceutically acceptable salts accession acid or its stereoisomeric forms on p. 2, characterized in that conduct dealkylation alkoxybenzenes the/SUP>6- C1- C6alkyl, in an acidic medium or by means of a strong nucleophile and, if necessary, make the target product, where R6or R13is (phenyl)1- C6alkyl, substituted oxo in C1- C6alkyl part, by restoring using tetraborate sodium1- C4alkanol, the target product of the formula (I), where R6or R13is (phenyl)1- C6alkyl, substituted hydroxy in C1- C6alkyl part.

 

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The invention relates to a new use some diphenylmethyl-piperazinecarboxamide, in particular amperozide, 4 [4,4-bis(forfinal)butyl] N-ethyl-1-piperazinecarboxamide and their salts in the treatment of substance abuse

The invention relates to pharmaceutical industry concerns (l)-(-)-2(aminocarbonyl)-N-(4-amino-2,6-dichlorophenyl) -4-[5,6-bis(4-forfinal)pentyl]-1-piperazineethanol, its pharmaceutically acceptable acid additive salt or hydrate and method of its production

Imidazopyridine // 2092487
The invention relates to certain imidazoquinolines that selectively bind to the GABA-a receptors

The invention relates to animal husbandry, in particular to the means immune stimulation and prevention of gastrointestinal diseases of newborn calves

The invention relates to heterocyclic compounds, specifically to piperazine derivatives, in which the piperazine one nitrogen atom is linked to a fragment of aryloxy or aaltio link oxypropylene or alkanoyloxy, and through another nitrogen atom with the rest of acetanilide

The invention relates to medicine, in particular to the field of production of canned medicines

The invention relates to agriculture, in particular for the treatment of bees from ascosphaerosis and gylcolic diseases, which allows you to save from death a bee colony and allows cured families to give products, i.e

The invention relates to the chemistry of physiologically active compounds

FIELD: veterinary science.

SUBSTANCE: invention proposes using disinfecting preparation "Lesiptik" as a preparation for prophylaxis or respiratory diseases in calves. Invention provides enhancing safety of claves to 100% and increasing daily average gains by 24.5%.

EFFECT: valuable properties of preparation.

1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: method involves cutting out mucoperiosteal flap, making curettage and antiseptic treatment. Bone defect is filled with medical composition comprising Furacilin, aminocapronic acid, dimethylsulfoxide, glycerol, Chitosan, gelatin and water. Membrane cover is applied. The membrane has Furacilin, dimethylsulfoxide, acetic acid, glycerol, Aerosyl, Chitosan and water. The wound is covered with the mucoperiosteal flap and sutured.

EFFECT: enhanced effectiveness of treatment; prolonged hemostatic, antimicrobial and wound-healing action.

FIELD: medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used in treatment of diseases of digestive tract accompanying with disturbance of acid formation in stomach and/or ulceration of stomach and/or duodenum mucosa. The composition comprises sucralfate in a single dose from 0.25 g to 1.0 g or aluminum phosphate in a single dose from 3.8 g to 16.0 g, and prebiotic - fructooligosaccharide in a single dose from 2.5 g to 16.0 g and this composition is taken 1-3 times per 24 h. Also, invention relates to a method for preparing and using this composition. Proposed pharmaceutical composition promotes to acceleration of ulcer defect epithelization being independently on areas of ulcer defect and acidity of the stomach content.

EFFECT: improved and valuable medicinal properties of pharmaceutical composition.

8 cl, 8 tbl, 8 ex

FIELD: medicine, in particular balneology and physical therapy.

SUBSTANCE: claimed additive contains dihydroquercetin or mixture of dihydroquercetin and milky whey in ratio from 2:1 to 1:2 as biologically active additive for balneological bath agent. Dalneological bath agent includes base, osmolytically active components such as glycerol and inorganic salts, as well as biologically active additive of plant and/or animal origin, wherein osmolytic activity is 7700-11000 mOsm/l. As biologically active additive of plant and/or animal origin it contains dihydroquercetin or mixture of dihydroquercetin and milky whey in ratio from 2:1 to 1:2 and as the base it contains water and/or concentrated milk in the next component ratio (mass %): glycerol 25.0-30.0; inorganic salts 10.0-15.0; dihydroquercetin or mixture of dihydroquercetin and milky whey 0.2-1.0; and balance: water and/or concentrated milk up to 100 %.

EFFECT: new effective additive for balneological bath agent.

5 cl, 9 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention concerns medical product for metabolic regulation associated with magnesium deficiency in organism. Medical product is solid dosage form containing magnesium di-(L-asparaginate) in amount 200 to 1000 mg and pyridoxine hydrochloride in amount 2 to 20 mg per unit dose (magnesium di-(L-asparaginate) and pyridoxine hydrochloride in weight ratio 50:1 to 200:1).

EFFECT: medical product provides high ion bioavailability and decreased excretory system burden.

8 cl, 5 ex, 3 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: are offered application of Safinamid from 0.5 to 1,2,3,4 or 5 mg/kg/day, in a combination with levodopa/PDI (peripheral antioxidant of decarboxylase: levodopa plus carbidopa (SINEMET®), levodopa plus carbidopa of controlled release (SINEMET-CR®), levodopa plus benserazide (MADOPAR®), levodopa plus benserazide of controlled release (MADOPAR-HBS) for treatment of Parkinson's disease, the corresponding set and the pharmaceutical composition.

EFFECT: additional effect of increase in frequency of revealing of the patients reacting to treatment with dopamine agonist.

8 cl, 2 tbl

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