Derivatives isoxazolidinone or their acid additive salts and methods for their preparation

 

(57) Abstract:

Usage: in heterocyclic chemistry, as compounds with anxiolytic activity. The inventive product derivatives isoxazolidinone f-ly I, where R1- C1- C6-alkyl or possibly substituted with halogen phenyl, R2is hydrogen or C1- C6-alkoxy, R3is hydrogen, C1- C6-alkyl, R4-radical f-crystals, II or III, R5is hydrogen, C1- C6- alkyl or C1- C6- alkoxy - C1- C2- alkyl. Reagent 1: amine derivative f-crystals IV. Reagent 2: 2 - azadian F.-ly (V). The second way to obtain the compounds of f-crystals of I lies in the interaction between the imidazole derivative f-VI crystals derived from acetylene f-crystals VII. The structure of the compounds f-l I-VII: 3 S. and 3 C. p. F.-ly, 2 tab.

The invention relates to derivatives of isoxazolidinone, their production and use in medicines.

It is known that imidazole derivatives have affinity to benzodiazepine receptors and affect the Central nervous system. Unexpectedly the imidazoles in accordance with the invention differ clearly improved metabolic stability that b is I imidazole derivatives of the formula I

< / BR>
(I) in which R1denotes hydrogen, optionally substituted balance WITH1-10-hydrocarbon or wearily balance or cyclic ether residue;

R2may denote hydrogen, halogen, optionally substituted amino, nitro, azide, Giacinto group, or cyano, optionally substituted with halogen WITH1-10is an alkyl residue with an unbranched or branched chain or or1c R1 in the above-mentioned meaning and R2may be single or multiple;

R1and R2together with an oxygen atom form a saturated or unsaturated 5 - to 7-tier ring which may contain another heteroatom, and

R3denotes hydrogen, C1-6is an alkyl group with unbranched or branched chain, or1-4-alkoxy-C1-2is an alkyl group, and R4means or where R5denotes hydrogen, C1-16-alkyl, C3-7-cycloalkyl,1-6-alkoxy, C1-4-alkoxy-C1-2-alkyl, C1-6-alkoxycarbonyl, benzyl or phenyl, and additive salts and their acids.

The substituents in the phenyl residue can be in the o-, m - or p-position, and in the formula may be one or two of the remainder R2and statuettes fluorine, chlorine, bromine or iodine.

Under the remainder of the hydrocarbon R1refers to a saturated or unsaturated, unbranched or branched chain, optionally substituted alkyl groups preferably containing up to 6 atoms of carbon, in addition, saturated or unsaturated cycloalkyl group or cycloalkenyl groups, respectively, containing from 3 to 7 atoms of carbon, and CH2group is optionally replaced by oxygen atom, and optionally aryl or oralkeely group containing up to 10 atoms of carbon.

As a saturated, branched or non-branched chain alkyl residue refers to respectively lower alkyl residues, for example methyl, ethyl, propyl, ISO-propyl, butyl, secondary butyl, isobutyl, tertiary butyl, and pentyl, hexyl, 2-methylbutyl, 2,2-dimethylpropyl.

As unsaturated alkyl groups, R1should be called mainly the following alkeneamine and alkyline remains: 1-propenyl, 2-propenyl, 3-methyl-2-propenyl, 2-PROPYNYL.

As Deputy alkyl group, R1fit is halogen, in particular fluorine, chlorine or bromine, hydrox the mi. If the Deputy has fluoride, it is preferable to consider performanceline connection.

Under cycloalkenyl residues should accordingly be understood saturated residues, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. As the unsaturated residue should be called, for example, cyclopentenyl. If the balance of the hydrocarbon denotes cycloalkyl-alkyl group, the preferred should be considered cyclopropylmethanol, cyclopropylethanol and cyclopentylmethyl group. Suitable cycloalkenyl groups interrupted by an oxygen atom are, for example, a cyclic ether group: 3-tetrahydrofuranyl and 3-tetrahydropyranyl. If the balance of the hydrocarbon denotes aryl or Kilkenny group, it may be substituted once or three times, for example by halogen, nitro, cyano, hydroxy, mercapto, C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio,1-4-alkylsulfonyl,1-4-alkylsulfonyl or if necessary WITH1-4the alkyl, acyl or sulfonyl-one-deputizing or disubstituted amino group.

If the radical R2denotes the amino group, the Agency preferred aryl residue should be called phenyl, if needed, once or twice substituted by halogen or cyano, a nitro-group or optionally saturated amino group, such as 2,4-dichlorophenyl, 2-cyanophenyl, 4-AMINOPHENYL.

Uralkaliy the remainder R1in the alkyl residue can be unbranched or branched chain, and the aryl residue may optionally be substituted once or twice, preferably by halogen, C1-4-alkoxy, C1-4-alkyl or optionally substituted amino. Preferred are AG-C1-2-alkali, in which the aryl residue may be substituted by 1-2 halogen, in particular bromine or chlorine, for example, benzyl, phenethyl, -methylbenzyl.

If R1refers to heteroaromatic residue, it can be a five-membered or six-membered and may contain 1 or 2 heteroatoms, such as sulfur, nitrogen and/or oxygen, and may be substituted mentioned for aryl residue substituents. Preferred are the six-membered heteroaromatic with one or two nitrogen atoms and five-membered heteroaromatic with one or two atoms of oxygen, sulfur and/or nitrogen, which may be substituted by halogen, for example pyridine, pyrazin, pyridazine, furan, thiophene, pyrrole, orodny bridge may contain 1-3 carbon atoms, for example, methylene, ethylene, ethylidene, propylene, and in addition another heteroatom, preferably oxygen. Preferred meanings of the substituent R5are hydrogen, C1-4-alkyl, C3-5-cycloalkyl,1-4-alkoxy-C1-2-alkyl, and the definition of the substituents corresponds specified for R1values and, in particular, the balance of R1hydrocarbon in the meaning of alkyl or cycloalkyl residue is saturated and unsubstituted. As a preferred variant for the substituent R2consider hydrogen or or1.

Physiologically compatible additive salts of acids derived from known inorganic and organic acids, for example hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, Glyoxylic acid, and alkanesulphonic acids, as, for example, methanesulfonate acid, econsultancy acid, benzolsulfonat acid, toluensulfonate acid, etc.

Compounds in accordance with the image the statistical effects and because of their biological effectiveness suitable as psychotropic drugs, in particular as antidepressants.

Effect of compounds of the formula I on the Central nervous system and metabolic stability was determined using a research known methods. Compounds in accordance with the invention are not only the antidepressant efficacy, and are compared with known imidazoles superior metabolic stability, as can be seen from the above table. 1 in comparison with the known 4-(5-ethyl-1,2,4-oxadiazol-3-yl)-5-methyl-1-(3-phenoxyphenyl)imidazole (A).

The stability of the compounds was measured as follows.

The test substance (1 μg/50 μl of ethanol) with 750 ál of phosphate buffer Krebs-Henseleit-ringer was brought to pH 7.3 and connected with 750 ml of liver homogenate at room temperature and mixed. To determine the zero point was selected 250 ál of the original mix and the original mix was incubated at temperature 37aboutWith prolonged driving on a water bath. After 120 min are selected aliquot part 250 µl, after 5 min stirring extracted with 3 ml diethyl ether, then centrifugeuse for 10 minutes while cooling, samararatne and the solution was analyzed using liquid chromatography. Used liver was obtained from NMPI-mice and after extraction immediately homogenized in four parts of 0.25 M sucrose solution in the mixer Potter-Elvehjem. Then homogenised was filtered through canvas and diluted in the same solution of sucrose to 1 ratio 10 (weight volume). Aliquot part of the solution was kept at a temperature of 18aboutC. the Results of this test are shown in the table, and the number of test substance specified in zero values, which was not reduced metabolic liver enzymes.

On the basis of their pharmacological properties the compounds according to the invention can be prepared for psychopharmaceuticals compositions, for example, for enteral and parenteral use.

To apply the compounds in accordance with the invention as medicines, they are transferred in the form of a pharmaceutical preparation, which, along with the active ingredient for enteral or parenteral administration contains pharmaceutical, organic or inorganic inert carrier, for example water, gelatin, gum Arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene Apso, or in liquid form, for example in the form of solutions, suspensions or emulsions. If necessary, they contain in addition auxiliary substances, such as preserving, stabilizing, wetting means, or emulsifiers, salts for changing the osmotic pressure or buffers. In particular, for parenteral use suitable solutions, administered by injection, or suspension, in particular aqueous solutions of the active compounds in polyhydroxyalkane castor oil.

As systems-carriers can be used as surface-active excipients, such as salts of bile acids, animal or vegetable phospholipids, but also mixtures thereof, as well as liposome or components thereof.

For oral administration suitable, in particular, tablets, coated tablets or capsules with talc and/or hydrocarbon carrier or binder, such as lactose, corn or potato starch. The application may also be in liquid form, in the form of juice, to which if necessary is added saccharin.

Compounds in accordance with the invention are injected in doses of 0.05 to 10 mg of the active substance in a physiologically compatible carrier.

Link the AI with diazepam.

Obtaining compounds of formula I in accordance with the invention is carried out by known methods, for example, due to the fact that

(a) aniline of the formula II

< / BR>
(II) in which R1and R2are specified in the formula I is, using 2-azadiene formula III

R

(III) in which R3and R4are specified in the formula I is the value and X and Y represent useplease group transform in the presence of acids or

b) imidazole derivative of the formula IV

< / BR>
(IV) in which R3and R4are specified in the formula I is, using an aromatic hydrocarbon of the formula V

OR1< / BR>
(V) in which R1and R2are specified in the formula I is the value and Z is a moving group, arriraw or

(C) imidazole derivative of the formula VI

< / BR>
(VI) in which R1, R2and R3are specified in the formula I is, using acetylene derivative of the formula VII

R5R5(VII) in which R5is specified in the formula I is the value converted into derived isoxazolidinone formula Ia

< / BR>
(Ia) in which R1, R2, R3and R5are specified in the formula I is the value, or

d) a derivative of imidazole which allows nitricoxide formula XI

RC N __ O

(IX) in which R5is specified in the formula I is the value converted into derived isoxazolidinone formula Ib

< / BR>
(Ib) in which R1, R2, R3and R5are specified in the formula I is, and if desired connection aeriferous with R1H in the presence of a base or nitrogroup is restored to the amino group and the latter, then if necessary alkiliruya or alliums or substituted by halogen, azide, cyano or thiocyanate or forms an additive salts of acids.

Conversion in accordance with the invention anilines of the formula II with 2-azadienes formula II in the imidazole derivatives of the formula I is carried out in the presence of acids at temperatures from 0 to 150aboutC. Useplease groups X and Y may be the same or different: in particular, are suitable WITH1-3-dialkylamines, for example dimethylamine, diethylamine and dipropylamine, and cyclic amines, such as pyrrolidine.

Converting, for example, is carried out in such a way that the derivative of aniline and azadian first mixed at room temperature in an organic acid, for example formic acid, acetic acid, propionic acid the belt can serve as a reagent means, and also as a solvent. But additionally can be used as solvents, for example alcohols, ethers, ketones, esters, such as ethyl acetate, hydrocarbons, such as toluene, or golozhabernyi hydrocarbons such as carbon tetrachloride. The amount of acid can vary within wide limits, but it is used in excess. Preferably selects a threefold to tenfold excess of acid relative to aniline and azadiene. For a successful conversion, the molar ratio of aniline and azadiene are not critical. In General use about the same molar quantities of reagents are preferably quantitative ratios: 1 mol of aniline and 1-3 mol azadiene. In principle, the conversion in accordance with the invention can be carried out in the above solvent with catalytic amounts of mineral acids, for example sulfuric acid, hydrochloric acid, Perlina acid, or organic acids, for example n-toluensulfonate and triperoxonane acid.

The advantage of the method in accordance with the invention according to method (a) is chemoselective the synthesis of derivatives of imida ossadnik imidazole of the formula IV can be carried out, for example, by the method described: N. W. Gilman et al. I. Heterocycl. Chem. 14, 1157 (1977). It is necessary that the hydrocarbon of the formula V was substituted by at least one attracts electrons group and one useplease group. In particular, as attracts electrons groups suitable NO2and CN, and as useplease groups Z are taken into account halogen, in particular fluorine and iodine. Atilirovanie method b) is carried out in the presence of a base, such as hydroxide of alkali metal, alkali metal hydride, optionally in the presence of catalysts migration phases of utility or sitedisability, preferably with alkali metal hydride. To convert a suitable temperature from -78 to 100aboutC, preferably from 0 to 50aboutC.

As solvents for arilirovaniya are taken into account appreticeship polar solvents, for example aliphatic and cyclic ethers, for example diethyl ether, tetrahydrofuran, and dimethylformamide. Convert nitrilosides formulas VI and IX using derivatives of acetylene of formula VII and VII may be carried out, for example, described by K. B., Torsella method (K. C. G. Torsel, suffix Oxides, Nitrones and Nitronates in Organic Synthesis, VCH 1988 Verlagsgesell the use of the derivative of acetylene. The molar ratio of nitriloside and acetylene can vary within wide limits. In General use about the same molar quantities of reactants, however, can often be a beneficial use of the derivative of acetylene in greater volume. The transformation is carried out in an aprotic solvent at temperatures of from -78 to 150aboutC, preferably -20 to 50aboutC.

As suitable solvents, for example, aliphatic and cyclic ethers, for example diethyl ether, tetrahydrofuran, dioxane, halogenated hydrocarbons, such as dichloroethane, methylene chloride, chloroform, hydrocarbons, such as hexane, pentane and dimethyl formamide, dimethylsulfoxide.

If the source compounds are gaseous, such as acetylene, in the reaction are preferably the corresponding liquid compounds, which then have easily split the group. As easily split the group are suitable, for example, trialkylsilyl group. Cleavage is carried out before the separation of the reaction mixture with known methods, for example by additions of bases at room temperature. Suitable bases are, for example, hidrosis is whether fluoride, for example, fluoride or cesium fluoride, Tetra-n-butylamine.

The advantage of the method in accordance with the invention by methods C) and d) is chemoselective the synthesis of derivatives of isoxazol with the formation of one isomer in a single stage. Further, if necessary, the esterification of compounds of the formula I is carried out using the R1H known methods. For example, suitable for the reaction of the derivative R1X can be converted into a polar solvent in the presence of a base at temperatures from room temperature up to the boiling point of the solvent, optionally in the presence of phasetransfer catalyst. In particular, as suitable for the reaction residue X is suitable halogen, for example chlorine, bromine or iodine, as well as mesyl or Casilina group. As bases are taken into account alkaline compounds such as sodium hydroxide or potassium hydroxide, sodium carbonate or potassium etc.

The restoration of the nitro group to the amino group can be carried out, for example, catalytically due to the fact that the hydrogenation is carried out at normal pressure or H2-pressure in polar solvents at room temperature. As the catalyst moreclosely as a catalyst is used mainly Raney Nickel. Suitable for recovery of polar solvents are, for example, alcohols or ethers, such as methanol, ethanol, diethyl ether, tetrahydrofuran or mixtures thereof. Introduction ceanography can be done by using the reaction of Sandmeyer, for example, formed from amino compounds with nitrite intermediate diazonium salts transform using cyanides of alkali metals in the presence of Cu-I-cyanide. The introduction of the Halogens chlorine, bromine or iodine with the amino group can be accomplished, for example, by Sandmeyer due to the fact that educated using nitrite intermediate diazonium salts transform using Cu(I) chloride or copper(I) bromide in the presence of the corresponding acid, hydrochloric acid or Hydrobromic acid or with potassium iodide. Introduction fluorine is possible, for example, by coupling reaction Shiman of tetrafluoroborate desonia. Introduction sidegroup or thiocyanatopropyl can also be carried out using reaction Sandmeyer diazonium salts with alkali metal azide or thiocyanate of an alkali metal. If it is desired alkylation or acylation, alkylation or acylation can be accomplished by conventional methods, for example using alkylhalogenide the first solvent, for example, in a small amount of alcohol and mixed with a concentrated solution of the desired acid.

If the starting compounds is not described, these are known or can be obtained by analogy with known compounds or by the way described here. For example, the synthesis of 2-azadienes in accordance with: hiebigs Ann. Chem. 1980, 344 and hiebigs Ann. Chem. 1986, 1749.

Nitricoxide formulas VI and IX can be obtained, for example, in accordance with European patent application N 305322 and K. B. G. Torsell: suffix Oxides, Nitrones and Nitronates in Organic Synthesis 1988. Used as starting substances, acetylene formula VIII is generally known or can be obtained, for example, in accordance with the following: L. Brandsma, Preparative Acetylenic Chemistry, Second Edition. 1988.

Getting 2-azadienes.

Azadian 1.

a). 3-Ethyl-5-(N-dimethylaminomethylphenol)isoxazol.

9 g 5-aminomethyl-3-utilizationa stirred in 12 ml of dimethylformamide with the exclusion of moisture for 8 hours at a temperature of 80aboutC (bath temperature). After distillation in a ball tube at a temperature of 145aboutC and a pressure of 0.03 Torr. obtain 12.8 g (98% of theoretical yield) of the desired product.

b) (e Z)-1-dimethylamino-3-(3-ethyl-isoxazol-5-and the ml dimethylethylenediamine, 90% and 5.8 ml of pyrrolidine stirred for 24 h at a temperature of 80aboutC. By distillation in a ball tube at a temperature of 210-220aboutC and a pressure of 0.1 Torr. get to 4.17 g (21% of theoretical yield) of the formed product.

Azadian 2.

a). 3-Methoxymethyl-5-(N,N-dimethylaminomethylphenol)isoxazol

The synthesis is carried out in accordance with azadienes 1A).

b). (E. Z)-1-dimethylamino-3-(3-methoxymethylethoxy-5-yl)-4-(1-pyrrolidinyl)-2-Tapu

The synthesis is carried out in accordance with azadienes 1b).

P R I m e R 1.

a). 4-(3-Ethyl-isoxazol-5-yl)-5-methyl-1-(3-phenoxyphenyl)imidazole.

3.6 g of azadiene 1 dissolved under cooling in 12 ml of glacial acetic acid and stirred for 15 min at room temperature. Then add 2.2 g 3-phenoxyimino and stirred the mixture for 48 h at room temperature and for 3 hours at a temperature of 100aboutC. glacial acetic acid Argonauts and the residue is mixed with a solution of NaHCO3and extracted with ethyl ether acetic acid. The original product is purified by chromatography on a column. Get 1,53 g (37% of theoretical yield) specified in the header connection point of the PLA is kemetyl-isoxazol-5-yl)-5-methyl-1-(3-phenoxyphenyl)imidazole by converting azadiene 2; melting point 83about(Isopropyl simple ether);

C) 4-(3-ethyl-isoxazol-5-yl)-5-methyl-(3-(4-chlorphenoxy)-phenyl) imidazole by transformation using azadiene 1 as an oil.

P R I m m e R 2.

a). 5-Methyl-1-(3-phenoxyphenyl)imidazole-4-carbaldehyde.

of 4.13 g of 5-methyl-1-(3-phenoxyphenyl)imidazole-4-carbonitrile dissolved in 200 ml of toluene. At a temperature of from -60 to -70aboutWith in toluene drops add 15 ml of diisobutylaluminium polyarnosti 1,2. Stirred for 2 h at -70aboutWith, add drops at -70aboutWith 2.5 ml water and bring to room temperature. Using 2 n hydrochloric acid set pH 4 and the mixture is extracted with toluene and the complex ester of acetic acid. The organic phases are combined and dried with MgSO4. After purification by chromatography on a column gain of 2.46 g (59% of theoretical yield) specified in the connection header in the form of butter.

b). 5-Methyl-1-(3-phenoxyphenyl)imidazole-4-carbaldehyde,hydrochloride.

of 2.23 g of 5-methyl-1-(3-phenoxyphenyl)imidazole-4-carbaldehyde are dissolved in 60 ml of ethanol and mixed with 0.70 g of the chloride of hydroxylamine. The mixture displaced the t in 3 ml of ethanol. Vykristallizovyvalas product. Get 2,46 g (93% of theoretical yield) specified in the title compound with a melting point 183aboutC.

C). 4-(5-Methoxymethylethoxy-3-yl)-5-methyl-1-(3-phenoxyphenyl)imidazole.

660 g of 5-methyl-1-(3-phenoxyphenyl)imidazole-4-carbaldehyde, hydrochloride dissolved in 4 ml of dimethylformamide. At a temperature of 0aboutWith add, and 0.28 ml of triethylamine and drops add a solution of 360 mg of N-bromamide succinic acid in 2 ml of dimethylformamide for 1 hour Then add 1.7 ml dimethylpropylene ether and 0.28 ml of triethylamine, and the mixture is stirred for 14 hours at room temperature. Again add a solution of 360 mg of N-bromamide succinic acid in 2 ml of dimethylformamide and 0.28 ml of triethylamine, and the mixture is stirred for 18 h at room temperature. After thickening, diluted with water and extracted with ether complex of acetic acid. The concentrated extract is stirred with diethyl ether and filtered. The filtrate is purified by chromatography on a column. Obtain 230 mg (32% of theoretical yield) specified in the connection header in the form of butter.

By analogy with example 2C) get:

d) 4-(5-utilization-3-yl)-5-methyl-1-(3 is Teal-1-(3-(4-chlorphenoxy)phenylimidazol

by interaction with 1-butyne, melting point 95aboutC.

P R I m e R 3. 7.0 g of 1-butyne miss while cooling with ice in 200 ml of absolute tetrahydrofuran. Add 9.0 ml of NaOCl solution. To this mixture is slowly added dropwise a solution of 2.8 g of 1-(3-phenoxyphenyl)imidazole-4-carbaldehyde in 200 ml of tetrahydrofuran at 0aboutC for 2 h, the Reaction mixture was stirred for further 1 h at 0aboutC and incubated over night at room temperature. The mixture is sucked off and the filtrate is condensed. The residue is mixed with water and extracted with acetic ether. Gain of 1.9 g of crude product, which chromatographic on silica gel with a mixture of toluene acetic ether 9 1. Receive 928 mg of 4-(5-utilization-3-yl)-1-(3-phenoxyphenyl)imidazole as a colourless oil.

P R I m e R 4. 48,17 g of 4-(5-utilization-3-yl)-5-methyl-1-(3-phenoxyphenyl)imidazo - La mixed with 700 ml of ethanol and heated on a steam bath until complete dissolution of the crystals. Add 12,56 g of oxalic acid and the solution concentrated in a rotary evaporator at 50aboutC and 120 mbar. The residue is supplemented with ethanol to 180 g, tatrallyay crystal oxalate, quickly process ultrasonic bath and cooled with ice. The crystals are sucked off and washed with 10-20 ml of et the ptx2">

P R I m e R 5. 9 g of acetylene is passed when cooled ice in 500 ml of absolute tetrahydrofuran. Add to 36.0 ml of NaOCl solution. To this mixture is slowly added dropwise a solution of 11.7 g of 5-methyl-1-(3-phenoxyphenyl)imidazole-4-carbaldehyde-oxime in 500 ml of tetrahydrofuran at 0aboutC for 2 h, the Reaction mixture was stirred for further 1 h at 0aboutC and incubated over night at room temperature. The mixture is sucked off and the filtrate is condensed. The residue is mixed with water and extracted with acetic ether. After column chromatography gain of 9.9 g of 4-(isoxazol-3-yl)-5-methyl-1-(3-phenoxyphenyl)imidazole as a colourless oil.

P R I m e R 6. 5.0 g of 1-butyne miss while cooling with ice in 20 ml of absolute tetrahydrofuran. Add 1,81 ml NaOCl. To this mixture is slowly added dropwise a solution of 0,520 g of 1-(3,3-acid)-5-Mei-4-kerbal-digitoxin in 100 ml of tetrahydrofuran at 0aboutC for 2 h, the Reaction mixture was stirred for further 1 h at 0aboutC and incubated over night at room temperature. The mixture is sucked off and concentrated the filtrate. The residue is mixed with water and extracted with acetic ether. After column chromatography receive 300 mg of 1-(3,4-acid)-4-(5-utilization - 3-yl)-5-methyl is tested according to the method Boole in Eur. J. Pharmacol. 4, 145-150 (1968). In table. 2 shows the minimum effective dose (MED), which increase the locomotor activity of mice after i-p processing.

1. Derivatives isoxazolidinone General formula I

< / BR>
where R1- C1- C6-alkyl or possibly substituted with halogen phenyl;

R2is hydrogen or C1- C6-alkoxy;

R3is hydrogen or linear or branched C1- C6is an alkyl group;

R4-

< / BR>
where R5is hydrogen, C1- C6-alkyl or C1- C4-alkoxy-C1- C2-alkyl.

or their acid additive salt.

2. Derivatives isoxazolidinone under item 1, which represents a 4-(3-utilization-5-yl)-5-methyl-1-(3-phenoxyphenyl)-imidazole; 4-(3-methoxymethylethoxy-5-yl)-5-methyl-1-(phenoxyphenyl)-imidazole; 4-(5-methoxymethylethoxy-3-yl)-5-methyl-1-(3-phenoxyphenyl)imidazole. 4-(5-utilization-3-yl)-5-methyl-1-(3-phenoxyphenyl)-imidazole; 4-(3-utilization-5-yl)-5-methyl-3-(4-chlorphenoxy)-phenyl)-imidazole; 4-(5-utilization-3-yl)-5-methyl-1-(4-chlorphenoxy)-phenyl)-imidazole.

3. The compounds of formula I under item 1, in which R2- hydrogen.

4. Derivatives isoxazolidinone on PP.1 to 3, with axial what I

< / BR>
where R1and R2have the specified values,

transform in the presence of acids using 2-azadiene formula III

< / BR>
where R3and R4have the specified values;

X and Y represent useplease group.

6. The method of obtaining compounds on p. 1, wherein the imidazole derivative of the formula VI

< / BR>
where R1, R2and R3matter,

convert using acetylene derivative of the formula VII

< / BR>
where R5has the specified values,

in the derived isoxazolidinone formula Ia

< / BR>
where R1, R2, R3and R5have the specified values.

 

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(I) where R1in position 4 means fluorine atom, chlorine or bromine, alkyl with 1-4 carbon atoms, cycloalkyl, vermeil, deformity or trifluoromethyl;

R2alkoxyl with 3-5 carbon atoms, substituted imidazolium in position 3, 4 or 5, alkoxyl with 2-5 carbon atoms, a substituted benzimidazole or tetrahydroimidazo in position 2, 3, 4 or 5, 2-(imidazol-1-yl)-ethoxyl provided that R4means 1H-tetrazolyl, alkylsulfonate with 1-4 carbon atoms, benzosulfimide or generalconclusions, unsubstituted or substituted at the nitrogen atom by alkyl with 1-6 carbon atoms, phenyl, cycloalkyl, phenylalkyl, cycloalkylation, bicyclohexyl or the biphenyl alluminare, in which the acyl radical is alkanoyl with 1-7 carbon atoms, alkoxycarbonyl with a total of 2-4 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, benzoyl, benzazolyl, generalkonsulin, naphthalenesulfonyl, cycloalkylcarbonyl, phenylalkanoic or Central electoral commissions substituents from the group includes fluorine atom, chlorine or bromine, methyl, methoxy, phthalimido, hemophthalmia, 2-carboxymethylamino or 2-carboxymethylamino, and one carbonyl group in phthalimidopropyl replaced by methylene, alkylamino or dialkylamino, one methylene group in hoofdlijnen may be substituted by one or two alkyl groups, and the phenyl nucleus may be optionally mono - or tizamidine the alkyl or alkoxyl, and the substituents may be the same or different and are wholly or partially gidrirovanny, unsubstituted or substituted by one or two alkyl groups or one tetramethylenebis or pentamethylene group 5-, 6 - or 7-membered, alkylamino or alkenylamine in which one methylene group may be replaced by a carbonyl or sulfonyl, imides bicycloalkyl-2,3-dicarboxylic acid and imine bicycloalkyl-2,3-dicarboxylic acid, where bicycloalkanes and bicycloalkanes part can contain 9 or 10 carbon atoms can be substituted by 1, 2 or 3 methyl groups, and endometrioma group may be replaced by oxygen atom, amidinopropane, unsubstituted or substituted by one or two alkyl groups is whether the two alkyl groups or tetramethylene or pentamethylene, maleinimide, unsubstituted or mono - or disubstituted by identical or different substituents from among alkyl and phenyl, linked through a carbon atom or aminogroup 5-membered heteroaromatic ring containing aminogroup, oxygen atom or sulfur, or aminogroup and atom oxygen, sulfur or nitrogen, or bound via a carbon atom of the 6-membered heteroaromatic ring containing 1 or 2 nitrogen atom, and mentioned heteroaromatic rings in the carbon skeleton may be substituted by alkyl with 1-6 carbon atoms or phenylalkyl to 5-membered and 6-membered heteroaromatic ring connected n-propylene, n-butylene or 1,3-butadienyl group via two adjacent carbon atom or n-propylene or n-butylene group through aminogroup and the adjacent carbon atom, resulting anilinophenol pyridine ring one methylene group may be replaced by a nitrogen atom, venelinova group in position 3 or 4 to the nitrogen atom of the formed pyridine ring with the sulfur atom, or formed anilinophenol phenyl ring by one or two methyl groups may be replaced by nitrogen atoms, and mentioned precondensation aromatic or heteroalkyl, alkoxyl, hydroxyl, phenyl, nitro, amino, alkylamino, dialkylamino, alkanolamine, cyano, carboxyla, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, formation, deformation, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminocarbonyl or dialkylaminoalkyl, or tizamidine fluorine atoms or chlorine, stands, metaxylem or hydroxyl, and two methyl substituent can be connected to each other in position 1,2 via a methylene or ethylene bridge, and available if needed in the imidazole ring NH group may be substituted by an alkyl group with 1-6 carbon atoms, phenylalkyl or cycloalkyl; bound through a carbon atom pyrolidine, piperidine or pyridine ring, and the pyridine ring via two adjacent carbon atoms may be precondensation phenyl, and the neighboring nitrogen atom of the methylene group in pyrolidine or piperidinium the ring may be replaced by carbonyl, imidazolidinedione group, unsubstituted or substituted alkyl, phenylalkyl, tetramethylene, pentamethylene or hexamethylene, pyridazin-3-one and dihydropyridin-3-one, which is in position 2 can be substituted and,

the group R7-NR6CO NR5where R5a hydrogen atom, alkyl with 1-8 carbon atoms, cycloalkyl with 5-7 carbon atoms or phenylalkyl;

R6a hydrogen atom, alkyl with 1-8 carbon atoms, alkenyl with 3-5 carbon atoms, phenyl, phenylalkyl or cycloalkyl with 5-7 carbon atoms,

R7a hydrogen atom or alkyl with 1-6 carbon atoms,

one of the radicals R5, R6or R7may mean bicyclohexyl or diphenylol, R6and R7together with the enclosed nitrogen atoms means the unbranched alkalinising with 4-6 carbon atoms, or R5and R6ashamed mean alkylen with 2-4 carbon atoms, 1H, 3H-hinzelin-2,4-Dion-3-yl, pentamethylene-oxazoline-2-yl, or R1a hydrogen atom or is in position 5, 6 or 7 atoms fluorine, chlorine or bromine, an alkyl group with 1-4 carbon atoms, vermeil, deformity or trifluoromethyl; R2bound through a carbon atom or aminogroup 5-membered heteroaromatic ring containing aminogroup and the oxygen atom or sulfur, or aminogroup and atom oxygen, sulfur or nitrogen, or bound via a carbon atom of the 6-membered heteroaromatic ring containing 1 or 2 nitrogen atom, and said heteroaromatics and 6-membered heteroaromatic ring connected n-propylene, n-butylene or 1,3-butadienyl group via two adjacent carbon atom, or n-propylene or n-butylene group through aminogroup and the adjacent carbon atom, resulting anilinophenol pyridine ring one methine group may be replaced by a nitrogen atom, venelinova group in position 3 or 4 to the nitrogen atom formed piperidino ring sulfur atom, or formed anilinophenol phenyl ring, one or two methine groups may be replaced by nitrogen atoms, and mentioned precondensation aromatic or heteroaromatic rings in the carbon skeleton may additionally be monogamist fluorine atom, chlorine or bromine, the alkyl, alkoxyl, hydroxyl, phenyl, nitro, amino, alkylamino, dialkylamino, alkanolamine, cyano, carboxyla, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, formation, deformation, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminocarbonyl or dialkylaminoalkyl, or tizamidine fluorine atoms or chlorine, stands, metaxylem or hydroxyl, and two methyl substituent can be connected to each other in position 1,2 via a methylene or ethylene my with 1-6 carbon atoms, phenylalkyl or cycloalkyl; bound through a carbon atom pyrolidine, piperidine or pyridine ring, and the pyridine ring via two adjacent carbon atoms may be precondensation phenyl, and the neighboring nitrogen atom of the methylene group in pyrolidine or piperidinium the ring may be replaced by carbonyl,

R3a hydrogen atom, an alkyl group with 1-5 carbon atoms in which one methylene group may be replaced by oxygen atom or sulfur, or cycloalkyl with 3-5 carbon atoms,

R4carboxyl, cyano, 1H-tetrazolyl, 1-triphenyl-methyl-tetrazolyl, alkoxycarbonyl with the total number of carbon atoms 2-5, alkanesulfonyl, arylsulfonamides, triftormetilfullerenov, and if nothing else is specified, then the above alcoolica, alkyl and CNS part can contain 1-3 carbon atoms, and cycloalkyl part of 3-7 carbon atoms, and moreover, if (a) R1a hydrogen atom, R3N-propyl and R4carboxyl, R2in position 6 does not mean 3-methylimidazo[4,5-b]pyridine-2-yl or 3-n-hexyl-imidazo[4,5-b]pyridine-2-yl, or if (b) R1a hydrogen atom, R3n-propyl or n-butyl and R41H-tetraza the sawdust and R4carboxyl, R2in position 5 or 6 does not mean 1-methylbenzimidazole-2-yl or 6 position 1H-butylbenzothiazole-2-yl, 1,5-dimethylbenzimidazole-2-yl or 1-methyl-5-trifluoromethyl-benzimidazole-2-yl, or if g) R1a hydrogen atom, R3n-butyl and R4carboxy or 1H-tetrazolyl, R2in position 6 does not mean 1-methylbenzimidazole-2-yl, or if d) R1a hydrogen atom, R3n-butyl and R4carboxyl, R2in position 6 does not mean benzimidazole-2-yl, mixtures of them 1-, 3-isomers or individual isomers and hydrates and salts, in particular their physiologically tolerated salts with inorganic or organic acids or bases which are used, for example, as antagonists of angiotensin II, the method of obtaining derivatives of benzimidazole containing the substances, medicinal product and method of its production

The invention relates to medicine, in particular to pharmacology and Oncology

The invention relates to new derivatives of benzimidazole, with a strong pharmacological action, as well as to intermediate compounds for their production
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